PMID- 25430906 TI - Sequencing and phylogenetic analysis identifies candidate members of a new picornavirus genus in terrestrial tortoise species. AB - Near-complete genome sequences of seven picornavirus (PV) strains isolated from different terrestrial tortoise species were determined and characterized. The genome organization of the strains proved to be similar and displayed a typical PV layout, and the polyprotein-encoding regions showed low similarity to those of other PVs. The predicted regions of the tortoise PV genomes were related to the corresponding genome parts of viruses belonging to distinct genera, implying modular evolution of these novel viruses. Our results suggest that these tortoise PVs belong to a prototype species in a separate proposed genus in the family Picornaviridae, tentatively called Topivirus (Tortoise picornavirus). PMID- 25430907 TI - Epidemiological profiles of hand, foot, and mouth disease, including meteorological factors, in Suzhou, China. AB - The purpose of this study was to examine the epidemiological profiles of hand, foot, and mouth disease (HFMD) activity in Suzhou, China, and the relationship between meteorological factors and enterovirus71 (EV71) and coxsackievirus A16 (CoxA16) infection. Children < 14 years old with probable HFMD at Soochow University Affiliated Children's Hospital were enrolled during January 2008 to December 2013. Samples from hospitalized children with HFMD were collected and tested using real-time reverse transcription PCR. Correlations between probable HFMD, laboratory-confirmed HFMD, and meteorological factors were analyzed using bivariate correlation, stepwise regression and time series analysis. A total of 29,530 probable cases were diagnosed with HFMD, and 1090 hospitalized cases were confirmed in the laboratory. The median age of individuals with HFMD was 28.6 months (interquartile range, 18-46.9 months), and the incidence was highest in children aged 12-36 months. Children infected with other enteroviruses were younger than those infected with EV71 and CoxA16. Mean temperature and total rainfall were strongly correlated with probable HFMD. In terms of the specific pathogen, only EV71 cases were associated with mean temperature during the study period of 2012-2013. Based on a simple seasonal model with a good fit, a seasonal pattern of HFMD activity could be predicted. This study provides quantitative evidence that probable HFMD was associated with mean temperature and total rainfall. Furthermore, a seasonal model could be used as an early and reliable monitoring system to predict seasonal pattern of HFMD in Suzhou, China. PMID- 25430908 TI - A Top Ten list for economically important plant viruses. AB - The concept of "Top Ten" lists of plant pathogens is in vogue in recent years, and plant viruses are no exception. However, the only list available has more to do with historical and scientific worth than it has to do with economic impact on humans and their animals. This review will discuss the most important plant viruses that cause serious harm to food plants that sustain the bulk of humankind. PMID- 25430910 TI - Low vitamin D levels found in 95 % of psychiatric inpatients within a forensic service. PMID- 25430909 TI - Fluorescent probes of the apoptolidins and their utility in cellular localization studies. AB - Apoptolidin A has been described among the top 0.1% most-cell-selective cytotoxic agents to be evaluated in the NCI 60 cell line panel. The molecular structure of apoptolidin A consists of a 20-membered macrolide with mono- and disaccharide moieties. In contrast to apoptolidin A, the aglycone (apoptolidinone) shows no cytotoxicity (>10 MUM) when evaluated against several tumor cell lines. Apoptolidin H, the C27 deglycosylated analogue of apoptolidin A, displayed sub micromolar activity against H292 lung carcinoma cells. Selective esterification of apoptolidins A and H with 5-azidopentanoic acid afforded azido-functionalized derivatives of potency equal to that of the parent macrolide. They also underwent strain-promoted alkyne-azido cycloaddition reactions to provide access to fluorescent and biotin-functionalized probes. Microscopy studies demonstrate apoptolidins A and H localize in the mitochondria of H292 human lung carcinoma cells. PMID- 25430911 TI - The use of clinical and biological characteristics to predict outcome following First Episode Psychosis. AB - OBJECTIVE: Psychotic illnesses such as schizophrenia and other non-affective psychoses are heterogeneous in disease course and functional outcomes. We review evidence from investigations in clinical psychiatry, neuroimaging, neurocognition, and blood biomarker research suggesting that distinct bio-psycho social patterns exist at the onset and during the early phase of a First Episode Psychosis (FEP), which can describe the risk of individual illness progression and functional trajectories. METHOD: A selective literature review was performed on articles drawn from Medline searches for relevant key words. A simulation model was constructed from data derived from two recent publications, selected as examples of studies that investigated multivariate predictors of long-term outcome following FEP. RESULTS: We illustrate how illness trajectories following FEP could be described based on multimodal sociodemographic, clinical, psychological, and neurobiological information. A clinical modeling simulation shows thatrisk trajectories for achieving long-term favorable or unfavorable outcomes can differ significantly depending on baseline characteristics in combination with MRI and functional measurements within 6 months of disease onset. CONCLUSIONS: Multimodal trajectory modeling may be useful to describe longitudinal outcomes following FEP. Richlongitudinal data on predictors and outcomes, and better integration of multimodal (sociodemographic, clinical, psychological, biological) data, are required to operationalize this approach. This technique may improve our understanding of course of illness and help to provide a more personalized approach to the assessment and treatment of people presenting with FEP. PMID- 25430912 TI - Perceptions of distress and positive consequences following exposure to a major disaster amongst a well-studied cohort. AB - OBJECTIVES: Research on the impact of natural disasters on health and well-being faces several methodological challenges, including: sampling issues; exposure assessment; and outcome measurement. The present study used a comprehensive measure of disaster exposure to assess relationships between exposure to the Canterbury (New Zealand) Earthquakes of 2010-2011 and both: (a) self-reported distress and (b) positive outcomes; and also investigated gender differences in reports. METHODS: Data were gathered from the Christchurch Health and Development Study, a 35-year longitudinal study. The study examined data from 495 individuals exposed to the Canterbury Earthquakes for who complete data on exposure and reactions to the earthquakes at age 35 were available. RESULTS: Participants with higher levels of exposure to the earthquakes reported significantly (p<0.0001) higher levels of distress due to fear, death and injury, and disruption caused by the earthquakes. Higher levels of exposure to the earthquakes were also associated with significantly (p<0.0001) higher levels of reporting positive consequences following the earthquakes. Women reported significantly (p<0.0001) greater distress than men and significantly (p<0.001) greater positive consequences. CONCLUSIONS: Higher levels of exposure to disaster were associated with higher levels of distress, but also with higher levels of self-reported positive outcomes, with females reporting higher levels of both positive and negative outcomes. The findings highlight the need for comprehensive assessment of disaster exposure, to consider gender and other group differences in reactions to disaster exposure, and for studies of disasters to examine both positive and negative consequences. PMID- 25430914 TI - Sleep in patients with remitted bipolar disorders: a meta-analysis of actigraphy studies. AB - OBJECTIVE: Sleep dysregulation is highly prevalent in bipolar disorders (BDs), with previous actigraphic studies demonstrating sleep abnormalities during depressive, manic, and interepisode periods. We undertook a meta-analysis of published actigraphy studies to identify whether any abnormalities in the reported sleep profiles of remitted BD cases differ from controls. METHOD: A systematic review identified independent studies that were eligible for inclusion in a random effects meta-analysis. Effect sizes for actigraphy parameters were expressed as standardized mean differences (SMD) with 95% confidence intervals (95% CI). RESULTS: Nine of 248 identified studies met eligibility criteria. Compared with controls (N=210), remitted BD cases (N=202) showed significant differences in SMD for sleep latency (0.51 [0.28-0.73]), sleep duration (0.57 [0.30-0.84]), wake after sleep onset (WASO) (0.28 [0.06-0.50]) and sleep efficiency (-0.38 [-0.70-0.07]). Moderate heterogeneity was identified for sleep duration (I2=44%) and sleep efficiency (I2=44%). Post hoc meta-regression analyses demonstrated that larger SMD for sleep duration were identified for studies with a greater age difference between BD cases and controls (beta=0.22; P=0.03) and non-significantly lower levels of residual depressive symptoms in BD cases (beta=-0.13; P=0.07). CONCLUSION: This meta-analysis of sleep in remitted bipolar disorder highlights disturbances in several sleep parameters. Future actigraphy studies should pay attention to age matching and levels of residual depressive symptoms. PMID- 25430913 TI - Use of rapid diagnostic techniques in ICU patients with infections. AB - BACKGROUND: Infection is a common complication seen in ICU patients. Given the correlation between infection and mortality in these patients, a rapid etiological diagnosis and the determination of antimicrobial resistance markers are of paramount importance, especially in view of today's globally spread of multi drug resistance microorganisms. This paper reviews some of the rapid diagnostic techniques available for ICU patients with infections. METHODS: A narrative review of recent peer-reviewed literature (published between 1995 and 2014) was performed using as the search terms: Intensive care medicine, Microbiological techniques, Clinical laboratory techniques, Diagnosis, and Rapid diagnosis, with no language restrictions. RESULTS: The most developed microbiology fields for a rapid diagnosis of infection in critically ill patients are those related to the diagnosis of bloodstream infection, pneumonia -both ventilator associated and non-ventilator associated-, urinary tract infection, skin and soft tissue infections, viral infections and tuberculosis. CONCLUSIONS: New developments in the field of microbiology have served to shorten turnaround times and optimize the treatment of many types of infection. Although there are still some unresolved limitations of the use of molecular techniques for a rapid diagnosis of infection in the ICU patient, this approach holds much promise for the future. PMID- 25430915 TI - Randomised trial of the fascia iliaca block versus the '3-in-1' block for femoral neck fractures in the emergency department. AB - INTRODUCTION: Femoral neck fractures are a common and painful injury. Femoral nerve blocks, and a variant of this technique termed the '3-in-1' block, are often used in this patient group, but their effect is variable. The fascia iliaca compartment block (FIB) has been proposed as an alternative, but the relative effectiveness of the two techniques in the early stages of care is unknown. We therefore compared the FIB versus the 3-in-1 block in a randomised trial conducted in two UK emergency departments. METHODS: Parallel, two-group randomised equivalence trial. Consenting patients >18 years with a femoral neck fracture were randomly allocated to receive either a FIB or a 3-in-1 block. The primary outcome was pain measured on a 100 mm visual analogue scale at 60 min. The between-group difference was adjusted for centre, age, sex, fracture type, pre-block analgesia and pre-block pain score. RESULTS: 178 patients were randomised and 162 included in the primary analysis. The mean 100 mm visual analogue pain scale score at 60 min was 38 mm in the FIB arm and 35 mm in the 3 in-1 arm. The adjusted difference between the arms was 3 mm, with a 95% CI (-4.7 to 10.8) that excluded a clinically important difference between the two interventions. CONCLUSIONS: FIB is equivalent to the 3-in-1 block for immediate pain relief in adult neck of femur fractures. TRIAL REGISTRATION NUMBER: ISRCTN16152419. PMID- 25430916 TI - The Medical Boomerang: will it come back? AB - OBJECTIVES: To explore the increasing numbers of emergency medicine (EM) registrars that obtained their primary medical degree from UK or Irish universities, who work in emergency departments (ED) throughout Australia and New Zealand. METHODS: The Victorian Emergency Registrar Study was published at the Australasian College for Emergency Medicine (ACEM) annual scientific meeting in Adelaide in November 2013. As a follow on, ACEM provided the authors with data regarding country of primary degree for international medical graduates (IMG) working as registrars in Australasian EDs. RESULTS: UK and Irish EM registrars make up the largest proportion of IMGs working in Australian and New Zealand EDs. These figures have increased from 34% in 2008 to 45% in 2013. In 2013, there was the highest yearly intake of UK and Irish ED IMG registrars, representing 41% of registrars joining the Australasian EM training programme. Current data show that >25% of all ED registrars working in Australasian EDs studied for their primary medical degree in a university either in Ireland or the UK. CONCLUSIONS: While there have been anecdotal reports of increased outflow of junior EM doctors from the UK and Ireland, we provide quantitative data on the extent of the recent (5 year trend data) emigration of UK/Irish EM trainees to Australia and New Zealand and discuss the impact of this on both the UK/Irish and Australasian health systems. PMID- 25430917 TI - Classical Swine Fever in Wild Hog: Report of its Prevalence in Northeast India. AB - Classical swine fever virus (CSFV) is the causative agent of a highly contagious disease, hog cholera in pigs. The disease is endemic in many parts of the world and vaccination is the only way to protect the animals from CSFV infection. Wild hogs belong to the species Sus Scrofa Cristatus under the family Suidae are quite susceptible to CSFV infection. The epidemiological role concerning classical swine fever (CSF) in India is largely unknown. We report here the three isolated cases of CSF in wild hogs from three National parks, namely Kaziranga National Park, Manas National Park and Jaldapara National Park, from north-east part of India. The post-mortem and histopathological findings were clearly indicative for CSFV infection. The presence of CSFV genome was demonstrated in several organs and tissues collected from hogs died due to viral infection. In addition, CSF specific antibodies were detected in two wild hogs as well as in eighteen feral pigs from the same locations. The phylogenetic analysis of the partial E2 protein gene and 5' untranslated region of CSFV isolates from the wild hog showed identities with genotype 2.2 of the Indian isolates. Occurrence of CSF in wild hogs may pose a potent threat in the epidemiology of the virus in Northeast part of India. To the best of our knowledge, the report presented in the manuscript is the first comprehensive report on CSF in wild hogs form Northeast India. The findings reported would help us to understand the epidemiology and biology of CSFV in wild animals. PMID- 25430918 TI - Measured and modeled interactive effects of potassium deficiency and water deficit on gross primary productivity and light-use efficiency in Eucalyptus grandis plantations. AB - Global climate change is expected to increase the length of drought periods in many tropical regions. Although large amounts of potassium (K) are applied in tropical crops and planted forests, little is known about the interaction between K nutrition and water deficit on the physiological mechanisms governing plant growth. A process-based model (MAESPA) parameterized in a split-plot experiment in Brazil was used to gain insight into the combined effects of K deficiency and water deficit on absorbed radiation (aPAR), gross primary productivity (GPP), and light-use efficiency for carbon assimilation and stem biomass production (LUEC and LUEs ) in Eucalyptus grandis plantations. The main-plot factor was the water supply (undisturbed rainfall vs. 37% of throughfall excluded) and the subplot factor was the K supply (with or without 0.45 mol K m(-2 ) K addition). Mean GPP was 28% lower without K addition over the first 3 years after planting whether throughfall was partly excluded or not. K deficiency reduced aPAR by 20% and LUEC by 10% over the whole period of growth. With K addition, throughfall exclusion decreased GPP by 25%, resulting from a 21% decrease in LUEC at the end of the study period. The effect of the combination of K deficiency and water deficit was less severe than the sum of the effects of K deficiency and water deficit individually, leading to a reduction in stem biomass production, gross primary productivity and LUE similar to K deficiency on its own. The modeling approach showed that K nutrition and water deficit influenced absorbed radiation essentially through changes in leaf area index and tree height. The changes in gross primary productivity and light-use efficiency were, however, driven by a more complex set of tree parameters, especially those controlling water uptake by roots and leaf photosynthetic capacities. PMID- 25430921 TI - [Genitoanal pruritus]. AB - BACKGROUND: Genitoanal pruritus is usually characterized by intense pruritus in the genital area, possibly also extending to the anal and gluteal regions. Besides pruritus, other sensations such as burning, stinging, heat sensations and pain may occur. Genital pruritus may be associated with specific skin lesions of dermatoses such as eczema, lichen sclerosus or others. The skin is often without pathological findings, but one should be alert to transient erythemas, fetor and excretions in the genital area. Caused by intense scratching, secondary lesions such as papules, excoriations and crusts may appear. Maceration also frequently develops. In chronic dermatoses such as eczema and psoriasis, the anogenital area is commonly involved, but often not mentioned by patients due to feelings of shame or because skin changes in other body areas are more prominent. DIAGNOSIS: In addition to a complete medical history and thorough physical examination, special attention must be paid to the anogenital area including the mucosa surfaces. Diagnostics should be performed according to the guidelines on chronic pruritus. Besides a gynecological and if necessary urological examination, allergy testing (patch test) and, in case of possible neuropathic causes, magnetic resonance tomography (MRT) should be performed. THERAPY: Therapy depends on the underlying cause. Symptomatic-antipruritic measures are available. Interdisciplinary medical care is often necessary, usually leading to a clarification of the causes and satisfactory therapy. Somatoform disorders should also be taken into account. CONCLUSION: In summary, genital pruritus forms a challenge that can, however, be met well by careful diagnostics, therapy and interdisciplinary care in the daily clinical practice. PMID- 25430920 TI - The metabolic regulator CodY links Listeria monocytogenes metabolism to virulence by directly activating the virulence regulatory gene prfA. AB - Metabolic adaptations are critical to the ability of bacterial pathogens to grow within host cells and are normally preceded by sensing of host-specific metabolic signals, which in turn can influence the pathogen's virulence state. Previously, we reported that the intracellular bacterial pathogen Listeria monocytogenes responds to low availability of branched-chain amino acids (BCAAs) within mammalian cells by up-regulating both BCAA biosynthesis and virulence genes. The induction of virulence genes required the BCAA-responsive transcription regulator, CodY, but the molecular mechanism governing this mode of regulation was unclear. In this report, we demonstrate that CodY directly binds the coding sequence of the L. monocytogenes master virulence activator gene, prfA, 15 nt downstream of its start codon, and that this binding results in up-regulation of prfA transcription specifically under low concentrations of BCAA. Mutating this site abolished CodY binding and reduced prfA transcription in macrophages, and attenuated bacterial virulence in mice. Notably, the mutated binding site did not alter prfA transcription or PrfA activity under other conditions that are known to activate PrfA, such as during growth in the presence of glucose-1-phosphate. This study highlights the tight crosstalk between L. monocytogenes metabolism and virulence, while revealing novel features of CodY-mediated regulation. PMID- 25430922 TI - A novel animal model of metabolic syndrome with non-alcoholic fatty liver disease and skin inflammation. AB - CONTEXT: Metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) are the emerging co-morbidities of skin inflammation. Occurrence of skin inflammation such as psoriasis is substantially higher in NAFLD patients than normal. Currently, there are no animal models to study the interaction between these co morbidities. OBJECTIVE: The present study seeks to develop a simple mouse model of NAFLD-enhanced skin inflammation and to study the effect of NAFLD on different parameters of skin inflammation. MATERIALS AND METHOD: Metabolic syndrome and NAFLD were induced in C57BL/6 mice by feeding high-fat diet (HFD, 60% kcal) and high fructose liquid (HFL, 40% kcal) in drinking water. Skin inflammation was induced by repeated application of oxazolone (1% sensitization and repeated 0.5% challenge) in both normal and NAFLD mice and various parameters of skin inflammation and NAFLD were measured. RESULTS: HFD and HFL diet induced obesity, hyperglycemia, hyperinsulinemia, and histological features of NAFLD in mice. Oxazolone challenge significantly increased ear thickness, ear weight, MPO activity, NF-kappaB activity, and histological features of skin inflammation in NAFLD mice as compared with normal mice. Overall, induction of oxazolone-induced skin inflammation was more prominent in NAFLD mice than normal mice. Hence, HFD and HFL diet followed by topical oxazolone application develops metabolic syndrome, NAFLD, and enhanced skin inflammation in mice. DISCUSSION AND CONCLUSION: This simple model can be utilized to evaluate a therapeutic strategy for the treatment of metabolic syndrome and NAFLD with skin inflammation and also to understand the nexus between these co-morbidities. PMID- 25430923 TI - We are what we eat--is it time to reconsider calcium-deficiency rickets in Nigeria? (FA). PMID- 25430924 TI - Fetal organ dosimetry for the Techa River and Ozyorsk Offspring Cohorts, part 2: radionuclide S values for fetal self-dose and maternal cross-dose. AB - One of the many objectives of the European Union's SOLO (Epidemiological Studies of Exposed Southern Urals Populations) project is to quantify the radiation dose response following chronic in utero exposures to ionizing radiation. The project is presently conducting a pooled analysis of two cohorts of individuals born to exposed mothers-the Techa River Offspring Cohort (TROC) and the Ozyorsk Offspring Cohort (OOC). The TROC includes the offspring of mothers with external exposures to contaminated riverbanks and internal ingestions of (89)Sr, (90)Sr/(90)Y, and (137)Cs/(137m)Ba, while the OOC includes the offspring of mothers with external exposures seen within the Mayak plutonium production facilities and internal inhalation of (239)Pu and possibly (131)I. In the present study, a newly created Urals-based series of fetal and maternal models is employed to assess S values for all seven radionuclides. Among all fetal ages, S values ranged in magnitude from 10(-14) to 10(-10) Gy per Bq-s for fetal source organs and from 10(-18) to 10(-14) Gy per Bq-s from maternal source organs, depending upon particle type, particle energy, and fetal age. For a given radionuclide and fetal age, S values for fetal source organs were approximately two orders of magnitude higher than for maternal source organs. Little variation in S values was observed among fetal source organs, while variations of over 100 % with respect to the mean were observed for maternal source organs near the fetus. S value variations from maternal cross-fire were highly dependent on fetal position and separation distance from the maternal source organ. These radionuclide S values have been coupled with biokinetic models for use in cohort dose assessment within the SOLO project. PMID- 25430925 TI - Spreader flaps for middle vault contour and stabilization. AB - Nasal hump excision is common during septorhinoplasty. Without appropriate restoration of the middle nasal vault, cosmetic and functional problems may ensue. Recently, spreader flaps have become an established alternative to traditional spreader grafts. Typical indications include primary rhinoplasty patients with hump noses, hump/tension noses, and moderately hooked or crooked noses. When suitable patients are selected, spreader flaps and their modifications represent a reliable alternative to the standard spreader graft, and when all of the necessary prerequisites are met, this technique obviates the need for additional cartilage grafting in most cases. PMID- 25430926 TI - Treatment of the scoliotic nose with extracorporeal septoplasty. AB - A septal deformity with severe deviation of the septal L strut is seen in nearly every crooked or scoliotic nose. Unless the underlying septal deformity is properly diagnosed and treated, the nasal axis cannot be completely straightened. In addition, because standard septoplasty techniques often fail to adequately address severe L-strut deformities, extracorporeal septoplasty is often a prerequisite for straightening the crooked nose. This article presents a detailed explanation of the extracorporeal technique, as well as representative long-term clinical results showing the efficacy and durability of extracorporeal septoplasty. Extracorporeal septoplasty a safe and reliable method for straightening the severely deviated nose. PMID- 25430927 TI - Lateral crural tensioning for refinement of the wide and underprojected nasal tip: rethinking the lateral crural steal. AB - Refinement of the wide, ptotic, under protected tip is one of the most difficult challenges in cosmetic nasal surgery yet also among the most common. Although excisional techniques can produce reductions in lobular width, long-term contour alterations are unpredictable and subject to stigmatic tip deformity. Preservation of natural tip support is a fundamental requirement of a successful rhinoplasty. The traditional lateral crural steal is a useful technique for tip refinement, but, when combined with a sturdy septal extension graft, the modified lateral crural steal (lateral crural tensioning) becomes a more potent and versatile rhinoplasty technique that can improve tip contour without jeopardizing function or structural stability. PMID- 25430928 TI - Lateral crural repositioning for treatment of cephalic malposition. AB - After completion of this article, the reader should be able to describe the indications for lateral crural repositioning, understand the key steps to performing the procedure, and be able to manage the complications associated with this treatment strategy. PMID- 25430929 TI - Techniques for diced cartilage with deep temporalis fascia graft. AB - Diced cartilage with deep temporalis fascia (DC-F) graft has become a popular technique for reconstruction of the nasal dorsum. Cartilage can be obtained from the septum, ear, or costal cartilage when employing the DC-F technique. The complications seen with DC-F grafts tend to occur early in the surgeon's implementation of this technique. Management of the complications varies depending on the severity of the problem. This article gives an overview of both the technique and the complications commonly encountered. PMID- 25430930 TI - Contemporary techniques for effective nasal lengthening. AB - The short nose deformity is a complex entity with diverse causes and variable characteristics. This article divides shortening into anterior and pan-nose shortening as well as mild, moderate, or severe. Mild anterior shortening can be corrected with shield grafting, whereas moderate to severe shortening can be corrected using septal extension grafts, composite grafts, or the tongue-and groove technique. Ancillary technical considerations are reviewed. General principles of patient assessment and rhinoplasty execution are discussed. Surgical cases are presented, and pertinent aspects of preoperative planning, surgical technique, and perioperative care are discussed. PMID- 25430931 TI - Nasal tip deprojection with crural cartilage overlap: the M-arch model. AB - Vertical arch division is a mainstay of tip surgery, and its applications are expanding. It allows deprojection of the overprojected tip, and modifies rotation, length, and lobule definition. These parameters can be altered in a controlled, predictable fashion when the alar cartilage is preserved and overlapped, maintaining its strength. Cartilage overlay techniques aim to preserve normal anatomy and establish support for the nasal framework. We discuss the uses of vertical arch division when applied to the M-arch model, an expansion of the nasal tip tripod concept, which provides for a utilitarian approach to surgical techniques for the nasal tip. PMID- 25430933 TI - Margaret McCartney: Stop playing politics with illegal drug use. PMID- 25430935 TI - Incidence and determinants of 1-month mortality after cancer-directed surgery. AB - BACKGROUND: Death within 1 month of surgery is considered treatment related and serves as an important health care quality metric. We sought to identify the incidence of and factors associated with 1-month mortality after cancer-directed surgery. PATIENTS AND METHODS: We used the Surveillance, Epidemiology and End Results Program to study a cohort of 1 110 236 patients diagnosed from 2004 to 2011 with cancers that are among the 10 most common or most fatal who received cancer-directed surgery. Multivariable logistic regression analyses were used to identify factors associated with 1-month mortality after cancer-directed surgery. RESULTS: A total of 53 498 patients (4.8%) died within 1 month of cancer-directed surgery. Patients who were married, insured, or who had a top 50th percentile income or educational status had lower odds of 1-month mortality from cancer directed surgery {[adjusted odds ratio (AOR) 0.80; 95% confidence interval (CI) 0.79-0.82; P < 0.001], (AOR 0.88; 95% CI 0.82-0.94; P < 0.001), (AOR 0.95; 95% CI 0.93-0.97; P < 0.001), and (AOR 0.98; 95% CI 0.96-0.99; P = 0.043), respectively}. Patients who were non-white minority, male, or older (per year increase), or who had advanced tumor stage 4 disease all had a higher risk of 1 month mortality after cancer-directed surgery, with AORs of 1.13 (95% CI 1.11 1.15), P < 0.001; 1.11 (95% CI 1.08-1.13), P < 0.001; 1.02 (95% 1.02-1.03), P < 0.001; and 1.89 (95% CI 1.82-1.95), P < 0.001 respectively. CONCLUSIONS: Unmarried, uninsured, non-white, male, older, less educated, and poorer patients were all at a significantly higher risk for death within 1 month of cancer directed surgery. Efforts to reduce 1-month surgical mortality and eliminate sociodemographic disparities in this adverse outcome could significantly improve survival among patients with cancer. PMID- 25430934 TI - CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis. AB - BACKGROUND: The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. METHODS: We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). RESULTS: 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. CONCLUSIONS: Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. CLINICAL TRIAL REGISTRATION: ID number NCT01193075. PMID- 25430936 TI - Thrombocytopenia, Platelet Transfusion, and Outcome Following Liver Transplantation. AB - Thrombocytopenia affects patients undergoing liver transplantation. Intraoperative platelet transfusion has been shown to independently influence survival after liver transplantation at 1 and 5 years. We examined the impact of thrombocytopenia and intraoperative platelet transfusion on short-term graft and overall survival after orthotopic liver transplantation (OLT). A total of 399 patients undergoing first OLT were studied. Graft and overall survival in patients with different degrees of thrombocytopenia and with or without intraoperative platelet transfusion were described. The degree of thrombocytopenia prior to OLT did not affect graft or overall survival after transplant. However, graft survival in patients receiving platelets was significantly reduced at 1 year (P= .023) but not at 90 days (P= .093). Overall survival was significantly reduced at both 90 days (P= .040) and 1 year (P= .037) in patients receiving platelets. We conclude that a consistently lower graft and overall survival were observed in patients receiving intraoperative platelet transfusion. PMID- 25430937 TI - ADAMTS13 Levels in Young Patients With beta-Thalassemia Major: Relation to Hepatitis C Virus Infection, Liver Cirrhosis, and Iron Overload. AB - We measured levels of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) in 50 children and adolescents with beta thalassemia major (25 without hepatitis C virus [HCV] infection and 25 with HCV infection) compared to 25 healthy controls and assessed their relation to iron overload, HCV infection, and liver cirrhosis. Hematological and coagulation profiles, serum ferritin, and von Willebrand factor antigen were assessed. Levels of ADAMTS13 were significantly lower in beta-thalassemia major with and without HCV infection compared to healthy controls, with a more significant reduction in levels among patients with HCV (P < .001). HCV-positive patients with thalassemia having liver cirrhosis had the lowest ADAMTS13 levels than those without cirrhosis (P = .012) or HCV-negative patients with thalassemia (P < .001). Levels of ADAMTS13 were positively correlated with platelet count while inversely correlated with partial thromboplastin time, serum ferritin, and VWF: Ag (P < .05). CONCLUSION: Patients with beta-thalassemia major infected with HCV have low ADAMTS13 levels, and a marked reduction was observed among patients with liver cirrhosis and, therefore, may be liable to thromboembolic manifestations. PMID- 25430938 TI - Platelets as potential link between diabetes and Alzheimer's disease. AB - Diabetes is a well-known risk factor for Alzheimer's disease (AD) development in the elderly. The molecular link between diabetes and AD is still not completely understood. Recent evidence suggests that platelet activation observed in diabetes may contribute to AD development. The present review summarizes the common molecular mechanisms involved in the pathophysiology of diabetes and AD and suggests novel therapeutic targets for prevention of the onset or slowing the progression of this disease. PMID- 25430939 TI - Sedation and mechanical antinociception after intravenous administration of detomidine in donkeys: a dosage-effect study. AB - There is limited, useful, scientific information on detomidine in donkeys. This study compared the effects of intravenous saline, detomidine (10, 13.5, 17 and 20 MUg/kg) and acepromazine (50 MUg/kg) in donkeys by computing areas under the curve for 0-30, 30-60 and 60-120 minutes (AUC0-30, AUC30-60 and AUC60-120) for sedation scores, head heights and mechanical nociceptive thresholds (MNTs). For sedation scores, all detomidine treatments, except 10 MUg/kg, increased AUC0-30 values compared with saline, and AUC0-30 values were larger for 17 MUg/kg detomidine than for acepromazine. All head height AUC values were lower for detomidine than for saline (except AUC60-120 for 10 MUg/kg detomidine) and acepromazine (except AUC0-30 for 10 and 20 MUg/kg detomidine, and AUC60-120 for 10 MUg/kg detomidine). For MNTs, all detomidine treatments increased AUC0-30 and AUC30-60 values compared with saline and acepromazine; AUC30-60 values were smaller for 10 MUg/kg than for 17 and 20 MUg/kg detomidine. MNT AUC60-120 values were larger for 20 MUg/kg detomidine than for saline, 10 MUg/kg detomidine and acepromazine. Detomidine induced sedation and antinociception, but only antinociception was dosage dependent. Selection of detomidine dosage for donkeys may depend on the required duration of sedation and/or degree of analgesia. PMID- 25430940 TI - Inclusion of trans women in pre-exposure prophylaxis trials: a review. AB - Trans women are at high risk of HIV infection. We conducted a review to determine the extent to which trans women were eligible for inclusion in and enrolled into pre-exposure prophylaxis (PrEP) efficacy trials. Out of seven trials analyzing PrEP efficacy, we found that trans women comprised only 1.2% of one trial and 0.2% of total trial enrollments. Although an additional PrEP trial to determine efficacy among trans women may not be warranted, further research is needed to determine the effectiveness of PrEP in this marginalized population, through observational and feasibility studies. These studies should focus on unique barriers that trans women may experience while obtaining access to PrEP, such as gender discrimination, transphobia, and violence. PMID- 25430941 TI - Sinusoidal haemangioma: are ultrasonographic features helpful? PMID- 25430942 TI - Isolation of the highly pathogenic and zoonotic agent Burkholderia pseudomallei from a pet green Iguana in Prague, Czech Republic. AB - BACKGROUND: Melioidosis caused by Burkholderia (B.) pseudomallei is an endemic zoonotic disease mainly reported from northern Australia and Southeast Asia. In Europe, cases of human melioidosis have been reported only from patients travelling to endemic regions. Besides humans, B. pseudomallei has a very broad host range in domestic and wild animals. There are some reports about importation of B. pseudomallei-infected animals from endemic areas into Europe. The present report describes the first case of B. pseudomallei infection of a pet iguana in Europe. CASE PRESENTATION: In a 5-year-old pet Iguana iguana living in a private household in Prague, Czech Republic, B. pseudomallei was isolated from pus of an abscess. The isolate VB976100 was identified by Vitek(r)2, MALDI-TOF mass spectrometry and polymerase chain reaction as B. pseudomallei. The molecular typing resulted in multi-locus sequence type 436 hitherto, which has been found only once worldwide in a B. pseudomallei strain isolated in the USA and originating from Guatemala. The identification as internal transcribed spacer type G indicates a close relatedness to strains mainly isolated in the Western Hemisphere. These findings support the hypothesis that the iguana became infected in this region or in a breeding facility through contact to other infected animals. CONCLUSIONS: The present case highlights the risk of importation of the highly pathogenic and zoonotic B. pseudomallei into non-endemic regions through animal trade. Therefore, veterinarians treating animals from these areas and physicians examining patients owning such animals should include melioidosis in differential diagnosis whenever specific symptoms appear. Furthermore, veterinary authorities responsible for supervision of traders and pet shops should be aware of this risk of zoonotic transmission. PMID- 25430943 TI - Anti-Nogo-A antibody: a treatment option for neurogenic lower urinary tract dysfunction? PMID- 25430944 TI - Examining the health care payment reforms in Abu Dhabi. AB - OBJECTIVE: The purpose of this paper is to provide an overview of the current health care payment reforms in Abu Dhabi and discuss the potential impact of these reforms on health care consumers and providers as we all as long-term sustainability of the mandatory health care insurance system. METHODS: A focused literature review was conducted to systematically identify and summarize relevant literature published on the recent payments reforms in Abu Dhabi along with a secondary review and analysis of existing related government documents, technical reports, and press releases by the Health Authority-Abu Dhabi (HAAD) and other relevant research groups. RESULTS: The implementation of the mandatory health insurance system allowed all UAE nationals and foreign workings in Abu Dhabi to have access to medical care insurance and access to care. Prospective payment reforms represent critical sustainability interventions for health care funding in Abu Dhabi. The full impact of payment reforms on affordability, system efficiency, and patient outcomes is yet to be documented. CONCLUSION: Given the Government of Abu Dhabi has identified the sustainability of healthcare funding as a key governmental policy, more research is needed to systematically examine the impact of the current payment reforms on multiple stakeholders. PMID- 25430945 TI - Public support for a sugar-sweetened beverage tax and pro-tax messages in a Mid Atlantic US state. AB - OBJECTIVE: To examine the characteristics of supporters and opponents of a sugar sweetened beverage (SSB) tax and to identify pro-tax messages that resonate with the public. DESIGN: A survey was administered by telephone in February 2013 to assess public opinion about a penny-per-ounce tax on SSB. Support was also examined for SSB consumption reduction and pro-tax messages. Individual characteristics including sociodemographics, political affiliation, SSB consumption behaviours and beliefs were explored as predictors of support using logistic regression. SETTING: A representative sample of voters was recruited from a Mid-Atlantic US state. SUBJECTS: The sample included 1000 registered voters. RESULTS: Findings indicate considerable support (50 %) for an SSB tax. Support was stronger among Democrats, those who believe SSB are a major cause of childhood obesity and those who believe childhood obesity warrants a societal intervention. Belief that a tax would be effective in lowering obesity rates was associated with support for the tax and pro-tax messages. Respondents reporting that a health-care provider had recommended they lose weight were less convinced by pro-tax messages. Women, Independents and those concerned about childhood obesity were more convinced by the SSB reduction messages. Overall, the most popular messages focused on the importance of reducing consumption among children without mentioning the tax. CONCLUSIONS: Understanding who supports and opposes SSB tax measures can assist advocates in developing strategies to maximize support for this type of intervention. Messages that focus on the effect of consumption on children may be useful in framing the discussion around SSB tax proposals. PMID- 25430946 TI - Interaction of DRD2TaqI, COMT, and ALDH2 genes associated with bipolar II disorder comorbid with anxiety disorders in Han Chinese in Taiwan. AB - It is hypothesized that dopaminergic genes-dopamine type-2 receptor (DRD2), aldehyde dehydrogenase 2 (ALDH2), and catechol-O-methyltransferase (COMT)-are associated with bipolar disorder (BP) and anxiety disorder (AD). Bipolar II (BP II) is reported to be highly comorbid with AD. We examined whether interactions among these three genes are susceptibility factors in BP-II with AD (BP-II(+AD)) and without AD (BP-II(-AD)). In this study, we hypothesize that the interaction of the dopaminergic genes between BP-II(+AD) and BP-II(-AD) is significant different. We recruited 1260 participants: 495 with BP-II(-AD), 170 with BP II(+AD), and 595 healthy controls without BP-II or AD. Genotyping was done using polymerase chain reactions plus restriction fragment length polymorphism analysis. Genotypic frequencies of the DRD2TaqIA, COMT, and ALDH2 polymorphisms between the two BP-II groups were nonsignificant. In logistic regression, the ALDH2 and DRD2TaqIA genes showed a main effect that was protective against BP-II( AD) (odds ratio [OR] = 0.497, p = 0.010, and OR = 0.415, p = 0.017, respectively). The interaction of DRD2TaqIA A1/A1 and ALDH2*1/*1 had a significant risk effect on the BP-II(-AD) group (OR = 7.177, p < 0.001). However, the interaction of DRD2TaqIA A1/A1, ALDH2*1/*1, and COMTMet/Met&Val/Met become a weak protective factor against BP-II(-AD) (OR = 0.205, p = 0.047). All of the significant results described above are found only in BP-II(-AD). This study supports the hypothesis the interaction of the dopaminergic genes between BP II(+AD) and BP-II(-AD) is significant different,, and provides additional evidence that the DRD2TaqIA A1/A1, ALDH2*1/*1 and COMT genes interact in BP-II( AD) but not in BP-II(+AD). PMID- 25430947 TI - Multiple sclerosis patients treated with intramuscular IFN-beta-1a autoinjector in a real-world setting: prospective evaluation of treatment persistence, adherence, quality of life and satisfaction. AB - OBJECTIVES: The 12-month observational PERSIST study (NCT01405872) evaluated adherence associated with the intramuscular IFNbeta-1a (i.m. IFN-beta-1a) autoinjector pen in multiple sclerosis (MS) patients. METHODS: MS patients initiating i.m. IFN-beta-1a autoinjector treatment were prospectively assessed for physician-reported persistence (percentage of patients remaining on therapy) and patient-reported outcomes, including adherence (percentage of unmissed injections), compliance (percentage of patients missing no injections), tolerability (injection-site reactions [ISRs] and pain) and satisfaction. RESULTS: The intent-to-treat population included 232 patients; of the 188 physician-reported 12-month completers, 182 patients remained on treatment (96.8% persistence). Monthly compliance rates were 87.5 - 96.2%. Mean monthly pain scores were 1.5 - 1.8 (scale: 0 = 'no pain'; 10 = 'extremely painful'). At 12 months, 73.5% of respondents reported no ISRs, 94.9% were satisfied/very satisfied with the autoinjector and 88.2% found using the device easy/very easy. Injection fear, injection anxiety and need for injection assistance by caregivers decreased from the initial visit to 12 months. No new safety signals were observed. CONCLUSIONS: The autoinjector pen is associated with high levels of persistence, compliance, adherence, and satisfaction, little-to-no pain and low need for caregiver assistance. Although these data are limited by reliance on patient questionnaires and the absence of a direct comparator group, this treatment may reduce barriers to injection therapy, while supporting long-term MS management. PMID- 25430948 TI - Non-cell-adhesive substrates for printing of arrayed biomaterials. AB - Cellular microarrays have become extremely useful in expediting the investigation of large libraries of (bio)materials for both in vitro and in vivo biomedical applications. An exceedingly simple strategy is developed for the fabrication of non-cell-adhesive substrates supporting the immobilization of diverse (bio)material features, including both monomeric and polymeric adhesion molecules (e.g., RGD and polylysine), hydrogels, and polymers. PMID- 25430949 TI - Occupational rhinitis: an update. AB - Occupational rhinitis is characterized by nasal congestion, rhinorrhea, nasal itching, and/or sneezing that occur secondary to exposures in the workplace. This disease can be classified into allergic or nonallergic subgroups based upon the underlying disease pathogenesis as well as the type of causative agent. While the true prevalence of occupational rhinitis is unknown, there are certain professions and occupational exposures that place workers at a higher risk for developing the disease. Additionally, occupational rhinitis can be associated with occupational asthma and upper airway symptoms may precede those of the lower respiratory tract. Taken together, occupational rhinitis is an important disease for study given its medical as well as socioeconomic implications. This review will focus on the classification of occupational rhinitis as well the prevalence, diagnosis, and treatment strategies. PMID- 25430950 TI - Biological and genetic markers in occupational asthma. AB - Occupational asthma (OA) is a complex disease that is often hard to diagnose due to difficulties in detecting relevant exposure, along with inherent differences in disease susceptibility. Numerous studies have attempted to identify relevant biological and genetic markers for OA and to devise tools capable of detecting exposure to the causative agent. Immunological markers, including skin prick test reactivity and specific IgE and IgG antibodies can be used to detect high molecular-weight allergens in cases of baker's asthma. For OA induced by low molecular-weight agents, such as isocyanate, potential biomarkers include serum specific IgE and IgG antibodies to isocyanate-HSA conjugate and IgG to cytokeratin 19 and transglutaminase-2. For protein-based markers, ferritin/transferrin and vitamin D-binding protein levels have been suggested for isocyanate-OA. Genetic markers of susceptibility to isocyanate-OA include human leukocyte antigen and CTNNA3. Further investigations will be needed to identify better biomarkers for OA, which may be used to inform clinical decision. PMID- 25430951 TI - Upper airway stem cells: understanding the nose and role for future cell therapy. AB - The nose together with the paranasal sinuses has an approximate surface area of 100 to 200 cm(2) in adults, which is lined with pseudostratified columnar ciliated epithelium. It serves several important physiological functions such as conditioning and filtration of the inspired air and the provision of end organ for the sense of smell. It is also a physical and immunological barrier as it is the first site of interaction between the host tissue and foreign invaders (viruses, bacteria, and allergens). Our understanding of the complex cellular events occurring in response to inhaled agents during the development of common airway diseases has been significantly enhanced by the current status of in vivo and in vitro nasal experimental models. This will allow the development of novel therapeutic strategies designed to improve the physiological and immune defense functions of the nasal epithelium, as well as novel therapies for other common nasal diseases. PMID- 25430952 TI - Autoimmune valvular carditis. AB - Autoimmune carditis is associated with many human rheumatic conditions, including rheumatic fever, systemic lupus erythematosus, and rheumatoid arthritis. The immune mechanisms that mediate the cardiovascular pathology connected to these diseases are poorly defined. Several animal models are used to recapitulate human pathophysiology in order to better characterize the immunopathogenic mechanisms driving autoimmune endocardial inflammation. These animal models point toward common mechanisms mediating autoimmune endocarditis; in particular, CD4+ T cells and pro-inflammatory macrophages play critical roles in directing the disease process. The goals of this review are to discuss the prevailing animal models of autoimmune endocarditis and their underlying immunologic mechanisms and to provide insight regarding potential therapeutic targets in humans. PMID- 25430953 TI - Carbohydrates as allergens. AB - Complex carbohydrates are effective inducers of Th2 responses, and carbohydrate antigens can stimulate the production of glycan-specific antibodies. In instances where the antigen exposure occurs through the skin, the resulting antibody production can contain IgE class antibody. The glycan-stimulated IgE may be non specific but may also be antigen specific. This review focuses on the production of cross-reactive carbohydrate determinants, the recently identified IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal), as well as discusses practical implications of carbohydrates in allergy. In addition, the biological effects of carbohydrate antigens are reviewed in setting of receptors and host recognition. PMID- 25430954 TI - Empty nose syndrome. AB - Empty nose syndrome (ENS) is a rare, late complication of turbinate surgery. The most common clinical symptoms are paradoxical nasal obstruction, nasal dryness and crusting, and a persistent feeling of dyspnea. Little is known about the pathogenesis of ENS, though it is speculated that anatomical changes leading to alterations in local environment, disruption of mucosal cooling, and disruption of neurosensory mechanisms are strongly implicated. The diagnosis is clinical, though often difficult to make due to the poor correlation between subjective and objective findings. Medical therapies include mucosal humidification, irrigations, and emollients. Surgical therapy should be reserved for refractory cases and may involve turbinate reconstruction, most commonly using implantable biomaterials. Ultimately, prevention of this feared complication through turbinate-sparing techniques is essential. PMID- 25430955 TI - The role of dendritic cells and monocytes in the maintenance and loss of respiratory tolerance. AB - Promoting tolerance to inhaled antigens is an active area of study with the potential to benefit the millions of Americans currently suffering from respiratory allergies and asthma. Interestingly, not all individuals with atopy are symptomatic, arguing that sensitization alone does not lead to an allergic clinical phenotype. Respiratory dendritic cells (rDCs), classically associated with inducing inflammatory responses, can actively promote tolerance. Tolerance can be broken when inflammatory stimuli, including viral infections and other environmental exposures, inhibit rDC-mediated tolerance by allowing innocuous antigen to be presented to initiate type-2 immunity. Importantly, rDCs are composed of multiple subsets, each with a unique response to an inhaled antigen that can lead to either tolerance or inflammation. In this review, we will discuss how rDC subsets actively maintain tolerance or, alternatively, break tolerance in response to environmental cues. PMID- 25430956 TI - What happens to lost nets: a multi-country analysis of reasons for LLIN attrition using 14 household surveys in four countries. AB - BACKGROUND: While significant focus has been given to net distribution, little is known about what is done with nets that leave a household, either to be used by others or when they are discarded. To better understand the magnitude of sharing LLIN between households and patterns of discarding LLIN, the present study pools data from 14 post-campaign surveys to draw larger conclusions about the fate of nets that leave households. METHODS: Data from 14 sub-national post-campaign surveys conducted in Ghana, Senegal, Nigeria (10 states), and Uganda between 2009 and 2012 were pooled. Survey design and data collection methods were similar across surveys. The timing of surveys ranged from 2-16 months following their respective mass LLIN distributions. RESULTS: Among the 14 surveys a total of 14,196 households reported owning 25,447 nets of any kind, of which 23,955 (94%) were LLINs. In addition, a total of 4,102 nets were reported to have left the households in the sample: 63% were discarded, and 34% were given away. Only 255 of the discarded nets were reported used for other purposes, representing less than 1% of the total sample of nets. The majority (62.5%) of nets given away were given to or taken by relatives, while 31.1% were given to non-relatives. Campaign nets were almost six times (OR 5.95, 4.25-8.32, p < 0.0001) more likely to be given away than non-campaign nets lost during the same period. Nets were primarily given away within the first few months after distribution. The overall rate of net redistribution was 5% of all nets. DISCUSSION AND CONCLUSION: Intra household re-allocation of nets does occur, but was sensitive to current household net ownership and the time elapsed since mass distribution. These factors can be addressed programmatically to further facilitate reallocation within a given community. Secondly, the overwhelming majority of nets were used for malaria prevention. Of the repurposed nets (<1% overall), the majority were already considered too torn, indicating they had already served out their useful life for malaria prevention. National programmes and donor agencies should remain confident that overall, their investments in LLIN are being appropriately used. PMID- 25430957 TI - Dynamic MR angiography in acute aortic dissection. AB - BACKGROUND: To evaluate the benefit (additional flow information), image quality, and diagnostic accuracy of a dynamic magnetic resonance angiography (MRA) combining high spatial and temporal resolution for the preinterventional assessment of acute aortic dissection. METHODS: Nineteen patients (12 men, 7 women; aged 32-78 years) with acute aortic dissection underwent contrast-enhanced four-dimensional (4D) MRA and 3D conventional high-resolution MRA (3D MRA) within one examination on a 1.5 Tesla MR system. Both MRA datasets for each patient were evaluated and compared for image quality and visualization of vascular details on a 5-point scale (5 = excellent image quality, 1 = nondiagnostic image quality). In addition, presence and relevance of additional hemodynamic information (flow direction and organ perfusion delay) gained by dynamic MRA were assessed. RESULTS: Conventional 3D MRA provided significantly higher values for image quality of the aorta and aortic side branches compared with dynamic MRA (aorta: 4.3 versus 3.3; P = 0.006 side branches: 4.2 versus 3.3; P = 0.02). However, in 10 of the 19 patients (53%) the additionally available information on flow dynamics due to dynamic MRA (e.g., delayed perfusion of parenchymal organs) led to a change in therapy planning and realization. CONCLUSION: Dynamic MRA is a technique that combines functional flow and morphological information. Thus, the combination of 3D and dynamic MRA provides all requested information for treatment planning in patients suffering from acute aortic dissection. PMID- 25430958 TI - A bacterial gene, mms6, as a new reporter gene for magnetic resonance imaging of mammalian cells. AB - Magnetic resonance imaging (MRI) allows for noninvasive, deep tissue imaging with high spatial resolution, making it an attractive modality for in vivo cellular imaging. Since reporter genes can generate magnetic resonance (MR) contrast based on molecular activity, they offer a potentially powerful tool for cellular imaging. The mms6 gene was originally identified in magnetotactic bacteria (MTB), which is known to play a key role in magnetic crystal formation. The purpose of the present work was to investigate the possibility of using mms6 as an MR reporter gene. We established a transgenic mammalian cell line that stably expresses mms6. In vitro experiments show that mms6-expressing cells form clusters of nanoparticles within and outside membrane-enclosed structures and produce changes in MR contrast, most likely by increasing iron uptake of intracellular iron. Additionally, in vivo MRI experiments demonstrate that mms6 expressing tumors can be distinguished from parental tumors not expressing mms6, even in the absence of exogenous iron supplementation. Our results demonstrate that mms6 can function as an MR reporter gene with the potential to monitor gene expression and to visualize the proliferation, migration, and metastasis of tumor cells expressing it. PMID- 25430959 TI - siRNA blocking the RAS signalling pathway and inhibits the growth of oesophageal squamous cell carcinoma in nude mice. AB - The aim of this study was to study RAS-siRNA blocking RAS pathway and suppressing cell growth in human oesophageal squamous cell carcinoma in nude mice. The methods in this study was to construct RAS-siRNA expression vector, establish 40 oesophageal squamous cell carcinoma xenograft animal models and divided them into five groups: control group, siRNA control group, RAS-siRNA group, paclitaxel group and RAS-siRNA and paclitaxel group. We observed tumour growth in nude mice, studied histology by HE staining, tumour growth inhibition by TUNEL assay and detected the RAS, MAPK and cyclin D1 protein expression by immunohistochemistry and western blot. We have obtained the following results: (i) successfully established animal models; (ii) nude mice in each group after treatment inhibited tumour volume was significantly reduced compared with the control group (p < 0.05); (iii) compared with the control group, the number of apoptotic cells were significantly increased in the siRNA control group and the RAS-siRNA group, and the number of apoptosis cells in the paclitaxel and RAS-siRNA group is significantly most than the paclitaxel group and RAS-siRNA group (p < 0.05); and (iv) after treatment, RAS, MAPK and cyclin D1 expression in five groups was decreasing gradually. After adding paclitaxel, the protein expression in the paclitaxel and RAS-siRNA group was significantly lower than that of paclitaxel group, negative control and paclitaxel group (p < 0.05). We therefore conclude that RAS-siRNA can block the RAS signal transduction pathway, reduce the activity of tumour cells, arrest tumour cell cycle, promote apoptosis, inhibit cell proliferation and increase tumour cell sensitivity to chemotherapeutic drugs. PMID- 25430960 TI - Access to novel graphene-like sheet of hydroboron: first-principles investigation. AB - We designed a cyclic borane (B6 H12 ) molecule with a benzene-like structure, in which the six B atoms are located in the same plane. Three methods of B3LYP, MP2, and CCSD with the 6-311++G** basis were used to investigate its structure, electronic property, and stability. Next, we calculated the stability and electronic property of three hydroboron derivatives with fused rings of B10 H18 , B14 H24 , and B16 H26 . Finally, we investigated three types of novel two dimensional infinite hydroboron sheets with diborane as a building block. The results of the phonon spectra ensure the dynamic stability of these predicted structures. Furthermore, the three types of hydroboron sheets are shown to have different band gap energies of less than 3.0 eV. Some investigations on the optical properties have also been performed. The predicted sheets are candidates for semiconductors, whose band gap energy can be tuned by the positions of the bridge hydrogen atoms in the sheets. PMID- 25430962 TI - Intramolecular C-N bond activation and ring-expansion reactions of N-heterocyclic carbenes. AB - Intramolecular ring-expansion reactions (RER) of the N-heterocyclic carbene 1,3 dimethylimidazolin-2-ylidene were observed upon vacuum ultraviolet (VUV) photoexcitation. Similarly to RERs reported in the solvent phase, for the reaction of NHCs with main-group-element hydrides, hydrogen transfer to the NHC carbon atom is the crucial initial step. In an ionization-mediated protonation, 1,3-dimethylimidazolin-2-ylidene forms an imidazolium ion, which is the rate limiting step on the pathway to two six-membered ring products, namely, methylpyrimidinium and -pyrazinium ions. To unravel the reaction path, we have used imaging photoelectron photoion coincidence spectroscopy with VUV synchrotron radiation, as well as high-level composite method calculations. Similarities and differences between the mechanism in the gas phase and in the condensed phase are discussed. PMID- 25430963 TI - Microbiota: A viral understudy for commensal bacteria. PMID- 25430961 TI - How do we use therapeutic drug monitoring to improve outcomes from severe infections in critically ill patients? AB - High mortality and morbidity rates associated with severe infections in the critically ill continue to be a significant issue for the healthcare system. In view of the diverse and unique pharmacokinetic profile of drugs in this patient population, there is increasing use of therapeutic drug monitoring (TDM) in attempt to optimize the exposure of antibiotics, improve clinical outcome and minimize the emergence of antibiotic resistance. Despite this, a beneficial clinical outcome for TDM of antibiotics has only been demonstrated for aminoglycosides in a general hospital patient population. Clinical outcome studies for other antibiotics remain elusive. Further, there is significant variability among institutions with respect to the practice of TDM including the selection of patients, sampling time for concentration monitoring, methodologies of antibiotic assay, selection of PK/PD targets as well as dose optimisation strategies. The aim of this paper is to review the available evidence relating to practices of antibiotic TDM, and describe how TDM can be applied to potentially improve outcomes from severe infections in the critically ill. PMID- 25430964 TI - Salience Not Status: How Category Labels Influence Feature Inference. AB - Two main uses of categories are classification and feature inference, and category labels have been widely shown to play a dominant role in feature inference. However, the nature of this influence remains unclear, and we evaluate two contrasting hypotheses formalized as mathematical models: the label special mechanism hypothesis and the label super-salience hypothesis. The special mechanism hypothesis is that category labels, unlike other features, trigger inference decision making in reference to the category prototypes. This results in a tendency for prototype-compatible inferences because the labels trigger a special mechanism rather than because of any influences they have on similarity evaluation. The super-salience hypothesis assumes that the large label influence is due to their high salience and corresponding impact on similarity without any need for a special mechanism. Application of the two models to a feature inference task based on a family resemblance category structure yields strong support for the label super-salience hypothesis and in particular does not support the need for a special mechanism based on prototypes. PMID- 25430965 TI - One-step generation of p53 gene biallelic mutant Cynomolgus monkey via the CRISPR/Cas system. PMID- 25430966 TI - The biodiversity-dependent ecosystem service debt. AB - Habitat destruction is driving biodiversity loss in remaining ecosystems, and ecosystem functioning and services often directly depend on biodiversity. Thus, biodiversity loss is likely creating an ecosystem service debt: a gradual loss of biodiversity-dependent benefits that people obtain from remaining fragments of natural ecosystems. Here, we develop an approach for quantifying ecosystem service debts, and illustrate its use to estimate how one anthropogenic driver, habitat destruction, could indirectly diminish one ecosystem service, carbon storage, by creating an extinction debt. We estimate that c. 2-21 Pg C could be gradually emitted globally in remaining ecosystem fragments because of plant species loss caused by nearby habitat destruction. The wide range for this estimate reflects substantial uncertainties in how many plant species will be lost, how much species loss will impact ecosystem functioning and whether plant species loss will decrease soil carbon. Our exploratory analysis suggests that biodiversity-dependent ecosystem service debts can be globally substantial, even when locally small, if they occur diffusely across vast areas of remaining ecosystems. There is substantial value in conserving not only the quantity (area), but also the quality (biodiversity) of natural ecosystems for the sustainable provision of ecosystem services. PMID- 25430967 TI - Safety and efficacy of expanded polytetrafluoroethylene-covered transjugular intrahepatic portosystemic shunts in children with acute or recurring upper gastrointestinal bleeding. AB - BACKGROUND: The transjugular intrahepatic portosystemic shunt (TIPS) is effective for treating complications of portal hypertension in cirrhotic adults but the experience in children is limited. OBJECTIVE: To retrospectively review the safety and efficacy of expanded polytetrafluoroethylene (ePTFE)-covered TIPS in children with acute or recurrent gastrointestinal bleeding. MATERIALS AND METHODS: We reviewed the medical records of children who received implants of 10 mm-diameter PTFE-covered endoprostheses for acute or recurring upper gastrointestinal bleeding caused by medically or endoscopically uncontrollable varices. The recurrence of upper gastrointestinal bleeding, associated complications and permeability were assessed with Doppler sonography sequentially or up to transplantation. RESULTS: In all children (n = 12; mean age 9 years; mean weight 30 kg) a single endoprosthesis was implanted with no associated mortality. The mean initial transhepatic gradient was 15 mmHg (range 3-21 mmHg), dropping to 7 mmHg (range 1-12 mmHg) after TIPS. Immediate complications were mild encephalopathy (n = 1) and acute occlusion of the TIPS (n = 1). Stenosis of the TIPS was observed in two children, at 9 months and 54 months follow-up, and thrombosis was observed in two children, at 7 months and 12 months follow-up. All four stenoses/occlusions were resolved with coaxial endoprostheses. CONCLUSION: The safety profile and efficacy of expanded polytetrafluoroethylene (ePTFE) covered TIPS were satisfactory in this small series of children with acute or recurrent gastrointestinal bleeding. PMID- 25430968 TI - Inorganic core-shell assemblies for closing the artificial photosynthetic cycle. AB - Co oxide (Co(3)O(4)) nanotubes are shown to act as an efficient water oxidation catalyst when driven with a visible light sensitizer (pH 7). The nanotubes form the core of a Co(3)O(4)-SiO(2) core-shell nanotube design for separating the carbon dioxide photoreduction from the oxygen evolution reaction. Amorphous dense phase silica of a few nanometers depth is shown to conduct protons while blocking molecular oxygen. Organic molecular wires embedded in the silica shell provide controlled charge transport between the light absorber on one side and the Co(3)O(4) catalyst on the other side. Hence, the silica shell is suitable as a membrane of an assembly for closing the photosynthetic cycle on the nanometer scale under product separation. PMID- 25430969 TI - Efficacy of magnesium chloride in the treatment of Hailey-Hailey disease: from serendipity to evidence of its effect on intracellular Ca(2+) homeostasis. AB - BACKGROUND: Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is a rare autosomal dominant inherited intraepidermal blistering genodermatosis. Mutations in the ATP2C1 gene encoding for the Golgi secretory pathway Ca(2+) /Mn(2+) -ATPasi protein 1 (SPCA1) affect the processing of desmosomal components and the epidermal suprabasal cell-cell adhesion by deregulating the keratinocyte cytosolic Ca(2+) concentration. We report the unexpected, dramatic, and persistent clinical improvement of the skin lesions of a patient affected with longstanding HHD with daily intake of a solution containing magnesium chloride hexahydrate (MgCl2 ). MATERIALS AND METHODS: We investigated the effect of MgCl2 on the intracellular Ca(2+) homeostasis and on the activity of particular Ca(2+) -effectors in HeLa cells transfected with chimeric aequorins (cytAEQ, mtAEQ, erAEQ and GoAEQ) targeted to different subcellular compartments (cytosol, mitochondria, endoplasmic reticulum, and Golgi, respectively). RESULTS: Experimental investigations on HeLa cells showed the effect of MgCl2 on the function of Ca(2+) -extrusor systems, resulting in increased cytosolic and mitochondrial Ca(2+) levels, without altering the mechanisms of intraluminal Ca(2+) -filling and Ca(2+) -release of stores. CONCLUSIONS: Based on our clinical observation and experimental results, it can be hypothesized that MgCl2 could act as an inhibitor of the Ca(2+) -extruding activity in keratinocytes favoring intracellular Ca(2+) -disponibility and Ca(2+) -dependent mechanisms in desmosome assembly. This may represent the molecular basis of the good response of the HHD clinical features with MgCl2 solution in the patient described. PMID- 25430970 TI - Inclusion of soil carbon lateral movement alters terrestrial carbon budget in China. AB - The lateral movement of soil carbon has a profound effect on the carbon budget of terrestrial ecosystems; however, it has never been quantified in China, which is one of the strongest soil erosion areas in the world. In this study, we estimated that the overall soil erosion in China varies from 11.27 to 18.17 Pg yr(-1) from 1982 to 2011, accounting for 7-21% of total soil erosion globally. Soil erosion induces a substantial lateral redistribution of soil organic carbon ranging from 0.64 to 1.04 Pg C yr(-1). The erosion-induced carbon flux ranges from a 0.19 Pg C yr(-1) carbon source to a 0.24 Pg C yr(-1) carbon sink in the terrestrial ecosystem, which is potentially comparable in magnitude to previously estimated total carbon budget of China (0.19 to 0.26 Pg yr(-1)). Our results showed that the lateral movement of soil carbon strongly alters the carbon budget in China, and highlighted the urgent need to integrate the processes of soil erosion into the regional or global carbon cycle estimates. PMID- 25430971 TI - Longing for the country's good old days: National nostalgia, autochthony beliefs, and opposition to Muslim expressive rights. AB - Four studies tested the prediction that feelings of national nostalgia (i.e. nostalgia on the basis of one's national ingroup membership) result in more opposition towards expressive rights for Muslim immigrants, because they strengthen the belief that a place belongs to its original inhabitants, and that they are therefore more entitled (i.e. autochthony). Study 1 found that national nostalgia can be distinguished from personal nostalgia, and that national (rather than personal) nostalgia was related to more opposition to Muslim rights via stronger endorsement of autochthony. This latter result was replicated in another survey study (Study 2) and in an experiment (Study 3) in which national nostalgia was manipulated. Study 4 provided preliminary evidence that the salience of autochthony increases opposition to Muslim rights. PMID- 25430972 TI - A Novel Protocol to Differentiate Induced Pluripotent Stem Cells by Neuronal microRNAs to Provide a Suitable Cellular Model. AB - Neurodegenerative diseases are one of the most challenging subjects in medicine. Investigation of their underlying genetic or epigenetic factors is hampered by lack of suitable models. Patient-specific induced pluripotent stem cells (iPS cells) represent a valuable approach to provide a proper model for poorly understood mechanisms of neuronal diseases and the related drug screenings. miR 124 and miR-128 are the two brain-enriched miRNAs with different time-points of expression during neuronal development. Herein, we transduced human iPS cells with miR-124 and miR-128 harboring lentiviruses sequentially. The transduced plasmids contained GFP and puromycin antibiotic-resistant genes for easier selection and identification. Morphological assessment and immunocytochemistry (overexpressions of beta-tubulin and neuron-specific enolase) confirmed that induced hiPS cells by miR-124 and miR-128 represent similar characteristics to those of mature neurons. In addition, the upregulation of neuron-specific enolase, beta-tubulin, Map2, GFAP, and BDNF was detected by quantitative real time PCR. In conclusion, it seems that our novel protocol remarks the combinatorial effect of miR-124 and miR-128 on neural differentiation in the absence of any extrinsic factor. Moreover, such cellular models could be used in personalized drug screening and applied for more effective therapies. PMID- 25430973 TI - Prostatic displacement during extreme hypofractionated radiotherapy using volumetric modulated arc therapy (VMAT). AB - BACKGROUND: To determine prostate displacement during extreme hypofractionated volume modulated arc radiotherapy (VMAT) using pre- and post-treatment orthogonal images with three implanted gold seed fiducial markers. METHODS: A total of 150 image pairs were obtained from 30 patients who underwent extreme hypofractionated radiotherapy to a dose of 40 Gy in five fractions on standard linear accelerators. Position verification was obtained with orthogonal x-rays before and after treatment and were used to determine intra-fraction prostate displacement. RESULTS: The mean prostate displacements were 0.03 +/- 1.23 mm (1SD), 0.18 +/- 1.55 mm, and 0.37 +/- 1.95 mm in the left-right, superior inferior, and anterior-posterior directions, respectively. The mean 3D displacement was 2.32 +/- 1.55 mm. Only 6 (4%) fractions had a 3D displacement of >5 mm. The average time of treatment delivery for a given fraction was 195 +/- 59 seconds. CONCLUSIONS: The mean intra-fraction prostate displacement during a course of extreme hypofractionated radiotherapy delivered via VMAT, continues to be small. Clinical margins typically used in a similar fixed-angle IMRT treatment are adequate. The use of VMAT in further extreme hypofractionation may limit prostatic motion uncertainties that would be otherwise be associated with longer treatment times. PMID- 25430975 TI - Daily variations in sleep: associated genes and effects on affect. PMID- 25430974 TI - Light-chain amyloidosis presenting as a change in bleeding phenotype in a patient with mild haemophilia A. PMID- 25430976 TI - Core-shell LiFePO4 /carbon-coated reduced graphene oxide hybrids for high-power lithium-ion battery cathodes. AB - Core-shell carbon-coated LiFePO4 nanoparticles were hybridized with reduced graphene (rGO) for high-power lithium-ion battery cathodes. Spontaneous aggregation of hydrophobic graphene in aqueous solutions during the formation of composite materials was precluded by employing hydrophilic graphene oxide (GO) as starting templates. The fabrication of true nanoscale carbon-coated LiFePO4 -rGO (LFP/C-rGO) hybrids were ascribed to three factors: 1) In-situ polymerization of polypyrrole for constrained nanoparticle synthesis of LiFePO4 , 2) enhanced dispersion of conducting 2D networks endowed by colloidal stability of GO, and 3) intimate contact between active materials and rGO. The importance of conducting template dispersion was demonstrated by contrasting LFP/C-rGO hybrids with LFP/C rGO composites in which agglomerated rGO solution was used as the starting templates. The fabricated hybrid cathodes showed superior rate capability and cyclability with rates from 0.1 to 60 C. This study demonstrated the synergistic combination of nanosizing with efficient conducting templates to afford facile Li(+) ion and electron transport for high power applications. PMID- 25430977 TI - Identification and molecular characterization of Medicago truncatula NRT2 and NAR2 families. AB - Nitrate transporters received little attention to legumes probably because these species are able to adapt to N starvation by developing biological N2 fixation. Still it is important to study nitrate transport systems in legumes because nitrate intervenes as a signal in regulation of nodulation probably through nitrate transporters. The aim of this work is to achieve a molecular characterization of nitrate transporter 2 (NRT2) and NAR2 (NRT3) families to allow further work that would unravel their involvement in nitrate transport and signaling. Browsing the latest version of the Medicago truncatula genome annotation (v4 version) revealed three putative NRT2 members that we have named MtNRT2.1 (Medtr4g057890.1), MtNRT2.2 (Medtr4g057865.1) and MtNRT2.3 (Medtr8g069775.1) and two putative NAR2 members we named MtNAR2.1 (Medtr4g104730.1) and MtNAR2.2 (Medtr4g104700.1). The regulation and the spatial expression profiles of MtNRT2.1, the coincidence of its expression with that of MtNAR2.1 and MtNAR2.2 and the size of the encoded protein with 12 transmembrane (TM) spanning regions strongly support the idea that MtNRT2.1 is a nitrate transporter with a major contribution to the high-affinity transport system (HATS), while a very low level of expression characterized MtNRT2.2. Unlike MtNRT2.1, MtNRT2.3 showed a lower level of expression in the root system but was expressed in the shoots and in the nodules thus suggesting an involvement of the encoded protein in nitrate transport inside the plant and/or in nitrate signaling pathways controlling post-inoculation processes that govern nodule functioning. PMID- 25430978 TI - An allosteric receptor by simultaneous "casting" and "molding" in a dynamic combinatorial library. AB - Allosteric synthetic receptors are difficult to access by design. Herein we report a dynamic combinatorial strategy towards such systems based on the simultaneous use of two different templates. Through a process of simultaneous casting (the assembly of a library member around a template) and molding (the assembly of a library member inside the binding pocket of a template), a Russian doll-like termolecular complex was obtained with remarkable selectivity. Analysis of the stepwise formation of the complex indicates that binding of the two partners by the central macrocycle exhibits significant positive cooperativity. Such allosteric systems represent hubs that may have considerable potential in systems chemistry. PMID- 25430980 TI - Intra-articular injection of synthetic microRNA-210 accelerates avascular meniscal healing in rat medial meniscal injured model. AB - INTRODUCTION: The important functions of the meniscus are shock absorption, passive stabilization and load transmission of the knee. Because of the avascularity of two-thirds of the meniscal center region, the treatment of tears in this area is hard. Recently, microRNAs have been proven to play an important role in the pathogenesis of diseases. We focused on microRNA (miR)-210, which plays a wide spectrum of roles comprising mitochondrial metabolism, angiogenesis, DNA repair and cell survival. This study aimed to investigate the effect of intra articular injection of synthetic miR-210 on the injured meniscus in the avascular zone. METHODS: The middle segments of the medial meniscus of Spraque Dawley rats were incised longitudinally with a scalpel. An intra-articular injection of double-stranded (ds) miR-210 (for control group using control dsRNA) with atelocollagen was administered immediately after injury. Four weeks and 12 weeks after the injection, we conducted a histologic evaluation, immunohistochemical evaluation and Real-time PCR analysis. In vitro, the inner meniscus and synovial cells were isolated from rat knee joint, and were transfected with ds miR-210 or control dsRNA. Real-time PCR and immunohistochemical evaluations were performed. RESULTS: Twenty-four hours after the injection, FAM (Fluorescein amidite) labeled miR-210 was observed in the cells around the injured site. Four weeks after the injection, the injured site of the miR-210 group was filled with repaired tissue while that of the control was not repaired. In gene expression analysis of the meniscus, the expression of miR-210, Collagen type 2 alpha 1 (Col2a1), Vascular endothelial growth factor (VEGF), and Fibroblast growth factor-2 (FGF2) in the miR-210 group was significantly higher than that in the control. At 12 weeks, the intra-articular injection of miR-210 had healed the injured site of the meniscus and had prevented articular cartilage degeneration. In vitro, miR-210 upregulated Col2a1 expression in the meniscus cells and VEGF and FGF2 expression in the synovial cells. CONCLUSIONS: An intra-articular injection of ds miR-210 was effective in the healing of the damaged white zone meniscus through promotion of the collagen type 2 production from meniscus cells and through upregulated of VEGF and FGF2 from synovial cells. PMID- 25430979 TI - Multi-drug resistant gram negative infections and use of intravenous polymyxin B in critically ill children of developing country: retrospective cohort study. AB - BACKGROUND: Patients in pediatric intensive care Units (PICU) are susceptible to infections with antibiotic resistant organisms which increase the morbidity, mortality and cost of care. To describe the clinical characteristics and mortality in patients with Multi-Drug Resistant (MDR) gram negative organisms. We also report safety of Polymyxin B use in these patients. METHODS: Files of patients admitted in PICU of Aga Khan University Hospital, from January 2010 to December 2011, one month to 15 years of age were reviewed. Demographic and clinical features of patients with MDR gram negative infections, antibiotic susceptibility pattern of isolates, discharge disposition and adverse effects of Polymyxin B were recorded. RESULTS: A total of 44.8/1000(36/803) admitted patients developed MDR gram negative infections, of which 47.2%(17/36) were male, with mean age of 3.4 yrs(+/-4.16). Acinetobacter Species (25.5%) was the most frequently isolated MDR organisms followed by Klebsiella Pneumoniae (17%). Sensitivity of isolates was 100% to Polymyxin B, followed by Imipenem (50%), and piperacillin/tazobactem (45%). The crude mortality rate of patients with MDR gram negative infections was 44.4% (16/36). Fourteen of 36 patients received Polymyxin B and 57.1%; (8/14) of them were cured. Nephrotoxicity was observed in 21.4% (3/14) cases, none of the patients showed signs of neuropathy. CONCLUSION: Our study highlights high rates of Carbapenem resistant gram negative isolates, leading to increasing use of Polymyxin B as the only drug to combat against these critically ill children. Therefore, we emphasizeon Stewardship of Antibiotics and continuous surveillance system as strategies in overall management of these critically ill children. PMID- 25430981 TI - Rice terpene synthase 20 (OsTPS20) plays an important role in producing terpene volatiles in response to abiotic stresses. AB - This study examined the volatile terpenes produced by rice seedlings in response to oxidative stress induced by various abiotic factors. Solid-phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) analyses revealed that when exposed to UV-B radiation, rice seedlings emitted a bouquet of monoterpene mixtures in a time-dependent manner. The mixtures comprised limonene, sabinene, myrcene, alpha-terpinene, beta-ocimene, gamma-terpinene, and alpha terpinolene. Among them, (S)-limonene was the most abundant volatile, discriminated by chiral SPME-GC-MS. The volatile profiles collected from rice plants treated with both gamma-irradiation and H2O2 were identical to those observed in the UV-B irradiated plants, thus indicating that the volatile mixtures were specifically produced in response to oxidative stress, particularly in the presence of H2O2. Using a reverse genetics approach, we isolated full length rice terpene synthase 20 (OsTPS20, 599 amino acids, 69.39 kDa), which was further characterized as an (S)-limonene synthase by removing the N-terminal signal peptide (63 amino acids) of the protein. The recombinant OsTPS20 protein catalyzed the conversion of geranyl diphosphate to (S)-limonene and other minor monoterpenes, essentially covering all of the volatile compounds detected from the plant. Moreover, qRT-PCR revealed that the transcript levels of OsTPS20 were significantly induced in response to oxidative stress, thereby suggesting that OsTPS20 plays a major role in producing terpene volatiles during abiotic stress. Detailed biochemical analyses and the unusual domain characteristics of OsTPS20 are also discussed in this report. PMID- 25430982 TI - [In Process Citation]. PMID- 25430983 TI - Risk of recurrence in patients with colon cancer stage II and III: a systematic review and meta-analysis of recent literature. AB - BACKGROUND: Adjuvant chemotherapy is established routine therapy for colon cancer (CC) patients with radically resected stage III and 'high-risk' stage II disease. The decision on recommending adjuvant chemotherapy, however, is based on data from older patient cohorts not reflecting improvements in pre-operative staging, surgery, and pathological examination. The aim is to review the current risk of recurrence in stage II and III patients and second, to estimate the relative importance of routinely assessed clinico-pathological variables. METHODS: The PubMed/MEDLINE and the Cochrane databases were systematically searched for randomized controlled studies and observational studies published after 1 January 2005 with patients included after January 1995 on prognosis in surgically treated stage II and III CC patients. RESULTS: Of 2596 studies identified, 37 met the inclusion criteria and 25 provided data for meta-analysis. The total patient sample size in the 25 studies reporting either disease-free (DFS) or recurrence free survival was 15 559 in stage II and 18 425 in stage III. Five-year DFS for stage II patients operated without subsequent adjuvant chemotherapy was 81.4% [95% confidence interval (CI) 75.4-87.4; in studies with good/very good quality of reporting 82.7%, (95% CI 80.8-84.6)]. For stage II patients treated with adjuvant chemotherapy, the five-year DFS was 79.3% (95% CI 75.6-83.1). For stage III patients without chemotherapy, five-year DFS was 49.0% (95% CI 23.2-74.8) and for those treated with adjuvant chemotherapy, 63.6% (95% CI 59.3-67.9). The prognostic impact of commonly investigated clinico-pathological parameters, (pT stage, pN-stage, differentiation, number of lymph nodes studied, MMR-status, and emergency surgery) were confirmed. CONCLUSIONS: In this meta-analysis, studies with good quality of reporting show a five-year DFS of 82.7% for stage II CC without adjuvant chemotherapy, whereas the five-year DFS is 63.8% for stage III CC with adjuvant chemotherapy. Due to insufficient reporting on treatment quality the presented DFS is likely an under-estimation of what is achieved at high quality centers today. PMID- 25430984 TI - Timing of epidural blood patch: clearing up the confusion. PMID- 25430985 TI - Local tumour hyperthermia as immunotherapy for metastatic cancer. AB - Abstract Local tumour hyperthermia for cancer treatment is currently used either for ablation purposes as an alternative to surgery or less frequently, in combination with chemotherapy and/or radiation therapy to enhance the effects of those traditional therapies. As it has become apparent that activating the immune system is crucial to successfully treat metastatic cancer, the potential of boosting anti-tumour immunity by heating tumours has become a growing area of cancer research. After reviewing the history of hyperthermia therapy for cancer and introducing methods for inducing local hyperthermia, this review describes different mechanisms by which heating tumours can elicit anti-tumour immune responses, including tumour cell damage, tumour surface molecule changes, heat shock proteins, exosomes, direct effects on immune cells, and changes in the tumour vasculature. We then go over in vivo studies that provide promising results showing that local hyperthermia therapy indeed activates various systemic anti-tumour immune responses that slow growth of untreated tumours. Finally, future research questions that will help bring the use of local hyperthermia as systemic immunotherapy closer to clinical application are discussed. PMID- 25430986 TI - Housing temperature influences the pattern of heat shock protein induction in mice following mild whole body hyperthermia. AB - PURPOSE: Researchers studying the murine response to stress generally use mice housed under standard, nationally mandated conditions as controls. Few investigators are concerned whether basic physical aspects of mouse housing could be an additional source of stress, capable of influencing the subsequent impact of an experimentally applied stressor. We have recently become aware of the potential for housing conditions to impact important physiological and immunological properties in mice. MATERIALS AND METHODS: Here we sought to determine whether housing mice at standard temperature (ST; 22 degrees C) vs. thermoneutral temperature (TT; 30 degrees C) influences baseline expression of heat shock proteins (HSPs) and their typical induction following a whole body heating. RESULTS: There were no significant differences in baseline expression of HSPs at ST and TT. However, in several cases, the induction of Hsp70, Hsp110 and Hsp90 in tissues of mice maintained at ST was greater than at TT following 6 h of heating (which elevated core body temperature to 39.5 degrees C). This loss of HSP induction was also seen when mice housed at ST were treated with propranolol, a beta-adrenergic receptor antagonist, used clinically to treat hypertension and stress. CONCLUSIONS: Taken together, these data show that housing temperature significantly influences the expression of HSPs in mice after whole body heating and thus should be considered when stress responses are studied in mice. PMID- 25430987 TI - Outdoor exercise performance in ambient heat: time to overcome challenging factors? PMID- 25430988 TI - Iterative procedures combining cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for isolated peritoneal recurrence. AB - PURPOSE: The aim of this study was to analyse feasibility, morbidity and outcome of repeat complete cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC). CRS combined with HIPEC is becoming the gold standard treatment for resectable peritoneal carcinomatosis in highly selected patients. As yet treatment of isolated peritoneal recurrence with iterative CRS and HIPEC has not been thoroughly explored. MATERIALS AND METHODS: We selected 16 patients presenting isolated peritoneal recurrence who had undergone iterative CRS and HIPEC from a dataset of 322 CRS associated with HIPEC performed between 1996 and 2012. RESULTS: Peritoneal carcinomatosis (PC) was due to colorectal and ovarian cancer, peritoneal mesothelioma and pseudomyxoma peritonei (PMP). Disease-free survival (DFS) was 13 months after the first procedure and 13.7 months after the second one. Overall morbidity rate was 43.7% (7/16) for all patients, with grade III-IV complications in three patients (18.7%). CONCLUSIONS: Iterative procedures combining cytoreductive surgery and HIPEC are feasible with acceptable morbidity and mortality rates in strictly selected patients. DFS following repeated CRS and HIPEC is comparable to that registered after the first procedure. PMID- 25430989 TI - In vivo optimisation study for multi-baseline MR-based thermometry in the context of hyperthermia using MR-guided high intensity focused ultrasound for head and neck applications. AB - PURPOSE: In this in vivo study, the feasibility to perform hyperthermia treatments in the head and neck using magnetic resonance image-guided high intensity focused ultrasound (MRgHIFU) was established using a porcine acute model. MATERIALS AND METHODS: Porcine specimens with a weight between 17 and 18 kg were treated in the omohyoid muscle in the neck. Hyperthermia was applied with a target temperature of 41 degrees C for 30 min using a Sonalleve MRgHIFU system. MR-based thermometry was calculated using water-proton resonance frequency shift and multi-baseline look-up tables indexed by peak-to-peak displacement (Dpp) measurements using a pencil-beam navigator. Three hyperthermia experiments were conducted at different Dpp values of 0.2, 1.0 and 3.0 mm. An optimisation study was carried out to establish the optimal parameters controlling the multi-baseline method that ensured a minimisation of spatial average peak-to-peak temperature (TSA-pp) and temperature direct current bias (TSA-DC). RESULTS: The multi-baseline technique reduced considerably the noise on both TSA-pp and TSA-DC. The reduction of noise was more important when Dpp was higher. For Dpp = 3 mm the average (+/-standard deviation (SD)) of TSA-pp and TSA DC was reduced from 4.5 (+/- 2.5) and 2.5 (+/-0.6) degrees C, respectively, to 0.8 (+/- 0.7) and 0.09 (+/- 0.2) degrees C. CONCLUSIONS: This in vivo study showed the level of noise in PRFS-based thermometry introduced by respiratory motion in the context of MRgHIFU hyperthermia treatment for head and neck and the feasibility of reducing this noise using a multi-baseline technique. PMID- 25430990 TI - Study of the relationship between the target tissue necrosis volume and the target tissue size in liver tumours using two-compartment finite element RFA modelling. AB - PURPOSE: The aim of this study was to investigate the relationship between the target tissue necrosis volume and the target tissue size during the radiofrequency ablation (RFA) procedure. MATERIALS AND METHODS: The target tissues with four different sizes (dxy = 20, 25, 30 and 35 mm) were modelled using a two-compartment radiofrequency ablation model. Different voltages were applied to seek the maximum target tissue necrosis volume for each target tissue size. The first roll-off occurrence or the standard ablation time (12 min) was taken as the sign for the termination of the RFA procedure. RESULTS: Four different maximum voltages without the roll-off occurrence were found for the four different sizes of target tissues (dxy = 20, 25, 30 and 35 mm), and they were 36.6, 35.4, 33.9 and 32.5 V, respectively. The target tissues with diameters of 20, 25 mm can be cleanly ablated at their own maximum voltages applied (MVA) but the same finding was not found for the 35-mm target tissue. For the target tissue with diameter of 30 mm, the 50 degrees C isothermal contour (IT50) result showed that the target tissue can be cleanly ablated, but the same result did not show in the Arrhenius damage model result. Furthermore, two optimal RFA protocols with a minimal thermal damage to the healthy tissues were found for the target tissues with diameters of 20 and 25 mm, respectively. CONCLUSIONS: The study suggests that target tissues of different sizes should be treated with different RFA protocols. The maximum target tissue volume was achieved with the MVA without the roll-off occurrence for each target tissue size when a constant RF power supply was used. PMID- 25430991 TI - Interactive effects of ocean acidification and rising sea temperatures alter predation rate and predator selectivity in reef fish communities. AB - Ocean warming and acidification are serious threats to marine life. While each stressor alone has been studied in detail, their combined effects on the outcome of ecological interactions are poorly understood. We measured predation rates and predator selectivity of two closely related species of damselfish exposed to a predatory dottyback. We found temperature and CO2 interacted synergistically on overall predation rate, but antagonistically on predator selectivity. Notably, elevated CO2 or temperature alone reversed predator selectivity, but the interaction between the two stressors cancelled selectivity. Routine metabolic rates of the two prey showed strong species differences in tolerance to CO2 and not temperature, but these differences did not correlate with recorded mortality. This highlights the difficulty of linking species-level physiological tolerance to resulting ecological outcomes. This study is the first to document both synergistic and antagonistic effects of elevated CO2 and temperature on a crucial ecological process like predator-prey dynamics. PMID- 25430992 TI - Refractory chronic cluster headache: a consensus statement on clinical definition from the European Headache Federation. AB - Chronic cluster headache (CCH) often resists to prophylactic pharmaceutical treatments resulting in patients' life damage. In this rare but pragmatic situation escalation to invasive management is needed but framing criteria are lacking. We aimed to reach a consensus for refractory CCH definition for clinical and research use. The preparation of the final consensus followed three stages. Internal between authors, a larger between all European Headache Federation members and finally an international one among all investigators that have published clinical studies on cluster headache the last five years. Eighty-five investigators reached by email. Proposed criteria were in the format of the International Classification of Headache Disorders III-beta (description, criteria, notes, comments and references). Following this evaluation eight drafts were prepared before the final. Twenty-four (28.2%) international investigators commented during two rounds. Refractory CCH is described in the present consensus as a situation that fulfills the criteria of ICHD-3 beta for CCH with at least three severe attacks per week despite at least three consecutive trials of adequate preventive treatments. The condition is rare, but difficult to manage and invasive treatments may be needed. The consensus addresses five specific clinical and paraclinical diagnostic criteria followed by three notes and specific comments. Although refractory CCH may be not a separate identity these specific diagnostic criteria should help clinicians and investigators to improve patient's quality of life. PMID- 25430993 TI - The pathogenic Th profile of human activated memory Th cells in early rheumatoid arthritis can be modulated by VIP. AB - Our aim is to study the behavior of memory Th cells (Th17, Th17/1, and Th1 profiles) from early rheumatoid arthritis (eRA) patients after their in vitro activation/expansion to provide information about its contribution to RA chronicity. Moreover, we analyzed the potential involvement of vasoactive intestinal peptide (VIP) as an endogenous healing mediator. CD4(+)CD45RO(+) T cells from PBMCs of HD and eRA were activated/expanded in vitro in the presence/absence of VIP. FACS, ELISA, RT-PCR, and immunocytochemistry analyses were performed. An increase in CCR6(+)/RORC(+) cells and in RORC-proliferating cells and a decrease in T-bet-proliferating cells and T-bet(+)/RORC(+) cells were shown in eRA. mRNA expression of IL-17, IL-2, RORC, RORA, STAT3, and Tbx21 and protein secretion of IL-17, IFNgamma, and GM-CSF were higher in eRA. VIP decreased the mRNA expression of IL-22, IL-2, STAT3, Tbx21, IL-12Rbeta2, IL-23R, and IL-21R in HD and it decreased IL-21, IL-2, and STAT3 in eRA. VIP decreased IL 22 and GM-CSF secretion and increased IL-9 secretion in HD and it decreased IL-21 secretion in eRA. VPAC2/VPAC1 ratio expression was increased in eRA. All in all, memory Th cells from eRA patients show a greater proportion of Th17 cells with a pathogenic Th17 and Th17/1 profile compared to HD. VIP is able to modulate the pathogenic profile, mostly in HD. Our results are promising for therapy in the early stages of RA because they suggest that targeting molecules involved in the pathogenic Th17, Th17/1, and Th1 phenotypes and targeting VIP receptors could have a therapeutic effect modulating these subsets. KEY MESSAGES: Th17 cells are more important than Th1 in the contribution to pathogenesis in eRA patients. Pathogenic Th17 and Th17/1 profile are abundant in activated/expanded memory Th cells from eRA patients. VIP decreases the pathogenic Th17, Th1, and Th17/1 profiles, mainly in healthy donors. The expression of VIP receptors is reduced in eRA patients respect to healthy donors, whereas the ratio of VPAC2/VPAC1 expression is higher. PMID- 25430994 TI - Structural basis for targeting the ribosomal protein S1 of Mycobacterium tuberculosis by pyrazinamide. AB - Pyrazinamide (PZA) is a first-line drug for tuberculosis (TB) treatment and is responsible for shortening the duration of TB therapy. The mode of action of PZA remains elusive. RpsA, the ribosomal protein S1 of Mycobacterium tuberculosis (Mtb), was recently identified as a target of PZA based on its binding activity to pyrazinoic acid (POA), the active form of PZA. POA binding to RpsA led to the inhibition of trans-translation. However, the nature of the RpsA-POA interaction remains unknown. Key questions include why POA exhibits an exquisite specificity to RpsA of Mtb and how RpsA mutations confer PZA resistance. Here, we report the crystal structures of the C-terminal domain of RpsA of Mtb and its complex with POA, as well as the corresponding domains of two RpsA variants that are associated with PZA resistance. Structural analysis reveals that POA binds to RpsA through hydrogen bonds and hydrophobic interactions, mediated mainly by residues (Lys303, Phe307, Phe310 and Arg357) that are essential for tmRNA binding. Conformational changes induced by mutation or sequence variation at the C-terminus of RpsA abolish the POA binding activity. Our findings provide insights into the mode of action of PZA and molecular basis of PZA resistance associated with RpsA mutations. PMID- 25430995 TI - Nardostachys chinensis induces granulocytic differentiation with the suppression of cell growth through p27(Kip1) protein-related G0/G1 phase arrest in human promyelocytic leukemic cells. AB - CONTEXT: Nardostachys chinensis Batalin (Valerianaceae) has been used in Korean traditional medicine to elicit stomachic and sedative effects. However, the anti leukemic activities of N. chinensis have not been well examined. OBJECTIVE: To investigate the effect of N. chinensis on differentiation and proliferation in the human promyelocytic leukemic HL-60 cells. MATERIALS AND METHODS: The dried roots and stems of N. chiensis are extracted using hot water and then freeze dried. The yield of extract was 12.82% (w/w). The HL-60 cells were treated with 25-200 MUg/ml of N. chinensis for 72 h or 100 MUg/ml of N. chinensis for 24-72 h. RESULTS: Nardostachys chinensis significantly inhibited cell viability dose dependently with an IC50 of 100 MUg/ml in HL-60 cells. Nardostachys chinensis induced differentiation of the cells as measured by reduction activity of NBT and expression of CD11b but not of CD14 as analyzed by flow cytometry, which indicates a differentiation toward the granulocytic lineage. Nardostachys chinensis also induced growth inhibition through G0/G1 phase arrest in the cell cycle of HL-60 cells. Among the G0/G1 phase in the cell cycle-related protein, the expression of cyclin-dependent kinase (CDK) inhibitor p27(Kip1) was increased in N. chinensis-treated HL-60 cells, whereas the expression levels of CDK2, CDK4, CDK6, cyclin D1, cyclin D3, cyclin E, and cyclin A were decreased. Interestingly, N. chinensis markedly enhanced the binding of p27(Kip1) with CDK2 and CDK6. DISCUSSION AND CONCLUSION: This study demonstrated that N. chinensis is capable of inducing cellular differentiation and growth inhibition through p27(Kip1) protein-related G0/G1 phase arrest in HL-60 cells. PMID- 25430996 TI - Effects of testosterone administration on cognitive function in hysterectomized women with low testosterone levels: a dose-response randomized trial. AB - PURPOSE: To determine the dose-dependent effects of testosterone administration on cognition in women with low testosterone levels. METHODS: 71 hysterectomized women with or without oophorectomy with total testosterone <31 ng/dl and/or free testosterone <3.5 pg/ml received a standardized transdermal estradiol regimen during the 12-week run-in period and were then randomized to receive weekly intramuscular injections of placebo, 3, 6.25, 12.5, or 25 mg testosterone enanthate for 24 weeks. Total testosterone was measured in serum by LC-MS/MS, and free testosterone levels were measured by equilibrium dialysis. Cognitive function was evaluated using a comprehensive battery of standardized neuropsychological tests at baseline and 24 weeks. RESULTS: 46 women who had baseline and end-of-treatment cognitive function data constituted the analytic sample. The five groups were similar at baseline. Mean on-treatment nadir total testosterone concentrations were 15, 89, 98, 134, and 234 ng/dl in the placebo, 3, 6.25, 12.5, and 25 mg groups, respectively. No significant changes in spatial ability, verbal fluency, verbal memory, or executive function were observed in any treatment arm compared to placebo even after adjustment for baseline cognitive function, age, and education. Multiple regression analysis did not show any significant relation between changes in testosterone concentrations and change in cognitive function scores. CONCLUSION: Short-term testosterone administration over a wide range of doses for 24 weeks in women with low testosterone levels was neither associated with improvements nor worsening of cognitive function. PMID- 25430997 TI - Effect of hydrocortisone replacement therapy on body mass index after pituitary surgery. PMID- 25430999 TI - Bone metastases and skeletal-related events from neuroendocrine tumors. AB - Neuroendocrine tumors (NETs) metastasize to bone; however, a multi-institution evaluation of the natural history and complications of bone metastases across multiple NET subtypes has not, to our knowledge, previously been conducted. At two tertiary academic centers, we identified patients with bone metastases from databases of patients with a diagnosis of NET between 2004 and 2008. Detection of bone metastases, occurrence of skeletal-related events (SREs), and interventions were analyzed using summary statistics and categorical methods. Time-to-event data were assessed using Kaplan-Meier estimates and log-rank tests. Between 2004 and 2008, 82 out of 691 NET patients (12%) were reported to have bone metastases. Of the 82 patients with bone metastases, 55% were men and their median age was 49. Bone metastases occurred in 25% of pheochromocytomas and paragangliomas, 20% of high-grade neuroendocrine carcinomas, 9% of carcinoid tumors, and 8% of pancreatic NETs. At time of detection of bone metastases, 60% reported symptoms, including pain; 10% developed cord compression, 9% suffered a pathological fracture, and 4% developed hypercalcemia. Occurrence of SREs did not differ significantly with regard to tumor histology. Of patients with bone metastases, 67 (82%) received at least one form of bone-directed treatment, 50% received radiation, 45% received a bisphosphonate, 18% underwent surgery, 11% received (131)I-MIBG, 5% received denosumab, and 46% were treated with more than one treatment modality. Bone metastases occur in a substantial number of patients diagnosed with NETs. Patients are often symptomatic and many develop SREs. Given the recent therapeutic advances and increasing life expectancy of patients with NETs, development of guidelines for surveillance and clinical care of bone metastases from NETs is needed. PMID- 25430998 TI - How homologous recombination maintains telomere integrity. AB - Telomeres protect the ends of linear chromosomes against loss of genetic information and inappropriate processing as damaged DNA and are therefore crucial to the maintenance of chromosome integrity. In addition to providing a pathway for genome-wide DNA repair, homologous recombination (HR) plays a key role in telomere replication and capping. Consistent with this, the genomic instability characteristic of HR-deficient cells and tumours is driven in part by telomere dysfunction. Here, we discuss the mechanisms by which HR modulates the response to intrinsic cellular challenges that arise during telomere replication, as well as its impact on the assembly of telomere protective structures. How normal and tumour cells differ in their ability to maintain telomeres is deeply relevant to the search for treatments that would selectively eliminate cells whose capacity for HR-mediated repair has been compromised. PMID- 25431001 TI - Development of a Mycoplasma gallisepticum infection model in turkeys. AB - Mycoplasma gallisepticum causes chronic respiratory disease in chickens and is also highly pathogenic in turkeys. Several live attenuated M. gallisepticum vaccines are available for prevention of disease in chickens but they are considered to be either not safe or not efficacious in turkeys. The studies presented here aimed to develop a suitable infection model in turkeys, a prerequisite for development of a vaccine against M. gallisepticum for turkeys. Two wild-type Australian M. gallisepticum strains, Ap3AS and 100809/31, were used and their capacity to induce lesions was evaluated in 5-week-old to 6-week-old turkeys exposed to aerosols of these strains. Gross air sac lesion scores in the group exposed to Ap3AS were significantly greater than those in the group exposed to 100809/31 (P < 0.05). Histological tracheal lesion scores and tracheal mucosal thicknesses were significantly greater in birds exposed to either strain than in the unexposed birds (P < 0.05), but no significant differences were observed between the two infected groups. In a subsequent experiment, 6-week-old to 7-week old turkeys were exposed to different doses of M. gallisepticum Ap3AS. Serology and M. gallisepticum re-isolation performed 14 days after infection showed that all birds exposed to Ap3AS were positive by rapid serum agglutination and by culture. Gross air sac lesion scores in the groups exposed to the highest dose, 8.17 * 10(8) colour-changing units Ap3AS/ml, as well as a 10-fold lower dose were significantly more severe than in the uninfected control group. Lesion scores and tracheal mucosal thicknesses were significantly greater in birds exposed to Ap3AS than in the unexposed birds (P < 0.05). However, no significant differences were seen in tracheal mucosal thicknesses or lesion scores between the groups exposed to the different doses of Ap3AS. This study has established a reliable challenge model for M. gallisepticum infection in turkeys, which will be useful for evaluation of potential M. gallisepticum vaccine candidates for this species. PMID- 25431000 TI - Sexually-dimorphic targeting of functionally-related genes in COPD. AB - BACKGROUND: There is growing evidence that many diseases develop, progress, and respond to therapy differently in men and women. This variability may manifest as a result of sex-specific structures in gene regulatory networks that influence how those networks operate. However, there are few methods to identify and characterize differences in network structure, slowing progress in understanding mechanisms driving sexual dimorphism. RESULTS: Here we apply an integrative network inference method, PANDA (Passing Attributes between Networks for Data Assimilation), to model sex-specific networks in blood and sputum samples from subjects with Chronic Obstructive Pulmonary Disease (COPD). We used a jack knifing approach to build an ensemble of likely networks for each sex. By adapting statistical methods to compare these network ensembles, we were able to identify strong differential-targeting patterns associated with functionally related sets of genes, including those involved in mitochondrial function and energy metabolism. Network analysis also identified several potential sex- and disease-specific transcriptional regulators of these pathways. CONCLUSIONS: Network analysis yielded insight into potential mechanisms driving sexual dimorphism in COPD that were not evident from gene expression analysis alone. We believe our ensemble approach to network analysis provides a principled way to capture sex-specific regulatory relationships and could be applied to identify differences in gene regulatory patterns in a wide variety of diseases and contexts. PMID- 25431002 TI - Rice stripe tenuivirus p2 may recruit or manipulate nucleolar functions through an interaction with fibrillarin to promote virus systemic movement. AB - Rice stripe virus (RSV) is the type species of the genus Tenuivirus and represents a major viral pathogen affecting rice production in East Asia. In this study, RSV p2 was fused to yellow fluorescent protein (p2-YFP) and expressed in epidermal cells of Nicotiana benthamiana. p2-YFP fluorescence was found to move to the nucleolus initially, but to leave the nucleolus for the cytoplasm forming numerous distinct bright spots there at later time points. A bimolecular fluorescence complementation (BiFC) assay showed that p2 interacted with fibrillarin and that the interaction occurred in the nucleus. Both the nucleolar localization and cytoplasmic distribution of p2-YFP fluorescence were affected in fibrillarin-silenced N. benthamiana. Fibrillarin depletion abolished the systemic movement of RSV, but not that of Tobacco mosaic virus (TMV) and Potato virus X (PVX). A Tobacco rattle virus (TRV)-based virus-induced gene silencing (VIGS) method was used to diminish RSV NS2 (encoding p2) or NS3 (encoding p3) during RSV infection. Silencing of NS3 alleviated symptom severity and reduced RSV accumulation, but had no obvious effects on virus movement and the timing of symptom development. However, silencing of NS2 abolished the systemic movement of RSV. The possibility that RSV p2 may recruit or manipulate nucleolar functions to promote virus systemic infection is discussed. PMID- 25431003 TI - Nationwide evaluation of malaria infections, morbidity, mortality, and coverage of malaria control interventions in Madagascar. AB - BACKGROUND: In the last decade, an important scale-up was observed in malaria control interventions. Madagascar entered the process for pre-elimination in 2007. Policy making needs operational indicators, but also indicators about effectiveness and impact of malaria control interventions (MCI). This study is aimed at providing data about malaria infection, morbidity, and mortality, and MCI in Madagascar. METHODS: Two nationwide surveys were simultaneously conducted in 2012-2013 in Madagascar: a study about non-complicated clinical malaria cases in 31 sentinel health facilities, and a cross-sectional survey (CSS) in 62 sites. The CSS encompassed interviews, collection of biological samples and verbal autopsies (VA). Data from CSS were weighted for age, sex, malaria transmission pattern, and population density. VA data were processed with InterVA-4 software. RESULTS: CSS included 15,746 individuals of all ages. Parasite rate (PR) as measured by rapid diagnostic tests was 3.1%, and was significantly higher in five to 19 year olds, in males, poorer socio-economic status (SES) quintiles and rural areas. Long-lasting insecticidal nets (LLIN) use was 41.7% and was significantly lower in five to 19 year olds, males and wealthier SES quintiles. Proportion of persons covered by indoor residual spraying (IRS) was 66.8% in targeted zones. Proportion of persons using other insecticides than IRS was 22.8%. Coverage of intermittent preventive treatment during pregnancy was 21.5%. Exposure to information, education and communication messages about malaria was significantly higher in wealthier SES for all media but information meetings. The proportion of fever case managements considered as appropriate with regard to malaria was 15.8%. Malaria was attributed as the cause of death in 14.0% of 86 VA, and 50% of these deaths involved persons above the age of five years. The clinical case study included 818 cases of which people above the age of five accounted for 79.7%. In targeted zones, coverage of LLIN and IRS were lower in clinical cases than in general population. CONCLUSIONS: This study provides valuable data for the evaluation of effectiveness and factors affecting MCI. MCI and evaluation surveys should consider the whole population and not only focus on under-fives and pregnant women in pre-elimination or elimination strategies. PMID- 25431004 TI - Empirical prediction of net splanchnic release of ketogenic nutrients, acetate, butyrate and beta-hydroxybutyrate in ruminants: a meta-analysis. AB - For energy feeding systems for ruminants to evolve towards a nutrient-based system, dietary energy supply has to be determined in terms of amount and nature of nutrients. The objective of this study was to establish response equations of the net hepatic flux and net splanchnic release of acetate, butyrate and beta hydroxybutyrate to changes in diet and animal profiles. A meta-analysis was applied on published data compiled from the FLuxes of nutrients across Organs and tissues in Ruminant Animals database, which pools the results from international publications on net splanchnic nutrient fluxes measured in multi-catheterized ruminants. Prediction variables were identified from current knowledge on digestion, hepatic and other tissue metabolism. Subsequently, physiological and other, more integrative, predictors were obtained. Models were established for intakes up to 41 g dry matter per kg BW per day and diets containing up to 70 g concentrate per 100 g dry matter. Models predicted the net hepatic fluxes or net splanchnic release of each nutrient from its net portal appearance and the animal profile. Corrections were applied to account for incomplete hepatic recovery of the blood flow marker, para-aminohippuric acid. Changes in net splanchnic release (mmol/kg BW per hour) could then be predicted by combining the previously published net portal appearance models and the present net hepatic fluxes models. The net splanchnic release of acetate and butyrate were thus predicted from the intake of ruminally fermented organic matter (RfOM) and the nature of RfOM (acetate: residual mean square error (RMSE)=0.18; butyrate: RMSE=0.01). The net splanchnic release of beta-hydroxybutyrate was predicted from RfOM intake and the energy balance of the animals (RMSE=0.035), or from the net portal appearance of butyrate and the energy balance of the animals (RMSE=0.050). Models obtained were independent of ruminant species, and presented low interfering factors on the residuals, least square means or individual slopes. The model equations highlighted the importance of considering the physiological state of animals when predicting splanchnic metabolism. This work showed that it is possible to use simple predictors to accurately predict the amount and nature of ketogenic nutrients released towards peripheral tissues in both sheep and cattle at different physiological status. These results provide deeper insight into biological processes and will contribute to the development of improved tools for dietary formulation. PMID- 25431005 TI - Antipsychotic use in elderly patients and the risk of pneumonia. AB - Antipsychotics are frequently and increasingly prescribed off-label for the treatment of behavioral and psychological symptoms associated with dementia, despite their modest efficacy. Instead, the safety profile of antipsychotics has been questioned repeatedly in recent years with various concerns, including death. Meta-analyses of randomized controlled trials found that one of the major causes of death associated with atypical antipsychotics use was pneumonia. Only few observational studies, however, have investigated the risk of pneumonia in elderly patients, especially among those receiving conventional antipsychotics. The aim of this editorial is to synthesize the current evidence from observational studies regarding the risk of pneumonia in elderly patients receiving either conventional or atypical antipsychotics. The studies conducted so far document that the risk of pneumonia is two- to threefold increased in a dose-dependent fashion with both classes compared to nonuse, with a possibly higher risk attributable to atypical antipsychotics. The risk seems to peak at the beginning of treatment (e.g., 7 - 30 days), and dissipates over time for both conventional and atypical antipsychotics. The risk-benefit ratio suggests that there will be 1 excess hospitalization for pneumonia for every 2 - 5 patients receiving any clinical improvement in symptoms. Considering the modest improvement in terms of efficacy, the risks associated with antipsychotics in elderly patients may outweigh their benefit. PMID- 25431006 TI - Characterization of leptin receptor gene in Bubalus bubalis and association analysis with body measurement traits. AB - Leptin has a pleiotropic effect on regulating appetite, energy metabolism, growth, reproduction, body composition and immunity. This property supports leptin and its receptor as candidate genes for evaluating genetic polymorphisms to associate with growth, milk yield and other economic traits. The aim of this study is to characterize the leptin receptor gene in Bubalus bubalis, to identify single-nucleotide polymorphism (SNP) sites in different coding and non-coding regions and to analyse potential associations between SNPs identified and the body measurements traits of growing buffalo heifers. A group of 64 animals were genotyped by direct sequencing and twenty-eight SNPs were detected. A sequence analysis revealed the presence of nine interesting SNPs in gene sequence. The association analysis of polymorphisms with the body measurements traits of growing buffalo heifers shows significant statistical effects on chest depth and sacrum height. Therefore according to the results obtained from this study, the leptin receptor gene appears to have potential effects on the body measurement traits of Bubalus bubalis. PMID- 25431008 TI - A simple method to improve the quality of diffusion-weighted magnetic resonance imaging with rapid histologic correlation in a murine model. AB - Diffusion-weighted magnetic resonance imaging (DW-MRI) has been used extensively in biomedical research. However, this technique has often suffered from distortion artifacts because of the magnetic field inhomogeneity surrounding the tissues. Histology is important for validating MRI interpretations, but correlating MRIs with tissue samples is challenging. Here we propose a method to improve DW-MRI and facilitate the matching between MRIs and tissue samples. A cryostat embedding medium, optimal cutting temperature (OCT) compound, was used to cover the examined target during the MRI studies. Frozen OCT compound could aid the examined target to be sectioned in parallel with the imaging plane. Phantom experiments demonstrated that embedding in OCT compound improved the magnetic field inhomogeneity while maintaining the apparent diffusion coefficient. Animal experiments revealed significantly reduced distortions in DW images in both the axial and coronal planes. The in vivo MRIs were easily matched with histologic specimens in a slice-to-slice fashion to examine the corresponding tissue microenvironment. This simple method might improve the quality of DW-MRI and provide histologic information for MRI to serve as an image biomarker. PMID- 25431009 TI - Bacterial community shift along with the changes in operational conditions in a membrane-aerated biofilm reactor. AB - Membrane-aerated biofilm reactor (MABR) is a promising wastewater treatment process. Although bacteria inhabiting the MABR biofilm are important in wastewater treatment, the community composition and its correlation with operating conditions were less clear. A laboratory-scale MABR was designed to investigate the shift of bacterial community through a complete operational process by pyrosequencing the bacterial 16S rRNA genes. From around 19,000 sequences, 175 bacterial genera were retrieved, mainly belonging to Betaproteobacteria, Gammaproteobacteria, Alphaproteobacteria, Bacteroidetes, and Actinobacteria. A large number of unclassified bacterial sequences were also detected in the biofilm, suggesting a wide variety of uncharacterized species in MABR. Redundancy analysis (RDA) revealed that influent chemical oxygen demand (COD), NH4-N, and NaHCO3 concentrations could exert distinct influences on the composition of the bacterial community. The influent COD and NaHCO3 concentrations stimulated proliferation of denitrification-related species such as Dokdonella, Azospira, Hydrogenophaga, Rhodocyclaceae, and Thauera, while inhibiting the growth of Acidovorax and Sinobacteraceae. Some denitrifying Thermomonas spp. tended to survive in NH4-N-rich environments, while Flavobacterium preferred to inhabit NH4-N-poor or COD-rich environments. Conversely, the influent NH4-N and NaHCO3, to some extent, appeared to be the growth-promoting factors for nitrifying bacteria. Furthermore, the presence of potential aerobic denitrifiers such as Comamonas, Enterobacter, and Aeromonas indicated that MABR could have the capability of simultaneous aerobic and anoxic denitrification particularly during treatment of low-ammonia nitrogen sewage. PMID- 25431010 TI - An invasive and low virulent Edwardsiella tarda esrB mutant promising as live attenuated vaccine in aquaculture. AB - Edwardsiella tarda is a leading fish pathogen haunting worldwide aquaculture industry. In E. tarda, two-component system EsrA-EsrB positively regulates type III and VI secretion systems (T3SS and T6SS) and negatively regulates hemolysin EthA, which has been demonstrated to be essential for the invasion processes in fish. In order to develop a live attenuated vaccine (LAV) with high invasiveness to be practically and economically used as immersion-administered vaccine in aquaculture, here, we generated a random mutation library of esrB sequences by error-prone PCR and introduced them into the E. tarda esrB deletion mutant. The mutant YWZ47 with significantly increased hemolytic activity and low T3SS and T6SS secretion was screened. Phenotypes including extracellular protein profiles, invasion in macrophages, lethality toward fish, and infection kinetics were investigated in the wild-type strain EIB202 and the mutants DeltaesrB, DeltaT3SS, DeltaT6SS, DeltaT3SS/DeltaT6SS, and YWZ47. Compared to the documented LAV strain DeltaesrB, YWZ47 showed higher invasive capability and low in vivo virulence toward fish. Significantly higher relative percent survival (RPS) could be generated in turbot (Scophthalmus maximus) against the challenge of the wild-type EIB202 when inoculated through immersion route, and the RPS was comparable with that of DeltaesrB through intraperitoneal (i.p.) injection inoculation. Two mutated points, K167M and H197L, were found by sequence analysis of EsrBYWZ47 variant. These structural modifications underpin the variations in the regulatory functions of the mutant and wild-type EsrB. This study promoted understanding of virulence regulation by EsrB in E. tarda and presented a promising candidate of invasive attenuated vaccine used in aquaculture industries. PMID- 25431007 TI - How to approach and treat viral infections in ICU patients. AB - Patients with severe viral infections are often hospitalized in intensive care units (ICUs) and recent studies underline the frequency of viral detection in ICU patients. Viral infections in the ICU often involve the respiratory or the central nervous system and can cause significant morbidity and mortality especially in immunocompromised patients. The mainstay of therapy of viral infections is supportive care and antiviral therapy when available. Increased understanding of the molecular mechanisms of viral infection has provided great potential for the discovery of new antiviral agents that target viral proteins or host proteins that regulate immunity and are involved in the viral life cycle. These novel treatments need to be further validated in animal and human randomized controlled studies. PMID- 25431011 TI - Methylotrophy in the thermophilic Bacillus methanolicus, basic insights and application for commodity production from methanol. AB - Using methanol as an alternative non-food feedstock for biotechnological production offers several advantages in line with a methanol-based bioeconomy. The Gram-positive, facultative methylotrophic and thermophilic bacterium Bacillus methanolicus is one of the few described microbial candidates with a potential for the conversion of methanol to value-added products. Its capabilities of producing and secreting the commercially important amino acids L-glutamate and L lysine to high concentrations at 50 degrees C have been demonstrated and make B. methanolicus a promising target to develop cell factories for industrial-scale production processes. B. methanolicus uses the ribulose monophosphate cycle for methanol assimilation and represents the first example of plasmid-dependent methylotrophy. Recent genome sequencing of two physiologically different wild type B. methanolicus strains, MGA3 and PB1, accompanied with transcriptome and proteome analyses has generated fundamental new insight into the metabolism of the species. In addition, multiple key enzymes representing methylotrophic and biosynthetic pathways have been biochemically characterized. All this, together with establishment of improved tools for gene expression, has opened opportunities for systems-level metabolic engineering of B. methanolicus. Here, we summarize the current status of its metabolism and biochemistry, available genetic tools, and its potential use in respect to overproduction of amino acids. PMID- 25431012 TI - Engineering propionibacteria as versatile cell factories for the production of industrially important chemicals: advances, challenges, and prospects. AB - Propionibacteria are actinobacteria consisting of two principal groups: cutaneous and dairy. Cutaneous propionibacteria are considered primary pathogens to humans, whereas dairy propionibacteria are widely used in the food and pharmaceutical industries. Increasing attention has been focused on improving the performance of dairy propionibacteria for the production of industrially important chemicals, and significant advances have been made through strain engineering and process optimization in the production of flavor compounds, nutraceuticals, and antimicrobial compounds. In addition, genome sequencing of several propionibacteria species has been completed, deepening understanding of the metabolic and physiological features of these organisms. However, the metabolic engineering of propionibacteria still faces several challenges owing to the lack of efficient genome manipulation tools and the existence of various types of strong restriction-modification systems. The emergence of systems and synthetic biology provides new opportunities to overcome these bottlenecks. In this review, we first introduce the major species of propionibacteria and their properties and provide an overview of their functions and applications. We then discuss advances in the genome sequencing and metabolic engineering of these bacteria. Finally, we discuss systems and synthetic biology approaches for engineering propionibacteria as efficient and robust cell factories for the production of industrially important chemicals. PMID- 25431013 TI - Potential applications of glucosyltransferases in terpene glucoside production: impacts on the use of aroma and fragrance. AB - The detection of glucoconjugated forms of monoterpene alcohols in rose petals in the late 1960s opened the new field of nonvolatile aroma precursors in flavor research. It is now well established that odorless glycosides represent a significant pool of aroma precursors in plants where they act as preformed but inactivated defense or attractive chemicals. Technical improvements in the separation and identification of plant secondary metabolites have provided a multitude of chemical structures, but functional characterization of glycosyltransferases that catalyze their formation lags behind. As technical efforts and costs for DNA sequencing dramatically dropped during the last decade, the number of plant genome sequences increased significantly, thus providing opportunities to functionally characterize the glycosyltransferase gene families in plants. These studies yielded the first glycosyltransferase genes that encode efficient biocatalysts for the production of monoterpene glucosides. They have applications in the food, feed, chemical, cosmetic, and pharmaceutical industries as slow release aroma chemicals. PMID- 25431014 TI - From fructans to difructose dianhydrides. AB - Fructans are the polymers of fructose molecules, normally having a sucrose unit at what would otherwise be the reducing terminus. Inulin and levan are two basic types of simple fructan, which contain beta-(2, 1) and beta-(2, 6) fructosyl fructose linkage, respectively. Fructans not only can serve as soluble dietary fibers for food industry, but also may be biologically converted into high-value products, especially high-fructose syrup and fructo-oligosaccharides. In recent years, much attention has been focused on production of difructose dianhydrides (DFAs) from fructans. DFAs are cyclic disaccharides consisting of two fructose units with formation of two reciprocal glycosidic linkages. They are expected to have promising properties and beneficial effects on human health. DFAs can be produced from fructans by fructan fructotransferases. Inulin fructotransferase (IFTase) (DFA III-forming) and IFTase (DFA I-forming) catalyze the DFA III and DFA I production from inulin, respectively, and levan fructotransferase (LFTase) (DFA IV-forming) catalyzes the production of DFA IV from levan. In this article, the DFA-producing microorganisms are summarized, relevant studies on various DFAs producing enzymes are reviewed, and especially, the comparisons of the enzymes are presented in detail. PMID- 25431015 TI - Synthesis and Antimicrobial Activity of the Hybrid Molecules between Sulfonamides and Active Antimicrobial Pleuromutilin Derivative. AB - A series of novel hybrid molecules between sulfonamides and active antimicrobial 14-o-(3-carboxy-phenylsulfide)-mutilin were synthesized, and their in vitro antibacterial activities were evaluated by the broth microdilution. Results indicated that these compounds displayed potent antimicrobial activities in vitro against various drug-susceptible and drug-resistant Gram-positive bacteria such as Staphylococci and streptococci, including methicillin-resistant Staphylococcus aureus, and mycoplasma. In particular, sulfapyridine analog (6c) exhibited more potent inhibitory activity against Gram-positive bacteria and mycoplasma, including Staphylococcus aureus (MIC = 0.016-0.063 MUg/mL), methicillin-resistant Staphylococcus aureus (MIC = 0.016 MUg/mL), Streptococcus pneumoniae (MIC = 0.032 0.063 MUg/mL), Mycoplasma gallisepticum (MIC = 0.004 MUg/mL), with respect to other synthesized compounds and reference drugs sulfonamide (MIC = 8-128 MUg/mL) and valnemulin (MIC = 0.004-0.5 MUg/mL). Furthermore, comparison between MIC values of pleuromutilin-sulfonamide hybrids 6a-f with pleuromutilin parent compound 3 revealed that these modifications at 14 position side chain of the pleuromutilin with benzene sulfonamide could greatly improve the antibacterial activity especially against Gram-positives. PMID- 25431016 TI - A simple stochastic model for complex coextinctions in mutualistic networks: robustness decreases with connectance. AB - Understanding and predicting species extinctions and coextinctions is a major goal of ecological research in the face of a biodiversity crisis. Typically, models based on network topology are used to simulate coextinctions in mutualistic networks. However, such topological models neglect two key biological features of species interactions: variation in the intrinsic dependence of species on the mutualism, and variation in the relative importance of each interacting partner. By incorporating both types of variation, we developed a stochastic coextinction model capable of simulating extinction cascades far more complex than those observed in previous topological models. Using a set of empirical mutualistic networks, we show that the traditional topological model may either underestimate or overestimate the number and likelihood of coextinctions, depending on the intrinsic dependence of species on the mutualism. More importantly, contrary to topological models, our stochastic model predicts extinction cascades to be more likely in highly connected mutualistic communities. PMID- 25431017 TI - A pediatric case with vasculitis-like viral eruption induced by Epstein-Barr virus. PMID- 25431018 TI - The anti-obesity effect of green tea polysaccharides, polyphenols and caffeine in rats fed with a high-fat diet. AB - Beneficial effects of green tea (Camellia sinensis, Theaceae) extracts against obesity have been reported; however, the anti-obesity ability of the major components of green tea, polysaccharides, polyphenols and caffeine is not clear. Therefore, experiments with total green tea extracts, polyphenols, polysaccharides, caffeine, and a complex of polysaccharide and polyphenol at a dose of 400 or 800 mg kg-1 were conducted on high-fat diet fed rats for 6 weeks to investigate their anti-obesity effects. The results indicated that polyphenols and polysaccharides were responsible for the suppressive effect of green tea extracts on body weight increase and fat accumulation. Moreover, polyphenols, polysaccharides, or caffeine can improve blood lipid and antioxidant levels, and effectively reduce rat serum leptin levels, inhibit the absorption of fatty acids, and markedly reduce the expression levels of the IL-6 and TNF-alpha gene. Furthermore, it was shown that polysaccharides and polyphenols were synergistic in reduction of serum leptin levels and in anti-inflammatory activity. These results suggest that the polysaccharide combination with polyphenols might be a potential therapy against obesity. PMID- 25431019 TI - Angiotensin II acting on brain AT1 receptors induces adrenaline secretion and pressor responses in the rat. AB - Angiotensin II (AngII) plays important roles in the regulation of cardiovascular function. Both peripheral and central actions of AngII are involved in this regulation, but mechanisms of the latter actions as a neurotransmitter/neuromodulator within the brain are still unclear. Here we show that (1) intracerebroventricularly (i.c.v.) administered AngII in urethane anesthetized male rats elevates plasma adrenaline derived from the adrenal medulla but not noradrenaline with valsartan- (AT1 receptor blocker) sensitive brain mechanisms, (2) peripheral AT1 receptors are not involved in the AngII induced elevation of plasma adrenaline, although AngII induces both noradrenaline and adrenaline secretion from bovine adrenal medulla cells, and (3) i.c.v. administered AngII elevates blood pressure but not heart rate with the valsartan sensitive mechanisms. From these results, i.c.v. administered AngII acts on brain AT1 receptors, thereby inducing the secretion of adrenaline and pressor responses. We propose that the central angiotensinergic system can activate central adrenomedullary outflow and modulate blood pressure. PMID- 25431020 TI - The role of radiotherapy in the management of POEMS syndrome. AB - BACKGROUND: POEMS syndrome is a paraneoplastic syndrome caused by an underlying plasma cell proliferative disease. In this study, we examined the treatment outcomes and role of radiotherapy in the management of POEMS syndrome. METHODS: In total, 33 patients diagnosed with POEMS syndrome were analyzed. These patients presented with osteosclerotic myeloma (OSM, n = 13), Castleman's disease (CD, n = 4), OSM with CD (n = 10), and vascular endothelial growth factor elevation without gross lesions (VEGFe, n = 6), respectively. The patients were treated by radiotherapy alone (n = 4), chemotherapy alone (n = 16), or a combination thereof (n = 9). RESULTS: The clinical response rates of radiotherapy, chemotherapy, and radiotherapy plus chemotherapy were 75%, 69%, and 89%, respectively. In addition, the hematologic response rates were 50%, 69%, and 71%, respectively. Among the six patients with limited multiple lesions who underwent radiotherapy, the clinical symptoms were improved in five patients after radiotherapy. The median progression-free survival (PFS) was 51 months, and the median overall survival (OS) was 65 months. In univariate analysis, the administration of chemotherapy was significantly associated with better PFS (p = 0.007) and OS (p = 0.020). In contrast, underlying VEGFe was a significant factor worsening PFS (p = 0.035) and OS (p = 0.008). CONCLUSIONS: Radiotherapy produces a reliable clinical response and is effective in improving POEMS-associated symptoms that are refractory to chemotherapy in selected patients with clustered or limited multiple lesions that can be covered by single radiation field. PMID- 25431021 TI - miR-27 regulates mitochondrial networks by directly targeting the mitochondrial fission factor. AB - Mitochondrial morphology is dynamically regulated by forming small, fragmented units or interconnected networks, and this is a pivotal process that is used to maintain mitochondrial homeostasis. Although dysregulation of mitochondrial dynamics is related to the pathogenesis of several human diseases, its molecular mechanism is not fully elucidated. In this study, we demonstrate the potential role of miR-27 in the regulation of mitochondrial dynamics. Mitochondrial fission factor (MFF) mRNA is a direct target of miR-27, whose ectopic expression decreases MFF expression through binding to its 3'-untranslated region. Expression of miR-27 results in the elongation of mitochondria as well as an increased mitochondrial membrane potential and mitochondrial ATP level. Our results suggest that miR-27 is a novel regulator affecting morphological mitochondrial changes by targeting MFF. PMID- 25431022 TI - Using patient flow simulation to improve access at a multidisciplinary sleep centre. AB - The lack of timely access to diagnosis and treatment for sleep disorders is well described, but little attention has been paid to understanding how multiple system constraints contribute to long waiting times. The objectives of this study were to identify system constraints leading to long waiting times at a multidisciplinary sleep centre, and to use patient flow simulation modelling to test solutions that could improve access. Discrete-event simulation models of patient flow were constructed using historical data from 150 patients referred to the sleep centre, and used to both examine reasons for access delays and to test alternative system configurations that were predicted by administrators to reduce waiting times. Four possible solutions were modelled and compared with baseline, including addition of capacity to different areas at the sleep centre and elimination of prioritization by urgency. Within the model, adding physician capacity improved time from patient referral to initial physician appointment, but worsened time from polysomnography requisition to test completion, and had no effect on time from patient referral to treatment initiation. Adding respiratory therapist did not improve model performance compared with baseline. Eliminating triage prioritization worsened time to physician assessment and treatment initiation for urgent patients without improving waiting times overall. This study demonstrates that discrete-event simulation can identify multiple constraints in access-limited healthcare systems and allow suggested solutions to be tested before implementation. The model of this sleep centre predicted that investments in capacity expansion proposed by administrators would not reduce the time to a clinically meaningful patient outcome. PMID- 25431023 TI - A pilot study to assess benefit of atrial rhythm control after cardiac resynchronization therapy and atrioventricular node ablation. AB - BACKGROUND: Atrial fibrillation (AF) is frequently comorbid in patients receiving cardiac resynchronization therapy (CRT), and suppression is typically difficult. Herein, we sought to understand the benefit of atrial rhythm control in the setting of ventricular rate and regularity control induced by atrioventricular node (AVN) ablation. METHODS: Fifty-two patients with heart failure, persistent AF, left ventricular (LV) ejection fraction <35%, and left bundle branch block underwent cardiac resynchronization therapy (CRT) + AVN ablation, and were randomized to one of the following groups: (1) Atrial Rhythm Control (ARC); (2) AF. Patients were subsequently followed for up to 1 year. RESULTS: Similar numbers of patients in each group were lost to follow-up or have withdrawn (ARC two; AF three). Rhythm control in four patients in the ARC group was inadequate. Among the remaining patients, the incidence of death (ARC=1, AF=2) or left ventricular assist device +/- transplantation (ARC=2, AF=1) were similar. Among the remaining patients (ARC 16, AF 19), at 1 year, there were no significant differences in CRT response rate, Minnesota Living with Heart Failure survey score, 6-minute hall walk distance, ventricular tachyarrhythmia occurrence, or LV dimensions. A significantly higher hospital encounter rate among ARC patients was attributable to efforts to maintain uniform atrial rhythm. CONCLUSIONS: In this pilot study, no incremental benefit for ARC was apparent. A larger study will be necessary to adequately examine these issues. PMID- 25431024 TI - Prevalence and genomic characterization of porcine parvoviruses detected in Chiangmai area of Thailand in 2011. AB - Porcine parvovirus (PPV) causes reproductive failure in sows and has spread worldwide. Several new types of porcine parvoviruses have recently been identified in pig herds. The prevalence of five porcine parvoviruses in the Chiangmai area of Thailand was studied. The prevalence in 80 pigs was 53% for PPV (PPV-Kr or -NADL2 being the new abbreviations), 83% for PPV2 (CnP-PARV4), 73% for PPV3 (P-PARV4), 44% for PPV4 (PPV4), and 18% for PBo-likeV (PBoV7). Over 60% of the pigs carried more than three of the five porcine parvoviruses and occurrence together of the two pairs of viral genes, PPV1/PPV3 and PPV2/PBo-likeV were observed. Phylogenetic analyses for PPV2 and PPV3 indicated the existence of only two major clades of PPV2 and one major clade of PPV3. PMID- 25431025 TI - Management of pregnancy in type 2B von Willebrand disease: case report and literature review. PMID- 25431026 TI - Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis. AB - Psoriasis is a systemic disease with cutaneous manifestations. MicroRNAs (miRNAs) are small non-coding RNA molecules that are differentially expressed in psoriatic skin; however, only few cell- and region-specific miRNAs have been identified in psoriatic lesions. We used laser capture microdissection (LCM) and next generation sequencing (NGS) to study the specific miRNA expression profiles in the epidermis (Epi) and dermal inflammatory infiltrates (RD) of psoriatic skin (N = 6). We identified 24 deregulated miRNAs in the Epi and 37 deregulated miRNAs in the RD of psoriatic plaque compared with normal psoriatic skin (FCH > 2, FDR < 0.05). Interestingly, 9 of the 37 miRNAs in RD, including miR-193b and miR-223, were recently described as deregulated in circulating peripheral blood mononuclear cells (PBMCs) from patients with psoriasis. Using flow cytometry and qRT-PCR, we found that miR-193b and miR-223 were expressed in Th17 cells. In conclusion, we demonstrate that LCM combined with NGS provides a robust approach to explore the global miRNA expression in the epidermal and dermal compartments of psoriatic skin. Furthermore, our results indicate that the altered local miRNA changes seen in the RD are reflected in the circulating immune cells, suggesting that miRNAs may contribute to the pathogenesis of psoriasis. PMID- 25431027 TI - Pitfalls of fine-needle aspiration cytology of parotid membranous basal cell adenoma-A review of pitfalls in FNA cytology of salivary gland neoplasms with basaloid cell features. AB - Membranous basal cell adenoma (MBCA) is a rare benign salivary gland neoplasm. It is difficult to diagnose MBCA based on fine-needle aspiration (FNA) cytology due to rare reporting of its FNA cytology and overlapping of its FNA cytologic features with some benign and malignant entities. We present a case of MBCA in a 67-year-old female that was originally misinterpreted as adenoid cystic carcinoma (ACC) on FNA cytology. The FNA smears showed numerous uniform small basaloid epithelial cells with round or oval nuclei and inconspicuous nucleoli, and scant cytoplasm. The basaloid cells surround acellular, dense, homogenous material or are surrounded by acellular or paucicellular dense homogeneous material possibly containing bland spindle cells. The basaloid cells are present in variably sized three-dimensional clusters, acini, or sheets with variable cohesion. The dense homogenous material surrounded by basaloid cells may be interconnected. High power magnification reveals the homogeneous material to have a fibrillar texture. The edges of dense homogenous materials were well-demarcated. We describe the diagnostic pitfalls of FNA for MBCA, particularly versus ACC, basal cell adenoma, cellular pleomorphic adenoma, myoepithelioma, basal cell adenocarcinoma, and basaloid squamous cell carcinoma in hope of improving clinical management and patient treatment. PMID- 25431028 TI - The excess risk of major osteoporotic fractures in hypothyroidism is driven by cumulative hyperthyroid as opposed to hypothyroid time: an observational register based time-resolved cohort analysis. AB - The long-term relationship between hypothyroidism and fracture risk is challenging to dissect because of the modifying influence of subsequent thyroxine replacement with the potential for excessive replacement doses. We studied changes in serum thyrotropin concentration (TSH) over time and association with fracture risk in real-world patients presenting with elevated TSH. All TSH determinations were done in the same laboratory, which served all hospitals and general practices. The study population consisted of all adults with a first measurement of TSH >4.0 mIU/L (n = 8414) or normal TSH (n = 222,138; comparator). We used a Cox proportional hazards analysis incorporating additional time dependent covariates to represent initiation of thyroxine replacement and cumulative number of periods with high versus low TSH after index date with a mean follow-up of 7.2 years. Elevated baseline TSH was not associated with an increased risk of hip fracture (HR 0.90; 95% CI, 0.80 to 1.02) or major osteoporotic fractures (HR 0.97; 95% CI, 0.90 to 1.05), nor was subsequent thyroxine prescription predictive of increased risk of fractures. The number of subsequent 6-month periods with low TSH-suggesting excessive thyroxine dosing-was significantly associated with increased risk of both hip fracture (HR 1.09; 95% CI, 1.04 to 1.15) and major osteoporotic fracture (HR 1.10; 95% CI, 1.06 to 1.14). When gender- and age-stratified analyses for major osteoporotic fractures were undertaken, hyperthyroid time was identified as a predictor of fracture risk in postmenopausal women whereas hypothyroid time predicted increased fracture risk in men below age 75 years. In conclusion, among patients who present with an elevated TSH, the long-term risk of hip and other osteoporotic fractures is strongly related to the cumulative duration of periods with low TSH-likely from excessive replacement. An independent effect of elevated TSH could only be observed in young and middle-aged men, suggesting gender-discrepant consequences on risk. PMID- 25431029 TI - Coping responses in the midst of terror: the July 22 terror attack at Utoya Island in Norway. AB - This study examined the peri-trauma coping responses of 325 survivors, mostly youth, after the July 22, 2011 terror attack on Utoya Island in Norway. The aim was to understand peri-trauma coping responses and their relation to subsequent post-traumatic stress (PTS) reactions. Respondents were interviewed face-to-face 4-5 months after the shooting, and most were interviewed at their homes. Peri trauma coping was assessed using ten selected items from the "How I Cope Under Pressure Scale" (HICUPS), covering the dimensions of problem solving, positive cognitive restructuring, avoidance, support seeking, seeking understanding, and religious coping. PTS reactions were assessed with the UCLA PTSD Reaction Index. The participants reported using a wide variety of coping strategies. Problem solving, positive cognitive restructuring, and seeking understanding strategies were reported most often. Men reported using more problem-solving strategies, whereas women reported more emotion-focused strategies. There were no significant associations between age and the use of coping strategies. Problem solving and positive cognitive restructuring were significantly associated with fewer PTS reactions. The results are discussed in light of previous research and may help to inform early intervention efforts for survivors of traumatic events. PMID- 25431030 TI - Short protecting group-free syntheses of camptothecin and 10-hydroxycamptothecin using cascade methodologies. AB - A convergent protecting group-free total synthesis route of camptothecin and 10 hydroxycamptothecin has been developed in this work. Cascade oxidation of 3 (hydroxymethyl)furan-2(5 H)-one and in situ intermolecular oxa Diels-Alder reaction with vinyl ether was developed and applied to construct the E-ring, and TMSCl-promoted cascade closure of the D-ring delivered the whole skeleton of the alkaloids in the total synthesis. The new short syntheses were advantageous with regard to step economy, low cost, easily available starting materials and reagents, and convenient operations. PMID- 25431031 TI - Rosiglitazone, a PPARgamma agonist, ameliorates palmitate-induced insulin resistance and apoptosis in skeletal muscle cells. AB - Palmitate induces insulin resistance and apoptosis in insulin target tissues. Rosiglitazone (RSG), a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, can activate both pro-apoptotic and anti-apoptotic pathways in different cells; however, its effect on palmitate-induced apoptosis in skeletal muscle cells remains to be elucidated. After differentiation of C2C12 cells, myotubes were treated with palmitate, RSG and GW9662 (PPARgamma antagonist). MTT and terminal deoxynucleotide transferase dUTP nick end labelling (TUNEL) assays and caspase-3 activity were used to investigate the apoptosis. To study the underlying mechanism, glucose uptake, gene expression and protein levels were evaluated. A total of 0.75 mM palmitate reduced cell viability by 43% and increased TUNEL-positive cells and caspase-3 activity by 15-fold and 6.6 fold, respectively. RSG (10 MUM) could markedly decrease the level of TUNEL positive cells and caspase-3 activity in palmitate-treated cells. The protective effect of RSG on apoptosis was abrogated by GW9662. To investigate the molecular mechanism of this effect, gene expression and protein level of protein tyrosine phosphatase 1B (PTP1B) were evaluated. Palmitate and RSG individually increased the expression and protein level of PTP1B, whereas combined treatment (palmitate and RSG) were able to further increase the expression of PTP1B in C2C12 cells. We also evaluated the effect of RSG on palmitate-induced insulin resistance in muscle cells. RSG could significantly improve glucose uptake by 0.4-fold in myotubes treated with palmitate. Moreover, RSG could restore the phosphorylation of Akt in palmitate-treated cells. These data suggest that RSG protects skeletal muscle cells against palmitate-induced apoptosis and this effect appears to be mediated via the PPARgamma-dependent and PTP1B-independent mechanisms. SIGNIFICANCE OF THE STUDY: Saturated free fatty acids (FFAs), such as palmitate, have been shown to induce cellular apoptosis. Strategies for preventing the cytotoxic effect of palmitate are useful in reduction of diabetes complications. In this study, we introduced RSG as an agent that protects skeletal muscle cells against palmitate-induced apoptosis and insulin resistance. It appears that RSG protects skeletal muscle cells against palmitate-induced apoptosis via the PPARgamma-dependent and PTP1B-independent mechanisms. Given the role of FFAs in skeletal muscle apoptosis, these findings support the idea that RSG can ameliorate diabetes complications such as skeletal muscle loss. PMID- 25431033 TI - Solvation dynamics of a single water molecule probed by infrared spectra--theory meets experiment. AB - The dynamics and energetics of water at interfaces or in biological systems plays a fundamental role in all solvation and biological phenomena in aqueous solution. In particular, the migration of water molecules is the first step that controls the overall process in the time domain. Experimentally, the dynamics of individual water molecules is nearly impossible to follow in solution, because signals from molecules in heterogeneous environments overlap. Although molecular dynamics simulations do not have this restriction, there is a lack of experimental data to validate the calculated dynamics. Here, we demonstrate a new strategy, in which the calculated dynamics are verified by measured time-resolved infrared spectra. The coexistence of fast and slow migrations of water molecules around a CONH peptide linkage is revealed for a model system representative of a hydrate peptide. PMID- 25431034 TI - Nitrogen dioxide exposure and airway responsiveness in individuals with asthma. AB - Controlled human exposure studies evaluating the effect of inhaled nitrogen dioxide (NO2) on the inherent responsiveness of the airways to challenge by broncho-constricting agents have had mixed results. In general, existing meta analyses show statistically significant effects of NO2 on the airway responsiveness of individuals with asthma. However, no meta-analysis has provided a comprehensive assessment of the clinical relevance of changes in airway responsiveness, the potential for methodological biases in the original papers, and the distribution of responses. This paper provides analyses showing that a statistically significant fraction (i.e. 70% of individuals with asthma exposed to NO2 at rest) experience increases in airway responsiveness following 30-min exposures to NO2 in the range of 200 to 300 ppb and following 60-min exposures to 100 ppb. The distribution of changes in airway responsiveness is log-normally distributed with a median change of 0.75 (provocative dose following NO2 divided by provocative dose following filtered air exposure) and geometric standard deviation of 1.88. About a quarter of the exposed individuals experience a clinically relevant reduction in their provocative dose due to NO2 relative to air exposure. The fraction experiencing an increase in responsiveness was statistically significant and robust to exclusion of individual studies. Results showed minimal change in airway responsiveness for individuals exposed to NO2 during exercise. PMID- 25431032 TI - Whole-brain quantitative mapping of metabolites using short echo three dimensional proton MRSI. AB - BACKGROUND: To improve the extent over which whole brain quantitative three dimensional (3D) magnetic resonance spectroscopic imaging (MRSI) maps can be obtained and be used to explore brain metabolism in a population of healthy volunteers. METHODS: Two short echo time (20 ms) acquisitions of 3D echo planar spectroscopic imaging at two orientations, one in the anterior commissure posterior commissure (AC-PC) plane and the second tilted in the AC-PC +15 degrees plane were obtained at 3 Tesla in a group of 10 healthy volunteers. B1 (+) , B1 (-) , and B0 correction procedures and normalization of metabolite signals with quantitative water proton density measurements were performed. A combination of the two spatially normalized 3D-MRSI, using a weighted mean based on the pixel wise standard deviation metabolic maps of each orientation obtained from the whole group, provided metabolite maps for each subject allowing regional metabolic profiles of all parcels of the automated anatomical labeling (AAL) atlas to be obtained. RESULTS: The combined metabolite maps derived from the two acquisitions reduced the regional intersubject variance. The numbers of AAL regions showing N-acetyl aspartate (NAA) SD/Mean ratios lower than 30% increased from 17 in the AC-PC orientation and 41 in the AC-PC+15 degrees orientation, to a value of 76 regions of 116 for the combined NAA maps. Quantitatively, regional differences in absolute metabolite concentrations (mM) over the whole brain were depicted such as in the GM of frontal lobes (cNAA = 10.03 + 1.71; cCho = 1.78 +/- 0.55; cCr = 7.29 +/- 1.69; cmIns = 5.30 +/- 2.67) and in cerebellum (cNAA = 5.28 +/- 1.77; cCho = 1.60 +/- 0.41; cCr = 6.95 +/- 2.15; cmIns = 3.60 +/- 0.74). CONCLUSION: A double-angulation acquisition enables improved metabolic characterization over a wide volume of the brain. PMID- 25431035 TI - Simultaneous UHPLC/DAD/(+/-)HESI-MS/MS analysis of phenolic acids and nepetalactones in methanol extracts of Nepeta species: a possible application in chemotaxonomic studies. AB - INTRODUCTION: Nepeta species contain a variety of secondary metabolites, including iridoid monoterpenes - nepetalactones and phenolic acids - that are considered the main bioactive constituents. This work represents the first attempt to comparatively explore variations in these two major groups of secondary metabolites within the genus. OBJECTIVE: To develop an efficient analytical methodology for simultaneous analysis of nepetalactones and phenolic acids in methanol extracts of selected Nepeta species, and to evaluate its potential application in chemotaxonomic studies. MATERIAL AND METHODS: A UHPLC combined with linear-trap quadrupole (LTQ) orbitrap MS method was used to characterise chemical diversity and complexity of phenolics among 12 selected Nepeta species. A targeted metabolomic approach using UHPLC coupled to a diode array detector (DAD) and combined with (+/-) heated electrospray ionisation (HESI) MS/MS was developed and validated for quantitative analysis of six hydroxycinnamic acid derivatives and four nepetalactones. RESULTS: Phenolic profiling provided a valuable database of bioactive compounds in the plant group studied, including phenolic acids (hydroxybenzoic and hydroxycinnamic acids) and flavonoids (flavones, flavonols and flavanones). Principal component analysis and cluster analysis suggested the applicability of 10 targeted compounds as chemomarkers for chemotaxonomic studies. Pearson's correlation analysis revealed significant positive correlations between metabolites involved in different biosynthetic pathways (phenylpropanoid or monoterpenoid). CONCLUSION: The described targeted metabolomic approach proved to be highly beneficial in designing a phytochemical overview of the genus Nepeta, and might have applications in further clarification of phylogenetic relations. Furthermore, it has the potential to be implemented in a routine quality control of plant material and herbal preparations. PMID- 25431036 TI - Clinical outcomes of children with acute asthma and pneumonia in Mulago hospital, Uganda: a prospective study. AB - BACKGROUND: Little attention has been paid to asthma in 'under-fives' in Sub Saharan Africa. In 'under-fives', acute asthma and pneumonia have similar clinical presentation and most children with acute respiratory symptoms are diagnosed with pneumonia according to the WHO criteria. The mortality associated with acute respiratory diseases in Uganda is high but improving, dropping from 24% in 2004 to 11.9% in 2012. We describe the immediate clinical outcomes of children with acute asthma and pneumonia and document the factors associated with prolonged hospitalization and mortality. METHODS: We enrolled 614 children aged 2 to 59 months with acute respiratory symptoms presenting at the emergency paediatric unit of Mulago hospital. Clinical histories, physical examination, blood and radiological tests were done. Children with asthma and bronchiolitis were collectively referred to as 'Asthma syndrome'. Hospitalized children were monitored every 12 hours for a maximum of 7 days. Survival analysis was done to compare outcome of children with asthma and pneumonia. Cox regression analysis was done to determine factors associated with prolonged hospitalization and mortality. RESULTS: Overall mortality was 3.6%. The highest case fatality was due to pneumocystis jirovecii pneumonia (2/4) and pulmonary tuberculosis (2/7). None of the children with asthma syndrome died. Children with 'asthma syndrome' had a significantly shorter hospital stay compared to those with pneumonia (p<0.001). Factors independently associated with mortality included hypoxemia (HR = 10.7, 95% CI 1.4- 81.1) and severe malnutrition (HR = 5.7, 95% CI 2.1- 15.8). Factors independently associated with prolonged hospitalization among children with asthma syndrome included age less than 12 months (RR = 1.2, 95% CI 1.0-1.4), hypoxemia (RR = 1.4, 95% CI 1.2-1.7), and severe malnutrition (RR = 1.5 95% CI 1.3-1.8). Similar factors were associated with long duration of hospital stay among children with pneumonia. CONCLUSION: This study identified a sharp decline in acute respiratory mortality compared to the previous studies in Mulago hospital. This may be related to focus on and treatment of asthma in this study, and will be analysed in a later study. Bacterial pneumonia is still associated with high case fatality. Hypoxemia, severe malnutrition, and being an infant were associated with poor prognosis among children with acute asthma and pneumonia and need to be addressed in the management protocols. PMID- 25431037 TI - Perceptions and understanding of genetics and genetic eye disease and attitudes to genetic testing and gene therapy in a primary eye care setting. AB - BACKGROUND: Genetic eye pathology represents a significant percentage of the causes of blindness in industrialized countries. This study explores the level of understanding and perceptions of genetics and inherited eye diseases and the attitudes to genetic testing and gene therapy. METHODS: The study was conducted in two parts. Participant groups included were: undergraduate students of optometry, primary eye care professionals and members of the general public. A preliminary study aimed to understand perceptions and to explore the level of knowledge about genetics in general, eye genetics and gene therapy. A second survey was designed to explore attitudes to genetic testing and gene therapy. RESULTS: The majority of participants (82%) perceived genetics as an important science. However, none of them showed a high level of understanding of genetics and inherited eye diseases. Undergraduate students and primary eye care professionals were better informed about inherited eye diseases than the general public (p = 0.001). The majority (80%) across all three groups had a positive attitude to genetic testing and gene therapy. There was a lack of knowledge about the genetic services available among all groups of participants. CONCLUSION: This calls for serious thinking about the level of dissemination of information about genetics and inherited eye diseases. It shows a broadly supportive attitude to genomic medicine among the public. Improving public awareness and education in inherited eye diseases can improve the utility of genetic testing and therapy. PMID- 25431038 TI - The association between prenatal environment and children's mental health trajectories from 2 to 14 years. AB - The prenatal period is recognised as a critical period for later behavioural development. This study aimed to elucidate how an adverse prenatal environment, as defined by the presence of a number of known prenatal risk factors, would influence mental health trajectories in children to 14 years of age. The Raine Study provided comprehensive data from 2,900 pregnancies. Offspring were followed up at ages 2, 5, 8, 10, and 14 years using the Child Behaviour Checklist (CBCL). We used linear mixed regression models with random intercept and slope (random effects models) to examine the extent to which the predictor variables considered influenced changes in continuous CBCL total, internalising, and externalising T scores from ages 2 to 14. In the final multivariate models, increased offspring CBCL T scores were significantly predicted by the mother not finishing high school, smoking during pregnancy, having a total family income below the poverty line, being diagnosed with gestational hypertension and experiencing stressful life events during pregnancy. Conversely, as maternal age increased, CBCL T scores were significantly decreased. Child age also significantly interacted with maternal education, total family income, and maternal stressful life events, such that these variables predicted increases in CBCL scores from age 2 to age 10, and from age 2 to age 14 years. In the Raine Study sample, children who experienced adverse prenatal environments experienced increased levels of problem behaviours in childhood, and more problematic mental health trajectories. Maternal health risk behaviours and other psychosocial variables more commonly affected child behaviour than obstetric complications. PMID- 25431040 TI - Ruthenium(II)-catalyzed C-H acyloxylation of phenols with removable auxiliary. AB - Intermolecular C-H acyloxylations of phenols with removable directing groups were accomplished with a versatile ruthenium catalyst. Specifically, a cationic ruthenium(II) complex, formed in situ, enabled the chemoselective C-H oxygenations of a broad range of substrates. The catalyst proved tolerant of synthetically valuable functional groups, and the substrate scope included both (hetero)aromatic and, the more challenging, aliphatic carboxylic acids. The proposed reaction mechanism involves a reversible C-H ruthenation and an oxidatively induced C-O-bond-forming reductive elimination. PMID- 25431039 TI - Lateral preference in Williams-Beuren syndrome is associated with cognition and language. AB - Williams-Beuren syndrome (WBS) is a genetically defined neurodevelopmental disorder presenting with intellectual disability associated with a specific neurocognitive profile characterized by anxiety, hypersociability, poor visuospatial skills and relatively preserved language. We have defined the lateral preference in 69 individuals (40 males and 29 females, age range 5-47 years) with WBS confirmed by molecular testing, and explored its correlation with cognition, behavior problems, the main aspects of the behavioral phenotype, and specific molecular variants (parental origin and size of the 7q11.23 deletion). Lateral preference (hand, foot, eye and ear) and neurobehavioral features [intelligence quotient (IQ), sociability, visuospatial construction, narrative skills and behavior] were assessed by a battery of tests and parental interviews. A large proportion of WBS individuals showed either left or mixed handedness (26 and 19%, respectively). Hand, foot and ear lateral preference showed significant association with IQ, with individuals with mixed lateral preference presenting lower general IQ, especially verbal IQ, with respect to subjects with well defined laterality. Approachability, visuospatial ability, behavior problems or molecular variants were not associated with lateral preference. Our results indicate that, as in other neurodevelopmental disorders, laterality is poorly defined in a significant proportion of WBS individuals, and reinforces the idea that a correct definition of lateral preference is important for cognition and language. PMID- 25431041 TI - Preliminary analysis of stem cell-like cells in human neuroblastoma. AB - BACKGROUND: Neuroblastoma is an embryonic neoplasm originating from the neural crest with cellular heterogeneity as one of its oncobiological characteristics. This study was undertaken to determine whether human neuroblastoma contains stem cell-like cells. METHODS: Twenty patients with neuroblastoma who have been treated in our hospital since January 2005 were divided into pre-operative chemotherapy (10 patients) and non-chemotherapy (10) groups. Tumor specimens of the patients were taken and paraffin sections were made. The expressions of stem cell markers CD133, ABCG2, CD117 and nestin were immunohistochemically detected in the specimens. Neuroblastoma cells were stained with Hoechst 33342 and PI. The side population (SP) cells were analyzed by the fluorescence-activated cell sorter. The disparity drug resistance to cisplatin (DDP) of SP and non-SP cells was measured with MTT colorimetric assay. The oncogenicity of SP and non-SP cells was identified in nude mice. RESULTS: There was no significant difference in the expression intensity of CD117 and nestin between the two groups of specimens (P>0.05). There was a significant difference between the two groups in terms of the expression intensity of CD133 and ABCG2 (P<0.05). The SP cells accounted for 0.2%-1.3% of the total human neuroblastoma cells and were decreased to 0.1%-0.5% after verapamil treatment. The SP and non-SP cells showed disparity in cell growth experiment and drug resistance to DDP. Oncogenicity experiment revealed that nude mice could erupt tumor by an injection of l*10(6) SHSY5Y and WIV SP cells. However, the nude mice could not form tumor by an injection of l*10(6) non SP cells. CONCLUSION: Neuroblastoma might contain cancer stem cell-like cells. PMID- 25431042 TI - Headache prevalence and characteristics among adolescents in the general population: a comparison between retrospect questionnaire and prospective paper diary data. AB - BACKGROUND: In the present school-based study, a convenience sample of 237 adolescents in grade 6-9 and second year in high school (age 12-18 years) was recruited from a city and a smaller town. The aim of the study was to compare information on the prevalence and various characteristics of headaches not related to disease in a retrospect questionnaire and prospective daily recordings of headaches in a standard paper diary during a 3-week period. METHODS: Besides headache severity, number of headache days, intensity levels and duration of headache episodes were estimated with both assessment methods. Most of the school children suffered from tension-type headaches and a smaller portion of migraine attacks. RESULTS: The overall results showed that school children significantly (p < 0.001) overestimated headache intensity in questionnaires as compared to diary recordings, whereas they underestimated frequency (p < 0.001) and duration (p < 0.001) of headaches. While the correlations on headache severity, frequency and duration between retrospect information in questionnaires and prospective diary recordings were low, the agreement varied with levels of headache characteristics. CONCLUSIONS: Our findings concur well with results from a few similar community studies on headache complaints in school-aged children. We recommend that prospective recordings in diaries should be systematically used in clinical practice but also in epidemiological surveys to increase the validity and reliability in estimates of point prevalence of headache complaints in children and adolescents. PMID- 25431044 TI - Radiofrequency ablation plus devascularization is the preferred treatment of hepatocellular carcinoma with esophageal varices. AB - BACKGROUND: Most hepatocellular carcinomas (HCCs) are associated with cirrhosis. Portal hypertension (PHT) and esophageal variceal bleeding (EVB) can limit the patient's treatment options. Surgical therapy in such patients is challenging. We performed devascularization plus liver resection or radiofrequency ablation (RFA) to treat HCC patients with concomitant EVB resulting from PHT secondary to cirrhosis. Such combined operations have never been reported for the management of HCC patients with variceal esophageal bleeding. AIM: To evaluate two different treatment regimens for patients with HCC and EVB. METHODS: We evaluated 35 BCLC stage 0/A patients with HCC and EVB who underwent either devascularization plus liver resection (Group A) or devascularization plus RFA (Group B). We reviewed the safety and outcomes of the two groups and assessed risk factors for patient survival and tumor recurrence. RESULTS: Significant factors for overall survival were surgical approach and Child-Pugh classification. Child-Pugh classification was the only independent risk factor for overall postoperative survival [hazard ratio (HR) 8.320, 95 % confidence interval (CI) 1.739-39.799, P = 0.008]. Age was the only independent risk factor for tumor recurrence (HR 4.025, 95 % CI 1.343 12.062, P = 0.013). CONCLUSIONS: RFA plus devascularization is the preferred treatment of HCC with EVB. RFA plus devascularization should be considered in Child-Pugh class A patients below 50 years of age. PMID- 25431043 TI - Transforming growth factor-beta 3 alters intestinal smooth muscle function: implications for gastroschisis-related intestinal dysfunction. AB - BACKGROUND: Gastroschisis (GS) is a congenital abdominal wall defect that results in the development of GS-related intestinal dysfunction (GRID). Transforming growth factor-beta, a pro-inflammatory cytokine, has been shown to cause organ dysfunction through alterations in vascular and airway smooth muscle. The purpose of this study was to evaluate the effects of TGF-beta3 on intestinal smooth muscle function and contractile gene expression. METHODS: Archived human intestinal tissue was analyzed using immunohistochemistry and RT-PCR for TGF-beta isoforms and markers of smooth muscle gene and micro-RNA contractile phenotype. Intestinal motility was measured in neonatal rats +/- TGF-beta3 (0.2 and 1 mg/kg). Human intestinal smooth muscle cells (hiSMCs) were incubated with fetal bovine serum +/- 100 ng/ml of TGF-beta 3 isoforms for 6, 24 and 72 h. The effects of TGF-beta3 on motility, hiSMC contractility and hiSMC contractile phenotype gene and micro-RNA expression were measured using transit, collagen gel contraction assay and RT-PCR analysis. Data are expressed as mean +/- SEM, ANOVA (n = 6-7/group). RESULTS: GS infants had increased immunostaining of TGF-beta3 and elevated levels of micro-RNA 143 & 145 in the intestinal smooth muscle. Rats had significantly decreased intestinal transit when exposed to TGF-beta3 in a dose-dependent manner compared with Sham animals. TGF-beta3 significantly increased hiSMC gel contraction and contractile protein gene and micro-RNA expression. CONCLUSION: TGF-beta3 contributed to intestinal dysfunction at the organ level, increased contraction at the cellular level and elevated contractile gene expression at the molecular level. A hyper-contractile response may play a role in the persistent intestinal dysfunction seen in GRID. PMID- 25431045 TI - Endoscopic ultrasound-guided fine-needle aspiration for duodenal obstruction without a discrete mass. PMID- 25431046 TI - Methods for estimating burden of tuberculosis in India need to be improved. PMID- 25431047 TI - Enterococcus faecalis pCF10-encoded surface proteins PrgA, PrgB (aggregation substance) and PrgC contribute to plasmid transfer, biofilm formation and virulence. AB - Enterococcus faecalis pCF10 transfers at high frequencies upon pheromone induction of the prgQ transfer operon. This operon codes for three cell wall anchored proteins - PrgA, PrgB (aggregation substance) and PrgC - and a type IV secretion system through which the plasmid is delivered to recipient cells. Here, we defined the contributions of the Prg surface proteins to plasmid transfer, biofilm formation and virulence using the Caenorhabditis elegans infection model. We report that a combination of PrgB and extracellular DNA (eDNA), but not PrgA or PrgC, was required for extensive cellular aggregation and pCF10 transfer at wild-type frequencies. In addition to PrgB and eDNA, production of PrgA was necessary for extensive binding of enterococci to abiotic surfaces and development of robust biofilms. However, although PrgB is a known virulence factor in mammalian infection models, we determined that PrgA and PrgC, but not PrgB, were required for efficient killing in the worm infection model. We propose that the pheromone-responsive, conjugative plasmids of E. faecalis have retained Prg-like surface functions over evolutionary time for attachment, colonization and robust biofilm development. In natural settings, these biofilms are polymicrobial in composition and constitute optimal environments for signal exchange, mating pair formation and widespread lateral gene transfer. PMID- 25431050 TI - Possible involvement of nitric oxide in antidepressant-like effect of silymarin in male mice. AB - CONTEXT: Silymarin (SM) is extracted from milk thistle Silybum marianum L. [Asteraceae (Compositae)] and known for antioxidative and anti-inflammatory effects. OBJECTIVE: The potential antidepressant-like effect of acute SM and possible involvement of nitric oxide (NO) were determined in male mice. MATERIAL AND METHODS: SM was administered orally (5, 10, 20, 50, 100, and 200 mg/kg; p.o.) 60 min before the tests. After assessment of locomotor activity, the immobility time was measured in forced swimming test (FST) and tail suspension test (TST). To assess the possible involvement of NO, a non-specific NO synthase inhibitor, L NAME (10 mg/kg, i.p.), and a specific iNOS inhibitor, aminoguanidine (AG) (50 mg/kg, i.p.), were administered separately 30 min before SM (20 and 100 mg/kg). RESULTS: SM at its effective doses 10, 20, 50, and 100 mg/kg decreased the immobility time in a dose-dependent manner (p < 0.01, p < 0.05, p < 0.05, and p < 0.001, respectively) in FST. SM (10, 20, 50, and 100 mg/kg) also lowered the immobility measure dose dependently in TST (p < 0.01, p < 0.05, p < 0.01, and p < 0.001, respectively). In addition, 50% of maximum response (ED50) of SM was around 10 mg/kg. The dose 100 mg/kg proved the most effective dose in both the tests. Further, this effect was not related to changes in locomotor activity. Moreover, L-NAME reversed the effect of SM (20 and 100 mg/kg) in FST and SM (100 mg/kg) in TST. However, AG did not influence this impact. CONCLUSION: The antidepressant-like effect of SM is probably mediated at least in part through NO and SM may increase NO tune. PMID- 25431049 TI - Initial insights into bacterial succession during human decomposition. AB - Decomposition is a dynamic ecological process dependent upon many factors such as environment, climate, and bacterial, insect, and vertebrate activity in addition to intrinsic properties inherent to individual cadavers. Although largely attributed to microbial metabolism, very little is known about the bacterial basis of human decomposition. To assess the change in bacterial community structure through time, bacterial samples were collected from several sites across two cadavers placed outdoors to decompose and analyzed through 454 pyrosequencing and analysis of variable regions 3-5 of the bacterial 16S ribosomal RNA (16S rRNA) gene. Each cadaver was characterized by a change in bacterial community structure for all sites sampled as time, and decomposition, progressed. Bacteria community structure is variable at placement and before purge for all body sites. At bloat and purge and until tissues began to dehydrate or were removed, bacteria associated with flies, such as Ignatzschineria and Wohlfahrtimonas, were common. After dehydration and skeletonization, bacteria associated with soil, such as Acinetobacter, were common at most body sites sampled. However, more cadavers sampled through multiple seasons are necessary to assess major trends in bacterial succession. PMID- 25431051 TI - Young people with features of gender dysphoria: Demographics and associated difficulties. AB - This article presents the findings from a cross-sectional study on demographic variables and associated difficulties in 218 children and adolescents (Mean age = 14 years, SD = 3.08, range = 5-17 years), with features of gender dysphoria, referred to the Gender Identity Development Service (GIDS) in London during a 1 year period (1 January 2012-31 December 2012). Data were extracted from patient files (i.e. referral letters, clinical notes and clinician reports). The most commonly reported associated difficulties were bullying, low mood/depression and self-harming. There was a gender difference on some of the associated difficulties with reports of self-harm being significantly more common in the natal females and autism spectrum conditions being significantly more common in the natal males. The findings also showed that many of the difficulties increased with age. Findings regarding demographic variables, gender dysphoria, sexual orientation and family features are reported, and limitations and implications of the cross-sectional study are discussed. In conclusion, young people with gender dysphoria often present with a wide range of associated difficulties which clinicians need to take into account, and our article highlights the often complex presentations of these young people. PMID- 25431053 TI - Neuronal cell death: an overview of its different forms in central and peripheral neurons. AB - The discovery of neuronal cell death dates back to the nineteenth century. Nowadays, after a very long period of conceptual difficulties, the notion that cell death is a phenomenon occurring during the entire life course of the nervous system, from neurogenesis to adulthood and senescence, is fully established. The dichotomy between apoptosis, as the prototype of programmed cell death (PCD ), and necrosis, as the prototype of death caused by an external insult, must be carefully reconsidered, as different types of PCD: apoptosis, autophagy, pyroptosis, and oncosis have all been demonstrated in neurons (and glia ). These modes of PCD may be triggered by different stimuli, but share some intracellular pathways such that different types of cell death may affect the same population of neurons according to several intrinsic and extrinsic factors. Therefore, a mixed morphology is often observed also depending on degrees of differentiation, activity, and injury. The main histological and ultrastructural features of the different types of cell death in neurons are described and related to the cellular pathways that are specifically activated in any of these types of PCD. PMID- 25431052 TI - Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. AB - OBJECTIVES: To investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate. METHODS: In this phase IIb study, 301 patients were randomised 2:1:1:1:1 to receive once daily doses of placebo or 1, 2, 4 or 8 mg baricitinib for 12 weeks. Patients assigned to 2, 4 and 8 mg baricitinib continued blinded treatment for an additional 12 weeks. Patients assigned to placebo or 1 mg baricitinib were reassigned to 2 mg twice daily or 4 mg once daily baricitinib between weeks 12-24. The primary endpoint was the proportion of patients in the combined 4 and 8 mg groups achieving an American College of Rheumatology 20% (ACR20) response versus placebo at week 12. RESULTS: Significantly more patients in the combined baricitinib 4 and 8 mg groups compared with placebo achieved an ACR20 response at week 12 (76% vs 41%, p<0.001). At week 12, significant differences versus placebo were also observed in patients achieving ACR50, ACR70 and remission as measured by Disease Activity Score for 28-joint counts, Clinical Disease Activity Index and Simplified Disease Activity Index. Patients receiving 2, 4, or 8 mg baricitinib maintained or improved in all measures through 24 weeks. Similar proportions of patients experienced at least one adverse event in the placebo and baricitinib groups. Serious infections developed in three patients receiving baricitinib. No cases of tuberculosis, herpes zoster, opportunistic infections or deaths were reported. Dose-dependent decreases in haemoglobin were observed with baricitinib. CONCLUSIONS: Baricitinib improved the signs and symptoms of RA in methotrexate inadequate responders with active disease. Baricitinib was well tolerated with no unexpected safety findings through week 24. TRIAL REGISTRATION NUMBER: NCT01185353. PMID- 25431054 TI - Cell volume regulation monitored with combined epifluorescence and digital holographic microscopy. AB - Quantitative phase imaging emerged recently as a valuable tool for cell observation, by enabling label-free imaging through the intrinsic phase-contrast provided by transparent living cells, thus greatly simplifying observation protocols. The quantitative phase signal, unlike the one provided by the widely used phase-contrast microscope, can be related to relevant biological indicators including dry mass, cell volume regulation or transmembrane water movements. Here, we present quantitative phase imaging coupled with live fluorescence, making it possible to follow the phase signal in time to monitor the cell volume regulation, an early indicator of cell viability, along with specific information such as intracellular Ca2+ imaging with Fura-2 ratiometric fluorescence. PMID- 25431055 TI - Flow cytometric analysis of DNA synthesis and apoptosis in central nervous system using fresh cell nuclei. AB - The use of flow cytometry in vertebrate nervous tissues is hampered by the morphological complexity and high level of interconnectivity intrinsic to their cellular constituents. Here we describe a simplified procedure for the identification and quantitative analysis of neural cells by flow cytometry based on the isolation and immunolabeling of fresh cell nuclei. We have applied this procedure for the quantitative analysis of apoptosis and DNA synthesis in the embryonic brain. PMID- 25431056 TI - Nuclear signs of pre-neurodegeneration. AB - Nuclear architecture is highly concerted including the organization of chromosome territories and distinct nuclear bodies, such as nucleoli, Cajal bodies, nuclear speckles of splicing factors, and promyelocytic leukemia nuclear bodies, among others. The organization of such nuclear compartments is very dynamic and may represent a sensitive indicator of the functional status of the cell. Here, we describe methodologies that allow isolating discrete cell populations from the brain and the fine observation of nuclear signs that could be insightful predictors of an early neuronal injury in a wide range of neurodegenerative disorders. The tools here described may be of use for the early detection of pre degenerative processes in neurodegenerative diseases and for validating novel rescue strategies. PMID- 25431057 TI - Multi-parametric O2 imaging in three-dimensional neural cell models with the phosphorescent probes. AB - Recent progress in bio-imaging has allowed detailed mechanistic studies of neural cell function in complex 3D tissue models including multicellular aggregates, neurospheres, excised brain slices, ganglia, and organoids. Molecular oxygen (O2 ) is an important metabolite and an environmental parameter which determines the viability and physiological status of neural cells within tissue. Here we describe standard method for monitoring O2 in 3D tissue models using phosphorescence lifetime imaging microscopy (PLIM ) and cell-penetrating O2 sensing probes. The O2 probes can be multiplexed with many conventional fluorescence based live cell biomarkers and also end-point immunofluorescence staining. The multi-parametric O2 imaging method is particularly useful for areas such as stem cell development and differentiation , hypoxia research, neurodegenerative disorders, regeneration of brain tissue, evaluation of new drugs, and development of novel tissue models. PMID- 25431058 TI - Calcium imaging in neuron cell death. AB - Intracellular Ca2+ is involved in control of a large variety of cell functions including apoptosis and neuron cell death. For example, intracellular Ca2+ overload is critical in neuron cell death induced by excitotoxicity. Thus, single cell monitoring of intracellular Ca2+ concentration ([Ca2+]cyt ) in neurons concurrently with apoptosis and neuron cell death is widely required. Procedures for culture and preparation of primary cultures of hippocampal rat neurons and fluorescence imaging of cytosolic Ca2+ concentration in Fura2/AM -loaded neurons are described. We also describe a method for apoptosis detection by immunofluorescence imaging. Finally, a simple method for concurrent measurements of [Ca2+]cyt and apoptosis in the same neurons is described. PMID- 25431059 TI - Monitoring mitochondrial membranes permeability in live neurons and mitochondrial swelling through electron microscopy analysis. AB - Maintenance of mitochondrial membrane integrity is essential for mitochondrial function and neuronal viability. Apoptotic stimulus or calcium overload leads to mitochondrial permeability transition pore (mPTP ) opening and induces mitochondrial swelling, a common feature of mitochondrial membrane permeabilization. The first phenomenon can be evaluated in cells loaded with the dye calcein -AM quenched by cobalt, and mitochondrial swelling can be detected by electron microscopy through the analysis of mitochondrial membrane integrity. Here, we describe a live cell imaging assay to detect mitochondrial permeability transition and the development of a detailed analysis of morphological and ultrastructural changes that mitochondria undergo during this process. PMID- 25431060 TI - Real-time visualization of caspase-3 activation by fluorescence resonance energy transfer (FRET). AB - As apoptosis occurs via a complex signaling cascade that is tightly regulated at multiple cell points, different methods exist to evaluate the activity of the proteins involved in the intracellular apoptotic pathways and the phenotype of apoptotic neurons. Detention of the activity of the enzyme caspase-3, the key executioner caspase in programmed cell death, by laser scanning confocal fluorescence microscopy and the fluorescence resonance energy transfer technology is an alternative approach to classical standard techniques, such as Western blotting, activity assays, or histological techniques, and allows working with both fixed and living cells. This technique combined with the organotypic culture approach ex vivo represents a valid tool for the study of the mechanisms of neuronal survival /death and neuroprotection. PMID- 25431061 TI - Design and cloning of short hairpin RNAs (shRNAs) into a lentiviral silencing vector to study the function of selected proteins in neuronal apoptosis. AB - Double-stranded RNA -mediated interference (RNAi ) is a new simple and fast research tool for shutting down genes and characterizes function of their respective proteins. Many strategies for design and delivery of siRNA to target cells are available. Here, we describe the use of lentiviral short hairpin RNA (shRNA) RNA silencing to identify the involvement of d-serine racemase (SR )- an enzyme that syntheses d-serine to modulate glutamate- N-methyl-D-aspartate receptor- in regulating rat cerebellar granule neurons (CGN ) apoptosis. Apoptosis is induced by serum and KCl withdrawal and is detected with fluorometric caspase 3 assay. PMID- 25431062 TI - Genomic analysis using Affymetrix standard microarray genechips (169 format) in degenerate murine retina. AB - Microarray is one of the most useful tools for gene expression profiling. The growing development of microarray genechip technology has enabled increasingly sophisticated studies on the differences in gene transcription between diseased and non-diseased tissues and provides clues to their contribution to the disease in a single experiment. Thus, microarray is used in not only in clinical diagnostics, but also to understand pathological processes and identify leads for new treatments. Here, we present a detailed protocol for performing genomic analysis of retinal tissue with Affymetrix genechip microarray together with additional guidelines from the authors. PMID- 25431063 TI - Genomic analysis of transcriptional changes underlying neuronal apoptosis. AB - Neuronal apoptosis represents an intrinsic "suicide" program, by which a neuron orchestrates its own destruction. Although engagement of apoptosis requires transcription and protein synthesis, the complete spectrum of genes involved in distinct temporal domains remained unknown until the advent of genomics. In the last 10 years, the genome sequences and the development of high-throughput genomic technologies, such as DNA microarrays, have offered the unprecedented experimental opportunities to explore the transcriptional mechanisms underlying apoptosis from a new systems-level perspective. This review goes over this genomic approach and illustrates the use of microarray methodology to dissecting the multigenic program underlying neuronal apoptosis. PMID- 25431064 TI - High-throughput cell death assays. AB - High-throughput screens (HTS ) are powerful tools that permit the rapid evaluation of thousands of samples in a cost-effective manner and minimize sample and reagent consumption. Such assays have recently begun to be utilized to evaluate cell death modalities and also the cytoprotective efficacy of compounds against a wide variety of stresses. Here we describe the design, preparation, and undertaking of HTS-appropriate assays that utilize simple and cost-effective fluorophore - and luminescence -based functional readouts of cell viability. These assays permit the examination of 96-384 compounds in a single multiwell plate with highly robust statistical significance at a fraction of the financial and work cost of traditional approaches. PMID- 25431065 TI - Staining of dead neurons by the Golgi method in autopsy material. AB - Golgi silver impregnation techniques remain ideal methods for the visualization of the neurons as a whole in formalin fixed brains and paraffin sections, enabling to obtain insight into the morphological and morphometric characters of the dendritic arbor, and the estimation of the morphology of the spines and the spinal density, since they delineate the profile of nerve cells with unique clarity and precision. In addition, the Golgi technique enables the study of the topographic relationships between neurons and neuronal circuits in normal conditions, and the following of the spatiotemporal morphological alterations occurring during degenerative processes. The Golgi technique has undergone many modifications in order to be enhanced and to obtain the optimal and maximal visualization of neurons and neuronal processes, the minimal precipitations, the abbreviation of the time required for the procedure, enabling the accurate study and description of specific structures of the brain. In the visualization of the sequential stages of the neuronal degeneration and death, the Golgi method plays a prominent role in the visualization of degenerating axons and dendrites, synaptic "boutons," and axonal terminals and organelles of the cell body. In addition, new versions of the techniques increases the capacity of precise observation of the neurofibrillary degeneration, the proliferation of astrocytes, the activation of the microglia, and the morphology of capillaries in autopsy material of debilitating diseases of the central nervous system. PMID- 25431066 TI - Image analysis algorithms for immunohistochemical assessment of cell death. AB - Light microscopy allows for the inexpensive and fast detection of neuronal /glial cell demise and estimation of infarct and traumatic lesion volumes; the direct correlates of cell death. Quantitative assessment of brain tissue damage following stroke, traumatic brain injury (TBI ) or neurodegenerative diseases, and recovery after therapeutic intervention has been facilitated by recent developments in computer-assisted image analysis technologies that enable more objective and accurate morphometric quantification of cell injury in whole brain sections. In this chapter, the proposed workflow describes what tasks need to be fulfilled to visualize and gauge cell death characterization by histological stains and immunohistochemical markers. PMID- 25431067 TI - In vitro oxygen-glucose deprivation to study ischemic cell death. AB - Oxygen-glucose deprivation (OGD ) is widely used as an in vitro model for stroke, showing similarities with the in vivo models of brain ischemia. In order to perform OGD, cell or tissue cultures, such as primary neurons or organotypic slices, and acutely prepared tissue slices are usually incubated in a glucose free medium under a deoxygenated atmosphere, for example in a hypoxic chamber. Here, we describe the step-by-step procedure to expose cultures and acute slices to OGD, focusing on the most suitable methods for assessing cellular death and/or viability. OGD is a simple yet highly useful technique, not only for the elucidation of the role of key cellular and molecular mechanisms underlying brain ischemia, but also for the development of novel neuroprotective strategies. PMID- 25431068 TI - Laser microbeam targeting of single nerve axons in cell culture. AB - By focusing a laser with short pulses to a diffraction-limited spot, single nerve axons can be precisely targeted and injured. Subsequent repair can be analyzed using various imaging and biochemical techniques to understand the repair process. In this chapter, we will describe a robotic laser microscope system used to injure nerve axons while simultaneously observing repair using phase and fluorescence microscopy. We provide procedures for controlled laser targeting and an experimental approach for studying axonal repair in embryonic rat hippocampus neurons. PMID- 25431069 TI - Real-time imaging of retinal cell apoptosis by confocal scanning laser ophthalmoscopy. AB - Retinal cell apoptosis occurs in many eye conditions, including glaucoma, diabetic retinopathy and Alzheimer's disease. Real-time detection of retinal cell apoptosis has potential clinical value in early disease detection, as well as evaluating disease progression and treatment efficacy. Here, we describe our novel imaging technology DARC (Detection of Apoptosing Retinal Cells), which can be used to visualize single retinal neurons undergoing apoptosis in real time, by using fluorescently labeled Annexin A5 and confocal scanning laser ophthalmoscopy (cSLO ). Clinical trials of DARC in glaucoma patients are due to start shortly, but in this chapter, we describe this technique in experimental animal models. PMID- 25431070 TI - Targeted toxicants to dopaminergic neuronal cell death. AB - Parkinson's disease (PD ) is mainly characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra resulting in chronic deficits in motor functions. Administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP ) produces PD symptoms and recapitulates the main features of PD in human and animal models. MPTP is converted to 1-methyl-4 phenylpyridine (MPP+ ), which is the active toxic compound that selectively destroys dopaminergic neurons. Here, we describe methods and protocols to evaluate MPTP/MPP+-induced dopaminergic neurodegeneration in both murine primary mesencephalic cultures and animal models. The ability of MPTP/MPP+ to cause dopaminergic neuronal cell death is assessed by immunostaining of tyrosine hydroxylase (TH). PMID- 25431071 TI - Stem cells, neural progenitors, and engineered stem cells. AB - Human pluripotent stem cells (hPSCs ) have the unique potential to form every cell type in the body. This potential provides opportunities for generating human progenitors and other differentiated cell types for understanding human development and for use in cell type-specific therapies. Equally important is the ability to engineer stem cells and their derived progenitors to mimic specific disease models. This chapter will focus on the propagation and characterization of human neural progenitors (hNPs ) derived from hPSCs with a particular focus on engineering hNPs to generate in vitro disease models for human neuro mitochondrial disorders. We will discuss the methodologies for culturing and characterizing hPSCs and hNPs; and protocols for engineering hNPs by using a novel mitochondrial transfection technology. PMID- 25431072 TI - Herpes simplex virus type 1 (HSV-1)-derived recombinant vectors for gene transfer and gene therapy. AB - Herpes simplex virus type 1 (HSV-1 ) is a human pathogen whose lifestyle is based on a long-term dual interaction with the infected host, being able to establish both lytic and latent infections. The virus genome is a 153-kilobase pair (kbp) double-stranded DNA molecule encoding more than 80 genes. The interest of HSV-1 as gene transfer vector stems from its ability to infect many different cell types, both quiescent and proliferating cells, the very high packaging capacity of the virus capsid, the outstanding neurotropic adaptations that this virus has evolved, and the fact that it never integrates into the cellular chromosomes, thus avoiding the risk of insertional mutagenesis. Two types of vectors can be derived from HSV-1, recombinant vectors and amplicon vectors, and different methodologies have been developed to prepare large stocks of each type of vector. This chapter summarizes the approach most commonly used to prepare recombinant HSV-1 vectors through homologous recombination, either in eukaryotic cells or in bacteria. PMID- 25431073 TI - Herpes simplex virus type 1 (HSV-1)-derived amplicon vectors for gene transfer and gene therapy. AB - Amplicons are defective, helper -dependent, herpes simplex virus type 1 (HSV-1 ) derived vectors. The main interest of these vectors as gene transfer tools stems from the fact that the amplicon vector genomes do not carry protein-encoding viral sequences. Consequently, they are completely safe for the host and non toxic for the infected cells. Moreover, the complete absence of virus genes provides space to accommodate very large foreign DNA sequences, up to almost 150 kbp, the size of the virus genome . This large transgene capacity can be used to deliver complete gene loci, including introns and exons, as well as long regulatory sequences, conferring tissue-specific expression, or stable maintenance of the transgene in proliferating cells. During many years the development of these vectors and their application in gene transfer experiments was hindered by the presence of contaminating toxic helper virus particles in the vector stocks. In recent years however, two different methodologies have been developed that allow generating amplicon stocks either completely free of helper particles or only faintly contaminated with fully defective helper particles. This chapter summarizes these two methodologies. PMID- 25431074 TI - Bone marrow transplantation for research and regenerative therapies in the central nervous system. AB - Bone marrow stem cells are probably the best known stem cell type and have been employed for more than 50 years, especially in pathologies related to the hematopoietic and immune systems. However, their potential for therapeutic application is much broader (because these cells can differentiate into hepatocytes, myocytes, cardiomyocytes, pneumocytes or neural cells, among others), and they can also presumably be employed to palliate neural diseases. Current research addressing the integration of bone marrow -derived cells in the neural circuits of the central nervous system together with their features and applications are hotspots in current Neurobiology. Nevertheless, as in other leading research lines the efficacy and possibilities of their therapeutic application depend on the technical procedures employed, which are still far from being standardized. In this chapter we shall explain one of these procedures in depth, namely the transplantation of whole bone marrow from harvested bone marrow stem cells for subsequent integration into the encephalon. PMID- 25431075 TI - Detection of activated caspase-8 in injured spinal axons by using fluorochrome labeled inhibitors of caspases (FLICA). AB - Here, we present a detailed protocol for the detection of activated caspase-8 in axotomized axons of the whole-mounted lamprey spinal cord. This method is based on the use of fluorochrome -labeled inhibitors of caspases (FLICA) in ex vivo tissue. We offer a very convenient vertebrate model to study the retrograde degeneration of descending pathways after spinal cord injury. PMID- 25431076 TI - Generation of zebrafish models by CRISPR /Cas9 genome editing. AB - The CRISPR /Cas system identified in archaea has been adopted and optimized for genome editing purposes in zebrafish. In vitro transcribed guide RNA and Cas9 mRNA are microinjected into fertilized zebrafish embryos to edit the zebrafish genome. Here, we describe how to design a gRNA, a fast method for in vitro transcription of gRNA from oligonucleotides , microinjection into fertilized zebrafish embryos, and a PCR -based restriction fragment length assay to identify mutations at the gRNA target site. PMID- 25431077 TI - In vivo assessment of neuronal cell death in Drosophila. AB - Following neuronal cell death at the cellular level and over several time points is challenging in living animal because of the difficulty of accessing and identifying individual neurons. In the eye of a living Drosophila, it is possible to visualize neurons thanks to the cornea neutralization technique. This technique can be coupled to the generation of mosaic clones by the Tomato /GFP FLP/FRT method to identify a group of photoreceptor neurons at a single-cell resolution. This method has proved to be efficient for the study of photoreceptor development and degeneration. In this chapter, I describe this method and focus on fatp mutant photoreceptor neuron degeneration. PMID- 25431078 TI - Drosophila model for studying phagocytosis following neuronal cell death. AB - During central nervous system (CNS ) development, a large number of neurons die by apoptosis and are efficiently removed through phagocytosis. Since apoptosis and apoptotic cell clearance are highly conserved in evolution, relatively simple and easily accessible Drosophila embryonic CNS provides a good model to study molecular and cellular mechanisms of these processes. Here, we describe how to assess neuronal apoptosis and glial phagocytosis of apoptotic neurons using immunohistochemistry of whole fixed embryos and live imaging of developing embryonic CNS. Combination of these different strategies allows a comprehensive analysis of neuronal cell death in vivo. PMID- 25431079 TI - Dim light at night increases body mass of female mice. AB - During the past century, the prevalence of light at night has increased in parallel with obesity rates. Dim light at night (dLAN) increases body mass in male mice. However, the effects of light at night on female body mass remain unspecified. Thus, female mice were exposed to a standard light/dark (LD; 16 h light at ~150 lux/8 h dark at ~0 lux) cycle or to light/dim light at night (dLAN; 16 h light at ~150 lux/8 h dim light at ~5 lux) cycles for six weeks. Females exposed to dLAN increased the rate of change in body mass compared to LD mice despite reduced total food intake during weeks five and six, suggesting that dLAN disrupted circadian rhythms resulting in deranged metabolism. PMID- 25431080 TI - Embryonic development and maternal regulation of murine circadian clock function. AB - The importance of circadian clocks in the regulation of adult physiology in mammals is well established. In contrast, the ontogenesis of the circadian system and its role in embryonic development are still poorly understood. Although there is experimental evidence that the clock machinery is present prior to birth, data on gestational clock functionality are inconsistent. Moreover, little is known about the dependence of embryonic rhythms on maternal and environmental time cues and the role of circadian oscillations for embryonic development. The aim of this study was to test if fetal mouse tissues from early embryonic stages are capable of expressing endogenous, self-sustained circadian rhythms and their contribution to embryogenesis. Starting on embryonic day 13, we collected precursor tissues for suprachiasmatic nucleus (SCN), liver and kidney from embryos carrying the circadian reporter gene Per2::Luc and investigated rhythmicity and circadian traits of these tissues ex vivo. We found that even before the respective organs were fully developed, embryonic tissues were capable of expressing circadian rhythms. Period and amplitude of which were determined very early during development and phases of liver and kidney explants are not influenced by tissue preparation, whereas SCN explants phasing is strongly dependent on preparation time. Embryonic circadian rhythms also developed in the absence of maternal and environmental time signals. Morphological and histological comparison of offspring from matings of Clock-Delta19 mutant and wild-type mice revealed that both fetal and maternal clocks have distinct roles in embryogenesis. While genetic disruptions of maternal and embryonic clock function leads to increased fetal fat depots, abnormal ossification and organ development, Clock gene mutant newborns from mothers with a functional clock showed a larger body size compared to wild-type littermates. These data may contribute to the understanding of the ontogenesis of circadian clocks and the risk of disturbed maternal or embryonic circadian rhythms for embryonic development. PMID- 25431081 TI - Interactions of cisplatin with non-DNA targets and their influence on anticancer activity and drug toxicity: the complex world of the platinum complex. AB - Since the discovery of its anticancer activity in 1970s, cisplatin and its analogs have become widely used in clinical practice, being administered to 40 80% of patients undergoing chemotherapy for solid tumors. The fascinating story of this drug continues to evolve presently, which includes advances in our understanding of complexity of molecular mechanisms involved in its anticancer activity and drug toxicity. While genomic DNA has been generally recognized as the most critical pharmacological target of cisplatin, the results reported across multiple disciplines suggest that other targets and molecular interactions are likely involved in the anticancer mode of action, drug toxicity and resistance of cancer cells to this remarkable anticancer drug. This article reviews interactions of cisplatin with non-DNA targets, including RNAs, proteins, phospholipids and carbohydrates in the context of its pharmacological activity and drug toxicity. Some of these non-DNA targets and associated mechanisms likely act in a highly concerted manner towards the biological outcome in cisplatin treated tumors; therefore, the understanding of complexity of cisplatin interactome may open new avenues for modulation of its clinical efficacy or for designing more efficient platinum-based anticancer drugs to reproduce the success of cisplatin in the treatment of highly curable testicular germ cell tumors in its therapeutic applications to other cancers. PMID- 25431083 TI - Effects of the deletion and over-expression of Fusarium graminearum gene FgHal2 on host response to mycovirus Fusarium graminearum virus 1. AB - The mycovirus Fusarium graminearum virus 1 (FgV1) is associated with reduced virulence (hypovirulence) of Fusarium graminearum. Transcriptomic and proteomic expression profiling have shown that many F. graminearum genes are differentially expressed as a consequence of FgV1 infection. Several of these genes may be related to the maintenance of the virus life cycle. The host gene, FgHal2, which has a highly conserved 3'-phosphoadenosine 5'-phosphatase (PAP phosphatase-like) domain or inositol monophosphatase (IMPase) superfamily domain, shows reduced expression in response to FgV1 infection. We generated targeted gene deletion and over-expression mutants to clarify the possible function(s) of FgHal2 and its relationship to FgV1. The gene deletion mutant showed retarded growth, reduced aerial mycelia formation and reduced pigmentation, whereas over-expression mutants were morphologically similar to the wild-type (WT). Furthermore, compared with the WT, the gene deletion mutant produced fewer conidia and these showed abnormal morphology. The FgHal2 expression level was decreased by FgV1 infection at 120 h post-inoculation (hpi), whereas the levels were nine-fold greater for both the virus-free and virus-infected over-expression mutant than for the WT. FgV1 RNA accumulation was decreased in the deletion mutant at 48, 72 and 120 hpi. FgV1 RNA accumulation in the over-expression mutant was reduced relative to that of the WT at 48 and 120 hpi, but was similar to that of the WT at 72 hpi. The vertical transmission rate of FgV1 in the gene deletion mutant was low, suggesting that FgHal2 may be required for the maintenance of FgV1 in the host cell. Together, these results indicate that the putative 3'(2'),5'-bisphosphate nucleotidase gene, FgHal2, has diverse biological functions in the host fungus and may affect the viral RNA accumulation and transmission of FgV1. PMID- 25431082 TI - Platycodin D induces tumor growth arrest by activating FOXO3a expression in prostate cancer in vitro and in vivo. AB - Platycodin D (PD), a major saponin derived from Platycodin grandiflorum, exerted cytotoxicity against prostate cancer cell lines (PC3, DU145 and LNCaP cells) with IC50 values in the range of 11.17 to 26.13 MUmol/L, whereas RWPE-1 cells (a non malignant human prostate epithelial cell line) were not significantly affected. A further study in these cell lines showed that PD could potently affect cell proliferation (indicated by the bromodeoxyuridine assay), induce cell apoptosis (determined by Annexin V-FITC flow cytometry) and cause cell cycle arrest (indicated by PI staining). After being treated with PD for 48 hours, DU145 and LNCaP cells were arrested in the G0 /G1 phase, and PC3 cells were arrested in the G2/M phase. A Western blotting analysis indicated that PD increased the expression of the FOXO3a transcription factor, decreased the expression of p FOXO3a and MDM2 and increased the expression of FOXO-responsive genes, p21 and p27. MDM2 silencing (transiently by siRNA-MDM2) increased the PD-induced FOXO3a protein expression, while MDM2 overexpression (in cells transiently transfected with a pcDNA3-MDM2 plasmid) decreased the PD-induced expression of the FOXO3a protein. Moreover, PD dose-dependently inhibited the growth of PC3 xenograft tumors in BALB/c nude mice. A Western blotting analysis of the excised xenograft tumors indicated that similar changes in protein expression also occurred in vivo. These results suggest that PD exhibits significant activity against prostate cancer in vitro and in vivo. The FOXO3a transcription factor appears to be involved in the activity of PD. Together, all of these findings provide a basis for the future development of this agent for human prostate cancer therapy. PMID- 25431084 TI - Defining adult asthma endotypes by clinical features and patterns of volatile organic compounds in exhaled air. AB - BACKGROUND: Several classifications of adult asthma patients using cluster analyses based on clinical and demographic information has resulted in clinical phenotypic clusters that do not address molecular mechanisms. Volatile organic compounds (VOC) in exhaled air are released during inflammation in response to oxidative stress as a result of activated leukocytes. VOC profiles in exhaled air could distinguish between asthma patients and healthy subjects. In this study, we aimed to classify new asthma endotypes by combining inflammatory mechanisms investigated by VOC profiles in exhaled air and clinical information of asthma patients. METHODS: Breath samples were analyzed for VOC profiles by gas chromatography-mass spectrometry from asthma patients (n = 195) and healthy controls (n = 40). A total of 945 determined compounds were subjected to discriminant analysis to find those that could discriminate healthy from asthmatic subjects. 2-step cluster analysis based on clinical information and VOCs in exhaled air were used to form asthma endotypes. RESULTS: We identified 16 VOCs, which could distinguish between healthy and asthma subjects with a sensitivity of 100% and a specificity of 91.1%. Cluster analysis based on VOCs in exhaled air and the clinical parameters FEV1, FEV1 change after 3 weeks of hospitalization, allergic sensitization, Junipers symptoms score and asthma medications resulted in the formation of 7 different asthma endotype clusters. We identified asthma clusters with different VOC profiles but similar clinical characteristics and endotypes with similar VOC profiles, but distinct clinical characteristics. CONCLUSION: This study demonstrates that both, clinical presentation of asthma and inflammatory mechanisms in the airways should be considered for classification of asthma subtypes. PMID- 25431085 TI - Temperament and its heritability in Corriedale and Merino lambs. AB - Temperament can be defined as the fearfulness and reactivity of an animal in response to humans and strange, novel or threatening environments. The productive performance of an animal is affected by its temperament, and selection of calm animals might improve their adaptation to the farming environment and handling, as well as improve productivity. The temperament was measured in lambs of two breeds of sheep in Uruguay. The effects of dam's age, type of birth, age of the lamb and contemporary group (CG; lambs belonging to the same year, flock, sex and rearing group) on the temperament of the lambs and the heritability of temperament were estimated with a Bayesian analysis using Gibbs sampling. Overall, 4962 Corriedale lambs and 2952 Merino lambs from 13 farms were tested. Temperament was measured using the isolation box test, isolating a lamb inside the box for 30 s, and recording the vibrations produced by its movements. The average temperament score (+/-s.e.m.) of the Corriedale lambs was 24.7 (+/-0.23) and that of the Merino was 36.8 (+/-0.45). Temperament was not associated with dam's age, type of birth or lamb's age. There were no relevant differences in the agitation score between lambs born in 2010 and 2011. The mean of the distribution of possible values of heritability (+/-s.d.) was 0.18 (+/-0.05) for the Corriedale and 0.31 (+/-0.06) for the Merino. The likelihood of heritability values to be greater than 0.15 exceeded 70% in the Corriedale and 90% in the Merino. The temperament of Merino and Corriedale sheep in Uruguay is moderately heritable. It is not related to dam's age, type of birth or age of the lambs; however, it is affected by some aspect of the CG. PMID- 25431086 TI - Insecticide-treated net use before and after mass distribution in a fishing community along Lake Victoria, Kenya: successes and unavoidable pitfalls. AB - BACKGROUND: Insecticide-treated nets (ITNs) have proven instrumental in the successful reduction of malaria incidence in holoendemic regions during the past decade. As distribution of ITNs throughout sub-Saharan Africa (SSA) is being scaled up, maintaining maximal levels of coverage will be necessary to sustain current gains. The effectiveness of mass distribution of ITNs, requires careful analysis of successes and failures if impacts are to be sustained over the long term. METHODS: Mass distribution of ITNs to a rural Kenyan community along Lake Victoria was performed in early 2011. Surveyors collected data on ITN use both before and one year following this distribution. At both times, household representatives were asked to provide a complete accounting of ITNs within the dwelling, the location of each net, and the ages and genders of each person who slept under that net the previous night. Other data on household material possessions, education levels and occupations were recorded. Information on malaria preventative factors such as ceiling nets and indoor residual spraying was noted. Basic information on malaria knowledge and health-seeking behaviours was also collected. Patterns of ITN use before and one year following net distribution were compared using spatial and multi-variable statistical methods. Associations of ITN use with various individual, household, demographic and malaria related factors were tested using logistic regression. RESULTS: After infancy (<1 year), ITN use sharply declined until the late teenage years then began to rise again, plateauing at 30 years of age. Males were less likely to use ITNs than females. Prior to distribution, socio-economic factors such as parental education and occupation were associated with ITN use. Following distribution, ITN use was similar across social groups. Household factors such as availability of nets and sleeping arrangements still reduced consistent net use, however. CONCLUSIONS: Comprehensive, direct-to-household, mass distribution of ITNs was effective in rapidly scaling up coverage, with use being maintained at a high level at least one year following the intervention. Free distribution of ITNs through direct-to-household distribution method can eliminate important constraints in determining consistent ITN use, thus enhancing the sustainability of effective intervention campaigns. PMID- 25431087 TI - Emerging drugs for sickle cell anemia. AB - INTRODUCTION: The search for effective therapeutic interventions for sickle cell disease (SCD) has been an ongoing endeavor for over 50 years. During this period, only hydroxyurea (HU), which received US FDA approval in February 1998, was identified as an effective therapeutic agent in preventing or ameliorating the frequency of vaso-occlusive crises, acute chest syndrome and the need for blood transfusion. Approximately 25% of patients with sickle cell anemia (SCA), however, do not respond to HU and some patients experiencing serious side effects of this chemotherapeutic agent. Nevertheless, the success of HU opened the sluice gates to identify other effective drug therapies. The objective of this review is to describe the emerging drug therapies for SCA. AREAS COVERED: In this review, we describe the pathophysiology of SCD and provide an in-depth analysis of the current and new pharmacologic therapies in the field. Literature searches involved multiple databases including Medline In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Scopus. EXPERT OPINION: SCA is a heterogeneous disease that has caused tremendous global morbidity and early mortality. More effective, individualized and inexpensive therapies are needed. New therapies targeting multiple pathways in its complex pathophysiology are under investigation. PMID- 25431088 TI - Antifungal activity of a liposomal itraconazole formulation in experimental Aspergillus flavus keratitis with endophthalmitis. AB - The aim of this study was to assess the efficacy of topical application of a liposomal formulation of itraconazole for the treatment of experimental keratitis with endophthalmitis caused by Aspergillus flavus. The liposomes were obtained by the lipid film hydration method followed by sonication. Adult female Wistar rats (weighing 200-220 g) were immunosuppressed by intraperitoneal injection of 150 mg/kg of cyclophosphamide 3 days before infection by exposure to the fungus A. flavus (10(7) spores/ml). Forty-eight hours later, the animals were treated with the liposomal formulation. For comparison, one group of animals (n = 6) was treated with the same drug not encapsulated. At the end of the experiment, the animals were evaluated for clinical signs and number of colony forming units (CFU/g), along with direct microscopic examination. The results indicated that the liposomal formulation of itraconazole has better antifungal activity than the unencapsulated drug in the treatment of fungal keratitis with endophthalmitis caused experimentally by A. flavus in Wistar rats. PMID- 25431089 TI - Cutaneous bacterial species from Lithobates catesbeianus can inhibit pathogenic dermatophytes. AB - Antibiotics are being successfully used to fight many infectious diseases caused by pathogenic microorganisms. However, new infectious diseases are continuously being identified, and some known pathogens are becoming resistant against known antibiotics. Furthermore, many antifungals are causing serious side effects in long-term treatments of patients, and many skin infections caused by dermatophytes are difficult to cure. The beneficial roles of resident cutaneous microbiota to inhibit pathogenic microorganisms have been shown for many vertebrate species. Microbial symbionts on the amphibian skin for example can be a source of powerful antimicrobial metabolites that can protect amphibians against diseases, such as chytridiomycosis, caused by a fungal pathogen. In this research, we investigated whether cutaneous bacterial species isolated from Lithobates catesbeianus (North American bullfrog), an invasive amphibian species that is resistant to chytridiomycosis, produce secondary metabolites that can be used to inhibit the growth of three species of dermatophytes (Microsporum gypseum, Epidermophyton floccosum, and Trichophyton mentagrophytes) which are known to cause topical or subdermal skin infections in humans. Strongly anti dermatophyte bacterial species that belonged to the Bacillaceae, Streptomycetaceae, Pseudomonadaceae, Xanthomonadaceae, Aeromonadaceae, and Enterobacteriaceae were identified. This research has provided evidence of the presence of cutaneous anti-dermatophyte bacteria from L. catesbeianus which might provide a basis for health care providers to experiment with new antifungals in the future. PMID- 25431090 TI - In vitro susceptibility of Brazilian Pythium insidiosum isolates to essential oils of some Lamiaceae family species. AB - The present study aimed to evaluate the in vitro antimicrobial action of Origanum vulgare, Origanum majorana, Mentha piperita and Rosmarinus officinalis on Pythium insidiosum oomycete zoospores. The antimicrobial activity evaluation was performed by the broth microdilution method according to CSLI M38-A2 documentation adapted to phytopharmaceuticals. Twenty-two P. insidiosum isolates were evaluated, and the minimum inhibitory concentration was determined at 100% growth inhibition. All P. insidiosum isolates evaluated showed a minimum inhibitory concentration ranging from 0.05 to 1.75 mg/mL when O. vulgare oil was used and from 0.11 to 3.5 mg/mL for O. majorana, M. piperita and R. officinalis oils. The results obtained indicate that the essential oils tested showed antimicrobial activity on P. insidiosum, with O. vulgare essential oil showing the best performance. These findings emphasize the potential use of plant essential oils as control agents in P. insidiosum infections; further research, however, is needed so as the in vivo activity of these oils can also be evaluated. PMID- 25431092 TI - Rehabilitation exercise assessment using inertial sensors: a cross-sectional analytical study. AB - BACKGROUND: Accurate assessments of adherence and exercise performance are required in order to ensure that patients adhere to and perform their rehabilitation exercises correctly within the home environment. Inertial sensors have previously been advocated as a means of achieving these requirements, by using them as an input to an exercise biofeedback system. This research sought to investigate whether inertial sensors, and in particular a single sensor, can accurately classify exercise performance in patients performing lower limb exercises for rehabilitation purposes. METHODS: Fifty-eight participants (19 male, 39 female, age: 53.9 +/- 8.5 years, height: 1.69 +/- 0.08 m, weight: 74.3 +/- 13.0 kg) performed ten repetitions of seven lower limb exercises (hip abduction, hip flexion, hip extension, knee extension, heel slide, straight leg raise, and inner range quadriceps). Three inertial sensor units, secured to the thigh, shin and foot of the leg being exercised, were used to acquire data during each exercise. Machine learning classification methods were applied to quantify the acquired data. RESULTS: The classification methods achieved relatively high accuracy at distinguishing between correct and incorrect performance of an exercise using three, two, or one sensor while moderate efficacy scores were also achieved by the classifier when attempting to classify the particular error in exercise performance. Results also illustrated that a reduction in the number of inertial sensor units employed has little effect on the overall efficacy results. CONCLUSION: The results revealed that it is possible to classify lower limb exercise performance using inertial sensors with satisfactory levels of accuracy and reducing the number of sensors employed does not reduce the accuracy of the method. PMID- 25431091 TI - Treatment of bloodstream infections in ICUs. AB - Bloodstream infections (BSIs) are frequent in ICU and is a prognostic factor of severe sepsis. Community acquired BSIs usually due to susceptible bacteria should be clearly differentiated from healthcare associated BSIs frequently due to resistant hospital strains. Early adequate treatment is key and should use guidelines and direct examination of samples performed from the infectious source. Previous antibiotic therapy knowledge, history of multi-drug resistant organism (MDRO) carriage are other major determinants of first choice antimicrobials in heathcare-associated and nosocomial BSIs. Initial antimicrobial dose should be adapted to pharmacokinetic knowledge. In general, a high dose is recommended at the beginning of treatment. If MDRO is suspected combination antibiotic therapy is mandatory because it increase the spectrum of treatment. Most of time, combination should be pursued no more than 2 to 5 days.Given the negative impact of useless antimicrobials, maximal effort should be done to decrease the antibiotic selection pressure. De-escalation from a broad spectrum to a narrow spectrum antimicrobial decreases the antibiotic selection pressure without negative impact on mortality. Duration of therapy should be shortened as often as possible especially when organism is susceptible, when the infection source has been totally controlled. PMID- 25431093 TI - Usefulness of increased 18F-FDG uptake for detecting local recurrence in patients with extremity osteosarcoma treated with surgical resection and endoprosthetic replacement. AB - OBJECTIVE: To investigate the changes of increased F-18 fluorodeoxyglucose ((18)F FDG) uptake around the prosthesis and its ability to differentiate local recurrence from postsurgical change after endoprosthetic replacement in extremity osteosarcoma. MATERIALS AND METHODS: A total of 355 positron emission tomography (PET)/computed tomography (CT) scans in 109 extremity osteosarcoma patients were retrospectively analyzed. All patients were followed up with (18)F-FDG PET/CT for more than 3 years after tumor resection. For semiquantitative assessment, we drew a volume of interest around the entire prosthesis of the extremity and measured the maximum standardized uptake value (SUV max). Independent samples t test was used to compare SUV max at each follow-up time. SUV max at 3 months (SUV1) and SUV max at the time of local recurrence in patients with recurrence or at the last follow-up in others (SUV2) were compared using the Mann-Whitney test. Diagnostic performances of PET parameters were assessed using ROC curve analyses. RESULTS: Nine patients (8 %) showed a local recurrence. Mean SUV max at 3, 12, 24, and 36 months was 3.1 +/- 1.5, 3.8 +/- 1.9, 3.6 +/- 1.9, and 3.7 +/- 1.5 respectively. In ROC curve analysis, the combination of SUV2 >4.6 and DeltaSUV >75.0 was a more useful parameter for predicting local recurrence than SUV2 or DeltaSUV alone. The sensitivity, specificity, and accuracy for identifying local recurrence were 89, 76, 77 % for SUV2; 78, 81, 81 % for DeltaSUV; and 78, 94, 93 % for the combined criterion respectively. CONCLUSION: The combination of SUV2 and DeltaSUV was more useful than the SUV2 or DeltaSUV used alone for the prediction of local recurrence. PMID- 25431094 TI - Diagnostic value of the nerve root sedimentation sign, a radiological sign using magnetic resonance imaging, for detecting lumbar spinal stenosis: a meta analysis. AB - OBJECTIVE: This study aimed to determine the diagnostic value of the nerve root sedimentation sign, a relatively new radiological sign using magnetic resonance imaging, for diagnosing lumbar spinal stenosis. MATERIALS AND METHODS: The literature search was based on PUBMED, EMBASE, Cochrane Library, Google Scholar, and the Chinese Biomedical Literature Database up to March 2014. A total of 120 articles were identified. Seven studies involving 1,182 patients were included. RESULTS: The quality of the methodology of the seven studies was good. Overall, the pooled weighted value showed that the sedimentation sign had moderate sensitivity of 0.80 [95 % confidence interval (CI) 0.77-0.83] and high specificity of 0.96 (95 % CI 0.94-0.98). The area under the curve was 0.76. Subgroup analysis showed that the degree of morphological spinal stenosis was responsible for the heterogeneity. In the patients with severe morphological lumbar spinal stenosis, the sedimentation sign had even higher sensitivity and specificity: 0.899 (95 % CI 0.87-0.92) and 0.99 (95 % CI 0.98-1.00), respectively. The area under the curve was 0.96. In the patients with lumbar spinal stenosis without definition of morphological stenosis, there was a notable threshold effect and significant heterogeneity. The area under the curve was 0.63. CONCLUSION: Current evidence suggests that the sedimentation sign has high sensitivity and specificity for diagnosing severe lumbar spinal stenosis. Its performance in diagnosing moderate and mild spinal stenosis, however, has yet to be corroborated in properly designed studies. PMID- 25431095 TI - [13N]Ammonia positron emission tomographic/computed tomographic imaging targeting glutamine synthetase expression in prostate cancer. AB - The purpose of this study was to investigate the expression of glutamine synthetase (GS) in prostate cancer (PCa) and the utility of [13N]ammonia positron emission tomography/computed tomography (PET/CT) in the imaging of PCa. The uptake ratio of [13N]ammonia and the expression of GS in PC3 and DU145 cells was measured. Thirty-four patients with suspected PCa underwent [13N]ammonia PET/CT imaging, and immunohistochemistry staining of GS was performed. The uptake of [13N]ammonia in PC3 and DU145 cells elevated along with the decrease in glutamine in medium. The expression of GS messenger ribonucleic acid and protein also increased when glutamine was deprived. In biopsy samples, the GS expression scores were significantly higher in PCa tissue than in benign tissues (p < .001), and there was a positive correlation between the maximum GS expression scores and Gleason scores (Spearman r = .52). In 34 patients, [13N]ammonia uptake in PCa segments was significantly higher than that in benign segments (p <= .01), and there was a weak correlation between GS expression scores and the uptake of [13N]ammonia (Spearman r = .47). The expression of GS in PCa cells upregulated along with the deprivation of glutamine. GS is the main reason for the uptake of [13N]ammonia, and [13N]ammonia is a useful tracer for PCa imaging. PMID- 25431096 TI - Vaccine therapies in malignant glioma. AB - Glioblastoma is a grade IV astrocytoma that is widely accepted in clinical neurosurgery as being an extremely lethal diagnosis. Long-term survival rates remain dismal, and even when tumors undergo gross resection with confirmation of total removal on neuroimaging, they invariably recur with even greater virulence. Standard therapeutic modalities as well as more contemporary treatments have largely resulted in disappointing improvements. However, the therapeutic potential of vaccine immunotherapy for malignant glioma should not be underestimated. In contrast to many of the available treatments, vaccine immunotherapy is unique because it offers the means of delivering treatment that is highly specific to both the patient and the tumor. Peptide, heat-shock proteins, and dendritic cell vaccines collectively encapsulate the majority of research efforts involving vaccine-based treatment modalities. In this review, important recent findings for these vaccine types are discussed in the context of ongoing clinical trials. Broad challenges to immunotherapy are also considered. PMID- 25431097 TI - Discovering intergenerativity: an evaluation of learning partnerships between student nurses and older adults. AB - BACKGROUND: The benefits of intergenerational contact between older and younger adults have been demonstrated, yet nursing programmes have generally failed to build upon this potential. Nursing students have been deterred from identifying gerontological nursing as a career choice because of poor placement experiences, suggesting a need to develop practicum placements that reveal the potential impact of nursing when working with older adults. This study describes an evaluation of a partnership approach to learning involving nursing students and older adults. AIMS AND OBJECTIVES: To explore the ways in which the practicum component of a course in gerontological nursing, incorporating sequential visits with an older adult, contributes to undergraduate nursing students' and older adults' understanding of experiences of ageing. To identify the benefits and challenges of participating in the course from the perspective of student nurses and older adults. DESIGN: Illuminative evaluation. METHODS: Data were drawn from the experiences of two cohorts of students who completed the programme in 2010/2011. Semistructured interviews were conducted with 32 students and with 22 older adults who participated in the programme. Eighty reflective journals completed by a sample of 59 students following visits with their designated older adult were also analysed. All data were analysed using the 'framework' approach. RESULTS: Four shared themes were identified across the data sets: becoming aware of generational experiences, seeing the unique person, valuing the relationship and discovering intergenerativity. These themes illuminated the shared benefits of the practicum experience. CONCLUSIONS: Structured conversations between nursing students and older adults within the context of a focused course in gerontological nursing enable the development of mutually beneficial intergenerational relationships. IMPLICATIONS FOR PRACTICE: Involving older adults as education partners in undergraduate nursing programmes has benefits for all participants and could form a valuable component of any undergraduate nursing programme. PMID- 25431098 TI - Protein-protein Interaction Networks of E. coli and S. cerevisiae are similar. AB - Only recently novel high-throughput binary interaction data in E. coli became available that allowed us to compare experimentally obtained protein-protein interaction networks of prokaryotes and eukaryotes (i.e. E. coli and S. cerevisiae). Utilizing binary-Y2H, co-complex and binary literature curated interaction sets in both organisms we found that characteristics of interaction sets that were determined with the same experimental methods were strikingly similar. While essentiality is frequently considered a question of a protein's increasing number of interactions, we found that binary-Y2H interactions failed to show such a trend in both organisms. Furthermore, essential genes are enriched in protein complexes in both organisms. In turn, binary-Y2H interactions hold more bottleneck interactions than co-complex interactions while both binary-Y2H and co-complex interactions are strongly enriched among co-regulated proteins and transcription factors. We discuss if such similarities are a consequence of the underlying methodology or rather reflect truly different biological patterns. PMID- 25431099 TI - Correspondence regarding Zhong et al., BMC Bioinformatics 2013 Mar 7;14:89. AB - Computational expression deconvolution aims to estimate the contribution of individual cell populations to expression profiles measured in samples of heterogeneous composition. Zhong et al. recently proposed Digital Sorting Algorithm (BMC Bioinformatics 2013 Mar 7;14:89) and showed that they could accurately estimate population-specific expression levels and expression differences between two populations. They compared DSA with Population-Specific Expression Analysis (PSEA), a previous deconvolution method that we developed to detect expression changes occurring within the same population between two conditions (e.g. disease versus non-disease). However, Zhong et al. compared PSEA derived specific expression levels across different cell populations. Specific expression levels obtained with PSEA cannot be directly compared across different populations as they are on a relative scale. They are accurate as we demonstrate by deconvolving the same dataset used by Zhong et al. and, importantly, allow for comparison of population-specific expression across conditions. PMID- 25431100 TI - Sixteen additional enhancers associated with the chicken Sox2 locus outside the central 50-kb region. AB - The transcription factor Sox2 plays a central role in the regulation of neuro sensory development, and many other developmental processes. To gain an in depth understanding of the Sox2 gene regulation, we previously investigated the Sox2 proximal 50-kb region of the chicken genome to determine enhancers based on functional assays using chicken embryo electroporation. We identified 11 enhancers with specificity for neuro-sensory tissues. In this study, we extended the analysis of Sox2 locus-associated enhancers to a 200-kb region and identified 16 additional enhancers with functions in neuro-sensory development. These enhancers roughly correspond to a fraction of the sequence blocks that are highly conserved between chicken and mammalian genomes. The neural enhancers were activated in sequence, thereby creating a complex pattern of functional overlaps in the developing central nervous system (CNS). The variations in the specificities of the sensory enhancers also reflected the intermediate steps of sensory tissue development. This study provides an example where a single transcription factor gene has numerous regulatory elements that allow it to fulfill many functional roles in different biological contexts. PMID- 25431101 TI - Simultaneous three-dimensional temperature and velocity field measurements using astigmatic imaging of non-encapsulated thermo-liquid crystal (TLC) particles. AB - A combination of cutting edge developments is presented to characterize three dimensional (3D) temperature and velocity fields in microscopic flows. An emulsion of non-encapsulated thermo-liquid crystal (TLC) micro spheres, with a narrow size distribution is used to track the flow's motion and temperature distribution. A state-of-the-art light engine, which combines the spectrum of six light pipes, provides a balanced illumination which allows for strong and detectable color patterns across the TLC's temperature response range. Lastly, the ability of the TLC material to reflect select wavelength bands with an unchanging and independent circular polarization chirality is exploited by a filter that blocks background noise, while exclusively transmitting the color signal of the TLC particles. This approach takes advantage of the peculiar physical properties of TLCs to allow the estimation of individual TLC particle's 3D position, for the first time, using Astigmatism Particle Tracking Velocimetry (APTV). PMID- 25431102 TI - Castleman's disease - a diagnostic dilemma. AB - Castleman's disease is a benign lymphoproliferative disease characterised by hyperplasia of lymphoid follicles. It can affect any lymph nodes in the body. Here we describe a caucasian patient who presented with six months history of shortness of breath with CT scan confirming an 8 cm segment of consolidated lung in left hilum. PET scan revealed a mass measuring 68x80x55 mm extending from the left hilum out into the left upper lobe containing area of calcification with SUV max 4.8. The differential diagnosis included atypical sequestration, hamartoma and primary lung malignancy. The patient underwent left video assisted enucleation of the lesion. The histology confirmed the diagnosis of Castleman's disease. PMID- 25431103 TI - Breathing life into fisheries stock assessments with citizen science. AB - Citizen science offers a potentially cost-effective way for researchers to obtain large data sets over large spatial scales. However, it is not used widely to support biological data collection for fisheries stock assessments. Overfishing of demersal fishes along 1,000 km of the west Australian coast led to restrictive management to recover stocks. This diminished opportunities for scientists to cost-effectively monitor stock recovery via fishery-dependent sampling, particularly of the recreational fishing sector. As fishery-independent methods would be too expensive and logistically-challenging to implement, a citizen science program, Send us your skeletons (SUYS), was developed. SUYS asks recreational fishers to voluntarily donate fish skeletons of important species from their catch to allow biological data extraction by scientists to produce age structures and conduct stock assessment analyses. During SUYS, recreational fisher involvement, sample sizes and spatial and temporal coverage of samples have dramatically increased, while the collection cost per skeleton has declined substantially. SUYS is ensuring sampling objectives for stock assessments are achieved via fishery-dependent collection and reliable and timely scientific advice can be provided to managers. The program is also encouraging public ownership through involvement in the monitoring process, which can lead to greater acceptance of management decisions. PMID- 25431104 TI - The reliability of thermoform retainers: a laboratory-based comparative study. AB - AIM: Despite a very significant increase in the use of thermoform retainers, within orthodontics, to date, there is no evidence regarding the quality of fit between the dental cast and retainer. The current study aims to compare the fit of different thermoform retainer materials, under laboratory standardized conditions. MATERIALS AND METHODS: A prospective, laboratory-based study design was adopted to compare the fit of four different commercially available thermoform retainer materials. A master dental cast was fabricated in dental stone, to which three and five specific reference points were located on the central incisors and upper first molars, respectively. The master cast was then duplicated to produce a total of 40 such dental casts. The performance of the following four test materials was investigated: ACE, C+ (Raintree Essix Glenroe), True Tain (True Tain Inc.), and Iconic Clear (DB Orthodontics). For each material, 10 thermoform retainers were fabricated within the dental laboratory. Subsequent scanning and analysing of the casts and thermoform retainers was performed in a dedicated area, using the co-ordinate measuring machine, in order to calculate their respective fit at the incisor and first molar regions. RESULTS: At all eight recorded landmark points, the mean values for the following thermoform materials: ACE, True Tain, and Iconic Clear, a similar trend was observed. At all eight points, there was a significant difference between the performance of the four different materials (P < 0.001), with the greatest difference observed in the mean values in relation to material C+. CONCLUSION: Statistically significant differences were observed in the fit behaviour of all four thermoform materials being tested. PMID- 25431105 TI - Quality of life among untreated sleep apnea patients compared with the general population and changes after treatment with positive airway pressure. AB - Obstructive sleep apnea leads to recurrent arousals from sleep, oxygen desaturations, daytime sleepiness and fatigue. This can have an adverse impact on quality of life. The aims of this study were to compare: (i) quality of life between the general population and untreated patients with obstructive sleep apnea; and (ii) changes of quality of life among patients with obstructive sleep apnea after 2 years of positive airway pressure treatment between adherent patients and non-users. Propensity score methodologies were used in order to minimize selection bias and strengthen causal inferences. The enrolled obstructive sleep apnea subjects (n = 822) were newly diagnosed with moderate to severe obstructive sleep apnea who were starting positive airway pressure treatment, and the general population subjects (n = 742) were randomly selected Icelanders. The Short Form 12 was used to measure quality of life. Untreated patients with obstructive sleep apnea had a worse quality of life when compared with the general population. This effect remained significant after using propensity scores to select samples, balanced with regard to age, body mass index, gender, smoking, diabetes, hypertension and cardiovascular disease. We did not find significant overall differences between full and non-users of positive airway pressure in improvement of quality of life from baseline to follow-up. However, there was a trend towards more improvement in physical quality of life for positive airway pressure-adherent patients, and the most obese subjects improved their physical quality of life more. The results suggest that co morbidities of obstructive sleep apnea, such as obesity, insomnia and daytime sleepiness, have a great effect on life qualities and need to be taken into account and addressed with additional interventions. PMID- 25431106 TI - Review: minimally invasive strabismus surgery. AB - This article reviews the principles and different techniques used to perform minimally invasive strabismus surgery (MISS). This term is used for strabismus surgeries minimizing tissue disruption. Muscles are not accessed through one large opening, but using several keyhole openings placed where needed for the surgical steps. If necessary, tunnels are created between cuts, which will allow performing additional surgical steps. To keep the keyhole openings small, transconjunctival suturing techniques are used. The cuts are always placed as far away from the limbus as feasible. This will reduce the risk for postoperative corneal complications and it will ensure that all cuts will be covered by the eyelids, minimizing postoperative visibility of surgery and patient discomfort. Benefits from minimizing anatomical disruption between the muscle and the surrounding tissue are a better preservation of muscle function, less swelling, and pain, and more ease to perform reoperations. MISS openings allow to perform all types of strabismus surgeries, namely rectus muscle recessions, resections, plications, reoperations, retroequatorial myopexias, transpositions, oblique muscle recessions, or plications, and adjustable sutures, even in the presence of restricted motility. PMID- 25431107 TI - Scar characteristics for prediction of ventricular arrhythmia in ischemic cardiomyopathy. AB - BACKGROUND: Better risk-stratification tools are needed to identify the best candidates for implantable cardioverter defibrillator implantation. Infarct characterization by cardiac magnetic resonance (CMR) has become an evolving potential tool for risk stratification. OBJECTIVE: We assessed the ability of scar characteristics by CMR in patients with postinfarction left ventricular (LV) dysfunction to predict sustained monomorphic ventricular tachycardia (SMVT). METHODS: Forty-eight patients with postinfarction LV dysfunction underwent CMR study. Twenty-four patients had history of SMVT and the other 24 were control group and underwent electrophysiological study to assess SMVT inducibilty. Various scar characteristics were assessed in the spontaneous SMVT group and were compared with the inducible and noninducible SMVT groups. RESULTS: Only six patients in the control group had inducible SMVT. In univariable analysis, total scar (absolute and as percent of LV), scar core (absolute and as percent of LV), peri-infarct zone (absolute and as percent of LV), mean infarct transmurality, and number of segments with late gadolinium enhancement (LGE) were statistically significant predictors of spontaneous SMVT experience and SMVT inducibility. In multivariable analysis, total infarct as percent of LV mass was the only significant independent predictor of spontaneous SMVT experience (odds ratio [OR] 1.33 per% change, 95% confidence interval [CI] 1.12-1.6, P = 0.001) and SMVT inducibility (OR 1.3 per% change, 95% CI 1.1-1.6, P = 0.004). CONCLUSION: Characterization of myocardial infarct by LGE-CMR, specifically total infarct size, is better predictor of spontaneous SMVT experience and SMVT inducibility than LV ejection fraction. PMID- 25431108 TI - Long-term entecavir or tenofovir disoproxil fumarate therapy in treatment-naive chronic hepatitis B patients in the real-world setting. AB - The aim of this study was to determine the long-term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on the natural course of disease in chronic hepatitis B patients (CHB) with/without cirrhosis in clinical practice. A total of 355 treatment-naive CHB patients were enrolled into the study. The primary outcome measure was viral suppression as defined by serum HBV DNA level <20 IU/mL. A secondary outcome measure was to determine the development of Hepatocellular carcinoma (HCC). Virological and biochemical responses were similar between the two treatment groups over time. The presence of cirrhosis and hepatitis B e antigen (HBeAg) positivity did not appear to impact viral suppression. The cumulative probability of HBeAg loss was 41% at 4 years of therapy. Hepatitis B surface antigen (HBsAg) loss occurred in four patients. Model for End-Stage Liver Disease score was significantly improved from baseline to week 48 and 96 under antiviral therapy (P = 0.013, P = 0.01). HCC was diagnosed in 17 patients (4.8%). The cumulative probability of the development of HCC was 3.3% at 1 year and 7.3% at 4 years of therapy. The development of HCC was independently associated with older age (P = 0.031) and the presence of cirrhosis (P = 0.004). Serum creatinine levels and creatinine clearance remained stable over time. ETV and TDF effectively maintained virological and biochemical responses in long-term follow-up of CHB patients with/without cirrhosis. HCC may still develop, although at a lower rate, and is more likely to develop in patients with cirrhosis, especially in older patients. PMID- 25431109 TI - Evaluation of carotenoids and reactive oxygen species in human skin after UV irradiation: a critical comparison between in vivo and ex vivo investigations. AB - UV irradiation is one of the most harmful exogenous factors for the human skin. In addition to the development of erythema, free radicals, that is reactive oxygen species (ROS), are induced under its influence and promote the development of oxidative stress in the skin. Several techniques are available for determining the effect of UV irradiation. Resonance Raman spectroscopy (RRS) measures the reduction of the carotenoid concentration, while electron paramagnetic resonance (EPR) spectroscopy enables the analysis of the production of free radicals. Depending on the method, the skin parameters are analysed in vivo or ex vivo. This study provides a critical comparison between in vivo and ex vivo investigations on the ROS formation and carotenoid depletion caused by UV irradiation in human skin. The oxygen content of tissue was also determined. It was shown that the antioxidant status measured in the skin samples in vivo and ex vivo was different. The depletion in the carotenoid concentration in vivo exceeded the value determined ex vivo by a factor of about 1.5, and the radical formation after UV irradiation was significantly greater in vivo by a factor of 3.5 than that measured in excised human skin, which can be explained by the lack of oxygen ex vivo. PMID- 25431110 TI - Influence of processing procedure on the quality of Radix Scrophulariae: a quantitative evaluation of the main compounds obtained by accelerated solvent extraction and high-performance liquid chromatography. AB - An improved high-performance liquid chromatography with diode array detection combined with accelerated solvent extraction method was used to simultaneously determine six compounds in crude and processed Radix Scrophulariae samples. Accelerated solvent extraction parameters such as extraction solvent, temperature, number of cycles, and analysis procedure were systematically optimized. The results indicated that compared with crude Radix Scrophulariae samples, the processed samples had lower contents of harpagide and harpagoside but higher contents of catalpol, acteoside, angoroside C, and cinnamic acid. The established method was sufficiently rapid and reliable for the global quality evaluation of crude and processed herbal medicines. PMID- 25431111 TI - Inadequate record keeping by dental practitioners. AB - BACKGROUND: When a dental practitioner is brought before a disciplinary body, a common finding is that dental records were poorly kept and inadequate to establish issues of consent for treatment or the nature of the treatment undertaken. Often this finding may be incidental to the actual issue that brought the practitioner before a regulatory body or the Courts. The aim of this study was to examine recent cases reported in the State of Victoria involving dental practitioners, specifically seeking those cases where the record keeping was found to be inadequate as an incidental finding. METHODS: Published rulings of formal complaints and notification cases brought before disciplinary hearings in the State of Victoria for the period January 2000 to June 2014 were analysed with regards to orders made in respect to record keeping. RESULTS: Complaints and notifications specific to dental record keeping accounted for less than 2% of formal complaints. And yet up to 75% of cases have made a finding of unprofessional conduct against a dental practitioner on the basis of inadequate record keeping, most often in combination with other breaches of conduct. CONCLUSIONS: Adherence to the traditional format of handwriting or typing entries into patient records may contribute to the problem of poor record keeping in a clinical dental setting. Newer technologies such as digital intraoral and extraoral photography and audio-recording of patient interactions may offer a solution to the problems of record keeping. PMID- 25431112 TI - Effect of T3 hormone on neural differentiation of human adipose derived stem cells. AB - Human adult stem cells, which are capable of self-renewal and differentiation into other cell types, can be isolated from various tissues. There are no ethical and rejection problems as in the case of embryonic stem cells, so they are a promising source for cell therapy. The human body contains a great amount of adipose tissue that contains high numbers of mesenchymal stem cells. Human adipose-derived stem cells (hADSCs) could be easily induced to form neuron-like cells, and because of its availability and abundance, we can use it for clinical cell therapy. On the other hand, T3 hormone as a known neurotropic factor has important impressions on the nervous system. The aim of this study was to explore the effects of T3 treatment on neural differentiation of hADSCs. ADSCs were harvested from human adipose tissue, after neurosphere formation, and during final differentiation, treatment with T3 was performed. Immunocytochemistry, real time RT-PCR, Western blotting techniques were used for detection of nestin, MAP2, and GFAP markers in order to confirm the effects of T3 on neural differentiation of hADSCs. Our results showed an increase in the number of glial cells but reduction in neuronal cells number fallowing T3 treatment. PMID- 25431113 TI - Potential biomarkers for oral squamous cell carcinoma: proteomics discovery and clinical validation. AB - Oral squamous cell carcinoma (OSCC) is the worldwide concerned cancer. In spite of the advances in treatment, the 5-year survival rate has only increased subtly during the past two decades, which is largely due to the advanced stages of disease at diagnosis and the frequent development of relapse and second primary tumors. Therefore, the identification of underlying OSCC protein biomarker during cancer initiation and progression could aid the diagnosis and treatment of OSCC. In this review, recent researches on proteomics analysis of tissue, saliva, and serum for early detection and evaluation aggressiveness and occurrence of OSCC were summarized. The emphasis is placed on early detection by tissues, saliva, and serum of patients with histologically defined OSCC patients. Although lots of researches for searching OSCC protein biomarker have done, few common protein biomarkers have been detected. Low-redundant protein in tissues, saliva, and serum from OSCC may more accurately reflected the progression of OSCC, so novel approach for the depth research strategy and the sample choice for proteomics are of importance in OSCC biomarker discovery. PMID- 25431114 TI - A DNA segment spanning the mouse Tnfsf11 transcription unit and its upstream regulatory domain rescues the pleiotropic biologic phenotype of the RANKL null mouse. AB - Receptor activator of NF-kappaB ligand (RANKL) is a TNFalpha-like cytokine that is produced by a diverse set of lineage-specific cells and is involved in a wide variety of physiological processes that include skeletal remodeling, lymph node organogenesis, mammary gland development, and thermal regulation. Consistent with these diverse functions, control of RANKL expression is accomplished in a cell specific fashion via a set of at least 10 regulatory enhancers that are located up to 170 kb upstream of the gene's transcriptional start site. Here we examined the in vivo consequence of introducing a contiguous DNA segment containing these components into a genetically deleted RANKL null mouse strain. In contrast to RANKL null littermates, null mice containing the transgene exhibited normalized body size, skeletal development, and bone mass as well as normal bone marrow cavities, normalized spleen weights, and the presence of developed lymph nodes. These mice also manifested normalized reproductive capacity, including the ability to lactate and to produce normal healthy litters. Consistent with this, the transgene restored endogenous-like RANKL transcript levels in several RANKL expressing tissues. Most importantly, restoration of RANKL expression from this segment of DNA was fully capable of rescuing the complex aberrant skeletal and immune phenotype of the RANKL null mouse. RANKL also restored appropriate levels of B220+ IgM+ and B220+ IgD+ B cells in spleen. Finally, we found that RANKL expression from this transgene was regulated by exogenously administered 1,25(OH)2 D3 , parathyroid hormone (PTH), and lipopolysaccharide (LPS), thus recapitulating the ability of these same factors to regulate the endogenous gene. These findings fully highlight the properties of the Tnfsf11 gene locus predicted through previous in vitro dissection. We conclude that the mouse Tnfsf11 gene locus identified originally through unbiased chromatin immunoprecipitation with DNA microarray (ChIP-chip) analysis contains the necessary genetic information to direct appropriate tissue-specific and factor-regulated RANKL expression in vivo. PMID- 25431116 TI - Detection of otoacoustic emissions in chinchilla when the middle ear contains amniotic fluid. AB - OBJECTIVES/HYPOTHESIS: Otoacoustic emissions have frequently been used for newborn hearing screening. However, they have low specificities and high referral rates. The presence of amniotic fluid in the middle ear is one reason for these problems. The aim of this study was to determine the effects of human amniotic fluid on otoacoustic emissions and on middle-ear function. METHODS: Forty-six chinchillas were randomly divided into eight groups based on the type (amniotic fluid or normal saline) and volume (0.5, 1, 1.5, 2 ml) of liquid introduced into the middle ear. Distortion product otoacoustic emission (DPOAE) and wideband reflectance (WBR) measurements were taken under inhalational anaesthesia before and after introduction of middle-ear liquid. The differences in these measurements were subjected to statistical analyses. STUDY DESIGN: Prospective controlled animal study. RESULTS: Significant reductions of DPOAE levels and increases in WBR occurred across all frequencies when there was liquid in the middle ear, and the changes became greater for increased volumes of liquid. Changes in the noise level had important effects on the otoacoustic-emission signal-to-noise ratio at the three lowest frequencies. CONCLUSION: Both human amniotic fluid and saline in the chinchilla middle ear resulted in changes in otoacoustic-emission detection patterns and WBR that may be relevant to newborn hearing screening. PMID- 25431115 TI - Highly pathogenic avian influenza virus infection in chickens but not ducks is associated with elevated host immune and pro-inflammatory responses. AB - Highly pathogenic avian influenza (HPAI) H5N1 viruses cause severe infection in chickens at near complete mortality, but corresponding infection in ducks is typically mild or asymptomatic. To understand the underlying molecular differences in host response, primary chicken and duck lung cells, infected with two HPAI H5N1 viruses and a low pathogenicity avian influenza (LPAI) H2N3 virus, were subjected to RNA expression profiling. Chicken cells but not duck cells showed highly elevated immune and pro-inflammatory responses following HPAI virus infection. HPAI H5N1 virus challenge studies in chickens and ducks corroborated the in vitro findings. To try to determine the underlying mechanisms, we investigated the role of signal transducer and activator of transcription-3 (STAT 3) in mediating pro-inflammatory response to HPAIV infection in chicken and duck cells. We found that STAT-3 expression was down-regulated in chickens but was up regulated or unaffected in ducks in vitro and in vivo following H5N1 virus infection. Low basal STAT-3 expression in chicken cells was completely inhibited by H5N1 virus infection. By contrast, constitutively active STAT-3 detected in duck cells was unaffected by H5N1 virus infection. Transient constitutively active STAT-3 transfection in chicken cells significantly reduced pro inflammatory response to H5N1 virus infection; on the other hand, chemical inhibition of STAT-3 activation in duck cells increased pro-inflammatory gene expression following H5N1 virus infection. Collectively, we propose that elevated pro-inflammatory response in chickens is a major pathogenicity factor of HPAI H5N1 virus infection, mediated in part by the inhibition of STAT-3. PMID- 25431117 TI - Formative evaluation of a multimedia self-administered computerized hearing loss prevention program. AB - OBJECTIVE: To determine which features make a computer-based hearing health education intervention effective, easy to use, and enjoyable. The study examined which features of a multimedia self-administered computerized hearing loss prevention program, developed by the National Center for Rehabilitative Auditory Research (referred to as the NCRAR-HLPP), users liked and disliked, and the reasons why. DESIGN: A formative evaluation was conducted in which participants completed a questionnaire to assess knowledge and attitudes towards hearing and hearing loss prevention, used the NCRAR-HLPP, completed the questionnaire for a second time, and were interviewed to learn their opinions about the NCRAR-HLPP. STUDY SAMPLE: Twenty-five male and four female Veterans recruited from the Portland VA Medical Center who were aged between 25 and 65 years. RESULTS: Participants reported that using the NCRAR-HLPP was a positive experience. Ease of use, multimedia content, personal relevance, and use of emotion were positive features of the program. The questionnaire showed increased knowledge and improved attitude scores following use of the program. CONCLUSION: This formative evaluation showed changes designed to target user preferences and improve user instructions will be made in future versions of the program. PMID- 25431118 TI - Combining organometallic reagents, the sulfur dioxide surrogate DABSO, and amines: a one-pot preparation of sulfonamides, amenable to array synthesis. AB - We describe a method for the synthesis of sulfonamides through the combination of an organometallic reagent, a sulfur dioxide equivalent, and an aqueous solution of an amine under oxidative conditions (bleach). This simple reaction protocol avoids the need to employ sulfonyl chloride substrates, thus removing the limitation imposed by the commercial availability of these reagents. The resultant method allows access to new chemical space, and is also tolerant of the polar functional groups needed to impart favorable physiochemical properties required for medicinal chemistry and agrochemistry. The developed chemistry is employed in the synthesis of a targeted 70 compound array, prepared using automated methods. The array achieved a 93% success rate for compounds prepared. Calculated molecular weights, lipophilicities, and polar surface areas are presented, demonstrating the utility of the method for delivering sulfonamides with drug-like properties. PMID- 25431119 TI - Direct analysis of mAb aggregates in mammalian cell culture supernatant. AB - BACKGROUND: Protein aggregation during monoclonal antibody (mAb) production can occur in upstream and downstream processing (DSP). Current methods to determine aggregate formation during cell culture include size exclusion chromatography (SEC) with a previous affinity chromatography step in order to remove disturbing cell culture components. The pre-purification step itself can already influence protein aggregation and therefore does not necessarily reflect the real aggregate content present in cell culture. To analyze mAb aggregate formation directly in the supernatant of Chinese hamster ovary (CHO) cell culture, we established a protocol, which allows aggregate quantification using SEC, without a falsifying pre-purification step. RESULTS: The use of a 3 MUm silica SEC column or a SEC column tailored for mAb aggregate analysis allows the separation of mAb monomer and aggregates from disturbing cell culture components, which enables aggregate determination directly in the supernatant. Antibody aggregate analysis of a mAb producing CHO DG44 cell line demonstrated the feasibility of the method. Astonishingly, the supernatant of the CHO cells consisted of over 75% mAb dimer and larger oligomers, representing a substantially higher aggregate content than reported in literature so far. CONCLUSION: This study highlights that aggregate quantification directly in the cell culture supernatant using appropriate SEC columns with suitable mAb aggregate standards is feasible without falsification by previous affinity chromatography. Moreover, our results indicate that aggregate formation should be addressed directly in the cell culture and is not only a problem in DSP. PMID- 25431120 TI - Does job insecurity deteriorate health? AB - This paper estimates the causal effect of perceived job insecurity - that is, the fear of involuntary job loss - on health in a sample of men from 22 European countries. We rely on an original instrumental variable approach on the basis of the idea that workers perceive greater job security in countries where employment is strongly protected by the law and more so if employed in industries where employment protection legislation is more binding; that is, in induastries with a higher natural rate of dismissals. Using cross-country data from the 2010 European Working Conditions Survey, we show that, when the potential endogeneity of job insecurity is not accounted for, the latter appears to deteriorate almost all health outcomes. When tackling the endogeneity issue by estimating an instrumental variable model and dealing with potential weak-instrument issues, the health-damaging effect of job insecurity is confirmed for a limited subgroup of health outcomes; namely, suffering from headaches or eyestrain and skin problems. As for other health variables, the impact of job insecurity appears to be insignificant at conventional levels. PMID- 25431121 TI - Development and validation of liquid chromatography combined with tandem mass spectrometry methods for the quantitation of simalikalactone E in extracts of Quassia amara L. and in mouse blood. AB - INTRODUCTION: Simalikalactone E (SkE) from Quassia amara, has been proved to be a valuable anti-malarial and anti-cancer compound. As SkE is very scarce, methods of quantitation are needed in order to optimise its isolation process and to determine pharmacokinetic data. OBJECTIVE: To validate methods using liquid chromatography coupled to mass spectrometry for the quantitation of SkE in plant extracts and in biological fluids. METHODS: High- and ultrahigh-performance liquid chromatography (UHPLC) coupled to ion trap mass spectrometry (MS) with single ion monitoring detection and to triple quadrupole-linear ion trap tandem mass spectrometry with multiple reaction monitoring detection methods were developed. Validation procedure was realised according to the International Conference on Harmonisation guideline. Methanol extracts of dried Quassia amara leaves, and mouse-blood samples obtained after various routes of administration, were analysed for SkE. RESULTS: Methods were validated and gave similar results regarding the content of SkE expressed per kilogram of dry leaves in the traditional decoction (160 +/- 12 mg/kg) and in the methanol extract (93 +/- 2 mg/kg). The recovery of the analyte from mouse blood ranged from 80.7 to 119.8%. Simalikalactone E was only detected using UHPLC-MS/MS (0.2 +/- 0.03 mg/L) in mouse blood after intravenous injection: none was detected following intraperitoneal or oral gavage administration of SkE. CONCLUSION: The LC-MS methods were used for the quantitation of SkE in plant extracts and in mouse blood. These methods open the way for further protocol optimisation of SkE extraction and the determination of its pharmacokinetic data. PMID- 25431122 TI - Anti-inflammatory and antioxidant properties of unripe papaya extract in an excision wound model. AB - CONTEXT: Carica papaya L. (Caricaceae) fruit was shown to exhibit wound healing properties. OBJECTIVES: We investigated anti-inflammatory and antioxidant potential of papaya fruit phosphate-buffered saline extract (PE) during wound healing and enhancement of the potentials due to trace ions addition. MATERIALS AND METHODS: Rat excision wounds were topically treated twice/day with 20 uL of PE (5 mg extract/mL), 0.5 ug Se(2+) added PE (PES), or 100 uM Zn(2+) added PE (PEZ). Control groups were treated with deionized water (negative) and deproteinized calf blood extract ointment (Solcoseryl(r), positive). Lipid peroxidation (LPX), antioxidant, proinflammatory, and arginine metabolic enzymes were estimated in the wound excised on days 4 and 10 post wounding. RESULTS: PE (5 mg/mL; 9.80 +/- 0.33 d) and PES (PE + 0.5 ug Se(2+); 8.90 +/- 0.23 d) significantly (p < 0.05) reduced the average time for complete wound closure compared with the negative (13.00 +/- 0.37 d) and positive (9.80 +/- 0.33 d) controls, respectively. Biochemical evaluations of LPX product (malondialdehyde), antioxidant (catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx)), and pro-inflammatory (cyclooxygenase-2 and myeloperoxidase (MPO)) enzyme activities and metabolites (nitrite and urea), on days 4 and 10 post wounding, confirmed the anti-inflammatory and antioxidant properties of PE and PES in this study. DISCUSSION AND CONCLUSION: Treatment of excision wounds with papaya extract, especially with the addition of selenium for 10 d, reduced inflammation associated oxidative damage apparently via cyclooxygenase specific inhibition, arginine metabolism, and up-regulation of antioxidant enzymes. PMID- 25431123 TI - Synthesis, characterization, and electrochemistry of the manganese(I) complexes of meso-substituted [14]tribenzotriphyrins(2.1.1). AB - Metalation of 6,13,20,21-tetraaryl-22H-[14]tribenzotriphyrins(2.1.1) (TriP, 1 a d) with [Mn(CO)5 Br] provided Mn(I) tricarbonyl complexes of [14]tribenzotriphyrins(2.1.1) 2 a-d in 85-93 % yield. The complexes were characterized by mass spectrometry and UV/Vis absorption, IR, and NMR spectroscopy. Single-crystal X-ray analyses revealed that 2 b and 2 c adopt bowl shaped conformations. The redox properties of [(TriP)Mn(I) (CO)3 ] (2 a-d) were studied by cyclic voltammetry. Each compound undergoes two reversible one electron reductions to form a porphyrin pi anion radical and a dianion in CH2 Cl2 . Two oxidation waves were observed, the first of which corresponds to a metal centered electron-transfer process. The redox potentials of 2 a-d are consistent with the optical spectroscopic data and the relatively narrow HOMO-LUMO gaps that were predicted in DFT calculations. The optical spectra can be assigned by using Michl's perimeter model. TDDFT calculations predict the presence of several metal to-ligand charge-transfer bands in the L-band region between 500 and 700 nm. PMID- 25431124 TI - Effect of a Probiotic Containing Bacillus licheniformis and Bacillus subtilis and Ferroin Solution on Growth Performance, Body Composition and Haematological Parameters in Kutum (Rutilus frisii kutum) Fry. AB - This study aimed to assess the efficacy of BioPlus 2B, a probiotic containing Bacillus licheniformis and B. subtilis and Ferroin solution on growth performance, body composition and haematological parameters in kutum, Rutilus frisii kutum, fry. The fish were fed dry pellets containing various ratios of probiotics and Ferroin for 60 days after absorption of the yolk sac. At the end of the trial, growth indices (final weight, weight gain, specific growth rate, daily growth rate, food conversion ratio and condition factor), body composition (crude protein, crude lipid, ash and moisture) and haematological parameters [haematocrit (Hct), haemoglobin (Hb), red blood cells (RBC), white blood cells (WBC), neutrophils (NEUTR), lymphocytes (LYM), mean cell volume (MCV), mean cell haemoglobin (MCH) and mean cell haemoglobin concentration (MCHC)] were assessed. Regarding body composition, total protein levels were higher, and ash, moisture and lipid levels were lower in fish receiving the probiotic and Ferroin treatments compared with the control group (P < 0.05). Fish receiving diets supplemented with probiotics and Ferroin solution showed significantly better growth than those fed the basal diet (control). RBC, Hct, Hb, MCV, MCH and LYM were all highest in fish fed probiotic (1.6 * 10(9) CFU/g dry pellet) + Ferroin solution (7 mg/kg dry pellet) + dry pellets. These results indicate that the combination of probiotic and Ferroin solution represents an effective dietary supplement for improving carcass quality, growth performance and haematological parameters in kutum fry. PMID- 25431125 TI - Transcriptome analysis during berry development provides insights into co regulated and altered gene expression between a seeded wine grape variety and its seedless somatic variant. AB - BACKGROUND: Seedless grapes are greatly appreciated for fresh and dry fruit consumption. Parthenocarpy and stenospermocarpy have been described as the main phenomena responsible for seedlessness in Vitis vinifera. However, the key genes underpinning molecular and cellular processes that play a significant role in seed development are not well characterized. To identify important regulators and mechanisms that may be altered in the seedless phenotype, we performed a comprehensive transcriptional analysis to compare the transcriptomes of a popular seeded wine cultivar (wild-type) and its seedless somatic variant (mutant) at three key developmental stages. RESULTS: The transcriptomes revealed by Illumina mRNA-Seq technology had approximately 98% of grapevine annotated transcripts and about 80% of them were commonly expressed in the two lines. Differential gene expression analysis revealed a total of 1075 differentially expressed genes (DE) in the pairwise comparison of developmental stages, which included DE genes specific to the wild-type background, DE genes specific to the mutant background and DE genes commonly shared in both backgrounds. The analysis of differential expression patterns and functional category enrichment of wild-type and mutant DE genes highlighted significant coordination and enrichment of pollen and ovule developmental pathways. The expression of some selected DE genes was further confirmed by real-time RT-PCR analysis. CONCLUSIONS: This study represents the most comprehensive attempt to characterize the genetic bases of seed formation in grapevine. With a high throughput method, we have shown that a seeded wine grape and its seedless somatic variant are similar in several biological processes. Nevertheless, we could identify an inventory of genes with altered expression in the mutant compared to the wild-type, which may be responsible for the seedless phenotype. The genes located within known genomic regions regulating seed content may be used for the development of molecular tools to assist table grape breeding. Therefore the data reported here have provided a rich genomic resource for practical use and functional characterization of the genes that potentially underpin seedlessness in grapevine. PMID- 25431126 TI - [Deep brain stimulation using simultaneous stereotactic electrode placement: an alternative to conventional functional stereotaxy?]. AB - BACKGROUND: Deep brain stimulation (DBS) has become a reliable method in the treatment of movement disorders, e.g. idiopathic Parkinson's disease (IPD) and is technically based on stereotaxy. The Starfix(r) platform is a new type of stereotactic frame that allows an individualized and patient-optimized therapeutic regimen in IPD. OBJECTIVES: The aim of this study was to retrospectively compare the outcomes of IPD patients who underwent surgery with the use of conventional stereotactic frames (31 patients) to those who underwent implantation of DBS with the use of Starfix(r) frames (29 patients). MATERIAL AND METHODS: Surgery time, the unified Parkinson's disease rating scale III (UPDRS/III) score, L-dopa and L-dopa equivalent doses (LED) were compared prior to surgery as well as 4 weeks, 12 weeks, 6 months and 1 year postoperatively. RESULTS: The IPD-related symptoms improved significantly in both groups with respect to the UPDRS III score (conventional 69.6% vs. 72.4% Starfix(r)). After surgery significant reductions of L-dopa and LED were seen in both groups. Inherent advantages of the Starfix(r) platform included simultaneous positioning of the stimulating electrodes and a significant reduction in surgical time. CONCLUSION: In summary, both stereotactic procedures are reliable and safe procedures for the placement of stimulating electrodes as well as the stimulation effect achieved. The logistical uncoupling of presurgical planning from surgical therapy emphasizes the benefits of the individualized stereotactic procedure. PMID- 25431127 TI - A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer. AB - INTRODUCTION: Diets high in cruciferous vegetables are associated with lower risk of incidence of prostate cancer, including aggressive forms of this disease. Human intervention studies with cruciferous vegetable-rich diets also demonstrate modulation of gene expression in important pathways in prostate cells. PURPOSE: Sulforaphane is a constituent of these foods postulated to harbor the anti neoplastic activity based on multiple tumor models. Our own work demonstrates that sulforaphane inhibits AR signaling in prostate cancer cells. Here, we report results from the first clinical trial of sulforaphane-rich extracts in men with prostate cancer. METHODS: We treated 20 patients who had recurrent prostate cancer with 200 MUmoles/day of sulforaphane-rich extracts for a maximum period of 20 weeks and determined the proportion of patients with >=50% PSA declines, the primary endpoint. Only one subject experienced a >=50% PSA decline. Thus, the primary endpoint was not achieved. Seven patients experienced smaller PSA declines (<50%). There was also a significant lengthening of the on-treatment PSA doubling time (PSADT) compared with the pre-treatment PSADT [6.1 months pre treatment vs. 9.6 months on-treatment (p = 0.044)]. Finally, treatment with sulforaphane-rich extracts was safe with no Grade 3 adverse events. CONCLUSIONS: Treatment with 200 MUmoles/day of sulforaphane-rich extracts did not lead to >=50% PSA declines in the majority of patients. However, because of the safety of treatment and the effects on PSADT modulation, further studies, including those with higher doses, may be warranted to clarify the role of sulforaphane as a prevention agent or treatment agent. PMID- 25431128 TI - Consistency in Administration and Response for the Backward Push and Release Test: A Clinical Assessment of Postural Responses. AB - BACKGROUND AND PURPOSE: The backward push and release test (PRT) is a standardized clinical test of postural responses elicited by perturbations. Our goal was to determine reliability of administration and response. This will inform clinical administration and determine whether to develop an instrumented version. METHODS: One examiner administered 10 backward PRT trials to adults with Parkinson disease (12), multiple sclerosis (14) and controls (12). We used three dimensional motion analysis, force plates and instrumented gloves to measure administration and response. Administration variables were angle of posterior trunk lean and the distance of the centre of mass (CoM) behind the ankle. Postural response variables were latency of postural response from release to step initiation and first compensatory step length. Reliability was measured using the range of variables across trials, comparison of first and later trials, intraclass correlations (ICCs) to measure consistency and correlations between administration and response. RESULTS: There was inherent variability in administration, which affected postural response characteristics. Larger trunk angle and greater CoM-ankle distance were correlated with shorter postural response latencies and larger step lengths. Participant height also had an effect; taller participants had larger trunk angles prior to release resulting in longer latencies and larger step lengths. Using ICCs, consistency of trunk angle was likely acceptable and CoM-ankle distance was high. Consistency of latency was low, while step length was likely acceptable. DISCUSSION: Despite variability in administration and inconsistency in response, different postural response characteristics were detected between patients with different disease states. Based on these results, we will create algorithms to instrument the PRT using inertial movement sensors to collect more sensitive measures of postural responses than observational clinical rating scales. Feedback for appropriate lean angle and calibration for participant height will improve consistency and usefulness of the instrumented PRT. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25431129 TI - Influence of shoulder pain on muscle function: implications for the assessment and therapy of shoulder disorders. AB - Shoulder pain is often a challenging clinical phenomenon because of the potential mismatch between pathology and the perception of pain. Current evidence clearly emphasizes an incomplete understanding of the nature of shoulder pain. Indeed, the effective diagnosis and treatment of shoulder pain should not only rely upon a detailed knowledge of the peripheral pathologies that may be present in the shoulder, but also on current knowledge of pain neurophysiology. To assess and treat shoulder pain, a comprehensive understanding of the way in which pain is processed is essential. This review reflects modern pain neurophysiology to the shoulder and aims to answer the following questions: why does my shoulder hurt? What is the impact of shoulder pain on muscle function? What are the implications for the clinical examination of the shoulder? And finally, what are the clinical implications for therapy? Despite the increasing amount of research in this area, an in-depth understanding of the bidirectional nociception-motor interaction is still far from being achieved. Many questions remain, especially related to the treatment of nociception-motor interactions. PMID- 25431130 TI - Pivoting neuromuscular control and proprioception in females and males. AB - PURPOSE: Noncontact ACL injuries occur most commonly in pivoting sports and are much more frequent in females than in males. However, information on sex differences in proprioceptive acuity under weight-bearing and leg neuromuscular control in pivoting is scarce. The objective of this study was to investigate sex differences in pivoting neuromuscular control during strenuous stepping tasks and proprioceptive acuity under weight-bearing. METHODS: 21 male and 22 female subjects were recruited to evaluate pivoting proprioceptive acuity under weight bearing, and pivoting neuromuscular control (in terms of leg pivoting instability, stiffness, maximum internal and external pivoting angles, and entropy of time-to-peak EMG in lower limb muscles) during strenuous stepping tasks performed on a novel offaxis elliptical trainer. RESULTS: Compared to males, females had significantly lower proprioceptive acuity under weight-bearing in both internal and external pivoting directions, higher pivoting instability, larger maximum internal pivoting angle, lower leg pivoting stiffness, and higher entropy of time-to-peak EMG in the gastrocnemius muscles during strenuous stepping tasks with internal and external pivoting perturbations. CONCLUSIONS: Results of this study may help us better understand factors contributing to ACL injuries in females and males, develop training strategies to improve pivoting neuromuscular control and proprioceptive acuity, and potentially reduce ACL and lower-limb musculoskeletal injuries. PMID- 25431131 TI - In vitro anti-aging activities of extracts from leaves of Ma Kiang (Cleistocalyx nervosum var. paniala). AB - CONTEXT: Cleistocalyx nervosum (DC.) Kosterm. var. paniala (Roxb.) J. Parn. & Chantaran. (Myrtaceae) or Ma Kiang contains high amounts of phenolic compounds. Antioxidant activity of its fruit and seed has been investigated. However, limited available information concerning the biological activities of its leaves has been reported. OBJECTIVE: To investigate the in vitro anti-aging potential of young and old leaves of Ma Kiang. MATERIALS AND METHODS: Ma Kiang leaves were extracted using water, methanol, and chloroform as the solvents by cold (sonication) and hot (boiling) processes. The extracts were determined for total phenolic and flavonoid contents. The extracts (at 0.001-10 mg/ml) were tested for antioxidative and tyrosinase inhibition activities using a colorimetric method. The cytotoxicity of extracts (at 0.0001-1 mg/ml) was determined with human skin fibroblasts. Also, the extracts at 0.001, 0.01, and 0.1 mg/ml which showed no toxicity were tested for MMP-2 inhibition. RESULTS: The cold methanol extract of the old leaves showed the highest total phenolic and flavonoid contents of 511.44 +/- 18.23 MUg GAE/mg and 262.96 +/- 2.98 MUg QE/mg, respectively. This extract also gave high free radical scavenging, lipid peroxidation inhibition, and tyrosinase inhibition activities with SC50, IPC50, and IC50 values of 0.02 +/- 0.004, 0.23 +/- 0.13, and 0.02 +/- 0.006 mg/ml, respectively. The extract at 0.1 mg/ml exhibited the highest MMP-2 inhibition of 91.14 +/- 1.67%. DISCUSSION AND CONCLUSION: The anti-aging potential of the cold methanol extract from old leaves of Ma Kiang can be further developed as an anti-aging agent. PMID- 25431132 TI - Exercise for vasomotor menopausal symptoms. AB - BACKGROUND: Evidence suggests that many perimenopausal and early postmenopausal women will experience menopausal symptoms; hot flushes are the most common. Symptoms caused by fluctuating levels of oestrogen may be alleviated by hormone therapy (HT), but a marked global decline in its use has resulted from concerns about the risks and benefits of HT. Consequently, many women are seeking alternatives. As large numbers of women are choosing not to take HT, it is increasingly important to identify evidence-based lifestyle modifications that have the potential to reduce vasomotor menopausal symptoms. OBJECTIVES: To examine the effectiveness of any type of exercise intervention in the management of vasomotor symptoms in symptomatic perimenopausal and postmenopausal women. SEARCH METHODS: Searches of the following electronic bibliographic databases were performed to identify randomised controlled trials (RCTs): Cochrane Menstrual Disorders and Subfertility Group Specialised Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley Internet interface), MEDLINE (Ovid), EMBASE (Ovid), PsycINFO (Ovid), the Science Citation Index and the Social Science Citation Index (Web of Science), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (Ovid) and SPORTDiscus. Searches include findings up to 3 March 2014. SELECTION CRITERIA: RCTs in which any type of exercise intervention was compared with no treatment/control or other treatments in the management of menopausal vasomotor symptoms in symptomatic perimenopausal/postmenopausal women. DATA COLLECTION AND ANALYSIS: Five studies were deemed eligible for inclusion. Two review authors independently selected the studies, and three review authors independently extracted the data. The primary review outcome was vasomotor symptoms, defined as hot flushes and/or night sweats. We combined data to calculate standardised mean differences (SMDs) with 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I(2) statistic. We assessed the overall quality of the evidence for main comparisons using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) methods. MAIN RESULTS: We included five RCTs (733 women) comparing exercise with no active treatment, exercise with yoga and exercise with HT. The evidence was of low quality: Limitations in study design were noted, along with inconsistency and imprecision. In the comparison of exercise versus no active treatment (three studies, n = 454 women), no evidence was found of a difference between groups in frequency or intensity of vasomotor symptoms (SMD -0.10, 95% CI -0.33 to 0.13, three RCTs, 454 women, I(2) = 30%, low-quality evidence). Nor was any evidence found of a difference between groups in the frequency or intensity of vasomotor symptoms when exercise was compared with yoga (SMD -0.03, 95% CI 0.45 to 0.38, two studies, n = 279 women, I(2) = 61%, low-quality evidence). It was not possible to include one of the trials in the meta-analyses; this trial compared three groups: exercise plus soy milk, soy milk only and control; results favoured exercise relative to the comparators, but study numbers were small. One trial compared exercise with HT, and the HT group reported significantly fewer flushes in 24 hours than the exercise group (mean difference 5.8, 95% CI 3.17 to 8.43, 14 participants). None of the trials found evidence of a difference between groups with respect to adverse effects, but data were very scanty. AUTHORS' CONCLUSIONS: Evidence was insufficient to show whether exercise is an effective treatment for vasomotor menopausal symptoms. One small study suggested that HT is more effective than exercise. Evidence was insufficient to show the relative effectiveness of exercise when compared with HT or yoga. PMID- 25431133 TI - Comparison of blood gas, electrolyte and metabolite results measured with two different blood gas analyzers and a core laboratory analyzer. AB - BACKGROUND: Blood gas analyzers (BGAs) are important in assessing and monitoring critically ill patients. However, the random use of BGAs to measure blood gases, electrolytes and metabolites increases the variability in test results. Therefore, this study aimed to investigate the correlation of blood gas, electrolyte and metabolite results measured with two BGAs and a core laboratory analyzer. METHODS: A total of 40 arterial blood gas samples were analyzed with two BGAs [(Nova Stat Profile Critical Care Xpress (Nova Biomedical, Waltham, MA, USA) and Siemens Rapidlab 1265 (Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA)) and a core laboratory analyzer [Olympus AU 2700 autoanalyzer (Beckman Coulter, Inc., Fullerton, CA, USA)]. The results of pH, pCO2, pO2, SO2, sodium (Na+), potassium (K+), calcium (Ca+2), chloride (Cl-), glucose, and lactate were compared by Passing-Bablok regression analysis and Bland-Altman plots. RESULTS: The present study showed that there was negligible variability of blood gases (pCO2, pO2, SO2), K+ and lactate values between the blood gas and core laboratory analyzers. However, the differences in pH were modest, while Na+, Cl-, Ca2+ and glucose showed poor correlation according to the concordance correlation coefficient. CONCLUSIONS: BGAs and core laboratory autoanalyzer demonstrated variable performances and not all tests met minimum performance goals. It is important that clinicians and laboratories are aware of the limitations of their assays. PMID- 25431134 TI - Sustained signalling by PTH modulates IP3 accumulation and IP3 receptors through cyclic AMP junctions. AB - Parathyroid hormone (PTH) stimulates adenylyl cyclase through type 1 PTH receptors (PTH1R) and potentiates the Ca(2+) signals evoked by carbachol, which stimulates formation of inositol 1,4,5-trisphosphate (IP3). We confirmed that in HEK cells expressing PTH1R, acute stimulation with PTH(1-34) potentiated carbachol-evoked Ca(2+) release. This was mediated by locally delivered cyclic AMP (cAMP), but unaffected by inhibition of protein kinase A (PKA), exchange proteins activated by cAMP, cAMP phosphodiesterases (PDEs) or substantial inhibition of adenylyl cyclase. Sustained stimulation with PTH(1-34) causes internalization of PTH1R-adenylyl cyclase signalling complexes, but the consequences for delivery of cAMP to IP3R within cAMP signalling junctions are unknown. Here, we show that sustained stimulation with PTH(1-34) or with PTH analogues that do not evoke receptor internalization reduced the potentiated Ca(2+) signals and attenuated carbachol-evoked increases in cytosolic IP3. Similar results were obtained after sustained stimulation with NKH477 to directly activate adenylyl cyclase, or with the membrane-permeant analogue of cAMP, 8-Br cAMP. These responses were independent of PKA and unaffected by substantial inhibition of adenylyl cyclase. During prolonged stimulation with PTH(1-34), hyperactive cAMP signalling junctions, within which cAMP is delivered directly and at saturating concentrations to its targets, mediate sensitization of IP3R and a more slowly developing inhibition of IP3 accumulation. PMID- 25431135 TI - Nuclear FAM21 participates in NF-kappaB-dependent gene regulation in pancreatic cancer cells. AB - The pentameric WASH complex is best known for its role in regulating receptor trafficking from retromer-rich endosomal subdomains. FAM21 functions to stabilize the WASH complex through its N-terminal head domain and localizes it to endosomes by directly binding the retromer through its extended C-terminal tail. Herein, we used affinity purification combined with mass spectrometry to identify additional FAM21-interacting proteins. Surprisingly, multiple components of the nuclear factor kappaB (NF-kappaB) pathway were identified, including the p50 and p65 (RelA) NF-kappaB subunits. We show that FAM21 interacts with these components and regulates NF-kappaB-dependent gene transcription at the level of p65 chromatin binding. We further demonstrate that FAM21 contains a functional monopartite nuclear localization signal sequence (NLS) as well as a CRM1/exportin1-dependent nuclear export signal (NES), both of which work jointly with the N-terminal head domain and C-terminal retromer recruitment domain to regulate FAM21 cytosolic and nuclear subcellular localization. Finally, our findings indicate that FAM21 depletion sensitizes pancreatic cancer cells to gemcitabine and 5-fluorouracil. Thus, FAM21 not only functions as an integral component of the cytoplasmic WASH complex, but also modulates NF-kappaB gene transcription in the nucleus. PMID- 25431136 TI - Selective synaptic targeting of the excitatory and inhibitory presynaptic organizers FGF22 and FGF7. AB - Specific formation of excitatory and inhibitory synapses is crucial for proper functioning of the brain. Fibroblast growth factor 22 (FGF22) and FGF7 are postsynaptic-cell-derived presynaptic organizers necessary for excitatory and inhibitory presynaptic differentiation, respectively, in the hippocampus. For the establishment of specific synaptic networks, these FGFs must localize to appropriate synaptic locations - FGF22 to excitatory and FGF7 to inhibitory postsynaptic sites. Here, we show that distinct motor and adaptor proteins contribute to intracellular microtubule transport of FGF22 and FGF7. Excitatory synaptic targeting of FGF22 requires the motor proteins KIF3A and KIF17 and the adaptor protein SAP102 (also known as DLG3). By contrast, inhibitory synaptic targeting of FGF7 requires the motor KIF5 and the adaptor gephyrin. Time-lapse imaging shows that FGF22 moves with SAP102, whereas FGF7 moves with gephyrin. These results reveal the basis of selective targeting of the excitatory and inhibitory presynaptic organizers that supports their different synaptogenic functions. Finally, we found that knockdown of SAP102 or PSD95 (also known as DLG4), which impairs the differentiation of excitatory synapses, alters FGF7 localization, suggesting that signals from excitatory synapses might regulate inhibitory synapse formation by controlling the distribution of the inhibitory presynaptic organizer. PMID- 25431137 TI - Leiomodin 3 and tropomodulin 4 have overlapping functions during skeletal myofibrillogenesis. AB - Precise regulation of thin filament length is essential for optimal force generation during muscle contraction. The thin filament capping protein tropomodulin (Tmod) contributes to thin filament length uniformity by regulating elongation and depolymerization at thin filament ends. The leiomodins (Lmod1-3) are structurally related to Tmod1-4 and also localize to actin filament pointed ends, but in vitro biochemical studies indicate that Lmods act instead as robust nucleators. Here, we examined the roles of Tmod4 and Lmod3 during Xenopus skeletal myofibrillogenesis. Loss of Tmod4 or Lmod3 resulted in severe disruption of sarcomere assembly and impaired embryonic movement. Remarkably, when Tmod4 deficient embryos were supplemented with additional Lmod3, and Lmod3-deficient embryos were supplemented with additional Tmod4, sarcomere assembly was rescued and embryonic locomotion improved. These results demonstrate for the first time that appropriate levels of both Tmod4 and Lmod3 are required for embryonic myofibrillogenesis and, unexpectedly, both proteins can function redundantly during in vivo skeletal muscle thin filament assembly. Furthermore, these studies demonstrate the value of Xenopus for the analysis of contractile protein function during de novo myofibril assembly. PMID- 25431138 TI - Permian-Triassic Osteichthyes (bony fishes): diversity dynamics and body size evolution. AB - The Permian and Triassic were key time intervals in the history of life on Earth. Both periods are marked by a series of biotic crises including the most catastrophic of such events, the end-Permian mass extinction, which eventually led to a major turnover from typical Palaeozoic faunas and floras to those that are emblematic for the Mesozoic and Cenozoic. Here we review patterns in Permian Triassic bony fishes, a group whose evolutionary dynamics are understudied. Based on data from primary literature, we analyse changes in their taxonomic diversity and body size (as a proxy for trophic position) and explore their response to Permian-Triassic events. Diversity and body size are investigated separately for different groups of Osteichthyes (Dipnoi, Actinistia, 'Palaeopterygii', 'Subholostei', Holostei, Teleosteomorpha), within the marine and freshwater realms and on a global scale (total diversity) as well as across palaeolatitudinal belts. Diversity is also measured for different palaeogeographical provinces. Our results suggest a general trend from low osteichthyan diversity in the Permian to higher levels in the Triassic. Diversity dynamics in the Permian are marked by a decline in freshwater taxa during the Cisuralian. An extinction event during the end-Guadalupian crisis is not evident from our data, but 'palaeopterygians' experienced a significant body size increase across the Guadalupian-Lopingian boundary and these fishes upheld their position as large, top predators from the Late Permian to the Late Triassic. Elevated turnover rates are documented at the Permian-Triassic boundary, and two distinct diversification events are noted in the wake of this biotic crisis, a first one during the Early Triassic (dipnoans, actinistians, 'palaeopterygians', 'subholosteans') and a second one during the Middle Triassic ('subholosteans', neopterygians). The origination of new, small taxa predominantly among these groups during the Middle Triassic event caused a significant reduction in osteichthyan body size. Neopterygii, the clade that encompasses the vast majority of extant fishes, underwent another diversification phase in the Late Triassic. The Triassic radiation of Osteichthyes, predominantly of Actinopterygii, which only occurred after severe extinctions among Chondrichthyes during the Middle Late Permian, resulted in a profound change within global fish communities, from chondrichthyan-rich faunas of the Permo-Carboniferous to typical Mesozoic and Cenozoic associations dominated by actinopterygians. This turnover was not sudden but followed a stepwise pattern, with leaps during extinction events. PMID- 25431139 TI - Is socioeconomic status associated with utilization of health care services in a single-payer universal health care system? AB - OBJECTIVES: To assess an association of Socio-economic status with utilization of health care services between years 2002 and 2008 in Israel. METHODS: We retrospectively analyzed the utilization of health care services in a cohort of 100,000 members, 21 years and older, of a Clalit Health Services. The research compared utilization according to the neighborhood SES status; and clinic's location as another SES proxy. Data included: Charlson Score morbidity factor, utilization of health care services (visits to primary physicians and specialists, purchase of pharmaceuticals, number of hospitalization days, visits to ED, utilization of laboratory tests and imaging). The analysis was performed using Generalized Linear Model (GLM) technique. RESULTS: People with lower SES visited more the ED and primary physicians and were hospitalized for longer periods. People with higher SES visited more specialists, bought more prescription drugs and used more medical imaging. The associations between SES and most of the services we analyzed did not change between 2002 and 2008. However, the gap between lower and higher SES levels in ED visits and the use of prescription drugs slightly increased over time, while the gap in visits to specialists decreased. CONCLUSIONS: The research shows that even in a universal health care system SES is associated with utilization of health care services. In order to improve equity in utilization of services the Israeli public health should reduce economic barriers and in parallel invest in making information accessible to improve "navigation skills" for all. PMID- 25431140 TI - Role of input self-sufficiency in the economic and environmental sustainability of specialised dairy farms. AB - Increasing input self-sufficiency is often viewed as a target to improve sustainability of dairy farms. However, few studies have specifically analysed input self-sufficiency, by including several technical inputs and without only focussing on animal feeding, in order to explore its impact on farm sustainability. To address this gap, our work has three objectives as follows: (1) identifying the structural characteristics required by specialised dairy farms located in the grassland area to be self-sufficient; (2) analysing the relationships between input self-sufficiency, environmental and economic sustainability; and (3) studying how the farms react to a decrease in milk price according to their self-sufficiency degree. Based on farm accounting databases, we categorised 335 Walloon specialised conventional dairy farms into four classes according to their level of input self-sufficiency. To this end, we used as proxy the indicator of economic autonomy - that is, the ratio between costs of inputs related to animal production, crop production and energy use and the total gross product. Classes were then compared using multiple comparison tests and canonical discriminant analysis. A total of 30 organic farms - among which 63% had a high level of economic autonomy - were considered separately and compared with the most autonomous class. We showed that a high degree of economic autonomy is associated, in conventional farms, with a high proportion of permanent grassland in the agricultural area. The most autonomous farms used less input - especially animal feeding - for a same output level, and therefore combined good environmental and economic performances. Our results also underlined that, in a situation of decrease in milk price, the least autonomous farms had more latitude to decrease their input-related costs without decreasing milk production. Their incomes per work unit were, therefore, less impacted by falling prices, but remained lower than those of more autonomous farms. In such a situation, organic farms kept stable incomes, because of a slighter decrease in organic milk price. Our results pave the way to study the role of increasing input self-sufficiency in the transition of dairy farming systems towards sustainability. Further research is required to study a wide range of systems and agro-ecological contexts, as well as to consider the evolution of farm sustainability in the long term. PMID- 25431141 TI - Long-term experience with onabotulinumtoxinA in the treatment of chronic migraine: What happens after one year? AB - BACKGROUND: OnabotulinumtoxinA (onabotA) has shown its efficacy over placebo in chronic migraine (CM), but clinical trials lasted only up to one year. OBJECTIVE: The objective of this article is to analyse our experience with onabotA treatment of CM, paying special attention to what happens after one year. PATIENTS AND METHODS: We reviewed the charts of patients with CM on onabotA. Patients were injected quarterly during the first year but the fifth appointment was delayed to the fourth month to explore the need for further injections. RESULTS: We treated 132 CM patients (mean age 47 years; 119 women). A total of 108 (81.8%) showed response during the first year. Adverse events, always transient and mild moderate, were seen in 19 (14.4%) patients during the first year; two showed frontotemporal muscle atrophy after being treated for more than five years. The mean number of treatments was 7.7 (limits 2-29). Among those 108 patients with treatment longer than one year, 49 (45.4%) worsened prior to the next treatment, which obliged us to return to quarterly injections and injections were stopped in 14: in 10 (9.3%) due to a lack of response and in four due to the disappearance of attacks. In responders, after an average of two years of treatment, consumption of any acute medication was reduced by 53% (62.5% in triptan overusers) and emergency visits decreased 61%. CONCLUSIONS: Our results confirm the long-term response to onabotA in three-quarters of CM patients. After one year, lack of response occurs in about one out of 10 patients and injections can be delayed, but not stopped, to four months in around 40% of patients. Except for local muscle atrophy in two cases treated more than five years, adverse events are comparable to those already described in short-term clinical trials. PMID- 25431142 TI - Diversity-oriented synthesis and activity evaluation of substituted bicyclic lactams as anti-malarial against Plasmodium falciparum. AB - BACKGROUND: Malaria remains the world's most important devastating parasitic disease. Of the five species of Plasmodium known to infect and cause human malaria, Plasmodium falciparum is the most virulent and responsible for majority of the deaths caused by this disease. Mainstream drug therapy targets the asexual blood stage of the malaria parasite, as the disease symptoms are mainly associated with this stage. The prevalence of malaria parasite strains resistance to existing anti-malarial drugs has made the control of malaria even more challenging and hence the development of a new class of drugs is inevitable. METHODS: Screening against different drug resistant and sensitive strains of P. falciparum was performed for few bicyclic lactam-based motifs, exhibiting a broad spectrum of activity with low toxicity generated via a focussed library obtained from diversity oriented synthesis (DOS). The synthesis and screening was followed by an in vitro assessment of the possible cytotoxic effect of this class of compounds on malaria parasite. RESULTS: The central scaffold a chiral bicyclic lactam (A) and (A') which were synthesized from (R)-phenylalaninol, levulinic acid and 3-(2-nitrophenyl) levulinic acid respectively. The DOS library was generated from A and from A', by either direct substitution with o nitrobenzylbromide at the carbon alpha- to the amide functionality or by conversion to fused pyrroloquinolines. Upon screening this diverse library for their anti-malarial activity, a dinitro/diamine substituted bicyclic lactam was found to demonstrate exceptional activity of >85% inhibition at 50 MUM concentration across different strains of P. falciparum with no toxicity against mammalian cells. Also, loss of mitochondrial membrane potential, mitochondrial functionality and apoptosis was observed in parasite treated with diamine substituted bicyclic lactams. CONCLUSIONS: This study unveils a DOS-mediated exploration of small molecules with novel structural motifs that culminates in identifying a potential lead molecule against malaria. In vitro investigations further reveal their cytocidal effect on malaria parasite growth. It is not the first time that DOS has been used as a strategy to identify therapeutic leads against malaria, but this study establishes the direct implications of DOS in scouting novel motifs with anti-malarial activity. PMID- 25431144 TI - Preparation, anticholinesterase activity, and docking study of new 2 butenediamide and oxalamide derivatives. AB - Several new oxalamide and 2-butenediamide derivatives have been designed, synthesized and evaluated as the acetyl- and butyryl-cholinesterase inhibitors for Alzheimer's disease. The enzyme inhibitory activity of the synthesized compounds was measured using Ellman's colorimetric method. It was revealed that compound 1a (N,N'-bis-(4-chloro-benzyl)-N,N'-diphenyl-oxalamide) showed maximum activity against BuChE with a half maximal inhibitory concentration (IC50) = 1.86 uM and compound 2a (but-2-enedioic acid bis-[(4-chloro-benzyl)-phenyl-amide]) exhibited optimum AChE (IC50 = 1.51 uM) inhibition with a high-selectivity index. To better understand the enzyme-inhibitor interaction of the most active compounds towards cholinesterase, molecular modelling studies were carried out. Docking simulations revealed that inhibitors 1a and 2a targeted both the catalytic active site and the peripheral anionic site of 1ACJ and 1P0I. PMID- 25431143 TI - Influence of renal function on mortality and ventricular arrhythmias in patients undergoing first implantable cardioverter-defibrillator generator replacement. AB - BACKGROUND: Impaired renal function is associated with increased mortality among patients with implantable cardioverter-defibrillators (ICDs). The relationship between renal function at time of ICD generator replacement and subsequent appropriate ICD therapies is not known. METHODS AND RESULTS: We identified 441 patients who underwent first ICD generator replacement between 2000 and 2011 and had serum creatinine measured within 30 days of their procedure. Patients were divided into tertiles based on estimated glomerular filtration rate (eGFR). Adjusted Cox proportional hazard and competing risk models were used to assess relationships between eGFR and subsequent mortality and appropriate ICD therapy. Median eGFR was 37.6, 59.3, and 84.8 mL/min/1.73 m(2) for tertiles 1-3, respectively. Five-year Kaplan-Meier survival probability was 34.8%, 61.4%, and 84.5% for tertiles 1-3, respectively (P < 0.001). After multivariable adjustment, compared to tertile 3, worse eGFR tertile was associated with increased mortality (HR 2.84, 95% CI [1.36-5.94] for tertile 2; HR 3.84, 95% CI [1.81-8.12] for tertile 1). At 5 years, 57.0%, 58.1%, and 60.2% of patients remained free of appropriate ICD therapy in tertiles 1-3, respectively (P = 0.82). After adjustment, eGFR tertile was not associated with future appropriate ICD therapy. Results were unchanged in an adjusted competing risk model accounting for death. CONCLUSIONS: At time of first ICD generator replacement, lower eGFR is associated with higher mortality, but not with appropriate ICD therapies. The poorer survival of ICD patients with reduced eGFR does not appear to be influenced by arrhythmia status, and there is no clear proarrhythmic effect of renal dysfunction, even after accounting for the competing risk of death. PMID- 25431145 TI - Fluorinated pyrrolidines and piperidines incorporating tertiary benzenesulfonamide moieties are selective carbonic anhydrase II inhibitors. AB - A series of substituted pyrrolidines and piperidines were synthesized using superacid HF/SbF5 chemistry. Investigated as inhibitors of several human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, i.e. the cytosolic hCA I and II as well as the tumor-associated transmembrane isoforms hCA IX and XII, these compounds showed a never yet reported selectivity toward the human carbonic anhydrase hCA II. In the tertiary benzenesulfonamide family, this class of inhibitors points out a new mechanism of action for human carbonic anhydrase II inhibition. PMID- 25431146 TI - Synthesis of quinolinylaminopyrimidines and quinazolinylmethylaminopyrimidines with antiproliferative activity against melanoma cell line. AB - Synthesis of a new series of quinolinylaminopyrimidines 1a-k and quinazolinylmethylaminopyrimidines 2a-i containing aminoquinoline and aminoquinazoline as hinge regions is described. Their in vitro antiproliferative activities against A375P human melanoma cell line were tested. Among them, compounds 1h and 1k exhibited the highest antiproliferative activities against A375P cell line with IC50 values in sub-micromolar scale. Compounds 1i, 2b and 2g showed similar potency against A375P to Sorafenib as a reference compound. The representative compound 1h showed high, dose-dependent inhibition of MEK and ERK kinases. PMID- 25431147 TI - Chiral resolution, determination of absolute configuration, and biological evaluation of (1,2-benzothiazin-4-yl)acetic acid enantiomers as aldose reductase inhibitors. AB - A novel series of (1,2-benzothiazin-4-yl)acetic acid enantiomers was prepared by chiral resolution, and their absolute configurations were determined using the PGME method. The biological evaluation of the racemate and single enantiomers has shown a remarkable difference for the aldose reductase inhibitory activity and selectivity. The (R)-(-)-enantiomer exhibited the strongest aldose reductase activity with an IC(50) value of 0.120 MUM, which was 35 times more active than the S-(+)-enantiomer. Thus, the stereocenter at the C4 position of this scaffold was shown to have a major impact on the activity and selectivity. PMID- 25431148 TI - Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent. AB - This study reports on the design, synthesis and antiparasitic activity of three new semi-synthetic naphthoquinones structurally related to the naturally occurring lapachol and lapachone. Of the compounds tested, 3-(3-methylbut-1-en-1 yl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate (1) was the most active against Plasmodium falciparum among both natural and semi-synthetic naphthoquinones, showing potent and selective activity. Compound 1 was able to reduce the in vitro parasite burden, in vitro parasite cell cycle, as well as the blood parasitemia in Plasmodium berghei-infected mice. More importantly, infection reduction under compound 1-treatment was achieved without exhibiting mouse genotoxicity. Regarding the molecular mechanism of action, this compound inhibited the hemozoin crystal formation in P. falciparum treated cells, and this was further confirmed by observing that it inhibits the beta-hematin polymerization process similarly to chloroquine. Interestingly, this compound did not affect either mitochondria structure or cause DNA fragmentation in parasite treated cells. In conclusion, we identified a semi-synthetic antimalarial naphthoquinone closely related to isolapachol, which had stronger antimalarial activity than lapachol. PMID- 25431151 TI - Chemoinformatics in metabolomics, from molecular mechanics, dynamics, and docking to complex metabolic networks, part 2. PMID- 25431150 TI - Impact of tumor location and pathological discordance on survival of children with midline high-grade gliomas treated on Children's Cancer Group high-grade glioma study CCG-945. AB - Children with high-grade glioma (HGG) have a poor prognosis compared to those with low-grade glioma (LGG). Adjuvant chemotherapy may be beneficial, but its optimal use remains undetermined. Histology and extent of resection are important prognostic factors. We tested the hypothesis that patients with midline HGG treated on Children's Cancer Group Study (CCG) CCG-945 have a worse prognosis compared to the entire group. Of 172 children eligible for analysis, 60 had midline tumors primarily localized to the thalamus, hypothalamus and basal ganglia. Time-to-progression and death were determined from the date of initial diagnosis, and survival curves were calculated. Univariate analyses were undertaken for extent of resection, chemotherapy regimen, anatomic location, histology, proliferation index, MGMT status and p53 over-expression. For the entire midline tumor group, 5-year PFS and OS were 18.3 +/- 4.8 and 25 +/- 5.4 %, respectively. Many patients only had a biopsy (43.3 %). The sub-groups with near/total resection and hypothalamic location appeared to have better PFS and OS. However, the effect of tumor histology on OS was significant for children with discordant diagnoses on central pathology review of LGG compared to HGG. Proliferative index (MIB-1 > 36 %), MGMT and p53 over-expression correlated with poor outcomes. Children treated on CCG-945 with midline HGG have a worse prognosis when compared to the entire group. The midline location may directly influence the extent of resection. Central pathology review and entry of patients on clinical trials continue to be priorities to improve outcomes for children with HGG. PMID- 25431152 TI - State of the art and development of a drug-drug interaction large scale predictor based on 3D pharmacophoric similarity. AB - Co-administration of drugs is a primary cause of Adverse Drug Reactions (ADRs) and a drain on the health care industry costing billions of dollars and reducing quality of life. Drug-Drug Interactions (DDIs) account for as much as 30% of all ADRs. Unfortunately, DDIs are not systematically explored pre-clinically and are difficult to detect in post-marketing drug surveillance. For this reason, the detection and prediction of DDIs is an important problem in both drug development and pharmacovigilance. The comparison of the 3D drug structures provides a powerful tool for DDI prediction. In this article, we present the first large scale model for predicting DDIs using the drug's 3D molecular structure. In addition to identifying putative drug interactions we can also isolate the pharmacological or clinical effect associated with the predicted interactions. The model has good performance in two different hold-out validations and in external test sets. We found that the top scored drug pairs were significantly enriched for known clinically relevant interactions and that 3D structure data is providing significantly independent information from other approaches, including 2D structure (p=0.003). We demonstrated the usefulness of the proposed methodology to systematically identify pharmacokinetic and pharmacodynamic interactions, provided an exploratory tool that can be used for patient safety and pre-clinical toxicity screening, and reviewed the state of the art methods used to detect DDIs. PMID- 25431149 TI - Using protein-binding microarrays to study transcription factor specificity: homologs, isoforms and complexes. AB - Protein-DNA binding is central to specificity in gene regulation, and methods for characterizing transcription factor (TF)-DNA binding remain crucial to studies of regulatory specificity. High-throughput (HT) technologies have revolutionized our ability to characterize protein-DNA binding by significantly increasing the number of binding measurements that can be performed. Protein-binding microarrays (PBMs) are a robust and powerful HT platform for studying DNA-binding specificity of TFs. Analysis of PBM-determined DNA-binding profiles has provided new insight into the scope and mechanisms of TF binding diversity. In this review, we focus specifically on the PBM technique and discuss its application to the study of TF specificity, in particular, the binding diversity of TF homologs and multi protein complexes. PMID- 25431153 TI - Review and research analysis of computational target methods using BioRuby and in silico screening of herbal lead compounds against pancreatic cancer using R programming. AB - Plants and their natural components sophisticated with the cornerstone of traditional conventional medicinal system throughout the globe for many years and extend to furnish mankind with latest remedies. Natural Products act as lead molecules for the synthesis of various potent drugs. In the current research a study is conducted on herbal small molecule and their potential binding chemical affinity to the effect or molecules of major diseases such as pancreatic cancer. Clinical studies demonstrate correlation between Cyclin- Dependent Kinase 4 (CDK4) and malignant progression of Pancreatic Cancer. Using Bioruby Gem's we were able to analyze better characteristics of the target protein. VegaZZ and NAMD were used to minimize the energy of the target protein. Therefore identification of effective, well- tolerated targets was analyzed. Further the target protein was subjected to docking with the anti cancer inhibitors which represents a rational chemo preventive strategy using AutoDock Vina. Later using the dock score top ranked phytochemicals were analyzed for Toxicity Analysis. Using the BioRuby gem we were able to measure the distance between the amino acid. Various R scripting libraries were used to hunt the best leads, as in this case the phytochemicals. Phytochemicals such as Wedelolactones and Catechin were analyzed computationally. This study has presented the various effects of naturally occurring anti pancreatic cancer compounds Catechin, Wedelolactones that inhibits Cyclin Dependent Kinase 4. The study results reveal that compounds use less binding energy to CDK4 and inhibit its activity. Future investigation of other various wet lab studies such as cell line studies will confirm results of these two herbal chemical formulations potential ones for treating Pancreatic Cancer. PMID- 25431154 TI - How to treat severe infections in critically ill neutropenic patients? AB - Severe infections in neutropenic patient often progress rapidly leading to life threatening organ dysfunction requiring admission to the Intensive Care Unit. Management strategies include early adequate appropriate empirical antimicrobial, early admission to ICU to avoid any delay in the diagnostic and therapeutic management of organ dysfunction. This review discusses the main clinical situations encountered in critically ill neutropenic patients. Specific diagnostic and therapeutic approaches have been proposed for acute respiratory failure, shock, neutropenic enterocolitis, catheter-related infections, cellulitis and primary bacteriemia. Non anti-infectious agents and recent advances will also be discussed. At present, most of large-scale studies and recommendations in neutropenic patients stem from hematological patients and will need further validation in ICU patients. PMID- 25431156 TI - Preclinical validation of 99mTc-annexin A5-128 in experimental autoimmune myocarditis and infective endocarditis: comparison with 99mTc-HYNIC-annexin A5. AB - Hydrazinonicotinamide-annexin A5 (HYNIC-Anx), a 99m technetium (99mTc)-labeled agent targeting phosphatidylserine, proved to be sensitive for the detection of apoptosis and thrombosis but is no longer available for clinical use. A mutant of human annexin designed for direct 99mTc labeling (referred to as Anx A5-128) showed improved binding affinity to phosphatidylserine and is expected to be used in humans. We compared both radiotracers with regard to pharmacokinetics and diagnostic ability in animal models. Biodistribution studies were performed in normal rats. Radiolabeled Anx A5-128 and HYNIC-Anx were compared in cardiovascular settings involving phosphatidylserine expression: experimental autoimmune myocarditis and infective endocarditis. Initial blood clearance was faster for Anx A5-128 than for HYNIC-Anx, and tissue biodistribution was similar overall for both tracers. The diagnostic sensitivity of Anx A5-128 was excellent and comparable to that of HYNIC-Anx. Anx A5-128 showed biodistribution and diagnostic ability similar to those of the HYNIC-Anx derivative, supporting its translation to clinical use. PMID- 25431155 TI - Characteristics of dorsal root ganglia neurons sensitive to Substance P. AB - BACKGROUND: Substance P modulates ion channels and the excitability of sensory neurons in pain pathways. Within the heterogeneous population of Dorsal Root Ganglia (DRG) primary sensory neurons, the properties of cells that are sensitive to Substance P are poorly characterized. To define this population better, dissociated rat DRG neurons were tested for their responsiveness to capsaicin, ATP and acid. Responses to ATP were classified according to the kinetics of current activation and desensitization. The same cells were then tested for modulation of action potential firing by Substance P. RESULTS: Acid and capsaicin currents were more frequently encountered in the largest diameter neurons. P2X3 like ATP currents were concentrated in small diameter neurons. Substance P modulated the excitability in 20 of 72 cells tested (28%). Of the Substance P sensitive cells, 10 exhibited an increase in excitability and 10 exhibited a decrease in excitability. There was no significant correlation between sensitivity to capsaicin and to Substance P. Excitatory effects of Substance P were strongly associated with cells that had large diameters, fired APs with large overshoots and slowly decaying after hyperpolarizations, and expressed acid currents at pH 7. No neurons that were excited by Substance P presented P2X3-like currents. In contrast, neurons that exhibited inhibitory effects of Substance P fired action potentials with rapidly decaying after hyperpolarizations. CONCLUSION: We conclude that excitatory effects of Substance P are restricted to a specific neuronal subpopulation with limited expression of putative nociceptive markers. PMID- 25431157 TI - "Feline" esophagus. PMID- 25431158 TI - Direct nanoscale imaging of evolving electric field domains in quantum structures. AB - The external performance of quantum optoelectronic devices is governed by the spatial profiles of electrons and potentials within the active regions of these devices. For example, in quantum cascade lasers (QCLs), the electric field domain (EFD) hypothesis posits that the potential distribution might be simultaneously spatially nonuniform and temporally unstable. Unfortunately, there exists no prior means of probing the inner potential profile directly. Here we report the nanoscale measured electric potential distribution inside operating QCLs by using scanning voltage microscopy at a cryogenic temperature. We prove that, per the EFD hypothesis, the multi-quantum-well active region is indeed divided into multiple sections having distinctly different electric fields. The electric field across these serially-stacked quantum cascade modules does not continuously increase in proportion to gradual increases in the applied device bias, but rather hops between discrete values that are related to tunneling resonances. We also report the evolution of EFDs, finding that an incremental change in device bias leads to a hopping-style shift in the EFD boundary--the higher electric field domain expands at least one module each step at the expense of the lower field domain within the active region. PMID- 25431159 TI - Synovial joints: from development to homeostasis. AB - Synovial joint morphogenesis occurs through the condensation of mesenchymal cells into a non-cartilaginous region known as the interzone and the specification of progenitor cells that commit to the articular fate. Although several signaling molecules are expressed by the interzone, the mechanism is poorly understood. For treatments of cartilage injuries, it is critical to discover the presence of joint progenitor cells in adult tissues and their expression gene pattern. Potential stem cell niches have been found in different joint regions, such as the surface zone of articular cartilage, synovium, and groove of Ranvier. Inherited joint malformations as well as joint-degenerating conditions are often associated with other skeletal defects and may be seen as the failure of morphogenic factors to establish the correct microenvironment in cartilage and bone. Therefore, exploring how joints form can help us understand how cartilage and bone are damaged and develop drugs to reactivate this developing mechanism. PMID- 25431161 TI - Leader in global influenza prevention and control retires after 37 years. PMID- 25431160 TI - Orthobiologics in the augmentation of osteoporotic fractures. AB - Many orthobiologic adjuvants are available and widely utilized for general skeletal restoration. Their use for the specific task of osteoporotic fracture augmentation is less well recognized. Common conductive materials are reviewed for their value in this patient population including the large group of allograft adjuvants categorically known as the demineralized bone matrices (DBMs). Another large group of alloplastic materials is also examined-the calcium phosphate and sulfate ceramics. Both of these materials, when used for the proper indications, demonstrate efficacy for these patients. The inductive properties of bone morphogenic proteins (BMPs) and platelet concentrates show no clear advantages for this group of patients. Systemic agents including bisphosphonates, receptor activator of nuclear factor kappabeta ligand (RANKL) inhibitors, and parathyroid hormone augmentation all demonstrate positive effects with this fracture cohort. Newer modalities, such as trace ion bioceramic augmentation, are also reviewed for their positive effects on osteoporotic fracture healing. PMID- 25431163 TI - Epilepsy surgery in patients with bilateral temporal lobe seizures: a systematic review. AB - We explored the association between magnetic resonance imaging (MRI) lesion, degree of seizure laterality on intracranial electroencephalography (iEEG), and seizure outcome in patients with ambiguous or presumed bilateral temporal lobe epilepsy (BiTLE) on scalp EEG. We systematically reviewed the literature using Embase and MEDLINE up to May 31, 2012. Patients with bilateral iEEG, temporal lobe surgery, and follow-up >=1 year were included. We undertook three separate analyses on patients whose scalp EEG showed ambiguous onset or BiTLE (1) group data of those whose iEEG demonstrated unilateral TLE, (2) group data of those whose iEEG demonstrated BiTLE, (3) individual patient analysis in those with BiTLE for whom iEEG seizure laterality data were provided. Of 1,403 patients with ambiguous or presumed BiTLE on scalp EEG, 1,027 (73%) proved to have unilateral TLE on iEEG and contributed to the first analysis. Of these, 58% had Engel class I and 9% Engel class II outcomes. Of 132 patients in the second analysis (true BiTLE), Engel class I and II outcomes were achieved in 23% and 14%, respectively. Of 41 patients in the third analysis, 66% and 2% had Engel class I and II outcomes, respectively. The median proportion of seizures ipsilateral to the resection on iEEG did not differ between BiTLE patients with Engel class I-II (76%) and Engel III-IV (78%) outcomes (p = 0.87). Patients with ambiguous or independent bitemporal seizure onset on scalp EEG achieved good surgical outcomes. Overall, a significantly higher proportion of patients achieved good outcomes when iEEG showed unilateral TLE (67%) than when it showed true BiTLE (45%). However, the degree of seizure lateralization in those with BiTLE was not associated with seizure outcome, and it has a limited role in selecting the side of surgery. PMID- 25431162 TI - PyTMs: a useful PyMOL plugin for modeling common post-translational modifications. AB - BACKGROUND: Post-translational modifications (PTMs) constitute a major aspect of protein biology, particularly signaling events. Conversely, several different pathophysiological PTMs are hallmarks of oxidative imbalance or inflammatory states and are strongly associated with pathogenesis of autoimmune diseases or cancers. Accordingly, it is of interest to assess both the biological and structural effects of modification. For the latter, computer-based modeling offers an attractive option. We thus identified the need for easily applicable modeling options for PTMs. RESULTS: We developed PyTMs, a plugin implemented with the commonly used visualization software PyMOL. PyTMs enables users to introduce a set of common PTMs into protein/peptide models and can be used to address research questions related to PTMs. Ten types of modification are currently supported, including acetylation, carbamylation, citrullination, cysteine oxidation, malondialdehyde adducts, methionine oxidation, methylation, nitration, proline hydroxylation and phosphorylation. Furthermore, advanced settings integrate the pre-selection of surface-exposed atoms, define stereochemical alternatives and allow for basic structure optimization of the newly modified residues. CONCLUSION: PyTMs is a useful, user-friendly modelling plugin for PyMOL. Advantages of PyTMs include standardized generation of PTMs, rapid time-to result and facilitated user control. Although modeling cannot substitute for conventional structure determination it constitutes a convenient tool that allows uncomplicated exploration of potential implications prior to experimental investments and basic explanation of experimental data. PyTMs is freely available as part of the PyMOL script repository project on GitHub and will further evolve. Graphical Abstract PyTMs is a useful PyMOL plugin for modeling common post translational modifications. PMID- 25431164 TI - Demonstration of unusual nanoantenna array modes through direct reconstruction of the near-field signal. AB - We perform complex investigation of the distribution of electromagnetic fields in the vicinity of an array of silver nanoantennas, which can operate as an efficient light trapping structure in the visible spectral range. In theory, this array should support unusual collective modes that possess an advantageous distribution of local electric fields, ensuring both strong field localization beneath nanoantennas and a low level of optical losses inside the metal. Using an aperture-type near-field scanning optical microscope (NSOM), we obtain near-field patterns that show excellent agreement with the NSOM signal, directly reconstructed from rigorous numerical simulations using an approach based on the electromagnetic reciprocity theorem. The agreement between theory and experiment allows us to claim the first-time experimental verification of the existence of collective modes with such properties in an array of silver nanoantennas. The confirmation of this physical phenomenon opens the door to a new class of light trapping structures for photovoltaics. PMID- 25431165 TI - Pregnancy complications in acquired thrombotic thrombocytopenic purpura: a case control study. AB - BACKGROUND: Pregnant women with a history of acquired thrombotic thrombocytopenic purpura (TTP) are considered at risk for disease recurrence and might be at risk for miscarriage, similar to other autoimmune disorders. However, the exact entity of these risks and their causes are unknown. The aim of this study was to evaluate risk factors associated with adverse pregnancy outcome, in terms of both gravidic TTP and miscarriage, in women affected by previous acquired TTP. METHODS: We conducted a nested case-control study in women with a history of acquired TTP enrolled in the Milan TTP registry from 1994 to October 2012, with strict inclusion criteria to reduce referral and selection bias. RESULTS: Fifteen out of 254 women with acquired TTP were included, namely four cases with gravidic TTP, five with miscarriage, and six controls with uncomplicated pregnancy. In the cases, ADAMTS13 activity levels in the first trimester were moderately-to severely reduced (median levels <3% in gravidic TTP and median levels 20% [range 14-40%] in the women with miscarriage) and anti-ADAMTS13 antibodies were invariably present, while in the control group ADAMTS13 activity levels were normal (median 90%, range 40-129%), with absence of detectable anti-ADAMTS13 antibodies. Reduced levels of ADAMTS13 activity (<25%) in the first trimester were associated with an over 2.9-fold increased risk for gravidic TTP and with an over 1.2-fold increased risk for miscarriage (lower boundary of the confidence interval of the odds ratio). In addition, the presence of anti-ADAMTS13 antibodies during pregnancy was associated with an over 6.6-fold increased risk for gravidic TTP and with an over 4.1-fold increased risk for miscarriage. CONCLUSIONS: ADAMTS13 activity evaluation and detection of anti-ADAMTS13 antibody could help to predict the risk of complications in pregnant women with a history of acquired TTP. PMID- 25431166 TI - Room temperature continuous-wave green lasing from an InGaN microdisk on silicon. AB - Optically pumped green lasing with an ultra low threshold has been achieved using an InGaN/GaN based micro-disk with an undercut structure on silicon substrates. The micro-disks with a diameter of around 1 MUm were fabricated by means of a combination of a cost-effective silica micro-sphere approach, dry-etching and subsequent chemical etching. The combination of these techniques both minimises the roughness of the sidewalls of the micro-disks and also produces excellent circular geometry. Utilizing this fabrication process, lasing has been achieved at room temperature under optical pumping from a continuous-wave laser diode. The threshold for lasing is as low as 1 kW/cm(2). Time-resolved micro photoluminescence (PL) and confocal PL measurements have been performed in order to further confirm the lasing action in whispering gallery modes and also investigate the excitonic recombination dynamics of the lasing. PMID- 25431167 TI - What are postpartum women doing while the rest of the world is asleep? AB - Large individual differences characterize maternal postpartum sleep and adjustment. Our goal was to explore aspects of mothers' nocturnal environments and behaviours that may explain differences in postpartum adjustment. A total of 201 mothers of infants aged 0-6 months completed an online survey with demographics, number and duration of nocturnal awakenings, caretaking behaviours, environment and nocturnal activities during 'one typical night during the past week'. Mothers reported 2.9 [standard deviation (SD) +/- 1.7] nocturnal awakenings, each lasting 33.9 (SD +/- 22.5) min. Infant age was related inversely to duration but unrelated to number of awakenings. Falling asleep while feeding was less frequent among exclusively formula-feeders. Among the entire sample, mothers used a cellphone (59%), backlit tablet (25%), TV (20%) and computer (16%) during nocturnal awakenings. Watching TV and using a computer were each associated with longer nocturnal awakenings. Eighty-nine per cent of women used >=1 extra light source during nocturnal awakenings: night light (35%), light from a cracked door (28%), desk lamp (25%), electronic device (19%) or room light (14%). Light source(s) was unrelated to number or duration of nocturnal awakenings. These data suggest that, although supplemental light sources were not associated with awakenings, TV and computer use accounted for longer awakenings. Feeding method and technology use may help to explain individual differences in postpartum adjustments and may be targets for more effective interventions. PMID- 25431168 TI - Melatonin promotes hepatic differentiation of human dental pulp stem cells: clinical implications for the prevention of liver fibrosis. AB - Melatonin's effect on hepatic differentiation of stem cells remains unclear. The aim of this study was to investigate the action of melatonin on hepatic differentiation as well as its related signaling pathways of human dental pulp stem cells (hDPSCs) and to examine the therapeutic effects of a combination of melatonin and hDPSC transplantation on carbon tetrachloride (CCl4 )-induced liver fibrosis in mice. In vitro hepatic differentiation was assessed by periodic acid Schiff (PAS) staining and mRNA expression for hepatocyte markers. Liver fibrosis model was established by injecting 0.5 mL/kg CCl4 followed by treatment with melatonin (5 mg/kg, twice a week) and hDPSCs. In vivo therapeutic effects were evaluated by histopathology and by means of liver function tests including measurement of alanine transaminase (ALT), aspartate transaminase (AST), and ammonia levels. Melatonin promoted hepatic differentiation based on mRNA expression of differentiation markers and PAS-stained glycogen-laden cells. In addition, melatonin increased bone morphogenic protein (BMP)-2 expression and Smad1/5/8 phosphorylation, which was blocked by the BMP antagonist noggin. Furthermore, melatonin activated p38, extracellular signal-regulated kinase (ERK), and nuclear factor-kappaB (NF-kappaB) in hDPSCs. Melatonin-induced hepatic differentiation was attenuated by inhibitors of BMP, p38, ERK, and NF-kappaB. Compared to treatment of CCl4 -injured mice with either melatonin or hDPSC transplantation alone, the combination of melatonin and hDPSC significantly suppressed liver fibrosis and restored ALT, AST, and ammonia levels. For the first time, this study demonstrates that melatonin promotes hepatic differentiation of hDPSCs by modulating the BMP, p38, ERK, and NF-kappaB pathway. Combined treatment of grafted hDPSCs and melatonin could be a viable approach for the treatment of liver cirrhosis. PMID- 25431169 TI - Evaluation of DNA extraction methods for PCR-based detection of Listeria monocytogenes from vegetables. AB - Epidemiological data indicate that raw vegetables are associated with outbreaks of Listeria monocytogenes. Therefore, there is a demand for the availability of rapid and sensitive methods, such as PCR assays, for the detection and accurate discrimination of L. monocytogenes. However, the efficiency of PCR methods can be negatively affected by inhibitory compounds commonly found in vegetable matrices that may cause false-negative results. Therefore, the sample processing and DNA isolation steps must be carefully evaluated prior to the introduction of such methods into routine practice. In this study, we compared the ability of three column-based and four magnetic bead-based commercial DNA isolation kits to extract DNA of the model micro-organism L. monocytogenes from raw vegetables. The DNA isolation efficiency of all isolation kits was determined using a triplex real-time qPCR assay designed to specifically detect L. monocytogenes. The kit with best performance, the PowerSoil(TM) Microbial DNA Isolation Kit, is suitable for the extraction of amplifiable DNA from L. monocytogenes cells in vegetable with efficiencies ranging between 29.6 and 70.3%. Coupled with the triplex real time qPCR assay, this DNA isolation kit is applicable to the samples with bacterial loads of 10(3) bacterial cells per gram of L. monocytogenes. SIGNIFICANCE AND IMPACT OF THE STUDY: Several recent outbreaks of Listeria monocytogenes have been associated with the consumption of fruits and vegetables. Real-time PCR assays allow fast detection and accurate quantification of microbes. However, the success of real-time PCR is dependent on the success with which template DNA can be extracted. The results of this study suggest that the PowerSoil(TM) Microbial DNA Isolation Kit can be used for the extraction of amplifiable DNA from L. monocytogenes cells in vegetable with efficiencies ranging between 29.6 and 70.3%. This method is applicable to samples with bacterial loads of 10(3) bacterial cells per gram of L. monocytogenes. PMID- 25431170 TI - Hepatitis C virus long-term persistence in peripheral blood mononuclear cells in patients with haemophilia. Detection of occult genotype 1. AB - Peripheral blood mononuclear cells (PBMC) from chronic hepatitis C virus-infected persons can harbour viral variants that are not detected in plasma samples. We explored the presence and persistence of HCV genotypes in plasma and PBMC cultures from 25 HCV-monoinfected and 25 HIV/HCV-coinfected patients with haemophilia. Cell cultures were performed at different time points between 1993 and 2010-2011, and the HCV genome was examined in culture supernatants. Sequential plasma samples were studied during the same time period. Analysing sequential plasma samples, 21% of patients had mixed-genotype infections, while 50% had mixed infections determined from PBMC culture supernatants. HIV coinfection was significantly associated with the presence of mixed infections (OR = 4.57, P = 0.02; 95% CI = 1.38-15.1). In our previous study, genotype 1 was found in 72% of 288 patients of this cohort. Similar results were obtained with the sequential plasma samples included in this study, 69% had genotype 1. However, when taking into account plasma samples and the results from PBMC supernatants, genotype 1 was identified in 94% of the population. The PBMC associated variants persisted for 10 years in some subjects, emphasizing their role as long-term reservoirs. The presence of genotype 1 in PBMC may be associated with therapeutic failure and should not be disregarded when treating haemophilic patients who have been infected by contaminated factor concentrates. The clinical implications of persistent lymphotropic HCV variants deserve further examination among multiple exposed groups of HCV-infected patients. PMID- 25431171 TI - Differentiation of mint (Mentha haplocalyx Briq.) from different regions in China using gas and liquid chromatography. AB - In this study, complex substances such as Mint (Mentha haplocalyx Briq.) samples from different growing regions in China were analyzed for phenolic compounds by high-performance liquid chromatography with diode array detection and for the volatile aroma compounds by gas chromatography with mass spectrometry. Chemometrics methods, e.g. principal component analysis, back-propagation artificial neural networks, and partial least squares discriminant analysis, were applied to resolve complex chromatographic profiles of Mint samples. A total of 49 aroma components and 23 phenolic compounds were identified in 79 Mint samples. Principal component analysis score plots from gas chromatography with mass spectrometry and high-performance liquid chromatography with diode array detection data sets showed a clear distinction among Mint from three different regions in China. Classification results showed that satisfactory performance of prediction ability for back-propagation artificial neural networks and partial least squares discriminant analysis. The major compounds that contributed to the discrimination were chlorogenic acid, unknown 3, kaempherol 7-O-rutinoside, salvianolic acid L, hesperidin, diosmetin, unknown 6 and pebrellin in Mint according to regression coefficients of the partial least squares discriminant analysis model. This study indicated that the proposed strategy could provide a simple and rapid technique to distinguish clearly complex profiles from samples such as Mint. PMID- 25431172 TI - A putative antipruritic mechanism of the phosphodiesterase-4 inhibitor E6005 by attenuating capsaicin-induced depolarization of C-fibre nerves. AB - E6005, a potent, selective phosphodiesterase (PDE) 4 inhibitor, has been developed as a novel topical agent of atopic dermatitis (AD). It has been shown to inhibit itching in patients with AD as well in mouse models. To study the mechanism underlying the anti-pruritic effect of E6005, we examined its effect on the activation of dorsal root ganglion (DRG) neurons associated with the itch sensation. Depolarization of DRG neurons by a transient receptor potential vanilloid 1 (TRPV 1) activator, capsaicin was attenuated by E6005 as well as by a 3',5'-cyclic adenosine monophosphate (cAMP) elevator, forskolin. E6005 elevated intracellular levels of cAMP in DRG cells. Taken together, these results suggest that E6005 suppresses TRPV1-mediated C-fibre depolarization through elevation of cAMP levels, thereby exerting an anti-pruritic effect. Thus, E6005 shows the potential to be a new agent for managing pruritus in various skin disorders, including AD. PMID- 25431174 TI - Diabetic encephalopathy-related depression: experimental evidence that insulin and clonazepam restore antioxidant status in rat brain. AB - There is increasing evidence suggesting that oxidative stress plays an important role in the development of many chronic and degenerative conditions such as diabetic encephalopathy and depression. Considering that diabetic rats and mice present higher depressive-like behaviour when submitted to the forced swimming test and that treatment with insulin and/or clonazepam is able to reverse the behavioural changes of the diabetic rats, the present work investigated the antioxidant status, specifically total antioxidant reactivity and antioxidant potential of insulin and clonazepam, as well as the effect of this drugs upon protein oxidative damage and reactive species formation in cortex, hippocampus and striatum from diabetic rats submitted to forced swimming test. It was verified that longer immobility time in diabetic rats and insulin plus clonazepam treatment reversed this depressive-like behaviour. Moreover, data obtained in this study allowed to demonstrate through different parameters such as protein carbonyl content, 2'7'-dichlorofluorescein oxidation, catalase, superoxide dismutase, glutathione peroxidase assay, total radical-trapping antioxidant potential and total antioxidant reactivity that there is oxidative stress in cortex, hippocampus and striatum from diabetic rats under depressive-like behaviour and highlight the insulin and/or clonazepam effect in these different brain areas, restoring antioxidant status and protein damage. PMID- 25431173 TI - Time-varying correlations between delta EEG power and heart rate variability in midlife women: the SWAN Sleep Study. AB - No studies have evaluated the dynamic, time-varying relationship between delta electroencephalographic (EEG) sleep and high frequency heart rate variability (HF HRV) in women. Delta EEG and HF-HRV were measured during sleep in 197 midlife women (M(age) = 52.1, SD = 2.2). Delta EEG-HF-HRV correlations in nonrapid eye movement (NREM) sleep were modeled as whole-night averages and as continuous functions of time. The whole-night delta EEG-HF-HRV correlation was positive. The strongest correlations were observed during the first NREM sleep period preceding and following peak delta power. Time-varying correlations between delta EEG-HF HRV were stronger in participants with sleep-disordered breathing and self reported insomnia compared to healthy controls. The dynamic interplay between sleep and autonomic activity can be modeled across the night to examine within- and between-participant differences including individuals with and without sleep disorders. PMID- 25431175 TI - Bimolecular crystals with an intercalated structure improve poly(p phenylenevinylene)-based organic photovoltaic cells. AB - The exciton dissociation, recombination, and charge transport of bulk heterojunction organic photovoltaic cells (OPVs) is influenced strongly by the nanomorphology of the blend, such as the grain size and the molecular packing. Although it is well known that polymers based on amorphous poly(p phenylenevinylene) (PPV) have a fundamental limit to their efficiency because of low carrier mobility, which leads to increased recombination and unbalanced charge extraction, herein, we demonstrate that the issue can be overcome by forming bimolecular crystals of an amorphous PPV-based polymer:phenyl-C61 butyric acid methyl ester (PCBM) intercalated structure. We used amorphous poly(2,5-dioctyloxy-p-phenylene vinylene-alt-2',5'-thienylene vinylene) (PPVTV), which has a simple chemical structure. A reasonably high power conversion efficiency (~3.5 %) was obtained, although the material has an intrinsically amorphous structure and a relatively large band gap (2.0 eV). We demonstrate a correlation between a well-ordered bimolecular crystal of PPVTV:PCBM and an improved hole mobility of a PPVTV:PCBM film compared to a pristine PPVTV film by using 2 D grazing incidence XRD and space-charge-limited current measurements. Furthermore, we show that the bimolecular crystal structure in high-performance OPVs is related to an optimum molecular packing, which is influenced by the PPVTV:PCBM blending ratio, side-chain length, and molecular weight of the PPVTV polymer. Improved charge transport in PPVTV:PCBM bimolecular crystals leads to a fast sweep out of charges and thus suppression of nongeminate recombination under the operating conditions. PMID- 25431176 TI - Genomewide comprehensive analysis reveals critical cooperation between Smad and c Fos in RANKL-induced osteoclastogenesis. AB - We have previously reported that transforming growth factor beta (TGF-beta) plays an essential role in receptor activator of nuclear factor-kappaB ligand (RANKL) induced osteoclastogenesis. However, the detailed underlying molecular mechanisms still remain unclear. Formaldehyde-assisted isolation of regulatory elements (FAIRE) and chromatin immunoprecipitation (ChIP) followed by sequencing (FAIRE seq and ChIP-seq) analyses indicated the cooperation of Smad2/3 with c-Fos during osteoclastogenesis. Biochemical analysis and immunocytochemical analysis revealed that physical interaction between Smad2/3 and c-Fos is required for their nuclear translocation. The gene expression of nuclear factor of activated T-cells, cytoplasmic 1 (Nfatc1), a key regulator of osteoclastogenesis, was regulated by RANKL and TGF-beta, and c-Fos binding to open chromatin sites was suppressed by inhibition of TGF-beta signaling by SB431542. Conversely, Smad2/3 binding to Nfatc1 was impaired by c-Fos deficiency. These results suggest that TGF-beta regulates RANKL-induced osteoclastogenesis through reciprocal cooperation between Smad2/3 and c-Fos. PMID- 25431177 TI - Influence of MDM2 SNP309 and SNP285 status on the risk of cancer in the breast, prostate, lung and colon. AB - MDM2 is a key regulator of the p53 tumor suppressor protein and is overexpressed in many human cancers. Two single nucleotide polymorphisms (SNPs) located in the MDM2 intronic promoter (P2) have been found to exert biological function. The G allele of SNP309T>G; rs2279744 increases MDM2 transcription and has been linked to increased cancer risk. In contrast, the less frequent SNP285G>C; rs117039649, which is in complete linkage disequilibrium with SNP309 (generating a SNP285C/309G variant haplotype), has been related to reduced MDM2 transcription and to reduced risk of breast, endometrial and ovarian cancer. In this large population-based case-control study, we genotyped SNP309 and SNP285 in 10,830 individuals, including cases with cancer of the breast (n=1,717), colon (n=1,532), lung (n=1,331) and prostate (n=2,501), as well as 3,749 non-cancer controls. We found a slightly reduced risk for lung cancer among individuals harboring the SNP309TG/GG genotypes compared to the SNP309TT genotype (OR= 0.86; CI = 0.67-0.98), but this association was restricted to women (OR = 0.77; CI = 0.63-0.95) and was not present among men (OR = 0.91; CI = 0.77-1.08). Consistent with previous findings, we found a reduced risk for breast cancer among individuals carrying the SNP285GC/309GG genotype versus the SNP285GG/309GG genotype (OR = 0.55; CI = 0.33-0.93). In conclusion, our data support the hypothesis that the effects of both SNP285 and SNP309 status are tissue dependent. PMID- 25431178 TI - Trend analysis of Trichinella in a red fox population from a low endemic area using a validated artificial digestion and sequential sieving technique. AB - Freezing of fox carcasses to minimize professional hazard of infection with Echinococcus multilocularis is recommended in endemic areas, but this could influence the detection of Trichinella larvae in the same host species. A method based on artificial digestion of frozen fox muscle, combined with larva isolation by a sequential sieving method (SSM), was validated using naturally infected foxes from Latvia. The validated SSM was used to detect dead Trichinella muscle larvae (ML) in frozen muscle samples of 369 red foxes from the Netherlands, of which one fox was positive (0.067 larvae per gram). This result was compared with historical Trichinella findings in Dutch red foxes. Molecular analysis using 5S PCR showed that both T. britovi and T. nativa were present in the Latvian foxes, without mixed infections. Of 96 non-frozen T. britovi ML, 94% was successfully sequenced, whereas this was the case for only 8.3% of 72 frozen T. britovi ML. The single Trichinella sp. larva that was recovered from the positive Dutch fox did not yield PCR product, probably due to severe freeze-damage. In conclusion, the SSM presented in this study is a fast and effective method to detect dead Trichinella larvae in frozen meat. We showed that the Trichinella prevalence in Dutch red fox was 0.27% (95% CI 0.065-1.5%), in contrast to 3.9% in the same study area fifteen years ago. Moreover, this study demonstrated that the efficacy of 5S PCR for identification of Trichinella britovi single larvae from frozen meat is not more than 8.3%. PMID- 25431179 TI - In reference to Vascularized tissue to reduce fistula following salvage total laryngectomy: a systematic review. PMID- 25431181 TI - Brain and liver fatty acid composition changes upon consumption of Lactobacillus rhamnosus LA68. AB - Recent reports suggest that the metabolic activity of the enteric microbiota may influence the fatty acid composition of the host tissue. There are many studies dealing with the influence of lactobacilli on various pathological conditions, and some of the effects are strain-specific. This study was designed to test the effects of a particular Lactobacillus strain, Lactobacillus rhamnosus LA68 on fatty acid composition of the liver and the brain of C57BL/6 mice in the absence of an underlying pathological condition. Female mice were supplemented with live L. rhamnosus LA68 bacteria for the duration of 1 month. Serum biochemistry was analyzed and liver and brain fatty acid composition was assessed by gas-liquid chromatography. Significant changes in liver and brain fatty acid composition were detected. In the liver tissue we detected an increase in palmitoleic acid (p = 0.038), while in the brain compartment we found an increase in palmitic (p = 0.042), stearic (p = 0.017), arachidonic acid (p = 0.009) and docosahexaenoic acid (p = 0.004) for control versus experimental group. These results show discrete changes caused by LA68 strain consumption. Even short duration of administration of LA68 influences the fatty acid composition of the host which adds to the existing knowledge about Lactobacillus host interaction, and adds to the growing knowledge of metabolic intervention possibilities. PMID- 25431180 TI - Enantioselective oxidative gold catalysis enabled by a designed chiral P,N bidentate ligand. AB - A newly developed P,N-bidentate ligand enables enantioselective intramolecular cyclopropanation by a reactive alpha-oxo gold carbene intermediate generated in situ. The ligand design is based on our previously proposed structure (with a well-organized triscoordinated gold center) of the carbene intermediate in the presence of a P,N-bidentate ligand. A C2-symmetric piperidine ring was incorporated in the ligand as the nitrogen-containing moiety. A range of racemic transformations of alpha-oxo gold carbene intermediates have been developed recently, and this new class of chiral ligands could enable their modification for asymmetric synthesis, as demonstrated in this study. PMID- 25431182 TI - The temporal rating of emergency non-technical skills (TRENT) index for self and others: psychometric properties and emotional responses. AB - BACKGROUND: To enhance the non-technical skills (NTS) assessment literature by developing a reliable and valid peer and self-assessment tool for NTS in a simulated ward setting to include emotional reactions: the Temporal Rating of Emergency Non-Technical skills (TRENT) Index. The paper aims to document (1) the psychometric properties of the TRENT index (e.g., reliability, idiosyncrasy biases) and (2) its validity in terms of performance-emotional associations in the high fidelity simulated ward environment. METHODS: Two samples of doctors (Ns =150 & 90) taking part in emergency simulations provided both self and peer assessment of NTS, with the second sample also providing self-assessments of mood. The psychometric properties of the TRENT were explored for self- and peer assessment, and pre- and post-simulation environment mood was used to assess validity. RESULTS: A psychometrically reliable and valid 5-factor assessment of NTS was developed. While there was evidence for both intra-rater and inter-rater reliability, inter-rater idiosyncrasy was also observed. Self-rated, but not peer rated, negative performance was positively associated with post simulation negative mood. CONCLUSION: These are the first results that pertain to inter-, intra-rater reliability as well as idiosyncratic biases in NTS assessment and the first to show that simulator performance can influence mood after assessment. Potential clinical carry-over effects of mood are discussed. PMID- 25431183 TI - Better Health With More Friends: The Role of Social Capital in Producing Health. AB - This paper estimates the effect of an individual's number of friends on own health outcomes. The identification strategy exploits the panel structure of the friendship data from the National Longitudinal Study of Adolescent Health to estimate individual fixed effects in the likelihood of friendship formation and then uses the fixed effect estimates as a control function in a model relating health outcomes to number of friends. Empirical results show that having a larger number of friends improves physical and mental health and also lowers the frequency of smoking cigarettes. Specifically, making one more friend increases an individual's general health measure by 6.6% of a standard deviation. This suggests that accumulating social capital through friendship interactions is beneficial to health. PMID- 25431184 TI - The evaluation of reduction of Fe(III) in 3-hydroxy-4-nitroso-2,7-naphthalene disulphonic medium as an alternative ferric reducing activity power assay. AB - INTRODUCTION: The growing interest in determination of anti-oxidant capacity through non-labour, effective and less costly methods encouraged the development of the spectrophotometric procedure presented in this study. OBJECTIVE: To investigate the reduction reaction of Fe(III) in 3-hydroxy-4-nitroso-2,7 naphthalenedisulphonic anion (NRS) medium as an alternative ferric reducing activity power (FRAP) assay for determining the total reduction capacity (RC). MATERIALS AND METHODS: The absorbance values at 730 nm were used to determine the RC of aqueous extracts of nine Brazilian plants. The results were compared with the values obtained with the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method and with the total polyphenol content (TPC). The RCs of phenolic derivatives, flavonoids, amino acids and other anti-oxidant compounds were determined. RESULTS: Paired t test with RC values obtained with both assays (proposed FRAP and DPPH) showed no statistically significant difference. In addition, the RC values from the proposed FRAP assay are proportional to those found with TPC values (r =0.916). In addition, the conditional reduction potential of the Fe(III)/Fe(II) couple (0.685 V vs NHE (normal hydrogen electrode)) and the molar absorptivities at 730 nm of the Fe(NRS)(3)(3-) and Fe(NRS)(3)(4-) complexes (1.88 * 10(3) and 1.77 * 10(4) L/cm * mol, respectively) were calculated because these values were not available. CONCLUSION: The proposed assay is adequate for determination of the RC of plant extracts, and the results infer that other samples derived from plants (e.g. beers and wines) and even biological samples (e.g. serum and urine) also could be analysed. PMID- 25431185 TI - Chemical analysis and in vitro antiviral and antifungal activities of essential oils from Glechon spathulata and Glechon marifolia. AB - CONTEXT: Glechon spathulata Benth. and Glechon marifolia Benth. (Lamiaceae, Mentheae) are aromatic plants used in traditional medicine for the treatment of viral infections. OBJECTIVE: The chemical composition and antiviral and antifungal activities of Glechon spathulata and Glechon marifolia essential oils were investigated. MATERIALS AND METHODS: The oils were obtained by hydrodistillation and analyzed by GC-FID and GC-MS. Anti-herpes virus (HSV-1) activity was examined in Vero cells by yield reduction assay, in doses of 0.0095% v/v and 0.039% v/v, for G. spathulata and G. marifolia oil, respectively. Antifungal activity was carried by the broth microdilution method, in oil concentrations that ranged from 5.2 to 500 ug/mL. RESULTS: beta-Caryophyllene (14.2% and 32.2% for G. spathulata and G. marifolia, respectively) and bicyclogermacrene (17.1% and 16.5%, respectively) were the major components of both oils. At noncytotoxic concentrations of the essential oils, the viral titer was reduced by up to 2 log10 for KOS and VR-733 strains. The antifungal activity was observed against Trichophyton rubrum (MIC 10-83 ug/mL) and Epidermophyton floccosum (MIC 83-500 ug/mL). The oil of G. spathulata exhibited activity against the three strains tested (KOS, VR733, and 29-R), whereas G. marifolia oil was active against two strains, KOS and VR733. DISCUSSION AND CONCLUSION: The chemical composition for G. spathulata and G. marifolia essential oils is very similar. The oil of G. spathulata can be promising as a new antifungal agent against dermatophytes. The findings add important information to the biological activity of Glechon species essential oils, specifically its antiviral and antidermatophytic properties. PMID- 25431186 TI - Quantile regression model for a diverse set of chemicals: application to acute toxicity for green algae. AB - The potential of quantile regression (QR) and quantile support vector machine regression (QSVMR) was analyzed for the definitions of quantitative structure activity relationship (QSAR) models associated with a diverse set of chemicals toward a particular endpoint. This study focused on a specific sensitive endpoint (acute toxicity to algae) for which even a narcosis QSAR model is not actually clear. An initial dataset including more than 401 ecotoxicological data for one species of algae (Selenastrum capricornutum) was defined. This set corresponds to a large sample of chemicals ranging from classical organic chemicals to pesticides. From this original data set, the selection of the different subsets was made in terms of the notion of toxic ratio (TR), a parameter based on the ratio between predicted and experimental values. The robustness of QR and QSVMR to outliers was clearly observed, thus demonstrating that this approach represents a major interest for QSAR associated with a diverse set of chemicals. We focused particularly on descriptors related to molecular surface properties. PMID- 25431187 TI - Exploratory conformational study of (+)-catechin. Modeling of the polarizability and electric dipole moment. AB - The extension of the study of the conformational space of the structure of (+) catechin at the B3LYP/6-31G(d,p) level of theory is presented in this paper. (+) Catechin belongs to the family of the flavan-3-ols, which is one of the five largest phenolic groups widely distributed in nature, and whose biological activity and pharmaceutical utility are related to the antioxidant activity due to their ability to scavenge free radicals. The effects of free rotation around all C-O bonds of the OH substituents at different rings are taken into account, obtaining as the most stable conformer, one that had not been previously reported. One hundred seven structures, and a study of the effects of charge delocalization and stereoelectronic effects at the B3LYP/6-311++G(d,p) level are reported by natural bond orbital analysis, streamlining the order of these structures. For further analysis of the structural and molecular properties of this compound in a biological environment, the calculation of polarizabilities, and the study of the electric dipole moment are performed considering the whole conformational space described. The results are analyzed in terms of accumulated knowledge for (4alpha -> 6", 2alpha -> O -> 1")-phenylflavans and (+)-catechin in previous works, enriching the study of both types of structures, and taking into account the importance of considering the whole conformational space in modeling both the polarizability and the electric dipole moment, also proposing to define a descriptive subspace of only 16 conformers. PMID- 25431188 TI - Glucose- and cellulose-derived Ni/C-SO3H catalysts for liquid phase phenol hydrodeoxygenation. AB - Sulfonated carbons were explored as functionalized supports for Ni nanoparticles to hydrodeoxygenate (HDO) phenol. Both hexadecane and water were used as solvents. The dual-functional Ni catalysts supported on sulfonated carbon (Ni/C SO3H) showed high rates for phenol hydrodeoxygenation in liquid hexadecane, but not in water. Glucose and cellulose were precursors to the carbon supports. Changes in the carbons resulting from sulfonation of the carbons resulted in variations of carbon sheet structures, morphologies and the surface concentrations of acid sites. While the C-SO3H supports were active for cyclohexanol dehydration in hexadecane and water, Ni/C-SO3H only catalysed the reduction of phenol to cyclohexanol in water. The state of 3-5 nm grafted Ni particles was analysed by in situ X-ray absorption spectroscopy. The results show that the metallic Ni was rapidly formed in situ without detectable leaching to the aqueous phase, suggesting that just the acid functions on Ni/C-SO3H are inhibited in the presence of water. Using in situ IR spectroscopy, it was shown that even in hexadecane, phenol HDO is limited by the dehydration step. Thus, phenol HDO catalysis was further improved by physically admixing C-SO3H with the Ni/C-SO3H catalyst to balance the two catalytic functions. The minimum addition of 7 wt % C-SO3H to the most active of the Ni/C-SO3H catalysts enabled nearly quantitative conversion of phenol and the highest selectivity (90%) towards cyclohexane in 6 h, at temperatures as low as 473 K, suggesting that the proximity to Ni limits the acid properties of the support. PMID- 25431189 TI - Pictorial review of normal postoperative cross-sectional imaging findings and infectious complications following laparoscopic appendectomy. AB - Laparoscopic appendectomy is increasingly accepted as the preferred surgical treatment for acute appendicitis and represents one of the most common emergency operations performed in both adult and paediatric populations. However, in patients with perforated appendicitis laparoscopy is associated with an increased incidence of postoperative intraabdominal infections compared to open appendectomy. Nowadays urgent imaging is commonly requested by surgeons when postoperative complications are suspected. Due to the widespread use of laparoscopy, in hospitals with active surgical practices clinicians and radiologists are increasingly faced with suspected postappendectomy complications. This pictorial essay illustrates the normal cross-sectional imaging findings observed shortly after laparoscopic appendectomy and the spectrum of appearances of iatrogenic intraabdominal infections observed in adults and adolescents, aiming to provide radiologists with an increased familiarity with early postoperative imaging. Emphasis is placed on the role of multidetector CT, which according to the most recent World Society of Emergency Surgery (WSES) guidelines is the preferred and most accurate modality to promptly investigate suspected intraabdominal infections and highly helpful for correct therapeutic choice, particularly to identify those occurrences that require in hospital treatment, drainage or surgical reintervention. In teenagers and young adults MRI represents an attractive alternative modality to detect or exclude iatrogenic abscesses without ionising radiation. Teaching points * Laparoscopic appendectomy is the preferred surgical treatment for uncomplicated acute appendicitis * In perforated appendicitis laparoscopy results in increased incidence of intraabdominal infections * Multidetector CT promptly assesses suspected iatrogenic intraabdominal infections * Interpretation of early postoperative CT requires knowledge of normal postsurgical imaging findings * Postsurgical infections include right-sided peritonitis, intraabdominal, pelvic or liver abscesses. PMID- 25431191 TI - Molecular characterization of the Gossypium Diversity Reference Set of the US National Cotton Germplasm Collection. AB - KEY MESSAGE: A core marker set containing markers developed to be informative within a single commercial cotton species can elucidate diversity structure within a multi-species subset of the Gossypium germplasm collection. An understanding of the genetic diversity of cotton (Gossypium spp.) as represented in the US National Cotton Germplasm Collection is essential to develop strategies for collecting, conserving, and utilizing these germplasm resources. The US collection is one of the largest world collections and includes not only accessions with improved yield and fiber quality within cultivated species, but also accessions possessing sources of abiotic and biotic stress resistance often found in wild species. We evaluated the genetic diversity of a subset of 272 diploid and 1,984 tetraploid accessions in the collection (designated the Gossypium Diversity Reference Set) using a core set of 105 microsatellite markers. Utility of the core set of markers in differentiating intra-genome variation was much greater in commercial tetraploid genomes (99.7 % polymorphic bands) than in wild diploid genomes (72.7 % polymorphic bands), and may have been influenced by pre-selection of markers for effectiveness in the commercial species. Principal coordinate analyses revealed that the marker set differentiated interspecific variation among tetraploid species, but was only capable of partially differentiating among species and genomes of the wild diploids. Putative species-specific marker bands in G. hirsutum (73) and G. barbadense (81) were identified that could be used for qualitative identification of misclassifications, redundancies, and introgression within commercial tetraploid species. The results of this broad-scale molecular characterization are essential to the management and conservation of the collection and provide insight and guidance in the use of the collection by the cotton research community in their cotton improvement efforts. PMID- 25431192 TI - Mitigation of environmental impacts due to ghat road formation in Palamalai Hills, South India, by optimizing cut and fill volumes using GPS and GIS techniques. AB - Formation of new roads generally brings about adverse impact on the environment, and in the case of hill roads, the impact is diverse and effective measures are required to mitigate it. The common problems in hill road formation are tree cutting, destruction of canopies, change in land use pattern, soil erosion, slope instability, induced landslides, invasion of foreign species, and so on. Removal of trees and vegetations causes rapid soil erosion, landslides, and invasion of foreign species posing danger to the survival of weak native species. Dumping of surplus earth materials on the valley side poses a significant threat to the environment as it would cause induced landslides. Using the cut earth for filling in road formation and dumping, the surplus cut earth in safe locations will reduce environmental degradation considerably. Conventionally, hill road alignments are finalized using traditional survey methods using ghat tracer, compass, and leveling surveys which require enormous complicated field and office works. Any revision to reduce the quantum of earthwork is difficult in this method due to its complex nature. In the present study at Palamalai Hills, South India, an alignment for a length of 7.95 km was prepared by traditional methods using ghat tracer and total station instruments for survey works. The earthwork quantities were ascertained from the longitudinal profile of the alignment. A GPS survey was also conducted along the alignment to examine its utility in alignment modification. To modify the stretches, where the earthwork cutting and filling are above normal and unbalanced and result in surplus earth, repeated GPS surveys were conducted along different paths to optimize the earthwork. The earthwork quantities of the original alignment were analyzed, and its correlation with environmental effect and the usefulness of the GPS survey in this task are presented in this paper. PMID- 25431190 TI - Differential gene expression and alternative splicing in insect immune specificity. AB - BACKGROUND: Ecological studies routinely show genotype-genotype interactions between insects and their parasites. The mechanisms behind these interactions are not clearly understood. Using the bumblebee Bombus terrestris/trypanosome Crithidia bombi model system (two bumblebee colonies by two Crithidia strains), we have carried out a transcriptome-wide analysis of gene expression and alternative splicing in bees during C. bombi infection. We have performed four analyses, 1) comparing gene expression in infected and non-infected bees 24 hours after infection by Crithidia bombi, 2) comparing expression at 24 and 48 hours after C. bombi infection, 3) determining the differential gene expression associated with the bumblebee-Crithidia genotype-genotype interaction at 24 hours after infection and 4) determining the alternative splicing associated with the bumblebee-Crithidia genotype-genotype interaction at 24 hours post infection. RESULTS: We found a large number of genes differentially regulated related to numerous canonical immune pathways. These genes include receptors, signaling pathways and effectors. We discovered a possible interaction between the peritrophic membrane and the insect immune system in defense against Crithidia. Most interestingly, we found differential expression and alternative splicing of immunoglobulin related genes (Dscam and Twitchin) are associated with the genotype-genotype interactions of the given bumblebee colony and Crithidia strain. CONCLUSIONS: In this paper we have shown that the expression and alternative splicing of immune genes is associated with specific interactions between different host and parasite genotypes in this bumblebee/trypanosome model. PMID- 25431193 TI - The structure of informal social networks of persons with profound intellectual and multiple disabilities. AB - BACKGROUND: Persons with less severe disabilities are able to express their needs and show initiatives in social contacts, persons with profound intellectual and multiple disabilities (PIMD), however, depend on others for this. This study analysed the structure of informal networks of persons with PIMD. MATERIALS AND METHODS: Data concerning the number, type and frequency of contacts were collected in 205 persons with PIMD. RESULTS: The mean number of contact persons was 5.1 (range: 0-26, SD: 4.2) per year. 79.4% of the contact persons are family, with an average of 72.3 contacts per year. Parents had significantly more contact compared to the other informal contact persons. In 2.2% of the sample contacts with peers were seen. CONCLUSIONS: The informal networks of persons with PIMD consist mainly of family. The question arises how informal networks can be expanded and which role professionals have in this process. PMID- 25431194 TI - Intestinal metaplasia of the sinonasal mucosa adjacent to intestinal-type adenocarcinoma. A morphologic, immunohistochemical, and molecular study. AB - It has been hypothesized that the development of sinonasal intestinal-type adenocarcinoma (ITAC) occurs through intestinal metaplasia (IM) of the respiratory and/or glandular epithelium. The aim of this study was to characterize the histological, immunohistochemical, and molecular features of sinonasal IM. Histologic slides from 29 consecutive surgical specimens of ITAC were retrieved. Sections were stained for CDX2, cytokeratin 20 (CK20), MUC2, and p53. The status of TP53 gene exons 4-9 was assessed separately in areas of IM and in ITAC. Foci of IM were detected in eight cases (27.5%). They were all positive for CK20 and CDX2, while MUC2 was detected in six cases (75%). In six cases (75%), the metaplastic foci showed signs of dysplasia, including nuclear enlargement with increased nucleus to cytoplasm ratio, nuclear hyperchromasia, loss of nuclear polarity, and presence of prominent nucleoli. P53 nuclear immunoreactivity was observed in four cases. TP53 gene sequencing was successfully performed in six cases and revealed the same mutation in both IM and ITAC in two cases (c.832C > T and c.215G > C), while another ITAC showed a mutation that was not present in the adjacent IM (c.536A > G). In conclusion, our study suggests a possible clonal relationship between areas of sinonasal IM and ITAC, indicating that IM may represent a precursor lesion of ITAC. Improving the knowledge on the morphological and molecular features of IM is a key step to identify reliable biomarkers to determine the risk of sinonasal ITAC development. PMID- 25431195 TI - RAGE mediates the inactivation of nAChRs in sympathetic neurons under high glucose conditions. AB - Autonomic dysfunction is a serious complication of diabetes and can lead to cardiovascular abnormalities and premature death. It was recently proposed that autonomic dysfunction is triggered by oxidation-mediated inactivation of neuronal nicotinic acetylcholine receptors (nAChRs), impairing synaptic transmission in sympathetic ganglia and resulting in autonomic failure. We investigated whether the receptor for advanced glycation end products (RAGE) and its role in the generation of reactive oxygen species (ROS) could be contributing to the events that initiate sympathetic malfunction under high glucose conditions. Using biochemical, live imaging and electrophysiological tools we demonstrated that exposure of sympathetic neurons to high glucose increases RAGE expression and oxidative markers, and that incubation with RAGE ligands (e.g. AGEs, S100 and HMGB1) mimics both ROS elevation and nAChR inactivation. In contrast, co treatment with either antioxidants or an anti-RAGE IgG prevented the inactivation of nAChRs. Lastly, a role for RAGE in this context was corroborated by the lack of sensitivity of sympathetic neurons from RAGE knock-out mice to high glucose. These data define a pivotal role for RAGE in initiating the events associated with exposure of sympathetic neurons to high glucose, and strongly support RAGE signaling as a potential therapeutic target in the autonomic complications associated with diabetes. PMID- 25431196 TI - Bioassay-guided isolation of Poliovirus-inhibiting constituents from Zephyranthes candida. AB - CONTEXT: Plants of the Zephyranthes genus are globally used in folk medicine. In a previous study, Zephyranthes candida Linn. (Amaryllidaceae) was identified as having antiviral properties; this led to anti-poliovirus assay-guided isolation of compounds from crude methanol extract of the plant. OBJECTIVE: Isolation of anti-poliovirus constituents from Z. candida. MATERIAL AND METHODS: Active chloroform fraction from crude methanol extract of Z. candida (whole plant) was subjected to bioassay-guided fractionation; repeated column and preparative thin layer chromatography led to isolation of active compounds. Chemical structures were identified using spectroscopic techniques. Using serial two-fold dilution of maximum non-toxic concentration (MNTC) of each compound (0.0625-1 ug/mL for lycorine and 0.625-10 ug/mL for trisphaeridine and 7-hydroxy-3',4' methylenedioxyflavan), the ability of extracts to inhibit viral-induced cell death in tissue culture was evaluated 72 h post-infection by the colorimetric method using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) dye. Regression analysis was used to determine 50% inhibitory concentration (IC50) and 50% cytotoxicity concentration (CC50), from which selective index (SI) was calculated. RESULTS: From the chloroform fraction, three compounds were isolated and identified, namely lycorine (1), trisphaeridine (2), and 7-hydroxy 3',4'-methylenedioxyflavan (3) as the anti-polioviral components. Lycorine was the most active, with an IC50 value of 0.058 ug/mL followed by trisphaeridine (2) with an IC50 of 0.1427 ug/mL, and 7-hydroxy-3',4'-methylenedioxyflavan (3) with an IC50 of 0.2384 ug/mL. DISCUSSIONS AND CONCLUSIONS: The antipoliovirus activity of trisphaeridine (2) and 7-hydroxy-3',4'-methylenedioxyflavan (3) is established in this report; these compounds are of moderate toxicity and have very good SI. They could be a potential template for the development of a new antiviral agent. PMID- 25431198 TI - The future role of biotechnology to enable next-generation biofuel production. PMID- 25431200 TI - Transient expression assays in grapevine: a step towards genetic improvement. AB - In the past few years, the usefulness of transient expression assays has continuously increased for the characterization of unknown gene function and metabolic pathways. In grapevine (Vitis vinifera L.), one of the most economically important fruit crops in the world, recent systematic sequencing projects produced many gene data sets that require detailed analysis. Due to their rapid nature, transient expression assays are well suited for large-scale genetic studies. Although genes and metabolic pathways of any species can be analysed by transient expression in model plants, a need for homologous systems has emerged to avoid the misinterpretation of results due to a foreign genetic background. Over the last 10 years, various protocols have thus been developed to apply this powerful technology to grapevine. Using cell suspension cultures, somatic embryos, leaves or whole plantlets, transient expression assays enabled the study of the function, regulation and subcellular localization of genes involved in specific metabolic pathways such as the biosynthesis of phenylpropanoids. Disease resistance genes that could be used for marker-assisted selection in conventional breeding or for stable transformation of elite cultivars have also been characterized. Additionally, transient expression assays have proved useful for shaping new tools for grapevine genetic improvement: synthetic promoters, silencing constructs, minimal linear cassettes or viral vectors. This review provides an update on the different tools (DNA constructs, reporter genes, vectors) and methods (Agrobacterium-mediated and direct gene transfer methods) available for transient gene expression in grapevine. The most representative results published thus far are then described. PMID- 25431199 TI - Understanding and engineering beneficial plant-microbe interactions: plant growth promotion in energy crops. AB - Plant production systems globally must be optimized to produce stable high yields from limited land under changing and variable climates. Demands for food, animal feed, and feedstocks for bioenergy and biorefining applications, are increasing with population growth, urbanization and affluence. Low-input, sustainable, alternatives to petrochemical-derived fertilizers and pesticides are required to reduce input costs and maintain or increase yields, with potential biological solutions having an important role to play. In contrast to crops that have been bred for food, many bioenergy crops are largely undomesticated, and so there is an opportunity to harness beneficial plant-microbe relationships which may have been inadvertently lost through intensive crop breeding. Plant-microbe interactions span a wide range of relationships in which one or both of the organisms may have a beneficial, neutral or negative effect on the other partner. A relatively small number of beneficial plant-microbe interactions are well understood and already exploited; however, others remain understudied and represent an untapped reservoir for optimizing plant production. There may be near-term applications for bacterial strains as microbial biopesticides and biofertilizers to increase biomass yield from energy crops grown on land unsuitable for food production. Longer term aims involve the design of synthetic genetic circuits within and between the host and microbes to optimize plant production. A highly exciting prospect is that endosymbionts comprise a unique resource of reduced complexity microbial genomes with adaptive traits of great interest for a wide variety of applications. PMID- 25431201 TI - Modifying plants for biofuel and biomaterial production. AB - The productivity of plants as biofuel or biomaterial crops is established by both the yield of plant biomass per unit area of land and the efficiency of conversion of the biomass to biofuel. Higher yielding biofuel crops with increased conversion efficiencies allow production on a smaller land footprint minimizing competition with agriculture for food production and biodiversity conservation. Plants have traditionally been domesticated for food, fibre and feed applications. However, utilization for biofuels may require the breeding of novel phenotypes, or new species entirely. Genomics approaches support genetic selection strategies to deliver significant genetic improvement of plants as sources of biomass for biofuel manufacture. Genetic modification of plants provides a further range of options for improving the composition of biomass and for plant modifications to assist the fabrication of biofuels. The relative carbohydrate and lignin content influences the deconstruction of plant cell walls to biofuels. Key options for facilitating the deconstruction leading to higher monomeric sugar release from plants include increasing cellulose content, reducing cellulose crystallinity, and/or altering the amount or composition of noncellulosic polysaccharides or lignin. Modification of chemical linkages within and between these biomass components may improve the ease of deconstruction. Expression of enzymes in the plant may provide a cost-effective option for biochemical conversion to biofuel. PMID- 25431202 TI - Rice transgene flow: its patterns, model and risk management. AB - Progress has been made in a 12 year's systemic study on the rice transgene flow including (i) with experiments conducted at multiple locations and years using up to 21 pollen recipients, we have elucidated the patterns of transgene flow to different types of rice. The frequency to male sterile lines is 10(1) and 10(3) higher than that to O. rufipogon and rice cultivars. Wind speed and direction are the key meteorological factors affecting rice transgene flow. (ii) A regional applicable rice gene flow model is established and used to predict the maximum threshold distances (MTDs) of gene flow during 30 years in 993 major rice producing counties of southern China. The MTD0.1% for rice cultivars is basically <=5 m in the whole region, despite climate differs significantly at diverse locations and years. This figure is particularly valuable for the commercialization and regulation of transgenic rice. (iii) The long-term fate of transgene integrated into common wild rice was investigated. Results demonstrated that the F1 hybrids of transgenic rice/O. rufipogon gradually disappeared within 3-5 years, and the Bt or bar gene was not detectable in the mixed population, suggesting the O. rufipogon may possess a strong mechanism of exclusiveness for self-protection. (iv) The flowering time isolation and a 2-m-high cloth-screen protection were proved to be effective in reducing transgene flow. We have proposed to use a principle of classification and threshold management for different types of rice. PMID- 25431203 TI - RNAi-based GM plants: food for thought for risk assessors. AB - RNA interference (RNAi) is an emerging technology that offers new opportunities for the generation of new traits in genetically modified (GM) plants. Potential risks associated with RNAi-based GM plants and issues specific to their risk assessment were discussed during an international scientific workshop (June 2014) organized by the European Food Safety Authority (EFSA). Selected key outcomes of the workshop are reported here. PMID- 25431204 TI - Expression and diagnostic implications of carbonic anhydrase IX in several tumours with predominantly clear cell morphology. AB - AIMS: High expression of carbonic anhydrase IX (CA IX) has been reported in clear cell renal cell carcinoma (ccRCC); few studies have reported CA IX expression in other tumours with predominantly clear cell morphology. The aim of study was to examine the expression and diagnostic implications of CA IX in these latter tumours. METHODS AND RESULTS: An immunohistochemical study was performed of 159 tumours with predominantly clear cell morphology. The results showed that, in addition to primary (25/25) and metastatic (10/11) ccRCC, CA IX was also expressed in breast (2/2), pulmonary (3/5) and hepatic (1/4) clear cell carcinoma, urothelial carcinoma with clear cell change (3/6), clear cell meningioma (4/6) and ependymoma (2/3), haemangioblastoma (10/10), and clear cell hidradenoma (5/6). However, while strong and diffuse positivity for CA IX was observed in ccRCC, clear cell breast carcinoma, haemangioblastoma, and clear cell hidradenoma, the other cases showed predominantly focal positivity for CA IX. In particular, CA IX staining was often seen at the periphery of necrotic areas. CONCLUSIONS: Our results indicate that strong and diffuse CA IX expression may be useful for differentiating ccRCC from several clear cell tumours, with the exception of clear cell breast carcinoma, haemangioblastoma, and clear cell hidradenoma. PMID- 25431205 TI - Trend in distribution of primary health care professionals in Jiangsu province of eastern China. AB - INTRODUCTION: Since the late 1990 s, the Chinese government has carried out several reforms on the primary health care, which is greatly improved but still left much to be desired, especially for the health workforces. The aim of this study was to analyze the number of health workforces and the trends in distribution of health workforces in Jiangsu province of eastern China from 2008 to 2012. METHODS: The time trends in number and distribution of health professionals were compared in study period. Lorenz curves were plotted and Gini coefficient, Atkinson index and Theil index were calculated for inequalities in the distribution of health workforces to population and area. RESULTS: The number of health workforces increased every year and the inequality in the distribution of health workforces showed a decline trend from 2008 to 2012. After 2009, these trends changed more rapidly. There was the disproportionality between physicians and nurses. The values of three inequality indicators based on area were larger than those based on population. CONCLUSION: The health reform in 2009 might play an important role in increasing the number of health workforces and improving the distribution of health workforces in primary health care facilities. The disproportionality between physicians and nurses was related to the shortage of number of nurses. PMID- 25431206 TI - The Ontario Brain Institute: completing the circle. AB - The Province of Ontario recognized the pressing need to improve the understanding, diagnosis, and treatment of brain disorders. It also recognized that maximizing the existing strengths through a province-wide integrated approach was a pivotal mechanism. To achieve this, the Province established the Ontario Brain Institute. The goal of this article is to introduce the elements of the Ontario Brain Institute to the neuroscience community: the motivation for establishing it, the philosophy behind its creation, the principles guiding its development, the rapid evolution of its functional structure, the tools available to achieve its vision, and the management structure to ensure success. The singular goal of the Province and the Ontario Brain Institute is a comprehensive system that assures that basic research is embedded in the clinical system and is facilitating product development to accelerate benefits to both health and the economy of health: science with impact. PMID- 25431207 TI - Endoscopic transphenoidal surgery for acromegaly improves quality of life. AB - BACKGROUND: Acromegaly has important effects on quality of life (QOL). This is the first study to measure QOL in acromegalic patients after endoscopic transsphenoidal surgery (ETSS). METHODS: We prospectively collected the RAND-36, Center for Epidemiologic Studies Depression (CES-D), and Pituitary QOL validated questionnaires and patients' demographics, clinical presentation, endocrine laboratory results, radiological studies, development of complications and remission rates from 20 consecutive acromegalic patients who had undergone endoscopic transphenoidal surgery. RESULTS: The eleven females and nine males had an average age of 42 years; 90 percent had macroadenomas and 70% had cavernous sinus invasion on their preoperative imaging. Ninety percent had improved symptoms post-operatively and 80% stated that treatment improved their QOL. Biochemically, 35% were cured, 35% had discordant results and 30% were not cured, while pan-hypopituitarism occurred in 4 patients. Physical health subscales and pituitary-related symptoms were similar to norms. "Social," "emotional health," and "energy levels" were significantly lower than norms. Seventy percent stated that their relationship with their physician "very much so" affected their quality of life. Pan hypopituitarism and adjuvant therapy were the most significant predictors of lower QOL subscale scores. CONCLUSION: Transsphenoidal surgery improves QOL in acromegaly. Attempts to achieve a cure, avoidance of surgically induced pan-hypotpituitarism and adjuvant therapy, will improve quality of life. Our study demonstrates the important role of the patient physician relationship to QOL and the need to measure QOL in addition to the traditional measures of outcome. PMID- 25431209 TI - Rate modulation drugs in atrial fibrillation: what is the clinical impact? PMID- 25431208 TI - OTUB1 promotes metastasis and serves as a marker of poor prognosis in colorectal cancer. AB - BACKGROUND: OTUB1 (OTU deubiquitinase, ubiquitin aldehyde binding 1) is a deubiquitinating enzyme (DUB) that belongs to the OTU (ovarian tumor) superfamily. The aim of this study was to clarify the role of OTUB1 in colorectal cancer (CRC) and to identify the mechanism underlying its function. METHODS: Two hundred and sixty CRC samples were subjected to association analysis of OTUB1 expression and clinicopathological variables using immunohistochemical (IHC) staining. Overexpression of OTUB1 was achieved in SW480 and DLD-1 cells, and downregulation of OTUB1 was employed in SW620 cells. Then, migration and invasion assays were performed, and markers of the epithelial-mesenchymal transition (EMT) were analyzed. In addition, hepatic metastasis models in mice were used to validate the function of OTUB1 in vivo. RESULTS: OTUB1 was overexpressed in CRC tissues, and the expression level of OTUB1 was associated with metastasis. A high expression level of OTUB1 was also associated with poor survival, and OTUB1 served as an independent prognostic factor in multivariate analysis. OTUB1 also promoted the metastasis of CRC cell lines in vitro and in vivo by regulating EMT. CONCLUSIONS: OTUB1 promotes CRC metastasis by facilitating EMT and acts as a potential distant metastasis marker and prognostic factor in CRC. Targeting OTUB1 may be helpful for the treatment of CRC. PMID- 25431210 TI - Convergent nociceptive input to spinal dorsal horn neurons after peripheral nerve injury. AB - The number of c-Fos protein-like immunoreactive (c-Fos-IR) neurons in the spinal dorsal horn evoked by noxious stimulation was previously shown to be increased following peripheral nerve injury, and this increase was proposed to reflect the neuropathic pain state. The aim of this study was to investigate whether anomalous convergent primary afferent input to spinal dorsal horn neurons contributed to nerve injury-induced c-Fos hyperinducibility. Double immunofluorescence labeling for c-Fos and phosphorylated extracellular signal regulated kinase (p-ERK) was performed to detect convergent synaptic input from different branches of the sciatic nerve after injury to the tibial nerve. c-Fos expression and the phosphorylation of ERK were induced by noxious heat stimulation of the hindpaw and also by electrical stimulation (ES) of the injured tibial nerve, respectively. The number of c-Fos-IR neurons was significantly decreased 3 days after the injury. However, the number of c-Fos-IR neurons returned to the control level 14 days after the injury. P-ERK immunoreactive (p ERK-IR) neurons were induced in the central terminal field of the tibial nerve by ES of the tibial nerve. The topographic distribution pattern and number of such p ERK-IR neurons remained unchanged after the nerve injury. The time course of changes in the number of double-labeled neurons, that presumably received convergent primary afferent input, showed a pattern similar to that of c-Fos-IR neurons after the injury. These results indicate that convergent primary nociceptive input through neighboring intact nerves may contribute to c-Fos hyperinducibility in the spinal dorsal horn. PMID- 25431211 TI - Treatment of Gram-positive infections in critically ill patients. AB - Gram-positive bacteria to include methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible Staphylococcus aureus (MSSA), and enterococci, to include vancomycin-resistant enterococci (VRE), display a remarkable array of resistance and virulence factors, which have contributed to their prominent role in infections of the critically ill. Over the last three decades infections with these pathogens has increased as has their overall resistance to available antimicrobial agents. This has led to the development of a number of new antibiotics for the treatment of Gram-positive bacteria. At present, it is important that clinicians recognize the changing resistance patterns and epidemiology of Gram-positive bacteria as these factors may impact patient outcomes. The increasing range of these pathogens, such as the emergence of community-associated MRSA clones, emphasizes that all specialties of physicians treating infections should have a good understanding of the infections caused by Gram-positive bacteria in their area of practice. When initiating empiric antibiotics, it is of vital importance that this therapy be timely and appropriate, as delays in treatment are associated with adverse outcomes. Although vancomycin has traditionally been considered a first-line therapy for serious MRSA infections, multiple concerns with this agent have opened the door for alternative agents demonstrating efficacy in this role. Similarly, the expansion of VRE as a pathogen in the ICU setting has required the development of agents targeting this important pathogen. PMID- 25431212 TI - A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: a pediatric brain tumor consortium study. AB - BACKGROUND: We sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cbeta, in children with recurrent central nervous system malignancies. METHODS: Enzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m(2)) and twice daily at 440 mg/m(2)/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated. Akt pathway activity was measured in pretreatment tumor samples. RESULTS: Thirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m(2) given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transaminase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m(2) dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease >3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma. CONCLUSION: Enzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m(2)/day administered once daily. PMID- 25431213 TI - Sphingosine 1-phosphate to p38 signaling via S1P1 receptor and Galphai/o evokes augmentation of capsaicin-induced ionic currents in mouse sensory neurons. AB - The perception of painful thermal stimuli by sensory neurons is largely mediated by TRPV1. Upon tissue injury or inflammation, S1P is secreted by thrombocytes as part of an inflammatory cocktail, which sensitizes nociceptive neurons towards thermal stimuli. S1P acts on G-protein coupled receptors that are expressed in sensory neurons and sensitize TRPV1 channels towards thermal stimuli. In this study, the S1P mediated signaling pathway required for sensitization of TRPV1 channels was explored.The capsaicin induced peak inward current (ICAPS) of sensory neurons was significantly increased after S1P stimulation within minutes after application. The potentiation of ICAPS resulted from activation of Galphai through G-protein coupled receptors for S1P. Consequently, Galphai led to a signaling cascade, involving phosphoinositide-3-kinase (PI3K) and protein kinase C, which augmented ICAPS in nociceptive neurons. The S1P1 receptor agonist SEW2871 resulted in activation of the same signaling pathway and potentiation of ICAPS. Furthermore, the mitogen-activated protein kinase p38 was phosphorylated after S1P stimulation and inhibition of p38 signaling by SB203580 prevented the S1P-induced ICAPS potentiation. The current data suggest that S1P sensitized ICAPS through G-protein coupled S1P1 receptor activation of Galphai-PI3K-PKC-p38 signaling pathway in sensory neurons. PMID- 25431214 TI - Relationship between apoptosis imaging and radioiodine therapy in tumor cells with different sodium iodide symporter gene expression. AB - The therapeutic efficacy of radioiodine (131I) therapy has been reported to be variable among cancer patients and even between metastatic regions in the same patients. Because the expression level of sodium iodide symporter (NIS) cannot reflect the efficacy of therapy, other strategies are required to predict the precise therapeutic effect of 131I therapy. In this research, we investigated the correlation between iodine (I) uptake, apoptosis imaging, and therapeutic efficacy. Two HT29 cell lines, cytomegalovirus (CMV)-NIS (or NIS+++) and TERT-NIS (or NIS+), were established by retroviral transfection. I uptake was estimated by I-uptake assay and gamma camera imaging. Apoptosis was evaluated by confocal microscopy and a Maestro fluorescence imaging system (CRi Inc., Woburn, MA) using ApoFlamma (BioACTs, Seoul, Korea), a fluorescent dye-conjugated apoptosis targeting peptide 1 (ApoPep-1). Therapeutic efficacy was determined by tumor size. The CMV-NIS showed higher I uptake and ApoFlamma signals than TERT-NIS. In xenograft models, CMV-NIS also showed high 99m technetium signals and ApoFlamma signals. Tumor reduction had a stronger correlation with apoptosis imaging signals than with gamma camera imaging signals, which reflect I uptake. Higher NIS-expressing tumors showed increased apoptosis and I uptake, resulting in a significant tumor reduction. Moreover, tumor reduction showed a strong correlation with ApoFlamma imaging compared to I-uptake imaging. PMID- 25431215 TI - Correction power and complications of first tarsometatarsal joint arthrodesis for hallux valgus deformity. AB - PURPOSE: First tarsometatarsal joint (TMTJ) arthrodesis is known as a powerful operative procedure to correct moderate to severe hallux valgus deformity. However, there is little evidence about actual complication rates and angular correctional power. The aims of the present study were to evaluate the (1) angular correction power and (2) complication rates of pooled data for this procedure and to perform subgroup analysis of different methods of fixation. METHODS: A systematic search for the MeSH terms "(hallux OR bunion) AND (lapidus OR TMT OR tarsometatarsal OR metatarsocuneiform) AND (fusion OR arthrodesis)" with use of the online databases MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews was conducted. RESULTS: Twenty-nine studies with a total amount of 1,470 operated feet in 1,268 patients with a mean age of 46.9 years (range, 16.5-61.9) and a mean follow-up period of 28.5 months (range, 6.0-75.6) were included. The correction of IMA averaged 9.12 degrees for screw fixation, 9.75 degrees for staple fixation, 12.41 degrees for combined locking plate with screw fixation, 14.36 degrees for screw with K-wire fixation, 8.50 degrees for pin fixation and 8.60 degrees for external fixation (p = .0251). The overall complication rate reached 16.05 % with a nonunion rate of 4.01 %. CONCLUSION: Based on meta analysis data, first TMTJ arthrodesis reveals higher corrective power compared to meta-analysis data on proximal, diaphyseal and distal metatarsal osteotomies. PMID- 25431216 TI - Glenoid rim fracture through anchor points after arthroscopic Bankart repair for shoulder instability. AB - PURPOSE: We studied the incidence of postoperative glenoid rim fractures and analysed the relationships of glenoid rim fracture with osteolysis, fracture pattern, number of anchors and postoperative activity after arthroscopic Bankart repair with suture anchor fixation. METHODS: Among 570 patients of the Bankart repair group, nine patients who had undergone revision arthroscopy for glenoid rim fracture after initial Bankart repair with at least two years post-revision follow-up were enrolled. Mean age was 28.8 years (range, 18-49 years), and mean follow-up was 36.4 months (range, 25-64 months). The mean time from Bankart repair to failure of initial surgery following trauma was 27.3 months (range, four to-84 months). Initial suture anchors were made of bioabsorbable composites (poly-D-L-lactic acid, PDLLA) without ceramic osteo-filler (seven cases) and metals (two cases). PDLLA without ceramic osteo-filler suture anchors were used for revision surgery. We reviewed 570 patients for relationship between osteolysis and glenoid rim fracture. RESULTS: Five patients including three and two with bioabsorbable and metal suture anchors, respectively, experienced glenoid rim fracture at more than two years postoperatively. Osteolysis around initial suture anchors groups showed higher glenoid rim fracture incidence compared with the control group (odd ratio =4.186 [95 % CI, 1.108-15.818]; p = 0.037). CONCLUSIONS: Osteolysis related to insertion of metal or PLDDA suture anchors may lead to glenoid rim fracture. Remnant metal or bioabsorbable suture anchors without ceramic composite could be a stress riser at two years postoperatively. PMID- 25431217 TI - Is there any difference in outcome of total hip arthroplasty patients with hip fibrous ankylosis and bony ankylosis? PMID- 25431218 TI - Elastic moduli of permanently densified silica glasses. AB - Modelling the mechanical response of silica glass is still challenging, due to the lack of knowledge concerning the elastic properties of intermediate states of densification. An extensive Brillouin Light Scattering study on permanently densified silica glasses after cold compression in diamond anvil cell has been carried out, in order to deduce the elastic properties of such glasses and to provide new insights concerning the densification process. From sound velocity measurements, we derive phenomenological laws linking the elastic moduli of silica glass as a function of its densification ratio. The found elastic moduli are in excellent agreement with the sparse data extracted from literature, and we show that they do not depend on the thermodynamic path taken during densification (room temperature or heating). We also demonstrate that the longitudinal sound velocity exhibits an anomalous behavior, displaying a minimum for a densification ratio of 5%, and highlight the fact that this anomaly has to be distinguished from the compressibility anomaly of a-SiO2 in the elastic domain. PMID- 25431219 TI - Using Ethical Reasoning to Amplify the Reach and Resonance of Professional Codes of Conduct in Training Big Data Scientists. AB - The use of Big Data--however the term is defined--involves a wide array of issues and stakeholders, thereby increasing numbers of complex decisions around issues including data acquisition, use, and sharing. Big Data is becoming a significant component of practice in an ever-increasing range of disciplines; however, since it is not a coherent "discipline" itself, specific codes of conduct for Big Data users and researchers do not exist. While many institutions have created, or will create, training opportunities (e.g., degree programs, workshops) to prepare people to work in and around Big Data, insufficient time, space, and thought have been dedicated to training these people to engage with the ethical, legal, and social issues in this new domain. Since Big Data practitioners come from, and work in, diverse contexts, neither a relevant professional code of conduct nor specific formal ethics training are likely to be readily available. This normative paper describes an approach to conceptualizing ethical reasoning and integrating it into training for Big Data use and research. Our approach is based on a published framework that emphasizes ethical reasoning rather than topical knowledge. We describe the formation of professional community norms from two key disciplines that contribute to the emergent field of Big Data: computer science and statistics. Historical analogies from these professions suggest strategies for introducing trainees and orienting practitioners both to ethical reasoning and to a code of professional conduct itself. We include two semester course syllabi to strengthen our thesis that codes of conduct (including and beyond those we describe) can be harnessed to support the development of ethical reasoning in, and a sense of professional identity among, Big Data practitioners. PMID- 25431220 TI - Beyond Ethical Frameworks: Using Moral Experimentation in the Engineering Ethics Classroom. AB - Although undergraduate engineering ethics courses often include the development of moral sensitivity as a learning objective and the use of active learning techniques, teaching centers on the transmission of cognitive knowledge. This article describes a complementary assignment asking students to perform an ethics "experiment" on themselves that has a potential to enhance affective learning and moral imagination. The article argues that the focus on cognitive learning may not promote, and may even impair, our efforts to foster moral sensitivity. In contrast, the active learning assignments and exercises, like the ethics "experiment" discussed, offer great potential to expand the scope of instruction in engineering ethics to include ethical behavior as well as knowledge. Engineering ethics education needs to extend beyond the narrow range of human action associated with the technical work of the engineer and explore ways to draw on broader lifeworld experiences to enrich professional practice and identity. PMID- 25431221 TI - Outcomes of direct and indirect medical intensive care unit admissions from the emergency department of an acute care hospital: a retrospective cohort study. AB - OBJECTIVES: This study aimed to determine if the risk of adverse outcomes (in hospital and 60-day mortality, intensive care unit (ICU) and total hospital length of stay (LOS)) was greater for medical ICU (MICU) or high dependency unit (HDU) patients indirectly admitted from the emergency department (ED) than for directly admitted patients. SETTING: This study was conducted at a large public acute care hospital in Singapore. PARTICIPANTS: In this retrospective cohort study, hospital records of patients who were admitted directly from the ED, or initially admitted to the general wards from the ED and subsequently transferred to the MICU/HDU within 24 h, were reviewed. Patients were included if they were: (A) discharged from the MICU/HDU in 2009 and were admitted from the ED and (B) transferred to the MICU/HDU within 24 h of presentation at the ED. Data from 706 patients were analysed; 58.4% were men with a median age of 61 years. PRIMARY AND SECONDARY OUTCOME MEASURES: The following outcomes were compared: in-hospital mortality, 60-day mortality, LOS at the MICU/HDU, as well as total hospital LOS. RESULTS: Of the 706 patients, 491 (69.5%) were directly admitted to the MICU/HDU. After adjusting for demographics, comorbidities, interventions at the ED and clinical parameters at the ED (heart rate, respiration, oxygen saturation, mean arterial pressure), as well as the Apache II score on arrival at the MICU/HDU, indirectly admitted patients had a higher risk of in-hospital mortality (OR=3.07, 95% CI 1.39 to 6.80), death within 60 days (OR=3.09, 95% CI 1.40 to 6.83) and risk of staying >1 day at the MICU/HDU (OR=2.54, 95% CI 1.48 to 4.36). There was no significant difference in total in-hospital LOS. CONCLUSIONS: Indirectly admitted MICU/HDU patients had generally poorer outcomes. As the magnitude of effect may vary across settings, context-specific studies may be useful for improving outcomes. PMID- 25431222 TI - Quality improvement strategies to optimise transition of patients with heart failure to independent living: protocol for a scoping review. AB - INTRODUCTION: Heart failure (HF) is a leading reason for hospitalisation and readmissions to hospital, particularly among individuals older than 65 years of age. The prognosis of patients with HF is grim, with high rates of mortality risk and hospital readmissions. The transition period early after hospital discharge represents a window of opportunity to positively influence patient outcomes using quality improvement (QI) strategies. However, little is known about which QI interventions exist for early events of HF after discharge, so the main objective of our study is to conduct a scoping review of the literature to determine which QI strategies are effective for reducing hospital readmissions and mortality for patients with HF who transition from the hospital back into independent living. We will also investigate which elements contribute to effective QI strategies. METHODS AND ANALYSIS: We will search the literature in MEDLINE, EMBASE, CINAHL and the Cochrane library for randomised controlled trials and systematic reviews evaluating QI interventions aimed at improving outcomes for patients with HF transitioning from the hospital back into the community. Two reviewers will independently apply our eligibility criteria at level 1 (abstract/title) and level 2 (full-text) screening; disagreements will be resolved through consensus. We will extract data in duplicate on study characteristics, population, setting, QI intervention and outcomes. We will synthesise results descriptively and explore QI elements to determine which aspect contributes to its impact. We will also consider synthesis of our data according to several conceptual frameworks such as Wagner's Chronic Care Model. DISCUSSION AND DISSEMINATION: The findings of this scoping review will be used to determine which elements should comprise a QI intervention aimed at facilitating the transition of newly admitted patients with HF back into the community. We will disseminate our findings through publications, presentations as well as through a stakeholder meeting to generate key messages most relevant to each. PMID- 25431223 TI - Clinicobiochemical prediction of biopsy-proven cases of severe hepatic fibrosis in patients with chronic hepatitis C infection. AB - OBJECTIVE: To evaluate clinicobiochemical factors predicting severe hepatic fibrosis in patients with chronic hepatitis C virus (HCV) infection. SETTING: Tertiary institution. PARTICIPANTS: 859 treatment-naive Korean patients with HCV who underwent liver biopsy. Severe fibrosis was defined as fibrosis stage >=3 based on the METAVIR system. PRIMARY OUTCOME MEASURES: Clinicobiochemical factors predicting severe hepatic fibrosis. RESULTS: The median serum alanine aminotransferase (ALT) level was 68 IU/L and body mass index (BMI) was 24.2 kg/m(2). Severe fibrosis was observed in 326 (39.7%) of the 859 patients. The frequencies of severe fibrosis were 0%, 37.8%, 41.9% and 42% in patients with serum ALT concentrations (IU/L) of <=20, 20-30, 30-40 and >40 (p<0.01), respectively, and 10.7%, 19.8%, 30.5%, 39.2% and 55.6% in patients <30, 30-40, 40 50, 50-60 and >=60 years old, respectively (p<0.01). Categorised age in years (50 60 (OR 4.26, p=0.03) and >=60 (OR 7.53, p<0.01) compared with <30), categorised ALT level in IU/L (20-30 (OR 16.76, p<0.01), 30-40 (OR 20.02, p<0.01) and >40 (OR 21.49, p<0.01) compared with <=20) and BMI >27.5 kg/m(2) (OR 1.65, p=0.03) were independently related to severe fibrosis in patients with chronic HCV. The severe fibrosis rate was 60.6% in patients aged >=50 years with ALT >20 IU/L and BMI >27.5 kg/m(2). CONCLUSIONS: More advanced age (>=50 years), obesity and serum ALT>20 IU/L are associated with severe fibrosis in patients with chronic HCV. Anti-HCV therapy may be considered for these patients without histological confirmation, regardless of HCV genotype. A wait-and-see policy may be justified for patients with serum ALT <=20 IU/L. PMID- 25431224 TI - A qualitative analysis of messages to promote smoking cessation among pregnant women. AB - OBJECTIVES: Although aware that smoking while pregnant presents serious risks to their unborn children, some women continue to smoke and rationalise their dissonance rather than quit. We explored metaphors women used to frame smoking and quitting, then developed cessation messages that drew on these metaphors and examined the perceived effectiveness of these. PARTICIPANTS: We used a two-phase qualitative study. Phase one involved 13 in-depth interviews with women who were smoking (or who had smoked) while pregnant. Phase two comprised 22 in-depth interviews with a new sample drawn from the same population. ANALYSES: Data were analysed using thematic analysis, which promoted theme identification independently of the research protocol. RESULTS: Participants often described smoking as a choice, a frame that explicitly asserted control over their behaviour. This stance allowed them to counter-argue messages to quit, and distanced them from the risks they created and faced. Messages tested in phase 2 used strong affective appeals as well as themes that stimulated cognitive reflection. Without exception, the messages depicting unwell or distressed children elicited strong emotional responses, were more powerful cessation stimuli, and elicited fewer counter-arguments. CONCLUSIONS: Cessation messages that evoke strong affective responses capitalise on the dissonance many women feel when smoking while pregnant and stimulate stronger consideration of quitting. Given the importance of promoting cessation among pregnant women, future campaigns could make greater use of emotional appeals and place less emphasis on informational approaches, which often prompt vigorous counter arguments. PMID- 25431226 TI - Metabolic and endocrine response to exercise: sympathoadrenal integration with skeletal muscle. AB - Skeletal muscle has the capacity to increase energy turnover by ~1000 times its resting rate when contracting at the maximum force/power output. Since ATP is not stored in any appreciable quantity, the muscle requires a coordinated metabolic response to maintain an adequate supply of ATP to sustain contractile activity. The integration of intracellular metabolic pathways is dependent upon the cross bridge cycling rate of myosin and actin, substrate availability and the accumulation of metabolic byproducts, all of which can influence the maintenance of contractile activity or result in the onset of fatigue. In addition, the mobilisation of extracellular substrates is dependent upon the integration of both the autonomic nervous system and endocrine systems to coordinate an increase in both carbohydrate and fat availability. The current review examines the evidence for skeletal muscle to generate power over short and long durations and discusses the metabolic response to sustain these processes. The review also considers the endocrine response from the perspective of the sympathoadrenal system to integrate extracellular substrate availability with the increased energy demands made by contracting skeletal muscle. Finally, the review briefly discusses the evidence that muscle acts in an endocrine manner during exercise and what role this might play in mobilising extracellular substrates to augment the effects of the sympathoadrenal system. PMID- 25431225 TI - CUPID: a protocol of a randomised controlled trial to identify characteristics of similar Chinese patent medicines. AB - INTRODUCTION: Traditional Chinese medicine (TCM) has accumulated some experience in curing stable angina pectoris (SAP) and efficacy has been demonstrated. Chinese patent medicines, known as modern dosage forms of TCM, can attain the desired effect in clinical application only with the guidance of TCM syndrome theory. However, due to their use by a large number of persons with little knowledge of TCM theories and practices, their efficacy and reputation have been seriously affected. METHOD AND ANALYSIS: Two common syndrome types of SAP in TCM, 'qi deficiency and blood stasis' and 'qi stagnation and blood stasis', will be studied in 144 subjects from four TCM hospitals in Tianjin in China using a partial crossover design. The two syndromes will be broken down into six symptom combinations; patients will select a combination of the most distressing to them, and then will be randomised into two groups. Each group, on the basis of routine medication, will be administered one kind of Chinese patent drug: Qishenyiqi Dripping Pills or Compound Danshen Dripping Pills. The treatment characteristics of the two medicines will be evaluated with the COME-PIO method developed by our research team. ETHICS AND DISSEMINATION: This protocol has been approved by the medical ethics committee of Tianjin University of TCM (registration number TJUTCM EC20130005). The study is safe and reliable. TRIAL REGISTRATION NUMBER: Chinese clinical trials register ChiCTR-TTRCC-14004406. PMID- 25431227 TI - Tree imbalance causes a bias in phylogenetic estimation of evolutionary timescales using heterochronous sequences. AB - Phylogenetic estimation of evolutionary timescales has become routine in biology, forming the basis of a wide range of evolutionary and ecological studies. However, there are various sources of bias that can affect these estimates. We investigated whether tree imbalance, a property that is commonly observed in phylogenetic trees, can lead to reduced accuracy or precision of phylogenetic timescale estimates. We analysed simulated data sets with calibrations at internal nodes and at the tips, taking into consideration different calibration schemes and levels of tree imbalance. We also investigated the effect of tree imbalance on two empirical data sets: mitogenomes from primates and serial samples of the African swine fever virus. In analyses calibrated using dated, heterochronous tips, we found that tree imbalance had a detrimental impact on precision and produced a bias in which the overall timescale was underestimated. A pronounced effect was observed in analyses with shallow calibrations. The greatest decreases in accuracy usually occurred in the age estimates for medium and deep nodes of the tree. In contrast, analyses calibrated at internal nodes did not display a reduction in estimation accuracy or precision due to tree imbalance. Our results suggest that molecular-clock analyses can be improved by increasing taxon sampling, with the specific aims of including deeper calibrations, breaking up long branches and reducing tree imbalance. PMID- 25431229 TI - An efficient algorithm to explore liquid association on a genome-wide scale. AB - BACKGROUND: The growing wealth of public available gene expression data has made the systemic studies of how genes interact in a cell become more feasible. Liquid association (LA) describes the extent to which coexpression of two genes may vary based on the expression level of a third gene (the controller gene). However, genome-wide application has been difficult and resource-intensive. We propose a new screening algorithm for more efficient processing of LA estimation on a genome-wide scale and apply its use to a Saccharomyces cerevisiae data set. RESULTS: On a test subset of the data, the fast screening algorithm achieved >99.8% agreement with the exhaustive search of LA values, while reduced run time by 81-93 %. Using a well-known yeast cell-cycle data set with 6,178 genes, we identified triplet combinations with significantly large LA values. In an exploratory gene set enrichment analysis, the top terms for the controller genes in these triplets with large LA values are involved in some of the most fundamental processes in yeast such as energy regulation, transportation, and sporulation. CONCLUSION: In summary, in this paper we propose a novel, efficient algorithm to explore LA on a genome-wide scale and identified triplets of interest in cell cycle pathways using the proposed method in a yeast data set. A software package named fastLiquidAssociation for implementing the algorithm is available through http://www.bioconductor.org . PMID- 25431228 TI - Education and coronary heart disease risk: potential mechanisms such as literacy, perceived constraints, and depressive symptoms. AB - OBJECTIVE: Education is inversely associated with coronary heart disease (CHD) risk; however the mechanisms are poorly understood. The study objectives were to evaluate the extent to which rarely measured factors (literacy, time preference, sense of control) and more commonly measured factors (income, depressive symptomatology, body mass index) in the education-CHD literature explain the associations between education and CHD risk. METHOD: The study sample included 346 participants, aged 38 to 47 years (59.5% women), of the New England Family Study birth cohort. Ten-year CHD risk was calculated using the validated Framingham risk algorithm that utilizes diabetes, smoking, blood pressure, total cholesterol, high-density lipoprotein cholesterol, age, and gender. Multivariable regression and mediation analyses were performed. RESULTS: Regression analyses adjusting for age, race/ethnicity, and childhood confounders (e.g., parental socioeconomic status, intelligence) demonstrated that relative to those with greater than or equal to college education, men and women with less than high school had 73.7% (95% confidence interval [CI; 29.5, 133.0]) and 48.2% (95% CI [17.5, 86.8]) higher 10-year CHD risk, respectively. Mediation analyses demonstrated significant indirect effects for reading comprehension in women (7.2%; 95% CI [0.7, 19.4]) and men (7.2%; 95% CI [0.8, 19.1]), and depressive symptoms (11.8%; 95% CI [2.5, 26.6]) and perceived constraint (6.7%, 95% CI [0.7, 19.1]) in women. CONCLUSIONS: Evidence suggested that reading comprehension in women and men, and depressive symptoms and perceived constraint in women, may mediate some of the association between education and CHD risk. If these mediated effects are interpreted causally, interventions targeting reading, depressive symptoms, and perceived constraint could reduce educational inequalities in CHD. PMID- 25431230 TI - Synthesis of nano-bowls with a Janus template. AB - Colloidal particles with two or more different surface properties (Janus particles) are of interest in catalysis, biological imaging, and drug delivery. Eccentric nanoparticles are a type of Janus particle consisting of a shell that envelops the majority of a core particle, leaving a portion of the core surface exposed. Previous work to synthesize eccentric nanoparticles from silica and polystyrene have only used microemulsion techniques. In contrast we report the sol-gel synthesis of eccentric Janus nanoparticles composed of a silica shell around a carboxylate-modified polystyrene core (Janus templates). In addition, we have synthesized nano-bowl-like structures after the removal of the polystyrene core by organic solvent. These Janus templates and nanobowls can be used as a versatile platform for site-specific functionalization or controlled theranostic delivery. PMID- 25431231 TI - The course of childhood-onset epilepsy over the first two decades: a prospective, longitudinal study. AB - OBJECTIVES: Determine frequency of remissions, relapses, and pharmacoresistance over two decades. Develop a composite measure of seizure control over that time. METHODS: Community-based cohort of children with newly diagnosed epilepsy prospectively followed for up to 21 years with frequent calls and periodic medical record review. Multiple periods of 1-, 2-, 3-, and 5-year remission with subsequent relapses were recorded. Other outcomes included pharmacoresistance (failure of two adequately used drugs), early remission and early pharmacoresistance by 2 years, and complete remission at last contact (CR-LC, 5 years both seizure- and drug-free at last contact). A composite summary of seizure course was created with eight categories ranging from early sustained remission and CR-LC (best) to never achieving a 1-year remission (worst). RESULTS: Five hundred sixteen of 613 participants were followed >=10 years. An initial 1- 2-, 3-, and 5-year remission occurred, respectively, in 95%, 92%, 89%, and 81%. Relapses followed in 52%, 41%, 29%, and 15%, respectively. Repeated remission after relapse was common. Up to seven 1-year, five 2-year and 3-year, and two 5-year remissions were recorded per participant. Pharmacoresistance at any time, early pharmacoresistance (<2 years), early remission, and CR-LC occurred in 118 (22.9%), 70 (13.6%), 283 (54.8%), and 311 (60.3%). Composite outcomes were early sustained remission with CR-LC (N=172, 33%); later but then sustained remission with CR-LC (N=51, 10%); one (N=61, 12%) or more (N=27, 5%) remission-relapse episodes but then CR-LC; various non-CR-LC outcomes (N=179, 35%); and never achieved 1-year remission (N=26, 5%). These patterns varied across groups defined by epilepsy type and presence of brain insults or neurodisability (p<0.0001). SIGNIFICANCE: The seizure prognosis of pediatric epilepsies is highly variable. Most patients follow complex courses not easily summarized by remission status at the end of a period of follow-up. These complexities may facilitate efforts to understand the impact epilepsy has on young people entering adulthood. PMID- 25431232 TI - Glycogen storage disease type III: modified Atkins diet improves myopathy. AB - BACKGROUND: Frequent feeds with carbohydrate-rich meals or continuous enteral feeding has been the therapy of choice in glycogen storage disease (Glycogenosis) type III. Recent guidelines on diagnosis and management recommend frequent feedings with high complex carbohydrates or cornstarch avoiding fasting in children, while in adults a low-carb-high-protein-diet is recommended. While this regimen can prevent hypoglycaemia in children it does not improve skeletal and heart muscle function, which are compromised in patients with glycogenosis IIIa. Administration of carbohydrates may elicit reactive hyperinsulinism, resulting in suppression of lipolysis, ketogenesis, gluconeogenesis, and activation of glycogen synthesis. Thus, heart and skeletal muscle are depleted of energy substrates. Modified Atkins diet leads to increased blood levels of ketone bodies and fatty acids. We hypothesize that this health care intervention improves the energetic balance of muscles. METHODS: We treated 2 boys with glycogenosis IIIa aged 9 and 11 years with a modified Atkins diet (10 g carbohydrate per day, protein and fatty acids ad libitum) over a period of 32 and 26 months, respectively. RESULTS: In both patients, creatine kinase levels in blood dropped in response to Atkins diet. When diet was withdrawn in one of the patients he complained of chest pain, reduced physical strength and creatine kinase levels rapidly increased. This was reversed when Atkins diet was reintroduced. One patient suffered from severe cardiomyopathy which significantly improved under diet. Patients with glycogenosis IIIa benefit from an improved energetic state of heart and skeletal muscle by introduction of Atkins diet both on a biochemical and clinical level. Apart from transient hypoglycaemia no serious adverse effects were observed. PMID- 25431234 TI - Sleep characteristics, chronotype and winter depression in 10-20-year-olds in northern European Russia. AB - The purpose of this work was to examine the relationships between geographical coordinates and the prevalence of winter depression (SADW ), and to compare the sleep characteristics and chronotype of youths with and without SADW . We conducted a cross-sectional study of self-reported sleep characteristics, chronotype and winter depression in northern European Russia. Two questionnaires, the Munich Chronotype Questionnaire (MCTQ) and the Seasonal Pattern Assessment Questionnaire (SPAQ), were administered to a total of 3435 adolescents aged 10-20 years (1517 males and 1918 females). The prevalence of SADW in the study population was 8.4% and sub-SADW 11.8%. Four variables predicted the likelihood of SADW in youths: sex [higher in females: odds ratio (OR): 1.87, P < 0.0001], age (increases with age: OR: 1.09, P < 0.001), latitude (higher in the North: OR: 1.49, P < 0.029) and position in the time zone (higher in the West: OR: 1.61, P < 0.001). Later sleeping and waking, longer sleep latencies, more severe sleep inertia, shorter total sleep times and lower sleep efficiencies were observed in both males and females with SADW . The influence of SADW on sleep characteristics was more pronounced on school days. Significant phase delays of the sleep-wake rhythm and severe social jetlag (the difference between the mid-point of sleep phase at weekends and on workdays) were observed in females with SADW , but not in males. There are significant differences in sleep characteristics and chronotype between people with SADW and no-SAD. We demonstrate that both latitude of residence and location within the time zone are significant predictors of SADW in young inhabitants of the North. PMID- 25431233 TI - Training improves visual processing speed and generalizes to untrained functions. AB - Studies show that manipulating certain training features in perceptual learning determines the specificity of the improvement. The improvement in abnormal visual processing following training and its generalization to visual acuity, as measured on static clinical charts, can be explained by improved sensitivity or processing speed. Crowding, the inability to recognize objects in a clutter, fundamentally limits conscious visual perception. Although it was largely considered absent in the fovea, earlier studies report foveal crowding upon very brief exposures or following spatial manipulations. Here we used GlassesOff's application for iDevices to train foveal vision of young participants. The training was performed at reading distance based on contrast detection tasks under different spatial and temporal constraints using Gabor patches aimed at testing improvement of processing speed. We found several significant improvements in spatio-temporal visual functions including near and also non trained far distances. A remarkable transfer to visual acuity measured under crowded conditions resulted in reduced processing time of 81 ms, in order to achieve 6/6 acuity. Despite a subtle change in contrast sensitivity, a robust increase in processing speed was found. Thus, enhanced processing speed may lead to overcoming foveal crowding and might be the enabling factor for generalization to other visual functions. PMID- 25431235 TI - Nuclear expression and gain-of-function beta-catenin mutation in glomangiopericytoma (sinonasal-type hemangiopericytoma): insight into pathogenesis and a diagnostic marker. AB - Glomangiopericytoma (sinonasal-type hemangiopericytoma) is a rare mesenchymal neoplasm with myoid phenotype (smooth muscle actin-positive), which distinguishes this tumor from soft tissue hemangiopericytoma/solitary fibrous tumor. Molecular genetic changes underlying the pathogenesis of glomangiopericytoma are not known. In this study, 13 well-characterized glomangiopericytomas were immunohistochemically evaluated for beta-catenin expression. All analyzed tumors showed strong expression and nuclear accumulation of beta-catenin. Following this observation, beta-catenin glycogen serine kinase-3 beta phosphorylation region, encoded by exon 3, was PCR amplified in all cases and evaluated for mutations using Sanger sequencing. Heterozygous mutations were identified in 12 of 13 tumors. All mutations consisted of single-nucleotide substitutions: three in codon 32 (c.94G>C (n=2) and c.95A>T), four in codon 33 (two each c.98C>G and c.98C>T), two in codon 37 (c.109T>G), one in codon 41 (c.121A>G), and two in codon 45 (c.133T>C). At the protein level, these substitutions would lead to p.D32H, p.D32V, p.S33C, p.S33F, p.S37A, p.T41A, and p.S45L mutations, respectively. Previously, similar mutations have been reported in different types of cancers and shown to trigger activation of beta-catenin signaling. All analyzed glomangiopericytomas showed prominent nuclear expression of cyclin D1, as previously shown for tumors with nuclear expression of beta-catenin as a sign of oncogenic activation. These results demonstrate that mutational activation of beta-catenin and associated cyclin D1 overexpression may be central events in the pathogenesis of glomangiopericytoma. In additon, nuclear accumulation of beta catenin is a diagnostic marker for glomangiopericytoma. PMID- 25431236 TI - Molecular and clinical support for a four-tiered grading system for bladder cancer based on the WHO 1973 and 2004 classifications. AB - Currently, the use of two classification systems for bladder cancer grade is advocated in clinical guidelines because the WHO2004 classification has not been sufficiently validated with biological markers and follow-up. The slides of 325 primary non-muscle invasive bladder cancers from three hospitals were reviewed by one uro-pathologist in two separate sessions for the WHO1973 (G1, G2 and G3) and 2004 (papillary urothelial neoplasm of low malignant potential (LMP), low-grade (LG) and high-grade (HG)) classifications. FGFR3 status was examined with PCR SNaPshot analysis. Expression of Ki-67, P53 and P27 was analyzed by immuno histochemistry. Clinical recurrence and progression were determined. We performed validation and cross-validation of the two systems for grade with molecular markers and clinical outcome. Multivariable analyses were done to predict prognosis and pT1 bladder cancer. Grade review resulted in 88 G1, 149 G2 and 88 G3 lesions (WHO1973) and 79 LMP, 101 LG and 145 HG lesions (WHO2004). Molecular validation of both grading systems showed that FGFR3 mutations were associated with lower grades whereas altered expression (Ki-67, P53 and P27) was found in higher grades. Clinical validation showed that the two classification systems were both significant predictors for progression but not for recurrence. Cross validation of both WHO systems showed a significant stepwise increase in biological (molecular markers) and clinical (progression) potential along the line: G1-LG-G2-HG-G3. The LMP and G1 categories had a similar clinical and molecular profile. On the basis of molecular biology and multivariable clinical data, our results support a four-tiered grading system using the 1973 and 2004 WHO classifications with one low-grade (LMP/LG/G1) category that includes LMP, two intermediate grade (LG/G2 and HG/G2) categories and one high-grade (HG/G3) category. PMID- 25431237 TI - Expression levels of SF3B3 correlate with prognosis and endocrine resistance in estrogen receptor-positive breast cancer. AB - De novo or acquired resistance to endocrine therapy limits its utility in a significant number of estrogen receptor-positive (ER-positive) breast cancers. It is crucial to identify novel targets for therapeutic intervention and improve the success of endocrine therapies. Splicing factor 3b, subunit 1 (SF3B1) mutations are described in luminal breast cancer albeit in low frequency. In this study, we evaluated the role of SF3B1 and SF3B3, critical parts of the SF3b splicing complex, in ER-positive endocrine resistance. To ascertain the role of SF3B1/SF3B3 in endocrine resistance, their expression levels were evaluated in ER positive/endocrine-resistant cell lines (MCF-7/LCC2 and MCF-7/LCC9) using a real time quantitative reverse transcription PCR (qRT-PCR). To further determine their clinical relevance, expression analysis was performed in a cohort of 60 paraffin embedded ER-positive, node-negative breast carcinomas with low, intermediate, and high Oncotype DX recurrence scores. Expression levels of SF3B1 and SF3B3 and their prognostic value were validated in large cohorts using publicly available gene expression data sets including The Cancer Genome Atlas. SF3B1 and SF3B3 levels were significantly increased in ERalpha-positive cells with acquired tamoxifen (MCF-7/LCC2; both P<0.0002) and fulvestrant/tamoxifen resistance (MCF 7/LCC9; P=0.008 for SF3B1 and P=0.0006 for SF3B3). Expression levels of both MCF 7/LCC2 and MCF-7/LCC9 were not affected by additional treatments with E2 and/or tamoxifen. Furthermore, qRT-PCR analysis confirmed that SF3B3 expression is significantly upregulated in Oncotype DX high-risk groups when compared with low risk (P=0.019). Similarly, in publicly available breast cancer gene expression data sets, overexpression of SF3B3, but not SF3B1, was significantly correlated with overall survival. Furthermore, the correlation was significant in ER positive, but not in ER-negative tumors.This is the first study to document the role of SF3B3 in endocrine resistance and prognosis in ER-positive breast cancer. Potential strategies for therapeutic targeting of the splicing mechanism(s) need to be evaluated. PMID- 25431238 TI - Scoring of MYC protein expression in diffuse large B-cell lymphomas: concordance rate among hematopathologists. AB - Recent studies have shown that immunohistochemical evaluation of MYC protein expression in diffuse large B-cell lymphoma is a useful prognostic tool with high concordance rate among pathologists. Concordance in these studies was assessed among few pathologists from one institution by scoring tissue microarrays. In daily practice, MYC evaluation is performed on entire tumor sections by a diverse group of pathologists. In our study, nine hematopathologists from two institutions scored whole-tissue sections of two sets of cases. The training set included 13 cases of diffuse large B-cell lymphoma and 4 cases of Burkitt lymphoma. The validation set included 18 cases of diffuse large B-cell lymphoma and 1 case of Burkitt lymphoma. MYC positivity was defined as >=40% of tumor cells demonstrating nuclear staining similar to prior studies. The mean score for each case was used to determine MYC status with discrepant cases defined as having any score causing a different MYC status designation. Discrepant cases from the training set were characterized by staining heterogeneity, extensive necrosis or crush artifact and had mean scores within 15 percentage points of 40%. Cases from the validation set that demonstrated any of these features were scored twice on two different days. Overall concordance was moderate (Kappa score: 0.68, P-value<0.001) with no significant change between the two sets (Kappa scores: 0.69 vs 0.67). Thirty-nine percent of cases were discrepant. The findings indicate that a significant number of diffuse large B-cell lymphomas are inherently difficult to score due to staining heterogeneity. The effect of heterogeneity can be under-represented when concordance is measured among few pathologists scoring tissue microarrays. Careful scoring strategy in our study failed to improve concordance. In the absence of specific instructions on how to deal with heterogeneity, caution is advised when evaluating MYC expression in diffuse large B-cell lymphoma. PMID- 25431239 TI - Fixed-dose combination ezetimibe+atorvastatin lowers LDL-C equivalent to co administered components in randomized trials: use of a dose-response model. AB - Co-administration of ezetimibe with atorvastatin is a generally well-tolerated treatment option that reduces LDL-C levels and improves other lipids with greater efficacy than doubling the atorvastatin dose. The objective of the study was to demonstrate the equivalent lipid-modifying efficacy of fixed-dose combination (FDC) ezetimibe/atorvastatin compared with the component agents co-administered individually in support of regulatory filing. Two randomized, 6-week, double blind cross-over trials compared the lipid-modifying efficacy of ezetimibe/atorvastatin 10/20 mg (n = 353) or 10/40 mg (n = 280) vs. separate co administration of ezetimibe 10 mg plus atorvastatin 20 mg (n = 346) or 40 mg (n = 280), respectively, in hypercholesterolemic patients. Percent changes from baseline in LDL-C (primary endpoint) and other lipids (secondary endpoints) were assessed by analysis of covariance; triglycerides were evaluated by longitudinal data analysis. Expected differences between FDC and the corresponding co administered doses were predicted from a dose-response relationship model; sample size was estimated given the expected difference and equivalence margins (+/-4%). LDL-C-lowering equivalence was based on 97.5% expanded confidence intervals (CI) for the difference contained within the margins; equivalence margins for other lipids were not prespecified. Ezetimibe/atorvastatin FDC 10/20 mg was equivalent to co-administered ezetimibe+atorvastatin 20 mg in reducing LDL-C levels (54.0% vs. 53.8%) as was FDC 10/40 mg and ezetimibe+atorvastatin 40 mg (58.9% vs. 58.7%), as predicted by the model. Changes in other lipids were consistent with equivalence (97.5% expanded CIs <+/-3%, included 0); triglyceride changes varied more. All treatments were generally well tolerated. Hypercholesterolemic patients administered ezetimibe/atorvastatin 10/20 and 10/40 mg FDC had equivalent LDL-C lowering. This FDC formulation proved to be an efficacious and generally well tolerated lipid-lowering therapy. PMID- 25431240 TI - Determination of catecholamines in urine using aminophenylboronic acid functionalized magnetic nanoparticles extraction followed by high-performance liquid chromatography and electrochemical detection. AB - A new method was developed for the simultaneous determination of three catecholamines in urine using aminophenylboronic acid functionalized magnetic nanoparticles extraction followed by high-performance liquid chromatography with electrochemical detection. Novel aminophenylboronic acid functionalized magnetic nanoparticles were prepared by multi-step covalent modification, and characterized by transmission electron microscopy, Fourier-transformed infrared spectroscopy, X-ray diffraction, and vibrating sample magnetometry. With the help of the high affinity between the boronate and cis-diol group, the particles were used for the highly selective separation and enrichment of three major catecholamines, norepinephrine, epinephrine, and dopamine. Effects of the pH of the feed solution, the extraction time, the composition of the buffer solution, the amount of the magnetic particles, the elution conditions, and the recycling of aminophenylboronic acid functionalized magnetic nanoparticles were explored. Under the optimized conditions, 13-17-fold enrichment factors were obtained. The linear ranges were 0.01-2.0 MUg/mL for the studied analytes. The limits of detection and quantification were in the range of 2.0-7.9 and 6.7-26.3 ng/mL, respectively. The relative recoveries were in the range of 92-108%, with intraday and interday relative standard deviations lower than 6.8%. This method was successfully applied to analysis of catecholamines in real urine. PMID- 25431241 TI - Novel ITGB6 mutation in autosomal recessive amelogenesis imperfecta. AB - OBJECTIVE: Hereditary defects in tooth enamel formation, amelogenesis imperfecta (AI), can be non-syndromic or syndromic phenotype. Integrins are signaling proteins that mediate cell-cell and cell-extracellular matrix communication, and their involvement in tooth development is well known. The purposes of this study were to identify genetic cause of an AI family and molecular pathogenesis underlying defective enamel formation. MATERIALS AND METHODS: We recruited a Turkish family with isolated AI and performed mutational analyses to clarify the underlying molecular genetic etiology. RESULTS: Autozygosity mapping and exome sequencing identified a novel homozygous ITGB6 transversion mutation in exon 4 (c.517G>C, p.Gly173Arg). The glycine at this position in the middle of the betaI domain is conserved among a wide range of vertebrate orthologs and human paralogs. Clinically, the enamel was generally thin and pitted with pigmentation. Thicker enamel was noted at the cervical area of the molars. CONCLUSIONS: In this study, we identified a novel homozygous ITGB6 mutation causing isolated AI, and this advances the understanding of normal and pathologic enamel development. PMID- 25431242 TI - Mitochondria inheritance is a key factor for tolerance to dehydration in wine yeast production. AB - Mitochondria are the cell's powerhouse when organisms are grown in the presence of oxygen. They are also the source of reactive oxygen species that cause damage to the biochemical components of the cell and lead to cellular ageing and death. Under winemaking conditions, Saccharomyces yeasts exclusively have a fermentative metabolism due to the high sugar content of grape must. However, their production as an active dry yeast (ADY) form required aerobic propagation and a dehydration process. In these industrial steps, oxidative stress is particularly harmful for the cell. In this work, we analysed the impact of the mitochondrial genome on oxidative stress response, longevity and dehydration tolerance using the synthetic interspecific hybrids obtained between two S. cerevisiae and S. uvarum strains. The isogenic nature of nuclear DNA of such hybrids allowed us to analyse the impact of mitochondrial DNA for fermentative and oxidative stress conditions. Under grape must conditions, the inheritance of mitochondrial DNA poorly impacted the fermentative performance of interspecific hybrids, unlike the hybrids with S. cerevisiae mitochondrial inheritance, which displayed increased tolerance to oxidative stress and dehydration, and showed an extended chronological longevity when cells were grown with aeration. SIGNIFICANCE AND IMPACT OF THE STUDY: In modern oenology, yeast starters are employed to inoculate grape juice, usually in the form of active dry yeast (ADY). The dehydration process implies stressful conditions that lead to oxidative damage. Other yeast species and interspecific hybrids other than Saccharomyces cerevisiae may be used to confer novel properties to the final product. However, these yeasts are usually more sensitive to drying. Understanding the causes of oxidative stress tolerance is therefore necessary for developing the use of these organisms in industry. This study indicates the impact of mitochondrial DNA inheritance for oxidative stress resistance in an interspecific context using isogenic Saccharomyces cerevisiae * Saccharomyces uvarum hybrids. PMID- 25431243 TI - Hair follicles and their potential in wound healing. PMID- 25431244 TI - Short-term food deprivation increases amplitudes of heartbeat-evoked potentials. AB - Nutritional state (i.e., fasting or nonfasting) may affect the processing of interoceptive signals, but mechanisms underlying this effect remain unclear. We investigated 16 healthy women on two separate days: when satiated (standardized food intake) and after an 18-h food deprivation period. On both days, heartbeat evoked potentials (HEPs) and cardiac and autonomic nervous system activation indices (heart rate, normalized low frequency heart rate variability [nLF HRV]) were assessed. The HEP is an EEG pattern that is considered an index of cortical representation of afferent cardiovascular signals. Average HEP activity (R wave +455-595 ms) was enhanced during food deprivation compared to normal food intake. Cardiac activation did not differ between nutritional conditions. Our results indicate that short-term food deprivation amplifies an electrophysiological correlate of the cortical representation of visceral-afferent signals originating from the cardiovascular system. This effect could not be attributed to increased cardiac activation, as estimated by heart rate and nLF HRV, after food deprivation. PMID- 25431245 TI - Propofol inhibits proliferation and induces neuroapoptosis of hippocampal neurons in vitro via downregulation of NF-kappaB p65 and Bcl-2 and upregulation of caspase-3. AB - Propofol is widely used in paediatric anaesthesia and intensive care unit because of its essentially short-acting anaesthetic effect. Recent data have shown that propofol induced neurotoxicity in developing brain. However, the mechanisms are not extremely clear. To gain a better insight into the toxic effects of propofol on hippocampal neurons, we treated cells at the days in vitro 7 (DIV 7), which were prepared from Sprague-Dawley embryos at the 18th day of gestation, with propofol (0.1-1000 MUM) for 3 h. A significant decrease in neuronal proliferation and a remarkable increase in neuroapoptosis were observed in DIV 7 hippocampal neurons as measured by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay and apoptosis assay respectively. Moreover, propofol treatment decreased the nuclear factor kappaB (NF-kappaB) p65 expression, which was accompanied by a reduction in B-cell lymphoma 2 (Bcl-2) mRNA and protein levels, increased caspase-3 mRNA and activation of caspase-3 protein. These results indicated that downregulation of NF-kappaB p65 and Bcl-2 were involved in the potential mechanisms of propofol-induced neurotoxicity. This likely led to the caspase-3 activation, triggered apoptosis and inhibited the neuronal growth and proliferation that we have observed in our in vitro systems. PMID- 25431246 TI - Alkaline stability of quaternary ammonium cations for alkaline fuel cell membranes and ionic liquids. AB - The alkaline stability of 26 different quaternary ammonium groups (QA) is investigated for temperatures up to 160 degrees C and NaOH concentrations up to 10 mol L(-1) with the aim to provide a basis for the selection of functional groups for hydroxide exchange membranes in alkaline fuel cells and of ionic liquid cations stable in basic conditions. Most QAs exhibit unexpectedly high alkaline stability with the exception of aromatic cations. beta-Protons are found to be far less susceptible to nucleophilic attack than previously suggested, whereas the presence of benzyl groups, nearby hetero-atoms, or other electron withdrawing species promote degradation reactions significantly. Cyclic QAs proved to be exceptionally stable, with the piperidine-based 6-azonia spiro[5.5]undecane featuring the highest half-life at the chosen conditions. Absolute and relative stabilities presented herein stand in contrast to literature data, the differences being ascribed to solvent effects on degradation. PMID- 25431247 TI - Cortical bone: a challenging geography. PMID- 25431248 TI - A prospective study of alcohol consumption and renal cell carcinoma risk. AB - Recent epidemiological studies suggest that alcohol consumption may reduce renal cell carcinoma (RCC) risk, although inconsistent findings have been reported by sex and alcoholic beverage type. To better understand the relationship between alcohol consumption and RCC risk, we conducted an analysis within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We followed up participants in the analytic cohort (N = 107,998) through 2010 for incident RCC (N = 408), and computed hazard ratios (HRs) and 95% confidence intervals (CIs) for alcohol intake using Cox regression with adjustment for age, sex, race, study center, hypertension, body mass index, and smoking status. In this study population increasing alcohol consumption was associated with reduced RCC risk compared to non-drinkers (>9.75 g day(-1) : HR, 0.67; 95%CI, 0.50 to 0.89; p trend = 0.002). We observed similar patterns of association for men and women as well as by alcohol beverage type. In analyses stratified by smoking status, the inverse association with consumption was apparent for ever smokers (HR, 0.51; 95%CI, 0.36 to 0.73; p trend<0.0001) but not among never smokers (HR, 1.08; 95%CI, 0.66 to 1.76; P trend = 0.78; p interaction = 0.01). Our study findings offer further support that alcohol consumption is associated with reduced RCC risk, regardless of sex or alcoholic beverage type. The finding of interaction with smoking is novel and requires confirmation. PMID- 25431249 TI - Hyaluronidase injection for the treatment of facial and neck hematomas. PMID- 25431250 TI - Molecular chirality in meteorites and interstellar ices, and the chirality experiment on board the ESA cometary Rosetta mission. AB - Life, as it is known to us, uses exclusively L-amino acid and D-sugar enantiomers for the molecular architecture of proteins and nucleic acids. This Minireview explores current models of the original symmetry-breaking influence that led to the exogenic delivery to Earth of prebiotic molecules with a slight enantiomeric excess. We provide a short overview of enantiomeric enhancements detected in bodies of extraterrestrial origin, such as meteorites, and interstellar ices simulated in the laboratory. Data are interpreted from different points of view, namely, photochirogenesis, parity violation in the weak nuclear interaction, and enantioenrichment through phase transitions. Photochemically induced enantiomeric imbalances are discussed more specifically in the topical context of the "chirality module" on board the cometary Rosetta spacecraft of the ESA. This device will perform the first enantioselective in situ analyses of samples taken from a cometary nucleus. PMID- 25431251 TI - Facial affect recognition and exit examination performance in medical students: a prospective exploratory study. AB - BACKGROUND: Facial affect recognition (FAR) abilities underpin emotional intelligence (EI). The latter is suggested to predict academic success and to be important for clinician-patient interaction. It is therefore of interest to investigate the possible association between FAR and academic performance in undergraduate medical students. METHODS: We assessed the association between the ability to recognize emotions through facial expression and exit examination performance, a measure of clinical proficiency, in undergraduate medical students stratified by gender at a South African tertiary institution using a prospective descriptive design. Data on the perception of facial expressions and exit examination marks were obtained from 144 (61%) females and 93 (39%) males with a mean age of 24.1 +/- 1.6 years. Facial affect recognition measures on the Hexagon and Animation tasks were individually correlated with academic performance indicators using Pearson correlation. RESULTS: The perceptual discrimination of anger was associated with improved performance in anaesthetics (r = .24; p = .004) and urology (r = .24; p = .001), while the recognition of happiness was associated with decreased performance in obstetrics (r = -.21, p = .002). Gender was an effect modifier in the relationship between perceptual discrimination of anger and urology performance (p = .03), with a strong positive relationship for males, but a non-significant relationship for females. CONCLUSION: There was no overall correlation between FAR and overall academic performance or with gender. However, subject (specialty) specific findings with recognition of specific emotions and with gender as effect modifier poses interesting questions about EI and FAR and prompts further research into FAR as a useful tool. Being an objective test and offering a more focused assessment makes FAR worthy of further application. PMID- 25431252 TI - MRT letter: Two-photon excitation-based 2pi light-sheet system for nano lithography. AB - We propose two-photon excitation-based light-sheet technique for nano lithography. The system consists of 2pi-configured cylindrical lens system with a common geometrical focus. Upon superposition, the phase-matched counter propagating light-sheets result in the generation of identical and equi spaced nano-bump pattern. Study shows a feature size of as small as few tens of nanometers with a inter-bump distance of few hundred nanometers. This technique overcomes some of the limitations of existing nano-lithography techniques, thereby, may pave the way for mass-production of nano-structures. Potential applications can also be found in optical microscopy, plasmonics, and nano electronics. PMID- 25431253 TI - Effects of Grifola frondosa non-polar bioactive components on high-fat diet fed and streptozotocin-induced hyperglycemic mice. AB - CONTEXT: Consumption of medicinal mushrooms for disease prevention and maintaining health has a very long history in Asia. Grifola frondosa (Fr) S.F. Gray (GF) (Meripilaceae) is a medicinal fungus popularly used for enhancing immune systems, lowering blood glucose, and improving spleen, stomach, and nerve functions. OBJECTIVE: This study examines the hypoglycemic effects of GF in vitro and in vivo, and analyzes the chemical profiles of its bioactive components. MATERIALS AND METHODS: In vitro hypoglycemic effects of GF was evaluated enzymatically using alpha-amylase and alpha-glucosidase inhibition assays, whereas in vivo study was conducted on high-fat diet fed and streptozotocin (HFD + STZ)-induced hyperglycemic mice. GC-MS was used to determine the chemical profiles of bioactive components. RESULTS: The non-polar fraction of GF exhibited a stronger anti-alpha-glucosidase activity (IC50: 0.0332 mg/ml) than acarbose, but its anti-alpha-amylase activity (IC50: 0.671 mg/ml) was weaker. Oral administration of GF at 600 mg/kg (GF600) significantly lowered the blood glucose, HbA1c, average blood glucose, and serum total cholesterol levels in hyperglycemic mice. Although GF was found to contain mainly oleic acid and linoleic acid, their levels in the fungus were low, suggesting that the effects of GF on HFD + STZ-induced hyperglycemic mice could be due to factors other than these fatty acids. CONCLUSION: These results conclude that GF possesses anti alpha-glucosidase activity, and hypoglycemic effect in HFD + STZ-induced hyperglycemic mice. PMID- 25431254 TI - The etiology of indirect inguinal hernia in adults: congenital or acquired? AB - PURPOSE: During hernioplasty focal thickened tissue containing smooth muscle is found at the neck of the hernia sac in most patients with indirect inguinal hernia. These thickenings may be related to the processus vaginalis and reveal the etiology of indirect inguinal hernia. METHODS: The study included 50 male adults with indirect inguinal hernia and 50 male adults with direct inguinal hernia, all of them were initial cases. Hernioplasty and excision of the hernia sac were performed, meanwhile anatomical features of the hernia sac and the spermatic cord were recorded, then followed by histological investigation of the hernia sacs. RESULTS: Focal thickenings were observed at the neck of the hernia sac in 88 % of adults with indirect inguinal hernia. Dense adhesion between the hernia sac and the spermatic cord was found where the thickening located. Histological examination identified smooth muscle cells in 57 % of the thickened tissues. No similar findings were observed in patients with direct inguinal hernia. CONCLUSIONS: The focal thickening which contains smooth muscle tissue may be remnant of the processus vaginalis after its obliteration. In other word, the presence of the thickening means that fusion of the processus vaginalis has previously taken place. Thus, most indirect inguinal hernias in adults may represent acquired diseases. PMID- 25431255 TI - Technical refinement of mini-laparoscopic hernia repair in infants and children. AB - BACKGROUND: In large, long-term series of laparoscopic pediatric groin hernia repairs, the recurrence rate is commonly higher compared with the open herniotomy. Thus, we refined our laparoscopic technique from a simple hernia sac ligation into combined posterior wall repair for pediatric groin hernias. METHODS: Between March 2010 and March 2013, 41 consecutive infants and children with primary inguinal hernia were treated surgically with our refined mini laparoscopic hernia technique. The mean patient age was 4.5 years. Before hernia repair, there were synchronous bilateral hernias in 4 (9.7 %), left inguinal hernias in 14 (34.2 %) and right inguinal hernias in 23 (56.1 %). The mini laparoscopic hernia repair was carried out with three 3.5 mm trocar ports including 3 mm telescope and 3 mm instruments. RESULTS: Totally 61 repairs were performed. The mean follow-up period was 12 months. The mean operation time was 45 min. None of the repaired groin hernias had a recurrence or procedure-related complication during the period of follow-up. None of them experienced a chronic pain postoperatively. To date there was no scrotal or testicular complication detected by regular ultrasonographic follow-up. CONCLUSIONS: Our refined laparoscopic technique is a safe and effective method in the management of groin hernias in infants and children with a minimal early recurrence rate. PMID- 25431256 TI - Highly selective detection of 2,4,6-trinitrophenol and Cu(2+) ions based on a fluorescent cadmium-pamoate metal-organic framework. AB - A luminescent cadmium-pamoate metal-organic framework, [Cd2 (PAM)2 (dpe)2 (H2 O)2 ]?0.5(dpe) (1), has been synthesized under hydrothermal conditions by using pi electron-rich ligands 4,4'-methylenebis(3-hydroxy-2-naphthalenecarboxylic acid) (H2 PAM) and 1,2-di(4-pyridyl)ethylene (dpe). Its structure is composed of both mononuclear and dinuclear Cd(II) building units, which are linked by the PAM and dpe ligands, resulting in a (4,8)-connected 3D framework. The pi-conjugated dpe guests are located in a 1D channel of 1. The strong emission of 1 could be quenched efficiently by trace amounts of 2,4,6-trinitrophenol (TNP), even in the presence of other competing analogues such as 4-nitrophenol, 2,6-dinitrotoluene, 2,4-dinitrotoluene, nitrobenzene, 1,3-dinitrobenzene, hydroquinone, dimethylbenzene, and bromobenzene. The high sensitivity and selectivity of the fluorescence response of 1 to TNP shows that this framework could be used as an excellent sensor for identifying and quantifying TNP. In the same manner, 1 also exhibits superior selectivity and sensitivity towards Cu(2+) compared with other metal ions such as Zn(2+) , Mn(2+) , Mg(2+) , K(+) , Na(+) , Ni(2+) , Co(2+) , and Ca(2+) . This is the first MOF that can serve as a dual functional fluorescent sensor for selectively detecting trace amounts of TNP and Cu(2+) . PMID- 25431257 TI - MALAT1 promotes the proliferation and metastasis of osteosarcoma cells by activating the PI3K/Akt pathway. AB - Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), one of the first found cancer-associated long noncoding RNAs (lncRNAs), involves in the development and progression of many types of tumors. An aberrant expression of MALAT1 was observed in hepatocellular carcinoma, cervical cancer, breast cancer, ovarian cancer, and colorectal cancer. However, the exact effects and molecular mechanisms of MALAT1 in osteosarcoma progression are still unknown up to now. Here, we investigated the role of MALAT1 in human osteosarcoma cell lines and clinical tumor samples in order to determine the function of this molecule. In our research, the MALAT1 messenger RNA (mRNA) was highly expressed in human osteosarcoma tissues, and its expression level was closely correlated with pulmonary metastasis. Then, we employed lentivirus-mediated knockdown of MALAT1 in U-2 OS and SaO2 to determine the role of MALAT1 in osteosarcoma cell lines. Lentivirus-mediated MALAT1 small interfering RNA (siRNA) could efficiently downregulated the expression level of MALAT1 in osteosarcoma cell lines. Knockdown of MALAT1 inhibited the proliferation and invasion of human osteosarcoma cell and suppressed its metastasis in vitro and vivo. At the same time, the proliferating cell nuclear antigen (PCNA), matrix metallopeptidase 9 (MMP-9), phosphorylated PI3Kp85alpha, and Akt expressions were significantly inhibited in MALAT1-deleted cells. These findings indicated that MALAT1 might suppress the tumor growth and metastasis via PI3K/AKT signaling pathway. Taken together, our data indicated that MALAT1 might be an oncogenic lncRNA that promoted proliferation and metastasis of osteosarcoma and could be regarded as a therapeutic target in human osteosarcoma. PMID- 25431258 TI - Glucose-regulated protein 78 (GRP78) regulates colon cancer metastasis through EMT biomarkers and the NRF-2/HO-1 pathway. AB - Glucose-regulated protein 78 (GRP78) is a key chaperone and stress response protein. Previous studies have demonstrated that high GRP78 expression may be correlated with cancer progression and therapeutic response. However, the role of GRP78 in the metastasis of colon cancer is unclear. In this study, we used small interfering RNA (siRNA) to knock down GRP78 expression in colon cancer cells (HT 29 and DLD-1 cells). In wound-healing migration assays, we found that GRP78 knockdown (GRP78KD) cells showed better wound-healing ability than control cells. We also found that GRP78KD cells displayed a better migratory ability than control cells in migration and invasion assays. As we further dissected the underlying molecular mechanism, we found that silencing GRP78 may cause an increase in vimentin expression and a decrease in the E-cadherin level, which was correlated with the increase in migratory ability. In addition, we found that GRP78KD may activate the NRF-2/HO-1 pathway, and this activation was also correlated with the increase in cell invasiveness. Furthermore, we examined GRP78 expression in a tissue array and found that the GRP78 expression in metastatic adenocarcinoma in lymph nodes tended to be weaker than that in primary colonic adenocarcinoma. In conclusion, a low level of GRP78 may cause an increase in metastasis ability in colon cancer cells by altering E-cadherin and vimentin expression and activating the NRF-2/HO-1 signaling pathway. Our study demonstrates that low expression of GRP78 may correlate with a high risk of metastasis in colon cancer. PMID- 25431259 TI - The clinical utility of microRNA-21 as novel biomarker for diagnosing human cancers. AB - With cancer being a major cause of death worldwide, microRNAs (miRNAs) have been investigated as novel and non-invasive biomarkers for cancer diagnosis. Recently, microRNA-21 (miR-21) attracts much attention for its aberrant expression and has been widely studied in various cancers. However, the inconsistent results from studies make it hard to evaluate the diagnostic value of miR-21 in cancer diagnosis, which lead us to conduct this meta-analysis. We conducted a comprehensive literature search in the Medline, Embase, PubMed, CNKI, and Web of Science before July 1, 2014. STATA 12.0 software was used for calculation and statistical analysis. The pooled sensitivity, specificity, positive and negative likelihood ratio (PLR, NLR), and diagnostic odds ratio (DOR) were used to assess the diagnostic performance of miR-21 for cancers. Seventy-three studies in 60 articles were involved in this meta-analysis, with a total of 4684 patients with cancer and 3108 controls. The overall parameters were calculated from all the included studies: sensitivity of 0.78 (95% confidence interval (CI) 0.74-0.81), specificity of 0.83 (95% CI 0.80-0.86), PLR of 4.5 (95% CI 3.8-5.4), NLR of 0.27 (95% CI 0.23-0.32); DOR of 17 (95% CI 12-23), and area under the curve (AUC) of 0.88 (95% CI 0.84-0.90). In addition, we performed subgroup analyses based on ethnicity, cancer types, and sample types. Results from subgroup analysis showed that cancer types and sample types were the sources of heterogeneity in our meta analysis. The overall diagnostic value of miR-21 is not very high for cancer diagnosis; however, it is affected significantly by the types of cancer and specimen. MiR-21 has a relatively high diagnostic value for detecting breast cancer, and miR-21 assays based on plasma, serum, and tissue achieved relatively higher accuracy. PMID- 25431260 TI - Antigenic Hsp70-peptide upregulate altered cell surface MHC class I expression in TAMs and increases anti-tumor function in Dalton's lymphoma bearing mice. AB - Major histocompatibility complex (MHC) class I molecules not only provide a mechanistic framework for the cell-to-cell communication, but also possess broader biological function. Due to their ability to regulate presentation of tumor-associated antigens (TAAs), viral peptides which play an essential role in the regulation of immune responses by presenting antigenic peptides to cytotoxic T lymphocytes and by regulating cytolytic activities of immune cells. Tumor cells frequently do not express MHC class I molecules; as a result, tumor cells escape from immune surveillance. Cells surviving in tumor microenvironment are often characterized by a profound immune escape phenotype with alterations in MHC class I way of antigen processing. Cellular components of the tumor microenvironment, in particular alternatively activated M2 phenotype, are involved in tumor progression and suppression of anti-tumor immunity. Hsp70 is well recognized for its role in activating macrophages leading to enhanced production of inflammatory cytokines. It has been observed that Hsp70 derived from normal tissues do not elicit tumor immunity, while Hsp70 preparation from tumor cell associated with antigen are able to elicit tumor immunity. The finding shows that the expression of MHC class I (H2D(b)) drastically decreases in TAMs and Hsp70-peptide complex enhances H2D(b) expression in TAMs and it reverts back the suppressed function of TAMs into the M1 state of immunoregulatory phenotype that promotes tumor regression by enhanced antigen presentation. PMID- 25431261 TI - Individualized chemotherapy for osteosarcoma and identification of gene mutations in osteosarcoma. AB - The study aims to identify novel gene mutations in osteosarcoma and to guide individualized preoperative chemotherapy for osteosarcoma based on the analysis of expression and mutations of the drug-metabolism-related genes. Twenty-eight osteosarcoma patients received individualized preoperative chemotherapy regimens. Expression levels and mutations of chemotherapy-related genes in samples collected from the patients were determined using real-time PCR and DNA sequencing, respectively. Patient sensitivity to chemotherapeutic agents was evaluated by systematic analysis of the PCR and sequencing results. Novel mutations were identified via high-throughput sequencing of 339 genes in 10 osteosarcoma samples. Individualized preoperative chemotherapy outcomes were valid for nine patients (n = 9/28, 32.1%). Chemosensitivity assays showed that all 28 patients were sensitive to ifosfamide, whereas 46.4 and 39.2% were sensitive to docetaxel and platinum, respectively. More importantly, patients receiving highly chemosensitive chemotherapy agents had better prognosis and treatment outcomes than those receiving less chemosensitive agents (P < 0.05). In addition, 39 gene mutations were detected in at least five osteosarcoma tumor samples. Analysis of the expression and mutation of drug-metabolism-related genes will aid in the design of effective individualized preoperative chemotherapy regimens for osteosarcoma. Determining the chemosensitivity of individual tumors to chemotherapeutic agents will facilitate the development of better therapeutic approaches. Individualized treatment of osteosarcoma may improve chemotherapy efficacy and the survival rate of osteosarcoma patients. High-throughput genotyping allows mapping of osteosarcoma mutations, and novel gene mutations offered new candidates for diagnosis and therapeutic targeting. PMID- 25431263 TI - Ginsenoside Rh2 inhibits growth of glioblastoma multiforme through mTor. AB - Being the most malignant primary brain tumor in humans, glioblastoma multiforme (GBM) has a fairly poor patient survival after current combined treatment with chemotherapy, radiation, and surgery. Ginsenoside Rh2 (GRh2) has been reported to have a therapeutic effect on some tumors, and we recently reported its inhibitory effect on GBM growth in vitro and in vivo, possibly through an epidermal growth factor receptor (EGFR) signaling pathway. Here, using specific inhibitors, we found that the activation of EGFR signaling promoted GBM growth through PI3k/Akt/mTor signaling pathways. Moreover, GRh2 efficiently inhibited activation of this pathway at the receptor level. Together with our previous findings, these data suggest that GRh2 may suppress GBM growth through its competition with EGFR ligands for binding to the EGFR, and binding to EGFR by GRh2 does not lead to receptor phosphorylation. Thus, our data highlight a previous unappreciated role for GRh2 to inhibit EGFR signaling. GRh2 thus appears to be a promising therapy for cancers that require EGFR signaling to growth. PMID- 25431262 TI - Warburg meets non-coding RNAs: the emerging role of ncRNA in regulating the glucose metabolism of cancer cells. AB - Unlike normal differentiated cells, cancer cells primarily rely on glycolysis to generate energy needed for cellular processes even in normoxia conditions. This phenomenon is called aerobic glycolysis or "the Warburg effect." Aerobic glycolysis is inefficient to generate ATP, but the advantages it confers to cancer cells remain to be fully explained. Several oncogenic signaling pathways, interplaying with enzymes and kinases involved in glucose metabolism, participate in the switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. Non coding RNAs (ncRNAs) are a family of functional RNA molecules that are not further translated into proteins, which exert regulatatory roles in gene transcription and translation. ncRNAs, especially miRNAs and long non-coding RNAs (lncRNAs), may also have great effect on glucose metabolism by targeting not only glycolysis enzymes directly but also oncogenic signaling pathways indirectly. A better understanding of the Warburg effect and the regulatory role of ncRNAs in cancer glucose metabolism may contribute to the treatment of cancers. PMID- 25431264 TI - Nucleos(t)ide analogue therapy for HBV-related HCC after hepatic resection: clinical benefits and unanswered questions. PMID- 25431265 TI - Guanine quadruplexes are formed by specific regions of human transposable elements. AB - BACKGROUND: Transposable elements form a significant proportion of eukaryotic genomes. Recently, Lexa et al. (Nucleic Acids Res 42:968-978, 2014) reported that plant long terminal repeat (LTR) retrotransposons often contain potential quadruplex sequences (PQSs) in their LTRs and experimentally confirmed their ability to adopt four-stranded DNA conformations. RESULTS: Here, we searched for PQSs in human retrotransposons and found that PQSs are specifically localized in the 3'-UTR of LINE-1 elements, in LTRs of HERV elements and are strongly accumulated in specific regions of SVA elements. Circular dichroism spectroscopy confirmed that most PQSs had adopted monomolecular or bimolecular guanine quadruplex structures. Evolutionarily young SVA elements contained more PQSs than older elements and their propensity to form quadruplex DNA was higher. Full length L1 elements contained more PQSs than truncated elements; the highest proportion of PQSs was found inside transpositionally active L1 elements (PA2 and HS families). CONCLUSIONS: Conservation of quadruplexes at specific positions of transposable elements implies their importance in their life cycle. The increasing quadruplex presence in evolutionarily young LINE-1 and SVA families makes these elements important contributors toward present genome-wide quadruplex distribution. PMID- 25431267 TI - Subclinical left ventricular dysfunction by echocardiographic speckle-tracking strain analysis relates to outcome in sarcoidosis. AB - AIMS: Limited data exist on the risk of developing cardiac sarcoidosis (CS) and/or adverse events in sarcoidosis patients. Using LV global longitudinal strain (GLS), an emerging sensitive parameter of LV function, we evaluated the prevalence of subclinical cardiac dysfunction in sarcoidosis and investigated whether LVGLS predicts adverse outcomes in this population. METHODS AND RESULTS: A total of 130 patients with proven sarcoidosis undergoing echocardiography at our referral centre were identified. Following exclusion of those with evidence of CS (n = 14) or other pre-existing structural heart disease (n = 16), 100 patients (55 +/- 13 years, 48% male, 90% pulmonary involvement) and 100 age- and gender-matched controls were included. LVGLS was measured by speckle-tracking analysis. The primary endpoint was a composite of all-cause mortality, heart failure hospitalization, device implantation, new arrhythmias, or future development of CS on advanced cardiac imaging modalities. LVGLS was significantly impaired in sarcoidosis patients compared with controls (-17.3 +/- 2.5 vs. -20.0 +/- 1.6%, P < 0.001). Overall, 27 patients (27%) reached the endpoint during a median follow-up of 35 months. On Cox proportional hazards model analysis, abnormal 24-h Holter, larger LV end-diastolic diameters, and more impaired LVGLS were significantly associated with the endpoint; however, only LVGLS remained independently associated on multivariate analysis [hazard ratio (HR) 1.4, 95% confidence interval (CI) 1.1-1.7, P = 0.006]. Patients with LVGLS less than 17.3% were significantly more likely to be free of the primary endpoint (log-rank P = 0.01). CONCLUSION: LVGLS is impaired in sarcoidosis patients, suggesting subclinical cardiac dysfunction despite the absence of conventional evidence of cardiac disease, and is independently associated with occurrence of cardiac events and/or development of CS. PMID- 25431266 TI - Age trajectories of glycaemic traits in non-diabetic South Asian and white individuals: the Whitehall II cohort study. AB - AIMS/HYPOTHESIS: South Asian individuals have an increased prevalence of type 2 diabetes, but little is known about the development of glycaemic traits in this ethnic group. We compared age-related changes in glycaemic traits between non diabetic South Asian and white participants. METHODS: In a prospective British occupational cohort with 5-yearly clinical examinations (n = 230/5,749 South Asian/white participants, age 39-79 years at baseline), age-related trajectories of fasting glucose (FG) and 2 h post-load glucose (PLG), log-transformed fasting insulin (FINS) and 2 h post-load insulin (PLINS), HOMA insulin sensitivity (HOMA2 %S) and HOMA insulin secretion (HOMA2-%B) were fitted for South Asian and white individuals who remained free of diabetes between 1991 and 2009. RESULTS: In sex adjusted multilevel models, FG was stable in white participants but increased with age in South Asians (0.12 [SE = 0.04] mmol/l per decade). PLG, FINS and PLINS levels were lower among white participants (by 0.271 [SE = 0.092] mmol/l, 0.306 [SE = 0.046] log pmol/l, 0.707 [SE = 0.059] log pmol/l at age 50, respectively) compared with South Asians, although their age-related trajectories were parallel. HOMA2-%S was higher (0.226 [SE = 0.038] at age 50) and HOMA2-%B lower (by 0.189 [SE = 0.026] at age 50) among white than South Asian participants. The age-related decline in HOMA2-%S was similar in these groups, but the age-related increase in HOMA2-%B was greater in white participants (0.04 [SE = 0.02] per decade). This difference was explained by obesity, lifestyle and social status. CONCLUSIONS/INTERPRETATION: Findings from a diabetes-free population suggest an inadequate pancreatic beta cell reserve in South Asians, as a significantly steeper age-related increase in FG was observed in this ethnic group compared with white individuals. PMID- 25431268 TI - Hypocretin/orexin antagonism enhances sleep-related adenosine and GABA neurotransmission in rat basal forebrain. AB - Hypocretin/orexin (HCRT) neurons provide excitatory input to wake-promoting brain regions including the basal forebrain (BF). The dual HCRT receptor antagonist almorexant (ALM) decreases waking and increases sleep. We hypothesized that HCRT antagonists induce sleep, in part, through disfacilitation of BF neurons; consequently, ALM should have reduced efficacy in BF-lesioned (BFx) animals. To test this hypothesis, rats were given bilateral IgG-192-saporin injections, which predominantly targets cholinergic BF neurons. BFx and intact rats were then given oral ALM, the benzodiazepine agonist zolpidem (ZOL) or vehicle (VEH) at lights out. ALM was less effective than ZOL at inducing sleep in BFx rats compared to controls. BF adenosine (ADO), gamma-amino-butyric acid (GABA), and glutamate levels were then determined via microdialysis from intact, freely behaving rats following oral ALM, ZOL or VEH. ALM increased BF ADO and GABA levels during waking and mixed vigilance states, and preserved sleep-associated increases in GABA under low and high sleep pressure conditions. ALM infusion into the BF also enhanced cortical ADO release, demonstrating that HCRT input is critical for ADO signaling in the BF. In contrast, oral ZOL and BF-infused ZOL had no effect on ADO levels in either BF or cortex. ALM increased BF ADO (an endogenous sleep promoting substance) and GABA (which is increased during normal sleep), and required an intact BF for maximal efficacy, whereas ZOL blocked sleep-associated BF GABA release, and required no functional contribution from the BF to induce sleep. ALM thus induces sleep by facilitating the neural mechanisms underlying the normal transition to sleep. PMID- 25431269 TI - Effect of smoking history on outcome of patients diagnosed with TB and HIV. PMID- 25431270 TI - Cystic fibrosis bone disease: is the CFTR corrector C18 an option for therapy? PMID- 25431271 TI - Towards a close computed tomography monitoring approach for screen detected subsolid pulmonary nodules? AB - Pulmonary subsolid nodules (SSNs) have a high likelihood of malignancy, but are often indolent. A conservative treatment approach may therefore be suitable. The aim of the current study was to evaluate whether close follow-up of SSNs with computed tomography may be a safe approach. The study population consisted of participants of the Dutch-Belgian lung cancer screening trial (Nederlands Leuvens Longkanker Screenings Onderzoek; NELSON). All SSNs detected during the trial were included in this analysis. Retrospectively, all persistent SSNs and SSNs that were resected after first detection were segmented using dedicated software, and maximum diameter, volume and mass were measured. Mass doubling time (MDT) was calculated. In total 7135 volunteers were included in the current analysis. 264 (3.3%) SSNs in 234 participants were detected during the trial. 147 (63%) of these SSNs in 126 participants disappeared at follow-up, leaving 117 persistent or directly resected SSNs in 108 (1.5%) participants available for analysis. The median follow-up time was 95 months (range 20-110 months). 33 (28%) SSNs were resected and 28 of those were (pre-) invasive. None of the non-resected SSNs progressed into a clinically relevant malignancy. Persistent SSNs rarely developed into clinically manifest malignancies unexpectedly. Close follow-up with computed tomography may be a safe option to monitor changes. PMID- 25431272 TI - Interaction between asthma and smoking increases the risk of adult airway obstruction. AB - The aim of the present study was to analyse the interaction between asthma and smoking in the risk of adult airway obstruction, accounting for atopy. In the European Community Respiratory Health Survey, 15 668 persons aged 20-56 years underwent spirometry in 1991-1993 and 9 years later (n=8916). Risk of airway obstruction and lung function decline associated with smoking and early-onset (<10 years of age) and late-onset (>10 years of age) asthma were analysed with generalised estimating equation models and random-effect linear models, adjusting for covariates. Interaction of asthma with smoking was expressed as relative excess risk due to interaction (RERI). A 20-fold increase in adult airway obstruction was found among those with early-onset asthma independently of smoking status (never-smokers: OR 21.0, 95% CI 12.7-35; current smokers: OR 23.7, 95% CI 13.9-40.6). Late-onset asthma was associated with airway obstruction, with a stronger association among current smokers (OR 25.6, 95% CI 15.6-41.9) than among never-smokers (OR 11.2, 95% CI 6.8-18.6) (RERI 12.02, 95% CI 1.96-22.07). Stratifying by atopy, the association between smoking and asthma was most pronounced among nonatopics. Early- and late-onset asthma were associated with 10 20-fold increased risk of adult airway obstruction. Smoking increased the risk of adult airway obstruction in subjects with asthma onset after age 10 years. Investigation of measures potentially preventive of chronic obstructive pulmonary disease development following asthma is urgently needed. PMID- 25431273 TI - Novel drugs against tuberculosis: a clinician's perspective. AB - The United Nations Millennium Development Goal of reversing the global spread of tuberculosis by 2015 has been offset by the rampant re-emergence of drug resistant tuberculosis, in particular fluoroquinolone-resistant multidrug resistant and extensively drug-resistant tuberculosis. After decades of quiescence in the development of antituberculosis medications, bedaquiline and delamanid have been conditionally approved for the treatment of drug-resistant tuberculosis, while several other novel compounds (AZD5847, PA-824, SQ109 and sutezolid) have been evaluated in phase II clinical trials. Before novel drugs can find their place in the battle against drug-resistant tuberculosis, linezolid has been compassionately used with success in the treatment of fluoroquinolone resistant multidrug-resistant tuberculosis. This review largely discusses six novel drugs that have been evaluated in phase II and III clinical trials, with focus on the clinical evidence for efficacy and safety, potential drug interactions, and prospect for using multiple novel drugs in new regimens. PMID- 25431274 TI - Growth performance and antioxidant enzyme activities in rainbow trout (Oncorhynchus mykiss) juveniles fed diets supplemented with sage, mint and thyme oils. AB - This study evaluated effects of dietary supplementation of sage (Salvia officinalis), mint (Mentha spicata) and thyme (Thymus vulgaris) oils on growth performance, lipid peroxidation level (melondialdehyde, MDA) and liver antioxidant enzyme activities (superoxide dismutase, SOD; catalase, CAT; glucose 6-phosphate dehydrogenase, G6PD; glutathione reductase, GR; glutathione-S transferase, GST and glutathione peroxidase, GPx) in rainbow trout (Oncorhynchus mykiss) juveniles. For this purpose, triplicate groups of rainbow trout were fed daily ad libitum with diets containing sage, mint and thyme oils at 500, 1,000 and 1,500 mg kg(-1) for 60 days. While weight gain percentage of fish fed the diets containing sage and thyme oils was significantly higher than the control group, that of fish fed mint oil was the lowest. Similarly, specific growth rate was found to be the highest in all groups of the sage and thyme oil feeding and the lowest in the mint groups. Moreover, feed conversion ratio was significantly higher in the mint oil administered groups. Survival rate was also significantly reduced in the fish fed the diet containing mint oil. It was observed that SOD, G6PD and GPx activities were significantly increased in liver tissues of all the treated fish groups compared to that of control diet-fed group. However, CAT, GST and GR activities were significantly decreased in experimental diet-fed fish groups at the end of the experiment. On the other hand, a significant reduction was found in MDA levels in the fish fed the diets with sage and thyme oils compared to control and mint diets on the 30th and 60th days of experiment. Overall, dietary inclusion of sage and thyme oils is effective in enhancing rainbow trout growth, reduction in MDA and least changing antioxidant enzyme activities at a low level of 500 mg kg(-1) diet, and they can be used as important feed supplements for rainbow trout production. PMID- 25431275 TI - Resting heart rate is associated with renal disease outcomes in patients with vascular disease: results of the ONTARGET and TRANSCEND studies. AB - BACKGROUND: Resting heart rate (RHR) is associated with cardiovascular disease outcomes in high-risk patients. It is not known whether RHR is predictive of renal outcomes such as albuminuria, end-stage renal disease (ESRD) or doubling of creatinine. We evaluated whether RHR could predict renal endpoints in patients at a high risk of cardiovascular disease. We also tested the effects of RHR at different levels of systolic blood pressure (SBP). METHODS: We analysed data from 28 757 patients in the ONTARGET and TRANSCEND trials. RHR and SBP were available for a mean of 4.9 +/- 0.4 visits (range 3-5) within the first 2 years of the studies. Albuminuria was determined at baseline, at 2 years and at study end. RESULTS: Mean RHR was predictive of incident micro-albuminuria [hazard ratio (HR) for RHR >=80 vs. <60 beats min(-1) 1.49, 95% confidence interval (CI) 1.29-1.71, P < 0.0001], incident macro-albuminuria (HR 1.84, 95% CI 1.39-2.42, P < 0.0001), doubling of creatinine (HR 1.47, 95% CI 1.00-2.17, P = 0.050) and ESRD (HR 1.78, 95% CI 1.00-3.16, P = 0.050), and the combined renal end-point (HR 1.51, 95% CI 1.32-1.74, P < 0.0001). Associations were robust at SBPs from <120 to >=150 mmHg, with the lowest risk at a SBP of 130-140 mmHg. CONCLUSION: Resting heart rate is a potent predictor of these renal outcomes, as well as their combination, in patients with cardiovascular disease. RHR at all SBP levels should be considered as a possible renal disease risk predictor and should be investigated as a treatment target with RHR-reducing agents. PMID- 25431276 TI - Characterization of antibiotic and disinfectant susceptibility profiles among Pseudomonas aeruginosa veterinary isolates recovered during 1994-2003. AB - AIMS: To evaluate susceptibility of Pseudomonas aeruginosa veterinary isolates to antibiotics and disinfectants. METHODS AND RESULTS: Pseudomonas aeruginosa isolates collected from dogs (n = 155) and other animals (n = 20) from sixteen states during 1994-2003 were tested for susceptibility. Most isolates were resistant to twenty-one antimicrobials tested, and the highest prevalence of resistance was to beta-lactams (93.8%) and sulphonamides (93.5%). Fluoroquinolone resistance did not increase from 1994 to 2003. Ciprofloxacin and enrofloxacin had a 5 and 16% prevalence of resistance, respectively, while sarafloxacin and nalidixic acid had a prevalence of resistance of 97 and 98%, respectively. Strains were pan-resistant to triclosan and chlorhexidine, were highly resistant to benzalkonium chloride and demonstrated high susceptibility to other disinfectants. Didecyldimethylammonium chloride was the most active ammonium chloride. Inducible resistance was observed to cetyl ammonium halides, chlorhexidine and benzyl ammonium chlorides, which formulate disinfectants used in veterinary clinics and dairies. Organic acid inhibition was associated with the dissociated acid species. CONCLUSIONS: Dissociated organic acids appear able to inhibit Ps. aeruginosa, and rates of fluoroquinolone resistance merit sustained companion animal isolate surveillance. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report of Ps. aeruginosa susceptibility to 24 disinfectants and illustrates the high resistance of Ps. aeruginosa to both antibiotics and disinfectants. PMID- 25431277 TI - Laterality in the first Neolithic and Chalcolithic farming communities in northern Iberia. AB - Laterality is a quality, widespread throughout the vertebrate kingdom. It consists in assigning different roles to each side of the body by granting predominance to one of the sides. Humans too display this quality and the specialization of each hemisphere in our brain was already present in the first vertebrates. We usually refer to right-handed and left-handed people depending on the upper limb that is assigned the dominant role. For a long time, it has been thought that the proportion of left-handed people in a population has remained constant in all cultures and during our evolution. However, laterality is affected by sociocultural influences and varies geographically and chronologically. Using archaeological remains, it is possible to obtain information about the laterality of our ancestors and determine laterality indices for past populations. We developed an experimental programme to determine which characteristics of a polished axe indicate the laterality of its maker. We describe a method based on the orientation of the edge and we study the Neolithic and Chalcolithic farming communities in northern Iberia to evaluate the laterality in those populations. The right/left laterality ratio for the Neolithic and Chalcolithic populations is very similar to the range detected for modern non-industrial societies. PMID- 25431280 TI - Hemodynamic response to resistance exercise with and without blood flow restriction in healthy subjects. AB - PURPOSE: To compare the hemodynamic response during resistance exercise at high intensity (HI), low intensity (LI) and low intensity with blood flow restriction (LI-BFR) in healthy subjects. METHODS: Twelve men performed three sets of unilateral knee extension exercises at LI-BFR and LI (15 repetitions; 20% of 1RM) and HI (8 repetitions; 80% of 1RM). The blood flow restriction was accomplished using a sphygmomanometer positioned on the thigh and inflated to the point of blood flow interruption (167.9 +/- 16.6 mmHg). The hemodynamic variables were obtained by continuous beat-to-beat photoplethysmography. Rating of perceived exertion (RPE) and blood lactate were also measured. RESULTS: The HI session showed higher values (P<0.05) in all sets than the LI and LI-BFR for diastolic blood pressure, heart rate and rate-pressure product. The LI-BFR showed higher values than the LI only in the 3rd set for systolic blood pressure, heart rate and rate-pressure product. Blood lactate was higher in the HI (4.2 +/- 0.2 mmol) and LI-BFR (4.1 +/- 0.3 mmol) than the LI (3.5 +/- 0.3 mmol). Rating of perceived exertion was higher in the LI-BFR (7.9 +/- 0.3) than the HI (6.4 +/- 0.4) and LI (3.2 +/- 0.4). CONCLUSION: The LI-BFR session exhibited similar blood lactate to the HI, a higher rating of perceived response than the HI and LI, and equal or lower hemodynamic responses than the HI. PMID- 25431279 TI - The effect of local dynamics of Atto 390-labeled lysozyme on fluorescence anisotropy modeling. AB - Fluorescence anisotropy decay is a popular optical technique to study the structure, size, shape, and even functions of biomolecules. The method measures the time dependence of the depolarization of a fluorophore and is therefore sensitive to the changes in the rotational motion (e.g., aggregation and binding) or changes in the mobility of segments of biopolymers (such as the ones associated with tertiary structure changes). Fluorescence anisotropy decay often requires the use of fluorescent dyes that need to be covalently attached to the biomolecule. The location of the attachment on the biomolecule (e.g., a protein) and the linker used, affect the mobility of the dye and its anisotropy decay. With this study we have combined the experimental data with molecular dynamic simulations to offer a more correct interpretation of the fluorescence anisotropy decay of a popular fluorescent dye (Atto 390) attached to the N-terminus of Hen Egg White Lysozyme (HEWL). Our model showed how the use of relatively simple molecular dynamics computation to simulate the motion of the dye, provide a model to interpret the experimental fluorescence anisotropy decay that yields a better estimate of the hydrodynamic radius of HEWL. The improvement is provided by a more detailed description of the segmental motion of the dye attached to the protein. PMID- 25431281 TI - Prevalence of methicillin-resistant Staphylococcus haemolyticus in companion animals: a cross-sectional study. AB - BACKGROUND: Among coagulase-negative staphylococci, Staphylococcus haemolyticus is the second most frequently isolated species from human blood cultures and has the highest level of antimicrobial resistance. This species has zoonotic character and is prevalent both in humans and animals. Recent studies have indicated that methicillin-resistant S. haemolyticus (MRSH) is one of the most frequent isolated Staphylococcus species among neonates in intensive care units. The aim of this study was to determine the presence of MRSH in different groups of companion animals and to characterize isolates according their antimicrobial resistance. METHODS: Samples (n = 754) were collected from healthy and diseased dogs and cats, female dogs in pure-breed kennels, healthy horses, and kennel owners. Classical microbiological tests along with molecular testing including PCR and 16S rRNA sequencing were performed to identify MRSH. Clonality of the isolates was assessed by Pulsed Field Gel Electrophoresis using the SmaI restriction enzyme. Antimicrobial susceptibility testing was performed using the broth micro-dilution method. Detection of genes encoding antimicrobial resistance was performed by PCR. Statistical analysis was performed using the R Project of Statistical Computing, "R 1.8.1" package. RESULTS: From a total of 754 samples tested, 12 MRSH isolates were obtained. No MRSH were found in horses and cats. Eleven isolates were obtained from dogs and one from a kennel owner. Ten of the dog isolates were detected in pure-breed kennels. The isolates demonstrated the same clonality only within separate kennels.The most frequent resistances of MRSH isolates was demonstrated to benzylpenicillin (91.7%), erythromycin (91.7%), gentamicin (75.0%), tetracycline (66.7%), fluoroquinolones (41.7%) and co trimoxazole (41.7%). One isolate was resistant to streptogramins. All isolates were susceptible to daptomycin, rifampin, linezolid and vancomycin. The clone isolated from the kennel owner and one of the dogs was resistant to beta-lactams, macrolides, gentamicin and tetracycline. CONCLUSIONS: Pure-breed kennels keeping 6 or more females were determined to be a risk factor for the presence of MRSH strains. MRSH isolated from companion animals were frequently resistant to some classes of critically important antimicrobials, although they remain susceptible to antibiotics used exclusively in human medicine. PMID- 25431282 TI - Asynchronous glands in secretory pattern endometrium: clinical associations and immunohistological changes. AB - AIMS: The significance and pathogenesis of irregular or asynchronous maturation within endometrial glands remains uncertain. The aim of this study was to investigate differences in epithelial hormone receptor immunoreactivity and stromal cell calretinin, CD34 and p16 expression in morphologically normal secretory endometrium and in asynchronous (non-secretory) endometrial glands (AEGs). METHODS AND RESULTS: Nineteen consecutive endometrial specimens showing AEGs were examined. The mean age of the patients was 42.8 years, and the most common presenting symptom was menorrhagia. Immunohistological expression of oestrogen receptor (ER) alpha, of ERbeta and of progesterone receptor (PR) were compared in normal secretory glands and in AEGs. Stromal cell expression of calretinin, CD34 and p16 was also investigated. In contrast to normal secretory glands, the epithelial cells lining AEGs were usually ERalpha/PR-positive and showed significantly increased ERbeta expression. Altered calretinin and CD34 expression within functional layer stromal cells was seen in five and two cases, respectively, but there were no differences in stromal cell immunoreactivity around AEGs. CONCLUSIONS: The most common clinical symptom associated with AEGs in this study was menorrhagia. Aberrant hormone receptor expression in AEGs suggests a localized, possibly clonal, defect in epithelial maturation. There were no immunophenotypic changes to suggest that AEGs are related to a primary endometrial stromal deficiency. PMID- 25431283 TI - Additive effects of postchallenge hyperglycemia and low-density lipoprotein particles on the risk of arterial stiffness in healthy adults. AB - BACKGROUND: To determine the effects of post-challenge hyperglycemia potentiate low-density lipoprotein cholesterol (LDL) particles on the risk of arterial stiffness in non-diabetic adults. METHODS: During 2009-2011, 592 adults without clinical diabetes (fasting glucose <7.0 mmol/L) or known coronary heart disease or stroke were recruited. All subjects underwent standard 75-g oral glucose tolerance test (OGTT) after overnight fasting. The glucose area under curve (GluAUC) after OGTT was defined as the postchallenge glucose load. Levels of LDL C and small dense LDL-C (sdLDL-C) were measured. Arterial stiffness in terms of brachial-ankle pulse wave velocity (baPWV) was also measured. RESULTS: The baPWV in tertile distributions were significantly associated with all conventional cardiovascular risk factors, LDL-C, and sdLDL-C. Multivariate logistic regression analyses revealed that LDL-C (or sdLDL-C) combined with one of the seven glycemic indices (glucose levels at 0, 30, 60, 90, and 120 min; GluAUC; HbA1C) was associated with arterial stiffness after covariates being adjusted. Further interaction analyses showed only concurrent higher levels of both glycemic indices and atherogenic LDL-C or sdLDL-C have significant risk for arterial stiffness. CONCLUSIONS: Additive effects of both postchallenge hyperglycemia and LDL subclass particles potentiate the risk of arterial stiffness. The adverse joint effects of hyperlipidemia and postchallenge hyperglycemia on subclinical cardiovascular function provide important information in primary prevention of cardiovascular disease in subjects without clinical diabetes. PMID- 25431284 TI - Is the conduction system involved in idiopathic ventricular arrhythmias arising from the region of aorto-mitral continuity? PMID- 25431285 TI - The genetic correlation between procrastination and impulsivity. AB - The reported genetic correlation of 1.0 between the traits of procrastination and impulsivity (Gustavson, D. E., Miyake, A., Hewitt, J. K., & Friedman, N. P. (2014). Psychological Science), which was held to support an evolutionary origin of the relationship between the two traits, was tested in data from two large samples of twins from Australia. A genetic correlation of 0.299 was obtained. It was concluded that, although the presence of a genetic correlation between the two traits was supported, the modest magnitude of the correlation was such as to be consistent with many possible hypotheses, evolutionary and otherwise, about causal relationships between the traits in question. PMID- 25431286 TI - Sex differences in genetic and environmental influences on educational attainment and income. AB - In many Western countries, women now reach educational levels comparable to men, although their income remains considerably lower. For the past decades, it has become increasingly clear that these measures of socio-economic status are influenced by genetic as well as environmental factors. Less is known about the relationship between education and income, and sex differences. The aim of this study was to explore genetic and environmental factors influencing education and income in a large cohort of young Norwegian twins, with special emphasis on gender differences. National register data on educational level and income were obtained for 7,710 twins (aged 29-41 years). Bivariate Cholesky models were applied to estimate qualitative and quantitative gender differences in genetic and environmental influences, the relative contribution of genetic and environmental factors to the correlation between education and income, and genetic correlations within and between sexes and phenotypes. The phenotypic correlation between educational level and income was 0.34 (0.32-0.39) for men and 0.45 (0.43-0.48) for women. An ACE model with both qualitative and quantitative sex differences fitted the data best. The genetic correlation between men and women (rg) was 0.66 (0.22-1.00) for educational attainment and 0.38 (0.01-0.75) for income, and between the two phenotypes 0.31 (0.08-0.52) for men and 0.72 (0.64-0.85) for women. Our results imply that, in relatively egalitarian societies with state-supported access to higher education and political awareness of gender equality, genetic factors may play an important role in explaining sex differences in the relationship between education and income. PMID- 25431287 TI - Risk factors influencing smoking behavior: a Turkish twin study. AB - AIM: In this study, we introduce the first twin study in Turkey, focusing on smoking behavior, and laying the foundation to register all twins born in Turkey for research purposes. Using Turkish twins will contribute to our understanding of health problems in the context of cultural differences. MATERIALS AND METHODS: We assessed 309 twin pairs (339 males and 279 females) aged between 15 and 45 years living in the Kirikkale and Ankara regions of Turkey, and administered a health and lifestyle interview that included questions about smoking status and smoking history. We analyzed the data using descriptive statistics, t-tests, chi square tests, and bivariate and multivariate clustered logistic regression. In addition, we fit bivariate Structural Equation Models (SEM) to determine contributions of latent genetic and environmental factors to smoking outcomes in this sample. RESULTS: One hundred seventy-eight participants (28.8%) were identified as smokers, smoking every day for a month or longer, of whom 79.2% were males and 20.8% were females. Mean values for number of cigarettes per day and the Fagerstrom Test of Nicotine Dependence (FTND; Fagerstrom, 1978) score were higher in males than in females, and age of onset was earlier in males. There was a significant positive correlation between the FTND score and number of cigarettes smoked per day, and a significant negative correlation between both variables and age at onset of smoking. Our study showed that gender, presence of a smoking twin in the family, age, alcohol use, marital status, daily sports activities, and feeling moody all played a significant role in smoking behavior among twins. The twin analysis suggested that 79.5% of the liability to FTND was influenced by genetic factors and 20.5% by unique environment, while familial resemblance for smoking initiation was best explained by common environmental factors. CONCLUSIONS: Marked differences in the prevalence of smoking behavior in men versus women were observed for the Turkish population. Genetic analyses showed that common environmental factors primarily contributed to smoking initiation, while genetic factors explained a greater proportion of variance in liability to nicotine dependence. Our study shows higher heritability estimate of the FTND scores and higher shared environmental influence on smoking initiation for both males and females than reported in previous studies. PMID- 25431288 TI - International network of twin registries (INTR): building a platform for international collaboration. AB - The International Network of Twin Registries (INTR) aims to foster scientific collaboration and promote twin research on a global scale by working to expand the resources of twin registries around the world and make them available to researchers who adhere to established guidelines for international collaboration. Our vision is to create an unprecedented scientific network of twin registries that will advance knowledge in ways that are impossible for individual registries, and includes the harmonization of data. INTR will also promote a broad range of activities, including the development of a website, formulation of data harmonization protocols, creation of a library of software tools for twin studies, design of a search engine to identify research partners, establishment of searchable inventories of data and biospecimens, development of templates for informed consent and data sharing, organization of symposia at International Society of Twin Studies conferences, support for scholar exchanges, and writing grant proposals. PMID- 25431289 TI - Human Genetics Society of Australasia position statement: population-based carrier screening for cystic fibrosis. AB - Since the discovery in 1989 that mutations in cystic fibrosis transmembrane conductance regulator (CFTR) underlie cystic fibrosis (CF), the most common life shortening genetic disorder in Caucasians, it has been possible to identify heterozygous mutation carriers at risk of having affected children. The Human Genetics Society of Australasia has produced a position statement with recommendations in relation to population-based screening for CF. These include: (1) that screening should be offered to all relatives of people with or carriers of CF (cascade testing) as well as to all couples planning to have children or who are pregnant; (2) the minimum CFTR mutation panel to be tested consists of 17 mutations which are those mutations that are associated with typical CF and occur with a frequency of 0.1% or higher among individuals diagnosed with CF in Australasia; (3) that genetic counselling is offered to all couples where both members are known to have one or two CFTR mutations and that such couples are given the opportunity to meet with a physician with expertise in the management of CF as well as a family/individual affected by the condition. PMID- 25431290 TI - Dichorionic triamniotic triplet pregnancy complicated by twin anemia polycythemia sequence: the place of fetal therapy. AB - Monochorionic twins as part of a high order multiple pregnancy can be an unintended consequence of the increasingly common practice of blastocyst transfer for couples requiring in vitro fertilisation (IVF) for infertility. Dichorionic triamniotic (DCTA) triplets is the most common presentation, and these pregnancies are particularly high risk because of the additional risks associated with monochorionicity. Surveillance for twin-to-twin transfusion syndrome, including twin anemia polycythemia sequence, may be more difficult, and any intervention to treat the monochorionic pair needs to balance the proposed benefits against the risks posed to the unaffected singleton. Counseling of families with DCTA triplets is therefore complex. Here, we report a case of DCTA triplets, where the pregnancy was complicated by threatened preterm labour, and twin anemia polycythemia sequence (TAPS) was later diagnosed at 28 weeks. The TAPS was managed with a single intraperitoneal transfusion, enabling safe prolongation of the pregnancy for over 2 weeks until recurrence of TAPS and preterm labour supervened. Postnatal TAPS was confirmed, and all three infants were later discharged home at term corrected age, and were normal at follow-up. This case highlights that in utero therapy has an important role in multiple pregnancies of mixed chorionicity, and can achieve safe prolongation of pregnancy at critical gestations. PMID- 25431293 TI - Presence of early CKD-related metabolic complications predict progression of stage 3 CKD: a case-controlled study. AB - BACKGROUND: Only a subset of patients who enter stage 3 chronic kidney disease (CKD) progress to stage 4. Identifying which patients entering stage 3 are most likely to progress could improve outcomes, by allowing more appropriate referrals for specialist care, and spare those unlikely to progress the adverse effects and costliness of an unnecessarily aggressive approach. We hypothesized that compared to non-progressors, patients who enter stage 3 CKD and ultimately progress have experienced greater loss of renal function, manifested by impairment of metabolic function (anemia, worsening acidosis and mineral abnormalities), than is reflected in the eGFR at entry to stage 3. The purpose of this case-controlled study was to design a prediction model for CKD progression using laboratory values reflecting metabolic status. METHODS: Using data extracted from the electronic health record (EHR), two cohorts of patients in stage 3 were identified: progressors (eGFR declined >3 ml/min/1.73 m2/year; n=117) and non progressors (eGFR declined <1 ml/min/1.713 m2; n=364). Initial laboratory values recorded a year before to a year after the time of entry to stage 3, reflecting metabolic complications (hemoglobin, bicarbonate, calcium, phosphorous, and albumin) were obtained. Average values in progressors and non-progressors were compared. Classification algorithms (Naive Bayes and Logistic Regression) were used to develop prediction models of progression based on the initial lab data. RESULTS: At the entry to stage 3 CKD, hemoglobin, bicarbonate, calcium, and albumin values were significantly lower and phosphate values significantly higher in progressors compared to non-progressors even though initial eGFR values were similar. The differences were sufficiently large that a prediction model of progression could be developed based on these values. Post-test probability of progression in patients classified as progressors or non-progressors were 81% (73% - 86%) and 17% (13% - 23%), respectively. CONCLUSIONS: Our studies demonstrate that patients who enter stage 3 and ultimately progress to stage 4 manifest a greater degree of metabolic complications than those who remain stable at the onset of stage 3 when eGFR values are equivalent. Lab values (hemoglobin, bicarbonate, phosphorous, calcium and albumin) are sufficiently different between the two cohorts that a reasonably accurate predictive model can be developed. PMID- 25431294 TI - Post-adolescent developmental changes in cortical complexity. AB - BACKGROUND: Post-adolescence is known to be a period of general maturation and development in the human brain. In brain imaging, volumetric and morphologic cortical grey-matter changes can easily be assessed, but the analysis of cortical complexity seems to have been broadly neglected for this age interval. METHODS: Magnetic resonance imaging (MRI) was used to acquire structural brain images. The study involved 17 adolescents (mean age 14.1 +/- 0.27, 11 girls) who were compared with 14 young adults (mean age 24.24 +/- 2.76, 7 women) for measures of brain complexity (fractal dimension--FD), grey matter (GM) volume and surface area of cortical ribbon. FD was calculated using box-counting and Minkowski Bouligand methods; FD and GM volume were measured for the whole brain, each hemisphere and lobes: frontal, occipital, parietal and temporal. RESULTS: The results show that the adults have a lower cortical complexity than the adolescents, which was significant for whole brain, left and right hemisphere, frontal and parietal lobes for both genders; and only for males in left temporal lobe. The GM volume was smaller in men than in boys for almost all measurements, and smaller in women than in girls just for right parietal lobe. A significant Pearson correlation was found between FD and GM volume for whole brain and each hemisphere in both genders. The decrease of the GM surface-area was significant in post-adolescence for males, not for females. CONCLUSIONS: During post adolescence there are common changes in cortical complexity in the same regions for both genders, but there are also gender specific changes in some cortical areas. The sex differences from different cortical measurements (FD, GM volume and surface-area of cortical ribbon) could suggest a maturation delay in specific brain regions for each gender in relation to the other and might be explained through the functional role of the corresponding regions reflected in gender difference of developed abilities. PMID- 25431295 TI - Unusual fibularis (peroneus) muscle. AB - Routine dissection has identified a previously unrecorded fibularis (peroneus) muscle in a 74-year-old male cadaver. The anomalous fibularis muscle was found lying immediately antero-medial to the fibularis longus (FL) muscle of the left leg. The anomalous muscle arose from the muscle belly of the FL in the proximal 1/2 of the leg. The muscle belly gave way to a long slender tendon that continued distally behind the lateral malleolus and inserted onto the superficial aspect of the inferior fibular retinaculum. The current finding and clinical significance are discussed. PMID- 25431296 TI - Response of two barley cultivars to increasing concentrations of cadmium or chromium in soil during the growing period. AB - The heavy metal contamination of soils is a serious environmental issue because excessive metal concentrations pose risks to the health of humans, animals, and plants. For this reason, the interest in understanding the toxic effects of metals on crop growth and physiology has increased in the last decades. A pot trial was performed in a greenhouse to evaluate the effects of contaminated soil with different concentrations of cadmium (Cd) or chromium (Cr) on barley growth and development. Two cultivars of barley were studied, Pedrezuela and CB502. Growth, chlorophyll content, chlorophyll fluorescence, and relative water content (RWC) were analyzed during the plant-growing period. After harvesting, the Cd and Cr contents in plant were analyzed. No significant differences were observed for chlorophyll content and chlorophyll fluorescence between control plants and those treated with Cd. In the case of Cr, a significant decrease of plant growth, chlorophyll content, chlorophyll fluorescence, and RWC was detected with respect to the control. The tolerance index (TI) and translocation factor (TF) were calculated. Data indicated that both varieties are tolerant to these metals; CB502 showed higher tolerance to Cr and Pedrezuela to Cd. The effect of Cd or Cr addition on nutrient concentrations in plants varied among elements and organs of the plant analyzed. The correlations between the physiological and agronomic studied traits were significant (p < 0.01, p < 0.001), so the stress induced by these metals affected the physiology and water relations of the plant, which provoked a decrease of plant biomass, especially in the plants treated with Cr. PMID- 25431297 TI - Novel rare earth tungstoarsenate heteropolyoxometalates K11[Ln(AsW 11O 39) 2].xH 2O (Ln = La, Nd, Sm) binding to bovine serum albumin: spectroscopic approach. AB - The rare earth salts of heteropoly have been widely applied in many fields. In this study, the biological activity of rare earth tungstoarsenate heteropolyoxometalates K11[Ln(AsW11O39)2].xH2O (abbr. LnW11, Ln = La (x = 24), Nd (x = 17), and Sm (x = 19)) were investigated by spectroscopic methods including fluorescence spectroscopy and UV-vis absorption spectroscopy at different temperatures. In the mechanism discussion, it was proved that the fluorescence quenching of bovine serum albumin (BSA) by LnW11 is initiated by complex formation. The thermodynamic parameters suggested that the binding of LnW11 to BSA is spontaneous, and the mainly force is electrostatic interactions. Site marker competitive experiments demonstrated that LaW11 binds with high affinity to site I (subdomain IIA) of BSA; but SmW11 and NdW11 bind with affinity to both site I (subdomain IIA) and site II (subdomain IIIA) of BSA. The results of synchronous fluorescence spectrum indicate that the secondary structure of BSA molecules was changed in the presence of LnW11. In addition, the binding parameters, binding site number, and effect of metal ions on LnW11-BSA were also discussed. PMID- 25431298 TI - Zinc enhances bone metabolism in ovariectomized rats and exerts anabolic osteoblastic/adipocytic marrow effects ex vivo. AB - Investigations of bone mass and marrow adiposity are critical for defining the role of zinc (Zn) in bone metabolism. Rats used for study were grouped as follows: control (sham), ovariectomy (OVX), ovariectomy + estradiol (OVX-E), ovariectomy + Zn treatment (OVX-Zn). Bone mineral density (BMD) was quantified (microCT); serum osteocalcin, adiponectin, RANKL, and TRAP levels were assayed (ELISA); and biochemical determinations of serum alkaline phosphatase (ALP), calcium (Ca), and phosphorus (P) were done. Cells derived from bone mesenchymal stem cell (BMSC) isolates of respective test groups were compared, identifying primary osteoblasts by MTT assay and adipocytes by Oil Red O stain. Osteocalcin and adiponectin levels in culture supernatants were determined by ELISA. Zn supplementation resulted in a modest increase in BMD, but serum osteocalcin and ALP activity increased significantly (P < 0.01, both). Serum levels of RANKL and TRAP were lower in OVX-Zn (vs OVX) rats (P < 0.01), whereas serum concentrations of adiponectin, Ca, and P did not differ by group. Osteocalcin level was significantly upregulated ex vivo (P < 0.01) in the supernatant of cultured OVX Zn (vs OVX) cells, accompanied by a slight upturn in osteoblastic differentiation. However, Oil Red O uptake and adiponectin level in supernatant were sharply diminished in cultured OVX-Zn (vs OVX) cells (P < 0.01). Overall, we concluded that Zn contributes to bone mass by marginally stimulating differentiation and proliferation of osteoblasts and by effectively inhibiting osteoclastic and adipocytic differentiation of BMSCs. PMID- 25431299 TI - Resveratrol synergistically triggers apoptotic cell death with arsenic trioxide via oxidative stress in human lung adenocarcinoma A549 cells. AB - Arsenic trioxide (As2O3) is a potent anticancer drug for the treatment of acute promyelocytic leukemia. However, the clinical applications of the agent to treat solid tumors are largely compromised by the drug resistance. Our previous study demonstrated that resveratrol, a plant-derived natural product, could potentiate the toxicity of arsenite in lung adenocarcinoma A549 cells at relatively high concentration, indicating that combination of resveratrol and As2O3 may be a helpful strategy to solve the drug resistance of As2O3 in tumor cells. To test this possibility, in the present study, we determined the combined effects of resveratrol and As2O3 in cultured A549 cells. Our results showed that co treatment of resveratrol with As2O3 resulted in a synergistic augmentation of cytotoxicity and apoptosis in cells at the tested concentration. To further reveal the detailed mechanism of this synergistic effect on cytotoxicity and apoptosis, apoptosis-related proteins, DNA and chromosomal damage, and the level of oxidative stress were also evaluated. Our data revealed that co-treatment with resveratrol and As2O3 caused more genotoxicity and serious oxidative stress in A549 cells than that of single agent treatment. Moreover, resveratrol and As2O3 could also corporately enhance the release of cytochrome c and the expressions of death receptor Fas and FasL. Together, our results suggest that resveratrol and As2O3 synergistically increase the apoptotic cell death in A549 cells through induction of oxidative stress, indicating that the combination of resveratrol with As2O3 may be a promising strategy to increase the clinical efficacy of As2O3 in the treatment of lung tumor. PMID- 25431300 TI - Protective effects of selenium on aflatoxin B1-induced mitochondrial permeability transition, DNA damage, and histological alterations in duckling liver. AB - Aflatoxin B1 (AFB1) is a mycotoxin that causes cytotoxicity through oxidative damage to its target organs. The liver is the first target of AFB1 damage. The aim of this study was to evaluate the protective effect of selenium on AFB1 induced hepatic mitochondrial damage in ducklings using molecular biological and histopathological techniques. Aflatoxin was administered via intragastric intubation (0.1 mg/kg body weight), daily for 21 days. The experimental group also received intragastric sodium selenite (1 mg/kg body weight), while the control group was given the same volume of dimethyl sulfoxide (DMSO). Sequence analysis of the mitochondrial DNA D-loop region showed that AFB1 induced damage. All AFB1-administrated ducklings were identified as having D-loop mitochondrial DNA mutations. Mutations were detected in two ducklings that had received both AFB1 and selenium. Mitochondrial swelling assays showed that opening of the mitochondrial permeability transition pores was increased in ducklings that had received AFB1 for 14 and 21 days (P < 0.05). Selenium significantly attenuated these adverse effects of AFB1. After AFB1 exposure, histological alterations were observed, including fat necrosis, steatosis, and formation of lymphoid nodules with infiltrated lymphocytes. These histological abnormalities were also attenuated by treatment with selenium. The overall data indicated that selenium exerts a potent protective effect against AFB1-induced hepatic mitochondrial damage, possibly through its antioxidant activity. PMID- 25431301 TI - Sexual maturity in western Atlantic bluefin tuna. AB - We introduce a novel endocrine approach for assessing the unresolved matter of the timing of sexual maturation in western Atlantic bluefin tuna (ABFT), a highly migratory population whose status remains uncertain. Ratios of follicle stimulating hormone to luteinizing hormone, a sexual maturity indicator, in all ABFT >= 134 cm curved fork length (CFL) were <0.4, similar to Mediterranean spawners, indicating that western ABFT mature at considerably smaller sizes and at a much younger age than currently assumed (>= 185 cm CFL). PMID- 25431302 TI - CAR: contig assembly of prokaryotic draft genomes using rearrangements. AB - BACKGROUND: Next generation sequencing technology has allowed efficient production of draft genomes for many organisms of interest. However, most draft genomes are just collections of independent contigs, whose relative positions and orientations along the genome being sequenced are unknown. Although several tools have been developed to order and orient the contigs of draft genomes, more accurate tools are still needed. RESULTS: In this study, we present a novel reference-based contig assembly (or scaffolding) tool, named as CAR, that can efficiently and more accurately order and orient the contigs of a prokaryotic draft genome based on a reference genome of a related organism. Given a set of contigs in multi-FASTA format and a reference genome in FASTA format, CAR can output a list of scaffolds, each of which is a set of ordered and oriented contigs. For validation, we have tested CAR on a real dataset composed of several prokaryotic genomes and also compared its performance with several other reference-based contig assembly tools. Consequently, our experimental results have shown that CAR indeed performs better than all these other reference-based contig assembly tools in terms of sensitivity, precision and genome coverage. CONCLUSIONS: CAR serves as an efficient tool that can more accurately order and orient the contigs of a prokaryotic draft genome based on a reference genome. The web server of CAR is freely available at http://genome.cs.nthu.edu.tw/CAR/ and its stand-alone program can also be downloaded from the same website. PMID- 25431303 TI - Investigation of the localized surface plasmon effect from Au nanoparticles in ZnO nanorods for enhancing the performance of polymer solar cells. AB - The organic polymer solar cell is recognized as one of the most competitive technologies of the next generation. Au nanoparticles and ZnO nanorods were combined to improve the inverted-structure low-bandgap polymer solar cells and enhance the absorption and efficiency of the devices. However, the Au nanoparticles tend to aggregate in solution, thus reducing the localized surface plasmon resonance (LSPR) effect. The cluster effect on the spectral range of enhancement in the absorption is investigated and the absorption characteristics of the LSPR receive proper modification through our experiment. After reducing the number of Au nanoparticle clusters, the LSPR effect in the devices was clearly verified. The proper combination of the Au nanoparticles and ZnO nanorods leads to the power conversion efficiency of the PTB7 : PC71BM inverted organic solar cell reaching 8.04% after optimizing the process conditions. PMID- 25431304 TI - Transient cardiac injury during H7N9 infection. AB - BACKGROUND: Recent reports have characterized virological and clinical features of the novel reassortant avian-origin influenza A (H7N9) virus. However, cardiovascular involvement during H7N9 infection is still unclear. In this study, we evaluate cardiac injury among H7N9-infected patients. MATERIALS AND METHODS: A total of 40 patients who were laboratory-confirmed with H7N9 infection were retrospectively included and grouped by Acute Physiology and Chronic Health Evaluation II (APACHE II) score into four subgroups I(0-10), II(11-20), III(21 30) and IV(31-71). Cardiovascular complications and markers of cardiac injury including creatinine kinase (CK), CK iso-enzyme (CK-MB), cardiac troponin I (cTNI) and brain natriuretic peptide (BNP) were assessed. Electrocardiogram (ECG) and echocardiography (ECHO) were also performed. RESULTS: Half of patients manifested with cardiovascular complications, with hypotension (47.5%) and heart failure (40.0%) the most prevalent. CK, CK-MB and cTNI showed marked increase with H7N9 virus infection but significantly decreased after H7N9 viral tests turned negative. More than half of patients presented with an abnormal ECG, but most of them are benign changes. ECHO examination showed different degree of impairment of cardiac function. Pulmonary artery systolic pressure was increased in all groups. Cardiac damage was more evident in patients with higher APACHE II score. CONCLUSIONS: H7N9 virus exerts a transient impairment on the cardiovascular system. Patients with a higher APACHE II score are more susceptible to cardiac damage. PMID- 25431306 TI - Coiling and clipping of middle cerebral artery aneurysms: a systematic review on clinical and imaging outcome. AB - BACKGROUND: There is an ongoing debate on the preferred treatment of middle cerebral artery (MCA) aneurysms. The purpose of this study was to assess the clinical and imaging outcomes comparing conventional coiling and clipping of unruptured and ruptured MCA aneurysms. METHODS: We searched the electronic databases PubMed, EMBASE, and Cochrane from January 1990 to May 2014. RESULTS: 51 studies were included in the analysis. Favorable outcome was reported in 97.0% and 77.1%, and in 97.2% and 72.8% of patients after coiling and clipping of unruptured and ruptured aneurysms, respectively. Death rates were 1.1% and 8.4% after coiling and 0.3% and 14.7% after clipping of unruptured and ruptured aneurysms, respectively. Initial adequate occlusion was obtained in 89.6% and 92.1% after coiling of unruptured and ruptured aneurysms, respectively. Only three studies on clipping reported on aneurysm occlusion during follow-up. CONCLUSIONS: Both coiling and clipping are procedures with low mortality and morbidity rates and, although it may seem that coiling is better for ruptured aneurysms and clipping for unruptured aneurysms, no firm conclusions can be drawn due to the variation in study design and lack of standardized reporting on MCA aneurysm treatments. Standardized observational studies from prospectively kept databases are needed to allow stronger conclusions to be drawn on what is the best treatment for MCA aneurysms. Comparable with aneurysms in other locations, a multidisciplinary approach is therefore recommended with selection of treatment modality based on the clinical condition of the patient and the morphological aspects of the aneurysm. PMID- 25431305 TI - Advances in prevention and therapy of neonatal dairy calf diarrhoea: a systematical review with emphasis on colostrum management and fluid therapy. AB - Neonatal calf diarrhoea remains the most common cause of morbidity and mortality in preweaned dairy calves worldwide. This complex disease can be triggered by both infectious and non-infectious causes. The four most important enteropathogens leading to neonatal dairy calf diarrhoea are Escherichia coli, rota- and coronavirus, and Cryptosporidium parvum. Besides treating diarrhoeic neonatal dairy calves, the veterinarian is the most obvious person to advise the dairy farmer on prevention and treatment of this disease. This review deals with prevention and treatment of neonatal dairy calf diarrhoea focusing on the importance of a good colostrum management and a correct fluid therapy. PMID- 25431307 TI - Association of industry sponsorship and positive outcome in randomised controlled trials in general and abdominal surgery: protocol for a systematic review and empirical study. AB - BACKGROUND: Industry sponsorship has been identified as a factor correlating with positive research findings in several fields of medical science. To date, the influence of industry sponsorship in general and abdominal surgery has not been fully studied. This protocol describes the rationale and planned conduct of a systematic review to determine the association between industry sponsorship and positive outcome in randomised controlled trials in general and abdominal surgery. METHODS/DESIGN: A literature search in the Cochrane Library, MEDLINE and EMBASE and additional hand searches in relevant citations will be conducted. In order to cover all relevant areas of general and abdominal surgery, a new literature search strategy called multi-PICO search strategy (MPSS) has been developed. No language restriction will be applied. The search will be limited to publications between January 1985 and July 2014. Information on funding source, outcome, study characteristics and methodological quality will be extracted.The association between industry sponsorship and positive outcome will be tested by a chi-squared test. A multivariate logistic regression analysis will be performed to control for possible confounders, such as number of study centres, multinational trials, methodological quality, journal impact factor and sample size. DISCUSSION: This study was designed to clarify whether industry-sponsored trials report more positive outcomes than non-industry trials. It will be the first study to evaluate this topic in general and abdominal surgery. The findings of this study will enable surgical societies, in particular, to give advice about cooperation with the industry and disclosure of funding source based on empirical evidence. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014010802. PMID- 25431308 TI - Difficult intubation in obese patients: incidence, risk factors, and complications in the operating theatre and in intensive care units. AB - BACKGROUND: Intubation procedure in obese patients is a challenging issue both in the intensive care unit (ICU) and in the operating theatre (OT). The objectives of the study were (i) to compare the incidence of difficult intubation and (ii) its related complications in obese patients admitted to ICU and OT. METHODS: We conducted a multicentre prospective observational cohort study in ICU and OT in obese (BMI>=30 kg m(-2)) patients. The primary endpoint was the incidence of difficult intubation. Secondary endpoints were the risk factors for difficult intubation, the use of difficult airway management techniques, and severe life threatening complications related to intubation (death, cardiac arrest, severe hypoxaemia, severe cardiovascular collapse). RESULTS: In cohorts of 1400 and 11 035 consecutive patients intubated in ICU and in the OT, 282 (20%) and 2103 (19%) were obese. In obese patients, the incidence of difficult intubation was twice more frequent in ICU than in the OT (16.3% vs 8.2%, P<0.01). In both cohorts, risk factors for difficult intubation were Mallampati score III/IV, obstructive sleep apnoea syndrome, and reduced mobility of cervical spine, while limited mouth opening, severe hypoxaemia, and coma appeared only in ICU. Specific difficult airway management techniques were used in 66 (36%) cases of difficult intubation in obese patients in the OT and in 10 (22%) cases in ICU (P=0.04). Severe life-threatening complications were significantly more frequent in ICU than in the OT (41.1% vs 1.9%, relative risk 21.6, 95% confidence interval 15.4 30.3, P<0.01). CONCLUSIONS: In obese patients, the incidence of difficult intubation was twice more frequent in ICU than in the OT and severe life threatening complications related to intubation occurred 20-fold more often in ICU. CLINICAL TRIAL REGISTRATION: Current controlled trials. Identifier: NCT01532063. PMID- 25431309 TI - Hospitalisation costs for infant bronchiolitis are up to 20 times higher if intensive care is needed. AB - AIM: Up to 3% of infants with bronchiolitis under 12 months of age are hospitalised, and up to 9% require intensive care. We evaluated the costs of bronchiolitis hospitalisation, with a special focus on whether infants needed intensive care. METHODS: Baseline and cost data were retrospectively collected, using electronic hospital files, for 80 infants under 12 months old who were treated in the paediatric intensive care unit (PICU) for bronchiolitis during a 13-year period. We calculated the daily costs for patients admitted to the PICU and compared them with 104 admitted to inpatient wards and 56 outpatients treated in the emergency department. RESULTS: The mean hospitalisation cost for PICU patients was ?8061 (95% CI 6193-9929), compared to ?1834 (1649-2020) for other inpatients and ?359 (331-387) for the outpatients. The hospitalisation cost per patient was associated with length of hospital stay, but not gender, age on admission or gestational age. There was no constant increase or decrease in hospitalisation costs during the study period. CONCLUSION: The hospitalisation costs of infants treated in the PICU for bronchiolitis at <12 months of age were approximately four times more than for other inpatients and over 20 times more than for outpatients. Strategies are needed to reduce the need for intensive care. PMID- 25431310 TI - Enkephalin is essential for the molecular and behavioral expression of cocaine sensitization. AB - Behavioral sensitization to cocaine is associated to neuroadaptations that contribute to addiction. Enkephalin is highly expressed in mesocorticolimbic areas associated with cocaine-induced sensitization; however, their influence on cocaine-dependent behavioral and neuronal plasticity has not been explained. In this study, we employed a knockout (KO) model to investigate the contribution of enkephalin in cocaine-induced behavioral sensitization. Wild-type (WT) and proenkephalin KO mice were treated with cocaine once daily for 9 days to induce sensitization. Additionally, to clarify the observations in KO mice, the same procedure was applied in C57BL/6 mice, except that naloxone was administered before each cocaine injection. All animals received a cocaine challenge on days 15 and 21 of the treatment to evaluate the expression of locomotor sensitization. On day 21, microdialysis measures of accumbal extracellular dopamine, Western blotting for GluR1 AMPA receptor (AMPAR), phosphorylated ERK2 (pERK2), CREB (pCREB), TrKB (pTrkB) were performed in brain areas relevant for sensitization from KO and WT and/or naloxone- and vehicle pre-treated animals. We found that KO mice do not develop sensitization to the stimulating properties of cocaine on locomotor activity and on dopamine release in the nucleus accumbens (NAc). Furthermore, pivotal neuroadaptations such as the increase in pTrkB receptor, pERK/CREB and AMPAR related to sensitized responses were absent in the NAc from KO mice. Consistently, full abrogation of cocaine-induced behavioral and neuronal plasticity after naloxone pre-treatment was observed. We show for first time that the proenkephalin system is essential in regulating long-lasting pivotal neuroadaptations in the NAc underlying behavioral sensitization to cocaine. PMID- 25431311 TI - Expressive and Instrumental Offending: Reconciling the Paradox of Specialisation and Versatility. AB - Although previous research into specialisation has been dominated by the debate over the existence of specialisation versus versatility, it is suggested that research needs to move beyond the restrictions of this dispute. The current study explores the criminal careers of 200 offenders based on their criminal records, obtained from a police database in the North West of England, aiming to understand the patterns and nature of specialisation by determining the presence of differentiation within their general offending behaviours and examining whether the framework of Expressive and Instrumental offending styles can account for any specialised tendencies that emerge. Fifty-eight offences were subjected to Smallest Space Analysis. Results revealed that a model of criminal differentiation could be identified and that any specialisation is represented in terms of Expressive and Instrumental offending styles. PMID- 25431312 TI - Early diagnosis of pulmonary tuberculosis using serum biomarkers. AB - The early diagnosis of tuberculosis (TB) remains the biggest obstacle to the global TB control, TB being the second leading cause of infectious disease death worldwide. As such, one of the pioneering investigations is made by Xu et al. (Proteomics 2015, 15, 58-67), which is of promising clinical application significance when used in clinics and in TB screening in the population. Xu et al. revealed that statistical differences among three serum proteins (S100A9, SOD3, and MMP9) exist between TB cases and other lung disease cases. The combination of the three biomarkers could give 92.5% sensitivity and 95% specificity to discriminate TB from healthy controls. PMID- 25431313 TI - Evaluation of a biofilm formation by Desulfovibrio fairfieldensis on titanium implants. AB - The aim of this study was to assess the capabilities of Desulfovibrio fairfieldensis to colonize the grade 4 titanium coupons (modSLA) used in dental implants. The effect of ampicillin, which is known to be a poorly penetrating agent in the matrix biofilm, was also compared with planktonic and sessile cells. The modSLA colonization by bacteria in KNO3 (0.05 mol l(-1)) and culture media (DSM 63 and fetal bovine serum) was determined by direct cell counts and field emission electronic microscopy. The surface of titanium (Ti) coupons was characterized by scanning electron microscopy and by Raman spectroscopy. Cells, mainly located in surface pores of modSLA coupons, appeared to be wrapped in a polymeric-like structure. The initial apparent rates of adhesion varied from 3 * 10(6) to 30 * 10(6) cells cm(-2) h(-1), and a plateau was reached at 1 day, regardless of the incubation medium. No cells have significantly adhered to polished Ti, and a minority was found on massive Ti. Finally, cells trapped on the modSLA surface were not lysed by ampicillin contrary to planktonic cells. Des. fairfieldensis is therefore able to colonize the rough surface of modSLA implant through a physical trapping in the microporosity of the surface, where they can produce a biofilm-like structure to improve their resistance to ampicillin. SIGNIFICANCE AND IMPACT OF THE STUDY: Desulfovibrio fairfieldensis is one of the most relevant sulphate-reducing bacteria of the human oral cavity suspected to be involved in peri-implantitis and implant corrosion. This study demonstrates for the first time that Des. fairfieldensis is able to initiate the formation of a biofilm-like structure on the microstructured titanium coupons used in dental implants and that it improves its resistance to antibiotic treatment. It gives new insight to understand the capacity of this opportunistic pathogen to colonize implant surfaces and to resist to biocide treatments. PMID- 25431314 TI - Earlier-born secondary hair follicles exhibit phenotypic plasticity. AB - The mouse pelage is composed of four distinct hair types. The fact that the follicles that generate these hair types form in successive waves during late embryonic development suggested the model that distinct epigenetic states of the inductive mesenchyme fixed when the follicles are formed specify the distinctive hair morphologies. This model is inconsistent with the observation that many follicles produce different hair types in successive hair cycles. In this study, the characteristics of the hair follicles that switch between the production of different hair types were examined. These follicles were born earlier than those that do not switch between hair types and made longer hairs. They also expressed a higher level of Sox2 in the dermal papilla and had more DP cells per follicle. These observations are consistent with the hypothesis that different birthdates specify the potential of different follicles. However, rather than directly specifying hair type, birthdate correlates with three types: guard hairs, a plastic population that can make awl, auchene or zigzag hairs, and a population that normally makes only zigzag hairs. Although Sox2 expression levels in the DP identify this subset during the morphogenetic cycle, Sox2 expression is not a fixed epigenetic state specified when the follicle is first formed. PMID- 25431315 TI - Hands4U: the effects of a multifaceted implementation strategy on hand eczema prevalence in a healthcare setting. Results of a randomized controlled trial. AB - BACKGROUND: Healthcare workers have an increased risk of developing hand eczema. A multifaceted implementation strategy was developed to implement a guideline to prevent hand eczema among healthcare workers. OBJECTIVES: To investigate the effects of the implementation strategy on self-reported hand eczema and preventive behaviour. METHODS: A randomized controlled trial was performed. A total of 48 departments (n = 1649) were randomly allocated to the multifaceted implementation strategy or the control group. The strategy consisted of education, participatory working groups, and role models. Outcome measures were self-reported hand eczema and preventive behaviour. Data were collected at baseline, and 3, 6, 9 and 12 months of follow-up. RESULTS: Participants in the intervention group were significantly more likely to report hand eczema [odds ratio (OR) 1.45; 95% confidence interval (CI) 1.03-2.04], and they reported significantly less hand washing (B, - 0.38; 95%CI: - 0.48 to - 0.27), reported significantly more frequent use of a moisturizer (B, 0.30; 95%CI: 0.22-0.39) and were more likely to report wearing cotton undergloves (OR 6.33; 95%CI: 3.23 12.41) than participants in the control group 12 months after baseline. CONCLUSIONS: The strategy implemented can be used in practice, as it showed positive effects on preventive behaviour. More research is needed to investigate the unexpected effects on hand eczema. PMID- 25431316 TI - Hes1 is upregulated by ischemic postconditioning and contributes to cardioprotection. AB - The expression of Hes1 is increased following myocardial infarct and other ischemic cardiomyopathies, but the role of Hes1 in cardioprotection provided by ischemic postconditioning (IPost) remains unclear. In this study, we used gain and loss of function approaches to investigate the role of Hes1 in cardioprotection during IPost. Primary cardiac myocytes exposed to ischemia reperfusion injury (IRI) and IPost were used as the experimental model. The results showed that Hes1 expression was increased during myocardial IPost, and Hes1 promoted the viability while inhibited the apoptosis of cardiomyocytes. Moreover, Hes1 inhibited the opening of mitochondrial permeability transition pore (mPTP) and the generation of reactive oxygen species in primary cardiac myocytes exposed to IRI. Mechanistically, we found that Hes1-mediated cardioprotection was related to the downregulation of phosphatase and tensin homolog and the activation of phosphatidylinositol 3-kinase/Akt and signal transducer and activator of transcription 3 signalling. These data demonstrate that Hes1 is upregulated and mediates cardioprotection provided by IPost and suggest that Hes1 is a potential new target for the treatment of ischemic cardiomyopathy. PMID- 25431317 TI - A hydrolytically-tunable photocrosslinked PLA-PEG-PLA/PCL-PEG-PCL dual-component hydrogel that enhances matrix deposition of encapsulated chondrocytes. AB - In this study, a series of photocrosslinked hydrogels were designed composed of both poly(lactide)-poly(ethylene glycol)-poly(lactide) (PEL) and poly(epsilon caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PEC) macromers. The PEL/PEC hydrogels at ratios of 100:0, 75:25, 50;50, 25:75 and 0:100 were studied for their degradation characteristics and their ability to support chondrogenesis of encapsulated chondrocytes. Difference in hydrolytic susceptibility between copolymers led to different degradation patterns where higher PEC content correlated with slower degradation. Increased chondrogenic gene expression was observed in chondrocyte-laden hydrogels within a 4-week culture period. Biochemical and histological evaluations revealed significant accumulation of extracellular matrix proteins such as glycosaminoglycans and collagen in the 50/50 hydrogel owing to appropriate tuning of hydrogel degradation. These results demonstrate that the dual-component photocrosslinked hydrogel system is suitable for use as scaffold to support chondrogenesis and, moreover, the tunability of these systems opens up possibilities for use in different cell culturing applications. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25431320 TI - EQ-5D-derived health utility values in patients undergoing surgery for chronic rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: Health utility value (HUV) is an index used to measure health-related quality of life for the valuation and comparison of treatments. The Euroqol 5-Dimension (EQ-5D) questionnaire is a widely used method for determining HUV, but it has not been applied for this purpose in patients with chronic rhinosinusitis (CRS) who undergo sinus surgery. STUDY DESIGN: Prospective cohort study. METHODS: Patients with CRS, who were recruited from 11 different otolaryngologic practices, completed the EQ-5D questionnaire at baseline, as well as 3, 12, and 24 months after surgery. HUVs calculated from the results of this questionnaire were compared to those reported in the general U.S. population and to patients suffering from other chronic diseases. RESULTS: Baseline EQ-5D surveys were completed by 242 patients. Mean baseline HUV (standard deviation) was 0.81 (0.13). Female gender, revision surgery, and the use of intraoperative image guidance were associated was significantly lower baseline values. HUV rose at 3 months to 0.89 (0.12) and remained improved at 12 months 0.88 (0.10) and 24 months 0.89 (0.10) (P < 0.001). Baseline HUV in CRS (0.81[0.13]) is lower than the general U.S. population (0.85 [0.18]) and appears appropriately positioned among other common chronic conditions including asthma (0.82-0.92), migraine (0.81-0.91), and seasonal allergies (0.94). CONCLUSIONS: Sinus surgery provides improvement in HUV in patients with CRS. These values may be paired with costs of care to perform cost-utility analysis on this group of patients. LEVEL OF EVIDENCE: 2c. PMID- 25431318 TI - Genetic variants of adiponectin and risk of colorectal cancer. AB - Circulating adiponectin has been associated with lower risk of colorectal cancer (CRC). Genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) associated with adiponectin levels. However, it is unclear whether these SNPs are associated with CRC risk. In addition, previous data on SNPs in the adiponectin pathway and their associations with CRC are inconsistent. Therefore, we examined 19 SNPs in genes related to adiponectin or its receptors and their associations with CRC using logistic regression among 7,020 cases and 7,631 controls drawn from ten studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium. Using data from a subset of two large cohort studies, we also assessed the contribution of individual SNPs and an adiponectin genetic score to plasma adiponectin after accounting for lifestyle factors among 2,217 women and 619 men. We did not find any statistically significant association between the 19 adiponectin-associated SNPs and CRC risk (multivariable-adjusted odds ratios ranged from 0.89 to 1.05, all p > 0.05). Each SNP explained less than 2.50% of the variance of plasma adiponectin, and the genetic score collectively accounted for 2.95 and 1.42% of the variability of adiponectin in women and men, respectively, after adjustment for age, body mass index, physical activity, smoking, alcohol consumption, regular use of aspirin or nonsteroidal anti-inflammatory drug and postmenopausal hormone use. In conclusion, our findings do not support an association between known adiponectin related common SNPs and CRC incidence. However, known common SNPs account for only a limited proportion of the interindividual variance in circulating adiponectin. Further work is warranted to investigate the relationship between adiponectin and CRC while accounting for other components in the pathway. PMID- 25431319 TI - Alteration in brain-derived neurotrophic factor (BDNF) after treatment of mice with herbal mixture containing Euphoria longana, Houttuynia cordata and Dioscorea japonica. AB - BACKGROUND: Literature data indicate that brain-derived neurotrophic factor (BDNF), cyclic-AMP response element-binding protein (CREB) and phospho-CREB (pCREB) may have a place in depression. BDNF belongs to the neurotrophin family that plays an important role in proliferation, survival and differentiation of different cell populations in the mammalian nervous system. The herbal mixture used in the present study consists of Euphoria longana, Houttuynia cordata and Dioscorea japonica. The purpose of the present study was to determine the neuroprotective effect of herbal mixture. We also tested the hypothesis that administration of herbs reverses memory deficits and promotes the protein expression of BDNF in the mouse brain. METHODS: Mice were randomized into four different treatment groups (n = 10/group). Normal and stress groups received regular lab chow without stress and under stress conditions, respectively, for 3 weeks. The animals in the stress group were immobilized for 4 hours a day for 2 weeks. Different doses of herbal mixture (206 and 618 mg/kg) were administered for 3 weeks to those mice under stress conditions. Mice were analyzed by behavioral tests and immunoblotting examination in the hippocampus and cortex. An additional in vitro investigation was performed to examine whether herbs induce neurotoxicity in a human neuroblastoma cell line, SH-SY5Y cells. RESULTS: No significant toxicity of herbs on human neuroblastoma cells was observed. These herbs demonstrated an inductive effect on the expression of BDNF, pCREB and pAkt. For spatial working memory test, herbal mixture fed mice exhibited an increased level of spontaneous alternation (p < 0.01) compared to those in stress conditions. Moreover, herbal mixture produced highly significant (p < 0.01) reduction in the immobility time in the tail suspension test. Mice in the herbal mixture groups demonstrated lower serum corticosterone concentration than mice in the stress group (p < 0.05). Effects of the oral administration of herbal mixture on protein levels of BDNF in the hippocampi and cortices were significant. CONCLUSIONS: Our study showed that herbal mixture administration has antidepressant effects in mice. It is proposed that adverse events such as stress and depression can modulate the expression of molecular players of cellular plasticity in the brain. PMID- 25431321 TI - Method to measure the 3D angular orientation of the aortic valve plane from a single image of a valvuloplasty balloon: findings of a large animal proof of concept experiment. AB - During transcatheter aortic valve replacement procedures, alignment of the interventional x-ray beam with the aortic valve plane is required to guide valve placement. The purpose of this work was to develop methods to measure x-ray beam angles which are aligned with the aortic valve plane from a single x-ray image of a valvuloplasty balloon inflated across the left ventricular outflow tract (LVOT). A custom valvuloplasty balloon and image analytics were developed. In vivo pig experiments demonstrated that the angular orientation of the LVOT can be measured with precision less than 3 degrees , including the influence of cardiac motion during rapid pacing. Using these methods, the angular orientation of the LVOT of a large mammal can be measured precisely and the continuous range of x ray projection angles which are aligned with the aortic valve plane can be calculated. PMID- 25431322 TI - Total synthesis of the protected aglycon of fidaxomicin (tiacumicin B, lipiarmycin A3). AB - Fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is a novel macrocyclic antibiotic that is used in hospitals for the treatment of Clostridium difficile infections. This natural product has also been shown to have excellent bactericidal activity against multidrug-resistant Mycobacterium tuberculosis. In spite of its attractive biological activity, no total synthesis has been reported to date. The enantioselective synthesis of the central 18-membered macrolactone is reported herein. The key reactions include ring-closing metathesis between a terminal olefin and a dienoate moiety for macrocyclization, a vinylogous Mukaiyama aldol reaction, and a Stille coupling reaction of sterically demanding substrates. The retrosynthesis involves three medium-sized fragments, thus leading to a flexible yet convergent synthetic route. PMID- 25431324 TI - Estimation of volume densities of hepatocytic peroxisomes in a model fish: catalase conventional immunofluorescence versus cytochemistry for electron microscopy. AB - Accurately accessing changes in the intracellular volumes (or numbers) of peroxisomes within a cell can be a lengthy task, because unbiased estimations can be made only by studies conducted under transmission electron microscopy. Yet, such information is often required, namely for correlations with functional data. The optimization and applicability of a fast and new technical proceeding based on catalase immunofluorescence was implemented herein by using primary hepatocytes from brown trout (Salmo trutta f. fario), exposed during 96 h to two distinct treatments (0.1% ethanol and 50 uM of 17alpha-ethynylestradiol). The time and cost efficiency, together with the results obtained by stereological analyses, specifically directed to the volume densities of peroxisomes, and additionally of the nucleus in relation to the hepatocyte, were compared with the well-established 3,3'-diaminobenzidine cytochemistry for electron microscopy. With the immuno technique it was possible to correctly distinguish punctate peroxisomal profiles, allowing the selection of the marked organelles for quantification. By both methodologies, a significant reduction in the volume density of the peroxisome within the hepatocyte was obtained after an estrogenic input. The most interesting point here was that the volume density ratios were quite correlated between both techniques. Overall, the immunofluorescence protocol for catalase was evidently faster, cheaper and provided reliable quantitative data that discriminated in the same way the compared groups. After this validation study, we recommend the use of catalase immunofluorescence as the first option for rapid screening of changes of the amount of hepatocytic peroxisomes, using their volume density as an indicator. PMID- 25431323 TI - Art-making in a family medicine clerkship: how does it affect medical student empathy? AB - BACKGROUND: To provide patient-centred holistic care, doctors must possess good interpersonal and empathic skills. Medical schools traditionally adopt a skills based approach to such training but creative engagement with the arts has also been effective. A novel arts-based approach may help medical students develop empathic understanding of patients and thus contribute to medical students' transformative process into compassionate doctors. This study aimed to evaluate the impact of an arts-making workshop on medical student empathy. METHODS: This was a mixed-method quantitative-qualitative study. In the 2011-12 academic year, all 161 third year medical students at the University of Hong Kong were randomly allocated into either an arts-making workshop or a problem-solving workshop during the Family Medicine clerkship according to a centrally-set timetable. Students in the arts-making workshop wrote a poem, created artwork and completed a reflective essay while students in the conventional workshop problem-solved clinical cases and wrote a case commentary. All students who agreed to participate in the study completed a measure of empathy for medical students, the Jefferson Scale of Empathy (JSE) (student version), at the start and end of the clerkship. Quantitative data analysis: Paired t-test and repeated measures ANOVA was used to compare the change within and between groups respectively. Qualitative data analysis: Two researchers independently chose representational narratives based on criteria adapted from art therapy. The final 20 works were agreed upon by consensus and thematically analysed using a grounded theory approach. RESULTS: The level of empathy declined in both groups over time, but with no statistically significant differences between groups. For JSE items relating to emotional influence on medical decision making, participants in the arts-making workshop changed more than those in the problem-solving workshop. From the qualitative data, students perceived benefits in arts-making, and gained understanding in relation to self, patients, pain and suffering, and the role of the doctor. CONCLUSIONS: Though quantitative findings showed little difference in empathy between groups, arts-making workshop participants gained empathic understanding in four different thematic areas. This workshop also seemed to promote greater self-awareness which may help medical students recognize the potential for emotions to sway judgment. Future art workshops should focus on emotional awareness and regulation. PMID- 25431325 TI - Hepatoprotective effect of ethanol extract from Berchemia lineate against CCl4 induced acute hepatotoxicity in mice. AB - CONTEXT: The roots of Berchemia lineate (L.) DC. (Rhamnaceae) have been long used as a remedy for the treatment of some diseases in Guangxi Province, China. OBJECTIVE: The present study investigates the hepatoprotective effect of Berchemia lineate ethanol extract (BELE) on CCl4-induced acute liver damage in mice. MATERIALS AND METHODS: Effect of BELE administrated for 7 consecutive days was evaluated in mice by the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), albulin (ALB), globulin (GLB), and total protein (TP) levels, as well as liver superoxide dismutase (SOD) activity and malondialdehyde (MDA) level. Moreover, histopathological examinations were also taken. RESULTS: Compared with the model group, administration of 400 mg/kg BELE for 7 d in mice significantly decreased the serum ALT (56.25 U/L), AST (297.67 U/L), ALP (188.20 U/L), and TBIL (17.90 mol/L), along with the elevation of TP (64.67 g/L). In addition, BELE (100, 200, and 400 mg/kg, i.g.) treated mice recorded a dose-dependent increment of SOD (291.17, 310.32, and 325.67 U/mg prot) and reduction of MDA (7.27, 6.77, and 5.33 nmol/mg prot) levels. Histopathological examinations also confirmed that BELE can ameliorate CCl4-induced liver injuries, characterized by extensive hepatocellular degeneration/necrosis, inflammatory cell infiltration, congestion, and sinusoidal dilatation. DISCUSSION AND CONCLUSION: The results indicated that BELE possessed remarkable protective effect against acute hepatotoxicity and oxidative injuries induced by CCl4, and that the hepatoprotective effects of BELE may be due to both the inhibition of lipid peroxidation and the increase of antioxidant activity. PMID- 25431326 TI - Rates of meniscal tearing in patients with chondrocalcinosis. AB - Internal derangement of the knee secondary to a meniscal tear has been recently observed in patients with chondrocalcinosis. However, there is no data about the prevalence of meniscal tears associated to chondrocalcinosis. Therefore, the aim of this study was to know the rates of meniscal tear in patients with chondrocalcinosis. The study population was a cohort of 1031 consecutive outpatients who underwent arthroscopy of the knee. Meniscal tear was present in 322 patients and 709 patients had intact meniscus. The specific subgroup of interest included 58 knees from 58 patients (25 males and 33 females) with arthroscopic evidences of chondrocalcinosis. Patients with chondrocalcinosis had significantly higher rates of meniscal tear compared to those without chondrocalcinosis (74.1 versus 28.7%, p < 0.001). An absolute and attributable risk of tear was 74 and 8%, respectively, in knees with chondrocalcinosis. Relative risk of tear in patients with chondrocalcinosis versus without chondrocalcinosis was 2.58 (95% confidence interval 2.16-3.10). In patients with chondrocalcinosis and meniscal tear, the duration of the disease was about 5.3 (range 1-8) years versus 4.9 (range 3-7) years in those patients with chondrocalcinosis and an intact meniscus (p = 0.75). In conclusion, our findings support that chondrocalcinosis predispose meniscal tearing even in the absence of any traumatic event. Further longitudinal studies are needed to characterize the impact of chondrocalcinosis and meniscal vulnerability. PMID- 25431327 TI - Can we prevent rapid radiological progression in patients with early rheumatoid arthritis? AB - The aim of this study is to test the performance of a matrix model to predict rapid radiological progression (RRP) in a study population of early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) patients. A matrix model using baseline CRP, erosion score, autoantibody status, and initial treatment choice to predict RRP (increase >=5 points in Sharp-van der Heijde score (SHS) in 1 year) was derived from the BeSt study where patients with active RA (1987-criteria) were treated with initial monotherapy or combination therapy, aiming at low disease activity. In the IMPROVED study, patients with early RA (2010 criteria) and UA were initially treated with methotrexate and prednisone aiming at remission. A receiver operating characteristics (ROC) curve was used to assess the discriminative value of the model to predict damage progression in the IMPROVED population. Four hundred thirty-one out of 479 patients with RA and 106/122 with UA could be categorized as high, intermediate, low, or very low risk for RRP. One patient, with a very low risk profile, showed RRP. Thirty-two other patients (5 %) showed radiological progression >=0.5 point SHS; none had a high risk profile and 22 had a very low risk profile. The area under the curve (AUC) of the ROC curve was 0.56 (95% CI 0.45; 0.68). A matrix model predicting RRP based on risk factors identified in recent onset active RA according to the 1987 criteria performed poorly in recent onset RA (2010 criteria) and UA. It appears that known risk factors for damage progression lose their impact with early remission steered treatment, so that RRP might be considered a phenomenon of the past. PMID- 25431328 TI - MGAS: a powerful tool for multivariate gene-based genome-wide association analysis. AB - MOTIVATION: Standard genome-wide association studies, testing the association between one phenotype and a large number of single nucleotide polymorphisms (SNPs), are limited in two ways: (i) traits are often multivariate, and analysis of composite scores entails loss in statistical power and (ii) gene-based analyses may be preferred, e.g. to decrease the multiple testing problem. RESULTS: Here we present a new method, multivariate gene-based association test by extended Simes procedure (MGAS), that allows gene-based testing of multivariate phenotypes in unrelated individuals. Through extensive simulation, we show that under most trait-generating genotype-phenotype models MGAS has superior statistical power to detect associated genes compared with gene-based analyses of univariate phenotypic composite scores (i.e. GATES, multiple regression), and multivariate analysis of variance (MANOVA). Re-analysis of metabolic data revealed 32 False Discovery Rate controlled genome-wide significant genes, and 12 regions harboring multiple genes; of these 44 regions, 30 were not reported in the original analysis. CONCLUSION: MGAS allows researchers to conduct their multivariate gene-based analyses efficiently, and without the loss of power that is often associated with an incorrectly specified genotype-phenotype models. AVAILABILITY AND IMPLEMENTATION: MGAS is freely available in KGG v3.0 (http://statgenpro.psychiatry.hku.hk/limx/kgg/download.php). Access to the metabolic dataset can be requested at dbGaP (https://dbgap.ncbi.nlm.nih.gov/). The R-simulation code is available from http://ctglab.nl/people/sophie_van_der_sluis. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25431330 TI - SNiPA: an interactive, genetic variant-centered annotation browser. AB - MOTIVATION: Linking genes and functional information to genetic variants identified by association studies remains difficult. Resources containing extensive genomic annotations are available but often not fully utilized due to heterogeneous data formats. To enhance their accessibility, we integrated many annotation datasets into a user-friendly webserver. AVAILABILITY AND IMPLEMENTATION: http://www.snipa.org/ CONTACT: g.kastenmueller@helmholtz muenchen.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25431329 TI - Tissue-aware data integration approach for the inference of pathway interactions in metazoan organisms. AB - MOTIVATION: Leveraging the large compendium of genomic data to predict biomedical pathways and specific mechanisms of protein interactions genome-wide in metazoan organisms has been challenging. In contrast to unicellular organisms, biological and technical variation originating from diverse tissues and cell-lineages is often the largest source of variation in metazoan data compendia. Therefore, a new computational strategy accounting for the tissue heterogeneity in the functional genomic data is needed to accurately translate the vast amount of human genomic data into specific interaction-level hypotheses. RESULTS: We developed an integrated, scalable strategy for inferring multiple human gene interaction types that takes advantage of data from diverse tissue and cell lineage origins. Our approach specifically predicts both the presence of a functional association and also the most likely interaction type among human genes or its protein products on a whole-genome scale. We demonstrate that directly incorporating tissue contextual information improves the accuracy of our predictions, and further, that such genome-wide results can be used to significantly refine regulatory interactions from primary experimental datasets (e.g. ChIP-Seq, mass spectrometry). AVAILABILITY AND IMPLEMENTATION: An interactive website hosting all of our interaction predictions is publically available at http://pathwaynet.princeton.edu. Software was implemented using the open-source Sleipnir library, which is available for download at https://bitbucket.org/libsleipnir/libsleipnir.bitbucket.org. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25431331 TI - MetaPSICOV: combining coevolution methods for accurate prediction of contacts and long range hydrogen bonding in proteins. AB - MOTIVATION: Recent developments of statistical techniques to infer direct evolutionary couplings between residue pairs have rendered covariation-based contact prediction a viable means for accurate 3D modelling of proteins, with no information other than the sequence required. To extend the usefulness of contact prediction, we have designed a new meta-predictor (MetaPSICOV) which combines three distinct approaches for inferring covariation signals from multiple sequence alignments, considers a broad range of other sequence-derived features and, uniquely, a range of metrics which describe both the local and global quality of the input multiple sequence alignment. Finally, we use a two-stage predictor, where the second stage filters the output of the first stage. This two stage predictor is additionally evaluated on its ability to accurately predict the long range network of hydrogen bonds, including correctly assigning the donor and acceptor residues. RESULTS: Using the original PSICOV benchmark set of 150 protein families, MetaPSICOV achieves a mean precision of 0.54 for top-L predicted long range contacts-around 60% higher than PSICOV, and around 40% better than CCMpred. In de novo protein structure prediction using FRAGFOLD, MetaPSICOV is able to improve the TM-scores of models by a median of 0.05 compared with PSICOV. Lastly, for predicting long range hydrogen bonding, MetaPSICOV-HB achieves a precision of 0.69 for the top-L/10 hydrogen bonds compared with just 0.26 for the baseline MetaPSICOV. AVAILABILITY AND IMPLEMENTATION: MetaPSICOV is available as a freely available web server at http://bioinf.cs.ucl.ac.uk/MetaPSICOV. Raw data (predicted contact lists and 3D models) and source code can be downloaded from http://bioinf.cs.ucl.ac.uk/downloads/MetaPSICOV. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25431332 TI - A logical model of HIV-1 interactions with the T-cell activation signalling pathway. AB - MOTIVATION: Human immunodeficiency virus type 1 (HIV-1) hijacks host cellular processes to replicate within its host. Through interactions with host proteins, it perturbs and interrupts signaling pathways that alter key cellular functions. Although networks of viral-host interactions have been relatively well characterized, the dynamics of the perturbation process is poorly understood. Dynamic models of infection have the potential to provide insights into the HIV-1 host interaction. RESULTS: We employed a logical signal flow network to model the dynamic interactions between HIV-1 proteins and key human signal transduction pathways necessary for activation of CD4+ T lymphocytes. We integrated viral-host interaction and host signal transduction data into a dynamic logical model comprised of 137 nodes (16 HIV-1 and 121 human proteins) and 336 interactions collected from the HIV-1 Human Interaction Database. The model reproduced expected patterns of T-cell activation, co-stimulation and co-inhibition. After simulations, we identified 26 host cell factors, including MAPK1&3, Ikkb-Ikky Ikka and PKA, which contribute to the net activation or inhibition of viral proteins. Through in silico knockouts, the model identified a further nine host cell factors, including members of the PI3K signalling pathway that are essential to viral replication. Simulation results intersected with the findings of three siRNA gene knockout studies and identified potential drug targets. Our results demonstrate how viral infection causes the cell to lose control of its signalling system. Logical Boolean modelling therefore provides a useful approach for analysing the dynamics of host-viral interactions with potential applications for drug discovery. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25431333 TI - Oxoanionic noble metal compounds from fuming nitric acid: the palladium examples Pd(NO3)2 and Pd(CH3SO3)2. AB - The oxidation of elemental palladium at 100 degrees C in a mixture of fuming nitric acid and a pyridine-SO3 complex leads to the anhydrous nitrate Pd(NO3)2 (monoclinic, P2(1)/n, Z=2, a=469.12(3) pm, b=593.89(3) pm, c=805.72(4) pm, beta=105.989(3) degrees , V=215.79(2) A(3)). The Pd(2+) ions are in square-planar coordination with four monodentate nitrate groups which are connected to further palladium atoms, leading to a layer structure. The reaction of elemental palladium with a mixture of fuming nitric acid and methanesulfonic acid at 120 degrees C leads to single crystals of Pd(CH3SO3)2 (monoclinic, P2(1)/n, Z=2, a=480.44(1) pm, b=1085.53(3) pm, c=739.78(2) pm, beta=102.785(1) degrees , V=376.254(17) A(3)). Also in this structure the Pd(2+) ions are in square-planar coordination with four monodentate anions; however, the connection to adjacent palladium atoms leads to a chain-type structure. The thermal decomposition of the compounds has been investigated by means of DSC/TG measurements. Furthermore, IR and Raman spectra have been recorded, and an assignment of the observed vibrational frequencies has been carried out based on theoretical investigations. PMID- 25431335 TI - Societal transformation in response to global environmental change: A review of emerging concepts. AB - The study of societal transformation in response to environmental change has become established, yet little consensus exists regarding the conceptual basis of transformation. This paper aims to provide structure to the dialog on transformation, and to reflect on the challenges of social research in this area. Concepts of transformation are identified through a literature review, and examined using four analytical criteria. It is found that the term 'transformation' is frequently used merely as a metaphor. When transformation is not used as a metaphor, eight concepts are most frequently employed. They differ with respect to (i) system conceptualization, (ii) notions of social consciousness (deliberate/emergent), and (iii) outcome (prescriptive/descriptive). Problem-based research tends to adopt concepts of deliberate transformation with prescriptive outcome, while concepts of emergent transformation with no prescriptive outcome tend to inform descriptive-analytical research. Dialog around the complementarities of different concepts and their empirical testing are priorities for future research. PMID- 25431334 TI - An SNP-based second-generation genetic map of Daphnia magna and its application to QTL analysis of phenotypic traits. AB - BACKGROUND: Although Daphnia is increasingly recognized as a model for ecological genomics and biomedical research, there is, as of yet, no high-resolution genetic map for the genus. Such a map would provide an important tool for mapping phenotypes and assembling the genome. Here we estimate the genome size of Daphnia magna and describe the construction of an SNP array based linkage map. We then test the suitability of the map for life history and behavioural trait mapping. The two parent genotypes used to produce the map derived from D. magna populations with and without fish predation, respectively and are therefore expected to show divergent behaviour and life-histories. RESULTS: Using flow cytometry we estimated the genome size of D. magna to be about 238 mb. We developed an SNP array tailored to type SNPs in a D. magna F2 panel and used it to construct a D. magna linkage map, which included 1,324 informative markers. The map produced ten linkage groups ranging from 108.9 to 203.6 cM, with an average distance between markers of 1.13 cM and a total map length of 1,483.6 cM (Kosambi corrected). The physical length per cM is estimated to be 160 kb. Mapping infertility genes, life history traits and behavioural traits on this map revealed several significant QTL peaks and showed a complex pattern of underlying genetics, with different traits showing strongly different genetic architectures. CONCLUSIONS: The new linkage map of D. magna constructed here allowed us to characterize genetic differences among parent genotypes from populations with ecological differences. The QTL effect plots are partially consistent with our expectation of local adaptation under contrasting predation regimes. Furthermore, the new genetic map will be an important tool for the Daphnia research community and will contribute to the physical map of the D. magna genome project and the further mapping of phenotypic traits. The clones used to produce the linkage map are maintained in a stock collection and can be used for mapping QTLs of traits that show variance among the F2 clones. PMID- 25431336 TI - Acute heart failure in elderly patients: worse outcomes and differential utility of standard prognostic variables. Insights from the PROTECT trial. AB - AIMS: Previous heart failure (HF) trials suggested that age influences patient characteristics and outcome; however, under-representation of elderly patients has limited characterization of this cohort. Whether standard prognostic variables have differential utility in various age groups is unclear. METHODS AND RESULTS: The PROTECT trial investigated 2033 patients (median age 72 years) with acute HF randomized to rolofylline or placebo. Patients were divided into five groups based on the quintiles of age: <=59, 60-68, 69-74, 75-79, and >=80 years. Baseline characteristics, medications, and outcomes (30-day death or cardiovascular/renal hospitalization, and death at 30 and 180 days) were explored. The prognostic utility of baseline characteristics for outcomes was investigated in the different groups and in those aged <80 years vs. >=80 years. With increasing age, patients were more likely to be women with hypertension, AF, and higher EF. Increased age was associated with increased risk of 30- and 180 day outcomes, which persisted after multivariable adjustment (hazard ratio for 180-day death = 1.17; 95% confidence interval 1.11-1.24 for each 5-year increase). The prognostic utility of baseline characteristics such as previous HF hospitalization and serum sodium, systolic blood pressure, and NYHA class was attenuated in the elderly for the endpoint of 180-day mortality. An increase in albumin was associated with a greater reduction in risk in patients aged >=80 years vs. <80 years. CONCLUSIONS: In a large trial of acute HF, there were differences in baseline characteristics and outcomes amongst patients of different ages. Standard prognostic variables exhibit different utility in elderly patients. PMID- 25431337 TI - A common variant in RAB27A gene is associated with fractional exhaled nitric oxide levels in adults. AB - BACKGROUND: Exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation in the airways and for responsiveness to corticosteroids in asthmatics. OBJECTIVE: We sought to identify in adults the genetic determinants of fractional exhaled nitric oxide (FeNO) levels and to assess whether environmental and disease-related factors influence these associations. METHODS: We performed a genome-wide association study of FeNO through meta-analysis of two independent discovery samples of European ancestry: the outbred EGEA study (French Epidemiological study on the Genetics and Environment of Asthma, N = 610 adults) and the Hutterites (N = 601 adults), a founder population living on communal farms. Replication of main findings was assessed in adults from an isolated village in Sardinia (Talana study, N = 450). We then investigated the influence of asthma, atopy and tobacco smoke exposure on these genetic associations, and whether they were also associated with FeNO values in children of the EAGLE (EArly Genetics & Lifecourse Epidemiology, N = 8858) consortium. RESULTS: We detected a common variant in RAB27A (rs2444043) associated with FeNO that reached the genome-wide significant level (P = 1.6 * 10(-7) ) in the combined discovery and replication adult data sets. This SNP belongs to member of RAS oncogene family (RAB27A) and was associated with an expression quantitative trait locus for RAB27A in lymphoblastoid cell lines from asthmatics. A second suggestive locus (rs2194437, P = 8.9 * 10(-7) ) located nearby the sodium/calcium exchanger 1 (SLC8A1) was mainly detected in atopic subjects and influenced by inhaled corticosteroid use. These two loci were not associated with childhood FeNO values. CONCLUSIONS AND CLINICAL RELEVANCE: This study identified a common variant located in RAB27A gene influencing FeNO levels specifically in adults and with a biological relevance to the regulation of FeNO levels. This study provides new insight into the biological mechanisms underlying FeNO levels in adults. PMID- 25431338 TI - The combined use of Camellia sinensis and metronomic zoledronic acid in a breast cancer-induced osteolysis mouse model. AB - PURPOSE: In previous studies, we demonstrated that green tea (Camellia sinensis, CS) water extract had potent anti-tumor and anti-metastasis effects in the 4T1 mouse breast cancer xenograft model, and the metronomic regimen (0.0125 mg/kg twice a week for 4 weeks) of zoledronic acid (ZOL) was also effective in decreasing tumor burden and metastasis when compared with the conventional regimen. This study aimed to investigate the combined use of CS water extract and metronomic ZOL against tumor metastasis and bone destruction in MDA-MB-231-TXSA human breast cancer. METHODS: Female nude mice were injected with MDA-MB-231-TXSA cells into the marrow space of tibia and were treated with CS water extract and/or metronomic ZOL for 4 weeks. Tumor growth and metastasis to lungs and livers were assessed by in vivo bioluminescence imaging. Abilities of migration and invasion of MDA-MB-231-TXSA cells were also evaluated in vitro. RESULTS: Our results demonstrated that combination of CS and ZOL had the most potent effects on tumor burden and metastasis to bone, lung and liver, while treatment with CS or ZOL alone significantly protected the bone from cancer-induced osteolysis. In vitro, the combined use of CS + ZOL significantly inhibited MDA-MB-231-TXSA cell migration and invasion. Mechanistic zymography studies showed that the enzyme activities of MMP-9 and MMP-2 were significantly suppressed by CS and CS + ZOL. CONCLUSIONS: The combination of CS plus metronomic ZOL demonstrated potent anti tumor, anti-metastasis and anti-osteolysis effects against breast cancer, suggesting the potential clinical application against breast cancer patients. PMID- 25431339 TI - BMP-2 inhibits tumor-initiating ability in human renal cancer stem cells and induces bone formation. AB - PURPOSE: We have previously shown that BMP-2 induces bone formation and inhibits tumorigenicity of cancer stem cells (CSCs) in a human osteosarcoma OS99-1 cell line. In this study, we sought to determine whether BMP-2 can similarly induce bone formation and inhibit the tumorigenicity of renal CSCs identified based on aldehyde dehydrogenase (ALDH) activity in renal cell carcinoma (RCC) cell lines and primary tumors. METHODS: Using a xenograft model in which cells from human RCC cell lines ACHN, Caki-2, and primary tumors were grown in NOD/SCID mice, renal CSCs were identified as a subset of ALDH(br) cells. The ALDH(br) cells possessed a greater colony-forming efficiency, higher proliferative output, increased expression of stem cell marker genes Oct3/4A, Nanog, renal embryonic marker Pax-2, and greater tumorigenicity compared to cells with low ALDH activity (ALDH(lo) cells), generating new tumors with as few as 25 cells in mice. RESULTS: In vitro, BMP-2 was found to inhibit the ALDH(br) cell growth, down-regulate the expression of embryonic stem cell markers, and up-regulate the transcription of osteogenic markers. In vivo, all animals receiving a low number of ALDH(br) cells (5 * 10(3)) from ACHN, Caki-2, and primary tumor xenografts treated with 30 ug BMP-2 per animal showed limited tumor growth with significant bone formation, while untreated cells developed large tumor masses without bone formation. CONCLUSIONS: These results suggest that BMP-2 inhibits the tumor-initiating ability of renal CSCs and induces osseous bone formation. BMP-2 may therefore provide a beneficial strategy for human RCC treatment by targeting the CSC enriched population. PMID- 25431340 TI - Determinants of adherence to recommendations for depressed elderly patients in primary care: a multi-methods study. AB - OBJECTIVE: It is logical that tailoring implementation strategies to address identified determinants of adherence to clinical practice guidelines should improve adherence. This study aimed to identify and prioritize determinants of adherence to six recommendations for elderly patients with depression. DESIGN AND SETTING: Group and individual interviews and a survey were conducted in Norway. METHOD: Individual and group interviews with healthcare professionals and patients, and a mailed survey of healthcare professionals. A generic checklist of determinants of practice was used to categorize suggested determinants. PARTICIPANTS: Physicians and nurses from primary and specialist care, psychologists, researchers, and patients. MAIN OUTCOME MEASURES: Determinants of adherence to recommendations for depressed elderly patients in primary care. RESULTS: A total of 352 determinants were identified, of which 99 were prioritized. The most frequently identified factors had to do with dissemination of guidelines, general practitioners' time constraints, the low prioritization of elderly patients with depression, and the patients' or relatives' wish for medication. Approximately three-quarters of the determinants were from three of the seven domains in the generic checklist: individual healthcare professional factors, patient factors, and incentives and resources. The survey did not provide useful information due to a low response rate and a lack of responses to open-ended questions. IMPLICATIONS: The list of prioritized determinants can inform the design of interventions to implement recommendations for elderly patients with depression. The importance of the determinants that were identified may vary across communities, practices. and patients. Interventions that address important determinants are necessary to improve practice. PMID- 25431341 TI - Antibiotic activity and microbial community of the temperate sponge, Haliclona sp. AB - AIMS: Sessile marine invertebrates engage in a diverse array of beneficial interactions with bacterial symbionts. One feature of some of these relationships is the presence of bioactive natural products that can defend the holobiont from predation, competition or disease. In this study, we investigated the antimicrobial activity and microbial community of a common temperate sponge from coastal North Carolina. METHODS AND RESULTS: The sponge was identified as a member of the genus Haliclona, a prolific source of bioactive natural products, based on its 18S rRNA gene sequence. The crude chemical extract and methanol partition had broad activity against the assayed Gram-negative and Gram-positive pathogenic bacteria. Further fractionation resulted in two groups of compounds with differing antimicrobial activity, primarily against Gram-positive test organisms. There was, however, notable activity against the Gram-negative marine pathogen, Vibrio parahaemolyticus. Microbial community analysis of the sponge and surrounding sea water via denaturing gradient gel electrophoresis (DGGE) indicates that it harbours a distinct group of bacterial associates. CONCLUSIONS: The common temperate sponge, Haliclona sp., is a source of multiple antimicrobial compounds and has some consistent microbial community members that may play a role in secondary metabolite production. SIGNIFICANCE AND IMPACT OF THE STUDY: These data suggest that common temperate sponges can be a source of bioactive chemical and microbial diversity. Further studies may reveal the importance of the microbial associates to the sponge and natural product biosynthesis. PMID- 25431342 TI - The pollen tube clear zone: clues to the mechanism of polarized growth. AB - Pollen tubes usually exhibit a prominent region at their apex called the "clear zone" because it lacks light refracting amyloplasts. A robust, long clear zone often associates with fast growing pollen tubes, and thus serves as an indicator of pollen tube health. Nevertheless we do not understand how it arises or how it is maintained. Here we review the structure of the clear zone, and attempt to explain the factors that contribute to its formation. While amyloplasts and vacuolar elements are excluded from the clear zone, virtually all other organelles are present including secretory vesicles, mitochondria, Golgi dictyosomes, and the endoplasmic reticulum (ER). Secretory vesicles aggregate into an inverted cone appressed against the apical plasma membrane. ER elements move nearly to the extreme apex, whereas mitochondria and Golgi dictyosomes move less far forward. The cortical actin fringe assumes a central position in the control of clear zone formation and maintenance, given its role in generating cytoplasmic streaming. Other likely factors include the tip-focused calcium gradient, the apical pH gradient, the influx of water, and a host of signaling factors (small G-proteins). We think that the clear zone is an emergent property that depends on the interaction of several factors crucial for polarized growth. PMID- 25431344 TI - Computerized image analysis of the Ki-67 proliferation index in mantle cell lymphoma. AB - AIMS: Manual counting of the fraction of Ki-67-positive cells (the Ki-67 index) in 1000 tumour cells is considered the 'gold standard' to predict prognosis in mantle cell lymphoma (MCL). This time-consuming method is replaced by the faster, but less accurate, semiquantitative estimation in routine practice. The aim of this study was to investigate the use of computerized image analysis software for scoring of Ki-67 in MCL. METHODS AND RESULTS: We developed an automated method for determining the Ki-67 index by computerized image analysis and tested it using a cohort of 62 MCL patients. The data were compared to Ki-67 scores obtained by semiquantitative estimation and image-based manual counting. When using the Ki-67 index as a continuous parameter, both image-based manual counting and computerized image analysis were related inversely to survival (P = 0.020 and P = 0.025, respectively). Ki-67 index obtained by semiquantitative estimation was not associated significantly with survival (P = 0.093). The results were validated in a second patient cohort with similar results. CONCLUSION: Computerized image analysis of the Ki-67 index in MCL is an attractive alternative to semiquantitative estimation and can be introduced easily in a routine diagnostic setting for risk stratification in MCL. PMID- 25431345 TI - Circadian distribution of ventricular tachyarrhythmias and association with mortality in the MADIT-CRT trial. AB - BACKGROUND: It is unknown whether circadian variation of ventricular tachyarrhythmias (VTA) affects clinical outcome in heart failure patients. METHODS: A total of 1,790 patients (males 75%) with heart failure, NYHA class I and II and implantable cardioverter defibrillators (ICD) or cardiac resynchronization (CRT-D) enrolled in the MADIT-CRT study were included. Time of first and all VTAs as detected and treated by the device with appropriate ICD therapy (antitachycardia pacing or shock) was evaluated by hours of the day and weekdays and related to all-cause mortality using Cox regression analyses. RESULTS: During a mean follow-up period of 40 months, a total of 3,300 VTA episodes were registered. Of all VTAs recorded, most of them (n = 2977, 90%) occurred in males. Recurrent as well as first VTA episodes were more common in the morning and evening with bimodal peaks from 7:00 to 10:59 (21%) and 18:00 21:59 (23%). VTAs that occurred during morning hours were associated with higher mortality when compared to VTA episodes occurring at other hours (hazard ratios [HR] = 2.07; confidence interval [CI]: 1.135-3.77; P = 0.018) with a significant gender interaction placing females at significantly higher risk of death (HR 6.78; CI 1.55-29.860; P = 0.011) than males (HR 1.79; CI 0.92-3.46; P = 0.086) (interaction P = 0.041) despite an overall lower probability for morning VTA among females (HR 0.32; CI 0.16-0.68; P = 0.003). CONCLUSIONS: The occurrence of VTAs in heart failure patients shows a circadian variation with highest incidence during morning hours that translates into a significant higher risk of all-cause mortality, with significantly higher risk among females than males. PMID- 25431347 TI - Antitumor efficacy of tangeretin by targeting the oxidative stress mediated on 7,12-dimethylbenz(a) anthracene-induced proliferative breast cancer in Sprague Dawley rats. AB - PURPOSE: The aim of the present study was to assess the chemopreventive and chemotherapeutic efficacy of tangeretin on DMBA-induced oxidative stress in breast cancer-bearing Sprague-Dawley rats. METHODS: In this study, the experimental animals were divided into five groups of six animals each. Group I was control, Group II was DMBA-induced breast cancer-bearing rats, Group III was tangeretin pre-treated (50 mg/kg body weight for 30 days orally) breast cancer bearing animals, Group IV was tangeretin post-treated (50 mg/kg body weight for 30 days orally) and Group V was tangeretin (50 mg/kg body weight) alone treated animals. RESULTS: We have observed the general characteristics of cancer, oxidative stress markers, breast cancer marker, antioxidants and histopathological changes in the experimental animals. We have recorded the body weight, tumor weights, tumor volume and antitumor activity of tangeretin in the experimental animals. Oxidative stress markers, like NO and LPO, and breast cancer marker CEA levels were significantly (p < 0.001, p < 0.05) increased as well as the antioxidants like SOD, CAT, GPx, GST, GSH, ascorbic acid and alpha tocopherol were found to be significantly (p < 0.05) decreased in cancer-bearing Group II animals. Whereas, the enzymic and non-enzymic antioxidant levels were found to be significantly decreased in cancer-bearing animals. However, in tangeretin pre-treated and post- treated animals, the levels of antioxidants and breast cancer marker were found to be significantly (p < 0.05) reduced with a concomitant increase in the activities of the antioxidants (p < 0.05). In tangeretin alone treated Group V animals, no significant changes were observed in the levels of antioxidants and breast cancer marker. These results were adequately supported by the histopathological studies in the mammary tissues of the experimental animals. CONCLUSION: From this study, we conclude that the administration of tangeretin was found to be beneficial against DMBA-induced oxidative stress in breast cancer-bearing animals. Hence, we strongly suggest that tangeretin is effective and efficient candidate for the treatment of experimental breast cancer. PMID- 25431349 TI - Genetics of familial melanoma: 20 years after CDKN2A. AB - Twenty years ago, the first familial melanoma susceptibility gene, CDKN2A, was identified. Two years later, another high-penetrance gene, CDK4, was found to be responsible for melanoma development in some families. Progress in identifying new familial melanoma genes was subsequently slow; however, with the advent of next-generation sequencing, a small number of new high-penetrance genes have recently been uncovered. This approach has identified the lineage-specific oncogene MITF as a susceptibility gene both in melanoma families and in the general population, as well as the discovery of telomere maintenance as a key pathway underlying melanoma predisposition. Given these rapid recent advances, this approach seems likely to continue to pay dividends. Here, we review the currently known familial melanoma genes, providing evidence that most additionally confer risk to other cancers, indicating that they are likely general tumour suppressor genes or oncogenes, which has significant implications for surveillance and screening. PMID- 25431346 TI - Virtual house calls for Parkinson disease (Connect.Parkinson): study protocol for a randomized, controlled trial. AB - BACKGROUND: Interest in improving care for the growing number of individuals with chronic conditions is rising. However, access to care is limited by distance, disability, and distribution of doctors. Small-scale studies in Parkinson disease, a prototypical chronic condition, have suggested that delivering care using video house calls is feasible, offers similar clinical outcomes to in person care, and reduces travel burden. METHODS/DESIGN: We are conducting a randomized comparative effectiveness study (Connect.Parkinson) comparing usual care in the community to usual care augmented by virtual house calls with a Parkinson disease specialist. Recruitment is completed centrally using online advertisements and emails and by contacting physicians, support groups, and allied health professionals. Efforts target areas with a high proportion of individuals not receiving care from neurologists. Approximately 200 individuals with Parkinson disease and their care partners will be enrolled at 20 centers throughout the United States and followed for one year. Participants receive educational materials, then are randomized in a 1:1 ratio to continue their usual care (control arm) or usual care and specialty care delivered virtually (intervention arm). Care partners are surveyed about their time and travel burden and their perceived caregiver burden. Participants are evaluated via electronic survey forms and videoconferencing with a blinded independent rater at baseline and at 12 months. All study activities are completed remotely.The primary outcomes are: (1) feasibility, as measured by the proportion of visits completed, and (2) quality of life, as measured by the 39-item Parkinson's Disease Questionnaire. Secondary outcomes include measures of clinical benefit, quality of care, time and travel burden, and caregiver burden. DISCUSSION: Connect.Parkinson will evaluate the feasibility and effectiveness of using technology to deliver care into the homes of individuals with Parkinson disease. The trial may serve as a model for increasing access and delivering patient centered care at home for individuals with chronic conditions. TRIAL REGISTRATION: This trial was registered on clinicaltrials.gov on January 8, 2014 [NCT02038959]. PMID- 25431348 TI - The Use of Biologic Therapies in Uveitis. AB - Therapy for autoimmune ophthalmic disease is currently evolving. The improved understanding of the abnormal immune response in the various forms of uveitis has resulted in targeted therapy. The aberrations of the immune system have been characterized by atypical cell populations, cytokine expression, and cell-cell interactions. Different patterns of cytokine expression have now been delineated in the abnormal uveal tract with exaggerated and/or abnormal expression of TNF, IL-1, IL-2, IL-6, and IL-17. The development of therapies for other conditions in which these cytokines play an important role has resulted in the availability of biological agents that have been adopted for use in the therapy for uveitis. Adalimumab and infliximab have been the best studied anti-TNF agents and indeed have now been recommended by an expert panel as first-line treatment of ocular manifestations of Behcet's disease and second-line treatment for other forms of uveitis (Levy-Clarke et al. (Ophthalmology, 2013). Other anti-TNF agents have been studied as well. Daclizumab, a monoclonal antibody directed against the IL-2 receptor, has also demonstrated utility in treating uveitis as have some of the anti-IL1 agents. Gevokizumab has been granted orphan drug designation for the treatment of resistant forms of uveitis. Therapies affecting IL-6, including tocilizumab are being studied, and available medications that block antigen presenting cell and T cell interaction such as abatacept have been reported to be effective in uveitis. Interferons as well as rituximab have also been evaluated in small studies. Although these biologic therapies have provided a larger armamentarium to treat uveitis, challenges remain. Uveitis is not a single illness; rather, it is a manifestation of many potential systemic diseases that may have very specific individual therapeutic targets. Identifying and characterizing these underlying diseases is not always achieved, and more importantly, the most effective therapies for each entity have not been defined. PMID- 25431351 TI - Metal-catalyzed formation of 1,3-cyclohexadienes: a catalyst-dependent reaction. AB - A metal-dependent and complementary catalytic method to synthesize the cyclohexadienes has been developed. When gold or indium salts were used as catalysts, 1,3-cyclohexadiene (1,3-CHD) could be obtained; when Cu(OTf)2 was used as the catalyst, however, another isomer 2,4-cyclohexadiene (2,4-CHD) was furnished instead. PMID- 25431350 TI - Meta-eQTL: a tool set for flexible eQTL meta-analysis. AB - BACKGROUND: Increasing number of eQTL (Expression Quantitative Trait Loci) datasets facilitate genetics and systems biology research. Meta-analysis tools are in need to jointly analyze datasets of same or similar issue types to improve statistical power especially in trans-eQTL mapping. Meta-analysis framework is also necessary for ChrX eQTL discovery. RESULTS: We developed a novel tool, meta eqtl, for fast eQTL meta-analysis of arbitrary sample size and arbitrary number of datasets. Further, this tool accommodates versatile modeling, eg. non parametric model and mixed effect models. In addition, meta-eqtl readily handles calculation of chrX eQTLs. CONCLUSIONS: We demonstrated and validated meta-eqtl as fast and comprehensive tool to meta-analyze multiple datasets and ChrX eQTL discovery. Meta-eqtl is a set of command line utilities written in R, with some computationally intensive parts written in C. The software runs on Linux platforms and is designed to intelligently adapt to high performance computing (HPC) cluster. We applied the novel tool to liver and adipose tissue data, and revealed eSNPs underlying diabetes GWAS loci. PMID- 25431352 TI - Stress and inflammatory biomarkers and symptoms are associated with bioimpedance measures. AB - BACKGROUND: This large cross-sectional, multi-centre study evaluated the association of body composition measurements by a novel dual frequency bioimpedance device (BIA-ACC) with chronic stress/inflammation biomarkers and the presence of medically unexplained symptoms (MUS). MATERIALS AND METHODS: Participants were adult Caucasians of both sexes and included 10,416 lean subjects with no MUS (Group A), 58,710 lean subjects with MUS (Group B) and 30,445 overweight/obese subjects with no MUS and excessive fat mass (FM) (Group C). RESULTS: Total body extracellular water (ECW) was higher, while intracellular water (ICW) was lower in Group B than both other groups (P < 0.01). Group A had significantly lower FM and higher skeletal mass (SK) and phase angle (PA) than Group B and lower circulating high sensitivity (hs) CRP levels than both other groups. hsCRP was higher in Group C than Group A though (P < 0.01). Salivary cortisol in Group B was lower in the morning and higher in the evening than both other groups (P < 0.001), indicating circadian rhythm obliteration or reversal in this group. ECW correlated positively with serum hsCRP and 8 p.m. salivary cortisol, but negatively with 8 a.m. salivary cortisol, while PA correlated positively with 8 a.m. and negatively with 8 p.m. salivary cortisol and serum hsCRP. Both 8 a.m. and 8 p.m. salivary cortisol and serum hsCRP were associated with the presence of MUS and BIA-ACC measurements, including ECW, ICW, FM, SK and PA. CONCLUSIONS: MUS is an index of chronic stress and inflammation and BIA-ACC may provide a useful, bloodless and rapid tool in the clinical setting, distinguishing patients with chronic stress/inflammation from healthy subjects and monitoring their response to treatment. PMID- 25431353 TI - Physical function in older men with hyperkyphosis. AB - BACKGROUND: Age-related hyperkyphosis has been associated with poor physical function and is a well-established predictor of adverse health outcomes in older women, but its impact on health in older men is less well understood. METHODS: We conducted a cross-sectional study to evaluate the association of hyperkyphosis and physical function in 2,363 men, aged 71-98 (M = 79) from the Osteoporotic Fractures in Men Study. Kyphosis was measured using the Rancho Bernardo Study block method. Measurements of grip strength and lower extremity function, including gait speed over 6 m, narrow walk (measure of dynamic balance), repeated chair stands ability and time, and lower extremity power (Nottingham Power Rig) were included separately as primary outcomes. We investigated associations of kyphosis and each outcome in age-adjusted and multivariable linear or logistic regression models, controlling for age, clinic, education, race, bone mineral density, height, weight, diabetes, and physical activity. RESULTS: In multivariate linear regression, we observed a dose-related response of worse scores on each lower extremity physical function test as number of blocks increased, p for trend <=.001. Using a cutoff of >=4 blocks, 20% (N = 469) of men were characterized with hyperkyphosis. In multivariate logistic regression, men with hyperkyphosis had increased odds (range 1.5-1.8) of being in the worst quartile of performing lower extremity physical function tasks (p < .001 for each outcome). Kyphosis was not associated with grip strength in any multivariate analysis. CONCLUSIONS: Hyperkyphosis is associated with impaired lower extremity physical function in older men. Further studies are needed to determine the direction of causality. PMID- 25431354 TI - "Skeletal muscle function deficit" in a nationally representative British birth cohort in early old age. AB - BACKGROUND: Recommendations for identifying age-related muscle dysfunction have recently been published. We aimed to compare definitions for clinically relevant weakness and low lean mass proposed by the Foundation for the National Institutes of Health (FNIH) Sarcopenia project with the definition of sarcopenia proposed by the European Working Group on Sarcopenia in Older People (EWGSOP). METHODS: A total of 1566 men and women from a British birth cohort had measures of appendicular lean mass, grip strength and timed up, and go speed at ages 60-64. Prevalence of low lean mass, weakness and slowness, identified using the FNIH and EWGSOP recommendations were estimated and compared: using kappa statistics and; by testing cross-sectional associations of both definitions of low lean mass and weakness with slowness and self-reported difficulties walking. RESULTS: The combined prevalence of low lean mass and weakness ranged from 1.1% in men using FNIH criteria to 6.4% in women using EWGSOP criteria. There was limited overlap between the groups identified using the different criteria, driven by limited agreement between the two definitions of low lean mass. Using FNIH criteria, both low lean mass and weakness were associated with higher odds of slowness and difficulties walking; whereas low lean mass classified using EWGSOP criteria was not associated with these markers of mobility impairment. CONCLUSIONS: At relatively young ages, signs of skeletal muscle function deficit with potential clinical relevance are already identifiable in the general population. This suggests that implementation of strategies to prevent mobility limitations, related to age-related muscle dysfunction, may need to start at least as early as midlife. PMID- 25431355 TI - Imputation of missing genotypes from low- to high-density SNP panel in different population designs. AB - Imputation of missing genotypes, in particular from low density to high density, is an important issue in genomic selection and genome-wide association studies. Given the marker densities, the most important factors affecting imputation accuracy are the size of the reference population and the relationship between individuals in the reference (genotyped with high-density panel) and study (genotyped with low-density panel) populations. In this study, we investigated the imputation accuracies when the reference population (genotyped with Illumina BovineSNP50 SNP panel) contained sires, halfsibs, or both sires and halfsibs of the individuals in the study population (genotyped with Illumina BovineLD SNP panel) using three imputation programs (fimpute v2.2, findhap v2, and beagle v3.3.2). Two criteria, correlation between true and imputed genotypes and missing rate after imputation, were used to evaluate the performance of the three programs in different scenarios. Our results showed that fimpute performed the best in all cases, with correlations from 0.921 to 0.978 when imputing from sires to their daughters or between halfsibs. In general, the accuracies of imputing between halfsibs or from sires to their daughters were higher than were those imputing between non-halfsibs or from sires to non-daughters. Including both sires and halfsibs in the reference population did not improve the imputation performance in comparison with when only including halfsibs in the reference population for all the three programs. PMID- 25431356 TI - Improved cutaneous wound healing after intraperitoneal injection of alpha melanocyte-stimulating hormone. AB - Skin wound healing is a complex process involving many types of cells and molecules and often results in scar tissue formation in adult mammals. However, scarless healing occurs in foetal skin and minimal scars may occur after cutaneous healing in the adult with reduced inflammation. Alpha-melanocyte stimulating hormone (alpha-MSH) is widely distributed within the central nervous system and in other body regions, such as the skin, and has strong anti inflammatory activity. The aim in the present experiments was to learn whether intraperitoneal (i.p) injection of alpha-MSH just before skin wounds antagonize inflammation and improves skin wound healing in adult mice. C57BL/6 young adult mice received an i.p. injection of 1 mg/kg of alpha-MSH and, 30 min later, two circular through-and-through holes (6.5 mm diameter) were made in their dorsal skin under anaesthesia. Control mice were wounded after vehicle injection. The wound healing process was analysed macroscopically and microscopically at 3, 7, 40 and 60 days. Skin samples were fixed in formalin, embedded in paraffin, sectioned at 5 MUm, stained with H&E or toluidine blue for cell analysis or Gomori's trichrome for extracellular matrix (ECM) analysis. Other samples were fixed in DMSO+methanol, embedded in paraplast and incubated with anti-CD45, antismooth muscle actin, anticollagen-I and anticollagen-III for immunofluorescence analysis. Alpha-MSH significantly reduced the number of leucocytes, mast cells and fibroblasts at 3 and 7 days after injury. On days 40 and 60, alpha-MSH reduced scar area and improved the organization of the collagen fibres indicating that it may direct the healing into a more-regenerative/less scarring pathway. PMID- 25431357 TI - Long-term effect of HCV eradication in patients with mixed cryoglobulinemia: a prospective, controlled, open-label, cohort study. AB - Limited data are available about the efficacy of antiviral treatment in hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC), especially concerning the long-term effects of HCV eradication. The aim of this study was to evaluate the influence of MC on the virological response and the long-term effects of viral eradication on MC. We prospectively enrolled 424 HCV(+) patients belonging to the following groups: MC syndrome (MCS)-HCV (121 patients with symptomatic MC), MC HCV (132 patients with asymptomatic MC), and HCV (158 patients without MC). Pegylated interferon plus ribavirin treatment was administered according to standard protocols. Posttreatment follow-up ranged from 35 to 124 months (mean 92.5 months). A significant difference was observed in the rate of sustained virological response between the HCV group and both the MC-HCV (P = 0.009) and MC HCV+MCS-HCV (P = 0.014) groups. Multivariate logistic regression analysis identified cryoglobulinemia as an independent prognostic factor of nonresponse. The clinical-immunological response in MCS-HCV correlated with the virological one. All patients with sustained virological response also experienced a sustained clinical response, either complete or partial. In the majority of sustained virological response patients all MCS symptoms persistently disappeared (36 patients, 57%); in only two (3%) did definite MCS persist. All virological nonresponders were also clinical nonresponders, in spite of a transient improvement in some cases. No evolution to lymphoma was observed. For the first time we have evaluated both the effects of interferon-based therapy on HCV patients with and without MC and with and without symptoms, as well as the long term effects of viral eradication on MC. CONCLUSION: MC is a negative prognostic factor of virological response. Clearance of HCV led to persistent resolution or improvement of MCS, strongly suggesting the need for a next generation of highly effective antiviral drugs. PMID- 25431358 TI - Combination effects of SMAC mimetic birinapant with TNFalpha, TRAIL, and docetaxel in preclinical models of HNSCC. AB - OBJECTIVES/HYPOTHESIS: Head and neck squamous cell carcinoma (HNSCC) cells are resistant to cell death induced by tumor necrosis factor ligands such as tumor necrosis factor alpha (TNFalpha) or TNF-related apoptosis-inducing ligand (TRAIL) and cytotoxic chemotherapies. Recently, genetic alterations in cell death pathways, including inhibitor of apoptosis proteins, have been demonstrated in HNSCC. We investigated the effects of birinapant, a novel, second mitochondria derived activator of caspases (SMAC)-mimetic that targets inhibitor of apoptosis proteins, alone and in combination with TNFalpha, TRAIL, or chemotherapy docetaxel. STUDY DESIGN: Experimental study using human HNSCC cell lines in vitro and xenograft mouse model in vivo. METHODS: A panel of HNSCC cell lines with varying genetic alterations in cell death pathway components were treated with birinapant +/- TNFalpha, TRAIL, and docetaxel and were assessed for effects on cell density, cell cycle, and death. Synergism was determined at varying concentrations of treatments using the Chou-Talalay method. Combination studies using birinapant +/- docetaxel were performed in a xenograft mouse model. RESULTS: Birinapant, alone or in combination with TNFalpha or TRAIL, decreased cell density in cell lines, with IC50 s ranging from 0.5 nM to > 1 uM. Birinapant alone or with TNF significantly increased subG0 cell death in different lines. Docetaxel showed synergism with birinapant +/- TNFalpha in vitro. Birinapant monotherapy-inhibited growth in a tumor xenograft model resistant to docetaxel, and combination treatment further delayed growth. CONCLUSIONS: Birinapant alone or in combination with TNFalpha or TRAIL and docetaxel decreased cell density, increased cell death, and displayed antitumor activity in a preclinical HNSCC xenograft exhibiting aberrations in cell death pathway components and docetaxel resistance. PMID- 25431359 TI - Should essays and other "open-ended"-type questions retain a place in written summative assessment in clinical medicine? AB - BACKGROUND: Written assessments fall into two classes: constructed-response or open-ended questions, such as the essay and a number of variants of the short answer question, and selected-response or closed-ended questions; typically in the form of multiple-choice. It is widely believed that constructed response written questions test higher order cognitive processes in a manner that multiple choice questions cannot, and consequently have higher validity. DISCUSSION: An extensive review of the literature suggests that in summative assessment neither premise is evidence-based. Well-structured open-ended and multiple-choice questions appear equivalent in their ability to assess higher cognitive functions, and performance in multiple-choice assessments may correlate more highly than the open-ended format with competence demonstrated in clinical practice following graduation. Studies of construct validity suggest that both formats measure essentially the same dimension, at least in mathematics, the physical sciences, biology and medicine. The persistence of the open-ended format in summative assessment may be due to the intuitive appeal of the belief that synthesising an answer to an open-ended question must be both more cognitively taxing and similar to actual experience than is selecting a correct response. I suggest that cognitive-constructivist learning theory would predict that a well constructed context-rich multiple-choice item represents a complex problem solving exercise which activates a sequence of cognitive processes which closely parallel those required in clinical practice, hence explaining the high validity of the multiple-choice format. SUMMARY: The evidence does not support the proposition that the open-ended assessment format is superior to the multiple choice format, at least in exit-level summative assessment, in terms of either its ability to test higher-order cognitive functioning or its validity. This is explicable using a theory of mental models, which might predict that the multiple choice format will have higher validity, a statement for which some empiric support exists. Given the superior reliability and cost-effectiveness of the multiple-choice format consideration should be given to phasing out open-ended format questions in summative assessment. Whether the same applies to non-exit level assessment and formative assessment is a question which remains to be answered; particularly in terms of the educational effect of testing, an area which deserves intensive study. PMID- 25431360 TI - Supporting the needs of public health decision-makers and review authors in the UK. PMID- 25431361 TI - Metal-atom impact on the self-assembly of cup-and-ball metalloporphyrin-fullerene conjugates. AB - A fullerene ammonium derivative has been combined with different metalloporphyrin crown ether receptors to generate very stable supramolecules. The combination of fullerene-porphyrin and ammonium-crown ether interactions leads to a strong chelate effect as evidenced by a high effective molarity (3.16 M). The different parameters influencing the stability of the supramolecular ensembles, in particular the nature of the metal in the porphyrin moiety, have been rationalized with the help of theoretical calculations thus providing new insights into fullerene-porphyrin interactions. PMID- 25431362 TI - Morphology of the lingual surface of South American fur seal (Arctocephalus australis) and sea lion (Otaria flavescens). AB - In this study, we aimed to describe the morphological characteristics of the lingual papillae in two species of Otariidae family by stereomicroscopy and scanning electron microscopy. We used tongues of two South American Otariidae species. The tongues were elongated and terminated in bifid apex and there was no median sulcus on the dorsal lingual surface. The most numerous type of lingual papilla was filiform in the South American fur seal (SASL) and entire dorsal lingual surface was covered by these filiform papillae but the dorsal surface of the tongue of the South American sea lion was covered by numerous polygonal projections, which were different in size. Fungiform papillae were detected in only SASL and they randomly distributed on the lingual apex and body, and some fungiform papillae were collected into twosome or threesome groups on the posterior part of the lingual body. Circumvallate papilla was found in the center of the lingual radix of South American sea lion. Thread-like conical papillae were common for both species and they located on the lingual radix. We determined that lingual surface morphology was completely different in each species, although they were members of the same family, Otariidae. PMID- 25431363 TI - A rapid method for breath analysis in cystic fibrosis patients. AB - For easy handling and speed of lung diseases diagnostics, approaches based on volatile organic compounds (VOCs), including those emitted by pathogenic microorganisms, are considered but currently require considerable sampling efforts. We tested whether easy-to-handle and fast detection of lung infections is possible using solid-phase microextraction (SPME) of 100 ml of exhaled breath. An analytical procedure for the detection of VOCs from the headspace of epithelial lung cells infected with four human pathogens was developed. The feasibility of this method was tested in a cystic fibrosis (CF) outpatient clinic in vivo. Exhaled breath was extracted by SPME and analyzed by gas chromatography mass spectrometry (GC-MS). The compositions of VOCs released in the infection model were characteristic for all individual pathogens tested. Exhaled breath of CF patients allowed clear distinction of CF patients and controls by their VOC compositions using multivariate analyses. Interestingly, the major specific VOCs detected in the exhaled breath of infected CF patients in vivo differed from those monitored during bacterial in vitro growth. SPME extraction of VOCs from 100 ml of human breath allowed the distinction between CF patients and healthy probands. Our results highlight the importance of assessing the entire pattern of VOCs instead of selected biomarkers for diagnostic purposes, as well as the need to use clinical samples to identify reliable biomarkers. This study provides the proof-of-concept for the approach using the composition of exhaled VOCs in human breath for the rapid identification of infectious agents in patients with lower respiratory tract infections. PMID- 25431365 TI - New polyoxometalates containing hybrid polymers and their potential for nano patterning. AB - Two new polyoxometalate (POM)-based hybrid monomers (Bu4 N)5 (H)[P2 V3 W15 O59 {(OCH2 )3 CNHCO(CH3 )C?CH2 }] (2) and (S(CH3 )2 C6 H4 OCOC(CH3 )=CH2 )6 [PV 2Mo10 O40 ] (5) were developed by grafting polymerizable organic units covalently or electrostatically onto Wells-Dawson and Keggin-type clusters and were characterized by analytical and spectroscopic techniques including ESI-MS and/or single-crystal X-ray diffraction analyses. Radical initiated polymerization of 2 and 5 with organic monomers (methacryloyloxy)phenyldimethylsulfonium triflate (MAPDST) and/or methylmethacrylate (MMA) yielded a new series of POM/polymer hybrids that were characterized by (1) H, (31) P NMR and IR spectroscopic techniques, gel-permeation chromatography as well as thermal analyses. Preliminary tests were conducted on these POM/polymer hybrids to evaluate their properties as photoresists using electron beam (E-beam)/extreme ultraviolet (EUV) lithographic techniques. It was observed that the POM/polymer hybrid of 2 with MAPDST exhibited improved sensitivity under EUV lithographic conditions in comparison to the MAPDST homopolymer resist possibly due to the efficient photon harvesting by the POM clusters from the EUV source. PMID- 25431364 TI - 2,4,6-Trichlorophenol cytotoxicity involves oxidative stress, endoplasmic reticulum stress, and apoptosis. AB - This study aims to evaluate the cytotoxicity and potential mechanisms of 2,4,6 trichlorophenol (2,4,6-TCP) in mouse embryonic fibroblasts. Our results show that 2,4,6-TCP causes morphological changes and reduces cell viability. The overproduction of reactive oxygen species, the upregulation of nuclear factor-E2 related factor 2 (Nrf2) and heme oxygenase 1 (HMOX1) messenger RNA (mRNA) expressions, and the nuclear translocation of Nrf2 protein demonstrate that 2,4,6 TCP induces oxidative stress, and the Nrf2/HMOX1 pathway might be involved in 2,4,6-TCP-induced antioxidative response. Simultaneously, our data also demonstrate that 2,4,6-TCP upregulates the expressions of binding immunoglobulin protein, inositol-requiring enzyme/endonuclease 1alpha, and C/EBP homologous protein; stimulates alpha subunit of eukaryotic translation initiation factor 2 phosphorylation; and induces the splicing of Xbp1 mRNA, suggesting that endoplasmic reticulum (ER) stress is triggered. Moreover, 2,4,6-TCP alters the mitochondrial membrane potential and increases the apoptosis rate, the caspase 3 activity, and the Bax/Bcl-2 ratio, demonstrating that the mitochondrial pathway is involved in the 2,4,6-TCP-induced apoptosis. Thus, these results show that 2,4,6-TCP induces oxidative stress, ER stress, and apoptosis, which together contribute to its cytotoxicity in vitro. PMID- 25431366 TI - Clinical characteristics of postherpetic pruritus: assessment using a questionnaire, von Frey filaments and Neurometer. PMID- 25431367 TI - Preparing an ICU room to welcome a critically ill patient with Ebola virus disease. PMID- 25431368 TI - Am I dead? A patient's experience with delirium. PMID- 25431370 TI - Meta-analysis study on the role of bone-derived neurotrophic factor Val66Met polymorphism in Parkinson's disease. AB - To evaluate a possible involvement of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in susceptibility to Parkinson's disease (PD), we performed a meta-analysis of all studies on the topic published from 2002 to 2014. This article reviews and compares the data from two previous meta-analyses, including two studies not previously considered. We selected studies referring to a genetic comparison between PD patients and healthy controls, so 15 studies involving 3754 cases and 4026 controls were included in our meta-analysis. We found no association between the Val66Met polymorphism and the risk of developing PD in our overall analysis. The ethnicity-specific meta-analysis produced no significant association either. Our data do not support a major role for the BDNF Val66Met polymorphism in the pathogenesis of PD. PMID- 25431369 TI - Prognostic significance of pre-operative C-reactive protein and the neutrophil lymphocyte ratio in resectable pancreatic cancer: a systematic review. AB - BACKGROUND: Better pre-operative risk stratification may improve patient selection for pancreatic resection in pancreatic cancer. C-reactive protein (CRP) and the neutrophil-lymphocyte ratio (NLR) have demonstrated prognostic value in some cancers. The role of CRP and NLR in predicting outcome in pancreatic cancer after curative resection is not well established. METHODS: An electronic search of MEDLINE, EMBASE and CINAHL was performed to identify studies assessing survival in patients after pancreatic cancer resection with high or low pre operative CRP or NLR. Systematic review was undertaken using the PRISMA protocol. RESULTS: In total, 327 studies were identified with 10 reporting on survival outcomes after a pancreatic resection in patients with high or low CRP, NLR or both. All but one paper showed a trend of lower inflammatory markers in patients with longer survival. Three studies from six showed low CRP to be independently associated with increased survival and two studies of eight showed the same for NLR. All studies were retrospective cohort studies of low to moderate quality. DISCUSSION: Inflammatory markers might prove useful guides to the management of resectable pancreatic cancer but, given the poor quality of evidence, further longitudinal studies are required before incorporating pre-operative inflammatory markers into clinical decision making. PMID- 25431371 TI - Endoscopic biopsies from gastrointestinal carcinomas and their suitability for molecular analysis: a review of the literature and recommendations for clinical practice and research. AB - Endoscopic biopsies (EBs) are the gold standard for diagnosing gastrointestinal carcinoma yet no guidelines address EB use for prognostic and predictive molecular testing. This review summarizes the reported quantity and quality of EBs, their relationship with molecular test failure rates and the resultant concordance between EB and resection specimen. Studies reporting molecular testing on gastrointestinal carcinoma EBs published between 2002 and 2014 were identified. Details regarding EB quantity, quality, tumour content, molecular test failure rates as well as causes and concordance with resection specimens were reviewed. Seventy-five studies were identified. Eighteen (24%) reported the mean EB number per patient (median: 2.1, range: 1-6.6 EBs). Sixty-one (81%) reported the frequency of test failure (median: 0%, range: 0-100%). Twenty-two (29%) investigated EB and resection specimen concordance (range: 0-100%). EB quantity and quality affected neither concordance nor failure rate. In summary, few studies currently report EB quantity, EB quality or EB and resection specimen concordance. Reliable molecular testing in EBs appears achievable, and can be representative of resection specimens. Concordance depends upon the testing methodology and biomarker heterogeneity within the tumour. To improve patient care, EB sampling, processing and reporting requires standardization and needs optimization for each biomarker individually. PMID- 25431373 TI - Looking beyond the horizon: what might the future hold? PMID- 25431372 TI - Predictors of the Nicotine Dependence Behavior Time to the First Cigarette in a Multiracial Cohort. AB - BACKGROUND: The time to first cigarette of the day (TTFC) is a strong indicator of nicotine dependence behaviors such as nicotine uptake and quit success in young and older smokers. There are substantial differences in levels of nicotine dependence by race and ethnic group. METHODS: Data from Wave III of the multiracial National Longitudinal Study of Adolescent Health were analyzed for young smokers between the ages of 21 and 28 (N = 1,425). Time to first cigarette data was compared between Hispanic, White, Black, Native American, and Asian smokers. RESULTS: Black smokers were significantly more likely to smoke within 5min of waking than White, Hispanic, and Asian smokers. Lower personal income predicted smoking within 5min of waking for both White and Black smokers. For White smokers, increased number of cigarettes per day and increased years of smoking also predicted smoking within 5min of waking. The number of days smoked or number of cigarettes per day did not predict smoking within 5min of waking among smokers. CONCLUSIONS: The higher prevalence of early TTFC among Blacks indicates increased nicotine and carcinogen exposure, and may help explain the increased lung cancer rates and failed cessation attempts among Black smokers. TTFC may be an important screening item, independent of cigarettes per day, for clinicians and interventions to identify those at highest risk for cessation failure and disease risk. PMID- 25431374 TI - Views sought on voluntary plan to control Johne's disease. PMID- 25431375 TI - Consortium aims to introduce precision farming into pork production. PMID- 25431376 TI - Avian influenza: biosecurity guidance on protecting poultry from wild birds. PMID- 25431377 TI - Antimicrobial resistance: One Health, one problem. AB - The roles that the medical and veterinary professions can play in tackling antimicrobial resistance were discussed at the BVA Congress at the London Vet Show last week. It was clear from the debate that, while action is already being taken, much more needs to be done by both professions in the UK and overseas. Kathryn Clark reports. PMID- 25431378 TI - Home and abroad: vets' role in dealing with rabies. AB - Manuela Herrera reports on a session at the BVA Congress which discussed the contributions that vets can make to tackling rabies, and how the profession can be at the forefront of a One Health approach to saving the lives of animals and people. PMID- 25431380 TI - Highlighting the importance of hygiene in keeping exotic pets. PMID- 25431381 TI - Improving animal health for poverty alleviation and sustainable livelihoods. AB - Animals are vital to ensuring food security for individuals, families and communities in countries around the world. In this, the latest article in Veterinary Record's series promoting One Health, Andy Stringer, director of veterinary programmes at the Society for the Protection of Animals Abroad, discusses how improving animal health, particularly of poultry and working equids, has the potential to reduce poverty and promote food security and sustainable livelihoods in low-income countries. PMID- 25431382 TI - Equine disease surveillance: quarterly summary. AB - Equine influenza in England and Scotland, Significant numbers of outbreaks of equine herpesvirus 1 neurological disease in the USA, Summary of surveillance testing, April to June 2014. These are among matters discussed in the most recent quarterly equine disease surveillance report, prepared by Defra, the Animal Health Trust and the British Equine Veterinary Association. PMID- 25431383 TI - Focus on: Hendra virus in Australia. AB - Cases of Hendra virus infection in horses in Australia have been seen regularly since the virus was first isolated in 1994. Kristopher Hughes, associate professor of equine medicine at Charles Sturt University in Australia, gives an overview of how knowledge of the virus has developed in the past 20 years. PMID- 25431384 TI - Better research reporting for better patient care. PMID- 25431385 TI - Bovine TB and badger control. PMID- 25431386 TI - Learning theoretical knowledge doesn't have to be boring. AB - Marta Kankofer was one of a small team that developed teaching materials for veterinary students to allow them to use their cognitive abilities to solve virtual problems. The VetVIP project promotes self-study based on solving problems and aims to increase satisfaction and motivation among second-year students, who find themselves in a theory-heavy stage of the veterinary course. PMID- 25431387 TI - Diary of a poultry intern. PMID- 25431388 TI - Renal denervation revised. PMID- 25431389 TI - Renal denervation for the treatment of hypertension: the Dutch consensus. AB - Since 2010, renal denervation (RDN) is being performed in the Netherlands. To make sure RDN is implemented with care and caution in the Netherlands, a multidisciplinary Working Group has been set up by the Dutch Society of Cardiology (NVVC). The main aim of this Working Group was to establish a consensus document that can be used as a guide for implementation of RDN in the Netherlands. This consensus document was prepared in consultation with the Dutch Association of Internal Medicine (NIV) and the Dutch Society of Radiology (NVVR). PMID- 25431390 TI - Electrocardiographic abnormalities in patients admitted for hip fracture. AB - BACKGROUND: Several risk factors for falls and hip fractures have been recognised, but controversy still exists regarding the importance of rhythm and conduction abnormalities as potentially modifiable risk factors for recurrent falls. The aim of this study was to determine the prevalence of clinically relevant ECG abnormalities in patients with a hip fracture versus controls. METHODS: The study was designed as a case-control study within consecutive hip surgery patients in an academic hospital. CASES: patients with traumatic hip fractures. CONTROLS: patients undergoing planned hip surgery (non-traumatic). CASES and controls were 1:1 matched for age and gender. INCLUSION CRITERIA: age ≥ 50 years. EXCLUSION CRITERIA: high-energy trauma, pathological and/or previous hip fracture. ECGs were scored using predefined categories. Multivariate logistic regression was performed to calculate odds ratios (OR) and to correct for confounders. RESULTS: We included 888 patients (444 cases). Mean age was 70.9 years (SD 9.3), 70% were female. After correction for potential confounders we found the following associations between clinically relevant ECG abnormalities and hip fractures: atrial fibrillation OR 2.7 (95% CI 1.2-6.1), abnormal QTc prolongation OR 3.9 (2.2-6.8), sinus tachycardia OR 5.0 (2.1-11.8) and sinus bradycardia OR 0.3 (0.1-0.5). Univariately, several markers for decreased cardiac function were also associated with hip fractures. CONCLUSIONS: Hip fracture patients are at higher risk for ECG abnormalities than matched patients undergoing hip surgery for other indications. To potentially reduce the risk of future (injurious) falls, increased awareness of these ECG abnormalities is warranted to assess the need for further cardiovascular fall risk assessment. PMID- 25431391 TI - Differences in interpretation of haemoglobin A1c values among diabetes care professionals. AB - BACKGROUND: To assess the expected precision of HbA1c measurements and the magnitude of HbA1c changes eliciting the advice to change treatment among diabetes care professionals. METHODS: A seven-item questionnaire was sent to participants through a website. The survey focused on physicians and nurses involved in diabetes care. RESULTS: In total, 104 physicians, 177 diabetes specialist nurses, and 248 primary care nurses responded to the survey. A large number of the nurses (44%) and only a small number of the physicians (4%) were not aware of the inherent uncertainty of HbA1c results. Nurses considered adjusting therapy based on very small changes in HbA1c whereas physicians in general adhere to 0.5% (5.5 mmol/mol) as a clinically meaningful cut-off point. After therapy adjustment, a very small (0.1%) or no increase in HbA1c was considered to be significant enough to conclude that glucose regulation has worsened by 49% of the nurses and only 13% of the physicians. CONCLUSION: Significant differences exist in the interpretation of changes in HbA1c results between physicians and nurses. Nurses consider therapy changes based on very small changes in HbA1c, whereas physicians preferably agree to the clinically relevant change of 0.5% (5.5 mmol/mol). Changing therapy based on relatively small changes in HbA1c might lead to undue adjustments in the treatment of patients with diabetes. There is a clear need for more training for all diabetes care professionals about both the clinical significance and accuracy of HbA1c measurements. PMID- 25431392 TI - Anticoagulant treatment of cancer patients with pulmonary embolism in the real world. Actual use of low-molecular-weight heparin in cancer. AB - BACKGROUND: Since 2004, guidelines recommend long-term treatment with low molecular-weight heparin (LMWH) in patients with cancer and pulmonary embolism (PE). We assessed the proportion of cancer patients with PE actually treated with LMWH and the duration of anticoagulant treatment in the Netherlands. METHODS: A retrospective cohort study in patients that were hospitalised for PE between 1998 2008. Patients with PE were selected from national hospital discharge records, after linkage to a national pharmacy database. Cancer patients with PE were matched for age, sex and year of diagnosis of PE to subjects with PE without cancer. RESULTS: 600 cancer patients with PE were matched to 1200 patients with PE without cancer. Long-term LMWH was prescribed in 82 (13.7%) of the cancer patients and in eight (0.7%) of the cancer-free patients (p < 0.001); all the other patients received vitamin K antagonists (VKA). From 1998-2008, there was an increase in the use of LMWH in cancer patients: in 2007-2008, LMWH was prescribed in 42 (32%) cases, compared with one (1.7%) of the cancer patients with PE in 1998-1999. Median duration of treatment was 5.8 months (interquartile range 3.1 8.8) in cancer patients, compared with 7.0 months (4.9-11) in patients without cancer (p < 0.001), a difference that persisted after adjustment for mortality. CONCLUSIONS: Although the use of LMWH in patients with cancer and PE is increasing, in 2008, patients in the Netherlands are still mostly treated with VKA, and not with LMWH as recommended by guidelines. Cancer patients with PE on average receive shorter treatment than matched patients without cancer. PMID- 25431393 TI - Ventilator setting in ICUs: comparing a Dutch with a European cohort. AB - BACKGROUND: From data collected during the third International Study on Mechanical Ventilation (ISMV), we compared data from a Dutch cohort with a European cohort. We hypothesised that tidal volumes were smaller and applied positive end-expiratory pressure (PEEP) was higher in the Netherlands, compared with the European cohort. We also compared use of non-invasive ventilation (NIV) and outcomes in both cohorts. METHODS: A post-hoc analysis of a prospective observational study of patients receiving mechanical ventilation. RESULTS: Tidal volumes were smaller (7.6 vs. 8.1 ml/kg predicted bodyweight) in the Dutch cohort and applied PEEP was higher (8 vs. 6 cm H2O). Fewer patients admitted in the Netherlands received NIV as first mode of mechanical ventilation (7.1 vs. 16.7%). Fewer patients in the Dutch cohort developed an ICU-acquired pneumonia (4.5 vs. 12.3%, p < 0.01) and sepsis (5.7 vs. 10.9%, p = 0.03), but more patients were diagnosed as having delirium (15.8 vs. 4.6%, p < 0.01). ICU and in-hospital mortality rates were 19% and 25%, respectively, in Dutch ICUs vs. 26% and 33% in Europe (p = 0.06 and 0.03). CONCLUSION: Tidal volumes were smaller and applied PEEP was higher in the Dutch cohort compared with international data, but both Dutch and international patients received larger tidal volumes than recommended for prevention or treatment of acute respiratory distress syndrome. NIV as first mode of mechanical ventilation is less commonly used in the Netherlands. The incidence of ICU-acquired pneumonia is lower and of delirium higher in the Netherlands compared with international data. PMID- 25431394 TI - Induction therapy with short-term high-dose intravenous cyclophosphamide followed by mycophenolate mofetil in proliferative lupus nephritis. AB - BACKGROUND: For decades, high-dose intravenous cyclophosphamide (ivCY) given for 24-30 months was regarded as the standard therapy for proliferative lupus nephritis, despite serious side effects. Our aim was to evaluate the effect of induction therapy with short-term high-dose ivCY followed by mycophenolate mofetil (MMF) on disease parameters, mortality and health-related quality of life (HRQoL) in patients with proliferative lupus nephritis. METHODS: Between January 2003 and November 2006, 71 patients with biopsy-proven proliferative lupus nephritis were included in the second Dutch Lupus Nephritis Study. All patients were treated with ivCY (750 mg/m2, six monthly pulses) plus oral prednisone, followed by MMF (2000 mg/day) plus oral prednisone for 18 months, and then azathioprine (2 mg/kg/day) plus oral prednisone. Study endpoints included the occurrence of renal relapse, end-stage renal disease (ESRD) and mortality. RESULTS: After a median follow-up of 3.8 years (range 0.1-4.5), four (5.6%) of the 71 patients had a renal relapse, one (1.4%) failed treatment, one (1.4%) reached ESRD, and two (2.8%) died. Systemic lupus erythematosus (SLE) Disease Activity Index, serum creatinine, proteinuria and antibodies against anti-dsDNA decreased significantly during treatment and serum levels of complement factor 3 and 4 increased significantly. Furthermore, six of eight domains of the Short Form-36 as well as the number of symptoms and total distress level according to the SLE Symptom Checklist improved significantly over time. CONCLUSIONS: This open-label study shows that induction therapy with short-term (six monthly pulses) high-dose ivCY followed by MMF is effective in preventing renal relapses, ESRD and mortality and improving HRQoL in patients with proliferative lupus nephritis. PMID- 25431395 TI - Reactivated Moraxella osteitis presenting as granulomatous disease. AB - Granulomatous infections are commonly associated with mycobacteria, brucellosis, actinomycosis, nocardiosis, spirochetes, and fungi. Rarely, granuloma formation is a host response to other bacterial infection. Osteomyelitis and osteitis that reactivate many years after the primary episode is a known phenomenon. A reactivation that presents as a granulomatous disease is rare. We present a case of reactivated osteitis due to Moraxella osloensis with consecutive granuloma formation. PMID- 25431396 TI - Initially unrecognised group A streptococcal pelvic inflammatory disease in a postmenopausal woman. AB - Invasive group A streptococcal infection is a severe disease with high mortality. Invasive group A streptococcal infection may arise after pelvic inflammatory disease. Pelvic inflammatory disease in postmenopausal women is rare. Here, we report a unique case of a postmenopausal woman with fatal invasive group A streptococcal infection due to pelvic inflammatory disease and an extraordinary course of diagnosis. PMID- 25431397 TI - Increase of baclofen intoxications: risks involved and management. AB - Baclofen has been increasingly used in the treatment of alcohol withdrawal syndrome (AWS). We present a patient with AWS and psychiatric comorbidity who ingested 700 mg of baclofen. ICU admission was necessary for ventilatory support and symptomatic treatment. The patient was dismissed without sequelae. PMID- 25431398 TI - A large lump in the left breast. PMID- 25431399 TI - A 22-year-old man with deep vein thrombosis of the left leg. PMID- 25431400 TI - A life-threatening complication of an ordinary urinary tract infection? PMID- 25431401 TI - Understanding dementia in the sociocultural context: a review. AB - BACKGROUND: The perception of old age differs in different societies and cultures: in the Western societies, the loss of youth, multiple losses of functions and independence resulting in inability produce a social stigma. Dementia is common among the elderly, regardless of their ethnic background. In countries dominated by Western philosophical thought, the cognitive domain has been privileged over other mental domains. Knowledge of cultural factors is essential to an understanding of aging and dementia; studies are currently dominated by biomedical models that consider dementing disorders solely as a pathological entity caused by neuronal and neurotrasmitters loss, and focus on the individual without regard to sociocultural context. AIM: The purpose of this study is to explore how the phenomenon of dementia is perceived in ethnically diverse groups and cultures. METHODS: Medline and Google Scholar searches were conducted for relevant articles, chapters and books published before 2014. Search terms used included anthropology, culture, ethnic elderly and dementia. Publications found through this indexed search were reviewed for further relevant references. RESULTS: The experience of dementia is not universal, but is profoundly shaped by culture in which the demented person lives. Sociocultural conceptualization of the symptoms of dementing diseases remains obscure in many countries. CONCLUSION: Sociocultural conceptualization of Alzheimer's disease and other dementias is of growing interest in shaping the interpretation of the symptoms of dementing diseases. To explore the intersection of culture with the expression of dementia may optimize the management of these complex and chronic conditions. PMID- 25431402 TI - Restraining the enhancers from straying. PMID- 25431403 TI - What history tells us XXXV. Enhancers: their existence and characteristics have raised puzzling issues since their discovery. PMID- 25431404 TI - Phosphorylation of DegU is essential for activation of amyE expression in Bacillus subtilis. AB - Alpha-amylase (amyE) is one of the major exo-enzymes secreted by Bacillus subtilis during the post-exponential phase. The DegS-DegU two-component system regulates expression of majority of post-exponentially expressed genes in B. subtilis. It has been demonstrated that varying levels of the phosphorylated form of DegU (DegU-P) control different cellular processes. Exo-protease production is observed when effective concentration of DegU-P rises in the cell, whereas swarming motility is favoured at very low amounts of DegU-P. In this study we show that like other exo-proteases, expression of amyE is positively regulated by increase in DegU-P levels in the cell. We also demonstrate that residues at the DNA-binding helix-turn-helix (HTH) motif of DegU are necessary for the amyE expression. This observation is further reinforced by demonstrating the direct interaction of DegU on amyE promoter. PMID- 25431405 TI - Variation in ion leakage parameters of two wheat genotypes with different Rht-B1 alleles in response to drought. AB - The reaction to soil drying was evaluated in two Triticum aestivum near-isogenic lines carrying different alleles of the height-reducing gene Rht-B1 based on an improved method for assessment of electrolyte leakage. The two lines were previously shown to differ in their physiological responses to induced water deficit stress. Drought was imposed for 6 days on 10-day-old seedlings. Ion efflux from leaves was measured conductometrically in multiple time points during the 24 h incubation period, and the obtained biphasic kinetics was interpreted according to a previously developed theoretical model proposing different leakage rates through the apoplast and the symplast. Most of the model parameters were able to properly differentiate the two closely related genotypes. The mutant Rht B1c displayed lower and slower electrolyte leakage in comparison with the wild type Rht-B1a. It was speculated that the Rht genes expressing defective DELLA proteins might be involved in water stress response through modulation of cell wall stiffness, which influences its capacity for ions retention, and also by their contribution to ROS detoxification, thus indirectly stabilizing cellular membranes. The presented analytical approach relating processes of ion and water flow in and out of the cell could be used for characterization of membrane and cell wall properties of different genotypes under normal and stress conditions. PMID- 25431406 TI - Quantum chemical investigations of AlN-doped C60 for use as a nano-biosensor in detection of mispairing between DNA bases. AB - Quantum chemical calculations were carried out to study the electronic structure and stability of adenine-thymine and the rare tautomer of adenine-thymine base pairs along with their Cu 2+ complexes and their interactions with AlN-modified fullerene (C58AlN) using Density Functional Theory (B3LYP method). Since, these two forms of base pairs and their Cu 2+ complexes have almost similar electronic structures, their chemical differentiation is an extremely difficult task. In this investigation, we have observed that AlN-doped C 60 could be used as a potentially viable nanoscale sensor to detect these two base pairs as well as their Cu2+ complexes. PMID- 25431407 TI - Identification and in silico analysis of helical lipid binding regions in proteins belonging to the amphitropic protein family. AB - The role of protein-lipid interactions is increasingly recognized to be of importance in numerous biological processes. Bioinformatics is being increasingly used as a helpful tool in studying protein-lipid interactions. Especially recently developed approaches recognizing lipid binding regions in proteins can be implemented. In this study one of those bioinformatics approaches specialized in identifying lipid binding helical regions in proteins is expanded. The approach is explored further by features which can be easily obtained manually. Some interesting examples of members of the amphitropic protein family have been investigated in order to demonstrate the additional features of this bioinformatics approach. The results in this study seem to indicate interesting characteristics of amphitropic proteins and provide insight into the mechanistic functioning and overall understanding of this intriguing class of proteins. Additionally, the results demonstrate that the presented bioinformatics approach might be either an interesting starting point in protein-lipid interactions studies or a good tool for selecting new focus points for more detailed experimental research of proteins with known overall protein-lipid binding abilities. PMID- 25431408 TI - Immobilization and characterization of inulinase from Ulocladium atrum on nonwoven fabrics. AB - Ulocladium atrum inulinase was immobilized on different composite membranes composed of chitosan/nonwoven fabrics. Km values of free and immobilized U. atrum inulinase on different composite membranes were calculated. The enzyme had optimum pH at 5.6 for free and immobilized U. atrum inulinase on polyester nonwoven fabric coated with 3 percent chitosan solution (PPNWF3), but optimum pH was 5 for immobilized U. atrum inulinase on polyester and polypropylene nonwoven fabrics coated with 1 percent chitosan solution. The enzyme had optimum temperature at 40 degree C for immobilized enzyme on each of polyester and polypropylene composite membranes coated with 1 percent chitosan, while it was 50 degree C for free and immobilized enzyme on polypropylene nonwoven fabric coated with 3 percent chitosan solution. Free U. atrum inulinase was stable at 40 degree C but thermal stability of the immobilized enzyme was detected up to 60 degree C. Reusability of immobilized enzyme was from 38 to 42 cycles of reuse; after this, the immobilized enzyme lost its activity completely. In conclusion, immobilized U. atrum inulinase was considerably more stable than the free enzyme, and could be stored for extended periods. PMID- 25431409 TI - LNA-modified isothermal oligonucleotide microarray for differentiating bacilli of similar origin. AB - Oligonucleotide microarray has been one of the most powerful tools in the 'Post Genome Era' for its high sensitivity, high throughput and parallel processing capability. To achieve high detection specificity, we fabricated an isothermal microarray using locked nucleic acid (LNA)-modified oligonucleotide probes, since LNA has demonstrated the advanced ability to enhance the binding affinity toward their complementary nucleotides. After designing the nucleotide sequences of these oligonucleotide probes for gram-positive bacilli of similar origin (Bacillus subtilis, Bacillus licheniformis, Bacillus pumilus, Bacillus megaterium and Bacillus circulans), we unified the melting temperatures of these oligonucleotide probes by modifying some nucleotides using LNA. Furthermore, we optimized the experimental procedures of hydrating microarray slides, blocking side surface as well as labelling the PCR products. Experimental results revealed that KOD Dash DNA polymerase could efficiently incorporate Cy3-dCTP into the PCR products, and the LNA-isothermal oligonucleotide microarray were able to distinguish the bacilli of similar origin with a high degree of accuracy and specificity under the optimized experimental condition. PMID- 25431410 TI - Isolation of a novel uric-acid-degrading microbe Comamonas sp. BT UA and rapid biosensing of uric acid from extracted uricase enzyme. AB - Uric-acid-utilizing soil bacteria were isolated, and 16s rRNA sequence was studied for strain identification. The most prominent uricase-producing bacterium was identified as Comamonas sp BT UA. Crude enzyme was extracted, freeze-dried and its Km and Vmax were determined as 40 meu M and 0.047 meu M min-1ml-1 using Line-weaver Burke plot. An activity of 80 U/mg of total protein was observed when cultured at 37 degree C for 84 h at pH 7. The purified enzyme was used to measure uric acid by spectrophotometric method and electrochemical biosensor. In the biosensing system the enzyme was immobilized on the platinum electrode with a biodegradable glutaraldehyde-crosslinked gelatin film having a swelling percentage of 109+/- 3.08, and response was observed by amperometry applying fixed potential. The electrochemical process as obtained by the anodic peak current and scan rate relationship was further configured by electrochemical impedance spectroscopy (EIS). The polymer matrix on the working electrode gave capacitive response for the electrode-electrolyte interaction. The sensitivity of the biosensor was measured as 6.93 meu A meu M -1 with a sensor affinity [Km(app)] of 50 mu M and 95 percent reproducibility after 50 measurements. The spectrophotometric method could be used in the range of 6-1000 mu M, whereas the biosensor generated linear response in the 1.5- 1000 mu M range with a response time of 24 s and limit of detection of 0.56 meu M. Uric acid was estimated in human blood samples by the biosensor and satisfactory results were obtained. PMID- 25431411 TI - Modulation of phagolysosome maturation by bacterial tlyA gene product. AB - The pathogenic traits of TlyA proteins of Mycobacterium tuberculosis are not known. Expressions of TlyA in bacteria that do not express endogenous TlyA adhere better to RAW264.7 macrophages and get phagocytosed efficiently. The internalized bacteria avoid acidification to the extent of greater than 65 percent in the case of both TlyA-expressing E. coli and M. smegmatis. Consistent with this observation, we have observed decreased co-localizaton of Lysosomal Membrane Associated Protein-1 (approx. 35 percent), Early Endosomal Antigen-1 (approx. 34 percent), Rab5 (approx. 30 percent) and Rab7 (approx. 35 percent) and enhanced colocalizaton of Rab14 (approx. 80 percent) on both TlyA-expressing bacteria as well as on TlyA-coated latex beads. These results suggest that the mycobacterial TlyA, in general, can modulate phagolysosome maturation pathway immediately after entry into macrophages, while other important molecules may aid the bacterium for long-term, intracellular survival at later point of time. PMID- 25431412 TI - Effects of nitric oxide modulating activities on development of enteric nervous system mediated gut motility in chick embryo model. AB - The enteric nervous system (ENS) arises from the enteric neural crest-derived cells (ENCCs), and many molecules and biochemical processes may be involved in its development. This study examined the effects of modulating embryonic nitric oxide (NO) activity on the intestinal motility induced by ENS. One-hundred-and twenty fertilized chicken eggs were assigned to three main groups and incubated at 37 degrees Centigrade and 60 percent humidity. The eggs were treated with NG nitro-Larginine methyl ester (L-NAME), sodium nitroprusside (SNP), L-arginine (L Arg) or vehicle from days 3 (1st group), 7 (2nd group) and 10 (3rd group) of incubation and continued up to day 18. On day 19, the embryos were sacrificed, the jejunal and colorectal segments were taken and the intestinal motility was assessed using isolated organ system. The intestinal motility was recorded normally and following cholinergic, adrenergic and non-adrenergic non-cholinergic (NANC) stimulations. The ENS structure was assessed by immunohistochemistry (IHC) using glial fibrillary acidic protein (GFAP). Rhythmic intestinal contractions were seen in all treatment groups, but inhibition of NO in the LNAME- treated embryos caused significant decrease (p less than 0.01) in the frequency and amplitude of the contraction. The responsiveness to adrenergic, cholinergic and NANC stimulations was also significantly decreased (p less than 0.05). The GFAP expression was significantly (p less than 0.05) reduced in the L-NAME-treated embryos. This study showed that the inhibition of NO caused a deficient development of the ENS, leading to a decrease in the frequency and amplitude of the intestinal contractions and reduced the responsiveness to adrenergic, cholinergic and NANC signalling. PMID- 25431413 TI - Recombination-activating gene 1 and 2 (RAG1 and RAG2) in flounder (Paralichthys olivaceus). AB - During the development of B and T lymphocytes, Ig and TCR variable region genes are assembled from germline V, D, and J gene segments by a site-specific recombination reaction known as V(D)J recombination. The process of somatic V(D)J recombination, mediated by the recombination-activating gene (RAG) products, is the most significant characteristic of adaptive immunity in jawed vertebrates. Flounder (Paralichthys olivaceus) RAG1 and RAG2 were isolated by Genome Walker and RT-PCR, and their expression patterns were analysed by RT-PCR and in situ hybridization on sections. RAG1 spans over 7.0 kb, containing 4 exons and 3 introns, and the full-length ORF is 3207 bp, encoding a peptide of 1068 amino acids. The first exon lies in the 5'-UTR, which is an alternative exon. RAG2 full length ORF is 1062 bp, encodes a peptide of 533 amino acids, and lacks introns in the coding region. In 6-month old flounders, the expression of RAG1 and RAG2 was essentially restricted to the pronephros (head kidney) and mesonephros (truck kidney). Additionally, both of them were mainly expressed in the thymus. These results revealed that the thymus and kidney most likely serve as the primary lymphoid tissues in the flounder. PMID- 25431414 TI - Prooxidative effects of aspartame on antioxidant defense status in erythrocytes of rats. AB - Since aspartame (L-aspartyl-L-phenylalanine methyl ester, ASP) is one of the most widely used artificial sweeteners, the aim of the present study was to investigate its effects on serum glucose and lipid levels as well as its effects on oxidative/antioxidative status in erythrocytes of rats. The experiment included two groups of animals: the control group was administered with water only, while the experimental group was orally administered with ASP (40 mg/kg b.w.) daily, for a period of six weeks. When compared with the control group, the group administrated with ASP indicated higher values of serum glucose, cholesterol and triglycerides. Significantly increased concentrations of superoxide anion (O2 .-), hydrogen peroxide (H2O2), peroxynitrite (?N??-) and lipid peroxides (LPO) were recorded in the erythrocytes of ASP treated group in comparison to the control group. In the course of chronic ASP administration, the following was observed: the concentration of reduced glutathione (GSH) and the activity of catalase (CAT) increased. Thus, these findings suggest that long-term consumption of ASP leads to hyperglycemia and hyperlipidemia, as well as to oxidative stress in erythrocytes. PMID- 25431415 TI - Uncoupling protein 2 gene (UCP2) 45-bp I/D polymorphism is associated with adiposity among Malaysian women. AB - This study investigated the association of Uncoupling Protein 2 gene (UCP2) 45-bp I/D polymorphism with obesity and adiposity in 926 Malaysian subjects (416 males;265 obese; 102/672/152 Malays/Chinese/Indians). The overall minor allele frequency (MAF) was 0.14, while MAFs according to Malay/Chinese/Indian were 0.17/0.12/0.21. The polymorphism was associated with ethnicity, obesity and overall adiposity (total body fat percentage, TBF), but not gender and central adiposity (waist-hip ratio, WHR). Gender- and ethnicity-stratified analysis revealed that within males, the polymorphism was not associated with ethnicity and anthropometric classes. However, within females, significantly more Indians, obese and those with high TBF carried I allele. Logistic regression analysis among females further showed the polymorphism was associated with obesity and overall adiposity; however, when adjusted for age and ethnicity, this association was abolished for obesity but remained significant for overall adiposity [Odds Ratio (OR) for ID genotype = 2.02 (CI=1.18, 3.45; p=0.01); I allele =1.81 (CI=1.15, 2.84; p=0.01)]. Indeed, covariate analysis controlling for age and ethnicity also showed that those carrying ID genotype or I allele had significantly higher TBF than the rest. In conclusion, UCP2 45-bp I/D polymorphism is associated with overall adiposity among Malaysian women. PMID- 25431416 TI - Interrelationships between Bacillus sp. CHEP5 and Bradyrhizobium sp. SEMIA6144 in the induced systemic resistance against Sclerotium rolfsii and symbiosis on peanut plants. AB - Plant-growth-promoting bacteria are often used to enhance crop yield and for biological control of phytopathogens. Bacillus sp. CHEP5 is a biocontrol agent that induces systemic resistance (ISR) in Arachis hypogaea L. (peanut) against Sclerotium rolfsii, the causal agent of root and stem wilt. In this work, the effect of the co-inoculation of Bacillus sp. CHEP5 and the peanut nodulating strain Bradyrhizobium sp. SEMIA 6144 was studied on induction of both systemic resistance and nodulation processes. Bradyrhizobium sp. SEMIA 6144 did not affect the ability of Bacillus sp. CHEP5 to protect peanut plants from S. rolfsii by ISR and the priming in challenged-plants, as evidenced by an increment in phenylalanine ammonia-lyase enzyme activity. Additionally, the capacity of Bradyrhizobium sp. SEMIA 6144 to induce nodule formation in pathogen-challenged plants was improved by the presence of Bacillus sp. CHEP5. PMID- 25431417 TI - Isolation and molecular characterization of an ethylene response factor NtERF1-1 in Nicotiana tabacum cv. Xanthi. AB - Apetala2/Ethylene Response Factors (AP2/ERF) play important roles in regulating gene expression under abiotic and biotic stress in the plant kingdom. Here, we isolated a member of the AP2/ERF transcription factors, NtERF1-1, from Nicotiana tabcum cv. Xanthi NN carrying the N gene, which is resistant to Tobacco mosaic virus (TMV). NtERF1-1 encoded a putative protein of 229 amino acids with a predicted molecular mass of 24.58 kDa. Nucleotide sequence analysis showed that NtERF1-1 contained a conserved DNA-binding domain at the N-terminal. Comparison of amino acid sequences revealed that NtERF1-1 possessed high similarities to ERFs from diverse plants. Semi-quantitative and real-time quantitative RT-PCR analyses indicated that NtERF1-1 was up-regulated following TMV infection. In addition, we speculated that NtERF1-1 might participate in the signal transduction pathway of defence response inducted by the interaction between the N gene and TMV. PMID- 25431418 TI - Evolution and expression analysis of the soybean glutamate decarboxylase gene family. AB - Glutamate decarboxylase (GAD) is an enzyme that catalyses the conversion of L glutamate into gamma-aminobutyric acid (GABA), which is a four-carbon non-protein amino acid present in all organisms. Although plant GAD plays important roles in GABA biosynthesis, our knowledge concerning GAD gene family members and their evolutionary relationship remains limited. Therefore, in this study, we have analysed the evolutionary mechanisms of soybean GAD genes and suggested that these genes expanded in the soybean genome partly due to segmental duplication events. The approximate dates of duplication events were calculated using the synonymous substitution rate, and we suggested that the segmental duplication of GAD genes in soybean originated 9.47 to 11.84 million years ago (Mya). In addition, all segmental duplication pairs (GmGAD1/3 and GmGAD2/4) are subject to purifying selection. Furthermore, GmGAD genes displayed differential expression either in their transcript abundance or in their expression patterns under abiotic stress conditions like salt, drought, and cold. The expression pattern of paralogous pairs suggested that they might have undergone neofunctionalization during the subsequent evolution process. Taken together, our results provide valuable information for the evolution of the GAD gene family and represent the basis for future research on the functional characterization of GAD genes in higher plants. PMID- 25431419 TI - Caspase-like proteins: Acanthamoeba castellanii metacaspase and Dictyostelium discoideum paracaspase, what are their functions? AB - Caspases are cysteine proteases that are important regulators of programmed cell death in animals. Two novel relatives to members of the caspase families metacaspases and paracaspase have been discovered. Metacaspase type-1 was identified in Acanthamoeba castellanii, an opportunistic protozoan parasite that causes severe diseases in humans. Paracaspase was found in the non-pathogenic protozoan Dictyostelium discoideum. Since their discovery in Acanthamoeba and Dictyostelium, metacaspases and paracaspases have remained poorly characterized. At present we do not have sufficient data about the molecular function of these caspase-like proteins or their role, if any, in programmed cell death. How these caspase proteins function at the molecular level is an important area of study that will provide insight into their potential for treatment therapies against Acanthamoeba infection and other similar parasitic protozoan. Additionally, finding the molecular functions of these caspase-like proteins will provide information concerning their role in more complex organisms.The aim of this article was to review recent discoveries about metacaspases and paracaspases as regulators of apoptotic and non-apoptotic processes. PMID- 25431420 TI - Functional genomics of tomato: opportunities and challenges in post-genome NGS era. AB - The Tomato Genome Sequencing Project represented a landmark venture in the history of sequencing projects where both Sanger's and next-generation sequencing (NGS) technologies were employed, and a highly accurate and one of the best assembled plant genomes along with a draft of the wild relative, Solanum pimpinellifolium, were released in 2012. However, the functional potential of the major portion of this newly generated resource is still undefined. The very first challenge before scientists working on tomato functional biology is to exploit this high-quality reference sequence for tapping of the wealth of genetic variants for improving agronomic traits in cultivated tomatoes. The sequence data generated recently by 150 Tomato Genome Consortium would further uncover the natural alleles present in different tomato genotypes. Therefore, we found it relevant to have a fresh outlook on tomato functional genomics in the context of application of NGS technologies in its post-genome sequencing phase. Herein, we provide an overview how NGS technologies vis-a-vis available reference sequence have assisted each other for their mutual improvement and how their combined use could further facilitate the development of other 'omics' tools, required to propel the Solanaceae research. Additionally, we highlight the challenges associated with the application of these cutting-edge technologies. PMID- 25431421 TI - Antifreeze proteins enable plants to survive in freezing conditions. AB - Overwintering plants secrete antifreeze proteins (AFPs) to provide freezing tolerance. These proteins bind to and inhibit the growth of ice crystals that are formed in the apoplast during subzero temperatures. Antifreeze activity has been detected in more than 60 plants and AFPs have been purified from 15 of these, including gymnosperms, dicots and monocots. Biochemical characterization of plant antifreeze activity, as determined by the high ice recrystallization inhibition (IRI) activities and low thermal hysteresis (TH) of AFPs, showed that their main function is inhibition of ice crystal growth rather than the lowering of freezing temperatures. However, recent studies showed that antifreeze activity with higher TH also exists in plants. Calcium and hormones like ethylene and jasmonic acid have been shown to regulate plant antifreeze activity. Recent studies have shown that plant AFPs bind to both prism planes and basal planes of ice crystals by means of two flat ice binding sites. Plant AFPs have been postulated to evolve from the OsLRR-PSR gene nearly 36 million years ago. In this review, we present the current scenario of plant AFP research in order to understand the possible potential of plant AFPs in generation of freezing-tolerant crops. PMID- 25431422 TI - A Drosophila XPD model links cell cycle coordination with neuro-development and suggests links to cancer. AB - XPD functions in transcription, DNA repair and in cell cycle control. Mutations in human XPD (also known as ERCC2) mainly cause three clinical phenotypes: xeroderma pigmentosum (XP), Cockayne syndrome (XP/CS) and trichothiodystrophy (TTD), and only XP patients have a high predisposition to developing cancer. Hence, we developed a fly model to obtain novel insights into the defects caused by individual hypomorphic alleles identified in human XP-D patients. This model revealed that the mutations that displayed the greatest in vivo UV sensitivity in Drosophila did not correlate with those that led to tumor formation in humans. Immunoprecipitations followed by targeted quantitative MS/MS analysis showed how different xpd mutations affected the formation or stability of different transcription factor IIH (TFIIH) subcomplexes. The XP mutants most clearly linked to high cancer risk, Xpd R683W and R601L, showed a reduced interaction with the core TFIIH and also an abnormal interaction with the Cdk-activating kinase (CAK) complex. Interestingly, these two XP alleles additionally displayed high levels of chromatin loss and free centrosomes during the rapid nuclear division phase of the Drosophila embryo. Finally, the xpd mutations showing defects in the coordination of cell cycle timing during the Drosophila embryonic divisions correlated with those human mutations that cause the neurodevelopmental abnormalities and developmental growth defects observed in XP/CS and TTD patients. PMID- 25431423 TI - A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors. AB - Current therapies for glioblastoma multiforme (GBM), the highest grade malignant brain tumor, are mostly ineffective, and better preclinical model systems are needed to increase the successful translation of drug discovery efforts into the clinic. Previous work describes a genetically engineered mouse (GEM) model that contains perturbations in the most frequently dysregulated networks in GBM (driven by RB, KRAS and/or PI3K signaling and PTEN) that induce development of Grade IV astrocytoma with properties of the human disease. Here, we developed and characterized an orthotopic mouse model derived from the GEM that retains the features of the GEM model in an immunocompetent background; however, this model is also tractable and efficient for preclinical evaluation of candidate therapeutic regimens. Orthotopic brain tumors are highly proliferative, invasive and vascular, and express histology markers characteristic of human GBM. Primary tumor cells were examined for sensitivity to chemotherapeutics and targeted drugs. PI3K and MAPK pathway inhibitors, when used as single agents, inhibited cell proliferation but did not result in significant apoptosis. However, in combination, these inhibitors resulted in a substantial increase in cell death. Moreover, these findings translated into the in vivo orthotopic model: PI3K or MAPK inhibitor treatment regimens resulted in incomplete pathway suppression and feedback loops, whereas dual treatment delayed tumor growth through increased apoptosis and decreased tumor cell proliferation. Analysis of downstream pathway components revealed a cooperative effect on target downregulation. These concordant results, together with the morphologic similarities to the human GBM disease characteristics of the model, validate it as a new platform for the evaluation of GBM treatment. PMID- 25431424 TI - Casein kinases I and 2alpha phosphorylate oryza sativa pseudo-response regulator 37 (OsPRR37) in photoperiodic flowering in rice. AB - Flowering time (or heading date) is controlled by intrinsic genetic programs in response to environmental cues, such as photoperiod and temperature. Rice, a facultative short-day (SD) plant, flowers early in SD and late in long-day (LD) conditions. Casein kinases (CKs) generally act as positive regulators in many signaling pathways in plants. In rice, Heading date 6 (Hd6) and Hd16 encode CK2alpha and CKI, respectively, and mainly function to delay flowering time. Additionally, the major LD-dependent floral repressors Hd2/Oryza sativa Pseudo Response Regulator 37 (OsPRR37; hereafter PRR37) and Ghd7 also confer strong photoperiod sensitivity. In floral induction, Hd16 acts upstream of Ghd7 and CKI interacts with and phosphorylates Ghd7. In addition, Hd6 and Hd16 also act upstream of Hd2. However, whether CKI and CK2alpha directly regulate the function of PRR37 remains unclear. Here, we use in vitro pull-down and in vivo bimolecular fluorescence complementation assays to show that CKI and CK2alpha interact with PRR37. We further use in vitro kinase assays to show that CKI and CK2alpha phosphorylate different regions of PRR37. Our results indicate that direct posttranslational modification of PRR37 mediates the genetic interactions between these two protein kinases and PRR37. The significance of CK-mediated phosphorylation for PRR37 and Ghd7 function is discussed. PMID- 25431425 TI - Prostaglandin E2 reverses curcumin-induced inhibition of survival signal pathways in human colorectal carcinoma (HCT-15) cell lines. AB - Prostaglandin E2 (PGE2) promotes tumor-persistent inflammation, frequently resulting in cancer. Curcumin is a diphenolic turmeric that inhibits carcinogenesis and induces apoptosis. PGE2 inhibits curcumin-induced apoptosis; however, the underlying inhibitory mechanisms in colon cancer cells remain unknown. The aim of the present study is to investigate the survival role of PGE2 and whether addition of exogenous PGE2 affects curcumin-induced cell death. HCT 15 cells were treated with curcumin and PGE2, and protein expression levels were investigated via Western blot. Reactive oxygen species (ROS) generation, lipid peroxidation, and intracellular glutathione (GSH) levels were confirmed using specific dyes. The nuclear factor-kappa B (NF-kappaB) DNA-binding was measured by electrophoretic mobility shift assay (EMSA). PGE2 inhibited curcumin-induced apoptosis by suppressing oxidative stress and degradation of PARP and lamin B. However, exposure of cells to the EP2 receptor antagonist, AH6809, and the PKA inhibitor, H89, before treatment with PGE2 or curcumin abolished the protective effect of PGE2 and enhanced curcumin-induced cell death. PGE2 activates PKA, which is required for cAMP-mediated transcriptional activation of CREB. PGE2 also activated the Ras/Raf/Erk pathway, and pretreatment with PD98059 abolished the protective effect of PGE2. Furthermore, curcumin treatment greatly reduced phosphorylation of CREB, followed by a concomitant reduction of NF-kappaB (p50 and p65) subunit activation. PGE2 markedly activated nuclear translocation of NF kappaB. EMSA confirmed the DNA-binding activities of NF-kappaB subunits. These results suggest that inhibition of curcumin-induced apoptosis by PGE2 through activation of PKA, Ras, and NF-kappaB signaling pathways may provide a molecular basis for the reversal of curcumin-induced colon carcinoma cell death. PMID- 25431426 TI - Stimulation of oligonucleotide-directed gene correction by Redbeta expression and MSH2 depletion in human HT1080 cells. AB - The correction of disease-causing mutations by single-strand oligonucleotide templated DNA repair (ssOR) is an attractive approach to gene therapy, but major improvements in ssOR efficiency and consistency are needed. The mechanism of ssOR is poorly understood but may involve annealing of oligonucleotides to transiently exposed single-stranded regions in the target duplex. In bacteria and yeast it has been shown that ssOR is promoted by expression of Redbeta, a single-strand DNA annealing protein from bacteriophage lambda. Here we show that Redbeta expression is well tolerated in a human cell line where it consistently promotes ssOR. By use of short interfering RNA, we also show that ssOR is stimulated by the transient depletion of the endogenous DNA mismatch repair protein MSH2. Furthermore, we find that the effects of Redbeta expression and MSH2 depletion on ssOR can be combined with a degree of cooperativity. These results suggest that oligonucleotide annealing and mismatch recognition are distinct but interdependent events in ssOR that can be usefully modulated in gene correction strategies. PMID- 25431427 TI - RNA interference-mediated knockdown of astrocyte elevated gene-1 inhibits growth, induces apoptosis, and increases the chemosensitivity to 5-fluorouracil in renal cancer Caki-1 cells. AB - Astrocyte elevated gene-1 (AEG-1) is a recently discovered oncogene that has been reported to be highly expressed in various types of malignant tumors, including renal cell carcinoma. However, the precise role of AEG-1 in renal cancer cell proliferation and apoptosis has not been clarified. In this study, we transfected the renal cancer cell line Caki-1 with a plasmid expressing AEG-1 short hairpin RNA (shRNA) and obtained cell colonies with stable knockdown of AEG-1. We found that AEG-1 down-regulation inhibited cell proliferation and colony formation and arrested cell cycle progression at the sub-G1 and G0/G1 phase. Western blot analysis indicated that the expression of proliferating cell nuclear antigen (PCNA), cyclin D1 and cyclin E were significantly reduced following AEG-1 down regulation. In addition, AEG-1 knockdown led to the appearance of apoptotic bodies in renal cancer cells, and the ratio of apoptotic cells significantly increased. Expression of the anti-apoptotic factor Bcl-2 was dramatically reduced, whereas the pro-apoptotic factors Bax, caspase-3 and poly (ADP-ribose) polymerase (PARP) were significantly activated. Finally, AEG-1 knockdown in Caki 1 cells remarkably suppressed cell proliferation and enhanced cell apoptosis in response to 5-fluorouracil (5-FU) treatment, suggesting that AEG-1 inhibition sensitizes Caki-1 cells to 5-FU. Taken together, our data suggest that AEG-1 plays an important role in renal cancer formation and development and may be a potential target for future gene therapy for renal cell carcinoma. PMID- 25431428 TI - Prevalence of serum N-methyl-D-aspartate receptor autoantibodies in refractory psychosis. AB - N-methyl-d-aspartate receptor (NMDA-R) autoantibodies have been reported in people with acute psychosis. We hypothesised that their presence may be implicated in the aetiology of treatment-refractory psychosis. We sought to ascertain the point prevalence of NMDA-R antibody positivity in patients referred to services for treatment-refractory psychosis. We found that 3 (7.0%) of 43 individuals had low positive NMDA-R antibody titres. This suggests that NMDA-R autoantibodies are unlikely to account for a large proportion of treatment refractory psychosis. PMID- 25431429 TI - Participant views on involvement in a trial of social recovery cognitive behavioural therapy. AB - BACKGROUND: The PRODIGY trial (Prevention of long term social disability amongst young people with emerging psychological difficulties, ISRCTN47998710) is a pilot trial of social recovery cognitive-behavioural therapy (SRCBT). AIMS: The PRODIGY qualitative substudy aimed to (a) explore individual experiences of participating in the pilot randomised, controlled trial (recruitment, randomisation, assessment) and initial views of therapy, and (b) to explore perceived benefits of taking part in research v. ethical concerns and potential risks. METHOD: Qualitative investigation using semi-structured interviews with thematic analysis. RESULTS: Analysis revealed participant experiences around the key themes of acceptability, disclosure, practicalities, altruism and engagement. CONCLUSIONS: Participants in both trial arms perceived themselves as gaining benefits from being involved in the study, above and beyond the intervention. This has implications for the design of future research and services for this client group, highlighting the importance of being flexible and an individualised approach as key engagement tools. PMID- 25431430 TI - Mindfulness group therapy in primary care patients with depression, anxiety and stress and adjustment disorders: randomised controlled trial. AB - BACKGROUND: Individual-based cognitive-behavioural therapy (CBT) is in short supply and expensive. AIMS: The aim of this randomised controlled trial (RCT) was to compare mindfulness-based group therapy with treatment as usual (primarily individual-based CBT) in primary care patients with depressive, anxiety or stress and adjustment disorders. METHOD: This 8-week RCT (ClinicalTrials.gov ID: NCT01476371) was conducted during spring 2012 at 16 general practices in Southern Sweden. Eligible patients (aged 20-64 years) scored >=10 on the Patient Health Questionnaire-9, >=7 on the Hospital Anxiety and Depression Scale or 13-34 on the Montgomery-Asberg Depression Rating Scale (self-rated version). The power calculations were based on non-inferiority. In total, 215 patients were randomised. Ordinal mixed models were used for the analysis. RESULTS: For all scales and in both groups, the scores decreased significantly. There were no significant differences between the mindfulness and control groups. CONCLUSIONS: Mindfulness-based group therapy was non-inferior to treatment as usual for patients with depressive, anxiety or stress and adjustment disorders. PMID- 25431432 TI - Gross morphological brain changes with chronic, heavy cannabis use. AB - We investigated the morphology of multiple brain regions in a rare sample of 15 very heavy cannabis users with minimal psychiatric comorbidity or significant exposure to other substances (compared with 15 age- and IQ-matched non-cannabis using controls) using manual techniques. Heavy cannabis users demonstrated smaller hippocampus and amygdala volumes, but no alterations of the orbitofrontal and anterior- and paracingulate cortices, or the pituitary gland. These findings indicate that chronic cannabis use has a selective and detrimental impact on the morphology of the mediotemporal lobe. PMID- 25431431 TI - Clinical usefulness of dopamine transporter SPECT imaging with 123I-FP-CIT in patients with possible dementia with Lewy bodies: randomised study. AB - BACKGROUND: Dementia with Lewy bodies (DLB) is underrecognised in clinical settings. AIMS: To investigate whether performing a (123)I-ioflupane injection ((123)I-FP-CIT also called DaTSCANTM) single photon emission computed tomography (SPECT) scan in patients with possible DLB would lead to a more certain diagnosis (probable DLB or non-DLB dementia). METHOD: We randomised 187 patients with possible DLB 2:1 to have a scan or not (control group). The outcome measure was a change in diagnosis to probable DLB or non-DLB. RESULTS: There were 56 controls and 114 scanned patients, of whom 43% had an abnormal scan. More patients in the imaging group had a change in diagnosis compared with controls at 8 and 24 weeks (61% (n = 70) v. 4% (n = 2) and 71% (n = 77) v. 16% (n = 9); both P<0.0001). Clinicians were more likely to change the diagnosis if the scan was abnormal (82%) than if it was normal (46%). CONCLUSIONS: Imaging significantly contributed to a more certain diagnosis, proving to be a useful adjunct in the work-up of patients with possible DLB. PMID- 25431433 TI - Work-related musculoskeletal disorders: are they truly declining? PMID- 25431434 TI - Comment: working conditions and health in Central America: a survey of 12 024 workers in six countries. by Benavides FG et al. PMID- 25431435 TI - Usefulness of the working conditions and health survey in central America in prevention. Author response to comments by Jensen. PMID- 25431436 TI - Reduction of opiate withdrawal symptoms with use of clonidine in a county jail. AB - Increasingly, addicted inmates admitted to jail in New Mexico are in the process of opiate withdrawal. While the standard for opiate detoxification is a narcotic taper, correctional policy restricts opiate use for safety reasons. An alternative for withdrawal is a supportive intervention with clonidine, a non opiate. Could clonidine be beneficial for acute opiate withdrawal symptoms in this population? Fifty-five inmates (37 male and 18 female) volunteered to participate in assessing clonidine for the reduction of withdrawal symptoms. Symptoms were assessed with the Subjective Opiate Withdrawal Scale and treated with a standard clonidine protocol. Clonidine significantly decreased the mean scores at 1 and 4 hours after medication use. Clonidine for opiate withdrawal reduces symptoms when opiate-assisted detoxification is not available. PMID- 25431437 TI - Screening Incarcerated Juveniles Using the MAYSI-2. AB - The high prevalence of mental health disorders among incarcerated juveniles is a matter of national and global concern. Juvenile justice personnel need accurate screening measures that identify youth requiring immediate mental health services. The purpose of this study was threefold: (a) to examine the utility of the Massachusetts Youth Screening Instrument, Version 2 (MAYSI-2) in identifying juveniles with mental health concerns in a large sample of juveniles (N = 4,009), (b) to provide data regarding rates of identified mental health needs in incarcerated youth, and (c) to provide descriptive comparisons to other studies using the MAYSI-2. Mean scores of subscales were compared with the MAYSI-2 normative samples and other recent studies. Results indicated that this population has a high occurrence of mental health symptoms and there is high variability in the severity of the symptoms. In addition, a multivariate analysis of variance test found significant differences in mental health problems across ethnic groups. PMID- 25431438 TI - Online medication history retrieval. AB - The difficulty of obtaining accurate medication history from inmates at the time of incarceration is daunting. This article summarizes the success of a large urban jail in the use of online data to identify medication history upon incarceration. This article describes the scope of available prescription data, the implementation of online retrieval, system limitations, planned improvements, and suggestions of additional applications of online retrieval services. PMID- 25431439 TI - Protocol for the Femoroacetabular Impingement Trial (FAIT): a multi-centre randomised controlled trial comparing surgical and non-surgical management of femoroacetabular impingement. AB - AIMS: Femoroacetabular Junction Impingement (FAI) describes abnormalities in the shape of the femoral head-neck junction, or abnormalities in the orientation of the acetabulum. In the short term, FAI can give rise to pain and disability, and in the long-term it significantly increases the risk of developing osteoarthritis. The Femoroacetabular Impingement Trial (FAIT) aims to determine whether operative or non-operative intervention is more effective at improving symptoms and preventing the development and progression of osteoarthritis. METHODS: FAIT is a multicentre superiority parallel two-arm randomised controlled trial comparing physiotherapy and activity modification with arthroscopic surgery for the treatment of symptomatic FAI. Patients aged 18 to 60 with clinical and radiological evidence of FAI are eligible. Principal exclusion criteria include previous surgery to the index hip, established osteoarthritis (Kellgren-Lawrence >= 2), hip dysplasia (centre-edge angle < 20 degrees ), and completion of a physiotherapy programme targeting FAI within the previous 12 months. Recruitment will take place over 24 months and 120 patients will be randomised in a 1:1 ratio and followed up for three years. The two primary outcome measures are change in hip outcome score eight months post-randomisation (approximately six-months post intervention initiation) and change in radiographic minimum joint space width 38 months post-randomisation. ClinicalTrials.gov: NCT01893034. Cite this article: Bone Joint Res 2014;3:321-7. PMID- 25431440 TI - MetaVelvet-SL: an extension of the Velvet assembler to a de novo metagenomic assembler utilizing supervised learning. AB - The assembly of multiple genomes from mixed sequence reads is a bottleneck in metagenomic analysis. A single-genome assembly program (assembler) is not capable of resolving metagenome sequences, so assemblers designed specifically for metagenomics have been developed. MetaVelvet is an extension of the single-genome assembler Velvet. It has been proved to generate assemblies with higher N50 scores and higher quality than single-genome assemblers such as Velvet and SOAPdenovo when applied to metagenomic sequence reads and is frequently used in this research community. One important open problem for MetaVelvet is its low accuracy and sensitivity in detecting chimeric nodes in the assembly (de Bruijn) graph, which prevents the generation of longer contigs and scaffolds. We have tackled this problem of classifying chimeric nodes using supervised machine learning to significantly improve the performance of MetaVelvet and developed a new tool, called MetaVelvet-SL. A Support Vector Machine is used for learning the classification model based on 94 features extracted from candidate nodes. In extensive experiments, MetaVelvet-SL outperformed the original MetaVelvet and other state-of-the-art metagenomic assemblers, IDBA-UD, Ray Meta and Omega, to reconstruct accurate longer assemblies with higher N50 scores for both simulated data sets and real data sets of human gut microbial sequences. PMID- 25431441 TI - Commodification of transitioning ethnic enclaves. AB - This literature review examines the changing roles of ethnic enclaves, the question of their authenticity, and their value as commodified spaces, giving special attention to Little Italy neighborhoods in the United States. Understanding the roles of ethnic enclaves requires some understanding about immigrants' identities. For some theorists, immigrants become blended into society over the course of generations; for other theorists, descendants of immigrants sometimes retain their cultural heritage and traits, helping form a multicultural or pluralist society. In the traditional sense, ethnic enclaves consist of both ethnic residents and ethnic businesses (such as restaurants, shops, and grocers). One way that ethnic enclaves change is when the area experiences a demographic shift, and people from outside the ethnic group move their residences and businesses to the neighborhood, resulting in the area becoming diversified in people and businesses. A second way that an ethnic enclave changes is when the ethnic group shrinks, but the shops and other businesses remain, resulting in the area becoming diversified in residents but not businesses. This latter situation may encourage commodification of the neighborhood's ethnic identity, where a municipality or business association seeks to preserve an enclave's ethnic reputation for tourism purposes. This commodification has implications for many individuals and groups within the enclave as well as outside of it. PMID- 25431443 TI - Can the identity of a behavior setting be perceived through patterns of joint action? An investigation of place perception. AB - "Behavior settings" are generated by joint actions of individuals in conjunction with the milieu features (or affordances) that are available. The reported research explores the hypothesis that the identity or meaning of a behavior setting can be perceived by means of the patterns of action collectively generated by the setting's participants. A set of computer animations was created based on detailed observation of activities in everyday settings. Three experiments were conducted to assess whether perceivers could extract "structure from motion" (in this case, collective actions) that was specific to the particular behavior setting displayed by way of the animations. Two experiments assessed whether individuals could accurately perceive the identity of the behavior settings with such displays, and a third experiment indirectly examined this possibility by evaluating whether setting possibilities and constraints were recognized. The results offered some support for the hypothesis, and suggested several refinements in how to conceptualize a typology of behavior settings. An ecological approach to place perception is also discussed. PMID- 25431442 TI - Definition of Impulsivity and Related Terms Following Traumatic Brain Injury: A Review of the Different Concepts and Measures Used to Assess Impulsivity, Disinhibition and other Related Concepts. AB - Impulsivity is a common and debilitating sequela following traumatic brain injury (TBI), but there is no consensual definition or measure to assess this construct. The following review aims to elucidate the differences and resemblances between impulsivity, disinhibition and other related terms following brain injury and the instruments that are commonly used to measure these constructs. To do so, a search through different databases was conducted in order to find articles that mention and define impulsivity, disinhibition, impulse control, regulation deficits, dyscontrol and risky behavior. The concepts that stand out from the literature, the measures used, the similarities, the differences between these concepts are observed. The fit with the UPPS model of impulsivity, according to which impulsivity is a multidimensional concept composed of four distinct dimensions (urgency, perseverance, premeditation and sensation-seeking) is discussed. PMID- 25431444 TI - The role of nature in coping with psycho-physiological stress: a literature review on restorativeness. AB - Physical settings can play a role in coping with stress; in particular experimental research has found strong evidence between exposure to natural environments and recovery from physiological stress and mental fatigue, giving support to both Stress Recovery Theory and Attention Restoration Theory. In fact, exposure to natural environments protects people against the impact of environmental stressors and offer physiological, emotional and attention restoration more so than urban environments. Natural places that allow the renewal of personal adaptive resources to meet the demands of everyday life are called restorative environments. Natural environments elicit greater calming responses than urban environments, and in relation to their vision there is a general reduction of physiological symptoms of stress. Exposure to natural scenes mediates the negative effects of stress reducing the negative mood state and above all enhancing positive emotions. Moreover, one can recover the decrease of cognitive performance associated with stress, especially reflected in attention tasks, through the salutary effect of viewing nature. Giving the many benefits of contact with nature, plans for urban environments should attend to restorativeness. PMID- 25431445 TI - Prescribing clinicians' perspectives on evidence-based psychotherapy for posttraumatic stress disorder. AB - Evidence-based psychotherapies (EBP) for Posttraumatic Stress Disorder are not utilized to their full extent within the Department of Veterans Affairs (VA). VA provides care to many persons with PTSD and has been in the forefront of clinical practice guidelines and EBP training and dissemination. Yet VA continues to find EBP implementation difficult. Veterans with PTSD often initially present to prescribing clinicians, who then help make care decisions. It is therefore critical that these clinicians correctly screen and triage appropriate mental health care. The purpose of this study was to assess VA prescribing clinicians' knowledge, perceptions, and referral behaviors related to EBPs for PTSD and to identify facilitators and barriers to implementing EBPs within VA. We conducted qualitative interviews with 26 VA prescribing clinicians. Limited access to EBPs was the most commonly noted barrier. The clinicians we interviewed also held specific beliefs and behaviors that may delay or deter EBPs. Strategies to improve utilization also emerged. Findings suggest the need for increased access to EBPs, training to optimize the role of prescribing clinicians in helping Veterans with PTSD make appropriate care decisions, and specific organizational changes to facilitate access and effective referral systems for EBPs. PMID- 25431446 TI - Wayfinding in healthcare facilities: contributions from environmental psychology. AB - The ability to successfully navigate in healthcare facilities is an important goal for patients, visitors, and staff. Despite the fundamental nature of such behavior, it is not infrequent for planners to consider wayfinding only after the fact, once the building or building complex is complete. This review argues that more recognition is needed for the pivotal role of wayfinding in healthcare facilities. First, to provide context, the review presents a brief overview of the relationship between environmental psychology and healthcare facility design. Then, the core of the article covers advances in wayfinding research with an emphasis on healthcare environments, including the roles of plan configuration and manifest cues, technology, and user characteristics. Plan configuration and manifest cues, which appeared early on in wayfinding research, continue to play a role in wayfinding success and should inform design decisions. Such considerations are joined by emerging technologies (e.g., mobile applications, virtual reality, and computational models of wayfinding) as a way to both enhance our theoretical knowledge of wayfinding and advance its applications for users. Among the users discussed here are those with cognitive and/or visual challenges (e.g., Down syndrome, age-related decrements such as dementia, and limitations of vision). In addition, research on the role of cross-cultural comprehension and the effort to develop a system of universal healthcare symbols is included. The article concludes with a summary of the status of these advances and directions for future research. PMID- 25431447 TI - Merging evidence-based psychosocial interventions in schizophrenia. AB - Psychosocial interventions are an essential part of the treatment for people with severe mental illness such as schizophrenia. The criteria regarding what makes an intervention "evidence-based" along with a current list of evidence-based interventions are presented. Although many evidence-based interventions exist, implementation studies reveal that few, if any, are ever implemented in a given setting. Various theories and approaches have been developed to better understand and overcome implementation obstacles. Among these, merging two evidence-based interventions, or offering an evidence-based intervention within an evidence based service, are increasingly being reported and studied in the literature. Five such merges are presented, along with their empirical support: cognitive behavior therapy (CBT) with skills training; CBT and family psychoeducation; supported employment (SE) and skills training; SE and cognitive remediation; and SE and CBT. PMID- 25431448 TI - A protocol for evaluating contextual design principles. AB - This paper explains how scientific data can be incorporated into urban design decisions, such as evaluating contextual design principles. The recommended protocols are based on the Cochrane Reviews that have been widely used in medical research. The major concepts of a Cochrane Review are explained, as well as the underlying mathematics. The underlying math is meta-analysis. Data are reported for three applications and seven contextual design policies. It is suggested that use of the Cochrane protocols will be of great assistance to planners by providing scientific data that can be used to evaluate the efficacies of contextual design policies prior to implementing those policies. PMID- 25431449 TI - Risk of dementia in older adults with low versus high occupation-based motivational processes: differential impact of frequency and proximity of social network. AB - OBJECTIVES: This study investigates the impact of occupation-based motivational processes and social network variables on the incidence of dementia over 8 years. METHOD: Data were derived from the Leipzig Longitudinal Study of the Aged (LEILA75+), a population-based longitudinal study of individuals aged 75 years and older (n=1692 at baseline). Motivational processes were estimated based on the main occupation using the Occupational Information Network database. RESULTS: In a Cox proportional hazard model, motivational processes were not associated with the risk of dementia (hazard ratio [HR]: 0.93, 95% confidence interval [CI]: 0.74-1.16). Individuals with a higher frequency of social contact at baseline had a significantly lower risk of dementia (HR: 0.96, 95% CI: 0.91-0.99), while proximity of social contacts was not linked to the risk of dementia (HR: 1.03, 95% CI: 0.98-1.08). In individuals with low indices of motivational processes, the frequency of social contacts was associated with a lower risk of dementia (HR: 0.94, 95% CI: 0.88-1.00). On the other hand, proximity of social contacts was linked to a higher risk of dementia in individuals with high indices of motivational processes (HR: 1.09, 95% CI: 1.01-1.19). DISCUSSION: Results indicate that the frequency and proximity of social contacts have a differential impact on the risk of dementia according to lower or higher indices of motivational processes, while the impact of motivational processes on risk of dementia could not be confirmed. Future studies should carefully disentangle different aspects of social interactions and their association with motivational processes. PMID- 25431450 TI - The 6-year trajectory of non-traumatic knee symptoms (including patellofemoral pain) in adolescents and young adults in general practice: a study of clinical predictors. AB - AIMS: (1) To assess the 1-year and 6-year courses of non-traumatic knee symptoms in adolescents and young adults presenting in general practice. (2) To identify prognostic factors for persistent knee symptoms at 1-year follow-up. METHODS: Adolescents and young adults (12-35 years; n=172) with non-traumatic knee symptoms were included in the cohort study by their general practitioner (GP) and followed for 6 years. Multivariable logistic regression analysis was used to identify prognostic factors for persistent knee symptoms at 1-year follow-up and the area under the receiver operating curve (AUC) was calculated. RESULTS: Persistent knee symptoms in patients receiving a GP diagnosis of unspecified knee symptoms were reported by 41% of the patients at 1-year follow-up and by 19% of the available patients at 6-year follow-up. Patients receiving a GP diagnosis of patellofemoral pain syndrome had the worse prognosis, with 40% reporting persistent knee symptoms at 6-year follow-up. Prognostic factors associated with persistent knee symptoms at 1-year follow-up were BMI >25, low/middle education level, bilateral symptoms and self-reported absence of crepitus of the knee (AUC 0.80) for patients receiving a GP diagnosis of unspecified knee symptoms. For patients receiving a GP diagnosis of patellofemoral pain syndrome, prognostic factors were low/middle education level, poor health, having bilateral symptoms and self-report of a swollen knee (AUC 0.76). CONCLUSIONS: The prognosis of non traumatic knee symptoms in adolescents and young adults in general practice is not as good as was previously assumed. Several prognostic factors collected at baseline were associated with persistent knee symptoms at follow-up. However, the results should be replicated in another larger study. PMID- 25431451 TI - "I Don't Shag Dirty Girls": Marginalized Masculinities and the Use of Partner Selection as a Sexual Health Risk Reduction Strategy in Heterosexual Young Men. AB - Understanding and addressing the sexual risk taking of young men remains a key research, policy, and practice concern in attempts to improve the emotional and physical sexual health of young men and their sexual partners. This article explores one of the ways in which young men attempt to mitigate sexual risk through the assigning of labels to particular young women and using these as a basis for their decisions in relation to sexual activity, contraception, and condom use. The article uses the lens of hegemonic masculinities theory to increase understanding of the role played by the construction and performance of marginalized masculinities and how these in turn are influenced by social exclusionary processes. The article draws on focus group and interview data from 46 young men aged 15 to 17 years living in the northwest of England, purposively selected on the basis of the prevailing policy definitions of social inclusion and exclusion. The article describes a form of marginalized masculinity pertaining to socially excluded young men, which as a result of limited access to other tenets of hegemonic masculinity, is disproportionately reliant on sexual expertise and voracity alongside overt demonstrations of their superiority over women. It is in this context that young women are assigned the labels of "dirty" or "clean" on the basis of a selection of arbitrary judgments relating to dress, demeanor, area of residence, and perceived sexual activities. The motivations of the young men, the impact on young women, and the policy and practice implications are all discussed. PMID- 25431452 TI - Cervical cancer screening with HPV testing in the Valcamonica (Italy) screening programme. AB - OBJECTIVE: We present the results of the first screening round and the first year of the second round of the Valcamonica Human Papillomavirus (HPV) pilot screening project. SETTING: From 2010 to 2012, the entire target female population (aged 25 64) was invited to the first HPV screening round in an area where Pap test screening had been active since 2002. METHODS: For HPV-negative women, the interval was three years. For HPV-positive women, a cytological smear was stained and interpreted. Positive cytologies were referred to colposcopy; negatives were referred to repeat HPV after one year. If HPV was persistently positive, women were referred to colposcopy; if negative, to normal screening. RESULTS: In 2010 12 18728 women were screened, slightly higher participation than with Pap test (18233 64.7%); 1633 were HPV-positive (8.7%); 843 were positive at cytology triage (referral rate at baseline 4.5%). Of those referred at the one year HPV test, 84% complied (660/780); 356 were persistently positive (1.9%). The total referral rate was 6.4% compared with 3.7% for the Pap test. The detection rate was 9.2/1000 compared with 5.0% for the Pap test. The HPV positivity rate during the second round in women previously negative was 3.9% and the detection rate in HPV-positive cytology-positive women was 0.8/1000. CONCLUSIONS: HPV-based screening increases colposcopies at the first round, but also strongly increases the detection rate. At the second round, HPV prevalence was much lower and the detection rate also fell, corroborating the need for longer screening intervals in HPV-negative women. PMID- 25431454 TI - Cognition enhancers for the treatment of dementia. AB - Dementia is a broad term used to describe several chronic progressive neurological disorders that adversely affect higher mental functions including memory, language, behaviour, abstract thinking, comprehension, calculation, learning capacity and judgement. Alzheimer's disease is the most common form of dementia but other neurological conditions such as Parkinson's disease, cerebrovascular disease and chronic infections such as syphilis can also lead to the clinical syndrome of dementia. Initial investigations should always focus on finding any treatable cause for dementia such as HIV, structural lesions such as subdural haematomas or specific nutritional deficiency states such as that due to vitamin B12 and treated appropriately. Where no treatable or reversible aetiology is found, a referral to a specialist should be considered who may initiate further investigations including magnetic resonance imaging or perfusion single photon emission computerised tomography scans of the brain, and sometimes cerebrospinal fluid examination or an electroencephalogram. PMID- 25431453 TI - Sildenafil Prevents Apoptosis of Human First-Trimester Trophoblast Cells Exposed to Oxidative Stress: Possible Role for Nitric Oxide Activation of 3',5'-cyclic Guanosine Monophosphate Signaling. AB - Human first-trimester trophoblast cells proliferate at low O2, but survival is compromised by oxidative stress, leading to uteroplacental insufficiency. The vasoactive drug, sildenafil citrate (Viagra, Sigma, St Louis, Missouri), has proven useful in reducing adverse pregnancy outcomes. An important biological function of this pharmaceutical is its action as an inhibitor of cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 activity, which suggests that it could have beneficial effects on trophoblast survival. To investigate whether sildenafil can prevent trophoblast cell death, human first-trimester villous explants and the HTR-8/SVneo cytotrophoblast cell line were exposed to hypoxia and reoxygenation (H/R) to generate oxidative stress, which induces apoptosis. Apoptosis was optimally inhibited during H/R by 350 ng/mL sildenafil. Sildenafil mediated survival was reversed by l-N(G)-nitro-l-arginine methyl ester hydrochloride or cGMP antagonist, indicating a dependence on both nitric oxide (NO) and cGMP. Indeed, either a cGMP agonist or an NO generator was cytoprotective independent of sildenafil. These findings suggest a novel intervention route for patients with recurrent pregnancy loss or obstetrical placental disorders. PMID- 25431457 TI - The human milk oligosaccharide 2'-fucosyllactose modulates CD14 expression in human enterocytes, thereby attenuating LPS-induced inflammation. AB - BACKGROUND: A major cause of enteric infection, Gram-negative pathogenic bacteria activate mucosal inflammation through lipopolysaccharide (LPS) binding to intestinal toll-like receptor 4 (TLR4). Breast feeding lowers risk of disease, and human milk modulates inflammation. OBJECTIVE: This study tested whether human milk oligosaccharides (HMOSs) influence pathogenic Escherichia coli-induced interleukin (IL)-8 release by intestinal epithelial cells (IECs), identified specific proinflammatory signalling molecules modulated by HMOSs, specified the active HMOS and determined its mechanism of action. METHODS: Models of inflammation were IECs invaded by type 1 pili enterotoxigenic E. coli (ETEC) in vitro: T84 modelled mature, and H4 modelled immature IECs. LPS-induced signalling molecules co-varying with IL-8 release in the presence or absence of HMOSs were identified. Knockdown and overexpression verified signalling mediators. The oligosaccharide responsible for altered signalling was identified. RESULTS: HMOSs attenuated LPS-dependent induction of IL-8 caused by ETEC, uropathogenic E. coli, and adherent-invasive E. coli (AIEC) infection, and suppressed CD14 transcription and translation. CD14 knockdown recapitulated HMOS-induced attenuation. Overexpression of CD14 increased the inflammatory response to ETEC and sensitivity to inhibition by HMOSs. 2'-fucosyllactose (2'-FL), at milk concentrations, displayed equivalent ability as total HMOSs to suppress CD14 expression, and protected AIEC-infected mice. CONCLUSIONS: HMOSs and 2'-FL directly inhibit LPS-mediated inflammation during ETEC invasion of T84 and H4 IECs through attenuation of CD14 induction. CD14 expression mediates LPS-TLR4 stimulation of portions of the 'macrophage migration inhibitory factors' inflammatory pathway via suppressors of cytokine signalling 2/signal transducer and activator of transcription 3/NF-kappaB. HMOS direct inhibition of inflammation supports its functioning as an innate immune system whereby the mother protects her vulnerable neonate through her milk. 2'-FL, a principal HMOS, quenches inflammatory signalling. PMID- 25431459 TI - Is hypertension in adult age related to unemployment at a young age? Results from the Northern Swedish Cohort. AB - AIM: The aim of this study was to analyse the relationship between early unemployment (ages 16-21 years) and adult hypertension after controlling for earlier hypertension, unemployment in adult life, risk factors for hypertension and confounders. METHODS: A cohort of 927 (86.6% of the original cohort) 9th grade school-leavers was followed from 1981 until 2008. Data were collected through questionnaires, health examinations, and national registers. Univariate and multivariate logistic regression were used as primary statistical methods. RESULTS: At ages 21 and 43, hypertension was significantly more prevalent among men than women (p < .001). Unemployment between the ages of 16 and 21 was related to hypertension at age 43 among women but not men. The odds ratio (OR) was persistently high (OR 3.16 [95% confidence interval 1.45-6.89]) after controlling for late unemployment, hypertension at age 16, risk factors for hypertension and confounders. There was no significant relationship between exposure to early unemployment and hypertension at age 21 for women or men. CONCLUSIONS: From a public health perspective, youth unemployment is a societal problem in need of more attention and intervention in order to prevent long-term adverse health outcomes. PMID- 25431456 TI - Comparative metabolomics in vegans and omnivores reveal constraints on diet dependent gut microbiota metabolite production. AB - OBJECTIVE: The consumption of an agrarian diet is associated with a reduced risk for many diseases associated with a 'Westernised' lifestyle. Studies suggest that diet affects the gut microbiota, which subsequently influences the metabolome, thereby connecting diet, microbiota and health. However, the degree to which diet influences the composition of the gut microbiota is controversial. Murine models and studies comparing the gut microbiota in humans residing in agrarian versus Western societies suggest that the influence is large. To separate global environmental influences from dietary influences, we characterised the gut microbiota and the host metabolome of individuals consuming an agrarian diet in Western society. DESIGN AND RESULTS: Using 16S rRNA-tagged sequencing as well as plasma and urinary metabolomic platforms, we compared measures of dietary intake, gut microbiota composition and the plasma metabolome between healthy human vegans and omnivores, sampled in an urban USA environment. Plasma metabolome of vegans differed markedly from omnivores but the gut microbiota was surprisingly similar. Unlike prior studies of individuals living in agrarian societies, higher consumption of fermentable substrate in vegans was not associated with higher levels of faecal short chain fatty acids, a finding confirmed in a 10-day controlled feeding experiment. Similarly, the proportion of vegans capable of producing equol, a soy-based gut microbiota metabolite, was less than that was reported in Asian societies despite the high consumption of soy-based products. CONCLUSIONS: Evidently, residence in globally distinct societies helps determine the composition of the gut microbiota that, in turn, influences the production of diet-dependent gut microbial metabolites. PMID- 25431458 TI - Clinical and virological predictors of hepatic flares in pregnant women with chronic hepatitis B. AB - BACKGROUND: Unique immunological changes occur during pregnancy; the impact of which, on virological and biochemical markers of hepatitis B infection is not well established. Rapid changes in the immunological profile post partum and consequent rebound of the inflammatory response may result in hepatic flares. METHODS: Women with chronic hepatitis B were recruited during pregnancy into this observational study. Demographic and clinical data were collected together with virological and biochemical parameters at two time points during pregnancy (early and late) and two time points post partum (between 6 weeks and 12 weeks and at 12 months). Outcomes analysed included changes in HBV DNA, hepatitis B e antigen (HBeAg) status and flares of hepatitis. RESULTS: One hundred and twenty-six women were recruited. Twenty-seven women out of 108 with postpartum bloods (25%) met our definition of a postpartum flare (ALT range 38-1654). Using univariate analysis HBeAg status, younger age, gravida and parity were associated with a flare. On multivariate analysis HBeAg positivity at baseline fell just outside of statistical significance in predicting a postpartum flare (p=0.051). CONCLUSIONS: 25% of women with chronic hepatitis B will demonstrate increased liver inflammation in the postpartum period. This is usually asymptomatic and resolves spontaneously. This is more likely if the woman is HBeAg-positive at baseline (2.56 times the risk), although flares also commonly occur in HBeAg-negative women. PMID- 25431460 TI - Muscular strength and physical function in elderly adults 6-18 months after a 12 week resistance exercise program. AB - AIMS: Benefits of resistance exercise in elderly people are well documented; however, sustaining these benefits can be difficult and adherence is often poor. Muscular strength and physical function usually decline after a supervised resistance exercise program (REP). We investigated these changes in older adults during an observational follow-up and whether leisure time physical activity (LTPA) or unsupervised resistance exercise (RE) limit these changes. METHODS: Subjects (N = 236, 73.7 +/- 5.7 years, 58.2% female) had participated in a supervised 12-week REP. Quadriceps strength and timed-up-and-go performance (TUG) at follow-up were compared to values before and after REP. Multivariate statistics were used to predict changes in strength or function. RESULTS: Two hundred and eleven (90.3%) participants completed REP and 149 (63.1%) completed follow-up (11.4 +/- 2.9 months). Quadriceps strength at follow-up decreased significantly compared to after REP (-27N), but was higher than before REP (+ 30N). TUG did not decrease during follow-up and was better than before REP (-0.9 seconds). LTPA (+ 38.0N, p < 0.001) and RE (+31.6N, p = 0.006) predicted strength at follow-up, although they did not completely prevent loss of strength during follow-up. CONCLUSIONS: quadriceps strength declines after a 12-week resistance exercise program in older adults. Neither LTPA nor RE completely prevents loss of quadriceps strength during follow-up, although they limited the loss. TUG did not change during follow-up and was better at follow-up than before the start of the resistance exercise program. PMID- 25431462 TI - Analysis of longitudinal censored semicontinuous data with application to the study of executive dysfunction: The Towers Task. AB - Executive dysfunction is a deficiency in skills of planning and problem solving that characterizes many neuropsychiatric disorders. The Towers Task is a commonly used measure of planning and problem solving for assessing executive function. Towers Task data are usually zero-inflated and right-censored, and ignoring these features can result in biased inference for the disease characterization of executive dysfunction. In this manuscript, a mixed-effects model for longitudinal censored semicontinuous data is developed for analyzing longitudinal Towers Task data from the PREDICT-HD study. The model is contrasted with current practice, and implications for general use are discussed. PMID- 25431464 TI - Republished: Cardiac MRI of patients with implanted electrical cardiac devices. AB - Implantable pulse generators and defibrillators have traditionally been considered contraindications to MRI. However, recent data have challenged this paradigm and demonstrated that patients with newer generation devices can safely undergo MRI, including cardiac MRI, provided basic precautions are taken. Indeed, the introduction of MRI conditional systems has led to a conceptual shift in clinical decision making-'can this patient undergo MRI safely?' is being superseded by 'should this patient be implanted with an MRI conditional device?'. This review outlines the risks associated with MRI in patients with implanted cardiac devices, and discusses practical measures to minimise risks and facilitate safe and diagnostic scanning. PMID- 25431461 TI - Joint UK societies' 2014 consensus statement on renal denervation for resistant hypertension. AB - Resistant hypertension continues to pose a major challenge to clinicians worldwide and has serious implications for patients who are at increased risk of cardiovascular morbidity and mortality with this diagnosis. Pharmacological therapy for resistant hypertension follows guidelines-based regimens although there is surprisingly scant evidence for beneficial outcomes using additional drug treatment after three antihypertensives have failed to achieve target blood pressure. Recently there has been considerable interest in the use of endoluminal renal denervation as an interventional technique to achieve renal nerve ablation and lower blood pressure. Although initial clinical trials of renal denervation in patients with resistant hypertension demonstrated encouraging office blood pressure reduction, a large randomised control trial (Symplicity HTN-3) with a sham-control limb, failed to meet its primary efficacy end point. The trial however was subject to a number of flaws which must be taken into consideration in interpreting the final results. Moreover a substantial body of evidence from non-randomised smaller trials does suggest that renal denervation may have an important role in the management of hypertension and other disease states characterised by overactivation of the sympathetic nervous system. The Joint UK Societies does not recommend the use of renal denervation for treatment of resistant hypertension in routine clinical practice but remains committed to supporting research activity in this field. A number of research strategies are identified and much that can be improved upon to ensure better design and conduct of future randomised studies. PMID- 25431465 TI - Republished: The association between inflammatory markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis. AB - OBJECTIVE: To examine the association of serum inflammatory markers (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) and serum lipid measures (low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol) with risk of myocardial infarction (MI) and ischaemic stroke (IS) among rheumatoid arthritis (RA) patients. METHODS: We conducted a retrospective cohort study using 2005-2010 data from a US commercial health plan. Eligible patients had two or more physician diagnoses of RA during a baseline period of at least 180 days with continuous medical and pharmacy coverage. We computed age-adjusted incidence rates of MI and IS, and used spline regression to assess non-linear associations and Cox-regression to quantify the independent association between the laboratory values and the outcomes. RESULTS: We identified 44 418 eligible RA patients (mean age 49 years; 76% women). CRP>10 mg/L compared with <1 mg/L was associated with increased MI risk (HR 2.12; 95% CI 1.02 to 4.38). ESR>42 mm/h compared with <14 mm/h was associated with increased risk of MI (HR 2.53; 95% CI 1.48 to 4.31) and IS (HR 2.51; 95% CI 1.33 to 4.75) risk. HDL-cholesterol >=60 mg/dL (1.6 mmol/L) compared with <40 mg/dL (1.0 mmol/L) was associated with reduced MI risk (HR 0.37; 0.21 to 0.66). The association between LDL and MI was not linear; the lowest risk was observed among patients with LDL between 70 mg/L (1.8 mmol/L) and 100 mg/L (2.6 mmol/L). We did not observe a significant association between LDL and IS. CONCLUSIONS: This study provides evidence supporting the hypothesis that RA-related systemic inflammation plays a role in determining cardiovascular risk and a complex relationship between LDL and cardiovascular risk. PMID- 25431466 TI - The breathtakingly simple facts of life. PMID- 25431467 TI - How to write a neurology newsletter. PMID- 25431470 TI - The view from the Acropolis.... PMID- 25431469 TI - Fidelity of implementation to a care team redesign and improved outcomes of diabetes care. AB - OBJECTIVE: We assessed fidelity of implementation (FOI) to the intended features of a primary care team redesign that integrated registered nurse care managers and patient health coaches onto existing care teams. The relation of FOI ranking and improvements in intermediate outcomes of diabetes care was examined. DESIGN: We assessed FOI by interviewing frontline primary care team members (n = 20). We explored the relation of FOI and outcomes of diabetes care (n = 10 206 patients) over a 3-year period (2010-12). Multilevel, multivariate regression estimated the relation of FOI and improvements in outcomes of diabetes care. SETTING: Five primary care practices in greater Los Angeles, CA, USA. PARTICIPANTS: Ten thousand, two hundred and six adult patients with diabetes; 20 frontline primary care clinicians and staff. MAIN OUTCOME MEASURES: Blood pressure, hemoglobin A1c (HbA1c) and low-density lipoprotein cholesterol (LDL-C) control among adult diabetic patients. RESULTS: All practices improved diabetic patients' LDL-C control over time. In adjusted analyses, the practice with the highest FOI achieved the largest improvement in blood pressure and HbA1c control among diabetic patients. In contrast, the practice with the lowest FOI had the least improvements in blood pressure, HbA1c and LDL-C control. FOI was an inconsistent predictor of intermediate outcomes of diabetes care for other practices. CONCLUSIONS: FOI assessment can be useful for identifying low FOI to a redesign so that technical assistance and resources can be provided to improve team functioning and patient outcomes. High FOI can enable greater improvements in patient outcomes in the context of primary care practice redesign. PMID- 25431468 TI - Cohort Profile Update: the TRacking Adolescents' Individual Lives Survey (TRAILS). AB - TRAILS consists of a population cohort (N=2230) and a clinical cohort (N=543), both of which were followed from about age 11 years onwards. To date, the population cohort has been assessed five times over a period of 11 years, with retention rates ranging between 80% and 96%. The clinical cohort has been assessed four times over a period of 8 years, with retention rates ranging between 77% and 85%. Since the IJE published a cohort profile on the TRAILS in 2008, the participants have matured from adolescents into young adults. The focus shifted from parents and school to entry into the labour market and family formation, including offspring. Furthermore, psychiatric diagnostic interviews were administered, the database was linked to a Psychiatric Case Registry, and the availability of genome-wide SNP variations opened the door to genome-wide association studies regarding a wide range of (endo)phenotypes. With some delay, TRAILS data are available to researchers outside the TRAILS consortium without costs; access can be obtained by submitting a publication proposal (see www.trails.nl). PMID- 25431471 TI - The international Ebola response: heroes and bystanders in the chronicle of an epidemic foretold. PMID- 25431473 TI - Factor VIII brand and immunogenicity. PMID- 25431472 TI - DNA barcoding of clinically relevant Cunninghamella species. AB - Mucormycosis caused, in part, by representatives of the genus Cunninghamella is a severe infection with high mortality in patients with impaired immunity. Several species have been described in the literature as etiologic agents. A DNA barcoding study using ITS rDNA and tef-1alpha provided concordance of molecular data with conventional characters. The currently accepted Cunninghamella species were well supported in phylogenetic trees of both markers except for C. septata with ITS that clustered in the C. echinulata clade. Sequence variability was distinctly higher for the ITS than for tef-1alpha. Intraspecific ITS variability of some of the species exceeded that between some closely related species, but the marker remained applicable for species identification. The most variable species for both markers was C. echinulata. Cunninghamella bertholletiae is the main pathogenic species; infections by C. blakesleeana, C. echinulata, and C. elegans are highly exceptional. PMID- 25431474 TI - Risk of RAS in relapsed childhood ALL. PMID- 25431475 TI - A FOXy target in B-cell survival. PMID- 25431476 TI - Allelic ratio: a marker of clonal dominance. PMID- 25431477 TI - A traffic jam to reduce morbidity in malaria. PMID- 25431478 TI - Eculizumab fails to inhibit generation of C5a in vivo. PMID- 25431479 TI - Ibrutinib-associated tumor lysis syndrome in a patient with chronic lymphocytic leukemia. PMID- 25431481 TI - Coalescent methods are robust to the simultaneous effects of long branches and incomplete lineage sorting. AB - It is well known that species with elevated substitution rates can give rise to disproportionately long branches in the species tree. This combination of long and short branches can contribute to long-branch artifacts (LBA). Despite efforts to remedy LBA via increased taxon sampling and methodological improvements in gene tree estimation, it remains unclear how long and short branches affect species tree estimation in the presence of incomplete lineage sorting (ILS). Here, we examine the combined influence of long external and short internal branches on concatenation and coalescent methods using both simulated and empirical data. Our results demonstrate that the presence of long and short branches alone does not obviously confound the consistency of concatenation and coalescent methods. However, when long external and short internal branches occur simultaneously with high ILS, concatenation methods can be misled, especially when two of these long branches are sister lineages. In contrast, coalescent methods are more robust under these circumstances. This is particularly relevant because this topological pattern also characterizes numerous ancient rapid radiations across the tree of life. Because short internal branches can increase the potential for ILS and gene tree discordance, our results collectively suggest that coalescent methods are more likely to infer the correct species tree in cases of ancient rapid radiations where long external and short internal branches are in close phylogenetic proximity. PMID- 25431482 TI - Head-to-toe whole-body MRI in psoriatic arthritis, axial spondyloarthritis and healthy subjects: first steps towards global inflammation and damage scores of peripheral and axial joints. AB - OBJECTIVES: By whole-body MRI (WBMRI), we aimed to examine the frequency and distribution of inflammatory and structural lesions in PsA patients, SpA patients and healthy subjects (HSs), to introduce global WBMRI inflammation/damage scores, and to assess WBMRI's reproducibility and correlation with conventional MRI (convMRI). METHODS: WBMRI (3.0-T) of patients with peripheral PsA (n = 18) or axial SpA (n = 18) and of HS (n = 12) was examined for proportion of evaluable features (readability) and the presence and pattern of lesions in axial and peripheral joints. Furthermore, global WBMRI scores of inflammation and structural damage were constructed, and WBMRI findings were compared with clinical measures and convMRI (SpA/HS: spine and SI joints; PsA/HS: hand). RESULTS: The readability (92-100%) and reproducibility (intrareader intraclass correlation coefficient: 0.62-1.0) were high in spine/SI joint, but lower in the distal peripheral joints. Wrists, shoulders, knees, ankles and MTP joints were most commonly involved, with frequency of synovitis > bone marrow oedema (BMO) > erosion. WBMRI global BMO scores of peripheral and axial joints were higher in PsA {median 7 [interquartile range (IQR) 3-15]} and SpA [8 (IQR 2-14)] than in HSs [2.5 (IQR 1-4.5)], both P < 0.05. WBMRI global structural damage scores (erosion, fat infiltration and ankylosis) were higher in SpA [7 (IQR 3-12)] than HSs [1.5 (IQR 0-4.5)], P = 0.012. Correlations between WBMRI and convMRI spine and SI joint scores were rho = 0.20-0.78. CONCLUSION: WBMRI allows simultaneous assessment of peripheral and axial joints in PsA and SpA, and the distribution of inflammatory and structural lesions and global scores can be determined. The study strongly encourages further development and longitudinal testing of WBMRI techniques and assessment methods in PsA and SpA. PMID- 25431480 TI - Genomic signatures reveal new evidences for selection of important traits in domestic cattle. AB - We investigated diverse genomic selections using high-density single nucleotide polymorphism data of five distinct cattle breeds. Based on allele frequency differences, we detected hundreds of candidate regions under positive selection across Holstein, Angus, Charolais, Brahman, and N'Dama. In addition to well-known genes such as KIT, MC1R, ASIP, GHR, LCORL, NCAPG, WIF1, and ABCA12, we found evidence for a variety of novel and less-known genes under selection in cattle, such as LAP3, SAR1B, LRIG3, FGF5, and NUDCD3. Selective sweeps near LAP3 were then validated by next-generation sequencing. Genome-wide association analysis involving 26,362 Holsteins confirmed that LAP3 and SAR1B were related to milk production traits, suggesting that our candidate regions were likely functional. In addition, haplotype network analyses further revealed distinct selective pressures and evolution patterns across these five cattle breeds. Our results provided a glimpse into diverse genomic selection during cattle domestication, breed formation, and recent genetic improvement. These findings will facilitate genome-assisted breeding to improve animal production and health. PMID- 25431484 TI - Tight control of rheumatoid arthritis in a resource-constrained setting: a randomized controlled study comparing the clinical disease activity index and simplified disease activity index. AB - OBJECTIVE: The aim of this study was to explore the clinical utility of the clinical disease activity index (CDAI). We compared the disease control with protocolized treatment adjustment following a tight control strategy utilizing either the simplified disease activity index (SDAI) or the CDAI. METHODS: In a prospective 12 month study, DMARD-naive RA patients were randomized to either a CDAI or SDAI arm and were treated with traditional DMARDs, increased on a monthly basis according to a predefined protocol to achieve low disease activity. RESULTS: Of 102 patients (84 females, 96 Black Africans), the mean symptom duration was 3.0 years (s.d. 3.8) and the mean 28-joint DAS (DAS28) at baseline was 6.2 (s.d. 1.2). By 12 months, the proportion of patients in the CDAI and SDAI groups achieving low disease activity (30% and 32%) and remission (33 and 34%) were similar. There were no significant differences in the mean DAS28 or its components or in HAQ Disability Index or health-related quality of life scores. Baseline predictors of low disease activity at 12 months were shorter symptom duration (P = 0.03) and lower HAQ-DI score (P = 0.04). CONCLUSION: Given that the CDAI performed as well as the SDAI, and considering the cost savings and convenience because no acute phase reactant test is necessary, we suggest the CDAI may be an appropriate tool for monthly disease activity monitoring as part of a tight control strategy in developing countries. PMID- 25431483 TI - Necrotizing and crescentic glomerulonephritis presenting with preserved renal function in patients with underlying multisystem autoimmune disease: a retrospective case series. AB - OBJECTIVE: Necrotizing and crescentic GN usually presents with rapidly declining renal function, often in association with multisystem autoimmune disease, with a poor outcome if left untreated. We aimed to describe the features of patients who have presented with these histopathological findings but minimal disturbance of renal function. METHODS: We conducted a retrospective review (1995-2011) of all adult patients with native renal biopsy-proven necrotizing or crescentic GN and normal serum creatinine (<120 MUmol/l) at our centre. RESULTS: Thirty-eight patients were identified. The median creatinine at presentation was 84 MUmol/l and the median proportion of glomeruli affected by necrosis or crescents was 32%. Clinicopathological diagnoses were ANCA-associated GN (74%), LN (18%), anti-GBM disease (5%) and HScP (3%). Only 18% of cases had pre-existing diagnoses of underlying multisystem autoimmune disease, although the majority (89%) had extra renal manifestations accompanying the renal diagnosis. All patients received immunosuppression and most had good long-term renal outcomes (median duration of follow-up 50 months), although two progressed to end-stage renal disease within 3 years. We estimate that renal biopsy had an important influence on treatment decisions in 82% of cases. CONCLUSION: Necrotizing and crescentic GN may present in patients with no or only minor disturbance of renal function. This often occurs in patients with underlying systemic autoimmune disease; early referral for biopsy may affect management and improve long-term outcomes in these cases. PMID- 25431485 TI - Effect of tube current modulation for dose estimation using a simulation tool on body CT examination. AB - The purpose of this study was to evaluate the effect of tube current modulation for dose estimation of a body computed tomography (CT) examination using a simulation tool. The authors also compared longitudinal variations in tube current values between iterative reconstruction (IR) and filtered back-projection (FBP) reconstruction algorithms. One hundred patients underwent body CT examinations. The tube current values around 10 organ regions were recorded longitudinally from tube current information. The organ and effective doses were simulated by average tube current values and longitudinal modulated tube current values. The organ doses for the bladder and breast estimated by longitudinal modulated tube current values were 20 % higher and 25 % lower than those estimated using the average tube current values, respectively. The differences in effective doses were small (mean, 0.7 mSv). The longitudinal variations in tube current values were almost the same for the IR and FBP algorithms. PMID- 25431486 TI - A biosphere assessment of high-level radioactive waste disposal in Sweden. AB - Licence applications to build a repository for the disposal of Swedish spent nuclear fuel have been lodged, underpinned by myriad reports and several broader reviews. This paper sketches out the technical and administrative aspects and highlights a recent review of the biosphere effects of a potential release from the repository. A comprehensive database and an understanding of major fluxes and pools of water and organic matter in the landscape let one envisage the future by looking at older parts of the site. Thus, today's biosphere is used as a natural analogue of possible future landscapes. It is concluded that the planned repository can meet the safety criteria and will have no detectable radiological impact on plants and animals. This paper also briefly describes biosphere work undertaken after the review. The multidisciplinary approach used is relevant in a much wider context and may prove beneficial across many environmental contexts. PMID- 25431487 TI - Radiation exposure to caregivers from patients undergoing common radionuclide therapies: a review. AB - The contribution of radionuclide therapies (RNTs) to effective patient treatment is widely appreciated. The administration of high doses has necessitated investigating the potential radiation hazard to caregivers from patients undergoing RNTs. This work aimed to review the literature regarding measured effective doses to caregivers from such patients. The main selection criterion was the presence of real radiation exposure measurements. The results were categorised according to the treatment protocol and dose parameters. Analysis of the collected data demonstrated that the measured effective dose values were within the dose constraints defined by the International Commission on Radiological Protection, provided that the radiation protection instructions were followed by both patients and caregivers. In conclusion, the radiation risk for caregivers was almost negligible. In this context, treatments could be administered more often on an outpatient basis, once cost-effectiveness criteria were established and radiation protection training and procedures were appropriately applied. PMID- 25431488 TI - Auditory hallucinations: debunking the myth of language supremacy. PMID- 25431489 TI - Interferon-lambda cures persistent murine norovirus infection in the absence of adaptive immunity. AB - Norovirus gastroenteritis is a major public health burden worldwide. Although fecal shedding is important for transmission of enteric viruses, little is known about the immune factors that restrict persistent enteric infection. We report here that although the cytokines interferon-alpha (IFN-alpha) and IFN-beta prevented the systemic spread of murine norovirus (MNoV), only IFN-lambda controlled persistent enteric infection. Infection-dependent induction of IFN lambda was governed by the MNoV capsid protein and correlated with diminished enteric persistence. Treatment of established infection with IFN-lambda cured mice in a manner requiring nonhematopoietic cell expression of the IFN-lambda receptor, Ifnlr1, and independent of adaptive immunity. These results suggest the therapeutic potential of IFN-lambda for curing virus infections in the gastrointestinal tract. PMID- 25431490 TI - Commensal microbes and interferon-lambda determine persistence of enteric murine norovirus infection. AB - The capacity of human norovirus (NoV), which causes >90% of global epidemic nonbacterial gastroenteritis, to infect a subset of people persistently may contribute to its spread. How such enteric viruses establish persistent infections is not well understood. We found that antibiotics prevented persistent murine norovirus (MNoV) infection, an effect that was reversed by replenishment of the bacterial microbiota. Antibiotics did not prevent tissue infection or affect systemic viral replication but acted specifically in the intestine. The receptor for the antiviral cytokine interferon-lambda, Ifnlr1, as well as the transcription factors Stat1 and Irf3, were required for antibiotics to prevent viral persistence. Thus, the bacterial microbiome fosters enteric viral persistence in a manner counteracted by specific components of the innate immune system. PMID- 25431492 TI - Catalytically active Au-O(OH)x-species stabilized by alkali ions on zeolites and mesoporous oxides. AB - We report that the addition of alkali ions (sodium or potassium) to gold on KLTL zeolite and mesoporous MCM-41 silica stabilizes mononuclear gold in Au-O(OH)x-(Na or K) ensembles. This single-site gold species is active for the low-temperature (<200 degrees C) water-gas shift (WGS) reaction. Unexpectedly, gold is thus similar to platinum in creating -O linkages with more than eight alkali ions and establishing an active site on various supports. The intrinsic activity of the single-site gold species is the same on irreducible supports as on reducible ceria, iron oxide, and titania supports, apparently all sharing a common, similarly structured gold active site. This finding paves the way for using earth abundant supports to disperse and stabilize precious metal atoms with alkali additives for the WGS and potentially other fuel-processing reactions. PMID- 25431497 TI - The Back Pocket Map: Social Class and Cultural Capital as Transferable Assets in the Advancement of Second-Generation Immigrants. AB - In this paper I move beyond current understandings of family- and school-related dynamics that explain the educational and occupational success of low-income immigrant children to investigate the role of cultural capital acquired in the country of origin. Class-related forms of knowledge acquired prior to migration can become invaluable assets in areas of destination through the realization of what Pierre Boutdieu calls habitus, that is, a series of embodied predispositions deployed by individuals in their pursuit of set objectives. Although the concept has attracted prolonged attention, the mechanisms by which the habitus is fulfilled remain unspecified. Here, I propose and examine three of those mechanisms: (a) cognitive correspondence, (b) positive emulation, and (c) active recollection. My study shows that class-related resources, like education, self definition, and remembrance of nation and ancestry play an important function, shaping youthful expectations and behaviors, and protecting the children of low income immigrants from downward mobility. PMID- 25431498 TI - Antioxidant Capacity of Rapeseed Extracts Obtained by Conventional and Ultrasound Assisted Extraction. AB - Ultrasound-assisted extraction (UAE) and conventional solid-liquid extraction were applied to extract total antioxidants from two rapeseed varieties. The antioxidant capacities (AC) of winter and spring rapeseed cultivars were determined by four different analytical methods: ferric reducing antioxidant power (FRAP), cupric reducing antioxidant capacity (CUPRAC), 2,2'-diphenyl-1 picrylhydrazyl (DPPH), 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS). The average AC of the studied rapeseed cultivars ranged between 4.21 10.03 mmol Trolox (TE)/100 g, 7.82-10.61 mmol TE/100 g, 8.11-51.59 mmol TE/100 g, 22.48-43.13 mmol TE/100 g for FRAP, CUPRAC, DPPH and ABTS methods, respectively. There are positive correlations between total phenolics (TPC = 804-1625 mg sinapic acid (SA)/100 g) and AC of the studied rapeseed extracts (r = 0.2650 0.9931). Results of the principal component analysis (PCA) indicate that there are differences between the total amounts of antioxidants in rapeseed samples extracted by different extraction techniques. Rapeseed extracts obtained after 18 min of ultrasonication revealed the highest content of total antioxidants. The UAE is a very useful, efficient and rapid technique of oilseed samples preparation for determination of AC by different analytical methods. PMID- 25431499 TI - Physiological and behavioural responses to weaning conflict in free-ranging primate infants. AB - Weaning, characterized by maternal reduction of resources, is both psychologically and energetically stressful to mammalian offspring. Despite the importance of physiology in this process, previous studies have reported only indirect measures of weaning stress from infants, because of the difficulties of collecting physiological measures from free-ranging mammalian infants. Here we present some of the first data on the relationship between weaning and energetic and psychological stress in infant mammals. We collected data on 47 free-ranging rhesus macaque infants on Cayo Santiago, Puerto Rico, showing that faecal glucocorticoid metabolite (fGCM) concentrations were directly related to the frequency of maternal rejection, with fGCM concentrations increasing as rates of rejection increased. Infants with higher fGCM concentrations also engaged in higher rates of mother following, and mother following was associated with increased time on the nipple, suggesting that infants that experienced greater weaning-related stress increased their efforts to maintain proximity and contact with their mothers. Infants experiencing more frequent rejection uttered more distress vocalizations when being rejected; however, there was no relationship between rates of distress vocalizations and fGCM concentrations, suggesting a disassociation between behavioural and physiological stress responses to weaning. Elevated glucocorticoid concentrations during weaning may function to mobilize energy reserves and prepare the infant for continued maternal rejection and shortage of energetic resources. PMID- 25431491 TI - Mosquito genomics. Extensive introgression in a malaria vector species complex revealed by phylogenomics. AB - Introgressive hybridization is now recognized as a widespread phenomenon, but its role in evolution remains contested. Here, we use newly available reference genome assemblies to investigate phylogenetic relationships and introgression in a medically important group of Afrotropical mosquito sibling species. We have identified the correct species branching order to resolve a contentious phylogeny and show that lineages leading to the principal vectors of human malaria were among the first to split. Pervasive autosomal introgression between these malaria vectors means that only a small fraction of the genome, mainly on the X chromosome, has not crossed species boundaries. Our results suggest that traits enhancing vectorial capacity may be gained through interspecific gene flow, including between nonsister species. PMID- 25431500 TI - Alcohol Exposure In Utero and Child Academic Achievement. AB - We examine the effect of alcohol exposure in utero on child academic achievement. As well as studying the effect of any alcohol exposure, we investigate the effect of the dose, pattern, and duration of exposure. We use a genetic variant in the maternal alcohol-metabolism gene ADH1B as an instrument for alcohol exposure, whilst controlling for the child's genotype on the same variant. We show that the instrument is unrelated to an extensive range of maternal and paternal characteristics and behaviours. OLS regressions suggest an ambiguous association between alcohol exposure in utero and children's academic attainment, but there is a strong social gradient in maternal drinking, with mothers in higher socio economic groups more likely to drink. In stark contrast to the OLS, the IV estimates show negative effects of prenatal alcohol exposure on child educational attainment. These results are very robust to an extensive set of model specifications. In addition, we show that that the effects are solely driven by the maternal genotype, with no impact of the child's genotype. PMID- 25431501 TI - Wheat ABA-insensitive mutants result in reduced grain dormancy. AB - This paper describes the isolation of wheat mutants in the hard red spring Scarlet resulting in reduced sensitivity to the plant hormone abscisic acid (ABA) during seed germination. ABA induces seed dormancy during embryo maturation and inhibits the germination of mature seeds. Wheat sensitivity to ABA gradually decreases with dry after-ripening. Scarlet grain normally fails to germinate when fully dormant, shows ABA sensitive germination when partially after-ripened, and becomes ABA insensitive when after-ripened for 8-12 months. Scarlet ABA insensitive (ScABI) mutants were isolated based on the ability to germinate on 5 uM ABA after only 3 weeks of after-ripening, a condition under which Scarlet would fail to germinate. Six independent seed-specific mutants were recovered. ScABI 1, ScABI2, ScABI3 and ScABI4 are able to germinate more efficiently than Scarlet at up to 25 uM ABA. The two strongest ABA insensitive lines, ScABI3 and ScABI4, both proved to be partly dominant suggesting that they result from gain of-function mutations. The ScABI1, ScABI2, ScABI3, ScABI4, and ScABI5 mutants after-ripen more rapidly than Scarlet. Thus, ABA insensi-tivity is associated with decreased grain dormancy in Scarlet wheat. This suggests that ABA sensitivity is an important factor controlling grain dormancy in wheat, a trait that impacts seedling emergence and pre-harvest sprouting resistance. PMID- 25431502 TI - sigma-Bond electron delocalization of branched oligogermanes and germanium containing oligosilanes. AB - In order to evaluate the influence of germanium atoms in oligo- and polysilanes, a number of oligosilane compounds were prepared where two or more silicon atoms were replaced by germanium. While it can be expected that the structural features of thus altered molecules do not change much, the more interesting question is, whether this modification would have a profound influence on the electronic structure, in particular on the property of sigma-bond electron delocalization. The UV-spectroscopic comparison of the oligosilanes with germanium enriched oligosilanes and also with oligogermanes showed a remarkable uniform picture. The expected bathochromic shift for oligogermanes and Ge-enriched oligosilanes was observed but its extent was very small. For the low energy absorption band the bathochromic shift from a hexasilane chain (256 nm) to a hexagermane chain with identical substituent patterns (259 nm) amounts to a mere 3 nm. PMID- 25431503 TI - A (Fluoroalkyl)Guanidine Modulates the Relaxivity of a Phosphonate-Containing T1 Shortening Contrast Agent. AB - Responsive magnetic resonance imaging (MRI) contrast agents, those that change their relaxivity according to environmental stimuli, have promise as next generation imaging probes in medicine. While several of these are known based on covalent modification of the contrast agents, fewer are known based on controlling non-covalent interactions. We demonstrate here accentuated relaxivity of a T1-shortening contrast agent, Gd-DOTP5- based on non-covalent, hydrogen bonding of Gd-DOTP5- with a novel fluorous amphiphile. By contrast to the phosphonate-containing Gd-DOTP5- system, the relaxivity of the analogous clinically approved contrast agent, Gd-DOTA- is unaffected by the same fluorous amphiphile under similar conditions. Mechanistic studies show that placing the fluorous amphiphile in proximity of the gadolinium center in Gd-DOTP5- caused an increase in tau m (bound-water residence lifetime or the inverse of water exchange rate, tau m = 1/kex) and an increase in tau R (rotational correlation time), with tau R being the factor driving enhanced relaxivity. Further, these effects were not observed when Gd-DOTA- was treated with the same fluorous amphiphile. Thus, Gd-DOTP5- and Gd-DOTA- respond to the fluorous amphiphile differently, presumably because the former binds to the amphiphile with higher affinity. (DOTP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraphosphonic acid; DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). PMID- 25431504 TI - Impaired development of fetal serotonergic neurons in intrauterine growth restricted baboons. AB - We studied development of the fetal serotonergic central nervous system in a baboon, non-human primate model of intrauterine growth restriction (IUGR). Fetal (90% of full-term) IUGR brains were comparable in size to controls, but have reduced expression of serotonergic proteins and mRNAs, as well as having fewer serotonergic neurons. PMID- 25431506 TI - Academic achievement and course taking among language minority youth in U.S. schools: Effects of ESL placement. AB - The 1974 Lau decision requires that U.S. public schools ensure a meaningful education for students learning English. English as a Second Language (ESL) placement is an institutional response to the linguistic needs of these students; however, its academic implications remain largely unexplored. Using nationally representative data from the Educational Longitudinal Study (ELS), the effects of ESL placement on college preparatory course enrollment and academic achievement of language minority students are estimated, first with fixed effects regression models and then with multi-level propensity score matching techniques. While numerous school and individual level factors beyond language proficiency predict ESL placement, a significant negative estimated effect of ESL placement on science enrollment and cumulative GPA is consistently found. Perhaps more important, however, no positive effects of ESL placement on the achievement of language minority youth are found when accounting for English proficiency and other potential covariates. PMID- 25431505 TI - Effort Deficits and Depression: The Influence of Anhedonic Depressive Symptoms on Cardiac Autonomic Activity During a Mental Challenge. AB - Motivational approaches to depression emphasize the role of dysfunctional motivational dynamics, particularly diminished reward and incentive processes associated with anhedonia. A study examined how anhedonic depressive symptoms, measured continuously across a wide range of severity, influenced the physiological mobilization of effort during a cognitive task. Using motivational intensity theory as a guide, we expected that the diminished incentive value associated with anhedonic depressive symptoms would reduce effort during a "do your best" challenge (also known as an unfixed or self-paced challenge), in which effort is a function of the value of achieving the task's goal. Using impedance cardiography, two cardiac autonomic responses were assessed: pre-ejection period (PEP), a measure of sympathetic activity and our primary measure of interest, and respiratory sinus arrhythmia (RSA), a measure of parasympathetic activity. As expected, PEP slowed from baseline to task as anhedonic depressive symptoms increased (as measured with the DASS Depression scale), indicating diminished effort-related sympathetic activity. No significant effects appeared for RSA. The findings support motivational intensity theory as a translational model of effort processes in depression and clarify some inconsistent effects of depressive symptoms on effort-related physiology found in past work. PMID- 25431507 TI - PREDICTION INTERVALS FOR INTEGRALS OF GAUSSIAN RANDOM FIELDS. AB - Methodology is proposed for the construction of prediction intervals for integrals of Gaussian random fields over bounded regions (called block averages in the geostatistical literature) based on observations at a finite set of sampling locations. Two bootstrap calibration algorithms are proposed, termed indirect and direct, aimed at improving upon plug-in prediction intervals in terms of coverage probability. A simulation study is carried out that illustrates the effectiveness of both procedures, and these procedures are applied to estimate block averages of chromium traces in a potentially contaminated region in Switzerland. PMID- 25431508 TI - SOCIAL SUPPORT, PSYCHOLOGICAL DISTRESS, AND PARENTING STRAINS IN MOTHERS OF VERY LOW BIRTHWEIGHT INFANTS. AB - This study investigated maternal psychological distress, perceptions of social supports, and parenting strains after the birth of a very low birthweight (VLBW) infant. Compared to mothers of term infants, mothers of VLBW infants had significantly higher incidence of psychological distress during the neonatal period, but did not differ from mothers of term infants in their feelings of role restriction, parenting competence, or social supports. Lower general social support predicted high distress levels, but only for mothers of VLBW infants. Mothers with a low sense of parenting competence, but support from spouse/partners reported lower maternal distress. PMID- 25431509 TI - Risk perception, motives and behaviours in university students. AB - Risky behaviours among young people are relatively frequent, with several motives and attitudes lying behind. Our objective was to evaluate the role of risk perception, attractiveness and motives for risk behaviour taking among university students in Lebanon. A cross-sectional study was carried out using a proportionate cluster sample of Lebanese students in public and private universities. Items of risk intake and perception scale, attractiveness of risky behaviours, and motives for risky behaviours were assessed, in addition to cigarette and waterpipe smoking and dependence, alcohol problematic consumption and mental distress scale. After verifying the validity of scales and reliability in the university students' population, we found that risk perception was associated with lower risk intake, while risk attractiveness was a driver for it. Moreover, motives differed in their driving of risky behaviour, a particular point was that women indicated more goal achievement objectives, the latter concept was associated with lower risk taking. University students in Lebanon, women in particular, demonstrated wiser behaviour and may benefit from heath education programme to increase their awareness about risky behaviours. Identifying other personal, environmental, social and psychological predictors may also be important to improve effectiveness of these programmes. PMID- 25431510 TI - I am no longer alone - How do university students perceive the possibilities of social media? AB - An increasing number of people have become users of social media, mostly looking for social contacts and networking. But what kind of social capital do social networking services (SNSs) provide? University students' (N = 90) experiences of and opinions on social media were studied through a semi-structured questionnaire. The following research questions were set for this study: (1) What kinds of benefits do university students perceive in the usage of social media? and (2) What kind of social capital does social media produce according to university students' opinions? Their answers were analysed with the qualitative content analysis method. The results revealed that SNSs can increase students' social capital in many ways, such as in the form of peer support groups and learning environments, and enhance bonding and communality in them. These possibilities should be better studied in educational contexts, as they can have a positive impact on students' well-being, engagement to studies and, thus, study success. PMID- 25431511 TI - Rural-to-urban migrations: acculturation experiences among university students in Botswana. AB - Many students in Botswana migrate from small rural villages and towns to the larger urban centres to attend university, and are subsequently required to adapt or acculturate to their new environments. However, the existing literature and research on acculturation experiences of students who migrate from rural-to-urban centres in Botswana is almost non-existent. The current study was therefore a qualitative exploratory investigation of the experiences of the students who migrate from rural-to-urban centres. Purposive sampling was used to recruit participants who contributed to a Talking Circle focus group. Researchers transcribed the interviews and used content analysis to uncover response themes. Findings indicated that the majority of students experienced some culture shock and a number of environmental and specific systemic stressors in their first two years of university life. Theoretical implications for understanding rural-to urban acculturation and practical implications for university counselling approaches are also discussed. PMID- 25431512 TI - Career unreadiness in relation to anxiety and authoritarian parenting among undergraduates. AB - Career unreadiness, covering career indecision and career myth, is an issue for universities to address. Supposedly, career unreadiness is responsible for the university student's anxiety and partly results from authoritarian parenting during the student's childhood. This is an uncharted concern for this study to clarify. The study surveyed 229 undergraduates in two universities in Hong Kong, China. It employed structural equation modelling to clarify nexuses among career unreadiness, authoritarian parenting and anxiety, after minimising their measurement errors. Career unreadiness mediated the negative effect of authoritarian parenting on anxiety. Nevertheless, authoritarian parenting still maintained a negative direct effect on anxiety, after controlling for career unreadiness. The findings imply that reducing undergraduates' career unreadiness is justifiable to prevent their anxiety. Such a reduction would benefit from neutralising the demands of authoritarian parenting. More fundamentally, diverting authoritarian parenting is advisable. PMID- 25431513 TI - Youth hedonistic behaviour: moderating role of peer attachment on the effect of religiosity and worldview. AB - This study was carried out on the moderating effect of peer attachment on the relationships between religiosity and worldview, and on how hedonistic behaviour among Malaysian undergraduate students is shaped by such influences. With regard to peer attachment, the study focused on the influences of communication, trust and alienation among youth. Bronfenbrenner's theory of human ecology and Armsden and Greenberg's attachment model were used as the framework. Drawing on a quantitative survey of 394 Malaysian university students (M age = 21.0, SD = 0.40), structural equation modelling and path analysis revealed a significant relationship between worldview and hedonistic behaviour. Peer attachment moderated the relationships between religiosity and religious worldview. The results further showed that the unique moderating effect of the lower level of attachment with peers is positively related to the hedonistic behaviour. Implications from the findings are discussed. PMID- 25431515 TI - Alkalinity production in intertidal sands intensified by lugworm bioirrigation. AB - Porewater profiles and sediment-water fluxes of oxygen, nutrients, pH, calcium, alkalinity, and sulfide were measured in intertidal sandflat sediments from the Oosterschelde mesotidal lagoon (The Netherlands). The influence of bioturbation and bioirrigation by the deep-burrowing polychaete Arenicola marina on the rates and sources of benthic alkalinity generation was examined by comparing measurements in intact and defaunated sediment cores before and after the addition of A. marina in summer and fall 2011. Higher organic matter remineralization rates, shallower O2 penetration, and greater sediment-water solute fluxes were observed in summer, consistent with higher sediment community metabolic rates at a higher temperature. Lugworm activity stimulated porewater exchange (5.1 * in summer, 1.9 * in fall), organic matter remineralization (6.2 * in summer, 1.9 * in fall), aerobic respiration (2.4 * in summer, 2.1 * in fall), alkalinity release (4.7 * in summer, 4.0 * in fall), nutrient regeneration, and iron cycling. The effects of lugworm activity on net sediment-water fluxes were similar but more pronounced in summer than in fall. Alkalinity release in fall was entirely driven by metabolic carbonate dissolution, while this process explained between 22 and 69% of total alkalinity production in summer, indicating the importance of other processes in this season. By enhancing organic matter remineralization and the reoxidation of reduced metabolites by the sediment microbial community, lugworm activity stimulated the production of dissolved inorganic carbon and metabolic acidity, which in turn enhanced metabolic CaCO3 dissolution efficiency. In summer, evidence of microbial long distance electron transport (LDET) was observed in defaunated sediment. Thus, alkalinity production by net carbonate dissolution was likely supplemented by anaerobic respiration and LDET in summer. PMID- 25431514 TI - HIV risk among young Ghanaians in high school: validation of a multidimensional attitude towards condom use scale. AB - Condom use remains low among sexually active youth in sub-Saharan Africa. Theoretical and empirical evidence suggests that attitudes towards condom use are important predictors of actual condom use. However, few attempts have been made to systematically develop a valid scale that measures attitudes towards condom use among youth, particularly high school students in sub-Saharan Africa. Using the health belief model, we developed an instrument that measures such attitudes. We analysed survey data collected from 6252 Ghanaian junior high school students. We assessed construct validity using confirmatory factor analysis. Results indicate that attitudes towards condom use among young Ghanaians are best represented by a multidimensional construct. Young Ghanaians differentiate constructs related to perception of benefits and barriers to condom use, as well as perception of severity and susceptibility to HIV. This instrument offers a valid tool for assessing high school students' attitudes towards condom use and their HIV risk. PMID- 25431516 TI - Learning and Remembering with Others: The Key Role of Retrieval in Shaping Group Recall and Collective Memory. AB - People frequently collaborate to learn and remember information, and this may help groups create a shared representation of the world (i.e., collective memories). However, contrary to intuitions, collaboration also lowers group recall levels. Such impairment occurs regardless of whether people collaborate when first experiencing, or encoding, an event (the collaborative encoding deficit), or when retrieving, or remembering, the event (the collaborative inhibition effect). In understanding how collaboration impairs group recall and enhances collective or shared memories it remains unknown as to where collaboration exerts the greatest influence - at encoding or at retrieval - to shape these distinct phenomena. The current study simultaneously compared collaboration at these two stages and revealed the power of collaborative retrieval. Collaboration impaired the group recall product at both time points, but especially so at retrieval. Furthermore, only collaborative retrieval played a significant role in the formation of collective memories. PMID- 25431517 TI - Bayesian Exploratory Factor Analysis. AB - This paper develops and applies a Bayesian approach to Exploratory Factor Analysis that improves on ad hoc classical approaches. Our framework relies on dedicated factor models and simultaneously determines the number of factors, the allocation of each measurement to a unique factor, and the corresponding factor loadings. Classical identification criteria are applied and integrated into our Bayesian procedure to generate models that are stable and clearly interpretable. A Monte Carlo study confirms the validity of the approach. The method is used to produce interpretable low dimensional aggregates from a high dimensional set of psychological measurements. PMID- 25431518 TI - Somebody's Children or Nobody's Children? How the Sociological Perspective Could Enliven Research on Foster Care. AB - Social scientists have long been concerned about how the fortunes of parents affect their children, with acute interest in the most marginalized children. Yet little sociological research considers children in foster care. In this review, we take a three-pronged approach to show why this inattention is problematic. First, we provide overviews of the history of the foster care system and how children end up in foster care, as well as an estimate of how many children ever enter foster care. Second, we review research on the factors that shape the risk of foster care placement and foster care caseloads and how foster care affects children. We close by discussing how a sociological perspective and methodological orientation-ranging from ethnographic observation to longitudinal mixed methods research, demographic methods, and experimental studies-can foster new knowledge around the foster care system and the families it affects. PMID- 25431519 TI - Does Encouragement by Others Increase Rape Reporting? Findings from a National Sample of Women. AB - Our study explores the role of victims' consultation with others about whether or not to report their rape to police. Three groups were observed within this sample of 435 rape victims from a national telephone household probability sample of women: those who did not consult with anyone about reporting (n = 364), those who consulted with someone and were encouraged to report to police (n = 40), and those who consulted with someone and were not encouraged to report (n = 31). Descriptive analyses indicated that the encouraged group was more likely to report to police than either of the other two groups (which did not differ from each other). Because there were no differences between the two consulting groups on demographic or rape-related variables, they were combined in subsequent analyses. Consulting with others about whether to report, peri-traumatic fear of injury or death, assault perpetration by a stranger, and concerns about contracting a sexually transmitted disease were significant predictors of reporting to police after controlling for other significant predictors in a multivariate regression analysis. Implications of these findings are discussed, including the benefits and consequences of formal rape reporting for victims, and the role that disclosure recipients may have in assisting victims post-rape (e.g., encouragement of reporting, emotional support). PMID- 25431520 TI - EFFECT OF DIET QUALITY ON NUTRIENT ALLOCATION TO THE TEST AND ARISTOTLE'S LANTERN IN THE SEA URCHIN LYTECHINUS VARIEGATUS (LAMARCK, 1816). AB - Small adult (19.50 +/- 2.01g wet weight) Lytechinus variegatus were fed eight formulated diets with different protein (12 to 36% dry weight as fed) and carbohydrate (21 to 39 % dry weight) levels. Each sea urchin (n = 8 per treatment) was fed a daily ration of 1.5% of the average body weight of all individuals for 9 weeks. Akaike information criterion scores were used to compare six different dietary composition hypotheses for eight growth measurements. For each physical growth response, different mathematical models representing a priori hypotheses were compared using the Akaike Information Criterion (AIC) score. The AIC is one of many information-theoretic approaches that allows for direct comparison of non-nested models with varying number of parameters. Dietary protein level and protein: energy ratio were the best models for prediction of test diameter increase. Dietary protein level was the best model of test with spines wet weight gain and test with spines dry matter production. When the Aristotle's lantern was corrected for size of the test, there was an inverse relationship with dietary protein level. Log transformed lantern to test with spines index was also best associated with the dietary protein model. Dietary carbohydrate level was a poor predictor for growth parameters. However, the protein * carbohydrate interaction model was the best model of organic content (% dry weight) of the test without spines. These data suggest that there is a differential allocation of resources when dietary protein is limiting and the test with spines, but not the Aristotle's lantern, is affected by availability of dietary nutrients. PMID- 25431521 TI - What can we learn from learning models about sensitivity to letter-order in visual word recognition? AB - Recent research on the effects of letter transposition in Indo-European Languages has shown that readers are surprisingly tolerant of these manipulations in a range of tasks. This evidence has motivated the development of new computational models of reading that regard flexibility in positional coding to be a core and universal principle of the reading process. Here we argue that such approach does not capture cross-linguistic differences in transposed-letter effects, nor do they explain them. To address this issue, we investigated how a simple domain general connectionist architecture performs in tasks such as letter-transposition and letter substitution when it had learned to process words in the context of different linguistic environments. The results show that in spite of of the neurobiological noise involved in registering letter-position in all languages, flexibility and inflexibility in coding letter order is also shaped by the statistical orthographic properties of words in a language, such as the relative prevalence of anagrams. Our learning model also generated novel predictions for targeted empirical research, demonstrating a clear advantage of learning models for studying visual word recognition. PMID- 25431522 TI - Family Violence and Children's Behavior Problems: Independent Contributions of Intimate Partner and Child-Directed Physical Aggression. AB - Using data from a diverse sample of 581 families living in predominantly low income, rural communities, the current study sought to investigate the longitudinal associations among father-perpetrated intimate partner violence (IPV) and child-directed physical aggression perpetrated by the mother. The unique contributions of each of these types of family violence on children's behavioral problems at school entry were also examined. Results confirm bidirectional associations between father-perpetrated IPV and maternal physical aggression directed toward the child, and indicate that both types of physical aggression contribute to child behavior problems at school entry. PMID- 25431523 TI - Adhesive forces and surface properties of cold gas plasma treated UHMWPE. AB - Cold atmospheric plasma (CAP) treatment was used on ultra-high molecular weight polyethylene (UHMWPE), a common articulating counter material employed in hip and knee replacements. UHMWPE is a biocompatible polymer with low friction coefficient, yet does not have robust wear characteristics. CAP effectively cross links the polymer chains of the UHMWPE improving wear performance (Perni et al., Acta Biomater. 8(3) (2012) 1357). In this work, interactions between CAP treated UHMWPE and spherical borosilicate sphere (representing model material for bone) were considered employing AFM technique. Adhesive forces increased, in the presence of PBS, after treatment with helium and helium/oxygen cold gas plasmas. Furthermore, a more hydrophilic surface of UHMWPE was observed after both treatments, determined through a reduction of up to a third in the contact angles of water. On the other hand, the asperity density also decreased by half, yet the asperity height had a three-fold decrease. This work shows that CAP treatment can be a very effective technique at enhancing the adhesion between bone and UHMWPE implant material as aided by the increased adhesion forces. Moreover, the hydrophilicity of the CAP treated UHMWPE can lead to proteins and cells adhesion to the surface of the implant stimulating osseointegration process. PMID- 25431524 TI - Enriching semantic knowledge bases for opinion mining in big data applications. AB - This paper presents a novel method for contextualizing and enriching large semantic knowledge bases for opinion mining with a focus on Web intelligence platforms and other high-throughput big data applications. The method is not only applicable to traditional sentiment lexicons, but also to more comprehensive, multi-dimensional affective resources such as SenticNet. It comprises the following steps: (i) identify ambiguous sentiment terms, (ii) provide context information extracted from a domain-specific training corpus, and (iii) ground this contextual information to structured background knowledge sources such as ConceptNet and WordNet. A quantitative evaluation shows a significant improvement when using an enriched version of SenticNet for polarity classification. Crowdsourced gold standard data in conjunction with a qualitative evaluation sheds light on the strengths and weaknesses of the concept grounding, and on the quality of the enrichment process. PMID- 25431525 TI - Explanation in personality psychology: "Verbal magic" and the five-factor model. AB - Scientific psychology involves both identifying and classifying phenomena of interest (description) and revealing the causes and mechanisms that contribute towards these phenomena arising (explanation). Within personality psychology, some propose that aspects of behavior and cognition can be explained with reference to personality traits. However, certain conceptual and logical issues cast doubt upon the adequacy of traits as coherent explanatory constructs. This paper discusses "explanation" in psychology and the problems of circularity and reification. An analysis of relations and intrinsic properties is then developed to address the logical requirements necessary for circumventing these problems. An examination of McCrae and Costa's defense of traits as explanatory constructs, in terms of "tendencies" and "dispositions" highlights logical issues that prevent traits, so defined, from explaining trait-like behaviors and cognitions. The logical requirements for a coherent trait-explanatory account are outlined and possible explanatory directions in trait-approaches are discussed. The ongoing tendency towards fallacious reasoning in psychology and suggestions for preventing this are further examined. PMID- 25431527 TI - Spatial and temporal variability of Alexandrium cyst fluxes in the Gulf of Maine: Relationship to seasonal particle export and resuspension. AB - Quantification of Alexandrium cyst fluxes through the Gulf of Maine water column is central to understanding the linkage between the source and fate of annual Alexandrium blooms in the offshore waters. These blooms often lead to paralytic shellfish poisoning (PSP) and extensive closures of shellfish beds. We report here on time-series sediment trap deployments completed at four offshore locations in the gulf between 2005 and 2010 as components of two ECOHAB-GOM field programs. Data presented documents the substantial spatial and temporal fluctuations in Alexandrium fundyense cyst fluxes in the gulf. Cyst delivery out of the euphotic zone peaked primarily between July and August following annual spring-summer Alexandrium blooms and was greatest in the western gulf. At all sites, cyst flux maxima to the subsurface waters were rarely coincident with seasonal peaks in the total mass export of particulate material indicating that cyst delivery was primarily via individually sinking cysts. Where persistent benthic nepheloid layers (BNLs) exist, significant sediment resuspension input of cysts to the near-bottom water column was evidenced by deep cyst fluxes that were up to several orders of magnitude greater than that measured above the BNL. The largest cyst fluxes in the BNL were observed in the eastern gulf, suggesting greater resuspension energy and BNL cyst inventories in this region. Temporal similarities between peak cyst export out of the upper ocean and peak cyst fluxes in the BNL were observed and document the contribution of seasonal, newly formed cysts to the BNL. The data however also suggest that many Alexandrium cells comprising the massive, short-lived blooms do not transition into cysts. Time series flow measurements and a simple 1D model demonstrate that the BNL cyst fluxes reflect the combined effects of tidal energy-maintained resuspension, deposition, and input of cysts from the overlying water column. PMID- 25431529 TI - Despite disparities, most LGBT elders are aging well. PMID- 25431526 TI - Modafinil effects on behavior and oxidative damage parameters in brain of wistar rats. AB - The effects of modafinil (MD) on behavioral and oxidative damage to protein and lipid in the brain of rats were evaluated. Wistar rats were given a single administration by gavage of water or MD (75, 150, or 300 mg/kg). Behavioral parameters were evaluated in open-field apparatus 1, 2, and 3 h after drug administration. Thiobarbituric acid reactive substances (TBARS) and protein carbonyl formation were measured in the brain. MD increased locomotor activity at the highest dose 1 and 3 h after administration. MD administration at the dose of 300 mg/kg increased visits to the center of open-field 1 h after administration; however, 3 h after administration, all administered doses of MD increased visits to the open-field center. MD 300 mg/kg increased lipid damage in the amygdala, hippocampus, and striatum. Besides, MD increased protein damage in the prefrontal cortex, amygdala, and hippocampus; however, this effect varies depending on the dose administered. In contrast, the administration of MD 75 and 300 mg/kg decreased the protein damage in the striatum. This study demonstrated that the MD administration induces behavioral changes, which was depending on the dose used. In addition, the effects of MD on oxidative damage parameters seemed to be in specific brain region and doses. PMID- 25431528 TI - Anxiety and Response to Reading Intervention among First Grade Students. AB - BACKGROUND: For school-aged children with reading difficulties, an emerging and important area of investigation concerns determining predictors of intervention response. Previous studies have focused exclusively on cognitive and broadly defined behavioral variables. What has been missing, however, are studies examining anxiety, which is among the most commonly experienced difficulty for youth. OBJECTIVE: The present study examined anxiety among children classified as typically achieving or showing inadequate/adequate response following an intervention for reading problems. METHODS: Participants were 153 ethnically diverse children (84 male, 69 female) evaluated in the winter and spring of their first-grade academic year. Children completed several standardized measures of reading achievement involving decoding and fluency along with a multidimensional anxiety rating scale. RESULTS: Repeated measures ANOVA revealed significant main effects for time and scale and significant interactions for time*scale and group*scale. Logistic regression examined whether anxiety predicted response to intervention (Y/N) at the end of the school-year. CONCLUSIONS: Results showed overall decreases in anxiety over time, with the exception of the harm avoidance area which increased and also interacted with group (children with decoding/fluency difficulties reported less harm avoidance than typically achieving children). The harm avoidance area was most pertinent across analyses highlighting the potential importance of targeting this area; however, none of the anxiety scales predicted response group at the end of the intervention. Ongoing research is needed in this area in order to identify characteristics of inadequate responders to reading intervention programs and/or inform interventions that incorporate these socioemotional factors. PMID- 25431530 TI - Elder Mistreatment among Chinese and Korean Immigrants: The Roles of Sociocultural Contexts on Perceptions and Help-Seeking Behaviors. AB - The purpose of this study was to identify dimensions of elder mistreatment in Chinese and Korean immigrant communities and to increase sociocultural understanding of such mistreatment by elucidating the complexities of abuse embedded in unique social and cultural contexts. In-depth interviews were conducted with 20 local professionals working primarily in Asian elderly advocacy, and six focus group discussions were conducted involving 60 community members in the San Francisco Bay area. Five dimensions of elder mistreatment were identified: psychological abuse, neglect by a trusted person, financial exploitation, physical abuse, and sexual abuse. In general, fewer Korean community member participants reported having observed physical or financial abuse than Chinese groups, but they reported greater knowledge of situations involving psychological abuse, neglect by a trusted person, and sexual abuse. The contexts of cultural influences and immigration and acculturation were salient themes that shaped participants' subjective perceptions and beliefs about elder abuse and hence help-seeking behaviors. PMID- 25431531 TI - Throwing Away the Key: The Ethics of Risk Assessment for Preventive Detention Schemes: R.G. Myers Memorial Lecture 2013. AB - Preventive detention schemes that aim to protect the community from certain 'dangerous' individuals have long existed. While risk assessment is now pervasive in the management and treatment of many individuals, it raises particular issues when a person's liberty is at stake on the basis of what that person might do. This R.G. Myers Memorial Lecture addresses the ethical issues raised by mental health practitioners providing risk assessments for legislative schemes that involve the deprivation of liberty. It will focus in particular on Australian post-sentence preventive detention schemes for sex offenders that have been held by the United Nations Human Rights Committee to breach fundamental human rights. However, the ethical issues discussed also have repercussions for civil commitment laws that enable the detention of those with severe mental or intellectual impairments. PMID- 25431532 TI - Perceptions of sugar mommy practices in South Africa. AB - The study sought to explore sugar mommy practices regarding their occurrence, acceptability as well as perceived reasons why older women and younger men enter into sugar mommy relationships. An exploratory qualitative study involving 135 participants from 11 diverse focus groups in terms of age, gender (females=27%) and geotype throughout the nine South African provinces was conducted. Data on the participants' views, opinions and experiences of sugar mommy practices were collected using focus group interviews. The data were thematically analyzed. The study found that sugar mommy practices were prevalent in South Africa. The perceived reasons for acceptability were: love, survival, and correctness. Perceived reasons why older women have sexual relationships with younger men included: sexual fulfilment, domination, reduction of stress, physical attraction, procreation, lack of self-control, youthful feeling, migrancy, difficulty in finding partners of compatible age and young men being seen as not demanding. Perceived reasons why younger men have sexual relationships with older women included: material gain, reduction of stress, being enticed, rejection by women of compatible age, peer influence and belief that older women are purer. Given the increase in sugar mommy practices, which may have significant implications for the prevalence of HIV/AIDS, it is necessary to understand the underlying perceptions of these practices, in order to develop culturally relevant and socially acceptable intervention programmes. PMID- 25431534 TI - Governing stem cell therapy in India: regulatory vacuum or jurisdictional ambiguity? AB - Stem cell treatments are being offered in Indian clinics although preclinical evidence of their efficacy and safety is lacking. This is attributed to a governance vacuum created by the lack of legally binding research guidelines. By contrast, this paper highlights jurisdictional ambiguities arising from trying to regulate stem cell therapy under the auspices of research guidelines when treatments are offered in a private market disconnected from clinical trials. While statutory laws have been strengthened in 2014, prospects for their implementation remain weak, given embedded challenges of putting healthcare laws and professional codes into practice. Finally, attending to the capacities of consumer law and civil society activism to remedy the problem of unregulated treatments, the paper finds that the very definition of a governance vacuum needs to be reframed to clarify whose rights to health care are threatened by the proliferation of commercial treatments and individualized negligence-based remedies for grievances. PMID- 25431533 TI - A community-based intervention in middle schools to improve HPV vaccination and cervical cancer screening in Japan. AB - AIM: Japan has low rates of cervical cancer screening and Human papilloma virus (HPV) vaccination. This research examines the effectiveness of a family medicine resident-led, intervention in increasing knowledge about HPV and cervical cancer in middle school-girls and increasing knowledge and intention to have cervical cancer screening in their mothers. METHODS: We utilized a pre-test/post-test intervention design in three rural middle schools with 7(th) grade middle school girls and their mothers. A school-based activity educated girls about HPV and cervical cancer. A home-based activity utilized a homework assignment for girls and their mothers. Pre/post intervention surveys were completed by the girls and their mothers. Major outcomes included changes in knowledge among girls and mothers and barriers to be screened for cervical cancer among mothers. RESULTS: Sixty-five students and sixty-three mothers completed the study. Two out five mothers were not in compliance with current screening recommendations. Identified barriers included: embarrassment (79%), poor access (56%), fear of having cancer (52%), and cervical cancer screening being an unknown procedure (46%). Forty-four percent of mothers deemed their daughters to be at risk for cervical cancer. Trusted sources of information included: doctors (97%), newspapers/television (89%), government (79%), the Internet (78%), and friends (62%). Student knowledge scores (7-point scale) improved significantly from pre- to post-intervention (4.8 vs. 5.9, p < 0.001). Knowledge scores (14-point scale) among mothers also significantly improved (11.7 vs. 12.0, p = 0.024). CONCLUSIONS: These data suggest a community-based intervention on a sensitive topic by family medicine residents can be implemented in middle schools, can improve school-girls' knowledge about HPV and cervical cancer, and can reach their mothers. Additional research could examine whether those intending to be screened receive screening and how to reach women who still resist screening. PMID- 25431535 TI - International law, public health, and the meanings of pharmaceuticalization. AB - Recent social science scholarship has employed the term "pharmaceuticalization" in analyses of the production, circulation and use of drugs. In this paper, we seek to open up further discussion of the scope, limits and potential of this as an analytical device through consideration of the role of law and legal processes in directing pharmaceutical flows. To do so, we synthesize a range of empirical and conceptual work concerned with the relationships between access to medicines and intellectual property law. This paper suggests that alongside documenting the expansion or reduction in demand for particular drugs, analysts of pharmaceuticalization attend to the ways in which socio-legal developments change (or not) the identities of drugs, and the means through which they circulate and come to be used by states and citizens. Such scholarship has the potential to more precisely locate the biopolitical processes that shape international agendas and targets, form markets, and produce health. PMID- 25431536 TI - Attitudes of nurses and physicians towards nurse-physician collaboration in northwest Ethiopia: a hospital based cross-sectional study. AB - BACKGROUND: Collaboration between professionals is important in health institutions where most activities are team-performed. Ineffective nurse physician collaboration affects patient outcome, nurses' job satisfaction and organizational cost and is challenged by personal, interpersonal and organizational factors. The main objective of this study was to assess attitudes of nurses and physicians towards nurse-physician collaboration and the level of satisfaction with regard to quality of collaboration between them at Referral Hospitals of Northwest Ethiopia, from February 1st to April 30, 2013. METHODS: An institution based cross-sectional study was conducted among 176 nurses and 53 physicians working in Felegehiwot and Gondar University Referral Hospitals. Data were collected using self-administered questionnaires. Attitudes of nurses and physicians were measured using Jefferson scale of attitudes towards nurse physician Collaboration. Results were summarized using descriptive statistics and difference of means and proportions were evaluated using student t test p <0.05 was considered as significant. RESULT: The overall response rate was 90.50%. Nurses demonstrate more favorable attitudes than physicians with mean score of 49.63 and 47.49 and standard error of mean 0.474 and 0.931 respectively with p = 0.043. For the Jefferson Scale Attitudes towards Nurse-Physician Collaboration includes four subscales, which are: 1) shared education and teamwork, 2) Caring vs curing, 3) nurses autonomy and 4) physician dominance. Nurses scored higher on three subscales (1, 2 and 4). However, statistically significant differences were noted with regard to subscales 2 and 4 (p = 0.01, p = 0.004, respectively). CONCLUSION: This study identified that neither nurses nor physicians were satisfied with their current collaboration and nurses demonstrated less satisfaction with the current nurse physician collaboration. As compared with physicians nurses had more favorable attitudes towards collaboration specifically toward nurses' contributions to the psychosocial and educational aspects of patient care, and stronger rejection of a totally dominant physician role. PMID- 25431537 TI - The Nature and Predictive Value of Mothers' Beliefs Regarding Infants' and Toddlers' TV/Video Viewing: Applying the Integrative Model of Behavioral Prediction. AB - Viewing television and video programming has become a normative behavior among US infants and toddlers. Little is understood about parents' decision-making about the extent of their young children's viewing, though numerous organizations are interested in reducing time spent viewing among infants and toddlers. Prior research has examined parents' belief in the educational value of TV/videos for young children and the predictive value of this belief for understanding infant/toddler viewing rates, though other possible salient beliefs remain largely unexplored. This study employs the integrative model of behavioral prediction (Fishbein & Ajzen, 2010) to examine 30 maternal beliefs about infants' and toddlers' TV/video viewing which were elicited from a prior sample of mothers. Results indicate that mothers tend to hold more positive than negative beliefs about the outcomes associated with young children's TV/video viewing, and that the nature of the aggregate set of beliefs is predictive of their general attitudes and intentions to allow their children to view, as well as children's estimated viewing rates. Analyses also uncover multiple dimensions within the full set of beliefs, which explain more variance in mothers' attitudes and intentions and children's viewing than the uni-dimensional index. The theoretical and practical implications of the findings are discussed. PMID- 25431538 TI - Passing in Command Line Arguments and Parallel Cluster/Multicore Batching in R with batch. AB - It is often useful to rerun a command line R script with some slight change in the parameters used to run it - a new set of parameters for a simulation, a different dataset to process, etc. The R package batch provides a means to pass in multiple command line options, including vectors of values in the usual R format, easily into R. The same script can be setup to run things in parallel via different command line arguments. The R package batch also provides a means to simplify this parallel batching by allowing one to use R and an R-like syntax for arguments to spread a script across a cluster or local multicore/multiprocessor computer, with automated syntax for several popular cluster types. Finally it provides a means to aggregate the results together of multiple processes run on a cluster. PMID- 25431539 TI - Religiosity After a Diagnosis of Cancer Among Older Adults. AB - Aspects of religiosity are important to health and quality of life of cancer patients. This analysis examined changes in religiosity among community-dwelling cancer survivors. Previously diagnosed and newly diagnosed cancer survivors age 65+ were interviewed at baseline and four years later to understand how components of religiosity may change. Religiosity was assessed as organizational, non-organizational, and intrinsic using the Duke Religiosity Scale. At four years, 45 persons had a new diagnosis of non-skin cancer in addition to the 94 diagnosed at baseline. In comparison to persons without a cancer diagnosis and participants with a baseline diagnosis, newly diagnosed participants were more likely to decrease church attendance. Although not statistically significant, a larger proportion of recently diagnosed persons increased non-organizational religiosity behaviors and intrinsic religiosity compared to those with cancer at baseline and those without cancer. African Americans were more likely than Caucasians to show increased non-organizational religiosity. Caucasians with a cancer diagnosis showed increased intrinsic religiosity, perhaps because of a ceiling effect among African Americans. Although all groups showed declines and increases in the measures, baseline religiosity was the strongest predictor of religiosity at 48 months, indicating stability in religiosity over time, even in the context of a cancer diagnosis. PMID- 25431540 TI - Evaluation of publicly available documents to trace chiropractic technique systems that advocate radiography for subluxation analysis: a proposed genealogy. AB - OBJECTIVE: The purpose of this study was to evaluate publicly available information of chiropractic technique systems that advocate radiography for subluxation detection to identify links between chiropractic technique systems and to describe claims made of the health effects of the osseous misalignment component of the chiropractic subluxation and radiographic paradigms. METHODS: The Internet and publicly available documents were searched for information representing chiropractic technique systems that advocate radiography for subluxation detection. Key phrases including chiropractic, x-ray, radiography, and technique were identified from a Google search between April 2013 and March 2014. Phrases in Web sites and public documents were examined for any information about origins and potential links between these techniques, including the type of connection to BJ Palmer, who was the first chiropractor to advocate radiography for subluxation detection. Quotes were gathered to identify claims of health effects from osseous misalignment (subluxation) and paradigms of radiography. Techniques were grouped by region of the spine and how they could be traced back to B.J Palmer. A genealogy model and summary table of information on each technique were created. Patterns in year of origination and radiographic paradigms were noted, and percentages were calculated on elements of the techniques' characteristics in comparison to the entire group. RESULTS: Twenty three techniques were identified on the Internet: 6 full spine, 17 upper cervical, and 2 techniques generating other lineage. Most of the upper cervical techniques (14/16) traced their origins to a time when the Palmer School was teaching upper cervical technique, and all the full spine techniques (6/6) originated before or after this phase. All the technique systems' documents attributed broad health effects to their methods. Many (21/23) of the techniques used spinal realignment on radiographs as one of their outcome measures. CONCLUSION: Chiropractic technique systems in this study (ie, those that advocate for radiography for subluxation misalignment detection) seem to be closely related by descent, their claims of a variety of health effects associated with chiropractic subluxation, and their radiographic paradigms. PMID- 25431541 TI - Chiropractic professionalization and accreditation: an exploration of the history of conflict between worldviews through the lens of developmental structuralism. AB - OBJECTIVE: The purpose of this commentary is to describe the conflicts in the history of chiropractic's professionalization and conflict through the path of increasing educational standards and accreditation using the lens of developmental structuralism. DISCUSSION: Within the story of chiropractic's professionalization and accreditation lie the battles between competing worldviews. Gibbons proposed 4 periods of chiropractic's educational history; this article proposes a fifth period along with a new methodological approach to explore the complexity of chiropractic's history. The methodology draws upon constructive developmental psychology and proposes 5 levels of thinking common to the individuals from chiropractic's history. By using a psychological framework to analyze historical events, it appears that the battle within chiropractic education continues at present. Several important issues are explored: the Council on Chiropractic Education's origins in the medical paradigm and rational thinking, the pre-rational, rational, and post-rational critics of the Council on Chiropractic Education, the schools of thought that were reified or emerged from the history, as well as the more recent legal, economic, and social pressures, which helped to shape chiropractic's accreditation and professionalization. CONCLUSION: A transrational approach, one that includes the partial truths of all perspectives, is a first step to allow for a richer understanding of how the interior worldviews, individual actions, and the exterior forces (legal, economic, political, and educational) brought forth the chiropractic clashes together. Viewing the conflicts within chiropractic from this approach may foster new educational structures to evolve. PMID- 25431542 TI - Improving Our Nation's Health Care System: Inclusion of Chiropractic in Patient Centered Medical Homes and Accountable Care Organizations. AB - OBJECTIVE: This report summarizes the closing plenary session of the Association of Chiropractic Colleges Educational Conference-Research Agenda Conference 2014. The purpose of this session was to examine patient-centered medical homes and accountable care organizations from various speakers' viewpoints and to discuss how chiropractic could possibly work within, and successfully contribute to, the changing health care environment. DISCUSSION: The speakers addressed the complex topic of patient-centered medical homes and accountable care organizations and provided suggestions for what leadership strategies the chiropractic profession may need to enhance chiropractic participation and contribution to improving our nation's health. CONCLUSION: There are many factors involved in the complex topic of chiropractic inclusion in health care models. Major themes resulting from this panel included the importance of building relationships with other professionals, demonstrating data and evidence for what is done in chiropractic practice, improving quality of care, improving health of populations, and reducing costs of health care. PMID- 25431543 TI - Learning from a lifetime of leading effective change. AB - OBJECTIVE: The purpose of this article is to report on the opening plenary session of the Association of Chiropractic Colleges Educational Conference Research Agenda Conference (ACC-RAC) 2014, "Aiming for Effective Change: Leadership in Chiropractic Education, Research and Clinical Practice." DISCUSSION: Speakers with extensive backgrounds with implementing substantial change on a broad level shared personal examples from their experiences in education, research, political organizations, and clinical practice. They described efforts, challenges, and opportunities that are encountered in order to implement effective change and shared their personal thoughts on leadership. CONCLUSION: Each of the speakers shared their diverse, unique insights and personal experiences to convey the process and meaning of leadership. PMID- 25431544 TI - An Analysis Pipeline with Statistical and Visualization-Guided Knowledge Discovery for Michigan-Style Learning Classifier Systems. AB - Michigan-style learning classifier systems (M-LCSs) represent an adaptive and powerful class of evolutionary algorithms which distribute the learned solution over a sizable population of rules. However their application to complex real world data mining problems, such as genetic association studies, has been limited. Traditional knowledge discovery strategies for M-LCS rule populations involve sorting and manual rule inspection. While this approach may be sufficient for simpler problems, the confounding influence of noise and the need to discriminate between predictive and non-predictive attributes calls for additional strategies. Additionally, tests of significance must be adapted to M LCS analyses in order to make them a viable option within fields that require such analyses to assess confidence. In this work we introduce an M-LCS analysis pipeline that combines uniquely applied visualizations with objective statistical evaluation for the identification of predictive attributes, and reliable rule generalizations in noisy single-step data mining problems. This work considers an alternative paradigm for knowledge discovery in M-LCSs, shifting the focus from individual rules to a global, population-wide perspective. We demonstrate the efficacy of this pipeline applied to the identification of epistasis (i.e., attribute interaction) and heterogeneity in noisy simulated genetic association data. PMID- 25431546 TI - When Do Socioeconomic Resources Matter Most in Early Childhood? AB - Research has established the importance of early socioeconomic advantage and disadvantage for understanding later life outcomes, but less is known about change in the relationship between socioeconomic status (SES) and child development within the period of early childhood. Competing hypotheses drawn from the literature posited: (1) a stable SES-development relationship, (2) a stronger relationship in infancy than at older ages, and (3) a stronger relationship at school entry than at younger ages. Using the nationally representative Early Childhood Longitudinal Study-Birth Cohort (2001-2007), we followed 8600 children from infancy through kindergarten entry to model change over time in the relationship between socioeconomic status and cognitive and behavioral development. The unexpected main finding was that the relationships between three socioeconomic measures (household income, assets, and maternal educational attainment) strengthened from infancy through age 4 or 41/2, then weakened slightly until the start of kindergarten. Indirect evidence suggested preschool education as one possible explanation. We argue for researchers to expand the school transition concept to include the now widespread prekindergarten year, as well as for attention to psychological and physiological developmental factors that may shape the relationship between SES and cognitive and behavioral development throughout early childhood. PMID- 25431547 TI - What do older people value when they visit their general practitioner? A qualitative study. AB - Older patients see their general practitioners (GPs) relatively often and so recognition of their preferences can lead to improvement of quality of care in general practice. This study aimed to identify which aspects of GPs' behaviour are the most important for older people in their assessment of the quality of their visits and to explore the application of Jung's taxonomy differentiating task and affective behaviour in this context. A qualitative approach to generating data was chosen. We conducted semi-structured interviews with a sample of 30 patients aged 65 and older using GP services in two demographically diverse big cities in Poland. Participants were interviewed in 2010 according to a pre determined topic guide. This research showed that older people assess both 'task performance' and 'affective performance' behaviours of general practitioners. There were nearly twice as many patient comments concerning affective performance behaviour relative to task performance behaviour. Older people expect that their physicians will be demonstrably friendly, kind, able to joke and have enough time for the consultation. PMID- 25431545 TI - The Anti-Inflammatory Actions of Exercise Training. AB - The list of diseases with a known inflammatory etiology is growing. Cardiovascular disease, osteoporosis, diabetes, geriatric cachexia, and Alzheimer's disease have all been shown to be linked to or exacerbated by aberrantly regulated inflammatory processes. Nevertheless, there is mounting evidence that those who are physically active, or who become physically active, have a reduction in biomarkers associated with chronic inflammation. There was strong early consensus that exercise-induced reductions in inflammation were explained by body mass index or body fatness, but recent studies provide support for the contention that exercise has body fat-independent anti-inflammatory effects. With few exceptions, the anti-inflammatory effects of exercise appear to occur regardless of age or the presence of chronic diseases. What remains unclear are the mechanisms by which exercise training induces these anti-inflammatory effects, but there are several intriguing possibilities, including release of endogenous products, such as heat shock proteins; selective reduction of visceral adipose tissue mass or reducing infiltration of adipocytes by macrophages; shift in immune cell phenotype; cross-tolerizing effects; or exercise-induced shifts in accessory proteins of toll-like receptor signaling. However, future research endeavors are likely to uncover additional potential mechanisms, and it could be some time before functional mechanisms are made clear. In summary, the potential anti-inflammatory influences of exercise training may provide a low-cost, readily available, and effective treatment for low-grade systemic inflammation and could contribute significantly to the positive effects of exercise training on chronic disease. PMID- 25431548 TI - De-regulation of gene expression and alternative splicing affects distinct cellular pathways in the aging hippocampus. AB - Aging is accompanied by gradually increasing impairment of cognitive abilities and constitutes the main risk factor of neurodegenerative conditions like Alzheimer's disease (AD). The underlying mechanisms are however not well understood. Here we analyze the hippocampal transcriptome of young adult mice and two groups of mice at advanced age using RNA sequencing. This approach enabled us to test differential expression of coding and non-coding transcripts, as well as differential splicing and RNA editing. We report a specific age-associated gene expression signature that is associated with major genetic risk factors for late onset AD (LOAD). This signature is dominated by neuroinflammatory processes, specifically activation of the complement system at the level of increased gene expression, while de-regulation of neuronal plasticity appears to be mediated by compromised RNA splicing. PMID- 25431549 TI - Intermingled cAMP, cGMP and calcium spatiotemporal dynamics in developing neuronal circuits. AB - cAMP critically modulates the development of neuronal connectivity. It is involved in a wide range of cellular processes that require independent regulation. However, our understanding of how this single second messenger achieves specific modulation of the signaling pathways involved remains incomplete. The subcellular compartmentalization and temporal regulation of cAMP signals have recently been identified as important coding strategies leading to specificity. Dynamic interactions of this cyclic nucleotide with other second messenger including calcium and cGMP are critically involved in the regulation of spatiotemporal control of cAMP. Recent technical improvements of fluorescent sensors facilitate cAMP monitoring, whereas optogenetic tools permit spatial and temporal control of cAMP manipulations, all of which enabled the direct investigation of spatiotemporal characteristics of cAMP modulation in developing neurons. Focusing on neuronal polarization, neurotransmitter specification, axon guidance, and refinement of neuronal connectivity, we summarize herein the recent advances in understanding the features of cAMP signals and their dynamic interactions with calcium and cGMP involved in shaping the nervous system. PMID- 25431550 TI - Effect of histone deacetylase inhibitors trichostatin A and valproic acid on hair cell regeneration in zebrafish lateral line neuromasts. AB - In humans, auditory hair cells are not replaced when injured. Thus, cochlear hair cell loss causes progressive and permanent hearing loss. Conversely, non mammalian vertebrates are capable of regenerating lost sensory hair cells. The zebrafish lateral line has numerous qualities that make it well-suited for studying hair cell development and regeneration. Histone deacetylase (HDAC) activity has been shown to have an important role in regenerative processes in vertebrates, but its function in hair cell regeneration in vivo is not fully understood. Here, we have examined the role of HDAC activity in hair cell regeneration in the zebrafish lateral line. We eliminated lateral line hair cells of 5-day post-fertilization larvae using neomycin and then treated the larvae with HDAC inhibitors. To assess hair cell regeneration, we used 5-bromo-2 deoxyuridine (BrdU) incorporation in zebrafish larvae to label mitotic cells after hair cell loss. We found that pharmacological inhibition of HDACs using trichostatin A (TSA) or valproic acid (VPA) increased histone acetylation in the regenerated neuromasts following neomycin-induced damage. We also showed that treatment with TSA or VPA decreased the number of supporting cells and regenerated hair cells in response to hair cell damage. Additionally, BrdU immunostaining and western blot analysis showed that TSA or VPA treatment caused a significant decrease in the percentage of S-phase cells and induced p21(Cip1) and p27(Kip1) expression, both of which are likely to explain the decrease in the amount of newly regenerated hair cells in treated embryos. Finally, we showed that HDAC inhibitors induced no observable cell death in neuromasts as measured by cleaved caspase-3 immunohistochemistry and western blot analysis. Taken together, our results demonstrate that HDAC activity has an important role in the regeneration of hair cells in the lateral line. PMID- 25431551 TI - FOXP2, retinoic acid, and language: a promising direction. PMID- 25431552 TI - Dendritic orientation and branching distinguish a class of multifunctional turtle spinal interneurons. AB - Spinal interneurons can integrate diverse propriospinal and supraspinal inputs that trigger or modulate locomotion and other limb movements. These synaptic inputs can occur on distal dendrites and yet must remain effective at the soma. Active dendritic conductances may amplify distal dendritic inputs, but appear to play a minimal role during scratching, at least. Another possibility is that spinal interneurons that integrate inputs on distal dendrites have unusually simple dendritic trees that effectively funnel current to the soma. We previously described a class of spinal interneurons, called transverse interneurons (or T neurons), in adult turtles. T neurons were defined as having dendrites that extend further in the transverse plane than rostrocaudally and a soma that extends further mediolaterally than rostrocaudally. T neurons are multifunctional, as they were activated during both swimming and scratching motor patterns. T neurons had higher peak firing rates and larger membrane potential oscillations during scratching than scratch-activated interneurons with different dendritic morphologies ("non-T" neurons). These characteristics make T neurons good candidates to play an important role in integrating diverse inputs and generating or relaying rhythmic motor patterns. Here, we quantitatively investigated additional dendritic morphological characteristics of T neurons as compared to non-T neurons. We found that T neurons have less total dendritic length, a greater proportion of dendritic length in primary dendrites, and dendrites that are oriented more mediolaterally. Thus, T neuron dendritic trees extend far mediolaterally, yet are unusually simple, which may help channel synaptic current from distal dendrites in the lateral and ventral funiculi to the soma. In combination with T neuron physiological properties, these dendritic properties may help integrate supraspinal and propriospinal inputs and generate and/or modulate rhythmic limb movements. PMID- 25431553 TI - The role of the lateral hypothalamus and orexin in ingestive behavior: a model for the translation of past experience and sensed deficits into motivated behaviors. AB - The hypothalamus has been recognized for its involvement in both maintaining homeostasis and mediating motivated behaviors. The present article discusses a region of the hypothalamus known as the lateral hypothalamic area (LHA). It is proposed that brain nuclei within the LHA including the dorsal region of the lateral hypothalamus (LHAd) and perifornical area (PeF) provide a link between neural systems that regulate homeostasis and those that mediate appetitive motivated behaviors. Functional and immunohistochemical data indicate that the LHA promotes many motivated behaviors including food intake, water intake, salt intake, and sexual behavior. Anatomical tracing experiments demonstrate that the LHA is positioned to receive inputs from brain areas involved in regulating body fluid and energy homeostasis. Regions within the LHA send dense projections to the ventral tegmental area (VTA), providing a pathway for the LHA to influence dopaminergic systems generally recognized to be involved in motivated behaviors and their reinforcement. Furthermore, the LHA contains neurons that synthesize orexin/hypocretin, a neuropeptide that promotes many appetitive motivated behaviors. The LHA also receives inputs from brain areas involved in reward related learning and orexin neuron activation can become conditioned to environmental stimuli that are associated with rewards. Therefore, it is hypothesized that the LHA integrates signaling from areas that regulate body fluid and energy balance and reward-related learning. In turn, this information is "fed into" mesolimbic circuitry to influence the performance of motivated behaviors. This hypothesis may foster experiments that will result in an improved understanding of LHA function. An improved understanding of LHA function may aid in treating disorders that are associated with an excess or impairment in the expression of ingestive behavior including obesity, anorexia, impairments in thirst, salt gluttony, and salt deficiency. PMID- 25431554 TI - Emotion regulation: exploring the impact of stress and sex. AB - Emotion regulation is a major prerequisite for adaptive behavior. The capacity to regulate emotions is particularly important during and after the encounter of a stressor. However, the impact of acute stress and its associated neuroendocrine alterations on emotion regulation have received little attention so far. This study aimed to explore how stress-induced cortisol increases affect three different emotion regulation strategies. Seventy two healthy men and women were either exposed to a stressor or a control condition. Subsequently participants viewed positive and negative images and were asked to up- or down-regulate their emotional responses or simultaneously required to solve an arithmetic task (distraction). The factors stress, sex, and strategy were operationalized as between group factors (n = 6 per cell). Stress caused an increase in blood pressure and higher subjective stress ratings. An increase in cortisol was observed in male participants only. In contrast to controls, stressed participants were less effective in distracting themselves from the emotional pictures. The results further suggest that in women stress enhances the ability to decrease negative emotions. These findings characterize the impact of stress and sex on emotion regulation and provide initial evidence that these factors may interact. PMID- 25431555 TI - EEG neurofeedback treatments in children with ADHD: an updated meta-analysis of randomized controlled trials. AB - OBJECTIVE: We undertook a meta-analysis of published Randomized Controlled Trials (RCT) with semi-active control and sham-NF groups to determine whether Electroencephalogram-neurofeedback (EEG-NF) significantly improves the overall symptoms, inattention and hyperactivity/impulsivity dimensions for probably unblinded assessment (parent assessment) and probably blinded assessment (teacher assessment) in children with Attention Deficit Hyperactivity Disorder (ADHD). DATA SOURCES: A systematic review identified independent studies that were eligible for inclusion in a random effects meta-analysis. DATA EXTRACTION: Effect sizes for ADHD symptoms were expressed as standardized mean differences (SMD) with 95% confidence intervals. RESULTS: Five identified studies met eligibility criteria, 263 patients with ADHD were included, 146 patients were trained with EEG-NF. On parent assessment (probably unblinded assessment), the overall ADHD score (SMD = -0.49 [-0.74, -0.24]), the inattention score (SMD = -0.46 [-0.76, 0.15]) and the hyperactivity/impulsivity score (SMD = -0.34 [-0.59, -0.09]) were significantly improved in patients receiving EEG-NF compared to controls. On teacher assessment (probably blinded assessment), only the inattention score was significantly improved in patients receiving EEG-NF compared to controls (SMD = 0.30 [-0.58, -0.03]). CONCLUSIONS: This meta-analysis of EEG-NF in children with ADHD highlights improvement in the inattention dimension of ADHD symptoms. Future investigations should pay greater attention to adequately blinded studies and EEG NF protocols that carefully control the implementation and embedding of training. PMID- 25431556 TI - Multi-voxel pattern analysis (MVPA) reveals abnormal fMRI activity in both the "core" and "extended" face network in congenital prosopagnosia. AB - The ability to identify faces is mediated by a network of cortical and subcortical brain regions in humans. It is still a matter of debate which regions represent the functional substrate of congenital prosopagnosia (CP), a condition characterized by a lifelong impairment in face recognition, and affecting around 2.5% of the general population. Here, we used functional Magnetic Resonance Imaging (fMRI) to measure neural responses to faces, objects, bodies, and body parts in a group of seven CPs and ten healthy control participants. Using multi voxel pattern analysis (MVPA) of the fMRI data we demonstrate that neural activity within the "core" (i.e., occipital face area and fusiform face area) and "extended" (i.e., anterior temporal cortex) face regions in CPs showed reduced discriminability between faces and objects. Reduced differentiation between faces and objects in CP was also seen in the right parahippocampal cortex. In contrast, discriminability between faces and bodies/body-parts and objects and bodies/body parts across the ventral visual system was typical in CPs. In addition to MVPA analysis, we also ran traditional mass-univariate analysis, which failed to show any group differences in face and object discriminability. In sum, these findings demonstrate (i) face-object representations impairments in CP which encompass both the "core" and "extended" face regions, and (ii) superior power of MVPA in detecting group differences. PMID- 25431557 TI - Granger causality analysis reveals distinct spatio-temporal connectivity patterns in motor and perceptual visuo-spatial working memory. AB - We employed spectral Granger causality analysis on a full set of 56 electroencephalographic recordings acquired during the execution of either a 2D movement pointing or a perceptual (yes/no) change detection task with memory and non-memory conditions. On the basis of network characteristics across frequency bands, we provide evidence for the full dissociation of the corresponding cognitive processes. Movement-memory trial types exhibited higher degree nodes during the first 2 s of the delay period, mainly at central, left frontal and right-parietal areas. Change detection-memory trial types resulted in a three peak temporal pattern of the total degree with higher degree nodes emerging mainly at central, right frontal, and occipital areas. Functional connectivity networks resulting from non-memory trial types were characterized by more sparse structures for both tasks. The movement-memory trial types encompassed an apparent coarse flow from frontal to parietal areas while the opposite flow from occipital, parietal to central and frontal areas was evident for the change detection-memory trial types. The differences among tasks and conditions were more profound in alpha (8-12 Hz) and beta (12-30 Hz) and less in gamma (30-45 Hz) band. Our results favor the hypothesis which considers spatial working memory as a by-product of specific mental processes that engages common brain areas under different network organizations. PMID- 25431558 TI - Fractional anisotropy of the fornix and hippocampal atrophy in Alzheimer's disease. AB - Decrease in the directionality of water diffusion measured with fractional anisotropy (FA) on diffusion tensor imaging has been linked to loss of myelin and axons in the white matter. Fornix FA is consistently decreased in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Furthermore, decreased fornix FA is one of the earliest MRI abnormalities observed in cognitively normal individuals who are at an increased risk for AD, such as in pre-symptomatic carriers of familial AD mutations and in pre-clinical AD. Reductions of FA at these early stages, which predicted the decline in memory function. Fornix carries the efferent projections from the CA1 and CA3 pyramidal neurons of the hippocampus and subiculum, connecting these structures to the septal nuclei, anterior thalamic nucleus, mammillary bodies, and medial hypothalamus. Fornix also carries the afferent cholinergic and GABAergic projections from the medial septal nuclei and the adjacent diagonal band back to the medial temporal lobe, interconnecting the core limbic structures. Because fornix carries the axons projecting from the hippocampus, integrity of the fornix is in-part linked to the integrity of the hippocampus. In keeping with that, fornix FA is reduced in subjects with hippocampal atrophy, correlating with memory function. The literature on FA reductions in the fornix in the clinical spectrum of AD from pre-symptomatic carriers of familial AD mutations to pre clinical AD, MCI, and dementia stages is reviewed. PMID- 25431559 TI - Surveying the floodgates: estimating protein flux into the endoplasmic reticulum lumen in Saccharomyces cerevisiae. AB - Endoplasmic reticulum resident proteins, along with all proteins traveling through the secretory pathway must enter endoplasmic reticulum lumen through membrane-embedded translocons. In Saccharomyces cerevisiae the heterotrimeric endoplasmic reticulum translocon is composed of the Sec61p, Sss1p, and Sbh1p core subunits. While the involvement of various molecules associated with the Sec61 complex has been thoroughly characterized, little attention has been given to the overall flux through these channels. In this work we carried out a meta-analysis to estimate the average and absolute flux of proteins into the endoplasmic reticulum lumen. We estimate an average of 460 proteins enter the endoplasmic reticulum every second, with an absolute minimum and maximum flux of 78 and 3700 molecules per second, respectively. With current technologies limiting the ability to obtain accurate measurements of these events, our estimates shed light on the flow of protein entering the endoplasmic reticulum lumen. PMID- 25431560 TI - The effect of phonics-enhanced Big Book reading on the language and literacy skills of 6-year-old pupils of different reading ability attending lower SES schools. AB - The purpose of this study was to improve the literacy achievement of lower socioeconomic status (SES) children by combining explicit phonics with Big Book reading. Big Book reading is a component of the text-centered (or book reading) approach used in New Zealand schools. It involves the teacher in reading an enlarged book to children and demonstrating how to use semantic, syntactic, and grapho-phonic cues to learn to read. There has been little research, however, to find out whether the effectiveness of Big Book reading is enhanced by adding explicit phonics. In this study, a group of 96 second graders from three lower SES primary schools in New Zealand were taught in 24 small groups of four, tracked into three different reading ability levels. All pupils were randomly assigned to one of four treatment conditions: a control group who received math instruction, Big Book reading enhanced with phonics (BB/EP), Big Book reading on its own, and Phonics on its own. The results showed that the BB/EP group made significantly better progress than the Big Book and Phonics groups in word reading, reading comprehension, spelling, and phonemic awareness. In reading accuracy, the BB/EP and Big Book groups scored similarly. In basic decoding skills the BB/EP and Phonics groups scored similarly. The combined instruction, compared with Big Book reading and phonics, appeared to have no comparative disadvantages and considerable advantages. The present findings could be a model for New Zealand and other countries in their efforts to increase the literacy achievement of disadvantaged pupils. PMID- 25431561 TI - Why do different people choose different university degrees? Motivation and the choice of degree. AB - Different people choose undergraduate degrees to study at university for different reasons. To date, there have been limited attempts to identify individual differences in motivation that drive undergraduate degree choice. We identified that people choose university degrees for four reasons: career concerns (Career), intrinsic interest in the subject (Interest), an opportunity to help others (Helping) and because they are looking for an easy option to get into higher education (Loafing). We investigated whether these motivations apply to the choice of undergraduate degree in two samples: (1) undergraduate (N = 989) and (2) prospective (N = 896) students. We developed the Motivations Influencing Course Choice (MICC) questionnaire to measure these motivations. Scales of Helping, Career, Loafing, and Interest showed good psychometric properties, showed validity with respect to general life goals and personality traits, and predicted actual and prospective degree choices. We demonstrated that medical degrees were chosen due to a mixture of Helping and Career, while engineering degrees were associated with Career and low Interest in the degree. The choice of arts and humanities degrees was driven by Interest and low concern about future career, accompanied with high Loafing. We also demonstrated gender differences: females were high in Helping (both samples) and Interest (only in the undergraduate sample) motivation, while males scored higher in Career (only in the undergraduate sample) and Loafing (both samples). The findings can feed into both theoretical accounts of proximal motivation as well as provide help to improve degree programmes at universities and support better career advice. PMID- 25431562 TI - The role of syllables in sign language production. AB - The aim of the present study was to investigate the functional role of syllables in sign language and how the different phonological combinations influence sign production. Moreover, the influence of age of acquisition was evaluated. Deaf signers (native and non-native) of Catalan Signed Language (LSC) were asked in a picture-sign interference task to sign picture names while ignoring distractor signs with which they shared two phonological parameters (out of three of the main sign parameters: Location, Movement, and Handshape). The results revealed a different impact of the three phonological combinations. While no effect was observed for the phonological combination Handshape-Location, the combination Handshape-Movement slowed down signing latencies, but only in the non-native group. A facilitatory effect was observed for both groups when pictures and distractors shared Location-Movement. Importantly, linguistic models have considered this phonological combination to be a privileged unit in the composition of signs, as syllables are in spoken languages. Thus, our results support the functional role of syllable units during phonological articulation in sign language production. PMID- 25431563 TI - Nurse work engagement impacts job outcome and nurse-assessed quality of care: model testing with nurse practice environment and nurse work characteristics as predictors. AB - AIM: To explore the mechanisms through which nurse practice environment dimensions, such as nurse-physician relationship, nurse management at the unit level and hospital management and organizational support, are associated with job outcomes and nurse-assessed quality of care. Mediating variables included nurse work characteristics of workload, social capital, decision latitude, as well as work engagement dimensions of vigor, dedication and absorption. BACKGROUND: Understanding how to support and guide nurse practice communities in their daily effort to answer complex care most accurate, alongside with the demand of a stable and healthy nurse workforce, is challenging. DESIGN: Cross-sectional survey. METHOD: Based on earlier empirical findings, a structural equation model, designed with valid measurement instruments, was tested. The study population included registered acute care hospital nurses (N = 1201) in eight hospitals across Belgium. RESULTS: Nurse practice environment dimensions predicted nurses' ratings of job outcome variables as well as quality of care. Features of nurses' work characteristics, e.g., perceived workload, decision latitude, social capital, and the three dimension of work engagement, played mediating roles between nurse practice environment and outcomes. A revised model, using various fit measures, explained 60% of job outcomes and 47% of nurse-assessed quality of care. CONCLUSION: The findings in this study show that nurse work characteristics as workload, decision latitude, and social capital, alongside with nurse work engagement (e.g., vigor, dedication, and absorption) influence nurses' perspective of their nurse practice environment, job outcomes, and quality of care. The results underline aspects to considerate for various stakeholders, such as executives, nurse managers, physicians, and staff nurses, in setting up and organizing health care services. PMID- 25431565 TI - Magic and memory: using conjuring to explore the effects of suggestion, social influence, and paranormal belief on eyewitness testimony for an ostensibly paranormal event. AB - This study uses conjuring to investigate the effects of suggestion, social influence, and paranormal belief upon the accuracy of eyewitness testimony for an ostensibly paranormal event. Participants watched a video of an alleged psychic seemingly bending a metal key by the power of psychokinesis. Half the participants heard the fake psychic suggest that the key continued to bend after it had been put down on a table and half did not. Additionally, participants were exposed to either a negative social influence (a stooge co-witness reporting that the key did not continue to bend), no social influence, or a positive social influence (a stooge co-witness reporting that the key did continue to bend). Participants who were exposed to the verbal suggestion were significantly more likely to report that the key continued to bend. Additionally, more participants reported that the key continued to bend in the positive social influence condition compared to the other two social influence conditions. Finally, believers in the paranormal were more likely to report that the key continued to bend than non-believers. PMID- 25431564 TI - Dissociable effects of game elements on motivation and cognition in a task switching training in middle childhood. AB - Although motivational reinforcers are often used to enhance the attractiveness of trainings of cognitive control in children, little is known about how such motivational manipulations of the setting contribute to separate gains in motivation and cognitive-control performance. Here we provide a framework for systematically investigating the impact of a motivational video-game setting on the training motivation, the task performance, and the transfer success in a task switching training in middle-aged children (8-11 years of age). We manipulated both the type of training (low-demanding/single-task training vs. high demanding/task-switching training) as well as the motivational setting (low motivational/without video-game elements vs. high-motivational/with video-game elements) separately from another. The results indicated that the addition of game elements to a training setting enhanced the intrinsic interest in task practice, independently of the cognitive demands placed by the training type. In the task-switching group, the high-motivational training setting led to an additional enhancement of task and switching performance during the training phase right from the outset. These motivation-induced benefits projected onto the switching performance in a switching situation different from the trained one (near-transfer measurement). However, in structurally dissimilar cognitive tasks (far-transfer measurement), the motivational gains only transferred to the response dynamics (speed of processing). Hence, the motivational setting clearly had a positive impact on the training motivation and on the paradigm-specific task-switching abilities; it did not, however, consistently generalize on broad cognitive processes. These findings shed new light on the conflation of motivation and cognition in childhood and may help to refine guidelines for designing adequate training interventions. PMID- 25431566 TI - Probability expression for changeable and changeless uncertainties: an implicit test. AB - "Everything changes and nothing remains still."We designed three implicit studies to understand how people react or adapt to a rapidly changing world by testing whether verbal probability is better in expressing changeable uncertainty while numerical probability is better in expressing unchangeable uncertainty. We found that the "verbal-changeable" combination in implicit tasks was more compatible than the "numerical-changeable" combination. Furthermore, the "numerical changeless" combination was more compatible than the "verbal-changeless" combination. Thus, a novel feature called "changeability" was proposed to describe the changeable nature of verbal probability. However, numerical probability is a better carrier of changeless uncertainty than verbal probability. These results extend the domain of probability predictions and enrich our general understanding of communication with verbal and numerical probabilities. Given that the world around us is constantly changing, this "changeability" feature may play a major role in preparing for uncertainty. PMID- 25431569 TI - Oligotyping reveals community level habitat selection within the genus Vibrio. AB - The genus Vibrio is a metabolically diverse group of facultative anaerobic bacteria, common in aquatic environments and marine hosts. The genus contains several species of importance to human health and aquaculture, including the causative agents of human cholera and fish vibriosis. Vibrios display a wide variety of known life histories, from opportunistic pathogens to long-standing symbionts with individual host species. Studying Vibrio ecology has been challenging as individual species often display a wide range of habitat preferences, and groups of vibrios can act as socially cohesive groups. Although strong associations with salinity, temperature and other environmental variables have been established, the degree of habitat or host specificity at both the individual and community levels is unknown. Here we use oligotyping analyses in combination with a large collection of existing Vibrio 16S ribosomal RNA (rRNA) gene sequence data to reveal patterns of Vibrio ecology across a wide range of environmental, host, and abiotic substrate associated habitats. Our data show that individual taxa often display a wide range of habitat preferences yet tend to be highly abundant in either substrate-associated or free-living environments. Our analyses show that Vibrio communities share considerable overlap between two distinct hosts (i.e., sponge and fish), yet are distinct from the abiotic plastic substrates. Lastly, evidence for habitat specificity at the community level exists in some habitats, despite considerable stochasticity in others. In addition to providing insights into Vibrio ecology across a broad range of habitats, our study shows the utility of oligotyping as a facile, high-throughput and unbiased method for large-scale analyses of publically available sequence data repositories and suggests its wide application could greatly extend the range of possibilities to explore microbial ecology. PMID- 25431567 TI - The application of electro- and magneto-encephalography in tinnitus research - methods and interpretations. AB - In recent years, there has been a significant increase in the use of electroencephalography (EEG) and magnetoencephalography (MEG) to investigate changes in oscillatory brain activity associated with tinnitus with many conflicting results. Current view of the underlying mechanism of tinnitus is that it results from changes in brain activity in various structures of the brain as a consequence of sensory deprivation. This in turn gives rise to increased spontaneous activity and/or synchrony in the auditory centers but also involves modulation from non-auditory processes from structures of the limbic and paralimbic system. Some of the neural changes associated with tinnitus may be assessed non-invasively in human beings with MEG and EEG (M/EEG) in ways, which are superior to animal studies and other non-invasive imaging techniques. However, both MEG and EEG have their limitations and research results can be misinterpreted without appropriate consideration of these limitations. In this article, I intend to provide a brief review of these techniques, describe what the recorded signals reflect in terms of the underlying neural activity, and their strengths and limitations. I also discuss some pertinent methodological issues involved in tinnitus-related studies and conclude with suggestions to minimize possible discrepancies between results. The overall message is that while MEG and EEG are extremely useful techniques, the interpretation of results from tinnitus studies requires much caution given the individual variability in oscillatory activity and the limits of these techniques. PMID- 25431568 TI - Gender differences in skeletal muscle substrate metabolism - molecular mechanisms and insulin sensitivity. AB - It has become increasingly apparent that substrate metabolism is subject to gender-specific regulation, and the aim of this review is to outline the available evidence of molecular gender differences in glucose and lipid metabolism of skeletal muscle. Female sex has been suggested to have a favorable effect on glucose homeostasis, and the available evidence from hyperinsulinemic euglycemic clamp studies is summarized to delineate whether there is a gender difference in whole-body insulin sensitivity and in particular insulin-stimulated glucose uptake of skeletal muscle. Whether an eventual higher insulin sensitivity of female skeletal muscle can be related to gender-specific regulation of molecular metabolism will be topic for discussion. Gender differences in muscle fiber type distribution and substrate availability to and in skeletal muscle are highly relevant for substrate metabolism in men and women. In particular, the molecular machinery for glucose and fatty acid oxidative and storage capacities in skeletal muscle and its implications for substrate utilization during metabolic situations of daily living are discussed, emphasizing their relevance for substrate choice in the fed and fasted state, and during periods of physical activity and recovery. Together, handling of carbohydrate and lipids and regulation of their utilization in skeletal muscle have implications for whole body glucose homeostasis in men and women. 17-beta estradiol is the most important female sex hormone, and the identification of estradiol receptors in skeletal muscle has opened for a role in regulation of substrate metabolism. Also, higher levels of circulating adipokines as adiponectin and leptin in women and their implications for muscle metabolism will be considered. PMID- 25431570 TI - A bioassay for the detection of benzimidazoles reveals their presence in a range of environmental samples. AB - Cobamides are a family of enzyme cofactors that include vitamin B12 (cobalamin) and are produced solely by prokaryotes. Structural variability in the lower axial ligand has been observed in cobamides produced by diverse organisms. Of the three classes of lower ligands, the benzimidazoles are uniquely found in cobamides, whereas the purine and phenolic bases have additional biological functions. Many organisms acquire cobamides by salvaging and remodeling cobamides or their precursors from the environment. These processes require free benzimidazoles for incorporation as lower ligands, though the presence of benzimidazoles in the environment has not been previously investigated. Here, we report a new purification method and bioassay to measure the total free benzimidazole content of samples from microbial communities and laboratory media components. The bioassay relies on the "calcofluor-bright" phenotype of a bluB mutant of the model cobalamin-producing bacterium Sinorhizobium meliloti. The concentrations of individual benzimidazoles in these samples were measured by liquid chromatography tandem mass spectrometry. Several benzimidazoles were detected in subpicomolar to subnanomolar concentrations in host-associated and environmental samples. In addition, benzimidazoles were found to be common contaminants of laboratory media components. These results suggest that benzimidazoles present in the environment and in laboratory media have the potential to influence microbial metabolic activities. PMID- 25431571 TI - Investigations of potential microbial methanogenic and carbon monoxide utilization pathways in ultra-basic reducing springs associated with present-day continental serpentinization: the Tablelands, NL, CAN. AB - Ultra-basic reducing springs at continental sites of serpentinization act as portals into the biogeochemistry of a subsurface environment with H2 and CH4 present. Very little, however, is known about the carbon substrate utilization, energy sources, and metabolic pathways of the microorganisms that live in this ultra-basic environment. The potential for microbial methanogenesis with bicarbonate, formate, acetate, and propionate precursors and carbon monoxide (CO) utilization pathways were tested in laboratory experiments by adding substrates to water and sediment from the Tablelands, NL, CAD, a site of present-day continental serpentinization. Microbial methanogenesis was not observed after bicarbonate, formate, acetate, or propionate addition. CO was consumed in the live experiments but not in the killed controls and the residual CO in the live experiments became enriched in (13)C. The average isotopic enrichment factor resulting from this microbial utilization of CO was estimated to be 11.2 +/- 0.20/00. Phospholipid fatty acid concentrations and delta(13)C values suggest limited incorporation of carbon from CO into microbial lipids. This indicates that in our experiments, CO was used primarily as an energy source, but not for biomass growth. Environmental DNA sequencing of spring fluids collected at the same time as the addition experiments yielded a large proportion of Hydrogenophaga-related sequences, which is consistent with previous metagenomic data indicating the potential for these taxa to utilize CO. PMID- 25431572 TI - Increasing Obesity in Treated Female HIV Patients from Sub-Saharan Africa: Potential Causes and Possible Targets for Intervention. AB - OBJECTIVES: To investigate changing nutritional demographics of treated HIV-1 infected patients and explore causes of obesity, particularly in women of African origin. METHODS: We prospectively reviewed nutritional demographics of clinic attenders at an urban European HIV clinic during four one-month periods at three yearly intervals (2001, 2004, 2007, and 2010) and in two consecutive whole-year reviews (2010-2011 and 2011-2012). Risk-factors for obesity were assessed by multiple linear regression. A sub-study of 50 HIV-positive African female patients investigated body-size/shape perception using numerical, verbal, and pictorial cues. RESULTS: We found a dramatic rise in the prevalence of obesity (BMI > 30 kg/m(2)), from 8.5 (2001) to 28% (2011-2012) for all clinic attenders, of whom 86% were on antiretroviral treatment. Women of African origin were most affected, 49% being obese, with a further 32% overweight (BMI 25-30 kg/m(2)) in 2012. Clinical factors strongly associated with obesity included female gender, black African ethnicity, non-smoking, age, and CD4 count (all P < 0.001); greater duration of cART did not predict obesity. Individual weight-time trends mostly showed slow long-term progressive weight gain. Investigating body-weight perception, we found that weight and adiposity were underestimated by obese subjects, who showed a greater disparity between perceived and actual adiposity (P < 0.001). Obese subjects targeted more obese target "ideal" body shapes (P < 0.01), but were less satisfied with their body shape overall (P = 0.02). CONCLUSION: Seropositive African women on antiretroviral treatment are at heightened risk of obesity. Although multifactorial, body-weight perception represents a potential target for intervention. PMID- 25431573 TI - Pathogen-Specific Immune Fingerprints during Acute Infection: The Diagnostic Potential of Human gammadelta T-Cells. PMID- 25431574 TI - Long Non-Coding RNAs Involved in Immune Responses. AB - A large number of human RNA transcripts, which do not encode proteins are defined as non-coding RNAs (ncRNAs). These ncRNAs are divided into two classes of different lengths; short and long ncRNAs. MicroRNAs are a major class of short ncRNAs, ~22 nucleotides in length that regulate gene expression at the post transcriptional level. Long non-coding RNAs (lncRNAs) are more than 200 nucleotides in length and play roles in various biological pathways. In this review, we summarize the functions of lncRNAs which regulate immune responses. PMID- 25431575 TI - Quantification of variability in trichome patterns. AB - While pattern formation is studied in various areas of biology, little is known about the noise leading to variations between individual realizations of the pattern. One prominent example for de novo pattern formation in plants is the patterning of trichomes on Arabidopsis leaves, which involves genetic regulation and cell-to-cell communication. These processes are potentially variable due to, e.g., the abundance of cell components or environmental conditions. To elevate the understanding of regulatory processes underlying the pattern formation it is crucial to quantitatively analyze the variability in naturally occurring patterns. Here, we review recent approaches toward characterization of noise on trichome initiation. We present methods for the quantification of spatial patterns, which are the basis for data-driven mathematical modeling and enable the analysis of noise from different sources. Besides the insight gained on trichome formation, the examination of observed trichome patterns also shows that highly regulated biological processes can be substantially affected by variability. PMID- 25431576 TI - Live imaging of developmental processes in a living meristem of Davidia involucrata (Nyssaceae). AB - Morphogenesis in plants is usually reconstructed by scanning electron microscopy and histology of meristematic structures. These techniques are destructive and require many samples to obtain a consecutive series of states. Unfortunately, using this methodology the absolute timing of growth and complete relative initiation of organs remain obscure. To overcome this limitation, an in vivo observational method based on Epi-Illumination Light Microscopy (ELM) was developed and tested with a male inflorescence meristem (floral unit) of the handkerchief tree Davidia involucrata Baill. (Nyssaceae). We asked whether the most basal flowers of this floral unit arise in a basipetal sequence or, alternatively, are delayed in their development. The growing meristem was observed for 30 days, the longest live observation of a meristem achieved to date. The sequence of primordium initiation indicates a later initiation of the most basal flowers and not earlier or simultaneously as SEM images could suggest. D. involucrata exemplarily shows that live-ELM gives new insights into developmental processes of plants. In addition to morphogenetic questions such as the transition from vegetative to reproductive meristems or the absolute timing of ontogenetic processes, this method may also help to quantify cellular growth processes in the context of molecular physiology and developmental genetics studies. PMID- 25431578 TI - Redundancy among phospholipase D isoforms in resistance triggered by recognition of the Pseudomonas syringae effector AvrRpm1 in Arabidopsis thaliana. AB - Plants possess a highly sophisticated system for defense against microorganisms. So called MAMP (microbe-associated molecular patterns) triggered immunity (MTI) prevents the majority of non-adapted pathogens from causing disease. Adapted plant pathogens use secreted effector proteins to interfere with such signaling. Recognition of microbial effectors or their activity by plant resistance (R) proteins triggers a second line of defense resulting in effector triggered immunity (ETI). The latter usually comprises the hypersensitive response (HR) which includes programmed cell death at the site of infection. Phospholipase D (PLD) mediated production of phosphatidic acid (PA) has been linked to both MTI and ETI in plants. Inhibition of PLD activity has been shown to attenuate MTI as well as ETI. In this study, we systematically tested single and double knockouts in all 12 genes encoding PLDs in Arabidopsis thaliana for effects on ETI and MTI. No single PLD could be linked to ETI triggered by recognition of effectors secreted by the bacterium Pseudomonas syringae. However, repression of PLD dependent PA production by n-butanol strongly inhibited the HR following Pseudomonas syringae effector recognition. In addition some pld mutants were more sensitive to n-butanol than wild type. Thus, the effect of mutations of PLDs could become detectable, and the corresponding genes can be proposed to be involved in the HR. Only knockout of PLDdelta caused a loss of MTI-induced cell wall based defense against the non-host powdery mildew Erysiphe pisi. This is thus in stark contrast to the involvement of a multitude of PLD isoforms in the HR triggered by AvrRpm1 recognition. PMID- 25431577 TI - Development of disease-resistant rice using regulatory components of induced disease resistance. AB - Infectious diseases cause huge crop losses annually. In response to pathogen attacks, plants activate defense systems that are mediated through various signaling pathways. The salicylic acid (SA) signaling pathway is the most powerful of these pathways. Several regulatory components of the SA signaling pathway have been identified, and are potential targets for genetic manipulation of plants' disease resistance. However, the resistance associated with these regulatory components is often accompanied by fitness costs; that is, negative effects on plant growth and crop yield. Chemical defense inducers, such as benzothiadiazole and probenazole, act on the SA pathway and induce strong resistance to various pathogens without major fitness costs, owing to their 'priming effect.' Studies on how benzothiadiazole induces disease resistance in rice have identified WRKY45, a key transcription factor in the branched SA pathway, and OsNPR1/NH1. Rice plants overexpressing WRKY45 were extremely resistant to rice blast disease caused by the fungus Magnaporthe oryzae and bacterial leaf blight disease caused by Xanthomonas oryzae pv. oryzae (Xoo), the two major rice diseases. Disease resistance is often accompanied by fitness costs; however, WRKY45 overexpression imposed relatively small fitness costs on rice because of its priming effect. This priming effect was similar to that of chemical defense inducers, although the fitness costs were amplified by some environmental factors. WRKY45 is degraded by the ubiquitin-proteasome system, and the dual role of this degradation partly explains the priming effect. The synergistic interaction between SA and cytokinin signaling that activates WRKY45 also likely contributes to the priming effect. With a main focus on these studies, I review the current knowledge of SA-pathway-dependent defense in rice by comparing it with that in Arabidopsis, and discuss potential strategies to develop disease-resistant rice using signaling components. PMID- 25431579 TI - Mitochondrial and Y chromosome haplotype motifs as diagnostic markers of Jewish ancestry: a reconsideration. AB - Several authors have proposed haplotype motifs based on site variants at the mitochondrial genome (mtDNA) and the non-recombining portion of the Y chromosome (NRY) to trace the genealogies of Jewish people. Here, we analyzed their main approaches and test the feasibility of adopting motifs as ancestry markers through construction of a large database of mtDNA and NRY haplotypes from public genetic genealogical repositories. We verified the reliability of Jewish ancestry prediction based on the Cohen and Levite Modal Haplotypes in their "classical" 6 STR marker format or in the "extended" 12 STR format, as well as four founder mtDNA lineages (HVS-I segments) accounting for about 40% of the current population of Ashkenazi Jews. For this purpose we compared haplotype composition in individuals of self-reported Jewish ancestry with the rest of European, African or Middle Eastern samples, to test for non-random association of ethno geographic groups and haplotypes. Overall, NRY and mtDNA based motifs, previously reported to differentiate between groups, were found to be more represented in Jewish compared to non-Jewish groups. However, this seems to stem from common ancestors of Jewish lineages being rather recent respect to ancestors of non Jewish lineages with the same "haplotype signatures." Moreover, the polyphyly of haplotypes which contain the proposed motifs and the misuse of constant mutation rates heavily affected previous attempts to correctly dating the origin of common ancestries. Accordingly, our results stress the limitations of using the above haplotype motifs as reliable Jewish ancestry predictors and show its inadequacy for forensic or genealogical purposes. PMID- 25431582 TI - Where is the friend's home? PMID- 25431580 TI - Chromatin associations in Arabidopsis interphase nuclei. AB - The arrangement of chromatin within interphase nuclei seems to be caused by topological constraints and related to gene expression depending on tissue and developmental stage. In yeast and animals it was found that homologous and heterologous chromatin association are required to realize faithful expression and DNA repair. To test whether such associations are present in plants we analyzed Arabidopsis thaliana interphase nuclei by FISH using probes from different chromosomes. We found that chromatin fiber movement and variable associations, although in general relatively seldom, may occur between euchromatin segments along chromosomes, sometimes even over large distances. The combination of euchromatin segments bearing high or low co-expressing genes did not reveal different association frequencies probably due to adjacent genes of deviating expression patterns. Based on previous data and on FISH analyses presented here, we conclude that the global interphase chromatin organization in A. thaliana is relatively stable, due to the location of its 10 centromeres at the nuclear periphery and of the telomeres mainly at the centrally localized nucleolus. Nevertheless, chromatin movement enables a flexible spatial genome arrangement in plant nuclei. PMID- 25431581 TI - Historical factors that have shaped the evolution of tropical reef fishes: a review of phylogenies, biogeography, and remaining questions. AB - Biodiversity patterns across the marine tropics have intrigued evolutionary biologists and ecologists alike. Tropical coral reefs host 1/3 of all marine species of fish on 0.1% of the ocean's surface. Yet our understanding of how mechanistic processes have underpinned the generation of this diversity is limited. However, it has become clear that the biogeographic history of the marine tropics has played an important role in shaping the diversity of tropical reef fishes we see today. In the last decade, molecular phylogenies and age estimation techniques have provided a temporal framework in which the ancestral biogeographic origins of reef fish lineages have been inferred, but few have included fully sampled phylogenies or made inferences at a global scale. We are currently at a point where new sequencing technologies are accelerating the reconstruction and the resolution of the Fish Tree of Life. How will a complete phylogeny of fishes benefit the study of biodiversity in the tropics? Here, I review the literature concerning the evolutionary history of reef-associated fishes from a biogeographic perspective. I summarize the major biogeographic and climatic events over the last 65 million years that have regionalized the tropical marine belt and what effect they have had on the molecular record of fishes and global biodiversity patterns. By examining recent phylogenetic trees of major reef associated groups, I identify gaps to be filled in order to obtain a clearer picture of the origins of coral reef fish assemblages. Finally, I discuss questions that remain to be answered and new approaches to uncover the mechanistic processes that underpin the evolution of biodiversity on coral reefs. PMID- 25431583 TI - A Weighted Two-Level Bregman Method with Dictionary Updating for Nonconvex MR Image Reconstruction. AB - Nonconvex optimization has shown that it needs substantially fewer measurements than l 1 minimization for exact recovery under fixed transform/overcomplete dictionary. In this work, two efficient numerical algorithms which are unified by the method named weighted two-level Bregman method with dictionary updating (WTBMDU) are proposed for solving lp optimization under the dictionary learning model and subjecting the fidelity to the partial measurements. By incorporating the iteratively reweighted norm into the two-level Bregman iteration method with dictionary updating scheme (TBMDU), the modified alternating direction method (ADM) solves the model of pursuing the approximated lp -norm penalty efficiently. Specifically, the algorithms converge after a relatively small number of iterations, under the formulation of iteratively reweighted l 1 and l 2 minimization. Experimental results on MR image simulations and real MR data, under a variety of sampling trajectories and acceleration factors, consistently demonstrate that the proposed method can efficiently reconstruct MR images from highly undersampled k-space data and presents advantages over the current state of-the-art reconstruction approaches, in terms of higher PSNR and lower HFEN values. PMID- 25431584 TI - Modeling design iteration in product design and development and its solution by a novel artificial bee colony algorithm. AB - Due to fierce market competition, how to improve product quality and reduce development cost determines the core competitiveness of enterprises. However, design iteration generally causes increases of product cost and delays of development time as well, so how to identify and model couplings among tasks in product design and development has become an important issue for enterprises to settle. In this paper, the shortcomings existing in WTM model are discussed and tearing approach as well as inner iteration method is used to complement the classic WTM model. In addition, the ABC algorithm is also introduced to find out the optimal decoupling schemes. In this paper, firstly, tearing approach and inner iteration method are analyzed for solving coupled sets. Secondly, a hybrid iteration model combining these two technologies is set up. Thirdly, a high performance swarm intelligence algorithm, artificial bee colony, is adopted to realize problem-solving. Finally, an engineering design of a chemical processing system is given in order to verify its reasonability and effectiveness. PMID- 25431585 TI - Modeling mode choice behavior incorporating household and individual sociodemographics and travel attributes based on rough sets theory. AB - Most traditional mode choice models are based on the principle of random utility maximization derived from econometric theory. Alternatively, mode choice modeling can be regarded as a pattern recognition problem reflected from the explanatory variables of determining the choices between alternatives. The paper applies the knowledge discovery technique of rough sets theory to model travel mode choices incorporating household and individual sociodemographics and travel information, and to identify the significance of each attribute. The study uses the detailed travel diary survey data of Changxing county which contains information on both household and individual travel behaviors for model estimation and evaluation. The knowledge is presented in the form of easily understood IF-THEN statements or rules which reveal how each attribute influences mode choice behavior. These rules are then used to predict travel mode choices from information held about previously unseen individuals and the classification performance is assessed. The rough sets model shows high robustness and good predictive ability. The most significant condition attributes identified to determine travel mode choices are gender, distance, household annual income, and occupation. Comparative evaluation with the MNL model also proves that the rough sets model gives superior prediction accuracy and coverage on travel mode choice modeling. PMID- 25431586 TI - Fuzzy temporal logic based railway passenger flow forecast model. AB - Passenger flow forecast is of essential importance to the organization of railway transportation and is one of the most important basics for the decision-making on transportation pattern and train operation planning. Passenger flow of high-speed railway features the quasi-periodic variations in a short time and complex nonlinear fluctuation because of existence of many influencing factors. In this study, a fuzzy temporal logic based passenger flow forecast model (FTLPFFM) is presented based on fuzzy logic relationship recognition techniques that predicts the short-term passenger flow for high-speed railway, and the forecast accuracy is also significantly improved. An applied case that uses the real-world data illustrates the precision and accuracy of FTLPFFM. For this applied case, the proposed model performs better than the k-nearest neighbor (KNN) and autoregressive integrated moving average (ARIMA) models. PMID- 25431587 TI - The Role of e-NOS in Chronic Cholestasis-Induced Liver and Renal Injury in Rats: The Effect of N-Acetyl Cysteine. AB - Introduction. The role of chronic cholestasis (CC) in liver injury and fibrosis remains unclear. The aims of this study were to define the role of endothelial nitric oxide synthase (e-NOS) in CC and the protective effect of N-acetyl-L cysteine (NAC) in liver and kidney injury. Materials and Methods. Group A (sham group); Group B (CBDL); and Group C (CBDL + NAC). Group C received daily dosage of NAC (100 mg/kg) intraperitoneally for up to 4 weeks. Results. The rate of bridging fibrosis was higher (100% versus 20%, P = .025), but the intensity of e NOS in liver was lower in rats that received NAC (1.3 versus 2.7, P = .046). The necrotic area in the kidneys among rats that received NAC was lower at week 4 (48% versus 57%; P < .001). The numbers of e-NOS stained cells in kidney were similar in sham group and the two groups with CBDL. Discussion. NAC reduced the stimulus for liver fibrosis in this rat model of CC and attenuated liver and kidney injury. Our study showed that e-NOS expression increased in liver tissue of rats with CC and that this was reversed by NAC. Treatment with NAC might restore e-NOS protein expression and prevent liver injury in CC. PMID- 25431588 TI - New evidence on the impact of antithrombotics in patients submitted to small bowel capsule endoscopy for the evaluation of obscure gastrointestinal bleeding. AB - Objectives. Small bowel capsule endoscopy (SBCE) plays a decisive role in the obscure gastrointestinal bleeding (OGIB) diagnosis. Antithrombotics may increase bleeding risk in patients with preexistent lesions or through direct mucosal aggression. We aimed to correlate antithrombotics usage with lesions with bleeding potential found in SBCE. Methods. Retrospective single-center study including 274 consecutive SBCE performed over 7 years for OGIB. The lesions were classified as P0 (no bleeding potential), P1 (uncertain bleeding potential: erosions), and P2 (high bleeding potential: angioectasias, ulcers, and tumors). We assessed antiplatelet and anticoagulant drug use during the 60 days preceding SBCE. Results. One-third of the patients were under antithrombotic therapy. The diagnostic yield of SBCE for P2 lesions was 30.0%. Angioectasias (20.4%) were the most frequently observed lesions. There was a significant correlation between anticoagulant drug use and a higher incidence of P2 lesions in the small bowel (43.2% versus 26.5%; OR = 2.11, P = 0.026). We found no significant correlation between antiplatelets and lesions with bleeding potential in SBCE. Conclusions. Small bowel lesions with high bleeding potential were more frequently detected when the patient was on anticoagulant drugs, resulting in a twofold risk. Antiplatelet drugs were not associated with small bowel lesions. PMID- 25431589 TI - A Cross-Sectional Study to Examine Factors Associated with Primary Health Care Service Utilization among Older Adults in the Irbid Governorate of Jordan. AB - Background. Recently, the percentage of older adults in developing countries has increased significantly. Objective. This study examined patterns and factors associated with primary health care services utilization in the past 1, 6, and 12 months. Method. A cross-sectional study design was used to collect data from 190 older adults in the Irbid governorate of Jordan. Results. Primary health care services were used by less than half of the participants in the past 1 month, by 68.4% in the past 6 months, and by 73.8% in the past 12 months. Primary health care (PHC) services use was associated with age, education level, tobacco use, chronic illnesses, perceived general health status today, a physical component summary score, employment, and perceived general health status in the past 6 and 12 months. The primary predictor of PHC services use at 1, 6, and 12 months was chronic illnesses (OR = 13.32), (OR = 19.63), and (OR = 17.91), respectively. Conclusion. Although many factors were associated with PHC service utilization, the strongest predictor of PHC service utilization was chronic illnesses. PMID- 25431591 TI - Correlations of vascular architecture and angiogenesis with pituitary adenoma histotype. AB - Vascular endothelial growth factor (VEGF) is a potent angiogenic factor in solid tumors. However, its role in angiogenesis in pituitary adenoma is controversial. Angiogenesis in solid tumors including pituitary adenoma is commonly evaluated by microvascular density (MVD). Here, we evaluated MVD and the role of VEGF in vascular architecture in 51 pituitary adenomas (24 nonfunctioning, 13 prolactin secreting, 10 growth hormone-secreting, 3 adrenocorticotropic hormone-secreting, and 1 thyroid-stimulating hormone-secreting). Paraffin sections were stained with CD34 and VEGF. MVD and vascular architecture parameters (vessel area, diameter, perimeter, and roundness) were evaluated in CD34-stained sections. Immunohistochemistry showed 27/51 tumors (53%) were VEGF-positive. There were no significant differences in MVD, any vascular parameter, or adenoma volume between VEGF-positive and VEGF-negative tumors. VEGF mRNA expression was significantly higher in VEGF-positive tumors. There were no significant correlations between VEGF mRNA expression and MVD or vascular parameters. However, vessel diameter and perimeter were significantly larger in prolactin-secreting than nonfunctioning and growth hormone-secreting macroadenomas. The difference in vessel diameter was observed among both VEGF-positive and all adenomas (micro- and macroadenoma). Thus, VEGF may have limited roles in the development of vascular architecture and tumor angiogenesis in pituitary adenomas, but the differences in vessel architecture by histotype (i.e., larger vessel diameter and perimeter in prolactin-secreting adenomas) suggest the hormonal regulation of vessel architecture rather than angiogenesis. PMID- 25431590 TI - Enucleation-induced rat adrenal gland regeneration: expression profile of selected genes involved in control of adrenocortical cell proliferation. AB - Enucleation-induced adrenal regeneration is a highly controlled process; however, only some elements involved in this process have been recognized. Therefore, we performed studies on regenerating rat adrenals. Microarray RNA analysis and QPCR revealed that enucleation resulted in a rapid elevation of expression of genes involved in response to wounding, defense response, and in immunological processes. Factors encoded by these genes obscure possible priming effects of various cytokines on initiation of regeneration. In regenerating adrenals we identified over 100 up- or downregulated genes involved in adrenocortical cell proliferation. The changes were most significant at days 2-3 after enucleation and their number decreased during regeneration. For example, expression analysis revealed a notable upregulation of the growth arrest gene, Gadd45, only 24 hours after surgery while expression of cyclin B1 and Cdk1 genes was notably elevated between days 1-8 of regeneration. These changes were accompanied by changes in expression levels of numerous growth factors and immediate-early transcription factors genes. Despite notable differences in mechanisms of adrenal and liver regeneration, in regenerating adrenals we identified genes, the expression of which is well recognized in regenerating liver. Thus, it seems legitimate to suggest that, in the rat, the general model of liver and adrenal regeneration demonstrate some degree of similarity. PMID- 25431592 TI - Incidence and outcomes of desmoplastic small round cell tumor: results from the surveillance, epidemiology, and end results database. AB - Desmoplastic small round cell tumor (DSRCT) is a rare but highly fatal malignancy. Due to the rarity of this neoplasm, no large population based studies exist. Procedure. This is a retrospective cohort analysis. Incidence rates were calculated based on sex and ethnicity and compared statistically. Gender-, ethnicity-, and treatment- based survival were calculated using the Kaplan-Meier method. Results. A total of 192 cases of DSRCT were identified. Peak incidence age was between 20 and 24 years. Age-adjusted incidence rate for blacks was 0.5 cases/million and for whites was 0.2 cases/million (P = 0.037). There was no statistically significant difference in survival based on gender or ethnicity. When adjusted for age, there was no statistically significant difference in survival amongst patients who received radiation therapy compared to those who did not (HRadj = 0.73; 95% CI 0.49, 1.11). There was a statistically significant survival advantage for patients who received radiation after surgery compared to those who did not (HR 0.49; 95% CI 0.30, 0.79). Conclusion. DSRCT is more common in males and in people of African-American descent. Although overall survival remains poor, radiation therapy following surgery seems to improve outcome in these patients. PMID- 25431593 TI - Determining risk factors of bleeding in patients on warfarin treatment. AB - Background. Warfarin is a commonly used oral anticoagulant agent. The most common adverse effects of warfarin are bleeding complications. Methods. We performed a 1 year retrospective chart review of emergency department patients using warfarin. A total of 65 patients with bleeding disorder (study group) and 63 patients without bleeding (control group) were included, making up a total of 128 subjects. Demographic data, frequency of international normalized ratio (INR) checks, and routine blood results were extracted. Logistic regression analysis was used to determine which factors were most closely associated with bleeding complications. Results. Median age was 62.0 +/- 14.4 and 61.9 +/- 14.5 for study group and control group, respectively. Educational status and frequency of INR checks were similar in both groups (P = 0.101 and P = 0.483, resp.). INR levels were higher in the study group (5.45 +/- 3.98 versus 2.63 +/- 1.71, P < 0.001). Creatinine levels were also higher in the study group (1.14 +/- 0.57 mg/dL versus 0.94 +/- 0.38 mg/dL, P = 0.042). Acetylsalicylic acid use was more frequent in the study group and was associated with a 9-fold increase in bleeding complications (P < 0.001). Conclusions. High INR levels, high creatinine levels, and acetylsalicylic acid use were associated with bleeding complications in ED patients using warfarin. PMID- 25431595 TI - Preeclampsia prediction and management. PMID- 25431594 TI - Radiation therapy with concurrent chemotherapy for locally advanced cervical carcinoma: outcome analysis with emphasis on the impact of treatment duration on outcome. AB - Objective. To assess the effectiveness and toxicity of carboplatin concurrent with pelvic external beam radiation and low-dose rate brachytherapy and to assess the impact that adherence to the treatment plan has on outcomes. Methods. Retrospective chart review of 56 patients treated from January 2001 to December 2010. Results. Median follow-up was 68 months. Optimal dose of radiation (ORT) was defined as a minimal cervical dose exceeding 70 Gy, point A dose of 80-90 Gy, and duration not exceeding 56 days. Only 50% received ORT. In multivariable analyses we only found ORT to be statistically significant predictor for progression-free survival (PFS) and overall survival (OS) (HR [95% CI] for non ORT vs. ORT: 2.4 [1.2, 5.1], P = 0.014 for PFS and 2.2 [1.1, 4.6], P = 0.035 for OS). The 5-year PFS in patients who received ORT was better than that in patients who received non-ORT, 56% vs. 22% (95% CI: [36%, 72%] vs. [9%, 39%]). Patients who received ORT had a better 5-year OS as well (59% vs. 33%; 95% CI: [38%, 75%] vs. [16%, 51%]). Conclusion. Patients with locally advanced cervical cancer treated with weakly carboplatin or cisplatin, teletherapy, and low dose-dose rate brachytherapy have poorer outcomes when treatment duration is prolonged. PMID- 25431596 TI - Rapunzel syndrome: a rare presentation with giant gastric ulcer. AB - The Rapunzel syndrome refers to an uncommon and rare form of trichobezoar that extends past the stomach into the small intestines. The Rapunzel syndrome is usually found in young female patients with a history of psychiatric disorders, mainly trichotillomania and trichophagia. We describe a case of Rapunzel syndrome in a 15-year-old girl who presented with abdominal pain, vomiting, and weight loss. We performed a surgical laparotomy and successfully removed a huge trichobezoar extending into the small intestine. PMID- 25431597 TI - Melanoma arising after imiquimod use. AB - Imiquimod belongs to the class of 1H-imidazo-[4,5-c]quinolones-drugs originally developed as nucleoside analogues with the aim of finding new potential antiviral agents (Harrison et al., 1988). Indeed, Imiquimod was first released as treatment for genital warts before its actions against skin cancer were studied. Imiquimod is a relatively small sized molecule (Mr = 240.3) and is hydrophobic, allowing it to penetrate the skin epidermal barrier and therefore making it suitable for topical formulations (Gerster et al., 2005). Imiquimod has shown itself effective against skin cancers and precancerous lesions, especially basal cell cancers and actinic keratosis (Salasche et al., 2002, Beutner et al., 1999). There have been reports of Imiquimod being used as topical treatment against cutaneous metastases of melanoma and some authors have reported its use as first-line therapy against melanoma in situ (Smyth et al., 2011, Gagnon, 2011). We report a case of an invasive malignant melanoma arising de novo at the specific site of application of Imiquimod (Aldara cream 5%) for a biopsy-proven superficial BCC. Therefore while Imiquimod has added to our topical armamentarium against skin cancer, care must be exercised in prescribing this treatment and it is especially important to follow up patients regularly. PMID- 25431598 TI - A challenging case of an ectopic cushing syndrome. AB - Bronchopulmonary carcinoids are rare pulmonary neoplasms although they account for most cases of ectopic ACTH syndromes. When feasible, the mainstay treatment is surgical resection of the tumor. We report the case of a 52-year-old woman with signs and symptoms suggestive of hypercortisolism for 12 months, admitted to our department because of community acquired pneumonia. Blood hormone analysis showed increased levels of ACTH and urinary free cortisol and nonsuppressibility to high- and low-dose dexamethasone tests. Pituitary MRI showed no lesion and no central-to-peripheral ACTH gradient was present in bilateral inferior petrosal sinus sampling. CRH stimulation test suggested an ectopic ACTH source. Thoracic CT scan revealed a nodular region measuring 12 mm located in the inferior lingular lobule of the left superior lung with negative uptake by (18)-FDG-PET scan and negative SRS. The patient was successfully treated with an atypical lung resection and histology revealed an atypical bronchial carcinoid tumor with positive ACTH immunoreactivity. This was an interesting case because the patient was admitted due to pneumonia that may have been associated with her untreated and chronic hypercortisolism and a challenging case of ectopic ACTH syndrome due to conflicting results on the diagnostic exams. PMID- 25431599 TI - An adult patient with systemic mastocytosis and B-acute lymphoblastic leukemia. AB - Mastocytosis is a myeloproliferative neoplasm characterized by clonal expansion of abnormal mast cells, ranging from the cutaneous forms of the disease to mast cell leukemia. In a significant proportion of patients, systemic mastocytosis (SM) coexists with another hematologic malignancy, termed systemic mastocytosis with an associated hematologic nonmast cell lineage disorder (SM-AHNMD). Despite the pronounced predominance of concomitant myeloid neoplasms, the much more unusual coexistence of lymphoproliferative diseases has also been reported. Imatinib mesylate (IM) has a role in the treatment of SM in the absence of the KITD816V mutation. In the setting of SM-AHNMD, eradicating the nonmast cell malignant clone greatly affects prognosis. We report a case of an adult patient with SM associated with B-lineage acute lymphoblastic leukemia (B-ALL). Three cases of concurrent adult ALL and mastocytosis have been reported in the literature, one concerning SM and two concerning cutaneous mastocytosis (CM), as well as six cases of concomitant CM and ALL in children. PMID- 25431600 TI - Hypernatremia: correction rate and hemodialysis. AB - Severe hypernatremia is defined as serum sodium levels above 152 mEq/L, with a mortality rate >=60%. 85-year-old gentleman was brought to the emergency room with altered level of consciousness after refusing to eat for a week at a skilled nursing facility. On admission patient was nonverbal with stable vital signs and was responsive only to painful stimuli. Laboratory evaluation was significant for serum sodium of 188 mmol/L and water deficit of 12.0 L. Patient was admitted to medicine intensive care unit and after inadequate response to suboptimal fluid repletion, hemodialysis was used to correct hypernatremia. Within the first fourteen hours, sodium concentration only changed 1 mEq/L with a fluid repletion; however, the concentration dropped greater than 20 mEq/L within two hours during hemodialysis. Despite such a drastic drop in sodium concentration, patient did not develop any neurological sequela and was at baseline mental status at the time of discharge. PMID- 25431601 TI - A Comparative View on Human Somatic Cell Sources for iPSC Generation. AB - The breakthrough of reprogramming human somatic cells was achieved in 2006 by the work of Yamanaka and Takahashi. From this point, fibroblasts are the most commonly used primary somatic cell type for the generation of induced pluripotent stem cells (iPSCs). Various characteristics of fibroblasts supported their utilization for the groundbreaking experiments of iPSC generation. One major advantage is the high availability of fibroblasts which can be easily isolated from skin biopsies. Furthermore, their cultivation, propagation, and cryoconservation properties are uncomplicated with respect to nutritional requirements and viability in culture. However, the required skin biopsy remains an invasive approach, representing a major drawback for using fibroblasts as the starting material. More and more studies appeared over the last years, describing the reprogramming of other human somatic cell types. Cells isolated from blood samples or urine, as well as more unexpected cell types, like pancreatic islet beta cells, synovial cells, or mesenchymal stromal cells from wisdom teeth, show promising characteristics for a reprogramming strategy. Here, we want to highlight the advantages of keratinocytes from human plucked hair as a widely usable, noninvasive harvesting method for primary material in comparison with other commonly used cell types. PMID- 25431603 TI - The long-term effectiveness of the International Child Development Programme (ICDP) implemented as a community-wide parenting programme. AB - Short-term effectiveness of the International Child Development Programme (ICDP) for parents in the general population has been studied. The aim of this paper was to investigate the longer term impact of the ICDP programme on parents looking for sustained changes 6-12 months after the programme. For this, a non-clinical caregiver group attending the ICDP programme (N = 79) and a non-attending comparison group (N = 62) completed questionnaires on parenting, psychosocial functioning, and child difficulties before, on completion and 6-12 months after the ICDP programme. Analyses compare changes in scores over time. The results revealed that the ICDP group showed significantly improved scores on parenting measures, less loneliness, and trends towards improved self-efficacy compared to the comparison group 6-12 months after programme completion. The ICDP group also reported that their children spent significantly less time on television and computer games and a trend towards fewer child difficulties. Key positive effects sustained over time but at a somewhat lower level, supporting community-wide implementation of ICDP as a general parenting programme. It is concluded that more intensive training with follow-up sessions should be considered to sustain and boost initial gains. PMID- 25431602 TI - Applicability of the environmental relative moldiness index for quantification of residential mold contamination in an air pollution health effects study. AB - The Near-Road Exposures and Effects of Urban Air Pollutants Study (NEXUS) investigated the impact of exposure to traffic-related air pollution on the respiratory health of asthmatic children in Detroit, Michigan. Since indoor mold exposure may also contribute to asthma, floor dust samples were collected in participants homes (n = 112) to assess mold contamination using the Environmental Relative Moldiness Index (ERMI). The repeatability of the ERMI over time, as well as ERMI differences between rooms and dust collection methods, was evaluated for insights into the application of the ERMI metric. ERMI values for the standard settled floor dust samples had a mean +/- standard deviation of 14.5 +/- 7.9, indicating high levels of mold contamination. ERMI values for samples collected from the same home 1 to 7 months apart (n = 52) were consistent and without systematic bias. ERMI values for separate bedroom and living room samples were highly correlated (r = 0.69, n = 66). Vacuum bag dust ERMI values were lower than for floor dust but correlated (r = 0.58, n = 28). These results support the use of the ERMI to evaluate residential mold exposure as a confounder in air pollution health effects studies. PMID- 25431604 TI - Psychological stress associated with cardiogenetic conditions. AB - AIM: Genetic testing now makes it possible to identify specific mutations that may lead to life-threatening cardiac arrhythmias. This article presents data from a qualitative research study that explored the subjective experiences of individuals and families with cardiogenetic conditions. We focus on describing patients' experiences of psychological stresses associated with having a cardiogenetic condition, illustrating the importance of integrating psychological and medical care. This integration of care is particularly important as personalized genomic medicine continues to evolve and the implications of genetic testing have a profound effect on individuals and families. METHODS: The researchers interviewed 50 participants from 32 families. The research team used a systematic, grounded theory procedure to code and analyze interview and focus group transcripts, incorporating multiple coders at several stages of the data analysis process. RESULTS: Three major themes emerged: a bereavement trajectory associated with sudden death in the absence of prior symptoms; high anxiety about transmitting a genetic mutation; and resilience reflected in positive lifestyle changes and participation in support groups. CONCLUSION: This article identifies patient perspectives on personalized genomic medicine in cardiogenetics that can improve clinical care, including: specialized bereavement counseling; improving education about cardiogenetic conditions for medical professionals; parent guidelines for discussing cardiogenetic conditions with their children; information about support groups; and the routine inclusion of clinical psychologists in interdisciplinary treatment teams. Given recent advances in technology and decreasing costs, whole-genome sequencing is likely to become common practice in the near future. Therefore, these recommendations are likely to be relevant for other genetic conditions, as well as the entire field of personalized genomic medicine. PMID- 25431605 TI - Coenzyme Q0 from Antrodia cinnamomea in Submerged Cultures Induces Reactive Oxygen Species-Mediated Apoptosis in A549 Human Lung Cancer Cells. AB - We investigated the anticancer effects of Antrodia cinnamomea, a medicinal mushroom from Taiwan, on A549 human lung cancer cells using the ethyl acetate extract from submerged culture filtrates. Our results showed that 2,3-dimethoxy-5 methyl-1,4-benzoquinone (coenzyme Q0; CoQ0) derived from A. cinnamomea submerged culture filtrates has anticancer activity. CoQ0 treatment reduced the viability of A549, HepG2, and SW480 cancer cell lines. Furthermore, CoQ0 induced reactive oxygen species (ROS) generation and apoptosis in A549 cells, which was inhibited by the antioxidant ascorbic acid. To our knowledge, these data demonstrate for the first time that CoQ0 derived from A. cinnamomea submerged culture filtrates exerts its anticancer effect through the induction of ROS-mediated apoptosis in A549 human lung cancer cells. PMID- 25431606 TI - Curcumin Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm by Inhibition of Inflammatory Response and ERK Signaling Pathways. AB - Background and Objectives. Curcumin has long been used to treat age-related diseases, such as atherosclerosis and coronary heart disease. In this study, we explored the effects of curcumin on the development of abdominal aortic aneurysm (AAA). Methods. ApoE(-/-) mice were randomly divided into 3 groups: AngII group, AngII + curcumin (AngII + Cur) group (100 mg/kg/d), and the control group. Miniosmotic pumps were implanted subcutaneously in ApoE(-/-) mice to deliver AngII for 28 days. After 4-week treatment, abdominal aortas with AAA were obtained for H&E staining, immunohistochemistry, and Western blotting. Results. The results showed that curcumin treatment significantly decreased the occurrence of AAA. The levels of macrophage infiltration, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factors-alpha (TNF-alpha) were significantly lower in AngII + Cur group than those in AngII group (all P < 0.01). The level of superoxide dismutase (SOD) was significantly higher in AngII + Cur group than those in AngII group (P < 0.01). The ERK1/2 phosphorylation in AngII + Cur group was significantly lower than that in AngII group (P < 0.01). Conclusions. These results suggested that curcumin can inhibit the AngII-induced AAA in ApoE(-/-) mice, whose mechanisms include the curcumin anti-inflammation, antioxidative stress, and downregulation of ERK signaling pathway. PMID- 25431608 TI - Subacute Oral Toxicity of Yukmijiwhang-Tang in Crl:CD Sprague-Dawley Rats and Its Cytotoxicity. AB - Background. The traditional herbal formula Yukmijiwhang-tang (YMJ) consists of six medicinal herbs and has been used to treat dysuria, diabetic mellitus, and neurosis in Korea, China, and Japan. Here we report safety information on its subacute toxicity and the cytotoxicity. Methods. YMJ extract was administered to SD rats at various dosages for 4 weeks. We monitored clinical signs, mortality, body and organ weights, food intake, and hematological and serum biochemistry factors. For cytotoxicity testing, each cell line was treated with various concentrations of YMJ for 24 h. Results. YMJ treatment had no significant effects on changes in clinical signs, body weight, or food intake in male or female rats. In male rats, YMJ treatment decreased the absolute weights of the epididymides and serum Na levels. In female rats, YMJ significantly reduced the prothrombin time (PT) and serum creatine level. However, the changes were not severe and were considered to be in the normal physiological range for rats. The no-observed adverse-effect-level (NOAEL) was estimated to be 2000 mg/kg/day. YMJ extract did not exert any cytotoxicity against 23 tested cell lines. Conclusions. Our data provide scientific evidence on the safety of YMJ for potential development as a prescription drug. PMID- 25431607 TI - A review of in vitro and in vivo studies on the efficacy of herbal medicines for primary dysmenorrhea. AB - Purpose. Primary dysmenorrhea (PD) is a common gynecological complaint among adolescent girls and women of reproductive age. This study aims to review the findings of published articles on the in vitro and in vivo efficacy of herbal medicines for PD. Methods. In vitro and in vivo studies of herbal compounds, individual herbal extracts, or herbal formula decoctions published from their inception to April 2014 were included in this review. Results. A total of 18 studies involving herbal medicines exhibited their inhibitory effect on PD. The majority of in vitro studies investigated the inhibition of uterine contractions. In vivo studies suggest that herbal medicines exert a peripheral analgesic effect and a possible anti-inflammatory activity via the inhibition of prostaglandin (PG) synthesis. The mechanisms of herbal medicines for PD are associated with PG level reduction, suppression of cyclooxygenase-2 expression, superoxide dismutase activation and malondialdehyde reduction, nitric oxide, inducible nitric oxide synthase, and nuclear factor-kappa B reduction, stimulation of somatostatin receptor, intracellular Ca(2+) reduction, and recovery of phospholipid metabolism. Conclusions. Herbal medicines are thought to be promising sources for the development of effective therapeutic agents for PD. Further investigations on the appropriate herbal formula and their constituents are recommended. PMID- 25431609 TI - Antioxidative Effects of Germinated Brown Rice-Derived Extracts on H2O2-Induced Oxidative Stress in HepG2 Cells. AB - The antioxidant properties of germinated brown rice (GBR) are likely mediated by multiple bioactives. To test this hypothesis, HepG2 cells pretreated with GBR extracts, rich in acylated steryl glycoside (ASG), gamma amino butyric acid GABA), phenolics or oryzanol, were incubated with hydrogen peroxide (H2O2) and their hydroxyl radical (OH(*)) scavenging capacities and thiobarbituric acid reactive substances (TBARS) generation were evaluated. Results showed that GBR extracts increased OH(*) scavenging activities in both cell-free medium and posttreatment culture media, suggesting that the extracts were both direct- and indirect-acting against OH(*). The levels of TBARS in the culture medium after treatment were also reduced by all the extracts. In addition, H2O2 produced transcriptional changes in p53, JNK, p38 MAPK, AKT, BAX, and CDK4 that were inclined towards apoptosis, while GBR-extracts showed some transcriptional changes (upregulation of BAX and p53) that suggested an inclination for apoptosis although other changes (upregulation of antioxidant genes, AKT, JNK, and p38 MAPK) suggested that GBR-extracts favored survival of the HepG2 cells. Our findings show that GBR bioactive-rich extracts reduce oxidative stress through improvement in antioxidant capacity, partly mediated through transcriptional regulation of antioxidant and prosurvival genes. PMID- 25431610 TI - Simultaneous Determination of Nine Active Compounds of the Traditional Chinese Medicinal Prescription Shaoyao-Gancao-Tang and Analysis of the Relationship between Therapeutical Effect and Compatibility of Medicines. AB - A simple and sensitive HPLC-DAD detection method was established for the simultaneous determination of nine compounds including oxypaeoniflorin, albiflorin, paeoniflorin, benzoylpaeoniflorin, glycyrrhizic acid, liquiritin, isoliquiritin, liquiritigenin, and isoliquiritigenin in the Traditional Chinese Medicinal Prescription Shaoyao-Gancao-Tang (SGT) and we analyze the relationship between therapeutical effect and compatibility of medicines by using an Agilent extend-C18 column at a flow rate of 1 mL/min. The column temperature was maintained at 30 degrees C and the detection wavelength was set at 230 nm for oxypaeoniflorin, albiflorin, paeoniflorin, benzoylpaeoniflorin, and glycyrrhizic acid; 276 nm for liquiritin and liquiritigenin; 360 nm for isoliquiritin and isoliquiritigenin. The total contents of the nine compounds in SGT varied from 4.65 to 20.06 mg/mL. The results of this study showed that the content of chemical compounds of Traditional Chinese Medicinal Prescription is mainly influenced by the dosage and compatibility of medicines and the therapeutical effect of Traditional Chinese Medicinal prescription is mainly influenced by the dosage and compatibility of medicines. The method could be suitable for quality control of SGT with bioactive multicompounds. PMID- 25431611 TI - Ginsenosides Rg1 from Panax ginseng: A Potential Therapy for Acute Liver Failure Patients? AB - Acute liver failure (ALF) is a rapidly progressing critical illness with a high mortality rate. Circulating inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), play a significant role in the pathophysiology of ALF through promoting hepatocellular apoptosis. Ginsenoside Rg1, the primary active ingredient in Panax ginseng (also termed Asian or Korean ginseng), has been reported to inhibit TNF-alpha production and has been shown to significantly attenuate liver fibrosis development. Here, we assessed ginsenoside Rg1's potential as a therapy for ALF by investigating the effect of ginsenoside Rg1 treatment on circulating inflammatory markers, hepatocellular apoptosis, and relevant apoptotic signaling pathways in a well-established murine ALF model. We found that ginsenoside Rg1 significantly reduces liver damage in a murine ALF model through inhibiting TNF-alpha-induced, caspase-dependent hepatocellular apoptosis. These results support the further investigation of ginsenoside Rg1 as a therapeutic candidate for ALF. PMID- 25431612 TI - Transcutaneous Neuromodulation at Posterior Tibial Nerve and ST36 for Chronic Constipation. AB - The aims of this study were to investigate the effects and possible mechanisms of transcutaneous neuromodulation (TN) in patients with chronic constipation. Twelve patients were recruited. The treatment consisted of 2-week TN and 2-week sham-TN which was performed in a crossover design. Bowel habit diary, Patient Assessment of Constipation Symptom (PAC-SYM), Patient Assessment of Constipation Quality of Life (PAC-QOL), and anorectal motility were evaluated. Electrocardiogram was recorded for the assessment of autonomic function during acute TN therapy. It was found that (1) TN improved the frequency of spontaneous defecation. After 2-week TN therapy, 83% patients had more than 3 times bowel movements per week which was significantly different from sham-TN (P = 0.01). (2) TN improved PAC-SYM and PAC QOL scores (P < 0.001, resp.). (3) TN significantly decreased the threshold volume to elicit RAIR (P < 0.05), ameliorated rectal sensory threshold (P = 0.04), and maximum tolerance (P = 0.04). (4) TN, but not sham-TN, increased the vagal activity (P = 0.01 versus baseline) and decreased the sympathetic activity (P = 0.01, versus baseline). It was concluded that needleless TN at posterior tibial nerve and ST36 using a watch-size stimulator is effective in chronic constipation, and the effect was possibly mediated via the autonomic mechanism. PMID- 25431614 TI - A case study of 'The Good School:' Examples of the use of Peterson's strengths based approach with students. AB - This applied case study centers on two aspects of Peterson's research as introduced into a large K-12 school in Australia: (i) creating enabling institutions and (ii) applications of character strengths. The paper describes five character strengths initiatives. Four of the strengths initiatives have been integrated into existing school experiences such as English curriculum, school sport, student leadership, and counseling. The fifth initiative involved a brand new program which introduced a Positive Education Curriculum for years K-10. We describe these five initiatives and then explain how students at the school may experience these in a more holistic and integrated way. We hope that this article will act as a fitting tribute to the legacy of Christopher Peterson. PMID- 25431613 TI - Preclinical Safety of the Root Extract of Polygala tenuifolia Willdenow in Sprague-Dawley Rats and Beagle Dogs. AB - The root of Polygala tenuifolia Willdenow has been used for the treatment of insomnia, depression, and amnesia. However, the toxicological properties of the herb have been overlooked, because it has been used for a long time for various purposes. In this study, we evaluated the preclinical safety of the root extract in rats and beagle dogs. First, the acute oral toxicity was tested in both rats and dogs. In the rats, only one female of 2 g/kg died, but no treatment-related death or clinical and gross findings were observed after the administration. No toxicological changes or mortalities related to the test substance were also observed after the administration in the dogs. Although vomiting, discoloration, or hemorrhage was found in some dogs, there were no serious abnormalities. Second, the subchronic toxicity was investigated in the rats. Two animals were found dead in the female group of 1,000 mg/kg/day, but there were no abnormal findings associated with the test substance. There also were no adverse effects on the clinical signs, body weight, and hematological and biochemical findings. Therefore, our results showed that the acute or subchronic toxicity of the root extract of Polygala tenuifolia might not be toxic to rats and dogs. PMID- 25431615 TI - The road to HIV-1 integrase inhibitors: the case for supporting basic research. AB - AIDS has been transformed from a death sentence to a manageable disease for many patients with access to combination antiviral therapy. It is informative to look back on some of the key advances that have led to this transformation. The arsenal of tools currently available to clinicians now includes inhibitors of the viral reverse transcriptase, protease and integrase enzymes. The author discusses some of the key advances that have led to this transformation with an emphasis on the role of basic science in developing integrase inhibitors. Many of the stepping-stones could not easily have been foreseen to lead to medical advances. Treatments for diseases that are yet to emerge will likely depend on the progress made in basic science today. PMID- 25431616 TI - The RNA-dependent RNA polymerase of the influenza A virus. AB - The influenza A virus causes a highly contagious respiratory disease that significantly impacts our economy and health. Its replication and transcription is catalyzed by the viral RNA polymerase. This enzyme is also crucial for the virus, because it is involved in the adaptation of zoonotic strains. It is thus of major interest for the development of antiviral therapies and is being intensively studied. In this article, we will discuss recent advances that have improved our knowledge of the structure of the RNA polymerase and how mutations in the polymerase help the virus to spread effectively among new hosts. PMID- 25431617 TI - Dance program for physical rehabilitation and participation in children with cerebral palsy. AB - Objective: This pilot study aimed to examine a classical ballet program created for children with cerebral palsy (CP) as an emerging physical rehabilitation modality. The main program goals were to promote participation and to provide an artistic, physically therapeutic activity. Methods: The study was conducted in collaboration with a tertiary rehabilitation hospital, one outpatient physical therapy clinic, and one community center. As a pilot exploratory study, the research design included questionnaires to assess the participants' (children (n = 16), parents (n = 16), and therapists (n = 13)) perceptions on the therapeutic benefit of the dance program. A binomial statistical model was adopted for the analysis of the results. Results: Main results were that the children reported high enjoyment level (p < .0001) and desire for more classes (.0001); the parents reported perceived therapeutic benefit (p < .0001); and the therapists viewed the class as a positive adjunct to therapy (p < .0001). Conclusions: The main limitation of this work was the utilization of subjective outcome measures. However, this is the first step toward the development of objective measures of an intervention that, to our knowledge, has not been analyzed in the past. We conclude that the program has the potential of developing into an evidence based rehabilitation resource for children with CP. PMID- 25431619 TI - A Reply to Commentaries on "How the Object of Affect Guides Its Impact" AB - Commentaries focused on the emotional appraisal part of our article. Cunningham and Van Bavel argued for distinguishing core disgust from moral disgust, and we describe how the theory might accommodate their proposal. They also suggested that temporal and other comparisons could account for emotional variety. We concur, but see such comparisons as inherent in the different emotional objects. Winkielman emphasized unconscious affect, but we suggest its power flows from the absence of situational constraints on its meaning. He characterized our appraisal model as coldly cognitive rather than embodied, but the complaint is misdirected, as the model addresses emotional structure, not emotional process. Indeed, embodied accounts will still require structural accounts to determine why one emotion rather than another is elicited. PMID- 25431618 TI - How the Object of Affect Guides its Impact. AB - In this article, we examine how affect influences judgment and thought, but also how thought transforms affect. The general thesis is that the nature and impact of affective reactions depends largely on their objects. We view affect as a representation of value, and its consequences as dependent on its object or what it is about. Within a review of relevant literature and a discussion of the nature of emotion, we focus on the role of the object of affect in governing both the nature of emotional reactions and the impact of affect and emotion on cognition and action. Although emotion is always about the here and now, the capacity for abstract thought means that the human here and now includes imagination as well as perception. Indeed, the hopes and fears that dominate human lives often involve things only imagined. PMID- 25431620 TI - Psychological Construction in the OCC Model of Emotion. AB - This article presents six ideas about the construction of emotion: (a) Emotions are more readily distinguished by the situations they signify than by patterns of bodily responses; (b) emotions emerge from, rather than cause, emotional thoughts, feelings, and expressions; (c) the impact of emotions is constrained by the nature of the situations they represent; (d) in the OCC account (the model proposed by Ortony, Clore, and Collins in 1988), appraisals are psychological aspects of situations that distinguish one emotion from another, rather than triggers that elicit emotions; (e) analyses of the affective lexicon indicate that emotion words refer to internal mental states focused on affect; (f) the modularity of emotion, long sought in biology and behavior, exists as mental schemas for interpreting human experience in story, song, drama, and conversation. PMID- 25431621 TI - Expansion of the genetic toolkit for metabolic engineering of Clostridium pasteurianum: chromosomal gene disruption of the endogenous CpaAI restriction enzyme. AB - BACKGROUND: Clostridium pasteurianum is one of the most promising biofuel producers within the genus Clostridium owing to its unique metabolic ability to ferment glycerol into butanol. Although an efficient means is available for introducing foreign DNA to C. pasteurianum, major genetic tools, such as gene knockout, knockdown, or genome editing, are lacking, preventing metabolic engineering of C. pasteurianum. RESULTS: Here we present a methodology for performing chromosomal gene disruption in C. pasteurianum using the programmable lactococcus Ll.ltrB group II intron. Gene disruption was initially found to be impeded by inefficient electrotransformation of Escherichia coli-C. pasteurianum shuttle vectors, presumably due to host restriction. By assessing the ability of various vector deletion derivatives to electrotransform C. pasteurianum and probing the microorganism's methylome using next-generation sequence data, we identified a new C. pasteurianum Type I restriction-methylation system, CpaAII, with a predicted recognition sequence of 5'-AAGNNNNNCTCC-3' (N = A, C, G, or T). Following rescue of high-level electrotransformation via mutation of the sole CpaAII site within the shuttle vectors, we retargeted the intron to the cpaAIR gene encoding the CpaAI Type II restriction endonuclease (recognition site of 5' CGCG-3'). Intron insertion was potentially hindered by low retrohoming efficiency, yet this limitation could be overcome by a procedure for enrichment of the intron insertion. The resulting DeltacpaAIR mutant strain was efficiently electrotransformed with M.FnuDII-unmethylated plasmid DNA. CONCLUSIONS: The markerless and plasmidless DeltacpaAIR mutant strain of C. pasteurianum developed in this study can serve as a general host strain for future genetic and metabolic manipulation. Further, the associated gene disruption protocol should not only serve as a guide for chromosomal gene inactivation studies involving mobile group II introns, but also prove invaluable for applying metabolic engineering strategies to C. pasteurianum. PMID- 25431622 TI - Aerobic and sequential anaerobic fermentation to produce xylitol and ethanol using non-detoxified acid pretreated corncob. AB - BACKGROUND: For economical bioethanol production from lignocellulosic materials, the major technical challenges to lower the production cost are as follows: (1) The microorganism should use efficiently all glucose and xylose in the lignocellulose hydrolysate. (2) The microorganism should have high tolerance to the inhibitors present in the lignocellulose hydrolysate. The aim of the present work was to combine inhibitor degradation, xylitol fermentation, and ethanol production using a single yeast strain. RESULTS: A new process of integrated aerobic xylitol production and anaerobic ethanol fermentation using non detoxified acid pretreated corncob by Candida tropicalis W103 was proposed. C. tropicalis W103 is able to degrade acetate, furfural, and 5-hydromethylfurfural and metabolite xylose to xylitol under aerobic conditions, and the aerobic fermentation residue was used as the substrate for ethanol production by anaerobic simultaneous saccharification and fermentation. With 20% substrate loading, furfural and 5-hydroxymethylfurfural were degraded totally after 60 h aerobic incubation. A maximal xylitol concentration of 17.1 g l(-1) was obtained with a yield of 0.32 g g(-1) xylose. Then under anaerobic conditions with the addition of cellulase, 25.3 g l(-1) ethanol was produced after 72 h anaerobic fermentation, corresponding to 82% of the theoretical yield. CONCLUSIONS: Xylitol and ethanol were produced in Candida tropicalis W103 using dual-phase fermentations, which comprise a changing from aerobic conditions (inhibitor degradation and xylitol production) to anaerobic simultaneous saccharification and ethanol fermentation. This is the first report of integrated xylitol and ethanol production from non-detoxified acid pretreated corncob using a single microorganism. PMID- 25431623 TI - Description of a multidisciplinary initiative to improve SCIP measures related to pre-operative antibiotic prophylaxis compliance: a single-center success story. AB - BACKGROUND: The Surgical Care Improvement Project (SCIP) was launched in 2005. The core prophylactic perioperative antibiotic guidelines were created due to recognition of the impact of proper perioperative prophylaxis on an estimated annual one million inpatient days and $1.6 billion in excess health care costs secondary to preventable surgical site infections (SSIs). An internal study was conducted to create low cost, standardized processes on an institutional level to improve compliance with prophylactic antibiotic administration. METHODS: We assessed the impact of auditing and notifying providers of SCIP errors on overall compliance with inpatient antibiotic guidelines and on net financial gain or loss to a large tertiary center between March 1st 2010 and September 31st 2013. We hypothesized that direct physician-to-physician feedback would result in significant compliance improvements. RESULTS: Through physician notification, our hospital was able to significantly improve SCIP compliance and emphasis on patient safety within a year of intervention implementation. The hospital earned an additional $290,612 in 2011 and $209,096 in 2012 for re-investment in patient care initiatives. CONCLUSIONS: Provider education and direct notification of SCIP prophylactic antibiotic dosing errors resulted in improved compliance with national patient improvement guidelines. There were differences between the anesthesiology and surgery department feedback responses, the latter likely attributed to diverse surgical department sub-divisions, frequent changes in resident trainees and supervising attending staff, and the comparative ability. Provider notification of guideline non-compliance should be encouraged as standard practice to improve patient safety. Also, the hospital experienced increased revenue for re-investment in patient care as a secondary result of provider notification. PMID- 25431624 TI - Depression symptoms in people with diabetes attending outpatient podiatry clinics for the treatment of foot ulcers. AB - BACKGROUND: The purpose of this study was to examine the prevalence of depressive symptoms, diabetes self-management, and quality of life in people with diabetes and foot ulcers. Ulcer status, mortality and amputations were also assessed at six months follow-up. METHODS: This was a cross-sectional survey of people attending outpatient podiatry clinics at a major tertiary referral hospital. Depressive symptoms were measured using the Patient Health Questionnaire (PHQ). Diabetes self-care was assessed using the Summary of Diabetes Self Care Activities (SDSCA) measure. Health-related quality of life was measured using the physical component summary score (PCS) and the mental component summary score (MCS) of the SF-12. RESULTS: Of the 60 participants in the study 14 (23.3%) reported mild symptoms of depression (PHQ score 5-9) and 17 (28.3%) moderate to severe depressive symptoms (PHQ score > 9). Twenty-one (35%) met the criteria for previously recognized depression (on antidepressants and/or a diagnosis of depression in the last 12 months) and 17 (28.3%) for depression not previously recognized (PHQ > 4). Seventeen (28%) participants had been receiving antidepressant treatment for a median duration of 104 weeks (IQR 20, 494 weeks). Despite antidepressant treatment 12 participants (70.6% of those taking antidepressants) still reported moderate to severe depressive symptoms at the time of the study. Patients with PHQ scores > 4 reported poorer adherence to diabetes self-care activities including general diet, exercise, blood sugar monitoring and foot care when compared to those participants with PHQ scores < 5. No association was found between physical functioning (PCS) and depressive symptoms. Decreasing mental wellbeing (MCS) was associated with increasing depressive symptoms. At six months follow-up, there were three deaths and three amputations in participants with PHQ scores > 4 compared with no deaths and 2 amputations in participants with PHQ scores < 5. There was no association between depressive symptoms and ulcer healing or ulcer recurrence at the six-month follow up. CONCLUSIONS: This study found a high prevalence of depressive symptoms both recognized and unrecognized in people with diabetes and foot ulcers. Depressive symptoms were associated with overall poorer diabetes self-management and health related quality of life (HRQoL). There was no association between depressive symptoms and ulcer outcomes at six-months follow-up. PMID- 25431625 TI - Quantum and Molecular Mechanical (QM/MM) Monte Carlo Techniques for Modeling Condensed-Phase Reactions. AB - A recent review (Acc. Chem. Res. 2010, 43:142-151) examined our use and development of a combined quantum and molecular mechanical (QM/MM) technique for modelling organic and enzymatic reactions. Advances included the PDDG/PM3 semiempirical QM (SQM) method, computation of multi-dimensional potentials of mean force (PMF), incorporation of on-the-fly QM in Monte Carlo simulations, and a polynomial quadrature method for rapidly treating proton-transfer reactions. The current article serves as a follow up on our progress. Highlights include new reactions, alternative SQM methods, a polarizable OPLS force field, and novel solvent environments, e.g., "on water" and room temperature ionic liquids. The methodology is strikingly accurate across a wide range of condensed-phase and antibody-catalyzed reactions including substitution, decarboxylation, elimination, isomerization, and pericyclic classes. Comparisons are made to systems treated with continuum-based solvents and ab initio or density functional theory (DFT) methods. Overall, the QM/MM methodology provides detailed characterization of reaction paths, proper configurational sampling, several advantages over implicit solvent models, and a reasonable computational cost. PMID- 25431626 TI - Paper-based electrochemical immunoassay for rapid, inexpensive cancer biomarker protein detection. AB - Inexpensive, reusable electrochemical sensor chips were fabricated from gold CDs. All reagents were loaded onto a paper disk sequentially, then placed on the chip to detect cancer biomarker prostate specific antigen (PSA) in serum at pg mL-1 levels in ~15 mins. PMID- 25431627 TI - A review of neuroimaging biomarkers of Alzheimer's disease. AB - Neuroimaging biomarkers have potential role in the early diagnosis as well as periodic follow-up of neurodegenerative diseases such as Alzheimer's disease (AD). Structural imaging biomarkers can be used to predict those who are at risk or in preclinical stages of AD. It could possibly be useful even in predicting the conversion of Mild Cognitive Impairment (MCI) an early stage of AD to AD. In addition there has been a lot of progress in molecular imaging in AD. This article presents a review of recent progress in selected imaging biomarkers for early diagnosis, classification, and progression, of AD. A comprehensive integrative strategy initiated early in the cognitive decline is perhaps the most effective method of controlling progression to Alzheimer's disease. PMID- 25431628 TI - Click Triazoles for Bioconjugation. AB - Click Chemistry is a set of rapid, selective and robust reactions that give near quantitative yield of the desired product in aqueous solutions. The Cu(I) catalyzed azide-alkyne cycloaddition (CuAAC) that forms 1,4-disubstituted triazoles is a prototypical example of click chemistry that features exquisite selectivity and bioorthogonality-that is, non-interacting with biological components while proceeding under physiological conditions. Over the past ten years, CuAAC has found extensive applications in the field of chemical biology. In this chapter, we describe the discovery of Cu(I) catalysts for this transformation and the recent development of the strain-promoted azide-alkyne cycloaddition that eliminate the use of copper. We also highlight several recent applications toward conjugating biomolecules, including proteins, nucleic acids, lipids and glycans, with biophysical probes for both in vitro and in vivo studies. PMID- 25431629 TI - Associations between daily mortality in London and combined oxidant capacity, ozone and nitrogen dioxide. AB - Both nitrogen dioxide (NO2) and ozone (O3) are powerful oxidants in ambient air that are intimately linked through atmospheric chemistry and which continuously interchange over very short timescales. Based upon atmospheric chemistry alone, there is a strong, a priori, reason for considering O3 and NO2 together in epidemiological studies, rather than either of the two pollutants separately in single-pollutant models. This paper compares two approaches to this, using Ox, defined as O3 + NO2, as a single metric and also using O3 and NO2 together in two pollutant models. We hypothesised that the magnitude of the association between Ox and daily mortality would be greater than for NO2 and O3 individually. Using collocated hourly measurements for O3 and NO2 in London, from 2000 to 2005, we carried out a time series analysis of daily mortality. We investigated O3, NO2 and Ox individually in single-pollutant Poisson regression models and NO2 and O3 jointly in two-pollutant models in both all-year and season-specific analyses. We observed larger associations for mean 24-h concentrations of Ox (1.30 % increase in mortality per 10 ppb) than for O3 (0.87 %) and NO2 (0 %) individually. However, when analysed jointly in two-pollutant models, associations for O3 (1.54 %) and NO2 (1.07 %) were comparable to the Ox association. Season-specific analyses broadly followed this pattern irrespective of whether the Ox concentrations were driven by O3 production (summer) or depletion (winter). This novel approach in air pollution epidemiology captures the simultaneous impact of both oxidants whilst avoiding many of the statistical issues associated with two pollutant models and potentially simplifies health impact calculations. PMID- 25431630 TI - Traffic-related pollution and asthma prevalence in children. Quantification of associations with nitrogen dioxide. AB - Ambient nitrogen dioxide is a widely available measure of traffic-related air pollution and is inconsistently associated with the prevalence of asthma symptoms in children. The use of this relationship to evaluate the health impact of policies affecting traffic management and traffic emissions is limited by the lack of a concentration-response function based on systematic review and meta analysis of relevant studies. Using systematic methods, we identified papers containing quantitative estimates for nitrogen dioxide and the 12 month period prevalence of asthma symptoms in children in which the exposure contrast was within-community and dominated by traffic pollution. One estimate was selected from each study according to an a priori algorithm. Odds ratios were standardised to 10 MUg/m3 and summary estimates were obtained using random- and fixed-effects estimates. Eighteen studies were identified. Concentrations of nitrogen dioxide were estimated for the home address (12) and/or school (8) using a range of methods; land use regression (6), study monitors (6), dispersion modelling (4) and interpolation (2). Fourteen studies showed positive associations but only two associations were statistically significant at the 5 % level. There was moderate heterogeneity (I2 = 32.8 %) and the random-effects estimate for the odds ratio was 1.06 (95 % CI 1.00 to 1.11). There was no evidence of small study bias. Individual studies tended to have only weak positive associations between nitrogen dioxide and asthma prevalence but the summary estimate bordered on statistical significance at the 5 % level. Although small, the potential impact on asthma prevalence could be considerable because of the high level of baseline prevalence in many cities. Whether the association is causal or indicates the effects of a correlated pollutant or other confounders, the estimate obtained by the meta-analysis would be appropriate for estimating impacts of traffic pollution on asthma prevalence. PMID- 25431631 TI - Cognitive Enhancement: Perceptions Among Parents of Children with Disabilities. AB - Cognitive enhancement is an increasingly discussed topic and policy suggestions have been put forward. We present here empirical data of views of parents of children with and without cognitive disabilities. Analysis of the interviews revealed six primary overarching themes: meanings of health and treatment; the role of medicine; harm; the 'good' parent; normality and self-perception; and ability. Interestingly none of the parents used the term ethics and only one parent used the term moral twice. PMID- 25431632 TI - Delusions and Responsibility for Action: Insights from the Breivik Case. AB - What factors should be taken into account when attributing criminal responsibility to perpetrators of severe crimes? We discuss the Breivik case, and the considerations which led to holding Breivik accountable for his criminal acts. We put some pressure on the view that experiencing certain psychiatric symptoms or receiving a certain psychiatric diagnosis is sufficient to establish criminal insanity. We also argue that the presence of delusional beliefs, often regarded as a key factor in determining responsibility, is neither necessary nor sufficient for criminal insanity. PMID- 25431633 TI - ANALYSIS OF MULTIPLE SCLEROSIS LESIONS VIA SPATIALLY VARYING COEFFICIENTS. AB - Magnetic resonance imaging (MRI) plays a vital role in the scientific investigation and clinical management of multiple sclerosis. Analyses of binary multiple sclerosis lesion maps are typically "mass univariate" and conducted with standard linear models that are ill suited to the binary nature of the data and ignore the spatial dependence between nearby voxels (volume elements). Smoothing the lesion maps does not entirely eliminate the non-Gaussian nature of the data and requires an arbitrary choice of the smoothing parameter. Here we present a Bayesian spatial model to accurately model binary lesion maps and to determine if there is spatial dependence between lesion location and subject specific covariates such as MS subtype, age, gender, disease duration and disease severity measures. We apply our model to binary lesion maps derived from T2-weighted MRI images from 250 multiple sclerosis patients classified into five clinical subtypes, and demonstrate unique modeling and predictive capabilities over existing methods. PMID- 25431634 TI - From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. AB - This unit describes how to use BWA and the Genome Analysis Toolkit (GATK) to map genome sequencing data to a reference and produce high-quality variant calls that can be used in downstream analyses. The complete workflow includes the core NGS data processing steps that are necessary to make the raw data suitable for analysis by the GATK, as well as the key methods involved in variant discovery using the GATK. PMID- 25431635 TI - Using SomaticSniper to Detect Somatic Single Nucleotide Variants. AB - Detecting somatic single nucleotide variants (SNVs) is an essential component of cancer research with next generation sequencing data. This protocol describes how to run the SomaticSniper somatic SNV detector and then filter the output to eliminate most false positives. It also includes support protocols detailing the compilation of the software. PMID- 25431636 TI - Synthesis of G-N2-(CH2)3-N2-G Trimethylene DNA interstrand cross-links. AB - The synthesis of G-N2-(CH2)3-N2-G trimethylene DNA interstrand cross-links (ICLs) in a 5'-CG-3' and 5'-GC-3' sequence from oligodeoxynucleotides containing N2-(3 aminopropyl)-2'-deoxyguanosine and 2-fluoro-O6-(trimethylsilylethyl)inosine is presented. Automated solid-phase DNA synthesis was used for unmodified bases and modified nucleotides were incorporated via their corresponding phosphoramidite reagent by a manual coupling protocol. The preparation of the phosphoramidite reagents for incorporation of N2-(3-aminopropyl)-2'-deoxyguanosine is reported. The high-purity trimethylene DNA interstrand cross-link product is obtained through a nucleophilic aromatic substitution reaction between the N2-(3 aminopropyl)-2'-deoxyguanosine and 2-fluoro-O6-(trimethylsilylethyl)inosine containing oligodeoxynucleotides. PMID- 25431637 TI - The Evolving Role of Circulating Tumor Cells in the Personalized Management of Breast Cancer: from Enumeration to Molecular Characterization. AB - Circulating Tumor cells (CTCs) represent tumor cells in the blood stream dislodged from the primary tumor. The presence of CTCs in the bloodstream provides a unique opportunity to sample cancer tissue by means of a relatively less-invasive "liquid biopsy." Over the past decade, there has been a tremendous increase in the amount of research examining the potential clinical utility of CTCs in the management of cancer. A number of techniques to refine the sensitivity and range of CTC assays are also in development. In this article, we review the recent developments in the current and potential clinical applications of CTCs in breast cancer. CTC enumeration already has an established role as a prognostic biomarker in metastatic breast cancer, while molecular characterization of CTCs can serve as a potential predictive biomarker for therapy selection, pharmacodynamic evaluation, and identification of novel actionable targets for novel therapies. The role of CTCs in breast cancer screening and detection of recurrence is currently limited. Further development in techniques will be pivotal in enhancing the broad applicability of CTCs and advancing the field of personalized breast cancer therapy. PMID- 25431638 TI - 103Pd versus 125I ophthalmic plaque brachytherapy: preoperative comparative radiation dosimetry for 319 uveal melanomas. AB - OBJECTIVE: This study was conducted to compare the relative, clinical intraocular dose distribution for palladium-103 (103Pd) versus iodine-125 (125I) ophthalmic plaque radiation therapy. METHODS: Preoperative comparative radiation dosimetry was performed to evaluate 319 consecutive uveal melanomas treated between 2006 and 2012. RESULTS: There were 68 (21.3 %) anterior (iris and/or ciliary body) and 251 (78.7 %) choroidal melanomas examined in this study. According to AJCC staging, 7th edition, 146 (45.8 %) were T1, 126 (39.5 %) T2, 40 (12.5 %) T3, and 7 (2.2 %) T4. All were prescribed an equivalent tumor-apex dose. When compared to 125I, 103Pd was associated with a mean 41.9 % lower radiation dose to the opposite eye wall (p < 0.001), 12.7 % to the lens center (p < 0.001), 7.5 % to the optic disc (p = 0.008), and a 3.8 % decrease to the fovea (p = 0.034). However, subgroup analysis of smaller (T1-staged) tumors showed greater dose reductions to normal ocular structures compared to larger (T4-staged) tumors. Tumor and therefore plaque location also affected intraocular dose distribution. For example, palladium-103-related dose reductions to the fovea, optic nerve, and opposite eye wall were significantly greater for iris and ciliary body tumors compared to posterior choroidal melanomas (p < 0.001). After comparative dosimetry, 98.7 % (n = 315/319) were treated with 103Pd. CONCLUSION: Preoperative comparative radiation dosimetry was performed for a large cohort of patients with uveal melanoma. It influenced radionuclide selection, offered an opportunity for radiation sparing of critical vision-related intraocular structures, and typically increased radiation within the tumors. PMID- 25431639 TI - Spontaneous pneumomediastinum and Macklin effect: Overview and appearance on computed tomography. AB - Spontaneous pneumomediastinum (SPM) is described as free air or gas located within the mediastinum that is not associated with any noticeable cause such as chest trauma. SPM has been associated with many conditions and triggers, including bronchial asthma, diabetic ketoacidosis, forceful straining during exercise, inhalation of drugs, as well as other activities associated with the Valsalva maneuver. The Macklin effect appears on thoracic computed tomography (CT) as linear collections of air contiguous to the bronchovascular sheaths. With the recent availability of multidetector-row CT, the Macklin effect has been seen in the clinical setting more frequently than expected. The aim of this review article is to describe the CT imaging spectrum of the Macklin effect in patients with SPM, focusing on the common appearance of the Macklin effect, pneumorrhachis, and persistent SPM with pneumatocele. PMID- 25431640 TI - Partial volume effect modeling for segmentation and tissue classification of brain magnetic resonance images: A review. AB - Quantitative analysis of magnetic resonance (MR) brain images are facilitated by the development of automated segmentation algorithms. A single image voxel may contain of several types of tissues due to the finite spatial resolution of the imaging device. This phenomenon, termed partial volume effect (PVE), complicates the segmentation process, and, due to the complexity of human brain anatomy, the PVE is an important factor for accurate brain structure quantification. Partial volume estimation refers to a generalized segmentation task where the amount of each tissue type within each voxel is solved. This review aims to provide a systematic, tutorial-like overview and categorization of methods for partial volume estimation in brain MRI. The review concentrates on the statistically based approaches for partial volume estimation and also explains differences to other, similar image segmentation approaches. PMID- 25431641 TI - Multimodality imaging of renal inflammatory lesions. AB - Spectrum of acute renal infections includes acute pyelonephritis, renal and perirenal abscesses, pyonephrosis, emphysematous pyelonephritis and emphysematous cystitis. The chronic renal infections that we routinely encounter encompass chronic pyelonephritis, xanthogranulomatous pyelonephritis, and eosinophilic cystitis. Patients with diabetes, malignancy and leukaemia are frequently immunocompromised and more prone to fungal infections viz. angioinvasive aspergillus, candida and mucor. Tuberculosis and parasitic infestation of the kidney is common in tropical countries. Imaging is not routinely indicated in uncomplicated renal infections as clinical findings and laboratory data are generally sufficient for making a diagnosis. However, imaging plays a crucial role under specific situations like immunocompromised patients, treatment non responders, equivocal clinical diagnosis, congenital anomaly evaluation, transplant imaging and for evaluating extent of disease. We aim to review in this article the varied imaging spectrum of renal inflammatory lesions. PMID- 25431642 TI - Impact of dose calculation algorithm on radiation therapy. AB - The quality of radiation therapy depends on the ability to maximize the tumor control probability while minimize the normal tissue complication probability. Both of these two quantities are directly related to the accuracy of dose distributions calculated by treatment planning systems. The commonly used dose calculation algorithms in the treatment planning systems are reviewed in this work. The accuracy comparisons among these algorithms are illustrated by summarizing the highly cited research papers on this topic. Further, the correlation between the algorithms and tumor control probability/normal tissue complication probability values are manifested by several recent studies from different groups. All the cases demonstrate that dose calculation algorithms play a vital role in radiation therapy. PMID- 25431643 TI - Association between facet joint osteoarthritis and the Oswestry Disability Index. AB - AIM: To investigate the correlation of facet joint osteoarthritis (FJOA) at lumbar levels L4/L5 and L5/S1 and the Oswestry Disability Index (ODI). METHODS: The study involved lumbar MRIs of 591 patients with a mean age of 47.3 years. The MRIs of the lumbar spine were performed on a 1.5 Tesla scanner (Magnetom((r)) Avanto, Siemens AG, Erlangen, Germany) using a dedicated receive only spine coil. After initial blinding, each dataset was evaluated by 2 board certified radiologist with more than 5 years experience in musculoskeletal imaging. In total 2364 facet joints were graded. Degenerative changes of the facet joints were evaluated according to the 4-point scale as proposed by Weishaupt et al Functional status was assessed using the ODI. The index is scored from 0 to 100 and interpreted as follows: 0%-20%, minimal disability; 20%-40%, moderate disability; 40%-60%, severe disability; 60%-80%, crippled; 80%-100%, patients are bedbound. Spearman's coefficient of rank correlation was used for statistical analysis, with significance set at P < 0.05. RESULTS: In total 2364 facet joints at lumbar levels L4/5 and L5/S1 were analysed in 591 individuals. FJOA was present in 97% (L4/L5) and 98% (L5/S1). At level L4/5 (left/right) 17/15 (2.9%/2.5%) were described as grade 0, 146/147 (24.7%/24.9%) as grade 1, 290/302 (49.1%/51.1%) as grade 2 and 138/127 (23.4%/21.5%) as grade 3. At level L5/S1 (left/right) 10/11 (1.7%/1.9%) were described as grade 0, 136/136 (23.0%/23.0%) as grade 1, 318/325 (53.8%/55.0%) as grade 2 and 127/119 (21.5%/20.1%) as grade 3. Regarding the ODI scores, patients' disability had a minimum of 0% and a maximum of 91.11% with an arithmetic mean of 32.77% +/- 17.02%. The majority of patients (48.39%) had moderate functional disability (21%-40%). There was no significant correlation between FJOA and ODI on both sides of lumbar level L4/5 and on the left side of lumbar level L5/S1. A weak positive correlation was evaluated between ODI and FJOA on the right side of lumbar level L5/S1. CONCLUSION: The missing correlation of FJOA and ODI confirms our clinical experience that imaging alone is an insufficient approach explaining low back pain. Clinical correlation is imperative for an adequate diagnostic advance in patients with low back pain. PMID- 25431644 TI - Truncus arteriosus: Diagnosis with dual-source computed tomography angiography and low radiation dose. AB - Truncus arteriosus is an uncommon congenital cardiac abnormality which is characterized by a single arterial trunk origin from the heart that supplies both the systemic, pulmonary and coronary circulation. We present a preterm newborn female patient with type 2 truncusarteriosus, left superior vena cava and aberrant subclavian artery diagnosed with low dose dual-source cardiac computed tomography (CT). We discuss that low dose dual-source cardiac CT has more advantages than other imaging methods and it is an important modality for assessment of patients with conotruncal anomalies such as truncusarteriosus. PMID- 25431645 TI - Cytoprotective effects of hydrogen sulfide-releasing N-methyl-D-aspartate receptor antagonists are mediated by intracellular sulfane sulfur. AB - Hydrogen sulfide (H2S) exerts a host of biological effects ranging from cytotoxicity to cytoprotection. Cytotoxicity of H2S in neurodegenerative diseases may be mediated by N-methyl-D-aspartate receptor (NMDAR) activation. To exploit cytoprotective effects of H2S while minimizing its toxicity, we synthesized a series of H2S-releasing NMDAR antagonists and examined their effects against 1 methyl-4-phenylpyridinium (MPP+)-induced cell death, a cellular model of Parkinson's disease. We observed that cytoprotective effect of H2S-releasing NMDAR antagonists correlated with their ability to increase intracellular sulfane sulfur, but not H2S, levels. These studies suggest that H2S-donor compounds that increase intracellular sulfane sulfur are potentially useful neuroprotective agents against neurodegenerative diseases. PMID- 25431646 TI - Microfluidic continuous-flow radiosynthesis of [18F]FPEB suitable for human PET imaging. AB - The synthesis of fluorine-18 labeled 3-fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ([18F]FPEB) for imaging metabotropic glutamate receptor subtype type 5 (mGluR5) was achieved with a commercial continuous-flow microfluidics device. This work represents the first positron emission tomography (PET) radiopharmaceutical that is suitable for human use with this technology. We also describe a validated synthesis of [18F]FPEB with a commercial reactor-based system. PMID- 25431647 TI - Anti-bacterial glycosyl triazoles - Identification of an N-acetylglucosamine derivative with bacteriostatic activity against Bacillus. AB - N-acetylglucosaminidases (GlcNAcases) play an important role in the remodeling and recycling of bacterial peptidoglycan. Inhibitors of bacterial GlcNAcases can serve as antibacterial agents and provide an opportunity for the development of new antibiotics. We report the synthesis of triazole derivatives of N acetylglucosamine using a copper promoted azide-alkyne coupling reaction between 1-azido-N-acetylglucosamine and a small library of terminal alkynes prepared via the Ugi reaction. These compounds were evaluated for their ability to inhibit the growth of bacteria. Two compounds that show bacteriostatic activity against Bacillus were identified, with MIC values of approximately 60 MUM in both cases. Bacillus subtilis cultured in the presence of sub-MIC amounts of the glycosyl triazole inhibitors exhibit an elongated phenotype characteristic of impaired cell division. This represents the first report of inhibitors of bacterial cell wall GlcNAcases that demonstrate inhibition of cell growth in whole cell assays. PMID- 25431648 TI - Synthesis and biological evaluation of panitumumab-IRDye800 conjugate as a fluorescence imaging probe for EGFR-expressing cancers. AB - To investigate panitumumab-IRDye800 as an intraoperative optical imaging agent for epidermal growth factor receptor (EGFR)-expressing cancers, we developed clinical-quality panitumumab-IRDye800 and evaluated its specificity and sensitivity to visualize tumors by fluorescence imaging in a variety of mouse xenograft models with different levels of EGFR-expression. Panitumumab was chemically conjugated to NIR-dye (Li-COR 800CW) at well-defined and limited substitution ratio (1:1-2) for the characterization of fluorescence signals. Yield and purity of the conjugate was 80+/-5% and 95+/-2% respectively (n= 6). Quality control (QC) tests showed that product was suitable for clinical development. Female athymic nude xenograft tumor bearing mice (n=5 per tumor model) with very low (BT-474), moderate (MDA-MB-231), and high (MDA-MB-468) EGFR expression levels were administered panitumumab-IRDye800 formulations (100 MUg of mAb in 100 MUL of 0.9% saline) via tail-vein injection. Animal imaging and biodistribution experiments were conducted on the FMT 2500 (Perkin Elmer) fluorescence scanner at 24, 48, 72, 96, and 144 hours post injection. Immuno fluorescence images of panitumumab-IRDye conjugate recorded in mouse xenograft models showed a good correlation (R2 = 0.91) between EGFR-expression level and tumor uptake. Uptake of panitumumab labeled with IR-Dye or [89Zr] in different tumor xenografts with high, medium, and low EGFR expression, as measured by fluorescence or radioactive counts are highly correlated (r2= 0.99). This preclinical in-vivo study proved that panitumumab-IRDye800 is specific and optical imaging in conjunction with this probe is sensitive enough to detect EGFR expressing tumors. PMID- 25431649 TI - A cell-permeable gadolinium contrast agent for magnetic resonance imaging of copper in a Menkes disease model. AB - We present the synthesis and characterization of octaarginine-conjugated Copper Gad-2 (Arg8CG2), a new copper-responsive magnetic resonance imaging (MRI) contrast agent that combines a Gd3+-DO3A scaffold with a thioether-rich receptor for copper recognition. The inclusion of a polyarginine appendage leads to a marked increase in cellular uptake compared to previously reported MRI-based copper sensors of the CG family. Arg8CG2 exhibits a 220% increase in relaxivity (r1 = 3.9 to 12.5 mM-1 s-1) upon 1 : 1 binding with Cu+, with a highly selective response to Cu+ over other biologically relevant metal ions. Moreover, Arg8CG2 accumulates in cells at nine-fold greater concentrations than the parent CG2 lacking the polyarginine functionality and is retained well in the cell after washing. In cellulo relaxivity measurements and T1-weighted phantom images using a Menkes disease model cell line demonstrate the utility of Arg8CG2 to report on biological perturbations of exchangeable copper pools. PMID- 25431650 TI - Enantioselective Synthesis of Tetrahydroquinolines, Tetrahydroquinoxalines, and Tetrahydroisoquinolines via Pd-Catalyzed Alkene Carboamination Reactions. AB - A catalyst composed of Pd2(dba)3 and (S)-Siphos-PE provides excellent results in Pd-catalyzed alkene carboamination reactions between aniline derivatives bearing pendant alkenes and aryl or alkenyl halides. These transformations generate tetrahydroquinolines and tetrahydroquinoxalines that contain quaternary carbon stereocenters with high levels of asymmetric induction. In addition this catalyst also effects the asymmetric synthesis of tetrahydroisoquinolines via related transformations of 2-allylbenzylamines. In contrast to most other approaches to the asymmetric synthesis of these compounds, which frequently involve functional group interconversion or a single C-C or C-N bond-forming event, the carboamination reactions generate both a C-N bond, a C-C bond, and a stereocenter. PMID- 25431651 TI - Regioselective and Diastereoselective Aminoarylation of 1,3-Dienes. AB - The 1,4-functionalization of dienes is a synthetically useful strategy for incorporating molecular complexity into a class of simple substrates. We report the aminoarylation of acyclic and cyclic 1,3-dienes via the sequential [4+2] cycloaddition with a sulfurdiimide reagent and copper-catalyzed allylic substitution with Grignard reagents. The regioselective and diastereoselective aminoarylation of unsymmetrical dienes is also presented, which highlights the utility of this method for generating products with multiple functional groups and stereocenters. PMID- 25431652 TI - State Rumination: Associations with Emotional Stress Reactivity and Attention Biases. AB - Within dysphoria, rumination has been identified as a particularly maladaptive emotion regulation strategy linked to prolonged negative affect and the onset of depressive episodes. Until now, the majority of research assessing naturally occurring rumination has utilized trait rumination measures; however, additional information may be obtained by assessing state rumination. The current study examined the association between state rumination and participants' emotional recovery from stress. In addition, biased attention toward emotional information was investigated as a mechanism that might underlie state rumination. Participants completed the exogenous cuing task to assess attentional engagement and disengagement from emotional facial expressions followed by a psychosocial stressor. State rumination and self-reported sadness were measured during the recovery period. As expected, state rumination was associated with less recovery in sadness scores, even after controlling for trait rumination and depressive symptoms. Moreover, within the high dysphoria group, participants who had more difficulty disengaging from emotional expressions reported higher levels of rumination in response to the stressor. Results highlight an important association between state rumination and individuals' recovery from stress, and suggest that difficulty disengaging attention from emotional expressions might be one mechanism underlying state rumination in dysphoria. PMID- 25431653 TI - Synthesis and Characterization of a Poly(ethylene glycol)-Poly(simvastatin) Diblock Copolymer. AB - Biodegradable polyesters are commonly used as drug delivery vehicles, but their role is typically passive, and encapsulation approaches have limited drug payload. An alternative drug delivery method is to polymerize the active agent or its precursor into a degradable polymer. The prodrug simvastatin contains a lactone ring that lends itself to ring-opening polymerization (ROP). Consequently, simvastatin polymerization was initiated with 5 kDa monomethyl ether poly(ethylene glycol) (mPEG) and catalyzed via stannous octoate. Melt condensation reactions produced a 9.5 kDa copolymer with a polydispersity index of 1.1 at 150 degrees C up to a 75 kDa copolymer with an index of 6.9 at 250 degrees C. Kinetic analysis revealed first-order propagation rates. Infrared spectroscopy of the copolymer showed carboxylic and methyl ether stretches unique to simvastatin and mPEG, respectively. Slow degradation was demonstrated in neutral and alkaline conditions. Lastly, simvastatin, simvastatin-incorporated molecules, and mPEG were identified as the degradation products released. The present results show the potential of using ROP to polymerize lactone-containing drugs such as simvastatin. PMID- 25431654 TI - Development of a Concise Synthetic Approach to Access Oroxin A. AB - A novel environment-friendly method to access bioactive oroxin A through a one pot/two-step process from naturally abundant and inexpensive baicalin is described. The procedure presented here has several advantages including clean, one-pot, synthetic ease, and large-scale feasibility. This work also provides a model strategy for rapid and diverse access to natural molecules sharing the common skeleton of this family. PMID- 25431656 TI - Effects of storage time and temperature on the antimony and some trace element release from polyethylene terephthalate (PET) into the bottled drinking water. AB - BACKGROUND AND OBJECTIVES: Heavy metals are considered as one of the major contaminants that can enter into the bottled waters. Antimony (Sb) is a contaminant, which may leach from the polyethylene terephthalate (PET) bottles into the water. The aim of this study was to investigate the content of antimony and other trace elements in bottled waters which was kept in varied storage conditions and temperatures. MATERIALS AND METHODS: Five time-temperature treatments were carried out on five different brands of commercially available bottled waters. Heavy metal measurement was performed by Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES) method. Analysis of the collected data was processed by SPSS software. RESULTS: Antimony concentration was the main concern in our study. The concentrations increased in each of the sample during storage period at all temperatures. The results for different conditions were as follow: at 40 degrees C, in outdoor and at room temperature the Sb concentrations were below the MCLs, i e. 6 ppb. However, at 65 degrees C and 80 degrees C for longer storage times Sb concentration exceeded the MCLs, and variations between the samples were significant (p <= 0.05). Storage time and temperature effects on the content of some other trace elements such as Al, Fe were also significant (p <= 0.05). CONCLUSION: By increasing the duration of storage time and temperatures, antimony leaching from the PET bottles into the bottled water increased. The concentration of Al demonstrated an increase in higher temperatures and storage duration, whereas the content of Fe demonstrated no significant differences. PMID- 25431655 TI - Behavioral effects of the cannabinoid CB1 receptor allosteric modulator ORG27569 in rats. AB - The cannabinoid CB1 receptor system is involved in feeding behaviors and the CB1 receptor antagonist SR141716A is an effective antiobesity drug. However, SR141716A also has serious side effects, which prompted the exploration of alternative strategies to modulate this important drug target. Recently a CB1 receptor allosteric modulating site has been discovered and the allosteric modulating activity of several modulators including ORG27569 has been characterized in vitro. Yet, little is known of the in vivo pharmacological effects of ORG27569. This study examined the behavioral pharmacology of ORG27569 in rats. ORG27569 (3.2-10 mg/kg, i.p.) selectively attenuated the hypothermic effects of CB1 receptor agonists CP55940 (0.1-1 mg/kg) and anandamide (3.2-32 mg/kg). In contrast, SR141716A only attenuated the hypothermic effects of CP55940 but not anandamide. SR141716A but not ORG27569 blocked CP55940-induced catalepsy and antinociception. In addition, ORG27569 did not modify SR141716A-elicited grooming and scratching behaviors. In feeding studies, ORG27569 decreased palatable and plain food intake which was partially blocked by CP55940. The hypophagic effect of ORG27569 developed tolerance after 4 days of daily 5.6 mg/kg treatment; however, the effect on body weight gain outlasted the drug treatment for 10 days. These data suggest that ORG27569 may not function as a CB1 receptor allosteric modulator in vivo, although its hypophagic activity still has potential therapeutic utility. PMID- 25431657 TI - Spatial distribution of heavy metals in soil, water, and vegetables of farms in Sanandaj, Kurdistan, Iran. AB - BACKGROUND: Heavy metals are ubiquitous elsewhere in nature and their measurement in environment is necessary to develop health management strategies. In this study, we aimed to find out concentrations and spatial patterns of heavy metals in main farms of Sanandaj in Kurdistan, Iran. METHODS: Over May to October 2012, six farms were selected to analyze concentrations and spatial patterns of several heavy metals, namely aluminum (Al), arsenic (As), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), nickel (Ni), lead (Pb), and zinc (Zn) in their soil, irrigation water, and edible vegetables. Overall, 36 samples of soil and water and 72 samples of vegetables including coriander (Coriandrum sativum), dill (Anethum graveolens), radish (Raphanus sativus) root and radish leaf were collected. The concentrations of metals were determined by inductively coupled plasma optical emission spectrometry. The spatial surfaces of heavy metals were created using geospatial information system. RESULTS: The order of metals in soil was Al > Zn > Ni > Cu > Cr > Pb > Co > As > Cd while in water it was Cr > Co > Zn > Pb > Cu > Ni > Al = As = Cd. The order of heavy metals in vegetables was Al > Zn > Cu > Cr > Ni > Pb > Co > As > Cd. Totally, the minimum concentrations of Al, Cu, Pb, and Zn were found in radish root while the maximum of Al, Co, Cr, and Ni were found in radish leaf. The minimum concentrations of Cd and Cr and maximum concentrations of Cu and Zn were also deciphered in dill. Noteworthy, coriander had the minimum concentrations of Co and Ni. The concentrations of Cr and Pb in vegetables were more than maximum allowable limits of the Food and Agriculture Organization (FAO) and the World Health Organization (WHO). CONCLUSION: In summary, albeit the concentrations of heavy metals in soil and water samples were below FAO and the WHO standards, vegetables were contaminated by chromium and lead. PMID- 25431658 TI - A Non-Diazo Strategy to Cyclopropanation via Oxidatively Generated Gold Carbene: the Benefit of A Conformationally Rigid P,N-Bidentate Ligand. PMID- 25431659 TI - Variations in eyeball diameters of the healthy adults. AB - The purpose of the current research was to reevaluate the normative data on the eyeball diameters. Methods. In a prospective cohort study, the CT data of consecutive 250 adults with healthy eyes were collected and analyzed, and sagittal, transverse, and axial diameters of both eyeballs were measured. The data obtained from the left eye and from the right eye were compared. The correlation analysis was performed with the following variables: orbit size, gender, age, and ethnic background. Results. We did not find statistically significant differences correlated with gender of the patients and their age. The right eyeball was slightly smaller than the left one but this difference was statistically insignificant (P = 0.17). We did not find statistically significant differences of the eyeball sizes among the ethnicities we dealt with. Strong correlation was found between the transverse diameter and the width of the orbit (r = 0.88). Conclusion. The size of a human adult eye is approximately 24.2 mm (transverse) * 23.7 mm (sagittal) * 22.0-24.8 mm (axial) with no significant difference between sexes and age groups. In the transverse diameter, the eyeball size may vary from 21 mm to 27 mm. These data might be useful in ophthalmological, oculoplastic, and neurological practice. PMID- 25431660 TI - Latent Toxoplasma gondii Infection and Associated Risk Factors among HIV-Infected Individuals at Arba Minch Hospital, South Ethiopia. AB - Toxoplasmosis is a parasitic disease caused by Toxoplasma gondii (T. gondii). The parasite has cosmopolitan distribution, infecting almost all species of warm blooded animals. Latent T. gondii infection in HIV/AIDS patients is a risk for development of cerebral toxoplasmosis (CT). The aim of this study is to determine seroprevalence of latent T. gondii infection and assess its associated factors among individuals infected with HIV in Arba Minch Hospital, south Ethiopia. A facility-based cross-sectional study involving 170 HIV-infected individuals attending Arba Minch Hospital antiretroviral therapy (ART) clinic was conducted from April to June 2013. Data on demographic profile of the study participants and factors associated with T. gondii infection were gathered using a questionnaire. Serum was tested for IgG anti-T. gondii antibody by enzyme-linked immunosorbent assay (ELISA). Data were analyzed using SPSS version 20 software. Seroprevalence of latent T. gondii infection among the study participants was 88.2%. Consumption of raw meat (AOR = 4.361; 95% CI: 1.409-13.496) and involvement in farming/gardening activities (AOR = 4.051; 95% CI: 1.112-14.758) were independent predictors of T. gondii seropositivity. This study revealed high prevalence of latent T. gondii infection, similar to other studies. Monitoring of the patients to prevent reactivation of the latent T. gondii infection is recommended. PMID- 25431661 TI - Plasma and Intracellular Antiretroviral Concentrations in HIV-Infected Patients under Short Cycles of Antiretroviral Therapy. AB - Study of plasma and intracellular concentrations of atazanavir, lopinavir, nevirapine, and efavirenz was conducted on 48 patients under short cycles of antiretroviral therapy. Intracellular concentrations (IC) were still measurable for all drugs after 85 h or 110 h drug intake despite the absence of drug in plasma for atazanavir and lopinavir. A linear relationship between plasma and intracellular efavirenz was observed. Further studies to fully understand the impact of IC in the intermittent antiviral treatment are required. PMID- 25431662 TI - The Unsteady Mainstay of the Family: Now Adult Children's Retrospective View on Social Support in Relation to Their Parent's Heart Transplantation. AB - The needs for support among children with a seriously ill parent, who is waiting for heart transplantation, are unknown today. The aim was to describe now adult children's experiences of social support in relation to a parent's heart transplant during childhood. Nine females and four males were interviewed. The median age for the children was 18 at the transplantation and their parents had been ill before for 18 months (median) and on waiting list for 161 days (mean). Three categories emerged: health care professionals' approaches, family and friends' approaches, and society approaches. Our results show that there was lack of support for children of heart transplantation patients. Support in the shape of information was in most cases provided by the sick or healthy parent. It is of great clinical importance to develop psychosocial support programs for children with a seriously ill parent waiting for heart transplantation (before, during, and after surgery). PMID- 25431663 TI - Ureteral stenting after uncomplicated ureteroscopy for distal ureteral stones: a randomized, controlled trial. AB - Objectives. We compared outcome and complications after uncomplicated ureteroscopic treatment of distal ureteral calculi with or without the use of ureteral stents. Materials and Methods. 117 patients, prospectively divided into three groups to receive a double j stent (group 1, 42 patients), ureteral stent (group 2, 37 patients), or no stent (group 3, 38 patients), underwent ureteroscopic treatment of distal ureteral calculi. Stone characteristics, operative time, postoperative pain, lower urinary tract symptoms (LUTS), analgesia need, rehospitalization, stone-free rate, and late postoperative complications were all studied. Results. There were no significant differences in preoperative data. There was no significant difference between the three groups regarding hematuria, fever, flank pain, urinary tract infection, and rehospitalisation. At 48 hours and 1 week, frequency/urgency and dysuria were significantly less in the nonstented group. When comparing group 1 and group 3, patients with double j stents had statistically significantly more bladder pain (P = 0.003), frequency/urgency (P = 0.002), dysuria (P = 0.001), and need of analgesics (P = 0.001). All patients who underwent imaging postoperatively were without evidence of obstruction or ureteral stricture. Conclusions. Uncomplicated ureteroscopy for distal ureteral calculi without intraoperative ureteral dilation can safely be performed without placement of a ureteral stent. PMID- 25431664 TI - Effect of extracorporeal shock wave treatment on deep partial-thickness burn injury in rats: a pilot study. AB - Extracorporeal shock wave therapy (ESWT) enhances tissue vascularization and neoangiogenesis. Recent animal studies showed improved soft tissue regeneration using ESWT. In most cases, deep partial-thickness burns require skin grafting; the outcome is often unsatisfactory in function and aesthetic appearance. The aim of this study was to demonstrate the effect of ESWT on skin regeneration after deep partial-thickness burns. Under general anesthesia, two standardized deep partial-thickness burns were induced on the back of 30 male Wistar rats. Immediately after the burn, ESWT was given to rats of group 1 (N = 15), but not to group 2 (N = 15). On days 5, 10, and 15, five rats of each group were analyzed. Reepithelialization rate was defined, perfusion units were measured, and histological analysis was performed. Digital photography was used for visual documentation. A wound score system was used. ESWT enhanced the percentage of wound closure in group 1 as compared to group 2 (P < 0.05). The reepithelialization rate was improved significantly on day 15 (P < 0.05). The wound score showed a significant increase in the ESWT group. ESWT improves skin regeneration of deep partial-thickness burns in rats. It may be a suitable and cost effective treatment alternative in this type of burn wounds in the future. PMID- 25431665 TI - (18)F-fluorodeoxyglucose positron emission tomography/computed tomography accuracy in the staging of non-small cell lung cancer: review and cost effectiveness. AB - Aim of the performed clinical study was to compare the accuracy and cost effectiveness of PET/CT in the staging of non-small cell lung cancer (NSCLC). Material and Methods. Cross-sectional and prospective study including 103 patients with histologically confirmed NSCLC. All patients were examined using PET/CT with intravenous contrast medium. Those with disease stage <=IIB underwent surgery (n = 40). Disease stage was confirmed based on histology results, which were compared with those of PET/CT and positron emission tomography (PET) and computed tomography (CT) separately. 63 patients classified with >=IIIA disease stage by PET/CT did not undergo surgery. The cost-effectiveness of PET/CT for disease classification was examined using a decision tree analysis. Results. Compared with histology, the accuracy of PET/CT for disease staging has a positive predictive value of 80%, a negative predictive value of 95%, a sensitivity of 94%, and a specificity of 82%. For PET alone, these values are 53%, 66%, 60%, and 50%, whereas for CT alone they are 68%, 86%, 76%, and 72%, respectively. Incremental cost-effectiveness of PET/CT over CT alone was ?17,412 quality-adjusted life-year (QALY). Conclusion. In our clinical study, PET/CT using intravenous contrast medium was an accurate and cost-effective method for staging of patients with NSCLC. PMID- 25431666 TI - Influenceable and Avoidable Risk Factors for Systemic Air Embolism due to Percutaneous CT-Guided Lung Biopsy: Patient Positioning and Coaxial Biopsy Technique-Case Report, Systematic Literature Review, and a Technical Note. AB - Following the first case of a systemic air embolism due to percutaneous CT-guided lung biopsy in our clinic we analysed the literature regarding this matter in view of influenceable or avoidable risk factors. A systematic review of literature reporting cases of systemic air embolism due to CT-guided lung biopsy was performed to find out whether prone positioning might be a risk factor regarding this issue. In addition, a technical note concerning coaxial biopsy practice is presented. Prone position seems to have relevance for the development and/or clinical manifestation of air embolism due to CT-guided lung biopsy and should be considered a risk factor, at least as far as lesions in the lower parts of the lung are concerned. Biopsies of small or cavitary lesions in coaxial technique should be performed using a hemostatic valve. PMID- 25431667 TI - Evaluation of Antiarthritic Potential of Methanolic Extract of Gentiana kurroo Royle. AB - Rheumatoid arthritis is a systemic disorder which involves the activation of immune system against the self-tissues. The main targets of this disease are the joints. Being systemic the development of this disease involves different mechanisms and thus the exact cause of this disease remains unknown. Although different drugs have been developed, none has been found to be the cure for this disease. In the current study the rat carrageenin paw was used as a model for acute inflammation and mycobacterium induced adjuvant arthritic model was used for exploring the antiarthritic potential of methanolic extract of Gentiana kurroo. In this study the different extracts tested showed less inhibition of acute inflammation than methanolic extract. The methanolic extract was further used in different doses and the anti-inflammatory efficacy was found to be dose dependent. The results obtained were significant with the control and the standard groups. In the arthritic model the methanolic extract showed decrease in the paw volume of arthritic animals and also in the arthritic symptoms. Again the results obtained were found to be significantly dose dependent. From the results obtained it can be concluded that this extract may serve as a source of drug against the rheumatoid arthritis. PMID- 25431668 TI - Knowledge, Attitudes, and Motivations towards Blood Donation among King Abdulaziz Medical City Population. AB - Background. Blood donation is remarkably safe medical procedure. However, attitudes, beliefs, and level of knowledge may affect it. Objectives. To measure the level of knowledge regarding blood donation, find out positive and negative attitudes, identify the obstacles, and suggest some motivational factors. Methodology. A cross-sectional study was conducted at King Abdulaziz Medical City (KAMC). Participants were selected by convenient nonrandom sampling technique. A self-created questionnaire was used for data collection. Results. The study included 349 individuals. About 45.8% of the participants claimed that they have a history of blood donation. Reported causes for not donating blood were blood donation not crossing their mind (52.4%), no time for donation (45%), and difficulty in accessing blood donation center (41.3%). Reported motivating factors for donating blood were one day off (81.4%), mobile blood donation caravans in public areas (79.1%), token gifts (31.5%), and finally paying money (18.9%). Conclusion. People in the age group 31-50 years, males, higher education and military were more likely to donate blood as well as People who showed higher knowledge level and positive attitude towards blood donation. More educational programs to increase the awareness in specific targeted populations and also to focus on some motivational factors are recommended. PMID- 25431669 TI - Microwave-assisted synthesis and biological evaluation of dihydropyrimidinone derivatives as anti-inflammatory, antibacterial, and antifungal agents. AB - A simple protocol for the efficient preparation of aryl and heteroaryl substituted dihydropyrimidinone has been achieved via initial Knoevenagel, subsequent addition, and final cyclization of aldehyde, ethylcyanoacetate, and guanidine nitrate in the presence of piperidine as a catalyst in solvent-free under microwave irradiation. The synthesized compounds showed a good anti inflammatory, antibacterial, and antifungal activity. PMID- 25431670 TI - A possible molecular mechanism of immunomodulatory activity of bilirubin. AB - Bilirubin is an endogenous product of heme degradation in mammals. Bilirubin has long been considered as a cytotoxic waste product that needs to be excreted. However, increasing evidence suggests that bilirubin possesses multiple biological activities. In particular, recent studies have shown that bilirubin should be a protective factor for several autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. Since these autoimmune diseases are closely associated with specific types of human leukocyte antigens (HLAs), we have hypothesized that bilirubin might bind to the antigenic peptide-binding groove of the HLA molecules and exert its immunosuppressive actions. In order to evaluate the hypothesis, theoretical docking studies between bilirubin and the relevant HLA molecules have been undertaken. The in silico studies have clearly shown that bilirubin may bind to the antigenic peptide binding groove of the HLA molecules relevant to the autoimmune diseases with significant affinity. The bound bilirubin may block the binding of antigenic peptides to be presented to T cell receptors and lead to suppression of the autoimmune responses. Based on this hypothesis new drug discovery research for autoimmune diseases will be conducted. PMID- 25431671 TI - Classification of Five Uremic Solutes according to Their Effects on Renal Tubular Cells. AB - Background/Aims. Uremic solutes, which are known to be retained in patients with chronic kidney disease, are considered to have deleterious effects on disease progression. Among these uremic solutes, indoxyl sulfate (IS) has been extensively studied, while other solutes have been studied less to state. We conducted a comparative study to examine the similarities and differences between IS, p-cresyl sulfate (PCS), phenyl sulfate (PhS), hippuric acid (HA), and indoleacetic acid (IAA). Methods. We used LLC-PK1 cells to evaluate the effects of these solutes on viable cell number, cell cycle progression, and cell death. Results. All the solutes reduced viable cell number after 48-hour incubation. N Acetyl-L-cysteine inhibited this effect induced by all solutes except HA. At the concentration that reduced the cell number to almost 50% of vehicle control, IAA induced apoptosis but not cell cycle delay, whereas other solutes induced delay in cell cycle progression with marginal impact on apoptosis. Phosphorylation of p53 and Chk1 and expression of ATF4 and CHOP genes were detected in IS-, PCS-, and PhS-treated cells, but not in IAA-treated cells. Conclusions. Taken together, the adverse effects of PCS and PhS on renal tubular cells are similar to those of IS, while those of HA and IAA differ. PMID- 25431672 TI - Increasing Incidence in Relapsing-Remitting MS and High Rates among Young Women in Finland: A Thirty-Year Follow-Up. AB - Object. Gender and disease course specific incidences were studied in high- and medium-risk regions of MS in Finland. Methods. Age- and gender-specific incidences with 95% CIs were calculated in 10-year periods from 1981 to 2010. Poser diagnostic criteria were used and compared with the McDonald criteria from 2001 to 2010. Association between age and diagnostic delay over time was assessed by using the Kruskal-Wallis test. Results. 1419 (89%) RRMS and 198 (11%) PPMS cases were included. RRMS incidence increased with the female to male ratio (F/M) from 4,2/10(5) (F/M 1.9) to 9,7 (2.3), while that of PPMS decreased from 1,2 (1.6) to 0,7 (1.2). The use of McDonald criteria did not change the conclusion. The decreasing diagnostic delay and age at diagnosis in RRMS were associated within the 10-year periods and contrasted those in PPMS. Increasing female risk in RRMS was observed in the high-risk region. Conclusion. Increasing RRMS incidence and high female ratios shown in each age group indicate gender-specific influences acting already from childhood. A more precise definition of the risk factors and their action in MS is needed to provide a better understanding of underlying pathological processes and a rationale for the development of new preventive and treatment strategies. PMID- 25431673 TI - Sun Protection Beliefs among Hispanics in the US. AB - Purpose. We reviewed the literature on sun protection beliefs in Hispanics living in the United States to explore what challenges are faced by area of research. Method. A review of PubMED, PsycINFO, and CINAHL databases was performed. Studies were published in peer-reviewed journals (in all years available) and written in English. The search terms used were ["skin cancer" OR "sun protection"] AND ["Latino" OR "Hispanic"] AND "beliefs." Eligible papers were included in the final analysis after meeting the following inclusion criteria: (1) the records had to quantitatively examine and report sun protection beliefs in Hispanics, (2) the number of Hispanic participants in the sample had to be clearly specified, and (3) studies reporting differences in sun protection beliefs between Hispanics and other racial and ethnic groups were included in the review. Results. Of the 92 articles identified, 11 met inclusion criteria and addressed sun protection beliefs regarding skin cancer seriousness and susceptibility, and benefits and barriers of sun protection and skin cancer risk behaviors. Characteristics of studies and results were examined. Conclusion. There is insufficient evidence to determine a pattern of sun protection beliefs among Hispanics in the United States. More quality studies are needed which focus on sun protection beliefs in Hispanics. PMID- 25431675 TI - MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders. AB - Aim. Autism is a subgroup of autism spectrum disorders, classified as a heterogeneous neurodevelopmental disorder and symptoms occur in the first three years of life. The etiology of autism is largely unknown, but it has been accepted that genetic and environmental factors may both be responsible for the disease. Recent studies have revealed that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. In particular, C677T polymorphism in the MTHFR gene as a possible risk factor for autism is still controversial. We aimed to investigate the possible effect of C677T polymorphism in a Turkish cohort. Methods. Autism patients were diagnosed by child psychiatrists according to DSM-IV and DSM-V criteria. A total of 98 children diagnosed as autistic and 70 age and sex-matched children who are nonautistic were tested for C677T polymorphism. This polymorphism was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) methods. Results. MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%), but it was not found statistically significant. Conclusions. We conclude that other MTHFR polymorphisms such as A1298C or other folate/homocysteine pathway genes may be studied to show their possible role in autism. PMID- 25431674 TI - CHEK2 (*) 1100delC Mutation and Risk of Prostate Cancer. AB - Although the causes of prostate cancer are largely unknown, previous studies support the role of genetic factors in the development of prostate cancer. CHEK2 plays a critical role in DNA replication by responding to double-stranded breaks. In this review, we provide an overview of the current knowledge of the role of a genetic variant, 1100delC, of CHEK2 on prostate cancer risk and discuss the implication for potential translation of this knowledge into clinical practice. Currently, twelve articles that discussed CHEK2 (*)1100delC and its association with prostate cancer were identified. Of the twelve prostate cancer studies, five studies had independent data to draw conclusive evidence from. The pooled results of OR and 95% CI were 1.98 (1.23-3.18) for unselected cases and 3.39 (1.78-6.47) for familial cases, indicating that CHEK2 (*)1100delC mutation is associated with increased risk of prostate cancer. Screening for CHEK2(*)1100delC should be considered in men with a familial history of prostate cancer. PMID- 25431676 TI - A Longitudinal Low Dose MUCT Analysis of Bone Healing in Mice: A Pilot Study. AB - Low dose microcomputed tomography (MUCT) is a recently matured technique that enables the study of longitudinal bone healing and the testing of experimental treatments for bone repair. This imaging technique has been used for studying craniofacial repair in mice but not in an orthopedic context. This is mainly due to the size of the defects (approximately 1.0 mm) in long bone, which heal rapidly and may thus negatively impact the assessment of the effectiveness of experimental treatments. We developed a longitudinal low dose MUCT scan analysis method combined with a new image segmentation and extraction software using Hounsfield unit (HU) scores to quantitatively monitor bone healing in small femoral cortical defects in live mice. We were able to reproducibly quantify bone healing longitudinally over time with three observers. We used high speed intramedullary reaming to prolong healing in order to circumvent the rapid healing typical of small defects. Bone healing prolongation combined with MUCT imaging to study small bone defects in live mice thus shows potential as a promising tool for future preclinical research on bone healing. PMID- 25431677 TI - Assessment of Patients with a DePuy ASR Metal-on-Metal Hip Replacement: Results of Applying the Guidelines of the Spanish Society of Hip Surgery in a Tertiary Referral Hospital. AB - The prognosis associated with the DePuy ASR hip cup is poor and varies according to the series. This implant was withdrawn from use in 2010 and all patients needed to be assessed. We present the results of the assessment of our patients treated with this device, according to the Spanish Society of Hip Surgery (SECCA) algorithm published in 2011. This retrospective study evaluates 83 consecutive ASR cups, followed up at a mean of 2.9 years. Serum levels of chromium and cobalt, as well as the acetabular abduction angle, were determined in order to assess their possible correlation with failure, defined as the need for revision surgery. The mean Harris Hip Score was 83.2 (range 42-97). Eight arthroplasties (13.3%) required revision due to persistent pain and/or elevated serum levels of chromium/cobalt. All the cups had a correct abduction angle, and there was no correlation between elevated serum levels of metal ions and implant failure. Since two previous ASR implants were exchanged previously to the recall, the revision rate for ASR cups in our centre is 18.2% at 2.9 years. PMID- 25431678 TI - Multilevel and urban health modeling of risk factors for diabetes mellitus: a new insight into public health and preventive medicine. AB - This study aimed to apply multidisciplinary analysis approaches and test two hypotheses that (1) there was a significant increase in the prevalence of diabetes mellitus (DM) from 2002 to 2010 in the city of Philadelphia and that (2) there were significant variations in the prevalence of DM across neighborhoods, and these variations were significantly related to the variations in the neighborhood physical and social environment (PSE). Data from the Southeastern Pennsylvania Household Health Surveys in 2002-2004 (period 1, n = 8,567) and in 2008-2010 (period 2, n = 8,747) were analyzed using a cross-sectional comparison approach. An index of neighborhood PSE was constructed from 8 specific measures. The results show that age-adjusted prevalence of DM increased from period 1 (10.20%) to period 2 (11.91%) (P < 0.001). After adjusting age, sex, and survey years, an estimate of 12.14%, 18.33%, and 11.89% of the odds ratios for DM was related to the differences in the neighborhood PSE disadvantage, the prevalence of overweight/obesity, and those with lower education attendance, respectively. In conclusion, prevalence of DM significantly increased from 2002 to 2010 in the city of Philadelphia. In addition to risk factors for DM at personal level, neighborhood PSE disadvantage may play a critical role in the risk of DM. PMID- 25431679 TI - Operational efficiency of an immunization clinic attached to rural health training centre in delhi, India: a time and motion study. AB - Background. Obtaining baseline data about current patterns of work is important for assessing the effects of interventions designed to improve care delivery. Time and motion studies allow for the most accurate measurement of structured components. Therefore, the present study was conducted to study the operational efficiency of an immunization clinic in Delhi, India. Methods. An observational cross-sectional study was conducted at the immunization clinic of Rural Health Training Centre in Delhi, India, from January 2014 to March 2014. The study composed two stage evaluations, a passive observation and a time and motion study. Systemic random sampling method was used to select 863 mothers/caregivers attending the immunization clinic. Results. At the immunization clinic, the study participants spent 64.1% of their total time in waiting. For new cases, the mean time taken for initial registration and receiving postvaccination advice was found to be significantly longer than old cases. Delivering health care services took more time during Mondays and also during the first hour of the day. Conclusion. Results of this study will guide public health decision-makers at all government levels in planning and implementation of immunization programs in developing countries. PMID- 25431680 TI - Laparoscopic cholecystectomy in a patient with previous pneumonectomy: a case report and discussion of anaesthetic considerations. AB - Increasing numbers of patients require cholecystectomy after previous pneumonectomy, but there are little data to guide anaesthetic management. A laparoscopic approach is associated with less postoperative respiratory compromise than open cholecystectomy but may be relatively contraindicated due to the undesirable effects of pneumoperitoneum on respiratory function. We describe the case of a 72-year-old patient who successfully underwent elective laparoscopic cholecystectomy 23 years after left pneumonectomy. An understanding of the combined physiological consequences of pneumonectomy and pneumoperitoneum facilitated the provision of safe and uneventful anaesthesia. We propose that laparoscopic cholecystectomy is feasible and safe to perform in patients with a single lung. PMID- 25431681 TI - Postanesthetic Severe Oral Angioedema in Patient's Taking Angiotensin-Converting Enzyme Inhibitor. AB - Angiotensin-converting enzyme (ACE) inhibitors are the leading cause of a drug induced angioedema. This occurrence is frequently underdiagnosed, but its relapse can be life-threatening. The authors' intention in reporting this clinical case is to sound a warning about reviewing attitudes and surveillance to try to improve patient perioperative safety. PMID- 25431682 TI - Aortic balloon valvuloplasty prior to orthotopic liver transplantation: a novel approach to aortic stenosis and end-stage liver disease. AB - The combination of severe aortic stenosis and end-stage liver disease increases the morbidity and mortality of surgical aortic valve replacement or orthotopic liver transplantation resulting in a prohibitive operative risk. We propose a staged approach of balloon aortic valvuloplasty prior to orthotopic liver transplantation as a bridge to definitive aortic valve replacement. Between 2010 and 2012, four patients with severe aortic stenosis and end-stage liver disease underwent staged balloon aortic valvuloplasty followed by orthotopic liver transplantation. All patients had been deemed to be inappropriate candidates for liver transplantation or aortic valve surgery due to their comorbidity. One patient died of complications from a perivalvular abscess. Three patients went on to successful graft implantation and function and surgical recovery. Two of the three patients proceeded to definitive surgical aortic valve replacement with the remainder currently undergoing evaluation. In this case series, we present a novel approach of balloon aortic valvuloplasty prior to liver transplantation as a potential bridge to definitive treatment of severe aortic stenosis in the end stage liver patient. PMID- 25431683 TI - Late presentation of persistent left superior caval vein in a univentricular heart with successful transcutaneous occlusion using cera lifetech atrial septal occluder. AB - We present a case of persistent left superior caval vein in a univentricular heart presenting with progressive and disabling cyanosis in a 35-year-old man eighteen years after his Kawashima operation. The vein was successfully occluded using an atrial septal occluder with significant improvement of symptoms and oxygen saturation. PMID- 25431684 TI - Complete heart block and persistent lactic acidosis as an initial presentation of non-hodgkin lymphoma in a critically ill newly diagnosed AIDS patient. AB - A 66-year-old male with newly diagnosed untreated acquired immunodeficiency syndrome (AIDS) presented with chronic nonspecific complaints of weakness, fatigue, myalgia, and weight loss. His initial EKG showed complete heart block necessitating temporary pacemaker placement. He had no previous history of cardiac disease. He was also found to have a persistent lactic acidosis and imaging studies showed abdominal lymphadenopathy. The patient underwent biopsy of these lymph nodes and was found to have diffuse large B-cell lymphoma. The hospital course was complicated by respiratory failure requiring mechanical ventilator support and cardiac arrest. Patient remained critically ill; he was not a candidate for chemotherapy and, after a month of hospitalization, he died. Lactic acidosis and heart block as an initial presentation of non-Hodgkin lymphoma in an AIDS patient are an unusual and unique presentation. PMID- 25431685 TI - Prolonged QT Syndrome in a 27-Year-Old Female Presenting as a Cardiac Arrest after Elective Surgery. AB - Cardiac arrest is a true medical emergency and clinicians should base the management on American Heart Association advanced cardiac life support algorithm. The potential triggers of cardiac arrest should be sought. We present a case of a 27-year-old female who developed cardiac arrest and was later found to have congenital long QT syndrome. The patient's outcome was favorable. Discussion of the key management options will be discussed in the text. PMID- 25431686 TI - Norepinephrine as a potential aggravator of symptomatic cerebral vasospasm: two cases and argument for milrinone therapy. AB - Background. During hypertensive therapy for post-subarachnoid hemorrhage (SAH) symptomatic vasospasm, norepinephrine is commonly used to reach target blood pressures. Concerns over aggravation of vasospasm with norepinephrine exist. Objective. To describe norepinephrine temporally related deterioration in neurological examination of two post-SAH patients in vasospasm. Methods. We retrospectively reviewed two charts of patients with delayed cerebral ischemia (DCI) post-SAH who deteriorated with norepinephrine infusions. Results. We identified two patients with DCI post-SAH who deteriorated during hypertensive therapy with norepinephrine. The first, a 43-year-old male presented to hospital with DCI, failed MABP directed therapy with rapid deterioration in exam with high dose norepinephrine and MABP of 140-150 mm Hg. His exam improved on continuous milrinone and discontinuation of norepinephrine. The second, a 39-year-old female who developed DCI on postbleed day 8 responded to milrinone therapy upfront. During further deterioration and after angioplasty, norepinephrine was utilized to drive MABP to 130-140 mm Hg. Progressive deterioration in examination occurred after angioplasty as norepinephrine doses escalated. After discontinuation of norepinephrine and continuation of milrinone, function dramatically returned but not to baseline. Conclusions. The potential exists for worsening of DCI post-SAH with hypertensive therapy directed by norepinephrine. A potential role exists for vasodilation and inotropic directed therapy with milrinone in the setting of DCI post-SAH. PMID- 25431687 TI - Single-tooth morse taper connection implant placed in grafted site of the anterior maxilla: clinical and radiographic evaluation. AB - The aim of this study was to achieve aesthetically pleasing soft tissue contours in a severely compromised tooth in the anterior region of the maxilla. For a right-maxillary central incisor with localized advanced chronic periodontitis a tooth extraction followed by reconstructive procedures and delayed implant placement was proposed and accepted by the patient. Guided bone regeneration (GBR) technique was employed, with a biphasic calcium-phosphate (BCP) block graft placed in the extraction socket in conjunction with granules of the same material and a resorbable barrier membrane. After 6 months of healing, an implant was installed. The acrylic provisional restoration remained in situ for 3 months and then was substituted with the definitive crown. This ridge reconstruction technique enabled preserving both hard and soft tissues and counteracting vertical and horizontal bone resorption after tooth extraction and allowed for an ideal three-dimensional implant placement. Localized severe alveolar bone resorption of the anterior maxilla associated with chronic periodontal disease can be successfully treated by means of ridge reconstruction with GBR and delayed implant insertion; the placement of an early-loaded, Morse taper connection implant in the grafted site was effective to create an excellent clinical aesthetic result and to maintain it along time. PMID- 25431688 TI - Er:YAG Laser Dental Treatment of Patients Affected by Epidermolysis Bullosa. AB - Aim. The purpose of this study was to evaluate the efficacy of Er:YAG laser used for treating hard dental tissue in patients with epidermolysis bullosa (EB). Methods. We report two cases of EB in which an Er:YAG laser was used for conservative treatments. In the first case, the Er:YAG laser (2,940 MUm, 265 mJ, 25 Hz) was used to treat caries on a deciduous maxillary canine in an 8-year-old male patient affected by dystrophic EB. In the second case, we treated a 26-year old female patient, affected by junctional EB, with generalized enamel hypoplasia, and an Er:YAG laser (2,940 MUm, 265 mJ, 25 Hz) was used to remove the damaged enamel on maxillary incisors. Results. The use of the Er:YAG laser, with the appropriate energy, was effective in the selective removal of carious tissue and enamel hypoplasia. During dental treatment with the Er:YAG laser, patients required only a few interruptions due to the absence of pain, vibration, and noise. Conclusions. Laser treatment of hard dental tissues is a valuable choice for patients affected by EB since it is less invasive compared to conventional treatment, resulting in improved patient compliance. PMID- 25431689 TI - Paradigm shift in the management of the atrophic posterior maxilla. AB - When the posterior maxilla is atrophic, the reference standard of care would be to perform sinus augmentation with an autologous bone graft through the lateral approach and delayed implant placement. However, placement of short implants with the osteotome sinus floor elevation technique and without graft can be proposed for an efficient treatment of clinical cases with a maxillary residual bone height of 4 to 8 mm. The use of grafting material is recommended only when the residual bone height is <=4 mm. Indications of the lateral sinus floor elevation are limited to cases with a residual bone height <= 2 mm and fused corticals, uncompleted healing of the edentulous site, and absence of flat cortical bone crest or when the patient wishes to wear a removable prosthesis during the healing period. The presented case report illustrates osteotome sinus floor elevation with and without grafting and simultaneous implant placement in extreme conditions: atrophic maxilla, short implant placement, reduced healing time, and single crown rehabilitation. After 6 years, all placed implants were functional with an endosinus bone gain. PMID- 25431690 TI - Boon of MTA Apexification in Young Permanent Posterior Teeth. AB - Single visit apexification using mineral trioxide aggregate (MTA) is a new boon in effective management of nonvital tooth with an open apex which has steadily gained popularity with clinicians; also it shortens the treatment period and improves patient compliance. Importance of this approach lies in expedient cleaning and shaping of the root canal system, followed by its apical seal with MTA. There are several case reports available describing the use of MTA as an apexification agent in incisors and premolar, but presented cases are the unique case reports demonstrating successful apexification procedure using MTA in young permanent mandibular molars. After eight-month follow-up, teeth were without any abnormal clinical symptoms; rather there were radiographic resolution of the periapical lesion and induction of root end closure with new hard tissue formation over MTA. PMID- 25431691 TI - Class III Malocclusion Surgical-Orthodontic Treatment. AB - The aim of the present case report is to describe the orthodontic-surgical treatment of a 17-year-and-9-month-old female patient with a Class III malocclusion, poor facial esthetics, and mandibular and chin protrusion. She had significant anteroposterior and transverse discrepancies, a concave profile, and strained lip closure. Intraorally, she had a negative overjet of 5 mm and an overbite of 5 mm. The treatment objectives were to correct the malocclusion, and facial esthetic and also return the correct function. The surgical procedures included a Le Fort I osteotomy for expansion, advancement, impaction, and rotation of the maxilla to correct the occlusal plane inclination. There was 2 mm of impaction of the anterior portion of the maxilla and 5 mm of extrusion in the posterior region. A bilateral sagittal split osteotomy was performed in order to allow counterclockwise rotation of the mandible and anterior projection of the chin, accompanying the maxillary occlusal plane. Rigid internal fixation was used without any intermaxillary fixation. It was concluded that these procedures were very effective in producing a pleasing facial esthetic result, showing stability 7 years posttreatment. PMID- 25431692 TI - Endodontic treatment of a mandibular second premolar with three roots and three canals. AB - Complex root canal system with atypical variations is a common finding among mandibular premolars. Endodontic treatment in these teeth may not be successful due to the failure to recognise and treat multiple canals. This paper presents endodontic treatment of a mandibular second premolar with three roots and three canals. PMID- 25431693 TI - A life threatening rash, an unexpected cause. AB - We describe a 74-year-old man with purpura fulminans and altered sensorium following an acute febrile illness. Intensive sepsis management was to no avail, until institution of doxycycline therapy following confirmation of scrub typhus. Empirical doxycycline needs to be considered in endemic areas for patients presenting with purpura fulminans. PMID- 25431694 TI - A gigantic anogenital lesion: buschke-lowenstein tumor. AB - Buschke-Lowenstein tumor is a relatively rare sexually transmitted disease. It is a neoplasm of the anogenital region which has benign appearance on histopathology but is locally destructive. It carries a high recurrence rate and a significant potential for malignant transformation. Human papilloma virus has been implicated as an etiologic agent for this tumor. Since this disease is rare and no controlled studies exist, radical excision of this anogenital lesion is generally recommended as the first line therapy and close vigilance and followup are essential. We have discussed an overview of etiopathogenesis, clinical presentation, diagnosis, and management of this uncommonly encountered disease. PMID- 25431695 TI - Expansion of natural killer cells in peripheral blood in a Japanese elderly with human T-cell lymphotropic virus type 1-related skin lesions. AB - Natural killer (NK) cells were proposed to play an important role in the pathogenesis of human T-cell lymphotropic virus type 1- (HTLV-1-) associated neurologic disease. Our patient was a 77-year-old Japanese man, who had been treated for infective dermatitis associated with HTLV-1 for nearly 10 years. When referred to us, he had facial eczema/edema as well as extensive dermatitis at the neck/upper chest and nuchal area/upper back regions. Dermal lesions had CD3+CD4+ cells, but no NK cells. Flow cytometry of his peripheral blood showed a phenotype of CD2+ (97%), CD3+ (17%), CD4+ (12%), CD7+ (94%), CD8+ (6%), CD11c+ (70%), CD16+ (82%), CD19+ (0%), CD20+ (0%), CD56+ (67%), HLA-DR+ (68%), and NKp46+ (36%). Absolute numbers of CD56+NK cells in the peripheral blood were in a range of 986/MUL-1,270/MUL. The expanded NK cells in the peripheral blood are considered to be reactive, to maintain the confinement of the HTLV-1-positive CD4+ cells in the skin, and to prevent the progression of the disease. PMID- 25431696 TI - A case of lemierre syndrome secondary to otitis media and mastoiditis. AB - Lemierre's syndrome is a rare clinical condition that generally develops secondary to oropharyngeal infection caused by Fusobacterium necrophorum, which is an anaerobic bacteria. A 62-year-old patient with diabetes mellitus presented with internal jugular vein and sigmoid sinus-transverse sinus thrombophlebitis, accompanying otitis media and mastoiditis that developed after an upper airway infection. Interestingly, there were air bubbles in both the internal jugular vein and transverse sinus. Vancomycin and meropenem were started and a right radical mastoidectomy was performed. The patient's clinical picture completely resolved in 14 days. High mortality and morbidity may be prevented with a prompt diagnosis of Lemierre's syndrome. PMID- 25431697 TI - A Case of Rathke's Cleft Cyst Associated with Transient Central Adrenal Insufficiency and Masked Diabetes Insipidus. AB - A 73-year-old woman admitted to our hospital because of headache, poor appetite, malaise, weight loss, and vomiting was found to have central adrenal insufficiency and thyrotoxicosis due to silent thyroiditis. Polyuria developed after replacement with glucocorticoid (masked diabetes insipidus), which was controlled with nasal administration of desmopressin. Magnetic resonance imaging of the brain showed a large cystic pituitary mass (18 * 18 * 12 mm) extending suprasellarly to the optic chiasm. Transsphenoidal surgery revealed that the pituitary tumor was Rathke's cleft cyst. Following surgery, replacement with neither glucocorticoid nor desmopressin was needed any more. Therefore, it is suggested that Rathke's cleft cyst is responsible for the masked diabetes insipidus and the central insufficiency. Furthermore, it is speculated that thyrotoxicosis with painless thyroiditis might induce changes from subclinical adrenal insufficiency to transiently overt insufficiency. PMID- 25431698 TI - Acquired Factor XI Inhibitor Presenting as Spontaneous Bilateral Subdural Hematoma in an Elderly Patient. AB - Development of autoantibodies against coagulation factors is an uncommon bleeding disorder associated with cancer, autoimmune conditions, pregnancy, or no apparent disease. Spontaneous FVIII inhibitors are the most frequently encountered; those against FXI have been only anecdotally reported. We report a case of acquired FXI inhibitor presenting as fatal intracranial spontaneous bleeding in an elderly patient with history of cancer and previous transfusions. Few cases of acquired FXI inhibitor have been reported in association with connective tissue disease, cancer, or surgery. Bleeding includes mucocutaneous bleeding, postsurgical hemorrhage, or life-threatening events. Treatment consists of arresting the bleeding and inhibitor eradication. High degree of suspicion is essential to promptly diagnose and treat this uncommon condition. PMID- 25431699 TI - Primary cardiac burkitt lymphoma presenting with abdominal pain. AB - We describe the case of a 44-year-old woman with primary Burkitt lymphoma of the heart who presented with abdominal bloating and epigastric discomfort secondary to tamponade physiology caused by a large pericardial effusion. The pericardial fluid contained a large number of highly atypical lymphocytes with moderate basophilic cytoplasm, rare punched-out vacuoles, a vesicular nuclear chromatin, large nucleolus, and marginated chromatin that by FISH were positive for the 8;14 translocation. She had no other sites of disease. She was treated with four alternating cycles of modified CODOX-M and IVAC in combination with rituximab and remains in remission more than 5 years since diagnosis. PMID- 25431700 TI - Chronic idiopathic neutrophilia in two twins. AB - Neutrophilia in adults refers to an alteration in the total number of blood neutrophils that is in excess of about 7500 cells/MUL. This definition is restrictive in childhood as neutrophil count is age-dependent. Chronic Idiopathic Neutrophilia (CIN) refers to a condition that persists for many years in individuals who appear otherwise healthy. CIN is rarely mentioned in scientific literature and in academic books of hematology; only few words are dedicated to this topic. We report a case study of two twins with CIN followed from the first year of life to 24 years of age. To the best of our knowledge this is the first case report of two twins with CIN followed through a long period of time. We believe that our observation may contribute to better understand and characterize this hematologic abnormality. PMID- 25431701 TI - Hypofractionated stereotactic radiotherapy after transarterial chemoembolisation failure in an unresectable hepatocellular carcinoma: a case presentation. AB - Introduction. Transarterial chemoembolization is the first-line treatment in unresectable hepatocellular carcinoma. There is no standard treatment after transarterial chemoembolization failure. We report the case of a patient with advanced hepatocellular carcinoma who showed a complete response and a long cancer control with hypofractionated stereotactic radiotherapy after transarterial chemoembolization failure. Case Presentation. A 70-year-old Caucasian woman was treated with transarterial chemoembolization for advanced hepatocellular, but no cancer control was obtained. A hypofractionated stereotactic radiotherapy was planned delivering 40 Gy in 5 fractions. A dramatic reduction in alpha-fetoprotein was observed. Contrast-enhanced ultrasonography at 1 and 2 months showed large necrotic areas. Computerised tomography scan showed a 90% objective tumour response, then a complete remission at 3 and 6 months after treatment, respectively. Status of patient remained unchanged for 2 years. Conclusions. Hypofractionated stereotactic radiotherapy can improve survival and prognosis of unresectable hepatocellular carcinoma patient. PMID- 25431702 TI - Spontaneous intraperitoneal rupture of a hepatic hydatid cyst with subsequent anaphylaxis: a case report. AB - Hydatid cyst rupture into the abdomen is a serious complication of cystic hydatid disease of the liver (Cystic Echinococcosis) with an incidence of up to 16% in some series and can result in anaphylaxis or anaphylactoid reactions in up to 12.5% of cases. At presentation, 36-40% of hydatid cysts have ruptured or become secondarily infected. Rupture can be microscopic or macroscopic and can be fatal without surgery. Hydatid disease of the liver is primarily caused by the tapeworm Echinococcus granulosus and occurs worldwide, with incidence of up to 200 per 100,000 in endemic areas. Our case describes a 24-year-old Bulgarian woman presenting with epigastric pain and evidence of anaphylaxis. Abdominal CT demonstrated a ruptured hydatid cyst in the left lobe of the liver. A partial left lobe hepatectomy, cholecystectomy, and peritoneal washout was performed with good effect. She was treated for anaphylaxis and received antihelminthic treatment with Albendazole and Praziquantel. She made a good recovery following surgery and medical treatment and was well on follow-up. Intraperitoneal rupture with anaphylaxis is a rare occurrence, and there do not seem to be any reported cases from UK centres prior to this. PMID- 25431703 TI - Drug-induced liver injury caused by adalimumab: a case report and review of the bibliography. AB - The most serious adverse drug reaction of adalimumab (ADR) is tuberculosis reactivation. We describe a case of a 35-year-old man, with rheumatoid arthritis (RA) and hepatitis C virus genotype 1a with a liver biopsy in 2001 with a METAVIR score pattern A1 F0; he received interferon alpha 2b for six months, but treatment was suspended because of reactivation of RA. Liver function tests after treatment were similar to previous ones showing a minimal cholestatic pattern. In 2008, methotrexate was prescribed, but the drug was withdrawn at the third month because of the appearance of pruritus and Ggt rise. Viral load at that moment was 9300000 UI/mL, log 6,9. The liver biopsy showed a Metavir Score A2 F1. Adalimumab was started in 2010, and at the third month of treatment, Ggt showed a rise of 23 times normal value (NV), alkaline phosphatase 2,5 times NV with AST and ALT with no change. A new liver biopsy showed portal inflammation with eosinophils and a METAVIR A1 F2. We think that adalimumab appears to be responsible for the liver injury, because of temporal relationship, liver biopsy findings, other clinical conditions being discarded, and the improvement of clinical symptoms and biochemical abnormalities when adalimumab was suspended. PMID- 25431704 TI - Acute cholestatic hepatitis a virus infection presenting with hemolytic anemia and renal failure: a case report. AB - Hepatitis A virus is the most common acute viral hepatitis worldwide with approximately 1.5 million cases annually. Hepatitis A virus infection in general is self-limited. In rare cases, hepatitis A virus infection may cause renal failure, hemolytic anemia, and/or cholestasis. We report the first case of acute cholestatic hepatitis A virus infection complicated by hemolytic anemia, and renal failure in one patient. A 42-year-old Caucasian male presented with cholestasis, hemolytic anemia and renal failure after consuming street tacos in Central and South America while on a business trip. His protracted course required corticosteroid therapy, multiple sessions of plasma exchange, and numerous units of packed red blood cells. This case demonstrates the importance of vaccination in high-risk adults. A prompt diagnosis of acute hepatitis A virus infection is essential, as uncommon presentations may delay diagnosis leading to permanent morbidity and potentially death in fulminant cases. We also demonstrate the efficacy of treatment of cholestatic hepatitis A virus infection, hemolytic anemia, and renal failure with corticosteroids and plasma exchange. PMID- 25431705 TI - A case of solitary necrotic nodule treated with laparoscopic hepatectomy: spontaneous regression of hepatocellular carcinoma? AB - Solitary necrotic nodule of the liver is a rare benign lesion with a completely necrotic core and a hyalinized fibrotic capsule containing elastic fibers. The pathogenetic mechanism is still unclear. We here describe a case of SNN, whose central reticulin fibers within the nodule suggest the origin as hepatocellular carcinoma or other hepatocyte-origin tumors, treated with laparoscopic anatomical segmentectomy of the liver. A 76-year-old Japanese female, with no prior medical history and no symptom, visited our hospital with the heterogeneous hypoechoic lesion in the liver segment VI incidentally pointed out in abdominal ultrasonography. Computed tomography with contrast demonstrated a 1.1 cm sized low-density lesion with mild ring enhancement on the rim in the arterial phase. Since the possibility of malignant tumor with necrotic change could not be ruled out, she underwent laparoscopic anatomical segmentectomy of the liver. In the histological examination of the surgical specimen, the liver nodule was necrotic tissue without viable cells and signs of inflammation, which had fibrous capsule and central cystic change and showed trabecular pattern alignment of ghost cells and reticulin fibers orthogonal to the capsule. Also, the findings of chronic hepatitis were observed in the background liver. PMID- 25431706 TI - Chinese skullcap in move free arthritis supplement causes drug induced liver injury and pulmonary infiltrates. AB - Herbal medications are being increasingly used by the American population especially for common conditions like arthritis. They have been reported to cause adverse effects, including significant hepatotoxicity, but reporting remains sporadic. We report here a patient who developed drug induced liver injury following the intake of Move Free, which is an over-the-counter arthritis supplement. We propose that Chinese skullcap, which is one of the herbal ingredients of the medication, is responsible for the adverse event. There was a strong temporal association between the intake of supplement and onset of symptoms, and also there have been a few recent case reports implicating the same component. A unique observation in our case is the occurrence of pulmonary infiltrates simultaneously with the hepatotoxicity, and this side effect has not been well documented before. Both the hepatic and pulmonary complications completely resolved over few weeks after the patient stopped taking the medication. Since these supplements are readily available over the counter, we feel that it is important to document possible adverse outcomes to raise awareness in the medical community and also among patients. PMID- 25431707 TI - Leptomeningeal dissemination in gall bladder carcinoma: sequelae of long-term survival? AB - Patients with gall bladder malignancies usually present at an advanced stage with less than 20% cases being resectable at presentation and over a half harbouring distant metastases to liver or paraaortic nodes. Long-term cure is uncommon and so is the presence of central nervous system metastases. We present the case of a middle-aged woman with adenocarcinoma gall bladder, treated with postoperative locoregional irradiation following simple cholecystectomy, who developed headache, backache, vision loss, and multiple joint pains six years following adjuvant therapy. A diagnosis of leptomeningeal carcinomatous meningitis was established with cerebrospinal fluid cytology positivity for carcinoma. She deteriorated on palliative cranial irradiation and was managed with best supportive care. PMID- 25431708 TI - Failed Reverse Total Shoulder Arthroplasty Caused by Recurrent Candida glabrata Infection with Prior Serratia marcescens Coinfection. AB - This report describes a 58-year-old insulin-dependent diabetic male patient who initially sustained a proximal humerus fracture from a fall. The fracture fixation failed and then was converted to a humeral hemiarthroplasty, which became infected with Candida glabrata and Serratia marcescens. After these infections were believed to be cured with antibacterial and antifungal treatments and two-stage irrigation and debridement, he underwent conversion to a reverse total shoulder arthroplasty. Unfortunately, the C. glabrata infection recurred and, nearly 1.5 years after implantation of the reverse total shoulder, he had a resection arthroplasty (removal of all implants and cement). His surgical and pharmacologic treatment concluded with (1) placement of a tobramycin-impregnated cement spacer also loaded with amphotericin B, with no plan for revision arthroplasty (i.e., the spacer was chronically retained), and (2) chronic use of daily oral fluconazole. We located only three reported cases of Candida species causing infection in shoulder arthroplasties (two C. albicans, one C. parapsilosis). To our knowledge, a total shoulder arthroplasty infected with C. glabrata has not been reported, nor has a case of a C. glabrata and S. marcescens periprosthetic coinfection in any joint. In addition, it is well known that S. marcescens infections are uncommon in periprosthetic joint infections. PMID- 25431709 TI - Postoperative atypical hemolytic uremic syndrome associated with complement c3 mutation. AB - Atypical hemolytic uremic syndrome (aHUS) can be distinguished from typical or Shiga-like toxin-induced HUS. The clinical outcome is unfavorable; up to 50% of affected patients progress to end-stage renal failure and 25% die during the acute phase. Multiple conditions have been associated with aHUS, including infections, drugs, autoimmune conditions, transplantation, pregnancy, and metabolic conditions. aHUS in the nontransplant postsurgical period, however, is rare. An 8-month-old boy underwent surgical repair of tetralogy of Fallot. Neurological disturbances, acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia developed 25 days later, and aHUS was diagnosed. Further evaluation revealed that his complement factor H (CFH) level was normal and that anti-FH antibodies were not detected in his plasma. Sequencing of his CFH, complement factor I, membrane cofactor protein, complement factor B, and thrombomodulin genes was normal. His ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin-1 repeats 13) activity was also normal. However, he had a potentially causative mutation (R425C) in complement component C3. Restriction fragment length polymorphism analysis revealed that his father and aunt also had this mutation; however, they had no symptoms of aHUS. We herein report a case of aHUS that developed after cardiovascular surgery and was caused by a complement C3 mutation. PMID- 25431710 TI - Stroke after Initiating IV Penicillin for Neurosyphilis: A Possible Jarisch Herxheimer Reaction. AB - Introduction. Syphilis incidence has increased in the US in the last decade. Jarisch-Herxheimer reaction (JHR) is a well-documented adverse effect of penicillin treatment in syphilis. Stroke has not been reported as part of its phenomenology. Case Report. A 57-year-old man presented with worsening memory. His minimental status examination score was 14/30. Serum RPR test was positive and VDRL test in the CSF was reactive. Within six hours of first dose of IV crystalline penicillin G, he was found to have hemineglect and difficulty moving the left leg. MRI of the brain showed multiple acute ischemic strokes. Immediate MRA ruled out vascular occlusion. Penicillin treatment was stopped. Four hours later, he was found to be febrile and had two episodes of generalized tonic clonic seizures. Conclusions. We report a case of confirmed neurosyphilis with no known modifiable stroke risk factors, who developed acute ischemic stroke and other constitutional symptoms consistent with JHR after IV penicillin. This is the first reported case in literature where an acute ischemic stroke can be attributed to Jarisch-Herxheimer reaction. Given an increase in incidence of syphilis in recent years, our case underlies the importance of keeping in mind potential catastrophic drug adverse reactions in neurosyphilis patients. PMID- 25431712 TI - Pemphigoid gestationis in a third trimester pregnancy. AB - Pemphigoid gestationis (PG) is a rare vesiculobullous dermatosis of pregnancy. It is commonly seen in second or third trimester. The diagnosis is frequently made with direct immunofluorescence studies of perilesional skin. Prompt recognition and appropriate management may reduce morbidity of this disease. Herein we present a case of pemphigoid gestationis occurring in a 33-year-old primigravida woman with symptoms of generalized pruritus. PMID- 25431711 TI - Osmotic demyelination syndrome as the initial manifestation of a hyperosmolar hyperglycemic state. AB - Osmotic demyelination syndrome (ODS) is a life-threatening demyelinating syndrome. The association of ODS with hyperosmolar hyperglycemic state (HHS) has been seldom reported. The aim of this study was to present and discuss previous cases and the pathophysiological mechanisms involved in ODS secondary to HHS. A 47-year-old man arrived to the emergency room due to generalized tonic-clonic seizures and altered mental status. The patient was lethargic and had a Glasgow coma scale of 11/15, muscle strength was 4/5 in both lower extremities, and deep tendon reflexes were diminished. Glucose was 838 mg/dL; serum sodium and venous blood gas analyses were normal. Urinary and plasma ketones were negative. Brain magnetic resonance revealed increased signal intensity on T2-weighted FLAIR images with restricted diffusion on the medulla and central pons. Supportive therapy was started and during the next 3 weeks the patient progressively regained consciousness and muscle strength and was able to feed himself. At 6 month follow-up, the patient was asymptomatic and MRI showed no residual damage. In conclusion, the association of ODS with HHS is extremely rare. The exact mechanism by which HHS produces ODS still needs to be elucidated, but we favor a rapid hypertonic insult as the most plausible mechanism. PMID- 25431713 TI - Cornual heterotopic pregnancy after bilateral salpingectomy and uterine septum resection resulting in term delivery of a healthy infant. AB - Heterotopic pregnancy is the simultaneous occurrence of two or more implantation sites. A 25-year-old infertile patient with a history of bilateral salpingectomy, uterine septum resection, and left cornual resection was diagnosed with heterotopic pregnancy in her second in vitro fertilization trial. She attended our clinic when she was 7-week pregnant, complaining initially of severe abdominal pain. Findings associated with peritoneal irritation were positive during the physical examination. Transvaginal ultrasound revealed right cornual ectopic pregnancy with a live fetus in the middle of the uterine cavity. Also free fluid was noted in the pelvis. A diagnosis of heterotopic pregnancy with rupture of the cornual pregnancy was made. She underwent emergency laparoscopy with aspiration of the ruptured ectopic pregnancy, suturing to the entire visible cornual margins, and assurance of good haemostasis. Her recovery was uneventful and she continued receiving care in our obstetric unit. She delivered a healthy newborn by cesarean section at term. PMID- 25431714 TI - Successful management of a cesarean scar defect with dehiscence of the uterine incision by using wound lavage. AB - Cesarean scar defects (CSDs) that can be visualized using transvaginal ultrasonography (TVUS) may cause prolonged menstruation, irregular genital bleeding, and secondary infertility; surgical repair is sometimes necessary. We present a case of CSD, with dehiscence of the uterine incision, which was managed using wound lavage. A 38-year-old woman (gravida 4, para 4) had delivered her third and fourth children by cesarean section. Upon the resumption of menstruation, 9 months after her second cesarean section, she demonstrated prolonged menstruation and the presence of a menstrual fistula due to dehiscence of the cesarean section incision from the myometrium to the serosa. We treated the defect by lavaging with a physiological saline solution. After lavaging the wound 3 times, spontaneous healing of the dehiscent muscle layer was successfully achieved. The treatment was complication-free and the healing of the muscle layer has been maintained for more than 8 months. PMID- 25431715 TI - Transcatheter Arterial Chemoembolization and Chemotherapy plus Sorafenib in a Large Hepatocellular Carcinoma with Arterioportal Shunt. AB - Introduction. Arterioportal shunts (APS) are sometimes encountered in patients with hepatocellular carcinoma (HCC) and associated with poor prognosis. The management of HCC with APS is a challenge so far. Case Presentations. We report here in detail a 37-year-old man who was diagnosed as an advanced HCC accompanied with severe APS and treated by two sessions of transcatheter arterial chemoembolization (TACE) and three sessions of transcatheter arterial chemotherapy (TAC) plus sorafenib therapy. The tumor shrinks were revealed continuously during 152 days after the diagnosis. Although tumor progress emerged at 209 days after the diagnosis, the patient remarkably achieved 366-day survival. Discussion. TACE plus sorafenib may be a promising treatment for advanced HCC accompanied with APS. Prospective case-control studies should be advocated to evaluate the combination of TACE, TAC, and sorafenib in the management of HCC with APS. PMID- 25431716 TI - Ground-level geriatric falls: a not-so-minor mechanism of injury. AB - Introduction. Ground-level falls are typically regarded as a minor mechanism of injury that do not necessitate trauma team activation; however, they represent a significant proportion of hospitalised trauma and can result in multisystem injury. Case Presentation. A 79-year-old nursing home resident was brought to the emergency department following an unwitnessed fall. She suffered dementia and had a seizure in the department resulting in a reduced GCS, making history and examination difficult. She was diagnosed with a right proximal humerus fracture and admitted under joint orthopedic and medical care. Following orthopedic review, further X-rays were requested which showed bilateral neck of femur fractures. The following day she had bilateral hip hemiarthroplasties and K-wire stabilisation of the right shoulder. Several days later, when cognition had improved, she was noted to be avoiding use of the left arm and was found to also have a left proximal humerus fracture which was managed conservatively. Conclusion. Trauma patients with reduced cognitive function should undergo full ATLS assessment, and a prospective trial is required to see if age should be incorporated as a criteria for trauma team activation. More liberal use of advanced imaging such as a full body CT-scan may be beneficial. PMID- 25431717 TI - Severe Heterotopic Ossification following Total Knee Replacement. AB - Although the incidence of minor heterotopic ossification is probably higher than what is usually expected, severe heterotopic ossification (HO) is an extremely rare event following total knee replacement surgery. We present the case of a 66 year-old woman who initially had achieved an excellent range of motion following bilateral uncemented rotating platform total knee replacement, before presenting with pain and loss of range of motion at 2 months after surgery. Severe HO was diagnosed on X-rays. Treatment consisted of nonoperative measures only, including physiotherapy with hydrotherapy and anti-inflammatories. She eventually regained her range of motion when seen at 8 months after operation. This case illustrates that nonoperative treatment without the use of radiotherapy or surgery can be used to safely resolve stiffness caused by HO after total knee replacement. PMID- 25431718 TI - Rising Methicillin-Resistant Staphylococcus aureus Infections in Ear, Nose, and Throat Diseases. AB - The increasing incidence of methicillin-resistant Staphylococcus aureus infections (MRSA) in ENT diseases is becoming a big clinical concern. Here two patients are described who developed MRSA infections presented with unusual post FESS epistaxis and postmastoidectomy perichondrial abscess and failed treatment with broad spectrum intravenous antibiotics. Following treatment with oral linezolid combined with local mupirocin dressing both patients fully recovered. PMID- 25431719 TI - Recurrent bacterial meningitis in a child with mondini dysplasia. AB - Mondini dysplasia, also known as Mondini malformation, is a developmental abnormality of the inner and middle ears that can cause hearing loss, cerebrospinal fluid (CSF) leakage, and recurrent bacterial meningitis (RBM), which is defined as two or more episodes of meningitis separated by a period of convalescence and the complete resolution of all signs and symptoms. An accurate diagnosis of the underlying pathology is crucial to prevent further episodes from occurring. Herein, we present a three-year-old boy with RBM and unilateral sensorineural hearing loss. During the evaluation to determine the etiology of the RBM, cystic malformation in the cochlea and vestibular dilatation consistent with Mondini dysplasia were detected via computerized tomography (CT) of the temporal bone. PMID- 25431720 TI - Pyrethroid as a substance of abuse. AB - This is a case of a 22-year-old Hispanic male with a history of bipolar disorder and methamphetamine dependence who was admitted after presenting with suicidal ideations by slashing his throat with a machete. The patient had been smoking and inhaling "processed" pyrethroid for about eight weeks as an inexpensive methamphetamine substitute. He reported experiencing a "rush" similar to methamphetamine after using pyrethroid from liquid insecticide that had been heated (electrocuted) or sprayed on hot metal sheets until it crystallized. The patient presented with no significant physical markings or findings but claimed to have his suicidal ideations precipitated by concerns of ill effects of pyrethroid on his health. He also had positive urine drug screen for methamphetamine, which he admitted to using on the day of admission. We conclude that it is important for physicians to maintain a high level of suspicion for alternate and uncommon substances of abuse as well as risks for suicidal tendencies in these patients. PMID- 25431721 TI - Diagnosis and treatment of psychiatric comorbidity in a patient with charles bonnet syndrome. AB - Background. A significant proportion of patients with neurological disorders may have comorbid psychiatric symptomology, which may be managed by primary outpatient neurologists. Referral to their psychiatric colleagues is mediated by available consultation-liaison units and according to clinical opinion. Aims of Case Report. We present the case of a patient whose initial referral to epilepsy clinic led to a workup which ultimately diagnosed her with nonepileptic seizures (NES). In the course of her follow-up, she developed intractable headaches, and worsening mood symptoms and eventually exhibited Psychotic Features for which psychiatry became coinvolved in her care. Major Depression with Psychotic Features and Charles Bonnet syndrome were considered as a likely comorbid diagnoses. Her pharmacologic management on venlafaxine and quetiapine eventually caused substantial amelioration of her psychiatric symptomology as longitudinally followed by PHQ-9 and GAD-7 scores. Conclusion. Optimal evaluation and management of mental illness in patients with complex neurologic symptomology may require independent evaluation and treatment by psychiatrists when clinically appropriate. PMID- 25431722 TI - Spinal nerve root haemangioblastoma associated with reactive polycythemia. AB - Haemangioblastomas are uncommon tumours that usually occur in the cerebellum and, less commonly, in the intramedullary spinal cord. The extramedullary spinal canal is an uncommon location for these tumours. Also haemangioblastoma at this site is not known to be associated with polycythemia. We present the clinical, imaging, and histological findings of an adult patient with extramedullary spinal haemangioblastoma and reactive polycythemia. Radiography and computed tomography (CT) revealed a medium-sized tumour that most likely arose from an extramedullary spinal nerve root. This tumour appeared to be slow growing as evidenced by the accompanying well-defined bony resorption with a sclerotic rim and mild neural foraminal widening. Magnetic resonance imaging revealed prominent flow voids consistent with tumoural hypervascularity. CT-guided biopsy was performed. Although preoperative angiographic embolisation was technically successful, excessive intraoperative tumour bleeding necessitated tumour debulking rather than complete tumour resection. Histology of the resected specimen revealed haemangioblastoma. Seven months postoperatively, the patients back pain and polycythemia have resolved. PMID- 25431723 TI - A case of sarcoidosis with interstitial lung disease mimicking clinically amyopathic dermatomyositis and rapidly progressive interstitial lung disease. AB - Here, we report a patient with sarcoidosis who developed edematous erythema and interstitial lung disease. At the initial visit, clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP ILD) was suspected because he had progressive dyspnea but no muscle weakness. The presence of anti-CADM-140/MDA5 autoantibodies was immediately assessed to facilitate a precise diagnosis, with negative results. Thereafter, skin and transbronchial lung biopsies revealed noncaseating granuloma with Langhans giant cells in both specimens, leading to a diagnosis of sarcoidosis. In this case, clinical features of skin and lung were unable to distinguish DM (including CADM) from sarcoidosis, but the lack of anti-CADM-140/MDA5 antibody was useful for differentiating CADM with RP-ILD mimicking sarcoidosis from bona fide sarcoidosis. PMID- 25431724 TI - Acute onset polymyositis after prolactinoma extirpation. AB - Hyperprolactinemia has been related to autoimmune diseases. Herein, we describe a case of a female with a prolactin producer pituitary macroadenoma who developed severe polymyositis one month after its removal. The patient had very high levels of CPK and muscle biopsy showed remarkable inflammatory infiltration. Steroid therapy was followed with total recovery. To the best of our knowledge, this is the first case reported of acute polymyositis after pituitary macroadenoma exeresis. PMID- 25431725 TI - Leprosy mimicking common rheumatologic entities: a trial for the clinician in the era of biologics. AB - Rheumatoid arthritis and seronegative spondyloarthritis, which make up the lion's share of cases attending a rheumatology clinic, are relatively easy to diagnose. However, when an entity of infective aetiology like leprosy known to be a great mimic of different autoimmune conditions presents with features similar to these, the possibility of it being diagnosed at the outset is very slim indeed. The ease with which the diagnosis of leprosy can be missed assumes sinister proportions as the use of disease modifying agents can have deleterious effects in these patients. In the era of increasing availability and use of biologic disease modifying agents, it is imperative not only to actively rule out the presence of leprosy but also to make it a part of the prebiologic screening of patients in whom biologics are being planned to be administered, especially in leprosy endemic areas. PMID- 25431726 TI - Acute Abdomen due to Primary Omental Torsion and Infarction. AB - Background. Torsion of greater omentum is a quite uncommon cause of acute abdomen. It can be primary or secondary but in both cases omentum twists upon itself and causes omental segmentary or diffuse necrosis. Symptoms are unspecific and preoperative diagnosis is difficult. The widespread and increasing use of computer tomography (CT) in differential diagnosis of acute abdomen can be useful for making a specific diagnosis. Objectives. This work aims to describe primary omental torsion in order to help avoid misdiagnosis, especially with acute appendicitis, which is eventually based solely on a physical examination. Case Report. We present a case of primary omental torsion in a young man and discuss contemporary methods in diagnosis and management of the condition. Conclusions. When a right diagnosis has been posed, possible treatments for omental torsion and necrosis are two: conservative or surgical. Conservative treatment had been rarely carried out because of frequent and important sequelae just like abdominal abscesses. Nowadays, surgical treatment, laparoscopic or laparotomic, is preferred because it is a safe method in diagnosis and management of this condition. PMID- 25431727 TI - Asymptomatic pellet migration to the heart: report of a case and update on proper management. AB - We report a case of a 42-year-old male patient who was transferred to our emergency department suffering from a gunshot wound in his left lateral thigh. The patient was haemodynamically stable, and the physical examination of the abdomen and thorax was unremarkable. There was no obvious exit point and there were no other injuries. The radiologic control of the left thigh showed an intact femur and multiple pellets within the adjacent soft tissues. Routine X-ray evaluation of the thorax revealed a small-sized round object of metal density possibly a migrated pellet-in the proximity of the right heart atrium. Computed tomography imaging confirmed this finding and showed no other cardiac or mediastinal injury. Ultrasonography of the heart was unremarkable as well. The patient was managed conservatively for the discovered pellet, and remained asymptomatic throughout the entire hospital stay, and 6 months after the discharge. Pellet migration or embolism should be suspected in any gunshot victim without a corresponding exit wound or when the signs and symptoms do not correlate with the suspected course of the missile. Conservative management remains the first choice in asymptomatic patients, although close monitoring at first and regular observation after discharge are indicated. PMID- 25431728 TI - Successful Removal of Giant Intrapericardial Paraganglioma via Posterolateral Thoracotomy. AB - Intrapericardial paraganglioma remains a surgical challenge because of its hypervascular nature and firm adhesion to adjacent mediastinal structures. Here, we describe a 63-year-old female with a giant nonfunctioning intrapericardial paraganglioma tightly adhered to the left atrium. Marginal but complete resection of the tumor was achieved via right posterolateral thoracotomy. At the time of dissection between the tumor and the left atrial wall, we encountered massive hemorrhage leading to cardiac arrest. We were able to repair the wall laceration with minimal time under an optimal operative field, which avoids air embolism. She was discharged without complications and is currently in good health with no recurrence or metastasis for 15 months. Based on our experience, cardiopulmonary bypass should be considered, if surgeons are able to secure suitable sites for arterial and venous cannulations while right posterolateral thoracotomy is employed. PMID- 25431729 TI - An extremely rare complication of varicose vein surgery: retained foreign body. AB - Foreign body is among complications of surgery. But as a complication of varicose vein surgery it was reported extremely rarely and, to our knowledge, there is only one paper in the literature. A case with retained sponge which was detected five months after varicose vein surgery was presented. PMID- 25431730 TI - Difficulties of bariatric surgery after abdominoplasty. AB - During laparoscopy, the main problems of patients who have undergone previous abdominoplasty are inadequate pneumoperitoneum secondary to fibrosis and reconstructed anatomic landmarks for trocar placement. In this study, we present our laparoscopic bariatric experience in two patients with previous abdominoplasty. The procedures were a laparoscopic sleeve gastrectomy and a robotic Roux-en-Y gastric bypass. Both operations were done successfully by an abdominal wall traction technique, cutting fibrotic tissue and choosing new landmarks. We conclude that after abdominoplasty bariatric surgery can be performed safely either using conventional laparoscopic technique or robotically. PMID- 25431732 TI - Mediastinal cystic lymphangioma in a patient with situs inversus totalis. AB - We present a case of cystic lymphangioma of the mediastinum complicated with situs inversus totalis. The 70-year-old man underwent thoracoscopic resection of a mediastinal cystic tumor, which was diagnosed as cystic lymphangioma. Cystic lymphangiomas are congenital cystic abnormalities of the lymphatic system. The head and neck area is often involved while the mediastinum is rarely affected. The rarity of this case is further attributed to the coexistence of situs inversus totalis. PMID- 25431731 TI - A Case of Retroperitoneal Castleman's Disease and an Update on the Latest Evidence. AB - Castleman's disease is a benign lymphoproliferative condition with three distinct histological subtypes. Clinically it presents in either a unicentric or multicentric manner and can affect various anatomic regions, the mediastinum being the most frequent location. We herein present a rare case of unifocal retroperitoneal mass proved to be hyaline vascular Castleman's disease. We perform a review of the current literature pertaining to such lesions, focusing on the management of the various clinical and histological variants of the disease. Surgical excision is the treatment of choice for unifocal Castleman's disease. PMID- 25431733 TI - Cardiac failure after liver transplantation requiring a biventricular assist device. AB - Increased hepatic iron load in extrahepatic organs of cirrhotic patients with and without hereditary hemochromatosis portends a poorer long term prognosis after liver transplant. Hepatic as well as nonhepatic iron overload is associated with increased infectious and postoperative complications, including cardiac dysfunction. In this case report, we describe a cirrhotic patient with alpha 1 antitrypsin deficiency and nonhereditary hemochromatosis (non-HFE) that developed cardiogenic shock requiring mechanical circulatory support for twenty days after liver transplant. Upon further investigation, she was found to have significant iron deposition in both the liver and heart biopsies. Her heart regained complete and sustained recovery following ten days of mechanical biventricular support. This case highlights the importance of preoperatively recognizing extrahepatic iron deposition in patients referred for liver transplantation irrespective of etiology of liver disease as this may prevent postoperative complications. PMID- 25431734 TI - Choroidal and cutaneous metastasis from urothelial carcinoma of the bladder after radical cystectomy: a case report and literature review. AB - Bladder cancer is the second most common genitourinary malignancy and has variable metastatic potential; however, choroidal and cutaneous metastases are extremely rare. Generally, a patient with these uncommon metastases has a very poor prognosis. We present a bladder cancer patient with a visual disorder in the right eye and multiple nodules on head and lower abdomen that developed 17 months after a radical cystectomy. These symptoms were determined to be caused by choroidal and cutaneous metastasis of bladder cancer. Although two cycles of combination chemotherapy were performed, the patient died 5 months after diagnosis of multiple metastases. PMID- 25431735 TI - A unique presentation of an undiagnosed renal cell carcinoma. AB - We describe a 58-year-old lady who presented initially to her general practitioner with a palpable warty urethral nodule. She was subsequently referred to the urology department for further investigations. She underwent flexible cystoscopy and imaging, followed by rigid cystoscopy and excision of the nodule. Histological analysis was consistent with renal cell carcinoma (RCC). CT imaging confirmed the presence of an invading metastatic left renal cell carcinoma with bilateral metastatic deposits to the lungs and adrenal glands. The patient was enlisted on the Panther Trial and received a course of Pazopanib before undergoing radical nephrectomy. Two years later she is still alive with metastases remaining reduced in size and numbers. During this study we have performed a literature review of similar cases with this unusual presentation of RCC. PMID- 25431736 TI - A case of prostatic abscess with malignant lymphoma involving the prostate. AB - Here, we report a case of prostatic abscess probably due to malignant lymphoma of the prostate. An 82-year-old man was referred to our hospital with chief complaints of urinary frequency and discomfort on urination. Antibiotics were prescribed, but the symptoms remained and intermittent fever appeared. The patient was diagnosed with prostatic abscess by computed tomography (CT). Digital rectal examination (DRE) revealed soft prostate, and thick pus was milked out from the extrameatus by prostatic massage. For drainage, we performed transurethral resection of the prostate (TURP). Drainage by TURP was successful as CT clearly showed reduction of prostatic abscess after the operation. Nevertheless, intermittent fever did not improve and the patient's general condition deteriorated. The day before the patient died, histopathological analysis showed prostatic abscess probably due to malignant lymphoma of the prostate and incidental adenocarcinoma. This is the first report of prostatic abscess with malignant lymphoma involving the prostate. PMID- 25431737 TI - The infrapopliteal arterial occlusions similar to buerger disease: report of two cases. AB - We herein present two cases that required the differential diagnosis of Buerger disease. Case 1 involved a 55-year-old male with a smoking habit who was admitted with ulcers and coldness in his fingers and toes. Angiography showed blockage in both the radial and posterior tibial arteries, which led to an initial diagnosis of Buerger disease. However, a biopsy of the right posterior tibial artery showed pathological findings of fibromuscular dysplasia (FMD). Case 2 involved a 28-year old male with intermittent claudication who was examined at another hospital. Angiography showed occlusion of both popliteal and crural arteries, and the patient was suspected to have Buerger disease. However, computed tomography disclosed an abnormal slip on both sides of the popliteal fossa, and we diagnosed him with bilateral popliteal artery entrapment syndrome (PAES). These cases illustrate that other occlusive diseases, such as FMD and PAES, may sometimes be misdiagnosed as Buerger disease. PMID- 25431738 TI - Psychosocial Determinants of Tobacco Use among School Going Adolescents in Delhi, India. AB - Background. Tobacco use is one of the major preventable causes of premature death and disease in the world. Many psychosocial factors were found to influence tobacco use. Therefore the present study was designed to determine the role of psychosocial factors associated with tobacco use among school going adolescents in Delhi, India. Methods. Cross-sectional study was conducted from February 2013 to September 2013 in four government schools in South district of Delhi, India. The questionnaire contains questions adapted from GYTS (Global Youth Tobacco Survey) to find the prevalence and pattern of tobacco use among adolescents. Data were analyzed using SPSS version 21. Results. The prevalence of ever and current tobacco use was found in 16.4% and 13.1%. Current smoking and current tobacco chewing were found in 10.2% and 9.4% students, respectively. The risk of current tobacco use was found to be higher among males (P value = 0.000) and in those who got higher pocket money (P value = 0.000). Psychosocial factors like lower general self-efficacy and maladjustments with peers, teachers, and schools were also found to be significant predictors of current tobacco use. Conclusion. The study has revealed higher prevalence of ever and current tobacco use among adolescent students in Delhi, India. PMID- 25431739 TI - Experiences from a community based substance use treatment centre in an urban resettlement colony in India. AB - Background. There are limited community based treatment services for drug dependence in India. Rural areas and urban resettlement colonies are in particular deficient in such services. Aims. The current study aimed at preliminary assessment of substance use disorder management services at a community based substance use treatment clinic in an urban resettlement colony. Methods. The study was carried out at community based substance use treatment centre in a resettlement colony in India. The records of the centre were chart reviewed. Results. A total of 754 patients were registered at the clinic during the study period. Heroin was the primary drug of abuse for 63% of the patients. The mean duration of follow-up for the patients with opioid and alcohol dependence was 13.47 (SD +/- 10.37; range 0-39) months. A total of 220 patients of opioid dependence were prescribed substation or abstinence directed therapy. Buprenorphine (87), slow release oral morphine (SROM) (16), and dextropropoxyphene (98) were used for opioid substitution. Conclusion. It is possible to deliver substance use disorder treatment services in community setting. There is a need to develop area specific community based treatment services for substance abuse in socially disadvantaged populations such as urban resettlement colonies. PMID- 25431740 TI - Hemoglobin expression in nonerythroid cells: novel or ubiquitous? AB - Hemoglobin (Hb) is a major protein involved in transport of oxygen (O2). Red blood cells (RBCs) contain maximum amount of Hb and because of their unique structure and plasticity they transport O2 to various tissues of the body at an optimal concentration. Recently, it has been reported that, apart from RBCs, Hb is also expressed by nonerythroid cells such as epithelial cells of different origin. The cells expressing Hb are from the tissues where maintenance of O2 homeostasis is of paramount importance. Hb expression has been observed in the epithelial cells from human tissues including lungs, neurons, retina, and endometrium. Our group has recently demonstrated that Hb is expressed by the cervicovaginal epithelial cells. We further showed that, apart from maintaining O2 homeostasis, Hb and the peptides derived from it play an indispensable role in the protection of vaginal epithelium by exhibiting antimicrobial activity. In this review, we discuss the significance of Hb expression in vaginal epithelial cells and its role in the recognition of pathogens thereby reducing the risk and/or severity of inflammation and/or infections and the possible mechanism by which Hb exhibits antimicrobial and antioxidative functions. PMID- 25431741 TI - A population pharmacokinetic approach to describe cephalexin disposition in adult and aged dogs. AB - This study was conducted in order to characterize the pharmacokinetics of orally administered cephalexin to healthy adult and aged dogs, using a population pharmacokinetic approach. Two hundred and eighty-six cephalexin plasma concentrations obtained from previous pharmacokinetic studies were used. Sex, age, pharmaceutical formulation, and breed were evaluated as covariates. A one compartment model with an absorption lag-time (Tlag) best described the data. The final model included age (adult; aged) on apparent volume of distribution (Vd/F), apparent elimination rate (ke/F), and Tlag; sex (female; male) on ke/F, and breed (Beagle; mixed-breed) on Vd/F. Addition of the covariates to the model explained 78% of the interindividal variability (IIV) in Vd/F, 36% in ke/F, and 24% in Tlag, respectively. Formulation did not affect the variability of any of the pharmacokinetic parameters. Tlag was longer, whereas Vd/F and ke/F were lower in aged compared to adult animals; in female aged dogs ke/F was lower than in male aged dogs; however, the differences were of low magnitude. Different disposition of cephalexin may be expected in aged dogs. PMID- 25431742 TI - Factors associated with intention to donate blood: sociodemographic and past experience variables. AB - Background and Objectives. This study was conducted to assess the level of intention of the general public towards blood donation and the factors associated with it. Methods. A descriptive cross-sectional study was conducted in South-East Botswana amongst participants aged 21-65 years. An interviewer-administered questionnaire was completed for 384 participants. Results. Of the 384 participants, 104 (27.1%) reported that they had donated blood in the past and 269 (70.1%) stated that they were willing to donate blood in the future. Thirteen out of the 104 past donors (12.5%) reported that they had donated blood in the 12 months preceding the survey and only 10 (9.6%) participants reported that they have been regular donors. In the backward logistic regression analysis, the variables that remained significant predictors of the intention to donate blood were secondary education (adjusted odds ratio (AOR) (95% confidence interval (CI)): 2.92 (1.48, 5.77)), tertiary education (AOR (95% CI): 3.83 (1.52, 9.62)), and knowing a family member who had ever donated blood (AOR (95% CI): 2.84 (1.58, 5.12)). Conclusion. Being informed about blood transfusion and its life-saving benefits through either the education system or the experience made people more likely to intend to donate blood. Evidence-based interventions to retain blood donors as regular donors are recommended. PMID- 25431743 TI - SIMPLE MACHINE PERFUSION SIGNIFICANTLY ENHANCES HEPATOCYTE YIELDS OF ISCHEMIC AND FRESH RAT LIVERS. AB - The scarcity of viable hepatocytes is a significant bottleneck in cell transplantation, drug discovery, toxicology, tissue engineering, and bioartificial assist devices, where trillions of high-functioning hepatocytes are needed annually. We took the novel approach of using machine perfusion to maximize cell recovery, specifically from uncontrolled cardiac death donors, the largest source of disqualified donor organs. In a rat model, we developed a simple 3 hour room temperature (20+/-2 degrees C) machine perfusion protocol to treat non-premedicated livers exposed to 1 hour of warm (34 degrees C) ischemia. Treated ischemic livers were compared to fresh, fresh-treated and untreated ischemic livers using viable hepatocyte yields and in vitro performance as quantitative endpoints. Perfusion treatment resulted in both a 25-fold increase in viable hepatocytes from ischemic livers, and a 40% increase from fresh livers. While cell morphology and function in suspension and plate cultures of untreated warm ischemic cells was significantly impaired, treated warm ischemic cells were indistinguishable from fresh hepatocytes. Further, a strong linear correlation between tissue ATP and cell yield enabled accurate evaluation of the extent of perfusion recovery. Maximal recovery of warm ischemic liver ATP content appears to be correlated with optimal flow through the microvasculature. These data demonstrate that the inclusion of a simple perfusion-preconditioning step can significantly increase the efficiency of functional hepatocyte yields and the number of donor livers that can be gainfully utilized. PMID- 25431744 TI - Associations between Dietary Intake of Fruits and Vegetables in relation to Urinary Estrogen DNA Adduct Ratio. AB - BACKGROUND: Estrogen exposure plays a role in breast cancer (BC) development. A novel estrogen biomarker, the estrogen DNA adduct (EDA) ratio, was shown to be elevated in women at high-risk of BC and among BC cases. Modifiable factors may impact the EDA ratio, with studies demonstrating that resveratrol reduces EDA ratio in vitro. We sought to examine the hypothesis that dietary intake of fruits and vegetables is inversely associated with EDA ratio. METHODS: This analysis was conducted in 53 pre-menopausal, healthy women aged 40-45 years from a cross sectional study in which participants provided first-void urine samples and 3-day food records. Urine samples were analyzed using ultraperformance liquid chromatography/tandem mass spectrometry. The EDA ratio was calculated as the estrogen-DNA adducts divided by estrogen metabolites and conjugates. A trend test was used to assess associations between tertiles of dietary intake using linear regression. RESULTS: After adjustment for age, total energy, percent adiposity, serum estradiol and estrone-sulfate, we observed inverse associations of EDA ratio with carbohydrate consumption (P=0.01) and vegetable intake (P =0.01). EDA ratio was inversely associated with 5 botanical groups (Chenopodiaceae: P=0.02; Umbelliferae: P=0.03; Compositae: P=0.01; Ericaceae: P=0.01; Musaceae: P=0.03) but not fruit intake overall. CONCLUSION: Although these data require replication before conclusions are drawn, this report suggests an inverse association between vegetable and carbohydrate consumption and EDA ratio. IMPACT: While more information is still needed, these findings suggest a link between dietary intake and a biomarker that is both associated with high-risk BC status and associated with modifiable factors. PMID- 25431745 TI - Strategies for Management of Synchronous Colorectal Metastases. AB - The management of synchronous presentation of colorectal cancer and liver metastases has long been a topic of debate and discussion for surgeons due to the unique dilemma of balancing operative timing along with treatment strategy. Operative strategies for resection include staged resection with colon first approach, "reverse" staged resection with liver metastases resected first, and one-stage, or simultaneous, resection of both the primary tumor and liver metastases approach. These operative strategies can be further augmented with perioperative chemotherapy and other novel approaches that may improve resectability and patient survival. The decision on operative timing and approach, however, remains largely dependent on the surgeon's determination of disease resectability, patient fitness, and the need for neoadjuvant chemotherapy. PMID- 25431747 TI - Reader Profiles for Adults with Low Literacy Skills: A Quest to Find Resilient Readers. AB - Resilient readers are those who, despite their poor phonological decoding skills, have good comprehension abilities (Jackson & Doellinger, 2002). Thus far, these readers have been identified in college settings. The purpose of this study was to a) determine if this reader profile was present in a sample taken from an Adult Basic Education (ABE) population, and b) identify compensatory mechanisms these readers might use to better their reading comprehension. We administered a battery of tasks consisting of non-word reading, comprehension, fluency, and orthographic processing to a diverse sample of adults in ABE classes. Not only did we identify a group of resilient readers in this sample, we identified three other sub-groups: unskilled readers who had poor decoding and comprehension abilities, skilled readers who possessed good decoding and comprehension abilities, and a group of individuals who had good decoding skills but poor comprehension abilities. We found that the resilient readers and good decoders/poor comprehenders had better orthographic and fluency skills compared to the unskilled readers. However, these last two groups produced different error patterns on the orthographic and fluency tasks. We discuss the implications that these very different reader profiles have for ABE programs. PMID- 25431746 TI - Cryopreservation of transgenic Huntington's disease rhesus macaque sperm-A Case Report. AB - The cryoprotective effects of glycerol in three different semen freezing extenders, Tris-citrate (TRIS), TEST, and Tes-Tris-Egg yolk (TTE), on wild-type (WT) rhesus monkey (Macaca mulatta) sperm cryopreservation have been tested. Sperm motility and viability were examined to evaluate the integrity of frozen thawed sperm, and the best extender was selected to cryopreserve sperm from transgenic Huntington's disease (HD) rhesus monkey. The results showed no post thaw motility difference among the freezing extender tested (P>0.05). However, sperm membrane integrity in TEST and TTE were significantly better than in TRIS extender (P<0.05). TEST was chosen for HD rhesus monkey sperm cryopreservation. The results showed that post-thawed HD sperm motility and viability was not different compared with WT control group (P>0.05). The present study demonstrates that TEST and TTE were excellent extenders and suitable for rhesus monkey sperm cryopreservation and no detectible differences of post-thaw sperm motility and viability between HD and WT rhesus monkeys resulted from TEST extender. PMID- 25431748 TI - Literacy Skill Differences between Adult Native English and Native Spanish Speakers. AB - The goal of this study was to compare the literacy skills of adult native English and native Spanish ABE speakers. Participants were 169 native English speakers and 124 native Spanish speakers recruited from five prior research projects. The results showed that the native Spanish speakers were less skilled on morphology and passage comprehension tasks but were equally skilled on the phonology and vocabulary tasks. Morphology, coupled with phonology, was a stronger predictor of vocabulary and comprehension abilities for the native Spanish speakers, which suggests that instruction focused on morphology is likely to have a greater impact on this group. PMID- 25431749 TI - A high-density 3D localization algorithm for stochastic optical reconstruction microscopy. AB - BACKGROUND: Stochastic optical reconstruction microscopy (STORM) and related methods achieves sub-diffraction-limit image resolution through sequential activation and localization of individual fluorophores. The analysis of image data from these methods has typically been confined to the sparse activation regime where the density of activated fluorophores is sufficiently low such that there is minimal overlap between the images of adjacent emitters. Recently several methods have been reported for analyzing higher density data, allowing partial overlap between adjacent emitters. However, these methods have so far been limited to two-dimensional imaging, in which the point spread function (PSF) of each emitter is assumed to be identical. METHODS: In this work, we present a method to analyze high-density super-resolution data in three dimensions, where the images of individual fluorophores not only overlap, but also have varying PSFs that depend on the z positions of the fluorophores. RESULTS AND CONCLUSION: This approach can accurately analyze data sets with an emitter density five times higher than previously possible with sparse emitter analysis algorithms. We applied this algorithm to the analysis of data sets taken from membrane-labeled retina and brain tissues which contain a high-density of labels, and obtained substantially improved super-resolution image quality. PMID- 25431751 TI - Perioperative Glucose Control and Infection Risk in Older Surgical Patients. AB - The aging of the U.S. population is leading to an increasing number of surgical procedures performed on older adults. At the same time, the quality of medical care is being more closely scrutinized. Surgical site infection is a widely assessed outcome. Evidence suggests that strict perioperative serum glucose control among patients with or without diabetes can lower the risk of these infections, but it is unclear whether this control should be applied to older surgical patients. In this clinical review, we discuss current research on perioperative serum glucose management for cardiothoracic, orthopedic, and general/colorectal surgery. In addition, we summarize clinical recommendations and quality-of-care process indicators provided by surgical, diabetes, and geriatric medical organizations. PMID- 25431750 TI - Recent Insights into the Neurobiology of Impulsivity. AB - Impulsivity is associated with various psychopathologies, and elevated impulsivity is typically disadvantageous. This manuscript reviews recent investigations into the neurobiology of impulsivity using human imaging techniques and animal models. Both human imaging and preclinical pharmacological manipulations have yielded important insights into the neurobiological underpinnings of impulsivity. A more thorough understanding of the complex neurobiology underlying aspects of impulsivity may provide insight into new treatment options that target elevated impulsivity and psychopathologies such as addictions. PMID- 25431753 TI - Characterization of the shrimp neuroparsin (MeNPLP): RNAi silencing resulted in inhibition of vitellogenesis. AB - The full-length Metapenaeus ensis neuroparsin (MeNPLP) cDNA was cloned which encodes a shrimp protein homologous to the insect neuroparsin and vertebrate insulin-like growth factor binding protein (IGFBP). MeNPLP cDNA is 1389 bp in length and the longest open reading frame is 303 bp in length. The first 27 aa are predicted to be the signal peptide and aa 28-101 is the mature peptide with an estimated molecular weight of 7.83 kDa and pI of 5. It shows high amino acid sequence similarity (42-68%) to the neuroparsin of insects and N-terminal end of the IGFBP of vertebrates. The cysteine residues in MeNPLP responsible for disulfide bond formation are conserved as in other neuroparsin-like proteins. The expression level of MeNPLP is the highest in the hepatopancreas, followed by the nerve cord, brain, heart, ovary, and muscle. However, it was not expressed in the testis. Using an insect neuroparsin antibody, MeNPLP could only be detected in the hepatopancreatic tubules, suggesting that MeNPLP may be a secretary product. Although MeNPLP expression was stimulated in the ovary, it was inhibited in the hepatopancreas after treatment with neurotransmitter serotonin (5-HT). In vivo gene silencing of MeNPLP could cause a significant decrease of vitellogenin transcript level in the hepatopancreas and ovary. As a result, a corresponding decrease in vitellogenin protein level was observed in the hemolymph and ovary. In conclusion, this study has provided the first evidence that MeNPLP is involved in the initial stage of ovary maturation in shrimp. PMID- 25431752 TI - Strategies to Reduce 30-Day Readmissions in Older Patients Hospitalized with Heart Failure and Acute Myocardial Infarction. AB - Readmission within 30 days after hospital discharge for common cardiovascular conditions such as heart failure and acute myocardial infarction is extremely common among older persons. To incentivize investment in reducing preventable rehospitalizations, the United States federal government has directed increasing financial penalties to hospitals with higher-than-expected 30-day readmission rates. Uncertainty exists, however, regarding the best approaches to reducing these adverse outcomes. In this review, we summarize the literature on predictors of 30-day readmission, the utility of risk prediction models, and strategies to reduce short-term readmission after hospitalization for heart failure and acute myocardial infarction. We report that few variables have been found to consistently predict the occurrence of 30-day readmission and that risk prediction models lack strong discriminative ability. We additionally report that the literature on interventions to reduce 30-day rehospitalization has significant limitations due to heterogeneity, susceptibility to bias, and lack of reporting on important contextual factors and details of program implementation. New information is characterizing the period after hospitalization as a time of high generalized risk, which has been termed the post-hospital syndrome. This framework for characterizing inherent post-discharge instability suggests new approaches to reducing readmissions. PMID- 25431754 TI - Semi-quantitative Multispectral Optoacoustic Tomography (MSOT) for volumetric PK imaging of gastric emptying. AB - A common side effect of medication is gastrointestinal intolerance. Symptoms can include reduced appetite, diarrhea, constipation, GI inflammation, nausea and vomiting. Such effects often have a dramatic impact on compliance with a treatment regimen. Therefore, characterization of GI tolerance is an important step when establishing a novel therapeutic approach. In this study, Multispectral Optoacoustic Tomography (MSOT) is used to monitor gastrointestinal motility by in vivo whole body imaging in mice. MSOT combines high spatial and temporal resolution based on ultrasound detection with strong optical contrast in the near infrared. Animals were given Indocyanine Green (ICG) by oral gavage and imaged by MSOT to observe the fate of ICG in the gastrointestinal tract. Exponential decay of ICG signal was observed in the stomach in good correlation with ex vivo validation. We discuss how kinetic imaging in MSOT allows visualization of parameters unavailable to other imaging methods, both in 2D and 3D. PMID- 25431755 TI - Frequency domain optoacoustic tomography using amplitude and phase. AB - We introduce optoacoustic tomographic imaging using intensity modulated light sources and collecting amplitude and phase information in the frequency domain. Imaging is performed at multiple modulation frequencies. The forward modeling uses the Green's function solution to the pressure wave equation in frequency domain and the resulting inverse problem is solved using regularized least squares minimization. We study the effect of the number of frequencies and of the bandwidth employed on the image quality achieved. The possibility of employing an all-frequency domain optoacoustic imaging for experimental measurements is studied as a function of noise. We conclude that frequency domain optoacoustic tomography may evolve to a practical experimental method using light intensity modulated sources, with advantages over time-domain optoacoustics. PMID- 25431756 TI - Optimal self-calibration of tomographic reconstruction parameters in whole-body small animal optoacoustic imaging. AB - In tomographic optoacoustic imaging, multiple parameters related to both light and ultrasound propagation characteristics of the medium need to be adequately selected in order to accurately recover maps of local optical absorbance. Speed of sound in the imaged object and surrounding medium is a key parameter conventionally assumed to be uniform. Mismatch between the actual and predicted speed of sound values may lead to image distortions but can be mitigated by manual or automatic optimization based on metrics of image sharpness. Although some simple approaches based on metrics of image sharpness may readily mitigate distortions in the presence of highly contrasting and sharp image features, they may not provide an adequate performance for smooth signal variations as commonly present in realistic whole-body optoacoustic images from small animals. Thus, three new hybrid methods are suggested in this work, which are shown to outperform well-established autofocusing algorithms in mouse experiments in vivo. PMID- 25431757 TI - The Ionic DTI Model (iDTI) of Dynamic Diffusion Tensor Imaging (dDTI). AB - Measurements of water molecule diffusion along fiber tracts in CNS by diffusion tensor imaging (DTI) provides a static map of neural connections between brain centers, but does not capture the electrical activity along axons for these fiber tracts. Here, a modification of the DTI method is presented to enable the mapping of active fibers. It is termed dynamic diffusion tensor imaging (dDTI) and is based on a hypothesized "anisotropy reduction due to axonal excitation" ("AREX"). The potential changes in water mobility accompanying the movement of ions during the propagation of action potentials along axonal tracts are taken into account. Specifically, the proposed model, termed "ionic DTI model", was formulated as follows. First, based on theoretical calculations, we calculated the molecular water flow accompanying the ionic flow perpendicular to the principal axis of fiber tracts produced by electrical conduction along excited myelinated and non myelinated axons.Based on the changes in molecular water flow we estimated the signal changes as well as the changes in fractional anisotropy of axonal tracts while performing a functional task.The variation of fractional anisotropy in axonal tracts could allow mapping the active fiber tracts during a functional task. Although technological advances are necessary to enable the robust and routine measurement of this electrical activity-dependent movement of water molecules perpendicular to axons, the proposed model of dDTI defines the vectorial parameters that will need to be measured to bring this much needed technique to fruition. PMID- 25431759 TI - Soybean dihydrolipoamide dehydrogenase (ferric leghemoglobin reductase 2) interacts with and reduces ferric rice non-symbiotic hemoglobin 1. AB - Ferrous oxygenated hemoglobins (Hb2+O2) autoxidize to ferric Hb3+, but Hb3+ is reduced to Hb2+ by enzymatic and non-enzymatic mechanisms. We characterized the interaction between the soybean ferric leghemoglobin reductase 2 (FLbR2) and ferric rice non-symbiotic Hb1 (Hb13+). Spectroscopic analysis showed that FLbR2 reduces Hb13+. Analysis by tryptophan fluorescence quenching showed that FLbR2 interacts with Hb13+, however the use of ITC and IEF techniques revealed that this interaction is weak. In silico modeling showed that predicted FLbR2 and native Hb13+ interact at the FAD-binding domain of FLbR2 and the CD-loop and helix F of Hb13+. PMID- 25431760 TI - High precision mass measurements for wine metabolomics. AB - An overview of the critical steps for the non-targeted Ultra-High Performance Liquid Chromatography coupled with Quadrupole Time-of-Flight Mass Spectrometry (UPLC-Q-ToF-MS) analysis of wine chemistry is given, ranging from the study design, data preprocessing and statistical analyses, to markers identification. UPLC-Q-ToF-MS data was enhanced by the alignment of exact mass data from FTICR MS, and marker peaks were identified using UPLC-Q-ToF-MS(2). In combination with multivariate statistical tools and the annotation of peaks with metabolites from relevant databases, this analytical process provides a fine description of the chemical complexity of wines, as exemplified in the case of red (Pinot noir) and white (Chardonnay) wines from various geographic origins in Burgundy. PMID- 25431761 TI - Lack of Association of the Polymorphisms IL-17A (-197G/A) and IL-17F (+7488A/G) with Multibacillary Leprosy in Mexican Patients. AB - Background. Leprosy is a chronic infectious disease caused by the intracellular acid-fast bacilli Mycobacterium leprae; it has been determined that genetic factors of the host play an important role in the disease susceptibility. Thus, in this case-control study, we evaluated the possible association between the IL 17A G-197A (rs227593) and IL-17F A7488G (His161Arg, rs763780) gene SNPs and susceptibility to leprosy disease in Mexican population. Methods. Seventy-five leprosy patients and sixty-nine control subjects were included. Both SNPs were genotyped with the polymerase chain reaction-restriction fragment length polymorphism technique. Results. We found nonsignificant differences in genotype and allele frequencies related to IL-17A G-197A (rs227593) and IL-17F A7488G (His161Arg, rs763780) gene SNPs in MB as well as subclinical forms of leprosy disease versus healthy individuals. Conclusions. Since the sample size is not large enough, it is difficult to sustain an association of susceptibility to leprosy with genotypes or allele frequencies of IL-17A G-197A (rs227593) and IL 17F A7488G (His161Arg, rs763780), suggesting that IL-17 polymorphisms have no significant role in the genetic susceptibility to development of this disease in the Mexican Mestizo population. PMID- 25431762 TI - Mycobacterium avium subsp. hominissuis infection in swine associated with peat used for bedding. AB - Mycobacterium avium subsp. hominissuis is an environmental bacterium causing opportunistic infections in swine, resulting in economic losses. Additionally, the zoonotic aspect of such infections is of concern. In the southeastern region of Norway in 2009 and 2010, an increase in condemnation of pig carcasses with tuberculous lesions was seen at the meat inspection. The use of peat as bedding in the herds was suspected to be a common factor, and a project examining pigs and environmental samples from the herds was initiated. Lesions detected at meat inspection in pigs originating from 15 herds were sampled. Environmental samples including peat from six of the herds and from three peat production facilities were additionally collected. Samples were analysed by culture and isolates genotyped by MLVA analysis. Mycobacterium avium subsp. hominissuis was detected in 35 out of 46 pigs, in 16 out of 20 samples of peat, and in one sample of sawdust. MLVA analysis demonstrated identical isolates from peat and pigs within the same farms. Polyclonal infection was demonstrated by analysis of multiple isolates from the same pig. To conclude, the increase in condemnation of porcine carcasses at slaughter due to mycobacteriosis seemed to be related to untreated peat used as bedding. PMID- 25431758 TI - Immune responses to non-tumor antigens in the central nervous system. AB - The central nervous system (CNS), once viewed as an immune-privileged site protected by the blood-brain barrier (BBB), is now known to be a dynamic immunological environment through which immune cells migrate to prevent and respond to events such as localized infection. During these responses, endogenous glial cells, including astrocytes and microglia, become highly reactive and may secrete inflammatory mediators that regulate BBB permeability and recruit additional circulating immune cells. Here, we discuss the various roles played by astrocytes, microglia, and infiltrating immune cells during host immunity to non tumor antigens in the CNS, focusing first on bacterial and viral infections, and then turning to responses directed against self-antigens in the setting of CNS autoimmunity. PMID- 25431763 TI - Comparison of low urinary tract symptoms during pregnancy between primiparous and multiparous women. AB - BACKGROUND AND PURPOSE: Low urinary tract symptoms (LUTS) are a common problem during pregnancy. This study aimed to compare changes in the prevalence of LUTS during pregnancy between primiparous and multiparous women. METHODS: A chart review of consecutive pregnant women who attended our antenatal clinic from March 2002 to January 2006 was performed. All of the women were asked to respond to a LUTS questionnaire in either of the three trimesters. RESULTS: Of the 270 women included, 164 were nullipara and 106 were multipara. The most common LUTS during pregnancy were frequency (77%), followed by nocturia (75.6%), stress urinary incontinence (SUI) (51.1%), incomplete emptying (43.7%), dysuria (17.8%), and urgency incontinence (10.4%). There was a significantly higher prevalence of SUI (P<0.001) and urgency incontinence (P=0.005) in the multiparous compared to the nulliparous women. Increasing prevalence rates of frequency, nocturia, SUI, and incomplete emptying were reported with gestational age in both the nulliparous and multiparous women. CONCLUSIONS: Frequency and nocturia were the two most common LUTS during pregnancy. The prevalence rates of all LUTS increased with increasing gestational age except for frequency in the nulliparous women during the second trimester. In addition, multipara was a predictor of SUI during pregnancy. PMID- 25431764 TI - Heat shock protein 70 in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease that caused dementia which has no effective treatment. Growing evidence has demonstrated that AD is a "protein misfolding disorder" that exhibits common features of misfolded, aggregation-prone proteins and selective cell loss in the mature nervous system. Heat shock protein 70 (HSP70) attracts extensive attention worldwide, because it plays a crucial role in preventing protein misfolding and inhibiting aggregation and represents a class of proteins potentially involved in AD pathogenesis. Numerous studies have indicated that HSP70 could suppress the progression of AD with in vitro and in vivo experiments. Thus, targeting HSP70 and the related compounds might represent a promising strategy for the treatment of AD. PMID- 25431766 TI - The analysis of hand movement distinction based on relative frequency band energy method. AB - For the purpose of successfully developing a prosthetic control system, many attempts have been made to improve the classification accuracy of surface electromyographic (SEMG) signals. Nevertheless, the effective feature extraction is still a paramount challenge for the classification of SEMG signals. The relative frequency band energy (RFBE) method based on wavelet packet decomposition was proposed for the prosthetic pattern recognition of multichannel SEMG signals. Firstly, the wavelet packet energy of SEMG signals in each subspace was calculated by using wavelet packet decomposition and the RFBE of each frequency band was obtained by the wavelet packet energy. Then, the principal component analysis (PCA) and the Davies-Bouldin (DB) index were used to perform the feature selection. Lastly, the support vector machine (SVM) was applied for the classification of SEMG signals. Our results demonstrated that the RFBE approach was suitable for identifying different types of forearm movements. By comparing with other classification methods, the proposed method achieved higher classification accuracy in terms of the classification of SEMG signals. PMID- 25431765 TI - Chinese herbs containing aristolochic acid associated with renal failure and urothelial carcinoma: a review from epidemiologic observations to causal inference. AB - Herbal remedies containing aristolochic acid (AA) have been designated to be a strong carcinogen. This review summarizes major epidemiologic evidence to argue for the causal association between AA exposure and urothelial carcinoma as well as nephropathy. The exposure scenarios include the following: Belgian women taking slimming pills containing single material Guang Fang Ji, consumptions of mixtures of Chinese herbal products in the general population and patients with chronic renal failure in Taiwan, occupational exposure in Chinese herbalists, and food contamination in farming villages in valleys of the Danube River. Such an association is corroborated by detecting specific DNA adducts in the tumor tissue removed from affected patients. Preventive actions of banning such use and education to the healthcare professionals and public are necessary for the safety of herbal remedies. PMID- 25431767 TI - Borderline ovarian tumors and diagnostic dilemma of intraoperative diagnosis: could preoperative He4 assay and ROMA score assessment increase the frozen section accuracy? A multicenter case-control study. AB - The aim of our study was to assess the value of a preoperative He4-serum-assay and ROMA-score assessment in improving the accuracy of frozen section histology in the diagnosis of borderline ovarian tumors (BOT). 113 women presenting with a unilateral ovarian mass diagnosed as serous/mucinous BOT at frozen-section histology (FS) and/or confirmed on final pathology were recruited. Pathologists were informed of the results of preoperative clinical/instrumental assessment of all patients. For Group_A patients, additional information regarding He4, CA125, and ROMA score was available (in Group_B only CA125 was known). The comparison between Group A and Group B in terms of FS accuracy, demonstrated a consensual diagnosis in 62.8% versus 58.6% (P: n.s.), underdiagnosis in 25.6% versus 41.4% (P<0.05), and overdiagnosis in 11.6% versus 0% (P<0.01). Low FS diagnostic accuracy was associated with menopausal status (OR: 2.13), laparoscopic approach (OR: 2.18), mucinous histotype (OR: 2.23), low grading (OR: 1.30), and FIGO stage I (OR: 2.53). Ultrasound detection of papillae (OR: 0.29), septa (OR: 0.39), atypical vascularization (OR: 0.34), serum He4 assay (OR: 0.39), and ROMA score assessment (OR: 0.44) decreased the probability of underdiagnosis. A combined preoperative assessment through serum markers and ultrasonographic features may potentially reduce the risk of underdiagnosis of BOTs on FS while likely increasing the concomitant incidence of false-positive events. PMID- 25431768 TI - Long-term efficacy of postpartum intravenous iron therapy. AB - BACKGROUND: The potential benefits of administering a dose of intravenous iron in patients with moderate postpartum anaemia rather than oral iron alone remains unproven. AIMS: To determine whether a single injection of intravenous iron followed by a 6-week course of oral iron is as effective over 6 months in restoring normal haemoglobin levels and replenishing iron stores in women with moderate postpartum anaemia as a course of oral iron alone in women with mild postpartum anaemia. MATERIALS AND METHODS: Retrospective two-arm cohort study in women with mild postpartum anaemia (haemoglobin 9.6-10.5 g/dL) prescribed iron daily for 6 weeks (N=150) and women with moderate postpartum anaemia (haemoglobin 8.5-9.5 g/dL), given a single 500 mg injection of intravenous iron followed by iron daily for 6 weeks (N=75). Haemoglobin and ferritin were measured 6 months postpartum. RESULTS: Haemoglobin returned to similar mean levels in both groups. Ferritin levels were statistically significantly higher in the intravenous+oral group (57.7+/-49.3 MUg/L versus 32.9+/-20.1 MUg/L). CONCLUSIONS: Despite lower baseline haemoglobin, intravenous iron carboxymaltose was superior to oral iron alone in replenishing iron stores in moderate postpartum anaemia and may prove similarly beneficial in mild postpartum anaemia. PMID- 25431769 TI - Diseases of pregnancy and fetal programming: cell and molecular mechanisms. PMID- 25431771 TI - Mild cognitive impairment and depressive symptoms in elderly patients with diabetes: prevalence, risk factors, and comorbidity. AB - The aim of the study was to estimate the prevalence of mild cognitive impairment (MCI), depressive syndrome cases, and its comorbidity, and to identify predictors of these conditions. Methods. 276 diabetics elders were screened for MCI and depressive symptoms. Detailed information of history of diabetes, and data of BMI, HbA1c, and blood lipids were collected. Results. The prevalence of MCI was 31.5%, depressive syndrome was 29.7%, and MCI with coexisting depressive mood was 9.1%. The logistic regression analysis revealed that variables which increased the likelihood of having been diagnosed with MCI were: higher HbA1c level, previous CVD, hypertension, retinopathy, increased number of comorbidities, and less years of formal education. Significant predictors of having a depressive mood included female gender, single marital status, current and past smoking status, lack of physical activity, higher BMI and total cholesterol level, increased number of comorbidities, history of hypoglycemia, and insulin treatment. Factors associated with both MCI and depressive syndrome were female gender, single marital status, past smoking status, retinopathy, previous CVD or stroke, increased number of comorbidities, and insulin treatment. Conclusions. Depressive symptoms, MCI, and its comorbidity are common in elderly subjects with type 2 diabetes. Systematic screening could result in the identification of high risk patients. PMID- 25431770 TI - Unaffected arm muscle hypercatabolism in dysphagic subacute stroke patients: the effects of essential amino acid supplementation. AB - Alterations in muscle protein turnover of the unaffected side of stroke patients could contribute to physical disability. We investigated whether hypercatabolic activity occurred in unaffected arm muscle and whether supplemented essential amino acids (EAAs) could limit muscle hypercatabolism (MH). Thirty-eight dysphagic subacute stroke subjects (<3 months after acute event) (29 males+9 females; 69.7+/-11.4 yrs) were enrolled and randomized to receive 8 g/day EAAs (n=19; EAA group) or isocaloric placebo (maltodextrin; n=19, Plac group). Before randomization, all patients had their arterial (A) and venous (V) amino acids measured and muscle (A-V) differences calculated in the unaffected arm. Eight matched and healthy subjects served as controls. When compared to healthy controls, the entire stroke population showed significant muscle release (=negative value A-V) of the amino acid phenylalanine (phenyl-) indicating a prevalence of MH. Moreover, randomized EAA and Plac groups had similar rates of MH. After 38 days from the start of the protocol, the EAA group but not the Plac group had MH converted to balanced protein turnover or anabolic activity. We concluded that muscle protein metabolism of the unaffected arm of dysphagic subacute stroke individuals could be characterized by MH which can be corrected by supplemented EAAs. PMID- 25431772 TI - Evaluation of hypoglycemic efficacy of tangningtongluo formula, a traditional Chinese Miao medicine, in two rodent animal models. AB - Traditional Chinese medicines largely lack adequate and scientifically rigorous evidence regarding efficacy and functional mechanisms. The present study was aimed to confirm the hypoglycemic effect of Tangningtongluo (TNTL) formula, a traditional Chinese Miao medicine, in two animal models: high-fat diet and streptozotocin- (STZ-) induced diabetic rats and C57BL/KsJ-db/db diabetic mice. After 4 weeks, TNTL intervention in STZ-induced diabetic rats yielded in significant improvement on the glucose tolerance test. Moreover, the islet histopathology showed that oral TNTL reduced the severity of islet necrosis in pancreases tissue. Compared with diabetic controls, a 12-week TNTL treatment regimen (dosages = 0.9, 1.8, and 3.6 g/kg) in db/db mice significantly decreased fasting glucose and HbA1c. Additionally, oral glucose tolerance in TNTL-treated mice improved significantly, compared with diabetic mice receiving metformin. Finally, tissue histopathology and biochemical index evaluations revealed significant improvement in TNTL-treated mice. Taken together, our results show that TNTL exerted a strong hypoglycemic effect in two diabetic rodent animal models, preserving beta-cells in the pancreas islet and reducing the risk of diabetic retinopathy and nephropathy. PMID- 25431774 TI - Implant-related infection in the tibia: surgical revision strategy with vancomycin cement. AB - The development of a deep wound infection in the presence of internal hardware presents a clinical dilemma. The purpose of the present study was to evaluate the treatment outcomes of vancomycin cement with other advances of surgical techniques for implant-related infection (IRI) in the tibia. This study included 217 consecutive patients who had sustained IRI of the tibia. Of them, 152 patients had soft tissue defects and the internal hardware was exposed. Repeated debridement and negative pressure assisted closure were used. All the infected internal hardware was removed. External fixations and flaps were used. Custom made vancomycin cement was inserted into the dead space of the wounds and left in site for a month. The follow-up was from 12 months to 108 months, averaging 37.5 months. For all the 217 patients, the general osteomyelitis healing rate and bone union rate were 86.6% and 97.2%, respectively. This study shows high rates of healing of IRI in the tibia if the new advances of surgery could be effectively combined into the treatment strategy with vancomycin cement as an important treatment. PMID- 25431775 TI - Repeated high intensity bouts with long recovery: are bicarbonate or carbohydrate supplements an option? AB - The effects of varying recovery modes and the influence of preexercise sodium bicarbonate and carbohydrate ingestion on repeated high intensity performance, acid-base response, and recovery were analyzed in 12 well-trained males. They completed three repeated high intensity running bouts to exhaustion with intervening recovery periods of 25 min under the following conditions: sodium bicarbonate, active recovery (BIC); carbohydrate ingestion, active recovery (CHO); placebo ingestion, active recovery (ACTIVE); placebo ingestion, passive recovery (PASSIVE). Blood lactate (BLa), blood gases, heart rate, and time to exhaustion were collected. The three high intensity bouts had a duration of 138 +/- 9, 124 +/- 6, and 121 +/- 6 s demonstrating a decrease from bout 1 to bout 3. Supplementation strategy had no effect on performance in the first bout, even with differences in pH and bicarbonate (HCO3(-)). Repeated sprint performance was not affected by supplementation strategy when compared to ACTIVE, while PASSIVE resulted in a more pronounced decrease in performance compared with all other interventions. BIC led to greater BLa, pH, and HCO3(-) values compared with all other interventions, while for PASSIVE the opposite was found. BLa recovery was lowest in PASSIVE; recovery in pH, and HCO3(-) was lower in PASSIVE and higher in BIC. PMID- 25431777 TI - Genetic variability and selection criteria in rice mutant lines as revealed by quantitative traits. AB - Genetic based knowledge of different vegetative and yield traits play a major role in varietal improvement of rice. Genetic variation gives room for recombinants which are essential for the development of a new variety in any crop. Based on this background, this work was carried out to evaluate genetic diversity of derived mutant lines and establish relationships between their yield and yield components using multivariate analysis. To achieve this objective, two field trials were carried out on 45 mutant rice genotypes to evaluate their growth and yield traits. Data were taken on vegetative traits and yield and its components, while genotypic and phenotypic coefficients, variance components, expected genetic advance, and heritability were calculated. All the genotypes showed variations for vegetative traits and yield and its components. Also, there was positive relationship between the quantitative traits and the final yield with the exception of number of tillers. Finally, the evaluated genotypes were grouped into five major clusters based on the assessed traits with the aid of UPGMA dendrogram. So hybridization of group I with group V or group VI could be used to attain higher heterosis or vigour among the genotypes. Also, this evaluation could be useful in developing reliable selection indices for important agronomic traits in rice. PMID- 25431776 TI - Surgical treatment of perianal fistulizing Crohn's disease: from lay-open to cell based therapy--an overview. AB - BACKGROUND: Perianal Crohn's disease (CD) can be challenging. Despite the high incidence of fistulizing CD, literature lacks clear guidelines. Several medical, surgical, and combined treatment modalities have been proposed, but evidences are scarce. METHODS: We searched the literature to assess the facets of perianal CD, with particular focus on complex fistulae. Disease epidemiology, classification, diagnosis, activity scoring systems, and medical-surgical treatments were assessed. RESULTS: Perianal fistulizing CD is common, frequently associated with upper gastrointestinal and colorectal CD. Complex fistulas often require repeated treatments. Continence is a major concern when dealing with repeated procedures. A prudent pathway is to resolve active sepsis and to limit damages, delaying a definitive treatment to the time when acute phase has been controlled. The improved diagnostic techniques allow better preoperative planning and are useful in monitoring the response to treatment. Besides newer devices, cell-based treatments are promising tools which have recently enriched the treatment portfolio. However, the need for proctectomy is still disturbingly high in CD patients with complex perianal fistulae. CONCLUSIONS: Perianal CD can impair quality of life and lead to need for proctectomy. A staged approach is reasonable. Treatment success can be improved by multimodal treatment and collaborative management by experienced gastroenterologists and surgeons. PMID- 25431779 TI - Antimetastatic and anti-inflammatory potentials of essential oil from edible Ocimum sanctum leaves. AB - Antimetastatic and anti-inflammatory activities of Ocimum sanctum essential oil (OSEO) have been assessed in this study. OSEO at the concentration of 250 MUg/mL and above showed a significant ((*) P < 0.05) decrease in the number of migrated cancer cells. In addition, OSEO at concentration of 250 MUg/mL and above suppressed MMP-9 activity in lipopolysaccharide (LPS) induced inflammatory cells. A dose-dependent downregulation of MMP-9 expression was observed with the treatment of OSEO compared to the control. Our findings indicate that OSEO has both antimetastatic and anti-inflammatory potentials, advocating further investigation for clinical applications in the treatment of inflammation associated cancer. PMID- 25431780 TI - Thermal characteristics and bacterial diversity of forest soil in the Haean basin of Korea. AB - To predict biotic responses to disturbances in forest environments, it is important to examine both the thermophysical properties of forest soils and the diversity of microorganisms that these soils contain. To predict the effects of climate change on forests, in particular, it is essential to understand the interactions between the soil surface, the air, and the biological diversity in the soil. In this study, the temperature and thermal properties of forest soil at three depths at a site in the Haean basin of Korea were measured over a period of four months. Metagenomic analyses were also carried out to ascertain the diversity of microorganisms inhabiting the soil. The thermal diffusivity of the soil at the study site was 5.9 * 10(-8) m(2) . s(-1). The heat flow through the soil resulted from the cooling and heating processes acting on the surface layers of the soils. The heat productivity in the soil varied through time. The phylum Proteobacteria predominated at all three soil depths, with members of Proteobacteria forming a substantial fraction (25.64 to 39.29%). The diversity and richness of microorganisms in the soil were both highest at the deepest depth, 90 cm, where the soil temperature fluctuation was the minimum. PMID- 25431778 TI - A lectin from Dioclea violacea Interacts with midgut surface of Lutzomyia migonei, unlike its homologues, Cratylia floribunda lectin and Canavalia gladiata lectin. AB - Leishmaniasis is a vector-borne disease transmitted by phlebotomine sand fly. Susceptibility and refractoriness to Leishmania depend on the outcome of multiple interactions that take place within the sand fly gut. Promastigote attachment to sand fly midgut epithelium is essential to avoid being excreted together with the digested blood meal. Promastigote and gut sand fly surface glycans are important ligands in this attachment. The purpose of the present study was to evaluate the interaction of three lectins isolated from leguminous seeds (Diocleinae subtribe), D-glucose and D-mannose-binding, with glycans on Lutzomyia migonei midgut. To study this interaction the lectins were labeled with FITC and a fluorescence assay was performed. The results showed that only Dioclea violacea lectin (DVL) was able to interact with midgut glycans, unlike Cratylia floribunda lectin (CFL) and Canavalia gladiata lectin (CGL). Furthermore, when DVL was blocked with D-mannose the interaction was inhibited. Differences of spatial arrangement of residues and volume of carbohydrate recognition domain (CRD) may be the cause of the fine specificity of DVL for glycans in the surface on Lu. migonei midgut. The findings in this study showed the presence of glycans in the midgut with glucose/mannose residues in its composition and these residues may be important in interaction between Lu. migonei midgut and Leishmania. PMID- 25431781 TI - Development and characterization of poly(1-vinylpyrrolidone-co-vinyl acetate) copolymer based polymer electrolytes. AB - Gel polymer electrolytes (GPEs) are developed using poly(1-vinylpyrrolidone-co vinyl acetate) [P(VP-co-VAc)] as the host polymer, lithium bis(trifluoromethane) sulfonimide [LiTFSI] as the lithium salt and ionic liquid, and 1-ethyl-3 methylimidazolium bis(trifluoromethylsulfonyl) imide [EMImTFSI] by using solution casting technique. The effect of ionic liquid on ionic conductivity is studied and the optimum ionic conductivity at room temperature is found to be 2.14 * 10( 6) S cm(-1) for sample containing 25 wt% of EMImTFSI. The temperature dependence of ionic conductivity from 303 K to 353 K exhibits Arrhenius plot behaviour. The thermal stability of the polymer electrolyte system is studied by using thermogravimetric analysis (TGA) while the structural and morphological properties of the polymer electrolyte is studied by using Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction analysis (XRD), respectively. PMID- 25431782 TI - Lifetime prevalence of psychiatric disorders among parents of children with bipolar I disorder: parental difference. AB - BACKGROUND: Evaluation of family system is an important area in the context of child and adolescent mental health. This study aimed to estimate psychiatric disorders in parents of children and adolescents with bipolar I disorder (BID). METHODS AND MATERIALS: In this cross-sectional study, during 2012-2013, all of the children and adolescents diagnosed with BID based on Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version were included. All of the parents (both mother and father) were evaluated by Structured Clinical Interview for DSM-IV-TR. STATISTICAL ANALYSIS: Prevalence rates are reported and independent-sample t-test and chi-square test were used when appropriate. RESULTS: A total of 108 families were interviewed. 25% of mothers and 33% of fathers met the criteria for at least one psychiatric disorder, with major depressive disorder, BMD, and cluster B personality disorder being more prevalent. Fathers were more likely to receive a dual psychiatric diagnosis. Cluster B personality disorder and substance dependence were more prevalent among fathers while major depressive disorder was more prevalent among mothers. CONCLUSION: This study confirmed a higher prevalence of psychiatric disorders in parents of children with BID and emphasizes parental evolution. PMID- 25431784 TI - An observing system simulation experiment for the Western North Pacific region. AB - This study investigated the effectiveness of concentrated observations for ocean state estimation in a region remote from the observation site. I executed a twin observing system simulation experiment (OSSE) for the North Pacific region, using an ocean data synthesis system, to examine how the potential effectiveness is for a well-defined criterion, the representativeness of the subsurface salinity minimum corresponding to North Pacific Intermediate Water (NPIW). The results of the OSSE show that data synthesis confined to the region corresponding to the recent origin of the NPIW (35 degrees N-53 degrees N, 130 degrees E-170 degrees E) can affect the modeled extent of the NPIW in the central Pacific at 35 degrees N, 180 degrees . The interannual variability of the NPIW is not well reproduced in terms of the standard deviation value (std), only by the data input in the origin region. The root mean square difference between the "true" and the synthesized field is twice larger than the std although there the representativeness of the scale of salinity minimum is improved by about one third of the difference between the "true" and "first-guess" fields in a snapshot. These results imply that combinations of concentrated and other in situ observations should be required for the dynamic state estimation of the NPIW. PMID- 25431783 TI - The role of perioperative endoscopic retrograde cholangiopancreatography and biliary drainage in large liver hydatid cysts. AB - BACKGROUND: The best surgical technique for large liver hydatid cysts (LHCs) has not yet been agreed on. Objectives. The objective of this study was to examine the role of perioperative endoscopic retrograde cholangiopancreatography (ERCP) and biliary drainage in patients with large LHCs. MetHODS: A 20-year retrospective study of patients with LHCs treated surgically at the University Clinical Center of Kosovo (UCCK). We divided patients into 2 groups based on treatment period: 1981-1990 (Group I) and 2001-2010 (Group II). Demographic characteristics (sex, age), the surgical procedure performed, complications rate, and outcomes were compared. RESULTS: Of the 340 patients in our study, 218 (64.1%) were female with median age of 37 years (range, 17 to 81 years). 71% of patients underwent endocystectomy with partial pericystectomy and omentoplication, 8% total pericystectomy, 18% endocystectomy with capitonnage, and 3% external drainage. In Group I, 10 patients underwent bile duct exploration and T-tube placement; in Group II, 39 patients underwent bile duct exploration and T-tube placement. In addition, 9 patients in Group II underwent perioperative ERCP with papillotomy. The complication rate was 14.32% versus 6.37%, respectively (P = 0.001). CONCLUSION: Perioperative ERCP and biliary drainage significantly decreased the complication rate and improved outcomes in patients with large LHCs. PMID- 25431785 TI - Behavioral adjustments by a small neotropical primate (Callithrix jacchus) in a semiarid Caatinga environment. AB - We provide the first information on the behavior of a small primate (Callithrix jacchus) inhabiting a semiarid Caatinga environment in northeastern Brazil. We observed behavioral variations in response to temperature fluctuation throughout the day. Due to the high temperatures, low precipitation, and resource scarcity in the Caatinga, as well as the lack of physiological adaptations (e.g., a highly concentrated urine and a carotid rete to cool down the brain) of these primates, we expected that the common marmosets would exhibit behavioral adjustments, such as a prolonged resting period or the use of a large home range. During the six month period, we collected 246 hours of behavioral data of two groups (10 individuals) of Callithrix jacchus. Most of the observed behavioral patterns were influenced by temperature fluctuation. Animals rested longer and reduced other activities, such as foraging, when temperatures were higher. Both study groups exploited home ranges of 2.21-3.26 ha, which is within the range described for common marmosets inhabiting the Atlantic Forest. Our findings confirm that common marmosets inhabiting the Caatinga adjust their behavioral patterns to cope with the high temperatures that characterize this environment and highlight their ability to survive across a wide range of different environmental conditions. PMID- 25431787 TI - On complexities of impact simulation of fiber reinforced polymer composites: a simplified modeling framework. AB - Impact modeling of fiber reinforced polymer composites is a complex and challenging task, in particular for practitioners with less experience in advanced coding and user-defined subroutines. Different numerical algorithms have been developed over the past decades for impact modeling of composites, yet a considerable gap often exists between predicted and experimental observations. In this paper, after a review of reported sources of complexities in impact modeling of fiber reinforced polymer composites, two simplified approaches are presented for fast simulation of out-of-plane impact response of these materials considering four main effects: (a) strain rate dependency of the mechanical properties, (b) difference between tensile and flexural bending responses, (c) delamination, and (d) the geometry of fixture (clamping conditions). In the first approach, it is shown that by applying correction factors to the quasistatic material properties, which are often readily available from material datasheets, the role of these four sources in modeling impact response of a given composite may be accounted for. As a result a rough estimation of the dynamic force response of the composite can be attained. To show the application of the approach, a twill woven polypropylene/glass reinforced thermoplastic composite laminate has been tested under 200 J impact energy and was modeled in Abaqus/Explicit via the built-in Hashin damage criteria. X-ray microtomography was used to investigate the presence of delamination inside the impacted sample. Finally, as a second and much simpler modeling approach it is shown that applying only a single correction factor over all material properties at once can still yield a reasonable prediction. Both advantages and limitations of the simplified modeling framework are addressed in the performed case study. PMID- 25431786 TI - Vitamin B6 supplementation improves oxidative stress and enhances serum paraoxonase/arylesterase activities in streptozotocin-induced diabetic rats. AB - The purpose of this study was to investigate the effects of vitamin B6 (Vit B6) on oxidant and antioxidant status in streptozotocin-induced diabetic rats. Thirty two Wistar rats were divided into four groups: control (C), control + Vit B6 group (C + Vit B6), diabetes (D), and diabetes + Vit B6 group (D + Vit B6). Vit B6 (4 mg/kg body weight) was administered in drinking water for 4 weeks after the induction of diabetes. Vitamin B6 reduced serum total cholesterol level in the C + Vit B6 (P < 0.01) and D + Vit B6 (P < 0.05) groups. Plasma and tissue malondialdehyde levels were reduced in the C + Vit B6 and D + Vit B6 groups. Whole blood glutathione peroxidase (GSH-Px) and erythrocyte superoxide dismutase (SOD) activities were higher in the D group (P < 0.05). GSH-Px and SOD activities were increased in C + Vit B6 group while these parameters decreased in the D + Vit B6 group. Paraoxonase and arylesterase activities were decreased in the D group while they were increased in C + Vit B6 and D + Vit B6 groups. The results of present study suggest that vitamin B6 supplementation might be a promising adjunctive agent for improving oxidative stress and metabolic disturbances and for preventing diabetic complications including atherogenesis. PMID- 25431788 TI - Site specific effect of tobacco addiction in upper aerodigestive tract tumors: a retrospective clinicopathological study. AB - An institutional study was carried out in 102 patients to investigate the site specific effect of addictions, that is, tobacco smoking and tobacco chewing (smokeless), both independently and synergistically in development of malignancies in upper aerodigestive tract through retrograde questionnaire. The histopathologically proven cases were interviewed regarding different forms of addictions followed by clinical examination and investigations for grading (according to Modified Broadmann's method) and TNM staging (according to UICC) according to the tumor site. Statistical analysis was done by Pearson test. Out of all proven cases of cancers, 29.4% were only tobacco chewers (smokeless), 25.5% were only smokers, 42.2% were having both types of tobacco addictions (smoke and smokeless), and only 2.9% were having no addiction. Out of only tobacco chewers (smokeless), 83.3% were of oral cavity cancers, 6.7% were of oro- and hypopharynx and the rest were of others. Among only smokers, 69.2% cases were of laryngeal and oro- and hypopharynx as compared to 11.5% of oral cavity cancers (nearly 6 times). Tobacco (smokeless) chewing is associated with oral cancers whereas tobacco smoking is associated with laryngeal and hypopharyngeal carcinoma. Both smoking and smokeless tobacco act in synergy with each other. PMID- 25431789 TI - The anterior chamber depth and retinal nerve fiber layer thickness in children. AB - PURPOSE: To investigate the correlation of anterior chamber depth (ACD) with the peripapillary retinal nerve fiber layer (RNFL) thickness, age, axial length (AL), and spherical equivalent in children. SUBJECTS: Consecutive subjects aged 4 to 18 were recruited. Visually disabling eye conditions were excluded. Only the right eye was included for analysis. The ACD was correlated with RNFL thickness, age, spherical equivalent, and AL for all subjects. Subjects were then divided into 3 groups based on their postcycloplegic spherical equivalent: myopes (<-1.0 D), emmetropes (>=-1.0 to <=+1.0 D), and hyperopes (>+1.0 D). The ACD was compared among the 3 groups before and after age adjustment. RESULTS: In 200 subjects (mean age 7.6 +/- 3.3 years), a deeper ACD was correlated with thinner global RNFL (r = -0.2, r(2) = 0.06, P = 0.0007), older age (r = 0.4, r(2) = 0.1, P < 0.0001), myopic spherical equivalent (r = -0.3, r(2) = 0.09, P < 0.0001), and longer AL (r = 0.5, r(2) = 0.2, P < 0.0001). The ACD was deepest in myopes (3.5 +/- 0.4 mm, n = 67), followed by emmetropes (3.4 +/- 0.3, n = 60) and then hyperopes (3.3 +/- 0.2, n = 73) (all P < 0.0001). After age adjustment, myopes had a deeper ACD than the other 2 groups (all P < 0.0001). CONCLUSIONS: In children, a deeper ACD was associated with thinner RNFL thickness, older age, more myopic spherical equivalent, and longer AL. Myopes had a deeper ACD than emmetropes and hyperopes. PMID- 25431790 TI - Comparison of prevalence of synovitis by ultrasound assessment in subjects exposed or not to self-reported physical overexertion: the Monday's synovitis. AB - OBJECTIVE: To compare the proportion of synovitis detected by ultrasonographic study (USS) of the hands, in subjects with no rheumatologic known disease according to self-reported level of overexertion performed the day before. METHODS: 407 consecutive volunteers were enrolled in a twelve-month period and underwent an ultrasound assessment of the hand. All studies were performed on Monday or Friday. Subjects were grouped according to their self-reported overexertion carried out the day before. Presence or absence of ultrasonographic findings compatible with synovitis was compared between groups. RESULTS: 95.8% of those tested on Friday had made no overexertion the day before the study, while 30.2% of those assessed on Monday declared to have carried out an overexertion. Presence of carpal synovial hypertrophy, synovial fluid/effusion, and power Doppler signal was statistically higher in subjects who carried out an overexertion the day before the study than the rest of subjects when the dominant hand was assessed. Globally, presence of any synovitis ultrasonographic finding was statistically higher in subjects who were studied on Monday than Friday (34.9% versus 12.1%) and in subjects who self-reported an overexertion the day before compared to the rest of subjects (47.7 versus 11.5%). CONCLUSIONS: In general, we recommend performing the USS as many days as possible after the most recent overexertion. PMID- 25431792 TI - Land use intensification effects in soil arthropod community of an entisol in Pernambuco State, Brazil. AB - The interactions between soil invertebrates and land use and management are fundamental for soil quality assessment but remain largely unaddressed. The aim of this study was to evaluate the changes in soil arthropod community of an entisol brought about by different land use systems under semiarid climate in Pernambuco State, Brazil. The soil invertebrate community was sampled using pitfall traps from areas with eight vegetation types by the end of the austral winter. The land uses studied were native thorn forest plus seven agricultural fields planted with elephant grass, apple guava, passion fruit, carrot, maize, tomato, and green pepper. Native vegetation was considered as a reference, whereas the agricultural fields showed a range of soil use intensities. The abundance of organisms, the total and average richness, Shannon's diversity index, and the Pielou uniformity index were determined, and all of these were affected by several crop and soil management practices such as residue cover, weed control, and pesticide application. Our study found differences in community assemblages and composition under different land use systems, but no single taxa could be used as indicator of soil use intensity. PMID- 25431791 TI - Consequences of lethal-whole-body gamma radiation and possible ameliorative role of melatonin. AB - Gamma radiation induces the generation of free radicals, leading to serious cellular damages in biological systems. Radioprotectors act as prophylactic agents that are administered to shield normal cells and tissues from the deleterious effects of radiation. Melatonin synergistically acts as an immune stimulator and antioxidant. We investigated the possible radioprotective role of melatonin (100 mg/kg i.p.) against lethal-whole-body radiation- (10 Gy) induced sickness, body weight loss, and mortality in rats. Results of the present study suggest that exposure to lethal-whole-body radiation incurred mortality, body weight loss, and apoptosis and it also depleted the immunity and the antioxidant status of the rats. Our results show that melatonin pretreatment provides protection against radiation induced mortality, oxidative stress, and immune suppression. The melatonin pretreated irradiated rats showed less change in body weight as compared to radiation only group. On the other hand, melatonin appeared to have another radioprotective role, suggesting that melatonin may reduce apoptosis through a caspase-3-mediated pathway by blocking caspase-3 activity. PMID- 25431793 TI - Burden and depressive symptoms associated with adult-child caregiving for individuals with heart failure. AB - BACKGROUND: The primary purpose of this study was to investigate adult-child caregiver burden in heart failure (HF) patients. Secondary purpose of the study was to identify the possible influencing factors for caregiver burden and depressive symptoms in a young adult-child caregiver group. METHODS: A total of 138 adult-child caregivers and 138 patients with HF participated in this study. Caregivers' burden, depressive symptoms, and anxiety levels were assessed by using Zarit Caregiver Burden Scale (ZCBS), Beck Depression Inventory, and State Trait Anxiety Inventory, respectively. RESULTS: The mean ZCBS scores of the female caregivers were significantly higher than male caregivers. Approximately one-third of the adult-child caregivers had at least mild depressive symptoms. Caregivers with higher depressive symptoms had higher levels of caregiver burden. There were positive correlations between caregiving time, severity of depressive symptoms, and perceived caregiver burden. There was a negative correlation between education level of caregivers and perceived caregiver burden. Age, socioeconomic level, and marital status of patients were affecting factors for depressive symptoms in caregivers. Among caregiver characteristics, gender, marital status, and ZCBS scores seem to influence the depression in caregivers. CONCLUSIONS: The study findings suggest significant levels of burden and depressive symptoms even in adult-child caregivers of HF patients. PMID- 25431794 TI - A qualitative study on perceptions of changes reported by caregivers of patients in vegetative state and minimally conscious state: the "time gap experience". AB - OBJECTIVE: Our purpose was to provide a comprehensive understanding of how women informal caregivers of patients in vegetative state (VS) or minimally conscious state (MCS) describe, represent, and experience changes that occurred in their life after the acute event of their family member. METHODS: A qualitative study was conducted and fifteen women informal caregivers, mothers, or spouses of patients in VS or MCS were interviewed. RESULTS: Caregivers' narratives revealed (1) important personal and interpersonal changes and (2) difficulties while facing the complex situation and integrating past, present, and future, defined as a "time gap experience." This difficulty is expressed in two ways. First, the reduction of variety of roles into one, caregiver's role. Second, the relationship with the relative is characterised by fluctuation in the relational style between caregiver and relative; it shifts from an adult to adult interaction to an adult to child one. Another fluctuation can be observed in the mixed use of present and past tenses when caregivers speak about their relatives. CONCLUSIONS: Caregiving cause pervasive modifications in one's life. Targeted interventions aiming to empower the caregivers, to support them after the acute event in caregiving activities together with patient-focused interventions, and to promote their health should be implemented. PMID- 25431795 TI - Antioxidative activities and active compounds of extracts from Catalpa plant leaves. AB - In order to screen the Catalpa plant with high antioxidant activity and confirm the corresponding active fractions from Catalpa ovata G. Don, C. fargesii Bur., and C. bungei C. A. Mey., total flavonoid contents and antioxidant activities of the extracts/fractions of Catalpa plant leaves were determined. The determined total flavonoid content and antioxidant activity were used as assessment criteria. Those compounds with antioxidant activity were isolated with silica gel column chromatography and ODS column chromatography. Our results showed that the total flavonoid content in C. bungei C. A. Mey. (30.07 mg/g . DW) was the highest, followed by those in C. fargesii Bur. (25.55 mg/g . DW) and C. ovata G. Don (24.96 mg/g . DW). According to the determination results of total flavonoid content and antioxidant activity in 3 clones of leaves of C. bungei C. A. Mey., the total flavonoid content and antioxidant activity in crude extracts from C. bungei C. A. Mey. 6 (CA6) leaves were the highest. Moreover, the results showed that the total flavonoid content and antioxidant activities of ethyl acetate (EA) fraction in ethanol crude extracts in CA6 leaves were the highest, followed by n butanol, petroleum ether (PE), and water fractions. Two flavonoid compounds with antioxidant activity were firstly isolated based on EA fraction. The two compounds were luteolin (1) and apigenin (2), respectively. PMID- 25431796 TI - Cytotoxicity potentials of eleven Bangladeshi medicinal plants. AB - Various forms of cancer are rising all over the world, requiring newer therapy. The quest of anticancer drugs both from natural and synthetic sources is the demand of time. In this study, fourteen extracts of different parts of eleven Bangladeshi medicinal plants which have been traditionally used for the treatment of different types of carcinoma, tumor, leprosy, and diseases associated with cancer were evaluated for their cytotoxicity for the first time. Extraction was conceded using methanol. Phytochemical groups like reducing sugars, tannins, saponins, steroids, gums, flavonoids, and alkaloids were tested using standard chromogenic reagents. Plants were evaluated for cytotoxicity by brine shrimp lethality bioassay using Artemia salina comparing with standard anticancer drug vincristine sulphate. All the extracts showed potent to moderate cytotoxicity ranging from LC50 2 to 115 ug/mL. The highest toxicity was shown by Hygrophila spinosa seeds (LC50 = 2.93 ug/mL) and the lowest by Litsea glutinosa leaves (LC50 = 114.71 ug/mL) in comparison with standard vincristine sulphate (LC50 = 2.04 ug/mL). Among the plants, the plants traditionally used in different cancer and microbial treatments showed highest cytotoxicity. The results support their ethnomedicinal uses and require advanced investigation to elucidate responsible compounds as well as their mode of action. PMID- 25431797 TI - Intrinsic apoptosis pathway in fallopian tube epithelial cells induced by cladribine. AB - Cladribine is a purine nucleoside analog which initiates the apoptotic mechanism within cells. Moreover, the available data confirms that cladribine, with the participation of the p53 protein, as well as the proapoptotic proteins from the Bcl-2 family, also induces the activation of the intrinsic apoptosis pathway. However, while there has been a lot of research devoted to the effect of cladribine on lymphatic system cells, little is known about the impact of cladribine on the reproductive system. The aim of our study was to evaluate apoptosis in oviduct epithelial cells sourced from 15 different female rats. In so doing, the sections were stained with caspases 3, 9, and 8. Results suggest that cladribine also induces apoptosis in the oviduct epithelial cells by way of the intrinsic pathway. Indeed, the discontinuing of the administration of cladribine leads to a reduction in the amount of apoptotic cells in the oviduct epithelium. PMID- 25431798 TI - Effect of zirconium oxide and zinc oxide nanoparticles on physicochemical properties and antibiofilm activity of a calcium silicate-based material. AB - The aim of the present study was to evaluate the antibiofilm activity against Enterococcus faecalis, compressive strength. and radiopacity of Portland cement (PC) added to zirconium oxide (ZrO2), as radiopacifier, with or without nanoparticulated zinc oxide (ZnO). The following experimental materials were evaluated: PC, PC + ZrO2, PC + ZrO2 + ZnO (5%), and PC + ZrO2 + ZnO (10%). Antibiofilm activity was analyzed by using direct contact test (DCT) on Enterococcus faecalis biofilm, for 5 h or 15 h. The analysis was conducted by using the number of colony-forming units (CFU/mL). The compressive strength was performed in a mechanical testing machine. For the radiopacity tests, the specimens were radiographed together with an aluminium stepwedge. The results were submitted to ANOVA and Tukey tests, with level of significance at 5%. The results showed that all materials presented similar antibiofilm activity (P > 0.05). The addition of nanoparticulated ZnO decreased the compressive strength of PC. All materials presented higher radiopacity than pure PC. It can be concluded that the addition of ZrO2 and ZnO does not interfere with the antibiofilm activity and provides radiopacity to Portland cement. However, the presence of ZnO (5% or 10%) significantly decreased the compressive strength of the materials. PMID- 25431799 TI - Regulatory focus affects physician risk tolerance. AB - Risk tolerance is a source of variation in physician decision-making. This variation, if independent of clinical concerns, can result in mistaken utilization of health services. To address such problems, it will be helpful to identify nonclinical factors of risk tolerance, particularly those amendable to intervention-regulatory focus theory suggests such a factor. This study tested whether regulatory focus affects risk tolerance among primary care physicians. Twenty-seven primary care physicians were assigned to promotion-focused or prevention-focused manipulations and compared on the Risk Taking Attitudes in Medical Decision Making scale using a randomization test. Results provide evidence that physicians assigned to the promotion-focus manipulation adopted an attitude of greater risk tolerance than the physicians assigned to the prevention focused manipulation (p = 0.01). The Cohen's d statistic was conventionally large at 0.92. Results imply that situational regulatory focus in primary care physicians affects risk tolerance and may thereby be a nonclinical source of practice variation. Results also provide marginal evidence that chronic regulatory focus is associated with risk tolerance (p = 0.05), but the mechanism remains unclear. Research and intervention targeting physician risk tolerance may benefit by considering situational regulatory focus as an explanatory factor. PMID- 25431800 TI - Hormone Therapy plus mTOR Inhibitors in the Treatment of Endometrial Carcinoma. AB - Hormonal therapies such as progestins have only modest activity in the treatment of advanced endometrial cancer. Mechanisms of resistance to progestin therapy are not well understood. However, activation of the PI3K/AKT/mTOR pathway has been associated with resistance to hormonal therapy and alterations in components of the PI3K/AKT/mTOR pathway, including inactivating mutations in PTEN, activating mutations in PIK3CA, and mutations in PIK3R1, are very common in endometrial carcinomas. mTOR inhibitors, including temsirolimus, everolimus, and ridaforolimus, are also known to be active against endometrial cancer, and interest has been stimulated in combinations of hormonal treatment with mTOR inhibitors, as both therapies have single-agent activity, and it is hypothesized that mTOR inhibition would enhance sensitivity to hormonal therapy. PMID- 25431801 TI - Evaluation of health related quality of life changes after initial orthodontic treatment. AB - PURPOSE: To evaluate the changes of Oral Health Related Quality of Life (OHRQoL) in patients after the placement of a fixed orthodontic appliance. MATERIALS AND METHODS: This prospective study consisted of 148 adolescents (97 girls and 51 boys) between the ages of 14 and 17 who were patients of an orthodontic clinic. OHRQoL was assessed by a modified questionnaire that evaluated four domains: oral symptoms, functional limitations as well as emotional and social well-being in three time frames: before bonding and banding (T(0)), two months after initiating orthodontic treatment (T(1)) and six months after initiating orthodontic treatment (T(2)). The repeated measures test was used to compare the relative changes of OHRQoL among the different time frames. RESULTS: There were no significant differences between the levels of OHRQoL and its domains for boys or girls at any time point. The overall level of OHRQoL decreased significantly at T(1) relative to T(0); however, the emotional well-being domain improved at T(1) in comparison to T(0). At T(2), the OHRQoL level increased significantly relative to T(0) in all domains. CONCLUSION: The patients' quality-of-life level decreased by initiating orthodontic treatment; however, during that period, emotional well being increased. As orthodontic treatment progressed, the quality of life level increased. PMID- 25431802 TI - Developmental Enamel Defects of the Permanent First Molars and Incisors and Their Association with Dental Caries in the Region of Wielkopolska, Western Poland. AB - PURPOSE: To assess the prevalence of developmental defects of the enamel (DDE) in permanent first molars and incisors and their association with dental caries in two age groups of children living in Wielkopolska, Poland. MATERIALS AND METHODS: The sample consisted of 225 children ages 6-8 years and 245 children ages 12-14 years (mean age +/- SD = 9.9 +/- 2.6). Dental defects were described using the modified DDE index. Caries experience was recorded using the DMFT index (number of decayed, missing and filled teeth) for all permanent teeth and for first permanent molars and incisors (DMFT-IM). RESULTS: Overall, 25.7% of the subjects had at least one permanent first molar or incisor affected by DDE. Diffuse opacity was the most common type of DDE, while hypoplasia was the least prevalent. The mean number of teeth with caries (DT) and the mean number of molars and incisors with caries (DT-IM) were higher in subjects with enamel hypoplasia and/or demarcated opacity than in subjects without DDE or with diffuse opacities (p < 0.05). Caries prevalence was higher in children with hypoplasia and/or demarcated opacity than in subjects without DDE. The differences were statistically significant only for the younger group (p < 0.05). CONCLUSION: The overall tooth prevalence of DDE in molars and incisors is comparable to that observed in low-fluoride communities. However, a preponderance of diffuse defects suggests the need for further investigation into the aetiology of DDE among Polish children. The results confirm that demarcated opacities and hypoplasia should be considered important caries risk factors. PMID- 25431803 TI - Comparison of two oral health-related quality of life measures among adult dental patients. AB - PURPOSE: The most commonly used oral health related quality of life measures, Oral Health Impact Profile (OHIP) and Oral Impact on Daily Performances (OIDP), are affected by cultural and linguistic factors, which may be intensified in a treatment-need driven society. This study therefore aimed to compare the psychometric properties of the OHIP-14 and OIDP measures in adult patients in Nigeria where patients typically visit the dentist when dental problems arise. MATERIALS AND METHODS: This was a cross-sectional study in which 264 patients attending two dental clinics were recruited. Data were collected with OHIP-14 and OIDP structured interviewer-administered questionnaires, global self-report and perceived need for dental treatment questions and by oral examination. Data collected were subjected to statistical analysis using SPSS version 19 and the level of statistical significance was set at a p-value of 0.05. RESULTS: The majority (61.0%) rated their oral health status poorly and 203 (76.9%) perceived a need for treatment. The average OHIP and OIDP scores were 12.0 (range 0 to 56) and 8.9 (range 0 to 40), respectively. Both instruments showed a high index of validity and reliability; both had similar face and content validity, however, OIDP had better criterion validity while OHIP-14 had better construct validity and internal consistency. CONCLUSIONS: Both OHIP-14 and OIDP are precise, valid and reliable for evaluation of OHRQOL where dental care is treatment-need driven. They are able to discriminate between groups according to their perception of oral health status, but with OIDP detecting fewer impacts on daily activities. PMID- 25431804 TI - Casein Phosphopeptide-Amorphous Calcium Phosphate (CPP-ACP) May Be an Alternative Preventive Therapy in Children with Cerebral Palsy. AB - PURPOSE: To evaluate the effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) on the buffering capacity of saliva and plaque pH in individuals with cerebral palsy (CP). MATERIALS AND METHODS: A total of 15 3- to 8-year-old subjects with CP living in a governmental institution were included in this study. Dental plaque pH and the buffering capacity of saliva were measured at the first visit (baseline) and accepted as control values. CPP-ACP complex (GC Tooth Mousse) was applied to the children twice a day. Measurements were repeated after the 1st, 2nd, 3rd, 4th, 6th and 8th weeks. RESULTS: Plaque indicator data show decreased acidogenicity in the 8-week period. Although there were no significant differences between the baseline and the 1st, 2nd and 3rd weeks' pH scores, a statistically significant difference was observed between the initial and 4th, 6th and 8th weeks' plaque pH scores. Saliva buffer scores were found to statistically significant increase between baseline and the 3rd, 4th, 6th and 8th weeks. CONCLUSION: Daily application of 10% w/v CPP-ACP paste is effectively changes saliva buffering capacity and plaque pH, thus promoting caries prevention in the primary and mixed dentition of CP children. PMID- 25431805 TI - Comparative Efficacy of Aloe vera and Benzydamine Mouthwashes on Radiation induced Oral Mucositis: A Triple-blind, Randomised, Controlled Clinical Trial. AB - PURPOSE: To compare the efficacy of an Aloe vera mouthwash with a benzydamine mouthwash in the alleviation of radiation- induced mucositis in head and neck cancer patients using a triple-blind, randomised controlled trial. MATERIALS AND METHODS: Twenty-six eligible head and neck cancer patients who were to receive conventional radiation therapy at the radiation oncology department were randomised to receive an Aloe vera mouthwash or a benzydamine mouthwash. Mucositis severity was assessed during the course of radiation therapy using the WHO grading system. RESULTS: At baseline, there was no difference in the distribution of mucositis severity between the two groups. The mean interval between radiation therapy and onset of mucositis was similar for both groups (Aloe vera 15.69+/-7.77 days, benzydamine 15.85+/-12.96 days). The mean interval between the start of radiation therapy and the maximum severity of mucositis were was also similar in both the Aloe vera and benzydamine groups (Aloe vera 23.38+/ 10.75 days, benzydamine 23.54+/-15.45 days). Mean changes of mucositis severity over time in both groups were statistically similar and the effect of both treatments did not change signficantly with time (p=0.09). CONCLUSION: Aloe vera mouthwash was as beneficial as benzydamine mouthwash in alleviating the severity of radiation-induced mucositis and showed no side effects. The Aloe vera mouthwash could be an alternative agent in the treatment of radiation-induced mucositis in patients with head and neck cancers. PMID- 25431806 TI - Novel integrated and portable endotoxin detection system based on an electrochemical biosensor. AB - This paper describes the design, implementation and validation of a sensitive and integral technology solution for endotoxin detection. The unified and portable platform is based on the electrochemical detection of endotoxins using a synthetic peptide immobilized on a thin-film biosensor. The work covers the fabrication of an optimized sensor, the biofunctionalization protocol and the design and implementation of the measuring and signalling elements (a microfluidic chamber and a portable potentiostat-galvanostat), framed ad hoc for this specific application. The use of thin-film technologies to fabricate the biosensing device and the application of simple immobilization and detection methods enable a rapid, easy and sensitive technique for in situ and real time LPS detection. PMID- 25431807 TI - Antibody mimetic receptor proteins for label-free biosensors. AB - The development of high sensitivity biosensors, for example for clinical diagnostics, requires the identification of suitable receptor molecules which offer high stability, specificity and affinity, even when embedded into solid state biosensor transducers. Here, we present an electrochemical biosensor employing small synthetic receptor proteins (Mw < 15 kDa) which emulate antibodies but with improved stability, sensitivity and molecular recognition properties, in particular when immobilized on a solid sensor surface. The synthetic receptor protein is a non-antibody-based protein scaffold with variable peptide regions inserted to provide the specific binding, and was designed to bind anti-myc tag antibody (Mw ~ 150 kDa), as a proof-of-principle exemplar. Both the scaffold and the selected receptor protein were found to have high thermostability with melting temperatures of 101 degrees C and 85 degrees C, respectively. Furthermore, the secondary structures of the receptor protein were found to be very similar to that of the original native scaffold, despite the insertion of variable peptide loops that create the binding sites. A label-free electrochemical sensor was fabricated by functionalising a microfabricated gold electrode with the receptor protein. A change in the phase of the electrochemical impedance was observed when the biosensor was subjected to anti-myc tag antibodies at concentrations between 6.7 pM and 6.7 nM. These findings demonstrate that these non-antibody receptor proteins are excellent candidates for recognition molecules in label-free biosensors. PMID- 25431808 TI - Novel L-lactic acid biosensors based on conducting polypyrrole-block copolymer nanoparticles. AB - The development of advanced nanomaterials for the highly efficient electrical detection of biological species has attracted great attention. Here, novel polypyrrole-Pluronic F127 nanoparticles (PPy-F127 NPs) with conducting and biocompatibility properties were synthesized and used to construct a L-lactic acid biosensor that could be applied in biochemical assays. The PPy-F127 NPs were characterized by transmission electron microscopy (TEM), elemental analysis and UV-vis spectroscopy. Lactate oxidase (LOx) structure variation on the PPy-F127 NPs was investigated by circular dichroism (CD). The cyclic voltammetric results indicated that LOx immobilized on the PPy-F127 NPs exhibited direct electron transfer reaction with a formal potential value (E(0)') of 0.154 V vs. SCE. Moreover, the biosensor had good electrocatalytic activity toward L-lactic acid with a wide linear range (0.015-37.5 mM) and a low detection limit of 0.0088 mM. The regression equation was I (MUA) = 0.02353c (mM) + 1.4135 (R(2) = 0.9939). The L-lactic acid biosensor had a good anti-interference property towards uric acid (UA), ascorbic acid (AA), glucose and cysteine. The idea and method provide a promising platform for the rapid development of biosensors that can be used in the detection of biological species. PMID- 25431809 TI - Forensic analysis of ballpoint pen inks using paper spray mass spectrometry. AB - A novel analytical approach based on paper spray mass spectrometry (PS-MS) is developed for a fast and effective forensic analysis of inks in documents. Ink writings made in ordinary paper with blue ballpoint pens were directly analyzed under ambient conditions without any prior sample preparation. Firstly, the method was explored on a set of distinct pens and the results obtained in the positive ion mode, PS(+)-MS, demonstrated that pens from different brands provide typical profiles. Simple visual inspection of the PS(+)-MS led to the distinction of four different combinations of dyes and additives in the inks. Further discrimination was performed by using the concept of relative ion intensity (RII), owing to the large variability of dyes BV3 and BB26 regarding their demethylated homologues. Following screening and differentiation studies, the composition changes of ink entries subjected to light exposure were also monitored by PS-MS. The results of these tests revealed distinct degradation behaviors which were reflected on the typical chemical profiles of the studied inks, attesting that PS-MS may be also useful to verify the fading of dyes thus allowing the discrimination of entries on a document. As proof of concept experiments, PS-MS was successfully utilized for the analysis of archived documents and characterization of overlapped ink lines made on simulated forged documents. PMID- 25431810 TI - Disodium diselenide in colloidal nanocrystals: acting as an anion exchange precursor, a metal selenide precursor, and a chalcogenide ligand. AB - A new application area using a very simple alkali metal chalcogenide, disodium diselenide (Na2Se2), has been developed. The prepared alkali metal chalcogenide (disodium diselenide, Na2Se2) acts as an anionic exchange precursor (PbS to PbS PbSe), a Se precursor for metal selenide nanoparticles (Ag to Ag2Se), and a MCC (FeO-MCC) depending on the type of colloidal nanoparticles. PMID- 25431811 TI - Step-wise induction, amplification and inversion of molecular chirality through the coordination of chiral diamines with Zn(II) bisporphyrin. AB - For the first time, a clear and unambiguous rationalization of chirality induction, inversion and subsequent amplification process has been demonstrated for the 1 : 1 sandwich and 2 : 3 host-guest supramolecular complexes consisting of Zn(II) host and chiral diamines as guests that has so far remained the most outstanding issue for the chirogenic process. PMID- 25431812 TI - Intramolecular hydroalkoxylation catalyzed inside a self-assembled cavity of an enzyme-like host structure. AB - Self-assembled resorcin[4]arene hexamer catalyzes the intramolecular hydroalkoxylation of unsaturated alcohols to the corresponding cyclic ethers under mild conditions. The mode of catalysis and encapsulation-based substrate selectivity of the host efficiently mimic the basic principle of operation observed in enzymes. PMID- 25431813 TI - Heat-induced transformation of CdSe-CdS-ZnS core-multishell quantum dots by Zn diffusion into inner layers. AB - In this work, we investigate the thermal evolution of CdSe-CdS-ZnS core multishell quantum dots (QDs) in situ using transmission electron microscopy (TEM). Starting at a temperature of approximately 250 degrees C, Zn diffusion into inner layers takes place together with simultaneous evaporation of particularly Cd and S. As a result of this transformation, CdxZn1-xSe-CdyZn1-yS core-shell QDs are obtained. PMID- 25431814 TI - Efficient hydration of alkynes through acid-assisted Bronsted acid catalysis. AB - The combined acid catalyzed hydration of alkynes is an efficient one-step synthesis of carbonyl compounds. This atom-economical method is effective with a wide range of substrates, and the products are obtained in very good yields with low catalyst loading (0.2%). Furthermore, solid acids like Nafion were also efficient and could be easily recycled multiple times without loss of reactivity. PMID- 25431815 TI - Ultrasensitive SERS assay of lysozyme using a novel and unique four-way helical junction molecule probe for signal amplification. AB - A unique four-way helical junction molecule (FHJM) probe was ingeniously designed, and firstly introduced into DNA signal amplification as a novel Surface enhanced Raman scattering (SERS) probe. Significantly, a new FHJM-SERS method was successfully developed for lysozyme detection with high sensitivity and specificity. PMID- 25431816 TI - Mitochondrial DNA Haplogroup A may confer a genetic susceptibility to AIDS group from Southwest China. AB - The acquired immunodeficiency syndrome (AIDS) in humans was one of the chronic infections caused by human immunodeficiency virus (HIV), and the interactions between viral infection and mitochondrial energetic implicated that mitochondrial DNA (mtDNA) variation(s) may effect genetic susceptibility to AIDS. Thus, to illustrate the maternal genetic structure and further identify whether mtDNA variation(s) can effect HIV infection among southwest Chinese AIDS group, the whole mtDNA control region sequences of 70 AIDS patients and 480 health individuals from southwest China were analyzed here. Our results indicated the plausible recent genetic admixture results of AIDS group; comparison of matrilineal components between AIDS and matched Han groups showed that mtDNA haplogroup A (p = 0.048, OR = 3.006, 95% CI = 1.109-8.145) has a significant higher difference between the two groups; further comparison illustrated that mtDNA mutations 16,209 (p = 0.046, OR = 2.607, 95% CI = 0.988-6.876) and 16,319 (p = 0.009, OR = 2.965, 95% CI = 1.278-6.876) have significant differences between AIDS and matched control groups, and both of which were the defining variations of mtDNA haplogroup A, they further confirmed that mtDNA haplogroup A may confer genetic susceptibility to AIDS. Our results suggested that haplogroup A may confer a genetic susceptibility to AIDS group from Southwest China. PMID- 25431817 TI - Morphological and molecular description for Glyphocrangon investigatoris Wood Mason & Alcock, 1891 emphasizing its phylogenetic relationship. AB - Genus Glyphocrangon, the only representative of Family Glyphocrangonidae, comprises about 89 species. According to previous records, this species is known to inhabit a depth range of 145-410 fathoms in Bay of Bengal. A thorough scrutiny of literature revealed a detailed morphological description of G. investigatoris and little molecular database. As part of an exploratory research survey conducted in Bay of Bengal, specimens of this species were collected from trawl catches off Paradeep, Orissa. In our present study, an attempt was made to develop its DNA barcode based on mitochondrial Cytochrome oxidase subunit I (mtCOI) and to establish its phylogenetic relationship with other species of genus Glyphocrangon. The developed mtCOI sequences of G. investigatoris exhibited its genetic identity favoring its morphological description. PMID- 25431818 TI - Phylogeny based on two mtDNA genes (Co-1, Cyt-B) among Sculpins (Scorpaeniformes, Cottidae) and some other scorpionfish in the Russian Far East. AB - The average scores of p-distances at Co-1 and Cyt-b genes revealed a pattern of increased nucleotide diversity for four categories: (1) intraspecies, (2) intragenus, (3) intrafamily, and (4) intraorder. Scores for Co-1 genes were following: (1) 0.24 +/- 0.19% (n = 66), (2) 1.54 +/- 0.27% (n = 33), (3) 11.57 +/ 0.24% (n = 42), and (4) 12.91 +/- 0.16% (n = 102); while for Cyt-b genes, those values were (1) 1.92 +/- 0.55% (n = 24), (2) 8.19 +/- 0.09% (n = 812), (3) 15.42 +/- 0.07% (n = 1573), and (4) 23.13 +/- 0.19% (n = 211). A concordant increase in the distance score, as the rank of taxa grows, with the minimum at intraspecies level substantiates the concept that speciation in the order Scorpaeniformes mostly follows a geographic mode. Phylogenetic trees for 40 sequences of scorpionfish and four other fishes belonging to Actinopterigii were developed using Co-1 gene and four different analytical approaches: Bayesian, ML, MP, and NJ. Resolution of the Co-1 trees for the three genera that included different species branches was quite distinct in all approaches. Intrafamily branching for Cyt-b in Cottidae was also supported by all four kinds of trees but only for less numerous genera in the research. PMID- 25431819 TI - The complete mitochondrial genome of the Neochauliodes fraternus (Megaloptera: Corydalidae). AB - The mitochondrial genome of Neochauliodes fraternus (Megaloptera: Corydalidae) is a circular molecule of 15,768 bp in length, containing 37 typical mitochondrial genes: 13 protein-coding genes (PCGs), 2 ribosomal RNAs, 22 transfer RNAs and a non-coding AT-rich region. Its gene order and arrangement are identical to the common type found in most insect mitogenomes. All PCGs start with a typical ATN codon except for the ND1 which uses TTG as its start codon; all PCGs terminate in the common stop codon TAA or TAG, except for the COI, COIII, ND3, ND5, ND4 and CYTB which use single T as their stop codons. The non-coding AT-rich region is 1031 bp long, located between rrnS and tRNA(lle) genes. It contains some structures of repeated motifs and microsatellite-like elements characteristic of the megaloptera. PMID- 25431820 TI - The complete mitochondrial genome of Bombyx mori strain Huayu (Lepidoptera: Bombycidae). AB - The complete mitochondrial genome of Bombyx mori strain Huayu (Lepidoptera: Bombycidae) is determined in this study. The genome was 15,666 bp long, with 37 typical animal mitochondrial genes and 1 non-coding A + T-rich region. Its gene content and order were identical to those of other lepidopteran mitochondrial genomes. All protein-coding genes (PCGs) were initiated by ATN codons except for the COI gene, which began with uncertained codon. Eleven PCGs stopped with termination codon TAA, whereas the COI and COII genes ended with single T. All tRNAs have typical structures of insect mitochondrial tRNAs. The 494 bp AT-rich region contains several features common to other lepidopterans, such as the motif ATAGA followed by an 18 bp poly-T stretch and an 11 bp poly-A element upstream of transfer RNA M (trnM) gene. PMID- 25431821 TI - Next-generation sequencing and comparative analysis of Pyrrhocorax pyrrhocorax and Pyrrhocorax graculus (Passeriformes: Corvidae) mitochondrial genomes. AB - The complete mitochondrial genomes of Red-billed Chough (Pyrrhocorax pyrrhocorax) and Yellow-billed Chough (Pyrrhocorax graculus) were sequenced using the Ion Torrent PGM platform. These mitogenomes contain 16,889 bp (Red-billed Chough) and 16,905 bp (Yellow-billed Chough), including 13 protein-coding genes (PCGs), two ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and a control region (D loop). The gene content, orientation, and structure are similar to a wide range of other vertebrate species and the nucleotide composition is very similar to other Passeriformes. All PCGs start with ATG, except for COX1 that starts with GTG, and four stop codons and one incomplete stop codon are used (TAA, TAG, AGG, AGA, and T-). The size of PCGs is the same in both mitogenomes, except for ND6 that has one codon less in the Yellow-billed Chough. All the tRNAs can fold into a typical cloverleaf secondary structure. These mitogenomic data can be of great value in complementing forthcoming approaches on molecular ecology, comparative and functional genomics. PMID- 25431822 TI - The complete mitochondrial genome sequence of Herzensteinia microcephalus (Cypriniformes: Cyprinidae). AB - Herzensteinia microcephalus (Herzenstein, 1891) is the highest naturally occurring cyprinid in the world, and inhabits rivers in the Tibetan Plateau at elevations of 4500-5200 m. Few studies on this species have been contributed. In this study, we got the mitochondrial genome sequences of H. microcephalus. The mitogenome of H. microcephalus is16,726 in length, which includes 13 protein coding genes, 22 tRNA genes, two rRNA genes and two non-coding regions: control region (D-loop) and origin of light-strand replication (OL). The overall nucleotide base composition is 28.41% for A, 27.16% for T, 26.04% for C and 18.38% for G. This study can provide important molecular theory basis for carrying out the study on the genetics, phylogeny and adaptive evolution of Herzensteinia. PMID- 25431823 TI - Complete mitochondrial genome of the Japanese wood pigeon, Columba janthina janthina (Columbiformes, Columbidae). AB - The complete mitochondrial genome of Columba janthina janthina was sequenced and its total length was 17,469 bp, containing 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs and 1 non-coding control region (D-loop). The A+T content of the overall base composition of H-strand were 54.46% (30.38% A, 24.08% T, 32.00% C and 13.54% G). The arrangement of all genes was identical to the typical mitochondrial genomes of pigeon. Within the control region, conserved sequences were identified in three domains. These results provide basic information for phylogenetic analyses of pigeon, especially Columbiformes species. PMID- 25431824 TI - Does a global DNA barcoding gap exist in Annelida? AB - Accurate identification of unknown specimens by means of DNA barcoding is contingent on the presence of a DNA barcoding gap, among other factors, as its absence may result in dubious specimen identifications - false negatives or positives. Whereas the utility of DNA barcoding would be greatly reduced in the absence of a distinct and sufficiently sized barcoding gap, the limits of intraspecific and interspecific distances are seldom thoroughly inspected across comprehensive sampling. The present study aims to illuminate this aspect of barcoding in a comprehensive manner for the animal phylum Annelida. All cytochrome c oxidase subunit I sequences (cox1 gene; the chosen region for zoological DNA barcoding) present in GenBank for Annelida, as well as for "Polychaeta", "Oligochaeta", and Hirudinea separately, were downloaded and curated for length, coverage and potential contaminations. The final datasets consisted of 9782 (Annelida), 5545 ("Polychaeta"), 3639 ("Oligochaeta"), and 598 (Hirudinea) cox1 sequences and these were either (i) used as is in an automated global barcoding gap detection analysis or (ii) further analyzed for genetic distances, separated into bins containing intraspecific and interspecific comparisons and plotted in a graph to visualize any potential global barcoding gap. Over 70 million pairwise genetic comparisons were made and results suggest that although there is a tendency towards separation, no distinct or sufficiently sized global barcoding gap exists in either of the datasets rendering future barcoding efforts at risk of erroneous specimen identifications (but local barcoding gaps may still exist allowing for the identification of specimens at lower taxonomic ranks). This seems to be especially true for earthworm taxa, which account for fully 35% of the total number of interspecific comparisons that show 0% divergence. PMID- 25431825 TI - Polymorphism in mtDNA control region of Mizo-Mongloid Breast Cancer samples as revealed by PCR-RFLP analysis. AB - Mutations in mitochondrial D-loop region of DNA (mtDNA) may serve as a potential sensor for cellular DNA damage and marker for cancer development. We investigated the restriction fragment length polymorphism (RFLP) pattern of the D-loop region in the blood samples of breast cancer patients among Mizoram population. Significant differences were observed among breast cancer and healthy blood samples in the RFLP pattern using AluI, HaeIII and RsaI enzymes. Polymorphic information content (PIC - 0.258), band informativeness (?Ib - 3.283) and marker index (MI - 0.006) were highest in the case of RsaI enzyme. Our data suggest that the RsaI polymorphic site in the mitochondrial control region is an informative marker for breast cancer development in Mizo population. PMID- 25431826 TI - Genetic differentiation between red deer from different sample sites on the Tianshan Mountains (Cervus elaphus), China. AB - About 273 individuals were identified from 471 fecal samples from six different red deer populations in China. The genetic structure showed that the red deer from the western and eastern Tianshan Mountains was different. A total number of 12 haplotypes were defined by 97 variable sites by the control region (CR), and 10 haplotypes were defined by 34 variable sites by cytochrome b. There was no haplotype sharing between red deer populations from western and eastern Tianshan Mountains by the CR and the cytochrome b. The red deer populations from west were clade with wapiti from North American and red deer from Siberia, while red deer populations from east were clade with red deer from Crimea in Pleistocene rather than west at present. The result of NETWORK also showed that red deer populations from western and eastern Tianshan Mountains were different. The haplotype and the Fst value between western and eastern Tianshan red deer were significantly different. The AMOVA analysis showed that 97.34% and 1.14% of the total genetic variability were found within populations and among populations within groups, respectively, by microsatellite. AMOVA for mitochondria showed that most of the variance was explained among-group. The Fst, pairwise distance, and phylogenetic relationship result showed that red deer between western and eastern Tianshan were more different than some of the red deer from North-Asia, South-Asia, East Asia, and wapiti. All data from this study do support that the genetic characteristics of red deer between western and eastern Tianshan Mountains by microsatellite, control region, and cytochrome b were different. PMID- 25431827 TI - Effect of demineralized bone particle/poly(lactic-co-glycolic acid) scaffolds on the attachment and proliferation of mesenchymal stem cells. AB - The aim of this study was to investigate the effect of demineralized bone particle/ poly(lactic-co-glycolic acid) (DBP/PLGA) scaffolds on the proliferation of mesenchymal stem cells (MSCs). DBP/PLGA hybrid scaffolds were fabricated by solvent casting/salt-leaching with DBP contents of 0, 20, 40, and 80 wt%. MSCs were seeded on the DBP/PLGA scaffolds and then evaluated by a series of analytical process: SEM, MTT, RT-PCR, and in vivo histological assay. As the DBP contents increased, the cell attachment behavior and cell viability also increased. A DBP content of 80 wt% marked the best water absorption performance and the highest cell viability. Gene expression of aggrecan on DBP/PLGA scaffolds tended to increase, whereas that on PLGA scaffolds was decreased at 1 week. However, strong expression of aggrecan was observed at 2 weeks regardless of the contents of DBP. Scaffolds showed a trend of increasing type II and I collagen at 2 weeks. The results showed that MSCs on DBP/PLGA scaffolds showed more efficient cell proliferation and tissue formation in the presence of tissue-inductive stimuli. Suitable biomaterials could be more conducive to proliferation of MSCs. These results suggest that the DBP/PLGA scaffolds are a feasible biomaterial for intervertebral disc regeneration. PMID- 25431828 TI - The ALS ice bucket challenge - can a splash of water reinvigorate a field? PMID- 25431829 TI - Genetic variants and risk of esophageal squamous cell carcinoma: a GWAS-based pathway analysis. AB - This study was designed to identify candidate single-nucleotide polymorphisms (SNPs) that may affect the susceptibility to esophageal squamous cell carcinoma (ESCC) and elucidate their potential mechanisms to generate SNP-to-gene-to pathway hypotheses. A genome-wide association study (GWAS) dataset for ESCC, which included 453,852 SNPs from 1898 ESCC patients and 2100 control subjects of Chinese population, was reviewed. The identify candidate causal SNPs and pathways (ICSNPathway) analysis identified seven candidate SNPs, five genes, and seven pathways, which together revealed seven hypothetical biological mechanisms. The three strongest hypothetical biological mechanisms were as follows: rs4135113 >TDG->BASE EXCISION REPAIR; rs1800450->MBL2->MONOSACCHARIDE BINDING; and rs3769823->CASP8->d4gdiPathway. The GWAS dataset was evaluated using the ICSNPathway, which showed seven candidate SNPs, five genes, and seven pathways that may contribute to the susceptibility of patients to ESCC. PMID- 25431830 TI - Functional ability level development and validation: providing clinical meaning for Spinal Cord Injury Functional Index scores. AB - OBJECTIVES: To develop functional ability levels for the Spinal Cord Injury Functional Index (SCI-FI) and to validate them using calibration and reliability samples. DESIGN: Three-phase strategy involved (1) performing quantitative synthesis of SCI-FI data to create item maps; (2) using a panel of experts to identify functional ability levels after the bookmarking and Delphi consensus building process; and (3) performing quantitative analyses to examine demographic characteristics across 2 samples, assessing the distribution pattern across functional ability levels, and examining concurrent validity using the self reported functional measure and the observer-rated FIM. SETTING: Inpatient and community settings. PARTICIPANTS: People 18 years or older with traumatic spinal cord injury (N=1124) were recruited from the Spinal Cord Injury Model Systems programs and stratified by diagnosis, severity, and time since injury (n=855 and n=269 for calibration and reliability samples, respectively). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: SCI-FI. RESULTS: Five functional ability levels were identified for all SCI-FI domains, except fine motor having 4 functional ability levels. Statistical test results indicated no significant differences in the distribution pattern across the 2 samples across functional ability levels for all domains except for ambulation. Known-group comparisons were able to discern the spinal cord injury population as expected. Basic mobility, self-care, and wheelchair mobility domains had a cluster of persons with paraplegia and incomplete lesions at higher functional ability levels and persons with tetraplegia and complete lesions at lower functional ability levels. For the ambulation domain, the distribution was skewed to the lower end, with a relatively small percentage of persons with incomplete lesions (paraplegia and tetraplegia) at higher functional ability levels. For the fine motor domain, the distribution was skewed to higher functional ability levels, with a high percentage of persons with paraplegia at the highest level (complete and incomplete lesions). Concurrent validity analyses revealed SCI-FI functional levels to be significantly (P<.001) positively correlated with both the self reported functional measure and the observer-rated FIM. CONCLUSIONS: Clinicians can use functional ability levels to discuss patients' functional capabilities with them and their family. PMID- 25431831 TI - Use of social media across US hospitals: descriptive analysis of adoption and utilization. AB - BACKGROUND: Use of social media has become widespread across the United States. Although businesses have invested in social media to engage consumers and promote products, less is known about the extent to which hospitals are using social media to interact with patients and promote health. OBJECTIVE: The aim was to investigate the relationship between hospital social media extent of adoption and utilization relative to hospital characteristics. METHODS: We conducted a cross sectional review of hospital-related activity on 4 social media platforms: Facebook, Twitter, Yelp, and Foursquare. All US hospitals were included that reported complete data for the Centers for Medicare and Medicaid Services Hospital Consumer Assessment of Healthcare Providers and Systems survey and the American Hospital Association Annual Survey. We reviewed hospital social media webpages to determine the extent of adoption relative to hospital characteristics, including geographic region, urban designation, bed size, ownership type, and teaching status. Social media utilization was estimated from user activity specific to each social media platform, including number of Facebook likes, Twitter followers, Foursquare check-ins, and Yelp reviews. RESULTS: Adoption of social media varied across hospitals with 94.41% (3351/3371) having a Facebook page and 50.82% (1713/3371) having a Twitter account. A majority of hospitals had a Yelp page (99.14%, 3342/3371) and almost all hospitals had check-ins on Foursquare (99.41%, 3351/3371). Large, urban, private nonprofit, and teaching hospitals were more likely to have higher utilization of these accounts. CONCLUSIONS: Although most hospitals adopted at least one social media platform, utilization of social media varied according to several hospital characteristics. This preliminary investigation of social media adoption and utilization among US hospitals provides the framework for future studies investigating the effect of social media on patient outcomes, including links between social media use and the quality of hospital care and services. PMID- 25431832 TI - An oxidized liquid metal-based microfluidic platform for tunable electronic device applications. AB - Easy movement of oxidized Galinstan in microfluidic channels is a promising way for the wide application of the non-toxic liquid metal. In this paper, two different surface modification techniques (physical and chemical) are reported, which dramatically improve the non-wetting characteristics of oxidized Galinstan in the microfluidic channel. In the physical technique, normal paper textures are transferred to the inner wall of polydimethylsiloxane (PDMS) channels and four types of nanoparticles are then coated on the surface of the wall for further improvement of the non-wetting characteristics. Highest advancing angle of 167 degrees and receding angle of 151 degrees are achieved on the paper-textured PDMS with titanium oxide (TiO2) nanoparticles. In the chemical technique, three types of inorganic acids are employed to generate dual-scale structures on the PDMS surface. The inner wall surface treated with sulfuric acid (H2SO4) shows the highest contact angle of 167 degrees and a low hysteresis of ~14 degrees in the dynamic measurement. Creating, transporting, separating and merging of oxidized Galinstan droplets are successfully demonstrated in the fabricated PDMS microfluidic channels. After optimization of these modification techniques, the potential application of tunable capacitors and electronic filters is realized by using liquid metal-based microfluidic devices. PMID- 25431833 TI - An exploratory review of pre-qualification interprofessional education evaluations. AB - There are diverse perceptions about the primary purpose of evaluation. In interprofessional education (IPE), there has been a perceived focus on evaluating against the outcome of improved collaborative practice and quality of care. This paper presents an exploration of the nature and purpose of evaluation methods commonly utilized in the IPE literature with its focus on outcomes-based evaluation and particularly the Kirkpatrick framework. It categorises recent evaluations of pre-qualification (pre-certification) IPE interventions. Of the 90 studies included, most evaluated soon after the educational intervention, only five specifically referred to an evaluation framework and the most frequently used tool was the RIPLS. There was a noteworthy reliance on students' self-rated perceptions of their attitudes towards collaborative practice collected through surveys, focus groups and interviews. There appears to be a need to reconsider the type of evaluation required. In conclusion, this paper offers recommendations for evaluation practice that is moving towards realist approaches; describes the longer term effects of interventions on attitudes and behaviour; develops and validates data collection tools including direct observation of practice and more comprehensively engages with all stakeholders to ensure that evaluation activities are not only focused on improving IPE but also on enhancing our understanding of interprofessional practice. PMID- 25431834 TI - Rapid response systems and collective (in)competence: An exploratory analysis of intraprofessional and interprofessional activation factors. AB - The rapid response system (RRS) is a patient safety initiative instituted to enable healthcare professionals to promptly access help when a patient's status deteriorates. Despite patients meeting the criteria, up to one-third of the RRS cases that should be activated are not called, constituting a "missed RRS call". Using a case study approach, 10 focus groups of senior and junior nurses and physicians across four hospitals in Australia were conducted to gain greater insight into the social, professional and cultural factors that mediate the usage of the RRS. Participants' experiences with the RRS were explored from an interprofessional and collective competence perspective. Health professionals' reasons for not activating the RRS included: distinct intraprofessional clinical decision-making pathways; a highly hierarchical pathway in nursing, and a more autonomous pathway in medicine; and interprofessional communication barriers between nursing and medicine when deciding to make and actually making a RRS call. Participants also characterized the RRS as a work-around tool that is utilized when health professionals encounter problematic interprofessional communication. The results can be conceptualized as a form of collective incompetence that have important implications for the design and implementation of interprofessional patient safety initiatives, such as the RRS. PMID- 25431836 TI - Transcriptome sequencing and comparative analysis reveal long-term flowing mechanisms in Hevea brasiliensis latex. AB - BACKGROUND: The rubber tree, Hevea brasiliensis, is a major commercial source of natural rubber. Increasing the rubber yield of rubber trees is a very serious problem since the demands for high quality rubber materials are great. Establishment of a tapping system is based on an estimate of tapping intensity from the rubber tree. Latex flowing time is one of the most critical factors that determine the rubber yield. Long-term flow is a type of phenomenon of the rubber tree latex with longer flowing time than normal latex flow, and is always caused by intensive tapping. Thus, transcriptome and expression profiling data for long term flowing latex (LFL) are needed as an important resource to identify genes and to better understand the biological mechanisms of latex flow in rubber trees. RESULTS: The transcripts were sequenced using the Illumina sequencing platform. After cleaning, quality checks and sequencing, 98,697 transcripts and 38,584 unigenes were assembled with the mean size of 1437.31bp and 923.86bp, respectively. In BLAST searches of our database against public databases, 65.17% (25,147) of the unigenes were annotated with gene descriptions, conserved protein domains, or gene ontology terms. Functional categorization further revealed 853 individual unigenes related to long-term flow. According to KEGG classification, the clusters for "cysteine and methionine metabolism", "energy", "oxidative phosphorylation", "terpenoid backbone biosynthesis", "plant hormone signal transduction" and "copper, potassium transporter" were significantly enriched metabolic pathways. CONCLUSIONS: We conducted high-resolution transcriptome profiling related to LFL in H. brasiliensis. The research facilitates further studies on gene discovery and on the molecular mechanisms related to the estimation of tapping intensity and prolonging latex flowing time. We concluded that it was necessary to improve energy supplies for intensive tapping and the copper ion content of rubber tree latex could be considered as a standard to estimate tapping intensity. PMID- 25431837 TI - Bimetallic cleavage of aromatic C-H bonds by rare-earth-metal complexes. AB - A new type of C-H bond activation mediated by rare-earth metals under reducing conditions is reported. The synergy between reductants and rare-earth-metal complexes allows the cleavage of unactivated aromatic C-H bonds. The reaction between rare-earth-metal iodides supported by a 1,1'-ferrocenediamide ligand and potassium graphite in benzene leads to the formation of a 1:1 metal molar ratio of the corresponding metal hydride and metal phenyl complex. A proposed mechanism involving an inverse sandwich arene bimetallic intermediate is supported by experimental and computational studies. PMID- 25431835 TI - Social consequences of ethanol: Impact of age, stress, and prior history of ethanol exposure. AB - The adolescent period is associated with high significance of interactions with peers, high frequency of stressful situations, and high rates of alcohol use. At least two desired effects of alcohol that may contribute to heavy and problematic drinking during adolescence are its abilities to both facilitate interactions with peers and to alleviate anxiety, perhaps especially anxiety seen in social contexts. Ethanol-induced social facilitation can be seen using a simple model of adolescence in the rat, with normal adolescents, but not their more mature counterparts, demonstrating this ethanol-related social facilitation. Prior repeated stress induces expression of ethanol-induced social facilitation in adults and further enhances socially facilitating effects of ethanol among adolescent rats. In contrast, under normal circumstances, adolescent rats are less sensitive than adults to the social inhibition induced by higher ethanol doses and are insensitive to the socially anxiolytic effects of ethanol. Sensitivity to the socially anxiolytic effects of ethanol can be modified by prior stress or ethanol exposure at both ages. Shortly following repeated restraint or ethanol exposure, adolescents exhibit social anxiety-like behavior, indexed by reduced social preference, and enhanced sensitivity to the socially anxiolytic effects of ethanol, indexed through ethanol-associated reinstatement of social preference in these adolescents. Repeated restraint, but not repeated ethanol, induces similar effects in adults as well, eliciting social anxiety-like behavior and increasing their sensitivity to the socially anxiolytic effects of acute ethanol; the stressor also decreases sensitivity of adults to ethanol induced social inhibition. The persisting consequences of early adolescent ethanol exposure differ from its immediate consequences, with males exposed early in adolescence, but not females or those exposed later in adolescence, showing social anxiety-like behavior when tested in adulthood. Adult males exposed to ethanol early in adolescence also show enhanced sensitivity to the socially facilitating effects of ethanol, whereas adult males exposed to ethanol during late adolescence demonstrate insensitivity to the socially suppressing effects of ethanol. To the extent that these results are applicable to humans, stressful live events may make alcohol more attractive for stressed adolescents and adults due to its socially facilitating and socially anxiolytic properties, therefore fostering high levels of drinking. Retention of adolescent-typical responsiveness to alcohol in adult males following adolescent alcohol exposure, including enhanced sensitivity to the socially facilitating effects of ethanol following early exposure and insensitivity to the socially inhibiting effects following late adolescent exposure, may put these males at risk for the development of alcohol-related disorders later in life. PMID- 25431838 TI - Macrophage CGI-58 deficiency promotes IL-1beta transcription by activating the SOCS3-FOXO1 pathway. AB - Over-nutrition induces low-grade inflammation that dampens insulin sensitivity, but the underlying molecular mediators are not fully understood. Comparative gene identification-58 (CGI-58) is an intracellular lipolytic activator. In the present study, we show that in mouse visceral fat-derived macrophages or human peripheral blood monocytes, CGI-58 negatively and interleukin (IL)-1beta positively correlate with obesity. Saturated non-esterified fatty acid (NEFA) suppresses CGI-58 expression in macrophages and this suppression activates FOXO1 (forkhead box-containing protein O subfamily-1) through inhibition of FOXO1 phosphorylation. Activated FOXO1 binds to an insulin-responsive element in IL 1beta promoter region to potentiate IL-1beta transcription. Gain- and loss-of function studies demonstrate that NEFA-induced CGI-58 suppression activates FOXO1 to augment IL-1beta transcription by dampening insulin signalling through induction of SOCS3 (suppressor of cytokine signalling 3) expression. CGI-58 deficiency-induced SOCS3 expression is NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome-dependent. Our data thus identified a vicious cycle (IL-1beta-SOCS3-FOXO1-IL-1beta) that amplifies IL-1beta secretion and is initiated by CGI-58 deficiency-induced activation of the NLRP3 inflammasome in macrophages. We further show that blocking this cycle with a FOXO1 inhibitor, an antioxidant that inhibits FOXO1 or IL-1 receptor antagonist alleviates chronic inflammation and insulin resistance in high-fat diet (HFD)-fed mice. Collectively, our data suggest that obesity associated factors such as NEFA and lipopolysaccharide (LPS) probably adopt this vicious cycle to promote inflammation and insulin resistance. PMID- 25431839 TI - Role of the blood-brain barrier in multiple sclerosis. AB - Multiple sclerosis (MS) is an autoimmune disease of the central nervous system associated with demyelination and axonal loss eventually leading to neurodegeneration. MS exhibits many of the hallmarks of an inflammatory autoimmune disorder including breakdown of the blood-brain barrier (BBB). The BBB is a complex organization of cerebral endothelial cells, pericytes and their basal lamina, which are surrounded and supported by astrocytes and perivascular macrophages. In pathological conditions, lymphocytes activated in the periphery infiltrate the central nervous system to trigger a local immune response that ultimately damages myelin and axons. Cytotoxic factors including pro-inflammatory cytokines, proteases, and reactive oxygen and nitrogen species accumulate and may contribute to myelin destruction. Dysregulation of the BBB and transendothelial migration of activated leukocytes are among the earliest cerebrovascular abnormalities seen in MS brains and parallel the release of inflammatory cytokines. In this review we establish the importance of the role of the BBB in MS. Improvements in our understanding of molecular mechanism of BBB functioning in physiological and pathological conditions could lead to improvement in the quality of life of MS patients. PMID- 25431840 TI - Excitotoxicity triggered by neonatal monosodium glutamate treatment and blood brain barrier function. AB - It is likely that monosodium glutamate (MSG) is the excitotoxin that has been most commonly employed to characterize the process of excitotoxicity and to improve understanding of the ways that this process is related to several pathological conditions of the central nervous system. Excitotoxicity triggered by neonatal MSG treatment produces a significant pathophysiological impact on adulthood, which could be due to modifications in the blood-brain barrier (BBB) permeability and vice versa. This mini-review analyzes this topic through brief descriptions about excitotoxicity, BBB structure and function, role of the BBB in the regulation of Glu extracellular levels, conditions that promote breakdown of the BBB, and modifications induced by neonatal MSG treatment that could alter the behavior of the BBB. In conclusion, additional studies to better characterize the effects of neonatal MSG treatment on excitatory amino acids transporters, ionic exchangers, and efflux transporters, as well as the role of the signaling pathways mediated by erythropoietin and vascular endothelial growth factor in the cellular elements of the BBB, should be performed to identify the mechanisms underlying the increase in neurovascular permeability associated with excitotoxicity observed in several diseases and studied using neonatal MSG treatment. PMID- 25431841 TI - Particle engineering/different film approaches for earlier absorption of meloxicam. AB - Meloxicam (Mel) is a non-steroidal potent anti-inflammatory drug with effective analgesic effect for various situations; e.g. postoperative pain. The early systemic exposure to Mel and hence the rapid onset of pharmacological action is limited by its poor water solubility; a situation which may be more pronounced during acute pain episode because of reduced gastric motility that affects disintegration and dissolution of solid dosage forms. To overcome delayed absorption of Mel, improvement in the dissolution behavior of Mel is essential. Firstly, Mel spherical crystalline agglomerates (SCA) were prepared. Secondly, selected Mel SCA were integrated into intraoral fast disintegrating (OF) and edible (EF) films, they possess larger surface area that leads to rapid disintegration and release of the drug into the oral cavity within seconds and hence a rapid onset of action could be achieved. Stability study of formulations resulting in faster and higher extent of dissolution and suitable mechanical properties (G3 and G12) revealed their physical and chemical stability after three months of storage under different conditions. Both G3 and G12 successfully offered rapid absorption rate and accordingly an earlier systemic exposure to Mel compared to Mobic tablets as revealed by significantly earlier T max and higher AUC0-0.5h and AUC0-4h. T max following G3 fast disintegrating film administration was comparable to that reported following Mel parenteral administration but avoiding patient inconvenience. Both films may be suitable alternative to conventional oral and intramuscular Mel especially when earlier onset of action is required (in acute conditions). PMID- 25431842 TI - The Covidien LigaSure Maryland Jaw Device. AB - Since its invention nearly 20 years ago, the Covidien LigaSure device along with its ForceTriad generator has dominated the Electrothermal Bipolar Vessel Sealing market. The LigaSure was used for surgical procedures, both open and laparoscopic. The purpose of this review is to provide evidence of the safety and utility of the LigaSure device compared to more traditional means of hemostasis and its ultrasonic competitor, particularly in laparoscopic applications. We will provide evidence related to electrothermal bipolar vessel sealing in general and look specifically at Covidien's newest product, the LigaSure Maryland Jaw Device. PMID- 25431843 TI - Tissue adhesives for closure of surgical incisions. AB - BACKGROUND: Sutures (stitches), staples and adhesive tapes have been used for many years as methods of wound closure, but tissue adhesives have entered clinical practice more recently. Closure of wounds with sutures enables the closure to be meticulous, but the sutures may show tissue reactivity and can require removal. Tissue adhesives offer the advantages of an absence of risk of needlestick injury and no requirement to remove sutures later. Initially, tissue adhesives were used primarily in emergency room settings, but this review looks at the use of tissue adhesives in the operating room/theatre where surgeons are using them increasingly for the closure of surgical skin incisions. OBJECTIVES: To determine the effects of various tissue adhesives compared with conventional skin closure techniques for the closure of surgical wounds. SEARCH METHODS: In March 2014 for this second update we searched the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE and EBSCO CINAHL. We did not restrict the search and study selection with respect to language, date of publication or study setting. SELECTION CRITERIA: Only randomised controlled trials were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We conducted screening of eligible studies, data extraction and risk of bias assessment independently and in duplicate. We expressed results as random-effects models using mean difference for continuous outcomes and risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes. We investigated heterogeneity, including both clinical and methodological factors. MAIN RESULTS: This second update of the review identified 19 additional eligible trials resulting in a total of 33 studies (2793 participants) that met the inclusion criteria. There was low quality evidence that sutures were significantly better than tissue adhesives for reducing the risk of wound breakdown (dehiscence; RR 3.35; 95% CI 1.53 to 7.33; 10 trials, 736 participants that contributed data to the meta-analysis). The number needed to treat for an additional harmful outcome was calculated as 43. For all other outcomes - infection, patient and operator satisfaction and cost - there was no evidence of a difference for either sutures or tissue adhesives. No evidence of differences was found between tissue adhesives and tapes for minimising dehiscence, infection, patients' assessment of cosmetic appearance, patient satisfaction or surgeon satisfaction. However there was evidence in favour of using tape for surgeons' assessment of cosmetic appearance (mean difference (VAS 0 to 100) 9.56 (95% CI 4.74 to 14.37; 2 trials, 139 participants). One trial compared tissue adhesives with a variety of methods of wound closure and found both patients and clinicians were significantly more satisfied with the alternative closure methods than the adhesives. There appeared to be little difference in outcome for different types of tissue adhesives. One study that compared high viscosity with low viscosity adhesives found that high viscosity adhesives were less time-consuming to use than low viscosity tissue adhesives, but the time difference was small. AUTHORS' CONCLUSIONS: Sutures are significantly better than tissue adhesives for minimising dehiscence. In some cases tissue adhesives may be quicker to apply than sutures. Although surgeons may consider the use of tissue adhesives as an alternative to other methods of surgical site closure in the operating theatre, they need to be aware that sutures minimise dehiscence. There is a need for more well designed randomised controlled trials comparing tissue adhesives with alternative methods of closure. These trials should include people whose health may interfere with wound healing and surgical sites of high tension. PMID- 25431844 TI - Conjugated polymer dots-on-electrospun fibers as a fluorescent nanofibrous sensor for nerve gas stimulant. AB - A novel chemical warfare agent sensor based on conjugated polymer dots (CPdots) immobilized on the surface of poly(vinyl alcohol) (PVA)-silica nanofibers was prepared with a dots-on-fibers (DoF) hybrid nanostructure via simple electrospinning and subsequent immobilization processes. We synthesized a polyquinoxaline (PQ)-based CP as a highly emissive sensing probe and employed PVA silica as a host polymer for the elctrospun fibers. It was demonstrated that the CPdots and amine-functionalized electrospun PVA-silica nanofibers interacted via an electrostatic interaction, which was stable under prolonged mechanical force. Because the CPdots were located on the surface of the nanofibers, the highly emissive properties of the CPdots could be maintained and even enhanced, leading to a sensitive turn-off detection protocol for chemical warfare agents. The prepared fluorescent DoF hybrid was quenched in the presence of a chemical warfare agent simulant, due to the electron transfer between the quinoxaline group in the polymer and the organophosphorous simulant. The detection time was almost instantaneous, and a very low limit of detection was observed (~1.25 * 10( 6) M) with selectivity over other organophosphorous compounds. The DoF hybrid nanomaterial can be developed as a rapid, practical, portable, and stable chemical warfare agent-detecting system and, moreover, can find further applications in other sensing systems simply by changing the probe dots immobilized on the surface of nanofibers. PMID- 25431845 TI - Nanoscale phase behavior on flat and curved membranes. AB - The diverse physical properties of membranes play a critical role in many membrane associated biological processes. Proteins responsible for membrane transport can be affected by the lateral membrane order and lateral segregation of proteins is often controlled by the preference of certain membrane anchors for membrane phases having a physically ordered state. The dynamic properties of coexisting membrane phases are often studied by investigating their thermal behavior. Optical trapping of gold nanoparticles is a useful tool to generate local phase transitions in membranes. The high local temperatures surrounding an irradiated gold nanoparticle can be used to melt a part of a giant unilamellar lipid vesicle (GUV) which is then imaged using phase sensitive fluorophores embedded within the bilayer. By local melting of GUVs we reveal how a protein free, one component lipid bilayer can mediate passive transport of fluorescent molecules by localized and transient pore formation. Also, we show how tubular membrane curvatures can be generated by optical pulling from the melted region on the GUV. This will allow us to measure the effect of membrane curvature on the phase transition temperature. PMID- 25431846 TI - Robust detection of minimal sunburn in pigmented skin by 785 nm laser speckle contrast imaging of blood flux. PMID- 25431847 TI - Electrical stimulation enhances epidermal proliferation in human cutaneous wounds by modulating p53-SIVA1 interaction. AB - Cutaneous wounds establish endogenous "wound current" upon injury until re epithelialization is complete. Keratinocyte proliferation, regulated partly by p53, is required for epidermal closure. SIVA1 promotes human double minute 2 homolog (HDM2)-mediated p53 regulation. However, the role of SIVA1 in wound healing is obscure. Here, we report that electrical stimulation (ES) accelerates wound healing by upregulating SIVA1 and its subsequent ability to modulate p53 activities. Cultured donut-shaped human skin explants, subjected to ES, exhibited better epidermal stratification, increased proliferation, and upregulation of gene and protein expression of HDM2/SIVA1, compared with non-ES-treated explants. ES significantly increased in vitro keratinocyte proliferation and phospho-p53 SIVA1 interaction; however, this showed stable expression of phospho-p53, which increased significantly in the absence of SIVA1. Here, HDM2 alone was unable to downregulate nuclear-accumulated phospho-p53, which was evident from decreased proliferation and increased sub-G1 population seen by flow cytometry. Further examination of the epidermis of human cutaneous wounds showed higher p53-SIVA1 coexpression and proliferation 7 days after injury in ES-treated wounds compared with control wounds. In summary, ES-inducible SIVA1 modulates p53 activities in proliferating keratinocytes, and exogenous ES affects p53/HDM2/SIVA1 axis leading to increased proliferation during re-epithelialization. This highlights ES as a potential strategy for enhancing cutaneous repair. PMID- 25431848 TI - Two birds that exclude each other: the Renbok phenomenon. PMID- 25431849 TI - The Tryptophan-Derived Endogenous Aryl Hydrocarbon Receptor Ligand 6 Formylindolo[3,2-b]Carbazole Is a Nanomolar UVA Photosensitizer in Epidermal Keratinocytes. AB - Endogenous UVA chromophores may act as sensitizers of oxidative stress underlying cutaneous photoaging and photocarcinogenesis, but the molecular identity of non DNA key chromophores displaying UVA-driven photodyamic activity in human skin remains largely undefined. Here we report that 6-formylindolo[3,2-b]carbazole (FICZ), a tryptophan photoproduct and endogenous high-affinity aryl hydrocarbon receptor (AhR) agonist, acts as a nanomolar photosensitizer potentiating UVA induced oxidative stress irrespective of AhR ligand activity. In human HaCaT and primary epidermal keratinocytes, photodynamic induction of apoptosis was elicited by the combined action of solar-simulated UVA and FICZ, whereas exposure to the isolated action of UVA or FICZ did not impair viability. In a human epidermal tissue reconstruct, FICZ/UVA cotreatment caused pronounced phototoxicity inducing keratinocyte cell death, and FICZ photodynamic activity was also substantiated in a murine skin exposure model. Array analysis revealed pronounced potentiation of cellular heat shock, endoplasmic reticulum stress, and oxidative stress response gene expression observed only upon FICZ/UVA cotreatment. FICZ photosensitization caused intracellular oxidative stress, and comet analysis revealed introduction of formamidopyrimidine-DNA glycosylase (Fpg)-sensitive oxidative DNA lesions suppressible by antioxidant cotreatment. Taken together, our data demonstrate that the endogenous AhR ligand FICZ displays nanomolar photodynamic activity representing a molecular mechanism of UVA-induced photooxidative stress potentially operative in human skin. PMID- 25431850 TI - Peripheral neuro-immune pathology in recessive dystrophic epidermolysis bullosa. PMID- 25431851 TI - Alpha actinin-1 regulates cell-matrix adhesion organization in keratinocytes: consequences for skin cell motility. AB - The migration of keratinocytes in wound healing requires coordinated activities of the motility machinery of a cell, the cytoskeleton, and matrix adhesions. In this study, we assessed the role of alpha actinin-1 (ACTN1), one of the two alpha actinin isoforms expressed in keratinocytes, in skin cell migration via a small hairpin RNA-mediated knockdown approach. Keratinocytes deficient in ACTN1 exhibit changes in their actin cytoskeleton organization, a loss in front-rear polarity, and impaired lamellipodial dynamics. They also display aberrant directed motility and move slower compared with their wild-type counterparts. Moreover, they have abnormally arranged matrix adhesion sites. Specifically, the focal adhesions in ACTN1 knockdown keratinocytes are not organized as distinct entities. Rather, focal adhesion proteins are arranged in a circle subjacent to cortical fibers of actin. In the same cells, hemidesmosome proteins arrange in cat paw patterns, more typical of confluent, stationary cells, and beta4 integrin dynamics are reduced in knockdown cells compared with control keratinocytes. In summary, our data suggest a mechanism by which ACTN1 determines the motility of keratinocytes by regulating the organization of the actin cytoskeleton, focal adhesion, and hemidesmosome proteins complexes, thereby modulating cell speed, lamellipodial dynamics, and directed migration. PMID- 25431852 TI - Mutation in PIGA results in a CD52-negative escape variant in a Sezary syndrome patient during alemtuzumab treatment. PMID- 25431853 TI - The circadian clock controls sunburn apoptosis and erythema in mouse skin. AB - Epidemiological studies of humans and experimental studies with mouse models suggest that sunburn resulting from exposure to excessive UV light and damage to DNA confers an increased risk for melanoma and non-melanoma skin cancer. Previous reports have shown that both nucleotide excision repair, which is the sole pathway in humans for removing UV photoproducts, and DNA replication are regulated by the circadian clock in mouse skin. Furthermore, the timing of UV exposure during the circadian cycle has been shown to affect skin carcinogenesis in mice. Because sunburn and skin cancer are causally related, we investigated UV induced sunburn apoptosis and erythema in mouse skin as a function of circadian time. Interestingly, we observed that sunburn apoptosis, inflammatory cytokine induction, and erythema were maximal following an acute early-morning exposure to UV and minimal following an afternoon exposure. Early-morning exposure to UV also produced maximal activation of ataxia telangiectasia mutated and Rad3-related (Atr)-mediated DNA damage checkpoint signaling, including activation of the tumor suppressor p53, which is known to control the process of sunburn apoptosis. These data provide early evidence that the circadian clock has an important role in the erythemal response in UV-irradiated skin. The early morning is when DNA repair is at a minimum, and thus the acute responses likely are associated with unrepaired DNA damage. The prior report that mice are more susceptible to skin cancer induction following chronic irradiation in the AM, when p53 levels are maximally induced, is discussed in terms of the mutational inactivation of p53 during chronic irradiation. PMID- 25431854 TI - Real-time imaging of dendritic cell responses to sterile tissue injury. PMID- 25431855 TI - Use of digital media for the education of health professionals in the treatment of childhood asthma. AB - OBJECTIVES: Inhalation therapy is the main treatment for asthma and its adequate use has been a factor responsible for disease control; therefore, the aim of the study was to determine whether a digital media tool, which features portability on mobile phones, modifies the assimilation of the inhalation technique. METHODS: A total of 66 professionals working in the health care area with the pediatric population were selected. They were submitted to a pre-test on their knowledge of inhalation therapy. The professionals were randomized into two groups (A and B). Group A received a media application on their mobile phones showing the steps of inhalation therapy, while group B received the same information in written form only. A post-test was applied after 15 days. The results (pre- and post-) were analyzed by two pediatric pulmonologists. RESULTS: Of the 66 professionals, 87.9% were females. Of a total possible score of ten, the mean score obtained in the pre-test was 5.3 +/- 3, and in the second test, 7.5 +/- 2 (p<0.000). There were no significant differences when comparing the two groups (p=0.726). The nurses had the lowest mean scores in the initial test (2.3 +/- 2); however, they were the group that learned the most with the intervention, showing similar means to those of other groups in the second test (6.1 +/- 3). CONCLUSION: There was significant improvement in knowledge about inhalation therapy in all professional categories using both methods, demonstrating that education, when available to professionals, positively modifies medical practice. PMID- 25431856 TI - Growth of preterm low birth weight infants until 24 months corrected age: effect of maternal hypertension. AB - OBJECTIVE: To evaluate the growth pattern of low birth weight preterm infants born to hypertensive mothers, the occurrence of growth disorders, and risk factors for inadequate growth at 24 months of corrected age (CA). METHODS: Cohort study of preterm low birth weight infants followed until 24 months CA, in a university hospital between January 2009 and December 2010. INCLUSION CRITERIA: gestational age < 37 weeks and birth weight of 1,500-2,499 g. EXCLUSION CRITERIA: multiple pregnancies, major congenital anomalies, and loss to follow up in the 2nd year of life. The following were evaluated: weight, length, and BMI. OUTCOMES: growth failure and risk of overweight at 0, 12, and 24 months CA. Student's t-test, Repeated measures ANOVA (RM-ANOVA), and multiple logistic regression were used. RESULTS: A total of 80 preterm low birth weight infants born to hypertensive mothers and 101 born to normotensive mothers were studied. There was a higher risk of overweight in children of hypertensive mothers at 24 months; however, maternal hypertension was not a risk factor for inadequate growth. Logistic regression showed that being born small for gestational age and inadequate growth in the first 12 months of life were associated with poorer growth at 24 months. CONCLUSION: Preterm low birth weight born infants to hypertensive mothers have an increased risk of overweight at 24 months CA. Being born small for gestational age and inadequate growth in the 1st year of life are risk factors for growth disorders at 24 months CA. PMID- 25431857 TI - Brazilian pediatric research groups, lines of research, and main areas of activity. AB - OBJECTIVES: The Brazilian scientific production in the pediatrics field has been increasing significantly. It is important to identify the distribution and activity of these groups in the country and the main study areas, contributing with data for better resource allocation by institutions. METHODS: An active research was conducted in the National Council of Technological and Scientific Development (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [CNPq]) website, using as filters the macro area of the research group (Health Sciences), the area (Medicine), and descriptors related to pediatrics. Research lines and main area of pediatric research groups were classified according to the subject predominantly studied by each group. The scientific production of the leader of the pediatric research group between 2011 and 2014 was also analyzed. RESULTS: Most pediatric research groups in Brazil have more than five years of activity and are concentrated in the Southeast and South regions of the country; Sao Paulo, Rio Grande do Sul, and Minas Gerais are the states with most groups. Of the 132 specific pediatric research groups analyzed, 14.4% have lines of research in multiple areas and 11.4% in child and adolescent health. Among the 585 lines of research of these groups, the most prevalent areas were: oncology, infectious diseases, epidemiology, and gastroenterology. CONCLUSIONS: The pediatric research groups in Brazil have relevant scientific production, including works published in international publications, and are concentrated in regions with higher socioeconomic index. Most groups registered in CNPq started their activity in the last five years (46%), reflecting the recent growth of scientific production in this area. PMID- 25431858 TI - Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications. AB - Auristatins, synthetic analogues of the antineoplastic natural product Dolastatin 10, are ultrapotent cytotoxic microtubule inhibitors that are clinically used as payloads in antibody-drug conjugates (ADCs). The design and synthesis of several new auristatin analogues with N-terminal modifications that include amino acids with alpha,alpha-disubstituted carbon atoms are described, including the discovery of our lead auristatin, PF-06380101. This modification of the peptide structure is unprecedented and led to analogues with excellent potencies in tumor cell proliferation assays and differential ADME properties when compared to other synthetic auristatin analogues that are used in the preparation of ADCs. In addition, auristatin cocrystal structures with tubulin are being presented that allow for the detailed examination of their binding modes. A surprising finding is that all analyzed analogues have a cis-configuration at the Val-Dil amide bond in their functionally relevant tubulin bound state, whereas in solution this bond is exclusively in the trans-configuration. This remarkable observation shines light onto the preferred binding mode of auristatins and serves as a valuable tool for structure-based drug design. PMID- 25431859 TI - The effect of pregestational diabetes on fetal heart function. AB - Pregestational diabetes affects nearly 2% of all pregnancies. Moreover, Type 2 diabetes in child-bearing women is on the rise because of the childhood obesity epidemic. Pregestational diabetes can affect the fetal heart in several ways. First, the risk of fetal congenital heart disease is markedly increased; second, fetal hypertrophic cardiomyopathy may occur even with good glycemic control; third, studies have shown impaired function of the hearts of some infants and fetuses of diabetic pregnancies, which can occur with and without septal hypertrophy. Small-for-gestational-age infants of diabetic mothers may have diminished cardiovascular health in the long term. This review mainly discusses methods to detect fetal diabetic cardiomyopathy prenatally. The focus is on the noninvasive diagnostic markers that can serve as an outcome measure for future therapeutic trials, which are still lacking. There is some experimental research on treatment strategies to prevent fetal heart disease in diabetic pregnancies but little clinical data. PMID- 25431860 TI - Solid/liquid phase diagram of the ammonium sulfate/succinic acid/water system. AB - We have studied the low-temperature phase diagram and water activities of the ammonium sulfate/succinic acid/water system using differential scanning calorimetry and infrared spectroscopy of thin films. Using the results from our experiments, we have mapped the solid/liquid ternary phase diagram, determined the water activities based on the freezing point depression, and determined the ice/succinic acid phase boundary as well as the ternary eutectic composition and temperature. We also compared our results to the predictions of the extended AIM aerosol thermodynamics model (E-AIM) and found good agreement for the ice melting points in the ice primary phase field of this system; however, differences were found with respect to succinic acid solubility temperatures. We also compared the results of this study with those of previous studies that we have published on ammonium sulfate/dicarboxylic acid/water systems. PMID- 25431862 TI - [The 50th Publication Anniversary of the GPOH Biannual Conference in Clinical Pediatrics]. PMID- 25431863 TI - Increased relapse rates in early stage hodgkin lymphoma (HL) patients without radiotherapy: the German Society of Radiooncology (DEGRO) advises to treat all early stage HL patients with radiotherapy. PMID- 25431864 TI - Testicular germ cell tumors in adolescents - results of the protocol MAHO 98 and the identification of good risk patients. AB - BACKGROUND: In adolescents aged 10-15 years germ cell tumors of the testis (TGCT) are rare and information for a risk adapted therapy limited. AIMS OF THE STUDY: The protocol MAHO 98 for patients (pts) with TGCTs is stratified according to age, stage and histology. Pts >= 10 years received after tumororchiectomy 2 courses (crs) PVB and restaging. Residual tumor was resected and therapy continued in regard to inital stage and response. Chemotherapy: PVB: cisplatin (20 mg/m2/day 1-5), vinblastine (3 mg/m2/day 1+2), and bleomycin (15 U/m2/day 1 3). For consolidation 1 crs PVB has been given to stage II patients with CR. In case of PR, 2 crs PEB (vinblastine substituted by etoposide 100 mg/m2/day 1-3) or relapse 3 crs PEI (bleomycin substituted by ifosfamide 1 500 mg/m2/day 1-5) were given. RESULTS: Between Jan 1998 and Dec 2005, 34 pts (>= 10 year) were registered, 31 fulfilled the inclusion criteria. Median age: 15;6 years; months (range 13;5-20;2 ). Lugano staging: IA n=14, IB n=2, IC n=3, IIA n=4, IIB n=6, IIC n=1, IIIC n=1. The stage IIIC pt received preoperative chemotherapy, all other pts had tumororchiectomy first. Residual tumor after 2 crs PVB was detected in 4 pts and was resected. Late relapses occurred in 2 pts and were cured by additional therapy. All patients are surviving. CONCLUSION: Young patients with TGCT stage I and II have an excellent prognosis and further reduction of therapy has to be considered. PMID- 25431865 TI - Re-induction with L-DNR/FLAG improves response after AML relapse, but not long term survival. AB - BACKGROUND: According to the results of the international study Relapsed AML 2001/01 response was better after re-induction with L-DNR/FLAG (liposomal daunorubicin, fludarabine, cytarabine, G-CSF) compared to FLAG only but survival rate was not improved. However, the findings might be group-specific. METHOD: Patient characteristics, actual therapy given and long-term course of the disease in 155 pediatric patients (including non-randomized) with first relapse and 10 primary nonresponders treated in Germany were analyzed. RESULTS: Overall 4-year survival rates after relapse were similar in the 2 treatment groups L-DNR/FLAG and FLAG (0.43 +/- 0.05 vs. 0.47 +/- 0.06, p(log-rank)=0.47). The rate of randomization was low (65%) and 5% of the 101 randomized patients changed the treatment arm. Therefore, induction was based in 40% patients on an individual decision with preference for L-DNR/FLAG. There were less patients with favorable cytogenetics and morphology in the L-DNR/FLAG-group (p<0.04). Response to the first re-induction course at day 28 tended to be more unfavorable with FLAG only. In this patient group protocol intensifications were more frequent as compared to the L-DNR/FLAG-group (p=0.07), and late CR could be achieved after intensification in 9/18 poor responding patients. CONCLUSION: The initial selection bias of relapse patients with unfavorable risk factors to the disadvantage of the L-DNR/FLAG-group and the more drug- and time-intensive treatment after 1(st) re-induction given in the FLAG-group may have nullified the initial beneficial effect of L-DNR containing re-induction therapy and led to similar and relatively favorable survival rates in both treatment groups in Germany. PMID- 25431866 TI - Minimal residual disease-based treatment is adequate for relapse-prone childhood acute lymphoblastic leukemia with an intrachromosomal amplification of chromosome 21: the experience of the ALL-BFM 2000 trial. AB - BACKGROUND: Recently, the UK CCLG and COG reported that an intrachromosomal amplification of chromosome 21 (iAMP21) in acute lymphoblastic leukemia (ALL) loses its adverse prognostic impact with intensified therapy. PATIENT AND METHODS: We evaluated the prognosis of iAMP21 among patients from the ALL-BFM (Berlin-Frankfurt-Munster) 2000 trial with 46 of 2 637 (2%) patients iAMP21+. RESULTS: 8-year event-free-survival (EFS, 64 +/- 8% vs. 81 +/- 1%, p=0.0026) and cumulative incidence of relapse (CIR, 29 +/- 8% vs. 14 +/- 1%, p=0.008) of the iAMP21 cases were significantly worse compared with non-iAMP21 patients. Within the MRD low-risk group, iAMP21 cases (n=14) had an inferior 8-year EFS (76 +/- 12% vs. 92 +/- 1%, p=0.0081), but no increased CIR (10 +/- 10% vs. 6 +/- 1%, p=0.624). Within the MRD intermediate-risk group, iAMP21 cases (n=27) had a worse 8-year EFS (56 +/- 11% vs. 78 +/- 2%, p=0.0077) and CIR (44 +/- 11% vs. 20 +/- 2%, p=0.003) with 6/10 relapses occurring after 2 years. CONCLUSIONS: Conclusively, we believe that there is no necessity for enrolling all iAMP21 patients into the high-risk arm of ongoing ALL-BFM trials because MRD low-risk patients have a moderate relapse risk under current therapy. Whether the increased relapse risk in MRD intermediate-risk patients can be avoided by late treatment intensification remains to be answered by the AIEOP-BFM ALL 2009 trial randomly using protracted pegylated L-asparaginase during delayed intensification and early maintenance. PMID- 25431867 TI - [Childhood craniopharyngioma with hypothalamic obesity - no long-term weight reduction due to rehabilitation programs]. AB - BACKGROUND: Severe obesity due to hypothalamic involvement has major impact on prognosis in long-term survivors of childhood craniopharyngioma. The long-term effects of rehabilitation efforts on weight development and obesity in these patients are not analyzed up to now. PATIENTS AND METHODS: 108 patients with childhood craniopharyngioma recruited in HIT Endo before 2001 were included in the study. Long-term weight development (BMI SDS after >10 yrs follow-up) was analyzed in regard to rehabilitation, which was performed in 31 of 108 (29%) patients (one rehabilitation in 4 patients (13%), more than one in 21 patients (68%), 6 patients unknown) in 13 German rehabilitation -clinics. RESULTS: 84% of patients underwent rehabilitation in order to reduce hypothalamic obesity (BMI>+ 2 SD), whereas 12% of patients were normal weight. Childhood craniopharyngioma pa tients with rehabilitation presented with higher BMI at diagnosis (median BMI: +1.32 SD; range: -1.08 to + 7.00 SD) and at last evaluation (median BMI: +4.93 SD; range: -0.20 to + 13.13 SD) when compared with patients without rehabilitation (median BMI at diagnosis: +0.24 SD; range: -2.67 to + 6.98 SD; BMI at evaluation: +2.09 SD; range: -1.48 to + 10.23 SD). A long-term weight reducing effect of rehabilitation was no detectable regardless of degree of obesity, frequency of rehabilitation, and hospital of rehabilitation. CONCLUSION: Treatment options for hypothalamic obesity in terms of rehabilitation are limited. Accordingly, strategies for prevention of hypothalamic lesions and psychosocial effects of rehabilitation are currently in focus for improvement of prognosis in childhood craniopharyngioma patients. PMID- 25431868 TI - Children with relapsed or refractory nephroblastoma: favorable long-term survival after high-dose chemotherapy and autologous stem cell transplantation. AB - BACKGROUND: High-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) is a treatment option for pediatric patients with relapsed nephroblastoma. We present long term results of 9 patients treated between 1993 and 2013 at our center. PROCEDURE: Reinduction therapy was carried out according to GPOH and SIOP recommendations. The conditioning regimen consisted of carboplatin (1 200 mg/m2), etoposide (800 mg/m2 or 40 mg/kg) and melphalan (180 mg/m2). Purging of the grafts with immunomagnetic CD34 positive selection was performed in 5 patients. RESULTS: 8 of 9 Patients (90%) are alive without evidence of disease after a median follow-up of 8.5 years. Leukocyte engraftment occurred after a median of 10 days (range 8-12). Median numbers of 667/ul CD3+, 329/ul CD4+, 369/ul CD8+T cells and 949/ul B cells were reached after 180 days. No negative impact of CD34 selection was observed. No transplantation-related death occurred. Acute toxicity comprised mucositis III degrees -IV degrees in all and veno-occlusive disease in one patient. Long term effects probably related to treatment occurred in 3/7 evaluable patients and comprised hearing impairment, reduced renal phosphate reabsorption, mild creatinine elevation and hypothyroidism (n=1, each). CONCLUSION: Thus, in our experience HDC with ASCR is an effective treatment of recurrent or refractory nephroblastoma with acceptable side effects. However, a randomized trial proving its efficiency with a high level of evidence is needed. PMID- 25431869 TI - Constitutional mismatch repair-deficiency and whole-exome sequencing as the means of the rapid detection of the causative MSH6 defect. AB - BACKGROUND: Cases of children with more than one type of cancer either diagnosed simultaneously or successively, rarely occur in pediatric oncology. A second malignant neoplasm may be caused by mutagenic effects of the treatment of the primary malignancy and/or may point towards an underlying genetic cancer susceptibility syndrome. One example of such a syndrome is constitutional mismatch repair-deficiency, (CMMR-D) which carries an increased risk of various tumors including childhood hematologic malignancies and Lynch syndrome associated tumors. Timely diagnosis of CMMR-D is crucial, since this diagnosis has implications for the entire family. PATIENT: We report the case of a 15-year-old girl who was born to consanguineous parents. At the age of 20 months she was diagnosed with a T-cell non-Hodgkin lymphoma. Treatment was given according to NHL-BFM 95. 12 years later, an invasive adenocarcinoma of the colon was surgically removed which relapsed shortly afterwards. METHODS: Whole-exome sequencing of germline DNA was employed to rapidly detect the underlying mutation in this suspected CMMR-D patient. RESULTS: After a short turnaround time of less than 3 weeks, the diagnosis of CMMR-D could be confirmed by the identification of a homozygous 29-bp deletion in MSH6 (exon 6), which was confirmed by independent methods. CONCLUSIONS: We demonstrate that "bed-side" whole-exome sequencing is both feasible and cost-effective and may be the method of choice to rapidly uncover the genetical basis of (inherited) diseases. PMID- 25431870 TI - A massive intestinal vaso-occlusive crisis or "girdle syndrome" in a 6-year-old boy observed as a first manifestation of sickle cell disease. AB - Sickle cell disease is a chronic hematologic disease with variable but often severe systemic symptoms. In this report, we describe a 6-year-old boy presenting with acute bowel pseudo-obstruction. During this episode, previously undiagnosed sickle cell disease was discovered upon peripheral blood smear analysis. The condition was therefore interpreted as a massive intestinal vaso-occlusive crisis or "girdle syndrome". Conservative treatment with hydration therapy, analgesia and a manual partial exchange transfusion was initiated. The patient fully recovered within 5 days. CONCLUSION: Girdle syndrome is a rare but severe adverse event associated with sickle cell disease that must be considered as differential diagnosis in patients with sickle cell disease. PMID- 25431871 TI - Papillary thyroid carcinoma in an adolescent girl with graves' disease. PMID- 25431872 TI - [Germline mutations in children with cancer - leopoldina meeting report, september 26, 2014, jesuit monastery merzhausen]. AB - Under the umbrella of the Leopoldina, National Academy of Science Germany, a one day workshop took place with experts from Pediatric Oncology, Human Genetics, Jurisprudence and Science Ethics. Professor Dr. Matthias Brandis, former head of the Clinic of Pediatrics and Adolescent Medicine, Albert-Ludwigs-University Freiburg, encouraged the authors to organize this workshop near Freiburg and provided professional and logistic support. Professor Dr. Matthias Brandis serves as the chairmen of our pediatric-gynecological section within the Leopoldina. PMID- 25431873 TI - Summary of presentations from the International Workshop on Antiviral Drug Resistance: Meeting the Global Challenge, 3-7 June 2014, Berlin, Germany. PMID- 25431874 TI - Are biophilic-designed site office buildings linked to health benefits and high performing occupants? AB - This paper discusses the first phase of a longitudinal study underway in Australia to ascertain the broad health benefits of specific types of biophilic design for workers in a building site office. A bespoke site design was formulated to include open plan workspace, natural lighting, ventilation, significant plants, prospect and views, recycled materials and use of non synthetic materials. Initial data in the first three months was gathered from a series of demographic questions and from interviews and observations of site workers. Preliminary data indicates a strong positive effect from incorporating aspects of biophilic design to boost productivity, ameliorate stress, enhance well-being, foster a collaborative work environment and promote workplace satisfaction, thus contributing towards a high performance workspace. The longitudinal study spanning over two years will track human-plant interactions in a biophilic influenced space, whilst also assessing the concomitant cognitive, social, psychological and physical health benefits for workers. PMID- 25431875 TI - Patient-reported outcome measures and risk factors in a quality registry: a basis for more patient-centered diabetes care in Sweden. AB - Diabetes is one of the chronic diseases that constitute the greatest disease burden in the world. The Swedish National Diabetes Register is an essential part of the diabetes care system. Currently it mainly records clinical outcomes, but here we describe how it has started to collect patient-reported outcome measures, complementing the standard registry data on clinical outcomes as a basis for evaluating diabetes care. Our aims were to develop a questionnaire to measure patient abilities and judgments of their experience of diabetes care, to describe a Swedish diabetes patient sample in terms of their abilities, judgments, and risk factors, and to characterize groups of patients with a need for improvement. Patient abilities and judgments were estimated using item response theory. Analyzing them together with standard risk factors for diabetes comorbidities showed that the different types of data describe different aspects of a patient's situation. These aspects occasionally overlap, but not in any particularly useful way. They both provide important information to decision makers, and neither is necessarily more relevant than the other. Both should therefore be considered, to achieve a more complete evaluation of diabetes care and to promote person centered care. PMID- 25431876 TI - Oral health behaviour and social and health factors in university students from 26 low, middle and high income countries. AB - Poor oral health is still a major burden for populations throughout the world, particularly in developing countries. The aim of this study was investigate oral health behaviour (tooth brushing and dental attendance) and associated factors in low, middle and high income countries. Using anonymous questionnaires, data were collected from 19,560 undergraduate university students (mean age 20.8, SD = 2.8) from 27 universities in 26 countries across Asia, Africa and the Americas. Results indicate that 67.2% of students reported to brush their teeth twice or more times a day, 28.8% about once a day and 4.0% never. Regarding dental check up visit, 16.3% reported twice a year, 25.6% once a year, 33.9% rarely and 24.3% never. In a multivariate logistic regression analysis, being a male, coming from a wealthy or quite well off family background, living in low income or lower middle income, weak beliefs in the importance of regular tooth brushing, depression and PTSD symptoms, tobacco use and frequent gambling, low physical activity, and low daily meal and snacks frequency were associated with inadequate tooth brushing ( Tc) is transformed into a dielectric relaxation dominated by the diffusion of intrinsic ionic H3O(+)/OH(-) defects (at low temperature, T < Tc). In the framework of the model, we propose an analytical equation for the complex dielectric permittivity that takes into account the contribution of both types of defects. PMID- 25431878 TI - Exercise attenuates the major hallmarks of aging. AB - Regular exercise has multi-system anti-aging effects. Here we summarize how exercise impacts the major hallmarks of aging. We propose that, besides searching for novel pharmaceutical targets of the aging process, more research efforts should be devoted to gaining insights into the molecular mediators of the benefits of exercise and to implement effective exercise interventions for elderly people. PMID- 25431890 TI - Imaging features of primary and metastatic extremity synovial sarcoma: a single institute experience of 78 patients. AB - OBJECTIVE: To study the appearance of primary and metastatic extremity synovial sarcoma (SS) on cross-sectional imaging. METHODS: In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study, the imaging features of 78 patients (42 males and 36 females; mean age, 40 years) with primary and metastatic extremity SS on MRI and multidetector CT were reviewed, with baseline MRI of the primary available in 31 patients. RESULTS: Primary SSs were predominantly well-circumscribed (27/31) and heterogeneously enhancing solid (18/31) or solid-cystic (13/31) tumours. Imaging features visualized included the presence of perilesional oedema (14/31), interfascial (15/31) and intercompartmental extension (7/31), triple sign (11/31), intratumoral haemorrhage (10/31), calcification (6/31), bowl of grapes appearance (5/31) and bone involvement (3/31). Smaller T1 stage tumours (8/31) appeared as heterogeneously enhancing lesions, with some lesions demonstrating interfascial and intercompartmental extension and perilesional oedema. Recurrent/metastatic disease developed in 49/78 (63%) patients. Of these, 20/78 (26%) had metastasis at presentation, while the remaining developed metastatic disease at a median interval of 27 months (range, 3-161 months). Pleuropulmonary metastases (46/78) were the most common sites, with most of the metastases being pleural based. On univariate analysis, larger tumour size, the presence of perilesional oedema, intercompartmental extension, the presence of intralesional haemorrhage and bowl of grapes appearance on MRI were associated with a significantly higher incidence of metastatic disease. CONCLUSION: Certain imaging features of primary SS predict the risk of development of metastatic disease. Imaging features of T1 stage tumours included heterogeneous enhancement, interfascial extension and perilesional oedema. Pleural-based metastases are commonly seen in SSs. ADVANCES IN KNOWLEDGE: Imaging features of primary SS correlate with metastatic disease. Pleural-based metastases are often present in SSs. PMID- 25431891 TI - Mutation analysis and prenatal diagnosis in a Chinese family with succinic semialdehyde dehydrogenase and a systematic review of the literature of reported ALDH5A1 mutations. AB - AIMS: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a neurometabolic disease in which the degradation of gamma-aminobutyric acid (GABA) is impaired. The purpose of this study was to report two novel ALDH5A1 mutations responsible for SSADH deficiency in a Chinese family and the prenatal diagnosis of an at-risk fetus with DNA sequencing. RESULTS: Genetic analysis of ALDH5A1, in a child with SSADH deficiency, parents, and 10 weeks' gestation at-risk fetus and 100 healthy unrelated volunteers, was performed. The coding sequence and the intron/exon junctions of ALDH5A1 were analyzed by bidirectional DNA sequencing. The proband was identified to have a compound heterozygous mutations with c.496T>C (p.W166R) and c.589G>A (p.V197M). Each of his parents carried a deleterious mutation. DNA sequencing of chorionic villus revealed the fetus was a carrier, but not affected, and this was confirmed after birth by genetic analysis of umbilical cord blood and urine organic acid analysis. A study in 2003 described 35 mutations of ALDH5A1 in 54 unrelated families, and the current study and systematic literature review identified nine additional novel mutations in eight unrelated families bringing the total number of unique mutations of ALDH5A1 resulting in SSADH deficiency to 44, and the 44 mutations occur from exon 1 to exon 10. No mutational hotspots or prevalent mutations were observed, and all mutations appeared vital for the function of SSADH. CONCLUSIONS: Two novel ALDH5A1 mutations likely responsible for SSADH deficiency were identified, and DNA sequencing provided an accurate diagnosis for an at-risk fetus whose sibling had SSADH deficiency. PMID- 25431892 TI - Suicide risk assessment: searching for true positive. AB - Suicide is a major public health problem and the 10th leading cause of death in the United States. Due to low base rates and the numerous comorbid risk factors associated with suicide, accurate prediction is difficult. This is particularly true for adolescents and young adults. In this article, some associated risk factors are discussed in the context of two high-risk populations (young adult prison inmates and young adult veterans) and several recommendations are made for conducting suicide risk assesments. General prescriptions for intervention are also outlined with the goal of reducing overly defensive practice and increasing the likelihood that high-risk individuals will receive effective intervention. Finally, several suggestions for future research are made. PMID- 25431894 TI - Fletching-shaped Bi4Te3-ZnTe heterostructure nanowires. AB - We investigated Bi(4)Te(3)-ZnTe axial heterostructure nanowires grown by physical vapor transport at the substrate temperature of 450 degrees C, utilizing ZnTe as the source and Bi(2)Te(3) as the catalyst. The temperatures of the source and catalyst materials were individually controlled by separating the source and catalyst boats. The axial heterostructure nanowires consisted of ZnTe and Bi(4)Te(3) segments. The Bi(4)Te(3) segment had an interesting fletching shape with three wings surrounded by a ZnO shell. A systematic redshift in the nanowire's photoluminescence was observed as the excitation laser spot was moved from the heterojunction toward the root of the ZnTe segment, attributed to the formation of deep defect states under the Te-rich environment that resulted from using Bi(2)Te(3) as the catalyst instead of Bi. PMID- 25431895 TI - Enhanced cellular delivery and biocompatibility of a small layered double hydroxide-liposome composite system. AB - The various classes of gene delivery vectors possess distinct advantages and disadvantages, each of which impacts on cargo loading, delivery and, ultimately, its function. With this in mind, herein we report on a small layered double hydroxide (sLDH)-liposome composite system, drawing upon the salient features of LDH and liposome classes of vectors, while avoiding their inherent shortfalls when used independently. sLDH-liposome composites were prepared by the hydration of freeze-dried matrix method. These composite systems, with a Z-average size of ~200 nm, exhibited low cytotoxicity and demonstrated good suspension stability, both in water and cell culture medium after rehydration. Our studies demonstrate that short dsDNAs/ssDNAs were completely bound and protected in the composite system at an sLDH:DNA mass ratio of 20:1, regardless of the approach to DNA loading. This composite system delivered DNA to HCT-116 cells with ~3-fold greater efficiency, when compared to sLDH alone. Our findings point towards the sLDH-liposome composite system being an effective and biocompatible gene delivery system. PMID- 25431896 TI - Intracranial epidural empyema due to Cryptococcus neoformans in a 5-year-old neutered male European short hair cat. PMID- 25431897 TI - Spatial resolution in thin film deposition on silicon surfaces by combining silylation and UV/ozonolysis. AB - A simple procedure has been developed for the processing of silicon wafers in order to facilitate the spatially resolved growth of thin solid films on their surfaces. Specifically, a combination of silylation and UV/ozonolysis was tested as a way to control the concentration of the surface hydroxo groups required for subsequent atomic layer deposition (ALD) of metals or oxides. Water contact angle measurements were used to evaluate the hydrophilicity/hydrophobicity of the surface, a proxy for OH surface coverage, and to optimize the UV/ozonolysis treatment. Silylation with hexamethyldisilazane, trichloro(octadecyl)silane, or trimethylchlorosilane was found to be an efficient way to block the hydroxo sites and to passivate the underlying surface, and UV/O3 treatments were shown to effectively remove the silylation layer and to regain the surface reactivity. Both O3 and 185 nm UV radiation were determined necessary for the removal of the silylation layer, and additional 254 nm radiation was found to enhance the process. Attenuated total reflection-infrared absorption spectroscopy was employed to assess the success of the silylation and UV/O3 removal steps, and atomic force microscopy data provided evidence for the retention of the original smoothness of the surface. Selective growth of HfO2 films via TDMAHf + H2O ALD was seen only on the UV/O3 treated surfaces; total inhibition of the deposition was observed on the untreated silylated surfaces (as determined by x-ray photoelectron spectroscopy and ellipsometry). Residual film growth was still detected on the latter if the ALD was carried out at high temperatures (250 degrees C), because the silylation layer deteriorates under such harsh conditions and forms surface defects that act as nucleation sites for the growth of oxide grains (as identified by electron microscopy and scanning electron microscopy). We believe that the silylation-UV/O3 procedure advanced here could be easily implemented for the patterning of surfaces in many microelectronic applications. PMID- 25431893 TI - Pharmacogenetics of drug-metabolizing enzymes in US Hispanics. AB - Although the Hispanic population is continuously growing in the United States, they are underrepresented in pharmacogenetic studies. This review addresses the need for compiling available pharmacogenetic data in US Hispanics, discussing the prevalence of clinically relevant polymorphisms in pharmacogenes encoding for drug-metabolizing enzymes. CYP3A5*3 (0.245-0.867) showed the largest frequency in a US Hispanic population. A higher prevalence of CYP2C9*3, CYP2C19*4, and UGT2B7 IVS1+985 A>G was observed in US Hispanic vs. non-Hispanic populations. We found interethnic and intraethnic variability in frequencies of genetic polymorphisms for metabolizing enzymes, which highlights the need to define the ancestries of participants in pharmacogenetic studies. New approaches should be integrated in experimental designs to gain knowledge about the clinical relevance of the unique combination of genetic variants occurring in this admixed population. Ethnic subgroups in the US Hispanic population may harbor variants that might be part of multiple causative loci or in linkage-disequilibrium with functional variants. Pharmacogenetic studies in Hispanics should not be limited to ascertain commonly studied polymorphisms that were originally identified in their parental populations. The success of the Personalized Medicine paradigm will depend on recognizing genetic diversity between and within US Hispanics and the uniqueness of their genetic backgrounds. PMID- 25431898 TI - The multidisciplinary approach to the treatment of rectal cancer: 2015 update. AB - The multidisciplinary approach to the management of rectal cancer continues to evolve with developments in surgery, radiation therapy as well as systemic chemotherapy. Refinement of surgical techniques to improve organ preservation, selective use of neoadjuvant (or adjuvant) therapies, improvements in staging modalities and emerging criteria for the selection of tailored therapies are some of the advancements made over the last three decades. In addition, neoadjuvant treatment alternatives, multimodality sequencing and adaptive therapies based on treatment response continue to be a subject of clinical investigation. The current article reviews the salient topics related to the multidisciplinary treatment of resectable rectal cancer. PMID- 25431899 TI - Volumetric brain analysis in neurosurgery: Part 3. Volumetric CT analysis as a predictor of seizure outcome following temporal lobectomy. AB - OBJECT: The incidence of temporal lobe epilepsy (TLE) due to mesial temporal sclerosis (MTS) can be high in developing countries. Current diagnosis of MTS relies on structural MRI, which is generally unavailable in developing world settings. Given widespread effects on temporal lobe structure beyond hippocampal atrophy in TLE, the authors propose that CT volumetric analysis can be used in patient selection to help predict outcomes following resection. METHODS: Ten pediatric patients received preoperative CT scans and temporal resections at the CURE Children's Hospital of Uganda. Engel classification of seizure control was determined 12 months postoperatively. Temporal lobe volumes were measured from CT and from normative MR images using the Cavalieri method. Whole brain and fluid volumes were measured using particle filter segmentation. Linear discrimination analysis (LDA) was used to classify seizure outcome by temporal lobe volumes and normalized brain volume. RESULTS: Epilepsy patients showed normal to small brain volumes and small temporal lobes bilaterally. A multivariate measure of the volume of each temporal lobe separated patients who were seizure free (Engel Class IA) from those with incomplete seizure control (Engel Class IB/IIB) with LDA (p<0.01). Temporal lobe volumes also separate normal subjects, patients with Engel Class IA outcomes, and patients with Class IB/IIB outcomes (p<0.01). Additionally, the authors demonstrated that age-normalized whole brain volume, in combination with temporal lobe volumes, may further improve outcome prediction (p<0.01). CONCLUSIONS: This study shows strong evidence that temporal lobe and brain volume can be predictive of seizure outcome following temporal lobe resection, and that volumetric CT analysis of the temporal lobe may be feasible in lieu of structural MRI when the latter is unavailable. Furthermore, since the authors' methods are modality independent, these findings suggest that temporal lobe and normative brain volumes may further be useful in the selection of patients for temporal lobe resection when structural MRI is available. PMID- 25431900 TI - Internal carotid artery surgical revascularization in a pediatric patient with Schimke immuno-osseous dysplasia. AB - Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, episodic lymphopenia, renal failure, and cerebrovascular disease secondary to arteriosclerosis and myointimal hyperplasia. In this paper the authors report the first known application of internal carotid artery (ICA) surgical revascularization to relieve a high-grade focal stenosis of the ICA in a pediatric patient, a 6-year-old boy with SIOD. The clinical presentation, imaging features, operative technique, and postoperative course are described and the molecular genetics, pathophysiology, and treatment considerations in SIOD are discussed. PMID- 25431901 TI - Volumetric brain analysis in neurosurgery: Part 2. Brain and CSF volumes discriminate neurocognitive outcomes in hydrocephalus. AB - OBJECT: The evaluation of hydrocephalus remains focused on ventricular size, yet the goal of treatment is to allow for healthy brain development. It is likely that brain volume is more related to cognitive development than is fluid volume in children with hydrocephalus. This study tests this hypothesis by comparing brain and fluid volumes with neurocognitive outcome in pediatric patients with hydrocephalus. METHODS: Warf and colleagues previously acquired CT scans for pediatric patients in Uganda with myelomeningocele, measured frontal-occipital horn ratio (FOHR), and administered the modified Bayley Scales of Infant Development, third edition (BSID-III) to measure neurocognitive outcome that did not correlate with FOHR. In this present study, brain and fluid volumes were measured in 33 of these patients, 26 of whom required surgical treatment for hydrocephalus. Linear discrimination analysis (LDA) was used to test whether age normalized brain and fluid volumes can discriminate neurocognitive outcome. RESULTS: Hydrocephalic patients show normal to small brain volumes and substantially larger fluid volumes compared with normal values. FOHR correlates highly with fluid volume (r=0.84, p<0.001) and substantially less with brain volume (r=-0.37, p=0.03), while brain and fluid volumes do not correlate with each other (p=0.99). Brain and CSF volumes correlated best with fine motor (p=0.03, p=0.01), cognitive (p=0.05, p=0.09), and expressive communication (p=0.08, p=0.08) scores. A combination of these 3 scores was used as a multivariate measure of neurocognitive outcome. Brain volume alone, unlike fluid volume, could discriminate high from low cognitive outcome (by t-test and ANOVA). It was shown that a combination of age-normalized brain and fluid volumes can discriminate neurocognitive outcome by 2-way LDA (p<0.01) and 3-way LDA (p<0.01). The multivariate LDA demonstrated the contribution of large fluid volume to a decrement in cognition. CONCLUSIONS: Hydrocephalus is treated by normalizing CSF, but normal brain development depends on brain growth. A combination of brain and CSF volumes appears to be significantly more powerful at predicting good versus poor neurocognitive outcomes in patients with hydrocephalus than either volume alone. PMID- 25431902 TI - Volumetric brain analysis in neurosurgery: Part 1. Particle filter segmentation of brain and cerebrospinal fluid growth dynamics from MRI and CT images. AB - OBJECT: Accurate edge tracing segmentation remains an incompletely solved problem in brain image analysis. The authors propose a novel algorithm using a particle filter to follow the boundary of the brain in the style often used in autonomous air and ground vehicle navigation. Their goals were to create a versatile tool to segment brain and fluid in MRI and CT images of the developing brain, lay the foundation for an intelligent automated edge tracker that is modality independent, and segment normative data from MRI that can be applied to both MRI and CT. METHODS: Simulated MRI data sets were used to train and evaluate the particle filter segmentation algorithm. The method was then applied to produce normative growth curves for children and adolescents from 0 to 18 years of age for brain and fluid from MR images from the National Institutes of Health pediatric database and these data were compared to historical results. The authors further adapted this method for use with CT images of pediatric hydrocephalus and compared the results with hand-segmented data. RESULTS: Segmentation of simulated MRI data with varied levels of noise (0%-9%) and spatial inhomogeneity (0%-40%) resulted in percent errors ranging from 0.06% to 5.38% for brain volume and 2.45% to 22.3% for fluid volume. The authors used this tool to create normal brain and CSF growth curves from MR images. The calculated growth curves showed excellent consistency with historical data. Additionally, compared with manual segmentation the particle filter accurately segmented brain and fluid volumes from CT scans of 5 pediatric patients with hydrocephalus (p<0.001). CONCLUSIONS: The authors have produced the first normative brain and CSF growth curves for children and adolescents 0-18 years of age. In addition, this study includes the first use of a particle filter as an edge tracker in image segmentation and offers a semiautomatic method to segment both pediatric and adult brain data from MR and CT images. The particle filter has the potential to be further automated toward a clinical rather than research tool with both of these modalities. Because of its modality independence, it has the capability to allow CT to be a more effective diagnostic tool for neurological disorders, a task of substantial importance in emergency settings and in developing countries where CT is often the only available method of brain imaging. PMID- 25431903 TI - Bacteria causing ventriculoperitoneal shunt infections in a Kenyan population. AB - OBJECT: Ventriculoperitoneal shunt (VPS) infections are a major cause of morbidity and mortality in patients with hydrocephalus. Most data about these infections come from the Western literature. Few data about infecting organisms in Africa are available, yet knowledge of these organisms is important for the prevention and treatment of infectious complications. The purpose of this study was to determine the organisms cultured from infected shunts in a rural Kenyan hospital. METHODS: The authors conducted a retrospective study of patients with VPS infections recorded in the neurosurgical database of BethanyKids at Kijabe Hospital between September 2010 and July 2012. RESULTS: Among 53 VPS infections confirmed by culture, 68% occurred in patients who were younger than 6 months. Seventy-nine percent of the infections occurred within 2 months after shunt insertion. Only 51% of infections were caused by Staphylococcus species (Staphylococcus aureus 25%, other Staphylococcus species 26%), whereas 40% were caused by gram-negative bacteria. All S. aureus infections and 79% of other Staphylococcus infections were sensitive to cefazolin, but only 1 of 21 gram negative bacteria was sensitive to it. The majority of gram-negative bacterial infections were multidrug resistant, but 17 of the 20 gram-negative bacteria were sensitive to meropenem. Gram-negative bacterial infections were associated with worse outcomes. CONCLUSIONS: The high proportion of gram-negative infections differs from data in the Western literature, in which Staphylococcus epidermidis is by far the most common organism. Once a patient is diagnosed with a VPS infection in Kenya, immediate treatment is recommended to cover both gram positive and gram-negative bacterial infections. Data from other Sub-Saharan countries are needed to determine if those countries have the same increased frequency of gram-negative infections. PMID- 25431904 TI - Flying with a shunt. PMID- 25431905 TI - Regenerating blood: towards engineering HIV-1-resistant hematopoietic stem cells. PMID- 25431906 TI - Generating induced pluripotent stem cells for multiple sclerosis therapy. PMID- 25431908 TI - Triggering the switch from benign to malignant phenotypes in vitro through independent modulation of extracellular matrix stiffness and composition. PMID- 25431909 TI - Wharton's jelly mesenchymal stromal/stem cells derived under chemically defined animal product-free low oxygen conditions are rich in MSCA-1(+) subpopulation. AB - AIM: Umbilical cord contains, within Wharton's jelly (WJ), multipotent mesenchymal stromal/stem cells (MSCs) of fetal origin that can be isolated and expanded in vitro with a minimal manipulation and very high efficiency. Our aim was to develop a highly reproducible protocol that has the unique potential to be scaled up and adapted to cGMP requirements for the use in cellular therapy. RESULTS: We found that derivation of WJ MSCs under defined conditions in low oxygen resulted in several folds higher populations of MSCA-1(+) cells (6.0 19.2%) when compared with WJ MSCs derived in the presence of serum (0.1-2.8%) or clinical-grade bone marrow (BM) MSCs cultured under atmospheric O2 (20%). We demonstrate that WJ MSCs derived following our protocol display antiproliferative activity similar to clinical-grade BM MSCs. We also show that these WJ MSCs can be differentiated into adipo-, chondro- and osteo-genic lineages. CONCLUSION: Easy accessibility, abundance and genetic 'naivety' make WJ MSCs logistically a more attractive source for clinical applications than BM MSCs. PMID- 25431910 TI - Periadventitial adipose-derived stem cell treatment halts elastase-induced abdominal aortic aneurysm progression. AB - AIM: Demonstrate that periadventitial delivery of adipose-derived mesenchymal stem cells (ADMSCs) slows aneurysm progression in an established murine elastase perfusion model of abdominal aortic aneurysm (AAA). MATERIALS & METHODS: AAAs were induced in C57BL/6 mice using porcine elastase. During elastase perfusion, a delivery device consisting of a subcutaneous port, tubing and porous scaffold was implanted. Five days after elastase perfusion, 100,000 ADMSCs were delivered through the port to the aorta. After sacrifice at day 14, analyzed metrics included aortic diameter and structure of aortic elastin. RESULTS: ADMSC treated aneurysms had a smaller diameter and less fragmented elastin versus saline controls. CONCLUSION: Periadventitial stem cell delivery prevented the expansion of an established aneurysm between days 5 and 14 after elastase perfusion. PMID- 25431911 TI - Effect of autologous adipose tissue-derived mesenchymal stem cells on neovascularization of artificial equine tendon lesions. AB - AIMS: To investigate whether autologous adipose tissue-derived mesenchymal stem cells (AT-MSCs) treatment of tendon lesions increases neovascularization during tendon healing. MATERIALS & METHODS: A standardized surgical model was used to create lesions in both front limb superficial digital flexor tendons (SDFTs) of nine horses. Either AT-MSCs or control substance was injected intralesionally 2 weeks post-surgery. Color Doppler ultrasonography of SDFTs was performed at regular intervals. Horses were euthanized 22 weeks post-treatment and SDFTs were harvested for histology. RESULTS: The color Doppler ultrasonography signal was significantly more extensive at 2 weeks post-treatment and the number of vessels counted on histologic slides was significantly higher at 22 weeks post-treatment in AT-MSC-treated SDFTs. CONCLUSION: Our findings indicate that AT-MSC treatment has a beneficial effect on neovascularization of healing tendons. PMID- 25431912 TI - Fibronectin stimulates migration and proliferation, but not chondrogenic differentiation of human subchondral progenitor cells. AB - AIMS: To evaluate the impact of human plasma-derived fibronectin (FN) on human subchondral mesenchymal progenitor cells regarding cell migration, proliferation, and chondrogenic differentiation. MATERIALS & METHODS: Human subchondral mesenchymal progenitor cells were analyzed for their migration capacity upon treatment with human plasma-derived FN. Proliferation activity was evaluated by DNA content. For chondrogenesis, cells were cultured in high-density pellet cultures in the presence of FN, TGFbeta3, and a combination thereof. RESULTS: Treatment of progenitors with FN significantly increased the number of migrating cells and elevated proliferative activity. Histological staining indicated formation of an extracellular matrix with type II collagen. Gene expression analysis gave no evidence for chondrogenic differentiation mediated by FN, but revealed a significant induction of type II collagen expression. CONCLUSION: FN has a potential to recruit human subchondral mesenchymal progenitor cells, possibly supporting proliferation and matrix assembly in cartilage repair procedures using bioactive implants after microfracture treatment. PMID- 25431913 TI - Heterologous expression of mutated HLA-G1 reduces alloreactivity of human dermal fibroblasts. AB - AIM: To engineer a stable HLA-G molecule and evaluate its immunomodulatory properties in transgenic human dermal fibroblasts (HDFs). MATERIALS & METHODS: A mutated HLA-G1 (mHLA-G1) molecule was generated by modifying the endoplasmic reticulum retrieval motif and 3'-untranslated region miRNA-binding sites of HLA G1. Immunomodulatory properties of transgenic HDF-mHLA-G1 were evaluated in vitro. RESULTS: Stable mHLA-G1 expressing HDF cells were successfully generated and flow cytometry analysis revealed that mHLA-G1 efficiently localized to the cell surface. Natural killer cell-mediated cytolysis of HDF-mHLA-G1/green fluorescent protein (GFP) was reduced by 73% compared with HDF-GDP. HDF-mHLA G1/GFP decreased phytohemagglutinin-activated peripheral blood mononuclear cell proliferation by 30% versus HDF-GFP. CONCLUSION: We are the first to successfully create a human fibroblast source with reduced alloreactivity using a novel mHLA G1 construct. This approach may be extended to other cell types including human embryonic stem cells for use in allogeneic transplantation for cell-based regenerative medicine applications. PMID- 25431914 TI - Operating RegenMed: development of better in-theater strategies for handling tissue-engineered organs and tissues. AB - Tissue engineering ex vivo and direct cellular application with bioscaffolds in vivo has allowed surgeons to restore and establish function throughout the human body. The evidence for regenerative surgery is growing, and consequently there is a need for the development of more advanced regenerative surgery facilities. Regenerative medicine in the surgical field is changing rapidly and this must be reflected in the design of any future operating suite. The theater environment needs to be highly adaptable to account for future significant advances within the field. Development of purpose built, combined operating suites and tissue engineering laboratories will provide the facility for modern surgeons to treat patients with organ deficits, using bespoke, regenerated constructs without the need for immunosuppression. PMID- 25431915 TI - A training program in cardiovascular cell-based therapy: from the NHLBI Cardiovascular Cell Therapy Research Network. AB - Stem/progenitor cell-based therapies offer novel treatment for many prevalent diseases. However, most physicians are not trained or introduced to cell therapy. We describe a model of a training program aimed at empowering physician scientists with the knowledge and skills necessary for advancing the field of cardiovascular cell therapy. To date, five full-time scholars have completed this training program, obtained a full-time academic appointment in Cardiovascular Disease, and continue to actively contribute to the advancement of cell therapy applications. Another has returned to his parent institution to complete his PhD and several part-time scholars have continued in scholarly activities in other academic programs. PMID- 25431916 TI - Qualification of academic facilities for small-scale automated manufacture of autologous cell-based products. AB - Academic centers, hospitals and small companies, as typical development settings for UK regenerative medicine assets, are significant contributors to the development of autologous cell-based therapies. Often lacking the appropriate funding, quality assurance heritage or specialist regulatory expertise, qualifying aseptic cell processing facilities for GMP compliance is a significant challenge. The qualification of a new Cell Therapy Manufacturing Facility with automated processing capability, the first of its kind in a UK academic setting, provides a unique demonstrator for the qualification of small-scale, automated facilities for GMP-compliant manufacture of autologous cell-based products in these settings. This paper shares our experiences in qualifying the Cell Therapy Manufacturing Facility, focusing on our approach to streamlining the qualification effort, the challenges, project delays and inefficiencies we encountered, and the subsequent lessons learned. PMID- 25431917 TI - Wound healing: an update. AB - Wounds, both chronic and acute, continue to be a tremendous socioeconomic burden. As such, technologies drawn from many disciplines within science and engineering are constantly being incorporated into innovative wound healing therapies. While many of these therapies are experimental, they have resulted in new insights into the pathophysiology of wound healing, and in turn the development of more specialized treatments for both normal and abnormal wound healing states. Herein, we review some of the emerging technologies that are currently being developed to aid and improve wound healing after cutaneous injury. PMID- 25431918 TI - Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. AB - Fecal incontinence is a major public health issue that has yet to be adequately addressed. Obstetric trauma and injury to the anal sphincter muscles are the most common cause of fecal incontinence. New therapies are emerging aimed at repair or regeneration of sphincter muscle and restoration of continence. While regenerative medicine offers an attractive option for fecal incontinence there are currently no validated techniques using this approach. Although many challenges are yet to be resolved, the advent of regenerative medicine is likely to offer disruptive technologies to treat and possibly prevent the onset of this devastating condition. This article provides a review on regenerative medicine approaches for treating fecal incontinence and a critique of the current landscape in this area. PMID- 25431921 TI - Prophylaxis of febrile neutropenia in adults receiving chemotherapy needs to be adapted to the risk. AB - A major advance in the management of febrile neutropenia (FN) has been the stratification of the population of adult patients with FN for the risk of complications and death. Using validated reliable predictive instruments, such as the Multinational Association for Supportive Care in Cancer score, it is possible to identify a population of 'low-risk' patients, who can benefit from simplified and less expensive therapeutic approaches (e.g., orally administered antimicrobial therapy and early home return). Prevention of FN by the use of granulopoietic colony-stimulating factor (G-CSF) has been successfully applied to patients at 'high risk' of developing FN. In addition to the aggressiveness of chemotherapy, which usually defines the 'high-risk' status, the role of a series of factors that increase both the risk of FN and the complications rate has been recognized and should probably be taken into consideration when selecting patients for G-CSF prophylaxis. The cost of the G-CSF is the major limiting factor for their broad use; further efforts should be made to match the cost issue with the need of protecting from the development of FN most patients treated with chemotherapy for cancer. PMID- 25431923 TI - Variants of the low oxygen sensors EGLN1 and HIF-1AN associated with acute mountain sickness. AB - Two low oxygen sensors, Egl nine homolog 1 (EGLN1) and hypoxia-inducible factor 1 alpha inhibitor (HIF-1AN), play pivotal roles in the regulation of HIF-1alpha, and high altitude adaption may be involved in the pathology of acute mountain sickness (AMS). Here, we aimed to analyze single nucleotide polymorphisms (SNPs) in the untranslated regions of the EGLN1 and HIF-1AN genes and SNPs chosen from a genome-wide adaptation study of the Han Chinese population. To assess the association between EGLN1 and HIF-1AN SNPs and AMS in a Han Chinese population, a case-control study was performed including 190 patients and 190 controls. In total, thirteen SNPs were genotyped using the MassARRAY(r) MALDI-TOF system. Multiple genetic models were tested; The Akaike's information criterion (AIC) and Bayesian information criterion (BIC) values indicated that the dominant model may serve as the best-fit model for rs12406290 and rs2153364 of significant difference. However, these data were not significant after Bonferroni correction. No significant association was noted between AMS and rs12757362, rs1339894, rs1361384, rs2009873, rs2739513 or rs2486729 before and after Bonferroni correction. Further haplotype analyses indicated the presence of two blocks in EGLN1; one block consists of rs12406290-rs2153364, located upstream of the EGLN1 gene. Carriers of the "GG" haplotype of rs12406290-rs2153364 exhibited an increased risk of AMS after adjustments for age and smoking status. However, no significant association was observed among HIF-1AN 3'-untranslated region (3' UTR) polymorphisms, haplotype and AMS. Our study indicates that variants in the EGLN1 5'-UTR influence the susceptibility to AMS in a Han Chinese population. PMID- 25431924 TI - Interactome mapping reveals important pathways in skeletal muscle development of pigs. AB - The regulatory relationship and connectivity among genes involved in myogenesis and hypertrophy of skeletal muscle in pigs still remain large challenges. Presentation of gene interactions is a potential way to understand the mechanisms of developmental events in skeletal muscle. In this study, genome-wide transcripts and miRNA profiling was determined for Landrace pigs at four time points using microarray chips. A comprehensive method integrating gene ontology annotation and interactome network mapping was conducted to analyze the biological patterns and interaction modules of muscle development events based on differentially expressed genes and miRNAs. Our results showed that in total 484 genes and 34 miRNAs were detected for the duration from embryonic stage to adult in pigs, which composed two linear expression patterns with consensus changes. Moreover, the gene ontology analysis also disclosed that there were three typical biological events i.e., microstructure assembly of sarcomere at early embryonic stage, myofibril formation at later embryonic stage and function establishments of myoblast cells at postnatal stage. The interactome mappings of different time points also found the down-regulated trend of gene expression existed across the whole duration, which brought a possibility to introduce the myogenesis related miRNAs into the interactome regulatory networks of skeletal muscle in pigs. PMID- 25431922 TI - Looking into a conceptual framework of ROS-miRNA-atrial fibrillation. AB - Atrial fibrillation (AF) has been recognized as a major cause of cardiovascular related morbidity and mortality. MicroRNAs (miRNAs) represent recent additions to the collection of biomolecules involved in arrhythmogenesis. Reactive oxygen species (ROS) have been independently linked to both AF and miRNA regulation. However, no attempts have been made to investigate the possibility of a framework composed of ROS-miRNA-AF that is related to arrhythmia development. Therefore, this review was designed as an attempt to offer a new approach to understanding AF pathogenesis. The aim of this review was to find and to summarize possible connections that exist among AF, miRNAs and ROS to understand the interactions among the molecular entities underlying arrhythmia development in the hopes of finding unappreciated mechanisms of AF. These findings may lead us to innovative therapies for AF, which can be a life-threatening heart condition. A systemic literature review indicated that miRNAs associated with AF might be regulated by ROS, suggesting the possibility that miRNAs translate cellular stressors, such as ROS, into AF pathogenesis. Further studies with a more appropriate experimental design to either prove or disprove the existence of an ROS-miRNA-AF framework are strongly encouraged. PMID- 25431925 TI - Physiological and proteomic analysis in chloroplasts of Solanum lycopersicum L. under silicon efficiency and salinity stress. AB - Tomato plants often grow in saline environments in Mediterranean countries where salt accumulation in the soil is a major abiotic stress that limits its productivity. However, silicon (Si) supplementation has been reported to improve tolerance against several forms of abiotic stress. The primary aim of our study was to investigate, using comparative physiological and proteomic approaches, salinity stress in chloroplasts of tomato under silicon supplementation. Tomato seedlings (Solanum lycopersicum L.) were grown in nutrient media in the presence or absence of NaCl and supplemented with silicon for 5 days. Salinity stress caused oxidative damage, followed by a decrease in silicon concentrations in the leaves of the tomato plants. However, supplementation with silicon had an overall protective effect against this stress. The major physiological parameters measured in our studies including total chlorophyll and carotenoid content were largely decreased under salinity stress, but were recovered in the presence of silicon. Insufficient levels of net-photosynthesis, transpiration and stomatal conductance were also largely improved by silicon supplementation. Proteomics analysis of chloroplasts analyzed by 2D-BN-PAGE (second-dimensional blue native polyacrylamide-gel electrophoresis) revealed a high sensitivity of multiprotein complex proteins (MCPs) such as photosystems I (PSI) and II (PSII) to the presence of saline. A significant reduction in cytochrome b6/f and the ATP synthase complex was also alleviated by silicon during salinity stress, while the complex forms of light harvesting complex trimers and monomers (LHCs) were rapidly up-regulated. Our results suggest that silicon plays an important role in moderating damage to chloroplasts and their metabolism in saline environments. We therefore hypothesize that tomato plants have a greater capacity for tolerating saline stress through the improvement of photosynthetic metabolism and chloroplast proteome expression after silicon supplementation. PMID- 25431929 TI - Renal function in adult Jamaicans with homozygous sickle cell disease. AB - OBJECTIVES: As populations with sickle cell disease (SCD) live longer, it is likely that the burden of renal dysfunction will be an increasing challenge for patients. In this study, we aim to determine the prevalence of renal dysfunction and its possible predictors in persons with SCD. METHODS: Ninety-eight patients with the homozygous SCD (SS disease;55 females, 43 males; mean age 34 +/- 2.3 years) in their steady state had measurements of glomerular filtration rate (GFR) using 99mTc-DTPA nuclear renal scan, serum creatinine, and urinary albumin: creatinine ratio. Other haematological and biochemical measurements and data on clinical events were completed for each individual. RESULTS: Chronic kidney disease (CKD) stages 3 and above was present in 6% of the study population, and 65.3% had albuminuria. Hyperfiltration occurred in 24.5% patients with two-thirds having albuminuria as well. Serum creatinine was an insensitive marker of renal dysfunction as started rising after measured GFR fell below 50 mls/min/1.73 m(2). Multiple regression modelling showed serum creatinine and height to be significantly associated with GFR. Serum creatinine was also significantly associated with albuminuria, and age was not a predictor in any of the models. There was no association with markers of haemolysis. CONCLUSION: We conclude that the burden of renal dysfunction is quite high in this young cohort with SS disease. Serum creatinine is a late and insensitive marker of worsening glomerular function, and screening for albuminuria could begin early in life. Longitudinal studies will continue to increase our understanding of pathophysiological mechanisms that lead to CKD in this specific population. PMID- 25431926 TI - Real-time qPCR identifies suitable reference genes for Borna disease virus infected rat cortical neurons. AB - Quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR) is the most commonly-used technique to identify gene expression profiles. The selection of stably expressed reference genes is a prerequisite to properly evaluating gene expression. Here, the suitability of commonly-used reference genes in normalizing RT-qPCR assays of mRNA expression in cultured rat cortical neurons infected with Borna disease virus (BDV) was assessed. The expressions of eight commonly-used reference genes were comparatively analyzed in BDV-infected rat cortical neurons and non-infected control neurons mainly across 9 and 12 days post-infection. These reference genes were validated by RT-qPCR and separately ranked by four statistical algorithms: geNorm, NormFinder, BestKeeper and the comparative delta-Ct method. Then, the RankAggreg package was used to construct consensus rankings. ARBP was found to be the most stable internal control gene at Day 9, and ACTB at Day 12. As the assessment of the validity of the selected reference genes confirms the suitability of applying a combination of the two most stable references genes, combining the two most stable genes for normalization of RT-qPCR studies in BDV-infected rat cortical neurons is recommended at each time point. This study can contribute to improving BDV research by providing the means by which to obtain more reliable and accurate gene expression measurements. PMID- 25431930 TI - A pre-structured helix in the intrinsically disordered 4EBP1. AB - The eIF4E-binding protein 1 (4EBP1) has long been known to be completely unstructured without any secondary structures, which contributed significantly to the proposal of the induced fit mechanism for target binding of intrinsically disordered proteins. We show here that 4EBP1 is not completely unstructured, but contains a pre-structured helix. PMID- 25431932 TI - Nanoscale spinel LiFeTiO4 for intercalation pseudocapacitive Li(+) storage. AB - Intercalation pseudocapacitive Li(+) storage has been recognized recently in metal oxide materials, wherein Li(+) intercalation into the lattice is not solid state diffusion-limited. This may bridge the performance gap between electrochemical capacitors and battery materials. To date, only a few materials with desired crystal structure and with well-defined nanoarchitectures have been found to exhibit such attractive behaviour. Herein, we report for the first time that nanoscale spinel LiFeTiO4 as a cathode material for Li-ion batteries exhibits intercalation pseudocapacitive Li(+) storage behaviour. Nanoscale LiFeTiO4 nanoparticles with native carbon coating were synthesized by a sol-gel route. A fast and large-amount of Li(+) storage (up to 1.6 Li(+) per formula unit over cycling) in the nanoscale LiFeTiO4 host has been achieved without compromising kinetics. PMID- 25431933 TI - Transcutaneous oxygen tension measurements following peripheral transluminal angioplasty procedure has more specificity and sensitivity than ankle brachial index. AB - OBJECTIVE: To evaluate the superiority of transcutaneous oxygen pressure (TcPO2) before, during and after peripheral transluminal angioplasty (PTA) in comparison with ankle brachial index (ABI) in patients with diabetes. METHODS: 40 consecutive patients with diabetes treated by PTA where included. This study shows results before, during and after PTA and their progression for 8 weeks. RESULTS: The TcPO2 increased from 28.11 +/- 8.1 to 48.03 +/- 8.4 mmHg, 8 weeks after PTA (p < 0.001). The ABI increased from 0.48 +/- 0.38 to 0.77 +/- 0.39 after PTA (p < 0.001). After PTA, the stenosis of the vessel decreased from 58.33 +/- 20.07% to 21.87 +/- 13.57% (p < 0.001). TcPO2 was determined in all the patients, but ABI could not be determined in all patients. Furthermore, we determined patients with "false negatives" with an improvement in ABI and "false positives" in 12.5% of patients. Additionally, in this study, we monitored TcPO2 while performing PTA, revealing variations in each phase of the radiological procedure. CONCLUSION: The increase in TcPO2 measurements following PTA procedure has more specificity and sensitivity than does ABI. The use of TcPO2 may represent a more accurate alternative than traditional methods (ABI) used in assessing PTA results. The TcPO2 also allows the radiologist to assess changes in tissue oxygenation during PTA, allowing changes to the procedure and subsequent treatment. ADVANCES IN KNOWLEDGE: This is the first time that a graph is shown with TcPO2 results during PTA performance in many patients. PMID- 25431931 TI - Raptor ablation in skeletal muscle decreases Cav1.1 expression and affects the function of the excitation-contraction coupling supramolecular complex. AB - The protein mammalian target of rapamycin (mTOR) is a serine/threonine kinase regulating a number of biochemical pathways controlling cell growth. mTOR exists in two complexes termed mTORC1 and mTORC2. Regulatory associated protein of mTOR (raptor) is associated with mTORC1 and is essential for its function. Ablation of raptor in skeletal muscle results in several phenotypic changes including decreased life expectancy, increased glycogen deposits and alterations of the twitch kinetics of slow fibres. In the present paper, we show that in muscle specific raptor knockout (RamKO), the bulk of glycogen phosphorylase (GP) is mainly associated in its cAMP-non-stimulated form with sarcoplasmic reticulum (SR) membranes. In addition, 3[H]-ryanodine and 3[H]-PN200-110 equilibrium binding show a ryanodine to dihydropyridine receptors (DHPRs) ratio of 0.79 and 1.35 for wild-type (WT) and raptor KO skeletal muscle membranes respectively. Peak amplitude and time to peak of the global calcium transients evoked by supramaximal field stimulation were not different between WT and raptor KO. However, the increase in the voltage sensor-uncoupled RyRs leads to an increase of both frequency and mass of elementary calcium release events (ECRE) induced by hyper-osmotic shock in flexor digitorum brevis (FDB) fibres from raptor KO. The present study shows that the protein composition and function of the molecular machinery involved in skeletal muscle excitation-contraction (E-C) coupling is affected by mTORC1 signalling. PMID- 25431934 TI - The Agouti mouse: a biosensor for environmental epigenomics studies investigating the developmental origins of health and disease. PMID- 25431935 TI - Epigenetic activation and inactivation of centromeres. PMID- 25431936 TI - Interpreting 4C-Seq data: how far can we go? PMID- 25431937 TI - Drosophila genomic methylation: new evidence and new questions. PMID- 25431938 TI - The era of integrative genomics: more data or better methods? PMID- 25431939 TI - Exercise epigenetics and the fetal origins of disease. PMID- 25431940 TI - Epigenetic drug therapy based on bromodomain inhibition. PMID- 25431941 TI - Methylation of the FGFR2 gene is associated with high birth weight centile in humans. AB - AIMS: This study examined links between DNA methylation and birth weight centile (BWC), and explored the impact of genetic variation. MATERIALS & METHODS: Using HumanMethylation450 arrays, we examined candidate gene-associated CpGs in cord blood from newborns with low (<15th centile), medium (40-60th centile) and high (>85th centile) BWC (n = 12). Candidates were examined in an investigation cohort (n = 110) using pyrosequencing and genotyping for putative methylation-associated polymorphisms performed using standard PCR. RESULTS: Array analysis identified 314 candidate genes associated with BWC extremes, four of which showed >= 4 BWC linked CpGs. Of these, PM20D1 and MI886 suggested genetically determined methylation levels. However, methylation at three CpGs in FGFR2 remained significantly associated with high BWC (p = 0.004-0.027). CONCLUSION: We identified a novel biologically plausible candidate (FGFR2) for with BWC that merits further study. PMID- 25431943 TI - 5-hydroxymethylcytosine: a potential therapeutic target in cancer. AB - The ten-eleven translocation enzymes catalyze the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, a distinct epigenetic mark that has an integral role in active demethylation. Genes that regulate the distribution and amount of 5 hydroxymethylcytosine in the genome could be suitable therapeutic targets to correct abnormal methylation in cancer. Here, we present an overview of the role of the 5-hydroxymethylcytosine pathway in human disease and discuss the emergence of innovative techniques that can map the distribution of 5-hydroxymethylcytosine at high resolution. In the context of current epigenetic therapies and by using recent functional studies, we propose plausible mechanisms to target the 5 hydroxymethylcytosine pathway in cancer. As the study of 5-hydroxymethylcytosine is still in its infancy, we provide future perspectives. PMID- 25431942 TI - Can genome engineering be used to target cancer-associated enhancers? AB - Transcriptional misregulation is involved in the development of many diseases, especially neoplastic transformation. Distal regulatory elements, such as enhancers, play a major role in specifying cell-specific transcription patterns in both normal and diseased tissues, suggesting that enhancers may be prime targets for therapeutic intervention. By focusing on modulating gene regulation mediated by cell type-specific enhancers, there is hope that normal epigenetic patterning in an affected tissue could be restored with fewer side effects than observed with treatments employing relatively nonspecific inhibitors such as epigenetic drugs. New methods employing genomic nucleases and site-specific epigenetic regulators targeted to specific genomic regions, using either artificial DNA-binding proteins or RNA-DNA interactions, may allow precise genome engineering at enhancers. However, this field is still in its infancy and further refinements that increase specificity and efficiency are clearly required. PMID- 25431944 TI - Roles of imprinted genes in neural stem cells. AB - Imprinted genes and neural stem cells (NSC) play an important role in the developing and mature brain. A central theme of imprinted gene function in NSCs is cell survival and G1 arrest to control cell division, cell-cycle exit, migration and differentiation. Moreover, genomic imprinting can be epigenetically switched off at some genes to ensure stem cell quiescence and differentiation. At the genome scale, imprinted genes are organized in dynamic networks formed by interchromosomal interactions and transcriptional coregulation of imprinted and nonimprinted genes. Such multilayered networks may synchronize NSC activity with the demand from the niche resembling their roles in adjusting fetal size. PMID- 25431945 TI - Epigenetic regulation of human cytomegalovirus latency: an update. AB - Human cytomegalovirus (HCMV) is a ubiquitous virus which infects 50-90% of the population worldwide. In immunocompetent hosts, HCMV either remains unnoticed or causes mild symptoms. Upon primary infection it establishes latent infection in a few cells. However, in certain situations where immunity is either immature or compromised, HCMV may reactivate and cause mortality and morbidity. Therefore, it is utmost important to understand how HCMV establishes latent infection and associated mechanisms responsible for its reactivation. Several mechanisms are involved in the regulation of latency including chromatin remodeling by an array of enzymes and microRNAs. Here we will describe the epigenetic regulation of HCMV latency. Further we will discuss the unique HCMV latency signature and patho physiological relevance of latent HCMV infection. PMID- 25431946 TI - Histone deacetylase inhibitors: a potential epigenetic treatment for Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a life-threatening genetic disease that currently has no available cure. A number of pharmacological strategies that aim to target events downstream of the genetic defect are currently under clinical investigation, and some of these are outlined in this report. In particular, we focus on the ability of histone deacetylase inhibitors to promote muscle regeneration and prevent the fibro-adipogenic degeneration of dystrophic mice. We describe the rationale behind the translation of histone deacetylase inhibitors into a clinical approach, which inspired the first clinical trial with an epigenetic drug as a potential therapeutic option for DMD patients. PMID- 25431947 TI - Crystal lattice determination of ZnSe nanowires with polarization-dependent second harmonic generation microscopy. AB - We demonstrate a noninvasive optical microscopy technique based on polarization dependent second harmonic generation for determining the crystal lattice structure and microscopic heterogeneities within individual nanostructures. Differentiation between periodically twinned and wurtzite ZnSe nanowires (NWs) was demonstrated, and measurement of the cubic lattice rotation orientation around the NW axis was determined within 1 degrees accuracy. Zinc blende NWs were differentiated from wurtzite. The technique can be used for quality inspection and optimization of growth conditions for nanostructures. PMID- 25431948 TI - Genotypic analysis of Kaposi's sarcoma-associated herpesvirus from patients with Kaposi's sarcoma in Xinjiang, China. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the causal agent of all forms of Kaposi's sarcoma (KS), including AIDS-KS, endemic KS, classic KS and iatrogenic KS. Based on Open reading frame (ORF) K1 sequence analysis, KSHV has been classified into seven major molecular subtypes (A, B, C, D, E, F and Z). The distribution of KSHV strains varies according to geography and ethnicity. Xinjiang is a unique region where the seroprevalence of KSHV is significantly higher than other parts of China. The genotyping of KSHV strains in this region has not been thoroughly studied. The present study aimed to evaluate the frequency of KSHV genotypes isolated from KS tissues in Classical KS and AIDS KS patients from Xinjiang, China. ORF-K1 of KSHV from tissue samples of 28 KS patients was amplified and sequenced. Two subtypes of KSHV were identified according to K1 genotyping. Twenty-three of them belonged to subtype A, while five of them were subtype C. More genotype A than genotype C strains were found in both Classical KS and AIDS KS. No significant difference was found in the prevalence of different genotype between Classical KS and AIDS KS. PMID- 25431949 TI - High KIF18A expression correlates with unfavorable prognosis in primary hepatocellular carcinoma. AB - This study aimed to investigate KIF18A expression in hepatocellular carcinoma (HCC) and to determine the possibility of KIF18A expression being a biomarker in HCC diagnosis or being an independent predictor of disease-free survival (DFS) and overall survival (OS) in HCC patients underwent surgical resection. KIF18AmRNA was detected in 216 cases of HCC tissues by quantitative real-time PCR (qRT-PCR) and in 20 cases of HCC tissues by semi-quantitative RT-PCR. KIF18A protein was determined in 32 cases of HCC tissues by immunohistochemistry (IHC). The survival probability was analyzed by Kaplan-Meier method, and survival curves between groups were obtained by using the log-rank test. Independent predictors associated with DFS were analyzed with Stepwise Cox proportional hazard models. High KIF18A mRNA level was detected in 154 out of 216 (71.3%) cases of HCC. The positive rate of KIF18A expression was significantly higher in liver cancer tissues than that in adjacent normal liver tissues (ANLT) from HCC patients [65.6% (21 of 32) vs. 25.0% (8 of 32), P=0.001]. The KIF18A expression level had positive relevance to the alpha-fetoprotein (AFP) (>= 200 ng/ml), tumor size (>= 5 cm), clinical tumor-node-metastasis (TNM) stage and portal vein tumor thrombus (PVTT) in HCC (all P <0.05). A survival analysis indicated that HCC patients with higher KIF18A expression had a significantly shorter DFS and OS after resection. A multivariate analysis suggested that KIF18A upregualtion was an independent factor for DFS [hazard risk (HR)=1.602; 95% confidence interval (CI), 1.029 2.579; P=0.031] and OS (HR=1.682; 95% CI, 1.089-2.600; P=0.019). KIF18A might be a biomarker for HCC diagnosis and an independent predictor of DFS and OS after surgical resection. PMID- 25431950 TI - Pharmacologic down-regulation of EZH2 suppresses bladder cancer in vitro and in vivo. AB - The polycomb group gene, EZH2, is highly expressed in advanced bladder cancer. Here we demonstrated that down-regulation of EZH2 in tumor tissues after neo adjuvant chemotherapy correlated with good therapeutic response in advanced bladder cancer. We next developed a small molecule, NSC745885, derived from natural anthraquinone emodin, which down-regulated EZH2 via proteasome-mediated degradation. NSC745885 showed potent selective toxicity against multiple cancer cell lines but not normal cells. NSC745885 treatment overcame multiple-drug resistance and inhibited growth of resistant cancer cells. Over-expression of EZH2 in cancer cells attenuated effects of NSC745885, suggesting that down regulation of EZH2 was responsible for growth inhibition of NSC745885. NSC745885 also suppressed tumor growth and down-regulated EZH2 in vivo. These results indicate that NSC7455889 suppresses bladder cancer by targeting EZH2. PMID- 25431951 TI - Antitumor activity of S116836, a novel tyrosine kinase inhibitor, against imatinib-resistant FIP1L1-PDGFRalpha-expressing cells. AB - The FIP1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRalpha) fusion oncogene is the driver factor in a subset of patients with hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL). Most FIP1L1 PDGFRalpha-positive patients respond well to the tyrosine kinase inhibitor (TKI) imatinib. Resistance to imatinib in HES/CEL has been described mainly due to the T674I mutation in FIP1L1-PDGFRalpha, which is homologous to the imatinib resistant T315I mutation in BCR-ABL. Development of novel TKIs is imperative to overcome resistance to imatinib. We synthesized S116836, a novel TKI. In this study, we evaluated the antitumor activity of S116836 in FIP1L1-PDGFRalpha expressing cells. The results showed that S116836 potently inhibited PDGFRalpha and its downstream signaling molecules such as STAT3, AKT, and Erk1/2. S116836 effectively inhibited the growth of the WT and T674I FIP1L1-PDGFRalpha-expressing neoplastic cells in vitro and in nude mouse xenografts. Moreover, S116836 induced intrinsic pathway of apoptosis as well as the death receptor pathway, coincided with up-regulation of the proapoptotic BH3-only protein Bim-EL through the Erk1/2 pathway. In conclusion, S116836 is active against WT and T674I FIP1L1-PDGFRalpha expressing cells, and may be a prospective agent for the treatment of HES/CEL. PMID- 25431952 TI - H2AK119Ub1 and H3K27Me3 in molecular staging for survival prediction of patients with pancreatic ductal adenocarcinoma. AB - Polycomb group (PcG) proteins Ring1B and EZH2, which have been characterized as catalyzing the two epigenetic modifications H2AK119 monoubiquitination (H2AK119Ub1) and H3K27 trimethylation (H3K27Me3), are well-known epigenetic silencers implicated in embryonic development and tumorigenesis. However, the status of polycomb-associated histone modifications and their clinical implications in pancreatic cancer remain unclear. Here, we performed immunohistochemistry on tissue microarrays (TMAs) containing 80 pairs of human pancreatic cancer specimens to assess the expression levels of Ring1B, H2AK119Ub1, EZH2, and H3K27Me3 in tumors. More than 50% of the tumor cells showed a high expression of H2AK119Ub1, Ring1B, and EZH2, whereas more than 50% of the tumor cells showed a low level of H3K27Me3. Different expression patterns of H2AK119Ub1 and H3K27Me3 in tumors were negatively correlated (r = -0.247, P = 0.027). Both H2AK119Ub1 and H3K27Me3 independently predicted the clinical prognosis. In particular, a combinatorial pattern of elevated H2AK119Ub1 and decreased H3K27Me3 in tumors was significantly correlated with a poorer prognosis. Furthermore, compared to the tumor, lymph node, metastasis (TNM) staging system, histone modifications can discriminate the survival difference more accurately, especially for patients with stage I or stage II tumors. Simultaneous silencing of Ring1B and EZH2 via shRNA depleted H2AK119Ub1 and H3K27Me3 in the pancreatic cancer cells PanC1 and AsPC1, enhanced HOX gene derepression, and inhibited tumor cell growth in vitro and in tumor xenograft models. These results demonstrated that H2AK119Ub1 and H3K27Me3 cooperate in tumors and are associated with the clinical prognosis in combinatorial patterns. We have proposed that epigenetic modifications may serve as discriminatory biomarkers for molecular staging of pancreatic cancer. PMID- 25431953 TI - Medical treatment of orthotopic glioblastoma with transferrin-conjugated nanoparticles encapsulating zoledronic acid. AB - Glioblastomas are highly aggressive adult brain tumors with poor clinical outcome. In the central nervous system (CNS) the blood-brain barrier (BBB) is the most important limiting factor for both development of new drugs and drug delivery. Here, we propose a new strategy to treat glioblastoma based on transferrin (Tf)-targeted self-assembled nanoparticles (NPs) incorporating zoledronic acid (ZOL) (NPs-ZOL-Tf). NPs-ZOL-Tf have been assessed on the glioblastoma cell line U373MG-LUC that showed a refractoriness in vitro to temozolomide (TMZ) and fotemustine (FTM). NPs-ZOL-Tf treatment resulted in higher in vitro cytotoxic activity than free ZOL. However, the potentiation of anti proliferative activity of NPs-ZOL-Tf was superimposable to that one induced by NPs-ZOL (not armed with Tf). On the other hand, NPs-ZOL-Tf showed a higher antitumor efficacy if compared with that one caused by NPs-ZOL in immunosuppressed mice intramuscularly bearing U373MG-LUC xenografts, inducing a significant tumor weight inhibition (TWI). The experiments performed on mice with intracranial U373MG-LUC xenografts confirmed the efficacy of NPs-ZOL-Tf. These effects were paralleled by a higher intratumour localization of fluorescently labeled-NPs-Tf both in intramuscular and intracranial xenografts. In conclusion, our results demonstrate that the encapsulation of ZOL increases the antitumor efficacy of this drug in glioblastoma through the acquisition of ability to cross the BBB. PMID- 25431954 TI - Suppression of p53 by Notch3 is mediated by Cyclin G1 and sustained by MDM2 and miR-221 axis in hepatocellular carcinoma. AB - To successfully target Notch receptors as part of a multidrug anticancer strategy, it will be essential to fully characterize the factors that are modulated by Notch signaling. We recently reported that Notch3 silencing in HCC results in p53 up-regulation in vitro and, therefore, we focused on the mechanisms that associate Notch3 to p53 protein expression. We explored the regulation of p53 by Notch3 signalling in three HCC cell lines HepG2, SNU398 and Hep3B.We found that Notch3 regulates p53 at post-transcriptional level controlling both Cyclin G1 expression and the feed-forward circuit involving p53, miR-221 and MDM2. Moreover, our results were validated in human HCCs and in a rat model of HCC treated with Notch3 siRNAs. Our findings are becoming an exciting area for further in-depth research toward targeted inactivation of Notch3 receptor as a novel therapeutic approach for increasing the drug-sensitivity, and thereby improving the treatment outcome of patients affected by HCC. Indeed, we proved that Notch3 silencing strongly increases the effects of Nutilin-3.With regard to therapeutic implications, Notch3-specific drugs could represent a valuable strategy to limit Notch signaling in the context of hepatocellular carcinoma over-expressing this receptor. PMID- 25431956 TI - Phenotypic characterization and ERIC-PCR based genotyping of Paenibacillus larvae isolates recovered from American foulbrood outbreaks in honey bees from Italy. AB - BACKGROUND: Paenibacillus larvae is the etiological agent of American foulbrood (AFB), a widespread and severe bacterial brood disease of honey bees. The genomic characterization of P. larvae strains by enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) is able to differentiate four genotypes (ERIC I, ERIC II, ERIC III, ERIC IV). The information on the presence of P. larvae ERIC genotypes worldwide is few. OBJECTIVES: We have characterized P. larvae strains isolated in Italy from AFB outbreaks to obtain information on ERIC genotypes and phenotypes of the strains circulating in the country. METHODS: A total of 117 P. larvae isolates from 115 AFB outbreaks occurring in 2008-2012 were subjected to phenotypic and genetic characterization. RESULTS: The genomic characterization allowed the identification of ERIC I and ERIC II genotypes. Examining the data of Northern and Central Italy separately it was noted that in Northern Italy most outbreaks were caused by the ERIC I genotype (78.6%), followed by the ERIC II genotype (18.6%) and by co-infections (ERIC I + ERIC II) (2.6%). In Central Italy, only outbreaks caused by the ERIC I genotype were observed. With regard to phenotypic characteristics all examined strains of ERIC II genotype fermented fructose while no strains of ERIC I genotype possessed this ability. CONCLUSION: Both P. larvae ERIC I and ERIC II genotypes were isolated from the AFB outbreaks, but ERIC II genotype was isolated only in Northern Italy. The fermentation of fructose seems to be a genotype-specific biochemical marker. PMID- 25431957 TI - Atomic layer deposition of lithium phosphates as solid-state electrolytes for all solid-state microbatteries. AB - Atomic layer deposition (ALD) has been shown as a powerful technique to build three-dimensional (3D) all-solid-state microbattery, because of its unique advantages in fabricating uniform and pinhole-free thin films in 3D structures. The development of solid-state electrolyte by ALD is a crucial step to achieve the fabrication of 3D all-solid-state microbattery by ALD. In this work, lithium phosphate solid-state electrolytes were grown by ALD at four different temperatures (250, 275, 300, and 325 degrees C) using two precursors (lithium tert-butoxide and trimethylphosphate). A linear dependence of film thickness on ALD cycle number was observed and uniform growth was achieved at all four temperatures. The growth rate was 0.57, 0.66, 0.69, and 0.72 A/cycle at deposition temperatures of 250, 275, 300, and 325 degrees C, respectively. Furthermore, x-ray photoelectron spectroscopy confirmed the compositions and chemical structures of lithium phosphates deposited by ALD. Moreover, the lithium phosphate thin films deposited at 300 degrees C presented the highest ionic conductivity of 1.73 * 10(-8) S cm(-1) at 323 K with ~ 0.51 eV activation energy based on the electrochemical impedance spectroscopy. The ionic conductivity was calculated to be 3.3 * 10(-8) S cm(-1) at 26 degrees C (299 K). PMID- 25431955 TI - An NCR1-based chimeric receptor endows T-cells with multiple anti-tumor specificities. AB - The Ral (Ras-like) GTP-binding proteins (RalA and RalB), as effectors of the proto-oncogene Natural killer (NK) cells are an important component of the anti tumor response. Tumor recognition by NK cells was found to be partly triggered by molecules termed natural cytotoxic receptors (NCRs). Adoptive transfer of genetically-engineered tumor-reactive T-lymphocytes can mediate remarkable tumor regressions mostly in melanoma and leukemia patients. Yet, the application of such treatments to other cancers is needed and dependent on the isolation of receptors that could facilitate efficient recognition of these malignancies. Herein, we aimed at combining NK tumor recognition capability with the genetic modification of T-cells to provide the latter with a means to recognize several tumors in a non-MHC restricted way. Consequently, we generated and evaluated several chimeric receptors based on the extracellular domain of NCR1 (NKp46) fused to multiple signaling moieties and assess their antitumor activity when retrovirally expressed in T-cells. Following co-culture with different tumors, primary human T-lymphocytes expressing a chimeric NCR1 molecule recognized target cells derived from lung, cervical carcinoma, leukemia and pancreatic cancer. In addition, this receptor mediated an upregulation of surface activation markers and significant antitumor cytotoxicity both in vitro and in vivo. These results have meaningful implications for the immunotherapeutic treatment of cancer using gene-modified T-cells. PMID- 25431958 TI - Ramucirumab for gastric cancer. AB - In recent years, various molecular target agents have been investigated for gastric cancer. VEGF is one of the most potent angiogenic factors and is a signaling molecule secreted by many solid tumors. High VEGF expression is one of the characteristic features of gastric carcinomas, thus targeting VEGF is considered a promising strategy for gastric cancer. Ramucirumab, an anti-VEGF receptor antibody, has proven to be effective for previously treated advanced gastric cancer. Details of ramucirumab, including two pivotal Phase III studies, will be discussed in this review. Ramucirumab, with or without chemotherapy, improved survival in gastric cancer after previous systemic chemotherapy, thus becoming the standard of care for this patient population. Optimal timing of ramucirumab use and adequate biomarkers for patient selection as well as mechanism of resistance should be explored in future research. PMID- 25431959 TI - Impact of the chemical and physical stability of ketoprofen compounded in various pharmaceutical bases on its topical and transdermal delivery. AB - Increasing demands for individualized drug treatment has led to an increase in the practice of compounded medications. In this study, we determined the impact of the chemical and physical stability of ketoprofen (10%w/w) cream on its topical/transdermal delivery over a 6-month period. The shelf life of ketoprofen at 25 degrees C in the pharmaceutical bases LipoDerm and LipoBase (109.94 and 85.9 days) was significantly longer than that in Pluronic Lecithin Organogel (PLO; 44.81 days), justifying extending its beyond use date (BUD) from 30 (USP37/NF32) to at least 60 days in LipoDerm and LipoBase. All the creams evaluated exhibited shear-thinning flow behavior with moderate thixotropy, while the flow properties for LipoBase and PLO creams were altered at storage times greater than 90 days. The percentage of ketoprofen permeated through porcine ear skin was 13.7, 19.1 and 12.7% of the dose from LipoDerm, LipoBase and PLO, respectively and decreased 2- to 3-fold after 28 days of storage. Flux ranging from 85.3 to 446.7 ug/cm(2)/h and topical delivery, on the other hand, were not influenced by storage duration past 28 days. In conclusion, this study justifies extending the BUD of ketoprofen in LipoDerm and LipoBase to 60 days if used for topical delivery only. PMID- 25431960 TI - High-resolution direct microstimulation mapping of spinal cord motor pathways during resection of an intramedullary tumor. AB - Despite the use of advanced microsurgical techniques, resection of intramedullary tumors may result in significant postoperative deficits because of the vicinity or invasion of important functional tracts. Intraoperative monitoring of somatosensory evoked potentials and transcranial electrical motor evoked potentials has been used previously to limit such complications. Electromyography offers an opportunity for the surgeon to map the eloquent tissue associated with the tumor using intraoperative motor fiber stimulation. Similar to the use of cortical simulation in the resection of supratentorial gliomas, this technique can potentially advance the safety of intramedullary spinal cord tumor resection. The authors describe the use of intraoperative motor fiber tract stimulation to map the corticospinal tracts associated with an intramedullary tumor. This technique led to protection of these tracts during resection of the tumor. PMID- 25431961 TI - Fusion following lateral mass reconstruction in the cervical spine. AB - OBJECT: Recently, aggressive surgical techniques and a push toward en bloc resections of certain tumors have resulted in a need for creative spinal column reconstruction. Iatrogenic instability following these resections requires a thoughtful approach to adequately transfer load-bearing forces from the skull and upper cervical spine to the subaxial spine. METHODS: The authors present a series of 7 cases in which lateral mass reconstruction with a cage or fibular strut graft was used to provide load-bearing support, including 1 case of bilateral cage placement. RESULTS: The authors discuss the surgical nuances of en bloc resection of high cervical tumors and explain their technique for lateral mass cage placement. Additionally, they provide their rationale for the use of these constructs throughout the craniocervical junction and subaxial spine. CONCLUSIONS: Lateral mass reconstruction provides a potential alternative or adjuvant method of restoring the load-bearing capabilities of the cervical spine. PMID- 25431962 TI - The influence of injecting an epidural contrast agent into the sacral canal on the fluoroscopic visibility of bony landmarks for sacroiliac screw fixation: a feasibility study. AB - OBJECT: In sacroiliac screw fixation of unstable pelvic injuries in geriatric patients, poor bone quality often obscures important bony landmarks in fluoroscopic images. The authors analyzed the feasibility of injecting a transhiatal contrast agent (CA) into the sacral canal to improve fluoroscopic visualization in the sacral epidural space. METHODS: Eight fresh cadaveric whole body specimens from human donors whose mean age at the time of death was 78 years (range 69-87 years) were used. First, to identify bony landmarks without CA enhancement, the authors acquired fluoroscopy images of the native sacral canal, using lateral, inlet, and outlet projections. Through puncture of the sacral hiatus, 8-10 ml of CA was injected into the epidural space. Fluoroscopy images were then acquired in the standard pelvic views to identify the bony landmarks. To assess the effect of the CA enhancement, visibility of the landmarks was assessed before and after CA injection. Each identified landmark was scored as 1, and summative landmark scores of up to 10 were determined for each specimen. RESULTS: The cadaveric specimens were representative of bone structures in the geriatric population. In all specimens, epidural CA injection enhanced the fluoroscopic visualization of the sacral canal and of the S-1 foramina. The enhancement increased the total bony landmark score from 5.9 (range 4-8) without CA injection to 8.1 (range 6-10) after CA injection. Considering only intrasacral landmarks, the score was increased from 1.5 to 3. CONCLUSIONS: Injection of a transhiatal epidural CA improves fluoroscopic imaging of the sacral canal and of the neural foramina. Hence, this technique could be applied to help the surgeon identify anatomical landmarks during sacroiliac screw fixation in geriatric patients. PMID- 25431963 TI - Long-term clinical outcomes and radiological findings and their correlation with each other after standard open discectomy for lumbar disc herniation. AB - OBJECT: This retrospective study was designed to evaluate the clinical outcomes and radiological findings after open lumbar discectomy (OLD) in patients who were followed up for 10 years or longer. METHODS: The authors classified 79 patients who had a mean age (+/-SD) of 53.6+/-13.6 years (range 30-78 years) into 4 groups according to the length of their follow-up. Patients in Group 1 were followed up for 10-14 years, in Group 2 for 15-19 years, in Group 3 for 20-24 years, and in Group 4 for more than 25 years. In all of these patients, the clinical outcomes were assessed by using patients' self-reported scores on visual analog scales (VASs) measuring back and leg pain and by using scores from the Oswestry Disability Index (ODI). In addition, 10 radiological parameters suggesting degenerative changes or instability at the operated segment were recorded at various time points and used to calculate a numeric radiological finding (NRF) score by rating a presence for each finding of spinal degeneration or instability as 1. RESULTS: The authors observed that OLD decreased pain and disability scores in all groups. Numeric radiological findings were highest in Group 4, and a significant correlation was detected between NRFs and VAS scores of back pain (p=0.039). In this cohort, the reoperation rate was 13.9% during a mean follow-up period of 15.3 years. Clinical outcomes tended to be most favorable in Group 1, representing patients who had OLD most recently, and they tended to deteriorate in the other 3 groups, indicating some worsening of outcomes over time. Degeneration of the spine at the operated level measured with radiographic methods tended to increase over time, but some stabilization was observed. Although spinal degeneration was stable, clinical outcomes deteriorated over time. CONCLUSIONS: This cross-sectional assessment of a retrospective cohort indicates that outcomes after OLD deteriorate over time. Increased back pain indicated a worsening of clinical outcomes, and this worsening was correlated with radiological findings of degeneration at the operated segment. PMID- 25431964 TI - Correction: Ordered nanoparticle arrays interconnected by molecular linkers: electronic and optoelectronic properties. AB - Correction for 'Ordered nanoparticle arrays interconnected by molecular linkers: electronic and optoelectronic properties' by Jianhui Liao et al., Chem. Soc. Rev., 2015, DOI: . PMID- 25431965 TI - Firstline treatment for chronic phase chronic myeloid leukemia patients should be based on a holistic approach. AB - New selective and more potent drugs for the cure of chronic phase chronic myeloid leukemia patients are now available: physicians in some countries must decide the best option, selecting one of the drugs available. What the main prognostic factors are in order to make this selection remains a matter of discussion. Introducing a 'holistic approach' for the first time in chronic myeloid leukemia, as practiced in other diseases, and looking at the patient in a complete picture, considering several variables, such as comorbidities, age, concomitant drugs, lifestyle and patient expectations, may be of help to understand, patient by patient, the best therapeutic strategy. PMID- 25431966 TI - Joint research towards a better radiation protection-highlights of the Fifth MELODI Workshop. AB - MELODI is the European platform dedicated to low-dose radiation risk research. From 7 October through 10 October 2013 the Fifth MELODI Workshop took place in Brussels, Belgium. The workshop offered the opportunity to 221 unique participants originating from 22 countries worldwide to update their knowledge and discuss radiation research issues through 118 oral and 44 poster presentations. In addition, the MELODI 2013 workshop was reaching out to the broader radiation protection community, rather than only the low-dose community, with contributions from the fields of radioecology, emergency and recovery preparedness, and dosimetry. In this review, we summarise the major scientific conclusions of the workshop, which are important to keep the MELODI strategic research agenda up-to-date and which will serve to establish a joint radiation protection research roadmap for the future. PMID- 25431967 TI - Enzymatic transformation of phosphate decorated magnetic nanoparticles for selectively sorting and inhibiting cancer cells. AB - As an important and necessary step of sampling biological specimens, the separation of malignant cells from a mixed population of cells usually requires sophisticated instruments and/or expensive reagents. For health care in the developing regions, there is a need for an inexpensive sampling method to capture tumor cells for rapid and accurate diagnosis. Here we show that an underexplored generic difference-overexpression of ectophosphatases-between cancer and normal cells triggers the d-tyrosine phosphate decorated magnetic nanoparticles (Fe3O4 p(d-Tyr)) to adhere selectively on cancer cells upon catalytic dephosphorylation, which enables magnetic separation of cancer cells from mixed population of cells (e.g., cocultured cancer cell (HeLa-GFP) and stromal cells (HS-5)). Moreover, the Fe3O4-p(d-Tyr) nanoparticles also selectively inhibit cancer cells in the coculture. As a general method to broadly target cancer cells without highly specific ligand-receptor interactions (e.g., antibodies), the use of an enzymatic reaction to spatiotemporally modulate the state of various nanostructures in cellular environments will ultimately lead to the development of new theranostic applications of nanomaterials. PMID- 25431969 TI - Bioinformatics analysis of gene expression profiles in childhood B-precursor acute lymphoblastic leukemia. AB - OBJECTIVES: To explore the underlying molecular mechanisms of childhood B precursor acute lymphoblastic leukemia (ALL) by bioinformatics analysis and find potential targets for childhood ALL diagnosis and treatment. METHODS: Gene expression profile GSE28460 was downloaded from the Gene Expression Omnibus, including 49 diagnostic and relapse bone marrow samples with childhood B precursor ALL. The differentially expressed genes (DEGs) were identified by paired t-test. Pathway enrichment analysis of DEGs and transcription factors (TFs) enrichment analysis were performed, followed by construction of co expressed, DEGs, and susceptibility gene protein-protein interaction (PPI) network. Based on these three networks, relevant regulatory network modules and the important DEGs in the modules were identified. RESULTS: Total of 947 DEGs were identified. Up-regulated DEGs enriched 20 pathways including cell cycle, and down-regulated DEGs significantly enriched Jak-STAT signaling pathways. CDK1 and BRCA1 were found to have more hubs in both co-expressed network and PPI network. Besides, total of five modules in INTS10, MCM, BRCA1, GYPA, and VCAN1 families were identified and a pathway of INTS10-INTS6-POLR2A-MAGI2 was selected. CONCLUSION: Cell cycle and Jak-STAT signaling pathway were closely associated with relapse of childhood B-precursor ALL. The DEGs, such as PTTG1, PIK3CA, CDK1, and BRCA1 may be the potential targets for childhood ALL diagnosis and treatment. PMID- 25431970 TI - A discrete-time host-parasitoid model with an Allee effect. AB - We introduce a discrete-time host-parasitoid model with a strong Allee effect on the host. We adapt the Nicholson-Bailey model to have a positive density dependent factor due to the presence of an Allee effect, and a negative density dependence factor due to intraspecific competition. It is shown that there are two scenarios, the first with no interior fixed points and the second with one interior fixed point. In the first scenario, we show that either both host and parasitoid will go to extinction or there are two regions, an extinction region where both species go to extinction and an exclusion region in which the host survives and tends to its carrying capacity. In the second scenario, we show that either both host and parasitoid will go to extinction or there are two regions, an extinction region where both species go to extinction and a coexistence region where both species survive. PMID- 25431971 TI - Rapid authentication of coffee blends and quantification of 16-O-methylcafestol in roasted coffee beans by nuclear magnetic resonance. AB - Roasted coffee is subject to commercial frauds, because the high-quality Coffea arabica species, described as "100% Arabica" or "Highland coffee", is often mixed with the less expensive Coffea canephora var. Robusta. The quantification of 16-O methylcafestol (16-OMC) is useful to monitor the authenticity of the products as well as the Robusta content in blends. The German standard method DIN 10779 is used in the determination of 16-OMC in roasted coffee beans to detect C. canephora in blends, but it is laborious and time-consuming. Here, we introduce a new method that provides a quantitative determination of esterified 16-OMC directly in coffee extracts by means of high-resolution proton nuclear magnetic resonance spectroscopy. Limit of detection and limit of quantitation were 5 and 20 mg/kg, respectively, which are adequate to detect the presence of Robusta at percentages lower than 0.9%. The proposed method is much faster, more sensitive, and much more reproducible than the DIN standard method. PMID- 25431968 TI - Alternative methods for the detection of emerging marine toxins: biosensors, biochemical assays and cell-based assays. AB - The emergence of marine toxins in water and seafood may have a considerable impact on public health. Although the tendency in Europe is to consolidate, when possible, official reference methods based on instrumental analysis, the development of alternative or complementary methods providing functional or toxicological information may provide advantages in terms of risk identification, but also low cost, simplicity, ease of use and high-throughput analysis. This article gives an overview of the immunoassays, cell-based assays, receptor binding assays and biosensors that have been developed for the screening and quantification of emerging marine toxins: palytoxins, ciguatoxins, cyclic imines and tetrodotoxins. Their advantages and limitations are discussed, as well as their possible integration in research and monitoring programs. PMID- 25431973 TI - High-throughput synthesis of stable isotope-labeled transmembrane proteins for targeted transmembrane proteomics using a wheat germ cell-free protein synthesis system. AB - Using a wheat germ cell-free protein synthesis system, we developed a high throughput method for the synthesis of stable isotope-labeled full-length transmembrane proteins as proteoliposomes to mimic the in vivo environment, and we successfully constructed an internal standard library for targeted transmembrane proteomics by using mass spectrometry. PMID- 25431974 TI - Physical Properties and CO2 Reaction Pathway of 1-Ethyl-3-Methylimidazolium Ionic Liquids with Aprotic Heterocyclic Anions. AB - Ionic liquids (ILs) with aprotic heterocyclic anions (AHA) are attractive candidates for CO(2) capture technologies. In this study, a series of AHA ILs with 1-ethyl-3-methylimidazolium ([emim](+)) cations were synthesized, and their physical properties (density, viscosity, and ionic conductivity) were measured. In addition, CO(2) solubility in each IL was determined at room temperature using a volumetric method at pressures between 0 and 1 bar. The AHAs are basic anions that are capable of reacting stoichiometrically with CO(2) to form carbamate species. An interesting CO(2) uptake isotherm behavior was observed, and this may be attributed to a parallel, equilibrium proton exchange process between the imidazolium cation and the basic AHA in the presence of CO(2), followed by the formation of "transient" carbene species that react rapidly with CO(2). The presence of the imidazolium-carboxylate species and carbamate anion species was verified using (1)H and (13)C NMR spectroscopy. While the reaction between CO(2) and the proposed transient carbene resulted in cation-CO(2) binding that is stronger than the anion-CO(2) reaction, the reactions of the imidazolium AHA ILs were fully reversible upon regeneration at 80 degrees C with nitrogen purging. The presence of water decreased the CO(2) uptake due to the inhibiting effect of the neutral species (protonated form of AHA) that is formed. PMID- 25431972 TI - A directed-overflow and damage-control N-glycosidase in riboflavin biosynthesis. AB - Plants and bacteria synthesize the essential human micronutrient riboflavin (vitamin B2) via the same multi-step pathway. The early intermediates of this pathway are notoriously reactive and may be overproduced in vivo because riboflavin biosynthesis enzymes lack feedback controls. In the present paper, we demonstrate disposal of riboflavin intermediates by COG3236 (DUF1768), a protein of previously unknown function that is fused to two different riboflavin pathway enzymes in plants and bacteria (RIBR and RibA respectively). We present cheminformatic, biochemical, genetic and genomic evidence to show that: (i) plant and bacterial COG3236 proteins cleave the N-glycosidic bond of the first two intermediates of riboflavin biosynthesis, yielding relatively innocuous products; (ii) certain COG3236 proteins are in a multi-enzyme riboflavin biosynthesis complex that gives them privileged access to riboflavin intermediates; and (iii) COG3236 action in Arabidopsis thaliana and Escherichia coli helps maintain flavin levels. COG3236 proteins thus illustrate two emerging principles in chemical biology: directed overflow metabolism, in which excess flux is diverted out of a pathway, and the pre-emption of damage from reactive metabolites. PMID- 25431975 TI - Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. AB - BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is an allergic reaction to colonisation of the lungs with the fungus Aspergillus fumigatus and affects around 10% of people with cystic fibrosis. ABPA is associated with an accelerated decline in lung function. High doses of corticosteroids are the main treatment for ABPA; although the long-term benefits are not clear, their many side effects are well-documented. A group of compounds, the azoles, have activity against Aspergillus fumigatus and have been proposed as an alternative treatment for ABPA. Of this group, itraconazole is the most active. A separate antifungal compound, amphotericin B, has been employed in aerosolised form to treat invasive infection with Aspergillus fumigatus, and may have potential for the treatment of ABPA. Antifungal therapy for ABPA in cystic fibrosis needs to be evaluated. OBJECTIVES: The review aimed to test the hypotheses that antifungal interventions for the treatment of ABPA in cystic fibrosis:1. improve clinical status compared to placebo or standard therapy (no placebo);2. do not have unacceptable adverse effects.If benefit was demonstrated, we aimed to assess the optimal type, duration and dose of antifungal therapy. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings.In addition, pharmaceutical companies were approached.Date of the most recent search of the Group's Trials Register: 17 March 2014. SELECTION CRITERIA: Published or unpublished randomised controlled trials, where antifungal treatments have been compared to either placebo or no treatment, or where different doses of the same treatment have been used in the treatment of ABPA in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Four trials were identified by the searches; none of which was judged eligible for inclusion in the review. MAIN RESULTS: No completed randomised controlled trials were included. AUTHORS' CONCLUSIONS: At present, there are no randomised controlled trials to evaluate the use of antifungal therapies for the treatment of ABPA in people with cystic fibrosis, although trials in people who do not have cystic fibrosis have shown clinical and serological evidence of improvement and a reduction in the use of corticosteroids with no increase in adverse effects. Trials with clear outcome measures are needed to properly evaluate this potentially useful treatment for cystic fibrosis. PMID- 25431976 TI - In situ helicity inversion of self-assembled nano-helices. AB - The handedness of nanometrical helices based on surfactant assemblies was inverted when these helices were in contact with an excess solution of chiral anions with opposite enantiomers. An important difference in the kinetics of chirality inversion at the molecular level and mesoscopic level was observed. PMID- 25431977 TI - Optimization of sphingosine-1-phosphate-1 receptor agonists: effects of acidic, basic, and zwitterionic chemotypes on pharmacokinetic and pharmacodynamic profiles. AB - The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P1 receptors, while a variety of side effects have been ascribed to its S1P3 receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P1 receptor agonism. Here we describe a study of the tolerance of the S1P1 and S1P3 receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P1 receptor agonists with good selectivity vs S1P3 receptors, efficacy at <1 mg/kg oral doses, and developability properties suitable for progression into preclinical development. PMID- 25431978 TI - Family involvement in music impacts participation of children with cochlear implants in music education and music activities. AB - Objective Children with cochlear implants (CIs) participate in musical activities in school and daily lives. Considerable variability exists regarding the amount of music involvement and enjoyment. Using the Music Engagement Questionnaire Preschool/Elementary (MEQ-P/E), we wanted to determine patterns of musical participation and the impact of familial factors on engagement. Methods Parents of 32 children with CIs (16 preschool and 16 elementary) completed a questionnaire regarding the musical involvement of their child with an implant and a normal-hearing (NH) sibling (if one existed). We compared CI children's involvement to that of their NH siblings as well as across groups of children with and without CIs. Correlations between parent ratings of music importance, demographic factors, and involvement of CI and NH children were conducted within and across groups. Results No significant differences were found between children with CIs and NH siblings, meaning children from the same family showed similar levels of musical involvement. When compared at the same developmental stage, no significant differences were found between preschool children with and without CIs. Parents who rated the importance of music as 'low' or 'middle' had children (NH and CI) who were less involved in music activities. Children whose parents rated music importance as 'high' were involved in monthly to weekly music activities with 81.25% reporting daily music listening. Conclusion Despite a less than-ideal auditory signal for music, preschool and school-aged CI children enjoy and are involved in musical experiences. Families who enjoy and spend a greater amount of time involved in music tend to have children who also engage more actively in music. PMID- 25431979 TI - [Medicina del Lavoro and the impact factor]. PMID- 25431980 TI - Estimating number of workers potentially at risk of exposure to hardwood dust in certain industrial sectors in Italy using a national register. AB - BACKGROUND: Hardwood dust is a well-known human carcinogen and its use is common in several economic activities. OBJECTIVES: The aim of this study was to assess the extent of occupational exposure to hardwood dust in certain sectors of Italian industry. METHODS: Information on occupational exposures was collected from enterprise exposure registers that must by law be reported to the National Workers' Compensation Authority, as at 31 December 2011. Data stored in the database included economic activity sector, work force size and exposed workers. The number of workers potentially exposed was estimated for some of the industrial sectors from national occupational statistics in Italy. RESULTS: The economic sector with the highest number of potentially exposed workers to hardwood dust was that classified as the manufacture of other wooden furniture with 15,760 men and 2,771 women, while the highest percentage of enterprises that had sent data (according to the ISTAT 2001 census) was in building and repair of non-metallic ships (21%). CONCLUSIONS: The systematic recording of occupational exposures is a source of data that permits recognition of high risk situations and aids exposure assessment for epidemiological studies. PMID- 25431981 TI - [Occupational safety and health risks in dock work: a narrative literature review. ]. AB - BACKGROUND: Seaports are complex systems where workers can be exposed to a large variety of safety and health risks. Nevertheless, the literature available on this topic is scarce, if we exclude the specific area of the shipbuilding industry. OBJECTIVES AND METHODS: The aim of this paper is to provide a review of the scientific evidence concerning the occupational risks in seaports. Literature on this theme, obtained consulting the main databases (PubMed, Scholar and CCOHS) up to 2012, was reviewed. RESULTS: Loading/unloading procedures, transport and storage of goods in docks are identified as the major causes of injuries (such as falls, crushing and entrapments) and accidents (release of chemicals, fires or explosions). Moreover, attention is drawn to the risks related to goods handled: in particular, authors described risks of asphyxia or intoxication in restricted and poorly ventilated areas such as containers or ship holds. CONCLUSIONS: The following main prevention measures were identified by all authors as those most effective: implementation of workers' training and information and intensification of controls on ships, particularly concerning loading/unloading procedures and documents accompanying the goods. PMID- 25431982 TI - Women, work and health between the nineteenth and twentieth centuries from a national and international perspective. AB - BACKGROUND: A few years after a series of meetings of Italian scientists were convened prior to the unification of Italy, the first women qualified in medicine and other dedicated women participated in founding a movement for the improvement of living and working conditions of women and children in Italy. OBJECTIVES: analysis of Italian women's contributions in the proceedings of the International Council of Women Congresses and their impact on increasing the number of women's occupational health studies presented at the fourth National Congress on Occupational Diseases held in Rome in 1914. METHODS: Analysis of the proceedings of the International Council of Women Congresses (Washington, Chicago, London), and of the Women's National Council and other documents so as to obtain a picture of Italian women's working conditions at that time. RESULTS: Women and children worked an excessive number of hours per day, were underpaid, and had a legal status of inferiority. The main work sectors were sewing, embroidery, lace making, ironing, cooking, washing, dressmaking, millinery, fashion design, typing, weaving, artificial flowers, etc. The same sort of work was available to Italian women who emigrated to the United States of America. The success achieved by the women's movement is shown in the paper presented by Irene de Bonis "Occupational diseases among women" and published in the proceedings of the fourth National Congress on Occupational Diseases held in Rome, 9-14 June 1914. CONCLUSIONS: The article outlines the main features of the women's movement at the turn of the twentieth century, focussing on their publications describing Italian women's working conditions, considered in an international context. The movement's engagement in the promotion of women's occupational health at international and national level was successful but the First World War was to transform this achievement into the women's peace movement. PMID- 25431983 TI - [Judgment of fitness for work in employees with a history of malignant neoplastic disease and exposed to ionizing radiations: evaluation criteria and their application in a case-series study]. AB - INTRODUCTION: The increase in working age has many epidemiological consequences, one of which is an increased incidence of neoplastic diseases among the working population. Therefore it is more frequent than in the past that the Approved Physician ("Autorizzato" according to Italian legislation) have to judge working fitness in employees suffering from cancer and at the same time exposed to ionizing sources. AIMS: In this study we give suggestions for the decision if a worker, who have previously suffered from malignant tumors, is ready to go or not to go back to work. METHODS: Though we believe in the preventive theory of the linear correlation without threshold for stochastic effects ("Linear No Threshold" LNT), we considered data from the literature that highlight how very low doses of radiation exposure do not increase the risk of stochastic effects and how the potential occupational exposure to low doses does not introduce a significant additional risk of cancer in subjects with a history of malignant tumor. RESULTS: We identify "objective" elements of judgment related to the neoplastic disease of the worker and his activity, but we emphasize the importance of the psychological condition of the worker, as well as his professional interest and his career opportunities. CONCLUSIONS: The criteria we recommend were applied to a group of workers suffering from cancer and with different working activities at risk of exposure to ionizing radiations. The evaluation process is a first rational approach to the assessment of their suitability in worker suffering from neoplastic disease, with the need for custom handling for each individual. PMID- 25431984 TI - Health promotion in the workplace. PMID- 25431985 TI - [About the change of the name of the Italian Society of Ergonomics]. PMID- 25431986 TI - Fifth International Conference on the History of Occupational and Environmental Health. Rotterdam (The Netherlands), April 24-25, 2014. PMID- 25431988 TI - An evaluation of Admedus' tissue engineering process-treated (ADAPT) bovine pericardium patch (CardioCel) for the repair of cardiac and vascular defects. AB - Tissue engineers have been seeking the 'Holy Grail' solution to calcification and cytotoxicity of implanted tissue for decades. Tissues with all of the desired qualities for surgical repair of congenital heart disease (CHD) are lacking. An anti-calcification tissue engineering process (ADAPT TEP) has been developed and applied to bovine pericardium (BP) tissue (CardioCel, AdmedusRegen Pty Ltd, Perth, WA, Australia) to eliminate cytotoxicity, improve resistance to acute and chronic inflammation, reduce calcification and facilitate controlled tissue remodeling. Clinical data in pediatric patients, and additional pre-market authorized prescriber data demonstrate that CardioCel performs extremely well in the short term and is safe and effective for a range of congenital heart deformations. These data are supported by animal studies which have shown no more than normal physiologic levels of calcification, with good durability, biocompatibility and controlled healing. PMID- 25431990 TI - Nanostructured TiO2/carbon nanosheet hybrid electrode for high-rate thin-film lithium-ion batteries. AB - Heterogeneous nanostructured electrodes using carbon nanosheets (CNS) and TiO2 exhibit high electronic and ionic conductivity. In order to realize the chip level power sources, it is necessary to employ microelectronic compatible techniques for the fabrication and characterization of TiO2-CNS thin-film electrodes. To achieve this, vertically standing CNS grown through a catalytic free approach on a TiN/SiO2/Si substrate by plasma enhanced chemical vapour deposition (PECVD) was used. The substrate-attached CNS is responsible for the sufficient electronic conduction and increased surface-to-volume ratio due to its unique morphology. Atomic layer deposition (ALD) of nanostructured amorphous TiO2 on CNS provides enhanced Li storage capacity, high rate performance and stable cycling. The amount of deposited TiO2 masks the underlying CNS, thereby controlling the accessibility of CNS, which gets reflected in the total electrochemical performance, as revealed by the cyclic voltammetry and charge/discharge measurements. TiO2 thin-films deposited with 300, 400 and 500 ALD cycles on CNS have been studied to understand the kinetics of Li insertion/extraction. A large potential window of operation (3-0.01 V); the excellent cyclic stability, with a capacity retention of 98% of the initial value; and the remarkable rate capability (up to 100 C) are the highlights of TiO2/CNS thin-film anode structures. CNS with an optimum amount of TiO2 coating is proposed as a promising approach for the fabrication of electrodes for chip compatible thin-film Li-ion batteries. PMID- 25431989 TI - Evolutionary origin of a streamlined marine bacterioplankton lineage. AB - Planktonic bacterial lineages with streamlined genomes are prevalent in the ocean. The base composition of their DNA is often highly biased towards low G+C content, a possible source of systematic error in phylogenetic reconstruction. A total of 228 orthologous protein families were sampled that are shared among major lineages of Alphaproteobacteria, including the marine free-living SAR11 clade and the obligate endosymbiotic Rickettsiales. These two ecologically distinct lineages share genome sizes of <1.5 Mbp and genomic G+C content of <30%. Statistical analyses showed that only 28 protein families are composition homogeneous, whereas the other 200 families significantly violate the composition homogeneous assumption included in most phylogenetic methods. RAxML analysis based on the concatenation of 24 ribosomal proteins that fall into the heterogeneous protein category clustered the SAR11 and Rickettsiales lineages at the base of the Alphaproteobacteria tree, whereas that based on the concatenation of 28 homogeneous proteins (including 19 ribosomal proteins) disassociated the lineages and placed SAR11 at the base of the non-endosymbiotic lineages. When the two data sets were concatenated, only a model that accounted for compositional bias yielded a tree identical to the tree built with composition-homogeneous proteins. Ancestral genome analysis suggests that the first evolved SAR11 cell had a small genome streamlined from its ancestor by a factor of two and coinciding with an ecological transition, followed by further gradual streamlining towards the extant SAR11 populations. PMID- 25431991 TI - Radiation cross-linked collagen/dextran dermal scaffolds: effects of dextran on cross-linking and degradation. AB - Ionizing radiation effectively cross-links collagen into network with enhanced anti-degradability and biocompatibility, while radiation-cross-linked collagen scaffold lacks flexibility, satisfactory surface appearance, and performs poor in cell penetration and ingrowth. To make the radiation-cross-linked collagen scaffold to serve as an ideal artificial dermis, dextran was incorporated into collagen. Scaffolds with the collagen/dextran (Col/Dex) ratios of 10/0, 7/3, and 5/5 were fabricated via (60)Co gamma-irradiation cross-linking, followed by lyophilization. The morphology, microstructure, physicochemical, and biological properties were investigated. Compared with pure collagen, scaffolds with dextran demonstrated more porous appearance, enhanced hydrophilicity while the cross linking density was lower with the consequence of larger pore size, higher water uptake, as well as reduced stiffness. Accelerated degradation was observed when dextran was incorporated in both the in vitro and in vivo assays, which led to earlier integration with cell and host tissue. The effect of dextran on degradation was ascribed to the decreased cross-linking density, looser microstructure, more porous and hydrophilic surface. Considering the better appearance, softness, moderate degradation rate due to controllable cross-linking degree and good biocompatibility as well, radiation-cross-linked collagen/dextran scaffolds are expected to serve as promising artificial dermal substitutes. PMID- 25431992 TI - Embodiment and self in reorientation to everyday life following severe traumatic brain injury. AB - People with severe traumatic brain injury (sTBI) are often young and need long term follow-up as many suffer complex motor, sensory, perceptual and cognitive impairments. This paper aims to introduce phenomenological notions of embodiment and self as a framework to help understand how people with sTBI experience reorientation to everyday life, and to inform clinical practice in neurological physiotherapy. The impairments caused by the sTBI may lead to a sense of alienation of one's own body and changes in operative intentionality and in turn disrupt the reorganization of self, identity, everyday life and integration/co construction of meaning with others. Applying a first-person conception of the body may extend insights into the importance of an adapted and individualized approach to strengthen the sensory, perceptual and motor body functions, which underpin the pre-reflective and reflective aspects of the self. It seems important to integrate these aspects, while also paying attention to optimizing co-construction of meaning for the person with sTBI in the treatment context. This requires understanding the patient as an experiencing and expressive body, a lived body (body-as-subject) and not just the body-as-object as is favored in more traditional frameworks of physiotherapy. PMID- 25431993 TI - Monitoring and reversal strategies for new oral anticoagulants. AB - Thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban, apixaban and edoxaban form a new class of non-vitamin K antagonist oral anticoagulants and have been extensively studied in patients with venous thromboembolism and atrial fibrillation. They offer anticoagulation that is as effective and at least as safe compared to warfarin without the need for routine laboratory monitoring; however, no reversal strategies are currently validated in case of a non-vitamin K antagonist oral anticoagulant-associated bleed. In emergency situations, laboratory drug measurement and well-defined management for non-vitamin K antagonist oral anticoagulant-induced hemorrhage may improve clinical outcome. In this review, the merits and limitations of the routine coagulation tests and some of the more specific laboratory assays are compared. Furthermore, prohemostatic measures are reviewed and the recommended strategies in case of bleeding are summarized. Specific reversal agents are currently under development (idarucizumab for dabigatran, andexanet alfa for Xa inhibitors, and PER977 for both Xa- and thrombin inhibitors), which will facilitate clinical management of severe bleeding and emergency surgery. PMID- 25431994 TI - A graphene/zinc oxide nanocomposite film protects dental implant surfaces against cariogenic Streptococcus mutans. AB - Oral biofilms play a crucial role in the development of dental caries and other periodontal diseases. Streptococcus mutans is one of the primary etiological agents in dental caries. Implant systems are regularly employed to replace missing teeth. Oral biofilms accumulate on these implants and are the chief cause of dental implant failure. In the present study, the potential of graphene/zinc oxide nanocomposite (GZNC) against the cariogenic properties of Streptococcus mutans was explored and the anti-biofilm behaviour of artificial acrylic teeth surfaces coated with GZNC was examined. Acrylic teeth are a good choice for implants as they are low cost, have low density and can resist fracture. Microscopic studies and anti-biofilm assays showed a significant reduction in biofilm in the presence GZNC. GZNC was also found to be nontoxic against HEK-293 (human embryonic kidney cell line). The results indicate the potential of GZNC as an effective coating agent for dental implants by efficiently inhibiting S. mutans biofilms. PMID- 25431995 TI - Probing the binding mechanism of Mnk inhibitors by docking and molecular dynamics simulations. AB - Mitogen-activated protein kinases-interacting kinase 1 and 2 (Mnk1/2) activate the oncogene eukaryotic initiation factor 4E (eIF4E) by phosphorylation. High level of phosphorylated eIF4E is associated with various types of cancers. Inhibition of Mnk prevents eIF4E phosphorylation, making them potential therapeutic targets for cancer. Recently, we have designed and synthesized a series of novel imidazopyridine and imidazopyrazine derivatives that inhibit Mnk1/2 kinases with a potency in the nanomolar to micromolar range. In the current work we model the inhibition of Mnk kinase activity by these inhibitors using various computational approaches. Combining homology modeling, docking, molecular dynamics simulations, and free energy calculations, we find that all compounds bind similarly to the active sites of both kinases with their imidazopyridine and imidazopyrazine cores anchored to the hinge regions of the kinases through hydrogen bonds. In addition, hydrogen bond interactions between the inhibitors and the catalytic Lys78 (Mnk1), Lys113 (Mnk2) and Ser131 (Mnk1), Ser166 (Mnk2) appear to be important for the potency and stability of the bound conformations of the inhibitors. The computed binding free energies (DeltaGPred) of these inhibitors are in accord with experimental bioactivity data (pIC50) with correlation coefficients (r(2)) of 0.70 and 0.68 for Mnk1 and Mnk2 respectively. van der Waals energies and entropic effects appear to dominate the binding free energy (DeltaGPred) for each Mnk-inhibitor complex studied. The models suggest that the activities of these small molecule inhibitors arise from interactions with multiple residues in the active sites, particularly with the hydrophobic residues. PMID- 25431996 TI - Radiation protection: where are we after Fukushima? PMID- 25431997 TI - Passive cigarette smoke exposure and other risk factors for invasive pneumococcal disease in children: a case-control study. AB - OBJECTIVE: To investigate whether passive cigarette smoke exposure increases the risk of invasive pneumococcal disease in children. METHODS: In a population-based case-control study, 171 children aged 0 to 12 years with culture-confirmed invasive pneumococcal disease during the years 1994 to 2004 were identified. Two controls were matched to each case on age and patterns of Health Plan membership. We reviewed medical records of subjects and family members for information on household cigarette smoke exposure within 2 years of the diagnosis of invasive pneumococcal disease. We collected information on sex, race, pneumococcal vaccination, selected medical conditions, and medications in the 3 months before the diagnosis. RESULTS: Similar proportions of cases (25%) and controls (30%) had definite or probable passive smoke exposure (odds ratio [OR] = 0.76, 95% confidence interval [CI] = 0.47-1.2). Cases of invasive pneumococcal disease were more likely to be nonwhite than controls (OR = 4.4, 95% CI = 2.3-8.2). Elevated risk of invasive pneumococcal disease was found in subjects with recent pulmonary diagnoses (OR = 2.2, 95% CI = 1.2-4.0) and recent antibiotic use (OR = 1.6, 95% CI = 1.1-2.3). CONCLUSIONS: Passive cigarette smoke exposure was not associated with invasive pneumococcal disease in this pediatric population. Invasive pneumococcal disease was associated with recent pulmonary diagnoses and recent antibiotic use. PMID- 25431998 TI - Financial implications of the continuity of primary care. AB - BACKGROUND: The objective of this study was to assess the financial implications of the continuity of care, for patients with high care needs, by examining the cost of government-funded health care services in British Columbia, Canada. METHODS: Using British Columbia Ministry of Health administrative databases for fiscal year 2010-2011 and generalized linear models, we estimated cost ratios for 10 cost-related predictor variables, including patients' attachment to the practice. Patients were selected and divided into groups on the basis of their Resource Utilization Band (RUB) and placement in provincial registries for 8 chronic conditions (1,619,941 patients). The final dataset included all high- and very-high-care-needs patients in British Columbia (ie, RUB categories 4 and 5) in 1 or more of the 8 registries who met the screening criteria (222,779 patients). RESULTS: Of the 10 predictors, across 8 medical conditions and both RUBs, patients' attachment to the practice had the strongest relationship to costs (correlations = -0.168 to -0.322). Higher attachment was associated with lower costs. Extrapolation of the findings indicated that an increase of 5% in the overall attachment level, for the selected high-care-needs patients, could have resulted in an estimated cost avoidance of $142 million Canadian for fiscal year 2010-2011. CONCLUSIONS: Continuity of care, defined as a patient's attachment to his/her primary care practice, can reduce health care costs over time and across chronic conditions. Health care policy makers may wish to consider creating opportunities for primary care physicians to increase the attachment that their high-care-needs patients have to their practices. PMID- 25431999 TI - A plant-based diet, atherogenesis, and coronary artery disease prevention. AB - A plant-based diet is increasingly becoming recognized as a healthier alternative to a diet laden with meat. Atherosclerosis associated with high dietary intake of meat, fat, and carbohydrates remains the leading cause of mortality in the US. This condition results from progressive damage to the endothelial cells lining the vascular system, including the heart, leading to endothelial dysfunction. In addition to genetic factors associated with endothelial dysfunction, many dietary and other lifestyle factors, such as tobacco use, high meat and fat intake, and oxidative stress, are implicated in atherogenesis. Polyphenols derived from dietary plant intake have protective effects on vascular endothelial cells, possibly as antioxidants that prevent the oxidation of low-density lipoprotein. Recently, metabolites of L-carnitine, such as trimethylamine-N-oxide, that result from ingestion of red meat have been identified as a potential predictive marker of coronary artery disease (CAD). Metabolism of L-carnitine by the intestinal microbiome is associated with atherosclerosis in omnivores but not in vegetarians, supporting CAD benefits of a plant-based diet. Trimethylamine-N oxide may cause atherosclerosis via macrophage activation. We suggest that a shift toward a plant-based diet may confer protective effects against atherosclerotic CAD by increasing endothelial protective factors in the circulation while reducing factors that are injurious to endothelial cells. The relative ratio of protective factors to injurious endothelial exposure may be a novel approach to assessing an objective dietary benefit from a plant-based diet. This review provides a mechanistic perspective of the evidence for protection by a plant-based diet against atherosclerotic CAD. PMID- 25432000 TI - Upstream discussion provided in the ambulatory setting to assist patients with chronic kidney disease considering dialysis. AB - OBJECTIVES: Extensive discussion with renal patients about treatment intensity is not systematically integrated into their care and often occurs during an acute hospitalization. We conducted a "test-of-change" pilot study to assess the utility of providing an upstream discussion in the ambulatory setting as an additional nephrology consult to assist patients with chronic kidney disease considering treatment choices. METHODS: We randomly assigned patients with Stage 4 or Stage 5 chronic kidney disease who had not yet begun renal dialysis to 1 of 2 groups. The test group received the additional nephrology consult and met with an interdisciplinary team composed of a nephrologist, social worker, and clinical ethicist, and the control group did not. Qualitative data were collected in 2012 and 2013 via oral questionnaire. Both groups received a 6-month follow-up assessment. RESULTS: Patients who received the nephrology consult reported that they experienced help in forming a treatment plan, felt well understood, and had the opportunity to thoroughly discuss questions. The controls had a 26% increased probability of beginning dialysis and had a statistically significant increase in dialysis and clinic visits (p < 0.10 and p < 0.05). Controls also were likelier than the test group to be admitted to the hospital (0.5 vs 0.2 admissions per patient in the test group), spend more days hospitalized (2.8 vs 0.5 bed days per patient), and visit the emergency room (0.73 vs 0.66 visits per patient) and clinic (6.6 vs 3.6 visits per patient). CONCLUSIONS: An additional nephrology consultation proved helpful both qualitatively and quantitatively. PMID- 25432001 TI - Acupuncture safety in patients receiving anticoagulants: a systematic review. AB - INTRODUCTION: Theoretically, acupuncture in anticoagulated patients could increase bleeding risk. However, precise estimates of bleeding complication rates from acupuncture in anticoagulated patients have not been systematically examined. OBJECTIVE: To critically evaluate evidence for safety of acupuncture in anticoagulated patients. METHODS: We searched PubMed, EMBASE, the Physiotherapy Evidence Database, and Google Scholar. RESULTS: Of 39 potentially relevant citations, 11 met inclusion criteria: 2 randomized trials, 4 case series, and 5 case reports. Seven provided reporting quality sufficient to assess acupuncture safety in 384 anticoagulated patients (3974 treatments). Minor-moderate bleeding related to acupuncture in an anticoagulated patient occurred in one case: a large hip hematoma, managed with vitamin K reversal and warfarin discontinuation following reevaluation of its medical justification. Blood-spot bleeding, typical for any needling/injection and controlled with pressure/cotton, occurred in 51 (14.6%) of 350 treatments among a case series of 229 patients. Bleeding deemed unrelated to acupuncture during anticoagulation, and more likely resulting from inappropriately deep needling damaging tissue or from complex anticoagulation regimens, occurred in 5 patients. No bleeding was reported in 2 studies (74 anticoagulated patients): 1 case report and 1 randomized trial prospectively monitoring acupuncture-associated bleeding as an explicit end point. Altogether, 1 moderate bleeding event occurred in 3974 treatments (0.003%). CONCLUSION: Acupuncture appears to be safe in anticoagulated patients, assuming appropriate needling location and depth. The observed 0.003% complication rate is lower than the previously reported 12.3% following hip/knee replacement in a randomized trial of 27,360 anticoagulated patients, and 6% following acupuncture in a prospective study of 229,230 all-type patients. Prospective trials would help confirm our findings. PMID- 25432002 TI - Nasal methicillin-resistant Staphylococcus aureus polymerase chain reaction: a potential use in guiding antibiotic therapy for pneumonia. AB - CONTEXT: The role at admission of nasal polymerase chain reaction (PCR) for patients with methicillin-resistant Staphylococcus aureus (MRSA) in guiding antibiotic therapy for lower respiratory tract infection is unknown. OBJECTIVE: To determine whether nasal MRSA PCR at admission can predict the absence of MRSA in lower respiratory tract secretions. DESIGN: We performed a retrospective study of adult patients admitted to a large urban hospital. Patients had a nasal MRSA PCR test and a lower respiratory tract culture obtained within 48 hours of admission and the culture yielded S aureus. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values. RESULTS: Our results showed high sensitivity (93.3%) and negative predictive value (95.2%) of nasal PCR for MRSA in the lower respiratory tract. CONCLUSION: With its high sensitivity and negative predictive value, a nasal MRSA PCR test performed within 48 hours of hospital admission could help guide the discontinuation of MRSA directed empiric antibiotic therapy in patients who are unlikely to be infected with this organism. A prospective study is needed to confirm these findings. PMID- 25432004 TI - Natural occurrence of emerging Fusarium mycotoxins in feed and fish from aquaculture. AB - A new analytical method for the simultaneous determination of enniatins (ENs) and beauvericin (BEA) in fish feed and fish tissues by liquid chromatography coupled to mass spectrometry with linear ion trap (LC-MS/MS-LIT) was developed. Results showed that the developed method is precise and sensitive. The presence of emerging Fusarium mycotoxins, ENs and BEA, was determined in samples of aquaculture fish and feed for farmed fish, showing that all feed samples analyzed were contaminated with mycotoxins, with 100% coexistence. In aquacultured fish samples, the highest incidence was found in edible muscle and liver. As for the exposure assessment calculated, it was found that average consumer intake was lower than tolerable daily intake (TDI) values for other Fusarium mycotoxins. PMID- 25432003 TI - Recurrent Focal Segmental Glomerulosclerosis and Abatacept: Case Report. AB - Focal segmental glomerulosclerosis is a common cause of end-stage renal disease in children. Focal segmental glomerulosclerosis recurrence in renal transplants is a challenging disease, and can cause graft dysfunction and loss. Different therapies exist with varying responses, from complete remission to resistance to all modes of treatment. Abatacept was recently introduced as a treatment for primary focal segmental glomerulosclerosis in native kidneys and in recurrent disease after transplant. We present a pediatric case with immunosuppression resistant primary NPHS2-negative focal segmental glomerulosclerosis recur-rence after renal transplant. The standard therapy for recurrent focal segmental glomerulosclerosis (rituximab, plasmapheresis, high-dose cyclosporine, and corticosteroids) was tried but failed to induce remission. Abatacept (10 mg/kg) was given at 0, 2, and 4 weeks (total, 3 doses) with no good response. We conclude that abatacept may work in patients with B7-1-positive focal segmental glomerulosclerosis recurrence and its efficacy is uncertain in disease with B7-1 negative or unknown staining status. PMID- 25432005 TI - Goniolactone C, a styryl lactone derivative, inhibits PDGF-BB-induced vascular smooth muscle cell migration and proliferation via PDGFR/ERK signaling. AB - Platelet-derived growth factor-BB (PDGF-BB) and its downstream effector, extracellular signal-regulated kinase 1/2 (ERK1/2) MAP kinase, initiate a multitude of biological effects, including vascular smooth muscle cell (VSMC) proliferation and migration, which are critical events in the initiation and development of restenosis following percutaneous transluminal coronary angioplasty (PTCA). Styryl lactones are natural products that have been demonstrated to possess anti-proliferative activities. Goniolactone C is a styryl lactone derivative that was first extracted from Goniothalamus cheliensis Hu. In the present study, we investigated the effects of goniolactone C on VSMC migration and proliferation. We found that goniolactone C preferentially interacted with cellular systems that rely on PDGF signaling but not those that rely on epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) signaling. Goniolactone C strongly inhibited PDGF-BB-induced VSMC migration and proliferation. goniolactone C-mediated inhibition of VSMC proliferation was associated with cell cycle arrest, while goniolactone C-mediated inhibition of VSMC migration was associated with the suppression of adhesion molecule expression. In addition, goniolactone C directly inhibited PDGFR-beta kinase activity, thereby blocking the downstream effector of PDGF-BB. Thus, the results of the present study suggest a novel adjunctive pharmacological strategy that may be used to prevent angioplasty-related restenosis. PMID- 25432006 TI - Concise and straightforward asymmetric synthesis of a cyclic natural hydroxy amino acid. AB - An enantioselective total synthesis of the natural amino acid (2S,4R,5R)-4,5-di hydroxy-pipecolic acid starting from D-glucoheptono-1, 4-lactone is presented. The best sequence employed as a key step the intramolecular nucleophilic displacement by an amino function of a 6-O-p-toluene-sulphonyl derivative of a methyl D-arabino-hexonate and involved only 12 steps with an overall yield of 19%. The structures of the compounds synthesized were elucidated on the basis of comprehensive spectroscopic (NMR and MS) and computational analysis. PMID- 25432007 TI - Evaluation of the chemical and antioxidant properties of wild and cultivated mushrooms of Ghana. AB - Knowledge of the chemical composition of both wild and cultivated edible mushrooms in Ghana is limited. This study reports their nutritional value, composition in lipophilic and hydrophilic molecules, minerals and antioxidant properties. The samples were found to be nutritionally rich in carbohydrates, ranging from 64.14 +/- 0.93 g in Pleurotus ostreatus strain EM-1 to 80.17 +/- 0.34 g in Lentinus squarosullus strain LSF. The highest level of proteins (28.40 +/- 0.86 g) was recorded in the mentioned P. ostreatus strain. Low fat contents were registered in the samples, with Auricularia auricula recording the lowest value. High levels of potassium were also observed with the following decreasing order of elements: K > P ~ Na > Mg > Ca. High levels of antioxidants were also observed, thus making mushrooms suitable to be used as functional foods or nutraceutical sources. Furthermore, this study provides new information regarding chemical properties of mushrooms from Ghana, which is very important for the biodiversity characterization of this country. PMID- 25432008 TI - Some observations on the development of superior photocatalytic systems for application to water purification by the "adsorb and shuttle" or the interphase charge transfer mechanisms. AB - Adsorb and shuttle (A/S) and interfacial charge transfer are the two major strategies for overcoming recombination in photocatalysis in this era of nanoparticle composites. Their relationships are considered here. A review of key literature is accompanied by a presentation of three new experiments within the overall aim of assessing the relation of these strategies. The cases presented include: A/S by a high silica zeolite/TiO2 composite, charge transfer (CT) between phases in a TiO2/WO3 composite and both A/S and CT by composites of TiO2 with powered activated carbon (AC) and single-walled carbon nanotubes (SWCNT). The opportunities presented by the two strategies for moving toward photocatalysts that could support applications for the removal of contaminants from drinking water or that lead to a practical adsorbent for organics that could be regenerated photocatalytically link this discussion to ongoing research here. PMID- 25432009 TI - Influence of post-treatment operations on structural properties and photocatalytic activity of octahedral anatase titania particles prepared by an ultrasonication-hydrothermal reaction. AB - The influence of changes in structural and physical properties on the photocatalytic activity of octahedral anatase particles (OAPs), exposing eight equivalent {101} facets, caused by calcination (2 h) in air or grinding (1 h) in an agate mortar was studied with samples prepared by ultrasonication (US; 1 h) hydrothermal reaction (HT; 24 h, 433 K). Calcination in air at temperatures up to 1173 K induced particle shape changes, evaluated by aspect ratio (AR; d001/d101 = depth vertical to anatase {001} and {101} facets estimated by the Scherrer equation with data obtained from X-ray diffraction (XRD) patterns) and content of OAP and semi-OAP particles, without transformation into rutile. AR and OAP content, as well as specific surface area (SSA), were almost unchanged by calcination at temperatures up to 673 K and were then decreased by elevating the calcination temperature, suggesting that calcination at a higher temperature caused dull-edging and particle sintering, the latter also being supported by the analysis of particle size using XRD patterns and scanning electron microscopic (SEM) images. Time-resolved microwave conductivity (TRMC) showed that the maximum signal intensity (Imax), corresponding to a product of charge-carrier density and mobility, and signal-decay rate, presumably corresponding to reactivity of charge carriers, were increased with increase in AR, suggesting higher photocatalytic activity of OAPs than that of dull-edged particles. Grinding also decreased the AR, indicating the formation of dull-edged particles. The original non-treated samples showed activities in the oxidative decomposition of acetic acid (CO2 system) and dehydrogenation of methanol (H2 system) comparable to and lower than those of a commercial anatase titania (Showa Denko Ceramics FP-6), respectively. The activities of calcined and ground samples for the CO2 system and H2 system showed almost linear relations with AR and Imax, respectively, suggesting that those activities may depend on different properties. PMID- 25432010 TI - Special issue: redox active natural products and their interaction with cellular signalling pathways. AB - During the last decade, research into natural products has experienced a certain renaissance. The urgent need for more and more effective antibiotics in medicine, the demand for ecologically friendly plant protectants in agriculture, "natural" cosmetics and the issue of a sustainable and healthy nutrition in an ageing society have fuelled research into Nature's treasure chest of "green gold". Here, redox active secondary metabolites from plants, fungi, bacteria and other (micro )organisms often have been at the forefront of the most interesting developments. These agents provide powerful means to interfere with many, probably most cellular signaling pathways in humans, animals and lower organisms, and therefore can be used to protect, i.e., in form of antioxidants, and to frighten off or even kill, i.e., in form of repellants, antibiotics, fungicides and selective, often catalytic "sensor/effector" anticancer agents. Interestingly, whilst natural product research dates back many decades, in some cases even centuries, and compounds such as allicin and various flavonoids have been investigated thoroughly in the past, it has only recently become possible to investigate their precise interactions and mode(s) of action inside living cells. Here, fluorescent staining and labelling on the one side, and appropriate detection, either qualitatively under the microscope or quantitatively in flow cytometers and plate readers, on the other, enable researchers to obtain the various pieces of information necessary to construct a fairly complete puzzle of how such compounds act and interact in living cells. Complemented by the more traditional activity assays and Western Blots, and increasingly joined by techniques such as proteomics, chemogenetic screening and mRNA profiling, these cell based bioanalytical techniques form a powerful platform for "intracellular diagnostics". In the case of redox active compounds, especially of Reactive Sulfur Species (RSS), such techniques have recently unraveled concepts such as the "cellular thiolstat", yet considerably more research is required in order to gain a full understanding of why and how such compounds act-often selectively-in different organisms. PMID- 25432011 TI - The effect of Lycii Radicis Cortex extract on bone formation in vitro and in vivo. AB - Osteoporosis is a common skeletal disease caused by decreased bone mass; it enhances the risk of bone fracture. This study aimed to discover novel herbal extract(s) for the treatment of osteoporosis. We screened 64 ethanol extracts of edible plants native to Korea for their ability to increase the cellular proliferation and differentiation of two osteoblastic cell lines: C3H10T1/2 and MC3T3-E1. We selected a Lycii Radicis Cortex (LRC), Lycium Chinese root bark as the primary candidate. Treatment with LRC extract showed enhanced alkaline phosphatase activity and increased expression of bone metabolic markers Alpl, Runx2, and Bglap genes in both osteoblastic cell lines. There was no effect on the osteoclastic differentiation of primary-cultured monocytes from the mouse bone marrows. Furthermore, the study examined the effect of LRC extract in vivo in ovariectomizd (OVX) mice for 8 weeks and 16 weeks, respectively. Bone mineral density (BMD) was significantly higher in LRC extract-administered group than in the non-LRC-administered OVX control group. The results indicated that LRC extract prevented the OVX-induced BMD loss in mice via promoting the differentiation of osteoblast linage cells. These results suggest that LRC extract may be a good natural herbal medicine candidate for the treatment of osteoporosis. PMID- 25432012 TI - Recent advances in the chemical composition of propolis. AB - Propolis is a honeybee product with broad clinical applications. Current literature describes that propolis is collected from plant resins. From a systematic database search, 241 compounds were identified in propolis for the first time between 2000 and 2012; and they belong to such diverse chemical classes as flavonoids, phenylpropanoids, terpenenes, stilbenes, lignans, coumarins, and their prenylated derivatives, showing a pattern consistent with around 300 previously reported compounds. The chemical characteristics of propolis are linked to the diversity of geographical location, plant sources and bee species. PMID- 25432013 TI - Formation of combustible hydrocarbons and H2 during photocatalytic decomposition of various organic compounds under aerated and deaerated conditions. AB - A possibility of photocatalytic production of useful aliphatic hydrocarbons and H2 from various organic compounds, including acetic acid, methanol, ethanol and glucose, over Fe-modified TiO2 is discussed. In particular, the influence of the reaction atmosphere (N2, air) was investigated. Different gases were identified in the headspace volume of the reactor depending on the substrate. In general, the evolution of the gases was more effective in air compared to a N2 atmosphere. In the presence of air, the gaseous phase contained CO2, CH4 and H2, regardless of the substrate used. Moreover, formation of C2H6 and C3H8 in the case of acetic acid and C2H6 in the case of ethanol was observed. In case of acetic acid and methanol an increase in H2 evolution under aerated conditions was observed. It was concluded that the photocatalytic decomposition of organic compounds with simultaneous generation of combustible hydrocarbons and hydrogen could be a promising method of "green energy" production. PMID- 25432015 TI - High purcell factor due to coupling of a single emitter to a dielectric slot waveguide. AB - We demonstrate an all-dielectric quantum electrodynamical nanowire-slab system with a single emitter that concentrates the extremely intense light at the scale of 10 * 75 nm(2). The quantum dot exhibits a record high 31-fold spontaneous decay rate enhancement, its optical saturation and blinking are strongly suppressed, and 80% of emission couples into a waveguide mode. PMID- 25432014 TI - Microwave-assisted synthesis of novel 2H-chromene derivatives bearing phenylthiazolidinones and their biological activity assessment. AB - 6-Hydroxy-2-oxo-2H-chromene-4-carbaldehyde (2), 6-chloro-2-oxo-2H-chromene-4 carbaldehyde (3) and 6-hydrazinyl-4-methyl-2H-chromen-2-one (5) were prepared as single-pharmacophore motif key intermediates. Compounds 2, 3 and 5 were incorporated in a series of multicomponent reactions (MCRs), under microwave assistance as well as conventional chemical synthesis processes, to afford a series of three and/or four-pharmacophoric-motif conjugates 8a,b, 11, 13, 16, 17, 19 and 20 in good yields. The newly synthesized compounds were characterized by IR, NMR, 13C-NMR, MS and elemental analyses. Finally the synthesized compounds have been screened for their biological activity whereupon they exhibited remarkable antimicrobial activity on different classes of bacteria and the fungus. PMID- 25432016 TI - Exercise for reducing fear of falling in older people living in the community. AB - BACKGROUND: Fear of falling is common in older people and associated with serious physical and psychosocial consequences. Exercise (planned, structured, repetitive and purposive physical activity aimed at improving physical fitness) may reduce fear of falling by improving strength, gait, balance and mood, and reducing the occurrence of falls. OBJECTIVES: To assess the effects (benefits, harms and costs) of exercise interventions for reducing fear of falling in older people living in the community. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (July 2013), the Central Register of Controlled Trials (CENTRAL 2013, Issue 7), MEDLINE (1946 to July Week 3 2013), EMBASE (1980 to 2013 Week 30), CINAHL (1982 to July 2013), PsycINFO (1967 to August 2013), AMED (1985 to August 2013), the World Health Organization International Clinical Trials Registry Platform (accessed 7 August 2013) and Current Controlled Trials (accessed 7 August 2013). We applied no language restrictions. We handsearched reference lists and consulted experts. SELECTION CRITERIA: We included randomised and quasi-randomised trials that recruited community-dwelling people (where the majority were aged 65 and over) and were not restricted to specific medical conditions (e.g. stroke, hip fracture). We included trials that evaluated exercise interventions compared with no intervention or a non-exercise intervention (e.g. social visits), and that measured fear of falling. Exercise interventions were varied; for example, they could be 'prescriptions' or recommendations, group-based or individual, supervised or unsupervised. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently assessed studies for inclusion, assessed the risk of bias in the studies and extracted data. We combined effect sizes across studies using the fixed-effect model, with the random-effect model used where significant statistical heterogeneity was present. We estimated risk ratios (RR) for dichotomous outcomes and incidence rate ratios (IRR) for rate outcomes. We estimated mean differences (MD) where studies used the same continuous measures and standardised mean differences (SMD) where different measures or different formats of the same measure were used. Where possible, we performed various, usually prespecified, sensitivity and subgroup analyses. MAIN RESULTS: We included 30 studies, which evaluated 3D exercise (Tai Chi and yoga), balance training or strength and resistance training. Two of these were cluster randomised trials, two were cross-over trials and one was quasi-randomised. The studies included a total of 2878 participants with a mean age ranging from 68 to 85 years. Most studies included more women than men, with four studies recruiting women only. Twelve studies recruited participants at increased risk of falls; three of these recruited participants who also had fear of falling.Poor reporting of the allocation methods in the trials made it difficult to assess the risk of selection bias in most studies. All of the studies were at high risk of performance and detection biases as there was no blinding of participants and outcome assessors and the outcomes were self reported. Twelve studies were at high risk of attrition bias. Using GRADE criteria, we judged the quality of evidence to be 'low' for fear of falling immediately post intervention and 'very low' for fear of falling at short or long-term follow-up and all other outcomes.Exercise interventions were associated with a small to moderate reduction in fear of falling immediately post intervention (SMD 0.37 favouring exercise, 95% confidence interval (CI) 0.18 to 0.56; 24 studies; 1692 participants, low quality evidence). Pooled effect sizes did not differ significantly between the different scales used to measure fear of falling. Although none of the sensitivity analyses changed the direction of effect, the greatest reduction in the size of the effect was on removal of an extreme outlier study with 73 participants (SMD 0.24 favouring exercise, 95% CI 0.12 to 0.36). None of our subgroup analyses provided robust evidence of differences in effect in terms of either the study primary aim (reduction of fear of falling or other aim), the study population (recruitment on the basis of increased falls risk or not), the characteristics of the study exercise intervention or the study control intervention (no treatment or alternative intervention). However, there was some weak evidence of a smaller effect, which included no reduction, of exercise when compared with an alternative control.There was very low quality evidence that exercise interventions may be associated with a small reduction in fear of falling up to six months post intervention (SMD 0.17, 95% CI -0.05 to 0.38; four studies, 356 participants) and more than six months post intervention (SMD 0.20, 95% CI -0.01 to 0.41; three studies, 386 participants).Very low quality evidence suggests exercise interventions in these studies that also reported on fear of falling reduced the risk of falling measured either as participants incurring at least one fall during follow-up or the number of falls during follow-up. Very low quality evidence from four studies indicated that exercise interventions did not appear to reduce symptoms of depression or increase physical activity. The only study reporting the effects of exercise interventions on anxiety found no difference between groups. No studies reported the effects of exercise interventions on activity avoidance or costs. It is important to remember that our included studies do not represent the totality of the evidence of the effect of exercise interventions on falls, depression, anxiety or physical activity as our review only includes studies that reported fear of falling. AUTHORS' CONCLUSIONS: Exercise interventions in community-dwelling older people probably reduce fear of falling to a limited extent immediately after the intervention, without increasing the risk or frequency of falls. There is insufficient evidence to determine whether exercise interventions reduce fear of falling beyond the end of the intervention or their effect on other outcomes. Although further evidence from well-designed randomised trials is required, priority should be given to establishing a core set of outcomes that includes fear of falling for all trials examining the effects of exercise interventions in older people living in the community. PMID- 25432017 TI - Slow-release fluoride devices for the control of dental decay. AB - BACKGROUND: Slow-release fluoride devices have been investigated as a potentially cost-effective method of reducing dental caries in people with high risk of disease. OBJECTIVES: To evaluate the effectiveness and safety of different types of slow-release fluoride devices on preventing, arresting, or reversing the progression of carious lesions on all surface types of primary (deciduous) and permanent teeth. SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Group Trials Register (to 13 August 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 7), MEDLINE via Ovid (1946 to 13 August 2014), and EMBASE via Ovid (1980 to 13 August 2014). We searched the US National Institutes of Health Trials Register and the World Health Organization (WHO) International Clinical Trials Registry Platform. We placed no restrictions on the language or date of publication when searching the electronic databases.We first published the review in 2006. The update in 2013 found 302 abstracts, but none of these met the inclusion criteria of the review. SELECTION CRITERIA: Parallel randomised controlled trials (RCTs) comparing slow release fluoride devices with an alternative fluoride treatment, placebo, or no intervention in all age groups. The main outcomes measures sought were changes in numbers of decayed, missing, and filled teeth or surfaces (DMFT/DMFS in permanent teeth or dmft/dmfs in primary teeth), and progression of carious lesions through enamel and into dentine. DATA COLLECTION AND ANALYSIS: We conducted data collection and analysis using standard Cochrane review methods. At least two review authors independently performed all the key steps in the review such as screening of abstracts, application of inclusion criteria, data extraction, and risk of bias assessment. We resolved discrepancies through discussions or arbitration by a third or fourth review author. MAIN RESULTS: We found no evidence comparing slow-release fluoride devices against other types of fluoride therapy.We found only one double-blind RCT involving 174 children comparing a slow-release fluoride device (glass beads with fluoride were attached to buccal surfaces of right maxillary first permanent molar teeth) against control (glass beads without fluoride were attached to buccal surfaces of right maxillary first permanent molar teeth). This study was assessed to be at high risk of bias. The study recruited children from seven schools in an area of deprivation that had low levels of fluoride in the water. The mean age at the beginning of the study was 8.8 years and at the termination was 10.9 years. DMFT in permanent teeth or dmft in primary teeth was greater than one at the start of the study and greater than one million colony-forming units of Streptococcus mutans per millilitre of saliva.Although 132 children were still included in the trial at the two-year completion point, examination and statistical analysis was performed on only the 63 children (31 in intervention group, 32 in control group) who had retained the beads (retention rate was 47.7% at two years). Among these 63 children, caries increment was reported to be statistically significantly lower in the intervention group than in the control group (DMFT: mean difference -0.72, 95% confidence interval (CI) -1.23 to -0.21; DMFS: mean difference -1.52, 95% CI 2.68 to -0.36 (very low quality evidence)). Although this difference was clinically significant, it only holds true for those children who maintain the fluoride beads; over 50% of children did not retain the beads.Harms were not reported within the trial report. Evidence for other outcomes sought in this review (progression to of caries lesion, dental pain, healthcare utilisation data) were also not reported. AUTHORS' CONCLUSIONS: There is insufficeint evidence to determine the caries-inhibiting effect of slow-release fluoride glass beads. The body of evidence available is of very low quality and there is a potential overestimation of benefit to the average child. The applicability of the findings to the wider population is unclear; the study had included children from a deprived area that had low levels of fluoride in drinking water, and were considered at high risk of carries. In addition, the evidence was only obtained from children who still had the bead attached at two years (48% of all available children); children who had lost their slow-release fluoride devices earlier might not have benefited as much from the devices. PMID- 25432019 TI - Tetracycline repressor allostery does not depend on divalent metal recognition. AB - Genes that render bacteria resistant to tetracycline-derived antibiotics are tightly regulated by repressors of the TetR family. In their physiologically relevant, magnesium-complexed form, tetracyclines induce allosteric rearrangements in the TetR homodimer, leading to its release from the promoter and derepression of transcription. According to earlier crystallographic work, recognition of the tetracycline-associated magnesium ion by TetR is crucial and triggers the allosteric cascade. Nevertheless, the derivative 5a,6 anhydrotetracycline, which shows an increased affinity for TetR, causes promoter release even in the absence of magnesium. To resolve this paradox, it has been proposed that metal-free 5a,6-anhydrotetracycline acts via an exceptional, conformationally different induction mode that circumvents the normal magnesium requirement. We have tested this hypothesis by determining crystal structures of TetR-5a,6-anhydrotetracycline complexes in the presence of magnesium, ethylenediaminetetraacetic acid, or high concentrations of potassium. Analysis of these three structures reveals that, irrespective of the metal, the effects of 5a,6-anhydrotetracycline binding are indistinguishable from those of canonical induction by other tetracyclines. Together with a close scrutiny of the earlier evidence of a metal-triggered mechanism, these results demonstrate that magnesium recognition per se is not a prerequisite for tetracycline repressor allostery. PMID- 25432018 TI - Synthesis and structure-activity relationship studies of small molecule disruptors of EWS-FLI1 interactions in Ewing's sarcoma. AB - EWS-FLI1 is an oncogenic fusion protein implicated in the development of Ewing's sarcoma family tumors (ESFT). Using our previously reported lead compound 2 (YK-4 279), we designed and synthesized a focused library of analogues. The functional inhibition of the analogues was measured by an EWS-FLI1/NR0B1 reporter luciferase assay and a paired cell screening approach measuring effects on growth inhibition for human cells containing EWS-FLI1 (TC32 and TC71) and control PANC1 cell lines devoid of the oncoprotein. Our data revealed that substitution of electron donating groups at the para-position on the phenyl ring was the most favorable for inhibition of EWS-FLI1 by analogs of 2. Compound 9u (with a dimethylamino substitution) was the most active inhibitor with GI50 = 0.26 +/- 0.1 MUM. Further, a correlation of growth inhibition (EWS-FLI1 expressing TC32 cells) and the luciferase reporter activity was established (R(2) = 0.84). Finally, we designed and synthesized a biotinylated analogue and determined the binding affinity for recombinant EWS-FLI1 (Kd = 4.8 +/- 2.6 MUM). PMID- 25432020 TI - Epithelial-mesenchymal transition in pancreatic cancer: Is it a clinically significant factor? AB - Pancreatic cancer is one of the most aggressive solid malignancies. This aggressiveness is partly attributable to extensive local tumor invasion and early systemic dissemination as well as resistance to chemotherapy. Epithelial mesenchymal transition (EMT) plays fundamental roles in embryonic development and in the differentiation of normal tissues and organs. EMT also plays critical roles in tumor formation, dissemination and drug resistance in pancreatic cancer. Emerging data suggest that inhibiting EMT may reverse the EMT phenotype and enhance the efficacy of chemotherapeutic agents against pancreatic cancer cells. Thus, an understanding of the molecular biology of EMT in pancreatic cancer may provide insights into the mechanisms of tumor invasion and metastatic progression and facilitate the development of alternative therapeutic approaches to improve the treatment outcomes for patients suffering from pancreatic cancer. PMID- 25432021 TI - Phosphatidylinositol 3-kinase and COPII generate LC3 lipidation vesicles from the ER-Golgi intermediate compartment. AB - Formation of the autophagosome requires significant membrane input from cellular organelles. However, no direct evidence has been developed to link autophagic factors and the mobilization of membranes to generate the phagophore. Previously, we established a cell-free LC3 lipidation reaction to identify the ER-Golgi intermediate compartment (ERGIC) as a membrane source for LC3 lipidation, a key step of autophagosome biogenesis (Ge et al., eLife 2013; 2:e00947). We now report that starvation activation of autophagic phosphotidylinositol-3 kinase (PI3K) induces the generation of small vesicles active in LC3 lipidation. Subcellular fractionation studies identified the ERGIC as the donor membrane in the generation of small lipidation-active vesicles. COPII proteins are recruited to the ERGIC membrane in starved cells, dependent on active PI3K. We conclude that starvation activates the autophagic PI3K, which in turn induces the recruitment of COPII to the ERGIC to bud LC3 lipidation-active vesicles as one potential membrane source of the autophagosome. PMID- 25432024 TI - Regional differences of repeatability on visual analogue scale with experimental mechanical pain stimuli. AB - Pain-VAS is quite subjective as a scale, but has a tendency to assume differences in repeatability in accordance with perceived pain intensity. The aim of the present study was to investigate the repeatability of regional differences with ratings of pain-VAS. Three experimental mechanical stimuli were applied to twenty seven healthy volunteers across four sessions over four weeks within individuals. The same stimuli were also simultaneously measured in the same manner with an electric balance. The magnitude of mechanical stimuli was determined by 100 g, 300 g, and 600 g monofilaments. Standard deviations (SDs) across measurements with an electric balance showed a regular increase with stimulus magnitude, while coefficient variations (CVs) were constant in each stimulus. On the other hand, although SDs across pain-VAS measurements were significantly greater with the 300 g filament than with the 100 g and 600 g filaments, CVs showed a regular decrease in magnitude of stimulus. These results showed that the CVs of repeated measurement with electric balance were consistent regardless of stimulus intensity, in contrast, CVs of pain-VAS decreased with greater pain rating averaged by repeated measurement. These results suggest that a low rating in pain VAS is inherently less objective, indicating poor repeatability. In contrast, a high rating in pain-VAS is more objective with better repeatability for experimental pain perception. PMID- 25432022 TI - Disruption of thalamic functional connectivity is a neural correlate of dexmedetomidine-induced unconsciousness. AB - Understanding the neural basis of consciousness is fundamental to neuroscience research. Disruptions in cortico-cortical connectivity have been suggested as a primary mechanism of unconsciousness. By using a novel combination of positron emission tomography and functional magnetic resonance imaging, we studied anesthesia-induced unconsciousness and recovery using the alpha2-agonist dexmedetomidine. During unconsciousness, cerebral metabolic rate of glucose and cerebral blood flow were preferentially decreased in the thalamus, the Default Mode Network (DMN), and the bilateral Frontoparietal Networks (FPNs). Cortico cortical functional connectivity within the DMN and FPNs was preserved. However, DMN thalamo-cortical functional connectivity was disrupted. Recovery from this state was associated with sustained reduction in cerebral blood flow and restored DMN thalamo-cortical functional connectivity. We report that loss of thalamo cortical functional connectivity is sufficient to produce unconsciousness. PMID- 25432023 TI - CED-3 caspase acts with miRNAs to regulate non-apoptotic gene expression dynamics for robust development in C. elegans. AB - Genetic redundancy and pleiotropism have limited the discovery of functions associated with miRNAs and other regulatory mechanisms. To overcome this, we performed an enhancer screen for developmental defects caused by compromising both global miRISC function and individual genes in Caenorhabditis elegans. Among 126 interactors with miRNAs, we surprisingly found the CED-3 caspase that has only been well studied for its role in promoting apoptosis, mostly through protein activation. We provide evidence for a non-apoptotic function of CED-3 caspase that regulates multiple developmental events through proteolytic inactivation. Specifically, LIN-14, LIN-28, and DISL-2 proteins are known miRNA targets, key regulators of developmental timing, and/or stem cell pluripotency factors involved in miRNA processing. We show CED-3 cleaves these proteins in vitro. We also show CED-3 down-regulates LIN-28 in vivo, possibly rendering it more susceptible to proteasomal degradation. This mechanism may critically contribute to the robustness of gene expression dynamics governing proper developmental control. PMID- 25432026 TI - Anomalous weak values are proofs of contextuality. AB - The average result of a weak measurement of some observable A can, under postselection of the measured quantum system, exceed the largest eigenvalue of A. The nature of weak measurements, as well as the presence of postselection and hence possible contribution of measurement disturbance, has led to a long-running debate about whether or not this is surprising. Here, it is shown that such "anomalous weak values" are nonclassical in a precise sense: a sufficiently weak measurement of one constitutes a proof of contextuality. This clarifies, for example, which features must be present (and in an experiment, verified) to demonstrate an effect with no satisfying classical explanation. PMID- 25432025 TI - Discovery of a phosphodiesterase 9A inhibitor as a potential hypoglycemic agent. AB - Phosphodiesterase 9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of diabetes and Alzheimer's disease. Here we report a potent PDE9 inhibitor 3r that has an IC50 of 0.6 nM and >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that 3r inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of 3r, together with the reasonable pharmacokinetic properties and no acute toxicity at 1200 mg/kg dosage, suggest its potential as a hypoglycemic agent. The crystal structure of PDE9-3r reveals significantly different conformation and hydrogen bonding pattern of 3r from those of previously published 28s. Both 3r and 28s form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but 3r shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors. PMID- 25432027 TI - Anderson tower of states and nematic order of spin-1 bosonic atoms on a 2D lattice. AB - We investigate the structure of the spectrum of antiferromagnetically coupled spin-1 bosons on a square lattice using degenerate perturbation theory and exact diagonalizations of finite clusters. We show that the superfluid phase develops an Anderson tower of states typical of nematic long-range order with broken SU(2) symmetry. We further show that this order persists into the Mott-insulating phase down to zero hopping for one boson per site and down to a critical hopping for two bosons per site, in agreement with mean-field and quantum Monte Carlo results. The connection with the transition between a fragmented condensate and a polar one in a single trap is briefly discussed. PMID- 25432028 TI - General non-markovian structure of Gaussian master and stochastic Schrodinger equations. AB - General open quantum systems display memory features, their master equations are non-Markovian. We show that the subclass of Gaussian non-Markovian open system dynamics is tractable in a depth similar to the Markovian class. The structure of master equations exhibits a transparent generalization of the Lindblad structure. We find and parametrize the class of stochastic Schrodinger equations that unravel a given master equation, such a class was previously known for Markovian systems only. We show that particular non-Markovian unravelings known in the literature are special cases of our class. PMID- 25432029 TI - Creation of orbital angular momentum states with chiral polaritonic lenses. AB - Controlled transfer of orbital angular momentum to an exciton-polariton Bose Einstein condensate spontaneously created under incoherent, off resonant excitation conditions is a long-standing challenge in the field of microcavity polaritonics. We demonstrate, experimentally and theoretically, a simple and efficient approach to the generation of nontrivial orbital angular momentum states by using optically induced potentials-chiral polaritonic lenses. These lenses are produced by a structured optical pump with a spatial distribution of intensity that breaks the chiral symmetry of the system. PMID- 25432030 TI - Many-body mobility edge in a mean-field quantum spin glass. AB - The quantum random energy model provides a mean-field description of the equilibrium spin glass transition. We show that it further exhibits a many-body localization-delocalization (MBLD) transition when viewed as a closed quantum system. The mean-field structure of the model allows an analytically tractable description of the MBLD transition using the forward-scattering approximation and replica techniques. The predictions are in good agreement with the numerics. The MBLD transition lies at energy density significantly above the equilibrium spin glass transition, indicating that the closed system dynamics freezes well outside of the traditional glass phase. We also observe that the structure of the eigenstates at the MBLD critical point changes continuously with the energy density, raising the possibility of a family of critical theories for the MBLD transition. PMID- 25432031 TI - Permutation symmetry in spinor quantum gases: selection rules, conservation laws, and correlations. AB - Many-body systems of identical arbitrary-spin particles, with separable spin and spatial degrees of freedom, are considered. Their eigenstates can be classified by Young diagrams, corresponding to nontrivial permutation symmetries (beyond the conventional paradigm of symmetric-antisymmetric states). The present work obtains the following. (a) Selection rules for additional nonseparable (dependent on spins and coordinates) k-body interactions: the Young diagrams, associated with the initial and final states of a transition, can differ by relocation of no more than k boxes between their rows. (b) Correlation rules in which eigenstate averaged local correlations of k particles vanish if k exceeds the number of columns (for bosons) or rows (for fermions) in the associated Young diagram. It also elucidates the physical meaning of the quantities conserved due to permutation symmetry-in 1929, Dirac identified those with characters of the symmetric group-relating them to experimentally observable correlations of several particles. The results provide a way to control the formation of entangled states belonging to multidimensional non-Abelian representations of the symmetric group. These states can find applications in quantum computation and metrology. PMID- 25432033 TI - Peltier cooling of fermionic quantum gases. AB - We propose a cooling scheme for fermionic quantum gases, based on the principles of the Peltier thermoelectric effect and energy filtering. The system to be cooled is connected to another harmonically trapped gas acting as a reservoir. The cooling is achieved by two simultaneous processes: (i) the system is evaporatively cooled, and (ii) cold fermions from deep below the Fermi surface of the reservoir are injected below the Fermi level of the system, in order to fill the "holes" in the energy distribution. This is achieved by a suitable energy dependence of the transmission coefficient connecting the system to the reservoir. The two processes can be viewed as simultaneous evaporative cooling of particles and holes. We show that both a significantly lower entropy per particle and faster cooling rate can be achieved in this way than by using only evaporative cooling. PMID- 25432032 TI - Experimental realization of a one-way quantum computer algorithm solving Simon's problem. AB - We report an experimental demonstration of a one-way implementation of a quantum algorithm solving Simon's problem-a black-box period-finding problem that has an exponential gap between the classical and quantum runtime. Using an all-optical setup and modifying the bases of single-qubit measurements on a five-qubit cluster state, key representative functions of the logical two-qubit version's black box can be queried and solved. To the best of our knowledge, this work represents the first experimental realization of the quantum algorithm solving Simon's problem. The experimental results are in excellent agreement with the theoretical model, demonstrating the successful performance of the algorithm. With a view to scaling up to larger numbers of qubits, we analyze the resource requirements for an n-qubit version. This work helps highlight how one-way quantum computing provides a practical route to experimentally investigating the quantum-classical gap in the query complexity model. PMID- 25432034 TI - Axion dark matter detection using atomic transitions. AB - Dark matter axions may cause transitions between atomic states that differ in energy by an amount equal to the axion mass. Such energy differences are conveniently tuned using the Zeeman effect. It is proposed to search for dark matter axions by cooling a kilogram-sized sample to millikelvin temperatures and count axion induced transitions using laser techniques. This appears to be an appropriate approach to axion dark matter detection in the 10^{-4} eV mass range. PMID- 25432036 TI - Higgs couplings: disentangling new physics with off-shell measurements. AB - After the discovery of a scalar resonance, resembling the Higgs boson, its couplings have been extensively studied via the measurement of various production and decay channels on the invariant mass peak. Recently, the possibility of using off-shell measurements has been suggested: in particular, the CMS Collaboration has published results based on the high-invariant mass cross section of the process gg->ZZ, which contains a contribution from the Higgs boson. While this measurement has been interpreted as a constraint on the Higgs width after very specific assumptions are taken on the Higgs couplings, in this Letter, we show that a much more model-independent interpretation is possible. PMID- 25432037 TI - Removing gaps in the exclusion of top squark parameter space. AB - Light stops are a hallmark of the most natural realizations of weak-scale supersymmetry. While stops have been extensively searched for, there remain open gaps around and below the top mass, due to similarities of stop and top signals with current statistics. We propose a new fast-track avenue to improve light stop searches for R-parity-conserving supersymmetry by comparing top cross section measurements to the theoretical prediction. Stop masses below ~180 GeV can now be ruled out for a light neutralino. The possibility of a stop signal contaminating the top mass measurement is also briefly addressed. PMID- 25432038 TI - New exact solution of the relativistic Boltzmann equation and its hydrodynamic limit. AB - We present an exact solution of the relativistic Boltzmann equation for a system undergoing boost-invariant longitudinal and azimuthally symmetric transverse flow ("Gubser flow"). The resulting exact nonequilibrium dynamics is compared to first and second order relativistic hydrodynamic approximations for various shear viscosity to entropy density ratios. This novel solution can be used to test the validity and accuracy of different hydrodynamic approximations in conditions similar to those generated in relativistic heavy-ion collisions. PMID- 25432039 TI - Two-dimensional directional proton emission in dissociative ionization of H(2). AB - An intense phase-controlled orthogonally polarized two-color ultrashort laser pulse is used to singly ionize and dissociate H_{2} into a neutral hydrogen atom and a proton. Emission-direction and kinetic-energy dependent asymmetric dissociation of H_{2} is observed as a function of the relative phase of the orthogonally polarized two-color pulse. Significant asymmetric proton emission is measured in the direction between two polarization axes. Our numerical simulations of the time-dependent Schrodinger equation reproduce many of the observed features. The asymmetry is attributed to the coherent superposition of two-dimensional nuclear wave packets with opposite parities, which have the same energies and overlap in the same emission directions. PMID- 25432040 TI - Prethermalization of atoms due to photon-mediated long-range interactions. AB - Atoms can spontaneously form spatially ordered structures in optical resonators when they are transversally driven by lasers. This occurs when the laser intensity exceeds a threshold value and results from the mechanical forces on the atoms associated with superradiant scattering into the cavity mode. We treat the atomic motion semiclassically and show that, while the onset of spatial ordering depends on the intracavity-photon number, the stationary momentum distribution is a Gaussian function whose width is determined by the rate of photon losses. Above threshold, the dynamics is characterized by two time scales: after a violent relaxation, the system slowly reaches the stationary state over time scales exceeding the cavity lifetime by several orders of magnitude. In this transient regime the atomic momenta form non-Gaussian metastable distributions, which emerge from the interplay between the long-range dispersive and dissipative mechanical forces of light. We argue that the dynamics of self-organization of atoms in cavities offers a test bed for studying the statistical mechanics of long-range interacting systems. PMID- 25432041 TI - Magneto-optic modulator with unit quantum efficiency. AB - We propose a device for the reversible and quiet conversion of microwave photons to optical sideband photons that can reach 100% quantum efficiency. The device is based on an erbium-doped crystal placed in both an optical and microwave resonator. We show that efficient conversion can be achieved so long as the product of the optical and microwave cooperativity factors can be made large. We argue that achieving this regime is feasible with current technology and we discuss a possible implementation. PMID- 25432042 TI - Broadband noise limit in the photodetection of ultralow jitter optical pulses. AB - Applications with optical atomic clocks and precision timing often require the transfer of optical frequency references to the electrical domain with extremely high fidelity. Here we examine the impact of photocarrier scattering and distributed absorption on the photocurrent noise of high-speed photodiodes when detecting ultralow jitter optical pulses. Despite its small contribution to the total photocurrent, this excess noise can determine the phase noise and timing jitter of microwave signals generated by detecting ultrashort optical pulses. A Monte Carlo simulation of the photodetection process is used to quantitatively estimate the excess noise. Simulated phase noise on the 10 GHz harmonic of a photodetected pulse train shows good agreement with previous experimental data, leading to the conclusion that the lowest phase noise photonically generated microwave signals are limited by photocarrier scattering well above the quantum limit of the optical pulse train. PMID- 25432043 TI - Spatial coherence properties of one dimensional exciton-polariton condensates. AB - In this work, we combine a systematic experimental investigation of the power- and temperature-dependent evolution of the spatial coherence function, g^{(1)}(r), in a one dimensional exciton-polariton channel with a modern microscopic numerical theory based on a stochastic master equation approach. The spatial coherence function g^{(1)}(r) is extracted via high-precision Michelson interferometry, which allows us to demonstrate that in the regime of nonresonant excitation, the dependence g^{(1)}(r) reaches a saturation value with a plateau, which is determined by the intensity of the pump and effective temperature of the crystal lattice. The theory, which was extended to allow for treating incoherent excitation in a stochastic frame, matches the experimental data with good qualitative and quantitative agreement. This allows us to verify the prediction that the decay of the off-diagonal long-range order can be almost fully suppressed in one dimensional condensate systems. PMID- 25432044 TI - Dynamic control of the polarization of intense laser beams via optical wave mixing in plasmas. AB - When intense laser beams overlap in plasmas, the refractive index modulation created by the beat wave via the ponderomotive force can lead to optical wave mixing phenomena similar to those used in crystals and photorefractive materials. A new comprehensive analytical description of the modification of the polarization state of laser beams crossing at arbitrary angles in a plasma is presented. It is shown that a laser-plasma system can be used to provide full control of the polarization state of a separate "probe" laser beam; simple analytical estimates and practical considerations are provided for the design of novel photonics devices such as laser-plasma polarizers and wave plates. PMID- 25432045 TI - Ultracold dense samples of dipolar RbCs molecules in the rovibrational and hyperfine ground state. AB - We produce ultracold dense trapped samples of ^{87}Rb^{133}Cs molecules in their rovibrational ground state, with full nuclear hyperfine state control, by stimulated Raman adiabatic passage (STIRAP) with efficiencies of 90%. We observe the onset of hyperfine-changing collisions when the magnetic field is ramped so that the molecules are no longer in the hyperfine ground state. A strong quadratic shift of the transition frequencies as a function of applied electric field shows the strongly dipolar character of the RbCs ground-state molecule. Our results open up the prospect of realizing stable bosonic dipolar quantum gases with ultracold molecules. PMID- 25432047 TI - Pressure-induced symmetry-lowering transition in dense nitrogen to layered polymeric nitrogen (LP-N) with colossal Raman intensity. AB - We present the discovery of a novel nitrogen phase synthesized using laser-heated diamond anvil cells at pressures between 120-180 GPa well above the stability field of cubic gauche (cg)-N. This new phase is characterized by its singly bonded, layered polymeric (LP) structure similar to the predicted Pba2 and two colossal Raman bands (at ~1000 and 1300 cm^{-1} at 150 GPa), arising from two groups of highly polarized nitrogen atoms in the bulk and surface of the layer, respectively. The present result also provides a new constraint for the nitrogen phase diagram, highlighting an unusual symmetry-lowering 3D cg-N to 2D LP-N transition and thereby the enhanced electrostatic contribution to the stabilization of this densely packed LP-N (rho=4.85 g/cm^{3} at 120 GPa). PMID- 25432046 TI - Experimental demonstration of a multiphysics cloak: manipulating heat flux and electric current simultaneously. AB - Invisible cloaks have been widely explored in many different physical systems but usually for a single phenomenon for one device. In this Letter we make an experimental attempt to show a multidisciplinary framework that has the capability to simultaneously respond to two different physical excitations according to predetermined scenarios. As a proof of concept, we implement an electric-thermal bifunctional device that can guide both electric current and heat flux "across" a strong 'scatterer' (air cavity) and restore their original diffusion directions as if nothing exists along the paths, thus rendering dual cloaking effects for objects placed inside the cavity. This bifunctional cloaking performance is also numerically verified for a line-source nonuniform excitation. Our results and the fabrication technique presented here will help broaden the current research scope for multiple disciplines and may pave a way to manipulate multiple flows and create new functional devices, e.g., for on-chip applications. PMID- 25432048 TI - Anisotropic hypersonic phonon propagation in films of aligned ellipsoids. AB - A material with anisotropic elastic mechanical properties and a direction dependent hypersonic band gap is fabricated using ac electric field-directed convective self-assembly of colloidal ellipsoids. The frequency of the gap, which is detected in the direction perpendicular to particle alignment and entirely absent parallel to alignment, and the effective sound velocities can be tuned by the particle aspect ratio. We hypothesize that the band gap originates from the primary eigenmode peak, the m-splitted (s,1,2) mode, of the particle resonating with the effective medium. These results reveal the potential for powerful control of the hypersonic phononic band diagram by combining anisotropic particles and self-assembly. PMID- 25432049 TI - Dynamical quantum phase transitions in systems with broken-symmetry phases. AB - In this Letter it is shown that dynamical quantum phase transitions in Loschmidt echos control the nonequilibrium dynamics of the order parameter after particular quantum quenches in systems with broken-symmetry phases. A direct connection between Loschmidt echos and the order parameter dynamics is established which links nonequilibrium microscopic probabilities to the system's macroscopic dynamical properties. These concepts are illustrated numerically using exact diagonalization for quantum quenches in the XXZ chain with initial Neel states. An outlook is given on how to explore these predictions experimentally with ultracold gases in optical lattices. PMID- 25432050 TI - Electrostatic coupling between two surfaces of a topological insulator nanodevice. AB - We report on electronic transport measurements of dual-gated nanodevices of the low-carrier density topological insulator (TI) Bi_{1.5}Sb_{0.5}Te_{1.7}Se_{1.3}. In all devices, the upper and lower surface states are independently tunable to the Dirac point by the top and bottom gate electrodes. In thin devices, electric fields are found to penetrate through the bulk, indicating finite capacitive coupling between the surface states. A charging model allows us to use the penetrating electric field as a measurement of the intersurface capacitance C_{TI} and the surface state energy-density relationship MU(n), which is found to be consistent with independent angle-resolved photoemission spectroscopy measurements. At high magnetic fields, increased field penetration through the surface states is observed, strongly suggestive of the opening of a surface state band gap due to broken time-reversal symmetry. PMID- 25432035 TI - Search for a dark photon in e(+)e(-) collisions at BABAR. AB - Dark sectors charged under a new Abelian interaction have recently received much attention in the context of dark matter models. These models introduce a light new mediator, the so-called dark photon (A^{'}), connecting the dark sector to the standard model. We present a search for a dark photon in the reaction e^{+}e^{-}->gammaA^{'}, A^{'}->e^{+}e^{-}, MU^{+}MU^{-} using 514 fb^{-1} of data collected with the BABAR detector. We observe no statistically significant deviations from the standard model predictions, and we set 90% confidence level upper limits on the mixing strength between the photon and dark photon at the level of 10^{-4}-10^{-3} for dark photon masses in the range 0.02-10.2 GeV. We further constrain the range of the parameter space favored by interpretations of the discrepancy between the calculated and measured anomalous magnetic moment of the muon. PMID- 25432051 TI - In situ magnetotransport measurements in ultrathin Bi films: evidence for surface bulk coherent transport. AB - We performed in situ magnetotransport measurements on ultrathin Bi(111) films [4 30 bilayers (BLs), 16-120 A thick] to elucidate the role of bulk or surface states in the transport phenomena. We found that the temperature dependence of the film conductivity shows no thickness dependence for the 6-16 BL films and is affected by the electron-electron scattering, suggesting surface-state dominant contribution. In contrast, the weak antilocalization effect observed by applying a magnetic field shows clear thickness dependence, indicating bulk transport. This apparent inconsistency is explained by a coherent bulk-surface coupling that produces a single channel transport. For the films thicker than 20 BLs, the behavior changes drastically which can likely be interpreted as a bulk dominant conduction. PMID- 25432052 TI - Disorder dependence of the ferromagnetic quantum phase transition. AB - We quantitatively discuss the influence of quenched disorder on the ferromagnetic quantum phase transition in metals, using a theory that describes the coupling of the magnetization to gapless fermionic excitations. In clean systems, the transition is first order below a tricritical temperature T_{tc}. Quenched disorder is predicted to suppress T_{tc} until it vanishes for residual resistivities rho_{0} on the order of several MUOmega cm for typical quantum ferromagnets. We discuss experiments that allow us to distinguish the mechanism considered from other possible realizations of a first-order transition. PMID- 25432053 TI - Interface enhancement of Gilbert damping from first principles. AB - The enhancement of Gilbert damping observed for Ni_{80}Fe_{20} (Py) films in contact with the nonmagnetic metals Cu, Pd, Ta, and Pt is quantitatively reproduced using first-principles scattering calculations. The "spin-pumping" theory that qualitatively explains its dependence on the Py thickness is generalized to include a number of extra factors known to be important for spin transport through interfaces. Determining the parameters in this theory from first principles shows that interface spin flipping makes an essential contribution to the damping enhancement. Without it, a much shorter spin-flip diffusion length for Pt would be needed than the value we calculate independently. PMID- 25432054 TI - Elastic coupling between nonferroelastic domain walls. AB - We reveal a strong elastic interaction between nonferroelastic domain walls in ferroelectric thin films. This interaction, having no analogue in bulk materials, is governed by elastic fields that are associated with the domain walls and extends to distances comparable to the film thickness. Such elastic widening of the nonferroelastic domain walls is shown to be particularly strong in common ferroelectric perovskites. The results are especially relevant for the control of domain wall propagation and the understanding of polarization dynamics. PMID- 25432055 TI - Local orientational order in liquids revealed by resonant vibrational energy transfer. AB - We demonstrate that local orientational ordering in a liquid can be observed in the decay of the vibrational anisotropy caused by resonant transfer of vibrational excitations between its constituent molecules. We show that the functional form of this decay is determined by the (distribution of) angles between the vibrating bonds of the molecules between which energy transfer occurs, and that the initial drop in the decay reflects the average angle between nearest neighbors. We use this effect to observe the difference in local orientational ordering in the two hydrogen-bonded liquids ethanol and N methylacetamide. PMID- 25432056 TI - Shear banding of colloidal glasses: observation of a dynamic first-order transition. AB - We demonstrate that application of an increasing shear field on a glass leads to an intriguing dynamic first-order transition in analogy with equilibrium transitions. By following the particle dynamics as a function of the driving field in a colloidal glass, we identify a critical shear rate upon which the diffusion time scale of the glass exhibits a sudden discontinuity. Using a new dynamic order parameter, we show that this discontinuity is analogous to a first order transition, in which the applied stress acts as the conjugate field on the system's dynamic evolution. These results offer new perspectives to comprehend the generic shear-banding instability of a wide range of amorphous materials. PMID- 25432057 TI - Directing colloidal assembly and a metal-insulator transition using a quench disordered porous rod template. AB - Replica and effective-medium theory methods are employed to elucidate how to massively reconfigure a colloidal assembly to achieve globally homogeneous, strongly clustered, and percolated equilibrium states of high electrical conductivity at low physical volume fractions. A key idea is to employ a quench disordered, large-mesh rigid-rod network as a templating internal field. By exploiting bulk phase separation frustration and the tunable competing processes of colloid adsorption on the low-dimensional network and fluctuation-driven colloid clustering in the pore spaces, two distinct spatial organizations of greatly enhanced particle contacts can be achieved. As a result, a continuous, but very abrupt, transition from an insulating to metallic-like state can be realized via a small change of either the colloid-template or colloid-colloid attraction strength. The approach is generalizable to more complicated template or colloidal architectures. PMID- 25432058 TI - Tight lower bound for percolation threshold on an infinite graph. AB - We construct a tight lower bound for the site percolation threshold on an infinite graph, which becomes exact for an infinite tree. The bound is given by the inverse of the maximal eigenvalue of the Hashimoto matrix used to count nonbacktracking walks on the original graph. Our bound always exceeds the inverse spectral radius of the graph's adjacency matrix, and it is also generally tighter than the existing bound in terms of the maximum degree. We give a constructive proof for existence of such an eigenvalue in the case of a connected infinite quasitransitive graph, a graph-theoretic analog of a translationally invariant system. PMID- 25432059 TI - Percolation on sparse networks. AB - We study percolation on networks, which is used as a model of the resilience of networked systems such as the Internet to attack or failure and as a simple model of the spread of disease over human contact networks. We reformulate percolation as a message passing process and demonstrate how the resulting equations can be used to calculate, among other things, the size of the percolating cluster and the average cluster size. The calculations are exact for sparse networks when the number of short loops in the network is small, but even on networks with many short loops we find them to be highly accurate when compared with direct numerical simulations. By considering the fixed points of the message passing process, we also show that the percolation threshold on a network with few loops is given by the inverse of the leading eigenvalue of the so-called nonbacktracking matrix. PMID- 25432060 TI - Synthesis and carbonic anhydrase isoenzymes I, II, IX, and XII inhibitory effects of dimethoxybromophenol derivatives incorporating cyclopropane moieties. AB - Cyclopropylcarboxylic acids and esters and cyclopropylmethanols incorporating bromophenol moieties were investigated as inhibitors of the carbonic anhydrase enzyme (CA; EC 4.2.1.1). The cis- and trans-esters 5 and 6 were obtained from the reaction of 4-allyl-1,2-dimethoxybenzene (4) with ethyl diazoacetate, which after bromination with Br2 gave two isomeric monobromides (11 and 15), four isomeric dibromides (12, 13, 16, and 17), and two isomeric tribromides (14 and 18). The carboxylic acids 7, 8, and 19-26 were thereafter obtained by hydrolysis of the synthesized esters. All these bromophenol derivatives were tested against human (h) CA isoenzymes I and II (cytosolic, ubiquitous isoforms) and hCA IX and XII (transmembrane, tumor-associated enzymes). All tested bromophenols exhibited excellent inhibitory effects, in the low nanomolar range, with Ki values in the range of 0.54-59 nM against hCA I and in the range of 0.97-12.14 nM against hCA II, whereas they were low micromolar inhibitors against hCA IX and XII. The best hCA I inhibition was observed in new bromophenol derivative 20 (Ki = 0.54 nM). On the other hand, new bromophenol derivative 12 showed a powerful inhibition effect against hCA II (Ki = 0.97 nM). PMID- 25432061 TI - Non-pharmacological interventions for chronic pain in people with spinal cord injury. AB - BACKGROUND: Chronic pain is frequent in persons living with spinal cord injury (SCI). Conventionally, the pain is treated pharmacologically, yet long-term pain medication is often refractory and associated with side effects. Non pharmacological interventions are frequently advocated, although the benefit and harm profiles of these treatments are not well established, in part because of methodological weaknesses of available studies. OBJECTIVES: To critically appraise and synthesise available research evidence on the effects of non pharmacological interventions for the treatment of chronic neuropathic and nociceptive pain in people living with SCI. SEARCH METHODS: The search was run on the 1st March 2011. We searched the Cochrane Injuries Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), four other databases and clinical trials registers. In addition, we manually searched the proceedings of three major scientific conferences on SCI. We updated this search in November 2014 but these results have not yet been incorporated. SELECTION CRITERIA: Randomised controlled trials of any intervention not involving intake of medication or other active substances to treat chronic pain in people with SCI. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias in the included studies. The primary outcome was any measure of pain intensity or pain relief. Secondary outcomes included adverse events, anxiety, depression and quality of life. When possible, meta-analyses were performed to calculate standardised mean differences for each type of intervention. MAIN RESULTS: We identified 16 trials involving a total of 616 participants. Eight different types of interventions were studied. Eight trials investigated the effects of electrical brain stimulation (transcranial direct current stimulation (tDCS) and cranial electrotherapy stimulation (CES); five trials) or repetitive transcranial magnetic stimulation (rTMS; three trials). Interventions in the remaining studies included exercise programmes (three trials); acupuncture (two trials); self-hypnosis (one trial); transcutaneous electrical nerve stimulation (TENS) (one trial); and a cognitive behavioural programme (one trial). None of the included trials were considered to have low overall risk of bias. Twelve studies had high overall risk of bias, and in four studies risk of bias was unclear. The overall quality of the included studies was weak. Their validity was impaired by methodological weaknesses such as inappropriate choice of control groups. An additional search in November 2014 identified more recent studies that will be included in an update of this review.For tDCS the pooled mean difference between intervention and control groups in pain scores on an 11-point visual analogue scale (VAS) (0-10) was a reduction of -1.90 units (95% confidence interval (CI) -3.48 to -0.33; P value 0.02) in the short term and of -1.87 (95% CI -3.30 to -0.45; P value 0.01) in the mid term. Exercise programmes led to mean reductions in chronic shoulder pain of -1.9 score points for the Short Form (SF) 36 item for pain experience (95% CI -3.4 to -0.4; P value 0.01) and -2.8 pain VAS units (95% CI -3.77 to -1.83; P value < 0.00001); this represented the largest observed treatment effects in the included studies. Trials using rTMS, CES, acupuncture, self-hypnosis, TENS or a cognitive behavioural programme provided no evidence that these interventions reduce chronic pain. Ten trials examined study endpoints other than pain, including anxiety, depression and quality of life, but available data were too scarce for firm conclusions to be drawn. In four trials no side effects were reported with study interventions. Five trials reported transient mild side effects. Overall, a paucity of evidence was found on any serious or long-lasting side effects of the interventions. AUTHORS' CONCLUSIONS: Evidence is insufficient to suggest that non-pharmacological treatments are effective in reducing chronic pain in people living with SCI. The benefits and harms of commonly used non-pharmacological pain treatments should be investigated in randomised controlled trials with adequate sample size and study methodology. PMID- 25432063 TI - Intracellular sphingosine 1-phosphate contributes to collagen expression of hepatic myofibroblasts in human liver fibrosis independent of its receptors. AB - Sphingosine 1-phosphate (S1P) is involved in multiple pathological processes, including fibrogenesis. S1P participates in mouse liver fibrogenesis via a paracrine manner. Herein, we investigated the involvement of S1P in human liver fibrosis. Human fibrotic samples were obtained from livers of patients undergoing liver transplantation. Expression of sphingosine kinase (SphK1), collagen (Col) alpha1(I), Col alpha1(III), alpha-smooth muscle actin, and p-Smad2/3 was characterized by immunofluorescence, real-time RT-PCR, high-content analysis, or Western blot analysis in the fibrotic liver, human bone marrow-derived mesenchymal stem cells, and human hepatogenic profibrotic cells. The effect of SphK1 was assessed using siSphK1 or SphK-specific inhibitor. SphK1, which was expressed in human fibrotic liver myofibroblasts, could be detected in human bone marrow-derived mesenchymal stem cells or human hepatogenic profibrotic cells activated by transforming growth factor beta1 (TGF-beta1). TGF-beta1 evoked the activation of SphK1, increased intracellular S1P, and up-regulated expression of SphK1, Col alpha1(I), and Col alpha1(III) in a TGF-beta receptor-dependent manner. TGF-beta1 induced expression of Col alpha1(I) and Col alpha1(III) via SphK1, which was mediated by intracellular S1P, independent of S1P receptors. TGF beta1 evoked nuclear translocation of p-Smad2 and p-Smad3 in TGF-beta receptor dependent, but SphK1-independent, manner. In conclusion, intracellular S1P plays a crucial role in the TGF-beta1-induced expression of Col alpha1(I) and Col alpha1(III), which is required for human fibrosis development. S1P exerts its effects in S1P receptor-independent manner. PMID- 25432062 TI - Stromal androgen receptor roles in the development of normal prostate, benign prostate hyperplasia, and prostate cancer. AB - The prostate is an androgen-sensitive organ that needs proper androgen/androgen receptor (AR) signals for normal development. The progression of prostate diseases, including benign prostate hyperplasia (BPH) and prostate cancer (PCa), also needs proper androgen/AR signals. Tissue recombination studies report that stromal, but not epithelial, AR plays more critical roles via the mesenchymal epithelial interactions to influence the early process of prostate development. However, in BPH and PCa, much more attention has been focused on epithelial AR roles. However, accumulating evidence indicates that stromal AR is also irreplaceable and plays critical roles in prostate disease progression. Herein, we summarize the roles of stromal AR in the development of normal prostate, BPH, and PCa, with evidence from the recent results of in vitro cell line studies, tissue recombination experiments, and AR knockout animal models. Current evidence suggests that stromal AR may play positive roles to promote BPH and PCa progression, and targeting stromal AR selectively with AR degradation enhancer, ASC-J9, may allow development of better therapies with fewer adverse effects to battle BPH and PCa. PMID- 25432064 TI - CXCL9 is important for recruiting immune T cells into the brain and inducing an accumulation of the T cells to the areas of tachyzoite proliferation to prevent reactivation of chronic cerebral infection with Toxoplasma gondii. AB - T cells are required to maintain the latency of chronic infection with Toxoplasma gondii in the brain. Here, we examined the role of non-glutamic acid-leucine arginine CXC chemokine CXCL9 for T-cell recruitment to prevent reactivation of infection with T. gondii. Severe combined immunodeficient (SCID) mice were infected and treated with sulfadiazine to establish a chronic infection. Immune T cells from infected wild-type mice were transferred into the SCID mice in combination with treatment with anti-CXCL9 or control sera. Three days later, sulfadiazine was discontinued to initiate reactivation of infection. Numbers of CD4(+) and CD8(+) T cells isolated from the brains were markedly less in mice treated with anti-CXCL9 serum than in mice treated with control serum at 3 days after sulfadiazine discontinuation. Amounts of tachyzoite (acute stage form of T. gondii)-specific SAG1 mRNA and numbers of foci associated with tachyzoites were significantly greater in the former than the latter at 5 days after sulfadiazine discontinuation. An accumulation of CD3(+) T cells into the areas of tachyzoite growth was significantly less frequent in the SCID mice treated with anti-CXCL9 serum than in mice treated with control serum. These results indicate that CXCL9 is crucial for recruiting immune T cells into the brain and inducing an accumulation of the T cells into the areas where tachyzoites proliferate to prevent reactivation of chronic T. gondii infection. PMID- 25432066 TI - Application of multivariate curve resolution alternating least squares method for determination of caffeic acid in the presence of catechin interference. AB - In the current article, preparation and application of a graphene oxide nanosheets-based sensor for electrochemical determination of caffeic acid (CA) in the presence of catechin is described. This measurement was performed using the differential pulse voltammetry (DPV) technique and chemometric methods such as multivariate curve resolution-alternating least squares (MCR-ALS). The modified sensor was characterized by various techniques such as Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, ultraviolet-visible, X-ray diffraction (XRD), and scanning electron microscopy (SEM). Operating conditions and influencing variables (involving several chemical and instrumental variables) were optimized with central composite rotatable design and response surface methodology. The second-order electrochemical data were generated by changing the pulse height in DPV, and after potential shift correction MCR-ALS was applied. Under the optimized conditions, the dynamic range for CA was from 0.5 to 100.0 MUM and the detection limit was found to be 1.1*10(-9) M. The results revealed that the modified electrode shows an improvement in anodic oxidation activity of CA due to a marked enhancement in the current response compared with the bare carbon paste electrode. The modified electrode demonstrated good sensitivity, selectivity, and stability. The proposed method was successfully applied in determination of caffeic acid in the presence of unexpected electroactive interferences with a very high degree of overlapping such as catechin in real samples. PMID- 25432065 TI - Coronavirus nonstructural protein 1: Common and distinct functions in the regulation of host and viral gene expression. AB - The recent emergence of two highly pathogenic human coronaviruses (CoVs), severe acute respiratory syndrome CoV and Middle East respiratory syndrome CoV, has ignited a strong interest in the identification of viral factors that determine the virulence and pathogenesis of CoVs. The nonstructural protein 1 (nsp1) of CoVs has attracted considerable attention in this regard as a potential virulence factor and a target for CoV vaccine development because of accumulating evidence that point to its role in the downregulation of host innate immune responses to CoV infection. Studies have revealed both functional conservation and mechanistic divergence among the nsp1 of different mammalian CoVs in perturbing host gene expression and antiviral responses. This review summarizes the current knowledge about the biological functions of CoV nsp1 that provides an insight into the novel strategies utilized by this viral protein to modulate host and viral gene expression during CoV infection. PMID- 25432067 TI - Scorpion venom components as potential candidates for drug development. AB - Scorpions are well known for their dangerous stings that can result in severe consequences for human beings, including death. Neurotoxins present in their venoms are responsible for their toxicity. Due to their medical relevance, toxins have been the driving force in the scorpion natural compounds research field. On the other hand, for thousands of years, scorpions and their venoms have been applied in traditional medicine, mainly in Asia and Africa. With the remarkable growth in the number of characterized scorpion venom components, several drug candidates have been found with the potential to tackle many of the emerging global medical threats. Scorpions have become a valuable source of biologically active molecules, from novel antibiotics to potential anticancer therapeutics. Other venom components have drawn attention as useful scaffolds for the development of drugs. This review summarizes the most promising candidates for drug development that have been isolated from scorpion venoms. PMID- 25432069 TI - Neuroepigenetics: Introduction to the special issue on epigenetics in neurodevelopment and neurological diseases. PMID- 25432068 TI - Nrf2-ARE activator carnosic acid decreases mitochondrial dysfunction, oxidative damage and neuronal cytoskeletal degradation following traumatic brain injury in mice. AB - The importance of free radical-induced oxidative damage after traumatic brain injury (TBI) has been well documented. Despite multiple clinical trials with radical-scavenging antioxidants that are neuroprotective in TBI models, none is approved for acute TBI patients. As an alternative antioxidant target, Nrf2 is a transcription factor that activates expression of antioxidant and cytoprotective genes by binding to antioxidant response elements (AREs) within DNA. Previous research has shown that neuronal mitochondria are susceptible to oxidative damage post-TBI, and thus the current study investigates whether Nrf2-ARE activation protects mitochondrial function when activated post-TBI. It was hypothesized that administration of carnosic acid (CA) would reduce oxidative damage biomarkers in the brain tissue and also preserve cortical mitochondrial respiratory function post-TBI. A mouse controlled cortical impact (CCI) model was employed with a 1.0mm cortical deformation injury. Administration of CA at 15 min post-TBI reduced cortical lipid peroxidation, protein nitration, and cytoskeletal breakdown markers in a dose-dependent manner at 48 h post-injury. Moreover, CA preserved mitochondrial respiratory function compared to vehicle animals. This was accompanied by decreased oxidative damage to mitochondrial proteins, suggesting the mechanistic connection of the two effects. Lastly, delaying the initial administration of CA up to 8h post-TBI was still capable of reducing cytoskeletal breakdown, thereby demonstrating a clinically relevant therapeutic window for this approach. This study demonstrates that pharmacological Nrf2-ARE induction is capable of neuroprotective efficacy when administered after TBI. PMID- 25432070 TI - Reliability of movement control tests on the cervical spine. AB - BACKGROUND: Movement control impairment reduces active control of movement. Patients with this might form an important subgroup among patients with mechanical cervical pain. Diagnosis is based on the observation of active movement tests. Although widely used clinically, few studies have been performed to determine the reliability of a test battery. The aim of this study was to determine the inter-tester reliability of movement control impairment [MCI] tests on the cervical spine. METHODS: Forty-five subjects (31 patients with neck pain, 14 healthy controls) were videotaped while performing a standardized test battery consisting of 13 tests of active movement control. Using observation, two experienced physiotherapists independently rated test performances as correct or incorrect. One of them was blinded to all other patient information and both to each other. Kappa coefficients and 95% confidence intervals [CI] for inter-tester results were calculated. RESULTS: The kappa values for inter-tester reliability ranged in from 0.47-1.0 of the 13 tests, 2 demonstrated perfect reliability (k = 1.0), 4 excellent (k 0.81-0.99), 6 substantial (k 0.61-0.8) and 1 good (k 0.41 0.6). CONCLUSIONS: The physiotherapists were able reliably rate the majority the tests in this series of motor control tasks. There have been studies performed describing the assessment and treatment of movement control impairment problems and low back pain. However, no study has involved the assessment of the cervical dysfunction subgroup. This study presents a reliable test battery, for clinical use, to perform more specific examination of this subgroup. PMID- 25432071 TI - Production of fructanase by a wild strain of Saccharomyces cerevisiae on tequila agave fructan. AB - A new wild strain of Saccharomyces cerevisiae (CF3) isolated from tequila must was evaluated for production of fructanase on Agave tequilana Weber fructan (FT). Fructanase activity (F) was assessed by a 3(3) factorial design (substrate, temperature and pH). High enzymatic activity (31.1 U/ml) was found at 30 degrees C, pH 5, using FT (10 g/l) as substrate. The effect of initial substrate concentration on F (FT0, 5.7-66 g/l) was studied and it was found that F was highest (44.8 U/ml) at FT0 25 g/l. A 2(2) factorial experimental design with five central points was utilized to study the effect of stirring and aeration on fructanase activity; stirring exhibited a stronger effect on F. The ratio fructanase to invertase (F/S) was 0.57, which confirms that the enzymes are fructanase. Crude fructanase reached high substrate hydrolysis (48 wt%) in 10 h. It is shown that S. cerevisiae CF3 was able to produce large amounts of fructanase by growing it on fructan from A. tequilana. PMID- 25432073 TI - The effect of holding times of whole blood and its components during processing on in vitro and in vivo quality. AB - Whole blood is not usually collected close to the processing site, which results in a holding time between collection and processing. In some countries, the holding time is limited to 8 hours, after which the units are cooled, rendering them useless for platelet preparation. Other countries allow a 24-hour ("overnight") ambient hold to allow platelet preparation. The impact of this holding time on subsequent blood components will be reviewed in this article. In addition, there are various "in-process" holding times that further prolong the time before the final blood component is ready. Particularly, these in-process holding times are not well defined and poorly controlled,but can nevertheless affect the biochemical and functional characteristics of blood components. Furthermore, current, non-evidence-based, guidelines have restricted the length of some of these holding times. This article summarizes the evidence and fills gaps where evidence is lacking. PMID- 25432072 TI - Bacillus filamentosus sp. nov., isolated from sediment sample. AB - A novel Gram-stain positive, endospore-forming bacterium, designated SGD-14(T), was isolated from a marine sediment sample in Goa Province, India. Cells of the isolate were found to be strictly aerobic. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain SGD-14(T) showed a similarity of 99.5 % with Bacillus endophyticus and similarities to other Bacillus type strains were below 96 %. The whole-cell sugar pattern was found to consist of ribose, xylose and glucose. The predominant menaquinone was identified as MK-7 and the major fatty acids as anteiso-C15:0, iso-C15:0, iso-C16:0, anteiso-C17:0, C16:0 and iso C14:0. The strain was found to grow optimally at 30 degrees C and pH 7.0-7.5. DNA G + C content was determined to be 39.6 mol%. The phospholipid pattern was found to consist of diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. DNA-DNA hybridization studies between strain SGD-14(T) and B. endophyticus CIP106778(T) showed that strain SGD-14(T) exhibited <70 % similarity with B. endophyticus CIP106778(T). Differences in phenotypic and chemotaxonomic characteristics between the novel strain and B. endophyticus CIP106778(T) further confirmed that this isolate represents novel species. Phylogenetic analysis showed that strain SGD-14(T) fits in the same clade with B. endophyticus with 100 % bootstrap values. Strain SGD-14(T) is therefore considered to represent a novel species of the genus Bacillus, for which the name Bacillus filamentosus sp. nov. is proposed. The type strain of Bacillus filamentosus is SGD-14(T) = (=NCIM 5491(T) = DSM 27955(T)). PMID- 25432074 TI - Self-rated health is associated with the length of stay at the intensive care unit and hospital following cardiac surgery. AB - BACKGROUND: Recently, a considerable amount of evidence suggested that anxiety, depression and other psychosocial variables might influence the outcomes of cardiac surgery. This study investigated the relationship between length of stay at the intensive care unit (ICU) and hospital after surgery and different psychosocial variables (e.g. depression, anxiety, self rated health, happiness, satisfaction). METHODS: We enrolled prospective patients who were waiting for elective cardiac surgery (N = 267) and consented to take part in the study. We collected data of sociodemographic, medical and perioperative factors as well as psychosocial questionnaires completed 1.56 days (standard deviation [SD] = 0.7) before surgery. The primary clinical endpoint was an ICU stay of at least 3 days and the secondary was hospital stay of at least 10 days. RESULTS: Two hundred sixty-seven patients participated in this study. Four patients (1.5%) died in the hospital and 38 patients (14.5%) spent more than 3 days in the ICU and 62 patients (23.2%) spent more than 10 days in the hospital. After controlling for medical and sociodemographic factors, lower self rated health (Adjusted Odds Ratio [AOR]: 0.51, 95% confidence interval [CI]: 0.28-0.95; p = 0.03), lower rate of happiness (AOR: 0.76, 95% CI: 0.59-0.97, p = 0.03), postoperative cardiac failure (AOR: 7.09, 95% CI:1.21-41.54; p = 0.03) and postoperative complications (AOR: 9.52, 95% CI: 3.76-24.11; p < 0.001) were associated with longer ICU stay. More than 10 days of hospital stay was associated with higher occurrence of COPD (AOR 4.56, CI: 1.95-10.67, p < 0.001), NYHA stage (AOR 6.76, CI: 2.57-17.79, p < 0.001), operation time (AOR 1.45, CI: 1.19-1.76, p < 0.001), female gender (AOR 2.16, CI: 1.06-4.40, p = 0.034) and lower self-rated health (AOR 0.63, CI: 0.41 0.99, p = 0.044). CONCLUSIONS: Lower happiness and self-rated health may influence the outcome of cardiac surgery. Therefore, these variables should be assessed in patients. PMID- 25432076 TI - Present and future of developmental neuropsychopharmacology. AB - The field of child and adolescent psychiatry has always lagged behind adult psychiatry. With recent evidence that the vast majority of mental disorders, even when they emerge in adulthood, cause abnormal neurodevelopment and resultant emphasis on prevention and early intervention, there is a need to put child psychiatry at the top of the agenda in mental health research. This should also be the case for developmental neuropsychopharmacology. The target of drug discovery should shift toward a population younger than the one that is typically included in clinical trials. This is not only a matter of trying to replicate what has been found in individuals with mature brains; it is about searching for new strategies that address developing brains while the therapeutic window for their effect is still open. At present, major concerns in developmental psychopharmacology are over-prescription rates and use of psychotropic medications for conditions with a particularly underdeveloped evidence base, as well as adverse effects, especially potentially life-shortening cardiometabolic effects and suicidal ideation. The future of research in this area should focus on the use of drugs for primary and secondary prevention that would modify abnormal brain development. PMID- 25432075 TI - GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis. AB - Rhabdomyosarcoma (RMS) typically arises from skeletal muscle. Currently, RMS in patients with recurrent and metastatic disease have no successful treatment. The molecular pathogenesis of RMS varies based on cancer sub-types. Some embryonal RMS but not other sub-types are driven by sonic hedgehog (Shh) signaling pathway. However, Shh pathway inhibitors particularly smoothened inhibitors are not highly effective in animals. Here, we show that Shh pathway effectors GLI1 and/or GLI2 are over-expressed in the majority of RMS cells and that GANT-61, a specific GLI1/2 inhibitor dampens the proliferation of both embryonal and alveolar RMS cells-derived xenograft tumors thereby blocking their growth. As compared to vehicle-treated control, about 50% tumor growth inhibition occurs in mice receiving GANT-61 treatment. The proliferation inhibition was associated with slowing of cell cycle progression which was mediated by the reduced expression of cyclins D1/2/3 & E and the concomitant induction of p21. GANT-61 not only reduced expression of GLI1/2 in these RMS but also significantly diminished AKT/mTOR signaling. The therapeutic action of GANT-61 was significantly augmented when combined with chemotherapeutic agents employed for RMS therapy such as temsirolimus or vincristine. Finally, reduced expression of proteins driving epithelial mesenchymal transition (EMT) characterized the residual tumors. PMID- 25432077 TI - [Effectiveness of an integrated treatment for severe personality disorders. A 36 month pragmatic follow-up]. AB - INTRODUCTION: Over the past 25 years, several studies have shown the efficacy of a number of psychological interventions for severe personality disorders. However, the generalizability of these positive results from long traditional research settings to more ordinary ones has been questioned, requiring a need for replication in pragmatic studies. METHODS: This pragmatic study compares hospitalizations and Emergency Room visits before and during a 6-month therapeutic program for severe personality disorders, and at 36 months after starting it. The therapeutic program, which integrates several specific interventions within a coherent framework, was carried out in an ordinary clinical setting. Fifty-one patients, evaluated according DSM-IV criteria by using the Spanish version of the Structured Clinical Interview for Personality Disorders (SCID-II), were included. RESULTS: The clinical characteristics showed a group of severely disturbed patients, of which 78.4% met criteria for borderline personality disorder. The percentage of patients hospitalized and visiting the Emergency Room, as well as the number of days of hospitalization and Emergency Room visits was significantly reduced during the treatment, and this improvement was maintained throughout. CONCLUSIONS: An integrated treatment for severe personality disorders could be effective in preventing reliance on readmissions, or prolonged hospital stays, when it is implemented by clinicians in ordinary clinical settings. PMID- 25432078 TI - [New advances in electroconvulsive therapy. What is the influence of anaesthetic agents?]. PMID- 25432079 TI - Predicting the potential ankylosing spondylitis-related genes utilizing bioinformatics approaches. AB - Given that ankylosing spondylitis (AS) occurs in approximately 5 out of 1,000 adults of European descent and the unclear pathogenesis, the aim of the research was to further predict the molecular mechanism of this disease. The Affymetrix chip data GSE25101 were available from Gene Expression Omnibus database. First of all, differentially expressed genes (DEGs) were identified by Limma package in R. Moreover, DAVID was used to perform gene set enrichment analysis of DEGs. In addition, miRanda, miRDB, miRWalk, RNA22 and TargetScan were applied to predict microRNA-target associations. Meanwhile, STRING 9.0 was utilized to collect protein-protein interactions (PPIs) with confidence score >0.4. Then, the PPI networks for up- and down-regulated genes were constructed, and the clustering analysis was undergone using ClusterONE. Finally, protein-domain enrichment analysis of modules was conducted using DAVID. Total 145 DEGs were identified, including 103 up-regulated and 42 down-regulated genes. These DEGs were significantly enriched in phosphorylation (p = 1.21E-05) and positive regulation of gene expression (p = 1.25E-03). Furthermore, one module was screened out from the up-regulated network, which contained 39 nodes and 205 edges. Moreover, the nodes in the module were significantly enriched in ribosomal protein (RPL17, ribosomal protein L17 and MRPL22, mitochondrial ribosomal protein L22) and proteasome (PSMA6, proteasome subunit, alpha type 6, PSMA4)-related domains. Our findings that might explore the potential pathogenesis of AS and RPL17, MRPL22, PSMA6 and PSMA4 have the potential to be the biomarkers for the disease. PMID- 25432080 TI - Light-driven ion-translocating rhodopsins in marine bacteria. AB - Microbial rhodopsins are the photoreceptive membrane proteins found in diverse microorganisms from within Archaea, Eubacteria, and eukaryotes. They have a hep tahelical transmembrane structure that binds to an all-trans retinal chromophore. Since 2000, thousands of proteorhodopsins, genes of light-driven proton pump rhodopsins, have been identified from various species of marine bacteria. This suggests that they are used for the conversion of light into chemical energy, contribut-ing to carbon circulation related to ATP synthesis in the ocean. Furthermore, novel types of rhodopsin (sodium and chloride pumps) have recently been discovered. Here, we review recent progress in our understanding of ion transporting rhodopsins of marine bacteria, based mainly on biophysical and biochemical research. PMID- 25432081 TI - Clinical evaluation of pazopanib eye drops versus ranibizumab intravitreal injections in subjects with neovascular age-related macular degeneration. AB - PURPOSE: To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). DESIGN: Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose-ranging study of eye drops. PARTICIPANTS: A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by anti-vascular endothelial growth factor intravitreal injections. METHODS: Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n=73); pazopanib 5 mg/ml instilled 3 (n=72) or 4 times daily (n=74); pazopanib 10 mg/ml instilled 2 (n=73), 3 (n=73), or 4 times daily (n=72); or ranibizumab injection administered once every 4 weeks (n=73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed. MAIN OUTCOME MEASURES: The main outcome measures were best-corrected visual acuity (BCVA) and injection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concentrations were determined at weeks 4 and 24. RESULTS: At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3-1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by >=50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported. CONCLUSIONS: Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone. PMID- 25432083 TI - Ex-post analysis of landraces sympatric to a commercial variety in the center of origin of the potato failed to detect gene flow. AB - The possible introduction of genetically modified potato in the Andean region raises concerns about the unintentional introduction of transgenes into the native potato germplasm because it is perceived to convey negative impacts on biodiversity. We investigated this question by an ex-post analysis of existing landraces resulting from natural hybridization between an unknown landrace and the fertile commercial variety 'Yungay'. This variety can be regarded as exotic because it was bred in part from the southern Chilean germplasm of Solanum tuberosum Group Chilotanum. We sampled the landrace germplasm of 1,771 leaf samples comprising more than 400 different landraces from three regions where 'Yungay' and landraces have coexisted for 15-25 years in the Peruvian Andes. Simple sequence repeat (SSR) markers were used to identify putative hybrids based on allele sharing with those of 'Yungay'. The exclusion procedure was iterative, starting with the SSR markers with highest discriminating capacity based on allele frequency of the variety 'Yungay' in our large database of 688 landraces by 24 SSR makers. With only 12 of the 24 SSR markers assayed, all of the samples could be rejected as possible hybrids with 'Yungay' as a parent. This result demonstrates that the unintentional introduction of a transgene, not under farmers' selection, from a widely grown transgenic variety over a long period of time is unlikely to happen at a detectable scale. Our finding reinforces the prominent role of farmers in the selection and maintenance of landraces which, unlike hybrids, have specific characteristics that farmers appreciate. PMID- 25432082 TI - Biodegradation of atrazine by three transgenic grasses and alfalfa expressing a modified bacterial atrazine chlorohydrolase gene. AB - The widespread use of atrazine and other s-triazine herbicides to control weeds in agricultural production fields has impacted surface and groundwater in the United States and elsewhere. We previously reported the cloning, sequencing, and expression of six genes involved in the atrazine biodegradation pathway of Pseudomonas sp. strain ADP, which is initiated by atzA, encoding atrazine chlorohydrolase. Here we explored the use of enhanced expression of a modified bacterial atrazine chlorohydrolase, p-AtzA, in transgenic grasses (tall fescue, perennial ryegrass, and switchgrass) and the legume alfalfa for the biodegradation of atrazine. Enhanced expression of p-AtzA was obtained by using combinations of the badnavirus promoter, the maize alcohol dehydrogenase first intron, and the maize ubiquitin promoter. For alfalfa, we used the first intron of the 5'-untranslated region tobacco alcohol dehydrogenase gene and the cassava vein mosaic virus promoter. Resistance of plants to atrazine in agar-based and hydroponic growth assays was correlated with in vivo levels of gene expression and atrazine degradation. The in planta expression of p-atzA enabled transgenic tall fescue to transform atrazine into hydroxyatrazine and other metabolites. Results of our studies highlight the potential use of transgenic plants for bioremediating atrazine in the environment. PMID- 25432084 TI - Effects of simvastatin on cell viability and proinflammatory pathways in lung adenocarcinoma cells exposed to hydrogen peroxide. AB - Lung cancer is characterized by a high mortality rate probably attributable to early metastasis. Oxidative stress is involved in development and progression of lung cancer, through cellular and molecular mechanisms which at least in part overlap with proinflammatory pathways. Simvastatin is a statin with pleiotropic effects that can also act as an anti-oxidant agent, and these pharmacologic properties may contribute to its potential anti-cancer activity. Therefore, the aim of this study was to evaluate, in the human lung adenocarcinoma cell line GLC 82, the effects of a 24-hour treatment with simvastatin on hydrogen peroxide (H2O2)-induced changes in cell viability, ERK phosphorylation, matrix metalloproteinase (MMP) expression, innate immunity signaling, NF-kappaB activation and IL-8 secretion. Cell counting was performed after trypan blue staining, cell proliferation was assessed using MTT assay, and apoptosis was evaluated through caspase-3 activation and Tunel assay. Western blotting was used to analyze protein extracts, and IL-8 release into cell culture supernatants was assessed by ELISA. Our results show that simvastatin (30 MUM) significantly (P <0.01) inhibited the proliferative effect of H2O2 (0.5 mM) and its stimulatory actions on ERK1/2 phosphorylation, NF-kappaB activation and IL-8 production. Furthermore, simvastatin decreased H2O2-mediated induction of the cellular expression of MMP-2 and MMP-9, as well as of several components of the signaling complex activated by innate immune responses, including MyD88, TRAF2, TRAF6 and TRADD. In conclusion, these findings suggest that simvastatin could play a role in prevention and treatment of lung cancer via modulation of important proinflammatory and tumorigenic events promoted by oxidative stress. PMID- 25432087 TI - Use of tangential flow filtration for improving detection of viral adventitious agents in cell substrates. AB - In this study, we assessed the feasibility of tangential flow filtration (TFF) for primary concentration of viral adventitious agents (AAs) from large volumes of cell substrate-derived samples, such as cell-free Chinese hamster ovary (CHO) culture supernatants (500 mL) and CHO cell lysates (50 mL), prior to virus detection in them by nucleic acid-based methods (i.e., qPCR and massively parallel sequencing (MPS). The study was conducted using the samples spiked with four model DNA viruses (bovine herpesvirus type 4, human adenovirus type 5, simian polyomavirus SV-40, and bovine parvovirus). The results showed that the combined TFF/MPS approach enables reliable detection of as low as 1000 genome equivalents (GE) of each of the four viruses spiked into the cell substrate samples. The final achieved sensitivities of 2 GE/mL for cell culture supernatant and 20 GE/mL for cell lysate make this approach more sensitive than virus specific PCR and qPCR assays. The study results allowed us to propose that TFF might be useful and valuable method for simple and rapid concentration of potential AAs in cell substrate samples prior to AAs detection by conventional in vivo, in vitro, or molecular methods. PMID- 25432086 TI - Observational and clinical trial findings on the comparative effectiveness of diabetes drugs showed agreement. AB - OBJECTIVES: This study compares an observational study of diabetes treatment effectiveness to randomized controlled trials to assess their convergent validity. STUDY DESIGN AND SETTING: Multivariate models were developed using observational data to describe change in hemoglobin A1c (HbA1c; % unit) and weight (kilograms) after addition of a second-line oral diabetes drug to metformin monotherapy. Randomized trials of these scenarios were systematically identified. The models were used to simulate each trial, and simulated and actual results were compared by linear regression and meta-analysis. RESULTS: Thirty-two randomized trials of second-line diabetes oral therapy were identified. For all outcomes and drugs studied, simulation and actual results correlated (P < 0.001). There were no statistically significant differences between meta-analyzed randomized and simulated results for effect on HbA1c. For effect on weight, results were qualitatively comparable, but for sulfonylureas, the simulated weight gain was nominally greater than seen in the randomized controlled trials. CONCLUSION: An observational study of diabetes drug effectiveness showed convergent validity with randomized data. This supports cautious use of the observational research to draw conclusions about drug effectiveness in populations not studied in clinical trials. This approach may be useful in other situations where observational and randomized data need integration. PMID- 25432085 TI - Long-term treadmill exercise attenuates tau pathology in P301S tau transgenic mice. AB - BACKGROUND: Recent epidemiological evidence suggests that modifying lifestyle by increasing physical activity could be a non-pharmacological approach to improving symptoms and slowing disease progression in Alzheimer's disease and other tauopathies. Previous studies have shown that exercise reduces tau hyperphosphorylation, however, it is not known whether exercise reduces the accumulation of soluble or insoluble tau aggregates and neurofibrillary tangles, which are both neuropathological hallmarks of neurodegenerative tauopathy. In this study, 7-month old P301S tau transgenic mice were subjected to 12-weeks of forced treadmill exercise and evaluated for effects on motor function and tau pathology at 10 months of age. RESULTS: Exercise improved general locomotor and exploratory activity and resulted in significant reductions in full-length and hyperphosphorylated tau in the spinal cord and hippocampus as well as a reduction in sarkosyl-insoluble AT8-tau in the spinal cord. Exercise did not attenuate significant neuron loss in the hippocampus or cortex. Key proteins involved in autophagy-microtubule-associated protein 1A/1B light chain 3 and p62/sequestosome 1 -were also measured to assess whether autophagy is implicated in the exercised induced reduction of aggregated tau protein. There were no significant effects of forced treadmill exercise on autophagy protein levels in P301S mice. CONCLUSIONS: Our results suggest that forced treadmill exercise differently affects the brain and spinal cord of aged P301S tau mice, with greater benefits observed in the spinal cord versus the brain. Our work adds to the growing body of evidence that exercise is beneficial in tauopathy, however these benefits may be more limited at later stages of disease. PMID- 25432089 TI - Arizona Center For Integrative Medicine Receives HRSA Grant For Integrative Primary Care. PMID- 25432088 TI - Monitoring drug adherence. AB - TOPIC: Medication nonadherence is prevalent in transplant recipients and is a major reason for graft loss. The present review discusses the measurement of adherence in transplant recipients and strategies to improve adherence. SOURCES REVIEWED: Since adherence research is not confined to transplant recipients, our literature review included studies relevant to transplant recipients as well as adherence to medical recommendations more generally. We reviewed manuscripts in the English language indexed in PubMed Central, as well as ancillary sources of information such as textbook chapters that are not indexed. CONCLUSION: There is no consensus in the literature about an optimal way to monitor adherence, nor is there agreement about a preferred management strategy. Until definitive studies demonstrate the effectiveness of intervention strategies, knowledge of the monitoring as well as intervention methods that are described in this review is expected to give practitioners the initial tools to deal with nonadherence as an important aspect of patient care. PMID- 25432090 TI - Cognitive Function among HIV Infected Children in Pune. AB - OBJECTIVE: To assess cognitive function of school-aged, perinatally acquired human immunodeficiency virus (HIV)-infected, antiretroviral therapy (ART) naive children in Pune. METHODS: HIV infected ART naive children (n = 50) between 6 and 12 y attending outpatient clinic were administered the Indian Child Intelligence Test (ICIT) after their clinical evaluation. Age and gender matched HIV uninfected children (n = 50) were enrolled as controls. The test battery included measures of perception of form (Gestalt), concept formation, memory span, learning and remembering, associative memory span, transformation of visual field, quantitative concepts, spatial visualization and visual motor coordination. The information on adaptive behavior was obtained from the care giver and a brief interview with the child using Vineland Social Maturity Scale (VSMS). RESULTS: Mean age of the children was 9.3 y (SD: 1.3) and mean education was 4.3 y (SD: 1.3). The mean CD4 count of HIV infected children was 588 cells/mm(3) (SD: 324.4). There was no significant difference in the overall ICIT scores between HIV infected and uninfected children (p 0.209). The adaptive behavior (VSMS) scores were significantly less in HIV infected children as compared to others (p 0.028). CONCLUSIONS: There was no significant difference in the overall cognitive abilities in HIV infected children using ICIT as compared to HIV uninfected children, although significant difference in the adaptive behavior between the two groups was observed. It is important to conduct larger prospective studies using standardized test batteries that are inclusive of multiple cognitive domains sensitive to HIV effects in Indian children. PMID- 25432091 TI - Identification of Cephalosporium stripe resistance quantitative trait loci in two recombinant inbred line populations of winter wheat. AB - KEY MESSAGE: Identification of genome regions linked to Cephalosporium stripe resistance across two populations on chromosome 3BS, 4BS, 5AL, C5BL. Results were compared to a similar previous study. Cephalosporium stripe is a vascular wilt disease of winter wheat (Triticum aestivum L.) caused by the soil-borne fungus Cephalosporium gramineum Nisikado & Ikata. In the USA it is known to be a recurring disease when susceptible cultivars are grown in the wheat-growing region of Midwest and Pacific Northwest. There is no complete resistance in commercial wheat cultivars, although the use of moderately resistant cultivars reduces the disease severity and the amount of inoculum in subsequent seasons. The goal of this study was to detect and to compare chromosomal regions for resistance to Cephalosporium stripe in two winter wheat populations. Field inoculation was performed and Cephalosporium stripe severity was visually scored as percent of prematurely ripening heads (whiteheads) per plot. 'Tubbs'/'NSA-98 0995' and 'Einstein'/'Tubbs', each comprising a cross of a resistant and a susceptible cultivar, with population sizes of 271 and 259 F (5:6) recombinant inbred lines, respectively, were genotyped and phenotyped across four environments. In the quantitative trait loci (QTL) analysis, six and nine QTL were found, explaining in total, around 30 and 50 % of the phenotypic variation in 'Tubbs'/'NSA-98-0995' and 'Einstein'/'Tubbs', respectively. The QTL with the largest effect from both 'NSA-98-0995' and 'Einstein' was on chromosome 5AL.1 and linked to marker gwm291. Several QTL with smaller effects were identified in both populations on chromosomes 5AL, 6BS, and 3BS, along with other QTL identified in just one population. These results indicate that resistance to Cephalosporium stripe in both mapping populations was of a quantitative nature. PMID- 25432092 TI - Development and characterization of mutant winter wheat (Triticum aestivum L.) accessions resistant to the herbicide quizalofop. AB - KEY MESSAGE: New herbicide resistance traits in wheat were produced through the use of induced mutagenesis. While herbicide-resistant crops have become common in many agricultural systems, wheat has seen few introductions of herbicide resistance traits. A population of Hatcher winter wheat treated with ethyl methanesulfonate was screened with quizalofop to identify herbicide-resistant plants. Initial testing identified plants that survived multiple quizalofop applications. A series of experiments were designed to characterize this trait. In greenhouse studies the mutants exhibited high levels of quizalofop resistance compared to non-mutant wheat. Sequencing ACC1 revealed a novel missense mutation causing an alanine to valine change at position 2004 (Alopecurus myosuroides reference sequence). Plants carrying single mutations in wheat's three genomes (A, B, D) were identified. Acetyl co-enzyme A carboxylase in resistant plants was 4- to 10-fold more tolerant to quizalofop. Populations of segregating backcross progenies were developed by crossing each of the three individual mutants with wild-type wheat. Experiments conducted with these populations confirmed largely normal segregation, with each mutant allele conferring an additive level of resistance. Further tests showed that the A genome mutation conferred the greatest resistance and the B genome mutation conferred the least resistance to quizalofop. The non-transgenic herbicide resistance trait identified will enhance weed control strategies in wheat. PMID- 25432093 TI - Visual field changes following implantation of the Argus II retinal prosthesis. PMID- 25432094 TI - Statins in rhegmatogenous retinal detachment are associated with low intravitreal angiopoietin-2, VEGF and MMP-2 levels, and improved visual acuity gain in vitrectomized patients. AB - PURPOSE: In rhegmatogenous retinal detachment (RRD), intravitreal growth factors and cytokines may compromise post-vitrectomy outcomes. Here, we analysed perioperative intravitreal protein levels of potent vasoactive, pro-inflammatory, and extracellular matrix-remodelling factors in RRD eyes of patients treated with statins and evaluated post-vitrectomy outcome in the same study eyes. METHODS: Institutional, retrospective, observational study of 14 patients operated on for RRD while on statins compared to patients without statin medication (n = 82). Vitreous samples were subjected to protein measurements of angiopoietin (ANGPT)-1 and -2, transforming growth factor-beta1, and vascular endothelial growth factor (VEGF) by ELISA, and of matrix metalloproteinase (MMP)-2 and -9 by gelatin zymography. A 1-month best-corrected visual acuity (BCVA) gain was modelled by Student's T-test and multivariate linear regression with concomitant perioperative medication. Cumulative 12-month revitrectomy frequency was modelled by Kaplan-Meier log-rank test. RESULTS: Intravitreal levels of ANGPT-2 (49.2 +/- 33.1 vs. 112.8 +/- 134.1 pg/ml, mean +/- SD, p < 0.001), VEGF (2.3 +/- 2.4 vs. 17.7 +/- 57.8 pg/ml, p = 0.021), and MMP-2 (1107.1 +/- 884.6 vs 1976.4 +/- 970.1 AU/ml, p = 0.005) in RRD eyes of patients treated with statins were lower than in non-statin-treated controls. Patients on statins had better 1-month BCVA improvement than did those not on statins (p = 0.022), with no difference in 1 year re-vitrectomy rates. CONCLUSIONS: Intravitreal levels of ANGPT-2, VEGF, factors involved in vascular permeability and inflammation, and activity of MMP 2, the factor connected with breakdown of basement membrane and fibroproliferation, were lower in RRD eyes of patients with statin treatment. At 1-month, postoperative BCVA gain was improved in statin-treated RRD eyes, suggesting that statin administration may be effective in preventing inflammation related PVR formation. PMID- 25432096 TI - Aortojejunal fistula causing obscure massive gastrointestinal bleeding: repeated CT is the key. PMID- 25432095 TI - Modulation of GPCRs by monovalent cations and anions. AB - The recent resolution of G-protein-coupled receptor (GPCR) structures in complex with Na(+) bound to an allosteric modulatory site has renewed interest of the regulation of GPCRs by ions. Here, we summarise key data on ion modulation of GPCRs, obtained in pharmacological, crystallographic, mutagenesis and molecular modelling studies. We show that ion modulation is a highly complex process, involving not only cations but also, rather neglected until now, anions. Pharmacotherapeutic and toxicological aspects are discussed. We provide a mathematical framework for the analysis of ion effects. Finally, we discuss open questions in the field and future research directions. Most importantly, the in vivo relevance of the modulation of GPCR function by monovalent ions must be clarified. PMID- 25432097 TI - Cervical spondylodiscitis: change in clinical picture and operative management during the last two decades. A series of 50 patients and review of literature. AB - PURPOSE: The incidence of spondylodiscitis is increasing. This study evaluates the behavior of cervical spondylodiscitis over a period of two decades in a single institution and compares the findings with the literature. METHODS: Between 1994 and 1999, 20 consecutive patients (group A) suffering from cervical spondylodiscitis underwent surgical treatment in our institution. These were compared to another group consisting of 30 patients (group B) undergoing surgery for the same disease between 2004 and 2009 again in our institution. All patients in both series underwent surgical debridement and reconstruction followed by antibiotic therapy for 8-12 weeks. RESULTS: The mean age at presentation increased significantly from 59.7 to 64.5 years. Male predominance was noticed in both groups. Accompanying neurological deficit was almost the same (40-45 %), while septicaemia increased from 15 to 40 %. Radiologically, epidural abscess formation increased from 60 to 80 %. The disease was mostly monosegmental in group A (85 %); while in group B, the disease became significantly more aggressive affecting two and three segments in 43.3 % of the cases. There was an increased tendency toward anterior alone surgery in group B (56.7 %) in comparison to group A (35 %). Mean period of follow-up was 2.8 years. Healing of the inflammation was the rule. Mortality rate increased from 5 to 10 %. CONCLUSIONS: Cervical spondylodiscitis has increased and became more aggressive. While radical surgical debridement, stable reconstruction together with antibiotic therapy remained a reliable approach to achieve complete healing of the inflammation, anterior alone surgery became more applicable. PMID- 25432100 TI - The Puberty Video for Boys with Asperger Syndrome (and Autism Spectrum Disorder: Level 1) DVD $25.00, 48 Minutes and Managing Puberty, Social Challenges, and (Almost) Everything: A Video Guide for Girls: DVD, $25.00, 80 Minutes; Coulter Video (http://coultervideo.com). PMID- 25432099 TI - Caustic injury of the oesophagus. AB - Caustic ingestion continues to be a significant problem world-wide especially in developing countries and particularly in the under 6 years age group. The presence or absence of symptoms or oral lesions does not reliably predict the existence or severity of oesophageal lesions. Upper endoscopy remains the mainstay diagnostic modality for evaluation to define the extent and severity of the injury. The best predictor of morbidity and mortality is the extent of injury as assessed during initial evaluation. Early management strategies for caustic ingestion are well defined. Controversy still surrounds the use of steroids, antibiotics, antacid therapy in the acute phase, and the use of oesophageal stents and the frequency, timing and method of dilatation in the prevention and management of oesophageal strictures. There is a pressing need for non-invasive diagnostic modalities and effective therapeutic options to evaluate and treat the complications associated with caustic ingestion. Indications for definitive surgery or bypass and the type of procedure to use are also subject to ongoing debate. PMID- 25432101 TI - Maternal Smoking and Autism Spectrum Disorder: A Meta-analysis. AB - We conducted a meta-analysis of 15 studies on maternal prenatal smoking and ASD risk in offspring. Using a random-effects model, we found no evidence of an association (summary OR 1.02, 95% CI 0.93-1.12). Stratifying by study design, birth year, type of healthcare system, and adjustment for socioeconomic status or psychiatric history did not alter the findings. There was evidence that ascertaining exposure at the time of birth produced a lower summary OR than when this information was gathered after birth. There was no evidence of publication bias. Non-differential exposure misclassification was shown to have the potential for negligible influence on the results. We found no evidence to support a measurable association between maternal prenatal smoking and ASD in offspring. PMID- 25432102 TI - Health-related quality of life and cognitive emotion regulation strategies in the unemployed: a cross-sectional survey. AB - BACKGROUND: The loss of one's job has been conceptualized as a major stressful life event in an adult's life and has consistently been associated with lower health-related quality of life (HRQoL). The role of cognitive emotion regulation strategies after the experience of stressful events has emerged as an important predictor of adverse psychological and health outcomes. However, the effect of these coping strategies on the HRQoL of unemployed people has not been examined until now. We aimed to study the associations of these cognitive emotion regulation strategies on HRQoL of unemployed people. METHODS: Using cross sectional data, 1,125 unemployed adults were assessed using a Cognitive Emotion Regulation Questionnaire for cognitive coping and SF-12 to assess HRQoL. We studied the effect of cognitive emotion regulation strategies on mental and physical health composite separately, adjusting for gender, age, educational level and length of unemployment, using hierarchical regression analyses. RESULTS: Results showed unemployed men tended to express greater use of self blame, other-blame, and catastrophizing, and lower use of perspective taking strategies when confronted with unemployment. Moreover, self-blame (for mental health composite only), blaming others, rumination, and catastrophizing negatively correlated, while positive reappraisal, putting into perspective, planning, and positive refocusing positively correlated with both mental and physical health composite in unemployed people. Further hierarchical regression analyses indicate that five strategies (a lower reported use of self-blame, rumination, and catastrophizing, as well as higher scores of positive reappraisal and positive refocusing) and three strategies (lower scores of catastrophizing and rumination and high scores in planning) have significant and independent contributions, beyond gender, age, educational level and length of unemployment, to the prediction of mental health and physical health composite, respectively. CONCLUSIONS: Cognitive emotion regulation strategies appeared to be significantly correlated with HRQoL in unemployed people. Our findings suggest the potential value of including assistance programs focused on cognitive emotion regulation strategies to complement current psychosocial and health approaches aimed at preserving or improving unemployed people's HRQoL. PMID- 25432103 TI - Diastolic dysfunction and contrast-induced nephropathy in patients undergoing coronary angiography. AB - OBJECTIVES: It has been demonstrated that decreased left ventricular ejection fraction (LVEF) is associated with an increased risk of contrast-induced nephropathy (CIN). In this study, we aimed to assess whether there is a relationship between left ventricular (LV) diastolic dysfunction and renal function decline after coronary angiography (CAG). PATIENTS AND METHODS: The study consisted of two groups: group I, patients with normal diastolic function; group II, patients with cardiac symptoms and abnormal diastolic function. Serum creatinine (Crea) and glomerular filtration rates (GFR) were measured before and after 48 h of CAG. RESULTS: After the procedure, serum Crea values were higher in group II compared with group I (p = 0.051). Postprocedural 48-h GFR values determined by Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) equations were lower in group II compared with group I (p = 0.016 and p = 0.003, respectively). Delta (Delta) DeltaCrea and DeltaGFR determined by the Cockcroft Gault and MDRD equations were statistically higher in group II than in group I (p = 0.005, p = 0.052, p = 0.030). The presence of higher age (p = 0.025), E/E' lateral ratio (p = 0.030), and left atrial volume index (p = 0.05) were independent predictors of worsening renal function. CONCLUSION: The presence of diastolic dysfunction may play a role in determining the risk of CIN in patients with normal LVEF. PMID- 25432104 TI - Silencing and overexpression of human blood group antigens in transfusion: Paving the way for the next steps. AB - In the field of transfusion, controlling expression of blood group system antigens on the surface of RBCs has been envisioned as a major research objective for five decades. With the advent of gene transfer techniques in the 1980s, genetic manipulation acquired the tools and know-how necessary to propose this goal along with other strategies. Besides the use of gene transfer to study blood group antigens and to develop tools for transfusion purposes, since the beginning of the new millennium, technological advances in combination with the recognition of the clinical potential of gene transfer have led the transfusion domain into development of cell therapy approaches for therapeutic purposes based on genetic manipulation. PMID- 25432106 TI - 1990-2010 global cardiovascular disease atlas. PMID- 25432105 TI - N-terminal targeting of androgen receptor variant enhances response of castration resistant prostate cancer to taxane chemotherapy. AB - Taxane-based chemotherapy is an effective treatment for castration-resistant prostate cancer (CRPC) via stabilization of microtubules. Previous studies identified that the inhibitory effect of microtubule-targeting chemotherapy on androgen receptor (AR) activity was conferred by interfering with AR intracellular trafficking. The N-terminal domain (NTD) of AR was identified as a tubulin-interacting domain that can be effectively targeted by the novel small molecule inhibitor, EPI. Taken together this evidence provided the rationale that targeting AR nuclear translocation and activity via a combination of an antagonist of the AR NTD and taxane-based chemotherapy may enhance the therapeutic response in CRPC. The present study investigated the anti-tumor efficacy of a combination of EPI with Docetaxel chemotherapy, in cell models of CRPC, harboring the AR splice variants in addition to the full length AR. Our findings demonstrate that there was no significant effect on the androgen mediated nuclear transport of AR variants and AR transcriptional activity by Docetaxel. The therapeutic response to Docetaxel was enhanced by inhibition of the NTD of AR (by EPI) through cycling of epithelial-mesenchymal-transition (EMT) to mesenchymal-epithelial-transition (MET) among prostate cancer epithelial cells. These results support that transient "programming" of EMT by the AR NTD inhibitor, potentially drives the sensitivity of prostate tumors with differential distribution of AR variants to microtubule-targeting chemotherapy. This study is of major significance in dissecting mechanisms to overcome taxane resistance in advanced CRPC. PMID- 25432108 TI - Sub-Saharan Africa. PMID- 25432107 TI - North Africa & Middle East. PMID- 25432098 TI - Estimating minimum adult HIV prevalence: a cross-sectional study to assess the characteristics of people living with HIV in Italy. AB - In 2012, we conducted a retrospective cross-sectional study to assess the number of people living with HIV linked to care and, among these, the number of people on antiretroviral therapy. The health authority in each of the 20 Italian Regions provided the list of Public Infectious Diseases Clinics providing antiretroviral therapy and monitoring people with HIV infection. We asked every Public Infectious Diseases Clinic to report the number of HIV-positive people diagnosed and linked to care and the number of those on antiretroviral therapy during 2012. In 2012, 94,146 people diagnosed with HIV and linked to care were reported. The majority were males (70.1%), Italians (84.4%), and aged between 25 and 49 years (63.4%); the probable route of transmission was heterosexual contact in 37.5% of cases, injecting drug use in 28.1%, and male-to-male contact in 27.9%. Among people in care, 20.1% had less than 350 CD4 cells/MUl, 87.6% received antiretroviral therapy, and among these, 62.4% had a CD4 cell count higher than 350 cells/MUl. The overall estimated prevalence of individuals diagnosed and linked to care in 2012 in Italy was 0.16 per 100 residents (all ages). Adding the estimated proportion of undiagnosed people, the estimated HIV prevalence would range between 0.19 and 0.26 per 100 residents. In Italy, the majority of people diagnosed and linked to care receive antiretroviral therapy. A higher prevalence of individuals diagnosed and linked to care was observed in Northern Italy and among males. More information for developing the HIV care continuum is necessary to improve the entire engagement in care, focusing on test-and-treat strategies to substantially reduce the proportion of people still undiagnosed or with a detectable viral load. PMID- 25432109 TI - North America. PMID- 25432111 TI - Asia Pacific high income. PMID- 25432110 TI - Latin America & Caribbean. PMID- 25432112 TI - Australasia. PMID- 25432113 TI - East Asia. PMID- 25432114 TI - Southeast Asia. PMID- 25432115 TI - South Asia. PMID- 25432116 TI - Central Europe. PMID- 25432117 TI - Eastern Europe & Central Asia. PMID- 25432118 TI - Western Europe. PMID- 25432119 TI - The global burden of hemorrhagic stroke: a summary of findings from the GBD 2010 study. AB - This report summarizes the findings of the GBD 2010 (Global Burden of Diseases, Injuries, and Risk Factors) study for hemorrhagic stroke (HS). Multiple databases were searched for relevant studies published between 1990 and 2010. The GBD 2010 study provided standardized estimates of the incidence, mortality, mortality-to incidence ratios (MIR), and disability-adjusted life years (DALY) lost for HS (including intracerebral hemorrhage and subarachnoid hemorrhage) by age, sex, and income level (high-income countries [HIC]; low- and middle-income countries [LMIC]) for 21 GBD 2010 regions in 1990, 2005, and 2010. In 2010, there were 5.3 million cases of HS and over 3.0 million deaths due to HS. There was a 47% increase worldwide in the absolute number of HS cases. The largest proportion of HS incident cases (80%) and deaths (63%) occurred in LMIC countries. There were 62.8 million DALY lost (86% in LMIC) due to HS. The overall age-standardized incidence rate of HS per 100,000 person-years in 2010 was 48.41 (95% confidence interval [CI]: 45.44 to 52.13) in HIC and 99.43 (95% CI: 85.37 to 116.28) in LMIC, and 81.52 (95% CI: 72.27 to 92.82) globally. The age-standardized incidence of HS increased by 18.5% worldwide between 1990 and 2010. In HIC, there was a reduction in incidence of HS by 8% (95% CI: 1% to 15%), mortality by 38% (95% CI: 32% to 43%), DALY by 39% (95% CI: 32% to 44%), and MIR by 27% (95% CI: 19% to 35%) in the last 2 decades. In LMIC countries, there was a significant increase in the incidence of HS by 22% (95% CI: 5% to 30%), whereas there was a significant reduction in mortality rates of 23% (95% CI: -3% to 36%), DALY lost of 25% (95% CI: 7% to 38%), and MIR by 36% (95% CI: 16% to 49%). There were significant regional differences in incidence rates of HS, with the highest rates in LMIC regions such as sub-Saharan Africa and East Asia, and lowest rates in High Income North America and Western Europe. The worldwide burden of HS has increased over the last 2 decades in terms of absolute numbers of HS incident events. The majority of the burden of HS is borne by LMIC. Rates for HS incidence, mortality, and DALY lost, as well as MIR decreased in the past 2 decades in HIC, but increased significantly in LMIC countries, particularly in those patients <=75 years. HS affected people at a younger age in LMIC than in HIC. The lowest incidence and mortality rates in 2010 were in High Income North America, Australasia, and Western Europe, whereas the highest rates were in Central Asia, Southeast Asia, and sub-Saharan Africa. These results suggest that reducing the burden of HS is a priority particularly in LMIC. The GBD 2010 findings may be a useful resource for planning strategies to reduce the global burden of HS. PMID- 25432120 TI - The global burden of ischemic stroke: findings of the GBD 2010 study. AB - This study sought to summarize the findings of the GBD 2010 (Global Burden of Diseases, Injuries, and Risk Factors) study for ischemic stroke (IS) and to report the impact of tobacco smoking on IS burden in specific countries. The GBD 2010 searched multiple databases to identify relevant studies published between 1990 and 2010. The GBD 2010 analytical tools were used to calculate region specific IS incidence, mortality, mortality-to-incidence ratio, and disability adjusted life years (DALY) lost, including 95% uncertainty intervals (UI). In 2010, there were approximately 11,569,000 incident IS events (63% in low- and middle-income countries [LMIC]), approximately 2,835,000 deaths from IS (57% in LMIC), and approximately 39,389,000 DALY lost due to IS (64% in LMIC). From 1990 to 2010, there was a significant increase in global IS burden in terms of absolute number of people with incident IS (37% increase), deaths from IS (21% increase), and DALY lost due to IS (18% increase). Age-standardized IS incidence, DALY lost, mortality, and mortality-to-incidence ratios in high-income countries declined by about 13% (95% UI: 6% to 18%), 34% (95% UI: 16% to 36%), and 37% (95% UI: 19% to 39%), 21% (95% UI: 10% to 27%), respectively. However, in LMIC there was a modest 6% increase in the age-standardized incidence of IS (95% UI: -7% to 18%) despite modest reductions in mortality rates, DALY lost, and mortality-to incidence ratios. There was considerable variability among country-specific estimates within broad GBD regions. China, Russia, and India were ranked highest in both 1990 and 2010 for IS deaths attributable to tobacco consumption. Although age-standardized IS mortality rates have declined over the last 2 decades, the absolute global burden of IS is increasing, with the bulk of DALY lost in LMIC. Tobacco consumption is an important modifiable risk factor for IS, and in both 1990 and 2010, the top ranked countries for IS deaths that could be attributed to tobacco consumption were China, Russia, and India. Tobacco control policies that target both smoking initiation and smoking cessation can play an important role in the prevention of IS. In China, Russia, and India, even modest reductions in the number of current smokers could see millions of lives saved due to prevention of IS alone. PMID- 25432121 TI - Global burden of atrial fibrillation in developed and developing nations. AB - Atrial fibrillation is the most common heart rhythm disorder in the world, with major public health impact especially due to increased risk of stroke and hospitalizations. The recently published results on epidemiology of atrial fibrillation from the Global Burden of Diseases, Injuries, and Risk Factors Study confirm the existence of a significant and progressive worldwide increase in the burden of atrial fibrillation. However, there appears to be regional variation in both the burden of atrial fibrillation and availability of epidemiological data regarding this condition. In this review, the authors identify issues that are unique to the developed versus developing regions and outline a road map for possible approaches to surveillance, management, and prevention of atrial fibrillation at the global level. PMID- 25432122 TI - The global burden of myocarditis: part 1: a systematic literature review for the Global Burden of Diseases, Injuries, and Risk Factors 2010 study. AB - Myocarditis contributes to the global burden of cardiovascular disease primarily through sudden death and dilated cardiomyopathy. A systematic approach to identify the cardiovascular mortality and major morbidity attributable to myocarditis has not been performed. A writing group convened by the GBD 2010 (Global Burden of Diseases, Injuries and Risk Factors) Study systematically reviewed the world's literature by a manual review of all titles since 1966 on myocarditis identified using Ovid Medline, development of a disease model, and provision of estimates when possible of the incidence, prevalence, risk of death, and major morbidity for the world regions. Accurate population-based estimates of myocarditis incidence and prevalence are not directly available in any world region. However, a model that quantitates the risk of acute death and chronic heart failure following myocarditis was derived from the published data. Using hospital dismissal data, the burden of myocarditis as a percentage of prevalent heart failure varied by age and region from approximately 0.5% to 4.0%. The novel combination of multiple data sources may provide an estimate of the years of life lost and years of life disabled from myocarditis. Pending the integration of these data sources, the burden of dilated cardiomyopathy and myocarditis were reported together in the 2010 GBD report. The 2013 GBD project may refine these estimates with the inclusion of more comprehensive payor databases and more precise case definitions. PMID- 25432123 TI - Global and regional burden of infective endocarditis, 1990-2010: a systematic review of the literature. AB - Infective endocarditis (IE) is a life-threatening disease associated with serious complications. The GBD 2010 (Global Burden of Disease, Injuries, and Risk Factors) study IE expert group conducted a systematic review of IE epidemiology literature to inform estimates of the burden on IE in 21 world regions in 1990 and 2010. The disease model of IE for the GBD 2010 study included IE death and 2 sequelae: stroke and valve surgery. Several medical and science databases were searched for IE epidemiology studies in GBD high-, low-, and middle-income regions published between 1980 and 2008. The epidemiologic parameters of interest were IE incidence, proportions of IE patients who developed stroke or underwent valve surgery, and case fatality. Literature searches yielded 1,975 unique papers, of which 115 published in 10 languages were included in the systematic review. Eligible studies were population-based (17%), multicenter hospital-based (11%), and single-center hospital-based studies (71%). Population-based studies were reported from only 6 world regions. Data were missing or sparse in many low- and middle-income regions. The crude incidence of IE ranged between 1.5 and 11.6 cases per 100,000 people and was reported from 10 countries. The overall mean proportion of IE patients that developed stroke was 0.158 +/- 0.091, and the mean proportion of patients that underwent valve surgery was 0.324 +/- 0.188. The mean case fatality risk was 0.211 +/- 0.104. A systematic review for the GBD 2010 study provided IE epidemiology estimates for many world regions, but highlighted the lack of information about IE in low- and middle-income regions. More complete knowledge of the global burden of IE will require improved IE surveillance in all world regions. PMID- 25432124 TI - Global and regional burden of death and disability from peripheral artery disease: 21 world regions, 1990 to 2010. AB - A comprehensive and systematic assessment of disability and mortality due to lower extremity peripheral artery disease (PAD) is lacking. Therefore, we estimated PAD deaths, disability-adjusted life years (DALYs), and years of life lost in 21 regions worldwide for 1990 and 2010. We used the GBD (Global Burden of Diseases 2010) study causes of death database, and the cause of death ensemble modeling approach to assess levels and trends of PAD deaths and years of life lost over time, by age, sex, and region. Assessment of DALYs employed estimates of PAD prevalence from systematic reviews of epidemiologic data using a Bayesian meta-regression method. In 1990, the age-specific PAD death rate per 100,000 population ranged from 0.05 (95% confidence interval [CI]: 0.03 to 0.09) among those 40 to 44 years old to 16.63 (95% CI: 10.47 to 25.31) among the 80+ years group. In 2010, the corresponding estimates were 0.07 (95% CI: 0.04 to 0.13) and 28.71 (95% CI: 18.3 to 43.06). Death rates increased consistently with age in 1990 and 2010, and the rates in 2010 were higher than they were in 1990 in all age categories. The largest relative change in median death rate of +6.03 per 100,000 (95% CI: 1.50 to 11.85) was noted in the Asia Pacific-High Income region and was largely driven by higher rates in women: +17.36 (95% CI: 1.79 to 32.01) versus +1.25 (95% CI: 0.13 to 2.39) in men. The overall relative change in median DALYs was larger in developing nations than in developed nations: 1.15 (95% CI: 0.80 to 1.66) versus 0.77 (95% CI: 0.55 to 1.08). Of note, the overall relative change in median DALYs was higher among both men and women in developing versus developed countries: men: 1.18 (95% CI: 0.82 to 1.65) versus 0.51 (95% CI: 0.30 to 0.81), and women: 1.11 (95% CI: 0.58 to 2.02) versus 1 (95% CI: 0.67 to 1.47). Within developed nations, the overall relative change in median DALY rates was larger in women than in men: +1.00 (95% CI: 0.67 to 1.47) versus +0.51 (95% CI: 0.3 to 0.81). Similarly, the overall relative change in median years of life lost rate in developed countries was larger in women than in men: +1.64 (95% CI: 1.17 to 2.34) versus +0.53 (95% CI: 0.24 to 0.94). The relative increases in median years lived with nonfatal disease disability (YLD) rates in men and women were larger in developing versus developed nations: men: 0.87 (95% CI: 0.59 to 1.2) versus 0.49 (95% CI: 0.29 to 0.73), and women: 0.75 (95% CI: 0.46 to 1.09) versus 0.49 (95% CI: 0.29 to 0.73). Disability and mortality associated with PAD has increased over the last 20 years, and this increase in burden has been greater among women than among men. In addition, the burden of PAD is no longer confined to the elderly population, but now involves young adults. Furthermore, the relative increase in PAD burden in developing regions of the world is striking and exceeds the increases in developed nations. PMID- 25432125 TI - Estimation of global and regional incidence and prevalence of abdominal aortic aneurysms 1990 to 2010. AB - The global burden of abdominal aortic aneurysm (AAA) has not been studied previously. Such information is important given the emergence of cardiovascular diseases in developing countries. We conducted a systematic literature review and estimated the global and regional incidence and prevalence of AAA in 21 world regions by age and sex. The search for prevalence and incidence of AAA using standard clinical and epidemiological terms was conducted using MEDLINE (1950 to 2010), EMBASE (1980 to 2010), AMED (1985 to 2010), CINAHL (1982 to 2010), and LILACS (2008 to 2010). Data abstracted from the systematic review served as priors for Bayesian meta-regression analyses. The analysis drew from 26 high quality studies to estimate AAA prevalence and incidence. In 1990, the global age specific prevalence rate per 100,000 ranged from 8.43 (95% CI: 7.03 to 10.14) in the 40 to 44 years age group to 2,422.53 (95% CI: 2,298.63 to 2,562.25) in the 75 to 79 years age group; the corresponding range in 2010 was 7.88 (95% CI: 6.54 to 9.59) to 2,274.82 (95% CI: 2,149.77 to 2,410.17). Prevalence was higher in developed versus developing nations, and the rates within each development stratum decreased between 1990 and 2010. Globally, the age-specific annual incidence rate per 100,000 in 1990 ranged from 0.89 (95% CI: 0.66 to 1.17) in 40 to 44 years age group to 176.08 (95% CI: 162.72 to 190.28) in the 75 to 79 years age group. In 2010, this range was 0.83 (95% CI: 0.61 to 1.11) to 164.57 (95% CI: 152.20 to 178.78). The highest prevalence in 1990 was in Australasia and North America high income regions: 382.65 (95% CI: 356.27 to 410.88) and 300.59 (95% CI: 280.93 to 321.54), respectively. Australasia had the highest prevalence in 2010, although the prevalence decreased to 310.27 (95% CI: 289.01 to 332.94). Regional prevalence increased in Oceania, tropical Latin America, Asia Pacific high income, Southern Sub-Saharan Africa (SSA), Central SSA, South Asia, Western SSA, and Central Asia. AAA global prevalence and incidence rates have decreased over the last 20 years. However, rising rates in some regions highlight the need for policies to enhance global disease surveillance and prevention. PMID- 25432127 TI - The focus of action. PMID- 25432126 TI - Global and regional burden of aortic dissection and aneurysms: mortality trends in 21 world regions, 1990 to 2010. AB - A comprehensive and systematic assessment of the global burden of aortic aneurysms (AA) has been lacking. Therefore, we estimated AA regional deaths and years of life lost (YLL) in 21 regions worldwide for 1990 and 2010. We used the GBD (Global Burden of Disease) 2010 study causes of death database and the cause of death ensemble modeling approach to assess levels and trends of AA deaths by age, sex, and GBD region. The global AA death rate per 100,000 population was 2.49 (95% CI: 1.78 to 3.27) in 1990 and 2.78 (95% CI: 2.04 to 3.62) in 2010. In 1990 and 2010, the highest mean death rates were in Australasia and Western Europe: 8.82 (95% CI: 6.96 to 10.79) and 7.69 (95% CI: 6.11 to 9.57) in 1990 and 8.38 (95% CI: 6.48 to 10.86) and 7.68 (95% CI: 6.13 to 9.54) in 2010. YLL rates by GBD region mirrored the mortality rate pattern. Overall, men had higher AA death rates than women: 2.86 (95% CI: 1.90 to 4.22) versus 2.12 (95% CI: 1.33 to 3.00) in 1990 and 3.40 (95% CI: 2.26 to 5.01) versus 2.15 (95% CI: 1.44 to 2.89) in 2010. The relative change in median death rate was +0.22 (95% CI: 0.10 to 0.33) in developed nations versus +0.71 (95% CI: 0.28 to 1.40) in developing nations. The smallest relative changes in median death rate were noted in North America high income, Central Europe, Western Europe, and Australasia, with estimates of +0.07 (95% CI: -0.26 to 0.37), +0.08 (95% CI: -0.02 to 0.23), +0.09 (95% CI: -0.02 to 0.21), and +0.22 (95% CI: -0.08 to 0.46), respectively. The largest increases were in Asia Pacific high income, Southeast Asia, Latin America tropical, Oceania, South Asia, and Central Sub-Saharan Africa. Women rather than men drove the increase in the Asia Pacific high-income region: the relative change in median rates was +2.92 (95% CI: 0.6 to 4.35) versus +1.05 (95% CI: 0.61 to 2.42). In contrast to high-income regions, the observed pattern in developing regions suggests increasing AA burden, which portends future health system challenges in these regions. PMID- 25432128 TI - The global burden of cardiovascular diseases, 1990-2010. PMID- 25432129 TI - Evaluation of charge and agglomeration behavior of TiO2 nanoparticles in ecotoxicological media. AB - The dynamic nature of nanoparticle (NP) agglomeration behavior is of paramount interest to many current studies in environmental nanoscience and nano(eco)toxicology because agglomeration affects the NP bioavailability and toxicity. The present study investigates the surface charge and agglomeration behavior of TiO2 NPs in four different ecotoxicological media (OECD algae, OECD L_variegatus, hardwater and plant media) and two different electrolytes KCl (200 mM) and CaCl2 (50 mM). TiO2 NPs were positively charged, and the zeta potential varied from +1.9 mV in hardwater (at pH7.1) to +24.5 mV in CaCl2 electrolyte (at pH7.4) in all media except algae media, where the zeta potential was -6.7 mV (at pH7.7). Despite the differences in the pH and the surface charge of TiO2 NPs in the different media, an immediate agglomeration of the NPs in all standard ecotoxicological media was observed with aggregate sizes in the micrometer scale, as the measured zeta potentials were insufficient to prevent TiO2 NP agglomeration. The isoelectric point (pHiep) of TiO2 NPs in the studied media varied in the range (6.8-7.6), which was attributed to preferential association of anions and cations to TiO2; that is the pHiep decreases with the increased concentration of Cl and increases with the increased concentrations of Na and Mg. Despite the complexity of the ecotoxicological media and the presence of a mixture of different monovalent and divalent electrolytes, the agglomeration kinetics in the media follows the DVLO theory where two distinct agglomeration rates (slow, reaction limited regime and fast, diffusion limited regime) were observable. The critical coagulation concentration (CCC) of TiO2 NPs in the ecotoxicological media varied from 17.6 to 54.0% v/v standard media in UHPW, due to differences in media pH and TiO2 NP surface charge. In the ecotoxicological media (hardwater, L-variegatus and plant), where TiO2 NPs are positively charged, the CCC decrease with the increased divalent anions (act as counter ions) concentration in the media, again in good agreement with the DLVO theory. PMID- 25432130 TI - Room for improvement: noise on a maternity ward. AB - BACKGROUND: For mothers who have just given birth, the postpartum hospital stay is meant to promote an environment where resting, healing and bonding can take place. New mothers, however, face many interruptions throughout the day including multiple visitors and noise caused by medical equipment, corridor conversations and intercom announcements. This paper argues that disruptions and noise on a maternity ward are detrimental to the healing process for new mothers and their newborns and healthcare decision-makers need to act to improve the environment for these patients. This paper also provides recommendations on how to reduce the noise levels, or at least control the noise on a maternity ward, through the implementation of a daily quiet time. DISCUSSION: Hospital disruptions and its negative health effects in particular for new mothers and their children are illustrated in this paper. Hospital noise and interruptions act as a stressor for both new mothers and staff, and can lead to sleep deprivation and detrimental cardiovascular health effects. Sleep deprivation is associated with a number of negative mental and physical health consequences such as decreased immune function, vascular dysfunction and increased sympathetic cardiovascular modulation. Sleep deprivation can also increase the risk of postpartum mental health disorders in new mothers. Some efforts have been made to reduce the disruptions experienced by these patients within a hospital setting. For example, the introduction of a daily quiet time is one way of controlling noise levels and interruptions, however, these have mostly been implemented in intensive care units. Noise and disruptions are a significant problem during postpartum hospital stay. Healthcare institutions are responsible for patient-centered care; a quiet time intervention promises to contribute to a safe, healing environment in hospitals. PMID- 25432131 TI - Atypical antipsychotic augmentation in SSRI treatment refractory obsessive compulsive disorder: a systematic review and meta-analysis. AB - BACKGROUND: In 2006, the National Institute of Clinical and Health Excellence (NICE) guidelines for Obsessive Compulsive Disorder (OCD) recommended anti psychotics as a class for SSRI treatment resistant OCD. The article aims to systematically review and conduct a meta-analysis on the clinical effectiveness of atypical anti-psychotics augmenting an SSRI. METHODS: Studies that were double blind randomized controlled trials of an atypical antipsychotic against a placebo, for a minimum of 4 weeks, in adults with OCD, were included. Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores were the primary outcome measure. Inclusion criteria included Y-BOCS score of 16 or more and at least one adequate trial of a SSRI or clomipramine for at least 8 weeks prior to randomization. Data sources included Medline, Embase, PsycINFO, Cochrane Database of Systematic Reviews (CDSR), trial registries and pharmaceutical databases and manufacturers up to September 2013. Forest-plots were drawn to display differences between drug and placebo on the Y-BOCS. RESULTS: Two studies found aripiprazole to be effective in the short-term. There was a small effect-size for risperidone or anti-psychotics in general in the short-term. We found no evidence for the effectiveness of quetiapine or olanzapine in comparison to placebo. CONCLUSIONS: Risperidone and aripiprazole can be used cautiously at a low dose as an augmentation agent in non-responders to SSRIs and CBT but should be monitored at 4 weeks to determine efficacy. PMID- 25432132 TI - Downregulation of miR-25 modulates non-small cell lung cancer cells by targeting CDC42. AB - The current study aims to investigate the fuctional role of miRNA-25 in non-small cell lung cancer (NSCLC) cells. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-25 in NSCLC cell lines and 11 pairs of human NSCLC and non-cancerous tissues. The inhibitor of miR-25 was stably transfected into NSCLC cell line A549 cells. Then the effects of downregulating miR-25 on cancer cell proliferation, cell cycle arrest, chemosensitivity to cisplatin, and growth of in vivo xenograft were investigated. Direct regulation of miR-25 on its target gene, cell division cycle 42 (CDC42), was examined by luciferase reporter assay, qRT-PCR and western blot. CDC42 was then upregulated in A549 cells to investigate its effect on miR-25-mediated NSCLC cell proliferation and cell cycle arrest. The expression of miR-25 in NSCLC cells or human tissues was significantly higher than that in normal lung cells or adjacent non-cancerous tissues, respectively. Downregulation of miR-25 markedly inhibited A549 cell proliferation, induced G1 cell cycle arrest, increased cisplatin sensitivity, and suppressed the growth of caner cell xenograft in vivo. CDC42 was confirmed to be the directly regulated by miR-25 in A549 cells. Upregulation of CDC42 in A549 cells rescued the inhibitory effect on proliferation and the G1 cell cycle arrest induced by miR-25 downregulation. Our study demonstrates miR-25, by targeting CDC42, is an important regulator in NSCLC. PMID- 25432133 TI - The human epididymis protein 4 acts as a prognostic factor and promotes progression of gastric cancer. AB - Human epididymis protein 4 (HE4), represented as an epididymis-specific gene and designated a WAP four-disulfide core domain protein 2 (WFDC2), is amplified in many tumors. However, little is known about its clinical significance and biological function in gastric carcinomas. We found that HE4 was more commonly observed in gastric carcinoma tissues than in normal tissues and was significantly correlated with Lauren classification, TNM stage, and tumor size by immunohistochemistry. The overall survival rate of patients with HE4 low expression was significantly higher than that of the patients with HE4 high expression. In addition, silencing of HE4 expression inhibits cell proliferation and migration and enhances cell apoptosis. Subsequent studies reveal that the Src, Akt, and Erk1/2 signaling may be involved with pro-survival and anti apoptotic effects of the HE4 on gastric cancer cells. Taken together, this study provides new evidence on promotive effects of the HE4 on gastric cancer progression and indicates that HE4 might be a promising prognostic factor for gastric cancer diagnosis. PMID- 25432134 TI - Association between GSTM1 and GSTT1 polymorphisms and esophageal squamous cell carcinoma: results from a case-control study in Kashmir, India. AB - Polymorphisms in glutathione-S-transferases (GSTs), the phase II xenobiotic detoxifying enzymes, have been associated with increased cancer risk. In this study, we assessed the association of functional polymorphisms in GSTM1 and GSTT1 with esophageal cancer in Kashmir, India, an area with a high incidence of esophageal squamous cell carcinoma (ESCC). We analyzed genotypes of GSTM1 and GSTT1 using a multiplex PCR in 492 pairs of ESCC cases and individually matched controls. The associations between polymorphisms in these genes and ESCC risk were examined by conditional logistic regression models adjusted for multiple potential confounders. In addition, the interaction between these genes and several environmental exposures with regard to ESCC risk was assessed. Our results showed an association between the GSTT1 null genotype and ESCC risk (odds ratio (OR) = 1.58; 95% confidence interval (CI) 1.04-2.39). Although GSTM1 alone was not associated with ESCC risk, individuals with the GSTM1 (-)/GSTT1 (+) genotype showed an inverse relation with ESCC risk (OR = 0.55; 95% CI 0.32-0.93), compared to GSTM1 (+)/GSTT1 (+) individuals. We found a significant interaction between the GSTT1 and GSTM1 genotypes with regard to ESCC risk (P = 0.001); however, there were no interactions between environmental factors and GSTT1 and GSTM1 genotypes. This study indicates that GSTT1 null genotype is associated with ESCC risk in Kashmiri population. The association between GSTM1 and ESCC risk needs further investigations. Interactions of these genotypes with environmental exposures should be examined in multicentric studies with bigger sample sizes. PMID- 25432135 TI - Inhibition of metastasis of oral squamous cell carcinoma by anti-PLGF treatment. AB - Neovascularization plays a critical role in cancer metastasis. However, the molecular mechanism regulating the neovascularization in oral squamous cell carcinoma (OSCC) is poorly understood. Placental growth factor (PLGF) has been known to regulate pathological angiogenesis and has been recently shown to regulate matrix metalloproteinases (MMPs) for extracellular matrix degradation during neovascularization. Here we aimed to examine whether PLGF may regulate MMPs in the metastasis of OSCC. We found that PLGF and MMP9 levels strongly correlated in OSCC in the patients, both increased in the OSCC from the patients with metastasis of the primary OSCC. Thus, we used several human OSCC cell lines to examine the relationship between PLGF and MMP9. We found that overexpression of PLGF in OSCC cells increased expression of MMP9, while inhibition of PLGF in OSCC cells decreased expression of MMP9. However, adaptation of MMP9 levels in OSCC cells did not affect the levels of PLGF. These data suggest that PLGF may regulate MMP9 in OSCC cells, but not vice versa. Moreover, inhibition of ERK1/2, but not inhibition of PI3k or JNK pathways, substantially abolished the effect of PLGF on MMP9, suggesting that PLGF may increase expression of MMP9 via ERK/MAPK signaling pathway. Thus, our data demonstrate that PLGF-induced cancer neovascularization may be partially mediated through its effect on MMP9 activation in OSCC. PMID- 25432136 TI - Adult congenital heart disease: a growing epidemic. AB - Medical and surgical breakthroughs in the care of children born with heart defects have generated a growing population of adult survivors and spawned a new subspecialty of cardiology: adult congenital heart disease. The prevalence of adult congenital heart disease is escalating at a rampant rate, outpacing the relatively static prevalence of pediatric congenital heart disease, because adults now surpass children in numbers by a ratio of 2:1. As such, congenital heart disease can no longer be considered primarily a pediatric specialty. Most congenital heart defects are not curable and require lifelong specialized care. Health care systems worldwide are challenged to meet the unique needs of this increasingly complex patient population, including the development of supraregional centres of excellence to provide comprehensive and multidisciplinary specialized care. In this review, we explore the incidence and prevalence of congenital heart disease and their changing patterns, address organization and delivery of care, highlight the importance of appropriate training and dedicated research, summarize the high burden of health care resource utilization, and provide an overview of common issues encountered in adults with congenital heart disease. PMID- 25432137 TI - New directions in cardiac arrhythmia management: present challenges and future solutions. AB - Cardiac arrhythmias are a major contributor to population morbidity and mortality. Enormous advances in arrhythmia management have occurred over the 60 years since the founding of the Montreal Heart Institute, but important challenges remain. The purpose of this article is to identify the areas of cardiac arrhythmia therapy that need improvement and to discuss the evolving approaches that promise solutions. Challenges in diagnosis, detection, and risk stratification include difficulties in separating benign from high-risk syncope and pinpointing the underlying causes, the detection of silent atrial fibrillation in patients at risk of stroke, and inadequate identification of sudden-death risk. Implantable devices are limited by the need for battery and device replacements, device complications like infection and dysfunction, and lead complications like fracture, infection, or displacement. Antiarrhythmic drug therapy, although widely used, is plagued by a very limited range of available agents, supply issues, insufficient efficacy, and significant adverse effect risk. Health economic concerns include the high cost of new technologies, challenges in establishing cost effectiveness, and restrictive practices of government or third-party payers. Major improvements in arrhythmia management can be expected from new discoveries and technological developments in genetics, innovative diagnostic tools for arrhythmia monitoring, imaging and analysis, new approaches to antiarrhythmic drug development, biological therapies, and continuing improvement in implantable device technology like further miniaturization, leadless technology, and use of novel energy sources. As exciting as the developments in arrhythmia management have been in the past, we can look forward to exponential improvement in our ability to manage arrhythmia patients in the near future. PMID- 25432138 TI - The past, the present, and the future of cardiac arrhythmia ablation. AB - The development and evolution of percutaneous catheter ablation for the treatment of cardiac arrhythmias has advanced significantly since the early days of direct current shock ablation, and in parallel with an increasing understanding about arrhythmia mechanisms. Because of the ever-changing landscape that is cardiac electrophysiology, the purpose of this review is to discuss the future of invasive arrhythmia management within the context of the history and contemporary practice of this cardiac subspecialty. Topics of discussion include: (1) the evolution of ablation technologies from direct current shock and radiofrequency to alternative energy sources such as cryothermal ablation; (2) the use and development of nonfluoroscopic navigation systems; (3) the progression of ablation toolsets and modalities; and (4) the advancement of ablation strategies and techniques, including ablation of complex atrial and ventricular dysrhythmias tailored to the individual patient. PMID- 25432139 TI - Innovative approaches in the perioperative care of the cardiac surgical patient in the operating room and intensive care unit. AB - Perioperative care for cardiac surgery is undergoing rapid evolution. Many of the changes involve the application of novel technologies to tackle common challenges in optimizing perioperative management. Herein, we illustrate recent advances in perioperative management by focusing on a number of novel components that we judge to be particularly important. These include: the introduction of brain and somatic oximetry; transesophageal echocardiographic hemodynamic monitoring and bedside focused ultrasound; ultrasound-guided vascular access; point-of-care coagulation surveillance; right ventricular pressure monitoring; novel inhaled treatment for right ventricular failure; new approaches for postoperative pain management; novel approaches in specialized care procedures to ensure quality control; and specific approaches to optimize the management for postoperative cardiac arrest. Herein, we discuss the reasons that each of these components are particularly important in improving perioperative care, describe how they can be addressed, and their impact in the care of patients who undergo cardiac surgery. PMID- 25432140 TI - Reply: Takotsubo syndrome is a systemic, rather than merely a cardiac, disease: possible effects on the systemic and pulmonary vasculature. PMID- 25432141 TI - Determining the mechanisms underlying augmented renal drug clearance in the critically ill: use of exogenous marker compounds. AB - INTRODUCTION: The aim of this study was to explore changes in glomerular filtration (GFR) and renal tubular function in critically ill patients at risk of augmented renal clearance (ARC), using exogenous marker compounds. METHODS: This prospective, observational pharmacokinetic (PK) study was performed in a university-affiliated, tertiary-level, adult intensive care unit (ICU). Patients aged less than or equal to 60 years, manifesting a systemic inflammatory response, with an expected ICU length of stay more than 24 hours, no evidence of acute renal impairment (plasma creatinine concentration < 120 MUmol/L) and no history of chronic kidney disease or renal replacement therapy were eligible for inclusion. The following study markers were administered concurrently: sinistrin 2,500 mg (Inutest; Laevosan, Linz, Austria), p-aminohippuric acid (PAH) 440 mg (4% p-aminohippuric acid sodium salt; CFM Oskar Tropitzsch, Marktredwitz, Germany), rac-pindolol 5 or 15 mg (Barbloc; Alphapharm, Millers Point, NSW, Australia) and fluconazole 100 mg (Diflucan; Pfizer Australia Pty Ltd, West Ryde, NSW, Australia). Plasma concentrations were then measured at 5, 10, 15, 30, 60 and 120 minutes and 4, 6, 12 and 24 hours post-administration. Non-compartmental PK analysis was used to quantify GFR, tubular secretion and tubular reabsorption. RESULTS: Twenty patients were included in the study. Marker administration was well tolerated, with no adverse events reported. Sinistrin clearance as a marker of GFR was significantly elevated (mean, 180 (95% confidence interval (CI), 141 to 219) ml/min) and correlated well with creatinine clearance (r = 0.70, P < 0.01). Net tubular secretion of PAH, a marker of tubular anion secretion, was also elevated (mean, 428 (95% CI, 306 to 550) ml/min), as was net tubular reabsorption of fluconazole (mean, 135 (95% CI, 100 to 169) ml/min). Net tubular secretion of (S)- and (R)-pinodolol, a marker of tubular cation secretion, was impaired. CONCLUSIONS: In critically ill patients at risk of ARC, significant alterations in glomerular filtration, renal tubular secretion and tubular reabsorption are apparent. This has implications for accurate dosing of renally eliminated drugs. PMID- 25432142 TI - NAIF1 inhibits gastric cancer cells migration and invasion via the MAPK pathways. AB - PURPOSE: Nuclear apoptosis-inducing factor 1 (NAIF1) could induce apoptosis in gastric cancer cells. Previously, we have reported that the expression of NAIF1 protein is down-regulated in gastric cancer tissues compared with the adjacent normal tissues. However, the role of NAIF1 in gastric cancer cells is not fully understood. METHODS: The effects of NAIF1 on cell viability were evaluated by MTT and colony formation assays. The ability of cellular migration and invasion were analyzed by transwell assays. The expression levels of targeted proteins were determined by western blot. The relative RNA expression levels were analyzed using quantitative polymerase chain reaction assays. Xenograft experiment was employed to determine the anti-tumor ability of NAIF1 in vivo. RESULTS: The study demonstrates that transient transfection of NAIF1 in gastric cancer cells BGC823 and MKN45 could inhibit the cell proliferation, migration, and invasion of the two gastric cancer cell lines. The tumor size is smaller in NAIF1-overexpressed MKN45 cell xenograft mice than in unexpressed group. Further in-depth analysis reveals that NAIF1 reduces the expression of MMP2 as well as MMP9, and inhibits the activation of FAK, all of which are key molecules involved in regulating cell migration and invasion. In addition, NAIF1 inhibits the expression of c-Jun N terminal kinase (JNK) by accelerating its degradation through ubiquitin proteasome pathway. Meanwhile, NAIF1 reduces the mRNA and protein expression of ERK1/2. CONCLUSIONS: Our study revealed that NAIF1 plays a role in regulating cellular migration and invasion through the MAPK pathways. It could be a therapeutic target for gastric cancer. PMID- 25432144 TI - Prevalence of depression in type 2 diabetes mellitus. AB - BACKGROUND: The relationship between depression and diabetes has been widely documented but there have been methodological limitations such as the failure to conduct a diagnostic interview of the depressive condition. We have estimated the prevalence of depression in patients with type 2 diabetes mellitus (DM2) and its relationship with sociodemographic, lifestyle and clinical variables. PATIENTS AND METHODS: This was a cross-sectional, randomized study (stratified by sex and age) of patients with DM2 treated in a healthcare area with approximately 3000 eligible patients. The depressive symptoms were assessed using the Beck Depression Inventory (depression defined as a BDI score>16) and a psychiatric interview. We used a multivariate logistic regression model to evaluate the association between depression and DM2, after adjusting for known risk factors. RESULTS: We examined 275 patients with DM2 (mean age, 64.5 years; men, 56.4%). The prevalence of depression was calculated at 32.7% (95% CI 27.4-38.5) and increased with age. A greater prevalence of depression was found in women, widowers, patients with obesity, those with poor compliance with the prescription, those with poor glycemic control and those who developed complications from diabetes. Thirty-five percent (95% CI 26.4-45.8) of the patients who scored>16 on the BDI scale had not been diagnosed with depression. CONCLUSIONS: Depression is highly prevalent in patients with DM2, especially in women. For approximately one-third of the patients, a diagnosis of depression had not been reached. PMID- 25432145 TI - The challenge of caring for myocardial infarction in the elderly. PMID- 25432143 TI - Late-day intraocular pressure-lowering efficacy and tolerability of travoprost 0.004% versus bimatoprost 0.01% in patients with open-angle glaucoma or ocular hypertension: a randomized trial. AB - BACKGROUND: Medications to control intraocular pressure (IOP) are frequently preserved using benzalkonium chloride (BAK), which can negatively affect the ocular surface. Data are needed to assess efficacy and safety of prostaglandin drugs preserved with and without BAK. The present study compared the efficacy and safety of BAK-free travoprost 0.004% (TRAV) and BAK 0.02%-preserved bimatoprost 0.01% (BIM) during late-day time points in patients with open-angle glaucoma or ocular hypertension. METHODS: This was a 12-week, phase 4, randomized, investigator-masked, crossover study. 84 patients with IOP >=24 and <36 mmHg were randomized 1:1 to receive once-daily TRAV or BIM for 6 weeks followed by an additional 6-week crossover period. IOP was measured at the end of each treatment period at 4, 6, and 8 pm. TRAV was considered noninferior to BIM if the upper limit of the 95% CI of the between-group difference in mean IOP was <=1.5 mmHg. Adverse events were assessed throughout the study. RESULTS: One patient discontinued due to allergic conjunctivitis, and 2 patients with missing data were excluded; 81 patients were included in the per-protocol population (mean +/- SD age, 58.3 +/- 11.4 years; TRAV/BIM, n = 41; BIM/TRAV, n = 40). After 6 weeks, mean IOP with TRAV (17.4 +/- 2.7 mmHg; change from baseline, -6.0 mmHg) was similar to BIM (17.2 +/- 2.6 mmHg; change from baseline, -6.3 mmHg); the between group difference was 0.22 mmHg (95% CI, -0.22 to 0.67). Thus, noninferiority of TRAV versus BIM was demonstrated. Mean IOP at each time point and mean and percentage IOP change from baseline were not significantly different between treatments. All treatment-emergent adverse events were mild to moderate. The incidences of mild ocular hyperemia with TRAV and BIM were 31% and 39%, respectively; moderate hyperemia was observed in 2% of patients receiving BIM. CONCLUSION: Late-day IOP-lowering efficacy of BAK-free TRAV was noninferior to that of BAK 0.02%-preserved BIM; both reduced baseline IOP by 25%. Both treatments were well tolerated, although a higher incidence of moderate ocular hyperemia was observed with BIM. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01464424; registered November 1, 2011. PMID- 25432146 TI - Anticoagulant treatment in nonvalvular atrial fibrillation there is room for improvement. PMID- 25432148 TI - Knowledge and Attitudes About Tuberculosis Among U.S.-Born Blacks and Whites with Tuberculosis. AB - Non-Hispanic blacks represent 13% of the U.S.-born population but account for 37% of tuberculosis (TB) cases reported in U.S.-born persons. Few studies have explored whether this disparity is associated with differences in TB-related knowledge and attitudes. Interviews were conducted with U.S.-born, non-Hispanic blacks and whites diagnosed with TB from August 2009 to December 2010 in cities and states that accounted for 27% of all TB cases diagnosed in these racial groups in the U.S. during that time period. Of 477 participants, 368 (77%) were non-Hispanic black and 109 (23%) were non-Hispanic white. Blacks had significantly less knowledge and more misconceptions about TB transmission and latent TB infection than whites. Most TB patients in both groups recalled being given TB information; having received such information was strongly correlated with TB knowledge. Providing information to U.S.-born TB patients significantly increased their knowledge and understanding of TB. More focused efforts are needed to provide TB information to U.S.-born black TB patients. PMID- 25432149 TI - HPV Vaccine Awareness, Barriers, Intentions, and Uptake in Latina Women. AB - Latina women are at heightened risk of cervical cancer incidence and mortality. The human papillomavirus (HPV) is the principal cause of the majority of cervical cancer cases. A vaccine that protects against HPV was licensed in 2006. Eight years post-licensure, mixed research findings exist regarding the factors that predict vaccine uptake in Latinas. We conducted a population-based phone survey with a random sample of 296 Latinas living in a Midwestern U.S. City. Intention to vaccinate was significantly associated with health care provider recommendations, worry about side effects, knowing other parents have vaccinated, perceived severity of HPV, and worry that daughter may become sexually active following vaccination. Worry that daughter may become sexually active was the only factor related to vaccine uptake. Findings suggest that training providers to discuss the low risk of severe side effects, consequences of persistent HPV, and sexuality related concerns with Latino women may encourage vaccination. PMID- 25432147 TI - Tumor-induced myeloid dysfunction and its implications for cancer immunotherapy. AB - Immune function relies on an appropriate balance of the lymphoid and myeloid responses. In the case of neoplasia, this balance is readily perturbed by the dramatic expansion of immature or dysfunctional myeloid cells accompanied by a reciprocal decline in the quantity/quality of the lymphoid response. In this review, we seek to: (1) define the nature of the atypical myelopoiesis observed in cancer patients and the impact of this perturbation on clinical outcomes; (2) examine the potential mechanisms underlying these clinical manifestations; and (3) explore potential strategies to restore normal myeloid cell differentiation to improve activation of the host antitumor immune response. We posit that fundamental alterations in myeloid homeostasis triggered by the neoplastic process represent critical checkpoints that govern therapeutic efficacy, as well as offer novel cellular-based biomarkers for tracking changes in disease status or relapse. PMID- 25432150 TI - Computer-Based Clinical Decision Support Systems and Patient-Reported Outcomes: A Systematic Review. AB - BACKGROUND: Evidence-based treatment guidelines embedded in computer-based clinical decision support systems (CCDSS) may improve patient-reported outcomes (PRO). We systematically reviewed the literature for content and application of CCDSS, and their effects on PRO. METHODS: A systematic review in MEDLINE and EMBASE was conducted according to PRISMA standards. Searches were limited to the publication period 1996-May 2014 and the English language. The search terms covered "computerized clinical decision systems" and "patient-reported outcomes". Screening and extraction was done independently by two reviewers according to predefined inclusion (computer and guideline) and exclusion criteria (no trial, no PRO). Study and CCDSS quality was rated according to predefined criteria. RESULTS: The database searches identified 1,331 references. Eighty-seven full text articles were analyzed. The main reason for exclusion was no PRO as a study outcome measure. Fifteen studies met the inclusion criteria, representing 13,480 patients. Nine studies used a computerized device to fill in data; in four studies, this was used by the patients themselves. Most of the studies presented the data to the clinician at point of care and incorporated international guidelines. Three studies showed a positive effect on PRO, but only on symptoms. Overall, no negative effects were reported. There was no association with study quality or year of study publication. CONCLUSION: There are marginal positive effects of CCDSS on specific PRO. Factors that facilitate the use and effect are identified. Easy to use systems with difficult to ignore evidence-based advice need to be developed and tested. PMID- 25432151 TI - The relationship of apolipoprotein B and very low density lipoprotein triglyceride with hyperuricemia and gout. AB - INTRODUCTION: Gout results from an innate immune response to monosodium urate (MSU) crystals deposited in joints. Increased very low-density lipoprotein (VLDL) has been associated with gout. The apolipoprotein B (apo B), which is present on VLDL, regulates neutrophil response to MSU crystals and has been positively associated with gout. Furthermore, the gene (A1CF) encoding the complementation factor for the APOB mRNA-editing enzyme is associated with urate levels. However, the relationship of apo B and VLDL with gout and hyperuricaemia (HU) is still unclear. Therefore, we tested the association of VLDL and apo B with HU and with gout compared to HU. METHODS: New Zealand European (n = 90) and Maori and Pacific Island (Polynesian) (n = 90) male gout case and control sample sets were divided into normouricaemia (NU), asymptomatic HU and gout groups. Size exclusion chromatography and enzyme-linked immunosorbant assay was used to measure VLDL and apo B. Multivariate logistic regression was used to assess the risk of gout and HU per unit change in VLDL and apo B. RESULTS: Increased levels of VLDL triglycerides (Tg) were observed in the gout sample set compared to NU and HU in Europeans (P = 1.8 * 10(-6) and 1 * 10(-3), respectively), but only compared to NU in Polynesians (P = 0.023). This increase was driven by increased number of VLDL particles in the European participants and by the Tg-enrichment of existing VLDL particles in the Polynesian participants. Each mmol/L increase in VLDL Tg was significantly associated with gout in the presence of HU in Europeans, with a similar trend in Polynesians (OR = 7.61, P = 0.011 and 2.84, P = 0.069, respectively). Each MUmol/L increase in total apo B trended towards decreased risk of HU (OR = 0.47; P = 0.062) and, conversely, with increased risk of gout compared to HU (OR = 5.60; P = 0.004). CONCLUSIONS: Increased VLDL Tg is associated with the risk of gout compared to HU. A genetic approach should be taken to investigate the possibility for causality of VLDL in gout. Apolipoprotein B may have pleiotropic effects in determining HU and gout. PMID- 25432152 TI - Relation between playing position and coronary artery calcium scores in retired National Football League players. AB - Retired National Football League (NFL) linemen have an increased prevalence of risk factors for atherosclerosis and have an increased risk of cardiovascular death compared with nonlinemen and the general population. We evaluated whether playing in lineman position is independently associated with an increased risk of the presence and severity of subclinical atherosclerosis. Players were categorized as linemen if they reported playing on the offensive or defensive line during their careers. Subclinical atherosclerosis was assessed using coronary artery calcium (CAC) scores in 931 retired NFL players (310 linemen, 621 nonlinemen). CAC scores were evaluated for absence of subclinical atherosclerosis (CAC = 0), presence of mild subclinical atherosclerosis (CAC 1 to 100), and moderate to severe subclinical atherosclerosis (CAC >=100). We performed multivariate logistic regression to determine whether the lineman position is independently associated with the presence and severity of subclinical atherosclerosis. Linemen were noted to have a lesser likelihood of absence of subclinical atherosclerosis (CAC = 0, 33.8% vs 41.7%, p = 0.02), a similar likelihood of mild subclinical atherosclerosis (CAC 1 to 100, 33.2% vs 31.8%, p = 0.7), and a greater likelihood of moderate to severe subclinical atherosclerosis (CAC >100, 32.9% vs 26.4%, p = 0.04) compared with nonlinemen. Adjusting for demographic and metabolic covariates, lineman status remained independently associated with mild subclinical atherosclerosis (CAC 1 to 100, odds ratio [OR] 1.41, 95% confidence interval [CI] 1.05 to 2.2, p = 0.04) and moderate to severe subclinical atherosclerosis (CAC >=100, OR 1.67, 95% CI 1.05 to 2.2). The association was attenuated after adjustment for race (CAC 1 to 100, OR 1.24, 95% CI 0.82 to 1.8; CAC >100, OR 1.59, 95% CI 1.01 to 2.49). In conclusion, lineman status in retired NFL players is associated with presence and severity of subclinical atherosclerosis, which is partly explained by race. PMID- 25432154 TI - From acute decompensated to chronic heart failure. AB - An acute decompensation of heart failure resulting in hospital admission represents a critical juncture in the natural history of the disease, as evidenced by poor mortality and readmission outcomes after hospital discharge. For this reason, a number of new short-term vasoactive therapies have been or are being tested in clinical trials. Furthermore, in response to unacceptable readmission rates, there has been intense interest in improving the transition from hospital discharge to the outpatient arena. Between these 2 areas of focus exists an often overlooked internal transition from acute vasoactive therapies to oral chronic heart failure medications. This transition from acute presentation to the rest of the hospital stay forms the basis of this review. PMID- 25432153 TI - Comparison by magnetic resonance phase contrast imaging of pulse-wave velocity in patients with single ventricle who have reconstructed aortas versus those without. AB - Pulse-wave velocity (PWV), a measure of arterial stiffness, is a known independent risk factor for cardiovascular events. Patients with single ventricle who undergo aortic to pulmonary anastomosis (recon) have noncompliant patch material inserted into the neoaorta, possibly increasing vessel stiffness and afterload. The purpose of this study is to determine if PWV in patients with single ventricle differed between those who did and those who did not undergo aortic reconstruction (nonrecon). We retrospectively reviewed cardiac magnetic resonance anatomic, cine, and phase contrast evaluations in the ascending aorta and descending aorta (DAo) at the level of the diaphragm data from 126 patients with single ventricle (8.6 +/- 8.0 years) from January 2012 to May 2013. Significance = p <0.05. Seventy-five patients underwent recon and 51 did not. PWV in recon was significantly higher than in nonrecon (3.9 +/- 0.9 m/s vs 3.2 +/- 1.0 m/s, p = 0.008); in recon, patients >13 years old had a higher PWV than those <7 years (4.5 +/- 0.6 vs 3.5 +/- 0.7 m/s, p = 0.004). Whether <7 or >13 years old, PWV of those with recon was higher than nonrecon DAo distensibility was similar between both groups. There was no difference in age, body surface area, or cardiac index between recon and nonrecon. No correlations between various hemodynamic and ventricular function parameters with PWV were noted. In conclusion, PWV in recon is higher than in nonrecon with similar DAo distensibility implicating the aortic reconstruction as a possible cause of increased afterload; older recon patients have stiffer aortas than younger ones, possibly imposing an additional cardiovascular risk in the future. Other biomaterials may potentially moderate PWV if clinical outcome is adversely affected. PMID- 25432155 TI - Dehydration of corneal anterior donor tissue with polyethylene glycol (PEG) enriched media. AB - Anterior donor grafts (including scleral rim, without Descemet membrane) increase in thickness and become hazy upon storage in organ culture (OC) medium. Transfer of these grafts to standard dehydration media just before transplantation does not reduce their thickness to normal. Therefore, we assessed the efficacy of different media enriched with polyethylene glycol (PEG) as dehydrating agents for organ-cultured anterior donor grafts. Grafts were harvested and stored in the commercial OC medium 'Max' (without dextran) for 1 week, and subsequently dehydrated in the standard commercial dehydration medium 'Jet' (with dextran) supplemented with 4-20% PEG3350, or 'Max' supplemented with 20% PEG6000 and PEG20.000, or 5-20% PEG35.000. Central corneal thickness (CCT), as assessed by anterior segment-optical coherence tomography, and transparency were evaluated before, and at 1, 4 and 7 days of dehydration. Transfer of grafts after 1 week of OC (average 1,200 um) to 'Jet' supplemented with PEG3350 revealed a concentration dependent effect of dehydration; CCT was restored to normal (500-600 um) when 10% PEG3350 was added. However, transparency was only temporarily restored; after 1 day, the grafts turned hazy. In contrast, grafts transferred to 'Max' supplemented with 20% PEG35.000 were transparent throughout the evaluation period, but were dehydrated to beyond normal levels (average 300 um). 'Max' supplemented with 5% PEG35.000 dehydrated grafts to normal values and restored transparency throughout. Thus, dehydration of anterior donor grafts prior to surgery in dextran-free OC medium supplemented with 5% PEG35.000 reduces graft thickness to normal and may facilitate anterior keratoplasty procedures. PMID- 25432156 TI - Comparison of classification methods that combine clinical data and high dimensional mass spectrometry data. AB - BACKGROUND: The identification of new diagnostic or prognostic biomarkers is one of the main aims of clinical cancer research. Technologies like mass spectrometry are commonly being used in proteomic research. Mass spectrometry signals show the proteomic profiles of the individuals under study at a given time. These profiles correspond to the recording of a large number of proteins, much larger than the number of individuals. These variables come in addition to or to complete classical clinical variables. The objective of this study is to evaluate and compare the predictive ability of new and existing models combining mass spectrometry data and classical clinical variables. This study was conducted in the context of binary prediction. RESULTS: To achieve this goal, simulated data as well as a real dataset dedicated to the selection of proteomic markers of steatosis were used to evaluate the methods. The proposed methods meet the challenge of high-dimensional data and the selection of predictive markers by using penalization methods (Ridge, Lasso) and dimension reduction techniques (PLS), as well as a combination of both strategies through sparse PLS in the context of a binary class prediction. The methods were compared in terms of mean classification rate and their ability to select the true predictive values. These comparisons were done on clinical-only models, mass-spectrometry-only models and combined models. CONCLUSIONS: It was shown that models which combine both types of data can be more efficient than models that use only clinical or mass spectrometry data when the sample size of the dataset is large enough. PMID- 25432157 TI - Partial capitate shortening for Kienbock's disease. AB - The purpose of this study was to report our experience of partial capitate shortening in seven patients with a median 38 months follow-up. Staging was made by the Lichtman classification system and stage II and III-A patients were included in the study. The mean age was 34 years (range 22-52). Patients were assessed for pain, range of motion, grip and pinch strength, and satisfaction was recorded using a scale between 0 and 4. All these parameters showed improvement after surgery. The Lichtman stage, lunate height index and carpal height index were determined radiographically. Magnetic resonance images of the wrist were studied for lunate revascularization at the final follow-up and occurred in all patients. According to our study, partial capitate shortening seems an effective treatment for Lichtman stage II and III-A patients.Level IV case series study. PMID- 25432159 TI - [Panhypopituitarism secondary to pituitary metastasis in a patient with breast cancer]. PMID- 25432158 TI - Steroid sidestep: evading androgen ablation by abiraterone. AB - Tumor mechanisms of abiraterone resistance in clinical prostate cancer are not well defined. Chen and colleagues report that a T878A androgen receptor mutation occurs in a subset of patients progressing while receiving abiraterone, suggesting that this may be a therapeutically exploitable mechanism of abiraterone resistance in castration-resistant prostate cancer. PMID- 25432160 TI - Identification of diphtheria toxin R domain mutants with enhanced inhibitory activity against HB-EGF. AB - Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a ligand of EGF receptor, is involved in the growth and malignant progression of cancers. Cross-reacting material 197, CRM197, a non-toxic mutant of diphtheria toxin (DT), specifically binds to the EGF-like domain of HB-EGF and inhibits its mitogenic activity, thus CRM197 is currently under evaluation in clinical trials for cancer therapy. To develop more potent DT mutants than CRM197, we screened various mutant proteins of R domain of DT, the binding site for HB-EGF. A variety of R domain mutant proteins fused with maltose-binding protein were produced and their inhibitory activity was evaluated in vitro. We found four R domain mutants that showed much higher inhibitory activity against HB-EGF than wild-type (WT) R domain. These R domain mutants suppressed HB-EGF-dependent cell proliferation more effectively than WT R domain. Surface plasmon resonance revealed their higher affinity to HB-EGF than WT R domain. CRM197(R460H) carrying the newly identified mutation showed increased cell proliferation inhibitory activity and affinity to HB-EGF. These results suggest that CRM197(R460H) or other recombinant proteins carrying newly identified mutation(s) in the R domain are potential therapeutics targeting HB-EGF. PMID- 25432162 TI - Aetiology, epidemiology and clinical characteristics of acute moderate-to-severe diarrhoea in children under 5 years of age hospitalized in a referral paediatric hospital in Rabat, Morocco. AB - The objective of the study was to describe the aetiology, epidemiology and clinical characteristics of the principal causes of acute infectious diarrhoea requiring hospitalization among children under 5 years of age in Rabat, Morocco. A prospective study was conducted from March 2011 to March 2012, designed to describe the main pathogens causing diarrhoea in hospitalized children >2 months and less than 5 years of age. Among the 122 children included in the study, enteroaggregative Escherichia coli (EAEC) and rotavirus were the main aetiological causes of diarrhoea detected. Twelve (9.8 %) children were referred to an intensive care unit, while two, presenting infection by EAEC, and EAEC plus Shigella sonnei, developed a haemolytic uraemic syndrome. Additionally, six (4.9 %) deaths occurred, with EAEC being isolated in four of these cases. Diarrhoeagenic E. coli and rotavirus play a significant role as the two main causes of severe diarrhoea, while other pathogens, such as norovirus and parasites, seem to have a minimal contribution. Surveillance and prevention programmes to facilitate early recognition and improved management of potentially life-threatening diarrhoea episodes are needed. PMID- 25432163 TI - Mosquito behaviour and disease control. PMID- 25432164 TI - Medical journals and industry ties. PMID- 25432161 TI - An integrative neurocircuit perspective on psychogenic nonepileptic seizures and functional movement disorders: neural functional unawareness. AB - Functional neurological disorder (conversion disorder) is a neurobehavioral condition frequently encountered by neurologists. Psychogenic nonepileptic seizure (PNES) and functional movement disorder (FMD) patients present to epileptologists and movement disorder specialists respectively, yet neurologists lack a neurobiological perspective through which to understand these enigmatic groups. Observational research studies suggest that PNES and FMD may represent variants of similar (or the same) conditions given that both groups exhibit a female predominance, have increased prevalence of mood-anxiety disorders, frequently endorse prior abuse, and share phenotypic characteristics. In this perspective article, neuroimaging studies in PNES and FMD are reviewed, and discussed using studies of emotional dysregulation, dissociation and psychological trauma in the context of motor control. Convergent neuroimaging findings implicate alterations in brain circuits mediating emotional expression, regulation and awareness (anterior cingulate and ventromedial prefrontal cortices, insula, amygdala, vermis), cognitive control and motor inhibition (dorsal anterior cingulate, dorsolateral prefrontal, inferior frontal cortices), self-referential processing and perceptual awareness (posterior parietal cortex, temporoparietal junction), and motor planning and coordination (supplementary motor area, cerebellum). Striatal-thalamic components of prefrontal-parietal networks may also play a role in pathophysiology. Aberrant medial prefrontal and amygdalar neuroplastic changes mediated by chronic stress may facilitate the development of functional neurological symptoms in a subset of patients. Improved biological understanding of PNES and FMD will likely reduce stigma and aid the identification of neuroimaging biomarkers guiding treatment development, selection, and prognosis. Additional research should investigate neurocircuit abnormalities within and across functional neurological disorder subtypes, as well as compare PNES and FMD with mood-anxiety-dissociative disorders. PMID- 25432165 TI - Pediatric tracheostomy: timing of the first tube change. AB - OBJECTIVES: No consensus exists on appropriate timing for the first tracheostomy tube change. The purpose of this study is to evaluate the safety of early tracheostomy change in the pediatric population. METHODS: A case series of all children undergoing tracheostomy at a tertiary children's hospital between 2008 2013 was retrospectively reviewed. RESULTS: A total of 151 children undergoing tracheostomy were identified. The average age was 48.1+/-66 months and median age was 10 months. The initial tracheostomy tube change occurred on postoperative day 3 (POD 3) in 65 children (43.0%) safely without any complications. CONCLUSIONS: Early tracheostomy tube change was safely performed in a significant portion of this population. Routine tube change on POD 3 in many children could save resources by reducing the length of ICU and hospital stays. PMID- 25432166 TI - Faster sequence homology searches by clustering subsequences. AB - MOTIVATION: Sequence homology searches are used in various fields. New sequencing technologies produce huge amounts of sequence data, which continuously increase the size of sequence databases. As a result, homology searches require large amounts of computational time, especially for metagenomic analysis. RESULTS: We developed a fast homology search method based on database subsequence clustering, and implemented it as GHOSTZ. This method clusters similar subsequences from a database to perform an efficient seed search and ungapped extension by reducing alignment candidates based on triangle inequality. The database subsequence clustering technique achieved an ~2-fold increase in speed without a large decrease in search sensitivity. When we measured with metagenomic data, GHOSTZ is ~2.2-2.8 times faster than RAPSearch and is ~185-261 times faster than BLASTX. AVAILABILITY AND IMPLEMENTATION: The source code is freely available for download at http://www.bi.cs.titech.ac.jp/ghostz/ CONTACT: akiyama@cs.titech.ac.jp SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25432167 TI - PEASE: predicting B-cell epitopes utilizing antibody sequence. AB - Antibody epitope mapping is a key step in understanding antibody-antigen recognition and is of particular interest for drug development, diagnostics and vaccine design. Most computational methods for epitope prediction are based on properties of the antigen sequence and/or structure, not taking into account the antibody for which the epitope is predicted. Here, we introduce PEASE, a web server predicting antibody-specific epitopes, utilizing the sequence of the antibody. The predictions are provided both at the residue level and as patches on the antigen structure. The tradeoff between recall and precision can be tuned by the user, by changing the default parameters. The results are provided as text and HTML files as well as a graph, and can be viewed on the antigen 3D structure. AVAILABILITY AND IMPLEMENTATION: PEASE is freely available on the web at www.ofranlab.org/PEASE. CONTACT: yanay@ofranlab.org. PMID- 25432168 TI - Screening agrochemicals as potential protectants of plants against ozone phytotoxicity. AB - We tested seven contemporary agrochemicals as potential plant protectants against ozone phytotoxicity. In nine experiments, Bel-W3 tobacco plants were experienced weekly exposures to a) 80 nmol mol(-1) of ozone-enriched or ozone-free air in controlled environment chambers, b) an urban air polluted area, and c) an agricultural-remote area. Ozone caused severe leaf injury, reduced chlorophylls' and total carotenoids' content, and negatively affected photosynthesis and stomatal conductance. Penconazole, (35% +/- 8) hexaconazole (28% +/- 5) and kresoxim-methyl (28% +/- 15) showed higher plants' protection (expressed as percentage; mean +/- s.e.) against ozone, although the latter exhibited a high variability. Azoxystrobin (21% +/- 15) showed lower protection efficacy and Benomyl (15% +/- 9) even lower. Trifloxystrobin (7% +/- 11) did not protect the plants at all. Acibenzolar-S-methyl + metalaxyl-M (Bion MX) (-6% +/- 17) exhibited the higher variability and contrasting results: in some experiments it showed some protection while in others it intensified the ozone injury by causing phytotoxic symptoms on leaves, even in control plants. PMID- 25432169 TI - Health impact of bioaccessible metal in lip cosmetics to female college students and career women, northeast of China. AB - Actual measure-based studies have estimated ingestion rate of moderate and high daily use to female college students and career women in northeast of China. Sequential extraction analyses showed that total bioaccessible metals concentration in lipstick ranged from 2.103 to 31.103 MUg/g and in lip balm ranged from 0.100 to 3.716 MUg/g. The relationship between total bioaccessible metal concentrations and the cost of lip cosmetics showed a negative correlation. Lead was detected in all 30 products (100%), with an average concentration of 0.346 for lip balm and 0.407 MUg/g for lipstick. With the exception of chromium content in three lipsticks, the estimated exposure in female college students and career women to target metals via lipstick and lip balm ingestion (calculated for moderate and high use) were much lower than the acceptable reference limits. The findings strongly emphasize the need to focus on the health risk of lip balm. PMID- 25432170 TI - On-call resident outside study overreads: Our department's experience streamlining workflow and improving resident supervision while providing a new source of revenue. AB - Handling the interpretation of outside studies or "curbside" consults can be a daily problem for many radiology departments. In this article, we describe the efforts of a resident quality improvement project to create a more streamlined workflow for the interpretation of outside studies. The principle goal of this project was to ensure that at our teaching hospital, any outside study presented to a resident on call also received a final staff interpretation. An additional goal of this project was to use the digital tools available in our department to streamline the workflow for providing these outside interpretations. The result is an integrated workflow that allows for increased resident supervision as well as a potential new source of revenue in being able to generate billable interpretations. PMID- 25432171 TI - Practical imaging of the parotid gland. AB - The parotid gland may be affected by numerous pathologies, and physicians from many different medical and surgical specialties request parotid imaging. Mastering the typical imaging features of various types of parotid pathology is facilitated by understanding how various diseases produce their characteristic imaging findings. In this review article, we present succinct overviews of the normal anatomy and the common pathologies of the parotid gland and recommend a practical approach to differential diagnosis that can be easily implemented in day-to-day radiology practice. PMID- 25432172 TI - Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. AB - Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) results in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy may be limited by poor persistence of TIL after adoptive transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in virus specific murine models, but whether this approach enhances features of memory (e.g., long-term persistence) in TIL that are characteristically exhausted and senescent is not established. Here, we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic, and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of antitumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer. PMID- 25432174 TI - Crosstalk between KIT and FGFR3 Promotes Gastrointestinal Stromal Tumor Cell Growth and Drug Resistance. AB - Kinase inhibitors such as imatinib have dramatically improved outcomes for patients with gastrointestinal stromal tumor (GIST), but many patients develop resistance to these treatments. Although in some patients this event corresponds with mutations in the GIST driver oncogenic kinase KIT, other patients develop resistance without KIT mutations. In this study, we address this patient subset in reporting a functional dependence of GIST on the FGF receptor FGFR3 and its crosstalk with KIT in GIST cells. Addition of the FGFR3 ligand FGF2 to GIST cells restored KIT phosphorylation during imatinib treatment, allowing sensitive cells to proliferate in the presence of the drug. FGF2 expression was increased in imatinib-resistant GIST cells, the growth of which was blocked by RNAi-mediated silencing of FGFR3. Moreover, combining KIT and FGFR3 inhibitors synergized to block the growth of imatinib-resistant cells. Signaling crosstalk between KIT and FGFR3 activated the MAPK pathway to promote resistance to imatinib. Clinically, an IHC analysis of tumor specimens from imatinib-resistant GIST patients revealed a relative increase in FGF2 levels, with a trend toward increased expression in imatinib-naive samples consistent with possible involvement in drug resistance. Our findings provide a mechanistic rationale to evaluate existing FGFR inhibitors and multikinase inhibitors that target FGFR3 as promising strategies to improve treatment of patients with GIST with de novo or acquired resistance to imatinib. PMID- 25432173 TI - A urokinase receptor-Bim signaling axis emerges during EGFR inhibitor resistance in mutant EGFR glioblastoma. AB - EGFR is the most common genetically altered oncogene in glioblastoma (GBM), but small-molecule EGFR tyrosine kinase inhibitors (TKI) have failed to yield durable clinical benefit. Here, we show that in two novel model systems of acquired resistance to EGFR TKIs, elevated expression of urokinase plasminogen activator (uPA) drives signaling through the MAPK pathway, which results in suppression of the proapoptotic BCL2-family member protein BIM (BCL2L11). In patient-derived GBM cells and genetic GBM models, uPA is shown to suppress BIM levels through ERK1/2 phosphorylation, which can be reversed by siRNA-mediated knockdown of uPA. TKI resistant GBMs are resensitized to EGFR TKIs by pharmacologic inhibition of MEK or a BH3 mimetic drug to replace BIM function. A link between the uPA-uPAR-ERK1/2 pathway and BIM has not been previously demonstrated in GBM, and involvement of this signaling axis in resistance provides rationale for a new strategy to target EGFR TKI-resistant GBM. PMID- 25432176 TI - PI3K/mTOR dual inhibitor VS-5584 preferentially targets cancer stem cells. AB - Cancer stem cells (CSC) have been implicated in disease recurrence, metastasis, and therapeutic resistance, but effective targeting strategies for these cells are still wanting. VS-5584 is a potent and selective dual inhibitor of mTORC1/2 and class I PI 3-kinases. Here, we report that VS-5584 is up to 30-fold more potent in inhibiting the proliferation and survival of CSC compared with non-CSC in solid tumor cell populations. VS-5584 preferentially diminished CSC levels in multiple mouse xenograft models of human cancer, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Likewise, VS-5584 treatment ex vivo preferentially reduced CSC in surgically resected breast and ovarian patient tumors. In contrast, chemotherapeutics such as paclitaxel and cisplatin were less effective in targeting CSC than bulk tumor cells. Mechanistic investigations revealed that preferential targeting of CSC required inhibition of multiple components of the PI3K-mTOR pathway: coordinate RNAi-mediated silencing of PI3Kalpha, PI3Kbeta, and mTOR phenocopied the effect of VS-5584, exhibiting the strongest preferential targeting of CSC, while silencing of individual PI3K isoforms or mTOR failed to replicate the effect of VS-5584. Consistent with CSC ablation, VS-5584 delayed tumor regrowth following chemotherapy in xenograft models of small-cell lung cancer. Taken together, the preferential targeting of CSC prompts a new paradigm for clinical testing of VS-5584: clinical trials designed with CSC-directed endpoints may facilitate demonstration of the therapeutic benefit of VS-5584. We suggest that combining VS-5584 with classic chemotherapy that debulks tumors may engender a more effective strategy to achieve durable remissions in patients with cancer. PMID- 25432175 TI - Activin upregulation by NF-kappaB is required to maintain mesenchymal features of cancer stem-like cells in non-small cell lung cancer. AB - Soluble growth factors and cytokines within the tumor microenvironment aid in the induction of the epithelial-to-mesenchymal transition (EMT). Although EMT promotes the development of cancer-initiating cells (CIC), cellular mechanisms by which cancer cells maintain mesenchymal phenotypes remain poorly understood. Work presented here indicates that induction of EMT stimulates non-small cell lung cancer (NSCLC) to secrete soluble factors that function in an autocrine fashion. Using gene expression profiling of all annotated and predicted secreted gene products, we find that NF-kappaB activity is required to upregulate INHBA/Activin, a morphogen in the TGFbeta superfamily. INHBA is capable of inducing and maintaining mesenchymal phenotypes, including the expression of EMT master-switch regulators and self-renewal factors that sustain CIC phenotypes and promote lung metastasis. Our work demonstrates that INHBA mRNA and protein expression are commonly elevated in primary human NSCLC and provide evidence that INHBA is a critical autocrine factor that maintains mesenchymal properties of CICs to promote metastasis in NSCLC. PMID- 25432178 TI - Clinical manifestations of central neurocytoma. AB - Central neurocytomas (CNs) are rare central nervous system tumors that occur in the lateral ventricles. They are prevalent in young adults and are typically benign with excellent prognosis following surgical resection. Because of the rarity of the disease and its similar features with more common tumors, misdiagnosis becomes an issue. Optimal treatment is achieved only when the correct tumor types are distinguished. Typical clinical manifestations include symptoms of increased intracranial pressure, although no clinical feature is pathognomonic to CN. Radiologic imaging, histology, magnetic resonance spectroscopy, and immunohistochemistry must be used to elucidate tumor characteristics and properly diagnose CN. PMID- 25432177 TI - Central neurocytoma: establishment of the disease entity. AB - The establishment and identification of central neurocytoma as a distinct disease entity are invaluable in catalyzing investigations of neuronal differentiation in central nervous system tumors. The discovery of neuronal differentiation in neuroepithelial tumors has been extended to extraventricular tumors and potentially to various glial tumors undergoing neuronal differentiation. Understanding the disease spectrum of neuronal and mixed neuronal-glial tumors is important for deciphering the mechanism of gliomagenesis. PMID- 25432179 TI - Imaging of central neurocytomas. AB - Central neurocytoma (CN) is an important consideration in the differential diagnosis of any intraventricular lesion. Initial evaluation should include noncontrast CT, MRI with and without gadolinium contrast, and magnetic resonance (MR) spectroscopy, if available. CN classically appear as a partially calcified mass on CT, arising from the septum pellucidum or foramen of Monro, with a soap bubble multicystic appearance on MR T2-imaging and heterogeneous enhancement on MR T1 postcontrast imaging. MR perfusion/permeability and dynamic contrast imaging are experimental and promising tools in the diagnosis of CN. PMID- 25432181 TI - The characteristics of neuronal stem cells of central neurocytoma. AB - Angiographic findings suggest that central neurocytoma (CN) might originate from neuronal cells of the subventricular zone (SVZ) around the foramen of Monro rather than from the septum pellucidum. The majority of CN cells have neuroblast characteristics. Most importantly, CN-derived tumor spheres have a phenotype of transit-amplifying type C cells, implying that these cells might arise from transformed transit-amplifying type C cells that reside in the SVZ. These CN derived tumor spheres are also reminiscent of radial glial cells. Immunohistochemical and electrophysiologic studies show that these cells exhibit bipotential neuroglial differentiation in vitro. PMID- 25432180 TI - Histology and molecular aspects of central neurocytoma. AB - Central neurocytoma (CN) is a well-differentiated tumor of neural cells occurring within the ventricles. It is composed of monomorphic cells with round, regular nuclei within clear cytoplasm and must be distinguished from other clear cell tumors. Immunohistochemical markers of CN that aid in diagnosis include synaptophysin and neuronal nuclear antigen. The molecular biology of these tumors is becoming increasingly elucidated, particularly with the use of microarray analyses. Several oncogenic pathways have been suggested by these studies. Although progress continues to be made, knowledge of CN has yet to dictate targeted therapies in treating patients with these tumors. PMID- 25432182 TI - The management of central neurocytoma: radiosurgery. AB - Stereotactic radiosurgery (SRS) has evolved into a mainstay in the primary and adjuvant management of most intracranial tumors. Central neurocytomas are rare, usually benign, intraventricular tumors that can be challenging to completely resect and often recur. Adjuvant therapy has been suggested for residual or recurrent tumors, especially in the setting of atypical neurocytomas. The limited data available suggest that SRS is a highly effective treatment approach for primary and adjuvant therapy, with tumor control rates of 80% to 90%. Due to its highly conformal and selective nature, SRS avoids the inconvenience and delayed toxicity of conventional radiation therapy. PMID- 25432183 TI - The management of central neurocytoma: radiotherapy. AB - Intraventricular neurocytomas (IVNs) are rare tumors of neuronal differentiation, accounting for 0.1% to 0.5% of all primary brain tumors. Complete surgical resection is highly recommended, but at least one-third to one-half are subtotally resected. Stereotactic radiosurgery (SRS) and conventional radiotherapy have been used for management of residual and recurrent tumors, but the optimal treatment following subtotal surgical resection is less clear. Although there are trends toward higher local tumor control and survival rates with lower complications among IVNs treated with SRS, higher quality data are required to confirm these findings. PMID- 25432184 TI - The management of incidental central neurocytoma. AB - This article elucidates the role of stereotactic radiosurgery for the management of central neurocytoma. This rare intraventricular tumor is usually benign and is best treated with surgical excision if the tumor is large and symptomatic. However, some distinctive neuroimaging features are found in this tumor that help to identify the tumor based on detailed MRI and computed tomography examinations. The cumulative experience shows that single-session radiosurgery using Gamma Knife radiosurgery is an effective and safe alternative treatment of incidental central neurocytoma. After radiosurgery, a serial MRI examination performed every 6 months for long-term follow-up is necessary to monitor radiosurgical response of the tumor. PMID- 25432185 TI - The management of residual or recurrent central neurocytoma. AB - Treatment following neurosurgical resection or biopsy of a central neurocytoma depends on the pathologic analysis and proliferative activity demonstrated, the extent of surgical resection, the neuroanatomic location and accessibility of residual tumor, and the patient's postoperative condition. The risks and benefits of additional surgery, radiation therapy, and/or chemotherapy should be weighed and individualized based on these factors and guided by the existing literature. PMID- 25432186 TI - Clinical outcome and quality of life after treatment of patients with central neurocytoma. AB - Central neurocytoma (CN) is an uncommon, deep-seated tumor of the central nervous system. Optimal treatment strategies and long-term outcomes are not well established. The mainstay of initial treatment CN is total surgical resection whenever possible; however, CNs cannot be resected completely in more than half of patients. Advances in alternative and adjuvant treatments and their role in the treatment of CN is becoming significant. This article provides an overview of the clinical outcomes of various treatment modalities, recent advances, and recommendations for the treatment of CN, emphasizing functional outcomes and the quality of life. PMID- 25432187 TI - Atypical and rare variants of central neurocytomas. AB - This article reviews the variation in imaging, histopathology, clinical course, and management seen with central neurocytomas (CNs). CNs have often been misdiagnosed as oligodendrogliomas and ependymomas; however, synaptophysin positivity can correctly diagnose these neurocytic neoplasms. Atypical CNs, an important variant first described in 1997, are marked by increased proliferative potential and associated with worse clinical outcomes in terms of long-term survival and local tumor control. Complete surgical resection is the cornerstone of therapy, and postoperative radiation is recommended in the setting of residual disease. Other less aggressive variants of central neurocytomas, including liponeurocytomas, ganglioneurocytomas, and pigmented neurocytomas, are also discussed. PMID- 25432188 TI - Extraventricular neurocytomas. AB - Extraventricular neurocytomas (EVNs) are rare neoplasms with many similar morphologic features compared with central neurocytomas. EVNs have been reported in a variety of locations and mainly occur within the cerebral hemispheres. These lesions display wide variability in morphologic features, cellularity, and proliferation rates. In addition, given their aggressive biological nature and tendencies to affect eloquent areas, EVNs are associated with a poorer prognosis. The epidemiology of these rare tumors is not definitively known, and effective treatment strategies have not been developed. This article reviews these tumors, including their epidemiology, clinical presentation, locations, radiological findings, treatment options, and prognosis. PMID- 25432189 TI - Rare pediatric central neurocytomas. AB - Central neurocytoma is extremely rare in pediatrics. In a single institute's record, it represents about 0.2% of brain tumors in children. The treatment of central neurocytoma in children is not different from that for adult patients. Surgical resection is the mainstay of treatment. After complete resection, the long-term prognosis is excellent. Adjuvant radiation therapy or radiosurgery may be applied to residual or recurrent tumors. However, the exact indication for each modality should be refined by accumulation of clinical data for this rare disease in children. PMID- 25432190 TI - Neurocytoma of the spinal cord. AB - This article presents an overview of spinal neurocytomas. A rare manifestation of an uncommon tumor, extraventricular neurocytomas (EVNs) should be included in the differential for spinal intradural and intramedullary tumors. Spinal EVNs are generally benign with an indolent pathologic course but may display a variety of acute or chronic clinical behaviors, depending on their anatomic location. Only a handful of spinal EVNs have been described in the literature, often in the form of individual case reports or small case series. Discussion includes a review of the literature and an overview of the clinical, pathologic, and radiologic features of this rare tumor type, as well as the differential diagnosis, treatment options, and general prognosis. PMID- 25432191 TI - Glial tumors with neuronal differentiation. AB - Immunohistochemical studies for neuronal differentiation in glial tumors revealed subsets of tumors having both characteristics of glial and neuronal lineages. Glial tumors with neuronal differentiation can be observed with diverse phenotypes and histologic grades. The rosette-forming glioneuronal tumor of the fourth ventricle and papillary glioneuronal tumor have been newly classified as distinct disease entities. There are other candidates for classification, such as the glioneuronal tumor without pseudopapillary architecture, glioneuronal tumor with neuropil-like islands, and the malignant glioneuronal tumor. The clinical significance of these previously unclassified tumors should be confirmed. PMID- 25432192 TI - Central neurocytomas. Preface. PMID- 25432194 TI - Renal denervation in treating resistant hypertension: does it have a future? PMID- 25432193 TI - Preventive and clinical care provided to adolescents attending public oral health services New South Wales, Australia: a retrospective study. AB - BACKGROUND: Dental Therapists and Oral Health Therapists (Therapists) working in the New South Wales (NSW) Public Oral Health Service are charged with providing clinical dental treatment including preventive care for all children under 18 years of age. Adolescents in particular are at risk of dental caries and periodontal disease which may be controlled through health education and clinical preventive interventions. However, there is a dearth of evidence about the type or the proportion of clinical time allocated to preventive care.The aim of this study is to record the proportion and type of preventive care and clinical treatment activities provided by Therapists to adolescents accessing the NSW Public Oral Health Service. METHODS: Clinical dental activity data for adolescents was obtained from the NSW Health electronic Information System for Oral Health (ISOH) for the year 2011. Clinical activities of Therapists were examined in relation to the provision of different types of preventive care for adolescents by interrogating state-wide public oral health data stored on ISOH. RESULTS: Therapists were responsible for 79.7 percent of the preventive care and 83.0 percent of the restorative treatment offered to adolescents accessing Public Oral Health Services over the one year period. Preventive care provided by Therapists for adolescents varied across Local Health Districts ranging from 32.0 percent to 55.8 percent of their clinical activity. CONCLUSIONS: Therapists provided the majority of clinical care to adolescents accessing NSW Public Oral Health Services. The proportion of time spent undertaking prevention varied widely between Local Health Districts. The reasons for this variation require further investigation. PMID- 25432195 TI - Clinical presentation and management of stable coronary artery disease: insights from the international prospective CLARIFY registry - results from the Greek national cohort. AB - INTRODUCTION: Coronary artery disease (CAD) is highly prevalent worldwide, yet there is a paucity of data regarding the clinical characteristics and management of outpatients with stable CAD. In this paper, we report the baseline data of the Greek cohort and we compare our national data with the global results of the entire registry, as well as the results from the western European countries. METHODS: CLARIFY is an international, prospective, observational, longitudinal registry of outpatients with stable CAD, defined as prior myocardial infarction or revascularization procedure, evidence of coronary stenosis >50%, or chest pain associated with proven myocardial ischemia. A total of 33,283 patients from 45 countries in 4 continents were enrolled between November 2009 and July 2010; of these, 14,726 were from western European countries (Austria, Belgium, Denmark, France, Germany, Greece, Ireland, Italy, Netherlands, Portugal, Spain, Switzerland and the United Kingdom) and 559 patients were enrolled in Greece. RESULTS: Compared to their counterparts in western Europe and the entire cohort, Greeks were younger (p<0.0001, p<0.0001, respectively), more predominantly male (p<0.0039, p<0.0001), with a higher body mass index (p<0.0002, p<0.0001) and a larger waist circumference (p<0.0001, p<0.0001), as well as a higher prevalence of family history of CAD (p<0.0008, 0.0005), hyperlipidemia (p<0.0001, p<0.0001) and smoking (p<0.0001, p<0.0001). Noninvasive testing (p<0.0001, p<0.0001, respectively) and coronary angiography (p<0.0001, 0.0013) along with surgical revascularization (CABG) (p<0.0001, 0.0088) were performed more often in Greece. Antiplatelets, b-blockers and lipid lowering medications were used to an equal extent in Greece as in the other two cohorts. CONCLUSION: There are substantial differences in demographics, clinical profiles and treatment in patients with stable CAD within the data set, which are also observed for Greek data. Interestingly, these differences are consistent in relation to the global as well as the western European data. PMID- 25432196 TI - Sex differences regarding the impact of physical activity on left ventricular systolic function in elderly patients with an acute coronary event. AB - INTRODUCTION: Regular physical activity has been associated with less severity of an acute coronary syndrome (ACS), lower in-hospital mortality rates, and an improved short term prognosis. This study evaluated the relationship between physical activity status and the development of left ventricular systolic dysfunction (LVSD) according to inflammation and sex in elderly patients who had had an ACS. METHODS: We analyzed prospectively collected data from 355 male (age 74 +/- 6 years) and 137 female (76 +/- 6 years) patients who were hospitalized with an ACS. LVSD was evaluated by echocardiography on the 5th day of hospitalization and physical activity status was assessed by a self-reported questionnaire. Inflammatory response was evaluated by measuring C-reactive protein levels. Logistic regression models were applied to evaluate the effect of physical activity status on the development of LVSD and inflammatory response at entry. RESULTS: Physical inactivity had a higher prevalence in women who developed LVSD than in the female patients with preserved systolic function (46% vs. 20%, p=0.02). There was a significant positive association between physical activity levels and ejection fraction in women (p=0.06), but not in men (p=0.30). Multiadjusted logistic regression showed that women who were physically active had 76% lower odds (95%CI: 1-94%) of developing LVSD compared to their sedentary counterparts. Furthermore, physical activity was inversely associated with C reactive protein levels in both sexes (p=0.08). CONCLUSIONS: Long-term involvement in a physically active lifestyle seems to confer further cardio protection by reducing the inflammatory response and preserving left ventricular systolic function in elderly female, but not male patients with an ACS. PMID- 25432197 TI - Red blood cell distribution width is a significant prognostic marker in advanced heart failure, independent of hemoglobin levels. AB - INTRODUCTION: Advanced heart failure (HF) is associated with increased morbidity and mortality; traditionally used prognostic factors often fail to predict the outcome. Increased red blood cell distribution width (RDW) has recently been recognized as an important unfavorable prognostic factor in HF, independent of anemia; however, the role of RDW in patients with advanced HF has not yet been investigated. METHODS: Eighty consecutive patients with stage D heart failure, recently hospitalized for HF decompensation, were enrolled. A Cox proportional hazard model was used to determine whether RDW was independently associated with outcome. RESULTS: At study entry, ejection fraction (EF), pulmonary capillary wedge pressure (PCWP), hemoglobin (Hb) and RDW were 25 +/- 8.6%, 27.5 +/- 8 mmHg, 12.5 +/- 1.9 mg/dL and 18 +/- 3.5% (normal <14.5%) respectively. At 6 months, 44 patients (55%) had died. In this patient population, EF (p=0.45), PCWP (p=0.106), age (p=0.54), albumin (0.678), iron (p=0.37), creatinine (p=0.432), iron deficiency defined by bone marrow aspiration (p=0.37), bilirubin (p=0.422), peak VO2 (p=0.057) and Hb (p=0.95) were not significant predictors of a worse outcome. However, RDW was a significant marker for adverse prognosis (p=0.007, HR: 1.14, CI: 1.04-1.24) and retained its prognostic significance even when corrected for Hb values (HR: 1.15, CI: 1.05-1.27, p=0.003). CONCLUSIONS: RDW is a significant prognostic factor for an adverse outcome in patients with advanced stage heart failure who have experienced recent decompensation, independent of the presence of anemia or malnutrition, and is superior to more traditionally used indices. RDW may be associated with severe disease by reflecting subtle metabolic and proinflammatory abnormalities in HF. PMID- 25432198 TI - Surgical management of infective endocarditis: early and long-term mortality analysis. single-center experience and brief literature review. AB - INTRODUCTION: In this study we evaluated factors that affect the early and long term postoperative outcomes of patients with infective endocarditis. METHODS: We retrospectively reviewed 94 patients (68 male, 26 female, mean age 58.3 +/- 13.1 years, range 20-85 years) with proven infective native (n=85) or prosthetic valve (n=9) endocarditis who underwent heart valve surgery between September 1997 and December 2007. Fifty-four patients (57.4%) underwent aortic, 28 (29.8%) mitral, 3 (3.2%) tricuspid, 8 (8.5%) double, and one patient (1%) triple valve surgery. In 75.5% of the procedures we implanted mechanical valves, in 13.8% biological prostheses, and 10.7% were reconstructive or other procedures. Midterm follow up was 100% complete with a cumulative duration of 545 patient-years (maximum 12 years). RESULTS: Overall hospital mortality (30 days) was 8.5% (n=8). Causes of early mortality were low cardiac output syndrome in 2 cases, sepsis with multiple organ failure in 5 cases, and intracerebral bleeding in one patient. Development of postoperative low cardiac output syndrome (p=0.01) was identified as an independent predictor of early mortality. Overall late mortality was 25.6% (n=22) with a cumulative rate of 4.03% per patient-year. Causes of late death were predominantly of extracardiac origin. Kaplan-Meier survival analysis revealed a cumulative survival rate at 12 years of 57.2%. Cox regression analysis identified diabetes mellitus (p=0.016) and postoperative low cardiac output syndrome (p=0.03) as independent late mortality factors. CONCLUSIONS: Heart valve surgery in patients with infective endocarditis is associated with increased but acceptable early and long-term mortality. The mid-term prognosis is similar to that of patients undergoing elective valve replacement surgery. PMID- 25432199 TI - Assessment of health-related quality of life in a greek symptomatic population with atrial fibrillation: correlation with functional status and echocardiographic indices. AB - INTRODUCTION: Atrial fibrillation (AF) is known to have an unfavorable impact on quality of life. The purpose of this study was to assess the health-related quality of life (HRQOL) in a symptomatic population with AF seeking medical advice in a tertiary hospital, as well as to explore the relationship between HRQOL, functional status, and echocardiographic indices of left ventricular (LV) systolic and diastolic function. METHODS: The study sample consisted of 108 symptomatic patients suffering from AF who presented in the emergency department or were admitted to the cardiology department in an urban Greek tertiary hospital between January 1 and May 31, 2012. HRQOL was assessed using the SF-36 and EQ-5D instruments. RESULTS: In the study sample, AF was newly diagnosed in 16.5% of the patients, paroxysmal/persistent in 43.6% and permanent in 39.9%. The mean levels of physical and mental summary components of the SF-36 were 40.28 and 40.89, respectively. The EQ-VAS mean score was 59.63%, while the EQ-5D Europe VAS index and the York A1 Tariff index were 0.586 and 0.547, respectively. Reliability analysis found Cronbach's to be 0.890 for the SF-36 and 0.701 for the EQ-5D. Convergent validity was proved to be at satisfactory levels. Impaired HRQOL was associated with worse NYHA class and echocardiographic indices of impaired LV systolic and diastolic function. Apart from higher NYHA class, other predisposing factors for lower HRQOL were female sex, advanced age, low physical activity, and higher levels of brain natriuretic peptide. CONCLUSIONS: Symptomatic AF patients report impaired HRQOL. Functional status and echocardiographic indices of LV systolic and diastolic function appear to affect HRQOL significantly in these patients. The SF-36 and the EQ-5D are shown to be reliable and valid instruments in assessing HRQOL in patients with AF. PMID- 25432200 TI - Real-time three-dimensional transesophageal echocardiography is useful for percutaneous closure of multiple secundum atrial septal defects. AB - INTRODUCTION: The purpose of this study was to investigate the clinical value of real-time three-dimensional transesophageal echocardiography (RT-3D-TEE) for percutaneous transcatheter closure of multiple secundum atrial septal defects (ASDs) using a Chinese domestic occluder device. METHODS: From July 2008 to September 2011, 37 patients (mean age 28.4 +/- 9.7 years; 24 females) with multiple secundum ASDs underwent percutaneous transcatheter closure in our institution with custom-made occluder devices. RT-3D-TEE was used to clarify the diagnosis and to help determine the operation scheme before the procedure, for real-time monitoring and guiding the operation during the procedure, and for evaluating the result shortly after the procedure. RESULTS: The custom-made atrial septal occluders were successfully implanted in 36 patients under RT-3DTEE guidance. Twenty-seven patients were implanted with two devices and 9 patients with a single device. In two patients where the distance between the two defects was less than 7 mm (5.5 mm and 6 mm), double occluder devices were also successfully implanted. One patient underwent surgery for the complication of unstable occluder and increased residual shunt after closure. No other severe complications were observed. CONCLUSIONS: RT-3D-TEE provides reliable diagnostic evidence of multiple ASDs and can help the clinician to select an appropriate operation scheme according to the number and morphology of multiple defects prior to percutaneous transcatheter closure. It also allows for proper positioning of the devices during the procedure and provides an effective means of evaluating the success of the procedure. For two devices to be implanted simultaneously in multiple ASDs, the usual requirement for the distance between the two defects may differ between our domestically made devices and the Amplatzer occluder. PMID- 25432201 TI - Incidence of reversible defect seen on myocardial perfusion scintigraphy using dipyridamole pharmacologic test early after primary percutaneous coronary intervention: how safe is it to perform this protocol? AB - INTRODUCTION: The purpose of this study was to investigate the safety of performing a dipyridamole stress test and to explore the incidence of reversible perfusion defects on myocardial perfusion imaging, five to six days after primary percutaneous coronary intervention (PCI). METHODS: Forty-one patients underwent myocardial perfusion imaging using a dipyridamole stress test, five to six days after primary PCI. RESULTS: Headache, chest pain, and dizziness were the most common side effects seen after dipyridamole administration. All occurrences were mild and short lasting. ST changes on the electrocardiogram were also seen in 12% of patients. Reversible perfusion defects occurred in 17%. CONCLUSIONS: This is one of the few studies to investigate patients using a dipyridamole stress test early after primary PCI. We conclude that it is safe to perform myocardial perfusion imaging under dipyridamole administration, just a few days after primary PCI. Additionally, a high incidence (17%) of myocardial perfusion defects was seen in this group of patients. According to our investigational protocol, a second myocardial perfusion imaging examination is scheduled for six months later, in order to clarify how many of these patients suffer from restenosis, or whether the finding was merely due to early endothelial dysfunction. PMID- 25432202 TI - Gastrointestinal bleeding in patients receiving antiplatelet and anticoagulant therapy: practical guidance for restarting therapy and avoiding recurrences. PMID- 25432203 TI - Successful transapical transcatheter prosthetic mitral paravalvular leak closure. PMID- 25432204 TI - Acute ischemia of fingers caused by permeable foramen ovale and an elongated eustachian valve: role of cardiac magnetic resonance. PMID- 25432205 TI - Renal denervation with vincristine for the treatment of resistant hypertension: further investigations are needed to implement it globally. PMID- 25432206 TI - Renal denervation: the Irish experience. PMID- 25432207 TI - The European Society of Cardiology and the latest guidelines for "seafarers". PMID- 25432208 TI - Cardiovascular disease and medical technology: essential needs and realities. PMID- 25432210 TI - The effect of gender on health-related quality of life and related factors in post-lobectomy lung-cancer patients. AB - PURPOSE: While studies have documented gender differences by histologic type among lung cancer patients, the effect of these differences on the health-related quality of life (HRQoL) of post-lobectomy lungcancer patients and related factors remain uncertain. This study examines gender-specific HRQoL and related factors in post-lobectomy lung-cancer patients. METHODS: A cross-sectional study design was applied. A convenience sample of 231 post-lobectomy lungcancer patients was recruited from the thoracic surgery outpatient departments of two teaching hospitals in Taipei, Taiwan from March to December 2012. Patients performed a spirometry test and completed instruments that included a Beck Depression Inventory-II, an Interpersonal Support Evaluation List, and the symptom and function scales of the Quality of Life Questionnaire. Data analysis used descriptive statistics, including mean and standard deviations, frequency, and percentage values. Independent-sample Student's t-tests and multivariate analyses were used for comparative purposes. RESULTS: This study confirmed a significant gender effect on HRQoL and HRQoL-related factors such as marital status, religious affiliation, smoking status, histologic type, symptoms, pulmonary function, depression, and family support. Moreover, multivariate analysis found gender to be a significant determinant of the HRQoL aspects of physical functioning, emotional functioning, and cognitive functioning. Finally, results indicated that factors other than gender were also significant determinants of HRQoL. CONCLUSION: Gender impacts the HRQoL and related factors of postoperative lung-cancer patients. Therefore, gender should be considered in assessing and addressing the individual care needs of these patients in order to attain optimal treatment outcomes. PMID- 25432211 TI - Indian Academy of Pediatrics, integral part of India newborn action plan. PMID- 25432209 TI - A survey of food bank operations in five Canadian cities. AB - BACKGROUND: Food banks have emerged in response to growing food insecurity among low-income groups in many affluent nations, but their ability to manage this problem is questionable. In Canada, in the absence of public programs and policy interventions, food banks are the only source of immediate assistance for households struggling to meet food needs, but there are many indications that this response is insufficient. The purpose of this study was to examine the factors that facilitate and limit food bank operations in five Canadian cities and appraise the potential of these initiatives to meet food needs. METHODS: An inventory of charitable food provisioning in Halifax, Quebec City, Toronto, Edmonton, and Victoria, Canada was conducted in 2010. Of the 517 agencies that participated in a telephone survey of their operations, 340 were running grocery programs. Multivariate regression analyses were conducted to determine the association between program characteristics, volume of service, and indicators of strain in food banks' abilities to consistently achieve the standards of assistance they had established. RESULTS: Extensive, well-established food bank activities were charted in each city, with the numbers of people assisted ranging from 7,111 in Halifax to 90,141 in Toronto per month. Seventy-two percent of agencies indicated that clients needed more food than they provided. The number of people served by any one agency in the course of a month was positively associated with the proportion of food distributed that came from donations (beta 0.0143, SE 0.0024, p 0.0041) and the number of volunteers working in the agency (beta 0.0630, SE 0.0159, p 0.0167). Food banks only achieved equilibrium between supply and demand when they contained demand through restrictions on client access. When access to assistance was less restricted, the odds of food banks running out of food and invoking measures to ration remaining supplies and restrict access rose significantly. CONCLUSIONS: Despite their extensive history, food banks in Canada remain dependent on donations and volunteers, with available resources quickly exhausted in the face of agencies' efforts to more fully meet clients' needs. Food banks have limited capacity to respond to the needs of those who seek assistance. PMID- 25432212 TI - Programmatic response to malnutrition in India, room for more than one elephant. AB - Programming platforms need to recognize the diversity of malnutrition epidemiology in India and choose appropriate implementation designs. With severe chronic malnutrition as the dominant epidemiologic entity, the net needs to be cast wide, focusing on food security, health care, agriculture, water and sanitation, livelihoods and womens empowerment. Community-based malnutrition treatment and prevention programs need to collaborate to complement treatment with socioeconomic and preventive interventions. Expansion of nutrition rehabilitation centers should be limited to areas/districts with high wasting. Pediatric services with nested nutrition services (including counseling) requires urgent strengthening. Continuum of Care is a weak link and requires strengthening to make both hospital and community-based models meaningful. PMID- 25432213 TI - Hepatitis B immunization in public health mode in India. PMID- 25432214 TI - Utility of hepatitis B vaccination in India. PMID- 25432215 TI - Time to target rubella elimination. PMID- 25432216 TI - Effect of inclusion of hepatitis B vaccine in childhood immunization program in India: a retrospective cohort study. AB - OBJECTIVE: To assess the effectiveness of hepatitis B immunization program in a field setting in India. DESIGN: Serological survey of retrospective cohorts of children, vaccinated or not vaccinated with hepatitis B vaccine. SETTING: Rural field areas of five districts in Andhra Pradesh state, where childhood hepatitis B immunization began in 2003. PARTICIPANTS: Children aged 5-11 years who had received HB immunization (n=2674; 1357 boys) or not received such immunization (n=2350; 1236 boys). MAIN OUTCOME MEASURES: Serum HBsAg, anti-HBc and anti-HBs (quantitative) using automated enzyme-immunoassays in the year 2010. RESULTS: Anti-HBs positivity was higher among immunized than in unimmunized children (53% vs.18%; P<0.001), and anti-HBc positivity was lower (1.1% vs 10.8%: P<0.01). HBsAg positivity was low in both the groups (0.15% and 0.17%; P=0.855). Anti-HBs positivity rate declined with increasing age. CONCLUSIONS: Administration of hepatitis B vaccine as part of Universal immunization program led to anti-HBs in a large proportion of children and a reduction in anti-HBc positivity, a marker of hepatitis B virus infection. These data provide evidence supporting efficacy of hepatitis B immunization program in an Indian field setting, justifying the decision to include it in the universal immunization program. PMID- 25432217 TI - Teaching and assessing professionalism in the Indian context. AB - Developing professional values and behaviour is an indispensable part of training of medicine. Societal values have changed and there are increasing reports of unprofessional behaviour by physicians. It is now agreed that professionalism must also be 'taught' besides being 'caught'. Most regulatory documents in India mention professionalism in a cursory manner, and do not specify details of how it should be taught and assessed in the curriculum. Teaching-learning methods, assessment and the training schedule for professionalism need to be specified in the undergraduate and postgraduate curriculum for it to be taken seriously. This article discusses the concept of professionalism, its definitions and the various teaching and assessment methods that can be applied in the Indian context. PMID- 25432218 TI - Subclinical hypothyroidism in children. AB - NEED AND PURPOSE OF REVIEW: Subclinical hypothyroidism is a biochemical diagnosis characterized by raised thyroid stimulating hormone and normal free T4, without clinical features of hypothyroidism. This review analyzes the current evidence to arrive at a consensus and algorithm to manage this condition. METHODS: We searched Pubmed, Cochrane and Embase for articles published between 1990 to 2014, and identified 13 relevant articles dealing with pediatric subclinical hypothyroidism which were suitable to include in our review. CONCLUSIONS: Subclinical hypothyroidism is often a benign problem which requires expectant management with periodic monitoring of thyroid function tests and natural progression to overt hypothyroidism occur lot less frequently than expected. There is a paucity of robust randomized intervention studies, especially studies focusing on clinical outcomes. Thyroid replacement therapy is not justified in children with subclinical hypothyroidism when Thyroid stimulating hormone is <10 mIU/L. The main risk factors for progression to overt hypothyroidism are female sex, goiter, family history of thyroid disorder, strongly positive thyroid peroxidase antibodies and symptoms suggesting hypothyroidism. An algorithm for managing this condition is suggested. PMID- 25432219 TI - An outbreak of rubella in Chandigarh, India. AB - OBJECTIVE: To investigate an outbreak of fever with rash in an urbanized village in Chandigarh, India. METHODS: Active case search was performed by house-to-house survey. The etiological agent of the outbreak was confirmed by serology. Spot map was done using Geographical Information System (GIS) technology. RESULTS: Out of 7742 persons screened, 12 were serologically confirmed rubella cases and 83 were epidemiologically linked cases. Overall attack rate was 1.1, more among the age group 1-4 years (4.9). CONCLUSIONS: An outbreak mimicking measles was investigated only to be confirmed as rubella. PMID- 25432220 TI - Nasal intermittent positive pressure ventilation with heliox in premature infants with respiratory distress syndrome: a randomized controlled trial. AB - OBJECTIVE: To assess the efficacy of nasal intermittent positive pressure ventilation with heliox in preterm infants with respiratory distress syndrome. METHODS: Premature infants with mild respiratory distress syndrome requiring non invasive respiratory support were eligible. Infants were randomly assigned to heliox or air-oxygen group. The main outcome was the length of ventilation. RESULTS: Heliox significantly decreased the length of ventilation. The length of ventilation was positively correlated with interleukin-6 at baseline. Carbon dioxide elimination was better in the heliox group. CONCLUSION: Heliox delivered with nasal intermittent positive pressure ventilation may be effective in reducing length of ventilation and increasing carbon dioxide elimination. PMID- 25432221 TI - Child fluorosis in Chhattisgarh, India: a community-based survey. AB - OBJECTIVE: To assess the prevalence and type of fluorosis among children from randomly selected villages of Chhattisgarh, and its relationship with fluoride levels in drinking water. METHODS: A community based door-to-door survey was conducted in the sampled villages of seven districts of Chhattisgarh state during the year 2013-14. The field case definitions were used for labelling types of fluorosis. The fluoride concentration in drinking water was estimated by ion selective electrode method. RESULTS: The prevalence of fluorosis ranged between 12 to 44% in children of surveyed districts. The fluoride levels in drinking water of selected villages were in the range of 0.1-9.0 ppm. CONCLUSION: Dental and skeletal fluorosis is endemic among children in the surveyed districts of Chhattisgarh State, and is related to drinking water with fluoride content of =1.5 ppm. PMID- 25432222 TI - Cryptosporidium in children with diarrhea: a hospital-based Study. AB - OBJECTIVE: To estimate the proportionate contribution of Cryptosporidium to diarrhea in under-five children, and to study its demographic and clinical associates. METHODS: We collected stool specimens from children (age <5 yrs) suffering from diarrhea. The specimen was examined on the same day by Kinyouns acid-fast staining for the presence of Cryptosporidium parvum oocyst; rest of the sample was preserved for later cryptosporidium antigen detection by commercially available ELISA kit. RESULTS: Out of 175 children with diarrhea, 48 (27.4%) had Cryptosporidium antigen in their stool specimen. Gender, history of contact with domestic animal, hydration status, breastfeeding and nutritional status were not significantly associated with cryptosporidium infection in children with diarrhea. CONCLUSION: Cryptosporidium is present in a significant portion of children suffering from diarrhea in our setting. Antigen detection has much higher isolation rate than acid-fast staining. PMID- 25432223 TI - Spirometric evaluation in juvenile systemic lupus erythematosus. AB - OBJECTIVE: Spirometric evaluation in juvenile systemic lupus erythematosus. METHODS: Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FVC, forced expiratory flow between 25-75% of vital capacity (FEF25 75%) and peak expiratory flow rate (PEFR) of 21 patients with juvenile SLE (jSLE) were compared to controls. RESULTS: Reduced FVC and FEF25-75% was found in 18 and 9 patients, respectively. All had normal FEV1/FVC. None had respiratory complaint. When compared to controls, patients had significantly reduced FVC [mean (SD):1.97 (0.56) vs 2.35 (0.60), P=0.002] and FEF25-75% [2.19 (0.83) vs 2.63 (0.76), P=0.028] but similar FEV1/FVC [86.87(7.03) vs 86.72 (6.35), P=0.639]. CONCLUSION: jSLE patients had significant restrictive pattern and small airway involvement. PMID- 25432224 TI - How useful is pulse oximetry for screening of congenital heart disease in newborns? PMID- 25432227 TI - Delayed presentation of rickets in a child with labyrinthine aplasia, microtia and microdontia (LAMM) syndrome. AB - BACKGROUND: Labyrinthine Aplasia, Microtia and Microdontia (LAMM) syndrome is characterized by the complete absence of inner ear structures (Michel aplasia), microtia and microdontia. Hypophosphatemic rickets results from defects in the renal tubular reabsorption of filtered phosphate. CASE CHARACTERISTICS: 13-year old Indian girl presented with deafness since infancy and progressive wrist widening and genu valgum for last one year. OBSERVATION: Homozygous novel missense mutation in fibroblast growth factor 3. MESSAGE: LAMM syndrome and hypophosphatemic rickets may be associated. PMID- 25432228 TI - Radial artery pseudoaneurysm in a neonate with hemophilia A. AB - BACKGROUND: Pseudoaneurysm formation is a rare complication of arterial puncture. CASE CHARACTERISTICS: 3-week-old male developed an enlarging mass over the anterior aspect of left wrist following radial arterial puncture. OBSERVATION: Doppler ultrasonography revealed mass to be left radial arterial pseudoaneurysm. Subsequent presentation of ecchymoses and investigations confirmed factor VIII deficiency (Hemophilia A). OUTCOME: Pseudoaneurysm removed with primary end to end anastomosis. Patient is presently on regular factor VIII replacement therapy. MESSAGE: Hemophilia A can present as pseudoaneurysm in neonatal period. PMID- 25432229 TI - Type 0 spinal muscular atrophy with multisystem involvement. AB - BACKGROUND: The classical forms of severe SMA type 0 is well recognised by Pediatricians. CASE CHARACTERISTICS: A hypotonic neonate with severe respiratory distress at birth. OBSERVATIONS: Homozygous absence of exons 7 of the Survival Motor Neuron I gene. OUTCOME: Died 108 days after admission when respiratory support was withdrawn at the request of the parents. MESSAGE: Spinal Muscular Atrophy should be kept in mind in the differential diagnosis for unexplained severe generalized hypotonia and severe respiratory distress immediately after birth in the neonates. PMID- 25432230 TI - Severe calcinosis cutis with cutaneous ulceration in juvenile dermatomyositis. AB - BACKGROUND: Calcinosis cutis is usually seen in long standing and untreated cases of juvenile dermatomyositis. CASE CHARACTERISTICS: 7-year-old girl with severe calcinosis cutis who developed cutaneous ulceration, rash and myopathy. OBSERVATION: Myopathic changes in EMG, muscle edema in MRI, elevated muscle enzymes and Jo-1 positive antibodies. OUTCOME: Treatment with prednisolone and methotrexate resulted in improvement of the lesion. MESSAGE: Calcinosis cutis may be a presenting feature of juvenile dermatomyositis even in the absence of characteristic findings of rash and weakness. PMID- 25432231 TI - Small size, big joy,a pediatricians life. PMID- 25432232 TI - Human metapneumovirus infection among outpatient children in Dibrugarh. AB - We describe the prevalence of human metapneumovirus infection in children visiting outpatient department with symptoms of respiratory illness in rural areas of Dibrugarh District of Assam. Human metapneumovirus was observed in 7.2% (20/276) of children aged =5 years with detection of genotypes A2b and B2. PMID- 25432233 TI - Plasma vitamin C status of adolescent girls in a slum of Delhi. AB - A cross-sectional study was conducted among 775 adolescent girls (11-18 years) residing in a slum of Delhi to assess plasma vitamin C levels. The mean (SD) plasma levels of vitamin C were 0.76 (0.45) mg/dL. Overall, 6.3% and 27.6% girls had deficient (<0.2 mg/dL) and suboptimal levels (0.2-0.49 mg/dL) of plasma vitamin C, respectively. PMID- 25432234 TI - Clinical and demographic profile of snake envenomation in Himachal Pradesh, India. AB - We describe profile of 60 children [mean (SD) age, 9.5 (3.8) y] presenting to the department of Pediatrics with snake envenomation. Neurotoxic bites were predominant (53%) and required mean (SD) 21.5 (9.29) antisnake venom vials, while children with neurohemotoxic features required mean (SD) 31.2 (10.8) vials to improve. Duration of hospital stay was median (SD) 4.0 (2.71) days. The commonest complication was respiratory dysfunction; mortality rate was 13.3%. PMID- 25432235 TI - Encephalitis outbreaks in Muzaffarpur: five blind men describing an elephant! PMID- 25432236 TI - Encephalopathy clusters conflated with encephalitis outbreaks. PMID- 25432237 TI - Atypical manifestations of dengue Fever. PMID- 25432238 TI - Half expressions: a case of unilateral multiple cranial nerves hypoplasia. PMID- 25432239 TI - Benign cephalic histiocytosis. PMID- 25432240 TI - Pneumoscrotum. PMID- 25432241 TI - Differences between murine arylamine N-acetyltransferase type 1 and human arylamine N-acetyltransferase type 2 defined by substrate specificity and inhibitor binding. AB - BACKGROUND: The mouse has three arylamine N-acetyltransferase genes, (MOUSE)Nat1, (MOUSE)Nat2 and (MOUSE)Nat3. These are believed to correspond to (HUMAN)NAT1, (HUMAN)NAT2 and NATP in humans. (MOUSE)Nat3 encodes an enzyme with poor activity and human NATP is a pseudogene. (MOUSE)Nat2 is orthologous to (HUMAN)NAT1 and their corresponding proteins are functionally similar, but the relationship between (MOUSE)Nat1 and (HUMAN)NAT2 is less clear-cut. METHODS: To determine whether the (MOUSE)NAT1 and (HUMAN)NAT2 enzymes are functionally equivalent, we expressed and purified (MOUSE)NAT1*1 and analysed its substrate specificity using a panel of arylamines and hydrazines. To understand how specific residues contribute to substrate selectivity, three site-directed mutants of (MOUSE)NAT2*1 were prepared: these were (MOUSE)NAT2_F125S, (MOUSE)NAT2_R127G and (MOUSE)NAT2_R127L. All three exhibited diminished activity towards "(MOUSE)NAT2 specific" arylamines but were more active against hydrazines than (MOUSE)NAT1*1. The inhibitory and colorimetric properties of a selective naphthoquinone inhibitor of (HUMAN)NAT1 and (MOUSE)NAT2 were investigated. RESULTS: Comparing (MOUSE)NAT1*1 with other mammalian NAT enzymes demonstrated that the substrate profiles of (MOUSE)NAT1 and (HUMAN)NAT2 are less similar than previously believed. Three key residues (F125, R127 and Y129) in (HUMAN)NAT1*4 and (MOUSE)NAT2*1 were required for enzyme inhibition and the associated colour change on naphthoquinone binding. In silico modelling of selective ligands into the appropriate NAT active sites further implicated these residues in substrate and inhibitor specificity in mouse and human NAT isoenzymes. CONCLUSIONS: Three non-catalytic residues within (HUMAN)NAT1*4 (F125, R127 and Y129) contribute both to substrate recognition and inhibitor binding by participating in distinctive intermolecular interactions and maintaining the steric conformation of the catalytic pocket. These active site residues contribute to the definition of substrate and inhibitor selectivity, an understanding of which is essential for facilitating the design of second generation (HUMAN)NAT1-selective inhibitors for diagnostic, prognostic and therapeutic purposes. In particular, since the expression of (HUMAN)NAT1 is related to the development and progression of oestrogen-receptor-positive breast cancer, these structure-based tools will facilitate the ongoing design of candidate compounds for use in (HUMAN)NAT1 positive breast tumours. PMID- 25432243 TI - Whole-system change: case study of factors facilitating early implementation of a primary health care reform in a South African province. AB - BACKGROUND: Whole-system interventions are those that entail system wide changes in goals, service delivery arrangements and relationships between actors, requiring approaches to implementation that go beyond projects or programmes. METHODS: Drawing on concepts from complexity theory, this paper describes the catalysts to implementation of a whole-system intervention in the North West Province of South Africa. This province was an early adopter of a national primary health care (PHC) strategy that included the establishment of PHC outreach teams based on generalist community health workers. We interviewed a cross section of provincial actors, from senior to frontline, observed processes and reviewed secondary data, to construct a descriptive-explanatory case study of early implementation of the PHC outreach team strategy and the factors facilitating this in the province. RESULTS: Implementation of the PHC outreach team strategy was characterised by the following features: 1) A favourable provincial context of a well established district and sub-district health system and long standing values in support of PHC; 2) The forging of a collective vision for the new strategy that built on prior history and values and that led to distributed leadership and ownership of the new policy; 3) An implementation strategy that ensured alignment of systems (information, human resources) and appropriate sequencing of activities (planning, training, piloting, household campaigns); 4) The privileging of 'community dialogues' and local manager participation in the early phases; 5) The establishment of special implementation structures: a PHC Task Team (chaired by a senior provincial manager) to enable feedback and ensure accountability, and an NGO partnership that provided flexible support for implementation. CONCLUSIONS: These features resonate with the deliberative, multi-level and context sensitive approaches described as the "simple rules" of successful PHC system change in other settings. Although implementation was not without tensions and weaknesses, particularly at the front line of the PHC system, the case study highlights how a collective vision can facilitate commitment to and engagement with new policy in complex organisational environments. Successful adoption does not, however, guarantee sustained implementation at scale, and we consider the challenges to further implementation. PMID- 25432242 TI - Targeting TLR-4 with a novel pharmaceutical grade plant derived agonist, Immunomax(r), as a therapeutic strategy for metastatic breast cancer. AB - BACKGROUND: Previously we demonstrated that the resection of primary 4T1 tumors only slightly prolongs mouse survival, but importantly, creates a "window of opportunity" with attenuated suppressor cell and increased activated T cell populations. This suggests that additional activation of the immune system by immunostimulatory agents during this period may enhance anti-tumor immunity and potentially eradicate micro-metastatic disease in this stringent model. We hypothesized that the immunostimulator Immunomax(r), which is comprised of a plant-derived polysaccharide, is non-toxic in humans and stimulates immune defense during the infectious diseases treatment, may have also anti-tumor activity and be beneficial in the adjuvant setting when endogenous anti-tumor responses are present and during the "window of opportunity" in post-resection metastatic breast cancer model. Here we provide the initial report that Immunomax(r) demonstrates the capacity to eliminate micro-metastatic disease in the post-resection, 4T1 mouse model of breast cancer. METHODS: The efficacy of Immunomax(r) was evaluated by analyzing survival rate and the number of spontaneous clonogenic tumor cells in the lung homogenates of mice. The frequencies of activated NK, CD4(+) and CD8(+) cells as well as myeloid-derived suppressor cells and Treg cells were evaluated using flow cytometry. Highly purified mouse and human dendritic and NK cells were sorted and the effect of Immunomax(r) on activation status of these cells was assessed by flow cytometry. The property of Immunomax(r) as TLR-4 agonist was determined by NF-kappaB/SEAP reporter gene assay, WB, RT-PCR. RESULTS: Immunomax(r) injections significantly prolonged overall survival and cured 31% of mice. This immunostimulator activates DCs via the TLR-4, which in turn stimulates tumoricidal NK cells and in vitro, completely inhibits growth of 4T1 cells. Incubation of PBMC from healthy donors with Immunomax(r) activates NK cells via activation of plasmacytoid DC leading significantly higher efficacy in killing of human NK-target cells K562 compared with non-treated cells. CONCLUSION: This is the first demonstration that Immunomax(r) is a TLR-4 agonist and the first report of a documented role for this pharmaceutical grade immunostimulator in augmenting anti-tumor activity, suggesting that incorporation of Immunomax(r) into developing breast cancer therapeutic strategies may be beneficial and with less potential toxicity than checkpoint inhibitors. PMID- 25432244 TI - Your help is requested.... PMID- 25432245 TI - Pitching speed. PMID- 25432246 TI - Etiology of gingival recession. PMID- 25432247 TI - Authors' response. PMID- 25432248 TI - When the picture gets cloudy. PMID- 25432250 TI - Indirect vs direct bonding of mandibular fixed retainers in orthodontic patients: a single-center randomized controlled trial comparing placement time and failure over a 6-month period. AB - INTRODUCTION: The objective of this 2-arm parallel single-center trial was to compare placement time and numbers of failures of mandibular lingual retainers bonded with an indirect procedure vs a direct bonding procedure. METHODS: Sixty four consecutive patients at the postgraduate orthodontic clinic of the University of Geneva in Switzerland scheduled for debonding and mandibular fixed retainer placement were randomly allocated to either an indirect bonding procedure or a traditional direct bonding procedure. Eligibility criteria were the presence of the 4 mandibular incisors and the 2 mandibular canines, and no active caries, restorations, fractures, or periodontal disease of these teeth. The patients were randomized in blocks of 4; the randomization sequence was generated using an online randomization service (www.randomization.com). Allocation concealment was secured by contacting the sequence generator for treatment assignment; blinding was possible for outcome assessment only. Bonding time was measured for each procedure. Unpaired t tests were used to assess differences in time. Patients were recalled at 1, 2, 4, and 6 months after bonding. Mandibular fixed retainers having at least 1 composite pad debonded were considered as failures. The log-rank test was used to compare the Kaplan-Meier survival curves of both procedures. A test of proportion was applied to compare the failures at 6 months between the treatment groups. RESULTS: Sixty-four patients were randomized in a 1:1 ratio. One patient dropped out at baseline after the bonding procedure, and 3 patients did not attend the recalls at 4 and 6 months. Bonding time was significantly shorter for the indirect procedure (321 +/ 31 seconds, mean +/- SD) than for the direct procedure (401 +/- 40 seconds) (per protocol analysis of 63 patients: mean difference = 80 seconds; 95% CI = 62.4 98.1; P <0.001). The 6-month numbers of failures were 10 of 31 (32%) with the indirect technique and 7 of 29 (24%) with the direct technique (log rank: P = 0.35; test of proportions: risk difference = 0.08; 95% CI = -0.15 to 0.31; P = 0.49). No serious harm was observed except for plaque accumulation. CONCLUSIONS: Indirect bonding was statistically significantly faster than direct bonding, with both techniques showing similar risks of failure. REGISTRATION: This trial was not registered. PROTOCOL: The protocol was not published before trial commencement. FUNDING: No funding or conflict of interest to be declared. PMID- 25432251 TI - Root morphology and development of labial inversely impacted maxillary central incisors in the mixed dentition: a retrospective cone-beam computed tomography study. AB - INTRODUCTION: The aim of this study was to analyze 3-dimensional data of root morphology and development in labial inversely impacted maxillary central incisors. METHODS: Cone-beam computed tomography images from 41 patients with impacted incisors were divided into early and late dental age groups according to their dental age. Sagittal slices in which the labiolingual width of the tooth was the widest in the axial view were evaluated. The inverse angle, the dilaceration angle, and the length of both impacted and homonym teeth were evaluated with SimPlant Pro software (version 13.0; Materialise Dental NV, Leuven, Belgium). RESULTS: The Student t test indicated that the lengths of the impacted teeth were significantly shorter than those of the homonym teeth (P <0.05), and the root lengths of the early dental age group were significantly shorter than those of the late dental age group. The results from chi-square tests indicated that the incidence of dilacerations was significantly higher in the late dental age group when compared with the early dental age group. Multiple regression analyses indicated that the independent variables for root length of the impacted teeth were dental age (beta = 0.958; P <0.001) and length of the nondilacerated part of the root (beta = 0.435; P <0.001). CONCLUSIONS: Dilaceration was more common in the late dental age group. The roots of labial inversely impacted maxillary central incisors continue developing, but their potential is limited. PMID- 25432252 TI - Treatment outcomes after extraction and nonextraction treatment evaluated with the American Board of Orthodontics objective grading system. AB - INTRODUCTION: A controversy exists regarding better treatment outcomes when patients treated with extractions and without extractions are evaluated. The aims of this study were to use the American Board of Orthodontics objective grading system (ABO-OGS) to evaluate and compare treatment outcomes in extraction vs nonextraction Class I patients and to determine whether the treatment choice was a significant predictor of success according to the ABO examination. METHODS: Discriminant analysis was applied to a sample of 542 patients, and a borderline sample of 55 patients was obtained. Of these patients, 25 were treated with extractions and 30 without extraction of the 4 first premolars. Treatment results were then assessed using the 8 variables of the ABO-OGS. RESULTS: The total scores ranged from 11 to 41 (mean, 27.04; SD, 6.3) for the extraction group and from 16 to 44 (mean, 29.07; SD, 7.1) for the nonextraction group. The variable of buccolingual inclination had the highest scores in both groups (8.44 [SD, 3.3] for the extraction group; 8.90 [SD, 3.8] for the nonextraction group; mean difference, 0.46; 95% CI, -1.44, 2.37; P = 0.63). However, no statistically significant intergroup differences were found, either between the scores of the 8 ABO-OGS variables or between the total ABO-OGS scores. Regarding the success rates of the ABO examination, no significant difference was found between the 2 treatment groups (odds ratio, 2.55; 95% CI, 0.74, 0.85; P = 0.14). CONCLUSIONS: For a patient with a borderline Class I malocclusion, extraction and nonextraction treatment can achieve the same quality of results as assessed by the ABO-OGS. Additionally, in these Class I patients, the treatment modality (extraction or nonextraction) is not a significant predictor of passing the ABO examination. PMID- 25432253 TI - A more accurate soft-tissue prediction model for Class III 2-jaw surgeries. AB - INTRODUCTION: The use of bimaxillary surgeries to treat Class III malocclusions makes the results of the surgeries more complicated to estimate accurately. Therefore, our objective was to develop an accurate soft-tissue prediction model that can be universally applied to Class III surgical-orthodontic patients regardless of the type of surgical correction: maxillary or mandibular surgery with or without genioplasty. METHODS: The subjects of this study consisted of 204 mandibular setback patients who had undergone the combined surgical-orthodontic correction of severe skeletal Class III malocclusions. Among them, 133 patients had maxillary surgeries, and 81 patients received genioplasties. The prediction model included 226 independent and 64 dependent variables. Two prediction methods, the conventional ordinary least squares method and the partial least squares (PLS) method, were compared. When evaluating the prediction methods, the actual surgical outcome was the gold standard. After fitting the equations, test errors were calculated in absolute values and root mean square values through the leave-1-out cross-validation method. RESULTS: The validation result demonstrated that the multivariate PLS prediction model with 30 orthogonal components showed the best prediction quality among others. With the PLS method, the pattern of prediction errors between 1-jaw and 2-jaw surgeries did not show a significantly difference. CONCLUSIONS: The multivariate PLS prediction model based on about 30 latent variables might provide an improved algorithm in predicting surgical outcomes after 1-jaw and 2-jaw surgical corrections for Class III patients. PMID- 25432254 TI - Impact of bullying due to dentofacial features on oral health-related quality of life. AB - INTRODUCTION: The aim of this study was to investigate whether there is a relationship between self-reported bullying because of dentofacial features and oral health-related quality of life among a representative sample of Jordanian schoolchildren. METHODS: This was a cross-sectional study in which a representative sample of sixth-grade students (age, 11-12 years) from randomly selected schools in Amman, Jordan, were asked to complete questionnaires distributed in the classroom in the presence of the researchers. The questionnaire used for this purpose was the short form of the Child Perceptions Questionnaire for 11- to 14-year-old children. The final sample size was 920 children (470 girls, 450 boys). RESULTS: There were significant differences between the sexes for the total Child Perceptions Questionnaire score and for the oral symptoms and the social well-being subscales, with boys reporting higher scores and thus more negative effects on their oral health-related quality of life. Comparison of the total scores and subscales scores for boys and girls subdivided into those who reported being bullied and not being bullied about their teeth showed that bullied boys had significantly greater effects on overall oral health-related quality of life and on all subscales than did not-bullied boys (P <0.001 for all comparisons). Bullied girls also had significantly greater effects on the overall oral health-related quality of life and all subscales than did not-bullied girls (P <0.001 for all comparisons). However, bullied boys and girls reported similar scores for the different subscales of the Child Perceptions Questionnaire; there were no significant differences. CONCLUSIONS: This study demonstrated a significant relationship between bullying because of dentofacial features and negative effects on oral health-related quality of life. The results highlight the importance of addressing the bullying problem among schoolchildren and provide important data for educational authorities to create antibullying programs to help students receive education in a safe and healthy environment. PMID- 25432255 TI - Variability of the inclination of anatomic horizontal reference planes of the craniofacial complex in relation to the true horizontal line in orthognathic patients. AB - INTRODUCTION: The purpose of this study was to assess the reliability of the Frankfort horizontal (FH), sella-nasion horizontal, and optic planes in terms of their variabilities in relation to a true horizontal line in orthognathic surgery patients. METHODS: Thirty-six consecutive presurgical orthognathic patients (13 male, 23 female; age range, 16-35 years; 30 white, 6 African Caribbean) had lateral cephalometric radiographs taken in natural head position, with a plumb line orientating the true vertical line, and the true horizontal line perpendicular to the true vertical. The inclinations of the anatomic reference planes were compared with the true horizontal. RESULTS: The FH plane was found to be on average closest to the true horizontal, with a mean of -1.6 degrees (SD, 3.4 degrees ), whereas the sella-nasion horizontal and the optic plane had means of 2.1 degrees (SD, 5.1 degrees ) and 3.2 degrees (SD, 4.7 degrees ), respectively. The FH showed the least variability of the 3 anatomic planes. The ranges of variability were high for all anatomic planes: -8 degrees to 8 degrees for the FH, -8 degrees to 15 degrees for the sella-nasion horizontal, and -6 degrees to 13 degrees for the optic plane. No significant differences were found in relation to patients' sex, skeletal patterns, or ethnic backgrounds. CONCLUSIONS: The clinically significant variability in the inclinations of anatomic reference planes in relation to the true horizontal plane makes their use unreliable in orthognathic patients. PMID- 25432256 TI - Surgically assisted rapid maxillary expansion: cone-beam computed tomography evaluation of different surgical techniques and their effects on the maxillary dentoskeletal complex. AB - INTRODUCTION: The aims of this study were to evaluate and compare skeletal, dentoalveolar, dental, and periodontal changes in surgically assisted rapid maxillary expansion (SARME) patients with and without pterygomaxillary disjunction. METHODS: The records of 20 patients who underwent SARME in the clinics of the dental school at Marmara University in Turkey were collected and divided into 2 groups of 10 patients each, according to the surgical protocol followed. Cone-beam computed tomography images before the operation and 3 to 6 months after the end of active expansion were analyzed by 20 linear and 7 angular measurements. The reliability of the 3-dimensional analysis was investigated. RESULTS: All transversal measurements in the dentoalveolar and dental levels increased after expansion in both the SARME with pterygomaxillary disjunction and the SARME without pterygomaxillary disjunction groups with no significant differences between them. In the SARME without pterygomaxillary disjunction group, more pronounced buccal alveolar bending and buccal tipping of the posterior teeth were found, but the difference did not reach statistical significance. SARME reduces buccal alveolar width in the premolar region significantly when pterygoid disjunction is not performed. CONCLUSIONS: SARME with or without pterygomaxillary disjunction is an effective technique to treat maxillary transverse deficiency in adolescent and adult patients. Pterygomaxillary disjunction is advised in periodontally compromised patients. Cone-beam computed tomography scanning is a reliable method for studying the dentoskeletal effects of SARME. PMID- 25432257 TI - Three-dimensional cephalometric superimposition of the nasomaxillary complex. AB - INTRODUCTION: Two-dimensional maxillary superimposition techniques have been routinely used in clinical practice, but a 3-dimensional plane has yet to be introduced and validated. The purposes of this study were to propose a new plane for regional superimposition of the maxillary complex and then to validate it through clinical data. METHODS: Pretreatment and posttreatment palatal expansion records were used. The magnitudes of the transverse expansion at the levels of the first premolars and the first molars were assessed using the proposed superimposition plane and then were compared with the gold standard plaster model measurements. Descriptive statistics and agreement testing were performed to compare the methods. RESULTS: When comparing the superimposition and plaster measurement methods, the mean errors for intermolar and interpremolar distances were 0.57 and 0.59 mm, respectively. Both the intraclass correlation coefficient and the Bland-Altman plot demonstrated high agreement between the 2 methods (intraclass correlation coefficient greater than 0.9). CONCLUSIONS: The proposed maxillary superimposition plane yields clinically suitable results when compared with the gold standard technique, with a mean error of less than 0.6 mm for typical intra-arch measurements. This new landmark-derived maxillary plane for superimposition is a promising tool for evaluating maxillary dentoalveolar changes after treatment. PMID- 25432259 TI - Three-dimensional cone-beam computed tomography analysis of enlargement of the pharyngeal airway by the Herbst appliance. AB - INTRODUCTION: Pharyngeal airway size is increasingly recognized as an important factor in obstructive sleep apnea. However, few studies have examined the changes of pharyngeal airway form after dental procedures for treating obstructive sleep apnea during growth. The purpose of this study was to evaluate the effect of the Herbst appliance on the 3-dimensional form of the pharyngeal airway using cone beam computed tomography. METHODS: Twenty-four Class II subjects (ANB, >=5 degrees ; 11 boys; mean age, 11.6 years) who required Herbst therapy with edgewise treatment had cone-beam computed tomography images taken before and after Herbst treatment. Twenty Class I control subjects (9 boys; mean age, 11.5 years) received edgewise treatment only. The volume, depth, and width of the pharyngeal airway were compared between the groups using measurements from 3 dimensional cone-beam computed tomography images of the entire pharyngeal airway. RESULTS: The increase of the oropharyngeal airway volume in the Herbst group (5000.2 mm(3)) was significantly greater than that of the control group (2451.6 mm(3)). Similarly, the increase of the laryngopharyngeal airway volume in the Herbst group (1941.8 mm(3)) was significantly greater than that of the control group (1060.1 mm(3)). CONCLUSIONS: The Herbst appliance enlarges the oropharyngeal and laryngopharyngeal airways. These results may provide a useful assessment of obstructive sleep apnea treatment during growth. PMID- 25432260 TI - Premolar transplantation in a patient with solitary median maxillary central incisor syndrome. AB - This case report describes the orthodontic treatment of an 11-year-old girl with solitary median maxillary central incisor syndrome, a presumed microform of holoprosencephaly. Because both second premolars were missing in the maxilla, deciduous molar extraction and orthodontic space opening were performed, moving the solitary median maxillary central incisor electively off-center. A mandibular second premolar was transplanted to replace the missing incisor. The resulting spaces could be orthodontically closed in both arches. Prosthodontic reshaping of the transplanted tooth after debonding completed the dental treatment. PMID- 25432261 TI - Correction of facial asymmetry and maxillary canting with corticotomy and 1-jaw orthognathic surgery. AB - Although 2-jaw orthognathic surgery is a typical recommendation for the treatment of facial asymmetry, another good treatment alternative is maxillary corticotomy with temporary skeletal anchorage devices followed by mandibular orthognathic surgery. The corticotomy procedure described here can achieve unilateral molar intrusion and occlusal plane canting correction with potentially fewer complications than 2-jaw orthognathic surgery. The approach allows movement of dentoalveolar segments in less time than with conventional dental intrusion using temporary skeletal anchorage devices. A 2-jaw asymmetry with occlusal plane canting might be corrected using maxillary corticotomy and mandibular orthognathics rather than 2-jaw orthognathics. Two patients with facial asymmetry are presented here. In each one, the maxillary cant was corrected over a period of 2 to 3 months with 3.5 mm of intrusion of the unilateral buccal segment. After the preorthognathic cant correction, orthognathic surgery was done to correct the mandibular asymmetry. PMID- 25432262 TI - Interexaminer and intraexaminer reliabilities of 3-dimensional orthodontic digital setups. AB - INTRODUCTION: The use of digital orthodontic setups has grown quickly. The purpose of this study was to test the interexaminer and intraexaminer reliabilities of 3-dimensional orthodontic digital setups in OrthoCAD (Align Technology, San Jose, Calif). METHODS: Six clinicians made digital orthodontic setups on 6 digital models twice, with a minimum interval of 2 weeks and a maximum interval of 4 weeks. OrthoCAD software was used, and treatment goals were all set the same according to the American Board of Orthodontics Objective Grading System (ABO-OGS). Differences between the 72 setups were measured with the ABO-OGS scores. RESULTS: In comparing setups 1 and 2, the intraexaminer mean absolute differences in total ABO-OGS scores varied statistically significantly between 2.17 and 6.00 points. Interexaminer mean absolute differences varied statistically significantly between 4.77 and 5.56 points. All but 1 intraclass correlation coefficient (ICC) value showed significant excellent agreement (ICC, >0.8) for intraexaminer reliability. One ICC value was insignificant and showed moderate (ICC, 0.4-0.6) agreement. Interexaminer reliability showed significant good (ICC, 0.6-0.8) agreement. CONCLUSIONS: There is a significant difference in ABO-OGS score when using OrthoCAD. Although this difference was low, it could be clinically significant. Interexaminer and intraexaminer reliabilities are not redundant for general use of the 3-dimensional orthodontic digital setup in OrthoCAD. PMID- 25432263 TI - Litigation and legislation. Separate but equal. PMID- 25432264 TI - Interpretation of observational studies. PMID- 25432258 TI - Dimensions of central incisors, canines, and first molars in subjects with Down syndrome measured on cone-beam computed tomographs. AB - INTRODUCTION: The literature on tooth dimensions in subjects with Down syndrome (DS) is scarce. To our knowledge, no studies have yet been published in which the morphometry of the teeth in DS subjects has been determined using computed tomography. METHODS: The study group consisted of 40 subjects with DS, aged 10 to 40 years. An age- and sex-matched control group was selected. Cone-beam computed tomography images were retrieved from the archive of the Santiago de Compostela University in Spain. The maxillary central incisors, canines, and first molars were evaluated. The following variables were analyzed: overall tooth length, crown height, root length, mesiodistal diameter, vestibular-palatine diameter, crown-to-root ratio, and cervical circumference. RESULTS: The teeth of subjects with DS were smaller than those of the controls, although the crown-to-root ratio was maintained. No clear sexual dimorphism was detected, but the root lengths of the incisors were greater in male subjects. Crown height, mesiodistal diameter, and crown-to-root ratio showed progressive reductions with age. There appeared to be a degree of "fluctuating dental asymmetry" with respect to vestibular-palatine diameter and cervical circumference. CONCLUSIONS: Our findings confirm microdontia of the permanent teeth and progressive reductions in tooth sizes with age in persons with DS. These variations might be relevant to orthodontic treatment planning. PMID- 25432265 TI - The household economic burden of eating disorders and adherence to treatment in Australia. AB - BACKGROUND: This study investigated the household economic burden of eating disorders and cost-related non-adherence to treatment in Australia. METHODS: Multi-centre prospective observational study using a structured questionnaire. Ninety participants were recruited from two clinic settings in New South Wales, Australia and from the community using social media. The primary outcome measures were household economic burden of illness measured in terms of out-of-pocket expenditure, household economic hardship and cost-related non-adherence. RESULTS: The pattern of out-of-pocket expenditure varied by diagnosis, with Bulimia Nervosa associated with the highest total mean expenditure (per three months). Economic hardship was reported in 96.7% of participants and 17.8% reported cost related non-adherence. Those most likely to report cost-related non-adherence had a longer time since diagnosis. Cost-related non-adherence and higher out-of pocket expenditure were associated with poorer quality of life, a more threatening perception of the impact of the illness and poor self-reported health. CONCLUSIONS: This study is the first to empirically and quantitatively examine the household economic burden of eating disorders from the patient perspective. Results indicate that households experience a substantial burden associated with the treatment and management of an eating disorder. This burden may contribute to maintaining the illness for those who experience cost-related non-adherence and by negatively influencing health outcomes. Current initiatives to implement sustainable and integrated models of care for eating disorders should strive to minimise the economic impact of treatment on families. PMID- 25432266 TI - Mutations in the Arabidopsis homoserine kinase gene DMR1 confer enhanced resistance to Fusarium culmorum and F. graminearum. AB - BACKGROUND: Mutation of Arabidopsis DMR1, encoding homoserine kinase, leads to elevation in homoserine and foliar resistance to the biotrophic pathogens Hyaloperonospora arabidopsidis and Oidium neolycopersici through activation of an unidentified defence mechanism. This study investigates the effect of mutation of dmr1 on resistance to the ascomycete pathogens Fusarium graminearum and F. culmorum, which cause Fusarium Ear Blight (FEB) disease on small grain cereals. RESULTS: We initially found that the dmr1-2 mutant allele confers increased resistance to F. culmorum and F. graminearum silique infection, and decreased colonisation of rosette leaves. Meanwhile the dmr1-1 allele supports less rosette leaf colonisation but has wild type silique resistance. Three additional dmr1 alleles were subsequently examined for altered F. culmorum susceptibility and all showed increased silique resistance, while leaf colonisation was reduced in two (dmr1-3 and dmr1-4). Amino acid analysis of dmr1 siliques revealed homoserine accumulation, which is undetectable in wild type plants. Exogenous application of L-homoserine reduced bud infection in both dmr1 and wild type plants, whilst D homoserine application did not. Delayed leaf senescence was also observed in dmr1 plants compared to wild type and correlated with reduced Fusarium leaf colonisation. CONCLUSIONS: These findings suggest that common Arabidopsis DMR1 mediated susceptibility mechanisms occur during infection by both obligate biotrophic oomycete and hemi-biotrophic fungal pathogens, not only in vegetative but also in reproductive plant tissues. This has the potential to aid the development of cereal crops with enhanced resistance to FEB. PMID- 25432267 TI - Avulsion fracture of the coracoid process in a patient with chronic anterior shoulder instability treated with the Latarjet procedure: a case report. AB - INTRODUCTION: Shoulder dislocations can cause acute and chronic instabilities that need to be addressed in order to restore joint functioning. The transfer of the coracoid process has become a feasible surgical procedure in patients with shoulder instability. Several concomitant injuries after recurrent dislocations have been described. CASE PRESENTATION: A 32-year-old German man presented to our department with a history of recurrent shoulder dislocations. He was diagnosed with an avulsion fracture of the coracoid process and dislocation of an osseous piece with attachment to the conjoined tendons during the surgical transfer of the coracoid process. Therefore, we performed an open Latarjet procedure and reattached the bony piece with the conjoined tendons to the glenoid rim. Three months after the operation the patient presented with a satisfying range of motion and without instabilities or pain. He was able to return to his job. CONCLUSIONS: Patients suffering from anterior shoulder dislocation might develop accompanying lesions after numerous dislocations that are not present upon first visit. Different techniques for the reconstruction of the glenoid rim and the restoration of shoulder joint stability have been described in the literature. We opted for a coracoid transfer and achieved an optimal reconstruction, as shown on the postoperative computed tomography scan. An avulsion fracture of the coracoid process with dislocation of the conjoined tendons can not only be found in patients suffering a direct trauma as pointed out in the literature, but also in patients with anterior shoulder instability with recurrent anterior shoulder dislocation. PMID- 25432269 TI - Growth of Journal of School Psychology and accolades for contributors: every writer (and journal) needs a good editor. PMID- 25432268 TI - Shifting between self-governing and being governed: a qualitative study of older persons' self-determination. AB - BACKGROUND: Older persons' right to exercise self-determination in daily life is supported by several laws. Research shows that older persons' self-determination is not fully respected within the healthcare sector. In order to enable and enhance older persons' self-determination, extensive knowledge of older persons' self-determination is needed. The aim of this study was to explore experiences of self-determination when developing dependence in daily activities among community dwelling persons 80 years and older. METHODS: Qualitative interviews were performed in accordance with a grounded theory method, with 11 persons aged 84-95 years who were beginning to develop dependence in daily activities. RESULTS: The data analysis revealed the core category, "Self-determination - shifting between self-governing and being governed". The core category comprised three categories: "Struggling against the aging body", "Decision-making is relational", and "Guarding one's own independence". Self-determination in daily activities was related to a shifting, which was two-fold, and varied between self-governing and being governed by the aging body, or by others. CONCLUSIONS: The findings imply a need to adopt a person-centered approach where the older persons' own preferences and needs are in focus, in order to enhance their possibilities to exercise self determination. PMID- 25432271 TI - Navigating into, through, and beyond the middle grades: the role of middle grades attendance in staying on track for high school graduation. AB - In this longitudinal study, we investigated the use of attendance during middle school as a behavioral indicator of engagement to predict whether students are on track toward high school graduation. We used administrative data from four cohorts of students in New York City schools (N=303,845) to (a) explore patterns of change in attendance between Grades 4 and 8 and (b) determine the extent to which changes in attendance between Grades 4 and 8 predict which students are on track in Grade 9 for going on to graduate from high school. Results of latent growth modeling indicated that students demonstrate the most substantial declines in attendance during Grade 8 and that attendance changes are most variable in this year, with some students demonstrating much more dramatic declines than others. In addition, these changes in attendance were robust predictors of whether students were on track for high school graduation. To identify students who are at risk for not graduating for the purposes of providing appropriate interventions, educators should pay attention to their commonly collected data on attendance rates as a behavioral indicator of engagement. PMID- 25432270 TI - Evaluating the impact of feedback on elementary aged students' fluency growth in written expression: a randomized controlled trial. AB - The purpose of this randomized controlled trial was to evaluate elementary-aged students' writing fluency growth in response to (a) instructional practices, (b) sex differences, and (c) student's initial level of writing fluency. Third-grade students (n=133) in three urban elementary schools were randomly assigned to either an individualized performance feedback condition (n=46), a practice-only condition (i.e., weekly writing practice; n=39), or an instructional control condition (n=48) for 8weeks. Findings included support for use of performance feedback as an instructional component in general education classrooms (Hedges' g=0.66), whereas simple practice with curriculum-based measurement in written expression did not produce growth significantly greater than standard instructional practices. The hypothesis that girls write significantly more than boys was supported. However, girls and boys did not differ in their rate of growth. Finally, students' initial risk status in writing fluency did not differentially predict growth in writing fluency over the course of the study. Implications for incorporating feedback as a basic component of intervention in writing are discussed. PMID- 25432272 TI - Promoting an equitable and supportive school climate in high schools: the role of school organizational health and staff burnout. AB - In response to persistent racial disparities in academic and behavioral outcomes between Black and White students, equitable school climate has drawn attention as a potential target for school reform. This study examined differences in Black and White students' experiences of school climate and explored whether indicators of school organizational health and staff burnout moderated differences in students' school experiences by race. Utilizing hierarchical linear modeling with a sample of 18,397 Black students (n=6228) and White students (n=12,169) and 2391 school staff in 53 schools, we found a consistent pattern of racial inequalities, such that Black students reported less positive experiences than White students across three indicators of school climate (caring gamma=-0.08, p<.001; equity gamma=-0.05, p=.007; and engagement gamma=-0.05, p<.001). In addition, we found significant, positive associations between aggregated staff-report of school organizational health and student-reported school climate (e.g., staff affiliation and student-perceived equity, gamma=0.07, p<.001). Surprisingly, a number of school organizational health indicators were more strongly associated with positive perceptions of school climate among White students than Black students, translating into greater racial disparities in perceived school climate at schools with greater organizational health (e.g., supportive leadership by race on student-perceived engagement, gamma=-0.03, p=.042). We also found negative associations between staff-reported burnout and students' experience of equity, such that the racial gap was smaller in schools with high ratings of burnout (gamma=0.04, p=.002). These findings have implications for educators and education researchers interested in promoting school social contexts that equitably support student engagement and success. PMID- 25432273 TI - Fruits from ripening impaired, chlorophyll degraded and jasmonate insensitive tomato mutants have altered tocopherol content and composition. AB - Since isoprenoids are precursors in chlorophyll, carotenoid and tocopherol pathways, the study of their metabolism is of fundamental importance in understanding the regulatory cross-talk that contributes to the nutritional quality of tomato fruits. By means of an integrated analysis of metabolite and gene expression profiles, isoprenoid metabolism was dissected in ripening impaired (ripening inhibitor and non-ripening), senescence-related (lutescent1 and green flesh) and jasmonate insensitive (jasmonic acid insensitive 1-1) tomato mutants, all in the Micro-Tom genetic background. It was found that the more upstream the location of the mutated gene, the more extensive the effect on the transcriptional profiles of the isoprenoid-related genes. Although there was a distinct effect in the analyzed mutations on chlorophyll, carotenoid and tocopherol metabolism, a metabolic adjustment was apparent such the antioxidant capacity mostly remained constant. Transcriptional profiles from fruits of ripening and senescence-related tomato mutants suggested that maintenance of the de novo phytyl diphosphate synthesis might, in later ripening stages, compensate for the lack of chlorophyll-derived phytol used in tocopherol production. Interestingly, an impairment in jasmonate perception led to higher total tocopherol levels in ripe fruits, accompanied by an increase in antioxidant capacity, highlighting the contribution of tocopherols to this nutritionally important trait. PMID- 25432274 TI - Decision support tool for differential diagnosis of Acute Respiratory Distress Syndrome (ARDS) vs Cardiogenic Pulmonary Edema (CPE): a prospective validation and meta-analysis. AB - INTRODUCTION: We recently presented a prediction score providing decision support with the often-challenging early differential diagnosis of acute lung injury (ALI) vs cardiogenic pulmonary edema (CPE). To facilitate clinical adoption, our objective was to prospectively validate its performance in an independent cohort. METHODS: Over 9 months, adult patients consecutively admitted to any intensive care unit of a tertiary-care center developing acute pulmonary edema were identified in real-time using validated electronic surveillance. For eligible patients, predictors were abstracted from medical records within 48 hours of the alert. Post-hoc expert review blinded to the prediction score established gold standard diagnosis. RESULTS: Of 1,516 patients identified by electronic surveillance, data were abstracted for 249 patients (93% within 48 hours of disease onset), of which expert review (kappa 0.93) classified 72 as ALI, 73 as CPE and excluded 104 as "other". With an area under the curve (AUC) of 0.81 (95% confidence interval = 0.73 to 0.88) the prediction score showed similar discrimination as in prior cohorts (development AUC = 0.81, P = 0.91; retrospective validation AUC = 0.80, P = 0.92). Hosmer-Lemeshow test was significant (P = 0.01), but across eight previously defined score ranges probabilities of ALI vs CPE were the same as in the development cohort (P = 0.60). Results were the same when comparing acute respiratory distress syndrome (ARDS, Berlin definition) vs CPE. CONCLUSION: The clinical prediction score reliably differentiates ARDS/ALI vs CPE. Pooled results provide precise estimates of the score's performance which can be used to screen patient populations or to assess the probability of ALI/ARDS vs CPE in specific patients. The score may thus facilitate early inclusion into research studies and expedite prompt treatment. PMID- 25432275 TI - Prevalence of drug-drug interactions upon addition of simeprevir- or sofosbuvir containing treatment to medication profiles of patients with HIV and hepatitis C coinfection. AB - The objectives were to (1) compare the frequency of contraindicated drug-drug interactions (XDDI) when simeprevir (SIM)- and sofosbuvir (SOF)-containing regimens are theoretically added to a patient's medication profile; (2) identify which hepatitis C (HCV) regimen is associated with the lowest frequency of XDDIs within different types of antiretroviral treatment (ART) regimens; and (3) determine the risk factors for XDDIs with each regimen. A cross-sectional study was performed among adult HIV/HCV-coinfected patients. Demographics, comorbidities, and medication lists were collected from medical records. Medication lists were entered into Lexi-Interact drug interaction software and XDDI before/after the addition of SIM- and SOF-containing therapy was documented. Classification and regression tree (CART) analyses identified breakpoints in continuous variables. Before the addition of any HCV therapy, XDDIs were present in 20% of the 335 included patients. After the addition of SIM-containing therapy, the frequency of XDDIs significantly increased to 88.4% (p<0.001). After adding SOF-containing therapy, the prevalence of XDDIs increased to 24.5% (p<0.001). The prevalence of XDDIs was significantly lower for SOF-containing HCV therapy within various types of ART regimens. Use of >=7 non-HIV medications (CART breakpoint) was the only variable to predict XDDIs before the addition of any HCV therapy. Similarly, this was the only variable to predict XDDIs after the addition of SOF-containing therapy (PR: 4.80; 95% CI: 2.57-8.96, p<0.001). Variables independently associated with XDDIs after the addition of SIM containing therapy were NNRTI regimen (prevalence ratio, PR: 1.62; 95% confidence interval, CI: 1.38-1.91, p<0.001), PI regimen (PR: 1.64; 95% CI: 1.40-1.93, p<0.001), and >=7 non-HIV medications (PR: 1.06; 95% CI: 1.00-1.14, p=0.09). The addition of SOF-containing therapy was associated with a lower prevalence of XDDI than SIM-containing therapy. PMID- 25432276 TI - Effect of GABA derivatives on the rate of thrombus formation, platelet aggregation, and plasma coagulation capacity in rats with experimental gestosis. AB - Experimental gestosis induced by replacement of drinking water with 1.8% NaCl promoted hypercoagulation, increased the rate and degree of platelet aggregation, and reduced clotting time in pregnant females. GABA derivatives, compounds RGPU 151, RGPU-152, and phenibut normalized parameters of hemostasis and platelet aggregation and the rate of thrombus formation in the animals. The efficiency of the test substances did not significantly differ from that of the reference drug sulodexide. PMID- 25432277 TI - Camel thorn extract reduces activity of angiotensin-converting enzyme in rat aorta increased during aging and treatment with NO-synthase inhibitor. AB - We studied the effect of camel thorn extract on activity of angiotensin converting enzyme in rat aorta increased in animals during aging or treatment with NO-synthase inhibitor. Intake of camel thorn extract with drinking water reduced activity of angiotensin-converting enzyme; the effect increased with increasing the dose of the extract. Angiotensin-converting enzyme activity in older rats and animals treated with NO-synthase inhibitor decreased to the values observed in young control rats at extract concentration of 0.2%. Comparison of the effects of camel thorn extract with those of flavonoid taxifolin showed that the extract was not inferior to taxifolin in preventing the early stages of aortic atherosclerosis caused by increased activity of angiotensin-converting enzyme. PMID- 25432278 TI - Antiulcer activity of extracts of ecdysteroid-containing plants of genera Lychnis and Silene of the Caryophyllaceae family. AB - We studied antiulcer activity of the extracts of ecdysteroid-containing plants of the Caryophyllaceae family: Lychnis chalcedonica L., Silene viridiflora L.Sp.Pl., and Silene frivaldszkyana Hampe. Experiments on the model of neurogenic and aspirin-induced ulcerogenesis showed unidirectional and pronounced gastroprotective effects of S. viridiflora and L. chalcedonica extracts comparable to the efficacy of famotidine. In these models, a course of intragastric treatment with the extracts reduced ulcerative lesions of all types. PMID- 25432279 TI - Dose-dependent effects of beta-phenylglutamic acid hydrochloride (RGPU-135, neuroglutam) on animal behavior. AB - beta-Phenylglutamic acid hydrochloride (RGPU-135, neuroglutam) in doses of 13-650 mg/kg suppressed depressive behavior of animals in the Porsolt test (i.e. produced antidepressant properties), reduced anxiety in the open-field, elevated plus maze, and Vogel conflict tests (i.e. produced anxiolytic effects). RGPU-135 in doses of 26-130 mg/kg exhibited more pronounced antidepressant action and in doses of 26 and 52 mg/kg had more pronounced anxiolytic effects. RGPU-135 in doses of 13-78 mg/kg increased locomotor and exploratory activity of animals in the open-field test. Activating effects of this agent decreased with increasing the dose. RGPU-135 in the subtoxic dose (650 mg/kg) suppressed locomotor activity of animals (produced sedative effect). PMID- 25432280 TI - Phenylephrine potentiates the anticonvulsant effect and neutralizes the sedative effect of diazepam in rats upon combined intragastric administration. AB - High doses of phenylephrine and diazepam (1 and 10 mg/kg, respectively) suppressed the development of generalized tonic-clonic pentylenetetrazole-induced convulsions in 86-100% rats, but did not prevent local clonic pentylenetetrazole induced convulsions. Diazepam in the specified dose produced strong sedation, while phenylephrine had no sedative effect in the open-field test. Combined intragastric administration of phenylephrine in a medium and individually ineffective dose (0.3 mg/kg) and diazepam in a high dose (10 mg/kg) potentiated the anticonvulsant effect of diazepam: it prevented not only tonic-clonic, but also clonic pentylenetetrazole-induced convulsions in 100% rats and 2.6-fold increased anticonvulsant activity of diazepam. The specified combination of diazepam and phenylephrine had no sedative effect. The mechanism of potentiation of the anticonvulsive effect and elimination of the sedative side effect is based on stimulation of gastric mucosa afferents by phenylephrine. PMID- 25432281 TI - Role of glutathione-S-transferase M1 (GSTM1) and T1 (GSTT1) genes in the development and progress of chronic myeloid leukemia and in the formation of response to imatinib therapy. AB - The effects of GSTM1 and GSTT1 gene deletion ("zero") polymorphisms on the risk of chronic myeloid leukemia development and progress and on response to imatinib monotherapy were studied in the representatives of the Russian nationality in the Vyatka region of Russia. Homozygotic carriership of GSTT1 "zero" allele was associated with a 3.66 times higher risk of chronic myeloid leukemia development in residents of the Vyatka region (OR=3.66, 95% CI=2.12-6.30; p<0.0001). Combinations of the "zero" GSTM1 and GSTT1 genotypes were risk factors indicating the probable disease progress and failure of high cytogenetic response after 12 months of imatinib therapy (400 mg daily). PMID- 25432282 TI - Tumor clonality: research and clinical aspects. AB - Except for the rare exclusions, all sporadic tumors originate from the only cell. However, the majority of malignant cells proper, constituting the tumor, demonstrate significantly heterogeneous morphology and physiology, differing by mobility, expression profiles, receptor presentation on cell surface, proliferative and angiogenic potential. The data presented in this report confirm the existence of intratumorous clonal heterogeneity. Potential biological and clinical significance of clonal heterogeneity and the existence of genetic differences between the primary tumors and their metastases and the effects of clonal tumor heterogeneity on the metastatic process are discussed. PMID- 25432283 TI - Antitumor activity of ethanol extract from Hippophae rhamnoides L. leaves towards human acute myeloid leukemia cells in vitro. AB - We studied the effects of ethanol extract from Hippophae rhamnoides L. leaves on the growth and differentiation of human acute myeloid leukemia cells (KG-1a, HL60, and U937). The extract of Hippophae rhamnoides L. leaves inhibited cell growth depending on the cell strain and extract dose. In a high concentration (100 MUg/ml), the extract also exhibited a cytotoxic effect on HL60 cells. Hippophae rhamnoides L. leaves extract did not affect cell differentiation and did not modify the differentiating effect of calcitriol, active vitamin D metabolite. Inhibition of cell proliferation was paralleled by paradoxical accumulation of phase S cells (synthetic phase) with a reciprocal decrease in the count of G1 cells (presynthetic phase). The extract in a concentration of 100 MUg/ml induced the appearance of cells with a subdiploid DNA content (sub-G1 phase cells), which indicated induction of apoptosis. The antiproliferative effect of Hippophae rhamnoides L. extract on acute myeloid leukemia cells was at least partially determined by activation of the S phase checkpoint, which probably led to deceleration of the cell cycle and apoptosis induction. PMID- 25432284 TI - Studies of the structure and functions of blood cells in senile patients with pneumonia on the biological model of hypoxia by scanning probe microscopy. AB - Biological model of hypoxia can be used for the diagnosis of functional changes in human erythrocytes under the effect of the hypoxic factor. The use of this model together with modern methods of scanning probe microscopy for evaluation of the severity of pulmonological disease in senile patients will help to predict treatment efficiency and outcome. PMID- 25432285 TI - Dynamic mapping of the brain in substance-dependent individuals: functional magnetic resonance imaging. AB - Functional magnetic resonance imaging can be used to study numerous brain dysfunctions, including disorders of the self, in substance-dependent individuals. The self as the sum of human concepts about oneself is regulated by the brain system close to the default mode network: the medial prefrontal cortex, posterior cingulated gyrus, and some parietal regions. However, the composition and activity of this system in mental disease, specifically, in substance addiction, are virtually not described. Our study showed that self-appraisal task in addicts activates the superior frontal cortex, cuneus, precuneus, angular gyrus, and posterior cingulated cortex. The involvement of the parietal (postcentral and supramarginal gyri) and temporal (superior temporal and Heschl's gyri) sensory areas is diminished. Hence, published data on the involvement of the cingulate cortex and prefrontal cortex in functional regulation of the self are confirmed. Activation-deactivation patterns in the parietal and temporal regions differ significantly from the previous descriptions. PMID- 25432286 TI - Effects of nanodiamonds of explosive synthesis on the skin of experimental animals locally exposed to cobalt and chrome ions. AB - Experiments in vivo demonstrated the protective effect of modified nanodiamonds on guinea pig skin after local exposure cobalt ions, but not chrome ions. The observed differences are determined by different adsorption of these ions by nanodiamonds: in vitro experiments showed that nanodiamonds adsorbed cobalt ions, but not chrome ions from water solutions. The perspectives of using modified nanodiamonds as a new adsorbent for prevention of allergic contact dermatitis induced by ions of bivalent metals are discussed. PMID- 25432287 TI - Comparative characterization of the skull bones after implantation of titanium biocomposites containing BMP-2 in their coating structure. AB - The skull bone tissue was studied under conditions of implantation of Grey nanostructured titanium containing biocomposites and bone morphogenetic protein-2 in the coating structure. Implantation of sandblast processed titanium led to more rapid formation of the bone tissue than the use of titanium biocomposites with microarch oxidation (due to porous surface). The type of metal processing was inessential for nanocomposites. Morphogenetic proteins stimulated regeneration and facilitated the formation of structures characteristic of the bone tissue. PMID- 25432288 TI - Structural changes in the thymus in allogenic pregnancy in mice with high incidence of spontaneous and muramylpeptide-induced abortions. AB - Structural changes in the thymus over the course of allogenic pregnancy were studied in mice from highly fertile couples (CBA females and BALB/c males), animals with high spontaneous abortions (CBA females and DBA/2 males), and in experimental immunity-dependent pregnancy loss induced by muramyldipeptide beta heptylglycoside. Accidental involution of the thymus on days 8 and 14 of pregnancy was more pronounced in mice with high level of spontaneous embryo resorption than in females from highly fertile couples. Muramyldipeptide glycoside stimulated manifestations of thymus involution in fertile and "abortogenic" cross-breeding. PMID- 25432289 TI - Hemopoietic cell proliferation and death in the regenerating fetal rat liver. AB - The proliferation and death of hemopoietic cells in the regenerating liver of 17 day outbred albino rat fetuses were studied during 2 days after resection of 20% of the organ. The mitotic index of hemopoietic cells in the resected liver increased significantly 24 h after the operation in comparison with the control fetuses. No increase in the counts of apoptotic hemopoietic cells was detected in the regenerating liver. Hence, resection of 20% of the liver in rat fetuses stimulated the proliferation of hemopoietic cells and did not stimulate their apoptosis. PMID- 25432290 TI - Evaluation of serum antioxidant activity in patients with liver pathology by the chemiluminescent method. AB - Total antioxidant activity of the serum in patients with liver pathology was assessed by two chemiluminescent methods based on different models of free radical oxidation: Hb-H2O2-luminol and ABAP-luminol. Comparative analysis showed a significant, but not high correlation of the results (r=0.798), which can be explained by different mechanisms of induction of free radicals and effects of various serum components (proteins and bilirubin) on the initiation process. The influence of aphysiological concentration of analyzed values manifested in the Hb H2O2 model. Disagreement between the results of measurements was more pronounced in patients with abnormally high serum bilirubin content. The results suggested that ABAP-luminol chemiluminescent model is more preferable for evaluation of antioxidant activity in clinical practice. PMID- 25432291 TI - Magnetic resonance-imaging of the effect of targeted antiangiogenic gene delivery in a melanoma tumour model. AB - OBJECTIVES: We investigated the effect of targeted gene therapy to melanoma tumours (M21) by MR-imaging. METHODS: M21 and M21-L tumours were grown to a size of 850 mm(3). M21 and M21-L tumours were intravenously treated with an alphavbeta3-integrin-ligand-coupled nanoparticle (RGDNP)/RAF(-) complex five times every 72 hours. MRI was performed at set time intervals 24h and 72h after the i.v. injection of the complex. The MRI protocol was T1-wt-SE+/-CM, T2-wt-FSE, DCE-MRI, Diffusion-wt-STEAM-sequence, T2-time obtained on a 1.5-T-GE-MRI device. RESULTS: The size of the treated M21 tumours kept nearly constant during the treatment phase (847.8+/-31.4 mm(3) versus 904.8+/-44.4 mm(3)). The SNR value (T2 weighted images) of the tumours was 36.7+/-0.6 and dropped down to 30.6+/-1.9 (p=0.004). At the beginning the SNR value (T1-weighted images) of the tumours after contrast medium application was 42.3+/-1.9 and dropped down to 28.5+/-3.0 (p<0.001). In the treatment group the diffusion coefficient increased significantly under therapy (0.54+/-0.01x10(-3) mm(2)/s versus 0.67+/-0.04x10(-3) mm(2)/s). The DCE-MRI showed a reduction of the slope and of the Akep of 67.8+/ 4.3 % respectively 64.8+/-3.3 % compared to baseline. CONCLUSIONS: Targeted gene delivery therapy induces significant changes in MR-imaging. MRI showed a significant reduction of contrast medium uptake parameters and increase of the diffusion coefficient of the tumours. KEY POINT: * Treatment with targeted gene delivery therapy can be monitored by MR imaging * DCE and diffusion-weighted imaging are appropriate methods for monitoring this therapy * Functional changes are significant prior to any morphological changes. PMID- 25432292 TI - Radiofrequency ablation of chondroblastoma: long-term clinical and imaging outcomes. AB - OBJECTIVES: To investigate the long-term clinical and imaging outcomes of patients with chondroblastoma treated by radiofrequency ablation (RFA). METHODS: Retrospective analysis of 25 consecutive patients treated with RFA from September 2006 to December 2013. Patients were reviewed within one month of the procedure, then every 3-6 months, and yearly for up to three years. Serial magnetic resonance imaging (MRI) was performed at follow-up to monitor recovery. Functional outcome was assessed using the Musculoskeletal Tumour Society Score (MSTS). RESULTS: Pre-procedure MRI confirmed osteolytic lesions (size range 1.0 3.3 cm; mean 2.0 cm). Patients reported continued symptomatic improvement at four months review. Serial MRI confirmed progressive resolution of inflammation with fatty consolidation of cavity. 88 % of patients became asymptomatic during the follow up period. Three patients' (12 %) symptoms returned at 16, 22 and 24 months respectively after RFA. MRI and biopsy confirmed recurrence in these patients. Functional assessment using MSTS score had an average score of 97.5 %. Mean follow up for the study group was 49 months. CONCLUSION: RFA is an effective alternative to surgery in the management of chondroblastoma. We recommend a multi disciplinary approach and RFA should be considered as a first-line treatment. Long-term follow-up is required for timely detection of recurrences. KEY POINTS: * RFA is a safe and effective technique in the treatment of chondroblastoma. * Positive outcomes in 88 % patients at mean follow-up period of 49 months. * Local recurrences occurred in 12 % cases. * Long-term follow-up is required for timely detection of recurrences. * RFA should be considered as a first-line treatment for chondroblastoma. PMID- 25432293 TI - Contrast agent and radiation dose reduction in abdominal CT by a combination of low tube voltage and advanced image reconstruction algorithms. AB - OBJECTIVES: To assess image quality in abdominal CT at low tube voltage combined with two types of iterative reconstruction (IR) at four reduced contrast agent dose levels. METHODS: Minipigs were scanned with standard 320 mg I/mL contrast concentration at 120 kVp, and with reduced formulations of 120, 170, 220 and 270 mg I/mL at 80 kVp with IR. Image quality was assessed by CT value, dose normalized contrast and signal to noise ratio (CNRD and SNRD) in the arterial and venous phases. Qualitative analysis was included by expert reading. RESULTS: Protocols with 170 mg I/mL or higher showed equal or superior CT values: aorta (278-468 HU versus 314 HU); portal vein (205-273 HU versus 208 HU); liver parenchyma (122-146 HU versus 115 HU). In the aorta, all 170 mg I/mL protocols or higher yielded equal or superior CNRD (15.0-28.0 versus 13.7). In liver parenchyma, all study protocols resulted in higher SNRDs. Radiation dose could be reduced from standard CTDIvol = 7.8 mGy (6.2 mSv) to 7.6 mGy (5.2 mSv) with 170 mg I/mL. CONCLUSION: Combining 80 kVp with IR allows at least a 47 % contrast agent dose reduction and 16 % radiation dose reduction for images of comparable quality. KEY POINTS: * There is a balance between image quality, contrast dose and radiation dose. * Iterative reconstruction has a major, positive impact on this balance. * Both contrast dose and radiation dose can be reduced in abdominal CT. * The trade-off can be quantitatively described by a 3D model. * Contrast and radiation dose can be tailored according to specific safety concerns. PMID- 25432294 TI - Utilization of phosphogypsum in tannery sludge stabilization and evaluation of the radiological impact. AB - The current global trend towards increasingly stringent environmental standards and efforts for efficient utilization and re-use of available by-products and/or wastes, favors the use of low-cost sorbent materials for the treatment of heavy metal-contaminated solid wastes. In this study, the stabilization of tannery sludge, produced from the physicochemical and biological treatment of tannery wastewaters, was examined by the addition of phosphogypsum (PG) at a ratio of 1:1. Characterization of the tannery sludge leachates showed high amounts of chromium which exceeded the acceptable level for disposal in non-hazardous waste landfills, while the dissolved organic carbon (DOC) concentrations exceeded the limits for disposal in landfills for hazardous wastes, according to the EU Decision 2003/33/EC. Leachates of the waste stabilized with PG presented chromium and DOC concentrations below the regulation limits for disposal in landfills for non-hazardous wastes. Moreover, mixing PG with tannery sludge resulted in a stabilized waste with reduced radioactivity. PMID- 25432295 TI - Reactive oxygen species and cytotoxicity in rainbow trout hepatocytes: effects of medium and incubation time. AB - This study evaluated the effects of exposure medium and culture age on intracellular reactive oxygen species (ROS) development and cytotoxicity in fish hepatocytes following exposure to copper (Cu). ROS was quantified using the fluorescent probes DHR 123 and CM-H2DCFDA following exposure to Cu in Leibovitz' medium (L-15) or Tris-buffered saline (TBS). Similarly, culture age effects were investigated using 1-, 2- and 4-day-old cultured hepatocytes by exposing them to Cu in TBS. The exposure in L-15 resulted in significantly higher ROS compared to TBS using CM-H2DCFDA, but not DHR 123. The age of the primary cultures significantly affected the development of ROS for both probes. None of the exposures caused cytotoxicity in the hepatocytes. The results showed that both factors may affect responses to stressors, and suggested that the use of a simple medium such as TBS may be preferable for some applications. It is also preferable to use 1-day-old primary hepatocyte cultures. PMID- 25432296 TI - Spatial and temporal distribution and pollution assessment of trace metals in marine sediments in Oyster Bay, NSW, Australia. AB - The disposal of untreated urban and industrial wastewater has a deleterious effect on both the water and sediment quality of Oyster Bay located in south Sydney, Australia. The present investigation was undertaken to evaluate the potential pollution of marine sediments in Oyster Bay. The results of metals were compared with adverse biological effect values effect range low (ERL) and effect range median (ERM). Spatial distribution of trace metals was estimated by applying geographic information system. The results indicated that the sediments were polluted with Cu, Zn, As and Pb, which exceeded ERL levels. However, these metals were still below ERM values, and other metals Cr and Ni were below ERL. Moreover, the highest concentrations of metals were around discharge points and in the inner bay. Further, trace metals could be attributed to human activities within the bay as they declined in concentrations with increasing sediment depth. PMID- 25432297 TI - Production loss among employees perceiving work environment problems. AB - OBJECTIVES: The overall aim of this explorative study was to investigate the relationship between factors in the psychosocial work environment and work environment-related production loss. METHODS: Employees at a Swedish university were invited to answer a workplace questionnaire and were selected for this study if they reported having experienced work environment-related problems in the past 7 days (n = 302). A stepwise logistic regression and a modified Poisson regression were used to identify psychosocial work factors associated with work environment-related production loss as well as to identify at what level those factors are associated with production loss. RESULTS: Employees who reported having experienced work environment problems but also fair leadership, good social climate, role clarity and control of decision had significantly lower levels of production loss, whereas employees who reported inequality and high decision demands reported significantly higher levels of production loss. Never or seldom experiencing fair leadership, role clarity, equality, decision demands and good social climate increase the risk of production loss due to work environment problems, compared to those who experience these circumstances frequently, always or most of the time. CONCLUSIONS: Several psychosocial work factors are identified as factors associated with a reduced risk of production losses among employees despite the nature of the work environment problem. Knowledge of these factors may be important not only to reduce employee ill health and the corresponding health-related production loss, but also reduce immediate production loss due to work environment-related problems. PMID- 25432298 TI - Prediction of hearing loss among the noise-exposed workers in a steel factory using artificial intelligence approach. AB - PURPOSE: Prediction of hearing loss in noisy workplaces is considered to be an important aspect of hearing conservation program. Artificial intelligence, as a new approach, can be used to predict the complex phenomenon such as hearing loss. Using artificial neural networks, this study aims to present an empirical model for the prediction of the hearing loss threshold among noise-exposed workers. METHODS: Two hundred and ten workers employed in a steel factory were chosen, and their occupational exposure histories were collected. To determine the hearing loss threshold, the audiometric test was carried out using a calibrated audiometer. The personal noise exposure was also measured using a noise dosimeter in the workstations of workers. Finally, data obtained five variables, which can influence the hearing loss, were used for the development of the prediction model. Multilayer feed-forward neural networks with different structures were developed using MATLAB software. Neural network structures had one hidden layer with the number of neurons being approximately between 5 and 15 neurons. RESULTS: The best developed neural networks with one hidden layer and ten neurons could accurately predict the hearing loss threshold with RMSE = 2.6 dB and R(2) = 0.89. The results also confirmed that neural networks could provide more accurate predictions than multiple regressions. CONCLUSIONS: Since occupational hearing loss is frequently non-curable, results of accurate prediction can be used by occupational health experts to modify and improve noise exposure conditions. PMID- 25432299 TI - Low 25-hydroxyvitamin D concentrations may explain the link between breast cancer risk and shift work. PMID- 25432300 TI - Seroprevalence of Rift Valley fever virus infection in camels (dromedaries) in northern Tanzania. AB - Rift Valley fever (RVF) is an arthropod-borne viral zoonotic disease that affects a wide range of animals including sheep, goats, cattle, camels and humans. Camels have only recently been introduced into Tanzania and, as a result, there is no credible diseases status information concerning this population, estimated to be in the low hundreds. As part of a broader study on camel diseases in different localities of northern Tanzania, serum samples (n = 109) were collected from apparently healthy, non-vaccinated camels during the period June to August 2010 and tested for antibodies specific to RVF virus (RVFV) using the inhibition enzyme-linked immunosorbent assay (ELISA). Overall, herd and individual camel IgG seroprevalence was 78.5 % (11/14) and 27.5 % (30/109), respectively. IgG was found to be most prevalent in camels from Kilindi and Hai districts (45 %, each) and in introduced camels from other areas (37.1 %). The relationship between age and seropositivity showed that the seroprevalence was the highest (84.6 %) in age group of >=10 years and lowest (11.9 %) in age group of <=5 years.The results of this study reveal that evidence of camels being exposed to RVFV and that the risk of seropositivity varied according to district, being higher in Kilindi and Hai compared with other districts sampled. The risk of seropositivity increased with increasing animal age and the introduction of camels into the herd. Based on these study findings, continuous disease surveillance of camels for RVFV is indicated. PMID- 25432301 TI - Sternal closure with absorbable pins and cords in general thoracic surgery. AB - After median sternotomy, the sternum is commonly closed using metal wires, which sometimes cause complications because they are permanent foreign bodies. As an alternative, we used a combination of absorbable sutures and pins for full median sternotomy in 24 adult general thoracic surgery patients. There were three cases of sternal dehiscence detectable by computed tomography, none of which required re-operation. Two of these patients had diabetes mellitus (DM) and the third patient was on corticosteroid therapy. In an appropriately selected patient population that excludes patients with DM or who are undergoing corticosteroid therapy, we have not observed any sternal complications. We concluded that our technique is clinically feasible with appropriate patient selection. PMID- 25432302 TI - Professor Roger Sutton DM, FRCPC: in memoriam. PMID- 25432303 TI - Combining metabolomic non-targeted GC*GC-ToF-MS analysis and chemometric ASCA based study of variances to assess dietary influence on type 2 diabetes development in a mouse model. AB - Insulin resistance (IR) lies at the origin of type 2 diabetes. It induces initial compensatory insulin secretion until insulin exhaustion and subsequent excessive levels of glucose (hyperglycemia). A high-calorie diet is a major risk factor contributing to the development of this metabolic disease. For this study, a time course experiment was designed that consisted of two groups of mice. The aim of this design was to reproduce the dietary conditions that parallel the progress of IR over time. The first group was fed with a high-fatty-acid diet for several weeks and followed by 1 week of a low-fatty-acid intake, while the second group was fed with a low-fatty-acid diet during the entire experiment. The metabolomic fingerprint of C3HeB/FeJ mice liver tissue extracts was determined by means of two-dimensional gas chromatography time-of-flight mass spectrometry (GC*GC-ToF MS). This article addresses the application of ANOVA-simultaneous component analysis (ASCA) to the found metabolomic profile. By performing hyphenated high throughput analytical techniques together with multivariate chemometric methodology on metabolomic analysis, it enables us to investigate the sources of variability in the data related to each experimental factor of the study design (defined as time, diet and individual). The contribution of the diet factor in the dissimilarities between the samples appeared to be predominant over the time factor contribution. Nevertheless, there is a significant contribution of the time-diet interaction factor. Thus, evaluating the influences of the factors separately, as it is done in classical statistical methods, may lead to inaccurate interpretation of the data, preventing achievement of consistent biological conclusions. PMID- 25432304 TI - Discussion point: reporting guidelines for mass spectrometry imaging. PMID- 25432305 TI - Erratum to: Combined QCM-D/GE as a tool to characterize stimuli-responsive swelling of and protein adsorption on polymer brushes grafted onto 3D nanostructures. PMID- 25432316 TI - Progress and change. PMID- 25432317 TI - Acute function of secreted amyloid precursor protein fragment APPsalpha in synaptic plasticity. AB - The key role of APP in the pathogenesis of Alzheimer disease is well established. However, postnatal lethality of double knockout mice has so far precluded the analysis of the physiological functions of APP and the APLPs in the brain. Previously, APP family proteins have been implicated in synaptic adhesion, and analysis of the neuromuscular junction of constitutive APP/APLP2 mutant mice showed deficits in synaptic morphology and neuromuscular transmission. Here, we generated animals with a conditional APP/APLP2 double knockout (cDKO) in excitatory forebrain neurons using NexCre mice. Electrophysiological recordings of adult NexCre cDKOs indicated a strong synaptic phenotype with pronounced deficits in the induction and maintenance of hippocampal LTP and impairments in paired pulse facilitation, indicating a possible presynaptic deficit. These deficits were also reflected in impairments in nesting behavior and hippocampus dependent learning and memory tasks, including deficits in Morris water maze and radial maze performance. Moreover, while no gross alterations of brain morphology were detectable in NexCre cDKO mice, quantitative analysis of adult hippocampal CA1 neurons revealed prominent reductions in total neurite length, dendritic branching, reduced spine density and reduced spine head volume. Strikingly, the impairment of LTP could be selectively rescued by acute application of exogenous recombinant APPsalpha, but not APPsbeta, indicating a crucial role for APPsalpha to support synaptic plasticity of mature hippocampal synapses on a rapid time scale. Collectively, our analysis reveals an essential role of APP family proteins in excitatory principal neurons for mediating normal dendritic architecture, spine density and morphology, synaptic plasticity and cognition. PMID- 25432318 TI - Binding energy calculations for hevein-carbohydrate interactions using expanded ensemble molecular dynamics simulations. AB - Accurate estimation of protein-carbohydrate binding energies using computational methods is a challenging task. Here we report the use of expanded ensemble molecular dynamics (EEMD) simulation with double decoupling for estimation of binding energies of hevein, a plant lectin with its monosaccharide and disaccharide ligands GlcNAc and (GlcNAc)2, respectively. In addition to the binding energies, enthalpy and entropy components of the binding energy are also calculated. The estimated binding energies for the hevein-carbohydrate interactions are within the range of +/-0.5 kcal of the previously reported experimental binding data. For comparison, binding energies were also estimated using thermodynamic integration, molecular dynamics end point calculations (MM/GBSA) and the expanded ensemble methodology is seen to be more accurate. To our knowledge, the method of EEMD simulations has not been previously reported for estimating biomolecular binding energies. PMID- 25432319 TI - Managing water services in tropical regions: From land cover proxies to hydrologic fluxes. AB - Watershed investment programs frequently use land cover as a proxy for water based ecosystem services, an approach based on assumed relationships between land cover and hydrologic outcomes. Water flows are rarely quantified, and unanticipated results are common, suggesting land cover alone is not a reliable proxy for water services. We argue that managing key hydrologic fluxes at the site of intervention is more effective than promoting particular land-cover types. Moving beyond land cover proxies to a focus on hydrologic fluxes requires that programs (1) identify the specific water service of interest and associated hydrologic flux; (2) account for structural and ecological characteristics of the relevant land cover; and, (3) determine key mediators of the target hydrologic flux. Using examples from the tropics, we illustrate how this conceptual framework can clarify interventions with a higher probability of delivering desired water services than with land cover as a proxy. PMID- 25432320 TI - Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities. AB - We describe a family with QARS deficiency due to compound heterozygous QARS mutations, including c.1387G > A (p.R463*) in the catalytic core domain and c.2226C > G (p.Q742H) in the anticodon domain, both previously unreported and predicted damaging. The phenotype of the male index further confirms this specific aminoacyl-transfer RNA (tRNA) synthetase disorder as a novel genetic cause of progressive microcephaly with diffuse cerebral atrophy, severely deficient myelination, intractable seizures, and developmental arrest. However, in contrast to the two hitherto published families, the cerebellum and its myelination are not affected. An awareness that QARS mutations may cause isolated supratentorial changes is crucial for properly directing genetic analysis. PMID- 25432322 TI - Transient activation of an adaptor protein, disabled-2, in rat spinal cord injury. AB - We previously reported that disabled-2 (Dab-2), a cytosolic adaptor protein, was expressed in inflammatory and glial cells in the central nervous system (CNS) in experimental autoimmune encephalomyelitis and cerebral cryoinjury. Here, to determine the pattern of Dab-2 expression in a clip compression-induced rat spinal cord injury (SCI) model, the protein level and localization of Dab-2 in the spinal cord were investigated in rats with SCI using Western blotting and immunohistochemistry. Western blotting revealed that the expression of both the 75- and 100-kDa isoforms of Dab-2 peaked significantly in the spinal cord after clip compression injury 7 days post-injury compared to sham controls, and declined slightly thereafter. Immunohistochemistry revealed weak Dab-2 immunostaining in some neurons, glial cells, and ependymal cells in the spinal cords of the control animals, compared to staining in the macrophages and reactive astrocytes in lesions of the SCI animals. Overall, these findings suggest that both isoforms of Dab-2 are transiently upregulated in response to SCI and that the increased expression of Dab-2 is associated with the early activation of macrophages and astrogliosis in the course of CNS inflammation. PMID- 25432321 TI - RNase E in the gamma-Proteobacteria: conservation of intrinsically disordered noncatalytic region and molecular evolution of microdomains. AB - RNase E of Escherichia coli is a membrane-associated endoribonuclease that has a major role in mRNA degradation. The enzyme has a large C-terminal noncatalytic region that is mostly intrinsically disordered (ID). Under standard growth conditions, RhlB, enolase and PNPase associate with the noncatalytic region to form the multienzyme RNA degradosome. To elucidate the origin and evolution of the RNA degradosome, we have identified and characterized orthologs of RNase E in the gamma-Proteobacteria, a phylum of bacteria with diverse ecological niches and metabolic phenotypes and an ancient origin contemporary with the radiation of animals, plants and fungi. Intrinsic disorder, composition bias and tandem sequence repeats are conserved features of the noncatalytic region. Composition bias is bipartite with a catalytic domain proximal ANR-rich region and distal AEPV-rich region. Embedded in the noncatalytic region are microdomains (also known as MoRFs, MoREs or SLiMs), which are motifs that interact with protein and other ligands. Our results suggest that tandem repeat sequences are the progenitors of microdomains. We have identified 24 microdomains with phylogenetic signals that were acquired once with few losses. Microdomains involved in membrane association and RNA binding are universally conserved suggesting that they were present in ancestral RNase E. The RNA degradosome of E. coli arose in two steps with RhlB and PNPase acquisition early in a major subtree of the gamma Proteobacteria and enolase acquisition later. We propose a mechanism of microdomain acquisition and evolution and discuss implications of these results for the structure and function of the multienzyme RNA degradosome. PMID- 25432323 TI - Tumour response of osteosarcoma to neoadjuvant chemotherapy evaluated by magnetic resonance imaging as prognostic factor for outcome. AB - PURPOSE: This study evaluated the feasibility of computed magnetic resonance imaging (MRI) volumetry in conventional osteosarcomas. Secondly, we investigated whether computed volumetry provides new prognostic indicators for histological response of osteosarcomas after neoadjuvant chemotherapy. METHODS: In a retrospective cohort study, data from the Vienna Bone Tumour Registry was used. MR images from 14 patients (male:female = 1.8, mean age 19 years) were analysed prior to and after neoadjuvant chemotherapy according to current therapy regimens. Histological response to chemotherapy was graded according to the Salzer-Kuntschik classification. Computed volumetry was performed for the intraosseous part, as well as the soft-tissue component and the tumour as a whole. RESULTS: In a setting of appropriate radiological equipment, the method has been considered to be well implementable into clinical routine. The mean tumour volume prior to chemotherapy was 321 (+/-351) ml. In good responders (n = 6), overall tumour volume decreased by 47% (p = 0.345), whereas poor responders (n = 8) showed a 19% decrease (p = 0.128). Neoadjuvant multidrug therapy remarkably changed the tumour composition. This is seen in a decrease of the mean ratio of soft-tissue to intraosseous tumour volume from 8.67 in poor responders and 1.15 in good responders to 1.26 and 0.45 (p = 0.065), respectively. Interestingly, the bony compartment of good responders showed a volume increase during neoadjuvant chemotherapy (p = 0.073). However, we did not find prognostic markers for histological tumour response to pre-operative chemotherapy. CONCLUSIONS: Separated volumetry of tumour segments revealed interesting insights into therapy-induced growth patterns. If verified in a larger study population, these results should be taken into account when planning ablative surgery. PMID- 25432326 TI - Depth-resolution imaging of crystalline nanoclusters attached on and embedded in amorphous films using aberration-corrected TEM. AB - For observations of crystalline nanoclusters, the features and capabilities of depth-resolution imaging by aberration-corrected transmission electron microscopy (TEM) were investigated using image simulations and experiments for two types of samples. The first sample was gold clusters attached on an amorphous carbon film. The experimental through-focal series indicated that the focal plane for the cluster was shifted 3 nm from that for the supporting film. This difference is due to the depth-resolution imaging of the cluster and film, the mid-planes of which are separated by 3 nm along the depth direction (the electron incident direction). On the basis of this information, the three-dimensional configuration of the sample, such as the film thickness of 2 nm, was successfully illustrated. The second sample was a Zr66.7Ni33.3 metallic glass including a medium-range order (MRO) structure, which was approximately considered to be a crystalline cluster with a diameter of 1.6 nm. In the experimental through-focal series, the lattice fringe of the MRO cluster was visible at limited focal conditions. Image simulations reproduced well the focal conditions and also indicated a structural condition for the visualization that the embedded cluster must be apart from the mid-plane of the matrix film. Similar to the case of the first sample, this result can be explained by the idea that the "effective focal planes" for the film and cluster are at different heights. This type of depth-resolution phase contrast imaging is possible only in aberration-corrected TEM and when the sample has a simple structure and is sufficiently thin for the kinematical scattering approximation. PMID- 25432325 TI - 8-prenylnaringenin and tamoxifen inhibit the shedding of irradiated epithelial cells and increase the latency period of radiation-induced oral mucositis : cell culture and murine model. AB - PURPOSE: The major component in the pathogenesis of oral radiation-induced mucositis is progressive epithelial hypoplasia and eventual ulceration. Irradiation inhibits cell proliferation, while cell loss at the surface continues. We conceived to slow down this desquamation by increasing intercellular adhesion, regulated by the E-cadherin/catenin complex. We investigated if 8-prenylnaringenin (8-PN) or tamoxifen (TAM) decrease the shedding of irradiated human buccal epithelial cells in vitro and thus delay the ulcerative phase of radiation-induced mucositis in vivo. MATERIALS AND METHODS: In vitro, aggregates of buccal epithelial cells were irradiated and cultured in suspension for 11 days. 8-PN or TAM were investigated regarding their effect on cell shedding. In vivo, the lower tongue surface of mice was irradiated with graded single doses of 25 kV X-rays. The incidence, latency, and duration of the resulting mucosal ulcerations were analyzed after topical treatment with 8-PN, TAM or solvent. RESULTS: 8-PN or TAM prevented the volume reduction of the irradiated cell aggregates during the incubation period. This was the result of a higher residual cell number in the treated versus the untreated irradiated aggregates. In vivo, topical treatment with 8-PN or TAM significantly increased the latency of mucositis from 10.9 to 12.1 and 12.4 days respectively, while the ulcer incidence was unchanged. CONCLUSION: 8-PN and TAM prevent volume reduction of irradiated cell aggregates in suspension culture. In the tongues of mice, these compounds increase the latency period. This suggests a role for these compounds for the amelioration of radiation-induced mucositis in the treatment of head and neck tumors. PMID- 25432324 TI - A prospective randomized comparison of PEEK cage containing calcium sulphate or demineralized bone matrix with autograft in anterior cervical interbody fusion. AB - PURPOSE: A variety of bone substitutes have been successfully used to fill PEEK cages in cervical interbody fusion in order to avoid the complications related to bone harvesting from the donor site. However, no controlled study has previously been conducted to compare the effectiveness of PEEK interbody cages containing calcium sulphate/ demineralized bone matrix (CS/DBM) with autogenous cancellous bone for the treatment of cervical spondylosis. The objective of this prospective, randomized clinical study was to evaluate the effectiveness of implanting PEEK cages containing CS/DBM for the treatment of cervical radiculopathy and/or myelopathy. METHODS: Sixty-eight patients with cervical radiculopathy and/or myelopathy were randomly assigned to receive one- or two level discectomy and fusion with PEEK interbody cages containing CS/DBM or autogenous iliac cancellous bone (AIB). The patients were followed up for two years postoperatively. The radiological and clinical outcomes were assessed during a two-year follow-up. RESULTS: The mean blood loss was 75 +/- 18.5 ml in the CS/DBM group and 100 +/- 19.6 ml (P < 0.01) in the AIB group. The fusion rate was 94.3 % in the CS/DBM group and 100 % in the AIB group at 12-month follow-up. The fusion rate was 100 % at final follow-up in both groups. No significant difference (P > 0.05) was found regarding improvement of JOA score and segmental lordosis as well as neck and arm pain at all time intervals between the two groups. The total complication rate was significantly higher (P < 0.05) in the AIB group than in the CS/DBM group, but there was no significant difference between the two groups (P > 0.05) when comparing the complications in the neck. CONCLUSIONS: In conclusion, the PEEK interbody fusion cage containing CS/DBM or AIB following one- or two-level discectomy had a similar outcome for cervical spondylotic radiculopathy and/or myelopathy. The rate of fusion and the recovery rate of JOA score between the two groups were the same. The filling of CS/DBM in the PEEK cage instead of AIB has the advantage of less operative blood loss and fewer complications at the donor site. PMID- 25432327 TI - Cardiovascular risk factors and events in women with androgen excess. AB - Androgen excess (AE) was approximated to be present in 7% of the adult population of women. Polycystic ovary syndrome (PCOS) is the most prevalent among them, followed by idiopathic hirsutism (IH), congenital adrenal hyperplasia (CAH), hyperandrogenic insulin-resistant acanthosis nigricans (HAIRAN) syndrome, and androgen-secreting neoplasms (ASNs). Increased cardiovascular risk was implicated in women with AE. Serum testosterone independently increases risk for cardiovascular disease (CVD), and correlates even with indices of subclinical atherosclerosis in various populations of postmenopausal women. Hyperandrogenism in PCOS is closely related to the aggravation of abdominal obesity, and together with insulin resistance forming the metabolic core for the development of CVD. However, phenotypic variability of PCOS generates significant influence on the cardiometabolic risks. Numerous risk factors in PCOS lead to 5-7 times higher risk for CVD and over 2-fold higher risk for coronary heart disease and stroke. However, issue on the cardiometabolic risk in postmenopausal women with hyperandrogenic history is still challenging. There is a significant overlapping in the CVD characteristics of women with PCOS and variants of CAH. Relevant clinical data on the prevalence and cardiometabolic risk and events in women with IH, HAIRAN syndrome or ASNs are scarce. The effects of various oral contraceptives (OCs) and antiandrogenic compounds on metabolic profile are varying, and could be related to the selected populations and different therapy regiments mainly conducted in women with PCOS. It is assumed relation of OCs containing antiandrogenic progestins to the increased risk of cardiovascular and thromboembolic events. PMID- 25432328 TI - The evaluation of Nesfatin-1 levels in patients with OSAS associated with metabolic syndrome. AB - PURPOSE: The association of obstructive sleep apnea syndrome (OSAS) and metabolic syndrome (MS) has been demonstrated in studies and in recent years; the effect of OSAS on insulin resistance independent of the level of obesity is being investigated. Nesfatin-1 is a newly defined 82 amino acid protein with a precursor molecule of NUCB2 (nucleobindin 2). Nesfatin-1 is not only essential in regulation of food ingestion but also important in regulation of some brain functions, autonomic regulation, stress, mental state, and paradoxical sleep. We aimed to evaluate the relationship between OSAS and MS and the MS dependent or independent effect of Nesfatin-1 on this relationship. METHODS: Patients admitted with clinical signs of OSAS are included. Patients are divided into three groups based on Apnea-Hypopnea Index (AHI) on Polysomnography (PSG) as mild, moderate, and severe OSAS. A total of 59 patients were included the control patients. Several OSAS parameters and laboratory findings which are and are not MS dependent are compared. Nesfatin-1 levels are evaluated in all OSAS patients with and without MS. RESULTS: There were significantly more males in all groups (p = 0.007). There was no significant difference between groups in terms of Nesfatin-1 levels. Nesfatin-1 levels were significantly lower in MS group compared to non-MS group (p = 0.021). CONCLUSION: Nesfatin-1 which is known to play a role in the pathophysiology of insulin resistance can be a beneficial target in developing new therapeutic targets for treatment of patients with obesity without any toxic effects in the future. PMID- 25432329 TI - The effect of 17beta-estradiol on the expression of dipeptidyl peptidase III and heme oxygenase 1 in liver of CBA/H mice. AB - BACKGROUND: 17beta-estradiol (E2) has well-established cardioprotective, antioxidant and neuroprotective role, and exerts a vast range of biological effects in both sexes. Dipeptidyl peptidase III (DPP III) is protease involved as activator in Keap1-Nrf2 signalling pathway, which is important in cellular defense to oxidative and electrophilic stress. It is generally accepted that oxidative stress is crucial in promoting liver diseases. OBJECTIVE: To examine the effect of E2 on the expression of DPP III and haeme oxygenase 1 (HO-1) in liver of adult CBA/H mice of both sexes. METHODS: Gene and protein expressions of studied enzymes were determined by quantitative real-time PCR and Western blot analysis. Immunohistochemistry was performed to analyse the localization of both proteins in different liver cell types. RESULTS: Ovariectomy diminished expression of DPP III and HO-1 proteins. E2 administration abolished this effect, and even increased these proteins above the control. A significant enhancement in DPP III protein was found in E2-treated males, as well. A decrease in the expression of HO-1, but not of the DPP III gene, was detected in the liver of ovariectomized females. HO-1 protein was found localized in the pericentral areas of hepatic lobules (Kupffer cells and hepatocytes), whilst DPP III showed a uniform distribution within hepatic tissue. CONCLUSIONS: We demonstrate for the first time that E2 influences the protein level of DPP III in vivo, and confirm earlier finding on HO-1 gene upregulation by 17beta-estradiol. These results additionally confer new insights into complexity of protective action of E2. PMID- 25432330 TI - Activated macrophages as a feeder layer for growth of resident cardiac progenitor cells. AB - The adult heart contains a population of cardiac progenitor cells (CPCs). Growing and collecting an adequate number of CPCs demands complex culture media containing growth factors. Since activated macrophages secrete many growth factors, we investigated if activated isolated heart cells seeded on a feeder layer of activated peritoneal macrophages (PM) could result in CPCs and if these, in turn, could exert cardioprotection in rats with myocardial infarction (MI). Heart cells of inbred Wistar rats were isolated by collagenase digestion and cultured on PM obtained 72 h after intraperitoneal injection of 12 ml thioglycollate. Cells (1 * 10(6)) exhibiting CPC phenotype (immunohistochemistry) were injected in the periphery of rat MI 10 min after coronary artery occlusion. Control rats received vehicle. Three weeks later, left ventricular (LV) function (echocardiogram) was assessed, animals were euthanized and the hearts removed for histological studies. Five to six days after seeding heart cells on PM, spherical clusters composed of small bright and spherical cells expressing mostly c-Kit and Sca-1 antigens were apparent. After explant, those clusters developed cobblestone like monolayers that expressed smooth muscle actin and sarcomeric actin and were successfully transferred for more than ten passages. When injected in the MI periphery, many of them survived at 21 days after coronary ligature, improved LV ejection fraction and decreased scar size as compared with control rats. CPC derived cells with cardiocyte and smooth muscle phenotypes can be successfully grown on a feeder layer of activated syngeneic PM. These cells decreased scar size and improved heart function in rats with MI. PMID- 25432331 TI - Forgotten research from 19th century: science should not follow fashion. AB - The fine structure of cross-striated muscle and its changes during contraction were known already in considerable detail in the 19th century. This knowledge was the result of studying birefringence properties of muscle fibres under the polarization microscope, a method mainly established by Brucke (Denk Kais Akad Wiss Math Naturwiss Cl 15:69-84, 1858) in Vienna, Austria. The knowledge was seemingly forgotten in the first half of the 20th century before it was rediscovered in 1954. This rediscovery was essential for the formulation of the sliding filament theory which represents the commonly accepted concept of muscle contraction (A.F. Huxley and Niedergerke, Nature 173:971-973, 1954; H.E. Huxley and Hanson, Nature 173:973-976, 1954). The loss of knowledge was the result of prevailing views within the scientific community which could be attributed to "fashion": it was thought that the changes of cross-striations, which were observed under the microscope, were inconsequential for contraction since other types of movements like cell crawling and smooth muscle contraction were not associated with similar changes of the fine structure. The basis for this assumption was the view that all types of movements associated with life must be caused by the same mechanisms. Furthermore, it was assumed that the light microscopy was of little use, because the individual molecules that carry out life functions cannot be seen under the light microscope. This unfortunate episode of science history teaches us that the progress of science can severely be retarded by fashion. PMID- 25432332 TI - A track-event theory of cell survival. AB - PURPOSE: When fractionation schemes for hypofractionation and stereotactic body radiotherapy are considered, a reliable cell survival model at high dose is needed for calculating doses of similar biological effectiveness. In this work a simple model for cell survival which is valid also at high dose is developed from Poisson statistics. MATERIALS AND METHODS: An event is defined by two double strand breaks (DSB) on the same or different chromosomes. An event is always lethal due to direct lethal damage or lethal binary misrepair by the formation of chromosome aberrations. Two different mechanisms can produce events: one-track events (OTE) or two-track-events (TTE). The target for an OTE is always a lethal event, the target for an TTE is one DSB. At least two TTEs on the same or different chromosomes are necessary to produce an event. Both, the OTE and the TTE are statistically independent. From the stochastic nature of cell kill which is described by the Poisson distribution the cell survival probability was derived. RESULTS: It was shown that a solution based on Poisson statistics exists for cell survival. It exhibits exponential cell survival at high dose and a finite gradient of cell survival at vanishing dose, which is in agreement with experimental cell studies. The model fits the experimental data nearly as well as the three-parameter formula of Hug-Kellerer and is only based on two free parameters. It is shown that the LQ formalism is an approximation of the model derived in this work. It could be also shown that the derived model predicts a fractionated cell survival experiment better than the LQ-model. CONCLUSIONS: It was shown that cell survival can be described with a simple analytical formula on the basis of Poisson statistics. This solution represents in the limit of large dose the typical exponential behavior and predicts cell survival after fractionated dose application better than the LQ-model. PMID- 25432333 TI - An alpha-glucosidase inhibitor from an endophytic Cladosporium sp. with potential as a biocontrol agent. AB - This study highlights the importance of alpha-glucosidase inhibitors as mechanisms for endophyte-mediated resistance to insect pests. One of the major benefits which endophytes confer on plants is providing resistance against insect pests. This built-in defense mechanism of the plant can be used for exploring ecofriendly strategies for pest control. In the present study, 34 endophytic fungi were isolated from Tinospora cordifolia and screened for their ability to produce alpha-glucosidase inhibitors. Maximum inhibitory activity was observed in an isolate from T. cordifolia (TN-9S), identified to be Cladosporium sp. The inhibitor was purified using chromatographic techniques. The insecticidal activity of the purified inhibitor was evaluated against Spodoptera litura. The inhibitor induced a significant mortality in the larvae of S. litura and adversely affected its survival and development. It also inhibited the activity of alpha-glycosidases in vivo in the gut of the larvae. The purified inhibitor was determined to be a phenolic compound with amine groups, demonstrating a noncompetitive type of inhibition in vitro. The production of the inhibitor was optimized. Response surface methodology (RSM) analysis revealed a significant interaction between dextrose and malt extract, with first-order effect of pH. PMID- 25432334 TI - Expression, purification, and therapeutic implications of recombinant sFRP1. AB - Secreted frizzled-related proteins (sFRPs) constitute a family of proteins, which impede the Wnt signaling pathway. Upregulation of the Wnt cascade is one of the multiple facets of carcinogenesis. Herein, we report the expression, solubilization, purification, characterization, and anti-cell proliferative activity of a novel recombinant GST-tagged sFRP1 of human origin. sFRP1 was cloned into pGEX-4T2 bacterial expression vector, and the recombinant protein was overexpressed in Escherichia coli BL21 (DE3). It was solubilized from inclusion bodies with N-lauroylsarcosine and Triton X-100, before being purified to homogeneity using glutathione agarose affinity chromatography column. The purified protein was characterized using Western blotting, MALDI TOF-TOF, and circular dichroism spectroscopy analysis. Homology modeling and docking studies revealed that tagging GST with sFRP1 does not change the binding conformation of the cysteine-rich domain and hence, possibly does not alter its function. The novel anti-proliferative activity of GST-sFRP1 was demonstrated in a dose dependent manner on two cancer cell lines, viz., HeLa (cervical cancer) and MCF-7 (breast cancer). Also, combination therapy of the protein with chemotherapeutic drugs resulted in enhanced anti-cancer activity. This opens up a new avenue in the application of recombinant sFRP1 for cancer therapeutics. PMID- 25432335 TI - Insight into microwave-assisted lipase catalyzed synthesis of geranyl cinnamate: optimization and kinetic modeling. AB - Cinnamate esters have gained importance due to their unique antioxidant, flavor, and fragrance properties. Synergism of microwave irradiation and enzyme catalysis was investigated in transesterification of ethyl cinnamate and geraniol. Effects of different operating parameters such as biocatalyst, solvent, and temperature were first studied. An increase in initial rates up to 4.2-fold was observed under microwave irradiation vis-a-vis conventional heating. Further, the Taguchi L16 (4*4) orthogonal array design with four level-four variables and 16 run was employed for the optimization of parameters including enzyme loading, temperature, speed of agitation, and substrate mole ratio. Optimal conditions obtained via the Taguchi approach were as follows: enzyme loading, 60 mg; temperature, 65 degrees C; speed of agitation, 300 rpm; and substrate mole ratio, 1:2. The analysis of initial rate data established the validity of the ternary complex ordered bi-bi mechanism with inhibition by geraniol. The experimental data fitted very well with the model predictions. PMID- 25432336 TI - Overexpression of granulocyte macrophage colony stimulating factor in breast cancer cells leads towards drug sensitization. AB - This report describes the effect of overexpressing granulocyte macrophage colony stimulating factor (GMCSF) in breast cancer cells, which otherwise is involved in proliferation and differentiation of granulocyte and macrophage lineages. The purified recombinant GMCSF cytokine is known to exert dose-dependent proliferative response on various cancer cells, but its effect during overexpression is yet to be evaluated. In our present study, we have generated MCF-7 (breast cancer) cells overexpressing GMCSF. Interestingly, cell viability studies showed pronounced sensitivity of GMCSF overexpressing MCF-7 cells towards anticancer drugs, such as, doxorubicin, 5FU and cisplatin. These findings were substantiated by cell cycle analysis of the drug-treated GMCSF overexpressing MCF 7 cells. Semiquantitative reverse transcriptase-polymerase chain reaction (RT PCR) results revealed differential expressions of cyclins, and the carboxyfluorescein succinimidyl ester (CFSE)-based assay established decrease in doubling time of GMCSF overexpressed cells with respect to the control populations. Thus, overexpressing of proliferative GMCSF cytokine in breast cancer cells may increase susceptibility to anticancer drugs. PMID- 25432337 TI - A substrate-based approach for the selection of oil-bearing heterotrophs from nitrogen-deficient soil for lipid production. AB - In this study, nine heterotrophic yeast isolates were tested for their ability to assimilate crude glycerol and consecutive conversion to triacylglycerides (TGAs). All the organisms were initially screened on crude glycerol-based selection media, and those producing lipid globules were further evaluated for lipid production. Sudan Black B staining of eight isolates showed lipid globules. These strains were further studied at different C/N ratio. The molecular identification revealed that the isolates belonged to the genera of Yarrowia and Candida. Among these isolates, SKY7 (Yarrowia lipolytica) produced up to 42.04 +/- 0.11 % of lipid w/w) with a C/N ratio of 100 and fermentation time of 72 h. The other strains produced 5.82 +/- 0.4 to 34.57 +/- 0.44 % lipid (w/w). The GC-flame ionization detector (FID) lipid profile showed that the lipid produced by the strains had close resemblance with vegetable oil and could serve as a feedstock for biodiesel production. Biolog test of the isolates revealed a wide spectrum of carbon utilization. PMID- 25432338 TI - Enrichment and identification of cellulolytic bacteria from the gastrointestinal tract of Giant African snail, Achatina fulica. AB - The cellulolytic bacterial community structure in gastrointestinal (GI) tract of Achatina fulica was studied using culture-independent and -dependent methods by enrichment in carboxymethyl cellulose (CMC). Culture-dependent method indicated that GI tract of snail was dominated by Enterobacteriaceae members. When tested for cellulase activities, all isolates obtained by culture-dependent method showed both or either of CMCase or avicelase activity. Isolate identified as Citrobacter freundii showed highest CMCase and medium avicelase activity. Sequencing of clones from the 16S rRNA gene clone library identified ten operational taxonomic units (OTUs), which were affiliated to Enterobacteriaceae of phylum Gammaproteobacteria. Of these ten OTUs, eight OTUs closely matched with Enterobacter and Klebsiella genera. The most abundant OTU allied to Klebsiella oxytoca accounted for 70 % of the total sequences. The members of Klebsiella and Enterobacter were observed by both methods indicating their dominance among the cellulolytic bacterial community in the GI tract of the snail. PMID- 25432340 TI - The oxidative stress of Phanerochaete chrysosporium against lead toxicity. AB - Among the technologies for heavy metal remediation, bioremediation technology has gained extensive attention because of its low processing costs and high efficiency. The white-rot fungus Phanerochaete chrysosporium (P. chrysosporium) which has a good tolerance to heavy metals has been widely used in the heavy metal bioremediation. In order to figure out the molecular mechanisms involved in the oxidative stress of P. chrysosporium against metal toxicity, we examined the effect of Pb(2+) on the levels of reactive oxygen species and the production of malondialdehyde. Results showed that P. chrysosporium could adjust Pb-stressed condition by regulating the unique oxidation-antioxidation process in cells and kept a balance between oxidation and antioxidation when it was threatened by a different dose of Pb(2+). Investigations into the oxidative stress of P. chrysosporium to lead could not only provide a better understanding of the relationship between lead and oxidative stress in P. chrysosporium, but also offer important informations on the development of fungal-based remediation technologies to reduce the toxic effects of lead. PMID- 25432339 TI - Toxicity, activation process, and histopathological effect of Bacillus thuringiensis vegetative insecticidal protein Vip3Aa16 on Tuta absoluta. AB - Tuta absoluta is a destructive moth of Solanaceae plants and especially tomatoes. Here, we considered the entomopathogenic activity of the Bacillus thuringiensis Vip3Aa16 protein heterologously produced by Escherichia coli against T. absoluta. Purified Vip3Aa16 showed lower lethal concentration 50 % against third instar larvae (Toxin/tomato leaf) (335 +/- 17 ng/cm(2)) compared to that of B. thuringiensis kurstaki HD1 delta-endotoxins (955 +/- 4 ng/cm(2)) (P < 0.05). Action mode examination showed that Vip3Aa16 (88 kDa) was more sensitive to proteolysis activation by the chymotrypsin than the trypsin or the larvae gut soluble proteases, yielding derivative proteins essentially of about 62 and 33 kDa. The gut-soluble proteases could contain trypsin-like enzymes implicated in Vip3Aa16 activation since the proteolysis was inhibited using specific protease inhibitors. Additionally, we showed that the histopathological effect of Vip3Aa16 on T. absoluta larva midguts consisted on a microvillus damage and an epithelial cell rupture. PMID- 25432341 TI - Importance of the matrix and the matrix/sample ratio in MALDI-TOF-MS analysis of cathelicidins obtained from porcine neutrophils. AB - Qualitative and quantitative mass spectrometric studies of biomolecules for example proteins, peptides, or lipids contained in biological samples like physiologic fluids are very important for many fields of science such as medicine, veterinary medicine, biology, biochemistry, molecular biology, or environmental sciences. In the last two decades, MALDI TOF MS - matrix-assisted laser desorption mass spectrometry, proved to be an especially convenient tool for these analyses. The main advantages of this method are its rapidity and high sensitivity which is particularly appreciated in the case of studies of complex biological specimen. A major challenge for many researchers is to maximize this sensitivity, among others, by appropriate procedures of sample preparation for the measurement. The objective of this work was to optimize these procedures, selecting the optimal matrix and optimum proportions of the sample and the matrix solution in a mixture of both solutions, aiming at the achievement of the maximum intensity of ion current. In this respect, five low molecular mass cathelicidins were studied: prophenin-2, protegrins 1-3, PR-39. All of them were obtained directly from the porcine blood. As a result of studies, the authors determined such experimental conditions when the intensity of investigated ionic current had the highest value. PMID- 25432342 TI - Simultaneous heterotrophic nitrification and aerobic denitrification by the marine origin bacterium Pseudomonas sp. ADN-42. AB - Recent research has highlighted the existence of some bacteria that are capable of performing heterotrophic nitrification and have a phenomenal ability to denitrify their nitrification products under aerobic conditions. A high-salinity tolerant strain ADN-42 was isolated from Hymeniacidon perleve and found to display high heterotrophic ammonium removal capability. This strain was identified as Pseudomonas sp. via 16S rRNA gene sequence analysis. Gene cloning and sequencing analysis indicated that the bacterial genome contains N2O reductase function (nosZ) gene. NH3-N removal rate of ADN-42 was very high. And the highest removal rate was 6.52 mg/L . h in the presence of 40 g/L NaCl. Under the condition of pure oxygen (DO >8 mg/L), NH3-N removal efficiency was 56.9 %. Moreover, 38.4 % of oxygen remained in the upper gas space during 72 h without greenhouse gas N2O production. Keeping continuous and low level of dissolved oxygen (DO <3 mg/L) was helpful for better denitrification performance. All these results indicated that the strain has heterotrophic nitrification and aerobic denitrification abilities, which guarantee future application in wastewater treatment. PMID- 25432343 TI - Enzymatic activities in different strains isolated from healthy and brittle leaf disease affected date palm leaves: study of amylase production conditions. AB - The present study aimed to investigate and compare the enzymatic production of endophytic bacteria isolated from healthy and brittle leaf disease affected date palm leaves (pectinase, cellulase, lipase, and amylase). The findings revealed that the enzymatic products from the bacterial isolates of healthy date palm leaves were primarily 33% amylolytic enzyme, 33 % cellulase, 25 % pectinase, and 25 % lipase. The isolates from brittle leaf disease date palm leaves, on the other hand, were noted to produce 16 % amylolytic enzyme, 20 % cellulose, 50 % pectinase, and 50 % lipase. The effects of temperature and pH on amylase, pectinase, and cellulose activities were investigated. The Bacillus subtilis JN934392 strain isolated from healthy date palm leaves produced higher levels of amylase activity at pH 7. A Box Behnken Design (BBD) was employed to optimize amylase extraction. Maximal activity was observed at pH and temperature ranges of pH 6-6.5 and 37-39 degrees C, respectively. Under those conditions, amylase activity was noted to be attained 9.37 U/ml. The results showed that the enzyme was able to maintain more than 50 % of its activity over a temperature range of 50-80 degrees C, with an optimum at 70 degrees C. This bacterial amylase showed high activity compared to other bacteria, which provides support for its promising candidacy for future industrial application. PMID- 25432344 TI - Use of natural pH variation to increase the flocculation of the marine microalgae Nannochloropsis oculata. AB - Microalgae is largely used in aquaculture as feed. More recently, these microorganisms have been considered as an important feedstock for biodiesel production. However, the concentration of produced biomass represents a large parcel of production costs. In this study, we have evaluated the influence of natural pH variation of culture medium, caused by photosynthetic activity, on the flocculation of the marine microalgae Nannochloropsis oculata. Experiments were conducted with the same culture with different pH values (8.5 and 9.6), obtained after exposing the cells to different light conditions. For each pH value, different treatments were composed by adding 0, 5, 10, and 30 mM of NaOH and the flocculant Flopam(r) (FO4800 SH) at concentrations of 0, 0.5, 1, and 5 ppm. Higher flocculation efficiencies were obtained for the culture with pH 9.6 in comparison to 8.5 for the same NaOH and Flopam concentrations. Lower concentrations of base and flocculant were needed for flocculating the culture in higher pH, representing an economy of 20 % in the costs of crop harvesting. PMID- 25432345 TI - Production and purification of anti-bacterial biometabolite from wild-type Lactobacillus, isolated from fermented bamboo shoot: future suggestions and a proposed system for secondary metabolite onsite recovery during continuous fermentation. AB - Wild-type lactobacillus isolated form Khorisa, a fermented bamboo shoot product of Assam, India were evaluated for production anti-bacterial secondary biometabolites, against Staphylococcus aureus. Submerged fermentation technique was used for the production of secondary anti-microbial biometabolite by a single wild-type lactobacillus strain, which tested positive for the release of anti bacterial factor(s). Crude cell-free supernatant was obtained, followed by extraction in water-immiscible solvents viz., chloroform, hexane, petroleum ether. Chloroform extract of cell-free crude supernatant showed maximum yield (0.054 g/ml) and inhibited all indicator bacterial strains viz., Escherichia coli, Staphylococcus aureus, and Bacillus cereus. Yields of hexane and petroleum ether extract were 0.052 and 0.026 g/ml, respectively. Minimum lethal dose concentration assay of the chloroform extract showed LDmin values at 27, 1.68, and 1.68 mg/ml for E. coli, S. aureus, and B. cereus, respectively. Kill time for all the indicator bacterial strains were less than 12 h. The efficacy of the anti bacterial substance seemed to depend on the presence of organic acids, particularly lactic acid. Conceptual-based suggestion for the development of an onsite secondary metabolites recovery system during continuous fermentation has also been attempted. PMID- 25432346 TI - A new GH43 alpha-arabinofuranosidase from Humicola insolens Y1: biochemical characterization and synergistic action with a xylanase on xylan degradation. AB - A new alpha-arabinofuranosidase gene (Hiabf43) was cloned from Humicola insolens Y1 and successfully expressed in Pichia pastoris GS115. Deduced HiAbf43 contained a putative signal peptide and a catalytic domain of glycoside hydrolase (GH) family 43. Purified recombinant HiAbf43 showed optimal activity at pH 5.0 and 50 degrees C, and was active over a broad pH range. The enzyme was specific for the cleavage of alpha-1,3-linkage and showed high activity against 4-nitrophenyl alpha-L-arabinofuranoside, debranched arabinan, and sugar beet arabinan. Sequential addition of HiAbf43 followed by Xyn11A increased the degradation efficiency of birchwood and beechwood xylans but not wheat arabinoxylan. The synergy degree was high up to 1.21-fold. PMID- 25432347 TI - Purification, characterization, and mitogenic potential of a mucin-specific mycelial lectin from Aspergillus sparsus. AB - Lectins are carbohydrate binding proteins or glycoproteins that bind reversibly to specific carbohydrates present on the apposing cells, which is responsible for their ability to agglutinate red blood cells, lymphocytes, fibroblasts, etc. Due to their carbohydrate specificity, lectins have been used for purification and characterization of glycoproteins like antibodies, cytokines, tumor-associated glycoproteins, hormones, inhibitors, growth factors, various enzymes, membrane proteins (receptors), or even toxins and viruses. In the present study, a mycelial lectin from Aspergillus sparsus was purified, characterized, and evaluated for its mitogenic potential. Lectin could be effectively purified 17.8 fold in a single-step using affinity chromatography on mucin-sepharose column. Lectin migrated as a single band in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) with an apparent molecular mass of 100.2 kDa. Lectin showed pH optima of 6.5-8.0, and optimum temperature was determined to be 20-30 degrees C. Lectin was stable within a pH range of 5.5-10.0 and showed fairly good thermostability. Lectin activity was unaffected in the presence of EDTA, while activity reduced upon interaction with denaturants. MTT assay revealed strong mitogenic potential of A. sparsus lectin at a concentration up to 100 MUg/ml. PMID- 25432348 TI - Isolation of filamentous fungi exhibiting high endoxylanase activity in lignocellulose hydrolysate. AB - For complete degradation of hemicellulose into its monomers from lignocellulose biomass, the synergistic action of a broad range of hydrolytic enzymes is needed. Therefore, production of enzymes from their natural producer is desirable. To obtain a powerful beta-1,4-endoxylanase producing fungus, 304 environmental samples were collected from various locations in Singapore, leading to 603 isolates. Among them, 71 exhibiting beta-1,4-endoxylanase activity were identified belonging mainly to the genera of Aspergillus, Penicillium, and Trichoderma. Further analysis revealed Aspergillus niger DSM 26641 as a potential and stable beta-1,4-endoxylanase producer, being able to grow in hydrothermal lignocellulose hydrolysate exhibiting its maximal beta-1,4-endoxylanase activity at pH 4 and 60 degrees C. This strain is thought to be very suitable for lactic acid production in a simultaneous saccharification and fermentation at pH values below 5. PMID- 25432349 TI - Health adaptation policy for climate vulnerable groups: a 'critical computational linguistics' analysis. AB - BACKGROUND: Many countries are developing or reviewing national adaptation policy for climate change but the extent to which these meet the health needs of vulnerable groups has not been assessed. This study examines the adequacy of such policies for nine known climate-vulnerable groups: people with mental health conditions, Aboriginal people, culturally and linguistically diverse groups, aged people, people with disabilities, rural communities, children, women, and socioeconomically disadvantaged people. METHODS: The study analyses an exhaustive sample of national adaptation policy documents from Annex 1 ('developed') countries of the United Nations Framework Convention on Climate Change: 20 documents from 12 countries. A 'critical computational linguistics' method was used involving novel software-driven quantitative mapping and traditional critical discourse analysis. RESULTS: The study finds that references to vulnerable groups are relatively little present or non-existent, as well as poorly connected to language about practical strategies and socio-economic contexts, both also little present. CONCLUSIONS: The conclusions offer strategies for developing policy that is better informed by a 'social determinants of health' definition of climate vulnerability, consistent with best practice in the literature and global policy prescriptions. PMID- 25432351 TI - Identification of patient profile for treatment. AB - The WHO clinical definition of osteoporosis, based on a measurement of bone mineral density (BMD) by Dual Energy X-ray Absorptiometry, has been used globally since the mid-1990s. However, although this definition identifies those at greatest individual risk of fracture, in the population overall a greater total number of fractures occur in individuals with BMD values above the osteoporosis threshold. The inclusion of clinical risk factors, with or without BMD, in fracture prediction algorithms can improve the identification of individuals at high fracture risk; thus a number of web-based tools have been developed, the most commonly used globally being FRAX((r)). In this review, we will discuss the epidemiology of osteoporosis, clinical risk factors for fragility fracture, and how this knowledge is being used to aid risk stratification. Importantly, research is on-going to demonstrate the clinical efficacy and cost-effectiveness of such case-finding strategies. PMID- 25432352 TI - Pharmacogenetics of osteoporosis. AB - The challenge of personalized medicine is to move away from the traditional 'one size-fits-all' pharmacology to genotype-based individualized therapies. As an individual's response to drugs is under the control of genes, personal genetic profiles could help clinicians to predict individual drug response and prescribe the right drug and dose, thereby optimising efficacy and avoiding risk of adverse effects. Currently, the concrete application of pharmacogenetics into clinical practice is limited to a few drugs, and the genetic prediction of drug response is far from clear for many of thve principal complex disorders. This is even more evident in the field of osteoporosis and metabolic bone disorders, for which few pharmacogenetic studies have been conducted, and no conclusive results are available. In this chapter, we review recent research on pharmacogenetics of osteoporosis, evaluate criticisms, and offer possible suggestions for improvements in this field and for possible future applications into clinical practice. PMID- 25432353 TI - Nutritional aspects of bone health. AB - Bone mass, geometry and microstructure, and bony tissue material level properties determine bone strength, hence the resistance to fracture. At a given age, all these variables are the consequence of the amount accumulated and of the structure developed during growth, up to the so-called peak bone mass, and of the bone loss and microstructure degradation occurring later in life. Genetic factors primarily contribute to the variance of the determinants of bone strength. Nutritional intakes are environmental factors that influence both processes, either directly by modifying modelling and remodelling, or indirectly through changes in calcitropic hormone secretion and action. Some effects of nutrition on the offspring bone could take place during foetal life. There are interplays between genetic factors, nutritional intakes and physical exercise. Among the nutrients, sufficient dietary intakes of calcium and protein are necessary for bone health in childhood and adolescence as well as later in life. PMID- 25432355 TI - Monitoring of osteoporosis therapy. AB - Over the past two decades, major advances have been made in the number and range of agents available for the treatment of osteoporosis, all with proven anti fracture efficacy. Unfortunately, compliance with these treatments is not optimal, and a number of patients could be considered as non-responders. Consequently, monitoring anti-osteoporotic therapy could be part of successful osteoporosis management. Currently, no formal well-accepted clinical practice guidelines are available for monitoring anti-osteoporosis therapies. Changes in bone mineral density and bone turnover markers, while on therapy, have potential value in monitoring treatment but their assessment and, consequently, their benefits could be limited by metrological and clinical issues. Moreover, their effectiveness is probably drug dependant. Recommendation for the standardisation of the methodology when analysing the potential relevance of tools for the monitoring of osteoporosis therapy is needed. PMID- 25432354 TI - Efficacy and safety of currently marketed anti-osteoporosis medications. AB - During the past 2 decades, many interventions were proven effective in the management of postmenopausal osteoporosis. The objective of an anti-osteoporosis treatment is to reduce fracture rates, ideally at all skeletal sites (i.e. spine, hip, and other non-spine). The armamentarium against osteoporosis includes anti resorptive agents (i.e. bisphosphonates, selective estrogen receptor modulators and denosumab), bone-forming agents (i.e. peptides from the parathyroid hormone family) and one agent with a dual mechanism of action (i.e. strontium ranelate). All these medications combine antifracture efficacy with a reasonable benefit/risk profile. However, the choice of a particular chemical entity, in one individual patient is based on the knowledge and expertise of the physician. Prioritization of drugs should be based on the individual profile of the patient, the severity of osteoporosis and the specific contraindications, warnings and precautions of use of the various available medications. PMID- 25432356 TI - Novel approaches to the treatment of osteoporosis. AB - Despite the availability of efficacious treatments for fracture reduction in patients with osteoporosis, there are still unmet needs requiring a broader range of therapeutics. In particular, agents that are capable of replacing already lost bone and that also drastically reduce the risk of non-vertebral fractures are needed. Studies of rare bone diseases in humans and animal genetics have identified targets in bone cells for the development of therapies for osteoporosis with novel mechanisms of action. Here, we review these new developments, with emphasis on inhibitors of cathepsin K in osteoclasts and sclerostin in osteocytes, which are currently studied in phase 3 clinical trials. PMID- 25432357 TI - Future directions for new medical entities in osteoporosis. AB - Odanacatib, a selective cathepsin K inhibitor, decreases bone resorption, whereas osteoclast number increases and bone formation is maintained, perhaps even increased on some cortical surfaces. In a phase 2 clinical trial, post-menopausal women receiving odanacatib presented a sustained reduction of bone resorption markers, whereas procollagen type 1 N-terminal propeptide returned to normal. In turn areal bone mineral density increased continuously at both spine and hip for up to 5 years. Blosozumab and romosozumab are sclerostin neutralizing antibodies that exert potent anabolic effects on both trabecular and cortical compartments. A phase 2 clinical trial has reported areal bone mineral density gains at spine and hip that were greater with romosozumab compared with placebo, but also with teriparatide. It also showed that antagonizing sclerostin results in a transient stimulation of bone formation but progressive inhibition of bone resorption. Other new medical entities that are promising for the treatment of osteoporosis include abaloparatide, a parathyroid hormone-related analogue with improved bone formation-resorption ratio. PMID- 25432358 TI - Current and future treatments of osteoporosis in men. AB - One in three osteoporotic fractures occur in men and the consequences of a fracture in men tend to be more severe than in women. Still, only a small minority of men with high risk of fracture are detected and treated. Although there are gender differences in the pathophysiology of osteoporosis, such as in the pattern of bone loss, similarities predominate, which is also the case for clinical risk factors. It seems appropriate to consider treatment for men and women with a similar 10 year fracture risk. Drugs now approved for treatment of osteoporosis in men include the anti-resorptive bisphosphonates alendronate, residronate and zoledronic acid, the anti-resorptive drug denosumab, the bone forming agent teriparatide, and (not in the US) strontium ranelate with mild opposite effects on resorption and formation. Although the evidence level for efficacy and safety of these drugs in men is still relatively limited, available data indicate that treatment effects in men are very similar to what has been observed in the treatment of postmenopausal osteoporosis. Denosumab is also approved for treatment in men receiving androgen deprivation therapy for non metastatic prostate cancer; bisphosphonates and teriparatide are also available to clinicians for treatment of glucocorticoid-induced osteoporosis in men. Testosterone treatment may be indicated in men with documented symptomatic hypogonadism, but osteoporosis is neither a sufficient nor a specific indication for testosterone treatment. New compounds with well advanced clinical development include odanacatib, a selective inhibitor of the cysteine protease cathepsin-K, and romosozumab, a monoclonal antibody against sclerostin. PMID- 25432359 TI - Current and future treatments of secondary osteoporosis. AB - Osteoporosis is commonly associated with menopause and ageing. It can, however, also be caused by diseases, lifestyle, genetic diseases, drug therapies and other therapeutic interventions. In cases of secondary osteoporosis, a common rule is the management of the underlying condition. Healthy habits and calcium and vitamin D supplementation are also generally advised. In cases of high risk of fracture, specific antiosteoporosis medications should be prescribed. For most conditions, the available evidence is limited. Special attention should be paid to possible contraindications of drugs used for the treatment of postmenopausal or senile osteoporosis. Bisphosphonates are the most widely used drugs in secondary osteoporosis, and denosumab or teriparatide have been also assessed in some cases. Important research is needed to develop more tailored strategies, specific to the peculiarities of the different types of secondary osteoporosis. PMID- 25432360 TI - The application of health technology assessment in osteoporosis. AB - Because of the high costs to patients, health care payers and to society, it is important to allocate healthcare resources appropriately and efficiently. Health technology assessment aims to evaluate the clinical, economic, social, and ethical implications of a disease, and its prevention and treatment to guide national healthcare policies (e.g. clinical and research investment, reimbursement decisions). In this chapter, we review the various aspects of health technology assessment in osteoporosis, including epidemiology and burden of disease, and assessment of the cost-effectiveness of the treatment of osteoporosis and the prevention of fracture. Health technology assessment indicates an immense burden of osteoporotic fractures for patients and society that is set to increase as the number of elderly people increases. Prevention and treatment of osteoporosis have been shown to be a cost-effective way of allocating scarce healthcare resources. PMID- 25432361 TI - Secondary osteoporosis: pathophysiology & diagnosis. AB - Osteoporosis is a skeletal disease characterized by decreased bone mass and microarchitectural changes in bone tissue that increase the susceptibility to fracture. Secondary osteoporosis is loosely defined as low bone mineral density or increased risk of fragility fracture caused by any factor other than aging or postmenopausal status. The purpose of this review is to discuss the current understanding of the pathophysiology and contribution to fracture risk of many of the more common causes of secondary osteoporosis, as well as diagnostic considerations, outlined by organ system. While not comprehensive, included are a wide array of diseases, conditions, and medications that have been associated with bone loss and susceptibility to fractures. The hope is to highlight the importance to the general clinician of screening for and treating the osteoporosis in these patients, so to limit the resultant increased morbidity associated with fractures. PMID- 25432362 TI - The effect of photopolymerization on the degree of conversion, polymerization kinetic, biaxial flexure strength, and modulus of self-adhesive resin cements. AB - STATEMENT OF PROBLEM: Understanding the effect of the degree of conversion on the mechanical properties of auto- and dual-polymerizing self-adhesive resin cements leads to a better estimation of their performance in different clinical scenarios. PURPOSE: The purpose of this study was to evaluate the effect of photopolymerization on the degree of conversion (DC) and polymerization kinetic of 4 dual-polymerized resin cements, 20 minutes after mixing, and its effects on the mechanical properties (biaxial flexural strength [FS] and modulus [FM]) after short-term aging. MATERIAL AND METHODS: Conventional (RelyX ARC and Clearfil Esthetic Cement) and self-adhesive resin cements (RelyX Unicem and Clearfil SA Cement) were applied to a Fourier infrared spectrometer to assess the DC (n=5) under the following 3 polymerization conditions: direct light exposure (dual polymerizing mode), exposure through the prepolymerized disk, or autopolymerizing. The polymerization kinetic was recorded for 20 minutes. Then, disk-shaped specimens (n=11) were prepared to evaluate the effect of polymerization on the FS and FM in both extreme polymerization conditions (dual polymerizing or autopolymerizing). Data were statistically analyzed by 2-way repeated measure ANOVA (DC) and by 2-way ANOVA (FS and FM), followed by the Tukey Kramer post hoc test (alpha=.05). RESULTS: Autopolymerizing groups exhibited reduced DC means, whereas intermediate values were observed when resin cements were polymerized through the disk. All groups exhibited higher DC at the end of 20 minutes. The polymerization kinetic revealed a rising curve, and materials, when directly photopolymerized, reached a plateau immediately after light exposure. Regarding the flexural biaxial testing, most of the resin cements were affected by polymerization mode and differences among groups were product dependent. CONCLUSIONS: The resin cements achieved immediate higher DC and mechanical properties when photopolymerized. The total absence of photoactivation may still impair their mechanical properties even after short-term aging. PMID- 25432363 TI - Association between oral candidiasis and low CD4+ count among HIV positive patients in Hoima Regional Referral Hospital. AB - BACKGROUND: The aim of this study was to determine the prevalence of Human Immune Virus (HIV) related oral lesions and their association with Cluster of Differentiation 4 (CD4+) count among treatment naive HIV positive patients. METHODS: This was a descriptive and analytical cross sectional study. Participants were 346 treatment naive HIV positive adult patients. These were consecutively recruited from Hoima Regional Referral hospital between March and April 2012. Data collection involved interviews, oral examinations and laboratory analysis. RESULTS: A total of 168(48.6%) participants had oral lesions. The four commonest lesions were oral candidiasis (24.9%, CI = 20.6-29.7%), melanotic hyperpigmentation (17.3%, CI = 13.7-21.7%), kaposi sarcoma (9.3%, CI = 6.6-12.8%) and Oral Hairy Leukoplakia (OHL) (5.5%, CI = 3.5-8.4%). There was significant association between oral candidiasis and immunosuppression measured as CD4+ less than 350 cells/mm3 (OR = 2.69, CI = 1.608-4.502, p < 0.001). Oral candidiasis was the only oral lesion significantly predictive of immunosuppression (OR = 2.56, CI = 1.52-4.30, p < 0.001) with a Positive Predictive Value (PPV) of 48.2%, Negative Predictive Value (NPV) of 74.3%, 38.1% sensitivity and specificity of 81.4%. CONCLUSION: Oral candidiasis can be considered as a marker for immunesuppression, making routine oral examinations essential in the management of HIV positive patients. PMID- 25432364 TI - Cardioprotective efficacy depends critically on pharmacological dose, duration of ischaemia, health status of animals and choice of anaesthetic regimen: a case study with folic acid. AB - BACKGROUND: Acute, high-dose folic acid (FA) administration has recently been shown to possess unprecedented effective cardioprotection against ischaemia/reperfusion (I/R) injury. Here we explore the translation potential of FA as treatment modality for cardiac I/R. METHODS: Dependency of FA protection on dose, ischaemia duration, and eNOS was examined in an isolated mouse heart I/R model, whereas dependency on animal health status and anaesthesia was examined in an in vivo rat model of regional cardiac I/R. RESULTS: 50 MUM FA provided maximal reduction (by 95%) of I/R-induced cell death following 25 min ischaemia in isolated wild-type hearts, with protection associated with increased coupled eNOS protein. No protection was observed with 35 min I or in eNOS(-/-) hearts. Acute intravenous administration of FA during a 25 min ischaemic period reduced infarct size by 45% in in vivo pentobarbital-anaesthetised young, healthy rats. FA did not reduce infarct size in aged or pre-diabetic rats, although it did preserve hemodynamics in the pre-diabetic rats. Finally, using a clinically-relevant anaesthetic regimen of fentanyl-propofol anaesthesia, FA treatment was ineffective in young, aged and pre-diabetic animals. CONCLUSIONS: The protective potential of an initially promising cardioprotective treatment of high dose FA against cardiac I/R infarction, is critically dependent on experimental conditions with relevance to the clinical condition. Our data indicates the necessity of expanded pre-clinical testing of cardioprotective interventions before embarking on clinical testing, in order to prevent too many "lost-in translation" drugs and unnecessary clinical studies. PMID- 25432365 TI - [ITF increases the transcriptional activity of ITF promoter via the JAK-STAT3 signal transduction pathway]. AB - OBJECTIVE: To investigate the eff ect of intestinal trefoil factor (ITF) on the transcriptional activity of ITF promoter and to explore the regulatory mechanism of Janus kinase/signal transducers and activators of transcription (JAK/STAT) on ITF promoter. METHODS: The 5' flanking sequence of the ITF gene was cloned from human whole blood genomic DNA by PCR. ITF promoter fragment was cloned and inserted into the pGL3-Basic vector to construct recombinant vector. ITF promoter vector was stimulated with ITF at various concentrations and the luciferase activity was measured. The JAK-STAT3 signal transduction pathway was then blocked by a specific inhibitor AG490 to determine the signal pathway involved in ITF promoter activity. RESULTS: Restriction endonuclease analysis and DNA sequencing confirmed that the recombinant plasmid, containing ITF promoter, was constructed successfully. After transient transfection, the activity of ITF promoter was increased significantly in the presence of ITF (P<0.05). Blockage of the JAK STAT3 signal transduction pathway with AG490 significantly reduced the ITF promoter activity (P<0.05). CONCLUSION: ITF increases the transcriptional activity of ITF promoter via the JAK-STAT3 signal transduction pathway. PMID- 25432366 TI - [Effect of lavage with artificial cerebrospinal fluid on neural cell apoptosis and the ERK pathway after rat traumatic brain injury]. AB - OBJECTIVE: To explore the eff ect of lavage with artificial cerebrospinal fluid on neural cell apoptosis and the extracellular regulated kinase (ERK) pathway aft er traumatic brain injury. METHODS: A total of 192 SD rats were randomly divided into a sham group, a traumatic brain injury model group, a local artificial cerebrospinal fluid group, and a local saline group. Each group was divided into 4 sub-groups by the sacrificed time at 6 h, 12 h, 1 d and 3 d aft er the operation. Th e phosphorylation of extracellular regulated kinase 2 (P-ERK2), TNF alpha and cellular apoptosis were examined. RESULTS: Th e levels of P-ERK2 protein and TNF-alpha protein, as well as the number of apoptotic cells at each time point in the local artificial cerebrospinal fluid group were lower than those in the model group or in the saline group (P<0.05). CONCLUSION: Lavage with artificial cerebrospinal fluid can reduce apoptosis of neural cells after brain injury through the ERK pathway. PMID- 25432367 TI - [Meta-analysis for correlation between multiple lung lobe lesions and prognostic influence on acquired pneumonia in hospitalized elderly patients]. AB - OBJECTIVE: To explore the correlation regarding the prognostic influence between multiple lung lobe lesions and acquired pneumonia in hospitalized elderly patients by a Meta-analysis. METHODS: We collected all studies which investigated the correlation regarding the prognostic effect between multiple lung lobe lesions and acquired pneumonia by searching China National Knowledge Infrastructure, Wanfang Database, Chinese Science and Technology Periodical Database, Chinese Biological Medical Literature Database, PubMed, and EMBase in accordance with the inclusion and exclusion criteria. Th e retrieval limit time of searches was from databases establishment to July 2014. Th e Meta-analysis was performed by using RevMan5.2 soft ware. We calculated the odds ratio (OR) and 95% confidence interval (95% CI) by using heterogeneous tests. Publication bias was assessed by Egger's test and funnel plot, and the sensitivity was analyzed. RESULTS: Ten studies involving 1 836 patients were finally included, with 487 cases (the dead group) and 1 349 controls (the survival group). The Meta-analysis demonstrated that multiple lung lobe lesions was highly correlated with the prognosis for the aged acquired pneumonia (OR=3.22, 95% CI 1.84 to 5.63). CONCLUSION: Multiple lung lobe lesions increase the risk of death in the prognosis of the aged patients with acquired pneumonia. PMID- 25432368 TI - [Relationship between FAT10 expression and biological behaviors in infitrating ductal carcinoma of breast]. AB - OBJECTIVE: To study the relationship between FAT10 expression and biological behaviors in infitrating ductal carcinoma of breast. METHODS: The expressions of diubiquitin (FAT10), estrogen receptor (ER), progesterone receptor (PR) and c erbB2 in 50 cases of infitrating ductal carcinoma of breast were detected by immunohistochemistry. Western blot was used to detect FAT10 expression in MB-MDA 435, MB- MDA-435-transfected with FAT10 siRNA expression plasmid, MCF-7 and MCF-7 transfected with FAT10 expression plasmid, respectively. Transwell was used to detect invasion capability of MB- MDA-435, MB-MDA-435-transfected with FAT10 siRNA expression plasmid, MCF-7 and MCF-7-transfected with FAT10 expression plasmid. RESULTS: The expression intensity of FAT10 was significantly correlated to patho-grading, lymph nodes metastasis, distant metastasis and TNM staging (P<0.01), but not to age of patients and tumor sizes in infitrating ductal carcinoma of breast (P>0.05). The expression intensity of FAT10 in receptor- negative group was obviously stronger than that in receptor- positive group (P<0.01). The expression intensity of FAT10 in triple-negative breast cancer was significantly stronger than that in non- triple-negative breast cancer (P<0.01). The survival rate of patients with FAT10 positive expression was significantly lower than negative ones (P<0.05). Western blot results showed that FAT10 intensity in MB-MDA-435 significantly higher than that in MCF-7. Up-regulation expression of FAT10 could obviously increase the invasion capability of MCF-7, and downregulation of FAT10 could significantly decrease the invasion capability of MB-MDA-435 (P<0.01). CONCLUSION: FAT10 might increase the invasion capability of breast cancer cells by direct or indirect ways, and play an important role in invasion and metastasis of breast cancer. FAT10 might be an independent index for evaluation of breast cancer prognosis, and a potential target for breast cancer therapy, especially for triple-negative breast cancer. PMID- 25432369 TI - [Clinical study on chemotherapy of lobaplatin combined with docetaxel in patients with relapsed ovarian cancer]. AB - OBJECTIVE: To evaluate the efficacy and safety of lobaplatin combined with docetaxel in the treatment of the recurrent ovarian carcinoma. METHODS: We collected 31 patients who diagnosed as recurrent ovarian carcinoma according to the histopathology or cytology from Tumor Hospital of Hunan Province from January 2011 to January 2013. The patients received cisplatin-based chemotherapy or carboplatin-based chemotherapy before the combined chemotherapy of docetaxel and lobaplatin. For patients with the recurrence, they received a treatment at a dose of 80 mg/m2 for docetaxel on day 1 and a dose of 30 mg/m2 for lobaplatin on day 2, which lasted for 21 days as a treatment cycle. Th e patients received 6-cycle treatment at most. RESULTS: A total of 153 cycles of chemotherapy were given to 31 patients, with a median of 4 (2-6) cycles. Three patients showed complete response, 11 partial response, 2 stable disease, and 15 progressive disease. The objective response rate (ORR) was 45.16% (95% CI, 26.61%-63.72%), and the disease control rate (DCR) was 51.63% (95% CI, 32.98%-70.25%). The median progression free survival was 7 months (95% CI, 4.27-9.73 months). For the toxic and side effects among the 31 patients, the numbers of the grade 3, grade 2, and grade 1 leukopenia were 1, 8, and 13, respectively. Meanwhile, 18 were grade 1-2 neutropenia, 17 grade 1-2 anemia, and 2 grade 1 thrombocytopenia. At the same time, alimentary canal reaction followed by nausea and vomiting was relatively modest and could be controlled. The serious damage of hepatic-renal function was not found. CONCLUSION: The chemotherapy of lobaplatin combined with docetaxel is effective on recurrent and refractory ovarian cancer with low side effects, which has advantages over the second-line chemotherapy protocols. PMID- 25432370 TI - [Protective effect of minocycline on hepatic ischemia-reperfusion injury in rats]. AB - OBJECTIVE: To explore the protective eff ect of minocycline on hepatic ischemia reperfusion injury (IRI) in rats and the underlying mechanisms. METHODS: A total of 54 male Sprague-Dawley rats were randomly divided into 3 groups: the sham operated group (control group), the ischemic-reperfusion (IR group), and the minocycline preconditioning group (n=18 per group). The rats in the minocycline preconditioning group were given minocycline (45 mg/kg) by gastric irrigation at 36 h before operation and then were subsequently administered with minocycline (22.5 mg/kg) at every 12 h. Th e rats were sacrifi ced at 2, 6, 24 h after reperfusion. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were measured. HE staining of liver tissues was performed to detect the histological changes, and the degree of liver IRI according to Suzuki score were calculated. The levels of malondialdehyde (MDA) and myeloperoxidase (MPO) were determined by spectrophotometer; the mRNA expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) in the liver were measured by real-time PCR; Dickkopf-1 (DKK-1) and beta-catenin (beta-catenin) protein expression in the liver were detected by Western blot. RESULTS: After 2, 6, 24 h reperfusion, compared with the IR group, the liver function (ALT, AST and LDH) in the minocycline group was significantly improved (all P<0.05); the Suzuki's scores and the levels of hepatic TNF-alpha and IL-1beta mRNA were significantly decreased (all P<0. 05); the MDA and MPO levels the liver were decreased (both P<0.05); the protein expression of hepatic DKK-1 was decreased (P<0.05), while the protein expression of beta-catenin was increased (P<0.05). CONCLUSION: Minocycline can alleviate the ischemic-reperfusion injury mainly through reducing oxidative stress and inhibiting the release of pro-inflammatory cytokines depends on the activation of the Wnt/beta-catenin signaling pathway in the liver. PMID- 25432371 TI - [A clinical analysis of 188 cases of pregnancy complicated with critically heart disease]. AB - OBJECTIVE: To investigate the factors that affect the outcome of pregnancies complicated with critically heart disease admitt ed to obstetric Intensive Care Unit (ICU). METHODS: A retrospective study was conducted for 188 pregnant and postpartum patients complicated with heart disease who were admitted to the ICU in West China Second University Hospital from July 2009 to March 2013. RESULTS: During the 4 years, there were 619 cases of pregnancy complicated with heart disease hospitalization. Among them, 188 (30.37%) patients complicated with severe heart disease were admitted to the ICU, accounting for 39.17% of the total ICU admission (480); the mean maternal age was (28.45 +/- 6.08) years old and the mean gestational time was (36.03 +/- 4.19) weeks. 23 (12.23%) patients received regular antenatal care in our hospital. 61 (32.45%) patients never received antenatal care before hospitalization. Among them, 5 patients were dead. The ratio for diagnosis of heart disease before pregnancy, during pregnancy and after admission were 39.89%, 25.54% and 34.57%, respectively; the most common heart diseases during pregnancy were congenital cardiac disease (80, 42.55%) and rheumatic heart disease (45, 23.94%) followed by arrhythmias (20, 10.64%). The most common complication were pulmonary arterial hypertension (51, 27.13%), arrhythmias (47, 25.00%) and severe heart failure (30, 15.96%); the cardiac function of 164 (87.23%) patients was at stage I-II and 5 (2.66% ) patients died when discharged from hospital. 151 (80.32%) patients received multidisciplinary consultation and 34 (18.09%) used central venous catheterization to control central venous pressure (CVP). 21 (11.17%) patients required mechanical ventilation. 11 (5.85%) patients required emergency life support (cardiopulmonary resuscitation 9 + electric defibrillation 3). CONCLUSION: Pregnancy complicated with heart disease is the leading reason for admission to ICU. The congenital cardiac disease, rheumatic heart disease and arrhythmias are the main heart diseases during pregnancy. Multidisciplinary cooperation and intensive care are the key measures to improve the outcomes of patients with critically illness. It is very important for reduction of the maternal mortality rate through strengthening preconception care and antenatal care. PMID- 25432372 TI - [Activity of cathepsin D and alpha-1 antitrypsin in patients with hip or knee osteoarthritis]. AB - OBJECTIVE: To assess the activity of cathepsin D (CAT-D) and alpha-1 antitrypsin (AAT) in blood in patients with hip or knee osteoarthritis, and to explore whether these two enzymes could be served as serum biomarkers for cartilage degeneration. METHODS: Th e activity of CAT-D and AAT in blood serum of 44 women and 26 men with hip or knee osteoarthritis was determined by the method of ELISA before total joint replacement and on the 10th day aft er the surgery. One hundred healthy volunteers were chosen as the control. All data were analyzed by using SPSS19.0 software. RESULTS: Compared with the controls, the activity of CAT D in patients with osteoarthritis was decreased by 25% (P<0.05) and 50% (P<0.05) before and after the surgery, respectively. The activity of AAT in the osteoarthritis patients before the surgery was not significantly changed compared with the control group (P>0.05), but it was increased by 80% after the surgery than that in the control group (P<0.05). There was no significant difference in the activities of 2 enzymes between hip and knee osteoarthritis (P>0.05). The gender, hypertension, diabetes and age did not affect the activities of the 2 enzymes (P>0.05). CONCLUSION: AAT might be a possible inflammatory indicator in the osteoarthritis. CAT-D and AAT enzymes are not affected by gender, age, hypertension and diabetes, etc, and they might be served as potential biomarkers for cartilage degradation. PMID- 25432373 TI - [Anterolateral minimally invasive plate osteosynthesis technique for distal humeral shaft fracture]. AB - OBJECTIVE: To evaluate the clinical efficacy of the modified anterolateral minimally invasive plate osteosynthesis technique for distal humeral shaft fracture, and to explore its feasibility, security, advantage and disadvantage. METHODS: Th e clinical efficacy of 17 patients with distal humeral shaft fracture, who were treated with the anterolateral humerus minimally invasive plate osteosynthesis during 2009 to 2012, were retrospectively analyzed. Th e operative time, bleeding volume, complications, esseous union time and range of motion (ROM) of elbow were recorded, and the functional outcome of elbow joint was evaluated by Mayo elbow performance score (MEPs). The varus angle was measured in the malunion patients aft er the distal humeral shaft fracture healed. RESULTS: All of the 17 patients obtained bony union at an average of 19.2 weeks postoperatively, an average of 4.5 screwes were inserted in distal humerus. Th e mean ROM of elbows was 133 degrees and the MEPS were 98.2. Seven patients suffered humeral malalignment and the mean varus degrees were 8.3 degrees . CONCLUSION: The technique of anterolateral humerus minimally invasive plate osteosynthesis is safe and feasible for distal humeral shaft, and the satisfactory clinical outcomes can be obtained by this modified technique. However, some of the patients may appear malunion with varus angulation of humerus. PMID- 25432374 TI - [Geographical distribution of left ventricular Tei index based on principal component analysis]. AB - OBJECTIVE: To provide a scientific standard of left ventricular Tei index for healthy people from various region of China, and to lay a reliable foundation for the evaluation of left ventricular diastolic and systolic function. METHODS: The correlation and principal component analysis were used to explore the left ventricular Tei index, which based on the data of 3 562 samples from 50 regions of China by means of literature retrieval. Th e nine geographical factors were longitude(X1), latitude(X2), altitude(X3), annual sunshine hours (X4), the annual average temperature (X5), annual average relative humidity (X6), annual precipitation (X7), annual temperature range (X8) and annual average wind speed (X9). ArcGIS soft ware was applied to calculate the spatial distribution regularities of left ventricular Tei index. RESULTS: There is a significant correlation between the healthy people's left ventricular Tei index and geographical factors, and the correlation coefficients were -0.107 (r1), -0.301 (r2), -0.029 (r3), -0.277 (r4), -0.256(r5), -0.289(r6), -0.320(r7), -0.310 (r8) and -0.117 (r9), respectively. A linear equation between the Tei index and the geographical factor was obtained by regression analysis based on the three extracting principal components. The geographical distribution tendency chart for healthy people's left Tei index was fitted out by the ArcGIS spatial interpolation analysis. CONCLUSION: The geographical distribution for left ventricular Tei index in China follows certain pattern. The reference value in North is higher than that in South, while the value in East is higher than that in West. PMID- 25432375 TI - [Application of improved flushing method in anastomotic leakage after low anterior resection for rectal cancer]. AB - OBJECTIVE: To investigate clinical effect of improved flushing method applied in anastomotic leakage (AL) aft er low anterior resection for rectal cancer. METHODS: We performed a retrospective study to analyze the therapeutic eff ect for 39 AL from 438 patients who received Dixon surgery in the Affiliated Hospital of Luzhou Medical College. Among them, 23 patients received the traditional flushing method (the traditional group) and 16 received the improved flushing method (the improved group). RESULTS: Th e rate of AL was 8.9% (39/438). All patients were cured with non-operative treatment. Th e cleanliness degree of the surrounding skin of drainage tube in the improved group was higher than that in the traditional group. Th e duration of average hospitalization and extubation of drainage tube was shorter in the improved group than that in the traditional group (P<0.05). CONCLUSION: Compared with the traditional methods, the improved one is better for the AL patients. Both the patients themselves or their family members can chose it. The improved flushing method is worth to be spread in clinic. PMID- 25432376 TI - [Effect of chloride ion on corrosion of two commonly used dental alloys]. AB - OBJECTIVE: To investigate the eff ect of chloride concentration on the corrosion of Co-Cr alloy and pure Ti in a simulated oral environment. METHODS: The electrochemical corrosion tests of pure Ti and Co-Cr alloy were carried out in neutral artificial saliva solutions with different NaCl concentrations (0.9%, 2.0%, and 3.0%). Th e morphologies of corroded surface for pure Ti and Co-Cr alloy were observed by scanning electron microscope (SEM). RESULTS: Th e changes in the self-corrosion potentials (Ecorr) for pure Ti and Co-Cr alloy in three kinds of artificial saliva solutions was not obvious. However, the self-corrosion current densities (Icorr) of pure Ti were much lower than those of Co-Cr. The Icorr of Co-Cr alloy increased in a concentration-dependent manner of NaCl, whereas the breakdown potential (Eb) of Co-Cr alloy decreased in a concentration dependent manner. Th e potential ranged for the breakdown of oxide film (Ev) was shortened in a concentration-dependent manner of NaCl. There was no obvious difference in the Icorr of pure Ti with different concentrations of NaCl. The breakdown potential was not seen according to the polarization curves. CONCLUSION: In a certain range, the increase of the concentration of Cl- leads to accelerate the corrosion behavior of Co-Cr alloy, but it does not affect pure Ti. PMID- 25432377 TI - [A brief review of research on chronic disease management based on collaborative care model in China]. AB - OBJECTIVE: To evaluate the situation for chronic disease management in China, and to seek the method for improving the collaborative management for chronic diseases in community. METHODS: We searched literature between January 2008 and November 2013 from the Database, such as China Academic Journal Full-Text Database, and PubMed. The screening was strictly in accordance with the inclusion and exclusion criteria and a summary was made among the selected literature based on a collaboration model. RESULTS: We got 698 articles after rough screen and finally selected 33. All studies were involved in patient's self-management support, but only 9 studies mentioned the communication within the team, and 11 showed a clear team division of labor. CONCLUSION: Chronic disease community management in China displays some disadvantages. It really needs a general service team with clear roles and responsibilities for team members to improve the service ability of team members and provide patients with various forms of self management services. PMID- 25432378 TI - [Long noncoding RNAs in gene expression control]. AB - Studies have shown that most of the sequence in the mammalian genome is transcribed into long noncoding RNAs (lncRNAs). Their crucial roles in gene regulation are becoming a hotspot in current biomedical research. LncRNAs can control gene activities through multiple mechanisms such as: 1) direct or indirect regulation of gene expression via cis-/trans-action or function as protein baits in the nucleus; 2) affecting the stability and the translational process of mRNA; 3) functioning as competitors to regulation of microRNA; 4) binding to transcription factors. Recent studies have highlighted the significance of lncRNAs in development and diseases, and their potentials in future clinical application. PMID- 25432379 TI - [Research and clinical applications regarding endothelial progenitor cell transplantation]. AB - Endothelial injury or dysfunction leads to multiple cardiovascular diseases, such as atherosclerosis, myocardial infarction, stroke, hypertension and peripheral vascular disease. Endothelial progenitor cells (EPCs) are precursor cells of endothelial cells, including the early endothelial progenitor cells and the late endothelial progenitor cells. These two EPC types have different function and surface markers. EPC in this article mainly means late endothelial progenitors which could grow into endothelial cloning and form vessels in vivo. Late EPCs can express CD133, CD31, KDR, CD144, CD34 etc, take in low density lipoprotein, bind with ulex europaeus lectin 1 and form blood vessels in vitro and in vivo. EPCs not only participate in new blood vessels formation, but also are closely related to the repair of damaged endothelium. Many studies confirm that the transplanted EPCs are able to be mobilized to vascular injury location and repair the damaged endothelial cells thus promote new blood vessel formation, which provides a promising strategy for the treatment of cardiovascular diseases and ischemic diseases. PMID- 25432380 TI - [A case of iatrogenic ilio-iliac arteriovenous fistula initially misdiagnosed as deep venous thrombosis]. AB - Iliac arteriovenous fistula (AVF) usually manifests in a wide range of symptoms similar to typical deep venous thrombosis (DVT), which often lead to delayed diagnosis or misdiagnosis. We reported a 51-year old woman who was performed lumbar discectomy and showed a progressive abdominal distention, dyspnea, and swollen left leg. She was initially diagnosed as deep vein thrombosis and the fi nal diagnosis was arteriovenous fistula. Th e fistula was successfully sealed by an endovascular covered stent. No further recurrence was found aft er a half year's follow-up. Th is article summarized the experience regarding iliac arteriovenous fistula misdiagnosed, and discussed the differential diagnosis between arteriovenous fistula and pulmonary thromboembolism caused by deep vein thrombosis. PMID- 25432381 TI - [Model of multiple seasonal autoregressive integrated moving average model and its application in prediction of the hand-foot-mouth disease incidence in Changsha]. AB - OBJECTIVE: To establish multiple seasonal autoregressive integrated moving average model (ARIMA) according to the hand-foot-mouth disease incidence in Changsha, and to explore the feasibility of the multiple seasonal ARIMA in predicting the hand-foot-mouth disease incidence. METHODS: EVIEWS 6.0 was used to establish multiple seasonal ARIMA according to the hand-foot- mouth disease incidence from May 2008 to August 2013 in Changsha, and the data of the hand- foot-mouth disease incidence from September 2013 to February 2014 were served as the examined samples of the multiple seasonal ARIMA, then the errors were compared between the forecasted incidence and the real value. Finally, the incidence of hand-foot-mouth disease from March 2014 to August 2014 was predicted by the model. RESULTS: After the data sequence was handled by smooth sequence, model identification and model diagnosis, the multiple seasonal ARIMA (1, 0, 1)*(0, 1, 1)12 was established. The R2 value of the model fitting degree was 0.81, the root mean square prediction error was 8.29 and the mean absolute error was 5.83. CONCLUSION: The multiple seasonal ARIMA is a good prediction model, and the fitting degree is good. It can provide reference for the prevention and control work in hand-foot-mouth disease. PMID- 25432382 TI - [Effect of the morphology of S-shaped root canals with reciprocating single file system on root canal irrigation]. AB - OBJECTIVE: To evaluate eff ect of the morphology of simulated S-shaped root canals with Reciproc or Mtwo instruments on root canal irrigation. METHODS: A total of 40 simulated S-shaped resin blocks were randomly divided into 2 groups (n=20), which was prepared by Reciproc or Mtwo. Blue ink was injected with constant speed and volume into the canals using 30G lateral opening syringe. Th e distance from needle tip to apex and vapor lock length were measured. A type of 25# 0.04 gutt a-percha point was used to stir and remove the vapor lock. Th e time for removal of the vapor lock was recorded. Another syringe was used to inject saline into the canals and to measure the length of stagnant water. RESULTS: The distance from needle tip to apex in the Reciproc group was significantly longer than that in the Mtwo group [(4.276 +/- 0.221) mm vs (3.459 +/- 0.205) mm, P<0.05]. The vapor lock length in the Reciproc group was significantly longer than that in the Mtwo group [(4.472 +/- 0.230) mm vs (3.668 +/- 0.217) mm, P<0.05]. The time to remove vapor lock was significantly shorter in the Reciproc group than that in the Mtwo group [(10.13 +/- 1.79) s vs (15.29 +/- 2.15) s, P<0.05]. The length of stagnant water was also shorter in the Reciproc group than that in the Mtwo group [(1.351 +/- 0.142) mm vs (2.245 +/- 0.206) mm, P<0.05]. CONCLUSION: The morphology of S-shaped root canal affects the root canal irrigation. The effect of root canal irrigated by Reciproc is better than that by Mtwo. PMID- 25432383 TI - [Blood lead level in painters and the influential factors]. AB - OBJECTIVE: To investigate the blood lead level (BLL) in painters and the influential factors, and to provide the theory foundation for the prevention and control of lead poisoning in painters. METHODS: A total of 535 painters from Sany Heavy Industry Company Limited and Xiangjiang Kansai Paint Corporation, who participated in the health examination during October 2012 and December 2012, were recruited and divided into a positive blood lead group and a negative blood lead group according to the level of blood lead. Questionnaires survey and physical/biochemical examinations were performed. Chi-square Test and multivariate logistic regression were used to estimate the factors that contributed to the elevated blood lead. RESULTS: The results from 525 questionnaires and physical/ biochemical examination were collected. There were 55 workers (10.4%) whose BLL were 0.04 mg/L. The maximum value of BLLs was 0.35mg/L. The multivariate logistic regression showed that smoking (OR=2.424), smoking or eating in the workplace (OR=2.139), not washing hands before smoking or eating (OR=1.624), and the cycle of changing masks longer than two weeks (OR=2.158) were positively associated with BLL. CONCLUSION: Smoking, smoking or eating in the workplace, not washing hands before smoking or eating, and the cycle of changing masks longer than two weeks are risk factors for higher BLL. PMID- 25432384 TI - Diverse expression of selected cytokines and proteinases in synovial fluid obtained from osteoarthritic and healthy human knee joints. AB - BACKGROUND: Osteoarthritis (OA) is defined by signs and symptoms of inflammation within the affected joint. The aim of this study is to determine the mRNA expression levels of selected cytokines and matrix-metalloproteinases of cells found in synovial fluid (SF) obtained from osteoarthritic knee joints compared to healthy controls. METHODS: SF was obtained from 40 patients undergoing total knee arthroplasty due to evident OA and from 10 healthy controls. Expression of TNF alpha, IL-1beta, MMP-1 and MMP-3 was assayed among both groups by performing qPCR. Patients were configured concerning age, gender and BMI. RESULTS: IL-1beta, MMP-1 and MMP-3 showed significantly higher expression among the OA group compared to control (P < 0.001). Strong correlation appeared between expression of MMP-1 and MMP-3 among OA patients (r = 0.856); no correlation was found between age, gender or BMI and cytokine/proteinase expression. Expression of IL 1beta, MMP-1 and MMP-3 within SF was elevated in OA-patients. CONCLUSION: Consequently, cells within SF expressing cytokines and proteinases may play a relevant role in the progression of joint destruction. Considering the fact that SF in an OA joint comprises abnormal amounts of detrimental bioactive proteins, temporary clearance, dilution or suppression/modulation by means of lavage or disease-modifying medication may be promising to constitute interim relief or even postpone disease progression due to decreased inflammatory and/or degrading activity within the articular environment. PMID- 25432386 TI - High-resolution magnetic resonance imaging findings of basilar artery plaque in a patient with branch atheromatous disease: a case report. AB - INTRODUCTION: Intracranial branch atheromatous disease is a type of ischemic stroke that is caused by narrowing or occlusion of the orifice of the penetrating artery by atheromatous plaque. Pontine branch atheromatous disease is usually diagnosed using indirect findings such as the extension of a lesion to the basal surface of the pons because of the difficulty of demonstrating plaque in the basilar artery. CASE PRESENTATION: A 72-year-old Japanese man developed sudden dysarthria and left hemiparesis, and his symptoms deteriorated thereafter. Brain magnetic resonance imaging revealed an acute infarction in the territory of the right paramedian pontine artery extending to the basal surface. Non-contrast enhanced three-dimensional fast spin-echo T1 imaging with variable flip angles and three-dimensional fast imaging with steady-state acquisition revealed a plaque in the dorsal wall of the basilar artery that spread to the origin of the paramedian pontine artery that branched toward the infarction. Although antithrombotic agents were started, the left hemiparesis got worse and became flaccid on the following day. CONCLUSIONS: This is the first report to confirm the pathological basis of branch atheromatous disease by three-dimensional images using the new modalities of 3-Tesla magnetic resonance imaging. The use of these techniques will foster better understanding of the clinicopathological mechanisms of branch atheromatous disease. PMID- 25432385 TI - An evaluation of primary care led dementia diagnostic services in Bristol. AB - BACKGROUND: Typically people who go to see their GP with a memory problem will be initially assessed and those patients who seem to be at risk will be referred onto a memory clinic. The demographic forces mean that memory services will need to expand to meet demand. An alternative may be to expand the role of primary care in dementia diagnosis and care. The aim of this study was to contrast patient, family member and professional experience of primary and secondary (usual) care led memory services. METHODS: A qualitative, participatory study. A topic guide was developed by the peer and professional panels. Data were collected through peer led interviews of people with dementia, their family members and health professionals. RESULTS: Eleven (21%) of the 53 GP practices in Bristol offered primary care led dementia services. Three professional panels were held and were attended by 9 professionals; nine carers but no patients were involved in the three peer panels. These panels identified four main themes: GPs rarely make independent dementia diagnosis; GPs and memory nurses work together; patients and carers generally experience a high quality diagnostic service; an absence of post diagnostic support. Evidence relating to these themes was collected through a total of 46 participants took part; 23 (50%) in primary care and 23 (50%) in the memory service. CONCLUSIONS: Patients and carers were generally satisfied with either primary or secondary care led approaches to dementia diagnosis. Their major concern, shared with many health care professionals, was a lack of post diagnostic support. PMID- 25432387 TI - The 2013 American College of Cardiology/American Heart Association guidelines on treating blood cholesterol and assessing cardiovascular risk: a busy practitioner's guide. AB - The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults and Guideline on the Assessment of Cardiovascular Risk were released in mid-November 2013. This article explains the guidelines, the risk equations, and their derivations, and addresses criticisms so that practicing physicians may be more comfortable in using the guidelines and the risk equations to inform patients of their atherosclerotic cardiovascular risk and choices to reduce that risk. The article also addresses patient concerns about statin safety if lifestyle changes have been insufficient to reduce their risk. PMID- 25432388 TI - Coronary artery calcium scanning: the key to the primary prevention of coronary artery disease. AB - Coronary artery calcium scanning (CAC) is the most powerful prognosticator of cardiac risk in the asymptomatic primary prevention population, far exceeding the role of risk factor-based paradigms. The primary utility of risk factors is to identify treatable targets for risk reduction after risk has been determined by CAC. Serial calcium scanning to evaluate progression of calcified plaque is useful for determining the response to treatment. The 2013 cholesterol treatment guidelines understate the value of CAC scanning for atherosclerotic disease risk assessment. PMID- 25432389 TI - Beginning to understand high-density lipoproteins. AB - This article reconciles the classic view of high-density lipoproteins (HDL) associated with low risk for cardiovascular disease (CVD) with recent data (genetics studies and randomized clinical trials) casting doubt over the widely accepted beneficial role of HDL regarding CVD risk. Although HDL cholesterol has been used as a surrogate measure to investigate HDL function, the cholesterol content in HDL particles is not an indicator of the atheroprotective properties of HDL. Thus, more precise measures of HDL metabolism are needed to reflect and account for the beneficial effects of HDL particles. Current and emerging therapies targeting HDL are discussed. PMID- 25432390 TI - Lipoprotein(a): an important cardiovascular risk factor and a clinical conundrum. AB - Elevated plasma concentrations of lipoprotein(a) (Lp[a]) are an emerging risk factor for the development of coronary heart disease (CHD). Recent genetic and epidemiologic data have provided strong evidence for a causal role of Lp(a) in CHD. Despite these developments, which have attracted increasing interest from clinicians and basic scientists, many unanswered questions persist. The true pathogenic mechanism of Lp(a) remains a mystery. Significant uncertainty exists concerning the appropriate use of Lp(a) in the clinical setting. No therapeutic intervention remains that can specifically lower plasma Lp(a) concentrations, although the list of compounds that lower Lp(a) and LDL continues to expand. PMID- 25432391 TI - Recent findings of studies on the Mediterranean diet: what are the implications for current dietary recommendations? AB - There is evidence from epidemiologic studies and clinical trials demonstrating that the Mediterranean dietary pattern reduces the risk of many chronic diseases, including cardiovascular disease (CVD), and the attendant risk factors. A Mediterranean-style diet reflects most food and nutrient goals in current dietary guidelines. Minor modifications to reduce sodium and saturated fat intake can be made to further meet recommendations. Including the Mediterranean diet in the list of recommended evidence-based dietary patterns offers an additional strategy for improving dietary habits, which may help individuals achieve better long-term adherence to dietary guidelines and sustain optimal reductions in CVD risk. PMID- 25432393 TI - Combination therapy with statins: who benefits? AB - Many lipid-lowering drugs improve cardiovascular (CV) outcomes. However, when therapies have been studied in addition to statins, it has been challenging to show an additional clinical benefit in terms of CV event reduction, although overall safety seems acceptable. This debate has been complicated by recent guidelines that emphasize treatment with high-potency statin monotherapy. Combination therapy allows more patients to successfully reach their ideal lipid targets. Further testing of novel therapies may introduce an era of potent low density lipoprotein decrease without dependence on statins, but until then, they remain the mainstay of therapy. PMID- 25432394 TI - New therapies for reducing low-density lipoprotein cholesterol. AB - Although the past 4 decades have been the most productive in transitioning from an low-density lipoprotein cholesterol (LDL-C) hypothesis to demonstration of clinical benefit, cardiovascular disease remains a major cause of mortality and morbidity. It is fortunate that most of the effective lipid-lowering drugs, the statins, have become generic and inexpensive. However, there remains a large unmet medical need for new and effective agents that are also well tolerated and safe, especially for patients unable to either tolerate statins or achieve optimal LDL-C on current therapies. It is likely that the agents discussed in this review will fill that need. PMID- 25432395 TI - Lipids 2014: new guidelines, new concepts, new diets, new drugs. PMID- 25432392 TI - Pediatric lipid management: an earlier approach. AB - The National Heart, Lung and Blood Institute Expert Panel Integrated Guidelines promote the prevention of cardiovascular disease (CVD) events by encouraging healthy behaviors in all children, screening and treatment of children with genetic dyslipidemias, usage of specific lifestyle modifications, and limited administration of lipid pharmacotherapy in children with the highest CVD risk. These recommendations place children in the center of the fight against future CVD. Pediatric providers may be in a position to shift the focus of CVD prevention from trimming multiple risk factors to cutting out the causes CVD. PMID- 25432396 TI - Lipids. PMID- 25432397 TI - A rare presentation and diagnosis of juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia overlap syndrome. AB - We present a unique case of juvenile polyposis and hereditary hemorrhagic telangiectasia overlap syndrome. The patient was found to have polyps on colonoscopy leading to genetic testing revealing an SMAD4 mutation. In children with SMAD4 mutation and juvenile polyposis, this overlap syndrome needs to be considered in the differential diagnosis and prompt the clinician to look for telangiectasias on examination and consider surveillance imaging to look for arteriovenous malformations. Our case highlights this clinical relationship and shows how nontraditional imaging using computed tomography colonography (CTC) can provide complimentary information along with colonoscopy. Despite low-dose techniques, CTC does add a radiation burden in the evaluation of these children who are at high risk for malignancy and should be used cautiously. PMID- 25432398 TI - Initiatives supporting evidence informed health system policymaking in Cameroon and Uganda: a comparative historical case study. AB - BACKGROUND: There is a scarcity of empirical data on institutions devoted to knowledge brokerage and their influence in Africa. Our objective was to describe two pioneering Knowledge Translation Platforms (KTPs) supporting evidence informed health system policymaking (EIHSP) in Cameroon and Uganda since 2006. METHODS: This comparative historical case study of Evidence Informed Policy Network (EVIPNet) Cameroon and Regional East African Community Health Policy Initiative (REACH-PI) Uganda using multiple methods comprised (i) a descriptive documentary analysis for a narrative historical account, (ii) an interpretive documentary analysis of the context, profiles, activities and outputs inventories and (iii) an evaluative survey of stakeholders exposed to evidence briefs produced and policy dialogues organized by the KTPs. RESULTS: Both initiatives benefited from the technical and scientific support from the global EVIPNet resource group. EVIPNet Cameroon secretariat operates with a multidisciplinary group of part-time researchers in a teaching hospital closely linked to the ministry of health. REACH-PI Uganda secretariat operates with a smaller team of full time staff in a public university. Financial resources were mobilized from external donors to scale up capacity building, knowledge management, and linkage and exchange activities. Between 2008 and 2012, twelve evidence briefs were produced in Cameroon and three in Uganda. In 2012, six rapid evidence syntheses in response to stakeholders' urgent needs were produced in Cameroon against 73 in Uganda between 2010 and 2012. Ten policy dialogues (seven in Cameroon and three in Uganda) informed by pre-circulated evidence briefs were well received. Both KTPs contributed to developing and testing new resources and tools for EIHSP. A network of local and global experts has created new spaces for evidence informed deliberations on priority health policy issues related to MDGs. CONCLUSION: This descriptive historical account of two KTPs housed in government institutions in Africa illustrates how the convergence of local and global factors and agents has enabled in-country efforts to support evidence-informed deliberations on priority health policy issues and lays the ground for further work to assess their influence on the climate for EIHSP and specific health policy processes. PMID- 25432399 TI - Molecular evaluation of orphan Afghan common wheat (Triticum aestivum L.) landraces collected by Dr. Kihara using single nucleotide polymorphic markers. AB - BACKGROUND: Landraces are an important source of genetic diversity in common wheat, but archival collections of Afghan wheat landraces remain poorly characterised. The recent development of array based marker systems, particularly single nucleotide polymorphism (SNP) markers, provide an excellent tool for examining the genetic diversity of local populations. Here we used SNP analysis to demonstrate the importance of Afghan wheat landraces and found tremendous genetic diversity and province-specific characteristics unique to this geographic region. RESULTS: A total of 446 Afghan wheat landraces were analysed using genotype by sequencing (GBS) arrays containing ~10 K unique markers. Pair-wise genetic distance analyses revealed significant genetic distances between landraces, particularly among those collected from distanced provinces. From these analyses, we were able to divide the landraces into 14 major classes, with the greatest degree of diversity evident among landraces isolated from Badakhshan province. Population-based analyses revealed an additional 15 sub-populations within our germplasm, and significant correlations were evident in both the provincial and botanical varieties. Genetic distance analysis was used to identify differences among provinces, with the strongest correlations seen between landraces from Herat and Ghor province, followed closely by those between Badakhshan and Takhar provinces. This result closely resembles existing agro climatic zones within Afghanistan, as well as the wheat varieties commonly cultivated within these regions. Molecular variance analysis showed a higher proportion of intra-province variation among landraces compared with variation among all landraces as a whole. CONCLUSION: The SNP analyses presented here highlight the importance and genetic diversity of Afghan wheat landraces. Furthermore, these data strongly refute a previous analysis that suggested low genetic diverse within this germplasm. Ongoing analyses include phenotypic characterisation of these landraces to identify functional traits associated with individual genotypes. Taken together, these analyses can be used to help improve wheat cultivation in Afghanistan, while providing insights into the evolution and selective pressures underlying these distinct landraces. PMID- 25432400 TI - Mathematical modeling of a single stage ultrasonically assisted distillation process. AB - The ability of sonication phenomena in facilitating separation of azeotropic mixtures presents a promising approach for the development of more intensified and efficient distillation systems than conventional ones. To expedite the much needed development, a mathematical model of the system based on conservation principles, vapor-liquid equilibrium and sonochemistry was developed in this study. The model that was founded on a single stage vapor-liquid equilibrium system and enhanced with ultrasonic waves was coded using MATLAB simulator and validated with experimental data for ethanol-ethyl acetate mixture. The effects of both ultrasonic frequency and intensity on the relative volatility and azeotropic point were examined, and the optimal conditions were obtained using genetic algorithm. The experimental data validated the model with a reasonable accuracy. The results of this study revealed that the azeotropic point of the mixture can be totally eliminated with the right combination of sonication parameters and this can be utilized in facilitating design efforts towards establishing a workable ultrasonically intensified distillation system. PMID- 25432401 TI - Synergistic sonoelectrochemical removal of substituted phenols: implications of ultrasonic parameters and physicochemical properties. AB - The effects of ultrasonic conditions and physicochemical properties on the synergistic degradation in synthetic solution were investigated. A wide range of ultrasound frequencies, including 35, 170, 300, 500 and 700 kHz, and ultrasonic power densities, including 11.3, 22.5 and 31.5 W/L were used. It was revealed that the physical effect of ultrasound plays a major role in synergistic mechanism and 35 kHz was found to be the most effective frequency due to its more vigorous physical effect induced by high implosive energy released from collapse of cavitation bubbles. The highest ultrasonic power density (31.5 W/L) showed the highest synergy index as it increases the number of cavitation bubbles and the energy released when they collapse. The synergy indexes of various substituted phenols under identical condition were investigated. These results were correlated with physicochemical properties, namely octanol-water partition coefficient (Log K OW), water solubility (SW), Henry's law constant (KH) and water diffusivity (DW). Among these parameters, Log K OW and DW were found to have substantial effects on synergy indexes. PMID- 25432402 TI - Save Antibiotics: a call for action of the World Alliance Against Antibiotic Resistance (WAAAR). PMID- 25432403 TI - What is being researched in rectal cancer? AB - INTRODUCTION: Clinical evidence has a more significant role in medical specialties than in surgery. Rectal cancer (CR) is no exception. This paper explores what CR-related subjects are being investigated at the present time in a quantitative and qualitative way and analyzes this information to know what possible answers clinical research could give us in the future. METHODS: The data collection was carried out in April 2014 and was based on 3 sources: 2 institutional clinical trials registries -American (clinicaltrials.gov) and European (EU Clinical Trials Register)- and a survey given to members of the Asociacion Espanola de Coloproctologia (AECP). The obtained studies were exported to a database designed especially for this review, which included a number of descriptive elements that would allow the cataloging of the different studies. The AECP survey results were analyzed separately. RESULTS: There are currently 216 clinical trials ongoing related to CR. Two-thirds are primarily conducted by oncologists. Nearly a third are surgical. The research focuses on improving preoperative treatment: new drugs, new schemes of chemo-radiotherapy (usually induction or consolidation schemes) or optimization of radiotherapy and its effects. Surgical clinical trials are related to robotics, laparoscopy, stoma, low colorectal anastomosis, distal CR and local treatment. CONCLUSION: Most of the current clinical trials ongoing on CR are analyzing aspects of chemo radiotherapy and its effects. A third focus on purely surgical issues. PMID- 25432404 TI - An evaluation of human immunodeficiency virus oral screening test awareness and preferences in the West region of Cameroon. AB - HIV serological diagnosis has evolved during the last decade to give rise to rapid testing using biological materials, such as blood or oral mucosal transudate (OMT). However, blood collection is not always welcomed, justifying the evaluation of OMT-based devices. In a cross sectional study carried out in May 2011 aimed at evaluating the level of awareness about OMT based HIV tests, questionnaires were administered to participants who consented to take part in the study. Eighty-five percent (n = 1520) of participants reported a lack of awareness of HIV oral screening before the study, and surprisingly, no association was found between the awareness of participants and their educational level (p = 0.768). There was also no association (p = 0.743) found between having had previous screening tests and awareness of oral testing. The percentage of participants who accepted the oral test before being informed about it was 31.3% (n = 1520). After sensitization, 76.3% (n = 1520)preferred oral screening for future tests (p = 0). These results reveal that if the OMT based test is affordable, its implementation as a screening tool in the general population could greatly increase participation in screening campaigns and is welcomed by those who want to self-test in a non-invasive way. This will create a better estimation of the national HIV prevalence. Its use could then have a significant public health impact on HIV prevention and clinical management. PMID- 25432405 TI - NHS's care.data scheme is cautionary tale for safe data use, say MPs. PMID- 25432406 TI - Helicobacter pylori vacA and cagA genotype diversity and interferon gamma expression in patients with chronic gastritis and patients with gastric cancer. AB - BACKGROUND: Helicobacter pylori (H. pylori) is the main risk factor for the development of chronic gastritis, gastric ulcer, and gastric cancer. In H. pylori infected individuals, the clinical result is dependent on various factors, among which are bacterial components, the immune response, and environmental influence. AIMS: To compare IFN-gamma expression with the H. pylori vacA and cagA genotypes in patients with chronic gastritis and patients with gastric cancer. METHODS: Ninety-five patients diagnosed with chronic gastritis and 20 with gastric cancer were included in the study. Three gastric biopsies were taken; one was used for the molecular detection and genotyping of H. pylori; another was fixed in absolute alcohol and histologic sections were made for determining IFN-gamma expression through immunohistochemistry. RESULTS: No differences were found in the cells that expressed IFN-gamma between the patients with chronic gastritis (median percentage of positive cells: 82.6% in patients without H. pylori and 82% in infected persons) and those with gastric cancer (70.5% in H. pylori-negative patients and 78.5% in infected persons). IFN-gamma expression was 69% in chronic gastritis patients infected with H. pylori vacAs2m2/cagA- it was 86.5% in patients infected with H. pylori vacAs1m2/cagA-, 86.5% in vacAs1m1/cagA-, and 82% in vacAs1m1/cagA+. Similar data were found in the patients with gastric cancer. CONCLUSIONS: IFN-gamma expression varied depending on the H. pylori vacA and cagA genotype, but not in accordance with the presence of chronic gastritis or gastric cancer. PMID- 25432407 TI - Psychosocial/survivorship issues in breast cancer: are we doing better? AB - Modern breast cancer treatment offers many women greater prospects of cure or lengthier, good quality survival than was possible in the past. Advances include improved diagnostic and staging procedures, sophisticated onco-plastic surgery, enhanced radiotherapy techniques, and targeted systemic therapies. Much more attention has also been paid to cancer care delivery and access to specialist nurses, counsellors, support groups, and services provided by breast cancer charities. However, there are some concerns that these considerable improvements in treatment delivery and clinical outcomes have not led to similar benefits in the psychosocial, functional, and sexual well-being of women. The impact that non life threatening, long-term iatrogenic harms of otherwise efficacious anticancer treatments has on patients is often overlooked; this is in part because of the emphasis given to physician-reported safety data in trials and the general exclusion of patient-reported outcomes (PROs). A failure to utilise reliable PRO measures has meant that some problems are underreported, which consequently has hampered much-needed research into ameliorative interventions. Systematic monitoring of quality of life-threatening side effects would permit early implementation of effective interventions and enhance long-term survivorship. Some examples of the pervasive difficulties that continue to affect survivors and evidence that certain interventions might help are provided in this commentary. PMID- 25432408 TI - Generalizability of trial results to elderly Medicare patients with advanced solid tumors (Alliance 70802). AB - BACKGROUND: In the United States, patients who enroll in chemotherapy trials seldom reflect the attributes of the general population with cancer, as they are often younger, more functional, and have less comorbidity. We compared survival following three chemotherapy regimens according to the setting in which care was delivered (ie, clinical trial vs usual care) to determine the generalizability of clinical trial results to unselected elderly Medicare patients. METHODS: Using SEER-Medicare data, we estimated survival for elderly patients (ie, age 65 years or older, n = 14097) with advanced pancreatic or lung cancer following receipt of one of three guideline-recommended first-line chemotherapy regimens. We compared their survival to that of similarly treated clinical trial enrollees, without age restrictions, with the same diagnosis and stage (n = 937). All statistical tests were two-sided. RESULTS: Trial patients were 9.5 years younger than elderly Medicare patients. Medicare patients were more often white and tended to live in areas of greater educational attainment than trial enrollees. For each tumor type, Medicare patients who were 75 years or older had median survivals that were six to eight weeks shorter than those of trial patients (4.3 vs 5.8 months following treatment with single agent gemcitabine for advanced pancreatic cancer, P = .03; 7.3 vs 8.9 months following treatment with carboplatin and paclitaxel for stage IV non-small cell lung cancer, P = .91; 8.2 vs 10.2 months following treatment with CDDP/ VP16 for extensive stage small cell lung cancer, P <= .01), whereas younger Medicare patients had survival times that were similar to those of trial patients. CONCLUSIONS: Results of clinical trials for advanced pancreatic cancer and lung cancers tended to correctly estimate survival for Medicare patients aged 65 to 74 years, but to overestimate survival for older Medicare patients by six to eight weeks. These estimates of Medicare patients' survival may aid subsequent patients and their oncologists in treatment decision making. PMID- 25432410 TI - (R)Evolutionary therapy: the potential of immunotherapy to fulfill the promise of personalized cancer treatment. AB - Since the millennium, personalized medicine has been at the forefront of therapeutic endeavors in medical oncology. The latest technology has given researchers the ability to define cancer at its molecular core. This has led to the development of "targeted therapies," designed to eliminate driver mutations while leaving healthy cells unscathed. Unfortunately, more than 10 years into the targeted molecular therapy era, successes have been infrequent, and toxicity remains largely unchanged compared with relatively indiscriminant, traditional chemotherapy. Emerging data suggests that the malignant clonal heterogeneity within solid tumors is so diverse that targeting one or even several mutations is likely to have minimal, transient impact. In recent years, new therapies have emerged that can effectively stimulate the immune system and improve survival in patients with metastatic disease. Through immune activation, there is the potential to target the cancer with a biologic diversity that can potentially rival the multiplicity of malignant mutations within tumors. Stimulating the immune system to become an evolving adversary against malignant cells may revolutionize cancer therapy in the years to come. PMID- 25432411 TI - RE: net risk reclassification P Values: valid or misleading? PMID- 25432409 TI - Aspirin and COX-2 inhibitor use in patients with stage III colon cancer. AB - We conducted a prospective, observational study of aspirin and COX-2 inhibitor use and survival in stage III colon cancer patients enrolled in an adjuvant chemotherapy trial. Among 799 eligible patients, aspirin use was associated with improved recurrence-free survival (RFS) (multivariable hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.28 to 0.95), disease-free survival (DFS) (HR = 0.68, 95% CI = 0.42 to 1.11), and overall survival (OS) (HR = 0.63, 95% CI = 0.35 to 1.12). Adjusted HRs for DFS and OS censored at five years (in an attempt to minimize misclassification from noncancer death) were 0.61 (95% CI = 0.36 to 1.04) and 0.48 (95% CI = 0.23 to 0.99). Among 843 eligible patients, those who used COX-2 inhibitors had multivariable HRs for RFS, DFS, and OS of 0.53 (95% CI = 0.27 to 1.04), 0.60 (95% CI = 0.33 to 1.08), and 0.50 (95% CI = 0.23 to 1.07), and HRs of 0.47 (95% CI = 0.24 to 0.91) and 0.26 (95% CI = 0.08 to 0.81) for DFS and OS censored at five years. Aspirin and COX-2 inhibitor use may be associated with improved outcomes in stage III colon cancer patients. PMID- 25432412 TI - Response. PMID- 25432413 TI - Value of the "TAVI2-SCORe" versus surgical risk scores for prediction of one year mortality in 511 patients who underwent transcatheter aortic valve implantation. AB - A bedside-available transcatheter aortic valve implantation (TAVI)-dedicated prognostic risk score is an unmet clinical need. We aimed to develop such a risk score predicting 1-year mortality post-TAVI and to compare it with the performance of the logistic EuroSCORE (LES) I and LES-II and the Society of Thoracic Surgeons' (STS) score. Baseline variables of 511 consecutive patients who underwent TAVI that were independently associated with 1-year mortality post TAVI were included in the "TAVI2-SCORe." Discrimination and calibration abilities of the novel score were assessed and compared with surgical risk scores. One-year mortality was 17.0% (n = 80 of 471). Porcelain thoracic aorta (hazard ratio [HR] 2.56), anemia (HR 2.03), left ventricular dysfunction (HR 1.98), recent myocardial infarction (HR 3.78), male sex (HR 1.81), critical aortic valve stenosis (HR 2.46), old age (HR 1.68), and renal dysfunction (HR 1.76) formed the TAVI2-SCORe (all p <0.05). According to the number of points assigned (1 for each variable and 2 for infarction), patients were stratified into 5 risk categories: 0, 1 (HR 2.6), 2 (HR 3.6), 3 (HR 10.5), and >=4 (HR 17.6). TAVI2-SCORe showed better discrimination ability (Harrells' C statistic 0.715) compared with LES-I, LES-II, and STS score (0.609, 0.633, and 0.50, respectively). Cumulative 1-year survival rate was 54% versus 88% for patients with TAVI2-SCORE >=3 versus <3 points, respectively (p <0.001). Contrary to surgical risk scores, there was no significant difference between observed and expected 1-year mortality for all TAVI2-SCORe risk strata (all p >0.05, Hosmer-Lemeshow statistic 0.304), suggesting superior calibration performance. In conclusion, the TAVI2-SCORe is an accurate, simple, and bedside-available score predicting 1-year mortality post TAVI, outperforming conventional surgical risk scores for this end point. PMID- 25432414 TI - Frequency of high-risk patients not receiving high-potency statin (from a large managed care database). AB - We examined trends in low-density lipoprotein cholesterol (LDL-C) goal attainment in high-risk patients and use of high-potency statins (HPS) in a large, managed care database from 2004 to 2012. The 2013 American Heart Association/American College of Cardiology prevention guidelines recommend that subjects with atherosclerotic cardiovascular disease (ASCVD) should be prescribed HPS therapy, irrespective of LDL-C levels. Previous guidelines recommend an LDL-C target <70 mg/dl. Patients diagnosed with ASCVD based on International Classification of Diseases, Ninth Revision codes with >=1 LDL-C test from January 2004 to December 2012 were identified in the Optum Insight database. Patients were identified as treated if they received lipid-lowering therapy (LLT) within 90 days of the LDL-C measurement and untreated if they did not receive LLT treatment. LLT treated patients were stratified into HPS users or non-HPS LLT users. There were 45,101 eligible patients in 2004 and 40,846 in 2012. The proportion of high-risk patients who were treated with LLT increased from 61.4% (2004) to 70.5% (2008) then remained relatively constant until 2012 (67.9%). Mean LDL-C values in treated patients decreased from 103.7 +/- 32.1 (2004) to 90.8 +/- 31.4 mg/dl (2012). The proportion of patients treated with HPS increased from 13% in 2004 to 26% in 2012. Although the proportion of treated high-risk patients who achieve LDL-C <70 mg/dl levels has increased sharply from 2004, approximately 3 of 4 patients still did not meet this target. Only 1/4 of ASCVD patients are on HPS. In conclusion, our findings highlight the need for renewed efforts to support guideline-based LDL-C treatment for high-risk patients. PMID- 25432415 TI - Effects of niacin, statin, and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 levels in patients with dyslipidemia. AB - Recent trials demonstrated substantial improvement in lipid parameters with inhibition of proprotein convertase subtilisin-like/kexin type 9 (PCSK9). Although statins and fibrates have been reported to increase plasma PCSK9 levels, the effect of niacin on PCSK9 is unknown. We investigated the impact of niacin, atorvastatin, and fenofibrate on PCSK9 levels in 3 distinct studies. A statin only study randomized 74 hypercholesterolemic patients to placebo, atorvastatin 10 mg/day, or atorvastatin 80 mg/day for 16 weeks. A dose-related increase in PCSK9 was noted such that atorvastatin 80 mg increased PCSK9 by a mean +27% (95% confidence interval [CI] +12 to +42), confirming the effect of statin therapy on raising PCSK9. A second study randomized 70 patients with carotid atherosclerosis to simvastatin 20 mg/day, simvastatin 80 mg/day, or simvastatin 20 mg/extended release (ER) niacin 2 g/day. PCSK9 levels were increased with statin therapy, but decreased with the simvastatin 20 mg/ER niacin combination (mean -13%, CI -3 to 23). A final study involved 19 dyslipidemic participants on atorvastatin 10 mg with serial addition of fenofibric acid 135 mg followed by ER niacin 2 g/day. Fenofibric acid led to a +23% (CI +10 to +36, p = 0.001) increase in PCSK9; the addition of niacin resulted in a subsequent -17% decrease (CI -19 to -5, p = 0.004). A positive association was noted between change in PCSK9 and low-density lipoprotein cholesterol levels (r = 0.62, p = 0.006) with the addition of niacin. In conclusion, niacin therapy offsets the increase in PCSK9 levels noted with statin and fibrate therapy. A portion of the low-density lipoprotein cholesterol reduction seen with niacin therapy may be due to reduction in PCSK9. PMID- 25432417 TI - Stealth lipoplex decorated with triazole-tethered galactosyl moieties: a strong hepatotropic gene vector. AB - Mono-antennary galacto derivatives of cholesterol are being actively developed to direct lipoplexes to the asialoglycoprotein receptor (ASGP-R) on hepatocytes. Here we report on a novel ASGP-R ligand cholest-5-en-3-yl [1-(beta-D galactopyranosyl)-1H-1,2,3-triazol-4-yl]methylcarbamate (4), assembled by a copper(I)-catalyzed azide-alkyne cycloaddition (click chemistry), and compare it with cholest-5-en-3-yl-beta-D-galactopyranoside (2) and cholest-5-en-3-yl [1 (beta-D-galactopyranosyl-1'-oxy)phen-4-yl]carbamate (3), in liposome formulations with or without 5 mol% distearoylphosphatidylethanolamine poly(ethylene glycol)2000, intended for DNA delivery to ASGP-R-positive hepatocyte-derived HepG2 cells and the ASGP-R-negative embryo kidney cell line HEK293. Transfection levels attained with lipoplex 4 were 100 and 300% greater than those for lipoplexes 2 and 3 respectively in HepG2 cells, while competition assays reduced transfection levels by up to 98%. Transfection activities achieved in HEK293 cells were up to three orders of magnitude lower. Therefore, 4 is representative of a new class of promising hepatotropic ligands for gene delivery. PMID- 25432416 TI - Evaluation of proliferation and apoptosis markers in circulating tumor cells of women with early breast cancer who are candidates for tumor dormancy. AB - INTRODUCTION: Clinical dormancy is frequently observed in breast cancer. In the present study, we aimed to characterize circulating tumor cells (CTCs) in dormancy candidates (DC) with early breast cancer in terms of proliferation and apoptosis. METHODS: Cytospins of peripheral blood mononuclear cells (PBMCs) were obtained from DC (n = 122) who were disease-free for at least 5 years and from metastatic patients (n = 40) who relapsed more than 5 years after surgery. Sequential samples from eight DC (n = 36) who maintained a prolonged disease-free status and from eight DC (n = 27) presenting late relapse during follow-up, were also analyzed. PBMCs were triple stained with a pancytokeratin, antibody along with anti-Ki67 and anti-M30 antibodies as proliferation and apoptosis markers, respectively. RESULTS: CTCs were identified in 40 (33%) of 122 DC and in 15 (37.5%) of 40 metastatic patients. In total, twenty-five (62.5%) DC had exclusively dormant (Ki67(-)/M30(-)), seven (17.5%) had proliferative Ki67(+)/M30(-), four (10%) had apoptotic Ki67(-)/M30(+) and four (10%) had both phenotypes of proliferative and apoptotic CTCs. In comparison, 53.4% of CTC positive metastatic patients had exclusively dormant and 46.6% had proliferative CTCs; none had apoptotic CTCs (P = 0.039). Among all CTCs detected in DC patients, 82.4% were dormant, whereas in the nondormant population, 32.5% were proliferative and 67.5% apoptotic. The respective percentages in metastatic patients were 59.1%, 100% and 0% (P <0.0001). Moreover, apoptotic CTCs prevailed among nondormant CTCs detected in sequential samples from DC who remained in a prolonged disease-free status compared to those presenting late relapse during follow-up (70.6% versus 43.5% (P = 0.0002)). CONCLUSIONS: The apoptotic index of CTCs is increased during clinical dormancy, whereas the proliferation index is increased on relapse. In addition, apoptotic CTCs are more frequently encountered during follow-up in DC patients who remain disease-free compared to those with subsequent late relapse, suggesting that monitoring proliferation and apoptosis in CTCs during clinical dormancy merits further investigation as a tool for predicting late disease recurrence. PMID- 25432418 TI - Expression of an alkane monooxygenase (alkB) gene and methyl tert-butyl ether co metabolic oxidation in Pseudomonas citronellolis. AB - Pseudomonas citronellolis UAM-Ps1 co-metabolically transforms methyl tert-butyl ether (MTBE) to tert-butyl alcohol with n-pentane (2.6 mM), n-octane (1.5 mM) or dicyclopropylketone (DCPK) (4.4 mM), a gratuitous inducer of alkane hydroxylase (AlkB) activity. The reverse transcription quantitative real-time PCR was used to quantify the alkane monooxygenase (alkB) gene expression. The alkB gene was expressed in the presence of n-alkanes and DCPK and MTBE oxidation occurred only in cultures when alkB was transcribed. A correlation between the number of alkB transcripts and MTBE consumption was found (MUTauBetaEpsilon consumption in MUmol = 1.44e(-13) x DNA copies, R(2) = 0.99) when MTBE (0.84 mM) was added. Furthermore, alkB was cloned and expressed into Escherichia coli and the recombinant AlkB had a molecular weight of 42 kDa. This is the first report where the expression of alkB is related to the co-metabolic oxidation of MTBE. PMID- 25432419 TI - Ultrasonic measurement of rectal diameter and area in neurogenic bowel with spinal cord injury. AB - OBJECTIVE: The aim of this study was to determine the efficacy of measuring the diameter and area of the rectum using ultrasonography as an additional parameter for the evaluation of neurogenic bowel in patients with spinal cord injury (SCI). PARTICIPANTS: In total, 32 patients with SCI (16 patients with upper motor neuron neurogenic bowel (UMNB) and 16 patients with lower motor neuron neurogenic bowel (LMNB)) participated in this study. We divided the patients by the type of neurogenic bowel: UMNB, patients with supraconal lesions and recovery state of spinal shock or LMNB, patients with infraconal/caudal lesions or spinal shock state). INTERVENTION: Ultrasound was applied on the abdomen and measured the diameter and area of the rectum were measured twice each before and after defecation, respectively. OUTCOME MEASURE: We compared rectal diameter and area before/after defecation between the two groups, and significant differences were found in both rectal diameter and area before/after defecation in each group. RESULTS: After defecation, those in the UMNB group had smaller rectal diameters and areas than those in the LMNB group. Significant reduction of rectal diameter and area was observed after defecation as well. The LMNB group showed slightly increased rectal area after defecation, but the increase was not statistically significant. CONCLUSION: Using ultrasound to measure rectal diameter and area seems helpful for classifying neurogenic bowel types and for understanding the neurogenic bowel among SCI patients with symptoms of neurogenic bowel. PMID- 25432421 TI - Nutrition in the ICU: proof of the pudding is in the tasting. PMID- 25432420 TI - Effect of sauna-based heat acclimation on plasma volume and heart rate variability. AB - PURPOSE: We investigated the effect of post-exercise sauna bathing on plasma volume (PV) expansion and whether such responses can be tracked by changes in heart rate (HR)-based measures. METHODS: Seven, well-trained male cyclists were monitored for 35 consecutive days (17 days baseline training, 10 days training plus sauna, 8 days training). Sauna exposure consisted of 30 min (87 degrees C, 11 % relative humidity) immediately following normal training. Capillary blood samples were collected while resting seated to assess PV changes. HR (HRwake) and vagal-related HR variability (natural logarithm of square root mean squared differences of successive R-R intervals, ln rMSSDwake) were assessed daily upon waking. A sub-maximal cycle test (5 min at 125 W) was performed on days 1, 8, 15, 22, 25, 29, and 35 and HR recovery (HRR60s) and ln rMSSDpostex were assessed post exercise. Effects were examined using magnitude-based inferences. RESULTS: Compared with baseline, sauna resulted in: (1) peak PV expansion after four exposures with a likely large increase [+17.8 % (90 % confidence limits, 7.4; 29.2)]; (2) reduction of HRwake by a trivial-to-moderate amount [-10.2 % (-15.9; 4.0)]; (3) trivial-to-small changes for ln rMSSDwake [4.3 % (1.9; 6.8)] and ln rMSSDpostex [-2.4 % (-9.1; 4.9)]; and (4) a likely moderate decrease in HRR60s [ 15.6 % (-30.9; 3.0)]. Correlations between individual changes in PV and HR measures were all unclear. CONCLUSIONS: Sauna bathing following normal training largely expanded PV in well-trained cyclists after just four exposures. The utility of HR and HRV indices for tracking changes in PV was uncertain. Future studies will clarify mechanisms and performance benefits of post-training sauna bathing. PMID- 25432422 TI - Impact of intra-arrest therapeutic hypothermia on outcome of prehospital cardiac arrest: response to comment by Saigal and Sharma. PMID- 25432423 TI - Dendritic function in vivo. AB - Dendrites are the predominant entry site for excitatory synaptic potentials in most types of central neurons. There is increasing evidence that dendrites are not just passive transmitting devices but play active roles in synaptic integration through linear and non-linear mechanisms. Frequently, excitatory synapses are formed on dendritic spines. In addition to relaying incoming electrical signals, spines can play important roles in modifying these signals through complex biochemical processes and, thereby, determine learning and memory formation. Here, we review recent advances in our understanding of the function of spines and dendrites in central mammalian neurons in vivo by focusing particularly on insights obtained from Ca(2+) imaging studies. PMID- 25432424 TI - Usefulness of intermuscular coherence and cumulant analysis in the diagnosis of postural tremor. AB - OBJECTIVE: To investigate the potential value of two advanced EMG measures as additional diagnostic measures in the polymyographic assessment of postural upper limb tremor. METHODS: We investigated coherence as a measure of dependency between two EMG signals, and cumulant analysis to reveal patterns of synchronicity in EMG activity in muscle pairs. Eighty datasets were analyzed retrospectively, obtained from four groups: essential tremor (ET), Parkinson's disease (PD), enhanced physiological tremor (EPT), and functional tremor (FT). RESULTS: Intermuscular coherence was highest in the PD group (0.58), intermediate in FT (0.43) and ET (0.40), and weakest in EPT (0.16) (p=0.002). EPT patients could be distinguished by low coherence: coherence <0.18 in the wrist+elbow extensors differentiates EPT in this sample with a sensitivity of 86% and specificity of 84%. Cumulant analysis showed predominantly alternating activity between wrist and elbow extensor in ET patients, while a more synchronous pattern was predominant in PD, EPT and FT (p=0.008). EMG activity in wrist and elbow flexors tended to be more synchronous in PD (p=0.059). CONCLUSION: Our results suggest that coherence and cumulant analysis may be of additional value in the diagnostic work-up of postural tremor. SIGNIFICANCE: These additional measures may be helpful in diagnosing difficult tremor cases. PMID- 25432425 TI - Different effects of transcutaneous electric nerve stimulation and electroacupuncture at ST36-ST37 on the cerebral cortex. AB - BACKGROUND: The effects of transcutaneous electric nerve stimulation (TENS) and electroacupuncture (EA) on the cerebral cortex are largely unclear. The purpose of the present study was to investigate the effect of TENS and EA on the cerebral cortex by examining their effect on the median nerve-somatosensory evoked potentials (MN-SEPs). METHODS: Twenty volunteers were studied. The cortical and cervical spinal potentials were recorded by median nerve stimulation at the left wrist. Sham TENS, 2 Hz TENS and 2 Hz EA were applied to both ST36 and ST37. MN SEPs were recorded during sham TENS, 2 Hz TENS and 2 Hz EA, with at least 1 week interval for each subject. One-way analysis of variance was used to determine the differences in latency and amplitude of the MN-SEPs observed in the stimulation and post-stimulation periods compared with baseline. Scheffe's post hoc correction was employed to identify pairwise differences. RESULTS: No differences in mean latency were found between the stimulation procedures during the stimulation and post-stimulation periods. 2 Hz EA but not sham TENS or 2 Hz TENS caused higher mean amplitudes in N20 and N30 during the stimulation and post stimulation periods. CONCLUSIONS: EA, but not TENS, induces changes in certain components of the signal. PMID- 25432426 TI - Post-wildfire effects on carbon and water vapour dynamics in a Spanish black pine forest. AB - Two eddy covariance systems were installed in a high-severity burned zone (BZ) and an adjacent unburned (UNB) zone to monitor water vapour and carbon dioxide fluxes for 21 months (from June 2011 to February 2013) at a Spanish black pine forest affected by a stand-replacing wildfire and located in a mountainous area of central-eastern Spain. The differences between both sites were significant especially during the growing season, affecting gross primary productivity (GPP) more than ecosystem respiration (Reco). Net ecosystem exchange (NEE) for 2012 was -3.97 and 1.80 t C ha(-1) year(-1) for the unburned and burned sites, respectively, the GPP being 64% lower for the BZ than the UNB zone. Evapotranspiration (ET) at the UNB was 18% greater than at the BZ. Difference between sites was 160 mm during the whole studied period. This study reflects the effect of one of the major disturbances that can affect Mediterranean ecosystems, showing that carbon fluxes are more dramatically concerned than water vapour fluxes. PMID- 25432427 TI - Effluent characteristics of advanced treatment for biotreated coking wastewater by electrochemical technology using BDD anodes. AB - Effluent of biotreated coking wastewater comprises hundreds of organic and inorganic pollutants and has the characteristics of high toxicity and difficult biodegradation; thus, its chemical oxygen demand cannot meet drainage standards in China. A boron-doped diamond anode was selected for advanced treatment of biotreated coking wastewater, and considering the efficiency of the removal of total organic carbon and energy consumption, optimal conditions were obtained as current density of 75 mA cm(-2), electrolysis time of 1.5 h, and an electrode gap of 1.0 cm in an orthogonal test. Effluent characteristics were investigated at different electrolysis times. The ratio of the 5-day biochemical oxygen demand (BOD5) to the chemical oxygen demand increased from an initial value of 0.05 to 0.65 at 90 min. Fluorescence spectra were used to evaluate the evolution of refractory organics. Two fluorescence peaks for raw wastewater, corresponding to an aromatic protein-like substance II and humic acid-like substance, weakened at 30 and at 90 min, only the former was detected. The specific oxygen uptake rate was used to assess effluent toxicity, and an obvious inhibition effect was found at 15 min; then, it was significantly faded at 30 and 45 min. The BOD5/NO3 (-)-N ratio increased from an initial value of 0.48 to 1.25 at 45 min and then gradually dropped to 0.69 at 90 min. According to the above effluent characteristics, it is strongly suggested that electrochemical technology using boron-doped diamond anodes is combined with biological denitrification technology for the advanced treatment of biotreated coking wastewater. PMID- 25432428 TI - Effect of grain size and heavy metals on As immobilization by marble particles. AB - The effect of grain size and the interaction of heavy metals on As sorption by marble waste with different particle sizes was investigated. Acidic solutions containing only arsenic and a mixture of arsenic, lead, zinc, and cadmium were put in contact with the marble waste. The amount of metal(loid)s that were immobilized was calculated using the difference between the concentration in the acidic solution and in the liquid phase of the suspensions. Approximately 420 MUg As m(-2) was sorbed onto the marble grains, both nonspecifically and specifically, where >= 80 % of the total arsenic in the acidic solution remained soluble, which suggests that this amendment is not effective to immobilize arsenic. However, in mixed contamination, relatively stable Pb-Ca arsenates were formed on the surface of the marble particles, and the soluble arsenic was reduced by 95 %, which indicates that marble particles can effectively immobilize arsenic and lead when both appear together. PMID- 25432429 TI - Brain overgrowth in disorders of RTK-PI3K-AKT signaling: a mosaic of malformations. AB - Disorders of brain overgrowth are significant causes of intractable epilepsy, intellectual disability, autism, and other complex neurological problems. The pathology of these disorders is sometimes striking and characteristic, as in hemimegalencephaly, but can also be subtle, as in autism. Recent genetic studies have shown that many diverse forms of brain overgrowth are caused by de novo mutations that increase activity in the receptor tyrosine kinase (RTK) phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathway, a key mediator of signaling by growth factors in the developing brain, such as fibroblast growth factors. In cases where mutations arise in postzygotic embryos, brain regions exhibit mosaic pathology that reflects the distribution of mutant cells, ranging from focal cortical dysplasia to lobar or hemispheric overgrowth. In turn, the histopathology of these disorders is also remarkably varied. The common underlying mechanisms of RTK-PI3K-AKT overactivation suggest new possibilities for drugs that inhibit this pathway. PMID- 25432430 TI - Critical period for dopaminergic neuroprotection by hormonal replacement in menopausal rats. AB - The neuroprotective effects of menopausal hormonal therapy in Parkinson's disease have not yet been clarified, and it is not known whether there is a critical period. Estrogen induced significant protection against 6-hydroxydopamine-induced dopaminergic degeneration when administered immediately or 6 weeks, but not 20 weeks after ovariectomy. In the substantia nigra, ovariectomy induced a decrease in levels of estrogen receptor-alpha and increased angiotensin activity, NADPH oxidase activity, and expression of neuroinflammatory markers, which were regulated by estrogen administered immediately or 6 weeks but not 20 weeks after ovariectomy. Interestingly, treatment with angiotensin receptor antagonists after the critical period induced a significant level of neuroprotection. In cultures, treatment with 1-methyl-4-phenylpyridinium induced an increase in astrocyte derived angiotensinogen and dopaminergic neuron death, which were inhibited by estrogen receptor alpha agonists. In microglial cells, estrogen receptor beta agonists inhibited the angiotensin-induced increase in inflammatory markers. The results suggest that there is a critical period for the neuroprotective effect of estrogen against dopaminergic cell death, and local estrogen receptor alpha and renin-angiotensin system play a major role. PMID- 25432431 TI - Accuracy of three-dimensional soft tissue predictions in orthognathic surgery after Le Fort I advancement osteotomies. AB - Prediction of postoperative facial appearance after orthognathic surgery can be used for communication, managing patients' expectations,avoiding postoperative dissatisfaction and exploring different treatment options. We have assessed the accuracy of 3dMD Vultus in predicting the final 3-dimensional soft tissue facial morphology after Le Fort I advancement osteotomy. We retrospectively studied 13 patients who were treated with a Le Fort I advancement osteotomy alone. We used routine cone-beam computed tomographic (CT) images taken immediately before and a minimum of 6 months after operation, and 3dMD Vultus to virtually reposition the preoperative maxilla and mandible in their post operative positions to generate a prediction of what the soft tissue would look like. Segmented anatomical areas of the predicted mesh were then compared with the actual soft tissue. The means of the absolute distance between the 90th percentile of the mesh points for each region were calculated, and a one-sample Student's t test was used to calculate if the difference differed significantly from 3 mm.The differences in the mean absolute distances between the actual soft tissue and the prediction were significantly below 3 mm for all segmented anatomical areas (p < 0.001), and ranged from 0.65 mm (chin) to 1.17 mm (upper lip). 3dMD Vultus produces clinically satisfactory 3-dimensional facial soft tissue predictions after Le Fort I advancement osteotomy. The mass-spring model for prediction seems to be able to predict the position of the lip and chin, but its ability to predict nasal and paranasal areas could be improved. PMID- 25432432 TI - A model to investigate SNPs' interaction in GWAS studies. AB - Genome-wide association studies (GWAS) are able to identify the role of individual SNPs in influencing a phenotype. Nevertheless, such analysis is unable to explain the biological complexity of several diseases. We elaborated an algorithm that starting from genes in molecular pathways implicated in a phenotype is able to identify SNP-SNP interaction's role in association with the phenotype. The algorithm is based on three steps. Firstly, it identifies the biological pathways (gene ontology) in which the genes under analysis play a role (GeneMANIA). Secondly, it identifies the group of SNPs that best fits the phenotype (and covariates) under analysis, not considering individual SNP regression coefficients but fitting the regression for the group itself. Finally, it operates an analysis of SNP interactions for each possible couple of SNPs within the group. The sensitivity and specificity of our algorithm was validated in simulated datasets (HapGen and Simulate Phenotypes programs). The impact on efficiency deriving from changes in the number of SNPs/patients under analysis, linkage disequilibrium and minor allele frequency thresholds was analyzed. Our algorithm showed a strong stability throughout all analysis operated, resulting in an overall sensitivity of 81.67 % and a specificity of 98.35 %. We elaborated a stable algorithm that may detect SNPs interactions, especially those effects that pass undetected in classical GWAS. This method may contribute to face the two relevant limitations of GWAS: lack of biological informative power and amount of time needed for the analysis. PMID- 25432433 TI - Acetyl-L-carnitine and oxaloacetate in post-treatment against LTP impairment in a rat ischemia model. An in vitro electrophysiological study. AB - A high proportion of research relating to cerebral ischemia focuses on neuroprotection. The application of compounds normally present in the organism is popular, because they do not greatly influence the synaptic activity by receptor modulation, and can be administered without serious side effects. Oxaloacetate (OxAc) and acetyl-L-carnitine (ALC) are such favorable endogenous molecules. ALC can exert a protective effect by improving the energy state of the neurons under ischemic conditions. A promising neuroprotective strategy is glutamate scavenging, which can be achieved by the intravenous administration of OxAc. This study involved the possible protective effects of ALC and OxAc in different post treatment protocols against long-term potentiation (LTP) impairment. Ischemia was induced in rats by 2-vessel occlusion, which led to a decreased LTP relative to the control group. High-dose (200 mg/kg) ALC or OxAc post-treatment resulted in a higher potentiation relative to the 2VO group, but it did not reach the control level, whereas low-dose ALC (100 mg/kg) in combination with OxAc completely restored the LTP function. Many previous studies have concluded that ALC can be protective only as pretreatment. The strategy described here reveals that ALC can also be neuroprotective when utilized as post-treatment against ischemia. PMID- 25432434 TI - Disease duration of episodic migraine correlates with modified amplitudes and habituation of contingent negative variation. AB - Cortical habituation in episodic migraine patients without medication overuse headache (MOH), recorded by contingent negative variation (CNV), is often reduced compared with healthy controls. There is evidence that with longer duration of migraine disease (DOD) amplitudes and habituation of CNV become progressively abnormal. The aim of the study was to examine habituation characteristics of contingent negative variation in episodic migraine patients suffering from short- and long-lasting migraine compared to matched healthy controls. 32 migraine patients without aura and without MOH diagnosed according to the revised ICHD-II criteria and 16 age- and sex-matched healthy controls were included. According to DOD, the total sample of migraine patients was divided into two groups (group a: DOD <121 months, n = 17 subjects, group b: DOD >120 months, n = 15 subjects). Both migraine groups did not differ in the number of days of migraine and the duration of attacks. Overall CNV and initial CNV differed significantly between migraine patients and controls, whereas the former produced more negative amplitudes. In the migraine group lack of or deficient habituation occurred, whilst controls showed habituation. There were middle range correlations between the DOD and overall CNV, initial CNV, and y-intercept. Patients suffering from long-lasting migraine produced higher CNV amplitudes with a higher y-intercept. The results are interpreted as "maladaptive plasticity" with a risen intercept in long-lasting migraine. PMID- 25432435 TI - Clinical and phenotypic features of CD5-negative B cell chronic lymphoproliferative disease resembling chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) B cells are phenotypically identified by surface expression of CD5 and CD23 antigens. Infrequently, patients with a monoclonal B cell lymphocytosis clinically resembling classic B-CLL have been found to harbor leukemic B cells lacking expression of the CD5 antigen. Little information is available concerning such CLL-like lymphoproliferative syndromes. Here, we provide phenotypic and clinical characteristics of 13 patients with CD5 negative chronic lymphoproliferative disorders selected from among 400 B-CLL patients followed up at a single academic center. Phenotypic analysis was carried out by flow cytometry using a broad panel of monoclonal antibodies including activation, costimulatory, adhesion, and growth factor receptor molecules. Moreover, intracellular staining and stimulation experiments were performed to investigate whether CD5 antigen was either retained in the cytoplasm of clonal B cells or not expressed due to defective cellular activation, respectively. Overall, CD5-negative leukemic cells were found to express significantly different levels of several membrane molecules, including CD95, CD69, CD23, CD25, CD80, and CD20, compared to "classic" CLL B cells. CD5 antigen was not detected in the cytoplasm of CD5-negative clonal B cells, nor could it be induced following in vitro activation. CD3+ T cell proportions were found to be less affected in CD5-negative patients than in classic B-CLL. Although these data suggest that CD5-negative clonal B cells are phenotypically different from classic B-CLL, clinical outcomes were similar to those shown by B-CLL patients, with most of the patients experiencing a long-lasting disease requiring chemotherapeutic intervention at some time during the disease course. PMID- 25432436 TI - Bleeding complications after arthroscopy in a JAK2V617F-positive patient with essential thrombocythemia and acquired von Willebrand syndrome (AVWS). AB - Acquired von Willebrand syndrome (AVWS) is an acquired bleeding disorder with clinical and laboratory features similar to those of the inherited form of the disease. AVWS is reported in many disorders, most frequently in myeloproliferative neoplasms and in, among others, essential thrombocythemia (ET). Interestingly, ET is associated with both the thrombotic and haemorrhagic complications, which occur in 20 % and 5-30 % of patients, respectively. The present report concerns a 38-year-old man, suffering from ET, who presented with two episodes of post-arthroscopic joint bleeding after synovectomy required for the treatment of synovial hypertrophy and chronic left knee joint synovitis. We discuss the current diagnostic approaches, as well as the risk factors predisposing to bleeding and its management, in patients with essential thrombocythemia. PMID- 25432437 TI - Outcome of pediatric acute lymphoblastic leukemia with very late relapse: a retrospective analysis by the Tokyo Children's Cancer Study Group (TCCSG). AB - Relapse period is strongly associated with second relapse risk in relapsed acute lymphoblastic leukemia (ALL) in children. In this context, the treatment outcome of very late relapse should be better; however, data regarding very late relapse is limited. We retrospectively analyzed the outcomes of two consecutive Tokyo Children's Cancer Study Group (TCCSG) ALL trials (1995-2004) with a focus on late relapse, which was divided into two categories: late relapse (6-24 months from the end of therapy, n = 48) and very late relapse (>24 months from the end of therapy, n = 57). Forty-three patients (29 late relapse and 14 very late relapse) received allogeneic hematopoietic stem cell transplantation (HSCT) at second remission. The event-free survival (EFS) probabilities of late relapse and very late relapse were 54.5 +/- 7.3 and 64.8 +/- 6.8 % at 7 years, respectively (P = 0.36), and were not significantly different. However, the second relapse incidence of late relapse (34.7 +/- 7.1 %) was higher than that of very late relapse (15.5 +/- 5.1 %, P = 0.03). The second relapse risk was low for very late relapse ALL, which suggests that these patients should be treated without allogeneic HSCT. PMID- 25432438 TI - Protein structural studies by paramagnetic solid-state NMR spectroscopy aided by a compact cyclen-type Cu(II) binding tag. AB - Paramagnetic relaxation enhancements (PREs) are a rich source of structural information in protein solid-state NMR spectroscopy. Here we demonstrate that PRE measurements in natively diamagnetic proteins are facilitated by a thiol-reactive compact, cyclen-based, high-affinity Cu(2+) binding tag, 1-[2-(pyridin-2 yldisulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (TETAC), that overcomes the key shortcomings associated with the use of larger, more flexible metal-binding tags. Using the TETAC-Cu(2+) K28C mutant of B1 immunoglobulin-binding domain of protein G as a model, we find that amino acid residues located within ~10 A of the Cu(2+) center experience considerable transverse PREs leading to severely attenuated resonances in 2D (15)N-(13)C correlation spectra. For more distant residues, electron-nucleus distances are accessible via quantitative measurements of longitudinal PREs, and we demonstrate such measurements for (15)N-Cu(2+) distances up to ~20 A. PMID- 25432439 TI - Novel roles of perivascular nerves on neovascularization. AB - Neovascularization, including angiogenesis, arteriogenesis and vasculogenesis, occurs in physiological and pathological state. Efficient and controlled reconstruction of functional vascular network is necessary. Nerves and blood vessels establish intricate branching network in every organ which share anatomical and functional characteristics. Nerves direct vessel branching patterns and arterial differentiation in the developmental embryonic limb skin. Various neurotransmitters exert antiapoptotic, chemotactic and proliferative effect on EC and SMC, and modulate all the phases of neovascularization. Hence, we proposed that the perivascular nerves may play critical roles in neovascularization. PMID- 25432441 TI - Current methods for reducing intussusception: survey results. AB - BACKGROUND: Intussusception is a common pediatric abdominal emergency, treated with image-guided reduction. Available techniques include fluoroscopic and ultrasonographic monitoring of liquid and air. OBJECTIVE: The purpose of this study was to determine current practices and establish trends by comparing our findings with reports of previous surveys. MATERIALS AND METHODS: This study is based on an e-mail survey sent to all 1,538 members of the Society for Pediatric Radiology. It included questions about demographics, presence of parents/surgeon during procedure, patient selection/preparation, use of sedation, preferred methods of reduction and technical details, approach to unsuccessful reduction, and self-reported incidence of success/perforation. RESULTS: The 456 respondents (30%) reported attempting 3,834 reductions in the preceding 12 months. Of these, 96% use fluoroscopy and 4% use US guidance for reduction; 78% use air, 20% prefer fluid; 75% require intravenous access; 63% expect a surgeon to be present in hospital; 93% do not sedate. Although inflating a rectal balloon is controversial, 39% do so, and 50% employ a pressure-release valve. Seventy-two percent attempt reductions three times in the same position. In case of unsuccessful reductions, 64% wait and re-attempt later, 19% apply manual pressure, and 15% try again in left decubitus position. About 20% reattempt reduction after waiting 2 h or more. CONCLUSION: By providing a better understanding of both trends in and diversity of current practice, we hope to increase the confidence with which the individual practitioner will approach each case. PMID- 25432440 TI - Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes. AB - Copy number variation has emerged as an important cause of phenotypic variation, particularly in relation to some complex disorders. Autism spectrum disorder (ASD) is one such disorder, in which evidence is emerging for an etiological role for some rare penetrant de novo and rare inherited copy number variants (CNVs). De novo variation, however, does not always explain the familial nature of ASD, leaving a gap in our knowledge concerning the heritable genetic causes of this disorder. Extended pedigrees, in which several members have ASD, provide an opportunity to investigate inherited genetic risk factors. In this current study, we recruited 19 extended ASD pedigrees, and, using the Illumina HumanOmni2.5 BeadChip, conducted genome-wide CNV interrogation. We found no definitive evidence of an etiological role for segregating CNVs in these pedigrees, and no evidence that linkage signals in these pedigrees are explained by segregating CNVs. However, a small number of putative de novo variants were transmitted from BAP parents to their ASD offspring, and evidence emerged for a rare duplication CNV at 11p13.3 harboring two putative 'developmental/neuropsychiatric' susceptibility gene(s), GSTP1 and NDUFV1. PMID- 25432444 TI - The interleukin-6 and interleukin-1A gene promoter polymorphism is associated with the pathogenesis of acne vulgaris. AB - Acne vulgaris is a skin disorder with a complex pathogenesis. Better treatment strategies require comprehensive knowledge of molecular factors contributing to the acne pathophysiology. Recent studies are focused on investigating the influence of inflammatory cytokines on the disease. This case-control study investigated the association of IL-6-572 G/C and IL-1A-889 C/T gene polymorphisms with acne in a Pakistani population. Pakistani subjects (380 healthy controls and 430 acne patients) were enrolled in this study. Polymorphism in the promoter region of IL-6-572 and IL-1A-889 was determined by polymerase chain reaction and restriction fragment length polymorphism. The IL-6-572 and IL-1A-889 variant genotypes were significantly associated with the acne pathogenesis. The IL-6-572C and the IL-1A-889T alleles were significantly high in the patient vs. control group (p < 0.0001 for both loci). The IL-6-572 G/C and IL-1A-889 C/T variant allele haplotypes showed significantly high prevalence in patients with acne; G-T (P = 0.0014), C-C (P < 0.0001), and C-T (P < 0.0001). This is the first report on the association between the IL-6-572 G/C polymorphism and acne among any population. The IL-1A-889 C/T polymorphism is also significantly linked with acne in the study population; the -889 C/T association with acne has been reported in one ethnic group previously. Our findings suggest that the IL-6-572C and IL-1A 889T alleles may contribute to the pathogenesis of acne in a Pakistani population. Further studies are required to verify these findings in other populations. PMID- 25432442 TI - Magnetic resonance evaluation of the knee in children and adolescents with achondroplasia. AB - BACKGROUND: Achondroplasia is the most common form of skeletal dysplasia. Although the radiographic features are well described, MRI features of the knee in achondroplasia have not been reported. OBJECTIVE: To describe common MRI characteristics of the knee joint in symptomatic children and adolescents with achondroplasia. MATERIALS AND METHODS: We retrospectively evaluated 10 knee MRI examinations in 8 children and young adults (age range 11-20 years, mean 16.3 years) with achondroplasia. We measured modified Insall-Salvati index, knee flexion angle, anterior cruciate ligament (ACL)-Blumensaat line angle, ACL-tibial angle, posterior cruciate ligament (PCL) angle, intercondylar notch width index, and intercondylar notch depth index. We compared our findings with an age- and gender-matched control group of 20 children (age range 15-18 years; mean 16 years) with normal knee MRIs. RESULTS: All 10 knees in the achondroplasia group had discoid lateral meniscus; 8 meniscal tears were identified. Patella baja was present in half of the study cases. Greater knee flexion and increased ACL Blumensaat line and PCL angles were seen in all achondroplasia knees. ACL-tibial angle was similar in the study and in the control group. Children with achondroplasia had deeper A-shape femoral notches that extended more anteriorly than those seen in the control group. MRI findings were confirmed in all seven knees with arthroscopic correlation. CONCLUSION: Discoid lateral meniscus, often with tear, is a consistent feature in knee MRIs of symptomatic children and adolescents with achondroplasia. Other findings include patella baja, knee flexion, deep A-shape intercondylar notch, increased ACL-Blumensaat line angle and taut PCL. PMID- 25432443 TI - Pulmonary lymphomatoid granulomatosis in a 4-year-old girl. AB - Lymphomatoid granulomatosis is a rare lymphoproliferative disease associated with the Epstein-Barr virus that commonly affects the lung. There is limited literature on cases of pediatric lymphomatoid granulomatosis. Half of all cases of lymphomatoid granulomatosis develop during the treatment of leukemia. Herein, we describe a case of lymphomatoid granulomatosis in a previously healthy child without leukemia. PMID- 25432445 TI - Steroids and Sesquiterpenes From Cultures of the Fungus Phellinus igniarius. AB - Two new steroids, 3alpha,17alpha,19,20-tetrahydroxy-4alpha-methylpregn-8-ene (1) and 3alpha,12alpha,17alpha,20-tetrahydroxy-4alpha-methylpregn-8-ene (2) and three new sesquiterpenoids, 12-hydroxy-alpha-cadinol (3), 3alpha,12-dihydroxy-delta cadinol (4), and 3alpha,6alpha-dihydroxyspiroax-4-ene (5), have been isolated from cultures of the fungus Phellinus igniarius. Their structures were characterized based on extensive spectroscopic data. In preliminary in vitro assays, compounds 3 and 4 exhibited the vascular-activities against phenylephrine induced vasoconstriction with the relaxing rates of 11.0 % and 7.0 % at 3 * 10-4 M, respectively. PMID- 25432446 TI - Self-assembly and nanosphere lithography for large-area plasmonic patterns on graphene. AB - Plasmonic structures on graphene can tailor its optical properties, which is essential for sensing and optoelectronic applications, e.g. for the enhancement of photoresponsivity of graphene photodetectors. Control over their structural and, hence, spectral properties can be attained by using electron beam lithography, which is not a viable solution for the definition of patterns over large areas. For the fabrication of large-area plasmonic nanostructures, we propose to use self-assembled monolayers of nanospheres as a mask for metal evaporation and etching processes. An optimized approach based on self-assembly at air/water interface with a properly designed apparatus allows the attainment of monolayers of hexagonally closely packed patterns with high long-range order and large area coverage; special strategies are devised in order to protect graphene against damage resulting from surface treatment and further processing steps such as reactive ion etching, which could potentially impair graphene properties. Therefore we demonstrate that nanosphere lithography is a cost effective solution to create plasmonic patterns on graphene. PMID- 25432447 TI - Continuous operation of membrane capacitive deionization cells assembled with dissimilar potential of zero charge electrode pairs. AB - The performance of single stack membrane assisted capacitive deionization cells configured with pristine and nitric acid oxidized Zorflex (ZX) electrode pairs was evaluated. The potentials of zero charge for the pristine and oxidized electrodes were respectively -0.2V and 0.2V vs. SCE. Four cell combinations of the electrodes including a pristine anode-pristine cathode, oxidized anode pristine cathode, pristine anode-oxidized cathode, and oxidized anode-oxidized cathode were investigated. When the PZC was located within the polarization window of the electrode, diminished performance was observed. The cells were operated at 1.2 V and based on potential distribution results, the effective working potentials were ~0.9, 0.8, 1.2, and 1.1 V for the pristine anode-pristine cathode, oxidized anode-pristine cathode, pristine anode-oxidized cathode, and oxidized anode-oxidized cathode cells, respectively. The highest electrosorption capacity of 17 mg NaCl/g ZX was observed for the pristine anode-oxidized cathode cell, where both PZCs were outside of the polarization window. PMID- 25432448 TI - Hemorrhagic complications of dental extractions in 181 patients undergoing double antiplatelet therapy. AB - PURPOSE: There is limited information on hemorrhagic complications during invasive dental procedures in patients treated with double antiplatelet therapy. The objective of this study is to assess the frequency of hemorrhagic complications of patients taking dual antiplatelet medication undergoing dental extractions. PATIENTS AND METHODS: An observational, multicenter, prospective, cohort study was performed in 11 oral and dental care units of primary care. The study sample was derived from the population of patients aged 18 years or older who were undergoing double antiplatelet therapy and presented to the oral and dental care units requiring dental extraction. Double antiplatelet therapy is the combination of 100 mg per day of acetylsalicylic acid and a second antiplatelet agent. The predictor variables were type of extraction performed, number of extracted teeth, number of extracted roots, and presence of inflammation. The primary outcome variable was intraoperative hemorrhage, and the secondary outcome variables were hemorrhage at 24 hours and hemorrhage at 10 days. First, a univariate analysis that considered all studied variables was performed. All variables with P < .25 in the univariate analysis were included in a multivariate analysis. The association between hemorrhage severity and its relevant factors was evaluated using logistic regression analysis. RESULTS: The study included 181 patients. Light hemorrhage (<30 minutes) was observed in 165 patients (91.2%). Intraoperative hemorrhage lasted more than 30 minutes in 15 patients (8.3%) and more than 60 minutes in only 1 patient, whose hemorrhage was controlled by local hemostatic measures. The presence of inflammation and 3-root extractions increased the probability of hemorrhage persisting for more than 30 minutes by factors of 10 and 7.3, respectively. CONCLUSIONS: In 8.3% of patients treated with dual antiplatelet therapy, dental extractions cause hemorrhagic complications lasting more than 30 minutes are resolved using local hemostatic measures. The results of this study support the safety of dental extraction without withdrawal double antiplatelet therapy. PMID- 25432449 TI - Is erbium:yttrium-aluminum-garnet laser versus conventional rotary osteotomy better in the postoperative period for lower third molar surgery? Randomized split-mouth clinical study. AB - PURPOSE: Lasers have been extensively used in dentistry for several applications. We investigated and compared the use of an erbium:yttrium-aluminum-garnet laser and conventional rotary instruments for bone removal in third molar surgery. MATERIALS AND METHODS: We implemented a randomized, split-mouth clinical trial. Patients with bilateral and symmetrical third molar impaction referred to the Department of Oral and Maxillo-Facial Sciences, "Sapienza" University of Rome, were enrolled in the study. Each patient was treated once with the erbium:yttrium aluminum-garnet laser and once with conventional rotary instruments for bone removal during third molar surgery. Pain, swelling, and trismus were taken into account to match the 2 techniques.In addition, the times required to complete osteotomy and for the full operation were recorded. Descriptive and bivariate statistics were computed, and the P value was set at .05. RESULTS: The sample was composed of 15 patients (8 men and 7 women) ranging in age from 18 to 30 years. Pain perceived in the laser-treated group was significantly less than that in the conventional group(P = .0013). This also was true for trismus (P = .0002) and swelling. The operating time for osteotomy was longer in the laser group. CONCLUSIONS: The results of this study suggest that the laser could be an interesting alternative to conventional rotary instruments. Future studies with a larger number of patients are required to confirm the conclusions achieved from this work. PMID- 25432450 TI - Riparian land-use and rehabilitation: impact on organic matter input and soil respiration. AB - Rehabilitated riparian zones in agricultural landscapes enhance environmental integrity and provide environmental services such as carbon (C) sequestration. This study quantified differences in organic matter input, soil biochemical characteristics, and soil respiration in a 25-year-old rehabilitated (RH), grass (GRS), and undisturbed natural forest (UNF) riparian zone. Input from herbaceous vegetation was significantly greater (P < 0.05) in the GRS riparian zone, whereas autumnal litterfall was significantly greater (P < 0.05) in the RH riparian zone. Soil bulk density was significantly greater (P < 0.05) in the RH riparian zone, but its soil chemical characteristics were significantly lower. Soil respiration rates were lowest (P < 0.05) in the UNF (106 C m(-2) h(-1)), followed by the RH (169 mg C m(-2) h(-1)) and GRS (194 C m(-2) h(-1)) riparian zones. Soil respiration rates were significantly different (P < 0.05) among seasons, and were significantly correlated with soil moisture (P < 0.05) and soil temperature (P < 0.05) in all riparian zones. Soil potential microbial activity indicated a significantly different (P < 0.05) response of the microbial metabolic diversity in the RH compared to the GRS and UNF riparian zones, and principle component analysis showed a distinct difference in microbial activity among the riparian land-use systems. Rehabilitating degraded riparian zones with trees rather than GRS is a more effective approach to the long-term mitigation of CO2. Therefore, the protection of existing natural/undisturbed riparian forests in agricultural landscapes is equally important as their rehabilitation with trees, given their higher levels of soil organic C and lower soil respiration rates. PMID- 25432452 TI - Diffraction of collinear correlated photon pairs by an ultrasonic wave within Raman-Nath and intermediate region. AB - The phenomenon of collinear correlated photon pairs diffraction by an ultrasonic wave is investigated within Raman-Nath and intermediate region. The numbers of single photons and photon pairs counts in discrete diffraction orders were measured as functions of the Raman-Nath parameter. Similarly, the number of coincidence photon counts in separate diffraction orders was also investigated. It was shown experimentally that the phenomenon of photon pairs diffraction by an ultrasonic wave happens at angles identical to those corresponding to single photons diffraction. It was also demonstrated that in case of Raman-Nath diffraction the number of photon pairs in a selected, n(th), diffraction order varies with the Raman-Nath parameter changes as an n(th) order Bessel function of the first kind, raised to the fourth power. Whilst in the so-called intermediate diffraction zone, the number of diffracted photon pairs varies as squared intensity of a diffracted light beam consisting of single photons. Moreover, it was revealed that correlations between photons in selected diffraction orders change with the Raman-Nath parameter variation as products of relevant intensities of light in the considered diffraction orders. Finally, it should be emphasized that the presented formulae describing diffraction of collinear correlated proton pairs by an ultrasonic wave are in a very good agreement with corresponding experimental data, for both Raman-Nath and intermediate diffraction. PMID- 25432451 TI - A risk assessment approach to manage inundation of Elseya albagula nests in impounded waters: a win-win situation? AB - A risk assessment process was used to trial the impact of potential new operating rules on the frequency of nest inundation for the White-throated snapping turtle, Elseya albagula, in the impounded waters of the Burnett River, Queensland, Australia. The proposed operating rules would increase the barrage storage level during the turtle nesting season (May-July) and then would be allowed to reduce to a lower level for incubation for the rest of the year. These proposed operating rules reduce rates of nest inundation by altering water levels in the Ben Anderson Barrage impoundment of the Burnett River. The rules operate throughout the turtle reproductive period and concomitantly improve stability of littoral habitat and fishway operation. Additionally, the proposed rules are expected to have positive socio-economic benefits within the region. While regulated water resources will inherently have a number of negative environmental implications, these potential new operating rules have the capacity to benefit the environment while managing resources in a more sustainable manner. The operating rules have now been enacted in subordinate legislation and require the operator to maintain water levels to minimize turtle nest inundation. PMID- 25432453 TI - [Quality assurance in human genetic testing]. AB - BACKGROUND: Advances in technical developments of genetic diagnostics for more than 50 years, as well as the fact that human genetic testing is usually performed only once in a lifetime, with additional impact for blood relatives, are determining the extraordinary importance of quality assurance in human genetic testing. Abidance of laws, directives, and guidelines plays a major role. OBJECTIVES: This article aims to present the major laws, directives, and guidelines with respect to quality assurance of human genetic testing, paying careful attention to internal and external quality assurance. MATERIALS AND METHODS: The information on quality assurance of human genetic testing was obtained through a web-based search of the web pages that are referred to in this article. Further information was retrieved from publications in the German Society of Human Genetics and through a PubMed-search using term quality + assurance + genetic + diagnostics. RESULTS AND CONCLUSIONS: The most important laws, directives, and guidelines for quality assurance of human genetic testing are the gene diagnostics law (GenDG), the directive of the Federal Medical Council for quality control of clinical laboratory analysis (RiliBAK), and the S2K guideline for human genetic diagnostics and counselling. In addition, voluntary accreditation under DIN EN ISO 15189:2013 offers a most recommended contribution towards quality assurance of human genetic testing. Legal restraints on quality assurance of human genetic testing as mentioned in S 5 GenDG are fulfilled once RiliBAK requirements are followed. PMID- 25432454 TI - [Methodological challenges for genome-based prediction of diseases]. AB - The rapidly developing genotyping technology has led to the detection of many genetic factors that contribute to the pathogenesis of complex diseases. From this, the aim arose to use these results to offer tailored preventive measures or therapies based on an individual genetic profile. For this purpose, genetic tests are being developed that should allow us to identify individuals who belong to a high risk group with respect to a certain disease due to their genetic predisposition. Such tests are often based on known genetic risk factors that have been identified in genome-wide association studies. Typically, the effect estimates obtained from these studies are further used to construct a genetic risk measure to predict a certain phenotype. This paper describes several statistical and methodological challenges that must be coped with when establishing a genetic prediction model: Starting with the goal to obtain unbiased effect estimates to identify appropriate genetic risk predictors, genetic risk measures must be developed, and the predictive value of a new genetic test must be established. These key requirements of a statistical risk prediction in genetics will be discussed in three sections and finally discussed from a public health perspective. PMID- 25432455 TI - [Colonization-outbreak of two clonally different strains of Serratia marcescens in a neonatal intensive care unit]. AB - We describe an outbreak of two clonally different strains of Serratia marcescens in a neonatal intensive care unit. Three colonization cases in the first outbreak phase were related to contact transmission from an index patient during emergency respiratory treatment while eight colonizations in the second phase were caused by contaminated bathing lotion. All transmissions resulted in colonization only and no infections were recorded. Based on our experience and the literature review sufficient staffing levels, basic hygiene and a goal-directed investigation of the environment are the cornerstones of a rapid outbreak termination. The epidemiological search for parallels in cases should be assisted by sophisticated electronic records. PMID- 25432457 TI - A common-sense model of injury perceptions. AB - The aim of this study was to clarify the difference between perceptions of injury and illness. A qualitative study using semi-structured interviews was conducted with 38 individuals who had been injured in the past, 8 medical psychologists, 62 graduate psychology students, and 19 health professionals treating injured patients. Data were analyzed by modified analytic induction and constant comparison methods. Common-sense perceptions of injury overlapped with some perceptions of illness, and 4 new themes were elicited. It was concluded that there are themes unique to injury perceptions that should be recognized in research as well as in clinical interventions. PMID- 25432456 TI - In situ acidity and pH of size-fractionated aerosols during a recent smoke-haze episode in Southeast Asia. AB - The characterization of aerosol acidity has received increased attention in recent years due to its influence on atmospheric visibility, climate change and human health. Distribution of water soluble inorganic (WSI) ions in 12 different size fractions of aerosols was investigated under two different atmospheric conditions (smoke-haze and non-haze periods) in 2012 using the Micro-Orifice Uniform Deposit Impactor (MOUDI) and nano-MOUDI for the first time in Singapore. To estimate the in situ acidity ([H(+)]Ins) and in situ aerosol pH (pHIS), the Aerosol Inorganic Model version-IV under deliquescent mode of airborne particles was used at prevailing ambient temperature and relative humidity. The study revealed an increase in the levels of airborne particulate matter (PM) mass and concentrations of WSI ions for all size fractions during the smoke-haze period, which was caused by the trans-boundary transport of biomass burning-impacted air masses from Indonesia. A bimodal distribution was observed for concentrations of SO4(2-), NO3(-), Cl(-), K(+) and Na(+), whereas concentrations of NH4(+), Ca(2+) and Mg(2+) showed a single mode distribution. The concentration of WSI ions in PM1.8 during the smoke-haze period increased by 3.8 (for SO4(2-)) to 10.5 (for K(+)) times more than those observed during the non-haze period. The pHIS were observed to be lower during the smoke-haze period than that during the non-haze period for all size fractions of PM, indicating that atmospheric aerosols were more acidic due to the influence of biomass burning emissions. The particles in the accumulation mode were more acidic than those in the coarse mode. PMID- 25432458 TI - Social Return on Investment: Valuing health outcomes or promoting economic values? AB - Interventions and activities that influence health are often concerned with intangible outcomes that are difficult to value despite their potential significance. Social Return on Investment is an evaluation framework that explores all aspects of change and expresses these in comparable terms. It combines qualitative narratives and quantitative measurements with a financial approach to enable outcomes that can otherwise be overlooked or undervalued to be incorporated appropriately. This article presents Social Return on Investment as an effective tool for supporting the development of a holistic appreciation of how interventions impact on the health and well-being of individuals, communities and societies. PMID- 25432459 TI - Diagnostic Accuracy of Clinical Tests for Morton's Neuroma Compared With Ultrasonography. AB - The aim of the present study was to assess the diagnostic accuracy of 7 clinical tests for Morton's neuroma (MN) compared with ultrasonography (US). Forty patients (54 feet) were diagnosed with MN using predetermined clinical criteria. These patients were subsequently referred for US, which was performed by a single, experienced musculoskeletal radiologist. The clinical test results were compared against the US findings. MN was confirmed on US at the site of clinical diagnosis in 53 feet (98%). The operational characteristics of the clinical tests performed were as follows: thumb index finger squeeze (96% sensitivity, 96% accuracy), Mulder's click (61% sensitivity, 62% accuracy), foot squeeze (41% sensitivity, 41% accuracy), plantar percussion (37% sensitivity, 36% accuracy), dorsal percussion (33% sensitivity, 26% accuracy), and light touch and pin prick (26% sensitivity, 25% accuracy). No correlation was found between the size of MN on US and the positive clinical tests, except for Mulder's click. The size of MN was significantly larger in patients with a positive Mulder's click (10.9 versus 8.5 mm, p = .016). The clinical assessment was comparable to US in diagnosing MN. The thumb index finger squeeze test was the most sensitive screening test for the clinical diagnosis of MN. PMID- 25432460 TI - Hindfoot Deformity Corrected With Double Versus Triple Arthrodesis: Radiographic Comparison. AB - Hindfoot fusion is capable of correcting hindfoot deformities. Typically, this has been done through triple arthrodesis. Recently, there has been some discussion of a double arthrodesis, sparing the calcaneocuboid joint. We compared the radiographic corrective ability of these 2 fusion techniques. A retrospective radiographic review was performed of 20 consecutive triple arthrodeses (triple) and 20 consecutive talonavicular and subtalar arthrodesis with calcaneocuboid preservation (double). Additional midfoot arthrodesis or osteotomy was performed as needed in each group. The preoperative measurements were compared to those from standing weightbearing films after fusion postoperatively. The angular measurements included the anteroposterior and lateral talar-first metatarsal line (Meary's and Simmons) and the anteroposterior and lateral talocalcaneal angle. Both groups demonstrated a statistically significant reduction in deformity and a return to more normal radiographic findings after arthrodesis (p < .05). The 2 groups did not differ statistically in preoperative deformity or correction obtained (p > .05). Traditionally, triple arthrodesis has been advocated for significant hindfoot deformity that is irreducible. Recent studies have questioned the need for inclusion of the calcaneocuboid joint in the arthrodesis, in particular, in a pronated, valgus-type foot. In addition, others have advocated a strictly medial approach to hindfoot fusion, necessarily avoiding the calcaneocuboid joint. Our findings agree with the assertion that hindfoot deformity can be adequately and reliably corrected through hindfoot arthrodesis whether or not the calcaneocuboid joint is included. PMID- 25432461 TI - Targeting the Plantar Fascia for Corticosteroid Injection. AB - Plantar fasciitis is often a difficult condition to treat. It is related to repetitive strain of the fascia at its attachment to the heel bone. This condition quite often appears with the concomitant presence of a plantar calcaneal heel spur. Corticosteroid injection is a popular treatment choice for plantar fasciitis, and accurate localization of the injected medication is essential for successful resolution of symptoms after the injection. In the present brief technical communication, a method for targeting the attachment of the plantar fascia to the medial tubercle of the tuberosity of the calcaneus is described. The targeting method uses the lateral radiograph of the foot to aid in localization of the proximal attachment of the plantar fascia to the calcaneus. PMID- 25432462 TI - Protein tyrosine phosphatases: molecular switches in metabolism and diabetes. AB - Protein tyrosine phosphatases (PTPs) are a large family of enzymes that generally oppose the actions of protein tyrosine kinases (PTKs). Genetic polymorphisms for particular PTPs are associated with altered risk of both type 1 diabetes (T1D) and type 2 diabetes (T2D). Moreover, recent evidence suggests that PTPs play crucial roles in metabolism. They can act as regulators of liver homeostasis, food intake, or immune-mediated pancreatic b cell death. In this review we describe the mechanisms by which different members of the non-receptor PTP (PTPN) family influence metabolic physiology. This 'metabolic job' of PTPs is discussed in depth and the role of these proteins in different cell types compared. Understanding the pathways regulated by PTPs will provide novel therapeutic strategies for the treatment of diabetes. PMID- 25432464 TI - Evaluation of Sexual Function and Its Contributing Factors in Men With Spinal Cord Injury Using a Self-Administered Questionnaire. AB - Sexual activity is an important aspect of life in patients with spinal cord injury (SCI), rated as one of the top priorities for recovery of function. This study was conducted to establish an understanding of the severity of erectile dysfunction (ED), a major component of male sexual activity, and its correlates in patients with SCI in our community. In a cross-sectional study, 37 male veterans with SCI admitted for regular follow-up at our center were recruited. Demographic and SCI-related descriptive information was gathered through a self administered questionnaire. Sexual Health Inventory for Men was used to assess the presence and severity of ED. Euro Quality of Life questionnaire and General Health Questionnaire (GHQ-12) were also administered. The mean age of the participants was 45.7 +/- 6.5 years with injury duration of 24.7 +/- 6.2 years. Mean GHQ-12 score of 3.65 +/- 3.38 and mean Sexual Health Inventory for Men score of 11.57 +/- 5.28 were measured. All participants had ED, and 27% were suffering from severe ED. Sleep deprivation, worse GHQ-12 score, and hypertension were significantly associated with higher risk of much severe ED (p < .05). In conclusion, ED is a common problem in veterans with SCI and is inversely associated with their general health status. PMID- 25432463 TI - Biochanin A inhibits lipopolysaccharide-induced inflammatory cytokines and mediators production in BV2 microglia. AB - Biochanin A, one of the major isoflavonoids in red clover or cabbage, has been reported to have anti-inflammatory effects. However, the molecular mechanism underlying the anti-inflammatory effects of biochanin A has not been completely elucidated. The aim of this study was to investigate the anti-inflammatory effect and mechanism on lipopolysaccharide (LPS)-stimulated BV2 microglia. The results showed that biochanin A suppressed LPS-induced inflammatory mediators nitric oxide, prostaglandin E2 and inflammatory cytokines TNF-alpha and IL-1beta production. LPS-induced NF-kappaB activation was also inhibited by biochanin A. In addition, biochanin A up-regulated the expression of PPAR-gamma and the anti inflammatory effects of biochanin A can be abolished by PPAR-gamma antagonist GW9662. These results suggest that biochanin A exerts an anti-inflammatory property by activating PPAR-gamma, thereby attenuating NF-kappaB activation and the release of pro-inflammatory mediators. PMID- 25432465 TI - Use of Music Intervention for Reducing Anxiety and Promoting Satisfaction in First-Time Filipino Fathers. AB - Childbirth is an anxiety-provoking event in a man's life. Therefore, strategies to decrease paternal anxiety during childbirth are necessary. This study determined the effects of music and satisfaction of first-time Filipino fathers during childbirth. In the study, a prospective quasi-experimental design was utilized. Ninety-eight purposive samples of first-time fathers were included in the study, 50 were allocated in the experimental group (music group) and 48 in the control group (nonmusic group) during the months of August to October 2013. Paternal anxiety and satisfaction were measured using the State Trait Anxiety Inventory and the Visual Analogue Scale for Satisfaction, respectively. Results revealed that the first-time fathers in the experimental group had lower State Trait Anxiety Inventory scores (p < .05) and higher Visual Analogue Scale for Satisfaction scores (p < .05) than those in the control group. Findings of the study provide substantial evidence to support the use of music in reducing anxiety and promoting satisfaction among first-time fathers during childbirth. PMID- 25432468 TI - Cyberbullying of mental health patients: ethical and professional considerations for publication of case reports in the digital age. PMID- 25432467 TI - The remote exercise monitoring trial for exercise-based cardiac rehabilitation (REMOTE-CR): a randomised controlled trial protocol. AB - BACKGROUND: Exercise is an essential component of contemporary cardiac rehabilitation programs for the secondary prevention of coronary heart disease. Despite the benefits associated with regular exercise, adherence with supervised exercise-based cardiac rehabilitation remains low. Increasingly powerful mobile technologies, such as smartphones and wireless physiological sensors, may extend the capability of exercise-based cardiac rehabilitation by enabling real-time exercise monitoring for those with coronary heart disease. This study compares the effectiveness of technology-assisted, home-based, remote monitored exercise based cardiac rehabilitation (REMOTE) to standard supervised exercise-based cardiac rehabilitation in New Zealand adults with a diagnosis of coronary heart disease. METHODS/DESIGN: A two-arm, parallel, non-inferiority, randomised controlled trial will be conducted at two sites in New Zealand. One hundred and sixty two participants will be randomised at a 1:1 ratio to receive a 12-week program of technology-assisted, home-based, remote monitored exercise-based cardiac rehabilitation (intervention), or an 8-12 program of standard supervised exercise-based cardiac rehabilitation (control).The primary outcome is post treatment maximal oxygen uptake (VO2max). Secondary outcomes include cardiovascular risk factors (blood lipid and glucose concentrations, blood pressure, anthropometry), self-efficacy, intentions and motivation to be active, objectively measured physical activity, self-reported leisure time exercise and health-related quality of life. Cost information will also be collected to compare the two modes of delivery. All outcomes are assessed at baseline, post treatment, and 6 months, except for VO2max, blood lipid and glucose concentrations, which are assessed at baseline and post-treatment only. DISCUSSION: This novel study will compare the effectiveness of technology supported exercise-based cardiac rehabilitation to a traditional supervised approach. If the REMOTE program proves to be as effective as traditional cardiac rehabilitation, it has potential to augment current practice by increasing access for those who cannot utilise existing services. TRIAL REGISTRATION: Australian New Zealand Clinical Trials RegistryStudy ID number: ACTRN12614000843651. Registered 7 August 2014. PMID- 25432469 TI - Impact of biodiversity and seasonality on Lyme-pathogen transmission. AB - Lyme disease imposes increasing global public health challenges. To better understand the joint effects of seasonal temperature variation and host community composition on the pathogen transmission, a stage-structured periodic model is proposed by integrating seasonal tick development and activity, multiple host species and complex pathogen transmission routes between ticks and reservoirs. Two thresholds, one for tick population dynamics and the other for Lyme-pathogen transmission dynamics, are identified and shown to fully classify the long-term outcomes of the tick invasion and disease persistence. Seeding with the realistic parameters, the tick reproduction threshold and Lyme disease spread threshold are estimated to illustrate the joint effects of the climate change and host community diversity on the pattern of Lyme disease risk. It is shown that climate warming can amplify the disease risk and slightly change the seasonality of disease risk. Both the "dilution effect" and "amplification effect" are observed by feeding the model with different possible alternative hosts. Therefore, the relationship between the host community biodiversity and disease risk varies, calling for more accurate measurements on the local environment, both biotic and abiotic such as the temperature and the host community composition. PMID- 25432470 TI - Defining the system: contributors to exercise limitations in heart failure. AB - One of the primary hallmarks of patients diagnosed with heart failure (HF) is a reduced tolerance to exercise and compromised functional capacity. This limitation stems from poor pumping capacity but also major changes in functioning of the vasculature, skeletal muscle, and respiratory systems. Advances in the understanding of the central and peripheral mechanisms of exercise intolerance during HF are critical for the future design of therapeutic modalities devised to improve outcomes. The interrelatedness between systems cannot be discounted. This review summarizes the current literature related to the pathophysiology of HF contributing to poor exercise tolerance, and potential mechanisms involved. PMID- 25432471 TI - Reversing heart failure-associated pathophysiology with exercise: what actually improves and by how much? AB - Until the late 1980s, physical exercise training was a contraindication in patients with heart failure. Extensive research has demonstrated that exercise training reverses heart failure-associated pathology at the clinical and molecular levels. Exercise training has emerged as a class I recommendation in all major national and international guidelines for the treatment of chronic heart failure. Knowledge gained in clinical trials and molecular research builds a strong case for exercise training as a key therapeutic component of an evidence based treatment of chronic heart failure. It is long overdue to provide patients with an infrastructure that enables them to benefit from this class I intervention. PMID- 25432472 TI - Functional assessment of heart failure patients. AB - A hallmark of heart failure (HF) is exercise intolerance, along with fatigue and shortness of breath. Functional assessments provide important clinical information. As the disease progresses, HF patients experience a downward spiral leading to a functional disability. Reduced functional abilities restrict or prevent HF patients from performing occupational tasks, which may result in loss of work and reduced quality of life. Functional assessments provide a measure of functional capacity and information on prognosis, disease severity, degree of disability, and quality of life. Direct and indirect cardiovascular and muscular functional assessments for patients with HF are provided in this review. PMID- 25432473 TI - Reasonable expectations: how much aerobic capacity, muscle strength, and quality of life can improve with exercise training in heart failure. AB - In this article, the literature that describes the magnitude of functional and quality of life gains with a traditional moderate-intensity aerobic and resistance training programs is reviewed, and differences between the impact of exercise training in heart failure with preserved ejection fraction versus heart failure with reduced ejection fraction are discussed. PMID- 25432474 TI - Prognosis: does exercise training reduce adverse events in heart failure? AB - Patients with heart failure (HF) were once discouraged from participating in exercise programs because of concerns regarding safety and the potential for harm to an already damaged myocardium. However, studies over the last 3 decades have provided extensive insights into both the health outcome benefits of exercise and the mechanisms underlying these benefits. Studies on the outcome benefits of exercise training, including mortality and hospitalization, have been convincing. This article reviews the physiologic benefits of exercise training in HF, studies on exercise training in women, results and implications of the HF-ACTION trial, and recent meta-analyses using the Cochrane data base. PMID- 25432475 TI - Rehabilitation practice patterns for patients with heart failure: the South American perspective. AB - Heart failure (HF) is an important public health issue in South America. Economic impacts are substantial. Chagas heart disease is a prevalent HF etiology; it is caused by the protozoan Trypanosoma cruzi. Cardiac rehabilitation (CR) is an integral component of HF care. The benefits of CR in HF patients need to be assessed. The effectiveness and safety of CR delivery, such as home-based interventions, should be explored. Strategies to improve adherence in CR are imperative. We describe past and current CR trends for HF patients and discuss the future of this important intervention. PMID- 25432476 TI - Exercise therapy for heart failure patients in Canada. AB - Contemporary pharmacologic therapies have greatly improved outcomes in patients with heart failure (HF). Exercise therapy also has become increasingly recognized and utilized over the last decade. Patients with HF undergo significant central and peripheral deconditioning. Aerobic and resistance training in this patient population may improve quality of life, muscular strength, aerobic capacity, and potentially longevity. Those HF patients who are able to remain adherent to exercise training programs may improve their self-monitoring skills with respect to progressive volume overload, as well as their capacity for independent living, thereby reducing the likelihood of rehospitalization. PMID- 25432477 TI - Rehabilitation practice patterns for patients with heart failure: the United States perspective. AB - Many anticipate that the recent decision of the US Center for Medicare Services to expand cardiac rehabilitation (CR) reimbursement to include patients with systolic heart failure (HF) will lead to expanded application of exercise therapy for eligible HF patients. Nonetheless, US patterns of referral to and enrollment in CR for coronary heart disease have been notoriously poor, and such persistent under-enrollment suggests that there are entrenched obstacles that will impede the use of exercise therapy despite the new CR HF indication. However, application of CR for HF may still grow due to dynamic shifts in contemporary US health care. PMID- 25432478 TI - Rehabilitation practice patterns for patients with heart failure: the Asian perspective. AB - More countries around world have begun to use cardiac rehabilitation in patients diagnosed with chronic heart failure (HF). Asia is the largest continent in the world and, depending on its economy, culture, and beliefs, a given Asian country differs from Western countries as well as others in Asia. The cardiac rehabilitation practice patterns for patients with HF are somewhat different in Asia. In addition to the formal pattern of Western practice, it also includes special techniques and skills, such as Taiji, Qigong, and Yoga. This article describes cardiac rehabilitation patterns for patients with HF in most Asian countries and areas. PMID- 25432479 TI - Past, present, and future rehabilitation practice patterns for patients with heart failure: the European perspective. AB - The recent European Society of Cardiology position paper strongly advises participation of patients with stable heart failure (HF) in structured exercise training (ET) programs, and in most recent years considerable efforts have been put into standardization of exercise prescription. Up to now, 3 ET modalities are proposed for HF populations with variable combinations and extent of effects: (1) endurance aerobic (continuous and interval); (2) strength/resistance; (3) respiratory. Irrespective of ET modalities, most of the studies have clearly demonstrated significant improvements in exercise physiology (ie, oxygen consumption, muscle function, and ventilation), quality of life, and left ventricular function. PMID- 25432480 TI - Pharmacologic and surgical interventions to improve functional capacity in heart failure. AB - Heart failure (HF) is a clinical syndrome of breathlessness, lower extremity swelling, fatigue, and exercise intolerance affecting a large portion of the population worldwide, and associated with premature death. Despite improvement in the management of HF, many patients remain unable to complete activities of daily living without experiencing exertional symptoms. Although prevention of death in patients with HF is imperative, treatment of symptoms and improving functional capacity are equally important goals. This article discusses treatments (medical and surgical) associated with improved functional capacity in HF. PMID- 25432481 TI - Risks and benefits of weight loss in heart failure. AB - Obesity adversely affects many cardiovascular disease (CVD) risk factors and increases the risk of most CVD, including heart failure (HF). HF is markedly increased in the setting of obesity. However, obese patients with HF have a better prognosis than lean patients with HF, which has been termed the obesity paradox. Therefore, the role of weight loss, which generally improves ventricular structure, systolic and diastolic ventricular function, and New York Heart Association functional class in HF, remains controversial. This article discusses the pros and cons of weight loss and differentiates purposeful (healthy) from nonpurposeful (unhealthy) weight loss. PMID- 25432482 TI - Much potential but many unanswered questions for high-intensity intermittent exercise training for patients with heart failure. AB - There is a robust trove of scientific studies that support the positive physical and mental health benefits associated with aerobic exercise for healthy individuals. These recommendations suggest that more vigorous exercise can be performed on fewer days for the same benefit. High-intensity intermittent exercise (HIIE) training has begun to show promise. HIIE seems safe and improves physiology, quality of life, and functional capacity. This review defines HIIE, discusses its physiologic benefit for patients with heart failure, outlines the studies that have been conducted to date, and places it in the context of the current clinical environment of exercise training for these patients. PMID- 25432483 TI - Breathing exercises and inspiratory muscle training in heart failure. AB - Breathing exercises (BE) and inspiratory muscle training (IMT) have been demonstrated to improve ventilation and ventilation-to-perfusion matching, and to improve exercise, functional performance, and many pathophysiologic manifestations of heart failure (HF). This article provides an extensive review of BE and IMT in patients with HF and identifies several key areas in need of further investigation, including the role of expiratory muscle training, IMT targeted at various locations of inspiration (early, mid, or late inspiration), and alteration of the ratio of inspiratory time to total breath time, all of which have substantial potential to improve many pathophysiologic manifestations of HF. PMID- 25432484 TI - Technology to promote and increase physical activity in heart failure. AB - Regular physical activity is firmly recommended as part of a multifaceted approach to heart failure (HF) self-management. Unfortunately, research indicates that most patients are less likely to engage in and adhere to such activities. The widespread use of information and communication technology tools and resources offers an innovative and potentially beneficial avenue for increasing physical activity levels in HF patients. This article presents specific ways in which advances in information and communication technologies, including Internet- and mobile-based communications, social media platforms, and self-monitoring health devices, can serve as a means to broadly promote increasing levels of physical activity to improve health outcomes in the HF population. PMID- 25432485 TI - Get a move on heart failure. PMID- 25432486 TI - Functional capacity and exercise training have earned a primary role in the assessment and treatment of patients with heart failure. PMID- 25432487 TI - Structural characterization, antioxidant and anticancer properties of gold nanoparticles synthesized from leaf extract(decoction)of Antigonon leptopus Hook. &Arn. AB - Tea is an aromatic beverage prepared by pouring boiling water over alleviated leaves of the tea plant. Tea prepared from the aerial parts of Antigonon leptopus has been traditionally used as remedy for cold, diabetes and pain in many countries. The gold nanoparticles (Au NPs) synthesized from powdered leaf extract (decoction) of A. leptopus were characterized by UV-visible spectroscopy (UV vis), X-ray diffraction (XRD), Fourier transform-infrared (FT-IR), high resolution transmission electron microscopy (HR-TEM), selected area electron diffraction (SAED) pattern and energy dispersive X-ray (EDX) analyses to define the formation of Au NPs. Further, the synthesized Au NPs were well characterized based on their strong surface plasmon resonance (SPR), crystalline nature, functional groups, size and dispersed shapes, purity and Bragg's reflections of face centered cubic (fcc) structure of metallic gold. The Au NPs showed higher free radical scavenging property when compared to the effect of leaf extract. Cytotoxicity study of synthesized Au NPs exhibited the growth inhibitory property at the concentration (GI50) of 257.8 MUg/mL in human adenocarcinoma breast cancer (MCF-7) cells after 48 h. Thus, the Au NPs synthesized from the Mexican creeper, A. leptopus revealed the important biological properties: as a free radical as well as anticancer agent. We conclude that the A. leptopus derived biological materials have promising potential as a source for the development of anticancer drug in future. PMID- 25432488 TI - Disorders of bilirubin binding to albumin and bilirubin-induced neurologic dysfunction. AB - Bilirubin-induced neurologic dysfunction (BIND) is a syndrome of subtle bilirubin neurotoxic disorders. The risk for developing BIND in newborns usually increases with elevated serum/plasma concentrations of unconjugated bilirubin. This risk is further increased by disorders of bilirubin binding to albumin, which includes a reduction in serum albumin concentrations or in the bilirubin-binding capacity and affinity of albumin, and the presence of displacing substances or infection. Serum unbound bilirubin (UB) concentration may be an ideal marker that reflects changes in bilirubin binding to albumin. Kernicterus, the chronic and with the most severe manifestations beyond BIND, is diagnosed by the presence of motor impairments with athetosis, abnormal magnetic resonance imaging, and/or brainstem auditory-evoked potential findings during infancy and childhood. Preterm infants sometimes have acute bilirubin encephalopathy without marked hyperbilirubinemia, such that bilirubin neurotoxicity occurs at bilirubin thresholds lower than usually associated with kernicterus. Disorders of bilirubin binding to albumin may be associated with the clinical signs of neurological injury associated with the lower bilirubin levels observed in preterm infants. PMID- 25432489 TI - NK cells regulating T cell responses: mechanisms and outcome. AB - Natural killer (NK) cells are important innate effectors in immunity. NK cells also have a role in the regulation of the adaptive immune response, and have been shown, in different contexts, to stimulate or inhibit T cell responses. Recent findings have expanded our understanding of the mechanisms underlying this regulation, revealing that regulation by NK cells can result from both direct interactions between NK cells and T cells, as well as indirectly, involving interactions with antigen presenting cells and the impact of NK cells on infected cells and pathogen load. We review these recent findings here, and outline emerging principles of how this regulation influences the overall outcome of adaptive immunity in infection and disease. PMID- 25432490 TI - Effect of a monthly dose of calcidiol in improving vitamin D deficiency and secondary hyperparathyroidism in HIV-infected patients. AB - There are no data about the optimal supplementation therapy in HIV-infected patients with vitamin D (25OHD) deficiency. The aim of this study was to assess the effect of an oral monthly dose of 16,000 IU calcidiol. We performed a longitudinal cohort study of 365 HIV-infected patients (24 % females) was with sequential determinations of 25OHD, serum parathyroid hormone (PTH), calcium, and alkaline phosphatase. The efficacy and safety of supplementation in 123 patients were compared against dietary and sun exposure advice. Overall, mean baseline 25OHD levels were 19.1 ng/ml (IQR 12-23.6), 63 % of patients had 25OHD deficiency and 27 % secondary hyperparathyroidism. After a median time of 9.3 months (95.61 patients-year on-treatment), 25OHD levels increased in comparison with non supplemented patients (+16.4 vs. +3.2 ng/ml; p < 0.01), decreasing the rate of 25OHD deficiency (from 84 to 24 %), and decreasing serum PTH (-4.9 pg/ml) and the rate of secondary hyperparathyroidism (from 43 to 31 %; p < 0.001). This improvement was observed irrespective of HIV/HCV coinfection or the use of efavirenz. In a regression analysis, adjusting by seasonality, a lower baseline 25OHD was associated with persistence of deficiency (relative risk, RR 1.07; 95 % CI 1.03-1.1; p < 0.001), whereas calcidiol supplementation was the only factor associated with significant improvement (RR 0.38; 95 % CI 0.12-0.46; p < 0.001). This monthly dose showed no clinical toxicity, and no patient had 25OHD levels above 100 ng/ml, nor hypercalcemia. The use of monthly calcidiol is safe, easy to take, and largely effective to improve vitamin D deficiency and secondary hyperparathyroidism in HIV-infected patients. PMID- 25432492 TI - C677T gene polymorphism of MTHFR and metabolic syndrome: response to dietary intervention. AB - BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms were found associated with body mass index (BMI)-defined obesity and lean mass. The aim of our study was to examine the role of the C677T MTHFR gene polymorphism in the response to diet in the management of metabolic syndrome. We investigated the body composition and metabolic factor changes after an hysocaloric balanced diet (HBD), in Italian obese women affected by metabolic syndrome (MS). METHODS: Forty four obese women affected by MS were eligible for the study. A HBD for 12 weeks was assigned. Study participation included a complete screening for dietary habits, anthropometry, body composition, blood biochemical markers and C677T MTHFR polymorphism genotyping. The study has been registrated by ClinicalTrials.gov Id: NCT01890070. RESULTS: The highest number of responders to HBD nutritional intervention were T(-) carriers (p <= 0.05). In the 81% of the total population a loss of Total Body Lean was observed. A significative loss (p <= 0.05) of Total Body Lean was observed in the 47% of T(-) carriers and in the 53% of T(+) carriers. Diastolic and systolic blood pressure, and waist circumference were reduced (p <= 0.05). The prevalence of MS parameters decreased by 84% for systolic and diastolic blood pressure; 79,5% for HDL cholesterol, 82% for fasting glucose and 77% for triglycerides. CONCLUSIONS: MTHFR genetic variations analysis would be an innovative tool for the nutritional assessment. Our data provide the basis for personalized dietary recommendations based on the individual's genetic makeup and nutritional status. TRIAL REGISTRATION: The study has been registrated by ClinicalTrials.gov Id: NCT01890070. PMID- 25432493 TI - Randomized clinical trial of a bladder neck plication stitch during robot assisted radical prostatectomy. AB - Urinary incontinence after robot-assisted radical prostatectomy (RARP) is one of the most bothersome complications affecting patients' daily lives. The efficacy of the bladder neck plication stitch technique in promoting an earlier return of continence was prospectively evaluated in 158 patients who underwent RARP for clinically localized prostate cancer by a single surgeon at our institute from March 2012 to January 2013. Patients were randomized 1:1 to undergo surgery with (n = 79) or without (n = 79) the bladder neck plication stitch, and their time to recovery from incontinence, defined as being pad free, was compared. Recovery from incontinence at 1, 3, and 6 months were observed in 22 (27.8%), 42 (53.2%), and 57 (72.2%) patients, respectively, treated with, and 23 (29.1%), 47 (59.5%), and 59 (74.7%) patients, respectively, treated without the bladder neck plication stitch, with no significant difference in time to recovery from incontinence between the two groups. Multivariate analysis showed that age, membranous urethral length and shape of the prostatic apex on magnetic resonance imaging were independent predictors of early recovery from urinary incontinence after RARP. The bladder neck plication stitch had no effect on time to recovery from postoperative urinary incontinence following RARP. PMID- 25432491 TI - Immunohistochemical and molecular study on the protective effect of curcumin against hepatic toxicity induced by paracetamol in Wistar rats. AB - BACKGROUND: An overdose of paracetamol is a frequent reason for liver and renal toxicity and possible death and curcumin has hepatoprotective properties against liver damage. The exact mechanism of such protection is not clear. Therefore, this study was conducted to examine the molecular levels of the protective effect of curcumin on paracetamol overdose induced hepatic toxicity in rats. METHODS: Male Wistar rats were allocated into 4 groups. Control group, administered corn oil; curcumin group, administered curcumin (400 mg/kg BW daily intra-gastric) dissolved in corn oil; paracetamol group, administered corn oil with a single dose of paracetamol (500 mg/kg BW intra-gastric) and protective group, administered curcumin with a single dose of paracetamol. Curcumin was administered for 7 successive days, while paracetamol was administered at day six of treatment. Blood and liver tissues were collected for biochemical, histopathological, immunohistochemical and molecular examination. RESULTS: Serum analysis revealed an alteration in parameters of kidney and liver. A decrease in the antioxidant activity of liver was recorded in paracetamol group while curcumin administration restored it. Histopathological findings showed an extensive coagulative necrosis in hepatocytes together with massive neutrophilic and lymphocytic infiltration. Immunostaining of liver matrix metalloproteinase-8 (MMP-8) in paracetamol administered rats showed an increase in MMP-8 expression in the area of coagulative necrosis surrounding the central vein of hepatic lobules. Curcumin administration decreased MMP-8 expression in liver of paracetamol administered rats. Gene expression measurements revealed that paracetamol decreased the expression of antioxidant genes and increased the expression of interleukin-1beta (IL-1beta), IL-8, tumor necrosis factor-alpha (TNF-alpha) and acute phase proteins. Curcumin administration ameliorated paracetamol-induced alterations in genes expression of antioxidant and inflammatory cytokines. CONCLUSION: The results clarified the strong protective effect of curcumin on paracetamol induced hepatic toxicity in rats at the immunohistochemical and molecular levels. PMID- 25432494 TI - Early history of inflatable penile prosthesis surgery: a view from someone who was there. AB - The publication of the use of an inflatable penile prosthesis (IPP) in 1973 by Dr. FB Scott. changed the world of treatment options for erectile dysfunction (ED). Much has been written since then about techniques, improvements, management of difficult cases, complications and their management, and mechanical and device changes over time. Few reports, if any, are available in the medical literature regarding the early development, surgical techniques, and controversies surrounding its introduction to the world's urological community. This article is, for the most part, the observations of one who was "there" in the early and mid-1970's and was a witness to the history of this remarkable marvel of creativity, engineering, design, and to the personalities involved. PMID- 25432495 TI - Are men talking their reproductive health away? AB - The advent of mobile phones has revolutionized communication trends across the globe. As the popularity of mobile phone usage continues to escalate, there is now growing concern about the effects of radiofrequency electromagnetic waves (RF EMW) exposure on biological tissues, such as the brain and testes. Researchers have sought to link the much debated decline in human sperm quality in the last decade, with increased exposure to RF-EMW, particularly through mobile phone usage. In a recent systematic review and meta-analysis on the effect of mobile phone RF-EMW radiation on sperm quality, Adams et al. [1] demonstrated an association between mobile phone exposure and reduced sperm motility and viability, with inconsistent effects on sperm concentration. [1] Results from 10 pooled experimental (in vitro) and observational (in vivo)human studies (n = 1492) led these researchers to suggest that exposure to RF-EMW radiation from carrying a mobile phone in the trouser pocket negatively impacts sperm quality. PMID- 25432496 TI - Effect of testosterone replacement treatment on constitutional and sexual symptoms in type 2 diabetic men: need for rules. AB - In a recent publication, Gianatti and colleagues investigated the effect of testosterone treatment in obese, aging men with type 2 diabetes (T2D) with mild to moderate symptoms, a modest reduction in testosterone levels, mild to moderate aging male symptoms, and erectile dysfunction. [1] The authors could not show any significant improvement in constitutional or sexual symptoms in this group of men. This randomized double-blind, parallel, and placebo-controlled trial among other critically emphasizes the increased testosterone prescriptions worldwide and together with other corroborating or contradictory studies awakes the need for guidelines in the androgen replacement treatment. PMID- 25432497 TI - Appraising the European randomized study of screening for prostate cancer: what do the results mean? AB - The value of screening for prostate cancer has been a contentious issue within the medical literature for several decades. At the crux of the matter lies a judgment call of whether the potential benefits of screening, a reduction in prostate cancer and all-cause mortality, outweigh the limitations, overdiagnosis and overtreatment. The study by Schrphider et al. reports 9, 11 and 13-year follow-up data on men participating in the European randomized study of screening for prostate cancer (ERSPC). While the authors report a significant reduction in prostate cancer mortality, they conclude that potential harms associated with screening currently circumvent any recommendation for a population-based approach to screening for prostate cancer. PMID- 25432499 TI - Commentary on "Awareness of and attitudes toward infertility and its treatment: a cross-sectional survey of men in a United States primary care population". PMID- 25432498 TI - Analysis of expanded criteria to select candidates for active surveillance of low risk prostate cancer. AB - We aimed to analyze the value of each criterion for clinically insignificant prostate cancer (PCa) in the selection of men for active surveillance (AS) of low risk PCa. We identified 532 men who were treated with radical prostatectomy from 2006 to 2013 who met 4 or all 5 of the criteria for clinically insignificant PCa (clinical stage <= T1, prostate specific antigen [PSA] density <= 0.15, biopsy Gleason score <= 6, number of positive biopsy cores <= 2, and no core with > 50% involvement) and analyzed their pathologic and biochemical outcomes. Patients who met all 5 criteria for clinically insignificant PCa were designated as group A (n = 172), and those who met 4 of 5 criteria were designated as group B (n = 360). The association of each criterion with adverse pathologic features was assessed via logistic regression analyses. Comparison of group A and B and also logistic regression analyses showed that PSA density > 0.15 ng ml-1 and high (>=7) biopsy Gleason score were associated with adverse pathologic features. Higher (> T1c) clinical stage was not associated with any adverse pathologic features. Although <= 3 positive cores were not associated with any adverse pathology, >=4 positive cores were associated with higher risk of extracapsular extension. Among potential candidates for AS, PSA density > 0.15 ng ml-1 and biopsy Gleason score > 6 pose significantly higher risks of harboring more aggressive disease. The eligibility criteria for AS may be expanded to include men with clinical stage T2 tumor and 3 positive cores. PMID- 25432500 TI - Relationship between self-reported residential indoor remodeling and semen quality: a case-control study. AB - The present study examined the association between residential indoor remodeling and poor semen quality. Sperm donors aged 18-45 years old were recruited in Shanghai, China. Semen specimens were collected and analyzed. An in-person interview was conducted to obtain information on the history of indoor remodeling and potential confounders. A total of 70 participants with abnormal semen quality (case group) and 68 controls were examined. A total of 20 subjects reported indoor remodeling in the recent 24 months, and among them 17 subjects reported indoor remodeling in the recent 12 months. Compared with participants with no history of indoor remodeling, participants with a history of indoor remodeling in the recent 24 months were more than three times as likely to have poor sperm quality (adjusted odds ratio = 3.8, 95% confidence interval: 1.3-12.0) after controlling for potential confounders. The association was strengthened when the analysis was restricted to those who had indoor remodeling in the recent 12 months. Our findings provide preliminary evidence that indoor remodeling has an adverse effect on semen quality. PMID- 25432501 TI - Testosterone deficiency and cardiovascular mortality. AB - New concerns have been raised regarding cardiovascular (CV) risks with testosterone (T) therapy (TTh). These concerns are based primarily on two widely reported retrospective studies. However, methodological flaws and data errors invalidate both studies as credible evidence of risk. One showed reduced adverse events by half in T-treated men but reversed this result using an unproven statistical approach. The authors subsequently acknowledged serious data errors including nearly 10% contamination of the dataset by women. The second study mistakenly used the rate of T prescriptions written by healthcare providers to men with recent myocardial infarction (MI) as a proxy for the naturally occurring rate of MI. Numerous studies suggest T is beneficial, including decreased mortality in association with TTh, reduced MI rate with TTh in men with the greatest MI risk prognosis, and reduced CV and overall mortality with higher serum levels of endogenous T. Randomized controlled trials have demonstrated benefits of TTh in men with coronary artery disease and congestive heart failure. Improvement in CV risk factors such as fat mass and glycemic control have been repeatedly demonstrated in T-deficient men treated with T. The current evidence does not support the belief that TTh is associated with increased CV risk or CV mortality. On the contrary, a wealth of evidence accumulated over several decades suggests that low serum T levels are associated with increased risk and that higher endogenous T, as well as TTh itself, appear to be beneficial for CV mortality and risk. PMID- 25432503 TI - What is the next generation therapeutic strategy for castration-resistant prostate cancer. AB - Prostate cancer (PCa) is one of the most common cancers in the world. Since androgen receptor (AR) signal plays key roles in the PCa progression, targeting androgens via the current androgen deprivation therapy (ADT) is the main therapeutic strategy for advanced PCa. However, most patients who receive ADT, including the second generation anti-androgens enzalutamide (also known as MDV3100) may finally develop the castration (or anti-androgen) resistance after 12-24 months treatment. In the manuscript by Asangani et al., the authors demonstrated that targeting the amino-terminal bromodomains of BRD4 could preferentially suppress human castration-resistant prostate cancer (CRPC) cell lines. While further studies are required to understand the full impact of their findings, the innovative approach provides a potential novel epigenetic approach for the concerted blockade of oncogenic drivers in CRPC. PMID- 25432502 TI - The reference values for semen parameters of 1213 fertile men in Guangdong Province in China. AB - Semen samples were collected from 1213 fertile men whose partners had a time-to pregnancy (TTP) <=12 months in Guangdong Province in Southern China, and semen parameters including semen volume, sperm concentration, total counts, motility, and morphology were evaluated according to the World Health Organization (WHO) 2010 guideline. All semen parameters analyzed were normal in ~62.2% of the total samples, whereas ~37.8% showed at least one of the semen parameters below normal threshold values. The fifth centiles (with 95% confidence intervals) were 1.3 (1.2-1.5) ml for semen volume, 20 * 10 6 (18*10 6 -20*10 6 ) ml-1 for sperm concentration, 40 * 10 6 (38*10 6 -44*10 6 ) per ejaculate for total sperm counts, 48% (47%-53%) for vitality, 39% (36%-43%) for total motility, 25% (23% 27%) for sperm progressive motility, 5.0% (4%-5%) for normal morphology. The pH values ranged from 7.2 to 8.0 with the mean +/- standard deviation at 7.32 +/- 0.17. No effects of age and body mass index were found on semen parameters. Occupation, smoking and alcohol abuse, varicocele appeared to decrease semen quality. Sperm concentration, but not sperm morphology, is positively correlated with TTP, whereas vitality is negatively correlated with TTP. Our study provides the latest reference values for the semen parameters of Chinese fertile men in Guangdong Province, which are close to those described in the new WHO guidelines (5 th Edition). PMID- 25432504 TI - Oral health among preschool children with autism spectrum disorders: A case control study. AB - AIM: To assess and compare the oral health status of preschool children with and without autism spectrum disorders. METHODS: A random sample of 347 preschool children with autism spectrum disorder was recruited from 19 Special Child Care Centres in Hong Kong. An age- and gender-matched sample was recruited from mainstream preschools as the control group. Dental caries status, gingival health status, tooth wear, malocclusion, dental trauma and oral mucosal health were assessed and compared between the two groups. RESULTS: It was feasible to conduct a comprehensive oral health screening among 74.1% (257) of the children with autism spectrum disorder. The mean age was 59 +/- 10 months (range from 32 to 77 months), of whom 84.4% were males. Children with autism spectrum disorder had better gingival health than children without autism spectrum disorder (mean plaque score and gingival score p < 0.001). Children with autism spectrum disorder had less caries experiences than children without autism spectrum disorder (mean decayed, missing and filled surfaces and decayed surfaces, p < 0.05). Children with and without autism spectrum disorder had similar prevalence of tooth wear, malocclusion, dental trauma experience and oral mucosal lesions (p > 0.05). CONCLUSION: Differences in oral health status exist among preschool children with and without autism spectrum disorder. Preschool children with autism spectrum disorder exhibited lower caries experiences and better gingival health than children without autism spectrum disorder. PMID- 25432505 TI - Effectiveness of a fundamental motor skill intervention for 4-year-old children with autism spectrum disorder: A pilot study. AB - A wait-list control experimental design was employed to investigate the effectiveness of a fundamental motor skill intervention at improving the motor skills, adaptive behavior, and social skills of 4-year-old children with autism spectrum disorder (experimental n = 5, control n = 4); the impact of intervention intensity was also explored. The experimental group significantly improved their object manipulation and overall motor scores from pre- to post-intervention. The wait-list control design revealed no group-by-time interactions; however, with the groups combined time was a significant factor for all motor variables. There were no significant changes in adaptive behavior and social skills. These preliminary findings suggest that a fundamental motor skill intervention may benefit young children with autism spectrum disorder. Future research with larger samples is warranted. PMID- 25432507 TI - Knowledge synthesis to improve practice requires up-to-date definitions, content, methods, and techniques. PMID- 25432508 TI - Computer-aided planning in orthognathic surgery-systematic review. AB - The aim of this study was to conduct a systematic review to evaluate the accuracy and benefits of computer-aided planning in orthognathic surgery. The search was performed in PubMed, EMBASE, Cochrane Library, LILACS, and SciELO. The articles identified were assessed independently and in a blinded manner by two authors using selection criteria and eligibility criteria. The database search yielded 375 studies. Following the application of search and eligibility criteria, a final nine studies were included in the systematic review. The level of agreement between the authors in the study selection process was substantial (kappa=0.767) and study eligibility was considered excellent (kappa=0.863). The accuracy of translation was <1.2mm in the maxilla (vertical) and <1.1mm in the mandible (sagittal), and for rotation was <1.5 degrees in the maxilla (pitch) and <1.8 degrees in the mandible (pitch). Two studies showed a medium potential risk of bias and six studies showed a high potential risk of bias. Computer-aided planning in orthognathic surgery was considered accurate for the studies included in this systematic review. However, the low quality of these studies means that randomized clinical trials are needed to compare computer-aided planning to conventional planning in orthognathic surgery. PMID- 25432506 TI - Social engagement with parents in 11-month-old siblings at high and low genetic risk for autism spectrum disorder. AB - Infant siblings of children with an autism spectrum disorder are at heightened genetic risk to develop autism spectrum disorder. We observed high risk (n = 35) and low risk (n = 27) infants at 11 months during free play with a parent. Children were assessed for autism spectrum disorder in toddlerhood. High-risk infants with a later diagnosis (n = 10) were less socially engaged with their parents than were low-risk infants. Parent behavior during play did not vary by group. Within the high-risk group, ratings of social reciprocity at 11 months predicted Autism Diagnostic Observation Schedule severity scores at follow-up, suggesting that systematic observations of parent-infant play may be a useful addition to early assessments of emerging autism spectrum disorder. PMID- 25432509 TI - Classification of daily mental status in critically ill patients for research purposes. AB - PURPOSE: The purpose of this study is to develop a reliable tool for daily mental status classification in intensive care unit (ICU) patients for research purposes. Secondly, to identify patients with single, 1-day episodes of delirium and to compare them with patients having more delirium days or episodes. PATIENTS AND METHODS: A 5-step algorithm was designed, which includes Richmond Agitation Sedation Scale and Confusion Assessment Method for the ICU scores from bedside nurses, initiation of delirium treatment, chart review, and the Confusion Assessment Method for the ICU administered by researchers. This algorithm was validated against a reference standard of delirium experts. Subsequently, a cohort study was performed in patients admitted to a mixed ICU. RESULTS: In 65 paired observations, the algorithm had 0.75 sensitivity and 0.85 specificity. Applying the algorithm, interobserver agreement was high with mean Fleiss kappa of 0.94 (5 raters) and 0.97 (4 raters). In the cohort study, 1112 patients were included of whom 535 (48%) became delirious. Single, 1-day episodes occurred in 43% of the delirious patients, whom were characterized by lower age compared with those with more delirium days. CONCLUSIONS: The algorithm for daily mental status classification seems to be a valid tool. In a substantial proportion of patients, delirium occurs only once during ICU admission lasting only 1 day. PMID- 25432510 TI - Vaccines, emerging viruses, and how to avoid disaster. AB - Rino Rappuoli is a graduate of Siena University, where he also earned his PhD before moving to the Sclavo Research Center, the Italian vaccine institute, also in Siena. He then spent two years in the USA, mostly at Harvard with John Murphy and Alwin Pappenheimer working on a new diphtheria vaccine based on a non-toxic mutant of diphtheria toxin which has since become the basis for conjugate vaccines against haemophilus, meningococcus, and pneumococcal infections, before returning to the Sclavo Research Center where he developed an acellular vaccine based on a mutant pertussis toxin. With many achievements in vaccine development to his credit, he is now Global Head of Vaccines Research and Development for Novartis Vaccines in Siena, and has most recently pioneered reverse vaccinology, in which the genome of the pathogen is screened for candidate antigenic and immunogenic vaccine components. We spoke to him about the potential for outbreaks of the kind we are now seeing with Ebolavirus in West Africa, and what can be done to prevent them. PMID- 25432511 TI - International comparison of the factors influencing reimbursement of targeted anti-cancer drugs. AB - BACKGROUND: Reimbursement policies for anti-cancer drugs vary among countries even though they rely on the same clinical evidence. We compared the pattern of publicly funded drug programs and analyzed major factors influencing the differences. METHODS: We investigated reimbursement policies for 19 indications with targeted anti-cancer drugs that are used variably across ten countries. The available incremental cost-effectiveness ratio (ICER) data were retrieved for each indication. Based on the comparison between actual reimbursement decisions and the ICERs, we formulated a reimbursement adequacy index (RAI): calculating the proportion of cost-effective decisions, either reimbursement of cost effective indications or non-reimbursement of cost-ineffective indications, out of the total number of indications for each country. The relationship between RAI and other indices were analyzed, including governmental dependency on health technology assessment, as well as other parameters for health expenditure. All the data used in this study were gathered from sources publicly available online. RESULTS: Japan and France were the most likely to reimburse indications (16/19), whereas Sweden and the United Kingdom were the least likely to reimburse them (5/19 and 6/19, respectively). Indications with high cost-effectiveness values were more likely to be reimbursed (rho = -0.68, P = 0.001). The three countries with high RAI scores each had a healthcare system that was financed by general taxation. CONCLUSIONS: Although reimbursement policies for anti-cancer drugs vary among countries, we found a strong correlation of reimbursements for those indications with lower ICERs. Countries with healthcare systems financed by general taxation demonstrated greater cost-effectiveness as evidenced by reimbursement decisions of anti-cancer drugs. PMID- 25432512 TI - What can we learn from a critically ill mouse? PMID- 25432513 TI - Slow-cycling stem cells in hydra contribute to head regeneration. AB - Adult stem cells face the challenge of maintaining tissue homeostasis by self renewal while maintaining their proliferation potential over the lifetime of an organism. Continuous proliferation can cause genotoxic/metabolic stress that can compromise the genomic integrity of stem cells. To prevent stem cell exhaustion, highly proliferative adult tissues maintain a pool of quiescent stem cells that divide only in response to injury and thus remain protected from genotoxic stress. Hydra is a remarkable organism with highly proliferative stem cells and ability to regenerate at whole animal level. Intriguingly, hydra does not display consequences of high proliferation, such as senescence or tumour formation. In this study, we investigate if hydra harbours a pool of slow-cycling stem cells that could help prevent undesirable consequences of continuous proliferation. Hydra were pulsed with the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU) and then chased in the absence of EdU to monitor the presence of EdU-retaining cells. A significant number of undifferentiated cells of all three lineages in hydra retained EdU for about 8-10 cell cycles, indicating that these cells did not enter cell cycle. These label-retaining cells were resistant to hydroxyurea treatment and were predominantly in the G2 phase of cell cycle. Most significantly, similar to mammalian quiescent stem cells, these cells rapidly entered cell division during head regeneration. This study shows for the first time that, contrary to current beliefs, cells in hydra display heterogeneity in their cell cycle potential and the slow-cycling cells in this population enter cell cycle during head regeneration. These results suggest an early evolution of slow-cycling stem cells in multicellular animals. PMID- 25432514 TI - CCM proteins control endothelial beta1 integrin dependent response to shear stress. AB - Hemodynamic shear stress from blood flow on the endothelium critically regulates vascular function in many physiological and pathological situations. Endothelial cells adapt to shear stress by remodeling their cytoskeletal components and subsequently by changing their shape and orientation. We demonstrate that beta1 integrin activation is critically controlled during the mechanoresponse of endothelial cells to shear stress. Indeed, we show that overexpression of the CCM complex, an inhibitor of beta1 integrin activation, blocks endothelial actin rearrangement and cell reorientation in response to shear stress similarly to beta1 integrin silencing. Conversely, depletion of CCM2 protein leads to an elongated "shear-stress-like" phenotype even in the absence of flow. Taken together, our findings reveal the existence of a balance between positive extracellular and negative intracellular signals, i.e. shear stress and CCM complex, for the control of beta1 integrin activation and subsequent adaptation of vascular endothelial cells to mechanostimulation by fluid shear stress. PMID- 25432515 TI - McArdle disease does not affect skeletal muscle fibre type profiles in humans. AB - Patients suffering from glycogen storage disease V (McArdle disease) were shown to have higher surface electrical activity in their skeletal muscles when exercising at the same intensity as their healthy counterparts, indicating more muscle fibre recruitment. To explain this phenomenon, this study investigated whether muscle fibre type is shifted towards a predominance in type I fibres as a consequence of the disease. Muscle biopsies from the Biceps brachii (BB) (n = 9) or Vastus lateralis (VL) (n = 8) were collected over a 13-year period from male and female patients diagnosed with McArdle disease, analysed for myosin heavy chain (MHC) isoform content using SDS-PAGE, and compared to healthy controls (BB: n = 3; VL: n = 10). All three isoforms were expressed and no difference in isoform expression in VL was found between the McArdle patients and healthy controls (MHC I: 33+/-19% vs. 43+/-7%; MHC IIa: 52+/-9% vs. 40+/-7%; MHC IIx: 15+/-18% vs. 17+/-9%). Similarly, the BB isoform content was also not different between the two groups (MHC I: 33+/-14% vs. 30+/-11%; MHC IIa: 46+/-17% vs. 39+/ 5%; MHC IIx: 21+/-13% vs. 31+/-14%). In conclusion, fibre type distribution does not seem to explain the higher surface EMG in McArdle patients. Future studies need to investigate muscle fibre size and contractility of McArdle patients. PMID- 25432516 TI - Mate choice and body pattern variations in the Crown Butterfly fish Chaetodon paucifasciatus (Chaetodontidae). AB - Mate choice is an important ecological behavior in fish, and is often based on visual cues of body patterns. The Crown Butterfly fish Chaetodon paucifasciatus (Chaetodontidae) is a monogamist, territorial species; it swims in close proximity to its partner throughout most of its life. This species is characterized by a pattern of 6-8 vertical black stripes on a white background, on both sides of its body. Our aim was to define spatial features (variations) in body patterns by evaluating the level of dissimilarity between both sides of each individual fish, and the level of dissimilarity between patterns of different individuals. In addition, we tested whether the fish are attracted to or reject specific features of the body patterns. Features were defined and counted using photographs of body patterns. Attraction to or rejection of specific features were tested behaviorally using a dual-choice experiment of video animations of individuals swimming over a coral-reef background. We found that the patterns of each fish and sides of the body were no less dissimilar, compared intraspecificly to other fish, and that each side pattern was unique and distinguishable. Variations in the patterns occurred mostly in the last three posterior stripes. Individuals were mainly attracted to conspecifics with multiple crossing patterns (two or more consecutive crossings), and rejected patterns with holes. Our results suggest that in this species the unique body pattern of each fish is used for conspecific identification of mates and intruders. PMID- 25432517 TI - A CRISPR/Cas9 toolkit for multiplex genome editing in plants. AB - BACKGROUND: To accelerate the application of the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/ CRISPR-associated protein 9) system to a variety of plant species, a toolkit with additional plant selectable markers, more gRNA modules, and easier methods for the assembly of one or more gRNA expression cassettes is required. RESULTS: We developed a CRISPR/Cas9 binary vector set based on the pGreen or pCAMBIA backbone, as well as a gRNA (guide RNA) module vector set, as a toolkit for multiplex genome editing in plants. This toolkit requires no restriction enzymes besides BsaI to generate final constructs harboring maize-codon optimized Cas9 and one or more gRNAs with high efficiency in as little as one cloning step. The toolkit was validated using maize protoplasts, transgenic maize lines, and transgenic Arabidopsis lines and was shown to exhibit high efficiency and specificity. More importantly, using this toolkit, targeted mutations of three Arabidopsis genes were detected in transgenic seedlings of the T1 generation. Moreover, the multiple-gene mutations could be inherited by the next generation. CONCLUSIONS: We developed a toolkit that facilitates transient or stable expression of the CRISPR/Cas9 system in a variety of plant species, which will facilitate plant research, as it enables high efficiency generation of mutants bearing multiple gene mutations. PMID- 25432518 TI - Kidney function as an underestimated factor for reduced health related quality of life in patients with Fabry disease. AB - BACKGROUND: Impairments of health related quality of life (HRQoL) are frequently observed in Fabry disease (FD) and are known to be related to neuropathic pain and cardiovascular events. This study aimed to explore the role of chronic kidney disease (CKD) in a large cohort of patients with FD. METHODS: In 96 patients (53% female; age 40+/-12 yrs) with genetically proven FD, HRQoL was assessed by the Medical Outcomes Study (SF-36) questionnaire. All patients were naive to enzyme replacement therapy. Three categories for kidney dysfunction were chosen, eGFR>=/<60 ml/min/1.73 m2 or need of renal replacement therapy (RRT). Minor (e.g. arrhythmia, angina pectoris, etc.) and major (e.g. myocardial infarction, coronary artery bypass, stroke or implantable cardioverter-defibrillator) vascular events as well as pain and pain therapy were considered in linear regression analyses with the dimensions of HRQoL. RESULTS: Ten patients (10%) had impaired kidney function and a further nine were on RRT (9.4%). Kidney function and pain emerged as the main factors associated with lower scores on the SF 36, in particular on physical components (PCS beta-coefficients for CKD -6.2, for RRT -11.8, for pain -9.1, p<0.05, respectively), while controlling for gender, vascular event and pain-therapy. Relationships were found for mental aspects of HRQoL. Age and history of vascular events were not related to HRQoL. CONCLUSION: Cardiovascular events and pain are important factors related to HRQoL, social functioning and depression. Our study highlights impaired chronic kidney disease, in particular after initiation of RRT, as a strong determinant of reduced HRQoL in FD. PMID- 25432519 TI - Tumor-infiltrating immune cell profiles and their change after neoadjuvant chemotherapy predict response and prognosis of breast cancer. AB - INTRODUCTION: Tumor microenvironment immunity is associated with breast cancer outcome. A high lymphocytic infiltration has been associated with response to neoadjuvant chemotherapy, but the contribution to response and prognosis of immune cell subpopulations profiles in both pre-treated and post-treatment residual tumor is still unclear. METHODS: We analyzed pre- and post-treatment tumor-infiltrating immune cells (CD3, CD4, CD8, CD20, CD68, Foxp3) by immunohistochemistry in a series of 121 breast cancer patients homogeneously treated with neoadjuvant chemotherapy. Immune cell profiles were analyzed and correlated with response and survival. RESULTS: We identified three tumor infiltrating immune cell profiles, which were able to predict pathological complete response (pCR) to neoadjuvant chemotherapy (cluster B: 58%, versus clusters A and C: 7%). A higher infiltration by CD4 lymphocytes was the main factor explaining the occurrence of pCR, and this association was validated in six public genomic datasets. A higher chemotherapy effect on lymphocytic infiltration, including an inversion of CD4/CD8 ratio, was associated with pCR and with better prognosis. Analysis of the immune infiltrate in post-chemotherapy residual tumor identified a profile (cluster Y), mainly characterized by high CD3 and CD68 infiltration, with a worse disease free survival. CONCLUSIONS: Breast cancer immune cell subpopulation profiles, determined by immunohistochemistry based computerized analysis, identify groups of patients characterized by high response (in the pre-treatment setting) and poor prognosis (in the post-treatment setting). Further understanding of the mechanisms underlying the distribution of immune cells and their changes after chemotherapy may contribute to the development of new immune-targeted therapies for breast cancer. PMID- 25432521 TI - Gene expression and genetic analysis reveal diverse causes of recessive self compatibility in Brassica napus L. AB - BACKGROUND: Brassica napus (AACC) is self-compatible, although its ancestor species Brassica rapa (AA) and Brassica oleracea (CC) are self-incompatible. Most B.napus accessions have dominant self-compatibility (SC) resulting from an insertion of 3.6 kb in the promoter region of BnSCR-1 on the A genome, while recessive SC in B.napus has rarely been observed. Expression and cloning of SRK and SCR genes and genetic analysis were carried out to dissect bases of recessive SC in B.napus. RESULTS: Eleven accessions were screened to identify stable recessive SC and had the S genotype BnS-7 on the A genome and BnS-6 on the C genome similarly to BrS-29 and BoS-15, respectively. In eight SC accessions, BnSCR-7 and BnSCR-6 were nearly undetectable and harbored no structural mutations in the promoters, while SRK genes were expressed at normal levels and contained intact CDS, with the exception of BnSRK-7 in line C32. SRK and SCR genes were expressed normally but their CDSs had no mutations in three SC accessions. In self-incompatible S-1300 and 11 F1 hybrids, SRK genes and BnSCR-1300 transcripts were present at high levels, while expression of the BnSCR-7 and BnSCR-6 were absent. Plants of S genotype S1300S1300 were completely SI, while SI phenotypes of SBnS-7SBnS-7 and S1300SBnS-7 plants were segregated in BC1 and F2 populations. CONCLUSIONS: The recessive SC in eight accessions is caused by the loss of function of BnSCR-7 and BnSCR-6 in pollen. Translational repression contributes to the recessive SC in three accessions, whose SRK and SCR genes were expressed normally and had identical CDSs to BrS-29 or BoS-15. SI in 11 F1 hybrids relies on the expression of BnSCR-1300 rather than SRK genes. Other factor(s) independent of the S locus are involved in recessive SC. Therefore, diverse causes underlie recessive SC in B. napus, yielding insight into these complex mechanisms. PMID- 25432520 TI - Plasmalogens and fatty alcohols in rhizomelic chondrodysplasia punctata and Sjogren-Larsson syndrome. AB - Plasmalogens are a special class of ether-phospholipids, best recognized by their vinyl-ether bond at the sn-1 position of the glycerobackbone and by the observation that their deficiency causes rhizomelic chondrodysplasia punctata (RCDP). The complex plasmalogen biosynthetic pathway involves multiple enzymatic steps carried-out in peroxisomes and in the endoplasmic reticulum. The rate limiting step in the biosynthesis of plasmalogens resides in the formation of the fatty alcohol responsible for the formation of an intermediate with an alkyl linked moiety. The regulation in the biosynthesis of plasmalogens also takes place at this step using a feedback mechanism to stimulate or inhibit the biosynthesis. As such, fatty alcohols play a relevant role in the formation of ether-phospholipids. These advances in our understanding of complex lipid biosynthesis brought two seemingly distinct disorders into the spotlight. Sjogren Larsson syndrome (SLS) is caused by defects in the microsomal fatty aldehyde dehydrogenase (FALDH) leading to the accumulation of fatty alcohols and fatty aldehydes. In RCDP cells, the defect in plasmalogens is thought to generate a feedback signal to increase their biosynthesis, through the activity of fatty acid reductases to produce fatty alcohols. However, the enzymatic defects in either glyceronephosphate O-acyltransferase (GNPAT) or alkylglycerone phosphate synthase (AGPS) disrupt the biosynthesis and result in the accumulation of the fatty alcohols. A detailed characterization on the processes and enzymes that govern these intricate biosynthetic pathways, as well as, the metabolic characterization of defects along the pathway should increase our understanding of the causes and mechanisms behind these disorders. PMID- 25432522 TI - Outcome of meniscal allograft transplantation related to articular cartilage status: advanced chondral damage should not be a contraindication. AB - PURPOSE: Advanced chondral damage (bare bone) at presentation is considered a contraindication to meniscal allograft transplantation (MAT), yet there are few other options for young patients where arthroplasty is not appropriate. This study hypothesis is that MAT in patients with advanced chondral damage can obtain good clinical outcomes, equivalent to patients with minimal chondral damage. METHOD: A prospective longitudinal study of 99 consecutive patients who underwent MAT between May 2005 and Feb 2013, with a minimum of 1-year follow-up. Patients were categorised into two groups: 60 in Group A (Good) up to ICRS Chondral grade 3b involving <1 cm(2) and 39 in Group B (Bare) ICRS grade 3b involving >1 cm(2) or worse. Outcomes were assessed by PROMS (KOOS, IKDC, Lysholm, Tegner Activity Scale), with an endpoint of meniscal allograft failure. RESULTS: Mean follow-up was 2.9 years (range 1.1-9.1, SD 1.23), with a similar male to female and lateral to medial ratios between the groups (n.s). The age of Group B was significantly older than Group A (35 vs 29 years, p = 0.002). The status of the articular cartilage at the time of transplant was directly related to the number of years since index meniscectomy [(A) Mean 6.9 years, SD 6.3; (B) 11.9 years, SD 7.4; p = 0.001]. Pre-operatively, patients in Group B had significantly worse pain and functional outcome scores (KOOS p = 0.022, Lysholm p = 0.025, IKDC pain subset p = 0.035). The mean increase PROMs was significant in both groups at 1 year (KOOS p < 0.05, IKDC p < 0.001, Lysholm p < 0.001), and the pain and functional scores were no longer significantly different between groups (n.s.). The outcome measures continued to improve in both groups at 2 and 3 years, with slightly greater improvement in Group A. Failure of the meniscal allograft occurred in 9 patients (A:1, B:8) at a mean time of 1.1 years (SD 0.55). Kaplan-Meier survival at 2 years was 97.9% (A) and 78% (B) (p = 0.002). Logistic regression analysis demonstrated a relationship between survival and chondral grade (p = 0.001) and number of concomitant procedures (p < 0.001). CONCLUSION: Patients with advanced chondral damage should not be excluded from MAT. Though there is a higher initial failure rate, these patients obtain a similar therapeutic benefit to the traditional, ideal patient group. LEVEL OF EVIDENCE: III. PMID- 25432524 TI - Delirium on the intensive care unit. PMID- 25432523 TI - Surgery for recurrent goiter: complication rate and role of the thyroid stimulating hormone-suppressive therapy after the first operation. AB - PURPOSE: This report examines outcomes in our series of patients who underwent surgery for recurrent goiter to assess the efficacy of thyroid-stimulating hormone (TSH)-suppressive therapy after the first less than total thyroidectomy. A further outcome was to understand whether redo surgery was burdened with a higher rate of complications. METHODS: We evaluated 214 patients undergoing a completion thyroidectomy for recurrent goiter who had received, as their first surgery, a bilateral subtotal thyroidectomy. After the first operation, 84 patients were given TSH-suppressive therapy with levothyroxine, 32 were treated with antithyroid drugs, and 92 did not receive any suppressive treatment but only a substitutive therapy. The 84 patients who received levothyroxine at a suppressive dosage (group A) were compared with 92 patients who did not receive levothyroxine or received it only at substitutive dosage (group B). We further compared the complication rate of a similar group of 175 patients who had undergone a primary thyroidectomy. RESULTS: The average age at intervention for relapse in group A patients was significantly lower than that of group B patients: 54.18 vs 60.8 years (p < 0.001). The average interval between the first intervention and the intervention for relapse was significantly shorter in group A than in group B: 24 vs 27 years (p = 0.03). After the operation, temporary hypoparathyroidism occurred in 37.7 % of patients and definitive hypoparathyroidism in 7.2 %. CONCLUSIONS: Our results clearly show that the interval between the two surgical interventions was significantly reduced in patients undergoing TSH-suppressive therapy with levothyroxine. The incidence of hypoparathyroidism dramatically increased. PMID- 25432526 TI - A grip force model for the da Vinci end-effector to predict a compensation force. AB - A torque transfer system (TTS) that measures grip forces is developed to resolve a potential drawback of the current da Vinci robot system whose grip forces vary according to the different postures of its EndoWrist. A preliminary model of EndoWrist Inner Mechanism Model (EIMM) is also developed and validated with real grip force measurements. EndoWrist's grip forces, posture angles, and transferred torque are measured by using TTS. The mean measured grip forces of three different EndoWrist for 27 different postures were very diverse. The EndoWrist exerted different grip forces, with a minimum of 1.84-times more and a maximum of 3.37-times more in specific posture even if the surgeon exerted the same amount of force. Using the posture angles as input and the grip forces as output, the EIMM is constructed. Then, expected grip force values obtained from EIMM are compared with actual measurements of da Vinci EndoWrist to validate the proposed model. From these results, surgeons will be beneficial with the understandings of actual grip force being applied to tissue and mechanical properties of robotic system. The EIMM could provide a baseline in designing a force-feedback system for surgical robot. These are significantly important to prevent serious injury by maintaining a proper force to tissue. PMID- 25432525 TI - Preoperative mp-MRI of the prostate provides little information about staging of prostate carcinoma in daily clinical practice. AB - PURPOSE: To evaluate the staging accuracy of preoperative multiparametric MRI (mp MRI), its influence on the technique of radical retropubic prostatectomy (RRP), and its value for daily clinical practice. METHODS: A total of 106 patients underwent RRP (January 2011-June 2012) and had preoperative MRI staging data available for review. Staging results acquired by mp-MRI were correlated to both biopsy and histopathology results. Surgical reports were reviewed for intraoperative aspect of tumor extension, technique of RRP (nerve sparing or extended), and extent of lymphadenectomy. RESULTS: The accuracy of diagnosing extracapsular extension (ECE) was 72.2 %, with an overall sensitivity and specificity of 30.0 and 93.3 %, respectively. The negative predictive value was 72.7 %. The sensitivity and specificity to diagnose positive seminal vesical invasion (SVI) were 63.6 and 92.9 %, respectively. Neither higher field force nor the use of an endorectal coil could enhance the accuracy of mp-MRI. In case of awareness of an existing MRI, there was a significantly higher percentage of nerve protection (left: 93 %; right: 89 % vs. left 75 %; right: 75 %). The higher percentage of nerve sparing surgery did not result in a higher level of positive resection margins. CONCLUSIONS: In routine clinical practice, mp-MRI at non academic centers has very limited clinical value in predicting ECE and SVI. Our data support the current recommendations against the widespread preoperative use of mp-MRI because it is not adding reliable predictive information on the extent of prostate cancer. PMID- 25432527 TI - Characteristics of neck and shoulder pain in the Japanese general population. AB - BACKGROUND: Neck and shoulder pain (NSP) is very common in the general population. However, little is known about the epidemiology of this condition. The purpose of this study was to investigate the characteristics and the factors associated with NSP and to reveal its effect on health-related quality of life (HRQOL). METHODS: Medical checkups were conducted among the residents of a mountain village where agroforestry and tourism are the main industries. The participants comprised 863 residents, including 308 males and 555 females. NSP was defined as the symptoms of muscle tension, stiffness, pressure or dull pain extending from the neck to the scapular arch. The participants completed a questionnaire including information on the presence of NSP, age, gender, musculoskeletal pain at other anatomical sites and medical complications. The NSP associated factors obtained by the questionnaire were investigated using univariate and multivariate analyses. The EuroQol (i.e., EQ-5D and EQ-VAS) was also assessed. RESULTS: The prevalence of NSP was 48.3 %, and NSP was more common in females than males. The prevalence was higher in the generation from 20 to 50 years of age and decreased with age. NSP was associated with pain in the upper extremities and lower EuroQol scores, but not with pain in the lower extremities or medical complications. A multivariate logistic regression analysis showed that female gender and pain in the upper extremities were independently associated with NSP. CONCLUSIONS: We used a general concept of NSP, which allowed us to collect the unified data about this condition among the participants. NSP was a prevalent health problem that led to deterioration of the HRQOL in the general population. Female gender and pain in the upper extremities were the factors associated with NSP. The characteristics of NSP clarified in this study may provide a basis for the prevention and/or effective management of NSP. PMID- 25432528 TI - Identifying hereditary cancer: genetic counseling and cancer risk assessment. AB - The goal of cancer genetic counseling, risk assessment, and testing is to identify individuals and families at risk for hereditary cancer, such that targeted management strategies can be used to reduce associated morbidity and mortality. Involvement of a qualified cancer genetic service provider helps to ensure that at-risk individuals identified and offered appropriate education, risk assessment, genetic testing, and follow-up risk management strategies. There are multiple screening and hereditary risk models available to help the clinician identify who needs to be referred to cancer genetic counseling and to facilitate the cancer risk assessment process. Genetic testing should only be pursued with fully informed consent in the context of pretest counseling to ensure that the individual understands the benefits, risks, and limitations of genetic testing, possible results, and their implications. Incorporating psychosocial assessment throughout the counseling session may assist the individual in their understanding of genetic testing in the context of their support resources and coping mechanisms and may help with decision making. There is a growing public awareness of and interest in cancer genetic testing, as well as increasing complexity of available testing options and results. It is therefore essential that cancer genetic professionals, primary care providers, and oncology practitioners work together to ensure that genetic testing for hereditary cancer syndromes is used in the most appropriate and effective way. PMID- 25432529 TI - A novel method for esophageal stent placement: retroflexed endoscopic guidance from the stomach. PMID- 25432530 TI - Endoscopic stent combined with endovaginal clipping for resolution of rectovaginal fistula after colorectal anastomotic dehiscence. PMID- 25432531 TI - Endoscopic removal of a migrated duodenal stent into the ileum using double balloon enteroscopy. PMID- 25432532 TI - Emergency video capsule endoscopy in patients with acute severe GI bleeding and negative upper endoscopy results. AB - BACKGROUND: In mid-GI bleeding, video capsule endoscopy (VCE) shows the best diagnostic yield for ongoing overt bleeding. To date, the utility of VCE in acute severe GI bleeding has been analyzed rarely. OBJECTIVE: To evaluate the impact of VCE when performed on patients with acute severe GI bleeding immediately after an initial negative upper endoscopy result. DESIGN: Prospective study. SETTING: Tertiary-care center. PATIENTS: Patients with melena, dark-red or maroon stool, hemodynamic instability, drop of hemoglobin level >=2 g/dL/day, and/or need of transfusion >=2 units of packed red blood cells per day were included. INTERVENTIONS: After a negative upper endoscopy result, emergency VCE was performed by immediate endoscopic placement of the video capsule into the duodenum. MAIN OUTCOME MEASUREMENTS: Rate of patients in whom emergency VCE correctly guided further diagnostic and therapeutic procedures. RESULTS: Upper endoscopy showed the source of bleeding in 68 of 88 patients (77%). In the remaining 20 patients (23%), emergency VCE was performed, which was feasible in 19 of 20 patients (95%; 95% confidence interval [CI], 75%-99%). Emergency VCE correctly guided further diagnostic and therapeutic procedures in 17 of 20 patients (85%; 95% CI, 62%-97%) and showed a diagnostic yield of 75% (95% CI, 51% 91%). LIMITATIONS: Single-center study, small sample size. CONCLUSION: In patients with acute severe GI bleeding and negative upper endoscopy results, emergency VCE can be useful for the immediate detection of the bleeding site and is able to guide further therapy. (Clinical trial registration number: NCT01584869.) PMID- 25432533 TI - (Poly)phenols protect from alpha-synuclein toxicity by reducing oxidative stress and promoting autophagy. AB - Parkinson's disease (PD) is the most common movement neurodegenerative disorder and is associated with the aggregation of alpha-synuclein (alphaSyn) and oxidative stress, hallmarks of the disease. Although the precise molecular events underlying alphaSyn aggregation are still unclear, oxidative stress is known to contribute to this process. Therefore, agents that either prevent oxidative stress or inhibit alphaSyn toxicity are expected to constitute potential drug leads for PD. Both pre-clinical and clinical studies provided evidence that (poly)phenols, pure or in extracts, might protect against neurodegenerative disorders associated with oxidative stress in the brain. In this study, we analyzed, for the first time, a (poly)phenol-enriched fraction (PEF) from leaves of Corema album, and used in vitro and cellular models to evaluate its effects on alphaSyn toxicity and aggregation. Interestingly, the PEF promoted the formation of non-toxic alphaSyn species in vitro, and inhibited its toxicity and aggregation in cells, by promoting the autophagic flux and reducing oxidative stress. Thus, C. album (poly)phenols appear as promising cytoprotective compounds, modulating central events in the pathogenesis of PD, such as alphaSyn aggregation and the impairment of autophagy. Ultimately, the understanding of the molecular effects of (poly)phenols will open novel opportunities for the exploitation of their beneficial effects and for drug development. PMID- 25432534 TI - Mutant activated FGFR3 impairs endochondral bone growth by preventing SOX9 downregulation in differentiating chondrocytes. AB - Fibroblast growth factor receptor 3 (FGFR3) plays a critical role in the control of endochondral ossification, and bone growth and mutations that cause hyperactivation of FGFR3 are responsible for a collection of developmental disorders that feature poor endochondral bone growth. FGFR3 is expressed in proliferating chondrocytes of the cartilaginous growth plate but also in chondrocytes that have exited the cell cycle and entered the prehypertrophic phase of chondrocyte differentiation. Achondroplasia disorders feature defects in chondrocyte proliferation and differentiation, and the defects in differentiation have generally been considered to be a secondary manifestation of altered proliferation. By initiating a mutant activated knockin allele of FGFR3 (FGFR3K650E) that causes Thanatophoric Dysplasia Type II (TDII) specifically in prehypertrophic chondrocytes, we show that mutant FGFR3 induces a differentiation block at this stage independent of any changes in proliferation. The differentiation block coincided with persistent expression of SOX9, the master regulator of chondrogenesis, and reducing SOX9 dosage allowed chondrocyte differentiation to proceed and significantly improved endochondral bone growth in TDII. These findings suggest that a proliferation-independent and SOX9-dependent differentiation block is a key driving mechanism responsible for poor endochondral bone growth in achondroplasia disorders caused by mutations in FGFR3. PMID- 25432535 TI - A shower of second hit events as the cause of multifocal renal cell carcinoma in tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is a genetic disorder characterized by seizures and tumor formation in multiple organs, mainly in the brain, skin, kidney, lung and heart. Renal cell carcinoma (RCC) occurs in ~3% of TSC patients, and typically develops at age <50. Here we describe genetic findings in two TSC patients with multiple renal tumors, each of whom had the germline mutation TSC2 p.R905Q. The first (female) TSC patient had a left followed by a right nephrectomy at ages 24 and 27. Both kidneys showed multifocal TSC-associated papillary RCC (PRCC). Targeted, next-generation sequencing (NGS) analysis of TSC2 in five tumors (four from the left kidney, one from the right) showed loss of heterozygosity in one tumor, and four different TSC2 point mutations (p.E1351*, p.R1032*, p.R1713H, c.4178_4179delCT) in the other four samples. Only one of the 11 other tumors available from this patient had one of the TSC2 second hit mutations identified. Whole-exome analysis of the five tumors identified a very small number of additional mutated genes, with an average of 3.4 nonsilent coding, somatic mutations per tumor, none of which were seen in >1 tumor. The second (male) TSC patient had bilateral partial nephrectomies (both at age 36), with similar findings of multifocal PRCC. NGS analysis of TSC2 in two of these tumors identified a second hit mutation c.2355+1G>T in one sample that was not seen in other tumors. In conclusion, we report the first detailed genetic analysis of RCCs in TSC patients. Molecular studies indicate that tumors developed independently due to various second hit events, suggesting that these patients experienced a 'shower' of second hit mutations in TSC2 during kidney development leading to this severe phenotype. PMID- 25432538 TI - Set-up verification and 2-dimensional electronic portal imaging device dosimetry during breath hold compared with free breathing in breast cancer radiation therapy. AB - PURPOSE: To compare set-up and 2-dimensional (2D) electronic portal imaging device (EPID) dosimetry data of breast cancer patients treated during voluntary moderately deep inspiration breath hold (vmDIBH) and free breathing (FB). METHODS AND MATERIALS: Set-up data were analyzed for 29 and 51 consecutively treated patients, irradiated during FB and vmDIBH, respectively. Of the 51 vmDIBH patients, the first 25 had undergone an extra trained computed tomography (CT) scan and used an additional "breathing stick" (vmDIBH_trained). The last 26 patients did not use the breathing stick and did not undergo a trained CT (vmDIBH_untrained). The delivered 2D transit dose was measured with EPID in 15 FB and 28 vmDIBH patients and compared with a 2D predicted dose by calculating global gamma values gamma using 5% and 5 mm as dose difference and distance-to agreement criteria, respectively. Measurements with a percentage of pixels with an absolute gamma value > 1 (|gamma| > 1) greater than 10% were classified as deviating. RESULTS: Only small, sub-millimeter differences were seen in the set up data between the different patient groups. The mean of means, systematic error, and random error ranged from - 0.6 mm to 3.3 mm. The percentage of pixels with |gamma| > 1 for all patients was 9.8% (2-25.8). No statistically significant differences were observed between the patient groups. In total, 38% of the gamma images were classified as deviating: 43.6% in vmDIBH_untrained patients compared with 38.0% in vmDIBH_trained patients and 33.3% in FB patients (P > .05). CONCLUSION: Both set-up and 2D EPID dosimetry data indicate that reproducibility of radiation therapy for patients treated during FB and vmDIBH is similar. Small but not significant differences in 2D EPID dosimetry were observed. Further investigation with 3-dimensional EPID dosimetry is recommended to investigate the clinical relevance of deviant gamma images. PMID- 25432536 TI - Fragile X-like behaviors and abnormal cortical dendritic spines in cytoplasmic FMR1-interacting protein 2-mutant mice. AB - Silencing of fragile X mental retardation 1 (FMR1) gene and loss of fragile X mental retardation protein (FMRP) cause fragile X syndrome (FXS), a genetic disorder characterized by intellectual disability and autistic behaviors. FMRP is an mRNA-binding protein regulating neuronal translation of target mRNAs. Abnormalities in actin-rich dendritic spines are major neuronal features in FXS, but the molecular mechanism and identity of FMRP targets mediating this phenotype remain largely unknown. Cytoplasmic FMR1-interacting protein 2 (Cyfip2) was identified as an interactor of FMRP, and its mRNA is a highly ranked FMRP target in mouse brain. Importantly, Cyfip2 is a component of WAVE regulatory complex, a key regulator of actin cytoskeleton, suggesting that Cyfip2 could be implicated in the dendritic spine phenotype of FXS. Here, we generated and characterized Cyfip2-mutant (Cyfip2(+/-)) mice. We found that Cyfip2(+/-) mice exhibited behavioral phenotypes similar to Fmr1-null (Fmr1(-/y)) mice, an animal model of FXS. Synaptic plasticity and dendritic spines were normal in Cyfip2(+/-) hippocampus. However, dendritic spines were altered in Cyfip2(+/-) cortex, and the dendritic spine phenotype of Fmr1(-/y) cortex was aggravated in Fmr1(-/y); Cyfip2(+/-) double-mutant mice. In addition to the spine changes at basal state, metabotropic glutamate receptor (mGluR)-induced dendritic spine regulation was impaired in both Fmr1(-/y) and Cyfip2(+/-) cortical neurons. Mechanistically, mGluR activation induced mRNA translation-dependent increase of Cyfip2 in wild type cortical neurons, but not in Fmr1(-/y) or Cyfip2(+/-) neurons. These results suggest that misregulation of Cyfip2 function and its mGluR-induced expression contribute to the neurobehavioral phenotypes of FXS. PMID- 25432539 TI - Successful pregnancy after uterus-sparing chemoradiation therapy for vaginal cancer. PMID- 25432537 TI - PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43. AB - Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease for which there is no cure. We have previously developed a Drosophila model of ALS based on TDP-43 that recapitulates several aspects of disease pathophysiology. Using this model, we designed a drug screening strategy based on the pupal lethality phenotype induced by TDP-43 when expressed in motor neurons. In screening 1200 FDA-approved compounds, we identified the PPARgamma agonist pioglitazone as neuroprotective in Drosophila. Here, we show that pioglitazone can rescue TDP-43-dependent locomotor dysfunction in motor neurons and glia but not in muscles. Testing additional models of ALS, we find that pioglitazone is also neuroprotective when FUS, but not SOD1, is expressed in motor neurons. Interestingly, survival analyses of TDP or FUS models show no increase in lifespan, which is consistent with recent clinical trials. Using a pharmacogenetic approach, we show that the predicted Drosophila PPARgamma homologs, E75 and E78, are in vivo targets of pioglitazone. Finally, using a global metabolomic approach, we identify a set of metabolites that pioglitazone can restore in the context of TDP-43 expression in motor neurons. Taken together, our data provide evidence that modulating PPARgamma activity, although not effective at improving lifespan, provides a molecular target for mitigating locomotor dysfunction in TDP-43 and FUS but not SOD1 models of ALS in Drosophila. Furthermore, our data also identify several 'biomarkers' of the disease that may be useful in developing therapeutics and in future clinical trials. PMID- 25432540 TI - Are more of my patients developing side effects than expected? AB - PURPOSE: Modern radiation oncology treatments are typically associated with a certain level of acute or long-term complications. Whenever a new treatment is introduced into clinical practice, a clinician may have reason to question whether certain side effects occur more frequently in his or her patients than reported in the published literature. However, the clinician, lacking rigorous statistical methods to answer this question, may not draw the correct conclusion until treating a larger number of patients than necessary. METHODS AND MATERIALS: We propose a Bayesian framework to calculate (1) the probability that the rate of an adverse event (AE) is above a certain threshold and (2) the number of AEs to be observed before we can conclude with a certain confidence level that the AE rate is above a threshold. Both questions will be answered based on the formulation of a posterior distribution of the AE rate given the observed data. The proposed method does not rely on large sample assumptions, and the computation of the solution is quick and straightforward. The proposed methods are illustrated in 2 clinical scenarios. RESULTS: We tabulated the probability that an AE rate is greater than a threshold for a given number of patients experiencing events from an observed number of patients. In addition, we developed a free online interactive tool to facilitate the implementation of the method. CONCLUSIONS: The proposed method, including the presented tables and the online tool, provides clinicians with a practical means of determining if his or her patients are experiencing a greater (or lower) number of complications than expected. How to use the statistical result to guide a clinical decision depends upon the specifics of the clinical condition and the available treatment alternatives. PMID- 25432542 TI - Eruptive keratoacanthomas after radiation therapy for keratoacanthoma centrifugum marginatum. PMID- 25432541 TI - Recurrent radiation necrosis in the brain following stereotactic radiosurgery. PMID- 25432543 TI - The mass cannot be classified as malignant. PMID- 25432544 TI - The transcriptome of corona radiata cells from individual MII oocytes that after ICSI developed to embryos selected for transfer: PCOS women compared to healthy women. AB - BACKGROUND: Corona radiata cells (CRCs) refer to the fraction of cumulus cells just adjacent to the oocyte. The CRCs are closely connected to the oocyte throughout maturation and their gene expression profiles might reflect oocyte quality. Polycystic ovary syndrome (PCOS) is a common cause of infertility. It is controversial whether PCOS associate with diminished oocyte quality. The purpose of this study was to compare individual human CRC samples between PCOS patients and controls. METHODS: All patients were stimulated by the long gonadotropin releasing hormone (GnRH) agonist protocol. The CRC samples originated from individual oocytes developing into embryos selected for transfer. CRCs were isolated in a two-step denudation procedure, separating outer cumulus cells from the inner CRCs. Extracted RNA was amplified and transcriptome profiling was performed with Human Agilent(r) arrays. RESULTS: The transcriptomes of CRCs showed no individual genes with significant differential expression between PCOS and controls, but gene set enrichment analysis identified several cell cycle- and DNA replication pathways overexpressed in PCOS CRCs (FDR < 0.05). Five of the genes contributing to the up-regulated cell cycle pathways in the PCOS CRCs were selected for qRT-PCR validation in ten PCOS and ten control CRC samples. qRT-PCR confirmed significant up-regulation in PCOS CRCs of cell cycle progression genes HIST1H4C (FC = 2.7), UBE2C (FC = 2.6) and cell cycle related transcription factor E2F4 (FC = 2.5). CONCLUSION: The overexpression of cell cycle-related genes and cell cycle pathways in PCOS CRCs could indicate a disturbed or delayed final maturation and differentiation of the CRCs in response to the human chorionic gonadotropin (hCG) surge. However, this had no effect on the in vitro development of the corresponding embryos. Future studies are needed to clarify whether the up regulated cell cycle pathways in PCOS CRCs have any clinical implications. PMID- 25432545 TI - MRI evolution of CLIPPERS syndrome following herpes zoster infection. PMID- 25432546 TI - Stage-specific reprogramming of gene expression characterizes Lr48-mediated adult plant leaf rust resistance in wheat. AB - Wheat genotype CSP44 carrying a recessive gene Lr48 exhibits adult plant resistance (APR; incompatible reaction) but gives a compatible reaction (susceptibility) at the seedling stage against leaf rust. A comparative gene expression analysis involving cDNA-amplified fragment length polymorphism (cDNA AFLP) and quantitative PCR (qPCR) was carried out for incompatible and compatible reactions in the genotype CSP44. cDNA-AFLP analysis was conducted using RNA samples that were isolated from flag leaves following inoculation with leaf rust race 77-5 (the most virulent race) and also after mock inoculation. As many as 298 of a total of 493 expressed transcript-derived fragments (TDFs) exhibited differential expression (262 upregulated and 36 downregulated). Of these 298 TDFs, 48 TDFs were eluted from gels, re-amplified, cloned, and sequenced. Forty two of these 48 TDFs had homology with known genes involved in the following biological processes: energy production, metabolism, transport, signaling, defense response, plant-pathogen interaction, transcriptional regulation, translation, and proteolysis. The functions of the remaining six TDFs could not be determined; apparently, these represented some novel genes. The qPCR analysis for 18 TDFs (with known and unknown functions, but showing major differences in expression) was conducted using RNA isolated from the seedlings as well as from the adult plants. The expression of at least 11 TDFs was induced and that of 4 other TDFs attenuated or remained near normal in adult plants following leaf rust inoculations. The remaining three TDFs had non-specific/developmental stage specific expression. Functional annotation of TDFs that were upregulated suggest that the APR was supported by transient recruitment and reprogramming of processes like perception and recognition of pathogen effector by receptors, followed by CDPK and MAPK signaling, transport, metabolism, and energy release. PMID- 25432548 TI - Evaluation of antitumor activity of platelet microbicidal protein on the model of transplanted breast cancer in CBRB-Rb(8.17)1Iem mice. AB - Breast cancer is the most common women's cancer in the world. There is considerable current interest in developing anticancer agents with a new mode of action because of the development of resistance by cancer cells towards current anticancer drugs. Mamalian cells have been shown to contain small, cationic, microbicidal peptides. Antimicrobial peptides have drawn attention as a promising alternative to current antitumor agents. Such peptides have been isolated both from animal and human platelets and have been termed platelets microbicidal proteins (PMP). The aim of this work was to study antitumor activity of PMP in vivo on the model of mouse breast cancer in comparison with antitumor hexapeptide Arg-alpha-Asp-Lys-Val-Tyr-Arg (Immunofan). We demonstrated that the tumors treated with PMP were significant smaller than the control groups (P < 0.05). In experiments in vivo using CBRB-Rb(8.17)1Iem mice with transplanted tumors PMP inhibited tumor growth during the treatments and after its discontinuation. These findings indicate that PMP can exert antitumor effects. Therefore, PMP may be used for the development of therapy for the intervention of breast cancer. PMID- 25432547 TI - Carcinoma showing thymus-like elements of the thyroid gland: report of three cases including one case with breast cancer history. AB - Carcinoma showing thymus-like elements (CASTLE) is a rare malignant tumor of the thyroid or adjacent neck soft tissues, whose histogenesis is still debated. It may resemble other primary or metastatic poorly differentiated tumors histologically and the differential diagnosis is crucial for CASTLE has a better prognosis. However, CASTLE as a second primary tumor has not been reported in the literature. We report three cases of thyroid CASTLE, including a unique tumor following breast-conserving surgery for early-stage breast invasive carcinoma. There were two female and one male. All three tumors were located in the right lobe of the thyroid, and one tumor showed extension into the surrounding soft tissue. Histologically, all tumors showed expansive growth and consisted of cords, nests or sheets of epithelial cells divided into irregularly shaped lobules by fibrous connective tissue with lymphoplasmacytic infiltration. Focal squamous differentiation resembling Hassall's corpuscles were observed. All cases stained positively for CD5, CD117, high molecular weight cytokeratin, cytokeratin, P63, carcinoembryonic antigen and epithelial membrane antigen. Positive staining for Bcl-2 in two cases and chromogranin A in one case was noted. Ki-67 expression ranged from 15 to 25%. Thyroid transcription factor and CD3 were negative. There was no evidence of recurrent or metastatic disease at following surgery. These features demonstrated CASTLE may arise from branchial pouch remnants, the thyroid solid cell nests. CASTLE is a rare entity, awareness of its occurrence as a second primary tumor is important to avoid overtreatment because it is associated with a favorable prognosis. PMID- 25432549 TI - The value of HPV-HR DNA testing during the follow-up after treatment of CIN3/AIS. PMID- 25432550 TI - The debate on fluid management and haemodynamic monitoring continues: between Scylla and Charybdis, or faith and evidence.... PMID- 25432551 TI - Ten good reasons why everybody can and should perform cardiac ultrasound in the ICU. AB - Critical care ultrasonography (CCUS) has been defined as an ultrasound evaluation of the heart, abdomen, pleura and lungs at the bedside by the intensivist, 24/7. Within CCUS, critical care echocardiography (CCE) is used to assess cardiac function and more generally haemodynamics. Experts in haemodynamics have published a 'consensus of 16' regarding an update on haemodynamic monitoring. They reported the ten key properties of an 'ideal' haemodynamic monitoring system, which perfectly match the ten good reasons we describe here for performing CCE in critically ill patients. Even though unfortunately no evidence based medicine study is available to support this review, especially regarding CCE-related improvement of outcome, many clinical studies have demonstrated that CCE provides measurements of relevant, accurate, reproducible and interpretable variables, is easy to use, readily available, has a rapid response time, causes no harm, and is cost-effective. Whether it is operator-independent is obviously more debatable and is discussed in this review. All these characteristics are arguments for the extensive use of CCE by intensivists. This is why experts in the field have recommended that a basic level of CCE should be included in the training of all intensivists. PMID- 25432552 TI - Ten good reasons to practice ultrasound in critical care. AB - Over the past decade, critical care ultrasound has gained its place in the armamentarium of monitoring tools. A greater understanding of lung, abdominal, and vascular ultrasound plus easier access to portable machines have revolutionised the bedside assessment of our ICU patients. Because ultrasound is not only a diagnostic test, but can also be seen as a component of the physical exam, it has the potential to become the stethoscope of the 21st century. Critical care ultrasound is a combination of simple protocols, with lung ultrasound being a basic application, allowing assessment of urgent diagnoses in combination with therapeutic decisions. The LUCI (Lung Ultrasound in the Critically Ill) consists of the identification of ten signs: the bat sign (pleural line); lung sliding (seashore sign); the A-lines (horizontal artefact); the quad sign and sinusoid sign indicating pleural effusion; the fractal and tissue-like sign indicating lung consolidation; the B-lines and lung rockets indicating interstitial syndromes; abolished lung sliding with the stratosphere sign suggesting pneumothorax; and the lung point indicating pneumothorax. Two more signs, the lung pulse and the dynamic air bronchogram, are used to distinguish atelectasis from pneumonia. The BLUE protocol (Bedside Lung Ultrasound in Emergency) is a fast protocol (< 3 minutes), also including a vascular (venous) analysis allowing differential diagnosis in patients with acute respiratory failure. With this protocol, it becomes possible to differentiate between pulmonary oedema, pulmonary embolism, pneumonia, chronic obstructive pulmonary disease, asthma, and pneumothorax, each showing specific ultrasound patterns and profiles. The FALLS protocol (Fluid Administration Limited by Lung Sonography) adapts the BLUE protocol to be used in patients with acute circulatory failure. It makes a sequential search for obstructive, cardiogenic, hypovolemic, and distributive shock using simple real-time echocardiography in combination with lung ultrasound, with the appearance of B-lines considered to be the endpoint for fluid therapy. An advantage of lung ultrasound is that the patient is not exposed to radiation, and so the LUCI-FLR project (LUCI favouring limitation of radiation) can be unfolded in trauma patients. Although it has been practiced for 25 years, critical care ultrasound is a relatively young but expanding discipline and can be seen as the stethoscope of the modern intensivist. In this review, the usefulness and advantages of ultrasound in the critical care setting are discussed in ten points. The emphasis is on a holistic approach, with a central role for lung ultrasound. PMID- 25432553 TI - Why hydroxyethyl starch solutions should NOT be banned from the operating room. AB - This review summarises the new insights into the physiology of perioperative fluid therapy and analyses recent studies of the safety of the use of HES solutions in the fluid management of critically ill patients. This analysis reveals a number of methodological issues in the three major studies that have initiated the recommendation of the European Medicine Agency to ban hydroxyethyl starches from clinical practice. It is concluded that, when used in the proper indication, and taking into account the recommended doses, hydroxyethyl starches continue to have a place in perioperative fluid management. PMID- 25432554 TI - Why crystalloids will do the job in the operating room. AB - The current trend in anaesthesia is to choose crystalloid over colloid fluids for volume replacement in the operating room. Outcome-oriented studies and kinetic analyses have recently provided more insight into how crystalloid infusions should be managed. These fluids have a much better short-term effect on the plasma volume than previously believed. Their efficiency (i.e. the plasma volume expansion divided by the infused volume) is 50-80% as long as an infusion continues, while this fraction increases to 100% when the arterial pressure has dropped. Elimination is very slow during surgery, and amounts to only 10% of that recorded in conscious volunteers. Capillary refill further reduces the need for crystalloid fluid when bleeding occurs. These four factors limit the need for large volumes of crystalloid fluid during surgery. Adverse effects associated with crystalloid fluids mainly include prolonged gastrointestinal recovery time, which occurs when > 3 L has been infused. Clinicians who do not want to prolong the length of the hospital stay by 1-2 days due to such problems may use colloid fluid selectively, but calculations show that the therapeutic window for colloids is quite narrow. Inflammation is likely to decrease the fluid efficiency of colloid fluids, while its effect on crystalloids is unclear. However, some recent evidence suggests that inflammation accelerates the turnover of crystalloid fluid as well. PMID- 25432555 TI - Effects of intravenous solutions on acid-base equilibrium: from crystalloids to colloids and blood components. AB - Intravenous fluid administration is a medical intervention performed worldwide on a daily basis. Nevertheless, only a few physicians are aware of the characteristics of intravenous fluids and their possible effects on plasma acid base equilibrium. According to Stewart's theory, pH is independently regulated by three variables: partial pressure of carbon dioxide, strong ion difference (SID), and total amount of weak acids (ATOT). When fluids are infused, plasma SID and ATOT tend toward the SID and ATOT of the administered fluid. Depending on their composition, fluids can therefore lower, increase, or leave pH unchanged. As a general rule, crystalloids having a SID greater than plasma bicarbonate concentration (HCO3-) cause an increase in plasma pH (alkalosis), those having a SID lower than HCO3- cause a decrease in plasma pH (acidosis), while crystalloids with a SID equal to HCO3- leave pH unchanged, regardless of the extent of the dilution. Colloids and blood components are composed of a crystalloid solution as solvent, and the abovementioned rules partially hold true also for these fluids. The scenario is however complicated by the possible presence of weak anions (albumin, phosphates and gelatins) and their effect on plasma pH. The present manuscript summarises the characteristics of crystalloids, colloids, buffer solutions and blood components and reviews their effect on acid-base equilibrium. Understanding the composition of intravenous fluids, along with the application of simple physicochemical rules best described by Stewart's approach, are pivotal steps to fully elucidate and predict alterations of plasma acid-base equilibrium induced by fluid therapy. PMID- 25432556 TI - Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. AB - BACKGROUND: Sepsis is associated with generalised endothelial injury and capillary leak and has traditionally been treated with large volume fluid resuscitation. Some patients with sepsis will accumulate bodily fluids. The aim of this study was to systematically review the association between a positive fluid balance/fluid overload and outcomes in critically ill adults, and to determine whether interventions aimed at reducing fluid balance may be linked with improved outcomes. METHODS: We searched MEDLINE, PubMed, EMBASE, Web of Science, The Cochrane Database, clinical trials registries, and bibliographies of included articles. Two authors independently reviewed citations and selected studies examining the association between fluid balance and outcomes or where the intervention was any strategy or protocol that attempted to obtain a negative or neutral cumulative fluid balance after the third day of intensive care compared to usual care. The primary outcomes of interest were the incidence of IAH and mortality. RESULTS: Among all identified citations, one individual patient meta analysis, 11 randomised controlled clinical trials, seven interventional studies, 24 observational studies, and four case series met the inclusion criteria. Altogether, 19,902 critically ill patients were studied. The cumulative fluid balance after one week of ICU stay was 4.4 L more positive in non-survivors compared to survivors. A restrictive fluid management strategy resulted in a less positive cumulative fluid balance of 5.6 L compared to controls after one week of ICU stay. A restrictive fluid management was associated with a lower mortality compared to patients treated with a more liberal fluid management strategy (24.7% vs 33.2%; OR, 0.42; 95% CI 0.32-0.55; P < 0.0001). Patients with intra-abdominal hypertension (IAH) had a more positive cumulative fluid balance of 3.4 L after one week of ICU stay. Interventions to decrease fluid balance resulted in a decrease in intra-abdominal pressure (IAP): an average total body fluid removal of 4.9 L resulted in a drop in IAP from 19.3 +/- 9.1 mm Hg to 11.5 +/- 3.9 mm Hg. CONCLUSIONS: A positive cumulative fluid balance is associated with IAH and worse outcomes. Interventions to limit the development of a positive cumulative fluid balance are associated with improved outcomes. In patients not transgressing spontaneously from the Ebb to Flow phases of shock, late conservative fluid management and late goal directed fluid removal (de-resuscitation) should be considered. PMID- 25432557 TI - The use of bio-electrical impedance analysis (BIA) to guide fluid management, resuscitation and deresuscitation in critically ill patients: a bench-to-bedside review. AB - The impact of a positive fluid balance on morbidity and mortality has been well established. However, little is known about how to monitor fluid status and fluid overload. This narrative review summarises the recent literature and discusses the different parameters related to bio-electrical impedance analysis (BIA) and how they might be used to guide fluid management in critically ill patients. Definitions are listed for the different parameters that can be obtained with BIA; these include among others total body water (TBW), intracellular water (ICW), extracellular water (ECW), ECW/ICW ratio and volume excess (VE). BIA allows calculation of body composition and volumes by means of a current going through the body considered as a cylinder. Reproducible measurements can be obtained with tetrapolar electrodes with two current and two detection electrodes placed on hands and feet. Modern devices also apply multiple frequencies, further improving the accuracy and reproducibility of the results. Some pitfalls and conditions are discussed that need to be taken into account for correct BIA interpretation. Although BIA is a simple, noninvasive, rapid, portable, reproducible, and convenient method of measuring body composition and fluid distribution with fewer physical demands than other techniques, it is still unclear whether it is sufficiently accurate for clinical use in critically ill patients. However, the potential clinical applications are numerous. An overview regarding the use of BIA parameters in critically ill patients is given, based on the available literature. BIA seems a promising tool if performed correctly. It is non-invasive and relatively inexpensive and can be performed at bedside, and it does not expose to ionising radiation. Modern devices have very limited between-observer variations, but BIA parameters are population-specific and one must be aware of clinical situations that may interfere with the measurement such as visible oedema, nutritional status, or fluid and salt administration. BIA can help guide fluid management, resuscitation and de-resuscitation. The latter is especially important in patients not progressing spontaneously from the Ebb to the Flow phase of shock. More research is needed in critically ill patients before widespread use of BIA can be suggested in this patient population. PMID- 25432558 TI - The role of abdominal compliance, the neglected parameter in critically ill patients - a consensus review of 16. Part 1: definitions and pathophysiology. AB - Over the last few decades, increasing attention has been paid to understanding the pathophysiology, aetiology, prognosis, and treatment of elevated intra abdominal pressure (IAP) in trauma, surgical, and medical patients. However, there is presently a relatively poor understanding of intra-abdominal volume (IAV) and the relationship between IAV and IAP (i.e. abdominal compliance). Consensus definitions on Cab were discussed during the 5th World Congress on Abdominal Compartment Syndrome and a writing committee was formed to develop this article. During the writing process, a systematic and structured Medline and PubMed search was conducted to identify relevant studies relating to the topic. According to the recently updated consensus definitions of the World Society on Abdominal Compartment Syndrome (WSACS), abdominal compliance (Cab) is defined as a measure of the ease of abdominal expansion, which is determined by the elasticity of the abdominal wall and diaphragm. It should be expressed as the change in IAV per change in IAP (mL [mm Hg]-1). Importantly, Cab is measured differently than IAP and the abdominal wall (and its compliance) is only a part of the total abdominal pressure-volume (PV) relationship. During an increase in IAV, different phases are encountered: the reshaping, stretching, and pressurisation phases. The first part of this review article starts with a comprehensive list of the different definitions related to IAP (at baseline, during respiratory variations, at maximal IAV), IAV (at baseline, additional volume, abdominal workspace, maximal and unadapted volume), and abdominal compliance and elastance (i.e. the relationship between IAV and IAP). An historical background on the pathophysiology related to IAP, IAV and Cab follows this. Measurement of Cab is difficult at the bedside and can only be done in a case of change (removal or addition) in IAV. The Cab is one of the most neglected parameters in critically ill patients, although it plays a key role in understanding the deleterious effects of unadapted IAV on IAP and end-organ perfusion. The definitions presented herein will help to understand the key mechanisms in relation to Cab and clinical conditions and should be used for future clinical and basic science research. Specific measurement methods, guidelines and recommendations for clinical management of patients with low Cab are published in a separate review. PMID- 25432559 TI - The role of abdominal compliance, the neglected parameter in critically ill patients - a consensus review of 16. Part 2: measurement techniques and management recommendations. AB - The recent definitions on intra-abdominal pressure (IAP), intra-abdominal volume (IAV) and abdominal compliance (Cab) are a step forward in understanding these important concepts. They help our understanding of the pathophysiology, aetiology, prognosis, and treatment of patients with low Cab. However, there is still a relatively poor understanding of the different methods used to measure IAP, IAV and Cab and how certain conditions may affect the results. This review will give a concise overview of the different methods to assess and estimate Cab; it will list important conditions that may affect baseline values and suggest some therapeutic options. Abdominal compliance (Cab), defined as a measure of the ease of abdominal expansion, is measured differently than IAP. The compliance of the abdominal wall is only a part of the total abdominal pressure-volume (PV) relationship. Measurement or estimation of Cab is difficult at the bedside and can only be done in a case of change (removal or addition) in IAV. The different measurement techniques will be discussed in relation to decreases (ascites drainage, haematoma evacuation, gastric suctioning) or increases in IAV (gastric insufflation, laparoscopy with CO2 pneumoperitoneum, peritoneal dialysis). More specific techniques using the interactions between the thoracic and abdominal compartment during positive pressure ventilation will also be discussed (low flow PV loop, respiratory IAP variations, respiratory abdominal variation test, mean IAP and abdominal pressure variation), together with the concept of the polycompartment model. The relation between IAV and IAP is linear at low IAV and becomes curvilinear and exponential at higher volumes. Specific conditions in relation to increased (previous pregnancy or laparoscopy, gynoid fat distribution, ellipse-shaped internal abdominal perimeter) or decreased Cab (obesity, fluid overload, android fat distribution, sphere-shaped internal abdominal perimeter) will be discussed as well as their impact on baseline IAV, IAP, reshaping capacity and abdominal workspace volume. Finally, we suggest possible treatment options in situations of unadapted IAV according to existing Cab, which results in high IAP. A large overlap exists between the treatment of patients with abdominal hypertension and those with low Cab. The Cab plays a key role in understanding the deleterious effects of unadapted IAV on IAP and end organ perfusion and function. If we can identify patients with low Cab, we can anticipate and select the most appropriate surgical treatment to avoid complications such as IAH or ACS. PMID- 25432560 TI - The polycompartment syndrome: a concise state-of-the-art review. AB - A compartment syndrome is defined as an increase in the compartmental pressure to such an extent that the viability of the tissues and organs within the compartment are threatened. The term describes a syndrome and not a disease, and as such there are many diseases and underlying pathophysiological processes that may lead to such a scenario. The aim of this review is to give a state-of-the-art overview on the current knowledge on different compartment syndromes and how they may interact. Suggested definitions are included. There are four major compartments in the human body: the head, chest, abdomen, and the extremities. Initially, the term multicompartment syndrome was suggested when more than one compartment was affected. But this led to confusion as the term multi- or multiple compartment syndromes is mostly used in relation to multiple limb trauma leading to compartment syndrome requiring fasciotomy. Only recently was the term 'polycompartment syndrome' coined to describe a condition where two or more anatomical compartments have elevated pressures. When more than one compartment is affected, an exponential detrimental effect on end-organ function to both immediate and distant organs can occur. Within each compartment, the disease leading towards a compartment syndrome can be primary or secondary. The compliance of each compartment is the key to determining the transmission of a given compartmental pressure from one compartment to another. The intra-abdominal pressure helps to explain the severe pathophysiological condition occurring in patients with cardiorenal, hepatopulmonary and hepatorenal syndromes. Initial treatment of a compartment syndrome should be focused on the primary compartment and is based on three principles: lowering of compartmental pressure, supporting organ perfusion, and optimisation and prevention of specific adverse events. Clinicians need to be aware of the existence of the polycompartment syndrome and the interactions of increased compartmental pressures between compartments. PMID- 25432570 TI - Low control beliefs in relation to school dropout and poor health: findings from the SIODO case-control study. AB - BACKGROUND: There is cumulating evidence that health is compromised through adverse socioeconomic conditions negatively affecting how people think, feel, and behave. Low control beliefs might be a key mechanism. The reversed possibility that low control beliefs might set people on a pathway towards adverse socioeconomic and health-related outcomes is much less examined. METHODS: A case control design was used, consisting of 330 cases who dropped out of school in the 2010-2011 school year and 330 controls who still attended school at the end of that year. The respondents, aged between 18 and 23, came from Eindhoven and surrounding areas in the south-east of The Netherlands. A questionnaire asked for current health status, recalled socioeconomic and social background, and recalled control beliefs (mastery and general self-efficacy). Logistic regression analyses were used. RESULTS: Recalls of low mastery and low self-efficacy were strongly related to both dropout and less than good health. Low socioeconomic background was also associated to odds of dropout, but did not confound or moderate the associations of low control beliefs with dropout and health. Odds ratios of dropout and less than good health indicated at least twice the odds of a poor outcome with recalls of low control beliefs. CONCLUSIONS: Independent of the socioeconomic background, low control beliefs are related to heightened odds of both poor health and school dropout. Individual differences in control beliefs might thus be as fundamental as socioeconomic conditions in generating life course socioeconomic and health-related pathways. Although the findings should first be cross-validated in prospective studies, public health professionals working with youth might already start considering early interventions in youth with all too fatalistic and powerless mind-sets. PMID- 25432571 TI - Treatment of chronic pulmonary aspergillosis with voriconazole: review of a case series. AB - PURPOSE: Chronic pulmonary aspergillosis (CPA) is a rare disease that primarily affects subjects with moderate immunodepression and/or structural alterations in the lung. METHODS: Data for patients with probable CPA were collected over 24 months. Patients with probable CPA received oral voriconazole, and clinical, laboratory and radiological follow-up was performed at 3, 6 and 12 months. RESULTS: 21 patients (mean age 52.4 years) were evaluated. Factors predisposing to CPA were tuberculosis (n = 8), chronic obstructive pulmonary disease (n = 7), corticosteroids (n = 14), chemo- or radio-therapy (n = 6), tracheostomy or endotracheal prosthesis (n = 5), smoking (n = 4), asthma (n = 3), and chronic liver disease (n = 3). Sputum or bronchial aspirate cultures were positive for Aspergillus spp. in 14 cases (66.6 %). (1,3)-beta-D-glucan on serum was positive in 16 cases (76.2 %). Excavated pulmonary thickening was evident in 14 patients (66.6 %) and in 9 of these cases (64.2 %) aspergilloma was present. [(18)F]2 fluoro-2-deoxy-D-glucose-PET-CT was positive in 13/15 patients, and simple aspergilloma was diagnosed after surgical excision in one of the negative cases. All patients were treated with oral voriconazole. Therapy was discontinued due to skin toxicity (n = 3), liver toxicity (n = 2) and severe mental disorder (n = 1). At 12 months' follow-up, nine patients (42.9 %) were considered cured or improved. Seven patients (33.3 %) died during follow-up, mainly due to underlying disease. CONCLUSIONS: A reasonable proportion of patients achieved cure or improvement with voriconazole, but 28.5 % of treated patients had to discontinue therapy because of toxicity. The high mortality makes it difficult to fully assess the real efficacy of voriconazole and to establish the correct duration of therapy. PMID- 25432574 TI - Indirect human impacts turn off reciprocal feedbacks and decrease ecosystem resilience. AB - Creek bank salt marsh die-off is a conservation problem in New England, driven by predator depletion, which releases herbivores from consumer control. Many marshes, however, have begun to recover from die-off. We examined the hypothesis that the loss of the foundation species Spartina alterniflora has decreased facilitator populations, weakening reciprocal positive plant/animal feedbacks, resilience, and slowing recovery. Field surveys and experiments revealed that loss of Spartina leads to decreased biodiversity, and increased mortality and decreased growth of the ribbed mussel Geukensia demissa, a key facilitator of Spartina. Experimental addition of Geukensia facilitators to creek banks accelerated Spartina recovery, showing that their loss limits recovery and the reciprocal feedbacks that drive community resilience. Reciprocal positive feedbacks involving foundation species, often lost to human impacts, may be a common, but generally overlooked mechanism of ecosystem resilience, making their reestablishment a valuable restoration tool. PMID- 25432575 TI - Quantitative analysis of the thermal stability of the gamma phage endolysin PlyG: a biophysical and kinetic approach to assaying therapeutic potential. AB - Endolysins are lytic enzymes encoded by bacteriophage that represent an emerging class of protein therapeutics. Considering macromolecular thermoresistance correlates with shelf life, PlyG, a Bacillus anthracis endolysin, was thermally characterized to further evaluate its therapeutic potential. Results from a biophysical thermal analysis revealed full-length PlyG and its isolated domains comprised thermal denaturation temperatures exceeding 63 degrees C. In the absence of reducing agent, PlyG was determined to be kinetically unstable, a finding hypothesized to be attributable to the chemical oxidation of cysteine and/or methionine residues. The presence of reducing agent kinetically stabilized the endolysin, with PlyG retaining at least ~50% residual lytic activity after being heated at temperatures up to 80 degrees C and remaining enzymatically functional after being boiled. Furthermore, the endolysin had a kinetic half-life at 50 degrees C and 55 degrees C of 35 and 5.5h, respectively. PlyG represents a thermostable proteinaceous antibacterial with subsequent prolonged therapeutic shelf life expectancy. PMID- 25432573 TI - Trophic dynamics in an aquatic community: interactions among primary producers, grazers, and a pathogenic fungus. AB - Free-living stages of parasites are consumed by a variety of predators, which might have important consequences for predators, parasites, and hosts. For example, zooplankton prey on the infectious stage of the amphibian chytrid fungus, Batrachochytrium dendrobatidis (Bd), a pathogen responsible for amphibian population declines and extinctions worldwide. Predation on parasites is predicted to influence community structure and function, and affect disease risk, but relatively few studies have explored its consequences empirically. We investigated interactions among Rana cascadae tadpoles, zooplankton, and Bd in a fully factorial experiment in outdoor mesocosms. We measured growth, development, survival, and infection of amphibians and took weekly measurements of the abundance of zooplankton, phytoplankton (suspended algae), and periphyton (attached algae). We hypothesized that zooplankton might have positive indirect effects on tadpoles by consuming Bd zoospores and by consuming phytoplankton, thus reducing the shading of a major tadpole resource, periphyton. We also hypothesized that zooplankton would have negative effects on tadpoles, mediated by competition for algal resources. Mixed-effects models, repeated-measures ANOVAs, and a structural equation model revealed that zooplankton significantly reduced phytoplankton but had no detectable effects on Bd or periphyton. Hence, the indirect positive effects of zooplankton on tadpoles were negligible when compared to the indirect negative effect mediated by competition for phytoplankton. We conclude that examination of host-pathogen dynamics within a community context may be necessary to elucidate complex community dynamics. PMID- 25432572 TI - Cardiolipin remodeling: a regulatory hub for modulating cardiolipin metabolism and function. AB - Cardiolipin (CL), the signature phospholipid of mitochondria, is involved in a plethora of cellular processes and is crucial for mitochondrial function and architecture. The de novo synthesis of CL in the mitochondria is followed by a unique remodeling process, in which CL undergoes cycles of deacylation and reacylation. Specific fatty acyl composition is acquired during this process, and remodeled CL contains predominantly unsaturated fatty acids. The importance of CL remodeling is underscored by the life-threatening genetic disorder Barth syndrome (BTHS), caused by mutations in tafazzin, which reacylates monolysocardiolipin (MLCL) generated from the deacylation of CL. Just as CL-deficient yeast mutants have been instrumental in elucidating functions of this lipid, the recently characterized CL-phospholipase mutant cld1Delta and the tafazzin mutant taz1Delta are powerful tools to understand the functions of CL remodeling. In this review, we discuss recent advances in understanding the role of CL in mitochondria with specific focus on the enigmatic functions of CL remodeling. PMID- 25432576 TI - [Clostridium difficile in visceral surgery]. AB - BACKGROUND: For surgeons the early identification of patients with clostridium difficile infections (CDI) is important, because the incidence and virulence of this potentially life-threatening disease are increasing. OBJECTIVES: The aim of this study was to describe the frequency of CDI among surgical patients, to analyze which treatment was successful and to define which factors were associated with mortality. METHODS: A retrospective analysis of patients with CDI was performed. RESULTS: From January 2004 to June 2012 the overall incidence of CDI among all departments at the St. Josef Hospital, Ruhr University Bochum was 0.6 % (1669 out of 301,919 patients). In 2004 the number of surgical patients with CDI was 1 which increased to 41 in 2011. Before the diagnosis of CDI was made 84 % (151 out of 179) of patients had received an antibiotic treatment. Conservative management of CDI was performed with metronidazole in 75 % (134 out of 179), 60 % (107 out of 179) received vancomycin, while 44 % (79 out of 179) received a combination of metronidazole and vancomycin, tygecycline or fidaxomidin. The overall mortality was 7 % (12 out of 179). There was a significant association with mortality for patients with sepsis, readmission to the intensive care unit (ICU), requirement for vasopressor therapy and intubation with mechanical ventilation. In 4 % of patients (7 out of 179) colectomy was carried out. Despite maximum intensive care management, 86 % (6 out of 7) of patients who underwent colectomy ultimately died. CONCLUSION: Although conservative management is successful for most patients with CDI, the mortality is high for patients who require intensive care management secondary to CDI. Mortality after colectomy for CDI is almost 100 %, mostly because the operation is usually only performed as a last resort in patients with sepsis. The most important risk factor for CDI is a prior antibiotic therapy. PMID- 25432577 TI - Assessment of bacterial and archaeal community structure in Swine wastewater treatment processes. AB - Microbial communities from two field-scale swine wastewater treatment plants (WWTPs) were assessed by pyrosequencing analyses of bacterial and archaeal 16S ribosomal DNA (rDNA) fragments. Effluent samples from secondary (anaerobic covered lagoons and upflow anaerobic sludge blanket [UASB]) and tertiary treatment systems (open-pond natural attenuation lagoon and air-sparged nitrification-denitrification tank followed by alkaline phosphorus precipitation process) were analyzed. A total of 56,807 and 48,859 high-quality reads were obtained from bacterial and archaeal libraries, respectively. Dominant bacterial communities were associated with the phylum Firmicutes, Bacteroidetes, Proteobacteria, or Actinobacteria. Bacteria and archaea diversity were highest in UASB effluent sample. Escherichia, Lactobacillus, Bacteroides, and/or Prevotella were used as indicators of putative pathogen reduction throughout the WWTPs. Satisfactory pathogen reduction was observed after the open-pond natural attenuation lagoon but not after the air-sparged nitrification/denitrification followed by alkaline phosphorus precipitation treatment processes. Among the archaeal communities, 80% of the reads was related to hydrogeno-trophic methanogens Methanospirillum. Enrichment of hydrogenotrophic methanogens detected in effluent samples from the anaerobic covered lagoons and UASB suggested that CO2 reduction with H2 was the dominant methanogenic pathway in these systems. Overall, the results served to improve our current understanding of major microbial communities' changes downgradient from the pen and throughout swine WWTP as a result of different treatment processes. PMID- 25432580 TI - Mechanical stimulation of the foot sole in a supine position for ground reaction force simulation. AB - BACKGROUND: To promote early rehabilitation of walking, gait training can start even when patients are on bed rest. Supine stepping in the early phase after injury is proposed to maximise the beneficial effects of gait restoration. In this training paradigm, mechanical loading on the sole of the foot is required to mimic the ground reaction forces that occur during overground walking. A pneumatic shoe platform was developed to produce adjustable forces on the heel and the forefoot with an adaptable timing. This study aimed to investigate the stimulation parameters of the shoe platform to generate walking-like loading on the foot sole, while avoiding strong reflexes. METHODS: This study evaluated this platform in ten able-bodied subjects in a supine position. The platform firstly produced single-pulse stimulation on the heel or on the forefoot to determine suitable stimulation parameters, then it produced cyclic stimulation on the heel and the forefoot to simulate the ground reaction forces that occur at different walking speeds. The ankle angle and electromyography (EMG) in the tibialis anterior (TA) and soleus (SOL) muscles were recorded. User feedback was collected. RESULTS: When the forefoot or/and the heel were stimulated, reflexes were observed in the lower leg muscles, and the amplitude increased with force. Single-pulse stimulation showed that a fast-rising force significantly increased the reflex amplitudes, with the possibility of inducing ankle perturbation. Therefore a slow-rising force pattern was adopted during cyclic stimulation for walking. The supine subjects perceived loading sensation on the foot sole which was felt to be similar to the ground reaction forces during upright walking. The EMG generally increased with force amplitude, but no reflex-induced ankle perturbations were observed. The mean change in the ankle joint induced by the stimulation was about 1 degrees . CONCLUSIONS: The rate of force increase should be carefully adjusted for simulation of walking-like loading on the foot sole. It is concluded that the dynamic shoe platform provides adjustable mechanical stimulation on the heel and the forefoot in a supine position and has technical potential for simulation of ground reaction forces that occur during walking. PMID- 25432578 TI - cDNA structure and the effect of fasting on myostatin expression in walking catfish (Clarias macrocephalus, Gunther 1864). AB - We cloned and sequenced the myostatin (MSTN) gene of walking catfish and characterized its expression under different conditions. The full cDNA sequence of MSTN was 1,784 bp, containing an open reading frame of 1,191 bp, which encoded 396 amino acids. The deduced MSTN sequence contained functional sites similar to other members of TGF-beta superfamily, including the proteolytic processing site and nine conserved cysteines in the C-terminal. Walking catfish MSTN mRNA was strongly expressed in skeletal muscle and brain tissues, consistent with the expression profiles of MSTN-1 isoform in other teleosts. Temporal expression analysis revealed that the MSTN was expressed at the highest levels in 1-week-old larvae and adults, but was lowest in early juveniles. A fasting-re-feeding experiment was used to evaluate the effects of starvation on growth and MSTN expression in juvenile walking catfish for 28 days. MSTN transcript levels increased significantly (threefold) after 7 days of fasting (P < 0.05) compared with the fed control. Subsequently, MSTN expression levels decreased 1.6-fold when fasting was extended to 14 days. Although re-feeding decreased the MSTN expression relative to the levels of the fed control, the period was not long enough for growth recovery of the juveniles. Our results supported a role of MSTN as a negative regulator of muscle growth and, possibly, a role in energy conservation in fish. PMID- 25432579 TI - Effects of fructooligosaccharide on immune response, antioxidant capability and HSP70 and HSP90 expressions of blunt snout bream (Megalobrama amblycephala) under high ammonia stress. AB - This study aimed to determine the effects of fructooligosaccharide (FOS) on immune response, antioxidant capability and HSP70 and HSP90 mRNA expressions of blunt snout bream (Megalobrama amblycephala) under high ammonia stress. A total of 360 fish were randomly distributed into three groups (each with four replicates) and were fed three levels of FOS (0, 0.4 and 0.8 %) for 8 weeks. After the feeding trial, 24 fish per tank were exposed to ammonia at 10 mg L(-1). After stress, plasma cortisol and glucose levels of fish fed 0.4 % FOS were all significantly lower than that of the control group at 6 and 3 h, respectively. Plasma lysozyme and alternative complement pathway (ACH50) activities as well as nitrogen monoxide (NO) levels all increased significantly with the maximum levels being attained at 6, 6 and 3 h, respectively. Thereafter, these parameters all decreased significantly. In addition, fish fed 0.4 % FOS showed higher immune parameters under stress compared with that of control group. In addition, liver superoxide dismutase and catalase activities of fish fed 0.4 % FOS were both significantly higher than that of the control group before and after stress, while the opposite was true for malondialdehyde content. After stress, the expression of HSP70 and HSP90 of fish fed FOS was significantly higher than that of the control group at 6 and 12 h, respectively. After 12 h stress, the cumulative mortality of fish fed FOS was significantly lower than that of the control. The results indicated that the supplementation of 0.4 % FOS could increase the nonspecific immunity, antioxidant capacity and HSP70 and HSP90 expression of blunt snout bream and enhance its resistance to high ammonia stress. PMID- 25432581 TI - Arteriosclerosis can predict hypotension during anesthesia induction in patients 40 years and older. AB - STUDY OBJECTIVES: To identify the factors that predict blood pressure (BP) changes during induction of general anesthesia, and the relationship between the level of arteriosclerosis and BP changes during anesthesia induction. DESIGN: Prospective, case-control observational study. SETTINGS: Operating room of a university hospital. PATIENTS: Seventy-two patients who received general anesthesia for oral and maxillofacial surgery. MEASUREMENTS: Brachial-ankle pulse wave velocity (baPWV) and central BP were measured. The primary variable was the parameters affecting BP changes during the induction of general anesthesia. For additional analyses, the parameters were compared between high and low PWV groups (1606 cm/s was the cutoff value of baPWV). To measure the relationships between the parameters and BP changes, bivariate and multiple linear regression analyses were performed. RESULTS: Seventy-two patients (including 41 men) with a mean age of 61.7 years and a median baPWV value of 1606 cm/s were evaluated. Significantly higher values for age, central BP, preoperative systolic BP (SBP), amount of decrease in SBP and diastolic BP, and number of patients with diabetes mellitus (DM) and hypertension were observed in the high PWV group. Multiple linear regression analysis demonstrated that age, baPWV, and DM were factors independently associated with the amount of decrease in SBP. CONCLUSION: In patients 40 years and older, age, baPWV, and DM are thought to be effective predictors of the amount of decrease in SBP during induction of general anesthesia. PMID- 25432582 TI - Skeletal metastasis in gallbladder cancer from a high-volume tertiary care center of north India: a series of rare occurrence. AB - PURPOSE: Gallbladder carcinoma is usually characterized by late diagnosis and poor prognosis. Skeletal metastases in gallbladder cancer have been rarely reported in literature. In this study, we evaluated the incidence of skeletal metastasis in gallbladder cancer at our high-volume center and their clinical presentation, radiological imaging, treatment received, outcome, and survival. METHODS: Records of all gallbladder carcinoma patients registered in our department from October 2007-October 2012 were retrospectively reviewed to identify gallbladder cancer patients with skeletal metastasis and their data was collected and analyzed. RESULTS: Out of 340 cases of gallbladder carcinoma, 189 (55.58 %) were having stage IV disease. Of these, seven (2.1 %) patients had cytologically proven skeletal metastasis. All seven patients had advanced loco regional abdominal disease with coexistent liver metastasis. Presenting symptoms were predominantly weight loss and back pain with markedly elevated serum alkaline phosphatase (median = 1231 IU/ml). Dorsolumbar vertebral metastasis was the most common site of skeletal metastasis in our series (5/7), followed by pelvic bone (2/7) while skull and sternal metastasis were present in one patient each. All these patients had short median survival (median = 30 days, range = 15 60 days). CONCLUSIONS: Incidence of skeletal metastasis in gallbladder cancer is very low (2.1 %). Axial skeleton was the most common site of bone metastasis. Gallbladder cancer with skeletal metastasis portends poor prognosis with rapidly fatal course. PMID- 25432584 TI - Motivational interviewing: experiences of primary care nurses trained in the method. AB - Motivational interviewing is a person-centered counseling style used to promote behavioral change regarding a wide variety of lifestyle problems. Use of motivational interview is growing worldwide and among many different healthcare professions, including primary care nursing. The study aim was to describe motivational interview trained nurses' experiences of motivational interviewing in primary care settings. The study had a qualitative descriptive design. It was carried out in Swedish primary care settings in two county council districts, with 20 primary care nurses trained in motivational interviewing. Half of them used the method in their work, half did not. Qualitative semi-structured interviews were used. Data were analyzed using qualitative content analysis. The nurses experienced that openness to the approach and an encouraging working climate are required to overcome internal resistance and to increase use of motivational interviewing. They also experienced mutual benefit: motivational interviewing elicits and develops abilities in both nurses and patients. For the nurses using it, motivational interviewing is perceived to facilitate work with patients in need of lifestyle change. Lack of training/education, support, interest and appropriate work tasks/patients are reasons for not using motivational interviewing. PMID- 25432583 TI - Shifting paradigm in the management of anal canal carcinoma. AB - BACKGROUND: Anal canal is the lower most part of the gastrointestinal tract harbouring 4 % of all gastrointestinal cancer. Most common treatment for anal canal carcinoma includes chemoradiotherapy. METHODOLOGY: We reviewed the recent landmark trials to find a road map in the management of anal canal carcinoma. RESULTS: Concurrent chemoradiotherapy appears to be the most effective treatment schedule. Induction, as well as maintenance chemotherapy, has no definite role. Moderate dose radiation 50.4-54 Gy with concurrent mitomycin C (MMC) and 5 fluorouracil (5-FU) remains the standard. Split course is detrimental. Intensity modulated radiotherapy and targeted drugs are investigated. CONCLUSION: Combined modality therapy is the standard for anal canal carcinoma. PMID- 25432586 TI - A comparison of the effects of reading interventions on engagement and performance for fourth-grade students with learning disabilities. AB - Inexpensive software applications designed to teach reading, writing, mathematics, and other academic areas have become increasingly popular. Although previous research has demonstrated the potential efficacy of such applications, there is a paucity of research that compares applications instruction (AI) with traditional teacher-directed instruction (TDI), and the relative effectiveness and efficiency of these instructional approaches remains largely unknown. This study used an alternating treatment design to compare academic engagement and outcomes (i.e., word identification and reading fluency) during an AI condition and a TDI condition for four students with learning disabilities (LD) attending a charter school. Instructional conditions (i.e., TDI, AI) were randomly alternated 7 times each, for a total of 14 instructional sessions. Results indicated that both approaches fostered high levels of engagement although students were more engaged during AI. With regard to academic performance, visual and quantitative analysis suggest that TDI was more effective than AI in terms of passage fluency and word identification. Students completed social validity rating scales to examine instructional preference. Results indicated that both approaches, TDI and AI, were popular with the students. PMID- 25432585 TI - Wogonin modulates hydroperoxide-induced apoptosis via PI3K/Akt pathway in retinal pigment epithelium cells. AB - BACKGROUND: Oxidative stress causes the defects of retinal pigment epithelial (RPE) cells that contribute to age-related macular degeneration (AMD). This study was conducted to determine whether wogonin could prevent H2O2-induced oxidative stress in RPE cells. METHODS: A RPE cell line, ARPE-19, was obtained for the cell model. ARPE-19 cells were pre-treated with various concentrations of wogonin for 24 h before being exposed to H2O2 for 2 h to induce oxidative stress. Cell metabolic activity was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Cellular apoptosis was quantified by the flow cytometry. Protein level was assed by western blot. RESULTS: The RPE cells exposed to to 200 mM H2O2 demonstrated a significant depression in the cell viability; whereas pre-treatment with 50 and 100 mmol/l wogonin could significantly improve the cell viability in a dose-dependent manner. The proportion of PI-positive cells was increased significantly in RPE cells treated with H2O2 alone; whereas pretreatment with 100 mM wogonin significantly reduced H2O2 -induced RPE cell death rate. In protein level, the wogonin use could reduce the level of p-Akt significantly and this is the possible mechanism of the antioxidant effect of wogonin. CONCLUSIONS: Our study showed that wogonin pre treatment can protect RPE cells from H2O2-induced apoptosis. This suggests potential effect of wogonin in the prevention of retinal diseases associated with H2O2-induced oxidative stress such as AMD. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_154. PMID- 25432587 TI - Using Quality Improvement to Increase Access to Behavioral Health Care in Federally Qualified Health Centers. AB - OBJECTIVES: Integrated care programs, in which behavioral health is integrated in primary care settings, have been widely implemented as solution to rising health care expenditures. A number of recommendations for implementation of integrated care have been published in the past decade; however, data regarding how to produce the most effective system are lacking. This may be because of the fact that existing integrated care programs do not institute quality improvement initiatives that could generate this needed data. METHODS: A quality improvement program was instituted at an integrated Federally Qualified Health Center. As a result, productivity and no-show rates were analyzed for two psychology externs providing integrated care services. A process map was created to identify systematic methods to improve outcomes. RESULTS: There were statistically significant increases to productivity increased and decreases no-show rates through systematic changes. CONCLUSION: This case study provides evidence that quality improvement systems in integrated care can result in systemic changes that improve access to care. PMID- 25432588 TI - Factors Associated With Missed Opportunities for Influenza Vaccination: Review of Medical Records in a Diverse Sample of Primary Care Clinics, San Diego County, 2010-2011. AB - OBJECTIVE: Annual influenza vaccination rates remain well below health objectives. Most primary care clinic visits present opportunities for vaccination. The purpose of this study was to quantify missed opportunities (MOs) during the entire influenza season. Patients and clinic characteristics associated with vaccination and MOs are identified. METHODS: Influenza vaccinations recorded in random chart reviews of children 6 months to 5 years and of adults 50 years and older at 6 pediatric and 7 adult primary care clinics were assessed during the 2010-2011 influenza season. Patient-specific MOs accounted for variable timing and number of visits throughout the vaccination season. Data were assessed using descriptive, graphical, proportional hazards regression methods. RESULTS: Data for 1136 children and 1329 adults were analyzed. By the end of the season, influenza vaccination coverage recorded in medical records reached 56% and 26% for children and adults, respectively. MOs are common throughout the season and rise sharply after December. By the end of the season, 30.2% of children and 44.9% of adults had 2 or more MOs. Characteristics associated with MOs included age, insurance type, number of visits, and type of medical practice. CONCLUSIONS: Missed opportunities abound, especially after December. Strategies targeting patients most likely to have MOs and encouraging the use standing orders, reminders, and monitoring in order to reduce them need to be sustained. PMID- 25432589 TI - Royal college of physicians still opposes change in law on assisted dying. PMID- 25432591 TI - Prescriber beware: report of adverse effect of sodium-glucose cotransporter 2 inhibitor use in a patient with contraindication. PMID- 25432590 TI - Immunoglobulin G4-associated cholangitis mimicking cholangiocarcinoma treated by laparoscopic choledochectomy with intracorporeal Roux-en-Y hepaticojejunostomy. AB - Immunoglobulin G4 (IgG4)-associated disease is a recently recognized disease entity that is characterized by elevated serum IgG4 concentrations, abundant IgG4 lymphoplasmacytic infiltration, and dramatic steroid responses. IgG4-associated cholangitis is one manifestation of IgG4-associated disease. However, it is clinically challenging to make a preoperative differentiation between this rare disease and cholangiocarcinoma, especially for those with serum concentrations of IgG4 in the normal range. This article reports on a 57-year-old man with jaundice and upper abdominal discomfort. Imaging examination showed biliary stricture that closely resembled cholangiocarcinoma, and the patient's serum IgG4 concentration was normal. The patient underwent a laparoscopic choledochectomy with Roux-en-Y hepaticojejunostomy using an intracorporeal hand-sewn technique. He recovered quickly without any complications. We also present our experience in laparoscopic intracorporeal hand-sewn hepaticojejunostomy. PMID- 25432593 TI - Morning serum melatonin values in multiple sclerosis: A biochemical evaluation. PMID- 25432592 TI - Effectiveness of arterial, venous, and capillary blood lactate as a sepsis triage tool in ED patients. AB - OBJECTIVE: We evaluate the capacity of arterial (ABL), peripheral venous (VBL), and capillary (CBL) blood lactate concentration to early detect the presence of severe sepsis in patients admitted to the emergency department for a septic syndrome. METHODS: Patients with signs of sepsis presenting to the emergency department were prospectively enrolled. Blood lactate was measured using a handheld point-of-care analyzer on microsamples of arterial, peripheral venous, and capillary blood. An arterial blood sample was dispatched to the central laboratory as a reference measurement. RESULTS: A total of 103 patients were enrolled in the study, with 63 patients presenting with a severe sepsis. There was a strong correlation between the point of care and the reference blood lactate measurement. The CBL, VBL, and ABL were all significantly different (3.01+/-0.29, 2.51+/-0.21, and 2.03+/-0.18 mmol/L, respectively; P<.001). The VBL value was the most efficient to detect early the presence of severe sepsis (areas under the receiver operating characteristic curves were 0.85+/-0.04, 0.76+/-0.05, and 0.75+/-0.05 for VBL, ABL, and CBL, respectively; P<.01). Mortality at 28 days was related to the severity of sepsis (28.6% vs 7.5%) and to the number or organ dysfunctions (P<.01). Arterial blood lactate, VBL, and CBL were all significantly associated with the 28th-day mortality. CONCLUSIONS: Initial VBL may be used efficiently to assess the severity of sepsis, and it could even be more effective than ABL and CBL to early detect the presence of severe sepsis. PMID- 25432594 TI - Prognostic factors in resectable pathological N2 disease of non-small cell lung cancer. AB - BACKGROUND: N2-positive non-small cell lung cancer (NSCLC) exhibits extremely low survival rates. The role of surgery in operable locally advanced N2 NSCLC remains controversial. In this study, we tried to analyze the role of surgery in resectable N2 NSCLC and the relationship between survival and clinico-pathologic factors from a pathologic point of view. METHODS: 108 resectable pathologic N2 positive NSCLC patients, diagnosed from January 2005 to July 2012, were enrolled in this study. We retrospectively reviewed the medical records, image studies, and pathology reports to collect the clinico-pathologic factors in these patients. RESULTS: Those who received lobectomy (p = 0.002) and had a metastatic lymph node ratio less than 0.4 (p = 0.01) had a better overall survival rate. In addition, our study also showed that perineural invasion may play a significant role in disease-free survival (p = 0.01) CONCLUSIONS: Metastatic lymph node ratio greater than 0.4 and non-anatomic resection were poor prognostic factors for disease-free survival. Anatomic resection for selected N2 patients may play a crucial role in the overall survival rate. Perineural invasion showed an adverse impact on disease-free survival, but further investigation is warranted. PMID- 25432595 TI - Results of instrumented posterolateral fusion in treatment of lumbar spondylolisthesis with and without segmental kyphosis: A retrospective investigation. AB - BACKGROUND: Treatment by posterolateral fusion (PLF) with pedicle-screw instrumentation can be unsuccessful in one-segment and low-grade lumbar spondylolisthesis. Segmental kyphosis, either rigid or dynamic, was hypothesized to be one of the factors interfering with the fusion results. METHODS: From 2004 to 2005, 239 patients with single-segment and low-grade spondylolisthesis were recruited and divided into two groups: Group 1 consisting of 129 patients without segmental kyphosis and group 2 consisting of 110 patients with segmental kyphosis. All patients underwent instrumented PLF at the same medical institute, and the average follow-up period was 31 +/- 19 months. We obtained plain radiographs of the lumbosacral spine with the anteroposterior view, the lateral view, and the dynamic flexion-extension views before the operation and during the follow-ups. The results of PLF in the two groups were then compared. RESULTS: There was no significant difference in the demographic data of the two groups, except for gender distribution. The osseous fusion rates were 90.7% in group 1 and 68.2% in group 2 (p < 0.001). CONCLUSION: Instrumented PLF resulted in significantly higher osseous fusion rate in patients without segmental kyphosis than in the patients with segmental kyphosis. For the patients with sagittal imbalance, such as rigid or dynamic kyphosis, pedicle-screw fixation cannot ensure successful PLF. Interbody fusion by the posterior lumbar interbody fusion or transforaminal lumbar interbody fusion technique might help overcome this problem. PMID- 25432598 TI - Catching the invisible: mesial temporal source contribution to simultaneous EEG and SEEG recordings. AB - Mesial temporal sources are presumed to escape detection in scalp electroencephalographic recordings. This is attributed to the deep localization and infolded geometry of mesial temporal structures that leads to a cancellation of electrical potentials, and to the blurring effect of the superimposed neocortical background activity. In this study, we analyzed simultaneous scalp and intracerebral electroencephalographic recordings to delineate the contribution of mesial temporal sources to scalp electroencephalogram. Interictal intracerebral spike networks were classified in three distinct categories: solely mesial, mesial as well as neocortical, and solely neocortical. The highest and earliest intracerebral spikes generated by the leader source of each network were marked and the corresponding simultaneous intracerebral and scalp electroencephalograms were averaged and then characterized both in terms of amplitude and spatial distribution. In seven drug-resistant epileptic patients, 21 interictal intracerebral networks were identified: nine mesial, five mesial plus neocortical and seven neocortical. Averaged scalp spikes arising respectively from mesial, mesial plus neocortical and neocortical networks had a 7.1 (n = 1,949), 36.1 (n = 628) and 10 (n = 1,471) uV average amplitude. Their scalp electroencephalogram electrical field presented a negativity in the ipsilateral anterior and basal temporal electrodes in all networks and a significant positivity in the fronto-centro-parietal electrodes solely in the mesial plus neocortical and neocortical networks. Topographic consistency test proved the consistency of these different scalp electroencephalogram maps and hierarchical clustering clearly differentiated them. In our study, we have thus shown for the first time that mesial temporal sources (1) cannot be spontaneously visible (mean signal-to-noise ratio -2.1 dB) on the scalp at the single trial level and (2) contribute to scalp electroencephalogram despite their curved geometry and deep localization. PMID- 25432597 TI - Identification of candidate genes, regions and markers for pre-harvest sprouting resistance in wheat (Triticum aestivum L.). AB - BACKGROUND: Pre-harvest sprouting (PHS) of wheat grain leads to a reduction in grain yield and quality. The availability of markers for marker-assisted selection (MAS) of PHS resistance will serve to enhance breeding selection and advancement of lines for cultivar development. The aim of this study was to identify candidate regions and develop molecular markers for PHS resistance in wheat. This was achieved via high density mapping of single nucleotide polymorphism (SNP) markers from an Illumina 90 K Infinium Custom Beadchip in a doubled haploid (DH) population derived from a RL4452/'AC Domain' cross and subsequent detection of quantitative trait loci (QTL) for PHS related traits (falling number [FN], germination index [GI] and sprouting index [SI]). SNP marker sequences flanking QTL were used to locate colinear regions in Brachypodium and rice, and identify genic markers associated with PHS resistance that can be utilized for MAS in wheat. RESULTS: A linkage map spanning 2569.4 cM was constructed with a total of 12,201 SNP, simple sequence repeat (SSR), diversity arrays technology (DArT) and expressed sequence tag (EST) markers. QTL analyses using Multiple Interval Mapping (MIM) identified four QTL for PHS resistance traits on chromosomes 3B, 4A, 7B and 7D. Sequences of SNPs flanking these QTL were subject to a BLASTN search on the International Wheat Genome Sequencing Consortium (IWGSC) database (http://wheat-urgi.versailles.inra.fr/Seq Repository). Best survey sequence hits were subject to a BLASTN search on Gramene (www.gramene.org) against both Brachypodium and rice databases, and candidate genes and regions for PHS resistance were identified. A total of 18 SNP flanking sequences on chromosomes 3B, 4A, 7B and 7D were converted to KASP markers and validated with matching genotype calls of Infinium SNP data. CONCLUSIONS: Our study identified candidate genes involved in abscissic acid (ABA) and gibberellin (GA) metabolism, and flowering time in four genomic regions of Brachypodium and rice respectively, in addition to 18 KASP markers for PHS resistance in wheat. These markers can be deployed in future genetic studies of PHS resistance and might also be useful in the evaluation of PHS in germplasm and breeding material. PMID- 25432596 TI - Non-coding RNA gene families in the genomes of anopheline mosquitoes. AB - BACKGROUND: Only a small fraction of the mosquito species of the genus Anopheles are able to transmit malaria, one of the biggest killer diseases of poverty, which is mostly prevalent in the tropics. This diversity has genetic, yet unknown, causes. In a further attempt to contribute to the elucidation of these variances, the international "Anopheles Genomes Cluster Consortium" project (a.k.a. "16 Anopheles genomes project") was established, aiming at a comprehensive genomic analysis of several anopheline species, most of which are malaria vectors. In the frame of the international consortium carrying out this project our team studied the genes encoding families of non-coding RNAs (ncRNAs), concentrating on four classes: microRNA (miRNA), ribosomal RNA (rRNA), small nuclear RNA (snRNA), and in particular small nucleolar RNA (snoRNA) and, finally, transfer RNA (tRNA). RESULTS: Our analysis was carried out using, exclusively, computational approaches, and evaluating both the primary NGS reads as well as the respective genome assemblies produced by the consortium and stored in VectorBase; moreover, the results of RNAseq surveys in cases in which these were available and meaningful were also accessed in order to obtain supplementary data, as were "pre-genomic era" sequence data stored in nucleic acid databases. The investigation included the identification and analysis, in most species studied, of ncRNA genes belonging to several families, as well as the analysis of the evolutionary relations of some of those genes in cross-comparisons to other members of the genus Anopheles. CONCLUSIONS: Our study led to the identification of members of these gene families in the majority of twenty different anopheline taxa. A set of tools for the study of the evolution and molecular biology of important disease vectors has, thus, been obtained. PMID- 25432600 TI - Variation in trajectories of women's marital quality. AB - I examine variation in trajectories of women's marital quality across the life course. The analysis improves upon earlier research in three ways: (1) the analysis uses a sequential cohort design and data from the first 35years of marriage; (2) I analyze rich data from a national sample; (3) I examine multiple dimensions of marital quality. Latent class growth analyses estimated on data from women in the National Longitudinal Survey of Youth-1979 (N=2604) suggest multiple trajectories for each of three dimensions of marital quality, including two trajectories of marital happiness, two trajectories of marital communication, and three trajectories of marital conflict. Socioeconomic and demographic covariates are then used to illustrate how factors such as income, cohabitation, and race-ethnicity set individuals at risk of poor marital quality throughout the life course by differentiating between high and low trajectories of marital quality. Women on low marital quality trajectories are, as expected, at much greater risk of divorce. Taken together, these findings show how fundamental socioeconomic and demographic characteristics contribute to subsequent marital outcomes via their influence on trajectories of marital quality as well as providing a better picture of the complexity in contemporary patterns of marital quality. PMID- 25432601 TI - Adult non-response bias from a child perspective. Using child reports to estimate father's non-response. AB - Most parenting research on paternal involvement uses data from a father perspective. Nevertheless, research on bias in father non-response is scarce. In this study, we examine the non-response bias of fathers, hypothesizing that fathers who engage in parenting studies might already be fathers who are more involved with their children than fathers who do not engage in these studies. Furthermore, we expect a double non-response bias by socio-demographic characteristics of the father, which impacts both paternal participation as well as paternal involvement. Using the multi-actor dataset from the "Divorce in Flanders"-project, which provides data from children whose fathers actually participated (N=461) as well as data from children whose fathers did not (N=137) with children reporting on paternal involvement, we are able to test our hypotheses. Results confirm our first hypothesis, indicating that non participating fathers are significantly more uninvolved than participating fathers. Regarding our second hypothesis, an indirect effect of father's educational level and age on non-response was revealed for one out of three indicators of paternal involvement. PMID- 25432602 TI - Chinese people's intended and actual use of the court to resolve grievance/dispute. AB - China's legal reforms have promoted the use of law and legal system to solve disputes. Based on data from a nationwide sample, this study examined among people who have recently encountered grievance/dispute, what is the relationship between their intention to use the court and their actual use of the court to solve the grievance/dispute, and what are the correlates that affect their intentions and actions of using legal versus other modes of remedies. The results highlight the primacy of administrative petitioning and non-governmental remedies in handing disputes. There is only a low degree of conjunction between people's reported willingness to use the law and their actual use of the law in addressing grievance/dispute. Education and urbanization play a significant role in legal mobilization. Further, type of grievance/dispute is among the most significant predictors for both intended and actual appeals to the court. Implications for future research are provided. PMID- 25432599 TI - Response of sensitive behaviors to frequent measurement. AB - We study the influence of frequent survey measurement on behavior. Widespread access to the Internet has made important breakthroughs in frequent measurement possible-potentially revolutionizing social science measurement of processes that change quickly over time. One key concern about using such frequent measurement is that it may influence the behavior being studied. We investigate this possibility using both a population-based experiment with random assignment to participation in a weekly journal for twelve months (versus no journal) and a large-scale, population-based, journal-keeping study with weekly measurement for 30 months. Results reveal few of the measured behaviors are correlated with assignment to frequent measurement. Theoretical reasoning regarding the likely behavioral response to frequent measurement correctly predicts domains most vulnerable to this possibility. Overall, however, we found little evidence of behavioral response to frequent measurement. PMID- 25432603 TI - Long-term health and socioeconomic consequences of early-life exposure to the 1959-1961 Chinese Famine. AB - This research investigates long-term consequences of early-life malnutrition by examining effects of the 1959-1961 Chinese Famine. Taking into account temporal and geographic variations in famine severity, we construct a difference-in differences estimator to identify effects of early-life exposure to famine on perceived health and socioeconomic outcomes in midlife. Using a sample of 1716 adults born in 1955-1966 in rural China from a nationally representative survey the 2005 Chinese General Social Survey-we find that the famine had adverse effects on mid-life health for males born into families where at least one parent was a Communist Party member and females regardless of parental party membership. Being born during the famine had no effects on years of education or income for either gender. Quantile regressions suggest intense mortality selection among males who had no party-affiliated parents. Our study highlights the importance of timing and contexts of life experiences in shaping health. PMID- 25432604 TI - The skill-divide in job quality: a cross-national analysis of 28 countries. AB - This study focuses on the skill divide in job quality and the role of social institutions in structuring the relation of workers' qualifications to the attributes of their jobs. Four measures of job quality are examined: job security, job achievement, job content and work schedule flexibility. The study is based on the 2005 ISSP module on work orientations and encompasses 28 countries. Obtained through multilevel modeling, the findings show that low skilled workers are disadvantaged in all aspects of job quality. However, skill inequality in the quality of employment depends on countries' characteristics, with declining inequality in countries at higher levels of technological development and to some extent also in times of technological growth. At times of high unemployment, skill disparities in job security widen while on other measures of job quality they decline. Under high market regulation, the low skilled enjoy better job security but on other measures, skill inequalities increase. PMID- 25432605 TI - Immigration and earnings inequality in America's new small-town destinations. AB - Research on the relationship between immigrant population concentration and earnings inequality is divided between two perspectives. Supply-side arguments maintain that areas attracting large numbers of immigrants experience minimal wage growth at the bottom of the earnings distribution, which increases local levels of earnings inequality. Demand-side arguments contend that industrial restructuring reduces the pay of manual labor regardless of, and even prior to, the arrival of foreign-born workers. Adjudicating between these two perspectives is hindered by issues of potential endogeneity, which confound attempts to independently assess the effects of immigration on inequality or vice versa using OLS regression. We consider a third perspective called the reciprocal effects hypothesis which contends that immigrant concentration and earnings inequality emerge together through a mutually reinforcing feedback process. We explore this question in America's "new small-town destinations" using data from U.S. micropolitan statistical areas. We use three-stage least squares estimation to address the endogeneity problem and to test these three hypotheses. While we find support for both the supply- and demand-side perspectives, the results are best explained by the reciprocal effects hypothesis. PMID- 25432606 TI - School ethnic diversity and White students' civic attitudes in England. AB - The current paper focuses on White British students in lower secondary education and investigates the effect of school ethnic diversity on their levels of trust and inclusive attitudes towards immigrants. Use is made of panel data of the Citizenship Education Longitudinal Study (CELS) to explore these relationships. Ethnic diversity is measured with the proportion of students in a grade identifying with a minority. In agreement with contact theory, the paper initially finds a positive relation between diversity and inclusive attitudes on immigrants. However, this link disappears once controls for social background, gender and prior levels of the outcome are included in the model. This indicates that students with particular pre-enrolment characteristics have self-selected in diverse schools and that inclusive attitudes have stabilized before secondary education. Diversity further appears to have a negative impact on trust, irrespective of the number of controls added to the model. PMID- 25432607 TI - Feminists wrestle with testosterone: hormones, socialization and cultural interactionism as predictors of women's gendered selves. AB - Sociology of gender has developed beyond a personality-centered idea of "sex roles" to an approach that stresses interaction and social structure. At the same time, there has been a concurrent development in the psychological sex differences and medical literatures toward including the biological bases of sex typed behavior and gender identities. In this paper, while we conceptualize gender as a social structure, we focus only on the individual level of analysis: testing the relative strength of (maternal circulating) prenatal hormones, childhood socialization, and the power of expectations attached to adult social roles (cultural interactionist) as explanations for women's self-reported feminine and masculine selves. Our findings are complex, and support some importance of each theory. Prenatal hormones, childhood socialization, and cultural interactionism were all influential factors for gendered selves. While cultural expectations predicted only feminine selves, prenatal hormones were more robust predictors of masculine sense of self. While personality may be a relatively stable characteristic influenced by the body and childhood socialization, our results reinforce the importance of studying how the social world responds to and reinforces gendered personality. PMID- 25432608 TI - The downside of marketization: a multilevel analysis of housing tenure and types in reform-era urban China. AB - Based on data from the 2005 National Population Sample Survey and compiled covariates of 205 prefectures, this research adopted principal-component and multilevel-logistic analyses to study homeownership in urban China. Although the housing reform has severed the link between work units and residence, working in state sectors (government, state-owned enterprises and collective firms) remained significant in determining a household's entitlement to reform-era housing with heavy subsidies or better qualities. While the prefecture-level index of marketization reduced local homeownership of self-built housing, affordable housing and privatized housing, its effect is moderated by cross-level interactions with income, education and working in state sectors across different types of housing. Meanwhile, the index of political and market connections promoted all types of homeownership except for self-built housing. By situating the downside of marketization within a context of urban transformation, this research not only challenges the teleological premise of the neoliberal market transition theory but calls for research on institutional dynamics and social consequences of urban transformation in China. PMID- 25432609 TI - Languages, communication potential and generalized trust in Sub-Saharan Africa: evidence based on the Afrobarometer Survey. AB - The goal of this study is to investigate whether speaking other than home languages in Sub-Saharan Africa promotes generalized trust. Based on various psychological and economic theories, a simple model is provided to illustrate how languages might shape trust through various channels. Relying on data from the Afrobarometer Project, which provides information on home and additional languages, the Index of Communication Potential (ICP) is introduced to capture the linguistic situation in the 20 sample countries. The ICP, which can be computed at any desired level of aggregation, refers to the probability that an individual can communicate with a randomly selected person in the society based on common languages. The estimated two-level hierarchical models show that, however, individual level communication potential does not seem to impact trust formation, but living in an area with higher average communication potential increases the chance of exhibiting higher trust toward unknown people. PMID- 25432610 TI - Business structure, ethnic shifts in labor markets, and violence: the link between company size, local labor markets, and non-Latino homicide. AB - Combining several schools of thought, including the civic engagement thesis, we extend current research by linking three things at the county level; firm size, the ethnic composition of labor markets, and violent crime. Our results suggest that larger businesses (based on the average number of persons employed) are more likely to have an external orientation and long recruitment reach, and this is linked to ethnic shifts in labor markets toward Latino workers. Such shifts are in turn associated with high rates of homicide among non-Latinos. Through indirect effects modeling, we find that increases in Black homicide are linked to rises in concentrated poverty, while increases in White homicide are linked to changes in unemployment. We discuss the implications of our findings. PMID- 25432611 TI - The joint effect of ethnicity and gender on occupational segregation. An approach based on the Mutual Information Index. AB - In this article, we study the effects of ethnicity and gender on occupational segregation. Traditionally, researchers have examined the two sources of segregation separately. In contrast, we measure their joint effect by applying a multigroup segregation index-the Mutual Information or M index-to the product of the seven ethnic groups and two genders distinguished in our 2001 Census data for England and Wales. We exploit M's additive decomposability property to pose the following two questions: (i) Is there an interaction effect? (ii) How much does each source contribute to occupational segregation, controlling for the effect of the other? Although the role of ethnicity is non-negligible in the areas where minorities are concentrated, our findings confirm the greater importance of gender over ethnicity as a source of segregation. Moreover, we find a small "dwindling" interaction effect between the two sources of segregation: ethnicity slightly weakens the segregating power of gender and vice versa. PMID- 25432613 TI - Explaining the Muslim employment gap in Western Europe: individual-level effects and ethno-religious penalties. AB - It is well-documented that Muslims experience economic disadvantages in Western European labor markets. However, few studies comprehensively test individual level explanations for the Muslim employment gap. Using data from the European Social Survey, this research note briefly examines the role of individual-level differences between Muslims and non-Muslims in mediating employment differences. Results reveal that human capital, migration background, religiosity, cultural values, and perceptions of discrimination jointly account for about 40% of the employment variance between Muslims and non-Muslims. Model specifications for first- and second-generation Muslim immigrants reveal a similar pattern, with migration background and perceived discrimination being of key relevance in mediating employment difference. While individual-level effects are indeed relevant, unexplained variance suggests that symbolic boundaries against Islam may still translate into tangible ethno-religious penalties. PMID- 25432612 TI - Explaining the subjective well-being of urban and rural Chinese: income, personal concerns, and societal evaluations. AB - This study makes an integrated investigation of how subjective well-being is associated with income, personal concerns, and societal evaluations and how these social and psychological correlates of subjective well-being are contextualized within a country. Data used for the empirical analysis come from a nationally representative sample survey conducted in China in 2009. It is found that subjective well-being is independently linked to income, personal concerns, and societal evaluations. Comparisons of urban and rural Chinese further reveal that income, structural attributions of inequality, and evaluations of governance are related to subjective well-being among both groups. Nevertheless, different sets of other evaluative correlates of subjective well-being between urban and rural people stand out, which is conjectured to be related to the long-time institutional, economic, and social segmentation of the two groups. This study has contributed to both the subjective well-being theories and the understanding of the consequences of social inequality. PMID- 25432614 TI - Unemployment among Mexican immigrant men in the United States, 2003-2012. AB - Based on their socioeconomic characteristics, Mexican immigrant men should have very high unemployment. More than half do not have a high school diploma. One in four works in construction; at the height of the recent recession, 20% of construction workers were unemployed. Yet their unemployment rates are similar to those of native-born white men. After controlling for education and occupation, Mexican immigrant men have lower probabilities of unemployment than native-born white men - both before and during the recent recession. I consider explanations based on eligibility for unemployment benefits, out-migrant selection for unemployment, and employer preferences for Mexican immigrant labor. PMID- 25432615 TI - Getting support in polarized societies: income, social networks, and socioeconomic context. AB - This paper explores how unequal resources and social and economic polarization affects the size of social networks and their use to access resources. We argue that individual resource position generates divergent expectations with regard to the impact of polarization on the size of networks on one hand, and their usefulness for accessing resources on the other. Social and economic polarization encourages reliance on informal networks, but those at the bottom of the social structure are forced to rely on more extensive networks than the wealthy to compensate for their isolated and underprivileged position. At the same time, social and economic polarization limits the resources the poor can access through their networks. We provide evidence consistent with these propositions, based on data derived from the International Social Survey Programme 2001 "Social Networks" dataset combined with contextual information on the levels of economic inequality in particular countries along with whether they experienced postcommunism. PMID- 25432616 TI - Variable links within perceived police legitimacy?: fairness and effectiveness across races and places. AB - This work examines connections between two threads of community residents' perceptions of local police legitimacy, effectiveness and procedural fairness, and how those links depend on race, place, and race/place combinations. Previous works have connected these two threads, but have failed (a) to explore the variability of that connection by race, place, and race/place combinations across communities spanning the urban to suburban to rural continuum or (b) to model mutual influence. An extension of the group position thesis and work on minority views of police practices suggest how these variations might be patterned. Data were derived from a 2003 probability-based sampling survey of household respondents across Pennsylvania (n=1289). Generalized confirmatory factor analysis models built procedural fairness and effectiveness indices for four groups: whites in urban core counties, non-whites in urban core counties, whites in non-urban core counties, and non-whites in non-urban core counties. Non recursive structural equation models revealed variable impacts of perceived police effectiveness on perceived police fairness and, to a lesser extent, of fairness on effectiveness. Implications for a more structurally and contextually aware understanding of links in police legitimacy models are developed. PMID- 25432617 TI - Occupational conditions, self-care, and obesity among clergy in the United States. AB - Prior research has shown that a variety of occupational conditions such as long work hours are associated with increased likelihood of obesity. In this study, we use the specific case of the clergy to explore how occupational conditions are linked to increased or decreased odds of being obese. We hypothesize that stressful conditions are associated with increased odds of obesity and that self care practices are associated with decreased odds. Using the 2008/9 U.S. Congregational Life Survey's national sample of clergy from multiple religious traditions, we find support for our hypotheses. Clergy who experience more stress, work more hours, or are bi-vocational have higher odds of obesity. Those who take a day off each week, have taken a sabbatical, or are involved in a support group experience lower odds. For Protestant clergy, being involved in a support group or taking a day off moderates the association between certain stressful occupational conditions and obesity. PMID- 25432618 TI - Transforming wealth: using the inverse hyperbolic sine (IHS) and splines to predict youth's math achievement. AB - The natural log and categorical transformations commonly applied to wealth for meeting the statistical assumptions of research may not always be appropriate for adjusting for skewness given wealth's unique properties. Finding and applying appropriate transformations is becoming increasingly important as researchers consider wealth as a predictor of well-being. We present an alternative transformation-the inverse hyperbolic sine (IHS)-for simultaneously dealing with skewness and accounting for wealth's unique properties. Using the relationship between household wealth and youth's math achievement as an example, we apply the IHS transformation to wealth data from US and Ghanaian households. We also explore non-linearity and accumulation thresholds by combining IHS transformed wealth with splines. IHS transformed wealth relates to youth's math achievement similarly when compared to categorical and natural log transformations, indicating that it is a viable alternative to other transformations commonly used in research. Non-linear relationships and accumulation thresholds emerge that predict youth's math achievement when splines are incorporated. In US households, accumulating debt relates to decreases in math achievement whereas accumulating assets relates to increases in math achievement. In Ghanaian households, accumulating assets between the 25th and 50th percentiles relates to increases in youth's math achievement. PMID- 25432619 TI - The spatial extent of the effect of foreclosures on crime. AB - Although neighborhood stability has long been considered a substantial determinant of crime, foreclosures have not been the subject of concerted research among criminologists until recently. A number of recent studies have examined the linkage between home foreclosures and crime. Though generally finding a significant relationship, studies have used different approaches and units of analysis. This variation led us to examine the spatial extent to which foreclosures affect a relatively small surrounding area. In this paper, we consider the spatial extent of the foreclosure effect on crime by estimating fixed effect negative binomial models using geocoded UCR data for 2003-2008 and foreclosure data to predict crime counts using the number of foreclosures within various small area radii. Results show that, independently and jointly, foreclosures are a predictor of crime up to at least a distance of 2250 feet. Importantly, that effect declines with distance. We conclude with a discussion of the implications of those findings. PMID- 25432620 TI - Network effects across the earnings distribution: payoffs to visible and invisible job finding assistance. AB - This study makes three critical contributions to the "Do Contacts Matter?" debate. First, the widely reported null relationship between informal job searching and wages is shown to be mostly the artifact of a coding error and sample selection restrictions. Second, previous analyses examined only active informal job searching without fully considering the benefits derived from unsolicited network assistance (the "invisible hand of social capital") - thereby underestimating the network effect. Third, wage returns to networks are examined across the earnings distribution. Longitudinal data from the NLSY reveal significant wage returns for network-based job finding over formal job searching, especially for individuals who were informally recruited into their jobs (non searchers). Fixed effects quantile regression analyses show that contacts generate wage premiums among middle and high wage jobs, but not low wage jobs. These findings challenge conventional wisdom on contact effects and advance understanding of how social networks affect wage attainment and inequality. PMID- 25432622 TI - Intergenerational transmission of homeownership in Europe: revisiting the socialisation hypothesis. AB - Socialisation towards homeownership during childhood has been proposed as one transmission channel of homeownership across generations in previous literature, but tests of this socialisation hypothesis are scarce. This study presents the yet most rigorous test of the socialisation hypothesis using retrospective life history data (SHARELIFE, N=19,567 individuals) from 13 European countries. Event history and panel regression models are applied. Results show that socialisation in homeownership positively affects the hazard rates of entering homeownership for the first time and the probability to be a homeowner throughout individuals' lives net of other parental background variables and material transfers. We find a socialisation effect across divergent (but not all) examined countries. Further sensitivity analyses using a placebo test and a hypothetical confounder support the conclusion that being socialised in homeownership during childhood increases the chances of becoming and being a homeowner in later life. PMID- 25432621 TI - Exposure to violence, substance use, and neighborhood context. AB - Adolescent exposure to violence and substance use are both public health problems, but how neighborhood context contributes to these outcomes is unclear. This study uses prospective data from 1416 adolescents to examine the direct and interacting influences of victimization and neighborhood factors on adolescent substance use. Based on hierarchical Bernoulli regression models that controlled for prior substance use and multiple individual-level factors, exposure to violence significantly increased the likelihood of marijuana use but not alcohol use or binge drinking. There was little evidence that community norms regarding adolescent substance use influenced rates of substance use or moderated the impact of victimization. Community disadvantage did not directly impact substance use, but the relationship between victimization and marijuana use was stronger for those in neighborhoods with greater disadvantage. The results suggest that victimization is particularly likely to affect adolescents' marijuana use, and that this relationship may be contingent upon neighborhood economic conditions. PMID- 25432623 TI - Three experimental approaches to measure the social context dependence of prejudice communication and discriminatory behavior. AB - Empirical research on discrimination is faced with crucial problems stemming from the specific character of its object of study. In democratic societies the communication of prejudices and other forms of discriminatory behavior is considered socially undesirable and depends on situational factors such as whether a situation is considered private or whether a discriminatory consensus can be assumed. Regular surveys thus can only offer a blurred picture of the phenomenon. But also survey experiments intended to decrease the social desirability bias (SDB) so far failed in systematically implementing situational variables. This paper introduces three experimental approaches to improve the study of discrimination and other topics of social (un-)desirability. First, we argue in favor of cognitive context framing in surveys in order to operationalize the salience of situational norms. Second, factorial surveys offer a way to take situational contexts and substitute behavior into account. And third, choice experiments - a rather new method in sociology - offer a more valid method of measuring behavioral characteristics compared to simple items in surveys. All three approaches - which may be combined - are easy to implement in large-scale surveys. Results of empirical studies demonstrate the fruitfulness of each of these approaches. PMID- 25432624 TI - We trust in government, just not in yours: race, partisanship, and political trust, 1958-2012. AB - Although it is generally accepted that political trust is reflective of satisfaction with the performance of the incumbent administration, this is only considered true for White Americans. Because their trust reflects a larger discontent with the political system, Black Americans, it is held, do not respond in the same way in the short term. This argument has yet to be tested with over time data. Time matters. Not only does the race gap in trust change over time but the impact of partisanship and political winning is, by definition, time dependent. The results of an analysis of the 1958-2012 American National Election Studies data show that Black Americans and White Americans are equally likely to tie short-term performance to trust in government. However, the relationship between partisanship and political trust and, therefore, system discontent, clearly differs for the two groups. Aggregate models that do not take race partisan sub-group differences into account will therefore be misleading. PMID- 25432625 TI - Accelerated time course of saccadic inhibition of return in individuals with autism spectrum disorders. AB - The inhibition of return (IOR) refers the observer's slower response time when the target stimulus appears on the previously attended location. In the present study, we examined the time course of saccadic IOR by using five stimuli onset asynchronies (SOAs) in a group of adults with autism spectrum disorders (ASDs) and a comparison group. The results showed that the IOR effect occurred earlier (300 ms SOA) in participants with ASDs, relative to the comparison participants (500 and 700 ms SOAs). The ASD group also committed a greater number of anticipatory saccades, which positively correlated with scores on restricted and repetitive behaviors, as assessed by the Autism Diagnostic Interview-Revised (ADI R; Lord et al. in J Autism Dev Disord 24:659-685, 1994). These findings reveal an accelerated time course for saccadic IOR along with diminished volitional oculomotor control in participants with ASDs. We discussed these results with reference to the atypical and the superior visual search abilities often reported in this population. PMID- 25432626 TI - The relationship between spatial cognition and walking trajectory for passing through a doorway: evident in individuals with dominant right eye? AB - When individuals attempt to walk through the center of a doorway (i.e., spatial bisection), the body's midpoint at crossing can deviate from its true center. Such deviation could result from asymmetry in spatial cognition. However, previous studies failed to find a significant correlation between bisection performance during walking and that during line/spatial bisection. We investigated whether such failure would result from different effectors being used for bisection (i.e., body midpoint or finger/laser pointer). We also investigated whether the difference in an individual's eye dominance would affect the relationship. Thirty-two young adults (16 of them with right-eye dominance) participated. For a walking task, participants walked through the perceived center of a wide doorway. For a spatial bisection task, they observed the same doorway under two distance conditions (about 0.5 and 2 m) and aligned their body midpoint with the perceived center in the sagittal dimension. Both tasks were performed under three visual occlusion conditions (dominant eye, non-dominant eye, and no occlusion). The results showed that, for the spatial bisection task, occluding the dominant eye caused deviation of the bisected point to the contralateral side. However, for the walking task, such an effect was observed only in participants with a dominant right eye. Consequently, directional biases in both tasks were significantly correlated only for right-eye-dominant participants. These results suggest that, for right-eye-dominant individuals only, use of the same effector for both tasks showed a clear relationship between the two tasks. Possible explanations for these findings were discussed. PMID- 25432627 TI - Sensory feedback in cockroach locomotion: current knowledge and open questions. AB - The American cockroach, Periplaneta americana, provides a successful model for the study of legged locomotion. Sensory regulation and the relative importance of sensory feedback vs. central control in animal locomotion are key aspects in our understanding of locomotive behavior. Here we introduce the cockroach model and describe the basic characteristics of the neural generation and control of walking and running in this insect. We further provide a brief overview of some recent studies, including mathematical modeling, which have contributed to our knowledge of sensory control in cockroach locomotion. We focus on two sensory mechanisms and sense organs, those providing information related to loading and unloading of the body and the legs, and leg-movement-related sensory receptors, and present evidence for the instrumental role of these sensory signals in inter leg locomotion control. We conclude by identifying important open questions and indicate future perspectives. PMID- 25432628 TI - Boosting Wnt activity during colorectal cancer progression through selective hypermethylation of Wnt signaling antagonists. AB - BACKGROUND: There is emerging evidence that Wnt pathway activity may increase during the progression from colorectal adenoma to carcinoma and that this increase is potentially an important step towards the invasive stage. Here, we investigated whether epigenetic silencing of Wnt antagonists is the biological driver for this increased Wnt activity in human tissues and how these methylation changes correlate with MSI (Microsatelite Instability) and CIMP (CpG Island Methylator Phenotype) statuses as well as known mutations in genes driving colorectal neoplasia. METHODS: We conducted a systematic analysis by pyrosequencing, to determine the promoter methylation of CpG islands associated with 17 Wnt signaling component genes. Methylation levels were correlated with MSI and CIMP statuses and known mutations within the APC, BRAF and KRAS genes in 264 matched samples representing the progression from normal to pre-invasive adenoma to colorectal carcinoma. RESULTS: We discovered widespread hypermethylation of the Wnt antagonists SFRP1, SFRP2, SFRP5, DKK2, WIF1 and SOX17 in the transition from normal to adenoma with only the Wnt antagonists SFRP1, SFRP2, DKK2 and WIF1 showing further significant increase in methylation from adenoma to carcinoma. We show this to be accompanied by loss of expression of these Wnt antagonists, and by an increase in nuclear Wnt pathway activity. Mixed effects models revealed that mutations in APC, BRAF and KRAS occur at the transition from normal to adenoma stages whilst the hypermethylation of the Wnt antagonists continued to accumulate during the transitions from adenoma to carcinoma stages. CONCLUSION: Our study provides strong evidence for a correlation between progressive hypermethylation and silencing of several Wnt antagonists with stepping-up in Wnt pathway activity beyond the APC loss associated tumour-initiating Wnt signalling levels. PMID- 25432630 TI - Basaloid carcinoma of the pancreas--clinicopathological presentation and oncogenetic snapshot of a rare entity. AB - We report a case of basaloid pancreatic carcinoma with clinical, pathological, and genomic data. The 73-year-old male patient had jaundice, acholic stool, diarrhea, weight loss, and a large, painless gall bladder. His GGT was highly elevated. The pancreatic head contained a tumor, which was resected by partial pancreatoduodenectomy with pancreato-gastric anastomosis, cholecystectomy, and lymphadenectomy. On gross examination, a 3.8-cm white firm nodule was found, which microscopically was composed of basaloid cell nests with a less than usual desmoplastic stromal background and focally PANIN. Immunohistochemical profile displayed strong CK5/6, CK19, p63, EGFR, vimentin, and evident CK14 expression and absence of expression of CK7, chromogranin, synaptophysin, and BRCA1. A high Ki-67 index and p53 expression were noted. Sequencing of the most frequent 46 oncogenes with ionTorrent (AmpliSeq PCR) method identified PIK3CA, KRAS, and TP53 genes as drivers and variants of the FGFR3, PDGFRA, KIT, KDR, EGFR, RET, and ATM genes. The tumor we report displays histopathological appearances similar to the previously described case and a genomic landscape fitting to the general population of pancreatic carcinomas. We hypothesize that this tumor may belong to the group of DNA damage repair-deficient pancreatic carcinoma subgroup. PMID- 25432629 TI - Risk and protective factors for the development of depressive symptoms in children and adolescents: results of the longitudinal BELLA study. AB - Mental health problems in children and adolescents are frequent, with a high risk of persistence into adulthood. Therefore, the investigation of determinants of onset and course of mental health problems is of high importance. The present paper investigates the impact of protective and risk factors on the development of depressive symptoms in children and adolescents. The BELLA study is the mental health module of the German National Health Interview and Examination Survey for children and adolescents (KIGGS). Based on the first three measurement points of the BELLA study (covering a period of 2 years), the present analysis focused on children and adolescents aged 11-17 years at baseline (n = 1,643; 50.6 % female). A longitudinal growth modelling approach was used. Mental health problems in parents (parent-reports) predicted depressive symptoms in children and adolescents (self-reports) as well as the development of these symptoms over time. Further, child-reported protective factors of self-efficacy, positive family climate and social support were associated with less depressive symptoms at baseline. Additionally, positive changes in protective factors were associated with the development of less depressive symptoms over time. Finally, family climate and social support moderated the detrimental influence of parental psychopathology on child's depressive symptoms. The addressed determinants for the development of depressive symptoms in children and adolescents are highly relevant for prevention and intervention strategies. Future research should investigate specific risk and protective factors focusing in detail on further mental health disorders and their development in children and adolescents. PMID- 25432631 TI - Isocitrate dehydrogenase 1 mutations (IDH1) and p16/CDKN2A copy number change in conventional chondrosarcomas. AB - To determine whether IDH1 mutations are present in primary and relapsed (local and distal) conventional central chondrosarcomas; and secondly, to assess if loss of p16/CDKN2A is associated with tumour grade progression, 102 tumour samples from 37 patients, including material from presenting and relapse events, were assessed. All wild-type cases for IDH1 R132 substitutions were also tested for IDH2 R172 and R140 alterations. The primary tumour and the most recent relapse sample were tested for p16/CDKN2A by interphase fluorescence in situ hybridisation. An additional 120 central cartilaginous tumours from different patients were also tested for p16/CDKN2A copy number. The study shows that if an IDH1 mutation were detected in a primary central chondrosarcoma, it is always detected at the time of presentation, and the same mutation is detected in local recurrences and metastatic events. We show that p16/CDKN2A copy number variation occurs subsequent to the IDH1 mutation, and confirm that p16/CDKN2A copy number variation occurs in 75% of high grade central chondrosarcomas, and not in low grade cartilaginous tumours. Finally, p16/CDKN2A copy number variation is seen in both the IDH1 wild-type and mutant cartilaginous central tumours. PMID- 25432632 TI - Effect of low-level laser therapy on pain and swelling in women with breast cancer-related lymphedema: a systematic review and meta-analysis. AB - PURPOSE: This study aims to examine literature on effectiveness of low-level laser therapy (LLLT) in reducing limb volume and pain in adults with breast cancer-related lymphedema (BCRL). METHODS: PubMed, PEDro, CINAHL, and Cochrane databases were searched using (lymphedema OR edema OR swelling) AND (breast cancer OR mastectomy) AND (laser OR low-level laser therapy OR LLLT OR cold laser). Intervention studies or meta-analyses reporting LLLT for BCRL were included in the search. Pooled effect sizes (ES) and 95 % confidence intervals (CI) were calculated for volume and pain. No limitations were placed on length of follow-up, publication year, or language. Final search was conducted on October 16, 2014. RESULTS: Nine studies met criteria for inclusion. Within-group pooled ES for volume (six studies) was -0.52 (-0.78, -0.25), representing a 75.7-ml reduction in limb volume after LLLT. Between-group pooled ES for volume (four studies) was -0.62 (-0.97, -0.28), representing a 90.9-ml greater reduction in volume with treatment including LLLT versus not including LLLT. Within-group pooled ES for pain reduction (three studies) was -0.62 (-1.06, -0.19), pain reduction of 13.5 mm (0-100 mm VAS). Between-group pooled ES for pain reduction (two studies) was non-significant at -1.21 (-4.51, 2.10). CONCLUSION: Moderate strength evidence supports LLLT in the management of BCRL, with clinically relevant within-group reductions in volume and pain immediately after conclusion of LLLT treatments. Greater reductions in volume were found with the use of LLLT than in treatments without it. IMPLICATIONS FOR CANCER SURVIVORS: LLLT confers clinically meaningful reductions in arm volume and pain in women with BCRL. PMID- 25432633 TI - A systematic review and meta-analysis of social cognitive theory-based physical activity and/or nutrition behavior change interventions for cancer survivors. AB - PURPOSE: Little is known about how to improve and create sustainable lifestyle behaviors of cancer survivors. Interventions based on social cognitive theory (SCT) have shown promise. This review examined the effect of SCT-based physical activity and nutrition interventions that target cancer survivors and identified factors associated with their efficacy. METHODS: A systematic search of seven databases identified randomized controlled trials that (i) targeted adult cancer survivors (any point from diagnosis); (ii) reported a primary outcome of physical activity, diet, or weight management; and (iii) included an SCT-based intervention targeting physical activity or diet. Qualitative synthesis and meta analysis were conducted. Theoretical constructs and intervention characteristics were examined to identify factors associated with intervention efficacy. RESULTS: Eighteen studies (reported in 33 publications) met review inclusion criteria. Meta-analysis (n = 12) revealed a significant intervention effect for physical activity (standardized mean difference (SMD) = 0.33; P < 0.01). Most studies (six out of eight) that targeted dietary change reported significant improvements in at least one aspect of diet quality. No SCT constructs were associated with intervention effects. There were no consistent trends relating to intervention delivery method or whether the intervention targeted single or multiple behaviors. CONCLUSIONS: SCT-based interventions demonstrate promise in improving physical activity and diet behavior in cancer survivors, using a range of intervention delivery modes. Further work is required to understand how and why these interventions offer promise for improving behavior. IMPLICATIONS FOR CANCER SURVIVORS: SCT-based interventions targeting diet or physical activity are safe and result in meaningful changes to diet and physical activity behavior that can result in health improvements. PMID- 25432634 TI - Lower urinary tract dysfunction after nerve-sparing radical hysterectomy. AB - INTRODUCTION AND HYPOTHESIS: The aim of this review is to provide a comprehensive overview of the current role of nerve-sparing radical hysterectomy (NSRH) in reducing the incidence of postoperative lower urinary tract dysfunction (LUTD) and in improving quality of life. METHODS: A detailed online search was performed using the following keywords: nerve sparing, radical hysterectomy, cervical cancer, and all these terms in combination with urinary dysfunction or bladder dysfunction in order to analyze the effect of NSRH on urinary functional outcomes. Articles retrieved were analyzed and assigned a level of evidence (LE) according to the criteria of the Centre for Evidence-Based Medicine in Oxford, UK. RESULTS: Our review highlights the heterogeneity of conducting and reporting studies in the literature. Autonomic pelvic nerve injuries during the procedure are thought to be the major cause of LUTD. The amount of LUTD depends upon the extent and type of nerve injury. Anatomically based surgical techniques are developed to avoid nerve injury without compromising oncological control. All studies comparing NSRH to standard RH yielded promising results with respect to postoperative LUTD. A recent meta-analysis showed similar cancer control rates between the two techniques. However, controversies remain about the ideal surgical approach for nerve sparing and there is no consensus as to the level and landmarks of dissection to preserve the maximal amount of nerves without compromising oncological outcomes. CONCLUSIONS: Available evidence suggests that NSRH is safe and associated with lower incidence of LUTD. However, there is no standardized technique for NSRH and controversies remain about its oncological safety. Long-term oncological data from multicenter surgical trials are needed as well as a universally accepted standard to report studies on NSRH. PMID- 25432636 TI - Neurocognitive performance in family-based and case-control studies of schizophrenia. AB - BACKGROUND: Neurocognitive deficits in schizophrenia (SZ) are established and the Consortium on the Genetics of Schizophrenia (COGS) investigated such measures as endophenotypes in family-based (COGS-1) and case-control (COGS-2) studies. By requiring family participation, family-based sampling may result in samples that vary demographically and perform better on neurocognitive measures. METHODS: The Penn computerized neurocognitive battery (CNB) evaluates accuracy and speed of performance for several domains and was administered across sites in COGS-1 and COGS-2. Most tests were included in both studies. COGS-1 included 328 patients with SZ and 497 healthy comparison subjects (HCS) and COGS-2 included 1195 patients and 1009 HCS. RESULTS: Demographically, COGS-1 participants were younger, more educated, with more educated parents and higher estimated IQ compared to COGS-2 participants. After controlling for demographics, the two samples produced very similar performance profiles compared to their respective controls. As expected, performance was better and with smaller effect sizes compared to controls in COGS-1 relative to COGS-2. Better performance was most pronounced for spatial processing while emotion identification had large effect sizes for both accuracy and speed in both samples. Performance was positively correlated with functioning and negatively with negative and positive symptoms in both samples, but correlations were attenuated in COGS-2, especially with positive symptoms. CONCLUSIONS: Patients ascertained through family-based design have more favorable demographics and better performance on some neurocognitive domains. Thus, studies that use case-control ascertainment may tap into populations with more severe forms of illness that are exposed to less favorable factors compared to those ascertained with family-based designs. PMID- 25432638 TI - Postoperative complications of anterior cruciate ligament reconstruction after ambulatory surgery. AB - OBJECTIVE: To study postoperative complications of arthroscopic anterior cruciate ligament (ACL) reconstruction performed as an outpatient compared with same surgery performed as a regular admission (inpatient). MATERIAL AND METHOD: A study was conducted on a historical cohort of 342 patients (115 outpatients vs 227 inpatients) who underwent arthroscopic ACL primary ligamentoplasty (2004 2012). A review was performed on the demographic, surgical and hospital variables. A study was made of early complications (60 days postoperative) including visits to emergency department and readmissions. A descriptive and bivariate distribution analysis was performed between groups, with the grouping criterion: performing of the surgery with or without admission. The Chi-square test was used for qualitative variables and Mann-Whitney U test for quantitative. Limit significance p<0.05. RESULTS: Overall, there were 13.2% emergency department visits (mean of 1.24 visits) with an average delay of 8.22 days after discharge. COMPLICATIONS: pain not controlled with analgesia (6.7%), hemarthrosis that required arthrocentesis (4.4%), fever (3.2%), deep vein thrombosis (0.6%), cellulitis (0.6%), septic arthritis that required arthroscopic debridement (0.3%), and others (1.2%) including problems with immobilization. The hospital readmissions (2.3%) were for surveillance and monitoring of the surgical wound. In the bivariate analysis no statistically significant differences were found between groups as regards the sociodemographic characteristics of the patients or the complications recorded. DISCUSSION: The most frequent complications recorded were acute pain, hemarthrosis and fever. Serious complications (deep vein thrombosis, septic arthritis or need for hospital readmission) were rare. Outpatient arthroscopic ACL repair is a common technique that can be performed safely by surgery without admission, with an overall low complication rate with no differences between outpatients and inpatients. PMID- 25432639 TI - Postoperative irradiation in patients with pT3-4N0 laryngeal cancer: results and prognostic factors. AB - Approximately 60 % of patients with locally advanced laryngeal cancer (LALC) treated primarily with surgery require adjuvant radiotherapy. In the available literature predominate series of patients were with pathologically confirmed node positive status. Subgroups of pN0 patients with LALC are scarce. The aim of the study is to evaluate the efficacy of postoperative radiotherapy in patients with pathological stage T3-4N0M0 and identification of prognostic factors in this group. Between 1975 and 2005, 138 patients with squamous pT3-4N0 laryngeal cancer were irradiated postoperatively. Primary surgical treatment consisted of total laryngectomy and cervical lymphadenectomy. The median time between surgery and the implementation of radiotherapy was 56 days. The median total dose was 60 Gy (range 40-70 Gy). Five-year disease-free survival (DFS5) was achieved in 76 % of patients. Cancer recurrence was observed in 34 patients. In 28 (82 %) cases it was locoregional failure. DFS5 rates for pT3 and pT4 were 92 and 69 %, for margin status R0, R1 and R2 were 82, 72 and 67 %, respectively. The pharyngeal invasion was related to a decrease in DFS5 from 80 to 59 %. Postoperative irradiation in patients with pT3-4N0 LALC is an effective treatment method. The main reason of the failure is local recurrence. The following independent prognostic factors were identified in this group of patients: pT stage, surgical margin status and pharyngeal invasion. PMID- 25432640 TI - Long-term symptom relief after septoplasty. AB - The results for long-term symptom relief after septoplasty are contradictory in reviewed publications but the findings suggest that results are unsatisfactory. In this study, we analyzed and compared short- and long-term symptom relief after septoplasty and factors possibly associated with symptom relief. 111 patients that underwent septoplasty between 2008 and 2010 were included in the study. Medical charts were reviewed for preoperative characteristics and assessments. Data on short-term symptom relief (6 months) were retrieved from the Swedish National Quality Registry for Septoplasty; data on long-term symptom relief (34 70 months) were collected through a questionnaire. Upon the 34-70 month follow up, 53% of the patients reported that symptoms either remained or had worsened and 83% reported nasal obstruction. Degree of symptom relief was significantly higher among patients not reporting nasal obstruction than among patients reporting nasal obstruction at long-term follow-up. The proportion of patients that reported "my symptoms are gone" declined from 53% after 6 months to 18% after 34-70 months. None of the factors taken into consideration, age at surgery, gender, follow-up time, primary operation/reoperation, history of nasal trauma, self-reported allergy, rhinometric obstruction, or same sided rhinometric, clinical and subjective nasal obstruction were associated with symptom relief. The long-term results after septoplasty are unsatisfactory. A majority of patients report that their symptoms remain after septoplasty. PMID- 25432637 TI - GABA receptor subunit distribution and FMRP-mGluR5 signaling abnormalities in the cerebellum of subjects with schizophrenia, mood disorders, and autism. AB - Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. GABAergic receptor abnormalities have been documented in several major psychiatric disorders including schizophrenia, mood disorders, and autism. Abnormal expression of mRNA and protein for multiple GABA receptors has also been observed in multiple brain regions leading to alterations in the balance between excitatory/inhibitory signaling in the brain with potential profound consequences for normal cognition and maintenance of mood and perception. Altered expression of GABAA receptor subunits has been documented in fragile X mental retardation 1 (FMR1) knockout mice, suggesting that loss of its protein product, fragile X mental retardation protein (FMRP), impacts GABAA subunit expression. Recent postmortem studies from our laboratory have shown reduced expression of FMRP in the brains of subjects with schizophrenia, bipolar disorder, major depression, and autism. FMRP acts as a translational repressor and, under normal conditions, inhibits metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. In fragile X syndrome (FXS), the absence of FMRP is hypothesized to lead to unregulated mGluR5 signaling, ultimately resulting in the behavioral and intellectual impairments associated with this disorder. Our laboratory has identified changes in mGluR5 expression in autism, schizophrenia, and mood disorders. In the current review article, we discuss our postmortem data on GABA receptors, FMRP, and mGluR5 levels and compare our results with other laboratories. Finally, we discuss the interactions between these molecules and the potential for new therapeutic interventions that target these interconnected signaling systems. PMID- 25432641 TI - A randomized study of temperature-controlled versus bipolar radiofrequency for inferior turbinate reduction. AB - The objective of this study is to compare outcomes of temperature-controlled radiofrequency (TCRF) and bipolar radiofrequency (BRF) for inferior turbinate reduction in patients with chronic rhinitis (CR). This was a prospective, randomized non-inferiority trial. Eighty-four adult patients with CR refractory to medication were randomized into two intervention groups: TCRF(42) or BRF(42). Primary outcomes consisted of patient-orientated visual analog scale (VAS; 0-10) of nasal obstruction at 4th postoperative week. Secondary subjective outcomes included VAS of nasal discharge, sneezing, hyposmia, and postnasal drip. Objective outcomes included crusting, mucociliary transportation time, minimal cross-sectional area, total nasal volume, and nasal airway resistance performed by blind assessors before and at 4th postoperative week and 1-year follow-up. Baseline and perioperative data showed no statistically significant difference between both groups, except for longer operative time in TCRF (481.5 +/- 36.2 vs. 37.1 +/- 3.0 s, p < 0.001) and slightly more crusts in BRF group (p = 0.04). Both intention-to-treat and per-protocol analyses, TCRF(39) versus BRF(41), revealed no significant difference among subjective and objective outcomes between two groups at 4th postoperative week. The 95% confidence intervals of mean differences of VAS scores of all subjective symptoms were within defined margin ( 1.5 to 1.5), except for nasal discharge. At 1-year follow-up, there was still no significant difference in the outcomes. Minimal pain and minor bleeding without serious adverse effects from both interventions were reported. Both BRF and TCRF resulted in similar short-term outcomes, while less operative time was found in BRF group. Further studies, particularly, on cost-effectiveness should be conducted for better treatment selection. LEVEL OF EVIDENCE: 1b. PMID- 25432642 TI - A major pain in the ... Back and epigastrium: an unusual case of spontaneous celiac artery dissection. AB - A 60-year-old woman with mitral valve prolapse, chronic low back pain, and a 30 pack year smoking history presented for a second admission of poorly controlled mid-back pain 10 days after her first admission. She had concomitant epigastric pain, sharp/burning in quality, radiating to the right side and to the mid-back, not associated with food nor improving with pain medications. She denied nausea, vomiting, diarrhea, constipation, dark stools, or blood per rectum. Our purpose was to determine the cause of the patient's epigastric pain. Physical examination revealed epigastric and mid-back tenderness on palpation. Labs were normal except for a hemoglobin drop from 14 to 12.1 g/dL over 2 days. Abdominal ultrasound and subsequent esophagogastroduodenoscopy were normal. Contrast-enhanced abdominal computed tomographic (CT) scan revealed the development of a spontaneous celiac artery dissection as the cause of the epigastric pain. The patient was observed without stenting and subsequent CT angiography 4 days later did not reveal worsening of the dissection. She was discharged on aspirin and clopidogrel with outpatient follow-up. Thus far, less than 100 cases of isolated spontaneous celiac artery dissections have been reported. The advent of CT scans and magnetic resonance imaging has increasingly enabled its detection. Risk factors may include hypertension, arteriosclerosis, smoking, and cystic medial necrosis. There is a 5:1 male to female ratio with an average presenting age of 55. Management of dissections may include surgical repair, endovascular stenting, and selective embolization. Limited dissections can be managed conservatively with anti-platelet and/or anticoagulation agents and strict blood pressure control, as done in our patient. PMID- 25432643 TI - How to interpret the results of a sleep study. AB - With an increased level of awareness of sleep disorders among the public, there has been an increase in requests for sleep studies, and consequently, more referrals made to sleep specialists by primary care physicians and other health care providers. Understanding technical and clinical information provided in the sleep study report is crucial. It offers significant insight in to sleep pathophysiology in relation to patient symptoms. The purpose of this article is to provide a simple and easy method to interpret the reported results of polysomnography for primary care physicians. This will facilitate better understanding and management of patients with sleep disorders and related complications. PMID- 25432644 TI - An easily overlooked cause of abdominal pain. AB - A 63 year old female presented to the emergency department with a several month history of intermittent right upper quadrant abdominal pain, early satiety with loss of appetite, and an unintentional weight loss of 8. She underwent a battery of tests that returned negative and subsequently sent for Computed tomographic angiography (CTA) of the abdomen revealing luminal stenosis of the proximal 1 cm of the celiac axis estimating 90% occlusion and a patent SMA and IMA with, typical for median arcuate ligament syndrome. The symptoms, diagnosis, and treatment options are discussed. PMID- 25432646 TI - Job's syndrome presenting with a tension pneumothorax and a lung abscess. PMID- 25432645 TI - A survey of primary care resident attitudes toward continuity clinic patient handover. AB - BACKGROUND: Transfer of clinic patients from graduating residents to interns or junior residents occurs every year, affecting large numbers of patients. Breaches in care continuity may occur, with potential for risk to patient safety. Several guidelines have been developed for implementing standardized inpatient sign-outs, but no specific guidelines exist for outpatient handover. METHODS: Residents in primary care programs - internal medicine, family medicine, and pediatrics - at a US academic medical center were invited to participate in an online survey. The invitation was extended approximately 2 years after electronic medical record (EMR) rollout began at the institution. RESULTS: Of 71 eligible residents, 22 (31%) responded to the survey. Of these, 18 felt that handover of ambulatory patients was at least moderately important - but only one affirmed the existence of a system for handover. IM residents perceived that they had the highest proportion of high-risk patients (p=0.042); transition-of-care letters were more important to IM residents than other respondents (p=0.041). CONCLUSION: There is room for improvement in resident acknowledgement of handover processes in continuity clinics. In this study, IM residents attached greater importance to a specific handover tool than other primary care residents. Thus, the different primary care specialties may need to have different handover tools available to them within a shared EMR system. PMID- 25432647 TI - Mixed adenocarcinoma and neuroendocrine prostate cancer: a case report. AB - BACKGROUND: Neuroendocrine prostate cancer is rare but lethal. It is one of the most common extra pulmonary manifestations of small cell cancer. CASE PRESENTATION: Here we present a case report of a 53-year-old male who presents with a mixed adenocarcinoma and neuroendocrine prostate tumor on a background of previously normal prostate-specific antigen (PSA). His initial symptoms prior to diagnosis included decreased urine output and acute kidney injury (AKI). CONCLUSION: Neuroendocrine tumor does not elevate the PSA level and hence is often a late finding with a poor prognosis. Special staining on histopathogy is required to reveal this diagnosis. PMID- 25432648 TI - Sickle cell trait: not as benign as once thought. AB - We describe a case of renal papillary necrosis in a middle-aged female with sickle cell trait who presented with gross hematuria. We wish to highlight this case for several reasons. Sickle cell trait is often viewed as a benign condition despite the fact that it is associated with significant morbidity such as renal papillary necrosis and renal medullary carcinoma. Appropriate evaluation needs to be undertaken to promptly diagnose renal papillary necrosis and differentiate it from renal medullary carcinoma as this can result in deadly consequences for patients. CT urography has emerged as a diagnostic study to evaluate hematuria in such patients. We review the pathophysiology, diagnosis, and management of renal papillary necrosis in patients with sickle cell trait. PMID- 25432649 TI - Cardiac tamponade - presentation of type A aortic dissection. AB - Acute aortic dissection usually presents with severe chest and/or back pain but may have a varied presentation ranging from syncope, stroke, and heart failure to shock or tamponade. We present classic chest computed tomography images of a case of type A aortic dissection presenting with cardiac tamponade. PMID- 25432650 TI - Transthyretin cardiac amyloidosis: an under-diagnosed cause of heart failure. AB - INTRODUCTION: Cardiac amyloidosis is the most common cause of infiltrative cardiomyopathy and is associated with a poor prognosis. Transthyretin cardiac amyloidosis, particularly the type caused by the mutation that replaces the amino acid valine with the amino acid isoleucine at position 122 (Val122Ile), is most common among African- Americans above 65 years of age. Evidence suggests that this mutation is an important, though under-diagnosed, cause of heart failure in this population. CASE PRESENTATION: A 74-year-old African American male with a diagnosis of non-ischemic cardiomyopathy for several years, presented with gradually worsening dyspnea on exertion and lower extremity edema. There is no known cardiac disease in his family. An echocardiogram was done showing a decrease in ejection fraction to 30% from 45% in the span of a year. An endomyocardial biopsy analysis identified transthyretin amyloid with the Val122Ile mutation, confirming the diagnosis of familial transthyretin cardiomyopathy. DISCUSSION: Systemic amyloidosis is a group of diseases caused by the deposition of an abnormally folded, insoluble protein that can accumulate in multiple organs causing progressive and irreversible dysfunction. The mutations that most commonly induce variant transthyretin cardiac amyloidosis are Val122Ile, Val30Met and Thr60Ala. The Val122Ile mutation has been found to be present in 3-4% of the African American/Caribbean population. CONCLUSIONS: Familial amyloid cardiomyopathy is an uncommonly recognized cause of heart failure in the population, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration. Patients that meet the high-risk profile criteria - male gender, age 65 years and older, heart failure symptoms, symmetric left ventricular (LV) hypertrophy, and moderately depressed LV function - should likely undergo additional testing for cardiac amyloidosis. PMID- 25432651 TI - Apathetic thyrotoxicosis presenting with diabetes mellitus. AB - Apathetic form of thyrotoxicosis occurs in the elderly who can present with features of hyperglycemia, hypothyroidism, depression, or an internal malignancy. A clinical suspicion and timely diagnosis of hyperthyroidism is needed to define the correct etiology of existing problems, and to prevent grave complications. We discuss an 84-year-old woman who presented with fatigue and uncontrolled diabetes due to apathetic thyrotoxicosis. PMID- 25432652 TI - Oscillating hypothyroidism and hyperthyroidism - a case-based review. AB - OBJECTIVE/BACKGROUND: To discuss a unique clinical entity where inappropriate activity of inhibitory and stimulatory thyroid antibodies resulted in alternating hypothyroidism and hyperthyroidism. METHODS: We report the clinical history, laboratory data, and results of imaging studies, along with the pathophysiological mechanism and the subsequent treatment in a patient with fluctuating thyroid functional status. RESULTS: A 52-year-old female was treated for hypothyroidism for more than two decades. She started having symptoms of hyperthyroidism along with a suppressed thyroid-stimulating hormone (TSH). She continued to have persistent symptoms despite stopping her levothyroxine. Her free T3 and T4 were elevated along with an increased radioactive uptake scan. She was diagnosed with Graves' disease and started on methimazole, which relieved her symptoms for a few months. Subsequently, her TSH began to rise beyond expected level, her hypothyroid symptoms reappeared, and methimazole was discontinued. Following this, she again developed symptoms of hyperthyroidism and thyroid values revealed an undetectable TSH. She had at least two such documented cycles of hyperthyroidism alternating with hypothyroidism. She was eventually treated with radioactive iodine ablation followed by levothyroxine replacement. Swinging dominance of TSH-blocking autoantibodies (TBAb) and thyroid-stimulating autoantibodies (TSAb) triggered by methimazole and levothyroxine, respectively, is likely the underlying mechanism. CONCLUSIONS: Physicians should be vigilant to the phenomenon of spontaneous conversion of hypothyroidism to hyperthyroidism, or vice versa, in a subset of patients with autoimmune thyroid disease. Repeated assessment of thyroid function along with measurement of TBAb and TSAb are invaluable in identifying this rare clinical entity. PMID- 25432653 TI - A retrospective analysis of reported errata in five leading medical journals in 2012. AB - BACKGROUND: Although medical publications are frequently used as the source of information, the prevalence of errata remains unclear. The objective of this study was to examine peer-review and publication processes of medical journals as well as to determine the occurrence of reported errata in medical journals and timeliness in identifying and correcting errata. METHODS: Five medical journals, New England Journal of Medicine, Annals of Internal Medicine, British Medical Journal, Journal of American Medical Association, and Lancet, were evaluated. The characteristics of these journals were obtained from editors' survey. All these journals report errata noted in their prior publications. We retrospectively analyzed all errata reported from January 1, 2012, to December 31, 2012. The mean number of reported errata per issue, the most common errata, and the mean time to report errata were calculated. RESULTS: The journals had high impact factors (14 51), received 3,200 to more than 15,000 submissions in 2012, and utilized two or more external reviewers and usually two or more editors for any accepted articles. All the journals edited the accepted articles, including references, figures, and tables for style. A mean of 1.3 articles with >=1 errata was reported per issue (a total of 306 articles with errata in 226 issues). Errata in author's information, numeric errata, and errata in the figures and tables were the most common errata. The mean time to report the errata was 122 days. CONCLUSION: The high-impact journals, with extensive pre-publication review, reported relatively few errata per issue. The delay in reporting errata needs further exploration. PMID- 25432654 TI - How well do we need to control blood glucose before discharging DKA patients? A retrospective cohort study. AB - PURPOSE: To determine the ideal length of stay and glycemic control after resolution of acidosis in patients hospitalized for diabetic ketoacidosis, in order to reduce 30-day readmission. We hypothesized that both discharging patients within 24 hours of acidosis resolution and hyperglycemia at discharge are associated with higher probability of readmission. METHODS: We examined data from 208 consecutive patients hospitalized for diabetic ketoacidosis. Logistic regression was performed adjusting for age, blood glucose (BG) level at presentation, prior hospitalization within 30 days, season of current hospitalization, and length of hospital stay. RESULTS: Higher BG at discharge is associated with lower probability of readmission (odds ratio, 0.990; 95% CI, 0.983-0.996; P=0.002). Higher average BG over the 24 hours prior to discharge is also associated with lower readmission rate (odds ratio, 0.991; 95% CI, 0.982 1.000; P=0.044). The direction of the association remains the same even after these predictive variables are converted to categorical variables. In addition, discharge within 24 hours of acidosis resolution is not inferior to discharge after 24 hours of normalized BG (odds ratio, 0.431; 95% CI, 0.083-2.252; P=0.318). CONCLUSION: Neither discharging patients within 24 hours of acidosis resolution nor hyperglycemia at discharge is associated with higher readmission rate. Randomized prospective studies are needed to confirm or refute our study. PMID- 25432656 TI - Resident safety: the perspective of quality improvement. PMID- 25432655 TI - Before it crumbles: Fulminant Hepatic Failure secondary to Hodgkin's Lymphoma. AB - Fulminant hepatic failure (FHF) is a relatively rare manifestation of Hodgkin's lymphoma. Clinical features, laboratory findings, and imaging of the liver are usually inconclusive, and liver biopsy may be required for confirmation. We present a case of an FHF in a woman 1 week after the diagnosis of Hodgkin's lymphoma. Chemotherapy could not be instituted due to hepatic encephalopathy and other complications. Autopsy revealed diffuse infiltration of the liver parenchyma. This case illustrates the importance of early diagnosis and institution of chemotherapy, which may reverse the liver failure. PMID- 25432657 TI - Reply to letter to the editor - 'resident safety: the perspective of quality improvement'. PMID- 25432658 TI - JCHIMP: A proud 4 year old with the best yet to come. PMID- 25432659 TI - Epidural analgesia, neonatal care and breastfeeding. AB - The objective of our study is to evaluate the correlation between epidural analgesia during labor, start of breastfeeding and type of maternal-neonatal care.Two different assistance models were considered: Partial and Full Rooming in.In this cohort study, 2480 healthy infants were enrolled, 1519 in the Partial Rooming-in group and 1321 in the Full Rooming-in group; 1223 were born to women subjected to epidural analgesia in labor.In case of Partial Rooming-in the rate of exclusive or prevailing breastfeeding is significant more frequent in newborns born to mothers who didn't receive analgesia. Instead, in case of Full Rooming-in the rate of exclusive or prevailing breastfeeding is almost the same and there's no correlation between the use or not of epidural analgesia.The good start of lactation and the success of breastfeeding seems to be guaranteed by the type of care offered to the couple mother-infant, that reverses any possible adverse effects of the use of epidural analgesia in labor. PMID- 25432661 TI - Gastric intramucosal adenocarcinoma with an invasive micropapillary carcinoma component. AB - A 70-year-old woman was referred to our hospital because of early gastric cancer (lesser curvature of the antrum, 0-IIc, tub1, 15 mm) and underwent endoscopic submucosal dissection. Microscopically, the lesion was found to be confined to the mucosa, and predominantly composed of well-differentiated tubular adenocarcinoma with a micropapillary component. On immunohistochemical examination, the characteristic "inside-out pattern" of the micropapillary component was observed; thus, we diagnosed the lesion as gastric cancer with a micropapillary component. Invasive micropapillary carcinoma is a rare subtype of gastric carcinoma, and, to our knowledge, this is the first case of invasive micropapillary carcinoma of the stomach confined to the mucosa. PMID- 25432660 TI - Hepatic arterial infusion chemotherapy with fine-powder cisplatin and iodized-oil suspension in patients with intermediate-stage and advanced-stage (Barcelona Clinic Liver Cancer stage-B or stage-C) hepatocellular carcinoma: multicenter phase-II clinical study. AB - PURPOSE: This single-arm, multicenter, phase-II trial evaluated the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) using fine-powder cisplatin and iodized-oil suspension in patients with intermediate- and advanced stage [Barcelona Clinic Liver Cancer (BCLC) stage-B and stage-C] hepatocellular carcinomas (HCCs). METHODS: The Institutional Review Board approved this study and patients provided written informed consent. Thirty-five patients (24 men and 11 women, mean 74 +/- 6 years [range 60-87 years]) with BCLC stage-B (57 %, 20/35) or stage-C (43 %, 15/35) HCCs who were not candidates for other locoregional treatments were enrolled. HAIC was performed using a suspension of fine-powder cisplatin with a maximum dose of 65 mg/m(2) and iodized oil on demand. The primary endpoint was the response rate evaluated based on Response Evaluation Criteria in Solid Tumor (RECIST) and modified RECIST (mRECIST). Secondary endpoints were overall survival, progression-free survival, and safety. RESULTS: The initial and best overall response rates at 4 weeks and 3 months, respectively, were 14 and 17 % based on RECIST, and 57 and 23 % based on mRECIST. The median overall and progression-free survival times were 18 and 4 months, respectively. The most frequent grade-3 or grade-4 adverse events were elevation of serum alanine (23 %) and aspartate aminotransferase (20 %), and thrombocytopenia (17 %). CONCLUSION: This HAIC provides promising therapeutic effects with acceptable safety to patients with intermediate-stage and advanced stage HCCs. PMID- 25432662 TI - A case of left-sided absence and right-sided fenestration of the external jugular vein and a review of the literature. AB - The external jugular vein is increasingly being used as the recipient vein in head and neck tissue transfers, and for cannulation to conduct diagnostic procedures or intravenous therapies. The variations in the patterns of its course, and knowledge of these variations, are therefore important. We report on a bilateral external jugular vein anomaly found during the neck dissection of an approximately 75-year-old female cadaver, a case which has hitherto not been reported. The vein was absent on the left and fenestrated on the right. An embryological evaluation and the clinical implications of the anomaly are described. Clinicians and surgeons performing vascular or reconstructive surgery should be made aware of this variation of the external jugular vein to prevent inadvertent injury. PMID- 25432664 TI - Quality-of-life impairment in patients with hidradenitis suppurativa: a Canadian study. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic relapsing condition with a clinical picture that includes solitary nodules; diffuse, painful abscesses; malodorous drainage; sinus tract formation; and scarring. Treatment options are often unsatisfactory. The adverse effects of this disease on quality of life (QoL) is not extensively studied, especially in the Canadian population. OBJECTIVES: The objectives of this study were to (1) identify the impairment of QoL in patients with HS and the aspects that are most affected, and (2) assess the correlation between disease severity (based on Hurley's staging) and QoL impairment. METHODS: This prospective case series studied 55 patients (38 females and 17 males) from community dermatology clinics in Ontario. All patients filled out the questionnaires for QoL data using the Dermatology Life Quality Index (DLQI) and the Short Form 36 Version 2 (SF-36v2) health survey, either in the clinic or over the telephone. RESULTS: The mean DLQI score was 10 +/- 8.8, indicating a moderate effect on patients' lives. In keeping with this, SF-36v2 scores were significantly reduced with respect to both physical and mental health. The severity of disease, as measured by Hurley staging, the number of lesions, and patient-reported QoL were significantly correlated with the DLQI score (beta = 0.549, 0.285, 0.390, respectively; p = 0.000, 0.045, 0.004, respectively; alpha = 0.05). CONCLUSIONS: The impact on QoL for patients with HS is extensive yet underestimated; quantifying and assessing the burden of disease for the individual and society will lead to establishment of funding priorities and greater awareness of this condition. PMID- 25432665 TI - More blood for India. PMID- 25432663 TI - Genes related to emphysema are enriched for ubiquitination pathways. AB - BACKGROUND: Increased small airway resistance and decreased lung elasticity contribute to the airflow limitation in chronic obstructive pulmonary disease (COPD). The lesion that corresponds to loss of lung elasticity is emphysema; the small airway obstruction is due to inflammatory narrowing and obliteration. Despite their convergence in altered physiology, different mechanisms contribute to these processes. The relationships between gene expression and these specific phenotypes may be more revealing than comparison with lung function. METHODS: We measured the ratio of alveolar surface area to lung volume (SA/V) in lung tissue from 43 smokers. Two samples from 21 subjects, in which SA/V differed by >49 cm2/mL were profiled to select genes whose expression correlated with SA/V. Significant genes were tested for replication in the 22 remaining subjects. RESULTS: The level of expression of 181 transcripts was related to SA/V ( p < 0.05). When these genes were tested in the 22 remaining subjects as a replication, thirty of the 181 genes remained significantly associated with SA/V (P < 0.05) and the direction of association was the same in 164/181. Pathway and network analysis revealed enrichment of genes involved in protein ubiquitination, and western blotting showed altered expression of genes involved in protein ubiquitination in obstructed individuals. CONCLUSION: This study implicates modified protein ubiquitination and degradation as a potentially important pathway in the pathogenesis of emphysema. PMID- 25432666 TI - Identification of a potential third component of the male-produced pheromone of Anoplophora glabripennis and its effect on behavior. AB - The Asian longhorned beetle, Anoplophora glabripennis, is considered to be one of the most serious invasive pests of deciduous trees in North America. An efficient monitoring trap is needed to detect and delimit new introductions and assess population densities of established infestations. Previous studies on A. glabripennis have shown that males produce a two-component aggregation pheromone that consists of a 1:1 blend of 4-(n-heptyloxy)butan-1-ol and 4-(n heptyloxy)butanal. Moderate attraction in field trapping studies suggested that there may be additional chemical cues missing. Volatiles from male A. glabripennis were examined to identify other potential pheromone components. Gas chromatographic / electroantennographic (GC/EAD) analyses of male aerations detected a consistent EAD-active response to a previously unidentified compound. This compound was identified as (3E,6E)-alpha-farnesene. Both male and female beetles were antennally responsive to this sesquiterpene, and both sexes were attracted to it in olfactometer bioassays at different doses. When (3E,6E)-alpha farnesene was combined with 4-(n-heptyloxy)butan-1-ol and 4-(n-heptyloxy)butanal, attraction of both sexes increased compared to assays using 4-(n-heptyloxy)butan 1-ol and 4-(n-heptyloxy)butanal alone. PMID- 25432667 TI - Abutilon theophrasti's defense against the allelochemical benzoxazolin-2(3H)-one: support by Actinomucor elegans. AB - Abutilon theophrasti Medik., previously found to be rather insensitive to benzoxazinoid containing rye mulch and the allelochemical benzoxazolin-2(3H)-one (BOA), can be associated with the zygomycete Actinomucor elegans, whereby the fungus colonizes the root relatively superficially and mainly in the maturation zone. The fungus mitigates necrosis of the cotyledons when seedlings are incubated with 2 mM BOA, in contrast to those that lack the fungus. In liquid cultures of the fungus, tryptophan was identified. The accumulation of tryptophan is increased in presence of BOA. This amino acid seems to be important in protecting Abutilon against BOA and its derivatives since it suppressed the accumulation of BOA derived, highly toxic 2-aminophen-oxazin-3-one (APO) in the medium and on the root surface during BOA incubations of Abutilon seedlings. Although A. elegans is insensitive to BOA and APO, the fungus is not able to protect the plant against harmful effects of APO, when seedlings are treated with the compound. Abutilon can detoxify BOA via BOA-6-OH glucosylation probably by a cell wall associated glucosyltransferase, but only low amounts of the product accumulate. Low tryptophan concentrations can contribute to a degradation of the toxic intermediate BOA-6-OH by Fenton reactions, whereby the amino acid is oxidized. One of the oxidation products was identified as 4(1H)-quinolinone, which is the core substructure of the quorum sensing molecule 2-heptyl-3-hydroxy 4-quinolone. The mutualistic association of Abutilon theophrasti with Actinomucor elegans is considered as opportunistic and facultative. Such plant-fungus associations depend rather likely on environmental conditions, such as the mode of fertilization. PMID- 25432669 TI - Prevalence of oropharyngeal dysphagia in the Netherlands: a telephone survey. AB - Recent and specific data on the prevalence and/or incidence of oropharyngeal dysphagia in the general population are scarce. This study focuses on obtaining this data by means of a literature review and telephone survey. A literature review was performed to obtain data on the prevalence of dysphagia in the general population. Secondly, a quasi-random telephone survey using the functional health status questionnaire EAT-10 was conducted with the aim of establishing prevalence data on oropharyngeal dysphagia in the Netherlands. The literature review revealed six articles which met the inclusion criteria. The prevalence data on oropharyngeal dysphagia in the general population varied between 2.3 and 16 %. For the telephone survey, a total of 6,700 individuals were contacted by telephone, of which, 2,600 (39 %) participated in the study. Of the 2,600 participants, as many as 315 (12.1 %) were identified as having swallowing abnormalities and showed increased risk of oropharyngeal dysphagia with age. Prevalence data on oropharyngeal dysphagia in the Dutch general population were as high as 12.1 %. This data are in line with the retrieved prevalence data from the literature. PMID- 25432671 TI - [Posttraumatic adhesive ileus following pelvic ring fracture]. AB - We report on two cases of posttraumatic ileus after pelvic ring fracture in two patients aged 73 and 74 years, respectively. Although all conservative measures were exhausted, in both cases the ileus resulted in additional operative procedures and a significant extension of the hospital stay. Intraoperatively both patients presented with a mechanical ileus caused by adhesions which were unapparent for decades. Only the trauma-related motility disorder led to a clinical manifestation. Pathophysiological mechanisms and their implications on prophylaxis and therapy are discussed. PMID- 25432668 TI - Role of microsatellite instability-low as a diagnostic biomarker of Lynch syndrome in colorectal cancer. AB - Lynch syndrome is the most common Mendelian disorder predisposing persons to hereditary colorectal cancer. Carriers of MSH6 mutations constitute less than 10% of the total of cases with Lynch syndrome and present with a weaker clinical phenotype, including low levels of microsatellite instability (MSI-L) in colorectal tumors. The frequency of MSH6 mutation carriers among patients presenting with MSI-L colorectal cancer has yet to be determined, as has the appropriate genetic workup in this context. We have reviewed here the clinicopathologic characteristics, immunohistochemistry, and genetic testing results for 71 patients at a single institution diagnosed with MSI-L colorectal cancers. Of 71 patients with MSI-L tumors, 21 underwent genetic testing for MSH6 mutations, three of whom presented with loss of staining of MSH6 and only one of whom carried a pathogenic germline MSH6 mutation in exon 4 (c.2677_2678delCT; p.Leu893Alafs*6). This latter patient had a significant family history of cancer and had a rectal primary tumor that showed instability only in mononucleotide markers. In this cohort of MSI-L patients, we detected no notable clinicopathologic or molecular characteristic that would help to distinguish a group most likely to harbor germline MSH6 mutations. Therefore, we conclude that the prevalence of MSH6 mutations among patients with MSI-L tumors is very low. Microsatellite instability analysis combined with immunohistochemistry of mismatch repair proteins adequately detects potential MSH6 mutation carriers among MSI-L colorectal cancers. PMID- 25432670 TI - [Locking plate osteosynthesis of the radial head fractures : clinical and radiological results]. AB - BACKGROUND: Therapy of radial head fractures is still controversially discussed. Especially comminuted fractures are at risk of complications such as radial head necrosis, nonunion and secondary loss of reduction after open reduction and internal fixation. The aim of this study was to evaluate clinical and radiographic results of ORIF (open reduction internal fixation) of radial head fractures using a new radial head-specific locking plate system. PATIENTS AND METHODS: A total of 21 patients (13 men and 8 women) were treated with locking plate osteosynthesis of radial head fractures. Mean age was 50 years (range 29-67 years). According to the Mason classification, 15 were type III and 6 type IV. Mean time between trauma and surgery was 5.6 days (range 0-23 days). These patients were reexamined using the Mayo Elbow Performance Score and x-rays in two planes. RESULTS: In all, 21 patients were reexamined with a mean follow-up of 12.1 months (range 5-23 months). The mean Mayo Elbow Performance Score was 87.1. Excellent results were obtained in 12 patients, good results in 6 patients, and fair results in 3 patients. Mean extension deficit was 12.1 degrees , mean flexion 135.2 degrees , mean pronation 70.9 degrees , and mean supination 63.6 degrees . All fractures healed uneventfully. There was no complete radial head necrosis but one partial. Four cases of heterotopic ossification were detected: Hastings classification I (n = 2), IIb (n = 1), IIIb (n = 1). CONCLUSION: ORIF of radial head fractures using locking plates can lead to good and excellent results. Modern implants may allow for reconstruction of comminuted fractures avoiding arthroplasty in these young patients. PMID- 25432672 TI - Overview on the biotechnological production of L-DOPA. AB - L-DOPA (3,4-dihydroxyphenyl-L-alanine) has been widely used as a drug for Parkinson's disease caused by deficiency of the neurotransmitter dopamine. Since Monsanto developed the commercial process for L-DOPA synthesis for the first time, most of currently supplied L-DOPA has been produced by the asymmetric method, especially asymmetric hydrogenation. However, the asymmetric synthesis shows critical limitations such as a poor conversion rate and a low enantioselectivity. Accordingly, alternative biotechnological approaches have been researched for overcoming the shortcomings: microbial fermentation using microorganisms with tyrosinase, tyrosine phenol-lyase, or p-hydroxyphenylacetate 3-hydroxylase activity and enzymatic conversion by immobilized tyrosinase. Actually, Ajinomoto Co. Ltd commercialized Erwinia herbicola fermentation to produce L-DOPA from catechol. In addition, the electroenzymatic conversion system was recently introduced as a newly emerging scheme. In this review, we aim to not only overview the biotechnological L-DOPA production methods, but also to briefly compare and analyze their advantages and drawbacks. Furthermore, we suggest the future potential of biotechnological L-DOPA production as an industrial process. PMID- 25432673 TI - A simple recovery process for biodegradable plastics accumulated in cyanobacteria treated with ionic liquids. AB - Here, we proposed a simple recovery process for poly(3-hydroxybutyrate) (PHB) accumulated in cyanobacteria by using ionic liquids (ILs), which dissolve cyanobacteria but not PHB. First, we investigated the effects of IL polarity on hydrogen-bonding receipt ability (beta value) and hydrogen-bonding donating ability (alpha value) and evaluated the subsequent dissolution of cyanobacteria. We found that ILs having alpha values higher than approximately 0.4 and beta values of approximately 0.9 were suitable for dissolution of cyanobacteria. In particular, 1-ethyl-3-methylimidazolium methylphosphonate ([C2mim][MeO(H)PO2]) was found to dissolve cyanobacteria components, but not PHB. Thus, we verified that PHB produced in cyanobacteria could be separated and recovered by simple filtering after dissolution of cyanobacteria in [C2mim][MeO(H)PO2]. Using this technique, more than 98 % of PHB was obtained on the filter as residues separated from cyanobacteria. Furthermore, [C2mim][MeO(H)PO2] maintained the ability to dissolve cyanobacteria after a simple recycling procedure. PMID- 25432674 TI - Methylobacterium extorquens: methylotrophy and biotechnological applications. AB - Methylotrophy is the ability to use reduced one-carbon compounds, such as methanol, as a single source of carbon and energy. Methanol is, due to its availability and potential for production from renewable resources, a valuable feedstock for biotechnology. Nature offers a variety of methylotrophic microorganisms that differ in their metabolism and represent resources for engineering of value-added products from methanol. The most extensively studied methylotroph is the Alphaproteobacterium Methylobacterium extorquens. Over the past five decades, the metabolism of M. extorquens has been investigated physiologically, biochemically, and more recently, using complementary omics technologies such as transcriptomics, proteomics, metabolomics, and fluxomics. These approaches, together with a genome-scale metabolic model, facilitate system wide studies and the development of rational strategies for the successful generation of desired products from methanol. This review summarizes the knowledge of methylotrophy in M. extorquens, as well as the available tools and biotechnological applications. PMID- 25432675 TI - Efficient co-displaying and artificial ratio control of alpha-amylase and glucoamylase on the yeast cell surface by using combinations of different anchoring domains. AB - Recombinant yeast strains that display heterologous amylolytic enzymes on their cell surface via the glycosylphosphatidylinositol (GPI)-anchoring system are considered as promising biocatalysts for direct ethanol production from starchy materials. For the effective hydrolysis of these materials, the ratio optimization of multienzyme activity displayed on the cell surface is important. In this study, we have presented a ratio control system of multienzymes displayed on the yeast cell surface by using different GPI-anchoring domains. The novel gene cassettes for the cell-surface display of Streptococcus bovis alpha-amylase and Rhizopus oryzae glucoamylase were constructed using the Saccharomyces cerevisiae SED1 promoter and two different GPI-anchoring regions derived from Saccharomyces cerevisiae SED1 or SAG1. These gene cassettes were integrated into the Saccharomyces cerevisiae genome in different combinations. Then, the cell surface alpha-amylase and glucoamylase activities and ethanol productivity of these recombinant strains were evaluated. The combinations of the gene cassettes of these enzymes affected the ratio of cell-surface alpha-amylase and glucoamylase activities and ethanol productivity of the recombinant strains. The highest ethanol productivity from raw starch was achieved by the strain harboring one alpha-amylase gene cassette carrying the SED1-anchoring region and two glucoamylase gene cassettes carrying the SED1-anchoring region (BY AASS/GASS/GASS). This strain yielded 22.5 +/- 0.6 g/L of ethanol from 100 g/L of raw starch in 120 h of fermentation. PMID- 25432676 TI - Hydrogels for 3D mammalian cell culture: a starting guide for laboratory practice. AB - Hydrogels have become one of the most popular platforms for three-dimensional (3D) cultivation of mammalian cells. The enormous versatility of hydrogel materials makes it possible to design scaffolds with predefined mechanical properties, as well as with desired biofunctionality. 3D hydrogel constructs have been used for a variety of applications, including tissue engineering of microorgan systems, drug delivery, cytotoxicity testing, and drug screening. Moreover, 3D culture is applied for investigating cellular physiology, stem cell differentiation, and tumor models and for studying interaction mechanisms between the extracellular matrix and cells. In this paper, we review current examples of performance-based hydrogel design for 3D cell culture applications. A major emphasis is placed on a description of how standard analytical protocols and imaging techniques are being adapted to analysis of 3D cell culture in hydrogel systems. PMID- 25432677 TI - Distribution of sediment bacterial and archaeal communities in plateau freshwater lakes. AB - Both Bacteria and Archaea might be involved in various biogeochemical processes in lacustrine sediment ecosystems. However, the factors governing the intra-lake distribution of sediment bacterial and archaeal communities in various freshwater lakes remain unclear. The present study investigated the sediment bacterial and archaeal communities in 13 freshwater lakes on the Yunnan Plateau. Quantitative PCR assay showed a large variation in bacterial and archaeal abundances. Illumina MiSeq sequencing illustrated high bacterial and archaeal diversities. Bacterial abundance was regulated by sediment total organic carbon and total nitrogen, and water depth, while nitrate nitrogen was an important determinant of bacterial diversity. Proteobacteria, Acidobacteria, Actinobacteria, Bacteroidetes, Chlorobi, Chloroflexi, Cyanobacteria, Firmicutes, Gemmatimonadetes, Nitrospirae, Planctomycetes, and Verrucomicrobia were the major components of sediment bacterial communities. Proteobacteria was the largest phylum, but its major classes and their proportions varied greatly among different lakes, affected by sediment nitrate nitrogen. In addition, both Euryarchaeota and Crenarchaeota were important members in sediment archaeal communities, while unclassified Archaea usually showed the dominance. PMID- 25432679 TI - Evidence for canine rehabilitation and physical therapy. AB - This article reviews some important studies regarding canine physical rehabilitation. Bones, cartilage, muscles, ligaments, and tendons undergo atrophy if loading is decreased. Knowledge of the changes that occur with immobilization and the time course of events helps in the development of a rehabilitation program to improve tissue integrity. Outcome assessment instruments are clinically useful indicators of patient progress and the success of rehabilitation programs. A number of physical modalities are used in canine rehabilitation, although there are relatively few canine-specific studies. Rehabilitation has specific benefits in the treatment of various orthopedic and neurologic conditions. PMID- 25432680 TI - Physical agent modalities in physical therapy and rehabilitation of small animals. AB - Physical agent modalities can be effective components of the overall rehabilitation of small animals. This article reviews the effects, indications, contraindications, and precautions of cold, superficial heat, therapeutic ultrasound, and electrical stimulation. PMID- 25432678 TI - Cytogenetic evidences of genome rearrangement and differential epigenetic chromatin modification in the sea lamprey (Petromyzon marinus). AB - This work explores both the chromatin loss and the differential genome methylation in the sea lamprey (Petromyzon marinus) from a molecular cytogenetic point of view. Fluorescent in situ hybridization experiments on meiotic bivalents and mitotic chromosomes corroborate the chromatin loss previously observed during the development of the sea lamprey and demonstrate that the elimination affects not only to Germ1 sequences but also to the rpt200 satellite DNA and most part of the major ribosomal DNA present on the germinal line. 5-Methylcytosine immunolocation revealed that the GC-rich heterochromatin is highly methylated in the germ line but significantly less in somatic chromosomes. These findings not only support previous observations about genome rearrangements but also give new information about epigenetic changes in P. marinus. The key position of lampreys in the vertebrate phylogenetic tree makes them an interesting taxon to provide relevant information about genome evolution in vertebrates. PMID- 25432681 TI - Therapeutic laser in veterinary medicine. AB - Laser therapy is an increasingly studied modality that can be a valuable tool for veterinary practitioners. Mechanisms of action have been studied and identified for the reduction of pain and inflammation and healing of tissue. Understanding the basics of light penetration into tissue allows evaluation of the correct dosage to deliver for the appropriate condition, and for a particular patient based on physical properties. New applications are being studied for some of the most challenging health conditions and this field will continue to grow. Additional clinical studies are still needed and collaboration is encouraged for all practitioners using this technology. PMID- 25432682 TI - Principles and applications of therapeutic exercises for small animals. AB - Therapeutic exercises are the cornerstone of the rehabilitation programs of companion animals. Therapeutic exercises are used to improve active joint range of motion, to improve weight bearing and limb use, to build strength and muscle mass, and to increase conditioning (eg, endurance, speed). Each case is unique as chronicity, type of injury, patient signalment and temperament, owner compliance, and level of required functional recovery vary widely. Therapeutic exercises are also essential for partial return to work or performance and to learn to perform activities of daily living after injury or surgery. PMID- 25432683 TI - Rehabilitation and physical therapy for selected orthopedic conditions in veterinary patients. AB - A specific diagnosis is needed to perform optimal rehabilitation of orthopedic problems. A well-planned rehabilitation program is important for orthopedic patients when surgical repairs are mechanically weak (eg, when repairing fractures in skeletally immature patients or when repairing tendons or ligaments). Joint immobilization is sometimes used to protect weak surgical repairs. The duration of immobilization should be minimized, particularly in situations with potential loss of joint motion. Evidence-based information regarding specific modalities and techniques for rehabilitation of injured dogs and cats is generally lacking. The choice of modalities and techniques must be based on common sense, knowledge of rehabilitation techniques, and clinical experience. PMID- 25432684 TI - Physical rehabilitation after total joint arthroplasty in companion animals. AB - Patients who have total joint arthroplasty have varying needs related to rehabilitation. In the short term, rehabilitation should be used in all dogs to identify high-risk patients and to minimize the likelihood of postoperative complications. Many patients undergoing total hip replacement recover uneventfully without needing long-term physiotherapy. All patients undergoing total knee replacement and total elbow replacement need rehabilitation to restore limb use and maximize their functional recovery. This article presents rehabilitation considerations for companion animals undergoing total hip replacement, total knee replacement, and total elbow replacement; postoperative complications and how to mitigate risks; and anticipated patient outcomes. PMID- 25432685 TI - Orthoses and exoprostheses for companion animals. AB - Exoprostheses are devices that are secured to incomplete limbs to enable locomotion. By comparison, orthoses are devices externally applied to support or protect an injured body part. Orthoses also can be used to control, guide, protect, limit motion of, or immobilize an extremity, a joint, or a body segment. Exoprostheses and orthoses are a growing aspect of the physical rehabilitation of companion animals. They require precise design and fabrication. Patients and owners must be trained to use the devices. Exoprostheses and orthoses can have a profound beneficial impact on the mobility and the quality of life of companion animals. PMID- 25432686 TI - Feline rehabilitation. AB - Cats have orthopedic problems, including osteoarthritis, fractures, and luxations that are positively impacted by physical rehabilitation. Most cats have an independent behavior that requires using a tactful approach to rehabilitation. Cats often do well with manual therapy and electrophysical modalities. Feline rehabilitation sessions may be shorter than canine rehabilitation sessions. Cats do best with therapeutic exercises when these exercises are linked to hunting, playing, or feeding. PMID- 25432687 TI - Veterinary rehabilitation and physical therapy. Preface. PMID- 25432688 TI - A randomised trial of treating fibroids with either embolisation or myomectomy to measure the effect on quality of life among women wishing to avoid hysterectomy (the FEMME study): study protocol for a randomised controlled trial. AB - BACKGROUND: Uterine fibroids are the most common tumour in women of reproductive age. By the time they are 50-years-old around 80% of women will have developed one. Of these, around half will experience symptoms which will impact negatively on their quality of life. Hysterectomy is the traditional treatment for women with symptomatic fibroids. For women who do not wish to undergo a hysterectomy, two invasive treatments are commonly available: myomectomy or uterine artery embolization (UAE). DESIGN: FEMME is a pragmatic, randomised, open, multi-centre trial examining the quality of life menstruating women with symptomatic fibroids experience after treatment with UAE or myomectomy. METHODS: After providing informed consent, 216 women with symptomatic fibroids from 43 NHS Hospital Trusts and Health Boards across the United Kingdom will undergo randomisation by a centralised computer system to treatment by either UAE or myomectomy. A minimisation algorithm will be used in order to balance the groups with respect to the following three parameters: the longest dimension of the largest fibroid, the number of fibroids present, and whether the woman currently desires pregnancy.Using validated questionnaires the women's quality of life will be compared between groups at six months, one year, two years and four years post procedure, taking into account pre-procedure scores. An economic evaluation will be conducted alongside the trial to determine the cost-effectiveness of UAE compared with myomectomy.Validated diaries will also be used to compare menstrual blood loss at the same time-points. The plasma concentration of Anti-Mullerian hormone (AMH), which will act as a proxy measurement of ovarian reserve, will be recorded before the woman has her procedure and then again at six weeks, six months, and twelve months afterwards. Re-intervention rates will be recorded. DISCUSSION: The FEMME trial's primary outcome is the quality of life women with symptomatic uterine fibroids experience two years after they have been treated with either UAE or myomectomy, as measured by the disease-specific Uterine Fibroid Symptom Quality-of-Life (UFS-QoL) questionnaire. TRIAL REGISTRATION: Current Controlled Trials registration number: ISRCTN70772394, registered on 2 March 2013. PMID- 25432690 TI - Estimating the average treatment effects of nutritional label use using subclassification with regression adjustment. AB - Propensity score methods are common for estimating a binary treatment effect when treatment assignment is not randomized. When exposure is measured on an ordinal scale (i.e. low-medium-high), however, propensity score inference requires extensions which have received limited attention. Estimands of possible interest with an ordinal exposure are the average treatment effects between each pair of exposure levels. Using these estimands, it is possible to determine an optimal exposure level. Traditional methods, including dichotomization of the exposure or a series of binary propensity score comparisons across exposure pairs, are generally inadequate for identification of optimal levels. We combine subclassification with regression adjustment to estimate transitive, unbiased average causal effects across an ordered exposure, and apply our method on the 2005-2006 National Health and Nutrition Examination Survey to estimate the effects of nutritional label use on body mass index. PMID- 25432691 TI - Optimal combination of biomarkers for time-dependent receiver operating characteristic estimation and related problems. AB - The receiver operating characteristic curve is commonly used for assessing diagnostic test accuracy and for discriminatory ability of a medical diagnostic test in distinguishing between diseases and non-diseased individuals. With the advance of technology, many genetic variables and biomarker variables are easily collected. The most challenging problem is how to combine clinical, genetic, and biomarker variables together to predict disease status. If one is interested in predicting t-year survival, however, the status of "case" (death) and "control" (survival) at the given t-year is unknown for those individuals who were censored before t-year. To conduct a receiver operating characteristic analysis, one has to impute those ambiguous statuses. In this paper, we study a maximum pseudo likelihood method to estimate the underlying parameters and baseline distribution functions. The proposed approach produces more efficient and smoother estimate of the optimal time-dependent receiver operating characteristic curve and more stable estimation of the prediction rule for the t-year survivors. More importantly, the proposal is equipped with a goodness-of-fit test for the model assumption based on the bootstrap method. Two real medical data sets are used for illustration. PMID- 25432693 TI - Factors affecting nebulised medicine adherence in adult patients with cystic fibrosis: a qualitative study. AB - BACKGROUND: Nebulised medicines contribute to the high treatment burden experienced by patients with cystic fibrosis (CF). OBJECTIVES: This study explored experiences of adult patients with CF when using nebulised medicines, factors impacting on their adherence to nebulised therapy and strategies they used to facilitate adherence. SETTING: Community setting, in Sydney, Australia. METHODS: Ten patients with CF were recruited through a CF patient organisation. Semi-structured face-to-face interviews were conducted, addressing the study objectives. Interviews were audio-recorded, transcribed verbatim and content analysed for anticipated and emergent themes. MAIN OUTCOME MEASURE: Experiences with using nebulised medicines; and barriers and facilitators of adherence to nebulised medicines. RESULTS: Participants' age ranged from 22 to 45 years, with half being male. Four broad themes (with more specific sub-themes) were identified from the interviews: experiences with using nebulised medicines (cleaning nebuliser, time taken to use nebuliser medicine, flexibility in use of nebuliser); feelings about using nebulised medicines (necessary/important, dislike, part of life); factors impacting non-adherence (time consuming therapy, side effects/effects of medicine, work/social demands, lack of perceived importance); factors and strategies facilitating adherence (perceived medicine importance, habit/routine, support, health benefits, technology/medicine dose form, timetabling). CONCLUSIONS: Nebulised therapy for cystic fibrosis patients takes a substantial amount of time, with patients trying to alter their routine to incorporate nebulising into their daily lives. However there are still many factors that lead to low adherence, including work/social demands and travelling. Patients balance the necessity for nebulised therapy against the barriers, and engage in intentional non-adherence at times. Future strategies and resources should target and address specific factors identified by patients with CF as being important and impacting their adherence to nebulised medicines. PMID- 25432692 TI - A modified busulfan and cyclophosphamide preparative regimen for allogeneic transplantation in myeloid malignancies. AB - BACKGROUND: Busulfan/cyclophosphamide (Bu/Cy) is commonly used as a standard conditioning regimen without total body irradiation for patients with hematological myeloid malignancies undergoing hematopoietic stem cell transplantation (HSCT). OBJECTIVE: To develop a new myeloablative conditioning regimen incorporating fludarabine (Flu) and cytarabine (Ara-c). SETTING: A tertiary blood disease hospital in Tianjin, China. METHODS: A Bu/Cy preparative regimen was used, modified by Flu 90 mg/m(2) and Ara-c 6 g/m(2) in 57 unselected patients (median age 37 years) with hematological myeloid malignancies. The patients were to receive allogeneic hematopoietic stem cell transplantation (allo HSCT). Thirteen patients had high-risk leukemia, fifty patients had HLA matched sibling donors while seven patients had HLA mismatched sibling donors. Cy was given 50 mg/kg/day for 2 days while Bu was given 3.2 mg/kg/day intravenously for 3 days. MAIN OUTCOME MEASURE: Post-transplant donor chimerism, relapse tendency and minimal residual disease. RESULTS: Extramedullar toxicity was relatively limited; the incidence of treatment-related mortality (TRM) within 100 days was 3.5 %. The incidence of grade II-IV, grade III-IV acute graft versus host disease (GVHD) and chronic GVHD of the evaluable patients were 21.1, 8.8 and 36.4 %, respectively. With a median follow up of 59 (13-96.5) months, TRM and relapse rate (RR) at eight years were 24.1 +/- 5.8 and 14.7 +/- 4.8 %, respectively. Disease free survival at eight years was 67.9 +/- 6.2 % for the entire group, 60.0 +/- 8.9 % for patients with AML, 77.3 +/- 8.9 % for patients with CML, 70.0 +/- 6.5 and 42.9 +/- 18.7 % or matched sibling and mismatched sibling HSCT respectively. CONCLUSION: The new regimen was associated with a low relapse rate, low incidence and severity of graft versus host disease and satisfactory survival for patients with myeloid malignancies. PMID- 25432694 TI - Pirarubicin versus doxorubicin in neoadjuvant/adjuvant chemotherapy for stage IIB limb high-grade osteosarcoma: does the analog matter? AB - Pirarubicin (THP), a novel anthracycline derivative of doxorubicin (ADM), is effective in treating patients with advanced, relapsed or recurrent high-grade osteosarcoma. But its role in neoadjuvant/adjuvant chemotherapy of osteosarcoma is still not defined. We conducted a retrospective evaluation of THP-containing chemotherapy for osteosarcoma in comparison with ADM-containing chemotherapy to determine differences in efficacy and toxicities between THP- and ADM-containing regimens. From January 2008 to May 2011, 112 stage IIB limb high-grade osteosarcoma patients were treated in our institute. Fifty-four patients received a median 6 cycles of neoadjuvant/adjuvant chemotherapy consisted of THP (pirarubicin), DDP (cisplatin), IFO (ifosfamide) and MTX (methotrexate), while 58 patients received a median 6 cycles of neoadjuvant/adjuvant chemotherapy consisted of ADM (doxorubicin), DDP (cisplatin), IFO (ifosfamide) and MTX (methotrexate). Efficacy and toxicity of the 2 anthracyclines given as combination chemotherapy were assessed in these patients. The limb salvage rate, histologic response rate, 2-year recurrence rate, 2-year metastasis rate, 2-year disease-free survival rate, 2-year overall survival rate, median disease-free survival time (DFS) and median overall survival time (OS) in THP-containing group were similar to that in ADM-containing group. Toxicities were well balanced in two groups. No death related to chemotherapy was observed. Left ventricular ejection fraction was unchanged 1 and 2 years after chemotherapy in two groups. Efficacy and toxicity of THP-containing combination are similar to those of ADM containing combination in neoadjuvant/adjuvant chemotherapy for stage IIB limb high-grade osteosarcoma. PMID- 25432695 TI - Reevaluation of glypican-3 as a prognostic marker in HCC using X-tile software. AB - Glypican-3 (GPC3) is a widely used immunohistochemical marker for hepatocellular carcinoma (HCC); however, its prognostic value is unclear. Immunohistochemical evaluation of GPC3 expression was performed on 300 postoperative HCC tissue samples with paired adjacent non-tumor tissues on tissue microarray sections. The integral optic density, representing the expression level of GPC3 in each HCC sample, was calculated using Image-Pro Plus. The outcome-based cut-point optimization was performed using X-tile software. GPC3 was highly expressed in HCC tissues compared with adjacent non-tumor tissues. The expression level of GPC3 was significantly correlated with overall survival (OS) and time to recurrence (TTR). The lower the level of GPC3 expression in HCC tissue, the poorer the observed prognosis. Univariate and multivariate analyses showed that the expression level of GPC3 in HCC was an independent prognostic factor for both OS and TTR. In conclusion, GPC3 expression is an independent prognostic factor for postoperative HCC, and low expression levels of GPC3 in HCC may indicate poor outcome. PMID- 25432696 TI - MicroRNA-542-3p suppresses cell growth of gastric cancer cells via targeting oncogene astrocyte-elevated gene-1. AB - MicroRNAs (miRNAs) have been suggested to play critical roles in tumorigenesis as well as in the development of therapies for the treatment of cancers. However, the tumor-associated miRNAs in gastric cancers remain poorly understood. Here, we report on miR-542-3p in gastric cancers, which has been widely studied in other cancers as a tumor suppressor. Real-time quantitative PCR analysis demonstrated that miR-542-3p was significantly down-regulated in gastric cancer tissues (p < 0.0001) and cell lines (p < 0.001). Overexpression of miR-542-3p significantly inhibited cell growth of gastric cancer cells both in vitro (p < 0.01) and in vivo (p < 0.01). Notably, overexpression of miR-542-3p apparently reduced the protein expression of astrocyte-elevated gene-1 (AEG-1) (p < 0.01). The dual luciferase reporter assay validated that miR-542-3p directly bound the 3' untranslated region (UTR) of AEG-1, which could be abolished by mutation of the predicted miR-542-3p binding site. Furthermore, overexpression of miR-542-3p markedly inhibited the activation of oncogenic signaling pathways including the Akt, beta-catenin and nuclear factor-kappaB pathways. Additionally, overexpression of AEG-1 without the 3'-UTR partially reversed the cell growth arrest induced by miR-542-3p overexpression in gastric cancer cells (p < 0.05). Taken together, these data suggest that miR-542-3p might function as a tumor suppressor in gastric cancer, potentially by targeting the oncogene AEG-1, implying a potential role for miR-542-3p in the development of therapeutic methods for gastric cancer. PMID- 25432697 TI - Short hairpin RNA (shRNA) of type 2 interleukin-1 receptor (IL1R2) inhibits the proliferation of human osteosarcoma U-2 OS cells. AB - Type 2 interleukin-1 receptor (IL1R2) is a member of the IL1 family. It has been reported that IL1R2 is expressed and plays important roles in several cancers. However, its potential role in human osteosarcoma has not been reported. In the present study, a recombinant lentivirus harboring short hairpin RNA against IL1R2 was constructed and then transfected human osteosarcoma U-2 OS cells. The proliferation of infected cells was measured by 3-(4, 5- dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) assay and plate colony formation assay. Results showed that efficiency of lentivirus infection was more than 80 %. The knockdown efficiency of IL1R2 mRNA level was up to 95 % compared with control group. After treatment with lentiviruses containing shIL1R2 (Lv-shIL1R2), the proliferation and colony formation of U-2 OS cells were obviously reduced (P < 0.001). Cell cycle assay was used to investigate the mechanism of the inhibition of proliferation of U-2 OS cells. We found that after Lv-shIL1R2 treatment, the percentage of cells at G0/G1 phase decreased significantly, whereas cells at S and G2/M phases increased markedly (P < 0.05). In conclusion, shIL1R2 indeed inhibited the proliferation of U-2 OS cells which might be associated with the blockage of S and G2/M phases. The results suggested that IL1R2 could have oncogenic potential and shIL1R2 might represent a new and effective therapeutic treatment for osteosarcoma patients. PMID- 25432698 TI - Sonic hedgehog-Gli1 signals promote epithelial-mesenchymal transition in ovarian cancer by mediating PI3K/AKT pathway. AB - Epithelial-mesenchymal transition (EMT) has been reported to play an important role in distant metastasis in cancer-related disease. A large number of studies have shown that sonic hedgehog-glioma-associated oncogene 1 (Shh-Gli1) signals participate in the process of EMT; however, the role and mechanism of Shh-Gli1 signals in the progression of EMT in ovarian cancer remain largely unknown. First, we investigated the occurrence of EMT and invasion and migration ability in ovarian cancer cells stimulated by different concentration of Shh-Gli1 signals agonist purmorphamine in vitro. Then, Akt siRNA was transfected into ovarian cancer cells which already stimulated by purmorphamine to elucidate the molecular mechanism underlying the pathogenesis of EMT in ovarian cancer. Gli1 expression was significantly enhanced in ovarian cancer cells after stimulated by purmorphamine. In addition, Gli1 up-regulation promoted EMT, invasion and migration ability of ovarian cancer cells. Furthermore, we validated a cross talk between Shh-Gli1 signals and PI3K-Akt pathway in the occurrence of EMT in ovarian cancer cells. These findings revealed a novel role for Shh-Gli1 signals in EMT in ovarian cancer and provided for us a potential therapeutic target for the suppression of EMT, invasion and metastasis in ovarian cancer. PMID- 25432699 TI - Hypoxia-inducible factor 1-alpha up-regulates the expression of phospholipase D2 in colon cancer cells under hypoxic conditions. AB - Hypoxia is a common characteristic of solid tumors. Recent studies confirmed that phospholipase D2 (PLD2) plays significant roles in cancer progression. In this study, correlation between the expression of PLD2 and the change in the protein level of hypoxia-inducible factor 1-alpha (HIF1-alpha) was studied. Thirty human colon cancer tissues were examined for the expression of HIF1-alpha and PLD2 protein, and mRNA levels. SW480 and SW620 cells were exposed to normoxia (20 %) or hypoxia (<1 %). HIF1-alpha and PLD2 protein, and mRNA levels were analyzed by Western blot and qRT-PCR, respectively. Growth studies were conducted on cells with HIF1-alpha inhibition through xenograft tumor model. Finally, PLD2 protein was detected by Western blot analysis in vivo. There was a positive correlation between HIF1-alpha and PLD2 in colon cancer tissues. Hypoxic stress induced PLD2 mRNA and protein expression in SW480 and SW620 cells. Cells transfected with HIF1 alpha siRNA showed attenuation of hypoxia stress-induced PLD2 expression. In vivo growth decreased in response to HIF1-alpha and PLD2 inhibition. These results suggest that PLD2 expression in colon cancer cells is up-regulated via HIF1-alpha in response to hypoxic stress and underscores the crucial role of HIF1-alpha induced PLD2 in tumor growth. PMID- 25432700 TI - Topo2A as a prognostic biomarker for patients with resectable esophageal squamous cell carcinomas. AB - Topoisomerase 2alpha (Topo2A) is a key enzyme in replication. It functions as a cell proliferation and cell cycle-specific marker and it is identified mainly in the interphase nuclei of proliferating cells. Many studies have shown that Topo2A protein expression is up-regulated in various cancers including esophageal cancer. However, to date, no studies have adequately addressed the prognostic value of Topo2A in patients with resectable esophageal squamous cell carcinoma (ESCC). Therefore, we conducted a large-scale retrospective study investigating the expression of Topo2A and the clinicopathological characteristics or prognosis of ESCC patients. Eight hundred and twenty-nine specimens of ESCC from patients who underwent complete esophageal cancer resection were evaluated using an immunohistochemical assay. Among them, 404 (48.7 %) cases with a score >2 were determined to be positive for Topo2A expression. Topo2A overexpression was significantly associated with poorer differentiation (P = 0.007) and perineural invasion (P = 0.046). The median progression-free survival (PFS) of 319 patients with Topo2A-positive expression and 336 patients with Topo2A-negative expression was 19.5 and 26.5 months, respectively (P = 0.000). The overall survival (OS) in patients with and without Topo2A expression was 34.0 and 44.5 months, respectively (P = 0.002). In the multivariate analysis, Topo2A overexpression was identified as an independent prognostic factor for PFS (P = 0.001) and OS (P = 0.009). We determined that Topo2A overexpression was not only associated with poorer differentiation and perineural invasion, but it could also act as an independent risk factor for ESCC. PMID- 25432701 TI - Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue - a review. AB - BACKGROUND: Immunohistochemistry (IHC) is a well-established, widely accepted method in both clinical and experimental parts of medical science. It allows receiving valuable information about any process in any tissue, and especially in bone. Each year the amount of data, received by IHC, grows in geometric progression. But the lack of standardization, especially on the post-analytical stage (interpreting and reporting of results), makes the comparison of the results of different studies impossible. METHODS: Comprehensive PubMED literature search with a combination of search words "immunohistochemistry" and "scoring system" was performed and 773 articles describing IHC results were identified. After further manual analysis 120 articles were selected for detailed evaluation of used approaches. RESULTS: Six major approaches to the interpretation and presentation of IHC analysis results were identified, analyzed and described. CONCLUSIONS: The overview of the existing approaches in evaluation and interpretation of IHC data, which are provided in the article, can be used in bone tissue research and for either better understanding of existing scoring systems or developing a new one. Standard multiparametric, semiquantitative IHC scoring systems should simplify and clarify the process of interpretation and reporting of received data. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_221. PMID- 25432702 TI - Effects in cigarette smoke stimulated bronchial epithelial cells of a corticosteroid entrapped into nanostructured lipid carriers. AB - BACKGROUND: Nanomedicine studies have showed a great potential for drug delivery into the lung. In this manuscript nanostructured lipid carriers (NLC) containing Fluticasone propionate (FP) were prepared and their biocompatibility and effects in a human bronchial epithelial cell line (16-HBE) stimulated with cigarette smoke extracts (CSE) were tested. RESULTS: Biocompatibility studies showed that the NLC did not induce cell necrosis or apoptosis. Moreover, it was confirmed that CSE increased intracellular ROS production and TLR4 expression in bronchial epithelial cells and that FP-loaded NLC were more effective than free drug in modulating these processes. Finally, the nanoparticles increased GSH levels improving cell protection against oxidative stress. CONCLUSIONS: The present study shows that NLC may be considered a promising strategy to improve corticosteroid mediated effects in cellular models associated to corticosteroid resistance. The NLC containing FP can be considered good systems for dosage forms useful for increasing the effectiveness of fluticasone decreasing its side effects. PMID- 25432703 TI - Palliative distal gastrectomy offers no survival benefit over gastrojejunostomy for gastric cancer with outlet obstruction: retrospective analysis of an 11-year experience. AB - BACKGROUND: Either palliative distal gastrectomy or gastrojejunostomy are the initial treatment options for locally advanced gastric cancer with outlet obstruction when curative-intent resection is not feasible. Since chemotherapy is the mainstay for unresectable gastric cancer, the clinical value of palliative distal gastrectomy is controversial. METHODS: We retrospectively reviewed the clinical data of patients with gastric cancer with outlet obstruction treated at our institution between January 2002 and December 2012. We compared the clinical outcomes of palliative distal gastrectomy with those of gastrojejunostomy patients and the factors affecting overall survival were evaluated. RESULTS: Elective palliative distal gastrectomy and gastrojejunostomy were performed in 18 and 25 patients, respectively. The median overall survival times in the gastrojejunostomy and palliative distal gastrectomy groups were statistically equivalent at 8.8 and 8.3 months, respectively (P = 0.73), despite the more locally advanced tumors in the gastrojejunostomy as compared with the palliative distal gastrectomy group. A multivariate Cox regression analysis showed absence of postoperative chemotherapy and higher postoperative complication grade to be associated with worse clinical outcomes. CONCLUSIONS: Palliative distal gastrectomy offers neither survival nor palliative benefit as compared to gastrojejunostomy. Minimizing the morbidity of intervention for outlet obstruction, followed by chemotherapy, appears to be the optimal initial strategy for incurable gastric cancer with outlet obstruction. PMID- 25432705 TI - Structural mechanisms of RNA recognition: sequence-specific and non-specific RNA binding proteins and the Cas9-RNA-DNA complex. AB - RNA-binding proteins play crucial roles in RNA processing and function as regulators of gene expression. Recent studies have defined the structural basis for RNA recognition by diverse RNA-binding motifs. While many RNA-binding proteins recognize RNA sequence non-specifically by associating with 5' or 3' RNA ends, sequence-specific recognition by RNA-binding proteins is typically achieved by combining multiple modular domains to form complex binding surfaces. In this review, we present examples of structures from different classes of RNA-binding proteins, identify the mechanisms utilized by them to target specific RNAs, and describe structural principles of how protein-protein interactions affect RNA recognition specificity. We also highlight the structural mechanism of sequence dependent and -independent interactions in the Cas9-RNA-DNA complex. PMID- 25432704 TI - Engrailed homeoproteins in visual system development. AB - Engrailed is a homeoprotein transcription factor. This family of transcription factors is characterized by their DNA-binding homeodomain and some members, including Engrailed, can transfer between cells and regulate protein translation in addition to gene transcription. Engrailed is intimately involved in the development of the vertebrate visual system. Early expression of Engrailed in dorsal mesencephalon contributes to the development and organization of a visual structure, the optic tectum/superior colliculus. This structure is an important target for retinal ganglion cell axons that carry visual information from the retina. Engrailed regulates the expression of Ephrin axon guidance cues in the tectum/superior colliculus. More recently it has been reported that Engrailed itself acts as an axon guidance cue in synergy with the Ephrin system and is proposed to enhance retinal topographic precision. PMID- 25432706 TI - IKK-related genetic diseases: probing NF-kappaB functions in humans and other matters. AB - The transcription factor NF-kappaB plays a key role in numerous physiological processes such as inflammation, immunity, cell proliferation or control of cell death. Its activation is tightly controlled by a kinase complex, IkappaB kinase (IKK), composed of three core proteins: IKK1/IKKalpha, IKK2/IKKbeta and NEMO/IKKgamma. The first two are structurally related kinases whereas the third one is a regulatory subunit exhibiting affinity for upstream activators modified by polyubiquitin chains. Over the years, several inherited diseases caused by mutations of each of the three subunits of IKK have been identified in humans together with diseases caused by mutations of several of its substrates. They are associated with very specific and complex phenotypes involving a broad range of abnormalities such as impaired innate and acquired immune response, perturbed skin development and defects of the central nervous system. Here, we summarize the diverse clinical, cellular and molecular manifestations of IKK-related genetic diseases and show that studying patient-related mutations affecting the IKK subunits and some of their substrates offers the opportunity to understand the various functions of NF-kappaB in humans, complementing studies performed with mouse models. This analysis also provides glimpses about putative functions of IKK subunits that may be NF-kappaB-independent. PMID- 25432707 TI - Comments on the 2014 ESC/ESA Guidelines on Noncardiac Surgery: cardiovascular assessment and management. PMID- 25432708 TI - Clinical profile and incidence of ventricular arrhythmia in patients undergoing defibrillator generator replacement in Spain. AB - INTRODUCTION AND OBJECTIVES: Implantable cardioverter-defibrillators reduce mortality in some patients with heart disease. Battery replacement is a frequent occurrence in clinical practice and is required in up to 30% of implants. The benefit/risk ratio of defibrillators varies over time and should be reevaluated at the time of replacement. The aim of this study was to determine the clinical characteristics and incidence of defibrillator therapies in patients who underwent generator replacement. METHODS: This multicenter retrospective study involved patients from the UMBRELLA national registry who underwent replacement due to defibrillator battery depletion. The incidence of ventricular arrhythmias was determined via remote monitoring. Risk factors for sustained ventricular arrhythmia after replacement were analyzed. RESULTS: A total of 354 patients were included (mean age [standard deviation], 61.8 [14.5] years; men, 80%; secondary prevention, 42%; ventricular arrhythmias in the explanted generator, 62%). After a 25-month follow-up, 70 patients (20%) received appropriate therapies and 8 (2.3%) received inappropriate discharges. Male sex, structural heart disease, heart failure, and the absence of resynchronization were independent predictors of ventricular arrhythmia occurrence. CONCLUSIONS: One-fifth of patients had appropriate defibrillator therapies in the first 2 years after generator replacement. Determination of the factors associated with arrhythmia occurrence after replacement may be useful to optimize implantable cardioverter defibrillator treatment. PMID- 25432709 TI - QT interval heterogeneities induced through local epicardial warming/cooling. An experimental study. AB - INTRODUCTION AND OBJECTIVES: Abnormal QT interval durations and dispersions have been associated with increased risk of ventricular arrhythmias. The present study examines the possible arrhythmogenic effect of inducing QT interval variations through local epicardial cooling and warming. METHODS: In 10 isolated rabbit hearts, the temperatures of epicardial regions of the left ventricle were modified in a stepwise manner (from 22 degrees C to 42 degrees C) with simultaneous electrogram recording in these regions and in others of the same ventricle. QT and activation-recovery intervals were determined during sinus rhythm, whereas conduction velocity and ventricular arrhythmia induction were determined during programmed stimulation. RESULTS: In the area modified from baseline temperature (37 degrees C), the QT (standard deviation) was prolonged with maximum hypothermia (195 [47] vs 149 [12] ms; P<.05) and shortened with hyperthermia (143 [18] vs 152 [27] ms; P<.05). The same behavior was displayed for the activation-recovery interval. The conduction velocity decreased with hypothermia and increased with hyperthermia. No changes were seen in the other unmodified area. Repetitive responses were seen in 5 experiments, but no relationship was found between their occurrence and hypothermia or hyperthermia (P>.34). CONCLUSIONS: In the experimental model employed, local variations in the epicardial temperature modulate the QT interval, activation-recovery interval, and conduction velocity. Induction of heterogeneities did not promote ventricular arrhythmia occurrence. PMID- 25432713 TI - Epipericardial fat necrosis. PMID- 25432711 TI - Initial experience of percutaneous treatment of mitral regurgitation with MitraClip(r) therapy in Spain. AB - INTRODUCTION AND OBJECTIVES: Symptomatic mitral regurgitation has an unfavorable prognosis unless treated by surgery. However, the European registry of valvular heart disease reports that 49% of patients with this condition do not undergo surgery. Percutaneous treatment of mitral regurgitation with MitraClip(r) has been proved a safe, efficient adjunct to medical treatment in patients with this profile. The objective of the present study is to describe initial experience of MitraClip(r) therapy in Spain. METHODS: Retrospective observational study including all patients treated between November 2011 and July 2013 at the 4 Spanish hospitals recording the highest numbers of implantations. RESULTS: A total of 62 patients (77.4% men) were treated, mainly for restrictive functional mitral regurgitation (85.4%) of grade III (37%) or grade IV (63%), mean (standard deviation) ejection fraction 36% (14%), and New York Heart Association functional class III (37%) or IV (63%). Device implantation was successful in 98% of the patients. At 1 year, 81.2% had mitral regurgitation <= 2 and 90.9% were in New York Heart Association functional class <= II. One periprocedural death occurred (sepsis at 20 days post-implantation) and another 3 patients died during follow up (mean, 9.1 months). Two patients needed a second implantation due to partial dehiscence of the first device and 2 others underwent heart transplantation. CONCLUSIONS: In Spain, MitraClip(r) therapy has principally been aimed at patients with functional mitral regurgitation, significant systolic ventricular dysfunction, and high surgical risk. It is considered a safe alternative treatment, which can reduce mitral regurgitation and improve functional capacity. PMID- 25432710 TI - Comparison of paclitaxel and everolimus-eluting stents in ST-segment elevation myocardial infarction and influence of thrombectomy on outcomes. ESTROFA-IM study. AB - INTRODUCTION AND OBJECTIVES: We sought to compare the long-term clinical outcome of with ST-segment elevation myocardial infarction treated with paclitaxel eluting stents or everolimus-eluting stents and the influence of thrombectomy on outcomes. METHODS: The ESTROFA-IM is a multicenter retrospective registry collecting consecutive patients with infarction treated with these stents in 16 centers. Propensity-score matching was performed to select comparable stent groups and comparable groups with and without thrombectomy. RESULTS: After matching patients, 350 treated with everolimus-eluting stents and 350 with paclitaxel-eluting stents were included in the analysis. The clinical and angiographic characteristics were comparable in both groups. The 2-year incidence of death, infarction, and target lesion revascularization was 14.9% for paclitaxel-eluting stents and 11.5% for everolimus-eluting stents (P = .04) and the incidence of definite/probable thrombosis 4.3% and 1.4%, respectively (P = .01). The use of paclitaxel-eluting was an independent predictor for events (hazard ratio = 2.44, 95% confidence interval, 1.28-4.65; P = .006). The benefit of everolimus-eluting stents over paclitaxel-eluting stents regarding stent thrombosis was more evident in the nonthrombectomy subgroup (5.4% vs 1.4%; P = .01). A significant interaction was found in the subgroups with and without thombectomy in the comparison between paclitaxel-eluting stents and everolimus eluting stents for the end-point of stent thrombosis (P = .039). CONCLUSIONS: The results of this multicenter registry suggest better clinical outcomes with the everolimus-eluting stents in ST-segment elevation myocardial infarction. The lower risk of thrombosis with these stents could be more relevant in the absence of thrombectomy. PMID- 25432714 TI - Dislodgement and embolization of a left atrial appendage thrombus. PMID- 25432715 TI - Coronary aneurysm closure with pericardial covered stent evaluated with optical coherence tomography. PMID- 25432718 TI - A research-based strategy for managing housing adaptations: study protocol for a quasi-experimental trial. AB - BACKGROUND: The primary aim of this paper is to describe the design of a project evaluating the effects of using a research-based strategy for managing housing adaptations (HAs). The evaluation targets clients' perspectives in terms of activity, participation, usability, fear of falling, fall incidence, use of mobility devices, and health-related quality of life, and determines the societal effects of HAs in terms of costs. Additional aims of the project are to explore and describe this strategy in relation to experiences and expectations (a) among clients and cohabitants and (b) occupational therapists in ordinary practice. METHODS/DESIGN: This study is a quasi-experimental trial applying a multiphase design, combining quantitative and qualitative data. At the experimental sites, the occupational therapists (OTs) apply the intervention, i.e. a standardized research-based strategy for HA case management. At the control site, the occupational therapists are following their regular routine in relation to HA. Three municipalities in south Sweden will be included based on their population, their geographical dispersion, and their similar organizational structures for HA administration. Identical data on outcomes is being collected at all the sites at the same four time points: before the HA and then 3, 6, and 12 months after the HA. The data-collection methods are semi-structured qualitative interviews, observations, clinical assessments, and certificates related to each client's HA. DISCUSSION: The intervention in this study has been developed and tested through many years of research and in collaboration with practitioners. This process includes methodological development and testing research aimed at identifying the most important outcomes and research targeting current HA case-management procedures in Swedish municipalities. When the study is completed, the results will be used for further optimization of the practice strategy for HA, in close collaboration with the data-collecting OTs. TRIAL REGISTRATION: No: NCT01960582. PMID- 25432719 TI - Identifying structural variation in haploid microbial genomes from short-read resequencing data using breseq. AB - BACKGROUND: Mutations that alter chromosomal structure play critical roles in evolution and disease, including in the origin of new lifestyles and pathogenic traits in microbes. Large-scale rearrangements in genomes are often mediated by recombination events involving new or existing copies of mobile genetic elements, recently duplicated genes, or other repetitive sequences. Most current software programs for predicting structural variation from short-read DNA resequencing data are intended primarily for use on human genomes. They typically disregard information in reads mapping to repeat sequences, and significant post-processing and manual examination of their output is often required to rule out false positive predictions and precisely describe mutational events. RESULTS: We have implemented an algorithm for identifying structural variation from DNA resequencing data as part of the breseq computational pipeline for predicting mutations in haploid microbial genomes. Our method evaluates the support for new sequence junctions present in a clonal sample from split-read alignments to a reference genome, including matches to repeat sequences. Then, it uses a statistical model of read coverage evenness to accept or reject these predictions. Finally, breseq combines predictions of new junctions and deleted chromosomal regions to output biologically relevant descriptions of mutations and their effects on genes. We demonstrate the performance of breseq on simulated Escherichia coli genomes with deletions generating unique breakpoint sequences, new insertions of mobile genetic elements, and deletions mediated by mobile elements. Then, we reanalyze data from an E. coli K-12 mutation accumulation evolution experiment in which structural variation was not previously identified. Transposon insertions and large-scale chromosomal changes detected by breseq account for ~25% of spontaneous mutations in this strain. In all cases, we find that breseq is able to reliably predict structural variation with modest read depth coverage of the reference genome (>40-fold). CONCLUSIONS: Using breseq to predict structural variation should be useful for studies of microbial epidemiology, experimental evolution, synthetic biology, and genetics when a reference genome for a closely related strain is available. In these cases, breseq can discover mutations that may be responsible for important or unintended changes in genomes that might otherwise go undetected. PMID- 25432720 TI - Pathogenic mechanisms of neurodegeneration in Parkinson disease. AB - The last 2 decades represent a period of unparalleled advancement in the understanding of the pathogenesis of Parkinson disease (PD). The discovery of several forms of familial parkinsonism with mendelian inheritance has elucidated insights into the mechanisms underlying the degeneration of dopaminergic neurons of the substantia nigra that histologically characterize PD. alpha-Synuclein, the principal component of Lewy bodies, remains the presumed pathogen at the heart of the current model; however, concurrently, a diverse range of other mechanisms have been implicated. The creation of a coherent disease model will be crucial to the development of effective disease modifying therapies for sporadic PD. PMID- 25432721 TI - Treatment strategies in early and advanced Parkinson disease. AB - The initiation of therapy in Parkinson disease (PD), altering the medication, adding new substances, and switching to alternative therapies throughout the disease is always a matter of debate. In the past, experts in PD have propagated different medication strategies. Even though there is no new medical treatment on the horizon, much has changed in consideration of the known treatments in the early and advanced therapy for PD. Therapeutic regimens have to be adapted and adjusted on a regular basis to accomplish the best medical care for the predominant symptom of the individual patient with PD. PMID- 25432722 TI - Atypical parkinsonism: diagnosis and treatment. AB - Atypical parkinsonism comprises typically progressive supranuclear palsy, corticobasal degeneration, and mutilple system atrophy, which are distinct pathologic entities; despite ongoing research, their cause and pathophysiology are still unknown, and there are no biomarkers or effective treatments available. The expanding phenotypic spectrum of these disorders as well as the expanding pathologic spectrum of their classic phenotypes makes the early differential diagnosis challenging for the clinician. Here, clinical features and investigations that may help to diagnose these conditions and the existing limited treatment options are discussed. PMID- 25432723 TI - Medical and surgical treatment of tremors. AB - Tremor is a hyperkinetic movement disorder characterized by rhythmic oscillations of one or more body parts. Disease severity ranges from mild to severe with various degrees of impact on quality of life. Essential tremor and parkinsonian tremor are the most common etiologic subtypes. Treatment may be challenging; although several drugs are available, response may be unsatisfactory. For some tremor forms, controlled data are scarce or completely missing and treatment is often based on anecdotal evidence. In this article, we review the current literature on tremor treatment, with a focus on common forms. PMID- 25432725 TI - Huntington disease: pathogenesis and treatment. AB - Huntington disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by progressive motor, behavioral, and cognitive decline, culminating in death. It is caused by an expanded CAG repeat in the huntingtin gene. Even years before symptoms become overt, mutation carriers show subtle but progressive striatal and cerebral white matter atrophy by volumetric MRI. Although there is currently no direct treatment of HD, management options are available for several symptoms. A better understanding of HD pathogenesis, and more sophisticated clinical trials using newer biomarkers, may lead to meaningful treatments. This article reviews the current knowledge of HD pathogenesis and treatment. PMID- 25432726 TI - Tics and tourette syndrome. AB - Gilles de la Tourette syndrome is a common neuropsychiatric disorder spectrum with tics as the defining feature. Comorbidities such as attention deficit/hyperactivity disorder, obsessive-compulsive disorder, and autism spectrum disorder often complicate clinical presentation. Their recognition is paramount for the introduction of efficient treatment strategies to promote healthy development and good quality of life. Here, knowledge on the movement disorder of tics, the spectrum of associated comorbidities, and the list of differential diagnoses of tic disorders are summarized. Also, an account of the prevailing pathophysiologic models of tic generation is provided, and a concise update on contemporary treatment strategies is presented. PMID- 25432727 TI - Paroxysmal movement disorders. AB - Paroxysmal dyskinesias represent a group of episodic abnormal involuntary movements manifested by recurrent attacks of dystonia, chorea, athetosis, or a combination of these disorders. Paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, paroxysmal exertion-induced dyskinesia, and paroxysmal hypnogenic dyskinesia are distinguished clinically by precipitating factors, duration and frequency of attacks, and response to medication. Primary paroxysmal dyskinesias are usually autosomal dominant genetic conditions. Secondary paroxysmal dyskinesias can be the symptoms of different neurologic and medical disorders. This review summarizes the updates on etiology, pathophysiology, genetics, clinical presentation, differential diagnosis, and treatment of paroxysmal dyskinesias and other episodic movement disorders. PMID- 25432724 TI - Diagnosis and treatment of dystonia. AB - The dystonias are a group of disorders characterized by excessive involuntary muscle contractions leading to abnormal postures and/or repetitive movements. A careful assessment of the clinical manifestations is helpful for identifying syndromic patterns that focus diagnostic testing on potential causes. If a cause is identified, specific etiology-based treatments may be available. In most cases, a specific cause cannot be identified, and treatments are based on symptoms. Treatment options include counseling, education, oral medications, botulinum toxin injections, and several surgical procedures. A substantial reduction in symptoms and improved quality of life is achieved in most patients by combining these options. PMID- 25432728 TI - Drug-induced movement disorders. AB - Movement disorders are frequently a result of prescription drugs or of illicit drug use. This article focuses on prescribed drugs but briefly mentions drugs of abuse. The main emphasis is on movement disorders caused by dopamine receptor blocking agents. However, movement disorders caused by other drugs are also briefly discussed. PMID- 25432729 TI - Wilson disease and other neurodegenerations with metal accumulations. AB - Trace elements, such as iron, copper, manganese, and calcium, which are essential constituents necessary for cellular homeostasis, become toxic when present in excess quantities. In this article, we describe disorders arising from endogenous dysregulation of metal homeostasis leading to their tissue accumulation. Although subgroups of these diseases lead to regional brain metal accumulation, mostly in globus pallidus, which is susceptible to accumulate divalent metal ions, other subgroups cause systemic metal accumulation affecting the whole brain, liver, and other parenchymal organs. The latter group comprises Wilson disease, manganese transporter deficiency, and aceruloplasminemia and responds favorably to chelation treatment. PMID- 25432730 TI - Psychogenic movement disorders. AB - Psychogenic movement disorders (PMDs) can present with varied phenomenology that may resemble organic movement disorders. The diagnosis is based on clinical evaluation with a supporting history and classic features on neurologic examination. Ancillary testing, such as imaging and neurophysiologic studies, can provide supplementary information but is not necessary for diagnosis. There is no standard protocol for the treatment of PMDs, but a multidisciplinary approach has been recommended. This review discusses the clinical characteristics of various PMDs as well as ancillary testing, treatment, and research in the pathophysiology of this complex group of disorders. PMID- 25432732 TI - Gait disorders. AB - Gait disorders are frequently accompanied by loss of balance and falls, and are a common cause of disability, particularly among the elderly. In many cases the cause is multifactorial, involving both neurologic and nonneurologic systems. Physical therapy and training, coupled with pharmacologic and surgical therapy, can usually provide some improvement in ambulation, which translates into better quality of life. More research is needed on the mechanisms of gait and its disorders as well as on symptomatic therapies. Better understanding of the pathophysiology of gait disorders should lead to more specific, pathogenesis targeted therapies. PMID- 25432733 TI - Movement disorders in systemic diseases. AB - Movement disorders, classically involving dysfunction of the basal ganglia commonly occur in neurodegenerative and structural brain disorders. At times, however, movement disorders can be the initial manifestation of a systemic disease. In this article we discuss the most common movement disorders which may present in infectious, autoimmune, paraneoplastic, metabolic and endocrine diseases. Management often has to be multidisciplinary involving primary care physicians, neurologists, allied health professionals including nurses, occupational therapists and less frequently neurosurgeons. Recognizing and treating the underlying systemic disease is important in order to improve the neurological symptoms. PMID- 25432734 TI - Movement disorders. PMID- 25432731 TI - Ataxia. AB - Ataxia is a disorder of balance and coordination resulted from dysfunctions involving cerebellum and its afferent and efferent connections. While a variety of disorders can cause secondary ataxias, the list of genetic causes of ataxias is growing longer. Genetic abnormalities may involve mitochondrial dysfunction, oxidative stress, abnormal mechanisms of DNA repair, possible protein misfolding, and abnormalities in cytoskeletal proteins. Few ataxias are fully treatable while hope for efficacious gene therapy and pharmacotherapy is emerging. A discussion of the ataxias is presented here with brief mention of acquired ataxias, and a greater focus on inherited ataxias. PMID- 25432736 TI - Short-latency inhibitory reflex responses to inspiratory loading of the scalene muscles are impaired in spinal cord injury. AB - NEW FINDINGS: What is the central question of this study? The aim was to determine whether the reflex inhibition in the electromyographic activity of scalene muscles in response to inspiratory muscle loading is present in individuals with cervical spinal cord injury and to examine whether the intercostal muscle afferents are critical for genesis of the reflex. What is the main finding and its importance? The lack of reflex inhibition in response to inspiratory loading in individuals with complete cervical spinal cord injury suggests that the reflex critically requires input from intercostal afferents and/or an intact intersegmental neural network. In healthy individuals, transient loading of inspiratory muscles with a brief inspiratory occlusion produces a short-latency inhibitory response (IR) in the electromyographic activity of scalene muscles at ~40 ms, followed by an excitatory response (ER). It has been argued that this reflex plays a protective role in neuromuscular control of the inspiratory muscles and that it is co-ordinated by spinal segmental or supraspinal circuits. In this study, the reflex response to airway occlusion was recorded bilaterally from scalene muscles in 14 subjects and from the right costal diaphragm in seven subjects with spinal cord injury [SCI, C4-C6; American Spinal Injury Association (ASIA) Impairment Scale (AIS) A]. The incidence, latency and size of the reflex were compared with previously published data from able-bodied subjects. Only two subjects with SCI showed an IR, and six subjects had an ER. Latencies to the onset and peak of the IR and ER were 5-50 ms longer than in able-bodied subjects. However, when reflexes were identified, their size in individuals with SCI was similar to that of control subjects. We conclude that afferents from the scalene muscles and diaphragm are insufficient in most subjects with SCI to evoke the usual inhibition to airway occlusion and that input from chest wall afferents below the spinal cord lesion may be important for genesis of the short-latency inhibition in the able-bodied subjects. PMID- 25432735 TI - A case-control study of risk factors for fetal and early neonatal deaths in a tertiary hospital in Kenya. AB - BACKGROUND: It is important to understand the risk factors for fetal and neonatal mortality which is a major contributor to high under five deaths globally. Fetal and neonatal mortality is a sensitive indicator of maternal health in society. This study aimed to examine the risk factors for fetal and early neonatal mortality at the Moi Teaching and Referral Hospital in Kenya. METHODS: This was a case-control study. Cases were fetal and early neonatal deaths (n = 200). The controls were infants born alive immediately preceding and following the cases (n = 400). Bivariate comparisons and multiple logistic regression analyses were undertaken. RESULTS: The odds of having 0-1 antenatal visits relative to 2-3 visits were higher for cases than controls (Adjusted Odds Ratio (AOR) = 4.5; 95% CI: 1.2-16.7; p = 0.03)). There were lower odds among cases of having a doctor rather than a midwife as a birth attendant (AOR = 0.2; 95% CI: 0.1-0.6; p < 0.01). The odds of mothers having Premature Rupture of Membranes (AOR = 4.1; 95% CI: 1.4-12.1; p = 0.01), haemorrhage (AOR = 4.8; 95% CI: 1.1-21.9; p = 0.04) and dystocia (AOR = 3.6; 95% CI: 1.2-10.9; p = 0.02) were higher for the cases compared with the controls. The odds of gestational age less than 37 weeks (AOR = 7.0; 95% CI 2.4-20.4) and above 42 weeks (AOR = 16.2; 95% CI 2.8-92.3) compared to 37-42 weeks, were higher for cases relative to controls (p < 0.01). Cases had higher odds of being born with congenital malformations (AOR = 6.3; 95% CI: 1.2 31.6; p = 0.04) and with Apgar scores of below six at five minutes (AOR = 26.4; 95% CI: 6.1-113.8; p < 0.001). CONCLUSION: Interventions that focus on educating mothers on antenatal attendance, screening, monitoring and management of maternal conditions during the antenatal period should be strengthened. Doctor attendance at each birth and for emergency admissions is important to ensure early neonatal survival and avert potential risk factors for mortality. PMID- 25432737 TI - Peripheral chemoreceptors and cardiorespiratory coupling: a link to sympatho excitation. AB - NEW FINDINGS: What is the topic of this review? Chronic intermittent hypoxia (CIH), as observed in patients with obstructive sleep apnoea, is associated with the development of sympathetically mediated arterial hypertension. Nevertheless, the mechanisms underpinning the augmented sympathetic outflow in CIH still remain under investigation. What advances does it highlight? In this report, I present experimental evidence supporting the hypothesis that changes in the function of the respiratory network and coupling with the sympathetic nervous system may be considered as a novel and relevant mechanism for the increase in baseline sympathetic outflow in animals submitted to CIH. Chronic intermittent hypoxia (CIH) has been identified as a relevant risk factor for the development of enhanced sympathetic outflow and arterial hypertension. Several studies have highlighted the importance of peripheral chemoreceptors for the cardiovascular changes elicited by CIH. However, the effects of CIH on the central mechanisms regulating sympathetic outflow are not fully elucidated. Our research group has explored the hypothesis that the enhanced sympathetic drive following CIH exposure is, at least in part, dependent on alterations in the respiratory network and its interaction with the sympathetic nervous system. In this report, I discuss the changes in the discharge profile of baseline sympathetic activity in rats exposed to CIH, their association with the generation of active expiration and the interactions between expiratory and sympathetic neurones after CIH conditioning. Together, these findings are consistent with the theory that mechanisms of central respiratory-sympathetic coupling are a novel factor in the development of neurogenic hypertension. PMID- 25432740 TI - Indicators as a tool to evaluate waste management efficiency. PMID- 25432738 TI - Expression profiling of circulating tumor cells in metastatic breast cancer. AB - Circulating tumor cells (CTCs) are prognostic in all stages of breast cancer. However, since they are extremely rare, little is known about the molecular nature of these cells. We report a novel strategy for the isolation and expression profiling of pure populations of CTCs derived from peripheral blood. We developed a method to isolate CTCs based on immunomagnetic capture followed by fluorescence-activated cell sorting (IE/FACS). After assay validation using the BT474 cell line spiked into blood samples in vitro, RNA from CTCs isolated from the blood of five metastatic breast cancer (MBC) patients was linearly amplified and subjected to gene expression profiling via cDNA microarrays. We isolated a range of 9-993 captured CTCs from five MBC patients' blood and profiled their RNA in comparison to a diverse panel of primary breast tumors (n = 55). Unsupervised hierarchical clustering revealed that CTC profiles clustered with more aggressive subtypes of primary breast tumors and were readily distinguishable from peripheral blood (PB) and normal epithelium. Differential expression analysis revealed CTCs to have downregulated apoptosis, and they were distinguishable from PB by the relative absence of immune-related signals. As expected, CTCs from MBC had significantly higher risk of recurrence scores than primary tumors (p = 0.0073). This study demonstrates that it is feasible to isolate CTCs from PB with high purity through IE/FACS and profile them via gene expression analysis. Our approach may inform the discovery of therapeutic predictors and be useful for real-time identification of emerging resistance mechanisms in MBC patients. PMID- 25432739 TI - The bacteriological quality of different brands of bottled water available to consumers in Ile-Ife, south-western Nigeria. AB - BACKGROUND: The upsurge in the demand for bottled water has prompted the interest of many manufacturers in the production of bottled water and very many water bottling companies are therefore involved in its production. These range from large scale multinational companies to medium scale business enterprises, institutional and government business investment companies as well as small scale entrepreneurs. There is however little information on the comparative quality of bottled water brands produced by different classes of water bottling companies in Nigeria. This study was undertaken to determine the bacteriological quality of brands of bottled water available to consumers in Ile-Ife. METHODS: Forty-three samples of bottled water comprising of three batches each of thirteen bottled water brands and two batches of two brands were purchased and analyzed for total bacterial count, presence of coliform and the presence of other bacterial indicators of drinking water quality. RESULTS: Only 67.4% of the water samples representing the products of 10 companies or 66.7% of the brands had heterotrophic counts within the acceptable limits. Coliforms present in 100 ml of water were detected in 26.7% of the bottled water brands. Other indicator organisms detected included Staphylococci isolated from 27.9% of the samples (33.3% of the brands) and specifically Staphylococcus aureus found in four brands constituting 14% of the samples. Pseudomonas strains were consistently detected in consecutive batches of three brands of the water samples. CONCLUSIONS: Bottled water samples produced by the large scale multinational producers were of acceptable bacteriological quality unlike those produced by most small companies. SIGNIFICANCE AND IMPACT OF STUDY: There is need for a greater control of water bottling processes carried out by commercial bottled water producers in Nigeria. PMID- 25432741 TI - Hazardous and toxic waste management in Botswana: practices and challenges. AB - Hazardous and toxic waste is a complex waste category because of its inherent chemical and physical characteristics. It demands for environmentally sound technologies and know-how as well as clean technologies that simultaneously manage and dispose it in an environmentally friendly way. Nevertheless, Botswana lacks a system covering all the critical steps from importation to final disposal or processing of hazardous and toxic waste owing to limited follow-up of the sources and types of hazardous and toxic waste, lack of modern and specialised treatment/disposal facilities, technical know-how, technically skilled manpower, funds and capabilities of local institutions to take lead in waste management. Therefore, because of a lack of an integrated system, there are challenges such as lack of cooperation among all the stakeholders about the safe management of hazardous and toxic waste. Furthermore, Botswana does not have a systematic regulatory framework regarding monitoring and hazardous and toxic waste management. In addition to the absence of a systematic regulatory framework, inadequate public awareness and dissemination of information about hazardous and toxic waste management, slower progress to phase-out persistent and bio accumulative waste, and lack of reliable and accurate information on hazardous and toxic waste generation, sources and composition have caused critical challenges to effective hazardous and toxic waste management. It is, therefore, important to examine the status of hazardous and toxic waste as a waste stream in Botswana. By default; this mini-review article presents an overview of the current status of hazardous and toxic waste management and introduces the main challenges in hazardous and toxic waste management. Moreover, the article proposes the best applicable strategies to achieve effective hazardous and toxic waste management in the future. PMID- 25432742 TI - Riboswitch discovery by combining RNA-seq and genome-wide identification of transcriptional start sites. AB - Deep-sequencing technologies applied to RNA have tremendous potential to identify novel transcripts with single-nucleotide resolution. By combining whole transcript cDNA sequencing (RNA-seq) and genome-wide identification of transcription start sites (dRNA-seq), it is possible to characterize long 5' untranslated regions potentially endowed with regulatory capacities and to detect premature termination of transcription. This can be used to identify new potential riboswitches. In this chapter, we provide a detailed protocol of the dRNA-seq method based on differential pretreatment of RNAs with tobacco acid pyrophosphatase to differentiate between 5'-ends of primary and processed RNAs. We also give a briefer protocol of the preparation of RNA-seq libraries and of how to go through data bioinformatics analysis and data visualization using genome browsers. This approach is powerful to identify novel riboswitches and to demonstrate the functionality of riboswitches predicted in silico. PMID- 25432743 TI - Discovering human RNA aptamers by structure-based bioinformatics and genome-based in vitro selection. AB - In vitro selection and structure-based searches have emerged as useful techniques for the discoveries of structurally complex RNAs with high affinity and specificity toward metabolites. Here, we focus on the design of a human genomic library that serves as the DNA template for in vitro selection of RNA aptamers. In addition, the structural solutions obtained from the in vitro selection can be used for structure-based searches for discovery of analogous aptamers in various genomic databases. PMID- 25432744 TI - Affinity purification of in vitro transcribed RNA with homogeneous ends using a 3'-ARiBo tag. AB - Common approaches for purification of RNAs synthesized in vitro by the T7 RNA polymerase often denature the RNA and produce RNAs with chemically heterogeneous 5'- and 3'-ends. Thus, native affinity purification strategies that incorporate 5' and 3' trimming technologies provide a solution to two main disadvantages that arise from standard approaches for RNA purification. This chapter describes procedures for nondenaturing affinity purification of in vitro transcribed RNA using a 3'-ARiBo tag, which yield RNAs with a homogeneous 3'-end. The applicability of the method to RNAs of different sequences, secondary structures, and sizes (29-614 nucleotides) is described, including suggestions for troubleshooting common problems. In addition, this chapter presents three complementary approaches to producing 5'-homogeneity of the affinity-purified RNA: (1) selection of the starting sequence; (2) Cse3 endoribonuclease cleavage of a 5'-CRISPR tag; or (3) self-cleavage of a 5'-hammerhead ribozyme tag. The additional steps to express and purify the Cse3 endonuclease are detailed. In light of recent results, the advantages and limitations of current approaches to achieve 5'-homogeneity of affinity-purified RNA are discussed, such that one can select a suitable strategy to purify the RNA of interest. PMID- 25432745 TI - Deoxyribozyme-mediated ligation for incorporating EPR spin labels and reporter groups into RNA. AB - Preparation of site-specifically labeled RNA for spectroscopic studies is a multistep process and requires handling of delicate samples. This chapter is focused on the synthesis of spin-labeled RNA using convertible nucleosides and the application of the deoxyribozyme 9DB1* for the ligation of RNA fragments. The convertible nucleoside approach enables the attachment of nitroxyls as paramagnetic reporters at the exocyclic amino groups of cytidine, adenosine, and guanosine nucleobases in synthetic RNA. The deoxyribozyme 9DB1* is a synthetic single-stranded DNA with RNA ligase activity that can be used as an alternative to protein enzymes (T4 RNA/DNA ligases) for covalently joining RNA fragments via native 3'-5' phosphodiester bonds. The combination of solid-phase synthesis and DNA-catalyzed RNA ligation provides reliable access to site-specifically labeled functional RNAs for spectroscopic studies. A particular advantage of using deoxyribozymes for RNA ligation lies in the mild reaction conditions that prevent chemical damage to sensitive labels. As an example, we describe a detailed protocol for the synthesis of TEMPO-labeled SAM-I riboswitch RNA. PMID- 25432746 TI - A flexible, scalable method for preparation of homogeneous aminoacylated tRNAs. AB - Transfer RNAs (tRNAs) are cellular courier molecules that decipher the genetic code in messenger RNAs and enable the transfer of appropriate esterified amino acids to the growing peptide chain. The preparation of biophysical quantities of homogeneous aminoacylated tRNAs has remained a significant technical challenge. This is primarily due to the difficulty in removing contaminating nonaminoacylated tRNAs that are have very similar properties overall, as well as the hydrolytic instability of the aminoacyl linkage. We describe a flexible, scalable method to prepare homogeneous aminoacylated tRNAs that is also broadly compatible with mutant, misacylated, or otherwise aberrant tRNAs and other RNAs. This method combines ribozyme-mediated aminoacylation with reversible N pentenoylation of the esterified amino acid, which not only protects against spontaneous deacylation but also provides a hydrophobic purification handle. This protocol makes it straightforward to produce biophysical quantities of natural and unnatural aminoacylated tRNAs and has proven essential for mechanistic investigations of the T-box riboswitches. PMID- 25432747 TI - Synthesis of a biotinylated photocleavable nucleotide monophosphate for the preparation of natively folded RNAs. AB - RNAs are involved in many functional roles in the cell, and this functional diversity is predicated on RNAs adopting requisite three-dimensional architectures. Preparing such "natively folded" RNAs with a homogeneous population is sometimes problematic for structural or enzymatic studies. Yet, standard methods for RNA preparations denature the RNA and create a heterogeneous population of conformers. Therefore, preparation of "natively folded" RNAs without going through the process of denaturing and refolding is important to obtain maximal biological function. Here, we present a simple strategy using "click" chemistry to couple biotin to a "caged" photocleavable (PC) guanosine monophosphate (GMP) in high yield. This biotin-PC-GMP is readily accepted by T7 RNA polymerase to transcribe "natively folded" RNAs ranging in size from 27 to 493 nucleotides. This facile strategy allows efficient biotinylation of RNA and provides a traceless means to remove the biotin after the purification. Such preparation of natively folded RNAs should benefit biophysical and therapeutic applications. PMID- 25432748 TI - Chemo-enzymatic synthesis of selectively 13C/15N-labeled RNA for NMR structural and dynamics studies. AB - RNAs are an important class of cellular regulatory elements, and they are well characterized by X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy in their folded or bound states. However, the apo or unfolded states are more difficult to characterize by either method. Particularly, effective NMR spectroscopy studies of RNAs in the past were hampered by chemical shift overlap of resonances and associated rapid signal loss due to line broadening for RNAs larger than the median size found in the PDB (~25 nt); most functional riboswitches are bigger than this median size. Incorporation of selective site specific (13)C/(15)N-labeled nucleotides into RNAs promises to overcome this NMR size limitation. Unlike previous isotopic enrichment methods such as phosphoramidite, de novo, uniform-labeling, and selective-biomass approaches, this newer chemical-enzymatic selective method presents a number of advantages for producing labeled nucleotides over these other methods. For example, total chemical synthesis of nucleotides, followed by solid-phase synthesis of RNA using phosphoramidite chemistry, while versatile in incorporating isotope labels into RNA at any desired position, faces problems of low yields (<10%) that drop precipitously for oligonucleotides larger than 50 nt. The alternative method of de novo pyrimidine biosynthesis of NTPs is also a robust technique, with modest yields of up to 45%, but it comes at the cost of using 16 enzymes, expensive substrates, and difficulty in making some needed labeling patterns such as selective labeling of the ribose C1' and C5' and the pyrimidine nucleobase C2, C4, C5, or C6. Biomass-produced, uniformly or selectively labeled NTPs offer a third method, but suffer from low overall yield per labeled input metabolite and isotopic scrambling with only modest suppression of (13)C-(13)C couplings. In contrast to these four methods, our current chemo-enzymatic approach overcomes most of these shortcomings and allows for the synthesis of gram quantities of nucleotides with >80% yields while using a limited number of enzymes, six at most. The unavailability of selectively labeled ribose and base precursors had prevented the effective use of this versatile method until now. Recently, we combined an improved organic synthetic approach that selectively places (13)C/(15)N labels in the pyrimidine nucleobase (either (15)N1, (15)N3, (13)C2, (13)C4, (13)C5, or (13)C6 or any combination) with a very efficient enzymatic method to couple ribose with uracil to produce previously unattainable labeling patterns (Alvarado et al., 2014). Herein we provide detailed steps of both our chemo-enzymatic synthesis of custom nucleotides and their incorporation into RNAs with sizes ranging from 29 to 155 nt and showcase the dramatic improvement in spectral quality of reduced crowding and narrow linewidths. Applications of this selective labeling technology should prove valuable in overcoming two major obstacles, chemical shift overlap of resonances and associated rapid signal loss due to line broadening, that have impeded studying the structure and dynamics of large RNAs such as full-length riboswitches larger than the ~25 nt median size of RNA NMR structures found in the PDB. PMID- 25432749 TI - SHAPE analysis of small RNAs and riboswitches. AB - We describe structural analysis of small RNAs by SHAPE chemical probing. RNAs are treated with 1-methyl-7-nitroisatoic anhydride, a reagent that detects local nucleotide flexibility; and N-methylisatoic anhydride and 1-methyl-6-nitroisatoic anhydride, reagents which together detect higher-order and noncanonical interactions. Chemical adducts are quantified as stops during reverse transcriptase-mediated primer extension. Probing information can be used to infer conformational changes and ligand binding and to develop highly accurate models of RNA secondary structures. PMID- 25432751 TI - Crystallographic analysis of TPP riboswitch binding by small-molecule ligands discovered through fragment-based drug discovery approaches. AB - Riboswitches are structured mRNA elements that regulate gene expression in response to metabolite or second-messenger binding and are promising targets for drug discovery. Fragment-based drug discovery methods have identified weakly binding small molecule "fragments" that bind a thiamine pyrophosphate (TPP) riboswitch. However, these fragments require substantial chemical elaboration into more potent, drug-like molecules. Structure determination of the fragments bound to the riboswitch is the necessary next step. In this chapter, we describe the methods for co-crystallization and structure determination of fragment-bound TPP riboswitch structures. We focus on considerations for screening crystallization conditions across multiple crystal forms and provide guidance for building the fragment into the refined crystallographic model. These methods are broadly applicable for crystallographic analyses of any small molecules that bind structured RNAs. PMID- 25432752 TI - Methods for using new conceptual tools and parameters to assess RNA structure by small-angle X-ray scattering. AB - Understanding the biological activities of riboswitches and of RNA in general requires a thorough analysis of both the spatial arrangement of the residues and the dynamics of the structural ensemble. Specifically, evaluating the structural basis for riboswitch function requires analyses of many relevant states that include ligand-bound and -free, high Mg(2+), and quite possibly, the active transcription state, which is challenging to achieve by most methods. Small angle X-ray scattering (SAXS) is an enabling technique for comprehensive analyses of RNA structures in solution. Here, we describe recent SAXS tools and technologies that substantially improve the potential for accurate and comprehensive analyses of flexibility, unstructured elements, conformational selection, and induced fit in RNA function. We note equipment needed plus appropriate annealing and purification procedures. We describe key model-independent parameters (SAXS invariants) which can be used to monitor changes in a particle's thermodynamic state: the Guinier-based Rg, the volume-of-correlation (Vc), the Porod-Debye exponent (P(E)), and the power-law parameter, Q(R), that determines mass directly from the SAXS data. We also consider the value of real-space parameters and of multiphase modeling with MONSA to locate secondary structure elements within SAXS volumetric envelopes. For conformation changes, experiments with nanogold-labeled RNA analyzed using the SAXS structural comparison map and volatility ratio difference metric enable high-throughput evaluation of solution-state conformations. Collectively, the described tools and procedures enable quantitative and comprehensive measures of riboswitch structures with general implications for our views and strategies of RNA structural analysis. PMID- 25432750 TI - Experimental approaches for measuring pKa's in RNA and DNA. AB - RNA and DNA carry out diverse functions in biology including catalysis, splicing, gene regulation, and storage of genetic information. Interest has grown in understanding how nucleic acids perform such sophisticated functions given their limited molecular repertoire. RNA can fold into diverse shapes that often perturb pKa values and allow it to ionize appreciably under biological conditions, thereby extending its molecular diversity. The goal of this chapter is to enable experimental measurement of pKa's in RNA and DNA. A number of experimental methods for measuring pKa values in RNA and DNA have been developed over the last 10 years, including RNA cleavage kinetics; UV-, fluorescence-, and NMR-detected pH titrations; and Raman crystallography. We begin with general considerations for choosing a pKa assay and then describe experimental conditions, advantages, and disadvantages for these assays. Potential pitfalls in measuring a pKa are provided including the presence of apparent pKa's due to a kinetic pKa or coupled acid- and alkali-promoted RNA unfolding, as well as degradation of RNA, precipitation of metal hydroxides and poor baselines. Use of multiple data fitting procedures and the study of appropriate mutants are described as ways to avoid some of these pitfalls. Application of these experimental methods to RNA and DNA will increase the number of available nucleic acid pKa values in the literature, which should deepen insight into biology and provide benchmarks for pKa calculations. Future directions for measuring pKa's in nucleic acids are discussed. PMID- 25432753 TI - Use of 19F NMR methods to probe conformational heterogeneity and dynamics of exchange in functional RNA molecules. AB - Functional RNA molecules are often very plastic and often undergo changes in base pairing patterns to achieve alternative secondary and tertiary conformations associated with their roles in multiple events in gene expression. Solution NMR techniques are an excellent tool for the analysis of conformational heterogeneity and dynamic exchange. In this work, we measure the rates associated with spontaneous interconversion between major conformers in folded RNA sequences by use of a (19)F-(19)F EXSY NMR experiment, taking advantage of RNA samples carrying a single 5-(19)F-pyrimidine label. We first utilize this approach to determine kinetic exchange rates between conformers in a model RNA stem loop capable of adopting two conformations. We then probe the dynamics of conformational rearrangements in a larger RNA construct, the U2-U6 snRNA complex of the human spliceosome. In the case of the U2-U6 snRNA complex, such a rearrangement in the context of the intact spliceosome may have critical implications in splicing activity. PMID- 25432754 TI - Site-directed spin-labeling strategies and electron paramagnetic resonance spectroscopy for large riboswitches. AB - Genetic regulation effected by RNA riboswitches is governed by ligand-induced structural reorganization with modulation of RNA conformation and dynamics. Characterization of the conformational states of riboswitches in the presence or absence of salts and ligands is important for understanding how interconversion of riboswitch RNA folding states influences function. The methodology of site directed spin labeling (SDSL) coupled with electron paramagnetic resonance (EPR) spectroscopy is suitable for such studies, wherein site-specific incorporation of a nitroxide radical spin probe allows for local dynamics and conformational changes to be investigated. This chapter reviews a strategy for SDSL-EPR studies of large riboswitches and uses the full length 232 nucleotide (nt) kink-turn motif-containing Vibrio cholerae (VC) glycine riboswitch as an example. Spin labeling strategies and the challenges of incorporating spin labels into large riboswitches are reviewed and the approach to overcome these challenges is described. Results are subsequently presented illustrating changes in dynamics within the labeled region of the VC glycine riboswitch as observed using SDSL EPR. PMID- 25432755 TI - Using sm-FRET and denaturants to reveal folding landscapes. AB - RNA folding studies aim to clarify the relationship among sequence, tridimensional structure, and biological function. In the last decade, the application of single-molecule fluorescence resonance energy transfer (sm-FRET) techniques to investigate RNA structure and folding has revealed the details of conformational changes and timescale of the process leading to the formation of biologically active RNA structures with subnanometer resolution on millisecond timescales. In this review, we initially summarize the first wave of single molecule FRET-based RNA techniques that focused on analyzing the influence of mono- and divalent metal ions on RNA function, and how these studies have provided very valuable information about folding pathways and the presence of intermediate and low-populated states. Next, we describe a second generation of single-molecule techniques that combine sm-FRET with the use of chemical denaturants as an emerging powerful approach to reveal information about the dynamics and energetics of RNA folding that remains hidden using conventional sm FRET approaches. The main advantages of using the competing interplay between folding agents such as metal ions and denaturants to observe and manipulate the dynamics of RNA folding and RNA-ligand interactions is discussed in the context of the adenine riboswitch aptamer. PMID- 25432757 TI - Ribosome structure and dynamics by smFRET microscopy. AB - Composed of both RNA and protein components, the ribosome is one of the largest macromolecular machines in life responsible for the production of all protein. Interestingly, the major catalytic center of the ribosome (the peptidyl transferase center) and much of the binding regions for both mRNA and tRNA are composed of RNA making the ribosome one of the most complex and widely studied ribozymes. Further, large-scale conformational rearrangements throughout the ribosome are required for proper function making the ribosome a riboswitch as well. Recent advances in single-molecule biophysics have significantly augmented our understanding of ribosome function as both a ribozyme and riboswitch. Here, we discuss single-molecule Forster resonance energy transfer and its application to the study of the ribosome. Also, we describe how these experiments are designed from sample preparation to data acquisition and analysis. The general approach and methods described here can be generally applied to many other biological systems. PMID- 25432758 TI - Unraveling the thermodynamics and kinetics of RNA assembly: surface plasmon resonance, isothermal titration calorimetry, and circular dichroism. AB - The mechanisms and driving forces of the assembly of RNA tertiary structure are a topic of much current interest. In several systems, including our own work in the docking transition of the hairpin ribozyme, intramolecular RNA tertiary folding has been converted into an intermolecular binding event, allowing the full power of contemporary biophysical techniques to be brought to bear on the analysis. We review the use of three such methods: circular dichroism to isolate the binding of multivalent cations coupled to tertiary assembly, surface plasmon resonance to determine the rates of association and dissociation, and isothermal titration calorimetry to dissect the thermodynamic contributions to RNA assembly events. We pay particular attention to practical aspects of these studies, such as careful preparation of samples with fixed free concentrations of cations in order to avoid errors due to ion depletion effects that are common in RNA systems. Examples of applications from our own work with the hairpin ribozyme are shown. Distinctions among the data handling procedures for the various techniques used and solution conditions encountered are also discussed. PMID- 25432756 TI - Riboswitch structure and dynamics by smFRET microscopy. AB - Riboswitches are structured noncoding RNA elements that control the expression of their embedding messenger RNAs by sensing the intracellular concentration of diverse metabolites. As the name suggests, riboswitches are dynamic in nature so that studying their inherent conformational dynamics and ligand-mediated folding is important for understanding their mechanism of action. Single-molecule fluorescence energy transfer (smFRET) microscopy is a powerful and versatile technique for studying the folding pathways and intra- and intermolecular dynamics of biological macromolecules, especially RNA. The ability of smFRET to monitor intramolecular distances and their temporal evolution make it a particularly insightful tool for probing the structure and dynamics of riboswitches. Here, we detail the general steps for using prism-based total internal reflection fluorescence microscopy for smFRET studies of the structure, dynamics, and ligand-binding mechanisms of riboswitches. PMID- 25432759 TI - ITC analysis of ligand binding to preQ1 riboswitches. AB - Riboswitches regulate genes by binding to small-molecule effectors. Isothermal titration calorimetry (ITC) provides a label-free method to quantify the equilibrium association constant, K(A), of a riboswitch interaction with its cognate ligand. In addition to probing affinity and specific chemical contributions that contribute to binding, ITC can be used to measure the thermodynamic parameters of an interaction (DeltaG, DeltaH, and DeltaS), in addition to the binding stoichiometry (N). Here, we describe methods developed to measure the binding affinity of various preQ1 riboswitch classes for the pyrrolopyrimidine effector, preQ1. Example isotherms are provided along with a review of various preQ1-II (class 2) riboswitch mutants that were interrogated by ITC to quantify the energetic contributions of specific interactions visualized in the crystal structure. Protocols for ITC are provided in sufficient detail that the reader can reproduce experiments independently, or develop derivative methods suitable for analyzing novel riboswitch-ligand binding interactions. PMID- 25432760 TI - Facile characterization of aptamer kinetic and equilibrium binding properties using surface plasmon resonance. AB - Nucleic acid aptamers find widespread use as targeting and sensing agents in nature and biotechnology. Their ability to bind an extensive range of molecular targets, including small molecules, proteins, and ions, with high affinity and specificity enables their use in diverse diagnostic, therapeutic, imaging, and gene-regulatory applications. Here, we describe methods for characterizing aptamer kinetic and equilibrium binding properties using a surface plasmon resonance-based platform. This aptamer characterization platform is broadly useful for studying aptamer-ligand interactions, comparing aptamer properties, screening functional aptamers during in vitro selection processes, and prototyping aptamers for integration into nucleic acid devices. PMID- 25432761 TI - The AdoCbl-riboswitch interaction investigated by in-line probing and surface plasmon resonance spectroscopy (SPR). AB - The unique feature of riboswitches is to control selected gene expression by specific recognition of a cognate ligand. AdoCbl (adenosyl cobalamin, coenzyme B12) riboswitches regulate the expression of enzymes and transporters involved in bacterial AdoCbl biosynthesis or uptake on a transcriptional and/or translational level. The analysis of ligand recognition and the induced conformational changes requires a detailed knowledge of the kinetics and thermodynamics of ligand binding and of the secondary structure rearrangements. This chapter describes the investigation of coenzyme B12 binding to the btuB riboswitch from Escherichia coli by in-line probing assays and surface plasmon resonance spectroscopy. The experimental conditions, requirements, and performance of both methods are presented together with the evaluation of the experimental data to determine the associated conformational changes of the RNA and the kinetic and thermodynamic parameters of ligand binding. Owing to the light sensitivity of the cobalt(I)'carbon bond, these methods were specifically modified to ensure the chemical integrity of AdoCbl. PMID- 25432762 TI - Assessing RNA interactions with proteins by DRaCALA. AB - Discovery of RNA elements, including riboswitches and regulatory RNAs, has revealed additional regulatory mechanisms for transcript stability, transcript termination, and translational initiation. These regulatory RNA molecules act through direct binding to cellular targets including other RNA molecules, proteins, and low molecular weight metabolites. RNA-RNA interactions based on complementarity can be identified through bioinformatic analysis. However, identification of novel interactions between these regulatory RNA molecules and their partners other than complementary sequences is more challenging. We have developed a technique called Differential Radial Capillary Action of Ligand Assay (DRaCALA) to facilitate the detection of direct binding between RNA elements to proteins or low molecular weight ligands. Previously, we have described the adaptation of this technique to detect the binding interaction between Vc2 riboswitch to a signaling cyclic dinucleotide called cyclic-di-GMP. Here, we describe the adaptation of DRaCALA for identifying sequence-specific RNA-binding proteins directly from E. coli cell lysates expressing the recombinant binding protein. DRaCALA can be used to qualitatively and quantitatively assess RNA protein interaction in whole cell lysate, determine the kinetics of the binding, and test for competitors. Using DRaCALA in a high-throughput format has the potential to rapidly identify sequence-specific RNA-binding proteins. PMID- 25432763 TI - Methods in Enzymology. Riboswitch discovery, structure and function. Preface. PMID- 25432764 TI - How Academia Is Failing Academic Faculty. PMID- 25432765 TI - Multiple pregnancies, hepatitis C, and risk for hepatocellular carcinoma in Egyptian women. AB - BACKGROUND: The reasons for the worldwide sex disparity in the incidence of hepatocellular carcinoma (HCC) remain elusive. We investigated the role of multiple pregnancies on the associations between viral hepatitis C (HCV) infection and HCC risk among Egyptian women. METHODS: We used data collected from blood specimens and questionnaires administered to female HCC cases and controls in Cairo, Egypt, from 1999 through 2009. HCV infection was defined as being sero positive for either anti-HCV antibodies or HCV-RNA. Using logistic regression models we calculated odds ratios (OR) and 95% confidence intervals (CI) to estimate the associations between being HCV positive and HCC risk, and how it is modified by the number of pregnancies, after adjustment for other factors, including hepatitis B status. RESULTS: Among 132 confirmed female cases and 669 controls, the risk of HCV-related HCC increased with the number of pregnancies. Women infected with HCV had higher risk for HCC if they had more than five pregnancies, as compared to those who had five or fewer pregnancies (adjusted OR (95% CI): 2.33 (1.29-4.22)). The association of HCV infection with HCC risk was significantly greater among the former (21.42 (10.43-44.00)) than among the latter (6.57 (3.04-14.25)). CONCLUSION: Having multiple pregnancies increases the risk of HCV-related HCC among Egyptian women, raising questions about the roles of estrogens and other pregnancy-related hormones in modulating HCV infection and its progression to HCC. PMID- 25432766 TI - Hybrid stage I palliation for hypoplastic left heart syndrome has no advantage on ventricular energetics: a theoretical analysis. AB - A hybrid procedure combining bilateral pulmonary artery banding with ductal stenting has recently been used as stage I palliation for hypoplastic left heart syndrome. However, the advantage of the hybrid procedure over the Norwood procedure on ventricular energetics remains unclear. To clarify this, we performed a computational analysis with a combination of time-varying elastance chamber model and modified three-element Windkessel vascular model. Although mean pulmonary artery (PA) pressure, pulmonary flow, and oxygen saturation were almost equivalent with the Norwood procedure, the hybrid procedure delivered higher systolic and lower diastolic systemic arterial pressures compared to the Norwood procedure with right ventricle (RV) to PA shunt. As a result, the hybrid procedure yielded increased systolic pressure-volume area and impaired mechanical efficiency. Therefore, the hybrid procedure has probably no advantage on ventricular energetics compared to the Norwood procedure with a RV-PA shunt. PMID- 25432767 TI - Analysis of the bone microRNome in osteoporotic fractures. AB - Osteoporosis causes important morbidity among elderly individuals. Fragility fractures, and especially hip fractures, have a particularly negative impact on the patients' quality of life. The role of epigenetic mechanisms in the pathogenesis of many disorders is increasingly recognized, yet little is known about their role in non-malignant bone disorders such as osteoporosis. The aim of this study was to explore the expression of miRNAs in patients with osteoporotic hip fractures. Trabecular bone samples were obtained from the femoral heads of patients undergoing replacement surgery for osteoporotic hip fractures and non fracture controls with hip osteoarthritis. Levels of 760 miRNA were analyzed by real-time PCR. Thirteen miRNAs showed nominally significant (p < 0.05) differences between both groups. Six miRNAs (miR-187, miR-193a-3p, miR-214, miR518f, miR-636, and miR-210) were selected for the replication stage. These miRNAs were individually analyzed in a larger group of 38 bone samples. At this stage, we confirmed statistically significant differences across groups for mir 187 and miR-518f. The median relative expression levels of miR-187 were 5.3-fold higher in the non-fracture group (p = 0.002). On the contrary, miR-518f was preferentially expressed in bones from osteoporotic patients (8.6-fold higher in fractures; p = 0.046). In this first hypothesis-free study of the bone microRNome we found two miRNAs, miR-187, and miR-518f, differentially regulated in osteoporotic bone. Further studies are needed to elucidate the mechanisms involved in the association of these miRNAs with fractures. PMID- 25432769 TI - GP dementia payment scheme will end next year, NHS confirms. PMID- 25432768 TI - Reduced neurons in the ileum of proctocolectomized rat models. AB - Ileal pouch-anal anastomosis (IPAA) is the operation of choice following proctocolectomy for patients who suffer from ulcerative colitis and familial adenomatous polyposis. The aim of this study was to morphologically examine the neurons, endocrine cells and mast cells in the ileum of rats subjected to proctocolectomy followed by three different types of ileoanal anastomosis. Rats were subjected to either sham operation or proctocolectomy followed by ileoanal anastomosis end-to-end, side-to-end or IPAA (J-pouch). In comparison to sham operated rats, the body weight was reduced in rats that underwent proctocolectomy with end-to-end or side-to-end, but not IPAA procedure. In all three models of ileoanal anastomosis, the ileum displayed crypt hyperplasia with a chronic inflammatory infiltrate located in the interstitium, hyperplasia of goblet cells, but reduced protein gene product 9.5 (PGP 9.5)-immunoreactive neurons in the mucosa as well as submucosa. Numbers of endocrine cells in the mucosa (chromogranin A immunostaining) and mast cells in the mucosa and submucosa (Astra blue staining) were unchanged after proctocolectomy. In conclusion, neurons, but neither endocrine cells nor mast cells, were reduced in the ileum of proctocolectomized rats followed by either of three different types of ileoanal anastomosis. PMID- 25432770 TI - The connectome of the basal ganglia. AB - The basal ganglia of the laboratory rat consist of a few core regions that are specifically interconnected by efferents and afferents of the central nervous system. In nearly 800 reports of tract-tracing investigations the connectivity of the basal ganglia is documented. The readout of connectivity data and the collation of all the connections of these reports in a database allows to generate a connectome. The collation, curation and analysis of such a huge amount of connectivity data is a great challenge and has not been performed before (Bohland et al. PloS One 4:e7200, 2009) in large connectomics projects based on meta-analysis of tract-tracing studies. Here, the basal ganglia connectome of the rat has been generated and analyzed using the consistent cross-platform and generic framework neuroVIISAS. Several advances of this connectome meta-study have been made: the collation of laterality data, the network-analysis of connectivity strengths and the assignment of regions to a hierarchically organized terminology. The basal ganglia connectome offers differences in contralateral connectivity of motoric regions in contrast to other regions. A modularity analysis of the weighted and directed connectome produced a specific grouping of regions. This result indicates a correlation of structural and functional subsystems. As a new finding, significant reciprocal connections of specific network motifs in this connectome were detected. All three principal basal ganglia pathways (direct, indirect, hyperdirect) could be determined in the connectome. By identifying these pathways it was found that there exist many further equivalent pathways possessing the same length and mean connectivity weight as the principal pathways. Based on the connectome data it is unknown why an excitation pattern may prefer principal rather than other equivalent pathways. In addition to these new findings the local graph-theoretical features of regions of the connectome have been determined. By performing graph theoretical analyses it turns out that beside the caudate putamen further regions like the mesencephalic reticular formation, amygdaloid complex and ventral tegmental area are important nodes in the basal ganglia connectome. The connectome data of this meta-study of tract-tracing reports of the basal ganglia are available for further network studies, the integration into neocortical connectomes and further extensive investigations of the basal ganglia dynamics in population simulations. PMID- 25432772 TI - Considering structural connectivity in the triple code model of numerical cognition: differential connectivity for magnitude processing and arithmetic facts. AB - The current study provides a generalizable account of the anatomo-functional associations as well as the connectivity of representational codes underlying numerical processing as suggested by the triple code model (TCM) of numerical cognition. By evaluating the neural networks subserving numerical cognition in two specific and substantially different numerical tasks with regard to both grey matter localizations as well as white matter tracts we (1) considered the possibility of additional memory-related cortex areas crucial for arithmetic fact retrieval (e.g., the hippocampus); (2) specified the functional involvement of prefrontal areas in number magnitude processing, and, finally; (3) identified the connections between these anatomo-functional instantiations of the representations involved in number magnitude processing and arithmetic fact retrieval employing probabilistic fiber tracking. The resulting amendments to the TCM are summarized in a schematic update, and ideas concerning the possible functional interplay between number magnitude processing and arithmetic fact retrieval are discussed. PMID- 25432771 TI - White matter maturation profiles through early childhood predict general cognitive ability. AB - Infancy and early childhood are periods of rapid brain development, during which brain structure and function mature alongside evolving cognitive ability. An important neurodevelopmental process during this postnatal period is the maturation of the myelinated white matter, which facilitates rapid communication across neural systems and networks. Though prior brain imaging studies in children (4 years of age and above), adolescents, and adults have consistently linked white matter development with cognitive maturation and intelligence, few studies have examined how these processes are related throughout early development (birth to 4 years of age). Here, we show that the profile of white matter myelination across the first 5 years of life is strongly and specifically related to cognitive ability. Using a longitudinal design, coupled with advanced magnetic resonance imaging, we demonstrate that children with above-average ability show differential trajectories of myelin development compared to average and below average ability children, even when controlling for socioeconomic status, gestation, and birth weight. Specifically, higher ability children exhibit slower but more prolonged early development, resulting in overall increased myelin measures by ~3 years of age. These results provide new insight into the early neuroanatomical correlates of cognitive ability, and suggest an early period of prolonged maturation with associated protracted white matter plasticity may result in strengthened neural networks that can better support later development. Further, these results reinforce the necessity of a longitudinal perspective in investigating typical or suspected atypical cognitive maturation. PMID- 25432774 TI - Erratum to: Centromere sliding on a mammalian chromosome. PMID- 25432773 TI - Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial. AB - SUMMARY: Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. INTRODUCTION: Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. METHODS: The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score<=-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score<=-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. RESULTS: Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. CONCLUSIONS: This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants. PMID- 25432775 TI - Pre-treatment serum total bilirubin level as an indicator of optimal CPT-11 dosage. AB - BACKGROUND: Irinotecan (CPT-11), a highly effective chemotherapeutic agent, can cause severe neutropenia and diarrhea. The area under the curve of plasma levels over time of SN-38, an active metabolite of CPT-11, was previously reported to correlate with the pre-treatment serum total bilirubin level (PTB). However, there are no established criteria for selecting CPT-11 dose on the basis of PTB. Therefore, we evaluated PTB as an indicator for the optimal CPT-11 dose. METHODS: Retrospective analyses were conducted in patients administered CPT-11 as a single agent at the Osaka National Hospital from June 2006 to July 2013. Data obtained during the first 28 days following CPT-11 administration were analyzed to compare PTB between patients with and without grade 3-4 neutropenia and grade 3-4 diarrhea. Receiver operating characteristics (ROC) curve analysis was performed to determine the optimal PTB cutoff value for PTB-associated toxicity. Subgroup analysis was performed comparing the incidence of toxicity in patients with PTB values below or above the cutoff value. RESULTS: Although PTB incidence was significantly higher in patients who developed grade 3-4 neutropenia than in those who did not, PTB was not associated with grade 3-4 diarrhea. The PTB cutoff value for association with grade 3-4 neutropenia occurrence was set at 0.8 mg/dL. The incidence of febrile neutropenia (FN) significantly elevated to 21% in patients with PTB >=0.8 mg/dL, whereas that of patients with PTB <0.8 mg/dL was 4%. In the subgroup analysis, no difference was found in the neutropenia incidence between patients treated with a dose below 80 mg/m(2) and those treated on a weekly schedule. CONCLUSIONS: PTB can be used as a predictive marker of CPT 11-induced severe neutropenia and FN. In patients with PTB >=0.8 mg/dL, the CPT 11 dose should be reduced to less than 80 mg/m(2) with weekly dosing. PMID- 25432778 TI - Analyses of outcomes of one-stage operation for treatment of late-diagnosed developmental dislocation of the hip: 864 hips followed for 3.2 to 8.9 years. AB - BACKGROUND: The one-stage procedure for treatment of older developmental dislocation of the hip (DDH) is used widely. However, the best age group for this operation is still unknown. The aims of our study were to evaluate middle-term outcomes of one-stage surgical treatment of a large number of patients with late diagnosed DDH, and to explore the best age group for treatment. METHODS: We retrospectively reviewed 652 patients with a total of 864 hip joints with DDH, all aged >18 months. All the hip joints were treated with one-stage procedures including open reduction, pelvic osteotomy, and femoral shortening. The patients were divided into three groups according to age at surgery: Group I: 1.5-2.5 years; Group II: 2.5-8 years; and Group III: >8 years. The latest clinical and radiographic outcomes, complications and avascular necrosis (AVN) of the femoral head were evaluated and compared among the three groups. RESULTS: The mean age at surgery was 5.8 years (range: 1.5-13.2 years). The average time of follow-up was 6.2 years (range: 3.2-8.9 years). A total of 79.4% of good or excellent outcomes were obtained for clinical functional evaluation according to the McKay classification. For radiographic outcomes, 732 hips (84.7%) were classified as good or excellent according to the Severin classification. A total of 27.4% of all hips had a poor outcome according to the Kalamchi and MacEwen classification for AVN. The poorest outcomes were observed for clinical, radiographic and AVN results in Group III (p < 0.001). Compared with Group I, the better results for clinical and AVN outcomes were found in Group II (p < 0.001). However, similar clinical outcomes were observed between Groups I and II (p > 0.05). A significantly higher incidence of redislocation and residual acetabular dysplasia was observed in Tonnis grade II and III hip dislocation (p < 0.001). CONCLUSIONS: One-stage treatment of late-diagnosed DDH had a good outcome in young and middle group. Younger patients achieved better results than older patients. However, the best age group was 2.5-8 years. Tonnis grade II and III DDH is a risk factor for redislocation and residual acetabular dysplasia after the one-stage operation. PMID- 25432776 TI - Natural genetic variation impacts expression levels of coding, non-coding, and antisense transcripts in fission yeast. AB - Our current understanding of how natural genetic variation affects gene expression beyond well-annotated coding genes is still limited. The use of deep sequencing technologies for the study of expression quantitative trait loci (eQTLs) has the potential to close this gap. Here, we generated the first recombinant strain library for fission yeast and conducted an RNA-seq-based QTL study of the coding, non-coding, and antisense transcriptomes. We show that the frequency of distal effects (trans-eQTLs) greatly exceeds the number of local effects (cis-eQTLs) and that non-coding RNAs are as likely to be affected by eQTLs as protein-coding RNAs. We identified a genetic variation of swc5 that modifies the levels of 871 RNAs, with effects on both sense and antisense transcription, and show that this effect most likely goes through a compromised deposition of the histone variant H2A.Z. The strains, methods, and datasets generated here provide a rich resource for future studies. PMID- 25432779 TI - Comment on: "Zoo or savannah? Choice of training ground for evidence-based pharmacovigilance". PMID- 25432777 TI - Potential of fecal microbiota for early-stage detection of colorectal cancer. AB - Several bacterial species have been implicated in the development of colorectal carcinoma (CRC), but CRC-associated changes of fecal microbiota and their potential for cancer screening remain to be explored. Here, we used metagenomic sequencing of fecal samples to identify taxonomic markers that distinguished CRC patients from tumor-free controls in a study population of 156 participants. Accuracy of metagenomic CRC detection was similar to the standard fecal occult blood test (FOBT) and when both approaches were combined, sensitivity improved > 45% relative to the FOBT, while maintaining its specificity. Accuracy of metagenomic CRC detection did not differ significantly between early- and late stage cancer and could be validated in independent patient and control populations (N = 335) from different countries. CRC-associated changes in the fecal microbiome at least partially reflected microbial community composition at the tumor itself, indicating that observed gene pool differences may reveal tumor related host-microbe interactions. Indeed, we deduced a metabolic shift from fiber degradation in controls to utilization of host carbohydrates and amino acids in CRC patients, accompanied by an increase of lipopolysaccharide metabolism. PMID- 25432780 TI - Authors' reply to Harpaz et al. comment on: "Zoo or savannah? Choice of training ground for evidence-based pharmacovigilance". PMID- 25432782 TI - An independent validation of the Global Anti-Phospholipid Syndrome Score in a Japanese cohort of patients with autoimmune diseases. PMID- 25432781 TI - Increased Syk phosphorylation leads to overexpression of TRAF6 in peripheral B cells of patients with systemic lupus erythematosus. AB - OBJECTIVE: Activation of B cells is a hallmark of systemic lupus erythematosus (SLE). Syk and TRAF6 are key signaling molecules in B-cell activation through BCR and CD40/TLR, respectively. Nevertheless, whether expression of Syk and TRAF6 is altered in SLE B cells remains unknown. METHODS: Phosphorylation and/or expression of Syk and TRAF6 were analyzed by flow cytometry in peripheral blood mononuclear cells isolated from SLE patients. RESULTS: Pronounced phosphorylation and expression of Syk were noted in B cells from SLE patients compared with healthy donors. Levels of Syk phosphorylation correlated with the disease activity score. TRAF6 was significantly over-expressed in B cells of SLE patients as compared with healthy donors, and significant correlation of levels of TRAF6 expression and Syk phosphorylation was observed in SLE patients. Levels of TRAF6 expression were more pronounced in CD27+ memory B cells than in CD27-naive B cells. In vitro treatment of SLE B cells with a Syk inhibitor (BAY61-3606) reduced Syk phosphorylation as well as TRAF6 expression. CONCLUSION: Our results suggest that the activated Syk-mediated TRAF6 pathway leads to aberrant activation of B cells in SLE, and also highlight Syk as a potential target for B cell-mediated processes in SLE. PMID- 25432783 TI - 2015 NSGC Presidential Address: Gifts of genetic counselors: life's leadership lessons. PMID- 25432784 TI - Prognostic impact of 18F-FDG PET/CT staging and of pathological response to neoadjuvant chemotherapy in triple-negative breast cancer. AB - PURPOSE: Mortality is high in patients with locally advanced triple-negative breast cancer (TNBC), especially in those with residual tumour after neoadjuvant chemotherapy (NAC). The aim of this study was to determine if pretreatment (18)F FDG PET/CT staging and pathological findings after NAC could together allow stratification of patients into prognostic groups. METHODS: Initial staging with (18)F-FDG PET/CT was performed prospectively in 85 consecutive patients with stage II/III TNBC. Correlations between PET findings and disease-specific survival (DSS) were examined. In patients without distant metastases on PET staging, the impact of pathological response to NAC on DSS was examined. Patterns of recurrence were also analysed. RESULTS: (18)F-DG PET/CT revealed distant metastases in 11 of 85 patients (12.9 %). Among 74 M0 patients, 23 (31.1 %) showed a pathological complete response (pCR) at surgery, while 51 had residual invasive disease (no pCR). DSS differed considerably among the three groups of patients (log-rank P < .001): among patients with occult metastases on baseline PET/CT, 2-year DSS was 18.2 %, and among patients without initial metastases on PET/CT, 5-year DSS was 61.3 % in patients without pCR after NAC and 95.2 % in those with pCR. Of the 51 patients who did not achieve pCR, 21 relapsed (17 developed distant metastases). The sites of distant recurrence were: lung/pleura (nine patients), brain (eight patients), liver (six patients), distant lymph nodes (six patients) and bone (five patients). CONCLUSION: In patients with clinical stage II/III TNBC, (18)F-FDG PET/CT findings at initial staging and pathological response at the end of NAC allow three groups of patients with quite different prognoses to be defined. Extraskeletal recurrences predominated. Specific follow-up strategies in patients with TNBC who do not achieve pCR deserve investigation. PMID- 25432785 TI - [On the history of the German Democratic Republic Journal Psychiatry, Neurology and Medical Psychology (1949-1990)]. AB - Scientific journals were established in the Soviet occupied zone following WWII in order to distinguish themselves from the other occupying powers. Starting in 1949 a journal with the title "Psychiatry, Neurology and Medical Psychology" was founded as no publishing house existed in the field of psychiatry and neurology and it became necessary to establish a new journal that was competitive. The journal was primarily distributed in the German Democratic Republic (GDR) until 1990 but the interest internationally was very limited. State affairs had a great influence from the very beginning so that the political involvement was reflected in the selection of staff, such as the publishers and the head of the editorial department and by the close interconnection between the Society for Psychiatry and Neurology of the GDR and the editorship of the journal. The publishers who were primarily responsible and the authors were at the interface of politics and science. Nevertheless, in an international comparison many parallels can be found in the orientation with respect to the content. PMID- 25432786 TI - Human amnion mesenchymal stem cells promote proliferation and osteogenic differentiation in human bone marrow mesenchymal stem cells. AB - Human amnion mesenchymal stem cells (HAMSCs) can be obtained from human amniotic membrane, a highly abundant and readily available tissue. HAMSC sources present fewer ethical issues, have low immunogenicity, anti-inflammatory properties, considerable advantageous characteristics, and are considered an attractive potential treatment material in the field of regenerative medicine. We used a co culture system to determine whether HAMSCs could promote osteogenesis in human bone marrow mesenchymal stem cells (HBMSCs). We isolated HAMSCs from discarded amnion samples and collected them using pancreatin/collagenase digestion. We cultured HAMSCs and HBMSCSs in basal medium. Activity of alkaline phosphatase (ALP), an early osteogenesis marker, was increased in the co-culture system compared to the control single cultures, which we also confirmed by ALP staining. We used immunofluorescence testing to investigate the effects of co-culturing with HAMSCs on HBMSC proliferation, which revealed that the co-culturing enhanced EdU expression in HBMSCs. Western blotting and quantitative real-time PCR indicated that co-culturing promoted osteogenesis in HBMSCs. Furthermore, Alizarin red S staining revealed that extracellular matrix calcium levels in mineralized nodule formation produced by the co-cultures were higher than that in the controls. Using the same co-culture system, we further observed the effects of HAMSCs on osteogenic differentiation in primary osteoblasts by Western blotting, which better addressed the mechanism for HAMSCs in bone regeneration. The results showed HAMSCs are osteogenic and not only play a role in promoting HBMSC proliferation and osteogenic differentiation but also in osteoblasts, laying the foundation for new regenerative medicine methods. PMID- 25432787 TI - Health care costs attributable to overweight calculated in a standardized way for three European countries. AB - This article presents a tool to calculate health care costs attributable to overweight in a comparable and standardized way. The purpose is to describe the methodological principles of the tool and to put it into use by calculating and comparing the costs attributable to overweight for The Netherlands, Germany and Czech Republic. The tool uses a top-down and prevalence-based approach, consisting of five steps. Step one identifies overweight-related diseases and age and gender-specific relative risks. Included diseases are ischemic heart disease, stroke, hypertension, type 2 diabetes mellitus, colorectal cancer, postmenopausal breast cancer, endometrial cancer, kidney cancer and osteoarthritis. Step two consists of collecting data on the age- and gender specific prevalence of these diseases. Step three uses the population attributable prevalence to determine the part of the prevalence of these diseases that is attributable to overweight. Step four calculates the health care costs associated with these diseases. Step five calculates the costs of these diseases that are attributable to overweight. Overweight is responsible for 20-26% of the direct costs of included diseases, with sensitivity analyses varying this percentage between 15-31%. Percentage of costs attributable to obesity and preobesity is about the same. Diseases with the highest percentage of costs due to overweight are diabetes, endometrial cancer and osteoarthritis. Disease costs attributable to overweight as a percentage of total health care expenditures range from 2 to 4%. Data are consistent for all three countries, resulting in roughly a quarter of costs of included diseases being attributable to overweight. PMID- 25432788 TI - Afatinib versus placebo as adjuvant therapy after chemoradiation in a double blind, phase III study (LUX-Head & Neck 2) in patients with primary unresected, clinically intermediate-to-high-risk head and neck cancer: study protocol for a randomized controlled trial. AB - BACKGROUND: Over 50% of patients with head and neck squamous cell carcinoma (HNSCC) present with locoregionally advanced disease. Those at intermediate-to high risk of recurrence after definitive therapy exhibit advanced disease based on tumour size or lymph node involvement, non-oropharynx primary sites, human papillomavirus (HPV)-negative oropharyngeal cancer, or HPV-positive oropharynx cancer with smoking history (>10-pack-years). Non-surgical approaches include concurrent chemoradiotherapy, induction chemotherapy followed by definitive radiotherapy or chemoradiotherapy, or radiotherapy alone. Following locoregional therapies (including surgical salvage of residual cervical nodes), no standard intervention exists. Overexpression of epidermal growth factor receptor (EGFR), an ErbB family member, is associated with poor prognosis in HNSCC. EGFR-targeted cetuximab is the only targeted therapy that impacts overall survival and is approved for HNSCC in the USA or Europe. However, resistance often occurs, and new approaches, such as targeting multiple ErbB family members, may be required. Afatinib, an irreversible ErbB family blocker, demonstrated antiproliferative activity in preclinical models and comparable clinical efficacy with cetuximab in a randomized phase II trial in recurrent or metastatic HNSCC. LUX-Head & Neck 2, a phase III study, will assess adjuvant afatinib versus placebo following chemoradiotherapy in primary unresected locoregionally advanced intermediate-to high-risk HNSCC. METHODS/DESIGN: Patients with primary unresected locoregionally advanced HNSCC, in good clinical condition with unfavourable risk of recurrence, and no evidence of disease after chemoradiotherapy will be randomized 2:1 to oral once-daily afatinib (40 mg starting dose) or placebo. As HPV status will not be determined for eligibility, unfavourable risk is defined as non-oropharynx primary site or oropharynx cancer in patients with a smoking history (>10 pack years). Treatment will continue for 18 months or until recurrence or unacceptable adverse events occur. The primary endpoint measure is duration of disease-free survival; secondary endpoint measures are disease-free survival rate at 2 years, overall survival, health-related quality of life and safety. DISCUSSION: Given the unmet need in the adjuvant treatment of intermediate-to-high-risk HNSCC patients, it is expected that LUX-Head & Neck 2 will provide new insights into treatment in this setting and might demonstrate the ability of afatinib to significantly improve disease-free survival, compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov NCT01345669. PMID- 25432790 TI - Prospects of oral disease control in the future - an opinion. AB - The mouth supports a diverse microbiota which provides major benefits to the host. On occasions, this symbiotic relationship breaks down (dysbiosis), and disease can be a consequence. We argue that progress in the control of oral diseases will depend on a paradigm shift away from approaches that have proved successful in medicine for many diseases with a specific microbial aetiology. Factors that drive dysbiosis in the mouth should be identified and, where possible, negated, reduced or removed, while antimicrobial agents delivered by oral care products may function effectively, even at sub-lethal concentrations, by modulating the activity and growth of potentially pathogenic bacteria. In this way, the beneficial activities of the resident oral microbiota will be retained and the risk of dysbiosis occurring will be reduced. PMID- 25432789 TI - Overexpression of folate biosynthesis genes in rice (Oryza sativa L.) and evaluation of their impact on seed folate content. AB - Folate (vitamin B9) deficiency is a global health problem especially in developing countries where the major staple foods such as rice contain extremely low folates. Biofortification of rice could be an alternative complement way to fight folate deficiency. In this study, we evaluated the availability of the genes in each step of folate biosynthesis pathway for rice folate enhancement in the japonica variety kitaake genetic background. The first enzymes GTP cyclohydrolase I (GTPCHI) and aminodeoxychorismate synthase (ADCS) in the pterin and para-aminobenzoate branches resulted in significant increase in seed folate content, respectively (P < 0.01). Overexpression of two closely related enzymes dihydrofolate synthase (DHFS) and folypolyglutamate synthase (FPGS), which perform the first and further additions of glutamates, produced slightly increase in seed folate content separately. The GTPCHI transgene was combined with each of the other transgenes except ADCS to investigate the effects of gene stacking on seed folate accumulation. Seed folate contents in the gene-stacked plants were higher than the individual low-folate transgenic parents, but lower than the high folate GTPCHI transgenic lines, pointing to an inadequate supply of para aminobenzoic acid (PABA) precursor initiated by ADCS in constraining folate overproduction in gene-stacked plants. PMID- 25432792 TI - In planta production of flock house virus transencapsidated RNA and its potential use as a vaccine. AB - We have developed a transencapsidated vaccine delivery system based on the insect virus, Flock House virus (FHV). FHV is attractive due to its small genome size, simple organization, and nonpathogenic characteristics. With the insertion of a Tobacco mosaic virus (TMV) origin of assembly (Oa), the independently replicating FHV RNA1 can be transencapsidated by TMV coat protein. In this study, we demonstrated that the Oa-adapted FHV RNA1 transencapsidation process can take place in planta, by using a bipartite plant expression vector system, where TMV coat protein is expressed by another plant virus vector, Foxtail mosaic virus (FoMV). Dual infection in the same cell by both FHV and FoMV was observed. Though an apparent classical coat protein-mediated resistance repressed FHV expression, this was overcome by delaying inoculation of the TMV coat protein vector by 3 days after FHV vector inoculation. Expression of the transgene marker in animals by these in vivo-generated transencapsidated nanoparticles was confirmed by mouse vaccination, which also showed an improved vaccine response compared to similar in vitro-produced vaccines. PMID- 25432793 TI - Cloning and characterization of an inulinase gene from the marine yeast Candida membranifaciens subsp. flavinogenie W14-3 and its expression in Saccharomyces sp. W0 for ethanol production. AB - The INU1 gene encoding an exo-inulinase from the marine-derived yeast Candida membranifaciens subsp. flavinogenie W14-3 was cloned and characterized. It had an open reading frame of 1,536 bp long encoding an inulinase. The coding region of it was not interrupted by any intron. The cloned gene encoded 512 amino acid residues of a protein with a putative signal peptide of 23 amino acids and a calculated molecular mass of 57.8 kDa. The protein sequence deduced from the inulinase gene contained the inulinase consensus sequences (WMNDPNGL), (RDP), ECP FS and Q. The protein also had six conserved putative N-glycosylation sites. The deduced inulinase from the yeast strain W14-3 was found to be closely related to that from Candida kutaonensis sp. nov. KRF1, Kluyveromyces marxianus, and Cryptococcus aureus G7a. The inulinase gene with its signal peptide encoding sequence was subcloned into the pMIRSC11 expression vector and expressed in Saccharomyces sp. W0. The recombinant yeast strain W14-3-INU-112 obtained could produce 16.8 U/ml of inulinase activity and 12.5 % (v/v) ethanol from 250 g/l of inulin within 168 h. The monosaccharides were detected after the hydrolysis of inulin with the crude inulinase (the yeast culture). All the results indicated that the cloned gene and the recombinant yeast strain W14-3-INU-112 had potential applications in biotechnology. PMID- 25432794 TI - Solitary fibrous tumor - clinicopathologic, immunohistochemical and molecular analysis of 28 cases. AB - BACKGROUND: Solitary fibrous tumor is a mesenchymal tumor of fibroblastic type, which can affect any region of the body. Recently, a recurrent gene fusion NAB2 STAT6 has been identified as molecular hallmark. The NAB2-STAT6 fusion leads to EGR1 activation and transcriptional deregulation of EGR1-dependent target genes and is a driving event in initiation of SFT. In this study, we report the clinicopathologic and RT-PCR findings and evaluated expression of STAT6 and EGR1 protein in a cohort of 28 SFTs. METHODS: 28 patients with a median age of 54 years were included with SFTs originating at different sites, most occurring in the lung and pleura (9, 32%), 5 in soft tissues of the lower extremities (18%) and 5 in the head and neck (18%). For detection of the NAB2-STAT6 fusion gene, RT PCR was performed using RNA extracted from formalin-fixed and paraffin-embedded tissues. Immunohistochemistry was performed on all cases with antibodies against STAT6 and EGR1. RESULTS: All patients were treated by surgery, 3 with adjuvant chemo- or radiotherapy. Follow-up data of 18 patients could be obtained of which 2 patients died of metastatic disease 13 months and 52 years after first diagnosis. Sixteen patients have no evidence of disease with a median follow up of 29.5 months (range 7 - 120 months). NAB2-STAT6 fusion transcripts were found in 19/28 cases (68%). The most common fusion was between NAB2 exon 4 and STAT6 exon 3 (11/19, 58%), mainly occurring in pleuropulmonary lesions. All cases showed strong nuclear expression of STAT6 (28/28, 100%) while EGR1 showed low level variable nuclear expression in all samples, comparable with the EGR1 expression results of the control group. CONCLUSIONS: The identification of the NAB2-STAT6 fusion in SFTs can provide important diagnostic information, especially in cases with aberrant morphology or when biopsy material is limited. STAT6 immunohistochemistry is another useful tool in diagnosing SFT. EGR1 immunohistochemistry indicates low-level protein expression in accordance with EGR1 activation due to distorted NAB2 activity. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_224. PMID- 25432796 TI - Role of apparent diffusion coefficients with diffusion-weighted magnetic resonance imaging in differentiating between benign and malignant bone tumors. AB - BACKGROUND: Benign and malignant bone tumors can present similar imaging features. This study aims to evaluate the significance of apparent diffusion coefficients (ADC) in differentiating between benign and malignant bone tumors. METHODS: A total of 187 patients with 198 bone masses underwent diffusion weighted (DW) magnetic resonance (MR) imaging. The ADC values in the solid components of the bone masses were assessed. Statistical differences between the mean ADC values in the different tumor types were determined by Student's t-test. RESULTS: Histological analysis showed that 84/198 (42.4%) of the bone masses were benign and 114/198 (57.6%) were malignant. There was a significant difference between the mean ADC values in the benign and malignant bone lesions (P<0.05). However, no significant difference was found in the mean ADC value between non ossifying fibromas, osteofibrous dysplasia, and malignant bone tumors. When an ADC cutoff value>=1.10*10(-3) mm2/s was applied, malignant bone lesions were excluded with a sensitivity of 89.7%, a specificity of 84.5%, a positive predictive value of 82.6%, and a negative predictive value of 95.3%. CONCLUSIONS: The combination of DW imaging with ADC quantification and T2-weighted signal characteristics of the solid components in lesions can facilitate differentiation between benign and malignant bone tumors. PMID- 25432795 TI - Instrument development and validation of the stroke pre-hospital delay behavior intention scale in a Chinese urban population. AB - BACKGROUND: Several stroke impairment scales are currently available for stroke patients but none of them provide information regarding the pre-stroke behavioral intentions of high-risk stroke patients and their relatives. This study's objective was to generate and validate a new written tool, the Stroke Pre hospital Delay Behavior Intention (SPDBI) scale. It is suitable for use with high risk stroke patients and their relatives to predict the likelihood of pre hospital delay. METHODS: From a review of related studies, we formulated a prototype scale. We interviewed ten stroke patients in a semi-structured iterative process that included interviews with experts, high-risk patients, and their family members. Then, we pretested and filtered items. We next used a large sample size and factor analysis to determine the scale's structure. Finally, we checked the reliability and validity of the scale. RESULTS: We identified five sub-domains (stroke warning signs, non-treatment justification, symptom attributions, habitual response style, and emergency system use). The SPDBI demonstrated good internal consistency and test-retest reliability (Cronbach's alpha =0.808; Intraclass Correlation Coefficient [ICC] =0.797). CONCLUSIONS: This SPDBI scale is a reliable, and valid measure of the likeliness of pre-hospital delay in high-risk stroke patients and their family members. It may provide scientific assessment for targeted health education intervention. PMID- 25432797 TI - Prevalence of diabetes in Zimbabwe: a systematic review with meta-analysis. AB - OBJECTIVE: Diabetes appears to be a growing problem in the African region. This study aims to estimate the prevalence of diabetes in Zimbabwe by collating and analyzing previously published data. METHODS: Systematic review and meta-analysis of data reporting prevalence of diabetes in Zimbabwe was conducted based on the random effects model. We searched for studies published between January 1960 and December 2013 using MEDLINE, EMBASE and Scopus and University of Zimbabwe electronic publication libraries. In the meta-analysis, sub-groups were created for studies conducted before 1980 and after 1980, to understand the potential effect of independence on prevalence. RESULTS: Seven studies were included in the meta-analysis with a total of 29,514 study participants. The overall pooled prevalence of diabetes before 1980 was 0.44% (95% CI 0.0-1.9%), after 1980 the pooled prevalence was 5.7% (95% CI 3.3-8.6%). CONCLUSIONS: This study showed that the prevalence of diabetes in Zimbabwe has increased significantly over the past three decades. This poses serious challenges to the provision of care and prevention of disabling co-morbidities in an already disadvantaged healthcare setting. PMID- 25432800 TI - Testing the sexual imagination hypothesis for gender differences in response to infidelity. AB - BACKGROUND: Evolutionary psychologists hypothesized that men are more upset by sexual infidelity than women are, whereas women are more upset by emotional infidelity than men are. On the other hand, the sexual imagination hypothesis states that gender differences in infidelity responses are derived from explicit men's sexual imagery. Based on the latter hypothesis, we hypothesized that although men would report being more distressed by sexual infidelity than women who were not in a committed relationship (NCR), no gender difference would be reported in a committed relationship (CR). FINDINGS: These two hypotheses were tested with 598 participants in a CR and 1,643 participants in a NCR. No significant gender difference was found sexual infidelity response in the CR group (d=0.008, a power of .956), whereas men were more upset than women about sexual infidelity in the NCR group. Moreover, a significant interaction between gender and infidelity type was found in the NCR, whereas no significant interaction between gender and infidelity type was observed in the CR group (partial eta2=0.005, a power of .943). CONCLUSIONS: Our findings supported the sexual imagination hypothesis but were inconsistent with the EJM hypothesis. PMID- 25432799 TI - ContextD: an algorithm to identify contextual properties of medical terms in a Dutch clinical corpus. AB - BACKGROUND: In order to extract meaningful information from electronic medical records, such as signs and symptoms, diagnoses, and treatments, it is important to take into account the contextual properties of the identified information: negation, temporality, and experiencer. Most work on automatic identification of these contextual properties has been done on English clinical text. This study presents ContextD, an adaptation of the English ConText algorithm to the Dutch language, and a Dutch clinical corpus. We created a Dutch clinical corpus containing four types of anonymized clinical documents: entries from general practitioners, specialists' letters, radiology reports, and discharge letters. Using a Dutch list of medical terms extracted from the Unified Medical Language System, we identified medical terms in the corpus with exact matching. The identified terms were annotated for negation, temporality, and experiencer properties. To adapt the ConText algorithm, we translated English trigger terms to Dutch and added several general and document specific enhancements, such as negation rules for general practitioners' entries and a regular expression based temporality module. RESULTS: The ContextD algorithm utilized 41 unique triggers to identify the contextual properties in the clinical corpus. For the negation property, the algorithm obtained an F-score from 87% to 93% for the different document types. For the experiencer property, the F-score was 99% to 100%. For the historical and hypothetical values of the temporality property, F-scores ranged from 26% to 54% and from 13% to 44%, respectively. CONCLUSIONS: The ContextD showed good performance in identifying negation and experiencer property values across all Dutch clinical document types. Accurate identification of the temporality property proved to be difficult and requires further work. The anonymized and annotated Dutch clinical corpus can serve as a useful resource for further algorithm development. PMID- 25432798 TI - Years worked at night and body mass index among registered nurses from eighteen public hospitals in Rio de Janeiro, Brazil. AB - BACKGROUND: Employees working night shifts are at a greater risk of being overweight or obese. Few studies on obesity and weight gain analyze the years of exposure to night work. The aim of this study was to determine the relationship between the years of exposure to night work and body mass index (BMI) among registered nurses. METHODS: A cross-sectional analysis was performed in 18 largest public hospitals in Rio de Janeiro, Brazil. A total of 2,372 registered nurses (2,100 women) completed a comprehensive questionnaire concerning sociodemographic, professional, lifestyle, and health behavioral data. Current and past exposures to night shifts as well as BMI values were measured as continuous variables. A gamma regression model was used with an identity link function to establish the association. RESULTS: The association between years of exposure to night work and BMI was statistically significant for both women and men after adjusting for all covariates [beta = 0.036; CI95% = 0.009-0.063) and beta = 0.071 (CI95% = 0.012-0.129), respectively]. The effect of night work was greater among men than women. For example, for those women who have worked at night for 20 years the estimated average BMI was 25.6 kg/m2 [range, 25.0-26.2]. In relation to men, after 20 years of exposure to night work the estimated average BMI was 26.9 kg/m2 [range, 25.6-28.1]. CONCLUSIONS: These findings suggest that night shift exposure is related to BMI increases. Obesity prevention strategies should incorporate improvements in work environments, such as the provision of proper meals to night workers, in addition to educational programs on the health effects of night work. PMID- 25432801 TI - Transcriptional response of Saccharomyces cerevisiae to potassium starvation. AB - BACKGROUND: Ion homeostasis is essential for every cell and aberrant cation homeostasis is related to diseases like Alzheimer's disease and epilepsy. The mechanisms responsible for cation homeostasis are only partly understood. The yeast Saccharomyces cerevisiae is an excellent organism to study fundamental aspects of cation homeostasis. In this study we investigated the transcriptional response of this yeast to potassium starvation by using Serial Analysis of Gene Expression (SAGE)-tag sequencing. RESULTS: Comparison of transcript levels in cells grown for 60 min in media without potassium with those in cells grown under standard potassium concentrations showed that the mRNA levels of 105 genes were significantly (P < 0.01) up-regulated more than 2.0-fold during potassium starvation and the mRNA levels of 172 genes significantly down-regulated. These genes belong to several functional categories. Genes involved in stress response including HSP30, YRO2 and TPO2 and phosphate metabolism including PHO84, PHO5 and SPL2 were highly up-regulated. Analysis of the promoter of PHO84 encoding a high affinity phosphate transporter, revealed that increased PHO84 RNA levels are caused by both increased Pho4-dependent transcription and decreased RNA turnover. In the latter process antisense transcription may be involved. Many genes involved in cell cycle control, and to a lesser extent genes involved in amino acid transport, were strongly down-regulated. CONCLUSIONS: Our study showed that yeast cells respond to potassium starvation in a complex way and reveals a direct link between potassium homeostasis and phosphate metabolism. PMID- 25432803 TI - "Woodpecker" in the heart: unusual case of spontaneous chordae rupture of the mitral valve. PMID- 25432804 TI - Leprosy--an intriguing disease. PMID- 25432805 TI - Lepra: various etiologies from miasma to bacteriology and genetics. AB - Leprosy is a chronic infectious disease caused by a close relative of Mycobacterium tuberculosis: Mycobacterium leprae. There have been various beliefs in its etiology with two main concepts emerging: anticontagion and contagion. From ancient times through the early Middle Ages, the miasmatic theory of leprosy was the main anticontagion view. The development of histopathologic and cytologic studies in the second half of the 19th century provided a starting point to explain the etiology of leprosy bacteriologically. PMID- 25432802 TI - Physical activity and depressive symptoms after stillbirth: informing future interventions. AB - BACKGROUND: In the United States, approximately one in 110 pregnancies end in stillbirth affecting more than 26,000 women annually. Women experiencing stillbirth have a threefold greater risk of developing depressive symptoms compared to women experiencing live birth. Depression contributes negatively to health outcomes for both mothers and babies subsequent to stillbirth. Physical activity may improve depression in these women, however, little is known about acceptable physical activity interventions for women after stillbirth. This is the purpose of this descriptive exploratory study. METHODS: Eligible women were between ages 19 and 45, and experienced stillbirth within one year of the study. An online survey was used to ask questions related to 1) pregnancy and family information (i.e., time since stillbirth, weight gain during pregnancy, number of other children) 2) physical activity participation, 3) depressive symptomatology, and 4) demographics. RESULTS: One hundred seventy-five women participated in the study (M age = 31.26 +/- 5.52). Women reported participating in regular physical activity (at least 150 minutes of moderate activity weekly) before (60%) and during (47%) their pregnancy, as well as after their stillbirth (61%). Only 37% were currently meeting physical activity recommendations. Approximately 88% reported depression (i.e., score of >10 on depression scale). When asked how women cope with depression, anxiety, or grief, 38% said physical activity. Of those that reported using physical activity to cope after stillbirth, they did so to help with depression (58%), weight loss (55%), and better overall physical health (52%). To cope with stillbirth, women used walking (67%), followed by jogging (35%), and yoga (23%). Women who participated in physical activity after stillbirth reported significantly lower depressive symptoms (M = 15.10, SD = 5.32) compared to women who did not participate in physical activity (M = 18.06, SD = 5.57; t = -3.45, p = .001). CONCLUSIONS: Physical activity may serve as a unique opportunity to help women cope with the multiple mental sequelae after stillbirth. This study provides data to inform healthcare providers about the potential role of physical activity in bereavement and recovery for women who have experienced stillbirth. Additional research is necessary in this vulnerable population. PMID- 25432806 TI - Leprosy: a glossary. AB - Leprosy continues to afflict residents from a number of countries in Africa, South America, and southeast Asia, despite the marked reduction in the number of cases of leprosy worldwide, after the introduction of the multidrug regimens as recommended by the World Health Organization (WHO-MDT). With the increasing immigration of individuals from risk areas to Europe and the United States, knowledge of the basic concepts of leprosy would be helpful to clinicians caring for immigrants in nonendemic areas. We present a comprehensive, updated, and critical glossary of the most relevant terms related to leprosy. PMID- 25432807 TI - Protecting people against leprosy: chemoprophylaxis and immunoprophylaxis. AB - Elimination of leprosy cannot be achieved by multidrug therapy alone, and new tools are needed to prevent leprosy. A randomized controlled trial with chemoprophylaxis for contacts of leprosy patients using a single dose of rifampicin (SDR) has shown an overall protective effect of approximately 60%, effective in the first 2 years after the intervention. When a contact who previously received bacillus Calmette-Guerin (BCG) vaccination also receives SDR, the protective effect is additive, approximating 80%. Vaccine trials have been conducted with BCG, often in combination with Mycobacterium leprae or related Mycobacterium vaccines as immunoprophylaxis for contacts of leprosy patients, with BCG giving the best results. Meta-analysis shows that the protective effect of BCG vaccination is larger in observational studies than in trials, 60% versus 41%, and is higher among contacts of leprosy patients than among the general population, 68% versus 53%. We believe that a future leprosy control strategy should include contact management, consisting of a contact survey, at which time preventive interventions could be added, such as chemoprophylaxis and immunoprophylaxis. Modeling studies have shown that both interventions will lower the incidence of leprosy in the population. Implementation studies of such contact-based strategy are now called for. PMID- 25432808 TI - Clinical aspects of leprosy. AB - Leprosy is a chronic, infectious disease caused by Mycobacterium leprae. It mainly affects the peripheral nervous system, skin, and certain other tissues such as the reticulo-endothelial system, bones and joints, mucous membranes, eyes, testes, muscles, and adrenals. Leprosy clinical presentation varies from few to widespread lesions. In most patients, early leprosy presents as macular and hypopigmented lesions. This initial clinical presentation is known as indeterminate leprosy and occurs in individuals who have not developed cell mediated immunity against M. leprae yet. The number of lesions depends on the genetically determined cellular immunity of the patient. Individuals presenting a vigorous cellular immune response and limited humoral immune responses to M. leprae, usually present few skin lesions. Without treatment, those patients tend to evolve into the polar tuberculoid or borderline tuberculoid form of leprosy. Due to the inability to mount an effective cellular-mediated response to M. leprae and the consequent hematogenous spread of the bacilli, some patients may present with numerous and symmetrically distributed hypochromic lesions. Without treatment these patients evolve to a nonresistant form of leprosy, polar lepromatous. PMID- 25432809 TI - Histopathology of the lepromatous skin biopsy. AB - The histopathology of lepromatous skin varies according to the cell-mediated immunity of the host against Mycobacterium leprae. In tuberculoid and borderline tuberculoid leprosy, epithelioid noncaseating granulomas predominate, and acid fast bacilli (AFB) are absent or only rarely present. In borderline lepromatous and lepromatous leprosy, the infiltrate is composed of macrophages with a vacuolar cytoplasm, lymphocytes, and plasma cells. AFB are numerous. Edema inside and outside the epithelioid granulomas, together with the appearance of large giant cells, are the main features of type 1 reactions. A conspicuous neutrophilic infiltrate in the subcutis with or without vasculitis is found in erythema nodosum leprosum. The main histopathologic features of leprosy and its particular forms are discussed in this review. PMID- 25432810 TI - Mechanisms of nerve injury in leprosy. AB - All patients with leprosy have some degree of nerve involvement. Perineural inflammation is the histopathologic hallmark of leprosy, and this localization may reflect a vascular route of entry of Mycobacterium leprae into nerves. Once inside nerves, M. leprae are ingested by Schwann cells, with a wide array of consequences. Axonal atrophy may occur early in this process; ultimately, affected nerves undergo segmental demyelination. Knowledge of the mechanisms of nerve injury in leprosy has been greatly limited by the minimal opportunities to study affected nerves in man. The nine-banded armadillo provides the only animal model of the pathogenesis of M. leprae infection. New tools available for this model enable the study and correlation of events occurring in epidermal nerve fibers, dermal nerves, and nerve trunks, including neurophysiologic parameters, bacterial load, and changes in gene transcription in both neural and inflammatory cells. The armadillo model is likely to enhance understanding of the mechanisms of nerve injury in leprosy and offers a means of testing proposed interventions. PMID- 25432811 TI - Treatment of leprosy. AB - Leprosy is a curable disease, having been eliminated from many countries, including India. This has been possible due to the wide availability of effective and safe drugs. Treatment of leprosy has undergone considerable changes over decades, from chaulmoogra oil in 1915 to dapsone monotherapy in 1946, then eventually to multidrug therapy (MDT) in 1982. In the last two decades, reports of resistance to all first-line drugs have appeared in the literature, with the need to conduct clinical trials using newer but highly bactericidal drugs and their combinations against Mycobacterium leprae. PMID- 25432812 TI - Lucio's leprosy: a clinical and therapeutic challenge. AB - Leprosy has been a challenge in different areas of medicine; in underdeveloped countries it remains a public health problem, in which the social and economic problems facilitate the disease persistence. The diagnosis and consequently the treatment are delayed due to the clinical polymorphism of leprosy, which especially at the beginning the manifestations are not as evident, as is the case of diffuse lepromatous leprosy. This favors the disabilities and the development of the reaction episodes. Fortunately, reaction episodes have decreased with the use of multidrug therapy, and better control of the type 2 reactions has been managed with the use of thalidomide, as in Lucio's phenomenon. PMID- 25432813 TI - Ocular leprosy. AB - Ocular involvement in leprosy is estimated to be 70-75%, about 10-50% of leprosy patients suffer from severe ocular symptoms, and blindness occurs in about 5% of patients. The disease leads to many ophthalmologic symptoms and signs in the range of the eyeball itself, as well as of the bulb adnexa, ie, eyebrows, eyelids with eyelashes, and lacrimal drainage system. Especially dangerous are complications of lagophthalmos and corneal hypoanesthesia, neurotrophic or infectious keratitis, and iridocyclitis and cataract formation, which may lead to significant decrease of visual acuity or even blindness. Multidrug treatment rapidly interrupts transmission of Mycobacterium leprae by infectious patients, but even after being completed, it does not guarantee the withholding of ocular complications. PMID- 25432814 TI - Immunology of leprosy and diagnostic challenges. AB - Leprosy, caused by noncultivable Mycobacterium leprae (ML), has varied manifestations, which are associated with the host immune responses. The dermal involvement is accompanied by peripheral nerve damage, which leads to sensory motor loss and deformities. Both innate and acquired immune responses are involved. The main cell to be compromised is the CD4 + T helper cell, which shows antigen specific unresponsiveness to only ML and not to other common antigens in the bacilliferous generalized lepromatous form of the disease. In contrast, the paucibacillary localized tuberculoid form shows appropriate T cell functions and poor antibody response. The dichotomy between T cell functions and antibodies are discussed against the current information on cytokines, Th subsets, and regulatory T cells. During lepromatous reactions, there is a temporary, heightened T cell immunity, even in lepromatous subjects. The dermal lesions confirm many features observed with peripheral blood mononuclear cells and give additional information on local immune responses. Nerve damage involves both immune and nonimmune mechanisms. Leprosy is a model disease for understanding host immune responses to intracellular bacilli. There are challenges in diagnosing early leprosy. In spite of intensive efforts by many groups, consensus on a universal test suitable for endemic areas is awaited. PMID- 25432815 TI - Genetics of leprosy: expected and unexpected developments and perspectives. AB - A solid body of evidence produced over decades of intense research supports the hypothesis that leprosy phenotypes are largely dependent on the genetic characteristics of the host. The early evidence of a major gene effect controlling susceptibility to leprosy came from studies of familial aggregation, twins, and Complex Segregation Analysis. Later, linkage and association analysis, first applied to the investigation of candidate genes and chromosomal regions and more recently, to genome-wide scans, have revealed several leukocyte antigen complex and nonleukocyte antigen complex gene variants as risk factors for leprosy phenotypes such as disease per se, its clinical forms and leprosy reactions. In addition, powerful, hypothesis-free strategies such as Genome-Wide Association Studies have led to an exciting, unexpected development: Leprosy susceptibility genes seem to be shared with Crohn's and Parkinson's diseases. Today, a major challenge is to find the exact variants causing the biological effect underlying the genetic associations. New technologies, such as Next Generation Sequencing that allows, for the first time, the cost and time effective sequencing of a complete human genome, hold the promise to reveal such variants. Strategies can be developed to study the functional effect of these variants in the context of infection, hopefully leading to the development of new targets for leprosy treatment and prevention. PMID- 25432816 TI - The armadillo as an animal model and reservoir host for Mycobacterium leprae. AB - Apart from humans, armadillos are the only known natural hosts of Mycobacterium leprae. They are well developed as hosts for in vivo propagation of M leprae and are advancing as models for studying the pathogenesis of leprosy and translational research. Armadillos are immunologically intact. They exhibit the full Ridley-Jopling spectrum of histopathologic responses to M leprae and uniquely manifest extensive neurological involvement that closely recapitulates human leprosy. In addition, free-ranging armadillos in some regions are known to harbor a naturally occurring infection with M leprae, and zoonotic transmission between armadillos and humans has been implicated in a large number of new case presentations. We review the role of the armadillo as a model for leprosy and reservoir for human infection. PMID- 25432817 TI - Struck by lightning: Lichtenberg figures on a 19th-century wax model. AB - Wax models in dermatology were used to a large extent until the 1930s as three dimensional models to illustrate various pathologic conditions and in particular cutaneous signs of disease. As an example, a young woman who was struck by lightning and developed Lichtenberg figures is presented. Lichtenberg figures are a fernlike pattern on skin, characteristic of lightning. Such a wax model housed in the German Hygiene Museum Dresden, Germany, illustrates the significance of wax models and how, even today, they can play an important role in medical education. PMID- 25432819 TI - Memorial for Chris Heyns, M.D., Ph.D., F.C.S.S.A. PMID- 25432820 TI - Dietary habits may influence oxalate degradation by intestinal bacteria commentary on: the role of Oxalobacter formigenes colonization in calcium oxalate stone disease. PMID- 25432818 TI - 3D-image-guided HDR-brachytherapy versus 2D HDR - brachytherapy after external beam radiotherapy for early T-stage nasopharyngeal carcinoma. AB - BACKGROUND: Two-dimensional high-dose-rate brachytherapy (2D-HDR-BT) is an effective method of dose escalation for local tumor control in early T-stage nasopharyngeal carcinoma (NPC). Treatment outcomes for 3D-image-guided high-dose rate brachytherapy (3D-image-guided-HDR-BT) after external beam radiotherapy (ERT) have not been examined in early T-stage NPC patients. The current study was designed to evaluate whether addition of 3D-HDR-BT to ERT showed further improvement in treatment outcomes in patients with early T-stage NPC when compared to 2D-HDR-BT after ERT. METHODS: The current study retrospectively analyzed and compared treatment outcomes for patients with nonmetastatic stage T1 2b NPC treated with 2D-HDR-BT (n =101) or 3D-HDR-BT (n =118) after ERT. Patients in both groups were treated with ERT at a mean dose of 60 Gy and a brachytherapy dose of 12Gy (8 ~ 20Gy), 2.5 ~ 5Gy per fraction under local anesthesia. RESULTS: Compared to patients treated with 2D-HDR-BT after ERT, patients treated with 3D HDR-BT after ERT showed improvement in five-year actuarial local control survival rates (p = 0.024), local/regional relapse-free survival rates (p = 0.038), and disease-free survival rates (p = 0.021). Multivariate analysis showed that NPC patients treated with 3D-HDR-BT had improved local control survival (p = 0.042). The incidence rates of acute or chronic complications were similar between two groups. CONCLUSIONS: The current study showed that 3D-image-guided HDR-BT after ERT was an effective treatment modality for patients with stage T1-2 NPC with acceptable complications. The improvement in local tumor control and disease free survival is likely due to improved conformal dose distributions. PMID- 25432821 TI - The truth about laser fiber diameters. AB - OBJECTIVE: To measure the various diameters of laser fibers from various manufacturers and compare them with the advertised diameter. METHODS: Fourteen different unused laser fibers from 6 leading manufacturers with advertised diameters of 200, 270, 272, 273, 365, and 400 MUm were measured by light microscopy. The outer diameter (including the fiber coating, cladding, and core), cladding diameter (including the cladding and the fiber core), and core diameter were measured. Industry representatives of the manufacturers were interviewed about the diameter of their fibers. RESULTS: For all fibers, the outer and cladding diameters differed significantly from the advertised diameter (P <.00001). The outer diameter, which is of most practical relevance for urologists, exhibited a median increase of 87.3% (range, 50.7%-116.7%). The outer, cladding, and core diameters of fibers with equivalent advertised diameters differed by up to 180, 100, and 78 MUm, respectively. Some 200-MUm fibers had larger outer diameters than the 270- to 273-MUm fibers. All packaging material and all laser fibers lacked clear and precise fiber diameter information labels. Of 12 representatives interviewed, 8, 3, and 1 considered the advertised diameter to be the outer, the cladding, and the core diameter, respectively. Representatives within the same company frequently gave different answers. CONCLUSION: This study suggests that, at present, there is a lack of uniformity between laser fiber manufacturers, and most of the information conveyed to urologists regarding laser fiber diameter may be incorrect. Because fibers larger than the advertised laser fibers are known to influence key interventional parameters, this misinformation can have surgical repercussions. PMID- 25432822 TI - Completely intracorporeal robotic-assisted laparoscopic augmentation enterocystoplasty with continent catheterizable channel. AB - OBJECTIVE: To report our results from series of robotic-assisted laparoscopic augmentation enterocystoplasty (RALAE) performed in a completely intracorporeal fashion. METHODS: Patients who underwent RALAE with or without the creation of a catheterizable channel between 2006 and 2011 at the University of Texas, Houston and Northwestern Memorial Hospital were identified. Perioperative and follow-up data were analyzed. Preoperative and postoperative urodynamic data were analyzed when available. RESULTS: Twenty-two patients with neurogenic bladder underwent RALAE with or without the creation of a catheterizable channel. Fifteen patients underwent robotic augmentation enterocystoplasty alone, and 7 patients had creation of a catheterizable channel (4 Monti and 3 Mitrofanoff). There was 1 conversion to an open procedure in a patient undergoing concomitant creation of an appendicovesicostomy. Mean follow-up was 38.9 months (range, 6.2-72.1 months). Mean operative time was 365 minutes (range, 220-788 minutes); mean estimated blood loss was 110 mL (range, 30-250 mL). Median time to return of bowel function was 5 days (range, 2-17 days). Preoperative and postoperative urodynamic data were available for 13 patients. Mean cystometric capacity increased by 52%, and mean maximal bladder pressures decreased by 40. There were 5 minor complications (Clavien grade 1-2) and 4 major complications (Clavien grade 3-4). No patient experienced a wound infection. CONCLUSION: RALAE is a feasible approach that provides potential benefits over open bladder reconstruction in the neurogenic voiding dysfunction population. PMID- 25432824 TI - Editorial comment. PMID- 25432823 TI - Changes in adjuvant therapy utilization in stage I seminoma: are they enough to prevent overtreatment? AB - OBJECTIVE: To determine if utilization of surveillance or adjuvant chemotherapy has increased compared with that of adjuvant radiotherapy (ART) in clinical stage I seminoma (CSIS) and to estimate the impact of this utilization trend on secondary malignancies. METHODS: The National Cancer Data Base, a web-based data analysis tool was examined for first-course adjuvant therapy management in CSIS from 2000 to 2008. We assessed the utilization in academic vs community practice settings and changes in tumor stage. We also estimated the number of secondary malignancies based on the change in practice. RESULTS: There were 52,672 patients of testicular cancer diagnosed. Of those, 28,974 (55.0%) patients had seminoma with 22,210 (84.2%) patients classified as CSIS. Overall, 14,005 (65.4%), 6430 (30.1%), and 951 (4.4%) patients received ART, surveillance, and adjuvant chemotherapy (AC), respectively. In 2000, most patients received ART (71.7%), followed by surveillance (26.5%), and AC (1.9%). In 2008, the majority of patients still received ART (47.7%) but surveillance (39.6%) and AC (12.6%) totaled a larger proportion. We calculated that this ART utilization rate would lead to an additional 372 solid tumor cases per year, 40 years later, whereas the current surveillance rate would lead to 34 cases of secondary malignancy annually in the United States. CONCLUSION: ART was the leading adjuvant management strategy for CSIS, but its share drastically decreased with a concomitant increase in surveillance and AC, particularly after 2004. These trends were similar in both academic and community settings. The current level of ART, although decreasing, may nevertheless lead to additional cases of solid cancer comparable with testicular cancer deaths. PMID- 25432825 TI - Testicular sperm aspiration for nonazoospermic men: sperm retrieval and intracytoplasmic sperm injection outcomes. AB - OBJECTIVE: To evaluate testicular sperm aspiration (TESA) sperm retrieval rates and intracytoplasmic sperm injection outcomes in nonazoospermic men. MATERIALS AND METHODS: Data were collected retrospectively from 54 consecutive, nonazoospermic, infertile men who underwent TESA between March 2007 and September 2012. Sperm retrieval rates and clinical pregnancy outcomes were recorded. Patients were subgrouped based on clinical diagnosis: group 1, anejaculation (primary, situational); group 2, idiopathic severe oligoasthenozoospermia; and group 3, severe oligoasthenozoospermia after vasovasostomy. RESULTS: Mean (+/- standard deviation) paternal and maternal ages were 39 +/- 7 and 35 +/- 5 years, respectively. Using TESA, sperm recovery was successful in 94% (51 of 54) of the men overall and in 100% (17 of 17) of the men in group 1, 90% (28 of 31) in group 2, and 100% (6 of 6) in group 3. Overall, 35% of the couples achieved a clinical pregnancy using TESA sperm (with a mean of 1.7 +/- 0.9 embryos transferred per cycle). The clinical pregnancy rates were 40% in group 1, 33% in group 2, and 33% in group 3 with no significant difference in paternal or maternal age between groups. CONCLUSION: The data indicate that TESA yields high sperm retrieval rates in select groups of nonazoospermic infertile men, and this approach results in acceptable pregnancy rates regardless of the male infertility etiology. Randomized controlled trials comparing ejaculated vs testicular sperm are needed to assess the true benefit of TESA-intracytoplasmic sperm injection in these couples. PMID- 25432826 TI - Seminal Helicobacter pylori treatment improves sperm motility in infertile asthenozoospermic men. AB - OBJECTIVE: To assess the effect of treatment of seminal Helicobacter pylori in infertile asthenozoospermic men. METHODS: In all, 223 infertile asthenozoospermic men were consecutively selected. They were subjected to history taking, clinical examination, semen analysis, and estimation of H pylori IgA antibodies in their seminal fluid. Infertile men with high seminal H pylori IgA were subjected to triple drug treatment, omeprazole, 20 mg; tinidazole, 500 mg; and clarithromycin, 250 mg twice a day for 2 weeks. Semen analysis as well as H pylori IgA antibodies was estimated after 3 months. RESULTS: In all, 22 of 223 men (9.87%) demonstrated H pylori IgA antibodies in their seminal plasma. After treatment, mean seminal H pylori IgA levels demonstrated significant decrease (1.55 +/- 0.4 vs 0.52 +/- 0.26; 95% confidence interval, 0.83-1.21; P = .001) concomitant with improved progressive as well as nonprogressive sperm motility. H pylori IgA antibodies demonstrated significant negative correlation with progressive sperm motility, nonprogressive sperm motility, normal sperm morphology, and significant positive correlation with immotile sperm motility. CONCLUSION: H pylori treatment significantly improves sperm motility in infertile asthenozoospermic men with elevated seminal H pylori IgA. PMID- 25432827 TI - Objective assessment of residual nerve tissues in radical prostatectomy specimens by immunohistochemical staining of neuronal nitric oxide synthase-positive nerves and its impact on postoperative erectile function. AB - OBJECTIVE: To compare the quality of surgical management of the neurovascular bundle (NVB) by assessment of neuronal nitric oxide synthase (nNOS)-positive nerves in surgical specimens between open retropubic radical prostatectomy (RP; ORRP) and robot-assisted RP (RARP). METHODS: This study included 65 (99 sides, NVB resection; 31 sides, NVB preservation) and 83 (106 sides, NVB resection; 60 sides, NVB preservation) patients undergoing ORRP and RARP, respectively. The posterior sectors from the apex, mid, and base areas on each side were immunohistochemically stained with an nNOS antibody. RESULTS: On the sides with NVB resection, there were no significant differences in the numbers of nNOS positive nerves in any areas between the ORRP and RARP groups; however, on the sides with NVB preservation, the numbers of nNOS-positive nerves in the ORRP group were significantly higher than those in the RARP group at the apex (84.4 vs 59.2; P = .0028), mid (71.2 vs 52.4; P = .016), and base (148.0 vs 40.8; P <.001) areas. In 55 patients who were judged not to have severe erectile dysfunction before surgery and subsequently underwent nerve-sparing RP, there was a significantly inverse correlation between the total number of nNOS-positive nerves on both sides and the postoperative erectile function. CONCLUSION: These findings suggest that RARP might be suitable for performing precise nerve-sparing surgery compared with ORPP, particularly in the base area of the prostate and that the quantification of nNOS-positive nerves in surgical specimens could be a useful approach for predicting the postoperative erectile function. PMID- 25432828 TI - Editorial comment. PMID- 25432829 TI - Comparison of warm and cold ischemia on renal function after partial nephrectomy. AB - OBJECTIVE: To assess renal functional deterioration after partial nephrectomy with warm and cold ischemia using (99m)Tc-mercaptoacetyltriglycine ((99m)Tc-MAG3) renal scintigraphy parameters. METHODS: Open partial nephrectomy was performed in 59 patients with warm ischemia and 64 patients with cold ischemia. (99m)Tc-MAG3 renal scintigraphy was performed and effective renal plasma flow was calculated to evaluate split renal function. In addition, regional (99m)Tc-MAG3 uptake was analyzed in the surgically unaffected parts to evaluate ischemic damage. RESULTS: The mean tumor size in the warm and cold ischemia groups was 2.9 and 3.2 cm, respectively, and the mean ischemic time was 24.2 minutes (range, 8-46 minutes) and 26.7 min (range, 8-58 minutes), respectively. One week after surgery, effective renal plasma flow in the operated kidney decreased to 66.2% (from 160.2 to 105.4 mL/min/1.73 m(2)) in the warm ischemia group and to 77.4% (from 152.3 to 116.6 mL/min/1.73 m(2)) in the cold ischemia group. Regional (99m)Tc-MAG3 uptake changed to 89.2% of baseline in the warm ischemia group and 101.5% of baseline in the cold ischemia group. When the ischemic time was >= 25 minutes, regional (99m)Tc-MAG3 uptake in the warm ischemia group did not recover to the baseline level at 6 months. Multiple regression analyses demonstrated a significant correlation between ischemic time and the decrease in regional (99m)Tc-MAG3 uptake in the warm ischemia group, but not in the cold ischemia group. CONCLUSION: Warm ischemia for >= 25 minutes caused long lasting diffuse damage throughout the operated kidney, whereas cold ischemia for up to 58 minutes prevented ischemic injury to the renal remnant. PMID- 25432830 TI - Editorial comment. PMID- 25432831 TI - Reply: To PMID 25432829. PMID- 25432832 TI - NADiA ProsVue prostate-specific antigen slope, CAPRA-S, and prostate cancer- specific survival after radical prostatectomy. AB - OBJECTIVE: To assess whether NADiA ProsVue prostate-specific antigen slope, a prognostic biomarker for identifying men at a reduced risk of clinically recurrent prostate cancer after radical prostatectomy, is prognostic for prostate cancer--specific mortality (PCSM) and other outcomes. MATERIALS AND METHODS: We examined long-term outcome in the cohort of 304 men selected for the ProsVue 510(k) clinical trial. We assessed the prognostic value of a ProsVue result <= 2.0 pg/mL/mo and pathologic risk stratified by the Cancer of the Prostate Risk Assessment Postsurgical nomogram for a reduced risk of prostate cancer--specific survival. We also assessed its value for predicting clinical outcome in men given salvage treatment for biochemical recurrence. Efficacy was assessed using univariate and multivariate Cox regression and the Kaplan-Meier analyses. RESULTS: Median (interquartile range) overall survival for the groups of men with a ProsVue slope result <= 2.0 and >2.0 pg/mL/mo were 11.0 (9.4-12.9) and 9.2 (4.9 11.6) years, respectively. The ProsVue univariate hazard ratio (95% confidence interval) for PCSM was 20.6 (6.8-62.7), with P <.0001 for a ProsVue result >2.0 pg/mL/mo vs a result <= 2.0 pg/mL/mo. The multivariate hazard ratio of ProsVue adjusted by Cancer of the Prostate Risk Assessment Postsurgical nomogram remained significant (16.7 [4.7-58.6]; P <.0001). The inverse of the hazard ratio translates to a 94.0% risk reduction for PCSM for men with a ProsVue result <= 2.0 pg/mL/mo. Salvage treatment for biochemical recurrence did not significantly reduce the hazard of clinical recurrence or PCSM; however, this is based on only 18 events. CONCLUSION: A NADiA ProsVue slope result <= 2.0 pg/mL/mo was prognostic for a reduced risk of PCSM in men after radical prostatectomy. PMID- 25432833 TI - Editorial comment. PMID- 25432834 TI - Reply: To PMID 25432832. PMID- 25432836 TI - Editorial comment. PMID- 25432837 TI - Is the striated urethral sphincter at risk by standard suture ligation of the dorsal vascular complex in radical prostatectomy? An anatomic study. AB - OBJECTIVE: To perform an anatomic study of the dorsal vascular complex (DVC) and the underlying striated sphincter (SS) to investigate if the SS might be harmed by standard suture ligation in radical prostatectomy. METHODS: Transverse wholemount serial sections were created from adult male autopsy cadavers. The total surface area of the DVC and the SS were measured at the prostatic apex and 5 mm distal to it using the ImageJ software. The dorsal boundary of the DVC and the ventral border of the SS were defined digitally. The percentage of the surface area of the SS that would be entrapped by a ligation stitch including the entire DVC was then calculated. In addition, 3-dimensional reconstruction of the lower urinary tract was performed using the SURFdriver software. RESULTS: Five adult male cadavers were investigated. The mean surface area of the SS was 116.1 +/- 80.7 and 78.0 +/- 63.3 mm(2) at the apex and 5 mm distal to it, respectively. On average, 36.7% (42.6 +/- 41.4 mm(2)) and 29.9% (23.3 +/- 13.6 mm(2)) of the surface area of the SS were located ventral to the lower boundary of the DVC at the apex and 5 mm distal to it, respectively, and would thus be entrapped by standard suture ligation. CONCLUSION: Our anatomic findings suggest that standard suture ligation of the DVC is associated with the risk of affecting sphincter tissue. Our study is in accordance with recent clinical studies showing improved early postoperative continence rates by primary transection of the DVC followed by selective suture ligation. PMID- 25432835 TI - Racial disparities in oncologic outcomes after radical prostatectomy: long-term follow-up. AB - OBJECTIVE: To report race-based outcomes after radical prostatectomy (RP) in a cohort stratified by National Comprehensive Cancer Network (NCCN) risk category with updated follow-up. MATERIALS AND METHODS: Studies describing racial disparities in outcomes after RP are conflicting. We studied 15,993 white and 1634 African American (AA) pretreatment-naive men who underwent RP at our institution (1992-2013) with complete preoperative and pathologic data. Pathologic outcomes were compared between races using appropriate statistical tests; biochemical recurrence (BCR) for men with complete follow-up was compared using multivariate models that controlled separately for preoperative and postoperative covariates. RESULTS: Very low- and low-risk AA men were more likely to have positive surgical margins (P <.01), adverse pathologic features (P <.01), and be upgraded at RP (P <.01). With a median follow-up of 4.0 years after RP, AA race was an independent predictor of BCR among NCCN low-risk (HR, 2.16; P <.001) and intermediate-risk (hazard ratio [HR], 1.34; P = .024) classes and pathologic Gleason score <= 6 (HR, 2.42; P <.001) and Gleason score 7 (HR, 1.71; P <.001). BCR-free survival for very low-risk AA men was similar to low-risk white men (P = .890); BCR-free survival for low-risk AA men was similar to intermediate-risk white men (P = .060). CONCLUSION: When stratified by NCCN risk, AA men with very low-, low-, or intermediate-risk prostate cancer who undergo RP are more likely to have adverse pathologic findings and BCR compared with white men. AA men with "low risk" prostate cancer, especially those considering active surveillance, should be counseled that their recurrence risks can resemble those of whites in higher risk categories. PMID- 25432838 TI - Editorial comment. PMID- 25432839 TI - Editorial comment. PMID- 25432840 TI - Reply: To PMID 25432837. PMID- 25432841 TI - Association of high bladder neck elevation with urodynamic bladder outlet obstruction in patients with lower urinary tract symptoms and benign prostatic hyperplasia. AB - OBJECTIVE: To ascertain the association of cystourethroscopic findings of bladder neck elevation with urodynamic bladder outlet obstruction (BOO) in patients with lower urinary tract symptoms and benign prostatic hyperplasia (LUTS-BPH). MATERIALS AND METHODS: Study subjects were 646 consecutive men aged >40 years diagnosed with LUTS-BPH at Seoul National University Hospital from December 2005 through January 2012. We collected the International Prostatic Symptom Score, serum prostate-specific antigen levels, prostate volume measured by transrectal ultrasonography, uroflowmetry with postvoid residual volume, and urodynamics with a pressure flow study. We examined the degree of lateral lobe protrusion of prostate, bladder neck elevation degree (BNE-D), and bladder neck elevation angle (BNE-A) under a cystourethroscopic examination. RESULTS: When we examined BNE by cystourethroscope, the mean BNE-A was 26.1 degrees . Higher BNE-D was strongly positively correlated with BNE-A, but neither was associated with the degree of lateral lobe protrusion of prostate. Patients with higher BNE-A (>= 35 degrees ) had higher BOO index and more obstructed voiding patterns than those with lower BNE-A (<35 degrees ). BNE-A was positively correlated with BOO index (r = 0.186). However, we identified only total prostate volume (odds ratio [OR], 1.036), maximal flow rate (Qmax; OR, 0.843), and detrusor pressure at Qmax (PdetQmax; OR, 1.278) as significant predictors of BOO in the multivariate analysis. CONCLUSION: In sum, patients with higher BNE-A (>= 35 degrees ) by cystourethroscope had higher BOO index and more obstructed voiding patterns than those with lower BNE-A (<35 degrees ). Moreover, both BNE-D and BNE-A were positively correlated with BOO index. Thus, cystourethroscopic findings of BNE status can be helpful to predict urodynamic BOO in the patients with LUTS-BPH. PMID- 25432842 TI - Preoperative urodynamic factors predicting outcome of botulinum toxin-A intradetrusor injection in children with neurogenic detrusor overactivity. AB - OBJECTIVE: To investigate urodynamic (UD) parameters that predict outcome of intradetrusor botulinum toxin-A (BTX-A) injection in children with neurogenic detrusor overactivity (NDO), by reviewing clinical and UD data. METHODS: From January 2010 to March 2014, 56 cases of the first BTX-A intradetrusor injection were performed in pediatric patients with NDO. We excluded 19 cases based on these criteria: patient age <4 years, no preoperative UD study or postoperative outcome assessment, and simultaneous sphincter injection. Based on the Patient Global Impression of Improvement, patients were classified as responders or nonresponders. RESULTS: Thirty-seven cases were included finally. Mean number of pads used per day was significantly decreased after BTX-A injection (2.67 +/- 1.46 vs 1.37 +/- 1.15; P <.001). On postoperative UD study, maximum cystometric capacity and residual urine volume were significantly increased above baseline. Persistent NDO was only detected in 3 cases (8.1%). Regardless of UD improvements, 20 cases were responders, whereas 17 were nonresponders based on Patient Global Impression of Improvement. Preoperative bladder compliance was significantly lower in nonresponders (25.11 +/- 32.59 vs 8.64 +/- 6.52; P = .039). Open bladder neck (OBN) was seen in 9 cases and more likely occurred in nonresponders. Regression analysis revealed that poor bladder compliance (<10 mL/cm H2O; odds ratio, 6.041; 95% confidence interval, 1.189-30.677; P = .030) and presence of OBN (odds ratio, 16.889; 95% confidence interval, 1.825-156.282; P = .031) were independent predictors of poor response after BTX-A injection. CONCLUSION: Preoperative bladder compliance and OBN were important predictors of outcome after BTX-A intradetrusor injection. Thus, intradetrusor BTX-A injection should be considered in select patients to achieve optimal outcome. PMID- 25432843 TI - Sports-related testicular injuries and the use of protective equipment among young male athletes. AB - OBJECTIVE: To survey young male athletes to determine the self-reported prevalence of sports-related testicular injuries and use of protective equipment among adolescents and young adults. METHODS: A self-administered questionnaire was distributed to male students at local high schools and colleges. Respondents were asked about personal and team member usage of athletic cups and history of testicular injuries. Returned surveys were analyzed for descriptive statistics and compared between high school and college respondents. RESULTS: Approximately 1700 surveys were distributed and 731 returned. The mean age of all respondents was 17.7 years. Across all sports, 18% of athletes experienced a testicular injury during sports and 36.4% observed injuries in team members, whereas only 12.9% of respondents reported wearing athletic cups. The prevalence of testicular injuries for lacrosse, wrestling, baseball, and football was 48.5%, 32.8%, 21%, and 17.8%, respectively. Of athletes reporting a prior injury, 20.1% reported that they wear a cup now. Rates of athletic cup usage were significantly less for college baseball, football, and all respondents compared with their high school counterparts. CONCLUSION: Previously reported rates of testicular injury with sports participation may underestimate the prevalence of these injuries among adolescent and young adult athletes among whom testicular protective equipment is infrequently used. PMID- 25432844 TI - Congenital posterior urethroperineal fistula: a review and report of the 25th case in literature. AB - Duplications of the urethra are rare, but the congenital posterior urethroperineal fistula (CUPF) is an even rarer anomaly. CUPF resembles type II A2, Y-duplication described by Effmann but differs significantly because it has a normal functional dorsal urethra and a ventral hypoplastic accessory urethra. Excision or fulguration of the accessory urethra results in the resolution of patient's symptoms. The 25th case in English literature is reported with a review of literature; the addition of CUPF to Effmann classification as "type II A2, Y hypoplastic ventral urethra" is proposed. PMID- 25432845 TI - Granulomatous inflammation masquerading as an infected urachal cyst. AB - Errors in urachal obliteration may result in 4 clinical anomalies: patent urachus, urachal cyst, urachal sinus, or vesicourachal diverticulum. Despite the fact that urachal cysts are one of the more common of these anomalies, most go undetected, presenting in the setting of infection. There are reports in the literature of cysts misdiagnosed as other inflammatory processes; however, the converse is reported with less frequency. We present the case of a 3-year-old girl who was admitted to our institution with a suspected urachal cyst. This was subsequently diagnosed as a granulomatous mass caused by the gram negative bacterium Bartonella. PMID- 25432846 TI - Scrotal and perineal sensory neuropathy after urethroplasty for bulbar urethral stricture disease: an evaluation of the incidence, timing, and resolution. AB - OBJECTIVE: To examine the timing, incidence, and resolution of scrotal and perineal sensory neuropathy after urethroplasty for bulbar urethral stricture disease. MATERIALS AND METHODS: We performed an institutional review board- approved retrospective review of our urethroplasty database with specific attention paid to patient demographics, stricture location, repair type, and postoperative sensory neuropathy defined as the complaint of hypesthesia, anesthesia, paresthesia, hyperesthesia, and pain in the scrotal and perineal region after surgery. Incidence and reported times to onset and resolution of sensory neuropathy were compared among our cohort. RESULTS: A total of 155 men underwent urethroplasty for bulbar urethral stricture disease from January 2007 to December 2012. One hundred forty-three of 155 men (92%) had postoperative data available for analysis. The average age at surgery was 47 +/- 15 years and average stricture length was 2.1 +/- 1.4 cm. Repair types were excision and primary anastomosis (101 of 143; 71%), augmented anastomotic repair (31 of 143; 22%), onlay repair (4 of 143; 3%), and perineal urethrostomy (7/143, 5%). Twenty of 143 men (14%) experienced postoperative scrotal and perineal neuralgia at a median time of 108 days (range, 18-160 days) from surgery. Fourteen of 20 men (70%) had subsequent follow-up visits, and all of these men had resolution of the pain, without treatment, at a median reported time of 271 days from surgery. There were no significant differences in incidence, resolution, or timing of sensory neuropathy among repair types. CONCLUSION: Our findings indicate that approximately 14% of men who undergo urethroplasty for bulbar urethral stricture disease experience postoperative scrotal and perineal sensory neuropathy. This appears to be transient with 100% resolution in our patients with available follow-up. PMID- 25432848 TI - Editorial comment. PMID- 25432847 TI - Simple vs complex urethral diverticulum: presentation and outcomes. AB - OBJECTIVE: To determine whether complex anatomic configurations of urethral diverticula (UD), namely circumferential UD (cUD), present differently or confer a worse prognosis as compared with simple UD (sUD). METHODS: After institutional review board approval, a retrospective review of patients who underwent transvaginal urethral diverticulectomy at a single institution over an 8-year period was performed. A total of 43 patients were identified, of which 11 were found to have cUD. These lesions were repaired with complete division of the urethra to access the dorsally located portion of the UD, followed by end-to-end anastomosis for urethral reconstruction with a Martius flap and/or autologous fascial pubovaginal sling performed as needed. Presenting symptoms and surgical outcomes were reviewed. RESULTS: Mean age was 50.9 years in the cUD vs 52.7 years in the sUD. Patients with cUD were more likely to present with stress urinary incontinence than those with sUD (90.9% vs 56.3%; P = .04). There was no statistical difference in the rate of preoperative urgency, pelvic pain and/or dyspareunia, postvoid dribbling, and urinary tract infection. Postoperatively, patients with cUD were more likely to have a urinary tract infection (27% vs 3%; P = .2); otherwise, rates of postoperative results were similar. CONCLUSION: Urethral transection and end-to-end anastomosis for the repair of complex UD is a feasible approach and results in similar clinical outcomes compared with the repair of sUD. PMID- 25432849 TI - Laparoscopy-assisted continuous ambulatory peritoneal dialysis catheter placement using Amplatz dilators: a new technique with results. AB - OBJECTIVE: To describe a new modified technique of laparoscopic placement of continuous ambulatory peritoneal dialysis (CAPD) catheters and assess the early results. METHODS: CAPD catheter implantation was performed in 100 consecutive patients. The technique used laparoscopically guided, extraperitoneal tunneling of the CAPD catheter using Amplatz dilators. The extraperitoneal tunneling helped to maintain the catheter's orientation toward the deep pelvis. Omentopexy was performed on patients with long omentum. Wherever indicated, adhesiolysis was performed to eliminate compartmentalization that could affect the completeness of dialyzate drainage. The average duration of surgery, hospital stay, morbidity, mortality, and catheter survival were assessed. RESULTS: The average operative time was 40 +/- 7 minutes, and hospital stay was 3 +/- 1 days. There were no conversions from laparoscopy to conventional catheter insertion methods. Exit site or tunnel infections, hemorrhagic complications, abdominal wall hernias, or catheter cuff extrusions were not detected. No patient had either catheter migration or displacement. Peroperative mortality did not occur in this series of patients. Catheter survival was 97% at 6 months. CONCLUSION: The laparoscopic method described in this report is compliant with consensus guidelines for the best demonstrated practices in peritoneal access placement. Laparoscopy permits direct visualization of all procedure steps in a safe, efficient, and reproducible manner. The use of Amplatz dilators helps in better orientation of the catheter reducing the risk of catheter tip migration. PMID- 25432851 TI - High submuscular placement of urologic prosthetic balloons and reservoirs: 2-year experience and patient-reported outcomes. AB - OBJECTIVE: To present our updated experience and patient-reported outcomes of high submuscular (HSM) placement of urologic prosthetic balloons and reservoirs (UPBRs). METHODS: A retrospective review was performed of patients who underwent inflatable penile prosthesis and/or artificial urinary sphincter placement between 2011 and 2013. UPBRs were placed in an HSM location between the transversalis fascia and the rectus abdominis muscle by blunt dissection through the external inguinal ring via a trans-scrotal approach. Patient demographics, perioperative outcomes, and patient-reported outcomes were reviewed. RESULTS: During the study period, 146 patients received 158 HSM implants: inflatable penile prosthesis reservoirs (n = 93) or artificial urinary sphincter balloons (n = 65). Patients completed a standardized survey at a mean of 3.2 months (range, 1.1-23.4 months) after surgery and were last followed up at a mean of 5.5 months (range, 1.1-28.7 months). Overall, 94% (n = 149) of UPBRs caused no bother, and patients were satisfied with 96% (n = 151) of implants. Patients were unable to palpate 80% (n = 126) of UPBRs and minimally palpate 16% (n = 26). The primary surgeon was unable to palpate 72% (n = 115) of UPBRs and minimally palpate 20% (n = 31). Type of UPBR, body mass index, reservoir volume, and reservoir manufacturer were not associated with patient or surgeon palpability. Of the 158 UPBRs placed, only 2 (1.3%) were revised due to bothersome patient palpability. No bowel, bladder, ureteral, or vascular injuries occurred. CONCLUSION: HSM placement of UPBR is safe and feasible, well tolerated, and avoids deep retropubic dissection. Patient-reported outcomes support low palpability, low bother, and high patient satisfaction. PMID- 25432850 TI - Hybrid technique using a Satinsky clamp for right-sided transperitoneal hand assisted laparoscopic donor nephrectomy: comparison with left-sided standard hand assisted laparoscopic technique. AB - OBJECTIVE: To introduce our hybrid technique using a Satinsky clamp for right sided hand-assisted laparoscopic donor nephrectomy (HALDN) and to compare its effectiveness and safety with those of standard left-sided HALDN. METHODS: We conducted a retrospective analysis of 253 patients, who underwent HALDN (51 right and 202 left) from January 2003 to December 2012. Perioperative outcomes including operative time, estimated blood loss, warm ischemic time, hospital stay, complications, and recovery of renal function in recipients were collected and compared between the right hybrid HALDN (rhHALDN) and left-sided HALDN groups. RESULTS: The procedure was performed successfully in all 253 patients. No statistical difference in the mean operation time (224.3 vs 217.5 minutes), estimated blood loss (128.1 vs 123.6 mL), warm ischemic time (3.3 vs 3.1 minutes), average time to oral intake (2.4 vs 2.1 days), and mean hospital stay (4.9 vs 5.5 days) was observed between the rhHALDN and left-sided HALDN groups (P >.05). Perioperative complication rates were not statistically different between rhHALDN (2 intraoperative, 3 postoperative; 9.8%) and left-sided HALDN (6 intraoperative, 22 postoperative; 13.9%) group (P = .328). No significant difference in mean serum creatinine level and glomerular filtration rate in recipients from postoperative day 1 to 1 year was observed between the 2 groups. CONCLUSION: The perioperative outcomes of rhHALDN using a Satinsky clamp were comparable with those of the left-sided standard HALDN. This hybrid technique can be a technically safe and feasible option for minimally invasive organ donation when right kidney donation is indicated. PMID- 25432852 TI - Reply: To PMID 25432851. PMID- 25432853 TI - Editorial comment. PMID- 25432854 TI - The fate of transitional urology patients referred to a tertiary transitional care center. AB - OBJECTIVE: To determine the changes in management of children with neurogenic bladder (NGB) or genitourinary congenital anomalies as they moved to our transitional care clinic at the Center for Restorative Pelvic Medicine, a multidisciplinary center led by an adult urologic team dedicated to the long-term care of these patients. MATERIALS AND METHODS: We retrospectively reviewed charts of patients with NGB or genitourinary congenital abnormalities referred between 2010 and 2013. Analysis included patient characteristics, causes of NGB, bladder management, recurrent urinary tract infection, stones, renal function, upper tract studies, video urodynamics, and change in management. RESULTS: Twenty-four patients with an average age of 22.0 +/- 2.7 years were included in analysis. Management was altered in 70.8% of patients (n = 17). Surgical management was instituted in 58.3% (n = 14 of 24) of patients and included bladder augmentation or urinary diversion (n = 7), intravesical botulinum toxin A injections (n = 5), cystolitholapaxy, or cystolithotomy (n = 2). Conservative management was changed in 12.5% (n = 3) of patients and included initiating anticholinergic medication (n = 2) or self-catheterization (n = 1). Follow-up was 8.9 +/- 12.1 months. CONCLUSION: There is an immense need for transitional care of patients with NGB or genitourinary congenital abnormalities as they grow into adulthood. Nearly 71% of our patients had a change in their bladder management with 38% undergoing a major surgery. This study emphasizes the necessity for a dedicated adult urologic team in conjunction with a comprehensive team to care for these complex patients because their urologic care and needs may vary significantly from their childhood. PMID- 25432855 TI - Combined effect of confinement and affinity of crowded environment on conformation switching of adenylate kinase. AB - The actual conformation switching of proteins in the crowded cellular environment is completely different from that in vitro. Proteins in cytoplasm are continually subject to confinement and/or attraction to other molecules in their surroundings due to the existence of various biological species. To gain insight into the nature of crowded environments, we investigated the effects of confinement and affinity on the conformation switching of adenylate kinase (ADK) in a spherical cavity. It was found that even a small degree of confinement reduces the entropy of the open state and stabilizes the closed state, which leads to increased energy barriers for transition. Furthermore, the analysis of transition temperatures and mean first passage times indicates that the proper affinity can promote the transition of ADK from closed state to open state. This study reveals that the crowded cellular environment plays an important role in the thermodynamics and kinetics of proteins in vivo. PMID- 25432856 TI - Surgical management of complex multiloculated hydrocephalus in infants and children. AB - OBJECTIVE: Multiloculated hydrocephalus may occur as a consequence of intraventricular hemorrhage or infection and is characterized by enlargement of multiple noncommunicating intraventricular and/or periventricular cysts. In this study, we report the outcomes of open and endoscopic fenestration for multiloculated hydrocephalus at our institution. METHODS: Records of children who underwent endoscopic or open fenestration at St. Louis Children's Hospital from 1999 to 2011 were analyzed. The cause of MLH, operative parameters, length of hospital stay, and subsequent shunt intervention rate were recorded. RESULTS: Twenty-five subjects were identified for study. Twelve subjects underwent open craniotomy and 13 underwent endoscopic fenestration. Endoscopic fenestration was associated with decreased blood loss, operative time, and length of stay (p = 0.003, 0.002, 0.02, respectively). Subjects undergoing craniotomy had an average of 5.1 +/- 4.5 subsequent shunt-related interventions versus 3.1 +/- 4.0 in the endoscopy group (p = 0.25). The craniotomy group's median subsequent shunt revision rate was 0.74 interventions per year versus 0.50 interventions per year in the endoscopy group (p = 0.51). Fifty percent of subjects in the open fenestration group required additional fenestration surgery compared to 38.5% in the endoscopic group (p = 0.70). CONCLUSION: Both open and endoscopic fenestration appeared effective at improving shunt management. The endoscopic technique may offer advantages in operative time, blood loss, and length of hospital stay. These data suggest that endoscopic fenestration may be used as the initial approach for treatment of multiloculated hydrocephalus, with craniotomy and open fenestration used for more severe or refractory cases. PMID- 25432857 TI - Effects of porogen and cross-linking agents on improved properties of silica supported macroporous chitosan membranes for enzyme immobilization. AB - A series of silica-supported macroporous chitosan membranes (CM15, CM20, and CM25) was prepared by varying the ratio of 70-230-MUm-sized silica particles. These synthesized membranes were further cross-linked using different cross linking agents for covalent immobilization of biological macromolecules especially enzymes and in this study, Bovine serum albumin and laccase. Effects of silica particle and cross-linking agents on their flow rates, surface properties, and chemical and biological properties were explored. Pore size of as synthesized membranes was 0.1192, 0.1268, and 0.1623 MUm, respectively, for CM15, CM20, and CM25. The effect of various parameters such as temperature and pH on the relative activity of both free and immobilized enzymes was studied in details. The relative enzyme activity upon immobilization was greatly enhanced several folds of its original activity. The stability of enzymes over a range of temperature and pH was significantly improved by immobilization. The optimum temperature and pH were determined to be 50 degrees C and pH 3, respectively, for both the free and the immobilized enzymes. The immobilized enzyme possessed good operational stability and reusability properties that support its potentiality for practical applications. Among three membranes, CM25 is confirmed to be efficient candidate due to its improved characteristics. PMID- 25432858 TI - Non-traditional dosing of statins in statin-intolerant patients-is it worth a try? AB - In this manuscript, three manifestations of statin intolerance will be covered. The first, myopathy, is mostly subjective with variable complaints of myalgias often worsened by exercise, muscle cramping or weakness, and at times associated with a biomarker, elevations in creatine kinase (CK). A rare but serious manifestation can be rhabdomyolysis. The second, liver toxicity, is associated with reversible biochemical increases in transaminases and rarely other liver function tests. Finally, statin-related central nervous system (CNS) toxicity typically defined as cognitive impairment is quite rare and appears to be idiosyncratic. Statin dose alternatives will then be discussed and highlighted in the setting of the new cholesterol-lowering guidelines. Non-statin lipid-altering therapies as well as other alternative therapies will also be reviewed. PMID- 25432859 TI - Evaluation of the immunogenicity and protective efficacy of killed Leishmania donovani antigen along with different adjuvants against experimental visceral leishmaniasis. AB - Visceral leishmaniasis (VL) caused by Leishmania donovani is a life-threatening disease involving uncontrolled parasitization of vital organs. Drugs to treat leishmaniasis have one or more limitations or insufficiencies in the long run. A safe and efficacious vaccine to control this disease is needed. Killed antigens that could be safer as vaccines have shown limited efficacy in clinical trials. Immunogenic enhancement with appropriate adjuvants may thus be required to elicit protective immunity based on antibodies and effector T-cell functions. Therefore, it is essential to search for adjuvant to enhance the immunogenicity of killed vaccines and to induce protection against leishmaniasis. So, the aim of the present study was to compare the effectiveness of four adjuvants, i.e. alum, saponin, monophosphoryl lipid A, cationic liposome in combination with Killed Leishmania donovani (KLD) antigen against murine VL. Animals were immunized subcutaneously thrice at an interval of 2 weeks with a final volume of 100 MUl per dose. Challenge infection was given 2 weeks after last booster. Mice were sacrificed 15 days after last immunization and on 30, 60 and 90 post infection/challenge days. The protective efficacy of vaccines was revealed by significant reduction in parasite burden and enhanced DTH responses in comparison with the infected controls. Immunized animals also generated significant levels of Th1 cytokines and increased production of IgG2a, thus indicating the generation of a protective Th1 response. All the adjuvants imparted significant protection, but liposomal formulation was most effective followed by KLD + MPL-A, KLD + saponin, KLD + alum and KLD antigen. PMID- 25432860 TI - Detection of hypoxia markers in the cerebellum after a traumatic frontal cortex injury: a human postmortem gene expression analysis. AB - PURPOSE: The response to traumatic brain injury (TBI) is complex and induces various biological pathways in all brain regions that contribute to bad outcomes. The cerebellar hypoxia after a frontal cortex injury may potentiate the pathophysiological impacts of TBI. Therefore, a gene expression analysis was conducted to determine the influence of hypoxia on TBIs. MATERIAL AND METHODS: Total RNA, including microRNAs, was isolated from the cerebellum of individuals who had died from severe frontal cortex injuries or due to natural causes of death (reference group). RESULTS: From a total of 19,596 genes, an average of 59.56% messenger RNAs (mRNAs) appeared expressed with 42 of them showing significant >2-fold differences of upregulated (n = 18) and downregulated (n = 24) genes. The validity of 14 candidate genes (with low p values and high fold differences or based on cited literature) was confirmed using qRT-PCR (Spearman correlation r(2) = 0.93). Only four genes appeared to be either upregulated (FOSB and IL6) or downregulated (HSD11B1 and HSPA12B). From a total of 667 microRNAs, altogether, 248 microRNAs appeared expressed with 13 of them showing significant differences in the mean gene expression. The combination of two mRNAs (HSPA12B/FOSB or IL6/HSD11B1) or two microRNAs (either miR-138/miR-744 or miR 195/miR-324-5p) completely discriminated both groups, a finding unaltered by potential confounders such as age at biosampling, survival time, and the postmortem interval. CONCLUSIONS: Cerebellar hypoxia markers are important to understand the pathophysiology of TBIs and could be used for therapeutic strategies or forensic purposes, e.g., to assess the severity of a brain injury. PMID- 25432861 TI - Spatial distribution analysis of strontium in human teeth by laser-induced breakdown spectroscopy: application to diagnosis of seawater drowning. AB - The diagnosis of drowning can be extremely difficult, especially when the typical morphological signs of drowning are not present, or when the body is in an advanced stage of putrefaction. The main aim of this work is to demonstrate the applicability of laser-induced breakdown spectroscopy (LIBS) to the diagnosis of seawater drowning. Ten teeth samples were selected from eight medico-legal autopsies. A Nd:YAG laser operating at its fundamental wavelength (1,064 nm) was used to generate microplasmas at the sample surface. Strontium (Sr) concentration in tooth samples has been found to be a key factor for the diagnosis of seawater drowning. Spectral differences between the dentin and the enamel were observed. Greater Sr abundance was located in the dentin, with relative standard deviations in the range of 30 to 35%. In addition, chemical images were generated to study the spatial distribution of Sr along the piece. In all cases, Sr content was higher when the cause of the individual death was drowning. A blind experiment was performed to exclude the possibility that the increase of Sr is due to passive diffusion in the blood. The detection of Sr as well as the determination of its distribution by LIBS in dentin seems to be a promising complementary tool for the diagnosis of death by seawater drowning. PMID- 25432862 TI - Regulatory role of adenosine in insulin secretion from pancreatic beta-cells- action via adenosine A1 receptor and beyond. AB - Under physiological conditions, insulin secretion from pancreatic beta-cells is tightly regulated by different factors, including nutrients, nervous system, and other hormones. Pancreatic beta-cells are also influenced by paracrine and autocrine interactions. The results of rodent studies indicate that adenosine is present within pancreatic islets and is implicated in the regulation of insulin secretion; however, effects depend on adenosine and glucose concentrations. Moreover, species differences in adenosine action were found. In rat islets, low adenosine was demonstrated to decrease glucose-induced insulin secretion and this effect is mediated via adenosine A1 receptor. In the presence of high adenosine concentrations, other mechanisms are activated and glucose-induced insulin secretion is increased. It is also well established that suppression of adenosine action increases insulin-secretory response of beta-cells to glucose. In mouse islets, low adenosine concentrations do not significantly affect insulin secretion. However, in the presence of higher adenosine concentrations, potentiation of glucose-induced insulin secretion was demonstrated. It is also known that upon stimulation of insulin secretion, both rat and mouse islets release ATP. In rat islets, ATP undergoes extracellular conversion to adenosine. However, mouse islets are unable to convert extracellularly ATP to adenosine and adenosine arises from intracellular ATP degradation. PMID- 25432863 TI - Blocking ELISA using recombinant NcSRS2 protein for diagnosing bovine neosporosis. AB - Neospora caninum is the etiologic agent of neosporosis, which leads to economic impacts on cattle industry. The reference method for serodiagnosis of neosporosis is the indirect fluorescent antibody test (IFAT). However, IFAT is laborious, expensive, and is not practicable in high throughput screening. In order to facilitate the serological diagnosis of neosporosis, we developed a blocking enzyme-linked immunosorbent assay (b-ELISA) based on NcSRS2 recombinant protein (rNcSRS2) and polyclonal antibodies against rNcSRS2 (b-ELISA/rNcSRS2). Compared to IFAT, b-ELISA/rNcSRS2 showed 93.7 % accuracy (98.7 % sensitivity and 88.7 % specificity), suggesting its potential as diagnostic assay to detect N. caninum antibodies in cattle sera. PMID- 25432864 TI - Expression of periplasmic chaperones in Salmonella Typhimurium reduces its viability in vivo. AB - The efficacy of live attenuated bacterial vectors is dependent upon the fine tuning of a strain's immunogenicity and its virulence. Strains are often engineered to deliver heterologous antigens, but soluble expression of recombinant proteins can be troublesome. Therefore, secretion systems or chaperone proteins are routinely used to assist in attaining high levels of functional, soluble protein production. However, the effects of chaperone expression on the virulence of attenuated bacterial vectors have not been previously reported. In anticipation of utilizing periplasmic chaperone proteins to facilitate soluble production of immunomodulatory proteins in an attenuated strain of Salmonella Typhimurium, the production of the chaperones was tested for their effect on both culture growth and bacterial persistence in mouse tissues. Although no effect on growth of the bacteria was observed in vitro, the increased expression of the periplasmic chaperones resulted in over-attenuation of the Salmonella in vivo. PMID- 25432865 TI - Levosimendan attenuates multiple organ injury and improves survival in peritonitis-induced septic shock: studies in a rat model. AB - INTRODUCTION: The aim of this study was to investigate the effects of levosimendan on rodent septic shock induced by cecal ligation and puncture (CLP). METHODS: Three hours after peritonitis-induced sepsis, male Wistar rats were randomly assigned to receive an intravenous infusion of levosimendan (1.2 MUg/kg/min for 10 min and then 0.3 MUg/kg/min for 6 h) or an equivalent volume of saline and vehicle (5% dextrose) solution. RESULTS: The levosimendan-treated CLP animals had significantly higher arterial pressure and lower biochemical indices of liver and kidney dysfunction compared to the CLP animals (P < 0.05). Plasma interleukin-1beta, nitric oxide and organ superoxide levels in the levosimendan treated CLP group were less than those in CLP rats treated with vehicle (P < 0.05). In addition, the inducible nitric oxide synthase (iNOS) in lung and caspase-3 expressions in spleen were significantly lower in the levosimendan treated CLP group (P < 0.05). The administration of CLP rats with levosimendan was associated with significantly higher survival (61.9% vs. 40% at 18 h after CLP, P < 0.05). At postmortem examination, the histological changes and neutrophil filtration index in liver and lung were significantly attenuated in the levosimendan-treated CLP group (vs. CLP group, P < 0.05). CONCLUSIONS: In this clinically relevant model of septic shock induced by fecal peritonitis, the administration of levosimendan had beneficial effects on haemodynamic variables, liver and kidney dysfunction, and metabolic acidosis. (1) Lower levels of interleukin-1beta, nitric oxide and superoxide, (2) attenuation of iNOS and caspase-3 expressions, and (3) decreases of neutrophil infiltration by levosimendan in peritonitis-induced sepsis animals suggest that anti-inflammation and anti-apoptosis effects of levosimendan contribute to prolonged survival. PMID- 25432866 TI - "There are bugs in condoms": Tanzanian close-to-community providers' ability to offer effective adolescent reproductive health services. AB - OBJECTIVES: Young people in Tanzania are known to access reproductive health services from a range of close-to-community providers outside formal health settings such as drug stores, village AIDS committees, traditional healers and traditional birth attendants (TBAs). However, questions remain about the quality of services such agents provide. This study investigated their capacity to provide adolescent reproductive health (ARH) services and explored their readiness and ability to integrate with the mainstream health sector through community referral interventions. METHODS: Thirty-five focus group discussions exploring close-to-community provider experiences and attitudes to ARH service provision were carried out in two districts in Northern Tanzania. Discussions were conducted in Kiswahili, digitally recorded, verbatim-transcribed, translated and back-translated from Swahili to English. A thematic analysis was conducted using NVivo 9. RESULTS: The major close-to-community cadres providing reproductive health services were drug stores, traditional healers, TBAs and village health workers. They reported being the first port of call for adolescents seeking reproductive health services, but their knowledge of ARH needs was poor. They had negative attitudes to, and lacked the necessary resources for, the provision of such services for adolescents. Some were particularly unwilling to provide condom services and were prejudiced against adolescents using them. There was poor integration between the close-to-community providers and the formal health sector, further limiting their ability to provide adequate services. CONCLUSIONS: Although close-to-community providers are considered a key resource in the community, most have limited capacity to provide ARH services. Without capacity-building investments such as training and cooperation with the mainstream health sector, their contribution to positive reproductive health outcomes is limited, or could indeed lead to adverse outcomes. PMID- 25432867 TI - The interaction between informal cancer caregivers and health care professionals: a survey of caregivers' experiences of problems and unmet needs. AB - PURPOSE: In order to meet the caregiving challenges, informal caregivers often need a substantial level of interaction with health care professionals (HCPs). This study investigated to which extent the cancer caregivers' needs regarding the interaction with HCPs are met and the associations between dissatisfaction with the interaction and socio-demographic and disease-related variables. METHODS: In a cross-sectional questionnaire study, cancer patients with various diagnoses and disease stages were invited to pass on the 'cancer caregiving tasks, consequences and needs questionnaire' (CaTCoN) to up to three of their caregivers. RESULTS: A total of 590 caregivers (related to 415 (55 %) of 752 eligible patients) participated. Although many caregivers were satisfied, considerable proportions experienced problems or had unmet needs regarding the interaction with HCPs. Prominent problematic aspects included optimal involvement of the caregivers in the patients' disease, treatment and/or care (30 % were dissatisfied), attention to the caregivers' wellbeing (e.g., 51 % of the caregivers reported that HCPs only sometimes or rarely/never had shown interest in how the caregivers had been feeling), and provision of enough information to the caregivers (e.g. 39 % were dissatisfied with the amount of time spent on informing caregivers). The patients' adult children and siblings, younger caregivers and caregivers to younger patients tended to report the highest levels of interaction problems and unmet needs. CONCLUSIONS: The caregivers' dissatisfaction with the interaction with HCPs was pronounced. More focus on and involvement of the caregivers, in a way that matches the caregivers' needs, is still warranted. PMID- 25432868 TI - Approach to risk stratification in testicular germ cell tumors: a primer for radiologists. AB - Oncologists increasingly exploit differences in testicular germ cell tumors to deliver more personalized treatment. Imaging is essential in this process, aiding in the selection of risk-stratified management strategies. Consideration of relevant prognostic factors strengthens image interpretation, allowing for a more nuanced radiographic evaluation. This paper uses a clinically focused, stage-by stage approach to delineate the risk factors for relapse and metastasis that radiologists should consider during staging, response assessment, and surveillance. PMID- 25432869 TI - Celiomesenteric and hepatosplenomesenteric trunks: characterization of two rare vascular anomalies with CT. AB - OBJECTIVE: The purpose of this retrospective investigation is to characterize and illustrate the appearances of celiomesenteric trunk (CMT) and hepatosplenomesenteric trunk (HSMT) using CT with three-dimensional volume rendering with attention to the proximal branching patterns. We also correlate our results with an embryologic model and assess the accuracy of radiologists in recognizing these entities. METHODS: CT studies on 36 adult subjects with CMT and 10 with HSMT were analyzed to determine the proximal branching patterns and lengths of the common vascular trunks. The official reports in appropriately selected cases were reviewed to ascertain if the interpreting radiologists recognized the anomalies. RESULTS: Two types of CMT were found. In 29 of 36 cases (81%), the CMT bifurcated into the celiac trunk and superior mesenteric artery (Type A CMT), while in 7 cases the left gastric artery (LGA) arose from the CMT proximal to the hepatosplenic trunk and superior mesenteric artery (Type B CMT). Type A trunks (mean length = 10.4 mm) were significantly shorter (p = 0.007) than Type B trunks (mean length = 17.8 mm). Short common trunks (less than 1.0 cm) were only seen with Type A CMT. Branching patterns in all 10 cases of HSMT were identical with no short common trunks. The CMT was not mentioned in the radiology reports in 88% of the cases assessed. CONCLUSION: The location of the LGA origin distinguishes the two variants of CMT and differentiates CMT from HSMT. These anomalies are easily overlooked during evaluation of routine clinical cases. PMID- 25432870 TI - [Current classification of interstitial pulmonary diseases]. AB - BACKGROUND: The consensus classification of idiopathic interstitial pneumonia (IIP, also known as pulmonary fibrosis) in 2002 has undergone a significant revision in 2013. OBJECTIVES: What are the key points of the new consensus statement of the American Thoracic Society (ATS)/European Respiratory Society (ERS) from 2013 for the classification of pulmonary fibrosis? MATERIAL AND METHODS: Evaluation of the available literature on the subject of pulmonary fibrosis in Pubmed. RESULTS: The interdisciplinary approach (i.e. pulmonology, radiology and pathology) for the diagnosis of lung fibrosis subtypes is highlighted. Nonspecific interstitial pneumonia (NSIP) is now a separate specific form of pulmonary fibrosis. Smoking-associated respiratory bronchiolitis with interstitial lung disease (RB-ILD) is now frequently diagnosed without a lung biopsy on the basis of clinical findings, computed tomography and bronchoalveolar lavage. The heterogeneous course of idiopathic pulmonary fibrosis (IPF) is now recognized. The term "acute exacerbation" will now be used for acute attacks (< 30 days) in patients with chronic lung fibrosis (IPF and NSIP). It has been recognized that it is necessary to provide a clinical classification algorithm for the management of IIP cases. Pleuroparenchymal fibroelastosis (PPFE) is recognized as a rare new entity of pulmonary fibrosis. The rapidly evolving field of molecular markers is promising for improving the diagnostic approach. CONCLUSION: The 2013 ATS/ERS update is a supplement to the previous classification of lung fibrosis from 2002. It outlines progress in recent years and shows potential areas for future innovations. PMID- 25432871 TI - [Therapeutic relevance of HRCT findings from a pneumological viewpoint]. AB - The high-resolution computed tomography (HRCT) technique is an essential component in diagnosing interstitial lung disease (ILD) as it provides important and specialized information and a much greater accuracy than chest X-rays. It contributes to a narrowing down of the differential diagnoses and is also important for planning further invasive investigations, e.g. bronchoscopy, bronchoalveolar lavage, transbronchial lung biopsy and surgical lung biopsy, if needed. An accurate diagnosis of ILD is based on a multidisciplinary discussion involving pulmonologists, radiologists and pathologists experienced in the diagnosis of ILD.The therapy approaches of five different entities of ILD are shown as examples. In hypersensitivity pneumonitis the mainstay of treatment is complete avoidance of exposure to the provoking antigen. In cryptogenic organizing pneumonia most patients recover with corticosteroid therapy with prednisolone over a period of 6 months to 1 year. In cases of sarcoidosis therapy depends on organ involvement and functional impairment but there is no durable benefit to routine treatment of patients with acute pulmonary sarcoidosis, even among those with stage II or III chest radiographs. In general, patients with severe or progressive disease will require treatment.In idiopathic pulmonary fibrosis (IPF) a confident radiological diagnosis of definitive usual interstitial pneumonia (UIP) obviates the need for surgical lung biopsy. Other etiologies of a HRCT pattern of UIP, such as domestic and occupational environmental exposure, connective tissue disease and drug toxicity must be ruled out. In IPF antifibrotic therapy with pirfenidone (approval since 2011) or the triple tyrosine kinase inhibitor nintendanib (pending approval in 2015) can reduce disease progression but therapy with acetylcysteine alone or in combination with prednisolone and azathioprine failed to meet efficacy endpoints. In the management of scleroderma associated ILD rapid semiquantitative evaluation of the extent of the disease on HRCT > 20% is useful for identifying patients who require treatment. PMID- 25432872 TI - Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit. AB - This paper summarizes the pharmacologic properties of vasoactive medications used in the treatment of shock, including the inotropes and vasopressors. The clinical application of these therapies is discussed and recent studies describing their use and associated outcomes are also reported. Comprehension of hemodynamic principles and adrenergic and non-adrenergic receptor mechanisms are salient to the appropriate therapeutic utility of vasoactive medications for shock. Vasoactive medications can be classified based on their direct effects on vascular tone (vasoconstriction or vasodilation) and on the heart (presence or absence of positive inotropic effects). This classification highlights key similarities and differences with respect to pharmacology and hemodynamic effects. Vasopressors include pure vasoconstrictors (phenylephrine and vasopressin) and inoconstrictors (dopamine, norepinephrine, and epinephrine). Each of these medications acts as vasopressors to increase mean arterial pressure by augmenting vascular tone. Inotropes include inodilators (dobutamine and milrinone) and the aforementioned inoconstrictors. These medications act as inotropes by enhancing cardiac output through enhanced contractility. The inodilators also reduce afterload from systemic vasodilation. The relative hemodynamic effect of each agent varies depending on the dose administered, but is particularly apparent with dopamine. Recent large-scale clinical trials have evaluated vasopressors and determined that norepinephrine may be preferred as a first-line therapy for a broad range of shock states, most notably septic shock. Consequently, careful selection of vasoactive medications based on desired pharmacologic effects that are matched to the patient's underlying pathophysiology of shock may optimize hemodynamics while reducing the potential for adverse effects. PMID- 25432873 TI - Spearman's rank correlation coefficient. PMID- 25432874 TI - Genetic variants in lncRNA HOTAIR are associated with risk of colorectal cancer. AB - Long non-coding RNA HOX transcript antisenseRNA (HOTAIR) has been widely identified to participate in tumour pathogenesis, acting as a promoter in colorectal cancer carcinogenesis. However, the association between genetic variants in HOTAIR and cancer risk has not yet been reported. In the present study, we performed a two-stage case-control study to investigate the association between HOTAIR tagSNPs and the risk of colorectal cancer. We found that individuals with rs7958904 CC genotype had a significantly decreased risk of colorectal cancer in both Stage 1 and 2, compared with those carrying GG genotype [odds ratio (OR) = 0.70, 95% confidence interval (CI) = 0.51-0.97 in Stage 1; OR = 0.58, 95% CI = 0.37-0.91 in Stage 2; OR = 0.67, 95% CI = 0.51-0.87 in combined stage]. The subsequently stratified analyses showed that the protective effect of rs7958904 was more pronounced in several subgroups. In summary, our study showed that genetic variants in HOTAIR were associated with risk of colorectal cancer and rs7958904 may act as a potential biomarker for predicting the risk of colorectal cancer. PMID- 25432875 TI - HIV, STI and Behavioral Risk Among Men Who have Sex with Men in a Setting of Elevated HIV Prevalence Along Ecuador's Pacific Coast. AB - We assessed HIV and STI prevalence, risk behaviors and factors associated with HIV infection in men who have sex with men (MSM) in Guayaquil, Ecuador. Respondent-driven sampling was used to recruit 400 MSM in 2011-2012. Participants completed a computer-assisted self-interview and provided blood samples. Statistical analysis accounted for differential probability of selection and for recruitment patterns. HIV prevalence was 11.3 %, HSV-2 30.2 %, active syphilis 6.9 % and hepatitis B 1.2 %. In the previous 12 months, 84 % of MSM reported casual male sex partners and 25 % sex work. Only 48 % of MSM consistently used condoms with male partners and 54 % had ever been tested for HIV. Of 17 % of MSM reporting a female partner, consistent condom use was 6 %. HIV infection was associated with age 25 or older, active syphilis and homosexual self identification. Findings suggest continuing HIV risk and a need to strengthen prevention and testing among MSM. PMID- 25432876 TI - Prevalence of rape and client-initiated gender-based violence among female sex workers: Kampala, Uganda, 2012. AB - We utilized data from the 2012 Crane Survey in Kampala, Uganda to estimate prevalence of rape among female sex workers (FSWs) and to identify risk factors for and prevalence of client-initiated gender-based violence (GBV) among FSWs. Participants were recruited using respondent-driven sampling. Analyses were weighted using RDSAT-generated individualized weights for each of the five dependent GBV outcomes. Analyses were conducted utilizing SAS 9.3. Among 1,467 FSWs who were interviewed, 82 % (95 % CI: 79-84) experienced client-initiated GBV and 49 % (95 % CI: 47-53) had been raped at least once in their lifetime. GBV risk increased with increasing frequency of client demands for unprotected sex, length of time engaged in sex work, and FSW alcohol consumption. Risk decreased when sex with clients occurred at the FSW's or client's house or a hotel compared to when sex occurred in open spaces. Our findings demonstrate a high prevalence of GBV among FSWs. This research reinforces the urgent need for GBV prevention and response strategies to be integrated into FSW programming and the continuing need for GBV research among key populations. PMID- 25432878 TI - Understanding Concerns About Treatment-as-Prevention Among People with HIV who are not Using Antiretroviral Therapy. AB - The use of antiretroviral therapy to prevent HIV transmission is now advocated in many settings, yet little research has documented the views of people with HIV. Semi-structured interviews were conducted in Australia between 2012 and 2014 with 27 HIV-positive people not using treatment at the time of interview. Thematic analysis of views on treatment-as-prevention found that while many participants recognised potential prevention benefits, only a minority was in support of initiating treatment solely to achieve those benefits. A range of uncertain or critical views were expressed regarding who would benefit, risk reduction, and changing treatment norms. Participants resisted responsibility narratives that implied treatment should be used for the public good, in favour of making considered decisions about their preferred approach to managing HIV. Engaging communities in dialogue and debate regarding the risks and benefits of treatment will be critical if this new prevention strategy is to engender public trust. PMID- 25432877 TI - Understanding Adherence to Daily and Intermittent Regimens of Oral HIV Pre exposure Prophylaxis Among Men Who Have Sex with Men in Kenya. AB - A qualitative assessment of Kenyan men who have sex with men taking daily and intermittent oral HIV pre-exposure prophylaxis (PrEP) found stigma, sex work, mobility, and alcohol impacted adherence. We analyzed quantitative data from the same cohort to explore different definitions of intermittent adherence. Volunteers were randomized to daily emtricitabine/tenofovir or placebo, or intermittent (prescription: Mondays/Fridays/after sex, maximum 1 dose/day) emtricitabine/tenofovir or placebo (2:1:2:1), and followed for 4 months. By electronic monitoring, median adherence for daily dosing was 80 %. Median adherence for intermittent dosing was 71 % per a "relaxed" definition (accounting for off-prescription dosing) and 40 % per a "strict" definition (limited to the prescription). Factors associated with lower adherence included travel, transactional sex, and longer follow-up; higher adherence was associated with daily dosing and an income. The definition of intermittent dosing strongly affects interpretation of adherence. These findings suggest interventions should address challenges of mobility, sex work, and long-term PrEP. PMID- 25432879 TI - Correlates of Individual Versus Joint Participation in Online Survey Research with Same-Sex Male Couples. AB - Internet-based surveys are commonly utilized as a cost-effective mechanism for data collection in social and health psychology research. Little is known about the differences between partnered gay men who participate alone compared to those with partners who also agree to participate. A sample of 260 partnered gay/bisexual men from New York City completed an online survey covering demographic characteristics, sexual behavior, substance use, and relationship satisfaction. Upon completion, they had the option to send the study link to their partner. In total, 104 (40 %) participants successfully recruited their partners, 90 (34.6 %) were unsuccessful, and 66 (25.4 %) declined the option to refer their partners. Men who did not refer their partners were significantly older, in relationships longer, and reported higher personal income. Participants who successfully recruited partners reported significantly higher relationship satisfaction. While generalizability is limited given the diversity of methodological factors that influence research participation, these data provide an initial insight into the effects on sample composition imposed by the implementation of dyadic (vs. unpaired) designs in online studies. PMID- 25432880 TI - Let this be lattice? Dendritiform erosion in lattice dystrophy type I, a source of confusion. PMID- 25432882 TI - Vaginal Access Minimally Invasive Surgery (VAMIS): A New Approach to Hysterectomy. AB - Vaginal hysterectomy is the original natural orifice operation. Although one of the most common gynecologic operations performed, the surgical approach has not changed significantly during the past century. This article describes a new approach to hysterectomy using vaginal access minimally invasive surgery (VAMIS). VAMIS hysterectomy is successfully performed on a cadaveric model. The step-by step description of the surgical technique is depicted with video supplement. PMID- 25432883 TI - A promising new device for the prevention of parastomal hernia. AB - Parastomal hernia (PSH) is the most frequent long-term stoma complication with serious negative effects on quality of life. Surgical revision is often required and has a substantial morbidity and recurrence rate. The development of PSH requires revisional surgery with a substantial perioperative morbidity and high failure rate in the long-term follow-up. Prophylactic parastomal mesh insertion during stoma creation has the potential to reduce the rate of PSH, but carries the risk of early and late mesh-related complications such as infection, fibrosis, mesh shrinkage, and/or bowel erosion. We developed a new stomaplasty ring (KORING), which is easy to implant, avoids potential mesh-related complications, and has a high potential of long-term prevention of PSH. Here we describe the technique and the first use. PMID- 25432881 TI - A Novel Percutaneous Guide Wire (S-Wire) for Percutaneous Pedicle Screw Insertion: Its Development, Efficacy, and Safety. AB - PURPOSE: Minimally invasive spine stabilization (MISt) procedures, including MIS transforaminal lumbar interbody fusion (MIS-TLIF), rely on precise placement of percutaneous pedicle screws (PPS). Serious intraoperative complications associated with PPS placement include great vessel and bowel injuries due to the guide-wire's anterior migration and penetration through the anterior aspect of the vertebral body. To address this issue, we developed a novel percutaneous guide wire (S-wire) and compared the biomechanical characteristics of S-wire and conventional wire in cadaveric spines, and to evaluate the S-wire's efficacy and safety in a clinical trial. METHODS: The S-wire is hollow, with braided wires extending at one tip. We compared the push-out and penetration forces of the S wire and conventional wire in fresh cadaveric lumbar spines, from L1 to L5. RESULTS: Push-out forces caused the braided tip of the S-wire to bend or spread, and thus to resist anterior migration. The mean push-out forces for the S-wire and conventional wire were 15.5 +/- 1.9 and 5.7 +/- 0.8 N, respectively (P < .0001); the mean penetration forces were 69.1 +/- 4.2 and 37.1+/- 4.8 N, respectively (P < .0005). There was no wire breakage or anterior-wall penetration in a clinical trial of 922 S-wires; interestingly, the pull-out force increased in 780 (84.6%) S-wires after placement. CONCLUSIONS: The mean push-out and penetration forces for the S-wire were approximately 3 and 2 times greater than those of conventional wire, respectively. The S-wire effectively prevented guide wire anterior migration and penetration of the anterior vertebral-body wall. The S-wire device should effectively improve the safety of MISt procedures, including MIS-TLIF and percutaneous kyphoplasty in selected patient with osteoporosis. PMID- 25432884 TI - Insomnia, hypnotic use, and health-related quality of life in a nationally representative sample. AB - PURPOSE: To assess health-related quality of life (HRQoL) associated with insomnia and prescription hypnotic use. METHODS: Primary outcomes were mental component summary (MCS) and physical component summary (PCS) scores from the 12 item Short-Form Health Survey. Using multiple regression, subjects in the 2005 through 2009 Medical Expenditure Panel Survey with diagnosed insomnia were compared against those without that diagnosis. Among subjects with diagnosed insomnia, users of prescription hypnotics were compared against nonusers. RESULTS: Of 104,274 adults, 1.3 % (n = 1,401) had an insomnia diagnosis. Of those, 45.6 % (n = 639) used prescription hypnotics. For subjects with insomnia, mean PCS and MCS scores were 9.2 and 7.0 points lower (p < 0.001), respectively. After controlling for demographic and clinical covariates, differences remained significant (PCS:5.1; MCS: 6.2; p < 0.001). Among subjects with insomnia, HRQoL scores were not different between prescription hypnotic users (n = 639) and nonusers (n = 762). Analysis by drug class revealed lower PCS scores (difference: 7.5, p < 0.001) with benzodiazepine use (n = 129) versus benzodiazepine receptor agonist use (n = 493), but the adjusted difference was not significant (difference: 3.8, p = .018). CONCLUSIONS: Diagnosed insomnia was associated with consistent decreases in both physical and mental HRQoL scores, regardless of whether prescription hypnotics were used. Benzodiazepine use may be associated with a further decrease in physical HRQoL scores. Although limited by its retrospective design, this study provides a first look at real-world hypnotic use outcomes at a national level. Important next steps include studies with patients serving as their own controls, and further evaluation of the sensitivity of HRQoL instruments to the effects of insomnia treatments. PMID- 25432885 TI - Integrating health-related quality of life findings from randomized clinical trials into practice: an international study of oncologists' perspectives. AB - PURPOSE: Although health-related quality of life (HRQL) is increasingly assessed in randomized controlled trials (RCTs), HRQL findings are not always incorporated into clinical decision making. We examined the current perspectives of oncologists on the use of HRQL findings from RCTs, and variation of these perspectives between countries and specialties. METHODS: A cross-sectional e survey of oncologist members of the NCIC Clinical Trials Group, the United Kingdom National Cancer Research Institute Clinical Studies Groups, and the Australia/New Zealand cancer clinical trials network was conducted. Respondents reported their perceptions of the usefulness of RCT HRQL outcomes for informing practice, their use of HRQL findings in practice, barriers/facilitators to this use, and preferences for HRQL data presentation in RCT publications. Chi-square tests compared responses between countries and specialties. RESULTS: A total of 396 oncologists participated (estimated response rate: 30%). The most frequently reported specialties were medical (46%) and radiation (37%) oncology. HRQL findings from RCTs were reported as useful (73%), but were infrequently used to guide clinical decisions with patients. Perceived barriers were lack of time (67%) and understanding (57%), and concerns about generalizability of results (68%). Identified facilitators included joint publication of HRQL/clinical outcomes (96%) and summary of clinical implications of HRQL findings in RCT publications (76%). Use of HRQL findings, perceived barriers/facilitators, and presentation preferences did not differ by country or specialty. CONCLUSIONS: Oncologists support HRQL findings from RCTs, but perceive important barriers to their use in clinical decision making, regardless of country or specialty. Combined, clear reporting of HRQL/clinical data may facilitate their clinical application. PMID- 25432886 TI - Mn-SOD Upregulation by Electroacupuncture Attenuates Ischemic Oxidative Damage via CB1R-Mediated STAT3 Phosphorylation. AB - Electroacupuncture (EA) pretreatment elicits the neuroprotective effect against cerebral ischemic injury through cannabinoid receptor type 1 receptor (CB1R). In current study, we aimed to investigate whether the signal transducer and activator of transcription 3 (STAT3) and manganese superoxide dismutase (Mn-SOD) were involved in the antioxidant effect of EA pretreatment through CB1R. At 2 h after EA pretreatment, focal cerebral ischemic injury was induced by transient middle cerebral artery occlusion for 60 min in C57BL/6 mice. The expression of Mn SOD in the penumbra was assessed by Western blot and immunoflourescent staining at 2 h after reperfusion. In the presence or absence of Mn-SOD small interfering RNA (siRNA), the neurological deficit score, the infarct volume, the terminal deoxynucleotidyl transferase-mediated dUDP-biotin nick end labeling (TUNEL) staining, and oxidative stress were evaluated. Furthermore, the Mn-SOD protein expression and phosphorylation of STAT3 at Y705 were also determined in the presence and absence of CB1R antagonists (AM251, SR141716) and CB1R agonists (arachidonyl-2-chloroethylamide (ACEA), WIN 55,212-2). EA pretreatment upregulated the Mn-SOD protein expression and Mn-SOD-positive neuronal cells at 2 h after reperfusion. EA pretreatment also attenuated oxidative stress, inhibited cellular apoptosis, and induced neuroprotection against ischemic damage, whereas these beneficial effects of EA pretreatment were reversed by knockdown of Mn-SOD. Mn-SOD upregulation and STAT3 phosphorylation by EA pretreatment were abolished by two CB1R antagonists, while pretreatment with two CB1R agonists increased the expression of Mn-SOD and phosphorylation level of STAT3. Mn-SOD upregulation by EA attenuates ischemic oxidative damage through CB1R-mediated STAT3 phosphorylation in stroke mice, which may represent one new mechanism of EA pretreatment-induced neuroprotection against cerebral ischemia. PMID- 25432888 TI - Lack of JWA Enhances Neurogenesis and Long-Term Potentiation in Hippocampal Dentate Gyrus Leading to Spatial Cognitive Potentiation. AB - JWA (Arl6ip5), a homologous gene of glutamate-transporter-associated protein 3-18 (GTRAP3-18) and addicsin, is highly expressed in hippocampus. We generated systemic and neuronal JWA knockout (JWA-KO and JWA-nKO) mice to investigate the influence of JWA deficiency on spatial cognitive performance, process of neurogenesis, and induction of long-term potentiation (LTP) in hippocampal dentate gyrus (DG). In comparison with wild-type (WT) mice and JWA (loxP/loxP) (control of JWA-nKO) mice, 8-week-old JWA-KO mice and JWA-nKO mice showed spatial cognitive potentiation as assessed by Morris water maze test. In hippocampal DG of JWA-nKO mice, either survival and migration or neurite growth of newborn neurons were significantly enhanced without the changes in proliferation and differentiation of stem cells. In addition, the increase of LTP amplitude and the decline of LTP threshold were observed in DG, but not in CA1 region, of JWA-nKO mice compared to control mice. The levels of hippocampal FAK, Akt, and mTOR phosphorylation in JWA-nKO mice were higher than those in control mice. The PI3K or FAK inhibitor could abolish the enhanced neurogenesis and LTP induction in JWA nKO mice, which was accompanied by disappearance of the spatial cognitive potentiation. The treatment of JWA-nKO mice with 3'-azido-3'-deoxythymidine (AZT), a telomerase inhibitor, suppressed not only the enhanced neurogenesis but also the enhanced LTP induction in DG, but it did not affect the LTP induction in CA1 region. The results suggest that the JWA deficiency through cascading FAK PI3K-Akt-mTOR pathway increases the newborn neurons and enhances the LTP induction in hippocampal DG, which leads to the spatial cognitive potentiation. PMID- 25432887 TI - Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats. AB - Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic. PMID- 25432889 TI - AlzBase: an Integrative Database for Gene Dysregulation in Alzheimer's Disease. AB - Alzheimer's disease (AD) affects a significant portion of elderly people worldwide. Although the amyloid-beta (Abeta) cascade hypothesis has been the prevailing theory for the molecular mechanism of AD in the past few decades, treatment strategies targeting the Abeta cascade have not demonstrated effectiveness as yet. Thus, elucidating the spatial and temporal evolution of the molecular pathways in AD remains to be a daunting task. To facilitate novel discoveries in this filed, here, we have integrated information from multiple sources for the better understanding of gene functions in AD pathogenesis. Several categories of information have been collected, including (1) gene dysregulation in AD and closely related processes/diseases such as aging and neurological disorders, (2) correlation of gene dysregulation with AD severity, (3) a wealth of annotations on the functional and regulatory information, and (4) network connections for gene-gene relationship. In addition, we have also provided a comprehensive summary for the top ranked genes in AlzBase. By evaluating the information curated in AlzBase, researchers can prioritize genes from their own research and generate novel hypothesis regarding the molecular mechanism of AD. To demonstrate the utility of AlzBase, we examined the genes from the genetic studies of AD. It revealed links between the upstream genetic variations and downstream endo-phenotype and suggested several genes with higher priority. This integrative database is freely available on the web at http://alz.big.ac.cn/alzBase . PMID- 25432890 TI - Enriched Environment Attenuates Surgery-Induced Impairment of Learning, Memory, and Neurogenesis Possibly by Preserving BDNF Expression. AB - Postoperative cognitive dysfunction (POCD) is a significant clinical syndrome. Neurogenesis contributes to cognition. It is known that enriched environment (EE) enhances neurogenesis. We determined whether EE attenuated surgery-induced cognitive impairment and whether growth factors and neurogenesis played a role in the EE effect. Eight-week-old C57BL/6J mice were subjected to carotid artery exposure. Their learning and memory were assessed by Barnes maze, and fear conditioning started 2 weeks after the surgery. Growth factor expression and cell genesis were determined at various times after the surgery. Surgery increased the time for the mice to identify the target hole in the Barnes maze and reduced context-related freezing behavior. Surgery also reduced the expression of brain derived neurotrophic factor (BDNF) and neurogenesis in the hippocampus. These effects were attenuated by EE. EE also attenuated surgery-induced reduction of phosphorylated/activated tropomyosin-related kinase B (TrkB) and extracellular signal-regulated kinases (ERK), components of BDNF signaling pathway. ANA-12, a selective TrkB antagonist, blocked the effects of EE on cognition, phosphorylation of TrkB and ERK, and neurogenesis. These results provide initial evidence that surgery reduces BDNF expression and neurogenesis in the hippocampus. Our results suggest that EE reduces surgery-induced impairment of learning, memory, and neurogenesis by preserving BDNF expression. PMID- 25432892 TI - Bayesian long branch attraction bias and corrections. AB - Previous work on the star-tree paradox has shown that Bayesian methods suffer from a long branch attraction bias. That work is extended to settings involving more taxa and partially resolved trees. The long branch attraction bias is confirmed to arise more broadly and an additional source of bias is found. A by product of the analysis is methods that correct for biases toward particular topologies. The corrections can be easily calculated using existing Bayesian software. Posterior support for a set of two or more trees can thus be supplemented with corrected versions to cross-check or replace results. Simulations show the corrections to be highly effective. PMID- 25432891 TI - Strategy to Suppress Oxidative Damage-Induced Neurotoxicity in PC12 Cells by Curcumin: the Role of ROS-Mediated DNA Damage and the MAPK and AKT Pathways. AB - Oxidative damage plays a key role in causation and progression of neurodegenerative diseases. Inhibition of oxidative stress represents one of the most effective ways in treating human neurologic diseases. Herein, we evaluated the protective effect of curcumin on PC12 cells against H2O2-induced neurotoxicity and investigated its underlying mechanism. The results indicated that curcumin pre-treatment significantly suppressed H2O2-induced cytotoxicity, inhibited the loss of mitochondrial membrane potential (Deltapsim) through regulation of Bcl-2 family expression, and ultimately reversed H2O2-induced apoptotic cell death in PC12 cells. Attenuation of caspase activation, poly(ADP ribose) polymerase (PARP) cleavage, DNA damage, and accumulation of reactive oxygen species (ROS) all confirmed its protective effects. Moreover, curcumin markedly alleviated the dysregulation of the MAPK and AKT pathways induced by H2O2. Taken together, our findings suggest that the strategy of using curcumin could be a highly effective way in combating oxidative damage-mediated human neurodegenerative diseases. PMID- 25432893 TI - Bias and sensitivity in the placement of fossil taxa resulting from interpretations of missing data. AB - The utility of fossils in evolutionary contexts is dependent on their accurate placement in phylogenetic frameworks, yet intrinsic and widespread missing data make this problematic. The complex taphonomic processes occurring during fossilization can make it difficult to distinguish absence from non-preservation, especially in the case of exceptionally preserved soft-tissue fossils: is a particular morphological character (e.g., appendage, tentacle, or nerve) missing from a fossil because it was never there (phylogenetic absence), or just happened to not be preserved (taphonomic loss)? Missing data have not been tested in the context of interpretation of non-present anatomy nor in the context of directional shifts and biases in affinity. Here, complete taxa, both simulated and empirical, are subjected to data loss through the replacement of present entries (1s) with either missing (?s) or absent (0s) entries. Both cause taxa to drift down trees, from their original position, toward the root. Absolute thresholds at which downshift is significant are extremely low for introduced absences (two entries replaced, 6% of present characters). The opposite threshold in empirical fossil taxa is also found to be low; two absent entries replaced with presences causes fossil taxa to drift up trees. As such, only a few instances of non-preserved characters interpreted as absences will cause fossil organisms to be erroneously interpreted as more primitive than they were in life. This observed sensitivity to coding non-present morphology presents a problem for all evolutionary studies that attempt to use fossils to reconstruct rates of evolution or unlock sequences of morphological change. Stem-ward slippage, whereby fossilization processes cause organisms to appear artificially primitive, appears to be a ubiquitous and problematic phenomenon inherent to missing data, even when no decay biases exist. Absent characters therefore require explicit justification and taphonomic frameworks to support their interpretation. PMID- 25432894 TI - Erratum to: An approach to the symbolic representation of brain arteriovenous malformations for management and treatment planning. PMID- 25432896 TI - Hypertension and insulin resistance: implications of mitochondrial dysfunction. AB - Mitochondria are the primary generators of cellular reactive oxygen species (ROS); their pathophysiological roles in hypertension and insulin resistance are but imperfectly understood. Mitochondrial dysfunction has been linked to the etiologies of many complex diseases, but many other factors, including the upregulation of the renin-angiotensin system (RAS) and vitamin D deficiency, have also been implicated in hypertension pathogenesis. Hypertension resulting from the disruption of the RAS contributes to the risk of cardiovascular disease. Likewise, experimental and clinical evidence indicate that RAS stimulation and low vitamin D levels are inversely related and represent risk factors associated with the pathogenesis of hypertension. Furthermore, RAS activation induces insulin resistance, resulting in increases in ROS levels. High levels of ROS are harmful to cells, having the potential to trigger both mitochondrial-mediated apoptosis and the degradation of the mitochondrial DNA. Diabetes risk is also associated with high levels of oxidative stress; taking vitamin D, however, may reduce that risk. The finding that mitochondria possess both a functional RAS and vitamin D receptors is the starting point for improving our understanding of the interaction of mitochondria and chronic disease states, which understanding should lead to decreases in the chronic disease burden attributable to hypertension, diabetes, or both. PMID- 25432897 TI - Preventing the progression of prehypertension to hypertension: role of antihypertensives. AB - Recent guidelines for the diagnosis and management of hypertension reversed the historical trend to recommend lower blood pressure (BP) thresholds to diagnose hypertension in high-risk individuals, such as patients with diabetes and elderly patients. The decision to raise the BP thresholds for diagnosis of hypertension in patients with diabetes was mostly based on the findings of the ACCORD trial. Nonetheless, the results of the ACCORD trial are within the predicted benefit to prevent coronary artery disease and stroke by meta-analysis of randomized controlled trials (RCT), particularly in regard to the prevention of stroke. The Eighth Joint National Committee (JNC 8) did not address prehypertension. There are many RCT done in individuals with prehypertension and concomitant cardiovascular disease showing the benefit of treatment of these patients. Trials exploring the efficacy of interventions to prevent cardiovascular disease in individuals with prehypertension free of cardiovascular disease would be hardly feasible in face of the low absolute risk of these individuals. Considering the risks of prehypertension for cardiovascular disease and the fast progression to hypertension of a large proportion of individuals with prehypertension, it is worth to consider drug treatment for individuals with prehypertension. RCT showed that the progression to hypertension can be partially halted by BP-lowering agents. These and ongoing clinical trials are herein revised. Prehypertension may be a window of opportunity to prevent hypertension and its cardiovascular consequences. PMID- 25432895 TI - Treatment of hypertension in children with chronic kidney disease. AB - Hypertension (HTN) is increasingly recognized as a common feature of pediatric chronic kidney disease (CKD). A growing body of evidence demonstrates that HTN is both underdiagnosed and undertreated in this population. The consequences of untreated HTN include adverse effects on CKD progression, markers of cardiovascular morbidity, and neurocognitive functioning. Consensus guidelines issued over the past decade have incorporated recent research on the consequences of HTN in recommendations for the diagnosis and treatment of HTN in pediatric CKD and include lower BP targets. Agents which target the renin-angiotensin aldosterone system (RAAS) should be considered first-line therapy in CKD associated HTN in children, though multiple medications may be required to achieve sufficient BP control. PMID- 25432898 TI - Plasma renin testing to guide antihypertensive therapy. AB - Plasma renin activity (PRA)-guided therapy has been proposed as a strategy for selecting antihypertensive medications matched to the patient's underlying pathophysiology. To date, there are only a few studies that have sought to compare a PRA-guided strategy to usual care. In one trial of 363 untreated patients, based on home blood pressure (BP) averages, PRA was predictive of responses to beta-blocker and thiazide diuretic as monotherapy and add-on therapy. In another trial of 77 treated but uncontrolled patients, a PRA-guided strategy was superior to clinical hypertension specialist care for guiding add-on or subtraction (stopping an agent that might cause a paradoxical pressor response) therapy. In the ValVET study, PRA-guided therapy was not superior to fixed-dose therapy consisting of an angiotensin receptor blocker and hydrochlorothiazide. One modeling study found a PRA-guided strategy may be cost effective compared to standard care for younger patients and those with a greater number of cardiovascular risk factors. We conclude that additional, well-designed randomized trials with sufficient sample sizes comparing PRA-guided management to usual care are needed to clarify whether this strategy should be adopted broadly. PMID- 25432900 TI - Cognitive function in hypertensive children. AB - Young hypertensive adults demonstrate decreased performance on neurocognitive testing compared with that of normotensive controls. There is emerging, preliminary evidence that children with hypertension also manifest cognitive differences when compared to normotensive controls. These preliminary studies consist mostly of database and single-center studies that focus primarily on differences in neurocognitive test performance and differences in cerebrovascular reactivity between hypertensive and normotensive subjects. Lessons from the literature on cognition in adult hypertensives and experience from the preliminary studies in children informed the design of a current, multicenter, ongoing study of cognition in children with primary hypertension. PMID- 25432899 TI - Inflammation and hypertension: new understandings and potential therapeutic targets. AB - Research studying the role of inflammation in hypertension and cardiovascular disease has flourished in recent years; however, the exact mechanisms by which the activated immune cells lead to the development and maintenance of hypertension remain to be elucidated. The objectives of this brief review are to summarize and discuss the most recent findings in the field, with special emphasis on potential therapeutics to treat or prevent hypertension. This review will cover novel immune cell subtypes recently associated to the disease including the novel role of cytokines, toll-like receptors, and inflammasomes in hypertension. PMID- 25432901 TI - Familial aggregation and childhood blood pressure. AB - There is growing concern about elevated blood pressure (BP) in children. The evidence for familial aggregation of childhood BP is substantial. Twin studies have shown that a large part of the familial aggregation of childhood BP is due to genes. The first part of this review provides the latest progress in gene finding for childhood BP, focusing on the combined effects of multiple loci identified from the genome-wide association studies on adult BP. We further review the evidence on the contribution of the genetic components of other family risk factors to the familial aggregation of childhood BP including obesity, birth weight, sleep quality, sodium intake, parental smoking, and socioeconomic status. At the end, we emphasize the promise of using genomic-relatedness-matrix restricted maximum likelihood (GREML) analysis, a method that uses genome-wide data from unrelated individuals, in answering a number of unsolved questions in the familial aggregation of childhood BP. PMID- 25432902 TI - Accuracy of the days' supply and the number of refills allowed recorded in Quebec prescription claims databases for inhaled corticosteroids. AB - OBJECTIVES AND HYPOTHESES: Adherence to inhaled corticosteroids (ICS) is a major issue in asthma. This study aimed to estimate the accuracy of the days' supply and number of refills allowed, variables recorded in Quebec claims databases and used to estimate adherence, and to develop correction factors, if required. We hypothesised that the accuracy of the days' supply for ICS would be low whereas the accuracy of the number of refills allowed would be high. SETTING: 40 community pharmacies in Quebec (Canada) and a medication registry. PARTICIPANTS: We collected data for 1108 ICS original prescriptions stored in the 40 pharmacies (sample 1), and we obtained a second sample of 2676 ICS prescriptions selected from reMed, a medication registry (sample 2). PRIMARY AND SECONDARY OUTCOMES: We estimated the concordance of the days' supply and number of refills between Quebec claims databases and the original prescription from sample 1. We developed a correction factor for the days' supply in sample 1 and validated it in sample 2. Analyses were stratified by age: 0-11 and 12-64 years. RESULTS: In sample 1, the concordance for the days' supply was 39.6% (95% CI 37.6% to 41.6%) in those aged 0-11 years and 56% (54.9% to 57.2%) in those aged 12-64 years. The concordance increased to 59.4% (58.2% to 60.5%) in those aged 0-11 years and 74.2% (73.5% to 74.9%) in those aged 12-64 years after applying the correction factors in sample 2. The concordance for the refills allowed was 92.1% (91% to 93.1%) in those aged 0-11 years and 93.1% (92.5% to 93.7%) in those aged 12-64 years in sample 1. CONCLUSIONS: The accuracy of the days' supply was moderate among those aged 0-11 years and substantial among those aged 12-64 years after applying the correction factors. The accuracy of the number of refills was almost perfect in both groups. PMID- 25432904 TI - Norwich paediatric triad: malrotation, intussusception and small intestinal lymphoma. PMID- 25432905 TI - Paraneoplastic cerebellar degeneration associated with serous adenocarcinoma of the ovary. AB - We report a case of a 68-year-old woman who presented with symptoms of cerebellar degeneration which initiated a suspicion of underlying malignancy. The patient presented with progressive ataxia and dysarthria and after excluding primary cerebellar pathology, paraneoplastic syndrome was suspected and she was investigated for a malignancy. CT scan of the pelvis showed a left-sided ovarian mass later diagnosed as serous adenocarcinoma of the ovary. She underwent surgery and histology of the mass showed poorly-differentiated serous adenocarcinoma. Paraneoplastic neurological syndrome encompasses several neurological disorders including paraneoplastic cerebellar degeneration (PCD) caused by an immune mediated mechanism in patients with an underlying malignancy. PCD is a rare condition that occurs in less than 1% of patients with cancer and is associated with specific groups of cancer. It is important to identify PCD due to its association with certain cancers and also to limit the disabilities associated with the syndrome. PMID- 25432906 TI - A distinct imaging phenotype in amyotrophic lateral sclerosis confidently detected on T1 MTC. PMID- 25432903 TI - Are interventions for low-income groups effective in changing healthy eating, physical activity and smoking behaviours? A systematic review and meta-analysis. AB - OBJECTIVE: To conduct a systematic review and meta-analysis examining the effectiveness of behavioural interventions targeting diet, physical activity or smoking in low-income adults. DESIGN: Systematic review with random effects meta analyses. Studies before 2006 were identified from a previously published systematic review (searching 1995-2006) with similar but broader inclusion criteria (including non-randomised controlled trials (RCTs)). Studies from 2006 to 2014 were identified from eight electronic databases using a similar search strategy. DATA SOURCES: MEDLINE, EMBASE, PsycINFO, ASSIA, CINAHL, Cochrane Controlled Trials, Cochrane Systematic Review and DARE. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: RCTs and cluster RCTs published from 1995 to 2014; interventions targeting dietary, physical activity and smoking; low-income adults; reporting of behavioural outcomes. MAIN OUTCOME MEASURES: Dietary, physical activity and smoking cessation behaviours. RESULTS: 35 studies containing 45 interventions with 17,000 participants met inclusion criteria. At postintervention, effects were positive but small for diet (standardised mean difference (SMD) 0.22, 95% CI 0.14 to 0.29), physical activity (SMD 0.21, 95% CI 0.06 to 0.36) and smoking (relative risk (RR) of 1.59, 95% CI 1.34 to 1.89). Studies reporting follow-up results suggested that effects were maintained over time for diet (SMD 0.16, 95% CI 0.08 to 0.25) but not physical activity (SMD 0.17, 95% CI -0.02 to 0.37) or smoking (RR 1.11, 95% CI 0.93 to 1.34). CONCLUSIONS: Behaviour change interventions for low-income groups had small positive effects on healthy eating, physical activity and smoking. Further work is needed to improve the effectiveness of behaviour change interventions for deprived populations. PMID- 25432907 TI - Large cystic ductal carcinoma of the prostate: imaging findings and minimally invasive surgical treatment. PMID- 25432908 TI - Management of opioid painkiller dependence in primary care: ongoing recovery with buprenorphine/naloxone. AB - Opioid painkiller dependence is a growing problem and best-practice management is not well defined. We report a case of a young woman exhibiting dependence on codeine, originally prescribed for myalgic encephalopathy, after escalating use over a 10-year period. In 2012, a consultation with a new general practitioner, who had extensive experience of patients with substance abuse, revealed the underlying dependence. After building trust for 6 months, she was able to admit to medication abuse, and was referred to the community drug and alcohol team. On presentation to the team, the patient had no pain issues and the dihydrocodeine use--600 tablets/week--solely reflected her dependence. The patient successfully underwent rapid induction with buprenorphine/naloxone as opioid substitution treatment over 2 days. She is currently stable, engaged with recovery support services and psychosocial counselling, and has just returned to work. She is maintained on a therapeutic dose of buprenorphine 10 mg/naloxone 2.5 mg. PMID- 25432909 TI - beta-Thalassaemia intermedia masquerading as beta-thalassaemia major. PMID- 25432911 TI - Iatrogenic urethral prolapse following vaginal hysterectomy and anterior repair. AB - A 62-year-old woman presented 3 weeks following vaginal hysterectomy and anterior repair with exquisite urethral pain, incontinence and complete urethral prolapse. Following examination under anaesthesia and cystoscopy, anterior vaginal repair sutures were removed with spontaneous reduction of the prolapse. At a 5-week follow-up appointment, the patient was asymptomatic with resolution of the urethral prolapse. PMID- 25432910 TI - Spontaneous pneumomediastinum: an important differential in acute chest pain. AB - A 38-year-old man presented with pleuritic chest pain that was present on waking and localised to the left costal margin with no radiation. He was otherwise asymptomatic and denied preceding trauma, heavy lifting, coughing or recent vomiting. Observations and examination were unremarkable; however, a chest radiograph showed a pneumomediastinum. Spontaneous pneumomediastinum (SPM) is a rare condition that tends to follow a benign clinical course. A CT of the chest is generally only indicated if the chest X-ray fails to show an SPM in patients for whom there is a high index of clinical suspicion. A contrast-enhanced swallow study is only indicated if there is suspicion of an oesophageal tear or rupture. Evidence suggests that patients with SPM can be managed conservatively and observed for 24 h. PMID- 25432912 TI - Supraclavicular mass in a patient with chronic kidney disease. PMID- 25432913 TI - An unprecedented radiological presentation of a pulmonary cement embolism. PMID- 25432914 TI - Orgasmic dural tear: an unusual delayed presentation of postural headache following lumbar discectomy. AB - A 28-year-old woman presented with a severe unremitting frontal postural headache associated with photophobia. This started immediately after standing following reaching orgasm during sexual intercourse. Fifty-two days previously, the patient underwent bilateral L4-L5 decompression laminotomies and a left L4-L5 discectomy for excision of a large herniated intervertebral disc. Subarachnoid haemorrhage was excluded with a CT scan. Brain and lumbar MRI showed enhancement of the pachymeninges and a cerebrospinal fluid (CSF) leak into the deep soft tissue planes. Conservative treatment for 5 days failed to alleviate the patient's symptoms. An exploration and repair of a dural tear was performed. Subsequently, the headache subsided but the patient developed a low-grade infection requiring 12 weeks of antibiotics. Six months later the patient was asymptomatic. This is the first case report of a delayed presentation of a dural tear occurring during sexual intercourse following lumbar surgery. PMID- 25432915 TI - Vanishing bile duct syndrome in the context of concurrent temozolomide for glioblastoma. AB - Temozolomide, an oral alkylating agent, is used in the treatment of glioblastoma. We describe a case of a 62-year-old woman developing jaundice with significant derangement of liver function tests on day 17 of focal radiotherapy with concomitant temozolomide. There was no structural abnormality on imaging and liver biopsy was performed. Pathology revealed absence of small terminal bile ducts affecting up to 60% of sampled portal tracts and senescence of many of the remaining small bile ducts, in keeping with a diagnosis of acute vanishing bile duct syndrome. This is a rare syndrome. It has been documented in association with Hodgkin's lymphoma and viral causes. Drugs implicated as precipitating this condition include antiseizure medications, some antibiotics, ibuprofen and antifungals. Temozolomide was stopped. The patient received supportive care, ursodeoxycholic acid 750 mg daily and cholestyramine 4 g twice daily. She was otherwise asymptomatic and her blood results returned to normal by day 129. PMID- 25432917 TI - The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review. AB - STUDY QUESTION: Is preimplantation genetic diagnosis for aneuploidy (PGD-A) with analysis of all chromosomes during assisted reproductive technology (ART) clinically and cost effective? SUMMARY ANSWER: The majority of published studies comparing a strategy of PGD-A with morphologically assessed embryos have reported a higher implantation rate per embryo using PGD-A, but insufficient data has been presented to evaluate the clinical and cost-effectiveness of PGD-A in the clinical setting. WHAT IS KNOWN ALREADY: Aneuploidy is a leading cause of implantation failure, miscarriage and congenital abnormalities in humans, and a significant cause of ART failure. Preclinical evidence of PGD-A indicates that the selection and transfer of euploid embryos during ART should improve clinical outcomes. STUDY DESIGN, SIZE AND DURATION: A systematic review of the literature was performed for full text English language articles using MEDLINE, EMBASE, SCOPUS, Cochrane Library databases, NHS Economic Evaluation Database and EconLit. The Downs and Black scoring checklist was used to assess the quality of studies. Clinical effectiveness was measured in terms of pregnancy, live birth and miscarriage rates. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Nineteen articles meeting the inclusion criteria, comprising three RCTs in young and good prognosis patients and 16 observation studies were identified. Five of the observational studies included a control group of patients where embryos were selected based on morphological criteria (matched cohort studies). MAIN RESULTS AND ROLE OF CHANCE: Of the five studies that included a control group and reported implantation rates, four studies (including two RCTs) demonstrated improved implantation rates in the PGD-A group. Of the eight studies that included a control group, six studies (including two RCTs) reported significantly higher pregnancy rates in the PGD-A group, and in the remaining two studies, equivalent pregnancies rates were reported despite fewer embryos being transferred in the PGD-A group. The three RCTs demonstrated benefit in young and good prognosis patients in terms of clinical pregnancy rates and the use of single embryo transfer. However, studies relating to patients of advanced maternal age, recurrent miscarriage and implantation failure were restricted to matched cohort studies, limiting the ability to draw meaningful conclusions. LIMITATIONS, REASONS FOR CAUTION: Relevant studies may have been missed and findings from RCTs currently being undertaken could not be included. WIDER IMPLICATIONS OF THE FINDINGS: Given the uncertain role of PGD-A techniques, high-quality experimental studies using intention-to-treat analysis and cumulative live birth rates including the comparative outcomes from remaining cryopreserved embryos are needed to evaluate the overall role of PGD-A in the clinical setting. It is only in this way that the true contribution of PGD-A to ART can be understood. PMID- 25432918 TI - Sleep disturbances in a community-based sample of women with polycystic ovary syndrome. AB - STUDY QUESTION: Is there an excess of sleep disturbances in women with polycystic ovary syndrome (PCOS) in a community-based sample? STUDY ANSWER: Sleep disturbances are almost twice as common in women with PCOS compared with women of similar age without PCOS, with the association slightly accounted for by body weight and, to a greater extent, by depressive symptoms. WHAT IS KNOWN ALREADY: There is an excess of sleep-disordered breathing in clinical samples of women with PCOS, after accounting for their profile of body weight. Poor sleep patterns increase insulin resistance and thus may exacerbate PCOS symptoms and longer-term risk of metabolic disease. STUDY DESIGN, SIZE, DURATION: A cross-sectional study of 724 women, comprising 74% of a cohort study established retrospectively when women were around age 30 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Comparisons were made between 87 women with PCOS, diagnosed using the Rotterdam criteria, and 637 women without this diagnosis in Adelaide, South Australia. Differences in sleep disturbances, assessed using a modified version of the Jenkins questionnaire, were investigated using ordered logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: Sleep disturbances were twice as common in women with PCOS compared with those without. Specifically, PCOS was associated with increasing occurrence of difficulty falling asleep (odds ratio (OR) 1.94, 95% confidence interval (CI) 1.28-2.95); this association was attenuated but still statistically significant after accounting for BMI and depressive symptoms. Increasing occurrence of difficulty maintaining sleep (OR 1.92 95% CI 1.12-3.31) was mediated by obesity and depressive symptoms, together. Other factors did not change these findings. LIMITATIONS, REASONS FOR CAUTION: The cross-sectional nature of the study means that the direction of associations between PCOS and sleep disturbances is unclear, although bi-directionality for the mediators is likely based on data in the wider literature. WIDER IMPLICATIONS OF THE FINDINGS: Our results indicate that assessment and management of both sleep and mental health problems in women with PCOS should be undertaken. Longitudinal data would be valuable to see how poor sleep affects longer-term health profiles. PMID- 25432919 TI - Characterization of anastrozole effects, delivered by an intravaginal ring in cynomolgus monkeys. AB - STUDY QUESTION: Is it feasible to deliver anastrozole (ATZ), an aromatase inhibitor (AI), by a vaginal polymer-based drug delivery system in the cynomolgus monkey (Macaca fascicularis) to describe the pharmacokinetic profile? SUMMARY ANSWER: The present study showed the effective release of ATZ into the systemic circulation from intravaginal rings in cynomolgus monkeys. WHAT IS KNOWN ALREADY: ATZ is a marketed drug with well documented pharmacological and safety profiles for oral administration. Aromatase is the key enzyme catalyzing estrogen biosynthesis and is overexpressed in endometriotic lesions. AIs show therapeutic efficacy in endometriosis in exploratory clinical trials. STUDY DESIGN, SIZE, DURATION: The pharmacokinetics of the in vivo release and the pharmacodynamic activity of ATZ released by intravaginal rings (IVR) were investigated in healthy cycling female cynomolgus monkeys in three different dose groups (n = 5) for one menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: IVRs for the cynomolgus monkey, releasing three different doses of ATZ were designed and tested for in vitro/in vivo release for up to 42 days. For pharmacokinetic and pharmacodynamic evaluation, plasma samples were taken once daily from Day 1 to 3 and then every third day until menses occurred (17-42 days). MAIN RESULTS AND THE ROLE OF CHANCE: ATZ was shown to be compatible with the IVR drug delivery system. An average in vivo release of 277 ug/day/animal of ATZ for one menstrual cycle was effective in causing a decrease of systemic estradiol (E2) levels by ~30% without inducing counter regulation such as the elevation of FSH or the formation of ovarian cysts. LIMITATIONS, REASONS FOR CAUTION: The study was limited to three dose groups in which only the highest dose decreased the E2 level. Hence, additional research with IVRs releasing higher amounts of ATZ is required to define the threshold for an ATZ-dependent ovarian stimulation in cynomolgus monkeys. WIDER IMPLICATIONS OF THE FINDINGS: The release rate administered from IVRs is sufficient and in a range that supports feasibility of IVR administration of ATZ as a new approach for long-term therapy of estrogen-dependent diseases such as endometriosis in human. PMID- 25432920 TI - No benefit of culturing embryos in a closed system compared with a conventional incubator in terms of number of good quality embryos: results from an RCT. AB - STUDY QUESTION: Does culture in a closed system result in an increased number of good quality embryos (GQE) on Day 2 compared with culture in a conventional system? SUMMARY ANSWER: Culture in a closed system up to 2 days after microinjection results in similar embryo development and morphological quality compared with culture in a conventional incubation system. WHAT IS KNOWN ALREADY: Time-lapse imaging (TLI) incubators are rapidly being introduced into IVF laboratories worldwide, despite the lack of large prospective randomized trials demonstrating improvement in embryo development or pregnancy rates. STUDY DESIGN, SIZE, DURATION: A randomized controlled trial including 364 patients (365 cycles) was conducted between May 2010 and February 2014. After oocyte collection, randomization was carried out and all of a patients' oocytes were allocated to culture in either a conventional incubator or a closed incubator system in proportion 1:2 until embryo transfer on Day 2. A total of 1979 oocytes were injected and cultured in the closed system, and 1000 in the standard incubator. The primary end-point was the number of GQE in the two groups. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: In total, 364 patients undergoing their first IVF cycle using ICSI, where at least one oocyte was retrieved, were randomized in a university hospital setting. Two hundred and forty patients were randomized for culture in a closed system and 124 patients for culture in the conventional incubator system (control group). Embryo assessments and final morphological scoring before transfer and cryopreservation were carried out at the same time points for embryos cultured in the conventional incubator and in the closed system. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in the mean +/- SD number of GQEs between groups: 2.41 +/- 2.27 for the closed system group and 2.19 +/- 1.82 for the control group (P = 0.34, difference 0.23, 95% confidence interval 0.69; -0.24). No significant differences were found in the number of 4-cell embryos, implantation-, pregnancy- or ongoing pregnancy rates. A significantly higher miscarriage rate was found in the TLI group compared with the control group (33.3 and 10.2%, P = 0.01). LIMITATIONS, REASONS FOR CAUTION: Culture media, temperature and gas levels were similar in the open and closed incubator systems, but different culture dishes were used. Culturing embryos for longer time period (to the blastocyst stage) may give different results. Only ICSI patients were included, which may limit the generalizability of the results. Finally, the number of GQEs on Day 2 was used as a surrogate outcome for live birth. WIDER IMPLICATIONS OF THE FINDINGS: The results are consistent with other, smaller randomized trials showing no difference in embryo quality when comparing culture in a conventional incubator with that of a closed TLI incubator system. PMID- 25432921 TI - Endometriosis also affects the decidua in contact with the fetal membranes during pregnancy. AB - STUDY QUESTION: Are the fetal membranes of women affected with endometriosis similar to those from disease-free women? SUMMARY ANSWER: Decidua of women with endometriosis is able to generate endometriotic-like lesions in contact with the fetal membranes. WHAT IS KNOWN ALREADY: Eutopic endometrium of women affected with endometriosis presents compromised properties. Endometrium undergoes decidualisation to accept and to further control the conceptus development during pregnancy. Decidualized endometrium is in close contact with the chorionic membrane and forms the choriodecidual layer, a major maternal-fetal interface. STUDY DESIGN, SIZE, DURATION: This is a laboratory case-control study involving diseased versus control samples. Eleven case samples and 11 control samples were collected from women in a tertiary care/research center between November 2011 and December 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were consecutive pregnant women affected with confirmed endometriosis and disease free women, who underwent Cesarean section before labor for obstetrical indication. The choriodecidual tissues were characterized using histology, immunohistochemistry, transcriptomic and whole genome CpG methylation analyses. MAIN RESULTS AND THE ROLE OF CHANCE: We demonstrate for the first time the presence of endometriotic-like lesions within the decidual side of the choriodecidua of the fetal membranes from women affected with severe endometriosis. Fetal membranes from women affected with endometriosis exhibited glandular components in the choriodecidual layer surrounded by enlarged decidualized cells disseminated along the entire membrane surface. Significant deregulation (variation of expression >=2, P-value <=0.05) was observed for 2773 genes known to be enriched in processes involved in glandular function, endocrine and nervous system, neoangiogenesis, and autoimmune disease. CpG methylation analysis revealed 5999 differentially methylated regions with a P-value <=0.05. LIMITATIONS, REASONS FOR CAUTION: We studied women who delivered at term by Cesarean section before labor, following an uneventful pregnancy. Notwithstanding this, one cannot exclude that the presence of disseminated endometriotic lesions within the choriodecidual layer of the fetal membranes may disturb the anatomical integrity and/or the function of the membranes in some women with endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: Our results shed new light on the capability of the diseased decidua to develop lesions not only at ectopic autologous locations, but also on the semi-allogenous fetal membranes, a particularly immunotolerant environment. PMID- 25432922 TI - Does oocyte banking for anticipated gamete exhaustion influence future relational and reproductive choices? A follow-up of bankers and non-bankers. AB - STUDY QUESTION: What is the nature of the relational status, reproductive choices and possible regret of a pioneer cohort of women that either considered or actually performed oocyte banking for anticipated gamete exhaustion (AGE)? SUMMARY ANSWER: Only half of the women who banked oocytes anticipate using them in the future but the experience with oocyte banking is overwhelmingly positive, with the majority of AGE bankers preferring to have it performed at a younger age. WHAT IS KNOWN ALREADY: Most women who choose to cryopreserve oocytes for the prevention of age-related fertility decline are single and are hoping to buy time in their search for a suitable partner. The question of why some candidates actually embark on such treatment while others eventually prefer not to freeze remains unclear. There are no follow-up data available either on post-freezing changes in relational status, or on attitude towards the undergone treatment and the reproductive outcome. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study was performed with 140 women who visited the outpatient clinic between 2009 and 2011. All women (mean age 36.7 +/- SD 2.62) considered oocyte preservation for age-related infertility. At least 1 year after their initial visit (range 12 45 months), women were contacted by phone to participate in a standardized questionnaire developed to evaluate their actual relational and reproductive situation, their attitude towards banking and future reproductive plan. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eighty-six women (61.4%) completed at least one cryopreservation cycle. The non-bankers included 54 women who either preferred no treatment (n = 51) or attempted stimulation but cancelled because of poor response (n = 3). The response rate among bankers was 75.4% (65/86) while 55.8% (29/52) of the non-bankers were reached for interview. MAIN RESULTS AND THE ROLE OF CHANCE: Among bankers, 50.8% of women think they will use the oocytes at some point, while 29.2% indicated that they currently consider the use of frozen oocytes less likely than anticipated at time of oocyte retrieval. However, although 95.4% would decide to do it again, the majority (76.0%) would prefer to do it at a younger age. Among bankers, 96.1% would recommend the treatment to others. Women who banked accept a higher maximum age for motherhood when compared with non-bankers (43.6 versus 42.5 years; P < 0.05). Almost all bankers and 89.6% of the non-bankers still have a desire for a child. Bankers and non-bankers did not differ in terms of experiencing steady relations (47.7 versus 55.2%), attempting conception (35.4 versus 44.8%) and not conceiving within 1 year (17.4 versus 15.4%). LIMITATIONS, REASONS FOR CAUTION: The study has a limited follow up of 1-3 years and therefore does not provide information on the reproductive outcome of the cryopreserved oocytes. Although most women appear to be realistic about their chances of pregnancy, the outcome of such treatment could affect the attitude of women towards the treatment. Furthermore, the findings of non-bankers cannot be generalized to the general population because the control group of non bankers in this study actually visited a centre as a potential candidate for banking. WIDER IMPLICATIONS OF THE FINDINGS: Bankers and non-bankers have a surprising congruent relational status and reproductive choices, indicating that freezing oocytes does not appear to influence the life choices of the women. The study provides insights into the important psychological aspect of reassurance associated with preventive oocyte banking, expressed by high satisfaction after banking in combination with a decreased intention of ever using the eggs. PMID- 25432923 TI - Endometriotic ovarian cysts do not negatively affect the rate of spontaneous ovulation. AB - STUDY QUESTION: Do endometriotic ovarian cysts influence the rate of spontaneous ovulation? SUMMARY ANSWER: Endometriotic cysts, no matter what their volume, do not influence the rate of spontaneous ovulation in the affected ovary. WHAT IS KNOWN ALREADY: Endometriotic ovarian cysts may negatively affect spontaneous ovulation in the affected ovary. STUDY DESIGN, SIZE, DURATION: This was a prospective observational study performed between September 2009 and June 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included women of reproductive age with regular menstrual cycles and unilateral ovarian endometriomas (diameter >=20 mm) desiring to conceive. Exclusion criteria were: hormonal therapies in the 3 months prior to study entry and previous adnexal surgery. Patients underwent serial transvaginal ultrasound to assess the side of ovulation (for up to six cycles). MAIN RESULTS AND THE ROLE OF CHANCE: Ovulation was monitored in 1199 cycles in 244 women (age, mean +/- SD, 34.3 +/- 4.9 years). 55.3% of the patients had left endometriomas and 44.7% had right endometriomas (P = 0.024). The mean (+/-SD) diameter of the endometriomas was 5.3 cm (+/-1.7 cm). Ultrasonographically documented ovulation occurred in 596 cycles in the healthy ovary (49.7%; 95% CI, 46.8-52.6%) and in 603 cycles in the affected ovary (50.3%; 95% CI, 47.1-53.2%; P = 0.919). This observation was confirmed in patients with diameter of the cyst >=4 cm (n = 166) and in those with diameter of the cyst >=6 cm (n = 45). One hundred and five patients spontaneously conceived (43.0%; 95% CI, 36.7-49.5%). LIMITATIONS, REASON FOR CAUTION: The high pregnancy rate reported in this study was observed in a selected population of women with endometriomas and cannot be extrapolated to all patients with endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: Since ovarian endometriomas do not impair spontaneous ovulation, the impact on fertility of surgical excision of ovarian endometriomas should be further investigated. PMID- 25432924 TI - Recurrent miscarriage in translocation carriers: no differences in clinical characteristics between couples who accept and couples who decline PGD. AB - STUDY QUESTION: Do clinical characteristics of recurrent miscarriage couples with a chromosomal abnormality and who opt for PGD differ from couples that decline PGD after extensive genetic counselling? SUMMARY ANSWER: No differences in clinical characteristics are identified between recurrent miscarriage couples carrying a structural chromosomal abnormality who opt for PGD compared with those that decline PGD after extensive genetic counselling. WHAT IS KNOWN ALREADY: Couples who have experienced two or more miscarriages (recurrent miscarriage) are at increased recurrence risk if one of the partners carries a structural chromosomal abnormality. PGD can be offered to avoid (another) miscarriage or pregnancy termination when (invasive) prenatal diagnosis shows an abnormal result. To date, no reports are available that describe reproductive decision making after genetic counselling on PGD in these specific couples. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 294 couples carrying a structural chromosomal abnormality seeking genetic counselling on PGD between 1996 and 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were recurrent miscarriage couples carrying a structural chromosomal abnormality. They had been referred for genetic counselling to the only national licensed PGD centre. Clinical characteristics analysed included couple associated characteristics, characteristics concerning reproductive history and external characteristics such as type of physician that referred the couple for genetic counselling and the clinical geneticist performing the counselling on PGD. MAIN RESULTS AND THE ROLE OF CHANCE: Of 294 couples referred for counselling on PGD, 26 were not accepted because they did not meet the criteria for IVF-PGD. The remaining cohort of 268 couples consisted of two-thirds female and one-third male carriers. Main PGD indications were reciprocal translocations (83.9%) and Robertsonian translocations (16.7%). Following genetic counselling, 76.9% of included couples chose PGD as their reproductive option, the others declined PGD. Reproductive choice is not influenced by sex of the translocation carrier (P = 0.499), type of chromosomal abnormality (P = 0.346), number of previous miscarriages (P = 0.882), history of termination of pregnancy (TOP) because of an unbalanced fetal karyotype (P = 0.800), referring physician (P = 0.208) or geneticist who performed the counselling (P = 0.410). LIMITATIONS, REASONS FOR CAUTION: This study only included recurrent miscarriage couples carrying a structural chromosomal abnormality, who were actually referred to a PGD clinic for genetic counselling. We lack information on couples who were not referred for PGD. Some of these patients may not have been informed on PGD at all, while others were not referred for counselling because they did not opt for PGD to start with. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that reproductive choices in couples with recurrent miscarriage on the basis of a structural chromosomal abnormality are not influenced by characteristics of the couple itself, nor by their obstetric history or external characteristics. These findings suggest that a couples' intrinsic attitude towards PGD treatment is a major factor influencing their reproductive choice. Future research will focus on these personal motives that seem to push reproductive decision-making following genetic counselling in a given direction. PMID- 25432925 TI - Insulin-like growth factor 1 increases apical fibronectin in blastocysts to increase blastocyst attachment to endometrial epithelial cells in vitro. AB - STUDY QUESTION: Does insulin-like growth factor 1 (IGF1) increase adhesion competency of blastocysts to increase attachment to uterine epithelial cells in vitro? SUMMARY ANSWER: IGF1 increases apical fibronectin on blastocysts to increase attachment and invasion in an in vitro model of implantation. WHAT IS KNOWN ALREADY: Fibronectin integrin interactions are important in attachment of blastocysts to uterine epithelial cells at implantation. STUDY DESIGN, SIZE, DURATION: Mouse blastocysts (hatched or near completion of hatching) were cultured in serum starved (SS) medium with varying treatments for 24, 48 or 72 h. Treatments included 10 ng/ml IGF1 in the presence or absence of the PI3 kinase inhibitor LY294002, an IGF1 receptor (IGF1R) neutralizing antibody or fibronectin. Effects of treatments on blastocysts were measured by attachment of blastocysts to Ishikawa cells, blastocyst outgrowth and fibronectin and focal adhesion kinase (FAK) localization and expression. Blastocysts were randomly allocated into control and treatment groups and experiments were repeated a minimum of three times with varying numbers of blastocysts used in each experiment. FAK and integrin protein expression on Ishikawa cells was quantified in the presence or absence of IGF1. PARTICIPANTS/MATERIALS, SETTING, METHODS: Fibronectin expression and localization in blastocysts was studied using immunofluorescence and confocal microscopy. Global surface expression of integrin alphavbeta3, beta3 and beta1 was measured in Ishikawa cells using flow cytometry. Expression levels of phosphorylated FAK and total FAK were measured in Ishikawa cells and blastocysts by western blot and image J analysis. Blastocyst outgrowth was quantified using image J analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The presence of IGF1 significantly increased mouse blastocyst attachment to Ishikawa cells compared with SS conditions (P < 0.01). IGF1 treatment resulted in distinct apical fibronectin staining on blastocysts, which was reduced by the PI3 kinase inhibitor LY294002. This coincided with a significant increase in blastocyst outgrowth in the presence of IGF1 (P < 0.01) or fibronectin (P < 0.001), which was abolished by LY294002 (P < 0.001). Apical expression of integrin alphavbeta3, beta3 and beta1 in Ishikawa cells was unaltered by IGF1. However, IGF1 increased phosphorylated FAK (P < 0.05) and total FAK expression in Ishikawa cells. FAK signalling is linked to integrin activation and can affect the integrins' ability to bind and recognize extracellular matrix proteins such as fibronectin. Treatment of blastocysts with IGF1 before co-culture with Ishikawa cells increased their attachment (P < 0.05). This effect was abolished in the presence of LY294002 (P < 0.001) or an IGF1R neutralizing antibody (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: This study uses an in vitro model of attachment that uses mouse blastocysts and human endometrial cells. This involves a species crossover and although this use has been well documented as a model for attachment (as human embryo numbers are limited) the results should be interpreted carefully. WIDER IMPLICATIONS OF THE FINDINGS: This study presents mechanisms by which IGF1 improves attachment of blastocysts to Ishikawa cells and documents for the first time how IGF1 can increase adhesion competency in blastocysts. Failure of the blastocyst to implant is the major cause of human assisted reproductive technology (ART) failure. As growth factors are absent during embryo culture, their addition to embryo culture medium is a potential avenue to improve IVF success. In particular, IGF1 could prove to be a potential treatment for blastocysts before transfer to the uterus in an ART setting. PMID- 25432926 TI - Patient preference for a long-acting recombinant FSH product in ovarian hyperstimulation in IVF: a discrete choice experiment. AB - STUDY QUESTION: What factors or attributes of a long-acting recombinant FSH (rFSH) or daily-administrated rFSH influence women's preferences IVF? SUMMARY ANSWER: Patients' preferences for rFSH products are primary influenced by the attribute 'number of injections', but a low 'number of injections' is exchanged for a high 'number of injections' at a 6.2% decrease in 'risk of cycle cancellation due to low response' and at a 4.5% decrease in 'chance of OHSS'. WHAT IS KNOWN ALREADY: Injections of long-acting rFSH have been claimed to be preferred over daily-administrated rFSH injections, but patient preference studies to underpin this assumption have not been performed. STUDY DESIGN, SIZE, DURATION: A discrete choice experiment (DCE) was created to assess women's preference for long-acting or daily-administrated rFSH under varying attributes of efficiency, safety and burden. The selected attributes were the 'total number of injections', 'chance of ovarian hyperstimulation syndrome (OHSS)' and the 'risk of cycle cancellation due to low response'. Questionnaires were handed out during information gathering sessions in one academic hospital and two teaching hospitals in The Netherlands between April 2011 and April 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women at the start of their first IVF treatment were asked to participate in this patient preference study. Participation was voluntary. We analysed the data by using mixed logit models to estimate the utility of each attribute. MAIN RESULTS AND THE ROLE OF CHANCE: Questionnaires (n = 125) were handed out with a response rate of 77% (97/125). Four respondents did not complete the questionnaire. Hence, there were 93 questionnaires available for analysis. All attributes significantly influenced women's preference. Overall, the lower 'number of injections' was preferred above the higher 'number of injections' (mean coefficient 1.25; P < 0.001), while an increase of 1% in 'chance of OHSS' or 5% 'risk of cycle cancellation due to low response' was non-preferred (mean coefficients -0.31 and -0.24, respectively, P < 0.01). The majority of respondents was willing to trade-off a lower 'number of injections' for a higher 'number of injections' when gaining a 6.2% reduction in 'cycle cancellation due to low response', or a 4.5% reduction in 'chance of OHSS'. LIMITATIONS, REASONS FOR CAUTION: The generalizability of this DCE is limited in time-span. Women may choose differently when they have previous experience with long-acting rFSH, or when they have to pay for the medication, hospital visits and treatments themselves. WIDER IMPLICATIONS OF THE FINDINGS: The results of this DCE helps us to understand the trade-off women make in their preference for a long-acting rFSH product or a daily-administrated rFSH product in IVF and may support doctors when counselling patients. PMID- 25432927 TI - A retrospective evaluation of prognosis and cost-effectiveness of IVF in poor responders according to the Bologna criteria. AB - STUDY QUESTION: Do the Bologna criteria for poor responders successfully identify women with poor IVF outcome? SUMMARY ANSWER: The Bologna criteria effectively identify a population with a uniformly low chance of success. WHAT IS ALREADY KNOWN: Women undergoing IVF who respond poorly to ovarian hyper-stimulation have a low chance of success. Even if improving IVF outcome in this population represents a main priority, the lack of a unique definition of the condition has hampered research in this area. To overcome this impediment, a recent expert meeting in Bologna proposed a new definition of poor responders ('Bologna criteria'). However, data supporting the relevance of this definition in clinical practice are scanty. STUDY DESIGN, SIZE, DURATION: Retrospective study of women undergoing IVF-ICSI between January 2010 and December 2012 in two independent infertility units. Women could be included if they fulfilled the definition of poor ovarian response (POR) according to Bologna criteria prior to initiation of the cycle. Women were included only for one cycle. The main outcome was the live birth rate per started cycle. The perspective of the cost analysis was the one of the health provider. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three-hundred sixty-two women from two independent Infertility Units were selected. A binomial distribution model was used to calculate the 95% CI of the rate of success. Characteristics of women who did and did not obtain a live birth were compared. A logistic regression model was used to adjust for confounders. The economic analysis included costs for pharmacological compounds and for the IVF procedure. The benefits were estimated on quality-adjusted life years (QALY). To develop the model, we used the local life-expectancy tables, we applied a 3% discount of life years gained and we used a 0.07 improvement in quality of life associated with parenthood. Sensitivity analyses were performed varying the improvement of the quality of life and including/excluding the male partner. The reference values for cost-effectiveness were the Italian and the local (Lombardy) gross domestic product (GDP) pro capita per year in the studied period and the upper and lower limits suggested by NICE. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 23 women had a live birth (6%, 95% CI: 4-9%), in line with the previous evidence. This proportion did not significantly differ in the different subgroups of poor responders. Positive predictive factors of success were previous deliveries (adjusted OR = 3.0, 95% CI: 1.1-8.7, P = 0.039) and previous chemotherapy (adjusted OR = 13.9, 95% CI: 2.5-77.2, P = 0.003). Age, serum AMH, serum FSH and antral follicle count were not significantly associated with live birth. The total cost per live birth was 87 748 Euros, corresponding to 49 919 Euros per QALY. This is above both the limits suggested by NICE for cost-effectiveness and the Italian and local GDP pro capita. Sensitivity analyses mainly support the robustness of the conclusion. LIMITATIONS, REASONS FOR CAUTION: We lack a control group and we cannot thus exclude that an alternative definition of poor responders may be equally if not more valid. Moreover, independent validations are warranted prior to concluding that IVF is not cost-effective. Women should thus not be denied treatment based on our findings. Noteworthy, there is also not yet a consensus on the most appropriate economic model to be used. WIDER IMPLICATIONS OF THE FINDINGS: We recommend the use of the Bologna criteria when designing future studies on poor responders. Large multi-centred international studies are now required to draw definite conclusions on the economic profile of IVF in this situation. PMID- 25432928 TI - Reforming the cancer drug fund. PMID- 25432929 TI - Promotion of colorectal cancer invasion and metastasis through activation of NOTCH-DAB1-ABL-RHOGEF protein TRIO. AB - We have recently identified a metastasis suppressor gene for colorectal cancer: AES/Aes, which encodes an endogenous inhibitor of NOTCH signaling. When Aes is knocked out in the adenomatous epithelium of intestinal polyposis mice, their tumors become malignant, showing marked submucosal invasion and intravasation. Here, we show that one of the genes induced by NOTCH signaling in colorectal cancer is DAB1/Dab1. Genetic depletion of DAB1 suppresses cancer invasion and metastasis in the NOTCH signaling-activated mice. DAB1 is phosphorylated by ABL tyrosine kinase, which activates ABL reciprocally. Consistently, inhibition of ABL suppresses cancer invasion in mice. Furthermore, we show that one of the targets of ABL is the RAC/RHOGEF protein TRIO, and that phosphorylation at its Tyr residue 2681 (pY2681) causes RHO activation in colorectal cancer cells. Its unphosphorylatable mutation TRIO Y2681F reduces RHOGEF activity and inhibits invasion of colorectal cancer cells. Importantly, TRIO pY2681 correlates with significantly poorer prognosis of patients with colorectal cancer after surgery. SIGNIFICANCE: These results indicate that TRIO pY2681 is one of the downstream effectors of NOTCH signaling activation in colorectal cancer, and can be a prognostic marker, helping to determine the therapeutic modality of patients with colorectal cancer. PMID- 25432930 TI - Image Guidance-Based Target Volume Margin Expansion in IMRT of Head and Neck Cancer. AB - This study quantifies the setup uncertainties to optimize the planning target volume (PTV) margin based on daily image guidance, its dosimetric impact, and radiobiological implication for intensity-modulated radiation therapy (IMRT) in head and neck cancer. Ten patients were retrospectively chosen who had been treated with IMRT and with daily image-guided radiation therapy (IGRT). The daily setup errors of the 10 patients from on-board imaging for the entire treatment were analyzed. Planning target volumes were generated by expanding the clinical target volumes (CTVs) with 0 to 10 mm margins. The IMRT plans with the same dose volume constraints were created in an Eclipse treatment planning system. The effect of volume expansion was analyzed with biological indices such as tumor control probability, normal tissue complication probability (NTCP), and equivalent uniform dose. Analysis of 906 daily setup corrections using daily IGRT showed that 98% of the daily setups are within +/- 5 mm. The relative increase in PTV-CTV volume from 0 to 10 mm margins provides nearly 4-fold volume increase and is linearly related to monitor unit (MU). The increase in MU is about 5%/mm margin increase. The relative increase in NTCP of parotids from 5 to 10 mm margins is 3.2 +/- 1.15. Increase in PTV margin increases extra tissue volume with a corresponding increase in MU for treatment and NTCP values. Even a small margin increase (eg, 1 mm) may result in increase of more than 20% in relative extra volume and 15% in NTCP value of organs at risk (OARs). With image guidance, the setup uncertainty could be achieved within +/- 5 mm for 98% of the treatments, and a margin <5 mm for PTV may seem desirable to reduce the extra tissue irradiated, but at the expense of a more demanding setup accuracy. PMID- 25432931 TI - Distinguishing Cancerous Liver Cells Using Surface-Enhanced Raman Spectroscopy. AB - Raman spectroscopy has been widely used in biomedical research and clinical diagnostics. It possesses great potential for the analysis of biochemical processes in cell studies. In this article, the surface-enhanced Raman spectroscopy (SERS) of normal and cancerous liver cells incubated with SERS active substrates (gold nanoparticle) was measured using confocal Raman microspectroscopy technology. The chemical components of the cells were analyzed through statistical methods for the SERS spectrum. Both the relative intensity ratio and principal component analysis (PCA) were used for distinguishing the normal liver cells (QSG-7701) from the hepatoma cells (SMMC-7721). The relative intensity ratio of the Raman spectra peaks such as I937/I1209, I1276/I1308, I1342/I1375, and I1402/I1435 was set as the judge boundary, and the sensitivity and the specificity using PCA method were calculated. The results indicated that the surface-enhanced Raman spectrum could provide the chemical information for distinguishing the normal cells from the cancerous liver cells and demonstrated that SERS technology possessed the possible applied potential for the diagnosis of liver cancer. PMID- 25432932 TI - See-saw nystagmus, convergence-retraction nystagmus and contraversive ocular tilt reaction from a paramedian thalamomesencephalic infarct. PMID- 25432933 TI - Surprising ECG pattern suggestive of an anterior wall ischaemia in a patient with occluded distal LCX and non-occlusive RCA disease. PMID- 25432934 TI - Healing words: A study of poetry interventions in dementia care. AB - The personhood movement in dementia research has established the theoretical foundation for implementing cultural arts interventions in care practices. The underlying assumption is that professionals from the visual and the performance arts are well equipped to see the person behind the condition and to focus on possibilities for meaningful relationships in the here and now. This article focuses on poetry interventions as one example of cultural arts interventions. The use of poetry might seem counterintuitive, given that people with dementia lose their language abilities and that poetry is regarded to be the most complex literary form. I will argue that expanding on existing research on poetry interventions from a health and science perspective with a humanities approach will help illuminate how poetry works to enhance the exchange with people with dementia. Drawing on participant observations of poetry interventions by Gary Glazner (Alzheimer's Poetry Project, USA) at the New York Memory Center, I will frame poetry interventions as a specific form of oral poetry in which people with dementia are positioned as cocreators of embodied texts and directly benefit from the power of the spoken word. PMID- 25432935 TI - Implementation of a baby doll therapy protocol for people with dementia: Innovative practice. AB - Dementia is exhibited by both emotional and physical states such as agitation. Chemical restraints, often used for agitated behaviors, are not always effective and produce untoward effects. Baby doll therapy is a nonpharmacologic therapy that can affect agitated behavior in dementia patients, yet a protocol for the therapy did not exist. An implementation protocol for doll therapy for those with dementia was developed and implemented with 16 residents in a dementia care center. Outcomes were measurements of the impact of the dolls on six areas of the resident's behavior and their reactions to the doll. Participants had an increase in level of happiness, activity/liveliness, interaction with staff and others, and ease of giving care. There was also a reduction in the level of anxiety. The increase in happiness was a statistically significant outcome. Baby doll therapy is an effective nonpharmacological approach for improving the well-being of patients with moderate to severe dementia. PMID- 25432936 TI - Treatment Attrition of Probationers With Mental Illness From an Enhanced Day Reporting Center. AB - Treatment completion is an important outcome for both mental health and criminal justice agencies tasked with managing offenders with mental illness in the community. Previous research has shown that greater degrees of criminogenic risk factors (e.g., specific criminal history variables) predict treatment non completion among legally mandated populations. However, most studies were conducted with offenders without mental illness. In this study, demographic (e.g., age, gender), clinical (e.g., psychiatric diagnosis), and criminogenic risk factors (measured using the Level of Service Inventory-Revised [LSI-R]) were compared by treatment completion status using 167 probationers with mental illness treated at an enhanced day reporting center. Bivariate and multivariate (i.e., forward entry logistic regression) analyses revealed that while the LSI-R total score was unrelated to treatment completion, higher scores on the LSI-R Alcohol and Drug use subscale (odds ratio [OR] = 1.25, 95% confidence interval [CI] = [1.01, 1.54]) and older age (OR = 1.04, 95% CI = [1.00, 1.09]) were significantly predictive of non-completion. PMID- 25432938 TI - Did Chile's traffic law reform push police enforcement? Understanding Chile's traffic fatalities and injuries reduction. AB - BACKGROUND: The objective of the current study is to determine to what extent the reduction of Chile's traffic fatalities and injuries during 2000-2012 was related to the police traffic enforcement increment registered after the introduction of its 2005 traffic law reform. METHODS: A unique dataset with assembled information from public institutions and analyses based on ordinary least square and robust random effects models was carried out. Dependent variables were traffic fatality and severe injury rates per population and vehicle fleet. Independent variables were: (1) presence of new national traffic law; (2) police officers per population; (3) number of traffic tickets per police officer; and (4) interaction effect of number of traffic tickets per police officer with traffic law reform. Oil prices, alcohol consumption, proportion of male population 15-24 years old, unemployment, road infrastructure investment, years' effects and regions' effects represented control variables. RESULTS: Empirical estimates from instrumental variables suggest that the enactment of the traffic law reform in interaction with number of traffic tickets per police officer is significantly associated with a decrease of 8% in traffic fatalities and 7% in severe injuries. Piecewise regression model results for the 2007-2012 period suggest that police traffic enforcement reduced traffic fatalities by 59% and severe injuries by 37%. CONCLUSIONS: Findings suggest that traffic law reforms in order to have an effect on both traffic fatality and injury rates reduction require changes in police enforcement practices. Last, this case also illustrates how the diffusion of successful road safety practices globally promoted by WHO and World Bank can be an important influence for enhancing national road safety practices. PMID- 25432937 TI - Antibiotics in fetal and early life and subsequent childhood asthma: nationwide population based study with sibling analysis. AB - OBJECTIVE: To investigate the association between exposure to antibiotics in fetal and early life and asthma in childhood, with adjustment for confounding factors. DESIGN: Nationwide prospective population based cohort study, including sibling control design. SETTING: Swedish population identified from national demographic and health registers. PARTICIPANTS: 493,785 children born 2006-10; 180,894 of these were eligible for sibling analyses. MAIN OUTCOME MEASURE: Asthma defined as having both an asthma diagnosis and dispensed asthma drugs. The association between antibiotic exposure and asthma was investigated in the whole cohort with Cox proportional hazard regression. A stratified proportional hazards model conditional on sibling group was used to adjust for shared factors within families. Confounding by respiratory infections was assessed by investigating whether specific groups of antibiotics were associated with asthma. RESULTS: Antibiotic exposure in fetal life was associated with an increased risk of asthma in cohort analyses (hazard ratio 1.28, 95% confidence interval 1.25 to 1.32), but not in sibling analyses (0.99, 0.92 to 1.07). In cohort analyses, antibiotics used to treat respiratory infections in childhood were associated with a more pronounced increased risk of asthma (4.12, 3.78 to 4.50) than antibiotics used for urinary tract and skin infections (1.54, 1.24 to 1.92). In sibling analyses, the excess risks after exposure to antibiotics for respiratory infections decreased (2.36, 1.78 to 3.13) and disappeared for antibiotics for urinary tract and skin (0.85, 0.47 to 1.55). CONCLUSIONS: Previous positive associations between exposure to antibiotics in fetal and early life and subsequent childhood asthma could have been caused by confounding by shared familial factors, in addition to confounding by respiratory infections. PMID- 25432939 TI - The Safety Tips for ATV Riders (STARs) programme: short-term impact of a school based educational intervention. AB - BACKGROUND: Since 1985, one-third of all US all-terrain vehicle (ATV)-related injuries and one-quarter of deaths involved victims <16 years of age. ATV safety education of youth could help reduce these tragedies. OBJECTIVES: To assess the efficacy of the Safety Tips for ATV Riders (STARs) school-based programme targeting adolescents. METHODS: A survey was anonymously administered before and after the programme to determine demographics, knowledge and reported likelihood of using the information learned. RESULTS: Over 4600 students in 30 Iowa schools participated from November 2010 to April 2013. Initially, 52% knew most ATVs are designed for one rider, 25% knew the recommended vehicle size for their age range and 42% knew riding on Iowa's roads was legal only for agricultural purposes. After the programme, this increased to 92%, 82% and 76%, respectively (p<0.0001 in each case), with 61% of students correct on all three. Better preintervention scores were associated with being males, higher riding frequency and being from isolated rural communities. After the programme, 48% and 32% said they were likely/very likely versus unlikely/very unlikely to use the safety information learned, respectively; younger students, females and infrequent riders reported higher likelihoods. CONCLUSIONS: STARs increased short-term ATV safety knowledge and almost half the participants reported they would use the safety information presented. Males and frequent riders seemed more resistant, but some groups that may be more vulnerable to potential ATV crash and injury appeared amenable to the training with higher increases in postprogramme scores and greater intention of improving safety behaviours. PMID- 25432940 TI - Nemertean toxin genes revealed through transcriptome sequencing. AB - Nemerteans are one of few animal groups that have evolved the ability to utilize toxins for both defense and subduing prey, but little is known about specific nemertean toxins. In particular, no study has identified specific toxin genes even though peptide toxins are known from some nemertean species. Information about toxin genes is needed to better understand evolution of toxins across animals and possibly provide novel targets for pharmaceutical and industrial applications. We sequenced and annotated transcriptomes of two free-living and one commensal nemertean and annotated an additional six publicly available nemertean transcriptomes to identify putative toxin genes. Approximately 63-74% of predicted open reading frames in each transcriptome were annotated with gene names, and all species had similar percentages of transcripts annotated with each higher-level GO term. Every nemertean analyzed possessed genes with high sequence similarities to known animal toxins including those from stonefish, cephalopods, and sea anemones. One toxin-like gene found in all nemerteans analyzed had high sequence similarity to Plancitoxin-1, a DNase II hepatotoxin that may function well at low pH, which suggests that the acidic body walls of some nemerteans could work to enhance the efficacy of protein toxins. The highest number of toxin like genes found in any one species was seven and the lowest was three. The diversity of toxin-like nemertean genes found here is greater than previously documented, and these animals are likely an ideal system for exploring toxin evolution and industrial applications of toxins. PMID- 25432942 TI - Rewiring of genetic networks in response to modification of genetic background. AB - Genome-scale genetic interaction networks are progressively contributing to map the molecular circuitry that determines cellular behavior. To what extent this mapping changes in response to different environmental or genetic conditions is, however, largely unknown. Here, we assembled a genetic network using an in silico model of metabolism in yeast to explicitly ask how separate genetic backgrounds alter network structure. Backgrounds defined by single deletions of metabolically active enzymes induce strong rewiring when the deletion corresponds to a catabolic gene, evidencing a broad redistribution of fluxes to alternative pathways. We also show how change is more pronounced in interactions linking genes in distinct functional modules and in those connections that present weak epistasis. These patterns reflect overall the distributed robustness of catabolism. In a second class of genetic backgrounds, in which a number of neutral mutations accumulate, we dominantly observe modifications in the negative interactions that together with an increase in the number of essential genes indicate a global reduction in buffering. Notably, neutral trajectories that originate considerable changes in the wild-type network comprise mutations that diminished the environmental plasticity of the corresponding metabolism, what emphasizes a mechanistic integration of genetic and environmental buffering. More generally, our work demonstrates how the specific mechanistic causes of robustness influence the architecture of multiconditional genetic interaction maps. PMID- 25432941 TI - Bioenergetic evolution in proteobacteria and mitochondria. AB - Mitochondria are the energy-producing organelles of our cells and derive from bacterial ancestors that became endosymbionts of microorganisms from a different lineage, together with which they formed eukaryotic cells. For a long time it has remained unclear from which bacteria mitochondria actually evolved, even if these organisms in all likelihood originated from the alpha lineage of proteobacteria. A recent article (Degli Esposti M, et al. 2014. Evolution of mitochondria reconstructed from the energy metabolism of living bacteria. PLoS One 9:e96566) has presented novel evidence indicating that methylotrophic bacteria could be among the closest living relatives of mitochondrial ancestors. Methylotrophs are ubiquitous bacteria that live on single carbon sources such as methanol and methane; in the latter case they are called methanotrophs. In this review, I examine their possible ancestry to mitochondria within a survey of the common features that can be found in the central and terminal bioenergetic systems of proteobacteria and mitochondria. I also discuss previously overlooked information on methanotrophic bacteria, in particular their intracytoplasmic membranes resembling mitochondrial cristae and their capacity of establishing endosymbiotic relationships with invertebrate animals and archaic plants. This information appears to sustain the new idea that mitochondrial ancestors could be related to extant methanotrophic proteobacteria, a possibility that the genomes of methanotrophic endosymbionts will hopefully clarify. PMID- 25432943 TI - TB vaccine development: where are we and why is it so difficult? AB - The development of an effective TB vaccine remains paramount to achieving the goal of global eradication of TB by 2050. The only licensed vaccine, BCG, has variable efficacy and is poorly effective in high burden countries. The development of promising candidate vaccines to either 'boost' a BCG primed immune system or replace BCG altogether is a key area for innovative research. Here, we discuss some of the issues encountered in the development of potential candidate vaccines and the future challenges. PMID- 25432945 TI - Asthma biomarkers: what constitutes a 'gold standard'? PMID- 25432944 TI - Effects of CPAP on body weight in patients with obstructive sleep apnoea: a meta analysis of randomised trials. AB - INTRODUCTION: The impact of obstructive sleep apnoea (OSA) treatment with CPAP on weight is not clear. This meta-analysis was designed to assess whether OSA treatment with CPAP promotes changes in body mass index (BMI) and weight. METHODS: We searched PubMed, SCOPUS and Cochrane Central Register electronic databases through 1 October 2013 (including papers in press at that time), without language restrictions. We identified randomised trials of CPAP versus controls with a minimum treatment duration of 4 weeks that objectively measured BMI. Data were independently abstracted and reviewed by two investigators using a standardised protocol. RESULTS: We included a total of 3181 patients from 25 randomised trials that measured BMI and weight. All studies enrolled mainly overweight and obese patients. The fixed-effects meta-analysis revealed that CPAP promoted significant increase on BMI (Hedges' g=0.14, 95% CI 0.07 to 0.21, I(2)=16.2%) and weight (Hedges' g=0.17, 95% CI 0.10 to 0.24, I(2)=0%). The funnel plot revealed low risk of publication bias. Meta-regression analyses including age, gender, baseline BMI, baseline weight, OSA severity, CPAP compliance, use of sham CPAP, study duration, study design (crossover/parallel), study origin (Western/Eastern), recommendation for dietary changes or physical activity, revealed that no single predictor influenced the main outcome for weight. Baseline weight was a predictor of increased BMI after CPAP. CONCLUSIONS: OSA treatment with CPAP promotes significant increase in BMI and weight. Additional therapies for body weight reduction must be recommended for overweight or obese patients with OSA initiated on CPAP. PMID- 25432946 TI - Assessment of 8-methosypsoralen, lomefloxacin, sparfloxacin, and Pirfenidone phototoxicity in Long-Evans rats. AB - Phototoxicity has a strong impact on drug development. Although several animal models have been developed to quantitatively assess human risks, none have been validated for standardized use. In this study, we validated an in vivo phototoxicity model using Long-Evans (LE) rats treated with 4 well-known phototoxic drugs, namely 8-methoxypsoralen, lomefloxacin, sparfloxacin, and pirfenidone. Daily macroscopic observations of skin and eyes, ophthalmological examinations 4 days after dosing, and blood sampling for toxicokinetics (TKs) were performed after exposure of treated animals to ultraviolet, and dose dependent eye and/or skin reactions were noted for all compounds. Margins of safety were calculated when possible and correlated well with known relative phototoxicity of the 4 compounds. We conclude that the present in vivo phototoxicity assay using LE rats with TK analysis can be used to quantitatively predict the risk of pharmaceutical phototoxicity in humans. PMID- 25432947 TI - Late-onset multiple sclerosis presenting with cognitive dysfunction and severe cortical/infratentorial atrophy. AB - OBJECTIVE: Although cognitive dysfunction is a relevant aspect of multiple sclerosis (MS) from the earliest disease phase, cognitive onset is unusual thus jeopardizing early and accurate diagnosis. Here we describe 12 patients presenting with cognitive dysfunction as primary manifestation of MS with either mild or no impairment in non-cognitive neurological domains. METHODS: Twelve patients with cognitive onset who were subsequently diagnosed with MS (CI-MS) were included in this retrospective study. Twelve cognitively normal MS patients (CN-MS), 12 healthy controls and four patients having progressive supranuclear palsy (PSP) served as the reference population. RESULTS: Ten CI-MS patients had progressive clinical course and all patients had late disease onset (median age = 49 years; range = 40-58 years). Among cognitive functions, frontal domains were the most involved. Compared to CN-MS and healthy controls, significant cortical and infratentorial atrophy characterized CI-MS patients. Selective atrophy of midbrain tegmentum with relative sparing of pons, known as "The Hummingbird sign," was observed in eight CI-MS and in three PSP patients. DISCUSSION: Our observation suggests that MS diagnosis should be taken into consideration in case of cognitive dysfunction, particularly when associated with slowly progressive disease course and severe cortical, cerebellar and brainstem atrophy even in the absence of other major neurological symptoms and signs. PMID- 25432948 TI - Dimethyl fumarate associated lymphopenia in clinical practice. PMID- 25432949 TI - Visceral leishmaniasis infection in a fingolimod-treated multiple sclerosis patient. PMID- 25432950 TI - Focal demyelinative damage and neighboring white matter integrity: an optic neuritis study. AB - BACKGROUND: Neuronal loss following damage is often greater than expected from the severity of injury to the nerve itself. The visual pathways, which comprise a well-defined system, and optic neuritis (ON), which is usually a discrete event, make a fine model to study this phenomenon. OBJECTIVE: Understand the effect of focal optic nerve demyelination on neighboring white matter. METHODS: Diffusion tensor imaging and probabilistic tractography were used to identify and characterize the optic tracts and radiations of 17 ON and matched controls. Data were correlated with retinal nerve fiber layer (RNFL) thickness. RESULTS: Patients' optic tracts exhibited reduced axial diffusivity, which correlated with RNFL thickness values. Patients' optic radiations demonstrated intact axial diffusivity but reduced fractional anisotropy and elevated radial diffusivity, which could be explained by intra-bundle lesions. No correlations were found between diffusivity measurements in patients' optic tracts and radiations; or between RNFL thickness and optic radiations' diffusivity. CONCLUSIONS: Following ON, chronic axonal loss develops distally in the optic tracts, demonstrating Wallerian degeneration. Degeneration did not proceed to the optic radiations, opposing anterograde trans-neuronal changes. DTI in ON provides fine in-vivo human model for studying histological abnormalities in normal appearing white matter, localized in close proximity to damaged bundle. PMID- 25432951 TI - Impact of anger on the health-related quality of life of multiple sclerosis patients. AB - BACKGROUND: There is evidence of the presence of a disturbed pattern of anger in multiple sclerosis (MS). Emotion changes, including anger, are thought to influence health-related quality of life (HRQoL). However, although deleterious consequences of anger on physical health have been well reported, there are no studies that have analysed the effects of anger on the HRQoL in patients with MS. Our purpose was to assess the extent to which anger impacts on the HRQoL of a cohort of MS patients. METHODS: One hundred and fifty-seven consecutive MS patients were enrolled in the study. Participants were administered affective trait measures (Beck Depression Inventory, Beck Anxiety Inventory) and anger measures (the Spanish adapted version of the State-Trait Anger Expression Inventory-2). HRQoL was quantified using the Functional Assessment of MS. RESULTS: Linear regression analyses revealed that even after controlling for socio-demographic and clinical variables, higher levels of anger expression-in (tendency to handle anger by keeping it inside) independently predicted worse overall HRQoL of MS patients (beta = -0.15, p = 0.04). We further found that this relationship was moderated by gender, showing that anger expression-in is a more influential predictor of the HRQoL in women with MS. CONCLUSION: The present study provides evidence that anger negatively affects the HRQoL of MS patients. Our results may have implications for those involved in treating emotional complications of MS and especially regarding psychotherapeutic interventions to improve HRQoL of MS patients. PMID- 25432952 TI - Peginterferon beta-1a in multiple sclerosis: 2-year results from ADVANCE. AB - OBJECTIVE: To evaluate the efficacy and safety of subcutaneous peginterferon beta 1a over 2 years in patients with relapsing-remitting multiple sclerosis in the ADVANCE study. METHODS: Patients were randomized to placebo or 125 ug peginterferon beta-1a every 2 or 4 weeks. For Year 2 (Y2), patients originally randomized to placebo were re-randomized to peginterferon beta-1a every 2 weeks or every 4 weeks. Patients randomized to peginterferon beta-1a in Year 1 (Y1) remained on the same dosing regimen in Y2. RESULTS: Compared with Y1, annualized relapse rate (ARR) was further reduced in Y2 with every 2 week dosing (Y1: 0.230 [95% CI 0.183-0.291], Y2: 0.178 [0.136-0.233]) and maintained with every 4 week dosing (Y1: 0.286 [0.231-0.355], Y2: 0.291 [0.231-0.368]). Patients starting peginterferon beta-1a from Y1 displayed improved efficacy versus patients initially assigned placebo, with reductions in ARR (every 2 weeks: 37%, p<0.0001; every 4 weeks: 17%, p=0.0906), risk of relapse (every 2 weeks: 39%, p<0.0001; every 4 weeks: 19%, p=0.0465), 12-week disability progression (every 2 weeks: 33%, p=0.0257; every 4 weeks: 25%, p=0.0960), and 24-week disability progression (every 2 weeks: 41%, p=0.0137; every 4 weeks: 9%, p=0.6243). Over 2 years, greater reductions were observed with every 2 week versus every 4 week dosing for all endpoints and peginterferon beta-1a was well tolerated. CONCLUSIONS: Peginterferon beta-1a efficacy is maintained beyond 1 year, with greater effects observed with every 2 week versus every 4 week dosing, and a similar safety profile to Y1.Clinicaltrials.gov REGISTRATION NUMBER: NCT00906399. PMID- 25432953 TI - Effects of tailored risk communications for skin cancer prevention and detection: the PennSCAPE randomized trial. AB - BACKGROUND: Prevention and early detection measures for melanoma, such as sun avoidance and skin examinations, are important, but are practiced inconsistently. In this replication of the Project SCAPE trial, we sought to determine whether tailored print materials were more effective at improving adherence than generic print materials for patients at increased risk of skin cancer. METHODS: Participants were randomized to receive personalized mailed communications about their skin cancer risk and recommended sun protection, or generic mailings. Participants were Caucasian adults, at moderate or high risk for skin cancer, recruited in outpatient primary care. The main outcomes were overall sun protection behaviors and specific protective behaviors including use of sunscreen, shirt, hat, sunglasses, shade, and sun avoidance; recent sunburns; and skin self-examination and provider skin examination. RESULTS: One hundred ninety two (93.2%) subjects completed the study. Six outcome variables showed significant intervention condition effects in mixed effects models: overall sun protection behavior (P = 0.025); sunscreen use (P = 0.026); use of sunglasses (P = 0.011); sunburns in the past three months (P = 0.033); recency of last skin self-exam (P = 0.017); and frequency of skin exams by health care provider (P = 0.016). CONCLUSIONS: Relative to generic communications, tailored risk communications resulted in improved adherence to six skin cancer protective behaviors, including a composite sun protection behavior measure, sunburns, and health care provider skin examinations. IMPACT: Tailored interventions can be more effective in improving patient prevention behaviors than nontailored, generic information for patients at moderate to high risk of skin cancer. PMID- 25432954 TI - Offering Self-Sampling to Non-Attendees of Organized Primary HPV Screening: When Do Harms Outweigh the Benefits? AB - BACKGROUND: Human papillomavirus (HPV) self-sampling might be a promising tool to increase effectiveness of primary HPV screening programs when offered to non attendees. However, effectiveness could decrease if regular attendees "switch" to self-sampling, because self-sampling test characteristics may be inferior. We examined under which conditions the harms would outweigh the benefits. METHODS: The MISCAN-cervix model was used to estimate quality-adjusted life years (QALY) gained and costs of offering HPV self-sampling to non-attendees. We varied the relative CIN2(+) sensitivity and specificity (self-sampling vs. regular sampling), extra attendance, risk of extra attendees, and the switching percentage. RESULTS: Without switching, offering self-sampling is (cost )effective under every studied condition. If the attendance due to self-sampling increases by >=6 percentage points, higher primary background risk women (unscreened women who will never attend regular screening) attend and the relative CIN2(+) sensitivity and specificity are >=0.95; it is (cost-)effective to offer self-sampling to non-attendees, even if all regular attendees switch. If the relative sensitivity decreases to 0.90 combined with either a 3 percentage points extra attendance or the absence of higher primary background risk women, QALYs are lost when more than 30% to 20% of the regular attendees switch. CONCLUSIONS: Offering self-sampling will gain health effects if the relative CIN2(+) sensitivity is >=0.95, unscreened attendees are recruited, and the total attendance increases by >=6 percentage points. Otherwise, switching of regular attendees may decrease the total effectiveness of the program. IMPACT: Self sampling needs to be implemented with great care and advantages of office-based sampling need to be emphasized to prevent switching. PMID- 25432955 TI - Elimination of cap structures generated by mRNA decay involves the new scavenger mRNA decapping enzyme Aph1/FHIT together with DcpS. AB - Eukaryotic 5' mRNA cap structures participate to the post-transcriptional control of gene expression before being released by the two main mRNA decay pathways. In the 3'-5' pathway, the exosome generates free cap dinucleotides (m7GpppN) or capped oligoribonucleotides that are hydrolyzed by the Scavenger Decapping Enzyme (DcpS) forming m7GMP. In the 5'-3' pathway, the decapping enzyme Dcp2 generates m7GDP. We investigated the fate of m7GDP and m7GpppN produced by RNA decay in extracts and cells. This defined a pathway involving DcpS, NTPs and the nucleoside diphosphate kinase for m7GDP elimination. Interestingly, we identified and characterized in vitro and in vivo a new scavenger decapping enzyme involved in m7GpppN degradation. We show that activities mediating cap elimination identified in yeast are essentially conserved in human. Their alteration may contribute to pathologies, possibly through the interference of cap (di)nucleotide with cellular function. PMID- 25432956 TI - Regulation of anti-sense transcription by Mot1p and NC2 via removal of TATA binding protein (TBP) from the 3'-end of genes. AB - The activity and dynamic nature of TATA-binding protein (TBP) crucial to RNA polymerase II-mediated transcription is under control of the Mot1p and NC2 complexes. Here we show that both TBP regulatory factors play 'hidden' roles in ensuring transcription fidelity by restricting anti-sense non-coding RNA (ncRNA) synthesis. Production of anti-sense ncRNA transcripts is suppressed by Mot1p- and NC2-mediated release of TBP from binding sites at the 3'-end of genes. In this, Mot1p and NC2 collaborate with the Nrd1p-Nab3p-Sen1p (NNS) complex that terminates the synthesis of anti-sense ncRNAs. In several cases anti-sense ncRNA expression interferes with expression of the cognate sense transcript. Our data reveal a novel regulatory mechanism to suppress anti-sense ncRNA expression and pre-initiation complex (PIC) formation at spurious sites. PMID- 25432960 TI - Dr Felix Mann. PMID- 25432958 TI - Topological constraints strongly affect chromatin reconstitution in silico. AB - The fundamental building block of chromatin, and of chromosomes, is the nucleosome, a composite material made up from DNA wrapped around a histone octamer. In this study we provide the first computer simulations of chromatin self-assembly, starting from DNA and histone proteins, and use these to understand the constraints which are imposed by the topology of DNA molecules on the creation of a polynucleosome chain. We take inspiration from the in vitro chromatin reconstitution protocols which are used in many experimental studies. Our simulations indicate that during self-assembly, nucleosomes can fall into a number of topological traps (or local folding defects), and this may eventually lead to the formation of disordered structures, characterised by nucleosome clustering. Remarkably though, by introducing the action of topological enzymes such as type I and II topoisomerase, most of these defects can be avoided and the result is an ordered 10-nm chromatin fibre. These findings provide new insight into the biophysics of chromatin formation, both in the context of reconstitution in vitro and in terms of the topological constraints which must be overcome during de novo nucleosome formation in vivo, e.g. following DNA replication or repair. PMID- 25432957 TI - Estimating binding properties of transcription factors from genome-wide binding profiles. AB - The binding of transcription factors (TFs) is essential for gene expression. One important characteristic is the actual occupancy of a putative binding site in the genome. In this study, we propose an analytical model to predict genomic occupancy that incorporates the preferred target sequence of a TF in the form of a position weight matrix (PWM), DNA accessibility data (in the case of eukaryotes), the number of TF molecules expected to be bound specifically to the DNA and a parameter that modulates the specificity of the TF. Given actual occupancy data in the form of ChIP-seq profiles, we backwards inferred copy number and specificity for five Drosophila TFs during early embryonic development: Bicoid, Caudal, Giant, Hunchback and Kruppel. Our results suggest that these TFs display thousands of molecules that are specifically bound to the DNA and that whilst Bicoid and Caudal display a higher specificity, the other three TFs (Giant, Hunchback and Kruppel) display lower specificity in their binding (despite having PWMs with higher information content). This study gives further weight to earlier investigations into TF copy numbers that suggest a significant proportion of molecules are not bound specifically to the DNA. PMID- 25432963 TI - Sustainability and power in health promotion: community-based participatory research in a reproductive health policy case study in New Mexico. AB - Health promotion programs are commonly viewed as value-free initiatives which seek to improve health, often through behavior change. An opposing view has begun to emerge that health promotion efforts, especially ones seeking to impact health policy and social determinants of health, are vulnerable to political contexts and may depend on who is in power at the time. This community-based participatory research study attempts to understand these interactions by applying a conceptual model focused on the power context, diverse stakeholder roles within this context, and the relationship of political levers and other change strategies to the sustainability of health promotion interventions aimed at health policy change. We present a case study of a health promotion coalition, New Mexico for Responsible Sex Education (NMRSE), as an example of power dynamics and change processes. Formed in 2005 in response to federal policies mandating abstinence only education, NMRSE includes community activists, health promotion staff from the New Mexico Department of Health, and policy-maker allies. Applying an adapted Mayer's 'power analysis' instrument, we conducted semi-structured stakeholder interviews and triangulated political-context analyses from the perspective of the stakeholders.We identified multiple understandings of sustainability and health promotion policy change, including: the importance of diverse stakeholders working together in coalition and social networks; their distinct positions of power within their political contexts; the role of science versus advocacy in change processes; the particular challenges for public sector health promotion professionals; and other facilitators versus barriers to action. One problem that emerged consisted of the challenges for state employees to engage in health promotion advocacy due to limitations imposed on their activities by state and federal policies. This investigation's results include a refined conceptual model, a power-analysis instrument, and new understandings of the intersection of power and stakeholder strategies in the sustainability of health promotion and health in all policies. PMID- 25432964 TI - Cyclooxygenase-1 serves a vital hepato-protective function in chemically induced acute liver injury. AB - Cyclooxygenase-1 (COX-1) is the constitutive form of the COX enzyme family, which produces bioactive lipids called prostanoids. Although the role of COX-2 in liver diseases has been studied, little is known about the function of COX-1 in liver injury. We aimed to investigate the role and mechanism of COX-1 in acute liver injury. Carbon tetrachloride (CCl(4)) was administered to induce acute liver injury in wild-type or COX-1-deficient mice. Both genetic (partially or completely) deletion of COX-1 expression and pharmacological inhibition of COX-1 activity in mice exacerbated acute liver injury induced by CCl(4), revealing the (1) histopathological changes and increased serum levels of aminotransferases; (2) oxidative stress in the liver partly through the action of cytochrome P450 2E1-dependent pathway; (3) enhanced inflammatory and chemoattractive responses with increased number of activated macrophages; and (4) increased apoptosis through both intrinsic and extrinsic apoptotic pathways. These pathological changes were partly through the modulation of transcription factor-dependent pathways (eg, NF-kappaB and C/EBP-alpha). Pre-treatment with prostaglandin E2 (PGE(2)) or 5-lipoxygenase (5-LO) inhibitor in homozygous COX-1 knockout mice significantly ameliorated CCl(4)-induced hepatic injury. In addition, level of hepato-protective molecules (eg, OSM and OSMR) and associated liver regeneration pathway were significantly inhibited by the deficiency of COX-1 but restored by the addition of PGE(2) or the inhibition of 5-LO. Furthermore, the alternative arachidonic acid metabolism pathway of 5-LO, which induced additional inflammation in the liver, was activated in response to the deficiency of COX-1. In conclusion, basal expression of COX-1 is essential for the protection of liver against chemical-induced hepatotoxicity and required for hepatic homeostatic maintenance. PMID- 25432965 TI - The Application of Dynamic Time Warping to the Quality Evaluation of Radix Puerariae thomsonii: Correcting Retention Time Shift in the Chromatographic Fingerprints. AB - The application of dynamic time warping (DTW) to the correction of retention time shift in chromatographic fingerprints of Radix Puerariae thomsonii (RPT) was studied. The fingerprints of 27 RPT samples were established with their entire chromatograms. Because there is retention time shift in the obtained fingerprints, the quality of these samples cannot be correctly evaluated by applying similarity estimation and principal component analysis (PCA) to the unaligned fingerprints. Hence, the fingerprints were aligned by using DTW method. After alignment, the retention time shift was corrected satisfactorily and the quality of these RPT samples was correctly evaluated. It is demonstrated that DTW is a practical method for aligning the chromatographic fingerprints of RPT samples. The combination of similarity estimation, PCA and DTW is shown to be a promising method for evaluating the quality of herbal medicines. PMID- 25432966 TI - Soluble CD14, alpha-and beta-defensins in breast milk: association with the emergence of allergy in a high-risk population. AB - As innate immunity factors in breast milk (BM) modulate infants' immune responses, we investigated whether soluble CD14 (sCD14) and defensin levels in BM are associated with the emergence of allergy in childhood. The randomly selected group of 260 mother-child pairs belonged to a randomized, double-blind placebo controlled trial where 1223 mothers with fetuses at high risk for allergy received for the 4 last wk of pregnancy a mixture of probiotics, or placebo; after birth, the child received the treatment for 6 mo. Children were followed for the emergence of sensitization and allergic symptoms for 5 yr. IgE-mediated allergic disorder was diagnosed in 80 children by the age of 5 yr. Levels of sCD14, human neutrophil peptide (HNP) 1-3 and beta-defensin 2 (HBD2) in colostrum and in BM 3 mo post-partum were measured with ELISA. BM sCD14 levels decreased from 0 to 3 mo. HNP1-3 and HBD2 were detected in colostrum, but not in BM 3 mo post-partum. High sCD14 levels in BM 3 mo post-partum were associated with children developing an IgE-mediated allergic disorder by the age of 5 yr. BM HNP1 3, HBD2 or sCD14 levels were not associated with probiotics treatment. Our results suggest that sCD14 in BM influences the emergence of allergy in children with atopic heredity. PMID- 25432967 TI - Effects of gender, cytokine gene polymorphisms and environmental factors on inflammatory responses. AB - Previous studies have indicated that cytokine gene polymorphisms of Indigenous Australians were predominantly associated with strong pro-inflammatory responses. We tested the hypothesis that cells of donors with genetic profiles of inflammatory cytokine single nucleotide polymorphisms (SNPs) similar to Indigenous Australians produce higher pro-inflammatory responses. PBMCs from 14 donors with genetic profiles for a high risk of strong pro-inflammatory responses and 14 with low-risk profiles were stimulated with endotoxin and effects of gender, IFN-gamma, cigarette smoke extract (CSE) and testosterone on cytokine responses analysed. Cytokines were calculated from standard curves (Luminex 2.3 software). No significant differences were associated with SNP profile alone. Lower pro-inflammatory responses were observed for cells from males with low- or high-risk profiles. For cells from females with high-risk profiles, anti inflammatory IL-10 responses were significantly reduced. There was no effect of testosterone levels on responses from males. For females, results from IFN-gamma treated cells showed positive correlations between testosterone levels and IL 1beta responses to endotoxin for both risk groups and TNF-alpha for the high-risk group. If interactions observed among CSE, IFN-gamma, genetic background and testosterone reflect those in vivo, these might contribute to increased incidences of hospitalisations for infectious diseases among Indigenous women. PMID- 25432968 TI - MTGD: The Medicago truncatula genome database. AB - Medicago truncatula, a close relative of alfalfa (Medicago sativa), is a model legume used for studying symbiotic nitrogen fixation, mycorrhizal interactions and legume genomics. J. Craig Venter Institute (JCVI; formerly TIGR) has been involved in M. truncatula genome sequencing and annotation since 2002 and has maintained a web-based resource providing data to the community for this entire period. The website (http://www.MedicagoGenome.org) has seen major updates in the past year, where it currently hosts the latest version of the genome (Mt4.0), associated data and legacy project information, presented to users via a rich set of open-source tools. A JBrowse-based genome browser interface exposes tracks for visualization. Mutant gene symbols originally assembled and curated by the Frugoli lab are now hosted at JCVI and tie into our community annotation interface, Medicago EuCAP (to be integrated soon with our implementation of WebApollo). Literature pertinent to M. truncatula is indexed and made searchable via the Textpresso search engine. The site also implements MedicMine, an instance of InterMine that offers interconnectivity with other plant 'mines' such as ThaleMine and PhytoMine, and other model organism databases (MODs). In addition to these new features, we continue to provide keyword- and locus identifier-based searches served via a Chado-backed Tripal Instance, a BLAST search interface and bulk downloads of data sets from the iPlant Data Store (iDS). Finally, we maintain an E-mail helpdesk, facilitated by a JIRA issue tracking system, where we receive and respond to questions about the website and requests for specific data sets from the community. PMID- 25432969 TI - Triticeae resources in Ensembl Plants. AB - Recent developments in DNA sequencing have enabled the large and complex genomes of many crop species to be determined for the first time, even those previously intractable due to their polyploid nature. Indeed, over the course of the last 2 years, the genome sequences of several commercially important cereals, notably barley and bread wheat, have become available, as well as those of related wild species. While still incomplete, comparison with other, more completely assembled species suggests that coverage of genic regions is likely to be high. Ensembl Plants (http://plants.ensembl.org) is an integrative resource organizing, analyzing and visualizing genome-scale information for important crop and model plants. Available data include reference genome sequence, variant loci, gene models and functional annotation. For variant loci, individual and population genotypes, linkage information and, where available, phenotypic information are shown. Comparative analyses are performed on DNA and protein sequence alignments. The resulting genome alignments and gene trees, representing the implied evolutionary history of the gene family, are made available for visualization and analysis. Driven by the case of bread wheat, specific extensions to the analysis pipelines and web interface have recently been developed to support polyploid genomes. Data in Ensembl Plants is accessible through a genome browser incorporating various specialist interfaces for different data types, and through a variety of additional methods for programmatic access and data mining. These interfaces are consistent with those offered through the Ensembl interface for the genomes of non-plant species, including those of plant pathogens, pests and pollinators, facilitating the study of the plant in its environment. PMID- 25432970 TI - Defective copper transport in the copt5 mutant affects cadmium tolerance. AB - Cadmium toxicity interferes with essential metal homeostasis, which is a problem for both plant nutrition and the consumption of healthy food by humans. Copper uptake is performed by the members of the Arabidopsis high affinity copper transporter (COPT) family. One of the members, COPT5, is involved in copper recycling from the vacuole toward the cytosolic compartment. We show herein that copt5 mutants are more sensitive to cadmium stress than wild-type plants, as indicated by reduced growth. Exacerbated cadmium toxicity in copt5 mutants is due specifically to altered copper traffic through the COPT5 transporter. Three different processes which have been shown to affect cadmium tolerance are altered in copt5 mutants. First, ethylene biosynthesis diminishes under copper deficiency and, in the presence of cadmium, ethylene production diminishes further. Copper deficiency responses are also attenuated under cadmium treatment. Remarkably, while copt5 roots present higher oxidative stress toxicity symptoms than controls, aerial copt5 parts display lower oxidative stress, as seen by reduced cadmium delivery to shoots. Taken together, these results demonstrate that copper transport plays a key role in cadmium resistance, and suggest that oxidative stress triggers an NADPH oxidase-mediated signaling pathway, which contributes to cadmium translocation and basal plant resistance. The slightly lower cadmium levels that reach aerial parts in the copt5 mutants, irrespective of the copper content in the media, suggest a new biotechnological approach to minimize toxic cadmium entry into food chains. PMID- 25432971 TI - RNA-Seq-based transcriptome profiling of early nitrogen deficiency response in cucumber seedlings provides new insight into the putative nitrogen regulatory network. AB - Nitrogen (N) is both an important macronutrient and a signal for plant growth and development. However, the early regulatory mechanism of plants in response to N starvation is not well understood, especially in cucumber, an economically important crop that normally consumes excessive N during production. In this study, the early time-course transcriptome response of cucumber leaves under N deficiency was monitored using RNA sequencing (RNA-Seq). More than 23,000 transcripts were examined in cucumber leaves, of which 364 genes were differentially expressed in response to N deficiency. Based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, gene ontology (GO) and protein-protein interaction analysis, 64 signaling-related N-deficiency responsive genes were identified. Furthermore, the potential regulatory mechanisms of anthocyanin accumulation, Chl decline and cell wall remodeling were assessed at the transcription level. Increased ascorbic acid synthesis was identified in cucumber seedlings and fruit under N-deficient conditions, and a new corresponding regulatory hypothesis has been proposed. A data cross comparison between model plants and cucumber was made, and some common and specific N-deficient response mechanisms were found in the present study. Our study provides novel insights into the responses of cucumber to nitrogen starvation at the global transcriptome level, which are expected to be highly useful for dissecting the N response pathways in this major vegetable and for improving N fertilization practices. PMID- 25432972 TI - Sugar uptake in the Aril of litchi fruit depends on the apoplasmic post-phloem transport and the activity of proton pumps and the putative transporter LcSUT4. AB - The post-phloem unloading pathway and the mechanism of sugar accumulation remain unclear in litchi fruit. A combination of electron microscopy, transport of phloem-mobile symplasmic tracer (carboxyfluorescein, CF) and biochemical and molecular assays was used to explore the post-phloem transport pathway and the mechanism of aril sugar accumulation in litchi. In the funicle, where the aril originates, abundant plasmodesmata were observed, and CF introduced from the peduncle diffused to the parenchyma cells. In addition, abundant starch and pentasaccharide were detected and the sugar concentration was positively correlated with activities of sucrose hydrolysis enzymes. These results clearly showed that the phloem unloading and post-phloem transport in the funicle were symplastic. On the other hand, imaging of CF showed that it remained confined to the parenchyma cells in funicle tissues connecting the aril. Infiltration of both an ATPase inhibitor [eosin B (EB)] and a sucrose transporter inhibitor [p chloromercuribenzene sulfonate (PCMBS)] inhibited sugar accumulation in the aril. These results indicated an apoplasmic post-phloem sugar transport from the funicle to the aril. Although facilitated diffusion might help sucrose uptake from the cytosol to the vacuole in cultivars with high soluble invertase, membrane ATPases in the aril, especially tonoplast ATPase, are crucial for aril sugar accumulation. The expression of a putative aril vacuolar membrane sucrose transporter gene (LcSUT4) was highly correlated with the sugar accumulation in the aril of litchi. These data suggest that apoplasmic transport is critical for sugar accumulation in litchi aril and that LcSUT4 is involved in this step. PMID- 25432973 TI - A maize database resource that captures tissue-specific and subcellular-localized gene expression, via fluorescent tags and confocal imaging (Maize Cell Genomics Database). AB - Maize is a global crop and a powerful system among grain crops for genetic and genomic studies. However, the development of novel biological tools and resources to aid in the functional identification of gene sequences is greatly needed. Towards this goal, we have developed a collection of maize marker lines for studying native gene expression in specific cell types and subcellular compartments using fluorescent proteins (FPs). To catalog FP expression, we have developed a public repository, the Maize Cell Genomics (MCG) Database, (http://maize.jcvi.org/cellgenomics), to organize a large data set of confocal images generated from the maize marker lines. To date, the collection represents major subcellular structures and also developmentally important progenitor cell populations. The resource is available to the research community, for example to study protein localization or interactions under various experimental conditions or mutant backgrounds. A subset of the marker lines can also be used to induce misexpression of target genes through a transactivation system. For future directions, the image repository can be expanded to accept new image submissions from the research community, and to perform customized large-scale computational image analysis. This community resource will provide a suite of new tools for gaining biological insights by following the dynamics of protein expression at the subcellular, cellular and tissue levels. PMID- 25432975 TI - GenomicusPlants: a web resource to study genome evolution in flowering plants. AB - Comparative genomics combined with phylogenetic reconstructions are powerful approaches to study the evolution of genes and genomes. However, the current rapid expansion of the volume of genomic information makes it increasingly difficult to interrogate, integrate and synthesize comparative genome data while taking into account the maximum breadth of information available. GenomicusPlants (http://www.genomicus.biologie.ens.fr/genomicus-plants) is an extension of the Genomicus webserver that addresses this issue by allowing users to explore flowering plant genomes in an intuitive way, across the broadest evolutionary scales. Extant genomes of 26 flowering plants can be analyzed, as well as 23 ancestral reconstructed genomes. Ancestral gene order provides a long-term chronological view of gene order evolution, greatly facilitating comparative genomics and evolutionary studies. Four main interfaces ('views') are available where: (i) PhyloView combines phylogenetic trees with comparisons of genomic loci across any number of genomes; (ii) AlignView projects loci of interest against all other genomes to visualize its topological conservation; (iii) MatrixView compares two genomes in a classical dotplot representation; and (iv) Karyoview visualizes chromosome karyotypes 'painted' with colours of another genome of interest. All four views are interconnected and benefit from many customizable features. PMID- 25432974 TI - Adaptation to the local environment by modifications of the photoperiod response in crops. AB - Flowering plants produce a meristem at the shoot tip where specialized tissue generates shoot apical meristems at the appropriate time to differentiate into reproductive structures, pollinate and efficiently generate seeds. The complex set of molecular and phenological events culminating in development of a flowering meristem is referred to as 'flowering time'. Flowering time affects plant productivity because plants dedicate energy to produce flowers and seeds rather than vegetative tissue once the molecular decision to initiate flowering has been taken. Thus, initiation of flowering time is an important decision in plants, especially in annual plants including crops. Humans have introduced crops into latitudes and climate areas far from their origin or natural ecosystem, requiring in many cases modification of native flowering times. Recent molecular genetic studies shed light on the genetic basis related to such introductions. In this review, recent progress regarding crop introductions and their genetic bases are summarized, as well as the potential of other agricultural plants to be introduced into different climatic zones. PMID- 25432976 TI - Etiological Risk Factors for Sibling Incest: Data From an Anonymous Computer Assisted Self-Interview. AB - Retrospective data from 1,821 women and 1,064 men with one or more siblings, provided anonymously using a computer-assisted self-interview, were used to identify risk factors for sibling incest (SI); 137 were participants in SI. In order of decreasing predictive power, the risk factors identified by the multiple logistic regression analysis included ever having shared a bed for sleeping with a sibling, parent-child incest (PCI), family nudity, low levels of maternal affection, and ever having shared a tub bath with a sibling. The results were consistent with the idea that SI in many families was the cumulative result of four types of parental behaviors: (a) factors that lower external barriers to sexual behavior (e.g., permitting co-sleeping or co-bathing of sibling dyads), (b) factors that encourage nudity of children within the nuclear family and permit children to see the parent's genitals, (c) factors that lead to the siblings relying on one another for affection (e.g., diminished maternal affection), and (d) factors that eroticize young children (e.g., child sexual abuse [CSA] by a parent). Thirty-eight of the 137 SI participants were participants in coerced sibling incest (CSI). In order of decreasing predictive power, risk factors for CSI identified by multiple logistic regression analysis included ever having shared a bed for sleeping with a brother, PCI, witnessing parental physical fighting, and family nudity. SI was more likely to have been reported as CSI if the sibling had touched the reporting sibling's genitals, and less likely to have been reported as CSI if the siblings had shared a bed. PMID- 25432977 TI - Response to comment on: The infective endocarditis team: recommendations from an international working group by San Roman et al. PMID- 25432978 TI - T-wave inversions in athletes: a sheep in wolf's clothing? PMID- 25432979 TI - A meta-analysis of prospective randomized controlled trials evaluating endovascular therapies for acute ischemic stroke. AB - INTRODUCTION: A recent randomized controlled trial (RCT), the Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN), demonstrated better outcomes with endovascular treatment compared with medical therapy for acute ischemic stroke (AIS). However, previous trials have provided mixed results regarding the efficacy of endovascular treatment for AIS. A meta-analysis of all available trial data was performed to summarize the available evidence. METHODS: A literature search was performed to identify all prospective RCTs comparing endovascular therapies with medical management for AIS. Two datasets were created: (1) all patients randomized after confirmation of large vessel occlusion (LVO) (consistent with the contemporary standard of practice at the majority of centers); and (2) all patients with outcome data who underwent randomization regardless of qualifying vascular imaging. The pre-specified primary outcome measure was modified Rankin Scale score of 0-2 at 90 days. A fixed-effect model was used to determine significance. RESULTS: Five prospective RCTs comparing endovascular therapies with medical management were included in dataset 1 (1183 patients) and six were included in dataset 2 (1903 total patients). Endovascular therapies were associated with significantly improved outcomes compared with medical management (OR 1.67, 95% CI 1.29 to 1.16, p=0.0001) for patients with LVO (dataset 1). This benefit persisted when patients from all six RCTs were included, even in the absence of confirmation of LVO (OR 1.27, 95% CI 1.05 to 1.54, p=0.019; dataset 2). CONCLUSIONS: A meta-analysis of prospective RCTs comparing endovascular therapies with medical management demonstrates superior outcomes in patients randomized to endovascular therapy. PMID- 25432980 TI - A novel approach to the treatment of a direct carotid-cavernous fistula in a patient with Ehlers-Danlos syndrome type IV. AB - We report a case of a direct carotid-cavernous fistula (CCF) in a patient with Ehlers-Danlos syndrome type IV who presented with progressive chemosis and diplopia. To prevent potential lethal arterial wall injury due to the fragility of the arterial vessel wall, the ipsilateral carotid artery and internal jugular vein were surgically exposed for direct insertion of endovascular sheaths, and transvenous embolization was performed using triple microcatheters with detachable coils. The clinical course was uneventful, and chemosis and diplopia subsequently resolved. By the 6 month follow-up, MRI revealed no recurrence of the CCF. These techniques offer a unique access alternative for endovascular treatment, thereby reducing the risks associated with arterial dissection that often accompanies transfemoral access in this particular condition. PMID- 25432982 TI - Occupational class differences in later life hospital use by women who survived to age 80: the Renfrew and Paisley prospective cohort study. AB - BACKGROUND: population ageing challenges the sustainability of healthcare provision. OBJECTIVE: to investigate occupational class differences in hospital use in women aged 80+ years. METHODS: a total of 8,353 female residents, aged 45 64, took part in the Renfrew and Paisley prospective cohort study in 1972-76. Information on general and mental health hospital discharges was provided from computerised linkage with the Scottish Morbidity Records data to 31 December 2012. Numbers of admissions and bed-days after the 80th birthday were calculated for all and specific causes. Rate ratios by occupational class were calculated using negative binomial regression analysis, adjusting for age and a range of risk factors. RESULTS: four thousand and four hundred and seven (56%) women survived to age 80 and had 17,563 general admissions thereafter, with a mean stay of 19.4 days. There were no apparent relationships with occupational class for all general admissions, but lower occupational class was associated with higher rate ratios for coronary heart disease and stroke and lower rate ratios for cancer. Adjustment for risk factors could not fully explain the raised rate ratios. Bed-day use was higher in lower occupational classes, especially for stroke. There were strong associations with mental health admissions, especially dementia. Compared with the highest occupational class, admission rate ratios for dementia were higher for the lowest occupational class (adjusted rate ratio = 2.60, 95% confidence interval 1.79-3.77). CONCLUSION: in this population, there were no socio-economic gradients seen in hospital utilisation for general admissions in old age. However, occupational class was associated with mental health admissions, coronary heart disease, stroke and cancer. PMID- 25432981 TI - Optimal screening for increased risk for adverse outcomes in hospitalised older adults. AB - BACKGROUND: Screening for frailty might help to prevent adverse outcomes in hospitalised older adults. OBJECTIVE: To identify the most predictive and efficient screening tool for frailty. DESIGN AND SETTING: Two consecutive observational prospective cohorts in four hospitals in the Netherlands. SUBJECTS: Patients aged >=70 years, electively or acutely hospitalised for >=2 days. METHODS: Screening instruments included in the Dutch Safety Management Programme [VeiligheidsManagementSysteem (VMS)] on four geriatric domains (ADL, falls, undernutrition and delirium) were used and the Identification of Seniors At Risk, the 6-item Cognitive Impairment Test and the Mini-Mental State Examination were assessed. Three months later, adverse outcomes including functional decline, high healthcare demand or death were determined. Correlation and regression tree analyses were performed and predictive capacities were assessed. RESULTS: Follow up data were available of 883 patients. All screening instruments were similarly predictive for adverse outcome (predictive power 0.58-0.66), but the percentage of positively screened patients (13-72%), sensitivity (24-89%) and specificity (35-91%) highly differed. The strongest predictive model for frailty was scoring positive on >=3 VMS domains if aged 70-80 years; or being aged >=80 years and scoring positive on >=1 VMS domains. This tool classified 34% of the patients as frail with a sensitivity of 68% and a specificity of 74%. Comparable results were found in the validation cohort. CONCLUSIONS: The VMS-tool plus age (VMS+) offers an efficient instrument to identify frail hospitalised older adults at risk for adverse outcome. In clinical practice, it is important to weigh costs and benefits of screening given the rather low-predictive power of screening instruments. PMID- 25432983 TI - Zinc supplementation suppresses the progression of bile duct ligation-induced liver fibrosis in mice. AB - Metallothionein (MT) gene therapy leads to resolution of liver fibrosis in mouse model, in which the activation of collagenases is involved in the regression of liver fibrosis. MT plays a critical role in zinc sequestration in the liver suggesting its therapeutic effect would be mediated by zinc. The present study was undertaken to test the hypothesis that zinc supplementation suppresses liver fibrosis. Male Kunming mice subjected to bile duct ligation (BDL) resulted in liver fibrosis as assessed by increased alpha-smooth muscle actin (alpha-SMA) and collagen I production/deposition in the liver. Zinc supplementation was introduced 4 weeks after BDL surgery via intragastric administration once daily for 2 weeks resulting in a significant reduction in the collagen deposition in the liver and an increase in the survival rate. Furthermore, zinc suppressed gene expression of alpha-SMA and collagen I and enhanced the capacity of collagen degradation, as determined by the increased activity of total collagenases and elevated mRNA and protein levels of MMP13. Therefore, the results demonstrate that zinc supplementation suppresses BDL-induced liver fibrosis through both inhibiting collagen production and enhancing collagen degradation. PMID- 25432985 TI - PDE2 activity differs in right and left rat ventricular myocardium and differentially regulates beta2 adrenoceptor-mediated effects. AB - The important regulator of cardiac function, cAMP, is hydrolyzed by different cyclic nucleotide phosphodiesterases (PDEs), whose expression and activity are not uniform throughout the heart. Of these enzymes, PDE2 shapes beta1 adrenoceptor-dependent cardiac cAMP signaling, both in the right and left ventricular myocardium, but its role in regulating beta2 adrenoceptor-mediated responses is less well known. Our aim was to investigate possible differences in PDE2 transcription and activity between right (RV) and left (LV) rat ventricular myocardium, as well as its role in regulating beta2 adrenoceptor effects. The free walls of the RV and the LV were obtained from Sprague-Dawley rat hearts. Relative mRNA for PDE2 (quantified by qPCR) and PDE2 activity (evaluated by a colorimetric procedure and using the PDE2 inhibitor EHNA) were determined in RV and LV. Also, beta2 adrenoceptor-mediated effects (beta2-adrenoceptor agonist salbutamol + beta1 adrenoceptor antagonist CGP-20712A) on contractility and cAMP concentrations, in the absence or presence of EHNA, were studied in the RV and LV. PDE2 transcript levels were less abundant in RV than in LV and the contribution of PDE2 to the total PDE activity was around 25% lower in the microsomal fraction of the RV compared with the LV. beta2 adrenoceptor activation increased inotropy and cAMP levels in the LV when measured in the presence of EHNA, but no such effects were observed in the RV, either in the presence or absence of EHNA. These results indicate interventricular differences in PDE2 transcript and activity levels, which may distinctly regulate beta2 adrenoceptor mediated contractility and cAMP concentrations in the RV and in the LV of the rat heart. PMID- 25432986 TI - Enhanced infarct myocardium repair mediated by thermosensitive copolymer hydrogel based stem cell transplantation. AB - Mesenchymal stem cell (MSC) transplantation by intramyocardial injection has been proposed as a promising therapy strategy for cardiac repair after myocardium infarction. However, low retention and survival of grafted MSCs hinder its further application. In this study, copolymer with N-isopropylacrylamide/acrylic acid/2-hydroxylethyl methacrylate-poly(E-caprolactone) ratio of 88:9.6:2.4 was bioconjugated with type I collagen to construct a novel injectable thermosensitive hydrogel. The injectable and biocompatible hydrogel-mediated MSC transplantation could enhance the grafted cell survival in the myocardium, which contributed to the increased neovascularization, decreased interstitial fibrosis, and ultimately improved heart function to a significantly greater degree than regular MSC transplantation. We suggest that this novel hydrogel has the potential for future stem cell transplantation. PMID- 25432984 TI - Role of WW domain proteins WWOX in development, prognosis, and treatment response of glioma. AB - Glioblastoma multiforme (GBM) is the most aggressive and malignant brain tumor. Delicate microenvironment and lineage heterogeneity of GBM cells including infiltration, hypoxia, angiogenesis, and stemness make them highly resistant to current conventional therapies, with an average life expectancy for GBM patients of less than 15 months. Poor response to cytotoxic agents of GBM cells remains the major challenge of GBM treatment. Resistance of GBM to clinical treatment is a result of genomic alternation and deregulated signaling pathways, such as p53 mutation and apoptosis signaling blockage, providing cancer cells more opportunities for survival rather than cell death. WW domain-containing oxidoreductase (WWOX) is a tumor suppressor gene, commonly downregulated in various types of tumors, including GBM. It has been found that the reintroduction of WWOX induced p53-mutant GBM cells to undergo apoptosis, but not in p53 wild type GBM cells, indicating WWOX is likely to reopen apoptosis pathways in a p53 independent manner in GBM. Identifying the crucial target modulated by WWOX deficiency provides a potential therapeutic target for GBM treatment. Here, we have reviewed the literatures about the role of WWOX in development, signaling pathway, prognosis, and treatment response in malignant glioma. PMID- 25432987 TI - Suitability of antral follicle counts and computer-assisted analysis of ultrasonographic and magnetic resonance images for estimating follicular reserve in porcine, ovine and bovine ovaries ex situ. AB - This study was conducted to determine if correlations exist between the numbers of microscopic follicles comprising ovarian follicular reserve (OFR) and antral follicle counts (AFCs), and to assess the usefulness of computerized analyses of ovarian ultrasonograms and magnetic resonance (MR) images for estimating OFR in excised porcine, ovine and bovine ovaries. As a pre-requisite to these analyses, we characterized and compared ovarian cortical histomorphology and follicle populations in the three species varying in prolificacy and overall reproductive longevity, and hence the total number of microscopic and antral follicles. Ultrasonographic and MR images were obtained at the scanner settings optimized to provide opposing contrasts between antral follicles and the ovarian stroma. Commercially available ImageProPlus(r) analytical software was used to calculate numerical pixel values (NPVs) and pixel heterogeneity (standard deviation of the pixel values) along the computer-generated lines (4-6) placed in the area corresponding to the ovarian cortex. The numbers of primordial (r = 0.38, P < 0.01) and intermediate follicles (r = 0.37, P < 0.01) were correlated with the numbers of antral follicles in bovine ovarian sections. The numbers of primordial (r = 0.28, P < 0.05), intermediate (r = 0.31, P < 0.01) and primary follicles (r = 0.27, P < 0.05) correlated directly with mean NPVs of the ultrasonographic ovarian images in cattle. There was a negative correlation between primary follicle numbers and NPVs of MR images (3D FAST-SPOILED GRADIENT ECHO) of the porcine ovarian cortex (r = -0.31, P < 0.05). To summarize, the numbers of primordial and intermediate follicles could only be estimated from AFCs in cows. Using ultrasound NPVs, the numbers of primordial, intermediate and primary follicles could be directly estimated in bovine ovaries and the quantitative image attributes of MR images were useful for quantifying porcine primary follicles. The bovine ovarian model is compatible with human situation and hence future studies should be undertaken to ascertain the usefulness of AFCs and ultrasonographic image analyses for estimating OFR in women. PMID- 25432989 TI - Disparities in physician-patient communication by obesity status. AB - This study aimed to examine variations in patient-physician communication by obesity status. We pooled data from the 2005-2007 Medical Expenditure Panel Survey (MEPS),_included only individuals who completed the self-administered questionnaire themselves, and restricted the sample to patients who received care from primary care physicians. We included a total of 6,628 unique individuals between the ages of 18 and 65 who had at least one office or hospital outpatient visit during the past 12 months. There are six outcomes of interest in this study. The patient-physician communication composite score is based on five questions that the MEPS adapted from the Consumer Assessment of Healthcare Providers and Systems Survey. The other five variables were: respect from providers, providers' listening skills, explanations from providers, time spent with patients, and patient involvement in treatment decisions. The key independent variable was obesity. Bivariate and multivariate models such as ordinary least squares (OLS) and logistic regression were used to examine the relationship between patient-physician communication and obesity status. Multivariate models showed that obese patients had a reduced physician-patient communication composite score of 0.19 (95% CI 0.03-0.34, p=0.02), physicians' show of respect OR 0.77 (95% CI 0.61-0.98, p=0.04), listening ability OR 0.82 (95% CI 0.65-1.02, p=0.07), and spending enough time OR 0.80 (95% CI 0.62-0.99, p=0.04) compared to non-obese patients. We found a negative association between physician-patient communication and patients' obesity status. These findings may inform public health practitioners in the design of effective initiatives that account for the needs and circumstances of obese individuals. PMID- 25432990 TI - Individualized health care: moving from population health to care of the one. PMID- 25432991 TI - Exercise training for health-related quality of life in peripheral artery disease: a systematic review and meta-analysis. AB - We sought to quantify whether health-related quality of life (HRQoL) is improved through exercise training in people with peripheral artery disease (PAD) and to clarify which prescriptions were optimal for improving HRQoL when compared to usual care. We conducted a systematic search (PubMed, CINAHL, Cochrane Central Register of Controlled Trials; 1966 - 31 August 2014). We only included randomized controlled trials (RCTs) of exercise training versus usual medical care in persons with PAD that included the Walking Impairment Questionnaire (WIQ) and Short-Form Health Survey component summary scores as outcomes. Of 15 RCTs, 1257 participants were studied: 543 participated in supervised exercise, with only 61 undertaking resistance training and 316 unsupervised exercise. When compared to controls, participants who completed any form of exercise training significantly improved their WIQ speed [mean difference (MD) 9.60 (95% CI 6.98 to 12.23, p<0.00001)]; WIQ distance [MD 7.41 (95% CI 4.49 to 10.33, p<0.00001)] and WIQ stair-climbing [MD 5.07 (95% CI 3.16 to 6.99, p<0.00001)]. Walking also significantly improved the Short-Form Physical Component Summary (SF-PCS) score when compared to controls [MD 1.24 (95% CI 0.48 to 2.01, p=0.001)], but not the Mental Component Summary (SF-MCS) score [MD -0.55 (95% CI -1.27 to 0.18, p=0.14)]. Exercise training improves the SF-PCS dimension, as well as perceived walking distance, speed and stair-climbing as measured by the WIQ, but not the SF MCS score. Future studies should aim to blind assessors of such subjective measures, and study alternative modes and prescriptions of exercise alternative to walking. PMID- 25432992 TI - Drug addiction or false conviction? PMID- 25432993 TI - Commentary. PMID- 25432994 TI - Commentary. PMID- 25432996 TI - A lipemic sample? PMID- 25432995 TI - Multiple cerebrospinal fluid bands with accompanying serum bands. PMID- 25432998 TI - Finding Waldo: the emerging field of circulating tumor cells. PMID- 25432999 TI - Clinician teachers: Formulating an intellectual framework for modern medical education. PMID- 25433000 TI - Job and Professional Leaving Among Newly Licensed RNs: A Structural Equation Model. AB - With more than 50% of the nursing workforce close to retirement, it is especially important to keep younger nurses in nursing jobs and careers. This study empirically tests a structural equation model of registered nurse (RN) intent to leave the job and profession using data from a survey of newly licensed RNs (NLRNs). Job demands, difficulties and control, intent to leave the job, and intent to leave the profession were latent variables. A number of direct, indirect, and mediating relationships were modeled. Measurement models for all latent variables and the structural model had good fit. The final model showed a path from job demands, difficulties, and control to job satisfaction to intent to leave the job to intent to leave the profession. The results suggest that the process of an NLRN intending to leave the job and profession involves a number of mediators between the work environment and this intent. PMID- 25433001 TI - TEXAS: a Tool for EXposure ASsessment-Statistical models for estimating occupational exposure to chemical agents. AB - Measurements of occupational exposure to chemical agents are performed by sampling and analyzing workplace atmospheres. In France, this is done by the industrial hygienists of the prevention network of the Social Security Service, who collect and then enter the data in the COLCHIC database. More than 900000 measurements performed in French companies over the past 25 years have been collected. Using this amount of data is major challenge for obtaining knowledge and predicting occupational exposures. This study presents the way in which statistical models are built and used on the basis of almost 19000 recent measurements of 26 frequent chemical substances. For a given substance, the models use 13 exposure determinants as inputs, such as the task performed, the occupation of the operator or the type of process employed. The models permit to estimate two parameters: the geometric mean and geometric standard deviation. These parameters are used to build an exposure profile. By combining them with the limit value, an exposure index is estimated using a Bayesian network. A decision rule based on the interpretation of this probability is proposed to qualify the predicted situation as 'well-controlled situation', 'controlled situation', and 'poorly controlled situation'. On the basis of this decision rule, 62% of predictions are true for all substances confounded, an average of 36% of predictions are approximate and only 2% of them are wrong. The result of this study led to the development of a pragmatic software tool named TEXAS, tool for exposure assessment, which enables industrial hygienists to obtain a rapid estimation of the level of exposure control as a function of simple determinants of work situations. PMID- 25433002 TI - Bias and power in group-based epidemiologic studies of low-back pain exposure and outcome--effects of study size and exposure measurement efforts. AB - OBJECTIVES: Exposure-outcome studies, for instance on work-related low-back pain (LBP), often classify workers into groups for which exposures are estimated from measurements on a sample of workers within or outside the specific study. The present study investigated the influence on bias and power in exposure-outcome associations of the sizes of the total study population and the sample used to estimate exposures. METHODS: At baseline, lifting, trunk flexion, and trunk rotation were observed for 371 of 1131 workers allocated to 19 a-priori defined occupational groups. LBP (dichotomous) was reported by all workers during 3 years of follow-up. All three exposures were associated with LBP in this parent study (P < 0.01). All 21 combinations of n = 10, 20, 30 workers per group with an outcome, and k = 1, 2, 3, 5, 10, 15, 20 workers actually being observed were investigated using bootstrapping, repeating each combination 10000 times. Odds ratios (OR) with P values were determined for each of these virtual studies. Average OR and statistical power (P < 0.05 and P < 0.01) was determined from the bootstrap distributions at each (n, k) combination. RESULTS: For lifting and flexed trunk, studies including n >= 20 workers, with k >= 5 observed, led to an almost unbiased OR and a power >0.80 (P level = 0.05). A similar performance required n >= 30 workers for rotated trunk. Small numbers of observed workers (k) resulted in biased OR, while power was, in general, more sensitive to the total number of workers (n). CONCLUSIONS: In epidemiologic studies using a group-based exposure assessment strategy, statistical performance may be sufficient if outcome is obtained from a reasonably large number of workers, even if exposure is estimated from only few workers per group. PMID- 25433003 TI - Comparison of ordinal and nominal classification trees to predict ordinal expert based occupational exposure estimates in a case-control study. AB - OBJECTIVES: To evaluate occupational exposures in case-control studies, exposure assessors typically review each job individually to assign exposure estimates. This process lacks transparency and does not provide a mechanism for recreating the decision rules in other studies. In our previous work, nominal (unordered categorical) classification trees (CTs) generally successfully predicted expert assessed ordinal exposure estimates (i.e. none, low, medium, high) derived from occupational questionnaire responses, but room for improvement remained. Our objective was to determine if using recently developed ordinal CTs would improve the performance of nominal trees in predicting ordinal occupational diesel exhaust exposure estimates in a case-control study. METHODS: We used one nominal and four ordinal CT methods to predict expert-assessed probability, intensity, and frequency estimates of occupational diesel exhaust exposure (each categorized as none, low, medium, or high) derived from questionnaire responses for the 14983 jobs in the New England Bladder Cancer Study. To replicate the common use of a single tree, we applied each method to a single sample of 70% of the jobs, using 15% to test and 15% to validate each method. To characterize variability in performance, we conducted a resampling analysis that repeated the sample draws 100 times. We evaluated agreement between the tree predictions and expert estimates using Somers' d, which measures differences in terms of ordinal association between predicted and observed scores and can be interpreted similarly to a correlation coefficient. RESULTS: From the resampling analysis, compared with the nominal tree, an ordinal CT method that used a quadratic misclassification function and controlled tree size based on total misclassification cost had a slightly better predictive performance that was statistically significant for the frequency metric (Somers' d: nominal tree = 0.61; ordinal tree = 0.63) and similar performance for the probability (nominal = 0.65; ordinal = 0.66) and intensity (nominal = 0.65; ordinal = 0.65) metrics. The best ordinal CT predicted fewer cases of large disagreement with the expert assessments (i.e. no exposure predicted for a job with high exposure and vice versa) compared with the nominal tree across all of the exposure metrics. For example, the percent of jobs with expert-assigned high intensity of exposure that the model predicted as no exposure was 29% for the nominal tree and 22% for the best ordinal tree. CONCLUSIONS: The overall agreements were similar across CT models; however, the use of ordinal models reduced the magnitude of the discrepancy when disagreements occurred. As the best performing model can vary by situation, researchers should consider evaluating multiple CT methods to maximize the predictive performance within their data. PMID- 25433004 TI - Community-associated MRSA strain ST72-SCCmecIV causing bloodstream infections: clinical outcomes and bacterial virulence factors. AB - OBJECTIVES: Community-associated MRSA (CA-MRSA) has emerged in the community and has recently been spreading in healthcare settings. The objectives of this study were to evaluate the clinical outcomes and bacterial virulence factors of the Korean CA-MRSA (ST72-SCCmecIV) strain, which causes bloodstream infections. METHODS: All adult patients with MRSA bacteraemia were prospectively enrolled. Clinical outcomes, microbiological characteristics and 40 bacterial virulence factors were evaluated. RESULTS: Of the 352 typed MRSA isolates, 342 isolates (97.2%) belonged to three Panton-Valentine leucocidin-negative strains: ST5 SCCmecII (70.2%), ST72-SCCmecIV (22.4%) and ST239-SCCmecIII (4.6%). The remaining 10 (2.8%) isolates from minor strains were excluded from the final analysis. After controlling for several confounding factors, ST72-SCCmecIV was associated with the lowest mortality (compared with ST5-SCCmecII, adjusted OR=0.26; 95% CI=0.13-0.54). However, MRSA isolates with vancomycin MICs of >= 1.5 mg/L were more common in ST72-SCCmecIV compared with ST5-SCCmecII (84.8% versus 66.7%; P=0.002). Reduced vancomycin susceptibility and vancomycin heteroresistance were not associated with mortality. Compared with ST5-SCCmecII isolates, ST72-SCCmecIV isolates were less likely to harbour multiple virulence genes. Of these genes, three staphylococcal superantigen genes were associated with mortality: sec (OR=2.31; P=0.002), sel (OR=2.55; P=0.003) and tst (OR=2.76; P<0.001). CONCLUSIONS: After controlling for confounding factors, ST72-SCCmecIV was independently associated with lower mortality compared with ST5-SCCmecII, suggesting this CA-MRSA strain to be of lower virulence. The lack of virulence genes, including staphylococcal superantigen genes, may play a role in the lower virulence of this strain. PMID- 25433005 TI - Carbapenem and amikacin resistance on a large conjugative Acinetobacter baumannii plasmid. PMID- 25433007 TI - Identification of a novel fosXCC gene conferring fosfomycin resistance in Campylobacter. PMID- 25433008 TI - The dual CCR5 and CCR2 inhibitor cenicriviroc does not redistribute HIV into extracellular space: implications for plasma viral load and intracellular DNA decline. AB - OBJECTIVES: Cenicriviroc is a potent antagonist of the chemokine coreceptors 5 and 2 (CCR5/CCR2) and blocks HIV-1 entry. The CCR5 inhibitor maraviroc has been shown in tissue culture to be able to repel cell-free virions from the cell surface into extracellular space. We hypothesized that cenicriviroc might exhibit a similar effect, and tested this using clinical samples from the Phase IIb study 652-2-202, by measuring rates of intracellular DNA decline. We also monitored viral RNA levels in culture fluids. METHODS: We infected PM-1 cells with CCR5 tropic HIV-1 BaL in the presence or absence of inhibitory concentrations of cenicriviroc (20 nM) or maraviroc (50 nM) or controls. Viral load levels and p24 were measured by ELISA, quantitative PCR and quantitative real-time reverse transcription PCR at 4 h post-infection. Frozen PBMC DNA samples from 30 patients with virological success in the Phase IIb study were studied, as were early and late reverse transcript levels. Docking studies compared binding between cenicriviroc/CCR5 and maraviroc/CCR5. RESULTS: Unlike maraviroc, cenicriviroc did not cause an increase in the amount of virus present in culture fluids at 4 h compared with baseline. The use of cenicriviroc did, however, result in lower levels of intracellular viral DNA after 4 h. Structural modelling indicates that cenicriviroc binds more deeply than maraviroc to the hydrophobic pocket of CCR5, providing an explanation for the absence of viral rebound with cenicriviroc. CONCLUSIONS: In contrast to maraviroc, cenicriviroc does not repel virus back into extracellular space. Differences in results may be due to superior binding of cenicriviroc to CCR5 compared with maraviroc. PMID- 25433006 TI - Temocillin (6 g daily) in critically ill patients: continuous infusion versus three times daily administration. AB - OBJECTIVES: The growing incidence of infections caused by Enterobacteriaceae producing ESBLs has led to increased use of carbapenems. Temocillin, which resists most beta-lactamases, may be a useful alternative. The aim of this study was to assess the pharmacokinetics and target attainment rates of 6 g of temocillin daily divided into three administrations every 8 h (three times daily) or administered by continuous infusion in critically ill patients. PATIENTS AND METHODS: This was a prospective, two-centre, randomized, controlled study in patients with intra-abdominal or lower respiratory tract infections caused by Enterobacteriaceae. RESULTS: Thirty-two patients were included and analysed for clinical efficacy, and pharmacokinetics were measured in 29 of them. Four patients undergoing continuous veno-venous haemofiltration (CVVH) were analysed separately. Mean, median and range of percentages of the dosing interval during which the free drug concentration remained >16 mg/L were 76.4, 98 and 18.7-98.9 in patients treated three times daily and 98.9, 89.7 and 36.4-99.9 in patients with continuous infusion, respectively. Clinical cure rates were 79% and 93% in each of these groups, respectively (not significant). Patients with CVVH received a daily dose of 750 mg given by continuous infusion and had a mean free drug concentration of only 13.8 +/- 1.9 mg/L. No adverse event attributable to temocillin was observed. CONCLUSIONS: Temocillin (6 g daily) given by continuous infusion allows a larger proportion of critically ill patients to have free drug serum concentrations covering infections caused by Enterobacteriaceae with an MIC of 16 mg/L compared with administration three times daily. Clinical efficacy compared with carbapenems in documented severe infections needs to be further studied. PMID- 25433009 TI - Pretreatment HIV-1 drug resistance to first-line drugs: results from a baseline assessment of a large cohort initiating ART in Vietnam, 2009-10. AB - OBJECTIVES: The objective of this study was to determine the prevalence and correlates of pretreatment drug resistance (PDR) to first-line antiretroviral drugs among people initiating therapy for HIV in Vietnam. METHODS: Blood was collected during November 2009 to October 2010 from people consecutively initiating ART in four purposively selected public outpatient clinics in three Vietnamese cities. At each study site, recruitment lasted for 6-10 months until the target sample size (range 120-130 individuals) had been reached. The viral load was measured in 501 samples; 490 samples (viral load >=1000 copies/mL) were genotyped using a nucleotide population-based sequencing assay. Self-reported demographic and clinical data were elicited through interviews. We classified drug-resistance-associated mutations (DRMs) according to the 2009 WHO surveillance list. RESULTS: DRMs were identified in 17/490 participants (3.5%; 95% CI 2.2%-5.5%). The prevalence of DRMs was 1.6% (8/490) against NRTIs, 1.6% (8/490) against NNRTIs and 0.8% (4/490) against PIs; three (0.6%) participants were resistant to both NRTIs and NNRTIs. The overall prevalence of PDR to first line drugs was low [2.7% (13/490); 95% CI 1.6%-4.4%]. The prevalence of PDR to first-line drugs was greater among 198 HIV-infected participants who injected drugs than among 286 participants who reported risks for sexually acquired HIV (4.0% versus 1.4%, P = 0.079). Multivariable logistic regression analysis suggested that PDR to first-line drugs was significantly higher among people who injected drugs (OR = 3.94; 95% CI 1.13-13.68). CONCLUSIONS: With low PDR, first line ART may be effective in Vietnam and pretreatment genotyping may be unnecessary. Continuing strategies for the prevention and surveillance of antiretroviral resistance are important for maintaining a low prevalence of antiretroviral resistance in Vietnam. The association between resistance and injection drug use warrants further research. PMID- 25433012 TI - Comment on: Failure of combination therapy with daptomycin and synergistic ceftriaxone for enterococcal endocarditis. PMID- 25433011 TI - Cephalosporinases associated with outer membrane vesicles released by Bacteroides spp. protect gut pathogens and commensals against beta-lactam antibiotics. AB - OBJECTIVES: To identify beta-lactamase genes in gut commensal Bacteroides species and to assess the impact of these enzymes, when carried by outer membrane vesicles (OMVs), in protecting enteric pathogens and commensals. METHODS: A deletion mutant of the putative class A beta-lactamase gene (locus tag BT_4507) found in the genome of the human commensal Bacteroides thetaiotaomicron was constructed and a phenotypic analysis performed. A phylogenetic tree was built from an alignment of nine Bacteroides cephalosporinase protein sequences, using the maximum likelihood method. The rate of cefotaxime degradation after incubation with OMVs produced by different Bacteroides species was quantified using a disc susceptibility test. The resistance of Salmonella Typhimurium and Bifidobacterium breve to cefotaxime in liquid culture in the presence of B. thetaiotaomicron OMVs was evaluated by measuring bacterial growth. RESULTS: The B. thetaiotaomicron BT_4507 gene encodes a beta-lactamase related to the CepA cephalosporinase of Bacteroides fragilis. OMVs produced by B. thetaiotaomicron and several other Bacteroides species, except Bacteroides ovatus, carried surface associated beta-lactamases that could degrade cefotaxime. beta-Lactamase harbouring OMVs from B. thetaiotaomicron protected Salmonella Typhimurium and B. breve from an otherwise lethal dose of cefotaxime. CONCLUSIONS: The production of membrane vesicles carrying surface-associated beta-lactamases by Bacteroides species, which constitute a major part of the human colonic microbiota, may protect commensal bacteria and enteric pathogens, such as Salmonella Typhimurium, against beta-lactam antibiotics. PMID- 25433016 TI - An improved method for the analysis of GHB in human hair by liquid chromatography tandem mass spectrometry. AB - The abuse of gamma-hydroxybutyric acid (GHB) and its suspicion in cases of suspected drug-facilitated sexual assault is of keen interest to forensic toxicology laboratories. This paper reports an extraction, separation and detection procedure for GHB in hair utilizing a combination of liquid-liquid extraction and solid-phase extraction using ethyl acetate and Oasis Max((r)) cartridge, respectively, after the hair sample was digested. Analysis was by LC MS-MS using a gradient separation on an Acclaim((r)) Trinity(TM) P1 column performing three multiple-reaction monitoring (MRM) transitions each for GHB and its internal standard. The procedure was validated over a range from 0.4 to 50 ng/mg with estimated limit of detection (LOD) of 0.33 and an administratively set limit of quantitation (LOQ) of 1.2 ng/mg. Twenty hair specimens collected from individuals with no known exposure to GHB were analyzed for matrix interferences and to establish initial background levels of GHB. A wide range of endogenous GHB levels were observed in these samples (from less than the LOQ to 4.4 ng/mg). The results suggest the need for additional studies to better establish the full range of endogenous GHB levels in hair and that extreme caution is required in interpreting GHB findings in hair samples. PMID- 25433013 TI - Editorial commentary: New strategies for treatment of humans with acute lung injury/acute respiratory distress syndrome. PMID- 25433010 TI - Relationship between consumption of MRSA-active antibiotics and burden of MRSA in acute care hospitals in Catalonia, Spain. AB - OBJECTIVES: To analyse the possible relationship between consumption of old and new MRSA-active antibiotics and burden of MRSA in acute care hospitals in Catalonia during the period 2007-12. METHODS: Fifty-four hospitals participating in the VINCat Programme were included. Proportion of MRSA (resistant isolates of Staphylococcus aureus per 100 isolates of S. aureus tested), incidence of new cases of infection [new cases of MRSA per 1000 occupied bed-days (OBD)] and incidence of cases of bacteraemia (MRSA bacteraemia cases per 1000 OBD) were determined to estimate the annual MRSA burden. Antibiotic consumption was calculated in DDD/100 OBD. Cost was expressed in euros/100 OBD. RESULTS: MRSA rates remained stable over the study period, with the proportion of MRSA ranging from 20% to 22.82% in 2007 and 2012, respectively (P=0.864). Consumption of old MRSA-active antibiotics (vancomycin and teicoplanin) did not change significantly, with values from 1.51 to 2.07 DDD/100 OBD (P=0.693). Consumption of new MRSA-active antibiotics (linezolid and daptomycin) increased significantly, with values rising from 0.24 to 1.49 DDD/100 OBD (P<0.001). Cost increased by almost 200%. CONCLUSIONS: A widespread and steady increase in consumption of new MRSA-active antibiotics was observed among acute care hospitals in Catalonia, in spite of a stable MRSA burden. At the same time, consumption of old drugs remained stable. Such trends resulted in a significant increase in cost. Our findings suggest that factors other than the proportion of methicillin resistance among S. aureus may influence the use of old and new MRSA active antibiotics in the clinical setting. PMID- 25433014 TI - Treatment with anti-C5a antibody improves the outcome of H7N9 virus infection in African green monkeys. AB - BACKGROUND: Patients infected with influenza A(H7N9) virus present with acute lung injury (ALI) that is due to severe pneumonia and systemic inflammation. It is often fatal because there are few effective treatment options. Complement activation has been implicated in the pathogenesis of virus-induced lung injury; therefore, we investigated the effect of targeted complement inhibition on ALI induced by H7N9 virus infection. METHODS: A novel neutralizing specific antihuman C5a antibody (IFX-1) was used. This antibody blocked the ability of C5a to induce granulocytes to express CD11b while not affecting the ability of C5b to form the membrane attack complex. African green monkeys were inoculated with H7N9 virus and treated intravenously with IFX-1. RESULTS: The virus infection led to intense ALI and systemic inflammatory response syndrome (SIRS) in association with excessive complement activation. Anti-C5a treatment in H7N9-infected monkeys substantially attenuated ALI: It markedly reduced the lung histopathological injury and decreased the lung infiltration of macrophages and neutrophils. Moreover, the treatment decreased the intensity of SIRS; the body temperature changes were minimal and the plasma levels of inflammatory mediators were markedly reduced. The treatments also significantly decreased the virus titers in the infected lungs. CONCLUSIONS: Antihuman C5a antibody treatment remarkably reduced the ALI and systemic inflammation induced by H7N9 virus infection. Complement inhibition may be a promising adjunctive therapy for severe viral pneumonia. PMID- 25433018 TI - Adalimumab trough concentrations in patients with rheumatoid arthritis and psoriatic arthritis treated with concomitant disease-modifying antirheumatic drugs. PMID- 25433019 TI - Response to: 'Does adding the presence of MRI detected bone marrow oedema improve the accuracy of the 2010 EULAR/ACR criteria for rheumatoid arthritis?' by Nieuwenhuis et al. PMID- 25433022 TI - Transcatheter heart valve failure: the sword of Damocles over our heads? PMID- 25433020 TI - Systemic activity and mortality in primary Sjogren syndrome: predicting survival using the EULAR-SS Disease Activity Index (ESSDAI) in 1045 patients. AB - OBJECTIVE: To score systemic activity at diagnosis and correlate baseline activity with survival in a large cohort of patients with primary Sjogren syndrome (SS). PATIENTS AND METHODS: We include 1045 consecutive patients who fulfilled the 2002 classification criteria for primary SS. The clinical and immunological characteristics and level of activity (EULAR-SS Disease Activity Index (ESSDAI) scores) were assessed at diagnosis as predictors of death using Cox proportional hazards regression analysis adjusted for age at diagnosis. The risk of death was calculated at diagnosis according to four different predictive models. RESULTS: After a mean follow-up of 117 months, 115 (11%) patients died. The adjusted standardised mortality ratio for the total cohort was 4.66 (95% CI 3.85 to 5.60), and survival rates at 5, 10, 20 and 30 years were 96%, 90%, 81% and 60%, respectively. The main baseline factors associated with overall mortality in the multivariate analysis were male gender, cryoglobulins and low C4 levels. Baseline activity in the constitutional, pulmonary and biological domains was associated with a higher risk of death. High activity in at least one ESSDAI domain (HR 2.14), a baseline ESSDAI score >=14 (HR 1.85) and more than one laboratory predictive marker (lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4 and/or cryoglobulins) (HR 2.82) were associated with overall mortality; these HRs increased threefold to 10-fold when the analysis was restricted to mortality associated with systemic disease. CONCLUSIONS: Patients with primary SS, who present at diagnosis with high systemic activity (ESSDAI >=14) and/or predictive immunological markers (especially those with more than one), are at higher risk of death. PMID- 25433023 TI - Endomyocardial biopsy and ultrastructural changes in dilated cardiomyopathy: taking a 'deeper' look into patients' prognosis. PMID- 25433024 TI - Thrombus formation on the Amplatzer device: a need for critical attitude in percutaneous patent ovale closure decision-making. PMID- 25433021 TI - Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions. AB - A variety of systemic inflammatory rheumatic diseases associate with an increased risk of atherosclerotic events and premature cardiovascular (CV) disease. Although this recognition has stimulated intense basic science and clinical research, the precise nature of the relationship between local and systemic inflammation, their interactions with traditional CV risk factors, and their role in accelerating atherogenesis remains unresolved. The individual rheumatic diseases have both shared and unique attributes that might impact CV events. Understanding of the positive and negative influences of individual anti inflammatory therapies remains rudimentary. Clinicians need to adopt an evidence based approach to develop diagnostic techniques to identify those rheumatologic patients most at risk of CV disease and to develop effective treatment protocols. Development of optimal preventative and disease-modifying approaches for atherosclerosis in these patients will require close collaboration between basic scientists, CV specialists, and rheumatologists. This interface presents a complex, important, and exciting challenge. PMID- 25433026 TI - A link between Notch and progesterone maintains the functionality of the rat corpus luteum. AB - In this study, we investigated the interaction between the Notch pathway and progesterone to maintain the functionality of the corpus luteum (CL). When Notch signaling is activated, the gamma-secretase complex releases the active intracellular domains (NICD) of their receptors, which exert survival effects. We designed studies to analyze whether the in vitro inhibition of Notch affects progesterone production, steroidogenic regulators, apoptotic parameters, and signaling transduction pathways in the cultures of CL isolated from pregnant and superovulated rats. We detected a decrease in progesterone production when corpora lutea (CL) were incubated with N-(N-(3,5-difluorophenacetyl-l-alanyl))-S phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor. This effect could be in part due to the decrease detected in the CL protein levels of P450scc because STAR and 3beta-hydroxysteroid dehydrogenase were not affected by Notch inhibition. Besides, the addition of aminoglutethimide to the CL culture medium decreased NICD of NOTCH1. We observed an increase in the expression of active CASPASE3 (CASP3) after inhibition by Notch, which was reversed by the presence of progesterone. The BAX:BCLXL ratio was increased in CL treated with DAPT and the presence of progesterone reversed this effect. In addition, phosphorylation of AKT was inhibited in CL treated with DAPT, but had no effect on ERK activation. To demonstrate that the action of DAPT is specifically related with the inhibition of Notch, CLs were incubated with DLL4 antibody and a decrease in progesterone production was detected. These results suggest the existence of a novel link between progesterone and the Notch signaling pathway to maintain the functionality of the CL. PMID- 25433027 TI - HIF1A-dependent increase in endothelin 2 levels in granulosa cells: role of hypoxia, LH/cAMP, and reactive oxygen species. AB - Hypoxia-inducible factor 1 alpha (HIF1A) and endothelin 2 (EDN2) are transiently expressed during the same time window in the developing corpus luteum (CL). In this study, we sought to investigate the involvement of LH/cAMP, reactive oxygen species (ROS), and a hypoxia-mimetic compound (CoCl2) on HIF1A expression and how it affected EDN2 levels, using transformed human granulosa cells (thGCs) and primary bovine granulosa cells (GCs). CoCl2 elevated HIF1A protein levels in thGCs in a dose-dependent manner. Forskolin alone had no significant effect; however, forskolin and CoCl2 together further induced HIF1A protein and EDN2 mRNA expression in thGCs. Similarly, in primary GCs, LH with CoCl2 synergistically augmented HIF1A protein levels, which resulted in higher expression of EDN2 and another well-known hypoxia-inducible gene, VEGF (VEGFA). Importantly, LH alone elevated HIF1A mRNA but not its protein. The successful knockdown of HIF1A in thGCs using siRNA abolished hypoxia-induced EDN2 and also the additive effect of forskolin and CoCl2. We then examined the roles of ROS in thGCs: hydrogen peroxide (20 and 50 MUM) elevated HIF1A protein as well as the expression of EDN2, implying that induction of HIF1A protein levels is sufficient to stimulate the expression of EDN2 (and VEGF) in normoxia. A broad-range ROS scavenger, butylated hydroxyanisole, inhibited CoCl2-induced HIF1A protein with a concomitant reduction in the mRNA expression of EDN2 and VEGF in thGCs. The results obtained in this study suggest that HIF1A, induced by various stimuli, is an essential mediator of EDN2 mRNA expression. The results may also explain the rise in the levels of HIF1A-dependent genes (EDN2 and VEGF) in the developing CL. PMID- 25433025 TI - Identification, characterization, and structure analysis of the cyclic di-AMP binding PII-like signal transduction protein DarA. AB - The cyclic dimeric AMP nucleotide c-di-AMP is an essential second messenger in Bacillus subtilis. We have identified the protein DarA as one of the prominent c di-AMP receptors in B. subtilis. Crystal structure analysis shows that DarA is highly homologous to PII signal transducer proteins. In contrast to PII proteins, the functionally important B- and T-loops are swapped with respect to their size. DarA is a homotrimer that binds three molecules of c-di-AMP, each in a pocket located between two subunits. We demonstrate that DarA is capable to bind c-di AMP and with lower affinity cyclic GMP-AMP (3'3'-cGAMP) but not c-di-GMP or 2'3' cGAMP. Consistently the crystal structure shows that within the ligand-binding pocket only one adenine is highly specifically recognized, whereas the pocket for the other adenine appears to be promiscuous. Comparison with a homologous ligand free DarA structure reveals that c-di-AMP binding is accompanied by conformational changes of both the fold and the position of the B-loop in DarA. PMID- 25433028 TI - Inhibition of zygotic DNA repair: transcriptome analysis of the offspring in trout (Oncorhynchus mykiss). AB - Zygotic repair of the paternal genome is a key event after fertilization. Spermatozoa accumulate DNA strand breaks during spermatogenesis and can suffer additional damage by different factors, including cryopreservation. Fertilization with DNA-damaged spermatozoa (DDS) is considered to promote implantation failures and abortions, but also long-term effects on the progeny that could be related with a defective repair. Base excision repair (BER) pathway is considered the most active in zygotic DNA repair, but healthy oocytes contain enzymes for all repairing pathways. In this study, the effects of the inhibition of the BER pathway in the zygote were analyzed on the progeny obtained after fertilization with differentially DDS. Massive gene expression (GE; 61 657 unique probes) was analyzed after hatching using microarrays. Trout oocytes are easily fertilized with DDS and the high prolificacy allows live progeny to be obtained even with a high rate of abortions. Nevertheless, the zygotic inhibition of Poly (ADP-ribose) polymerase, upstream of BER pathway, resulted in 810 differentially expressed genes (DEGs) after hatching. DEGs are related with DNA repair, apoptosis, telomere maintenance, or growth and development, revealing a scenario of impaired DNA damage signalization and repair. Downregulation of the apoptotic cascade was noticed, suggesting a selection of embryos tolerant to residual DNA damage during embryo development. Our results reveal changes in the progeny from defective repairing zygotes including higher malformations rate, weight gain, longer telomeres, and lower caspase 3/7 activity, whose long-term consequences should be analyzed in depth. PMID- 25433029 TI - Polyols in grape berry: transport and metabolic adjustments as a physiological strategy for water-deficit stress tolerance in grapevine. AB - Polyols are important metabolites that often function as carbon and energy sources and/or osmoprotective solutes in some plants. In grapevine, and in the grape berry in particular, the molecular aspects of polyol transport and metabolism and their physiological relevance are virtually unknown to date. Here, the biochemical function of a grapevine fruit mesocarp polyol transporter (VvPLT1) was characterized after its heterologous expression in yeast. This H(+) dependent plasma membrane carrier transports mannitol (K m=5.4mM) and sorbitol (K m=9.5mM) over a broad range of polyols and monosaccharides. Water-deficit stress triggered an increase in the expression of VvPLT1 at the fully mature stage, allowing increased polyol uptake into pulp cells. Plant polyol dehydrogenases are oxireductases that reversibly oxidize polyols into monosaccharides. Mannitol catabolism in grape cells (K m=30.1mM mannitol) and mature berry mesocarps (K m=79mM) was, like sorbitol dehydrogenase activity, strongly inhibited (50-75%) by water-deficit stress. Simultaneously, fructose reduction into polyols via mannitol and sorbitol dehydrogenases was stimulated, contributing to their higher intracellular concentrations in water-deficit stress. Accordingly, the concentrations of mannitol, sorbitol, galactinol, myo-inositol, and dulcitol were significantly higher in berry mesocarps from water-deficit-stressed Tempranillo grapevines. Metabolomic profiling of the berry pulp by GC-TOF-MS also revealed many other changes in its composition induced by water deficit. The impact of polyols on grape berry composition and plant response to water deficit stress, via modifications in polyol transport and metabolism, was analysed by integrating metabolomics with transcriptional analysis and biochemical approaches. PMID- 25433030 TI - Value of left atrial strain: a highly promising field of investigation. PMID- 25433031 TI - Regulation of Drosophila intestinal stem cell maintenance and differentiation by the transcription factor Escargot. AB - Tissue stem cells divide to self-renew and generate differentiated cells to maintain homeostasis. Although influenced by both intrinsic and extrinsic factors, the genetic mechanisms coordinating the decision between self-renewal and initiation of differentiation remain poorly understood. The escargot (esg) gene encodes a transcription factor that is expressed in stem cells in multiple tissues in Drosophila melanogaster, including intestinal stem cells (ISCs). Here, we demonstrate that Esg plays a pivotal role in intestinal homeostasis, maintaining the stem cell pool while influencing fate decisions through modulation of Notch activity. Loss of esg induced ISC differentiation, a decline in Notch activity in daughter enteroblasts (EB), and an increase in differentiated enteroendocrine (EE) cells. Amun, an inhibitor of Notch in other systems, was identified as a target of Esg in the intestine. Decreased expression of esg resulted in upregulation of Amun, while downregulation of Amun rescued the ectopic EE cell phenotype resulting from loss of esg. Thus, our findings provide a framework for further comparative studies addressing the conserved roles of Snail factors in coordinating self-renewal and differentiation of stem cells across tissues and species. PMID- 25433032 TI - YME1L degradation reduces mitochondrial proteolytic capacity during oxidative stress. AB - Mitochondrial proteostasis is maintained by a network of ATP-dependent quality control proteases including the inner membrane protease YME1L. Here, we show that YME1L is a stress-sensitive mitochondrial protease that is rapidly degraded in response to acute oxidative stress. This degradation requires reductions in cellular ATP and involves the activity of the ATP-independent protease OMA1. Oxidative stress-dependent reductions in YME1L inhibit protective YME1L-dependent functions and increase cellular sensitivity to oxidative insult. Collectively, our results identify stress-induced YME1L degradation as a biologic process that attenuates protective regulation of mitochondrial proteostasis and promotes cellular death in response to oxidative stress. PMID- 25433034 TI - Using reaction time and co-contraction to differentiate acquired (secondary) from functional 'fixed' dystonia. PMID- 25433033 TI - Physiotherapy for functional motor disorders: a consensus recommendation. AB - BACKGROUND: Patients with functional motor disorder (FMD) including weakness and paralysis are commonly referred to physiotherapists. There is growing evidence that physiotherapy is an effective treatment, but the existing literature has limited explanations of what physiotherapy should consist of and there are insufficient data to produce evidence-based guidelines. We aim to address this issue by presenting recommendations for physiotherapy treatment. METHODS: A meeting was held between physiotherapists, neurologists and neuropsychiatrists, all with extensive experience in treating FMD. A set of consensus recommendations were produced based on existing evidence and experience. RESULTS: We recommend that physiotherapy treatment is based on a biopsychosocial aetiological framework. Treatment should address illness beliefs, self-directed attention and abnormal habitual movement patterns through a process of education, movement retraining and self-management strategies within a positive and non-judgemental context. We provide specific examples of these strategies for different symptoms. CONCLUSIONS: Physiotherapy has a key role in the multidisciplinary management of patients with FMD. There appear to be specific physiotherapy techniques which are useful in FMD and which are amenable to and require prospective evaluation. The processes involved in referral, treatment and discharge from physiotherapy should be considered carefully as a part of a treatment package. PMID- 25433035 TI - Epstein-Barr virus persistence and reactivation in neuromyelitis optica. AB - OBJECTIVE: Epstein-Barr virus (EBV) infection has been thought to be a key environmental factor in the development of multiple sclerosis (MS). The aim of this study is to investigate the association of EBV infection with neuromyelitis optica (NMO). METHODS: We measured levels of serum antibodies against EBV antigens, including anti-viral capsid antigen (VCA) IgM, anti-VCA IgG, anti-early antigen (EA) IgM, anti-EA IgG and anti-EBV nuclear antigen-1 IgG, in 50 patients with NMO (including 12 partial form with antiaquaporin 4 antibodies), 51 patients with MS, and 52 healthy controls, and cerebrospinal fluid (CSF) antibodies in 37 patients with NMO and 33 patients with MS with ELISA. RESULT: Compared with patients with MS and normal participants, patients with NMO more frequently had serum anti-EA IgG antibodies (52%), indicating more active viral replication than patients with MS (26%) and controls (25%). The antibody titres were significantly higher in the NMO group than in the MS (p=0.005) and control (p=0.005) groups. The CSF antibody titres were also higher in patients with NMO than in those with MS (p=0.03). CONCLUSIONS: Our results raise the hypothesis that persistent, active EBV replication is present in NMO, and may contribute to the immunological alterations that play a pathogenetic role in the disorder. PMID- 25433037 TI - Anxiety and working memory after stroke: implications for norm-referenced methods of identifying cognitive deficits. PMID- 25433036 TI - Disrupted small world topology and modular organisation of functional networks in late-life depression with and without amnestic mild cognitive impairment. AB - BACKGROUND: The topological architecture of the whole-brain functional networks in those with and without late-life depression (LLD) and amnestic mild cognitive impairment (aMCI) are unknown. AIMS: To investigate the differences in the small world measures and the modular community structure of the functional networks between patients with LLD and aMCI when occurring alone or in combination and cognitively healthy non-depressed controls. METHODS: 79 elderly participants (LLD (n=23), aMCI (n=18), comorbid LLD and aMCI (n=13), and controls (n=25)) completed neuropsychiatric assessments. Graph theoretical methods were employed on resting state functional connectivity MRI data. RESULTS: LLD and aMCI comorbidity was associated with the greatest disruptions in functional integration measures (decreased global efficiency and increased path length); both LLD groups showed abnormal functional segregation (reduced local efficiency). The modular network organisation was most variable in the comorbid group, followed by patients with LLD-only. Decreased mean global, local and nodal efficiency metrics were associated with greater depressive symptom severity but not memory performance. CONCLUSIONS: Considering the whole brain as a complex network may provide unique insights on the neurobiological underpinnings of LLD with and without cognitive impairment. PMID- 25433039 TI - Reliability of histopathological salivary gland biopsy assessment in Sjogren's syndrome: a multicentre cohort study. AB - OBJECTIVE: The aim of this study was to assess intraobserver and interobserver reliability of minor salivary gland biopsy (MSGB) in SS. METHODS: All MSGBs available from the Tolerance and Efficacy of Rituximab in Primary Sjogren's Syndrome (TEARS) study were subjected to a standardized blinded assessment by a single specifically trained pathologist twice at a 2 month interval; both the Chisholm-Mason (CM) grade and the focus score (FS) were determined. Baseline histopathological reports by local pathologists at each study centre were compared with the first standardized blinded assessment. Agreement was assessed for the dichotomized FS (dFS) and dichotomized CM (dCM) grade, as well as for nine other histopathological features. RESULTS: Eighty-nine MSGBs were studied. Intraobserver kappa values were 1 for dFS, 0.80 for dCM, 0.67 for germinal centre like structures, 0.44 for fibrosis and 0.29 for confluent foci. Most of the local histopathological reports based their diagnosis on the CM grade, although the FS was often reported or the data needed to determine it were provided. Interobserver agreement kappa values were 0.71 for dFS, 0.64 for dCM, 0.46 for focal lymphocytic sialadenitis, 0.42 for non-specific chronic inflammation and 0.16 for fibrosis. CONCLUSION: Although FS reliability was good, disparities were noted in the assessment methods used by local pathologists. The protocol for FS determination was not followed routinely, with the result that the FS was often overestimated. Germinal centre-like structures, which predict lymphoma, showed good reliability but were inconsistently reported. PMID- 25433038 TI - Subcellular optogenetics - controlling signaling and single-cell behavior. AB - Variation in signaling activity across a cell plays a crucial role in processes such as cell migration. Signaling activity specific to organelles within a cell also likely plays a key role in regulating cellular functions. To understand how such spatially confined signaling within a cell regulates cell behavior, tools that exert experimental control over subcellular signaling activity are required. Here, we discuss the advantages of using optogenetic approaches to achieve this control. We focus on a set of optical triggers that allow subcellular control over signaling through the activation of G-protein-coupled receptors (GPCRs), receptor tyrosine kinases and downstream signaling proteins, as well as those that inhibit endogenous signaling proteins. We also discuss the specific insights with regard to signaling and cell behavior that these subcellular optogenetic approaches can provide. PMID- 25433041 TI - Predictors of satisfactory improvements in pain for patients with early rheumatoid arthritis in a treat-to-target study. AB - OBJECTIVE: The aim of this study was to identify baseline predictors of achieving patient-perceived satisfactory improvement (PPSI) in pain after 6 months of treat to target in patients with early RA. METHODS: Baseline and 6 month data were used from patients included in the Dutch Rheumatoid Arthritis Monitoring remission induction cohort study. Simple and multivariable logistic regression analyses were used to identify significant predictors of achieving an absolute improvement of 30 mm or a relative improvement of 50% on a visual analogue scale for pain. RESULTS: At 6 months, 125 of 209 patients (59.8%) achieved an absolute PPSI and 130 patients (62.2%) achieved a relative PPSI in pain. Controlling for baseline pain, having symmetrical arthritis was the strongest independent predictor of achieving an absolute [odds ratio (OR) 3.17, P = 0.03] or relative (OR 3.44, P = 0.01) PPSI. Additionally, anti-CCP positivity (OR 2.04, P = 0.04) and having <=12 tender joints (OR 0.29, P = 0.01) were predictive of achieving a relative PPSI. The total explained variance of baseline predictors was 30% for absolute and 18% for relative improvements, respectively. CONCLUSION: Symmetrical joint involvement, anti-CCP positivity and fewer tender joints at baseline are prognostic signs for achieving satisfactory improvement in pain after 6 months of treat to target in patients with early RA. PMID- 25433040 TI - Second-line agents in myositis: 1-year factorial trial of additional immunosuppression in patients who have partially responded to steroids. AB - OBJECTIVE: Ciclosporin and MTX are used in idiopathic inflammatory myopathies (DM and PM) when patients incompletely respond to glucocorticoids. Their effectiveness is unproved in randomized controlled trials (RCTs). We evaluated their benefits in a placebo-controlled factorial RCT. METHODS: A 56-week multicentre factorial-design double-blind placebo-controlled RCT compared steroids alone, MTX (15-25 mg weekly) plus steroids, ciclosporin (1-5 mg/kg/day) plus steroids and all three treatments. It enrolled adults with myositis (by Bohan and Peter criteria) with active disease receiving corticosteroids. RESULTS: A total of 359 patients were screened and 58 randomized. Of the latter, 37 patients completed 12 months of treatment, 7 were lost to follow-up and 14 discontinued treatment. Patients completing 12 months of treatment showed significant improvement (P < 0.001 on paired t-tests) in manual muscle testing (14% change), walking time (22% change) and function (9% change). Intention to treat and completer analyses indicated that ciclosporin monotherapy, MTX monotherapy and ciclosporin/MTX combination therapy showed no significant treatment effects in comparison with placebo. CONCLUSION: Neither MTX nor ciclosporin (by themselves or in combination) improved clinical features in myositis patients who had incompletely responded to glucocorticoids. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number Register; http://www.controlled-trials.com/; ISRCTN40085050. PMID- 25433042 TI - The EULAR Study Group for Registers and Observational Drug Studies: comparability of the patient case mix in the European biologic disease modifying anti-rheumatic drug registers. AB - OBJECTIVE: Under the auspices of the European League Against Rheumatism (EULAR), a study group of investigators representing European biologic DMARD (bDMARD) registers was convened. The purpose of this initial assessment was to collect and compare a cross section of patient characteristics and collate information on the availability of potential confounders within these registers. METHODS: Baseline characteristics of patients starting their first bDMARD in an arbitrary year (2008) for the treatment of RA, including demographic and disease characteristics, bDMARD drug details and co-morbidities, were collected and compared across 14 European bDMARD registers. RESULTS: A total of 5320 patients were included. Half the registers had restricted recruitment to certain bDMARDs during the study year. All registers' collected data on age, gender, disease duration, seropositivity for IgM-RF and 28-joint DAS (DAS28). The mean DAS28 ranged from 4.2 to 6.6 and the mean HAQ from 0.8 to 1.9. Current smoking ranged from 9% to 34%. Nine registers reported co-morbidities with varying prevalence. CONCLUSION: In addition to demonstrating European-wide collaboration across rheumatology bDMARD registers, this assessment identified differences in prescribing patterns, recruitment strategies and data items collected. These differences need to be considered when applying strategies for combined analysis. The lack of a common data model across Europe calls for further work to harmonize data collection across registers. PMID- 25433044 TI - Comment on: induction treatment of ANCA-associated vasculitis with a single dose of rituximab: reply. PMID- 25433043 TI - An outsourced health-enhancing physical activity programme for people with rheumatoid arthritis: exploration of adherence and response. AB - OBJECTIVES: The aims of this study were to document adherence to and changes in health-enhancing physical activity (HEPA) levels and self-reported and assessed functioning and to explore aspects of adherence and response during the first year of an outsourced 2-year HEPA programme in people with RA. METHODS: Two hundred and twenty patients participated in this observational cohort study, which included daily physical activity, twice-weekly circuit training and biweekly support group meetings. Self-reported data included current (past week) and maintained (past 6 months) HEPA levels, sociodemographics and disease-related and psychosocial factors. Tests of aerobic capacity and muscle function were performed and anthropometric data were collected. RESULTS: Eighty-eight per cent of the participants completed 1 year assessments. Self-reported current and maintained HEPA increased. General health perception and a number of other self reported disease-related and psychosocial factors improved, while exercise self efficacy declined. Aerobic capacity, timed standing and grip strength improved and waist circumference decreased. The mean number of circuit training sessions performed was 48, the mean number of days with HEPA was 189 and the mean number of support group meetings attended was 9. Better adherence to circuit training improved general health, and better adherence to group meetings improved timed standing. Exercise self-efficacy improved among those adhering more to circuit training or support group meetings. CONCLUSION: The outsourced HEPA programme had high retention and reasonable adherence. A number of health outcomes improved. Relationships between adherence to the programme components and response were not clear-cut and need further attention. TRIAL REGISTRATION: ISRCTN register; http://www.controlled-trials.com. Trial registration number ISRCTN25539102. PMID- 25433045 TI - Predictors of emergency service use in adolescents and adults with autism spectrum disorder living with family. AB - INTRODUCTION: The use of emergency services among adolescents and adults with autism spectrum disorder (ASD) transitioning into adult health services has not been well described. OBJECTIVES: To describe emergency service use including emergency departments (EDs), paramedics, and police involvement among adolescents and adults with ASD and to examine predictors of using emergency services. METHODS: Caregivers of 396 adolescents and adults with ASD were recruited through autism advocacy agencies and support programmes in Ontario to complete a survey about their child's health service use. Surveys were completed online, by mail and over the phone between December 2010 and October 2012. Parents were asked to describe their child's emergency service use and provide information about potential predictive factors including predisposing, enabling and clinical need variables. RESULTS: According to parents, 13% of their children with ASD used at least one emergency service in a 2-month period. Sedation or restraints were used 23% of the time. A combination of need and enabling variables predicted emergency service use with previous ED use in the last year (OR 3.4, 95% CI 1.7 to 6.8), a history of hurting others (OR 2.3, 95% 1.2 CI to 4.7) and having no structured daytime activities (OR 3.2, 95% CI 1.4 to 7.0) being the strongest multivariate predictors in the model. CONCLUSIONS: Patients with ASD and their families are likely to engage with paramedics or police or visit the ED. Further education and support to families and emergency clinicians are needed to improve and, when possible, prevent such occurrences. PMID- 25433046 TI - Over-the-head two-thumb encircling technique as an alternative to the two-finger technique in the in-hospital infant cardiac arrest setting: a randomised crossover simulation study. AB - OBJECTIVE: To determine if the over-the-head two-thumb encircling technique (OTTT) provides better quality cardiopulmonary resuscitation (CPR) than the conventional two-finger technique (TFT) when performed by a lone rescuer in an in hospital infant cardiac arrest setting. METHODS: This prospective, randomised crossover design study recruited 50 nurses who voluntarily performed lone rescuer infant CPR for 2 min on a manikin. Participants who performed OTTT stood at the head of the manikin to compress the chest and provide bag-valve mask ventilations, whereas those who performed TFT stood by the side of the manikin to compress the chest and provide pocket-mask ventilations. Mean hands-off time, mean compression depths and rates, proportion of effective compressions and complete recoil, and fatigue score changes were assessed during the test, and a survey on the ease of use of the techniques was conducted after the test. RESULTS: Hands-off time, total ventilation volume and number of ventilations were not significantly different between the two techniques. OTTT resulted in greater depth of compressions (p<0.001), greater proportion of effective compressions (p<0.001), smaller proportion of complete recoil (p=0.001), and smaller fatigue score change (p=0.003) than TFT. In addition, subjects reported that compression, ventilation and changing compression to ventilation were easier using OTTT than TFT. CONCLUSIONS: OTTT performed by a lone rescuer in an in-hospital infant cardiac arrest setting resulted in greater compression depth, with no increase in hands-off time, compared with TFT. OTTT may therefore be a suitable alternative to TFT in the in-hospital infant cardiac arrest setting. PMID- 25433047 TI - Anaemia in mothers and infants living in disadvantaged communities. PMID- 25433048 TI - Effect of background and transport dose on the results of the personal dose equivalent Hp(10) measurements in photon fields obtained during the intercomparison 2013 of the African region. AB - As part of the intercomparison on the measurement of personal dose equivalent Hp(10), jointly organised by the International Atomic Energy Agency and the Algerian Secondary Standard Dosimetry Laboratory, for the African region, up to 12 dosemeters were added to the packages of the 28 participants to evaluate the background and transport dose (BGTD), received by the dosemeters before and after their irradiation at the SSDL (environmental irradiations, scanning process at the airports, etc.). Out of the 28 participants, only 17 reported the corresponding BGTD measured values, which lied between 0.03 and 0.8 mSv. The mean measured value of BG was (0.25+/-0.14) mSv, which is significantly high compared with the lowest dose value used in the intercomparison exercise. The BGTD correction shifted the overall results of the intercomparison from an overestimation of dose (~8 % before applying BGT dose correction) to an underestimation of dose (-9 % after correction). The measurement protocol and the detailed analysis of the results and applied corrections are discussed in this paper. PMID- 25433050 TI - Adenovirus urethritis and concurrent conjunctivitis: a case series and review of the literature. AB - We present eight cases and review the literature of concurrent urethritis and conjunctivitis where adenovirus was identified as the causative pathogen. The focus of this review concerns the identification of specific sexual practices, symptoms, signs and any serotypes that seem more commonly associated with such adenovirus infections. We discuss the seasonality of adenovirus infection and provide practical advice for clinicians to give to the patient. PMID- 25433049 TI - Filtration to reduce paediatric dose for a linear slot-scanning digital X-ray machine. AB - This paper describes modelling, application and validation of a filtration technique for a linear slot-scanning digital X-ray system to reduce radiation dose to paediatric patients while preserving diagnostic image quality. A dose prediction model was implemented, which calculates patient entrance doses using variable input parameters. Effective dose is calculated using a Monte Carlo simulation. An added filter of 1.8-mm aluminium was predicted to lower the radiation dose significantly. An objective image quality study was conducted using detective quantum efficiency (DQE). The PTW Normi 4FLU test phantom was used for quantitative assessment, showing that image contrast and spatial resolution were maintained with the proposed filter. A paediatric cadaver full body imaging trial assessed the diagnostic quality of the images and measured the dose reduction using a 1.8-mm aluminium filter. Assessment by radiologists indicated that diagnostic quality was maintained with the added filtration, despite a reduction in DQE. A new filtration technique for full-body paediatric scanning on the Lodox Statscan has been validated, reducing entrance dose for paediatric patients by 36 % on average and effective dose by 27 % on average, while maintaining image quality. PMID- 25433051 TI - A meta-analysis of the effect of new-media interventions on sexual-health behaviours. AB - BACKGROUND AND OBJECTIVES: Direct access to individuals in non-intrusive ways, as well as the technical abilities of new-media to provide tailored information in relatively inexpensive ways, creates a unique opportunity for the delivery of health-related information. The aim of the present research was to examine the effect that new-media-based sexual-health interventions have on sexual-health behaviours in non-clinical populations and to determine the factors that moderate the effect of technology-based sexual-health interventions on sexual--health behaviours. DATA SOURCES: A systematic literature search of the following databases was conducted: MEDLINE, psycINFO, Global health, and EMBASE, using terms that captured three subject areas-'Sexual-health', 'New Technology' and 'Intervention'. STUDY ELIGIBILITY CRITERIA: Randomised controlled trial, or a quasi-experiment; delivered exclusively via new-media; included sexual risk behaviour change as an outcome measure and delivered to non-clinical groups. RESULTS: Twelve studies tested the effect of new-media interventions on condom use, whereas nine tested the effect on sexually transmitted disease testing. Results indicated that new-media interventions led to significant increases in both outcomes; however, these effects were not homogeneous. Moderation analyses revealed that interactivity of the intervention, target population and study design influenced the efficacy of interventions on both sexual-health outcomes, whereas intervention duration influenced sexually transmitted infection testing. CONCLUSIONS AND IMPLICATIONS: Interventions aiming to improve condom use are more successful when an interactive component is used. Further research needs to be conducted to reach specific at-risk populations. PMID- 25433052 TI - Clinical examination and weighing of patients in small animal consultations. PMID- 25433053 TI - Intramuscular administration of alfaxalone for sedation in rabbits. AB - Alfaxalone is a neuroactive steroid derivative of pregnanedione that was recently reintroduced to the market for use as an induction agent in small animal anaesthesia. The aim of this study was to determine an intramuscular alfaxalone dose for safe immobilisation. Ten healthy New Zealand white rabbits were used to evaluate a single intramuscular injection of alfaxalone. The design of the study was a three-way, complete block, cross-over trial to compare the effect of alfaxalone at three doses (4, 6 and 8 mg). The mean duration of the effect for the 4, 6 and 8 mg/kg doses was, respectively, 36.9 (95% CI (31.6 to 42.3)), 51.8 (46.4 to 57.2) and 58.4 (52.8 to 63.9) minutes. The loss of the righting reflex was achieved after 3.1 (2.5 to 3.8), 2.4 (1.7 to 3.1) and 2.3 (1.6 to 2.9) minutes, respectively. The mean duration of the effect for the 6 and 8 mg doses was significantly higher than for the 4 mg dose (with estimated differences of 14.8 95% CI (8.8 to 20.8) minutes and 21.4 (15.3 to 27.6) minutes, respectively). No significant dose effect was observed before the loss of the righting reflex (P=0.14). Ear pinching and limb withdrawal were elicited in all groups at every dose. Doses of 4 or 6 mg/kg could be recommended; higher doses do not provide clinical benefits and can be associated with anaesthetic complication. PMID- 25433054 TI - Colonisation of pig gallbladders with Salmonella species important to public health. PMID- 25433055 TI - Validation of the accuracy of needle placement as used in diagnostic local analgesia of the maxillary nerve for investigation of trigeminally mediated headshaking in horses. AB - Diagnostic local anaesthesia of the maxillary nerve is a valuable aid in the diagnosis of trigeminally mediated headshaking in horses. Our objective is to validate the accuracy of needle placement in this procedure and to identify any correlation between accuracy of the technique and operator experience. Using a small volume of contrast medium, the procedure was performed bilaterally on 30 horse cadaver heads by three groups with different levels of experience with the technique. The location of deposition was then identified using computed tomography (CT). Contrast medium was deposited around the target site in 53.3% (32/60) of injections. An experienced operator succeeded in deposition around the target area significantly (p<0.05) more often (80%, 16/20) than did the less and non-experienced performers (40%, 16/40). A negative response to diagnostic local anaesthesia of the maxillary nerve does not disprove facial dysaesthesia as the cause of headshaking in that horse as a false negative response could arise due to failure to deposit local anaesthetic around the target area. Increased experience in performing the procedure decreases the probability of false negative results. PMID- 25433057 TI - [Reconsideration of cerebrospinal fluid formation and reabsorption]. PMID- 25433056 TI - Comparative efficacy and safety of mavacoxib and carprofen in the treatment of canine osteoarthritis. AB - A multi-site, masked, randomised parallel group study employing a double dummy treatment design was performed in canine veterinary patients to determine the comparative efficacy and safety of mavacoxib and carprofen in the treatment of pain and inflammation associated with osteoarthritis for a period of 134 days. Treatments were administered according to their respective summaries of product characteristics. Of 139 dogs screened, 124 were suitable for study participation: 62 of which were dosed with mavacoxib and 62 with carprofen. Both treatments resulted in a very similar pattern of considerable improvement as indicated in all parameters assessed by both owner and veterinarian. The primary efficacy endpoint 'overall improvement' was a composite score of owner assessments after approximately six weeks of treatment. Both drugs were remarkably effective, with 57/61 (93.4 per cent) of mavacoxib-treated dogs and 49/55 (89.1 per cent) of carprofen-treated dogs demonstrating overall improvement and with mavacoxib's efficacy being non-inferior to carprofen. The treatments had a similar safety profile as evidenced by documented adverse events and summaries of clinical pathology parameters. The positive clinical response to treatment along with the safety and dosing regimen of mavacoxib makes it an attractive therapy for canine osteoarthritis. PMID- 25433058 TI - [Long-term results of decompressive surgery without fusion for degenerative spondylolisthesis]. AB - PURPOSE: The long-term results of decompressive surgery for degenerative spondylolisthesis with symptomatic lumbar spinal stenosis were evaluated retrospectively with regard to the postoperative progression of slippage and clinical symptoms. MATERIALS AND METHODS: The study included 53 patients who underwent surgery, and for whom follow-up of at least 5 years was conducted. Spondylolisthesis was diagnosed based on the presence of sagittal vertebral translation greater than 3mm on lateral radiographs. The patients were divided into two groups:Group I:37 patients undergoing bilateral laminotomy, and Group II:16 patients undergoing laminectomy. The clinical results were evaluated according to McCulloch's classification and the Japanese Orthopaedic Association(JOA)score. RESULTS: The mean pre-and postoperative JOA scores were 14.6 and 22.9 in Group I and 14.7 and 21.0 in Group II, respectively. The JOA scores improved soon after surgery, after which the scores declined gradually in both groups. The recovery rate was 63.0% in Group I and 43.7% in Group II. The average amount of pre- and postoperative slippage was 7.3mm and 6.9mm in Group I and 6.2mm and 6.9mm in Group II, respectively. In Group I, the slippage progressed within the first year, after which the degree of slippage slowly decreased to lower values than those observed preoperatively, whereas slippage progressed for 5 years before declining in Group II. No correlations were observed between progression of slippage and clinical outcomes in either group. CONCLUSIONS: Laminotomy produces satisfactory long-term results both clinically and radiographically in patients with degenerative spondylolisthesis. PMID- 25433059 TI - [CT and histological findings and treatment outcomes after carotid endarterectomy for symptomatic cervical carotid artery stenosis in octogenarians]. AB - Symptomatic cervical carotid artery stenosis is one of the common causes of ischemic stroke in octogenarians. The records for 90 consecutive patients with symptomatic cervical carotid artery stenosis treated by carotid endarterectomy(CEA)were analyzed retrospectively. The patients were divided into two groups:21 patients aged 80 years or over and 69 patients aged less than 80 years. CT angiography revealed that ulcer formation was significantly more common and the length of carotid artery stenosis was significantly greater in the octogenarians. Histological examination of the plaque revealed no significant difference between the two groups in terms of ulcer formation, lipid content, and intraplaque hemorrhage. However, all three of these pathological findings were present in a significantly higher number of octogenarians. No significant difference was observed for new ischemic lesions on diffusion-weighted MR imaging, neurological complications, or cardiac and pulmonary complications. However, treatment with an albumin preparation and loop diuretics was significantly more common in octogenarians after CEA. The present study suggests that with careful postoperative management CEA can be safely performed in symptomatic patients aged 80 years or over with almost the same risk as that for patients aged less than 80 years. PMID- 25433060 TI - [A case of repeated shunt malfunctions with eosinophilic meningitis caused by silicone allergy]. AB - The ventricular-peritoneal shunt for hydrocephalus is a well-known and established method but is sometimes complicated by shunt malfunction due to several causes. Eosinophilic meningitis is a rare disease, but has occasionally been reported as a cause of shunt malfunction. Here, we report the case of a 74 year-old woman with repeated shunt malfunction and eosinophilic meningitis due to a silicone allergy. Originally, the patient received a ventricular-peritoneal shunt for normal pressure hydrocephalus secondary to subarachnoid hemorrhage. However, shunt malfunction was identified 6 weeks later, and the first shunt revision was performed using a new shunt system from a different company. Further evaluation to identify the cause of the shunt malfunction revealed no abnormal findings, except for eosinophilia in the serum and cerebrospinal fluid. A second shunt malfunction was identified 16 weeks after the first shunt revision. We therefore concluded that eosinophilic meningitis caused by a silicone allergy might be the real culprit and a second shunt revision was performed using a silicone "extracted" tube. Since then, the patient's course has been free from shunt malfunction. In this case, the serum and cerebrospinal fluid eosinophilia were useful markers for identifying the cause of repeated shunt malfunctions. The silicone "extracted" tube may be helpful for diagnosis and therapy. PMID- 25433061 TI - [Trigeminal neuralgia caused by cerebellopontine angle lipoma:a case report and review of the literature]. AB - A 59-year-old man presented with right trigeminal neuralgia of the second branch, which had been treated with carbamazepine. The pain could not be controlled adequately because of side effects. CT and MRI revealed a 2-cm lesion in the right cerebellopontine angle. Retrosigmoid lateral suboccipital craniectomy was performed, and a soft yellowish mass was found to be associated with the 5th, 7th, and 8th cranial nerves, anterior inferior cerebellar artery, and small vessels. The lipoma was partially resected from around the root entry zone(REZ)of the 5th nerve and small vessels were coagulated around the REZ. After surgery, there was no trigeminal neuralgia, but facial numbness and cerebellar signs were noted. Postoperative MRI showed decompression of the trigeminal nerve and venous infarction in the middle cerebellar peduncle. Reviewing similar cases, we found 19 lipoma patients presenting with trigeminal neuralgia. Symptoms of involvement of other cranial nerves were also present in 11 patients, and 14 were younger than 30 years old. Of 17 surgical cases, total resection was not attempted apart from one case. Although pain relief was achieved in all surgical cases, complications developed in 11. Surgery should be performed only in patients with disabling and uncontrolled symptoms. PMID- 25433062 TI - [Patients with intractable epilepsy who achieved good seizure control after craniotomy instead of vagal nerve stimulation]. AB - Vagal nerve stimulation(VNS)is an effective adjunctive therapy for medically intractable epilepsy. However, VNS is a palliative therapy, and craniotomy should preferably be performed when complete seizure remission can be expected after craniotomy. We report here three patients who were referred for VNS therapy, but underwent craniotomy instead of VNS based on the results of a comprehensive preoperative evaluation, and achieved good seizure control. Case 1 was a 48-year old woman with left temporal lobe epilepsy and amygdalar enlargement. Even though no left hippocampal sclerosis was observed on magnetic resonance imaging, she underwent left anterior temporal lobectomy and hippocampectomy. Case 2 was a 36 year-old woman with multiple bilateral subependymal nodular heterotopias, who underwent resection of the left medial temporal lobe including subependymal nodular heterotopias adjacent to the left inferior horn. Case 3 was a 25-year-old man with posttraumatic epilepsy. As the right hemisphere was most affected, multiple subpial transections were performed on the left frontal convexity. These three patients were referred to us for VNS therapy because there was a dissociation between the interictal electroencephalogram and magnetic resonance imaging findings, or because they had multiple or extensive epileptogenic lesions. Comprehensive preoperative evaluation including ictal electroencephalography can help to identify patients who are suitable candidates for craniotomy. PMID- 25433064 TI - [Lessons learned from a case of superior sagittal sinus dural arteriovenous fistula:strategy of endovascular treatment]. PMID- 25433063 TI - [Magnetic resonance vessel wall imaging reveals rupture site in subarachnoid hemorrhage with multiple cerebral aneurysms]. AB - We report a case of subarachnoid hemorrhage(SAH)with multiple cerebral aneurysms, in which magnetic resonance vessel wall imaging(MR-VWI)revealed the rupture site. A 68-year-old woman presented with SAH. Computed tomography(CT)showed diffuse SAH(Fisher group 3). 3D-CT angiography revealed two intracranial aneurysms:a 4.2 mm anterior communicating artery aneurysm(Acom An)and a 5.8-mm basilar tip aneurysm(BAtip An). As the BAtip An was the larger of the two, it was deemed the most likely site of rupture;however, high-resolution MR-VWI with gadolinium showed thick wall enhancement in the Acom An and no enhancement in the BAtip An. Thus, we performed a craniotomy for the Acom An. Intraoperative findings confirmed the rupture site at the Acom An. We concluded that high resolution MR VWI may be useful for identifying the rupture site in patients with spontaneous SAH and multiple cerebral aneurysms. PMID- 25433065 TI - [Required knowledge for stroke specialists(5)medical treatment for secondary stroke prevention]. PMID- 25433066 TI - Underrecognition and Undertreatment of Pain and Behavioral Symptoms in End-Stage Dementia. AB - End-stage dementia, a terminal condition, is associated with a high prevalence of physical pain and behavioral symptoms. As these patients often have a decreased ability to express their symptoms, they are often underrecognized and undertreated. This article proposes opportunities to improve patient care. The article underscores the role of assessment scales to optimize behavioral management for patients with dementia and discusses the value of pain management to improve behavioral symptoms. Additionally, a collaborative interdisciplinary team, including palliative medicine, pharmacy services, and spiritual support can optimize patient care and develop a plan of care. PMID- 25433067 TI - Concurrent Specialized Palliative Care Upon Initiation of First-Line Chemotherapy for Cancer Progression: Is It Early Enough? AB - PURPOSE: To evaluate the effectiveness of specialized palliative care (PC) administered at the time of administration of first-line chemotherapy for cancer progression. METHODS: Patients who received regular specialist PC concomitantly with first-line chemotherapy after being diagnosed with progressive disease assigned to PC group. Patients transferred to palliative care unit (PCU) after discontinuation of chemotherapy were assigned to standard care (SC) group. We evaluated quality of palliative care using Support Team Assessment Schedule, quality of life (QOL) using Good Death Inventory, and short-term mortality in PCU. RESULTS: A total of 28 and 63 patients patients were assigned to PC and SC groups, respectively. Physical symptoms, anxiety, communication scores, and QOL scores were significantly higher in the PC group (P < .001). Short-term mortality (<14 days) was significantly higher in the SC group (P = .0005). CONCLUSION: This approach may facilitate high quality of PC. PMID- 25433068 TI - Comparison of the Educational Needs of Neonatologists and Neonatal Nurses Regarding Palliative Care in Taiwan. AB - BACKGROUND: Education and training are very critical to development of high quality neonatal palliative care. However, little investigation has been done into Taiwanese neonatal clinicians' educational needs regarding neonatal palliative care. PURPOSES: The purposes of this study were to characterize and identify neonatal clinicians' educational needs regarding neonatal palliative care. METHODS: A cross-sectional descriptive surveyed method via a self administered questionnaire was used in this research. Thirty neonatologists were recruited by a convenience sampling and 30 nurses were recruited by a randomized sampling. RESULTS: Out of sixty neonatal clinicians' survey, few had received the education in neonatal palliative care. Most reported minimal training in, experience with, and knowledge of neonatal palliative care. For neonatologists, two of twelve most strongly-felt educational needs were "discussing palliative care and ethical decision-making with parents" (70%) and "informing parents the poor progress in neonates" (63.3%). In contrast, neonatal nurses wanted more training regarding pain control (50%). Communication skills, including the discussing poor prognosis, bad news, and code status and talking with neonates about end-of-life care, were the educational need most commonly felt by both neonatologists and nurses. CONCLUSIONS: Survey data from neonatologists and neonatal nurses in Taiwan indicate a need for further training on a range of neonatal palliative care competencies. PMID- 25433069 TI - In vivo roles for myosin phosphatase targeting subunit-1 phosphorylation sites T694 and T852 in bladder smooth muscle contraction. AB - KEY POINTS: Force production and maintenance in smooth muscle is largely controlled by myosin regulatory light chain (RLC) phosphorylation, which relies on a balance between Ca(2+)/calmodulin-dependent myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) activities. MYPT1 is the regulatory subunit of MLCP that biochemically inhibits MLCP activity via T694 or T852 phosphorylation in vitro. Here we separately investigated the contribution of these two phosphorylation sites in bladder smooth muscles by establishing two single point mutation mouse lines, T694A and T852A, and found that phosphorylation of MYPT1 T694, but not T852, mediates force maintenance via inhibition of MLCP activity and enhancement of RLC phosphorylation in vivo. Our findings reveal the role of MYPT1 T694/T852 phosphorylation in vivo in regulation of smooth muscle contraction. ABSTRACT: Force production and maintenance in smooth muscle is largely controlled by different signalling modules that fine tune myosin regulatory light chain (RLC) phosphorylation, which relies on a balance between Ca(2+)/calmodulin-dependent myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) activities. To investigate the regulation of MLCP activity in vivo, we analysed the role of two phosphorylation sites on MYPT1 (regulatory subunit of MLCP) that biochemically inhibit MLCP activity in vitro. MYPT1 is constitutively phosphorylated at T694 by unidentified kinases in vivo, whereas the T852 site is phosphorylated by RhoA-associated protein kinase (ROCK). We established two mouse lines with alanine substitution of T694 or T852. Isolated bladder smooth muscle from T852A mice displayed no significant changes in RLC phosphorylation or force responses, but force was inhibited with a ROCK inhibitor. In contrast, smooth muscles containing the T694A mutation showed a significant reduction of force along with reduced RLC phosphorylation. The contractile responses of T694A mutant smooth muscle were also independent of ROCK activation. Thus, phosphorylation of MYPT1 T694, but not T852, is a primary mechanism contributing to inhibition of MLCP activity and enhancement of RLC phosphorylation in vivo. The constitutive phosphorylation of MYPT1 T694 may provide a mechanism for regulating force maintenance of smooth muscle. PMID- 25433070 TI - Epitranscriptional regulation of cardiovascular development and disease. AB - Development, homeostasis and responses to stress in the heart all depend on appropriate control of mRNA expression programmes, which may be enacted at the level of DNA sequence, DNA accessibility and RNA-mediated control of mRNA output. Diverse mechanisms underlie promoter-driven transcription of coding mRNAs and their translation into protein, and the ways in which sequence alteration of DNA can make an impact on these processes have been studied for some time. The field of epigenetics explores changes in DNA structure that influence its accessibility by transcriptional machinery, and we are continuing to develop our understanding of how these processes modify cardiac RNA production. In this topical review, we do not focus on how DNA sequence and methylation, and histone interactions, may alter its accessibility, but rather on newly described mechanisms by which some transcribed RNAs may alter initial transcription or downstream processing of other RNAs, involving both short non-coding RNAs (microRNAs) and long non-coding RNAs (lncRNAs). Here we present examples of how these two classes of non-coding RNAs mediate widespread effects on cardiac transcription and protein output in processes for which we use the broad term 'epitranscriptional regulation' and that are complementary to the DNA methylation and histone modification events studied by classical epigenetics. PMID- 25433071 TI - Photoreleasable ligands to study intracrine angiotensin II signalling. AB - KEY POINTS: The renin-angiotensin system plays a key role in cardiovascular physiology and its overactivation has been implicated in the pathogenesis of several major cardiovascular diseases. There is growing evidence that angiotensin II (Ang-II) may function as an intracellular peptide to activate intracellular/nuclear receptors and their downstream signalling effectors independently of cell surface receptors. Current methods used to study intracrine Ang-II signalling are limited to indirect approaches because of a lack of selective intracellularly-acting probes. Here, we present novel photoreleasable Ang-II analogues used to probe intracellular actions with spatial and temporal precision. The photorelease of intracellular Ang-II causes nuclear and cytosolic calcium mobilization and initiates the de novo synthesis of RNA in cardiac cells, demonstrating the application of the method. ABSTRACT: Several lines of evidence suggest that intracellular angiotensin II (Ang-II) contributes to the regulation of cardiac contractility, renal salt reabsorption, vascular tone and metabolism; however, work on intracrine Ang-II signalling has been limited to indirect approaches because of a lack of selective intracellularly-acting probes. Here, we aimed to synthesize and characterize cell-permeant Ang-II analogues that are inactive without uncaging, but release active Ang-II upon exposure to a flash of UV-light, and act as novel tools for use in the study of intracrine Ang-II physiology. We prepared three novel caged Ang-II analogues, [Tyr(DMNB)(4)]Ang-II, Ang-II-ODMNB and [Tyr(DMNB)(4)]Ang-II-ODMNB, based upon the incorporation of the photolabile moiety 4,5-dimethoxy-2-nitrobenzyl (DMNB). Compared to Ang-II, the caged Ang-II analogues showed 2-3 orders of magnitude reduced affinity toward both angiotensin type-1 (AT1R) and type-2 (AT2R) receptors in competition binding assays, and greatly-reduced potency in contraction assays of rat thoracic aorta. After receiving UV-irradiation, all three caged Ang-II analogues released Ang-II and potently induced the contraction of rat thoracic aorta. [Tyr(DMNB)(4)]Ang-II showed the most rapid photolysis upon UV-irradiation and was the focus of subsequent characterization. Whereas Ang-II and photolysed [Tyr(DMNB)(4)]Ang-II increased ERK1/2 phosphorylation (via AT1R) and cGMP production (AT2R), caged [Tyr(DMNB)(4)]Ang-II did not. Cellular uptake of [Tyr(DMNB)(4)]Ang-II was 4-fold greater than that of Ang-II and significantly greater than uptake driven by the positive-control HIV TAT(48-60) peptide. Intracellular photolysis of [Tyr(DMNB)(4)]Ang-II induced an increase in nucleoplasmic Ca(2+) ([Ca(2+)]n), and initiated 18S rRNA and nuclear factor kappa B mRNA synthesis in adult cardiac cells. We conclude that caged Ang-II analogues represent powerful new tools for use in the selective study of intracrine signalling via Ang-II. PMID- 25433072 TI - Molecular mechanisms of temperature adaptation. AB - Thermal perception is a fundamental physiological process pertaining to the vast majority of organisms. In vertebrates, environmental temperature is detected by the primary afferents of the somatosensory neurons in the skin, which express a 'choir' of ion channels tuned to detect particular temperatures. Nearly two decades of research have revealed a number of receptor ion channels that mediate the perception of several temperature ranges, but most still remain molecularly orphaned. Yet even within this well-researched realm, most of our knowledge largely pertains to two closely related species of rodents, mice and rats. While these are standard biomedical research models, mice and rats provide a limited perspective to elucidate the general principles that drive somatosensory evolution. In recent years, significant advances have been made in understanding the molecular mechanism of temperature adaptation in evolutionarily distant vertebrates and in organisms with acute thermal sensitivity. These studies have revealed the remarkable versatility of the somatosensory system and highlighted adaptations at the molecular level, which often include changes in biophysical properties of ion channels from the transient receptor potential family. Exploiting non-standard animal models has the potential to provide unexpected insights into general principles of thermosensation and thermoregulation, unachievable using the rodent model alone. PMID- 25433073 TI - Protection of intestinal injury during heat stroke in mice by interleukin-6 pretreatment. AB - KEY POINTS: Heat stroke afflicts thousands of humans each year, worldwide. The immune system responds to hyperthermia exposure resulting in heat stroke by producing an array of immunological proteins, such as interleukin-6 (IL-6). However, the physiological functions of IL-6 and other cytokines in hyperthermia are poorly understood. We hypothesized that IL-6 plays a protective role in conditions of heat stroke. To test this, we gave small IL-6 supplements to mice prior to exposing them to hot environments sufficient to induce conditions of heat stroke. Pretreatment with IL-6 resulted in improved ability to withstand heat exposure in anaesthetized mice, it protected the intestine from injury, reducing the permeability of the intestinal barrier, and it attenuated the release of other cytokines involved in inflammation. The results support the hypothesis that IL-6 is a 'physiological stress hormone' that plays an important role in survival during acute life-threatening conditions such as heat stroke. ABSTRACT: The role of interleukin-6 (IL-6) in hyperthermia and heat stroke is poorly understood. Plasma IL-6 is elevated following hyperthermia in animals and humans, and IL-6 knockout mice are more intolerant of severe hyperthermia. We evaluated the effect of IL-6 supplementation on organ injury following severe hyperthermia exposure in anaesthetized mice. Two hours prior to hyperthermia, mice were treated with 0.6 MUg intraperitoneal IL-6, or identical volumes of saline in controls. Mice were anaesthetized, gavaged with FITC-dextran for measures of gastrointestinal permeability, and exposed to incremental (0.5 degrees C every 30 min) increases in temperature. Heating stopped when maximum core temperature (Tc) of 42.4 degrees C was attained (Tc,max). The mice recovered at room temperature (~22 degrees C) for 30 or 120 min, at which time plasma and tissues were collected. IL-6-treated mice, on average, required ~25 min longer to attain Tc,max . Injury and swelling of the villi in the duodenum was present in untreated mice after 30 min of recovery. These changes were blocked by IL-6 treatment. IL-6 also reduced gastrointestinal permeability, assayed by the accumulation of FITC-dextran in plasma. Plasma cytokines were also attenuated in IL-6-treated animals, including significant reductions in TNFalpha, MCP-1 (CXCL2), RANTES (CCL5) and KC (CCL5). The results demonstrate that IL-6 has a protective influence on the pattern of physiological responses to severe hyperthermia, suggesting that early endogenous expression of IL-6 may provide a protection from the development of organ damage and inflammation. PMID- 25433074 TI - Non-receptor tyrosine kinases and the actin cytoskeleton in contractile vascular smooth muscle. AB - The contractility of vascular smooth muscle cells within the walls of arteries is regulated by mechanical stresses and vasoactive signals. Transduction of these diverse stimuli into a cellular response occurs through many different mechanisms, one being reorganisation of the actin cytoskeleton. In addition to a structural role in maintaining cellular architecture it is now clear that the actin cytoskeleton of contractile vascular smooth muscle cells is a dynamic structure reacting to changes in the cellular environment. Equally clear is that disrupting the cytoskeleton or interfering with its rearrangement, has profound effects on artery contractility. The actin cytoskeleton associates with dense plaques, also called focal adhesions, at the plasma membrane of smooth muscle cells. Vasoconstrictors and mechanical stress induce remodelling of the focal adhesions, concomitant with cytoskeletal reorganisation. Recent work has shown that non-receptor tyrosine kinases and tyrosine phosphorylation of focal adhesion proteins such as paxillin and Hic-5 are important for actin cytoskeleton and focal adhesion remodelling and contraction. PMID- 25433075 TI - Electrophysiological properties of laryngeal motoneurones in rats submitted to chronic intermittent hypoxia. AB - KEY POINTS: The respiratory control of the glottis by laryngeal motoneurones is characterized by inspiratory abduction and post-inspiratory adduction causing decreases and increases in upper airway resistance, respectively. Chronic intermittent hypoxia (CIH), an important component of obstructive sleep apnoea, exaggerated glottal abduction (before inspiration), associated with active expiration and decreased glottal adduction during post-inspiration. CIH increased the inspiratory and decreased the post-inspiratory laryngeal motoneurone activities, which is not associated to changes in their intrinsic electrophysiological properties. We conclude that the changes in the respiratory network after CIH seem to be an adaptive process required for an appropriated pulmonary ventilation and control of upper airway resistance under intermittent episodes of hypoxia. ABSTRACT: To keep an appropriate airflow to and from the lungs under physiological conditions a precise neural co-ordination of the upper airway resistance by laryngeal motoneurones in the nucleus ambiguus is essential. Chronic intermittent hypoxia (CIH), an important component of obstructive sleep apnoea, may alter these fine mechanisms. Here, using nerve and whole cell patch clamp recordings in in situ preparations of rats we investigated the effects of CIH on the respiratory control of the upper airway resistance, on the electrophysiological properties of laryngeal motoneurones in the nucleus ambiguus, and the role of carotid body (CB) afferents to the brainstem on the underlying mechanisms of these effects. CIH rats exhibited longer pre-inspiratory and lower post-inspiratory superior laryngeal nerve activities than control rats. These changes produced exaggerated glottal abduction (before inspiration) and decreased glottal adduction during post-inspiration, indicating a reduction of upper airway resistance during these respiratory phases after CIH. CB denervation abolished these changes produced by CIH. Regarding choline acetyltransferase positive-laryngeal motoneurones, CIH increased the firing frequency of inspiratory and decreased the firing frequency of post-inspiratory laryngeal motoneurones, without changes in their intrinsic electrophysiological properties. These data show that the effects of CIH on the upper airway resistance and laryngeal motoneurones activities are driven by the integrity of CB, which afferents induce changes in the central respiratory generators in the brainstem. These neural changes in the respiratory network seem to be an adaptive process required for an appropriated pulmonary ventilation and control of upper airway resistance under intermittent episodes of hypoxia. PMID- 25433076 TI - Short-chain fatty acid sensing in rat duodenum. AB - KEY POINTS: Luminal lipid in the duodenum modulates gastroduodenal functions via the release of gut hormones and mediators such as cholecystokinin and 5-HT. The effects of luminal short-chain fatty acids (SCFAs) in the foregut are unknown. Free fatty acid receptors (FFARs) for long-chain fatty acids (LCFAs) and SCFAs are expressed in enteroendocrine cells. SCFA receptors, termed FFA2 and FFA3, are expressed in duodenal enterochromaffin cells and L cells, respectively. Activation of LCFA receptor (FFA1) and presumed FFA3 stimulates duodenal HCO3(-) secretion via a glucagon-like peptide (GLP)-2 pathway, whereas FFA2 activation induces HCO3(-) secretion via muscarinic and 5-HT4 receptor activation. The presence of SCFA sensing in the duodenum with GLP-2 and 5-HT signals further supports the hypothesis that luminal SCFA in the foregut may contribute towards the generation of functional symptoms. ABSTRACT: Intraduodenal fatty acids (FA) and bacterial overgrowth, which generate short-chain FAs (SCFAs), have been implicated in the generation of functional dyspepsia symptoms. We studied the mechanisms by which luminal SCFA perfusion affects duodenal HCO3(-) secretion (DBS), a measure of mucosal neurohumoral activation. Free fatty acid receptor (FFAR) 1 (FFA1), which binds long-chain FA (LCFA), and SCFA receptors FFA2 and FFA3 were immunolocalised to duodenal enteroendocrine cells. FFA3 colocalised with glucagon-like peptide (GLP)-1, whereas FFA2 colocalised with 5-HT. Luminal perfusion of the SCFA acetate or propionate increased DBS, enhanced by dipeptidyl peptidase-IV (DPPIV) inhibition, at the same time as increasing GLP-2 portal blood concentrations. Acetate-induced DBS was partially inhibited by monocarboxylate/HCO3(-) exchanger inhibition without affecting GLP-2 release, implicating acetate absorption in the partial mediation of DBS. A selective FFA2 agonist dose-dependently increased DBS, unaffected by DPPIV inhibition or by cholecystokinin or 5-HT3 receptor antagonists, but was inhibited by atropine and a 5-HT4 antagonist. By contrast, a selective FFA1 agonist increased DBS accompanied by GLP-2 release, enhanced by DPPIV inhibition and inhibited by a GLP 2 receptor antagonist. Activation of FFA1 by LCFA and presumably FFA3 by SCFA increased DBS via GLP-2 release, whereas FFA2 activation stimulated DBS via muscarinic and 5-HT4 receptor activation. SCFA/HCO3(-) exchange also appears to be present in the duodenum. The presence of duodenal fatty acid sensing receptors that signal hormone release and possibly signal neural activation may be implicated in the pathogenesis of functional dyspepsia. PMID- 25433078 TI - In the beginning: a personal reminiscence on the origin and legacy of ClC-0, the 'Torpedo Cl(-) channel'. AB - This unapologetically subjective essay recalls the Torpedo Cl(-) channel in the years when it had neither a molecular identity nor proper name (ClC-0), and membership in a large superfamily. I discuss the circumstances surrounding its discovery and subsequent research through the 1980s that revealed its unusual molecular architecture and other strange mechanistic characteristics. PMID- 25433077 TI - Silicon central pattern generators for cardiac diseases. AB - Cardiac rhythm management devices provide therapies for both arrhythmias and resynchronisation but not heart failure, which affects millions of patients worldwide. This paper reviews recent advances in biophysics and mathematical engineering that provide a novel technological platform for addressing heart disease and enabling beat-to-beat adaptation of cardiac pacing in response to physiological feedback. The technology consists of silicon hardware central pattern generators (hCPGs) that may be trained to emulate accurately the dynamical response of biological central pattern generators (bCPGs). We discuss the limitations of present CPGs and appraise the advantages of analog over digital circuits for application in bioelectronic medicine. To test the system, we have focused on the cardio-respiratory oscillators in the medulla oblongata that modulate heart rate in phase with respiration to induce respiratory sinus arrhythmia (RSA). We describe here a novel, scalable hCPG comprising physiologically realistic (Hodgkin-Huxley type) neurones and synapses. Our hCPG comprises two neurones that antagonise each other to provide rhythmic motor drive to the vagus nerve to slow the heart. We show how recent advances in modelling allow the motor output to adapt to physiological feedback such as respiration. In rats, we report on the restoration of RSA using an hCPG that receives diaphragmatic electromyography input and use it to stimulate the vagus nerve at specific time points of the respiratory cycle to slow the heart rate. We have validated the adaptation of stimulation to alterations in respiratory rate. We demonstrate that the hCPG is tuneable in terms of the depth and timing of the RSA relative to respiratory phase. These pioneering studies will now permit an analysis of the physiological role of RSA as well as its any potential therapeutic use in cardiac disease. PMID- 25433080 TI - Fused ureters in patient with horseshoe kidney and aortic abdominal aneurysm. AB - Horseshoe kidney (HSK) is a very common developmental abnormality in the kidney. They are associated with abnormalities like multiple renal arteries, abnormal position of the ureter in the renal pelvis and highly placed ureteropelvic junction. These can result in urological complications. However, the ureters run their separate course and empty individually into the urinary bladder. Surprisingly, anatomical anomalies do occur and can lead to unexpected findings on investigation or surgical treatment. Such anomalies can present diagnostic and management challenges to unsuspecting clinicians. This report deals with one of such anomalies that seem not to have been reported before in the literature. This case is a rare finding of fused ureters over the renal isthmus in a patient with HSK who also has aortic abdominal aneurysm (AAA). Simultaneous occurrences of HSK and AAA have been reported severally in the past, and the authors are paying attention on the ureteral anomaly. PMID- 25433082 TI - Temporal population genetic instability in range-edge western toads, Anaxyrus boreas. AB - In this article, we address the temporal stability of population genetic structure in a range-edge population that is undergoing continual, short-distance colonization events. We sampled western toad, Anaxyrus boreas, breeding populations over 2 seasons near their northern range limit in southeast Alaska. We sampled 20 ponds each during the summers of 2008 and 2009, with 14 ponds sampled in both summers. We found considerable turnover in the population genetic relationships among ponds in those 2 seasons, as well as biologically meaningful genetic differentiation between years within some ponds. We found relatively consistent relationships between major population centers, whereas the relationships between the central ponds and smaller, outlying populations differed year to year. This finding indicates that multiple years of genetic sampling may be important for understanding the genetic landscape of some populations. PMID- 25433079 TI - The role of gastrointestinal vagal afferent fibres in obesity. AB - Gastrointestinal (GI) vagal afferents are a key mediatory of food intake. Through a balance of responses to chemical and mechanical stimuli food intake can be tightly controlled via the ascending satiety signals initiated in the GI tract. However, vagal responses to both mechanical and chemical stimuli are modified in diet-induced obesity (DIO). Much of the research to date whilst in relatively isolated/controlled circumstances indicates a shift between a balance of orexigenic and anorexigenic vagal signals to blunted anorexigenic and potentiated orexigenic capacity. Although the mechanism responsible for the DIO shift in GI vagal afferent signalling is unknown, one possible contributing factor is the gut microbiota. Nevertheless, whatever the mechanism, the observed changes in gastrointestinal vagal afferent signalling may underlie the pathophysiological changes in food consumption that are pivotal for the development and maintenance of obesity. PMID- 25433083 TI - Multiple mating and reproductive skew in parental and introgressed females of the live-bearing fish Xiphophorus birchmanni. AB - Just as mating patterns can promote speciation or hybridization, the presence of hybridization can shape mating patterns within a population. In this study, we characterized patterns of multiple mating and reproductive skew in a naturally hybridizing swordtail fish species, Xiphophorus birchmanni. We quantified multiple mating using microsatellite markers to genotype embryos from 43 females collected from 2 wild populations. We also used a suite of single-nucleotide polymorphism markers to categorize females and their inferred mates as either parental X. birchmanni or as introgressed individuals, which carried alleles from a sister species, X. malinche. We found that parental and introgressed X. birchmanni females mated multiply with both parental and introgressed males. We found no difference in mating patterns or reproductive skew between parental and introgressed X. birchmanni females. However, nonintrogressed X. birchmanni males mated more often with large, fecund females. These females also had the greatest levels of skew in fertilization success of males. Thus, our results show that X. birchmanni has a polygynandrous mating system and that introgression of X. malinche alleles has only subtle effects on mating patterns in this species. PMID- 25433089 TI - Bayesian proteoform modeling improves protein quantification of global proteomic measurements. AB - As the capability of mass spectrometry-based proteomics has matured, tens of thousands of peptides can be measured simultaneously, which has the benefit of offering a systems view of protein expression. However, a major challenge is that, with an increase in throughput, protein quantification estimation from the native measured peptides has become a computational task. A limitation to existing computationally driven protein quantification methods is that most ignore protein variation, such as alternate splicing of the RNA transcript and post-translational modifications or other possible proteoforms, which will affect a significant fraction of the proteome. The consequence of this assumption is that statistical inference at the protein level, and consequently downstream analyses, such as network and pathway modeling, have only limited power for biomarker discovery. Here, we describe a Bayesian Proteoform Quantification model (BP-Quant)(1) that uses statistically derived peptides signatures to identify peptides that are outside the dominant pattern or the existence of multiple overexpressed patterns to improve relative protein abundance estimates. It is a research-driven approach that utilizes the objectives of the experiment, defined in the context of a standard statistical hypothesis, to identify a set of peptides exhibiting similar statistical behavior relating to a protein. This approach infers that changes in relative protein abundance can be used as a surrogate for changes in function, without necessarily taking into account the effect of differential post-translational modifications, processing, or splicing in altering protein function. We verify the approach using a dilution study from mouse plasma samples and demonstrate that BP-Quant achieves similar accuracy as the current state-of-the-art methods at proteoform identification with significantly better specificity. BP-Quant is available as a MatLab(r) and R packages. PMID- 25433090 TI - NEDD4-2 (NEDD4L): the ubiquitin ligase for multiple membrane proteins. AB - NEDD4-2 (also known as NEDD4L, neural precursor cell expressed developmentally down-regulated 4-like) is a ubiquitin protein ligase of the Nedd4 family which is known to bind and regulate a number of membrane proteins to aid in their internalization and turnover. Several of the NEDD4-2 substrates include ion channels, such as the epithelial and voltage-gated sodium channels. Given the critical function of NEDD4-2 in regulating membrane proteins, this ligase is essential for the maintenance of cellular homeostasis. In this article we review the biology and function of this important ubiquitin-protein ligase and discuss its pathophysiological significance. PMID- 25433091 TI - P38 participates in spermatogenesis and acrosome reaction prior to fertilization in Chinese mitten crab Eriocheir sinensis. AB - P38 mitogen-activated protein kinases (MAPKs) comprise a family of serine/threonine protein kinases that play important roles in cellular responses to inflammatory cytokines and environmental stresses. These kinases are involved in controlling cell division, differentiation and death in mammalian testes and therefore are critical to spermatogenesis. To explore their functions in male reproduction of Chinese mitten crabs, Eriocheir sinensis p38 (Es-p38) protein expression was determined in different tissues including testes at different developmental stages by Western blot. Es-p38 was expressed in various tissues, with higher levels in the heart, stomach, gills and testes. Total Es-p38 protein levels increased gradually during spermatogenesis, but phosphorylated Es-p38 was much higher in the spermatid (August-October) than the spermatocyte (July-August) and sperm (October-January) stages. Trypan blue staining and hematoxylin/eosin staining were both used to detect sperm motility and changes in sperm morphology during the acrosome reaction (AR) induced by pre-incubation with A23187 in vitro, activated Es-p38 proteins detected by fluorescent microscopy were translocated gradually to nuclear and apical cap regions, accumulating at the anterior of the acrosomal tubule. The results suggest the involvement of p38 MAPK in spermatogenesis and the AR in E. sinensis. PMID- 25433092 TI - On-going elucidation of mechanisms of primate specific synaptic spine development using the common marmoset (Callithrix jacchus). AB - Recently, pathophysiology of human psychiatry originates from abnormal numbers of synapses/spines. There are generally two-types of development of spines from birth depending on species. One is, after birth, synaptogenesis occurs, and there is a clear peak of spines, and then rapidly pruning occurring, which are called "overshoot-type" of development of synapses/spines. Primates including human belong to this type. In other type including rodents, even after a peak, general number of spines does not decrease so much. Although these differences, most of human psychiatric models have been genetic modified rodents. Now, transgenic primate (the common marmoset) became available. In near future, we can, examine pathophysiology of psychiatric disorders using this animal model, which is closer to human being. To begin with this endeavor, we should know how synapses/spines of normal marmosets developed, and molecular mechanisms of "overshoot-type" of spine development, which human being also shows. Here, we will present our recent effort to explore these questions, and future experiments will be discussed. PMID- 25433093 TI - The future of real-world neuroscience: imaging techniques to assess active brains in social environments. AB - The human brain is characterized by an evolutionarily new, highly developed neocortex, which has characteristic connections with phylogenically older structures to enable adaptation to complex social environments. Adaptive social behavior requires successful mental representations of the self and others' emotions and intentions. Measurement of brain activity under laboratory-based settings has been the gold standard in previous cognitive neuroscience studies. However, these measurement settings may be sub-optimal if we want to visualize brain function in active individuals in real-world environments. Neuroscience has historically developed through generations of the "sensing brain," "emotional brain," "social brain," and "ego brain." The next generation is the "action brain" combined with "real-world neuroscience" perspective. To enable in situ measurement of the action brain, real-world or two-person neuroimaging techniques are necessary to visualize brain dynamics during natural social situations, such as the presence of others. This review discusses recent literature describing non human primate (NHP) and human brain functions during active behaviors in social environments. Uncovering the neurobiological mechanisms of the active brain in the presence of others by using real-world neuroimaging will be an important step toward fully understanding the human brain and its mental functions. PMID- 25433094 TI - Effects of maternal separation on behavior and brain damage in adult rats exposed to neonatal hypoxia-ischemia. AB - Animal studies suggest that maternal separation, a widely used paradigm to study the effects of early life adversity, exerts a profound and life-long impact on both brain and behavior. The aim of the current study was to investigate whether adverse early life experiences interact with neonatal hypoxia-ischemia, affecting the outcome of this neurological insult at both functional and structural levels during adulthood. Rat pups were separated from their mothers during postnatal days 1-6, for either a short (15 min) or prolonged (180 min) period, while another group was left undisturbed. On postnatal day 7, a subgroup from each of the three postnatal manipulations was exposed to a hypoxic-ischemic episode. Behavioral examination took place approximately at three months of age and included tests of learning and memory (Morris water maze, novel object and novel place recognition), as well as motor coordination (rota-rod). We found that both prolonged maternal separation and neonatal hypoxia-ischemia impaired the animals' spatial learning and reference memory. Deficits in spatial but not visual recognition memory were detected only in hypoxic-ischemic rats. Interestingly, prolonged maternal separation prior to neonatal hypoxia-ischemia augmented the reference memory impairments. Histological analysis of infarct size, hippocampal area and thickness of corpus callosum did not reveal any exacerbation of damage in hypoxic-ischemic rats that were maternally separated for a prolonged period. These are the first data suggesting that an adverse postnatal environmental manipulation of just 6 days causes long-term effects on spatial learning and memory and may render the organism more vulnerable to a subsequent insult. PMID- 25433096 TI - Acute sleep deprivation enhances avoidance learning and spatial memory and induces delayed alterations in neurochemical expression of GR, TH, DRD1, pCREB and Ki67 in rats. AB - The current study investigated the effects of acute versus repeated periods of sleep deprivation on avoidance learning and spatial memory and on the expression of discrete biochemical brain signals involved in stress regulation, motivation and brain plasticity. Male Long-Evans rats were sleep deprived using the platform over-water method for a single 4 h period (ASD) or for daily 4h RSD period on five consecutive days (CSD). The Y maze passive avoidance task (YM-PAT) and the Morris water maze (MWM) were used to determine learning and memory 1h following the last SD period. Region-specific changes in glucocorticoid receptors (GR), tyrosine hydroxylase (TH), dopamine 1 receptors (DRD1), phospho-CREB (pCREB) and Ki-67 expression were assessed in the hippocampal formation, hypothalamus and mesolimbic regions 72 h following RSD. Behaviorally, our findings revealed increased latency to re-enter the aversive arm in the YM-PAT and reduced distance traveled and latency to reach the platform in the MWM in ASD rats compared to all other groups, indicative of improved avoidance learning and spatial memory, respectively. Acute SD enhanced TH expression in the ventral tegmental area, nucleus accumbens and A11 neurons of the hypothalamus and DRD1 expression in the lateral hypothalamus. Cell proliferation in the subventricular zone and pCREB expression in the dentate gyrus and CA3 regions was also enhanced following acute SD. In contrast, repeated SD significantly elevated GR-ir at the hypothalamic paraventricular nucleus and CA1 and CA3 layers of the hippocampus compared to all other groups. Our study supports that a brief 4h sleep deprivation period is sufficient to induce delayed neurochemical changes. PMID- 25433095 TI - Prefrontal engagement by cognitive reappraisal of negative faces. AB - Cognitive reappraisal has been associated with increased activation in prefrontal cortex (PFC) and cingulate regions implicated in cognitive control and affect regulation. To date, neuroimaging studies of reappraisal have primarily used emotionally evocative scenes, and it remains unclear whether the same cognitive strategy applied to emotional facial expressions would involve similar or different neural underpinnings. The present study used fMRI to examine brain activation during cognitive reappraisal of negatively valenced facial expressions relative to passive viewing of negative and neutral facial expressions. Twenty two healthy adults completed a cognitive reappraisal task comprised of three different conditions (Look-Neutral, Maintain-Negative, Reappraise-Negative). Results indicated that reappraisal was associated with a decrease in negative affect and engagement of PFC brain regions implicated in cognitive control and affect regulation (DLPFC, mPFC, and VLPFC). Furthermore, individual differences in habitual reappraisal use were associated with greater DLPFC and mPFC activation, while suppression use was associated with greater amygdala activation. The present study provides preliminary evidence that facial expressions are effective alternative 'targets' of prefrontal engagement during cognitive reappraisal. These findings are particularly relevant for future research probing the neural bases of emotion regulation in populations for whom aversive scenes may be less appropriate (e.g., children) and illnesses in which aberrant responses to social signals of threat and negative feedback are cardinal phenotypes. PMID- 25433098 TI - Aldosterone: a cardiometabolic risk hormone? AB - INTRODUCTION: A aldosterone is a component of the renin-angiotensin-aldosterone system, classically known for its role in sodium and water retention. Besides its effects, has been shown that the aldosterone is associated with the pathogenesis and progression of metabolic syndrome components. A better understanding of this system and interfering factors could help develop pharmacotherapeutic alternatives for several disorders. OBJECTIVES: Investigate the relationship between diet and aldosterone, and its influence on cardiometabolic risk factors. RESULTS AND DISCUSSION: Diet can affect plasma aldosterone levels; high fructose and fat intake can lead to increased aldosterone levels, whereas the effect of sodium intake remains controversial. Adipose tissue, particularly visceral tissue, appears to produce a lipid-soluble factor that increases aldosterone production. Patients with metabolic syndrome have higher aldosterone levels; moreover, an increased cardiometabolic risk associated with insulin resistance could be partially mediated by the action of aldosterone via mineralocorticoid receptors. Even a subtle activation of this hormonal system may have deleterious effects on the glucose and lipid metabolism related to metabolic syndrome. Nevertheless, additional studies are required to better understand the interactions among adipose tissue, aldosterone, and cardiovascular risk as well as the possible role of diet. PMID- 25433097 TI - Neural reactivity to monetary rewards and losses in childhood: longitudinal and concurrent associations with observed and self-reported positive emotionality. AB - Reward reactivity and positive emotion are key components of a theoretical, early emerging approach motivational system, yet few studies have examined associations between positive emotion and neural reactivity to reward across development. In this multi-method prospective study, we examined the association of laboratory observations of positive emotionality (PE) at age 3 and self-reported positive affect (PA) at age 9 with an event-related potential component sensitive to the relative response to winning vs. losing money, the feedback negativity (DeltaFN), at age 9 (N=381). Males had a larger DeltaFN than females, and both greater observed PE at age 3 and self-reported PA at age 9 significantly, but modestly, predicted an enhanced DeltaFN at age 9. Negative emotionality and behavioral inhibition did not predict DeltaFN. Results contribute to understanding the neural correlates of PE and suggest that the FN and PE may be related to the same biobehavioral approach system. PMID- 25433099 TI - [Is gluten the great etiopathogenic agent of disease in the XXI century?]. AB - INTRODUCTION: Gluten is a glycoprotein present in some cereals. The incidence of disorders related to gluten, including the EC, is increasing, even pathologies far from an etiology or treatment with GF D. AIMS: Review the scientific literature related to the ingestion of gluten and pathogenesis of different diseases. METHODS: A literature search in major scientific database. RESULTS: We obtained from the following diseases, gluten ataxia, multiple sclerosis, autism spectrum disorder, schizophrenia, attention deficit hyperactivity disorder, depressive disorders, headaches, irritable bowel syndrome, fibromyalgia, dermatitis herpetiformis and epilepsy, studies in which either a determination of gliadin was refered or a treatment, with/without gluten, was applied and evaluated. CONCLUSION: The ingestion of gluten seems to be related to disease, when there is no EC, SGNC or wheat allergy. Suspicions about the benefit of GF D as a complementary treatment is borne in semi-clinical trials and cohorts, either as a causal factor in the pathogenesis, or improvement of symptoms. PMID- 25433100 TI - [Adiposity in children and adolescents with type 1 diabetes: update and controversies]. AB - For years now, a stronger tendency towards overweight among diabetes 1 population has been described, a tendency already observed during childhood and pubescence. Insulin replacement therapy to be one of the main underlying factors. Clarifying these issues and determining whether this weight gain may bring in an increased cardiovascular risk in these patients during their adulthood is critical in order to develop strategies that prevent or at least diminish this evolution. This review aims at updating the anthropometric status and the presence of excess body fat in children and adolescents with type 1 diabetes as compared to healthy population, establishing the relevance of the different factors implied and their potential effect on cardiovascular risk. PMID- 25433101 TI - [Effect of hepcidin on iron metabolism in athletes]. AB - The role of iron in the human body is essential, and athletes must always try to keep an adequate iron status. Hepcidin is proposed as the main hormone responsible for the control of iron reserves in the body, given its ability to induce degradation of ferroportin. The action of hepcidin on ferroportin leads to a decreased dietary iron absorption, as well as to a decrease in macrophages. Several factors such as the iron status, the amount of dietary iron, the inflammation, the hypoxia, the testosterone and the physical exercise have been pointed out as affecting the synthesis of hepcidin. This study has aimed at analysing the researches on hepcidin response to exercise, as well as designing a specific strategy to prevent a potential ferropenic status in athletes. The main findings are an association between exercise at an intensity over 65% VO2max and transient increases in the synthesis of hepcidin, and a possible regulatory effect of intermittent hypoxic stimuli in the early post-exercise recovery. Other factors such as the training volume, sex, kind of exercise or the type of surface where the training takes place do not seem to affect the response of hepcidin to exercise. PMID- 25433102 TI - Revision surgery for one anastomosis gastric bypass with anti-reflux mechanism: a new surgical procedure using only not previously operated intestine. AB - INTRODUCTION: Obesity is now an epidemic in industrialized countries with high prevalence (U.S. with 67%, Europa from 40% to 50%). This had led to the development of many bariatric procedures. Nevertheless, the primary surgery could fails due to several conditions. There is no standard re-operative procedure of revision for primary bariatric failure. Re-operate in the place of the primary surgery imply high rate of risks. We have developed a new procedure for revision surgery working only on not previously operated tissue. METHODS: We measure the common channel from gastro- jejunal anastomosis until the ileocecal valve. Depending on the measure, we decide the length of intestine to be excluded (biliopancreatic limb and common channel). We interrupt the afferent loop before gastro-jejunostomy and the efferent loop 20 cm below the gastro-jejunostomy. For restoring the gastro-intestinal transit, we anastomose the upper part of the afferent and efferent loop side-to-side and the efferent loop segment to the upper part of the new common channel. DISCUSSION: There is no standard procedure for revision of primary surgery. Even, the gold standard surgery Roux-en-Y gastric bypass is one of the most failed procedure (<= 35%). We have developed the revision for One Anastomosis Gastric Bypass (BAGUA) working always in healthy tissue not previously used. CONCLUSIONS: A few number of patients with tailored BAGUA for morbid obesity will require a surgical rescue procedure due to excess or insufficient weight loss or weight regain. This new procedure has been proven to be easy and safe, avoiding the surgical difficulties of the classical revision through the scar tissue. PMID- 25433103 TI - [Study of the prevalence of overweight and obesity in a spanish prison]. AB - BACKGROUND: Overweight and obesity are a worldwide health problem. There are few researches about the prevalence of these conditions in penitentiaries; that is why this study aims at determining prevalence in a sample of inmates at a Spanish penitentiary. METHODS AND MATERIALS: 122 inmates from a Spanish penitentiary volunteered for this research in which 99 were men (81.1%) and 23 were women (18.9%), and the average age was 36.2 (DT 11.03). Weight and size measures were collected, and the body mass index (BMI) was assessed. RESULTS: 56.6 % of inmates are overweighed or obese, which is slightly below the prevalence values among the Spanish population. No significant differences can be observed in the prevalence of overweight or obesity between men and women. DEBATE: The results show that there are high levels of overweight and/or obesity prevalence among penitentiary inmates, matching the results from other international studies. This should encourage the implementation of prevention and/or intervention programs. PMID- 25433104 TI - Efficiency of the 24-hour food recall instrument for assessing nutrient intake before and after Roux-en-Y gastric bypass. AB - BACKGROUND: Nutritional and food intake assessments before and after bariatric surgery may be important to correct eating habits and nutritional deficiencies. AIM: To assess the efficiency of the 24-hour food recall (24hR) form as a fast method for assessing nutrient intake before and after a Roux-en-Y gastric bypass (RYGB). METHODS: This study analyzed data from 10 obese patients with type 2 diabetes mellitus (T2DM). Food intake (calories, macronutrients, and micronutrients) before and 3 months after RYGB were assessed with the 24hR as well as the seven-day food record (7dR) as the gold standard reference. Virtual Nutri Plus(r) software was used to quantify nutrients. RESULTS: The 7dR data revealed deficits in the estimated intake of total fiber and 14 out of 22 micronutrients pre- and postoperatively, combined; the 24hR failed to detect intake deficits in only two of these micronutrients (vitamins A and B3). Other postoperative deficits included carbohydrates, vitamin B1, copper, and iron, on which the 24hR was sensitive to only the iron deficit. In our pre- versus post operative comparison analyses, the 7dR revealed decreases in total calories, carbohydrates, total and all subclasses of fat and fiber, and 12 micronutrients; in the analogous comparison analyses, the 24hR failed to detect decreases in the ingestion of monounsaturated and saturated fats and in six of these micronutrients. CONCLUSIONS: In obese T2DM patients, the 24hR performed reasonably well for probing nutrient intake before and after RYGB, but is not recommended for tracking changes over time, including pre- versus postoperative deficits. PMID- 25433105 TI - Time-specific changes in DNA methyltransferases associated with the leptin promoter during the development of obesity. AB - OBJECTIVE: The role of epigenetic modifications on leptin expression during the development of obesity has not been clearly determined. This study aimed to investigate changes in the expression of DNA methyltransferases (DNMTs) at the leptin promoter and their effect on gene transcription during the development of obesity. METHODS: Using a high-fat diet (HFD)-induced obese (DIO) mouse model, we examined adipose expression of leptin, its promoter associated DNMTs and the methyl CpG-binding domain protein 2 (MBD2) at different time points after HFD feeding. RESULTS: The leptin expression levels in epididymal fat were significantly increased after feeding the mice a HFD for 4, 8, 12 and 18 weeks (w), as opposed to feeding them a standard diet (SD). However, the CpG promoter methylation fractions were significantly reduced at 8 w with a decreased association of MBD2 and DNMT1, and increased at 12 w and 18 w with an increased association of MBD2, DNMT3A and DNMT3B, after HFD feeding. Additionally, the binding of RNA polymerase II was increased at 8 w and decreased at 18 w after HFD feeding compared with SD feeding. CONCLUSIONS: These data indicate that time specific changes in promoter associated DNMTs may be associated with the regulation of leptin expression, indicating that a complex and dynamic epigenetic mechanism underlies aberrant leptin expression during the development of obesity. PMID- 25433106 TI - Vitamin D levels and bone turnover markers are not related to non-alcoholic fatty liver disease in severely obese patients. AB - BACKGROUND: Morbidly obese patients usually present vitamin D deficiency or secondary hyperparathyroidism. Low vitamin D levels have been recently related to non-alcoholic fatty liver disease (NAFLD). The aim of this study was to analyse the relationship between vitamin D, bone turnover markers and non-alcoholic fatty liver disease and metabolic syndrome in severely obese patients. METHODS: One hundred and ten patients who underwent bariatric surgery were included. Liver biopsy was taken during surgery. Two univariate analyses were carried out in order to i) analyse the relationship between liver histology and vitamin D-bone turnover markers (intact parathyroid hormone (PTH), osteocalcin and Carboxy terminal collagen crosslinks) and ii) establish the association between metabolic syndrome components-insulin resistance (HOMA) and vitamin D-bone turnover markers. RESULTS: 70% of the patients had lower levels of vitamin D or secondary hyperparathyroidism. None of the components of liver histology were associated with levels of vitamin D or with bone turnover parameters. Patients with metabolic syndrome showed lower levels of PTH and osteocalcin (72,42 (29,47) vs 61.25(19.59) p-Value: 0.022; 19.79 (10.43) vs 16.87(10.25) p-Value: 0,028, respectively). HOMA was not related to Vitamin D or bone turnover markers. CONCLUSION: Low levels of vitamin D or hyperparathyroidism are common in severely obese patients. Vitamin D and bone metabolism markers were associated neither to NAFLD nor with metabolic syndrome in our series of obese morbid patients. PMID- 25433107 TI - [Comparative analysis of the glycemic response and glycemic index of instant mashed potatoes in subjects undergoing laparoscopic sleeve gastrectomy and control subjects]. AB - BACKGROUND: The laparoscopic sleeve gastrectomy (LSG) is a successful surgical procedure for morbid obesity. However, post surgery weight regain is usual, thus applying the glycemic index could promote good weight control. OBJECTIVE: To compare the glycemic index (GI) and glycemic response (GR) obtained of instant mashed potatoes in individuals subjected to LSG versus control subjects. METHODS: GI and GR were assessed in 10 LSG subjects and compared with 10 controls. GI methodology proposed by FAO/WHO was used; instant mashed potatoes as test food and white bread as standard food (50g available CHO). Capillary blood sample 0 (fasting), 30, 60, 90 and 120 minutes. The GI was determined by trapezoidal method. ANOVA was used to compare a factor between RG and IG groups; t-student to compare RG between foods. Statistical significance p<0.05. RESULTS: The GR of instant mashed potatoes at 30 min was higher in the group operated (LSG 159,8 +/- 25,9 versus control subjects 135,3 +/- 17,3 mg/dl; p=0,023). In LSG group, the GR of instant mashed potatoes was higher than white bread at 30 min (159,8 +/- 25,9 versus 136,3 +/- 24,4 mg/dl respectively; p<0,01). The GI obtained from instant mashed potatoes was similar en both groups (LSG 119 versus control subjects 120; p=0,974). CONCLUSIONS: Instant mashed potatoes despite having similar GI in both groups, generates higher glycemic responses in LSG group, and its consumption possibly favoring weight regain. PMID- 25433108 TI - Prediction of body fat in a dolescents: comparison of two electric bioimpedance devices with dual-energy X-ray absorptiometry. AB - INTRODUCTION: An accurate estimate of body composition is important in assessing and monitoring the nutritional status of adolescents. OBJECTIVES: To compare the accuracy of 2 electrical bioimpedance devices with that of dual-energy X-ray absorptiometry (DXA) to predict body fat in Brazilian adolescents. METHODS: We evaluated 500 adolescents aged between 10 and 19 years, stratified by sex and divided into overweight and non-overweight groups. The percentage of body fat (%BF) was estimated using 2 types of electrical bioimpedance devices: BIA1 (horizontal tetrapolar bioimpedance equipment) and BIA2 (vertical 8-electrode bioimpedance equipment), as well as by DXA. A Bland- Altman plot was used to calculate the total errors and standard errors of estimate. RESULTS: Considering BMI for age, 19.4% were overweight and 47.4% as assessed by %BF of DXA were overweight. The %BF estimated by BIA2 correlated well (p < 0.05) with the %BF predicted by DXA, and only the total errors for BIA2 in the overweight group were acceptable (<=2.5%). The standard errors of estimate was <3.5%, with the lowest values observed for BIA2. Both BIA1 and BIA2 underestimated the %BF in overweight adolescents, while overestimating the %BF in male adolescents of normal weight. CONCLUSIONS: The BIA2 was found to be more effective in the evaluation of body fat. Regardless of the method used, the results should be carefully interpreted when assessing the body composition of adolescents. PMID- 25433109 TI - Soluble and insoluble dietary fibre intake and risk factors for metabolic syndrome and cardiovascular disease in middle-aged adults: the AWHS cohort. AB - INTRODUCTION: The Westernization of the Mediterranean lifestyle has led to a modification of certain dietary habits such as a decrease in the consumption of dietary fibre-rich foods. The impact of these changes on cardiovascular diseases (CVD) has been studied over the last few years and the effect of the different sources of fibre on cardiovascular risk parameters and coronary heart disease (CHD) continues to create controversy. OBJECTIVE: To evaluate the association between the source of dietary fibre and the prevalence of metabolic syndrome (MetS) and other cardiovascular risk factors in a Spanish working population. SUBJECTS AND METHODS: The study was carried out in a sample of 1592 Spanish workers free of CVD (40-55 years old) within the Aragon Workers' Health Study (AWHS) cohort. Sociodemographic, anthropometric, clinical and biochemical data were collected. Fibre intake was assessed by means of a validated 136-items semiquantitative food-frequency questionnaire. MetS was defined by using the modified National Cholesterol Education Programme - Adult Treatment Panel III (NCEP- ATP III) definition. RESULTS: After adjusting for possible confounding factors, we found an inverse association between insoluble fibre intake and systolic and diastolic blood pressure, total cholesterol, triglycerides, apolipoprotein B100 and ratio TG/HDL. Soluble fibre was inversely associated with triglycerides and apolipoprotein B100. Furthermore, prevalence of MetS was found to be lower (OR 0.62, 95% CI: 0.40-0.96) in those participants in the highest quartile of insoluble fibre intake. CONCLUSION: A higher intake of insoluble fibre could play an important role in the control and management of hypertension, lipid profile and MetS. PMID- 25433110 TI - [Percutaneous endoscopic gastrostomy in a myotrophic lateral sclerosis. Experience in a district general hospital]. AB - BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a degenerative disorder that affects the pyramidal tract, producing progressive motor dysfunctions leading to paralysis. These patients can present with dysphagia, requiring nutritional support with a nasogastric tube or Percutaneous Endoscopic Gastrostomy (PEG). PEG is associated with increased survival rates. However, the timing of PEG placement remains a significant issue for clinicians. OBJECTIVE: To analyse the characteristics of ALS patients at the moment of PEG placement and their progression. METHODS AND MATERIALS: Descriptive retrospective study including patients diagnosed with ALS and PEG who were assessed during the 2005-2014 period in our hospital. Nutritional parameters and respiratory function were assessed for all patients, as well as their progression. The data was analysed using SPSS15. RESULTS: 37 patients were included (56.8% men, 43.2% women) with an average age of 60 at diagnosis, and an average age of 63.1 at PEG placement. 48.6% started with spinal affection and 51.4%, with bulbar affection. 43.2% of the patients received oral nutritional supplements prior to PEG placement for a mean period of 11.3 months. The mean forced vital capacity at diagnosis was 65.45+/-13.67%, with a negative progression up to 39.47+/-14.69% at the moment of PEG placement. 86.5% of patients required non-invasive positive-pressure ventilation. 86.5% presented with dysphagia, 64.9% with weight loss > 5-10% from their usual weight, 8.1% with low Body Mass Index, 27% with malnutrition and 73% with aworsened breathing function; therefore, 100% met the criteria for PEG placement according to our protocol. The period on enteral feeding was extended for 10.1 months with a mortality of 50% during the first 6 months from PEG placement. CONCLUSIONS: There is evidence of a 3-year delay between diagnosis and PEG placement, with a survival rate of 50% at 6 months from PEG insertion. Further studies are required to establish whether an earlier placement might increase survival rates. PMID- 25433111 TI - Twenty-five years of home parenteral nutrition outsourcing: the experience at Hospital Universitario La Paz, Madrid. AB - INTRODUCTION: For the last 20 years, most adult patients following home parenteral nutrition (HPN) under the care of the Clinical Nutrition and Dietetics Dept. of the La Paz University Hospital (Unidad de Nutricion Clinica y Dietetica del Hospital Universitario La Paz), Madrid, Spain, have received their nutrition formula via a catering system (Nutriservice) responsible for its preparation and home distribution. AIM: To assess the clinical characteristics, quality of life and degree of satisfaction with the care received, of patients undergoing HPN who received their nutrition formulae via the named catering service. MATERIALS AND METHODS: The characteristics of the patients who received HPN via this service between 1992 and 2013 were retrospectively collected. Those patients still undergoing treatment completed a quality of life questionnaire, plus a survey of their satisfaction with the catering system and the care provided by our department. RESULTS: Seventy eight patients were examined; 57.7% were men. The mean age of the patients was 53.1+/-14.3 years. The most common underlying disease was cancer, both in advanced stage (33.8% of all cases) and in stages in which active treatment was being provided (34%). The most common indication for HPN was intestinal obstruction (46%). The median duration of HPN treatment was 96 [1-5334] days. The most common complication was catheter infection (72%). For the analysis of the results, the patients were divided depending on disease type: those with advanced stage cancer, those with cancer under active treatment and with a better prognosis, and those with non-oncological disease. The patients undergoing active oncological treatment believed the quality of their lives to have been improved by the Nutriservice catering system, and rated the care received by our department positively. CONCLUSION: In our experience, patients with cancer are those who most commonly receive HPN, especially those with advanced disease. Given the seriousness of their conditions, and the complexity surrounding the use of HPN, catering systems appear to offer a means of improving their quality of life. PMID- 25433112 TI - Refeeding with conjugated linoleic acid increases serum cholesterol and modifies the fatty acid profile after 48 hours of fasting in rats. AB - There is no consensus about the effects of conjugated linoleic acid (CLA) on lipid metabolism, especially in animals fed a high-fat diet. Therefore, the objective of the present study was to evaluate the incorporation of CLA isomers into serum, liver and adipose tissue, as well as the oxidative stress generated in rats refed with high-fat diets after a 48 hour fast. Rats were refed with diets containing soybean oil, rich in linoleic acid [7% (Control Group - C) or 20% (LA Group)], CLA [CLA Group - 20% CLA mixture (39.32 mole% c9,t11-CLA and 40.59 mole% t10,c12- CLA)], soybean oil + CLA (LA+CLA Group - 15.4% soybean oil and 4.6% CLA) or animal fat (AF, 20% lard). The CLA group showed lower weight gain and liver weight after refeeding, as well as increased serum cholesterol. The high dietary fat intake induced fat accumulation and an increase in ? tocopherol in the liver, which were not observed in the CLA group. Circulating ? tocopherol was increased in the CLA and CLA+LA groups. The high- fat diets reduced liver catalase activity. CLA isomers were incorporated into serum and tissues. In this shortterm refeeding experimental model, CLA prevented hepatic fat accumulation, although it produced an increase in serum cholesterol. PMID- 25433113 TI - [Relationship between nutritional status, level of physical activity and psychomotor development in preschoolers]. AB - BACKGROUND: Obesity and overweight have been included as a pandemic by the WHO; children are the group where intervention is recommended, given that they can enter physical activity (PA) and psychomotor development (PD) programs at education centres. Chile accounts for high rates of overweight, obesity and sedentary life, together with an absence of preschool PA programs. OBJECTIVE: To relate the nutritional status, the psychomotor development and the quantity and intensity of PA in school routine for 5 year-old preschoolers. METHODS: Pilot, non-experimental, transversal correlational study, including 23 preschoolers aged 5. We assessed three values: nutritional status with score z-IMC, PA with Actigraphy and PD with Da Fonseca Battery. RESULTS: 26% of the children presented with overweight and 52% with obesity. All of them had at least 60 minutes of moderate to vigorous PA (MVPA) during their school-day. 82.6% of the children were in the Normal category for PD and the rest were in the Dispraxia category. A significant inverse relationship was found (p=0,032) between z-IMC and PD. CONCLUSION: The percentage of obese children is notably above international average values and national surveys. 17.4% of children show dispraxia at the psychomotor assessment. Children with higher z-IMC have a lower score in Da Fonseca battery, which could be due to a higher weight in relation to size, and generating a lower PD in the long term. No relationships were detected within the other variables. PMID- 25433114 TI - Obese and unfit students dislike physical education in adolescence: myth or truth? The AVENA and UP&DOWN studies. AB - INTRODUCTION: In the physical education context a well- known myth suggest that obese and unfit youth dislike physical education. OBJECTIVE: To examine if adolescents who dislike physical education have higher levels of fatness and lower of fitness than their peers. METHODS: Participants included 2606 (49.3% girls) adolescents from AVENA and UP&DOWN studies. physical education enjoyment was assessed with a 7-point Likert scale. Fatness was assessed with BMI, skinfolds and waist circumference. Physical fitness was assessed with cardiorespiratory, motor and muscular fitness tests. RESULTS: Boys who dislike physical education had similar levels of fatness and fitness than their peers (all P>0.05). Adolescent girls who dislike physical education had higher levels in body fat (P=0.035), and lower levels in muscular (P=0.007) and motor (P=0.007) fitness than their peers. CONCLUSION: Since only girls who dislike physical education seem to have, albeit weak, higher levels of fatness and lower of fitness than their peers, it partially confirms the myth in adolescent girls. PMID- 25433115 TI - [Nutritional and psychological habits in people who practice exercise]. AB - INTRODUCTION: The distorted body image has become a global problem. The thinness as a standard of beauty for women, and fitness for men, has been linked to an increase in eating behavior disorders. The physical exercise with aesthetic or addictive purposes has increased, as well as the popularity of gyms. AIM: To analyze the orthorexics behavior, to know the influence of gender on psychological behavior and to analyze eating habits in a sample practicing physical activity. METHODS: Observational, descriptive and retrospective study in which an ad hoc questionnaire was performed, incorporating Adherence to Mediterranean diet test, the State-Trait Anger Expression Inventory (STAXI-2), Emotional Eater Questionnaire (EEQ) and adapted the Spanish version of the Multidimensional Body Self Relations Questionnaire (MBSRQ). Besides, anthropometric assessment was performed in each participant. RESULTS: 264 subjects were included in the study (156 men), 35.9 years (+/- 11.1 years). With mean BMI of 23.8 kg/m2 (+/- 3.1 kg/m2) and total body fat percentage 20.8 (+/- 8.7%). The average score Adherence to the Mediterranean diet was 5.9 (+/- 2.4). Orthorexic and obsessive behaviors were found, and between genders for some markers studied. CONCLUSION: The habits analyzed show a tendency to body worship, closer to a pathological condition rather than to a healthy aspect, causing alterations on perception, that result in dieting and alterations such as eating disorders. PMID- 25433116 TI - [Assessment of cardiorespiratory fitness in preschool children: adaptation of the 20 metres shuttle run test]. AB - Cardiorespiratory fitness is a strong indicator of present and future health in children and adolescents, however it is unknown whether it is for pre-schoolers, from 3 to 5 years. In the present study, we described the adaptation of the original 20m shuttle run test, it feasibility and acceptance in children from 3 to 5 years and its maximality and reliability. A total of 130 students (4.91 +/- 0.89 years; 77 boys) performed the test twice, two weeks apart. The test adaptation consisted mainly in reducing the initial speed of 8.5 km/h to 6.5 km/h. The test was feasible and was well accepted in both boys and girls and the three age groups, 3, 4 and 5 years. The maximum heart rate (MHR) achieved for the entire sample was 199.4 +/- 12.5 beats/min, equivalent to 97% of the estimated theoretical MHR, and no significant differences by gender or age. Mean test retest difference (systematic error) in the number of laps achieved was 2 laps, with no significant differences between sex or age. There was no evidence of heteroscedasticity. Our results suggest the test is maximum and reliable in this age group. Future longitudinal or intervention studies using this test should take into account that changes in the test performance of 2 laps may be due to the variability of the measure, while wider changes would be attributable to the intervention or changes associated with age. PMID- 25433117 TI - Malnutrition in hospitalized patients receiving nutritionally complete menus: prevalence and outcomes. AB - BACKGROUND: The prevalence of malnutrition in hospitals ranges from 20 to 50% and the hospital diet could be a potential risk factor. The aim of the study was to determine the overall and per services prevalence of hospital malnutrition, and assess its impact on clinical outcomes in patients receiving nutritionally complete menus. METHODOLOGY: Cross-sectional study in a university hospital. Nutritional status was assessed using Subjective Global Assessment (SGA), anthropometry, and biochemical parameters. For the assessment of outcomes during hospitalization, length of stay, rate of deaths, and readmissions were collected. RESULTS: 201 patients were evaluated. The median age was 71.59 (IQR 21.43) years old, and 51.20% were women. According to the results obtained by SGA, 37.8% of individuals were well nourished (WN), 50.2% were at nutritional risk (NR), and 11.9% were malnourished (MN). The prevalence of malnourished (NR+MN) was higher in oncology-hematology and medical wards (80.0% and 70.5%) than in surgical ones (52.4%) (p = 0.047). The worse nutritional status was, the longer the length of stay [WN: 8.0 (IQR 8.0) days; NR: 12.0 (IQR 13.5) days; MN: 18.5 (IQR 18.5) days, p < 0.001). CONCLUSIONS: The prevalence of malnutrition in the evaluated hospital was very high, being particularly striking in medical services, and doubling length of stay. PMID- 25433118 TI - [Food habits and nutritional assessment in a tunisian university population]. AB - INTRODUCTION: Nutrition and health are of great importance throughout life, in particular in adulthood due to active population is included among the adults. Therefore, it is essential to assess the quality of the diet and the possible conditioning factors. OBJECTIVES: The objectives of this study were to characterize food habits and assess the quality of the diet of university students from the Virtual University of Tunisia, a North African country in nutritional transition. METHODS: This is a cross-sectional study performed with data collected from a sample of 54 students from this University. For each individual a questionnaire involving socio-economic and demographic data was self reported. Food consumption was gathered by a 24 hours recall. The assessment of diet quality was conducted by Healthy Eating Index and Mediterranean Diet Score. RESULTS AND DISCUSSION: The study revealed that the diet of this population is hypocaloric. The percentage of total energy from proteins was 18% and the percentage of total energy from carbohydrates was about 40%. The diet was high in simple sugars, saturated fat and cholesterol. Apart from oils and fat, the main source of lipids had an animal origin from meat (19%), and the fish group only provided 3% of this macronutrient. According to Healthy Eating Index classification more than 50% of students scored "poor" and more than 40% "needs improvement" about the quality of their diet. The study also showed low adherence rates to the Mediterranean diet. PMID- 25433119 TI - [Variability in bioelectrical impedance assessment of body composition depending on measurement conditions: influence of fast and rest]. AB - BACKGROUND: Bioelectrical Impedance Assessment (BIA) is one of the main tools to measure body composition. BIA is recommended in fasting and after 60 minutes of rest; however, this cannot always be guaranteed in healthcare practice. OBJECTIVES: To establish the reliability of the body composition parameters assessed with BIA under different physiological conditions: fast + rest, fast + no-rest and no-fast + no-rest in healthy volunteers. METHODS: Transversal study including 25 healthy volunteers aged 18-34 (12 men, 13 women). A BIA was performed under three different conditions: 1) fast + 60 minute rest in cubito supino (gold standard), 2) fast + no rest and 3) no fast + no rest. The collected parameters were: lean mass and fat mass (Kg) and body water (in liters and as body weight percentage). The intraclass correlation coefficient (ICC) was applied for the assessment of concordance within the different measurements. RESULTS: Compared to the gold standard, the difference in lean mass means in the condition of fast + no-rest, was -0.15 (DE 1.44) in men and 0.98 (DE 1.36) in women; fat mass decreased in 0.06 (DE 1.55) in men and 0.82 (DE 1.5) in women; ICC ranged between 0.826-0.995 in all comparisons. In the condition of no-fast + no rest, lean mass decreased an average of 0.05 (DE 0.33) in men and it increased 0.62 (DE 0.46) in women; fat mass decreased 0.57 (DE 0.82) in men and 0.46 (DE 0.60) in women; ad ICC ranged between 0.942 and 0.999, except in body water in men, where it was 0.340. DISCUSSION: Although relevant, the differences observed in parameters from BIA when comparing the gold standard condition (fast + rest) with the other conditions (fast + no-rest and no-fast + no-rest) are of little magnitude. In clinical practice, the assessment of body composition allows to take decisions when planning treatment for patients with a poor physical condition. CONCLUSIONS: The reliability of the parameters acquired via BIA within different physiological conditions of fast and rest is excellent (CCI >0.75) in healthy adults aged 19-34. Although general recommendations on the use of BIA devices must be kept in place, the conditions of the performance could be modified according to the context and assuming a small difference of little clinical relevance. PMID- 25433120 TI - [Benefits of a cardiac rehabilitation program on some parameters of corporal composition]. AB - The cardiovascular diseases (CVD) are the principal reasons of morbidity and mortality in the world. The cardiac rehabilitation is a program of secondary prevention to complement the effects of the cardiological treatment with the participation of the patient in the control of their habits of life, as a way of promotion of its own cardiovascular health. The aim of the present study is to evaluate the long-term effects of a cardiac rehabilitation program on some parameters of corporal composition in patients that have attended or not, to the phase the III of the program. The study was performed in subjects that suffered a cardiovascular event and they were members of the Association of Cardiac Patients of Granada and Province. All the members were offered the possibility of forming a part of the study. Some parameters of body composition were measured and a nutritional evaluation was performed in all the subjects. The visceral and body fat and, which play a key role in the cardiovascular pathology, are lower in the patients attending to the cardiac rehabilitation program, revealing that are better predictors of the cardiovascular risk. Thanks to the nutritional advice received, an increase in healthy nutrients is observed and the subjects attending to the program feature major phase angle, indicating that they have a better state of hydration, together with a better integrity of the cell membranes and distribution of water between the compartments intra- and extracellular compartments. PMID- 25433121 TI - [Prevalence of malnutrition in not critically ill inpatients]. AB - BACKGROUND: Malnutrition is a frequent issue in our hospitals, and it is associated with an increase in morbi- mortality and financial costs, together with a decline in the patients' quality of life. This study is aimed at establishing the prevalence of malnutrition in our health centre, as much at admission as at discharge. METHODS: Transversal observational study assessing 277 adult patients, who were admitted consecutively, and applying the Nutritional Risk Screening 2002 (NRS-2002) in the first 48 hours from admission and then again at discharge. Cancer patients were also submitted the Patient Generated Subjective Global Assessment (PG-SGA) and the Mini Nutritional Assessment Short Form (MNA-SF) was applied to the population of 65 and over. RESULTS: 32.49% of patients were at malnutrition risk according to the results of NRS-2002 at admission. This percentage increased up to 40.98% at discharge. The NRS-2002 showed that 31.15% of cancer patients presented with nutritional risk; however, according to VGS-GP, 52.54% of the cases presented with nutritional risk to a certain extent (38.98% with moderate malnutrition and 13.56% with serious malnutrition). Among patients aged 65 and over, 29.31% were considered at risk according to the NRS-2002; the MNA-SF revealed nutritional alteration in 70.35% (54.65% with malnutrition risk, 15.7% with malnutrition). There are different groups of patients: 65 years old and over, transferred from the emergency department, multi-medicated, cancer patients and patients with heart failure, who present with a higher risk of nutritional deterioration at admission (p<0.05). CONCLUSIONS: There is a very high percentage of patients at nutritional risk in our centre, as much at admission as at discharge. It is therefore necessary to install a systematic screening of the nutritional status for all inpatients. PMID- 25433122 TI - [The food jaima, food guide for the Saharawi children host families]. AB - INTRODUCTION: During the summer months, a large group of children are welcomed by Spanish families in order to learn a different reality and improve their state of health and nutrition. Reviewing existing for this type of kids educational tools to foster families, was the need to develop an educational and specific dietary guide in order to solve any doubts about food and nutrition. OBJECTIVES: Elaboration of a food guide, the food jaima, to host families of the Saharawi children that will help improve their health during their stay in Spain. METHODS: Development of the food jaima and daily activities for the hosted Saharawi children. RESULTS: Our proposal is a food jaima, a graphic-chromatic model, similar to the well-known food pyramids. Different foods are listed in each of the steps and by descending order in recommended daily amount and to one side of it appear daily activities for the hosted Saharan children. DISCUSSION AND CONCLUSIONS: The food jaima is a food guide that allows you to meet the nutritional needs of this type of population in the prevention of diseases related to diet, such as anemia and goiter, and normal growth. PMID- 25433123 TI - [High output stoma: detection and approach]. AB - High output stoma is a frequent complication in patients with ileostomies that is not well identified and is not often properly addressed by clinicians. It has not been described properly, and can vary between debits of 2.000ml in 24 h to 1.500 ml in 3-5 days, according to different authors. Frequently presents both short term and long-term negative implications for patients and is associated with readmissions. We present a review of published literature focusing in surgical resection-related factors that influence a later appearance of this complication, causes involved in its development, the need to establish a clear and objective concept of high ouput as well as the negative implications it presents. Also we develop how should we the management of these patients regarding treatment and nutritional approach. PMID- 25433125 TI - Vascular changes in the developing rat retina in response to hypoxia. AB - This study was carried out to investigate the roles of tight junction (TJ) proteins and other factors in the increased permeability of the blood retinal barrier (BRB) affecting the immature neonatal retina following a hypoxic insult. The expression of endothelial TJ proteins such as claudin-5, occludin and zonula occludens-1 (ZO-1) and endothelial cell specific molecule-1 (ESM-1), and associated structural changes in the blood vessels were analyzed in the retinas of 1-day-old Wistar rats subjected to hypoxia for 2 h and subsequently sacrificed at different time points ranging from 3 h to 14 d. The mRNA and protein expression of claudin-5, occludin & ZO-1 was found to be reduced in the hypoxic retina, although, at the ultrastructural level, the TJ between the endothelial cells and retinal pigment epithelial cells appeared to be intact. Following the hypoxic insult vascular endothelial cells frequently showed presence of cytoplasmic vacuoles, vacuolated mitochondria and multivesicular aggregations projecting into the lumen of the capillaries. The expression of ESM-1 in the immature retinas was found to be increased following hypoxic exposure. The structural and molecular changes in the hypoxic neonatal retinas were consistent with a hypoxia induced impairment of the BRB. Hypoxia reduced the expression of TJ proteins in the neonatal retina, but the role of increased ESM-1 expression in this process warrants further investigation. PMID- 25433126 TI - A novel open-barrel structure of octameric translin reveals a potential RNA entryway. AB - The single-stranded DNA (ssDNA)/RNA binding protein translin was suggested to be involved in chromosomal translocations, telomere metabolism, and mRNA transport and translation. Oligonucleotide binding surfaces map within a closed cavity of translin octameric barrels, raising the question as to how DNA/RNA gain access to this inner cavity, particularly given that, to date, none of the barrel structures reported hint to an entryway. Here, we argue against a mechanism by which translin octamers may "dissociate and reassemble" upon RNA binding and report a novel "open"-barrel structure of human translin revealing a feasible DNA/RNA entryway into the cavity. Additionally, we report that translin not only is confined to binding of ssDNA oligonucleotides, or single-stranded extensions of double-stranded DNA (dsDNA), but also can bind single-stranded sequences internally embedded in dsDNA molecules. PMID- 25433127 TI - Post-translational modifications disclose a dual role for redox stress in cardiovascular pathophysiology. AB - Although some of the redox changes that occur in biological components may result in deleterious events, this process has recently been tackled as a modulatory event. Advances in our understanding regarding the role of some oxidative/nitrosative reactions revealed that proteins can be structurally and functionally modified by chemical reactions, an epigenetic event known as post translational modification (PTM). PTMs can function as an "on-off switch" for signaling cascades, and are dependent on the specific generation of redox components such as reactive oxygen species (ROS) and nitric oxide (NO). NO-driven modifications regulate a wide range of cellular processes and have been highlighted as an epigenetic event that protects proteins from proteolytic degradation. On the other hand, ROS-driven modifications are implicated in cell damage in a number of pathological conditions, especially in the cardiovascular system. Therefore, while mitochondrial uncoupling yields the massive production of ROS in the heart, some cellular redox-sensitive pathways trigger PTMs that may play a cardioprotective role. In this review, we present an overview of the oxidative/nitrosative milieu in cardiac pathologies and address the role of the main redox-driven PTMs as epigenetic events in cardioprotection, as well as its regulatory function in cardiomyocyte signaling. Improved understanding of the role of these PTMs in cardiovascular disease can help direct some approaches for future clinical research regarding health risk assessment, as well as inform strategies for disease treatment and prevention. PMID- 25433128 TI - Leptin influences estrogen metabolism and accelerates prostate cell proliferation. AB - AIM: The present study was designed to investigate the effect of leptin on estrogen metabolism in prostatic cells. MAIN METHODS: Malignant (PC-3) and benign (BPH-1) human prostate cells were treated with 17-beta-hydroxyestradiol (1 MUM) alone or in combination with leptin (0.4, 4, 40 ng/ml) for 72 h. Cell proliferation assay, immunocytochemical staining of estrogen receptor (ER), liquid chromatography-tandem mass spectrometry method (LC-MS) and semi quantitative reverse transcriptase polymerase chain reaction (RT-PCR) were used. KEY FINDINGS: Cell proliferation assay demonstrated that leptin caused significant growth potentiation in both cells. Immunocytochemical staining showed that leptin significantly increased the expression of ER-alpha and decreased that of ER-beta in PC-3 cells. LC-MS method revealed that leptin increased the concentration 4-hydroxyestrone and/or decreased that of 2-methoxyestradiol, 4 methoxyestradiol and 2-methoxyestrone. Interestingly, RT-PCR showed that leptin significantly up-regulated the expression of aromatase and cytochrome P450 1B1 (CYP1B1) enzymes; however down-regulated the expression of catechol-o methyltransferase (COMT) enzyme. SIGNIFICANCE: These data indicate that leptin induced proliferative effect in prostate cells might be partly attributed to estrogen metabolism. Thus, leptin might be a novel target for therapeutic intervention in prostatic disorders. PMID- 25433129 TI - Surface functional modification of self-assembled insulin nanospheres for improving intestinal absorption. AB - In this work we fabricated therapeutic protein drugs such as insulin as free carrier delivery system to improve their oral absorption efficiency. The formulation involved self-assembly of insulin into nanospheres (INS) by a novel thermal induced phase separation method. In consideration of harsh environment in gastrointestinal tract, surface functional modification of INS with E-poly-L lysine (EPL) was employed to form a core-shell structure (INS@EPL) and protect them from too fast dissociation before their arriving at target uptake sites. Both INS and INS@EPL were characterized as uniformly spherical particles with mean diameter size of 150-300 nm. The process of transient thermal treatment did not change their biological potency retention significantly. In vitro dissolution studies showed that shell cross-linked of INS with EPL improved the release profiles of insulin from the self-assembled nanospheres at intestinal pH. Confocal microscopy visualization and transport experiments proved the enhanced paracellular permeability of INS@EPL in Caco-2 cells. Compared to that of INS, enteral administration of INS@EPL at 20 IU/kg resulted in more significant hypoglycemic effects in diabetic rats up to 12 h. Accordingly, the results indicated that surface functional modification of self-assembled insulin nanospheres with shell cross-linked polycationic peptide could be a promising candidate for oral therapeutic protein delivery. PMID- 25433130 TI - Immunopotentiating nano-chitosan as potent vaccine carter for efficacious prophylaxis of filarial antigens. AB - Lymphatic filariasis (LF), a morbid vector-borne parasitic infection affects millions in tropical areas. Complete eradication can only be achieved by the development of a potent vaccine. Among the various filarial antigens that have been characterized, antigens Brugia malayi thioredoxin (TRX) and abundant larval transcript (ALT) have produced recognizable level of protection in Jirds, thereby evidenced to be good vaccine candidates. In this study an attempt was made to enhance their immunoprophylactic activity by encapsulating them in natural polysaccharide chitosan forming nanospheres (CN). High encapsulation efficiency for TRX (93%) in CN (TCN) and ALT-2 (90%) in CN (ACN) was achieved. Morphological studies confirmed the spherical and uniform distribution of nanospheres to be 220 nm. The electrostatic interaction between chitosan and the antigens were confirmed using differential scanning calorimetry and FT-IR. The study revealed the immunostimulatory property of chitosan providing enhanced level of proliferation for encapsulated antigens in peripheral blood mononuclear cells from endemic normal personals, at low concentration (TCN mean stimulation index (SI)=4.23+/-0.15 and ACN (SI)=4.05+/-0.33) compared to stimulation obtained by antigens alone. Hence, our study demonstrated that natural macromolecule derived CN can be used as efficacious immunostimulatory vaccine carter for LF thereby diminishing pathological sequel. PMID- 25433132 TI - The International Conference on Comparative Endocrinology and Physiology. PMID- 25433131 TI - Guanidine hydrochloride and urea effects upon thermal stability of Glossoscolex paulistus hemoglobin (HbGp). AB - Glossoscolex paulistus hemoglobin (HbGp) has a molecular mass of 3600kDa. It belongs to the hexagonal bilayer hemoglobin class, which consists of highly cooperative respiratory macromolecules found in mollusks and annelids. The present work focusses on oxy-HbGp thermal stability, in the presence of urea and guanidine hydrochloride (GuHCl), monitored by several techniques. Initially, dynamic light scattering data show that the presence of GuHCl induces the protein oligomeric dissociation, followed by a significant 11-fold increase in the hydrodynamic diameter (DH) values, due to the formation of protein aggregates in solution. In contrast, urea promotes the HbGp oligomeric dissociation, followed by unfolding process at high temperatures, without aggregation. Circular dichroism data show that unfolding critical temperature (Tc) of oxy-HbGp decreases from 57 degrees C, at 0.0 mol/L of the denaturant, to 45 degrees C, in the presence of 3.5 mol/L of urea, suggesting the reduction of HbGp oligomeric stability. Moreover, differential scanning calorimetry results show that at lower GuHCl concentrations, some thermal stabilization of the hemoglobin is observed, whereas at higher concentrations, the reduction of stability takes place. Besides, HbGp is more stable in the presence of urea when compared with the guanidine effect, as deduced from the differences in the concentration range of denaturants. PMID- 25433133 TI - Molecular epidemiology of enterovirus B77 isolated from non polio acute flaccid paralytic patients in Pakistan during 2013. AB - Human enteroviruses are associated with various clinical syndromes and severe neurological disorders. The aim of this study was to determine the molecular epidemiology of non polio enteroviruses and their correlation with acute flaccid paralysis (AFP) patients living in Khyber Pakhtunkhwa (KP) and Federally Administered Tribal Areas (FATA) of Pakistan. The stool samples collected from these patients were used for isolation of non polio enteroviruses (NPEVs). Out of 38 samples, 29 (76.3%) were successfully typed by microneutralization assay into eleven serotypes including echovirus (E)-3 (5.3%), E-7 (2.6%), E-11 (13.2%), E-12 (7.9%), E-13 (10.5%), E-20 (7.9%), E-27 (5.3%), E-29 (10.5%), E-30 (7.9%), E-33 (2.6%), coxsackievirus (CV) B5 (2.6%) and nine isolates (23.7%) remained untyped which were confirmed as NPEVs by real time RT-PCR. Complete VP1 genetic sequencing data characterized untypeable isolates into enterovirus B77 (EV-B77). Moreover, molecular phylogenetic analysis classified these viruses into two new genotypes having high genetic diversity (at least 17.7%) with prototype. This study provides valuable information on extensive genetic diversity of EV-B77 genotypes. Although, its association with neurological disorder has not yet been known but isolation of nine EV-B77 viruses from AFP cases highlights the fact that they may have a contributing role in the etiology of AFP. In addition, it is needed to establish enterovirus surveillance system and laboratory diagnostic facilities for early detection of NPEVs that may cause poliomyelitis like paralysis especially in the situation when we are at the verge of polio eradication. PMID- 25433134 TI - Adler hantavirus, a new genetic variant of Tula virus identified in Major's pine voles (Microtus majori) sampled in southern European Russia. AB - Although at least 30 novel hantaviruses have been recently discovered in novel hosts such as shrews, moles and even bats, hantaviruses (family Bunyaviridae, genus Hantavirus) are primarily known as rodent-borne human pathogens. Here we report on identification of a novel hantavirus variant associated with a rodent host, Major's pine vole (Microtus majori). Altogether 36 hantavirus PCR-positive Major's pine voles were identified in the Krasnodar region of southern European Russia within the years 2008-2011. Initial partial L-segment sequence analysis revealed novel hantavirus sequences. Moreover, we found a single common vole (Microtusarvalis) infected with Tula virus (TULV). Complete S- and M-segment coding sequences were determined from 11 Major's pine voles originating from 8 trapping sites and subjected to phylogenetic analyses. The data obtained show that Major's pine vole is a newly recognized hantavirus reservoir host. The newfound virus, provisionally called Adler hantavirus (ADLV), is closely related to TULV. Based on amino acid differences to TULV (5.6-8.2% for nucleocapsid protein, 9.4-9.5% for glycoprotein precursor) we propose to consider ADLV as a genotype of TULV. Occurrence of ADLV and TULV in the same region suggests that ADLV is not only a geographical variant of TULV but a host-specific genotype. High intra-cluster nucleotide sequence variability (up to 18%) and geographic clustering indicate long-term presence of the virus in this region. PMID- 25433135 TI - Multigenerational immune priming in an invertebrate parthenogenetic Artemia to a pathogenic Vibrio campbellii. PMID- 25433136 TI - In vitro and in vivo protective effect of arginine against lipopolysaccharide induced inflammatory response in the intestine of juvenile Jian carp (Cyprinus carpio var. Jian). AB - The present study was designed to assess the possible protective effects of arginine (Arg) against lipopolysaccharide (LPS) induced inflammatory response in juvenile Jian carp (Cyprinus carpio var. Jian) in vivo and in enterocytes in vitro. Firstly, inflammatory response was established by exposing enterocytes to different concentrations of LPS for 24 h. Secondly, the protective effects of Arg against subsequent LPS exposure were studied in enterocytes. Finally, we investigated whether dietary Arg supplementation could attenuate immune challenge induced by LPS in vivo. The result indicated that 10 mg/L LPS could induced inflammatory response in enterocytes. Cells exposed to LPS (10-30 mg/L) alone for 24 h resulted in a significant increase in lactate dehydrogenase release (LDH) (P < 0.05). The cell viability, protein content, alkaline phosphatase activity were decreased by LPS (P < 0.05). Moreover, LPS exposure significantly increased TNF alpha, IL-1beta, and IL-6 mRNA expression in vitro (P < 0.05). However, pre treatment with Arg remarkably prevented the increase of TNF-alpha, IL-1beta, and IL-6 by inhibiting the excessive activation of TLR4-Myd88 signaling pathway through down-regulating TLR4, Myd88, NFkappaB p65, and MAPK p38 mRNA expression (P < 0.05). Interestingly, the experiment in vivo showed that Arg pre supplementation could attenuate immune challenge induced by LPS via TLR4-Myd88 signaling pathway, and thus protect fish against LPS-induced inflammatory response. In conclusion, all of these results indicated pre-supplementation with Arg decreased LPS induced immune damage and regulated TLR4-Myd88 signaling pathway in juvenile Jian carp in vivo and in enterocytes in vitro. PMID- 25433137 TI - Effects of single and repeated infections with Neoparamoeba perurans on antibody levels and immune gene expression in Atlantic salmon (Salmo salar). AB - Amoebic gill disease (AGD) is the main health problem for the salmon industry in Tasmania, Australia and is now reported in most salmon producing countries. Antibody and gene expression responses to the pathogen, Neoparamoeba perurans, have been studied independently following primary exposure; however, the effects of sequential reinfection, which can often occur during net-pen culture of salmon, remain unclear. The association between the transcription of immunoglobulin (Ig) and their systemic and mucosal antibody levels in regards to AGD is unknown. Herein, we assessed the antibody responses as well as Ig transcription in the gills of Atlantic salmon infected only once and also sequentially with N. perurans. After four successive AGD challenges, no significant differences in plasma or skin mucus levels of IgM were observed between AGD-naive and challenged fish. However, IgM gene expression in gill lesions of AGD-affected fish increased up to 31 d after infection, while no changes in IgT, TCR and CD8 transcription were observed. Changes at IgM transcription level did not match the lack of antibody response in mucus, which is possibly explained by weak correlations existing between protein and mRNA abundances in cells and tissues. In the second experiment, which investigated Ig responses to AGD at the transcriptional as well as antibody production level in salmon after a single infection, the levels of serum or skin mucus IgM antibody were not affected and no changes in the IgM or IgT transcription were induced. PMID- 25433138 TI - A potential Kazal-type serine protease inhibitor involves in kinetics of protease inhibition and bacteriostatic activity. AB - Kazal-type serine protease inhibitor (KSPI) is a pancreatic secretary trypsin inhibitor which involves in various cellular component regulations including development and defense process. In this study, we have characterized a KSPI cDNA sequence of freshwater striped murrel fish Channa striatus (Cs) at molecular level. Cellular location analysis predicted that the CsKSPI was an extracellular protein. The domain analysis showed that the CsKSPI contains a Kazal domain at 47 103 along with its family signature between 61 and 83. Phylogenetically, CsKSPI is closely related to KSPI from Maylandia zebra and formed a sister group with mammals. The 2D structure of CsKSPI showed three alpha-helical regions which are connected with random coils, one helix at signal sequence and two at the Kazal domain region. The relative gene expression showed that the CsKSPI was highly expressed in gills and its expression was induced upon fungus (Aphanomyces invadans), bacteria (Aeromonas hydrophila) and poly I:C (a viral analogue) challenge. The CsKSPI recombinant protein was produced to characterize and study the CsKSPI gene specific functions. The recombinant CsKSPI strongly inhibited trypsin compared to other tested proteases. The results of the kinetic activity of CsKSPI against trypsin was V(max)s = 1.62 nmol/min, K(M)s = 0.21 mM and K(i)s = 15.37 nM. Moreover, the recombinant CsKSPI inhibited the growth of Gram negative bacteria A. hydrophila at 20 MUM and Gram-positive bacteria Bacillus subtilis at the MIC50 of 15 MUM. Overall, the study indicated that the CsKSPI was a potential trypsin inhibitor which involves in antimicrobial activity. PMID- 25433139 TI - Dental implants inserted in fresh extraction sockets versus healed sites: a systematic review and meta-analysis. AB - OBJECTIVES: To test the null hypothesis of no difference in the implant failure rates, postoperative infection and marginal bone loss for the insertion of dental implants in fresh extraction sockets compared to the insertion in healed sites, against the alternative hypothesis of a difference. DATA: Main search terms used in combination: dental implant, oral implant, resh extraction socket, immediate placement, immediate insertion, immediate implant. SOURCES: An electronic search was undertaken in July/2014, in PubMed, Web of Science, Cochrane Oral Health Group Trials Register plus hand-searching. STUDY SELECTION: Eligibility criteria included clinical human studies, either randomized or not. CONCLUSIONS: The search strategy resulted in 73 publications, with 8,241 implants inserted in sockets (330 failures, 4.00%), and 19,410 in healed sites (599 failures, 3.09%). It is suggested that the insertion of implants in fresh extraction sockets affects the failure rates (RR 1.58, 95% CI 1.27-1.95, P<0.0001). The difference was not statistically significant when studies evaluating implants inserted in maxillae or in mandibles were pooled, or when the studies using implants to rehabilitate patients with full-arch prostheses were pooled; however, it was significant for the studies that rehabilitated patients with implant-supported single crowns and for the controlled studies. There was no apparent significant effect on the occurrence of postoperative infection or on the magnitude of marginal bone loss. The results should be interpreted with caution due to the potential for biases and to the presence of uncontrolled confounding factors in the included studies, most of them not randomized. CLINICAL SIGNIFICANCE: The question whether immediate implants are more at risk for failure than implants placed in mature bone has received increasing attention in the last years. As the philosophies of treatment alter over time, a periodic review of the different concepts is necessary to refine techniques and eliminate unnecessary procedures. This would form a basis for optimum treatment. PMID- 25433140 TI - Does flow cytometry have a role in preliminary differentiation between urinary tract infections sustained by gram positive and gram negative bacteria? An Italian polycentric study. AB - BACKGROUND: Urine culture is the most frequently requested test for a Microbiology Lab. A reliable screening tool would be of paramount importance both to clinicians and laboratorians, provided that it could get fast and accurate negative results in order to rule-out urinary tract infection (UTI). MATERIALS AND METHODS: We evaluated 1907 consecutive urine samples from outpatients. Culture was performed on chromogenic agar with 1MUL loop, using 10(5)CFU/mL as a limit of positive growth. Using Sysmex Uf-1000i analyzer we evaluated bacteria forward scatter (B_FSC) and fluorescent light scatter (B_FLH) in a preliminary discrimination step for UTI caused by Gram+ or Gram- bacteria. RESULTS: We got 512 positive samples. A mono-microbial infection was observed in 490 samples; two bacterial strains were isolated in 22 samples, so 534 bacterial strains were found: 392 Gram-, 133 Gram+ and 9 yeasts. Comparing Gram+ and Gram- bacteria we observed a statistically significant difference for B_FSC but not for B_FLH. In this application experimental cut-off value for B_FSC was 25ch. Using this cut off to perform a presumptive identification of UTI sustained by Gram-+ bacteria, we observed a SE 0.68, SP 0.84. CONCLUSION: Our data although preliminary suggest that B_FSC could be useful in presumptive exclusion of UTI caused by Gram positive bacteria. PMID- 25433141 TI - Plasma adrenomedullin levels and nasopharyngeal carcinoma prognosis. AB - BACKGROUND: Adrenomedullin has been identified as a tumor growth factor. However, few studies have reported its relationship with cancer survival. We evaluated the prognostic value of pretreatment plasma adrenomedullin levels in nasopharyngeal carcinoma (NPC). METHODS: Plasma adrenomedullin levels of 258 NPC patients and 100 healthy controls were determined using enzyme-linked immunosorbent assay. Adverse event was defined as tumor progression or death from any cause during 5 year follow-up. The relationships between plasma adrenomedullin levels and 5-year mortality, adverse event, tumor-free survival and overall survival were evaluated using multivariate analysis. RESULTS: Pretreatment plasma adrenomedullin levels were substantially higher in patients than in healthy subjects and were correlated highly with tumor classification, lymph node classification and tumor node metastasis stage positively. Adrenomedullin was identified as an independent predictor of 5-year mortality, adverse event, tumor-free survival and overall survival. Based on receiver operating characteristic curve analysis, pretreatment plasma adrenomedullin level had high predictive value for 5-year mortality and adverse event and had high diagnostic value for NPC. CONCLUSIONS: Adrenomedullin may be a reliable biomarker for predicting the long-term prognosis of patients with NPC and also has potential diagnostic utility for NPC. PMID- 25433142 TI - Features of intrinsic ganglionated plexi in both atria after extensive pulmonary isolation and their clinical significance after catheter ablation in patients with atrial fibrillation. AB - BACKGROUND: The features of intrinsic ganglionated plexi (GP) in both atria after extensive pulmonary vein isolation (PVI) and their clinical implications have not been clarified in patients with atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to assess the features of GP response after extensive PVI and to evaluate the relationship between GP responses and subsequent AF episodes. METHODS: The study population consisted of 216 consecutive AF patients (104 persistent AF) who underwent an initial ablation. We searched for the GP sites in both atria after an extensive PVI. RESULTS: GP responses were determined in 186 of 216 patients (85.6%). In the left atrium, GP responses were observed around the right inferior GP in 116 of 216 patients (53.7%) and around the left inferior GP in 57 of 216 (26.4%). In the right atrium, GP responses were observed around the posteroseptal area: inside the CS in 64 of 216 patients (29.6%), at the CS ostium in 150 of 216 (69.4%), and in the lower right atrium in 45 of 216 (20.8%). The presence of a positive GP response was an independent risk factor for AF recurrence (hazard ratio 4.04, confidence interval 1.48-11.0) in patients with paroxysmal, but not persistent, AF. The incidence of recurrent atrial tachyarrhythmias in patients with paroxysmal AF with a positive GP response was 51% vs 8% in those without a GP response (P = .002). CONCLUSION: The presence of GP responses after extensive PVI was significantly associated with increased AF recurrence after ablation in patients with paroxysmal AF. PMID- 25433143 TI - Diminished exercise capacity and chronotropic incompetence in pediatric patients with congenital complete heart block and chronic right ventricular pacing. AB - BACKGROUND: Chronic right ventricular (RV) pacing has been associated with decreased exercise capacity and left ventricular (LV) function in adults with congenital complete atrioventricular block (CCAVB), but not in children. OBJECTIVE: The purpose of this study was to evaluate the exercise capacity and LV function in pediatric patients with CCAVB receiving chronic RV pacing. METHODS: We prospectively evaluated pediatric patients with isolated CCAVB receiving atrial synchronous RV pacing for at least 5 years. Supine bicycle ergometry was performed, and LV ejection fraction (EF) was evaluated by echocardiography. RESULTS: Ten CCAVB subjects and 31 controls were matched for age, gender, and body surface area. CCAVB subjects had normal resting EF (63.1% +/- 4.0%) and had been paced for 7.9 +/- 1.4 years. Exercise testing demonstrated reduced functional capacity in CCAVB patients compared to controls with a lower VO2peak (26.0 +/- 6.6 mL/kg/min vs 39.9 +/- 7.0 mL/kg/min, P <.001), anaerobic threshold (15.6 +/- 3.9 mL/kg/min vs 18.8 +/- 2.7 mL/kg/min, P = .007), and oxygen uptake efficiency slope (1210 +/- 406 vs 1841 +/- 452, P <.001). Maximum heart rate (165 +/- 8 bpm vs 185 +/- 9 bpm, P <.001) and systolic blood pressure (159 +/- 17 mm Hg vs 185 +/- 12 mm Hg, P <.019) also were reduced in CCAVB patients despite maximal effort (respiratory exchange ratio 1.2 +/- 0.1). EF was augmented with exercise in controls but not in CCAVB patients (13.2% +/- 9.3% vs 0.2% +/- 4.8% increase, P <.001). CONCLUSION: Clinically asymptomatic children with chronic RV pacing due to CCAVB have significant reductions in functional capacity accompanied by chronotropic incompetence and inability to augment EF with exercise. PMID- 25433144 TI - Multicenter study of the safety and effects of magnetic resonance imaging in patients with coronary sinus left ventricular pacing leads. AB - BACKGROUND: Magnetic resonance imaging (MRI) in patients with left ventricular (LV) leads may cause tissue or lead heating, dislodgment, venous damage, or lead dysfunction. OBJECTIVE: The purpose of this study was to determine the safety of MRI in patients with LV pacing leads. METHODS: Prospective data on patients with coronary sinus LV leads undergoing clinically indicated MRI at 3 institutions were collected. Patients were not pacemaker-dependent. Scans were performed under pacing nurse, technician, radiologist, and physicist supervision using continuous vital sign, pulse oximetry, and ECG monitoring and a 1.5-T scanner with specific absorption rate <1.5 W/kg. Devices were interrogated pre- and post-MRI, programmed to asynchronous or inhibition mode with tachyarrhythmia therapies off (if present), and reprogrammed to their original settings post-MRI. RESULTS: MRI scans (n = 42) were performed in 40 patients with non-MRI conditional LV leads between 2005 and 2013 (mean age 67 +/- 9 years, n = 16 [40%] women, median lead implant duration 740 days with interquartile range 125-1173 days). MRIs were performed on the head/neck/spine (n = 35 [83%]), lower extremities (n = 4 [10%]), chest (n = 2 [5%]), and abdomen (n = 1 [2%]). There were no overall differences in pre- and post-MRI interrogation LV lead sensing (12.4 +/- 6.2 mV vs 12.9 +/- 6.7 mV, P = .38), impedance (724 +/- 294 Omega vs 718 +/- 312 Omega, P = .67), or threshold (1.4 +/- 1.1 V vs 1.4 +/- 1.0 V, P = .91). No individual LV lead changes required intervention. CONCLUSION: MRI scanning was performed safely in non-pacemaker-dependent patients with coronary sinus LV leads who were carefully monitored during imaging without clinically significant adverse effect on LV lead function. PMID- 25433146 TI - An algebraic model for the kinetics of covalent enzyme inhibition at low substrate concentrations. AB - This article describes an integrated rate equation for the time course of covalent enzyme inhibition under the conditions where the substrate concentration is significantly lower than the corresponding Michaelis constant, for example, in the Omnia assays of epidermal growth factor receptor (EGFR) kinase. The newly described method is applicable to experimental conditions where the enzyme concentration is significantly lower than the dissociation constant of the initially formed reversible enzyme-inhibitor complex (no "tight binding"). A detailed comparison with the traditionally used rate equation for covalent inhibition is presented. The two methods produce approximately identical values of the first-order inactivation rate constant (kinact). However, the inhibition constant (Ki), and therefore also the second-order inactivation rate constant kinact/Ki, is underestimated by the traditional method by up to an order of magnitude. PMID- 25433145 TI - The molecular mechanism of rotenone-induced alpha-synuclein aggregation: emphasizing the role of the calcium/GSK3beta pathway. AB - Environmental toxin exposure is associated with the development of Parkinson's disease (PD), and environmental factors can influence the onset of the majority of sporadic PD cases via genetically mediated pathways. Rotenone, a widespread pesticide, induces Parkinsonism and the formation of Lewy bodies in animals; however, the molecular mechanism that underlies alpha-synuclein aggregation remains unclear. Here, we assessed the aggregation of alpha-synuclein in PC12 cells with or without cross-linking following rotenone exposure via a variety of methods, including western blotting, immunofluorescence and electron microscopy. We demonstrated that rotenone increased the intracellular calcium levels and induced the aggregation and phosphorylation of alpha-synuclein in a calcium dependent manner. Aggregated alpha-synuclein is typically degraded by autophagy, and rotenone impaired this process. The attenuation of autophagy and alpha synuclein alterations were reversed by scavenging calcium. Calcium regulates the activity of AKT-glycogen synthase kinase 3 (GSK3)beta. We demonstrated that rotenone attenuated the phosphorylation of AKT and GSK3beta, and the elimination of calcium reversed these phenomena. As a GSK3beta inhibitor, lithium promoted autophagy and decreased the aggregation and phosphorylation of alpha-synuclein. GSK3beta activation through overexpression depressed autophagy and increased the total protein level and phosphorylation of alpha-synuclein. These results suggest that rotenone-induced alpha-synuclein aggregation is mediated by the calcium/GSK3beta signaling pathway. PMID- 25433147 TI - Determination of DNase activity by degradation of ethidium bromide-DNA complexes using a fluorescence plate reader. AB - The long known toxicity of free chromatin mediated by histones regained attention after discovery of neutrophil extracellular traps (NETs). Free histones from necrotic cells or NETs can damage prokaryotic and eukaryotic cells and are responsible for the aggravation of a growing list of diseases. DNases degrade the toxic chromatin polymer to nucleosomes and efficiently reduce local high histone concentrations. Therefore, DNase activity as a biomarker is of growing interest in basic and clinical research. Here a detailed one-step protocol is presented that allows rapid and sensitive detection of DNases down to 400 fg/MUl per reaction based on the detection of fluorescent ethidium bromide/DNA complexes in a 96-well plate reader. The flexible protocol uses an internal standard for background correction and allows convenient and reliable data analysis using common laboratory equipment and chemicals without elaborate preparations. The DNase activity of a sample is clearly defined by substrate amount, incubation time, and (if appropriate) a DNase standard for absolute quantification in Kunitz units per milligram sample protein. Quantitative kinetic determination is possible within less than 1h down to 5 pg DNases/MUl per reaction. PMID- 25433148 TI - The role of the M4 lipid-sensor in the folding, trafficking, and allosteric modulation of nicotinic acetylcholine receptors. AB - With the availability of high resolution structural data, increasing attention has focused on the mechanisms by which drugs and endogenous compounds allosterically modulate nicotinic acetylcholine receptor (nAChR) function. Lipids are potent modulators of the nAChR from Torpedo. Membrane lipids influence nAChR function by both conformational selection and kinetic mechanisms, stabilizing varying proportions of pre-existing resting, open, desensitized, and uncoupled conformations, as well as influencing the transitions between these conformational states. Structural and functional data highlight a role for the lipid-exposed M4 transmembrane alpha-helix of each subunit in lipid sensing, and suggest that lipids influence gating by altering the binding of M4 to the adjacent transmembrane alpha-helices, M1 and M3. M4 has also been implicated in both the folding and trafficking of nAChRs to the cell surface, as well as in the potentiation of nAChR gating by neurosteroids. Here, we discuss the roles of M4 in the folding, trafficking, and allosteric modulation of nAChRs. We also consider the hypothesis that variable chemistry at the M4-M1/M3 transmembrane alpha-helical interface in different nAChR subunits governs the capacity for potentiation by activating lipids. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID- 25433150 TI - Determination of the Clostridium perfringens-binding site on fibronectin. AB - The extracellular matrix protein fibronectin (Fn) is known to bind to the surface of Clostridium perfringens cells. Fn is a disulfide-linked homodimer protein, with each Fn polypeptide consisting of three types of repeating modules: 12 type I, 2 type II, and 15-17 type III modules. To determine the epitope on Fn recognized by C. perfringens cells, anti-Fn monoclonal antibodies (mAbs) and various Fn fragments (III2-10, rIII2-4, rIII5-7, rIII8, rIII9, rIII10) were employed. Although two C. perfringens-derived Fn-binding proteins, FbpA and FbpB, have been reported, they appear not to be the bacterium's surface Fn receptor. Moreover, both FbpA and FbpB were found to bind to C. perfringens cells. To avoid confusion, a mutant C. perfringens lacking both the fbpA and fbpB genes (MW5) was prepared using an in-frame deletion system. MW5 cells bound Fn on their surface, suggesting the presence of a putative Fn receptor(s) on C. perfringens cells. Of several anti-Fn mAbs, both HB39 and MO inhibited the binding of Fn to MW5 cells. HB39 reacted strongly with III2-10 and rIII9, and weakly with rIII2-4, rIII10 and rIII5-7 in Western blotting analysis. Binding of HB39 to Fn was inhibited in the presence of either rIII9 or rIII10, but not in the presence of rIII2-4, rIII5-7, or rIII8. Binding of Fn to MW5 cells was strongly inhibited by both III2-10 and rIII9, marginally inhibited by rIII2-4, but not affected by rIII5-7, rIII8, or rIII10. Significant binding of MW5 cells to immobilized rIII9 and rIII10 as well as immobilized III2-10 was observed. The region of Fn recognized by C. perfringens was thus mapped to the region encompassed by III9 and III10. PMID- 25433151 TI - Minilaparoscopic sacrocolpopexy for vaginal prolapse after hysterectomy. AB - Genital prolapse repair is one of the most common indications for benign gynecologic surgery. The lifetime risk of undergoing a single operation for prolapse in the female population is rising. Many different surgical techniques have been described. We report 4 cases of minilaparoscopic sacrocolpopexy to correct vaginal apical prolapse after previous total hysterectomy. For each patient we collected some socio-demographic data, vaginal apical prolapse grade using the Pelvic Organ Prolapse Quantification (POP-Q), intraoperative details and postoperative outcomes. Operative time was recorded as well as difficulties and complications (Clavien-Dindo Classification) at each step of the procedure. The range of women's ages was from 57 to 71 years old. The mean BMI was 24.75 +/- 3.2 Kg/m2. Three patients had a stage III POP-Q prolapses and there was one case of a symptomatic stage II POP-Q prolapse. The mean surgical time was 119 minutes and there were no intraoperative complications. The postoperative pain assessment revealed very positive recovery in every patient. An ambulatory consult and an anatomic assessment were done 1 and 3 months after surgery. The incision scars were almost invisible after 1 month, and the anatomic cure rate was 100%. We confirmed the feasibility of a minilaparoscopic surgical approach for vaginal vault prolapse after total hysterectomy. PMID- 25433153 TI - Thrombosis prevention in lower extremity arthroplasty: mobile compression device or pharmacological therapy. AB - Venous thromboembolic (VTE) events, either deep vein thromboses (DVT) or pulmonary emboli (PE), are important complications in patients undergoing knee or hip arthroplasty. Symptomatic VTE rates observed in total joint arthroplasty patients using the mobile compression device with home use capability were non inferior to rates reported for pharmacological prophylaxis, including warfarin, enoxaparin, rivaroxaban, and dabigatran. Major bleeding in total hip arthroplasty was less using the mobile compression device than using low molecular weight heparin. A cost analysis demonstrated a cost savings based on decreased major bleeding. Use of a mobile compression device with or without aspirin for patients undergoing total joint arthroplasty provides a non-inferior risk for developing VTE compared with current pharmacological protocols. PMID- 25433152 TI - Sexual function after hysterectomy and myomectomy. AB - Sexual function after hysterectomy and myomectomy is a controversial topic and influenced by several factors. With regard to hysterectomy, there is not a consensus whether the removal of the cervix will modify sexual function after surgery, and patients who choose to preserve their cervix should be counseled about the possibility of continued vaginal bleeding and the need for continued pap smear surveillance after surgery. In most studies, hysterectomy has been found to improve sexual function because usually patients have symptoms that indicated the surgery, such as abnormal uterine bleeding and pelvic pain, and as these symptoms cease, they report an improvement in their sexual life. In regards to myomectomy, literature is scarce, however few studies have shown an improvement in sexual function due to the same reasons as hysterectomy. For purposes of research, it is important to standardize sexual questionnaires when performing studies about this outcome. It is also important to emphasize that during discussion of your patient, sexual outcomes should be addressed and that the surgeon should consider all patients' personal, religious, and cultural background during the decision-making process because it will minimize patient's disappointment if she develops a negative response after surgery. PMID- 25433154 TI - Cement extractor device in revision prosthesis of the humerus. AB - In revision arthroplasty the surgeon is often faced with the problem of removal of residual cement in the medullary canal. Conventional manual cement removal by hand or power-driven instruments can be time-consuming, can require osteotomy, and can be associated with complications such as cortical perforation, fracture, or bone loss. Ultrasonic devices offer an alternative method of cement removal, but the potential for thermal injury exists, in particular for the humerus and the radial nerve. Considering these problems with the use of ultrasound, and whereas the old cement mantle may be left in place in the hip or knee but not in the shoulder, we tried this new mechanical cement extractor also in the humerus. We utilized this extractor in 5 cases, and we eliminated all residual resin in an accurate and complete way without bone loss and without iatrogenic fractures in all cases. We believe this system, which was designed for revisions of hip and knee surgery, is also suitable for the shoulder. PMID- 25433155 TI - Short-stay Sutureless Thyroidectomy is Safe and Effective: Cerrahpasa Experience. AB - Hospitalizing patients up to 72 hours after thyroidectomy is a classical approach. However, the length of hospitalization has decreased following surgical procedures with new technological devices. Seven hundred one consecutive patients who underwent sutureless total thyroidectomy (STT) between October 2011 and 2013 were included in this study. Six hundred seventy-two (95.9%) were discharged before 24 hours following surgery (short-stay = SS), and 29 were discharged later (delayed-discharge = DD). This study aims to assess short-stay STT with early postoperative complications and readmission to hospital. One hundred forty-three SS patients were male and 529 were female. Mean age was 48 +/- 13 years, BMI was 28.7 +/- 8.3 kg/m2. Mean hospital stay for SS was 18.13 +/- 1.97 (17-23) hours. Histopathology was benign in 443 (65.92%) and malignant in 229 (34.08%) in the SS group. In three (0.4%) of the SS group drainage was required because of hematoma, and in seven (1%) wound infection was observed. One hundred seven (7.9%) [permanent = 7 (0.52%)] of 1344 recurrent laryngeal nerves (RLNs) in SS were seen paralyzed in postoperative vocal cord examination. Hypocalcemia (all transient) was observed in 52 (7.74%) of the SS group. Eight of those 52 readmitted to hospital with symptomatic hypocalcemia and were treated as outpatients. There was no mortality. Of the DD group, two stayed in the intensive care unit, two had dysphonia, two had hematoma with anti-coagulant use, one had fever, four did not tolerate diet, five refused discharge, and 13 had symptomatic hypocalcemia. Sutureless total thyroidectomy can be performed safely and effectively as short stay surgery. PMID- 25433156 TI - Vergence responses to vertical binocular disparity during lexical identification. AB - Humans typically make use of both eyes during reading, which necessitates precise binocular coordination in order to achieve a unified perceptual representation of written text. A number of studies have explored the magnitude and effects of naturally occurring and induced horizontal fixation disparity during reading and non-reading tasks. However, the literature concerning the processing of disparities in different dimensions, particularly in the context of reading, is considerably limited. We therefore investigated vertical vergence in response to stereoscopically presented linguistic stimuli with varying levels of vertical offset. A lexical decision task was used to explore the ability of participants to fuse binocular image disparity in the vertical direction during word identification. Additionally, a lexical frequency manipulation explored the potential interplay between visual fusion processes and linguistic processes. Results indicated that no significant motor fusional responses were made in the vertical dimension (all p-values>.11), though that did not hinder successful lexical identification. In contrast, horizontal vergence movements were consistently observed on all fixations in the absence of a horizontal disparity manipulation. These findings add to the growing understanding of binocularity and its role in written language processing, and fit neatly with previous literature regarding binocular coordination in non-reading tasks. PMID- 25433157 TI - Reference-frame specificity of perceptual learning: the effect of practice. AB - One of the hallmarks of perceptual learning is specificity, the lack of transfer of the improved discriminative ability when the trained stimulus changes retinal location, orientation or other basic visual attributes. Specificity has been found also for the trained task and the corresponding attended stimulus feature. Here, we provide evidence for a new form of specificity, called reference-frame specificity, which does not follow from changes in the sensory input or the attended stimulus feature. In our paradigm, specificity was the consequence of the mental frame of reference (vertical or horizontal) used to perform the orientation discrimination task. In addition, we found that reference-frame specificity was exacerbated by prolonged practice. Overall the present findings are in agreement with the "selective reweighting" hypothesis of perceptual learning. PMID- 25433149 TI - New mechanisms and perspectives in nicotine withdrawal. AB - Diseases associated with tobacco use constitute a major health problem worldwide. Upon cessation of tobacco use, an unpleasant withdrawal syndrome occurs in dependent individuals. Avoidance of the negative state produced by nicotine withdrawal represents a motivational component that promotes continued tobacco use and relapse after smoking cessation. With the modest success rate of currently available smoking cessation therapies, understanding mechanisms involved in the nicotine withdrawal syndrome are crucial for developing successful treatments. Animal models provide a useful tool for examining neuroadaptative mechanisms and factors influencing nicotine withdrawal, including sex, age, and genetic factors. Such research has also identified an important role for nicotinic receptor subtypes in different aspects of the nicotine withdrawal syndrome (e.g., physical vs. affective signs). In addition to nicotinic receptors, the opioid and endocannabinoid systems, various signal transduction pathways, neurotransmitters, and neuropeptides have been implicated in the nicotine withdrawal syndrome. Animal studies have informed human studies of genetic variants and potential targets for smoking cessation therapies. Overall, the available literature indicates that the nicotine withdrawal syndrome is complex, and involves a range of neurobiological mechanisms. As research in nicotine withdrawal progresses, new pharmacological options for smokers attempting to quit can be identified, and treatments with fewer side effects that are better tailored to the unique characteristics of patients may become available. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID- 25433158 TI - Thioredoxin: a novel, independent diagnosis marker in children with autism. AB - BACKGROUND: Oxidative stress increases serum thioredoxin (TRX), a redox regulating protein with antioxidant activity recognized as an oxidative-stress marker. The aim of this study was to assess the clinical significance of serum TRX levels in Autism spectrum disorders (ASD). METHODS: Eighty patients diagnosed with ASD and 100 sex and age matched typically developing children were assessed for serum TRX content at admission. TRX were assayed with solid-phase sandwich ELISA, and severity of ASD was evaluated with the Childhood Autism Rating Scale (CARS) Score. RESULTS: The results indicated that the median serum TRX levels were significantly (P<0.0001) higher in children with ASD as compared to typically developing children [17.9(IQR: 10.7-25.8)ng/ml and 5.5(3.6-9.2)ng/ml, respectively]. Levels of TRX increased with increasing severity of ASD as defined by the CARS score. After adjusting for all other possible covariates, TRX still was an independent diagnosis marker of ASD with an adjusted OR of 1.454 (95% CI, 1.232-1.892; P<0.0001). Based on the receiver operating characteristic (ROC) curve, the optimal cut-off value of serum TRX levels as an indicator for auxiliary diagnosis of autism was projected to be 10.6ng/ml. Further, we found that an increased diagnosis of ASD was associated with TRX levels >=10.6ng/ml (adjusted OR 15.31, 95% CI: 7.36-31.85) after adjusting for possible confounders. CONCLUSIONS: Our study demonstrated that serum TRX levels were associated with ASD, and elevated levels could be considered as a novel, independent diagnosis indicator of ASD. PMID- 25433160 TI - Roles of alcohol consumption in fatty liver: a longitudinal study. AB - BACKGROUND & AIMS: Roles of alcohol consumption in non-alcoholic fatty liver disease are still controversial, although several cross-sectional studies have suggested the beneficial effect of light to moderate drinking on fatty liver. We analyzed the longitudinal relationship between drinking pattern and fatty liver. METHODS: We included 5297 Japanese individuals (3773 men and 1524 women) who underwent a baseline study in 2003 and follow-up at least once from 2004 to 2006. Generalized estimating equation was used to estimate any association between drinking pattern and fatty liver assessed by ultrasonography. RESULTS: At baseline, 1179 men (31.2%) and 235 women (15.4%) had fatty liver; 2802 men (74.2%) and 436 women (28.6%) reported alcohol consumption. At the latest follow up, 348 of 2594 men (13.4%) and 101 of 1289 women (7.8%) had newly developed fatty liver; 285 of 1179 men (24.2%) and 70 of 235 women (29.8%) demonstrated a remission of fatty liver. In men, drinking 0.1-69.9 g/week (odds ratio, 0.79 [95% confidence interval, 0.68-0.90]), drinking 70.0-139.9 g/week (0.73 [0.63-0.84]), drinking 140.0-279.9 g/week (0.69 [0.60-0.79]), and drinking ?280.0 g/week (0.68 [0.58-0.79]) were inversely associated with fatty liver after adjusting for obesity, exercise, and smoking. In women, drinking 0.1-69.9 g/week (0.71 [0.52 0.96]) and drinking 70.0-139.9 g/week (0.67 [0.45-0.98]) were inversely associated with fatty liver after the adjustment. CONCLUSIONS: Light to moderate alcohol consumption, or even somewhat excessive amounts especially in men, was likely to protect most individuals against fatty liver over time. PMID- 25433159 TI - The association of liver enzymes with biomarkers of subclinical myocardial damage and structural heart disease. AB - BACKGROUND & AIMS: Patients with non-alcoholic fatty liver disease (NAFLD) are thought to be at increased risk of cardiovascular morbidity and mortality. However, the relationships between NAFLD and subclinical myocardial injury or structural heart disease are unknown. METHODS: We conducted a cross-sectional analysis of 8668 participants from the Atherosclerosis Risk in Communities (ARIC) Study, who showed no clinical evidence of cardiovascular disease. We used levels of liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST] and gamma-glutamyl transpeptidase [GGT]), in the context of no history of elevated alcohol consumption as non-invasive surrogates of NAFLD. We used highly sensitive cardiac troponin T (hs-cTnT) and N-terminal pro-Brain natriuretic peptide (NT-proBNP) as biomarkers of myocardial damage and function. RESULTS: In this population-based study (mean age 63 years, 60% women, 78% white), higher levels of ALT, AST, and GGT, even within the normal range, were significantly and independently associated with detectable (hs-cTnT >3 ng/L) and elevated (hs-cTnT ?14 ng/L) concentrations of hs-cTnT. The adjusted odds ratios (95% confidence interval) for elevated liver enzymes (vs. normal levels) with elevated hs-cTnT were: 1.65 (1.28-2.14) for ALT, 1.90 (1.36-2.68) for AST, and 1.55 (1.13-2.12) for GGT. Furthermore, there was evidence for inverse associations of ALT and AST with NT-proBNP. CONCLUSIONS: Our results suggest that elevated liver enzyme levels in the absence of elevated alcohol consumption may be associated with subclinical myocardial injury. The inverse association between NT-proBNP and both ALT and AST supports the recently described metabolic role of natriuretic peptides. PMID- 25433161 TI - Vagus nerve contributes to the development of steatohepatitis and obesity in phosphatidylethanolamine N-methyltransferase deficient mice. AB - BACKGROUND & AIMS: Phosphatidylethanolamine N-methyltransferase (PEMT), a liver enriched enzyme, is responsible for approximately one third of hepatic phosphatidylcholine biosynthesis. When fed a high-fat diet (HFD), Pemt(-/-) mice are protected from HF-induced obesity; however, they develop steatohepatitis. The vagus nerve relays signals between liver and brain that regulate peripheral adiposity and pancreas function. Here we explore a possible role of the hepatic branch of the vagus nerve in the development of diet induced obesity and steatohepatitis in Pemt(-/-) mice. METHODS: 8-week old Pemt(-/-) and Pemt(+/+) mice were subjected to hepatic vagotomy (HV) or capsaicin treatment, which selectively disrupts afferent nerves, and were compared to sham-operated or vehicle-treatment, respectively. After surgery, mice were fed a HFD for 10 weeks. RESULTS: HV abolished the protection against the HFD-induced obesity and glucose intolerance in Pemt(-/-) mice. HV normalized phospholipid content and prevented steatohepatitis in Pemt(-/-) mice. Moreover, HV increased the hepatic anti inflammatory cytokine interleukin-10, reduced chemokine monocyte chemotactic protein-1 and the ER stress marker C/EBP homologous protein. Furthermore, HV normalized the expression of mitochondrial electron transport chain proteins and of proteins involved in fatty acid synthesis, acetyl-CoA carboxylase and fatty acid synthase in Pemt(-/-) mice. However, disruption of the hepatic afferent vagus nerve by capsaicin failed to reverse either the protection against the HFD induced obesity or the development of HF-induced steatohepatitis in Pemt(-/-) mice. CONCLUSIONS: Neuronal signals via the hepatic vagus nerve contribute to the development of steatohepatitis and protection against obesity in HFD fed Pemt(-/ ) mice. PMID- 25433163 TI - Redox regulation of differentiation in symbiotic nitrogen fixation. AB - BACKGROUND: Nitrogen-fixing symbiosis between Rhizobium bacteria and legumes leads to the formation of a new organ, the root nodule. The development of the nodule requires the differentiation of plant root cells to welcome the endosymbiotic bacterial partner. This development includes the formation of an efficient vascular tissue which allows metabolic exchanges between the root and the nodule, the formation of a barrier to oxygen diffusion necessary for the bacterial nitrogenase activity and the enlargement of cells in the infection zone to support the large bacterial population. Inside the plant cell, the bacteria differentiate into bacteroids which are able to reduce atmospheric nitrogen to ammonia needed for plant growth in exchange for carbon sources. Nodule functioning requires a tight regulation of the development of plant cells and bacteria. SCOPE OF THE REVIEW: Nodule functioning requires a tight regulation of the development of plant cells and bacteria. The importance of redox control in nodule development and N-fixation is discussed in this review. The involvement of reactive oxygen and nitrogen species and the importance of the antioxidant defense are analyzed. MAJOR CONCLUSIONS: Plant differentiation and bacterial differentiation are controlled by reactive oxygen and nitrogen species, enzymes involved in the antioxidant defense and antioxidant compounds. GENERAL SIGNIFICANCE: The establishment and functioning of nitrogen-fixing symbiosis involve a redox control important for both the plant-bacteria crosstalk and the consideration of environmental parameters. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. PMID- 25433162 TI - Outcomes in liver transplantation: does sex matter? AB - A growing literature has highlighted important differences in transplant-related outcomes between men and women. In the United States there are fewer women than men on the liver transplant waitlist and women are two times less likely to receive a deceased or living-related liver transplant. Sex-based differences exist not only in waitlist but also in post-transplant outcomes, particularly in some specific liver diseases, such as hepatitis C. In the era of individualized medicine, recognition of these differences in the approach to pre and post-liver transplant care may impact short and long-term outcomes. PMID- 25433165 TI - Interplay between the prostaglandin transporter OATP2A1 and prostaglandin E2 mediated cellular effects. AB - Prostaglandins such as prostaglandin E2 (PGE2) play a pivotal role in physiological and pathophysiological pathways in gastric mucosa. Little is known about the interrelation of the prostaglandin E (EP) receptors with the prostaglandin transporter OATP2A1 in the gastric mucosa and gastric carcinoma. Therefore, we first investigated the expression of OATP2A1 and EP4 in normal and carcinoma gastric mucosa. Different PGE2-mediated cellular pathways and mechanisms were investigated using human embryonic kidney cells (HEK293) and the human gastric carcinoma cell line AGS stably transfected with OATP2A1. Colocalization and expression of OATP2A1 and EP4 were detected in mucosa of normal gastric tissue and of gastric carcinomas. OATP2A1 reduced the PGE2 mediated cAMP production in HEK293 and AGS cells overexpressing EP4 and OATP2A1. The expression of OATP2A1 in AGS cells resulted in a reduction of [(3)H] thymidine incorporation which was in line with a higher accumulation of AGS OATP2A1 cells in S-phase of the cell cycle compared to control cells. In contrast, the expression of OATP2A1 in HEK293 cells had no influence on the distribution in the S-phase compared to control cells. OATP2A1 also diminished the PGE2-mediated expression of interleukin-8 mRNA (IL-8) and hypoxia-inducible factor 1alpha (HIF1alpha) protein in AGS-OATP2A1 cells. The expression of OATP2A1 increased the sensitivity of AGS cells against irinotecan which led to reduced cell viability. Taken together, these data show that OATP2A1 influences PGE2 mediated cellular pathways. Therefore, OATP2A1 needs to be considered as a key determinant for the understanding of the physiology and pathophysiology of prostaglandins in healthy and tumorous gastric mucosa. PMID- 25433164 TI - Variability of permeability estimation from different protocols of subculture and transport experiments in cell monolayers. AB - INTRODUCTION: In vitro models with high predictive ability have been revealed as strong tools for pharmaceutical industry. However, the variability in permeability estimations complicates the comparison and combination of data from different laboratories and it makes necessary the careful validation of the model and the continuous suitability demonstration. The adequate standardization of pre experimental, experimental and post-experimental factors might help to reduce the inter- and intra-laboratory variability in permeability values. METHODS: The objective of this paper is the evaluation of the effect of passage number, experimental protocol, time after seeding and calculation method on the permeability values and their variability in transport experiments in Caco-2, MDCK and MDCK-MDR1 cells. Metoprolol, Lucifer yellow and Rhodamine-123 were used to check the performance of the cell lines. Protocols used differ mainly in the differentiation time and the filter support coating with collagen. Data was analyzed with sink and non-sink approaches. The final purpose was to explore pre experimental, experimental and post-experimental conditions in order to select the best experimental scenarios for permeability assays. RESULTS: Results indicated that for passive diffusion studies, coating helps cell differentiation in a more stable manner in all cell lines compared to protocol without coating which showed permeability changes with passages and more variable values. In both protocols the paracellular route became more restricted with higher passage numbers. Functionality of P-gp assessed with Rhodamine permeability did not change with passage number in Caco-2 cells with any of the protocols but increased in both protocols in MDCK and MDCK-MDR1 cells. Protocol without coating showed the less variable results in these cell lines. Rhodamine permeabilities increased with higher maturation times due to a higher expression of the transporter. Nevertheless for compounds absorbed by passive diffusion there was not a clear trend neither in permeability values nor in variability. DISCUSSION: As a conclusion, we have confirmed the influence of maturation conditions and passage number in permeability values and in their variability. Based on our results protocol with coating would be more adequate for studies of compounds absorbed by passive diffusion but the protocol without coating gave us better results for studies about P-gp interactions. PMID- 25433166 TI - The relationship among psychological and psychophysiological characteristics of fibromyalgia patients. AB - This study examined the relationship of psychophysiological response patterns in fibromyalgia with psychological characteristics and comorbid mental disorders. Surface electromyographic data, systolic and diastolic blood pressure, heart rate (HR), and skin conductance levels were recorded continuously during baseline, stress, and relaxation tasks. Cluster analysis revealed 4 subgroups of patients who differed on pain characteristics and cognitive, affective, and behavioral responses to pain and stress. The largest group (46.7%) was characterized by elevated blood pressure levels and stress reactivity (a disposition assumed to be a vulnerability factor for the development of diseases) associated with pain, anxiety, physical interference, low activity, and pain behaviors. A second group (41.6%) showed low baseline blood pressure and reactivity, and high activity and stress. A third group (9.2%) displayed high baseline skin conductance level, reactivity, and depression, and a fourth small group (2.5%) displayed elevated baseline electromyographic response and reactivity with high levels of anxiety and depression. These data suggest that unique psychophysiological response patterns are associated with psychological coping and mental disorders in fibromyalgia patients. The identification of the mechanisms that contribute to these group differences will further our understanding of the mechanisms involved in the development and maintenance of fibromyalgia and suggest differential treatment strategies. PERSPECTIVE: This article presents psychological characteristics and comorbidity with mental disorders of psychophysiological subgroups of fibromyalgia patients. This mechanistic analysis will assist scientific identification of systems-based pathways that contribute to autonomic and stress mechanisms that mediate chronic pain. Demonstration of distinct, homogeneous subgroups is an important step towards personalized, mechanism oriented treatments. PMID- 25433167 TI - Structure-function analyses of tyrosine phosphatase PTP69D in giant fiber synapse formation of Drosophila. AB - PTP69D is a receptor protein tyrosine phosphatase (RPTP) with two intracellular catalytic domains (Cat1 and Cat2) and has been shown to play a role in axon guidance of embryonic motoneurons as well as targeting of photoreceptor neurons in the visual system of Drosophila melanogaster. Here, we characterized the developmental role of PTP69D in the giant fiber (GF) neurons, two interneurons in the central nervous system (CNS) that control the escape response of the fly. Our studies revealed that PTP69D has a function in synaptic terminal growth in the CNS. We found that missense mutations in the first immunoglobulin (Ig) domain and in the Cat1 domain, present in Ptp69D10 and Ptp69D20 mutants, respectively, did not affect axon guidance or targeting but resulted in stunted terminal growth of the GFs. Cell autonomous rescue experiments demonstrated a function for the Cat1 and the first Ig domain of PTP69D in the GFs but not in its postsynaptic target neurons. In addition, complementation studies and structure-function analyses revealed that for GF terminal growth Cat1 function of PTP69D requires the immunoglobulin and the Cat2 domains, but not the fibronectin III or the membrane proximal region domains. In contrast, the fibronectin III but not the immunoglobulin domains were previously shown to be essential for axon targeting of photoreceptor neurons. Thus, our studies uncover a novel role for PTP69D in synaptic terminal growth in the CNS that is mechanistically distinct from its function in photoreceptor targeting. PMID- 25433168 TI - Integrating valve-inspired design features into poly(ethylene glycol) hydrogel scaffolds for heart valve tissue engineering. AB - The development of advanced scaffolds that recapitulate the anisotropic mechanical behavior and biological functions of the extracellular matrix in leaflets would be transformative for heart valve tissue engineering. In this study, anisotropic mechanical properties were established in poly(ethylene glycol) (PEG) hydrogels by crosslinking stripes of 3.4 kDa PEG diacrylate (PEGDA) within 20 kDa PEGDA base hydrogels using a photolithographic patterning method. Varying the stripe width and spacing resulted in a tensile elastic modulus parallel to the stripes that was 4.1-6.8 times greater than that in the perpendicular direction, comparable to the degree of anisotropy between the circumferential and radial orientations in native valve leaflets. Biomimetic PEG peptide hydrogels were prepared by tethering the cell-adhesive peptide RGDS and incorporating the collagenase-degradable peptide PQ (GGGPQG?IWGQGK) into the polymer network. The specific amounts of RGDS and PEG-PQ within the resulting hydrogels influenced the elongation, de novo extracellular matrix deposition and hydrogel degradation behavior of encapsulated valvular interstitial cells (VICs). In addition, the morphology and activation of VICs grown atop PEG hydrogels could be modulated by controlling the concentration or micro-patterning profile of PEG RGDS. These results are promising for the fabrication of PEG-based hydrogels using anatomically and biologically inspired scaffold design features for heart valve tissue engineering. PMID- 25433169 TI - Multiple drug resistance-associated protein 4 (MRP4), prostaglandin transporter (PGT), and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) as determinants of PGE2 levels in cancer. AB - The cyclooxygenase-2 (COX-2) enzyme and major lipid product, prostaglandin E2 (PGE2) are elevated in many solid tumors including those of the breast and are associated with a poor prognosis. Targeting this enzyme is somewhat effective in preventing tumor progression, but is associated with cardiotoxic secondary effects when used chronically. PGE2 functions by signaling through four EP receptors (EP1-4), resulting in several different cellular responses, many of which are pro-tumorigenic, and there is growing interest in the therapeutic potential of targeting EP4 and EP2. Other members in this signaling pathway are gaining more attention. PGE2 is transported out of and into cells by two unique transport proteins. Multiple Drug Resistance-Associated Protein 4 (MRP4) and Prostaglandin Transporter (PGT) modulate PGE2 signaling by increasing or decreasing the levels of PGE2 available to cells. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) metabolizes PGE2 and silences the pathway in this manner. The purpose of this review is to summarize the extensive data supporting the importance of the COX-2 pathway in tumor biology with a focus on more recently described pathway members and their role in modulating PGE2 signaling. This review describes evidence supporting roles for MRP4, PGT and 15-PGDH in several tumor types with an emphasis on the roles of these proteins in breast cancer. Defining the importance of these latter pathway members will be key to developing new therapeutic approaches that exploit the tumor-promoting COX-2 pathway. PMID- 25433171 TI - Polyuric kidneys and uveitis: an oculorenal syndrome. AB - BACKGROUND: Tubulointerstitial nephritis and uveitis syndrome (TINU syndrome) is a diagnosis of exclusion based on the presence of uveitis and acute tubulointerstitial nephritis in the absence of other disease entities known to cause both of these disorders. The proximal tubule is frequently affected by this syndrome, resulting in a wide range of presentations that vary from proteinuria to full picture of Fanconi syndrome. However, distal tubular involvement is not common. CASE REPORT: A 32-year-old female patient presented with polyuria, polydipsia and painful red eyes. Her water deprivation test and desmopressin test results were consistent with nephrogenic diabetes insipidus. Her kidney biopsy showed acute tubulointerstitial nephritis. Her eye exam was consistent with uveitis. To our knowledge, this is the first reported case of nephrogenic diabetes insipidus due to tubulointerstitial nephritis and uveitis syndrome. CONCLUSIONS: Tubulointerstitial nephritis and uveitis syndrome (TINU) syndrome can present with multiple renal tubular defects, including nephrogenic diabetes insipidus. PMID- 25433172 TI - ALX-chemy: adding spice to the inflammatory soup of atherosclerosis. PMID- 25433173 TI - European Initial Hands-On Experience with HEMOPATCH, a Novel Sealing Hemostatic Patch: Application in General, Gastrointestinal, Biliopancreatic, Cardiac, and Urologic Surgery. AB - Topical hemostatic agents that can seal tissues and assist in the coagulation cascade of patients undergoing surgery have been readily available for several decades. Using either synthetic or animal/plant-derived materials, these agents represent a powerful tool to reduce postoperative bleeding complications in cases where mechanical or energy-driven hemostasis is not possible or insufficient. Recently, a novel sealing hemostatic patch, HEMOPATCH (Baxter International, Deerfield, IL), was developed. The device is a thin and flexible patch consisting of a specifically-formulated porous collagen matrix, coated on one side with a thin protein-binding layer. This gives the patch a dual mechanism of action, in which the two components interact to achieve hemostasis by sealing off the bleeding surface and initiating the body's own clotting mechanisms. Here we present a series of case reports that outline the quick, effective hemostatic sealing of HEMOPATCH in a variety of clinical applications, including solid organ, gastrointestinal, biliopancreatic, endocrine, cardiovascular, and urologic surgeries. Essentially a feasibility study, these reports demonstrate how HEMOPATCH can be applied to seal almost any bleeding surface encountered during a range of procedures. Our results show that the device is eminently capable in both via laparotomy and laparoscopic approaches, and in patients with impaired coagulation or highly variable anatomies. In conclusion, our cases document the ease-of-use, application, and immediate hemostatic effect of the patch across a broad range of surgical settings and paves the way for future randomized clinical trials with more extensive follow-up. PMID- 25433174 TI - Topical antimicrobial toolkit for wound infection. AB - Increased bacterial burden and formation of biofilm has been recognized as one of the key factors contributing to delayed wound healing. There is a toolbox of topical antimicrobial wound dressings that incorporate silver, iodine, polyhexamethylene biguanide, methylene blue/gentian violet, and honey. This article reviews a diverse range of evidence to discuss the advantages and disadvantage of topical antimicrobial dressings. Discussion will provide guidance on when and how to use topical antimicrobial dressings to achieve optimal outcomes and cost-effective wound care. Chronic wounds do not follow a predictable and expected healing trajectory, and they may persist for months or years due to underlying disease processes, recurrent injury, and comorbidities.1 With an aging population and increased prevalence of chronic diseases, the majority of wounds are refractory to healing, placing a significant burden on the health system and individual patients. Bacterial burden and biofilm have been recognized as key factors contributing to persistent inflammation, tissue destruction, delayed wound healing, and other serious complications (especially in individuals who are frail and immune-compromised).2 It has been demonstrated that when bacterial growth reaches a critical threshold of 105 bacteria per gram of tissue, bacterial toxins can cause tissue damage in the superficial wound compartment, delaying healing.2 In the literature, this phenomenon is referred to as critical colonization, increased bacterial burden, superficial infection, or localized infection. According to a recent review, over 50% of chronic wounds exhibit signs and symptoms that are consistent with localized infection.3. PMID- 25433170 TI - Microglia inflammatory responses are controlled by an intrinsic circadian clock. AB - The circadian system regulates many physiological functions including inflammatory responses. For example, mortality caused by lipopolysaccharide (LPS) injection varies depending on the time of immunostimulation in mammals. The effects of more subtle challenges on the immune system and cellular mechanisms underlying circadian differences in neuroinflammatory responses are not well understood. Here we show that adult male Sprague-Dawley rats injected with a sub septic dose of LPS during the light phase displayed elevated sickness behaviors and hippocampal cytokine production compared to rats injected during the dark phase. Microglia are the primary central nervous system (CNS) immune cell type and may mediate diurnal differences in sickness response, thus we explored whether microglia demonstrate temporal variations in inflammatory factors. Hippocampal microglia isolated from adult rats rhythmically expressed inflammatory factors and circadian clock genes. Microglia displayed robust rhythms of TNFalpha, IL1beta and IL6 mRNA, with peak cytokine gene expression occurring during the middle of the light phase. Microglia isolated during the light phase were also more reactive to immune stimulation; such that, ex vivo LPS treatment induced an exaggerated cytokine response in light phase-isolated microglia. Treating microglia with corticosterone ex vivo induced expression of the circadian clock gene Per1. However, microglia isolated from adrenalectomized rats maintained temporal differences in clock and inflammatory gene expression. This suggests circadian clock gene expression in microglia is entrained by, but oscillates in the absence of, glucocorticoids. Taken together, these findings demonstrate that microglia possess a circadian clock that influences inflammatory responses. These results indicate time-of-day is an important factor to consider when planning inflammatory interventions such as surgeries or immunotherapies. PMID- 25433175 TI - Comparison of bariatric restrictive operations: laparoscopic sleeve gastrectomy and laparoscopic gastric greater curvature plication. AB - Morbid obesity continues to increase in prevalence, becoming a major socioeconomic and medical problem. The success in treating morbid obesity with surgery has been well documented. The categories of surgical treatment include restrictive, malabsorptive, and combination operations. Two of the restrictive operations at the forefront of today's treatments are laparoscopic sleeve gastrectomy (LSG) and laparoscopic gastric greater curvature plication (LGCP). A literature review has been completed to compare the current technique and results for LSG and LGCP. LSG is a restrictive technique in which reduced gastric volume is achieved by partial greater curvature resection. The benefits of LSG include ease of operation, sustainable weight loss, and low complication rate. The disadvantages include risk for severe complications such as gastric leak and bleeding. LGCP is a novel restrictive technique which reduces gastric volume by plication of the greater curvature; it is still in the investigational stages for use in the United States. A gastric tube is formed with the plication, but no portion of the stomach is excised. The benefits of LGCP include low cost, low risk of complication, such as gastric perforation and bleeding, as well as adequate short term weight loss. The disadvantages include higher risk of nausea and vomiting post-op, a non-zero risk of perforation and bleeding, and likely an unsustainable weight loss. In comparison, LGCP is considered feasible and safe in the short term and especially suited for institutions requiring lower-cost procedures. However, LGCP weight loss may be unsustainable compared to LSG. While LSG complication rates are slightly higher, LGCP is an inferior restrictive procedure for weight loss. Further studies are needed to evaluate the long term outcomes for procedural comparison. PMID- 25433176 TI - Electrosurgery in Gynecology - a Comparison of Available Instruments that Coagulate and Cut Tissue. AB - In the field of minimally invasive gynecology the use of electrosurgical or energy-based devices has become extremely important for rapid preparation and short reconvalescence. The instruments that are on the market vary regarding their technical characteristics, specifications, and handling. We provide an overview of selected instruments that are appropriate for gynecological laparoscopy and review possible indications and limitations. PMID- 25433177 TI - Second-Generation Annealed Highly Crosslinked Polyethylene has Low Wear at Mean Seven Year Follow-up. AB - First-generation once annealed highly crosslinked polyethylene (HXLPE) has perfomed well for over 10 years but the presence of free radicals remain a concern. A second-generation sequentially annealed HXLPE was developed to further reduce wear, maintain mechanical strength, and enhance oxidative resistance. PMID- 25433179 TI - The effect of aging on the center-of-pressure power spectrum in foam posturography. AB - To assess age-related frequency-domain characteristics of the sway of center of pressure (COP) in foam posturography, two-legged stance tasks were performed by 163 controls in 4 conditions: eyes open with and without foam rubber, and eyes closed with and without foam rubber. The areas under the curve (AUCs) of power spectral density of the COP were calculated across low frequency (>=0.02 Hz and <0.1 Hz, LF-AUC), middle frequency (>=0.1 Hz and <1 Hz, MF-AUC) and high frequency (>=1 Hz and <10 Hz, HF-AUC) ranges. We categorized the controls into 7 age groups and analyzed each AUC in the 4 conditions. MF- and HF-AUCs tended to show a difference between younger and older age-groups in all 4 conditions. Comparing the number of pairs in which a significant difference was shown, the condition with foam rubber, especially with eyes open, tended to highlight age related changes. In the medial-lateral axis in the eyes open/foam rubber condition, the MF-AUC of the >= 75 years group was significantly larger than that of the 65-74 years group, and the MF-AUC of the 65-74 years group was significantly higher than that of the 55-64 years group, although there were no significant differences of MF-AUC among age groups under 54 years. In this condition, although HF-AUC did not change in groups over 35 years old, HF-AUC of each age group over 35 years old was significantly larger than that of the group under 24 years old. This result suggests that, in the medial-lateral axis in the eyes open/foam rubber condition, MF-AUC is specifically affected by age in late middle-aged (ages 55-64) and older subjects, while HF-AUC is specifically affected by age in early-middle-aged (ages 35-44) subjects. PMID- 25433178 TI - Structural and physiochemical characterization of rhamnolipids produced by Acinetobacter calcoaceticus, Enterobacter asburiae and Pseudomonas aeruginosa in single strain and mixed cultures. AB - Rhamnolipids are naturally occurring biosurfactants with a wide range of potential commercial applications. As naturally derived products they present an ecological alternative to synthetic surfactants. The majority of described rhamnolipid productions are single strain Pseudomonas spp. cultivations. Here we report rhamnolipids producing bacteria Acinetobacter calcoaceticus, Enterobacter asburiae and Pseudomonas aeruginosa that were cultivated separately and as mixed populations. The ratio and composition of rhamnolipid congeners was determined by tandem mass spectrometry with negative electrospray ionization. Mono-rhamnolipid and di-rhamnolipid homologues containing one or two saturated or monounsaturated 3-hydroxy fatty acids were found in all strains. Physiochemical characterization of rhamnolipids was evaluated by the critical micelle concentration determination, the emulsification test, oil displacement test and phenanthrene solubilization. Critical micelle concentrations of rhamnolipids produced by both single strain and mixed cultures were found to be very low (10-63 mg/l) and to correspond with saturated/unsaturated fatty acid content of rhamnolipid homologues. The rhamnolipids produced by all strains effectively emulsified crude petroleum in comparison with synthetic surfactants Tween 80 and sodium dodecyl sulfate (SDS). Good performance of phenanthrene solubilization was exhibited by rhamnolipids from E. asburiae. The single strain and co-cultures cultivations were proposed as a possible way to produce rhamnolipid mixtures with a specific composition and different physiochemical properties, which could be exploited in bioremediation of various hydrophobic contaminants. PMID- 25433181 TI - Published research in all its glory or lack thereof. PMID- 25433180 TI - Effects of clonidine and methylphenidate on motor activity in Fmr1 knockout mice. AB - Fragile X syndrome (FXS), a disorder caused by a mutation in the FMR1 gene, is often associated with Attention Deficit Hyperactivity Disorder (ADHD). Common treatments for the hyperactivity often seen in ADHD involve the use of stimulants and alpha2-adrenergic agonists. The Fmr1 knockout (KO) mouse has been found to be a valid model for FXS both biologically and behaviorally. Of particular interest to our research, the Fmr1 KO mouse has been demonstrated to show increased locomotion in comparison to wild type (WT) littermates. In the present study, we assessed the effects of clonidine (0.05 mg/kg) and methylphenidate (5 mg/kg) on motor activity in Fmr1 KO mice and their WT littermates in the open field test. Results showed that methylphenidate increased motor activity in both genotypes. Clonidine decreased motor activity in both genotypes, but the effect was delayed in the Fmr1 KO mice. PMID- 25433182 TI - Value and challenges of research on health professions' core subjects in education. AB - Professions are organized around central concerns, or core subjects. Knowledge of a field's core subject is indispensable to effective practice, reasoning, and professional identity. In health professions education, however, core subjects are often obscured by the plethora of topics and skills that must be taught, rendering them largely implicit in the learning process. Core subjects and how they are addressed in curricula thus remain under-researched in health professions education. The scarcity of research can be attributed to the need for (1) explicating core subjects as the basis for learning, (2) language that describes professional education as connecting all learning to a field's core, and (3) research methods that go beyond early phases of research development, including a conceptual framework for understanding and studying core subjects. This paper presents strategies addressing each of these challenges that were developed through a pilot and a subsequent large national study of occupational therapy education. These strategies provide a foundation for dialogue and future research on the nature and function of core subjects in health professions education. PMID- 25433183 TI - Impact on physical therapy and audiology students of an interprofessional case based learning experience in education of vestibular disorders. AB - Vestibular disorders are quite common and can cause significant disability. Diagnosis and treatment of these disorders is very complex, requiring multidisciplinary input including physical therapy (PT) and audiology (AUD). The purpose of this research was to determine if an interprofessional educational experience between the PT and AUD students will increases the students' confidence in their knowledge of the role of the other discipline, circumstances which would require referral to the other discipline, and communication with individuals from the other discipline. PT and AUD students were divided into small groups and worked through an unfolding case. A paper-and-pencil survey was utilized to evaluate the effectiveness of the experience. Mann-Whitney U-tests demonstrated no significant difference between the confidence levels of PT and AUD students pre-test and post-test. Wilcoxon signed ranks tests demonstrated statistically significant gains in confidence levels on all items from pre-test to posttest. The authors attribute these gains to interprofessional collaboration, case-based learning, and discipline- specific facilitation. In the future, this exercise would benefit from additional disciplines. The outcomes strengthen the research that interprofessional education and case-based learning are effective methods of education. This should lead to increased communication in clinical settings and ultimately improved patient outcomes. PMID- 25433184 TI - Applying social cognitive career theory to registered dietitian research involvement: a randomized controlled trial. AB - The purpose of this study was to measure the effect of a social cognitive career theory (SCCT)-based educational intervention combined with an evidence-based practice (EBP) continuing professional education (CPE) program (standard-plus group) as compared to the EBPCPE program alone (standard group) and a no treatment control on research outcome constructs (research self-efficacy, research outcome expectations, research interest and research involvement) in dietitians. METHODS: This randomized controlled trial measured the effect of an online 14-week educational intervention, with measurements made pre- and post intervention and at 3-month follow-up. A randomly selected list of registered dietitians (RDs), who reported clinical nutrition as their primary practice area, was obtained from the Commission on Dietetic Registration. Subjects (n=580) were randomly assigned to three study groups, and 47.2% (n=272) completed data collection. RESULTS: The treatment effect between the groups was significantly different for research self-efficacy (p<0.001) and research involvement (p=0.005), with positive effects observed in the standard-plus and standard groups. There were no significant effects for research outcome expectations and research interest. CONCLUSIONS: This is the first known application of SCCT to RD research involvement as a career-related behavioral outcome, and it demonstrated that a significant increase in research self-efficacy occurs following participation in an educational intervention on EBP. PMID- 25433185 TI - Promoting health, wellness, and quality of life at the end of life: hospice interdisciplinary perspectives on creating a good death. AB - The purpose of this phenomenological study was to answer the broad questions: what do professional caregivers for the dying think about what they do, and how does that thinking influence their practice in end-of-life care? The participants were 12 hospice professionals working in four specific disciplines: occupational therapy, physical therapy, social work, and nursing. In-depth interviews were conducted and audiotaped, and transcripts were printed. Constant comparison and thematic analysis was performed. One overarching theme and five subthemes were generated. The central theme, "promoting a good death," emerged from the data, as the participants continually discussed health, wellness, and quality-of-life work in which they engaged that were discipline-specific yet overlapping. The subthemes that emerged were: holism; framing and re-framing practice; client- and family-centered care; being with dying; and interdisciplinary team. All participants concluded that their work emanated from a health and wellness lens, and that quality of life at the end of life was their ultimate goal. Quality of life, for each discipline, included doing, being, and becoming one's authentic self until the end of life. PMID- 25433186 TI - A preliminary qualitative exploration of dietitians' engagement with genetics and nutritional genomics: perspectives from international leaders. AB - This qualitative study explored the underlying determinants of dietitians' current practice and attitudes about nutritional genomics. METHODS: Sixteen semi structured interviews were conducted with international leaders selected across each domain of dietetics practice from Australia (n=8) and the United Kingdom (n=8). Interviews explored knowledge, involvement, perceived role, and attitudes about the benefits and barriers of genetics and nutritional genomics. Interviews were transcribed and analysed using thematic analysis. RESULTS: Five key themes were identified: (i) acknowledgment that there are wide applications for nutritional genomics; (ii) a general lack of awareness of nutritional genomics that underlies a knowledge, skills, and confidence gap; (iii) dietitians are patient-orientated and thus are receptive to the public's needs; (iv) the legitimacy of commercialised nutritional genomics products and services; and (v) prioritisation of nutritional genomics amongst other practice-related commitments as well as the influence of the workplace setting. CONCLUSIONS: In order for healthcare services to prepare for the application of nutritional genomics, these social, political, attitudinal, and awareness issues amongst dietitians need to be addressed. Further education in nutritional genomics may help to build awareness, continued research is crucial in determining utility, whilst establishing a healthcare system that supports and rewards this approach may cultivate its adoption. PMID- 25433187 TI - Mobility and gait outcomes following intensive rehabilitation, onabotulinumtoxin A, and baclofen treatment chronic post-stroke: a case report. AB - PURPOSE. This case report describes the effects of intensive rehabilitation with systemic antispasticity and local neurotoxin pharmacological interventions on gait and activity outcomes for a patient with chronic impairments post-stroke. CASE DESCRIPTION. The 56-year-old male patient was 13 months post-stroke with left hemiparesis and hypertonicity in the left upper and lower extremities. The patient received oral baclofen for widespread hypertonicity and intramuscular onabotulinumtoxin A injections in muscles of the left upper and lower extremities to target local areas of hypertonicity. The patient received weight-supported treadmill training, over-ground gait training, neuromuscular re-education, and balance training three times per week during 20 of the 25 weeks of the study period. OUTCOMES. The patient demonstrated improvements in balance (Berg Balance Scale), mobility (Timed Up and Go test), and motor function (Stroke Rehabilitation Assessment of Movement Measure). Kinematic measures of gait also improved in ankle and knee range of motion during both stance and swing phases. DISCUSSION. This case demonstrates that improvements in impairment and activity outcomes can occur in an individual with significant post-stroke chronic impairments after receiving intensive physical therapy in conjunction with pharmacologic interventions to control hypertonicity. The persistence and generalizability of these results need to be determined. PMID- 25433188 TI - Relating admissions criteria to dental hygiene student retention. AB - PURPOSE. The purpose of this study was to identify preadmission variables that relate to dental hygiene student retention. METHODS. An online survey was sent by email to 309 dental hygiene chairs/program directors. The survey comprised 18 questions to collect program demographic information, program admissions requirements, and program student retention rates. RESULTS. There were 139 respondents who participated in the survey for a 45% return rate. The mean for program retention of participating accredited dental hygiene programs was 91%. Stepwise regression analysis discovered three independent variables (aE=0.15) that relate to dental hygiene program retention rates. These independent variables include interviews (p=0.054), overall college GPA (p=0.029), and overall high school GPA (p=0.141). CONCLUSION. Preadmission requirements that include overall high school GPA, overall college GPA, and interviews can be used by admissions committees to predict dental hygiene student retention. PMID- 25433189 TI - Factors associated with HPV vaccine use among Hispanic college students. AB - Human papillomavirus (HPV) infection is the most common sexually transmitted disease in the United States and is linked strongly to cervical cancer. Hispanic women are at increased risk of cervical cancer from HPV due to lower screening rates with women in their early 20s at increased risk. PURPOSE: The purpose of this project was to describe HPV vaccination rates and possible barriers to vaccination among a sample of U.S. collegeaged Hispanic women. METHODS: A secondary analysis of the American College Health Association's National College Health Assessment was completed to determine HPV vaccine rates and factors influencing vaccine use among college-aged Hispanic women (n=4,718). Descriptive statistics were calculated and binary logistic regression employed to determine the association of various socioeconomic and health-seeking behaviors on HPV vaccine utilization. RESULTS: Only 46.2% of Hispanic women in the NCHA reported receiving an HPV vaccine. Binary logistic regression analysis indicates that having health insurance, use of preventive care, and good health status are significantly associated with HPV vaccine use. DISCUSSION: Hispanic college women ages 18-26 demonstrated lower HPV vaccination rates as compared to Caucasian women. Tailoring health promotion activities to specific racial populations such as Hispanic women is necessary to decrease disparities in HPV vaccination rates. The fact that racial/ethnic minority women in the U.S. have lower HPV vaccination rates and gynecological exam rates indicates that specialized health promotion activities may be an avenue for designing educational strategies to lessen disparities. PMID- 25433190 TI - The effect of the graduate record examination on minority applications: experience at New York Institute of Technology. AB - PURPOSE: The purpose of this study is to determine if requiring the graduate record exam (GRE) had an effect on minority applications submitted to New York Institute of Technology's (NYIT) physician assistant (PA) program. METHODS: Minorities applying from 2008-2011 were identified by the Central Application Service for Physician Assistants (CASPA). Data was obtained from two application cycles before and after the GRE was made an admissions requirement. Data was analyzed using descriptive statistics. RESULTS: Despite the CASPA pool of minority applicants remaining stable NYIT's pool of Black/African American applicants decreased substantially from 8.6% to 4.8% after the GRE was added to our admissions criteria. This resulted in a 44.1% decrease in NYIT's pool of Black/African American applicants. CONCLUSION: Adopting the GRE as part of our admissions criteria appears to have created an additional barrier for minority applicants, specifically Black/African American applicants. Every program should question whether or not the benefit of the GRE as an academic predictor outweighs the negative effect it may have on their program's minority application pool. Using the GRE as part of the admissions process appears to be a potential barrier and may result in greater ethnic disparity as more programs adopt its use. PMID- 25433191 TI - Evaluation of physician assistant student knowledge and perception of competence in palliative symptom management. AB - PURPOSE: To assess the impact of the current curriculum for physician assistant (PA) students in palliative medicine and end-of-life care. METHODS: PA students were invited to participate in an anonymous online survey evaluating seven domains of knowledge in palliative medicine coupled with a self-assessment in competence. Participants were also asked to identify current and desired educational formats in palliative medicine education. There were 1,313 emailed surveys with 139 total responses. RESULTS: Our results demonstrate that a year of clinical training only resulted in minimal improvement in factual knowledge. This suggests that there is insufficient exposure to palliative medicine education during their clinical training. CONCLUSION: PA students recognize their knowledge gaps and lack of exposure in palliative medicine. A more focused curriculum is needed in training experiences for PA students. PMID- 25433192 TI - A comparison of student outcomes in a physical therapy neurologic rehabilitation course based on delivery mode: hybrid vs traditional. AB - BACKGROUND: Physical therapy (PT) educators have been charged by the American Physical Therapy Association's Vision 2020 with the aim of developing critically reflective knowledge about teaching and learning using innovative teaching methods. Computer-assisted learning (CAL) affords the opportunity to supplement face-to-face teaching methods. The purpose of this study was to compare student performance and preferred instruction mode between a hybrid model using CAL modules and a traditional lecture-based model. METHODS: The posttest-only control design used mixed methods to assess two successive student cohorts (2011 and 2012). Cohort 1 was instructed using only traditional teaching methods of lecture and laboratory experiences, while Cohort 2 was taught using both traditional teaching methods and the CAL modules created for 10 content areas. Students viewed each CAL module after the in-class lecture, prior to the corresponding laboratory. Student performance was assessed with weekly 10-question quizzes. One minute papers and focus group discussions were administered to Cohort 2 to gauge satisfaction and perceptions of the CAL modules. RESULTS: Results revealed that the mean quiz grades for Cohort 2 were higher than those for Cohort 1, 86.1 vs 80.4. When comparing final exam grades and final grades for the course between groups, a statistically significant difference exists with the final exam grade, p<0.01. DISCUSSION: It appears that the CAL modules were useful to supplement this course content. Innovative, interactive, and varied teaching methodologies will serve to better engage students as lifelong learners. PMID- 25433193 TI - The efficacy of self-directed modules for clinical learning: advanced competencies in entry-level physical therapy education. AB - BACKGROUND: Prior to graduation, students often express an interest to advance clinical and professional skills in teaching, research, administration, and various niche practice areas. The acquisition of advanced education in selected areas of practice is believed to improve employment opportunities, accelerate career advancement including eligibility for professional certifications, and contribute to personal satisfaction in the profession. PURPOSE: The purpose of this paper is to (1) describe an innovative model of education, the Directed Practice Experience (DPE) elective, that incorporates a student-initiated learning process designed to achieve student-identified professional goals, and (2) report the outcomes for graduates who have completed the DPE in an entry level program in physical therapy education. METHODS: Students who met select criteria were eligible to complete a DPE. Applicants designed a 4- to 6-week clinical education experience consisting of stated rationale for personal and professional growth, examples of leadership and service, and self-directed objectives that are beyond entry-level expectations as measured by the revised Physical Therapist Clinical Performance Instrument, version 2006. RESULTS: Twenty six students have completed DPEs since 2005. Fifty percent resulted in new academic partnerships. At least 25% of graduates now serve as clinical instructors for the entry-level program. Those who participated in DPEs have also completed post-graduate residencies, attained ABPTS Board certifications, authored peer-reviewed publications, and taught in both PT and residency programs. CONCLUSION: The DPE model allows qualified students to acquire advanced personal skills and knowledge prior to graduation in areas of professional practice that exceed entry-level expectations. The model is applicable to all CAPTE accredited physical therapy education programs and is especially beneficial for academic programs desiring to form new community partnerships for student clinical education. PMID- 25433194 TI - Urokinase type plasminogen activator mediates Interleukin-17-induced peripheral blood mesenchymal stem cell motility and transendothelial migration. AB - Mesenchymal stem cells (MSCs) have the potential to migrate toward damaged tissues increasing tissue regeneration. Interleukin-17 (IL-17) is a proinflammatory cytokine with pleiotropic effects associated with many inflammatory diseases. Although IL-17 can modulate MSC functions, its capacity to regulate MSC migration is not well elucidated so far. Here, we studied the role of IL-17 on peripheral blood (PB) derived MSC migration and transmigration across endothelial cells. IL-17 increased PB-MSC migration in a wound healing assay as well as cell mobilization from collagen gel. Concomitantly IL-17 induced the expression of urokinase type plasminogen activator (uPA) without affecting matrix metalloproteinase expression. The incremented uPA expression mediated the capacity of IL-17 to enhance PB-MSC migration in a ERK1,2 MAPK dependent way. Also, IL-17 induced PB-MSC migration alongside with changes in cell polarization and uPA localization in cell protrusions. Moreover, IL-17 increased PB-MSC adhesion to endothelial cells and transendothelial migration, as well as increased the capacity of PB-MSC adhesion to fibronectin, in an uPA-dependent fashion. Therefore, our data suggested that IL-17 may act as chemotropic factor for PB-MSCs by incrementing cell motility and uPA expression during inflammation development. PMID- 25433195 TI - Mathematical modelling of p53 basal dynamics and DNA damage response. AB - The p53 tumour suppressor protein is a transcription factor that activates genes that result in cell cycle arrest, DNA damage repair, senescence or apoptosis. Recent individual cell studies have indicated that p53 activation is highly regulated in response to stressed conditions and non-stressed (normal proliferating) conditions in cells. The aim of this research is to investigate the design principles behind the precise regulation of p53 activation, under normal and stressed conditions. We extended the Sun et al. (2011) mathematical model of delay differential equations by incorporating the most recently found molecular interactions and hypotheses. In particular, we found that the core regulatory network consists of ATM, Mdm2, MdmX, Wip1 and p53. Our model of the p53 core regulatory feedback mechanisms can reproduce a series of repeated pulses in stressed conditions with appropriate induction of cell cycle arrest, and one or two spontaneous pulses (basal dynamics) in non-stressed conditions and these are consistent with the recent experimental findings. Our results show that the p53 spontaneous pulses are due to intrinsic DNA double strand breaks in normal proliferating cells, and p53 auto-regulation (positive feedback loop) allows threshold activation of p53 in generating these pulses. It also shows that the p53 dynamics are excitable; bifurcation analysis revealed a spectrum of p53 behaviour under stressed and non-stressed (normal) conditions on the basis of stress signal activation rate, and characterised p53 dynamics as Type II excitability. Additionally, the model makes testable predictions on pharmacological intervention to reactivate p53. Importantly, we reveal novel findings on the mechanism of threshold activation of p53 pulsatile and oscillatory dynamics that are important for its physiological function as the guardian of the genome. PMID- 25433196 TI - Modeling the effect of insulin-like growth factor-1 on human cell growth. AB - Insulin-like growth factor-1 (IGF-1) plays a key role in human growth and development. The interactions of IGF-1 with IGF-1 receptors and IGF-1 binding proteins (IGFBPs) regulate IGF-1 function. Recent research suggests that a metabolite of IGF-1, cyclo-glycyl-proline (cGP), has a role in regulating IGF-1 homeostasis. A component of this interaction is believed to be the competitive binding of IGF-1 and cGP to IGFBPs. In this paper we describe a mathematical model of the interaction between IGF-1 and cGP on human cell growth. The model can be used to understand the interaction between IGF-1, IGFBPs, cGP and IGF-1 receptors along with the kinetics of cell growth. An explicit model of the known interactions between IGF-1, cGP, IGFBPs, IGF-1 receptors explained a large portion of the variance in cell growth (R(2) = 0.83). An implicit model of the interactions between IGF-1, cGP, IGFBPs, IGF-1 receptors that included a hypothesized feedback of cGP on IGF-1 receptors explained nonlinear features of interaction between IGF-1 and cGP not described by the explicit model (R(2) = 0.84). The model also explained the effect of IGFBP antibody on the interaction between cGP and IGF-1 (R(2) = 0.78). This demonstrates that the competitive binding of IGF-1 and cGP to IGFBPs plays a large role in the interaction between IGF-1 and cGP, but that other factors potentially play a role in the interaction between cGP and IGF-1. These models can be used to predict the complex interaction between IGF-1 and cGP on human cell growth and form a basis for further research in this field. PMID- 25433197 TI - Hepatic involvement in IgG4-related disease: IgG4-hepatopathy and IgG4-autoimmune hepatitis. PMID- 25433198 TI - Properties of polidocanol foam in view of its use in sclerotherapy. AB - Foam sclerotherapy is a widely used method to treat varicose veins disease. It is easy to use and apply, affordable, and has high efficiency that depends on foam stability upon injection. Since sclerotherapy is usually applied in a medical doctor's office, one of the most employed methods to generate foam is based on the Tessari technique which uses pumping cycles of liquid and air in-and-out of a double syringe system. Finally, the produced foam exits through a small orifice (~2mm) at the output of a three-way valve. The present work shows results regarding the factors that may influence foam stability (liquid to air ratio, type of connector, syringe diameter, number of pumping cycles, etc.) of a commonly used sclerosing agent (polidocanol). Furthermore, an effort is made to evaluate the effect of adding different substances on the stability of polidocanol foams (0.5% w/w) by altering the surface tension or/and the bulk and interfacial rheological properties of the fluids. It is shown that adding small concentrations of nonionic surfactants can increase foam stability with just a very small variation of the mean bubbles size. PMID- 25433199 TI - Gene delivery efficiency and intracellular trafficking of novel poly(allylamine) derivatives. AB - Non-viral gene carriers for safe and efficient gene transfection have become of particular interest among researchers of different disciplines ranging from physical chemistry to biotechnology. Recently polymeric vectors have been extensively studied as potentially new gene transfer agents. Until now most of the research efforts were made to optimize the gene-to-polymer weight ratio of polyplexes for safe and efficient gene transfection. In this work, we report on the development of novel poly(allylamine) derivatives with different balance of the primary, secondary, tertiary, and quaternary amino groups. All derivatives were able to complex pDNA into polyplexes at low gene-to-polymer weight ratios i.e., 1:1 or 1:2. Moreover, the examined polyplexes were less cytotoxic and showed better transfection efficiency when compared to linear poly(ethyleneimine). These results indicate that the presence of quaternary ammonium groups is important in the formation of stable polyplexes. Polymers with all types of amino groups showed large potential for gene delivery. Furthermore, polyplexes with such derivatives were well internalized by cells and ended up into acidic late endosomes. PMID- 25433200 TI - Relationships between surface free energy, surface texture parameters and controlled drug release in hydrophilic matrices. AB - The study of controlled release and drug release devices has been dominated by considerations of the bulk or average properties of material or devices. Yet the outermost surface atoms play a central role in their performance. The objective of this article has been to characterize the surface of hydrophilic matrix tablets using the contact angle (CA) method to ascertain the surface free energy, and atomic force microscopy (AFM) and confocal microscopy (CM) for the physical characterization of the surface of the hydrophilic matrix. The surface free energy results obtained show that hydroxypropylmethylcellulose K15M hinders the spreading of water on the surface of the tablet, such that the concentration of HPMC K15M increases the reaction rate of the hydrophobic interactions between the chains of HPMC K15M which increases with respect to the rate of penetration of water into the tablet. In this study, we developed a new method to characterize the swelling of the tablets and established a relationship between the new method based on microswelling and the swelling ratio parameter. The surface texture parameters have been determined and the morphology of the tablets of the different formulations and the evolution of the surface morphology after interacting with the water, swelling and forming a gel layer were characterized. This work represents significant progress in the characterization of matrix tablets. PMID- 25433201 TI - Gemcitabine and gamma-cyclodextrin/docetaxel inclusion complex-loaded liposome for highly effective combinational therapy of osteosarcoma. AB - The aim of the present investigation was to formulate a docetaxel (DTX) and gemcitabine (GEM) co-loaded PEGylated liposome (DTX/GEM-L) to increase the therapeutic efficacy in osteosarcoma (OS). 2-Hydroxypropyl-gamma-cyclodextrin/DTX inclusion complex was made to increase DTX aqueous solubility. DTX/GEM-L was characterized for morphological shape and size parameters. Release study showed a sustained release pattern for both the drugs. The nanocarriers based combinational drug significantly increased the cytotoxic effect than the free drug combination at the same concentration. The cell cycle analysis showed a predominant G2/M phase arrest for combinational drug. Importantly, more than 20% of cells were in late apoptosis chamber for DTX/GEM-L treatment with significant proportion of cells in the early apoptosis and necrotic phases. The antitumor efficacy was tested in MG63 cancer cell bearing xenograft nude mice. Results showed that DTX/GEM-L significantly reduced the tumor burden comparing to that of free combination cocktail. The PEGylated liposome successfully delivered the anticancer drugs in the osteosarcoma tumor interstitial spaces via EPR effect. DTX/GEM-L showed excellent safety profile along with the remarkable tumor suppression ability. Overall, results suggest that nanocarriers-based delivery system remarkably enhanced the apoptosis and cytotoxicity and increased the potency of combinational drug regimen. PMID- 25433202 TI - Rationale and design: impact of intravascular ultrasound guidance on long-term clinical outcomes of everolimus-eluting stents in long coronary lesions. AB - BACKGROUND: Although the use of drug-eluting stents (DESs) in patients with coronary artery disease has contributed to a significant reduction in in-stent restenosis and repeat revascularization, treating diffuse long lesions using DESs remains challenging due to the high rates of in-stent restenosis and stent thrombosis. Intravascular ultrasound (IVUS) provides tomographic images of coronary vascular structure and is useful for evaluating lesion morphology and stent optimization during percutaneous coronary intervention. However, it remains controversial whether IVUS guidance in DES implantation for long coronary lesions could reduce adverse clinical outcomes. HYPOTHESIS: We hypothesize that the long term clinical outcomes of IVUS-guided DES implantation would be superior to those of angiography-guided DES implantation in a subset of patients with long coronary lesions. STUDY DESIGN: This study is a randomized, prospective, multi-center trial comparing the long-term clinical outcomes of IVUS-guided and angiography guided everolimus-eluting stent implantation in patients with long coronary lesions (implanted stent >=28 mm in length). The primary end point is a composite of major adverse cardiac events, including cardiac death, target lesion-related myocardial infarction, or target lesion revascularization at 1 year following intervention. A total of 1,400 patients will be required to be enrolled according to sample size calculations. CONCLUSION: This study will test the hypothesis that IVUS guidance improves long-term clinical outcomes in patients treated with everolimus-eluting stents for long coronary lesions compared with angiographic guidance. PMID- 25433204 TI - Impact of maternal diabetes mellitus on mortality and morbidity of very low birth weight infants: a multicenter Latin America study. AB - OBJECTIVES: To compare mortality and morbidity in very low birth weight infants (VLBWI) born to women with and without diabetes mellitus (DM). METHODS: This was a cohort study with retrospective data collection (2001-2010, n=11.991) from the NEOCOSUR network. Adjusted odds ratios and 95% confidence intervals were calculated for the outcome of neonatal mortality and morbidity as a function of maternal DM. Women with no DM served as the reference group. RESULTS: The rate of maternal DM was 2.8% (95% CI: 2.5-3.1), but a significant (p=0.019) increase was observed between 2001-2005 (2.4%, 2.1-2.8) and 2006-2010 (3.2%, 2.8-3.6). Mothers with DM were more likely to have received a complete course of prenatal steroids than those without DM. Infants of diabetic mothers had a slightly higher gestational age and birth weight than infants of born to non-DM mothers. Distribution of mean birth weight Z-scores, small for gestational age status, and Apgar scores were similar. There were no significant differences between the two groups regarding respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, and patent ductus arteriosus. Delivery room mortality, total mortality, need for mechanical ventilation, and early-onset sepsis rates were significantly lower in the diabetic group, whereas necrotizing enterocolitis (NEC) was significantly higher in infants born to DM mothers. In the logistic regression analysis, NEC grades 2 3 was the only condition independently associated with DM (adjusted OR: 1.65 [95% CI: 1.2 -2.27]). CONCLUSIONS: VLBWI born to DM mothers do not appear to be at an excess risk of mortality or early morbidity, except for NEC. PMID- 25433203 TI - Motivators and barriers to Latinas' participation in clinical trials: the role of contextual factors. AB - OBJECTIVE: Latinas are underrepresented in clinical trials despite the rise in Hispanic population. This study examines the factors associated with Latinas' willingness to participate in preventive breast cancer randomized clinical trials (RCTs). METHODS: Women self-identifying as Latina, over age 40, with no prior history of breast cancer were eligible. Using the Behavior Model for Vulnerable Populations, we administered a survey (n=168) to assess predisposing (e.g., knowledge), enabling (e.g., trust) and need factors (e.g., risk perception). Intention to participate was defined using a lenient (maybe, probably or definitely) and a stringent criterion (probably and definitely). Chi-square tests and logistic regression models examined the associations of predisposing, enabling, and need factors with women's intentions to participate in RCTs. RESULTS: Most participants (74.9%) were monolingual Spanish-speaking immigrants. Most (83.9%) reported willing to participate in clinical trials using the lenient definition (vs. 43.1% under the stringent definition). Using the lenient definition, the odds of willing to participate in RCTs were significantly lower for unmarried women (OR=.25, 95% CI=.08-.79) and those with lower cancer risk perceptions (OR=.20, 95% CI=.06-.63), while being significantly higher for women with lower language acculturation (OR=6.2, 95% CI=1.8-20.9). Using the stringent definition, women who did not endorse a motivation to enroll to help family members (if they had cancer) had significantly lower odds to report intent (OR=.33, 95% CI=.13-.86). CONCLUSION: Many RCTs may have limited generalizability due to the low representation of minorities. Culturally targeted interventions that address the importance of family for Latinos may ultimately increase their participation in RCTs. PMID- 25433205 TI - Paracrine control of steroidogenesis by serotonin in adrenocortical neoplasms. AB - Serotonin (5-hydroxytryptamine; 5-HT) is able to activate the hypothalamo pituitary-adrenal axis via multiple actions at different levels. In the human adrenal gland, 5-HT, released by subcapsular mast cells, stimulates corticosteroid production through a paracrine mode of communication which involves 5-HT receptor type 4 (5-HT4) primarily located in zona glomerulosa. As a result, 5-HT is much more efficient to stimulate aldosterone secretion than cortisol release in vitro and administration of 5-HT4 receptor agonists to healthy individuals is followed by an increase in plasma aldosterone levels without any change in plasma cortisol concentrations. Interestingly, adrenocortical hyperplasias and tumors responsible for corticosteroid hypersecretion exhibit various cellular and molecular defects which tend to reinforce the intraadrenal serotonergic tone. These pathophysiological mechanisms, which are summarized in the present review, include an increase in adrenal 5-HT production and overexpression of 5-HT receptors in adrenal neoplastic tissues. Altogether, these data support the concept of adrenal serotonergic paracrinopathy and suggest that 5-HT and its receptors may constitute valuable targets for pharmacological treatments of primary adrenal diseases. PMID- 25433206 TI - Estrogen receptors in breast carcinogenesis and endocrine therapy. AB - Excessive exposure to estrogen has long been associated with an increased risk for developing breast cancer and anti-estrogen therapy is the gold standard of care in the treatment of estrogen receptor (ER) alpha-positive breast cancers. However, there are several mysteries concerning both anti-estrogen, tamoxifen, and estrogen. The most important of these are: (1) some ERalpha-positive breast cancers do not respond to tamoxifen; (2) some ERalpha-negative breast cancers do respond to tamoxifen; (3) initial or acquired resistance to tamoxifen occurs with recurrent tumors; (4) estrogen can cause marked tumor regression in long-term tamoxifen-resistant ERalpha-positive breast cancer. These mysteries indicate that we do not know enough about estrogen signaling to understand the effects of targeting these receptors in cancer. The discovery of ERbeta, the second estrogen receptor, has added another level of complexity to estrogen signaling. This review summarizes recent publications and makes an updated portrait of ERalpha and ERbeta in breast carcinogenesis and endocrine cancer therapy. PMID- 25433208 TI - Structural foundation for DNA behavior in hydrated ionic liquid: An NMR study. AB - A well known rule of high thermal stability of GC-rich DNA helices can be reversed with the use of certain ions, rendering AT-rich duplexes more stable. We have sought to elucidate the structural basis of this phenomenon for choline dihydrogen phosphate, an ionic liquid known for extension of long-term chemical stability of biomolecules. NMR experiments complemented with CD spectroscopy revealed subtle changes of GC and AT-rich double helix structures in choline dihydrogen phosphate compared to NaCl solution. Chemical shift changes observed for different environments were used as a guide to determine choline ions' localization hotspots. For d(5'-AAATATATTT-3') choline ions are localized in the central part, especially in the minor groove near sugar protons of thymidine and H2 protons of adenine residues. In agreement with NMR data, thermodynamic analysis points to the involvement of choline ions in the hydration network as a crucial part of thermal stabilization of AT-rich helices. Analysis for GC-rich d(5'-GGGCGCGCCC-3') oligonucleotide showed preference of choline ions for major groove with less clearly defined localizations spots than in the case of its AT rich counterpart. PMID- 25433209 TI - Roles of ribosomal proteins in the functioning of translational machinery of eukaryotes. AB - Ribosomal proteins (rps) are constituents of ribosomal subunits together with the rRNAs, and the work of the ribosomes is based on highly cooperative interactions involving these biopolymers. Eukaryotic ribosomal subunits contain proteins that have bacterial counterparts as well as proteins specific only to eukaryotes and archaea and proteins unique to eukaryotes. Roles of eukaryotic rps in functioning of the translation machinery are studied in less detail than those of bacterial ones. However, application of various structural, biochemical and genetic approaches made it possible to obtain data suggesting implication of many particular eukaryotic rps in binding of participants of translation process (ribosomal ligands). Here we present a review on these data as well as their analysis aimed to reveal conserved and eukaryote-specific functions of eukaryotic rps in the work of translational machinery. PMID- 25433207 TI - Nf2-Yap signaling controls the expansion of DRG progenitors and glia during DRG development. AB - Molecular mechanisms governing the maintenance and proliferation of dorsal root ganglia (DRG) progenitors are largely unknown. Here we reveal that the Hippo pathway regulates the expansion of DRG progenitors and glia during mammalian DRG development. The key effectors of this pathway, transcriptional coactivators Yap and Taz, are expressed in DRG progenitors and glia during DRG development but are at least partially inhibited from activating transcription. Aberrant YAP activation leads to overexpansion of DRG progenitor and glial populations. We further show that the Neurofibromatosis 2 (Nf2) tumor suppressor inhibits Yap during DRG development. Loss of Nf2 leads to similar phenotypes as does YAP hyperactivation, and deleting Yap suppresses these phenotypes. Our study demonstrates that Nf2-Yap signaling plays important roles in controlling the expansion of DRG progenitors and glia during DRG development. PMID- 25433210 TI - New crystal structures of HSC-70 ATP binding domain confirm the role of individual binding pockets and suggest a new method of inhibition. AB - In recent years the chaperone HSC-70 has become a target for drug design with a strong focus in anticancer therapies. In our study of possible inhibitors of HSC 70 enzymatic activity we screened compounds by NMR as well as X-ray crystallography. As part of our screening efforts we crystallized the human HSC 70 ATP binding domain and obtained novel crystal forms in addition to known structures. The new crystal structures highlight the mobility of the entire domain previously described by NMR, which was linked to its chaperone activity but not yet demonstrated by X-ray crystallography. Conformational changes across the entire molecule have been elucidated in response to the binding of small molecule ligands and show a pattern of mobility consistent with postulated signal transduction modes between the nucleotide binding domain (NBD) and the substrate binding domain (SBD). In addition, two crystal structures contained glycerol bound at a new site. Binding studies performed with glycerol analogs proved inhibitory properties of the site, which were further characterized by isothermal calorimetry and in silico docking studies. The presence of two binding pockets enabled us to explore a novel method of inhibition by compounds that bridge the adjacent phosphate and glycerol binding sites. Finally, an example of such a bridged inhibitor is proposed. PMID- 25433213 TI - A microscale mathematical model for metabolic symbiosis: Investigating the effects of metabolic inhibition on ATP turnover in tumors. AB - Cancer cells are notorious for their metabolic adaptations to hypoxic and acidic conditions, and especially for highly elevated glycolytic rates in tumor tissues. An end product of glycolysis is lactate, a molecule that cells can utilize instead of glucose to fuel respiration in the presence of oxygen. This could be beneficial to those cells that do not have sufficient oxygen as it conserves glucose for glycolysis. To better quantify this phenomenon we develop a diffusion reaction mathematical model for nutrient concentrations in cancerous tissue surrounding a single cylindrical microvessel. We use our model to analyze the interdependence between cell populations' metabolic behaviors on a microscopic scale, specifically the emerging paradigm of metabolic symbiosis that exists between aerobic and glycolytic cells. The ATP turnover rates are calculated as a function of distance from the blood vessel, which exhibit a lactate-consuming population at intermediate distances from the vessel. We also consider the ramifications of the Warburg effect where cells utilize aerobic glycolysis along with this lactate-consuming respiration. We also investigate the effect of inhibiting metabolic pathways on cancer cells since insufficient ATP can trigger cell apoptosis. Effects that could be induced by metabolic inhibitors are analyzed by calculating the total ATP turnover in a unit tissue annulus in various parameter regimes that correspond to treatment conditions where specific metabolic pathways are knocked out. We conclude that therapies that target glycolysis, e.g. lactate dehydrogenase inhibitors or glycolytic enzyme inhibition, are the keys to successful metabolic repression. PMID- 25433212 TI - DR-BUDDI (Diffeomorphic Registration for Blip-Up blip-Down Diffusion Imaging) method for correcting echo planar imaging distortions. AB - We propose an echo planar imaging (EPI) distortion correction method (DR-BUDDI), specialized for diffusion MRI, which uses data acquired twice with reversed phase encoding directions, often referred to as blip-up blip-down acquisitions. DR BUDDI can incorporate information from an undistorted structural MRI and also use diffusion-weighted images (DWI) to guide the registration, improving the quality of the registration in the presence of large deformations and in white matter regions. DR-BUDDI does not require the transformations for correcting blip-up and blip-down images to be the exact inverse of each other. Imposing the theoretical "blip-up blip-down distortion symmetry" may not be appropriate in the presence of common clinical scanning artifacts such as motion, ghosting, Gibbs ringing, vibrations, and low signal-to-noise. The performance of DR-BUDDI is evaluated with several data sets and compared to other existing blip-up blip-down correction approaches. The proposed method is robust and generally outperforms existing approaches. The inclusion of the DWIs in the correction process proves to be important to obtain a reliable correction of distortions in the brain stem. Methods that do not use DWIs may produce a visually appealing correction of the non-diffusion weighted images, but the directionally encoded color maps computed from the tensor reveal an abnormal anatomy of the white matter pathways. PMID- 25433211 TI - Does degree of gyrification underlie the phenotypic and genetic associations between cortical surface area and cognitive ability? AB - The phenotypic and genetic relationship between global cortical size and general cognitive ability (GCA) appears to be driven by surface area (SA) and not cortical thickness (CT). Gyrification (cortical folding) is an important property of the cortex that helps to increase SA within a finite space, and may also improve connectivity by reducing distance between regions. Hence, gyrification may be what underlies the SA-GCA relationship. In previous phenotypic studies, a 3-dimensional gyrification index (3DGI) has been positively associated with cognitive ability and negatively associated with mild cognitive impairment, Alzheimer's disease, and psychiatric disorders affecting cognition. However, the differential genetic associations of 3DGI and SA with GCA are still unclear. We examined the heritability of 3DGI, and the phenotypic, genetic, and environmental associations of 3DGI with SA and GCA in a large sample of adult male twins (N = 512). Nearly 85% of the variance in 3DGI was due to genes, and 3DGI had a strong phenotypic and genetic association with SA. Both 3DGI and total SA had positive phenotypic correlations with GCA. However, the SA-GCA correlation remained significant after controlling for 3DGI, but not the other way around. There was also significant genetic covariance between SA and GCA, but not between 3DGI and GCA. Thus, despite the phenotypic and genetic associations between 3DGI and SA, our results do not support the hypothesis that gyrification underlies the association between SA and GCA. PMID- 25433214 TI - Spanish Validation of the Premie-Neuro Scale in Premature Infants. AB - This study was an observational cross-validation of a Spanish version of the Premie-Neuro, a neurological examination for preterm infants. A cross-cultural translation was used to generate a Spanish version of the scale. The results showed an internal consistency of 0.72 according to Cronbach's alpha coefficient. The intra-class coefficient of correlation for the overall scores was 0.78. Factor analysis provided evidence of construct validity. The Spanish version of the Premie-Neuro was found to be a reliable and valid instrument for evaluating neurological and physical statements for premature infants admitted to a neonatal intensive care unit. PMID- 25433215 TI - Post-stroke treatment with miR-181 antagomir reduces injury and improves long term behavioral recovery in mice after focal cerebral ischemia. AB - miR-181 has deleterious effects on stroke outcome, and reducing miR-181a levels prior to middle cerebral artery occlusion (MCAO) was shown previously to be protective. Here we tested the effect of post-ischemic treatment with miR-181a antagomir by intracerebroventricular and intravenous routes of administration on infarct size, neurological outcome, inflammatory response and long term behavioral outcome. Post-treatment with miR-181a antagomir significantly reduced infarction size, improved neurological deficits and reduced NF-kappaB activation, numbers of infiltrating leukocytes and levels of Iba1. Targets affected by miR 181a antagomir administered after stroke onset include BCL2 and X-linked inhibitor of apoptosis protein (XIAP). Post-treatment with miR-181a antagomir significantly improved behavioral outcome assessed by rotarod at one month. These findings indicate that post-treatment with miR-181a antagomir has neuroprotective effects against ischemic neuronal damage and neurological impairment in mice, and the protection is long lasting including recovery of motor function and coordination over one month. The ability to protect the brain with post-treatment with miR-181a antagomir with long lasting effect makes this a promising therapeutic target and may be an innovative and effective new approach for stroke therapy. PMID- 25433216 TI - Specific and cross-reactive immune response to oral Salmonella Typhi Ty21a and parenteral Vi capsular polysaccharide typhoid vaccines administered concomitantly. AB - BACKGROUND: Since protective efficacy of the current typhoid vaccines-oral whole cell Salmonella Typhi Ty21a and parenteral Vi-capsular polysaccharide preparation is not optimal, and no vaccines are available against paratyphoid or non typhoidal Salmonella (NTS) serotypes, new approaches deserve to be explored. The immunological mechanisms elicited by the two typhoid vaccines are mainly targeted against different structures. We studied whether these vaccines would enhance S. Typhi-specific immune response and cross-reactivity against other Salmonellae, if administered concomitantly. MATERIALS AND METHODS: Volunteers were immunized simultaneously with Ty21a and Vi vaccines (Ty21a+Vi group) or with either of the two singly (Ty21a and Vi groups). All volunteers were investigated for circulating specific and cross-reactive plasmablasts, identified by ELISPOT as IgA, IgG or IgM antibody-secreting cells (ASC) reactive with S. Typhi, S. Paratyphi A/B/C, or selected NTS serotypes (S. Enteritidis, S. Typhimurium). RESULTS: In the Ty21a+Vi group, no specific or cross-reactive plasmablasts were detected before vaccination. After vaccination, the number of S. Typhi-specific plasmablasts (878 ASC/10(6) PBMC, 95%CI 554-1201) proved higher than in the Ty21a (339 ASC/10(6) PBMC; p<0.001) and Vi (149 ASC/10(6) PBMC; p<0.001) groups. Likewise, cross-reactive responses in the Ty21a+Vi group were higher than in the Ty21a and Vi groups (Ty21a+Vi vs Ty21a: ASC against S. Paratyphi A/B, S. Enteritidis and S. Typhimurium p<0.05, against S. Paratyphi C p<0.01; Ty21a+Vi vs Vi: against S. Paratyphi C not significant, others p<0.0001). A gut-directed homing profile was seen among O antigen-specific and a systemic one among Vi antigen-specific plasmablasts. CONCLUSIONS: Concomitant administration of Ty21a and Vi vaccines is well tolerated and induces an additive immune response to the two vaccines. Thus it enhances the magnitude of both typhoid-specific plasmablast responses and those cross-reacting with paratyphoid and most important NTS serotypes. The data encourage concomitant use of Ty21 and Vi vaccines for those at risk. PMID- 25433217 TI - In vitro and in vivo replication of a chemically synthesized consensus genome of hepatitis B virus genotype B. AB - Hepatitis B virus (HBV) genotypes vary in their geographical distribution and virological features. Previous investigations have shown that HBV genotype B is a predominant HBV genotype in China. Studies on HBV concerning different isolates frequently meet the question about the HBV reference strain and its representativeness. Although HBV consensus sequences can be generated easily by sequence alignment, they may not exist in nature or could not usually be isolated from patient samples. Thus, the construction of a consensus HBV genome has been proposed. In this study, an HBV genotype B consensus sequence was established by comparing 42 full-length HBV genotype B sequences and the genome was generated by chemical synthesis. This consensus genome was fully replication competent by in vitro transfection into hepatoma cells. The plasmid pHBV1.3B carrying a 1.3* full length HBV consensus genome was hydrodynamically injected into Balb/c mice. HBsAg, anti-HBs, HBeAg, anti-HBe, and anti-HBc detection indicated expression and replication of this HBV genome in mice, similar to other HBV isolates. This approach represents a strategy to design and create consensus HBV genomes for future studies. PMID- 25433218 TI - Comparative detection of rotavirus RNA by conventional RT-PCR, TaqMan RT-PCR and real-time nucleic acid sequence-based amplification. AB - Rotavirus is one of the major viral pathogens leading to diarrhea. Diagnosis has been conducted by either traditional cultural, serological methods or molecular biology techniques, which include RT-PCR and nucleic acid sequence-based amplification (NASBA). However, their differences regarding accuracy and sensitivity remain unknown. In this study, an in-house conventional RT-PCR assay and more importantly, an in-house real-time NASBA (RT-NASBA) were established, and compared with a commercial TaqMan RT-PCR assay. The results showed that all of these methods were able to detect and distinguish rotavirus from other diarrhea viruses with a 100% concordance rate during the course of an evaluation on 20 clinical stool samples. However, RT-NASBA was much quicker than the other two methods. More importantly, the limit of detection of RT-NASBA could reach seven copies per reaction and was one to two logs lower than that of conventional RT-PCR and TaqMan RT-PCR. These results indicate that this in-house assay was more sensitive, and thus could be used as an efficient diagnosis tool for rotavirus. To the best of our knowledge, this is the first direct comparison among three different assays for the detection of rotavirus. These findings would provide implication for the rational selection of diagnosis tool for rotavirus. PMID- 25433219 TI - Improved cognitive performance following aerobic exercise training in people with traumatic brain injury. AB - OBJECTIVE: To examine cognitive function in individuals with traumatic brain injury (TBI) prior to and after participation in an aerobic exercise training program. DESIGN: Pre-post intervention study. SETTING: Medical research center. PARTICIPANTS: Volunteer sample of individuals (N=7) (age, 33.3+/-7.9y) with chronic nonpenetrating TBI (injury severity: 3=mild, 4=moderate; time since most current injury: 4.0+/-5.5y) who were ambulatory. INTERVENTION: Twelve weeks of supervised vigorous aerobic exercise training performed 3 times a week for 30 minutes on a treadmill. MAIN OUTCOME MEASURES: Cognitive function was assessed using the Trail Making Test Part A (TMT-A), Trail Making Test Part B (TMT-B), and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Sleep quality and depression were measured with the Pittsburgh Sleep Quality Index (PSQI) and Beck Depression Inventory, version 2 (BDI-II). Indices of cardiorespiratory fitness were used to examine the relation between improvements in cognitive function and cardiorespiratory fitness. RESULTS: After training, improvements in cognitive function were observed with greater scores on the TMT-A (10.3+/-6.8; P=.007), TMT-B (9.6+/-7.0; P=.011), and RBANS total scale (13.3+/ 9.3; P=.009). No changes were observed in measures of the PSQI and BDI-II. The magnitude of cognitive improvements was also strongly related to the gains in cardiorespiratory fitness. CONCLUSIONS: These findings suggest that vigorous aerobic exercise training may improve specific aspects of cognitive function in individuals with TBI and cardiorespiratory fitness gains may be a determinant of these improvements. PMID- 25433220 TI - Effect of a self-determination theory-based communication skills training program on physiotherapists' psychological support for their patients with chronic low back pain: a randomized controlled trial. AB - OBJECTIVE: To examine the effects of communication skills training on physiotherapists' supportive behavior during clinical practice. DESIGN: Randomized trial. SETTING: Hospital outpatient physiotherapy clinics. PARTICIPANTS: Physiotherapists (N=24) and patients (N=24) with chronic low back pain. INTERVENTIONS: Two hospital clinics were randomly assigned to the intervention arm. Physiotherapists (n=12) received 8 hours of communication skills training focused on supporting patients' psychological needs. Physiotherapists (n=12) from 2 other hospital clinics formed a waitlist control arm. MAIN OUTCOME MEASURES: Verbal communication between each physiotherapist and a patient was recorded on an audiotape, and independent, blinded raters used the Health Care Climate Questionnaire to assess physiotherapists' needs-supportive behavior (primary outcome). RESULTS: Independent raters' Health Care Climate Questionnaire scores favored the intervention arm (Cohen's d=2.27; P<.01). CONCLUSIONS: Compared with controls, independent ratings demonstrated that physiotherapists who completed the Communication style and exercise compliance in physiotherapy training were found to provide greater support for patients' needs in a single assessed session. Long-term maintenance of this needs-supportive behavior should be examined. PMID- 25433221 TI - Autophagy-related protein 7 deficiency in amyloid beta (Abeta) precursor protein transgenic mice decreases Abeta in the multivesicular bodies and induces Abeta accumulation in the Golgi. AB - Alzheimer disease (AD) is biochemically characterized by increased levels of amyloid beta (Abeta) peptide, which aggregates into extracellular Abeta plaques in AD brains. Before plaque formation, Abeta accumulates intracellularly in both AD brains and in the brains of AD model mice, which may contribute to disease progression. Autophagy, which is impaired in AD, clears cellular protein aggregates and participates in Abeta metabolism. In addition to a degradative role of autophagy in Abeta metabolism we recently showed that Abeta secretion is inhibited in mice lacking autophagy-related gene 7 (Atg7) in excitatory neurons in the mouse forebrain. This inhibition of Abeta secretion leads to intracellular accumulation of Abeta. Here, we used fluorescence and immunoelectron microscopy to elucidate the subcellular localization of the intracellular Abeta accumulation which accumulates in Abeta precursor protein mice lacking Atg7. Autophagy deficiency causes accumulation of p62(+) aggregates, but these aggregates do not contain Abeta. However, knockdown of Atg7 induced Abeta accumulation in the Golgi and a concomitant reduction of Abeta in the multivesicular bodies. This indicates that Atg7 influences the transport of Abeta possibly derived from Golgi to multivesicular bodies. PMID- 25433222 TI - The Limulus Amebocyte Lysate assay may be unsuitable for detecting endotoxin in blood of healthy female subjects. AB - We examined the factors that may influence the outcome of the Limulus Amebocyte Lysate (LAL) assay, when it is used for quantifying Gram-negative bacterial endotoxin, also referred to as lipopolysaccharide (LPS), in samples of human blood. We found that the method recommended by the manufacturers, based on the reaction time, was inaccurate with any type of serum samples due to the slowing of the initial phase of reaction, likely by serum proteins. We describe an alternative method that is more accurate for use with heated serum samples. Further, we found that components of fresh serum irreversibly sequester endotoxin but that this action may be largely prevented by dilution and heating, but only if this occurs prior to the addition of endotoxin. The tests also indicated that a number of types of proprietary plastic vacutainers appeared to contain significant amounts of endotoxin. However, even when appropriate blood collection containers and calculation methods were used, the levels of endotoxin in serum samples detected by LAL assay were unlikely to reflect the total quantities of endotoxin in that sample and more likely to reflect the capacity of a given serum sample to sequester endotoxin. PMID- 25433225 TI - Initial experience with a new epidermal harvesting system: overview of epidermal grafting and case series. AB - INTRODUCTION: Skin grafts have long been an important tool in reconstructive surgery. However, traditional autografts have several disadvantages, including the need for a surgical procedure with anesthesia, creation of a second wound at the donor site, difficulty in obtaining uniform graft thickness, scarring, and pain. Epidermal skin grafts offer an alternative to split- and full-thickness skin grafts in that only the epidermal skin layer is removed at the donor site, resulting in minimal to no bleeding, minimal scarring and donor site pain, improved cosmetic outcome, and no need for anesthesia. Although epidermal grafts have been successfully used for many decades in treating pigmentation disorders, its expanded use for wounds has been limited largely due to lack of a reliable method of harvesting patient epidermal skin. We present our experience using a new automated, epidermal harvesting system to harvest epidermal grafts in patients with multiple comorbidities; an overview of the history and mechanisms of epidermal grafting is included to help inform clinical practice. The epidermal harvesting system applies heat and suction concurrently to normal skin to induce epidermal microdome formation within 30 to 45 minutes, and harvested epidermal grafts are transferred to recipient sites via a film dressing. In this patient series, donor sites healed completely without scarring within one to two weeks. Complete re-epithelialization occurred in three of four wounds, and 50% re epithelialization occurred in one wound. New technology in epidermal grafting offers a simple, relatively quick, low-risk option that can be performed by a non surgically trained clinician in an outpatient setting. New technology in epidermal grafting offers a simple, relatively quick, low-risk option that can be performed by a non-surgically trained clinician in an outpatient setting. PMID- 25433223 TI - Williams syndrome: a surprising deficit in oromotor praxis in a population with proficient language production. AB - Williams Syndrome (WS) is a neurodevelopmental disorder of known genetic origin, characterized by serious delays in language onset yet relatively verbose, intelligible and fluent speech in late childhood and adulthood. How do motor abilities relate to language in this group? We investigated planning and co ordination of the movement of the speech articulators (oromotor praxis) in 28 fluent-speaking individuals with WS, aged between 12 and 30 years. Results indicate that, despite their fluent language, oromotor praxis was impaired in WS relative to two groups of typically-developing children, matched on either vocabulary or visuospatial ability. These findings suggest that the ability to plan, co-ordinate and execute complex sensorimotor movements contribute to an explanation of the delay in expressive language early in development in this neurodevelopmental disorder. In the discussion, we turn to more general issues of how individual variation in oromotor praxis may account for differences in speech/language production abilities across developmental language disorders. PMID- 25433226 TI - A Review on Vacuum-assisted Closure Therapy for Septic Peritonitis Open Abdomen Management. AB - This article presents a literature review undertaken to identify advantages of vacuum-assisted closure (VAC) methods compared with other temporary abdominal closure (TAC) methods for septic peritonitis open abdomen (OA) management. A literature review was conducted through the U.S. National Library of Medicine at the National Institutes of Health. OA management and septic peritonitis were the main topics considered for this purpose. Online available information from papers discussed at relevant meetings and congresses was also included for review. The search was designed following the Patient Intervention Comparison Outcome Criteria. All shortlisted articles were reviewed by two authors independently. The review resulted in 79 items. Only one randomized study was found and considered for review. A large variety of TAC methods for OA are reported in the available literature to date and are described with a heterogeneous set of names. VAC methods allow the possibility of draining and accounting for fluids collecting in the peritoneal cavity. VAC may offer a solution to fascial closure problems. VAC helps prevent peritoneal contamination. Intra-abdominal hypertension prevention is one factor undoubtedly favoring VAC methods against non-VAC ones for OA management in septic peritonitis. PMID- 25433224 TI - Congenital amusia: a cognitive disorder limited to resolved harmonics and with no peripheral basis. AB - Pitch plays a fundamental role in audition, from speech and music perception to auditory scene analysis. Congenital amusia is a neurogenetic disorder that appears to affect primarily pitch and melody perception. Pitch is normally conveyed by the spectro-temporal fine structure of low harmonics, but some pitch information is available in the temporal envelope produced by the interactions of higher harmonics. Using 10 amusic subjects and 10 matched controls, we tested the hypothesis that amusics suffer exclusively from impaired processing of spectro temporal fine structure. We also tested whether the inability of amusics to process acoustic temporal fine structure extends beyond pitch by measuring sensitivity to interaural time differences, which also rely on temporal fine structure. Further tests were carried out on basic intensity and spectral resolution. As expected, pitch perception based on spectro-temporal fine structure was impaired in amusics; however, no significant deficits were observed in amusics' ability to perceive the pitch conveyed via temporal-envelope cues. Sensitivity to interaural time differences was also not significantly different between the amusic and control groups, ruling out deficits in the peripheral coding of temporal fine structure. Finally, no significant differences in intensity or spectral resolution were found between the amusic and control groups. The results demonstrate a pitch-specific deficit in fine spectro-temporal information processing in amusia that seems unrelated to temporal or spectral coding in the auditory periphery. These results are consistent with the view that there are distinct mechanisms dedicated to processing resolved and unresolved harmonics in the general population, the former being altered in congenital amusia while the latter is spared. PMID- 25433227 TI - Pros and cons of tacking in laparoscopic hernia repair. AB - Present available fixation devices in laparoscopic hernia repair include transfascial sutures, (permanent or absorbable) tacks, and fibrin or synthetic sealants, all of which have advantages and disadvantages. Tack fixation has been applied since the introduction of laparoscopic inguinal and ventral hernia repair during the end of the 1980s and the beginning of the 1990s, respectively. However, although this type of penetrating fixation offers a reliable method to keep the mesh in place, several negative aspects have been highlighted in recent years. Permanent metallic fixation devices such as helical titanium tacks (ProtackTM ) provide greater fixation strength than absorbable fixation devices (AbsorbaTackTM, PermasorbTM, or SorbaFixTM), but as the titanium tacks remain in the body permanently, they have been associated with serious adverse events. Dense adhesion formation and erosion of tacks in hollow viscera have been reported as well as the formation of so-called "tack hernias." However, the most clinically important negative aspect might be the increased acute and chronic postoperative pain. As pain and quality of life, rather than recurrence rate, gained the attention of clinicians, researchers, and patients, recent developments have been focusing on different types of absorbable materials. However, studies that investigated these issues comparing different tack materials for mesh fixation did not show any benefit from any type of fixation. Despite the postoperative short- and long-term sequellae, tack fixation is still the most widely applied technique for laparoscopic mesh fixation. PMID- 25433228 TI - Vaginal reconstruction/rejuvenation: is there data to support improved sexual function? An update and review of the literature. AB - Vaginal rejuvenation is a term that is commonly utilized to describe surgical repair of the vaginal canal and introitus following childbirth and/or aging to treat sexual dysfunction related to vaginal relaxation. It is well known that vaginal prolapse may lead to sexual dysfunction and in many studies repair of prolapse improves this dysfunction. During the progression of prolapse, sexual dysfunction or decreased vaginal sensation due to vaginal wall laxity may be one of the early symptoms that women suffer prior to the prolapse itself becoming symptomatic. Surgical repair or reconstruction of this type of vaginal defect may be indicated if repair will improve symptoms of sexual dysfunction caused by vaginal wall laxity. In this review, we will examine the existing data and make conclusions regarding vaginal rejuvenation and its impact on female sexual function. Core tip: This is the first review of vaginal rejuvenation that shows improvement of sexual function. In this review, we covered the topic of relaxed vagina and sexual function, prolapse repair and sexual function, vaginal rejuvenation surgical techniques, and data to support vaginal rejuvenation techniques. PMID- 25433229 TI - Recurrent twin pregnancy, with the second a heterotopic pregnancy, following clomiphene citrate stimulation: an unusual case and a review of the literature. AB - Multiple gestations are on the rise with the advent of artificial reproductive technologies. Even with ovulation induction using clomiphene citrate alone, the twinning rate can reach up to 9 percent. We report a case of recurrent twin gestation after treatment with clomiphene citrate, with the second pregnancy being heterotopic. We also review, using Medline and PubMed, previously reported cases of recurrent twin gestation after treatment with clomiphene citrate published before June 2014. Patients undergoing ovulation induction for oligoovulation, anovulation, or unexplained infertility should always be counseled about the possibility of multiple gestation prior to the treatment including the probability, although low, of a heterotopic pregnancy. PMID- 25433231 TI - Unraveling liver complexity from molecular to organ level: challenges and perspectives. AB - Biological responses are determined by information processing at multiple and highly interconnected scales. Within a tissue the individual cells respond to extracellular stimuli by regulating intracellular signaling pathways that in turn determine cell fate decisions and influence the behavior of neighboring cells. As a consequence the cellular responses critically impact tissue composition and architecture. Understanding the regulation of these mechanisms at different scales is key to unravel the emergent properties of biological systems. In this perspective, a multidisciplinary approach combining experimental data with mathematical modeling is introduced. We report the approach applied within the Virtual Liver Network to analyze processes that regulate liver functions from single cell responses to the organ level using a number of examples. By facilitating interdisciplinary collaborations, the Virtual Liver Network studies liver regeneration and inflammatory processes as well as liver metabolic functions at multiple scales, and thus provides a suitable example to identify challenges and point out potential future application of multi-scale systems biology. PMID- 25433232 TI - A call for virtual experiments: accelerating the scientific process. AB - Experimentation is fundamental to the scientific method, whether for exploration, description or explanation. We argue that promoting the reuse of virtual experiments (the in silico analogues of wet-lab or field experiments) would vastly improve the usefulness and relevance of computational models, encouraging critical scrutiny of models and serving as a common language between modellers and experimentalists. We review the benefits of reusable virtual experiments: in specifying, assaying, and comparing the behavioural repertoires of models; as prerequisites for reproducible research; to guide model reuse and composition; and for quality assurance in the translational application of models. A key step towards achieving this is that models and experimental protocols should be represented separately, but annotated so as to facilitate the linking of models to experiments and data. Lastly, we outline how the rigorous, streamlined confrontation between experimental datasets and candidate models would enable a "continuous integration" of biological knowledge, transforming our approach to systems biology. PMID- 25433230 TI - Identifying functional gene regulatory network phenotypes underlying single cell transcriptional variability. AB - Recent analysis of single-cell transcriptomic data has revealed a surprising organization of the transcriptional variability pervasive across individual neurons. In response to distinct combinations of synaptic input-type, a new organization of neuronal subtypes emerged based on transcriptional states that were aligned along a gradient of correlated gene expression. Individual neurons traverse across these transcriptional states in response to cellular inputs. However, the regulatory network interactions driving these changes remain unclear. Here we present a novel fuzzy logic-based approach to infer quantitative gene regulatory network models from highly variable single-cell gene expression data. Our approach involves developing an a priori regulatory network that is then trained against in vivo single-cell gene expression data in order to identify causal gene interactions and corresponding quantitative model parameters. Simulations of the inferred gene regulatory network response to experimentally observed stimuli levels mirrored the pattern and quantitative range of gene expression across individual neurons remarkably well. In addition, the network identification results revealed that distinct regulatory interactions, coupled with differences in the regulatory network stimuli, drive the variable gene expression patterns observed across the neuronal subtypes. We also identified a key difference between the neuronal subtype-specific networks with respect to negative feedback regulation, with the catecholaminergic subtype network lacking such interactions. Furthermore, by varying regulatory network stimuli over a wide range, we identified several cases in which divergent neuronal subtypes could be driven towards similar transcriptional states by distinct stimuli operating on subtype-specific regulatory networks. Based on these results, we conclude that heterogenous single-cell gene expression profiles should be interpreted through a regulatory network modeling perspective in order to separate the contributions of network interactions from those of cellular inputs. PMID- 25433233 TI - Erythrocytes under osmotic stress - modeling considerations. AB - Various modeling approaches have been applied to describe structural changes of the erythrocyte constituents under osmotic stress. The constituents: (1) the lipid bilayer, (2) the actin-spectrin cortex, (3) the trans-membrane protein band 3, (4) the intracellular hemoglobin contribute to the relaxation phenomenon. Cells response includes the successive sub-bioprocesses: (1) erythrocyte swelling, (2) lifetime of the lipid structural integrity and the rearrangements of trans-membrane protein band 3, (3) the reversible hemolytic hole formation and hemoglobin release to surrounding solution. Herein, an attempt is made to discuss and connect various modeling approaches on various time scales which have been proposed in the literature in order to shed further light to this complex phenomenon which induces the erythrocyte to ghost phase transition. The results indicate that the erythrocyte swelling rate represents the key control factor for the structural ordering of the cell parts which induces anomalous nature of energy dissipation. PMID- 25433235 TI - Young woman smokers gain significantly more weight over 2-year follow-up than non smokers. How Virginia doesn't slim. AB - OBJECTIVE: Although young women often report smoking for weight control purposes, no prospective study has tested whether smokers subsequently gain less weight over time than non-smokers. As this is an important lacuna because smoking results in greater mortality than obesity, the present study addresses this question. METHOD: Female college students (N = 398; M age = 18.4, SD =0.6; M BMI = 23.7, SD =4.3) recruited for a body acceptance intervention trial provided data on smoking behavior and had their body mass measured at baseline and at 1-mo, 6 mo, 1-yr, and 2-yr follow-ups. RESULTS: Counter to the belief that smoking is an effective weight control strategy, baseline smokers (n = 29) gained significantly more weight (r = .29) than baseline non-smokers (n = 304), controlling for baseline BMI, parental obesity status, socio-economic status, and intervention condition; over 2-yr follow-up smokers gained 2.9 kg versus 0.9 kg for non smokers. Descriptive data indicated that weight gain was greater for young women who quit smoking during follow-up (n = 13; M = 4.8 kg) than for persistent smokers (n = 16; M = 1.4 kg), though both groups gained more weight than non smokers. CONCLUSIONS: RESULTS challenge the widely held belief that smoking is an effective weight control strategy, ironically suggesting that smokers gain more weight than non-smokers during young adulthood, though non-experimental prospective studies do not establish causal relations and future research with larger representative samples is needed. PMID- 25433234 TI - In vitro exposure to the herbicide atrazine inhibits T cell activation, proliferation, and cytokine production and significantly increases the frequency of Foxp3+ regulatory T cells. AB - The herbicide atrazine (2-chloro-4-[ethylamino]-6-[isopropylamino]-s-triazine) is the most common water contaminant in the United States. Atrazine is a phosphodiesterase inhibitor and is classified as an estrogen disrupting compound because it elevates estrogen levels via induction of the enzyme aromatase. Previous studies have shown that atrazine exposure alters the function of innate immune cells such as NK cells, DC, mast cells, and macrophages. In this study we have examined the impact of in vitro atrazine exposure on the activation, proliferation, and effector cytokine production by primary murine CD4(+) T lymphocytes. We found that atrazine exposure significantly inhibited CD4(+) T cell proliferation and accumulation as well as the expression of the activation markers CD25 and CD69 in a dose-dependent manner. Interestingly, the effects were more pronounced in cells from male animals. These effects were partially mimicked by pharmacological reagents that elevate intracellular cAMP levels and addition of exogenous rmIL-2 further inhibited proliferation and CD25 expression. Consistent with these findings, atrazine exposure during T cell activation resulted in a 2- to 5-fold increase in the frequency of Foxp3(+) CD4(+) T cells. PMID- 25433236 TI - A role for the outer retina in development of the intrinsic pupillary light reflex in mice. AB - Mice do not require the brain in order to maintain constricted pupils. However, little is known about this intrinsic pupillary light reflex (iPLR) beyond a requirement for melanopsin in the iris and an intact retinal ciliary marginal zone (CMZ). Here, we study the mouse iPLR in vitro and examine a potential role for outer retina (rods and cones) in this response. In wild-type mice the iPLR was absent at postnatal day 17 (P17), developing progressively from P21-P49. However, the iPLR only achieved ~ 30% of the wild-type constriction in adult mice with severe outer retinal degeneration (rd and rdcl). Paradoxically, the iPLR increased significantly in retinal degenerate mice >1.5 years of age. This was accompanied by an increase in baseline pupil tone in the dark to levels indistinguishable from those in adult wild types. This rejuvenated iPLR response was slowed by atropine application, suggesting the involvement of cholinergic neurotransmission. We could find no evidence of an increase in melanopsin expression by quantitative PCR in the iris and ciliary body of aged retinal degenerates and a detailed anatomical analysis revealed a significant decline in melanopsin-positive intrinsically photosensitive retinal ganglion cells (ipRGCs) in rdcl mice >1.5 years. Adult mice lacking rod function (Gnat1(-/-)) also had a weak iPLR, while mice lacking functional cones (Cpfl5) maintained a robust response. We also identify an important role for pigmentation in the development of the mouse iPLR, with only a weak and transient response present in albino animals. Our results show that the iPLR in mice develops unexpectedly late and are consistent with a role for rods and pigmentation in the development of this response in mice. The enhancement of the iPLR in aged degenerate mice was extremely surprising but may have relevance to behavioral observations in mice and patients with retinitis pigmentosa. PMID- 25433237 TI - Passive or simulated displacement of one arm (but not its mirror reflection) modulates the involuntary motor behavior of the other arm. AB - Recent studies of both healthy and patient populations have cast doubt on the mirror paradigm's beneficial effect on motor behavior. Indeed, the voluntary arm displacement that accompanies reflection in the mirror may be the determining factor in terms of the motor behavior of the contralateral arm. The objective of the present study was to assess the respective effects of mirror reflection and arm displacement (whether real or simulated) on involuntary motor behavior of the contralateral arm following sustained, isometric contraction (Kohnstamm phenomenon). Our results revealed that (i) passive displacement of one arm (displacement of the left arm via a motorized manipulandum moving at 4 degrees /s) influenced the velocity of the Kohnstamm phenomenon (forearm flexion occurring shortly after the cessation of muscle contraction) in the contralateral arm and (ii) mirror vision had no effect. Indeed, the velocity of the Kohnstamm phenomenon tended to be adjusted to match the velocity of the passive displacement of the other arm. In a second experiment, arm displacement was simulated by vibrating the triceps at 25, 50 or 75 Hz. Results showed that the velocity of the Kohnstamm phenomenon in one arm increased with the vibration frequency applied to the other arm. Our results revealed the occurrence of bimanual coupling because involuntary displacement of one arm was regulated by muscle-related information generated by the actual or simulated displacement of the other arm. In line with the literature data on voluntary motor behavior, our study failed to evidence an additional impact of mirror vision on involuntary motor behavior. PMID- 25433238 TI - P2 purinergic receptor activation of neuronal nitric oxide synthase and guanylyl cyclase in the dorsal facial area of the medulla increases blood flow in the common carotid arteries of cats. AB - In the dorsal facial area (DFA) of the medulla, an activation of either P2 purinergic receptor or nitric oxide synthase (NOS) results in the release of glutamate, leading to an increase in blood flow of the common carotid artery (CCA). It is not known whether activation of the P2 receptor by ATP may mediate activation of NOS/guanylyl cyclase to cause glutamate release and/or whether L Arg (nitric oxide (NO) precursor) may also cause ATP release from any other neuron, to cause an increase in CCA flow. We demonstrated that microinjections of P2 receptor agonists (ATP, alpha,beta-methylene ATP) or NO precursor (L-arginine) into the DFA increased CCA blood flow. The P2-induced CCA blood flow increase was dose-dependently reduced by pretreatment with NG-nitro-arginine methyl ester (L NAME, a non-specific NOS inhibitor), 7-nitroindazole (7-NI, a relatively selective neuronal NOS inhibitor) or methylene blue (MB, a guanylyl cyclase inhibitor) but not by that with D-NAME (an isomer of L-NAME) or N5-(1-iminoethyl) L-ornithine (L-NIO, a potent endothelial NOS inhibitor). Involvement of glutamate release in these responses were substantiated by microdialysis studies, in which perfusions of ATP into the DFA increased the glutamate concentration in dialysates, but co-perfusion of ATP with L-NAME or 7-NI did not. Nevertheless, the arginine-induced CCA blood flow increase was abolished by combined pretreatment of L-NAME and MB, but not affected by pretreatment with a selective P2 receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). In conclusion, ATP activation of the P2 receptor in the DFA induced activation of neuronal NOS/guanylyl cyclase, which causes glutamate release leading to an increase in CCA blood flow. However, arginine activation of neuronal NOS/guanylyl cyclase, which also caused glutamate release and CCA blood flow increase, did not induce activation of P2 receptors. These findings provide important information for drug design and/or developing therapeutic strategies for the diseases associated with CCA blood flow that supplies intra- and extra cranial tissues. PMID- 25433239 TI - Seeing the whole picture: A comprehensive imaging approach to functional mapping of circuits in behaving zebrafish. AB - In recent years, the zebrafish has emerged as an appealing model system to tackle questions relating to the neural circuit basis of behavior. This can be attributed not just to the growing use of genetically tractable model organisms, but also in large part to the rapid advances in optical techniques for neuroscience, which are ideally suited for application to the small, transparent brain of the larval fish. Many characteristic features of vertebrate brains, from gross anatomy down to particular circuit motifs and cell-types, as well as conserved behaviors, can be found in zebrafish even just a few days post fertilization, and, at this early stage, the physical size of the brain makes it possible to analyze neural activity in a comprehensive fashion. In a recent study, we used a systematic and unbiased imaging method to record the pattern of activity dynamics throughout the whole brain of larval zebrafish during a simple visual behavior, the optokinetic response (OKR). This approach revealed the broadly distributed network of neurons that were active during the behavior and provided insights into the fine-scale functional architecture in the brain, inter individual variability, and the spatial distribution of behaviorally relevant signals. Combined with mapping anatomical and functional connectivity, targeted electrophysiological recordings, and genetic labeling of specific populations, this comprehensive approach in zebrafish provides an unparalleled opportunity to study complete circuits in a behaving vertebrate animal. PMID- 25433240 TI - Behavioral and molecular alterations in mice resulting from chronic treatment with dexamethasone: relevance to depression. AB - Chronic stress, the administration of glucocorticoids and the prolonged activation of glucocorticoid receptors (GRs) are reported to induce affective changes in humans and rodents that resemble a depressive state. However, data concerning the behavioral and molecular effects of the selective activation of specific GRs are limited, and the conclusions derived remain debatable. In this study, our goal was to investigate the behavioral and molecular changes following the prolonged activation of GRs in mice via exposure to the specific agonist dexamethasone (DEX). C57BL/6J mice were injected daily with DEX (4 mg/kg, i.p.) or saline, and the behavior of the animals was assessed in the following paradigms: the forced swimming test (FST), the light-dark box test, the saccharin preference test and activity boxes. The mRNA expression levels of the corticosteroid receptors mineralocorticoid (MR, Nr3c2) and glucocorticoid (GR, Nr3c1), selected stress dependent genes and glial markers were analyzed in the prefrontal cortex, hippocampus and striatum. DEX-treated mice exhibited a variety of depression-like behaviors: increased time of immobility in the FST, a reduced preference for saccharin consumption and increased anxiety-like behavior. Behavioral alterations were accompanied by a decrease in the mRNA expression of GR and the increased expression of Fkbp5 and Sgk1 in the prefrontal cortex, hippocampus and striatum of DEX-treated mice. Furthermore, our results indicate a decrease in the mRNA expression of glutamate aspartate transporter (GLAST, Slc1a3), an astroglial cell marker, in the hippocampus and prefrontal cortex. These results demonstrate that the prolonged activation of GR receptors induced a depression-like state in mice, activated stress-related genes and induced a decrease in the mRNA expression of GLAST, an astroglial marker, in the prefrontal cortex and hippocampus. Together, the results reported here challenge several hypotheses concerning the role of GRs in the development of behavioral and molecular alterations relevant to stress-related disorders, such as depression, under the same experimental conditions. PMID- 25433241 TI - SIRT3 protects cells from hypoxia via PGC-1alpha- and MnSOD-dependent pathways. AB - Reports suggest that silent information regulation 2 homolog 3 (SIRT3) protects cardiomyocytes from oxidative stress-mediated death. SIRT3, a mitochondrial protein, is an essential regulator of mitochondrial function, and this regulation is important in many cerebrovascular diseases, especially stroke. Here, we investigated the role of SIRT3 in ischemia-induced neuronal death due to oxygen glucose deprivation (OGD) using an in vitro model of cerebral ischemia. We found that exposure of differentiated PC12 cells to OGD for 6h caused a marked decrease in cell viability and up regulated SIRT3. SIRT3 knockdown using short interfering RNA (siRNA) exacerbated OGD-induced injury whereas application of recombinant SIRT3 protected against OGD-induced cell death. Pre-treatment of the cells in which the SIRT3 gene was knocked down with recombinant SIRT3 before OGD partially restored cell viability and concomitantly reduced lactate dehydrogenase (LDH) release and increased ATP generation in mitochondria. Recombinant SIRT3 treatment resulted in increased expression of peroxisome proliferator activated receptor (PPAR)-gamma co-activator 1-alpha (PGC-1alpha) and manganese superoxide dismutase (MnSOD). After knockdown of PGC-1alpha or MnSOD, recombinant SIRT3 failed to protect against OGD-induced injury. We also found that the protein and mRNA expression of PGC-1alpha was down regulated following SIRT3 knockdown. The expression level of SIRT3 was reduced when the PGC-1alpha gene was knocked down. Both SIRT3 and PGC-1alpha knockdown led to reduced mitochondrial membrane potential (Deltapsi) and Ca(2+) transients, especially under OGD conditions. Thus, our data suggest that SIRT3 protects PC12 cells from hypoxic injury via a mechanism that may involve PGC-1alpha and MnSOD. SIRT3 and PGC-1alpha regulate each other under physiologic and OGD conditions, thereby partially protecting against hypoxia or ischemia. PMID- 25433242 TI - Ceftibuten-induced filamentation of extended spectrum beta lactamase (ESBL) producing uropathogenic Escherichia coli alters host cell responses during an in vitro infection. AB - Inadequate and delayed antibiotic treatment of extended spectrum beta-lactamase (ESBL)-producing isolates have been associated with increased mortality of affected patients. The purpose of this study was to compare the host response of human renal epithelial cells and polymorphonuclear leucocyte (PMN) cells when infected by ESBL-producing uropathogenic Escherichia coli (UPEC) isolates in the presence or absence of ineffective antibiotics. The renal epithelial cell line A498 and PMN cells were stimulated with ESBL-producing UPEC isolates in the presence or absence of three different antibiotics (trimetoprim, ceftibuten and ciprofloxacin). Host cell responses were evaluated as release of cytokines (IL-6, IL-8), reactive oxygen species (ROS), ATP and endotoxins. Bacterial morphology and PMN phagocytosis were evaluated by microscopy. In the presence of ceftibuten, 2 out of 3 examined ESBL-isolates changed their morphology into a filamentous form. The presence of ceftibuten enhanced IL-6, IL-8 and ROS-production from host cells, but only from cells stimulated by the filamentous isolates. The bacterial supernatant and not the filamentous bacteria per se was responsible for the increased release of IL-6, IL-8 and ROS. Increased endotoxin and ATP levels were found in the bacterial supernatants from filamentous isolates. Apyrase decreased IL-6 secretion from A498 cells and polymyxin B abolished the increased ROS production from PMN cells. PMN were able to inhibit the bacterial growth of some ESBL-isolates in the presence of ceftibuten. In conclusion, antibiotic-induced filamentation of ESBL-producing UPEC isolates and the associated release of ATP and endotoxins can alter the host cell response in the urinary tract. PMID- 25433243 TI - Transmembrane proteins of the tight junctions at the blood-brain barrier: structural and functional aspects. AB - The blood-brain barrier (BBB) is formed by microvascular endothelial cells sealed by tetraspanning tight junction (TJ) proteins, such as claudins and TAMPs (TJ associated marvel proteins, occludin and tricellulin). Claudins are the major components of the TJs. At the BBB, claudin-5 dominates the TJs by preventing the paracellular permeation of small molecules. On the other hand, TAMPs regulate the structure and function of the TJs; tricellulin may tighten the barrier for large molecules. This review aims at integrating and summarizing the most relevant and recent work on how the BBB is influenced by claudin-1, -3, -5, -12 and the TAMPs occludin and tricellulin, all of which are four-transmembrane TJ proteins. The exact functions of claudin-1, -3, -12 and TAMPs at this barrier still need to be elucidated. PMID- 25433244 TI - The versatile electron microscope: an ultrastructural overview of autophagy. AB - Both light microscopy (LM) and electron microscopy (EM) are able to reveal important information about the formation and function of various autophagic compartments. In this article we will outline the various techniques that are emerging in EM, focusing on analyzing three-dimensional morphology, collectively known as volume electron microscopy (volume EM), as well as on methods that can be used to localize proteins and antigenic epitopes. Large cell volumes can now be visualized at the EM level by using one of the two complementary imaging techniques, namely Serial Block-face Scanning Electron Microscopy (SB-SEM) or Focused Ion Beam Scanning Electron Microscopy (FIB-SEM). These two block-face imaging methods reveal ultrastructural information from all membrane-bound organelles such as autophagic compartments to be visualized in a three dimensional space, in association with their surrounding organelles. Another method which falls into the volume EM category is dual-axis electron tomography (ET). This method is more suited to reconstructing smaller volumes from areas of interest that require nano-structural detail to be confirmed such as membrane contact sites (MCSs) between autophagic compartments and various organelles. Further to this, to complement the morphological identification of autophagic compartments, immunolabeling can be carried out at the EM level to confirm the nature of various autophagic compartments depending on the localization of various antigens at a sub-cellular level. To determine this, various immunolabeling techniques can be carried out, namely the pre-embedding or the post-embedding immunolabeling methods. Examples of both of these methods will be described in this chapter. Correlative light-electron microscopy (CLEM) can be used to visualize the same autophagic organelles under the LM, followed by high resolution imaging under the EM. Finally, cryofixation has revolutionized the EM field by allowing rapid immobilization of cells and tissue in the near native state, so samples are no longer prone to artefacts induced by chemical fixation. Collectively, this chapter will discuss the aforementioned capabilities of the EM in more detail, with a particular focus on autophagy, namely the impact of EM in the study of the morphology and biogenesis of the phagophore/isolation membrane (referred to as the phagophore hereafter). PMID- 25433245 TI - Recombinant human lactoferrin-Fc fusion with an improved plasma half-life. AB - Lactoferrin (LF), an 80-kDa iron-binding glycoprotein found in mammalian exocrine secretions, has potential therapeutic efficacy due to its extensive health promoting effects. However, LF is rapidly cleared from the circulation (~12.6min half-life for recombinant human LF [rhLF] in rats), which limits its therapeutic potential. Therefore, to improve plasma stability, we developed a recombinant human LF (hLF)-immunoglobulin G1 (IgG1) fragment crystallizable domain (Fc) fusion (hLF-hinge-CH2-CH3) expressed in a Chinese Hamster Ovary cell (CHO) expression system and evaluated the in vitro bioactivities and pharmacokinetic properties of the purified fusion. CHO DG44 cells were transfected with an expression vector coding for recombinant hLF-hinge-CH2-CH3. Iron binding, Caco-2 uptake, and thermal stability were investigated in vitro, and pharmacokinetic parameters were investigated in vivo. hLF-hinge-CH2-CH3 was significantly expressed in CHO cells (~100mg/l culture), was readily purified, and exhibited 98.3% of the non-fused rhLF iron-binding activity. Caco-2 uptake and thermal stability were improved for hLF-Fc fusion relative to rhLF. Moreover, hLF-hinge CH2-CH3 demonstrated a plasma half-life that was 9.1-fold longer than that of rhLF as well as longer than that of the PEGylated bovine LFs that we previously developed. Thus, CHO-derived hLF-hinge-CH2-CH3, with enhanced pharmacokinetic properties, is a promising candidate drug for potential parenteral administration. PMID- 25433246 TI - Evaluation of fasted state human intestinal fluid as apical solvent system in the Caco-2 absorption model and comparison with FaSSIF. AB - To date, the Caco-2 model is considered as the gold standard to predict intestinal drug absorption. Often, aqueous phosphate buffers are used as apical medium. The purpose of this study was to use fasted state human intestinal fluid (FaHIF) as apical solvent system to generate biorelevant permeability values for a series of 16 model drugs that can be used as reference data to critically evaluate fasted state simulated intestinal fluid (FaSSIF) as possible substitute medium. Caco-2 compatibility with FaHIF was achieved when 50mg/ml mucus was applied on top of the cells before adding the apical medium. The use of FaHIF as solvent system generated a broad range of apparent permeability values (Papp) for the series of model compounds. When Papp values obtained with FaHIF were compared to those obtained with FaSSIF, a strong correlation was observed (R=0.951). The use of FaSSIF in the absence of mucus did not significantly alter this correlation. For FaHIF, FaSSIF and reference phosphate buffer blank FaSSIF, a strong sigmoidal relationship was found between Papp and fahuman, illustrated by correlation coefficients of 0.961, 0.893 and 0.868, respectively. In terms of inter-subject variability, the use of FaHIF from different volunteers originating from two distinct age groups (18-25 years; 65-72 years) exhibited an average coefficient of variance (CV) of 30%. However, no age dependency in permeability could be observed. In conclusion, the data generated in this article justify the use of FaSSIF as biorelevant apical medium in the Caco-2 assay to accurately predict in vivo drug absorption. Also, the optimized mucus-containing Caco-2 model can be used in combination with intestinal fluid samples aspirated after drug administration to further investigate intraluminal drug and formulation behavior. PMID- 25433247 TI - Chromatographic purification of adenoviral vectors on anion-exchange resins. AB - Anion-exchange chromatography is a useful and effective tool for adenoviral vectors purification. However, due to the different functional groups and matrices, both binding capacity and resolution of most AEC resins are different. In this study, four different AEC resins are compared by the binding capacity, resolution and recovery. Using Fractogel TMAE as an adsorbent to purify adenoviral vectors has obvious advantages over the other resins, namely (1) dynamic binding capacity is higher than other resins; (2) unprecedented sharpness (1,570,000+/-250,000) and symmetry of adenoviral vectors peak (1.67+/-0.06); (3) higher resolution with other contaminants (2.16+/-0.08); (4) no enzymatic treatment; (5) the recovery can reach 75%; (6) the purity is higher and the total virion to infectious particle ratios can reach 18.9. In the present work, we confirmed the possibility of purifying pharmaceutical-grade adenoviral vectors by AEC. PMID- 25433248 TI - Implementation of a new tool to improve the efficacy and safety of surgical handovers. AB - AIMS: Compliance with European working time regulations in surgical practice has resulted in an increase in the number of clinicians caring for individual patients and subsequently an increase in the frequency of handovers. In 2007, the Royal College of Surgeons of England produced guidelines on the minimum data-set for 'safe handover'. This audit examined compliance with these guidelines before and after adopting a more detailed electronic handover 'template' with the intention of improving handover quality and patient safety. METHODS: Pre-existing surgical 'take' electronic handover sheets were reviewed daily for two weeks to assess compliance with published guidance. A new proforma was introduced, training delivered and compliance re-audited. chi2 analysis was performed to determine statistical significance. RESULTS: The handovers of 118 patients were audited before, and 114 after, the implementation of the new proforma. Name and responsible consultant were recorded in all cases. Age (52% vs. 85%, p=<0.01), location (77% vs. 95%, p=<0.01), admission date (0% vs. 39%, p=<0.01), medical history (82% vs. 94%, p=0.01), diagnosis (55% vs. 93%, p=<0.01) and management plan (81% vs. 97%, p=<0.01) showed a statistically significant improvement with the new proforma. Presenting complaint (93% vs. 98%) and investigation (90% vs. 90%) data remained good. Review frequency (5%vs.11%) and outstanding tasks (21% vs. 27%) were poorly documented. CONCLUSIONS: Significant improvement was seen in the completeness of information handed-over following the introduction of the new proforma with likely positive implications for patient safety and standard of care. Opportunity for improvement still remains however, and more specific focussed tuition for trainees is required. PMID- 25433249 TI - The incidence, age at diagnosis of breast cancer in the Iraqi Kurdish population and comparison to some other countries of Middle-East and West. AB - BACKGROUND: Studies on breast cancer among Iraqi Kurdish are limited. The incidence of breast cancer is lower, more common in younger age and a significant proportion of cases occur in premenopausal women. The aims of this study are to estimate the age-standardized incidence rate, age-specific rates and their comparison with some countries of Middle-East and West, and clarify the association of family history and premenopausal status with breast cancer. MATERIALS AND METHODS: This retrospective case control study was conducted in Sulaimanyah governorate (North of Iraq). Data were collected regarding demographical profile of 536 patients who were registered in Hewa Hematology and Oncology Hospital during 2011-2013, and 496 age-matched controls. RESULTS: There were 536 cases of breast cancer, 526 of them were female. The age range was 20-82 years. The mean age at diagnosis was 49.42+/-11.66 years compared to control 46.7+/-10.2 (p?0.001, 95% CI: 1.7-3.7). The age-standardized rate was 17.9/100,000 Kurdish women population/year. Five year age-specific rates show the peak incidence for the age group 45-49 years (79.3/100,000). A significant percentage of patients were premenopausal at the time of diagnosis, which is account 55.52% of cases compared to control 59.67% (p=0.53). About 13.49% of cases have family history of breast cancer compared to control 3.2% (p=0.02). CONCLUSION: Among Kurdish people in Iraq, the incidence of breast cancer is less than Middle-East and Western countries with higher incidence in younger age group than western society, but similar to Middle-East countries. More than half of Kurdish women with breast cancer are premenopausal. PMID- 25433250 TI - Pharmacological basis for the medicinal use of Linum usitatissimum (Flaxseed) in infectious and non-infectious diarrhea. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Linum usitatissimum, commonly known as Flaxseed has traditionally been used for the management of diarrhea and gastrointestinal infections. This study was planned to assess pharmacological basis for the medicinal use of Flaxseed in infectious and non-infectious diarrhea. MATERIALS AND METHODS: The crude aqueous-methanolic extract of Flaxseed was studied using the in vivo castor oil-induced diarrhea, gut motility and enteropooling assays. Mechanistic basis was further elucidated by testing the inhibitory effect on spontaneously contracting isolated rabbit jejunum preparations, suspended in a 10ml tissue bath containing Tyrode' solution, maintained at 37 degrees C and aerated with carbogen. Antibacterial efficacy of the Flaxseed extract was tested against different enteric and non-enteric pathogenic bacteria using in vitro antibacterial assays. RESULTS: Flaxseed extract reduced the diarrheal score in mice, by 39%, 63.90% and 68.34% at the respective doses of 100, 300 and 500mg/kg. Intestinal secretions were reduced by 24.12%, 28.09% and 38.80%, whereas the intestinal motility was reduced by 31.66%, 46.98% and 56.20% at respective doses of 100, 300 and 500mg/kg. When tested on isolated rabbit jejunum preparations, Flaxseed extract produced a dose-dependent inhibition of both spontaneous and high K(+) (80mM)-induced contractions, and shifted the concentration-response curves of Ca(++) to the right with suppression of the maximum response, similar to that caused by verapamil. Flaxseed extract was found to possess bactericidal activity at the tested concentrations of 12.5mg/ml, against vancomycin-resistant Enterococcus faecalis (100%), Escherichia coli K1 (88.88%), methicillin-resistant Staphylococcus aureus (98.76%), Bacillus cereus (92.64%), Pseudomonas aeruginosa (76.83%) and Salmonella typhi (26.91+/-3.35%). The concentration of 10mg/ml showed bactericidal effects against all the aforementioned pathogens except Escherichia coli K1, whereas for Pseudomonas aeruginosa and Salmonella typhi, it was bacteriostatic at this concentration. CONCLUSIONS: Our results indicate that Linum usitatissimum (Flaxseed) extract exhibits antidiarrheal and antispasmodic activities by virtue of its antimotility and antisecretory effects which are mediated possibly through inhibition of Ca(++) channels, though additional mechanism(s) cannot be ruled out. Flaxseed extract proved effective against both enteric and non-enteric pathogens causing diarrhea, thus ensuring wide coverage and rationalizing its medicinal use in both the infectious and non-infectious diarrhea. PMID- 25433252 TI - Alcohol consumption among the over 50s: international comparisons. AB - AIM: Research exploring alcohol consumption patterns and behaviour change among older adults is relatively scarce, often necessitating reliance on international evidence. To understand the degree to which findings may be generalizable across countries, this review compares recent epidemiological evidence from developed countries on the prevalence of abstention and potentially problematic alcohol consumption in older adults. METHODS: Medline, EMBASE, Web of Science and PsychInfo were searched for English language publications, identifying 21 peer reviewed publications and six reports, including data from 17 national surveys and 10 general practice and community samples published since 2000. RESULTS: Of the developed countries for which data are available on adults aged over 50 years, rates of past 12-month abstention and former drinking are lowest in England and Finland, and highest in Korea and the USA. The prevalence of binge drinking varies widely between studies, whilst rates of alcohol dependence are broadly similar. CONCLUSIONS: Older adults in developed countries report different rates of abstention and alcohol consumption. This places obvious limitations on the extrapolation of results from specific research findings and policy strategies to other countries. PMID- 25433251 TI - Relationship between the thyroid axis and alcohol craving. AB - AIMS: A few studies have suggested a relationship between thyroid hormones and alcohol dependence (AD) such as a blunted increase of thyroid stimulating hormone (TSH) in response to thyrotropin-releasing hormone (TRH), lower levels of circulating free triiodothyronine (fT3) and free thyroxine (fT4) levels and down regulation of the TRH receptors. The current study aimed to explore the relationship between the hormones of the thyroid axis and alcohol-seeking behaviors in a sample of alcohol-dependent patients. METHODS: Forty-two treatment seeking alcohol-dependent individuals enrolled in a 12-week treatment study were considered. The Timeline Follow Back (TLFB) was used to assess the number of drinks consumed during the 12-week period. Blood levels of thyroid hormones (TSH, fT3 and fT4) were measured prior to and at the end of treatment. Questionnaires were administered to evaluate craving for alcohol [Penn Alcohol Craving Scale (PACS) and the Obsessive Compulsive Drinking Scale (OCDS) and its two subscales ODS for obsessions and CDS for compulsions] as well as anxiety [State and Trait Inventory (STAI)], depression [the Zung Self-Rating Depression Scale (Zung)] and aggression [the Aggressive Questionnaire (AQ)]. RESULTS: At baseline, we found significant positive correlations between fT3 and OCDS (r = 0.358, P = 0.029) and CDS (r = 0.405, P = 0.013) and negative correlations between TSH levels and STAI (r = -0.342, P = 0.031), and AQ (r = -0.35, P = 0.027). At the end of the 12-week study period, abstinent patients had a greater change in TSH than those who relapsed (-0.4 vs. -0.25, F(1,24) = 5.4, P = 0.029). CONCLUSION: If confirmed in larger samples, these findings could suggest that the thyroid axis might represent a biomarker of alcohol craving and drinking. PMID- 25433253 TI - Effect of a musicians' exercise intervention on performance-related musculoskeletal disorders. AB - PURPOSE: To evaluate the effect of a purpose-designed exercise program on performance-related musculoskeletal disorders (PRMDs) and associated risk factors in a sample of professional orchestral musicians. METHODS: A 10-week exercise program was made available to full-time musicians employed by the eight premier symphony orchestras of Australia. Questionnaires were administered before, immediately after (T1), and 6 months after interventions (T2) containing questions relating to change in frequency and severity of PRMDs, ratings of perceived exertion (RPE) during rehearsal, private practice, and performance, as well as nine performance-related factors. Participants were also asked to rate whether these performance-related factors affected their overall playing capacity during different playing situations. A comparative control group of musicians had no intervention and completed a modified questionnaire at the same time points. RESULTS: Exercise participants (n=30) reported a reduction in frequency (p<0.05) and severity (p<0.05) of PRMDs at T1 but not at T2 compared to controls (n=23). The exercise group reported a significant improvement in RPE during private practice at T1 (p<0.01) and T2 (p<0.01), but not during rehearsal and performance. At T1, the intervention was rated to be moderately to highly effective for three performance-related factors: strengthening muscles that support playing, learning techniques that support playing, and posture. Further, participants reported an intervention effect on overall playing capacity during rehearsal at T1 and T2. CONCLUSIONS: A tailored exercise program for musicians was effective at managing PRMDs, especially in reducing the frequency and severity of PRMDs. Physical therapy exercises should be considered in modifying performance-related factors that have been reported to be predictors of PRMDs. PMID- 25433254 TI - Lumbar lordosis in female collegiate dancers and gymnasts. AB - OBJECTIVE: Postural deviations can predispose an individual to increased injury risk. Specifically, lumbar deviations are related to increased low back pain and injury. Dancers and gymnasts are anecdotally suggested to have exaggerated lumbar lordosis and subsequently may be at increased risk of lumbar pathologies. Our objective was to examine lumbar lordosis levels in dancers and gymnasts. METHODS: We examined lumbar lordosis in 47 healthy collegiate females (17 dancers, 29 gymnasts; mean age 20.2 +/- 1.6 yrs) using 2-dimensional sagittal plane photographs and the Watson MacDonncha Posture Analysis instrument. Participants' lordosis levels were cross-tabulated and a Mann-Whitney U-test compared lumbar lordosis between groups (p<0.05). RESULTS: Most participants (89.4%, n=42) exhibited either marked (dancers 50%, n=9; gymnasts 62.1%, n=18; combined 57.4%, n=27) or moderate (dancers 27.8%, n=5; gymnasts 34.5%, n=10; combined 31.9%, n=15) lumbar lordosis deviations. The distribution of lordosis was similar across groups (p=0.22). CONCLUSIONS: Most dancers and gymnasts had moderate or marked lumbar lordosis. The extreme ranges of motion required during dancing and gymnastics may contribute to the participants' high lumbar lordosis. Instructors should be aware that there may be links between repetitive hyperextension activities and lumbar lordosis levels in dancers and gymnasts. Thus, they should proactively examine lumbar lordosis in their dancers and gymnasts. How much age of training onset, regimens, survivor bias, or other factors influence lumbar lordosis requires study. Longitudinal studies are also needed to determine if lumbar lordosis levels influence lumbar injury incidence in dancers and gymnasts. PMID- 25433255 TI - Metatarsal pain and plantar hyperkeratosis in the forefeet of female professional flamenco dancers. AB - OBJECTIVES: The objectives of this study were to determine the frequency of metatarsal pain and of hyperkeratosis on the plantar forefoot in female professional flamenco dancers, and to determine whether there is a relationship between the two disorders. METHOD: Forty-four female professional flamenco dancers, with a minimum activity of 25 hrs/wk, participated in this cross sectional study. The presence or absence of metatarsal pain while dancing was recorded, and plantar pressures were measured on a pressure platform, both barefoot and shod with the usual dance shoe. The heel height of the dance shoe was also measured. RESULTS: Of the dancers, 80.7% experienced metatarsal pain while dancing, and 84.1% presented with plantar hyperkeratosis. Plantar hyperkeratosis coincided with the presence of metatarsal pain in 67.04% of the feet studied. The maximum load point in the feet when the dancers were barefoot was located 59.5% in the rearfoot and 40.5% in the forefoot; when dancers wore their specific flamenco dancing shoes, it was located 52.4% in the rearfoot and 47.6% in the forefoot. CONCLUSIONS: Metatarsal pain and plantar hyperkeratosis in the forefoot are common foot disorders in female flamenco dancing. The incidence of the maximum load point being located in the forefoot, and the difference between the results of the tests while shod or barefoot, are both too low to support the idea that the raised heels of flamenco shoes are a major contributing factor for these injuries. Therefore, these disorders may be caused by chronic repetitive trauma suffered during the practice of footwork dancing. PMID- 25433256 TI - Foot and ankle pain and injuries in elite adult Irish dancers. AB - BACKGROUND: In Irish dance, the foot and ankle are the structures most commonly affected by pain and injury, but there is scant research examining the potential factors placing Irish dancers at risk of sustaining pain and injury in the foot and ankle. STUDY DESIGN: An observational study examining the factors linked to pain and injury in the foot and ankle in elite adult Irish dancers. METHODS: The biopsychosocial characteristics of 29 subjects with no previous pain and injury in the foot and ankle were compared to 53 subjects who cited the foot and ankle as their most troublesome bodily area. These 82 subjects were professional, competitive, and student Irish dancers, of both sexes aged 18 years or older, and were allocated to "never troublesome" (NT) and "most troublesome" (MT) groups, respectively. RESULTS: Factors found to be statistically significant for membership of the MT group included female gender (p=0.004), greater gastrocnemius flexibility (p=0.021), better single leg balance (p=0.019), and a higher number of endurance jumps (p=0.009). The MT group reported more severe levels of day-to-day pain (p=0.038), greater bothersomeness of daily pain (p=0.005), more subjective health complaints (p=0.024), more psychological complaints (p=0.030), and a greater number of bodily areas experiencing pain and injury (p=0.025). CONCLUSIONS: Pain and injury in the foot and ankle in elite adult Irish dancers is commonplace and comparable to levels of injury in other elite forms of dance. A complex mix of biopsychosocial factors is associated with pain and injury in the foot and ankle in this cohort. PMID- 25433257 TI - The m/r SEBT: development of a functional screening tool for dance educators. AB - Dance screenings provide direct and indirect data bearing on a dancer's readiness to undertake rigorous physical training. Rarely, however, are dance teachers able to translate results from these screenings into practical technical knowledge. In this article, an example of a preseason assessment tool is presented that translates scientific findings into useful information for dance teachers conducting auditions. Designed as a baseline assessment of the dancer during auditioning, the m/r SEBT tool helps teachers stratify technical levels, identify injury risk, and consequently assist with immediate and appropriate recommendations for supplemental training and//or follow-up with a medical professional. The tool evolved out of more than 3 years of collaborative, multisite research utilizing the Star Excursion Balance Test (SEBT) as a dynamic test of balance. Modifications were made to render the test more dance-specific and to increase balance challenges. Within the 3-year period, more than 100 dancers were tested in four sites, two in the United States and two in the United Kingdom. Despite the relatively large collective sample size, neither the original SEBT nor its modifications (m/r SEBT) held robust face or content validity as balance screens. What did emerge, however, were qualitative criteria that the authors organized into a feasible assessment tool for preseason auditions. While this tool awaits further validation, its current evolution helps serve as a bridge between dance teachers' clinical and practical knowledge. PMID- 25433258 TI - Postural stability does not differ among female sports with high risk of anterior cruciate ligament injury. AB - Dancers have a lower incidence of anterior cruciate ligament (ACL) injury compared to athletes in sports that involve cutting and landing motions. Balance can impact ACL injury risk and is related to neuromuscular control during movement. The purpose of this study was to investigate whether balance differences exist among female dancers and female soccer and basketball athletes. Fifty-eight female dancers, soccer, and basketball athletes (16.5 +/- 1.6 yrs, 1.6 +/- 0.2 m, 60.2 +/- 14.1 kg) completed the Stability Evaluation Test (SET) on the NeuroCom VSR Sport (NeuroCom International, Clackamas, OR) to measure sway velocity. Video records of the SET test were used for Balance Error Scoring System (BESS) test scoring. A oneway ANCOVA compared composite sway velocity and BESS scores among sports. There was no statistically significant difference for sway velocity or BESS among sports (sway velocity soccer 2.3 +/- 0.4, dance 2.2 +/- 0.4, and basketball 2.4 +/- 0.4; BESS soccer 13.6 +/- 5.0, dance 11.9 +/- 5.5, and basketball 14.9 +/- 5.1, p>0.05). Balance was similar among athletes participating in different sports (dance, basketball, and soccer). Quasi-static balance may not play a significant role in neuromuscular control during movement and not be a significant risk factor to explain the disparity in ACL injury incidence among sports. Future research should examine the effects of dynamic balance and limb asymmetries among sports to elucidate on the existing differences on ACL injury incidence rates. PMID- 25433259 TI - Achilles and patellar tendon morphology in dancers with and without tendon pain. AB - OBJECTIVES: To examine Achilles and patellar tendon morphology in dancers with and without tendon pain. METHODS: Fifty-three dancers with and without Achilles and/or patellar tendon pain participated. Eleven age-matched non-dancers served as controls. Longitudinal ultrasound images of the middle and distal Achilles and proximal and distal patellar tendons were acquired. To assess macromorphology, the thickness of the middle and distal Achilles and proximal and distal patellar tendons were measured. Micromorphology was analyzed by selecting 2 x 2-mm2 regions of interest in the tendons; spectral analysis using the fast Fourier transform was run for several kernels (2 x 2-mm2 subimages) within each image, and the peak spatial frequency (PSF) was extracted. A one-way ANOVA compared asymptomatic, symptomatic, and control tendon thickness and PSF. RESULTS: Macromorphology: There was no significant difference between asymptomatic and symptomatic dancers in middle or distal Achilles tendon thickness and distal patellar tendon thickness. Proximal patellar tendons in control subjects were thinner than those in asymptomatic (p=0.036) and symptomatic (p=0.003) dancers. Micromorphology: There was no significant difference in PSF between asymptomatic and symptomatic dancers and controls in the Achilles or patellar tendon. CONCLUSION: Increased proximal patellar tendon thickness without changes in tendon micromorphology suggests that tendon adaptations are more likely activity related and less likely influenced by degeneration. PMID- 25433260 TI - An international study on dietary supplementation use in dancers. AB - Little is known of the prevalence and motives of dietary supplement use amongst dancers from different cultures. Investigating supplement use, presumed effects, and other factors may be crucial for improving educational and nutritional advice provided for this cohort. Therefore, this study investigated the use of dietary supplements in 334 dancers from 53 countries, who completed a digitally based 35 question survey detailing demographic information and the use of dietary supplementation. Supplement use was prevalent amongst this international cohort, with 48% reporting regular supplement use. Major motives for supplement use were to improve health, boost immunity, and reduce fatigue. Forty-five percent believed that dancing increased the need for supplementation, whilst 30% recognized that there were risks associated with nutritional supplementation. The most frequently consumed supplements were vitamin C (60%), multivitamins (67%), and caffeine (72%). A smaller group of participants declared the use of whey protein (21%) or creatine (14%). Supplements were mainly obtained from pharmacies, supermarkets, and health-food stores. Dancers recognized their lack of knowledge in dietary supplement use and relied on peer recommendations instead of sound evidence-based advice from acknowledged nutrition or health care professionals. This study demonstrates that dietary supplement use is internationally prevalent amongst dancers. Continued efforts are warranted with regard to information dissemination. PMID- 25433261 TI - Injury patterns and rates amongst students at the national institute of circus arts: an observational study. AB - Despite the ever-growing global participation in circus arts, very little research has been conducted into injuries associated with this physical discipline. To date, no studies have examined the incidence of injuries in circus training institutions and schools. In this study, data were collected over an academic year from all student injury presentations to the physiotherapy staff at one Australian circus school. A total of 351 injuries resulting in 1,948 treatments occurred in 33 female and 30 male circus students. The most common mechanisms of injury were acrobatics/tumbling (23%), handstands (12%), adagio (11%), and Chinese pole (10%). The most commonly injured body parts were the ankle (25%), lumbar spine (14%), and shoulder (12%). Interestingly, combined spinal injuries (cervical, thoracic, and lumbar) contributed to 35% of all initial injuries. Females sustained 71% of all hip injuries, but only 33% of all forearm injuries. Males accounted for 59% of all ankle injuries. There were no significant gender-based differences in other body areas. Results indicated that there is no gender-based difference in the overall rate of injury. However, females sustained significantly higher rates of hip injuries and males presented with more forearm and ankle injuries, perhaps reflecting the specific form and style of circus training and contortion undertaken. Spinal injuries had the highest overall rate of initial and follow-up presentations, indicating that both preventative and rehabilitative strategies could be addressed. It is suggested that the most common mechanisms of injury reflect both the amount of time spent training specific disciplines and the extreme physical difficulties and demands placed on the body. PMID- 25433262 TI - Typical musculoskeletal patterns in upper string players with neck and arm problems. AB - Upper string players face a very high risk of playing-related disorders. Based on a questionnaire and a physical examination, this study investigated if a typical musculoskeletal pattern emerges. It was found that the typical upper string musician shows problems with the neck, shoulders (with equal probability for left and right side, X2 = 0.53, p>0.05), right elbow (X2 = 4.80, p<0.05) and hand (X2 = 3.90, p<0.05), and fingers of the left hand (X2 = 9.53, p<0.01). This finding can be used to improve planning of preventive measures and therapeutic treatments. PMID- 25433263 TI - Ergonomic piano keyboards. PMID- 25433265 TI - Experimental Nephrectomies Using a Novel Telesurgical System: (The Telelap ALF-X) A Pilot Study. AB - PURPOSE: The SOFAR(r) Telelap Alf-X (Milan, Italy) is a novel telesurgical system which combines the advantages of both laparoscopy and open surgery. It offers some new features like tactile perception, open site view, eye-tracking control of the camera, and optimal ergonomics. OBJECTIVE: The aim of this study is to examine the feasibility and the safety of nephrectomy using a novel telesurgical system with haptic sensation: the Telelap Alf-X. MATERIALS AND METHODS: Twelve female swine underwent nephrectomies using the Telelap Alf-X system. Data regarding operative times, estimated blood loss (EBL), surgical methodology, and intraoperative complications are presented. RESULTS: The Telelap Alf-X's docking took less than one minute, the system was versatile during each step of the nephrectomy and the operative times have reduced dramatically along the learning curve. One intraoperative complication was recorded (Vena Cava injury-repaired using the robotic system) and the estimated blood loss was minimal. CONCLUSIONS: The Telelap Alf-X proved to be safe and reliable and can be easily used by the surgeon. The porcine model nephrectomies proved to be an excellent way to gain experience and avoid future complications. PMID- 25433264 TI - Oxidation and phosphorylation of MAP kinase 4 cause protein aggregation. AB - Mitogen-activated protein kinase (MPK) cascades are highly conserved signaling pathways that respond to environmental cues. Arabidopsis MPK4 has been identified as a stress-responsive protein kinase. Here we demonstrate that Brassica napus MPK4 (BnMPK4) is activated by hydrogen peroxide (H2O2) and phytohormone abscisic acid (ABA). Transient expression of a constitutively active BnMPK4 causes H2O2 production and cell death in Nicotiana benthamiana leaves. However, little is known about how H2O2 contributes to the regulation of MPK4 kinase function. Biochemical analysis revealed that recombinant BnMPK4 autophosphorylates on both threonine and tyrosine residues in the activation loop. In the presence of H2O2, phosphorylation of BnMPK4 caused protein aggregation in vitro. The aggregation of BnMPK4 could be reversed to the monomeric form by reducing reagents. Point mutation of cysteine codons indicated that cysteine 232 is involved in protein aggregation. Our results suggest that BnMPK4 is involved in reactive oxygen species (ROS) signaling and metabolism, and its aggregation may be modulated by redox. PMID- 25433266 TI - Downsizing annuloplasty in ischemic mitral regurgitation: double row overlapping suture to avoid ring disinsertion in valve repair. AB - The long-term outcomes of undersizing annuloplasty for the treatment of ischemic mitral regurgitation (IMR) is affected by the progressive dilation of the annulus, which carries increased risk for ring disinsertion. Reasons underlying this phenomenon might be found in the excess of physical stress on the annuloplasty sutures during the ventricular remodeling process. We report a technique based on the placement of a double row of overlapping sutures aiming at reducing the potential for ring disinsertion. Eleven patients with IMR undergoing mitral valve repair associated with coronary bypass grafting were treated with this technique and echocardiographically followed up at 6 and 12 months. The overall annular dimension decreased significantly with a significant reduction of the tenting area and no recurrence of mitral regurgitation at 1 year. A double row of overlapping sutures allowed firm attachment of the prosthetic ring while downsizing the annulus in IMR, limiting the consequences of changes in subannular ventricular geometry. This technique might therefore be considered a useful aid during mitral valve repair. PMID- 25433267 TI - Clinical and radiographic outcomes after spinous process fixation and posterior fusion in an elderly cohort. AB - Spinous process fixation (SPF) has gained attention as a less invasive option for lumbar fusion surgery. Minimally invasive techniques are of interest in an elderly population due to decreased surgical time and post-operative complications. Clinical outcomes and fusion rates have not been determined in a large cohort. Our objective was to describe significant predictors of visual analog scale (VAS), length of stay, blood loss, fusion rates, and complication rates for patients treated for degenerative lumbar spondolysis with ISP fixation with and without supplemental instrumentation. Charts were assessed for post operative VAS vs. pre-operative VAS at: 1-3, >3-6, and >6-12 months. To control confounding variables, VAS scores were modeled as a repeated-measures linear mixed-model. In a sub-cohort CT images were assessed for interspinous and interbody (IB) fusion. The images were reviewed by an independent radiologist to evaluate fusion status. Eighty-six SPF patients (91 levels, mean age 67 years) were identified. After determining the model, age and sex remained predictors of VAS. Adjusting for age and sex, patients saw a decrease of 3.6 VAS points from baseline to three months (95% CI: 2.9-4.4, p<0.0001) that was maintained over the six to 12 month follow-up period. A sub-cohort of 50 patients with CT scans were identified and assessed for ISP and IB fusion at a mean of 181 days postoperatively. Ninety-four percent of levels demonstrated ISP fusion. Sixty-one percent of solid ISP fusion patients also had an interbody cage, but this did not impact fusion rates. Eighty-six percent of these levels showed solid IB fusion (BSF-3). Of the four pseudoarthrosed levels, two had pedicle screw fixation, and two were IB and ISP fixation. Only two patients went on to re-exploration and explantation due to pain secondary to spinous process and/or lamina fracture. This elderly cohort treated with SPF demonstrated significant improvement in VAS with reliable fusion rates. PMID- 25433268 TI - Sonographic evaluation of autologous fat transfer to the biceps and triceps. AB - Autologous fat transfer (AFT) for increased tissue bulk has been reported on since the 1990s, and has increased by 26.6% from 2009 to 2010. Despite this increase, there is relatively little published data. While the described method of AFT to muscle tissue has advantages of being matched to the patient and retaining all the properties of tissue, challenges arise due to the size of muscles, the ability to measure immediate and long term placement and retention, and frequency of aberrant anatomy in order to avoid vasculature and potential complications; reportedly 10% to 27%. We present the results of a study using ultrasound visualization to assist in AFT to the biceps and triceps. Ten male subjects were treated with AFT to the biceps and triceps under intraoperative ultrasonic visualization. Pre- and post-operative circumferential measurements were collected as well as follow-up at weeks six and 12. A mean of 90 cc and 110 cc were injected subfascially into the biceps and triceps, respectively, of 10 study subjects. Post-operative circumferential measurements increased by a mean of 3.0 cm and follow-up measurements were found to have increased by a mean of 3.3 cm over baseline. No compartment syndrome, fat emboli or significant pain were experienced by any subject in this study. Autologous fat transfer to smaller muscle areas such as the bicep and tricep is both feasible and safe with consistent and durable results. The addition of pre-operative ultrasound imaging provides a means to safely avoid critical structures such as vasculature; and intra-operative ultrasound allows the surgeon to directly visualize the relevant anatomy as each injection is performed confirming intramuscular placement. PMID- 25433269 TI - Lysophosphatidic acid contributes to angiogenic homeostasis. PMID- 25433270 TI - PKCepsilon is a negative regulator of PVAT-derived vessel formation. AB - RATIONALE: Vessel formation is a crucial event in tissue repair after injury. Thus, one assumption of innovative therapeutic approaches is the understanding of its molecular mechanisms. Notwithstanding our knowledge of the role of Protein Kinase C epsilon (PKCepsilon) in cardio-protection and vascular restenosis, its role in vessel progenitor differentiation remains elusive. OBJECTIVE: Given the availability of PKCepsilon pharmacological modulators already tested in clinical trials, the specific aim of this study is to unravel the role of PKCepsilon in vessel progenitor differentiation, with implications in vascular pathology and vasculogenesis. METHODS AND RESULTS: Mouse Peri-Vascular Adipose Tissue (PVAT) was used as source of mesenchymal vessel progenitors. VEGF-induced differentiation of PVAT cells down-regulates both PKCepsilon and p-PAK1 protein expression levels. PKCepsilon overexpression and activation: i) reduced the expression levels of SMA and PECAM in endothelial differentiation of PVAT cells; ii) completely abrogated tubules formation in collagen gel assays; iii) increased the expression of p-PAK1. CONCLUSION: PKCepsilon negatively interferes with vessel progenitor differentiation via interaction with PAK-1. PMID- 25433271 TI - Diverse roles of LPA signaling in the intestinal epithelium. AB - Lysophosphatidic acid (LPA) is a lipid mediator that modulates a wide variety of cellular functions. Elevated LPA signaling has been reported in patients with colorectal cancer or inflammatory bowel diseases, and the tumorigenic role of LPA has been demonstrated in experimental models of colon cancer. However, emerging evidence indicates the importance of LPA signaling in epithelial wound healing and regulation of intestinal electrolyte transport. Here, we briefly review current knowledge of the biological roles of LPA signaling in the intestinal tract. PMID- 25433272 TI - Lidocaine potentiates the deleterious effects of triamcinolone acetonide on tenocytes. AB - BACKGROUND: Local anesthetics are commonly used for the treatment of a variety of tendinopathies in combination with corticosteroids injection. The goal of this study was to evaluate the effects of lidocaine and triamcinolone acetonide (TA) on cultured rat tenocytes and to determine whether there is a synergistic effect. MATERIAL/METHODS: Rat patellar tendon-derived tenocytes were cultured with or without TA and lidocaine, and the culture without any additive served as the control. Cell morphology and cell viability were evaluated. Expressions of tenocyte-related genes were measured by qRT-PCR. RESULTS: TA, when exposed to tenocytes in vitro, significantly decreased cell viability. The cells cultured with TA had a flattened shape. Moreover, the expressions of tenocyte-related genes in tenocytes were markedly decreased in the TA-treated group. We found that 1% lidocaine synergistically increased the deleterious effects of TA. CONCLUSIONS: Our data provide evidence of the detrimental effects of these drugs on tendon tissues. Injection of TA in combination with 1% lidocaine should be used with caution. PMID- 25433273 TI - Role of selenoprotein S (SEPS1) -105G>A polymorphisms and PI3K/Akt signaling pathway in Kashin-Beck disease. AB - OBJECTIVE: To investigate the relationship between SEPS1 polymorphism and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in Kashin-Beck disease (KBD) and further explore the pathogenesis of KBD. METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect SEPS1 -105G>A polymorphism in 232 cases and 331 controls. The protein expressions of PI3K/Akt signaling molecules in whole blood and chondrocytes were detected by Western blot. RESULTS: The frequencies of SEPS1 -105G>A genotype AA (21.1% vs 3.0%) and minor allele A (34.1% vs 16.0%) in KBD are significantly higher than those in controls (OR: 8.020, 95% confidence interval (95% CI) 6.341-10.290, P < 0.0001; OR: 2.470, 95% CI 2.001-4.463, P < 0.0001, respectively). SEPS1 AA genotype was an independent risk factor for KBD (adjusted OR: 9.345, 95% CI 4.254 20.529; P < 0.0001). The expression of Gbetagamma, PI3Kp110, pAkt and pGSK3beta in KBD group were higher than that in control group (all P < 0.05). Gbetagamma, pAkt and pGSK3beta protein expression of AA and GA increased than GG (all P < 0.05). Cell apoptosis was increasing and molecule expression of PI3K/Akt signaling pathway were up-regulated in the tert-Butyl hydroperoxide (tBHP) injured group, the cell apoptosis and expression levels of PI3K/Akt in Na2SeO3 group were decreased. CONCLUSIONS: The SEPS1 -105G>A is associated with an increased risk of KBD and influences the expression of PI3K/Akt signaling pathway in KBD patients. Apoptosis induced by tBHP in chondrocyte might be mediated via up-regulation of PI3K/Akt, Na2SeO3 has an effect of anti-apoptosis by down regulating of PI3K/Akt signaling pathway. PMID- 25433274 TI - Investigation of resins suitable for the preparation of biological sample for 3-D electron microscopy. AB - In the last two decades, the third-dimension has become a focus of attention in electron microscopy to better understand the interactions within subcellular compartments. Initially, transmission electron tomography (TEM tomography) was introduced to image the cell volume in semi-thin sections (~ 500 nm). With the introduction of the focused ion beam scanning electron microscope, a new tool, FIB-SEM tomography, became available to image much larger volumes. During TEM tomography and FIB-SEM tomography, the resin section is exposed to a high electron/ion dose such that the stability of the resin embedded biological sample becomes an important issue. The shrinkage of a resin section in each dimension, especially in depth, is a well-known phenomenon. To ensure the dimensional integrity of the final volume of the cell, it is important to assess the properties of the different resins and determine the formulation which has the best stability in the electron/ion beam. Here, eight different resin formulations were examined. The effects of radiation damage were evaluated after different times of TEM irradiation. To get additional information on mass-loss and the physical properties of the resins (stiffness and adhesion), the topography of the irradiated areas was analysed with atomic force microscopy (AFM). Further, the behaviour of the resins was analysed after ion milling of the surface of the sample with different ion currents. In conclusion, two resin formulations, Hard Plus and the mixture of Durcupan/Epon, emerged that were considerably less affected and reasonably stable in the electron/ion beam and thus suitable for the 3-D investigation of biological samples. PMID- 25433275 TI - Layered growth of crayfish gastrolith: about the stability of amorphous calcium carbonate and role of additives. AB - Previous studies on pre-molt gastroliths have shown a typical onion-like morphology of layers of amorphous mineral (mostly calcium carbonate) and chitin, resulting from the continuous deposition and densification of amorphous mineral spheres on a chitin-matrix during time. To investigate the consequences of this layered growth on the local structure and composition of the gastrolith, we performed spatially-resolved Raman, X-ray and SEM-EDS analysis on complete pre molt gastrolith cross-sections. Results show that especially the abundance of inorganic phosphate, phosphoenolpyruvate (PEP)/citrate and proteins is not uniform throughout the organ but changes from layer to layer. Based on these results we can conclude that ACC stabilization in the gastrolith takes place by more than one compound and not by only one of these additives. PMID- 25433276 TI - Characterisation of non-toxigenic Clostridium spp. strains, to use as surrogates for non-proteolytic Clostridium botulinum in chilled food challenge testing. AB - Under many of the conditions studied, a two-strain cocktail of non-toxigenic Clostridium spp. was found to be suitable as a surrogate for non-proteolytic Clostridium botulinum, and has the potential for use in chilled food challenge tests measuring growth. Non-toxigenic surrogates could also be used in thermal process screening studies. PMID- 25433278 TI - Kissing of Ovaries: Laparoscopic View of Uterine Inversion After Vaginal Delivery With Postpartum Hemorrhage. PMID- 25433277 TI - The association of combination of disc degeneration, end plate signal change, and Schmorl node with low back pain in a large population study: the Wakayama Spine Study. AB - BACKGROUND CONTEXT: Disc degeneration (DD) reportedly causes low back pain (LBP) and is often observed concomitantly with end plate signal change (ESC) and/or Schmorl node (SN) on magnetic resonance imaging. PURPOSE: The purpose of this study was to examine the association between DD and LBP, considering ESC and/or SN presence, in a large population study. STUDY DESIGN/SETTING: Cross-sectional population-based study in two regions of Japan. PATIENT SAMPLE: Of 1,011 possible participants, data from 975 participants (324 men, 651 women; mean age, 66.4 years; range, 21-97 years) were included. OUTCOME MEASURES: Prevalence of DD, ESC, and SN alone and in combination in the lumbar region and the association of these prevalence levels with LBP. METHODS: Sagittal T2-weighted images were used to assess the intervertebral spaces between L1-L2 and L5-S1. Disc degeneration was classified using the Pfirrmann classification system (grades 4 and 5 indicated degeneration); ESC was defined as a diffuse high signal change along either area of the end plate, and SN was defined as a small well-defined herniation pit with a surrounding wall of hypointense signal. Logistic regression analysis was used to determine the odds ratios (ORs) and confidence intervals (CIs) for LBP in the presence of radiographic changes in the lumbar region and at each lumbar intervertebral level, compared with patients without radiographic change, after adjusting for age, body mass index, and sex. RESULTS: The prevalence of lumbar structural findings was as follows: DD alone, 30.4%; ESC alone, 0.8%; SN alone, 1.5%; DD and ESC, 26.6%; DD and SN, 12.3%; and DD, ESC, and SN, 19.1%. These lumbar structural findings were significantly associated with LBP in the lumbar region overall, as follows: DD, ESC, and SN, OR 2.17, 95% CI 1.2-3.9; L1-L2, OR 6.00, 95% CI 1.9-26.6; L4-L5, OR 2.56, 95% CI 1.4-4.9; and L5-S1, OR 2.81, 95% CI 1.1-2.3. The combination of DD and ESC was significantly associated with LBP as follows: L3-L4, OR 2.43, 95% CI 1.5-4.0; L4-L5, OR 1.82, 95% CI 1.2-2.8; and L5-S1, OR 1.60, 95% CI 1.1-2.3. CONCLUSIONS: Our data suggest that DD alone is not associated with LBP. By contrast, the combination of DD and ESC was highly associated with LBP. PMID- 25433279 TI - Use of ultrasound debridement as an adjunctive tool for treating infected prosthetic vascular grafts in the lower extremities. AB - BACKGROUND: To evaluate the role of an ultrasound (US) debridement system to treat conservatively patients with poor medical conditions who presented with infection of a prosthetic vascular graft in the lower extremities. METHODS: Data of all patients who underwent debridement of the grafts and/or surrounding tissue using an ultrasonic generator (Genera, Italia Medica, Milan, Italy) were recorded and retrospectively reviewed. Based on cultures, patients received specific antibiotic therapy. Partial graft removal, sartorius muscle flap rotation, or negative pressure wound treatment (NPWT) was selectively used. Early and late morbidity and mortality and recurrence were analyzed. RESULTS: Thirteen patients (median age, 72 years; range, 57-92 years; 8 men) were treated (12 Szilagyi grade III and 1 grade II infections) with US debridement without removing the graft (8 cases) or with partial excision and "in situ" reconstruction with a silver prosthetic graft (5 cases). Sartorius flap rotation was associated in 6 and NPWT in 1 case. One patient died perioperatively because of pulmonary edema because of sepsis secondary to treatment failure. Estimated freedom from reinfection was 90.9 +/- 9% at 6 months and 77.9 +/- 14% at 1 and 2 years. Estimated limb survival was 78.7 +/- 13% at 6 months, 65.6 +/- 16% at 1 year, and 52.5 +/- 18% at 2 years. CONCLUSIONS: US debridement proved to be a valuable aid in the treatment of patients with infected grafts and poor medical conditions. Used in conjunction with antibiotics, it allowed us to be more conservative without compromising the chance of success. PMID- 25433280 TI - Endovascular hypogastric artery preservation during endovascular aneurysm repair: a review of current techniques and devices. AB - Despite the improvement in endovascular techniques, one aspect of aneurysmal disease that continues to be challenging is the management of aortoiliac aneurysms. Sacrificing the hypogastric artery (HGA) for effective treatment is not without sequelae, which may include buttocks claudication, colonic ischemia, spinal cord ischemia, as well as buttock and scrotal necrosis. This should be taken into consideration particularly in patients with previous intervention or potential additional future interventions. This review describes the current endovascular techniques for preservation of HGA perfusion. PMID- 25433281 TI - A case of difficult catheterization of the contralateral limb of the Ovation Abdominal Stent Graft System in challenging aortoiliac anatomy, facilitated through the brachial access: a word of caution. AB - The Ovation Stent Graft System is a new trimodular endoprosthesis for the treatment of abdominal aortic aneurysms. A long nitinol stent with anchors serves the suprarenal fixation, whereas inflatable rings in the main body achieve sealing. This dissociation precludes the presence of a nitinol skeleton in the endograft, thus, avoiding competing for the same space within the delivery system, enabling the latter to achieve ultra-low profiles. However, the lack of nitinol support may render the endograft's docking limb prone to collapse in cases of narrow aortoiliac anatomy. We present a case of challenging contralateral limb catheterization, facilitated effectively through the brachial access. Preparing for the brachial route remains a useful and time-sparing adjunctive measure that guarantees the device's safety and effectiveness in challenging anatomies. PMID- 25433282 TI - Hydrogen sulfide reduces inflammation following abdominal aortic occlusion in rats. AB - BACKGROUND: Remote renal ischemia-reperfusion injury (IRI) following infra-renal aortic occlusion leads to acute kidney injury and systemic inflammation. Hydrogen sulfide is a mediator of IRI and can ameliorate tissue injury in many organ systems. Its role in vascular surgery has yet to be established. We assessed the role of hydrogen sulfide in a rodent model of aortic occlusion. METHODS: Wistar rats were divided into sham, control, and treatment groups (n = 6). Inflammation was assessed using a nonrecovery protocol. The infra-renal aorta was cross clamped for 60 min and animals were reperfused for 120 min. Ten minutes before clamp release, treatment animals received hydrogen sulfide (10, 30, or 50 MUg/kg) and control animals received 0.9% saline injected into the retroperitoneum. Renal injury and histology were assessed by a recovery protocol. The procedure was identical to the nonrecovery arm but with a single dose of hydrogen sulfide (30 MUg/kg) and animals were recovered for 7 days. RESULTS: There was no difference in animal weight between the groups (P = 0.337). In the nonrecovery arm, there was a reduction in serum levels of tumor necrosis factor alpha in sulfide-treated animals compared with controls (909 +/- 98 vs. 607 +/- 159 pg/mL; P = 0.0038). There was also a reduction in myeloperoxidase-positive cells in renal tissue in the sulfide-treated animals compared with controls (8 +/- 4 vs. 17 +/- 9; P = 0.03). There was no difference in histological injury score or endothelin-1 levels. In the recovery arm, there was no difference in renal function, Kidney Injury Molecule-1 levels, or histological injury scores. CONCLUSION: Hydrogen sulfide has systemic and renal anti-inflammatory effects in remote IRI following aortic occlusion in rats. PMID- 25433283 TI - Hypothermic, initially oxygen-free, controlled limb reperfusion for acute limb ischemia. AB - BACKGROUND: Controlled limb reperfusion has been shown to prevent the deleterious effects of ischemia-reperfusion (IR) syndrome following revascularization of acute limb ischemia (ALI). To reduce the production of cell-toxic oxygen-free radicals, we have established a new initially oxygen-free, hypothermic, heparin coated perfusion and hemofiltration system and report on our first results. METHODS: In a retrospective single-center study, controlled limb reperfusion was applied in 36 patients (64.7 +/- 15 years) with ALI of category IIA to III (33.7 +/- 20.7 hr ischemic time). 52.8% had central (aortic and bifurcation) and 47.2% had peripheral (common iliac artery and distal) vascular occlusions. The common femoral artery and vein were cannulated, and a hypothermic (22 degrees C), initially oxygen-free, potassium-free ringer's solution was perfused using a heparin-coated extracorporeal membrane oxygenation (ECMO) and hemofiltration system with low-dose heparinization. Thirty-day mortality, clinical recovery of neurological dysfunction, limb amputation, and fasciotomy rate were analyzed. Laboratory parameters associated with ischemia and IR injury were determined. RESULTS: Average perfusion time was 94 +/- 35 min. Thirty-day mortality was 27.8%. 55.5% of patients showed complete recovery of motor and sensory dysfunction. A total of 27.8% of patients developed a compartment syndrome and required fasciotomy. Lower leg amputation was necessary in 11.1% of patients. Lactate levels were reduced in ischemic limbs by 25.3% within 60 min (P < 0.05). Preoperative negative base excess of -1.96 +/- 0.96 mmol/L was equalized after 12 hr (P < 0.05), while pH stayed balanced at 7.4. Serum potassium stayed within normal limits throughout 24 hr, and therefore systemic hyperkalemia was prevented and imminent metabolic acidosis was corrected. CONCLUSIONS: An initially oxygen free, hypothermic, heparin-coated ECMO counteracts local and systemic effects of IR injury. Reduced mortality and morbidity might result from this new treatment, although this could not be conclusively proven in our study. A prospective, randomized controlled trial is needed to prove superiority of this new concept. PMID- 25433284 TI - Unrecognized arteriosclerosis is associated with wound complications after below knee amputation. AB - BACKGROUND: Guillotine below-knee amputation (BKA) for wet gangrene is an unfortunate complication of poorly controlled diabetes. We examined risk factors associated with wound complications after amputation formalization in this patient population. METHODS: Retrospective data over a 4-year period were collected for patients undergoing guillotine BKA for wet gangrene followed by staged formalization. Patients with abnormal distal pulses underwent evaluation before formalization to stratify for peripheral arterial disease (PAD). Those patients with palpable pulses and no known PAD went to formalization without further investigation. Poor operative candidates underwent delayed formalization to allow for preoperative optimization. Patient history, interval between surgeries, pathology, and preformalization laboratories were tested for significance. Primary outcome was postformalization wound complication. RESULTS: Fifty-six amputations in 55 patients met inclusion criteria. Wound complications after formalization occurred in 18 cases, all BKAs (32%). A history of PAD was present in 19 patients (34.5%). On pathology, 23 patients (41%) had small-vessel atherosclerosis or arteriosclerosis. There was no association between wound complications and history of PAD (P = 0.4), preformalization albumin (P = 0.09), glucose (P = 0.9), white blood cell count (P = 0.4), or delayed versus expedited formalization (P = 0.8). Only the presence of microvascular disease on formal pathology was predictive of wound complications (P = 0.03). There was no association between microvascular disease on pathology and a history of PAD (P = 0.07). CONCLUSIONS: After formalization of lower extremity amputation for wet gangrene, traditional markers of PAD were not predictive of wound complications. Although formalization of guillotine BKA can safely be performed without significant delay, more thorough assessment of microvascular disease in the perioperative period may be useful in identifying patients at risk for wound failure. PMID- 25433285 TI - Endo first is not appropriate in some patients with critical limb ischemia because "bridges are burned". AB - BACKGROUND: The aims of this study were to determine the effect of failed prior endovascular treatment (EV) on early and midterm outcomes of subsequent lower extremity open surgical (OS) bypass. METHODS: Patients undergoing infrainguinal bypass for critical limb ischemia (CLI) from January 2008 to December 2011 were retrospectively reviewed. The results after first-line bypass and bypass after failure of EV treatment were compared. A total of 213 patients (65.25% men; average age, 73.30 years) underwent bypass. OS patients were then divided into 2 groups: group 1 consisted of 138 patients who underwent primary OS for CLI without prior EV (control group) and group 2 consisted of 75 patients who had OS after a failed attempt at elective EV for peripheral vascular disease. Of the 213 bypass performed, 34% had a prior infrainguinal failed EV. The primary study end points were early and 1-year major amputations and graft occlusion. The secondary outcomes included early and 1-year mortality and the level of distal revascularization. RESULTS: Secondary patency and limb salvage rates were significantly better in group 1 up to 1 year (99% vs. 86%; P < 0.001 at 1 month and 95% vs. 76%, P < 0.05 at 12 months, respectively). CONCLUSIONS: Previous failed EV should be predictive of poor outcome in patients undergoing distal OS for CLI. PMID- 25433286 TI - Evidence of a tomato spotted wilt virus resistance-breaking strain originated through natural reassortment between two evolutionary-distinct isolates. AB - A Tsw resistance-breaking tomato spotted wilt virus field isolate (TSWV-p331) found in northern Italy originated via reassortment from two evolutionary distinct TSWV strains, as revealed by recombination and phylogenetic analysis. Compared to the closest isolate present in the database, p331 NSs protein carries an unusually high number of amino acid substitutions, but no differences in the nucleocapsid protein. Despite these substitutions, p331 NSs is a potent silencing suppressor. As shown by phylogenetic analyses of TSWV nucleocapsid sequences collected over fifteen years, one likely p331 parental lineage has never been detected in northern Italy, allowing speculations on the origin of TSWV-p331. PMID- 25433287 TI - HCV infection induces the upregulation of miR-221 in NF-kappaB dependent manner. AB - The upregulation of miR-221 has been reported in variety of cancer, including HCV associated HCC, the mechanism of upregulation of miR-221 however remains unclear. In this study, it was found that miR-221 was significantly upregulated in serum of patients with HCV associated chronic hepatitis (cHCV), which suggested the possible biological significance of miR-221 in HCV infection. Important, the upregulated miR-221 was positive correlation with serum miR-122, alanine aminotransferase (ALT) and aspartate transaminase (AST), which are reported as biomarkers for liver injuries. Further studies indicated that HCVcc infection activated nuclear factor-kappa B (NF-kappaB) and the upregulation of miR-221 by HCVcc infection could totally blocked by NF-kappaB inhibitor (pyrrolidine dithiocarbamate, PDTC). In conclusion, HCVcc infection could upregulate the expression of miR-221 in NF-kappaB dependent manner. PMID- 25433289 TI - Brown adipose tissue and novel therapeutic approaches to treat metabolic disorders. AB - In humans, 2 functionally different types of adipose tissue coexist: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is involved in energy storage, whereas BAT is involved in energy expenditure. Increased amounts of WAT may contribute to the development of metabolic disorders, such as obesity associated type 2 diabetes mellitus and cardiovascular diseases. In contrast, the thermogenic function of BAT allows high consumption of fatty acids because of the activity of uncoupling protein 1 in the internal mitochondrial membrane. Interestingly, obesity reduction and insulin sensitization have been achieved by BAT activation-regeneration in animal models. This review describes the origin, function, and differentiation mechanisms of BAT to identify new therapeutic strategies for the treatment of metabolic disorders related to obesity. On the basis of the animal studies, novel approaches for BAT regeneration combining stem cells from the adipose tissue with active components, such as melatonin, may have potential for the treatment of metabolic disorders in humans. PMID- 25433288 TI - A tribal level phylogeny of Lake Tanganyika cichlid fishes based on a genomic multi-marker approach. AB - The species-flocks of cichlid fishes in the East African Great Lakes Victoria, Malawi and Tanganyika constitute the most diverse extant adaptive radiations in vertebrates. Lake Tanganyika, the oldest of the lakes, harbors the morphologically and genetically most diverse assemblage of cichlids and contains the highest number of endemic cichlid genera of all African lakes. Based on morphological grounds, the Tanganyikan cichlid species have been grouped into 12 16 distinct lineages, so-called tribes. While the monophyly of most of the tribes is well established, the phylogenetic relationships among the tribes remain largely elusive. Here, we present a new tribal level phylogenetic hypothesis for the cichlid fishes of Lake Tanganyika that is based on the so far largest set of nuclear markers and a total alignment length of close to 18kb. Using next generation amplicon sequencing with the 454 pyrosequencing technology, we compiled a dataset consisting of 42 nuclear loci in 45 East African cichlid species, which we subjected to maximum likelihood and Bayesian inference phylogenetic analyses. We analyzed the entire concatenated dataset and each marker individually, and performed a Bayesian concordance analysis and gene tree discordance tests. Overall, we find strong support for a position of the Oreochromini, Boulengerochromini, Bathybatini and Trematocarini outside of a clade combining the substrate spawning Lamprologini and the mouthbrooding tribes of the 'H-lineage', which are both strongly supported to be monophyletic. The Eretmodini are firmly placed within the 'H-lineage', as sister-group to the most species-rich tribe of cichlids, the Haplochromini. The phylogenetic relationships at the base of the 'H-lineage' received less support, which is likely due to high speciation rates in the early phase of the radiation. Discordance among gene trees and marker sets further suggests the occurrence of past hybridization and/or incomplete lineage sorting in the cichlid fishes of Lake Tanganyika. PMID- 25433290 TI - ROG1 encodes a monoacylglycerol lipase in Saccharomyces cerevisiae. AB - Lipid metabolism is extensively studied in Saccharomyces cerevisiae. Here, we report that revertant of glycogen synthase kinase mutation-1 (Rog1p) possesses monoacylglycerol (MAG) lipase activity in S. cerevisiae. The lipase activity of Rog1p was confirmed in two ways: through analysis of a strain with a double deletion of ROG1 and monoglyceride lipase YJU3 (yju3Deltarog1Delta) and by site directed mutagenesis of the ROG1 lipase motif (GXSXG). Rog1p is localized in both the cytosol and the nucleus. Overexpression of ROG1 in a ROG1-deficient strain resulted in an accumulation of reactive oxygen species. These results suggest that Rog1p is a MAG lipase that regulates lipid homeostasis. PMID- 25433291 TI - MicroRNA-1 promotes apoptosis of hepatocarcinoma cells by targeting apoptosis inhibitor-5 (API-5). AB - Although microRNA-1 (miR-1) is a known liver cancer suppressor, the role of miR-1 in apoptosis of hepatoma cells has remained largely unknown. Our study shows that ectopic miR-1 overexpression induced apoptosis of liver hepatocellular carcinoma (HepG2) cells. Apoptosis inhibitor 5 (API-5) was found to be a potential regulator of miR-1 induced apoptosis, using a bioinformatics approach. Furthermore, an inverse relationship between miR-1 and API-5 expression was observed in human liver cancer tissues and adjacent normal liver tissues. Negative regulation of API-5 expression by miR-1 was demonstrated to promote apoptosis of HepG2 cells. Our study provides a novel regulatory mechanism of miR 1 in the apoptosis of hepatoma cells. PMID- 25433292 TI - Protein-protein interaction studies provide evidence for electron transfer from ferredoxin to lipoic acid synthase in Toxoplasma gondii. AB - The only known redox system in the apicoplast, a plastid-like organelle of apicomplexan parasites, is ferredoxin and ferredoxin-associated reductase. Ferredoxin donates electrons to different enzymes, presumably including lipoate synthase (LipA), which is essential for fatty acid biosynthesis. We recombinantly expressed and characterized LipA from the protozoan parasite Toxoplasma gondii, generated LipA-specific antibodies and confirmed the apicoplast localization of LipA. Electron transfer from ferredoxin to LipA would require direct protein protein interaction. Such a robust interaction between the two proteins was demonstrated in both yeast and bacterial two-hybrid systems. Taken together, our results provide strong evidence for a role of ferredoxin as an electron donor to LipA. PMID- 25433293 TI - Do not attempt cardiopulmonary resuscitation (DNACPR) orders: a systematic review of the barriers and facilitators of decision-making and implementation. AB - Most people who die in hospital do so with a DNACPR order in place, these orders are the focus of considerable debate. AIM: To identify factors, facilitators and barriers involved in DNACPR decision-making and implementation. METHODS: All study designs and interventions were eligible for inclusion. Studies were appraised guided by CASP tools. A qualitative analysis was undertaken. DATA SOURCES: Included electronic databases: Medline, Embase, ASSIA, Cochrane library, CINAHL, PsycINFO, Web of Science, the King's Fund Library and scanning reference lists of included studies. RESULTS: Four key themes were identified: Considering the decision - by senior physicians, nursing staff, patients and relatives. Key triggers included older age, co-morbidities, adverse prognostic factors, quality of life and the likelihood of success of CPR. Discussing the decision - levels, and combinations, of physician and nursing skills, patient understanding and family involvement produced various outcomes. Implementing the decision - the lack of clear documentation resulted in a breakdown in communications within health teams. Staff knowledge and support of guidelines and local policies varied. Consequences of a DNACPR decision - inadequate understanding by staff resulted in suboptimal care, and incorrect withdrawal of treatment. CONCLUSION: Significant variability was identified in DNACPR decision-making and implementation. The evidence base is weak but the absence of evidence does not indicate an absence of good practice. Issues are complex, and dependent on a number of factors. Misunderstandings and poor discussions can be overcome such as with an overall care plan to facilitate discussions and reduce negative impact of DNACPR orders on aspects of patient care. PMID- 25433295 TI - Aggregate National Early Warning Score (NEWS) values are more important than high scores for a single vital signs parameter for discriminating the risk of adverse outcomes. AB - INTRODUCTION: The Royal College of Physicians (RCPL) National Early Warning Score (NEWS) escalates care to a doctor at NEWS values of >=5 and when the score for any single vital sign is 3. METHODS: We calculated the 24-h risk of serious clinical outcomes for vital signs observation sets with NEWS values of 3, 4 and 5, separately determining risks when the score did/did not include a single score of 3. We compared workloads generated by the RCPL's escalation protocol and for aggregate NEWS value alone. RESULTS: Aggregate NEWS values of 3 or 4 (n=142,282) formed 15.1% of all vital signs sets measured; those containing a single vital sign scoring 3 (n=36,207) constituted 3.8% of all sets. Aggregate NEWS values of either 3 or 4 with a component score of 3 have significantly lower risks (OR: 0.26 and 0.53) than an aggregate value of 5 (OR: 1.0). Escalating care to a doctor when any single component of NEWS scores 3 compared to when aggregate NEWS values >=5, would have increased doctors' workload by 40% with only a small increase in detected adverse outcomes from 2.99 to 3.08 per day (a 3% improvement in detection). CONCLUSIONS: The recommended NEWS escalation protocol produces additional work for the bedside nurse and responding doctor, disproportionate to a modest benefit in increased detection of adverse outcomes. It may have significant ramifications for efficient staff resource allocation, distort patient safety focus and risk alarm fatigue. Our findings suggest that the RCPL escalation guidance warrants review. PMID- 25433296 TI - Do not attempt cardiopulmonary resuscitation documentation: do doctors respond to national changes? PMID- 25433294 TI - Perception of CPR quality: Influence of CPR feedback, Just-in-Time CPR training and provider role. AB - AIM: Many healthcare providers rely on visual perception to guide cardiopulmonary resuscitation (CPR), but little is known about the accuracy of provider perceptions of CPR quality. We aimed to describe the difference between perceived versus measured CPR quality, and to determine the impact of provider role, real time visual CPR feedback and Just-in-Time (JIT) CPR training on provider perceptions. METHODS: We conducted secondary analyses of data collected from a prospective, multicenter, randomized trial of 324 healthcare providers who participated in a simulated cardiac arrest scenario between July 2012 and April 2014. Participants were randomized to one of four permutations of: JIT CPR training and real-time visual CPR feedback. We calculated the difference between perceived and measured quality of CPR and reported the proportion of subjects accurately estimating the quality of CPR within each study arm. RESULTS: Participants overestimated achieving adequate chest compression depth (mean difference range: 16.1-60.6%) and rate (range: 0.2-51%), and underestimated chest compression fraction (0.2-2.9%) across all arms. Compared to no intervention, the use of real-time feedback and JIT CPR training (alone or in combination) improved perception of depth (p<0.001). Accurate estimation of CPR quality was poor for chest compression depth (0-13%), rate (5-46%) and chest compression fraction (60 63%). Perception of depth is more accurate in CPR providers versus team leaders (27.8% vs. 7.4%; p=0.043) when using real-time feedback. CONCLUSION: Healthcare providers' visual perception of CPR quality is poor. Perceptions of CPR depth are improved by using real-time visual feedback and with prior JIT CPR training. PMID- 25433297 TI - Normobaric hyperoxia alters the microcirculation in healthy volunteers. AB - The use of high concentrations of inhaled oxygen has been associated with adverse effects but recent data suggest a potential therapeutic role of normobaric hyperoxia (NH) in sepsis and cerebral ischemia. Hyperoxia may induce vasoconstriction and alter endothelial function, so we evaluated its effects on the microcirculation in 40 healthy adult volunteers using side-stream dark field (SDF) video-microscopy on the sublingual area and near-infrared spectroscopy (NIRS) on the thenar eminence. In a first group of volunteers (n=18), measurements were taken every 30 min: at baseline in air, during NH (close to 100% oxygen via a non-rebreathing mask) and during recovery in air. In a second group (n=22), NIRS measurements were taken in NH or ambient air on two separate days to prevent any potential influence of repeated NIRS measurements. NH significantly decreased the proportion of perfused vessels (PPV) from 92% to 66%, perfused vessel density (PVD) from 11.0 to 7.3 vessels/mm, perfused small vessel density (PSVD) from 9.0 to 5.8 vessels/mm and microvascular flow index (MFI) from 2.8 to 2.0, and increased PPV heterogeneity from 7.5% to 30.4%. Thirty minutes after return to air, PPV, PVD, PSVD and MFI remained partially altered. During NH, NIRS descending slope and NIRS muscle oxygen consumption (VO2) decreased from 8.5 to 7.9%/s and 127 to 103 units, respectively, in the first group and from 10.7 to 9.4%/s and 150 to 115 units in the second group. NH, therefore, alters the microcirculation in healthy subjects, decreasing capillary perfusion and VO2 and increasing the heterogeneity of the perfusion. PMID- 25433298 TI - Putting a name on it: Ebstein's anomaly. PMID- 25433299 TI - Caveats to consider when calculating healthcare value. PMID- 25433300 TI - Antiphospholipid syndrome: an important differential diagnosis for culture negative endocarditis. PMID- 25433301 TI - Recurrent back pain of eosinophilic esophagitis. PMID- 25433302 TI - Temporal trends for secondary prevention measures among patients hospitalized with coronary artery disease. AB - BACKGROUND: Prior studies have noted that in-hospital adherence to secondary prevention measures varied among patients undergoing coronary artery bypass graft surgery, percutaneous coronary revascularization, or no intervention. We sought to study contemporary temporal trends in the in-hospital management of patients with coronary artery disease. METHODS: By using data from the Get With The Guidelines-Coronary Artery Disease registry, we compared adherence to 6 performance measures (aspirin within 24 hours, discharge on aspirin, discharge on beta-blockers, patients with low ejection fraction discharged on angiotensin converting enzyme inhibitor/angiotensin receptor blocker, smoking cessation counseling, and use of lipid-lowering medications) in eligible patients with coronary artery disease who underwent coronary artery bypass graft surgery, percutaneous coronary intervention, or no intervention between 2003 and 2008. RESULTS: A total of 113,971 patients with coronary artery disease were treated at 193 hospitals. Overall adherence to all 6 quality of care measures improved over time in all 3 treatment groups, but was highest at all time periods in the percutaneous coronary intervention group compared with the coronary artery bypass graft surgery group, whereas the no intervention group had the lowest use of prevention measures at all time points (P < .0001). Likewise, 100% adherence to all 6 measures was superior in the percutaneous coronary intervention group at all time points (P < .0001). On multivariable adjustment for case-mix of patients, the majority of these differences persisted. CONCLUSIONS: Over the last decade, overall adherence with secondary prevention measures improved significantly in patients hospitalized with coronary artery disease regardless of revascularization strategy. However, there still exist select opportunities for improving adherence, particularly among patients undergoing coronary artery bypass graft surgery or no intervention. PMID- 25433303 TI - Clinical features and prognosis of type 2 myocardial infarction in vasospastic angina. AB - BACKGROUND: Although generally the prognosis of vasospastic angina is considered excellent, vasospasm has been shown to be a cause of type 2 myocardial infarction. This study was performed to investigate the clinical characteristics and prognosis of patients with vasospastic angina complicated with type 2 myocardial infarction. METHODS: We performed a retrospective analysis of 171 consecutive patients with definite vasospastic angina (median age, 64 years; 55.0% were male) who visited the Kameda Medical Center with chest pain and in whom cardiac troponin I level was measured between 2005 and 2013. The patients were divided into type 2 myocardial infarction and non-type 2 myocardial infarction groups. A diagnosis of type 2 myocardial infarction was based on a serum cardiac troponin I value >99th percentile upper reference limit. The primary end point was a combination of nonfatal myocardial infarction or death by any cause. RESULTS: A total of 42 patients (24.6%) were diagnosed with type 2 myocardial infarction, and the type 2 myocardial infarction group had a higher incidence of combined end point than the non-type 2 myocardial infarction group during the median follow-up of 4.4 years (26.2% vs 9.3%, respectively, P = .008). Type 2 myocardial infarction remained an independent predictor of combined end point even after adjusting by the Japanese Coronary Spasm Association risk factors for combined end point (hazard ratio, 2.84; 95% confidence interval, 1.22 6.61; P = .02). CONCLUSIONS: Approximately one quarter of patients with vasospastic angina were associated with type 2 myocardial infarction, and this population should be identified as a new high-risk subgroup of those with vasospastic angina requiring an alternative treatment strategy. PMID- 25433304 TI - Too much of a good thing: digitalis toxicity. PMID- 25433305 TI - Clinical aspects for survivin: a crucial molecule for targeting drug-resistant cancers. AB - Drug resistance is frequently found in cancer patients who have prolonged chemotherapeutic treatments. Overcoming this phenomenon to make therapy available to these patients is one of the most important features in developing effective cancer therapeutic strategies. Identification of drug resistance causative molecules is one of the most focused areas of cancer research today. Many molecules have been identified in conferring cancer cells the property of drug resistance, and various small molecule inhibitors have been developed to target these molecules to restore the sensitivity of different traditional chemotherapeutic agents, which are frequently found to exhibit reduced potency during prolonged treatment, in cancer patients. Survivin, a member of the inhibitor of apoptosis proteins (IAP) family, has been identified as one of the most crucial biomarkers in the recognition of drug resistance. Survivin is overexpressed in tumor cells, helping in its proliferation and survival, and its overexpression is positively correlated with poor prognosis for cancer patients. Targeted therapeutic measures to inhibit survivin in cancers, particularly drug resistant tumors, are the recent focus of research for cancer treatment. PMID- 25433306 TI - Prognostic factors in patients receiving third line targeted therapy for metastatic renal cell carcinoma. AB - PURPOSE: Several prognostic models have been proposed for metastatic renal cell carcinoma but none has been validated in patients who receive third line targeted agents. We evaluated prognostic factors in patients with metastatic renal cell carcinoma who received a third line targeted agent. MATERIALS AND METHODS: We retrospectively reviewed data on 2,065 patients with clear cell metastatic renal cell carcinoma who were treated with targeted therapy at a total of 23 centers in Italy. Included in final analysis were 281 patients treated with 3 targeted agents. Overall survival was the main outcome. Cox proportional hazards regression followed by bootstrap validation was used to identify independent prognostic factors. RESULTS: Three clinical characteristics (ECOG performance status greater than 1, metastasis at diagnosis and liver metastasis) and 2 biochemical factors (hemoglobin less than the lower limit of normal and neutrophil count greater than the upper limit of normal, respectively) were prognostic. Patients were classified into 3 risk categories, including low-zero or 1, intermediate-2 and high risk-more than 2 risk factors. Median overall survival was 19.7, 10.1 and 5.5 months, and 1-year overall survival was 71%, 43% and 15%, respectively. The major limitation was the retrospective nature of this study and absent external validation. CONCLUSIONS: This nomogram included clinical and biochemical prognostic factors. In clinical trials it may be useful to select patients and define the prognosis. PMID- 25433307 TI - Combination treatment of renal cell carcinoma with belinostat and 5-fluorouracil: a role for oxidative stress induced DNA damage and HSP90 regulated thymidine synthase. AB - PURPOSE: Despite several therapeutic options renal cell carcinoma is associated with a poor clinical outcome. Therefore, we investigated whether combining 5 fluorouracil with the histone deacetylase inhibitor belinostat would exert a synergistic effect on renal cell carcinoma cells in vitro and in vivo. MATERIALS AND METHODS: We used SN12C cells treated with 5-fluorouracil and/or belinostat in vitro and in xenograft experiments in vivo. Cell viability and death mechanisms were assessed by MTS assay and Western blot. To investigate the role of reactive oxygen species we used H2DCF-DA, reactive oxygen species scavengers and the roGFP2 construct. RESULTS: Belinostat potentiated the anticancer effect of 5 fluorouracil. It synergistically induced apoptosis by activating caspases and increasing the subG1 cell population. Effects on reactive oxygen species mediated DNA damage included decreased thioredoxin expression and increased levels of TBP 2, gamma-H2AX and Ac-H3. Furthermore, belinostat attenuated the 5-fluorouracil mediated induction of thymidylate synthase via HSP90 hyperacetylation. Co administration of 5-fluorouracil with belinostat similarly reduced tumor volume and weight, and increased gamma-H2AX and Ac-H3 levels in the SN12C xenograft model. CONCLUSIONS: In combination with 5-fluorouracil the targeted inhibitor of histone deacetylase synergistically inhibited renal cancer cell growth by the blockade of thymidylate synthase induction and the induction of reactive oxygen species mediated DNA damage in vitro and in vivo. Our results suggest that combined treatment with belinostat and 5-fluorouracil may represent a promising new approach to renal cancer. PMID- 25433309 TI - Dichloroacetate induces cell cycle arrest in human glioblastoma cells persistently infected with measles virus: a way for controlling viral persistent infection. AB - We have previously established a human glioblastoma cell line persistently infected with mutant measles virus (MV), and found increased functions of mitochondria in MV persistently infected cells compared with uninfected or acutely infected cells. Moreover, impairment of mitochondria functions induced a breakdown of persistent infection, which suggested that mitochondria might play an important role in the maintenance of persistent infection and loss or functional alterations of mitochondria might be a candidate for possible intervention in persistent infection. In this study we examined the effect of dichloroacetate (DCA), which is known to increase pyruvate oxidation, on mitochondrial functions in MV persistently infected cells. DCA caused mitochondrial dysfunction and cell cycle arrest in MV persistently infected cells; consequently, the expression level of MV proteins were decreased in a DCA dependent manner. Here, we present a new therapeutic approach for persistent infection targeting mitochondrial respiration. Advantage to targeting mitochondrial respiration is that the impairment of mitochondrial functions by DCA is found in MV persistently infected cells not in uninfected cells, which may offer a promising chemotherapeutic strategy with few adverse effects. PMID- 25433308 TI - Viperin protein expression inhibits the late stage of respiratory syncytial virus morphogenesis. AB - We examined the effect of respiratory syncytial virus (RSV) infection on viperin protein expression in the permissive HEp2 and non-permissive RAW 264.7 macrophage cell lines. In RSV-infected HEp2 cells low levels of the viperin protein was localized to the virus-induced inclusion bodies and did not impair virus transmission in these cells. In contrast, RSV-infected RAW 264.7 cells increased expression of the STAT1 protein occurred at between 6 and 12h post-infection, which coincided with the appearance of P-STAT1. A relatively high level of viperin protein expression was detected in infected RAW 264.7 cells, and it was extensively localized throughout the cytoplasm of infected cells. The effect of early viperin protein expression on RSV infection in cells that are normally permissive to RSV cultivation was examined by using either transient transfected HEp2 cells or stable transfected HeLa cells that expressed the viperin protein. The early expression of viperin in HeLa cells did not prevent virus infection, and no significant inhibitory effect on either virus protein expression or targeting of virus proteins to the cell surface was noted. However, while inclusion body formation was not inhibited, early viperin protein expression was associated with the inhibition of virus filament formation and reduced cell-to cell virus transmission. Inhibition of virus filament formation was also observed in HEp2 cells expressing viperin. Collectively our data suggested that viperin impaired RSV transmission by inhibiting virus filament formation, providing a basis for its anti-virus activity in RSV-infected cells. PMID- 25433313 TI - Detection of presumptive mycoparasites associated with Entomophaga maimaiga resting spores in forest soils. AB - The fungal pathogen Entomophaga maimaiga can provide high levels of control of the gypsy moth, Lymantria dispar, an important forest defoliator. This fungus persists in the soil as resting spores and occurs naturally throughout many areas where gypsy moth is established. Studies on the spatial dynamics of gypsy moth population have shown high variability in infection levels, and one possible biological factor could be the variable persistence of E. maimaiga resting spores in the soil due to attacks by mycoparasites. We surveyed presumptive mycoparasites associated with parasitized E. maimaiga resting spores using baiting and molecular techniques and identified an ascomycete (Pochonia sp.) and oomycetes (Pythium spp.). PMID- 25433312 TI - Characterisation of novel Bacillus thuringiensis isolates against Aedes aegypti (Diptera: Culicidae) and Ceratitis capitata (Diptera: Tephridae). AB - Bacillus thuringiensis is successfully used in pest management strategies as an eco-friendly bioinsecticide. Isolation and identification of new strains with a wide variety of target pests is an ever growing field. In this paper, new B. thuringiensis isolates were investigated to search for original strains active against diptera and able to produce novel toxins that could be used as an alternative for the commercial H14 strain. Biochemical and molecular characterization revealed a remarkable diversity among the studied strains. Using the PCR method, cry4C/Da1, cry30Ea, cry39A, cry40 and cry54 genes were detected in four isolates. Three strains, BLB355, BLB196 and BUPM109, showed feeble activities against Aedes aegypti larvae. Interestingly, spore-crystal mixtures of BLB361, BLB30 and BLB237 were found to be active against Ceratitis capitata with an LC50 value of about 65.375, 51.735 and 42.972 MUg cm(-2), respectively. All the studied strains exhibited important mortality levels using culture supernatants against C. capitata larvae. This suggests that these strains produce a wide range of soluble factors active against C. capitata larvae. PMID- 25433315 TI - Non-adherence to medication: a challenge for person-centred pharmacotherapy to resolve the problem. AB - Pharmacotherapy today is claimed to be fascinating, scientific, rational, and objective, very much evidence-based, powerful and fundamental form of treatment for many medical conditions. Non-adherence to medication as an invisible epidemic is argued to be an Achilles' heel of evidence based medicine. Person-centered psychiatry has an important role in helping medicine to better understand human nature, human behavior and patients' choice in complex interactions. Non adherence is a major target for interventions to improve the quality and outcomes of health care. PMID- 25433314 TI - Chronic consumption of trans fat can facilitate the development of hyperactive behavior in rats. AB - In recent decades, the increased consumption of processed foods, which are rich in hydrogenated vegetable fat (HVF), has led to a decreased consumption of fish and oilseed, rich in omega-3 fatty acids. This eating habit provides an increased intake of trans fatty acids (TFA), which may be related to neuropsychiatric conditions, including inattention and hyperactivity. In this study, we evaluated the potential connection between prolonged trans fat consumption and development of hyperactivity-like symptoms in rats using different behavioral paradigms. Trans fat intake for 10 months (Experiment 1), as well as during pregnancy and lactation across two sequential generations of rats, (Experiment 4) induced active coping in the forced swimming task (FST). In addition, HVF supplementation was associated with increased locomotion before and after amphetamine (AMPH) administration (Experiment 2). Similarly, HVF supplementation during pregnancy and lactation were associated with increased locomotion in both young and adult rats (Experiment 3). Furthermore, trans fat intake across two sequential generations increased locomotor and exploratory activities following stressors (Experiment 4). From these results, we suggest that chronic consumption of trans fat is able to enhance impulsiveness and reactivity to novelty, facilitating hyperactive behaviors. PMID- 25433310 TI - T cell responses in hepatitis C virus infection: historical overview and goals for future research. AB - Hepatitis C virus (HCV)-specific T cells are key factors in the outcome of acute HCV infection and in protective immunity. This review recapitulates the steps that immunologists have taken in the past 25years to dissect the role of T cell responses in HCV infection. It describes technical as well as disease-specific challenges that were caused by the inapparent onset of acute HCV infection, the difficulty to identify subjects who spontaneously clear HCV infection, the low frequency of HCV-specific T cells in the blood of chronically infected patients, and the lack of small animal models with intact immune systems to study virus host interaction. The review provides a historical perspective on techniques and key findings, and identifies areas for future research. PMID- 25433311 TI - Influence of the lipid membrane environment on structure and activity of the outer membrane protein Ail from Yersinia pestis. AB - The surrounding environment has significant consequences for the structural and functional properties of membrane proteins. While native structure and function can be reconstituted in lipid bilayer membranes, the detergents used for protein solubilization are not always compatible with biological activity and, hence, not always appropriate for direct detection of ligand binding by NMR spectroscopy. Here we describe how the sample environment affects the activity of the outer membrane protein Ail (attachment invasion locus) from Yersinia pestis. Although Ail adopts the correct beta-barrel fold in micelles, the high detergent concentrations required for NMR structural studies are not compatible with the ligand binding functionality of the protein. We also describe preparations of Ail embedded in phospholipid bilayer nanodiscs, optimized for NMR studies and ligand binding activity assays. Ail in nanodiscs is capable of binding its human ligand fibronectin and also yields high quality NMR spectra that reflect the proper fold. Binding activity assays, developed to be performed directly with the NMR samples, show that ligand binding involves the extracellular loops of Ail. The data show that even when detergent micelles support the protein fold, detergents can interfere with activity in subtle ways. PMID- 25433317 TI - Computer representation of osteosynthesis stability in locking plates used for the treatment of osteoporotic proximal humerus fractures. AB - BACKGROUND: Proximal humerus fractures are represented as 4-5% of all fractures, with incidence notably growing with age. Since surgical internal fixation in treatment of proximal humeral fractures is used, fractures of osteoporotic bone and choice of plate for their osteosynthesis represent particular problem. The aim of the study was to test two locking plates: Philos plate with locking screws with determinated direction, and Arthrex plate with poliaxial locking screws, using the finite element method. SUBJECTS AND METHODS: This study used version 6.10 of Abaqus FEA software package for simulation and fine element analysis of Philos and Artrex plates attached to the osteotomy models of proximal humerus with fracture gap at 0 degrees , 10 degrees and 20 degrees in four types of static load: abduction, adduction, axial compression and flexion. Simulation results of loads in abduction, adduction, axial loads and flexion, were described with the total bone displacement (U) and maximum bone displacement in the fracture gap (Uf). RESULTS: When examining the Philos plate in axial load on the bone with fracture gap angle from 0 degrees , 10 degrees and 20 degrees no significant differences between the results for the displacements were observed. Therefore, results for other loads are related to total displacements of the bone only at the angle of 0 degrees . Given that the results of the total bone displacement and maximum bone displacement in the fracture gap with Artrex plate were mostly higher, for comparison with the results of bone displacement in Philos plate it was taken that total bone displacement and maximum displacement in the fracture gap in Artrex plate represent 100% of the total displacement. Philos plate showed 60.71% for abduction, 76.07% for adduction, 102.24% for axial loads and 79.59% for flexion of total bone displacement in Artrex plate, and 60.48% for abduction, 76.07% for adduction, 96.05% for axial load and 79.96% for flexion of maximum displacement in the fracture gap in Artrex plate. CONCLUSIONS: Osteosynthesis for osteoporotic fractures of proximal humerus with Philos plate in computer simulation proved to be more stable than with Arthrex plate. PMID- 25433316 TI - Correlation between biochemical and histopathological parameters in patients with chronic hepatitis C treated with pegylated interferon and ribavirin. AB - AIM: The main goal of this study was to compare the biochemical and histopathological findings in patients with sustained virological response (SVR) before and two years after the therapy with pegylated interferon alpha-2a and ribavirin in chronic hepatitis C. SUBJECTS AND METHODS: The study was conducted at the Department of Internal Medicine and the Clinic for Infectious Diseases of the Clinical Hospital Mostar. The study included 48 patients whose treatment for chronic hepatitis C with pegylated interferon alpha-2a and ribavirin was finished two years prior to the achieved SVR at the end of the treatment. The main criterion for inclusion was a negative result of HCV RNA, determined by the RealTime HCV assay. After taking a history, physical examination, laboratory tests: AST, ALT, GGT, a liver biopsy were performed with the help of the ultrasound. The assessment of necroinflamatory score was determined by histologic activity index (HAI) score, and the stage of fibrosis according to Knodell's numerical score. RESULTS: The values of AST and ALT levels were statistically significantly decreased after the successful treatment (p<0.001), as well as the value of HAI score (p=0.001) and the stage of fibrosis (p=0.010), in contrast to GGT (p=0.054). For the components of HAI score like focal necrosis (0.001) and portal inflammation (0.042) the result showed that they were significantly higher before the therapy, which was not true for the piecemeal (p=0.054) and confluated necrosis (p=0.078). The improvement of HAI score after therapy was found in 36 patients (75.0%), and 27 patients (56.2%) showed an improvement in the degree of fibrosis with the most common improvement of 1 degree (85.7%). One third of patients (31.3%) had the same result in the degree of fibrosis before and after the therapy. Before the treatment, a positive correlation was observed between ALT (p=0.039) and AST (p=0.04) with HAI, AST and the stage of fibrosis (p=0.04). In contrast, after the treatment the only correlation was observed between AST and the stage of fibrosis (p=0.042). CONCLUSION: Virological and biochemical responses in patients with SVR may not reflect the histopathological effects of the treatment and therefore these patients should be monitored for the possible development of the liver cirrhosis and hepatocellular carcinoma. PMID- 25433318 TI - The Results of Internal Fixation of Proximal Humeral Osteoporotic Fractures with PHILOS Locking Plate. AB - BACKGROUND: In the last fifty years since plate and screw osteosynthesis has been implemented in fracture treatment, osteosporotic bone fractures were observed as a special problem. Due to special histologic, anatomic, physical and biomehanic properties of osteoporotic changed bone the laws of biomechanics suggest that stable osteosynthesis for osteoporotic bone is necessary to increase the contact surface of metallic implants and bone and the stability of the screw-plate-bone compound. There are numerous surgical techniques and methods for treatment of osteoporotic proximal humeral fractures. Every surgical procedure has to establish anatomical reduction and stable fixation that will enable early mobilisation. SUBJECTS AND METHODS: The aim of this study was to present results of internal fixation of proximal humeral osteoporotic fractures with PHILOS locking plate. Between 2007 and 2012, a total of 67 patients older than 65 years with closed proximal humerus fractures underwent surgical treatment with PHILOS plate system (Synthes, Switzerland). 42 patients were operated with deltopectoral approach and 25 with deltoid split approach. After a mean follow up period of 14.68 (6-28) months functional and radiologic results were assessed. RESULTS: We noted 9 postoperative complications related to surgical technique (1 intraarticular screw placement, 1 displacement in major tuberculum fragment, 1 displacement in major tuberculum fragment along with oblique placement of the plate, 2 cases of inadequate reduction, 1 case of humeral head avascular necrosis, varus humeral head fixation in 3 cases). None of the patients developed superficial or deep surgical infection. There was no nonunions. In the final evaluation, the Constant shoulder score was 91.75 (72-100). CONCLUSIONS: In this study PHILOS locking plate showed good applicability, respecting bone biologic properties because of negligible interference with blood supply of the humeral head. There was no requirement to shape the plate enabling stabilization at constant angles as clear benefit of this plate. All that enables early mobilisation, and no implant insufficiency resulting in satisfactory treatment results and high Constant shoulder scores. PMID- 25433319 TI - Postoperative infections after posterior spondylodesis of thoracic and lumbal spine. Surgical spine infections. AB - BACKGROUND: Postoperative infection after posterior spondylodesis of thoracic and lumbal spine is the most common complication, and a reason for revision surgery. Aim of this work is to analyze rate of postoperative spine infections at our institution, and to determine eventual risk factors. SUBJECTS AND METHODS: In our paper we analyze incidence of deep surgical infections after posterior spondylodesis, performed on our Spine department during last 5 years (September 1, 2008 - September 1, 2013). Including criteria were: posterior spondylodesis with transpedicular screws from Th1 to S2 due to different spine indications (injuries, degenerations, deformities, tumors), absence of local or general infection prior the index surgery, surgery performed by the same surgeon (MB). Excluding criteria were: needle procedures (kypho/vertebro-plasties, nerve root and faset blocades), anterior spine surgeries, cervical spine surgeries, and decompresive surgeries. RESULTS: One hundred sixty five patients with 183 surgeries have been included in this study. Early surgical infection (within a month after the surgery) has appeared at five patients (2.7%). There have been no late surgical infections. Analyzing patients' charts, we have found that Meticillin-susceptible Staphylococcus aureus (MSSA) and Methicillin-resistant Staphylococcus aureus (MRSA) have caused infections in two patients, while Clebisiela pneumoniae ESBL has caused infection in one patient. Those five patients with infections have had further risk factors: long preoperative hospitalization at four patients, polytrauma, diabetes and advanced age at one patient, each. Three patients with postoperative infection had completely non titanium surface of implants, and other two had about 20% of non-titanium implant surface, although vast majority of surgeries have been performed by implants whose surface was completely titanium alloy. Infections have appeared between 10 30 postoperative days. In two patients where revision surgeries (debridement, drainage, antibiotic according the species) had been performed in two weeks after appearance of infection, infections have been cured. In three patients where revisions had been postponed for longer than two weeks, additional surgeries (removal of implants) were necessary for curing the infections. CONCLUSIONS: This study presented that rate of infection, microbiological species and risk factors are similar to the other orthopedics procedures and other institutions. Early revision is preferable, since it effectively avoids implant removal. PMID- 25433320 TI - The impact of socio-economic processes on the health of the adult population. AB - BACKGROUND: A cross-sectional study in the Primary Care Medical Centre Mostar and Regional Medical Center "Safet Mujic" was conducted. Family physicians randomly surveyed, examined, and analyzed laboratory tests from 300 subjects divided into three age groups from 20-39, 40-54 and 55-65 years, totally 100 subjects. Data for age, sex, smoking status, alcohol consumption, body mass index, blood pressure, blood glucose, triglycerides and cholesterol, and the presence of chronic non-communicable diseases, including diagnosis of depression and the presence of stress were entered in medical records. RESULTS: Levels of cholesterol were significantly higher in rural population as well as among students, and high triglyceride levels most frequently were presented in the student population. A group of farmers had a significantly higher prevalence of hypertension, DM and CVD compared to other investigated groups. The largest number of smokers and people who drink alcohol was present in group with the highest incomes, while obesity was significantly expressed in people with lower incomes. The group of examinees with the highest incomes had the greatest exposure to stress. CONCLUSIONS: Socioeconomic processes have an impact on risk behavior of the adult population, and the presence of a number of chronic diseases that are accompanied with increased laboratory blood glucose, cholesterol and triglycerides levels. PMID- 25433321 TI - Risk behaviour of prison inmates in relation to HIV/STI. AB - INTRODUCTION: Persons serving a prison sentence are identified as a population exposed to a higher risk of HIV/STIs due to a high incidence of risk behaviour, especially intravenous drug misuse. To show results of research on prevalence of HIV/STIs in relation to spread of risk behaviour and other risk factors. SUBJECTS AND METHODS: Cross-sectional study on a sample of 620 respondents in 10 prisons. A specially structured questionnaire was applied as a research instrument, together with blood sample taking for laboratory analysis of HIV, HBV, HCV and syphilis. RESULTS: Majority of respondents show insufficient knowledge about HIV/AIDS, ways of transmission prevention, especially knowledge on ways of HIV transmission. Every sixth respondent has experience of intravenous drug use, of which 58% exchanged drug injection equipment. Every fifth respondent with a tattoo had their tattoo done in prison. Below 2% of respondents quote being victims of sexual abuse, and having wilful anal sexual intercourse in prison. Test results in this research: HIV (0), HBV (1.5%), HCV (14.3%) syphilis (0.5%). CONCLUSION: Intravenous drug use presents the strongest risk factor for HCV, and therefore for HIV/ STIs. Other risk factors - tattooing with kit exchange, sexual risk intercourse, abuse, insufficient knowledge and information about HIV/AIDS, ways of transmission and way of protection, and lack of access to measures of prevention and "Harm reduction" programme. PMID- 25433322 TI - Epidemiological characteristics of children born with Down syndrome in western Herzegovina in the period of the last twenty years (1994-2013). AB - BACKGROUND: Children with Down syndrome (DS) are an everyday casuistry of pediatric clinical medicine. The prevalence of DS is dependent on socio demographic and cultural conditions of a community. Antenatal screening is not carried out mainly due to religious views, and the prevalence of DS in our region is really considered a "natural phenomenon". The aim of the study was to analyze some epidemiological characteristics of infants with Down syndrome in the western region of Herzegovina in the period between year 1994-2013. SUBJECTS AND METHODS: We performed a retrospective analysis of hospital records of children who were supervised and treated at Children's Hospital through the twenty-year period. RESULTS: In this period there were 44,100 liveborn infants. Down syndrome was detected in 78 children (54 male and 24 female). The prevalence is estimated at 1.8/1,000 of live births. Aborted fetuses and stillbirths were not analyzed. 37 (47%) of the parent couples were over 35 years of age. Out of that 65 cytogenetic analysis, a regular type of trisomy 21 was found in 94% of cases, and the translocation in 6%. From major malformations (MM) heart failure was more often present (47%), then the anomaly of the gastrointestinal and genitourinary systems. Ten children (12%) died, most often in the early period of infancy due to complications of the cardiovascular system. CONCLUSION: The prevalence of DS throughout these two decades has been uniform in the region of western Herzegovina. Improvement in perinatal care in recent years caused higher survival and a better quality of life for the children with DS and thus their families. DS is less a desirable family tragedy, and increasingly a tolerable family fate. PMID- 25433324 TI - Psychiatric Saturday in Mostar: the torchbearer of Mostar academic medicine. PMID- 25433323 TI - Adrenal ganglioneuroma in an adult - case report. PMID- 25433326 TI - Histone deacetylase inhibitors reverse manic-like behaviors and protect the rat brain from energetic metabolic alterations induced by ouabain. AB - Studies have revealed alterations in mitochondrial complexes in the brains of bipolar patients. However, few studies have examined changes in the enzymes of the tricarboxylic acid cycle. Several preclinical studies have suggested that histone deacetylase inhibitors may have antimanic effects. The present study aims to investigate the effects of lithium, valproate and sodium butyrate, a histone deacetylase inhibitor, on the activity of tricarboxylic acid cycle enzymes in the brains of rats subjected to an animal model of mania induced by ouabain. Wistar rats received a single intracerebroventricular injection of ouabain or cerebrospinal fluid. Starting on the day following the intracerebroventricular injection, the rats were treated for 7days with intraperitoneal injections of saline, lithium, valproate or sodium butyrate. Risk-taking behavior, locomotor and exploratory activities were measured using the open-field test. Citrate synthase, succinate dehydrogenase, and malate dehydrogenase were examined in the frontal cortex and hippocampus. All treatments reversed ouabain-related risk taking behavior and hyperactivity in the open-field test. Ouabain inhibited tricarboxylic acid cycle enzymes in the brain, and valproate and sodium butyrate but not lithium reversed this ouabain-induced dysfunction. Thus, protecting the tricarboxylic acid cycle may contribute to the therapeutic effects of histone deacetylase inhibitors. PMID- 25433327 TI - Evidence from peptidomic analysis of skin secretions that allopatric populations of Xenopus gilli (Anura:Pipidae) constitute distinct lineages. AB - The International Union for Conservation of Nature (IUCN) Endangered Cape Platanna Xenopus gilli inhabits disjunct ranges at the tip of Cape Peninsula and near the town of Kleinmond on opposite sides of False Bay in the extreme southwest of Africa. Peptidomic analysis of host-defense peptides in norepinephrine-stimulated skin secretions from frogs from the Cape Peninsula range resulted in the identification of two magainins, two peptide glycine leucine-amide (PGLa) peptides, two xenopsin-precursor fragment (XPF) peptides, nine caerulein-precursor fragment (CPF) peptides, and a peptide related to peptide glycine-glutamine (PGQ) previously found in an extract of Xenopus laevis stomach. The primary structures of the peptides indicate a close phylogenetic relationship between X. gilli and X. laevis but only magainin-1, PGLa and one CPF peptide are identical in both species. Consistent with previous data, the CPF peptides show the greatest antimicrobial potency but are hemolytic. There are appreciable differences in the expression of host-defense peptide genes in frogs from the population of animals sampled near Kleinmond as peptides corresponding to magainin-G2, XPF-G1, XPF-G2, and four CPF peptides, present in secretions from the Cape Peninsula frogs, were not identified in the skin secretions from Kleinmond frogs. Conversely, PGLa-G3, XPF-G3, and three CPF peptides were identified in the Kleinmond frogs but not in the Cape Peninsula animals. The data support the conclusion from morphometric analyses and comparisons of the nucleotide sequences of mitochondrial genes that the disjunct populations of X. gilli have undergone appreciable genetic, morphological, and phenotypic divergence. PMID- 25433325 TI - Repeated effects of the neurotensin receptor agonist PD149163 in three animal tests of antipsychotic activity: assessing for tolerance and cross-tolerance to clozapine. AB - Neurotensin is an endogenous neuropeptide closely associated with the mesolimbic dopaminergic system and shown to possess antipsychotic-like effects. In particular, acute neurotensin receptor activation can inhibit conditioned avoidance response (CAR), attenuate phencyclidine (PCP)-induced prepulse inhibition (PPI) disruptions, and reverse PCP-induced hyperlocomotion. However, few studies have examined the long term effects of repeated neurotensin receptor activation and results are inconsistent. Since clinical administration of antipsychotic therapy often requires a prolonged treatment schedule, here we assessed the effects of repeated activation of neurotensin receptors using an NTS1 receptor selective agonist, PD149163, in 3 behavioral tests of antipsychotic activity. We also investigated whether reactivity to the atypical antipsychotic clozapine was altered following prior PD149163 treatment. Using both normal and prenatally immune activated rats generated through maternal immune activation with polyinosinic:polycytidylic acid, we tested PD149163 in CAR, PCP (1.5mg/kg) induced PPI disruption, and PCP (3.2mg/kg)-induced hyperlocomotion. For each paradigm, rats were first repeatedly tested with vehicle or PD149163 (1.0, 4.0, 8.0mg/kg, sc) along with vehicle or PCP for PPI and hyperlocomotion tests, then challenged with PD149163 after 2 drug-free days. All rats were then challenged with clozapine (5.0mg/kg, sc). During the repeated test period, PD149163 exhibited antipsychotic-like effects in all three models. On the PD149163 challenge day, prior drug treatment only caused a tolerance effect in CAR. This tolerance in CAR was transferrable to clozapine, as it enhanced clozapine tolerance in the same group of animals. Although no tolerance effect was seen in the PD149163 challenge for the PCP-induced hyperlocomotion test, the clozapine challenge showed increased sensitivity in groups previously exposed to repeated PD149163 treatment. Our findings suggest that repeated exposure to NTS1 receptor agonists can induce a dose-dependent tolerance and cross-tolerance to clozapine to some of its behavioral effects but not others. PMID- 25433328 TI - Heat shock protein 70 gene family in the Glanville fritillary butterfly and their response to thermal stress. AB - Temperature variation in the environment is a great challenge to organisms. Induction of heat shock protein 70 (HSP70) is a common genetic mechanism to cope with thermal stress. The Glanville fritillary butterfly (Melitaea cinxia) is a model species in population and evolutionary biology, and its behavior and life history are greatly influenced by ambient temperature. We cloned and sequenced the full coding sequences of seven hsp70 genes from the Glanville fritillary. Of those genes, McHsc70-1 and McHsc70-2 were identified as heat shock cognate 70 (hsc70), of which the latter located in endoplasmic reticulum. We analyzed the expression patterns of different hsp70s under various thermal stresses using quantitative PCR. Heat shock at 40 degrees C for 2h induced high expression of McHsp70-1, McHsp70-2 and McHsc70-2. Only McHsc70-2 had a small increase after cold shock at 0 degrees C for 2h. Acclimation at 35 degrees C for three days before heat shock reduced expression of McHsp70 after heat shock. The maximum mRNA level of McHsp70s was reached in the first 2h after the heat shock. This study uncovers the complexity of the hsp70 system, and provides the valuable information for further temperature-related research in the Glanville fritillary butterfly. PMID- 25433329 TI - eNOS and coronary artery disease: publication bias and the eclipse of hypothesis driven meta-analysis in genetic association studies. AB - Genome-wide association studies have eclipsed candidate gene association studies in genetic epidemiology in providing robust, unbiased evidence for the role of genetic variants in complex traits and diseases. The hypothesis-free nature of GWAS inherently minimises the risk of publication bias, and where available these studies should be considered in any meta-analysis of genetic association studies. PMID- 25433330 TI - Molecular and functional characterization of opsins in barfin flounder (Verasper moseri). AB - Green light irradiation facilitates the somatic growth of barfin flounder (Verasper moseri). However, the V. moseri visual system, which may be associated with somatic growth by acting on the endocrine system upon exposure to this particular wavelength, remains largely unexplored. Herein, we characterized the visual opsin repertoire of V. moseri to understand the molecular basis underlying this effect. The five types of visual opsins that are found in vertebrates were cloned from RNA that was extracted from the eyes of V. moseri. Notably, V. moseri possessed one pseudogene (RH2-A) and two intact (RH2-B and RH2-C) copies of "green-sensitive" opsin genes. The wavelengths of maximum absorption spectra (lambdamax) for each of the reconstituted photopigments were 552nm for "red sensitive" LWS, 506nm for RH2-B, 490nm for RH2-C, 482nm and 416nm for "blue sensitive" SWS2A and SWS2B, respectively, 367nm for "ultraviolet-sensitive" SWS1, and 494nm for "dim-light sensitive rhodopsin" RH1. The lambdamax of SWS2A was longer than that of any other reported vertebrate SWS2 opsin. By measuring the expression level of these opsin genes with quantitative RT-PCR in 3-, 15-, and 27 month-old fish, we found that RH2-B and SWS2A were expressed at a constant level, whereas the expression of LWS, RH2-C, SWS2B, and SWS1 opsin genes decreased, and that of RH1 increased with age. Barfin flounders inhabit inshore waters at a young age and expand their habitat to deep sea areas as they age, and green light is relatively abundant in deep water compared to the lights of other wavelengths in shallow water. Our results indicate that gene repertoire and expression profile of the opsin genes of barfin flounder are adaptive to their habitat shift that occurs during development, with some opsins acquiring a distinct lambdamax. PMID- 25433331 TI - The influence of XRCC1 genetic variants on lung cancer susceptibility in Chinese Han population. AB - Growing evidence suggests that genetic variants of X-ray repair cross complementing group 1 proteins (XRCC1) contribute to genetic effects on the development of lung cancer. This case-control study aims to evaluate the genetic effects of XRCC1 c.482C>T and c.1686C>G single nucleotide polymorphisms (SNPs) on lung cancer susceptibility. 391 lung cancer patients and 398 cancer-free controls were enrolled in this study. The genotypes of c.482C>T and c.1686C>G genetic variants were detected by the created restriction site-polymerase chain reaction (CRS-PCR), PCR-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing methods. The genetic effects on lung cancer susceptibility were evaluated using association analyses by the unconditional logistic regression model. Our data indicated that there were significant differences in the distribution of allelic and genotypic frequencies between lung cancer patients and cancer-free controls. The XRCC1 c.482C>T and c.1686C>G genetic variants were significantly associated with the susceptibility to lung cancer (for c.482C>T, TT versus (vs.) CC: OR=2.14, 95% CI 1.31-3.48, P=0.002; T vs. C: OR=1.37, 95% CI 1.10-1.69, P=0.004; for c.1686C>G, GG vs. CC: OR=2.53, 95% CI 1.46-4.38, P=0.001; G vs. C: OR=1.33, 95% CI 1.06-1.65, P=0.012). These preliminary results suggested that the XRCC1 c.482C>T and c.1686C>G genetic variants might play genetic effects on the susceptibility to lung cancer in the studied population. PMID- 25433332 TI - The inflammation and estrogen metabolism impacts of polychlorinated biphenyls on endometrial cancer cells. AB - Polychlorinated biphenyls (PCBs) are persistent and bio-accumulative chemicals that provoke a wide range of toxic effects. Their adverse impacts on the reproductive system are of great concern, however, the effects of PCBs on endometrium are still unclear. In the study, the endometrial adenocarcinoma Ishikawa cells were exposed to both dioxin-like CB126 and non-dioxin-like CB153 at the nominal concentrations of 0.3, 3, and 30MUM. The inflammatory and endocrine effects were detected after treatment by PCBs. Results showed that CB126 stimulated the proliferation of Ishikawa cells at lower concentrations of 0.3 and 3MUM. By contrast, CB153 did not affect the viability of the cells. Both congeners exerted the stimulatory effects on the enzymatic activity of SOD1. CB126 decreased the abundance of Interleukin-8 both at the mRNA and protein levels. Blocking of estrogen receptor or aryl hydrocarbon receptor by the antagonist abolished the effects of CB126 on the expressions of inflammatory factors. The levels of testosterone and 17beta-estradiol were not changed after exposure to lower doses of PCBs. In accordance, PCBs did not affect the mRNA expressions of estrogen metabolism-related genes. In all, our study revealed that PCBs affected the expression of inflammatory factors through ER and AHR receptors, however, no toxic effects were observed on estrogen metabolism. PMID- 25433333 TI - Effects of CoCr metal wear debris generated from metal-on-metal hip implants and Co ions on human monocyte-like U937 cells. AB - Hip resurfacing with cobalt-chromium (CoCr) alloy was developed as a surgical alternative to total hip replacement. However, the biological effects of nanoparticles generated by wear at the metal-on-metal articulating surfaces has limited the success of such implants. The aim of this study was to investigate the effects of the combined exposure to CoCr nanoparticles and cobalt ions released from a resurfacing implant on monocytes (U937 cells) and whether these resulted in morphology changes, proliferation alterations, toxicity and cytokine release. The interaction between prior exposure to Co ions and the cellular response to nanoparticulate debris was determined to simulate the situation in patients with metal-on-metal implants receiving a second implant. Effects on U937 cells were mainly seen after 120h of treatment. Prior exposure to Co ions increased the toxic effects induced by the debris, and by Co ions themselves, suggesting the potential for interaction in vivo. Increased TNF-alpha secretion by resting cells exposed to nanoparticles could contribute to osteolysis processes in vivo, while increased IFN-gamma production by activated cells could represent cellular protection against tissue damage. Data suggest that interactions between Co ions and CoCr nanoparticles would occur in vivo, and could threaten the survival of a CoCr metal implant. PMID- 25433334 TI - Differential immunomodulatory responses to nine polycyclic aromatic hydrocarbons applied by passive dosing. AB - Studying the effects of hydrophobic chemicals using in vitro cell based methods is hindered by the difficulty in bringing and keeping these chemicals in solution. Their effective concentrations are often lower than their nominal concentrations. Passive dosing is one approach that provides defined and stable dissolved concentrations during in vitro testing, and was applied to control and maintain freely dissolved concentrations of polycyclic aromatic hydrocarbons (PAHs) at levels up to their aqueous solubility limit. The immunomodulatory effects of 9 different PAHs at aqueous solubility on human bronchial epithelial cells were determined by analysing the cytokine promoter expression of 4 different inflammatory cytokines using stably transfected recombinant A549 cell lines. Diverse immunomodulatory responses were found with the highest induction observed for the most hydrophobic PAHs chrysene, benzo(a)antracene and benzo(a)pyrene. Cytokine promoter expression was then studied in dose response experiments with acenaphthene, phenanthrene and benzo(a)anthracene. The strongest induction was observed for benzo(a)anthracene. Cell viability analysis was performed and showed that none of the PAHs induced cytotoxicity at any of the concentrations tested. Overall, this study shows that (1) immunomodulatory effects of PAHs can be studied in vitro at controlled freely dissolved concentrations, (2) the most hydrophobic PAHs were the strongest inducers and (3) induction was often higher at lower exposure levels and decreased then with concentration despite the apparent absence of cytotoxicity. PMID- 25433335 TI - Acute combined pressure and temperature exposures on a shallow-water crustacean: novel insights into the stress response and high pressure neurological syndrome. AB - Little is known about the ecological and physiological processes governing depth distribution limits in species. Temperature and hydrostatic pressure are considered to be two dominant factors. Research has shown that some marine ectotherms are shifting their bathymetric distributions in response to rapid anthropogenic ocean surface warming. Shallow-water species unable to undergo latitudinal range shifts may depend on bathymetric range shifts to seek refuge from warming surface waters. As a first step in constraining the molecular basis of pressure tolerance in shallow water crustaceans, we examined differential gene expression in response to acute pressure and temperature exposures in juveniles of the shallow-water shrimp Palaemonetes varians. Significant increases in the transcription of genes coding for an NMDA receptor-regulated protein, an ADP ribosylation factor, beta-actin, two heat shock protein 70 kDa isoforms (HSP70), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were found in response to elevated pressure. NMDA receptors have been implicated in pathways of excitotoxic damage to neurons and the onset of high pressure neurological syndrome (HPNS) in mammals. These data indicate that the sub-lethal effects of acute barotrauma are associated with transcriptional disturbances within the nervous tissue of crustaceans, and cellular macromolecular damage. Such transcriptional changes lead to the onset of symptoms similar to that described as HPNS in mammals, and may act as a limit to shallow water organisms' prolonged survival at depth. PMID- 25433336 TI - Effect of temperature on acoustic communication: sound production in the croaking gourami (labyrinth fishes). AB - Sound communication comprising the production and detection of acoustic signals is affected by ambient temperature in ectothermic animals. In the present study we investigated the effects of temperature on sound production and characteristics in the croaking gourami Trichopsis vittata, a freshwater fish from Southeast Asia possessing a highly specialized sound-generating mechanism found only in a single genus. The croaking gourami produces pulsed sounds by stretching and plucking two enhanced pectoral fin tendons during rapid pectoral fin beating. Croaking sounds typically consist of a series of double-pulsed bursts with main energies between 1 and 1.5 kHz. Sounds were recorded during dyadic contests between two males at three different temperatures (25 degrees , 30 degrees and 35 degrees C). The mean dominant frequency increased with rising temperature from 1.18 to 1.33 kHz, whereas temporal characteristics decreased. The sound interval dropped from 492 to 259 ms, the burst period from 51 to 35 ms and the pulse period from 5.8 to 5.1 ms. In contrast, the number of sounds and number of bursts within a sound were not affected by temperature. The current study shows that spectral and temporal characteristics of sounds are affected in different ways by temperature in the croaking gourami, whereas the numbers of sounds and bursts remain unaffected. We conclude that acoustic communication in gouramis is affected by changes in ambient temperature. PMID- 25433337 TI - Baseline defense system of commercial male king crab Lithodes santolla from the Beagle Channel. AB - Environmental and physiological variations influence the steady-state concentration of free oxygen radicals in cells. Because of the seasonal life cycle of Lithodes santolla in the Beagle Channel, a baseline study of the antioxidant physiological variations along the seasons is necessary for a better understanding of its ecophysiology. The aim of this study was to evaluate the seasonal variations in gills, hemolymph, muscle and hepatopancreas of the: i) enzymatic activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione transferase; ii) ascorbic acid and total glutathione; iii) lipid peroxidation and protein oxidation; iv) glucose, proteins and pH. Seasonality found in the antioxidant defense system of L. santolla from the Beagle Channel acts in a collaborative way during the most relevant life cycle phases (reproduction and molting), avoiding a long term oxidative stress. The antioxidant system also shows changes in the enzymatic activities likely caused by the environmental factors, such as low temperatures during winter and spring seasons. PMID- 25433338 TI - The alpha4beta1 integrin and the EDA domain of fibronectin regulate a profibrotic phenotype in dermal fibroblasts. AB - Prompt deposition of fibronectin-rich extracellular matrix is a critical feature of normal development and the host-response to injury. Fibronectin isoforms that include the EDA and EDB domains are prominent in these fibronectin matrices. We now report using human dermal fibroblast cultures that the EDA domain of fibronectin or EDA-derived peptides modeled after the C-C' loop promote stress fiber formation and myosin-light chain phosphorylation. These changes are accompanied by an increase in fibronectin synthesis and fibrillogenesis. These effects are blocked by pretreating cells with either siRNA or blocking antibody to the alpha4 integrin. Our data indicate that the interaction between the alpha4beta1 integrin and the EDA domain of fibronectin helps to drive tissue fibrosis by promoting a contractile phenotype and an increase in fibronectin synthesis and deposition. PMID- 25433340 TI - The relationship between porosity and specific surface in human cortical bone is subject specific. AB - A characteristic relationship for bone between bone volume fraction (BV/TV) and specific surface (BS/TV) has previously been proposed based on 2D histological measurements. This relationship has been suggested to be bone intrinsic, i.e., to not depend on bone type, bone site and health state. In these studies, only limited data comes from cortical bone. The aim of this paper was to investigate the relationship between BV/TV and BS/TV in human cortical bone using high resolution micro-CT imaging and the correlations with subject-specific biometric data such as height, weight, age and sex. Images from femoral cortical bone samples of the Melbourne Femur Collection were obtained using synchrotron radiation micro-CT (SPring8, Japan). Sixteen bone samples from thirteen individuals were analysed in order to find bone volume fraction values ranging from 0.20 to 1. Finally, morphological models of the tissue microstructure were developed to help explain the relationship between BV/TV and BS/TV. Our experimental findings indicate that the BV/TV vs BS/TV relationship is subject specific rather than intrinsic. Sex and pore density were statistically correlated with the individual curves. However no correlation was found with body height, weight or age. Experimental cortical data points deviate from interpolating curves previously proposed in the literature. However, these curves are largely based on data points from trabecular bone samples. This finding challenges the universality of the curve: highly porous cortical bone is significantly different to trabecular bone of the same porosity. Finally, our morphological models suggest that changes in BV/TV within the same sample can be explained by an increase in pore area rather than in pore density. This is consistent with the proposed mechanisms of age-related endocortical bone loss. In addition, these morphological models highlight that the relationship between BV/TV and BS/TV is not linear at high BV/TV as suggested in the literature but is closer to a square root function. PMID- 25433339 TI - Improvement of the skeletal and dental hypophosphatasia phenotype in Alpl-/- mice by administration of soluble (non-targeted) chimeric alkaline phosphatase. AB - Hypophosphatasia (HPP) results from ALPL gene mutations, which lead to a deficiency of tissue-nonspecific alkaline phosphatase (TNAP), and accumulation of inorganic pyrophosphate, a potent inhibitor of mineralization that is also a natural substrate of TNAP, in the extracellular space. HPP causes mineralization disorders including soft bones (rickets or osteomalacia) and defects in teeth and periodontal tissues. Enzyme replacement therapy using mineral-targeting recombinant TNAP has proven effective in preventing skeletal and dental defects in TNAP knockout (Alpl(-/-)) mice, a model for life-threatening HPP. Here, we show that the administration of a soluble, intestinal-like chimeric alkaline phosphatase (ChimAP) improves the manifestations of HPP in Alpl(-/-) mice. Mice received daily subcutaneous injections of ChimAP at doses of 1, 8 or 16 mg/kg, from birth for up to 53 days. Lifespan and body weight of Alpl(-/-) mice were normalized, and vitamin B6-associated seizures were absent with 16 mg/kg/day of ChimAP. Radiographs, MUCT and histological analyses documented improved mineralization in cortical and trabecular bone and secondary ossification centers in long bones of ChimAP16-treated mice. There was no evidence of craniosynostosis in the ChimAP16-treated mice and we did not detect ectopic calcification by radiography and histology in the aortas, stomachs, kidneys or lungs in any of the treatment groups. Molar tooth development and function improved with the highest ChimAP dose, including enamel, dentin, and tooth morphology. Cementum remained deficient and alveolar bone mineralization was reduced compared to controls, though ChimAP-treated Alpl(-/-) mice featured periodontal attachment and retained teeth. This study provides the first evidence for the pharmacological efficacy of ChimAP for use in the treatment of skeletal and dental manifestations of HPP. PMID- 25433343 TI - Multiple Ipsilateral Inguinal Hernias: More Frequent Than Imagined, If Undetected Source of Discomfort, Pain, and Re-interventions. AB - The article reports the incidence of multiple inguinal protrusions in the same groin in a patient collect who underwent open hernia repair. Multiple ipsilateral inguinal hernias compose an almost neglected topic that, if not identified during hernia repair, could lead to unclear discomfort, pain, and reoperation. A collect of 100 consecutive open anterior inguinal hernia procedures was analyzed. The patients were divided into two subsets-A: patients with a single protrusion and B: patients with more than one protrusion simultaneously arising from the inguinal floor. The single hernias from cohort A and the multiple hernias from cohort B were further categorized using the Nyhus classification system. Eighty eight single unilateral hernias were detected and 12 multiple inguinal hernias were ipsilaterally arising from the same groin. Nine percent of the multiple protrusions were double (three double indirect and six in combination direct + indirect). Three patients (3%) presented with triple protrusions; of those two individuals, one had a combination of double indirect, one had a direct hernia, and the third patient showed a tricomponent protrusion (hernia of the fossa supravescicalis + hernia of the fossa inguinalis media + indirect hernia). These numbers demonstrate that multiple ipsilateral inguinal hernias are more frequent than imagined. If undiscovered during a herniorrhaphy, the "forgotten" protrusion may generate unclear groin pain requiring reoperation. Consequently, is to envisage that many re-interventions will likely involve false "recurrences." Therefore, during hernia repair, more attention and adhesiolysis is essential during inspection of the inguinal floor. In fact, a careful exposure of the anatomical structures of the groin could be very advantageous in properly managing such conditions. This kind of surgical approach can help to prevent patient's discomfort and re-interventions. PMID- 25433342 TI - Paeoniflorin attenuates allergic inflammation in asthmatic mice. AB - Paeoniflorin (PF), one of the major active ingredients of Chinese peony, has demonstrated anti-inflammatory and immunoregulatory effects. However, it has remained unclear whether PF treatment can inhibit allergic inflammation in asthma. In this study, we evaluated the effects of PF on pulmonary function and airway inflammation in asthmatic mice. The allergic asthma models were established in BALB/c mice. The mice were sensitized and challenged with ovalbumin. Airway hyperresponsiveness was detected by direct airway resistance analysis. Lung tissues were examined for inflammatory cell infiltration. IL-5, IL 13, IL-17, and eotaxin in bronchoalveolar lavage fluid (BALF) and their mRNA expression in lung tissue were examined by ELISA and realtime PCR, respectively. The total IgE level in serum was measured by ELISA. The protein expression of p ERK and p-JNK was detected by western blot. Our data showed that PF oral administration significantly reduced airway hyperresponsiveness to aerosolized methacholine and decreased IL-5, IL-13, IL-17 and eotaxin levels in the BALF, and decreased IgE level in the serum. Histological studies showed that PF administration markedly decreased inflammatory infiltration. Similarly, treatment with PF significantly inhibited IL-5, IL-13, IL-17 and eotaxin mRNA expression in lung tissues. The protein expression levels of p-ERK and p-JNK were substantially decreased after oral administration of PF. In summary, PF displayed anti inflammatory effects in the OVA-induced asthmatic model by decreasing the expression of IL-5, IL-13, IL-17 and eotaxin. These effects were mediated at least partially by inhibiting the activation of MAPK pathway. PMID- 25433344 TI - Scar assessment for patients undergoing minimal invasive hysterectomy. AB - Surgical innovations have positively impacted the way hysterectomy procedures are performed by surgeons and the results experienced by patients. Patients with benign disease requiring a hysterectomy are no longer subjected to living with a large incisional scar that was common only 20 years ago. With the advent of minimally invasive surgery, surgeons can now provide hysterectomy patients with cosmetically pleasing results. To better understand the impact of surgical scars from hysterectomy incisions, 200 subjects answered a surgical incision questionnaire. Cosmetic issues (i.e., hysterectomy scars) were self-reported as important in 93% of subjects, of which 24% indicated this was extremely important. Of these same subjects, 11% indicated they were extremely bothered about their current scars. Subject interest in surgery without scars was 92% and 45% noted extreme interest. Concern about the surgical incision appearance was cited by 85% of subjects. Familiarity about incisions associated with the different hysterectomy procedures resulted in 26% of subjects who were not at all familiar. Low placed incision locations were considered cosmetically superior by 86% of the subjects. The least desirable incision location was above the belly button (69%) whereas the most desirable incision location was below the bikini line (68%). Discussion about the location, number, and incision size prior to surgery was cited to be important by 93% of subjects. Study subjects show there is value in discussing the number and placement of surgical incisions prior to surgery. Cosmesis of the surgical scars is a concern for many women, but most subjects knew little about the hysterectomy incision options. Based on these findings, surgeons can improve patient satisfaction scores by discussing incisional placement and surgical options prior to the procedure. PMID- 25433345 TI - A new approach for the management of bladder injury in retropubic slings: one side transobturator/ one side retropubic sling. AB - The aim of this study was to establish a new management modality for bladder perforation during retropubic slings. In 2013, among 102 retropubic slings, there were five bladder injuries. All procedures were performed by one of the fourth year residents under direct supervision of experienced surgeons. Bladder perforation was detected in cystoscopic examination. In the bladder perforated side, tape was retracted and placed by transobturator approach and the Foley catheter remained in place for seven days. Demographic features, preoperative urodynamic examination, and preoperative and postoperative life quality questionnaires (IIQ-7 and UDI-6) were recorded. The mean age of the patients was 44 +/- 2.5 years and body mass index was 29.4 +/- 1.7 kg/ m2. Mean parity was 2.8 +/- 1.8 and all the patients delivered with vaginal route. None of the patients were in menopause. Of the five bladder perforations, 40%(2) occurred on the right side, 60%(3) on the left side. All the surgeons were right handed. All patients underwent other vaginal reconstructive procedures like anterior colporraphy and posterior colporraphy. None of the patients had previous anti-incontinence surgery. Mean follow-up was 10.2 +/- 2.4 months. All patients had negative stress tests and improvement in IIQ-7 and UDI-6 at postoperative sixth month. There was no postoperative voiding dysfunction in any of the patients. If bladder perforation occurs in patients who undergo retropubic sling, the tape can be placed by transobturator approach in the bladder perforated side. PMID- 25433346 TI - New advances in limb salvage. AB - Critical limb ischemia (CLI) is an already significant and growing epidemiologic problem with substantial implications for patient mortality, quality of life, and healthcare costs. Considerable progress has been made in its treatment and prevention; however, poor outcomes, especially with regard to limb loss, warrant further development of treatment options. This article will examine new advances being made in the area of limb salvage for this morbid disease. Open surgical techniques and materials such as distal vein patches and heparin-bonded PTFE will be discussed. Additionally, new developments in endovascular therapies with particular regard to infrapopliteal interventions and drug-eluting stents will be reviewed. Beyond the simple techniques and materials, there is a growing movement in the world of vascular surgery to examine surgical and endovascular interventions with regard to angiosome-oriented revascularization of ulceration and gangrene. This paradigm has the potential to change prioritization and planning of both types of therapies as further research into this concept develops. PMID- 25433341 TI - Insights into the role of the unusual disulfide bond in copper-zinc superoxide dismutase. AB - The functional and structural significance of the intrasubunit disulfide bond in copper-zinc superoxide dismutase (SOD1) was studied by characterizing mutant forms of human SOD1 (hSOD) and yeast SOD1 lacking the disulfide bond. We determined x-ray crystal structures of metal-bound and metal-deficient hC57S SOD1. C57S hSOD1 isolated from yeast contained four zinc ions per protein dimer and was structurally very similar to wild type. The addition of copper to this four-zinc protein gave properly reconstituted 2Cu,2Zn C57S hSOD, and its spectroscopic properties indicated that the coordination geometry of the copper was remarkably similar to that of holo wild type hSOD1. In contrast, the addition of copper and zinc ions to apo C57S human SOD1 failed to give proper reconstitution. Using pulse radiolysis, we determined SOD activities of yeast and human SOD1s lacking disulfide bonds and found that they were enzymatically active at ~10% of the wild type rate. These results are contrary to earlier reports that the intrasubunit disulfide bonds in SOD1 are essential for SOD activity. Kinetic studies revealed further that the yeast mutant SOD1 had less ionic attraction for superoxide, possibly explaining the lower rates. Saccharomyces cerevisiae cells lacking the sod1 gene do not grow aerobically in the absence of lysine, but expression of C57S SOD1 increased growth to 30-50% of the growth of cells expressing wild type SOD1, supporting that C57S SOD1 retained a significant amount of activity. PMID- 25433347 TI - Bone grafts as carriers for local antibiotic delivery for the treatment and prevention of bone infections. AB - Osteomyelitis is a bone infection accompanied by inflammatory process, which can lead to destruction and bone necrosis. It is difficult to manage, and there are no commonly accepted guidelines. While most acute bone infections are usually successfully treated with intravenous antibiotics, chronic infections and infections in the presence of foreign materials usually require operative treatment with debridement, removal of metals, intravenous antibiotics, and very often local antibiotics. The aim of this study was to perform a systematic review of the existing literature concerning the use of bone grafts as carriers for local antibiotic delivery for the treatment and prevention of bone infections. According to the literature, antibiotic-loaded autologous bone grafts for the treatment of infected tibial nonunion is a good option (Grade-B recommendations). Although there are several studies concerning the use of antibiotic-loaded allogenic bone grafts in infected joint arthroplasty revisions, there is a lack of comparative studies (Grade-C recommendations). Studies concerning spinal fusion and spondylodiscitis are limited (Grade-I recommendations). PMID- 25433348 TI - The hospitalized patient as a partner in the survey on safe care in the Czech Republic. AB - OBJECTIVES: The study examined the extent to which patients in the Czech Republic are involved in decisions regarding their treatment and whether they are interested in ensuring safety during hospitalization. METHODS: Patients were interviewed to determine their perspectives regarding the previously stated objectives. The sample consisted of 514 patients who had been admitted to hospital for a minimum of three days. RESULTS: It is clear that patients in the Czech Republic are unaware of safety issues associated with provided care, but 52.2% of respondents expressed a desire to be more involved in decisions pertaining to their treatment. Widowed patients, as well as those hospitalized for more than six days, expressed less of a desire for such involvement. Half of the patients enrolled in the study stated that health care professionals had encouraged them to ask questions about their treatment. With regard to errors associated with surgical reversals, 58.3% of respondents stated that nursing staff had performed checkups to avoid confusion in surgery. Another patient safety issue is nosocomial infection acquired through improper hand-washing techniques of medical personnel. 73.5% of patients said they would not have the courage to ask medical staff (doctors or nurses) whether they had washed their hands prior to examination. CONCLUSION: Patients in the Czech Republic are unaware of the safety issues associated with provided care, but more than half expressed a desire to be more involved in decisions that pertain their treatment. PMID- 25433349 TI - Quality of life in patients with chronic diseases. AB - OBJECTIVES: A quality of life assessment is of great importance for patients with chronic diseases, because problems caused by specific diseases impact specific areas of their lives. The goal of this work was to determine, in which areas select diseases (rheumatoid arthritis, Crohn's disease, ischemic disease of the lower extremities and chronic obstructive pulmonary disease) affect patients' quality of life. METHODS: The Czech version of the WHOQOL-100 instrument and specific standardized questionnaires for individual diseases: EuroQol, EQ-5D-5L, IBDQ, PAQ were used to assess quality of life. This paper presents the results of the WHOQOL-100 questionnaire. In total, 5 research samples were put together. The first sample consisted of 200 respondents with rheumatoid arthritis (RA); the second sample included 100 respondents with inflammatory bowel disease (IBD); the third sample was comprised of 404 respondents with ischemic disease of the lower extremities (IDLE); the fourth sample consisted of 449 respondents with chronic obstructive pulmonary disease (COPD); and the fifth sample was represented by 1,456 healthy respondents. The acquired data were then statistically analyzed. A statistical data analysis was performed in two steps. In the first step descriptive statistical analyses were performed in the SASD program (absolute and relative frequencies of respondents' answers, median values and variability characteristics). In the second step differences in means of the subjectively perceived quality of life in patients with individual diseases and in control group were tested using the Mann-Whitney U test and the non-parametric Wilcoxon pair test. These analyses were computed in the SPSS (Statistical Package for the Social Sciences) program. RESULTS: The results show that a statistically significant difference in average domain score values was found between the healthy population and patients diagnosed with RA in the domains of "physical health", "level of independence", "environment", and "spirituality/religion/personal beliefs". A statistically significant difference was found in all domains for patients with IDLE and COPD. A statistically significant difference was found in four domains for patients with IBD, namely those of "physical health", "level of independence", "social relationships" and "spirituality/religion/personal beliefs". CONCLUSION: All therapeutic and nursing interventions that can contribute to improving QoL in poorly performing domains should be utilized. PMID- 25433350 TI - The reflection of the quality of life of people with Crohn's disease in nursing. AB - OBJECTIVES: To determine the quality of life of patients with Crohn's disease and to determine if this is reflected by the quality of nursing care. METHODS: For the purpose of this research, we used a generic standardized questionnaire of the quality of life, published by the World Health Organization (WHOQOL-100). The questionnaire was distributed among 100 patients with Crohn's disease and among 1456 and members of healthy population. To analyze the results, we used the SPSS program and appropriate statistical methods. RESULTS: The comparison of the domain scores of population standards in the Czech Republic and the respondents with Crohn's disease revealed a difference in the domain "physical condition", where the mean value was at the limit of the lower interval of the standard, and in the domain of "independence". CONCLUSION: The results given in this study define the possibilities of nurses and their functioning associated with altered quality of life. An evaluation of the most affected areas allows nurses to determine an appropriate intervention. Providing nursing care, in accordance with the latest knowledge, must be based on the quality of life. This newly incorporated area offers healthcare professionals a new dimension for assessing and determining subsequent interventions. PMID- 25433351 TI - The nurse's role in preventive care in the field of community nursing. AB - OBJECTIVES: According to published reports from the WHO, health care is undergoing a transformation that reflects the increasing importance of community care based on social, group, and individual needs. Community health care is provided by multidisciplinary teams, with nurses occupying irreplaceable positions. Nurse competencies constitute significant potential in the area of community based preventive care as well as the more traditional roles in treatment and recovery. METHODS: Data was obtained from health care professionals and the public through a structured interview. The study population included 1,007 physicians, 1,005 nurses and 2,022 laypersons. Respondents were selected randomly with the aid of quotas. The parameters for the selection of health care workers (nurses and physicians) were constructed based on registration data from the Institute of Health Information and Statistics. Layperson selection was based on data from the Czech Statistical Office. The Statistical Analysis of Social Data program (version 1.4.4) was used to process the data, which was in the form of 1st and 2nd degree contingency tables. The dependence level was determined based on chi2 and other testing criteria (according to the character of the signs). RESULTS: The results show that respondents perceive the concept of a "community nurse" as a nurse working independently in local neighborhoods and communities. Results also showed that work in senior care, followed by home care, and care for chronically ill patients were the most preferred. A role for nurses in health care education centers was only supported by 13.1% of physicians, 13.8% of nurses, and 6.8% of laypersons. The results also reveal that community nursing is perceived by both health care professionals and laypersons as fieldwork (i.e. work not based in a hospital or clinic environment), yet, at the same time, it was perceived as work that dealt with people needing health care. The results also reflect the opinion that the establishment of an independent nurse in the workplace (in the form of preventive care) could lead to an increase in the quality of care for employees (65.7% of physicians and 70.8% of nurses), an improvement in workplace health education (33% of physicians and 34.7% of nurses) and would provide support for healthy work environments (31.4% of physicians and 30.4% of nurses). CONCLUSION: Our results lead us to conclude that the health care system in the Czech Republic needs to better utilize the potential of trained nurses in the field of community health care. Additionally, steps need to be taken to increase job opportunities and staffing for nurses wanting to work in community health and preventive care. PMID- 25433352 TI - Epicardial left ventricular lead for cardiac resynchronization therapy. AB - Cardiac resynchronization therapy is now recognized as an effective and safe therapeutic modality in heart failure patients and leads to a reduction in mortality and morbidity. Today, transvenous implantation is considered to be the gold standard for lead placement. However, transvenous LV lead implantation fails in 2-10% of patients undergoing the implantation procedure. In these cases surgical LV lead implantation is preferred. The present article reviews LV pacing lead implantation strategies in cases where standard transvenous implantation failed. PMID- 25433353 TI - The benefits of remote monitoring in long-term care for patients with implantable cardioverter-defibrillators. AB - OBJECTIVE: The increasing number of patients with implantable cardiac devices raises the need for more efficient outpatient follow-up care. Due to technological progress in communication and transmission systems and in the implantable devices themselves, telemonitoring can be widely used as an important part of care for patients and devices. Our objective was to evaluate the benefits of continuous remote monitoring using the BIOTRONIK Home Monitoring(r) (HM) system compared to standard outpatient follow-ups. METHODS: 198 patients with single- or dual-chamber implantable cardioverter-defibrillator (ICD) implanted for primary or secondary prevention of sudden cardiac death were randomized into a group of patients followed through standard outpatient visits ( HM-) and a group telemonitored by the HM system (HM+). Planned and emergency visits, ICD related hospitalizations, and delivered shocks and their appropriateness were evaluated in the respective groups. RESULTS: A significant reduction was achieved in the number of planned (by 48%, p<0.001) and total visits (by 45%, p<0.001) during a three-year evaluation. A comparable number of patients experienced one or more shocks. Mortality rates were equivalent, as was the number of patients hospitalized in relation to their ICD. However, there was a significant reduction in the number and proportion of inappropriate shocks delivered in the HM+ patient group: by 80% (p=0.002) in outpatient follow-up care and by 90% (p<0.001) when multiple shocks requiring hospitalization were included. CONCLUSIONS: The HM system was an effective and safe method of follow-up in patients with an implanted ICD. Remote monitoring reduces the number of outpatient visits and inappropriate shocks. PMID- 25433354 TI - Nursing and quality of life in patients with atrial fibrillation before and after radiofrequency ablation. AB - The importance of nursing and patient quality of life is a top concern for medical professionals. Therefore, participation by medical professionals in raising awareness and continuously supporting improvements in nursing care is an essential part of improving patient quality of life. Modern medical techniques and procedures are changing rapidly, particularly in the field of cardiology. This has resulted in changing roles and increased responsibility for nurses and confirms the necessity for changing the perception of nurses relative to their role in the medical environment and to patient care. This paper presents the results from the first phase of a research project and focuses on quality of life and problematic areas associated with the needs of patients with atrial fibrillation before and after radiofrequency catheter ablation. Atrial fibrillation is one of the most common supraventricular arrhythmias. Its incidence in the general population has risen significantly over the last twenty years. The objective of this research was to assess those areas, which are considered by patients to be problematic before therapeutic intervention. The research was realized through a quantitative survey using a modified questionnaire. Results showed that AF reduced the quality of life both physically and psychologically (i.e. increased levels of anxiety and depression). Results also showed that radiofrequency catheter ablation was able to alleviate symptoms associated with AF and was also able to increase patient quality of life. PMID- 25433355 TI - Factors influencing psychological status and quality of life in patients with implantable cardioverter-defibrillators. AB - Various mental and social problems can negatively impact the quality of life and overall health in patients with implantable cardiac defibrillators (ICD). In this report, we review and summarize the main studies and research related to this topic. Depression, anxiety, panic attacks, stress and post-traumatic stress are the most common symptoms of ICD-related disorders that can negatively impact mental status. Factors than can influence the impact of these psychological disorders include socio-demographic variables (younger age, gender, and employment), variables related to the ICD (number of ICD shocks, generator size, time from ICD implant, etc.) and psycho-social variables (negative coping strategies, lack of social support and personality type). Fortunately, these disorders, and their symptoms, can be prevented, treated or managed, if recognized. PMID- 25433356 TI - Interdisciplinary collaboration between medical and non-medical professions in health and social care. AB - OBJECTIVES: This paper addresses the issue of interdisciplinary collaboration between medical and non-medical professions in health and social care. The introduction defines basic terms such as interdisciplinary cooperation, interdisciplinary team, and health and social care. Additionally, it highlights the significance and contribution of interdisciplinary collaboration in the care of the patient/client in health and social care. The aim of the paper is to identify factors influencing the process of interdisciplinary collaboration between, in particular, social workers and physicians. In compliance with the main goal of the research, the following partial goals were included: 1) to identify factors that limit the process of interdisciplinary collaboration between social workers and physicians, and 2) to identify factors which support the process of interdisciplinary collaboration between social workers and physicians. METHODS: Based on the research goals, a systematic review was selected as the research method for the paper. The research dataset consisted of articles obtained from the following databases: EBSO, PUBMED/MEDLINE, SCIENCE DIRECT and SCOPUS. The databases were search using the following keywords: interprofessional cooperation, interdisciplinary, collaboration, social work, and physicians/doctors. RESULTS: Using the results, the following factors supporting interdisciplinary collaboration were identified: acknowledgement of colleagues' expertise, recognition of roles, positive level of communication, and mutual respect. Factors that limit interdisciplinary processes included the following: varying professional perspectives, theoretical differences, lack of knowledge, and poor communication. PMID- 25433357 TI - Medical and salutogenic approaches and their integration in taking prenatal and postnatal care of immigrants. AB - OBJECTIVES: To compile a proposal of the system of taking complex prenatal, perinatal and postnatal care of pregnant immigrants in the Czech Republic with taking into account medical and salutogenic approaches. MATERIAL AND METHODS: The research was implemented by the form of a controlled interview and was based on a questionnaire comprising 50 questions focused on the evaluation of taking the prenatal, natal and postnatal care of immigrants. The data were accumulated among immigrants from Vietnam, Mongolia and Ukraine. RESULTS: It is possible to conclusively state that no principal dissatisfaction with taking care of pregnant women in the Czech Republic compared to native countries was demonstrated. There is a difference in a more considerable participation of midwives in the prenatal and natal care compared to the native countries. Failures in taking care of mothers-immigrants in the Czech Republic are considered to be the poor communication, particularly in association with the language barrier, limited possibilities of the participation of family members in the delivery and persisting unsuitable behaviour of certain healthcare professionals. CONCLUSION: In the Czech Republic, the medical care is at a higher level compared to native countries. For the improvement of the salutogenic attitude, it is necessary to take into consideration certain results and provide their application to practice. PMID- 25433358 TI - Medical and salutogenic approaches and their integration in taking prenatal and postnatal care of Czech women. AB - OBJECTIVE: To compile a proposal of the system of taking complex prenatal, perinatal and postnatal care of pregnant women and their children in the Czech Republic with taking into account medical and salutogenic approaches. MATERIAL AND METHODS: A questionnaire was prepared comprising questions for mothers and making it possible to exactly use specified data from their healthcare documentation. The method thus consisted of a secondary data analysis and subsequent contact with mothers. This was implemented in the form a qualitative and narrative interview. The study included 541 women from five Czech regions. RESULTS: In this group, there was a high level of the preventive care with persisting preference of prenatal consulting rooms conducted by physicians. Most deliveries occurred in institutions in the presence of physicians. In the groups evaluated, there were, however, no significant differences. In spite of this, the evaluation of delivering women indicated that there is a high level of the perinatal care in terms of the medical approach. However, the salutogenic care calls for increasing the active participation of midwives in the prenatal, perinatal and postnatal care and extension and intensification of activities particularly in the psychosocial area. CONCLUSION: In the group monitored, there were no significant correlations of determined perinatal interventions with the method and result of the delivery and condition of the mother and newborn. It is to mention that the medical perinatal care is at a high level. PMID- 25433359 TI - Subjective Social Status in select Ukrainians, Vietnamese, and Mongolians living in the Czech Republic. AB - OBJECTIVES: This article discusses methods of examining subjective social status (SSS), which is based on the concept of social determinants of health described by Wilkinson and Marmot in 1998. METHODS: SSS research was conducted with Cooperation from the Scientific and Technical Research (COST) program, with financial support from the Czech Ministry of Education, Youth and Sports. This study is part of a project entitled the "Health and Social Status of Immigrants and Asylum Seekers in the Czech Republic" (registration number OC 10031), which was started in 2010 and concluded in May 2011. The study included 246 respondents of which: 69 (28.1%) had emigrated from Vietnam; 93 (37.8%) from the Ukraine; and 84 (34.1%) from Mongolia. In terms of qualitative strategies, 13 individual immigrants and asylum seekers were personally interviewed. This research was thus conceived as being both quantitative-qualitative, which included the use of the appropriate technical tools (i.e., questionnaires and interviews with select immigrants and asylum seekers). SSS was determined using the Pearson's chi-square test, as well as through correspondence and cluster analyzes. Sign schemes were used to detect select significant relationships in contingency tables. The minimum significance level chosen was alpha <= 0.05. RESULTS: When examining the SSS of select nationalities, differences were observed in the perception of subjective social status. The correspondence analysis results clearly show that Ukrainians best perceived their social status (within the selected parameters). One measure of subjectively perceived social status related to Czech language proficiency (i.e., one criterion was the comprehension of spoken Czech; e.g., whether the respondent could read or speak Czech, or how they assessed their own Czech proficiency). CONCLUSION: The SSS study clearly revealed typical links among select nationalities living in the Czech Republic, and highlighted risks related to the degree of integration (and its relationship to social exclusion). This study served as a pilot project for follow-up research conducted by the second COST project entitled: "Social Determinants of Health and their Impact on the Health of Immigrants Living in the Czech Republic" (registration number LD 13044 COST). The follow-up study included 1 000 respondents of Slovak, Vietnamese, Ukrainian, Russian and Polish nationality and is currently underway at the Faculty of Health and Social Studies at the University of South Bohemia in the Czech Republic. The methodological tools used were taken from the COST pilot project (which is the topic of this article) and were adjusted as needed (i.e., both objective and subjective criteria were used for examining social status). PMID- 25433360 TI - Patterns of cardiac toxicity associated with irreversible proteasome inhibition in the treatment of multiple myeloma. AB - Carfilzomib is a novel irreversible proteasome inhibitor (PI) used with increasing frequency to treat patients with relapsed and/or refractory multiple myeloma (RRMM). This agent is an effective treatment for this challenging population, but proteasome inhibition has the potential of significant cardiac toxicity via the accumulation of intracellular protein aggregates. Although large clinical trials have not suggested an excess of heart failure with PI therapy, nonhuman animal studies and case reports in humans with the PI bortezomib have suggested otherwise. We describe the clinical presentation and management of 6 patients with RRMM who experienced significant cardiac toxicity associated with carfilzomib treatment. A common clinical syndrome of dyspnea associated with left ventricular systolic and/or diastolic dysfunction was identified. These abnormalities were largely reversible with prompt cessation of PI therapy and initiation of traditional heart failure treatments. Safe readministration of carfilzomib with dose modification was possible in some cases. PMID- 25433361 TI - Heart transplantation versus continuous-flow left ventricular assist device: comprehensive cost at 1 year. AB - BACKGROUND: With health care reform firmly on the horizon, it is critical to understand the costs associated with new technologies such as continuous-flow left ventricular assist device (CF-LVAD) compared with well established treatments such as heart transplantation (HT). Scarce data exist describing the costs of these 2 therapies after 1 year of support. METHODS AND RESULTS: The study population consisted of 20 consecutive subjects who underwent implantation of a CF-LVAD and 20 consecutive subjects who underwent HT and survived >=1 year. Comprehensive cost calculation included all direct and indirect costs from day of operation through 365 days and were inflation adjusted to 2010 US dollars. Hospital charges were converted to costs with the use of hospital-specific cost to-charge ratios and were analyzed by time segment as well as cost center. The total 1-year cost was higher in the CF-LVAD group, although this difference did not reach statistical significance ($369,519 [interquartile range [IQR] $321,020 $520,395] vs $329,648 [IQR $278,924-$395,456]; P = .242). In both groups, the index admission constituted >50% of the total 1-year cost and the major drivers of expense by cost center were organ/device acquisition, room and board, and professional fees. CONCLUSIONS: Patients surviving to 1 year on CF-LVAD support accrued costs similar to those of HT recipients; however, the total cost, at more than one-third of a million dollars, remains high. Reduction in the postoperative length of stay offers an avenue for significant cost savings. PMID- 25433362 TI - The potential role of natriuretic peptide-guided management for patients hospitalized for heart failure. AB - There are >1 million hospitalizations for heart failure (HF) in the United States annually. After discharge, 25% of these patients are rehospitalized within 30 days, and 30% are dead within 1 year. To date, all trials in patients with acute HF (AHF) have failed to improve post-discharge outcomes. There remains a need for an effective objective risk stratification strategy that is capable of reliably identifying patients at heightened risk for readmission and informing discharge decision making. Natriuretic peptide (NP) levels during and after AHF hospitalization can provide valuable information regarding congestion status and chronic remodeling stress. The lack of sensitivity and inter-rater reliability of physical examination, and failure to achieve dry weight in many patients before discharge, renders the use of NP to guide therapy to prevent readmission an attractive option. NP levels can be used across the spectrum of AHF care settings, ranging from the emergency department and inpatient stay to post discharge follow-up and chronic management. This review summarizes available data and provides an expert opinion on the potential role of NPs to reduce HF readmissions. PMID- 25433363 TI - Improving hospital bed occupancy and resource utilization through queuing modeling and evolutionary computation. AB - Scarce healthcare resources require carefully made policies ensuring optimal bed allocation, quality healthcare service, and adequate financial support. This paper proposes a complex analysis of the resource allocation in a hospital department by integrating in the same framework a queuing system, a compartmental model, and an evolutionary-based optimization. The queuing system shapes the flow of patients through the hospital, the compartmental model offers a feasible structure of the hospital department in accordance to the queuing characteristics, and the evolutionary paradigm provides the means to optimize the bed-occupancy management and the resource utilization using a genetic algorithm approach. The paper also focuses on a "What-if analysis" providing a flexible tool to explore the effects on the outcomes of the queuing system and resource utilization through systematic changes in the input parameters. The methodology was illustrated using a simulation based on real data collected from a geriatric department of a hospital from London, UK. In addition, the paper explores the possibility of adapting the methodology to different medical departments (surgery, stroke, and mental illness). Moreover, the paper also focuses on the practical use of the model from the healthcare point of view, by presenting a simulated application. PMID- 25433364 TI - Plasma-activated medium induces A549 cell injury via a spiral apoptotic cascade involving the mitochondrial-nuclear network. AB - Plasma medicine is a rapidly expanding new field of interdisciplinary research that combines physics, chemistry, biology, and medicine. Nonthermal atmospheric pressure plasma can be applied to living cells and tissues and has emerged as a novel technology for cancer therapy. Plasma has recently been shown to affect cells not only directly, but also by indirect treatment with previously prepared plasma-activated medium (PAM). The objective of this study was to demonstrate the inhibitory effects of PAM on A549 cell survival and elucidate the signaling mechanisms responsible for cell death. PAM maintained its ability to suppress cell viability for at least 1 week when stored at -80 degrees C. The severity of PAM-triggered cell injury depended on the kind of culture medium used to prepare the PAM, especially that with or without pyruvate. Hydrogen peroxide (H2O2) and/or its derived or cooperating reactive oxygen species reduced the mitochondrial membrane potential, downregulated the expression of the antiapoptotic protein Bcl2, activated poly(ADP-ribose) polymerase-1, and released apoptosis-inducing factor from mitochondria with endoplasmic reticulum stress. However, the activation of caspase 3/7 and attenuation of cell viability by the addition of caspase inhibitor were not observed. The accumulation of adenine 5' diphosphoribose as a product of the above reactions activated transient receptor potential melastatin 2, which elevated intracellular Ca(2+) levels and subsequently led to cell death. These results demonstrated that H2O2 and/or other reactive species in PAM disturbed the mitochondrial-nuclear network in cancer cells through a caspase-independent apoptotic pathway. Moreover, damage to the plasma membrane by H2O2-cooperating charged species not only induced apoptosis, but also increased its permeability to extracellular reactive species. These phenomena were also detected in PAM-treated HepG2 and MCF-7 cells. PMID- 25433367 TI - Hybridisation and diversification in the adaptive radiation of clownfishes. AB - BACKGROUND: The importance of hybridisation during species diversification has long been debated among evolutionary biologists. It is increasingly recognised that hybridisation events occurred during the evolutionary history of numerous species, especially during the early stages of adaptive radiation. We study the effect of hybridisation on diversification in the clownfishes, a clade of coral reef fish that diversified through an adaptive radiation process. While two species of clownfish are likely to have been described from hybrid specimens, the occurrence and effect of hybridisation on the clade diversification is yet unknown. RESULTS: We generate sequences of three mitochondrial genes to complete an existing dataset of nuclear sequences and document cytonuclear discordance at a node, which shows a drastic increase of diversification rate. Then, using a tree-based jack-knife method, we identify clownfish species likely stemming from hybridisation events. Finally, we use molecular cloning and identify the putative parental species of four clownfish specimens that display the morphological characteristics of hybrids. CONCLUSIONS: Our results show that consistently with the syngameon hypothesis, hybridisation events are linked with a burst of diversification in the clownfishes. Moreover, several recently diverged clownfish lineages likely originated through hybridisation, which indicates that diversification, catalysed by hybridisation events, may still be happening. PMID- 25433366 TI - How and why overcome the impediments to resolution: lessons from rhinolophid and hipposiderid bats. AB - The phylogenetic and taxonomic relationships among the Old World leaf-nosed bats (Hipposideridae) and the closely related horseshoe bats (Rhinolophidae) remain unresolved. In this study, we generated a novel approximately 10-kb molecular data set of 19 nuclear exon and intron gene fragments for 40 bat species to elucidate the phylogenetic relationships within the families Rhinolophidae and Hipposideridae. We estimated divergence times and explored potential reasons for any incongruent phylogenetic signal. We demonstrated the effects of outlier taxa and genes on phylogenetic reconstructions and compared the relative performance of intron and exon data to resolve phylogenetic relationships. Phylogenetic analyses produced a well-resolved phylogeny, supporting the familial status of Hipposideridae and demonstrated the paraphyly of the largest genus, Hipposideros. A fossil-calibrated timetree and biogeographical analyses estimated that Rhinolophidae and Hipposideridae diverged in Africa during the Eocene approximately 42 Ma. The phylogram, the timetree, and a unique retrotransposon insertion supported the elevation of the subtribe Rhinonycterina to family level and which is diagnosed herein. Comparative analysis of diversification rates showed that the speciose genera Rhinolophus and Hipposideros underwent diversification during the Mid-Miocene Climatic Optimum. The intron versus exon analyses demonstrated the improved nodal support provided by introns for our optimal tree, an important finding for large-scale phylogenomic studies, which typically rely on exon data alone. With the recent outbreak of Middle East respiratory syndrome, caused by a novel coronavirus, the study of these species is urgent as they are considered the natural reservoir for emergent severe acute respiratory syndrome (SARS)-like coronaviruses. It has been shown that host phylogeny is the primary factor that determines a virus's persistence, replicative ability, and can act as a predictor of new emerging disease. Therefore, this newly resolved phylogeny can be used to direct future assessments of viral diversity and to elucidate the origin and development of SARS-like coronaviruses in mammals. PMID- 25433365 TI - The basics of thiols and cysteines in redox biology and chemistry. AB - Cysteine is one of the least abundant amino acids, yet it is frequently found as a highly conserved residue within functional (regulatory, catalytic, or binding) sites in proteins. It is the unique chemistry of the thiol or thiolate group of cysteine that imparts to functional sites their specialized properties (e.g., nucleophilicity, high-affinity metal binding, and/or ability to form disulfide bonds). Highlighted in this review are some of the basic biophysical and biochemical properties of cysteine groups and the equations that apply to them, particularly with respect to pKa and redox potential. Also summarized are the types of low-molecular-weight thiols present in high concentrations in most cells, as well as the ways in which modifications of cysteinyl residues can impart or regulate molecular functions important to cellular processes, including signal transduction. PMID- 25433368 TI - Buccal localization of Crohn's disease with long-term infliximab therapy: a case report. AB - INTRODUCTION: Cheilitis granulomatosa causes persistent idiopathic lip swelling and ulceration and it can sometimes be recognized as a unique or early manifestation of Crohn's disease. Spontaneous remission is rare and with the lack of controlled trials, different therapeutic approaches have been used. Some cases have been treated with an exclusion diet in the attempt to rule out diet allergens, while the most popular treatments include antibiotics such as tetracycline and clofazimine tranilast, benzocaine topical or intralesional steroids, and cheiloplasty, with different outcomes. CASE PRESENTATION: We describe the case of a 23-year-old Caucasian man, primarily diagnosed with cheilitis granulomatosa for a severe lower lip swelling, and then with Crohn's disease of the terminal ileum and anus. Treatment of Crohn's disease with an anti tumor necrosis factor alpha agent (infliximab) successfully induced remission of both the gastrointestinal disease and the oral lesion. CONCLUSIONS: Our recommendation is that physicians should be able to recognize cheilitis granulomatosa as a possible marker of a more complex systemic disease and proceed first with an accurate physical examination, and further suggest investigations of the bowel. In cases of Crohn's disease, a therapy with biological agents can be successful. PMID- 25433369 TI - Comparison between the cranial magnetic resonance imaging features of neuromyelitis optica spectrum disorder versus multiple sclerosis in Taiwanese patients. AB - BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the central nervous system with different pathogenesis, brain lesion patterns, and treatment strategies. However, it is still difficult to distinguish these two disease entities by neuroimaging studies. Herein, we attempt to differentiate NMOSD from MS by comparing brain lesion patterns on magnetic resonance imaging (MRI). METHODS: The medical records and cranial MRI studies of patients with NMOSD diagnosed according to the 2006 Wingerchuk criteria and the presence of anti-aquaporin 4 (anti-AQP4) antibodies, and patients with MS diagnosed according to the Poser criteria, were retrospectively reviewed. RESULTS: Twenty-five NMOSD and 29 MS patients were recruited. The NMOSD patients became wheelchair dependent earlier than MS patients (log rank test; P = 0.036). Linear ependymal (28% vs. 0%, P = 0.003) and punctate lesions (64% vs. 28%, P = 0.013) were more frequently seen in NMOSD patients. Ten NMOSD patients (40%) had brain lesions that did not meet the Matthews criteria (MS were separated from NMOSD by the presence of at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or the presence of a subcortical U-fiber lesion or a Dawson finger-type lesion). The different image patterns of NMOSD didn't correlate with the clinical prognosis. However, NMOSD patients with more (?10) brain lesions at onset became wheelchair dependence earlier than those with fewer (<10) brain lesions (log rank test; P < 0.001). CONCLUSIONS: The diagnostic sensitivity of NMOSD criteria can be increased to 56% by combining the presence of linear ependymal lesions with unmet the Matthews criteria. The prognoses of NMOSD and MS are different. A specific imaging marker, the linear ependymal lesion, was present in some NMOSD patients. The diagnosis of NMOSD can be improved by following the evolution of this imaging feature when anti-AQP4 antibody test results are not available. PMID- 25433370 TI - Enablers and barriers to using patient decision aids in early stage breast cancer consultations: a qualitative study of surgeons' views. AB - BACKGROUND: For early stage breast cancer, randomized controlled trials (RCTs) have shown that patient decision aids (PtDAs), when used by surgeons, result in increased patient knowledge about options and different patient treatment choices as compared to standard care. Yet, recent data suggests that PtDAs are used by less than 25% of Canadian cancer physicians. We conducted a study to explore breast cancer surgeons' views on enablers and barriers to the use of PtDAs in their practice. METHODS: Purposeful sampling was used to select breast cancer surgeons in three Ontario health regions to participate in semi-structured interviews. Inductive coding and the constant comparative method were used to identify the main themes. RESULTS: Twenty-two surgeons (79%) agreed to participate (median age, 50 years; 9 (40%) female). Surgeons practiced in academic (n = 7, 32%) or community (n = 15, 68%) hospitals. Fourteen surgeons were aware of PtDAs, nine had used a PtDA with patients as part of an RCT, and six had developed their own informal PtDA for use in their practice. Enablers of informal PtDA use included surgeon exposure during training and surgeon perceived need for a systematic approach when communicating risks and benefits of surgical treatments with patients. Barriers to formal PtDA use included high surgeon confidence in their verbal communication skills, surgeon belief that patients understood conveyed information, and difficulties embedding such tools in practice routines. CONCLUSIONS: Surgeons in this study valued systematic communication with patients. Several surgeons changed their practice to include formal or informal PtDAs provided they perceived there was a clear benefit to themselves or to patients. However, high surgeon confidence in their personal communications skills coupled with beliefs that patients understand conveyed information may be key barriers to PtDA uptake once surgeons have established communication routines. PMID- 25433371 TI - Store-operated Ca(2+) entry regulates glioma cell migration and invasion via modulation of Pyk2 phosphorylation. AB - BACKGROUND: The ubiquitous second messenger Ca(2+) has been demonstrated to play an important role in cancer progression. Store-operated Ca(2+) entry (SOCE) is the main Ca(2+) entry pathway regulating intracellular Ca(2+) concentration in a variety of cancer types. The present study aimed to explore the specific mechanisms of SOCE in the processes of glioma migration and invasion. METHODS: The expression of Orai1, a key component of SOCE, was examined in glioma samples and glioma cell lines by immunohistochemistry and western blot analysis. Both pharmacological intervention and RNA interference were employed to investigate the role of SOCE in glioma cell migration and invasion in vitro. The intracellular Ca(2+) was certified through Fluo-4/AM based Ca(2+) measurement. The effect of SOCE on cell viability, migration, and invasion was explored by methyl thiazolyl tetrazolium (MTT) assay, wound healing assay, transwell invasion assay. Western blot analysis and immunofluorescence assay were used to observe the changes of downstream related protein and cell morpholog. RESULTS: Orai1 expression was elevated in glioma tissues and several glioma cell lines compared with non-neoplastic brain tissues. Either inhibition of SOCE by a pharmacological inhibitor or Orai1 downregulation suppressed glioma cell migration and invasion. However, re-expression of Orai1 could rescue glioma cell motility. Furthermore, phosphorylation of proline-rich tyrosine kinase 2 (Pyk2) participated in the mechanisms by which SOCE regulated focal adhesion turnover and epithelial-to mesenchymal (-like) transition in glioma cells, both of which are considered to be critical for tumor progression. CONCLUSIONS: The SOCE-Pyk2 pathway is essential for glioma migration and invasion. The study indicates the potential value of Orai1 as a molecular target for anti-invasion therapy. PMID- 25433372 TI - Designing effective visualizations of habits data to aid clinical decision making. AB - BACKGROUND: Changes in daily habits can provide important information regarding the overall health status of an individual. This research aimed to determine how meaningful information may be extracted from limited sensor data and transformed to provide clear visualization for the clinicians who must use and interact with the data and make judgments on the condition of patients. We ascertained that a number of insightful features related to habits and physical condition could be determined from usage and motion sensor data. METHODS: Our approach to the design of the visualization follows User Centered Design, specifically, defining requirements, designing corresponding visualizations and finally evaluating results. This cycle was iterated three times. RESULTS: The User Centered Design method was successfully employed to converge to a design that met the main objective of this study. The resulting visualizations of relevant features that were extracted from the sensor data were considered highly effective and intuitive to the clinicians and were considered suitable for monitoring the behavior patterns of patients. CONCLUSIONS: We observed important differences in the approach and attitude of the researchers and clinicians. Whereas the researchers would prefer to have as many features and information as possible in each visualization, the clinicians would prefer clarity and simplicity, often each visualization having only a single feature, with several visualizations per page. In addition, concepts considered intuitive to the researchers were not always to the clinicians. PMID- 25433374 TI - Association between audiological profile and primary language impairment in children. AB - OBJECTIVES: The aim of the present study was to characterize the Brazilian Portuguese speaking children seen at the Speech-Language Pathology Service of a Health Center, between 1985 and 2009, diagnosed with primary language impairments (PLI): language development impairment (LDI), phonological disorder (PD) and reading and writing impairment (RWI) regarding demographic and audiological profile; as well as investigate the association between PLI and demographic variables, and the association between PLI and hearing disorders. METHODS: A survey of medical records was carried out, collecting audiological and language impairment diagnostic data, totaling 2424 individuals in the study group. In addition, audiological evaluation data of 186 children without language disorders complaints were collected so that they constituted the control group. RESULTS: From the study group,1524 children (62.87%) had PLI. Considering the PLIs, the following occurrences were observed: PD=58.84%, LDI=30.75% and RWI=10.41%, with a predominance of males (64.19%) and age range up to 6 years (67.15%). For the audiological profile, there was a predominance of normal hearing thresholds (81.34%), followed by conductive hearing loss (15.47%). Tympanogram type A was more prevalent (56.24%), followed by B and C types (21.84% and 18.16%). Acoustic reflexes were present in the majority of subjects (51.7%). There was a significant association between belonging to the 7-12 years-old group and presenting with PD, belonging to the group up to 6 years and having LDI, and belonging to the older group and presenting with RWI. There was a significant association between males and presenting with LDI. There was statistically significant association between PLI and abnormal audiological profile. Individuals with abnormal audiological profile were 63% more likely to have PLI than those who had normal audiological profile. CONCLUSIONS: It is suggested that having an abnormal audiological profile would be a risk factor for PLI. Hence, these findings can serve as a basis for children hearing and speech-language monitoring, and as an important tool for the planning of health promotion and prevention actions, as well as the development and implementation of intervention programs. PMID- 25433375 TI - One size does not fit all! PMID- 25433376 TI - Mapping dustfall distribution in urban areas using remote sensing and ground spectral data. AB - The aim of this study was to utilize remote sensing and ground-based spectral data to assess dustfall distribution in urban areas. The ground-based spectral data denoted that dust has a significant impact on spectral features. Dusty leaves have an obviously lower reflectance than clean leaves in the near-infrared bands (780-1,300 nm). The correlation analysis between dustfall weight and spectral reflectance showed that spectroscopy in the 350-2,500-nm region produced useful dust information and could assist in dust weight estimation. A back propagation (BP) neutral network model was generated using spectral response functions and integrated remote sensing data to assess dustfall weight in the city of Beijing. Compared with actual dustfall weight, validation of the results showed a satisfactory accuracy with a lower root mean square error (RMSE) of 3.6g/m(2). The derived dustfall distribution in Beijing indicated that dustfall was easily accumulated and increased in the south of the city. In addition, our results showed that construction sites and low-rise buildings with inappropriate land use were two main sources of dust pollution. This study offers a low-cost and effective method for investigating detailed dustfall in an urban environment. Environmental authorities may use this method for deriving dustfall distribution maps and pinpointing the sources of pollutants in urban areas. PMID- 25433373 TI - Improving the experience of dementia and enhancing active life--living well with dementia: study protocol for the IDEAL study. AB - BACKGROUND: Enabling people with dementia and carers to 'live well' with the condition is a key United Kingdom policy objective. The aim of this project is to identify what helps people to live well or makes it difficult to live well in the context of having dementia or caring for a person with dementia, and to understand what 'living well' means from the perspective of people with dementia and carers. METHODS/DESIGN: Over a two-year period, 1500 people with early-stage dementia throughout Great Britain will be recruited to the study, together with a carer wherever possible. All the participants will be visited at home initially and again 12 months and 24 months later. This will provide information about the way in which well-being, life satisfaction and quality of life are affected by social capitals, assets and resources, the challenges posed by dementia, and the ways in which people adjust to and cope with these challenges. A smaller group will be interviewed in more depth. DISCUSSION: The findings will lead to recommendations about what can be done by individuals, communities, health and social care practitioners, care providers and policy-makers to improve the likelihood of living well with dementia. PMID- 25433377 TI - Polluted dust derived from long-range transport as a major end member of urban aerosols and its implication of non-point pollution in northern China. AB - The contribution of polluted dust transported from local and distal sources remains poorly constrained due to their similar geophysical and geochemical properties. We sampled aerosols in three cities in northern China (Xi'an, Beijing, Xifeng) during the spring of 2009 to determine dust flux, magnetic susceptibility and elemental concentrations. Combining dust fluxes with wind speed and regional visibility records enabled to differentiate between dust transported from long range and derived from local sources, while the combination of magnetic susceptibility and enrichment factors (EF) of heavy metals (Pb, Zn) allowed to distinguish natural aerosols from polluted ones. Our results indicate that polluted dust from long-range transport became a major end member of urban dust aerosols. Human settlements as its potential sources were confirmed by a pollutant enriched regional dust event originating from populated areas to the south as inferred by back trajectory modeling, implying their non-point source nature of dust pollution. PMID- 25433378 TI - Integrating the provision of ecosystem services and trawl fisheries for the management of the marine environment. AB - The species interaction and their biological traits (BT) determine the function of benthic communities and, hence, the delivery of ecosystem services. Therefore, disturbance of benthic communities by trawling may compromise ecosystem service delivery, including fisheries' catches. In this work, we explore 1) the impact of trawling activities on benthic functional components (after the BTA approach) and 2) how trawling impact may affect the ecosystem services delivered by benthic communities. To this aim, we assessed the provision of ecosystem services by adopting the concept of Ecosystem Service Providers (ESP), i.e. ecological units that perform ecosystem functions that will ultimately deliver ecosystem services. We studied thirteen sites subjected to different levels of fishing effort in the Mediterranean. From a range of environmental variables included in the study, we found ESPs to be mainly affected by fishing effort and grain size. Our results suggested that habitat type has significant effects on the distribution of ESPs and this natural variability influences ESP response to trawling at a specific site. In order to summarize the complex relationships between human uses, ecosystem components and the demand for ecosystem services in trawling grounds, we adapted a DPSIR (Drivers-Pressures-State Change-Impact-Response) framework to the study area, emphasizing the role of society as Drivers of change and actors demanding management Responses. This integrative framework aims to inform managers about the interactions between all the elements involved in the management of trawling grounds, highlighting the need for an integrated approach in order to ensure ecosystem service provision. PMID- 25433379 TI - Categorization of the trophic status of a hydroelectric power plant reservoir in the Brazilian Amazon by statistical analyses and fuzzy approaches. AB - The Amazon area has been increasingly suffering from anthropogenic impacts, especially due to the construction of hydroelectric power plant reservoirs. The analysis and categorization of the trophic status of these reservoirs are of interest to indicate man-made changes in the environment. In this context, the present study aimed to categorize the trophic status of a hydroelectric power plant reservoir located in the Brazilian Amazon by constructing a novel Water Quality Index (WQI) and Trophic State Index (TSI) for the reservoir using major ion concentrations and physico-chemical water parameters determined in the area and taking into account the sampling locations and the local hydrological regimes. After applying statistical analyses (factor analysis and cluster analysis) and establishing a rule base of a fuzzy system to these indicators, the results obtained by the proposed method were then compared to the generally applied Carlson and a modified Lamparelli trophic state index (TSI), specific for trophic regions. The categorization of the trophic status by the proposed fuzzy method was shown to be more reliable, since it takes into account the specificities of the study area, while the Carlson and Lamparelli TSI do not, and, thus, tend to over or underestimate the trophic status of these ecosystems. The statistical techniques proposed and applied in the present study, are, therefore, relevant in cases of environmental management and policy decision making processes, aiding in the identification of the ecological status of water bodies. With this, it is possible to identify which factors should be further investigated and/or adjusted in order to attempt the recovery of degraded water bodies. PMID- 25433380 TI - Dynamic behaviour of trace metals in the Deule River impacted by recurrent polluted sediment resuspensions: from diel to seasonal evolutions. AB - An automatic trace metal monitoring station (ATMS) have been implemented in the river bank of the Deule canal in the city of Auby (northern France), in the vicinity of metallurgical industries that have heavily polluted sediments, in Cd, Pb and Zn. Additionally, the fluvial traffic in this river is intense and surface sediments are resuspended several times per day. This paper is the following part of that published recently (Superville et al., 2014) in this journal. The main purpose of this paper is to present new information on diel and seasonal variations of trace metals in the Deule River and highlight the potential role of sediments in the contamination of the water column. To this end, Cd, Zn and Pb were monitored at a high frequency (~1h(-1)) by voltammetry, distinguishing an electrolabile and an acid-leachable fraction. Our measurements revealed that (i) acid-leachable Cd is mainly bound to light particles such as clays and carbonates and its daily behaviour does not really depend on the intensity of sediment remobilisation process; (ii) acid-leachable Pb and Zn exhibit some seasonal variations which are explained here, suggesting they should at least partly depend on the ageing of hydrous ferric oxides in the sediments; (iii) in spring, the electrolability of Zn increases in agreement with the biological activity that may break some strong association between Zn and ligands and/or particles (e.g., organic matter, hydrous ferric oxides, etc.). This trend is observed for electrolabile Pb later in summer, but on a smaller scale since this metal is generally more strongly scavenged and less labile than Zn; and (iv) electrolabile Mn concentrations increase during the day due to desorption process of resuspended sediment particles in the water. PMID- 25433381 TI - Use of electrical tomography methods to determinate the extension and main migration routes of uncontrolled landfill leachates in fractured areas. AB - This study focuses on the uses of the electrical tomography and its relationship with hydrochemical data in order to characterize contaminated groundwater flows in fractured aquifers. The studied area is contaminated with different hazardous substances like lyndanes, organochlorinated compounds and benzenes coming from the old non-controlled Sardas landfill. The enormous volumes of wastes filling the landfill have generated a convoluted mixture of leachates. Due to the lack of a landfill liner, the leachates have migrated through the fractured Eocene marls towards the Gallego River. The striking correlation between high concentrations of polluted groundwater and low electrical resistivity of the subsurface (<8Omega.m) allows defining the principal contaminant migration route thanks to the distribution of these conductive anomalies. This mapping verifies that there is intense tectonical-structural control of the leachate migration, because the deep migration presents the same direction as the geological axis fold. PMID- 25433382 TI - Disaggregation of silver nanoparticle homoaggregates in a river water matrix. AB - Silver nanoparticles (Ag NPs) could be found in aquatic systems in the near future. Although the interplay between aggregate formation and disaggregation is an important factor for mobility, bioavailability and toxicity of Ag NPs in surface waters, the factors controlling disaggregation of Ag NP homoaggregates are still unknown. In this study, we investigated the reversibility of homoaggregation of citrate coated Ag NPs in a Rhine River water matrix. We characterized the disaggregation of Ag NP homoaggregates by ionic strength reduction and addition of Suwannee River humic acid (SRHA) in the presence of strong and weak shear forces. In order to understand the disaggregation processes, we also studied the nature of homoaggregates and their formation dynamics under the influence of SRHA, Ca(2+) concentration and nanoparticle concentration. Even in the presence of SRHA and at low particle concentrations (10 MUg L(-1)), aggregates formed rapidly in filtered Rhine water. The critical coagulation concentration (CCC) of Ca(2+) in reconstituted Rhine water was 1.5 mmol L(-1) and was shifted towards higher values in the presence of SRHA. Analysis of the attachment efficiency as a function of Ca(2+) concentration showed that SRHA induces electrosteric stabilization at low Ca(2+) concentrations and cation-bridging flocculation at high Ca(2+) concentrations. Shear forces in the form of mechanical shaking or ultrasound were necessary for breaking the aggregates. Without ultrasound, SRHA also induced disaggregation, but it required several days to reach a stable size of dense aggregates still larger than the primary particles. Citrate stabilized Ag NPs may be in the form of reaction limited aggregates in aquatic systems similar to the Rhine River. The size and the structure of these aggregates will be dynamic and be determined by the solution conditions. Seasonal variations in the chemical composition of natural waters can result in a sedimentation-release cycle of engineered nanoparticles. PMID- 25433384 TI - Iodinated contrast media electro-degradation: process performance and degradation pathways. AB - The electrochemical degradation of six of the most widely used iodinated contrast media was investigated. Batch experiments were performed under constant current conditions using two DSA(r) electrodes (titanium coated with a proprietary and patented mixed metal oxide solution of precious metals such as iridium, ruthenium, platinum, rhodium and tantalum). The degradation removal never fell below 85% (at a current density of 64 mA/cm(2) with a reaction time of 150 min) when perchlorate was used as the supporting electrolyte; however, when sulphate was used, the degradation performance was above 80% (at a current density of 64 mA/cm(2) with a reaction time of 150 min) for all of the compounds studied. Three main degradation pathways were identified, namely, the reductive de-iodination of the aromatic ring, the reduction of alkyl aromatic amides to simple amides and the de-acylation of N-aromatic amides to produce aromatic amines. However, as amidotrizoate is an aromatic carboxylate, this is added via the decarboxylation reaction. The investigation did not reveal toxicity except for the lower current density used, which has shown a modest toxicity, most likely for some reaction intermediates that are not further degraded. In order to obtain total removal of the contrast media, it was necessary to employ a current intensity between 118 and 182 mA/cm(2) with energy consumption higher than 370 kWh/m(3). Overall, the electrochemical degradation was revealed to be a reliable process for the treatment of iodinated contrast media that can be found in contaminated waters such as hospital wastewater or pharmaceutical waste-contaminated streams. PMID- 25433383 TI - Environmental fate and dietary exposures of humans to TCDD as a result of the spraying of Agent Orange in upland forests of Vietnam. AB - The fate and transport of 2,3,7,8-tetrachloro-p-dibenzodioxin (TCDD) released into the environment of South Vietnam (SVN) as a consequence of the aerial application of the herbicidal defoliant Agent Orange (AO) were simulated for a generic upland forest scenario and followed over a 50-year period (1965, 1968 and 1970 onwards). Modeled concentrations of TCDD in the environment were then used as inputs to a human exposure model, which focused on long-term exposures via the food chain. Intake rates and body burdens of TCDD were estimated for adult males over the course of the simulation period and compared to available biomonitoring data. One of the most important factors determining the magnitude of the simulated human exposure to TCDD was the fraction of the chemical deposited directly to soil (where it was assumed to have a degradation half-life of 10 or 15years) relative to the fraction assumed to remain on/in the forest canopy following the spray application (where it was assumed to have a degradation half life of <=48h). The simulated body burdens under the various scenarios considered were broadly consistent with the biomonitoring data from SVN collected in the mid 1980s to late 1990s. Taken together, the modeling results and empirical data suggest that highly elevated exposures to TCDD (i.e., body burdens in the several 100s of pg/g lipid range and greater) were not common among people inhabiting upland forest locations in SVN sprayed with AO and that peak and average body burdens were broadly similar to those of the general population of the U.S. in the 1970s and early 1980s. The model-based assessment is consistent with the 'hot spot' hypothesis i.e., potential exposures to TCDD linked to activities conducted on or near former bases where AO was stored are greater than potential exposures in areas subjected to aerial spraying. PMID- 25433385 TI - A comparison of HYSPLIT backward trajectories generated from two GDAS datasets. AB - The Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) model is widely used to generate backward trajectories in given starting locations. However, differences exist between trajectories generated from the model with different input datasets. In this study, backward trajectories in Hong Kong in the entire year of 2011 are derived by HYSPLIT model. Two sets of Global Data Assimilation System (GDAS) output data associated with different horizontal and vertical resolutions (GDAS1 and GDAS0P5) are used as drivers in an attempt to quantify the differences between the results and discover the underlying reasons responsible for discrepancy. The results reveal that the significant differences between back trajectories generated from the two GDAS datasets can be mainly attributed to different vertical velocity calculation methods due to the absence of vertical velocity in GDAS0P5 dataset. The HYSPLIT trajectories are also sensitive to the horizontal and vertical resolutions of the input meteorological data, but to lesser extents. Results of cluster analysis indicate that when the air mass is from the north, northeast, or west with a long-to-medium range, the HYSPLIT backward trajectories are sensitive to the vertical advection calculation method and data resolution, whereas when the air mass is from the south or southwest with a long range, the trajectories are more likely to remain unchanged with the shifting of vertical velocity or data resolution. By comparing the vertical velocities with the observations and the performance in retrieving PM contributions from different directions, we conclude that GDAS1 dataset is more plausible in backward trajectory analysis in the Pearl River Delta. PMID- 25433386 TI - Assessment of the health status of wild fish inhabiting a cotton basin heavily impacted by pesticides in Benin (West Africa). AB - To determine the impact of agricultural pesticides used in cotton cultivation on the health status of fish living in a Beninese cotton basin, we compared the reproductive and hepatic systems of fish sampled from rivers located in both contaminated and pristine conditions. Different types of biomarkers, including biometric indices (a condition factor K, a gonadosomatic index GSI, and a hepatosomatic index HSI), plasma levels of sex steroids (11-ketotestosterone 11 KT, testosterone T and estradiol-17beta E2) and the histopathology of the gonads and liver, were investigated for two different trophic levels of the following two fish species: the Guinean tilapia Tilapia guineensis and the African catfish Clarias gariepinus. The fish were captured during both the rainy season (when there is heavy use of pesticides on cotton fields) and the dry season from one site, in Pendjari River (reference site), which is located outside the cotton producing basin, and from three other sites on the Alibori River within the cotton-producing basin. Comparing fish that were sampled from contaminated (high levels of endosulfan, heptachlor and DDT and metabolites) and reference sites, the results clearly indicated that agricultural pesticides significantly decreased K and GSI while they increased HSI, regardless of the season, species and sex of the fish. These pesticides also induced a decrease in the plasma levels of 11-KT and T and increased those of E2. The histopathology of the testes revealed, in both species, a high rate of testicular oocytes, up to 50% in the African catfish, downstream of the Alibori River, which indicated estrogenic effects from the pesticides. The disruption of male spermatogenesis primarily included necrosis, fibrosis and the presence of foam cells in the lobular lumen. The histopathology of the ovaries revealed high levels of pre-ovulatory follicular atresia, impaired oogenesis, a decrease in the oocyte vitellogenic diameter and other lesions, such as fibrosis, vacuolation and melano-macrophagic centers. The histopathology of the liver revealed the presence of necrosis, hypertrophic hepatocytes, foci of vacuolation, glycogen depletion and hemosiderin. An assessment of the general health of the fish indicated that all of the sampled fish from the polluted sites were in poorer health compared with those from the reference site but that the African catfish appeared much more affected than the Guinean tilapia, regardless of the sex and season. In conclusion, the overall results indicated that agricultural pesticides significantly impair the endocrine regulation of fish living in the Beninese cotton basin and that this would most likely be one of the causes of the severe damage observed in the liver and gonads and the reduced health condition. PMID- 25433387 TI - Bromine enrichment in marsh sediments as a marker of environmental changes driven by Grand Solar Minima and anthropogenic activity (Caminha, NW of Portugal). AB - A sediment core collected in Caminha tidal marsh, NW Portugal, was used to assess bromine (Br) signal over the last ca. 1,700 years. The Br temporal variability reflects its close relationship with soil/sediment organic matter (OM) and also alterations in Br biogeochemical recycling in marsh environment. The highest Br enrichment in sediments was found during the Maunder Solar Minimum, a major solar event characterized by lower irradiance (TSI) and temperature, increased cloudiness and albedo. The obtained results suggest that those climate-induced changes weakened the natural mechanisms that promote Br biochemical transformations, driven by both living plants metabolism and plant litter degradation, with the ensuing generation of volatile methyl bromide (CH3Br). It seems that the prevailing climate conditions during the Maunder favoured the retention of more Br in marsh ecosystem, ultimately decreasing the biogenic Br emissions to the atmosphere. During the 20th century, the Br pattern in sediments appears to mirror likewise anthropogenic sources. The significant correlation (p<0.05) between Br/OM ratios and Pb contents in sediments after 1934 suggests a common source. This is most probably related with the rise, massive consumption and prohibition of leaded gasoline, where ethylene dibromide was added as lead scavenger to antiknock mixtures. More regionally, the concerted use of flame retardants on forest fire management, covering the 1980s through mid-1990s in the north of Portugal and Galicia, could be responsible for the observed increase of sediment Br (relatively to Pb) pool of this tidal marsh. Although man-made brominated compounds are being phased-out since the inception of the 1992 Montreal Protocol, the Caminha tidal marsh sedimentary record showed that Br levels only started to decline after 2002. PMID- 25433388 TI - Cysteamine (Lynovex(r)), a novel mucoactive antimicrobial & antibiofilm agent for the treatment of cystic fibrosis. AB - BACKGROUND: There remains a critical need for more effective, safe, long-term treatments for cystic fibrosis (CF). Any successful therapeutic strategy designed to combat the respiratory pathology of this condition must address the altered lung physiology and recurrent, complex, polymicrobial infections and biofilms that affect the CF pulmonary tract. Cysteamine is a potential solution to these unmet medical needs and is described here for the first time as (Lynovex(r)) a single therapy with the potential to deliver mucoactive, antibiofilm and antibacterial properties; both in oral and inhaled delivery modes. Cysteamine is already established in clinical practice for an unrelated orphan condition, cystinosis, and is therefore being repurposed (in oral form) for cystic fibrosis from a platform of over twenty years of safety data and clinical experience. METHODS: The antibacterial and antibiofilm attributes of cysteamine were determined against type strain and clinical isolates of CF relevant pathogens using CLSI standard and adapted microbiological methods and a BioFlux microfluidic system. Assays were performed in standard nutrient media conditions, minimal media, to mimic the low metabolic activity of microbes/persister cells in the CF respiratory tract and in artificial sputum medium. In vivo antibacterial activity was determined in acute murine lung infection/cysteamine nebulisation models. The mucolytic potential of cysteamine was assessed against DNA and mucin in vitro by semi-quantitative macro-rheology. In all cases, the 'gold standard' therapeutic agents were employed as control/comparator compounds against which the efficacy of cysteamine was compared. RESULTS: Cysteamine demonstrated at least comparable mucolytic activity to currently available mucoactive agents. Cysteamine was rapidly bactericidal against both metabolically active and persister cells of Pseudomonas aeruginosa and also emerging CF pathogens; its activity was not sensitive to high ionic concentrations characteristic of the CF lung. Cysteamine prevented the formation of, and disrupted established P. aeruginosa biofilms. Cysteamine was synergistic with conventional CF antibiotics; reversing antibiotic resistance/insensitivity in CF bacterial pathogens. CONCLUSIONS: The novel mucolytic-antimicrobial activity of cysteamine (Lynovex(r)) provides potential for a much needed new therapeutic strategy in cystic fibrosis. The data we present here provides a platform for cysteamine's continued investigation as a novel treatment for this poorly served orphan disease. PMID- 25433389 TI - Lasiodiplodia sp. ME4-2, an endophytic fungus from the floral parts of Viscum coloratum, produces indole-3-carboxylic acid and other aromatic metabolites. AB - BACKGROUND: Studies on endophytes, a relatively under-explored group of microorganisms, are currently popular amongst biologists and natural product researchers. A fungal strain (ME4-2) was isolated from flower samples of mistletoe (Viscum coloratum) during a screening program for endophytes. As limited information on floral endophytes is available, the aim of the present study is to characterise fungal endophytes using their secondary metabolites. RESULTS: ME4-2 grew well in both natural and basic synthetic media but produced no conidia. Sequence analysis of its internal transcribed spacer rDNA demonstrated that ME4-2 forms a distinct branch within the genus Lasiodiplodia and is closely related to L. pseudotheobromae. This floral endophyte was thus identified as Lasiodiplodia sp. based on its molecular biological characteristics. Five aromatic compounds, including cyclo-(Trp-Ala), indole-3 carboxylic acid (ICA), indole-3-carbaldehyde, mellein and 2-phenylethanol, were found in the culture. The structures of these compounds were determined using spectroscopic methods combined with gas chromatography. To the best of our knowledge, our work is the first to report isolation of these aromatic metabolites from a floral endophyte. Interestingly, ICA, a major secondary metabolite produced by ME4-2, seemed to be biosynthesized via an unusual pathway. Furthermore, our results indicate that the fungus ME4-2 is a potent producer of 2 phenylethanol, which is a common component of floral essential oils. CONCLUSIONS: This study introduces a fungal strain producing several important aromatic metabolites with pharmaceutical or food applications and suggests that endophytic fungi isolated from plant flowers are promising natural sources of aromatic compounds. PMID- 25433390 TI - Primary cultivation: factors affecting contamination and Mycobacterium ulcerans growth after long turnover time of clinical specimens. AB - BACKGROUND: While cultivation of pathogens represents a foundational diagnostic approach in the study of infectious diseases, its value for the confirmation of clinical diagnosis of Buruli ulcer is limited by the fact that colonies of Mycobacterium ulcerans appear only after about eight weeks of incubation at 30 degrees C. However, for molecular epidemiological and drug sensitivity studies, primary isolation of M. ulcerans remains an essential tool. Since for most of the remote Buruli ulcer endemic regions of Africa cultivation laboratories are not easily accessible, samples from lesions often have to be stored for extended periods of time prior to processing. The objective of the current study therefore was to determine which transport medium, decontamination method or other factors decrease the contamination rate and increase the chance of primary isolation of M. ulcerans bacilli after long turnover time. METHODS: Swab and fine needle aspirate (FNA) samples for the primary cultivation were collected from clinically confirmed Buruli ulcer patients in the Mape Basin of Cameroon. The samples were either stored in the semi-solid transport media 7H9 or Amies or dry for extended period of time prior to processing. In the laboratory, four decontamination methods and two inoculation media were evaluated and statistical methods applied to identify factors that decrease culture contamination and factors that increase the probability of M. ulcerans recovery. RESULTS: The analysis showed: i) that the use of moist transport media significantly increased the recovery rate of M. ulcerans compared to samples kept dry; ii) that the choice of the decontamination method had no significant effect on the chance of M. ulcerans isolation; and iii) that Lowenstein-Jensen supplemented with antibiotics as inoculation medium yielded the best results. We further found that, ten extra days between sampling and inoculation lead to a relative decrease in the isolation rate of M. ulcerans by nearly 20%. Finally, collection and processing of multiple samples per patient was found to significantly increase the M. ulcerans isolation rate. CONCLUSIONS: Based on our analysis we suggest a procedure suitable for the primary isolation of M. ulcerans strains from patients following long delay between sample collection and processing to establish a M. ulcerans strain collection for research purposes. PMID- 25433391 TI - Infant and child feeding index reflects feeding practices, nutritional status of urban slum children. AB - BACKGROUND: Infant and child feeding index (ICFI) an age-specific index, can be used to assess child feeding practices. We used the ICFI to assess feeding practices for urban slum children and the association between ICFI and child nutritional status. METHODS: 446 children aged 6 to 24 months from urban slums of Mumbai, India were studied. We used the 24-hour diet recall to study dietary diversity and a food frequency questionnaire for consumption of food groups during the preceding week. ICFI was computed using five components, namely, breastfeeding, use of bottle, dietary diversity score (DDS), food group frequency score (FGFS) and feeding frequency scores (FFS). Weight, height and Mid-Upper Arm Circumference (MUAC) were measured, and z scores were calculated. Association between ICFI scores and nutritional status was examined. RESULTS: The mean total ICFI score for all was 5.9 +/- 1.9. Among the five components, FGFS and FFS differed between children <12 months of age and >12 months and by breast feeding status. In contrast, there were no differences vis-a-vis dietary diversity scores (DDS), breast feeding, and use of bottle. Non-breastfed children had significantly higher DDS scores than did breastfed children. The mean feeding frequency score (FFS) for children <12 months of age was slightly but not significantly lower than scores for children >12 months of age. Mother's age and child's age were significant determinants of ICFI. Multivariate analysis indicated that ICFI was significantly associated with Length-for-Age z scores (LAZ) and BMI-for-Age z scores (BAZ). Sensitivity of ICFI was lower than its specificity. CONCLUSIONS: The results of the present study confirmed that the ICFI can be used to collect information on key components of young child feeding practices and be incorporated into public-health programmes. Further, it could be used to determine the influence of complementary feeding practices on nutritional status of children. PMID- 25433392 TI - A comparison of male partners' reactions to different intrauterine device strings. PMID- 25433393 TI - Interactions between an anti-sigma protein and two sigma factors that regulate the pyoverdine signaling pathway in Pseudomonas aeruginosa. AB - BACKGROUND: Synthesis and uptake of pyoverdine, the primary siderophore of the opportunistic pathogen Pseudomonas aeruginosa, is dependent on two extra cytoplasmic function (ECF) sigma factors, FpvI and PvdS. FpvI and PvdS are required for expression of the ferri-pyoverdine receptor gene fpvA and of pyoverdine synthesis genes respectively. In the absence of pyoverdine the anti sigma factor FpvR that spans the cytoplasmic membrane inhibits the activities of both FpvI and PvdS, despite the two sigma factors having low sequence identity. RESULTS: To investigate the interactions of FpvR with FpvI and PvdS, we first used a tandem affinity purification system to demonstrate binding of PvdS by the cytoplasmic region of FpvR in P. aeruginosa at physiological levels. The cytoplasmic region of FpvR bound to and inhibited both FpvI and PvdS when the proteins were co-expressed in Escherichia coli. Each sigma factor was then subjected to error prone PCR and site-directed mutagenesis to identify mutations that increased sigma factor activity in the presence of FpvR. In FpvI, the amino acid changes clustered around conserved region four of the protein and are likely to disrupt interactions with FpvR. Deletion of five amino acids from the C terminal end of FpvI also disrupted interactions with FpvR. Mutations in PvdS were present in conserved regions two and four. Most of these mutations as well as deletion of thirteen amino acids from the C-terminal end of PvdS increased sigma factor activity independent of whether FpvR was present, suggesting that they increase either the stability of PvdS or its affinity for core RNA polymerase. CONCLUSIONS: These data show that FpvR binds to PvdS in both P. aeruginosa and E. coli, inhibiting its activity. FpvR also binds to and inhibits FpvI and binding of FpvI is likely to involve conserved region four of the sigma factor protein. PMID- 25433394 TI - Concurrent transcriptional profiling of Dirofilaria immitis and its Wolbachia endosymbiont throughout the nematode life cycle reveals coordinated gene expression. AB - BACKGROUND: Dirofilaria immitis, or canine heartworm, is a filarial nematode parasite that infects dogs and other mammals worldwide. Current disease control relies on regular administration of anthelmintic preventives, however, relatively poor compliance and evidence of developing drug resistance could warrant alternative measures against D. immitis and related human filarial infections be taken. As with many other filarial nematodes, D. immitis contains Wolbachia, an obligate bacterial endosymbiont thought to be involved in providing certain critical metabolites to the nematode. Correlations between nematode and Wolbachia transcriptomes during development have not been examined. Therefore, we detailed the developmental transcriptome of both D. immitis and its Wolbachia (wDi) in order to gain a better understanding of parasite-endosymbiont interactions throughout the nematode life cycle. RESULTS: Over 215 million single-end 50 bp reads were generated from total RNA from D. immitis adult males and females, microfilariae (mf) and third and fourth-stage larvae (L3 and L4). We critically evaluated the transcriptomes of the various life cycle stages to reveal sex biased transcriptional patterns, as well as transcriptional differences between larval stages that may be involved in larval maturation. Hierarchical clustering revealed both D. immitis and wDi transcriptional activity in the L3 stage is clearly distinct from other life cycle stages. Interestingly, a large proportion of both D. immitis and wDi genes display microfilarial-biased transcriptional patterns. Concurrent transcriptome sequencing identified potential molecular interactions between parasite and endosymbiont that are more prominent during certain life cycle stages. In support of metabolite provisioning between filarial nematodes and Wolbachia, the synthesis of the critical metabolite, heme, by wDi appears to be synchronized in a stage-specific manner (mf-specific) with the production of heme-binding proteins in D. immitis. CONCLUSIONS: Our integrated transcriptomic study has highlighted interesting correlations between Wolbachia and D. immitis transcription throughout the life cycle and provided a resource that may be used for the development of novel intervention strategies, not only for the treatment and prevention of D. immitis infections, but of other closely related human parasites as well. PMID- 25433396 TI - Levels of PCDDs, PCDFs and dl-PCBs in the blood of childbearing-aged women living in the vicinity of a chemical plant in Tianjin: a primary study. AB - Several studies have suggested that maternal exposure to Polychlorinated dibenzo p-dioxins (PCDDs), poly-chlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (PCBs) may affect foetal growth and infant development. The aim of our study was to determine whether the childbearing-aged residents living near a chemical plant have a greater exposure risk. Concentrations of 17 PCDD/Fs congeners and 12 non-ortho and mono-ortho dioxin-like PCBs were measured using HRGC-HRMS in the blood of 30 non-occupational childbearing-aged women living near a chemical plant (Dagu) that had been producing chlorinated pesticides from 1958 to 2004. The factors that influenced the body burden were investigated based on responses to a questionnaire. Levels of PCDD/Fs+PCBs were in the range of 16.43-155.29pg WHO 2005-TEQg(-1) lipid. PCDDs and PCDFs contributed 56.72% and 34.44%, respectively, to the total TEQ value. Total WHO TEQ was approximately tenfold higher in the participants living in the vicinity of the plant (distance: 1.52+/-0.148km) than in the groups living farther away (distance: 4.93+/-1.124km). A negative correlation between total WHO-TEQ and distance to Dagu was observed by multiple linear regression models. The data provide basic information for monitoring dioxin-like chemicals in the district and for the future study of the relationship between POPs and pregnancy outcomes. PMID- 25433397 TI - Distribution and excretion of 2,2',3,4',5,5',6-heptachlorobiphenyl (CB187) and its metabolites in rats and guinea pigs. AB - 4-Hydroxy (OH)-2,2',3,4',5,5',6-heptachlorobiphenyl (CB187) is a polychlorinated biphenyl (PCB) metabolite present in human serum at the highest concentration of the PCB metabolites. Our previous study demonstrated that CB187 was metabolized by rat and guinea pig liver microsomes to the major metabolite 4'-OH 2,2',3,3',5,5',6-heptachlorobiphenyl (CB178), and the two minor metabolites 4-OH CB187 and 4'-OH-2,2',3,5,5',6-hexachlorobiphenyl (CB151). In this study, the distribution of these metabolites in serum, liver and kidney, and their fecal excretion, were examined in rats and guinea pigs intraperitoneally dosed with CB187. Similarly to the in vitro study, 4'-OH-CB178 was a major metabolite in the liver, serum and feces of both animal species on day 4 after CB187 injection, and the level in the liver was about 20 times higher in untreated guinea pigs than in untreated rats. In addition, 4-OH-CB187, a minor metabolite, was detected in the serum and kidneys, but not in the feces, of both guinea pigs and rats. Another minor metabolite, 4'-OH-CB151, was detected at a lower level only in guinea pig feces; little was found in the serum or liver of either animals. Over the 30d following CB187 injection into guinea pigs, 4'-OH-CB178 and 4-OH-CB187 in the serum was observed at higher level on day 4 and day 16 after injection, respectively. The majority of the 4'-OH-CB178 was rapidly excreted to the feces following unmetabolized CB187, whereas 4-OH-CB187 was not found in guinea pig feces and liver during 30d. These results support previous reports that 4-OH CB187 is retained persistently in animal blood. PMID- 25433398 TI - Levels and patterns of organochlorine pesticides and their degradation products in rainwater in Kibaha Coast Region, Tanzania. AB - The levels and patterns of organochlorine pesticides and degradation products in rainwater samples collected in relation to a contaminated site in Kibaha district, Tanzania were investigated. The compounds detected in the samples by GC MS and isotope dilution methodology included DDT, DDE, DDD, HCHs, dieldrin, heptachlor, chlordane, endrin and hexachlorobenzene. The concentrations of total DDT and total HCH ranged 0.005-3200MUgL(-1) and 0.01-170MUgL(-1), respectively and they indicated input of significantly non-degraded technical mixtures. The highest concentrations for other compounds ranged 0.001-1.3MUgL(-1). The highest concentrations were found in samples collected in the vicinity of the contaminated site and the concentrations at other points showed a general even distribution suggesting repeated volatilization and deposition mechanisms. The strong positive correlations in the concentrations of the compounds indicated a common source. A decrease in concentrations with time was indicated, although the decrease was not significant during the period of sampling. The findings indicate risks and concerns for public and environmental health. PMID- 25433395 TI - MITF in melanoma: mechanisms behind its expression and activity. AB - MITF (microphthalmia-associated transcription factor) represents a melanocytic lineage-specific transcription factor whose role is profoundly extended in malignant melanoma. Over the last few years, the function of MITF has been tightly connected to plasticity of melanoma cells. MITF participates in executing diverse melanoma phenotypes defined by distinct gene expression profiles. Mutation-dependent alterations in MITF expression and activity have been found in a relatively small subset of melanomas. MITF activity is rather modulated by its upstream activators and suppressors operating on transcriptional, post transcriptional and post-translational levels. These regulatory mechanisms also include epigenetic and microenvironmental signals. Several transcription factors and signaling pathways involved in the regulation of MITF expression and/or activity such as the Wnt/beta-catenin pathway are broadly utilized by various types of tumors, whereas others, e.g., BRAF(V600E)/ERK1/2 are more specific for melanoma. Furthermore, the MITF activity can be affected by the availability of transcriptional co-partners that are often redirected by MITF from their own canonical signaling pathways. In this review, we discuss the complexity of a multilevel regulation of MITF expression and activity that underlies distinct context-related phenotypes of melanoma and might explain diverse responses of melanoma patients to currently used therapeutics. PMID- 25433399 TI - Uptake and distribution of chlordecone in radish: different contamination routes in edible roots. AB - Chlordecone (CLD) was an organochlorine insecticide mainly used to struggle against banana weevils in the French West Indies. Forbidden since 1993, it has been a long-term contaminant of soils and aquatic environments. Crops growing in contaminated soils lead to human exposure by food consumption. We used radiolabeled [(14)C]-CLD to investigate the contamination ways into radish, a model of edible roots. Radish plants were able to accumulate CLD in both roots (RCF35d 647) and tubers (edible parts, CF35d 6.3). CLD was also translocated to leaves (CF35d 1.7). The contamination of tuber was mainly due to peridermic adsorption or CLD systemic translocation to the pith. TSCF was 3.44*10(-)(3). CLD diffused across periderm to internal tissues. We calculated a mean flux of diffusion J through periderm about 5.71*10(-)(14)gcm(-)(2)s(-)(1). We highlighted different contamination routes of the tuber, (i) adsorption on periderm followed by diffusion of CLD towards underlying tissues, cortex, xylem, and pith (ii) adsorption by roots and translocation by the transpiration stream followed by diffusion from xylem vessels towards inner tissues, pith, and peripheral tissues, cortex and periderm. Concerning chemical risk assessment for other tubers, contamination would depend on various parameters, the thickness of periderm and CLD periderm permeance, the origin of secondary tissues - from cortex and/or pith - , the importance of xylem flow in tuber, and the lipid amount within tuber. PMID- 25433400 TI - Interaction of 2-(2',4'-bromophenoxyl)-benzoquinone with deoxynucleosides and DNA in vitro. AB - Polybrominated diphenyl ethers (PBDEs) may be metabolized to form hydroxylated and quinone products. Study on the formation of DNA adducts altered by PBDEs quinones was conducted. Various types of DNA adducts generated from in vitro reaction of deoxyguanosine (dG), 2'-deoxyadenosine (dA), 2'-deoxycytidine (dC), thymidine (T) and DNA with a PBDE-quinone metabolite, namely 2-(2',4' bromophenoxyl)-benzoquinone (2'4'BrPhO-BQ) were characterized. The results suggest that the quinone compound could form various DNA adducts with dG, dA and dC via Michael Addition, which was confirmed from analyses by electrospray ionization tandem mass spectrometry. Two adducts were respectively generated from the reactions of 2'4'BrPhO-BQ with dC and dG, while three adducts were produced with dA. The formation of adducts of 2'4'BrPhO-BQ-deoxynucleoside changed with different pH of reaction solution. The obtained results demonstrated that 2'4'BrPhO-BQ could covalently bind to DNA mediated by quinone group. The in vitro data of the formation of DNA adducts might be valuable to elucidate the mechanism of interaction between PBDEs and DNA in vivo. PMID- 25433402 TI - Primary health care use from the perspective of gender and morbidity burden. AB - BACKGROUND: Sex and gender can interact to contribute to differences in morbidity and mortality between men and women. To detect such differences is an important issue for health policy planners when designing programmes for the provision of healthcare services for the whole population. Our aim was to study differences between men and women in the use of Primary Health Care (PHC) resources, taking into account age and morbidity burden. METHODS: An observational retrospective study was carried out using the information gathered in electronic medical records from 79,809 adult patients who attended a PHC centre at least once in 2008. The ACG(r) System was used to quantify the morbidity burden of patients. Poisson regression models were applied to analyse differences in the number of visits to the PHC centre by men and women. RESULTS: Morbidity burden was significantly higher in women of all age groups. The gross number of visits to the PHC centre was also higher for women in all age groups. However, when adjusting by age and morbidity burden, we did not find a higher utilization by women compared to men. For high levels of morbidity burden, the attendance by men was even significantly higher. CONCLUSIONS: The overall higher use of PHC by women seems to be associated with their higher morbidity burden. The interaction between biology and socially constructed roles could also underlie this higher use by women, and is therefore an area that deserves further in-depth research. PMID- 25433403 TI - Impact of monitoring blood volume in the BD BACTECTM FX blood culture system: virtual volume versus actual volume. AB - The BACTECTM FX (BD, USA) has been recently upgraded to measure virtual blood volume (VV) in batches of 25 PLUS Aerobic/F bottles. VVs were compared with manually measured actual volumes (AVs). The mean AV was larger in anaerobic bottles: 2.6+/-1.9mL in 2995 Aerobic/F bottles and 3.3+/-1.8mL in 3053 Lytic/10 Anaerobic/F bottles (P<0.001). The VV of Aerobic/F bottles was 2.4+/-1.4mL, and there was a significant correlation between the VVs and AVs of each department (P<0.001). The potential positivity in aerobic bottles increased 1.2-fold with a 1-mL increase in the AV (P<0.001). AV and VV were consistently less than adequate. Although the proportional effect of volume on positivity can be proven only with the AV, VVs are a reliable substitute for AVs to monitor the overall blood volumes and provide feedback to the individual departments or locations. PMID- 25433401 TI - Systematic review of management for treatment-resistant depression in adolescents. AB - BACKGROUND: Current guidelines for treatment-resistant depression in adolescents remain inadequate. This study aimed to systematically review the management of treatment-resistant depression in adolescent patients. METHODS: We conducted an electronic database search of PUBMED, EMBASE, Cochrane, Web of Science and PsycINFO for studies with adolescent treatment-resistant depression published up to January 2014. Treatment-resistant depression was defined as failure to respond to at least one course of psychological or pharmacological treatment for depression with an adequate dosage, duration, and appropriate compliance during the current illness episode. The Cochrane risk-of-bias method was used to assess the quality of randomized controlled trials. A meta-analysis of all active treatments was conducted. RESULTS: Eight studies with 411 depressed adolescents that fit predetermined criteria investigated pharmacological treatments and psychotherapies. Six were open-label studies, and two were randomized controlled trials. The overall response rate for all active treatments investigated was 46% (95% CI 33 to 59; N = 411) with a moderately high degree of heterogeneity (I2 = 76.1%, 95% CI = 47%-86%). When only the two randomized trials were included, the overall response rate of active treatment was 53% (95% CI = 38-67; N = 347). In these randomized trials, SSRI therapy plus CBT was significantly more effective than SSRI therapy alone, while amitriptyline was not more effective than placebo. CONCLUSIONS: Approximately half of the adolescents who presented with treatment refractory depression responded to active treatment, which suggests that practitioners should remain persistent in managing these challenging cases. The combination of antidepressant medication and psychotherapy should be recommended for adolescents who present with treatment-resistant depression. PMID- 25433404 TI - Decision-making in a changing world: a study in autism spectrum disorders. AB - To learn to deal with the unexpected is essential to adaptation to a social, therefore often unpredictable environment. Fourteen adults with autism spectrum disorders (ASD) and 15 controls underwent a decision-making task aimed at investigating the influence of either a social or a non-social environment, and its interaction with either a stable (with constant probabilities) or an unstable (with changing probabilities) context on their performance. Participants with ASD presented with difficulties in accessing underlying statistical rules in an unstable context, a deficit especially enhanced in the social environment. These results point out that the difficulties people with ASD encounter in their social life might be caused by impaired social cues processing and by the unpredictability associated with the social world. PMID- 25433405 TI - Support needs of fathers and mothers of children and adolescents with autism spectrum disorder. AB - Little research has examined the support needs of mothers versus fathers of children and adolescents with autism spectrum disorder (ASD). We identified and compared the important and unmet support needs of mothers and fathers, and evaluated their association with family and child factors, within 73 married couples who had a child or adolescent with ASD. Mothers had a higher number of important support needs and higher proportion of important support needs that are unmet than fathers. Multilevel modeling indicated that child age, co-occurring behavior problems, presence of intellectual disability, parent education, and household income were related to support needs. Findings offer insight into the overlapping and unique support needs of mothers and fathers of children and adolescents with ASD. PMID- 25433407 TI - Evaluation of monitoring indicators for the post-closure care of a landfill for MSW characterized with low lignin content. AB - To understand the applicability of the termination indicators for landfill municipal solid waste (MSW) with low initial lignin content, four different accelerated landfill stabilization techniques were applied to anaerobic landfilled waste, including anaerobic flushing with water, anaerobic flushing with Fenton-treated leachate, and aerobic flushing with Fenton-treated and UV/H2O2-treated leachate. Termination indicators, including total organic carbon (TOC), ammonia-N (NH4(+)-N), the ratio of UV absorbance at 254 nm to TOC concentration (SUVA254), fluorescence spectra of leachate, methane production, oxygen consumption, lignocellulose content, and humus-like content were evaluated. Results suggest that oxygen consumption related indicators used as a termination indicator for low-lignin-content MSW were more sensitive than methane consumption related indicators. Aeration increased humic acid (HA) and (HA+FA)/HyI content by 2.9 and 1.7 times compared to the anaerobically stabilized low-lignin-content MSW. On the other hand, both the fulvic acid (FA) and hydrophilic (HyI) fractions remained constant regardless of stabilization technique. The target value developed for low-lignin-content MSW was quite different than developed countries mainly due to low residual biodegradable organic carbon content in stabilized low-lignin-content MSW. PMID- 25433406 TI - Food allergy enhances allergic asthma in mice. AB - BACKGROUND: Atopic march refers to the typical transition from a food allergy in early childhood to allergic asthma in older children and adults. However the precise interplay of events involving gut, skin and pulmonary inflammation in this process is not completely understood. OBJECTIVES: To develop a mouse model of mixed food and respiratory allergy mimicking the atopic march and better understand the impact of food allergies on asthma. METHODS: Food allergy to ovalbumin (OVA) was induced through intra-peritoneal sensitization and intra gastric challenge, and/or a respiratory allergy to house dust mite (HDM) was obtained through percutaneous sensitization and intra-nasal challenges with dermatophagoides farinae (Der f) extract. Digestive, respiratory and systemic parameters were analyzed. RESULTS: OVA-mediated gut allergy was associated with an increase in jejunum permeability, and a worsening of Der f-induced asthma with stronger airway hyperresponsiveness and pulmonary cell infiltration, notably eosinophils. There was overproduction of the pro-eosinophil chemokine RANTES in broncho-alveolar lavages associated with an enhanced Th2 cytokine secretion and increased total and Der f-specific IgE when the two allergies were present. Both AHR and lung inflammation increased after a second pulmonary challenge. CONCLUSION: Gut sensitization to OVA amplifies Der f-induced asthma in mice. PMID- 25433409 TI - Advancing availability of papillary muscle sandwich plasty from functional to organic mitral valve regurgitation. AB - An original papillary muscle heads approximation procedure, commonly known as a sandwich plasty, has been successfully used for the treatment of functional mitral regurgitation (MR) associated with ischemic cardiomyopathy (ICM) and aortic valve disease (AVD). In this study, we evaluated the availability of this method as the concomitant procedure for the plasty of organic MR in comparison with the operative results in patients with functional MR. Fifty-six patients who underwent sandwich plasty were reviewed, including 45 functional MR (29 ICM and 16 AVD) patients and 11 organic MR patients. The mean age of patients was 67 years. In the organic MR patients, predominant cardiac diseases were solitary MR in six patients and combined valve diseases including aortic valve stenosis in five. Mitral valve changes included prolapse in six patients and moderate cusp thickening with calcification in five. Two heads of the papillary muscle connecting to the choldae of both the anterior and posterior leaflets are fixed with two teflon-pledgeted 3-0 TiCronTM (Covidien, Dublin, Ireland) sutures in order to achieve coaptation of the two leaflets. Prominent MR was observed in a patient with functional MR after surgery, however residual MR was not detected in organic MR patients. The tenting height (coaptation distance) of mitral valve significantly decreased after surgery from 11+/-1 to 7+/-2mm in the organic MR patients, which was similar to the results in the functional MR patients (from 12+/-2 to 7+/-2 mm). The postoperative mean mitral orifice area in the organic MR patients was 4.3+/-0.1cm2 without stenosis. Sandwich plasty reduces the distance of choldae connecting to anterior and posterior leaflets and achieves the better coaptation of two leaflets. This procedure is effective in the treatment of both functional and organic MR. PMID- 25433408 TI - Translation and psychometric properties of the Chinese (Mandarin) version of the Child Oral Health Impact Profile-Short Form 19 (COHIP-SF 19) for school-age children. AB - BACKGROUND: Although caries and malocclusion occur with a high prevalence in Chinese school-age children, there were no appropriate instrument to assess the oral health-related quality of life (OHRQoL) for this population. The aim of our study was to develop a Chinese (Mandarin) version of the Child Oral Health Impact Profile-Short Form 19 (COHIP-SF 19) and provide a preliminary test of its psychometric properties. METHODS: The Chinese version of COHIP-SF 19 was developed through a standard translation and back translation procedure. The psychometric properties of the instrument were tested among 644 school-age children in Beijing, China, including the internal consistency, test-retest reliability, discriminant and convergent validity. A Mann-Whitney U test was used to determine the capability of the instrument to differentiate children with different caries and malocclusion outcomes. And partial Spearman correlations were used to determine the relationships between the OHRQoL scores and clinical severity indicators and self-perceived health ratings, respectively. RESULTS: Chinese school-age children had relatively high OHRQoL scores, in spite of the fact that oral impacts were quite common (56.3%). The internal consistency and retest reliability were good to excellent with a Chronbach's alpha of 0.81 and an intra-class correlation coefficient (ICC) of 0.77. Children who had active tooth decay or severe malocclusion had significantly lower COHIP-SF 19 scores (P <=0.001). Girls had somewhat higher scores in the oral health and functional well being subscales (P <0.05), while children from rural districts had lower scores than children from urban areas (P <0.05). We observed a low to moderate correlation between the overall COHIP-SF 19, subscale scores and clinical severity indicators as well as self-perceived health ratings, after adjustment for children's age, gender, and school district (?r s ? =0.11 - 0.51, P <0.05). CONCLUSION: We confirmed satisfactory psychometric properties for the Chinese version of COHIP-SF 19 in a community sample of Chinese school-age children. The OHRQoL instrument should play a more important role in future clinical studies, epidemiological surveys and potential public health policy in China. PMID- 25433410 TI - Use of exercise tests in primary care: importance for referral decisions and possible bias in the decision process; a prospective observational study. AB - BACKGROUND: The utility of clinical exercise tests depends on their support of treatment decisions. We sought to assess the utility of exercise tests for the selection of primary-care patients for referral to cardiologic care, and to determine whether referral decisions were biased by gender or socioeconomic status. We also evaluated referral rates and cardiovascular events in patients with positive exercise tests. METHODS: We designed a prospective observational study of 438 men and 427 women from 28 Swedish primary-care clinics who were examined with exercise testing for suspected coronary disease. All participants were followed-up with respect to cardiologist referrals and cardiovascular events (hospitalisation for unstable angina, myocardial infarction, and cardiovascular death) within six months and revascularisation within 250 days. Variables associated with referral were identified by multivariable logistic regression. Socioeconomic status was determined by educational level and employment. RESULTS: Positive/inconclusive exercise tests and exertional chest pain predicted referral in men and women. Of 865 participants, patients with positive, inconclusive, or negative exercise tests were referred to cardiologists in 67.3%, 26.1%, and 3.5% of cases, respectively. Overall, there was no significant difference in referral rates related to gender or socioeconomic level. Self-employed women were referred more frequently compared to other women (odds ratio (OR) 3.62, 95% confidence interval (CI) 1.19-10.99). Among non-manual employees, women were referred to cardiologic examination less frequently than men (OR 0.40, 95% CI 0.16-1.00; p = 0.049; ORs adjusted for age, exertional chest pain, and exercise test result). In patients with positive exercise tests, the referral rate decreased continuously with age (OR 0.48, 95% CI 0.23-0.97; adjusted for cardiovascular co-morbidity). Cardiovascular events occurred in 22.2% (4/18) of non-referred patients with positive exercise tests; 56% (10/18) of these patients were not considered for cardiologic care, with continuity problems in primary care as one possible contributing cause. CONCLUSIONS: Exercise tests are important for selecting patients for referral to cardiologic care. Interactions related to gender and socioeconomic status affected referral rates. In patients with positive exercise tests, referral rates decreased with age. An increased awareness of possible bias regarding age, gender, and socioeconomic status, which may influence medical decisions, is therefore necessary. PMID- 25433411 TI - Diagnostic signs of motor neuropathy in MR neurography: nerve lesions and muscle denervation. AB - OBJECTIVE: To investigate the diagnostic contribution of T2-w nerve lesions and of muscle denervation in peripheral motor neuropathies by magnetic resonance neurography (MRN). METHODS: Fifty-one patients with peripheral motor neuropathies underwent high-resolution MRN by large coverage axial T2-w sequences of the upper arm, elbow, and forearm. Images were evaluated by two blinded readers for T2-w signal alterations of median, ulnar, and radial nerves, and for denervation in respective target muscle groups. RESULTS: All 51 patients displayed nerve lesions in at least one of three nerves, and 43 out of 51 patients showed denervation in at least one target muscle group of these nerves. In 21 out of 51 patients, the number of affected nerves matched the number of affected target muscle groups. In the remaining 30 patients, T2-w lesions were encountered more frequently than target muscle group denervation. In 153 nerve-muscle pairs, 72 showed denervation, but only one had increased muscle signal without a lesion in the corresponding nerve. CONCLUSIONS: MRN-based diagnosis of peripheral motor neuropathies is more likely by visualization of peripheral nerve lesions than by denervation in corresponding target muscles. Increased muscular T2-w signal without concomitant nerve lesions should raise suspicion of an etiology other than peripheral neuropathy. KEY POINTS: * In peripheral neuropathy, T2-w nerve lesions are more frequent than muscle denervation. * Muscle denervation almost never occurs without detectable lesions in corresponding nerves. * MRN-aided diagnosis of peripheral motor neuropathy should focus primarily on nerve lesions. * Increased muscular T2-w signal intensity without concomitant nerve lesions indicates other aetiology. PMID- 25433412 TI - Differentiation of focal-type autoimmune pancreatitis from pancreatic carcinoma: assessment by multiphase contrast-enhanced CT. AB - OBJECTIVES: To evaluate the utility of multiphase contrast-enhanced computed tomography (CT) findings alone and in combination for differentiating focal-type autoimmune pancreatitis (f-AIP) from pancreatic carcinoma (PC). METHODS: The study group comprised 22 f-AIP lesions and 61 PC lesions. Two radiologists independently evaluated CT findings. Frequencies of findings were compared between f-AIP and PC. Statistical, univariate and multivariate analyses were performed. RESULTS: Homogeneous enhancement during the portal phase (AIP, 59 % vs. PC, 3 %; P < 0.001), dotted enhancement during the pancreatic phase (50 % vs. 7 %; P < 0.001), duct-penetrating sign (46 % vs. 2 %; P < 0.001), enhanced duct sign (36 % vs. 2 %; P < 0.001) and capsule-like rim (46 % vs. 3 %; P < 0.001) were more frequently observed in AIP. Ring-like enhancement during the delayed phase (5 % vs. 46 %; P < 0.001) and peripancreatic strands with a length of at least 10 mm (5 % vs. 39 %; P = 0.001) were more frequently observed in PC. AIP was identified with 82 % sensitivity and 98 % specificity using four of these seven findings. Multivariate analysis revealed significant differences in dotted enhancement (P = 0.004), duct-penetrating sign (P < 0.001) and capsule-like rim (P = 0.007). CONCLUSIONS: The combination of CT findings may allow improvements in differentiating f-AIP from PC. KEY POINTS: * f-AIP can mimic PC on imaging findings. * The differentiation of f-AIP from PC is important in patient management. * Some CT findings can be used to identify AIP. * The combination of CT findings will improve differentiation from PC. PMID- 25433413 TI - Assessment of early-stage optic nerve invasion in retinoblastoma using high resolution 1.5 Tesla MRI with surface coils: a multicentre, prospective accuracy study with histopathological correlation. AB - OBJECTIVES: To assess the accuracy of high-resolution (HR) magnetic resonance imaging (MRI) in diagnosing early-stage optic nerve (ON) invasion in a retinoblastoma cohort. METHODS: This IRB-approved, prospective multicenter study included 95 patients (55 boys, 40 girls; mean age, 29 months). 1.5-T MRI was performed using surface coils before enucleation, including spin-echo unenhanced and contrast-enhanced (CE) T1-weighted sequences (slice thickness, 2 mm; pixel size <0.3 * 0.3 mm(2)). Images were read by five neuroradiologists blinded to histopathologic findings. ROC curves were constructed with AUC assessment using a bootstrap method. RESULTS: Histopathology identified 41 eyes without ON invasion and 25 with prelaminar, 18 with intralaminar and 12 with postlaminar invasion. All but one were postoperatively classified as stage I by the International Retinoblastoma Staging System. The accuracy of CE-T1 sequences in identifying ON invasion was limited (AUC = 0.64; 95 % CI, 0.55 - 0.72) and not confirmed for postlaminar invasion diagnosis (AUC = 0.64; 95 % CI, 0.47 - 0.82); high specificities (range, 0.64 - 1) and negative predictive values (range, 0.81 - 0.97) were confirmed. CONCLUSION: HR-MRI with surface coils is recommended to appropriately select retinoblastoma patients eligible for primary enucleation without the risk of IRSS stage II but cannot substitute for pathology in differentiating the first degrees of ON invasion. KEY POINTS: * HR-MRI excludes advanced optic nerve invasion with high negative predictive value. * HR-MRI accurately selects patients eligible for primary enucleation. * Diagnosis of early stages of optic nerve invasion still relies on pathology. * Several physiological MR patterns may mimic optic nerve invasion. PMID- 25433414 TI - Implications of imaging criteria for the management and treatment of intraductal papillary mucinous neoplasms - benign versus malignant findings. AB - OBJECTIVES: Evaluation of computed tomography (CT) and magnetic resonance imaging (MRI) for differentiation of pancreatic intraductal papillary mucinous neoplasm (IPMN) subtypes based on objective imaging criteria. METHODS: Fifty-eight patients with 60 histologically confirmed IPMNs were included in this retrospective study. Eighty-three imaging studies (CT,n = 42; MRI,n = 41) were analysed by three independent blinded observers (O1-O3), using established imaging criteria to assess likelihood of malignancy (-5, very likely benign; 5, very likely malignant) and histological subtype (i.e., low-grade (LGD), moderate grade (MGD), high-grade dysplasia (HGD), early invasive carcinoma (IPMC), solid carcinoma (CA) arising from IPMN). RESULTS: Forty-one benign (LGD IPMN,n = 20; MGD IPMN,n = 21) and 19 malignant (HGD IPMN,n = 3; IPMC,n = 6; solid CA,n = 10) IPMNs located in the main duct (n = 6), branch duct (n = 37), or both (n = 17) were evaluated. Overall accuracy of differentiation between benign and malignant IPMNs was 86/92 % (CT/MRI). Exclusion of overtly malignant cases (solid CA) resulted in overall accuracy of 83/90 % (CT/MRI). The presence of mural nodules and ductal lesion size >=30 mm were significant indicators of malignancy (p = 0.02 and p < 0.001, respectively). CONCLUSIONS: Invasive IPMN can be identified with high confidence and sensitivity using CT and MRI. The diagnostic problem that remains is the accurate radiological differentiation of premalignant and non invasive subtypes. KEY POINTS: * CT and MRI can differentiate benign from malignant forms of IPMN. * Identifying (pre)malignant histological IPMN subtypes by CT and MRI is difficult. * Overall, diagnostic performance with MRI was slightly (not significantly) superior to CT. PMID- 25433415 TI - 3.0 Tesla breast magnetic resonance imaging in patients with nipple discharge when mammography and ultrasound fail. AB - OBJECTIVES: To compare 3.0 Tesla breast magnetic resonance imaging (MRI) with galactography for detection of benign and malignant causes of nipple discharge in patients with negative mammography and ultrasound. METHODS: We prospectively evaluated 56 breasts of 50 consecutive patients with nipple discharge who had inconspicuous mammography and ultrasound, using 3.0 Tesla breast MRI with a dedicated 16-channel breast coil, and then compared the results with galactography. Histopathological diagnoses and follow-ups were used as reference standard. Lesion size estimated on MRI was compared with the size at histopathology. RESULTS: Sensitivity and specificity of MRI vs. galactography for detecting pathologic findings were 95.7 % vs. 85.7 % and 69.7 % vs. 33.3 %, respectively. For the supposed concrete pathology based on MRI findings, the specificity was 67.6 % and the sensitivity 77.3 % (PPV 60.7 %, NPV 82.1 %). Eight malignant lesions were detected (14.8 %). The estimated size at breast MRI showed excellent correlation with the size at histopathology (Pearson's correlation coefficient 0.95, p < 0.0001). CONCLUSIONS: MRI of the breast at 3.0 Tesla is an accurate imaging test and can replace galactography in the workup of nipple discharge in patients with inconspicuous mammography and ultrasound. KEY POINTS: * Breast MRI is an excellent diagnostic tool for patients with nipple discharge. * MRI of the breast reveals malignant lesions despite inconspicuous mammography and ultrasound. * MRI of the breast has greater sensitivity and specificity than galactography. * Excellent correlation of lesion size measured at MRI and histopathology was found. PMID- 25433416 TI - Oral propranolol and intravitreal ranibizumab for refractory serous macular detachment secondary to retinal capillary hemangioblastoma. PMID- 25433417 TI - Choroidal neovascularization secondary to choroideremia. AB - CASE REPORT: The case is presented of a 30 year-old man, with night blindness and decreased visual acuity (VA) in both eyes, but more significant in the left eye (LE) of 20/100. Lesions consistent with choroideremia and LE macular hemorrhage was observed in the fundus. CNV was confirmed by OCT. A definitive diagnosis was obtained by genetic study. No treatment was given as the patient did not return. At 6 months there was a regression of CNV with VA 20/25 in the LE. CONCLUSIONS: CNV associated with choroideremia is uncommon. Treatment would antiangiogenic therapy, however spontaneous resolution is possible. PMID- 25433418 TI - Percutaneous jejunostomy through the liver parenchyma for palliation of afferent loop syndrome. AB - In the treatment of afferent loop syndrome, jejunostomy or Roux-en-Y gastrojejunostomy have tended to represent the preferred procedures. In patients who are not good candidates for surgery, palliative treatment-i.e., percutaneous transhepatic biliary drainage or percutaneous direct transperitoneal jejunostomy techniques-have been applied. Transhepatic biliary drainage confers a risk of ascending cholangitis. Direct percutaneous transperitoneal drainage may be impractical when overlying bowel loops prevent access to deeply located afferent loops. In the present case, percutaneous jejunostomy through the liver parenchyma was performed successfully for palliation of afferent loop syndrome. PMID- 25433419 TI - A retrospective statistical analysis of the late complications associated with central venous port placements. AB - PURPOSE: Central venous (CV) ports are being used increasingly in both hospital and home care settings. Here, we investigated the rates and causes of CV port complications. MATERIALS AND METHODS: We retrospectively analyzed the placement of 264 consecutive CV ports in 239 consecutive patients admitted to our hospital between September 2009 and February 2012. All CV ports were inserted under fluoroscopy and ultrasound visualization by interventional radiologists using maximum barrier precautions. CV port complications were checked in detail and analyzed statistically. RESULTS: Total indwelling time for all CV ports was 51,033 catheter days. Of the 264 CV ports assessed, 50 were removed during the study period because of any complication and 147 remained at the end of the study period. In 33 cases, the patient died before the end of the study. Of the 50 patients who underwent CV port removal, 13 were diagnosed as having catheter related bloodstream infection (CRBSI). The total rate of CV port removal because of any complication was 0.98 cases per 1,000 catheter days, that of catheter troubles was 0.22 cases per 1,000 catheter days and that of CRBSI was 0.25 cases per 1,000 catheter days. Steroid administration and total parenteral nutrition (TPN) were associated with increased rates of infection. It seems that chemotherapy and indwelling time were also considered important factors. CONCLUSION: Steroid administration and TPN were associated with increased rates of infection. In addition, patients receiving chemotherapy or whose CV ports are left in place for a long time should be carefully observed to decrease these complications. PMID- 25433420 TI - [Analysis of how elderly internet users react to unexpected situations]. AB - BACKGROUND: Although internet usage among older adults is steadily increasing, there is still a digital divide between generations. Younger internet users seem to be more open towards new media. Recent studies showed the negative influence of computer anxiety on internet usage. It is not known how older adults deal with computer and internet issues in their home environment and which problem-solving strategies they apply. AIM: The behavior of elderly people in unexpected situations when using an internet portal was analyzed to establish whether older users can solve the problems without assistance and what individual reactions (e.g. facial expressions and gesticulations) they show during the interaction. MATERIAL AND METHODS: In a clinical trial with 50 older adults aged 60 years and older various typical problems which may occur while using web platforms were simulated and user behavior was analyzed using logging data, videography and with questionnaires to measure the subjective opinion of the study participants. RESULTS: The study participants had severe problems in solving the tasks on their own and many of them could not find a suitable solution at all. Overall, the videography data indicated an increased concentration of the participants during the whole session, which is in contrast to the low levels of perceived mental workload reported by the participants. Regarding task completion, no differences were found between seniors with and without cognitive impairment. CONCLUSION: The results showed the serious difficulties of older adults when dealing with unexpected events while using a web platform. For developers of internet platforms for inexperienced seniors, it seems to be crucial to incorporate a simple integration of all available features within the platform, without including features requiring high multi-tasking skills. PMID- 25433421 TI - General surgery training in Spain: core curriculum and specific areas of training. AB - The royal decree RD 639/2014 has been published, regulating among others, the core curriculum, and specific areas of training (SAT). It is of great interest for the specialty of General and Digestive Surgery (GS and DS). The aim is to expose and clarify the main provisions and reflect on their implications for the practical application of the core curriculum and SAT in the specialty of General and Digestive Surgery, to promote initiatives and regulations. This RD will be a milestone in our specialty that will test the strength of the specialty, if it does not finally culminate in its degradation against the emergence of new surgical specialties. A new stage begins in which the Spanish Association of Surgeons should be involved to define the conceptual basis of GS and DS in the XXI century, and the creation of new SAT to continue to maintain the "essence of our specialty". PMID- 25433422 TI - Two-stage right hepatic trisectionectomy with interval portal embolization: another alternative for advanced liver disease with large tumour volume in segment IV and small residual volume. PMID- 25433423 TI - Synthesis and antiprotozoal activities of new 3-azabicyclo[3.2.2]nonanes. AB - Some antimalarial agents in use typically bear basic side chains as ligands. Such ligands were attached to the amino substituent of a bridgehead atom of already antiprotozoal active 3-azabicyclo[3.2.2]nonanes. Structure verification was done by NMR measurements. The new compounds were tested for their antiplasmodial and antitrypanosomal activities against Plasmodium falciparum K 1 (multiresistant) and Trypanosoma brucei rhodesiense as well as for their cytotoxicity against L6 cells. Their activities are compared to those of already prepared compounds and structure-activity relationships are discussed. PMID- 25433425 TI - Development and application of a diagnostic algorithm for posttraumatic stress disorder. AB - Intact cognitive functions rely on synchronous neural activity; conversely, alterations in synchrony are thought to underlie psychopathology. We recently demonstrated that anomalies in synchronous neural interactions (SNI) determined by magnetoencephalography represent a putative PTSD biomarker. Here we develop and apply a regression-based diagnostic algorithm to further validate SNI as a PTSD biomarker in 432 veterans (235 controls; 138 pure PTSD; 59 PTSD plus comorbid disorders). Correlation coefficients served as proximities in multidimensional scaling (MDS) to obtain a two-dimensional representation of the data. In addition, least absolute shrinkage and selection operator (LASSO) regression was used to derive a diagnostic algorithm for PTSD. Performance of this algorithm was assessed by the area under the receiver operating characteristic (ROC) curves, sensitivity, and specificity in 1000 randomly divided testing and validation datasets and in independent samples. MDS revealed that individuals with PTSD, regardless of comorbid psychiatric conditions, are highly distinct from controls. Similarly, application of the LASSO regression derived prediction model demonstrated remarkable classification accuracy (AUCs>=0.93 for men, AUC=0.82 for women). Neural functioning in individuals with PTSD, regardless of comorbid psychiatric diagnoses, can be used as a diagnostic test to determine patient disease status, further validating SNI as a PTSD biomarker. PMID- 25433424 TI - Decreased amygdala-insula resting state connectivity in behaviorally and emotionally dysregulated youth. AB - The Research Domain Criteria (RDoC) adopts a dimensional approach for examining pathophysiological processes underlying categorically defined psychiatric diagnoses. We used this framework to examine relationships among symptom dimensions, diagnostic categories, and resting state connectivity in behaviorally and emotionally dysregulated youth selected from the Longitudinal Assessment of Manic Symptoms study (n=42) and healthy control youth (n=18). Region of interest analyses examined relationships among resting state connectivity, symptom dimensions (behavioral and emotional dysregulation measured with the Parent General Behavior Inventory-10 Item Mania Scale [PGBI-10M]; dimensional severity measures of mania, depression, anxiety), and diagnostic categories (Bipolar Spectrum Disorders, Attention Deficit Hyperactivity Disorder, Anxiety Disorders, and Disruptive Behavior Disorders). After adjusting for demographic variables, two dimensional measures showed significant inverse relationships with resting state connectivity, regardless of diagnosis: 1) PGBI-10M with amygdala-left posterior insula/bilateral putamen; and 2) depressive symptoms with amygdala right posterior insula connectivity. Diagnostic categories showed no significant relationships with resting state connectivity. Resting state connectivity between amygdala and posterior insula decreased with increasing severity of behavioral and emotional dysregulation and depression; this suggests an intrinsic functional uncoupling of key neural regions supporting emotion processing and regulation. These findings support the RDoC dimensional approach for characterizing pathophysiologic processes that cut across different psychiatric disorders. PMID- 25433427 TI - Diabetes and tuberculosis in the Pacific Islands region. PMID- 25433426 TI - Infected complex renal cysts during crizotinib therapy in a patient with non small cell lung cancer positive for ALK rearrangement. AB - Crizotinib is the first clinically available tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) and is associated with the development of complex renal cysts. We now describe a 39-year-old woman who developed infected complex renal cysts during crizotinib treatment. After 10 months of such treatment, she presented with a high fever and low back pain. Computed tomography findings were consistent with complex renal cysts and perilesional inflammation. Interventions including cyst drainage and antibiotic administration contributed to diagnosis and management of the infected cysts. PMID- 25433428 TI - Novel compound heterozygous ALS2 mutations in two Chinese siblings with infantile ascending hereditary spastic paralysis. PMID- 25433429 TI - Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis. PMID- 25433430 TI - Incretin-based therapies and pancreatitis risk: myth or reality. PMID- 25433431 TI - A new multi-label classifier in identifying the functional types of human membrane proteins. AB - Membrane proteins were found to be involved in various cellular processes performing various important functions, which are mainly associated to their type. Given a membrane protein sequence, how can we identify its type(s)? Particularly, how can we deal with the multi-type problem since one membrane protein may simultaneously belong to two or more different types? To address these problems, which are obviously very important to both basic research and drug development, a new multi-label classifier was developed based on pseudo amino acid composition with multi-label k-nearest neighbor algorithm. The success rate achieved by the new predictor on the benchmark dataset by jackknife test is 73.94%, indicating that the method is promising and the predictor may become a very useful high-throughput tool, or at least play a complementary role to the existing predictors in identifying functional types of membrane proteins. PMID- 25433432 TI - JcCBF2 gene from Jatropha curcas improves freezing tolerance of Arabidopsis thaliana during the early stage of stress. AB - High chilling-susceptibility is becoming the bottleneck for cultivation and commercialization of Jatropha curcas L. For insights to chilling resistance ability of this plant species, a cold response transcription factor, JcCBF2, was cloned and studied. It codes a 26 kDa protein, which contains all conserved motifs unique to the C-repeat binding factor (CBF) family and has high similarity to CBFs of Ricinus communis and Populus. Its transcripts express specifically in leaves of Jatropha at cold temperature. After transmitting the report vector, 35S::JcCBF2-GFP, into Arabidopsis thaliana, JcCBF2 protein is main detected in cell nucleus, being consistent to the nuclear orientation signal in its N terminal. Compared to the control Arabidopsis, the frozen leaves of JcCBF2 overexpressed seedlings grow stronger with less malondialdehyde, smaller leaf conductivity and activer superoxide dismutase, showing their higher freezing tolerance. RT-PCR tests revealed that JcCBF2 functioned mainly at the early stage (0-6 h) of resistance events in Arabidopsis, and its transcripts reduced after 6 h. In addition, JcCBF2 could quickly regulate transcripts of some cold-responsive (COR) genes such as RD29A, COR105A and COR6.6, also during the early stage of frozen treatment. This study not only proves the chilling resistance roles of JcCBF2, but also presents a candidate gene engineering for improvement of chilling tolerance in J. curcas. PMID- 25433433 TI - Complete mitogenome of the edible sea urchin Loxechinus albus: genetic structure and comparative genomics within Echinozoa. AB - The edible Chilean red sea urchin, Loxechinus albus, is the only species of its genus and endemic to the Southeastern Pacific. In this study, we reconstructed the mitochondrial genome of L. albus by combining Sanger and pyrosequencing technologies. The mtDNA genome had a length of 15,737 bp and encoded the same 13 protein-coding genes, 22 transfer RNA genes, and two ribosomal RNA genes as other animal mtDNAs. The size of this mitogenome was similar to those of other Echinodermata species. Structural comparisons showed a highly conserved structure, composition, and gene order within Echinoidea and Holothuroidea, and nearly identical gene organization to that found in Asteroidea and Crinoidea, with the majority of differences explained by the inversions of some tRNA genes. Phylogenetic reconstruction supported the monophyly of Echinozoa and recovered the monophyletic relationship of Holothuroidea and Echinoidea. Within Holothuroidea, Bayesian and maximum likelihood analyses recovered a sister-group relationship between Dendrochirotacea and Aspidochirotida. Similarly within Echinoidea, these analyses revealed that L. albus was closely related to Paracentrotus lividus, both being part of a sister group to Strongylocentrotidae and Echinometridae. In addition, two major clades were found within Strongylocentrotidae. One of these clades comprised all of the representative species Strongylocentrotus and Hemicentrotus, whereas the other included species of Mesocentrotus and Pseudocentrotus. PMID- 25433434 TI - A theoretical view of the C3d:CR2 binding controversy. AB - The C3d:CR2(SCR1-2) interaction plays an important role in bridging innate and adaptive immunity, leading to enhanced antibody production at sites of complement activation. Over the past decade, there has been much debate over the binding mode of this interaction. An initial cocrystal structure (PDB: 1GHQ) was published in 2001, in which the only interactions observed were between the SCR2 domain of CR2 and a side-face of C3d whereas a cocrystal structure (PDB: 3OED) published in 2011 showed both the SCR1 and SCR2 domains of CR2 interacting with an acidic patch on the concave surface of C3d. The initial 1GHQ structure is at odds with the majority of existing biochemical data and the publication of the 3OED structure renewed uncertainty regarding the physiological relevance of 1GHQ, suggesting that crystallization may have been influenced by the presence of zinc acetate in the crystallization process. In our study, we used a variety of computational approaches to gain insight into the binding mode between C3d and CR2 and demonstrate that the binding site at the acidic patch (3OED) is electrostatically more favorable, exhibits better structural and dissociative stability, specifically at the SCR1 domain, and has higher binding affinity than the 1GHQ binding mode. We also observe that nonphysiological zinc ions enhance the formation of the C3d:CR2 complex at the side face of C3d (1GHQ) through increases in electrostatic favorability, intermolecular interactions, dissociative character and overall energetic favorability. These results provide a theoretical basis for the association of C3d:CR2 at the acidic cavity of C3d and provide an explanation for binding of CR2 at the side face of C3d in the presence of nonphysiological zinc ions. PMID- 25433435 TI - IGF-1 attenuates LPS induced pro-inflammatory cytokines expression in buffalo (Bubalus bubalis) granulosa cells. AB - Interaction between immune and endocrine system is a diverse process influencing cellular function and homeostasis in animals. Negative energy balance (NEB) during postpartum period in dairy animals usually suppresses these systems resulting in reproductive tract infection and infertility. These negative effects could be due to competition among endocrine and immune signaling pathways for common signaling molecules. The present work studied the effect of IGF-1 (50 ng/ml) on LPS (1 MUg/ml) mediated pro-inflammatory cytokine expression (IL-1beta, TNF-alpha, IL-6) and aromatase (CYP19A1) genes' expressions as well as proliferation of buffalo granulosa cells. The crosstalk between LPS and IGF-1 was also demonstrated through studying the activities of downstream signaling molecules (ERK1/2, Akt, NF-kappaB) by western blot and immunostaining. Gene expression analysis showed that IGF-1 significantly reduced the LPS induced expression of IL-1beta, TNF-alpha and IL-6. LPS alone inhibited the CYP19A1 expression. However, co-treatment with IGF-1 reversed the inhibitory effect of LPS on CYP19A1 expression. LPS alone did not affect granulosa cell proliferation, but co-treatment with IGF-1, and IGF-1 alone enhanced the proliferation. Western blot results demonstrated that LPS caused the nuclear translocation of the NF kappaB and increased the phosphorylation of ERK1/2 and Akt maximum at 15 min and 60 min, respectively. Nonetheless, co-treatment with IGF-1 delayed LPS induced phosphorylation of ERK1/2 (peak at 120 min), while promoting early Akt phosphorylation (peak at 5 min) with no effect on NF-kappaB translocation. Overall, IGF-1 delayed and reversed the effects of LPS, suggesting that high IGF 1 levels may combat infection during critical periods like NEB in postpartum dairy animals. PMID- 25433436 TI - IFN-beta inhibits T cells accumulation in the central nervous system by reducing the expression and activity of chemokines in experimental autoimmune encephalomyelitis. AB - Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are chronic neuroinflammatory autoimmune diseases characterized by axonal loss, demyelination and neurodegeneration of the central nervous system (CNS). Overactivation of CD4(+)T cells, especially the Th1 and Th17 subsets, is thought to play a causal role in this disease. In this study, we investigated the immunomodulatory effects of IFN-beta treatment in EAE. IFN-beta significantly inhibits disease severity, and decreases levels of CCR2, CCR4, CCR5, CCR6 and CXCR3 in the CNS. This was associated with fewer Th1/Th17 cells expressing these chemokine receptors. Furthermore, levels of their corresponding ligands CCL2, CCL3, CCL4, CCL5, CCL20, CCL22 and CXCL10 were also reduced, coinciding with reduced CNS inflammation and demyelination. Chemokine expression significantly correlated with disease severity. Furthermore, we demonstrate that IFN-beta reduces CCL2/CCL5 induced-T cell migration by inhibiting p38-MAPK and ERK1/2 activation. Our results reveal that IFN-beta reduces the expression of chemokines and chemokine receptors expressed by encephalitogenic Th1/Th17 cells, thereby decreasing their migration into the CNS. PMID- 25433437 TI - Diabetes medications and bone. AB - Type 2 diabetes mellitus (T2DM) is a common chronic disease that may be associated with an increased risk of fracture. Evidence that thiazolidinediones (TZDs) increase fracture risk in women with T2DM has focused attention on the skeletal effects of treatments for diabetes. Only scant, low-quality evidence is available for non-TZD diabetes medications and bone health, but it suggests that there are no clinically important effects. PMID- 25433438 TI - Hyponatremia as an independent prognostic factor in patients with terminal cancer. AB - PURPOSE: Hyponatremia is a common and associated with poor clinical outcome in cancer patients. But little is known regarding hyponatremia in terminal cancer patients. The purpose of this study is to investigate the prognostic role of the hyponatremia in terminal cancer patients. METHODS: A retrospective observational study was conducted between January 2010 and December 2012 in a tertiary hospital palliative care unit. Medical records were collected from hospitalized patients who were eligible for obtaining serum sodium level. Hyponatremia was defined as serum sodium <136 mEq/L. And we classified patients into three groups; eunatremia (sodium 136-145 mEq/L), mild to moderate hyponatremia (sodium 126-135 mEq/L), and severe hyponatremia (sodium <=125 mEq/L). Univariate and multivariate Cox regression analyses were performed to determine factors affecting survival time. RESULTS: Of the 576 patients, hyponatremia was present in 367 individuals (63.7 %). In the univariate analysis, serum CRP, PPS, and sodium <=125 mEq/L were associated with survival time (HR = 1.22; p < 0.001, HR = 0.69; p < 0.001, HR = 1.91; p < 0.001). In the multivariate analysis, serum CRP, PPS, sodium 126-135 mEq/L, and sodium <=125 mEq/L were associated with survival time (HR = 1.16; p < 0.001, HR = 0.70; p < 0.001, HR = 1.19; p = 0.048, HR = 1.75; p < 0.001). CONCLUSIONS: Hyponatremia is an independent prognostic factor in terminal cancer patients and careful clinical concern is needed. In the future, large prospective study is warranted in terminal cancer patients. PMID- 25433439 TI - A prospectively validated nomogram for predicting the risk of chemotherapy induced febrile neutropenia: a multicenter study. AB - PURPOSE: There is clinical need to predict risk of febrile neutropenia before a specific cycle of chemotherapy in cancer patients. METHODS: Data on 3882 chemotherapy cycles in 1089 consecutive patients with lung, breast, and colon cancer from four teaching hospitals were used to construct a predictive model for febrile neutropenia. A final nomogram derived from the multivariate predictive model was prospectively confirmed in a second cohort of 960 consecutive cases and 1444 cycles. RESULTS: The following factors were used to construct the nomogram: previous history of febrile neutropenia, pre-cycle lymphocyte count, type of cancer, cycle of current chemotherapy, and patient age. The predictive model had a concordance index of 0.95 (95 % confidence interval (CI) = 0.91-0.99) in the derivation cohort and 0.85 (95 % CI = 0.80-0.91) in the external validation cohort. A threshold of 15 % for the risk of febrile neutropenia in the derivation cohort was associated with a sensitivity of 0.76 and specificity of 0.98. These figures were 1.00 and 0.49 in the validation cohort if a risk threshold of 50 % was chosen. CONCLUSIONS: This nomogram is helpful in the prediction of febrile neutropenia after chemotherapy in patients with lung, breast, and colon cancer. Usage of this nomogram may help decrease the morbidity and mortality associated with febrile neutropenia and deserves further validation. PMID- 25433440 TI - Outcome of chemotherapy extravasation in a large patient series using a standardised management protocol. AB - PURPOSE: In a longitudinal observation, extravasation of antitumoural compounds and the efficacy of its structured interdisciplinary management were assessed in a routine setting. METHODS: One hundred sixty-nine patients with extravasation of cytotoxics were managed according to a prospective approach documenting the extravasated compound, localisation, duration until full symptom resolution and sequelae. Surgery was implemented in the case of failure of conservative measures. RESULTS: In 155 (91.7 %) out of 169 patients, conservative management was successful (surgical intervention, 14 patients). Extravasations of anthracyclines (N = 44), platinum compounds (N = 41), vinca alkaloids (N = 20) and taxanes (N = 19) were often associated with erythema, oedema and pain. The median period until full resolution of symptoms differed among the administered cytotoxics (anthracyclines, 55 days; taxanes and vinca alkaloids, 27 days; platinum compounds, 14 days) with statistical significance between the vesicants. Histologically, surgically resected specimens showed extensive necrotic areas with inflammatory infiltrates at the periphery of the removed lesions. CONCLUSIONS: In a routine setting, the standardised management of cytotoxic extravasations by an interdisciplinary task force resulted in a satisfactory outcome. When surgical intervention was indicated, complete remission of the lesions within a median of 14 days reduced the delay in the administration of further chemotherapy to a minimum. The proposed approach is therefore considered as suitable to manage extravasations in cancer chemotherapy in a large number of subjects and to ensure patient adherence to cytotoxic treatment. PMID- 25433441 TI - The relationship between oral mucositis and levels of pro-inflammatory cytokines in serum and in gingival crevicular fluid in allogeneic stem cell recipients. AB - PURPOSE: Oral mucositis (OM) is a severe side effect of conditioning for allogeneic hematopoietic stem cell transplantation (HSCT). The aim of the present study was to investigate the relationship between oral mucositis and the levels of pro-inflammatory cytokines-both in serum and in gingival crevicular fluid (GCF), in relation to different conditioning regimens. METHODS: We analyzed the levels of pro-inflammatory cytokines IL-1beta, TNF-alpha, IL-6, and IL-7, as well as anti-inflammatory cytokine IL-10 in gingival crevicular fluid (GCF) and in serum from 43 HSCT patients. Twenty-five received reduced intensity conditioning (RIC) and 18 received myeloablative conditioning (MAC). Cytokine levels were determined in GCF and serum before the start of conditioning, and 1 week and 1 month after HSCT. All patients experienced OM with a median score of 2.1 and median peak on day 11. RESULTS: There was a significant correlation between OM and MAC (p = 0.035). There were no significant differences in GCF volume at the three time points examined. The levels of IL-6 in GCF increased 1 week after transplantation and then returned to baseline (p < 0.001). The levels of IL-10 in GCF decreased after HSCT (p < 0.001) and remained unchanged. The levels of IL-6 in serum significantly (p < 0.001) increased 1 week after HSCT and decreased to baseline levels after 1 month. The levels of IL-10 in serum significantly (p = 0.02) increased 1 month after HSCT. CONCLUSION: No correlations between cytokine levels in gingival crevicular fluid and oral mucositis were observed. There was a correlation between severity of OM score and increase in IL-6 in serum. No correlations between cytokine levels in gingival crevicular fluid and in serum were observed. PMID- 25433442 TI - A horizon scan of global conservation issues for 2015. AB - This paper presents the results of our sixth annual horizon scan, which aims to identify phenomena that may have substantial effects on the global environment, but are not widely known or well understood. A group of professional horizon scanners, researchers, practitioners, and a journalist identified 15 topics via an iterative, Delphi-like process. The topics include a novel class of insecticide compounds, legalisation of recreational drugs, and the emergence of a new ecosystem associated with ice retreat in the Antarctic. PMID- 25433443 TI - Application of credibility ceilings probes the robustness of meta-analyses of biomarkers and cancer risk. AB - OBJECTIVES: Meta-analyses of biomarkers often present spurious significant results and large effects. We applied sensitivity analyses with the use of credibility ceilings to assess whether and how the results of meta-analyses of biomarkers and cancer risk would change. STUDY DESIGN AND SETTING: We evaluated 98 meta-analyses, 43 (44%) of which had nominally statistically significant results. We assumed that any single study cannot give more than a maximum certainty 100 - c% (c, credibility ceiling) that the effect estimate [odds ratio (OR)] exceeds 1 (null) or 1.2. RESULTS: Nominal statistical significance was maintained for 21 (21%) meta-analyses, for c = 10% and OR >1, and these proportions changed to 7%, 3%, and 6% with ceilings of 20%, 30%, and 40%, respectively. For ceilings for OR >1.2, the respective proportions were 37%, 21%, 7%, and 3%. Seven meta-analyses on infectious agents retained statistical significance even with a high ceiling of c = 20% for OR >1.00. Meta-analyses without other hints of bias (large between-study heterogeneity, small-study effects, excess significance) were more likely to retain statistical significance than those that had such hints of bias. CONCLUSION: Credibility ceilings may be helpful in meta-analyses of biomarkers to understand the robustness of the results to different levels of uncertainty. PMID- 25433444 TI - Reporting of covariate selection and balance assessment in propensity score analysis is suboptimal: a systematic review. AB - OBJECTIVES: To assess the current practice of propensity score (PS) analysis in the medical literature, particularly the assessment and reporting of balance on confounders. STUDY DESIGN AND SETTING: A PubMed search identified studies using PS methods from December 2011 through May 2012. For each article included in the review, information was extracted on important aspects of the PS such as the type of PS method used, variable selection for PS model, and assessment of balance. RESULTS: Among 296 articles that were included in the review, variable selection for PS model was explicitly reported in 102 studies (34.4%). Covariate balance was checked and reported in 177 studies (59.8%). P-values were the most commonly used statistical tools to report balance (125 of 177, 70.6%). The standardized difference and graphical displays were reported in 45 (25.4%) and 11 (6.2%) articles, respectively. Matching on the PS was the most commonly used approach to control for confounding (68.9%), followed by PS adjustment (20.9%), PS stratification (13.9%), and inverse probability of treatment weighting (IPTW, 7.1%). Balance was more often checked in articles using PS matching and IPTW, 70.6% and 71.4%, respectively. CONCLUSION: The execution and reporting of covariate selection and assessment of balance is far from optimal. Recommendations on reporting of PS analysis are provided to allow better appraisal of the validity of PS-based studies. PMID- 25433445 TI - Benzyladenine and gibberellin treatment of developing "Pink Lady" apples results in mature fruits with a thicker cuticle comprising clusters of epidermal cells. AB - A mixture of 6-benzyladenine (BA) and gibberellins GA4 plus GA7 applied to "Pink Lady" apple at early phenological stages was previously shown to result in an immediate increase in epidermal cell density and associated reduction in calyx end cracking disorder in the mature fruit, implying a long-term effect of the BA + GA4+7 mixture. Here, we analyzed the anatomical changes in the mature peel at the calyx end 210 days after full bloom (DAFB), following application of the plant growth regulators (PGRs) at the cell-division phase of fruit development, 21-50 DAFB. Experiments were conducted in northern Israel, and the PGRs were applied as the commercial formulation SuperlonTM (Fine Agrochemicals Ltd.), composed of 19 g l(-1) BA and 19 g l(-1) GA4+7. Trees were sprayed with 0.025, 0.1, or 0.2 % (v/v) SuperlonTM. The most obvious phenomenon was the presence of epidermal cell clusters within the cuticular matrix that were detached from the native epidermal layer located at the bottom of the cuticle and which could not be detected in the untreated control fruits. Treatment with 20 mg l(-1) BA + GA4+7 (0.1 % SuperlonTM) resulted in a markedly thicker cuticle, a higher percentage of detached epidermal cells within the cuticular membrane and a significant reduction in calyx-end cracking at harvest. The presence of cuticle embedded epidermal cell clusters may have contributed to strengthening the peel by adding more cell-wall components, thickening the cuticle layer and possibly enhancing crack repair. PMID- 25433446 TI - Germ cell cluster organization and oogenesis in the tardigrade Dactylobiotus parthenogeneticus Bertolani, 1982 (Eutardigrada, Murrayidae). AB - Germ cell cluster organization and the process of oogenesis in Dactylobiotus parthenogeneticus have been described using transmission electron microscopy and light microscopy. The reproductive system of D. parthenogeneticus is composed of a single, sac-like, meroistic ovary and a single oviduct that opens into the cloaca. Two zones can be distinguished in the ovary: a small germarium that is filled with oogonia and a vitellarium that is filled with germ cell clusters. The germ cell cluster, which has the form of a modified rosette, consists of eight cells that are interconnected by stable cytoplasmic bridges. The cell that has the highest number of stable cytoplasmic bridges (four bridges) finally develops into the oocyte, while the remaining cells become trophocytes. Vitellogenesis of a mixed type occurs in D. parthenogeneticus. One part of the yolk material is produced inside the oocyte (autosynthesis), while the second part is synthesized in the trophocytes and transported to the oocyte through the cytoplasmic bridges. The eggs are covered with two envelopes: a thin vitelline envelope and a three layered chorion. The surface of the chorion forms small conical processes, the shape of which is characteristic for the species that was examined. In our paper, we present the first report on the rosette type of germ cell clusters in Parachela. PMID- 25433447 TI - Cutting efficiency of nickel-titanium rotary and reciprocating instruments after prolonged use. AB - The aim of the present study was to compare the cutting efficiency of Twisted File instruments used in continuous rotation or TF Adaptive motion and evaluate if prolonged use significantly affected their cutting ability. 20 new NiTi instruments were used in the present study (TF tip size 35, 0.06 taper; Sybron Endo, Orange, CA, USA), divided into 2 subgroups of 10 instruments each, depending on which movement was selected on the endodontic motor. Group 1: TF instruments were activated using the program TF continuous rotation at 500 rpm and torque set at 2 N; Group 2: TF instruments were activated using the reciprocating TF Adaptive motion. Cutting efficiency was tested in a device developed to test the cutting ability of endodontic instruments. Each instrument cut 10 plastic blocks (10 uses) and the length of the surface cut in a plastic block after 1 min was measured in a computerized program with a precision of 0.1 mm. Maximum penetration depth was calculated after 1 use and after 10 uses, and mean and standard deviation (SD) of each group was calculated. Data were statistically analyzed with a one-way ANOVA test (P < 0.05). TF instruments used in continuous rotation (Group 1) cut a mean depth of 10.4 mm (SD = 0.6 mm) after the first use and 10.1 mm (SD 1.1 mm) after 10 uses, while TF instruments used with the Adaptive motion cut a mean depth of 9.9 mm (SD = 0.7 mm) after the first use and 9.6 mm (SD = 0.9 mm) after 10 uses. There was no statistically significant difference between the two groups investigated (P > 0.05) nor between instruments after 1 or 10 uses. In conclusion, the TFA motion showed a lateral cutting ability similar to continuous rotation and all tested instruments exhibited the same cutting ability after prolonged use. PMID- 25433448 TI - Immunocytochemical characterisation of ensheathing glia in the olfactory and vomeronasal systems of Ambystoma mexicanum (Caudata: Ambystomatidae). AB - The olfactory and vomeronasal systems of vertebrates are characterised by neurogenesis occurring throughout life. The regenerative ability of olfactory receptor neurons relies on specific glial cells, the olfactory and vomeronasal axon-surrounding cells. Numerous studies have examined mammalian olfactory ensheathing cells which are considered potential candidates for spinal cord injury repair using cell-based therapy. With regard to non-mammalian vertebrates, limited information is available on these glial cells in fish, and there is no information on them in terrestrial anamniotes, the amphibians. In the present research, we studied the immunocytochemical characteristics of axon-surrounding cells in Ambystoma mexicanum. Urodeles have relatively simple olfactory and vomeronasal systems, and represent a good model for studying ensheathing cells in extant representatives of basal tetrapods. Sections from the decalcified heads of A. mexicanum were immunocytochemically processed for the detection of proteins used in research on mammalian olfactory-ensheathing cells. S100, GFAP and NCAM were clearly observed. p75NTR, Gal-1 and PSA-NCAM showed weak staining. No vimentin immunopositivity was observed. The corresponding areas of the olfactory and vomeronasal pathways displayed the same staining characteristics, with the exception of Gal-1, p75NTR and PSA-NCAM in the mucosae. The degree of marker expression was not uniform throughout the sensory pathways. In contrast to fish, both olfactory and vomeronasal nerves displayed uniform staining intensity. This study showed that some markers for mammalian and fish-ensheathing glia are also applicable in urodeles. The olfactory systems of vertebrates show similarities, and also clear dissimilarities. Further investigations are required to ascertain the functional significance of these regional and interspecific differences. PMID- 25433449 TI - Tonic effects of the dopaminergic ventral midbrain on the auditory cortex of awake macaque monkeys. AB - This study shows that ongoing electrical stimulation of the dopaminergic ventral midbrain can modify neuronal activity in the auditory cortex of awake primates for several seconds. This was reflected in a decrease of the spontaneous firing and in a bidirectional modification of the power of auditory evoked potentials. We consider that both effects are due to an increase in the dopamine tone in auditory cortex induced by the electrical stimulation. Thus, the dopaminergic ventral midbrain may contribute to the tonic activity in auditory cortex that has been proposed to be involved in associating events of auditory tasks (Brosch et al. Hear Res 271:66-73, 2011) and may modulate the signal-to-noise ratio of the responses to auditory stimuli. PMID- 25433450 TI - Pesticide exposure during pregnancy, like nicotine, affects the brainstem alpha7 nicotinic acetylcholine receptor expression, increasing the risk of sudden unexplained perinatal death. AB - This study indicates the impact of nicotine and pesticides (organochlorine and organophosphate insecticides used in agriculture) on neuronal alpha7-nicotinic acetylcholine receptor expression in brainstem regions receiving cholinergic projections in human perinatal life. An in-depth anatomopathological examination of the autonomic nervous system and immunohistochemistry to analyze the alpha7 nicotinic acetylcholine receptor expression in the brainstem from 44 fetuses and newborns were performed. In addition, the presence of selected agricultural pesticides in cerebral cortex samples of the victims was determined by specific analytical procedures. Hypodevelopment of brainstem structures checking the vital functions, frequently associated with alpha7-nicotinic acetylcholine receptor immunopositivity and smoke absorption in pregnancy, was observed in high percentages of victims of sudden unexpected perinatal death. In nearly 30% of cases however the mothers never smoked, but lived in rural areas. The search for pesticides highlighted in many of these cases traces of both organochlorine and organophosphate pesticides. We detain that exposition to pesticides in pregnancy produces homologous actions to those of nicotine on neuronal alpha7-nicotinic acetylcholine receptor, allowing to developmental alterations of brainstem vital centers in victims of sudden unexplained death. PMID- 25433451 TI - Symptomatic nonconvulsive status epilepticus erroneously suggestive of sporadic Creutzfeldt-Jakob disease. PMID- 25433452 TI - Do pathological parameters differ with regard to breast density and mode of detection in breast cancer? The Malmo Diet and Cancer Study. AB - Our aim was to study how breast density relates to tumor characteristics in breast cancer with emphasis on mode of detection. Among 17,035 women in the Malmo Diet and Cancer Study 826 incident cases have been diagnosed (1991-2007). Data on tumor characteristics, mode of detection, and density at diagnosis were collected. Associations between density and tumor characteristics were analyzed using logistic and ordinal logistic regression models yielding OR and 95% CI. Adjustments for age at diagnosis, BMI at baseline, and the mode of detection, were performed. In denser breasts, large tumor size was more frequent (ORadj 1.59 (1.26-2.01)) as was lymph node involvement (ORadj 1.32 (1.00-1.74)). Further, the higher the density, the lower the grade (ORadj 0.73 (0.53-1.02) for having higher grade), in screening-detected invasive breast cancer. Our findings stress the importance of considering the impact of density in mammography image interpretation and the possible associations with tumor aggressiveness. PMID- 25433453 TI - A20 promotes Brucella intracellular growth via inhibition of macrophage cell death and activation. AB - The zinc-finger protein A20 has crucial physiological functions as a dual inhibitor of macrophage activation and apoptosis in tumor necrosis factor receptor1 (TNFR1) signaling pathway. Brucella infection can induce A20 expression in macrophages. Here, we hypothesize that A20 promotes Brucella intracellular growth via inhibition of activation and apoptosis of macrophages. To test this hypothesis, we stably incorporated mouse A20-shRNA into the RAW264.7 cells by lentiviral gene transfer to successfully knockdown A20. A20-deficient RAW264.7 cells were subsequently challenged with Brucella abortus and colony formation units (CFUs) of bacteria, TNFalpha production, NF-kB activation, macrophages apoptosis and cell death were evaluated. The A20 knockdown was shown to effectively promote B. abortus-stimulated TNFalpha release, NF-kB activation and macrophage cell death, which suppressed B. abortus intracellular replication. Unexpectedly, deficiency of A20 failed to lead to B. abortus-induced macrophage apoptosis. A20 deficiency coupled NF-kB inhibition promoted caspase-8 dependent B. abortus-induced macrophage apoptosis. These findings provide a novel mechanism by which Brucella intracellular growth within macrophages occurs through up regulation of A20 thereby limiting activation and macrophages cell death. PMID- 25433455 TI - Profiles Associated Respectively with Substance Dependence Only, Mental Disorders Only and Co-occurring Disorders. AB - This study sought to identify profiles associated with substance dependence only, mental disorders only and co-occurring disorder respectively, using a broad range of socio-demographic, socio-economic, health beliefs, clinical and health services utilization variables concurrently. Based on a broad analytic framework, 423 participants diagnosed with substance dependence only, mental disorders only or co-occurring disorders within a 12-months period were studied. The study used comparison analysis, and a multinomial logistic regression model. Participants with dependence only and mental disorders only were in contrast in terms of gender, age, marital status, self-perception of physical health, perception of the physical conditions of their neighbourhood, impulsiveness, psychological distress and visit with a family physician in previous 12-months, while those with co-occurring disorders were in an intermediary position between the other two groups. Public authorities should especially promote strategies that could increase the capacity of family physicians to take care of individuals with substance dependence only. PMID- 25433456 TI - Striatum and entorhinal cortex atrophy in AD mouse models: MRI comprehensive analysis. AB - Alzheimer's disease is experimentally modeled in transgenic (Tg) mice overexpressing mutated forms of the human amyloid precursor protein either alone or combined with mutated presenilins and tau. In the present study, we developed a systematic approach to compare double (TASTPM) and triple (APP/PS2/Tau) Tg mice by serial magnetic resonance imaging and spectroscopy analysis from 4 to 26 months of age to define homologous biomarkers between mice and humans. Hippocampal atrophy was found in Tg mice compared with WT. In APP/PS2/Tau the effect was age-dependent, whereas in TASTPM it was detectable from the first investigated time point. Importantly, both mice displayed an age-related entorhinal cortex thinning and robust striatal atrophy, the latter associated with a significant loss of synaptophysin. Hippocampal magnetic resonance spectroscopy revealed lower glutamate levels in both Tg mice and a selective myo inositol increase in TASTPM. This noninvasive magnetic resonance imaging analysis, revealed common biomarkers between humans and mice, and could, thus, be promoted as a fully translational tool to be adopted in the preclinical investigation of therapeutic approaches. PMID- 25433458 TI - Low concentrations of ethanol protect against synaptotoxicity induced by Abeta in hippocampal neurons. AB - Epidemiological studies have reported a reduction in the prevalence of Alzheimer's disease in individuals that ingest low amounts of alcohol. Also, it has been found that moderate consumption of ethanol might protect against beta amyloid (Abeta) toxicity. However, the mechanism underlying its potential neuroprotection is largely unknown. In the present study, we found that ethanol improved the cognitive processes of learning and memory in 3xTgAD mice. In addition, we found that a low concentration of ethanol (equivalent to moderate ethanol consumption) decreased the binding of Abeta (1 and 5 MUM) to neuronal membranes and, consequently, its synaptotoxic effect in rat hippocampal and cortical neurons under acute (30 minutes) and chronic (24 hours) incubation conditions. This effect appears to be exerted by a direct action of ethanol on Abeta because electron microscopy studies showed that ethanol altered the degree of Abeta aggregation. The action of ethanol on Abeta also prevented the peptide from perforating the neuronal membrane, as assayed with patch clamp experiments. Taken together, these results contribute to elucidating the mechanism by which low concentrations of ethanol protect against toxicity induced by Abeta oligomers in primary neuronal cultures. These results may also provide an explanation for the decrease in the risk of Alzheimer's disease in people who consume moderate doses of alcohol. PMID- 25433457 TI - Relevance of parahippocampal-locus coeruleus connectivity to memory in early dementia. AB - Neuropathology suggests an important role for the locus coeruleus (LC) in Alzheimer's disease (AD) pathophysiology. Neuropathology and structural damage in the LC appears to be one of the earliest changes. We hypothesize that reduced functional integration of the LC reflected by lower brain functional connectivity contributes to early memory dysfunction. To test this, we examined resting-state functional connectivity from the LC in 18 healthy older individuals and 18 mildly cognitively impaired patients with possible AD. Connectivity measures were correlated with memory scores. The left LC showed strong connectivity to the left parahippocampal gyrus that correlated with memory performance in healthy persons. This connectivity was reduced in aMCI patients. Lateralization of connectivity memory correlations was altered in less impaired aMCI patients: greater right LC left parahippocampal gyrus connectivity was associated with better memory performance, in particular for encoding. Our results provide new evidence that the LC, in interaction with the parahippocampal gyrus, may contribute to episodic memory formation. They suggest functional impairment and the possibility that associated compensatory changes contribute to preserved memory functions in early AD. Structural and functional LC-related measures may provide early AD markers. PMID- 25433459 TI - Cognitive reserve and the risk for Alzheimer's disease: a longitudinal study. AB - This study investigates how cognitive reserve (CR) interacts with neurodegeneration (quantified by medial temporal atrophy, MTA) and macroscopic white matter lesions (WMLs) in delaying the conversion from amnestic mild cognitive impairment to Alzheimer's disease (AD). Forty-two amnestic mild cognitive impairment patients were consecutively recruited. They underwent magnetic resonance imaging and a comprehensive questionnaire to classify them as individuals with low or high CR. Patients were then clinically followed-up for 2 years. The patients' risk for conversion to AD because of CR was estimated by controlling for cognitive efficiency, MTA, and WMLs at baseline. Global cognition was the best predictor of conversion to AD in low CR patients. Conversely, in high CR patients only, WMLs (but not MTA) highly contributed in increasing the risk for conversion to AD. In conclusion, CR interacts with both patients' cognitive features and WMLs in modulating the impact of AD pathology. This seems relevant for clinical prognosis and therapeutic strategies. PMID- 25433460 TI - Aging, but not tau pathology, impacts olfactory performances and somatostatin systems in THY-Tau22 mice. AB - Somatostatin (SOM) cortical levels decline in Alzheimer's disease (AD) in correlation with cognitive impairment severity, the latter being closely related to the presence of neurofibrillary tangles. Impaired olfaction is another hallmark of AD tightly related to tau pathology in the olfactory pathways. Recent studies showed that SOM modulates olfactory processing, suggesting that alterations in SOM levels participate to olfactory deficits in AD. Herein, we first observed that human olfactory peduncle and cortex are enriched in SOM cells and fibers, in aged postmortem brains. Then, the possible link between SOM alterations and olfactory deficits was evaluated by exploring the impact of age and tau hyperphosphorylation on olfactory SOM networks and behavioral performances in THY-Tau22 mice, a tauopathy transgenic model. Distinct molecular repertoires of SOM peptide and receptors were associated to sensory or cortical olfactory processing structures. Aging mainly affected SOM neurotransmission in piriform and entorhinal cortex in wild-type mice, although olfactory performances decreased. However, no further olfactory impairment was evidenced in THY-Tau22 mice until 12 months although tau pathology early affected olfactory cortical structures. Thus, tau hyperphosphorylation per se has a limited impact on olfactory performances in THY-Tau22 mice. PMID- 25433454 TI - Multilocus sequence typing of Mycoplasma bovis reveals host-specific genotypes in cattle versus bison. AB - Mycoplasma bovis is a primary agent of mastitis, pneumonia and arthritis in cattle and the bacterium most frequently isolated from the polymicrobial syndrome known as bovine respiratory disease complex. Recently, M. bovis has emerged as a significant health problem in bison, causing necrotic pharyngitis, pneumonia, dystocia and abortion. Whether isolates from cattle and bison comprise genetically distinct populations is unknown. This study describes the development of a highly discriminatory multilocus sequencing typing (MLST) method for M. bovis and its use to investigate the population structure of the bacterium. Genome sequences from six M. bovis isolates were used for selection of gene targets. Seven of 44 housekeeping genes initially evaluated were selected as targets on the basis of sequence variability and distribution within the genome. For each gene target sequence, four to seven alleles could be distinguished that collectively define 32 sequence types (STs) from a collection of 94 cattle isolates and 42 bison isolates. A phylogeny based on concatenated target gene sequences of each isolate revealed that bison isolates are genetically distinct from strains that infect cattle, suggesting recent disease outbreaks in bison may be due to the emergence of unique genetic variants. No correlation was found between ST and disease presentation or geographic origin. MLST data reported here were used to populate a newly created and publicly available, curated database to which researchers can contribute. The MLST scheme and database provide novel tools for exploring the population structure of M. bovis and tracking the evolution and spread of strains. PMID- 25433461 TI - p62/SQSTM1 analysis in frontotemporal lobar degeneration. AB - Mutations in the gene p62/SQSTM1 have been reported as a relatively rare cause of frontotemporal lobar degeneration (FTLD). To establish whether this was the case for cases of FTLD from the United Kingdom, we sequenced the sequenced the entire open reading frame of this gene in a large cohort of patients. We identified 3 novel mutations in p62/SQSTM1 in 4 patients. One of these was a premature stop codon that removed the last 101 amino acids of the protein that presumably has a negative effect on protein function. Another mutation was also found in a case with a repeat expansion mutation in C9orf72 confirmed by Southern blot. These findings confirm a role of p62/SQSTM1 as a cause of FTLD. PMID- 25433462 TI - [The choice of inhalation device: A medical act]. AB - Inhaled treatments are essential for respiratory diseases management, including COPD and asthma. Optimal control of the disease largely depends on patient's compliance and proper use of these treatments. Different types of ready-to-use inhaler devices are available: metered dose inhaler, dry powder inhaler or soft mist inhaler. Each of these devices presents specific characteristics and constraints that have to be evaluated and taken into account before prescription. In order to optimize adherence and treatment efficacy, the choice of inhaler device should depend on the specific needs, abilities and preferences of each patient and a specific education to treatment should be provided. Inhaled treatments, even containing the same drug, have different technical constraints and are thus not easily interchangeable. Their substitution without prior medical consent and without proper training can lead to errors in taking treatment, treatment failures and increased health care consumption. In France, substitution by the pharmacist is not authorized. While patient education must be carried out in collaboration with all health professionals, it is preferable that the choice of inhaler device remains the responsibility of the physician. PMID- 25433463 TI - Evaluation of zraP gene expression characteristics and construction of a lead (Pb) sensing and removal system in a recombinant Escherichia coli. AB - A ZraP-based lead sensing and removal system was constructed in E. coli. It was regulated by the ZraS/ZraR two-component system. The expression profile of the zraP gene towards extracellular lead was studied via real-time PCR. A dual function bacterial system was also designed to express GFP and OmpC-lead binding peptide under the control of zraP for the simultaneous sensing and adsorption of environmental lead without additional manipulation. The constructed bacterial system can emit fluorescence and it adsorbed a maximum of 487 umol lead/g cell DCW. From a study of artificial wastewater, the constructed bacteria adsorbed lead highly selectively (427 umol lead/g cell DCW) among other metal ions. The newly-constructed dual function bacterial system can be applied for the development of an efficient process for the removal of lead from polluted wastes. PMID- 25433464 TI - Oxytocin increases bias, but not accuracy, in face recognition line-ups. AB - Previous work indicates that intranasal inhalation of oxytocin improves face recognition skills, raising the possibility that it may be used in security settings. However, it is unclear whether oxytocin directly acts upon the core face-processing system itself or indirectly improves face recognition via affective or social salience mechanisms. In a double-blind procedure, 60 participants received either an oxytocin or placebo nasal spray before completing the One-in-Ten task-a standardized test of unfamiliar face recognition containing target-present and target-absent line-ups. Participants in the oxytocin condition outperformed those in the placebo condition on target-present trials, yet were more likely to make false-positive errors on target-absent trials. Signal detection analyses indicated that oxytocin induced a more liberal response bias, rather than increasing accuracy per se. These findings support a social salience account of the effects of oxytocin on face recognition and indicate that oxytocin may impede face recognition in certain scenarios. PMID- 25433465 TI - CompareSVM: supervised, Support Vector Machine (SVM) inference of gene regularity networks. AB - BACKGROUND: Predication of gene regularity network (GRN) from expression data is a challenging task. There are many methods that have been developed to address this challenge ranging from supervised to unsupervised methods. Most promising methods are based on support vector machine (SVM). There is a need for comprehensive analysis on prediction accuracy of supervised method SVM using different kernels on different biological experimental conditions and network size. RESULTS: We developed a tool (CompareSVM) based on SVM to compare different kernel methods for inference of GRN. Using CompareSVM, we investigated and evaluated different SVM kernel methods on simulated datasets of microarray of different sizes in detail. The results obtained from CompareSVM showed that accuracy of inference method depends upon the nature of experimental condition and size of the network. CONCLUSIONS: For network with nodes (<200) and average (over all sizes of networks), SVM Gaussian kernel outperform on knockout, knockdown, and multifactorial datasets compared to all the other inference methods. For network with large number of nodes (~500), choice of inference method depend upon nature of experimental condition. CompareSVM is available at http://bis.zju.edu.cn/CompareSVM/ . PMID- 25433466 TI - Discriminative pattern mining and its applications in bioinformatics. AB - Discriminative pattern mining is one of the most important techniques in data mining. This challenging task is concerned with finding a set of patterns that occur with disproportionate frequency in data sets with various class labels. Such patterns are of great value for group difference detection and classifier construction. Research on finding interesting discriminative patterns in class labeled data evolves rapidly and lots of algorithms have been proposed to specifically address this problem. Discriminative pattern mining techniques have proven their considerable value in biological data analysis. The archetypical applications in bioinformatics include phosphorylation motif discovery, differentially expressed gene identification, discriminative genotype pattern detection, etc. In this article, we present an overview of discriminative pattern mining and the corresponding effective methods, and subsequently we illustrate their applications to tackling the bioinformatics problems. In the end, we give a general discussion of potential challenges and future work for this task. PMID- 25433467 TI - Virtual Reference Environments: a simple way to make research reproducible. AB - 'Reproducible research' has received increasing attention over the past few years as bioinformatics and computational biology methodologies become more complex. Although reproducible research is progressing in several valuable ways, we suggest that recent increases in internet bandwidth and disk space, along with the availability of open-source and free-software licences for tools, enable another simple step to make research reproducible. In this article, we urge the creation of minimal virtual reference environments implementing all the tools necessary to reproduce a result, as a standard part of publication. We address potential problems with this approach, and show an example environment from our own work. PMID- 25433469 TI - Challenges and choices in prostate cancer irradiation: from the three dimensional conformal radiotherapy to the era of intensity modulated, image-guided and adaptive radiation treatment. AB - In the last decades the status of radiotherapy was tremendously increased in terms of conformity to the target as well as image-guided techniques in conjunction with intensity-modulated radiotherapy (IMRT). The technological improvement had a significant clinical outcome for better response and lower toxicity to the surrounding normal tissues. Nowadays the incidence of rectal toxicity has been significantly decreased, especially with image guided radiation therapy (IGRT), whereas the dose escalation to the prostate has driven the clinical practice to the fact that radical radiotherapy for low or intermediate risk prostate cancer is definitely equivalent to surgery. The treatment volume can be reduced by reducing the size of the necessary margins to count for inaccuracies in target position and patient setup. This can be achieved either by improving the daily localization of the target before treatment or by adapting the treatment in response to feedback. This is the goal of image-guided and adaptive radiotherapy, respectively. These techniques improve the accuracy of dose delivery with a significant impact on clinical outcome and toxicity. PMID- 25433468 TI - Compliance with continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea among privately paying patients- a cross sectional study. AB - BACKGROUND: To evaluate the compliance, benefits and side effects associated with continuous positive airway pressure (CPAP) therapy among Pakistani patients treated for obstructive sleep apnea (OSA) in private sector. METHODS: Patients diagnosed to have OSA based on overnight study who were recommended for CPAP therapy, between 1998 and 2003, were evaluated by telephonic survey and review of hospital notes. Compliance, benefits and side effects associated with CPAP therapy were assessed. RESULTS: Out of 135 patients who were prescribed CPAP therapy, 75 could be contacted. Sixty (80%) started using CPAP within one month of diagnosis and 46 (61%) continued to use it long-term (beyond one year). Compliance with CPAP therapy was associated with higher body mass index, higher Epworth sleepiness scale score, history of witnessed apnea, and reduction in daytime sleepiness with CPAP therapy. OSA severity as assessed by apnea-hypopnea index did not affect compliance with CPAP therapy. Use of anti-depressants and CPAP induced sleep disturbances were associated with poor compliance with CPAP therapy. CONCLUSIONS: Obesity, excessive daytime sleepiness, witnessed apnea and improvement of daytime symptoms following use of CPAP were predictors of improved compliance. Use of antidepressants and CPAP induced sleep disturbances were predictors of poor compliance. PMID- 25433470 TI - Comparison of safety and efficacy of laparoscopic pyelolithotomy versus percutaneous nephrolithotomy in patients with renal pelvic stones: a randomized clinical trial. AB - PURPOSE: A randomized clinical trial was designed to compare the efficacy, success rate and surgical complications of percutaneous nephrolithotomy (PCNL) and laparoscopic pyelolithotomy (LP). MATERIALS AND METHODS: Sixty patients with renal pelvic stones larger than 2 cm were randomly divided into two groups of LP and PCNL. All patients were followed up to three months after surgery using renal diethylenetriamine­pentaaceticacid (DTPA) scan and determining the glomerular filtration rate (GFR). RESULTS: Mean operation time (149 ± 31 vs. 107 ± 26 min) and mean hospital stay (3.4 vs. 2.16 days) were significantly higher in LP, but mean hemoglobin drop (0.85 vs. 1.88 g/dL) and the rate of blood transfusion were significantly lower. Stone free rate was 90% and 86.6% for LP and PCNL, respectively (P =.59), while the changes in GFR were not statistically significant 3 days after surgery between two groups. Those in LP group showed better improvement in GFR at three months postoperatively. Improvement of the affected split kidney function was significantly higher in LP group (P =.04). No major complications were observed in both groups according to Clavien grading system. CONCLUSION: PCNL remains the gold standard treatment for most large kidney stones, nevertheless, laparoscopic pyelolithotomy can be considered for selected cases especially in whom maximal preservation of renal function is necessary. PMID- 25433471 TI - The effect of stone localization on the success and complication rates of percutaneous nephrolithotomy. AB - PURPOSE: To evaluate the effect of stone localization on the success and complication rates of the percutaneous nephrolithotomy (PNL) procedure. MATERIALS AND METHODS: Five hundred seventy-eight PNL procedures that were performed in our clinic were retrospectively evaluated. The patients were divided into seven groups according to the localization of the renal stones as: group 1, patients having stones only in the upper calyx; group 2, patients having stones only in the pelvis; group 3, patients having stones only in the lower calyx; group 4, patients having partial staghorn stones; group 5, patients having multiple calyx stones; group 6, patients having stones in both the pelvis and lower calyx and group 7, patients having complete staghorn stones. The first three groups were defined as simple stones, and the other four groups were defined as complex stones. RESULTS: The mean stone clearance rate was 77% in simple stones and 53% in complex stones (P = .005). The complication rate was significantly higher only in the group with complex staghorn stones at a rate of 19.5% (P = .006). The difference between preoperative and postoperative hematocrit concentrations was the least in the group that had stones in the pelvis and this value was statistically significantly lower than the patients with complex staghorn stones (P = .027). The mean duration of the operation and the number of ports was higher in patients with complex stones. CONCLUSION: The localization of stone affects the success and complication rates of the operation. PMID- 25433472 TI - Quality of life survey following laparoscopic and open radical nephrectomy. AB - PURPOSE: To compare the quality of life (QoL) of renal cancer patients following laparoscopic and open radical nephrectomy. MATERIALS AND METHODS: Seventy-two (64.9%) patients who were treated with open radical nephrectomy (ORN group) and 39 (35.1%) patients who were treated with laparoscopic radical nephrectomy (LRN group) were included in this study. QoL was evaluated by Short Form-36 (SF-36) physical domain scores obtained before surgery, 1 and 6 months after surgery. Analgesic requirement and visual analog scale (VAS) pain scores following surgeries were recorded. RESULTS: The demographic features of the groups were similar. There was a significant difference in tumor size be-tween the ORN group (71.59 & plusmn; 29.83 mm) and LRN group (57.08 & plusmn; 19.33 mm) (P = .011). In the LRN group there was less blood loss, a lower transfusion rate, earlier ambulation, more rapid convalescence and shorter hospitalization; however, the difference in surgical duration between the ORN group (122.86 & plusmn; 36.8 min) and LRN group (140.17 & plusmn; 50.71 min) was not significant (P = .383). Analgesic requirement and VAS pain scores were similar in both groups. In terms of SF-36 physical domain scores, the general health perception score in the LRN group was higher than that in the ORN group at pre-surgery, 1 and 6 months after surgery. SF-36 physical functioning and general health perception scores in both groups were significantly lower in 1 month after surgery and were higher in 6 months after surgery, as compare to before surgery. Bodily pain scores in LRN group did not change significantly after surgery (P = .376). CONCLUSION: LRN exhibited some technical advantages, including less blood loss, shorter hospitalization and more rapid recovery. Although the ORN patients had relatively larger tumors, analgesic requirement, postoperative complications, body pain, and physical functioning weren't significantly different between the groups. QoL was higher 6 months after surgery than before surgery in both groups. & nbsp; PMID- 25433473 TI - Prostate cancer antigen 3 gene expression in peripheral blood and urine sediments from prostate cancer and benign prostatic hyperplasia patients versus healthy individuals. AB - PURPOSE: To determine the expression of prostate cancer antigen 3 (PCA3) gene in peripheral blood and urine sediments from patients with prostate cancer (PCa) and benign prostatic hyperplasia (BPH) and normal subjects. MATERIALS AND METHODS: A total number of 48 patients [24 with biopsy proven prostate cancer (PCa) and 24 with benign prostate hyperplasia (BPH)] were studied. Twenty-four healthy individuals were also recruited as control group. After blood and urine sampling, total RNA was extracted and cDNA was synthesized. Expression of PCA3 gene was assessed by quantitative reverse transcription polymerase chain reaction. RESULTS: Comparison of PCA3 gene expression between control and BPH groups indicated no statistically significant differences in both urine and blood samples. Patients with PCa demonstrated an increased PCA3 gene expression rate compared to control and BPH groups (10.64 and 7.17 folds, respectively). The rate of fold increased PCA3 gene expression in urine was 20.90, 20.90, and 20.35 in patients with PCa, BPH and normal subjects, respectively. CONCLUSION: Evaluation of PCA3 gene expression can be considered as a reliable marker for detection of PCa. Increased level of this marker in urine sediments is more sensitive than blood for distinguishing between cancerous and non-cancerous groups. PMID- 25433474 TI - Prostate cancer antigen 3 gene expression in peripheral blood and urine sediments from prostate cancer and benign prostatic hyperplasia patients versus healthy individuals. PMID- 25433475 TI - Korean version of the functional assessment of cancer therapy (FACT)-vanderbilt cystectomy index (VCI): translation and linguistic. AB - PURPOSE: To develop a Korean version of the Functional Assessment of Cancer Therapy (FACT)-Vanderbilt Cystectomy Index (VCI) from the original English version, with subsequent linguistic validation in Korean patients who underwent radical cystectomy with urinary diversion. MATERIALS AND METHODS: Translation and linguistic validation were carried out between January and May of 2013, which consisted of the following stages:(1) permission for translation;(2) forward translation;(3) reconciliation;(4) backward translation;(5) cognitive debriefing and(6) final proof-reading. RESULTS: During the forward translation phases,word as such as "bother","spend time", "support", "coping" and "concern" were adjusted to be more comprehensible to the target population. There conciled Korean version was accepted without certain objections because the original version and the backward translation were almost congruent except for minor differences in a subset of questions. The translation was tested using 5 Korean-speaking subjects. The subjects took an average of 8.2 minutes to complete the questionnaire, without difficulty and found the questionnaire clear and easy to understand. The panel discussed each of the issues raised by subjects and most terms were judged by the panel as to not require further changes because the overall comprehension levels were relatively high and because the translated terms were accurately rendered in the target languages. CONCLUSION: This report has demonstrated that despite translation difficulties, the linguistic validation of the FACT-VCI in the Korean language was successful. The next step is to assess the psychometric properties of the Korean version of FACT-VCI. PMID- 25433477 TI - The utility of fluorescence in situ hybridization for diagnosis and surveillance of bladder urothelial carcinoma. AB - PURPOSE: To evaluate the clinical value of fluorescence in situ hybridization (FISH) for diagnosis and surveillance of bladder urothelial carcinoma (BUC). MATERIALS AND METHODS: Between November 2010 and December 2013, patients suspected of having BUC were examined using urine cytology and FISH assay. Based on histopathological examination results, FISH results were com-pared with urine cytology. In addition, patients with a history of non-muscle invasive BUC were also examined using urine cytology and FISH assay at the first time of visit and then monitored with cystoscopy during follow-up period. RESULTS: A total of 162 patients included in this study and 12 patients were excluded due to uninformative FISH assays. The remaining 150 patients consisted of 108 patients suspected for BUC and 42 patients with a history of non-muscle invasive BUC. The sensitivities of FISH analysis and urine cytology were 72.8% and 27.2%, respectively, and the difference was statistically significant (P <.05). Difference between specificity of urine cytology (100%) and FISH assay (85%) was not statistically significant (P >.05). At the first visit, of 42 patients, one patient had positive cystoscopy, and FISH assay was positive in 26 of 41 patients with negative cystoscopy. During the follow-up period (mean, 29.5 months), 18 of 26 patients developed recurrence, and recurrence occurred in only one of 15 patients with negative FISH analysis. CONCLUSION: Our results suggest that FISH analysis can be used as a non-invasive diagnostic tool for patients suspect-ed of having new BUC. In addition, FISH analysis may provide important prognostic information to better define the individual risk for BUC recurrence.& nbsp; PMID- 25433476 TI - Role of steroid hormone receptors in formation and progression of bladder carcinoma: a case-control study. AB - PURPOSE: To compare the expression rate of sex steroid hormone receptors of estrogen (ER), progesterone (PR) and androgen (AR) in normal urothelium and urothelial bladder cancer (UBC) and to evaluate the possible associations of these receptors expression with cancer progression and patient's survival. MATERIALS AND METHODS: We evaluated the clinical data and tumor specimens of 120 patients with pathologically confirmed primary UBC with 132 normal healthy controls. Both patients and controls selected from list of subjects who have been referred to Sina Urology clinic, and had a minimum of one year follow-up duration. Data collected from medical cords. For evaluation of expression, immunohistochemistry was performed on paraffin-embedded tissue sections using a monoclonal antibody for androgen, estrogen and progesterone receptors. Presence of at least 10% positive cells defined as positive expression. RESULTS: None of the control subjects showed AR expression, while 22% of the patients were AR positive. ER/PR expressions were observed in 4.2%/ and 2.5% of the cases and in 2.3% and 1.5% of the controls, respectively. A statistically significant correlation was found between AR expression and tumor stage and grade (P < .001). AR-positive patients showed a significantly poorer prognosis than AR-negative cases (log-rank test, P = .02, hazard ratio = 2.12; 95% confidence interval: 1.36 4.65). CONCLUSION: AR expression was significantly associated with higher grade and poorly differentiated tumors with unfavorable outcome. AR expression test might be useful as a diagnostic tool for determining the malignancy and outcome of UBC patients. PMID- 25433478 TI - Clinical application of computed tomography on prostate volume estimation in patients with lower urinary tract symptoms. AB - PURPOSE: To compare estimated prostate volume (PV) based on computed tomography (CT) scan and transrectal ultrasonography (TRUS) in patients with lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: Between January 2010 and October 2012, 107 consecutive patients with LUTS were analyzed, retrospectively. PV measures were performed by the means of ellipsoid formula (PV = pi/6 [width (cm) thick-ness (cm) length (cm)]) from TRUS (PVTRUS) and CT (PVCT ellipsoid). In addition, PV was calculated as the sum of the area of each slice and the CT slice interval using commercial software program (PVCT 3D reconstruction). RESULTS: Mean PVCT ellipsoid was 40.63 & plusmn; 31.06 cm3 (range, 8.34-217.46). Mean PVTRUS and PVCT 3D reconstruction were 39.20 & plusmn; 33.04 (range, 4.00-223.81) and 45.30 & plusmn; 32.98 (range, 8.90-248.30), respectively. PVCT ellipsoid was highly correlated with PVTRUS and PVCT 3D reconstruction (r = 0.935, P < .001; r = .970, P < .001, respectively). Moreover, there was very strong agreement for PV measurements with all three methods (intraclass correlation coefficient = 0.934, P < .001). CONCLUSION: PVCT ellipsoid is adequate method for quick volume assessment with reasonable accuracy. Therefore, we can easily predict PV by CT scan using ellipsoid formula without performing additional TRUS in patients with LUTS.& nbsp; PMID- 25433479 TI - No suspicion, no disease! renal infarction: case series. PMID- 25433480 TI - A rare case of prostatic brucellosis mimicking prostate cancer. PMID- 25433481 TI - Proteomic analysis of the extraembryonic tissues from cloned porcine fetus at day 35 of pregnancy. AB - BACKGROUND: Somatic cell cloning by nuclear transfer (SCNT) in pig is clearly of great benefit for basic research and biomedical applications. Even though cloned offspring have been successfully produced in pig, SCNT is struggling with the low efficiency. RESULTS: In the present study, we investigated differentially expressed proteins of the extraembryonic tissue from pig SCNT fetus compared to control (normal) fetus. We obtained the extraembryonic tissue from embryos at day 35 of pregnancy and examined the protein expression profiles using two dimensional electrophoresis (2-D) and Western blotting. The extraembryonic tissue of fetus in control pregnancy was compared to the extraembryonic tissue of SCNT fetus, which showed an abnormally small size and shape as well as exhibited abnormal placental morphology compared to control fetus. A proteomic analysis showed that the expression of 33 proteins was significantly increased or decreased in the extraembryonic tissue of SCNT fetus compared to control fetus. The differentially expressed proteins in the extraembryonic tissue of SCNT fetus included ATP or lipid binding proteins, antioxidant proteins, translation elongation factors, and transcription factors. Western blotting analysis indicated that antioxidant enzymes and anti-apoptotic proteins were down regulated; however, the expression levels of apoptotic proteins, Bax and Hsp27, were increased in the extraembryonic tissue of SCNT fetus. Moreover, immunohistochemical analysis also showed that the expression of the catalase or GPX genes was decreased in the extraembryonic tissue with SCNT fetus compared to those with control fetus. In addition, we observed a significant decrease in DNA methytransferase1 (Dnmt1) expression in SCNT extraembryonic tissue, and the expression levels of Dnmt3a and Dnmt3b were abnormally higher in SCNT fetus compared to control fetus. Moreover, a marked increase in the frequency of TUNEL positive cells was observed in the extraembryonic tissue in SCNT fetus. CONCLUSION: These results demonstrated that pig SCNT fetus showed abnormal protein expression in the extraembryonic tissue, and extensive apoptosis occurred in the extraembryonic tissue of the SCNT fetus due to an increase in apoptotic protein expression or a decrease in antioxidant protein expression. PMID- 25433482 TI - Neglect-like characteristics of developmental disregard in children with cerebral palsy revealed by event related potentials. AB - BACKGROUND: Children with unilateral Cerebral Palsy (CP) often show diminished awareness of the remaining capacity of their affected upper limb. This phenomenon is known as Developmental Disregard (DD). DD has been explained by operant conditioning. Alternatively, DD can be described as a developmental delay resulting from a lack of use of the affected hand during crucial developmental periods. We hypothesize that this delay is associated with a general delay in executive functions (EF) related to motor behavior, also known as motor EFs. METHODS: Twenty-four children with unilateral CP participated in this cross sectional study, twelve of them diagnosed with DD. To test motor EFs, a modified go/nogo task was presented in which cues followed by go- or nogo-stimuli appeared at either the left or right side of a screen. Children had to press a button with the hand corresponding to the side of stimulus presentation. Apart from response accuracy, Event-Related Potentials (ERPs) extracted from the ongoing EEG were used to register covert cognitive processes. ERP N1, P2, N2, and P3 components elicited by cue-, go-, and nogo-stimuli were further analyzed to differentiate between different covert cognitive processes. RESULTS: Children with DD made more errors. With respect to the ERPs, the P3 component to go-stimuli was enhanced in children with DD. This enhancement was related to age, such that younger children with DD showed stronger enhancements. In addition, in DD the N1 component to cue- and go-stimuli was decreased. CONCLUSIONS: The behavioral results show that children with DD experience difficulties when performing the task. The finding of an enhanced P3 component to go-stimuli suggests that these difficulties are due to increased mental effort preceding movement. As age in DD mediated this enhancement, it seems that this increased mental effort is related to a developmental delay. The additional finding of a decreased N1 component in DD furthermore suggests a general diminished visuo-spatial attention. This effect reveals that DD might be a neuropsychological phenomenon similar to post-stroke neglect syndrome that does not resolve during development. These findings suggest that therapies aimed at reducing neglect could be a promising addition to existing therapies for DD. PMID- 25433483 TI - Impact of tooth loss related to number and position on oral health quality of life among adults. AB - BACKGROUND: The objective of this study was to evaluate the impact of tooth loss on oral health-related quality of life (OHRQoL) in adults with emphasis on the number of teeth lost and their relative position in the mouth. METHODS: The study population was a cross-sectional household probability sample of 248, representing 149,635 20-64 year-old residents in Piracicaba-SP, Brazil. OHRQoL was measured using the OHIP-14. Socioeconomic, demographic, health literacy, dental services use data and clinical variables were collected. Oral examinations were performed using WHO criteria for caries diagnosis, using the DMFT index; that is, the sum of decayed, missing and filled teeth (DMFT). An ordinal scale for tooth loss, based on position and number of missing teeth, was the main explanatory variable. The total OHIP score was the outcome for negative binomial regression and OHIP prevalence was the outcome for logistic regression at 5% level. A hierarchical modeling approach was adopted according to conceptual model. RESULTS: OHIP score was 10.21 (SE 1.16) with 48.1% (n=115) reporting one or more impacts fairly/very often (OHIP prevalence). Significant prevalence rate ratios (PRRs) for OHIP severity were observed for those who had lost up to 12 teeth, including one or more anterior teeth (PRR=1.63, 95%CI 1.06-2.51), those who had lost 13-31 teeth (PRR=2.33, 95%CI 1.49-3.63), and the edentulous (PRR=2.66, 95%CI 1.55-4.57) compared with fully dentate adults. Other significant indicators included those who only sought dental care because of dental pain (PRR=1.67, 95%CI 1.11-2.51) or dental needs (PRR=1.84, 95%CI 1.24-2.71) and having untreated caries (PRR=1.57 95%CI 1.09-2.26). Tooth loss was not significantly associated with OHIP prevalence; instead using dental services due to dental pain (PR=2.43, 95%CI 1.01-5.82), having untreated caries (PR=3.96, 95%CI 1.85-8.51) and low income (PR=2.80, 95%CI 1.26-6.42) were significant risk indicators for reporting OHIP prevalence. CONCLUSION: Our analyses showed OHRQoL gradients consistent with the number and position of teeth missing due to oral disease. These findings suggest that the quantity of teeth lost does not necessarily reflect the impact of tooth mortality on OHRQoL and that future studies should take this into consideration. PMID- 25433484 TI - Meta-analysis of Hsa-mir-499 polymorphism (rs3746444) for cancer risk: evidence from 31 case-control studies. AB - BACKGROUND: MicroRNAs (miRNAs) are a family of endogenous, small and non-coding RNAs that regulate gene expression negatively at the post-transcriptional level by suppressing translation or degrading target mRNAs, and are involved in diverse biological and pathological processes. Single nucleotide polymorphisms (SNPs) which are located in the miRNA-coding genes may participate in the process of development and diseases by altering the expression of mature miRNA. Recent studies investigating the association between hsa-mir-499 polymorphism (rs3746444) and cancer risk have yielded conflicting results. METHODS: In this meta-analysis, we conducted a search of case-control studies on the associations of SNP rs3746444 with susceptibility to cancer in electronic databases. A total of 31 studies involving 12799 cases and 14507 controls were retrieved and the strength of the association was estimated by pooled odds ratios (ORs) and 95% confidence intervals (CIs). Hardy-Weinberg equilibrium (HWE) was assessed by the goodness-of-fit chi-square test in controls. Subgroup analyses were done by racial descent and cancer type. Publication bias of literatures was evaluated by visual inspection of funnel plots and the linear regression asymmetry test by Egger et al. Sensitivity analysis was conducted by excluding one study at a time to examine the influence of individual data set on the pooled ORs. RESULTS: Overall, significant association between rs3746444 polymorphism and susceptibility to cancer was identified in TC versus TT and TC/CC versus TT (dominant) models. In the stratified analyses, increased risks were found in Asians, but not in Caucasians in all comparison models tested. Moreover, significant association with an increased risk was found in Chinese population. Also, much higher significant association with increased cancer risks were found in Iranian population. In different cancer types, a decreased risk was found in esophageal cancer. CONCLUSION: Our meta-analysis suggested that hsa-mir-499 rs3746444 T > C polymorphism is associated with the risk of cancer in Asians, mainly in Iranian and Chinese population. However, rs3746444 T > C polymorphism is negatively associated with the risk of esophageal cancer. PMID- 25433485 TI - Ancient DNA provides new insight into the maternal lineages and domestication of Chinese donkeys. AB - BACKGROUND: The donkey (Equus asinus) is an important domestic animal that provides a reliable source of protein and method of transportation for many human populations. However, the process of domestication and the dispersal routes of the Chinese donkey are still unclear, as donkey remains are sparse in the archaeological record and often confused with horse remains. To explore the maternal origins and dispersal route of Chinese donkeys, both mitochondrial DNA D loop and cytochrome b gene fragments of 21 suspected donkey remains from four archaeological sites in China were amplified and sequenced. RESULTS: Molecular methods of species identification show that 17 specimens were donkeys and three samples had the maternal genetic signature of horses. One sample that dates to about 20,000 years before present failed to amplify. In this study, the phylogenetic analysis reveals that ancient Chinese donkeys have high mitochondrial DNA diversity and two distinct mitochondrial maternal lineages, known as the Somali and Nubian lineages. These results indicate that the maternal origin of Chinese domestic donkeys was probably related to the African wild ass, which includes the Nubian wild ass (Equus africanus africanus) and the Somali wild ass (Equus africanus somaliensis). Combined with historical records, the results of this study implied that domestic donkeys spread into west and north China before the emergence of the Han dynasty. The number of Chinese domestic donkeys had increased primarily to meet demand for the expansion of trade, and they were likely used as commodities or for shipping goods along the Silk Road during the Tang Dynasty, when the Silk Road reached its golden age. CONCLUSIONS: This study is the first to provide valuable ancient animal DNA evidence for early trade between African and Asian populations. The ancient DNA analysis of Chinese donkeys also sheds light on the dynamic process of the maternal origin, domestication, and dispersal route of ancient Chinese donkeys. PMID- 25433486 TI - Construction of a mariner-based transposon vector for use in insertion sequence mutagenesis in selected members of the Rhizobiaceae. AB - BACKGROUND: The Rhizobiaceae family of Gram-negative bacteria often engage in symbiosis with plants of economic importance. Historically, genetic studies to identify the function of individual genes, and characterize the biology of these bacteria have relied on the use of classical transposon mutagenesis. To increase the rate of scientific discovery in the Rhizobiaceae there is a need to adapt high-throughput genetic screens like insertion sequencing for use in this family of bacteria. Here we describe a Rhizobiaceae compatible MmeI-adapted mariner transposon that can be used with insertion sequencing for high-throughput genetic screening. RESULTS: The newly constructed mariner transposon pSAM_Rl mutagenized R. leguminosarum, S. meliloti, and A. tumefaciens at a high frequency. In R. leguminosarum, mutant pools were generated that saturated 88% of potential mariner insertions sites in the genome. Analysis of the R. leguminosarum transposon insertion sequencing data with a previously described hidden Markov model-based method resulted in assignment of the contribution of all annotated genes in the R. leguminosarum 3841 genome for growth on a complex medium. Good concordance was observed between genes observed to be required for growth on the complex medium, and previous studies. CONCLUSIONS: The newly described Rhizobiaceaee compatible mariner transposon insertion sequencing vector pSAM_Rl has been shown to mutagenize at a high frequency and to be an effective tool for use in high-throughput genetic screening. The construction and validation of this transposon insertion sequencing tool for use in the Rhizobiziaceae will provide an opportunity for researchers in the Rhizobiaceae community to use high throughput genetic screening, allowing for significant increase in the rate of genetic discovery, particularly given the recent release of genome sequences from many Rhizobiaceae strains. PMID- 25433487 TI - General practitioners uses and perceptions of voluntary electronic feedback on treatment outcomes - a qualitative study. AB - BACKGROUND: Currently, there is a strong focus on the diffusion and implementation of indicator-based technologies for assessing and improving the quality of care in general practice. The aim of this study was to explore how and for what purposes indicator-based feedback is used by the general practitioners (GPs) and how they perceive it to contribute to their work. METHODS: Qualitative interviews with nine GPs in two regions in Denmark. The main selection criterion was that the informants had experience with retrieving electronic feedback. The data generation was explorative and open-ended and the analysis took an iterative approach with continuous refinement of themes that emerged from the data. RESULTS: The study identified two main uses of feedback: i) Administration of a regular disease control schedule for patients with chronic disease and ii) Routine monitoring of outcomes for purposes of resource prioritisation and medication management. Both uses were deemed valuable by the GPs, but also as an additional extra to the clinical core task. All the GPs experienced the feedback to be of limited relevance to the most central and challenging aspects of clinical work understood as the care for individuals. This led to different reactions: Some GPs would use the feedback as a point of departure for broader deliberations about individual patient needs and treatment approaches. For others, the perceived limitations decreased their overall motivation to seek feedback. CONCLUSIONS: The study points to the importance of clarifying limitations as well as possibilities with respect to different aspects of clinical quality when introducing indicator-based technologies to practitioners. The results also emphasize that an indicator-based approach to quality improvement should not stand alone in general practice since some of the most central and challenging aspects of clinical work are not covered by this approach. PMID- 25433488 TI - Real-time comparative evaluation of bioMerieux VITEK MS versus Bruker Microflex MS, two matrix-assisted laser desorption-ionization time-of-flight mass spectrometry systems, for identification of clinically significant bacteria. AB - BACKGROUND: Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS) recently became available for the identification of bacteria in routine diagnostic laboratories. It is rapid and cost-effective and likely to replace phenotypic identification. This study was undertaken to compare two MALDI-TOF MS-based, Bruker Microflex MS (BMS) and VITEK MS (VMS) systems, for identification (ID) of clinically significant bacterial isolates. Clinically relevant broad diversity of bacterial isolates obtained during a 6-consecutive months of routine laboratory processing of clinical specimens were subjected to ID by the BMS and VMS in parallel with Vitek 2, a conventional phenotypic system (CPS). For the BMS, the isolates were tested in duplicates directly and after pretreatment. Identification was provided with accompanying scores according to manufacturers' instructions. With VMS, single deposits of the same sets of isolates were tested in duplicates directly on MALDI-plate. Results were interpreted according to the manufacturer's protocols. Discrepant results were resolved by 16S rRNA gene amplification and sequencing. RESULTS: A total of 806 pathogens comprising 507 Gram-negative bacilli (GNB), 16 Gram-negative cocci (GNC), 267 Gram-positive cocci (GPC), and 16 Gram-positive bacilli (GPB) were tested. BMS and VMS correctly identified isolates to genus and species levels (ID 97.3% and 93.2%, and 99.8% and 99.0%, respectively). Both systems as well as the CPS correctly identified the majority of the species in the family Enterobacteriaceae, Pseudomonas spp., and Acinetobacter baumannii. Turnaround time for identification by BMS and VMS was <20 min compared with 24-48 h by the CPS. CONCLUSIONS: VMS performed slightly better than BMS with GPC ID, especially the Streptococcus spp. Some S. mitis isolates were identified as S. pneumoniae by BMS. BMS and VMS were rapid and proved to be consistently accurate for producing bacterial identification in a fraction of time it takes for identification by CPS. PMID- 25433489 TI - Development of a culturally appropriate computer-delivered tailored Internet based health literacy intervention for Spanish-dominant Hispanics living with HIV. AB - BACKGROUND: Low health literacy is associated with poor medication adherence in persons with human immunodeficiency virus (HIV), which can lead to poor health outcomes. As linguistic minorities, Spanish-dominant Hispanics (SDH) face challenges such as difficulties in obtaining and understanding accurate information about HIV and its treatment. Traditional health educational methods (e.g., pamphlets, talking) may not be as effective as delivering through alternate venues. Technology-based health information interventions have the potential for being readily available on desktop computers or over the Internet. The purpose of this research was to adapt a theoretically-based computer application (initially developed for English-speaking HIV-positive persons) that will provide linguistically and culturally appropriate tailored health education to Spanish-dominant Hispanics with HIV (HIV + SDH). METHODS: A mixed methods approach using quantitative and qualitative interviews with 25 HIV + SDH and 5 key informants guided by the Information-Motivation-Behavioral (IMB) Skills model was used to investigate cultural factors influencing medication adherence in HIV + SDH. We used a triangulation approach to identify major themes within cultural contexts relevant to understanding factors related to motivation to adhere to treatment. From this data we adapted an automated computer-based health literacy intervention to be delivered in Spanish. RESULTS: Culture-specific motivational factors for treatment adherence in HIV + SDH persons that emerged from the data were stigma, familismo (family), mood, and social support. Using this data, we developed a culturally and linguistically adapted a tailored intervention that provides information about HIV infection, treatment, and medication related problem solving skills (proven effective in English-speaking populations) that can be delivered using touch-screen computers, tablets, and smartphones to be tested in a future study. CONCLUSION: Using a theoretically-grounded Internet based eHealth education intervention that builds on knowledge and also targets core cultural determinants of adherence may prove a highly effective approach to improve health literacy and medication decision-making in this group. PMID- 25433490 TI - Role of chromatin and transcriptional co-regulators in mediating p63-genome interactions in keratinocytes. AB - BACKGROUND: The Transcription Factor (TF) p63 is a master regulator of epidermal development and differentiation as evident from the remarkable skin phenotype of p63 mouse knockouts. Furthermore, ectopic expression of p63 alone is sufficient to convert simple epithelium into stratified epithelial tissues in vivo and p63 is required for efficient transdifferentiation of fibroblasts into keratinocytes. However, little is known about the molecular mechanisms of p63 function, in particular how it selects its target sites in the genome. p63, which acts both as an activator and repressor of transcription, recognizes a canonical binding motif that occurs over 1 million times in the human genome. But, in human keratinocytes less than 12,000 of these sites are bound in vivo suggesting that underlying chromatin architecture and cooperating TFs mediate p63-genome interactions. RESULTS: We find that the chromatin architecture at p63-bound targets possess distinctive features and can be used to categorize p63 targets into proximal promoters (1%), enhancers (59%) and repressed or inactive (40%) regulatory elements. Our analysis shows that the chromatin modifications H3K4me1, H3K27me3, along with overall chromatin accessibility status can accurately predict bonafide p63-bound sites without a priori DNA sequence information. Interestingly, however there exists a qualitative correlation between the p63 binding motif and accessibility and H3K4me1 levels. Furthermore, we use a comprehensive in silico approach that leverages ENCODE data to identify several known TFs such as AP1, AP2 and novel TFs (RFX5 for e.g.) that can potentially cooperate with p63 to modulate its myriad biological functions in keratinocytes. CONCLUSIONS: Our analysis shows that p63 bound genomic locations in keratinocytes are accessible, marked by active histone modifications, and co-targeted by other developmentally important transcriptional regulators. Collectively, our results suggest that p63 might actively remodel and/or influence chromatin dynamics at its target sites and in the process dictate its own DNA binding and possibly that of adjacent TFs. PMID- 25433491 TI - Differential low uptake of free vitamin D supplements in preterm infants: the Quebec experience. AB - BACKGROUND: Vitamin D is essential for bone mineralization, particularly in premature infants. For nearly 20 years, Quebec has offered a program of free vitamin D supplements via its public medication insurance plan Regie de l'Assurance Maladie du Quebec (RAMQ). The objective of this study is to evaluate the number of preterm infants that obtained at least one bottle (50 doses) of vitamin D supplement through this program and to determine if uptake varied by gestational age. METHODS: This was a retrospective cohort study of preterm infants covered by RAMQ and born from 1998 to 2008; all infants had 1 year of follow-up data regarding supplement use. Data were extracted from the Quebec Pregnancy Cohort, a linked administrative database and were stratified by early (<34 weeks) or late gestational age premature infants. The number of infants obtaining supplements was the primary outcome and their characteristics were compared across gestational age groups. Predictors for participation (obtaining at least 1 bottle) or adherence (2 or more bottles) were identified via logistic regression (GEE). RESULTS: 10288 infants were eligible; the percentage exposed to vitamin D was 24.5% (37.4%- early; 20.7%-late preterm infants, p < 0.001). The median number of bottles obtained was 2 for early and 1 for late preterms. For all premature infants, there was an apparent geometric decline in the infants obtaining subsequent bottles of supplements over the 12 month period. Additionally, there was a significant decline in program participation over time (OR = 0.90/year, 95% CI: 0.89-0.90) regardless of gestational age. Older or more educated mothers were positive predictors for participation. A prescription from a pediatrician significantly increased the odds of obtaining the supplement. CONCLUSION: Early preterm infants were more likely to obtain the supplement post discharge; uptake was low and decreased with time for both age categories. Specifically, targeting late preterm infants and young mothers with less education could improve vitamin D uptake. PMID- 25433492 TI - Effectiveness of cladribine therapy in patients with pulmonary Langerhans cell histiocytosis. AB - BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare disorder characterised by granulomatous proliferation of CD1a-positive histiocytes forming granulomas within lung parenchyma, in strong association with tobacco smoking, and which may result in chronic respiratory failure. Smoking cessation is considered to be critical in management, but has variable effects on outcome. No drug therapy has been validated. Cladribine (chlorodeoxyadenosine, 2-CDA) down regulates histiocyte proliferation and has been successful in curbing multi system Langerhans cell histiocytosis and isolated PLCH. METHODS AND PATIENTS: We retrospectively studied 5 patients (aged 37-55 years, 3 females) with PLCH who received 3 to 4 courses of cladribine therapy as a single agent (0.1 mg/kg per day for 5 consecutive days at monthly intervals). One patient was treated twice because of relapse at 1 year. Progressive pulmonary disease with obstructive ventilatory pattern despite smoking cessation and/or corticosteroid therapy were indications for treatment. Patients were administered oral trimethoprim/sulfamethoxazole and valaciclovir to prevent opportunistic infections. They gave written consent to receive off-label cladribine in the absence of validated treatment. RESULTS: Functional class dyspnea improved with cladribine therapy in 4 out of 5 cases, and forced expiratory volume in 1 second (FEV1) increased in all cases by a mean of 387 ml (100-920 ml), contrasting with a steady decline prior to treatment. Chest high-resolution computed tomography (HRCT) features improved with cladribine therapy in 4 patients. Hemodynamic improvement was observed in 1 patient with pre-capillary pulmonary hypertension. The results suggested a greater treatment effect in subjects with nodular lung lesions and/or thick-walled cysts on chest HRCT, with diffuse hypermetabolism of lung lesions on positron emission tomography (PET)-scan, and with progressive disease despite smoking cessation. Infectious pneumonia developed in 1 patient, with later grade 4 neutrocytopenia but without infection. DISCUSSION: Data interpretation was limited by the retrospective, uncontrolled study design and small sample size. CONCLUSION: Cladribine as a single agent may be effective therapy in patients with progressive PLCH. PMID- 25433493 TI - The role of microRNA-133b and its target gene FSCN1 in gastric cancer. AB - BACKGROUND: Increasing evidences have documented that microRNAs (miRNAs) act as oncogenes or tumor suppressors in gastric cancer (GC). In this study, we aimed to investigate the expression of miR-133b in a large number of GC samples and elucidate its role in GC carcinogenesis and the detailed mechanism. METHODS: We used Taqman probe stem-loop real-time PCR to accurately measure the levels of miR 133b in 100 pairs of gastric cancer tissues and the adjacent non-neoplastic tissues. miR-133b mimics were overexpressed in GC cell lines, miR-133b inhibitors were also introduced in GES cells to investigate its role on regulating cell proliferation, cell migration and cell invasion. The target of miR-133b was identified by luciferase reporter assay and western blot. Fascin actin-bundling protein 1 (FSCN1) siRNA was used to achieve the knockdown of FSCN1 in GC cells and to investigate its role on modulating GC cell proliferation and invasion. RESULTS: miR-133b was significantly down-regulated in GC cell lines and in GC tissues compared with adjacent normal tissues. Moreover, lower-level of miR-133b was also associated with venous invasion and a more aggressive tumor phenotype. Re-introduction of miR-133b in GC cells can inhibit cell proliferation, cell migration and invasion. In contrary, knockdown of miR-133b in GES cells can promote cell proliferation and invasion. Further investigation indicated that miR 133b targeted FSCN1 in GC cells and knockdown of FSCN1 can also inhibit GC cell growth and invasion. CONCLUSION: Our findings demonstrated that miR-133b was significantly down-regulated in GC tissues and exerted its tumor suppressor role in GC cells. The investigation of the detailed mechanism showed that miR-133b directly targeted FSCN1 which functioned as an oncogenic gene in GC cells. These results suggested that miR-133b can be developed as a new diagnostic marker or therapeutic target for GC. PMID- 25433494 TI - Using the collaborative intervention planning framework to adapt a health-care manager intervention to a new population and provider group to improve the health of people with serious mental illness. AB - BACKGROUND: Health-care manager interventions improve the physical health of people with serious mental illness (SMI) and could be widely implemented in public mental health clinics. Local adaptations and customization may be needed to increase the reach of these interventions in the public mental health system and across different racial and ethnic communities. In this study, we describe how we used the collaborative intervention planning framework to customize an existing health-care manager intervention to a new patient population (Hispanics with SMI) and provider group (social workers) to increase its fit with our local community. METHODS: The study was conducted in partnership with a public mental health clinic that serves predominantly Hispanic clients. A community advisory board (CAB) composed of researchers and potential implementers (e.g., social workers, primary care physicians) used the collaborative intervention planning framework, an approach that combines community-based participatory research principles and intervention mapping (IM) procedures, to inform intervention adaptations. RESULTS: The adaptation process included four steps: fostering collaborations between CAB members; understanding the needs of the local population through a mixed-methods needs assessment, literature reviews, and group discussions; reviewing intervention objectives to identify targets for adaptation; and developing the adapted intervention. The application of this approach enabled the CAB to identify a series of cultural and provider level adaptations without compromising the core elements of the original health-care manager intervention. CONCLUSIONS: Reducing health disparities in people with SMI requires community engagement, particularly when preparing existing interventions to be used with new communities, provider groups, and practice settings. Our study illustrates one approach that can be used to involve community stakeholders in the intervention adaptation process from the very beginning to enhance the transportability of a health-care manager intervention in order to improve the health of people with SMI. PMID- 25433495 TI - Antipsychotic patterns of use in patients with schizophrenia: polypharmacy versus monotherapy. AB - BACKGROUND: The objective of this study was to characterize real-world treatment patterns in the prescription of antipsychotic polypharmacy (>= 2 concurrent antipsychotics) compared with antipsychotic monotherapy for patients with schizophrenia. METHODS: This study was a retrospective claims-based analysis of patients (aged 13-64 years) with schizophrenia belonging to an employer-based health plan. Duration of therapy was measured as the number of treatment days over one year following the initial date of antipsychotic therapy. Discontinuation was defined as a 90-day gap in antipsychotic treatment (or in at least one antipsychotic for the polypharmacy group). Logistic regression analyses were used to predict discontinuation within one year. Ordinary Least Squares (OLS) regressions were used to predict duration of therapy (by type of therapy) when controlling for gender, region, number of somatic and psychiatric comorbidities, Deyo-Charlson comorbidity score, and number of psychiatric and somatic medications. RESULTS: Of the 4,156 patients, 3,188 received monotherapy and 968 received polypharmacy. Mean age was 40 years (37.8 years for polypharmacy vs 40.3 years for monotherapy, p < 0.001). Within one year, 77% of the polypharmacy group and 54% of the monotherapy group discontinued treatment. The average duration of therapy was 163 [SD = 143] days in the polypharmacy group vs 253 [SD = 147] days in the monotherapy group. In both cohorts, patients <25 years had a higher frequency of discontinuations than those >= 26 years. Age and polypharmacy were independent predictors of treatment duration and discontinuation prior to one year. CONCLUSIONS: One quarter of patients with schizophrenia received antipsychotic polypharmacy. Discontinuation was higher in the polypharmacy group. Age and polypharmacy were significant predictors of treatment discontinuation. PMID- 25433497 TI - Genetic analysis and molecular mapping of a seedling crown rust resistance gene in oat. AB - KEY MESSAGE: Genetic analysis and genome mapping of a major seedling oat crown rust resistance gene, designated PcKM, are described. The chromosomal location of the PcKM gene was identified and linked markers were validated. Crown rust (Puccinia coronata Corda f. sp. avenae Eriks) is the most important foliar disease of oats and can cause considerable yield loss in the absence of appropriate management practices. Utilization of novel resistant genes is the most effective, economic and environmentally sound approach to control the disease. Crown rust resistance present in the cultivar 'Morton' was evaluated in a population developed from the cross OT3019 * 'Morton' to elucidate the genetic basis of resistance. Crown rust reaction evaluated in field nurseries and greenhouse tests demonstrated that resistance provided by 'Morton' was controlled by a single gene, temporarily designated as PcKM. The gene was initially linked to a random amplified polymorphic DNA band and subsequently converted into a sequence characterized amplified region (SCAR) marker. Genotyping with the PcKM SCAR on the 'Kanota' * 'Ogle' population, used to create the first oat chromosome anchored linkage map, placed the PcKM gene on chromosome 12D. Consensus map markers present in the same region as the PcKM SCAR were tested on the OT3019 * 'Morton' population and two additional phenotyped populations segregating for PcKM to identify other markers useful for marker-assisted selection. Three markers were perfectly linked to the PcKM phenotype from which TaqMan and KBioscience competitive allele-specific PCR assays were developed and validated on a set of 25 oat lines. The assays correctly identified PcKM carriers. The markers developed in this study will facilitate fine mapping of the PcKM gene and simplify selection for this crown rust resistance. PMID- 25433496 TI - The T-box transcription factor Brachyury promotes renal interstitial fibrosis by repressing E-cadherin expression. AB - BACKGROUND: Epithelial-to-mesenchymal transition (EMT) induced by TGF-beta1 is one of well-recognized factors contributing to renal fibrosis. However, the underlying molecular mechanisms of EMT are not fully understood. Brachyury, an evolutionarily conserved transcription factor, was recently identified as an important factor promoting EMT in human carcinoma cell lines. There is no evidence that Brachyury is involved in renal tubular EMT. RESULTS: Our results demonstrated that Brachyury was prominently induced in TGF-beta1-treated human proximal tubular epithelial (HK-2) cells and that this induction was accompanied by changes characteristic of EMT. Blockage of Brachyury expression by short interfering RNA (siRNA) in HK-2 cells effectively reversed the TGF-beta1-induced EMT phenotype. Brachyury induction repressed E-cadherin transcription; the E cadherin promoter contains a Brachyury binding site, and decreased expression of E-cadherin occurred in Brachyury-overexpressing cells when they were transfected with reporter constructs using the promoter. This effect was partially mediated by Slug and Snail, as knockdown of Snail and Slug by siRNA effectively reversed Brachyury-mediated EMT and partially restored E-cadherin expression. The expression of Brachyury also presented in a rat model of obstructive nephropathy and in tubulointerstitial fibrosis tissues of IgA nephropathy, suggesting that it may have a role in EMT and renal fibrosis in vivo. CONCLUSION: Our results demonstrate for the first time that Brachyury plays an important role in regulating TGF-beta1-mediated renal EMT and could be an attractive target for progression of renal disease therapies. PMID- 25433499 TI - 1-butyltryptophan inhibits cell proliferation, migration, and invasion through the Akt pathway in human gastric cancer cells. AB - We have previously demonstrated that novel 1-alkyl-tryptophan analogs 1 butyltryptophan (1-BT) can serve as a potential antitumor agent. However, the molecular mechanisms of 1-BT on cancer cells remain to be elucidated. The effect of 1-BT on cell proliferation was detected by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and clone formation assay in SGC7901 and AGS cells. Cell cycle was determined by flow cytometry. Cell migration and invasion was determined by wound healing assay and transwell assay. The expression of cyclin-dependent kinase 4 (CDK4), cyclin D1, p16, PCNA, phosphorylated Akt, total Akt, phosphorylated ERK1/2, and total ERK1/2 was examined using Western blotting. Our data demonstrated that 1-BT inhibited cell proliferation in a dose- and time-dependent manner by the downregulation of expression of cyclin D1 and CDK4 and by the upregulation of p16 expression. The inhibition of cell growth was also demonstrated by cell cycle arrest at the G1/S phase. Furthermore, 1-BT inhibited cell migration and invasion in SGC7901 cells. In addition, we found that phosphorylated Akt was suppressed in 1-BT treated SGC7901 cells. Overexpression of activated Akt reversed the effects of 1-BT on cell migration and invasion in SGC7901 cells. These results indicated that 1-BT inhibited gastric cancer cells proliferation and migration through the Akt pathway, which has the potential clinical significance in the prevention and treatment of gastric cancer. PMID- 25433498 TI - Intravenous fenoldopam for early acute kidney injury after liver transplantation. AB - PURPOSE: Acute kidney injury remains a serious complication after orthotopic liver transplantation. To date, several 'renal-protective' agents have been explored in this setting but with conflicting and disappointing results. Therefore, our aim is to evaluate the effects of fenoldopam in liver transplant patients with an established renal injury. METHODS: In this prospective study, intravenous fenoldopam 0.1 ug/kg/min was administered to consecutive liver transplant patients with postoperative (within 7 days from surgery) stage 2 acute kidney injury (AKI) according to the Acute Kidney Injury Network classification. Actual glomerular filtration rate (GFR; calculated by the iohexol plasma clearance), serum creatinine (SCr) and cystatin C (SCyC) were used to assess the effect of the medication on the patients. RESULTS: During the study, 295 patients underwent liver transplant. Fifty-one patients (17.6%) met the inclusion criteria and the data from 48 patients were analysed. SCr and SCyC levels decreased (p < 0.001 after 48 h; p < 0.0001 after 72 h) and GFR increased (p < 0.001 after 24 h; p < 0.0001 after 72 h). When compared to a cohort of comparable patients with AKI from our historical series, the patients in the present study showed better SCr and SCyC levels. It was not necessary to discontinue the infusion of fenoldopam in any patient because of the occurrence of adverse events potentially attributable to it. CONCLUSION: We showed that fenoldopam was capable of improving some renal function parameters in postoperative liver transplantation patients with on-going AKI. This preliminary study now sets the stage for a multicenter, randomized, placebo-controlled trial in order to provide definite evidence. PMID- 25433500 TI - Serum autoantibodies in the early detection of esophageal cancer: a systematic review. AB - Antibodies against tumor-associated antigens (TAAs) have been found in serum of patients with various types of cancers and may serve as biomarkers for early detection of esophageal cancer as well. This systematic review aims to give an overview about known autoantibodies and their diagnostic value in esophageal cancer. We conducted a systematic literature search in two databases to identify studies which performed serological testing for autoantibodies in esophageal cancer patients and controls. Data on study characteristics and results were extracted independently by two reviewers. Overall, 45 articles reporting the detection of 35 different autoantibodies met the inclusion criteria of this review. The most common antibody detection method was enzyme-linked immunosorbent assay (ELISA), and the most frequently assessed autoantibody was anti-p53, which was tested in 17 studies and for 15 studies of which a meta-analysis was conducted to comprehensively evaluate the diagnostic value. Most antibodies were assessed in only one study, and only few authors have evaluated the diagnostic value of combinations of multiple autoantibodies. For single autoantibodies, specificity was generally very high (median 98.3 %), but sensitivity was mostly rather low (median 26.7 %). For some autoantibody combinations, substantially higher sensitivity at reasonably high levels of specificity could be achieved. Development of extended and optimized multimarker panels of autoantibodies might be a promising approach for esophageal cancer early detection. PMID- 25433501 TI - Lung cancer cells induce senescence and apoptosis of pleural mesothelial cells via transforming growth factor-beta1. AB - Pleural dissemination is commonly associated with metastatic advanced lung cancer. The injury of pleural mesothelial cells (PMCs) by soluble factors, such as transforming growth factor-beta1 (TGF-beta1), is a major driver of lung cancer pleural dissemination (LCPD). In this study, we examine the effects of TGF-beta1 on PMC injury and the ability of TGF-beta1 inhibition to alleviate this effect both in vitro and in vivo. PMCs were co-cultured with the high TGF-beta1 expressing lung cancer cell line A549 and with various TGF-beta1 signaling inhibitors. Expression of cleaved-caspase 3, cleaved-caspase 9, p21, and p16 were evaluated by Western blot and immunofluorescent confocal imaging. Apoptosis was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltrazoliumbromide assay and AnnexinV-propidium iodide (PI) staining. PMC senescence was assessed by staining for senescence-associated beta-galactosidase (SA-beta-Gal). The ability of lung cancer cells (LCCs) to adhere to injured PMCs was investigated using an LCC-PMC adhesion assay. In our mouse model, PMC injury status was monitored by hematoxylin-eosin (H&E) and Masson's trichrome staining. LCCs expressing high levels of TGF-beta1 induce apoptosis and senescence of PMCs in a co-culture system. Injured PMCs adhere to LCCs, which may further promote LCPD. Importantly, PMC monolayer injury could be reversed with TGF-beta1 inhibitors. This was consistent with our in vivo data showing that the TGF-beta1 inhibitor SB-431542 attenuated PMC barrier injury induced by A549 culture medium in our mouse model. Our study highlights the importance of TGF-beta1 signaling in LCPD and establishes this signaling pathway as a potential therapeutic target in the disease. PMID- 25433502 TI - Effects of regular consumption of different forms of almonds and hazelnuts on acceptance and blood lipids. AB - PURPOSE: Regular nut consumption is inversely associated with cardiovascular disease risk. No study has compared the effects of regular consumption of different types and forms of nuts on acceptance, which is a crucial determinant of long-term compliance to consume nuts regularly. METHODS: This study examined the effects of different types and forms of raw, unpeeled nuts on acceptance and the effects of nut consumption on blood lipids through a randomised crossover study with six dietary phases: 30 g/day of ground, sliced, or whole almonds or hazelnuts for 5 days each (n = 74). Acceptance ('desire' and 'liking') for nuts was measured daily using visual analogue scales. Blood lipids were measured at baseline and week 6. RESULTS: Acceptance was stable over all conditions, but there were differences between nut forms (ground < sliced < whole, P < 0.001 for both 'desire' and 'liking') with some nut type-nut form interactions. Compared with baseline, week 6 HDL-C was higher (0.06 mmol/L, 95% CI 0.02-0.10, P = 0.002) while LDL-C and total-C:HDL-C ratio were lower (0.15 mmol/L, 95% CI 0.06-0.25, P = 0.002 and 0.25, 95% CI 0.07-0.43, P = 0.006). CONCLUSIONS: In conclusion, acceptance was stable for all combinations but was highest for whole nuts. Six weeks of nut consumption improved blood lipids. PMID- 25433503 TI - Trace elements in urinary stones: a preliminary investigation in Fars province, Iran. AB - In view of the high incidence rate of urinary stones in the south and southwest of Iran, this paper investigates trace elements content including heavy metals in 39 urinary stones, collected from patients in Fars province, Iran. The mineralogy of the stones is investigated using X-ray diffractometry. The samples are classified into five mineral groups (calcium oxalate, uric acid, cystine, calcium phosphate and mixed stone). Major and trace elements in each group were determined using ICP-MS method. P and Ca constitute the main elements in urinary stones with Ca being more affine to oxalates while other alkali and alkaline earths precipitate with phosphate. Significant amounts of trace elements, especially Zn and Sr, were found in urinary calculi (calcium oxalate and phosphates) relative to biominerals (uric acid and cystine). Among urinary calculi, calcium phosphate contains greater amounts of trace metal than calcium oxalate. Phosphates seem to be the most important metal-bearing phases in urinary stones. Results indicate that concentrations of elements in urinary stones depend on the type of mineral phases. Significant differences in elements content across various mineralogical groups were found by applying statistical methods. Kruskal Wallis test reveals significant difference between Ca, P, K, Na, Mg, S, Zn, Sr, Se, Cd, and Co content in different investigated mineral groups. Moreover, Mann Whitney test differentiates Ca, Na, Zn, Sr, Co, and Ni between minerals in oxalate and uric acid stones. This study shows that urinary stone can provide complementary information on human exposure to elements and estimate the environmental risks involved in urinary stones formation. PMID- 25433504 TI - Urgent percutaneous nephrolithotomy for acute kidney injury secondary to bilateral stones: is it safe and effective in infants? AB - PURPOSE: To evaluate the efficacy and safety of urgent percutaneous nephrolithotomy (PNL) for acute kidney injury secondary to bilateral upper urinary stones in infants. METHODS: A total of seven infants (five boys and two girls), aged from 5 to 12 months, underwent urgent PNL for calculus anuria from September 2011 to March 2013. The initial blood test revealed acute renal injury in all infants. After correcting electrolyte imbalance and acid-base status through medical treatment in a short time without dialysis, all urgent PNL procedures were performed with 16F percutaneous access and small-diameter nephroscopes designed specifically for pediatric surgery on the side with the more dilated pelvis. Stones were fragmented with a pneumatic lithotripter. RESULTS: Stones were completely removed from the operative side kidneys. The operating time ranged from 35 to 57 min. Blood BUN, serum creatinine, and electrolyte levels returned to normal on postoperative 36 h. There were no major perioperative or postoperative complications and deaths. CONCLUSIONS: When performed by experienced endourologists, urgent PNL is a safe and effective procedure in infants for acute kidney injury secondary to bilateral upper urinary stones. PMID- 25433505 TI - Renal cell carcinoma and tumour thrombus in the inferior vena cava: clinical outcome of 98 consecutive patients and the prognostic value of preoperative parameters. AB - OBJECTIVES: To evaluate the outcome of patients after nephrectomy and removal of tumour thrombus and to assess the prognostic value of preoperative parameters. PATIENTS AND METHODS: Ninety-eight patients who were surgically treated between 2002 and 2011 were included. Patients' charts were reviewed, and patients with renal cell carcinoma (RCC) and concomitant tumour thrombus in the renal vein (RV) were compared with those with extended inferior vena cava (IVC) thrombus. Wilcoxon rank-sum test, Kaplan-Meier analysis and uni- and multivariate Cox regression analysis were used for statistical evaluation. RESULTS: Follow-up was 36 months (20-122 months), and 5-year disease-specific survival (DSS) and overall survival were 68.4 and 54.1 %, respectively. Patients with extended thrombus (levels 2-4) had higher intraoperative transfusion rates of concentrated red cells (CRC) and fresh-frozen plasma (FFP) compared with patients with thrombus confined to the RV (CRC: 5.8 vs. 1.5, p < 0.0001; FFP: 2.3 vs. 0.4, p = 0.0032). Surgery time (190 vs. 107 min, p < 0.0001), duration of hospitalisation (16 vs. 11 days, p = 0.0269), serum phosphate (3.64 vs. 3.29 mmol/l, p = 0.0369) and CRP levels (6.7 vs. 4.4 mg/dl, p = 0.0194) as well as aPTT were increased (33.7 vs. 29.6 s, p = 0.0059) in extended thrombus disease. In multivariate analysis, the presence of distant metastasis (p = 0.03) and lymphovascular invasion (p = 0.001), high platelet counts (p = 0.001) and high serum potassium levels (p = 0.032) proved to be independent prognostic factors. CONCLUSION: The surgical treatment of RCC with tumour thrombus in the RV or IVC has favourable results. Extended thrombus disease requires multidisciplinary approach. High serum potassium levels and platelet counts are associated with reduced DSS. PMID- 25433508 TI - The living with asthma study: issues affecting the perceived health and well being of Irish adults with asthma. AB - INTRODUCTION: Ireland has the fourth highest incidence of asthma in the world, with an estimated 14.7 % of the population having asthma, making it the most common chronic disease in childhood and the most common respiratory illness in Ireland. METHOD: The aim of this qualitative enquiry, involving participant focus groups, was to investigate the health and well-being of Irish adults who have asthma, with particular interest in the influences on their health and well being. The study population was recruited from the Asthma Society of Ireland database of members. Data were collected in eight focus group interviews and analysed for themes. RESULTS: Asthma was found to have a significant impact on the health and well-being of participants due to symptom experience, treatments they had to undertake, and the repercussions of uncontrollable events or triggers. The unrelenting pressure of managing their asthma took a toll on many of the participants, who felt their lifestyle had changed dramatically and they had lost some or all of their control over their health and well-being. PMID- 25433507 TI - Post-operative nomogram for predicting freedom from recurrence after surgery in localised breast cancer receiving adjuvant hormone therapy. AB - PURPOSE: To develop a prognostic nomogram to predict freedom from recurrence for patients treated with adjuvant hormonal therapy (HT) for localised breast cancer (BC). METHODS: We performed a retrospective analysis of 142 patients treated with adjuvant HT between 1996 and 2000. Clinical and pathological parameters were analysed. RESULTS: A nomogram that predicts the probability of remaining free of recurrence for 5 years after surgery with adjuvant HT was developed using a Cox proportional hazards regression model. The progesterone receptor status (p < 0.001), nodal status (p = 0.008) and cathepsin-D (p < 0.001) were retained to construct the nomogram (C-index 0.734). CONCLUSIONS: The nomogram we developed may be useful for estimating the probability of successful treatment 5 years after surgery for localised BC. PMID- 25433506 TI - In vitro effects and ex vivo binding of an EGFR-specific immunotoxin on rhabdomyosarcoma cells. AB - PURPOSE: Rhabdomyosarcoma (RMS) is a rare and aggressive soft tissue sarcoma with limited treatment options and a high failure rate during standard therapy. New therapeutic strategies based on targeted immunotherapy are therefore much in demand. The epidermal growth factor receptor (EGFR) has all the characteristics of an ideal target. It is overexpressed in up to 80 % of embryonal RMS and up to 50 % of alveolar RMS tumors. We therefore tested the activity of the EGFR specific recombinant immunotoxin (IT) 425(scFv)-ETA' against EGFR(+) RMS cells in vitro and ex vivo. METHODS: We tested the specific binding and internalization behavior of 425(scFv)-ETA' in RMS cell lines in vitro by flow cytometry, compared to the corresponding imaging probe 425(scFv)-SNAP monitored by live cell imaging. The cytotoxic activity of 425(scFv)-ETA' was tested using cell viability and apoptosis assays. Specific binding of the IT was confirmed on formalin-fixed paraffin-embedded tissue samples from two RMS patients. RESULTS: We confirmed the specific binding of 425(scFv)-ETA' to RMS cells in vitro and ex vivo. Both the IT and the corresponding imaging probe were rapidly internalized. The IT killed EGFR(+) RMS cells in a dose-dependent manner, while showing no effect against control cells. It showed specific apoptotic activity against one selected RMS cell line. CONCLUSIONS: This is the first study showing the promising therapeutic potential of a recombinant, EGFR-targeting, ETA'-based IT on RMS cells. We confirmed the selective killing with IC50 values of up to 50 pM, and immunohistochemical staining confirmed the specific ex vivo binding to primary RMS material. PMID- 25433509 TI - Occurrence of Arthroderma benhamiae genotype in Japan. AB - In this study, we epidemiologically investigated on clinical isolates of Arthroderma benhamiae from humans and animals in Japan by internal transcribed spacer (ITS) region sequence analysis and mating type (MAT)-specific PCR. Seven of 8 A. benhamiae isolates from a human, rabbits and guinea pigs were identified as group I (white phenotype) by morphological characters and ITS region sequence analysis. One strain isolated from a degus (Octodon degus) produced colonies with few irregular folds and yellow velvety mycelium without macro- and microconidia. This strain resembled to group II (yellow phenotype) strain. ITS sequence analysis was also 100% identical to that of group II. MAT-specific PCR indicated that 6 of these 7 isolates of group I contained an alpha-box gene and that one strain contained high-mobility-group (HMG) gene. One strain of group II was revealed to have an alpha-box gene and no HMG gene. To our knowledge, it is the first A. benhamiae isolate of group II found in Japan. The A. benhamiae may be more widespread in worldwide than our surpassing what is common or usual or expected. PMID- 25433510 TI - Faster pediatric 3-T abdominal magnetic resonance imaging: comparison between conventional and variable refocusing flip-angle single-shot fast spin-echo sequences. AB - BACKGROUND: Single-shot fast spin echo (SSFSE) is particularly appealing in pediatric patients because of its motion robustness. However radiofrequency energy deposition at 3 tesla forces long pauses between slices, leading to longer scans, longer breath-holds and more between-slice motion. OBJECTIVE: We sought to learn whether modulation of the SSFSE refocusing flip-angle train could reduce radiofrequency energy deposition without degrading image quality, thereby reducing inter-slice pauses and overall scan times. MATERIALS AND METHODS: We modulated the refocusing flip-angle train for SSFSE to minimize energy deposition while minimizing blurring and motion-related signal loss. In a cohort of 50 consecutive patients (25 boys, mean age 5.5 years, range 1 month to 17 years) referred for abdominal MRI we obtained standard SSFSE and variable refocusing flip-angle (vrfSSFSE) images and recorded sequence scan times. Two readers independently scored the images in blinded, randomized order for noise, tissue contrast, sharpness, artifacts and left lobe hepatic signal uniformity on a four point scale. The null hypothesis of no difference between SSFSE and vrfSSFSE image-quality was assessed with a Mann-Whitney U test, and the null hypothesis of no scan time difference was assessed with the paired t-test. RESULTS: SSFSE and vrfSSFSE mean acquisition times were 54.3 and 26.2 s, respectively (P-value <0.0001). For each reader, SSFSE and vrfSSFSE noise, tissue contrast, sharpness and artifacts were not significantly different (P-values 0.18-0.86). However, SSFSE had better left lobe hepatic signal uniformity (P < 0.01, both readers). CONCLUSION: vrfSSFSE is twice as fast as SSFSE, with equivalent image quality with the exception of left hepatic lobe signal heterogeneity. PMID- 25433512 TI - Placenta-derived angiogenic proteins and their contribution to the pathogenesis of preeclampsia. AB - Placental angiogenesis is critical to the success of human pregnancy. Angiogenesis is defined as the formation of new blood vessels from existing vasculature. Angiogenesis is necessary for the establishment of adequate placental perfusion, which is important for providing the optimum in utero environment to support fetal development. Defective placental angiogenesis is associated with several pregnancy complications, the most clinically important of which is preeclampsia; the multisystem disorder is characterized by maternal hypertension, proteinuria, and endothelial dysfunction. Here, we review our current understanding of several key angiogenic factors that are associated with placental angiogenesis. We also discuss their importance with respect to preeclampsia, where aberrant expression and release of these factors into the maternal circulation is thought to contribute to the pathogenesis and pathophysiology of preeclampsia. PMID- 25433511 TI - Contribution of fibrinolysis to the physical component summary of the SF-36 after acute submassive pulmonary embolism. AB - Acute pulmonary embolism (PE) can diminish patient quality of life (QoL). The objective was to test whether treatment with tenecteplase has an independent effect on a measurement that reflects QoL in patients with submassive PE. This was a secondary analysis of an 8-center, prospective randomized controlled trial, utilizing multivariate regression to control for predefined predictors of worsened QoL including: age, active malignancy, history of PE or deep venous thrombosis (DVT), recurrent PE or DVT, chronic obstructive pulmonary disease and heart failure. QoL was measured with the physical component summary (PCS) of the SF-36. Analysis included 76 patients (37 randomized to tenecteplase, 39 to placebo). Multivariate regression yielded an equation f(8, 67), P < 0.001, with R(2) = 0.303. Obesity had the largest effect on PCS (beta = -8.6, P < 0.001), with tenecteplase second (beta = 4.73, P = 0.056). After controlling for all interactions, tenecteplase increased the PCS by +5.37 points (P = 0.027). In patients without any of the defined comorbidities, the coefficient on the tenecteplase variable was not significant (-0.835, P = 0.777). In patients with submassive PE, obesity had the greatest influence on QoL, followed by use of fibrinolysis. Fibrinolysis had a marginal independent effect on patient QoL after controlling for comorbidities, but was not significant in patients without comorbid conditions. PMID- 25433513 TI - Optimal Symmetric Multimodal Templates and Concatenated Random Forests for Supervised Brain Tumor Segmentation (Simplified) with ANTsR. AB - Segmenting and quantifying gliomas from MRI is an important task for diagnosis, planning intervention, and for tracking tumor changes over time. However, this task is complicated by the lack of prior knowledge concerning tumor location, spatial extent, shape, possible displacement of normal tissue, and intensity signature. To accommodate such complications, we introduce a framework for supervised segmentation based on multiple modality intensity, geometry, and asymmetry feature sets. These features drive a supervised whole-brain and tumor segmentation approach based on random forest-derived probabilities. The asymmetry related features (based on optimal symmetric multimodal templates) demonstrate excellent discriminative properties within this framework. We also gain performance by generating probability maps from random forest models and using these maps for a refining Markov random field regularized probabilistic segmentation. This strategy allows us to interface the supervised learning capabilities of the random forest model with regularized probabilistic segmentation using the recently developed ANTsR package--a comprehensive statistical and visualization interface between the popular Advanced Normalization Tools (ANTs) and the R statistical project. The reported algorithmic framework was the top-performing entry in the MICCAI 2013 Multimodal Brain Tumor Segmentation challenge. The challenge data were widely varying consisting of both high-grade and low-grade glioma tumor four-modality MRI from five different institutions. Average Dice overlap measures for the final algorithmic assessment were 0.87, 0.78, and 0.74 for "complete", "core", and "enhanced" tumor components, respectively. PMID- 25433514 TI - Improved automatic centerline tracing for dendritic and axonal structures. AB - Centerline tracing in dendritic structures acquired from confocal images of neurons is an essential tool for the construction of geometrical representations of a neuronal network from its coarse scale up to its fine scale structures. In this paper, we propose an algorithm for centerline extraction that is both highly accurate and computationally efficient. The main novelties of the proposed method are (1) the use of a small set of Multiscale Isotropic Laplacian filters, acting as self-steerable filters, for a quick and efficient binary segmentation of dendritic arbors and axons; (2) an automated centerline seed points detection method based on the application of a simple 3D finite-length filter. The performance of this algorithm, which is validated on data from the DIADEM set appears to be very competitive when compared with other state-of-the-art algorithms. PMID- 25433515 TI - HealthPathways: creating a pathway for health systems reform. AB - Inefficiencies in the co-ordination and integration of primary and secondary care services in Australia, have led to increases in waiting times, unnecessary presentations to emergency departments and issues around poor discharge of patients. HealthPathways is a program developed in Canterbury, New Zealand, that builds relationships between General Practitioners and Specialists and uses information technology so that efficiency is maximised and the right patient is given the right care at the right time. Healthpathways is being implemented by a number of Medicare Locals across Australia however, little is known about the impact HealthPathways may have in Australia. This article provides a short description of HealthPathways and considers what it may offer in the Australian context and some of the barriers and facilitators to implementation. PMID- 25433516 TI - Isolation and epithelial co-culture of mouse renal peritubular endothelial cells. AB - BACKGROUND: Endothelial-mesenchymal transition (EndoMT) has been shown to be a major source of myofibroblasts, contributing to kidney fibrosis. However, in vitro study of endothelial cells often relies on culture of isolated primary endothelial cells due to the unavailability of endothelial cell lines. Our recent study suggested that peritubular endothelial cells could contribute to kidney fibrosis through EndoMT. Therefore, successful isolation and culture of mouse peritubular endothelial cells could provide a new platform for studying kidney fibrosis. This study describes an immunomagnetic separation method for the isolation of mouse renal peritubular endothelial cells using anti-CD146 MicroBeads, followed by co-culture with mouse renal proximal tubular epithelial cells to maintain endothelial phenotype. RESULTS: Flow cytometry showed that after isolation and two days of culture, about 95% of cells were positive for endothelial-specific marker CD146. The percentage of other cells, including dendritic cells (CD11c) and macrophages (F4/80), was less than 1%. Maintenance of endothelial cell phenotype required vascular endothelial growth factor (VEGF) and co-culture with mouse proximal tubular epithelial cells. CONCLUSION: In this study, we established a method for the isolation of mouse renal peritubular endothelial cells by using immunomagnetic separation with anti-CD146 MicroBeads, followed by co-culture with mouse renal proximal tubular epithelial cells to maintain phenotype. PMID- 25433518 TI - Psychological therapies versus antidepressant medication, alone and in combination for depression in children and adolescents. AB - BACKGROUND: Depressive disorders are common in children and adolescents and, if left untreated, are likely to recur in adulthood. Depression is highly debilitating, affecting psychosocial, family and academic functioning. OBJECTIVES: To evaluate the effectiveness of psychological therapies and antidepressant medication, alone and in combination, for the treatment of depressive disorder in children and adolescents. We have examined clinical outcomes including remission, clinician and self reported depression measures, and suicide-related outcomes. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) to 11 June 2014. The register contains reports of relevant randomised controlled trials (RCTs) from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). SELECTION CRITERIA: RCTs were eligible for inclusion if they compared i) any psychological therapy with any antidepressant medication, or ii) a combination of psychological therapy and antidepressant medication with a psychological therapy alone, or an antidepressant medication alone, or iii) a combination of psychological therapy and antidepressant medication with a placebo or'treatment as usual', or (iv) a combination of psychological therapy and antidepressant medication with a psychological therapy or antidepressant medication plus a placebo.We included studies if they involved participants aged between 6 and 18 years, diagnosed by a clinician as having Major Depressive Disorder (MDD) based on Diagnostic and Statistical Manual (DSM) or International Classification of Diseases (ICD) criteria. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted data and assessed the quality of the studies. We applied a random-effects meta-analysis, using the odds ratio (OR) to describe dichotomous outcomes, mean difference (MD) to describe continuous outcomes when the same measures were used, and standard mean difference (SMD) when outcomes were measured on different scales. MAIN RESULTS: We included eleven studies, involving 1307 participants in this review. We also identified one ongoing study, and two additional ongoing studies that may be eligible for inclusion. Studies recruited participants with different severities of disorder and with a variety of comorbid disorders, including anxiety and substance use disorder, therefore limiting the comparability of the results. Regarding the risk of bias in studies, just under half the studies had adequate allocation concealment (there was insufficient information to determine allocation concealment in the remainder), outcome assessors were blind to the participants' intervention in six studies, and in general, studies reported on incomplete data analysis methods, mainly using intention-to-treat (ITT) analyses. For the majority of outcomes there were no statistically significant differences between the interventions compared. There was limited evidence (based on two studies involving 220 participants) that antidepressant medication was more effective than psychotherapy on measures of clinician defined remission immediately post intervention (odds ratio (OR) 0.52, 95% confidence interval (CI) 0.27 to 0.98), with 67.8% of participants in the medication group and 53.7% in the psychotherapy group rated as being in remission. There was limited evidence (based on three studies involving 378 participants) that combination therapy was more effective than antidepressant medication alone in achieving higher remission from a depressive episode immediately post-intervention (OR 1.56, 95% CI 0.98 to 2.47), with 65.9% of participants treated with combination therapy and 57.8% of participants treated with medication, rated as being in remission. There was no evidence to suggest that combination therapy was more effective than psychological therapy alone, based on clinician rated remission immediately post intervention (OR 1.82, 95% CI 0.38 to 8.68).Suicide-related Serious Adverse Events (SAEs) were reported in various ways across studies and could not be combined in meta-analyses. However, some trials measured suicidal ideation using standardised assessment tools suitable for meta-analysis. In one study involving 188 participants, rates of suicidal ideation were significantly higher in the antidepressant medication group (18.6%) compared with the psychological therapy group (5.4%) (OR 0.26, 95% CI 0.09 to 0.72) and this effect appeared to remain at six to nine months (OR 0.26, 95% CI 0.07 to 0.98), with 13.6% of participants in the medication group and 3.9% of participants in the psychological therapy group reporting suicidal ideation. It was unclear what the effect of combination therapy was compared with either antidepressant medication alone or psychological therapy alone on rates of suicidal ideation. The impact of any of the assigned treatment packages on drop out was also mostly unclear across the various comparisons in the review.Limited data and conflicting results based on other outcome measures make it difficult to draw conclusions regarding the effectiveness of any specific intervention based on these outcomes. AUTHORS' CONCLUSIONS: There is very limited evidence upon which to base conclusions about the relative effectiveness of psychological interventions, antidepressant medication and a combination of these interventions. On the basis of the available evidence, the effectiveness of these interventions for treating depressive disorders in children and adolescents cannot be established. Further appropriately powered RCTs are required. PMID- 25433517 TI - A three month controlled intervention of intermittent whole body vibration designed to improve functional ability and attenuate bone loss in patients with rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune condition that results in pain and disability. Patients with RA have a decreased functional ability and are forced into a sedentary lifestyle and as such, these patients often become predisposed to poor bone health. Patients with RA may also experience a decreased health related quality of life (HRQoL) due to their disease. Whole body vibration (WBV) is a form of exercise that stimulates bone loading through forced oscillation. WBV has also been shown to decrease pain and fatigue in other rheumatic diseases, as well as to increase muscle strength. This paper reports on the development of a semi randomised controlled clinical trial to assess the impact of a WBV intervention aiming to improve functional ability, attenuate bone loss, and improve habitual physical activity levels in patients with RA. METHODS/DESIGN: This study is a semi randomised, controlled trial consisting of a cohort of patients with established RA assigned to either a WBV group or a CON (control) group. Patients in the WBV group will undergo three months of twice weekly intermittent WBV sessions, while the CON group will receive standard care and continue with normal daily activities. All patients will be assessed at baseline, following the three month intervention, and six months post intervention. Main outcomes will be an improvement in functional ability as assessed by the HAQ. Secondary outcomes are attenuation of loss of bone mineral density (BMD) at the hip and changes in RA disease activity, HRQoL, habitual physical activity levels and body composition. DISCUSSION: This study will provide important information regarding the effects of WBV on functional ability and BMD in patients with RA, as well as novel data regarding the potential changes in objective habitual physical activity patterns that may occur following the intervention. The sustainability of the intervention will also be assessed. TRIAL REGISTRATION: PACTR201405000823418 (19/05/2014). PMID- 25433520 TI - Health status of and health-care provision to asylum seekers in Germany: protocol for a systematic review and evidence mapping of empirical studies. AB - BACKGROUND: There are more than 100,000 asylum seekers registered in Germany, who are granted limited access to health services. This study aims to provide a systematic overview of the empirical literature on the health status of and health-care provision to asylum seekers in Germany in order to consolidate knowledge, avoid scientific redundance, and identify research gaps. METHODS/DESIGN: A systematic review and evidence mapping of empirical literature on the health status of and health-care provision to asylum seekers in Germany will be performed. We will apply a three-tiered search strategy: 1. search in databases (PubMed/MEDLINE, Web of Science, IBSS, Sociological Abstracts, Worldwide Political Science Abstracts, CINAHL, Sowiport, Social Sciences Citation Index, ASSIA, MedPilot, DNB), dissertation and theses databases, and the internet (Google); 2. screening references of included studies; 3. contacting authors and civil society organizations for grey literature. Included will be studies which report quantitative and/or qualitative data or review articles on asylum seekers in Germany, published in German or English language. Outcome measures will include physical, mental, or social well-being, and all aspects of health-care provision (access, availability, affordability, and quality). Search results will be screened for eligibility by screening titles, abstracts and full texts. Data extraction comprises information on study characteristics, research aims, and domains of health or health-care services analyzed. The quality of studies will be appraised and documented by appropriate assessment tools. A descriptive evidence map will be drawn by categorizing all included articles by research design and the health conditions and/or domains of health-care provision analyzed. The body of evidence will be evaluated, and a narrative evidence synthesis will be performed by means of a multi-level approach, whereby quantitative and qualitative evidence are analyzed as separate streams and the product of each stream is configured in a final summary. DISCUSSION: This systematic review will provide an evidence map and synthesis of available research findings on the health status of and health-care provision to asylum seekers in Germany. In anticipation of identifying areas which are amenable to health-care interventions, deserve immediate action, or further exploration, this review will be of major importance for policy-makers, health-care providers, as well as researchers. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2014: CRD42014013043. PMID- 25433519 TI - Symptom changes in multiple sclerosis following psychological interventions: a systematic review. AB - BACKGROUND: Multiple Sclerosis is a disease of the central nervous system involving a variety of debilitating physical, sensory, cognitive and emotional symptoms. This literature review evaluated the impact of psychological interventions on the physiological symptoms associated with the illness. METHODS: A systematic literature search was conducted using Medline, PsycINFO, Scopus, and the Cochrane Library databases, as well as reference lists. Relevant studies were selected and assessed according to a preset protocol. RESULTS: The search produced 220 articles, with 22 meeting inclusion criteria for the review. A total of 5,705 subjects with Multiple Sclerosis were analyzed. Results from the included studies indicate a general improvement in both psychological and physiological outcomes following psychological treatment. The most highly influenced physical symptoms include fatigue, sleep disturbances, pain, and physical vitality. CONCLUSIONS: Findings from the review suggest a positive relationship between psychological interventions and physiological Multiple Sclerosis symptoms. Implications for future research are discussed. PMID- 25433521 TI - Aging, Gender and Quality of Life (AGEQOL) study: factors associated with good quality of life in older Brazilian community-dwelling adults. AB - BACKGROUND: In Brazil, a rapidly aging country suffering from large inequalities, the study of the quality of life (QOL) of aged people is important for the future health. The aim of this study was to examine the associations among QOL, gender, and physical and psychosocial health in older Brazilian community-dwelling adults to identify factors that are associated with better QOL. METHODS: The "Aging, Gender and Quality of Life (AGEQOL)" study, which included 2,052 respondents aged 60 or older, was conducted in Sete Lagoas, Brazil between January and July 2012. The respondents answered questions regarding their socioeconomic and demographic information, health and social situations, cognitive impairment, depressive symptoms and family satisfaction. The authors also applied the Brazilian version the World Health Organization Quality of Life QOL Assessment-Brief Instrument (WHOQOL-BREF) and the World Health Organization Quality of Life Instrument-Older Adults Module (WHOQOL-Old). Ordinal logistic regression with the Proportional Odds and Logit function was used to test the association between QOL and physical and psychosocial health according to age and socioeconomic status. RESULTS: Older adults of both genders with five or more years of education, good self-rated health, an absence of depressive symptoms, and no family dysfunction reported better QOL. Retired men had a better QOL compared to non-retired men (OR = 2.2; 95% CI = 1.4-3.2), but this association was not observed in females. Men living in mixed arrangements (OR = 0.5; p = 0.033) and women who did not practice physical activity (OR = 0.7; p = 0.022) tended to have poorer QOL. CONCLUSIONS: We conclude that there are gender differences related to better QOL in this sample. Women with good physical and psychosocial health are more likely to have a better QOL. For men, the best QOL was associated with high socioeconomic conditions and good physical and psychosocial health. PMID- 25433522 TI - Hypothesis testing of meiotic recombination rates from population genetic data. AB - BACKGROUND: Meiotic recombination, one of the central biological processes studied in population genetics, comes in two known forms: crossovers and gene conversions. A number of previous studies have shown that when one of these two events is nonexistent in the genealogical model, the point estimation of the corresponding recombination rate by population genetic methods tends to be inflated. Therefore, it has become necessary to obtain statistical evidence from population genetic data about whether one of the two recombination events is absent. RESULTS: In this paper, we formulate this problem in a hypothesis testing framework and devise a testing procedure based on the likelihood ratio test (LRT). However, because the null value (i.e., zero) lies on the boundary of the parameter space, the regularity conditions for the large-sample approximation to the distribution of the LRT statistic do not apply. In turn, the standard chi squared approximation is inaccurate. To address this critical issue, we propose a parametric bootstrap procedure to obtain an approximate p-value for the observed test statistic. Coalescent simulations are conducted to show that our approach yields accurate null p-values that closely follow the theoretical prediction while the estimated alternative p-values tend to concentrate closer to zero. Finally, the method is demonstrated on a real biological data set from the telomere of the X chromosome of African Drosophila melanogaster. CONCLUSIONS: Our methodology provides a necessary complement to the existing procedures of estimating meiotic recombination rates from population genetic data. PMID- 25433523 TI - Expanded spectrum of exon 33 and 34 mutations in SRCAP and follow-up in patients with Floating-Harbor syndrome. AB - BACKGROUND: Floating-Harbor syndrome is a rare autosomal dominant short stature syndrome with retarded speech development, intellectual disability and dysmorphic facial features. Recently dominant mutations almost exclusively located in exon 34 of the Snf2-related CREBBP activator protein gene were identified to cause FHS. METHODS: Here we report the genetic analysis of 5 patients fulfilling the diagnostic criteria of FHS obtained by Sanger sequencing. All of them presented with short stature, speech delay as well as psychomotor delay and typical facial dysmorphism. Three patients showed a good response to growth hormone treatment. RESULTS: Two patients demonstrate novel, heterozygous de novo frameshift mutations in exon 34 (c.7396delA and c.7218dupT) leading to premature stop mutations in SRCAP (p.Val2466Tyrfs*9 and p.Gln2407Serfs*36, respectively). In two further patients we found already known SRCAP mutations in exon 34, c.7330C > T and c.7303C > T, respectively, which also lead to premature stop codons: p.Arg2444* and p.Arg2435*. In one patient, we identified a novel de novo stop mutation in exon 33 (c.6985C > T, p.Arg2329*) demonstrating that not all FHS cases are caused by mutations in exon 34 of SRCAP. CONCLUSIONS: Our data confirm a mutational hot spot in the final exon of SRCAP in the majority of FHS patients but also show that exon 33 of this gene can be affected. PMID- 25433524 TI - SinR is a mutational target for fine-tuning biofilm formation in laboratory evolved strains of Bacillus subtilis. AB - BACKGROUND: Bacteria often form multicellular, organized communities known as biofilms, which protect cells from a variety of environmental stresses. During biofilm formation, bacteria secrete a species-specific matrix; in Bacillus subtilis biofilms, the matrix consists of protein polymers and exopolysaccharide. Many domesticated strains of B. subtilis have a reduced ability to form biofilms, and we conducted a two-month evolution experiment to test whether laboratory culturing provides selective pressure against biofilm formation in B. subtilis. RESULTS: Bacteria grown in two-month-long batch culture rapidly diversified their biofilm-forming characteristics, exhibiting highly diverse colony morphologies on LB plates in the initial ten days of culture. Generally, this diversity decreased over time; however, multiple types of colony morphology remained in our final two month-old populations, both under shaking and static conditions. Notably, while our final populations featured cells that produce less biofilm matrix than did the ancestor, cells overproducing biofilm matrix were present as well. We took a candidate-gene approach to identify mutations in the strains that overproduced matrix and found point mutations in the biofilm-regulatory gene sinR. Introducing these mutations into the ancestral strain phenocopied or partially phenocopied the evolved biofilm phenotypes. CONCLUSIONS: Our data suggest that standard laboratory culturing conditions do not rapidly select against biofilm formation. Although biofilm matrix production is often reduced in domesticated bacterial strains, we found that matrix production may still have a fitness benefit in the laboratory. We suggest that adaptive specialization of biofilm-forming species can occur through mutations that modulate biofilm formation as in B. subtilis. PMID- 25433525 TI - Predictors of patient self-report of chronic kidney disease: baseline analysis of a randomised controlled trial. AB - BACKGROUND: Improving the quality of care for patients with vascular disease is a priority. Clinical guidance has emphasised the importance of early identification and active management of chronic kidney disease (CKD) in primary care in order to maintain vascular health. However, awareness of stage 3 CKD amongst patients remains limited. We aimed to identify predictors of patient self-report of CKD to inform tailoring of conversations around CKD in primary care for diverse patient populations. METHODS: We conducted a cross-sectional analysis of baseline data from 436 patients with stage 3 CKD from 24 GP practices taking part in a randomised controlled trial (RCT) evaluating a complex self-management intervention, which aimed to support the maintenance of vascular health in patients with stage 3 CKD. Potential predictors of patient self-report of CKD included demographics, stage of CKD, cardiovascular risk, self-reported co morbidities, health status, self-management ability, and health service utilisation. RESULTS: Around half (52%, n = 227) of patients did not self-report CKD. Self-report rates did not appreciably differ by practice. Multivariate analysis revealed that female patients (p = 0.004), and patients with stage 3b CKD (p < 0.001), and with higher anxiety levels (p < 0.001), were more likely to self-report CKD. CONCLUSIONS: Self-report of kidney problems by patients on CKD registers was variable and patterned by sociodemographic factors. Although it cannot be assumed that failure to self-report indicates a lack of awareness of CKD, our data do suggest the need for greater consistency in discussions around kidney health, with meaningful and relevant clinical dialogue that is aligned with existing clinical encounters to enable shared decision making and minimise anxiety. PMID- 25433526 TI - RMS: a platform for managing cross-disciplinary and multi-institutional research project collaboration. AB - BACKGROUND: Cross-institutional cross-disciplinary collaboration has become a trend as researchers move toward building more productive and innovative teams for scientific research. Research collaboration is significantly changing the organizational structure and strategies used in the clinical and translational science domain. However, due to the obstacles of diverse administrative structures, differences in area of expertise, and communication barriers, establishing and managing a cross-institutional research project is still a challenging task. We address these challenges by creating an integrated informatics platform to reduce the barriers to biomedical research collaboration. RESULTS: The Request Management System (RMS) is an informatics infrastructure designed to transform a patchwork of expertise and resources into an integrated support network. The RMS facilitates investigators' initiation of new collaborative projects and supports the management of the collaboration process. In RMS, experts and their knowledge areas are categorized and managed structurally to provide consistent service. A role-based collaborative workflow is tightly integrated with domain experts and services to streamline and monitor the life-cycle of a research project. The RMS has so far tracked over 1,500 investigators with over 4,800 tasks. The research network based on the data collected in RMS illustrated that the investigators' collaborative projects increased close to 3 times from 2009 to 2012. Our experience with RMS indicates that the platform reduces barriers for cross-institutional collaboration of biomedical research projects. CONCLUSION: Building a new generation of infrastructure to enhance cross-disciplinary and multi-institutional collaboration has become an important yet challenging task. In this paper, we share the experience of developing and utilizing a collaborative project management system. The results of this study demonstrate that a web-based integrated informatics platform can facilitate and increase research interactions among investigators. PMID- 25433527 TI - Intravenous immunoglobulin may be an effective therapy for refractory, active diffuse cutaneous systemic sclerosis. AB - OBJECTIVE: We sought to retrospectively review a single-center experience using intravenous immunoglobulin (IVIG) for the treatment of refractory, active diffuse cutaneous systemic sclerosis (dcSSc). METHODS: The mean modified Rodnan Skin score (mRSS) at baseline was compared to the mRSS at 6, 12, 18, and 24 months post-IVIG initiation by the paired Student t test. Changes in mRSS at 6 and 12 months were also compared to data from historical controls of 3 large, negative, multicenter, randomized clinical trials of other medications [D-penicillamine (D pen), recombinant human relaxin (relaxin), and oral bovine type I collagen (collagen)] and to patients treated with mycophenolate mofetil (MMF) alone using the Student t test. RESULTS: Thirty patients were treated with adjunctive IVIG (2 g/kg/mo) for refractory, active dcSSc. The mean baseline mRSS of our cohort was 29.6 +/- 7.2, and this significantly decreased to 24.1 +/- 9.6 (n = 29, p = 0.0011) at 6 months, 22.5 +/- 10.0 (n = 25, p = 0.0001) at 12 months, 20.6 +/- 11.8 (n = 23, p = 0.0001) at 18 months, and 15.3 +/- 6.4 (n = 15, p < 0.0001) at 24 months. The mean change in mRSS at 6 months was not significantly different in the IVIG group (-5.3 +/- 7.9) compared to the relaxin trial (-4.8 +/- 6.99, p = 0.74) or MMF group (-3.4 +/- 7.4, p = 0.26); however, at 12 months, the mean change in mRSS was significantly better in the IVIG group (-8 +/- 8.3) than in the D-pen (-2.47 +/- 8.6, p = 0.005) and collagen (-3.4 +/- 7.12, p = 0.005) groups, and was comparable to the group of primary MMF responders (-7.1 +/- 9, p = 0.67). CONCLUSION: Our observational study suggests that IVIG may be an effective adjunctive therapy for active dcSSc in patients failing other therapies. PMID- 25433528 TI - Echocardiographic abnormalities in new-onset polymyositis/dermatomyositis. AB - OBJECTIVE: To identify early echocardiographic abnormalities at the time of diagnosis of polymyositis (PM) and dermatomyositis (DM) and follow the echocardiographic findings during the first 3 months of therapy. METHODS: We included 30 PM/DM patients (23/7) with a mean age of 42.3 +/- 1.6 years and without cardiovascular symptoms. Age-matched healthy patients served as controls. Clinical characteristics were recorded. Traditional echocardiography and tissue Doppler imaging (TDI) were performed to measure systolic [ejection fraction, right ventricular fractional area change (RV FAC), lateral and tricuspid annulus s velocities] and diastolic echocardiographic variables (mitral inflow velocities: E, A; deceleration time: DT; lateral and tricuspid annulus e', a' velocities, lateral E/e'). RESULTS: The left and right ventricular systolic dysfunction detected by TDI at the time of the PM/DM diagnosis improved, and characteristic values at the end of the followup period were comparable to those of the controls (lateral s: 10.6 +/- 0.2, 8.7 +/- 0.4, 9.6 +/- 0.3, 11.3 +/- 0.2 cm/s; RV FAC: 45.2 +/- 2.3, 36.9 +/- 1.5, 42.2 +/- 1.3, 46.9 +/- 1.2%; tricuspid s: 13.3 +/- 0.2, 9.5 +/- 0.4, 10.3 +/- 0.3, 11.6 +/- 0.5 cm/s; control, 0, 1, and 3 mos, respectively). Measurements indicated the development of diastolic dysfunction at 3 mos (E/A: 1.4 +/- 0.1, 1.29 +/- 0.05, 1.03 +/- 0.05, 0.92 +/- 0.05; DT: 148.6 +/- 3.6, 157.3 +/- 5.7, 168.3 +/- 6.0, 184.3 +/- 6.2 ms; lateral e': 12.8 +/- 0.3, 12.1 +/- 0.5, 10.2 +/- 0.6, 10.8 +/- 0.8 cm/s; E/e': 5.6 +/- 0.1, 5.0 +/- 0.22, 6.92 +/- 0.46, 7.64 +/- 0.47; control, 0, 1, and 3 mos, respectively). CONCLUSION: TDI is a useful method to detect early cardiac abnormalities complementing the conventional echocardiographic measurements. LV and RV systolic dysfunction found in the acute phase significantly improved during the first 3 months of therapy; however, deterioration of diastolic dysfunction was also observed. PMID- 25433529 TI - Inhibition of PCSK6 may play a protective role in the development of rheumatoid arthritis. AB - OBJECTIVE: To assess the effect of proprotein convertase subtilisin/kexin type 6 (PCSK6) in the synovial fibroblasts of rheumatoid arthritis (RA). PCSK6 is a proteinase implicated in the proteolytic activity of various precursor proteins and involved in the regulation of protein maturation. METHODS: PCSK6 expression was detected in the synovial tissue of 10 patients with RA, 10 controls with osteoarthritis, and 10 controls with ankylosing spondylitis using Western blotting and quantitative real-time PCR. Genotyping of 67 tag single-nucleotide polymorphisms (SNP) was performed using an Illumina VeraCode (Illumina) microarray in a case-control study including 267 patients with RA and 160 healthy controls. Genotyping of 4 other tag SNP was performed using a TaqMan probe genotyping assay in 1056 healthy controls and 1151 patients with RA. Cultured RA synovial fibroblasts (RASF) were transfected with PCSK6 small interfering RNA to study changes in the proliferation, invasion, migration capacity, secretion of inflammatory cytokines, cell cycle, and expression profiles of the RASF. RESULTS: Expression of PCSK6 mRNA and protein was significantly higher in the synovial tissues of individuals with RA than in control tissues. One SNP, rs8029797, was significantly associated with RA (p = 0.011). Knockdown of PCSK6 by RNA interference significantly decreased proliferation, invasion, and migration of RASF. These changes in RASF appeared to be related to reduced tumor necrosis factor-alpha secretion, G0/G1 arrest, and altered expression of various proteins including those involved in angiogenesis (matrix metalloproteinase 9, nitric oxide synthase trafficking), hypoxia (hypoxia-inducible factor-alpha, thioredoxin domain containing 5), proliferation (chromosome 10 open reading frame 116), and inflammation [CCL7, chemokine (C-X-C motif) ligand 9, interleukin 26]. CONCLUSION: PCSK6 is upregulated in the synovial tissues of patients with RA and has a genetic effect on the risk of RA. Inhibition of PCSK6 may play a protective role in the development of RA. PMID- 25433530 TI - Patient-reported joint count in juvenile idiopathic arthritis: the reliability of a manikin format. AB - OBJECTIVE: To evaluate the reliability of a manikin format, patient-reported joint count in juvenile idiopathic arthritis (JIA), and to detect changes in agreement at a second visit. METHODS: Patients with JIA aged 12-21 were asked to mark joints with active arthritis on a manikin before their regular clinic visit. The physician then performed a joint count without having seen the patient's assessment. Agreement between scores of physician-reported and patient-reported joint counts was assessed using ICC. Kappa statistics were used to assess reliability of scoring individual joints. RESULTS: The study included 75 patients with JIA. In general, patients had a low number of active joints (median 1 joint, indicated by the physician). ICC was moderate (0.61) and kappa ranged from 0.3 0.7. At the second visit, kappa were similar; the ICC was 0.19. When a patient scored 0 joints, the physician confirmed this 93%-100% of the time. When the patient marked >= 1 joints, the physician confirmed arthritis 59%-76% of the time. Sensitivity to change was moderate. CONCLUSION: Agreement between physician and patient on the number of joints with active arthritis was reasonable. Untrained patients tended to overestimate the presence of arthritis when they marked active joints on a manikin-format joint count. When the patient indicated absence of arthritis, the physician usually confirmed this. As the agreement did not improve at followup, future research should focus on the possibility of achieving this through training. For now, the patient-reported joint count cannot replace the physicians' joint count in clinical practice; it may be used in epidemiological studies with caution. PMID- 25433531 TI - Imbalance of prevalence and specialty care for osteoarthritis for first nations people in Alberta, Canada. AB - OBJECTIVE: To estimate the population-based prevalence and healthcare use for osteoarthritis (OA) by First Nations (FN) and non-First Nations (non-FN) in Alberta, Canada. METHODS: A cohort of adults with OA (>= 2 physician claims in 2 yrs or 1 hospitalization with ICD-9-Clinical Modification code 715x or ICD-10 Canadian Adaptation code M15-19, 1993-2010) was defined with FN determination by premium payer status. Prevalence rates (2007/8) were estimated from the cohort and the population registered with the Alberta Health Care Insurance Plan. Rates of outpatient primary care and specialist visits (orthopedics, rheumatology, internal medicine), arthroplasty (hip and knee), and all-cause hospitalization were estimated. RESULTS: OA prevalence in FN was twice that of the non-FN population [16.1 vs 7.8 cases/100 population, standardized rate ratio (SRR) adjusted for age and sex 2.06, 95% CI 2.00-2.12]. The SRR (adjusted for age, sex, and location of residence) for primary care visits for OA was nearly double in FN compared with non-FN (SRR 1.88, 95% CI 1.87-1.89), and internal medicine visits were increased (SRR 1.25, 95% CI 1.25-1.26). Visit rates with an orthopedic surgeon (SRR 0.49, 95% CI 0.48-0.50) or rheumatologist (SRR 0.62, 95% CI 0.62 0.63) were substantially lower in FN with OA. Hip and knee arthroplasties were performed less frequently in FN with OA (SRR 0.48, 95% CI 0.47-0.49), but all cause hospitalization rates were higher (SRR 1.59, 95% CI 1.58-1.60). CONCLUSION: We estimate a 2-fold higher prevalence of OA in the FN population with differential healthcare use. Reasons for higher use of primary care and lower use of specialty services and arthroplasty compared with the general population are not yet understood. PMID- 25433533 TI - In vitro antimicrobial, antioxidant and cytotoxic properties of Streptomyces lavendulae strain SCA5. AB - BACKGROUND: Actinomycetes are Gram-positive, often filamentous, bacteria known for their unsurpassed capacity for the production of secondary metabolites with diverse biological activities. The aim of the present study was to evaluate the antimicrobial, cytotoxic and antioxidant properties of Streptomyces lavendulae strain SCA5. RESULTS: The ethyl acetate extract of SCA5 broth (EA-SCA5) showed antimicrobial activity with MIC value of 31.25 MUg/ml. EA-SCA5 showed good antioxidant potential by scavenging 2, 2-diphenyl-picrylhydrazyl (DPPH) (IC50 507.61 +/- 0.66 MUg/ml), hydroxyl radical (IC50 617.84 +/- 0.57 MUg/ml), nitric oxide (IC50 730.92 +/- 0.81 MUg/ml) and superoxide anion radical (IC50 864.71 +/- 1.15 MUg/ml). The EA-SCA5 also showed strong suppressive effect on rat liver lipid peroxidation (IC50 838.83 +/- 1.18 MUg/ml). The total phenolic content of SCA5 was 577.12 mg of GAE equivalents/gram extract. EA-SCA5 exhibited cytotoxic activity on A549 adenocarcinoma lung cancer cell line. It showed 84.9% activity at 500 MUg/ml with IC50 value of 200 MUg/ml. The gas chromatography mass spectrometry (GC-MS) analysis revealed the presence of one major bioactive compound actinomycin C2. CONCLUSIONS: The results of this study indicate that the EA-SCA5 could be probed further for isolating some medically useful compounds. PMID- 25433534 TI - Early exposure of infants to natural rotavirus infection: a review of studies with human rotavirus vaccine RIX4414. AB - BACKGROUND: Rotaviruses are the leading cause of severe acute gastroenteritis in children aged <5 years worldwide. A live attenuated human rotavirus vaccine, RIX4414 has been developed to reduce the global disease burden associated with rotavirus gastroenteritis. Serum anti-rotavirus immunoglobulin A (IgA) antibody measured in unvaccinated infants during clinical trials of RIX4414 reflects natural rotavirus exposure, and may inform the optimal timing for rotavirus vaccination. METHODS: We reviewed phase II and III randomized, placebo-controlled clinical trials conducted by GlaxoSmithKline Vaccines, Wavre, Belgium between 2000 and 2008 which used the commercial formulation of RIX4414 lyophilized vaccine. We included trials for which demographic data and pre-dose-1 and post last-dose anti-rotavirus IgA antibody status were available from placebo recipients. RESULTS: Sixteen clinical trials met the inclusion criteria. The studies were conducted across Africa (N = 3), Asia (N = 4), Latin America (N = 4), Europe (N = 4) and North America (N = 1). Overall, 46,398 infants were enrolled and among these, 20,099 received placebo. The mean age at pre-dose-1 time point ranged from 6.4 - 12.2 weeks while the mean age at post-last-dose time point ranged from 13.5 - 19.6 weeks. The anti-RV IgA seropositivity rates at both time points were higher in less developed countries of Africa, Asia and Latin America (pre-dose-1: 2.1%-26.3%; post-last-dose: 6.3%-34.8%) when compared to more developed countries of Asia, Europe and North America (pre-dose-1: 0%-9.4%; post-last-dose: 0%-21.3%), indicating that rotavirus infections occurred at a younger age in these regions. CONCLUSION: Exposure to rotavirus infection occurred early in life among infants in most geographical settings, especially in developing countries. These data emphasize the importance of timely rotavirus vaccination within the Expanded Program on Immunization schedule to maximize protection. PMID- 25433532 TI - Gene expression profiling by cDNA-AFLP reveals potential candidate genes for partial resistance of 'President Roulin' against Venturia inaequalis. AB - BACKGROUND: Scab, caused by the fungus Venturia inaequalis, is one of the most important diseases of cultivated apple. While a few scab resistance genes (R genes) governing qualitative resistance have been isolated and characterized, the biological roles of genes governing quantitative resistance, supposed to be more durable, are still unknown. This study aims to investigate the molecular mechanisms involved in the partial resistance of the old Belgian apple cultivar 'President Roulin' against V. inaequalis. RESULTS: A global gene expression analysis was conducted in 'President Roulin' (partially resistant) and in 'Gala' (susceptible) challenged by V. inaequalis by using the cDNA-AFLP method (cDNA Amplified Fragment Length Polymorphism). Transcriptome analysis revealed significant modulation (up- or down-regulation) of 281 out of approximately 20,500 transcript derived fragments (TDFs) in 'President Roulin' 48 hours after inoculation. Sequence annotation revealed similarities to several genes encoding for proteins belonging to the NBS-LRR and LRR-RLK classes of plant R genes and to other defense-related proteins. Differentially expressed genes were sorted into functional categories according to their gene ontology annotation and this expression signature was compared to published apple cDNA libraries by Gene Enrichment Analysis. The first comparison was made with two cDNA libraries from Malus x domestica uninfected leaves, and revealed in both libraries a signature of enhanced expression in 'President Roulin' of genes involved in response to stress and photosynthesis. In the second comparison, the pathogen-responsive TDFs from the partially resistant cultivar were compared to the cDNA library from inoculated leaves of Rvi6 (HcrVf2)-transformed 'Gala' lines (complete disease resistance) and revealed both common physiological events, and notably differences in the regulation of defense response, the regulation of hydrolase activity, and response to DNA damage. TDFs were in silico mapped on the 'Golden Delicious' apple reference genome and significant co-localizations with major scab R genes, but not with quantitative trait loci (QTLs) for scab resistance nor resistance gene analogues (RGAs) were found. CONCLUSIONS: This study highlights possible candidate genes that may play a role in the partial scab resistance mechanisms of 'President Roulin' and increase our understanding of the molecular mechanisms involved in the partial resistance against apple scab. PMID- 25433537 TI - Successful surgical intervention for delayed chylopericardial tamponade following aortic valve replacement: a case report. AB - Chylopericardium is one of the rarest complications of cardiac surgery. It is related to direct or indirect injury to the thoracic duct or its tributaries and can result in serious morbidity or even death. A 77-year-old Japanese woman who had severe aortic stenosis underwent routine aortic valve replacement. At 15 days after surgery, she developed cardiac tamponade, which was caused by chylopericardium. She was successfully treated by direct clipping of a thoracic duct tributary and mass ligation of the thymus. This rare condition needs to be kept in mind as a possible cause of postoperative cardiac tamponade. PMID- 25433535 TI - Overcoming the barriers to diagnosis of Morquio A syndrome. AB - BACKGROUND: Morquio A syndrome is an autosomal recessive lysosomal storage disease often resulting in life-threatening complications. Early recognition and proficient diagnosis is imperative to facilitate prompt treatment and prevention of clinical complications. METHODS: Experts in Asia Pacific reviewed medical records focusing on presenting signs and symptoms leading to a diagnosis of Morquio A syndrome. RESULTS: Eighteen patients (77% female) had a mean (median; min, max) age of 77.1 (42.0; 0.0, 540.0) months at symptom onset, 78.9 (42.0; 4.5, 540.0) months at presentation and 113.8 (60.0; 7.0, 540.0) months at diagnosis. Orthopedic surgeons and pediatricians were most frequently consulted pre-diagnosis while clinical geneticists/metabolic specialists most frequently made the diagnosis. Delayed diagnoses were due to atypical symptoms for 5 patients (28%), while 4 patients (22%) experienced each of subtle symptoms, symptoms commonly associated with other diseases, or false-negative urine glycosaminoglycan analysis. Two patients (11%) each experienced overgrowth within the first year of life. Two patients with Morquio A syndrome (11%) were diagnosed with craniosynostosis and 1 (6%) for each of Legg-Calve-Perthes disease, Leri Weill syndrome, and pseudoachondroplasia. Early radiographic features of Morquio A syndrome led to more efficient diagnosis. CONCLUSIONS: Increased awareness of clinical symptomology overlapping with Morquio A syndrome is essential. Clinicians encountering patients with certain skeletal dysplasia should consider Morquio A syndrome in their differential diagnosis. Atypical or subtle symptoms should not eliminate Morquio A syndrome from the differential diagnosis, especially for patients who may have non-classical phenotype of Morquio A syndrome. PMID- 25433536 TI - Accuracy of invasive arterial pressure monitoring in cardiovascular patients: an observational study. AB - INTRODUCTION: Critically ill patients and patients undergoing high-risk and major surgery, are instrumented with intra-arterial catheters and invasive blood pressure is considered the "gold standard" for arterial pressure monitoring. Nonetheless, artifacts due to inappropriate dynamic response of the fluid-filled monitoring systems may lead to clinically relevant differences between actual and displayed pressure values. We sought to analyze the incidence and causes of resonance/underdamping phenomena in patients undergoing major vascular and cardiac surgery. METHODS: Arterial pressures were measured invasively and, according to the fast-flush Gardner's test, each patient was attributed to one of two groups depending on the presence (R-group) or absence (NR-group) of resonance/underdamping. Invasive pressure values were then compared with the non invasive ones. RESULTS: A total of 11,610 pulses and 1,200 non-invasive blood pressure measurements were analyzed in 300 patients. Ninety-two out of 300 (30.7%) underdamping/resonance arterial signals were found. In these cases (R group) systolic invasive blood pressure (IBP) average overestimation of non invasive blood pressure (NIBP) was 28.5 (15.9) mmHg (P <0.0001) while in the NR group the overestimation was 4.1(5.3) mmHg (P < 0.0001). The mean IBP-NIBP difference in diastolic pressure in the R-group was -2.2 (10.6) mmHg and, in the NR-group -1.1 (5.8) mmHg. The mean arterial pressure difference was 7.4 (11.2) mmHg in the R-group and 2.3 (6.4) mmHg in the NR-group. A multivariate logistic regression identified five parameters independently associated with underdamping/resonance: polydistrectual arteriopathy (P = 0.0023; OR = 2.82), history of arterial hypertension (P = 0.0214; OR = 2.09), chronic obstructive pulmonary disease (P = 0.198; OR = 2.61), arterial catheter diameter (20 vs. 18 gauge) (P < 0.0001; OR = 0.35) and sedation (P = 0.0131; OR = 0.5). The ROC curve for the maximal pressure-time ratio, showed an optimum selected cut-off point of 1.67 mmHg/msec with a specificity of 97% (95% CI: 95.13 to 99.47%) and a sensitivity of 77% (95% CI: 67.25 to 85.28%) and an area under the ROC curve by extended trapezoidal rule of 0.88. CONCLUSION: Physicians should be aware of the possibility that IBP can be inaccurate in a consistent number of patients due to underdamping/resonance phenomena. NIBP measurement may help to confirm/exclude the presence of this artifact avoiding inappropriate treatments. PMID- 25433538 TI - Cervical cancer screening program in Thimphu, Bhutan: population coverage and characteristics associated with screening attendance. AB - BACKGROUND: Bhutan has been engaged in good-quality cytology-based cervical screening since 2000 and has vaccinated >90% girls against human papillomavirus (HPV) since 2010. We explored the characteristics associated with lack of previous screening and screening coverage in women age >=25 years. METHODS: Women were invited at home or during their attendance at 2 outpatient clinics, in the capital, Thimphu, and nearby Lungthenphu. Age-adjusted odds ratios for lack of previous screening by selected characteristics were computed among 1,620 participating women. In Thimphu an invitation registry allowed to estimate screening history not only among participating women but also among additional 500 women who did not accept to join our study. RESULTS: Among women who had a Pap smear, lack of previous screening was associated with age <35 or >=45 years. It was also associated with some occupations; being single, or widowed/separated; and presence of HPV infection. Multiparity and use of contraceptive methods were associated with having been screened. In women invited at home in Thimphu screening history substantially differed by participation. Past screening attendance was 59% among women recruited in the 2 clinics, 53% in women who were invited from home and accepted the invitation, but only 25% in those who refused it. Based on all women recruited from home the estimate of population-based coverage in Thimphu is 34% (95% CI: 31-37). CONCLUSIONS: Transition from an opportunistic screening to an all-reaching population-based screening is yet to be achieved in Bhutan, even in the capital. Better ways to target never-screened women are needed. PMID- 25433540 TI - SEURAT: Safety Evaluation Ultimately Replacing Animal Testing--recommendations for future research in the field of predictive toxicology. AB - The development of non-animal methodology to evaluate the potential for a chemical to cause systemic toxicity is one of the grand challenges of modern science. The European research programme SEURAT is active in this field and will conclude its first phase, SEURAT-1, in December 2015. Drawing on the experience gained in SEURAT-1 and appreciating international advancement in both basic and regulatory science, we reflect here on how SEURAT should evolve and propose that further research and development should be directed along two complementary and interconnecting work streams. The first work stream would focus on developing new 'paradigm' approaches for regulatory science. The goal here is the identification of 'critical biological targets' relevant for toxicity and to test their suitability to be used as anchors for predicting toxicity. The second work stream would focus on integration and application of new approach methods for hazard (and risk) assessment within the current regulatory 'paradigm', aiming for acceptance of animal-free testing strategies by regulatory authorities (i.e. translating scientific achievements into regulation). Components for both work streams are discussed and may provide a structure for a future research programme in the field of predictive toxicology. PMID- 25433539 TI - Repetitive transcranial magnetic stimulation as an augmentative strategy for treatment-resistant depression, a meta-analysis of randomized, double-blind and sham-controlled study. AB - BACKGROUND: Dozens of randomized controlled trials (RCTs) and meta-analyses have demonstrated the efficacy of repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder (MDD) treatment, but there has not been a meta analysis report which evaluates the efficacy and tolerability of rTMS used as an augmentative strategy for antidepressants in treatment-resistant depression (TRD) treatment. We thus conducted this meta-analysis, aimed at clarifying whether rTMS enhances the efficacy of TRD. METHODS: We searched MEDLINE and Cochrane Central Register of Controlled Trials for RCTs for studying the efficacy of rTMS versus (vs) sham condition when combined with antidepressants in TRD treatment, and screened the references of the previous meta-analysis about the rTMS for MDD treatment. Response rates and NNT were chose as the primary outcomes, and remission rates, change from baseline of HAMD scores, dropouts were used as secondary outcomes. For dichotomous data, an intention-to-treat analysis principle was applied; for continuous data, we calculated the standard mean difference between groups with a random-effect model. Sensitivity analysis was done to explore the source of heterogeneity and the factors which potentially impact the efficacy. RESULTS: Seven RCTs were finally included in the meta analysis. The total sample size was 279, with 171 in the rTMS group and 108 in the sham group. The pooled response and remission rate for the rTMS and sham group was 46.6% and 22.1%, respectively; the pooled odds ratio (OR) was 5.12 [95% confidence interval (CI) 2.11-12.45, z = 3.60, p = 0.0003, and the associated number needed to treat (NNT) was 3.4. rTMS group achieved a significant reduction of HAMD score than the sham group, the pooled SMD of change from baseline was 0.86 [95% confidence interval (CI) 0.57-1.15, z = 5.75, p < 0.00001]. Because of the small number of included RCTs, the preplanned sensitivity and subgroup analyses were finally abandoned. The dropouts in both groups were relatively low, indicating the high acceptability of rTMS. CONCLUSIONS: For TRD patients, augmentative rTMS after the failure of medications significantly increases the effect of antidepressants, and rTMS was a safe strategy with relatively low adverse events and low dropout rate, suggesting that augmentative rTMS is an effective intervention for TRD. PMID- 25433541 TI - Magnetic controlled growth rods versus conventional growing rod systems in the treatment of early onset scoliosis: a cost comparison. AB - PURPOSE: To evaluate the cost differences between a conventional growth rod system (CGRS) and magnetic controlled growth rods (MCGR) in treating early onset scoliosis (EOS) over a projected 5 year period. We hypothesise that the high initial outlay for MCGR would be recouped from fewer admissions and surgical procedures over the lifetime of the implant. METHODS: The costs of all aspects of treatment for 14 patients undergoing conversion from CGRS to MGRS were collected over a 3 year period. The costs of all aspects of each treatment including clinic visits, hospital stay, theatre and complications were calculated and projected over the lifetime of each device. RESULTS: The initial outlay for insertion for MCGR was L12,913 more than the CGRS. There were significant cost savings for each lengthening which projected over the 5 year lifetime amounted to a cost saving of over L8,000 per patient. CONCLUSIONS: Magnetic controlled growth rods reduce the need for multiple invasive procedures in the management of EOS. The implant has a significant projected cost saving in comparison to CGRS. PMID- 25433542 TI - Fraction distribution and bioavailability of sediment heavy metals in the environment surrounding MSW landfill: a case study. AB - The aim of this study was to characterize the sediment samples from vicinity of a landfill in Qayen City, Iran. The samples were obtained from four different sampling stations. Sequential extraction was performed via a four-step procedure defined to evaluate the distribution of the element fraction in various samples. In the stations 3 and 4, Cd was found in large quantities during the first extraction F1, accounting for 40.4 and 38.7%, respectively. Pb was primarily presented in F2 of station 1 (approximately 44.80%), station 2 (approximately 41.8%), and station 4 (approximately 37.7%). Moreover, principal component analysis showed that heavy metal fraction in the sediment samples can be explained by two principal components (PCs). PC1 represented Cd, Cr, Ni, and Zn, while PC2 represented Pb and Cu. Pearson correlation coefficient indicated significant correlations in Cu-Pb, Zn-Cu, and Cr-Zn pairings. The present study concluded that the spatial distributions of sediment heavy metals were influenced by MSW landfill. PMID- 25433543 TI - Influence of organic carbon and metal oxide phases on sorption of 2,4,6 trichlorobenzoic acid under oxic and anoxic conditions. AB - Chlorobenzoic acids represent crucial recalcitrant metabolites in the environment; thus, the influence of soil components on the sorption of 2,4,6 trichlorobenzoic acid (TCB) under oxic and anoxic conditions was studied. The surficial physiognomies of untreated and isolated soil samples were studied using FTIR, XRD, specific surface area, and PZC determination. The roles of redox potential, dissolved organic carbon (DOC), and pH, particularly under anoxic condition, were appraised. Batch equilibrium adsorption studies on soils of variable Fe/Mn oxides and organic carbon showed that adsorption was low across all components (log Koc = 0.82-3.10 Lg(-1)). The sorption of 2,4,6-TCB was well described by the pseudo second-order kinetic model. The fluctuation of both redox potential and pH during anoxic experiment had a negative impact on the sorption, partitioning, and the oxidation of organic matter. Linear relationships were observed for Kd with both soil total organic carbon (TOC) and surface area (SA). The results showed the existence of DOC-mediated sorption of 2,4,6-TCB which seems to be enhanced at lower pH. The reductive dissolution, particularly of iron compounds, possibly impeded sorption of 2,4,6-TCB under anoxic condition. It could be inferred that habitats dominated by fluctuating oxygen concentrations are best suited for the development of environmental conditions capable of mineralizing 2,4,6-TCB and similar xenobiotics. PMID- 25433544 TI - Heavy metals in apple orchard soils and fruits and their health risks in Liaodong Peninsula, Northeast China. AB - This study aimed to assess the heavy metal concentrations in soils and fruits and their possible human health risk in apple orchards of Liaodong Peninsula-a well known fruit-producing area of China. The soil pollution index (PI) and health risk assessment methods (daily intake of metals (DIM) and health risk index (HRI)) were employed to explore the soil pollution levels and the potential health hazards of heavy metals in fruits. The results showed that all orchard soils were with low PI values (PI <=1) for Cd and Zn, while 2.78 and 5.56% of the soil samples exceeded the allowable levels of Cr and Cu for orchard soil, respectively. The Cd, Cu, and Zn concentrations for the apple flesh samples were all lower than the national maximum permissible concentrations. While 6.34% of apple peel samples for Cd, 76.5% of apple peel samples and 65.6% of apple flesh samples for Cr, and 28.1% of apple peel samples for Zn exceeded the national maximum permissible levels, respectively. Furthermore, both the DIM and the HRI values for all the apple flesh samples were within the safe limits, indicating that no health risk was found for heavy metals in the fruits of the study area. In order to protect the consumers from fruits that might cause health risks, results from this study suggested that the regular survey of heavy metal pollution levels should be conducted for the orchards of Liaodong Peninsula. PMID- 25433545 TI - Assessment of water quality parameters using multivariate analysis for Klang River basin, Malaysia. AB - This case study uses several univariate and multivariate statistical techniques to evaluate and interpret a water quality data set obtained from the Klang River basin located within the state of Selangor and the Federal Territory of Kuala Lumpur, Malaysia. The river drains an area of 1,288 km(2), from the steep mountain rainforests of the main Central Range along Peninsular Malaysia to the river mouth in Port Klang, into the Straits of Malacca. Water quality was monitored at 20 stations, nine of which are situated along the main river and 11 along six tributaries. Data was collected from 1997 to 2007 for seven parameters used to evaluate the status of the water quality, namely dissolved oxygen, biochemical oxygen demand, chemical oxygen demand, suspended solids, ammoniacal nitrogen, pH, and temperature. The data were first investigated using descriptive statistical tools, followed by two practical multivariate analyses that reduced the data dimensions for better interpretation. The analyses employed were factor analysis and principal component analysis, which explain 60 and 81.6% of the total variation in the data, respectively. We found that the resulting latent variables from the factor analysis are interpretable and beneficial for describing the water quality in the Klang River. This study presents the usefulness of several statistical methods in evaluating and interpreting water quality data for the purpose of monitoring the effectiveness of water resource management. The results should provide more straightforward data interpretation as well as valuable insight for managers to conceive optimum action plans for controlling pollution in river water. PMID- 25433546 TI - Geostatistics-based groundwater-level monitoring network design and its application to the Upper Floridan aquifer, USA. AB - A geostatistical method was applied to optimize an existing groundwater-level monitoring network in the Upper Floridan aquifer for the South Florida Water Management District in the southeastern United States. Analyses were performed to determine suitable numbers and locations of monitoring wells that will provide equivalent or better quality groundwater-level data compared to an existing monitoring network. Ambient, unadjusted groundwater heads were expressed as salinity-adjusted heads based on the density of freshwater, well screen elevations, and temperature-dependent saline groundwater density. The optimization of the numbers and locations of monitoring wells is based on a pre defined groundwater-level prediction error. The newly developed network combines an existing network with the addition of new wells that will result in a spatial distribution of groundwater monitoring wells that better defines the regional potentiometric surface of the Upper Floridan aquifer in the study area. The network yields groundwater-level predictions that differ significantly from those produced using the existing network. The newly designed network will reduce the mean prediction standard error by 43% compared to the existing network. The adoption of a hexagonal grid network for the South Florida Water Management District is recommended to achieve both a uniform level of information about groundwater levels and the minimum required accuracy. It is customary to install more monitoring wells for observing groundwater levels and groundwater quality as groundwater development progresses. However, budget constraints often force water managers to implement cost-effective monitoring networks. In this regard, this study provides guidelines to water managers concerned with groundwater planning and monitoring. PMID- 25433547 TI - Different exposure of infants and adults to ultrafine particles in the urban area of Barcelona. AB - Air pollutants have been linked with a number of adverse health effects. Children are especially sensitive, particularly when they get close to the exhaust emissions of the vehicles on the street. The objective of this study was to measure the different exposure of infants and adults to ultrafine particles (UFP) as a surrogate marker of air pollution and of risk of deleterious health effects. Two different portable P-TRAK were used to measure simultaneously exposure to UFPs at different heights, one corresponding to the height of an infant in a stroller (0.55 m) and the other one to the height of the face of an adult pedestrian (1.70 m). Measurements were taken on three different streets with high traffic density in Barcelona, in 10 consecutive days during spring, with two sampling sessions of 1 h each day, moving afoot and taking into account temperature, humidity, and wind speed. Fifty-two thousand and eight (52,008) paired values were obtained, and the results showed about 10% higher levels of UFP concentration at 0.55 m (48,198 +/- 25,296 pt/cm(3)) compared to 1.70 m (43,151 +/- 22,517 pt/cm(3)). Differences between working and nonworking days were observed. Concentration patterns and variation by days of the week and time periods were related to traffic intensity. This study revealed that infants transported by stroller in urban areas are more exposed to air pollution than walking adults. As infants are more vulnerable and UFP have more effects on their health, measures should be taken to protect this population when it is transported in the street. PMID- 25433548 TI - Atypical presentation of a newborn with Apert syndrome. AB - INTRODUCTION: Apert syndrome is a rare syndrome characterized by a consistent phenotype including bilateral coronal suture synostosis with an enlarged anterior fontanel, midface hypoplasia, and complex symmetric syndactyly of hands and feet. CASE REPORT: We present a boy with Apert syndrome caused by the pathogenic c.755C > G p.Ser252Trp mutation in the FGFR2 gene with atypical characteristics, including premature fusion of the metopic suture with a small anterior fontanel, hypotelorism, and a massive posterior fontanel. Directly after birth, he showed papilledema, epilepsy, and central apneas. CONCLUSION: We present a newborn with Apert syndrome with atypical craniofacial presentation. PMID- 25433549 TI - Apoptosis induction by an analog of curcumin (BDMC-A) in human laryngeal carcinoma cells through intrinsic and extrinsic pathways. AB - BACKGROUND: Head and neck cancer is the sixth most frequently occurring cancer worldwide and accounts for about 2% of all cancer-related deaths annually. Curcumin is a well-known chemopreventive agent, and apoptosis induction by curcumin has been reported in many cancer cell types. We synthesized an ortho hydroxy substituted analog of curcumin, bisdemethoxycurcumin analog (BDMC-A), and aimed to demarcate the apoptotic effects induced by BDMC-A on human laryngeal cancer Hep-2 cells and to compare these effects with those induced by curcumin. METHODS: We evaluated the apoptotic effects of BDMC-A in comparison to those of curcumin on Hep-2 cells by performing Western blotting, RT-PCR, fluorescent staining and DNA fragmentation assays. In addition, we carried out an in silico molecular docking study on the EGFR kinase domain. RESULTS: We found that BDMC-A can induce apoptosis in Hep-2 cells by regulating the expression of both intrinsic and extrinsic apoptotic proteins, i.e., Bcl-2, Bax, apoptososme complex and death receptors, more efficiently than curcumin. We also observed increased nuclear fragmentation and chromatin condensation after BDMC-A treatment compared to curcumin treatment. Depolarized mitochondria and ROS generation was well pronounced in both BDMC-A and curcumin treated Hep-2 cells. Our in silico molecular docking study on the EGFR kinase domain revealed that BDMC-A may dock more efficiently than curcumin. CONCLUSIONS: From our results we conclude that BDMC-A can induce apoptosis in Hep-2 laryngeal carcinoma cells more effectively than curcumin, and that this activity can be attributed to the presence of a hydroxyl group at the ortho position within this compound. PMID- 25433551 TI - Synergistic action modes of arabinan degradation by exo- and endo-arabinosyl hydrolases. AB - Two recombinant arabinosyl hydrolases, alpha-L-arabinofuranosidase from Geobacillus sp. KCTC 3012 (GAFase) and endo-(1,5)-alpha-L-arabinanase from Bacillus licheniformis DSM13 (BlABNase), were overexpressed in Escherichia coli, and their synergistic modes of action against sugar beet (branched) arabinan were investigated. Whereas GAFase hydrolyzed 35.9% of L-arabinose residues from sugar beet (branched) arabinan, endo-action of BlABNase released only 0.5% of L arabinose owing to its extremely low accessibility towards branched arabinan. Interestingly, the simultaneous treatment of GAFase and BlABNase could liberate approximately 91.2% of L-arabinose from arabinan, which was significantly higher than any single exo-enzyme treatment (35.9%) or even stepwise exo- after endo enzyme treatment (75.5%). Based on their unique modes of action, both exo- and endo-arabinosyl hydrolases can work in concert to catalyze the hydrolysis of arabinan to L-arabinose. At the early stage in arabinan degradation, exo-acting GAFase could remove the terminal arabinose branches to generate debranched arabinan, which could be successively hydrolyzed into arabinooligosaccharides via the endoaction of BlABNase. At the final stage, the simultaneous actions of exo- and endo-hydrolases could synergistically accelerate the L-arabinose production with high conversion yield. PMID- 25433550 TI - MiRNA expression profile and miRNA-mRNA integrated analysis (MMIA) during podocyte differentiation. AB - The podocyte is a prominent cell type, which encases the capillaries of glomerulus. Podocyte-selective deletion of Dicer or Drosha was reported to induce proteinuria and glomerulosclerosis, suggesting the essential role of microRNA (miRNA) in podocytes for renal function. However, no comprehensive miRNA expression or miRNA-mRNA integrated analysis (MMIA) can be found during podocyte differentiation. Herein, miRNA and mRNA microarrays are presented, which were carried out in differentiated and undifferentiated mouse podocyte cell lines (MPC5). A total of 50 abnormal miRNAs (26 down-regulated and 24 up-regulated) were identified in differentiated and undifferentiated podocytes. Using MMIA, 80 of the 743 mRNAs (>twofold change) were predicted for potential crosstalk with 30 miRNAs of the 50 abnormal miRNAs. In addition, the gene ontology of mRNAs and the pathway analysis of miRNAs revealed a new potential-regulated network during podocyte differentiation. The expressions of three remarkably changed miRNAs (miR 34c, miR-200a and miR-467e) and four mRNAs (Runx1t1, Atp2a2, Glrp1, and Mmp15), were randomly chosen for further validation by the quantitative real-time polymerase chain reaction, and their expression trends were consistent with the microarray data. Reference searching was also conducted to confirm our data and to find potential new molecules and miRNA-target pairs involved in the podocyte differentiation. The dual luciferase reporter assay for miR-200a/GLRX and let 7b/ARL4D confirmed the prediction of MMIA. The results of this study provide a detailed integration of mRNA and miRNA during podocyte differentiation. The molecular integration mode will open up new perspectives for a better understanding of the mechanism during podocyte differentiation. PMID- 25433552 TI - A Simple, Single Triplex PCR of IS6110, IS1081, and 23S Ribosomal DNA Targets, Developed for Rapid Detection and Discrimination of Mycobacterium from Clinical Samples. AB - Tuberculosis (TB) is the most common mycobacterial infection in developing countries, requiring a rapid, accurate, and well-differentiated detection/diagnosis. For the rapid detection and discrimination of Mycobacterium tuberculosis complex (MTC) from nontuberculous mycobacteria (NTM), a novel, simple, and primer-combined single-step multiplex PCR using three primer pairs (6110F-6110R, 1081F-1081R, and 23SF-23SR; annealing on each of IS6110, IS1081, and 23S rDNA targets), hereafter referred to as a triplex PCR, has been developed and evaluated. The expected product for IS6110 is 416 bp, for IS1081 is 300 bp, and for 23S rDNA is 206 bp by single PCR, which was used to verify the specificity of primers and the identity of MTC using DNA extracted from the M. tuberculosis H37Rv reference strain (ATCC, USA) and other mycobacteria other than tuberculosis (MOTT) templates. The triplex PCR assay showed 100% specificity and 96% sensitivity; the limit of detection for mycobacteria was ~100 fg; and it failed to amplify any target from DNA of MOTT (50 samples tested). Of 307 blinded clinical samples, overall 205 positive M. tuberculosis samples were detected by single PCR, 142 by conventional culture, and 90 by AFB smear methods. Remarkably, the triplex PCR could subsequently detect 55 positive M. tuberculosis from 165 culture-negative and 115 from 217 AFB smear-negative samples. The triplex PCR, targeting three regions in the M. tuberculosis genome, has proved to be an efficient tool for increasing positive detection/ discrimination of this bacterium from clinical samples. PMID- 25433553 TI - Lactobacillus rhamnosus GG Reverses Insulin Resistance but Does Not Block Its Onset in Diet-Induced Obese Mice. AB - Recently, Lactobacillus rhamnosus GG (LGG) was shown to exert insulin-sensitizing and adiposity-reducing effects in high-fat (HF) diet-fed mice. In the present study, we observed that the effects were correlated with the extent of dysbiosis induced by HF diet feeding before LGG administration. LGG-treated mice were protected from HF diet-induced adiposity and/ or insulin resistance when LGG was treated after, not along with, HF diet feeding. Results indicate that, under HF dietary condition, supplemented LGG reverses insulin resistance, but does not block its onset. PMID- 25433554 TI - A review of statin use and prostate cancer. AB - Prostate cancer is the second most common cause of cancer and, when it metastasizes, has a high mortality rate. Statins may affect prostate cancer progression through cholesterol- and pleiotropic-mediated effects. The data on statin effects on prostate cancer has been mixed with benefit most likely occurring in reducing prostate cancer recurrence after radiation therapy and reduced mortality due to prostate cancer. More research is needed in this area to better characterize potential statin-mediated mechanisms that affect cancer. Also, future studies should report patients' anatomic/prognostic stage based on the updated staging system of the American Joint Committee on Cancer, which is a more effective predictor of recurrence and mortality than anatomic stage alone. PMID- 25433556 TI - Patterns of progression in pediatric patients with high-grade glioma or diffuse intrinsic pontine glioma treated with Bevacizumab-based therapy at diagnosis. AB - There is a paucity of data regarding patterns of progression in children with high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG) treated with bevacizumab (BVZ) at diagnosis. We performed a retrospective study of 20 children with HGG or DIPG who received BVZ-based therapy at diagnosis on, or according to, a bi-institutional study. Magnetic resonance imaging (MRI) characteristics of first and most recent progressions were reviewed. Comparison was made to a control group of 19 patients who never received BVZ. Imaging definitions of progressive disease (PD) were local: at primary site or within 2 cm, contiguous; diffuse: >2 cm away but contiguous with primary site, ill-defined and infiltrative; distant: new, non-contiguous disease. In the BVZ-treated group, 14 patients had DIPG, six patients had HGG. Median age was 7 years (range: 3-21). Median time to PD and follow-up were 8.8 months (range 4-21) and 11 months (range: 6-25), respectively. Among 14 patients with PD, 8 (57.1 %) had local PD, 6 (42.9 %) had local and diffuse/distant PD, at initial progression. At most recent progression, a median of 10.8 months (range 6-25) from diagnosis, 10 of 14 (71.4 %) had at least diffuse (n = 8), or distant (n = 6) PD. In the comparable control group, 15 patients had PD: 11(73.3 %) local, 4 (26.7 %) local and diffuse/distant PD at first and most recent progressions. Based on these data, we postulate that BVZ may lead to a higher incidence of distant and diffuse disease in newly-diagnosed children with HGG or DIPG who received BVZ-based therapy. PMID- 25433555 TI - Epigenetic reprogramming in atherosclerosis. AB - Recent data support the involvement of epigenetic alterations in the pathogenesis of atherosclerosis. The most widely investigated epigenetic mechanism is DNA methylation although also histone code changes occur during the diverse steps of atherosclerosis, such as endothelial cell proliferation, vascular smooth muscle cell (SMC) differentiation, and inflammatory pathway activation. In this review, we focus on the main genes that are epigenetically modified during the atherogenic process, particularly nitric oxide synthase (NOS), estrogen receptors (ERs), collagen type XV alpha 1 (COL15A1), vascular endothelial growth factor receptor (VEGFR), and ten-eleven translocation (TET), which are involved in endothelial dysfunction; gamma interferon (IFN-gamma), forkhead box p3 (FOXP3), and tumor necrosis factor-alpha (TNF-alpha), associated with atherosclerotic inflammatory process; and p66shc, lectin-like oxLDL receptor (LOX1), and apolipoprotein E (APOE) genes, which are regulated by high cholesterol and homocysteine (Hcy) levels. Furthermore, we also discuss the role of non-coding RNAs (ncRNA) in atherosclerosis. NcRNAs are involved in epigenetic regulation of endothelial function, SMC proliferation, cholesterol synthesis, lipid metabolism, and inflammatory response. PMID- 25433558 TI - An in silico target identification using Boolean network attractors: Avoiding pathological phenotypes. AB - Target identification aims at identifying biomolecules whose function should be therapeutically altered to cure the considered pathology. An algorithm for in silico target identification using Boolean network attractors is proposed. It assumes that attractors correspond to phenotypes produced by the modeled biological network. It identifies target combinations which allow disturbed networks to avoid attractors associated with pathological phenotypes. The algorithm is tested on a Boolean model of the mammalian cell cycle and its applications are illustrated on a Boolean model of Fanconi anemia. Results show that the algorithm returns target combinations able to remove attractors associated with pathological phenotypes and then succeeds in performing the proposed in silico target identification. However, as with any in silico evidence, there is a bridge to cross between theory and practice. Nevertheless, it is expected that the algorithm is of interest for target identification. PMID- 25433557 TI - CXXC5 regulates differentiation of C2C12 myoblasts into myocytes. AB - CXXC5 is a member of the CXXC-type zinc-finger domain containing protein family, which is suggested to function in gene transcription, cell adhesion and cytoskeleton organization. Previous studies have revealed that CXXC5 is expressed in skeletal muscle, but whether it regulates skeletal myogenesis is yet unknown. Here, we screened for the possible signaling pathways in which CXXC5 might participate using luciferase gene reporters. The results indicated that CXXC5 significantly increased the activities of the promoters of genes involved in skeletal muscle differentiation. We therefore studied the role of CXXC5 during skeletal myogenesis in C2C12 myoblasts. Our findings suggest that overexpression of CXXC5 in C2C12 myoblasts facilitated myocyte differentiation, while RNAi interference of CXXC5 significantly inhibited the differentiation of C2C12 myoblasts. This study suggests that CXXC5 plays a significant role in regulating skeletal myogenesis. PMID- 25433559 TI - Bicoid mRNA diffusion as a mechanism of morphogenesis in Drosophila early development. AB - We show that mRNA diffusion is the main morphogenesis mechanism that consistently explains the establishment of Bicoid protein gradients in the embryo of Drosophila, contradicting the current view of protein diffusion. Moreover, we show that if diffusion for both bicoid mRNA and Bicoid protein were assumed, a steady distribution of Bicoid protein with a constant concentration along the embryo would result, contradicting observations. PMID- 25433560 TI - Characterization of P5CS gene in Calotropis procera plant from the de novo assembled transcriptome contigs of the high-throughput sequencing dataset. AB - The wild plant known as Calotropis procera is important in medicine, industry and ornamental fields. Due to spread in areas that suffer from environmental stress, it has a large number of tolerance genes to environmental stress such as drought and salinity. Proline is one of the most compatible solutes that accumulate widely in plants to tolerate unfavorable environmental conditions. Plant proline synthesis depends on Delta-pyrroline-5-carboxylate synthase (P5CS) gene. But information about this gene in C. procera is unavailable. In this study, we uncovered and characterized P5CS (P5CS, NCBI accession no. KJ020750) gene in this medicinal plant from the de novo assembled transcriptome contigs of the high throughput sequencing dataset. A number of GenBank accessions for P5CS sequences were blasted with the recovered de novo assembled contigs. Homology modeling of the deduced amino acids (NCBI accession No. AHM25913) was further carried out using Swiss-Model, accessible via the EXPASY. Superimposition of C. procera P5CS like full sequence model on Homo sapiens (P5CS_HUMAN, UniProt protein accession no. P54886) was constructed using RasMol and Deep-View programs. The functional domains of the novel P5CS amino acids sequence were identified from the NCBI conserved domain database (CDD) that provide insights into sequence structure/function relationships, as well as domain models imported from a number of external source databases (Pfam, SMART, COG, PRK, TIGRFAM). PMID- 25433561 TI - Cytogenetic abnormalities in Tunisian women with premature ovarian failure. AB - To identify the distribution of chromosome abnormalities among Tunisian women with premature ovarian failure (POF) referred to the department of Cytogenetic at the Pasteur Institute of Tunis (Tunisia), standard cytogenetic analysis was carried out in a total of 100 women younger than 40 affected with premature ovarian failure. We identified 18 chromosomal abnormalities, including seven X numerical anomalies in mosaic and non-mosaic state (45,X; 47,XXX), four sex reversal, three X-structural abnormalities (terminal deletion and isochromosomes), one autosomal translocation and one supernumerary marker. The overall prevalence of chromosomal abnormalities was 18% in our cohort. X chromosome aneuploidy was the most frequent aberration. This finding confirms the essential role of X chromosome in ovarian function and underlies the importance of cytogenetic investigations in the routine management of POF. PMID- 25433562 TI - Spatio-temporal variability of faunal and floral assemblages in Mediterranean temporary wetlands. AB - Six temporary wetlands in the region of Sejenane (Mogods, NW Tunisia) were studied in order to characterize the aquatic flora and fauna and to quantify their spatio-temporal variability. Samplings of aquatic fauna, phytosociological releves, and measurements of the physicochemical parameters of water were taken during four different field visits carried out during the four seasons of the year (November 2009-July 2010). Despite the strong anthropic pressures on them, these temporary wetlands are home to rich and diversified biodiversity, including rare and endangered species. Spatial and temporal variations affect fauna and flora differently, as temporal variability influences the fauna rather more than the plants, which are relatively more dependent on spatial factors. These results demonstrate the interest of small water bodies for maintaining biodiversity at the regional level, and thus underscore the conservation issues of Mediterranean temporary wetlands that are declining on an ongoing basis currently. PMID- 25433563 TI - Resurrection of Indian Ocean humbug damselfish, Dascyllus abudafur (Forsskal) from synonymy with its Pacific Ocean sibling, Dascyllus aruanus (L.). AB - Previous phylogeographic studies of the humbug damselfish, a widespread Indo-West Pacific coral reef fish, have revealed a split of two main mitochondrial lineages distributed on either side of the Indo-Pacific barrier. This has been interpreted as the result of vicariance. It has been hypothesized that reproductive barriers might currently limit gene flow between humbug damselfish populations from the Indian Ocean and the Pacific Ocean. In this study, we review the published phylogeographic information to update the distribution of the two main mitochondrial lineages of humbug damselfish. The Indian lineage was distributed from the Red Sea to the eastern extremity of the Sunda Shelf while the Pacific lineage, which diverged from the former by 0.6% net nucleotide divergence and diagnostic substitutions at three nucleotide sites at the cytochrome b locus, was distributed east and north of the Sunda Shelf. The two forms, which are also genetically distinct at nuclear loci, were also characterized by distinct pigmentation patterns. We argue that the two forms represent geminate species. Epithet aruanus Linnaeus is maintained for the Pacific Ocean humbug damselfish while epithet abudafur (Forsskal) is here resurrected for the Indian Ocean humbug damselfish. Future studies should focus on the population genetic structure of the transition zone between Dascyllus abudafur and D. aruanus. PMID- 25433564 TI - Contrasting land uses in Mediterranean agro-silvo-pastoral systems generated patchy diversity patterns of vascular plants and below-ground microorganisms. AB - The aims of this paper were (i) to define how contrasting land uses affected plant biodiversity in Mediterranean agro-silvo-pastoral-systems across a gradient of disturbance regimes: cork oak forests, secondary grasslands, hay crops, grass covered vineyards, tilled vineyards; (ii) to determine whether these patterns mirrored those of below-ground microorganisms and whether the components of gamma diversity followed a similar model. The disturbance regimes affected plant assemblage composition. Species richness decreased with increasing land use intensity, the Shannon index showed the highest values in grasslands and hay crops. Plant assemblage composition patterns mirrored those of Basidiomycota and Ascomycota. Richness in Basidiomycota, denitrifying bacteria and microbial biomass showed the same trend as that observed for vascular plant richness. The Shannon index pattern of below-ground microorganisms was different from that of plants. The plant gamma-diversity component model weakly mirrored those of Ascomycota. Patchy diversity patterns suggest that the maintenance of contrasting land uses associated with different productions typical of agro-silvo-pastoral systems can guarantee the conservation of biodiversity. PMID- 25433565 TI - [Role of imaging in cases of bleeding after spontaneous or induced abortion]. AB - Post-abortum hemorrhage is a common clinical situation and etiological diagnosis has to be made early to avoid further complications such as persistent bleeding, infection or adhesions that may compromise fertility. Retained products of conception are the most common cause of bleeding. The diagnosis is based on endovaginal color doppler ultrasound showing a thickened and hypervascular endometrial echo-complex extending partly to the myometrium. The main differential diagnosis is uterine arteriovenous malformation, mostly iatrogenic. Diagnosis is based on the presence of myometrial confluent cystic lesions filled with turbulent and high velocity arterial flow on endovaginal color doppler ultrasound. The distinction between these two etiologies of post-abortion bleeding is mandatory because of totally different treatment: typically medical and/or surgical in case of retained products of conception and by selective arterial embolization in case of vascular malformation. PMID- 25433566 TI - Myh11(R247C/R247C) mutations increase thoracic aorta vulnerability to intramural damage despite a general biomechanical adaptivity. AB - Genetic studies in patients reveal that mutations to genes that encode contractile proteins in medial smooth muscle cells can cause thoracic aortic aneurysms and dissections. Mouse models of such mutations, including Acta2(-/-) and Myh11(R247C/R247C), surprisingly do not present with any severe vascular phenotype under normal conditions. This observation raises the question whether these mutations nevertheless render the thoracic aorta increasingly vulnerable to aneurysms or dissections in the presence of additional, epigenetic, factors such as hypertension, a known risk factor for thoracic aortic disease. Accordingly, we compared the structure and biaxial mechanical properties of the ascending and descending thoracic aorta from male wild-type and Myh11(R247C/R247C) mice under normotension and induced hypertension. On average, the mutant aortas exhibited near normal biomechanics under normotensive hemodynamics and near normal adaptations to hypertensive hemodynamics, yet the latter led to intramural delaminations or premature deaths in over 20% of these mice. Moreover, the delaminated vessels exhibited localized pools of mucoid material, similar to the common histopathologic characteristic observed in aortas from humans affected by thoracic aortic aneurysms and dissections. The present findings suggest, therefore, that mutations to smooth muscle cell contractile proteins may place the thoracic aorta at increased risk to epigenetic factors and that there is a need to focus on focal, not global, changes in aortic structure and properties, including the pooling of glycosaminoglycans/proteoglycans that may lead to thoracic aortic dissection. PMID- 25433567 TI - Error analysis of cine phase contrast MRI velocity measurements used for strain calculation. AB - Cine Phase Contrast (CPC) MRI offers unique insight into localized skeletal muscle behavior by providing the ability to quantify muscle strain distribution during cyclic motion. Muscle strain is obtained by temporally integrating and spatially differentiating CPC-encoded velocity. The aim of this study was to quantify CPC measurement accuracy and precision and to describe error propagation into displacement and strain. Using an MRI-compatible jig to move a B-gel phantom within a 1.5 T MRI bore, CPC-encoded velocities were collected. The three orthogonal encoding gradients (through plane, frequency, and phase) were evaluated independently in post-processing. Two systematic error types were corrected: eddy current-induced bias and calibration-type error. Measurement accuracy and precision were quantified before and after removal of systematic error. Through plane- and frequency-encoded data accuracy were within 0.4 mm/s after removal of systematic error - a 70% improvement over the raw data. Corrected phase-encoded data accuracy was within 1.3 mm/s. Measured random error was between 1 to 1.4 mm/s, which followed the theoretical prediction. Propagation of random measurement error into displacement and strain was found to depend on the number of tracked time segments, time segment duration, mesh size, and dimensional order. To verify this, theoretical predictions were compared to experimentally calculated displacement and strain error. For the parameters tested, experimental and theoretical results aligned well. Random strain error approximately halved with a two-fold mesh size increase, as predicted. Displacement and strain accuracy were within 2.6 mm and 3.3%, respectively. These results can be used to predict the accuracy and precision of displacement and strain in user-specific applications. PMID- 25433568 TI - A new stage of sentinel node navigation surgery in early gastric cancer. AB - Sentinel node (SN) navigation surgery is expected to realize organ- and function preserving surgery with SN mapping, and has been applied in operations for breast cancer and melanoma. But there has been no definite evidence for the SN concept in gastric cancer. A prospective multicenter trial to confirm the SN concept for gastric cancer conducted by the Japan Society of Sentinel Node Navigation Surgery reported that the SN detection rate, sensitivity of positive SNs, and accuracy of nodal status are 97.5% (387/397), 93% (53/57), and 99% (383/387), respectively. A detailed analysis of the trial suggested that strictly the "lymphatic basin concept" rather than the "SN concept" was confirmed in early gastric cancer. The Japan Society of Sentinel Node Navigation Surgery started a new trial of function preserving gastrectomy with lymphatic basin dissection (LBD) for early gastric cancer without metastasis in SNs on the basis of this promising outcome of the trial. It is supposed that LBD guarantees curability in SN navigation surgery for early gastric cancer. Full-thickness resection or endoscopic submucosal dissection in combination with laparoscopic LBD will soon be a new treatment option for early gastric cancer. PMID- 25433569 TI - [Congenital afibrinogenemia: a case report]. AB - Afibrinogenemia is a rare autosomal recessive disease. Its clinical manifestations vary in severity, ranging from minimal bleeding to cataclysmic hemorrhage, and can begin at birth or, sometimes, later. We report a case of a female infant, 10 months of age, hospitalized in the pediatrics department because of a postvaccination hematoma. Biologic exploration found congenital afibrinogenemia. Through this case, we review the clinical features of this disease and its management. PMID- 25433570 TI - [Large hilum in a child with sickle cell anemia. Extramedullary hematopoiesis]. PMID- 25433571 TI - All in the family: Clueing into the link between metabolic syndrome and hematologic malignancies. AB - Metabolic syndrome constitutes a constellation of findings including central obesity, insulin resistance/type 2 diabetes mellitus (DM), dyslipidemia and hypertension. Metabolic syndrome affects 1 in 4 adults in the United States and is rapidly rising in prevalence, largely driven by the dramatic rise in obesity and insulin resistance/DM. Being central to the development of metabolic syndrome and its other related diseases, much focus has been placed on identifying the mitogenic effects of obesity and insulin resistance/DM as mechanistic clues of the link between metabolic syndrome and cancer. Pertinent mechanisms identified include altered lipid signaling, adipokine and inflammatory cytokine effects, and activation of PI3K/Akt/mTOR and RAS/RAF/MAPK/ERK pathways via dysregulated insulin/insulin-like growth factor-1 (IGF-1) signaling. Through variable activation of these multiple pathways, obesity and insulin resistance/DM pre dispose to hematologic malignancies, imposing the aggressive and chemo-resistant phenotypes typically seen in cancer patients with underlying metabolic syndrome. Growing understanding of these pathways has identified druggable cancer targets, rationalizing the development and testing of agents like PI3K inhibitor idelalisib, mTOR inhibitors everolimus and temsirolimus, and IGF-1 receptor inhibitor linsitinib. It has also led to exploration of obesity and diabetes directed therapies including statins and oral hypoglycemic for the management of metabolic syndrome-related hematologic neoplasms. PMID- 25433572 TI - The effect of bupivacaine with fentanyl temperature on initiation and maintenance of labor epidural analgesia: a randomized controlled study. AB - BACKGROUND: Labor epidural analgesia is highly effective, but can be limited by slow onset and incomplete blockade. The administration of warmed, compared to room temperature, bupivacaine has resulted in more rapid onset epidural anesthesia. We hypothesized that the administration of bupivacaine with fentanyl at 37 degrees C versus 20 degrees C would result in improved initial and ongoing labor epidural analgesia. METHODS: In this prospective, randomized, doubled blinded study, 54 nulliparous, laboring women were randomized to receive epidural bupivacaine 0.125% with fentanyl 2 MUg/mL (20 mL initial and 6 mL hourly boluses) at either 37 degrees C or 20 degrees C. Pain verbal rating scores (VRS), sensory level, oral temperature, and side effects were assessed after epidural loading (time 0), at 5, 10, 15, 20, 30, 60 min, and at hourly intervals. The primary outcome was the time to achieve initial satisfactory analgesia (VRS ?3). Secondary outcomes included ongoing quality of sensory blockade, body temperature and shivering. RESULTS: There were no differences between groups in patient demographics, initial pain scores, cervical dilatation, body temperature or mode of delivery. Epidural bupivacaine at 37 degrees C resulted in shorter mean (+/ SD) analgesic onset time (9.2+/-4.7 vs. 16.0+/-10.5 min, P=0.005) and improved analgesia for the first 15 min after initial bolus (P=0.001-0.03). Although patient temperature increased during the study (P<0.01), there were no differences between the groups (P=0.09). Six (24%) and 10 (40%) patients experienced shivering in the 37 degrees C and 20 degrees C groups, respectively (P=0.23). CONCLUSIONS: The administration of epidural 0.125% bupivacaine with fentanyl 2MUg/mL at 37 degrees C versus 20 degrees C resulted in more rapid onset and improved labor analgesia for the first 15 min. There was no evidence of improved ongoing labor analgesia or differences in side effects between groups. PMID- 25433573 TI - Maternal satisfaction with analgesia following hospital discharge after caesarean section. PMID- 25433574 TI - Spinal anaesthesia for emergency caesarean delivery in a parturient with falciparum malaria. PMID- 25433575 TI - Spontaneous coronary artery dissection in a parturient with Nail-Patella syndrome. AB - Spontaneous coronary artery dissection is an uncommon cause of acute coronary syndrome, occurring predominantly in women during and immediately after pregnancy; it carries a mortality rate of greater than 50%. While the exact etiology is unknown, possible contributing factors include pregnancy-related hormonal, connective tissue and hemodynamic changes. We present a case of a 35 year-old multigravid woman with Nail-Patella syndrome who developed an acute myocardial infarction secondary to spontaneous coronary artery dissection during labor which was not diagnosed until after delivery. We hypothesize that abnormal collagen fiber formation found in Nail-Patella syndrome may have put her at an increased risk of coronary dissection and myocardial infarction. Regardless of etiology, a delay in diagnosis of myocardial ischemia can lead to significant morbidity and mortality. In light of the increasing burden of cardiac disease in the obstetric population, clinicians should remain vigilant for signs of myocardial infarction and prepare for definitive diagnosis and treatment. PMID- 25433576 TI - Measurement of blood loss during postpartum haemorrhage. AB - BACKGROUND: We set out to validate the accuracy of gravimetric quantification of blood loss during simulated major postpartum haemorrhage and to evaluate the technique in a consecutive cohort of women experiencing major postpartum haemorrhage. The study took part in a large UK delivery suite over a one-year period. All women who experienced major postpartum haemorrhage were eligible for inclusion. METHODS: For the validation exercise, in a simulated postpartum haemorrhage scenario using known volumes of artificial blood, the accuracy of gravimetric measurement was compared with visual estimation made by delivery suite staff. In the clinical observation study, the blood volume lost during postpartum haemorrhage was measured gravimetrically according to our routine institutional protocol and was correlated with fall in haemoglobin. The main outcome measure was the accuracy of gravimetric measurement of blood loss. RESULTS: Validation exercise: the mean percentage error of gravimetrically measured blood volume was 4.0+/-2.7% compared to visually estimated blood volume with a mean percentage error of 34.7+/-32.1%. Clinical observation study: 356 out of 6187 deliveries were identified as having major postpartum haemorrhage. The correlation coefficient between measured blood loss and corrected fall in haemoglobin for all patients was 0.77; correlation was stronger (0.80) for postpartum haemorrhage >1500mL, and similar during routine and out-of-hours working. CONCLUSION: The accuracy of the gravimetric method was confirmed in simulated postpartum haemorrhage. The clinical study shows that gravimetric measurement of blood loss is correlated with the fall in haemoglobin in postpartum haemorrhage where blood loss exceeds 1500mL. The method is simple to perform, requires only basic equipment, and can be taught and used by all maternity services during major postpartum haemorrhage. PMID- 25433577 TI - Assessing the incidence of peripartum subclinical myocardial ischemia using the troponin T assay: an observational pilot study. AB - BACKGROUND: Cardiac disease is the leading cause of maternal death. Non-fatal ischemic events may go unnoted during the time of delivery. The aim of this study was to assess the incidence of subclinical myocardial ischemia amongst parturients, as evidenced by a raised troponin assay in the postpartum period. METHODS: We undertook a prospective observational pilot study in a tertiary obstetric hospital with over 7000 deliveries a year. Targeted sampling was used to enter subjects in pre-defined high- or low-risk groups for myocardial strain, according to their clinical history and a brief questionnaire. Troponin T levels of 140 women were assessed between 8 and 24h postpartum. RESULTS: Ninety-one women considered to be at high risk and 49 at low risk women for myocardial strain were enrolled. The overall mean (+/-SD) serum troponin T level at 24h postpartum was 8.7+/-19.7ng/L (normal range <14ng/L). The incidence of a positive troponin result was 4.3% (95% CI 1.6, 9.1). Four patients (8.2%) of the low-risk group and two (2.2%) in the high-risk group had elevated troponin T assays. CONCLUSION: This study found that 4% of women had elevated postpartum troponin assays, within levels in the range suggestive of myocardial damage. However, we were unable to ascertain how to identify this group of women prospectively. At this time, we recommend a low threshold for investigation should be maintained. PMID- 25433578 TI - Management of persistent cerebrospinal fluid leak using tissue adhesive. PMID- 25433579 TI - Osteogenesis imperfecta: cesarean deliveries in identical twins. AB - Osteogenesis imperfecta is a congenital disorder resulting in multiple fractures and extremely short stature, usually necessitating cesarean delivery. Identical twins with severe osteogenesis imperfecta each of whom underwent a cesarean delivery with different anesthetic modalities are presented. A review of the literature and anesthetic options for cesarean delivery and postoperative analgesia for women with osteogenesis imperfecta are discussed. PMID- 25433581 TI - Molybdenum and copper in four varieties of common bean (Phaseolus vulgaris): new data of potential utility in designing healthy diet for diabetic patients. AB - Experimental evidence indicates that diabetic patients and individuals with impaired copper homeostasis could be at risk of molybdenum toxicity. A self administered food frequency questionnaire revealed that in central Mexico, diabetic patients with severe complications tend to consume beans more often than individuals with less advanced disease. Four varieties of Phaseolus vulgaris were comparatively evaluated as the dietary sources of two elements; the results showed molybdenum concentration decreasing in the order peruvian > pinto > mayflower > black, whereas for copper, the order was peruvian > pinto ~ black > mayflower. The two elements were determined in pre-soaking water, cooked legumes, and broth obtained in cooking procedure; an in vitro gut model was also applied to assess potentially bioavailable fraction of both elements in cooked beans. The results indicated that the black variety would be the healthiest bean choice for diabetic patients and individuals susceptible to Mo toxicity. Relatively low total molybdenum was found in this variety (2.9 +/- 1.4 versus 4.3-10.9 MUg g(-1) in other types), element availability was also low (15 % in supernatant from enzymolysis, 24.9 % in combined broth + supernatant fractions), and the molar ratio of Cu/Mo was the highest among four types (41, versus Cu/Mo <10 in peruvian, pinto, or mayflower). Considering peruvian and pinto beans, broth elimination would help to lower molybdenum intake with marginal effect on Cu/Mo molar ratio. This recommendation would be especially important for peruvian variety, which provided 1090, 803, and 197 MUg day(-1) of molybdenum in raw grains, broth + supernatant, and supernatant, respectively (based on 100-g portion), exceeding the recommended daily allowance of 45 MUg day(-1). PMID- 25433580 TI - Effects of Calcium Fructoborate on Levels of C-Reactive Protein, Total Cholesterol, Low-Density Lipoprotein, Triglycerides, IL-1beta, IL-6, and MCP-1: a Double-blind, Placebo-controlled Clinical Study. AB - Calcium fructoborate (CFB) has been reported as supporting healthy inflammatory response. In this study, we assess the effects of CFB on blood parameters and proinflammatory cytokines in healthy subjects. This was a randomized, double blinded, placebo-controlled trial. Participants received placebo or CFB at a dose of 112 mg/day (CFB-1) or 56 mg/day (CFB-2) for 30 days. Glucose, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), C-reactive protein (CRP), homocysteine, interleukin 1 beta (IL-1beta), IL-6, and monocyte chemoattractant protein-1 (MCP-1) were determined before and after supplementation. CFB-1 showed a reduction in blood levels of CRP by 31.3 % compared to baseline. CFB-1 and CFB-2 reduced LDL levels by 9.8 and 9.4 %, respectively. CFB-1 decreased blood homocysteine by 5.5 % compared with baseline, whereas CFB-2 did not have a significant effect. Blood levels of TG were reduced by 9.1 and 8.8 % for CFB-1 and CFB-2, respectively. Use of both CFB 1 and CFB-2 resulted in significantly reduced IL-6 levels, when compared within and between groups. IL-1beta was reduced by 29.2 % in the CFB-1 group. Finally, CFB-1 and CFB-2 reduced MCP-1 by 31 and 26 %, respectively. Our data indicate that 30-day supplementation with 112 mg/day CFB (CFB-1) resulted in a significant reduction of LDL, TG, TC, IL-1beta, IL-6, MCP-1, and CRP. HDL levels were increased, when compared to baseline and placebo. These results suggest that CFB might provide beneficial support to healthy cardiovascular systems by positively affecting these blood markers (ClinicalTrials.gov, ISRCTN90543844; May 24, 2012 ( http://www.controlled-trials.com/ISRCTN90543844 )). PMID- 25433582 TI - Fragment screening for drug discovery: efficient approaches for exploring chemical space. PMID- 25433584 TI - [Clinical research in pneumology in French general hospitals]. PMID- 25433583 TI - Stability and resilience of oral microcosms toward acidification and Candida outgrowth by arginine supplementation. AB - Dysbiosis induced by low pH in the oral ecosystem can lead to caries, a prevalent bacterial disease in humans. The amino acid arginine is one of the pH-elevating agents in the oral cavity. To obtain insights into the effect of arginine on oral microbial ecology, a multi-plaque "artificial mouth" (MAM) biofilm model was inoculated with saliva from a healthy volunteer and microcosms were grown for 4 weeks with 1.6 % (w/v) arginine supplement (Arginine) or without (Control), samples were taken at several time-points. A cariogenic environment was mimicked by sucrose pulsing. The bacterial composition was determined by 16S rRNA gene amplicon sequencing, the presence and amount of Candida and arginine deiminase system genes arcA and sagP by qPCR. Additionally, ammonium and short-chain fatty acid concentrations were determined. The Arginine microcosms were dominated by Streptococcus, Veillonella, and Neisseria and remained stable in time, while the composition of the Control microcosms diverged significantly in time, partially due to the presence of Megasphaera. The percentage of Candida increased 100-fold in the Control microcosms compared to the Arginine microcosms. The pH-raising effect of arginine was confirmed by the pH and ammonium results. The abundances of sagP and arcA were highest in the Arginine microcosms, while the concentration of butyrate was higher in the Control microcosms. We demonstrate that supplementation with arginine serves a health-promoting function; it enhances microcosm resilience toward acidification and suppresses outgrowth of the opportunistic pathogen Candida. Arginine facilitates stability of oral microbial communities and prevents them from becoming cariogenic. PMID- 25433585 TI - [Ten-year evolution in non-small-cell lung cancer according to sex. Results of the KBP-2010-CPHG study by the College of General Hospital Respiratory Physicians]. AB - INTRODUCTION: Comparison by sex and presenting features between 2000 and 2010 of the characteristics of new cases of non-small-cell lung cancer (NSCLC). METHODS: Observational KBP-2010-CPHG study similar to KBP-2000-CPHG. Both studies were promoted by the French College of General Hospital Respiratory Physicians (CPHG). KBP-2010-CPHG collected data for 6083 NSCLC diagnosed between January 1st and December 31st, 2010, and followed in the respiratory departments of 119 French general hospitals. RESULTS: In 2010, 24.4 % of the patients were women (16 % in 2000, p<0.0001). Compared to men, women were more commonly non-smokers (34.2 vs 4.7 %) or lighter consumers (37.2 vs 43.7 pack per years) (p<0.0001). Their tumours (mostly adenocarcinoma: 64.6 vs 48.7 %, p<0.0001) were more frequently diagnosed at stage IV (62.4 vs 56.9 %, p=0.0008). EGFR mutation research was more frequently performed (48.5 vs 31.0 %, p<0.0001) and positive (20.6 vs 5.2 %, p<0.0001) in women than men. Their treatment more frequently included targeted therapy (13.4 vs 5.7 %, p<0.0001). Compared to 2000, the percentage of non smokers increased in men (4.7 vs 2.5 %, p<0.0001) while remaining stable in women (36.1 vs 34.2 %, p=0.32). The percentage of adenocarcinomas increased, particularly in men (48.7 vs 31.5 %, p<0.0001). CONCLUSIONS: The percentage of women with NSCLC has increased in 10years in France. In 2010, the main gender differences persist, but have decreased with the increasing proportion of non smokers and adenocarcinomas in men. Various hypotheses to explain these changes are discussed. PMID- 25433586 TI - [Adjuvant chemotherapy of non-small cell lung cancer: Tolerance of combined cisplatin-pemetrexed therapy]. AB - RATIONALE: Adjuvant chemotherapy is standard for non-small cell lung cancer (NSCLC) after surgical resection. In this context, the tolerance of the treatment is an essential criterion in the choice of chemotherapy. This exploratory study evaluated, in the situation of adjuvant chemotherapy, the tolerance of combined cisplatin-pemetrexed. The study analyzed a cohort of non-squamous NSCLC patients treated in an adjuvant setting by combined cisplatin (75 mg/m(2)) and pemetrexed (500 mg/m(2)), under vitamin B12 and folic acid cover, 4 cycles at 21-day intervals. RESULTS: The analysis included 23 patients (age: 58.7 +/- 5 years, men: 56%, average creatinin clearance (Clea): 94 +/- 22 mL/min, average haemoglobin: 13.8 +/- 1.6g/dL). Over 92 planned courses, 7.6% are postponed (neutropenia), 4.3% were not given (asthenia). We noted 7 episodes of vomiting (4 grade 3), with two hospitalizations in the same patient; 5 episodes of anaemia grade 1-2 not requiring EPO prescription or transfusion and no febrile neutropenia. At the end of the treatment, three patients had a Clea<50 mL/mn and 5 a haemoglobin between 9 and 11 g/dL. CONCLUSION: Combined cisplatin-pemetrexed in an adjuvant situation has a satisfactory tolerance. PMID- 25433587 TI - [Peripherally inserted central catheter antibiotic therapy for cystic fibrosis patients]. AB - INTRODUCTION: Peripherally inserted central catheters (PICC) are more and more used for intravenous antibiotic infusions in cystic fibrosis (CF) patients in the Grenoble area (France). The aim of this study was to assess the use of this technique in this indication. METHODS: 1. Retrospective evaluation of 102 consecutive PICC insertions over 3years and the incidence of adverse events during the therapy. 2. Prospective evaluation of 12 patient's satisfaction and their nurses over a 3-month period. 3. Comparative analysis of single domiciliary treatment costs using PICC versus peripheral catheter (PC). RESULTS: 102 PICC insertions were attempted in 31 patients. Seven failures and 7 complications occurred during the treatment requiring removal of the PICC, i.e. an overall success rate of 86.2% (88/102). Pain during PICC introduction was 4.2/10 (visual analogical scale). Mean satisfaction levels during therapy were 9.3/10 for patients and 8.7/10 for nurses. Compared with PC, all the patients said that PICC was "more comfortable". Differential costs of treatment with PC and with PICC at home were estimated at 57.15? and 590.16? respectively. CONCLUSION: PICC is an alternative to CP for intravenous antibiotherapy in CF patients, providing better safety and comfort. PICC use should be promoted in this indication. PMID- 25433588 TI - [Smoker's clinical characteristics at a tobacco cessation consultation (Sousse university hospital, Tunisia)]. AB - BACKGROUND: Smoking cessation intervention is among the most vital elements of the prevention of tobacco smoking. Our study aimed to describe the clinical profile of patients attending our smoking cessation unit. METHODS: We conducted a cross-sectional study from December 2009 to June 2012. The patients were recruited in the Tobacco cessation unit of Sahloul Hospital (Sousse, Tunisia). The data were collected from the consultants' records. RESULTS: A total of 279 patients attended. They were mostly men (92.8 %). The mean age was 41.7 +/- 13.4 years. Among medical conditions, a history of cardiovascular and respiratory disease was the most frequent (31 %). Anxiety was present in 46.2 % of patients. More than half of the patients (51.2 %) were heavy smokers and 50.5 % were strongly nicotine dependent (Fagerstrom's score>7). Seventy percent were motivated to stop smoking and 53.8 % had tried to quit at least once. CONCLUSION: The majority of our patients could be considered as heavy smokers. Therapeutic combinations and medical treatment are suggested to assist practitioners trying to help them. PMID- 25433589 TI - [Choosing the best panel of aeroallergen prick-tests for patients in Lebanon with rhinitis and asthma: A retrospective study of 2350 patients]. AB - INTRODUCTION: The aim of this study was to evaluate the profile of skin prick test reactivity to different aeroallergens in patients with rhinitis and asthma in Lebanon and its geographic variation within the country. It was also to suggest a minimal panel of allergens that should be used to detect sensitized patients. METHODS: All patients who underwent skin prick-testing, because of rhinitis and/or symptoms suggesting asthma, between 2004 to 2011 in the hotel Dieu de France university hospital of Beirut, were studied. The total number of patients was 2350 and all were tested with the same panel of 24 aeroallergens. A further series of 208 patients were added because Cupressaceae antigens were not included in the initial series. RESULTS: The overall rate of sensitization to any allergen was 75.6%. A battery of eleven allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, Blomia, Parietaria, grass, Salicaceae, oak, Oleaceae, dog, cat, and cockroaches) was found to identify sensitized patients with a sensitivity of 96% and a negative predictive value of 90%. Cupressaceae should be added to this battery in view of the results of the additional series. The Bekaa region had a unique profile of sensitization. CONCLUSION: Twelve allergens are able to detect almost all sensitized patients suffering from respiratory symptoms in Lebanon. PMID- 25433590 TI - [Interstitial lung disease-associated with amyopathic dermatomyositis and anti MDA5 autoantibodies]. AB - INTRODUCTION: Amyopathic dermatomyositis associated with anti-MDA5 autoantibodies is a rare and very recently described clinical entity. CASE REPORT: A 58-year-old woman was admitted with subacute onset of dyspnea (NYHA class IV) associated with cough, oligoarthritis of the wrists, myalgia and intermittent fever. Examination demonstrated skin lesions with heliotrope rash, Gottron's papules, "mechanics hands", and basal inspiratory crackles on lung auscultation. Pulmonary function tests showed a restrictive ventilatory defect, with decreased carbon monoxide diffusion capacity and marked hypoxemia (PaO2 61 mmHg). The chest high-resolution computed tomography appearances were consistent with organizing pneumonia. Bronchoalveolar lavage differential cell count demonstrated 22 % neutrophils. Serum creatine kinase and electromyography were normal ; the serum ferritin level was elevated. Antinuclear antibodies were present and anti-MDA5 autoantibodies were identified. Significant improvement was obtained with systemic corticosteroids, later converted to mycophenolate mofetil as a steroid-sparing agent. CONCLUSION: Amyopathic dermatomyositis associated with anti-MDA5 autoantibodies shares some characteristics with those associated with anti synthetase antibodies. Muscular involvement may be mild or absent. Early diagnosis and treatment may improve outcome. PMID- 25433591 TI - [Voluminous Pott's abscess]. AB - Osteoarticular tuberculosis was frequent throughout the world a decade ago but antituberculous chemotherapy and prophylactic measures have clearly contributed to the reduction of its frequency. However, Pott's disease is frequently complicated by an abscess and some locations are exceptional on account of their gravity. We report a case of dorsal spondylodiscitis with a voluminous Pott's abscess compressing the mediastinal structures with a risk of perforating into the trachea. PMID- 25433592 TI - [Post-infectious autobullectomy]. AB - INTRODUCTION: Bullous emphysema is defined as an airspace of more than 10mm in diameter. The spontaneous regression or disappearance of a bulla is unusual, described as an "autobullectomy". CASE REPORT: We report the case of a 37-year old man with a 10-pack/year history of smoking, a history of pneumothorax surgically treated in 2005, and emphysema with a bulla in the right upper lobe. In September 2010, the patient was hospitalized for a community-acquired pneumonia associated with an air-fluid level in the bulla. Clinical symptoms improved with a course of antibiotics (levofloxacin, ceftriaxone) for 3 weeks. Chest X-rays showed a progressive decrease in the size of the bulla. In June 2011, a chest CT scan showed complete regression of the bulla in the right upper lobe. CONCLUSIONS: We report the complete regression of a bulla after infection, leading to an "autobullectomy". It can be hypothesized that the mechanisms might involve fibrosis of the walls and/or the obstruction of the bronchus supplying the bulla. PMID- 25433593 TI - [Double bronchogenic cyst]. AB - Bronchogenic cysts are rare congenital malformations of the tracheobronchial tree and are mostly found in an intrathoracic location. We report a very rare case of a double location - cervical and mediastinal - in a young female patient. PMID- 25433594 TI - [Parasitic pneumonia and HTLV-1 infection]. PMID- 25433595 TI - [A lung parenchymal cavitation]. PMID- 25433596 TI - [Contribution of mineralogical analysis in thoracic oncology: The example of asbestos]. PMID- 25433597 TI - [Contribution of mineralogical analysis in thoraciconcology: The example of asbestos. Answer from Morelle et al]. PMID- 25433598 TI - An interpretation of the phenol nitration mechanism in the gas phase using G3(MP2)//B3-CEP theory. AB - G3(MP2)//B3-CEP theory was applied to study the mechanism of phenol nitration in the gas phase, as promoted by the electrophile NO2 (+). The results of studying this mechanism at the G3(MP2)//B3-CEP level pointed to the occurrence of a single electron transfer (SET) from the aromatic pi-system to the nitronium ion prior to sigma-complex formation. The formation of an initial pi-complex between the nitronium ion and phenol was not observed. Excellent agreement between the activation barriers predicted by G3(MP2)//B3-CEP and those yielded by other, more accurate, versions of the G3 theory showed that the former is a useful tool for studying reaction mechanisms, as G3(MP2)//B3-CEP is much less computationally expensive than other high-level methods. PMID- 25433599 TI - Dynamic characterization and substrate binding of cis-2,3-dihydrobiphenyl-2,3 diol dehydrogenase-an enzyme used in bioremediation. AB - In recent years, techniques involving the use of organisms to remove or neutralize pollutants from contaminated sites have attracted great attention. The aim of bioremediation is to use naturally occurring organisms to degrade dangerous substances to less toxic or non toxic molecules. The gram-negative bacterium Pandoraea pnomenusa strain B-356 (Pp) has been found to be able to transform a persistent class of organic pollutant compounds, namely the biphenyl and polychlorinated biphenyls (PCBs). A key enzyme in the PCB catabolic pathway is NAD-dependent cis-2,3-dihydrobiphenyl-2,3-diol dehydrogenase (BphB), for which the crystal structure from Pp has been crystallized in apo-, NAD-bound and biphenyldiol-/NAD-bound forms. The substrate binding loop structure has not been completely resolved to date in the former two bound states. Here we report the results of the first extensive molecular dynamics simulations on the three different states of PpBphB. This allowed an in depth characterization of the mechanism of ligand uptake and binding, including unraveling of the gating mechanism. Our simulations give a deep insight into several dynamic features of the enzyme that were not captured by crystal structures. PMID- 25433600 TI - A theoretical investigation of one-dimensional lithium-bonded chain: enhanced first hyperpolarizability and little red-shift. AB - We present a theoretical investigation of the electric properties of two kinds of one-dimensional lithium bonded chains: (NC-Li)n and (NC-CC-Li)n (n = 1-8). The resulting (NC-Li)n and (NC-CC-Li)n were found to exhibit enhanced first hyperpolarizabilities (beta 0) with increasing n, and a slight change in the absorption maximum wavelength lambdamax at the crucial transition. Comparing with (NC-Li)n, (NC-CC-Li)n exhibited particularly drastically enhanced beta 0 values due to clearly enhanced coupled oscillators and double-degenerated charge transitions. beta 0 is known to be the microscopic origin of the second-order non linear optical (NLO) property, and lambdamax is an approximate measure of the transparency achievable, thus both are important indices of high-performance NLO molecules. Therefore, our investigations into one-dimensional lithium bond chains will be beneficial to understanding the relationship between beta 0 and lambdamax, thus aiding the design of one-dimensional NLO materials with excellent transparence-efficiency. PMID- 25433601 TI - Computational evaluation of unsaturated carbonitriles as neutral receptor model for beryllium(II) recognition. AB - Design of neutral receptor molecules (ionophores) for beryllium(II) using unsaturated carbonitrile models has been carried out via density functional theory, G3, and G4 calculations. The first part of this work focuses on gas phase binding energies between beryllium(II) and 2-cyano butadiene (2-CN BD), 3-cyano propene (3-CN P), and simpler models with two separate fragments; acrylonitrile and ethylene. Interactions between beryllium(II) and cyano nitrogen and terminal olefin in the models have been examined in terms of geometrical changes, distribution of charge over the entire pi-system, and rehybridization of vinyl carbon orbitals. NMR shieldings and vibrational frequencies probed charge centers and strength of interactions. The six-membered cyclic complexes have planar structures with the rehybridized carbon slightly out of plane (16 degrees in 2 CN BD). G3 results show that in 2-CN BD complex participation of vinyl carbon further stabilizes the cyclic adduct by 16.3 kcal mol(-1), whereas, in simpler models, interaction between beryllium(II) and acetonitrile is favorable by 46.4 kcal mol(-1) compared with that of ethylene. The terminal vinyl carbon in 2-CN BD rehybridizes to sp (3) with an increase of 7 % of s character to allow interaction with beryllium(II). G4 calculations show that the Be(II) and 2-CN BD complex is more strongly bound than those with Mg(II) and Ca(II) by 98.5 and 139.2 kcal mol(-1) (-1), respectively. QST2 method shows that the cyclic and acyclic forms of Be(II)-2-CN BD complexes are separated by 12.3 kcal mol(-1) barrier height. Overlap population analysis reveals that Ca(II) can be discriminated based on its tendency to form ionic interaction with the receptor models. PMID- 25433602 TI - [Amyotrophic lateral sclerosis and dysphagia in the elderly]. PMID- 25433603 TI - Bioengineered transplantable porcine livers with re-endothelialized vasculature. AB - Donor shortage remains a continued challenge in liver transplantation. Recent advances in tissue engineering have provided the possibility of creating functional liver tissues as an alternative to donor organ transplantation. Small bioengineered liver constructs have been developed, however a major challenge in achieving functional bioengineered liver in vivo is the establishment of a functional vasculature within the scaffolds. Our overall goal is to bioengineer intact livers, suitable for transplantation, using acellular porcine liver scaffolds. We developed an effective method for reestablishing the vascular network within decellularized liver scaffolds by conjugating anti-endothelial cell antibodies to maximize coverage of the vessel walls with endothelial cells. This procedure resulted in uniform endothelial attachment throughout the liver vasculature extending to the capillary bed of the liver scaffold and greatly reduced platelet adhesion upon blood perfusion in vitro. The re-endothelialized livers, when transplanted to recipient pigs, were able to withstand physiological blood flow and maintained for up to 24 h. This study demonstrates, for the first time, that vascularized bioengineered livers, of clinically relevant size, can be transplanted and maintained in vivo, and represents the first step towards generating engineered livers for transplantation to patients with end-stage liver failure. PMID- 25433605 TI - Non-invasive monitoring of transplanted endothelial progenitor cells in diabetic ischemic stroke models. AB - Endogenous endothelial progenitor cells (EPCs) are functionally impaired in hyperglycemia through the p38 MAPK signaling pathway. However, the number and function of transplanted exogenous EPCs in diabetic animals remains unclear. The objectives of this study were to establish a non-invasive imaging strategy to monitor the homing of transplanted EPCs in diabetic stroke mice and to assess the effect of RWJ 67657, an inhibitor of p38 MAPK, on the homing ability of exogenous EPCs. Bone marrow-derived EPCs were labeled in vitro with a multi-functional nanoprobe modified with paramagnetic chelators and fluorophores before being infused into stroke mice. The signal of the nanoprobe reached its peak on day 5 in both magnetic resonance imaging and near-infrared fluorescence imaging after EPC transplantation in wild-type stroke models. The signal enhancement of diabetic stroke models was significantly lower than that of wild-type controls. However, the signal intensity of diabetic stroke models significantly increased after oral administration of RWJ 67657, indicating that more transplanted EPCs migrated to the ischemic brain. Furthermore, the increased exogenous EPCs induced remarkably greater angiogenesis after stroke. These results suggest that this dual-modal imaging strategy is feasible for non-invasively monitoring transplanted cells in vivo. PMID- 25433604 TI - Characterization of sequential collagen-poly(ethylene glycol) diacrylate interpenetrating networks and initial assessment of their potential for vascular tissue engineering. AB - Collagen hydrogels have been widely investigated as scaffolds for vascular tissue engineering due in part to the capacity of collagen to promote robust cell adhesion and elongation. However, collagen hydrogels display relatively low stiffness and strength, are thrombogenic, and are highly susceptible to cell mediated contraction. In the current work, we develop and characterize a sequentially-formed interpenetrating network (IPN) that retains the benefits of collagen, but which displays enhanced mechanical stiffness and strength, improved thromboresistance, high physical stability and resistance to contraction. In this strategy, we first form a collagen hydrogel, infuse this hydrogel with poly(ethylene glycol) diacrylate (PEGDA), and subsequently crosslink the PEGDA by exposure to longwave UV light. These collagen-PEGDA IPNs allow for cell encapsulation during the fabrication process with greater than 90% cell viability via inclusion of cells within the collagen hydrogel precursor solution. Furthermore, the degree of cell spreading within the IPNs can be tuned from rounded to fully elongated by varying the time delay between the formation of the cell-laden collagen hydrogel and the formation of the PEGDA network. We also demonstrate that these collagen-PEGDA IPNs are able to support the initial stages of smooth muscle cell lineage progression by elongated human mesenchymal stems cells. PMID- 25433606 TI - Functional remodeling after vocal fold injury by small intestinal submucosa gel containing hepatocyte growth factor. AB - A biomaterial derived from porcine small intestinal submucosa (SIS) was used in smart drug delivery and tissue remodeling. SIS suspensions were easily formulated by simple mixing with the drug of choice and formed an in situ gel upon injection into tissues, enabling them to act as protein drug depots. This study was conducted to determine whether functional remodeling of an injured vocal fold (VF) could be achieved by hepatocyte growth factor (HGF)-containing SIS in situ forming gel after VF injury in a rabbit model. To accomplish this, we loaded HGF in SIS suspensions and observed a gradual, sustained release of HGF for at least 21 days in vitro. Evaluation of the in vivo efficacy demonstrated that the HGF and HGF-loaded SIS treated VFs showed improved mucosal healing when compared with the PBS-injected VFs. Histopathological evaluations revealed that treatment with the HGF/SIS group alone successfully ameliorated the deposition of type I collagen and increased synthesis of hyaluronic acids relative to the PBS group at three months post-injury. Functional analyses showed that the HGF/SIS group prevented deterioration of mucosal vibration and induced significant improvement in the mean viscoelastic modulus, but that other groups failed to achieve functional rescue of VF biomechanics. Additionally, the VF oscillation in the HGF/SIS group was superior to that in the HGF group. The results of this study suggest that SIS in situ gel has the potential for use as an HGF delivery carrier for enhancement of wound healing and improvement of functional remodeling following VF injury. PMID- 25433607 TI - TPGS-stabilized NaYbF4:Er upconversion nanoparticles for dual-modal fluorescent/CT imaging and anticancer drug delivery to overcome multi-drug resistance. AB - Multi-drug resistance (MDR) is a major cause of failure in cancer chemotherapy. Tocopheryl polyethylene glycol 1000 succinate (TPGS) has been extensively investigated for overcoming MDR in cancer therapy because of its ability to inhibit P-glycoprotein (P-gp). In this work, TPGS was for the first time used as a new surface modifier to functionalize NaYbF4:Er upconversion nanoparticles (UNCPs) and endowed the as-prepared products (TPGS-UCNPs) with excellent water solubility, P-gp inhibition capability and imaging-guided drug delivery property. After the chemotherapeutic drug (doxorubicin, DOX) loading, the as-formed composites (TPGS-UCNPs-DOX) exhibited potent killing ability for DOX-resistant MCF-7 cells. Flow-cytometric assessment and Western blot assay showed that the TPGS-UCNPs could potently decrease the P-gp expression and facilitate the intracellular drug accumulation, thus achieving MDR reversal. Moreover, considering that UCNPs process efficient upconversion emission and Yb element contained in UCNPs has strong X-ray attenuation ability, the as-obtained composite could also serve as a dual-modal probe for upconversion luminescence (UCL) imaging and X-ray computed tomography (CT) imaging, making them promising for imaging-guided cancer therapy. PMID- 25433609 TI - Fabrication of new single cell chip to monitor intracellular and extracellular redox state based on spectroelectrochemical method. AB - Probing the local environment of target cells has been considered a challenging task due to the complexity of living cells. Here, we developed new single cell based chip to investigate the intracellular and extracellular redox state of PC12 cells using spectroelectrochemical tool that combined surface-enhanced Raman scattering (SERS) and linear sweep voltammetry (LSV) techniques. PC12 cells immobilized on gold nanodots/ITO surface were subjected to LSV and their intracellular biochemical changes were successfully monitored by SERS simultaneously. Moreover, paired gold microelectrodes with micrometer-sized gap containing hexagonal array of gold nanodots were fabricated to detect electrochemical activity and changes in the redox environment of single PC12 cell based on SERS-LSV tool. This showed very effective detecting method. The used technology included the utilization of gold nanodots array inside micro-gap to enhance the Raman signals and the electrochemical activity of single cell. This could be used as an effective research tool to analyze cellular processes. PMID- 25433608 TI - Mesenchymal stromal cells form vascular tubes when placed in fibrin sealant and accelerate wound healing in vivo. AB - Non-healing, chronic wounds are a growing public health problem and may stem from insufficient angiogenesis in affected sites. Here, we have developed a fibrin formulation that allows adipose-derived mesenchymal stromal cells (ADSCs) to form tubular structures in vitro. The tubular structures express markers of endothelium, including CD31 and VE-Cadherin, as well as the pericyte marker NG2. The ability for the MSCs to form tubular structures within the fibrin gels was directly dependent on the stoichiometric ratios of thrombin and fibrinogen and the resulting gel concentration, as well as on the presence of bFGF. Fibrin gel formulations that varied in stiffness were tested. ADSCs that are embedded in a stiff fibrin formulation express VE-cadherin and CD31 as shown by PCR, FACS and immunostaining. Confocal imaging analysis demonstrated that tubular structures formed, containing visible lumens, in the stiff fibrin gels in vitro. There was also a difference in the amounts of bFGF secreted by ADSCs grown in the stiffer gels as compared to softer gels. Additionally, hAT-MSCs gave rise to perfusable vessels that were VE-cadherin positive after subcutaneous injection into mice, whereas the softer fibrin formulation containing ADSCs did not. The application of ADSCs delivered in the stiff fibrin gels allowed for the wounds to heal more quickly, as assessed by wound size, amount of granulation tissue and collagen content. Interestingly, following 5 days of healing, the ADSCs remained within the fibrin gel and did not integrate into the granulation tissue of healing wounds in vivo. These data show that ADSCs are able to form tubular structures within fibrin gels, and may also contribute to faster wound healing, as compared with no treatment or to wounds treated with fibrin gels devoid of ADSCs. PMID- 25433610 TI - Influence of lamina cribrosa thickness and depth on the rate of progressive retinal nerve fiber layer thinning. AB - OBJECTIVE: To determine whether lamina cribrosa (LC) depth (LCD) and LC thickness (LCT) are associated with a faster rate of progressive retinal nerve fiber layer (RNFL) thinning in primary open-angle glaucoma (POAG). DESIGN: Prospective, observational study. PARTICIPANTS: One hundred ten eyes diagnosed with POAG (n = 110 patients) in which RNFL thickness had been measured by serial spectral-domain (SD) optical coherence tomography (OCT) for at least 2.5 years. METHODS: The participants underwent enhanced depth imaging volume scanning of the optic nerve, and circumpapillary RNFL thickness measurements were obtained using SD OCT. The participants were followed up regularly with serial RNFL thickness measurements at 6-month or longer intervals. Lamina cribrosa depth was measured at 7 equidistant planes and LCT was measured at 3 locations (superior midperipheral, midhorizontal, and inferior midperipheral). The rate of RNFL thinning was determined by linear regression of serial OCT RNFL thickness measurements over time. MAIN OUTCOME MEASURES: Factors associated with the rate of OCT RNFL thinning. RESULTS: A faster rate of RNFL thinning was associated with disc hemorrhage during follow-up (P < 0.001), wider beta-zone parapapillary atrophy with Bruch's membrane (P = 0.037), larger global RNFL thickness (P = 0.026), larger LCD (P < 0.001), and smaller LCT (P = 0.002). The association between LCD and the rate of RNFL thinning was explained better using a fractional polynomial model (R(2) = 0.223) than a linear model (R(2) = 0.134; P = 0.010). Davies' test revealed a statistically significant breakpoint for LCD (489.7 MUm), above which a faster rate of global RNFL thinning was associated with a larger LCD. CONCLUSIONS: A thinner LC and a larger LC displacement had a significant influence on the rate of progressive RNFL thinning. PMID- 25433611 TI - Gender-based violence: more research (funding) please. PMID- 25433612 TI - Setting targets, achieving goals: can analysis of past progress help? PMID- 25433613 TI - The neglected global burden of tuberculosis in pregnancy. PMID- 25433614 TI - The challenge of silent rheumatic heart disease. PMID- 25433615 TI - Prevention of neonatal pneumonia and sepsis via maternal immunisation. PMID- 25433616 TI - Political economy analysis for nutrition policy. PMID- 25433617 TI - Research priorities for elimination of visceral leishmaniasis. PMID- 25433618 TI - Ebola in urban slums: the elephant in the room. PMID- 25433619 TI - Hyperimmune serum from healthy vaccinated individuals for Ebola virus disease? PMID- 25433620 TI - Feasible HCV targets in Egypt. PMID- 25433621 TI - Feasible HCV targets in Egypt - authors' reply. PMID- 25433622 TI - Challenges and opportunities for new medical schools in Africa. PMID- 25433623 TI - Southern Africa consortium for research excellence (SACORE): successes and challenges. PMID- 25433624 TI - Time for civil registration with verbal autopsy. PMID- 25433625 TI - Annual rates of decline in child, maternal, HIV, and tuberculosis mortality across 109 countries of low and middle income from 1990 to 2013: an assessment of the feasibility of post-2015 goals. AB - BACKGROUND: Measuring a country's health performance has focused mostly on estimating levels of mortality. An alternative is to measure rates of decline in mortality, which are more sensitive to changes in health policy than are mortality levels. Historical rates of decline in mortality can also help test the feasibility of future health goals (eg, post-2015). We aimed to assess the annual rates of decline in under-5, maternal, tuberculosis, and HIV mortality over the past two decades for 109 low-income and middle-income countries. METHODS: For the period 1990-2013, we estimated annual rates of decline in under-5 mortality (deaths per 1000 livebirths), the maternal mortality ratio (deaths per 100 000 livebirths), and tuberculosis and HIV mortality (deaths per 100 000 population per year) using published data from UNICEF and WHO. For every 5-year interval (eg, 1990-95), we defined performance as the size of the annual rate of decline for every mortality indicator. Subsequently, we tested the feasibility of post 2015 goals by estimating the year by which countries would achieve 2030 targets proposed by The Lancet's Commission on Investing in Health (ie, 20 deaths per 1000 for under-5 mortality, 94 deaths per 100 000 for maternal mortality, four deaths per 100 000 for tuberculosis mortality, and eight deaths per 100 000 for HIV mortality) at observed country and aspirational best-performer (90th percentile) rates. FINDINGS: From 2005 to 2013, the mean annual rate of decline in under-5 mortality was 4.3% (95% uncertainty interval [UI] 3.9-4.6), for maternal mortality it was 3.3% (2.5-4.1), for tuberculosis mortality 4.1% (2.8 5.4), and for HIV mortality 2.2% (0.1-4.3); aspirational best-performer rates per year were 7.1% (6.8-7.5), 6.3% (5.5-7.1), 12.8% (11.5-14.1), and 15.3% (13.2 17.4), respectively. The top two country performers were Macedonia and South Africa for under-5 mortality, Belarus and Bulgaria for maternal mortality, Uzbekistan and Macedonia for tuberculosis mortality, and Namibia and Rwanda for HIV mortality. At aspirational rates of decline, The Lancet's Commission on Investing in Health target for under-5 mortality would be achieved by 50-64% of countries, 35-41% of countries would achieve the 2030 target for maternal mortality, 74-90% of countries would meet the goal for tuberculosis mortality, and 66-82% of countries would achieve the target for HIV mortality. PMID- 25433626 TI - Tuberculosis in pregnancy: an estimate of the global burden of disease. AB - BACKGROUND: The estimated number of maternal deaths in 2013 worldwide was 289 000, a 45% reduction from 1990. Non-obstetric causes such as infectious diseases including tuberculosis now account for 28% of maternal deaths. In 2013, 3.3 million cases of tuberculosis were estimated to occur in women globally. During pregnancy, tuberculosis is associated with poor outcomes, including increased mortality in both the neonate and the pregnant woman. The aim of our study was to estimate the burden of tuberculosis disease among pregnant women, and to describe how maternal care services could be used as a platform to improve case detection. METHODS: We used publicly accessible country-level estimates of the total population, distribution of the total population by age and sex, crude birth rate, estimated prevalence of active tuberculosis, and case notification data by age and sex to estimate the number of pregnant women with active tuberculosis for 217 countries. We then used indicators of health system access and tuberculosis diagnostic test performance obtained from published literature to determine how many of these cases could ultimately be detected. FINDINGS: We estimated that 216 500 (95% uncertainty range 192 100-247 000) active tuberculosis cases existed in pregnant women globally in 2011. The greatest burdens were in the WHO African region with 89 400 cases and the WHO South East Asian region with 67 500 cases in pregnant women. Chest radiography or Xpert RIF/MTB, delivered through maternal care services, were estimated to detect as many as 114 100 and 120 300 tuberculosis cases, respectively. PMID- 25433627 TI - Active surveillance for rheumatic heart disease in endemic regions: a systematic review and meta-analysis of prevalence among children and adolescents. AB - BACKGROUND: Rheumatic heart disease accounts for up to 250 000 premature deaths every year worldwide and can be regarded as a physical manifestation of poverty and social inequality. We aimed to estimate the prevalence of rheumatic heart disease in endemic countries as assessed by different screening modalities and as a function of age. METHODS: We searched Medline, Embase, the Latin American and Caribbean System on Health Sciences Information, African Journals Online, and the Cochrane Database of Systematic Reviews for population-based studies published between Jan 1, 1993, and June 30, 2014, that reported on prevalence of rheumatic heart disease among children and adolescents (>= 5 years to <18 years). We assessed prevalence of clinically silent and clinically manifest rheumatic heart disease in random effects meta-analyses according to screening modality and geographical region. We assessed the association between social inequality and rheumatic heart disease with the Gini coefficient. We used Poisson regression to analyse the effect of age on prevalence of rheumatic heart disease and estimated the incidence of rheumatic heart disease from prevalence data. FINDINGS: We included 37 populations in the systematic review and meta-analysis. The pooled prevalence of rheumatic heart disease detected by cardiac auscultation was 2.9 per 1000 people (95% CI 1.7-5.0) and by echocardiography it was 12.9 per 1000 people (8.9-18.6), with substantial heterogeneity between individual reports for both screening modalities (I2 = 99.0% and 94.9%, respectively). We noted an association between social inequality expressed by the Gini coefficient and prevalence of rheumatic heart disease (p = 0.0002). The prevalence of clinically silent rheumatic heart disease (21.1 per 1000 people, 95% CI 14.1-31.4) was about seven to eight times higher than that of clinically manifest disease (2.7 per 1000 people, 1.6-4.4). Prevalence progressively increased with advancing age, from 4.7 per 1000 people (95% CI 0.0-11.2) at age 5 years to 21.0 per 1000 people (6.8-35.1) at 16 years. The estimated incidence was 1.6 per 1000 people (0.8-2.3) and remained constant across age categories (range 2.5, 95% CI 1.3-3.7 in 5-year old children to 1.7, 0.0-5.1 in 15-year-old adolescents). We noted no sex-related differences in prevalence (p = 0.829). PMID- 25433629 TI - Antibiotic oxylipins from Alternanthera brasiliana and its endophytic bacteria. AB - Bioassay-guided fractionation of Alternanthera brasiliana stem extracts resulted in the isolation of an antibiotically active fraction. Five human pathogenic bacteria were used to guide the fractionation process for the isolation of antimicrobial compounds. Finally, 17 linoleate oxylipins were identified by LC MS/MS and NMR spectroscopy. Five of the isolated compounds present in A. brasiliana tissues were also detected to be synthesized by endophytic bacteria of the genus Bacillus that were isolated from A. brasiliana. It is speculated that the antibiotic oxylipins from A. brasiliana might derive from bacteria and be involved in an ecological relationship between this plant and its endophytes. PMID- 25433630 TI - Allosteric substrate inhibition of Arabidopsis NAD-dependent malic enzyme 1 is released by fumarate. AB - Plant mitochondria can use L-malate and fumarate, which accumulate in large levels, as respiratory substrates. In part, this property is due to the presence of NAD-dependent malic enzymes (NAD-ME) with particular biochemical characteristics. Arabidopsis NAD-ME1 exhibits a non-hyperbolic behavior for the substrate L-malate, and its activity is strongly stimulated by fumarate. Here, the possible structural connection between these properties was explored through mutagenesis, kinetics, and fluorescence studies. The results indicated that NAD ME1 has a regulatory site for L-malate that can also bind fumarate. L-Malate binding to this site elicits a sigmoidal and low substrate-affinity response, whereas fumarate binding turns NAD-ME1 into a hyperbolic and high substrate affinity enzyme. This effect was also observed when the allosteric site was either removed or altered. Hence, fumarate is not really an activator, but suppresses the inhibitory effect of l-malate. In addition, residues Arg50, Arg80 and Arg84 showed different roles in organic acid binding. These residues form a triad, which is the basis of the homo and heterotrophic effects that characterize NAD-ME1. The binding of L-malate and fumarate at the same allosteric site is herein reported for a malic enzyme and clearly indicates an important role of NAD ME1 in processes that control flow of C4 organic acids in Arabidopsis mitochondrial metabolism. PMID- 25433628 TI - Protective efficacy of prolonged co-trimoxazole prophylaxis in HIV-exposed children up to age 4 years for the prevention of malaria in Uganda: a randomised controlled open-label trial. AB - BACKGROUND: WHO recommends daily co-trimoxazole for children born to HIV-infected mothers from 6 weeks of age until breastfeeding cessation and exclusion of HIV infection. We have previously reported on the effectiveness of continuation of co trimoxazole prophylaxis up to age 2 years in these children. We assessed the protective efficacy and safety of prolonging co-trimoxazole prophylaxis until age 4 years in HIV-exposed children. METHODS: We undertook an open-label randomised controlled trial alongside two observational cohorts in eastern Uganda, an area with high HIV prevalence, malaria transmission intensity, and antifolate resistance. We enrolled HIV-exposed infants between 6 weeks and 9 months of age and prescribed them daily co-trimoxazole until breastfeeding cessation and HIV status confirmation. At the end of breastfeeding, children who remained HIV uninfected were randomly assigned (1:1) to discontinue co-trimoxazole or to continue taking it up to age 2 years. At age 2 years, children who continued co trimoxazole prophylaxis were randomly assigned (1:1) to discontinue or continue prophylaxis from age 2 years to age 4 years. The primary outcome was incidence of malaria (defined as the number of treatments for new episodes of malaria diagnosed with positive thick smear) at age 4 years. For additional comparisons, we observed 48 HIV-infected children who took continuous co-trimoxazole prophylaxis and 100 HIV-unexposed uninfected children who never received prophylaxis. We measured grade 3 and 4 serious adverse events and hospital admissions. All children were followed up to age 5 years and all analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00527800. FINDINGS: 203 HIV-exposed infants were enrolled between Aug 10, 2007, and March 28, 2008. After breastfeeding ended, 185 children were not infected with HIV and were randomly assigned to stop (n=87) or continue (n=98) co trimoxazole up to age 2 years. At age 2 years, 91 HIV-exposed children who had remained on co-trimoxazole prophylaxis were randomly assigned to discontinue (n=46) or continue (n=45) co-trimoxazole from age 2 years to age 4 years. We recorded 243 malaria episodes (2.91 per person-years) in the 45 HIV-exposed children assigned to continue co-trimoxazole until age 4 years compared with 503 episodes (5.60 per person-years) in the 46 children assigned to stop co trimoxazole at age 2 years (incidence rate ratio 0.53, 95% CI 0.39-0.71; p< 0.0001). There was no evidence of malaria incidence rebound in the year after discontinuation of co-trimoxazole in the HIV-exposed children who stopped co trimoxazole at age 2 years, but incidence increased significantly in HIV-exposed children who stopped co-trimoxazole at age 4 years (odds ratio 1.78, 95% CI 1.19 2.66; p= 0.005). Incidence of grade 3 or 4 serious adverse events, hospital admissions, or deaths did not significantly differ between HIV-exposed, HIV unexposed, and HIV-infected children. PMID- 25433631 TI - Sesquiterpene lactones from the aerial parts of Vernonia blumeoides growing in Nigeria. AB - Four eudesmanolide sesquiterpene lactones (1-4) were isolated from the aerial parts of Vernonia blumeoides used in Nigerian ethnomedicine for the treatment of diarrhea and malaria. Compound 1 demonstrated limited but interesting antibacterial activity against Bacillus, Staphylococcus and Streptococcus species. The crystal structure of 1 allowed the absolute configuration of the stereocentres in the molecule to be assigned. PMID- 25433632 TI - Biosynthetic relationship between C28-brassinosteroids and C29-brassinosteroids in rice (Oryza sativa) seedlings. AB - A crude enzyme solution was prepared from young rice seedlings, and the metabolism of C29-brassinosteroids identified from the seedlings was examined. When 28-homoteasterone was added as a substrate, 28-homotyphasterol, teasterone, and 26-nor-28-homoteasterone were characterized as enzyme products by GC-MS/SIM analysis. With 28-homotyphasterol, 28-homoteasterone, typhasterol, 28 homocastasterone, and 26-nor-28-homotyphasterol were formed and identified as products. When 28-homocastasterone was used, castasterone and 26-nor-28 homocastasterone were identified as products. Together with the reduced biological activity of C29-brassinosteroids and their metabolites in the rice lamina inclination assay, these metabolic studies suggest a biosynthetic sequence, 28-homoteasterone<->28-homotyphasterol->28-homocastasterone for C29 brassinosteroid biosynthesis is connected to the biosynthetic sequence teasterone<->typhasterol->castasterone for C28-brassinosteroids by C-28 demethylation, i.e., in order to increase biological activity in the rice plant. Additionally, the C29-brassinosteroids seem to bio-degrade their C-26 demethylated C28-brassinosteroid analogs to reduce brassinosteroid activity in planta. In conclusion, the biosynthesis of C29-brassinosteroids is a likely alternative route to the biologically-active brassinosteroid, castasterone, in rice. PMID- 25433633 TI - Truffles contain endocannabinoid metabolic enzymes and anandamide. AB - Truffles are the fruiting body of fungi, members of the Ascomycota phylum endowed with major gastronomic and commercial value. The development and maturation of their reproductive structure are dependent on melanin synthesis. Since anandamide, a prominent member of the endocannabinoid system (ECS), is responsible for melanin synthesis in normal human epidermal melanocytes, we thought that ECS might be present also in truffles. Here, we show the expression, at the transcriptional and translational levels, of most ECS components in the black truffle Tuber melanosporum Vittad. at maturation stage VI. Indeed, by means of molecular biology and immunochemical techniques, we found that truffles contain the major metabolic enzymes of the ECS, while they do not express the most relevant endocannabinoid-binding receptors. In addition, we measured anandamide content in truffles, at different maturation stages (from III to VI), through liquid chromatography-mass spectrometric analysis, whereas the other relevant endocannabinoid 2-arachidonoylglycerol was below the detection limit. Overall, our unprecedented results suggest that anandamide and ECS metabolic enzymes have evolved earlier than endocannabinoid-binding receptors, and that anandamide might be an ancient attractant to truffle eaters, that are well equipped with endocannabinoid-binding receptors. PMID- 25433634 TI - Differential immune-stimulatory effects of LTAs from different lactic acid bacteria via MAPK signaling pathway in RAW 264.7 cells. AB - OBJECTIVE: Lipoteichoic acid (LTA) is an immune-stimulatory component found in the cell wall of lactic acid bacteria, which are a major group of Gram-positive bacteria known to have beneficial health effects in humans. In this study, we evaluated the stimulatory effects of LTAs isolated from different lactobacilli species with mouse macrophage RAW 264.7 cells. METHODS: RAW 264.7 cells were stimulated with pLTA (isolated from Lactobacillus plantarum K8), rLTA (isolated from Lactobacillus rhamnosus), dLTA (isolated from Lactobacillus delbreukii), and sLTA (isolated from Lactobacillus sakei K101). Tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 production were examined by ELISA, and nitric oxide (NO) production was assayed using Griess reaction. The mRNA and protein expression levels of inducible nitric oxide synthase (iNOS) was examined by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting. Signaling molecules were also examined by Western blotting. RESULTS: pLTA and rLTA moderately induced TNF-alpha, IL-10, and NO production compared with stimulation of RAW 264.7 cells with dLTA and sLTA. Similar results were obtained for the mRNA and protein expression levels of iNOS. Western blot analysis showed that treatment of cells with pLTA or rLTA resulted in minimal phosphorylation of ERK, JNK and p38 MAPK while, dLTA and sLTA were strong activators of MAPK signaling. In addition, the glycolipid structure of LTAs was found to be composed of different fatty acid chain groups and lengths. Taken together, these results suggest that the differential immuno-stimulatory effects of LTAs isolated from different lactobacillus species may be related to their different ability to activate the MAPK signaling pathway, which are modulated by a unique glycolipid structure of LTA. PMID- 25433635 TI - Receptor activating NF-kappaB ligand (RANKL) is a constitutive intracellular protein in resting human basophils and is strongly induced on their surface by interleukin 3. AB - Receptor activating NF-kappaB ligand (RANKL) is a member of the TNF superfamily that plays a pivotal role in bone homeostasis as being the major osteoclastogenesis factor. RANKL also has pleiotropic effects in the immune system in which it is expressed by activated T and B cells and some innate lymphoid cells. RANKL-RANK interactions mediate lymph node organogenesis and immunoregulatory functions in autoimmune disease and carcinogenesis as well as cross talk between the immune system and bone. In this study, we show that basophils were the strongest RANKL mRNA-expressing cells amongst major leukocyte subsets in human blood. RANKL was preformed as an intracellular protein in resting basophils and was rapidly and strongly expressed on their surface upon stimulation with IL-3, but not other stimuli. This expression was stable for at least 6 days. Activated basophils could also release soluble RANKL in small quantities upon interaction with DCs or monocytes. In the blood, basophils were the sole cells to express membrane RANKL in response to IL-3. This study indicates that basophils should be considered as new players in the pleiotropic and complex RANKL-RANK interaction system and suggests a role for RANKL in the interaction between basophils and immune cells in inflammatory allergic tissues and secondary lymphoid organs. PMID- 25433636 TI - Vesicular glutamate transporters use flexible anion and cation binding sites for efficient accumulation of neurotransmitter. AB - Vesicular glutamate transporters (VGLUTs) accumulate the neurotransmitter glutamate in synaptic vesicles. Transport depends on a V-ATPase-dependent electrochemical proton gradient (DeltaMUH+) and requires chloride ions, but how chloride acts and how ionic and charge balance is maintained during transport is controversial. Using a reconstitution approach, we used an exogenous proton pump to drive VGLUT-mediated transport either in liposomes containing purified VGLUT1 or in synaptic vesicles fused with proton-pump-containing liposomes. Our data show that chloride stimulation can be induced at both sides of the membrane. Moreover, chloride competes with glutamate at high concentrations. In addition, VGLUT1 possesses a cation binding site capable of binding H+ or K+ ions, allowing for proton antiport or K+ / H+ exchange. We conclude that VGLUTs contain two anion binding sites and one cation binding site, allowing the transporter to adjust to the changing ionic conditions during vesicle filling without being dependent on other transporters or channels. PMID- 25433637 TI - A dopamine D2 receptor-DISC1 protein complex may contribute to antipsychotic-like effects. AB - Current antipsychotic drugs primarily target dopamine D2 receptors (D2Rs), in conjunction with other receptors such as those for serotonin. However, these drugs have serious side effects such as extrapyramidal symptoms (EPS) and diabetes. Identifying a specific D2R signaling pathway that could be targeted for antipsychotic effects, without inducing EPS, would be a significant improvement in the treatment of schizophrenia. We report here that the D2R forms a protein complex with Disrupted in Schizophrenia 1 (DISC1) that facilitates D2R-mediated glycogen synthase kinase (GSK)-3 signaling and inhibits agonist-induced D2R internalization. D2R-DISC1 complex levels are increased in conjunction with decreased GSK-3alpha/beta (Ser21/9) phosphorylation in both postmortem brain tissue from schizophrenia patients and in Disc1-L100P mutant mice, an animal model with behavioral abnormalities related to schizophrenia. Administration of an interfering peptide that disrupts the D2R-DISC1 complex successfully reverses behaviors relevant to schizophrenia but does not induce catalepsy, a strong predictor of EPS in humans. PMID- 25433638 TI - Spatially selective holographic photoactivation and functional fluorescence imaging in freely behaving mice with a fiberscope. AB - Correlating patterned neuronal activity to defined animal behaviors is a core goal in neuroscience. Optogenetics is one large step toward achieving this goal, yet optical methods to control neural activity in behaving rodents have so far been limited to perturbing all light-sensitive neurons in a large volume. Here we demonstrate an all-optical method for precise spatial control and recording of neuronal activity in anesthetized and awake freely behaving mice. Photoactivation patterns targeted to multiple neuronal somata, produced with computer-generated holography, were transmitted to the mouse brain using a micro-objective-coupled fiber bundle. Fluorescence imaging through the same device, via epifluorescence, structured illumination, or scanless multipoint confocal microscopy, allowed imaging of neurons and recording of neuronal activity. The fiberscope was tested in mice coexpressing ChR2-tdTomato and GCaMP5-G in cerebellar interneurons, delivering near-cellular resolution photoactivation in freely behaving mice. PMID- 25433639 TI - Pervasive axonal transport deficits in multiple sclerosis models. AB - Impaired axonal transport can contribute to axon degeneration and has been described in many neurodegenerative diseases. Multiple sclerosis (MS) is a common neuroinflammatory disease, which is characterized by progressive axon degeneration-whether, when, and how axonal transport is affected in this condition is unknown. Here we used in vivo two-photon imaging to directly assay transport of organelles and the stability of microtubule tracks in individual spinal axons in mouse models of MS. We found widespread transport deficits, which preceded structural alterations of axons, cargos, or microtubules and could be reversed by acute anti-inflammatory interventions or redox scavenging. Our study shows that acute neuroinflammation induces a pervasive state of reversible axonal dysfunction, which coincides with acute disease symptoms. Moreover, perpetuated transport dysfunction, as we found in a model of progressive MS, led to reduced distal organelle supply and could thus contribute to axonal dystrophy in advanced stages of the disease. PMID- 25433640 TI - Signaling switch of the axon guidance receptor Robo3 during vertebrate evolution. AB - Development of neuronal circuits is controlled by evolutionarily conserved axon guidance molecules, including Slits, the repulsive ligands for roundabout (Robo) receptors, and Netrin-1, which mediates attraction through the DCC receptor. We discovered that the Robo3 receptor fundamentally changed its mechanism of action during mammalian evolution. Unlike other Robo receptors, mammalian Robo3 is not a high-affinity receptor for Slits because of specific substitutions in the first immunoglobulin domain. Instead, Netrin-1 selectively triggers phosphorylation of mammalian Robo3 via Src kinases. Robo3 does not bind Netrin-1 directly but interacts with DCC. Netrin-1 fails to attract pontine neurons lacking Robo3, and attraction can be restored in Robo3(-/-) mice by expression of mammalian, but not nonmammalian, Robo3. We propose that Robo3 evolution was key to sculpting the mammalian brain by converting a receptor for Slit repulsion into one that both silences Slit repulsion and potentiates Netrin attraction. PMID- 25433641 TI - Alternative right ventricular assist device implantation technique for patients with perioperative right ventricular failure. AB - OBJECTIVES: Temporary right ventricular assist devices (RVADs) may be required to support patients with perioperative refractory right ventricular failure (RVF). We report on our experience using a different technique of RVAD implantation that does not necessitate resternotomy at the time of RVAD removal. METHODS: Patients with perioperative RVF who underwent temporary RVAD implantation between January 2010 and February 2014 were reviewed. A dacron graft was attached to the pulmonary artery and passed through a subxiphoid exit, where the RVAD outflow cannula was inserted. The inflow cannula was percutaneously cannulated in the femoral vein, and the sternum was primarily closed. On the day of RVAD explantation, the outflow graft of the RVAD was pulled and ligated, and the insertion site was secondarily closed. The RVAD inflow cannula was removed, and direct pressure was applied. RESULTS: Twenty-one patients (age 58 +/- 14 years) were supported. Seventeen patients (81%) had RVF after left ventricular assist device implantation, and 4 patients developed postcardiotomy RVF. The median duration of RVAD support was 9 days (range: 2-88 days). Eleven patients (52%) were successfully weaned from the RVAD. Two patients were bridged to transplantation. Eight patients died on left ventricular assist device and/or RVAD support. The survival rates to discharge or heart transplantation, and to 1 year, were 62% and 52%, respectively. CONCLUSIONS: No technical issues were encountered in this large series of RVAD implantations using the described technique for various forms of postoperative RVF. Extended support duration and reduction of resternotomy risks may be the main advantages of this technique compared with conventional RVAD implantation methods. PMID- 25433642 TI - The effect of postoperative medical treatment on left ventricular mass regression after aortic valve replacement. AB - OBJECTIVE: The study objective was to analyze factors associated with left ventricular mass regression in patients undergoing aortic valve replacement with a newer bioprosthesis, the Trifecta valve pericardial bioprosthesis (St Jude Medical Inc, St Paul, Minn). METHODS: A total of 444 patients underwent aortic valve replacement with the Trifecta bioprosthesis from 2007 to 2009 at 6 US institutions. The clinical and echocardiographic data of 200 of these patients who had left ventricular hypertrophy and follow-up studies 1 year postoperatively were reviewed and compared to analyze factors affecting left ventricular mass regression. RESULTS: Mean (standard deviation) age of the 200 study patients was 73 (9) years, 66% were men, and 92% had pure or predominant aortic valve stenosis. Complete left ventricular mass regression was observed in 102 patients (51%) by 1 year postoperatively. In univariate analysis, male sex, implantation of larger valves, larger left ventricular end-diastolic volume, and beta-blocker or calcium-channel blocker treatment at dismissal were significantly associated with complete mass regression. In the multivariate model, odds ratios (95% confidence intervals) indicated that male sex (3.38 [1.39-8.26]) and beta-blocker or calcium-channel blocker treatment at dismissal (3.41 [1.40-8.34]) were associated with increased probability of complete left ventricular mass regression. Patients with higher preoperative systolic blood pressure were less likely to have complete left ventricular mass regression (0.98 [0.97-0.99]). CONCLUSIONS: Among patients with left ventricular hypertrophy, postoperative treatment with beta-blockers or calcium-channel blockers may enhance mass regression. This highlights the need for close medical follow-up after operation. Labeled valve size was not predictive of left ventricular mass regression. PMID- 25433643 TI - Proteinuria predicts postcardiotomy acute kidney injury in patients with preserved glomerular filtration rate. AB - OBJECTIVE: Acute kidney injury is a common and serious problem after cardiac surgery. Postoperative acute kidney injury is independently associated with in hospital mortality and long-term morbidity, even after adjustment for comorbid diseases. Chronic kidney disease has been recognized as a strong risk factor of acute kidney injury after cardiac surgery. The association between proteinuria and postcardiotomy acute kidney injury in patients with preserved glomerular filtration rate remains uncertain. METHODS: Patients with an estimated glomerular filtration rate greater than 60 mL/min/1.73 m(2) who underwent cardiac surgery between January 2003 and December 2007 in a tertiary medical center were retrospectively analyzed. Dipstick urinalysis was performed before surgery. Proteinuria was categorized into negative, trace, 1+, 2+, or 3+. Postoperative acute kidney injury was defined by the Acute Kidney Injury Network criteria. Multinomial logistic regression was used to clarify whether proteinuria is an independent risk factor of postoperative acute kidney injury. RESULTS: A total of 1246 patients were included in this study, with a mean estimated glomerular filtration rate of 80 +/- 13 mL/min/1.73 m(2). Proteinuria was present in 290 patients (23.4%). Postoperative acute kidney injury developed in 434 patients (34.8%), and 36 patients (2.9%) required renal replacement therapy. Proteinuria was independently associated with all stages of postcardiotomy acute kidney injury and dialysis-requiring acute kidney injury. The crude risk of acute kidney injury was greater in patients with a higher grade of proteinuria. In subgroup analysis for gender, diabetes, and surgical type, preoperative proteinuria remains a strong risk factor of acute kidney injury after cardiac surgery. CONCLUSIONS: Urine analysis is usually neglected before cardiac surgery despite the fact that proteinuria is the earliest manifestation of kidney dysfunction. In the current study, we show that urine protein is strongly and independently associated with postoperative acute kidney injury in subjects with preserved estimated glomerular filtration rate. These data suggest that such a relatively simple and clinically easy to use tool as a urinary dipstick may be useful to identify patients at high risk of acute kidney injury before cardiac surgery. PMID- 25433644 TI - Living related donor middle lobe lung transplant in a pediatric patient. PMID- 25433645 TI - Preoperative pain level and patient expectation predict hospital length of stay after total hip arthroplasty. AB - The purpose of this study was to identify preoperative predictors of length of stay after primary total hip arthroplasty in a patient population reflecting current trends toward shorter hospitalization and using readily obtainable factors that do not require scoring systems. A retrospective review of 112 consecutive patients was performed. High preoperative pain level and patient expectation of discharge to extended care facilities (ECFs) were the only significant multivariable predictors of hospitalization extending beyond 2 days (P=0.001 and P<0.001 respectively). Patient expectation remained significant after adjusting for Medicare's 3-day requirement for discharge to ECFs (P<0.001). The study was adequately powered to analyze the variables in the multivariable logistic regression model, which had a concordance index of 0.857. PMID- 25433646 TI - Alteration in clinico-biochemical profile and oxidative stress indices associated with hyperglycaemia with special reference to diabetes in cattle--a pilot study. AB - The present study aimed to assess hyperglycaemia with special reference to diabetes mellitus in cattle by clinico-biochemical estimation and evaluation of oxidative stress indices. A total of 256 cattle exhibiting weakness, poor body condition and reduced milk yield in lactating cattle were included in the study. These animals were screened with blood glucose level, urine glucose and ketone bodies. Out of these, 32 (12.5%) cattle showed hyperglycaemia and glycosuria, of which 25% exhibited ketonuria. Diabetes was confirmed in five cattle by estimation of fasting blood glucose, glycated haemoglobin, serum fructosamine, intravenous glucose tolerance test and insulin level. This reports first confirmation of diabetes in cattle in India. All these five animals revealed low level of serum insulin suggestive of insulin-dependent diabetes mellitus in cattle. The level of aspartate aminotransferase (AST) and gamma glutamyl transferase (GGT) was found to be increased in diabetic cattle. Oxidant/antioxidant balance was assessed in hyperglycaemic cattle and five age matched Holstein Friesian (HF) cross-bred healthy control animals. Diabetic cattle revealed significantly higher (P <= 0.01) levels of erythrocytic lipid peroxides in comparison with other hyperglycaemic cattle and healthy controls whereas the level of superoxide dismutase (SOD) and catalase was found to be significantly lower in diabetes-affected animals in comparison to healthy controls. Reduced glutathione did not show a significant difference between hyperglycaemic and control groups. It is concluded from the present study that oxidative stress associated with diabetes in cattle is obvious compared with other hyperglycaemic cattle. PMID- 25433647 TI - Breeding objectives for pigs in Kenya. II: economic values incorporating risks in different smallholder production systems. AB - This study estimated economic values for production traits (dressing percentage (DP), %; live weight for growers (LWg), kg; live weight for sows (LWs), kg) and functional traits (feed intake for growers (FEEDg), feed intake for sow (FEEDs), preweaning survival rate (PrSR), %; postweaning survival (PoSR), %; sow survival rate (SoSR), %, total number of piglets born (TNB) and farrowing interval (FI), days) under different smallholder pig production systems in Kenya. Economic values were estimated considering two production circumstances: fixed-herd and fixed-feed. Under the fixed-herd scenario, economic values were estimated assuming a situation where the herd cannot be increased due to other constraints apart from feed resources. The fixed-feed input scenario assumed that the herd size is restricted by limitation of feed resources available. In addition to the tradition profit model, a risk-rated bio-economic model was used to derive risk rated economic values. This model accounted for imperfect knowledge concerning risk attitude of farmers and variance of input and output prices. Positive economic values obtained for traits DP, LWg, LWs, PoSR, PrSR, SoSR and TNB indicate that targeting them in improvement would positively impact profitability in pig breeding programmes. Under the fixed-feed basis, the risk-rated economic values for DP, LWg, LWs and SoSR were similar to those obtained under the fixed herd situation. Accounting for risks in the EVs did not yield errors greater than +/-50 % in all the production systems and basis of evaluation meaning there would be relatively little effect on the real genetic gain of a selection index. Therefore, both traditional and risk-rated models can be satisfactorily used to predict profitability in pig breeding programmes. PMID- 25433648 TI - Syndromic surveillance of peste des petits ruminants and other animal diseases in Koinadugu district, Sierra Leone, 2011-2012. AB - PURPOSE: The purpose of this study was to conduct syndromic surveillance for important veterinary diseases in Koinadugu district, Northern Province, Sierra Leone. METHODS: This study examined all veterinary syndromic surveillance reports submitted to the district veterinary office from January 2011 through December 2012. RESULTS: In total, 5679 case reports were submitted, including 2394 fatalities. The most common syndrome reported was consistent with peste de petits ruminants (PPR) in goats (n = 1649). PPR cases were reported from eight of 11 chiefdoms in the district, with a 42 per 1000 reported incidence rate and a 48 % case fatality rate. Other syndromes reported were consistent with trypanosomiasis in cattle (n = 1402), Newcastle disease in poultry (n = 911), black quarter in cattle (n = 691), and haemorrhagic septicaemia in cattle (n = 542). CONCLUSIONS: Expanded use of the PPR virus vaccine may be required to help control the spread of the infection. Improved community-based prevention efforts may be effective for better control of trypanosomiasis and all these conditions. PMID- 25433649 TI - Smallholder farmers' attitudes toward the provision of drinking water for dairy cows in Kagera, Tanzania. AB - Agriculture's large share of Tanzanian GDP and the large percentage of rural poor engaged in the sector make it a focus for many development projects that see it as an area of attention for reducing rural poverty. This paper uses a case of the Kamachumu community, where a dairy cow loan project was implemented using the heifer-in-trust (HIT) model. This study finds that productivity is limited by how the cows are being managed, particularly with many animals not having ad lib access to drinking water. The paper explores reasons why farmers do or do not provide their cows with unlimited access to drinking water. The study concludes that there are many barriers farmers face, including water accessibility, education and training, infrastructure, simple negligence, and security. These results suggest an increase in extension services and national and local livestock policies that consider the specific realities of small-scale dairy farmers. PMID- 25433650 TI - Seroprevalence of contagious bovine pleuropneumonia (CBPP) in Mali. AB - A serological survey to determine the prevalence of contagious bovine pleuropneumonia (CBPP) in Mali was carried out by using the competitive enzyme linked-immunosorbent test (c-ELISA) on 8007 serum samples systematically collected from 199 cattle herds collected throughout the whole country. Results showed a national prevalence of 18.11 % at the individual level and 85.93 % at the herd level. Significant variations in the individual prevalence were observed between regions of the country and ranged from 4.63 % in Tombouctou to 54.88 % in Kidal. At the herd level, although there were variations between regions, a high prevalence was constantly observed ranging from 60 to 100 %, hence confirming the endemic nature of the disease across the country. The CBPP risk varied also between regions and was very low in Tombouctou (odds ratio (OR) = 0.4) but very high in Kidal (OR = 9.8). Similarly, the risk seemed higher in the animals of the over 3-year age group (OR = 1.6) compared to the other age groups. It was also observed that there was a slightly higher risk (OR = 1.3) in the females than in the males. This study confirms the presence of CBPP across the country and should help to elaborate strategies for the effective control of the disease. PMID- 25433651 TI - Engagement in HIV Prevention Advocacy Associated with Increased Consistent Condom Use Among HIV Clients in Uganda. AB - We examined whether engagement in prevention advocacy among HIV clients is associated with their own condom use and HIV care adherence. Longitudinal data merged from three studies in Uganda produced a sample of 1,882 participants who were administered assessments at baseline and months 6 and 12. The measure of prevention advocacy was the mean of two Likert scale items assessing encouragement of others to (1) use condoms, and (2) get HIV tested. In regression analyses controlling for demographics and known correlates of the dependent variables, increased prevention advocacy from baseline to month 12 was significantly associated with increased consistent condom use and marginally associated with increased antiretroviral adherence and clinic attendance. These results suggest that empowering HIV clients to engage in prevention advocacy with others may benefit their own HIV protective behaviors and should be promoted as a component to interventions targeting positive living among people living with HIV. PMID- 25433652 TI - Comparison of pharmacy-based measures of adherence to antiretroviral therapy as predictors of virological failure. AB - We compared multiple pharmacy refill-based adherence indicators for antiretroviral therapy, as well as thresholds for defining non-adherent behavior, based on ability to predict virological failure. A total of 29,937 pharmacy visits with corresponding viral load assessments were contributed by 8,695 patients attending a large clinic in Johannesburg, South Africa. Indicators based on pill coverage and timing of refill pickup performed comparably using the strictest thresholds for adherence [100 % pill coverage: odds ratio (OR) (95 % confidence interval (CI)) : 1.26 (1.15, 1.39); prescription picked up on or before scheduled refill date: 1.27 (1.16,1.38)]. For both types of indicators, the association between non-adherence and virological failure increased as the threshold defining adherent behavior was lowered. All measures demonstrated high specificity (range 84-98 %), but low sensitivity (5-19 %). In this setting, patients identified as non-adherent using pharmacy-based indicators are likely correctly classified and in need of interventions to improve compliance. Pharmacy based measures alone, however, are inadequate for identifying most cases of nonadherence. PMID- 25433654 TI - Gender inequalities in the treatment of osteoporosis. AB - INTRODUCTION: Our aim was to perform both gender- and age-specific analysis regarding the utilisation of anti-osteoporotic drugs in Hungary, between 2007 and 2011, and to compare our results with other European countries. METHODS: The database of the Hungarian National Health Insurance Fund was screened for anti osteoporotic medications, covering 100% of the Hungarian population (10 million people). ICD coding system (International Classification of Diseases) and WHO ATC/DDD methodology were used for medication screening and analysis. RESULTS: In Hungary, the total bisphosphonate use was 6.66 DDD/TID (Defined Daily Dose/1000 inhabitants/day) in 2007, and 6.22 DDD/TID in 2011; the rate of bisphosphonate combinations slightly increased from 1.60 to 2.81 DDD/TID. The total vitamin D use almost doubled (13.73 DDD/TID in 2011), while the calcium supplementation tripled (4.47 DDD/TID in 2011), and so did the strontium ranelate utilisation (0.70 DDD/TID in 2011) within the investigated time period. Denosumab consumption was marginal. Male patients were disproportionately, 10-20 times undertreated in all age groups, and treatment choice was restricted among men. Several differences were seen in our results compared to those in Baltic countries, Finland and in Norway. CONCLUSIONS: Men were significantly undertreated in all age groups, compared to women. The 10 to 20-fold difference calls attention to this unrecognised problem. PMID- 25433655 TI - In vivo imaging of Nematostella vectensis embryogenesis and late development using fluorescent probes. AB - BACKGROUND: Cnidarians are the closest living relatives to bilaterians and have been instrumental to studying the evolution of bilaterian properties. The cnidarian model, Nematostella vectensis, is a unique system in which embryology and regeneration are both studied, making it an ideal candidate to develop in vivo imaging techniques. Live imaging is the most direct way for quantitative and qualitative assessment of biological phenomena. Actin and tubulin are cytoskeletal proteins universally important for regulating many embryological processes but so far studies in Nematostella primarily focused on the localization of these proteins in fixed embryos. RESULTS: We used fluorescent probes expressed in vivo to investigate the dynamics of Nematostella development. Lifeact-mTurquoise2, a fluorescent cyan F-actin probe, can be visualized within microvilli along the cellular surface throughout embryonic development and is stable for two months after injection. Co-expression of Lifeact-mTurquoise2 with End-Binding protein1 (EB1) fused to mVenus or tdTomato-NLS allows for the visualization of cell-cycle properties in real time. Utilizing fluorescent probes in vivo helped to identify a concentrated 'flash' of Lifeact-mTurquoise2 around the nucleus, immediately prior to cytokinesis in developing embryos. Moreover, Lifeact-mTurquoise2 expression in adult animals allowed the identification of various cell types as well as cellular boundaries. CONCLUSION: The methods developed in this manuscript provide an alternative protocol to investigate Nematostella development through in vivo cellular analysis. This study is the first to utilize the highly photo-stable florescent protein mTurquoise2 as a marker for live imaging. Finally, we present a clear methodology for the visualization of minute temporal events during cnidarian development. PMID- 25433656 TI - Comparison of PAX6 and PAX8 as immunohistochemical markers for pancreatic neuroendocrine tumors. AB - To compare the utility of PAX6 and PAX8 as immunohistochemical markers for neuroendocrine tumors (NETs) of pancreatic origin, we performed PAX6 and PAX8 immunostains on 178 NETs, including 110 primary NETs (26 pancreatic, 10 gastric, 12 duodenal, 22 jejuno-ileal, 10 rectal, 30 pulmonary) and 68 NETs metastatic to the liver (24 pancreatic, 1 duodenal, 37 jejuno-ileal, 1 rectal, 5 pulmonary). Among primary NETs, PAX6 and PAX8 were positive in 65 % (17/26) and 73 % (19/26) of pancreatic, 0 % (0/10) and 10 % (1/10) of gastric, 92 % (11/12) and 92 % (11/12) of duodenal, 0 % (0/22) and 0 % (0/22) of jejuno-ileal, 90 % (9/10) and 80 % (8/10) of rectal, and 0 % (0/30) and 23 % (7/30) of pulmonary NETs, respectively. PAX6 and PAX8 positivity was seen in 46 % (11/24) and 50 % (12/24) of metastatic pancreatic NETs to the liver, respectively. None of the nonpancreatic NETs metastatic to the liver were immunoreactive for either PAX6 or PAX8. PAX6 showed a slightly but statistically significant higher specificity for pancreatic NETs than did PAX8 (P = 0.039), while the sensitivities were similar (P = 0.51). PAX6 had the additional advantages over PAX8 of not exhibiting nonspecific cytoplasmic staining of tumor cells and only infrequently staining background lymphocytes. Since rectal NETs rarely present with metastatic disease, positive staining of a metastatic NET of unknown primary origin for PAX6 and/or PAX8 favors a pancreatic or duodenal origin. This information may be helpful in directing further diagnostic studies to identify the primary site of the metastatic tumor. PMID- 25433653 TI - Evaluating a Brief, Video-Based Sexual Risk Reduction Intervention and Assessment Reactivity with STI Clinic Patients: Results from a Randomized Controlled Trial. AB - We report results from a randomized controlled trial designed to evaluate the efficacy of a video-based sexual risk reduction intervention and to measure assessment reactivity. Patients (N = 1010; 56 % male; 69 % African American) receiving care at a sexually transmitted infection (STI) clinic were assigned to one of four conditions formed by crossing assessment condition (i.e., sexual health vs. general health) with intervention condition (i.e., sexual risk reduction intervention vs. general health promotion). After completing their assigned baseline assessment, participants received their assigned intervention, and subsequently returned for follow-up assessments at 3, 6, 9, and 12 months. Participants in all conditions reduced their self-reported sexual risk behavior, and the incidence of new STIs declined from baseline through the follow-ups; however, there was no effect of intervention or assessment condition. We conclude that further risk reduction will require more intensive interventions, especially in STI clinics that already provide excellent clinical care. PMID- 25433658 TI - Oral health status and oral health knowledge, attitudes and behavior among rural children in Shaanxi, western China: a cross-sectional survey. AB - BACKGROUND: The current oral health status and possible dental risk factors among children in rural Shaanxi Province, western China are unreported. This study aimed to describe the oral health status and to analyze the possible risk factors for the oral health status in this population. METHODS: A multi-stage cluster sampling method was used to survey 12- to 15-year-olds and 4- to 6-year-olds in villages in Shaanxi Province. The structured questionnaires were provided to the 12- to 15-year-olds and to the caregivers of the 4- to 6-year-olds to collect information on the subjects' oral health knowledge, attitudes and behavior. A clinical examination was performed to assess dental caries and gingival bleeding (only 12- to 15-year-olds). SPSS 17.0 statistical software was used to analyze the data. RESULTS: The decayed, missing, filled teeth (DMFT) index scores of 12- to 15-year-olds and 4-to 6-year-olds averaged 0.45 and 3.05, respectively. The caries prevalence was 23.9% in 12- to 15-year-olds and 67% in 4-to 6-year-olds. Additionally, 45.2% of the 12- to 15-year-olds had gingival bleeding and 62.8% had calculus. The oral health knowledge of the subjects was generally poor, whereas they held very positive attitudes toward oral health. A low number of participants reported that they brushed their teeth at least twice daily. Moreover, a statistically significant relationship was found between oral health knowledge scores, tooth brushing frequency and DMFT scores as well as gingival bleeding in the 12- to 15-year-olds. Frequency of sweets consumption was strongly related to dmft scores in the 4- to 6-year-olds. CONCLUSION: The oral health status, oral health knowledge and behaviors among village children in Shaanxi Province are poor. Oral health education to improve oral health knowledge and to increase the frequency of tooth brushing should be undertaken in the rural schools in western China. PMID- 25433657 TI - Cyclohexane produces behavioral deficits associated with astrogliosis and microglial reactivity in the adult hippocampus mouse brain. AB - Cyclohexane is a volatile substance that has been utilized as a safe substitute of several organic solvents in diverse industrial processes, such as adhesives, paints, paint thinners, fingernail polish, lacquers, and rubber industry. A number of these commercial products are ordinarily used as inhaled drugs. However, it is not well known whether cyclohexane has noxious effects in the central nervous system. The aim of this study was to analyze the effects of cyclohexane inhalation on motor behavior, spatial memory, and reactive gliosis in the hippocampus of adult mice. We used a model that mimics recreational drug use in male Balb/C mice (P60), divided into two groups: controls and the cyclohexane group (exposed to 9,000 ppm of cyclohexane for 30 days). Both groups were then evaluated with a functional observational battery (FOB) and the Morris water maze (MWM). Furthermore, the relative expression of AP endonuclease 1 (APE1), and the number of astrocytes (GFAP+ cells) and microglia (Iba1+ cells) were quantified in the hippocampal CA1 and CA3 areas. Our findings indicated that cyclohexane produced severe functional deficits during a recreational exposure as assessed by the FOB. The MWM did not show statistically significant changes in the acquisition and retention of spatial memory. Remarkably, a significant increase in the number of astrocytes and microglia cells, as well as in the cytoplasmic processes of these cells were observed in the hippocampal CA1 and CA3 areas of cyclohexane-exposed mice. This cellular response was associated with an increase in the expression of APE1 in the same brain regions. In summary, cyclohexane exposure produces functional deficits that are associated with an important increase in the APE1 expression as well as the number of astrocytes and microglia cells and their cytoplasmic complexity in the CA1 and CA3 regions of the adult hippocampus. PMID- 25433660 TI - Partial Androgen Insensitivity Syndrome Presenting with Gynecomastia. AB - Gynecomastia is a benign enlargement of the male breast caused by the proliferation of glandular breast tissue. Determining the various causes of gynecomastia such as physiological causes, drugs, systemic diseases, and endocrine disorders is important. Androgen insensitivity syndrome (AIS) is a rare endocrine disorder presenting with gynecomastia and is a disorder of male sexual differentiation caused by mutations within the androgen receptor gene. All individuals with AIS have the 46 XY karyotype, although AIS phenotypes can be classified as mild, partial or complete and can differ among both males and females including ambiguous genitalia or infertility in males. We experienced a case of partial AIS presenting with gynecomastia and identified the androgen receptor gene mutation. PMID- 25433661 TI - Associations between Dietary Acid-Base Load and Cardiometabolic Risk Factors in Adults: The Tehran Lipid and Glucose Study. AB - BACKGROUND: In this study we investigated the associations of dietary acid-base load, identified by potential renal acid load (PRAL) and protein to potassium (Pro:K) ratio, with cardiometabolic risk factors in Tehranian adults. METHODS: A cross-sectional study was conducted within the framework of the fourth phase of the Tehran Lipid and Glucose Study (2009 to 2011) on 5,620 men and women aged 19 to 70 years. Dietary data were collected by a trained dietitian using a validated, 147-food item, semi-quantitative food frequency questionnaire, and dietary PRAL and Pro:K ratio were calculated. Multiple linear regression models with adjustment for potential confounding variables were used to evaluate the associations of dietary acid-base load with anthropometric measures, blood pressure, serum triglycerides, high density lipoprotein cholesterol (HDL-C), serum creatinine, and fasting blood glucose. RESULTS: The mean+/-SD age of the participants was 39.8+/-12.8 years and 54% of participants were women. Mean+/-SD PRAL was -22.0+/-29.1; mean PRAL was -15.6 in men and -26.8 in women. Dietary PRAL was associated with weight (beta=0.098, P<0.001), waist circumference (beta=0.062, P<0.01), serum triglycerides (beta=0.143, P<0.01), HDL-C (beta= 0.11, P<0.01), diastolic blood pressure (beta=0.062, P<0.01), and serum creatinine (beta=0.142, P<0.001). Pro:K ratio was associated with weight (beta=0.055, P<0.001), waist circumference (beta=0.04, P<0.01), serum HDL-C (beta=-0.06, P<0.01), serum triglycerides (beta=0.03, P<0.05), diastolic blood pressure (beta=0.026, P<0.05), and serum creatinine (beta=0.07, P<0.01). CONCLUSION: A more acidic dietary acid-base load may be a risk factor for the development of metabolic disorders. PMID- 25433662 TI - Lack of Associations between Body Mass Index and Clinical Outcomes in Patients with Papillary Thyroid Carcinoma. AB - BACKGROUND: Obesity is associated with aggressive pathological features and poor clinical outcomes in breast and prostate cancers. In papillary thyroid carcinoma (PTC), these relationships remain still controversial. This study aimed to evaluate the associations between body mass index (BMI) and the clinical outcomes of patients with PTC. METHODS: This retrospective study included 1,189 patients who underwent total thyroidectomy for PTCs equal to or larger than 1 cm in size. Clinical outcomes were evaluated and compared based on the BMI quartiles. RESULTS: There were no significant associations between BMI quartiles and primary tumor size, extrathyroidal invasion, cervical lymph node metastasis, or distant metastasis. However, an increase in mean age was associated with an increased BMI (P for trend <0.001). Multifocality and advanced tumor-node-metastasis (TNM) stage (stage III or IV) were significantly associated with increases of BMI (P for trend 0.02 and <0.001, respectively). However, these associations of multifocality and advanced TNM stage with BMI were not significant in multivariate analyses adjusted for age and gender. Moreover, there were no differences in recurrence-free survivals according to BMI quartiles (P=0.26). CONCLUSION: In the present study, BMI was not associated with the aggressive clinicopathological features or recurrence-free survivals in patients with PTC. PMID- 25433663 TI - Discontinuation of tenofovir disoproxil fumarate for presumed renal adverse events in treatment-naive HIV-1 patients: meta-analysis of randomized clinical studies. AB - BACKGROUND: Safety and efficacy of tenofovir disoproxil fumarate (TDF) as a component of antiretroviral therapy (ART) have been demonstrated in clinical trials. TDF nephrotoxicity has been reported in both HIV-infected and noninfected patients. This meta-analysis explored the frequency of discontinuation attributed to renal adverse events (AEs) in randomized, controlled clinical studies that used TDF-containing regimens for ART-naive, HIV-infected patients. METHODS: A literature search of 4 electronic databases through October 31, 2013 was utilized. RCTs included were limited to randomized, prospective, comparative design in ART treatment-naive adults with HIV-1 infections receiving ART. Studies included trials containing TDF treatment regimens, with or without a non-TDF control group. Study design, follow-up, size of study population, treatment group, patient demographics, number of patients exposed to TDF or non-TDF control, baseline characteristics, investigator-defined criteria for renal AEs, and number of discontinuations due to a presumed renal AEs were extracted. RESULTS: Twenty-one clinical studies met the selection criteria. Treatment duration ranged from 48 to 288 weeks. Renal AEs led to study drug discontinuation in 44 of 10,129 patients exposed to TDF (0.43%; 95% CI, 0.32%-0.58%) and 2 of 2,013 patients exposed to non-TDF-containing regimens (0.10%; 95% CI, 0.01% 0.36%). In 5 randomized, controlled studies that included a non-TDF comparator, the estimated risk difference between the treatment groups (TDF vs non-TDF) was 0.50% (95% CI, 0.13%-0.86%; P = .007). CONCLUSIONS: In clinical studies using TDF containing regimens, the rate of discontinuations due to renal AEs was low, but was slightly higher than in studies using non-TDF comparators. PMID- 25433665 TI - Effectiveness and safety of rilpivirine, a non-nucleoside reverse transcriptase inhibitor, in treatment-naive adults infected with HIV-1: a meta-analysis. AB - OBJECTIVE: The aim of this study was to determine the effectiveness and safety of rilpivirine in treatment-naive adults infected with HIV-1. METHODS: We ran duplicate searches of multiple databases and searchable Web sites of major HIV conferences (May to October 2013) to identify randomized controlled trials reporting the effectiveness and safety of rilpivirine in treatment-naive adults infected with HIV-1. Reference lists from retrieved articles were also reviewed. Data were extracted independently in duplicate using predefined data fields. All analyses used random effects models to calculate the summary treatment effect estimates. RESULTS: Four randomized controlled trials with a total of 2,522 patients were included. The primary efficacy endpoint was the proportion of patients with confirmed HIV-1 RNA levels of <50 copies/mL (viral load) at 48 weeks. Rilpivirine demonstrated noninferior antiviral efficacy in viral load comparable with efavirenz at 48 weeks (relative risk [RR], 1.03; 95% CI, 0.99 1.07). The mean changes from baseline in CD4 count were similar in both rilpivirine and efavirenz (RR, 1.05; 95% CI, 0.85-1.24). Rilpivirine showed higher and significant difference in virological failure rates compared with the efavirenz group (RR, 1.70; 95% CI, 1.21-2.38). The incidences of the most commonly reported adverse events related to study medication, including rash and neurological events, were lower with rilpivirine than with efavirenz (RR, 0.11; 95% CI, 0.03-0.33; RR, 0.52; 95% CI, 0.45-0.60, respectively). CONCLUSIONS: Current evidence suggests a range of favorable effects and a generally favorable safety profile of rilpivirine in treatment-naive adults infected with HIV-1 at week 48. PMID- 25433666 TI - Cobicistat-boosted protease inhibitors in HIV-infected patients with mild to moderate renal impairment. AB - BACKGROUND: Cobicistat (COBI) is a pharmacoenhancer that optimizes systemic exposures of protease inhibitors (PIs) such as atazanavir (ATV) and darunavir (DRV). OBJECTIVE: To evaluate the efficacy and safety of switching ritonavir (RTV) to COBI in patients with creatinine clearance (CrCl) 50 to 89 mL/min who are virologically suppressed on a stable regimen containing ritonavir (RTV) boosted ATV or DRV. Other components of the regimen remained unchanged. METHODS: A phase 3, non-comparative, open-label clinical trial. RESULTS: Seventy-three patients were enrolled. At week 48, 82% maintained virologic suppression. No emergent resistance developed. Serious adverse events (AEs) occurred in 7%, and study drug discontinuation due to AEs occurred in 10% (7 patients). There were 2 renal discontinuations and no cases of proximal renal tubulopathy. Small reductions in CrCl (median [IQR]) were observed as early as week 2, after which they were nonprogressive through week 48 (-3.8 [-9 to 0.8]). Changes in CrCl by baseline CrCl (< 70 vs >= 70) were -1.1 [-6.5 to 6.3] versus -6.6 [-12.4 to 0.7], respectively. CONCLUSIONS: In HIV-1-infected patients with CrCl 50 to 89 mL/min switching from RTV to COBI, COBI-boosted PIs in combination with 2 nucleos(t)ide reverse transcriptase inhibitors were well-tolerated and effective in maintaining virologic suppression. The renal safety profile of COBI in this study was consistent with the long-term data in patients without renal impairment from the phase 3 studies of COBI-containing regimens. PMID- 25433667 TI - Prediction of recurrent stroke with ABCD2 and ABCD3 scores in patients with symptomatic 50-99% carotid stenosis. AB - BACKGROUND: Although it is preferable that all patients with a recent Transient Ischemic Attack (TIA) undergo acute carotid imaging, there are centers with limited access to such acute examinations. It is controversial whether ABCD2 or ABCD3 scores can be used to triage patients to acute or delayed carotid imaging. It would be acceptable that some patients with a symptomatic carotid stenosis are detected with a slight delay as long as those who will suffer an early recurrent stroke are detected within 24 hours. The aim of this study is to analyze the ability of ABCD2 and ABCD3 scores to predict ipsilateral ischemic stroke among patients with symptomatic 50-99% carotid stenosis. METHODS: In this secondary analysis of the ANSYSCAP-study, we included 230 consecutive patients with symptomatic 50-99% carotid stenosis. We analyzed the risk of recurrent ipsilateral ischemic stroke before carotid endarterectomy based on each parameter of the ABCD2 and ABCD3 scores separately, and for total ABCD2 and ABCD3 scores. We used Kaplan-Meier analysis. RESULTS: None of the parameters in the ABCD2 or ABCD3 scores could alone predict all 12 of the ipsilateral ischemic strokes that occurred within 2 days of the presenting event, but clinical presentation tended to be a statistically significant risk factor for recurrent ipsilateral ischemic stroke (p = 0.06, log rank test). An ABCD2 score >=2 and an ABCD3 score >=4 could predict all 12 of these strokes as well as all 25 ipsilateral ischemic strokes that occurred within 14 days. To use ABCD3 score seems preferable over the ABCD2 score because a higher proportion of low risk patients were identified (17% of the patients had an ABCD3 score <4 while only 6% had an ABCD2 < 2). CONCLUSIONS: Although it is preferable that carotid imaging be performed within 24 hours, our data support that an ABCD3 score >=4 might be used for triaging patients to acute carotid imaging in clinical settings with limited access to carotid imaging. However, our findings should be validated in a larger cohort study. PMID- 25433668 TI - Is hypoglycemia fear independently associated with health-related quality of life? AB - OBJECTIVE: Patients may fear the symptoms and consequences associated with hypoglycemia. We tested whether fear of hypoglycemia is independently associated with poorer health-related quality of life (HRQOL). RESEARCH DESIGN AND METHODS: Data were collected using direct-mail survey and enrollment information from adult commercial health plan enrollees with type 2 diabetes during a 12-month period (12/01/2008 to 11/30/2009). HRQOL was evaluated by the EuroQol (EQ)-5D index and 12-item Short Form Health Survey Mental Component Summary (SF-12 MCS) and Physical Component Summary (SF-12 PCS). Fear of hypoglycemia was assessed using the Hypoglycemia Fear Survey (HFS). Two ordinary least-squares (OLS) models of HRQOL controlling for demographics and illness characteristics were specified, and OLS regression coefficients and statistical inferences were compared. Model 1 included 1 variable of hypoglycemia symptoms; Model 2 included both hypoglycemia symptoms and HFS score. RESULTS: Of 3999 patients contacted, 813 responded to the survey. Model 1: hypoglycemia symptoms alone were associated with worse HRQOL (SF 12 MCS and SF-12 PCS scores and EQ-5D utility score; all P < 0.05). Model 2: hypoglycemia symptoms were significantly associated only with SF-12 MCS score. HFS total score was significantly associated with all 3 HRQOL scores. Hypoglycemia symptoms, Hispanic ethnicity, and longer diabetes duration were associated with greater hypoglycemia fear. Higher income, white race, and treatment without sulfonylurea or insulin were associated with less hypoglycemia fear (all P < 0.05). CONCLUSIONS: In addition to the effect of symptomatic hypoglycemia on HRQOL, fear of hypoglycemia was independently associated with lower overall health status and mental and physical health. PMID- 25433664 TI - Renal and metabolic toxicities following initiation of HIV-1 treatment regimen in a diverse, multinational setting: a focused safety analysis of ACTG PEARLS (A5175). AB - BACKGROUND: Convenient dosing, potency, and low toxicity support use of tenofovir disoproxil fumarate (TDF) as preferred nucleotide reverse transcriptase inhibitor (NRTI) for HIV-1 treatment. However, renal and metabolic safety of TDF compared to other NRTIs has not been well described in resource-limited settings. METHODS: This was a secondary analysis examining the occurrence of renal abnormalities (RAs) and renal and metabolic serious non-AIDS-defining events (SNADEs) through study follow-up between participants randomized to zidovudine (ZDV)/lamivudine/ efavirenz and TDF/emtricitabine/efavirenz treatment arms within A5175/PEARLS trial. Exact logistic regression explored associations between baseline covariates and RAs. Response profile longitudinal analysis compared creatinine clearance (CrCl) over time between NRTI groups. RESULTS: Twenty-one of 1,045 participants developed RAs through 192 weeks follow-up; there were 15 out of 21 in the TDF arm (P = .08). Age 41 years or older (odds ratio [OR], 3.35; 95% CI, 1.1-13.1), his- tory of diabetes (OR, 10.7; 95% CI, 2.1-55), and lower baseline CrCl (OR, 3.1 per 25 mL/min decline; 95% CI, 1.7-5.8) were associated with development of RAs. Renal SNADEs occurred in 42 participants; 33 were urinary tract infections and 4 were renal failure/insufficiency; one event was attributed to TDF. Significantly lower CrCl values were maintained among patients receiving TDF compared to ZDV (repeated measures analysis, P = .05), however worsening CrCl from baseline was not observed with TDF exposure over time. Metabolic SNADEs were rare, but were higher in the ZDV arm (20 vs 3; P < .001). CONCLUSIONS: TDF is associated with lower serious metabolic toxicities but not higher risk of RAs, serious renal events, or worsening CrCl over time compared to ZDV in this randomized multinational study. PMID- 25433669 TI - Differential regulation of interleukin-8 and human beta-defensin 2 in Pseudomonas aeruginosa-infected intestinal epithelial cells. AB - BACKGROUND: The human opportunistic pathogen, Pseudomonas aeruginosa (P. aeruginosa) carries the highest case fatality rate of all gram-negative infections. Unfortunately, antimicrobial therapy has not been demonstrated to improve clinical outcome and the emergence of multidrug resistant P. aeruginosa has become a major concern in the hospital setting. Fever and diarrhea are the two most common initial symptoms in P. aeruginosa sepsis in previously healthy infants and children. This implies that intestinal epithelial cells in first contact with the pathogen may play an important role in innate immunity to P. aeruginosa infection. Human beta-defensins-2 (hBD-2) and interleukin-8 (IL-8) are crucial for host defense at mucosa but IL-8 may give rise to characteristic pathology of colitis. RESULTS: Pseudomonas aeruginosa strain PAO1 was used to infect SW480, an intestinal epithelial cell. IL-8 and hBD-2 mRNA expression and protein secretion were then assessed in SW480 cells using RT-PCR and enzyme linked immunosorbent assay (ELISA), respectively. Intracellular signaling pathways and nucleotide-binding oligomerization domain (NOD) 1 protein expression were analyzed by Western blot in SW480 cells in the presence or absence of inhibitors or transfected with siRNA. We demonstrate that prolonged infection by P. aeruginosa results in suppression of IL-8 but enhancement of hBD-2, either protein secretion and mRNA expression, in SW480 cells. Inhibitors of ERK suppressed but inhibitor of PI3K enhanced P. aeruginosa-induced IL-8 mRNA expression in SW480 cells while both signaling had no effect on P. aeruginosa induced hBD-2 expression in SW480 cells. On the other hand, NOD 1 was illustrated to get involved in P. aeruginosa-induced hBD-2 mRNA expression and protein production in SW480 cells. CONCLUSIONS: The P. aeruginosa-induced antimicrobial peptide in IECs continuously protect the host against prolonged infection, while modulation of proinflammatory responses prevents the host from the detrimental effects of overwhelming inflammation. Thus, P. aeruginosa-induced innate immunity in IECs represents a host protective mechanism, which may provide new insight into the pathogenesis of inflammatory bowel diseases. PMID- 25433670 TI - Neutralizing antibodies and fatigue as predictors of low response to interferon beta treatment in patients with multiple sclerosis. AB - BACKGROUND: The clinical impact of neutralizing antibodies against interferon beta (NAb) is controversial. Their presence can lead to a decrease in interferon beta (IFNbeta) efficacy. Fatigue reported in patients with multiple sclerosis (MS) may be associated with an unfavorable clinical course. We conducted a prospective multicentre study to assess the association between response to IFNbeta, NAb and fatigue. METHODS: Patients with relapsing-remitting MS on IFNbeta treatment were included. During the second year of treatment, the patients were analyzed for NAb status and non-response criteria to IFNbeta (number of relapses >=1 during the follow-up period, increase in the Expanded Disability Status Scale >=0.5). The score on the Modified Fatigue Impact Scale (MFIS pathological if score >=35) was noted for each patient. RESULTS: Of the 176 patients included: 22.3% were NAb positive, 54.5% presented non-response criteria to IFNbeta, and 57.4% had a pathological MFIS score. Fatigue was increased in NAb + patients (p = 0.0014) and they were more likely to present non-response criteria to IFNbeta (p = 0.041) than NAb- patients. Multivariate logistic regression analysis showed that the presence of NAb was related to fatigue (p = 0.0032) and denoted disease activity in these patients (p = 0.026). CONCLUSIONS: This study demonstrates the impact of NAb on the non-clinical response to IFNbeta. Fatigue assessment is an indicator of IFNbeta responsiveness and a predictive biomarker of deterioration on patient's neurological status. PMID- 25433671 TI - Analysis of the transcriptional responses in inflorescence buds of Jatropha curcas exposed to cytokinin treatment. AB - BACKGROUND: Jatropha curcas L. is a potential biofuel plant. Application of exogenous cytokinin (6-benzyladenine, BA) on its inflorescence buds can significantly increase the number of female flowers, thereby improving seed yield. To investigate which genes and signal pathways are involved in the response to cytokinin in J. curcas inflorescence buds, we monitored transcriptional activity in inflorescences at 0, 3, 12, 24, and 48 h after BA treatment using a microarray. RESULTS: We detected 5,555 differentially expressed transcripts over the course of the experiment, which could be grouped into 12 distinct temporal expression patterns. We also identified 31 and 131 transcripts in J. curcas whose homologs in model plants function in flowering and phytohormonal signaling pathways, respectively. According to the transcriptional analysis of genes involved in flower development, we hypothesized that BA treatment delays floral organ formation by inhibiting the transcription of the A, B and E classes of floral organ-identity genes, which would allow more time to generate more floral primordia in inflorescence meristems, thereby enhancing inflorescence branching and significantly increasing flower number per inflorescence. BA treatment might also play an important role in maintaining the flowering signals by activating the transcription of GIGANTEA (GI) and inactivating the transcription of CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) and TERMINAL FLOWER 1b (TFL1b). In addition, exogenous cytokinin treatment could regulate the expression of genes involved in the metabolism and signaling of other phytohormones, indicating that cytokinin and other phytohormones jointly regulate flower development in J. curcas inflorescence buds. CONCLUSIONS: Our study provides a framework to better understand the molecular mechanisms underlying changes in flowering traits in response to cytokinin treatment in J. curcas inflorescence buds. The results provide valuable information related to the mechanisms of cross-talk among multiple phytohormone signaling pathways in woody plants. PMID- 25433673 TI - Best practice and needs for improvement in the chain of care for persons with dementia in Sweden: a qualitative study based on focus group interviews. AB - BACKGROUND: Persons with dementia receive health care and social services from a wide range of professional care providers during the disease trajectory, presenting risks of miscommunication, duplication and/or missed nursing interventions. Accordingly, the aim of this study was to investigate professional care providers' views on conditions for best practice in terms of collaboration and improvement needs in the chain of care from early to end-of-life stage for persons with dementia in Sweden. METHODS: The study had a qualitative design based on three focus group interviews. A strategic sample of 23 professional care providers was included. Data were subjected to content analysis based on the three stages of dementia (early, moderate, end-of-life). RESULTS: The results were divided into five categories: Diagnosis is a prerequisite for specialized dementia care, Creating routines in the chain of care, Competent staff a prerequisite for high-quality care, Day care facilitates transition in the chain of care and Next-of-kin participation is a prerequisite for continuity in the chain of care. It was clear that, according to the participants, best practice in dementia care in Sweden is not achieved in every respect. It appeared that transitions of care between different organizations are critical events which need to be improved. The further the disease progresses, the less collaboration there seems to be among professional care providers, which is when the next of kin are usually called upon to maintain continuity in the chain of care. CONCLUSIONS: The results indicate that, according to the care providers, best practice in terms of collaboration is achieved to a higher degree during the early stage of dementia compared with the moderate and end-of-life stages. Lack of best practice strategies during these stages makes it difficult to meet the needs of persons with dementia and reduce the burden for next of kin. These are experiences to be taken into account to improve the quality of dementia care. Implementation research is needed to develop strategies for best practice on the basis of national knowledge-based guidelines and to apply these strategies in the moderate and end-of-life stages. PMID- 25433672 TI - Effect of 5-HT7 receptor blockade on liver regeneration after 60-70% partial hepatectomy. AB - BACKGROUND: Serotonin exhibits a vast repertoire of actions including cell proliferation and differentiation. The effect of serotonin, as an incomplete mitogen, on liver regeneration has recently been unveiled and is mediated through 5-HT2 receptor. The aim of the present study was to investigate the effect of 5 HT7 receptor blockade on liver regeneration after partial hepatectomy. METHODS: Male Wistar rats were subjected to 60-70% partial hepatectomy. 5-HT7 receptor blockade was applied by intraperitoneal administration of SB-269970 hydrochloride two hours prior to and sixteen hours after partial hepatectomy and by intraperitoneal administration of SB-258719 sixteen hours after partial hepatectomy. Animals were sacrificed at different time points until 72 h after partial hepatectomy. Liver regeneration was evaluated by [(3)H]-thymidine incorporation into hepatic DNA, the mitotic index in hematoxylin-eosin (HE) sections and by immunochemical detection of Ki67 nuclear antigen. Reversion of 5 HT7 blockade was performed by intraperitoneal administration of AS-19. Serum and liver tissue lipids were also quantified. RESULTS: Liver regeneration peaked at 24 h ([(3)H]-thymidine incorporation into hepatic DNA and mitotic index by immunochemical detection of Ki67) and at 32 h (mitotic index in HE sections) in the control group of rats. 5-HT7 receptor blockade had no effect on liver regeneration when applied 2 h prior to partial hepatectomy. Liver regeneration was greatly attenuated when blockade of 5-HT7 receptor was applied (by SB-258719 and SB-269970) at 16 h after partial hepatectomy and peaked at 32 h ([(3)H] thymidine incorporation into hepatic DNA and mitotic index by immunochemical detection of Ki67) and 40 h (mitotic index in HE sections) after partial hepatectomy. AS-19 administration totally reversed the observed attenuation of liver regeneration. CONCLUSIONS: In conclusion, 5-HT7 receptor is a novel type of serotonin receptor implicated in hepatocyte proliferation. PMID- 25433674 TI - Study of adherence to exercise in heart failure: the HEART camp trial protocol. AB - BACKGROUND: Adherence to the Heart Failure Society of America (HFSA) 2010 guidelines recommending 30 minutes of supervised moderate intensity exercise five days per week is difficult for patients with heart failure (HF). Innovative programs are needed to assist HF patients to adhere to long-term exercise. The objective of this prospective randomized two-group repeated measures experimental design is to determine the efficacy of a behavioral exercise training intervention on long-term adherence to exercise at 18 months in patients with heart failure. METHODS/DESIGN: A sample size of 246 subjects with heart failure will be recruited over a 3 year period. All subjects receive a cardiopulmonary exercise test and 9 supervised exercise training sessions during a 3 week run-in period prior to randomization. Subjects completing at least 6 of 9 training sessions are randomized to the HEART Camp Intervention group (HC) or to a standard care (SC) exercise group. The HC intervention group receives cognitive behavioral strategies that address the intervention components of knowledge, attitudes, self-efficacy, behavioral self-management skills and social support. The SC group is provided access to the exercise facility and regular facility staff for the 18 month study period. The primary aim is to evaluate the effect of HEART Camp on adherence to exercise, with our central hypothesis that the HC group will have significantly better adherence to exercise at 18 months. Secondary aims include evaluating which components of the HEART Camp intervention mediate the effects of the intervention on adherence; evaluating the effect of HEART Camp on specific health outcomes; exploring selected demographic variables (race, gender, age) as potential moderators of the effect of the HEART Camp intervention on adherence; and exploring the perceptions and experiences that contextualize exercise adherence. DISCUSSION: The HEART Camp intervention is the first to test a multi-component intervention designed to improve long-term adherence to exercise behavior in patients with HF. Improving long-term adherence to exercise is the logical first step to ensure the required dose of exercise that is necessary to realize beneficial health outcomes and reduce costs in this burdensome chronic illness. TRIAL REGISTRATION: Clincaltrials.gov NCT01658670. PMID- 25433675 TI - Characterization of a novel orthoreovirus isolated from fruit bat, China. AB - BACKGROUND: In recent years novel human respiratory disease agents have been described for Southeast Asia and Australia. The causative pathogens were classified as pteropine orthoreoviruses with a strong phylogenetic relationship to orthoreoviruses of bat origin. RESULTS: In this report, we isolated a novel Melaka-like reovirus (named "Cangyuan virus") from intestinal content samples of one fruit bat residing in China's Yunnan province. Phylogenetic analysis of the whole Cangyuan virus genome sequences of segments L, M and S demonstrated the genetic diversity of the Cangyuan virus. In contrast to the L and M segments, the phylogenetic trees for the S segments of Cangyuan virus demonstrated a greater degree of heterogeneity. CONCLUSIONS: Phylogenetic analysis indicated that the Cangyuan virus was a novel orthoreovirus and substantially different from currently known members of Pteropine orthoreovirus (PRV) species group. PMID- 25433677 TI - Microbes on the edge of Occam's razor. AB - Our body harbors hundreds of microbial species and contains many more bacterial than human cells. These microbes are not passive riders but rather a vital component of the organism. The human microbiota affects our health in multiple ways, both positively and negatively. One of the new attractive directions in microbiome biology is the "microbiome-brain axis". Several groups of researchers have described the ability of the gut microbiota to communicate with the brain and thus modulate human behavior. These limited experimental data became the foundation of the "biomeme hypothesis" of possible microbial origin of some religious rituals that has recently appeared in Biology Direct. Here I propose a critical analysis of this hypothesis. I conclude that there is no evidence of the microbial origin of religious practices but there are strong indications of their psychological and social roots. PMID- 25433676 TI - The association between occupational stress and depressive symptoms and the mediating role of psychological capital among Chinese university teachers: a cross-sectional study. AB - BACKGROUND: Depression is a major public health problem that affects both individuals and society. Previous studies report that university teachers are particularly susceptible to high levels of occupational stress and depressive symptoms. The aims of this study were to explore the association between occupational stress and depressive symptoms in a group of university teachers, and assess the mediating role of psychological capital between these variables. METHODS: A cross-sectional study was performed between November 2013 and January 2014. Teachers from six universities were randomly sampled in Shenyang. The Center for Epidemiologic Studies Depression Scale, effort-reward imbalance scale, and psychological capital questionnaire (PCQ-24), as well as questions about demographic and working factors, were administered in questionnaires distributed to 1,500 university teachers. Completed questionnaires were received from 1,210 participants. Hierarchical linear regression analysis was used to examine the mediating role of psychological capital. RESULTS: In the present study, 58.9% (95% CI (Confidence Intervals): 56.1% to 61.7%) of university teachers had a CES D score equal to or above the cut-off of 16. Both effort-reward ratio (ERR) and scores of over-commitment were positively associated with depressive symptoms, whereas psychological capital was negatively associated with depressive symptoms among university teachers. Psychological capital partially mediated the relationship between occupational stress and depressive symptoms. CONCLUSIONS: Among Chinese university teachers, occupational stress may be a risk factor for depressive symptoms, whereas psychological capital might be protective against depressive symptoms. Our results suggest that college administrators could support the development of psychological capital in their staff to alleviate depressive symptoms. PMID- 25433678 TI - Treatable inborn errors of metabolism presenting as cerebral palsy mimics: systematic literature review. AB - BACKGROUND: Inborn errors of metabolism (IEMs) have been anecdotally reported in the literature as presenting with features of cerebral palsy (CP) or misdiagnosed as 'atypical CP'. A significant proportion is amenable to treatment either directly targeting the underlying pathophysiology (often with improvement of symptoms) or with the potential to halt disease progression and prevent/minimize further damage. METHODS: We performed a systematic literature review to identify all reports of IEMs presenting with CP-like symptoms before 5 years of age, and selected those for which evidence for effective treatment exists. RESULTS: We identified 54 treatable IEMs reported to mimic CP, belonging to 13 different biochemical categories. A further 13 treatable IEMs were included, which can present with CP-like symptoms according to expert opinion, but for which no reports in the literature were identified. For 26 of these IEMs, a treatment is available that targets the primary underlying pathophysiology (e.g. neurotransmitter supplements), and for the remainder (n = 41) treatment exerts stabilizing/preventative effects (e.g. emergency regimen). The total number of treatments is 50, and evidence varies for the various treatments from Level 1b, c (n = 2); Level 2a, b, c (n = 16); Level 4 (n = 35); to Level 4-5 (n = 6); Level 5 (n = 8). Thirty-eight (57%) of the treatable IEMs mimicking CP can be identified by ready available metabolic screening tests in blood or urine, while the remaining IEMs require more specific and sometimes invasive tests. CONCLUSIONS: Limited by the rare nature of IEMs and incomplete information in the literature, we conclude that (1) A surprisingly large number of IEMs can present with CP symptoms, as 'CP mimics', (2) although individually rare, a large proportion of these diseases are treatable such that neurological damage can either be reversed or prevented, (3) clinician awareness of treatable CP mimics is important for appropriate screening, diagnosis, and early intervention, and (4) systematic studies are required to elucidate the collective frequency of treatable IEMs in CP. PMID- 25433679 TI - Ethical and scientific considerations for patient enrollment into concurrent clinical trials. AB - Researchers and institutional review boards often consider it inappropriate for patients to be asked to consent to more than one study despite there being no regulatory prohibition on co-enrollment in most countries. There are however ethical, safety, statistical, and practical considerations relevant to co enrollment, particularly in surgery and perioperative medicine, but co-enrollment can be done if such concerns can be resolved. Preventing eligible patients from co-enrolling in studies which they would authentically value participating in, and whose material risks and benefits they understand, violates their autonomy- and thus contravenes a fundamental principle of research ethics. Statistical issues must be considered but can be addressed. In most cases each trial can be analyzed separately and validly using standard intention to treat principles; selection and other biases can be avoided if enrollment into the second trial is not dependent upon randomized treatment in the first trial; and valid interaction analyses can be performed for each trial by considering the patient's status in the other trial at the time of randomization in the index trial. Clinical research with a potential to inform and improve clinical practice is valuable and should be supported. The ethical, safety, statistical, and practical aspects of co-enrollment can be managed, providing greater opportunity for research-led improvements in clinical practice. PMID- 25433680 TI - Implementing a pilot leadership course for internal medicine residents: design considerations, participant impressions, and lessons learned. AB - BACKGROUND: Effective clinical leadership is associated with better patient care. We implemented and evaluated a pilot clinical leadership course for second year internal medicine residents at a large United States Academic Medical Center that is part of a multi-hospital health system. METHODS: The course met weekly for two to three hours during July, 2013. Sessions included large group discussions and small group reflection meetings. Topics included leadership styles, emotional intelligence, and leading clinical teams. Course materials were designed internally and featured "business school style" case studies about everyday clinical medicine which explore how leadership skills impact care delivery. Participants evaluated the course's impact and quality using a post-course survey. Questions were structured in five point likert scale and free text format. Likert scale responses were converted to a 1-5 scale (1 = strongly disagree; 3 = neither agree nor disagree; 5 = strongly agree), and means were compared to the value 3 using one-way T-tests. Responses to free text questions were analyzed using the constant comparative method. RESULTS: All sixteen pilot course participants completed the survey. Participants overwhelmingly agreed that the course provided content and skills relevant to their clinical responsibilities and leadership roles. Most participants also acknowledged that taking the course improved their understanding of their strengths and weaknesses as leaders, different leadership styles, and how to manage interpersonal conflict on clinical teams. 88% also reported that the course increased their interest in pursuing additional leadership training. CONCLUSIONS: A clinical leadership course for internal medicine residents designed by colleagues, and utilizing case studies about clinical medicine, resulted in significant self-reported improvements in clinical leadership competencies. PMID- 25433683 TI - A microfluidic digital single-cell assay for the evaluation of anticancer drugs. AB - Digital single-cell assays hold high potentials for the analysis of cell apoptosis and the evaluation of chemotherapeutic reagents for cancer therapy. In this paper, a microfluidic hydrodynamic trapping system was developed for digital single-cell assays with the capability of monitoring cellular dynamics over time. The microfluidic chip was designed with arrays of bypass structures for trapping individual cells without the need for surface modification, external electric force, or robotic equipment. After optimization of the bypass structure by both numerical simulations and experiments, a single-cell trapping efficiency of ~90 % was achieved. We demonstrated the method as a digital single-cell assay for the evaluation of five clinically established chemotherapeutic reagents. As a result, the half maximal inhibitory concentration (IC50) values of these compounds could be conveniently determined. We further modeled the gradual decrease of active drugs over time which was often observed in vivo after an injection to investigate cell apoptosis against chemotherapeutic reagents. The developed method provided a valuable means for cell apoptotic analysis and evaluation of anticancer drugs. PMID- 25433682 TI - An ultrasensitive electrochemiluminescent biosensor for the detection of concanavalin A based on poly(ethylenimine) reduced graphene oxide and hollow gold nanoparticles. AB - A highly sensitive electrochemiluminescent (ECL) biosensor was designed for the detection of concanavalin A (ConA) based on glucose oxidase (GOx) as a recognition element by carbohydrate-lectin biospecific interaction, and poly(ethylenimine) (PEI) reduced graphene and hollow gold nanoparticles (HAuNPs) as supporting matrix and signal amplifier. The modification process and detection principle of the biosensor are briefly described as follows. First, PEI reduced graphene oxide with abundant amino groups was cast onto the surface of glassy carbon electrode to adsorb HAuNPs for improving the signal intensity in luminol/H2O2 ECL system. Next, GOx was further assembled onto the electrode by the interaction between Au and -NH2. In the presence of glucose in the detection solution, GOx catalyzed glucose to generate H2O2 in situ, which served as a co reactant of luminol to enhance ECL signal of luminol. Based on the fact that ConA could result in a decrease in ECL signal when immobilized on the electrode, an ECL biosensor was prepared for the determination of ConA. The ECL signal intensity was linear with the logarithm of ConA concentration and the linear range was from 1.0 to 20 ng/mL with a low detection limit of 0.31 ng/mL (signal to noise ratio =3). This strategy led to a nearly 1000-fold improvement in detection limit for ConA assays compared with previously reported method, thus exhibiting a great potential application in sensitive bioassays of ConA. PMID- 25433681 TI - A qualitative study of the background and in-hospital medicolegal response to female burn injuries in India. AB - BACKGROUND: Most burns happen in low- and middle-income countries. In India, deaths related to burns are more common in women than in men and occur against a complex background in which the cause - accidental or non-accidental, suicidal or homicidal - is often unclear. Our study aimed to understand the antecedents to burns and the problem of ascribing cause, the sequence of medicolegal events after a woman was admitted to hospital, and potential opportunities for improvement. METHODS: We conducted semi-structured interviews with 33 women admitted to two major burns units, their families, and 26 key informant doctors, nurses, and police officers. We used framework analysis to examine the context in which burns occurred and the sequence of medicolegal action after admission to hospital. RESULTS: Interviewees described accidents, attempted suicide, and attempted homicide. Distinguishing between these was difficult because the underlying combination of poverty and cultural precedent was common to all and action was contingent on potentially conflicting narratives. Space constraint, problems with cooking equipment, and inflammable clothing increased the risk of accidental burns, but coexisted with household conflict, gender-based violence, and alcohol use. Most burns were initially ascribed to accidents. Clinicians adhered to medicolegal procedures, the police carried out their investigative requirements relatively rapidly, but both groups felt vulnerable in the face of the legal process. Women's understandable reticence to describe burns as non accidental, the contested nature of statements, their perceived history of changeability, the limited quality and validity of forensic evidence, and the requirement for resilience on the part of clients underlay a general pessimism. CONCLUSIONS: The similarities between accident and intention cluster so tightly as to make them challenging to distinguish, especially given women's understandable reticence to describe burns as non-accidental. The contested status of forensic evidence and a reliance on testimony means that only a minority of cases lead to conviction. The emphasis should be on improving documentation, communication between service providers, and public understanding of the risks of burns. PMID- 25433684 TI - Pipette-tip solid-phase extraction by use of a sol-gel hybrid adsorbent: a new pretreatment strategy for rapid screening of cucumbers for cyanazine and atrazine. AB - A pipette-tip solid-phase extraction (PT-SPE) method using a sol-gel hybrid adsorbent has been developed. The method could be used for rapid screening of vegetable matrices for cyanazine and atrazine; assay of cucumbers is reported as an example. The sol-gel hybrid adsorbent was synthesized from tetraethyl orthosilicate (TEOS) as the precursor and gamma (methacryloyloxy)propyltrimethoxysilane (KH570) as both surface modifying agent and monomer for the polymerization. Under the optimized conditions, good calibration linearity was obtained in the range 0.022-1.65 MUg g(-1) with correlation coefficients (r) >=0.9996. Recovery at three spike levels ranged from 87.6 to 93.8 % with relative standard deviations <=7.8 %. This extraction strategy has several advantages, for example ease of assembly, low cost, and high extraction efficiency, and is a potential pretreatment strategy for rapid screening of cyanazine and atrazine in vegetables. PMID- 25433685 TI - Bipolar disorder: recent advances and future trends in bioanalytical developments for biomarker discovery. AB - In this manuscript we briefly describe bipolar disorder (a depressive and manic mental disease), its classification, its effects on the patient, which sometimes include suicidal tendencies, and the drugs used for treatment. We also address the status quo with regard to diagnosis of bipolar disorder and recent advances in bioanalytical approaches for biomarker discovery. These approaches focus on blood samples (serum and plasma) and proteins as the main biomarker targets, and use various strategies for protein depletion. Strategies include use of commercially available kits or other homemade strategies and use of classical proteomics methods for protein identification based on "bottom-up" or "top-down" approaches, which used SELDI, ESI, or MALDI as sources for mass spectrometry, and up-to-date mass analyzers, for example Orbitrap. We also discuss some future objectives for treatment of this disorder and possible directions for the correct diagnosis of this still-unclear mental illness. PMID- 25433686 TI - Liquid chromatography with isotope-dilution mass spectrometry for determination of water-soluble vitamins in foods. AB - Vitamins are essential for improving and maintaining human health, and the main source of vitamins is the diet. Measurement of the quantities of water-soluble vitamins in common food materials is important to understand the impact of vitamin intake on human health, and also to provide necessary information for regulators to determine adequate intakes. Liquid chromatography (LC) and mass spectrometry (MS) based methods for water-soluble vitamin analysis are abundant in the literature, but most focus on only fortified foods or dietary supplements or allow determination of only a single vitamin. In this work, a method based on LC/MS and LC/MS/MS has been developed to allow simultaneous quantitation of eight water-soluble vitamins, including multiple forms of vitamins B3 and B6, in a variety of fortified and unfortified food-matrix Standard Reference Materials (SRMs). Optimization of extraction of unbound vitamin forms and confirmation using data from external laboratories ensured accuracy in the assigned values, and addition of stable isotope labeled internal standards for each of the vitamins allowed for increased precision. PMID- 25433688 TI - A rapid and highly sensitive microchip electrophoresis of mono- and mucin-type oligosaccharides labeled with 7-amino-4-methylcoumarin. AB - A selective separation method using a poly(methylmethacrylate) microchip was developed for 7-amino-4-methylcoumarin-labeled saccharides in a crude reaction mixture. In an alkaline borate buffer, saccharide derivatives formed strong anionic borate complexes. These complexes moved from the cathode to the anode in an electric field and were detected near the anode. Excess labeling reagents and other foreign substances remained at the inlet reservoir. A confocal fluorimetric detection system enabled the determination of monosaccharide derivatives with good linearity between at least 5 and 100 nM, corresponding to 50 fmol to 1 pmol per injection. The lower limit of detection (signal-to-noise = 5) was 2 nM. The sensitivity and linear quantitation range were comparable to reported values using fluorometric detection, capillary electrophoresis, or liquid chromatography. Application of the method showed excellent resolution in the analysis of O-linked glycans chemically released from glycoproteins. PMID- 25433687 TI - Identification of lipid- and protein-based binders in paintings by direct on plate wet chemistry and matrix-assisted laser desorption ionization mass spectrometry. AB - Direct on-target plate processing of small (ca. 100 MUg) fragments of paint samples for MALDI-MS identification of lipid- and protein-based binders is described. Fragments were fixed on a conventional stainless steel target plate by colloidal graphite followed by in situ fast tryptic digestion and matrix addition. The new protocol was first developed on paint replicas composed of chicken egg, collagen, and cow milk mixed with inorganic pigments and then successfully applied on historical paint samples taken from a fifteenth century Italian panel painting. The present work contributes a step forward in the simplification of binder identification in very small paint samples since no conventional solvent extraction is required, speeding up the whole sample preparation to 10 min and reducing lipid/protein loss. PMID- 25433689 TI - Flexor hallucis longus tendon transfer in the reconstruction of extensive insertional Achilles tendinopathy in elderly: an improved technique. AB - BACKGROUND: Insertional Achilles tendinopathy is a degenerative disease associated with disabling posterior heel pain, gait dysfunction and significant morbidity. The aim of this prospective study was to evaluate the outcomes of complete excision of the pathological tendo-achilles segment in elderly patients with extensive involvement, and reconstructing the defect using a modified technique which was proposed to allow early weight-bearing and rehabilitation. PATIENTS AND METHODS: Thirteen patients (mean age 58.2 years) with extensive insertional Achilles tendinopathy (seven with spontaneous rupture and six without rupture) were operated between January 2008 and July 2012. The average tendon gap after debridement was 6.8 cm. All patients were reconstructed with flexor hallucis longus tendon transfer augmented with a modified turn-down flap. Patient's satisfaction was evaluated using the American orthopedic foot and ankle society (AOFAS)-ankle-hindfoot scale. RESULTS: The mean follow-up period was 24.5 months. The AOFAS scores improved from 57.5+/-8.44 preoperatively to 98.3+/-1.01 at final follow-up (p<0.001). Complete pain relieve was achieved in ten patients, while the other three had mild occasional pain. Eleven patients had excellent results, and two had good results. There was no single case of re-rupture, and two patients acquired superficial wound infection which was resolved conservatively. CONCLUSIONS: The modified technique provides a transfer with sufficient length and strength that can restore large tendo-achilles defects in elderly, and is stable enough to allow early protected weight-bearing and rehabilitation with favorable clinical result and minimal morbidity. Resection of all degenerated tendon tissue alleviates pain and improves function. PMID- 25433690 TI - Methyl glycol, methanol and DMSO effects on post-thaw motility, velocities, membrane integrity and mitochondrial function of Brycon orbignyanus and Prochilodus lineatus (Characiformes) sperm. AB - The aim of this study was to use more accurate techniques to investigate the effects of cryoprotectants (CPAs) and extenders on post-thaw sperm quality of Brycon orbignyanus and Prochilodus lineatus. Six freezing media comprising the combination of three CPAs (DMSO, methanol and methyl glycol) and two extenders (BTS and glucose) were used. Sperm was diluted in each medium, loaded into 0.5-mL straws, frozen in a nitrogen vapor vessel (dry-shipper), and stored in liquid nitrogen at -196 degrees C. Post-thaw sperm motility rate and velocities (curvilinear = VCL; straight line = VSL; average path = VAP) were evaluated using a computer-assisted sperm analyzer. Membrane integrity and mitochondrial function were determined using fluorochromes. Post-thaw quality was considered high when samples presented the following minimum values: 60 % motile sperm, 140 um/s of VCL, 50 % intact sperm membrane and 50 % mitochondrial function integrity. High post-thaw quality was observed in B. orbignyanus sperm frozen in BTS-methyl glycol and in P. lineatus sperm frozen in BTS-methyl glycol, glucose-methyl glycol and glucose-methanol. All samples frozen in DMSO yielded low quality. The presence of ions in the BTS extender affected post-thaw sperm quality positively in B. orbignyanus and negatively in P. lineatus. Methyl glycol was the most suitable CPA for both fish species, leading to a good protection of cell membrane, mitochondrial function and motility apparatus during the cryopreservation process. For an improved protection, B. orbignyanus sperm should be frozen in an ionic freezing medium. PMID- 25433691 TI - Biliary-enteric reconstruction with hepaticoduodenostomy following laparoscopic excision of choledochal cyst is associated with better postoperative outcomes: a single-centre experience. AB - BACKGROUND: With the advent of laparoscopic surgery, more choledochal cysts are excised laparoscopically. In this study, we compared the outcomes from laparoscopic hepaticojejunostomy (HJ) and hepaticoduodenostomy (HD) for biliary enteric reconstruction. METHODS: A retrospective analysis of patients who had undergone laparoscopic choledochal cyst excision between February 2005 and January 2014 in a tertiary referral centre was performed. Demographics data, operative techniques and surgical outcomes were analysed according to the way of biliary-enteric reconstruction. RESULTS: A total of 31 patients were identified, 20 of whom underwent HJ and 11 underwent HD. There were no significant differences in terms of demographics. Median operative time was significantly shorter in HD group (211.0 +/- 96.4 vs. 386.0 +/- 90.4 min, p = 0.001). Although postoperative enteral feeding was initiated later in HD group (5.0 +/- 0.8 vs. 4.0 +/- 3.6 days, p = 0.036), postoperative stay in intensive care unit (ICU) (0.7 +/- 1.0 vs. 2.4 +/- 1.7 days, p = 0.007) and overall hospital stay (9.1 +/- 1.0 vs. 14.4 +/- 12.2 days, p = 0.157) favoured HD group. There was no perioperative mortality. Median follow-up duration was 24.0 (+/-11.0) months in HD group and 67.5 (+/-23.7) months in HJ group. One patient in HJ group had postoperative cholangitis related to anastomotic stricture whereas no cholangitis noted in HD group. In total, five patients in HJ group required second operation for complications and residual diseases whereas none in HD group required reoperation. CONCLUSIONS: Laparoscopic excision of choledochal cyst with hepaticoduodenostomy reconstruction is safe and feasible with shorter operative time, ICU stay and overall hospital stay. It is not inferior to HJ in terms of short-term postoperative outcomes. PMID- 25433692 TI - When the going gets tough...: Self-motivation is associated with invigoration and fun. AB - Personality systems interaction (PSI) theory postulates two executive control modes in volitional action: Self-control and self-regulation (self-motivation). Self-control should deplete energy whereas self-motivation should maintain energy and result in invigoration. There were three groups of participants: Self control, self-motivation, and pretend, who performed a resource-demanding Stroop Shift and an anagram task. Performance and energy expenditure were examined in each task. Compared to the other groups, the self-motivation group showed increments in blood glucose throughout the experiment, indicating invigoration, and had better performance on the difficult Stroop-Shift task than the self control group. Additionally, for the self-motivation group anagram performance correlated with less effort and ease of concentration and was moderated by fun in the task. These results are consonant with the predictions of PSI and self determination theories. It is concluded that self-control depletes resources whereas self-motivation is associated with invigoration in carrying resource demanding tasks. PMID- 25433693 TI - Geometry of nutrition in field studies: an illustration using wild primates. AB - Nutritional geometry has shown the benefits of viewing nutrition in a multidimensional context, in which foraging is viewed as a process of balancing the intake and use of multiple nutrients. New insights into nutrient regulation have been generated in studies performed in a laboratory context, where accurate measures of amounts (e.g. eaten, converted to body mass, excreted) can be made and analysed using amounts-based nutritional geometry. In most field situations, however, proportional compositions (e.g. of foods, diets, faeces) are the only measures readily available, and in some cases are more relevant to the problem at hand. For this reason, a complementary geometric method was recently introduced for analysing multi-dimensional data on proportional compositions in nutritional studies, called the right-angled mixture triangle (RMT). We use literature data from field studies of primates to demonstrate how the RMT can provide insight into a variety of important concepts in nutritional ecology. We first compare the compositions of foods, using as an example primate milks collected in both the wild and the laboratory. We next compare the diets of different species of primates from the same habitat and of the same species (mountain gorillas) from two distinct forests. Subsequently, we model the relationships between the composition of gorilla diets in these two habitats and the foods that comprise these diets, showing how such analyses can provide evidence for active nutrient specific regulation in a field context. We provide a framework to relate concepts developed in laboratory studies with field-based studies of nutrition. PMID- 25433694 TI - Effects of predation risk across a latitudinal temperature gradient. AB - The nonconsumptive effects (NCEs) of predators on prey behavior and physiology can influence the structure and function of ecological communities. However, the strength of NCEs should depend on the physiological and environmental contexts in which prey must choose between food and safety. For ectotherms, temperature effects on metabolism and foraging rates may shape these choices, thereby altering NCE strength. We examined NCEs in a rocky intertidal food chain across a latitudinal sea surface temperature gradient within the Gulf of Maine. The NCEs of green crabs (Carcinus maenas) on the foraging, growth, and growth efficiency of prey snails (Nucella lapillus) were consistent across a broad (~8.5 degrees C) temperature range, even though snails that were transplanted south consumed twice as many mussels (Mytilus edulis) and grew twice as much as snails that were transplanted north. The positive effects of warmer temperatures in the south allowed snails under high risk to perform similarly to or better than snails under low risk at cooler temperatures. Our results suggest that for prey populations residing at temperatures below their thermal optimum, the positive effects of future warming may offset the negative effects of predation risk. Such effects may be favorable to prey populations facing increased predation rates due to warmer temperatures associated with climate change. Attention to the direct and indirect effects of temperature on species interactions should improve our ability to predict the effects of climate change on ecological communities. PMID- 25433695 TI - Inter-annual variation in American redstart (Setophaga ruticilla) plumage colour is associated with rainfall and temperature during moult: an 11-year study. AB - Carotenoid-based colouration plays an important role in sexual signaling in animals as an honest indicator of individual quality during mate choice and competitive interactions. However, few studies have examined how natural variation in weather conditions influences inter-annual variation in the expression of ornamentation, potentially through affecting the dietary availability of carotenoids. In this study, we examine variation in the expression of carotenoid-based plumage colouration in relation to temperature and rainfall during the pre-moulting and moulting period over 11 years in a population of American redstarts, Setophaga ruticilla, breeding in eastern Canada. We used reflectance spectrometry of tail feathers collected from male and female redstarts to relate feather colour with weather conditions the previous breeding season during the months over which redstarts are likely to moult (June September). At a population level, birds expressed feathers with higher red chroma and lower brightness in years following high July rainfall and low August temperature. The pattern was stronger in males, but was generally consistent across ages and sexes. Analyses of feathers from repeatedly captured birds indicated that the above patterns could be explained by individual change in feather colour. We suggest that higher rainfall during the moulting period may increase insect abundance and the availability of dietary carotenoids. This is among the first studies to show effects of weather conditions on a sexual signalling trait, which may have important consequences for sexual selection, mate choice, and the reliability of putative signals. PMID- 25433696 TI - LigDig: a web server for querying ligand-protein interactions. AB - LigDig is a web server designed to answer questions that previously required several independent queries to diverse data sources. It also performs basic manipulations and analyses of the structures of protein-ligand complexes. The LigDig webserver is modular in design and consists of seven tools, which can be used separately, or via linking the output from one tool to the next, in order to answer more complex questions. Currently, the tools allow a user to: (i) perform a free-text compound search, (ii) search for suitable ligands, particularly inhibitors, of a protein and query their interaction network, (iii) search for the likely function of a ligand, (iv) perform a batch search for compound identifiers, (v) find structures of protein-ligand complexes, (vi) compare three dimensional structures of ligand binding sites and (vii) prepare coordinate files of protein-ligand complexes for further calculations. AVAILABILITY AND IMPLEMENTATION: LigDig makes use of freely available databases, including ChEMBL, PubChem and SABIO-RK, and software programs, including cytoscape.js, PDB2PQR, ProBiS and Fconv. LigDig can be used by non-experts in bio- and chemoinformatics. LigDig is available at: http://mcm.h-its.org/ligdig. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25433697 TI - Exploiting hidden information interleaved in the redundancy of the genetic code without prior knowledge. AB - MOTIVATION: Dozens of studies in recent years have demonstrated that codon usage encodes various aspects related to all stages of gene expression regulation. When relevant high-quality large-scale gene expression data are available, it is possible to statistically infer and model these signals, enabling analysing and engineering gene expression. However, when these data are not available, it is impossible to infer and validate such models. RESULTS: In this current study, we suggest Chimera-an unsupervised computationally efficient approach for exploiting hidden high-dimensional information related to the way gene expression is encoded in the open reading frame (ORF), based solely on the genome of the analysed organism. One version of the approach, named Chimera Average Repetitive Substring (ChimeraARS), estimates the adaptability of an ORF to the intracellular gene expression machinery of a genome (host), by computing its tendency to include long substrings that appear in its coding sequences; the second version, named ChimeraMap, engineers the codons of a protein such that it will include long substrings of codons that appear in the host coding sequences, improving its adaptation to a new host's gene expression machinery. We demonstrate the applicability of the new approach for analysing and engineering heterologous genes and for analysing endogenous genes. Specifically, focusing on Escherichia coli, we show that it can exploit information that cannot be detected by conventional approaches (e.g. the CAI-Codon Adaptation Index), which only consider single codon distributions; for example, we report correlations of up to 0.67 for the ChimeraARS measure with heterologous gene expression, when the CAI yielded no correlation. AVAILABILITY AND IMPLEMENTATION: For non-commercial purposes, the code of the Chimera approach can be downloaded from http://www.cs.tau.ac.il/~tamirtul/Chimera/download.htm. CONTACT: tamirtul@post.tau.ac.il SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25433698 TI - Lipid-Pro: a computational lipid identification solution for untargeted lipidomics on data-independent acquisition tandem mass spectrometry platforms. AB - A major challenge for mass spectrometric-based lipidomics, aiming at describing all lipid species in a biological sample, lies in the computational and bioinformatic processing of the large amount of data that arises after data acquisition. Lipid-Pro is a software tool that supports the identification of lipids by interpreting large datasets generated by liquid chromatography--tandem mass spectrometry (LC-MS/MS) using the advanced data-independent acquisition mode MS(E). In the MS(E) mode, the instrument fragments all molecular ions generated from a sample and records time-resolved molecular ion data as well as fragment ion data for every detectable molecular ion. Lipid-Pro matches the retention time aligned mass-to-charge ratio data of molecular- and fragment ions with a lipid database and generates a report on all identified lipid species. For generation of the lipid database, Lipid-Pro provides a module for construction of lipid species and their fragments using a flexible building block approach. Hence, Lipid-Pro is an easy to use analysis tool to interpret complex MS(E) lipidomics data and also offers a module to generate a user-specific lipid database. AVAILABILITY AND IMPLEMENTATION: Lipid-Pro is freely available at: http://www.neurogenetics.biozentrum.uni wuerzburg.de/en/project/services/lipidpro/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25433699 TI - Computer-assisted curation of a human regulatory core network from the biological literature. AB - MOTIVATION: A highly interlinked network of transcription factors (TFs) orchestrates the context-dependent expression of human genes. ChIP-chip experiments that interrogate the binding of particular TFs to genomic regions are used to reconstruct gene regulatory networks at genome-scale, but are plagued by high false-positive rates. Meanwhile, a large body of knowledge on high-quality regulatory interactions remains largely unexplored, as it is available only in natural language descriptions scattered over millions of scientific publications. Such data are hard to extract and regulatory data currently contain together only 503 regulatory relations between human TFs. RESULTS: We developed a text-mining assisted workflow to systematically extract knowledge about regulatory interactions between human TFs from the biological literature. We applied this workflow to the entire Medline, which helped us to identify more than 45 000 sentences potentially describing such relationships. We ranked these sentences by a machine-learning approach. The top-2500 sentences contained ~900 sentences that encompass relations already known in databases. By manually curating the remaining 1625 top-ranking sentences, we obtained more than 300 validated regulatory relationships that were not present in a regulatory database before. Full-text curation allowed us to obtain detailed information on the strength of experimental evidences supporting a relationship. CONCLUSIONS: We were able to increase curated information about the human core transcriptional network by >60% compared with the current content of regulatory databases. We observed improved performance when using the network for disease gene prioritization compared with the state-of-the-art. AVAILABILITY AND IMPLEMENTATION: Web-service is freely accessible at http://fastforward.sys-bio.net/. CONTACT: leser@informatik.hu berlin.de or nils.bluethgen@charite.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25433701 TI - Integration of genomic data enables selective discovery of breast cancer drivers. AB - Identifying driver genes in cancer remains a crucial bottleneck in therapeutic development and basic understanding of the disease. We developed Helios, an algorithm that integrates genomic data from primary tumors with data from functional RNAi screens to pinpoint driver genes within large recurrently amplified regions of DNA. Applying Helios to breast cancer data identified a set of candidate drivers highly enriched with known drivers (p < 10(-14)). Nine of ten top-scoring Helios genes are known drivers of breast cancer, and in vitro validation of 12 candidates predicted by Helios found ten conferred enhanced anchorage-independent growth, demonstrating Helios's exquisite sensitivity and specificity. We extensively characterized RSF-1, a driver identified by Helios whose amplification correlates with poor prognosis, and found increased tumorigenesis and metastasis in mouse models. We have demonstrated a powerful approach for identifying driver genes and how it can yield important insights into cancer. PMID- 25433702 TI - Hematopoietic stem cell transplantation for treatment of patients with leukemia concomitant with active tuberculosis infection. AB - BACKGROUND: Currently, hematopoietic stem cell transplantation is still an essential treatment approach for leukemia. However, patients with leukemia often have weakened immune function, especially more seriously compromised cellular immune response, and appear to be at greater risk for tuberculosis infection during the transplantation process. We aimed to investigate the efficacy and safety of hematopoietic stem cell transplantation for the treatment of patients with leukemia accompanying active tuberculosis infection. MATERIAL/METHODS: We retrospectively analyzed records of 7 consecutive patients who were diagnosed with leukemia concomitant with active tuberculosis infection and who underwent hematopoietic stem cell transplantation in our hospital from January 2006 to December 2012. RESULTS: Among these 7 patients (4 males and 3 females; median age: 38 years; range: 30-46 years), the mean duration of anti-TB treatment before transplantation was 3 months (range: 2-4.5 months). All patients acquired engraftment, with an implantation rate of 100%. After transplantation, the mean duration of anti-TB treatment was 12 months. All patients had response after receiving anti-TB treatment. One patient died of leukemia relapse 6 months after the transplantation, but no tuberculosis infection-related death was reported. CONCLUSIONS: Patients with leukemia concomitant with active tuberculosis infection can be treated with hematopoietic stem cell transplantation if they receive an effective anti-TB treatment regimen. The anti-TB treatment regimen had no effect against hematopoietic stem cell transplantation and was well-tolerated. All post-transplanted patients experienced no relapse of tuberculosis during the immune-suppression period. The findings in the present investigation deserve further in-depth study. PMID- 25433703 TI - Data Resource Profile: The sentinel panel of districts: Tanzania's national platform for health impact evaluation. AB - The Sentinel Panel of Districts (SPD) consists of 23 districts selected to provide nationally representative data on demographic and health indicators in Tanzania. The SPD has two arms: SAVVY and FBIS. SAVVY (SAmple Vital registration with Verbal autopsY) is a demographic surveillance system that provides nationally representative estimates of mortalities based on age, sex, residence and zone. SAVVY covers over 805 000 persons, or about 2% of the Tanzania mainland population, and uses repeat household census every 4-5 years, with ongoing reporting of births, deaths and causes of deaths. The FBIS (Facility-Based Information System) collects routine national health management information system data. These health service use data are collected monthly at all public and private health facilities in SPD districts, i.e. about 35% of all facilities in Mainland Tanzania. Both SAVVY and FBIS systems are capable of generating supplementary information from nested periodic surveys. Additional information about the design of the SPD is available online: access to some of SPD's aggregate data can be requested by sending an e-mail to [hmasanja@ihi.or.tz]. PMID- 25433704 TI - Health & Demographic Surveillance System Profile: The Taabo Health and Demographic Surveillance System, Cote d'Ivoire. AB - The Taabo Health and Demographic Surveillance System (HDSS) is located in south central Cote d'Ivoire, approximately 150 km north-west of Abidjan. The Taabo HDSS started surveillance activities in early 2009 and the man-made Lake Taabo is a key eco-epidemiological feature. Since inception, there has been a strong interest in research and integrated control of water-associated diseases such as schistosomiasis and malaria. The Taabo HDSS has generated setting-specific evidence on the impact of targeted interventions against malaria, schistosomiasis and other neglected tropical diseases. The Taabo HDSS consists of a small town, 13 villages and over 100 hamlets. At the end of 2013, a total population of 42 480 inhabitants drawn from 6707 households was under surveillance. Verbal autopsies have been conducted to determine causes of death. Repeated cross sectional epidemiological surveys on approximately 5-7% of the population and specific, layered-on haematological, parasitological and questionnaire surveys have been conducted. The Taabo HDSS provides a database for surveys, facilitates interdisciplinary research, as well as surveillance, and provides a platform for the evaluation of health interventions. Requests to collaborate and to access data are welcome and should be addressed to the secretariat of the Centre Suisse de Recherches Scientifiques en Cote d'Ivoire: [secretariat@csrs.ci]. PMID- 25433706 TI - [Flexor tendon surgery in 2015]. PMID- 25433705 TI - Increased alcohol consumption as a cause of alcoholism, without similar evidence for depression: a Mendelian randomization study. AB - BACKGROUND: Increased alcohol consumption has been associated with depression and alcoholism, but whether these associations are causal remains unclear. We tested whether alcohol consumption is causally associated with depression and alcoholism. METHODS: We included 78,154 men and women aged 20-100 years randomly selected in 1991-2010 from the general population of Copenhagen, Denmark, and genotyped 68,486 participants for two genetic variants in two alcohol dehydrogenase (ADH) genes, ADH-1B (rs1229984) and ADH-1C (rs698). We performed observational and causal analyses using a Mendelian randomization design with antidepressant medication use and hospitalization/death, with depression and alcoholism as outcomes. RESULTS: In prospective analyses, the multifactorially adjusted hazard ratio for participants reporting >6 drinks/day vs participants reporting 0.1-1 drinks/day was 1.28 (95% confidence interval, 1.00-1.65) for prescription antidepressant use, with a corresponding hazard ratio of 0.80 (0.45 1.45) for hospitalization/death with depression and of 11.7 (8.77-15.6) for hospitalization/death with alcoholism. For hospitalization/death with alcoholism, instrumental variable analysis yielded a causal odds ratio of 28.6 (95 % confidence interval 6.47-126) for an increase of 1 drink/day estimated from the combined genotype combination, whereas the corresponding multifactorially adjusted observational odds ratio was 1.28 (1.25-1.31). Corresponding odds ratios were 1.11 (0.67-1.83) causal and 1.04 (1.03-1.06) observational for prescription antidepressant use, and 4.52 (0.99-20.5) causal and 0.98 (0.94-1.03) observational for hospitalization/death with depression. CONCLUSIONS: These data indicate that the association between increased alcohol consumption and alcoholism is causal, without similar strong evidence for depression. PMID- 25433700 TI - The structure and regulation of human muscle alpha-actinin. AB - The spectrin superfamily of proteins plays key roles in assembling the actin cytoskeleton in various cell types, crosslinks actin filaments, and acts as scaffolds for the assembly of large protein complexes involved in structural integrity and mechanosensation, as well as cell signaling. alpha-actinins in particular are the major actin crosslinkers in muscle Z-disks, focal adhesions, and actin stress fibers. We report a complete high-resolution structure of the 200 kDa alpha-actinin-2 dimer from striated muscle and explore its functional implications on the biochemical and cellular level. The structure provides insight into the phosphoinositide-based mechanism controlling its interaction with sarcomeric proteins such as titin, lays a foundation for studying the impact of pathogenic mutations at molecular resolution, and is likely to be broadly relevant for the regulation of spectrin-like proteins. PMID- 25433707 TI - Dynamic interactive events in gene regulation using E. coli dehydrogenase as a model. AB - Different approaches in gene expression analysis always provide a snapshot view of cellular events. During the bacterial growth, the decisions are dynamically made with participation of various genes and their interactions with modulating factors. We have selected Escherichia coli dehydrogenases as a model to capture these interactions. We have treated the cells with hydrogen peroxide with very low level and asked the questions how cellular physiology has modulated itself to survive post-shock conditions. We hypothesized that while global regulators and associated gene network dictate the overall cellular intelligence, specific redox sensitive classes of enzymes like dehydrogenase-mediated modulation could provide the option to cell for survival under peroxide after-effect. To understand the dynamic gene interaction, we used multidimensional scaling of genes and overlaid with minimum spanning tree to understand the clustering patterns under different conditions. Study shows that under peroxide after-effect, it is the interplay of ArcA (global regulator), with ldhA (involved in intermediary metabolism) and ndh (managing co-factor NADH), that emerges as modulating association. Knockout mutants of global regulators confirmed the promoter activity trend through gene expression change for dehydrogenases. PMID- 25433711 TI - Diffuse idiopathic skeletal hyperostosis as an acute airway presentation requiring urgent tracheostomy. PMID- 25433710 TI - Effect of norfloxacin and moxifloxacin on melanin synthesis and antioxidant enzymes activity in normal human melanocytes. AB - Fluoroquinolone antibiotics provide broad-spectrum coverage for a number of infectious diseases, including respiratory as well as urinary tract infections. One of the important adverse effects of these drugs is phototoxicity which introduces a serious limitation to their use. To gain insight the molecular mechanisms underlying the fluoroquinolones-induced phototoxic side effects, the impact of two fluoroquinolone derivatives with different phototoxic potential, norfloxacin and moxifloxacin, on melanogenesis and antioxidant enzymes activity in normal human melanocytes HEMa-LP was determined. Both drugs induced concentration-dependent loss in melanocytes viability. The value of EC50 for these drugs was found to be 0.5 mM. Norfloxacin and moxifloxacin suppressed melanin biosynthesis; antibiotics were shown to inhibit cellular tyrosinase activity and to reduce melanin content in melanocytes. When comparing the both analyzed fluoroquinolones, it was observed that norfloxacin possesses greater inhibitory effect on tyrosinase activity in melanocytes than moxifloxacin. The extent of oxidative stress in cells was assessed by measuring the activity of antioxidant enzymes: SOD, CAT, and GPx. It was observed that norfloxacin caused higher depletion of antioxidant status in melanocytes when compared with moxifloxacin. The obtained results give a new insight into the mechanisms of fluoroquinolones toxicity directed to pigmented tissues. Moreover, the presented differences in modulation of biochemical processes in melanocytes may be an explanation for various phototoxic activities of the analyzed fluoroquinolone derivatives in vivo. PMID- 25433708 TI - Genes regulating lipid and protein metabolism are highly expressed in mammary gland of lactating dairy goats. AB - Dairy goats serve as an important source of milk and also fulfill agricultural and economic roles in developing countries. Understanding the genetic background of goat mammary gland is important for research on the regulatory mechanisms controlling tissue function and the synthesis of milk components. We collected tissue at four different stages of goat mammary gland development and generated approximately 25 GB of data from Illumina de novo RNA sequencing. The combined reads were assembled into 51,361 unigenes, and approximately 60.07 % of the unigenes had homology to other proteins in the NCBI non-redundant protein database (NR). Functional classification through eukaryotic Ortholog Groups of Protein (KOG), gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that the unigenes from goat mammary glands are involved in a wide range of biological processes and metabolic pathways, including lipid metabolism and lactose metabolism. The results of qPCR revealed that genes encoding FABP3, FASN, SCD, PLIN2, whey proteins (LALBA and BLG), and caseins (CSN1S1, CSN1S2, CSN2 and CSN3) at 100 and 310 days postpartum increased significantly compared with the non-lactating period. In addition to their role in lipid and protein synthesis, the higher expression at 310 days postpartum could contribute to mammary cell turnover during pregnancy. In conclusion, this is the first study to characterize the complete transcriptome of goat mammary glands and constitutes a comprehensive genomic resource available for further studies of ruminant lactation. PMID- 25433709 TI - Plastid DNA insertions in plant nuclear genomes: the sites, abundance and ages, and a predicted promoter analysis. AB - The transfer of plastid DNA sequences into plant nuclear genomes plays an important role in the genomic evolution of plants. The abundance of nuclear localized plastid DNA (nupDNA) correlates positively with nuclear genome size, but the genetic content of nupDNA remains unknown. In this mini review, we analyzed the number of nuclear-localized plastid gene fragments in known plant genomic data. Our analysis suggests that nupDNAs are abundant in plant nuclear genomes and can include multiple complete copies of protein-coding plastid genes. Mutated nuclear copies of plastid genes contained synonymous and nonsynonymous substitutions. We estimated the age of the nupDNAs based on the time when each integration occurred, which was calculated by comparing the nucleotide substitution rates of the nupDNAs and their respective plastid genes. These data suggest that there are two distinct age distribution patterns for nupDNAs in plants, and Oryza sativa and Zea mays were found to contain a very high proportion of young nupDNAs. Expressed sequence tags and predicted promoters of nupDNAs were identified, revealing that certain nuclear-localized plastid genes may be functional and that some have undergone positive natural selection pressure. PMID- 25433712 TI - Access to care issues and the role of EDs in the wake of the Affordable Care Act. AB - CONTEXT: Americans who received public insurance under the Affordable Care Act use the emergency department (ED) more frequently than before they were insured. If newly enrolled patients cannot access primary care and instead rely on the ED, they may not enjoy the full benefits of health care services. OBJECTIVE: The objective of the study is to characterize reasons for ED utilization among American adults by insurance status and usual source of care. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of adult sample respondents to the 2013 National Health Interview Survey reporting 1 or more ED visits in the preceding 12 months. MAIN OUTCOMES AND MEASURES: Among American ED users that reported no usual source of care and who reported relying on the ED, 27.7% (95% confidence interval [CI], 23.6%-32.2%) and 35.1% (95% CI, 28.0%-43.0%) noted at least 1 issue of access and none of acuity as a reason for their last ED visit, as compared to 17.7% (95% CI, 16.3%-19.2%) among those with a stable usual source of care. CONCLUSIONS AND RELEVANCE: Although past research has shown that those who lack a stable usual source of care use the ED more often, this is the first population-level study to demonstrate their propensity for lack of access-based utilization. In the wake of the Affordable Care Act, EDs will need to evolve into outlets that service a wider range of health care needs rather than function in their current capacity, which is largely to address acute issues in isolation. PMID- 25433715 TI - Erratum to: Fine Mapping of Type 2 Diabetes Susceptibility Loci. PMID- 25433714 TI - Are sleep disturbances preclinical markers of Parkinson's disease? AB - Parkinson's disease (PD) is a neurobehavioral disorder characterized by motor symptoms and signs, and non-motor abnormalities such as olfactory dysfunction, pain, sleep disorders and cognitive impairment. Amongst these alterations, sleep disturbances play an important role in the pathology, but presence of disturbed sleep is not currently considered in diagnosis. However, sleeping problems may precede by many years the classic motor abnormalities of PD and should be clinically evaluated as a potential marker before disease onset. The first disturbance reported with this potential was the disorder REM sleep behaviour and currently several other disturbances have gained importance as potential markers, such as excessive daytime sleepiness, restless legs syndrome and new evidence also points to changes in circadian rhythms. Here we present a brief review of the major evidence indicating that sleep disturbances precede the motor symptoms in PD and neurodegeneration occurs in regions that could underlie these phenomena in order to provide support for the conclusion that disturbances of sleep should be considered as valuable preclinical markers for PD. PMID- 25433716 TI - On-farm characteristics and biosecurity protocols for small-scale swine producers in eastern Australia. AB - Pigs are considered high risk for the introduction and spread of foot and mouth disease (FMD) in Australia. Facilities where animals from different origins are commingled, such as saleyards, pose a high risk for disease spread. Sound on-farm management practices and biosecurity protocols are the first line of defence against a potential on-farm disease outbreak. This study evaluated the practices of 104 producers (vendors who sold pigs and purchasers of live pigs for grow-out) who traded pigs at 6 peri-urban and rural saleyards in eastern Australia. Specifically, management and on-farm biosecurity practices were assessed using an in-depth questionnaire. Univariable and multivariable logistic regression analyses were used to investigate (1) producer associations: producer type, State, motivation to keep pigs, farm type, gender, years having owned pigs, and the acquisition of formal livestock qualifications; and (2) pig associations: herd size, housing, management (husbandry and feeding) practices and biosecurity (including pig movement) practices. Backyard operations (<20 sows) were undertaken by 60.6% of participants, followed by small-scale pig operations (28.8%; 21-100 sows). Few producers (16.3%) reported residing in close proximity (<5 km) to commercial operations; however, less rural producers had neighbouring hobby pig operations within 5 km of their property (P=0.033). Motivation for keeping pigs was significantly associated with a number of biosecurity practices. Producers who kept pigs for primary income were more likely to provide footwear precautions (P=0.007) and ask visitors about prior pig contacts (P=0.004). Approximately 40% of backyard and small-scale producers reported not having any quarantine practices in place for incoming pigs, compared to only 9.1% among larger producers. The main reasons cited for not adopting on-farm biosecurity practices in this study included having no need on their property (43.1%) and a lack of information and support (by the industry and/or authorities; 18.5%). Up to three-quarters of all producers maintained an open breeding herd, regularly introducing new pigs to the main herd. Saleyards are an important source of income for backyard and small-scale producers as well as an important risk factor for the introduction and dissemination of endemic and emerging animal diseases. Differing management and biosecurity practices as well as the motivations of these producers keeping pigs in small numbers and trading pigs at saleyards need to be taken into account in the development of successful biosecurity extension programmes for this sector of the Australian pork industry. PMID- 25433713 TI - Energy metabolism of synaptosomes from different neuronal systems of rat cerebellum during aging: a functional proteomic characterization. AB - Functional proteomics was used to characterize age-related changes in energy metabolism of different neuronal pathways within the cerebellar cortex of Wistar rats aged 2, 6, 12, 18, and 24 months. The "large" synaptosomes, derived from the glutamatergic mossy fibre endings which make synaptic contact with the granule cells of the granular layer, and the "small" synaptosomes, derived from the pre synaptic terminals of granule cells making synaptic contact with the dendrites of Purkinje cells, were isolated by a combined differential/gradient centrifugation technique. Because most brain disorders are associated with bioenergetic changes, the maximum rate (Vmax) of selected enzymes of glycolysis, Krebs' cycle, glutamate and amino acids metabolism, and acetylcholine catabolism were evaluated. The results show that "large" and "small" synaptosomes possess specific and independent metabolic features. This study represents a reliable model to study in vivo (1) the physiopathological molecular mechanisms of some brain diseases dependent on energy metabolism, (2) the responsiveness to noxious stimuli, and (3) the effects of drugs, discriminating their action sites at subcellular level on specific neuronal pathways. PMID- 25433717 TI - Oral administration of antimicrobials increase antimicrobial resistance in E. coli from chicken--a systematic review. AB - Antimicrobials play an important role in animal and human health care. It was the aim of this systematic review to assess the effects of oral administration of antimicrobials on the development of antimicrobial resistance (AMR) in Escherichia coli (E. coli) from chickens. Moreover, the effects of the administration of more than one antimicrobial and of different dosages were studied. Literature was searched in November 2012 from the electronic databases ISI Web of Science, PubMed, Scopus and a national literature database (DIMDI) as well as the database ProQuest LLC. The search was updated in March 2014. Original studies describing a treatment (A) and a control group of either non-treatment (C) or initial value (0) and determining AMR in E. coli at different sample points (SP) were included. The literature search resulted in 35 full text articles on the topic, seven (20%) of which contained sufficient information on the administered antimicrobial and the impact of treatment on AMR. Most papers described the use of more than one antimicrobial, several dosages, controls (non treatment or pre-treatment) and measured AMR at different SPs leading to a total of 227 SPs on the impact of the use of antimicrobials on AMR in chickens. 74% of the SPs (168/227) described a higher AMR-rate in E. coli from treated animals than from controls. After the administration of a single antimicrobial, AMR increased at 72% of the SPs. Administration of more than one antimicrobial increased AMR at 82% of the SPs. Higher dosages were associated with similar or higher AMR rates. The limited number of studies for each antimicrobial agent and the high variability in the resistance effect call for more well designed studies on the impact of oral administration on AMR development and spread. PMID- 25433718 TI - Risk of bleeding associated with interventional musculoskeletal radiology procedures. A comprehensive review of the literature. AB - This review compiles the current literature on the bleeding risks in common musculoskeletal interventional procedures and attempts to provide guidance for practicing radiologists in making decisions regarding the periprocedural management of patients on antithrombotic therapy. The practitioner must weigh the risk of bleeding if therapy is continued against the possibility a thromboembolic occurring if anticoagulation therapy is withheld or reversed. Unfortunately, there is little empirical data to guide evidence-based decisions for many musculoskeletal interventions. However, a review of the literature shows that for low-risk procedures, such as arthrograms/arthrocenteses or muscle/tendon sheath injections, bleeding risks are sufficiently small that anticoagulants and antiplatelet therapies need not be withheld. Additionally, relatively higher-risk procedures, such as needle biopsies of bone and soft tissue, may be safely performed without holding antithrombotic therapy, provided pre-procedural INR is within therapeutic range. Thus, while a patient's particular clinical circumstances should dictate optimal individualized management, anticoagulation alone is not a general contraindication to most interventional musculoskeletal radiology procedures. PMID- 25433719 TI - Complementary roles of bone scintigraphy and MR imaging in the detection and long term follow-up of primary non-Hodgkin's bone lymphoma in a child-case report. AB - The aim of our report is to demonstrate the complementary roles of bone scintigraphy (BS), magnetic resonance imaging (MR), and positron emission tomography using 2-deoxy-2-[18F]fluoro-D-glucose (F-18-FDG PET/CT) in the diagnosis and treatment monitoring of a child with primary non-Hodgkin's lymphoma of bone (PLB). Increased blood flow, high tissue accumulation, and markedly increased uptake on the late BS pointed toward an active bone process in the left femoral region. Bone marrow infiltration of the left femur and cortical sclerosis, which were both demonstrated by MR imaging, were later confirmed as PLB by bone marrow biopsy. The normalizations of the flow and tissue phases of BS a year after treatment and during the entire follow-up were in keeping with inactive disease and clinical remission. However, even 8 years after treatment and complete remission, MR imaging demonstrated persistent unmodified bone marrow alteration and appreciable cortical involvement. A slightly increased metabolic activity of the left femoral epiphysis demonstrated by F-18-FDG PET/CT and mild activity in the same region on delayed BS were demonstrated in the late follow up. Our results strongly suggest that BS and MR imaging should be included in the diagnostic algorithm of children with undefined bone symptoms. However, mild metabolic activity on the F-18-FDG PET/CT scan could not reliably differentiate between the presence or absence of disease in a patient with PLB in clinical remission. PMID- 25433720 TI - Regulation of human enteric alpha-defensins by NOD2 in the Paneth cell lineage. AB - Human enteric alpha-defensins (HD5 and HD6), major antimicrobial peptides produced by Paneth cells in the intestine, play important roles in intestinal innate immunity. Since their expression is decreased in Crohn's disease (CD), with decreased expression being more pronounced in the presence of NOD2 mutations, it would be extremely interesting to investigate the mechanism by which NOD2 may regulate expression of human enteric alpha-defensins. Here we show that although NOD2 by itself can slightly up-regulate expression of enteric alpha defensins mainly through activation of the NF-kappaB pathway, it can strongly down-regulates their expression during differentiation of the Paneth cell lineage mainly by inhibiting activation of the MAPK pathway. Since NOD2 is over-expressed in CD and mutant NOD2 cannot result in NF-kappaB activity, our finding can provide an explanation of the previous observation showing decreased expression of human enteric alpha-defensin in CD and even more so in the presence of NOD2 mutations. In addition, this finding provides a new view on the function of NOD2 in regulating intestinal innate immunity. PMID- 25433721 TI - Perivascular microenvironment in primary central nervous system lymphomas: the role of chemokines and the endothelin B receptor. AB - Chemokines are peptides that function as chemoattractant cytokines in cell activation, differentiation and trafficking. Endothelin B receptor (ETBR) is a receptor for endothelin, which is known to function as a vasoconstrictor. In the present study, to clarify the immune escape mechanism of primary central nervous system lymphomas (PCNSLs), the expression of ETBR and of subsets of chemokines (CXCL12, 13) in 24 PCNSLs was investigated. CXCL12 was expressed by lymphoma cells in different resident brain cell populations in 22/24 cases. CXCL13 expression was identified in tumor cells in 19/24 cases, but was only expressed by tumor cells and by proliferating vascular endothelial cells. In addition, tumor-infiltrated lymphocytes (TILs) accumulated in areas with expression of chemokines, particularly of CXCL13. ETBR expression was detected in 12/24 cases. Positive ETBR cases were associated with a paucity of TILs, particularly of cytotoxic T cells, whereas negative ETBR cases were associated with an abundance of TILs. The combined data indicate that CXCL12 and CXCL13 up-regulation may be differently linked to the development of PCNSLs and to the accumulation of TILs. In addition, ETBR expression by lymphoma and endothelial cells may mediate trafficking of TILs, which may explain the immune escape processes of PCNSLs. PMID- 25433722 TI - Quantitative endoscopic ultrasound elastography in the nodal staging of esophageal cancer. PMID- 25433723 TI - The Changes in the Expression of NF-KB in a Degenerative Human Intervertebral Disc model. AB - We aim at determining the changes in the expression of NF-kB signaling pathway in degenerative intervertebral discs. We collected normal and degenerated intervertebral discs tissues. The normal and degenerated cells were cultivated and their histopathology and immunofluoresence studies were used to observe the position of NF-kB p65 in the cell. We also treated the nucleus pulposus cells with inflammatory factors and inhibitors. Western blot was used to analyze the expression of different proteins. Real time fluorescence-based quantitative PCR was used for observation of NF-kB regulation of change in gene expression. Immunofluorescence showed that in the non-degenerative group the p65 was found in the cytoplasm of the nucleus pulposus cell while in the degenerated cell group the p65 protein was found in the nucleus of the cell. The expression of p65 increased with increase in the degree of degenerative change of the nucleus pulposus cell. RT-PCR showed that the expression of matrix metalloproteinases, aggrecanases and IL-6 was higher in the degenerative group. The amount of aggrecan and type II collagen was significantly decreased in the degenerative group. IL-1beta was able to upregulate the activation of NF-kB and the expression of MMP-13 and ADAMTS-4 was also significantly increased. The effect of these proteins can be inhibited by the NF-kB inhibitor, BAY11-7082. The activation of the NK-kB signaling pathway in a degenerative intervertebral disc is gradually increased, regulating the over-expression of matrix-degrading enzymes. It plays an important role in the degradation of extracellular matrix. PMID- 25433724 TI - Surgical Treatment of Hashimoto's with Thyroid Microcarcinoma. AB - The aim of this study is to explore the surgical strategies for treating Hashimoto's disease complicated with thyroid microcarcinoma. We analyzed the clinical data of 25 patients with Hashimoto's disease with thyroid microcarcinoma who were treated in our hospital from January 1995 to September 2011. The incidence of Hashimoto's disease with thyroid microcarcinoma was 9.8 % (25/256) in our hospital. Amongst them, 19 patients had papillary thyroid carcinoma and six had follicular thyroid carcinoma. There were 24 cases (96 %) confirmed by the frozen section examination and one (4 %) after surgery. One patient did not undergo remedial surgery. The surgical approaches were determined based on preoperative examinations and intraoperative frozen pathology, including thyroid lobe and isthmus resection with contralateral lobe subtotal resection in 19 cases, and bilateral subtotal thyroid lobectomy in one case. Central lymph node dissection was conducted for all patients except one who was not diagnosed until after the surgery. No recurrence occurred during the follow-up (range: 6 months to 17 years) and all patients have survived to date. The preoperative diagnosis rate of Hashimoto's disease with thyroid cancer (in particular thyroid microcarcinomas) is low. Preoperative palpation, color Doppler ultrasound, fine needle aspiration, and the frozen section examination are helpful to improve the diagnosis rate of Hashimoto's disease with thyroid microcarcinoma. Surgery procedure is the most effective approach. PMID- 25433725 TI - Multicenter evaluation of pharmacologic management and outcomes associated with severe resistant alcohol withdrawal. AB - INTRODUCTION: A subset of patients with alcohol withdrawal syndrome does not respond to benzodiazepine treatment despite escalating doses. Resistant alcohol withdrawal (RAW) is associated with higher incidences of mechanical ventilation and nosocomial pneumonia and longer intensive care unit (ICU) stay. The objective of this study is to characterize pharmacologic management of RAW and outcomes. METHODS: Adult patients were identified retrospectively via International Classification of Diseases, Ninth Revision codes for severe alcohol withdrawal from 2009 to 2012 at 3 hospitals. Data collected included pharmacologic management and clinical outcomes. RESULTS: A total of 184 patients met inclusion criteria. Sixteen medications and 74 combinations of medications were used for management. Propofol was the most common adjunct agent, with dexmedetomidine and antipsychotics also used. One hundred seventy-five patients (96.2%) were admitted to the ICU, with 149 patients (81.9%) requiring ventilator support. Median time to resolution of alcohol withdrawal syndrome from RAW designation was 6.0 days. Median ICU and hospital length of stay were 9.0 and 12.7 days, respectively. CONCLUSION: Diverse patterns exist in the management of patients meeting RAW criteria, indicating lack of refined approach to treatment. High doses of sedatives used for these patients may result in a high level of care, illustrating a need for evidence-based clinical guidelines to optimize outcomes. PMID- 25433727 TI - Teaching sonoanatomy to anesthesia faculty and residents: utility of hands-on gel phantom and instructional video training models. AB - STUDY OBJECTIVE: Thousands of patients worldwide annually receive neuraxial anesthesia and analgesia. Obesity, pregnancy, and abnormal spinal anatomy pose challenges for accurate landmark palpation. Further, spinal sonoanatomy is not uniformly taught in residency education, even though its use has previously been shown to improve identification of relevant structures and decrease procedural complications and failure rates. The aim of this study was to evaluate the use of hands-on gel phantom and instructional video training for teaching spinal sonoanatomy among anesthesiology faculty and residents. DESIGN: Twenty-three residents and 27 anesthesiologists were randomized to gel phantom, video teaching, and control groups. SETTING: Academic Hospital. MEASUREMENTS: Successful identification of spinal sonoanatomy was attempted on a human volunteer before and immediately after the respective intervention and 3 weeks later. Perceived knowledge and training modality satisfaction were assessed using modified Likert scales. INTERVENTIONS: Gel phantom and video teaching groups compared with control (no intervention). MAIN RESULTS: Both interventions significantly improved spine sonoanatomy identification accuracy. Logistic regression analysis demonstrated both interventions improved the odds of transverse process (gel 12.61, P = .013; video 7.93, P = .030) and lamina (gel 65.12, P = .003; video 8.97, P = .031) identification. Perceived knowledge of basic spinal anatomy and spinal sonoanatomy improved in the intervention versus control groups. Mean (SD) modified Likert scale scores for learning satisfaction (1 = unsatisfied, 10= very satisfied) were 8.1 (1.5) and 8.0 (1.7) for hands-on gel phantom and instructional video training participants, respectively. CONCLUSION: Use of hands-on gel phantom or instructional video training can improve anesthesia staff and resident knowledge of lumbar spine sonoanatomy. PMID- 25433726 TI - Persistent paralysis after spinal anesthesia for cesarean delivery. AB - Anterior spinal artery syndrome has rarely been reported as a cause of permanent neurologic complications after neuraxial anesthesia in obstetric patients. A parturient developed anterior spinal artery syndrome after spinal anesthesia for cesarean delivery. A healthy 32-year-old parturient presented at 41(2/7) weeks for primary elective caesarean delivery for breech presentation. Spinal anesthesia was easily performed with clear cerebrospinal fluid, and block height was T4 at 5 minutes. Intraoperative course was uneventful except for symptomatic bradycardia (37-40 beats per minute) and hypotension (88/44 mm Hg) 4 minutes postspinal anesthesia, treated with ephedrine and atropine. Dense motor block persisted 9 hours after spinal anesthesia, and magnetic resonance imaging of the lumbosacral region was normal, finding no spinal cord compression or lesion. Physical examination revealed deficits consistent with a spinal cord lesion at T6, impacting the anterior spinal cord while sparing the posterior tracts. PMID- 25433728 TI - Prognostic analysis of submucosa-invasive gastric cancer with lymph node metastasis. AB - BACKGROUND: The aims of this study were to identify prognostic factors of patients with submucosa-invasive (T1b) gastric cancer and to verify the validity of adjuvant chemotherapy for this disease. METHODS: We retrospectively examined the cases of 1,236 consecutive patients in our prospectively maintained database with T1b gastric cancer who underwent gastrectomy in 1995-2012. We used 11 clinicopathologic characteristics to identify prognostic factors by univariate and multivariate analyses. We compared the survival of the 160 node-positive T1b gastric cancer patients with that of 133 patients in the same database who had node-positive muscularis propria-invasive (T2) gastric cancer and had undergone gastrectomy without adjuvant chemotherapy during the same period, as a reference cohort. RESULTS: The 5-year overall survival rate was 91.4% for all 1,236 patients. Advanced age (hazard ratio [HR] 4.51; 95% confidence interval [CI] 3.26 6.24; P < .01), male sex (HR 2.26; 95% CI 1.56-3.26; P < .01), and the presence of lymph node metastasis (HR 1.89; 95% CI 1.33-2.70; P < .01) were independent prognostic factors. The 5-year overall survival rates were 92.5% in node-negative patients, 84.5% in patients with 1 or 2 metastatic nodes, and 80.1% in patients with 3 or more metastatic nodes (P < .01). The 5-year overall survival rates of the node-positive T1b and T2 gastric cancer patients were 83.6% and 81.2%, respectively (P = .73). CONCLUSION: The prognosis of node-positive T1b gastric cancer patients after curative gastrectomy was unsatisfactory. Adjuvant chemotherapy should be considered for these patients, especially those with 3 or more metastatic nodes. PMID- 25433729 TI - Commentary on "Can we improve the morbidity and mortality associated with the associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) procedure in the management of colorectal liver metastases?". PMID- 25433731 TI - Commentary on "can we improve the morbidity and mortality associated with the associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) procedure in the management of colorectal liver metastases?". PMID- 25433730 TI - Papillary thyroid microcarcinomas located at the middle part of the middle third of the thyroid gland correlates with the presence of neck metastasis. AB - BACKGROUND: Papillary thyroid microcarcinomas (PTMCs), located at upper poles of the thyroid, are associated with lateral neck metastasis (LNM) according to previous reports. Controversy remains regarding the correlation between the location of PTMCs and central neck metastasis (CNM). METHODS: Medical records of 949 patients with PTMCs diagnosed between 2010 and 2013 were reviewed retrospectively. With a subdivision of the middle third of the thyroid gland, correlations between tumor location and CNM/LNM along with other clinicopathologic factors were analyzed by binary logistic regression. RESULTS: PTMCs located in the middle part of the middle third of the thyroid gland (MPMT) showed the greatest rate of CNM (57.5%) among all locations. PTMCs located at isthmus showed the second greatest rate of CNM (44.3%). In the multivariate analysis, MPMT, tumor size >0.5 cm, young and middle age, male sex, multifocality within the affected lobe, and capsular invasion were correlated with CNM. PTMCs located at upper poles and MPMT showed comparatively high rates of LNM (8.6% and 8.3%). Consistent with previous reports, an upper pole location, MPMT, and a tumor size >0.5 cm greatly correlated with LNM in the multivariate analysis. Eleven patients had skip metastases, which only occurred with upper/lower pole locations and MPMT. CONCLUSION: PTMCs located in the MPMT correlated with both CNM and LNM. Tumor location along with other clinicopathologic factors such as young and middle age, male sex, and tumor size >0.5 cm could facilitate preoperative stratification and guide operative management for patients with PTMC. PMID- 25433732 TI - Density functional theory study of the capacitance of single file ions in a narrow cylinder. AB - The differential capacitance of a model organic electrolyte in a cylindrical pore that is so narrow that the ions can form only a single file is studied by means of density functional theory (DFT). Kornyshev (2013), has studied this system and found the differential capacitance to have only a double hump shape (the so called camel shape) whereas other geometries show this behavior only at low ionic concentrations that are typical for aqueous electrolytes. However, his calculation is rather approximate. In this DFT study we find that the double hump shape occurs only at low ionic concentrations. At high concentrations, the capacitance has only a single hump. Kornyshev considers a metallic cylinder and approximately includes the contributions of electrostatic images. Electrostatic images are not easily incorporated into DFT. As a result, images are not considered in this study and the question of whether Kornyshev's result is due to his approximations or images cannot be answered. Simulations to answer this question are planned. PMID- 25433734 TI - 53rd annual Walter Wright day: glaucoma management review. PMID- 25433733 TI - Computational prediction of protein interactions related to the invasion of erythrocytes by malarial parasites. AB - BACKGROUND: The invasion of red blood cells (RBCs) by malarial parasites is an essential step in the life cycle of Plasmodium falciparum. Human-parasite surface protein interactions play a critical role in this process. Although several interactions between human and parasite proteins have been discovered, the mechanism related to invasion remains poorly understood because numerous human parasite protein interactions have not yet been identified. High-throughput screening experiments are not feasible for malarial parasites due to difficulty in expressing the parasite proteins. Here, we performed computational prediction of the PPIs involved in malaria parasite invasion to elucidate the mechanism by which invasion occurs. RESULTS: In this study, an expectation maximization algorithm was used to estimate the probabilities of domain-domain interactions (DDIs). Estimates of DDI probabilities were then used to infer PPI probabilities. We found that our prediction performance was better than that based on the information of D. melanogaster alone when information related to the six species was used. Prediction performance was assessed using protein interaction data from S. cerevisiae, indicating that the predicted results were reliable. We then used the estimates of DDI probabilities to infer interactions between 490 parasite and 3,787 human membrane proteins. A small-scale dataset was used to illustrate the usability of our method in predicting interactions between human and parasite proteins. The positive predictive value (PPV) was lower than that observed in S. cerevisiae. We integrated gene expression data to improve prediction accuracy and to reduce false positives. We identified 80 membrane proteins highly expressed in the schizont stage by fast Fourier transform method. Approximately 221 erythrocyte membrane proteins were identified using published mass spectral datasets. A network consisting of 205 interactions was predicted. Results of network analysis suggest that SNARE proteins of parasites and APP of humans may function in the invasion of RBCs by parasites. CONCLUSIONS: We predicted a small scale PPI network that may be involved in parasite invasion of RBCs by integrating DDI information and expression profiles. Experimental studies should be conducted to validate the predicted interactions. The predicted PPIs help elucidate the mechanism of parasite invasion and provide directions for future experimental investigations. PMID- 25433736 TI - Intraocular pressure variations: causes and clinical significance. AB - Reduction of intraocular pressure (IOP) is the only known effective treatment for glaucoma. However, IOP is a highly variable and dynamic parameter, undergoing virtually constant changes from numerous factors, including body position and circadian rhythms. Despite this variability, evidence for the efficacy of IOP reduction in glaucoma is based on studies designed to assess mean IOP and not IOP variations. Post hoc analysis of data from major clinical trials has suggested that IOP variations may be an independent risk factor for the development of glaucoma or glaucomatous progression, at least in some patients, but the evidence is incomplete and further studies are required. In the interim, judicious selection of existing therapies can help to minimize IOP variations. In general, therapies that improve outflow instead of suppressing aqueous humor production result in more stable IOP. However, new technology to allow better monitoring of IOP, ideally in a continuous 24-hour manner, is required to fully understand the role of IOP variations in glaucoma. PMID- 25433737 TI - Ocular hypertension: an approach to assessment and management. AB - Ocular hypertension is a common and important problem seen by eye care providers. This review presents a practical approach to individuals with ocular hypertension. It describes the common functional and structural investigations used in evaluation, as well as the advantages and disadvantages of each test. This review also discusses several landmark studies on ocular hypertension and provides a practical guide to the management of this problem. PMID- 25433739 TI - Indications for a systemic work-up in glaucoma. AB - Most glaucomas are primary in nature. However, many adult and childhood glaucomas are secondary, and they require systemic evaluation to pick up associated systemic disease. Conditions such as nocturnal hypotension and sleep apnea may contribute to glaucomatous progression, whereas neurologic diseases may mimic normal tension glaucoma based on disc appearance. This review highlights those conditions in which a focused systemic work-up can improve glaucoma management and potentially discover life-threatening disease. PMID- 25433738 TI - Selecting visual field tests and assessing visual field deterioration in glaucoma. AB - Testing the peripheral field of vision is the mainstay for detection of glaucoma deterioration. Various methods and algorithms are currently available for detection of early glaucoma or establishing disease progression. Alternative testing strategies such as frequency doubling technology perimetry or short wavelength automated perimetry have been extensively explored over the last 2 decades. The former has been found most promising for detection of earliest evidence of functional glaucoma damage when the standard achromatic perimetry results are still within the normal range. However, standard achromatic perimetry remains the standard technique for establishing deterioration of the disease. Both trend and event analyses are used for establishing change within series of visual fields. Trend analyses provide the clinician with rates of progression, putting the speed of glaucoma progression in the context of patient longevity, whereas event analyses demonstrate a "step" change regardless of the length of time it took for this amount of change to occur. The two techniques are complementary and should be used concurrently. PMID- 25433740 TI - Case-based approach to managing angle closure glaucoma with anterior segment imaging. AB - This is a case-based approach to the diagnosis and management of angle closure glaucoma of a variety of causative factors, with a special emphasis on the use of advanced anterior segment imaging including ultrasound biomicroscopy and anterior segment optical coherence tomography. Although all angle closure is caused by iridotrabecular contact, the cause of angle closure glaucoma is classified based on the site of primary blockage of aqueous movement from anterior to posterior: pupillary block, plateau iris, lens-related, and posterior causative factors. Although gonioscopy is traditionally used to visualize the angle structures and estimate the angle width, objective and reproducible measurement of the anterior chamber angle can best be obtained with advanced anterior segment imaging. In this review article, we demonstrate the utility of anterior advanced imaging to identify underlying mechanisms in cases of angle closure glaucoma in guiding directed management. PMID- 25433741 TI - Selective laser trabeculoplasty as a first-line therapy: a review. AB - Poor adherence with glaucoma medications has been well documented. There remains a significant unmet need for a relatively safe intraocular pressure (IOP) lowering procedure that minimizes or eliminates patient participation, and thus reduce the incidence of treatment failures attributable to nonadherence. Selective laser trabeculoplasty (SLT) offers several advantages: It effectively reduces IOP in most patients with open-angle glaucoma, it is cost-effective compared with eye drops, it can be repeated if needed, and it eliminates the issue of adherence to medications when used as an initial treatment. This article reviews the evidence supporting the use of SLT as a first-line therapy in glaucoma. PMID- 25433742 TI - The optimal trabeculectomy: patient and procedure. AB - Guarded external fistulization procedures remain important surgical options for patients who are experiencing progressive vision loss caused by glaucoma. The progenitor procedure, the trabeculectomy, has undergone continuous modifications over the past 40 or more years, rendering the surgery safer and the outcomes more predictable. Studies are cumulating to show that very low intraocular pressures can both reduce glaucomatous vision loss and positively change the rate of progression. Optimal patient selection and patient preparation, as well as some guiding procedural principles, are described in this review. PMID- 25433743 TI - Minimally invasive glaucoma surgery: current implants and future innovations. AB - Traditionally, invasive surgical management of glaucoma is recommended when medication and/or laser trabeculoplasty fail to control intraocular pressure (IOP). Filtering procedures, such as trabeculectomy and glaucoma drainage devices, are effective in lowering IOP, but they have significant associated adverse events and rates of failure. For these reasons, a new group of surgical procedures has emerged that seeks to decrease IOP with lower associated rates of complications. The acronym MIGS, usually described as minimally invasive glaucoma surgery, has been coined to describe this group of procedures. As new devices become available, MIGS procedures will help to fill the gap between conservative medical and laser therapy and invasive surgical treatment of glaucoma to offer patients an earlier and safer transition to surgical management of their disease. In this review, we define the characteristics of an ideal MIGS procedure and discuss implants currently in use or under investigation. PMID- 25433745 TI - Orbital extension of anterior uveal melanoma after Baerveldt tube shunt implantation. PMID- 25433747 TI - Periorbital necrotizing fasciitis in a previously healthy male. PMID- 25433746 TI - Re-emphasizing Thygeson's warning: conjunctival phlyctenulosis as presenting sign of impending clinical tuberculosis. PMID- 25433748 TI - Toxic granulomatous anterior uveitis in live intracameral cysticercosis masquerading as leukocoria. PMID- 25433744 TI - Exciting directions in glaucoma. AB - Glaucoma is a complex, life-long disease that requires an individualized, multifaceted approach to treatment. Most patients will be started on topical ocular hypotensive eyedrop therapy, and over time multiple classes of drugs will be needed to control their intraocular pressure. The search for drugs with novel mechanisms of action, to treat those who do not achieve adequate intraocular pressure control with, or become refractory to, current therapeutics, is ongoing, as is the search for more efficient, targeted drug delivery methods. Gene transfer and stem-cell applications for glaucoma therapeutics are moving forward. Advances in imaging technologies improve our understanding of glaucoma pathophysiology and enable more refined patient evaluation and monitoring, improving patient outcomes. PMID- 25433749 TI - Bilateral posterior scleritis as a presenting manifestation of giant cell arteritis: A case report. PMID- 25433750 TI - Fundus autofluorescence and optical coherence tomography findings in pigmented paravenous retinochoroidal atrophy. PMID- 25433751 TI - Emergency department visits after intravitreal bevacizumab and ranibizumab injections in diabetic patients. PMID- 25433752 TI - Intratarsal keratinous cyst mimicking a large chalazion. PMID- 25433753 TI - Fungal hyphae growing into anterior chamber from cornea. PMID- 25433754 TI - Endophthalmitis after penetrating ocular injury in the dentist's chair. PMID- 25433755 TI - Glucose transporter isoform-1 receptor-positive infantile capillary hemangiomas: case report and literature review. PMID- 25433756 TI - Isolated choroidal macrovessel: a tracklike choroidal lesion. PMID- 25433757 TI - Serial intracameral bevacizumab for uveitis-glaucoma-hyphema syndrome: a case report. PMID- 25433758 TI - Interactive effects of acupuncture on pain and distress in major burns: An experiment with rats. AB - This study sought to investigate the interactive effects of acupuncture on pain and distress and the local progress in the burn wound in an experimental major burn model. Forty-eight male Sprague-Dawley rats were divided into six groups: S group (sham/observation during 7 days after injury); SA group (sham/acupuncture/observation during 7 days after injury); B1 group (burns/observation during 1h after injury); BA1 group (burns/acupuncture/observation during 1 h after injury); B7 group (burns/observation during 7 days after injury); and BA7 group (burns/acupuncture/observation during 7 days after injury). Pain and distress scores were evaluated throughout the study. The amounts of neutrophils and mononuclear cells were evaluated semiquantitatively, and the number of microvessels was evaluated quantitatively. Our data indicated that the average pain score of BA7 group was significantly lower than the other study groups. Histopathologic investigations indicate that the amounts of neutrophil and mononuclear cell and numbers of microvessels in the unburned skin were higher in acupuncture-applied groups. The number of microvessels in burn wounds of BA7 group was significantly higher than that of the other groups. Our data suggest that acupuncture provides low pain and distress scores in experimental rat model, and it contributes to wound healing with an enhanced angiogenesis during the acute phase of burns. Future clinical and experimental studies should be conducted to discern the benefits from acupuncture in pain management of burn patients. PMID- 25433759 TI - Spatiotemporal distribution of carbonyl compounds in China. AB - A sampling campaign was carried out at nine Chinese cities in 2010/2011. Fifteen monocarbonyls (C# = 1-9) were quantified. Temperature is the rate-determining factor of the summertime carbonyl levels. The carbonyl emissions in winter are mainly driven by the primary anthropogenic sources like automobile. A molar ratio of propionaldehyde to nonaldehyde is a barometer of the impact of atmospheric vegetation emission which suggesting that strong vegetation emissions exist in summer and high propionaldehyde abundance is caused by fossil fuel combustion in winter. Potential health risk assessment of formaldehyde and acetaldehyde was conducted and the highest cumulative risks were observed at Chengdu in summer and Wuhan in winter. Because of the strong photochemical reaction and large amount of anthropogenic emissions, high concentrations of carbonyl compounds were observed in Chengdu. The use of ethanol-blended gasoline in Wuhan is the key reason of acetaldehyde emission and action should be taken to avoid potential health risks. PMID- 25433760 TI - Malignant obstructive jaundice in situs inversus: demonstration of precut and biliary drainage. PMID- 25433761 TI - Reproductive isolation between Stigmaeopsis celarius and its sibling species sympatrically inhabiting bamboo (Pleioblastus spp.) plants. AB - Stigmaeopsis celarius Banks (hereafter Sc) is a spider mite living and feeding on the leaves of various bamboo species such as Moso bamboo [Phyllostachys edulis (=P. pubescens)] and Pleioblastus spp. (Poaceae). A previous phylogenetic study revealed a cryptic, phylogenetic sister species to Sc (hereafter Ss). Although its life type appears to be similar to that of Sc, individuals of Ss make much smaller nests compared with Sc, and the nests have been found mostly on Nezasa bamboo (Pleioblastus argenteostriatus). To investigate whether Sc and Ss are reproductively isolated, we explored their populations in southwestern Japan, and crossed them to examine mating behaviors and fertilization success. Field surveys revealed that the nests of these two species occur on the same leaves and, thus, the individuals of these species may make frequent contact. Reciprocal crosses suggested that the two species are reproductively isolated. Though Sc males have tried to mate with Ss females, copulation seldom occurred because of their long opisthosoma (hind body), which prevented the insertion of the aedeagus into the genitalia of Ss females. In contrast, most Ss males ignored Sc females, and eggs were not fertilized even in the few cases where copulation appeared to occur. These results suggest that strong selection pressure is imposed on body length to prevent interspecific hybridization in the contact area of these species. PMID- 25433764 TI - Value of dermoscopy in the diagnosis and prognostic evaluation of linear pigmented lichen planus. PMID- 25433763 TI - Seance: reference-based phylogenetic analysis for 18S rRNA studies. AB - BACKGROUND: Marker gene studies often use short amplicons spanning one or more hypervariable regions from an rRNA gene to interrogate the community structure of uncultured environmental samples. Target regions are chosen for their discriminatory power, but the limited phylogenetic signal of short high throughput sequencing reads precludes accurate phylogenetic analysis. This is particularly unfortunate in the study of microscopic eukaryotes where horizontal gene flow is limited and the rRNA gene is expected to accurately reflect the species phylogeny. A promising alternative to full phylogenetic analysis is phylogenetic placement, where a reference phylogeny is inferred using the complete marker gene and iteratively extended with the short sequences from a metagenetic sample under study. RESULTS: Based on the phylogenetic placement approach we built Seance, a community analysis pipeline focused on the analysis of 18S marker gene data. Seance combines the alignment extension and phylogenetic placement capabilities of the Pagan multiple sequence alignment program with a suite of tools to preprocess, cluster and visualise datasets composed of many samples. We showcase Seance by analysing 454 data from a longitudinal study of intestinal parasite communities in wild rufous mouse lemurs (Microcebus rufus) as well as in simulation. We demonstrate both improved OTU picking at higher levels of sequence similarity for 454 data and show the accuracy of phylogenetic placement to be comparable to maximum likelihood methods for lower numbers of taxa. CONCLUSIONS: Seance is an open source community analysis pipeline that provides reference-based phylogenetic analysis for rRNA marker gene studies. Whilst in this article we focus on studying nematodes using the 18S marker gene, the concepts are generic and reference data for alternative marker genes can be easily created. Seance can be downloaded from http://wasabiapp.org/software/seance/ . PMID- 25433762 TI - MicroRNAs as potential circulating biomarkers for amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a condition primarily characterized by the selective loss of upper and lower motor neurons. Motor neuron loss gives rise to muscle tissue malfunctions, including weakness, spasticity, atrophy, and ultimately paralysis, with death typically due to respiratory failure within 2 to 5 years of symptoms' onset. The mean delay in time from presentation to diagnosis remains at over 1 year. Biomarkers are urgently needed to facilitate ALS diagnosis and prognosis as well as to act as indicators of therapeutic response in clinical trials. MicroRNAs (miRNAs) are small molecules that can influence posttranscriptional gene expression of a variety of transcript targets. Interestingly, miRNAs can be released into the circulation by pathologically affected tissues. This review presents therapeutic and diagnostic challenges associated with ALS, highlights the potential role of miRNAs in ALS, and discusses the diagnostic potential of these molecules in identifying ALS-specific miRNAs or in distinguishing between the various genotypic and phenotypic forms of ALS. PMID- 25433765 TI - Facial erythema: keys to the differential diagnosis. PMID- 25433766 TI - [Registration of observational studies: it is time to comply with the Declaration of Helsinki requirement]. AB - Publication bias is a serious deficiency in the current system of disseminating the results of human research studies. Clinical investigators know that, from an ethical standpoint, they should prospectively register clinical trials in a public registry before starting them. In addition, it is believed that this approach will help to reduce publication bias. However, most studies conducted in humans are observational rather than experimental. It is estimated that less than 2% out of 2 million concluded or ongoing observational studies have been registered. The 2013 revision of the Declaration of Helsinki requires registration of any type of research study involving humans or identifiable samples or data. It is proposed that funding agencies, such as the Fondo de Investigaciones Sanitarias, as well as private companies, require preregistration of observational studies before providing funding. It is also proposed that Research Ethics Committees which, following Spanish regulation, have been using the Declaration as the framework for assessing the ethics of clinical trials with medicines since 1990, should follow the same provisions for the assessment of health-related observational studies: therefore, they should require prospective registration of studies before granting their final approval. This would allow observational study investigators to be educated in complying with an ethical requirement recently introduced in the most important ethical code for research involving humans. PMID- 25433767 TI - [Overweight, sedentary lifestyle, and insulin resistance]. PMID- 25433769 TI - Current and emerging therapies for multiple sclerosis. PMID- 25433768 TI - Comparative effectiveness analysis of monotherapy with cytotoxic agents in triple negative metastatic breast cancer in a community setting. AB - PURPOSE: There has been considerable progress in the treatment of metastatic breast cancer. However, the identification of optimal cytotoxic agents in patients with triple-negative breast cancer (TNBC) (negative for hormone receptors and human epidermal growth factor receptor 2) remains a therapeutic challenge. We conducted a comparative effectiveness analysis of 4 cytotoxic agents in patients with TNBC. METHODS: We retrospectively identified patients who received single-agent chemotherapy with eribulin, capecitabine, gemcitabine, or vinorelbine from 19 community oncology clinics across the United States. Data collection included baseline patient and disease characteristics, prior therapies, performance status, duration of current therapy, growth-factor use and other supportive care, and dose-limiting toxicities and associated dose reductions or delays or skipped doses. Time to treatment failure (TTF) was measured from the first cycle of chemotherapy until disease progression, discontinuation due to toxicity, or death. TTF was estimated using the Kaplan Meier method and Cox proportional hazards modeling adjusted for clustering on the practice site. To control for selection bias, which is inherent in observational studies, a propensity score-weighted TTF analysis was also conducted. FINDINGS: Data from 225 patients were included in the analysis (eribulin, 47 patients; capecitabine, 69; gemcitabine, 56; and vinorelbine, 53). The median age of each group was <60 years, with the exception of the gemcitabine group (63 years). The 4 groups were comparable with respect to age, performance status, duration of disease-free survival, presence of comorbidities, and hemoglobin level before the start of chemotherapy. Median lines of therapy of eribulin, capecitabine, gemcitabine, and vinorelbine and were 4th, 2nd, 3rd, and 3rd, respectively. The median durations of treatment were ~2 months with eribulin, capecitabine, and gemcitabine compared with 1.6 months with vinorelbine. Using eribulin as the reference drug, and with adjustment for line of therapy and associated prognostic factors, the propensity score-weighted Cox regression analysis did not identify significant between-treatment differences in TTF (hazard ratios [95% CI] vs eribulin: capecitabine, 1.15 [0.75-1.76]; gemcitabine, 0.62 [0.34-1.13]; and vinorelbine, 1.0 [0.67-1.67]). IMPLICATIONS: In this assessment of patients with TNBC treated in a community oncology setting, eribulin was utilized in later lines compared with the other agents. However, comparable drug activity was reported among the 4 agents. PMID- 25433770 TI - Genome-wide association studies (GWAS) and their importance in asthma. AB - Asthma is a complex disease determined by the interaction of different genes and environmental factors. The first genetic investigations in asthma were candidate gene association studies and linkage studies. In recent years research has focused on association studies that scan the entire genome without any prior conditioning hypothesis: the so-called genome-wide association studies (GWAS). The first GWAS was published in 2007, and described a new locus associated to asthma in chromosome 17q12-q21, involving the ORMDL3, GSDMB and ZPBP2 genes (a description of the genes named in the manuscript are listed in Table 1). None of these genes would have been selected in a classical genetic association study since it was not known they could be implicated in asthma. To date, a number of GWAS studies in asthma have been made, with the identification of about 1000 candidate genes. Coordination of the different research groups in international consortiums and the application of new technologies such as new generation sequencing will help discover new implicated genes and improve our understanding of the molecular mechanisms underlying the disease. PMID- 25433771 TI - Protective effect of breastfeeding with regard to children's behavioral and cognitive problems. AB - BACKGROUND: Breastfeeding has been associated with a lower risk for behavioral problems in childhood. However, it is uncertain whether these associations are mediated by the mother's or child's IQ. We examined the association between breastfeeding and attention-deficit hyperactivity disorder (ADHD) and other behavioral problems in childhood and assessed the role of the child's IQ and the mother's IQ in generating this association. FINDINGS: The current study included 874 children (8-11 years) recruited from schools in five Korean cities. Mothers were asked about nursing, and the prevalence of attention-deficit hyperactivity disorder (ADHD) and behavioral problems were compared between children who were breastfed and those who were not breastfed. After adjusting for age, gender, area of residence, and yearly family income, a lack of breastfeeding was associated with increased internalizing, externalizing, and overall behavioral problems as well as the diagnosis of ADHD. These associations weakened but mostly remained significant after adjusting for child's IQ and maternal IQ. In addition, a lack of breastfeeding was associated with low child's IQ and this association weakened, but remained significant even after adjusting for maternal IQ and the diagnosis of ADHD. CONCLUSIONS: This study suggests that there is a protective effect of breastfeeding on childhood behavioral outcomes with a partial mediation of this effect by the child's IQ, and there is a positive effect of breastfeeding on childhood intelligence with a partial mediation of this effect by the child's attention problem. PMID- 25433772 TI - [Pancreatic panniculitis post-endoscopic retrograde cholangiopancreatography]. PMID- 25433773 TI - [Atypical hemolytic uremic syndrome]. AB - The hemolytic uremic syndrome (HUS) is a clinical entity characterized by thrombocytopenia, non-immune hemolytic anemia and renal impairment. Kidney pathology shows thrombotic microangiopathy (TMA) with endothelial cell injury leading to thrombotic occlusion of arterioles and capillaries. Traditionally, HUS was classified in 2 forms: Typical HUS, most frequently occurring in children and caused by Shiga-toxin-producing bacteria, and atypical HUS (aHUS). aHUS is associated with mutations in complement genes in 50-60% of patients and has worse prognosis, with the majority of patients developing end stage renal disease. After kidney transplantation HUS may develop as a recurrence of aHUS or as de novo disease. Over the last years, many studies have demonstrated that complement dysregulation underlies the endothelial damage that triggers the development of TMA in most of these patients. Advances in our understanding of the pathogenic mechanisms of aHUS, together with the availability of novel therapeutic options, will enable better strategies for the early diagnosis and etiological treatment, which are changing the natural history of aHUS. This review summarizes the aHUS clinical entity and describes the role of complement dysregulation in the pathogenesis of aHUS. Finally, we review the differential diagnosis and the therapeutic options available to patients with aHUS. PMID- 25433774 TI - [Endoscopical removal of an accidentally ingested spoon]. PMID- 25433775 TI - [Perifollicular purpura: classical sign of scurvy]. PMID- 25433776 TI - [Body mass index and prognosis in the elderly patients with acute coronary syndromes]. AB - BACKGROUND AND OBJECTIVE: Little information exists about the prognostic impact of body mass index (BMI) in the elderly with acute coronary syndromes (ACS). We aimed to prospectively assess the association between BMI and midterm mortality in consecutive elderly patients with ACS. PATIENTS AND METHOD: We included consecutive ACS patients aged 75 years or older admitted to the Coronary Care Unit. Patients were stratified into 5 BMI subgroups (<20, 20-24.9, 25-29.9, 30 35, > 35 kg/m(2)). Primary endpoint was overall midterm mortality. Analyses were performed by Cox regression method. RESULTS: During the study period 600 patients were admitted, of whom 579 had known BMI values. Low weight patients (BMI<20 kg/m(2)) were older, with higher prevalence of vasculopathy and lower creatinine clearance. Median follow up was 315 days. Patients with BMI< 20 kg/m(2) had higher mortality as compared to the rest of groups. Adjusted analysis showed an attenuation of these differences, while maintaining significance for the groups of BMI 20-24.9 and 30-35 kg/m(2). CONCLUSIONS: The association between BMI and mortality was mainly due to worse prognosis in low weight patients. Prospective assessment of comorbidities and other variables linked to ageing should contribute to better understand the association between BMI and mortality. PMID- 25433777 TI - [Epidermal growth factor, innovation and safety]. AB - Bioidentical recombinant human epidermal growth factor (rhEGF) is available in concentrations and purity suitable for therapeutic use in long time stable formulations. Beneficial effects in several skin pathologies and lesions have been reported (traumatic and surgical wound healing, laser induced wounds, abnormal scars, keloids, radiation or chemotherapy induced dermatitis, post inflammatory hyperpigmentation or for skin aging damage repairing) and also may be considered for the treatment of several oropharingeal and high gastroesophageal tract mucosa diseases (mouth sores, pharyngeal fistulas, ulcers), and several corneal or conjunctive mucosa lesions. rhEGF has not shown any important side or collateral effects in humans or in laboratory experimentation animals, showing optimal tolerability and safety with continuous use for months. Compounding gives advantages of versatility, individualization, personalization, molecular stability, safety and effectiveness in ideal conditions, showing good tissue penetration, both on intact skin and skin lesions that expose the lower planes to the surface. rhEGF compounds can be considered for prevention or as a treatment of diverse skin and mucosa diseases and conditions through compounding preparations. PMID- 25433778 TI - [Positron emission tomography combined with computed tomography in the initial evaluation and response assessment in primary central nervous system lymphoma]. AB - OBJECTIVE: To evaluate the role of positron emission tomography combined with computed tomography (PET-CT) in the initial evaluation and response assessment in primary central nervous system lymphoma (PCNSL). MATERIAL AND METHOD: Fourteen patients (8 males) with a median age 59.5 years diagnosed of PCNSL. A brain PET CT and magnetic resonance imaging (MRI) were performed in the initial evaluation. In 7 patients a PET-CT after treatment was performed. RESULTS: PET-CT showed at diagnosis 31 hypermetabolic focuses and MRI showed 47 lesions, with a good grade of concordance between both (k = 0.61; P = .005). In the response assessment, correlation between both techniques was good, and PET-CT was helpful in the appreciation of residual MRI lesions. Overall survival at 2 years of negative vs. positive PET-CT at the end of treatment was 100 vs. 37.5%, respectively (P = .045). CONCLUSIONS: PET-CT can be useful in the initial evaluation of PCNSL, and especially in the assessment of response. Despite the fact that PET-CT detects less small lesions than MRI, a good correlation between MRI and PET-CT was observed. It is effective in the evaluation of residual lesions. Prospective studies are needed to confirm their possible prognostic value. PMID- 25433779 TI - [Pain assessment using the Facial Action Coding System. A systematic review]. AB - Self-reporting is the most widely used pain measurement tool, although it may not be useful in patients with loss or deficit in communication skills. The aim of this paper was to undertake a systematic review of the literature of pain assessment through the Facial Action Coding System (FACS). The initial search found 4,335 references and, within the restriction "FACS", these were reduced to 40 (after exclusion of duplicates). Finally, only 26 articles meeting the inclusion criteria were included. Methodological quality was assessed using the GRADE system. Most patients were adults and elderly health conditions, or cognitive deficits and/or chronic pain. Our conclusion is that FACS is a reliable and objective tool in the detection and quantification of pain in all patients. PMID- 25433780 TI - [Modulating the survival and maturation system of B lymphocytes: Current and future new therapeutic strategies in systemic lupus erythematosus]. AB - Systemic lupus erythematosus is an autoimmune disease associated with an aberrant production of autoantibodies by self-reactive B lymphocytes. The study of the phenotypic characteristics of B lymphocytes and the identification of their surface receptors such as BAFF-R, TACI and BCMA, which are responsible of their survival and maturation, have contributed to the development of new therapeutic strategies in recent years. PMID- 25433781 TI - [About plagiarism]. PMID- 25433782 TI - [Thyroid dysfunction during pregnancy]. AB - Recent clinical practice guidelines on thyroid dysfunction and pregnancy have changed health care provided to pregnant women, although their recommendations are under constant revision. Trimester- and area-specific reference ranges for serum thyroid-stimulating hormone are required for proper diagnosis of hypothyroidism and hyperthyroidism. There is no doubt on the need of therapy for overt hypothyroidism, while therapy for subclinical hypothyroidism is controversial. Further research is needed to settle adverse effects of isolated hypothyroxinemia and thyroid autoimmunity. Differentiation between hyperthyroidism due to Graves' disease and the usually self-limited gestational transient thyrotoxicosis is critical. It is also important to recognize risk factors for postpartum thyroiditis. Supplementation with iodine is recommended to maintain adequate iodine nutrition during pregnancy and avoid serious consequences in offspring. Controversy remains about universal screening for thyroid disease during pregnancy or case-finding in high-risk women. Opinions of some scientific societies and recent cost-benefit studies favour universal screening. Randomized controlled studies currently under development should reduce the uncertainties that still remain in this area. PMID- 25433783 TI - [Allergic asthma]. PMID- 25433784 TI - [Mortality in early-stage, surgically resected non-small cell lung cancer less than 3 cm of size: Competing risk analysis]. AB - BACKGROUND AND OBJECTIVE: Survival studies of non-small cell lung cancer (NSCLC) are usually based on the Kaplan-Meier method. However, other factors not covered by this method may modify the observation of the event of interest. There are models of cumulative incidence (CI), that take into account these competing risks, enabling more accurate survival estimates and evaluation of the risk of death from other causes. We aimed to evaluate these models in resected early stage NSCLC patients. PATIENTS AND METHOD: This study included 263 patients with resected NSCLC whose diameter was <= 3 cm without node involvement (N0). Demographic, clinical, morphopathological and surgical variables, TNM classification and long-term evolution were analysed. To analyse CI, death by another cause was considered to be competitive event. For the univariate analysis, Gray's method was used, while Fine and Gray's method was employed for the multivariate analysis. RESULTS: Mortality by NSCLC was 19.4% at 5 years and 14.3% by another cause. Both curves crossed at 6.3 years, and probability of death by another cause became greater from this point. In multivariate analysis, cancer mortality was conditioned by visceral pleural invasion (VPI) (P=.001) and vascular invasion (P=.020), with age>50 years (P=.034), smoking (P=.009) and the Charlson index >= 2 (P=.000) being by no cancer. CONCLUSIONS: By the method of CI, VPI and vascular invasion conditioned cancer death in NSCLC >3 cm, while non tumor causes of long-term death were determined. PMID- 25433785 TI - [Eagle syndrome]. PMID- 25433786 TI - [Quality of off-label prescriptions in advanced oncologic diseases]. PMID- 25433788 TI - [Fibromyalgia as a comorbid phenomenon in autoinflammatory diseases]. PMID- 25433787 TI - [Efficacy of bosentan in the treatment of digital ulcers secondary to thromboangiitis obliterans]. PMID- 25433790 TI - [Dermatomyositis associated with erythematous and reticular lesions on the trunk]. PMID- 25433789 TI - [Quality control of oral anticoagulant therapy in Primary Care in Madrid City, Spain: CHRONOS-TAO study]. AB - OBJECTIVES: To determine quality control of patients with oral anticoagulant treatment recruited in Primary Care (PC) using the Rosendaal method to estimate time in therapeutic range (TTR) and comparing it with fraction of international normalized ratio (INR) in range and cross-sectional analysis (last INR registred). MATERIAL AND METHOD: A retrospective observational study based on electronic medical record in routine clinical practice. SETTING: PC centers (262) in Madrid. We included all patients with acenocumarol treatment, with an INR therapeutic range established between 2 and 3. We excluded patients with valvular pathology and disrupted clinical follow up in PC (<3 INR determinations in the studied period, a period of>90 days or >= 3 periods of>60 days between 2 determinations). The final population was 49,312 patients. The variables considered were all INR values and their respective dates. TTR was calculated by the 3 methods above mentioned. We considered "therapeutic range" INR between 2-3 and "adjusted range" INR between 1.8-3.2. Optimal control for each patient was considered TTR>60%. RESULTS: By using Rosendaal method, TTR was 66.8% (81.7% adjusted), with a percentage of total INR in range was 58.8% (66.5% adjusted), and, with the cross-sectional analysis, it was 70.5% (76.8% adjusted). Mean TTR was 65% (standard deviation 20.3), and the percentage of patients with TTR>60% was 63.3% (88.1% adjusted). CONCLUSION: The quality control of patients with oral anticoagulants in PC in Madrid is acceptable, similar or higher to other studies and pivotal trials of new anticoagulants. Compared to the Rosendaal method, total fraction of INR underestimates quality control, and cross-sectional analysis slightly overestimates it. PMID- 25433791 TI - [Diagnostic and therapeutic guidelines of thrombotic microangiopathies of the Spanish Apheresis Group]. AB - Thrombotic microangiopathies (TMA) are disorders defined by the presence of a microangiopathic hemolytic anemia (with the characteristic hallmark of schistocytes in the peripheral blood smear), thrombocytopenia and organ malfunction of variable intensity. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are the most important forms of TMA and, without the adequate treatment, they are associated with high morbimortality. In recent years, significant advances in the knowledge of the pathophysiology of TMA have occurred. Those advances have allowed us to move from a syndromic diagnosis with a similar treatment to all entities to the search of etiologic diagnosis which would lead to a specific treatment, finally leading to a better outcome of the patient. This document pretends to summarize the current status of knowledge of the pathophysiology of TMA and the therapeutic options available, and to offer a diagnostic and therapeutic practical tool to the professionals caring for the patients. PMID- 25433792 TI - [Atherosclerotic ischemic renal disease: clinical challenges]. PMID- 25433794 TI - The social life of cognition. AB - We begin by illustrating that long before the cognitive revolution, social psychology focused on topics pertaining to what is now known as social cognition: people's subjective interpretations of social situations and the concepts and cognitive processes underlying these interpretations. We then examine two questions: whether social cognition entails characteristic concepts and cognitive processes, and how social processes might themselves shape and constrain cognition. We suggest that social cognition relies heavily on generic cognition but also on unique concepts (e.g., agent, intentionality) and unique processes (e.g., projection, imitation, joint attention). We further suggest that social processes play a prominent role in the development and unfolding of several generic cognitive processes, including learning, attention, and memory. Finally, we comment on the prospects of a recently developing approach to the study of social cognition (social neuroscience) and two potential future directions (computational social cognition and social-cognitive robotics). PMID- 25433793 TI - [Contribution of pleural fluid analysis to the diagnosis of pleural effusion]. AB - Analysis of pleural fluid can have, on its own, a high diagnostic value. In addition to thoracocentesis, a diagnostic hypothesis based on medical history, physical examination, blood analysis and imaging tests, the diagnostic effectiveness will significantly increase in order to establish a definite or high probable diagnosis in a substantial number of patients. Differentiating transudates from exudates by the classical Light's criteria helps knowing the pathogenic mechanism resulting in pleural effusion, and it is also useful for differential diagnosis purposes. An increased N-terminal pro-brain natriuretic peptide, both in the fluid and in blood, in a due clinical context, is highly suggestive of heart failure. The presence of an increased inflammatory marker, such as C-reactive protein, together with the presence of over 50% of neutrophils is highly suggestive of parapneumonic pleural effusion. If, in these cases, the pH is<7.20, then the likelihood of complicated pleural effusion is high. There remains to be demonstrated the usefulness of other markers to differentiate complicated from uncomplicated effusions. An adenosine deaminase > 45 U/L and>50% lymphocytes is suggestive of tuberculosis. If a malignant effusion is suspected but the cytological result is negative, increased concentrations of some markers in the pleural fluid can yield high specificity values. Increased levels of mesothelin and fibruline-3 are suggestive of mesothelioma. Immunohistochemical studies can be useful to differentiate reactive mesothelial cells, mesothelioma and metastatic adenocarcinoma. An inadequate use of the information provided by the analysis of pleural fluid would results in a high rate of undiagnosed effusions, which is unacceptable in current clinical practice. PMID- 25433795 TI - Construct validity and impact of mode of administration of the PedsQLTM among a pediatric injury population. AB - BACKGROUND: The purpose of this study was to determine the construct validity of the PedsQLTM health related quality of life (HRQoL) instrument for use among injured children and to examine the impact of using different modes of administration, including paper and pencil, online and telephone. METHODS: Two hundred thirty-three participants (aged 0 - 16) were recruited from hospital wards and the emergency department of a pediatric hospital in a large urban center in British Columbia, Canada. Data used to evaluate the construct validity of the PedsQLTM were collected from participants at the time of seeking injury treatment (baseline) to capture a retrospective measure of pre injury health, and one month post injury. Data used to compare different modes of administration (n = 44) were collected at baseline. To assess construct validity repeated measures analysis of variance (rANOVA) was used to determine whether the PedsQLTM tool was able to discriminate between patients pre and post injury while investigating possible interaction by category of length of stay in hospital. The impact of different modalities of administering the PedsQLTM on item responses was investigated using Bland-Altman plots. RESULTS: rANOVA showed significant differences in PedsQLTM total score between baseline and one month post injury (p < .001), and differences in mean total score at one month post injury by category of injury severity (p < .001). There was also significant interaction by category of injury severity for the change in PedsQLTM total score from baseline to one month (p < .001). Pearson's correlations were highly significant across three modalities of survey administration: paper and pencil, computer and telephone administration (range: .92 to .97, p < .001). Bland-Altman plots showed strong consistency. CONCLUSION: The PedsQLTM instrument is able to discriminate between pre and post injury HRQoL, as well as HRQoL post injury for injuries of varying severity. These findings are an indication that this instrument has good construct validity for the purpose of evaluating HRQoL of injured children. Data collected via paper-pencil, online and telephone administration were highly consistent. This is important as depending on the setting, clinical or research, different modalities of completing this instrument may be more appropriate. PMID- 25433796 TI - Epithelial-mesenchymal transition (EMT) markers have prognostic impact in multiple primary oral squamous cell carcinoma. AB - Multiple primary tumors can occur in up to 35 % of the patients with head and neck cancer, however its clinicopathological features remain controversial. Deregulation of epithelial-mesenchymal transition (EMT) signaling has been associated with aggressive malignancies and tumor progression to metastasis in several cancer types. This study is the first to explore EMT process in multiple primary oral squamous cell carcinomas (OSCC). Immunohistochemical analysis of E cadherin, catenin (alpha, beta, and gamma), APC, collagen IV, Ki-67, cyclin D1, and CD44 were performed in a tissue microarray containing multiple representative areas from 102 OSCC patients followed-up by at least 10 years. Results were analysed in relation to clinicopathological characteristics and survival rates in patients presenting multiple primary tumors versus patients without second primary tumors or metastatic disease. Significant association was observed among multiple OSCCs and protein expression of E-cadherin (P = 0.002), beta-catenin (P = 0.047), APC (P = 0.017), and cyclin D1 (P = 0.001) as well as between lymph nodes metastasis and Ki-67 staining (P = 0.021). OSCCs presenting vascular embolization were associated with negative beta-catenin membrane expression (P = 0.050). There was a significantly lower survival probability for patients with multiple OSCC (log-rank test, P < 0.0001), for tumors showing negative protein expression for E-cadherin (log-rank test, P = 0.003) and beta-catenin (log-rank test, P = 0.031). Stratified multivariate survival analysis revealed a prognostic interdependence of E-cadherin and beta-catenin co-downexpression in predicting the worst overall survival (log-rank test, P = 0.007). EMT markers have a predicted value for invasiveness related to multiple primary tumors in OSCC and co-downregulation of E-cadherin and beta-catenin has a significant prognostic impact in these cases. PMID- 25433797 TI - Early onset frontotemporal dementia with psychiatric presentation due to the C9ORF72 hexanucleotide repeat expansion: a case report. AB - BACKGROUND: Frontotemporal dementia (FTD) may present with psychiatric symptoms, usually together with neurological ones and in cases with a family history of dementia. We describe the case of an FTD behavioural variant with a psychiatric presentation and a normal neurological examination, due to a C9Orf72 gene mutation. CASE PRESENTATION: The patient was a 57 years-old Caucasian woman with a recent onset of bizarre behaviours and mystic delusions. She had a negative clinical history for previous psychiatric disorders and treatments and this was her first admission to a Psychiatry Ward. A careful assessment was performed including, beyond psychiatric evaluation, the following: blood sampling, neurological examination (including electroencephalogram, electroencephalogram with zygomatic electrodes, Positron Emission Tomography, Cerebrospinal Fluid Analysis), carotid artery Doppler ultrasound, brain Magnetic Resonance Imaging - angio Magnetic Resonance Imaging. Blood sampling for the genetic assessment of mutations associated to primary dementias was performed as well: the genes investigated were FUS, C9Orf72, PSEN-1, PSEN-2. CONCLUSIONS: Serological tests were negative, neurological examination was normal, instrumental examinations showed theta waves in the posterior temporal areas bilaterally and frontotemporal cortical atrophy bilaterally. The genetic assessment of mutations associated revealed she carried a GGGGCC hexanucleotide repeat expansion (at least 80 repeats) in C9Orf72 intron 1. Patients carrying the C9Orf72 mutation are likely to receive a psychiatric diagnosis (mainly mood disorder or schizophrenia) prior to correct diagnosis; this may be particularly problematic for those patients with no neurological signs to orientate diagnosis. Understanding the manner in which such FTD variant may present as a psychiatric syndrome, with a negative neurological examination, is essential to provide the best treatment for patients, as soon as possible, especially when the behavioural anomalies interfere with their care. PMID- 25433798 TI - An ontology for microbial phenotypes. AB - BACKGROUND: Phenotypic data are routinely used to elucidate gene function in organisms amenable to genetic manipulation. However, previous to this work, there was no generalizable system in place for the structured storage and retrieval of phenotypic information for bacteria. RESULTS: The Ontology of Microbial Phenotypes (OMP) has been created to standardize the capture of such phenotypic information from microbes. OMP has been built on the foundations of the Basic Formal Ontology and the Phenotype and Trait Ontology. Terms have logical definitions that can facilitate computational searching of phenotypes and their associated genes. OMP can be accessed via a wiki page as well as downloaded from SourceForge. Initial annotations with OMP are being made for Escherichia coli using a wiki-based annotation capture system. New OMP terms are being concurrently developed as annotation proceeds. CONCLUSIONS: We anticipate that diverse groups studying microbial genetics and associated phenotypes will employ OMP for standardizing microbial phenotype annotation, much as the Gene Ontology has standardized gene product annotation. The resulting OMP resource and associated annotations will facilitate prediction of phenotypes for unknown genes and result in new experimental characterization of phenotypes and functions. PMID- 25433799 TI - Investigating the genetic regulation of the ECF sigma factor sigmaS in Staphylococcus aureus. AB - BACKGROUND: We previously identified an ECF sigma factor, sigmaS, that is important in the stress and virulence response of Staphylococcus aureus. Transcriptional profiling of sigS revealed that it is differentially expressed in many laboratory and clinical isolates, suggesting the existence of regulatory networks that modulates its expression. RESULTS: To identify regulators of sigS, we performed a pull down assay using S. aureus lysates and the sigS promoter. Through this we identified CymR as a negative effector of sigS expression. Electrophoretic mobility shift assays (EMSAs) revealed that CymR directly binds to the sigS promoter and negatively effects transcription. To more globally explore genetic regulation of sigS, a Tn551 transposon screen was performed, and identified insertions in genes that are involved in amino acid biosynthesis, DNA replication, recombination and repair pathways, and transcriptional regulators. In efforts to identify gain of function mutations, methyl nitro-nitrosoguanidine mutagenesis was performed on a sigS-lacZ reporter fusion strain. From this a number of clones displaying sigS upregulation were subject to whole genome sequencing, leading to the identification of the lactose phosphotransferase repressor, lacR, and the membrane histidine kinase, kdpD, as central regulators of sigS expression. Again using EMSAs we determined that LacR is an indirect regulator of sigS expression, while the response regulator, KdpE, directly binds to the promoter region of sigS. CONCLUSIONS: Collectively, our work suggests a complex regulatory network exists in S. aureus that modulates expression of the ECF sigma factor, sigmaS. PMID- 25433800 TI - Effects of differences in serum total homocysteine, folate, and vitamin B12 on cognitive impairment in stroke patients. AB - BACKGROUND: Vascular cognitive impairment-no dementia (VCIND) refers to the early or mild cognitive impairment induced by cerebral vascular injury. Research shows that serum total homocysteine (tHcy) level is an independent risk factor for cerebral vascular disease and may be closely related to cognitive function.Current studies on the tHcy level in VCIND patients are limited, and the relationship of tHcy with cognitive function remains unclear. This study aims to investigate the tHcy levels in patients with VCIND and to determine their correlation with cognitive function, as well as to provide useful clues for preventing and treating VCIND. METHODS: The tHcy, folate, and vitamin B12 levels in 82 patients with VCIND were reviewed retrospectively and compared with those of 80 stroke patients without cognitive impairment and 69 healthy controls by using the Montreal Cognitive Assessment (MoCA) scale and the event-related potential P300 to evaluate cognitive function. RESULTS: The tHcy levels in the VCIND group were higher than those in the other two groups, whereas the folate and Vitamin B12 levels in the VCIND group were lower than those of the other two groups. The tHcy levels in the stroke group were higher than those in the control group, and the folate and vitamin B12 levels in the stroke group were lower than those in the control group. The patients in the VCIND group with high tHcy exhibited lower MoCA scores and prolonged P300 latency than those in with normal tHcy. Correlation analysis showed that tHcy level is positively correlated with P300 latency period and negatively correlated with MoCA score. CONCLUSION: The tHcy levels were significantly higher and the vitamin B12 and folate levels were significantly lower in the patients with VCIND than those in the other groups. The high tHcy levels in the VCIND patients may be correlated with impaired cognitive function. PMID- 25433801 TI - Using a discrete choice experiment to inform the design of programs to promote colon cancer screening for vulnerable populations in North Carolina. AB - BACKGROUND: Screening for colorectal cancer (CRC) is suboptimal, particularly for vulnerable populations. Effective intervention programs are needed to increase screening rates. We used a discrete choice experiment (DCE) to learn about how vulnerable individuals in North Carolina value different aspects of CRC screening programs. METHODS: We enrolled English-speaking adults ages 50-75 at average risk of CRC from rural North Carolina communities with low rates of CRC screening, targeting those with public or no insurance and low incomes. Participants received basic information about CRC screening and potential program features, then completed a 16 task DCE and survey questions that examined preferences for four attributes of screening programs: testing options available; travel time required; money paid for screening or rewards for completing screening; and the portion of the cost of follow-up care paid out of pocket. We used Hierarchical Bayesian methods to calculate individual-level utilities for the 4 attributes' levels and individual-level attribute importance scores. For each individual, the attribute with the highest importance score was considered the most important attribute. Individual utilities were then aggregated to produce mean utilities for each attribute. We also compared DCE-based results with those from direct questions in a post-DCE survey. RESULTS: We enrolled 150 adults. Mean age was 57.8 (range 50-74); 55% were women; 76% White and 19% African-American; 87% annual household income under $30,000; and 51% were uninsured. Individuals preferred shorter travel; rewards or small copayments compared with large copayments; programs that included stool testing as an option; and greater coverage of follow-up costs. Follow-up cost coverage was most frequently found to be the most important attribute from the DCE (47%); followed by test reward/copayment (33%). From the survey, proportion of follow-up costs paid was most frequently cited as most important (42% of participants), followed by testing options (32%). There was moderate agreement (45%) in attribute importance between the DCE and the single question in the post-DCE survey. CONCLUSIONS: Screening test copayments and follow-up care coverage costs are important program characteristics in this vulnerable, rural population. PMID- 25433802 TI - Characterization of TM8, a MADS-box gene expressed in tomato flowers. AB - BACKGROUND: The identity of flower organs is specified by various MIKC MADS-box transcription factors which act in a combinatorial manner. TM8 is a MADS-box gene that was isolated from the floral meristem of a tomato mutant more than twenty years ago, but is still poorly known from a functional point of view in spite of being present in both Angiosperms and Gymnosperms, with some species harbouring more than one copy of the gene. This study reports a characterization of TM8 that was carried out in transgenic tomato plants with altered expression of the gene. RESULTS: Tomato plants over-expressing either TM8 or a chimeric repressor form of the gene (TM8:SRDX) were prepared. In the TM8 up-regulated plants it was possible to observe anomalous stamens with poorly viable pollen and altered expression of several floral identity genes, among them B-, C- and E-function ones, while no apparent morphological modifications were visible in the other whorls. Oblong ovaries and fruits, that were also parthenocarpic, were obtained in the plants expressing the TM8:SRDX repressor gene. Such ovaries showed modified expression of various carpel-related genes. No apparent modifications could be seen in the other flower whorls. The latter plants had also epinastic leaves and malformed flower abscission zones. By using yeast two hybrid assays it was possible to show that TM8 was able to interact in yeast with MACROCALIX. CONCLUSIONS: The impact of the ectopically altered TM8 expression on the reproductive structures suggests that this gene plays some role in the development of the tomato flower. MACROCALYX, a putative A-function MADS-box gene, was expressed in all the four whorls of fully developed flowers, and showed quantitative variations that were opposite to those of TM8 in the anomalous stamens and ovaries. Since the TM8 protein interacted in vitro only with the A-function MADS-box protein MACROCALYX, it seems that for the correct differentiation of the tomato reproductive structures possible interactions between TM8 and MACROCALYX proteins might be important. PMID- 25433803 TI - Differences in K-ras and mitochondrial DNA mutations and microsatellite instability between colorectal cancers of Vietnamese and Japanese patients. AB - BACKGROUND: The incidence of early-onset (under 50 years of age) colorectal cancer (CRC) in the Vietnamese has been reported to be quite higher than that in the Japanese. To clarify the differences in genetic alterations between Vietnamese and Japanese CRCs, we investigated mutations in K-ras and mitochondrial DNA (mtDNA) and high-frequency microsatellite instability (MSI-H) in the CRCs of Vietnamese and Japanese patients. METHODS: We enrolled 60 Vietnamese and 233 Japanese patients with invasive CRCs. DNA was extracted from formalin-fixed, paraffin-embedded tissue sections. K-ras mutations were examined with PCR-single-strand conformation polymorphism analysis. mtDNA mutations and MSI-H were examined with microsatellite analysis using D310 and BAT-26, respectively. RESULTS: K-ras mutations were examined in 60 Vietnamese and 45 Japanese CRCs. The frequency of the mutations in the Vietnamese CRCs was significantly higher than that in the Japanese CRCs (8 of 24 [33%] vs 5 of 45 [11%], p =0.048). MSI-H was examined in 60 Vietnamese and 130 Japanese CRCs. The frequency of MSI-H in the Vietnamese CRCs was also significantly higher than that in the Japanese CRCs (6 of 27 [22%] vs 10 of 130 [8%], p =0.030). mtDNA mutations were examined in 60 Vietnamese and 138 Japanese CRCs. The frequency of mtDNA mutations in the Vietnamese CRCs was significantly higher than that in the Japanese CRCs (19 of 44 [43%] vs 11 of 133 [9%], p <0.001). There were no significant differences in clinicopathologic characteristics, such as age, sex, tumour location, and depth, in terms of tumours with/without each genetic alteration in the CRCs of the Vietnamese and Japanese patients. CONCLUSIONS: These results indicate that the developmental pathways of CRCs in the Vietnamese may differ from those of CRCs in the Japanese. PMID- 25433804 TI - Possible infectious causes of spontaneous splenic rupture: a case report. AB - INTRODUCTION: Spontaneous atraumatic splenic rupture is a rare but dramatic occurrence that is most commonly attributed to infection or neoplasia. Deciphering the etiology can be challenging with many cases remaining unclear despite full investigation. CASE PRESENTATION: We report the case of a previously healthy and immunocompetent 52-year-old Caucasian woman with a remote history of clinically diagnosed infectious mononucleosis who experienced sudden atraumatic splenic rupture after an untreated stray cat bite. CONCLUSIONS: The differential diagnosis for atraumatic splenic rupture, specifically its infectious causes, is reviewed. Key clinical and laboratory findings that differentiate Bartonella henselae infection and Epstein-Barr virus reinfection are reviewed. PMID- 25433805 TI - The prevalence of estrogen receptor-negative breast cancer in Ethiopia. AB - BACKGROUND: In contrast with breast cancers (BCs) in other parts of the world, most previous studies reported that the majority of BCs in sub-Saharan Africa are estrogen-receptor (ER) negative. However, a recent study using the US SEER database showed that the proportion of ER-negative BC is comparable between US born blacks and West-African born blacks but substantially lower in East African born blacks, with over 74% of patients Ethiopians or Eritreans. In this paper, we provide the first report on the proportion of ER-negative BC in Ethiopia, and the relation to progesterone-receptor (PgR) status. METHODS: We analysed 352 female patients with ER results available out of 1208 consecutive female BC patients treated at Addis Ababa-University Hospital, Ethiopia, from June 2005 through December 2010. The influences of age, stage, and histology on the probability of ER-negative tumours were assessed by a log-linear regression model. RESULTS: Of the 352 patients, only 35% were ER-negative. The proportion of ER-negative tumours decreased with advancing age at diagnosis and was not affected by histology or stage. For age, the proportion decreased by 6% for each additional 5 years (stage-adjusted prevalence ratio PR=0.94, 95% CI: 0.89-1.00). About 31% were ER- and PgR-negative, and 69% were ER- and/or PgR-positive. CONCLUSIONS: Contrary to most previous reports in other parts of sub-Saharan Africa, the majority of patients in Ethiopia are ER-positive rather than ER-negative. These findings are in line with low proportions of ER-negative BCs from East African immigrants within the SEER database, and they have clinical implications for management of BC patients in Ethiopia and other parts of sub-Saharan Africa where ER-status is not ascertained as part of routine management of the disease. Since the majority of patients showed ER-positive BC, Tamoxifen-therapy should be given to all patients even with unknown ER status. PMID- 25433806 TI - Preventive Effects of Protocatechuic Acid on LPS-Induced Inflammatory Response in Human Gingival Fibroblasts via Activating PPAR-gamma. AB - Protocatechuic acid (PCA), a major metabolite of anthocyanins, has been shown to have antioxidant, antitumoral, and anti-inflammatory activities. In this study, we investigated the anti-inflammatory effects of PCA on lipopolysaccharide (LPS) induced inflammatory response in human gingival fibroblasts (HGFs). The effects of PCA on LPS-induced inflammatory cytokines IL-6 and chemokines IL-8 in HGFs were detected by ELISA. The expression of NF-kappaB and PPAR-gamma was detected by Western blot analysis. Our results demonstrated that PCA suppressed IL-6 and IL-8 production in LPS-stimulated HGFs. We also found that PCA inhibited LPS induced NF-kappaB activation. Furthermore, the inhibition of PCA on LPS-induced IL-6 and IL-8 production can be reversed by PPAR-gamma antagonist GW9662. In conclusion, the anti-inflammatory mechanism of PCA is associated with activating PPAR-gamma, thereby inhibiting LPS-induced inflammatory response. PMID- 25433807 TI - Patterns of initiation of second generation antipsychotics for bipolar disorder: a month-by-month analysis of provider behavior. AB - BACKGROUND: Several second generation antipsychotics (SGAs) received FDA approval for bipolar disorder in the 2000s. Although efficacious, they have been costly and may cause significant side effects. Little is known about the factors associated with prescribers' decisions to initiate SGA prescriptions for this condition. METHODS: We gathered administrative data from the Department of Veterans Affairs on 170,713 patients with bipolar disorder between fiscal years 2003-2010. Patients without a prior history of taking SGAs were considered eligible for SGA initiation during the study (n =126,556). Generalized estimating equations identified demographic, clinical, and comorbidity variables associated with initiation of an SGA prescription on a month-by-month basis. RESULTS: While the number of patients with bipolar disorder using SGAs nearly doubled between 2003 and 2010, analyses controlling for patient characteristics and the rise in the bipolar population revealed a 1.2% annual decline in SGA initiation during this period. Most medical comorbidities were only modestly associated with overall SGA initiation, although significant differences emerged among individual SGAs. Several markers of patient severity predicted SGA initiation, including previous hospitalizations, psychotic features, and a history of other antimanic prescriptions; these severity markers became less firmly linked to SGA initiation over time. Providers in the South were somewhat more likely to initiate SGA treatment. CONCLUSIONS: The number of veterans with bipolar disorder prescribed SGAs is rising steadily, but this increase appears primarily driven by a corresponding increase in the bipolar population. Month-by-month analyses revealed that higher illness severity predicted SGA initiation, but that this association may be weakening over time. PMID- 25433808 TI - Osteoarthritis medical labelling and health-related quality of life in the general population. AB - BACKGROUND: Osteoarthritis is the most common chronic joint disease. In the absence of an effective medical treatment and due to the chronic nature of this condition, an osteoarthritis medical diagnosis may finally result in decreased health-related quality of life. Therefore, the aim of this study was to measure the impact of the osteoarthritis medical labelling on physical and mental health related quality of life. METHODS: Subjects (n = 1132, 58.7% women) were approached as participants of an urban population-based cohort (EPIPorto). Self reported information on previous diagnosis of knee, hip or hand osteoarthritis was obtained and rheumatologists established knee, hip or hand osteoarthritis clinical diagnosis in symptomatic individuals. Physical and mental dimensions of health-related quality of life were evaluated using the self-administered Medical Outcomes Study: 36-Item Short Form Survey. Crude and adjusted linear regression coefficients (beta) and the corresponding 95% confidence intervals (95% CI) were computed to estimate the associations between being labelled as an osteoarthritis case and health-related quality of life. RESULTS: Regardless of disease medical labelling, individuals with osteoarthritis scored significantly lower physical health-related quality of life when compared to those without joint disease (kneeunexposed: beta = -5.3, 95% CI: -7.6, -3.1; kneeexposed: beta = -6.0, 95% CI: -8.4, -3.7; hipunexposed: beta = -6.0, 95% CI: -9.8, -2.3; hipexposed: beta = -11.0, 95% CI: -15.6, -6.4; handunexposed: beta = -4.3, 95% CI: -6.5, -2.0; handexposed: beta = -4.3, 95% CI: -6.6, -2.1). The same was not observed regarding mental health-related quality of life. Among subjects with clinically confirmed osteoarthritis, the medical labelling of this joint disease was not significantly associated to health-related quality of life. CONCLUSIONS: The labelling of knee, hip and hand osteoarthritis diagnosis may not add specific benefit to osteoarthritis patients in terms of its capability to improve health related quality of life. PMID- 25433809 TI - MicroRNA-mediated regulation of KRAS in cancer. AB - While microRNAs (miRNAs) and the KRAS oncogene are known to be dysregulated in various cancers, little is known about the role of miRNAs in the regulation of KRAS in cancer. Here we review a selection of studies published in 2014 that have contributed to our understanding of the molecular mechanisms of KRAS regulation by miRNAs and the clinical relevance of sequence variants that may interfere with functional miRNA-mediated KRAS regulation. PMID- 25433811 TI - [End-of-life practices of physicians in Germany]. AB - BACKGROUND: Ethical questions at the end of life are at the centre of scientific and public debates. Up to the present there is scarcity of empirical data regarding physicians' end-of-life practices in Germany. METHODS: Cross-sectional study among a random sample of German physicians by means of the questionnaire of the EURELD Consortium with additional questions on experiences and attitudes regarding physician assisted suicide. RESULTS: 734 physicians from five state chambers of physicians responded (response rate 36.9 %). 403 physicians reported about end-of-life practices regarding adult patients. Alleviation of symptoms took place in 86.7 % of cases and in 50.7 % medical treatment had been withheld. In three cases death was the consequence of a drug which was provided or administered by respondents. 20.7 % of respondents had been requested to perform physician-assisted suicide (PAS). 41.7 % of participants could not imagine participating in PAS, whereas 40.2 % could imagine this under certain circumstances. A prohibition of PAS by professional law war rejected by 33.7 %, 25.0 % support such a ban and 41.4 % were undecided. CONCLUSION: Physicians in Germany perform a broad spectrum of end-of-life practices. The empirical findings can serve as a starting point for the reflection about an appropriate normative framework for physicians' end-of-life practices. PMID- 25433810 TI - Urea cycle disorders in Spain: an observational, cross-sectional and multicentric study of 104 cases. AB - BACKGROUND: Advances in the diagnosis and treatment of urea cycle disorders (UCDs) have led to a higher survival rate. The purpose of this study is to describe the characteristics of patients with urea cycle disorders in Spain. METHODS: Observational, cross-sectional and multicenter study. Clinical, biochemical and genetic data were collected from patients with UCDs, treated in the metabolic diseases centers in Spain between February 2012 and February 2013, covering the entire Spanish population. Heterozygous mothers of patients with OTC deficiency were only included if they were on treatment due to being symptomatic or having biochemistry abnormalities. RESULTS: 104 patients from 98 families were included. Ornithine transcarbamylase deficiency was the most frequent condition (64.4%) (61.2% female) followed by type 1 citrullinemia (21.1%) and argininosuccinic aciduria (9.6%). Only 13 patients (12.5%) were diagnosed in a pre-symptomatic state. 63% of the cases presented with type intoxication encephalopathy. The median ammonia level at onset was 298 MUmol/L (169-615). The genotype of 75 patients is known, with 18 new mutations having been described. During the data collection period four patients died, three of them in the early days of life. The median current age is 9.96 years (5.29-18), with 25 patients over 18 years of age. Anthropometric data, expressed as median and z-score for the Spanish population is shown. 52.5% of the cases present neurological sequelae, which have been linked to the type of disease, neonatal onset, hepatic failure at diagnosis and ammonia values at diagnosis. 93 patients are following a protein restrictive diet, 0.84 g/kg/day (0.67-1.10), 50 are receiving essential amino acid supplements, 0.25 g/kg/day (0.20-0.45), 58 arginine, 156 mg/kg/day (109-305) and 45 citrulline, 150 mg/kg/day (105-199). 65 patients are being treated with drugs: 4 with sodium benzoate, 50 with sodium phenylbutyrate, 10 with both drugs and 1 with carglumic acid. CONCLUSIONS: Studies like this make it possible to analyze the frequency, natural history and clinical practices in the area of rare diseases, with the purpose of knowing the needs of the patients and thus planning their care. PMID- 25433812 TI - Synovial T cell hyporesponsiveness to myeloid dendritic cells is reversed by preventing PD-1/PD-L1 interactions. AB - INTRODUCTION: The aim of this study was to investigate PD-1/PD-L1 involvement in the hyporesponsiveness of rheumatoid arthritis (RA) synovial fluid (SF) CD4 T cells upon stimulation by thymic stromal lymphopoietin (TSLP)-primed CD1c myeloid dendritic cells (mDCs). METHODS: Expression of PD-1 on naive (Tn), central memory (Tcm) and effector memory (Tem) CD4 T cell subsets was assessed by flow cytometry. PD-L1 expression and its regulation upon TSLP stimulation of mDCs from peripheral blood (PB) and SF of RA patients were investigated by quantitative RT PCR and flow cytometry. The involvement of PD-1/PD-L1 interactions in SF T cell hyporesponsiveness upon (TSLP-primed) mDC activation was determined by cell culture in the presence of PD-1 blocking antibodies, with or without interleukin 7 (IL-7) as a recognized suppressor of PD-1 expression. RESULTS: PD-1 expression was increased on CD4 T cells derived from SF compared with PB of RA patients. TSLP increased PD-L1 mRNA expression in both PB and SF mDCs. PD-L1 protein expression was increased on SF mDCs compared with PB mDCs and was associated with T cell hyporesponsiveness. Blockade of PD-1, as well as IL-7 stimulation, during cocultures of memory T cells and (TSLP-primed) mDCs from RA patients significantly recovered T cell proliferation. CONCLUSION: SF T cell hyporesponsiveness upon (TSLP-primed) mDC stimulation in RA joints is partially dependent on PD-1/PD-L1 interactions, as PD-1 and PD-L1 are both highly expressed on SF T cells and mDCs, respectively, and inhibiting PD-1 availability restores T cell proliferation. The potential of IL-7 to robustly reverse this hyporesponsiveness suggests that such proinflammatory cytokines in RA joints strongly contribute to memory T cell activation. PMID- 25433813 TI - Differential CD133 expression distinguishes malignant from benign papillary lesions of the breast. AB - Malignant papillary lesions are, in contrast to their benign counterpart, rare malignant tumors in the breast. To differentiate between benign or atypical and malignant papillary lesions can be difficult, especially in core biopsy specimens. In the present study, excisional or more extensive surgical specimens of 33 papillary carcinomas, 2 micropapillary carcinomas, and 17 atypical papillomas of the breast were reviewed and classified according to the latest WHO classification. Thirty-three intraductal papillomas and 49 invasive carcinomas, no special type (NST), were included in the study for comparison. CD133 expression in papillary carcinomas was significantly lower than that in benign and atypical papillomas (p < 0.001). CD133 expression in invasive carcinoma NST was also significantly higher than that in papillary carcinomas. Our data suggests that absence of expression of CD133 can be a useful marker in the differential diagnosis between malignant papillary lesions and their benign or atypical mimics. The characteristic loss of CD133 expression in papillary carcinomas of the breast also indicates that these lesions are distinct from other types of breast cancer. PMID- 25433814 TI - Bruton's tyrosine kinase (Btk) is a useful marker for Hodgkin and B cell non Hodgkin lymphoma. AB - Bruton's tyrosine kinase (Btk) is a member of the Tec family of protein tyrosine kinases involved in B cell development and proliferation in neoplastic human lymphoid tissues. We used immunohistochemistry to evaluate a polyclonal anti-Btk antibody on formalin-fixed paraffin-embedded tissue blocks. The tested samples included normal lymphoid tissues, tissue samples of 395 different lymphomas and 14 malignant lymphoid cell lines. Btk was expressed more often in B cell lymphomas than in T cell lymphomas. This correlated well with the results obtained on B cell lymphoma cell lines, which strongly expressed Btk, in contrast to T cell lymphoma cell lines. More than 60% of myelomas expressed Btk. Among Hodgkin lymphomas, the nodular lymphocyte predominant variant was more often positive (14/16) than the classical variant (6/27). Only one out of three Hodgkin lymphoma-derived cell lines showed a few atypical large cells expressing Btk. Btk represents a useful marker to identify B cell non-Hodgkin lymphomas. Furthermore, Btk might help to distinguish the nodular lymphocyte predominant variant of Hodgkin lymphomas from the classical form. Finally, in view of the recently discovered therapeutic potential of Btk inhibitors in lymphoma, we report the pattern of expression of Btk in a large collection of different types of lymphoma. PMID- 25433815 TI - Significance of estimated glomerular filtration rate in predicting brain or heart attacks in obese and non-obese populations. AB - BACKGROUND: The Japanese Specific Health Checkup mainly focuses on metabolic syndrome for preventing cardiovascular events. Subjects are stratified by measuring waist circumference, body mass index, blood pressure, triglycerides, and fasting plasma glucose. However, estimated glomerular filtration rate (eGFR) is not considered essential. METHODS: A longitudinal cohort study assessed the association of eGFR with new-onset brain or heart attacks in a large Japanese nationwide Specific Health Checkup database. A total of 109,349 Japanese subjects (mean age 63.2 years, 39.5 % men) were examined for the events 2 years later. The odds ratios were calculated for new events in the total and subgroup populations divided by BMI < or >=25 kg/m(2), obese and non-obese, respectively. RESULTS: Obese subjects were more often male and had proteinuria (dipstick test >=1+), lower eGFR, and higher systolic and diastolic BP, fasting plasma glucose, hemoglobin A1c, and triglycerides (TG). Rates of new-onset brain or heart attacks were 3.1 and 4.0 % in the groups of non-obese and obese subjects, respectively. In the total population, eGFR as well as higher BMI (>=25 kg/m(2)), higher BP (high-normal hypertension or greater), higher TG (>=150 mg/dl), and proteinuria were significant risk factors for developing brain or heart attacks. The eGFR was significant in non-obese subjects, but not in the obese. CONCLUSION: As the ultimate aim of 'Specific Health Checkup' is to prevent cardiovascular events, our study suggests that eGFR should be evaluated in non-obese subjects. PMID- 25433816 TI - Medical professionalism in the formal curriculum: 5th year medical students' experiences. AB - BACKGROUND: The standards and outcomes outlined in the General Medical Council's publication 'Tomorrow's Doctors' include proposals that medical professionalism be included in undergraduate curricula. Learning the values and attitudes necessary to become a 'doctor as a professional' has traditionally been left largely to the informal and hidden curricula. There remains no consensus or confirmed evidence upon which to base best practice for teaching in this area. In 2010, as part of a revision of the fifth year curriculum the University of Bristol Medical School introduced tutorials which focused on students' achievement of the learning objectives in 'Tomorrow's Doctors Outcomes 3: the doctor as a professional'. This study sought to explore the students' experiences of these tutorials in order to develop the evidence base further. METHODS: Sixteen medical students participated in three focus-group interviews exploring their experiences of medical professionalism tutorials. A course evaluation questionnaire to all fifth year students also provided data. Data were analysed using the principles of Interpretative Phenomenological Analysis. RESULTS: Four main themes were identified: students' aversion to 'ticking-boxes', lack of engagement by the students, lack of engagement by the tutors and students' views on how medical professionalism should be taught. CONCLUSIONS: A curriculum innovation which placed the achievement of medical professionalism in the formal curriculum was not unanimously embraced by students or faculty. Further consideration of the students' aversion to 'ticking-boxes' is warranted. With continued demand for increased accountability and transparency in medical education, detailed check-lists of specific learning objectives will continue to feature as a means by which medical schools and learners demonstrate attainment. Students' experiences and acceptance of these check-lists deserves attention in order to inform teaching and learning in this area. Learner and faculty 'buy in' are imperative to the success of curriculum change and vital if the students are to attain the intended learning objectives. Effective faculty development and student induction programmes could be employed to facilitate engagement by both parties. PMID- 25433817 TI - Body matters: rethinking the ethical acceptability of non-beneficial clinical research with children. AB - The involvement of children in non-beneficial clinical research is extremely important for improving pediatric care, but its ethical acceptability is still disputed. Therefore, various pro-research justifications have been proposed throughout the years. The present essay aims at contributing to the on-going discussion surrounding children's participation in non-beneficial clinical research. Building on Wendler's 'contribution to a valuable project' justification, but going beyond a risk/benefit analysis, it articulates a pro research argument which appeals to a phenomenological view on the body and vulnerability. It is claimed that children's bodies are not mere physical objects, but body-subjects due to which children, as persons, can contribute to research that may hold no direct clinical benefit to them even before they can give informed consent. PMID- 25433818 TI - Sacral neuromodulation for faecal incontinence: is the outcome compromised in patients with high-grade internal rectal prolapse? AB - BACKGROUND: High-grade internal rectal prolapse appears to be one of the contributing factors in the multifactorial origin of faecal incontinence. Whether it affects the outcome of sacral neuromodulation is unknown. We compared the functional results of sacral neuromodulation for faecal incontinence in patients with and without a high-grade internal rectal prolapse. METHOD: One hundred six consecutive patients suffering from faecal incontinence, who were eligible for sacral neuromodulation between 2009 and 2012, were identified from a prospective database. All patients underwent preoperative defaecating proctography, anorectal manometry and ultrasound. Symptoms were assessed preoperatively and at 12 months after operation using a standardized questionnaire incorporating the Faecal Incontinence Severity Index (FISI range = 0-61) and the Gastrointestinal Quality of Life Index (GIQLI). Success was defined as a decrease in the FISI score of 50 % or more. RESULTS: High-grade internal rectal prolapse (HIRP) was found in 36 patients (34%). The patient characteristics were similar in both groups. Temporary test stimulation was successful in 60 patients without HIRP (86%) and in 25 patients with HIRP (69 %) (p = 0.03). A permanent pulse generator was then implanted on these patients. After 1-year follow-up, the median FISI was reduced in patients without HIRP from 37 to 23 (p < 0.01). No significant change in FISI score was observed in patients with a HIRP (FISI, 38 to 34; p = 0.16). Quality of life (GIQLI) was only improved in patients without HIRP. A successful outcome per protocol was achieved in 31 patients without HIRP (52%) versus 4 patients with HIRP (16%) (p < 0.01). CONCLUSION: The presence of a high-grade internal rectal prolapse has a detrimental effect on sacral neuromodulation for faecal incontinence. PMID- 25433819 TI - Natural history of outpatient-onset ischemic colitis compared with other lower gastrointestinal bleeding: a long-term cohort study. AB - PURPOSES: The long-term clinical course of outpatient-onset ischemic colitis remains unknown. Our aims are to elucidate the in- and out-of-hospital clinical outcomes of ischemic colitis and compare them with those of lower gastrointestinal bleeding (LGIB). METHOD: A cohort of 370 outpatients was hospitalized for ischemic colitis (n = 57) or other LGIB (n = 313). All patients had undergone colonoscopy. During hospitalization, the need for transfusion or interventions, further bleeding, mortality, and length of hospital stay were measured. After discharge, long-term recurrence and mortality were analyzed by the Kaplan-Meier method. RESULTS: Colonoscopy revealed that 88% of ischemic colitis cases were left sided. Compared with other LGIB, ischemic colitis cases had significantly lower transfusion requirements (p < 0.01), further bleeding (p = 0.02), endoscopic intervention (p < 0.01), and shorter hospital stay (p = 0.03). No significant differences between the groups were noted in the need for surgery, angiographic procedures, or mortality during hospitalization. During a mean follow-up of 22 months, rebleeding was significantly lower (log-rank test; p < 0.01) in ischemic colitis cases (5.3%) than in other LGIB cases (19.4%) after discharge. During the mean follow-up period of 29 months, 1 patient (1.8%) with ischemic colitis and 18 patients (5.8%) with other LGIB died (log-rank test; p = 0.41). CONCLUSIONS: Outpatient-onset ischemic colitis patients usually had left sided colitis, recovered with conservative short-term treatment and had lower transfusion requirements and further bleeding compared with other LGIB patients. After discharge, patients with outpatient-onset ischemic colitis had lower recurrence over the long term than other LGIB patients. PMID- 25433820 TI - A systematic review and meta-analysis of adjuvant chemotherapy after neoadjuvant treatment and surgery for rectal cancer. AB - BACKGROUND: Current guidelines support the use of adjuvant chemotherapy (CT) following neoadjuvant chemoradiotherapy (CTRT) and surgery to treat rectal cancer, although clinical trials have provided little evidence that it is effective. We performed a systematic review of published studies to assess whether adjuvant CT improves outcome after neoadjuvant therapy and radical surgery in cases of rectal cancer. MATERIALS AND METHODS: We conducted an electronic database search for randomized and nonrandomized studies in PubMed, EMBASE, Web of Science, Scopus and the Cochrane Register of Controlled Trials. We then carried out a meta-analysis by using the fixed- or random-effects models. The primary endpoint was 5-year overall survival (OS) reported as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Two randomized controlled trials (RCTs), one pooled analysis of five RCTs and 10 retrospective studies that included a total of 5,457 patients matched our selection criteria. Meta-analysis showed that for rectal cancer patients treated with surgery and neoadjuvant CTRT, adjuvant CT improves 5-year OS (OR, 0.64; 95% CI, 0.46-0.88; p = 0.006) and 5 year disease-free survival (DFS) (OR, 0.71; 95% CI, 0.6-0.83; p < 0.0001). The 5 year OS benefit was significantly larger in downstaged patients and in retrospective series. A better DFS was instead noted in all studies due to a reduced risk of local relapse. CONCLUSIONS: Amongst rectal cancer patients treated with neoadjuvant therapy and surgery, adjuvant CT seems to improve the 5 year DFS and OS rates and may be discussed with patients. However, the benefit derives mainly from retrospective evidence. PMID- 25433821 TI - Individual and Contextual Factors Associated with Pre-Kindergarten Teachers' Responsiveness to the MyTeachingPartner Coaching Intervention. AB - With research findings indicating positive associations between teacher-child interaction quality and children's development and learning, many professional development efforts now focus on improving the ways in which teachers interact with children. Previous work found that MyTeachingPartner (MTP), a web-mediated coaching intervention, improved teachers' classroom interactions with children, and further analysis found that improvement in teachers' interactions was mediated by their responsiveness to the MTP intervention. The current study assessed how teacher characteristics, including demographics, beliefs, and psychological factors, as well as contextual characteristics related to multiple measures of teachers' responsiveness to MTP. Findings show that related factors vary across the different indicators of responsiveness. Specifically, the psychological factors of anxiety and readiness to change related to multiple indicators of responsiveness. Further, readiness to change and self-efficacious beliefs moderated the associations between classroom poverty and responsiveness. Study findings provide new insights into key teacher characteristics that might identify teachers in need of intervention adaptation or support to ultimately increase overall responsiveness. PMID- 25433822 TI - Interventions during pregnancy and childbirth - challenges and opportunities. PMID- 25433823 TI - Intervention or interference? The need for expectant care throughout normal labour. AB - BACKGROUND: Medico-technical intervention rates in labour, such as induction and augmentation of labour, are rising worldwide. Such interventions have adverse as well as beneficial consequences, so any intervention introduced must be based on evidence and result in more good than harm, otherwise it is just interference. AIM: To describe three common medico-technical interventions in normal pregnancy or labour in terms of their effects on women and neonates. METHOD: A comprehensive review of literature was undertaken to provide evidence of benefits and adverse effects of three routine medico-technical interventions: induction of labour, episiotomy, and active management of third stage of labour (including early cord clamping). FINDINGS: All three interventions have benefits, but can also cause distress, pain, or morbidity to mothers and babies and should not, therefore, be used routinely, but in response to clinical need. In particular, the over-use of episiotomy, and active management of the third stage (including early cord clamping), in addition to the physical harms they cause, result in an undesirable disruption of the precious minutes following birth when the new family is coming together for the first time. CONCLUSION: Further research is needed into alternative methods of inducing labour, ways to preserve the perineum intact, and trials of expectant and active management of the third stage in low risk women cared for by midwives skilled in using both methods. Clinicians need to develop their skills in these areas and reduce unnecessary reliance on these three medico-technical interventions, to provide the best possible care for women and babies. PMID- 25433824 TI - Routine testing of umbilical cord blood after normal delivery should be discontinued. AB - On many newborns in Sweden routine samples of blood are taken from the umbilical cord after birth to measure the acid-base balance. These tests were introduced with the aim to objectively measure the well-being and stress levels of the newborn. The information was to be used as a measurement of quality of care, for research and as a tool to help guide decisions around the care-needs of the newborn. After 10 years of routine analysis it has become clear that the results of these tests have limited clinical value and that they are a poor measurement of quality of care. PMID- 25433825 TI - Interventions during labor and birth in the United States: a qualitative analysis of women's experiences. AB - OBJECTIVE: To explore and describe hospital-birthing women's understandings of and experiences with interventions during labor and birth. METHODS: Qualitative data was collected as part of a larger ethnographic study of childbirth in the United States. The grounded theory method was employed to analyze interviews with 59 women from three states who had recently given birth in hospitals with physicians or certified nurse-midwives in attendance. RESULTS: Four themes emerged from the data. The themes safety/risk and provider match, described women's expectations regarding intervention and their interactions with providers. A third theme addressed how women experienced interventions and their perceptions of control over decision-making. A final theme characterized women's satisfaction with maternity care. CONCLUSIONS: Women who received interventions expressed varying levels of comfort or apprehension associated with both expectations of maternity care and provider match. Women whose expectations matched those of the provider reported more positive experiences. Regardless of provider match, women expressed ambivalence about the use of interventions and confusion over their appropriate place. Women's ability to make sense of interventions was related to how well they navigated a complicated and bureaucratic maternity system. Increasing attention needs to be paid to the impact of these factors on women's perceptions of care during pregnancy and childbirth. PMID- 25433826 TI - Integrating couple relationship education in antenatal education - a study of perceived relevance among expectant Danish parents. AB - Little is known about which elements antenatal education should encompass to meet the needs of parents today. Psycho-social aspects relating to couple- and parenthood have generally not been covered in Danish antenatal education, although studies suggest that parents need this information. The aim of this study was to examine perceived relevance of couple relationship topics integrated in an antenatal programme among intervention participants in the NEWBORN trial. Our study shows that 84% of the participants found it relevant to learn about communication skills and changes in the relationship during and after pregnancy. PMID- 25433827 TI - A standardised individual unsupervised water exercise intervention for healthy pregnant women. A qualitative feasibility study. AB - INTRODUCTION: Low back pain during pregnancy is common and associated with sick leave. Studies suggest that exercise may reduce low back pain during pregnancy. Before carrying out a randomised controlled trail with individual water exercise as intervention a qualitative feasibility study was done. OBJECTIVE: To explore women's views and experiences of the acceptability and benefits of and possible barriers to the standardised individual unsupervised water exercise intervention. MATERIALS AND METHODS: Eleven women were interviewed after participating in a water exercise intervention. Content analysis was used. RESULTS: Four main categories emerged: motivation to participate, attitudes towards the exercise programme, perception of benefits, and acceptability of supportive components. The women had a desire to stay physically active during pregnancy and found water exercise a suitable, type of exercise to perform during pregnancy. The intervention was experienced to have benefits on both their physical health and their mental well-being. Crowded swimming pools were perceived as the greatest barrier. CONCLUSION: It is feasible to perform a RCT using the described intervention. The intervention was accepted by the participants because it supported their desire to be physically active during pregnancy. The main barrier was crowded swimming pools and this issue must be addressed in a future RCT. PMID- 25433828 TI - Pregnant women's interest in a website or mobile application for healthy gestational weight gain. AB - We examined pregnant women's interest in using a website or mobile application to help them gain a healthy amount of weight during pregnancy. Pregnant women (N = 64) completed a short questionnaire during routine prenatal care at hospital based obstetric clinics in central Massachusetts during April-August 2012. Eighty six percent reported interest in using a website or mobile application to help them gain a healthy amount of weight; interest ranged from 67% to 100% across demographics, clinical characteristics, and technology use. The Internet is a promising modality for delivering interventions to prevent excessive gestational weight gain and associated maternal and child health consequences. PMID- 25433829 TI - Is it possible to detect malposition of the vertex at an early stage in labour? A case-control study. AB - OBJECTIVES: The aim of this study was to investigate if there are clinical signs which allow detection of malposition of the vertex on admission to the delivery unit, or when crossing the action line on the partogram. STUDY DESIGN: Case control study from 2007 to 2010 conducted on the delivery unit of Nordland Hospital, Bodo. Labours with malposition of the vertex (n = 171) were compared with a group with normal vertex presentation (n = 165). The positive predictive value was estimated for each sign using Bayes' rule. MAIN OUTCOME MEASURES: Magnitude of positive predictive value for each clinical sign. RESULTS: The positive predictive values for malposition were 9% if the foetus were in a right position, 11% if the labour was induced, 5% if the foetus was above the ischial spines, 4% if the reason for admission was contractions and 6% if cervix was <3 cm. CONCLUSION: The ability of clinical assessment to predict malposition, either on admission or when crossing the action line on the partogram, was poor. Diagnosing malposition of the vertex requires other methods with a higher predictive value. PMID- 25433830 TI - Race inequality in epidural use and regional anesthesia failure in labor and birth: an examination of women's experience. AB - OBJECTIVE: A known racial disparity in medical care is that white women receive epidurals more often in labor than do women from other racial and ethnic groups. Medical researchers have framed this disparity as due to some women's lack of access to anesthesia. Further, an unexamined racial disparity in medical care is that anesthesia failure in labor and birth may also have racial disparity. We explore the organizational processes that may lead to racial disparity an epidural use and regional anesthesia failure in labor and birth. METHODS: We draw on semi-structured, in-depth interviews conducted with 83 women in June through December, 2010 the day after they gave birth at a New England tertiary care hospital. RESULTS: Among women who did not plan to have an epidural, women of color were more likely to face pressure to accept the epidural by hospital medical staff. Further, among women who received anesthesia (either during vaginal delivery or a C-section), women of color were more likely to experience failure in their pain medication and were less likely to have their pain and anxiety taken seriously by doctors. CONCLUSION: Overall we challenge the contention that access is the primary way women's epidural experiences are influenced by race and suggest an alternative lens through which to understand racial dynamics and epidural use and anesthesia failure in labor and birth. PMID- 25433831 TI - Single versus pairwise interpretation of cardiotochography, a comparative study from six Swedish delivery units. AB - OBJECTIVE: The aim of the study was to evaluate whether interpreting CTG pairwise brings about a higher level of correctly classified CTG recordings in a non selected population of midwives and physicians. STUDY DESIGN: A comparative study. SETTING: Five delivery units in Stockholm and one delivery unit in Uppsala, with 1589, 3740, 3908, 4539, 6438, and 7331 deliveries in 2011, respectively. SUBJECTS: 536 midwives and physicians classified one randomly selected CTG recording individually followed by a pairwise classification. The pairs consisted of two midwives (119 pairs) or one midwife and one physician (149 pairs), a total of 268 pairs. MAIN OUTCOME MEASURE: The proportion of individually correctly classified CTG recordings versus the proportion of pairwise correctly classified CTG recordings. RESULTS: The proportion of individually correctly classified CTG's was 75% and the proportion of pairwise correctly classified CTG's was 80% (difference 5%, p = 0.12). CONCLUSIONS: There was no statistically significant difference when CTG's were classified pairwise compared to individual classifications. The proportion of individually correctly classified CTG's was high (75%). There were differences in the proportion of correctly classified CTG recordings between the delivery units, indicating potential areas of improvement. PMID- 25433832 TI - The delivery room: is it a safe place? A hermeneutic analysis of women's negative birth experiences. AB - BACKGROUND: Women's negative experiences in the delivery room can have significance for later fear of childbirth. Therefore, it is important to critically evaluate the care during childbirth. The aim was to gain a deeper understanding of women's negative experiences in the delivery room. METHODS: This study is based on original data from three qualitative studies on Swedish women's experiences of fear of childbirth. Data were collected from interviews with 21 women; 15 pregnant women (6 + 9) with intense fear of childbirth, and six women who had experienced intense fear of childbirth 7-11 years prior to the interview. The analysis had a hermeneutic approach, with focus on the women's descriptions of their previous negative birth experiences. FINDINGS: The interpretation showed that in the delivery room the women were objects of surveillance, and they endured suffering related to the care during childbirth. This involves experiences of midwives as uncaring, feelings of being suppressed, unprotected and lacking safety, of feeling disconnected and of the body as incompetent in giving birth. The birth environments are understood as power structures, containing views of women's birthing bodies as machines, and delivery rooms as surveillance environments, involving interventions such as foetal heart monitoring, induction and augmentation of labour. CONCLUSIONS: The delivery room was, for these women, a place creating fear of childbirth. To avoid negative birth experiences and future fear, women must be offered not only medical, but also emotional and existential safety in the delivery room. PMID- 25433833 TI - Effect of immunization against GnRH on hypothalamic and testicular function in rams. AB - The objective was to determine effects of active immunization against GnRH on reproductive function in Tibetan rams. Peripubertal Tibetan rams (n = 30) were randomly and equally allocated into three groups: control (no treatment); surgically castrated; or immunized against 100-MUg d-Lys6-GnRH-tandem-dimer peptide conjugated to ovalbumin in Specol adjuvant at 24 weeks of age (with a booster 8 weeks later). Blood samples (for antibody titers and hormone concentrations) were collected at 4-week intervals until rams were killed (40 weeks). Immunization triggered a good antibody response in all immunized rams (P < 0.01). Compared with intact controls, anti-GnRH immunization reduced (P < 0.01) serum concentrations of testosterone, inhibin A, LH, and FSH, and it induced testicular atrophy (suppression of spermatogenesis). Androstenone concentrations in fat tissues of GnRH-immunized rams were also rendered nondetectable (P < 0.001). Furthermore, mRNA expressions of GnRH receptor, LH-beta, and FSH-beta in the pituitary and of LH receptor, FSH receptor, and inhibin alpha and betaA subunits in the testes were decreased in immunized rams compared with intact controls (P < 0.05). This was apparently the first report that active immunization against GnRH-tandem-dimer-ovalbumin conjugate in Specol adjuvant was an effective alternative to surgical castration for Tibetan rams under practical Tibetan plateau conditions. PMID- 25433834 TI - The effect of maternal body condition on in vivo production of zygotes and behavior of delivered offspring in mice. AB - This study investigated the effects of maternal body condition on oocyte quality and zygote production. Additionally, we examined the possible consequences on somatic parameters and behavior of naturally delivered offspring. We used an experimental model based on overfeeding of outbred mice during intrauterine and early postnatal development to produce the following four types of females: physiological (7%-8%), slightly increased (8%-11%), highly increased (>11%), and low (<7%) body fat content (Echo Magnetic Resonance Imaging). The fertilized females with slightly increased body fat showed increased numbers of spontaneously ovulated oocytes and an increased fertilization index compared with control animals. On the contrary, mice with slightly and highly increased body fat showed increased numbers of isolated immature oocytes and degenerates. Furthermore, animals with increased body fat had significantly decreased deposits of neutral lipids in the cytoplasm of mature oocytes (Nile red staining) and showed lower reduction in DNA cytosine methylation signal in parental pronuclei (5-methylcytosine immunohistochemistry). The highly increased amount of body fat in mothers was accompanied with lower weights in newborn pups and 5-week-old offspring. We also observed several deviations from normal behavior (open-field test and forced swimming test). The females with low body fat displayed a lower fertilization index, a lower percentage of zygotes at pronuclear stage 4 with demethylated DNA cytosine in parental pronuclei, and lower newborn weights. Although delivered offspring were able to gain normal weight by the fifth week of life, there were several deviations from normal behavior observed. Our results show that periconceptional status of maternal body condition adversely affects the quality of oocytes and might be correlated with significant changes during postnatal offspring development. The data documenting later onset of DNA demethylation in zygotes and decreased amounts of neutral lipids in oocytes suggest that the observed alterations in offspring might originate in modifications established at the earliest stages of conceptus development. PMID- 25433835 TI - Current practice in patient selecting for long-term mechanical circulatory support. AB - With the advances of mechanical circulatory support, the selection of patients has undergone many changes over the last decade. Determining who is suitable for left ventricular assist device (LVAD) implantation is important to understanding the overall risk and outcomes. As devices improve, it is expected that changes will continue in this field. This review describes current state of patient selection, evaluation, and optimization prior to implantation of a long-term circulatory support device. PMID- 25433836 TI - Bullous fixed drug eruption masquerading as recurrent Stevens Johnson syndrome. AB - BACKGROUND: Fixed drug eruptions (FDE) are peculiar drug rashes that tend to be violaceous, hyperpigmented, and round to oval-shaped plaques with dusky gray centers. The lesions tend to recur in a similar dermatologic distribution upon re exposure to the offending medication, leading to intensified inflammation and sometimes the formation of blisters, bullae, and erosions. This bullous form of FDE can be mistaken clinically for Stevens Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). CASE REPORT: We report two cases of patients presenting to the emergency department (ED) with characteristic blistering skin lesions and reports of similar prior episodes; both patients were initially diagnosed in the ED as "recurrent SJS" and admitted to the burn intensive care unit. Each patient was evaluated emergently by dermatology consultants, identified as cases of FDE rather than SJS, and transferred to the general medical ward with an uncomplicated hospital course and complete re epithelialization within 7 days after removal of the inciting agent. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We discuss distinguishing features of bullous FDE and SJS/TEN in order to highlight this entity and aid in diagnostic accuracy and appropriate management by emergency physicians. In cases identified as classic or suspected SJS/TEN, the patient warrants aggressive resuscitation and admission to a burn unit, while cases identified as obvious bullous FDE can be managed much more conservatively. Although the clinical clues outlined here may help distinguish classic cases of FDE from SJS/TEN, it is always advisable to admit to a higher level of care or obtain an urgent dermatology consult when diagnostic uncertainty remains. PMID- 25433837 TI - Educating women about congenital cytomegalovirus: assessment of health education materials through a web-based survey. AB - BACKGROUND: Congenital cytomegalovirus (CMV) is the most common congenital infection in the U.S. and can result in permanent disabilities, such as hearing and vision loss, intellectual disability, and psychomotor and language impairments. Women can adopt prevention behaviors in an attempt to reduce their exposure to CMV. Currently, few women are familiar with CMV. To increase awareness of CMV, the Centers for Disease Control and Prevention (CDC) developed draft health education materials. The purpose of this study was to pilot test two health education materials to gauge their appeal and to determine if they increase knowledge about CMV and motivate audiences to seek additional information on CMV and adopt CMV prevention behaviors. METHODS: African-American (n = 404) and Caucasian women (n = 405), who had a young child and were either pregnant or planning a pregnancy, were recruited to participate in a 15-minute web survey. Participants were randomly assigned to view one of two CMV health education materials, either a factsheet or video. Pre and post survey measures were used to assess changes in knowledge of CMV and motivation to adopt prevention behaviors. We also examined audience preferences regarding materials and motivation. RESULTS: CMV knowledge score increased significantly after presentation of either the video or factsheet (from 3.7 out of 10 to 9.1 out of 10, p <0.001). The average materials appeal score was high, with a mean of 3.6 on a four-point scale, indicating women responded very positively to both materials. Regression analyses indicated that appeal, message involvement (e.g., information seeking, discussing with others), post materials knowledge score, and viewing the video (vs. factsheet) were significantly positively associated with increased support for CMV prevention behaviors. CONCLUSIONS: Overall, we found that the health education materials improved women's knowledge of CMV and encouraged them to adopt prevention behaviors. Given the low awareness levels among women currently, these findings suggest that appropriate education materials have the potential to greatly increase knowledge of CMV. As women become more knowledgeable about CMV and transmission routes, we expect they will be more likely to adopt prevention behaviors, thereby reducing their risk of CMV infection. PMID- 25433838 TI - Amplification of TERT and TERC genes in cervical intraepithelial neoplasia and cervical cancer. AB - OBJECTIVES: Telomerase is activated in various stages of oncogenesis. For cervical cancer, telomerase is already active in precancerous lesions. In our study we focused on the analysis of the amplification patterns of telomerase genes TERT and TERC. DESIGN AND SETTING: We included 39 patients in our study between January 2012 and April 2013. Each patient underwent a classical gynaecological examination and a colposcopy. During the colposcopic examination we collected material for a Pap smear, HPV DNA test (HC2) and LBC (LiquiPrepTM), and performed punch biopsies for histopathological evaluation. Residual cytologic sample was hybridized with the FISH probe and telomerase genes were analysed. RESULTS: The amplification of the TERT gene showed us a very similar amplification pattern as TERC and gradually corresponded with both histolopathological (p<0.001) and cytopathological findings (p<0.001). The specificity and sensitivity of TERC gene amplification for the detection of CIN2+ lesions (cut off value 2.3) was 88.2% and 95.5% respectively (PPV 91.3%, NPV 93.8%). CONCLUSIONS: We identified increasing amplification pattern of telomerase genes in cervical lesions. According to our results telomerase genes could help in the future to determine the malignant potential of cervical lesions and could be tested together with cytology and HPV DNA in order to obtain the highest combined sensitivity and specificity for CIN2+ lesion detection. PMID- 25433839 TI - Changes in the mechanical parameters of hair in a group of women in reproductive age. AB - OBJECTIVE: Hair quality and scalp characteristics are considered to be a significant marker of health. This marker is reflected in mechanical properties of hair. To investigate these properties, hair samples have been collected among women of different age and then analyzed. The thickness, Young's modulus of elasticity and ultimate strength limit were the main observed parameters. METHODS: The diameter of each hair has been measured using an optical microscope equipped with a digital camera. The hair was then clipped into the uniaxial tensile testing device. Each sample has been stretched to failure at a speed of 2 mm/min and force vs. elongation was recorded. The mechanical results were converted with respect to the diameter and Stress-Strain curve was obtained for each sample. In addition, all the analyzed samples were divided into two groups in dependence on the age, namely samples from women younger than 35 and over 35 years of age. All the measured parameters were statistically evaluated. RESULTS: Young's modulus, yield and elongation parameters showed no significant difference among samples. On the other hand there was a significant difference among the samples in ultimate strength values. Findings from group analysis showed that women under 35 years show about 5 times greater variability in hair strength than that of women above that age. CONCLUSION: The results of our study indicate that hair tendency to grow persists up to 30 years of age, then slowly decreases and then achieves a steady state around 60 years of age. PMID- 25433840 TI - Chemerin serum levels in girls with anorexia nervosa. AB - BACKGROUND: The regulatory function of chemerin (CHEM) in the process of adipogenesis and the metabolism of adipocytes has been confirmed. Data from several studies have shown higher serum CHEM in obesity. To date, there are no available studies on serum CHEM concentrations in patients with anorexia nervosa (AN), which is recognized as a good biological model of the chronic atrophy of adipose tissue and energy metabolism disorders in humans. OBJECTIVES: The aim of the study was to assess serum CHEM concentrations in girls with AN in comparison to healthy and obese subjects and determine its relationship with body mass, BMI and insulin. METHODS: CHEM serum concentrations were evaluated using commercially available ELISA kit in 65 Polish girls with restrictive AN, in 39 healthy controls (H) and 64 girls with simple obesity (OB). RESULTS: The mean serum CHEM concentration in the AN group was significantly lower than in the H and OB groups. After adjusting for BMI, CHEM concentrations in the AN group were significantly lower than in the H group, but statistically higher than in the OB group. Significant correlations between serum CHEM and body mass (r=0.77), BMI (r=0.82), Cole index (r=0.81) and serum insulin (r=0.78) were observed. PMID- 25433841 TI - Correlation of plasma and salivary oxytocin in healthy young men - experimental evidence. AB - OBJECTIVES: The neuroactive hormone oxytocin (OT) has significant influence on human behavior, and it has been measured peripherally in venous blood and in saliva in many behavioral neuroscience studies. Assessment of salivary hormone levels is popular due to non-invasiveness, but there is a controversy as to whether OT can be reliably measured in saliva and how possible time lags between plasma and salivary OT levels influence correlation. DESIGN AND METHODS: In order to shed light on the question whether salivary and plasma OT levels correlate, we designed an experiment where healthy young men had to look at a presentation of trustworthy faces on a computer screen (faces were taken from an established database in trust research). During three points in time, plasma and saliva samples were collected and analyzed using ELISA. RESULTS: Plasma and salivary OT levels did not correlate even when considering a time lag of 15 or 30 minutes. CONCLUSIONS: Our results suggest that plasma and salivary OT levels do not correlate in healthy young men, and hence comparison of results across plasma and salivary studies is neither informative nor warranted. However, we recommend replicating this study based on mixed-gender samples. PMID- 25433842 TI - Dot1L mediated histone H3 lysine79 methylation is essential to meiosis progression in mouse oocytes. AB - OBJECTIVES: Post-translational modifications of lysine residues of histones can result in a series of functional changes. Lysine 79 of histone H3 (H3K79) can be methylated specifically by the Dot1 family of histone lysine methyltransferases. Although multiple developmental abnormalities in Dot1L-deficient mouse embryos have been studied, the biological function of H3K79 methylation in mammal oocytes remains unclear. Here, the distribution of Dot1L, methyltransferase of residue lys79 of histone H3 (H3K79) in mouse, and its effect on mouse oocytes meiosis were investigated to examine whether there are changes in the pattern of distribution and effect of Dot1L on mouse oocytes meiosis. METHODS: The mRNA level of Dot1l in mouse oocytes was examined using real-time qPCR (RT-qPCR) technique. The distribution and level of Dot1L protein and H3K79 methylation were examined using immunofluorescence and western-blot techniques, respectively. The down regulation of Dot1l in mouse oocytes was conducted using siRNA injection technique. RESULTS: Dot1L was detected diffuse staining in the nuclear of mouse GV (Germinal Vesicle) stage oocytes. The Dot1l expression and H3K79 methylation level were suppressed effectively with anti-Dot1l siRNA injection. In Dot1L deficient, accompanying with BubR1 (MAD3/Bub1b) remains on the chromosome, the mouse oocytes was blocked in metaphase of meiosis I. The histone deacetylation was also incomplete in Dot1L-deficient mouse oocytes. CONCLUSION: Dot1L protein is well distributed in mouse GV stage oocytes. Dot1L and H3K79 methylation play important roles in meiosis progression and are supposed to be associated with chromosome deacetylation of mouse oocytes. PMID- 25433843 TI - Evidence for the existence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with and without abdominal discomfort (irritable bowel) syndrome. AB - BACKGROUND: There is evidence that Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is accompanied by gastro-intestinal symptoms; and IgA and IgM responses directed against lipopolysaccharides (LPS) of commensal bacteria, indicating bacterial translocation. METHODS: This study was carried out to examine gastro-intestinal symptoms in subjects with ME/CFS versus those with chronic fatigue (CF). The two groups were dissected by dichotomizing those fulfilling and not fulfilling Fukuda's critera. In these groups, we examined the association between gastro-intestinal symptoms and the IgA and IgM responses directed against commensal bacteria. RESULTS: Using cluster analysis performed on gastro-intestinal symptoms we delineated that the cluster analysis-generated diagnosis of abdominal discomfort syndrome (ADS) was significantly higher in subjects with ME/CFS (59.6%) than in those with CF (17.7%). The diagnosis of ADS was strongly associated with the diagnosis of irritable bowel syndrome (IBS). There is evidence that ME/CFS consists of two subgroups, i.e. ME/CFS with and without ADS. Factor analysis showed four factors, i.e. 1) inflammation hyperalgesia; 2) fatigue-malaise; 3) gastro-intestinal symptoms/ADS; and 4) neurocognitive symptoms. The IgA and IgM responses to LPS of commensal bacteria were significantly higher in ME/CFS patients with ADS than in those without ADS. CONCLUSIONS: The findings show that ADS is a characteristic of a subset of patients with ME/CFS and that increased bacterial translocation (leaky gut) is associated with ADS symptoms. This study has defined a pathway phenotype, i.e bacterial translocation, that is related to ME/CFS and ADS/IBS and that may drive systemic inflammatory processes. PMID- 25433844 TI - High-density lipoprotein profile in newly-diagnosed lower extremity artery disease in Slovak population without diabetes mellitus. AB - OBJECTIVE: To assess the relationship of high density lipoprotein subfractions to newly-diagnosed lower extremity artery disease (LEAD) in individuals without diabetes mellitus and without hypolipidemic therapy. METHODS: This cross sectional study involves 106 subjects: 51 had newly diagnosed LEAD and no diabetes anamnesis and were not on hypolipidemic therapy; and 55 controls were without clinical presentation of LEAD and were normolipidemic. Analysis of HDL subclasses was performed by an innovative electrophoresis method on polyacrylamide gel (PAG), the Lipoprint HDL System. RESULTS: In LEAD subjects, total HDL-C levels as well as HDL2 (intermediate-to-large particles) subfraction levels were decreased (p<0.0001 and p<0.019 respectively). Interestingly the HDL3 (small particles) subfraction was significantly higher and lost its proportional relationship within the HDL cholesterol fraction (p<0.025, p<0.01 respectively). CONCLUSION: These findings pointed out that: (i) the reduction of HDL-C and especially HDL2 subpopulation opposite to the increase of small HDL3 subclass may be considered as important predictors of cardiovascular diseases. (ii) there are undisputable advantages of using Lipoprint HDL to identify HDL subfractions; the presence of high concentration of small HDL in patients with PAD/LEAD emphasizes that the potentially proatherogenic subclass of HDL family is linked to small HDL. PMID- 25433845 TI - Neuroeconomics of psychopathy: risk taking in probability discounting of gain and loss predicts psychopathy. AB - BACKGROUND: This study investigated the relationships between psychopathy and impulsive and risky decision making, by utilizing intertemporal and probabilistic choices for both gain and loss, in addition to the Iowa gambling task. METHODS: The Psychopathic Personality Inventory-Revised - a 154-item measure that assesses psychopathic traits by self-report - was used with a 4-point response scale to assess 113 undergraduate students from three Japanese universities. Participants' performance on the Iowa Gambling Task and four behavioral neuroeconomic tasks of discounting - delayed gain, delayed loss, uncertain gain, and uncertain loss - were estimated. RESULTS: Risky decisions in probability discounting of gain and loss were associated with psychopathy. Psychopathic traits had no relationship with performance on the Iowa Gambling and were not significantly related to delay discounting. CONCLUSIONS: Psychopathy is predicted by risky decision in probability discounting of gain and loss, but not strongly associated with future myopia. Implications of the present findings for neuroeconomics and neurolaw are discussed. PMID- 25433846 TI - Peripheral endothelial dysfunction as a marker of cardiovascular risk in physically healthy patients with schizophrenia and related psychoses: a matched case control study. AB - OBJECTIVES: Our aim was to assess endothelial function in physically healthy patients with schizophrenia and related psychoses and to compare the results with healthy controls. Endothelial dysfunction was shown to predict future cardiovascular events in general population so we assumed to find a higher prevalence of endothelial dysfunction in patients with psychosis, as their cardiovascular morbidity is markedly higher than in general population, and to confirm the referred correlation with the traditional cardiovascular (CV) risk factors. DESIGN: We assessed the traditional CV risk factors and endothelial function using non-invasive peripheral arterial tonometry (EndoPAT2000) in 50 stabilized and medicated schizophrenic patients (aged between 18 and 50 years) without any history of cardiovascular diseases and compared the results with 50 age-matched healthy controls. SETTING: Psychiatric Clinic, University Hospital, Hradec Kralove and 2nd Department of Internal Medicine, General University Hospital, Prague, Czech Republic RESULTS: There was no difference in relative hyperaemia index as an endothelial function measure between patients and controls (2.19+/-0.68 vs. 1.98+/-0.57, p=NS) and there were also no correlations between reactive hyperaemia index and the traditional CV risk factors, illness duration or psychotic symptoms. On the other hand, the two study groups differed significantly in almost all traditional CV risk factors. PMID- 25433847 TI - Preference for normal, reversed or chimeric self-faces with neutral emotional expression in patients with schizophrenia and control subjects. AB - OBJECTIVES: Self-face recognition is one of the most distinctive features in human beings. Disturbances of self-face recognition in people with schizophrenia may reflect the underlying neurobiological and psychological factors of the disorder. Our aim was to establish whether differences in preference for the similarity to the true self-face appearance could be found between patients with schizophrenia and a matched control group. SUBJECTS AND METHODS: 14 right-handed patients with schizophrenia and 14 control subjects were enrolled. Subjects were photographed, the pictures were converted to black and white, halved vertically, and four faces were used: normal face (NF), mirrored face (MF), face composed from two left halves of the face (LLF) and from two right halves of face (RRF). Four pairs of faces were exposed to subjects and they chose which they felt was closest to their true appearance. RESULTS: No significant differences for preference were found between the patients and control subjects. Post-hoc analysis of the pooled groups showed a significant difference for preference of NF vs. RRF (20 vs. 8 probands; chi2=5.14, df=1, p<0.05). 18 subjects from the two groups did not change the right-left visual field focus through all four exposures. CONCLUSIONS: The absence of significant differences for preference for true self-image between schizophrenia patients and control subjects might show that self-face recognition is of little importance from the evolutionary perspective. Additional measurements such as eye-tracking control and random multiple projections of the same pairs of faces would contribute to a more thorough interpretation of the findings in future studies of similar design. PMID- 25433848 TI - Prenatal stress, anxiety and depression: a mechanism involving CRH peptide family. AB - Prenatal stress (PNS) is associated with increased biological risk for mental disorders such as anxiety and depression later in life, and stress appear to be additive to the PNS influences. Among the most widely cited and accepted alternative hypotheses of anxiety and depression is dysfunction of the HPA axis, a system that is central in orchestrating the stress response. Therefore, understanding how PNS exerts profound effects on the HPA axis and stress sensitive brain functions including anxiety and depression has significant clinical importance. In this mini-review, we will focus on novel and evolving concepts regarding the potential mechanisms underlying the short and long-term effects of PNS involving CRH peptide family. We present evidence demonstrating prenatal hypoxia exposure induced anxiety-like behavior in adult male rat offspring and CRHR1 in PVN of the hypothalamus is involved. PMID- 25433850 TI - Self-stigma and suicidality in patients with neurotic spectrum disorder - a cross sectional study. AB - BACKGROUND: Self-stigmatization is a step-by-step process during which the person uncritically accepts the societal negative evaluation and applies it to himself. Relation between self-stigma and suicidality in neurotic disorders is not known. The aim of our study was to find connection between self-stigma and the level of suicidality in neurotic spectrum disorders. METHOD: It was a cross-sectional study of 198 inpatients with pharmacoresistant neurotic spectrum disorders hospitalized at the psychotherapeutic ward of the Department of Psychiatry, University Hospital Olomouc. Patients were diagnosed using the ICD-10 research diagnostic criteria. The assessments included Internalized Stigma Of Mental Illness (ISMI), Beck Depression Inventory-second edition (BDI-II), objective and subjective Clinical Global Impression (CGI), Morin sleep scale, Dissociative Experience Scale (DES) and Montgomery and Asberg Depression Rating Scale, item 10 Suicidal Thoughts (MADRS item 10 suicidality) for the assessment. RESULTS: The subjective rate of suicidality and also the objective rate of suicidality were strongly positively correlated with the total score of ISMI. There were also significant correlations with all subscores except for the correlation between the BDI 9 and the sub score Resistance against stigma, which barely missed the level of statistical significance. CONCLUSIONS: More attention should be paid to self-stigma in neurotic patients, especially in those with suicidal thoughts and tendencies. PMID- 25433851 TI - Suitable application of selected biochemical and biophysical markers during the first trimester screening. AB - Normal trophoblast growth is one of the more important stages of early pregnancy that has a deciding factor on its later development and normal outcome. Identifying pregnant women who have a high risk of complications connected to hypertension during pregnancy is currently one of the most important tasks of perinatal medicine. Abnormal placentation is related not only to the appearance of preeclampsia, but also to many other complications, such as premature placental abruption, intrauterine fetal demise, and intrauterine growth restriction. Preeclampsia and eclampsia are one of the major causes of maternal morbidity and mortality and appear in about 5% of all pregnancies. Clinical symptoms are a far-removed consequence of abnormal placentation. When they become visible, it is definitely too late for preventive action, and there is essentially no effective treatment. New research data suggests that a chance of prophylactic intervention might exist as early as in the first trimester of the pregnancy. One of the clinically documented possibilities is to apply low doses of acetylsalicylic acid before the 16th week of gestation. Despite the great importance of the placenta in the physiology of pregnancy, not much attention has been paid to the way it functions. This paper reviews selected biochemical and biophysical markers which are, or could be, used in clinical practice in the future. PMID- 25433849 TI - Pyridoindole antioxidant-induced preservation of rat hippocampal pyramidal cell number linked with reduction of oxidative stress yet without influence on cognitive deterioration in Alzheimer-like neurodegeneration. AB - BACKGROUND: The idea of antioxidant therapy attenuating Alzheimer disease (AD) neuropathology starts to be attractive. Animal models are often used in these studies. An AD-like model of trimethyltin (TMT)-induced neurodegeneration, targeting the hippocampus, involves neuronal cell death and cognitive impairment. OBJECTIVES: Effect of the pyridoindole SMe1EC2 (3*50 mg/kg) and vitamin C (3*50mg/kg) was analyzed in the model of TMT-induced (8 mg/kg) neurodegeneration. METHODS: The study was focused on the effect of the antioxidants tested on learning performance in the Morris water maze (MWM) on days 21-25 after TMT administration, on biochemical variables - malondyaldehyde (MDA) and lysosomal enzyme NAGA in brain cortex and blood serum, and on pyramidal cell number in the CA1 area of the hippocampus on day 31 after TMT administration in adult male Wistar rats (n=32). RESULTS: Critical deterioration of learning performance was observed due to the TMT administration in the MWM. Further, apparent reduction of pyramidal cell number to 21% in the CA1 area of the hippocampus, increased MDA and NAGA activity in serum and increased NAGA activity in the cortex were determined contrary to controls. In serum, an increase of MDA level was prevented by both antioxidants tested without any effect on NAGA activity. SMe1EC2 apparently preserved pyramidal cell viability in the CA1 area. Both substances tested failed to ameliorate the detrimental effect of TMT on spatial memory. CONCLUSION: The biochemical and morphometrical findings suggest that reduction of oxidative stress may play a role in AD-like neurodegeneration. Different doses and timing of SMe1EC2 administration might bring improvement in next learning performance. PMID- 25433852 TI - The relationship between somatic symptoms and depression. AB - OBJECTIVE: We investigated the influence of somatic symptoms on the severity and clinical outcomes in female Korean patients with major depressive disorder (MDD) in routine practice. METHODS: Two hundred and seven female patients with MDD were prospectively recruited. Patients with somatic symptoms (PSS) was defined as a total score >= 10 on the Patient Health Questionnaire-15 (PHQ-15), others were classified as non PSS (NPSS). The PHQ-9 for de-pression, the Generalized Anxiety Disorder Scale (GAD-7) for anxiety, the Clinical Global Impression-Severity (CGI S) for clinical status, and the Visual Analogue Scale (VAS) for health status were utilised. RESULTS: Of 207 participants, 126 (60.9%) were PSS and 81 (39.1%) were classified as NPSS. The proportion of patients showing severe symptoms (65.1% vs. 24.7%) and recurrence of depression (74.6% vs. 49.4%), the CGI-S (4.6 vs. 4.1), the PHQ-9 (16.8 vs. 11.1), and the GAD-7 (8.3 vs 6.7) scores were significantly higher in PSS than in NPSS, while the VAS (39.4 vs. 51.2) was significantly lower in PSS than in NPSS. The improvement of depressive symptoms ( 1.3 vs. -2.0) measured by the changes in CGI-S was also significantly less in PSS than in NPSS after 6 months treatment. CONCLUSION: Our findings have shown the significant impact of somatic symptoms on the symptomatology as well as treatment outcomes in Korean female patients with MDD, indicating that clinicians should carefully evaluate somatic symptoms in patients with MDD in routine clinical practice. Due to the methodological shortcomings of the present study, further adequately powered and well-designed investigations are necessary. PMID- 25433853 TI - The role of calcium and nicotinic acid adenine dinucleotide phosphate (NAADP) in human osteoclast formation and resorption. AB - Osteoclasts are specialised bone resorbing cells which form by fusion of circulating mononuclear phagocyte precursors. Bone resorption results in the release of large amounts of calcium into the extracellular fluid (ECF), but it is not certain whether changes in extracellular calcium concentration [Ca(2+)]e influence osteoclast formation and resorption. In this study, we sought to determine the effect of [Ca(2+)]e and NAADP, a potent calcium mobilising messenger that induces calcium uptake, on human osteoclast formation and resorption. CD14+ human monocytes were cultured with M-CSF and RANKL in the presence of different concentrations of calcium and NAADP and the effect on osteoclast formation and resorption evaluated. We found that the number of TRAP+ multinucleated cells and the extent of lacunar resorption were reduced when there was an increase in extracellular calcium and NAADP. This was associated with a decrease in RANK mRNA expression by CD14+ cells. At high concentrations (20 mM) of [Ca(2+)]e mature osteoclast resorption activity remained unaltered relative to control cultures. Our findings indicate that osteoclast formation is inhibited by a rise in [Ca(2+)]e and that RANK expression by mononuclear phagocyte osteoclast precursors is also [Ca(2+)]e dependent. Changes in NAADP also influence osteoclast formation, suggesting a role for this molecule in calcium handling. Osteoclasts remained capable of lacunar resorption, even at high ECF [Ca(2+)]e, in keeping with their role in physiological and pathological bone resorption. PMID- 25433854 TI - Benign osseous and articular abnormalities of the pelvis: a review of CT imaging findings. AB - Computed tomography (CT) has become the standard of care for evaluation and follow-up for a wide range of abdominal and pelvic pathology. Many incidental osseous and articular abnormalities of the pelvis are detected on these studies, most of which have a benign etiology. However, most of these studies are interpreted by nonmusculoskeletal radiologists, who may not be familiar with the CT appearances of these benign musculoskeletal abnormalities. Uncertainty often leads to mischaracterization or unnecessary follow-up, resulting in increased health care costs and patient anxiety. This article reviews the CT appearance of the benign musculoskeletal entities that occur in pelvis. PMID- 25433855 TI - Assessment of diffusion-weighted imaging for characterizing focal liver lesions. AB - In 150 patients, 153 hepatic lesions (39 metastases, 27 hemangiomas, 26 hepatocellular carcinomas, 25 cysts, 15 adenomas, 8 focal nodular hyperplasias, 5 abscesses, 4 hamartomas, and 4 cholangiocarcinomas) were evaluated during a 24 month period. Apparent diffusion coefficient (ADC) values of benign lesions (1.994*10(-3) mm(2) s(-1)) were significantly higher than ADC values of malignant lesions (1.070*10(-3) mm(2) s(-1)). Mean ADC value for solid benign lesions (1.143*10(-3) mm(2) s(-1)+/-0.214*10(-3) mm(2) s(-1)) was not significantly different from malignant lesions. ADC values did not allow differentiating malignant from benign solid lesions (area under the curve=0.61). ADC cutoff value threshold of 1.6*10(-3) mm(2) s(-1) yielded higher accuracy for differentiating benign from malignant lesions. PMID- 25433856 TI - The rice OsAMT1;1 is a proton-independent feedback regulated ammonium transporter. AB - KEY MESSAGE: Functional identification of a relatively lower affinity ammonium transporter, OsAMT1;1, which is a proton-independent feedback regulated ammonium transporter in rice. Rice genome contains at least 12 ammonium transporters, though their functionality has not been clearly resolved. Here, we demonstrate the functional properties of OsAMT1;1 applying functional complementation and (15)NH4 (+) uptake determination in yeast cells in combination with electrophysiological measurements in Xenopus oocytes. Our results show that OsAMT1;1 is a NH4 (+) transporter with relatively lower affinity to NH4 (+) (110 129 MUM in oocytes and yeast cells, respectively). Under our experimental conditions, OsAMT1;1-mediated NH4 (+) uptake or current is not significantly modulated by extra- or intracellular pH gradient, suggesting that this transporter probably functions as a NH4 (+) uniporter. Inhibition of yeast growth or currents elicited from oocytes by ammonium assimilation inhibitor L-methionine sulfoximine indicates that NH4 (+) transport by OsAMT1;1 is likely feedback regulated by accumulation of the substrate. In addition, effects of phosphorylation inhibitors imply that NH4 (+) uptake by OsAMT1;1 is also modulated by tyrosine-specific protein kinase or calcium-regulated serine/threonine-specific protein phosphatase involved phosphorylation processes. PMID- 25433858 TI - Accumulation of high contents of free amino acids in the leaves of Nicotiana benthamiana by the co-suppression of NbClpC1 and NbClpC2 genes. AB - KEY MESSAGE: We report the significant increase of the content of free amino acids in Nicotiana benthamiana by the co-suppression of the ClpC1 and ClpC2 genes, which are translated to be the chaperonic part in the Clp protease at plastids. Clp protease with ClpC1 and ClpC2 proteins as the chaperonic part degrades denatured or improperly folded protein in plastids. Nicotiana benthamiana ClpC1 and ClpC2 genes (NbClpC1 and NbClpC2: NbClpC1/C2) share 93% similarities; therefore, co-suppression of the NbClpC1/C2 was possible using a single virus-induced silencing vector. Co-suppression of NbClpC1/C2 resulted in a pleiotropic phenotype including disappearance of apical dominance and formation of chlorotic leaves. NbClpC1/C2 co-suppressed leaves accumulated 11.9-fold more free amino acids than the GFP-silenced leaves. The co-suppression of NbClpC1/C2 did not change the expression levels of some selected genes in the biosynthetic pathways for the free amino acids, but reduced the total protein amounts to 32.5%, indicating that co-suppression affected the incorporation of free amino acids in proteins during translation. The loosely packed mesophyll cells and abnormal vascular bundles in the leaves suggested structural problems associated with translocation of free amino acids to sink tissues. NbClpC1/C2 co-suppression can offer a novel strategy for accumulation of free amino acids though it results in stunted growth. PMID- 25433857 TI - Microalgal lipid droplets: composition, diversity, biogenesis and functions. AB - Lipid droplet is the major site of neutral lipid storage in eukaryotic cells, and increasing evidence show its involvement in numerous cellular processes such as lipid homeostasis, signaling, trafficking and inter-organelle communications. Although the biogenesis, structure, and functions of lipid droplets have been well documented for seeds of vascular plants, mammalian adipose tissues, insects and yeasts, relative little is known about lipid droplets in microalgae. Over the past 5 years, the growing interest of microalgae as a platform for biofuel, green chemicals or value-added polyunsaturated fatty acid production has brought algal lipid droplets into spotlight. Studies conducted on the green microalga Chlamydomonas reinhardtii and other model microalgae such as Haematococcus and Nannochloropsis species have led to the identification of proteins associated with lipid droplets, which include putative structural proteins different from plant oleosins and animal perilipins, as well as candidate proteins for lipid biosynthesis, mobilization, trafficking and homeostasis. Biochemical and microscopy studies have also started to shed light on the role of chloroplasts in the biogenesis of lipid droplets in Chlamydomonas. PMID- 25433860 TI - Bacillus subtilis degSU operon is regulated by the ClpXP-Spx regulated proteolysis system. AB - The DegS-DegU two-component regulatory system regulates many cellular events in Bacillus subtilis. Genes for DegSU constitutes an operon directed by the P1 promoter and downstream degU is autoregulated via the P3 promoter activated by phosphorylated DegU. In the Gram-positive bacteria, Spx plays a major role in the protection system against oxidative stresses as a transcriptional regulator. Spx is a substrate of the ATP-dependent ClpXP protease. It regulates diamide-stress regulon in addition to many genes with unknown functions. We have found that null mutations for clpX and clpP, which encode the subunits for the protease ClpXP, enhanced the DegU level through activation of the P1 promoter. We isolated four suppressors for the clpP-enhancing effect. Whole-genome sequencing of the suppressors revealed that two have a point mutation in spx and the rest have a deletion of spx. The clpP-enhancing effect on degS-lacZ expression was abolished in the spx disruptant. These results show that the degSU operon is a new target of Spx-mediated positive regulation. Furthermore, we found that the P1 promoter was induced by glucose and that this induction was greatly reduced in the spx mutant. These results suggested that Spx-mediated glucose induction at the P1 promoter. PMID- 25433859 TI - beta-Cyclodextrin-hemin complex-induced lateral root formation in tomato: involvement of nitric oxide and heme oxygenase 1. AB - KEY MESSAGE: beta-Cyclodextrin-hemin complex-induced tomato lateral root formation was associated with nitric oxide and heme oxygenase 1 by modulating cell cycle regulatory genes. beta-Cyclodextrin-hemin complex (beta-CDH), a complex by combining beta-cyclodextrin (beta-CD) with hemin, a heme oxygenase 1 (HO1) inducer, was a trigger of cucumber adventitious root formation by enhancing HO1 gene expression. In this report, our results identified the previously unknown function of beta-CDH in plants: the inducer of tomato lateral root (LR) formation. beta-CDH-triggered LR formation is hemin-specific, since beta-CD failed to induce LR development. Because nitric oxide (NO) is involved in LR formation, the correlation of beta-CDH with NO and HO1 was investigated. Our analysis suggested that beta-CDH induced an increase in endogenous NO production, followed by up-regulation of tomato HO1 gene and LR formation, all of which were mimicked by hemin and two NO-releasing compounds (SNP and GSNO). The induction of HO1 gene expression and LR formation triggered by beta-CDH or hemin were significantly blocked by an inhibitor of HO1. Further results revealed that both beta-CDH- and SNP-stimulated HO1 gene expression and thereafter LR formation were sensitive to the removal of NO with a potent NO scavenger, and the responses of SNP were significantly blocked by an inhibitor of HO1. Molecular evidence illustrated that representative cell cycle regulatory genes, including SlCDKA1, SlCYCA3;1, SlCYCA2;1, and SlCYCD3;1, were significantly up-regulated by beta-CDH and SNP, but obviously blocked when seedlings were co-treated with the scavenger of NO or the inhibitor of HO1. In summary, our physiological and molecular evidence demonstrated that both NO and HO1 were involved in the beta-CDH-induced LR formation with, at least partially, HO1 acting downstream of NO signaling. PMID- 25433861 TI - A C-type lectin isolated from the skin of Japanese bullhead shark (Heterodontus japonicus) binds a remarkably broad range of sugars and induces blood coagulation. AB - The aim of this study was to determine the physiological role of skin lectins of the Japanese bullhead shark (Heterodontus japonicus). A skin extract was subjected to affinity chromatography using seven different sugars as ligands. Molecular mass and N-terminal amino acid sequence analyses indicated elution of the same protein by each of the seven respective cognate ligands from sugar affinity columns. The predicted amino acid sequence encoded by the cDNA of this protein [designated as H. japonicus C-type-lectin (HjCL)] identified it as a novel fish subgroup VII C-type lectin evolutionarily related to snake venom lectins. HjCL was predicted to bind to mannose because of the presence of a Glu Pro-Asn (EPN) motif; however, haemagglutination inhibition assays and glycoconjugate microarray analysis demonstrated its binding to numerous structurally diverse sugars. Competitive sugar-binding assays using affinity chromatography indicated that HjCL bound multiple sugars via a common carbohydrate-recognition domain. The mRNA encoding HjCL was specifically detected in the skin, and immunohistochemical analysis detected its expression in uncharacterized large cells in the epidermis. HjCL agglutinated the bacterial pathogen Edwardsiella tarda and promoted immediate clotting of shark blood, indicating that HjCL is involved in host defence on the skin surface especially when the shark is injured and bleeds. PMID- 25433862 TI - Ovariectomized Rats with Established Osteopenia have Diminished Mesenchymal Stem Cells in the Bone Marrow and Impaired Homing, Osteoinduction and Bone Regeneration at the Fracture Site. AB - We investigated deleterious changes that take place in mesenchymal stem cells (MSC) and its fracture healing competence in ovariectomy (Ovx)-induced osteopenia. MSC from bone marrow (BM) of ovary intact (control) and Ovx rats was isolated. (99m)Tc-HMPAO (Technitium hexamethylpropylene amine oxime) labeled MSC was systemically transplanted to rats and fracture tropism assessed by SPECT/CT. PKH26 labeled MSC (PKH26-MSC) was bound in scaffold and applied to fracture site (drill-hole in femur metaphysis). Osteoinduction was quantified by calcein binding and microcomputed tomography. Estrogen receptor (ER) antagonist, fulvestrant was used to determine ER dependence of osteo-induction by MSC. BM-MSC number was strikingly reduced and doubling time increased in Ovx rats compared to control. SPECT/CT showed reduced localization of (99m)Tc-HMPAO labeled MSC to the fracture site, 3 h post-transplantation in Ovx rats as compared with controls. Post-transplantation, Ovx MSC labeled with PKH26 (Ovx PKH26-MSC) localized less to fracture site than control PKH26-MSC. Transplantation of either control or Ovx MSC enhanced calcein binding and bone volume at the callus of control rats over placebo group however Ovx MSC had lower efficacy than control MSC. Fulvestrant blocked osteoinduction by control MSC. When scaffold bound MSC was applied to fracture, osteoinduction by Ovx PKH26-MSC was less than control PKH26-MSC. In Ovx rats, control MSC/E2 treatment but not Ovx MSC showed osteoinduction. Regenerated bone was irregularly deposited in Ovx MSC group. In conclusion, Ovx is associated with diminished BM-MSC number and its growth, and Ovx MSC displays impaired engraftment to fracture and osteoinduction besides disordered bone regeneration. PMID- 25433864 TI - Process versus outcome: the sugar window. PMID- 25433865 TI - Indications for revascularization in patients with left ventricular dysfunction: evidence and uncertainties. PMID- 25433866 TI - Surgery for the low-birth-weight infant with congenital heart disease: where is the problem? PMID- 25433863 TI - Pluripotent stem cells for Schwann cell engineering. AB - Tissue engineering of Schwann cells (SCs) can serve a number of purposes, such as in vitro SC-related disease modeling, treatment of peripheral nerve diseases or peripheral nerve injury, and, potentially, treatment of CNS diseases. SCs can be generated from autologous stem cells in vitro by recapitulating the various stages of in vivo neural crest formation and SC differentiation. In this review, we survey the cellular and molecular mechanisms underlying these in vivo processes. We then focus on the current in vitro strategies for generating SCs from two sources of pluripotent stem cells, namely embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Different methods for SC engineering from ESCs and iPSCs are reviewed and suggestions are proposed for optimizing the existing protocols. Potential safety issues regarding the clinical application of iPSC-derived SCs are discussed as well. Lastly, we will address future aspects of SC engineering. PMID- 25433867 TI - Apples, oranges, and lemons: making sense of lung volume reduction surgery. PMID- 25433868 TI - On-pump coronary revascularization should be our preferred surgical revascularization strategy. PMID- 25433869 TI - Should off-pump coronary artery bypass surgery be abandoned: a potential solution. PMID- 25433870 TI - Aortic valve repair: defining the patient population and timing of the intervention. PMID- 25433871 TI - The conclusion of papers published in the Journal should be supported by an appropriate statistical analysis. PMID- 25433872 TI - Closing in on the perfect Fontan. PMID- 25433873 TI - To fenestrate or not: the Fontan debate gets more complicated. PMID- 25433874 TI - Management of residual lesions following surgery for congenital heart defects: evidence versus judgment. PMID- 25433875 TI - Losartan for progressive pulmonary vein stenosis: a possible solution? PMID- 25433876 TI - Validation accepted, but look at what else was revealed. PMID- 25433877 TI - Who belongs on the "fast track"? PMID- 25433878 TI - Percutaneous edge-to-edge repair for degenerative mitral regurgitation: a journey to the edge of the bell-shaped curve. PMID- 25433879 TI - Minimally invasive Perceval S implantation: Does this fill a sizable niche between sutured and transcatheter aortic valve replacement? PMID- 25433880 TI - Hypothermic circulatory arrest is not just about temperature. PMID- 25433881 TI - Innominate artery cannulation: the Toronto technique for antegrade cerebral perfusion in aortic arch reconstruction--a clinical trial opportunity for the International Aortic Arch Surgery Study Group. PMID- 25433882 TI - Clinical features of acute aortic dissection from the Registry of Aortic Dissection in China. AB - OBJECTIVE: To establish a systematic registry of aortic dissection in China, assess the clinical features of Chinese patients with acute aortic dissection (AAD), and compare our results with the data published by the International Registry of Acute Aortic Dissection (IRAD). METHODS: We established the first Registry of Aortic Dissection in China (Sino-RAD) in 2011. Then we evaluated 1003 patients with AAD in Sino-RAD and compared our results with those reported by IRAD. RESULTS: Compared with IRAD, the patients with AAD in Sino-RAD were significantly younger. Also, the ratio of male patients in Sino-RAD was significantly greater for the total cohort and the type A and B cohorts. The overall in-hospital mortality was 10.3% in Sino-RAD. For type A dissection, more patients in Sino-RAD received medical treatment and fewer received surgical treatment. The overall mortality, mortality of medical treatment, and mortality of surgical treatment was lower in Sino-RAD. In type B dissection, fewer patients in Sino-RAD received medical and surgical treatment and more received endovascular treatment. CONCLUSIONS: The first Sino-RAD, including 15 large cardiovascular centers throughout China, was established. Our data were compared with those reported by IRAD. We found that, compared with Western populations, Chinese patients with AAD showed 6 differences, including earlier onset, more male patients, a low incidence of hypertension, a low incidence of chest pain, a high incidence of back pain, great differences in the choice of therapeutic strategies, and relatively low in-hospital mortality. PMID- 25433883 TI - Examining the face of aortic dissection outside the Western world. PMID- 25433884 TI - Association of operative risk with the outcome of concomitant Cox Maze procedure: a comparison of results across risk groups. AB - OBJECTIVES: Cardiac surgery patients with atrial fibrillation face increased risks for perioperative morbidity and decreased survival, yet only 39% of patients presenting with atrial fibrillation undergo concomitant surgical ablation. This low percentage may relate to the perception of lower yield for surgical ablation, especially in patients with complex clinical presentations. In this study, we compared outcomes after a concomitant Cox maze III/IV procedure in patients with high, intermediate, and low predicted operative risk. METHODS: Outcome data were prospectively captured after surgery. The additive European System for Cardiac Operative Risk Evaluation (EuroSCORE) was greater than 6 for high-risk patients (n = 145), 3 or less for low-risk patients (n = 76), and greater than 3 and 6 or less for intermediate-risk patients (n = 149). RESULTS: No differences were found for perioperative morbidities, including operative mortality (high vs low risk, 2% vs 1%, P = 1.00; high vs intermediate risk, 2% vs 0.7%, P = .37). Median length of stay was longer in high-risk patients versus low risk patients (8 vs 5 days, P < .001) and intermediate-risk patients (8 vs 6 days, P < .001). Return to sinus rhythm was comparable for high-risk versus low- and intermediate-risk patients at 6, 12, and 24 months. Physical health-related quality of life scores improved similarly for all groups at 12 months. No difference in long-term survival was found (log rank = 0.40; P = .82). CONCLUSIONS: The Cox maze III/IV procedure can be performed safely and effectively in patients with higher operative risk, who fare well when compared with lower-risk patients. The Cox maze III/IV procedure should be considered carefully in patients with a significant history of atrial fibrillation. PMID- 25433885 TI - Why do most patients with atrial fibrillation referred for other cardiac surgery not receive concomitant ablation? A plea for a more aggressive surgical approach. PMID- 25433886 TI - Quality assessment in cardiac surgery: measuring accurately, fairly, and easily, focusing on what can be changed. PMID- 25433887 TI - Frailty: it's hard to define, but you know it when you see it. PMID- 25433888 TI - You can't get there from here without more robust data. PMID- 25433889 TI - Volatile anesthetics in cardiac surgery: renoprotective, cardioprotective, neither, or both? PMID- 25433890 TI - To give or not to give? Are we ready to use noninvasive monitors to guide fluid management in cardiothoracic surgical patients? PMID- 25433891 TI - Cardiac stem cell therapy: checkered past, promising future? PMID- 25433892 TI - The quest for a durable bioengineered tissue for the treatment of valvular heart disease. PMID- 25433893 TI - Re: Interpapillary muscle distance independently affects severity of functional mitral regurgitation in patients with systolic left ventricular dysfunction. PMID- 25433894 TI - Why does papillary separation play a major role in functional mitral regurgitation caused by left ventricular function? PMID- 25433895 TI - Management of mild aortic valve stenosis in rheumatic mitral surgery. PMID- 25433896 TI - Antiplatelet therapy as sole anticoagulant in patients with aortic mechanical prostheses. PMID- 25433897 TI - Routine aortic valve replacement for mild stenosis is not necessary during rheumatic mitral surgery. PMID- 25433898 TI - Re: Predictors of outcome and different management of aortobronchial and aortoesophageal fistulas. PMID- 25433899 TI - The key for successfully managing aortobronchial and aortoesophageal fistulae may lay in their etiology. PMID- 25433900 TI - Evaluating the potential of immobilized bacterial consortium for black liquor biodegradation. AB - Two indigenous bacterial strains, Bacillus megaterium ETLB-1 (accession no. KC767548) and Pseudomonas plecoglossicida ETLB-3 (accession no. KC767547), isolated from soil contaminated with paper mill effluent, were co-immobilized on corncob cubes to investigate their biodegradation potential against black liquor (BL). Results exhibit conspicuous reduction in color and lignin of BL upto 913.46 Co-Pt and 531.45 mg l(-1), respectively. Reduction in chlorophenols up to 12 mg l(-1) was recorded with highest release of chloride ions, i.e., 1290 mg l(-1). Maximum enzyme activity for lignin peroxidase (LiP), manganese peroxidase (MnP), and laccase (LAC) was recorded as 5.06, 8.13, and 8.23 U ml(-1), respectively, during the treatment. Scanning electron microscopy (SEM) revealed successful immobilization of bacterial strains in porous structures of biomaterial. Gas chromatography/mass spectroscopy (GC/MS) showed formation of certain low molecular weight metabolites such as 4-hydroxy-benzoic acid, 3-hydroxy-4 methoxybenzaldehyde, ferulic acid, and t-cinnamic acid and removal of majority of the compounds (such as teratogenic phthalate derivatives) during the period of treatment. Results demonstrated that the indigenous bacterial consortium possesses excellent decolorization and lignin degradation capability which enables its commercial utilization in effluents treatment system. PMID- 25433902 TI - Global cortical thinning in acute anorexia nervosa normalizes following long-term weight restoration. AB - BACKGROUND: Anorexia nervosa (AN) is a serious eating disorder characterized by self-starvation, extreme weight loss, and alterations in brain structure. Structural magnetic resonance imaging studies have documented brain volume reductions in acute AN, but it is unclear whether they are 1) regionally specific, or 2) reversible following weight restoration. Here, we measured cortical thickness (CT) for the first time in AN. METHODS: Structural magnetic resonance imaging data were acquired from adolescent and young adult female patients with acute AN (n = 40), recovered patients following long-term weight restoration (n = 34), and an equal number of age-matched healthy control subjects. Group differences in CT were tested with well-validated procedures implemented in FreeSurfer. The mediating role of clinical variables including body mass index and drive for thinness were explored. For completeness, we also used FreeSurfer's subcortical segmentation stream to test group differences in volumes of select gray matter regions of interest. RESULTS: Vertex-wise analyses revealed significant thinning of over 85% of the cortical surface in patients with acute AN and CT normalization in recovered patients following long-term weight restoration, although normal age-related trajectories were absent in the disorder. This pattern of results was largely mirrored in subcortical volumes. We also observed a strong negative correlation between CT and drive for thinness in extrastriate regions involved in body perception. CONCLUSIONS: Structural brain anomalies in AN as expressed in CT and subcortical volume are primarily the consequence of malnutrition and unlikely to reflect premorbid trait markers or permanent scars, but longitudinal data are needed. PMID- 25433903 TI - The anterior cingulate cortex is a critical hub for pain-induced depression. AB - BACKGROUND: Besides chronic stress, chronic pain is a prevalent determinant for depression. Changes induced in specific brain regions by sustained pain may alter the processing of affective information, thus resulting in anxiodepressive disorders. Here, we compared the role of the anterior cingulate cortex (ACC) and the posterior insular cortex in the anxiodepressive, sensory, and affective aspects of chronic pain. METHODS: Neuropathic pain was induced by cuffing the right sciatic nerve of C57BL/6J mice. Lesions were performed by local injection of ibotenic acid and chronic activation of the ACC by optogenetic stimulation. Anxiodepressive-related behaviors were evaluated through the novelty suppressed feeding, marble burying, splash, and forced swimming tests. Mechanical thresholds were determined using von Frey filaments, and the relief of spontaneous pain was determined by using place conditioning. RESULTS: The ACC lesion prevented the anxiodepressive consequences of chronic pain without affecting the sensory mechanical allodynia. Conversely, the tonic or spontaneous pain and the anxiodepressive consequences of pain remained present after posterior insular cortex lesion, even though the mechanical allodynia was suppressed. Furthermore, optogenetic stimulation of the ACC was sufficient to induce anxiety and depressive-like behaviors in naive animals. CONCLUSIONS: Our results show that, at cortical level, the sensory component of chronic pain remains functionally segregated from its affective and anxiodepressive components. Spontaneous tonic pain and evoked allodynia can be experimentally dissociated. Furthermore, the ACC appears as a critical hub for mood disorders, including for the anxiodepressive consequences of chronic pain, and thus constitutes an important target for divulging the underlying mechanism. PMID- 25433906 TI - Sleep coaches: characterization of a burgeoning pediatric provider group from Internet advertisements for services. AB - Sleep coaches are an emerging group of pediatric providers whose scope of services and regional distribution have not been well characterized. This descriptive analysis used Internet data to identify sleep coaches and certification programs in the US; we found a sizeable diversity of backgrounds, training, services offered, and pricing. PMID- 25433905 TI - "Blaschkoid dyspigmentation" in a child: don't forget fibroblast chromosomal analysis. PMID- 25433901 TI - The central amygdala as an integrative hub for anxiety and alcohol use disorders. AB - The central amygdala (CeA) plays a central role in physiologic and behavioral responses to fearful stimuli, stressful stimuli, and drug-related stimuli. The CeA receives dense inputs from cortical regions, is the major output region of the amygdala, is primarily GABAergic (inhibitory), and expresses high levels of prostress and antistress peptides. The CeA is also a constituent region of a conceptual macrostructure called the extended amygdala that is recruited during the transition to alcohol dependence. We discuss neurotransmission in the CeA as a potential integrative hub between anxiety disorders and alcohol use disorder, which are commonly co-occurring in humans. Imaging studies in humans and multidisciplinary work in animals collectively suggest that CeA structure and function are altered in individuals with anxiety disorders and alcohol use disorder, the end result of which may be disinhibition of downstream "effector" regions that regulate anxiety-related and alcohol-related behaviors. PMID- 25433904 TI - Altered glutamate protein co-expression network topology linked to spine loss in the auditory cortex of schizophrenia. AB - BACKGROUND: Impaired glutamatergic signaling is believed to underlie auditory cortex pyramidal neuron dendritic spine loss and auditory symptoms in schizophrenia. Many schizophrenia risk loci converge on the synaptic glutamate signaling network. We therefore hypothesized that alterations in glutamate signaling protein expression and co-expression network features are present in schizophrenia. METHODS: Gray matter homogenates were prepared from auditory cortex gray matter of 22 schizophrenia and 23 matched control subjects, a subset of whom had been previously assessed for dendritic spine density. One hundred fifty-five selected synaptic proteins were quantified by targeted mass spectrometry. Protein co-expression networks were constructed using weighted gene co-expression network analysis. RESULTS: Proteins with evidence for altered expression in schizophrenia were significantly enriched for glutamate signaling pathway proteins (GRIA4, GRIA3, ATP1A3, and GNAQ). Synaptic protein co-expression was significantly decreased in schizophrenia with the exception of a small group of postsynaptic density proteins, whose co-expression increased and inversely correlated with spine density in schizophrenia subjects. CONCLUSIONS: We observed alterations in the expression of glutamate signaling pathway proteins. Among these, the novel observation of reduced ATP1A3 expression is supported by strong genetic evidence indicating it may contribute to psychosis and cognitive impairment phenotypes. The observations of altered protein network topology further highlight the complexity of glutamate signaling network pathology in schizophrenia and provide a framework for evaluating future experiments to model the contribution of genetic risk to disease pathology. PMID- 25433907 TI - Vitamin K3 increased BMD at 1 and 2 months post-surgery and the maximum stress of the middle femur in the rat. AB - The therapeutic effects of vitamin K3 (VK3) on osteoporosis are still unknown. In this study, we hypothesized that VK3 possesses therapeutic effects on osteoporosis; to verify this hypothesis, the ovariectomized rat was used as an osteoporosis model. Fifty-six Sprague-Dawley female rats aged 8 to 9 months were randomly assigned to 4 groups: sham surgery, ovariectomy with saline, ovariectomy with low-dose VK3, and ovariectomy with high-dose VK3. Intramuscular injection of VK3 was performed every other day beginning 1 month postoperatively. The therapeutic effects of VK3 on osteoporosis were evaluated by measurement of bone mineral density (BMD), bone biochemical markers, biomechanical properties, and bone morphometric parameters. The overall average BMD in VK3-treated groups increased to a level between those of the ovariectomy group and the sham surgery group. The procollagen I N-terminal peptide level peaked at 2 months after surgery in all groups except in the group that had undergone ovariectomy with low dose VK3. The tartrate-resistant acid phosphatase 5b level increased more slowly at 4 months after surgery than at 2 months after surgery in the VK3-treated groups. The ovariectomy with high-dose VK3 group had the highest maximum stress of the middle femur of all groups. With VK3 treatment, the trabecular bone area percentage increased. All morphometric indicators for the middle tibia in the VK3 treated groups reached the levels found in the sham surgery group. In summary, VK3 therapy increased BMD at 1 and 2 months postsurgery and the maximum stress of the middle femur. In addition, VK3 therapy slowed the increase in bone turnover in ovariectomized rats. Furthermore, VK3 can improve morphometric indicators for the middle tibia. Our preliminary study indicates that VK3 has a potential therapeutic effect on osteoporosis and is worthy of further investigation. PMID- 25433908 TI - Moderate maternal food restriction in mice impairs physical growth, behavior, and neurodevelopment of offspring. AB - Intrauterine growth retardation (IUGR) occurs in 3% to 7% of all pregnancies. Recent human studies have indicated that neurodevelopmental disabilities, learning disorders, memory impairment, and mood disturbance are common in IUGR offspring. However, the interactions between IUGR and neurodevelopmental disorders are unclear because of the wide range of causes of IUGR, such as maternal malnutrition, placental insufficiency, pregnancy toxemia, and fetal malformations. Meanwhile, many studies have shown that moderate food restriction enhances spatial learning and improves mood disturbance in adult humans and animals. To date, the effects of maternal moderate food restriction on fetal brain remain largely unknown. In this study, we hypothesized that IUGR would be caused by even moderate food restriction in pregnant females and that the offspring would have neurodevelopmental disabilities. Mid-pregnant mice received moderate food restriction through the early lactation period. The offspring were tested for aspects of physical development, behavior, and neurodevelopment. The results showed that moderate maternal food restriction induced IUGR. Offspring had low birth weight and delayed development of physical and coordinated movement. Moreover, IUGR offspring exhibited mental disabilities such as anxiety and poor cognitive function. In particular, male offspring exhibited significantly impaired cognitive function at 3 weeks of age. These results suggested that a restricted maternal diet could be a risk factor for developmental disability in IUGR offspring and that male offspring might be especially susceptible. PMID- 25433910 TI - Methadone-induced acute toxic leukoencephalopathy. PMID- 25433909 TI - Brief cognitive and behavioral screening in children with new-onset epilepsy: a pilot feasibility trial. AB - BACKGROUND: Minimal work has used psychometrically robust measures in a systematic fashion to identify and monitor children at risk for cognitive and behavioral comorbidities in current epilepsy care. We piloted a computerized cognitive battery and behavioral questionnaire for children with newly diagnosed epilepsy to determine clinical feasibility and acceptability to parents and patients. METHODS: We recruited medication-naive children (ages 8-17 years) with recent-onset seizures and typical developmental history from an outpatient child neurology clinic. Children completed the CNS Vital Signs computerized battery, whereas parents completed the Strengths and Difficulties Questionnaire. Post-test interviews with parents and patients were completed regarding the acceptability of the assessment procedures. RESULTS: Forty-four families were eligible, and 39 agreed to participate (89%). All assessments were completed in less than 45 minutes. Parents rated testing in clinic as convenient and important, expressing strong interest in the cognitive and behavioral impact of epilepsy and medication. Children also rated the testing procedure as acceptable and agreed that they would recommend it to peers. CONCLUSIONS: Our brief battery was tolerated and well received by children and their parents. Computerized testing of children along with a parent questionnaire is a psychometrically viable approach that is acceptable to families. Our protocol is time efficient for clinical use with the potential to detect early cognitive and behavioral difficulties related to epilepsy. Ongoing longitudinal study will provide further information regarding the success of our screening methods in monitoring for disease- or treatment-related changes. PMID- 25433911 TI - Development of a validated LC-MS/MS method for the determination of ailanthone in rat plasma with application to pharmacokinetic study. AB - Ailanthone, a natural compound isolated from Chinese herb Ailanthus altissima, has drawn a lot of attention for its antitumor activity. In this study, a simple and sensitive method for determination of ailanthone in rat plasma was developed for the first time, using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Brusatol was used as an internal standard. Separation was achieved on an Agilent Zorbax Eclipse Plus C18 column with gradient elution using water-methanol as mobile phase at a flow rate of 0.2 mL/min. A triple quadrupole mass spectrometer operating in the negative electrospray ionization mode with multiple reaction monitoring (MRM) was used to detect ailanthone and IS transitions of 375.2 -> 301.1 and 519.1 -> 437.4, respectively. The lower limit of quantification was 5 ng/mL with a linear range of 5-2000 ng/mL. The intra- and inter-day accuracy (RE) ranged from -3.6 to 1.5% and -0.7 to 4.7% and the intra- and inter-day precision (RSD) was between 2.8-6.7% and 3.1-8.0%. The validated method has been successfully applied to a pharmacokinetic study of ailanthone in rats. The elimination half-lives (t1/2) were 105.5 +/- 13.6, 113.3 +/- 39.6, and 95.8 +/- 23.9 min after single intravenous administration of 0.5, 1.0, and 1.5mg/kg ailanthone, respectively. The area under the plasma concentration versus time curve (AUC0-6h) and initial plasma concentration (C0) were linearly related to dose. PMID- 25433912 TI - Obtaining optic disc center and pixel region by automatic thresholding methods on morphologically processed fundus images. AB - Development of automatic retinal disease diagnosis systems based on retinal image computer analysis can provide remarkably quicker screening programs for early detection. Such systems are mainly focused on the detection of the earliest ophthalmic signs of illness and require previous identification of fundal landmark features such as optic disc (OD), fovea or blood vessels. A methodology for accurate center-position location and OD retinal region segmentation on digital fundus images is presented in this paper. The methodology performs a set of iterative opening-closing morphological operations on the original retinography intensity channel to produce a bright region-enhanced image. Taking blood vessel confluence at the OD into account, a 2-step automatic thresholding procedure is then applied to obtain a reduced region of interest, where the center and the OD pixel region are finally obtained by performing the circular Hough transform on a set of OD boundary candidates generated through the application of the Prewitt edge detector. The methodology was evaluated on 1200 and 1748 fundus images from the publicly available MESSIDOR and MESSIDOR-2 databases, acquired from diabetic patients and thus being clinical cases of interest within the framework of automated diagnosis of retinal diseases associated to diabetes mellitus. This methodology proved highly accurate in OD center location: average Euclidean distance between the methodology-provided and actual OD-center position was 6.08, 9.22 and 9.72 pixels for retinas of 910, 1380 and 1455 pixels in size, respectively. On the other hand, OD segmentation evaluation was performed in terms of Jaccard and Dice coefficients, as well as the mean average distance between estimated and actual OD boundaries. Comparison with the results reported by other reviewed OD segmentation methodologies shows our proposal renders better overall performance. Its effectiveness and robustness make this proposed automated OD location and segmentation method a suitable tool to be integrated into a complete prescreening system for early diagnosis of retinal diseases. PMID- 25433913 TI - The genomic diversity of prostate cancer: our Achilles heel explored. PMID- 25433916 TI - Parkinson's disease in GTP cyclohydrolase 1 mutation carriers. PMID- 25433914 TI - Vision and vision-related outcome measures in multiple sclerosis. AB - Visual impairment is a key manifestation of multiple sclerosis. Acute optic neuritis is a common, often presenting manifestation, but visual deficits and structural loss of retinal axonal and neuronal integrity can occur even without a history of optic neuritis. Interest in vision in multiple sclerosis is growing, partially in response to the development of sensitive visual function tests, structural markers such as optical coherence tomography and magnetic resonance imaging, and quality of life measures that give clinical meaning to the structure function correlations that are unique to the afferent visual pathway. Abnormal eye movements also are common in multiple sclerosis, but quantitative assessment methods that can be applied in practice and clinical trials are not readily available. We summarize here a comprehensive literature search and the discussion at a recent international meeting of investigators involved in the development and study of visual outcomes in multiple sclerosis, which had, as its overriding goals, to review the state of the field and identify areas for future research. We review data and principles to help us understand the importance of vision as a model for outcomes assessment in clinical practice and therapeutic trials in multiple sclerosis. PMID- 25433915 TI - Motion area V5/MT+ response to global motion in the absence of V1 resembles early visual cortex. AB - Motion area V5/MT+ shows a variety of characteristic visual responses, often linked to perception, which are heavily influenced by its rich connectivity with the primary visual cortex (V1). This human motion area also receives a number of inputs from other visual regions, including direct subcortical connections and callosal connections with the contralateral hemisphere. Little is currently known about such alternative inputs to V5/MT+ and how they may drive and influence its activity. Using functional magnetic resonance imaging, the response of human V5/MT+ to increasing the proportion of coherent motion was measured in seven patients with unilateral V1 damage acquired during adulthood, and a group of healthy age-matched controls. When V1 was damaged, the typical V5/MT+ response to increasing coherence was lost. Rather, V5/MT+ in patients showed a negative trend with coherence that was similar to coherence-related activity in V1 of healthy control subjects. This shift to a response-pattern more typical of early visual cortex suggests that in the absence of V1, V5/MT+ activity may be shaped by similar direct subcortical input. This is likely to reflect intact residual pathways rather than a change in connectivity, and has important implications for blindsight function. It also confirms predictions that V1 is critically involved in normal V5/MT+ global motion processing, consistent with a convergent model of V1 input to V5/MT+. Historically, most attempts to model cortical visual responses do not consider the contribution of direct subcortical inputs that may bypass striate cortex, such as input to V5/MT+. We have shown that the signal change driven by these non-striate pathways can be measured, and suggest that models of the intact visual system may benefit from considering their contribution. PMID- 25433917 TI - High lifetime inbreeding depression counteracts the reproductive assurance benefit of selfing in a mass-flowering shrub. AB - BACKGROUND: Decreases in mate and/or pollinator availability would be expected to affect the selective pressure on plant mating systems. An increase in self fertilization may evolve to compensate for the negative effects of pollination failure. However, the benefit of selfing in variable pollination environments depends on the relative fitnesses of selfed and outcrossed progeny. We investigated the potential for selfing to provide reproductive assurance over the lifetime of a long-lived perennial species and its variation between plant patches of various sizes. Patch size is likely to affect mate and pollinator availabilities, thereby affecting pollination success and the rate of selfing. We estimated fruit and seed set, reproductive assurance, self-compatibility, the multilocus patch selfing rate and lifetime inbreeding depression in natural patches of Rhododendron ferrugineum (Ericaceae), a mass-flowering species characterized by considerable patch size variation (as estimated by the total number of inflorescences). RESULTS: Open seed set declined linearly with increasing patch size, whereas pollinator-mediated seed set (emasculated flowers) was not significantly affected. Progeny array analysis indicated that the selfing rate declined with increasing patch size, consistent with greater reproductive assurance in small sparse patches than in large, dense patches. However, fruit set and adult fitness decreased with decreasing patch size, with an estimated mean lifetime inbreeding depression of 0.9 (obtained by comparing F values in adults and progenies). CONCLUSIONS: Lifetime inbreeding depression strongly counteracts the advantage of reproductive assurance due to selfing in this long lived species. The poor fitness of selfed offspring should counteract any evolution towards selfing, despite its potential to alleviate the negative consequences of pollen limitation. This study highlights the need to estimate lifetime inbreeding depression, together with mating system and pollination parameters, if we are to understand the actual benefit of selfing and avoid the overestimation of reproductive assurance. PMID- 25433918 TI - Methotrexate revisited: considerations for subcutaneous administration in RA. AB - Rheumatoid arthritis (RA) is associated with significant disability, morbidity, early mortality, and substantial financial burden. Despite newer antirheumatics, methotrexate (MTX) remains the most widely used disease-modifying antirheumatic drug. Subcutaneous (SC) MTX provides consistent, reliable delivery, with improved absorption and enhanced polyglutamization leading to increased response rates and fewer gastrointestinal side effects than oral MTX. Optimizing MTX with use of the SC formulation can improve outcomes and may delay or negate the need for costly biologics. PMID- 25433919 TI - Pro-apoptotic gene regulation and its activation by gamma-irradiation in the Caribbean fruit fly, Anastrepha suspensa. AB - Transcriptional activation of pro-apoptotic genes in response to cytotoxic stimuli is a conserved feature of the cell death pathway in metazoans. However, understanding the extent of this conservation in insects has been limited by the lack of known pro-apoptotic genes in non-drosophilids. Recently, we described the pro-apoptotic genes, Asrpr and Ashid, from the tephritid, Anastrepha suspensa, that now allow us to explore the conservation of pro-apoptotic gene regulation between a tephritid and drosophilids. In this study, we determined the developmental profiles of Asrpr and Ashid transcripts during embryogenesis and in embryos exposed to gamma-irradiation. Transcript levels of both genes determined by qRT-PCR were low throughout embryogenesis, with strong Ashid expression occurring during early to mid-embryogenesis and Asrpr expression peaking in late embryogenesis. This correlated to acridine orange stained apoptotic cells first appearing at 17 h and increasing over time. However, when irradiated at 16 h post oviposition embryos exhibited significant levels of apoptosis consistent with strong induction of Asrpr and Ashid transcript levels by gamma-irradiation in young embryos <24 h post-oviposition. Furthermore, embryos irradiated <24 h post oviposition failed to hatch, those irradiated between 24 and 32 h had increased hatching rates, but between 48 and 72 h irradiation had no effect on egg hatching. This indicates a transition of embryos from an irradiation-sensitive to irradiation-resistance stage between 24 and 48 h. Throughout post-embryonic development, the two pro-apoptotic genes share similar patterns of up-regulated gene expression, which correlate to ecdysone-induced developmental events, especially during metamorphosis. Together these results provide the first direct evidence for a conserved molecular mechanism of the programmed cell death pathway in insects. PMID- 25433920 TI - Evidence for organic cation transporter-mediated metformin transport and 5' adenosine monophosphate-activated protein kinase activation in rat skeletal muscles. AB - OBJECTIVE: 5'-Adenosine monophosphate-activated protein kinase (AMPK) is a key molecule of metabolic enhancement in skeletal muscle. We investigated whether metformin (MET) acts directly on skeletal muscle, is transported into skeletal muscle via organic cation transporters (OCTs), and activates AMPK. MATERIALS/METHODS: Isolated rat epitrochlearis and soleus muscles were incubated in vitro either in the absence or in the presence of MET. The activation status of AMPK, the intracellular energy status, and glucose and MET transport activity were then evaluated. The effect of cimetidine, which is an OCT inhibitor, on AMPK activation was also examined. RESULTS: MET (10 mmol/L, >=60 min) increased the phosphorylation of Thr172 at the catalytic alpha subunit of AMPK in both muscles. AMPK activity assays showed that both AMPKalpha1 and AMPKalpha2 activity increased significantly. The AMPK activation was associated with energy deprivation, which was estimated from the ATP, phosphocreatine (PCr), and glycogen content, and with increased rates of 3-O-methyl-D-glucose (3MG) transport. MET did not change the basal phosphorylation status of insulin receptor signaling molecules. MET was transported into the cytoplasm in a time dependent manner, and cimetidine suppressed MET-induced AMPK phosphorylation and 3MG transport. CONCLUSION: These results suggest that MET is acutely transported into skeletal muscle by OCTs, and stimulates AMPKalpha1 and alpha2 activity in both fast- and slow-twitch muscle types, at least in part by reducing the energy state. PMID- 25433922 TI - Is it worth performing suture of the cauda equina roots after traumatic penetrating lumbar injury in a combat support Hospital? PMID- 25433921 TI - Fibromyalgia symptoms and cirrhosis. AB - BACKGROUND: An association between fibromyalgia and hepatitis C virus (HCV) has been previously described. However, the relationship between nonalcoholic steatohepatitis (NASH) and fibromyalgia symptoms has not been assessed, though they share several risk factors. AIM: We aimed to assess the factors associated with fibromyalgia symptoms across etiologies of liver disease. METHODS: Patients with cirrhosis due to HCV, NASH, or alcohol were recruited from an outpatient hepatology clinic and administered the Hospital Anxiety and Depression Score, Pittsburgh Sleep Quality Index, and the modified 2010 American College of Rheumatology Diagnostic Criteria for Fibromyalgia. Serum inflammatory markers were measured with standard luminex assays. RESULTS: Of 193 participants, 53 (27 %) met criteria for fibromyalgia. Fibromyalgia symptoms were significantly associated with etiology of liver disease (HCV: 35 %, NASH: 30 %, alcohol-related liver disease: 12 %, p < 0.01). Using logistic regression, mood symptoms (OR 1.14, 95 % CI 1.06, 1.22), sleep disturbance (OR 1.32, 95 % CI 1.16, 1.52), and etiology of liver disease (NASH vs. HCV not different, alcohol vs. HCV OR 0.19, 95 % CI 0.05, 0.63) were associated with fibromyalgia symptoms. If abdominal pain was included in the model, etiology became nonsignificant, indicating that it may be central sensitization due to abdominal pain in patients with chronic liver disease that explains fibromyalgia symptoms rather than the etiology of liver disease or inflammation. CONCLUSIONS: Fibromyalgia symptoms were significantly associated with HCV and NASH cirrhosis and with psychiatric symptoms. Future work should focus on the underlying pathophysiology and management of widespread pain in patients with cirrhosis. PMID- 25433923 TI - Response to Mavridis' area as a target for either selective or combined accumbens/ventral internal capsule deep brain stimulation. PMID- 25433924 TI - [Is a checkup required for general itching?]. PMID- 25433925 TI - [Incidence and characteristics of calciphylaxis in Martinique (2006-2012)]. AB - BACKGROUND: Calciphylaxis is a rare and severe disease with an annual incidence of around 1 % in dialysis patients. The main study aim was to determine its incidence in Martinique, where there is a significant population of patients on dialysis. PATIENTS AND METHODS: All patients diagnosed with calciphylaxis between 2006 and 2012 and living in Martinique were included, retrospectively. Social, demographic, biological, anatomic, pathological, histological and outcome data were analysed. RESULTS: Fifteen patients were included (8 women, 7 men). The incidence of calciphylaxis in this population was about 4.62/1,000,000 inhabitants per year. All patients presented very painful skin ulcerations and necrosis, chiefly on the lower extremities in 53.3 % of cases. All patients were on haemodialysis and two had undergone renal transplantation. Fourteen of the 15 patients were presenting secondary hyperparathyroidism, 12 had hypertension, 9 peripheral arterial disease, 8 obesity and 8 diabetes mellitus. Raised calcium and phosphorus were noted in 8 patients, with hypoalbuminaemia in 9 patients. Treatment with sodium thiosulfate was given for 8 patients, and was beneficial for all after a mean duration of 3.4 months. After 6 months of follow-up, 8 of the 15 patients were cured, 1 showed improvement and 6 had died. CONCLUSION: To our knowledge, this is the first study to examine the incidence of calciphylaxis in the general population. The relatively large number of patients could be accounted for by the high number of comorbidities in end-stage renal disease patients in Martinique, including obesity, diabetes, hypertension and arteritis. Treatment with sodium thiosulfate was beneficial for 8 patients. PMID- 25433926 TI - [Two new trichoscopic signs in alopecic and aseptic nodules of the scalp: "Eastern pancake sign" and comedo-like structures]. AB - BACKGROUND: The purpose of this study is to describe two new trichoscopic signs, "Eastern pancake sign" and "comedo-like structures", not previously reported to our knowledge and seen in 5 patients with alopecic and aseptic nodules of scalp (AANS). PATIENTS AND METHODS: We report on 5 patients presenting AANS. Demographic and ethnic characteristics, disease duration, clinical description, treatment and evolution were noted. Trichoscopy was performed for all patients. RESULTS: In all cases of NAAS, trichoscopy revealed 2 signs: "Eastern pancake sign" resulting in heterogeneous dilated follicular orifices without trichoscopic signs of alopecia areata, and "comedo-like structures" resembling comedones. DISCUSSION: To our knowledge, there have been no previous reports in the literature of the 2 new trichoscopic signs of AANS described herein: "Eastern pancake sign" and "comedo-like structures". The trichoscopic feature of comedo like structures suggests the potential role of follicular occlusion in this disease. We consider that follicular occlusion may be a triggering factor in AANS. PMID- 25433927 TI - [Acute localized exanthematous pustulosis on the face: 6 cases in Tunisia]. AB - BACKGROUND: Acute localized exanthematous pustulosis (ALEP) is a rare and localized variant of acute generalized exanthematous pustulosis (AGEP). Only 15 cases of ALEP have been reported to date in the literature, with all cases following drug administration. We report 6 paediatric cases of ALEP occurring in springtime, with no associated drug administration in any case. PATIENTS AND METHODS: Over the last three years (2011, 2012 and 2013), we observed 6 cases of ALEP in 6 Tunisian children aged between 9 and 14 years. All cases were observed during the spring months. Diagnosis of ALEP was based in all cases on the EuroSCAR criteria and on the definition of ALEP proposed by Prange et al. A drug related aetiology was ruled out in all cases, with exposure to a specific planned plant (Thapsia garganica) being retained as an aetiological factor in one case. DISCUSSION: Drug administration is the most frequent though not the sole cause of ALEP. The seasonal nature of this dermatosis may suggest other causes, mainly viral infection, plant contact or airborne allergens. PMID- 25433928 TI - [Two cases of severe pruritus revealing Hodgkin's disease in children]. AB - BACKGROUND: Pruritus in children is a frequent reason for consultation, most often related to a common dermatosis. Where dermatological investigation fails to reveal a dermatological cause, a general cause may be suspected. We report three cases of pruritus revealing Hodgkin's lymphoma in children. PATIENTS AND METHODS: Case 1: a 14-year-old girl presented pruritus with diffuse scratching lesions present for 6 months, associated with right cervical lymph nodes occurring after the onset of pruritus. Tomodensitometry revealed involvement of the supra- and sub-diaphragmatic lymph nodes as well as pulmonary involvement. Lymph node biopsy confirmed nodular sclerosing Hodgkin's lymphoma. Case 2: a 14-year-old boy was hospitalized for suspected psychogenic pruritus. He presented intense itching, predominantly in the lower extremities and at night, occurring over the previous 6 months as well as night sweats. Examination showed that the patient had lost 5kg in 1 month and had a low-grade fever of 38 degrees C; he presented linear striated scratching lesions on both legs. Cervical and inguinal lymphadenopathy was seen. The chest scan also revealed supra-diaphragmatic adenomegalies. The biopsy confirmed Hodgkin's lymphoma. DISCUSSION: Systemic causes of pruritus in children are poorly described in the literature. In these two cases, pruritus allowed a diagnosis of Hodgkin's lymphoma to be made, emphasizing the important role of dermatologists in the early diagnosis of haematological malignancy. PMID- 25433929 TI - [Alopecia reconstruction by expansion after a scalp burn injury caused by Taser((r)): a case report]. AB - BACKGROUND: Scarring alopecia resulting from burns may be difficult to treat and involves various plastic surgery techniques such as expanded scalp flaps. OBSERVATION: Herein, we report the case of a 19-year-old male patient who suffered burning of the scalp with scarring alopecia following an attack with a Taser((r)) electrical gun. Given the extent and site of alopecia, we decided to create a prosthesis by means of scalp expansion. The cosmetic result was satisfactory. DISCUSSION: Several scalp reconstruction techniques have been described for scarring alopecia, with the most widely used being expansion, scalp flaps, repeated excision and hair implants. CONCLUSION: The present case suggests that scalp expansion offers an effective method for the reconstruction of scarring alopecia following burns with a Taser((r)) device. PMID- 25433930 TI - [Urticarial vasculitis associated with essential thrombocythaemia progressing to myelofibrosis]. AB - BACKGROUND: Urticarial vasculitis (UV) is a rare form of leukocytoclastic vasculitis in which skin lesions resemble urticaria. UV comprises hypocomplementemic and normocomplementemic subtypes. To date, only 4 cases of UV associated with myeloproliferative disorders have been described, including 3 cases with essential thrombocythaemia (ET) and one case with polycythaemia vera. PATIENTS AND METHODS: We describe the case of a 59-year-old male patient with JAK2-positive TE and secondary myelofibrosis and who developed multiple urticarial papules persisting for more than 24hours. Skin biopsy showed perivascular neutrophilic infiltrate with margination of neutrophils in the lumen of vessels and some leukocytoclastic patterns, and with red cell extravasation consistent with UV. Treatment with ruxolitinib (a JAK2 inhibitor) induced transient and partial control of the haematological symptoms but did not prevent UV flare. Prednisolone 20mg once daily was added, with good clinical response. DISCUSSION AND CONCLUSION: To our knowledge, this is the fourth reported case of UV associated with ET and the first case associated with MF. PMID- 25433932 TI - [Chickenpox in adults in Conakry, Guinea: a retrospective monocentric study of 42 cases]. PMID- 25433931 TI - [T-cell prolymphocytic leukemia: potential diagnostic pitfalls]. AB - BACKGROUND: Sezary syndrome (SS) presents clinically as erythroderma, which may be pigmented, and pruritic, associated with peripheral lymphadenopathies. Erythroderma may also occur in a broad range of reactive and malignant conditions including T-cell prolymphocytic leukemia (T-PLL). We report a case initially diagnosed as SS but ultimately diagnosed as T-PLL based upon skin involvement. CASE REPORT: A 70-year-old man was referred by his hematologist for management of SS. Physical examination revealed lymphadenopathies and mild diffuse erythema without infiltration. His WBC count was elevated at 8.3 G/L. A peripheral blood smear showed Sezary-like cells. Flow cytometry of peripheral blood revealed prolymphocytic T-cells staining positively for CD2, CD3, CD4 and CD7. Cytogenetic studies showed chromosomal abnormalities in terms of number and structure with missing chromosomes 6 and13, as well as deletion of chromosome 17. Finally, a diagnosis of T-PLL was made. Pentostatin was initiated pending treatment with alemtuzumab, but the patient's overall condition deteriorated rapidly and he died 10 days later. DISCUSSION: Diagnosis of LPLT is based upon a number of factors. In the case presented herein, the clinically atypical nature of the skin lesions prompted the dermatologist to review the diagnosis. The morphology of the circulating T-lymphocytes and their immunologic and phenotypic characteristics finally ruled out the diagnosis of Sezary syndrome, while their association with compatible cytogenetic anomalies enabled a diagnosis of prolymphocytic leukemia to be made instead. CONCLUSION: Prolymphocytic leukemia involves complex differential diagnosis with regard to Sezary syndrome, posing potential pitfalls for hematologists and dermatologists. PMID- 25433933 TI - [In vivo confocal microscopy for the diagnosis of lysosomal storage diseases]. PMID- 25433934 TI - [Atypical fibroxanthoma]. PMID- 25433935 TI - [Saying no]. PMID- 25433936 TI - [Retronychia]. PMID- 25433937 TI - [Allergic patch test and contact dermatitis by in vivo reflectance confocal microscopy]. PMID- 25433938 TI - [Early aggressive systemic inflammatory vascular diseases: mutations in adenosine desaminase 2 and interferonopathies]. PMID- 25433939 TI - [Granuloma annulare: an atypical site]. PMID- 25433940 TI - [Yellowish papules revealing a homozygous familial hypercholesterolemia]. PMID- 25433941 TI - [Adverse effects of Sutent((r)): pseudoporphyria and scrotal necrosis]. PMID- 25433942 TI - A design of a robust discrete-time controller. AB - In this paper, we proposed a robust discrete-time controller. This control system, which is derived from the idea of the normalized plant, does not include plant parameters. Thus, we obtain a control system independent of plant parameters and that has the same structure as a conventional optimal servo control system. Simulation and experimental results show that the proposed method is fairly robust to plant parameter variations and external disturbances. PMID- 25433943 TI - Detection of decoupled input/output pairs in multivariable systems. AB - A method is proposed to detect if there is no coupling between an input and an output in systems operating in open-loop, that is, without a supervisory controller. The proposed technique is applicable to multiple input multiple output (MIMO) systems, whose intent is to detect no-model input/output (IO) combinations in a transfer matrix. Traditional approaches for selecting IO pairs are usually performed after the plant model is identified. The presented approach is applied during the pre-identification stage and is based on IO cross correlation, signal filtering and fuzzy logic analysis. A case study involving the identification of a 7*6 simulated Fluid Catalytic Cracking (FCC) is discussed, as well as an influence analysis of detecting no-model IO pairs in the identification process and in the performance index of a Model Predictive Controller (MPC) applied to a 2*2 simulated distillation column. Finally, the method is tested with a real dataset obtained from an FCC unit of a petrol refinery. PMID- 25433944 TI - Correlation and malignant transformation of MSCs with the overexpression of SIL R/GP130 under the tumor microenvironment. AB - Mesenchymal stem cells (MSCs) can differentiate into chondrogenesis, osteogenesis, myocardium and nerve in specific conditions, but it may undergo malignant transformation when cultivated with tumor cells. This research was to provide preliminary experimental basis for the safe application of MSCs and seek for drugs to avoid the malignant transformation of MSCs in the treatment of tumor. Accordingly, four groups including experimental group, positive control group, negative contrast group and blank group were set. Experimental group was the co-culture group of MSCs and C6 glioma cells. Positive control group was the regular culture group of C6 glioma cells. Negative control group was the co culture group of MSCs and astrocyte. And blank group was the regular culture group of MSCs. The results showed the expression of IL-6, and IL-6R significantly increased in the group of co-culture with C6; the proliferation situation of MSCs was obviously strengthened; MSCs performed a high expression of GP130, STAT-3, CyclinD1 and BCL-xl, which had statistical significance compared with the contrast group. It can be concluded that the malignant expression of MSCs was related to the overexpression and activation of SIL-R/GP130; and the excessive expression and activation of SIL-6R and GP130 might be one of the important reasons for malignant transformation of MSCs under the microenvironment. PMID- 25433945 TI - Knockdown of CDC2 expression inhibits proliferation, enhances apoptosis, and increases chemosensitivity to temozolomide in glioblastoma cells. AB - Cell division cycle 2 (CDC2) is always overexpressed in malignant tumor cells and is correlated with chemosensitivity, but it is unclear whether CDC2 overexpression contributes to the chemoresistance potential of glioma cells. The aim of study was to determine the relationship of CDC2 expression with the prognosis and chemoresistance of glioblastoma. In this study, the glioblastoma U87 and U251 cell lines were steadily transfected with a lentivirus vector expressing a short hairpin RNA-targeting CDC2. Expression of CDC2 was evaluated in glioblastoma and cell lines by immunohistochemistry and Western blot analysis. The relationship between CDC2 expression and clinicopathological characteristics was analyzed. Using RNA interference, the effects of CDC2 on chemosensitivity to temozolomide (TMZ) were investigated in U87 and U251 cell lines in vitro. Combined CDC2 knockdown and TMZ treatment inhibited cell proliferation and induced apoptosis in vitro more effectively than either treatment alone. qRT-PCR and Western blot analysis showed that cells underexpressing CDC2 revealed lower expression of the anti-apoptotic protein B cell lymphoma-2 and increased expression of the apoptosis effector caspase-3 compared to U87 and U251 cells transfected with a control vector. Furthermore, expression levels of CDC2 in U87 and U251 cells were related to the IC50 of the antitumor drug TMZ. Knockdown of CDC2 expression was associated with decreased expression of Ral-binding protein 1, a classical chemotherapy drugs transporter. These results indicate that the ability to suppress the malignant phenotype by down-regulating CDC2 expression may provide a new gene therapy approach for overcoming CDC2-associated chemoresistance in patients with malignant glioma. PMID- 25433946 TI - Terahertz time-domain spectroscopy combined with fuzzy rule-building expert system and fuzzy optimal associative memory applied to diagnosis of cervical carcinoma. AB - Combined with terahertz time-domain spectroscopy, the feasibility of fast and reliable diagnosis of cervical carcinoma by a fuzzy rule-building expert system (FuRES) and a fuzzy optimal associative memory (FOAM) had been studied. The terahertz spectra of 52 specimens of cervix were collected in the work. The original data of samples were preprocessed by Savitzky-Golay first derivative (chiderivative), principal component orthogonal signal correction (PC-OSC) and emphatic orthogonal signal correction to improve the performance of FuRES and FOAM models. The effect of the different pretreating methods to improve prediction accuracy was evaluated. The FuRES and FOAM models were validated using bootstrapped Latin-partition method. The obtained results showed that the FuRES and FOAM model optimized with the combination S-G first derivative and PC-OSC method had the better predictive ability with classification rates of 92.9 +/- 0.4 and 92.5 +/- 0.4 %, respectively. The proposed procedure proved that terahertz spectroscopy combined with fuzzy classifiers could supply a technology which has potential for diagnosis of cancerous tissue. PMID- 25433947 TI - Expressions of fatty acid synthase and HER2 are correlated with poor prognosis of ovarian cancer. AB - The present study was designed to explore the cross talk between fatty acid synthase (FASN) and HER2 (ErbB2) in ovarian cancer. A total of 60 ovarian cancer patients and 15 normal ovarian tissues were enrolled. Tissue array was conducted by using a tissue microarray instrument. Immunohistochemistry was performed to quantify the expressions of HER2 and FASN. The FASN was detected to be distributed in the cell cytoplasm and was significantly correlated with cancer grade (p = 0.000) and FIGO staging (p = 0.000). Patients with FASN overexpression in ovarian cancer tend to have a worse overall survival rate (p = 0.000). HER2 was also stained to be distributed in the cell cytoplasm associated with higher expression in high-grade cancer. It was also disclosed that FASN expression level is not correlated with HER2 status in ovarian cancer. These results for the first time indicated that a cross talk in FASN and HER2 expressions might be associated with prognosis in malignant ovarian cancer. PMID- 25433948 TI - Five COX-2 gene polymorphisms and risk of breast cancer: an updated meta-analysis based on 19 case-control studies. AB - The correlationship between COX-2 gene polymorphisms and breast cancer has been wildly studied, but the results remain controversial. Hence, the present meta analysis aimed to investigate the association between COX-2 SNPs (rs5275, rs20417, rs689466, rs5277, rs2206593) and risk of breast cancer. Data were collected from PubMed, Embase and China National Knowledge Infrastructure. Summary odds ratio (OR) with 95 % confidence interval (CI) was applied to assess the relationship. Heterogeneity test, sensitivity analysis and publication bias test were also performed. There were 17 articles that contained 19 studies in this research. Fourteen case-control studies with 15,007 breast cancer cases and 20,005 controls were concerning rs5275 polymorphism, and 8 case-control studies with 10,216 cases and 12,839 controls were about rs20417 polymorphism. Other three polymorphisms (rs689466, rs2206593, rs5277) were studied in 5, 3 and 3 studies, respectively. COX-2-rs20417 CC genotype was significantly associated with increased risk of breast cancer when comparing to G allele [ORs were 1.231 (1.050-1.444) for CC vs. GG, P = 0.01, 1.223 (1.045-1.432) for CC vs. G carrier, P = 0.01]. Furthermore, the results of the subgroup analysis by ethnicity suggested that C allele significantly contributed to the risk of breast cancer for Asians [1.459 (1.182-1.802) for GC vs. GG, 1.472 (1.201-1.805) for C carrier vs. GG]. However, no association was found for rs5275, rs689466, rs5277 and rs2206593 in all comparison modes. This meta-analysis indicated that the COX-2 rs20417 polymorphism contributed to genetic susceptibility of breast cancer. In contrast, COX-2 rs5275, rs689466, rs2206593 and rs5277 polymorphisms might be not associated with the risk of breast cancer. PMID- 25433949 TI - Polymorphism of DNA methyltransferase 3B -149C/T and cancer risk: a meta analysis. AB - Published data on the association between DNA methyltransferase (DNMT) 3B -149C/T polymorphism and cancer risk remain inconclusive. To derive a more precise estimation for this association, we performed a meta-analysis of 5,903 cancer cases and 8,132 controls from 22 published case-control studies. We used odds ratios (ORs) with 95 % confidence intervals (CIs) to assess the strength of the association. Our meta-analysis suggested that DNMT3B -149C/T polymorphism was associated with the risk of head and neck cancer under heterozygote comparison (OR 0.73, 95 % CI 0.59-0.90) and dominant model (OR 1.75, 95 % CI 0.62-0.92), although no evidence of association between DNMT3B -149C/T polymorphism and cancer risk was observed as we compared in the pooled analyses (homozygote comparison: OR 0.96, 95 % CI 0.86-1.09; heterozygote comparison: OR 1.07, 95 % CI 0.86-0.32; dominant model: OR 1.03, 95 % CI 0.85-1.25; recessive model: OR 0.93, 95 % CI 0.8-1.08). More studies are needed to detect DNMT3B -149C/T polymorphism and its association with cancer in different ethnic populations incorporated with environment exposures in the susceptibility of different kinds of cancer. PMID- 25433950 TI - CNS metastases in breast cancer patients: prognostic implications of tumor subtype. AB - Development of brain metastases (BM) in breast cancer leads to limited survival. The therapeutical options are limited. There are less data about the risk factors and prognostic importance in BM. Objective is to investigate predictors of central nervous system metastases and outcome after diagnosis of BM according to tumor subtype. Based on medical records, 80 consecutive patients with primary non metastatic operable breast cancer, treated at Department of Gynecology, University of Tubingen, and who developed BM during follow-up, were retrospectively analyzed. Clinicopathological parameters and their prognostic impact were evaluated. A node involvement (40 %), ER/PR negative (53.75 vs. 61.25 %), triple negative (28.75 %) and HER2+ status (40 %) were associated with BM. BM in breast cancer patients lead to a shortened survival. In cerebral metastatic breast cancer patients with HER2-negative and triple-negative, patients had significant shorter survival after detection of BM compared with HER2-positive and non-triple-negative patients (p = 0.001; p = 0.03). Risk of BM varies significantly by subtype. Understanding the biology of metastases can help categorize patients into prognostically useful categories and tailor treatment regimens for individual patients. Prospective clinical trials would be required for evaluating the potential role of screening for asymptomatic BM and of treatment of triple-negative patients. PMID- 25433951 TI - Clinicopathological analysis of colorectal carcinoid tumors and patient outcomes. AB - BACKGROUND: Colorectal carcinoid tumors are often described as being low-grade malignant. The objective of the current study was to address the clinicopathological features and outcomes of patients with colorectal carcinoid tumors. METHODS: A total of 63 patients with colorectal carcinoid tumors were identified and evaluated using surgical pathology files and medical records between January 2000 and June 2012 at the Veterans General Hospital, Taipei, Taiwan. RESULTS: The median age of the 63 patients was 57.0 years; 38 (60.3%) were male and 25 (39.7%) female. The rectum was the most common tumor site (90.5%). Tumor size was 10.8+/-7.4 mm, ranging from 2 to 50 mm in diameter. There were 40 patients (63.5%) who received endoscopic treatment for a tumor size of 7.7+/-4.0 mm, 15 (23.8%) who underwent transanal excision for a mean size of 9.2+/-4.5 mm and eight (12.7%) who underwent radical surgical resection (mean size: 29.5+/-13.0 mm). Lymph node metastasis was significantly associated with tumor size. Totally distant metastases (liver) were demonstrated in four (6.3%), patients with mean tumor size of 31.3+/-9.4 mm (20 to 50 mm). The extent of the disease was associated with survival and the five-year overall survival rate was 92.1%. CONCLUSIONS: With widespread colorectal cancer screening, heightened awareness and improved diagnostic modalities, the incidence of colorectal carcinoid tumors will continue to increase. We demonstrated that small-sized colorectal carcinoid tumors and those localized in the mucosa or submucosa may be safely and effectively removed via endoscopic or transanal local excision. PMID- 25433953 TI - Complex interventions reduce use of urgent healthcare in adults with asthma: systematic review with meta-regression. AB - INTRODUCTION: Asthma accounts for considerable healthcare expenditure, a large proportion of which is attributable to use of expensive urgent healthcare. This review examines the characteristics of complex interventions that reduce urgent healthcare use in adults with asthma. METHOD: Electronic searches of MEDLINE, EMBASE, PSYCINFO, CINAHL, the British Nursing Library and the Cochrane library, from inception to January 2013 were conducted. Studies were eligible for inclusion if they: i) included adults with asthma ii) assessed the efficacy of a complex intervention using randomised controlled trial design, and iii) included a measure of urgent healthcare utilisation at follow-up. Data on participants recruited, methods, characteristics of complex interventions and the effects of the intervention on urgent healthcare use were extracted. RESULTS: 33 independent studies were identified resulting in 39 comparisons altogether. Pooled effects indicated that interventions were associated with a reduction in urgent healthcare use (OR = 0.79, 95% CI = 0.67, 0.94). When study effects were grouped according to the components of the interventions used, significant effects were seen for interventions that included general education (OR = 0.77, 95% CI = 0.64, 0.91), skills training (OR = 0.64, 95% CI = 0.48, 0.86) and relapse prevention (OR = 0.75, 95% CI = 0.57, 0.98). In multivariate meta-regression analysis, only skills training remained significant. CONCLUSIONS: Complex interventions reduced the use of urgent healthcare in adults with asthma by 21%. Those complex interventions including skills training, education and relapse prevention may be particularly effective in reducing the use of urgent healthcare in adults with asthma. PMID- 25433952 TI - Pulmonary morbidity improves after autologous stem cell transplantation in POEMS syndrome. AB - BACKGROUND: POEMS syndrome is a plasma cell disorder manifested by Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes. Pulmonary morbidity includes restriction, decreased diffusing capacity for carbon monoxide (DLCO), respiratory muscle weakness, abnormal imaging, and pulmonary hypertension. Autologous peripheral blood stem cell transplantation (aPBSCT) is an effective treatment for POEMS syndrome. It is unknown if aPBSCT improves pulmonary morbidity. We hypothesize pulmonary morbidity will improve following aPBSCT. METHODS: Retrospective cohort study of POEMS syndrome aPBSCT recipients from 2000 to 2010. Demographic, pulmonary function test (PFT), echocardiogram, cytokine, and imaging data at baseline and after aPBSCT were abstracted. Pre- and post-transplant data were compared using Wilcoxon signed rank and McNemar's tests. RESULTS: 53 patients met criteria. Median improvements in forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and total lung capacity (TLC) after transplant were 180, 315 and 350 ml respectively (median follow-up of 1.1 years). DLCO, maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) improved by a median of 11, 12.5 and 10% predicted respectively. RVSP and chest imaging also improved. Vascular endothelial growth factor and IL-6 decreased by a median of 334 and 2 pg/ml respectively. All comparisons were statistically significant. Longitudinal data demonstrated stability in FEV1, MEP, and TLC and continued improvement in FVC, MIP and DLCO on subsequent PFTs (median follow-up 26.5 months). CONCLUSION: Patients with POEMS syndrome treated with aPBSCT have significant improvement in PFTs, respiratory muscle strength, imaging, and post-transplant IL-6. The improvement in PFTs persists during long-term follow-up. PMID- 25433954 TI - Monotherapy with indacaterol once daily reduces the rate of exacerbations in patients with moderate-to-severe COPD: Post-hoc pooled analysis of 6 months data from three large phase III trials. AB - BACKGROUND: In patients with COPD, exacerbations are associated with poor quality of life and may shorten survival. Prevention of exacerbations is, therefore, a key objective in COPD management. Indacaterol, a once-daily ultra-long-acting beta2-agonist, has been shown to reduce exacerbations in various studies. This pooled analysis evaluated the effect of indacaterol on exacerbations versus placebo. METHODS: Six-month data were pooled from three randomized, double-blind, and placebo-controlled studies: indacaterol 300 MUg versus placebo (1 year); indacaterol 150 MUg and 300 MUg versus placebo (6 months); and indacaterol 150 MUg versus placebo (6 months). All treatments were administered once daily. Data from other treatment groups were excluded. All three studies enrolled patients aged >=40 years with moderate-to-severe COPD and smoking history >=20 pack-years. Time to exacerbation and exacerbation rate were analyzed. RESULTS: Overall, the pooled data set included 2716 patients (indacaterol 150 MUg [n = 746], indacaterol 300 MUg [n = 819], placebo [n = 1151]). Both indacaterol doses 150 and 300 MUg significantly reduced the COPD exacerbation rates compared with placebo (Rate ratios, RR [95% Confidence Interval, CI]: 0.69 [0.55-0.87], 0.71 [95% CI: 0.57-0.88] respectively; both p = 0.002). Over 6 months, indacaterol 150 and 300 MUg also significantly prolonged the time to first moderate-to-severe exacerbation versus placebo (Hazard ratios, HR [95% CI]: 0.74: [0.59-0.93], p = 0.009; 0.73 [0.59-0.90], p = 0.004, respectively). At months 3 and 6, clinically relevant improvements in lung function versus placebo were observed with indacaterol 150 MUg (Least squares mean treatment differences: Month 3 = 170 mL; Month 6 = 160 mL) and 300 MUg (170 mL at both time-points; all p < 0.001). CONCLUSIONS: In this pooled analysis, both indacaterol doses, 150 and 300 MUg, were associated with significant reductions in exacerbations and significant improvements in bronchodilation versus placebo. The results suggest once-daily indacaterol is an effective treatment option for providing sustained bronchodilation and preventing exacerbations in patients with COPD. PMID- 25433955 TI - Elevated striatal dopamine attenuates nigrothalamic inputs and impairs transthalamic cortico-cortical communication in schizophrenia: a hypothesis. AB - Schizophrenia has been found to involve source-monitoring deficits, whereby perceptions that result from self-initiated motor output become attributed to outside sources. One example of this phenomenon are the so called passivity experiences, such as delusions of control, during which the individual feels that own actions are controlled remotely by someone else. To explain these phenomena, it has been proposed that this illness involves efference copy failure. In other words, brain mechanism that prepare perceptual processes for the sensory consequences of self-initiated actions are impaired leading to their misattribution and to psychosis. In earlier work, it was argued that efference copy failure in schizophrenia is related to thalamic abnormalities. Namely, the thalamus can be thought of as a hub for cortico-cortical interactions, and these transthalamic cortico-cortical interactions were found to play a part in internal motor monitoring. Cortico-cortical communication via the thalamus can be impaired in a number of ways. For example, one way to impair these interactions is by interfering with the ability of the thalamus to display bursts of firing. As the burst firing mode in the thalamus requires a preceding period of prolonged hyperpolarization (100ms), one way to reduce the burst propensity of thalamic neurons is to interfere with the ability to display prolonged hyperpolarizations. In this paper, we argue that elevated striatal dopaminergic activity in schizophrenia attenuates nigrothalamic GABAergic inputs, and thereby reduces burst propensity of the mediodorsal (MD) thalamic nucleus in schizophrenia, with the ultimate result of reduced transthalamic cortico-cortical communication, relative disconnection between functionally associated cortical areas and to psychosis. Conversely, dopamine D2 receptor blockers (antipsychotics) may help restore nigrothalamic GABAergic inputs, thereby increasing the burst propensity in the thalamus. PMID- 25433957 TI - Outcomes after resection of leiomyosarcomas of the inferior vena cava: a pooled data analysis of 377 cases. AB - BACKGROUND: Primary leiomyosarcomas of the inferior vena cava (IVC) pose unique surgical challenges. Due to the rarity of the disease, little definitive data exists on prognosis and treatment options. METHODS: A pooled data analysis was performed on all cases of initial IVC leiomyosarcoma resection identified by literature search (n = 371) and our institutional database (n = 6). Kaplan-Meier and Cox regression analyses were performed to identify factors associated with disease-free survival (DFS) and overall survival (OS). RESULTS: Patients were predominantly female (76%, n = 286); the median age of presentation was 55 years. Five-year DFS and OS were 6% and 55%, respectively. Preoperative factors independently associated with decreased OS included older age (HR:1.05, 95% CI:1.00-1.09), larger tumor size (HR:1.14, 95% CI:1.04-1.24), resection of adjacent organ(s) (HR:3.62, 95% CI:1.34-9.77), and R2 resection (HR:7.80, 95% CI:1.94-32.05). Isolated involvement of the suprarenal infrahepatic IVC was associated with longer OS (HR:0.22, 95% CI:0.06-0.78). A scoring system incorporating independent predictors of OS stratified outcomes: score 4-5 (n = 10, median OS 6 months), score 2-3 (n = 88, median OS 23 months) compared to a score of 0-1 (n = 44, median OS 29 months). CONCLUSIONS: Following resection of IVC leiomyosarcomas, recurrence is a near certainty; long-term survival, however is possible. The dominant predictors of survival include margin status, tumor size and radical resection. These can be combined into a risk score that has prognostic value. PMID- 25433956 TI - How to mechanistically explain the CONDOR study data. AB - Results of the CONDOR study suggest that in osteoarthritis and rheumatoid arthritis patients at elevated risk of gastrointestinal (GI) events, treatment with celecoxib, a cyclooxygenase (COX)-2 selective non-steroidal anti inflammatory drug (NSAID), demonstrated significantly lower toxicity in the upper and lower (GI) tract when compared to the non-selective NSAID diclofenac plus a proton-pump-inhibitor (PPI), omeprazole. According to current knowledge, traditional NSAIDs (tNSAIDs) as non-selective COX-inhibitors exert their damaging effects on the upper GI tract, largely by reduction of the COX-1 related synthesis of gastro-protective prostaglandins. Thus, the question arises, how NSAIDs do exert their damaging effects especially in the lower GI tract and how to explain the reduced risk of a COX-2 selective inhibitor, celecoxib. Here we hypothesize, that the toxicity of celecoxib on enteral mucosa cells is lower than observed with other NSAIDs, and can be explained COX-independently by typical physicochemical properties of the NSAID substances (e.g., acidic, lipophilic, amphiphilic, surfactant properties). As a consequence these features account for differences in (1) uncoupling effects on mitochondria, (2) effects on cell membrane integrity, and/or (3) formation of "toxic micelles" with bile salts. The evidence for these differences is mainly based on experimental findings. However, several phenomena show differences in extent (e.g., uncoupling effects). The reduced toxicity appears to be rather a substance-specific characteristic. This is an unconditional reason to carry on investigating these phenomena in experimental and large-scale clinical trials. PMID- 25433958 TI - Altered white matter connectivity as a neural substrate for social impairment in Autism Spectrum Disorder. AB - BACKGROUND: Autism Spectrum Disorder (ASD) symptoms have been hypothesized to result from altered brain connectivity. The 'disconnectivity' hypothesis has been used to explain characteristic impairments in socio-emotional function, observed clinically in ASD. Here, we review the evidence for impaired white matter connectivity as a neural substrate for socio-emotional dysfunction in ASD. A review of diffusion tensor imaging (DTI) studies, and focused discussion of relevant post-mortem, structural, and functional neuroimaging studies, is provided. METHODS: Studies were identified using a sensitive search strategy in MEDLINE, Embase and PsycINFO article databases using the OvidSP database interface. Search terms included database subject headings for the concepts of pervasive developmental disorders, and DTI. Seventy-two published DTI studies examining white matter microstructure in ASD were reviewed. A comprehensive discussion of DTI studies that examined white matter tracts linking socio emotional structures is presented. RESULTS: Several DTI studies reported microstructural differences indicative of developmental alterations in white matter organization, and potentially myelination, in ASD. Altered structure within long-range white matter tracts linking socio-emotional processing regions was implicated. While alterations of the uncinate fasciculus and frontal and temporal thalamic projections have been associated with social symptoms in ASD, few studies examined association of tract microstructure with core impairment in this disorder. CONCLUSIONS: The uncinate fasciculus and frontal and temporal thalamic projections mediate limbic connectivity and integrate structures responsible for complex socio-emotional functioning. Impaired development of limbic connectivity may represent one neural substrate contributing to ASD social impairments. Future efforts to further elucidate the nature of atypical white matter development, and its relationship to core symptoms, may offer new insights into etiological mechanisms contributing to ASD impairments and uncover novel opportunities for targeted intervention. PMID- 25433959 TI - Thermodynamic, kinetic and conformational analysis of proteins diffusion-sorption on a solid surface. AB - In this paper we examine particularly some of the more fundamental properties of protein conformational changes at a solid surface coupled with diffusion from the bulk of an aqueous solution and with the adsorption-desorption processes. We focus our attention on adsorbed protein monolayers upon a solid surface using a thermodynamic and kinetic analytical development. Account is also taken of the effects on the overall rate of the conformational change on a solid surface of deviation from ideality, of protein flexibility, of surface free energy and of interaction with reactive solid sites. Our theory applied to steady states is illustrated by examples such as folding-misfolding-unfolding of RNase and SNase on a solid surface after diffusion and adsorption from an aqueous solution. For this purpose, we put forward the determining steps which shall lead to the steady state. The existence of three situations is highlighted according to the values of the typical constants relevant for the protein considered: reaction rate determining step, diffusion and sorption determining steps, mixed adsorption diffusion and reaction rate. Finally, we have tried to link the developments of our theories to a large literature based on experimental results encountered during proteins diffusion-sorption-reaction processes, fundamental topics that has been since long investigated by Miller's team in MPKG. PMID- 25433961 TI - Statement on surgical preresidency preparatory courses. AB - The following statement on surgical pre-residency preparatory courses has been approved by the American Board of Surgery, the American College of Surgeons, the Association of Program Directors in Surgery, and the Association for Surgical Education: The leadership of the surgical community is actively engaged in improving the preparation of incoming residents to assume responsibility and accountability for key elements of care and stewardship. To better prepare for this transition, it is essential that all matriculants to surgery residency successfully complete a preparatory course of blended learning that specifically addresses essential components of quality care and patient safety before the start of their training. A national multidimensional curriculum, along with objective assessment tools, has been developed to accelerate readiness, responsibility, and accountability during the transition from medical school to surgery residency. We strongly endorse this effort and encourage medical schools to adopt this or a similar program. We stand ready to assist medical schools and medical students in implementation of this important initiative. PMID- 25433962 TI - MOC part IV: Implications for resident training and practice activity. PMID- 25433963 TI - Workplace bullying of general surgery residents by nurses. AB - OBJECTIVE: Workplace bullying is at the forefront of social behavior research, garnering significant media attention. Most of the medical research has addressed bullying of nurses by physicians and demonstrates that patient care and outcomes may suffer. The intent of this study was to determine if general surgery residents are bullied by nurses. DESIGN: A survey instrument previously validated (Negative Acts Questionnaire-Revised) to evaluate for workplace bullying was modified to reflect the resident-nurse relationship. After institutional review board approval, the piloted online survey was sent to general surgery program directors to forward to general surgery residents. Demographic data are presented as percentages, and for negative acts, percentages of daily, weekly, and monthly frequencies are combined. SETTING: Allopathic general surgery residencies in the United States. PARTICIPANTS: General surgery residents. RESULTS: The response rate was 22.1% (n = 452). Most respondents were men (55%) and had a mean age of 29 years (standard deviation = 7). Although 27.0% of the respondents were interns, the remaining classes were equally represented (12%-18% of responses/class). The respondents were primarily from medium-sized residency programs (45%), in the Midwest (28%), training in university programs (72%), and rotating primarily in a combined private and county hospital that serves both insured and indigent patients (59%). The residents had experienced each of the 22 negative acts (11.5%-82.5%). Work-related bullying occurs more than person related bullying and physical intimidation. Ignoring of recommendations or orders by nurses occurs on a daily, weekly, or monthly basis for 30.2% of residents (work-related bullying). The most frequent person-related bullying act is ignoring the resident when they approach or reacting in a hostile manner (18.0%), followed by ignoring or excluding the resident (17.1%). CONCLUSIONS: Workplace bullying of general surgery residents by nurses is prominent. Future research is needed to determine the toll on the resident's well-being and patient outcomes. PMID- 25433960 TI - Metabolic and inflammatory genes in schizophrenia. AB - Energy metabolism and immunity are characterized as abnormal in schizophrenia. Because these two systems are highly coordinated, we measured expression of prototypic obesogenic and immunogenic genes in freshly harvested PBMC from controls and participants with schizophrenia. We report significant increases in PPARgamma, SREBP1, IL-6 and TNFalpha, and decreases in PPARalpha and C/EPBalpha and mRNA levels from patients with schizophrenia, with additional BMI interactions, characterizing dysregulation of genes relating to metabolic inflammation in schizophrenia. PMID- 25433964 TI - Catering to millennial learners: assessing and improving fine-needle aspiration performance. AB - OBJECTIVES: Fine-needle aspiration (FNA) of a palpable cervical lymph node is a straightforward procedure that should be safely performed by educated general surgery (GS) trainees. Retention of technical skill is suspect, unless sequential learning experiences are provided. However, voluntary learning experiences are no guarantee that trainees will actually use the resource. DESIGN: A 3-minute objective structured assessment of technical skill-type station was created to assess GS trainee performance using FNA. Objective criteria were developed and a checklist was generated (perfect score = 24). Following abysmal performance of 11 postgraduate year (PGY)-4 trainees on the FNA station of our semiannual surgical skills assessment ("X-Games"), we provided all GS residents with electronic access to a 90-second YouTube video clip demonstrating proper FNA technique. PGY 2 (n = 11) and PGY-3 (n = 10) residents subsequently were tested on FNA technique 5 and 12 days later, respectively. RESULTS: All 32 trainees completed the station in less than 3 minutes. Overall scores ranged from 4 to 24 (mean = 14.9). PGY-4 residents assessed before the creation of the video clip scored lowest (range: 4 18, mean = 11.4). PGY-3 residents (range: 10-22, mean = 17.8) and PGY-2 residents (range: 10-24, mean = 15.8) subsequently scored higher (p < 0.05). Ten residents admitted watching the 90-second FNA video clip and scored higher (mean = 21.7) than the 11 residents that admitted they did not watch the clip (mean = 13.1, p < 0.001). Of the 11 trainees who did not watch the video, 6 claimed they did not have time, and 5 felt it would not be useful to them. CONCLUSIONS: Overall performance of FNA was poor in 32 midlevel GS residents. However, a 90-second video clip demonstrating proper FNA technique viewed less than 2 weeks before the examination significantly elevated scores. Half of trainees given the chance to learn online did not take the opportunity to view the video clip. Although preemptive learning is effective, future efforts should attempt to improve self directed learning habits of trainees and evaluate actual long-term skill retention. PMID- 25433965 TI - Association between altered brain morphology and elevated peripheral endothelial markers--implications for psychotic disorders. AB - BACKGROUND: Increased inflammation, endothelial dysfunction, and structural brain abnormalities have been reported in both schizophrenia and bipolar disorder, but the relationships between these factors are unknown. We aimed to identify associations between markers of inflammatory and endothelial activation and structural brain variation in psychotic disorders. METHODS: We measured von Willebrand factor (vWf) as a marker of endothelial cell activation and six inflammatory markers (tumor necrosis factor-receptor 1, osteoprotegerin, interleukin-1-receptor antagonist, interleukin-6, C-reactive protein, CD40 ligand) in plasma and 16 brain structures obtained from MRI scans of 356 individuals (schizophrenia spectrum; n=121, affective spectrum; n=95, healthy control subjects; n=140). The relationship between the inflammatory and endothelial markers and brain measurements were investigated across groups. RESULTS: There was a positive association (p=2.5*10(-4)) between plasma levels of vWf and total volume of the basal ganglia which remained significant after correction for multiple testing. Treatment with first generation antipsychotics was associated with basal ganglia volume only (p=0.009). After adjusting for diagnosis and antipsychotic medication, vWf remained significantly associated with increased basal ganglia volume (p=0.008), in particular the right globus pallidus (p=3.7*10(-4)). The relationship between vWf and basal ganglia volume was linear in all groups, but the intercept was significantly higher in the schizophrenia group (df=2, F=8.2, p=3.4*10(-4)). CONCLUSION: Our results show a strong positive correlation between vWf levels and basal ganglia volume, in particular globus pallidus, independent of diagnosis. vWf levels were significantly higher in schizophrenia, which could indicate a link between endothelial cell activation and basal ganglia morphology in schizophrenia patients. PMID- 25433966 TI - Comparison of standardized patients and real patients as an experiential teaching strategy in a nutrition counseling course for dietetic students. AB - OBJECTIVES: To compare the quality of communication and behavioral change skills among dietetic students having two nutrition encounters with either a real patient or a standardized patient in the simulation laboratory at Drexel University, Philadelphia, PA, United States. METHODS: A retrospective analysis of video recordings (n=138) containing nutrition encounters of dietetic students (n=75) meeting with a standardized patient (SP) or a real patient (RP). Trained raters evaluated communication skills with the 28 item Calgary Cambridge Observation Guide (CCOG) and skills promoting behavior change using the 11 item Behavior Change Counseling Index (BECCI) tool. RESULTS: Using the CCOG, there was a significantly greater mean score in the SP group for the category of "Gathering Information" in encounter one (p=0.020). There were good to excellent ratings in all categories of the CCOG and the BECCI scores for the SP and the RP groups at both encounters. There was no significant differences in change scores from encounter one to encounter two between groups. CONCLUSIONS: Encounters with SPs and RPs are both effective strategies for dietetic students to demonstrate their communication and behavior change skills. PRACTICE IMPLICATIONS: Utilizing SPs is an effective experiential strategy for nutrition counseling curricula. PMID- 25433967 TI - Self-evaluation and peer-feedback of medical students' communication skills using a web-based video annotation system. Exploring content and specificity. AB - OBJECTIVE: Self-evaluation and peer-feedback are important strategies within the reflective practice paradigm for the development and maintenance of professional competencies like medical communication. Characteristics of the self-evaluation and peer-feedback annotations of medical students' video recorded communication skills were analyzed. METHOD: Twenty-five year 4 medical students recorded history-taking consultations with a simulated patient, uploaded the video to a web-based platform, marked and annotated positive and negative events. Peers reviewed the video and self-evaluations and provided feedback. Analyzed were the number of marked positive and negative annotations and the amount of text entered. Topics and specificity of the annotations were coded and analyzed qualitatively. RESULTS: Students annotated on average more negative than positive events. Additional peer-feedback was more often positive. Topics most often related to structuring the consultation. Students were most critical about their biomedical topics. Negative annotations were more specific than positive annotations. Self-evaluations were more specific than peer-feedback and both show a significant correlation. Four response patterns were detected that negatively bias specificity assessment ratings. CONCLUSION: Teaching students to be more specific in their self-evaluations may be effective for receiving more specific peer-feedback. PRACTICE IMPLICATIONS: Videofragmentrating is a convenient tool to implement reflective practice activities like self-evaluation and peer-feedback to the classroom in the teaching of clinical skills. PMID- 25433968 TI - Quality assessment of practice nurse communication with type 2 diabetes patients. AB - OBJECTIVE: Nurse self-management support for type 2 diabetes patients may benefit from applying theory-based behavior change counseling. The 5As model was used to assess if, and how, nurses applied the five key elements of self-management support in standard care. METHODS: Seven practice nurses audio-recorded consultations with 66 patients. An existing instrument for assessing counseling quality was used to determine if the 5As were applied. Applied As were compared with quality criteria, to provide an in-depth assessment. RESULTS: In almost every consultation, nurses assessed health behaviors, and arranged a follow-up meeting. However, nurses advised behavior change in less than half of the consultations, while setting goals and assisting patients to overcome barriers were used even less. Comparing applied As with quality criteria revealed several issues that could be improved. CONCLUSION: Nurses consistently discussed health behaviors with patients, but important elements of self-management support were not applied. PRACTICE IMPLICATIONS: Self-management support may benefit from training nurses in performing assessments that form the base for specific advice, setting goals, and addressing barriers to behavior change. Nurses also have to learn how to combine being medical expert and behavioral counselor. Clarifying both roles to patients may facilitate communication and establishing a collaborative relationship. PMID- 25433969 TI - Effect of the size of the apical enlargement with rotary instruments, single-cone filling, post space preparation with drills, fiber post removal, and root canal filling removal on apical crack initiation and propagation. AB - INTRODUCTION: The purpose of this study was to investigate the incidence of apical crack initiation and propagation in root dentin after several endodontic procedures. METHODS: Sixty intact mandibular premolars were sectioned perpendicular to the long axis at 1 mm from the apex, and the apical surface was polished. Thirty teeth were left unprepared and served as a control, and the remaining 30 teeth were instrumented with ProTaper Universal instruments (Dentsply Maillefer, Ballaigues, Switzerland) up to size F5. The root canals were filled with the single-cone technique. Gutta-percha was removed with drills of the Rebilda post system (VOCO, Cuxhaven, Germany). Glass fiber-reinforced composite fiber posts were cemented using a dual-cure resin cement. The fiber posts were removed with a drill of the post system. Retreatment was completed after the removal of the gutta-percha. Crack initiation and propagation in the apical surfaces of the samples were examined with a stereomicroscope after each procedure. The absence/presence of cracks was recorded. Logistic regression was performed to analyze statistically the incidence of crack initiation and propagation with each procedure. RESULTS: The initiation of the first crack and crack propagation was associated with F2 and F4 instruments, respectively. The logistic regression analysis revealed that instrumentation and F2 instrument significantly affected apical crack initiation (P < .001). Post space preparation had a significant effect on crack propagation (P = .0004). The other procedures had no significant effects on crack initiation and propagation (P > .05). CONCLUSIONS: Rotary nickel-titanium instrumentation had a significant effect on apical crack initiation, and post space preparation with drills had a significant impact on crack propagation. PMID- 25433970 TI - Effect of operator and subject gender on injection pain: a randomized double blind study. AB - INTRODUCTION: Studies have found women try to avoid pain more than men, accept it less, and fear it more. The role of operator gender on subject gender pain in a clinical setting needs further study. The purpose of this randomized, double blind investigation was to evaluate operator gender and its influence on reported subject gender pain in maxillary anterior infiltrations. METHODS: Two hundred subjects (100 male and 100 female) participated. At the initial appointment, each subject randomly received an infiltration over the maxillary lateral incisor of a cartridge of 2% lidocaine with 1:100,000 epinephrine by 1 of 20 calibrated male or female operators. At the second appointment (separated by at least 2 weeks), each subject received an infiltration of the same anesthetic at the same location by an operator of the opposite gender. Immediately after each infiltration, subjects rated the pain of injection (needle insertion, needle placement, and solution deposition) on 170-mm visual analogue scale. Dental anxiety was determined for each subject by using the Corah Dental Anxiety Scale. RESULTS: No significant differences were detected between male and female participants on the Corah Dental Anxiety Scale. For all 4 operator-gender combinations, no significant difference was found in reported pain for needle insertion or placement. A significant difference (P = .0357) was found during the solution deposition phase among female subjects receiving injections from male operators. CONCLUSIONS: Gender had a statistically significant effect for solution deposition pain when a male operator administered the injection to female subjects. PMID- 25433971 TI - Effect of QMix 2in1 on sealer penetration into the dentinal tubules. AB - INTRODUCTION: The purpose of this study was to evaluate the effect of final irrigation with a new endodontic irrigant, QMix 2in1 (Dentsply Tulsa Dental, Tulsa, OK), on sealer penetration into dentinal tubules using confocal laser scanning microscopy. METHODS: Thirty recently extracted human maxillary incisors were used in the present study. The teeth were instrumented with sodium hypochlorite (NaOCl) irrigation and then divided into 3 groups according to the final irrigation regimen used: (1) control group, 2.5% NaOCl; (2) EDTA + CHX group, 17% (EDTA) followed by 2% chlorhexidine (CHX); and (3) QMix group, QMix 2in1. All teeth were dried and then obturated with gutta-percha and rhodamine B labeled AH26 sealer (Dentsply DeTrey, Konstanz, Germany). After setting, the roots were sectioned horizontally 3, 5, and 8 mm from the root apex. Sealer penetration into the dentinal tubules was examined by confocal laser scanning microscopy. RESULTS: In the apical sections of the roots, no significant difference was detected in the percentage of sealer penetration between any of the final irrigation groups (P > .05). Both the EDTA + CHX and QMix groups showed significantly more sealer penetration than the control group in the middle and coronal sections. However, no difference was found between the EDTA + CHX and QMix groups in either of these areas (P > .05) CONCLUSIONS: Use of EDTA + CHX or QMix during final irrigation significantly improved sealer penetration when compared with the control group in the middle and coronal sections of the roots; however, no effect was observed in the apical sections. PMID- 25433972 TI - Use of ambulatory anesthesia with manually assisted ventilation for tympanic membrane regeneration therapy in children. AB - PURPOSE: To present the utility of ambulatory anesthesia using manually assisted ventilation via a facemask for tympanic membrane (TM) regeneration therapy in children. MATERIAL AND METHODS: The study included 10 children (age 4-11years) in whom the duration of perforation before treatment exceeded 6months and who were followed for at least 1year after treatment between December 2009 and December 2012. Under ambulatory anesthesia using manually assisted ventilation via a facemask, TM regenerative therapy with atelocollagen combined with basic fibroblast growth factor was performed in children who could not tolerate the procedure under local anesthesia alone. RESULTS: All of the children completed the TM regenerative therapy under ambulatory anesthesia in less than 5min. Complete closure was achieved in nine (81.8%) ears after 1year of postoperative follow-up. CONCLUSION: TM regenerative therapy can be performed under local anesthesia in less than 5min without a skin incision. However, local anesthesia is often insufficient in small children undergoing this procedure. Therefore, ambulatory anesthesia using manually assisted ventilation via a facemask is appropriate to complete this procedure safely in small children. PMID- 25433973 TI - HIV/AIDS in mid-sized cities in Senegal: From individual to place-based vulnerability. AB - In Senegal, recent data indicates that the HIV epidemic is increasingly driven by concurrent sexual partners among men and women in stable relationships. In order to respond to this changing epidemiological profile in Senegal, multi-lateral and national AIDS actors require information about these emerging trends in unstudied populations. To that end, this study has several objectives, first, to assess local dynamics of sexual behaviors among individuals at popular socializing venues in areas at increased risk of HIV transmission; and then to examine how particular venues may influence risks of HIV transmission. In 2013 we collected data at 314 venues in 10 cities in Senegal using PLACE methodology. These venues were listed with collaboration of 374 community informants. They are places where commercial sex workers, MSM, and individuals who are not part of any identified risk group socialize and meet new sexual partners. We conducted 2600 interviews at the 96 most popular venues. A significant portion of the sample reports buying or selling sex and the majority engaged in behavior considered high-risk for transmitting sexual infections. Almost a quarter of patrons interviewed in venues were young people aged 15-24 years. Types of venues described were very diverse. Half of them were venues (n = 156) where sex workers could be solicited and almost a third were venues where MSM could meet male partners (n = 90). The study showed existing pockets of vulnerability to HIV in Thies, Bignona or Saly that are not evident from aggregate HIV data. These early findings suggest links between risky behaviors and type of venue on the one hand and type of city on the other hand. Finally, these findings offer complementary insight to existing studies of HIV vulnerability in Senegal and support a case for venue-based interventions. PMID- 25433974 TI - Burnout and cortisol: evidence for a lower cortisol awakening response in both clinical and non-clinical burnout. AB - OBJECTIVE: Although the relationship between burnout and cortisol levels has been examined in previous studies, the results are mixed. By adopting a design in which we attempted to overcome important limitations of earlier research, the purpose of the present study was to improve the understanding of the biological underpinnings of burnout and to further the knowledge about the relationship between burnout and cortisol. METHODS: A clinical burnout patient group (n =32), a non-clinical burnout group (n =29), and a healthy control group (n =30) were compared on burnout symptoms, physical and psychological complaints, and on cortisol levels. In order to examine a broad range of cortisol indices, including different measures of the cortisol awakening response (CAR) and several day-curve measures, salivary cortisol was collected six times a day during two consecutive non-workdays. RESULTS: As expected, the clinical burnout group reported more burnout symptoms, and physical and psychological complaints than the non-clinical burnout group, which in turn reported more burnout symptoms and physical and psychological complaints than the healthy control group. With regard to cortisol levels, we found that until 30 min after awakening, the CAR of both the clinical and the non-clinical burnout group was lower compared with the healthy control group. Furthermore, there was some evidence that the decline of cortisol during the day was smaller in the non-clinical burnout group than in the healthy control group. CONCLUSION: The results of the present study provide support for lowered cortisol in both clinical and non-clinical burnout. PMID- 25433976 TI - The importance of fatigue cognitions in chronic hepatitis C infection. AB - Chronic Hepatitis C virus (HCV) infection is a source of significant public health burden worldwide. Fatigue is a cardinal patient reported consequence of the disease. HCV infection associated fatigue leads to significant impairment in the quality of life and day-to-day functioning. Despite its clinical significance, the factors that contribute to adverse impact of fatigue in HCV infection are largely unknown. OBJECTIVES: This study evaluated the contributions of insomnia, depression symptoms, and fatigue-specific cognitions to fatigue related functional impairment. METHODS: Fatigue, insomnia, depression symptoms, as well as fatigue cognitions were assessed in participants (36% females; age>18 years, N=115) with chronic HCV infection at a tertiary hepatitis clinic. RESULTS: Sixty percent of participants reported clinically significant fatigue (Fatigue Severity Index FSS >= 4). Comorbidities and fatigue perceptions accounted for 61% of the variation of fatigue. Fatigue perceptions were the main predictors of adverse fatigue outcomes (B=.114, 95% CI=.054-.154). Patients with clinically significant fatigue were four-times more likely than less fatigued patients to believe that the main cause of their fatigue was the infection. CONCLUSION: Patients' beliefs about their fatigue were the main predictors of adverse fatigue outcomes. These results suggest that fatigue associated with chronic hepatitis C infection can be conceptualized using a cognitive behavioral approach. This was the first study to evaluate the role of both comorbid mood/sleep and cognitive predictors of fatigue in a single model. Integrating the findings into existing treatment strategies could improve patient reported outcomes in chronic hepatitis C infection. PMID- 25433975 TI - Psychiatric disorders and gestational weight gain among women who quit smoking during pregnancy. AB - OBJECTIVE: Pregnancy is a common time for women to quit using cigarettes and other substances. Such changes in substance use as well as other psychiatric and psychosocial changes during pregnancy can affect gestational weight gain (GWG). Thus, we evaluated the relationship between psychiatric disorders and GWG among pregnant women who had quit smoking. METHODS: Pregnant former smokers (n = 281) enrolled in a larger trial for postpartum relapse prevention completed semi structured psychiatric interviews and measures of prepregnancy nicotine dependence and smoking behavior, and were weighed to estimate gestational weight gain. Using linear regression and mixed-effect models, the relationship between a lifetime prevalence of each psychiatric disorder and total GWG was evaluated, controlling for variables previously related to GWG. RESULTS: Average GWG was 15.6 (+/- 8.5) kg, and 56% (n = 157) of women exceeded the GWG recommended by the Institute of Medicine (IOM) according to prepregnancy BMI. Over one-third (34.3%) of pregnant former smokers had a history of at least one diagnosable psychiatric disorder. History of psychiatric disorder was unrelated to GWG, with one exception; lifetime history of alcohol use disorder was associated with significantly larger GWG. CONCLUSION: Women who quit smoking during pregnancy gain a considerable amount of gestational weight, and a previous history of alcohol use disorder is related to GWG. However, the benefits of smoking cessation to maternal and fetal health likely outweigh the disadvantage of weight gain, and other psychiatric disorders are not linked to GWG. PMID- 25433977 TI - Cadaveric validation of dry needle placement in the lateral pterygoid muscle. AB - OBJECTIVE: The aim of this anatomical study was to determine if a needle is able to reach the lateral pterygoid muscle during the application of dry needling technique. METHODS: A dry needling approach using 2 needles of 50 to 60 mm in length, one inserted over the zygomatic process posterior at the obituary arch (for the superior head) and other inserted below the zygomatic process between the mandibular condyle and the coronoid process (for the inferior head), was proposed. A progressive dissection into 3 stages was conducted into 2 heads of fresh male cadavers. First, dry needling of the lateral pterygoid muscle was applied on the cadaver. Second, a block dissection containing the lateral pterygoid was harvested. Finally, the ramus of the mandible was sectioned by osteotomy to visualize the lateral pterygoid muscle with the needle placements. RESULTS: With the needles inserted into the cadaver, the block dissection revealed that the superior needle reached the superior (sphenoid) head of the lateral pterygoid muscle and the inferior needle reached the inferior (pterygoid) head of the muscle. At the final stage of the dissection, when the ramus of the mandible was sectioned by osteotomy, it was revealed that the superior needle entered into the belly of the superior head of the lateral pterygoid muscle. CONCLUSIONS: This anatomical study supports that dry needling technique for the lateral pterygoid muscle can be properly conducted with the proposed approach. PMID- 25433978 TI - Coprecipitated arsenate inhibits thermal transformation of 2-line ferrihydrite: implications for long-term stability of ferrihydrite. AB - 2-line ferrihydrite, a ubiquitous iron oxy-hydroxide found in natural and engineered systems, is an efficient sink for the toxic metalloids such as arsenic. While much is known of the excellent capacity of ferrihydrite to coprecipitate arsenate, there is little information concerning the long-term stability of arsenate-accumulated ferrihydrite. By thermal treatment methodology, the expedited transformation of ferrihydrite in the presence of coprecipitated arsenate was studied at varying As/Fe ratios (0-0.5) and different heating temperature (40, 300, 450, 600 degrees C). Pure and transformed minerals were characterized by thermogravimetry (TG), X-ray diffraction (XRD), Electron Spin Resonance (ESR), Scanning Electron Microscopy-Energy Dispersive X-ray Spectroscopy (SEM-EDX) and Fourier Transform Infrared Spectroscopy (FTIR). Arsenate was found to retard the thermal transformation of ferrihydrite. The extents of ferrihydrite transformation to hematite decreased with increasing As/Fe ratios, but increased at a higher heating temperature. It is predicted that the coprecipitated arsenate can stabilize the amorphous iron oxides against the transformation to more crystalline solids. Arsenate concentration appears to play an important role in this predicted long-term stability. PMID- 25433979 TI - Evaluation of the relationship between bulk organic precursors and disinfection byproduct formation for advanced oxidation processes. AB - Advanced oxidation processes (AOPs) are gaining traction as they offer mineralization potential rather than transferring contaminants between media. However, AOPs operated with limited energy and/or chemical inputs can exacerbate disinfection byproduct (DBP) formation, even as precursors such as dissolved organic carbon, UV254, and specific UV absorbance (SUVA) decrease. This study examined the relationship between DBP precursors and formation using TiO2 photocatalysis experiments, external AOP and non-AOP data, and predictive DBP models. The top-performing indicator, SUVA, generally correlated positively with trihalomethanes and haloacetic acids, but limited-energy photocatalysis yielded contrasting negative correlations. The accuracy of predicted DBP values from models based on bulk parameters was generally poor, regardless of use and extent of AOP treatment and type of source water. Though performance improved for scenarios bounded by conditions used in model development, only 0.5% of the model/dataset pairings satisfied all measured parameter boundary conditions, thereby introducing skepticism toward model usefulness. Study findings suggest that caution should be employed when using bulk indicators and/or models as a metric for AOP mitigation of DBP formation potential, particularly for limited energy/chemical inputs. PMID- 25433981 TI - Improving health professionals' communication skills: a major global endeavour. PMID- 25433980 TI - Low-concentration tailing and subsequent quicklime-enhanced remediation of volatile chlorinated hydrocarbon-contaminated soils by mechanical soil aeration. AB - Mechanical soil aeration has long been regarded as an effective ex-situ remediation technique and as suitable for remediation of large-scale sites contaminated by volatile organic compounds (VOCs) at low cost. However, it has been reported that the removal efficiency of VOCs from soil is relatively low in the late stages of remediation, in association with tailing. Tailing may extend the remediation time required; moreover, it typically results in the presence of contaminants residues at levels far exceeding regulations. In this context, the present study aimed to discuss the tailing that occurs during the process of remediation of soils contaminated artificially with volatile chlorinated hydrocarbons (VCHs) and to assess possible quicklime-enhanced removal mechanisms. The results revealed the following conclusions. First, temperature and aeration rate can be important controls on both the timing of appearance of tailing and the levels of residual contaminants. Furthermore, the addition of quicklime to soil during tailing can reduce the residual concentrations rapidly to below the remedial target values required for site remediation. Finally, mechanical soil aeration can be enhanced using quicklime, which can improve the volatilization of VCHs via increasing soil temperature, reducing soil moisture, and enhancing soil permeability. Our findings give a basic understanding to the elimination of the tailing in the application of mechanical soil aeration, particularly for VOCs contaminated soils. PMID- 25433982 TI - Psychosocial consequences in the Danish randomised controlled lung cancer screening trial (DLCST). AB - OBJECTIVES: To measure the psychosocial consequences in the Danish lung cancer screening trial (DLCST) and compare those between the computed tomography (CT) group and the control group. MATERIALS AND METHODS: This study was a single centre randomised controlled trial with five annual screening rounds. Healthy current or former heavy smokers aged 50-70 years (men and women) were randomised 1:1 to a CT group and a control group. Heavy smokers were defined by having smoked >=20 pack years and former smokers by being abstinent <=10 years. Both groups were invited annually to the screening clinic to complete the validated lung-cancer-specific questionnaire consequences of screening lung cancer (COS LC). The CT group was also offered a low dose CT scan of the lungs. The COS-LC measures nine scales with psychosocial properties: Anxiety, Behaviour, Dejection, Negative impact on sleep, Self-blame, Focus on Airway Symptoms, Stigmatisation, Introvert, and Harm of Smoking. RESULTS: 4104 participants were randomised to the DLCST and the COS-LC completion rates for the CT group and the control group were 95.5% and 73.6%, respectively. There was a significant increase in negative psychosocial consequences from baseline through rounds 2-5 for both the CT group and the control group (mean increase >0, p<.0001 for 3 of 4 possible scales). During rounds 2-5 the control group experienced significantly more negative psychosocial consequences in seven of nine scales compared with the CT group (mean Delta score >0 and p<.033). CONCLUSIONS: Lung cancer CT-screening trials induced more negative psychosocial reactions in both the CT group and the control group compared with the baseline psychosocial profile. The CT group experienced less negative psychosocial consequences compared with the control group, which might be explained by reassurance among those with normal screening results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00496977. PMID- 25433983 TI - FGFR1 amplification in lung squamous cell carcinoma: a systematic review with meta-analysis. AB - INTRODUCTION: Current targeted therapy proves no effective outcomes in lung squamous cell carcinoma (SQCC). Recent studies suggested that FGFR1 would be promising. This systematic review elaborated FGFR1 amplification in lung SQCC. METHODS: An electronic search was conducted on PubMed, EMBASE, Web of SCI, Google Scholar and Cochrane Library. Eligible studies regarding incidence of FGFR1 amplification in lung SQCC and correlation between FGFR1 amplification and clinicopathological features or survival were extracted and analyzed. RESULTS: We identified 13 eligible studies with a total of 1798 patients. The results showed about 19% of FGFR1 amplification (95% CI: 0.15-0.24; I(2)=84.5%; p=0.000). Using the same test method: FISH, definition and ethnicity, the rates were 17% (95% CI: 0.14-0.20; I(2)=53.1%; p=0.037), 21% (95% CI: 0.18-0.24; I(2)=0; p=0.615), and 16% (95% CI: 0.13-0.19; I(2)=72.1%; p=0.028), respectively. Pearson's correlation analysis suggested that smoking status was highly correlated with FGFR1 amplification (coefficient=0.961, p<0.001). FGFR1 amplification was significantly correlated with lymph node metastasis (OR: 2.27; 95% CI: 1.62-3.20; p=0.000), but not correlated with gender (OR: 1.12; 95% CI: 0.90-1.38; p=0.91), differentiation (OR: 1.02; 95% CI: 0.76-1.38; p=0.959) and stage (OR: 0.93; 95% CI: 0.73-1.19; p=0.877) in lung SQCC patients. With respect to survival, FGFR1 amplification had no influence on PFS (HR: 1.57; 95% CI: 0.85-2.30; p=0.259) and OS (HR: 1.40; 95% CI: 0.90-1.89; p=0.416) for SQCC patients. CONCLUSION: FGFR1 amplification is about 19%. Gender, stage, differentiation, ethnicities and test methods have no influence on FGFR1 amplification. FGFR1 amplification trends to correlate with lymph node metastasis and smoking. Whether FGFR1 amplification has effect on survival remains controversial. PMID- 25433984 TI - EFGR-mutant lung adenocarcinoma and Li-Fraumeni syndrome: report of two cases and review of the literature. AB - We report two cases of non-smoker patients diagnosed with EGFR-mutated lung adenocarcinoma and bearing germinal TP53 gene mutation, also known as Li-Fraumeni syndrome (LFS). We describe for the first time an EGFR-TKI resistance mutation in this population. Finally, we provide an analysis of discerning epidemiological data obtained from the IARC database and from all the published cases of EGFR mutated lung cancer in TP53 germline mutation carriers. PMID- 25433985 TI - The effectiveness of varied levels of simulation fidelity on integrated performance of technical skills in midwifery students--a randomised intervention trial. AB - BACKGROUND: Simulation as a pedagogical approach is used in health professional education to address the need to safely develop effective clinical skills prior to undertaking clinical practice, in complex healthcare environments. Evidence for the use of simulation in midwifery is largely anecdotal, and research evaluating the effectiveness of different levels of simulation fidelity is lacking. OBJECTIVES: To evaluate the effectiveness of varying levels of fidelity on simulated learning experiences and identify which best contributes to integrated and global clinical skills development in midwifery students. DESIGN: Randomised three arm intervention trial. PARTICIPANTS: Midwifery students who had yet to receive theoretical instruction in the performance of the clinical skill of vaginal examination. METHODS: Midwifery students (n=69) received theoretical instruction in the performance of vaginal examination following random allocation into one of three intervention arms. Participants were recorded performing the procedure using low fidelity (part task trainer only), medium fidelity (part task trainer and life sized poster of a pregnant woman) or progressive fidelity (part task trainer and a simulated standardised patient). Senior midwifery students were recruited to act in the role of standardised patients. RESULTS: There was a statistically significant difference in the mean total Global Rating Scale score between at least two of the three groups (p=0.009). The progressive fidelity group revealed as different from both the low fidelity group (p=0.010) and medium fidelity group (p=0.048). There was a statistically significant difference in the mean total Integrated Procedural Performance Instrument score between at least two of the three groups (p=0.012). The progressive fidelity group revealed as different from both the low fidelity group (p=0.026) and medium fidelity group (p=0.026). CONCLUSIONS: Progressive and medium fidelity simulation yields better outcomes than low fidelity simulation and where resources are constrained medium fidelity equipment, such as a life sized poster can produce effective learning experiences for midwifery students. PMID- 25433986 TI - Representativeness of online purposive sampling with Australian cannabis cultivators. PMID- 25433987 TI - A combined chemical and biological approach to transforming and mineralizing PAHs in runoff water. AB - The water quality of lakes, rivers and streams associated with metropolitan areas is declining from increased inputs of urban runoff that contain polycyclic aromatic hydrocarbons (PAHs). Our objective was to transform and mineralize PAHs in runoff using a combined chemical and biological approach. Using (14)C-labeled phenanthrene, (14)C-benzo(a)pyrene and a mixture of 16 PAHs, we found that ozone transformed all PAHs in a H2O matrix within minutes but complete mineralization to CO2 took several weeks. When urban runoff water (7.6 mg CL(-1)) replaced H2O as the background matrix, some delays in degradation rates were observed but transforming a mixture of PAHs was still complete within 10 min. Comparing the biodegradability of the ozonated products to the parent structures in unsaturated soil microcosms showed that the 3-ring phenanthrene was more biodegradable (as evidence by (14)CO2 released) than its ozonated products but for the 5-ring benzo(a)pyrene, the products produced by ozone were much more biodegradable (22% vs. 3% mineralized). For phenanthrene, we identified diphenaldehyde as the initial degradation product produced from ozonation. By continuing to pump the ozonated products ((14)C-labeled diphenaldehyde or ozone-treated benzo(a)pyrene) onto glass beads coated with microorganisms, we verified that biological mineralization could be achieved in a flow-through system and mineralization rates improved with acclimation of the microbial population (i.e., time and exposure to the substrate). These results support a combined ozone and biological approach to treating PAHs in urban runoff water. PMID- 25433988 TI - Effect of drying-wetting cycles on leaching behavior of cement solidified lead contaminated soil. AB - Lead contaminated soil was treated by different concentration of ordinary Portland cement (OPC). Solidified cylindrical samples were dried at 40 degrees C in oven for 48 h subsequent to 24h of immersing in different solution for one drying-wetting. 10 cycles were conducted on specimens. The changes in mass loss of specimens, as well as leaching concentration and pH of filtered leachates were studied after each cycle. Results indicated that drying-wetting cycles could accelerate the leaching and deterioration of solidified specimens. The cumulative leached lead with acetic acid (pH=2.88) in this study was 109, 83 and 71 mg respectively for solidified specimens of cement-to-dry soil (C/Sd) ratios 0.2, 0.3 and 0.4, compared to 37, 30, and 25mg for a semi-dynamic leaching test. With the increase of cycle times, the cumulative mass loss of specimens increased linearly, but pH of filtered leachates decreased. The leachability and deterioration of solidified specimens increased with acidity of solution. Increases of C/Sd clearly reduced the leachability and deterioration behavior. PMID- 25433989 TI - Effects of mixing and covering with mature compost on gaseous emissions during composting. AB - This study investigated effects of mature compost on gaseous emissions during composting using pig manure amended with corn stalks. Apart from a control treatment, three treatments were conducted with the addition of 5% (wet weight of raw materials) of mature compost: (a) mixing raw materials with mature compost at the beginning of composting; (b) covering raw materials with mature compost throughout the experimental period; and (c) covering raw materials with mature compost at the start of composting, but incorporating it into composting pile on day 6 of composting. Mature compost used for the last treatment was inoculated with 2% (wet weight) of raw materials of strain M5 (a methanotrophic bacterium) solution. During 30-d of composting, three treatments with the addition of mature compost could reduce CH4 emission by 53-64% and N2O emission by 43-71%. However, covering with mature compost throughout the experimental period increased cumulative NH3 emission by 61%, although it could reduce 34% NH3 emission in the first 3d. Inoculating strain M5 in mature compost covered on the top of composting pile within first 6d enhanced CH4 oxidation, but simultaneously increased N2O emission. In addition, mixing with mature compost could improve compost maturity. Given the operational convenience in practice, covering with mature compost and then incorporating it into composting pile is a suitable approach to mitigate gaseous emissions during composting. PMID- 25433990 TI - The role of a combined coagulation and disk filtration process as a pre-treatment to microfiltration and reverse osmosis membranes in a municipal wastewater pilot plant. AB - A pilot study was conducted to assess the performance of a municipal wastewater reclamation plant consisting of a combined coagulation-disk filtration (CC-DF) process, microfiltration (MF) and reverse osmosis (RO) membranes, in terms of the removal of water contaminants and changes in characteristics of effluent organic matter (EfOM). The CC-DF and MF membranes were not effective for the removal of dissolved water contaminants. However, they could partially reduce the turbidity associated with the cake layer formation by particulate materials on the membrane surfaces. Furthermore, most of water contaminants were completely removed by the RO membranes. Although the CC-DF process could remove approximately 20% of turbidity, the aluminium concentrations considerably increased after the CC-DF process due to the residual coagulants complexed with both carboxylic acid and alcohol functional groups of EfOM. Those aluminium-EfOM complexes had a lower negative charge and higher molecular weight (>0.1 MUm pore size of the MF membranes) compared to non-complexed EfOM. These results indicate that the control of the formation of the aluminium-EfOM complexes should be considered as a key step to use the CC-DF process as a pre-treatment of the MF and RO membranes for mitigation of membrane fouling in the tested pilot plant. PMID- 25433991 TI - Effects of Cd(II) on wastewater biological nitrogen and phosphorus removal. AB - Short-term and long-term effects of Cd(II) on wastewater biological nitrogen and phosphorus removal were investigated with respect to microorganism abundances, enzyme activities, and polyhydroxyalkanoates (PHAs) and glycogen transformations. Though no obvious effects on wastewater biological nutrient removal were observed after short-term exposure, the long-term exposure of 10 mg L(-)(1) Cd(II) inhibited nitrification and phosphorus uptake. Compared with the absence of Cd(II), the presence of 10 mg L(-1) of Cd(II) decreased total nitrogen and phosphorus removal efficiencies from 97% and 98% to 88% and 18%, respectively. Mechanism studies revealed that Cd(II) affected the transformations of intracellular PHAs and glycogen, and the activities of oxidoreductase and polyphosphate kinase, resulted in the decrease of nitrite oxidizing bacteria and polyphosphate accumulating organisms abundance, which might be the major reason for the negative effects of long-term exposure to 10 mg L(-1) Cd(II) on biological nitrogen and phosphorus removal. PMID- 25433992 TI - The effect of low-temperature transformation of mixtures of sewage sludge and plant materials on content, leachability and toxicity of heavy metals. AB - The aim of the study was to determine the influence of the process of low temperature transformation and the addition of plant material to sewage sludge diversifying the content of mobile forms of heavy metals and their ecotoxicity. The experimental design included: sewage sludge+rape straw, sewage sludge+wheat straw, sewage sludge+sawdust, sewage sludge+bark and sewage sludge with no addition. The mixtures were subjected to thermal transformation in a chamber furnace, under conditions without air. The procedure consisted of two stages: the first stage (130 degrees C for 40 min) focused on drying the material, whereas in the second stage (200 degrees C for 30 min) proper thermal transformation of materials took place. Thermal transformation of the materials, caused an increase in total contents of heavy metals in comparison to the material before transformation. From among elements, the cadmium content changed the most in materials after thermal transformation. As a result of thermal transformation, the content of water soluble form of the heavy metals decreased significantly in all the prepared mixtures. Low toxicity of the extracts from materials for Vibrio fischeri and Lepidium sativum was found in the research, regardless of transformation process. L. sativum showed higher sensitivity to heavy metals occurring in the studied extracts from materials than V. fischeri, evidence of which are the positive significant correlations between the content of metals and the inhibition of root growth of L. sativum. PMID- 25433993 TI - A comparative study of honeycombing on high resolution computed tomography with histologic lung remodeling in explants with usual interstitial pneumonia. AB - BACKGROUND: There is little information comparing high-resolution computed tomography (HRCT) findings in UIP with different components that make up remodeling histologically. DESIGN: We compared histologic features with HRCT scans from 69 explants with UIP. The extent of 7 histologic features were semi quantitated: respiratory-lined cysts, bronchiolectasis, pulmonary interstitial emphysema (PIE), lobular remodeling, areas resembling non-specific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP)-like pattern, and mucus pooling within cysts extending into surrounding parenchyma. Subpleural cystic spaces and areas of lobular remodeling were measured morphometrically. Histologic features were compared to three findings on HRCT: diagnostic pattern (UIP, probable UIP, or inconsistent with UIP pattern), degree of honeycombing, and degree of ground-glass opacities. RESULTS: Histologically, respiratory-lined cysts were observed in 78%, bronchiolectasis in 83%, interstitial emphysema in 22%, lobular remodeling in 96%, NSIP-like areas in 87%, DIP-like reaction in 10%, and mucin extravasation in 78%. Morphometrically, cysts of PIE measured 6.2+/-2.9 mm, respiratory-lined cysts 3.5+/-2.4 mm, and bronchiolectatic cysts 3.3+/-1.5 mm. Remodeled lobules measured 3.6+/-1.1 mm. UIP pattern on CT correlated strongly with histologic extent of bronchiolectasis (p=0.001). HRCT honeycombing showed a positive correlation with histologic bronchiolectasis (p=0.001) and respiratory-lined cysts (p=0.001). GGO was positively associated with NSIP-like areas (p=0.02) and extravasated mucus (p=0.05). CONCLUSIONS: HRCT findings typical of UIP and HRCT honeycombing correlate best with bronchiolectasis histologically. NSIP pattern is common, and is associated with CT finding of GGO. PMID- 25433994 TI - Role of neurotransmitter Substance P in progression of oral squamous cell carcinoma. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most frequent type of head and neck cancers. OBJECTIVES: In the present study, we evaluated the expression and distribution of Substance P (SP) in different grades of OSCC and role of SP in its proliferation and progression. SUBJECTS AND METHODS: Forty OSCC biopsies were immunohistochemically analyzed by using SP antibody, including 29 male and 11 female cases. 35% were well differentiated, 35% moderately differentiated and 30% poorly differentiated OSCC. The majority of patients were in the age range of 41-80 years. 62% of the cases were positive for SP. SP positivity was expressed in the cytoplasm of the tumor cells. Most of the positive cases were from the tongue region. RESULTS: 93% of moderately differentiated, 92% of poorly differentiated and 8% of well-differentiated carcinomas were SP-positive, but SP expression intensity was highest in poorly differentiated cases (+3). More positive patients were males (68.96% of all male patients) with moderately and poorly differentiated OSCC. Among all positive cases, 48% were poorly differentiated, 48% moderately differentiated and 4% well differentiated. CONCLUSION: Strong expression of SP in poorly and moderately differentiated cases suggests a role of SP in the progression and development of tumor. Expression of SP in the current study increased as the proliferation of cells increased. Prevalence of oral cancer in males may be due to the fact that they smoke and use pan, chewing gum, beetle nut etc. in this region. SP antagonists can help in the reduction and inhibition of oral cancer. SP has a diagnostic value with sensitivity of 92.5% and specificity of 93.7%. The positive predictive value is 96.2% and the negative predictive value 88.2%. PMID- 25433995 TI - Expression of HSPA12B in acute cardiac allograft rejection in rats. AB - HSP70 may play a more important role in regulating antigen-specific immune response than other HSPs; however, HSPA12B production in transplanted heart remains obscure, which was identified as the newest member of the HSP70 family. In the current study, we performed a heart transplantation model in adult rats and investigated the dynamic changes of HSPA12B expression in the cardiac grafts. The cardiac grafts of allogeneic (Wistar-Lewis rat) and syngeneic (Lewis-Lewis rat) rat models were subjected to histopathological and immunohistochemical analyses for HSPA12B expression on days 0-7 after operation. We also examined the expression profiles of active caspase-3, whose changes were correlated with the expression profiles of HSPA12B. Our results demonstrated that HSPA12B protein exhibited biphasic patterns in transplanted heart. The first expression phase correlated with ischemical reperfusion injury over 2 days post-transplant. The second peak of HSPA12B expression was found only in allografts on day 5, concurrent with the expression of caspase-3. Immunohistochemical assay showed that compared with rare expression in isografts, there were significant protein expressions of HSPA12B and caspase-3 in heart allografts from day 5 to 7 post transplant. Furthermore, double immunofluorescence staining for active caspase-3 and HSPA12B in isografts and allografts at day 5 post-transplant were analyzed and colocalization of HSPA12B/active caspase-3 was detected in allografts. In conclusion, this is the first description of HSPA12B expression in acute cardiac allograft rejection. Our results suggested that HSPA12B might play crucial roles in heart pathophysiology after transplantation. PMID- 25433996 TI - NUT midline carcinoma of the mediastinum showing two types of poorly differentiated tumor cells: a case report and a literature review. AB - Nuclear protein in testis (NUT) midline carcinoma (NMC) is an extremely aggressive carcinoma that is genetically defined by rearrangement of the NUT gene. Herein, we describe a case of NMC in a young Japanese man, and review 31 cases of NMC in the literature. The present case was of a massive tumor of the anterior and middle mediastinum in a 26-year-old man. The tumor included 2 types of poorly differentiated tumor cells and was immunohistochemically positive for the NUT-specific antigen, epithelial membrane antigen (EMA), cluster of differentiation 99 (CD99) antigen, CD45RO antigen, keratins, p63, and p40. The patient died 2 months after the initial diagnosis. At least two-thirds of the 31 NMC cases in the literature were immunohistochemically positive for EMA, p63, and AE1/AE3. However, some exceptional NMC cases are keratins-negative/CD99-positive like Ewing sarcoma or CD45RO-positive like the present case. PMID- 25433997 TI - Dysregulation of apoptotic signaling pathways by interaction of RPLP0 and cathepsin X/Z in gastric cancer. AB - Cathepsin X (CTSX, also called cathepsin Z/P) is a cysteine protease that still plays an unknown role in human cancer. It has been shown to bind cell surface heparin sulphate proteoglycans and integrins, indicating possible functions of CTSX in cellular adhesion, phagocytosis, and immune response. Our previous studies have shown an association between Helicobacter pylori (H. pylori) infection, a strong up-regulation of CTSX, and development of gastric cancer. In this study, yeast two-hybrid analysis revealed that RPLP0, a ribosomal protein P0, interacts with the human CTSX protein in gastric cancer. The CTSX/RPLP0 interaction was confirmed by co-immunoprecipitation assays. In addition, co localization studies in cancer cell line N87 and gastric cancer tissue samples were performed. Laserscan microscopy revealed a shuttling of RPLP0 (and CTSX) from cytoplasm to the nucleus after CTSX knockdown. Down-regulation of RPLP0 resulted in G1 arrest of gastric cancer cells, whereas knockdown of CTSX led to G1 arrest and apoptosis after 48 h. Knockdown of both proteins caused increased apoptosis. RPLP0 deficiency could suppress cell growth and cell cycle progression by down-regulating CDK2. It was further demonstrated that RPLP0 affected p21 expression, but did not change the expression of Cyclin E. Down-regulation of both proteins at least through CDK2 suggests an anti-apoptotic effect on gastric cancer cells and opens up new possibilities for apoptotic immune modulation and gastric cancer therapy. PMID- 25433999 TI - Synthesis and characterization of monodisperse poly(ethylene glycol)-conjugated collagen pentapeptides with collagen biosynthesis-stimulating activity. AB - Although collagen pentapeptide (Lys-Thr-Thr-Lys-Ser, KTTKS) has received a great deal of attention owing to its collagen biosynthesis-stimulating effects, its enzymatic instability in the skin is an obstacle to effective topical application. PEGylation is a useful approach for improving the chemical and biological stability of peptides. However, the polydispersity of poly(ethylene glycol) (PEG) produces conjugates with different molecular sizes, which may create difficulties in chemical characterization and purity control, and in variability of biological properties. To overcome these difficulties, monodisperse PEG was site-specifically conjugated to the N-terminal amine of KTTKS to produce a single molecular conjugate, enabling more complete chemical characterization and more exact product specifications. PEG-KTTKS conjugates prepared using monodisperse PEG with two different molecular weights, monodisperse PEG220 and PEG572, were characterized by mass spectrometry. These monodisperse PEG-KTTKS conjugates showed no cytotoxicity (1-100 MUM) and stimulated collagen biosynthesis in human skin fibroblasts. They also had high stability against proteolytic enzymes in rat skin. This study demonstrates the usefulness of monodisperse PEG for preparing chemically defined conjugates and suggests that monodisperse PEG-KTTKS would be a good candidate for use as a collagen biosynthesis-stimulating agent. PMID- 25433998 TI - Involvement of p29/SYF2/fSAP29/NTC31 in the progression of NSCLC via modulating cell proliferation. AB - p29, also known as SYF2/fSAP29/NTC31, is a protein associated with chromatin and involved in DNA damage response, cell cycle arrest and pre-mRNA splicing. In p29 depleted cells, DNA replication was reduced and cell population in G1 phase increased. In this study, we investigated the potential role of p29 in the regulation of non-small cell lung cancer (NSCLC) progression. Western blot and immunohistochemistry staining showed that p29 was up-regulated in clinical NSCLC tissues compared with adjacent non-cancerous tissues, and the expression of p29 had a positive correlation with clinical stage and histological differentiation, as well as expression of Ki-67, a proliferating marker. Kaplan-Meier analysis indicated that patients with high level of p29 expression had poor overall survival. In addition, small interfering RNA of p29 was performed, and the effects on NSCLC growth were examined. Interference of p29 blocked S phase entry, inhibited proliferation of A549 cells and up-regulated level of p21 expression. Taken together, these results suggested that p29 might contribute to the progression of NSCLC by enhancing cell proliferation, implicating that targeting p29 might provide beneficial effects on the clinical therapy of NSCLC. PMID- 25434000 TI - Enediynes: Exploration of microbial genomics to discover new anticancer drug leads. AB - The enediyne natural products have been explored for their phenomenal cytotoxicity. The development of enediynes into anticancer drugs has been successfully achieved through the utilization of polymer- and antibody-drug conjugates (ADCs) as drug delivery systems. An increasing inventory of enediynes would benefit current application of ADCs in many oncology programs. Innovations in expanding the enediyne inventory should take advantage of the current knowledge of enediyne biosynthesis and post-genomics technologies. Bioinformatics analysis of microbial genomes reveals that enediynes are underexplored, in particular from Actinomycetales. This digest highlights the emerging opportunities to explore microbial genomics for the discovery of novel enediyne natural products. PMID- 25434001 TI - Modification of amphipathic non-opioid dynorphin A analogues for rat brain bradykinin receptors. AB - It has been shown that under chronic pain or nerve injury conditions, up regulated dynorphin A (Dyn A) interacts with bradykinin receptors (BRs) to cause hyperalgesia in the spinal cord. Thus BRs antagonist can modulate hyperalgesia by blocking Dyn A's interaction with the BRs in the central nervous system. In our earlier structure-activity relationship (SAR) study, [des-Arg(7)]-Dyn A-(4-11) 13 was discovered as a minimum pharmacophore for rat brain BRs with its antagonist activity (anti-hyperalgesic effect) in in vivo tests using naive or injured animals. We have pursued further modification on the [des-Arg(7)]-Dyn A analogues and identified a key insight into the pharmacophore of the rat brain BRs: amphipathicity. PMID- 25434002 TI - New anti-inflammatory tocopherol-derived metabolites from the Taiwanese soft coral Cladiella hirsuta. AB - Two new tocopherol-derived metabolites, hirsutocospiro A (1) and hirsutocoquinone A (2), were isolated from the soft coral Cladiella hirsuta. The structures of 1 and 2 were determined by extensive spectroscopic analysis. The in vitro anti inflammatory activity of compounds 1 and 2 was evaluated by measuring their ability in suppressing superoxide anion generation and elastase release in fMLP/CB-induced human neutrophils. Compound 1 was shown to exhibit significant anti-inflammatory activity. PMID- 25434003 TI - Compound heterozygosity of low-frequency promoter deletions and rare loss-of function mutations in TXNL4A causes Burn-McKeown syndrome. AB - Mutations in components of the major spliceosome have been described in disorders with craniofacial anomalies, e.g., Nager syndrome and mandibulofacial dysostosis type Guion-Almeida. The U5 spliceosomal complex of eight highly conserved proteins is critical for pre-mRNA splicing. We identified biallelic mutations in TXNL4A, a member of this complex, in individuals with Burn-McKeown syndrome (BMKS). This rare condition is characterized by bilateral choanal atresia, hearing loss, cleft lip and/or palate, and other craniofacial dysmorphisms. Mutations were found in 9 of 11 affected families. In 8 families, affected individuals carried a rare loss-of-function mutation (nonsense, frameshift, or microdeletion) on one allele and a low-frequency 34 bp deletion (allele frequency 0.76%) in the core promoter region on the other allele. In a single highly consanguineous family, formerly diagnosed as oculo-oto-facial dysplasia, the four affected individuals were homozygous for a 34 bp promoter deletion, which differed from the promoter deletion in the other families. Reporter gene and in vivo assays showed that the promoter deletions led to reduced expression of TXNL4A. Depletion of TXNL4A (Dib1) in yeast demonstrated reduced assembly of the tri-snRNP complex. Our results indicate that BMKS is an autosomal-recessive condition, which is frequently caused by compound heterozygosity of low-frequency promoter deletions in combination with very rare loss-of-function mutations. PMID- 25434004 TI - Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy. AB - Respiratory chain deficiencies exhibit a wide variety of clinical phenotypes resulting from defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mtDNA or mutations in nuclear genes coding for mitochondrial proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial physiology. By whole-exome and candidate gene sequencing, we identified 11 individuals from 9 families carrying compound heterozygous or homozygous mutations in GTPBP3, encoding the mitochondrial GTP-binding protein 3. Affected individuals from eight out of nine families presented with combined respiratory chain complex deficiencies in skeletal muscle. Mutations in GTPBP3 are associated with a severe mitochondrial translation defect, consistent with the predicted function of the protein in catalyzing the formation of 5-taurinomethyluridine (taum(5)U) in the anticodon wobble position of five mitochondrial tRNAs. All case subjects presented with lactic acidosis and nine developed hypertrophic cardiomyopathy. In contrast to individuals with mutations in MTO1, the protein product of which is predicted to participate in the generation of the same modification, most individuals with GTPBP3 mutations developed neurological symptoms and MRI involvement of thalamus, putamen, and brainstem resembling Leigh syndrome. Our study of a mitochondrial translation disorder points toward the importance of posttranscriptional modification of mitochondrial tRNAs for proper mitochondrial function. PMID- 25434005 TI - Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with alpha-synuclein pathology. AB - Advances in understanding the etiology of Parkinson disease have been driven by the identification of causative mutations in families. Genetic analysis of an Australian family with three males displaying clinical features of early-onset parkinsonism and intellectual disability identified a ~45 kb deletion resulting in the complete loss of RAB39B. We subsequently identified a missense mutation (c.503C>A [p.Thr168Lys]) in RAB39B in an unrelated Wisconsin kindred affected by a similar clinical phenotype. In silico and in vitro studies demonstrated that the mutation destabilized the protein, consistent with loss of function. In vitro small-hairpin-RNA-mediated knockdown of Rab39b resulted in a reduction in the density of alpha-synuclein immunoreactive puncta in dendritic processes of cultured neurons. In addition, in multiple cell models, we demonstrated that knockdown of Rab39b was associated with reduced steady-state levels of alpha synuclein. Post mortem studies demonstrated that loss of RAB39B resulted in pathologically confirmed Parkinson disease. There was extensive dopaminergic neuron loss in the substantia nigra and widespread classic Lewy body pathology. Additional pathological features included cortical Lewy bodies, brain iron accumulation, tau immunoreactivity, and axonal spheroids. Overall, we have shown that loss-of-function mutations in RAB39B cause intellectual disability and pathologically confirmed early-onset Parkinson disease. The loss of RAB39B results in dysregulation of alpha-synuclein homeostasis and a spectrum of neuropathological features that implicate RAB39B in the pathogenesis of Parkinson disease and potentially other neurodegenerative disorders. PMID- 25434006 TI - MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections. AB - Thoracic aortic aneurysm and dissection (TAAD) is an autosomal-dominant disorder with major life-threatening complications. The disease displays great genetic heterogeneity with some forms allelic to Marfan and Loeys-Dietz syndrome, and an important number of cases still remain unexplained at the molecular level. Through whole-exome sequencing of affected members in a large TAAD-affected family, we identified the c.472C>T (p.Arg158(*)) nonsense mutation in MFAP5 encoding the extracellular matrix component MAGP-2. This protein interacts with elastin fibers and the microfibrillar network. Mutation screening of 403 additional probands identified an additional missense mutation of MFAP5 (c.62G>T [p.Trp21Leu]) segregating with the disease in a second family. Functional analyses performed on both affected individual's cells and in vitro models showed that these two mutations caused pure or partial haploinsufficiency. Thus, alteration of MAGP-2, a component of microfibrils and elastic fibers, appears as an initiating mechanism of inherited TAAD. PMID- 25434009 TI - Innovative sampling and extraction methods for the determination of nonsteroidal anti-inflammatory drugs in water. AB - Two different innovative approaches were used for the determination of nonsteroidal anti-inflammatory drugs (NSAIDs) in water: stir bar sorptive extraction (SBSE) and passive sampling, followed by electrospray ionization liquid chromatography-tandem mass spectrometry. SBSE was developed by comparing EG-Silicone and PDMS stir bars and optimizing main parameters to attain high preconcentration. Quantitative analysis was carried out by mass spectrometry in negative ionization mode and multiple reaction monitoring. The SBSE-LC-MS/MS method provided satisfactory figures of merit with LOD (7.5-71 ng L(-1)) and LOQ (22.5-213 ng L(-1)). The developed method was successfully applied to real samples collected from river water and wastewater effluents. The obtained results showed the presence of all analytes at trace levels, in a wide range of concentrations. The passive sampling approach was carried out by using Polar Organic Chemical Integrative Sampler (POCIS); samplers were deployed for 15 days in river and tap water, allowing to detect analytes at ultra-trace levels. Time Weighted Average concentration of NSAIDs in river water was estimated in the range 0.33-0.46 ng L(-1), using the sampling rates previously obtained by means of a simple calibration system. PMID- 25434010 TI - History of hepatic bile formation: old problems, new approaches. AB - Studies of hepatic bile formation reported in 1958 established that it was an osmotically generated water flow. Intravenous infusion of sodium taurocholate established a high correlation between hepatic bile flow and bile acid excretion. Secretin, a hormone that stimulates bicarbonate secretion, was also found to increase hepatic bile flow. The sources of the water entering the biliary system with these two stimuli were differentiated by the use of mannitol. An increase in its excretion parallels the increase in bile flow in response to bile acids but not secretin, which led to a quantitative distinction between canalicular and ductular water flow. The finding of aquaglyceroporin-9 in the basolateral surface of the hepatocyte accounted for the rapid entry of mannitol into hepatocytes and its exclusion from water movement in the ductules where aquaporin-1 is present. Electron microscopy demonstrated that bile acids generate the formation of vesicles that contain lecithin and cholesterol after their receptor-mediated canalicular transport. Biophysical studies established that the osmotic effect of bile acids varies with their concentration and also with the proportion of mono-, di-, and trihydroxy bile acids and provides a basis for understanding their physiological effects. Because of the varying osmotic effect of bile acids, it is difficult to quantify bile acid independent flow generated by other solutes, such as glutathione, which enters the biliary system. Monohydroxy bile acids, by markedly increasing aggregation number, severely reduce water flow. Developing biomarkers for the noninvasive assessment of normal hepatic bile flow remains an elusive goal that merits further study. PMID- 25434008 TI - Organ-specific protective role of NKT cells in virus-induced inflammatory demyelination and myocarditis depends on mouse strain. AB - Theiler's murine encephalomyelitis virus (TMEV) can induce demyelination or myocarditis in susceptible mouse strains. A deficiency of NKT cells exacerbated TMEV-induced demyelinating disease (TMEV-IDD) in SJL/J and BALB/c mice. In C57BL/6 background, however, NKT-cell-deficient Jalpha18 KO mice remained as resistant to TMEV-IDD as wild-type mice. Echocardiography and histology showed that Jalpha18 KO mice developed more severe myocarditis (greater T cell infiltration and fibrosis) than wild-type mice, suggesting a protective role of NKT cells in myocarditis in C57BL/6 mice. Jalpha18 KO mice had higher cardiac viral RNA and anti-viral antibody titers, but had lower lymphoproliferation and IL-4 and IL-10 production. PMID- 25434011 TI - Resolving an 80-yr-old controversy: the beginning of the modern era of renal physiology. AB - Marcello Malpighi discovered the glomerulus that bears his name in the 17th century, but it was not until the middle of the 19th century, in 1842, that William Bowman in London published his studies of the histological structure of the glomerulus and proposed that urine formation begins with glomerular secretion. At nearly the same time in Marburg, Carl Ludwig, unaware of Bowman's findings, proposed that urine formation begins with glomerular filtration followed by tubule reabsorption. The controversy lasted 80 yr. Prominent investigators weighed in on both sides. Rudolph Heidenhain's findings in 1874 swung the pendulum toward Bowman's theory until Arthur Cushny published his book, The Secretion of Urine, in 1917, in which he found the evidence insufficient to prove either theory. In 1921, a young physician, Joseph Wearn, began his postresidency training in the laboratory of Alfred N. Richards. He read Cushny's book and learned how to expose the glomerulus of a living frog. Richards proposed that Wearn use that experimental preparation to inject epinephrine into the glomerulus. Wearn proposed a different experiment: instead of using injection, collect fluid from the glomerulus and analyze it. Richards agreed, and the landmark results of that experiment, published in 1924, settled the controversy. The modern era of renal physiology was born. PMID- 25434007 TI - A rare functional noncoding variant at the GWAS-implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder. AB - Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ~6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) <0.5%. The rare variant burden in promoters and enhancers, but not insulators, was associated with SZ (p = 0.021 for MAF < 0.5%, p = 0.003 for MAF < 0.1%). A rare enhancer SNP, 1:g.98515539A>T, presented exclusively in 11 SZ cases (nominal p = 4.8 * 10( 4)). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression. PMID- 25434014 TI - Use of the NBME Comprehensive Basic Science Examination as a progress test in the preclerkship curriculum of a new medical school. AB - In the present study, we describe the innovative use of the National Board of Medical Examiners (NBME) Comprehensive Basic Science Examination (CBSE) as a progress test during the preclerkship medical curriculum. The main aim of this study was to provide external validation of internally developed multiple-choice assessments in a new medical school. The CBSE is a practice exam for the United States Medical Licensing Examination (USMLE) Step 1 and is purchased directly from the NBME. We administered the CBSE five times during the first 2 yr of medical school. Student scores were compared with scores on newly created internal summative exams and to the USMLE Step 1. Significant correlations were observed between almost all our internal exams and CBSE scores over time as well as with USMLE Step 1 scores. The strength of correlations of internal exams to the CBSE and USMLE Step 1 broadly increased over time during the curriculum. Student scores on courses that have strong emphasis on physiology and pathophysiology correlated particularly well with USMLE Step 1 scores. Student progress, as measured by the CBSE, was found to be linear across time, and test performance fell behind the anticipated level by the end of the formal curriculum. These findings are discussed with respect to student learning behaviors. In conclusion, the CBSE was found to have good utility as a progress test and provided external validation of our new internally developed multiple choice assessments. The data also provide performance benchmarks both for our future students to formatively assess their own progress and for other medical schools to compare learning progression patterns in different curricular models. PMID- 25434015 TI - Fostering improved anatomy and physiology instructor pedagogy. AB - Despite widespread calls for reform in undergraduate science, technology, engineering, and mathematics education, effecting lasting change in instructor practice is challenging to achieve. This article describes the results of a 2-yr research study that involved efforts to develop the pedagogical expertise of a group of anatomy and physiology instructors at the college level. Data were collected through a series of individual interviews that included the use of the Teacher Beliefs Inventory questionnaire (23) along with observations onsite in participants' college classrooms and at process-oriented guided inquiry learning (POGIL) curriculum writing workshops. Findings indicated attitudinal shifts on the part of participants from teacher-centered to more student-centered pedagogy and supported the benefits of long-term professional development for instructors. Here, we documented the successful progress of these professors as they participated in a curriculum development process that emphasized student-centered teaching with the goal of promoting broader change efforts in introductory anatomy and physiology. PMID- 25434013 TI - Exercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle. AB - Exercise is a well-established tool to prevent and combat type 2 diabetes. Exercise improves whole body metabolic health in people with type 2 diabetes, and adaptations to skeletal muscle are essential for this improvement. An acute bout of exercise increases skeletal muscle glucose uptake, while chronic exercise training improves mitochondrial function, increases mitochondrial biogenesis, and increases the expression of glucose transporter proteins and numerous metabolic genes. This review focuses on the molecular mechanisms that mediate the effects of exercise to increase glucose uptake in skeletal muscle. PMID- 25434012 TI - Aerobic exercise and other healthy lifestyle factors that influence vascular aging. AB - Cardiovascular diseases (CVDs) remain the leading cause of death in the United States and other modern societies. Advancing age is the major risk factor for CVD, primarily due to stiffening of the large elastic arteries and the development of vascular endothelial dysfunction. In contrast, regular aerobic exercise protects against the development of large elastic artery stiffness and vascular endothelial dysfunction with advancing age. Moreover, aerobic exercise interventions reduce arterial stiffness and restore vascular endothelial function in previously sedentary middle-aged/older adults. Aerobic exercise exerts its beneficial effects on arterial function by modulating structural proteins, reducing oxidative stress and inflammation, and restoring nitric oxide bioavailability. Aerobic exercise may also promote "resistance" against factors that reduce vascular function and increase CVD risk with age. Preventing excessive increases in abdominal adiposity, following healthy dietary practices, maintaining a low CVD risk factor profile, and, possibly, selective use of pharmaceuticals and nutraceuticals also play a major role in preserving vascular function with aging. PMID- 25434016 TI - Positive impact of integrating histology and physiology teaching at a medical school in China. AB - To modernize its stagnant, traditional curriculum and pedagogy, the Medical School of Wuhan University in China adopted (with modifications) the University of Chicago's medical curriculum model. The reform effort in basic sciences was integrating histology and physiology into one course, increasing the two subjects' connection to clinical medicine, and applying new pedagogies and assessment methods. This study assessed the results of the reform by comparing the attitudes and academic achievements of students in the reform curriculum (n = 41) and their traditional curriculum peers (n = 182). An attitude survey was conducted to obtain students' views of their respective histology and physiology instruction. Survey items covered lectures, laboratory teaching, case analyses and small-group case discussions, assessment of students, and overall quality of the courses and instruction. A knowledge test consisting of questions from three sources was given to measure students' mastery of topics that they had learned. Results showed that reform curriculum students were rather satisfied with their course and new teaching methods in most cases. When these students' attitudes were compared with those of their traditional curriculum peers, several significant differences favoring the reform were identified regarding physiology teaching. No other significant difference was found for physiology or histology teaching. Reform curriculum students outperformed their peers on four of five subcategories of the knowledge test questions. These findings support the benefits of integration and state-of-the-art teaching methods. Our study may offer lessons to medical schools in China and other countries whose medical education is in need of change. PMID- 25434017 TI - The flipped exam: creating an environment in which students discover for themselves the concepts and principles we want them to learn. AB - Students are naturally curious and inquisitive with powerful intrinsic motives to probe, learn, and understand their world. Accordingly, class activities must capitalize on this inherently energetic and curious nature so that learning becomes a lifelong activity where students take initiative for learning, are skilled in learning, and want to learn new things. This report describes a student-centered class activity, the "flipped exam," designed to achieve this goal. The flipped exam was a collaborative, group effort, and learning was interactive. It included a significant proportion (~30-35%) of material not covered in class. This required students to actively search for content and context, dynamically making connections between what they knew and what they learned, grappling with complexity, uncertainty, and ambiguity, and finally discovering answers to important questions. Accordingly, the need or desire to know was the catalyst for meaningful learning. Student assessment was determined by behavioral noncognitive parameters that were based on the observation of the student and the student's work as well as cognitive parameters (i.e., the student's score on the examination). It is our view that the flipped exam provided a student-centered activity in which students discovered, because of the need to know and opportunities for discussion, the important concepts and principles we wanted them to learn. PMID- 25434018 TI - Combining simulated patients and simulators: pilot study of hybrid simulation in teaching cardiac auscultation. AB - Auscultation torsos are widely used to teach position-dependent heart sounds and murmurs. To provide a more realistic teaching experience, both whole body auscultation mannequins and torsos have been used in clinical examination skills training at the Medical Faculty of the University of Muenster since the winter term of 2008-2009. This training has since been extended by simulated patients, which are normal, healthy subjects who have undergone attachment of the electronic components of the auscultation mannequins to their chests to mimic pathophysiological conditions ("hybrid models"). The acceptance of this new learning method was examined in the present pilot study. In total, 143 students in their second preclinical year who were participating in auscultation training were randomized into an intervention group (hybrid models) and a control group (auscultation mannequins). One hundred forty-two (99.3%) of these students completed a self-assessment Likert-scale questionnaire regarding different teaching approaches (where 1 = "very poor" to 100 = "very good"). The questionnaire focused on the "value of learning" of different teaching approaches. Direct comparison showed that students evaluated the hybrid models to be significantly more effective than the auscultation mannequins (median: 83 vs. 64, P < 0.001). The cardiac auscultation training was generally assessed positively (median: 88). Additionally, verbal feedback was obtained from simulated patients and tutors (trained students who had successfully passed the course a few semesters earlier). Personal feedback showed high satisfaction from student tutors and simulated patients. Hybrid simulators for teaching cardiac auscultation elucidated positive responses from students, tutors, and simulated patients. PMID- 25434019 TI - Investigation of physiological properties of nerves and muscles using electromyography. AB - The measurement and representation of the electrical activity of muscles [electromyography (EMG)] have a long history from the Victorian Era until today. Currently, EMG has uses both as a research tool, in noninvasively recording muscle activation, and clinically in the diagnosis and assessment of nerve and muscle disease and injury as well as in assessing the recovery of neuromuscular function after nerve damage. In the present report, we describe the use of a basic EMG setup in our teaching laboratories to demonstrate some of these current applications. Our practical also illustrates some fundamental physiological and structural properties of nerves and muscles. Learning activities include 1) displaying the recruitment of muscle fibers with increasing force development; 2) the measurement of conduction velocity of motor nerves; 3) the assessment of reflex delay and demonstration of Jendrassik's maneuver; and 4) a Hoffman reflex experiment that illustrates the composition of mixed nerves and the differential excitability thresholds of fibers within the same nerve, thus aiding an understanding of the reflex nature of muscle control. We can set up the classes at various levels of inquiry depending on the needs/professional requirements of the class. The results can then provide an ideal platform for a discovery learning session/tutorial on how the central nervous system controls muscles, giving insights on how supraspinal control interacts with reflexes to give smooth, precise muscular activation. PMID- 25434020 TI - Using stimulation of the diving reflex in humans to teach integrative physiology. AB - During underwater submersion, the body responds by conserving O2 and prioritizing blood flow to the brain and heart. These physiological adjustments, which involve the nervous, cardiovascular, and respiratory systems, are known as the diving response and provide an ideal example of integrative physiology. The diving reflex can be stimulated in the practical laboratory setting using breath holding and facial immersion in water. Our undergraduate physiology students complete a laboratory class in which they investigate the effects of stimulating the diving reflex on cardiovascular variables, which are recorded and calculated with a Finapres finger cuff. These variables include heart rate, cardiac output, stroke volume, total peripheral resistance, and arterial pressures (mean, diastolic, and systolic). Components of the diving reflex are stimulated by 1) facial immersion in cold water (15 degrees C), 2) breathing with a snorkel in cold water (15 degrees C), 3) facial immersion in warm water (30 degrees C), and 4) breath holding in air. Statistical analysis of the data generated for each of these four maneuvers allows the students to consider the factors that contribute to the diving response, such as the temperature of the water and the location of the sensory receptors that initiate the response. In addition to providing specific details about the equipment, protocols, and learning outcomes, this report describes how we assess this practical exercise and summarizes some common student misunderstandings of the essential physiological concepts underlying the diving response. PMID- 25434021 TI - Use of analogies in the study of diffusion. PMID- 25434022 TI - PHARMAVIRTUA: educational software for teaching and learning basic pharmacology. PMID- 25434023 TI - High-fidelity patient simulators to expose undergraduate students to the clinical relevance of physiology concepts. PMID- 25434024 TI - What gets a cell excited? Kinky curves. PMID- 25434025 TI - Inspiring careers through medical simulation: reasons for caution. PMID- 25434026 TI - Reply to Walsh. PMID- 25434027 TI - Pollen tube cell walls of wild and domesticated tomatoes contain arabinosylated and fucosylated xyloglucan. AB - BACKGROUND AND AIMS: In flowering plants, fertilization relies on the delivery of the sperm cells carried by the pollen tube to the ovule. During the tip growth of the pollen tube, proper assembly of the cell wall polymers is required to maintain the mechanical properties of the cell wall. Xyloglucan (XyG) is a cell wall polymer known for maintaining the wall integrity and thus allowing cell expansion. In most angiosperms, the XyG of somatic cells is fucosylated, except in the Asterid clade (including the Solanaceae), where the fucosyl residues are replaced by arabinose, presumably due to an adaptive and/or selective diversification. However, it has been shown recently that XyG of Nicotiana alata pollen tubes is mostly fucosylated. The objective of the present work was to determine whether such structural differences between somatic and gametophytic cells are a common feature of Nicotiana and Solanum (more precisely tomato) genera. METHODS: XyGs of pollen tubes of domesticated (Solanum lycopersicum var. cerasiforme and var. Saint-Pierre) and wild (S. pimpinellifolium and S. peruvianum) tomatoes and tobacco (Nicotiana tabacum) were analysed by immunolabelling, oligosaccharide mass profiling and GC-MS analyses. KEY RESULTS: Pollen tubes from all the species were labelled with the mAb CCRC-M1, a monoclonal antibody that recognizes epitopes associated with fucosylated XyG motifs. Analyses of the cell wall did not highlight major structural differences between previously studied N. alata and N. tabacum XyG. In contrast, XyG of tomato pollen tubes contained fucosylated and arabinosylated motifs. The highest levels of fucosylated XyG were found in pollen tubes from the wild species. CONCLUSIONS: The results clearly indicate that the male gametophyte (pollen tube) and the sporophyte have structurally different XyG. This suggests that fucosylated XyG may have an important role in the tip growth of pollen tubes, and that they must have a specific set of functional XyG fucosyltransferases, which are yet to be characterized. PMID- 25434029 TI - Planthopper (Hemiptera: Flatidae) parasitized by larval erythraeid mite (Trombidiformes: Erythraeidae)-a description of two new species from western Madagascar. AB - Descriptions of Dambullaeus adonis Makol et Moniuszko SP NOV: (Trombidiformes: Erythraeidae, Callidosomatinae) and Latois nigrolineata Swierczewski et Stroinski SP NOV: (Hemiptera: Fulgoromorpha, Flatidae) from Madagascar are provided. The first host record for ectoparasitic larvae of Dambullaeus Haitlinger, 2001 and the first evidence on host-parasite association between flatid adult and erythraeid larvae are given. Genus Dambullaeus, known exclusively from larvae and now comprising two species of Gondwanan distribution, is critically reappraised. PMID- 25434028 TI - Population divergence in the ontogenetic trajectories of foliar terpenes of a Eucalyptus species. AB - BACKGROUND AND AIMS: The development of plant secondary metabolites during early life stages can have significant ecological and evolutionary implications for plant-herbivore interactions. Foliar terpenes influence a broad range of ecological interactions, including plant defence, and their expression may be influenced by ontogenetic and genetic factors. This study investigates the role of these factors in the expression of foliar terpene compounds in Eucalyptus globulus seedlings. METHODS: Seedlings were sourced from ten families each from three genetically distinct populations, representing relatively high and low chemical resistance to mammalian herbivory. Cotyledon-stage seedlings and consecutive leaf pairs of true leaves were harvested separately across an 8-month period, and analysed for eight monoterpene compounds and six sesquiterpene compounds. KEY RESULTS: Foliar terpenes showed a series of dynamic changes with ontogenetic trajectories differing between populations and families, as well as between and within the two major terpene classes. Sesquiterpenes changed rapidly through ontogeny and expressed opposing trajectories between compounds, but showed consistency in pattern between populations. Conversely, changed expression in monoterpene trajectories was population- and compound-specific. CONCLUSIONS: The results suggest that adaptive opportunities exist for changing levels of terpene content through ontogeny, and evolution may exploit the ontogenetic patterns of change in these compounds to create a diverse ontogenetic chemical mosaic with which to defend the plant. It is hypothesized that the observed genetically based patterns in terpene ontogenetic trajectories reflect multiple changes in the regulation of genes throughout different terpene biosynthetic pathways. PMID- 25434031 TI - Trichoptera biodiversity of the Aegean and Adriatic sea basins in the republic of Kosovo. AB - We present the first preliminary inventory of Trichoptera taxa in the Aegean and Adriatic Sea basins in Kosovo that have previously received poor and fragmentary attention. Adult caddisflies were collected using ultraviolet (UV) light traps in 13 stations in areas of the Aegean Sea and Adriatic Sea drainage basins in Kosovo. Nineteen species out of 82, reported in this article, are first records for the Kosovo caddisfly fauna. Five genera are recorded for the first time in Kosovo: Brachycentrus, Ecclisopteryx, Psilopteryx, Thremma, and Oecetis. During this investigation, we found several Southeastern European endemic and rare species whose previous known distribution was limited to particular areas of this region, as well as other species whose distribution is considerably enlarged by this investigation: Polycentropus ierapetra, Polycentropus irroratus, Chaetopteryx stankovici, Drusus schmidi, Drusus tenellus, Potamophylax goulandriourum, Oecetis notata, and Notidobia melanoptera. Even though this article is a result of a limited sampling effort, it increases the number of Trichoptera taxa recorded for the Republic of Kosovo to 131. PMID- 25434030 TI - A genome-wide identification of basic helix-loop-helix motifs in Pediculus humanus corporis (Phthiraptera: Pediculidae). AB - Basic helix-loop-helix (bHLH) proteins comprise a large superfamily of transcription factors, which are involved in the regulation of various developmental processes. bHLH family members are widely distributed in various eukaryotes including yeast, fruit fly, zebrafish, mouse, and human. In this study, we identified 55 bHLH motifs encoded in genome sequence of the human body louse, Pediculus humanus corporis (Phthiraptera: Pediculidae). Phylogenetic analyses of the identified P. humanus corporis bHLH (PhcbHLH) motifs revealed that there are 23, 11, 9, 1, 10, and 1 member(s) in groups A, B, C, D, E, and F, respectively. Examination to GenBank annotations of the 55 PhcbHLH members indicated that 29 PhcbHLH proteins were annotated in consistence with our analytical result, 8 were annotated different with our analytical result, 12 were merely annotated as hypothetical protein, and the rest 6 were not deposited in GenBank. A comparison on insect bHLH gene composition revealed that human body louse possibly has more hairy and E(spl) genes than other insect species. Because hairy and E(spl) genes have been found to negatively regulate the differentiation of insect preneural cells, it is suggested that the existence of additional hairy and E(spl) genes in human body louse is probably the consequence of its long period adaptation to the relatively dark and stable environment. These data provide good references for further studies on regulatory functions of bHLH proteins in the growth and development of human body louse. PMID- 25434032 TI - Identification of larvae of endangered Cucujus cinnaberinus and C. haematodes (Coleoptera: Cucujidae). AB - The red flat bark beetle Cucujus cinnaberinus (Scopoli, 1763) is included as a protected species in the Berne Convention and the European Habitat Directive Annex II and IV (92/43 EU of 21 May 1992) which requires the establishment of special areas of conservation in the European Union, and listing the species in the International Union for Conservation of Nature Red List of Threatened Species under the near-threatened category. Cucujus haematodes Erichson, 1845 is considered to be one of the most threatened saproxylic species, a relic of primeval forests, in many European countries (including Poland) under protection. Morphology of the larvae of two rare European species of the genus Cucujus (cinnaberinus and haematodes) is compared here. We point out differences which allow the two species to be properly distinguished and which, until now, have been omitted or misinterpreted in literature. The best characteristics seem to be the arrangement of minor spines on the top of basal tooth, the shape of frontal suture, size of stemmata, shape of I antennal joint, localization of basal tooth, and morphology of VIII abdominal tergites. PMID- 25434033 TI - Insect fauna associated with Anacardium occidentale (Sapindales: Anacardiaceae) in Benin, West Africa. AB - Cashew, Anacardium occidentale L. (Sapindales: Anacardiaceae), is an important cash crop in Benin. However, its production is threatened by several biotic factors, especially insects. In Benin, very few studies have focused on insects and just listed species commonly found on cashew worldwide. The present investigation fills this gap by presenting an exhaustive inventory of insect species associated with this crop in the country. The survey was carried out from September 2009 to August 2010 in 22 cashew orchards (5 young and 17 mature) distributed over three major agroecological zones where cashew is most produced in the country. Insects were collected using chemical knock-down technique and visual observation followed by capture with sweep net. In addition, infested plant organs were sampled and incubated to collect emerging insects. In total, 262 insect species were recorded and identified. Among them, the wood borer Apate terebrans Pallas, the leafminer Eteoryctis gemoniella Stainton, and the mirid bugs Helopeltis schoutedeni Reuter., and Helopeltis anacardii Miller., appeared as the most important insect species attacking cashew in Benin. Beneficial insects encountered included some predators, parasitoids, and pollinators. Few vertebrate predators were also recorded on the trees. Differences in agroecological conditions or in field cleanliness did not affect the number of insect species encountered in the cashew orchards. The results of this study represent an important baseline data for the design and implementation of strategies for cashew protection in Benin. PMID- 25434034 TI - Establishment of Vespa bicolor in Taiwan (Hymenoptera: Vespidae). AB - The establishment of a hornet, Vespa bicolor F., in Taiwan was confirmed based on successful field collection of adults of both sexes and two subterranean colonies. Information on nesting habitat, nest measurement, and colony composition of this species are provided in this article. V. bicolor is the ninth hornet species ever recorded from Taiwan. Possible pathway for the introduction of this alien species is also discussed. PMID- 25434035 TI - Expression and characterization of a recombinant endoglucanase from western corn rootworm, in Pichia pastoris. AB - The endoglucanase cDNA, Dvv-ENGase I, from western corn rootworm, Diabrotica virgifera virgifera LeConte was expressed using the GS115 methylotrophic strain of Pichia pastoris. The Dvv-ENGase I gene was cloned into the integrative plasmid pPICZalphaA under the control of AOX1, which is a methanol-inducible promoter. Positive clones were selected for their ability to produce the recombinant endoglucanase upon continuous methanol induction. The secreted recombinant insect endoglucanase Dvv-ENGase I has an apparent molecular mass of 29 kDa. The recombinant endo-1,4-beta-glucanase (ENGase) was able to digest the substrates: hydroxyethyl cellulose (HEC), carboxymethyl cellulose (CMC), and Whatman No. 1 filter paper. A higher accumulation of reducing sugar was evident when the P. pastoris expression medium contained HEC (1%) instead of CMC (1%). An enzymatic activity band was detected after performing electrophoretic separation under nondenaturing conditions. The biological activity of the recombinant Dvv-ENGase I was influenced by the presence of protease inhibitors in the culture medium. PMID- 25434036 TI - Molecular cloning and characterization of a novel P450 gene encoding CYP6BK18 from Dastarcus helophoroides (Coleoptera: Bothrideridae). AB - A novel cDNA clone encoding a cytochrome P450 gene, named CYP6BK18 (GenBank KC683905), was isolated by reverse transcription PCR from Dastarcus helophoroides (Fairmaire) (Coleoptera: Bothrideridae), a natural enemy of beetles. The full length cDNA sequence is 1,659 bp, containing a 1,533 bp open reading frame predicting a 510-amino acid protein possessing a transmembrane domain with a calculated molecular weight of 59.4 kDa and a theoretical pI of 8.94. The deduced amino acid sequence of CYP6BK18 showed a 59% identity with CYP6BK17 (GenBank XP_970481.1) from Tribolium castaneum. Phylogenetic analysis indicated that CYP6BK18 was most closely related to CYP6BK17 and CYP6BK14 (GenBank EFA05731.1) from T. castaneum. Expression patterns of CYP6BK18 in different tissues (head, oviduct, midgut, fat bodies, and Malpighian tubules), developmental stages (first to sixth-instar larvae and adult) and 10 age groups of adult were analyzed by real-time quantitative PCR (RT-qPCR). The results showed that CYP6BK18 was highly expressed in adulthood. Also, RT-qPCR analysis among different age groups of adult showed that CYP6BK18 transcripts were abundant in the spawning period and peaked at the early stage of the adult development. Moreover, the tissue-specific expression levels of CYP6BK18 were in the order of midgut, Malpighian tubes and fatty body from high to low. These results suggest that cytochrome P450 CYP6BK18 may play a role in regulating the development and aging of D. helophoroides. PMID- 25434037 TI - Temperature-dependent development of two neotropical parasitoids of Liriomyza sativae (Diptera: Agromyzidae). AB - We studied two species of neotropical parasitoids that occur naturally in northeastern Brazil and are associated with Liriomyza sativae (Blanchard): Opius (Gastrosema) scabriventris Nixon (Hymenoptera: Braconidae) and Chrysocharis vonones (Walker) (Hymenoptera: Eulophidae). We evaluated the influence of seven temperatures on the duration of the egg-adult period and on the survivorship of the immature stages of the parasitoids. A temperature increase from 15 to 30 degrees C shortened the egg-adult period of O. scabriventris and C. vonones. However, at 32 degrees C, the developmental time for the braconid was prolonged, and no difference was observed for the eulophid, compared with 30 degrees C. The highest temperature, 35 degrees C, proved to be lethal for both species. At 15 degrees C, C. vonones pupal survivorship was drastically reduced, whereas that of O. scabriventris was unaffected. At most temperatures, the eulophid had an egg adult period shorter than or similar to the braconid, except at 15 degrees C. The threshold temperature (Tt) of the egg-adult period for O. scabriventris was 7.3 degrees C with a thermal constant (K) of 257.1 degree days (DD). For C. vonones the Tt was 7.4 degrees C for the total cycle and 6.2 degrees C for the pupal stage, with a thermal constant of 246.3 and 140.3 DD, respectively. These data allow an estimate of 29.4 annual generations for O. scabriventris and 30.5 for C. vonones in a melon production region in northeastern Brazil, values that are equivalent to 4.9 and 6.0 more generations than the host. These results demonstrate that both species have potential for application in biological control programs against the leafminer fly L. sativae. PMID- 25434039 TI - First report of Zaprionus indianus (Diptera: Drosophilidae) in commercial fruits and vegetables in Pennsylvania. AB - Zaprionus indianus (Gupta) (Diptera: Drosophilidae), an invasive vinegar fly, was found for the first time in Adams County, Pennsylvania, in 2011. It was found in a commercial tart cherry orchard using apple cider vinegar (ACV) traps that were monitoring another invasive vinegar fly, the spotted wing drosophila, Drosophila suzukii (Matsumura) (Diptera: Drosophilidae). Coincidentally, the first record of D. suzukii found in Pennsylvania was also found in this same cherry orchard only 3 months earlier as part of a spotted wing drosophila survey effort in raspberry, blackberry, grape, and tart cherry in Adams County. These same crops plus blueberry and tomato were monitored again in 2012. In this article, adult Z. indianus captures in ACV traps and other traps deployed in the aforementioned crops during 2012 season are presented and the economic importance of Z. indianus is discussed. PMID- 25434038 TI - Cloning, expression, and purification of a new antibacterial substance gene from larvae of Musca domestica (Diptera: Muscidae). AB - Musca domestica L. (Diptera: Muscidae), the housefly, exhibits unique immune defenses and can produce antibacterial substances upon stimulation with bacteria. On the basis of the cDNA library constructed using the suppression subtractive hybridization method, a 1188-bp antibacterial substance gene, which we named AS566, was amplified by rapid amplification of cDNA ends from M. domestica larva stimulated with Salmonella pullorum (Enterobacteriaceae: Salmonella). In this study, the full-length AS566 gene was cloned and inserted into a His-tagged Escherichia coli (Enterobacteriaceae: Escherichia) prokaryotic expression system to enable production of the recombinant protein. The recombinant AS566 protein was purified in denatured form from inclusion bodies and renatured to obtain functionally active AS566 protein. The bacteriostatic activity of the recombinant purified AS566 protein was assessed using the Oxford plate assay system and the results indicated that AS566 had antibacterial activity against six bacteria, including an E. coli clinical isolate, S. pullorum, Streptococcus bovis (Streptococcaceae: Streptococcus), Streptococcus suis, and Staphylococcus aureus (Staphylococcaceae: Staphylococcus) in vitro. The antibacterial activity of AS566 toward Gram- bacteria was two times greater than that against Gram+ bacteria. The sequencing results and BLAST analysis showed that the antibacterial substance gene AS566 was not homologous to any other antibacterial substance genes in GenBank. The antibacterial mechanisms of the newly discovered AS566 protein warrant further study. PMID- 25434040 TI - Sensitivity of Bemisia tabaci (Hemiptera: Aleyrodidae) to several new insecticides in China: effects of insecticide type and whitefly species, strain, and stage. AB - Whitefly biotypes B and Q are the two most damaging members of the Bemisia tabaci (Hemiptera: Aleyrodidae) species complex. Control of B. tabaci (and especially of Q) has been impaired by resistance to commonly used insecticides. To find new insecticides for B. tabaci management in China, we investigated the sensitivity of eggs, larvae, and adults of laboratory strains of B and Q (named Lab-B and Lab Q) and field strains of Q to several insecticides. For eggs, larvae, and adults of B. tabaci and for six insecticides (cyantraniliprole, chlorantraniliprole, pyriproxyfen, buprofezin, acetamiprid, and thiamethoxam), LC50 values were higher for Lab-Q than for Lab-B; avermectin LC50 values, however, were low for adults of both Lab-Q and Lab-B. Based on the laboratory results, insecticides were selected to test against eggs, larvae, and adults of four field strains of B. tabaci Q. Although the field strains differed in their sensitivity to the insecticides, the eggs and larvae of all strains were highly sensitive to cyantraniliprole, and the adults of all strains were highly sensitive to avermectin. The eggs, larvae, and adults of B. tabaci Q were generally more resistant than those of B. tabaci B to the tested insecticides. B. tabaci Q eggs and larvae were sensitive to cyantraniliprole and pyriproxyfen, whereas B. tabaci Q adults were sensitive to avermectin. Field trials should be conducted with cyantraniliprole, pyriproxyfen, and avermectin for control of B. tabaci Q and B in China. PMID- 25434041 TI - Analysis of the mating and reproductive traits of Plutella xylostella (Lepidoptera: Plutellidae). AB - The reproductive traits of the diamondback moth, Plutella xylostella (L.) (Lepidoptera: Plutellidae) were investigated and analyzed by different analytical methods. Simple statistical analysis showed relatively higher mating rates maintained from 21:00 to 2:00, thereafter dropping to a minimum at about 18:00. Mating rates were affected by female and male age. Mating was most likely to take place between females and males that were 1 d old. Correlation and factor analysis indicated that mating delayed females have a relatively lower and unsuccessful mating rate and relatively shorter copulation duration, with lower egg hatchability and fecundity; in addition, the mating delayed male would reduce female's fertility. Delay of mating prolonged life of both males and females. A higher and successful mating rate would cause a higher egg hatchability and fecundity. Canonical correlation analysis showed that mating age and successful copulation of female play a decisive role for her fecundity and longevity, and mating age and mating rates of male play a decisive role for his longevity. PMID- 25434042 TI - Evidence for Ixodes holocyclus (Acarina: Ixodidae) as a vector for human lyme Borreliosis infection in Australia. AB - Ixodes holocyclus (Acarina: Ixodidae) and Ixodes cornuatus (Acarina: Ixodidae) are two tick species found in the more densely populated areas of Australia and are known to be the cause of the neurotoxic disease tick paralysis in humans and mammals. Borreliosis otherwise known as Lyme disease is an emerging infectious disease in humans in Australia. Borrelia burgdorferi sensu stricto (Spirochaetales: Spirochaetaceae) and sensu lato are closely related spirochetal species that are the causative agents of Lyme disease in humans. Clinical transmission of this tick-borne disease can be identified in several but not all cases by a characteristic rash known as erythema migrans. However, there has been no study of the tick vectors of this infection in Australia. We used morphological and molecular techniques to identify unequivocally the ticks on the patients of this study to be I. holocyclus and then show the presence of B. burgdorferi sensu stricto infection in erythema migrans biopsies. I. holocyclus has not previously been associated with erythema migrans or Lyme disease. Two patients presented to the lead author's medical practice with erythema migrans in mid and late 2012. The morphology and cytochrome oxidase 1 and ITS2 genes of the two ticks were studied. The skin at the attachment site was sampled by central biopsy for both real time and endpoint Borrelia polymerase chain reaction (PCR) analysis and subsequent sequencing. Morphologically, the two ticks were either I. holocyclus or I. cornuatus. Molecular studies and nucleotide sequencing revealed that both ticks were I. holocyclus. Real time and endpoint PCR on the central tissue biopsy samples returned positive results for B. burgdorferi DNA. Our results are evidence for transmission of B. burgdorferi sensu stricto species to humans by the tick I. holocyclus in Australia. I. holocyclus is commonly associated with human tick bites on virtually the entire eastern coastline of Australia. PMID- 25434043 TI - A longitudinal examination of health-related quality of life in children and adolescents with spina bifida. AB - OBJECTIVE: The current study examined (1) spina bifida (SB) youths' health related quality of life (HRQOL) compared with nonclinical and chronic health condition (CHC) samples, (2) parent-child agreement regarding HRQOL, and (3) prospective changes in HRQOL. METHODS: Child and parent-proxy reports of Pediatric Quality of Life were collected at two time waves (Time 1: N = 134, ages 8-15 years; Time 2: N = 109, ages 10-17 years) as part of a larger longitudinal study. RESULTS: SB youth had statistically and clinically reduced physical HRQOL compared with the nonclinical and CHC samples at both time points. There were significant discrepancies between youth and parent-proxy reports of HRQOL; youth reported higher levels of physical and social HRQOL than parents. The majority of parent- and child-reported HRQOL domains remained stable, yet youth-reported social HRQOL increased over time. CONCLUSIONS: Youth with SB are at risk for poor HRQOL. Examining modifiable condition and social-environmental predictors of youth HRQOL will be important in informing future interventions. PMID- 25434050 TI - Acute tubulointerstitial nephritis in Scotland. AB - BACKGROUND AND AIMS: Acute tubulointerstitial nephritis (ATIN) is a potentially reversible cause of acute kidney injury with the majority of cases drug related. Our aims were to examine the incidence profile of patients with ATIN in Scotland and to assess the impact of corticosteroid treatment. DESIGN AND METHODS: All adult patients with biopsy-proven ATIN, diagnosed between 2000 and 2012, presenting to renal units serving 1.9 of Scotland's 5 million population were included. Patient demographics, presenting, aetiologic and pathologic features, treatment given and outcome were extracted from patient records. RESULTS: In total, 171 cases representing 4.7% of native renal biopsies were identified. Median serum creatinine (sCr) was 327 MUmol/l at biopsy (106 MUmol/l at baseline). Eosinophilia, fever or rash was present in 57% with all 3 in only 1.1%. Active urinary sediment was found in 68%. Aetiology appeared drug induced in 73%. Proton pump inhibitors (PPIs) were likely causative in almost as many cases as antibiotics (35% each) and were more frequently implicated than non steroidal anti-inflammatory drugs (20%). Number of PPI-related cases paralleled the rising prescription of these drugs. Corticosteroids were prescribed in 59% of drug-induced ATIN (median sCr at biopsy: 356 MUmol/l vs. 280 MUmol/l in those managed conservatively). There was no difference in sCr at 1, 6 and 12 months, with similar proportions of both groups experiencing complete renal recovery (48% vs. 41%) and becoming dialysis dependent (10% in both). CONCLUSIONS: Incidence of biopsy-proven ATIN in Scotland has been rising over the past decade with the majority of cases drug induced. Evidence supporting corticosteroid treatment is lacking. PMID- 25434051 TI - Central retinal artery occlusion and brain infarctions after nasal filler injection. PMID- 25434052 TI - Orphan drugs: expensive yet necessary. AB - Whether the prices of certain orphan treatments are justified is highly controversial. One argument is that such therapies should not be funded through the public purse or private health plans because a patient with a rare disease requires more than their 'fair share' of a limited health care budget. Orphan medications can also be denied because they fare poorly in the cost-effectiveness assessments of drugs. This paper takes the unusual line that life-saving treatments should be provided regardless of their cost. This contention is based on the Harvard philosopher John Rawls' theory of justice. We offer three rules to limit the use of cost-effectiveness approaches: efficiency assessments should not be deployed (i) when the choice is between an only treatment and no treatment, or to (ii) prioritise between different patients and patient groups. However a well considered cost efficiency calculation may have its place (iii) where a patient has a choice between two or more equally safe and effective treatments. We rebut potential objections to this analysis, and conclude that there has been a tendency to classify appeals for orphan treatments as a minority interest and in conflict with the aims of public health and society at large. Rawls' concept of societal justice shows that a distinction between the individual and society in this context is bogus. The funding of orphan therapies is as much a matter for public health as the funding of treatments for other conditions. Treatment must not be withheld on economic grounds. PMID- 25434053 TI - Empyema thoracic necessitans mimicking a tuberculoma. PMID- 25434054 TI - Pericardial absence--is symptomatic partial defect an enigmatic cardiovascular risk? PMID- 25434055 TI - When does a human being die? AB - For most of human history there has been no particular importance of establishing the exact time of a person's death, only whether the person is alive or dead. With modern medical advances, however, more precise answers are looked for. For a definition of death to succeed is important that it is a universal definition and that under it, all human beings are correctly identified as alive or dead. This article initially examines the most commonly proposed positions on when a human being dies those of cardiopulmonary death, whole brain death, brainstem death and higher brain death and for each describes scenarios that provide counter intuitive results. Intuition is used as a benchmark as this is what our patients most commonly use. The second part of the article seeks to establish a more robust definition of death. We argue that death is an event that takes place at a set point in time, when the collection of bodily processes that maintains homoeostasis finally cease. Based upon defining 'human being' as being in possession of human DNA and Olsen's Animalism, the model is applicable to a full lifespan and maintains personal identity throughout the course of life. That this conclusion will interfere with clinical practice concerning organ transplantation is considered, but countered with the argument that there has been a conflation of the normative question of timing of organ retrieval for transplantation with the metaphysical question of what is death. PMID- 25434056 TI - Simple errors in interpretation and publication can be costly--response. PMID- 25434057 TI - Stress and patients' ability to comply with or adhere to treatment regimens. PMID- 25434058 TI - Retraction. PMID- 25434059 TI - Application of psychometric testing for validation in the field of orofacial pain. PMID- 25434060 TI - Special double issue of Monash bioethics review inaugurating the Journal's transition to publication by Springer in 2014. PMID- 25434061 TI - Embracing complexity: theory, cases and the future of bioethics. AB - This paper reflects on the relationship between theory and practice in bioethics, by using various concepts drawn from debates on innovation in healthcare research -in particular debates around how best to connect up blue skies 'basic' research with practical innovations that can improve human lives. It argues that it is a mistake to assume that the most difficult and important questions in bioethics are the most abstract ones, and also a mistake to assume that getting clear about abstract cases will automatically be of much help in getting clear about more complex cases. It replaces this implicitly linear model with a more complex one that draws on the idea of translational research in healthcare. On the translational model, there is a continuum of cases from the most simple and abstract (thought experiments) to the most concrete and complex (real world cases). Insights need to travel in both directions along this continuum--from the more abstract to the more concrete and from the more concrete to the more abstract. The paper maps out some difficulties in moving from simpler to more complex cases, and in doing so makes recommendations about the future of bioethics. PMID- 25434062 TI - The proper scope of the principle of procreative beneficence revisited. AB - The principle of procreative beneficence (PB), first suggested by Julian Savulescu, argues that: If couples (or single reproducers) have decided to have a child, and selection is possible, then they have a significant moral reason to select the child, of the possible children they could have, whose life is expected, in light of the relevant available information, to go best or at least not worse than any.of the others. (Savulescu and Kahane 2009, p. 274). While the validity of this moral principle has been widely contested, in this paper we move away from these issues and grant, for the sake of argument, that PB is a valid moral principle, and that the justification for PBprovided by Savulescu and co authors is sound. We do this in order to explore the implications and consequences of accepting PB and show that even if we put aside questions about the validity and theoretical foundations of this principle, PB has many interesting, astonishing and highly problematic implications that have not been made explicit in the writing of Savulescu and others who support the notion of an obligation to bring to birth the best child possible (Glover, in: Justice between age groops and generations, 1992; Harris, J Med Ethics 28(3):204, 2002). We suggest that these implications should be taken into account when considering both the soundness and strength of PB. PMID- 25434063 TI - Valuing hope. AB - This article argues that hope is of value in clinical ethics and that it can be important for clinicians to be sensitive to both the risks of false hope and the importance of retaining hope. However, this sensitivity requires an understanding of the complexity of hope and how it bears on different aspects of a well functioning doctor-patient relationship. We discuss hopefulness and distinguish it, from three different kinds of hope, or 'hopes for', and then relate these distinctions back to differing accounts of autonomy. This analysis matters because it shows how an overly narrow view of the ethical obligations of a clinician to their patient, and autonomy, might lead to scenarios where patients regret the choices they make. PMID- 25434064 TI - Disability, discrimination and death: is it justified to ration life saving treatment for disabled newborn infants? AB - Disability might be relevant to decisions about life support in intensive care in several ways. It might affect the chance of treatment being successful, or a patient's life expectancy with treatment. It may affect whether treatment is in a patient's best interests. However, even if treatment would be of overall benefit it may be unaffordable and consequently unable to be provided. In this paper we will draw on the example of neonatal intensive care, and ask whether or when it is justified to ration life-saving treatment on the basis of disability. We argue that predicted disability is relevant both indirectly and directly to rationing decisions. PMID- 25434065 TI - Setting risk thresholds in biomedical research: lessons from the debate about minimal risk. AB - One of the fundamental ethical concerns about biomedical research is that it frequently exposes participants to risks for the benefit of others. To protect participants' rights and interests in this context, research regulations and guidelines set out a mix of substantive and procedural requirements for research involving humans. Risk thresholds play an important role in formulating both types of requirements. First, risk thresholds serve to set upper risk limits in certain types of research (e.g., pediatric research that offers the participating children no prospect of clinical benefit). Second, risk thresholds serve to demarcate risk categories that streamline risk-adapted systems of ethical oversight (e.g., expedited or no prospective ethical review of minimal risk research). But although risk thresholds play such an important role in research governance, there is a need both to better define the existing risk thresholds and to delineate new thresholds in order to develop more risk-adapted systems of research oversight. The present paper examines the existing minimal risk threshold and the surrounding debates with the goal of deriving a systematic approach to setting thresholds of research risk. PMID- 25434066 TI - The dual-use problem, scientific isolationism and the division of moral labour. AB - The dual-use problem is an ethical quandary sometimes faced by scientists and others in a position to influence the creation or dissemination of scientific knowledge. It arises when (i) an agent is considering whether to pursue some project likely to result in the creation or dissemination of scientific knowledge, (ii) that knowledge could be used in both morally desirable and morally undesirable ways, and (iii) the risk of undesirable use is sufficiently high that it is not clear that the agent may permissibly pursue the project or policy. Agents said to be faced with dual-use problems have frequently responded by appealing to a view that I call scientific isolationism. This is, roughly, the view that scientific decisions may be made without morally appraising the likely uses of the scientific knowledge whose production or dissemination is at stake. I consider whether scientific isolationism can be justified in a form that would indeed provide a way out of dual-use problems. I first argue for a presumption against a strong form of isolationism, and then examine four arguments that might be thought to override this presumption. The most promising of these arguments appeals to the idea of a division of moral labour, but I argue that even this argument can sustain at most a highly attenuated form of scientific isolationism and that this variant of isolationism has little practical import for discussions of the dual-use problem. PMID- 25434067 TI - Information, choice and the ends of health promotion. AB - In this paper I provide a critique of a set of assumptions relating to agency, choice and the legitimacy of actions impacting health that can be seen in some approaches to health promotion. After a brief discussion about the definition of health promotion, I outline two contrasting approaches to this area of health care practice. The first is focused on the provision of information and the second is concerned with seeking to change people's preferences in a particular way. It has been argued by a number of critics of health promotion that only the first approach is ethical, as it is for individuals to make their own lifestyle choices and adopt their own conception of the good life. I argue against this 'information' approach to health promotion on two grounds. First, I suggest that given the aims of health promotion, the provision of information is, as a matter of fact, of limited effectiveness in achieving these aims (and it may worsen health inequalities). Second, I argue that we have good reasons to question the appropriateness of respecting many of the preferences that individuals happen to have, given the origins and quality of such preferences. I then go on to argue, that by contrast we have good reasons to focus on changing at least some of the preferences that people have related to their lifestyle choices. This involves a commitment to both paternalism and a defence of a certain conception of the good life, but both can be defended. I use the example of potential responses to the growing problem of obesity to illustrate my argument, arguing that only policy that, at least sometimes, aims at preference change will be both effective and ethical. PMID- 25434068 TI - Public health ethics and obesity prevention: the trouble with data and ethics. AB - In recent years policy makers and public health professionals have described obesity and its associated diseases as a major global public health problem. Bioethicists have tried to address the normative implications of proposed public health interventions by developing guidelines or proposing ethical principles that ethically grounded health policy responses should take into consideration. We are reviewing here relevant literature and conclude that while there are clearly health (and health care cost) implications resulting from the increasing number of seriously obese people across the globe, there appear to be legitimate questions about the scope of the problem as well as questions about whether particular demonstrable correlations are indicative of causations. These empirical questions require further clinical and epidemiological research. We then review currently discussed public health ethics guidance documents and proposals. Suffering from the same conceptual problems that are known features of principle-based bioethics, insofar as their capacity to ground ethically justifiable policies is concerned, they are unsuitable for actual policy development. Even if the empirical questions were resolved, health policy makers could not rely on currently existing prominent public health ethics guidance documents to develop ethically defensible policies. Further empirical and ethics research is necessary to develop ethically defensible public health policies targeting obesity. PMID- 25434069 TI - Are health nudges coercive? AB - Governments and policy-makers have of late displayed renewed attention to behavioural research in an attempt to achieve a range of policy goals, including health promotion. In particular, approaches which could be labelled as 'nudges' have gained traction with policy-makers. A range of objections to nudging have been raised in the literature. These include claims that nudges undermine autonomy and liberty, may lead to a decrease in responsibility in decision making, lack transparency, involve deception, and involve manipulation, potentially occasioning coercion. In this article I focus on claims of coercion, examining nudges within two of the main approaches to coercion-the pressure approach and the more recent enforcement approach. I argue that coercion entails an element of control over the behaviour of agents which is not plausibly displayed by the kinds of serious examples of nudges posited in the literature. PMID- 25434070 TI - Postpartum thyroiditis. AB - Postpartum thyroiditis (PPT) is a syndrome of transient or permanent thyroid dysfunction occurring in the first year after delivery or abortion. It is the most common thyroid disease in the postpartum period with incidence between 5 and 9%. In essence, it is an autoimmune inflammation of the thyroid, caused by changes in humoral and cell-mediated immune response. It has a characteristic biphasic course with an episode of transient thyrotoxicosis followed by transient or permanent hypothyroidism. Of all predisposing factors positive titers of thyroid peroxidase antibodies have the greatest importance. In some of the affected patients the disease course is marked by expressed hormonal disorders causing significant subjective symptoms. This underlines the need for early identification of risk groups aimed at prophylaxis and adequate treatment of thyroid dysfunction in the postpartum period. The frequency of PPT varies between analyses and studies on risk factors do not establish reliable predictive models for progression of the disease. This is due to the different methodology of research and the involvement of a number of genetic and non-genetic factors in different geographic regions. That is why implementation of mass screening programs is now controversial. The discrepancy in the opinions of researchers makes it necessary to have studies of the problem in performed in every clinical center in which the possible risk specific to the region and the population covered might be defined prognostically. The results of these studies can be used to introduce targeted and cost-effective screening for early detection of risk patients and prevention of morbidity and complications of PPT. PMID- 25434071 TI - Subgingival microbial profile and production of proinflammatory cytokines in chronic periodontitis. AB - This review examines literature data concerning the bacterial findings in chronic periodontitis depending on pocket depth, and presents the latest published information on the presence of proinflammatory factors in periodontal environment. It has been found that chronic periodontitis affects as much as 80% of the middle-aged population; by comparison, the prevalence of aggressive periodontitis reaches up to 1-1.5%. It is accepted that this social disease is multifactorial in etiology, but the evidence in the literature suggests that the levels of specific Gram-negative organisms in subgingival plaque biofilm play a major role in the initiation and progression of the disease. Of the many bacterial species inhabiting the periodontal environment, three types- Porphyromonas gingivalis (PG), Treponema denticola (TD), Tannerella forsythia (TF)--are strongly associated with the initiation and progression of periodontitis. Microbiological studies suggest that Porphyromonas gingivalis should be considered a major etiologic agent. Currently, Porphyromonas gingivalis is strongly associated with the pathogenesis of chronic periodontitis. On the other hand, the presence of Aggregatibacter actinomycetemeomitans in patients with chronic periodontitis may be related to the severity of the disease and thus modify the therapeutic plan. The increased amount of periodontal pathogens in the subgingival area can activate a cascade of defense mechanisms of the body associated with the production of factors causing inflammation and destruction, which suggests a correlation between the bacterial findings and the body response implemented by enhancing the local cytokine expression. Studies in the literature show that the presence of certain micro-organisms in the periodontal environment is associated to increased levels of proinflammatory cytokines in the gingival fluid and gingival tissue. These levels have been associated with destructive tissues response. There is little evidence in the literature on the correlation of the levels of periodontal pathogens of sites with different pocket depth with periodontal disease activity defined by the degree of the proinflammatory cytokine expression such as tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). PMID- 25434072 TI - Oocyte and embryo vitrification in the IVF laboratory: a comprehensive review. AB - Vitrification is an excellent tool in the IVF laboratory, enabling options and offering flexibility in assisted reproduction. The technology of cryopreservation has been underway since the early 20th century. The advent of vitrification has advanced the expectations in routine clinical practice in the IVF laboratory presenting impressive results both in post-thaw survival, and in clinical pregnancy rates, as well as significantly enhancing clinical results on preimplantation genetic diagnosis (PGD). Contradicting opinions have been published recently on the limitations and potential that vitrification has in the laboratory, as well as on the optimal approach to employ vitrification in IVF. This review aims to present a comprehensive analysis of the practical aspects of vitrification including concerns and options regarding its use on oocytes and embryos while comparing it with the traditional "slow-freezing" cryopreservation technique. PMID- 25434073 TI - Lash ptosis as a characteristic sign of floppy eyelid syndrome. AB - AIM: To find a correlation between the floppy eyelid syndrome and the clinical sign of lash ptosis and loss of eyelash parallelism and develop an algorithm for early diagnosis. MATERIALS AND METHODS: This is a prospective case-control study including 97 consecutive patients diagnosed with floppy eyelid and 81 healthy sex and age-matched controls. The study was conducted in Professor Pashev Eye Hospital, Sofia between January 2011 and December 2012. The clinical sign of lash ptosis and loss of eyelash parallelism was investigated in two stages. The condition was graded using a specially designed algorithm. RESULTS: Lash ptosis and loss of eyelash parallelism was documented in all 97 (100%) patients with floppy eyelid and only in 8 patients (9%) in the control group. Statistical analysis of the results showed a very strong association between this sign and the floppy eyelid syndrome (p <0.0001), and a correlation between the degree of lash ptosis and stage of the disease (p < 0.001). CONCLUSION: The clinical sign of lash ptosis and loss of eyelash parallelism is characteristic for the syndrome. Recognizing this sign during a routine eye examination can facilitate a timely diagnosis of the frequently overlooked and improperly treated disorder of floppy eyelid. PMID- 25434074 TI - Correlations between human somatotype components and some anthropometric parameters in male patients with type 2 diabetes mellitus. AB - The aim of the present study was to find and compare the correlations between somatotype and some anthropological parameters in Bulgarian male patients with type 2 diabetes mellitus. PATIENTS AND METHODS: Anthropometric measurements were taken from 165 male patients with type 2 diabetes mellitus. All patients were ethnic Bulgarians. They were divided into two age groups: a 40-60-year group (58 patients, mean age 52.05 +/- 0.73 yrs), and a 61-80-year group (111 patients, mean age 68.02 +/- 0.53 yrs). The controls were allocated into similar age matched groups. Direct anthropometric measurements were body height and weight, biepicondylar breadth of the humerus and biepicondylar breadth of the femur. Circumferential measurements were taken from the relaxed and contracted upper arm, the forearm, the waist, the hip, the thigh and the medial calf. Skin folds were measured below the inferior angle of the scapula, above the X rib, above the crista iliaca, at the abdomen, triceps brachii, forearm, thigh and the medial calf. The components of human somatotype according to the criteria of Heath Carter, body mass index (BMI) and waist-to-hip ratio (WHR) were calculated. RESULTS: We found very strong positive correlations (PC > 0.70) between BMI and the endomorphic and mesomorphic components of somatotype in 40-60-year-old male diabetic patients. The correlation between the endomorphic and mesomorphic components of somatotype and the anthropometric measurements characterizing the central accumulation of adipose tissue (waist circumference, hip circumference, WHR) was very strong positive (PC = 0.5-0.7). Male diabetic patients aged 61-80 years: we found a very strong positive correlation between endomorphic and mesomorphic components and BMI, a strong correlation between these components and the waist circumference, and a good correlation between the components and the circumferences of the waist and hip and WHR. CONCLUSIONS: In male patients with type 2 diabetes aged 40-60 years, the endomorphic and mesomorphic components of somatotype are strongly positively correlated with the parameters which characterize the total adipose tissue accumulation in the human body (BMI). There is a good positive correlation between the two components of somatotype and the parameters showing visceral adipose tissue accumulation (circumferences of waist, hip, thigh and WHR). In male patients with type 2 diabetes aged 61-80 years we found a strong positive correlation of the endomorphic and mesomorphic components of somatotype with BMI and a good positive correlation with the circumferences of the waist, hip, thigh and WHR. PMID- 25434075 TI - Micromeritic procedures in assessing antinuclear antibody patterns in immunofluorescent assay. AB - AIM: The aim of this study was to introduce a micromeritic procedure (a statistical approach for small objects) in indirect immunofluorescence assay (IFA) to find objective quantitative parameters of antinuclear antibody (ANA) patterns which could support a diagnosis of auto-immune diseases. MATERIALS AND METHODS: Sera of patients with systemic autoimmune diseases, McCoy-Plovdiv serum free cell line, goat anti-human immunoglobulin-G FITC-conjugate, fluorescent microscope, computer-assisted digital image processing, analysis using a micromeritic procedure, ANOVA. RESULTS: Three ANA fluorescent patterns (homogeneous, rim and speckled) were analyzed by the micromeritic procedure. Parameters for the image brightness of the pixels (pixel grey value) were obtained and discussed as objective characteristics of fluorescent patterns: maximum ANA-linkage volume and surface density were established for the objects with speckled localization pattern. CONCLUSION: The micromeritic method for getting objective quantitative values of ANA fluorescent patterns in indirect immunofluorescent assay might be a valuable tool aiding in immunological diagnosing if integrated in a laboratory software package. PMID- 25434076 TI - Formulation and performance evaluation of betahistine dihydrochloride microspheres as sustained release systems. AB - Betahistine dihydrochloride is a histamine-like drug widely used in relieving the symptoms associated with Meniere's syndrome. Pharmacokinetic studies of betahistine have demonstrated that it has a short plasma half-life of 3-4 hours. In such cases frequent administration of the drug is required in order to keep plasma concentration within the therapeutic range. However, this may lead to noncompliance and aggravate patients' comfort. An advanced approach for achieving sustained release of drugs is their incorporation in microparticulate carriers. AIM: To design a sustained release microsphere formulation of betahistine providing reduced dose frequency and lower risk of side effects occurrence. MATERIALS AND METHODS: Betahistine-loaded chitosan microspheres were obtained via W/O emulsion solvent evaporation technique and were characterized for particle size, drug loading and entrapment efficiency. Drug release into phosphate buffer saline pH 7.4 was performed and dissolution profiles of the formulations were obtained. To study the mechanism of drug release from the microspheres the dissolution data was fitted to various mathematic models. RESULTS: Betahistine loaded microspheres were produced with a high drug loading and entrapment efficiency. The microcarriers were spherical in shape with mean particle size of 3.82 MUm to 7.69 MUm. Betahistine release studies from the microspheres showed similar and slightly increasing dissolution profiles. The drug release proceeded in a controlled manner following Fickian diffusion. CONCLUSION: The obtained results suggest that betahistine-loaded chitosan microspheres prepared by solvent evaporation method are capable of sustained release of drugs and therefore can be used as drug delivery systems in the treatment of Meniere's syndrome. PMID- 25434077 TI - A comparative study of LAMPs and YKL-40 tissue expression in glial tumors. AB - INTRODUCTION: YKL-40 is a glycoprotein believed potentially to be a marker of various pathological processes. High levels of YKL-40 have been found in cancer and chronic inflammatory diseases. The function of the glycoprotein is not completely known yet. A possible involvement in angiogenesis and tumor aggressiveness is supposed. Lysosome-associated membrane glycoproteins (LAMP) 1 and 2 are highly conserved proteins with still undefined biological functions. There is evidence that they are implicated in autophagy, angiogenesis and tissue remodeling. AIM: The aim of the present study was to investigate the potential relationship between the tissue expression of YKL-40, LAMP-1 and LAMP-2 in glial tumors. MATERIAL AND METHODS: LAMPs and YKL-40 expression was determined by immunohistochemistry in 36 glial tumors. A morphometric analysis of the intensity of tissue expression was performed with the Quick-photo Micro 2.3. system. Area (MUm), perimeter (MUm), and expression level (%) of the three glycoproteins were calculated. RESULTS: LAMPs were found on cell membranes of glial and endothelial cells, while YKL-40 was detected in the cytoplasm of these cells. Intensive immunohistochemical reaction was present in tumor cells. LAMP-2 showed a more intensive staining compared to LAMP-1. CONCLUSION: We present the first comparative study of YKL-40 and LAMPs in astroglial tumors. The relationship between the expression of the three glycoconjugates indicates a possible participation in the processes of angiogenesis and tissue remodeling during tumor development. PMID- 25434078 TI - Memory effects of Aronia melanocarpa fruit juice in a passive avoidance test in rats. AB - AIM: To study the effect of Aronia melanocarpa fruit juice on memory in male Wistar rats. MATERIALS AND METHODS: The juice was administered orally for 7, 14, 21 and 30 days at doses of 2.5 ml/kg, 5 ml/kg and 10 ml/kg. Memory was assessed in the one-way passive avoidance task (step through) which consisted of one training session and two retention tests (3 hours and 24 hours after training). The variables measured were the latency time to step into the dark compartment of the apparatus and the learning criterion (remaining in the illuminated compartment for at least 180 sec). RESULTS: Oral administration of Aronia melanocarpa fruit juice for 7 and 14 days resulted in a dose-dependent tendency to increase the latency time and the learning criterion compared to saline treated controls but the effect failed to reach statistical significance. After 21 days of treatment, the juice dose-dependently prolonged the latency time at the retention tests, the effect being significant at doses of 5 ml/kg and 10 ml/kg. Applied for 30 days, the juice in all the tested doses increased significantly the latency time at the retention tests and the dose of 10 ml/kg significantly increased the percentage of rats reaching the learning criterion. CONCLUSION: These findings suggest that Aronia melanocarpa fruit juice could improve memory in rats. The effect is probably due to the polyphenolic ingredients of the juice which have been shown to be involved in learning and memory processes. PMID- 25434079 TI - Noise exposure during pregnancy, birth outcomes and fetal development: meta analyses using quality effects model. AB - BACKGROUND: Many women are exposed daily to high levels of occupational and residential noise, so the effect of noise exposure on pregnancy should be considered because noise affects both the fetus and the mother herself. However, there is a controversy in the literature regarding the adverse effects of occupational and residential noise on pregnant women and their fetuses. AIM: The aim of this study was to conduct systematic review of previously analyzed studies, to add additional information omitted in previous reviews and to perform meta-analyses on the effects of noise exposure on pregnancy, birth outcomes and fetal development. MATERIAL AND METHODS: Previous reviews and meta-analyses on the topic were consulted. Additionally, a systematic search in MEDLINE, EMBASE and Internet was carried out. Twenty nine studies were included in the meta analyses. Quality effects meta-analytical model was applied. RESULTS: Women exposed to high noise levels (in most of the studies >= 80 dB) during pregnancy are at a significantly higher risk for having small-for-gestational-age newborn (RR = 1.19, 95% CI: 1.03, 1.38), gestational hypertension (RR = 1.27, 95% CI: 1.03, 1.58) and infant with congenital malformations (RR = 1.47, 95% CI: 1.21, 1.79). The effect was not significant for preeclampsia, perinatal death, spontaneous abortion and preterm birth. CONCLUSION: The results are consistent with previous findings regarding a higher risk for small-for-gestational-age. They also highlight the significance of residential and occupational noise exposure for developing gestational hypertension and especially congenital malformations. PMID- 25434080 TI - Glioblastoma multiforme classified as mesenchymal subtype. AB - INTRODUCTION: Recently, researchers have been considering as adverse prognostic factors in primary glioblastomas not only clinical indicators but also various cellular, genetic and immunological markers. The aim of the present article was to report a case of primary glioblastoma multiforme with poor survival in a patient after surgical intervention, and to determine the unfavorable prognostic markers. CASE REPORT: We present a 71-year-old man with histologically verified glioblastoma multiforme and a postoperative survival of 48 days. The patient did not receive any radiotherapy and adjuvant therapy with temozolomide because of the short survival. Serum and transcription levels of TNF-alpha, CD44, YKL-40 and IL-6 were determined by molecular-biological and immunological analyses. We found very high transcription levels of the genes CD44, YKL-40 and IL-6, increased gene expression of TNF-alpha, and elevated serum concentrations of TNF-alpha, YKL-40 and IL-6 and reduced serum concentration of CD44. CONCLUSION: Molecular biological and immunological analyses support the hypothesis that glioblastoma multiforme is presented by a heterogeneous group of glial tumors with different clinical course and prognosis. The high expression levels of TNF-alpha, CD44, YKL 40, and IL-6 indicate that the tumor can be categorized as mesenchymal subtype of glioblastoma multiforme, which accounts for the rapid clinical course and lethal outcome of the condition. PMID- 25434081 TI - Association of eosinophilic fasciitis with morphea. AB - Eosinophilic fasciitis is a rare inflammatory disease of unknown etiology, described for the first time by Shulman in 1974. The disease presents with induration of the skin, connective tissue and the underlying muscle fascia, sometimes accompanied by myalgia, most commonly in the lower extremities. Unlike scleroderma, it presents with absence of visceral organ involvement and Raynaud's phenomenon. Hypergammaglobulinemia and eosinophilia have been reported. Eosinophilic fasciitis is often associated with hematological disorders--there are reports of combinations with other autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, Hashimoto thyroiditis, Sjogren syndrome, vitiligo, etc. Occurrence of morphea, in the course of eosinophil fasciitis is considered a rarity. We have observed such a case with the simultaneous presence of both types of lesions. A 20-year-old female patient is reported, wherein the clinical picture developed for 6 months. The initial erythematous edema and subsequently the livedo-like painful plaques in both lower legs gradually swell, thicken and hyperpigment. Almost simultaneously with these complaints small brown livid body plaques emerged. The patient was diagnosed based on history, clinical picture, peripheral eosinophilia and histological findings from the affected areas. There was no systemic involvement and accompanying hematologic or other disease. Therapeutic management and significant clinical improvement were achieved using systemic corticosteroid therapy combined with methotrexate. PMID- 25434082 TI - [Analysis of biochemical markers in serum of guinea pigs after death caused by hypothermia]. AB - OBJECTIVE: To explore the changes and rules of biochemical markers in serum of guinea pigs after death caused by hypothermia and to provide references for fatal hypothermia diagnosis by serum biochemical markers. METHODS: Twenty guinea pigs were randomly divided into experimental group and control group. The guinea pigs in the experimental group were kept at -30 degrees C until death, while the ones in control group were decapitated after same survival intervals at 25 degrees C. The serum was extracted from the whole blood of right ventricular immediately. Subsequently, a series of serum biochemical markers were analyzed by auto bio chemical analyzer. RESULTS: The levels of glucose, uric acid, creatinine and urea nitrogen in the experimental group were significantly higher than those in control group, respectively (P<0.05). Compared with the control group, the levels of total protein and albumin were significantly lower in the experimental group (P<0.05). There were no significantly differences of the levels of other markers such as serum enzymes and ions observed between the two groups. CONCLUSION: There are characteristic changes of some specific serum biochemical markers in fatal hypothermia, which may be potentially useful for auxiliary diagnosis of fatal hypothermia. PMID- 25434083 TI - [Correlation between five RNA markers of rat's skin and PMI at different temperatures]. AB - OBJECTIVE: To explore the correlation between postmortem interval (PMI) and five RNA markers of rat's skin--beta-actin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 18S ribosomal RNA(18S rRNA), 5S ribosomal RNA (5S rRNA), and microRNA 203 (miR-203), at different temperatures. METHODS: Eighteen SD rats were randomly divided into three environmental temperature groups: 4 degrees C, 15 degrees C and 35 degrees C, respectively. Skin samples were taken at 11 time points from 0 h to 120 h post-mortem. The total RNA was extracted from the skin samples and the five RNA levels were detected by real-time fluorescent quantitative PCR. Proper internal reference was selected by geNorm software. Regression analysis of the RNA markers was conducted by GraphPad software. RESULTS: 5S rRNA and miR-203 were most suitable internal references. A good linear relationship between PMI and RNA levels (beta-actin and GAPDH) was observed in two groups (4 degrees C and 15 degrees C), whereas the S type curve relationship between the expression levels of the two markers (beta-actin and GAPDH) and PMI was observed in the 35 degrees C group. The partial linear relationship between 18S rRNA and PMI was observed in the groups (15 degrees C and 35 degrees C). CONCLUSION: Skin could be a suitable material for extracting RNA. The RNA expression levels of beta-actin and GAPDH correlate well with PMI, and these RNA markers of skin tissue could be additional indice for the estimation of PMI. PMID- 25434084 TI - [Nitric oxide mediated TNF-alpha, IL-1beta gene expression in liver induced by crush injury of rat's soft tissues]. AB - OBJECTIVE: To explore the effect of nitric oxide (NO) on the gene expression of hepatic TNF-alpha and IL-1beta by crush injury of rat's soft tissues. METHODS: Rats were randomly divided into sham group, crush group, crush+aminoguanidine (AG) group, and crush+L-arginine (L-Arg) group. Activities of ALT and AST as well as NO level in serum were measured. Gene expressions of TNF-alpha and IL-1beta were detected with RT-PCR. RESULTS: Obvious increase in TNF-alpha and IL-1beta mRNA expression was detected in the crush group compared with the sham group (P<0.05). After pretreated L-Arg, expressions of TNF-alpha and IL-1beta mRNA were markedly increased (P<0.05). After pretreated AG, those indices obviously decreased (P<0.05). Activities of ALT and AST enhanced and NO level increased in the crush group compared with the sham group (P<0.05). Pretreatment with L-Arg or AG led to substantial increased or reduced activities of ALT and AST as well as NO levels, respectively. CONCLUSION: Endogenous NO mediated TNF-alpha, IL-1beta mRNA up expression in liver induced by increased production of NO after crush injury of rat's soft tissues. PMID- 25434085 TI - [Cathepsin L expression in plasma after acute myocardial ischemia and ischemia reperfusion in rats]. AB - OBJECTIVE: To test cathepsin L as a biomarker of myocardial ischemia by examination of cathepsin L expression in plasma after myocardial ischemia and ischemia-reperfusion in rats. METHODS: The rat models were established and divided in acute myocardial ischemia model (myocardial ischemia 30 min, 1 h, 2 h groups), ischemia-reperfusion model (ischemia-reperfusion group), and isoflurane pretreated ischemia-reperfusion model (isoflurane-pretreated group), respectively. Normal control group and sham-operated group were established as contrast. The contents of cathepsin L in plasma were examined by ELISA and myocardial infarction areas were measured after TTC staining. RESULTS: No statistical significant changes were found among the experimental groups compared with the normal control group and sham-operated group (P>0.05). The cathepsin L from the ischemia-reperfusion group increased to 2.37 times compared with the normal control group (P<0.05). The cathepsin L and myocardium infarction size of isoflurane-pretreated group decreased compared with the ischemia-reperfusion group (P<0.05). CONCLUSION: The cathepsin L in plasma is not a promising biomarker of acute myocardial ischemia. Isoflurane preconditioning can reduce the cathepsin L in plasma caused by ischemia-reperfusion injury. PMID- 25434087 TI - [Comparison of anterior chamber angle examination by UBM, SL-OCT and gonioscopy]. AB - OBJECTIVE: To compare the agreement of anterior chamber angle examination by ultrasound biomicroscope (UBM), slit lamp optical coherence tomography (SL-OCT), and gonioscopy in angle recession and angle closure. METHODS: The anterior chamber angle was measured with UBM, SL-OCT and gonioscopy in turns for temporal, nasal, superior and inferior quadrant in the same dark room. The results were compared with the agreement of the three methods in angle recession and angle closure by chi2 test and Kappa test. RESULTS: There were no statistically significant differences of the three methods in testing angle closure and angle recession (P>0.05). The consistency of UBM and gonioscopy was better (Kappa value of 0.882) than that of SL-OCT and gonioscopy (Kappa value of 0.624). CONCLUSION: When testing angle recession, UBM is better than SL-OCT with gonioscopy as the standard. When testing angle closure, UBM, SL-OCT and gonioscopy have good agreement. PMID- 25434086 TI - [Protective effects of intermedin preconditioning on hypoxic injury in rat's cardiac myocytes]. AB - OBJECTIVE: To observe the effects of intermedin preconditioning on hypoxic injury in rat's cardiac myocytes and to provide the hypothetical mechanism of sudden cardiac death in the field of forensic pathology. METHODS: The H9c2 cultured rat cardiac myocytes were randomly divided into control group, hypoxia group and IMD group. The myocardial cell viability, cellular ultrastructure, intracellular calcium concentration and apoptosis rate were determined by MTT assay, transmission electron microscopy, laser scanning confocal microscope and flow cytometry, respectively. RESULTS: Compared with the control group, cell viability obviously decreased with inner ultrastructure injury in the hypoxia group (P<0.05), while cell viability significantly increased in the IMD group by reducing the hypoxia injury of cardiac myocytes (P<0.05). Compared with the control group, [Ca2+]i (fluorescence intensity) and apoptosis rate significantly increased in the hypoxia group, but decreased in the IMD group (P<0.05). CONCLUSION: IMD increases the cell survival rate and decreases the cell apoptosis inhibited by intracellular calcium overload from hypoxia. This finding may reveal the mechanism of protective effects of myocardial hypoxia, and provide a scientific basis for the identification sudden cardiac death. PMID- 25434088 TI - [Correlation between visual acuity and fixation characteristics]. AB - OBJECTIVE: To explore the feasibility of fixation characteristics to evaluate visual acuity. METHODS: The fixation characteristics were examined in 75 subjects by MP-1 microperimeter. These subjects were divided into 3 groups: central fixation group, uncertain group and eccentric fixation group, and the differences of visual acuity among them were analyzed. Pearson correlation and regression analysis were performed on visual acuity and average retinal light sensitivity. RESULTS: (1) The visual acuity was 4.80+/-0.16 for central fixation group; 4.20+/ 0.45 for uncertain group; and 3.40+/-0.57 for eccentric fixation group, respectively. Based on the one-way ANOVA, the visual acuities in the three groups had statistically significant differences (P<0.05). (2) There was linear relationship between visual acuity (y) and average retinal light sensitivity (x). And the linear regression equations was y=-18.76+6.21x. The Pearson correlation coefficient was 0.707 (P<0.05). CONCLUSION: There is significant positive correlation between visual acuity and fixation characteristics. Testing of fixation characteristics could be used to assess visual acuity objectively, which has a practical value in forensic clinical medicine. PMID- 25434089 TI - [Death caused by anaphylactic shock: a forensic pathological analysis of 142 cases]. AB - OBJECTIVE: To explore the forensic pathological features of death caused by anaphylactic shock. METHODS: One hundred and forty-two death cases of anaphylactic shock were retrospectively analyzed. The IgE level in the serum of anaphylactic shock cases were statistically compared with that of 62 non anaphylactic shock cases. RESULTS: Most cases (77.46%) of anaphylactic shock death occurred in the medical institutes, with intravenous drug administration accounting for 53.53% of anaphylactic shock death. beta-Lactam antibiotics, glucocorticoid and herbal medications were responsible for a significant proportion of such cases. Although characteristic histopathological changes were absent in vast majority of these anaphylactic shock cases, the differences of IgE levels in the serum between anaphylactic shock group and non-anaphylactic shock group were statistically significant (P<0.05). CONCLUSION: Combined information including clinical data, autopsy results, IgE level, and other specific test results should be evaluated together in the forensic pathological diagnosis of anaphylactic shock. PMID- 25434090 TI - [Analysis of false-positive hyoid fractures: 12 forensic identification cases]. AB - OBJECTIVE: To study the causes of false-positive hyoid fractures and forensic identification. METHODS: Twelve cases of false-positive hyoid fractures were collected and analyzed. RESULTS: Improper dissection technique (4 cases) and congenital separation (8 cases) were the main reasons for false-positive hyoid fractures. CONCLUSION: True fractures can be differentiated from false-positive hyoid fractures. False-positive hyoid fracture caused by improper dissection technique can be identified through examination of peripheral muscle, soft tissue hemorrhage, and the characteristics of fracture end. PMID- 25434092 TI - Touch DNA of shed skin cells from the deployed airbag to address drunken driving crimes. AB - In the criminal cases of driving under the influence (DUI), DNA evidence can be collected from the deployed airbag of the motor vehicle and submitted to the crime lab for touch DNA analysis. The evidence can be acquired when the skin cells are observed on the surface of the airbag in a traffic accident. However, the low quantity or quality of the evidence collected from a crime scene prevents further identification analysis in many cases. In the current study, we reported a case of identifying touch DNA extraction from the shed skin cells from the deployed airbag of a motor vehicle. We managed to collect DNA evidence from the shed skin cells in an airbag using a proper approach of collection and extraction. The 5.87 ng of extracted DNA was sufficient for genotyping and forensic identification, which helped to identify the driver of the car in collision with a pier in the street. In DUI cases and other traffic accidents, therefore, the amount of touch DNA extracted from the deployed airbag can be sufficient for DNA marker genotyping and further analysis. PMID- 25434091 TI - [Histopathological analysis of organs submitted by legal medicine experts in Baojii City: 358 forensic identification cases]. AB - OBJECTIVE: To analyze pathological characteristics of organs recovered during forensic autopsy submitted by legal medicine experts. METHODS: From Baoji city, 358 cases of forensic autopsy specimens from a series of routine exams were collected. And histopathological diagnoses were reviewed. RESULTS: Majority of the 358 cases were young men. The major causes of death were trauma, sudden death and poisoning. The cause of death was determined with histology in 250 cases. No typical histological changes were noted in 101 cases. The tissue autolysis and decomposition were present in 7 cases. The major pathological diagnosis was cardiovascular disease, followed by diseases in respiratory, nervous, and digestive systems. CONCLUSION: Forensic autopsy with its professional characteristics, is different from regular autopsy. When diagnosing cause of death by histopathological examination, pathologists should collaborate with legal medicine experts to know the details of the cases, circumstances surrounding the death, and specific forensic pathological characteristics. PMID- 25434093 TI - [Development of CBCT technique and its application on dental age assessment]. AB - Teeth are the hardest organs in the human body. They are not easily affected by external physical and chemical factors to degrade or deform. Dental age assessment has been widely used in forensic practice. Dental image is one of the most common methods in the age estimation. The emergence of cone beam computed tomography (CBCT) technology provides a new way to obtain three-dimensional image of teeth. It has many advantages such as low-dose radiation, short-time scanning, high-precision image, and finical convenience. Recent development of CBCT technology and its application on age estimation are reviewed in this paper. PMID- 25434094 TI - [Allele-specific PCR and its application in forensic science]. AB - Allele-specific polymerase chain reaction (AS-PCR) is a technique based on allele specific primers, which can be used to analyze single nucleotide polymorphism (SNP) effectively including the transition, transversion and insertion/deletion polymorphism and has been exploited in the study of diseases research, molecular diagnosis, and forensic biological evidence. The article systematically reviews the principle, the detection methods, improvement of AS-PCR, and its research updates in the fields of autosome, Y chromosome and mitochondrial SNP, as well as its application in forensic science. PMID- 25434095 TI - Severe hypokalemia due to combination use of dexamethasone and calcium gluconate for diabetics with infection: a case report. AB - The combination use of dexamethasone and calcium gluconate can be applied to hypersensitivity. Severe hypokalemia is a usual complication of dexamethasone and calcium gluconate therapy, which occurs frequently with therapeutic use. Fatal cases, accidental and intentional, occur frequently in forensic practice. The current case report presented a 43-year-old man with diabetes mellitus with infection, to whom dexamethasone and calcium gluconate were administered in the private clinic. With the development of such clinical symptoms of severe hypokalemia as quadriplegia, he was confirmed to have severe hypokalemia through a biochemical test before dying of arrhythmia. And also it presented pathophysiologic mechanism underlying severe hypokalemia as well as suggestions for clinical practice regarding combination use of dexamethasone and calcium gluconate. PMID- 25434096 TI - Advances in biotechnology and bioinformatics. PMID- 25434097 TI - Production, purification and properties of fungal chitinases--a review. AB - After cellulose, chitin is the second most abundant organic and renewable polysaccharide in nature. This polymer is degraded by enzymes called chitinases which are a part of the glycoside hydrolase family. Chitinases have many important biophysiological functions and immense potential applications especially in control of phytopathogens, production of chito- oligosaccharides with numerous uses and in treatment and degradation of chitinous biowaste. At present many microbial sources are being explored and tapped for chitinase production which includes potential fungal cultures. With advancement in molecular biology and gene cloning techniques, research on fungal chitinases have made fast progress. The present review focuses on recent advances in fungal chitinases, containing a short introduction to types of chitinases, their fermentative production, purification and characterization and molecular cloning and expression. PMID- 25434098 TI - Purified dextransucrase from Pediococcus pentosaceus CRAG3 as food additive. AB - The extracellular crude dextransucrase (0.67 U/mg) from P. pentosaceus CRAG3 (GenBank accession number JX679020) after PEG-1500 fractionation gave specific activity, 20.0 U/mg which by gel filtration resulted in 46.0 U/mg. The purified dextransucrase displayed molecular size of approximately, 224 kDa. The optimum assay conditions for dextransucrase activity were 5% sucrose in 20 mM sodium acetate buffer (pH 5.4) and 30 degrees C. The dextransucrase was stable up to 40 degrees C and at pH range of 5.4-7.0. The metal ions such as Co2+, Ca2+, Mg2+ and Zn2+ stimulated the dextransucrase activity by 56, 44, 14 and 12%, respectively. It was most stable at -20 degrees C with half-life of 307 days. Amongst various additives used, glycerol and Tween 80 provided significant stability to the enzyme with half-life 15.5 and 85.5 h, respectively as compared to control (6.9 h). The solidification of sucrose supplemented milk by purified dextransucrase due to dextran synthesis displayed its application as additive for improving the texture of dairy products. PMID- 25434099 TI - Kinetic constraints and features imposed by the immobilization of enzymes onto solid matrices: a key to advanced biotransformation. AB - The kinetics of immobilized enzymes can not be analyzed by means of the simple Michaelis-Menten concept, which generally fails to describe the immobilized state due to both its probable barriers, and because the active concentration of the enzyme approaches, or even exceeds this of its substrate(s). In such cases, the various experimental data are usually treated by complex rate equations comprising too many parameters acquiring different natures and meanings, depending on both the properties of the immobilization state and the experimental conditions; thus, more likely, only apparent values of the Michaelis-Menten kinetic parameters can be estimated experimentally. Likewise, immobilization is often a key method in optimizing the operational performance of enzymes, in both laboratory and industrial scale, and affects considerably the kinetics in non aqueous and non-conventional media due to several issues as the structural changes of the enzyme molecule, the heterogeneity of the system, and the partial or total absence of water. In this work a theoretical approach is described on the formulation of simplified rate equations, reflecting also the actual mass balances of the reactants, in the case where esterification synthetic reactions are catalyzed by immobilized lipases, in either a non-aqueous organic solvent or in a non-solvent system. PMID- 25434100 TI - Differential toxicological endpoints of di(2-ethylhexyl) phthalate (DEHP) exposure in MCF-7 and MDA-MB-231 cell lines: possible estrogen receptor alpha (ERalpha) independent modulations. AB - Wide spread use of Di-(2-ethylhexyl) phthalate (DEHP) has made it a ubiquitous contaminant in today's environment, responsible for possible carcinogenic and endocrine disrupting effects. In the present investigation an integrative toxicoproteomic approach was made to study the estrogenic potential of DEHP. In vitro experiments carried out with DEHP (0.1-100 microM) induced proliferations (E-screen assay) in human estrogen receptors-alpha (ERalpha) positive MCF-7 and ERalpha negative MDA-MB-231 breast cancer cells irrespective of their ERa status. Further, DEHP suppressed tamoxifen (a potent anti-breast cancer drug) induced apoptosis in both cell types as shown by flowcytometric cell cycle analysis. Label-free quantitative proteomics analysis of the cell secretome of both the cell lines indicated a wide array of stress related, structural and receptor binding proteins that were affected due to DEHP exposure. The secretome of DEHP treated MCF-7 cells revealed the down regulation of lactotransferrin, an ERalpha responsive iron transport protein. The results indicated that toxicological effects of DEHP did not follow an ERa signaling pathway. However, the differential effects in MCF-7 and MDA-MB-231 cell lines indicate that ERa might have an indirect modulating effect on DEHP induced toxicity. PMID- 25434101 TI - Synthesis, DNA cleavage and antimicrobial activity of 4-thiazolidinones benzothiazole conjugates. AB - Antimicrobial screening of several novel 4-thiazolidinones with benzothiazole moiety has been performed. These compounds were evaluated for antimicrobial activity against a panel of bacterial and fungal strains. The strains were treated with these benzothiazole derivatives at varying concentrations, and MIC's were calculated. Structures of these compounds have been determined by spectroscopic studies viz., FT-IR, 1H NMR, 13C NMR and elemental analysis. Significant antimicrobial activity was observed for some members of the series, and compounds viz. 3-(4-(benzo[d]thiazol-2-yl) phenyl-2-(4 methoxyphenyl)thiazolidin-4-one and 3-(4-(benzo[d]thiazol-2-yl)phenyl)-2-(4 hydroxy phenyl)thiazolidin-4-one were found to be the most active against E.coli and C. albicans with MIC values in the range of 15.6-125 microg/ml. Preliminary study of the structure-activity relationship revealed that electron donating groups associated with thiazolidine bearing benzothiazole rings had a great effect on the antimicrobial activity of these compounds and contributes positively for the action. DNA cleavage experiments gave valuable hints with supporting evidence for describing the mechanism of action and hence showed a good correlation between their calculated MIC's and its lethality. PMID- 25434102 TI - Development of bioconjugate from Streptomyces tyrosinase and gold nanoparticles for rapid detection of phenol constituents. AB - Most of the phenol compounds are toxic and have been considered as hazardous pollutants. Several physicochemical and biological methods are available to detect and monitor the phenol pollutants in water and soil. In the present study, phenol constituents of winery, paper and plastic industrial effluents were successfully detected employing tyrosinase-gold nanoparticles bioconjugate. The synthesis of extracellular tyrosinase and gold nanoparticles was achieved by a single isolate of Streptomyces sp. DBZ-39. Enhanced production (369.41 IU) of tyrosinase was produced in submerged bioprocess employing response surface method with central composite design. Extracellular gold nanoparticles synthesized (12 18 nm) by Streptomyces sp. DBZ-39 were characterized with TEM, EDAX and FTIR analysis. A rapid detection (within 10 min) of phenol constituents from winery effluents was achieved by bioconjugate, when compared to tyrosinases and gold nanoparticles independently. Streptomyces tyrosinase could exhibit relatively a better performance than commercially available mushroom tyrosinase in the detection of phenol constituents. Winery effluent has shown much higher content (0.98 O.D) of phenol constituents than paper and plastic effluents based on the intensity of color and U.V absorption spectra. PMID- 25434103 TI - Dilute acid pretreatment and enzymatic hydrolysis of sorghum biomass for sugar recovery--a statistical approach. AB - Sorghum is one of the commercially feasible lignocellulosic biomass and has a great potential of being sustainable feedstock for renewable energy. As with any lignocellulosic biomass, sorghum also requires pretreatment which increases its susceptibility to hydrolysis by enzymes for generating sugars which can be further fermented to alcohol. In the present study, sorghum biomass was evaluated for deriving maximum fermentable sugars by optimizing various pretreatment parameters using statistical optimization methods. Pretreatment studies were done with H2SO4, followed by enzymatic saccharification. The efficiency of the process was evaluated on the basis of production of the total reducing sugars released during the process. Compositional analysis was done for native as well as pretreated biomass and compared. The biomass pretreated with the optimized conditions could yield 0.408 g of reducing sugars /g of pretreated biomass upon enzymatic hydrolysis. The cellulose content in the solid portion obtained after pretreatment using optimised conditions was found to be increased by 43.37% with lesser production of inhibitors in acid pretreated liquor. PMID- 25434104 TI - Assessment of phagosomes infected with Mycobacterium tuberculosis as a vaccine candidate against tuberculosis. AB - The present study describes a novel and simple vaccination strategy that involve culturing of M. tuberculosis in the macrophage cells. Isolation of phagosome from macrophage (cell line J774) infected with M. tuberculosis (H37) and M. bovis (BCG) at early and late phase of infection was done ensuing the identification and characterization of these phagosome. In vitro study of apoptosis induced by phagosome infected with (H37) and (BCG) was performed. The vaccine candidate with H1137 MOI- 1:10 at 3 h, MOI- 1:20 at 1, 1.5, 2.5 and 3 h and BCG MOI- 1:20 at 3.5 h showed percentage apoptosis as 38.64, 39.93, 34.66, 22.56,34.59 and 37.81% respectively. The results designates that macrophages provide cellular niche during infection and illustrate considerable immunogenic property. Novel antigens expressed or secreted by H37 in infected macrophages can provide evidence to be a successful vaccine candidate as it endures enhanced immune response than BCG. PMID- 25434105 TI - Modulation of small intestinal homeostasis along with its microflora during acclimatization at simulated hypobaric hypoxia. AB - At high altitude (HA) hypobaric hypoxic environment manifested several pathophysiological consequences of which gastrointestinal (GI) disorder are very common phenomena. To explore the most possible clue behind this disorder intestinal flora, the major player of the GI functions, were subjected following simulated hypobaric hypoxic treatment in model animal. For this, male albino rats were exposed to 55 kPa (approximately 4872.9 m) air pressure consecutively for 30 days for 8 h/day and its small intestinal microflora, their secreted digestive enzymes and stress induced marker protein were investigated of the luminal epithelia. It was observed that population density of total aerobes significantly decreased, but the quantity of total anaerobes and Escherichia coli increased significantly after 30 days of hypoxic stress. The population density of strict anaerobes like Bifidobacterium sp., Bacteroides sp. and Lactobacillus sp. and obligate anaerobes like Clostridium perfringens and Peptostreptococcus sp. were expanded along with their positive growth direction index (GDI). In relation to the huge multiplication of anaerobes the amount of gas formation as well as content of IgA and IgG increased in duration dependent manner. The activity of some luminal enzymes from microbial origin like a-amylase, gluco-amylase, proteinase, alkaline phosphatase and beta-glucuronidase were also elevated in hypoxic condition. Besides, hypoxia induced in formation of malondialdehyde along with significant attenuation of catalase, glutathione peroxidase, superoxide dismutase activity and lowered GSH/GSSG pool in the intestinal epithelia. Histological study revealed disruption of intestinal epithelial barrier with higher infiltration of lymphocytes in lamina propia and atrophic structure. It can be concluded that hypoxia at HA modified GI microbial imprint and subsequently causes epithelial barrier dysfunction which may relate to the small intestinal dysfunction at HA. PMID- 25434106 TI - Development of bioprocess for the production of laccase by Pleurotus ostreatus MTCC 1802 using evolutionary optimization technique. AB - For cost effective production of laccase enzyme (benzenediol: oxygen oxidoreductase) from P. ostreatus MTCC 1802 through solid sate fermentation, physico-chemical parameters such as temperature (20-35 degrees C), incubation period (9-17 days) and substrate (Neem bark and wheat bran, in various ratios, w/w) were optimized first by one parameter at time approach and then obtained optimum conditions were considered as zero level in evolutionary optimization factorial design technique. At statistically optimized conditions yield of laccase was found 303.59 + 16.8) U/gds after 13 days of incubation at 25 degrees C taking wheat bran and neem bark as substrate at a ratio of 3:2 (w/w). The results obtained could be a base line for industrial scale production of laccase. PMID- 25434107 TI - In vitro regeneration and ploidy level analysis of Eulophia ochreata Lindl. AB - Various parameters including explant-type, medium compositions, use of phytohormones and additives were optimized for direct and indirect regeneration of E. ochreata, a medicinal orchid under threat. Protocorm-like-bodies (PLBs) proved to be the best explants for shoot initiation, proliferation and callus induction. Murashige and Skoog's (MS) medium containing 2.5 mg L(-1) 6 benzylaminopurine (BAP), 1.0 mg L(-1) kinetin (Kin) and additives (adenine sulfate, arginine, citric acid, 30 mg L(-1) each and 50 mg L(-1) ascorbic acid) was optimal for shoot multiplication (12.1 shoots and 7.1 PLBs per explant with synchronized growth), which also produced callus. Shoot number was further increased with three successive subcultures on same media and approximately 40 shoots per explant were achieved after 3 cycles of 30 days each. Additives and casein hydrolysate (CH) showed advantageous effects on indirect shoot regeneration via protocorm-derived callus. Optimum indirect regeneration was achieved on MS containing additives, 500 mg L(-1) CH, 2.5 mg L(-1) BAP and 1.0 mg L(-1) Kin with 30 PLBs and 6 shoots per callus mass (approximately 5 mm size). The shoots were rooted (70% frequency) on one by fourth-MS medium containing 2.0 mg L(-1) indole-3-butyric acid, 200 mg L(-1) activated charcoal and additives. The rooted plantlets were hardened and transferred to greenhouse with 63% survival rate. Flow-cytometry based DNA content analysis revealed that the ploidy levels were maintained in in vitro regenerated plants. This is the first report for in vitro plant regeneration in E. ochreata. PMID- 25434108 TI - In vitro callus induction and estimation of plumbagin content from Plumbago auriculata Lam. AB - The medicinal plant Plumbago contains a very potent secondary metabolite, plumbagin having many therapeutic properties. Callus culture was induced using explants, leaf, stem and shoot apex, from P. auriculata. Murashige and Skoog media fortified with various growth hormones like NAA, IAA, IBA and 2, 4-D individually and in various combinations were checked for callus induction. Among the growth hormones used, 1 mg/L 2, 4-D showed best callusing. The hormonal combinations of 1 mg/L IAA and 1.5 mg/L NAA in the media exhibited best callus induction using stem internode as an explant. Plumbagin content from root, stem, leaf and callus was analyzed by using thin layer chromatographic technique. The callus derived from stem showed comparable plumbagin content to the in vivo plant parts. Quantitative spectrophotometric analysis of plumbagin from plant samples and callus indicated that plumbagin content was maximum in roots which was followed by callus, stem and leaf samples respectively. Generation of in vitro sources for p!umbagin, for therapeutic applications will serve as a continuous supply and will contribute to preserve the natural plant recourses. PMID- 25434109 TI - Mannitol-induced drought stress on calli of Trigonellafoenum-graecum L. Var. RMt 303. AB - Different explants of fenugreek, T. foenum-graecum L. (Var. RMt-303), were compared for their callus induction and subsequent shoot regeneration capabilities on Murashige and Skoog media supplemented with different phytohormones in varying concentration. The highest percentage of callus induction frequency was observed in 1 ppm benzylaminopurine (BAP). Maximum shoots were induced on media supplemented with 0.5 ppm BAP using leaf and stem tissues as explants. However, root tissues showed only callusing with no subsequent shooting. Cotyledonary node responded better than hypocotyls in terms of shoot induction on media supplemented with thidiazuron (0.1 ppm). The callus was subjected to drought stress as simulated by reduced water potential of growth media due to addition of mannitol. Calli could withstand -2 MPa water potential till 30 days indicating that the drought stress tolerance mechanisms are functional in this variety. Chlorophyll a and b and total chlorophyll, proline and total phenolic contents, total peroxidase and catalase activities increased under stress conditions suggesting the tolerance of callus to drought stress. However, ascorbate peroxidase, guaiacol peroxidase activities were found to decrease slightly. Malondialdehyde and H2O2 contents were found to decrease while only a slight disturbance was found in membrane stability index. These results underline the mechanisms that are crucial for drought stress tolerance in fenugreek. PMID- 25434110 TI - Anti-fungal potentials of extracellular metabolites of Western Ghats isolated Streptomyces sp. NII 1006 against moulds and yeasts. AB - Realization of hazardious effects of chemical fungicides has led to an interest in the usage of biocontrol agents. The present study, therefore, evaluates the biocontrol efficacy of Western Ghats (India) soil bacterial isolates. A potential strain NII 1006 was evaluated for its antagonistic property against a diverse range of moulds and yeasts. The strain was characterized morphologically, biochemically and molecularly, which revealed the isolate belonged to Streptomyces genus. Organic solvent extracts of NII 1006 culture filtrates inhibited the growth of the test pathogens indicating that growth suppression was due to extracellular anti-fungal metabolites present in the culture filtrates. The strain produced extracellular chitinase enzyme in addition to some stable partially purified anti-fungal compounds. Morphological changes such as hyphae degradation into debris and abnormal shapes were observed in test fungi and yeast grown on potato dextrose broth that contained the NII 1006 culture filtrate. The cell free supernatant has a tolerance to wide range of pH, temperature and enzymes such as lipase and protease. The biocontrol potential of NII 1006 strain may be correlated significantly with their ability to produce antibiotics as well as extracellular hydrolytic enzymes particularly chitinolytic enzyme. PMID- 25434111 TI - Potential of Microbispora sp. V2 as biocontrol agent against Sclerotium rolfsii, the causative agent of southern blight of Zea mays L (Baby corn)--in vitro studies. AB - The study was undertaken with the aim of exploring novel and beneficial agro activities of rare actinomycetes like Microbispora sp. V2. The antagonistic activity of Microbispora sp. V2 was evaluated as a biocontrol agents against Sclerotium rolfsii, a soil-borne fungal plant pathogen. The methodology performed for evaluation of biocontrol agent was in vitro evaluation assay which comprised of three tests viz., cellophane overlay technique, seed germination test and Thiram (fungicide) tolerance of Microbispora sp. V2. The isolate was found to inhibit the fungal pathogen Sclerotium rolfsii to 91.43% in cellophane assay. In seed germination assay, Microbispora sp. V2 treated seeds resulted in 25.75% increased germination efficiency, as compared to seeds infected by Sclerotium rolfsii. The isolate Microbispora sp. V2 could tolerate 1000 microg mL(-1) of Thiram (fungicide). The in vitro assay studies proved that Microbispora sp. V2 can be used as antifungal antagonist and thus posses' great potential as biocontrol agent against southern blight caused by Sclerotium rolfsii in Zea mays L (Baby corn) which causes large economical losses. PMID- 25434112 TI - [Preparation and evaluation of pepsin affinity organic polymer capillary monolithic column]. AB - The protein modified monolithic column in affinity capillary electrochromatography (CEC) has attracted considerable attention over the past decades because of its great enantioseparation ability. A porous polymethacrylate ester-based capillary monolithic column poly (glycidyl methacrylate-co ethyleneglycol dimethacrylate) (poly (GMA-co-EDMA)) was prepared by in situ co polymerization. The process was initiated thermally by azobisisobutyronitrile (AIBN). The polymerization mixture contained GMA as the function monomer and EDMA as the crosslinking agent with 1,4-butanediol and 1-propanol as the binary porogen solvent. Under the optimized reaction conditions, including the proportion of monomer and porogens, reaction temperature etc, the column exhibited a uniform structure, sufficient permeability and excel- lent pressure resistance. The separation of alkyl benzenes on the column was mainly based on typical reversed-phase chromatographic retention mechanism. The reproducibility and stability were good with RSDs less than 9. 0%. A pepsin functionalized organic polymer monolith was prepared by covalently bonded pepsin to poly(GMA-co EDMA) monolith with glutaraldehyde as a spacer based on the activity of epoxide group. The enantioseparation performance of the pepsin affinity monolith for basic enantiomers has been investigated by CEC. Nefopam, amlodipine, citalopram and chlorpheniramine were resolved, and baseline separations of nefopam, amlodipine, citalopram were achieved. The influences of pH, operating voltage, temperature and sample quantity used on the chiral separation were studied. The chiral recognition mechanism of enantiomers on the monolithic column in CEC is discussed. This work developed a new method for the prepataion and application of protein affinity monolith in CEC. PMID- 25434113 TI - [Preparation and application of an emodin-bonded silica gel chromatographic column for high performance liquid chromatography]. AB - An emodin-bonded silica gel stationary phase (ESP) for high performance liquid chromatography has been synthesized by the intermediate method. The preparation process was as follows: gamma-glycidoxypropyltrimethoxy silane (KH-560) firstly reacted with emodin ligand; then the intermediate was chemically immobilized to the surface of silica gel. Characterization of ESP was carried out with Fourier transform infrared spectroscopy (FTIR), elemental analysis and thermogravimetric analysis. Naphthalene was used as a probe to determine the column efficiency with methanol-water (60:40, v/v) as binary mobile phase at a flow rate of 0. 8 mL/min. In order to elucidate the related separation mechanism, ESP was used to separate a series of neutral, basic and acidic aromatic compounds, as well as a sample of wind medicated oil. The conventional C18 column and phenyl column were also tested under the same chromatographic conditions for comparison. The results showed that the emodin ligand was successfully bonded to the surface of spherical silica gel with a 0.23 mmol/g of bonded amount, and the theoretical plate number of ESP column was about 19,874 N/m. The coupling reagent chains and anthraquinone rings in ESP offered a structural basis for hydrophobic interaction. Meanwhile, the emodin ligands provided pi-pi or pi-rho charge transfer, hydrogen bonding, dipole-dipole action sites for different analytes. The synergistic reaction of various action sites endowed ESP column special and excellent chromatographic separation selectivity. And a baseline separation of polar compounds such as amines and phenols on ESP was easily achieved by using common and cheap methanol water mobile phases without buffer salts. The experimental conditions were simple and convenient. PMID- 25434114 TI - Non-targeted metabolomics study for the analysis of chemical compositions in three types of tea by using gas chromatograph-mass spectrometry and liquid chromatography-mass spectrometry. AB - Tea is one of the most widely consumed beverages in the world for its benefits to daily life and health. To discover the difference and correlation of chemical compositions in the three typical types of tea, a non-targeted metabolomics method was developed. After the optimization of extraction methods, gas chromatography-time-of-flight mass spectrometry and liquid chromatography quadrupole time-of-flight mass spectrometry were applied for metabolomics analysis, 1,812 and 2,608 features were obtained, respectively. By comparing with the known compounds in public and/or commercial databases, 173 compounds were tentatively identified, and 109 of them were experimentally confirmed by standards. Totally, 33 tea samples including 12, 12 and 9 samples of green, oolong and black tea, respectively, were analyzed by using the above two methods. Multivatiate analysis, Mann-Whitney U test and hierarchical cluster analysis were used to find and visualize the differential components in the three types of tea. Finally, 90 compounds, which contain catechins, amino acids, organic acids, flavonol glycosides, alkaloids, carbohydrates, lipids, etc, were found with a significant difference among them. This study demonstrates the potentials and power of metabolomics methods to understand the chemical secrets of tea. This should help a lot to optimize the processes of agriculture, storage, preparation and consumption. PMID- 25434115 TI - [Determination of tetrabromobisphenol A and bisphenol A in environmental water using carboxylated multiwalled carbon nanotubes as sorbent for solid-phase extraction combined with liquid chromatography-tandem mass spectrometry]. AB - A method for the determination of tetrabromobisphenol A and bisphenol A in environmental water using carboxyl-functionalized multiwalled carbon nanotubes as solid-phase extraction sorbent and liquid chromatography-tandem mass spectrometry was established. Comparison of three nanomaterials including multiwalled carbon nanotubes, C60 and carboxyl-functionalized multiwalled carbon nanotubes used as solid-phase extraction sorbents was made. After preconcentration by solid-phase extraction, tetrabromobisphenol A and bisphenol A were separated on a Thermo Scientific Hypersil C18 column (150 mm x 4. 6 mm, 3 MUm) and then detected by tandem mass spectrometry in negative electrospray ionization (ESI) mode. The results showed a good linear response in the concentration range of 0. 02-1. 0 mg/L for tetrabromobisphenol A and bisphenol A, and the limits of detection (S/N= 3) were 0. 04 pg/L and 0. 2 MUg/L for tetrabromobisphenol A and bisphenol A, respectively. The application of the proposed approach has been carried out for the determination of tetrabromobisphenol A and bisphenol A in spiked lake water and sea water samples. The recoveries varied from 82% to 99% with the relative standard deviations below 5. 0%. The proposed method can be used for the determination of tetrabromobisphe- nol A and bisphenol A at trace level in complex environmental samples. PMID- 25434116 TI - [Simultaneous determination of nine antidepressants in traditional Chinese medicines and health food by ultra performance liquid chromatography with tandem mass spectrometry]. AB - A sensitive method was developed for the simultaneous determination of nine antidepressants in traditional Chinese medicines and health food by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) based on the sonication-assisted extraction. The separation was performed on a Waters ACQUITY UPLC BEH C18 column (100 mm x 2. 1 mm, 1. 7 MUm) by using 0. 1% (v/v) formic acid aqueous solution and acetonitrile as the mobile phases with gradient elution at a flow rate of 0. 2 mL/min. The electrospray ionization (ESI) source in positive ion mode was used for the analysis of the nine antidepressants in the multiple reaction monitoring (MRM) mode. The standard curves for the nine antidepressants were obtained with good correlation coefficients (R2>0. 998) in the concentration range of 0.04-20 MUg/L. The limits of detection for the nine antidepressants were in the range of 0. 0068-0. 034 MUg/L. The average recoveries at three spiked levels (0.5, 1, 5 MUg/L) were 77.7% - 100. 8% with the relative standard deviation of 0. 9% -9. 1%. The method is accurate, simple, rapid and feasible for the simultaneous determination of the antidepressants in traditional Chinese medicines and health food. PMID- 25434117 TI - [Simultaneous determination of eight additives in polymer food packaging materials by ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry]. AB - An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS) method was proposed for the simultaneous determination of eight additives (Irgafos 168 (tri(2.4-di-tert-butylphenyl)phosphite), Irganox 1076 (octadecyl beta-(4-hydroxy-3, 5-di-tert-butylphenyl)propionate), Irganox 1010 (pentaerythritol tetrakys 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate), BHA (butyl hydroxy anisole), TBHQ (tertiary butylhydroquinone), PG (propyl gallate), DG (dodecyl gallate), UV-326 (2-( 2'-hydroxyl-3'-tert-butyl-5'-methylphenyl)-5 chlorobenzotriazole) in food packaging materials. After extracted by chloromethane through ultrasonic extraction, the samples were analyzed by UPLC MS/MS. The chromatographic conditions were optimized, and the best separation was obtained on a Waters BEH-C18 column (50 mm x 2. 1 mm, 1.7 MUm) with gradient elution of 0. 05% acetic acid solu- tion and methanol. The analysis was performed by UPLC-MS/MS with electrospray ionization (ESI) source in switching between the positive and negative ion modes in one run for multiple reaction monitoring. The eight additives showed good linear relationships in the ranges with all the correlation coefficients (R2) more than 0. 993. The limits of detection (LODs, S/N= 3) and limits of quantitation (LOQs, S/N= 10) of this method were 0. 13-5.50 MUg/L and 0.45-17.50 MUg/L, respectively. The recoveries were in the range of 63. 9% - 127. 0% with all the RSDs < 15. 8% (n= 6). This method is simple, accurate and effective for the analysis of the eight additives in food packaging materials. PMID- 25434118 TI - [Chiral separation of six tetralone derivative enantiomers using immobilized cellulose chiral stationary phase]. AB - A high performance liquid chromatographic method (HPLC) was developed for the chiral separation of six alpha-aryl tetralone derivatives, using a Chiralpak IC column. The factors influencing the chiral separation including the type and concentration of organic modifier, column temperature and flow rate were investigated. The results showed that high enantiomeric separation can be obtained with isopropanol as modifier for the six compounds. The thermodynamic study indicated that the enantioseparation was enthalpically driven and showed that low column temperature was beneficial to separation. Complete separation of compound I was achieved with a binary solvent mixture of n-hexane-isopropanol (90 :10, v/v) as the recommended mobile phase. The compounds II , II and IV were separated with the mobile phase of the mixture of n-hexane-isopropanol (99:1, v/v) and the compound V was separated with the mixture of n-hexane-isopropanol (85:15, v/v). The compound VI was separated with the mixture of n-hexane isopropanol (80:20, v/v). The column temperature was 25 degrees C, and the flow rate was 1. 0 mL/min. The six tetralone derivative enantiomers were separated on a chiral stationary phase of Chiralpak IC by HPLC. The column has high enantiomeric selectivity to the six tetralone derivative enantiomers. PMID- 25434119 TI - [Detection of 1,4-dioxane in water by membrane extraction-gas chromi?atgraphy/differential mobility spectrometry]. AB - The method of detecting trace 1,4-dioxane in water using membrane extraction coupled with gas chromatography/differential mobility spectrometry (GC/DMS) was developed. The parameters including radio frequency voltage, sampling flow rate, permeation time and trapping time were optimized to 1000 V, 50 mL/min, 30 min and 150 s, respectively. The linear range for dioxane was obtained from 2.0 MUg/L to 20.0 MUg/L. The LOD was found to be 0. 67 MUg/L. The specificity towards 1,4 dioxane in the presence of five chlorinated hydrocarbons was improved by using two-dimensional GC separation with optimized DMS compensation voltage. This method paves a way for developing field-deployable sensors for real-time monitoring contaminants in groundwater. PMID- 25434120 TI - [Pollution status of phenolic compounds in the soil and sediment from a chemical industrial park along the Yangtze River]. AB - A determination method of 12 phenolic compounds in soil and sediment samples by gas chromatography-mass spectrometry (GC-MS) analysis coupled with accelerated solvent extraction (ASE) and gel permeation chromatography (GPC) for clean-up was developed. The method detection limits (MDLs) varied from 0. 410 MUg/kg to 13. 1 MUg/kg (dry weight), and the average recoveries ranged from 70. 7% to 122% with the relative standard deviations (RSDs) of 1. 2% to 16%. Based on this method, the levels of 12 phenolic compounds were investigated in 17 soil surrounding a chemical industrial park along the Yangtze River and seven sediment samples collected in the river. It was found that 11 of the 12 phenolic compounds were detected in all of the 24 samples, and only hydroquinone was below the MDL. The contents of the total 12 phenolic compounds were 10. 16-30. 66 mg/kg in the soil and 18. 00-29. 83 mg/kg in the sediment, with the average contents of 18. 26 and 22. 51 mg/kg respectively. It showed that 4-nitro- phenol, 4-chloro-3 methylphenol, 2-chlorohydroquinone, 2-methyl-4,6-dinitrophenol and 2,4,6- trichlorophenol were five major phenolic contaminants in the soil and sediment in this study. The pollution levels of the 12 phenolic compounds were low in the soil of the chemical industrial park as well as in the sediment of the Yangtze River, which implied a comparatively low risk for the environment. PMID- 25434121 TI - [Determination of flumorph and dimethomorph residues in vegetables by improved QuEChERS-gas chromatography-mass spectromery]. AB - To determine the residues of flumorph and dimethomorph in vegetables, a method was established with improved QuEChERS-gas chromatography coupled to mass spectrometry (GC-MS). With acetonitrile as the extraction solvent, the samples were pretreated with the improved QuEChERS method including extraction, salting out and purification processes. Then all the sample extracts were analyzed with GC-MS in selected-ion monitoring (SIM) mode, and quantified by matrix-matched standard solution in external standard method. Under electron ionization conditions, the analysis was carried out with a capillary column (DB-5 MS, 30 mx 0. 25 mm x 0. 25 MUm) at a flow rate of 1. 1 mL/min. The quantitation was performed to detect ions of m/z 285, 371, 165 for flumorph and m/z 301, 387, 165 for dimethomorph. Good linearity was obtained in the range of 10-1 000 MUg/kg for both pesticides with correlation coefficients greater than 0. 999. The recovery experiments were carried out by spiking blank samples of ginger, tomato, carrot, spinach, cabbage and tremella at the three levels of 10, 20 and 100 MUg/kg. For both pesticides in different matrices, the limits of detection (S/N=3) were in the range of 0. 67-2. 42 MUg/kg. The average recoveries of flumorph and dimethomorph ranged from 71% to 116% with the relative standard deviations (RSDs) in the range of 1. 8%- 14. 7%. Meanwhile, the pyrolysis mechanism and matrix effect for the determination of flumorph and dimethomorph in vegetables were investigated in this study. The method is simple, rapid and accurate, and can be used for the routine analysis of flumorph and dimethomorph in vegetables. PMID- 25434122 TI - [Simultaneous determination of cyhexatin, triphenyltin and fenbutatin oxide residues in fruits and vegetables by Grignard derivatization and gas chromatography coupled to tandem mass spectrometry]. AB - A method for the simultaneous determination of cyhexatin, triphenyltin and fenbutatin oxide residues in fruits and vegetables was developed by Grignard derivatization and gas chromatography coupled to tandem mass spectrometry (GC MS/MS). The samples were firstly digested by HC1/THF (1 :10, v/v), then extracted by hexane and followed by the derivatization with Grignard reagent (EtMgBr). Then after purification using florisil SPE columns, the sample extracts were finally analyzed by GC-MS/MS. The qualitative and quantitative determinations of the three organotin pesticides were performed by the tandem mass in multiple reaction monitoring (MRM) mode. By using apple as a representative matrix, the limits of detection (LODs) obtained by the proposed method for cyhexatin, triphenyltin and fenbutatin oxide were 2. 0, 1. 5 and 3.4 MUg/kg (as Sn), respectively. The average recoveries for the three organotin pesticides were in the range of 72.4% 107. 1% at the spiked levels of 10, 20, 50 and 200 MUg/kg (as Sn) and the relative standard deviations (RSDs) ranged from 0. 4% to 14. 2%. The proposed method was validated to have good linearity, high sensitivity, selectivity and accuracy for the simultaneous determination of cyhexatin, triphenyltin and fenbutatin oxide in fruits and vegetables. The sensitivity of this method can meet the requirements of the inspection for the three organotin pesticides at the level of maximum residue limits (MRLs) set by China and some other countries. PMID- 25434123 TI - [Simultaneous determination of ten phytohormones in five parts of Sargasum fusiforme (Hary.) Seichell by high performance liquid chromatography-triple quadrupole mass spectrometry]. AB - A method for the simultaneous determination of indole-3-acetic acid, N6-(2 isopentenyl) adenosine, N6-(2-isopentenyl) adenine, trans-zeatin riboside, zeatin, strigolactone, abscisic acid, salicylic acid, gibberellin A3 and jasmonic acid in five different parts of main branch, lateral branch, primary leaf, secondary leaf and stem of Sargasum fusiforme (Hary.) Seichell was established by high performance liquid chromatography-triple quadrupole mass spectrometry (HPLC TQMS). The samples were extracted with methanol/water/formic acid (15 : 4 :1, v/v/v) (containing 0.5% 2, 6-di-tert-butyl-4-methylphenol, BHT) after vacuum freeze-drying. The separation was performed on a Hypersil Gold C18 column by using methanol and water as mobile phases with gradient elution. The analytes were detected by tandem mass spectrometry in selected reaction monitoring (SRM) mode. The electrospray ionization (ESI) source was used for the quantitative analysis in the positive mode or negative mode. Under the optimized conditions, the correlation coefficients (r) of the ten phytohormones were from 0. 9989 to 1. 0000 in the linear ranges. The detection limits of the ten phytohormones were 0. 001 2-4. 651 2 MU/L. The average recoveries were 72. 24% -91. 31% with the relative standard deviations not more than 6. 59%. In the five parts of fresh Sargasum fusiforme (Hary.) Seichell samples, the contents of the ten phytohormones were from not detected to 4 041. 431 ng/g. This method has good sensitivity, precision, recovery, and can be used to simultaneously determine the phytohormones. PMID- 25434124 TI - [Simultaneous determination of 18 beta-agonist residues in feed using QuEChERS sample preparation and high performance liquid chromatography-tandem mass spectrometry]. AB - A multi-residue method was developed for the simultaneous determination of 18 beta-agonist residues (clenbuterol, ractopamine, penbutolol, tulobuterol, etc) in feed by using QuEChERS sample preparation and high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The feed samples were dispersed by water, then the analytes were extracted with acetonitrile containing 4% (v/v) ammonia and cleaned up by QuEChERS method with 25 mg octadecylsilyl (C18) and 50 mg primary secondary amine (PSA) adsorbents. The separation of compounds was carried on an Agilent ZORBAX Eclipse XDB-C,8 column (50 mm x 4. 6 mm, 1. 8 MUm) by a gradient elution using methanol-0. 1% (v/v) formic acid aqueous solution as mobile phase. The analytes were detected by tandem mass spectrometry under multiple reaction monitoring (MRM) mode with positive electrospray ionization (ESI+) and quantified by the matrix-matched external standard method. The results showed that the calibration curves of the 18 beta agonists were linear in the range of 5 - 200 MUg/L with correlation coefficients of 0. 9912-0. 9995. The average recoveries of the 18 analytes at three spiked levels of 0.05, 0.1 and 0. 5 mg/kg ranged from 78. 4% to 107. 1% with the relative standard deviations (RSDs) of 3.5%-12.3%. The limit of quantification (LOQ, S/N>=10) was 0. 05 mg/kg for each analyte. The developed method is simple and sensitive, and can be applied as a screen and confirmatory method for the analysis of beta-agonists in feed. PMID- 25434125 TI - [Determination of 14 sulfonamide residues in shrimps by high performance liquid chromatography coupled with post-column derivatization]. AB - A method for the determination of 14 sulfonamide residues in shrimps by high performance liquid chromatography coupled with post-column derivatization was established. The sulfonamide residues were extracted with ethyl acetate after adding sulfapyridine as internal standard. The extracts were vacuum-concentrated and reverse-extracted by 2 mol/L hydrochloric acid solution for clean-up, and then the hydrochloric acid solution was defatted with n-hex- ane. The solution after filtration was blended with a mixed solution of methanol, acetonitrile and 3. 5 mol/L sodium acetate solution (5:5:20, v/v/v). The sulfonamides were separated on a C18 column by RP-HPLC and on-line derivatized with a fluorescamine and detected with a fluorescence detector. The standard addition method was used for quantitative analysis. The parameters of post-column derivatization system, such as concentration of fluorescamine solution, velocity of reagent solution and reaction temperature, were optimized. The calibration curves of the method showed good linearity in the range of 5 - 200 MUg/L. The limits of quantification (LOQ, S/N= 10) were 1.0-5.0 MUg/kg for the 14 sulfonamides. The recoveries were 77.8%- 103. 6% in the spiked range of 1. 0-100.0 MUg/kg in shrimps with the relative standard deviations of 2.9%-9.1% (n= 6). The results indicated that the method is sensitive, efficient and more accurate. It is suitable for the simultaneous determination of the 14 sulfonamide residues in shrimps. PMID- 25434126 TI - [Chromatographic separation of aminoglutethimide enantiomers on cellulose tris(3,5-dimethylphenylcarbamate) chiral stationary phase]. AB - Aminoglutethimide (AG) has been used clinically as a drug in the treatment of hormone-dependent metastatic breast cancer. It was reported that S-(-)-AG enantiomer had small activity and sometimes might cause side effects. Therefore, it was of great significance to obtain the high-purity R-(+)-AG by enantioseparation. In this work, aminoglutethimide enantiomers were separated by high performance liquid chromatography (HPLC) using an analytical column which was packed with cellulose tris(3,5-dimethylphenylcarbamate) stationary phase (Chiralcel OD-H). The solubilities of racemic AG in two different solvent compositions, n-hexane/ethanol and n-hexane/isopropanol, were measured, separately. The effects of alcohol content and monoethanolamine additive on the separation performance of racemic AG by HPLC were investigated. According to the experiments, n-hexane-ethanol (30:70, v/v) with 0.1% monoethanolamine additive was selected as the mobile phase. The separation factor, resolution, asymmetry factor, number of theoretical plates and maximum column capacity were measured and analyzed for the chromatographic separation of racemic AG at a flow-rate of 0. 6 mL/min and column temperature of 25-40 degrees C, with Chiralcel OD-H as stationary phase and n-hexane-ethanol (30:70, v/v) with 0. 1% monoethanolamine as mobile phase. This work provides the basic information of chromatographic separation for the batch and continuous production of aminoglutethimide enantiomers. PMID- 25434127 TI - [Determination of propargite, tebuconazole and bromopropylate pesticide residues in Taiwan green jujubes by gas chromatography-tandem mass spectrometry]. AB - An analytical method was established for the determination of propargite, tebuconazole and bromopropylate in Taiwan green jujubes (Zizyphus mauritiana Lam) by gas chromatography-tandem mass spectrometry (GC-MS/MS). The sample was extracted with acetonitrile from the Taiwan green jujubes after treated with a homogenizer. The organic phase was then separated from water phase by adding NaCl. The extract was further purified on a carbon/ NH2 cartridge with elution solvents of acetonitrile/toluene (3:1, v/v). Finally, the target analytes were separated by a capillary gas chromatographic column SLB-5MS (30 m x 0. 25 mm x 0. 25 MUm). A tandem quadrupole mass spectrometer operated in either full scan mode or in MS/MS mode for multiple reaction monitoring (MRM) was used for the qualitative and quantitative analysis of the constituents, respectively. The results showed that the average recoveries of the three pesticides ranged from 75. 8% to 103. 6% with the RSDs of 1. 7%-9. 3% at the spiking levels from 0.01 mg/kg to 0. 50 mg/kg (n= 5). The calibration curves showed good linearity in the range of 0.01-0.50 mg/kg, with the determination coefficients over 0.99 (R2>0.99). The limits of quantification (LOQs) were 0.01 mg/kg for propargite, tebuconazole and bromopropylate in Taiwan green jujubes. The method is available for the determination of propargite, tebuconazole and bromopropylate pesticide residues in Taiwan green jujubes. PMID- 25434128 TI - [Determination of residual glycol ethers in leather and leather products by gas chromatography/mass spectrometry]. AB - An effective method was established for the simultaneous determination of residual glycol ethers in leather and leather products by gas chromatography/mass spectrometry. Glycol ethers in leather and leather products were ultrasonically extracted at 45 degrees C, using ethyl acetate as the extraction solvent. The extracts were purified by solid phase extraction (SPE) columns, and then analyzed by gas chromatography/mass spectrometry in selected ion monitoring mode. The content of each analyte was calibrated by external standard method. The limit of detection of ethylene glycol ethyl ether (EGEE) was 0. 10 mg/kg under the condition of signal to noise (S/N) of 3 and the limits of the other 11 glycol ethers were all less than 0.05 mg/kg. The spiked recoveries varied from 81. 2% to 95. 5% at three different spiked levels with the relative standard deviations (RSDs) ranged from 1.4% to 6. 6%. The proposed method is simple, rapid and accurate, with the limits of detection much less than the requirements of the Regulation Concerning Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) of European Union. It is applicable to the determination of residual glycol ethers in leather and leather products, and provides a reference for the relevant testing standards. PMID- 25434129 TI - [Matrix effect and application of field-amplified sample injection in the analysis of four tetracyclines in waters by capillary electrohoresis]. AB - The system abilities of two chromatographic techniques, capillary electrophoresis (CE) and high performance liquid chromatography (HPLC), were compared for the analysis of four tetracyclines (tetracycline, chlorotetracycline, oxytetracycline and doxycycline). The pH, concentration of background electrolyte (BGE) were optimized for the analysis of the standard mixture sample, meanwhile, the effects of separation voltage and water matrix (pH value and hardness) effects were investigated. In hydrodynamic injection (HDI) mode, a good quantitative linearity and baseline separation within 9. 0 min were obtained for the four tetracyclines at the optimal conditions; the analytical time was about half of that of HPLC. The limits of detection (LODs) were in the range of 0. 28 - 0. 62 mg/L, and the relative standard deviations (RSDs) (n= 6) of migration time and peak area were 0. 42% - 0. 56% and 2. 24% - 2. 95%, respectively. The obtained recoveries spiked in tap water and fishpond water were at the ranges of 96. 3% - 107. 2% and 87. 1% - 105. 2%, respectively. In addition, the stacking method, field-amplified sample injection (FASI), was employed to improve the sensitivity, and the LOD was down to the range of 17.8-35.5 MUg/L. With FASI stacking, the RSDs (n=6) of migration time and peak area were 0. 85%-0. 95% and 1. 69%-3.43%, respectively. Due to the advantages of simple sample pretreatment and fast speed, CE is promising in the analysis of the antibiotics in environmental water. PMID- 25434130 TI - [Clinical manifestations and treatment of schistosomiasis hematobia]. AB - Schistosomiasis hematobia is one major human schistosomiasis. The disease is endemic in Africa and Mediterra- nean region, and is the main cause of urogenital diseases. Although only Schistosoma japonicum is spreading across the Mainland China, now more schistosomiasis hematobia cases are reported among aid projects and migrant workers to Africa, with the economy development and the increasing degree of foreign exchanges. Meanwhile, the relevant clinical data of.schistosomiasis hematobia are rare in China. This article reviews the clinical manifestations and progress in diagnosis and treatment of the disease. PMID- 25434131 TI - [Spatial-time cluster analysis of distribution of schistosomiasis in Jiangling County]. AB - OBJECTIVE: To analyze the spatial-time distribution characteristics of schistosomiasis in Jiangling County, Hubei Province from 2006 to 2011. METHODS: The surveillance data of schistosomiasis of Jiangling County from 2006 to 2011 were collected, and a spatial database was established. The spatial-time permutation cluster analysis was performed by SaTScan 9.1.1 to detect the spatial time cluster areas of schistosomiasis, and a risk map was drawn by ArcGIS 10.0. RESULTS: Compared to 2006, the infection rates of human, cattle and Oncomelania hupensis snails decreased by 47.67%, 93.34% and 52.41%, respectively in 2011. The space-time permutation clustering analysis of the infection rates of human, cattle and snails showed 4, 3 and 4 clusters, respectively, and all the clustered areas were distributed in inner embankment areas. CONCLUSIONS: From 2006 to 2011, the schistosomiasis endemic situation presents a decline trend in Jiangling County. The detected cluster areas are the important areas for schistosomiasis control. The space-time permutation statistics could be used in the analysis of endemic situation of schistosomiasis. PMID- 25434132 TI - [Monitoring of Enterobius vermicularis infection among children from 2006 to 2010 and SWOT analysis]. AB - OBJECTIVE: To understand the infection status and variation tendeNcy of Enterobius vermicularis infection among children at national monitoring spots of soil-transmitted nematodosis from 2006 to 2010, and master the epidemic regularity, so as to provide the evidence for making control strategy and evaluating the control effect. METHODS: A total of 22 national monitoring spots of soil-transmitted nematodosis were established according to the National Surveillance Program of Soil-Transmitted Nematodiasis (Trial), and the children aged 3-12 years were examined through adhesive cellophane anal swabs, thenthe infection rates of children with different ages, genders, nationalities and education levels were analyzed. In addition, the advantage, disadvantage, opportunity and threat of the monitoring work were analyzed by SWOT analysis. Results: A total of 17 068 children were examined in 22 monitoring spots from 2006 to 2010, and 1 363 of them were found being infected with E. vermnicularis, the average infection-rate was 7.99%, and the infection rates of male and female children were 7.39% and 8.70%, respectivel; the average infection rates in each year were 10.01%, 9.68%, 7.41%, 6.96% and 6.57%, respectively. From 2006 to 2009, the infection rates of E. vermicularis in children in Fujian Province was the highest, which were 56.15%, 53.42%, 37.82% and 49.53%, respectively, but in 2010, the infection rate in Guangdong Province (46.06%) was the highest. The fur- ther analysis demonstrated that the female children, 3-6 age group, Li nationality and children at kindergarten stage had relatively high infection rates. The SWOT analysis showed that the advantage of E. vermicularis monitoring in China was its wide coverage and continuity, and the disadvantage was the relatively small investment from the government, the opportunity was that the national monitoring Spot could drive the monitoring work at the provincial, county and other levels, and the threat was that the work was paid less and less attention to in recent years. CONCLUSION: Though the infection rate of E. vermicularis in children at national monitoring spots of soil-transmitted nematodosis has been decreased year by year, high-endemic areas still exist, and thus the work on enterobiasis control and prevention still needs to be strengthened. PMID- 25434133 TI - [Survey of intestinal parasitic infections and related knowledge and behavior of residents in Jiaodong area of Shandong Province]. AB - OBJECTIVE: To understand the status of intestinal parasitic infections and the related knowledge and behavior in residents of Jiaodong area of Shandong Province, so as to provide the evidence for making an appropriate preventive and control strategy. METHODS: A total of 18 villages from 6 counties in Jiaodong area were selected as investigation sites according to the stratified sampling method. The feces samples of the permanent residents aged above 3 years were collected and examined by Kato-Katz technique to find the intestinal parasite eggs, and the children under 12 years old were examined by the method of cellophane anal swab to detect the Enterobius vennrmicularis eggs. In addition, 50 households in each survey sites were randomly selected to investigate the basic family situation and the condition of awareness on prevention knowledge and formation of correct behavior of residents by using a structured questionnaire. RESULTS: Totally 6 163 residents involved in the feces examinations, and the total infection rate of intestinal parasites was 6.91%. The infection rates of Trichuris trichiura, Ascaris lumbricoides and hookworm were 6.56%, 0.62% and 0.21%, respectively. The infection rate of E. vermicularis in children under 12 years old was 0.51%. The eggs of Clonorchis sinensis and Taenia solium were not found in this survey. The awareness rate of knowledge about preventing parasitic diseases was 49.54%. The formation rates of washing hands before eating, washing hands after using the toilet, never eating raw fruit and vegetable without washing clean, never working in the field with bare feet, and never drinking unboiled water were 97.78%, 91.95%, 88.81%, 92.42% and 86.48% respectively. CONCLUSIONS: The infection rate of intestinal parasites is low in Jiaodong area, but there is a significant difference among different counties. The awareness rate of knowledge about preventing parasitic diseases is low, but the formation rate of healthy behavior is high. In the future, the health education and the strategy of taking medicine among the key population should be enhanced, and the project of reconstructing safe water supply and lavatory should be advanced. PMID- 25434134 TI - [Surveillance of malaria in provincial surveillance sites in Jiangsu Province, 2013]. AB - OBJECTIVE: To understand the epidemic situation and influencing factors of malaria in Jiangsu Province and grasp its epidemic regularity and trend. METHODS: According to the malaria prevalence in Jiangsu Province, 6 counties (city, district) including Yixing, Suining, Wujin, Hai'an, Ganyu and Xuyi were selected as provincial surveillance sites to survey malaria epidemic conditions. The basic information, blood test results of fever patients, case investigation, information of malaria patients, monitoring data of investigation and disposition of the malaria focus were collected and analyzed. RESULTS: In 2013, the blood tests of 66 723 fever patients were performed, the average blood smear checking rate was 1.10%, and the average positive rate was 0.08% (52 plasmodium positive individuals) in the 6 areas. For these 52 plasmodium positive individuals, the blood retests and case investigations were completed within 3 days after these cases were reported by the network system, and the investigation confirmed that they were foreign imported malaria cases. The malaria focus investigation and disposition were finished within 1 week and the data were reported by the Parasitic Diseases Information System. Four of 52 cases were recrudescence during the follow-up. Among the 52 cases, 20 people went abroad themselves and 4 were labors of private enterprises, 21 people came back without the accompanied. CONCLUSIONS: With the development of the malaria elimination program in Jiangsu Province, the eliminating malaria "targeted 1-3-7" working pattern has been comprehensively implemented. The personnel monitoring for labors who returned from overseas working will be a key in the future. PMID- 25434135 TI - [Analysis of malaria situation and discussion of control strategy in Shandong Province, 2013]. AB - OBJECTIVE: To understand the malaria situation of Shandong Province in 2013, so as to provide the evidence for formulating targeted prevention and control strategy and measures. METHODS: The data of malaria cases of Shandong Province in 2013 were collected from the Information Management System for Infectious Diseases Report and Information Management System for Parasitic Diseases Control and Prevention. The data of epidemiological characteristics of malaria situation and the diagnosis and treatment of malaria cases were analyzed by Microsoft Excel 2007. RESULTS: There were 131 malaria cases reported in 2013, all of them were imported cases, and 127 cases (96.95%) were imported from African countries. A total of 116 cases (88.55% ) were falciparum malaria cases. Totally 97.71% of the cases were male and the average age of malaria cases was 39 years. A total of 61.83% of the cases were peasants and 65.65% of the cases only received junior high school education. The distribution of malaria cases was concentrated in Tai'an City (32 cases), Yantai City (19 cases) and Weihai City (17 cases),totally acounting for 53.13%. There was no significant seasonal variation in the reporting time of the cases. The median time from on- set to seeing doctor was four days and the median time from seeing doctor to being diagnosed was one day. Totally 35.88% of the cases were misdiagnosed when the first visit to a doctor. All of the cases were laboratory confirmed and 100% of them received the standard treatment after diagnosis. CONCLUSIONS: All of the malaria cases were imported cases in Shandong Province in 2013. To control the imported malaria in Shandong Province, it is necessary to further strengthen the multi-sectoral cooperation, health education, malaria screening and professional training. PMID- 25434136 TI - [Epidemiological analysis of imported malaria prevalence in Luoyang City from 2010 to 2013]. AB - OBJECTIVE: To understand the epidemiological characteristics of imported malaria in Luoyang City, so as to provide the evidence for malaria prevention and control in this city. METHODS: The Epidemic situation data from network reports, as well as the case survey and the epidemiological investigation data of imported malaria were collected and analyzed in Luoyang City from 2010 to 2013. RESULTS: A total of 98 imported malaria cases were reported in Luoyang City from 2010 to 2013, including 35 cases of vivax malaria, 57 cases of falciparum malaria, 4 cases of ovale malaria and 2 cases of quartan malaria. All the cases were confirmed by laboratory detection. Seventy-one cases (72.44%) returned from African countries, and 27 (27.55%) cases returned from Southeast Asian countries. The majority cases were young man, and 78.57% of the cases were diagnosed by different levels of centers for disease control and prevention. There was no significant seasonal variation in onset time. The median time from onset to seeing doctor was 6 days. CONCLUSIONS: The epidemic situation of imported malaria is quite serious in Luoyang City. It is necessary to further strengthen the professional training and multi-sectoral cooperation, and take effective pre- vention and control measures to reduce the hazard of imported malaria. PMID- 25434137 TI - [Cloning, expression and immuno-protection analysis of a gene encoding troponin T of Schistosoma japonicum (SjTnT)]. AB - OBJECTIVE: To clone cDNA encoding troponin T of Schistosoma japonicum (SjTnT), and evaluate the protective efficacy induced by recombinant SjTnT in BALB/c mice against S. japonicum challenge infection. METHODS: The SjTnT gene was amplified from 28-day-schistosome cDNAs by PCR and then subcloned into pET28a(+). The recombinant SjTnT protein (rSjTnT) was expressed in Escherichia coli BL21 (DE3) cells. The serum specific to rSjTnT was prepared by immunized BALB/c mice with the recombinant antigen, and the immunogenicity of rSjTnT was detected by Western blotting and ELISA. The immuno-protective efficacy induced by rSjTnT in BALB/c mice was evaluated according to the reduction in worm and egg counts. RESULTS: The cDNA encoding SjTnT was successfully cloned and expressed in E. coli. Western blotting showed that rSjTnT had a good immunogenicity. The high level of specific IgG antibodies was detected, and 33.89% worm reduction and 43.94% liver egg reduction were obtained in mice vaccinated with rSjTnT combined with Seppic 206 adjuvant compared with those in the adjuvant control group. CONCLUSIONS: rSjTnT could induce partial immuno-protection against S. japonicum infection in BALB/c mice. This study provided a basic for understanding the biological function of SjTnT. PMID- 25434138 TI - [Influence of kaempferol on TGF-beta1/Smads signal path in liver tissue of mice with Schistosoma japonicum infection]. AB - OBJECTIVE: To investigate the influence of kaempferol on transforming growth factor(TGF-beta1/Smads signal tiransduction in liver tissue of mice with schistosomiasis liver fibrosis. METHODS: Forty BALB/c mice were randomly divided into a normal control group (8 mice), a praziquantel group (8 mice ), and 4 praziquantel + kaempferol groups with different kaempferol dosages (5, 10, 15, 20 mg/kg respectively, 6 mice each group). Besides the normal control group, all the mice in the other 5 groups were infected with Schistosoma japonicum. After the infection for 6 weeks, the praziquantel group and the 4 praziquantel + kaempferol groups were treated with praziquantel 500 mg/(kg.d) for 2 d, then the mice in the praziquantel group were drenched with normal saline for 6 weeks, and those in the 4 praziquantel + kaempferol groups were drenched with kaempferol 5, 10, 15, 20 mg/kg respectively for 6 weeks. After the treatment, all the animals were sacrificed by the cervical dislocation method, and the area of egg granuloma and the degree of fibrosis in the livers of the mice were observed by HE and Masson staining. The expressions of TGF-beta1, Smad2/3, Smad7 proteins were measured by the immunohistochemical method, and the mRNA levels of the 3 proteins were detected by RT-PCR. RESULTS: Compared with the mice in the praziquantel group, the areas of egg granuloma of the liver of the mice in the 4 praziquantel + kaempferol groups were smaller, and the degrees of the hepatic fibrosis of the mice were lesser, and their expressions of Smad2 and Smad3 at protein and their mRNA levels were significantly lower (all P < 0.05), while the expression of Smad7 at protein and its mRNA level were significantly higher (all P < 0.05). CONCLUSION: By decreasing the expressions of TGF-beta1 and Smad2/3, and increasing the expression of Smad7, kaempferol can significantly reduce the degrees of hepatic fibrosis and granuloma caused by schistosome eggs after the praziquantel treatment. PMID- 25434139 TI - [Relationship between multi-gene proteins in colorectal carcinoma complicated with chronic schistosomiasis: an immunohistochemical study by using tissue microarray techniques]. AB - OBJECTIVE: To investigate the relationship between p53, COX-2, Bax, c-myc genes and colorectal carcinoma complicated with chronic schistosomiasis. METHODS: One hundred and sixty patients with colorectal carcinoma were selected and divided into two groups; a schistosomiasis group (colorectal carcinoma complicated with chronic schistosomiasis, n = 80) and a non-schistosomiasis group (colorectal carcinoma uncomplicated with chronic schistosomiasis, n = 80). The tissue microarray techniques and immunohistochemistry method were used in all the patients to detect the expressions of p53, COX-2, Bax and c-myc proteins. RESULTS: The positive rate and level of p53 protein expression in the schistosomiasis group were lower than those in the non-schistosomiasis group, but there were no significant differences between the two groups (both P > 0.05). The COX-2 protein in both groups was positive, but the positive expression level of COX-2 in the schistosomiasis group was higher than that in the nonschistosomiasis group, and there was a significant difference between the two groups (P < 0.01). The positive rate and level of Bax protein expression were not significantly different between the two groups (both P > 0.05). The positive rate of c-myc expression in the schistosomiasis group was higher than that in the non schistosomiasis group, with a significant difference (P < 0.01), but the positive expression level was lower than that in the non-schistosomiasis group, and there was a significant difference between the two groups (P < 0.01). CONCLUSIONS: Schistosome infection may impact on the deficiency of p53 of human colorectal cancer cells. It may promote the excessive expression of COX-2 protein, which is an indirect carcinogenic factor. The expression of Bax gene has no correlation with schistosome infection. The schistosome chronic infection may cause a persistent low level expression of c-myc gene. PMID- 25434140 TI - [Immune response of purified Plasmodium falciparum antigen on human peripheral blood T lymphocytes in vitro]. AB - OBJECTIVE: To explore the effects of the purified Plasmodiumfalciparum (P. f) antigen on the T lymphocytes of the peripheral blood of healthy people in vitro. METHODS: The peripheral blood mononuclear cells (PBMCs) isolated from healthy donators were cultured with purified P. fantigen (5 MUg/ml) and normal RBC (nRBC) antigen (5 MUg/ml), in addition, the group in which only IL-2 added was set as a negative control. After cultured for 12 d, the corresponding antigens were used to re-stimulated the activated T cells in the two stimulated groups for 20 h. Then the cells were collected, the proliferations of the T cells labeled by CFSE were analyzed, and the secretion condition of IL-4 and IFN-gamma of the cells were detected by flow cytometry. RESULTS: After amplification, the proliferative index (PI) of CD4+ T cells that were stimulated with P. f antigen was significantly higher than those in the nRBC antigen group and the negative control group (both P <0.05), but there was no significant difference between the PIs of gammadelta T cells in the above three groups (P > 0.05). Meanwhile, the percentages of the CD4' T cells secreting IL-4+ in the P. f antigen group was significantly higher than those in the other two groups (both P <0.05), while the percentages of T cells secreting IFN-gamma in the 3 groups had no significant difference (P > 0.05). CONCLUSION: The purified P.fanti- gen could effectively stimulate the proliferation of CD4+ T cells in peripheral blood of healthy people, and the latter can play a role in immunoregulation through secreting IL-4 preferentially. PMID- 25434141 TI - [Prediction and identification of T-cell epitopes in major group 3 allergen derived from Dermatophagoides farina]. AB - OBJECTIVE: To predict and identify T cell epitopes of major group 3 allergen derived from Dermatophagoidesfarina (Der f 3). METHODS: The T cell epitopes of Der f 3 were analyzed through the sequence analysis by using the bioinformatics online tools. The five predicted peptides of T-cell epitopes were artificially synthesized. The spleen lymphocytes were co-cultured with the five T cell epitopes by using the modified MTT method and the levels of IL-2, IFN-gamma, IL-4 and IL-5 in the supernatant of the cultures were detected by ELISA. RESULTS: Five T cell epitopes of Der f 3 were predicted and three of which could promote the proliferation of the mouse spleen lymphocytes. The secretions of IL-2 and IFN gamma were significantly induced and the secretions of IL-4 and IL-5 were significantly decreased by three of five prediction epitopes of Der f 3: 37GDCPYQISLQSSSHFCGG54, 98IYQHENYDSMTIDNDVALIKLKTPMT123 and 164SELQRVDIDVVSREQCDQLYS184. CONCLUSION: Three T cell epitopes of Der f 3 have been initially identified, which lays the foundation of the diagnosis and treatment of asthma. PMID- 25434142 TI - [Construction and expression of a chimeric gene with T-/B-cell epitopes of major allergen group 1 from Dermatophagoides farina]. AB - OBJECTIVE: To construct and express a chimeric gene with T-/B-cell epitopes of the major allergen group 1 from Dermatophagoidesfarina (Der f 1). METHODS: Two chimeric genes, Der f 1A and Der f 1B, were synthesized as B1-T1-B2-T2- B3-T3-B4 T4-B5-T5-B6 and B1-B2-B3-B4-B5-B6-T1-T2-T3-T4-T5 pattens. Two recombinant vectors, pET-28a(+)-Der f 1A and pET-28a(+)-Der f 1B, were constructed for prokaryotic expression. These chimeric genes were induced by 1 mmol/L IPTG (final concentration), digested with restriction enzymes and sequenced. The chimeric proteins were analyzed by SDS-PAGE and Western blotting. RESULTS: After digestion by restriction enzymes and sequencing, the recombinant vectors were constructed successfully. The specific bands for chimeric proteins were visible by SDS-PAGE and Western blotting, suggesting that these proteins were purified successfully. Further analyses were performed for IgE-binding properties of Der f 1A and Der f 1B to sera from patients sensitized to house dust mite. Compared with the parental allergens Der f 1, Der f 1A and Der f 1B had reduced IgE -binding capacity (both P < 0.05), whereas the difference between Der f 1A and Der f 1B was not statistically significant (P > 0.05). CONCLUSION: Two chimeric proteins are expressed successfully, which contain T-/B-cell epitopes of Der f 1 and provide a basis for specific immunotherapy. PMID- 25434143 TI - [Application of health education path in advanced schistosomiasis patients with splenomegaly in perioperative period]. AB - OBJECTIVE: To evaluate the effect of health education path on advanced schistosomiasis patients with splenomegaly in perioperative period. METHODS: A total of 60 advanced schistosomiasis patients with splenomegaly in perioperative period were randomly divided into an observation group and a control group (30 cases each group). The patients in the observation group were intervened by the nursing and health education from admission to discharge according to the standardized process of health education path, while those in the control group were implemented with the conventional health education. Then the satisfaction of nursing work, hospital stays, hospitalization expenses and mastery of health knowledge of the patients in the two groups were investigated and the results were compared. RESULTS: The satisfaction rates of nursing work of patients in the observation group and the control group were 90% and 60%, respectively, the difference between them was statistically significant (chi2 = 7.57, P < 0.05). The average hospitals stays of the above two groups were 14.0 +/- 3.5 d and 19.0 +/- 6.8 d (t = 2.85, P < 0.01), respectively, and the average hospitalization expenses were (1.5 +/- 0.5) thousand Yuan and (2.2 +/- 0.7) thousand Yuan (t = 24.57, P < 0.01), respectively, both of the differences were statistically significant. On the 10th day after surgery, the mastery rates of the health knowledge of the two groups were 96.7% and 50.0%, respectively, the difference was statistically significant (chi2 = 16.86, P < 0.001). CONCLUSIONS: The implementation of the health education path can promote the rehabilitation of advanced schistosomiasis patients with splenomegaly, and increase the satisfaction as well as improve the mastery of the health knowledge of the patients. Meanwhile, it also can cut down the hospital stays and save the hospitalization expenses. PMID- 25434144 TI - [Investigation of wild feces pollution in schistosomiasis endemic areas in Yunnan Province]. AB - OBJECTIVES: To understand the status of wild feces distribution and pollution in schistosomiasis endemic areas in Yunnan Province. METHODS: According to the distribution of Oncomelania hupensis snails and characteristics of human and animal activities in recent five years, 6 schistosomiasis endemic villages in Weishan, Nanjian and Midu counties (2 villages each county) were selected as the investigated areas and. more than 4 hm2 area with snails around each village were investigated for the types and densities of wild feces. The schistosome infested feces was detected with the hatching method. RESULTS: Totally 63 hm2 were investigated and 420 wild feces were found in all kinds of environments. The densities of wild feces were 0.066 7 piles/100 nm2, and the densities of wild feces of the road and the hillside were the highest (0.098 7 piles/100 m2 and 0.088 0 piles/100 m2 respectively). Totally 260 fresh wild feces were collected, including the feces of human being, cattle, horse, dog, sheep and pig, and the feces of cattle and dog was the most (37.38% and 30.71%, respectively). No schistosome positive feces was found. CONCLUSIONS: There are a lot of wild feces in snail areas in Yunnan Province, and the risk of schistosomiasis transmission is still high. Therefore, we should strengthen the banning grazing measures and the investigation of dogs. PMID- 25434145 TI - [Effect of Parasep(r) feces centrifuge tube method on detecting schistosome eggs]. AB - OBJECTIVE: To evaluate the effect of the Parasep(r) feces centrifuge tube method on detecting schistosome eggs. METHODS: A total of 803 residents aged from 6-65 years were selected in 2 schistosomiasis endemic villages, Jiangling County, Hubei Province, and their stool samples were collected and detected parallelly by the Kato-Katz technique, nylon silk egg hatching method, and Parasep(r) feces centrifuge tube method at the same time. RESULTS: Among the 803 people, 15 cases were found of schistosome egg positive, and the positive rate was 1.87%. The positive rates of the Kato-Katz technique, nylon silk egg hatching method, and Parasep(r) feces centrifuge tube method were 0.75%, 1.49% and 1.12%, respectively. The schistosome eggs got with the Parasep(r) feces centrifuge tube method were clear and easy to identify. CONCLUSION: In low endemic areas of schistosomiasis, the Parasep(r) feces centrifuge tube method can be used as schistosomiasis japonica etiology diagnosis method. PMID- 25434146 TI - [Comparation of Toxoplasma gondii separated from HIV-positive people and RH strain GRA6 gene]. AB - OBJECTIVE: To comparatively analyze Toxoplasma gondii separated from HIV-positive people and RH strain GRA6 gene. METHODS: By using the nested PCR, the amplification of Dali HIV-positive blood samples and RH strains of Toxoplasma GRA6 genome was performed. The GRA6 gene amplification positive product was selected and the electrophoresis imaging was performed by being digested with the Mse I endonuclease, and the gene sequences were measured and analyzed. RESULTS: The GRA6 gene fragment (800 bp) was successfully amplified, and about 600 bp and 200 bp bands were got by Mse I. The sequencing results showed that T. gondii GRA6 gene positive samples had 2 nucleotide variation compared with T. gondii strain RH, namely 447 base pair at C becoming G, and 623 base pair at G becoming T. At 146 bp and 690 bp, the Mse I restriction sites (TTAA) were found. CONCLUSION: The preliminary judgment shows that the Dali HIV-positive T. gondii genotype is consistent with RH strain, belonging to genotype I. PMID- 25434147 TI - [Toxoplasma gondii infection status in abnormal pregnancy women]. AB - OBJECTIVE: To investigate the relationship between Toxoplasma gondii (TOX) infection and abnormal pregnancy outcomes. METHODS: A total of 126 cases of abnormal pregnancy women in the Department of Obstetrics and Gynecology, the Fourth People' s Hospital of Langfang from March to December 2013 were chosen as an experimental group, and 263 cases of normal pregnancy women of childbearing age as a control group. The TOX-IgM and -IgG antibodies were detected by ELISA. The data in the two groups were processed and analyzed by SPSS13.0. RESULTS: The positive rates of TOX-IgM, -IgG in 126 cases of abnormal pregnancy women were 7.94% and 19.84% respectively, and 1.90% and 8.75% in the control group respectively, and there were significant differences between them (chi2IgM = 6.82, chi2IgG = 9.70, both P <0.01). The positive rates of TOX-IgM, -IgG in the normal pregnancy women were lower than those in 4 sub-groups of abnormal pregnancy women, and all the differences were statistically significant (chi2 spontaneous abortion = 10.40, chi2 premature delivery = 9.03 chi2 embryo damage = 4.32, chi2 birth defet = 4.04, all P< 0.05). However, the TOX-IgM, -IgG positive rates in the 4 sub-groups of abnormal pregnancy women had no statistically significant difference (P > 0.05). CONCLUSIONS: TOX infection could cause serious abnormal pregnancy outcomes. Therefore, the comprehensive control measures should be strengthened. PMID- 25434148 TI - [Research on competency building standards of institutions of schistosomiasis prevention and control in Hubei Province I Investigation of institution management]. AB - OBJECTIVE: To investigate the current situation of management of institutions of schistosomiasis prevention and control in Hubei Province, so as to explore the probable competency building standards for these institutions at the county and township levels. METHODS: By using a combination of quantitative and qualitative methods, the institutions of schistosomiasis prevention and control at county and township levels were investigated for the institutional setup, staffing and fulfillment functions since the reform of 2004. RESULTS: Among 63 schistosomiasis endemic counties (cities, districts) of Hubei Province, there were 26 independent schistosomiasis control institutions (41.27%), there were 24 institutions which were incorporated into CDC (38.10%), and there were no institutions in 13 counties (20.63%). Among 518 endemic towns, there were 299 institutions (57.72%). The total staffing size were 1 932, but there were 1 586 (82.09%) people actually working in the post, and therefore there were 346 (17.91%) empty positions. The average rates of carrying out the six functions were 91.48%-71.19%, but only 19.23% of the institutions participated in the comprehensive schistosomiasis control management project and its effect assessment. CONCLUSION: According to the management model for schistosomiasis control institutions under the current institutional mechanisms, we need a rigorous industry standard to constrain, guide and standardize the management and capacity-building of the institutions in different historical periods. PMID- 25434149 TI - [Current situation of scientific research capacity of schistosomiasis control institutions of municipal cities in Hubei Province]. AB - OBJECTIVE: To evaluate the levels of the Chinese literature published by the schistosomiasis control institutions of 17 municipal cities of Hubei Province. METHODS: The related literature published from 2008 to 2012 was searched from the databases of CNKI, VIP and Wanfang and then screened by the exclusion criteria. NoteExpress and Excel softwares were applied to collect the literature and carry out the bibliometric analysis. RESULTS: A total of 168 papers were included and the schistosomiasis control institutes of Jingzhou City and Wuhan City had the highest amount. The literature was mainly published in Chinese Journal of Schistosomiasis Control and Journal of Public Health and Preventive Medicine. The comprehensive influence indexes of the schistosomiasis control institutes of Jingzhou, Wuhan and Qianjiang cities were higher. The schistosomiasis control institutes of Jingzhou City had an extensive content of literature while Wuhan was mainly focused on epidemiology, case report and Oncomelania hupensis snail control. CONCLUSION: The research of schistosomiasis in each municipal city has an extensive content and the research capacity of the schistosomiasis control institute of Jingzhou City is relatively outstanding. PMID- 25434150 TI - [Enolase and parasitic infection]. AB - Enolase is one kind of important glycolytic enzymes which widely exists in most organisms. A number of recent studies confirm that this enzyme has the functions of activating the plasminogen, involving in the processes of infection and migration of parasites, reducing the immune function of the host as well as preventing parasites from the immune attack of the host. This paper reviews the current research advances in the parasite enolase, and explores its potential for diagnosis, drug development and vaccine target of parasitic diseases. PMID- 25434151 TI - [Multilocus sequence typing and its application on population genetic structure analysis of parasites]. AB - Multilocus sequence typing (MLST) with high solution, sensitivity and specificity, is widely used to study the population genetic structure of pathogen by amplification and sequencing of the housekeeping genes. MLST also provides more evidence and plays an important role in parasite research. This paper reviews the principle and method of MLST, and its application on population genetic structure analysis of parasites. PMID- 25434152 TI - [Research progress of interaction between Toxoplasma gondii rhoptry proteins and host cells]. AB - Rhoptry proteins are the major virulence factors of Toxoplasma gondii. They locate in different parts of the host cells, and can affect the membrane, cytoskeleton structure and active factors of the host cells, so as to block the cell intrinsic defense mechanisms of the host, and let T. gondii invade, parasitize and proliferate in the host successfully. The function and ac- tion mode of rhoptry proteins reflect the pathogenic mechanism of T. gondii, which holds great significance to looking for toxoplasmosis drug targets and developing molecule vaccines. This paper reviews the research progess of the interaction between rhoptry proteins of T. gondii and host cells. PMID- 25434153 TI - [Schistosomiasis status of staff in Hydrology Bureau of Yangtze Water Resources Committee in 2013]. AB - OBJECTIVE: To understand the status of schistosomiasis of staff in the Hydrology Bureau of Yangtze Water Resources Committee and the Oncomelania hupensis snail condition of their work areas in 2013, so as to provide the evidences for the schistosomiasis control in the industry. METHODS: The physical examination data about schistosomiasis of the staff from 2006 to 2013 were collected and analyzed to understand the schistosomiasis prevalence condition of the staff and the changes of their liver parenchyma. Meanwhile, the snail status in the work areas was surveyed. RESULTS: There were 1,393 staff involved in the physical examinations of schistosomiasis in 2003, 197 of them were schistosomiasis patients, the prevalence rate was 14.14%, and no new acute schistosomiasis case occurred. The cases whose liver parenchyma were classified as Grade 0, I , II , III occupied 28.9%, 67.0%, 3.05% and 1.02%, respectively. A total of 24 work areas were involved in the snail survey, and 71 snails were captured. Among the whole snails captured, 39 were living snails, but no schistosome infected snails were found. CONCLUSIONS: The prevalence rate of schistosomiasis in staff of the Hydrology Bureau of Yangtze Water Resources Committee is relatively high, so the schistosomiasis surveillance as well as the snail survey and control still should be carried out consistently. PMID- 25434154 TI - [Sampling survey of schistosomiasis prevention knowledge among middle school students in endemic areas of Hubei Province]. AB - OBJECTIVE: To understand the schistosomiasis prevention knowledge of middle school students from areas with different endemic levels in Hubei Province. METHODS: The schistosomiasis endemic regions were divided into transmission controlled areas and endemic controlled areas in Hubei Province, middle school students from different types of areas were selected through stratified randomized cluster sampling and were investigated by questionnaire. RESULTS: A total of 3,204 students were selected and investigated. The awareness rate of schistosomiasis prevention and control knowledge among the students ranged from 65.1%-90.3%. Overall, the students from endemic controlled areas had higher knowledge rates of all the items than those from transmission controlled areas (all P <0.05). The middle school students acquired schistosomiasis prevention knowledge mainly from the teachers, parents, doctors and schistosomiasis staff. CONCLUSION: Health education to students should adopt different ways targeting at different endemic levels in the future. PMID- 25434155 TI - [Molluscicidal effects of 3 molluscicides by spraying and poudrage methods in dry season]. AB - OBJECTIVE: To evaluate the effects of 3 molluscicides namely 5% niclosamide ethanolamine granules, 4% "Luowei" (Tea-seed distilled saponins, TDS) and 50% wettable powder of niclosamide ethanolamine salt (WPN) by spraying and poudrage methods in marshland and lake regions in dry season. METHODS: An environment with a high snail density was chosen as the experimental field, then the spraying and poudrage experiments were carried out in the field to assess the molluscicidal effects of 5% niclosamide ethanolamine granules, TDS and WPN delivered by spraying and poudrage methods with a concentration of 30, 6 and 2 g/m2, respectively, and the molluscicidal effects of the 3 drugs by the two methods were evaluated and compared in different time. RESULTS: After the delivery for 15 d, the adjusted snail death rates of the 5% niclosamide ethanolamine granules, TDS and WPN in the spraying experiment were 79.00%, 82.29% and 84.83%, respectively, and those in the poudrage experiments were 97.42%, 95.27% and 96.62%, respectively. CONCLUSION: The molluscicidal effect of poudrage method is better than the spraying method, and the former is worthy of further extension and application in the marshland in dry season. PMID- 25434156 TI - [Current status of advanced schistosomiasis in Pukou District, Nanjing City, 2013]. AB - OBJECTIVE: To understand the current status of advanced schistosomiasis in Pukou District, Nanjing City, so as to provide the evidence for its appropriate treatment. METHOD: An epidemiological investigation and medical examinations were carried out based on the national standard for the people who either had been already identified as advanced schistosomiasis or were new suspects. RESULTS: There were 55 cases of advanced schistosomiasis in Pukou District, 2013. Among them, 51 cases (92.73%) were splenomegaly type and 4 cases (7.27%) were ascites type. Fifty-three cases (96.36%) were clinically cured, 1 case (1.82%) was in the stable condition and 1 case (1.82%) still needed further treatment. In terms of the age, the youngest was 49 years and the oldest was 86 years. The gender distribution was male accounting for 58.18% (32 cases) and female 41.82% (23 cases). CONCLUSION: The condition of patients with advanced schistosomiasis in Pukou District, Nanjing City is complicated. The investigation and treatment to the patients should be conducted regularly. PMID- 25434157 TI - [Protective effect of Fangyouling on Schistosoma japonicum infection]. AB - OBJECTIVE: To evaluate the protective effect of Fangyouling (extracted from herb) on Schistosomajaponicum infection in the field. METHODS: The residents in 2 villages, Zhaonao Village and Miaochang Village, were divided into Group A (139 persons) and Group B (162 persons), and the residents in Group A embrocated Fangyouling before their contacting the infested water and the residents in Group B did not. All the residents were investigated with questionnaires, and received the blood and stool examinations for schistosomiasis. RESULTS: The positive rates of blood tests were 3.13% and 9.34% in Group A and Group B respectively, the positive rates of stool examinations were 1.92% and 6.44% in Group A and Group B respectively (both P values < 0.05). CONCLUSION: Fangyouling has a good protective effect on S. japonicum infection. PMID- 25434158 TI - [Experimental study on quick determination of viability of Oncomelania hupensis by staining]. AB - OBJECTIVE: To find out a quick, simple and convenient method of determining the viability of Oncomelania hupensis. METHODS: O. hupensis snails were stained for 30 minutes by 0.05% water soluble dye neutral red, 0.5% methylene blue, red ink, methylene blue-eosin-borax (MEB) and 0.4% trypan blue, respectively. The soft tissue samples of the snails were observed by a stereoscopic microscope after crushing their shells. RESULTS: The vital snails were stained and the dead were unstained in the neutral red. The vital and dead snails were unstained in methylene blue. However, the vital and dead snails were stained in red ink. The partial vital and dead snails were stained in MEB. The vital snails were stained and the partial dead were stained in trypan blue. CONCLUSION: The use of 0.05% water soluble dye neutral red is simple, rapid and accurate in determination of the viability of O. hupensis. PMID- 25434159 TI - [Surveillance of malaria in Huai'an District, Huai'an City, 2009-2013]. AB - OBJECTIVE: To analyze the results of malaria surveillance in Huai' an District in the recent 5 years, so as to provide the evidences for the establishment of suitable control strategy in the district. METHODS: The febrile patients among permanent and floating populations in Huai'an District from 2009 to 2013 were examined by immunity and etiology methods and the mosquito vector in this district were investigated. Results In recent 5 years, a total of 48,203 person times among permanent population were examined, and no positives ones were found, and totally 360 person-times among floating population were examined, and 53 cases of malaria were detected, including 2 vivax malaria cases, 48 falciparum malaria cases and 2 undifferentiated cases, and the positive rate of the floating population was 14.72%. All the cases were exported workers infected in Africa and Southeast Asia. A total of 1,048 Anopheles sinensis mosquitoes were captured in 2003, no other Anopheles mosquitoes were found. CONCLUSIONS: In recent 5 years, no local malaria cases have been found in Huai' an District, but the imported cases increase, and moreover, the mosquito vector and the transmission condition of malaria still exist. PMID- 25434160 TI - [Investigation on knowledge of malaria prevention and control in residents of Suining County]. AB - OBJECTIVE: To understand the status of knowledge of malaria prevention and control in residents of Suining County, so as to provide the reference for improving the implementation of malaria elimination. METHODS: Nine villages in 3 townships (3 villages per township) were randomly selected as the study areas, and 200 residents aged above 15 years of each village were investigated with questionnaire for the knowledge of malaria prevention and control. RESULTS: The awareness rates of "malaria transmission way", main symptoms of malaria", "life threatening of falciparum malaria", "how to treat malaria", and "how to prevent malaria" were 96.27%, 95.01%, 81.46%, 98.19% and 96.27%, respectively. There were no significant differences between the different genders and among the different areas (all P >0.05), but there were significant differences among different age groups (all P <0.05). CONCLUSION: The awareness of malaria prevention and control in residents of Suining County is relatively high, which means the health education is effective. PMID- 25434161 TI - [Investigation on infections of human intestinal parasites in Taixing City]. AB - OBJECTIVE: To understand the current status of infections of intestinal parasites of population in Taixing City, Jiangsu Province. METHODS: The infection rates and densities of human intestinal parasites were investigated according to the methods of the National Investigation Scheme on Human Principal Parasites, and the data of society, economy and disease control were collected and analyzed. RESULTS: Among 2 556 people investigated in five villages, 16 persons were found with intestinal parasites, with an infection rate of 0.63%. The infection rate was higher in residents with a low education level than in others and it was higher in the age group over 50 years than in the group under 50 years. The infection density was mild and the most was the single parasite infection. CONCLUSIONS: The current status of intestinal parasite infections of population in Taixing City has reached the county-level control standard of Jiangsu Province. Therefore, the preventive strategy and measures should be adjusted and the monitoring work should be strengthened. PMID- 25434162 TI - [Awareness and infection of Toxoplasma gondii in married childbearing women in Chengde Region]. AB - OBJECTIVE: To understand Toxoplasma gondii infection and awareness condition of married childbearing women in Chengde Region, so as to provide the evidence for the establishment of control measures. METHODS: Totally 733 married childbearing women who took physical examination in Chengde Hospital of Traditional Chinese Medicine from July to December in 2013 were investigated by questionnaire to understand the awareness condition on T. gondii infection, then 490 women among them from 3 counties and 2 districts were randomly chosen to detect the Toxoplasma antibodies by ELISA. RESULTS: A total of 733 questionnaires were returned, and 126 women knew related knowledge about T. gondii infection, and the awareness rate was 17.19%( 126/733). Sixty-three women were determined as infected cases, and the infection rate was 12.86%( 63/490). The infection rates of the women who with higher educational level, working as medical staff and living in urban were lower, and the awareness rates of them were higher. CONCLUSIONS: The infection rate of T. gondii among the married childbearing women in Chengde Region is high, and the awareness rate of them is low. In order to decrease the infection rate as well as to increase the awareness rate of the population, the health education should be strengthened. PMID- 25434163 TI - [One case report of overseas imported quartan malaria]. AB - This paper reports one case of overseas imported quartan malaria and the diagnosis and treatment process. By using dihydroartemisinin combined with piperaquine, the treatment results are satisfactory. PMID- 25434164 TI - [Experimental study of the therapeutic efficiency of the lithium salt of glutathione disulphide in the conditions of acute external gamma-irradiation]. AB - Experimental studies on white outbred male mice subjected to gamma-irradiation at doses LD(80/30) have found that the therapeutic use of Litan contributes to the increase (by 40-50%) in the survival rate of the animals. Introduction to irradiated animals of Litan increases the intensity of the inclusion of 3H thymidine in the DNA of the bone marrow cells and is associated with a growing number of splenic endogenous colonies, which can testify to the stimulating influence of the drug on the proliferation and differentiation of hematopoietic cells, as well as on the deficit restoration of full-fledged mature cell forms in the peripheral blood. PMID- 25434165 TI - [The classification of radiation protective agents as the reflection of the present state and development perspective, of current radiation pharmacology]. AB - Pharmacological drugs which can reduce the radiation damage to the organism when applied in the nearest time before or after exposure to radiation can be referred to as radiation protective agents. The classification of radiation protective agents, which has been well established to date, is a reflection of the history of the formation and current state of radiation pharmacology: the most significant historical landmarks in the screening of radiation protective agents among different groups of pharmaceutical preparations and the formation of the theoretical knowledge about the mechanism for their radiation protective effects. It consists of: (1) radioprotectors which realize their radiation protective effect at the physical, chemical and biochemical levels in the course of the energy absorption of ionizing radiation via partial neutralization of the "oxygen effect" as a radiobiological phenomenon; (2) radiomitigators, which realize their effect at the system level by accelerating the post-radiation recovery of radiosensitive tissues through an activation of proinflammatory signaling pathways and an increase of secretion of hematopoietic growth factors, are used in the early period after exposure to radiation prior to the development of clinical manifestations of acute radiation damage as drugs of emergency and early treatment for radiation injuries; (3) radiomodulators--pharmaceutical drugs and food nutritional supplements which elevate the resistance of the organism to adverse environmental factors, including mutagenic effects of exposure to low dose ionizing radiation, by means of modulating the gene expression through "substrate" maintenance of adaptive changes resulting in an increased antioxidant protection of the organism; (4) pharmaceutical drugs to protect against the incorporation of technogenic radionu- clides into the organism; (5) pharmaceutical drugs to prevent (arrest) manifestations of the primary response to radiation. PMID- 25434166 TI - [The experimental evaluation of antiradiation effectiveness of genistein by survival rates and bone marrow hemopoiesis of mice irradiated by X-rays]. AB - The study was aimed at evaluating the radioprotective effectiveness of genistein administered at different times before or after acute irradiation. Evaluation ofradioprotective efficiency was performed by studying the 30-day survival rate, life expectancy, bone marrow hemapoiesis using the method of endogenous and exogenous colony formation. We have established that genistein at a dose of 200 mg/kg when administered 1 hour prior to irradiation has the highest radioprotective efficiency. In this case, genistein protects mice against death due to X-ray radiation at doses LD(50-90/30), increasing their survival rate by 30-44%, and reduces expression of post radiation disorders of bone marrow hematopoiesis. PMID- 25434167 TI - [Protection from radiation by selenium]. AB - We examined acute toxicity and radioprotective activity of inorganic (calcium selenites, manganese, strontium and lanthanum) and organic selenium compounds. Results from animal experiments indicate that some of the organic selenium compounds are protective against ionizing radiation and promising as radioprotective agents. The time required to achieve the maximum radioprotective activity for selenium compounds depends on the degree of oxidation. Optimal duration of prophylactic administration of drugs with a degree of oxidation of Se+4 is 24 hours, and Se+2--1 hour. The radioprotective mechanism of selenium may be associated with the antioxidant properties. PMID- 25434168 TI - [Experimental estimation of application efficacy of wound coverings as a means of conservative therapy of local radiation burns formed at combined radiation injures]. AB - The study was aimed at experimental evaluating the efficacy of experimental wound collagen coverings "Sangvikol", "Gemasept", "Kolotsil" and "Biatravm" for treatment of deep radiation burns which form at combined radiation injures. The combined radiation injures were modeled by consecutive local X-ray radiation of skin at a dose of 120 Gy and the total whole body gamma-irradiation from a source of 137Cs at a dose of4 Gy. It is established that wound collagen coverings are well modeled on a wound, absorb excess exudate, maintain optimum humidity in a wound; protect a wound from infection, and medicinal fillers contribute to the activation of reparative processes in the irradiated skin. Wound coverings do not require frequent dressings and more effectively prevent post-radiation depression recovery processes in irradiated skin than ointments. PMID- 25434169 TI - [Search problems of human radiation protection in the world of genetics of aging]. AB - Currently, the urgency for protection from negative effects of radiation in the range of low and medium dose where classic radioprotectors are ineffective is increased. In this respect it seems promising to study the molecular pathways that increase, on the one hand, the stability of the genome against radiation damage (inducers of carcinogenesis), and, on the other hand, elevate the radiation sensitivity of cell populations in order to eliminate potentially carcinogenic cells. This approach requires modification of cascade mechanisms of signal transduction to apoptosis and responses to DNA damage. Research plan is similar to the Genetics of Aging, where a number of hypotheses about the mechanism of aging have been proposed, including a decrease in the stability of the genome to external influences. Proceedings of the 2nd International Conference "The genetics of aging and longevity" (Moscow, April 2012) demonstrated, however, that patterns of aging mechanisms identified in model animals (nematodes, drosophila and mice) are far from the possibility of their practical application. Discovered genes that may be responsible for life expectancy (stress-inducible protein and other components of the signal transduction cascade, as well as suppressors and inducers) rarely find significance in the study of the genomes of centenarian cohorts. This may be due to the difficulty in transferring molecular genetic patterns from model objects to large mammals, including humans, with respect to systems of signal transduction. This point must be taken into account during the search for a new generation of radioprotective agents that promote anti-carcinogenic potential of human cells exposed to radiation at low and moderate doses. It may be necessary to search for such tools in large laboratory animals and in human tissue cultures obtained through genetic engineering or cloning. PMID- 25434170 TI - [The radioprotective properties of nitric oxide (NO) donors]. AB - In harmony withnumerous literary data, endo- and exogenic nitric oxide plays an important role in regulation of cell and organism resistance to damage factors of various nature including ionizing radiation. The experiments with mice and rats have shown that some potential NO-donors among drugs can manifest both prophylactic and treatment radioprotective activity. Sidnopharm has been patented as a new remedy in the early therapy of acute radiation injury. PMID- 25434171 TI - [The experimental evaluation of influence of exogenous melatonin on the genetic damage induced by radiation exposure]. AB - It is shown in experiments on the rats subjected to gamma-radiation at various doses that preventive introduction of exogenous melatonin reduces the quantity ofchromosomal aberrations in cells ofbone marrow and decreases the expression of oxidative stress. After introduction of melatonin, the activity of leucocytes in peripheral blood and proliferation activity of splenocytes increase, which can play a role in the mechanisms for the genoprotective effect of the studied medication. PMID- 25434172 TI - [Influence of new thiazole and tetrazole derivatives on the antioxidant status of natural mouse populations having elevated 90Sr]. AB - The studies on Apodemus (S.) uralensis captured on the control, not contaminated, territories and within the East Ural Radioactive Trace (EURT) area with soil pollution by 90Sr up to 16.7 MBq/m2 (451 Ci/km2), an average concentration of 90Sr up to 160 Bq/g of wet bone were performed. Thiazole or tetrazole derivatives, fluoroquinolone (antibacterial medication pefloxacin) were administered intraperitoneally or orally for ten days. The biochemical parameters of lipid peroxidation and antioxidant system in the peripheral blood plas- ma, erythrocytes, liver and spleen were studied. The effect of the preparations on the reduction of the con- centration of TBA-reactive substances (TBARS), the degree of osmotic hemolysis of cells, as well as the RNA/DNA ratio on the increase of the catalase activity, ceruloplasmin content was reflected. It characterizes the orientation on the normalization of the redox balance of homeostasis, the level of destructive processes in cells and tissues and the functional activity of the genome. It helps to increase the radioresistance and non- specific resistance of the organism under conditions of radioactive contamination of the environment. PMID- 25434173 TI - [Actual problems of searching and studying radiation countermeasures]. AB - The state of radiation counterdrug elaboration has been analyzed. The main criterion of estimation is how various possible radiation incidents are provided with radiation countermeasures. The latter are differentiated in 3 principal groups: radioprotectors, radiomodificators (these are able to have a positive effect when administered preliminary, before the exposure, or provide a delayed nonspecific protection after the exposure--urgent therapy) and hemopoietic growth factors demanding course administration. It should be underlined that the list ofofficinal radiation countermeasures is rather short. The most dynamic now are investigations aimed at developing a home preparation of recombinant human interleukine-1beta named betaleukine, and the preparation CBLB502, a modified microbe polypeptide elaborated in the USA. Also elaborated is a scheme of emergency exposure treatment. It includes urgent administration of the cytokine combination (betaleukine and thrombopoietin) with subsequent supportive therapy and a hemopoietic growth factors course. In the case of medical radiation- and chemotherapy the preparations betaleukine and thiol compound amifostine are used rather seldom. Official countermeasures for protection against low dose rate prolonged exposure are still absent. The problem of an indicator/marker of the radioresistance induced by a radioprotector or radiomodificator still remains unsolved. Reliable indicators/markers are needed to provide the 2nd stage of clinical trials of radioprotectors/modificators. PMID- 25434174 TI - [Radiation protection agents to provide the radiation safety of astronauts]. AB - Taking into consideration the complexity of radiation factors and stressogenic factors of non-radiation nature in cosmic flights and prognostic difficulties of radiation situation, the authors propose to distinguish several stages of pharmacological protection for cosmonauts. The preparatory stage is realized on the Earth. The next stage is monitoring and correction of radioresistance during a flight. A possible stage consists of treatment of the radiation damage using a traditional protocol. The permanent stage includes pharmacological prevention of the distant consequences of irradiation. PMID- 25434175 TI - [Complex pathogenetic treatment schemes of vascular dyscirculatory disorders in the remote period after exposure to low dose radiation]. AB - Complex studies including modern methods of investigation of structures and functions of nervous system: electroencephalograsphy (EEG), coherent analysis, neuropsychological study and methods of neuroimaging were performed in 517 participants in liquidation of consequences of the accident (LCA) at the Chernobyl NPP in 1986-1987. Dyscirculatory metabolic encephalopathy was revealed to be the main pathology with the etiological mechanism based on dyscirculatorhypoxic and metabolic disorders. Complexity of the revealed symptoms testified to an early organism aging in remote periods after exposure to low dose radiation. Pathogenetic schemes were developed for treatment of dyscirculatory encephalopathy in liquidators, which include drugs improving blood supply, antiaggregants, antioxidants and metabolites of the brains in various combinations. Taking into consideration that early appearance of vascular dyscirculatory disorders observed in liquidators is the sign of early aging of the organism, geroprotectors were added to treatment schemes. PMID- 25434176 TI - [Peculiarities of antioxidants as radioprotectors under radiation damage of different extent]. AB - Results of the own and literature data about the effectiveness of antioxidants as radioprotectors under the action of ionizing irradiation in animals are generalized dependingon the extent of the radiation damage and the linear energy loss of radiation. The initial antioxidant status of tissues is shown to make a different con- tribution in the manifestation of the radioprotective properties of natural and synthetic antioxidants owing to the non-linearity of the lipid peroxidation processes depending on the radiation dose and dose rate. Thus, a complex approach and consideration of the time factor are necessary when estimating radioprotective effectiveness of antioxidants as radoprotectors under radiation damage of different extent. PMID- 25434177 TI - [Bacterial toxin-antitoxin systems and perspectives for their application in medicine: a review]. AB - The structure of various toxin-antitoxin (TA) families and the principles of their action are reviewed. TA loci are widely distributed in the genomes of eubacteria and archaea. Most TA systems are two-component and function in a similar way: a stable toxin alters vitally important cell functions and can be inactivated by a labile antitoxin. PMID- 25434178 TI - [Purification of recombinant Bacillus cereus ResD-ResE proteins expressed in Escherichia coli strains]. AB - Recombinant E. coli strains expressing the Bacillus cereus ATCC 14579T resD and resEgenes fused with the ubiquitin gene were constructed, and purification of the ResD and ResE proteins was performed. The approach used in the study allowed us to increase the protein yield of the electrophoretic homogeneous ResD andResE proteins without denaturation steps up to 150 mg per gram of wet cell weight. PMID- 25434179 TI - [Peculiarities of the Brevundimonas diminuta Gl7ACA-Acylase quaternary structure formation and obtaining stable enzyme analogues]. AB - The physicochemical and enzymatic properties of hybrid analogues of the Brevundimonas diminuta Gl7ACA-acylase (BrdGIA), containing the N-terminal chitin binding domain of the bacterial chitinase (BrdG1A/NmChBD) or the C-terminal oligohistidine sequence (BrdGIA/H), were studied. An enhanced thermostability level of BrdG1A/NmChBD could suggest the stabilizing effect of the chitin-binding domain. An analysis of pH profiles of the enzymatic activity of recombinat BrdGIA analogues did not reveal significant differences: the catalytic activity of both variants changed slightly in the.interval ofpH values from 6.0 to 9.0 but drastically decreased at lower pH values. Both analogues demonstrated similar sensitivity towards denaturing agents: addition of 2.0 M ofguanidine chloride resulted in the complete inactivation of both enzymes. A scheme was developed for obtaining isolated recombinant alpha- and beta-subunits of BrdGLA. In vitro enzyme reconstructions indicated that the alpha-subunit was necessary for the formation of a correct spatial structure of the beta-subunit and for the formation of a functionally active enzyme. PMID- 25434180 TI - [Leaching of nonferrous metals from copper-smelting slag with acidophilic microorganisms]. AB - The leaching process of copper and zinc from copper converter slag with sulphuric solutions of trivalent iron sulphate obtained using the association of acidophilic chemolithotrophic microorganisms was investigated. The best parameters of chemical leaching (temperature 70 degrees C, an initial concentration of trivalent iron in the leaching solution of 10.1 g/L, and a solid phase content in the suspension of 10%) were selected. Carrying out the process under these parameters resulted in the recovery of 89.4% of copper and 39.3% of zinc in the solution. The possibility of the bioregeneration of trivalent iron in the solution obtained after the chemical leaching of slag by iron oxidizingacidophilic chemolithotrophic microorganisms without inhibiting their activity was demonstrated. PMID- 25434181 TI - [Production of extracellular proteinases (protein C activators in blood plasma) by the micromycete Aspergillus ochraceus during submerged and solid-state cultivation]. AB - The conditions for the submerged and solid-state cultivation of the micromycete Aspergillus ochraceus VKM F-4104D, producing extracellular proteinases that activate protein C in human blood plasma, were optimized. It is shown that the protein C-activating activity of the micromycete in a solid-state culture was 1.5 3.5 times higher than in a submerged culture (as calculated per milliliter of culture medium). Among the extracellular proteins secreted by A. ochraceus VKM F 4104D during submerged and solid-state cultivation, a protein C-activating proteinase with a pI of 6.0-6.3 was identified. PMID- 25434182 TI - Antioxidant properties of fungal metabolite nigerloxin in vitro. AB - We have recently reported the beneficial influence of the fungal metabolite nigerloxin, a new aldose reductase inhibitor and a lipoxygenase inhibitor on oxidative stress in streptozotocin induced diabetic rats. In the present study we have investigated the antioxidant potential of nigerloxin in vitro as compared to one of the well known natural antioxidant, curcumin. The fungal metabolite nigerloxin was found to be an effective antioxidant in different in vitro assays including the phosphomolybdenum, 2,2-diphenyl-1-picrylhydrazyl (DPPH.),2,2'-azino bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS.+) and ferric reducing antioxidant power (FRAP) methods. The antioxidant potency of nigerloxin may be attributed to its electron donating nature. The ferric reducing potency of nigerloxin as demonstrated by FRAP assay method was even found to be superior to that of the natural antioxidant curcumin. PMID- 25434183 TI - Purification and characterization of laccase secreted by Phellinus linteus MTCC 1175 and its role in the selective oxidation of aromatic methyl group. AB - A laccase from the culture filtrate of Phellinus linteus MTCC-1175 has been purified to homogeneity. The method involved concentration of the culture filtrate by ammonium sulphate precipitation and an anion exchange chro- matography on DEAE-cellulose. The SDS-PAGE and native-PAGE gave single protein band indicating that the enzyme preparation was pure. The molecular mass of the enzyme determined from SDS-PAGE analysis was 70 kDa. Using 2,6-dimethoxyphenol, 2,2'[azino-bis-(3-ethylbonzthiazoline-6-sulphonic acid) diammonium salt] (ABTS) and 4-hydroxy-3,5-dimethoxybenzaldehyde azine as the substrates, the Kin, kcat and kt/Km values of the laccase were found to be 160 microM, 6.85 s(-1), 4.28 x 10(4) M(-1) s(-1), 42 microM, 6.85 s(-1), 16.3 x 10(4) M(-1) s(-1) and 92 microM, 6.85 s(-1), 7.44 x 10(4) M(-1) s(-1), respectively. The pH and the temperature optima of the P. linteus MTCC-1175 laccase were 5.0 and 45 degrees C, respectively. The activation energy for thermal denaturation of the enzyme was 38.20 kJ/mole/K. The enzyme was the most stable at pH 5.0 after 1 h reaction. In the presence ofABTS as the mediator, the enzyme transformed toluene, 3 nitrotoluene and 4-chlorotoluene to benzaldehyde, 3-nitroben-zaldehyde and 4 chlorobenzaldehyde, respectively. PMID- 25434184 TI - Determination of hydration properties and thermal behavior of Paecilomyces variotii by differential scanning calorimetry. AB - Due to the structure and the composition of Paecilomyces variotii, the mycelia of this fungus could have potential applications as ingredients in wettable foods. For this use, drying could be employed, justifying the study of thermal behavior of P. variotii. The objectives of this work were to perform a study of thermal behavior of P. variotii isolates, to evaluate the hydration properties of these mycelia and to analyze the effect of different technological parameters on the latter properties. Wet cultures exhibited a wide endothermic transition, with mean values of peak temperature of 61 degrees C and denaturation enthalpy of4 J/g dry matter. Initial (50 degrees C) and final (80 degrees C) temperatures of the endothermic transition were used to dry the mycelia. Freeze-drying was also assayed. For all dried mycelia, a decrease in denaturation enthalpy between 40 and 50% was observed for drying at 50 degrees C and freeze-drying, and a drastic decrease of almost 100% for drying at 80 degrees C. According to the hydration properties, wet mycelia exhibited water holding capacity (WHC) value of 45 g water/g dry matter. Significant differences among dried mycelia, resulting WHC values in order: 50 degrees C > freeze-dried > 80 degrees C (p < 0.05) were revealed for each P. variotii strain. Fungi obtained by drying at 50 degrees C and by freeze-drying, showed a rapid water absorption (t(1/2) < 0.1 min). Ionic strength, pH and particle size of dried mycelia influenced the hydration properties. PMID- 25434185 TI - [Properties of modified amperometric biosensors based on methanol dehydrogenase and Methylobacterium nodulans cells]. AB - The properties of amperometric biosensors based on methanol dehydrogenase (MDH), Methylobacterium nodulans cells, and the ferrocene-modified carbon paste electrode were investigated. It was shown that the addition ofhydroxyapatite (HA) to a carbon paste increased the sensitivity and operating stability of MDH biosensors. The linear range of the electrode was 0.0135-0.5 and 0.032-1.5 mM for methanol and formaldehyde, respectively. The detection limit of methanol and formaldehyde was 4.5 and 11.0 microM, respectively. The loss of activity of the electrode within 10 days of storage in the presence of 2.0 mM KCN did not exceed 12%. Cyanide (10 mM) completely inhibited the sensor responses to formaldehyde (1.0 mM), which allowed for the selective determination of methanol in the presence of formaldehyde. The biosensor based on cells exhibited lower stability and sensitivity toward methanol and formaldehyde; the sensitivity coefficients were 980 and 21 nA/mM, respectively. PMID- 25434186 TI - [A new conceptual approach for searching for molecular causes of diabetes mellitus, based on the study of functioning of hormonal signaling systems]. AB - The review deals with analysis and generalization of the data obtained by authors on abnormalities in hormonal signal systems in diabetes mellitus (DM)--in rats with experimental models of DM of the types 1 and 2, in patients with DM, and in invertebrates (mollucs) with experimental diabetes-like state. Changes of functional state of hormonal signal systems regulated by different hormones, including biogenic amines and peptides of the insulin group, in a wide spectrum of tissues are discussed. The conclusion is made that disturbances in hormonal signal systems are the key molecular causes of physiological and metabolic abnormalities occurring in the types 1 and 2 DM. A concept on polyhormonal genesis of DM and the systemic nature of disturbances in the hormone-regulated signaling cascades under conditions of DM is formulated. PMID- 25434190 TI - [A change of the medium salinity as a functional load for evaluation of physiological state of the crayfish Astacus leptodactylus]. AB - The necessity of developing criteria for evaluation of the functional state of benthic invertebrates for toxicological studies or for their use as biosensors in systems of the water quality biomonitoring is emphasized. It is proposed to evaluate the organism state with aid of standard test actions dosed by strength and duration. For freshwater crayfish, such action--the functional load--can be the medium salinity change by 1%o, which can be achieved by addition of sodium chloride. Peculiarities of the response reaction of the crayfish cardiac system to such action have been shown by non-invasive method of recording of cardiac activity. PMID- 25434188 TI - [How aliphatic alcohols and ph affect reactional capability of the horse blood serum cholinesterase at its interaction with organophosphorus inhibitors]. AB - There was studied action of aliphatic alcohols (ethanol, propanol, isopropanol, n butanol, isobutanol, secbutanol, tretbetanol) and pH on various kinds of reactional capability the serum cholinesterase. At the alcohols-affected inhibition of the cholinesterase hydrolytic activity, the determining role was played not the total number carbon atoms in the alcohol molecule, but by the "effective length" of the carbohydrate chain. The fact that the presence of alcohols did not affect parameters of the reverse cholinesterase inhibition with onium ions tetramethylammonium and choline allows suggesting the absence of effect solvents on specific acetylcholine sorption in the enzyme active center. With aid of two rows of hydrophobic organophosphorus inhibitors (OPI), we have managed to estimate both the degree and the character itself of the modifying action of alcohols and pH on the process of irreversible inhibition of serum cholinesterase. PMID- 25434187 TI - [Advances in the investigation of structure and function of G protein-coupled receptors (by awarding the Nobel Prize for Chemistry in 2012 to Robert Lefkowitz and Bryan Kobilka)]. AB - The Nobel Prize for Chemistry in 2012 was awarded to Robert Lefkowitz and Bryan Kobilka "for studies in G-protein-coupled receptors" (GPCR). In this review the most important discoveries of these Nobel Prize winners dealing with investigation of the structure and functions of GPCR were discussed and analyzed. In the 1980s, they were the first in the world to clone GPCR--the 32-adrenergic receptor. After 20 years, the team led by B. Kobilka for the first time prepared this receptor in the crystalline form and established its three-dimensional structure. In these studies, unique approaches for purification and crystallization of other receptors were developed. In 1980s, R. Lefkowitz and his colleagues discovered beta-arrestins that regulate signal transduction occurring via GPCR. Later they revealed that beta-arrestins were the most important members of signal transduction and were responsible for the signal transduction from the hormone-activated receptor to intracellular signaling cascades independently of heterotrimeric G-proteins. These and other outstanding discoveries of R. Lefkowitz and B. Kobilka have become the basis for the novel area of molecular biology and pharmacology--the molecular endocrinology of GPCR. PMID- 25434189 TI - [Effect of diazoxide on the AS-30D rat ascites hepatoma cells treated by Cd2+]. AB - For the last years, in several investigations, including ours, it was shown that oxidative stress and mitochondrial dysfunction mediated by disturbance of the mitochondrial respiratory chain and by induction of Ca2+ -dependent nonselective high-conductance pore of the inner mitochondrial membrane are involved in mechanism(s) of cytotoxic action of heavy metals. At the same time, possible interaction of heavy metals with other channels, in particular, with selective potassium channels, such as ATP-dependent potassium channels, which are generally considered to be protective for the cells, have not been studied. The aim of the present work was to examine the effect of diazoxide, an activator of mitochondrial ATP-dependent potassium channels, on mitochondrial physiology and cell survival in the presence of Cd2+. As a model system, we used AS-30D rat ascites hepatoma cells and isolated rat liver mitochondria. We found that diazoxide enhanced intracellular production of reactive oxygen species and induced significant stimulation of the resting respiration rate of the cells. Besides, diazoxide had a protective effect on AS-30D cells by increasing their survival that was substantially decreased in the presence of the tested concentrations of Cd2+ (50 and 100 microM). The protective effect of diazoxide was completely suppressed by increasing duration of incubation of the cells with Cd2+, and partially by addition to the assay medium of 5-hydroxyde- canoic acid (100 or 300 microM), a blocker of mitochondrial ATP-dependent potassium channels. In isolated rat liver mitochondria we found that diazoxide did not prevent the toxic action of Cd2+, since it produced no significant effects on the mitochondrial swelling and the respiration changes evoked by the heavy metal in the KCl assay media. Possible molecular mechanisms of the cytoprotective action of diazoxide are discussed. PMID- 25434192 TI - [Changes in the heart of neonatal rats after cryptosporidial gastroenteritis of different degrees of severity]. AB - Disturbances at the childhood age increase risk of the appearance of cardiovascular diseases decades later. The nature of this interconnection called ontogenetic programming is not completely understood. Valuable sources of knowledge about mechanisms of ontogenetic programming are data of interspecies study of biology of the body life cycles and of heart physiological capabilities. Taken into account the interspecies differences, these data allow finding the correct direction of experimental investigations. Results of studies of almost 100 homoiothermal species have shown the slow growth and a high loading on the heart at postnatal development to decrease its aerobic capability in adults. Basing on these data, we suggested that the neonatal gastroenteritis causing tachyarrhythmia, malabsorption, and the growth deceleration might lead to pathological changes in the heart. Our task was to evaluate the effect of cryptosporidial gastroenteritis of different degrees of severity on heart of the neonatal rats. By using methods of Real-Time PCR, immunocytochemistry, image analysis, and study of interatrial septum, we have established that a gradual increase of intensity of infestation with Cryptosporidium parvum oocytes causes sharp changes corresponding to the "all or nothing" response. At a weak infestation the interatrial septum was close (like in control), while significant changes in expression of isoforms of heavy chains of alpha- and beta-myosin were absent. At the intermediate and severe infestation, in the interatrial septum the foramen ovale was visualized and there were observed cardiac atrophy and a strong shift of ration of expression of myosin heavy chains toward the low-velocity beta chain. Thus, by disturbing the frequency-strength ratios and causing outflow of resources from the formed heart, the neonatal gastroenteritis produces pathological changes of the organ molecular and anatomical structures. Our results can be interest to evolutionary biologists and physicians, as they show importance of knowledge of evolutionary-comparative investigations for the search for novel risk factors of heart diseases and demonstrate interconnection between gastroenteritis, pathology of interatrial septum, and a change of composition of the main contractile proteins in cardiomyocytes. PMID- 25434191 TI - [Modeling of schizophrenia with Levodopa + Carbidopa]. AB - Animal experimental modeling of mental disorders helps revealing mechanisms of the diseases and identifying effective methods of their treatment. The aim this study was to develop a new model of schizophrenia by oral Levodopa + Carbidopa (LC) administration. It was found that introduction of LC to rats induced a significant reduction of emotional reactions, hypersensitivity to a sound, a decreased exploratory activity and stereotype behavior, locomotor hyperactivity in some rats. It is concluded that LC introduction to rats may be used as an alternative dopaminergic animal model of schizophrenia. PMID- 25434193 TI - [Calcium-binding proteins and cytochrome oxidase activity in the turtle optic tectum characterzing the visual tectofugal pathway]. AB - Using immunohistochemistry and tracer technique, we studied in the optic tectum of turtles (Emys orbicularis and Testudo horsfieldi) the distribution of CaBPr (parvalbumin, PV, calbindin, CB, calretinin, CR) before and after horseradish peroxidase delivery into nucleus rotundus (Rot). In parallel, activity of cytochrome oxidase (CO) was studied. In the main link of the tectofugal visual pathway (the central gray layer, SGC) in the both chelonian species rare PV-ir, as well CB- and CR-ir neurons were found to vary significantly both in the number and the immunoreactivity degree of their bodies and dendrites. The superficial (SGFS) and deep periventricular (SGP) tectal layers, on the contrary, contained numerous cells immunoreactive to all three CaBPr in different quantitative proportions. Only a small part of the retrogradely labeled tectorotundal neurons contained PV, CB or CR. Very large PV-ir neurons were not retrogradely labeled; by their morphological characteristics, they corresponded to efferent neurons with descending projections. SFC neurons of two chelonian species differed in the degree of CO activity. In SGFS, dense immunoreactivity of neuropil to all three CaBPr and the high CO activity were observed in both species with some differences in sublaminar distribution for every of proteins. Peculiarities of distribution of CaBPr-ir and of CO activity in various segments of SGC neurons are discussed with respect to laminar organization of the turtle tectum and to patterns of its retinal innervations. It was proposed that in projectional tectorotundal SGC neurons, the studied CaBPr are concentrated mainly in their distal dendrites contacting with retinal afferents in the superficial retinorecipient tectal layer. PMID- 25434194 TI - [Parasite fauna of the European Pilchard (Sardina Pilchardus Walbaum, 1792) from the Atlantic coastal water of North Africa: application of latitudinal patterns analysis for the host intraspecific structure]. AB - Two stocks of the European pilchard (Sardina pilchardus Walb.) from the Atlantic co- ast of Northwestern Africa were discriminated with the use of parasites as biological tags. A total of 646 fishes (TL = 15-25 cm; modal age 1-3) were examined for parasites in the area between 30-18 degree N during 2005-2010 winter and summer seasons. Fourteen species of parasites were found. Mean prevalence constituted 62%. The most abundant species (with prevalence 5% in at least one of the samples) included Goussia clupearum, Ceratonmyxa truncata, Cocomnxa morovi, Aphanurus stossichi, Lecitaster con!filsus, Bacciger bacciger, Hysterothylacium sp., and Anilocra capensis. All fishes were grouped into one-degree latitudinal groups. Analysis of parasite component communities in latitudinal groups allowed combining parasite component communities into northern (30-28 degree N) and southern (24-18 degree N) groups only in winter spawning season. These two groups cor- respond with two sardine stocks--"A + B" and "C" that were separated by FAO working group on the base of ecological and fishery data. Parasite component community of the stock "A + B" was characterized as balanced with dominant species B. bacciger. The parasite component community of the stock "C" was characterized as an unbalanced stock with Hysterothylacium sp. as the dominant species. Significant values of prevalence for G. clupearum A. stossichi, B. hacciger, Hysterothylacium sp., and A. capensis were revealed in fishes from stocks "A + B" and "C". These parasites may be used as biological tags that characterize specific of host-parasite complexes of northern and southern subareas examined. PMID- 25434195 TI - [Behavioral responses of Diplostomum chromatophora (Trematoda, Diplostomidae) cercariae to light]. AB - Behavioral responses of D. chromatophora cercariae to light were studied in laboratory experiments. Cercariae demonstrated positive phototaxis that was especially pronoun- ced during the first hour of cercarial free life in the environment. After 6 h, the photoreac- tion is weakened but it retains the character of positive phototaxis. The photo-orientation helps cercariae to localize themselves in the areas of the water body ("host-space") where contact with the second intermediate host (fish fry) is most likely. It is assumed that the increase of the locomotory activity in D. chromratophora cercariae under sudden shading or lighting should be considered as a case of manifestation of the "fifixed behaviuor" trigged PMID- 25434196 TI - [English and Russian terminology for the thoracic skeletal structures of mosquitoes (Diptera: Culicidae): a critical review]. AB - The authors analyze different names of thoracic skeletal structures in mosquitoes (Dip- tera: Culicidae), used by various authors (Kirkpatrick, 1925; Edwards, 1932; Stackelberg, 1937; Sazonova, 1958; Belkin, 1962a, b: Maslov, 1967: Gutsevich et al., 1970; Knight, Laffoon, 1970; McAlpine, 1981; Becker et al., 2010). In the abovementioned publications, a small number of skeletal structures, morphologically very important for the identification of species and genera of the family Culicidae, are denoted by multiple synonymic names, while certain completely different skeletal structures are represented under a single homonymous name. Duplicated synonymic names for thoracic sclerites, setae, and scales on sclerites considerably hamper the work of specialists determining species of the family Culicidae. In some cases, this fact results in erroneous diagnostics of species. We provide a detailed description of the thoracic morphology of mosquitoes, pointing to existing synonymic Russian and English names for each skeletal structure and also recommend the use of a single Russian term for each structure. PMID- 25434197 TI - [Landscape and zonal distribution of bloodsucking mosquitoes and horse flies (Diptera: Culicidae, Tabanidae) in the northeastern Russian Plain]. AB - The data on the distribution of 34 species of bloodsucking mosquitoes and on 42 horsefly species of the fauna of the northeastern Russian Plain are given. The analysis of the landscape and zonal changes in species diversity and their abundance was performed. Species diversity of these families increased northwards. Two borders of the fauna's depletion were discovered: at the border between the middle and northern taiga subzones (mosquitoes and horseflies) and at the border between the northernmost taiga subzone and the forest-tundra zone (horseflies only). The northern and southern boundaries of species ranges in the region are identified. PMID- 25434198 TI - [Ectoparasites of the particoloured bat (Vespertilio murinus Linnaeus, 1758, Chiroptera, mammalia) from the Urals and adjacent regions]. AB - The fauna of ectoparasites of the particoloured bat (Vespertilio murinus Linnaeus, 1758), the most common synanthropic bat in the Urals, is examined. The core of the ectoparasite fauna consists of temporary ectoparasites--gamasid mites belonging to the genus Steatonyssus. New findings of the poorly known species Steatonyvssus superans are described. PMID- 25434199 TI - [A new trematode species, Gonocerca pecitorali sp. n. (Hemiurata: Derogenidae) from Albatrossia pectoralis (Gilbert, 1891) (Gadiformes: Macrouridae)]. AB - A new trematode species, Gonocerca pectorali sp. n. was revealed in the collection of fish trematodes from the Pacific Ocean (Kuril Islands region). A brief review of publications on the species composition of the genus Gonocerca is given and points of view of some researchers on the genus structure were analyzed. The description of G. pectorali is given together with the differential diagnosis of the new species and the discussion on its position in the structure of the genus. PMID- 25434200 TI - [Origin of arthropods and of the clades of ecdysozoa]. AB - The problem of the origin of the phylum Arthropoda was long considered solved based on evolutionary morphology data. But molecular biological studies of recent years have put forward a new solution that contradicts the old one. Hence, the need arises to review the argumentation of both sides and search for ways to reach a consensus. These two subjects constitute the scope of this paper. PMID- 25434201 TI - [Follicular cells of the amphibian ovary: origin, structure, and functions]. AB - Formation of the follicular envelopes surrounding oocytes in the developing ovary and their subsequent morphological differentiation go hand-in-hand with succession of the steroidogenesis stages, arrest of meiosis and its maintenance, establishment of the conditions necessary for vitellogenesis, oocyte growth, and maturation. Metabolites are exchanged via gap junctions and receptor-mediated transport through the perioocytic space. The ion transport in follicular cells (FCs) regulates the plasma membrane potential, creating the conditions for efficient directed transport through gap junctions. Manifold biologically active substances accepted by follicular cells are an additional adjusting lever for regulating the state of follicle system. In this review, we have attempted to emphasize the amphibian FCs as key players in the follicle system; the more so as we have failed to find any review that would bring together the data on the origin of amphibian FCs, their morphology, as well as regulation of oocyte growth and development. As a rule, recent works in this field focus on the molecular mechanisms providing for regulation of individual stages in oocyte development. This review describes the origin and changes in the morphology of follicular cells during the development of Xenopus laevis oocyte as well as the data on their regulatory functions in vitellogenesis and their involvement in steroidogenesis, maintenance of meiotic arrest, and subsequent maturation. PMID- 25434202 TI - [Universal intracellular transducer RAS and its role in the development of Drosophila]. AB - Ras genes were first identified in the 1960s as transforming oncogenes that caused tumors in rats infected with Harvey and Kirsten sarcoma viruses (Ha-ras and Ki-ras oncogenes, accordingly). Subsequently, transforming ras genes were found in human cancer cells. Further investigations of neuroblastoma cells resulted in the finding of the third ras gene in the human, which was called N ras. Ras gene products play an important role in the processes of cellular proliferation and differentiation and are controlled by receptor tyrosine kinases. Using drosophila as a model object allowed us to perform a successful genetic analysis while studying the functions of ras genes. Three polytene chromosome bands were detected in D. melanogaster with the help of the v-Ha ras sampling. According to Bridges' map, all three bands (Dras1, Dras2, Dras3) were mapped to regions 85D, 64B, and 62B of chromosome 3. Among them, only Drasl has a common origin with ras genes of mammals. Although there are numerous investigations of the role played by ras genes in the de- velopment of insects, this problem is still not fully understood. The importance of ras gene variations in the course of the evolutionary process has been insufficiently studied as well. Currently, Ras target proteins are actively identified, their signal pathways, as well as effects of influencing these pathways in the drosophila tissues, are studied in the cells of yeast and mammals. The main functions of Ras protein is in the signaling pathways controlling mutations during drosophila's morphogenesis and the connections of ras gene with phenotypic symptoms of tumors. PMID- 25434203 TI - [Establishment of visceral left-right asymmetry in mammals: the role of ciliary action and leftward fluid flow in the region of Hensen's node]. AB - During individual development of vertebrates, the anteroposterior, dorsoventral, and left-right axes of the body are established. Although the vertebrates are bilaterally symmetric outside, their internal structure is asymmetric. Of special interest is the insight into establishment of visceral left-right asymmetry in mammals, since it has not only basic but also an applied medical significance. As early as 1976, it was hypothesized that the ciliary action could be associated with the establishment of left-right asymmetry in mammals. Currently, the majority of researchers agree that the ciliary action in the region of Hensen's node and the resulting leftward laminar fluid flow play a key role in the loss of bilateral symmetry and triggering of expression of the genes constituting the Nodal-Ptx2 signaling cascade, specific of the left side of the embryo. The particular mechanism underlying this phenomenon is still insufficiently clear. There are three competing standpoints on how leftward fluid flow induces expression of several genes in the left side of the embryo. The morphogen gradient hypothesis postulates that the leftward flow creates a high concentration of a signaling biomolecule in the left side of Hensen's node, which, in turn, stimulates triggering of.gene expression of the Nodal-Ptx2 cascade. The biomechanical hypothesis (or two-cilia model) states that the immotile cilia located in the periphery of Hensen's node act as mechanosensors, activate mechanosensory ion channels, and trigger calcium signaling in the left side of the embryo. Finally, the "shuttle-bus model" holds that leftward fluid flow carries the lipid vesicles, which are crashed when colliding immotile cilia in the periphery of Hensen's node to release the contained signaling biomolecules. It is also noteworthy that the association between the ciliary action and establishment of asymmetry has been recently discovered in representatives of the lower invertebrates. In this paper, the author considers evolution of concepts on the mechanisms underlying establishment of visceral left right asymmetry since 1976 until the present and critically reexamines the current concepts in this field of science. According to the author, serious arguments favoring the biomechanical hypothesis for determination of left-right asymmetry in mammals have been obtained. PMID- 25434204 TI - [Concerning one obsolete tradition: does gastrulation in sponges exist?]. AB - The analysis of comparative-embryological and molecular-biological data leads to the conclusion that universal basic mechanisms of morphogenesis occurred first in the evolution of animals in the ancestors of modern sponges and eumetazoans, which served as a basis of different evolution of individual development in Parazoa and Eumetazoa lines. In the former, morphogenesis in early embryogenesis led to formation of the water-current system as a means for capturing and delivery of food particles to different parts of the animal. In the latter, morphogenetic movements manifested themselves as gastrulation, during which the germ layers and the digestive system formed. The morphogenetic movements of cells in Metazoa emerged independently of cell specification. They are primary relative to cell differentiation. Theunity of all Metazoa is based on the similarity of mechanisms of morphogenesis rather than on the presence of germ layers. PMID- 25434205 TI - [Crucial stages of embryogenesis of Rana arvalis: Part 3. Modularity or developmental integrity]. AB - Static analysis of the morphometry of larvae of the postembryonic stages of development of Rana arvalis made it possible to estimate the extent and nature of correlations between developing structures. Considering a correlation as a manifestation of multiple physiological interactions between developing structures, we showed that the most likely scenario is the development of larval structures as a holistic process that is accompanied by an increase in the proportion of minor correlative interactions with an increase in the total number of structures. During the critical periods of development, an increase in the proportion of stronger correlative interactions between the structures that form at this stage of development is observed. PMID- 25434206 TI - [Non-invasive method of sex identification of crane chicks by the DNA from capillary vessels of alantois]. AB - The non-invasive method of determining the sex of chicks after hatching based on the DNA isolated from capillary vessels of allantois of the egg-shell membranes was demonstrated on four crane species (Gruinae, Aves), which were bred in the Crane Breeding Centre of the Oka Nature Reserve in 2009-2012. Using the EE0.6 molecular marker of sex, the gender of 26 Siberian (Grus leucogeranus), 15 Red crowned (G. japonensis), 4 Common (G. grus) and 1 Demoiselle (Anthropoides virgo) crane chicks was identified. This method can be recommended for determining the sex of chicks and the ratio of sexes in cranes that reproduce both in captivity and natural populations. PMID- 25434207 TI - [To the memory of Valerii Ivanovich Starostin (1939-2012)]. PMID- 25434208 TI - [Physiological and biochemical properties of the Lactobacillus plantarum, isolated from traditional fermented products of Ukraine]. AB - Physiological and biochemical properties of the 109 lactobacillus strains, isolated from traditional fermented products of Ukraine, has been investigated. Was showed that the 109 strains isolated from fermented vegetables grew at 10 degrees C, and 23% strains in the medium with 8% NaCl in contrast to the strains of L. plantarum isolated from dairy products. Formation of milk-clot, using strains of the dairy products, occurs within 20 +/- 4 hours, when using strains of the fermented vegetables considerably longer to 48 hours. 22% of strains of L. plantarum did not synthesize biogenic amines. Most of the strains did not produce acetoin, and were sensitive to broad-spectrum antibiotics. Antibiotic resistance of the tested strains did not depend of the source of L. plantarum strains isolation. PMID- 25434209 TI - [Component composition of Cryptococcus albidus and Eupenicillium erubescens alpha L-rhamnosidases]. AB - The component composition of Cryptococcus albidus and Eupenicillium erubescers alpha-L-rhamnosidases have studied. It was shown that enzymes have a monomeric structure. Enzyme preparations of C. albidus and E. erubescens have similar qualitative but differ in quantitative amino acid composition. alpha-L rhamnosidase of C. albidus characterised by high amount of histidine, proline, cysteine, methionine in compared with alpha-L-rhamnosidase of E. erubescens. alpha-L-Rhamnosidase of E. erubescens, in contrast to the alpha-L-rhamnnosidase of C. albidus, contained higher levels of lysine, arginine, threonine, alanine, isoleucine, leucine, tyrosine, phenylalanine. It is shown that purified preparations of alpha-L-rhamnosidase C. albidus and E. erubescens contained 5 and 1% carbohydrates respectively. Enzyme preparations differ in quantitative monosaccharide composition, which represented by rhanmose, xylose, mannose, galactose and glucose. Furthermore, alpha-L-rhannosidase C. albidus contained fuicose, whereas alpha-L-rhamnosidase E. erubescens--ribose and arabinose. A significant percentage of hydrophobic amino acids, which is 31 and 34% of the total content, and the presence of the carbohydrate component are essential in stabilization of enzymes molecule. PMID- 25434210 TI - [Antagonistic acttvity of Bacillus amyloliquefaciens strains--potential biocontrol agents for cereal crops]. AB - The antagonistic activity of strains Bacillus amyloliquefaciens YKM B-7243 and YKM B-7404 against bacterial and fungal agents of winter wheat diseases was demonstrated. Low antagonistic level against bacterial agents of plant diseases was shown. Antifungal activity of strains against agents of winter wheat was on the low level. High biological efficiency was shown under binary compositions of the studied strains. It was concluded that the enhancing of fungicide and growth stimulation effects in binary compositions were found. PMID- 25434211 TI - [Microbial biom of different soils and soil-climatic zones of Poltava region]. AB - Researches of microbiological diversity of soil on natural grassland and farmland in conditions of soil- climatic zones of Poltava oblast were conducted. General microbiological activities of soil (intensity of linen decomposition, %), numerosity of the main ecological-trophic groups of soil microorganisms, numerosity of fungi were detected. Coefficients of mineralization-mobilization, pedotroficity, oligotrophicity were calculated in accordance with correlation of the main ecological-trophic groups of soil microorganisms. Results of soil microbiological monitoring are analyzed and generalized. Was determined that soil of natural ecosystem (natural grassland and virgin land) has highest intensity of decomposition of organic matter and was the most provided of nutrient in comparison with farmland. PMID- 25434212 TI - [Yeasts--the pathogen of weed diseases]. AB - Plant pathogenic yeast were isolated from infected weeds that occur in cereal crops. On the basis of morphological, physiological and biochemical properties the yeast isolated from sow thistle and dandelion have been identified as Rhodosporidium diobovatum Newell & Hunter and Rhodotorula sp. In the experiment the yeast caused pathological process on the weeds, from which they are isolated, on other types of weeds, but also on wheat, oat and soybean. PMID- 25434213 TI - [Influence of different adhesive composition on sporulation and protein synthesis by Bacillus thuringiensis collection strains]. AB - The influence of different sticky-gene composition on sporulation and protein synthesis by B. thuringiensis collection strains has been investigated. It has been detemined that the most effective according this characteristics were B. thuringiensis collection strains 0293 and 98. It has been shown that the best on protein synthesis processes and sporulation by investigated B. thuringiensis strains influences adding to the culture medium sticky-gene compositions A and E in a concentration of from 10 to 15%. PMID- 25434214 TI - Exclusion of polyvalent T7-like phages by prophage elements. AB - The study presents new insights into the process of interaction of T7-like bacteriophages FE44 and BA14 with lysogenic cells. It was demonstrated that single and double lysogens possess Abiphenotype regardless of genera, species and strain of bacteria that initially had normal phage sensitivity. Efficiency of plating of these phages is reduced by two orders of magnitude on monolysogens, whereas it decreases by 4-6 orders on bilysogens. In the latter case, phage infection leads to formation of more than 60% of aberrant capsids in phage progeny. Abortive phage infection is suggested to be associated with defects in general dynamics of the bacterial chromosome in single and double lysogens of Erwinia "horticola" and Escherichia coli. PMID- 25434215 TI - [Carotenoids of the human eye in prenatal and early postnatal development]. AB - The review deals with the role of carotenoids in the formation of the structural and functional differentiation of the macula--the area of the highest visual acuity of the human retina. The review also presents the data on detection of carotenoids (lutein) in the vitreous body of the human eye during its prenatal development and discusses their possible role in the development of the retina, particularly in relation to differentiation of the macular area. Macular dystrophy has been considered till recently as senile pathology. According to modern ophthalmologic observations, the number of cases of appearance of this pathology increases in young humans. Such a shift can be prevented by addition of carotenoids to the diet. This permits a conclusion that the permanent presence of carotenoids in the course of the whole human life is necessary for the formation and retention of structural and functional integrity of the macula. PMID- 25434216 TI - [The ability of NMDA glutamate receptor blockers to prevent a pentylenetetrazole kindling in mice and morphological changes in the hippocampus]. AB - We investigated in mice the relationship between convulsions and morphological changes of hippocampal neurons that arise in the development of pentylentetrazol (PTZ)-induced kindling. The kindling was caused by of 35 mg/kg PTZ i.p. 3 times a week for a month. By the end of this period, 70% of the mice responded to the injections of PTZ with pronounced clonic or tonic-clonic seizures. The hippocampal slices (layer stratum pyramidale, CA1, Nissl's stain) obtained from mice exhibiting seizures revealed a large number of modified cells (24.7 +/- 2.1%). These hyperchromic neurons have been characterized by a decrease of the size cell body, there was a loss of turgor, the body cells shrink, and dendritic spines curl. Part of the cells took the shape of elongated neck. Such modified the dark type of neurons contained only 2.3 +/- 2.3% in the hippocampus of intact mice, and 30% of the mice resistant to the convulsive action ofPTZ during the period of observation. The expression of protein NeuN (Fox3) in hippocamal neuron including the hyperchromic once suggests that neurons on the whole did not die and were relatively viable. Preventive administration of NMDA receptor blockers (0.5 mg/kg, memantine 0.1 mg/kg or IEM-1958 1 mg/kg, s.c.) 30 minutes prior to PTZ reduced the proportion of mice which exhibited PTZ kindling from 70% to 40%. The modified neurons were observed in which the PTZ kindling due to the blocker presence did not develop, i.e., the same as in intact mice. Contrary, 24.0 +/- 5.6% of hyperchromic neurons were found in the hippocampal slices from mice manifested seizures, despite the co-administration of NMDA blockers. The data obtained indicate that modified neurons are the result of seizures suffered by the animals in the course of PTZ kindling, and that the blockade of NMDA glutamate receptors can suppress manifestations of seizures and the accompanying morphological changes of hippocampal neurons. PMID- 25434217 TI - [A role of AGRP on dopamine brain neurons regulation]. AB - In rats and mice in different dopaminergic brain structures the immunoreactive axons with agouti-related protein (AGRP) were identified. The double immunofluorescence method shows the presence of AGRP-immunoreactive processes around the bodies of dopaminergic neurons. In experiments in vitro after incubation of brain tissue from ventral tegmental area or hypothalamus with AGRP (83-132) the significant decrease of tyrosine hydroxylase optical density was indicated. The data indicate possible direct inhibitory action of AGRP on tyrosine hydroxylase level in dopaminergic brain neurons and its role as a modulator of the functional activity of dopaminergic neurons. PMID- 25434218 TI - [Depressive state of rats in conditions of chronic combined stress caused by the combination of differently modal stressors]. AB - Chronic combined stress with the change of differently modal stressors (noise, vibration and pulsating bright light) according to the stochastic scheme against the background of constant stressors (restriction of movement, fluctuations of the temperature of the environment) causes symptoms of depression-like animal behavior, having the pronounced phenomenological simila rity with the clinical presentation of depression: anxiety, behavioral correlates of despair, hypodynamia, anhedonia, as well as morphosomatic consequences of chronic stress: involution of the thymus and spleen, hypertrophy of epinephros, ulceration of the mucous stomach membrane. Imipramine and fluoxetine effectively reduce the stated behavioral disorders, their effectiveness corresponds to the results of clinical studies and the data received from other models of depression. The described model of depression, has satisfactory, corresponding, constructive and predictive validity and can be used for physiological, ethological, and pharmacological studies. PMID- 25434219 TI - [Specialties of singlet oxygen and ozone inhalations action on lipoperozydation and antioxidant system of rats blood and tissues]. AB - The aim of this work was the analysis of singlet oxygen and the ozone effect on lipid peroxidation and antioxidant activity of rat organs and blood. Wistar rats were randomly divided into five groups: control group (without any manipulations; n = 10) and four main groups (n = 10 in each group) with inhalations by dry, moisture and oil-processed ozone-oxygen mixture (ozone concentration 60 micro g/l) or singlet oxygen, respectively. Activity of pro- and antioxidant systems was estimated in blood and tissues (lungs, heart, liver and kidney) by inducing biochemiluminescence. Singlet oxygen was shown to exert the "mildest" effect with stimulation of blood antioxidant potential and saving tissue oxidative potential without hyperactivation of lipid peroxidation. Use of moistened ozone-oxygen mixture caused moderate stimulating action on antioxidant re serves of blood and tissues. Dry ozone-oxygen mixture clearly decreased lipid peroxidation intensity. PMID- 25434220 TI - [Influence of thyroxine on display of dexamethasone's effects on M-response's parameters of skeletal muscle of white rats]. AB - In the studies on white rats-females it was studied the dynamics of the change of some parameters of the M-response of a forward tibial muscle in the process of dexamethasone injection (in a dose of 0.25 mg/kg), applied separately and combined with injection of thyroxine (in a dose of 10 mkg/kg). It was established that the application of thyroxine in a complex with dexamethasone prevented the lengthening of the latent period, the decrease of amplitude and the shortening of the duration of the M-responses, taking place at the isolated injection of dexamethasone and also caused an essential decrease of frequency of polyphase potentials of the muscle. Besides, thyroxine prevented the development of the essential decrement of the amplitude and the lengthening of the latent period of M-responses in the process of indirect electric stimulation of the muscle with a frequency of 4 imp/s, typical of the isolated application of dexamethasone. PMID- 25434221 TI - [The effect of destruction of rat capsaicin-sensitive nerves on blood pressure in rats with metabolic syndrome]. AB - The effect of destruction of capsaicin-sensitive nerve (capsaicin 150 mg/kg, s/c) on blood pre- ssure was investigated in rats with metabolic syndrome induced by fructose (12.5% in drinking water for 10 weeks). The blood plasma concentrations of glucose, triglyceride (TG) and products of lipid perioxidation were defined in these rats. The systolic blood pressure was measured by non-invasive method using the Coda system (Coda, Kent Scientific, USA). The fructose diet caused impaired tolerance glucose, arterial hypertension, increased the contents of TG and products of lipid peroxidation. In capsaicin--pretreated rats (deafferentiation of capsaicin-sensitive nerve) the fructose intake did not evoke impairment tolerance glucose, the increase of systolic blood pressure and the plasma content of triglyceride. The increase of lipid perioxidation in fructose fed rats was not prevented by capsaicin pretreatment. The authors suggest that capsaicin-sensitive nerves contribute to the development of insulin resistance and arterial hypertension in the metabolic syndrome. PMID- 25434222 TI - [Thermal homeostasis of the rabbit in thermoneutral zone (mathematic modeling)]. AB - The thermal homeostasis of rabbits in thermoneutral zone were studied in the paper. Both in the experiment and in the model were shown that the temperature in the shell of the animal was changed without changing the core (nuclear) temperature when the temperature of the environment was changed and the heat production and delivery were remained unchanging. In the model was obtained this phenomenon was due to changing the shell and the core values, and was connected with blood flow variations in the shell. The latter mechanism was assessed as a principal one for active and quick regulation of the organism temperature and support of constant core temperature without significant and energy consumed is changing the heat production and delivery in thermoneutral zone of the mammalians. So, the thermoneutral zone is supported by the mechanism described, and the value of the thermoneutral zone is due to the shell size. PMID- 25434223 TI - [Dynamics of duration and frequency characteristics the vowels over the first seven years of life of children]. AB - On Russian material we traced dynamics of the acoustic characteristics of vowels and vowel sounds of the words 115 children aged 3 months to 7 years. There was a significant reduction in the duration and frequency values of the pitch vowels to 7 years of age children. We are the first to show that to 7 years relevant forms for Russian language sign the stressed vowel--long duration of the stressed vowel compared to unstressed vowel. Articulation of vowels is not fully formed. Data presented in this paper on the dynamics of the duration and frequency characteristics of vowels, on the one hand confirm the general laws of formation acoustic aspects of speech in ontogenesis. On the other--are original, as they reflect the assimilation of child articulations implemented in the Russian language. PMID- 25434224 TI - [Influence of long-term adaptation to cold on the state of cardiovascular system]. AB - The inhabitancy in Far North increases a probability of development of coronary heart disease, acute myocardial infarction and arterial hypertension. Catecholamines and NO deficiency play a substantial role in the development of cold hypertension, but these are not involved in acclimatization cardiac hypertrophy. Data of in vivo experiments indicate in favor of an involvement of alpha-adrenergic receptors (ARs) in the mechanism of an appearance of cold hypertension. Cold acclimatization promotes an elevation of beta3-AR density and decrease in beta1-AR and beta2-AR quantity on sarcolemma of cardiomyocytes. Experimental data indicate the important role of aldosterone and angiotensin II in the development of acclimatization hypertension. Catecholamines, aldosterone and angiotensin II are not involved in cold hypertrophy of heart. Experimental data demonstrate the important role of endothelin ETA receptor in the formation of cold hypertrophy of heart and cardiofibrosis. Thyroid hormones play substantial role in the development of cold hypertension and cardiac hypertrophy. PMID- 25434225 TI - [Brain-derived neurotrophic factor: the influence on the genetically and epigenetically determined behavioral disorders]. AB - Recent investigations have widened the knowledge concerning the brain derived neurotrophic factor (BDNF). The review concentrates on the data of literature and original data of authors on BDNF effects on genetically and epigenetically defined behavioral disorders. Specifically it describes the implication of the brain serotonergic system and the role of genotype in the neuroprotective effects of BDNF. The review provides evidence that: 1) genes encoding key elements of the brain serotonergic system (tryptophan hydroxylase-2, 5-HT1A and 5-HT2A receptors) are implicated in the effect ofBDNF; 2) acute central administration of BDNF produced long-term ameliorative effects on some animal models of genetically defined behavior disorders; 3) BDNF decreased behavioral disorders induced by prenatal stress and ethanol exposure and may play an important role in the treatment of epigenetically defined pathological behavior. PMID- 25434226 TI - [Leptin as a neuroprotector and functional stability factor in the central neural system]. AB - Adipokines secreted by adipose tissue are recognized to be crucial for the regulation and maintenance of energy homeostasis. Leptin is the best characterized adipokine involved in energy metabolism and inflammatory status, being associated with the development of a number of diseases, including atherosclerosis, diabetes, certain cancers and immune-mediated processes. Recently leptin was found to exert neurotrophic effects and neuroprotective activity slowing down neuronal damage after acute brain injuries as well as during long-term neurodegenerative processes. Moreover there are the evidences that leptin influences receptor signalling as well as the synthesis and releasing of several neurotransmitters. The aim of this review is to discuss the role of leptin in the neuroprotection and the regulation of diverse neuronal functions in the health and disease. PMID- 25434227 TI - [Features of an existential organization of a bioelectric activity of the brain at posterity from rats with a lateral injury of the brain]. AB - Features of the existential organization of a bioelectric activity of a brain at posterity from rats with a lateral injury of the brain were investigated. The EEG analysis revealed in one month animals significantly increased the proportion of advanced and lagging decrease in the activity of the right frontal derivation towards the right occipital region. Change between structural ties in terms of the rats were correlated with the severity of behavioral disorders in the test "open field" (OF). The most significant change in the existential organization of a bioelectrical activity (the reduction of synchronous communications between the frontal derivations) recorded in rats with severe conduct disorder compared with animals of the same groups, in which the behavior was not significantly different from the norm. The violation of the behavior in the test OF was accompanied by a decrease in synchronous activity between the left frontal and right occipital region or the decline in the anticipatory activity in the right frontal region in relation to the right occipital region. By maintaining the integrity of the behavior of these parameters were increased in comparison with an intact control. PMID- 25434228 TI - [The role of p53 in the regulation of proliferation and differentiation of the neural progenitors in mouse hippocampal organotypic culture]. AB - In the present work we have studied the effects of p53 on the proliferation and differentiation of neural progenitor cells (NPC) in mouse hippocampal organotypic culture. To study the role of p53 the selective p53 inhibitor pifithrin-alpha (PFT) and activator tenovin 1 (TEN) were used in the experiments. Obtained data demonstrated that the injections of PFT did not affect on the amount of phospho H3 positive cells in the subgranular zone of hippocampus. This data revealed that p53 inhibition does not change the proliferation level of the NPC. In opposite, at the TEN treatments we observed increased of the proliferation activity. Analysis of Pim-1 and Phb 1, which regulate cell cycle progression, demonstrated that p53 activation led to increased level of Pim-1 as well as the proliferation. Thus, our data correlate with published ones and proposed that Pim-1 positively regulates NPC cell cycle progression. In opposite to Pim-1, Phb 1 has anti proliferative action. Our obtained data demonstrated that TEN diminished Phb 1 expression. Primarily PFT injections led to the increasing Phbl level, but then dramatically decreased it that accompanied with unchanged proliferation level. In other words, increased proliferation level after TEN treatments, which we observed, can be partly depend from the inhibition of anti-proliferative activity of Phb. In our study we demonstrated that both TEN and in a greater degree PFT stimulates neuronal differentiation by activation of CRMP-2 expression, but do not affect on gliogenesis. Thus, obtained data revealed that p53 is an important factor of neuronal differentiation and, probably, p53 action is mediated by cell cycle regulator protein such as Pim-1 and Phbl. PMID- 25434229 TI - [Direct evidences of calcium traffic through pacemaker channel]. AB - Recently, it was shown that pacemaker f/HCN channel might be permeable not only for Na+ and K+, but also for calcium ions. Pacemaker channel HCN2 was expressed in ovarian cell culture of Chinese hamster. In the patch clamp experiments the calcium current with low amplitude 0.06+/--0.87 nA and open probability 0.48% (+/ 3.02 at -110 mV, n = 6, Ca2+ 2 mmol) was measured. HCN2-Ca2+ current significantly activated with cyclic adenosinemonophosphate by increasing of open probability and inhibited by specific If-blocker ivabradine. The calcium ion current was also shown in f-channels of neonatal rats ventriculocytes. Thus, the calcium ions conduction through HCN2 and native f-channel at physiological concentrations of extracellular fluid and physiological membrane potentials of cardiomyocytes was demonstrated. PMID- 25434230 TI - [Sexual motivation in posterity of animals with chronic alcohol-induced injury of the hepatobiliary system]. AB - The research was carried out in 60 days old posterity of female rats which suffer chronic alcohol-induced liver injury. In this work we studied motivational element of sexual behavior under conditions of "barrier" experiment. Intensity of sexual motivational behavior was estimated by the change of activity near the barrier, under which there was a receptive oestrous female. The appearance of sexual activity with the animals under experiment was estimated in the experiment of direct interaction of sexual partners. It was found, that "alcoholic" animals have the symptoms of malfunction of sexual motivation formation. The experiment shows that males which had mothers with chronic alcohol-induced hepatobiliary system injury have the deviations of sexual behavior display. These deviations show the weak form of sexual behavior induction of "alcoholic" males that can be the result of nervous system disorders. PMID- 25434231 TI - [Relationship between electrical activities of different areas of the myometrium in rats]. AB - The work is dedicated to the study of the influence of separate rhythmogenic areas on spontaneous activity of the remained areas in the non-pregnant rat myometrium. The main characteristics of pacemaker activity (spike frequency, spike amplitude, duration of burst discharges, summarized period of the active state) of each active region were analyzed under the conditions blocking the influence of others. Parameters of the ovarian horn area did not undergo significant changes unlike the cervical horn area and uterine corpus. The greatest suppression of spike activity parameters was shown in the uterine corpus. It was also revealed that certain activity characteristics (the amplitude of the spikes, duration of burst discharges, summarized period of the active state) are more subjected to change than other parameters. It is concluded that the ovarian horn area may have a controlling role in the interaction of asynchronous pacemaker activities of the rhythmogenic areas in the uterus. PMID- 25434232 TI - [Action of insulin on contraction and electrical responses of rat skeletal muscle]. AB - The effect of insulin on contractility of directly stimulated skeletal muscles was studied in experiments in isolated preparations of rat fast, extensor digitorum longus (m. EDL), slow, soleus (m. SOL) and mixed, diaphragm muscles. In addition (diaphragm only) characteristics of extracellularly recorded muscle fiber action potentials (APs) were evaluated before and after addition of insulin to a bath solution. Insulin (0.5-10 nM) decreased muscle twitch force. This negative inotropic effect of insulin was dose-dependent, with m. SOL appearing to be more sensitive to insulin than either m. EDL or diaphragm. Insulin did not affect strength of isotonic KCL- or caffeine-induced muscle contractures, but decreased second and increased first and third phases of extracellularly recorded muscle fiber APs. The analysis of the data obtained in this study and the data from the literature suggests changes in electrogenesis of the muscle fiber's t tubular plasma membrane as a key element of the negative inotropic effect of the hormone on contractility of mammalian skeletal musculature. Possible mechanisms of such putative changes are discussed. PMID- 25434233 TI - [Resuscitation of vital activity in intensively cooled animals by physiological methods without rewarming]. AB - White rat males (Wistar) were cooled in the water (9-10 degrees C) to the stop breathing (at rectal temperature 14.7 +/- 0.5 degrees , brain 16.0 +/- 0.3 degrees C). After the removal of water animals were injected 0.5% solution disodium salt ethylenediaminetetraacetic acid (Na2EDTA) intravenously, which reduced the concentration of Ca2+ in the blood. Breathing rats were resumed after 4-8 min after administration Na2EDTA. Then one group of rats was cooled to the temperature of the body 12.2 +/- 0.7 (brain 14.9 +/- 0.3 degrees C). At such a low temperatures the breath of rats was long-term (2-3 hours) supported at the level of 12 +/- 3 cycle/min. The second group of rats was not additionally cooled after the resumption of breathing. The same dose of Na2EDTA caused the rise of the respiratory rate to a higher level--29 +/- 4 cycles/min at a temperature in the rectum and the brain 15-16 degrees . Apparently, the process of accumulation of Ca2+ in the cytoplasm of the respiratory center's cells was slowed after the Na2EDTA injection to hypothermal rats in the bloodstream. It is assumed that the Na2EDTA injection under the hypothermia conditions was activated the cell's protection mechanisms from cold damage. The obtained results and the literature data allowed to conclude that nonhibernators are able to maintain basic life functions under significant reduction in the body temperature. PMID- 25434234 TI - [The effect of antioxidants on erythrocytes in rats during an exhaustive run]. AB - The run of trained rats until exhaustion affected changes of red-ox balance in red blood cells (RBC) and deteriorated the acid stability of RBC. The oral administration of quercetin, 20 mg/kg, caused expansion of oxidative stress in RBC and a significant decrease in RBC acid stability. Pro-oxidant activity of quercetin could contribute accelerated intravascular hemolysis. It was accompanied by a significant reticulocytosis compared with a control group of rats no fed on antioxidant but exposed to run. Green tea extract (GTE) oral administration, 12 mg/kg, resulted in preventing oxidative stress in RBC, increasing in acid stability of RBC and reducing reticulocytosis. Thus, prooxidant activity of quercetin and the high antioxidant efficacy of GTE are indicative of the advantages of the complex preparations containing several antioxidant compounds. Such complex preparations may counteract an oxidative stress and save mechanical stability of erythrocytes under exhausted run. PMID- 25434235 TI - The influence of trematode metacercariae on the individual fecundity of Bithynia troscheli (Gastropnoda: Bithyniidlae). AB - Fifteen trematode species belonging to seven families parasitizing the females of Bithynia troscheli (Paasch, 1842) at metacercarial stage, were recorded in Kargat River (Lake Chany, South of West Siberia, Russia). The breeding mollusk females have less metacercarial diversity (9 species vs. 15) and lower mean parasite abundance, comparing to non-ovigerous mollusks. The hypothesis of the metacercarial influence on individual fecundity of aquatic gastropods was tested. The individual fecundit pariameters of the-B. troscheli females, uninfected and infected with the trematode metacercariae belonging to fam. Echinostomatidae, Cyathocotilidae, Strigeidae, Cyclocoelidae, were compared. The percentage of the breeding B. troscheli females--was less and their fecundity parameters were lower for the hosts infected (with the Strigeidae or Cyclocoelidae metacercariae) comparing to non-infected ones. Trematode metacercariae found in the mantle or somatic musculature had no significant effects on the fecundity of the host. However, our results showed that trematode metacercariae affect the reproduction of B. troscheli in dual ways. All fecundity parameters of the mollusk females with the high infection rate were, significantly lower than those for uninfected females: the percentage of fecund females (chi2 = 6.73 ,p < 0.01), number of clutches per female, number of egg capsules per clutch and number of normal egg capsules per female (Tukey HSD, p < 0.001). Although the females with-low intensity of metacercarial infection lay egg clutches significantly more frequently than uninfected ones (chi2 = = 4.18, P = 0.04); the fecundity parameters were approximately equal for both groups of the mollusk females. These pioneer results prove the reality of influence of metacercariae on the individual fecundity of aquatic gastropods. The regulatory population mechanisms that may compensate the host reproduction loss caused by metacercaria, are discussed. PMID- 25434236 TI - [Life cycle of the taiga tick ixodes persulcatus in taiga forests of the eastern Sayan Plateau]. AB - The Ixodes persulcatus life cycle has been studied in natural environments of taiga fo- rests in The Eastern Sayan Plateau (56 10' N, 91 30' E). Engorged larvae and nymphs de- velop with a morphogenetic diapause or without diapause, with ratio of these two ways of development for larvae and nymphs 77.25/22.75% and 43.43/56.57%, respectively. The hypothetic season hemipopulation consists of 34.5 +/- 4.5, 50.1 +/- 1.3, 13.2 +/- 4.0 n 2.2% of unfed imagoes, completing 3 year, 4-year, 5-year, and 6-year life cycles, respectively. Mean life span is 3.83 +/- 0.10 years per generation. The "life table" predicting the probability to complete life cycle through phases from egg to adult, was developed. PMID- 25434237 TI - [DNA detection of pathogens transmitted by Ixodid ticks in blood of small mammals inhabiting the forest biotopes in Middle Irtysh Area (Omsk Region, West Siberia)]. AB - Microtine rodents were captured in two disconnected sampling sites in Omsk region where Ixodes pesulrcatus and Ixodes trianguliceps are sympatric. In blood samples of rodents the DNA was revealed belonging to several ixodid-transmitted pathogens: Borrelia burgdorferi sensu lato (prevalence 20.0 and 6.0%, here and further values are given for the first and second site, respectively), Borrelia miyamotoi (8.3 and 2.0%), Anlaplasnma phagocytophilum (33.3 and 48.0%), Ehrlichia muris (30.0 and 2.0%) and Babesia microti (33.3 and 42.0%). Three genetic groups of A. phagocytophilhm based on 16S rRNA gene and groESL operon, as well as two genetic groups of B. microti, B. microti 'US'-type and B. microti 'Munich'-type, were detected. PMID- 25434238 TI - [Seasonal dynamics of the parasite fauna and of the component community structure of parasites of the minnow Phoxinus phoxinus (L.) from the Pechora River. 3]. AB - During January May, 2007, 105 specimens of minnow of the 2+ -- 3+ age were col- lected from the Pechora River in the central homestead of the Pechora-Ilechsky Natural Reserve, and studied using the standard technique of the general parasitological dissection. It was concluded that in a period of studies the component parasite community was in a formation process. PMID- 25434239 TI - [Immunolocalization of microsporidium paranosema locustae canning lSP70 family proteins in locust infected fat body]. AB - Immunolabeling method of microsporidium Paranosema locustae proteins on cryosections of locust infected fat body was proposed. In contrast to single parasite cells and artificially infected host cell cultures, this method allows to study molecular mechanisms of host-parasite relationships and in particular the secretory microsporidial proteins either at cellular or tissue level. Immunolocalization of the EPR-specific and cytoplasmic forms of Hsp70 family of molecular chaperones on cryosections showed accumulation of these proteins in the respective compartments of intracellular developmental stages of P. locustae and their absence in host structures. This allows to use them in diagnostics of microsporidiosis lesions in infected tissues as well as in colocalization analysis with P. lociustatre secretory proteins as a marker of parasite. The cytoplasmic chaperone stains cytoplasmic compartment homogeneously, but in the infected host cell during sporogony it disappears partially from the intracellular stages of development which damaged by maturing spores. Thereby study of molecular mechanisms of host-parasite relationships is to be carried out at the earlier stages of infection before active sporogony. PMID- 25434241 TI - [International conference "Fundamental and applied aspects of parasitic arthropods studies in XXI century" (Saint-Petersburg, 21-25 October 2013)]. PMID- 25434240 TI - [Information system on insects of the "gnus" complex from the north-eastern European Russia]. AB - The structure of the information system "Biodiversity of dipteran insects of the "gnus" complex of the northeastern European Russia, is described. Perspectives of its use in regional parasitological studies and for the public information on bloodsucking insects control are discussed. PMID- 25434242 TI - [Exercise for a healthier life and better community]. PMID- 25434243 TI - [Physical exercise, fitness and health: a decade of sport for all and health promotion in China]. AB - In the 21st century, physical inactivity was identified as the fourth leading risk factor in the global scope of deaths. Followed by an introduction about the studies that have been conducted on health promotion through physical activities, this article presents related programs, policies and guidelines worked out for promoting physical activity participation in both developed and developing countries in addition to those designed by WHO over the past ten years. Discussion is focused on Chinese people's physical activity participation, people's fitness and health, and research results in respect to scientific instructions contributing to sports and physical activities. The latest findings achieved in the field of health promotion are also covered in this review. PMID- 25434244 TI - [Exercise is medicine: development and evidence-based practice in clinical exercise physiology]. AB - It has been well established that appropriate physical activity and exercise play an important role in promotion of health and fitness, prevention of disease and treatment and rehabilitation of health conditions. However, practice based on scientific evidence, in respect of the role and effectiveness of exercise interventions in prevention and treatment of diseases, has only been promoted and implemented in the fields of clinical exercise physiology, public health and medicine in recent years. This brief review provides an introduction of the concept of "Exercise is Medicine", the development and evidence-based practice in Clinical Exercise Physiology, and the role and training of Clinical Exercise Physiologist in the health care system of some other countries. PMID- 25434245 TI - [Exercise and health: from evaluation of health-promoting effects of exercise to exploration of exercise mimetics]. AB - Regular endurance exercise promotes favorable structure and metabolism adaptations in contracting organ (skeletal muscle) and "far-sited" organ (heart, brain, liver, adipose tissue). Exercise induced skeletal muscle remodeling by activating a series of signaling and transcriptional circuitry (e. g., PPARdelta, AMPK, SIRT1 and PGC-1alpha). In addition, contracting skeletal muscle is an endocrine organ producing and releasing myokines (e. g. IL-6, BDNF and Irisin), which work in a hormone-like fashion, exerting specific endocrine effects on " far-sited" organ. It has been suggested that myokines may contribute to exercise induced protection against several chronic disease. In this review, we discuss recent discoveries that raise the possibility of synthetically mimicking exercise with pathway-specific drugs to improve health. PMID- 25434246 TI - [Advance on exercise and health genomics and metabolomics]. AB - Kinetism and fitness effects have high heritability. 10%~20% of people experiences no effects or lower 5% after exercise training, and the adverse responders also reached 10%-20%. Genomics and metabolomics are introduced to expound the individual difference and molecular mechanism that exercise training benefits health. In this essay, the research progress is reviewed. PMID- 25434247 TI - [Exercise and redox signaling regulation]. AB - ROS, identified as signaling molecules, are responsible for maintaining redox homeostasis in vivo. Appropriate exercise promotes the generation of physiological ROS, enhances the antioxidative potential, promotes exercise performance, and improves metabolism, as well as retards aging and related diseases; whereas overload exercise causes excess ROS, resulting in exercise induced fatigue or even exercise-induced injury. Mitochondria are the main pool of ROS production and act as the key organelles in modulating intracellular redox homeostasis. Mitochondrial nutrients not only maintain physiological redox homeostasis, but also ameliorate oxidative stress and fatigue induced by overload exercise, eventually improving exercise performance and preventing/ameliorating exercise-induced injury. PMID- 25434248 TI - [Cardiovascular protection and mechanisms of actions of aerobic exercise]. AB - It is well established that aerobic exercise exerts beneficial effect on cardiovascular system, but the underlying mechanisms are yet to be elucidated. Recent studies have shown that aerobic exercise ameliorates insulin resistance, inflammation and mitochondrial dysfunction which play important roles in the development of cardiovascular disease. In this review, we discussed the underlying mechanisms of the cardioprotective role of aerobic exercise, especially the latest progress in this field. PMID- 25434249 TI - [Current developments in exercise immunology]. AB - The aim of this review is to highlight the research and review papers that reflect the current developments in Exercise Immunology, including the interventions on immunosuppression after extreme performance, the effect of exercise on immunosenescence, and the immunomodulating role of exercise in stress and disease. We discuss the papers in accordance with these themes, summarizing their important contributions, and providing directions for future research. PMID- 25434250 TI - [Research advance on cardiomyocyte proliferation induced by aerobic exercise and stem cell mobilization]. AB - Appropriate exercise is the effective way for the prevention and treatment of heart diseases. Its mechanism has not been completely elucidated, and the safe and effective exercise prescription needs to be studied systematically. Exercises give rise to secretion of various cell factors, effective stem cell mobilization, physiological hypertrophy and differentiation and proliferation of cardiomyocytes. The cell sources of adult cardiomyocyte proliferation included viable cardiomyocytes, cardiac stem/progenitor cells, bone marrow stem cells, peripheral stem cells. Stem cell mobilization, homing and differentiation are the cellular basis of myocardial repair after injury. From the potential of cardiomyocyte proliferation, stem cell therapy after myocardial infarction and cardiac myocyte proliferation induced by exercise, this review focused on the stem cells mobilization promoted by aerobic exercise, the possible mechanism of cardiac repair and functional amelioration induced by the differentiation of those stem cells after myocardial infarction, the problems remained to be further studied and correlative research progress. PMID- 25434251 TI - [Advanced research in the pathogenesis of stress cardiomyopathy]. PMID- 25434252 TI - [Cardiovascular bioactive peptides and atherosclerosis]. PMID- 25434253 TI - [The role of apelin in cardiovascular disease]. PMID- 25434254 TI - [Extracellular miRNAs and their biological functions]. PMID- 25434255 TI - [Research progress of relationship between SIRT6 function and diseases]. PMID- 25434256 TI - [Network of neuroendocrine regulation of puberty]. PMID- 25434257 TI - [Effect of lipid raft on the pathogenesis of Alzheimer's disease]. PMID- 25434258 TI - [The progress of HMGB1 research in viral diseases]. PMID- 25434259 TI - [Astrocytic swelling and cysts formation resulting from gene mutation in megalencephalic leukoencephalopathy with subcortical cysts]. PMID- 25434260 TI - [The role of VDAC1 in Alzheimer's disease pathogenesis]. PMID- 25434261 TI - The mechanism of coal gas desulfurization by iron oxide sorbents. AB - This study aims to understand the roles of hydrogen and carbon monoxide during the desulfurization process in a coal gasification system that H2S of the syngas was removed by Fe2O3/SiO2 sorbents. The Fe2O3/SiO2 sorbents were prepared by incipient wetness impregnation. Through the breakthrough experiments and Fourier transform infrared spectroscopy analyses, the overall desulfurization mechanism of the Fe2O3/SiO2 sorbents was proposed in this study. The results show that the major reaction route is that Fe2O3 reacts with H2S to form FeS, and the existence of CO and H2 in the simulated gas significantly affects equilibrium concentrations of H2S and COS. The formation of COS occurs when the feeding gas is blended with CO and H2S, or CO2 and H2S. The pathways in the formation of products from the desulfurization process by the reaction of Fe2O3 with H2S have been successfully established. PMID- 25434262 TI - Measurement of cyclic volatile methylsiloxanes in the aquatic environment using low-density polyethylene passive sampling devices using an in-field calibration study--challenges and guidance. AB - Cyclic volatile methylsiloxanes (cVMS) are used in personal care products and are hydrophobic, volatile and persistent. Their environmental water concentrations are low and are difficult to detect using conventional sampling methods. This study shows the potential of passive sampling for cVMS. We used low-density polyethylene (LDPE) samplers and in-field calibration methods for octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5). (13)C-D4 and (13)C-D5, methyltris(trimethylsiloxy)silane (MT), tetrakis(trimethylsiloxy)silane (TK), and five deuterated polycyclic aromatic hydrocarbons (PAHs) were used as performance reference compounds (PRCs). Samplers were calibrated (7-d) using effluent at a treatment plant, with uptake of cVMS and losses of the PRCs measured at 12 time-points. Concentrations of D4 (53ngL( 1)) and D5 (1838ngL(-1)) were stable in the effluent. Uptake of D4 and loss of (13)C-D4 were isotropic and equilibrium was approached by 7-d. Two estimates of sampler uptake rate (Rs) were 2.1Ld(-1) and 2.5Ld(-1). The estimated log LDPE/water partition coefficient was 4.4. The uptake of D5 was slower (Rs=0.32Ld( 1)) and equilibrium was not reached. Offloading of (13)C-D5, MT and TK were slow, and isotropic behaviour was not demonstrated for D5. Offloading of PAHs followed the predicted pattern for LDPE. Uptake of cVMS appeared to be under membrane control, due to low diffusion coefficients in LDPE. Samplers can monitor time weighted average concentrations of D4 for less than a week, and D5 for longer periods. LDPE samplers allow cVMS to be determined at lower concentrations than by spot sampling methods. PMID- 25434264 TI - Mineral composition and heavy metal contamination of sediments originating from radium rich formation water. AB - Radium rich formation water is often associated with fossil fuels as crude oil, natural gas and hard coal. As a result of fossil fuels exploitation high amount of such water is released into environment. In spite of the high radium content such waters create a serious radiation risk neither to humans nor biota directly. First and foremost due to very high mineralization they are not drinkable at all. But after discharge chemical and physical conditions are substantially changed and sediments which additionally concentrated radium are arising. Due to features of technological processes such phenomenon is very intensive in underground coal mining where huge volume of such water must be pumped into surface in order to keep underground galleries dry. Slightly different situation occurs in oil rigs, but finally also huge volume of so called process water is pumped into environment. Regardless their origin arising sediments often contain activity concentration of radium isotopes exceeding the clearance levels set for naturally occurring radioactive materials (NORM) (Council Directive, 2013). The analysis of metals and minerals content showed that besides radioactivity such sediments contain high amount of metals geochemically similar to radium as barium, strontium and lead. Correlation analysis proved that main mechanism leading to sediment creation is co-precipitation radium with these metals as a sulfate. The absorption on clay minerals is negligible even when barium is not present in significant quantities. Owing to very low solubility of sulfates radium accumulated in this way should not migrate into environment in the neighborhood of a site where such sediment were deposited. PMID- 25434263 TI - In utero bisphenol A concentration, metabolism, and global DNA methylation across matched placenta, kidney, and liver in the human fetus. AB - While urine has been an easily accessible and feasible matrix for human biomonitoring, analytical measurements in internal tissues and organs can provide more accurate exposure assessments to understand disease etiology. This is especially important for the endocrine active compound, bisphenol A (BPA), where studies investigating internal doses at sensitive periods of human development are currently lacking. Herein, BPA concentrations, BPA-specific metabolizing enzyme gene expression, and global DNA methylation were characterized across three matched tissues from elective pregnancy terminations of 2nd trimester human fetuses: the placenta, liver, and kidney (N=12 each; N=36 total). Compared to liver (free: 0.54-50.5 ng g(-1)), BPA concentrations were lower in matched placenta (<0.05-25.4 ng g(-1)) and kidney (0.08-11.1 ng g(-1)) specimens. BPA specific metabolism gene expression of GUSB, UGT2B15, STS, and SULT1A1 differed across each tissue type; however, conjugation and deconjugation expression patterns were similar across the fetus. Average LINE1 and CCGG global methylation were 58.3% and 59.2% in placenta, 79.5% and 66.4% in fetal liver, and 77.9% and 77.0% in fetal kidney, with significant tissue-specific DNA methylation differences in both LINE1 (p-value<0.001) and CCGG content (p-value<0.001). Total BPA concentrations were positively associated with global methylation for the placenta only using the LINE1 assay (p-value: 0.002), suggesting organ-specific biological effects after fetal exposure. Utilizing sensitive human clinical specimens, results are informative for BPA toxicokinetics and toxicodynamics assessment in the developing human fetus. PMID- 25434265 TI - Stereochemistry of enzymatic transformations of (+)beta- and (-)beta-HBCD with LinA2--a HCH-degrading bacterial enzyme of Sphingobium indicum B90A. AB - LinA2, a bacterial enzyme expressed in various Sphingomonadaceae, catalyzes the elimination of HCl from hexachlorocyclohexanes (HCHs) and, as discussed here, the release of HBr from certain hexabromocyclododecanes (HBCDs). Both classes of compounds are persistent organic pollutants now regulated under the Stockholm Convention. LinA2 selectively catalyzes the transformation of beta-HBCDs; other stereoisomers like alpha-, gamma-, and delta-HBCDs are not converted. The transformation of (-)beta-HBCD is considerably faster than that of its enantiomer. Here, we present the XRD crystal structure of 1E,5S,6S,9R,10S pentabromocyclododecene (PBCDE) and demonstrate that its enantiomer with the 1E,5R,6R,9S,10R-configuration is the only metabolite formed during LinA2 catalyzed dehydrobromination of (-)beta-HBCD. Formation of this product can be rationalized by HBr elimination at C5 and C6. A reasonable enzyme-substrate complex with the catalytic dyad His-73 and Asp-25 approaching the hydrogen at C6 and a cationic pocket of Lys-20, Try-42 and Arg-129 binding the leaving bromine at C5 was found from in silico docking experiments. A second PBCDE of yet unknown configuration was obtained from (+)beta-HBCD. We predicted its stereochemistry to be 1E,5S,6S,9S,10R-PBCDE from docking experiments. The enzyme-substrate complex obtained from LinA2 and an activated conformation of (+)beta-HBCD allows the HBr elimination at C9 and C10 leading to the predicted product. Both modeled enzyme substrate complexes are in line with 1,2-diaxial HBr eliminations. In conclusion, LinA2, a bacterial enzyme of the HCH-degrading strain Sphingobium indicum B90A was able to stereoselectively convert beta-HBCDs. Configurations of both PBCDE metabolites were predicted by molecular docking experiments and confirmed in one case by XRD data. PMID- 25434266 TI - Organic compounds leached from fast pyrolysis mallee leaf and bark biochars. AB - Characterization of organic compounds leached from biochars is essential in assessing the possible toxicity of the biochar to the soils' biota. In this study the nature of the leached organic compounds from Mallee biochars, produced from pyrolysis of Mallee leaf and bark in a fluidised-bed pyrolyser at 400 and 580 degrees C was investigated. Light bio-oil compounds and aromatic organic compounds were investigated. The 'bio-oil like' light compounds from leaf and bark biochars 'surfaces were obtained after leaching the chars with a solvent, suitable to dissolve the respective bio-oils. GC/MS was implemented to investigate the leachates. Phenolics, which are potentially harmful toxins, were detected and their concentration shown to be dependent on the char's origin and the char production temperature. Further, to simulate biochars amendment to soils, the chars were leached with water. The water-leached aromatic compounds from leaf and bark biochars were characterized using UV-fluorescence spectroscopy. Those results suggested that biochars contain leachable compounds of which the nature and amount is dependent on the biomass feedstock, pyrolysis temperature and leaching time. PMID- 25434267 TI - Influence of cypermethrin on avoidance behavior, survival and reproduction of Folsomia candida in soil. AB - Cypermethrin is a pyrethroid widely used in agriculture and in control of animal ectoparasites, being effective against a large number of insects. Therefore, this study aimed to evaluate the effects of cypermethrin on soil fauna using reproduction and behavior ecotoxicological tests with the springtail Folsomia candida. The surface layer of a soil characteristic of the western region of the Santa Catarina State, classified as Typic Dystrupept, was used as test substrate. The treatments on both tests consisted of five concentrations of cypermethrin (0, 7.5, 15.0, 22.5, and 30.0mgkg(-)(1)) corresponding to 0, 1.5, 3.0, 4.5, and 6.0gm(-2), respectively. This range was chosen according to technical instruction for the use of this product in broilers beds (that are used afterwards as organic fertilizer in soil) that recommends 15mgkg(-1) (3.0gm(-2)). The results obtained with tests for F. candida showed toxicity at all doses tested, following a dose related response resulting in reduction in survival rate (LC50 of 18.41mgkg(-1), equivalent to 3.8gm(-2)), in the number of juveniles (EC50 of 15.05mgkg(-1), corresponding to 3.01gm(-2)), and an increase in avoidance response (AC50 of 29mgkg(-1), corresponding to 5.8gm(-2)). Although more studies are needed focusing on the fate of cypermethrin in soil when the poultry beds are used as fertilizer and how it may affect soil fauna, data obtained in this study, by showing effects within the range of the doses that are recommended implies that caution and possible mitigation measures should be taken when using this compound. PMID- 25434269 TI - A national statistical survey assessment of mercury concentrations in fillets of fish collected in the U.S. EPA national rivers and streams assessment of the continental USA. AB - The U.S. EPA conducted a national statistical survey of fish fillet tissue with a sample size of 541 sites on boatable rivers =>5th order in 2008-2009. This is the first such study of mercury (Hg) in fish tissue from river sites focused on potential impacts to human health from fish consumption to also address wildlife impacts. Sample sites were identified as being urban or non-urban. All sample mercury concentrations were above the 3.33ugkg(-1) (ppb) quantitation limit, and an estimated 25.4% (+/-4.4%) of the 51663 river miles assessed exceeded the U.S. EPA 300ugkg(-1) fish-tissue based water quality criterion for mercury, representing 13144+/-181.8 river miles. Estimates of river miles exceeding comparable aquatic life thresholds (translated from fillet concentrations to whole fish equivalents) in avian species were similar to the number of river miles exceeding the human health threshold, whereas some mammalian species were more at risk than human from lower mercury concentrations. A comparison of means from the non-urban and urban data and among three ecoregions did not indicate a statistically significant difference in fish tissue Hg concentrations at p<0.05. PMID- 25434268 TI - Determination of low methylmercury concentrations in peat soil samples by isotope dilution GC-ICP-MS using distillation and solvent extraction methods. AB - Most often, only total mercury concentrations in soil samples are determined in environmental studies. However, the determination of extremely toxic methylmercury (MeHg) in addition to the total mercury is critical to understand the biogeochemistry of mercury in the environment. In this study, N2-assisted distillation and acidic KBr/CuSO4 solvent extraction methods were applied to isolate MeHg from wet peat soil samples collected from boreal forest catchments. Determination of MeHg was performed using a purge and trap GC-ICP-MS technique with a species-specific isotope dilution quantification. Distillation is known to be more prone to artificial MeHg formation compared to solvent extraction which may result in the erroneous MeHg results, especially with samples containing high amounts of inorganic mercury. However, methylation of inorganic mercury during the distillation step had no effect on the reliability of the final MeHg results when natural peat soil samples were distilled. MeHg concentrations determined in peat soil samples after distillation were compared to those determined after the solvent extraction method. MeHg concentrations in peat soil samples varied from 0.8 to 18 MUg kg(-1) (dry weight) and the results obtained with the two different methods did not differ significantly (p=0.05). The distillation method with an isotope dilution GC-ICP-MS was shown to be a reliable method for the determination of low MeHg concentrations in unpolluted soil samples. Furthermore, the distillation method is solvent-free and less time-consuming and labor intensive when compared to the solvent extraction method. PMID- 25434270 TI - Aquatic hazard assessment of a commercial sample of naphthenic acids. AB - This paper presents chemical composition and aquatic toxicity characteristics of a commercial sample of naphthenic acids (NAs). Naphthenic acids are derived from the refining of petroleum middle distillates and can contribute to refinery effluent toxicity. NAs are also present in oil sands process-affected water (OSPW), but differences in the NAs compositions from these sources precludes using a common aquatic toxicity dataset to represent the aquatic hazards of NAs from both origins. Our chemical characterization of a commercial sample of NAs showed it to contain in order of abundance, 1-ring>2-ring>acyclic>3-ring acids (~84%). Also present were monoaromatic acids (7%) and non-acids (9%, polyaromatic hydrocarbons and sulfur heterocyclic compounds). While the acyclic acids were only the third most abundant group, the five most abundant individual compounds were identified as C(10-14) n-acids (n-decanoic acid to n-tetradecanoic acid). Aquatic toxicity testing of fish (Pimephales promelas), invertebrate (Daphnia magna), algae (Pseudokirchneriella subcapitata), and bacteria (Vibrio fischeri) showed P. promelas to be the most sensitive species with 96-h LL50=9.0 mg L(-1) (LC50=5.6 mg L(-1)). Acute EL50 values for the other species ranged 24-46 mg L( 1) (EC50 values ranged 20-30 mg L(-1)). Biomimetic extraction via solid-phase microextraction (BE-SPME) suggested a nonpolar narcosis mode of toxic action for D. magna, P. subcapitata, and V. fischeri. The BE analysis under-predicted fish toxicity, which indicates that a specific mode of action, besides narcosis, may be a factor for fishes. PMID- 25434272 TI - Plant leaves as indoor air passive samplers for volatile organic compounds (VOCs). AB - Volatile organic compounds (VOCs) enter indoor environments through internal and external sources. Indoor air concentrations of VOCs vary greatly but are generally higher than outdoors. Plants have been promoted as indoor air purifiers for decades, but reports of their effectiveness differ. However, while air purifying applications may be questionable, the waxy cuticle coating on leaves may provide a simple, cost-effective approach to sampling indoor air for VOCs. To investigate the potential use of plants as indoor air VOC samplers, a static headspace approach was used to examine the relationship between leaf and air concentrations, leaf lipid contents and octanol-air partition coefficients (Koa) for six VOCs and four plant species. The relationship between leaf and air concentrations was further examined in an actual residence after the introduction of several chlorinated VOC emission sources. Leaf-air concentration factors (LACFs), calculated from linear regressions of the laboratory headspace data, were found to increase as the solvent extractable leaf lipid content and Koa value of the VOC increased. In the studies conducted in the residence, leaf concentrations paralleled the changing air concentrations, indicating a relatively rapid air to leaf VOC exchange. Overall, the data from the laboratory and residential studies illustrate the potential for plant leaves to be used as cost effective, real-time indoor air VOC samplers. PMID- 25434271 TI - Electrochemical disinfection using boron-doped diamond electrode--the synergetic effects of in situ ozone and free chlorine generation. AB - This work investigated the capability of using a boron-doped diamond (BDD) electrode for bacterial disinfection in different water matrices containing varying amounts of chloride. The feed water containing Pseudomonas aeruginosa was electrochemically treated while applying different electrode conditions. Depending on the applied current density and the exposure time, inactivation between 4- and 8-log of the targeted microorganisms could be achieved. The disinfection efficiency was driven by the generation of free chlorine as a function of chloride concentration in the water. A synergetic effect of generating both free chlorine and ozone in situ during the disinfection process resulted in an effective bactericidal impact. The formation of the undesired by products chlorate and perchlorate depended on the water matrix, the applied current density and the desired target disinfection level. In case of synthetic water with a low chloride concentration (20 mg L(-1)) and an applied current density of 167 mA cm(-2), a 6-log inactivation of Pseudomonas aeruginosa could be achieved after 5 min of exposure. The overall energy consumption ranged between 0.3 and 0.6 kW h m(-3) depending on the applied current density and water chemistry. Electrochemical water disinfection represents a suitable and efficient process for producing pathogen-free water without the use of any chemicals. PMID- 25434273 TI - Evaluating the mutagenicity of leachates obtained from the bottom ash of a municipal solid waste incinerator by using a Salmonella reverse mutation assay. AB - The mutagenic potential of leachates derived from the bottom ash of a municipal solid waste incinerator in Taiwan were evaluated using an Ames Salmonella mutagenicity assay with three standard tester strains, TA98, TA100, and TA1535. Three types of leachants, leachant A (pH 4.93), leachant B (pH 2.88), and leachant C (deionized water, pH 6.0), were carried out according to toxicity characteristic leaching procedure (TCLP). Moreover, two types of bottom ash, nonsieved and sieved bottom ash (particle size <4.75 mm), were analyzed with the TCLP and the Ames assay. The concentrations of five heavy metals (Cd, Cr, Cu, Pb, and Zn) in the leachates were also estimated with an ICP-OES. The results indicated that the metal concentrations in the TCLP leachates of bottom ash were all below the limits set by Taiwanese regulations. However, leachate A from nonsieved and <4.75-mm-sieved bottom ash showed mutagenicity. Moreover, leachate A from <4.75 mm-sieved bottom ash displayed stronger mutagenicity than that from nonsieved ash. The leachate A from <4.75-mm-sieved bottom ash, that were diluted by 100-fold showed no mutagenicity. In conclusion, our results suggested that the chemical composition and mutagenic potential of leachates should be monitored to evaluate the safety of bottom ash. PMID- 25434274 TI - Dioxins, PCBs and heavy metals in Chinese mitten crabs from Dutch rivers and lakes. AB - Chinese mitten crab is an invasive species in many European rivers and lakes. Data from the UK indicated high levels of dioxins and PCBs, in particular in the brown meat in the body. This was confirmed by studies in the Netherlands, showing average levels of dioxins and PCBs in the meat in the body of 43 pg TEQ g(-1) ww in crabs caught in the large rivers. Levels in crab of lakes in the Northern part of the Netherlands were on average 3.7-fold lower. Consumption of crabs from polluted areas results in a relatively high dose of dioxins and dl-PCBs and could significantly increase the intake above the TWI. However, in general consumption of these crabs is low, even in the Asian sub-population in the Netherlands. Cadmium and lead levels were higher in crabs from contaminated areas, but for mercury and arsenic there was no clear difference. Consumption of crabs would not result in significant risks for cadmium and mercury. For lead the daily intake could be raised above the BMDL01 for neurodevelopmental toxicity, but this would only occur on a limited number of days. For arsenic the exposure would exceed the lower end of the BMDL01 values for certain cancers, but again, the infrequent consumption by most consumers reduces this risk. Furthermore, speciation showed that most arsenic in crabs was probably not a toxic inorganic form, but likely to be in an organic form. PMID- 25434275 TI - Saccharomyces cerevisiae SHSY detoxifies petroleum n-alkanes by an induced CYP52A58 and an enhanced order in cell surface hydrophobicity. AB - Environmental hydrocarbon contamination has a serious hazard to human health. Alkanes, the major component of hydrocarbons, can be consumed by various species of yeast. We previously identified a new strain SHSY of Saccharomyces cerevisiae with a remarkable ability to utilize the petroleum crude-oil (PCO) in aqueous solution. The current study demonstrated that the n-alkanes-assimilation activity of S. cerevisiae SHSY was related to an induced microsomal protein of 59 kDa approximately. The identified ORF encoded a protein of 517 amino acids and shared 93% sequence identity with an alkane-inducible hydroxylase CYP52A53 isolated from Scheffersomyces stipitis CBS. It was therefore referred as CYP52A58. The catalytic activity of the recombinant CYP52A58 was confirmed by the hydroxylation of n-alkanes, it showed an optimal mono-terminal hydroxylation activity toward n hexadecane. Moreover, the ability of the yeast to use n-alkanes was accompanied with an increasing level in cell wall mannoproteins. Two differential protein bands were detected in the mannoproteins extracted from PCO-grown yeast. In parallel, a significant increase in the fatty acids content with a high degree of unsaturation was subsequently detected in the PCO-grown yeast. This study characterizes a safe and potential microorganism to remove n-alkanes from the aquatic environment. PMID- 25434276 TI - Potential of multisyringe chromatography for the on-line monitoring of the photocatalytic degradation of antituberculosis drugs in aqueous solution. AB - In this study, a multisyringe chromatography system (MSC) using a C18 monolithic column was proposed for the on-line monitoring of the photocatalytic degradation of isoniazid (INH, 10 mg L(-1)) and pyrazinamide (PYRA, 5mgL(-1)) mixtures in aqueous solution using a small sample volume (200 MUL) with an on-line filtration device in a fully automated approach. During the photocatalytic oxidation using TiO2 or ZnO semiconductor materials, total organic carbon (TOC) and the formed intermediates were analyzed off-line using ion chromatography, ion exclusion HPLC, and ESI-MS/MS. The results showed that TiO2 exhibits a better photocatalytic activity than ZnO under UV irradiation (365 nm) for the degradation of INH and PYRA mixtures, generating 97% and 92% degradation, respectively. The optimal oxidation conditions were identified as pH 7 and 1.0 g L(-1) of TiO2 as catalyst. The mineralization of the initial organic compounds was confirmed by the regular decrease in TOC, which indicated 63% mineralization, and the quantitative release of nitrate and nitrite ions, which represent 33% of the nitrogen in these compounds. The major intermediates of INH degradation included isonicotinamide, isonicotinic acid, and pyridine, while the ESI-MS/MS analysis of PYRA aqueous solution after photocatalytic treatment showed the formation of pyrazin-2-ylmethanol, pyrazin-2-ol, and pyrazine. Three low molecular weight compounds, acetamide, acetic acid and formic acid, were detected during INH and PYRA decomposition. PYRA was more resistant to photocatalytic degradation due to the presence of the pyrazine ring, which provides greater stability against OH attack. PMID- 25434278 TI - Can rove beetles (Staphylinidae) be excluded in studies focusing on saproxylic beetles in central European beech forests? AB - Monitoring saproxylic beetle diversity, though challenging, can help identifying relevant conservation sites or key drivers of forest biodiversity, and assessing the impact of forestry practices on biodiversity. Unfortunately, monitoring species assemblages is costly, mainly due to the time spent on identification. Excluding families which are rich in specimens and species but are difficult to identify is a frequent procedure used in ecological entomology to reduce the identification cost. The Staphylinidae (rove beetle) family is both one of the most frequently excluded and one of the most species-rich saproxylic beetle families. Using a large-scale beetle and environmental dataset from 238 beech stands across Europe, we evaluated the effects of staphylinid exclusion on results in ecological forest studies. Simplified staphylinid-excluded assemblages were found to be relevant surrogates for whole assemblages. The species richness and composition of saproxylic beetle assemblages both with and without staphylinids responded congruently to landscape, climatic and stand gradients, even when the assemblages included a high proportion of staphylinid species. At both local and regional scales, the species richness as well as the species composition of staphylinid-included and staphylinid-excluded assemblages were highly positively correlated. Ranking of sites according to their biodiversity level, which either included or excluded Staphylinidae in species richness, also gave congruent results. From our results, species assemblages omitting staphylinids can be taken as efficient surrogates for complete assemblages in large scale biodiversity monitoring studies. PMID- 25434277 TI - Biomonitoring of arsenic, cadmium, lead, manganese and mercury in urine and hair of children living near mining and industrial areas. AB - Huelva (South West Spain) and its surrounding municipalities represent one of the most polluted estuaries in the world owing to the discharge of mining and industrial related pollutants in their proximity. A biomonitoring study was conducted to assess exposure to arsenic and some trace metals (cadmium, mercury, manganese and lead) in urine and scalp hair from a representative sample of children aged 6-9 years (n=261). This is the only study simultaneously analyzing those five metal elements in children urine and hair. The potential contribution of gender, water consumption, residence area and body mass index on urinary and hair metal concentrations was also studied. Urine levels of cadmium and total mercury in a proportion (25-50%) of our children population living near industrial/mining areas might have an impact on health, likely due to environmental exposure to metal pollution. The only significant correlation between urine and hair levels was found for mercury. Children living near agriculture areas showed increased levels of cadmium and manganese (in urine) and arsenic (in hair). In contrast, decreased urine Hg concentrations were observed in children living near mining areas. Girls exhibited significantly higher trace metal concentrations in hair than boys. The greatest urine arsenic concentrations were found in children drinking well/spring water. Although human hair can be a useful tool for biomonitoring temporal changes in metal concentrations, levels are not correlated with those found in urine except for total mercury, thus providing additional information. PMID- 25434279 TI - [On the use of Winters' formula in chronic metabolic acidosis]. PMID- 25434282 TI - Pathology reporting of pancreatic cancer following neoadjuvant therapy: challenges and uncertainties. AB - An increasing number of studies investigate the use of neoadjuvant treatment for ductal adenocarcinoma of the pancreas. While a strong rationale supports this approach, study results are difficult to interpret and compare due to marked variance in multiple aspects of study design and performance. Divergence in pathology examination and reporting as a cause for heterogeneity and incomparability of study results has not been brought into this discussion yet, despite the fact that several key outcome measures for neoadjuvant treatment are pathology-based. This article discusses areas of controversy and difficulty regarding the evaluation of the extent of residual tumour tissue, grading of tumour regression and assessment of the margins, and explains the important clinical implications of the present uncertainty and divergence in pathology practice. PMID- 25434280 TI - Improvement of anticipatory postural adjustments for balance control: effect of a single training session. AB - Humans use anticipatory and compensatory postural strategies to maintain and restore balance when perturbed. Inefficient generation and utilization of anticipatory postural adjustments (APAs) is one of the reasons for postural instability. The aim of the study was to investigate the role of training in improvement of APAs and its effect on subsequent control of posture. Thirteen healthy young adults were exposed to predictable external perturbations before and after a single training session consisting of catches of a medicine ball thrown at the shoulder level. 3-D body kinematics, EMG activity of thirteen trunk and lower limb muscles, and ground reaction forces were recorded before and immediately after a single training session. Muscle onsets, EMG integrals, center of pressure (COP), and center of mass (COM) displacements were analyzed during the anticipatory and compensatory phases of postural control. The effect of a single training session was seen as significantly early muscle onsets and larger anticipatory COP displacements. As a result, significantly smaller peak COM displacements were observed after the perturbation indicating greater postural stability. The outcome of this study provides a background for examining the role of training in improvement of APAs and its effect on postural stability in individuals in need. PMID- 25434281 TI - Splenectomy reduces infarct volume and neuroinflammation in male but not female mice in experimental stroke. AB - The peripheral immune response contributes to neurodegeneration after stroke yet little is known about how this process differs between males and females. The current study demonstrates that splenectomy prior to experimental stroke eliminates sex differences in infarct volume and activated brain monocytes/microglia. In the periphery of both sexes, activated T cells correlate directly with stroke outcome while monocytes are reduced by splenectomy only in males. This study provides new information about the sex specific mechanisms of the peripheral immune response in neurodegeneration after stroke and demonstrates the need for representation of both sexes in basic and clinical stroke research. PMID- 25434283 TI - C21-steroids inactivation and glucocorticoid synthesis in the developing lung. AB - Glucocorticoids (GCs) are important regulators of lung development. The genes normally involved in GC synthesis in adrenals are co-expressed with 20alpha hydroxysteroid dehydrogenase (20alpha-HSD) in the developing lung. In this study, C21-steroid metabolism was investigated in fetal and postnatal mouse lungs. Incubation of [(3)H]-progesterone with lung explant cultures of different perinatal developmental time points revealed two different (antenatal vs. postnatal) complex metabolization patterns. Progesterone inactivation was predominant. 20alphaOH-derivatives were more abundant after birth and some metabolites were 5alpha-reduced. Using [(3)H]-progesterone as substrate, corticosterone synthesis was only observed in a fraction of lung explants from gestation day (GD) 15.5. Neither aldosterone synthase nor P450c17 activity was observed. With epithelial-enriched primary cell cultures, deoxycorticosterone synthesis from [(3)H]-progesterone was observed. With lung explants incubated with [(3)H]-corticosterone as substrate, [(3)H]-4-pregnen-21-ol-3,11,20-trione (11-dehydrocorticosterone), the product of 11beta-HSD2, accumulated in higher proportion on GD 15.5 than at later developmental time points. The temporal correlation observed between levels of progesterone inactivation by 20alpha-HSD (higher after birth) and the sensitivity of lung development to GCs suggests a role for 20alpha-HSD in the modulation of GR occupancy through the control of 21 hydroxylase substrate and product levels. In conclusion, the developing lung is characterized by effective inactivation of c21-steroids by 20alpha-HSD. The formation of active GCs from the "adrenal"-like pathway was observed with some lung explants and primary epithelial cell cultures. Coexistence of this GC synthesis pathway with 20alpha-HSD activity strongly suggests local regulation of GC action and is compatible with intracrine/paracrine actions of GC. PMID- 25434284 TI - The potential of class 3 semaphorins as both targets and therapeutics in cancer. AB - INTRODUCTION: Semaphorins have been originally identified as a family of evolutionary conserved soluble or membrane-associated proteins involved in diverse developmental phenomena. This family of proteins profoundly influences numerous pathophysiological processes, including organogenesis, cardiovascular development and immune response. Apart from steering the neural networking process, these are implicated in a broad range of biological operations including regulation of tumor progression and angiogenesis. AREAS COVERED: Members of class 3 semaphorin family are known to modulate various cellular processes involved in malignant transformation. Some of the family members trigger diverse signaling processes involved in tumor progression and angiogenesis by binding with plexin and neuropilin. A better understanding of the various signaling mechanisms by which semaphorins modulate tumor progression and angiogenesis may serve as crucial tool in crafting new semaphorin-based anticancer therapy. These include treatment with recombinant tumor suppressive semaphorins or inhibition of tumor promoting semaphorins by their specific siRNAs, small-molecule inhibitors or specific receptors using neutralizing antibodies or blocking peptides that might serve as novel strategies for effective management of cancers. EXPERT OPINION: This review focuses on all the possible avenues to explore various members of class 3 semaphorin family to serve as therapeutics for combating cancer. PMID- 25434285 TI - An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. AB - Psoriasis is a skin disease where various cytokines play a detrimental role, yet our understanding of the disease is still limited. TNF is a validated drug target in psoriasis and other autoimmune diseases, but its use is associated with side effects. Some paradoxical side effects of anti-TNF treatment are supposedly associated with type I IFNs, which are also implicated in the pathogenesis of psoriasis. Recently, the IL-23/IL-17 axis has been associated with psoriasis as well, and new drugs targeting this axis have already been developed. Findings suggest that these cytokines are interwoven. We discuss recent findings reinforcing the role of TNF, Type I IFNs and IL-17 in the pathogenesis of psoriasis and the apparent inflammatory interplay between these three cytokines. PMID- 25434286 TI - Orexin in the toad Rhinella schneideri: The location of orexinergic neurons and the role of orexin in ventilatory responses to hypercarbia and hypoxia. AB - Recent reports have suggested that orexins, also known as hypocretins, play an important role in the modulation of respiratory control in mammals, but there are no data available describing the role of the orexinergic system in the peripheral and central chemoreception of non-mammalian vertebrates. Therefore, the present study was designed to examine the localization of orexin-immunoreactive neurons in the brain of toads (Rhinella schneideri) and to investigate the contribution of orexin receptor-1 (OX1R) to the hypoxic and hypercarbic ventilatory responses of these animals during light and dark phases. Our results demonstrated that the orexinergic neurons of R. schneideri are located in the suprachiasmatic nucleus of the diencephalon. Additionally, the intracerebroventricular injection of SB 334867 (OX1R selective antagonist) attenuated the ventilatory response to hypercarbia during the dark phase by acting on tidal volume and breathing frequency, while during the light phase, SB-334867 attenuated the ventilatory response to hypoxia by acting on tidal volume only. We conclude that in the toad R. schneideri, orexinergic neurons are located in the suprachiasmatic nucleus and that OX1R contributes to hypercarbic and hypoxic chemoreflexes. PMID- 25434287 TI - An advanced navigational surgery system for dental implants completed in a single visit: an in vitro study. AB - In this study, we have developed an advanced navigational implant surgery system to overcome some disadvantages of the conventional method and have evaluated the accuracy of the system under in vitro environment. The patient splint for registration and tracking was improvised using a bite splint without laboratory work and the offset of an exchanged drill was calibrated directly without pivoting during surgery. The mean target registration errors (TRE) were 0.35 +/- 0.11 mm using the registration body, 0.34 +/- 0.18 mm for the registration method with prerecorded fiducials, and 0.35 +/- 0.16 mm for the direct calibration of a drill offset. The mean positional deviations between the planned and placed implants in 110 implant surgeries were 0.41 +/- 0.12 mm at the center point of the platform and 0.56 +/- 0.14 mm at the center point of the apex. The mean angular deviation was 2.64 degrees +/- 1.31 for the long axis of the implant. In conclusion, the developed system exhibited high accuracy, and the improved tools and simplified procedures increased the convenience and availability. With this advanced approach, it will be possible to complete dental implant surgery during a single visit at local clinics using a navigational guidance involving cone-beam computed tomographic images. PMID- 25434288 TI - Accuracy of fibular sectioning and insertion into a rapid-prototyped bone plate, for mandibular reconstruction using CAD-CAM technology. AB - Modern techniques of mandibular reconstruction, such as CAD-CAM technology and rapid prototyping, offer new means by which reconstructive surgery can be planned to optimise aesthetic outcomes and prosthetic rehabilitation. The high degree of accuracy afforded by these approaches is principally attributable to high precision fibular sectioning and insertion of the bone into a customised bone plate. CAD-CAM mandibular reconstruction procedures using vascularised bone free flap transfers were performed on 10 patients with benign or malignant neoplasms. Five were not treated with the aid of CAD-CAM technology, and served as the control group. Five were scheduled for maxillofacial surgery using surgical cutting guides and customised bone plates. A generalised linear model for linear measures was used to compare the accuracy of reconstruction between the two groups. A difference, even though not significant, in the lateral shift of the mesial and distal positions of the fibular units was evident between groups. CAD CAM-generated fibular surgical guides afford improved accuracy when used to restore native anatomy, especially in the context of mandibular arch restoration, and both operating room time and related costs are reduced during fibular sectioning. PMID- 25434290 TI - Dependence of solvent quality on the composition of copolymers: experiment and theory for solutions of P(MMA-ran-t-BMA) in toluene and in chloroform. AB - The interaction of toluene with P(MMA-ran-t-BMA) and with the corresponding homopolymers was determined via vapor pressure measurements at 30, 50 and 70 degrees C. A unified thermodynamic approach served for the modeling of the results. It is capable of describing the behavior of the different solutions by means of two adjustable parameters, one representing the effective number of solvent segments and the other accounting for the interactions between the components. The solvent quality of toluene passes a maximum, a minimum and another maximum upon an increase of the t-BMA content of the copolymer at all temperatures. A similar behavior is discernable from vapor pressure data of chloroform published for the same copolymers. The heats of mixing for toluene depend strongly on temperature; at 50 degrees C they are all endothermal with the exception of PMMA, for which the value obtained from vapor pressures at 30 degrees C agrees very well with published caloric data. PMID- 25434289 TI - The bright side of brooding: State orientation increases positive emotions about positive outcomes. AB - Research has by and large shown the negative effects of state orientation, that brooding over past events (i.e., state orientation) leads to more negative emotions and less well-being than quickly getting over past events (i.e., action orientation). However, this past research has primarily focused on how people cope with negative events and bad outcomes. The present research focuses on how people cope with positive events with good outcomes. Study 1 found that state oriented people felt better after a windfall than action-oriented people. Study 2 found that state-oriented people felt not only worse when things turned out bad but also better when things turned out well than action-oriented people. Study 3 replicated the positive effect of state orientation on positive emotions with an experimental induction of action vs. state orientation. These results show that in positive situations state orientation can have emotional benefits - in other words, they show the bright side of brooding. PMID- 25434291 TI - Relationship between diabetes and grayscale fractal dimensions of retinal vasculature in the Indian population. AB - BACKGROUND: Diabetes mellitus is rapidly increasing in the Indian population. The purpose of this study was to identify changes in the retinal vasculature of diabetic people, ahead of visual impairments. Grayscale Fractal Dimension (FD) analysis of retinal images was performed on people with type 2 diabetes from an Indian population. METHODS: A cross-sectional study comprising 189 Optic Disc (OD) centred retinal images of healthy and diabetic individuals aged 14 to 73 years was conducted. Grayscale Box Counting FD of these retinal photographs was measured without manual supervision. Statistical analysis was conducted to determine the difference in the FD between diabetic and healthy (non-diabetic) people. RESULTS: The results show that grayscale FD values for diabetic cases are higher compared to controls, irrespective of the gender. It was also observed that FD was higher for male compared with females. CONCLUSIONS: There is difference in the grayscale fractal dimension of retinal vasculature of diabetic patients and healthy subjects, even when there is no reported retinopathy. PMID- 25434292 TI - The V-val subtype Epstein-Barr virus nuclear antigen 1 promotes cell survival after serum withdrawal. AB - Epstein-Barr virus (EBV) can establish latent infection and has been associated with various human cancers. Epstein-Barr nuclear antigen 1 (EBNA1) is the only viral protein that is expressed in all EBV-associated malignant tissues. The N- and C-terminal domains of EBNA1, which are connected by internal glycine/alanine rich short repeat sequences of various sizes, show sequence divergence across EBV strains isolated from around the world. At least five subtypes have been described, according to the amino acid at residue 487: P-ala, P-thr, V-val, V pro, and V-leu. Whether the variations of EBNA-1 contribute to the pathogenesis of EBV or simply reflect the geographical distribution of EBV remain to be investigated. Furthermore, the cell effects conferred by EBNA1 subtypes that differ from that of the B95.8 prototype, which belongs to the P-ala subtype, remain to be elucidated. In this study, PCR was amplified with the full-length V val EBNA1 gene from the CG3 cell line, an EBV-carrying lymphoblastoid cell line derived from a Taiwanese chronic myeloid leukemia patient. Plasmids expressing His-tagged EBNA1 fusion proteins in E. coli were constructed and used to raise antibodies in rabbit. The V-val EBNA1 gene was then cloned into a eukaryotic expression vector and successfully expressed in the transfected cultured cells. Expression of V-val EBNA1 rendered 293 cells able to undergo serum-independent cell proliferation, providing them with anti-apoptotic abilities, which are two characteristics of cancer cells. These data suggested that use of EBNA1 originally derived from tumor cells, rather than the more commonly utilized prototype, when investigating the potential role of EBNA1 in the oncogenesis of EBV-associated malignancies, is crucial. PMID- 25434294 TI - Cancer epigenetics: now harvesting fruit and seeding for common diseases. PMID- 25434293 TI - The effect of changes in visibility and price on fruit purchasing at a university cafeteria in Lima, Peru. AB - OBJECTIVE: To determine the effect of increasing fruit visibility, adding information and lowering price on fruit purchasing at a university cafeteria in Lima, Peru. DESIGN: Quasi-experimental pilot study of a three-phase stepped intervention. In Phase 1, fruit was displayed >3 m from the point of purchase with no additional information. Phase 2 consisted in displaying the fruit near the point of purchase with added health and price information. Phase 3 added a 33% price reduction. The duration of each phase was 3 weeks and phases were separated by 2-week breaks. Primary outcomes were total pieces of fruit and number of meals sold daily. SETTING: A university cafeteria in Lima, Peru. SUBJECTS: Approximately 150 people, students and non-student adults, who purchased food daily. Twelve students participated in post-intervention interviews. RESULTS: Fruit purchasing doubled from Phase 1 to Phase 3 (P<0.01) and remained significant after adjusting for the number of meals sold daily (P<0.05). There was no evidence of a difference in fruit sold between the other phases. Females purchased 100% of the fruit in Phase 1, 82% in Phase 2 and 67% in Phase 3 (P<0.01). Males increased their purchasing significantly between Phase 1 and 3 (P<0.01). Non-student adults purchased more fruit with each phase (P<0.05) whereas students did not. Qualitatively, the most common reason for not purchasing fruit was a marked preference to buy unhealthy snack foods. CONCLUSIONS: Promoting fruit consumption by product placement close to the point of purchase, adding health information and price reduction had a positive effect on fruit purchasing in a university cafeteria, especially in males and non student adults. PMID- 25434295 TI - Morphology of the fetal bladder during the second trimester: comparing genders. AB - OBJECTIVES: The aim of the present study was to determine, by histological and stereological analysis, whether there are between-gender structural differences in the bladder in the second gestational trimester in human fetuses. MATERIAL AND METHODS: Forty bladders, which were obtained from 40 human fetuses (20 males and 20 females) ranging in age from 13 to 23 weeks post-conception (WPC), were studied. The fetuses were macroscopically well preserved, without anomalies of the urinary and genital systems; the cases with syndromes were abandoned. The bladders were dissected and embedded in paraffin, from which 5-MUm thick sections were obtained and stained with: Masson's trichrome, to quantify connective and smooth muscle tissue; Weigert's resorcin fuchsin, to observe elastic fibers; picrosirius red with polarization, to observe collagen; and anti-beta III tubulin antibody, to observe the bladder nerves. The images were captured with an Olympus BX51 microscope and Olympus DP70 camera. The stereological analysis was performed with the Image Pro and Image J programs, using a grid to determine volumetric densities (Vv). Means were statistically compared using simple linear regression and the paired t-test (P<0.05). RESULTS: The fetuses weighed between 60 and 490 g, and had crown-rump lengths between 9.5 and 20.4 cm. No elastic system fibers were observed in any bladders. Quantitative analysis indicated no differences in the Vv of the smooth muscle cells in the male bladders (26.19-50.16%; mean=35.66%) compared to the female ones (30.60-45.63%; mean=38.73%) (P=0.740) and there were also no differences in the Vv of the connective tissue in females (40.52-60.40%; mean=50.69%) and males (38.84-70.16%; mean=57.04%) (P=0.0506). There were no differences observed in the distribution of the nerves and collagen between the genders. CONCLUSION: The histological analysis of the smooth muscle, collagen, nerves and connective tissue of the developing bladders revealed that there are no gender differences during weeks 13-23 of gestation. PMID- 25434296 TI - Commentary to 'Multidisciplinary consensus on the classification of prenatal and postnatal urinary tract dilation (UTD classification system)'. PMID- 25434298 TI - Editorial comment. PMID- 25434300 TI - Ecosystem regime change inferred from the distribution of trace metals in Lake Erie sediments. AB - Many freshwater and coastal marine ecosystems across the world may have undergone an ecosystem regime change due to a combination of rising anthropogenic disturbances and regional climate change. Such a change in aquatic ecosystems is commonly seen as shifts in algal species. But considerably less detail is known about the eutrophication history in terms of changes in algal productivity, particularly for a large lake with a great deal of spatial variability. Here we present an analysis of trace metals (Cu, Ni, Cd, and Pb) on a sediment core recovered from Lake Erie, off the Vermilion coast of northern Ohio, USA, to reconstruct the eutrophication history of the lake over the past 210 years. Following a slow eutrophication during European settlement, Lake Erie experienced a period of accelerated eutrophication, leading to an ecosystem regime transition into a eutrophic lake state in 1950. Our results suggested that the lake's biological productivity has ever since maintained fairly high even though a significant input reduction was realized from rigorous nutrient abatements that began as early as in 1969. This work underscored the role of in-lake biogeochemical cycling in nutrient dynamics of this already eutrophic lake. PMID- 25434299 TI - Subjective deficits of attention, cognition and depression in patients with narcolepsy. AB - OBJECTIVE: Patients with narcolepsy often complain about attention deficits in everyday situations. In comparison with these subjective complaints, deficits in objective testing are subtler. The present study assessed the relationships between subjective complaints, objectively measured cognitive performance, disease-related variables, and mood. PATIENTS/METHODS: A total of 51 patients with narcolepsy and 35 healthy controls responded to questionnaires regarding subjectively perceived attention deficits, sleepiness, anxiety and depression. Moreover, they performed an extensive neuropsychological assessment tapping into attention, executive functions, and memory. RESULTS: Patients rated their level of attention in everyday situations to be relatively poor. In an objective assessment of cognitive functioning, they showed only slight attention and executive function deficits. The subjective ratings of attention deficits significantly correlated with ratings of momentary sleepiness, anxiety, and depression, but not with objectively measured cognitive performance. Momentary sleepiness and depression predicted almost 39% of the variance in the ratings of subjectively perceived attention deficits. CONCLUSION: The present study showed that sleepiness and depression, more than objective cognitive deficits, might play a role in the subjectively perceived attention deficits of patients with narcolepsy. The results suggested that when counselling and treating patients with narcolepsy, clinicians should pay attention to potential depression because subjective cognitive complaints may not relate to objective cognitive impairments. PMID- 25434301 TI - Serum zinc is associated with plasma leptin and Cu-Zn SOD in elite male basketball athletes. AB - This paper investigates the relationship between plasma trace element and plasma leptin, as well as percent fat mass, in 16 male basketball athletes. Blood samples were obtained before intensive training and 24h after intensive training to measure plasma zinc (Zn), copper (Cu), calcium (Ca), magnesium (Mg), iron (Fe), and leptin levels. High-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglyceride (TG), total and cholesterol (TC) levels were determined using commercially available kits for humans. Subjects presented similar values in terms of age (21.1+/-2.2 years old), body mass index (23.9+/-2.00kg/m(2)), percent body fat (14.40+/-1.52%), plasma hemoglobin (150.1+/-9.4g/L), plasma Zn (17.47+/-1.28MUmol/l), plasma Cu (13.42+/ 1.40MUmol/L), plasma Ca (2.41+/-0.14mmol/L), and plasma Mg (0.96+/-0.02mmol/L). The correlation analysis between degree of plasma leptin and plasma element contents was performed using the SPSS 16.0 software. Plasma Zn correlated positively with plasma leptin (r=0.746, P<0.01), Cu-Zn SOD (r=0.827, P<0.01), and negatively with percent fat mass (r=-0.598, P<0.05) under no-training conditions. Meanwhile, plasma Cu, Ca, Mg, and Fe did not correlate with plasma leptin or percent fat mass (P>0.05). In conclusion, plasma Zn may be involved in the regulation of plasma leptin and may serve as a lipid-mobilizing factor in Chinese men's basketball athletes. PMID- 25434302 TI - A survey on unmanipulated haploidentical hematopoietic stem cell transplantation in adults with acute leukemia. AB - The use of unmanipulated graft is increasingly adopted in the setting of allogeneic hematopoietic stem cell transplantation from haploidentical family donors (haplo-SCT) in acute leukemia (AL). We analyzed the outcome of 229 adult patients with de novo AL, who received an unmanipulated haploidentical transplant as their first allo-SCT between 2007 and 2011. Median follow-up was 30 months. Disease status at transplant was: first complete remission (CR1) for 77, second CR (CR2) for 56, and advanced for 96 patients. One hundred and seventy-one patients received in vivo T-cell depletion by monoclonal antibodies (75%). The 60 day cumulative incidence (CI) of engraftment was 93+/-2%. The 100-day CI of acute graft-versus-host disease (GvHD) was 32+/-3% for grade II-IV, 12+/-3% for grade III-IV. The 3-year CI of chronic GvHD was 34+/-3%. The 3-year CI of non-relapse mortality was 31+/-4% with in vivo T-cell depletion and 17+/-5% without. At 3 years, for patients transplanted in CR1, CR2 or advanced disease leukemia-free survival was 44+/-6, 42+/-7 and 12+/-3%, overall survival was 55+/-6, 51+/-7 and 14+/-4% and CI of relapse was 32+/-6, 24+/-6 and 61+/-5%, respectively. These data suggest that unmanipulated haplo-SCT is a valid treatment option for adult AL patients in complete remission lacking a matched donor. PMID- 25434304 TI - p38MAPK activation mediates tumor necrosis factor-alpha-induced apoptosis in glioma cells. AB - Gliomas are a type of heterogeneous primary central nervous system tumor, which arise from the glial cells; these types of tumor generally respond poorly to surgery, radiation and conventional chemotherapy. Tumor necrosis factor-alpha (TNF-alpha) has been suggested to produce an antitumor effect by binding to specific receptors on the tumor cell membrane to induce apoptosis. TNF-alpha is known to activate a number of signaling pathways, including extracellular signal regulated protein kinase, c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38MAPK), nuclear factor-kappaB and caspase cascades, depending on the cell type. However, the involvement of p38MAPK signaling in TNF-alpha induced apoptosis in glioma cells remains unclear. In the current study, the role of p38MAPK in TNF-alpha-induced apoptosis in rat glioma C6 cells was investigated. TNF-alpha was observed to induce cell apoptosis and the phosphorylation of p38MAPK in C6 cells. In addition, the inhibition of p38MAPK markedly reduced TNF-alpha-induced apoptosis, while JNK inhibition did not affect apoptosis. Furthermore, p38MAPK transfection altered the cell cycle of glioma cells and increased the rate of apoptosis. It also led to an increase in the level of soluble TNF-alpha in the culture supernatant and membrane TNF receptor I levels in tumor cells. In conclusion, the results of the current study demonstrated that the activation of p38MAPK mediates TNF-alpha-induced apoptosis in glioma C6 cells, suggesting p38MAPK as a potential target for glioma therapy. PMID- 25434305 TI - Highly dispersed Fe2O3 on carbon nanotubes for low-temperature selective catalytic reduction of NO with NH3. AB - Highly dispersed Fe2O3 nanoparticles supported on carbon nanotubes, prepared by a simple ethanol-assisted impregnation method, showed above 90% NO conversion and selectivity at low temperatures (200-325 degrees C). Moreover excellent durability and stability towards SO2/H2O was obtained. PMID- 25434303 TI - Hematopoietic cell transplantation in patients with intermediate and high-risk AML: results from the randomized Study Alliance Leukemia (SAL) AML 2003 trial. AB - The optimal timing of allogeneic hematopoietic stem cell transplantation (HCT) in acute myeloid leukemia (AML) is controversial. We report on 1179 patients with a median age of 48 years who were randomized upfront. In the control arm, sibling HCT was scheduled in the first complete remission for intermediate-risk or high risk AML and matched unrelated HCT in complex karyotype AML. In the experimental arm, matched unrelated HCT in first remission was offered also to patients with an FLT3-ITD (FMS-like tyrosine kinase 3-internal tandem duplication) allelic ratio >0.8, poor day +15 marrow blast clearance and adverse karyotypes. Further, allogeneic HCT was recommended in high-risk AML to be performed in aplasia after induction chemotherapy. In the intent-to-treat (ITT) analysis, superiority of the experimental transplant strategy could not be shown with respect to overall survival (OS) or event-free survival. As-treated analyses suggest a profound effect of allogeneic HCT on OS (HR 0.73; P=0.002) and event-free survival (HR 0.67; P<0.001). In high-risk patients, OS was significantly improved after allogeneic HCT in aplasia (HR 0.64; P=0.046) and after HCT in remission (HR 0.74; P=0.03). Although superiority of one study arm could not be demonstrated in the ITT analysis, secondary analyses suggest that early allogeneic HCT is a promising strategy for patients with high-risk AML. PMID- 25434306 TI - Pyridostigmine prevents haemodynamic alterations but does not affect their nycthemeral oscillations in infarcted mice. AB - The increase in acetylcholine yielded by pyridostigmine (PYR), an acetylcholinesterase inhibitor, was evaluated for its effect on the haemodynamic responses-mean arterial pressure (MAP) and heart rate (HR)-and their nycthemeral oscillation in mice before and one week after myocardial infarction (MI). Mice were anesthetized (isoflurane), and a telemetry transmitter was implanted into the carotid artery. After 5 days of recovery, the MAP and HR were recorded for 48 h (10 s every 10 min). Following this procedure, mice were submitted to surgery for sham or coronary artery ligation and received drinking water (VEHICLE) with or without PYR. Five days after surgery, the haemodynamic recordings were recommenced. Sham surgery combined with VEHICLE did not affect basal MAP and HR; nevertheless, these haemodynamic parameters were higher during the night, before and after surgery. MI combined with VEHICLE displayed decreased MAP and increased HR; these haemodynamic parameters were also higher during the night, before and after surgery. Sham surgery combined with PYR displayed similar results for MAP as sham combined with VEHICLE; however, PYR produced bradycardia. Nevertheless, MI combined with PYR exhibited no change in MAP and HR, but these haemodynamic parameters were also higher during the night, before and after surgery. Therefore, MI decreased MAP and increased HR, while PYR prevented these alterations. Neither MI nor PYR affected nycthemeral oscillations of MAP and HR. These findings indicate that the increase in acetylcholine yielded by PYR protected the haemodynamic alterations caused by MI in mice, without affecting the nycthemeral haemodynamic oscillations. PMID- 25434307 TI - Synergistic antitumor effect of puerarin combined with 5-fluorouracil on gastric carcinoma. AB - Combination chemotherapy is a crucial method in the treatment of gastric cancer. The aim of the present study was to investigate the inhibitory effects of puerarin and 5-fluorouracil (5-FU) on BGC-823 gastric cancer cells in vitro and in vivo. The in vitro growth inhibition of puerarin or 5-FU alone or combined on BGC-823 cells was determined using a cell counting kit 8 (CCK-8) on living cells. Apoptotic morphological features and proteins expression levels were detected by Hoechst 33258 staining, an Annexin V/propidium iodide apoptosis kit and western blot analysis, respectively. Tumor xenografts were established in nude mice and the inhibitory effects and side effects were detected. Results of the CCK-8, Hoechst 33258 staining and flow cytometry revealed that the combined treatment was more effective than the separate treatments. The tumor volume was 90.65% of that of the controls and the mean tumor weight was only 0.125 g at the end of the experiment in the combination group compared with the control group (0.822 g). In addition, it was determined that liver and renal toxicity did not increase in combined treatment. These findings showed that puerarin and 5-FU produced a significant synergic effect on gastric cancer cells, while there was no increase in side effects. PMID- 25434308 TI - Furazolidone induces apoptosis through activating reactive oxygen species dependent mitochondrial signaling pathway and suppressing PI3K/Akt signaling pathway in HepG2 cells. AB - Furazolidone (FZD), a synthetic nitrofuran with a broad spectrum of antimicrobial activities, has been shown to be genotoxic and potentially carcinogenic in several types of cells. However, the proper molecular mechanisms of FZD toxicity remain unclear. This study was aimed to explore the effect of FZD on apoptosis in HepG2 cells and uncover signaling pathway underlying the cytotoxicity of FZD. The results showed that FZD induced apoptosis in HepG2 cells in a dose-dependent manner characterized by nuclei morphology changes, cell membrane phosphatidylserine translocation, poly (ADP-ribose) polymerase (PARP) cleavage and a cascade activation of caspase-9 and -3. FZD could enhance reactive oxygen species (ROS) generation, up-regulate Bax/Bcl-2 ratio, disrupt mitochondrial membrane potential (MMP) and subsequently cause cytochrome c release. Both ROS scavenger (N-acetyl cysteine, NAC) and caspase inhibitors suppressed FZD-induced apoptosis. Furthermore, NAC attenuated FZD-induced ROS generation and mitochondrial dysfunction. Meanwhile, FZD treatment inhibited both the activation and expression of Akt, and PI3K/Akt inhibitor LY294002 promoted FZD-induced apoptosis. On the contrary, PI3K/Akt activator insulin-like growth factor-1 (IGF 1) attenuated lethality of FZD in HepG2 cells. In conclusion, it is first demonstrated that FZD-induced apoptosis in HepG2 cells might be mediated through ROS-dependent mitochondrial signaling pathway and involves PI3K/Akt signaling. PMID- 25434309 TI - Toxicological evaluation of two flavors with modifying properties: 3-((4-amino 2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2,2-dimethyl-N propylpropanamide and (S)-1-(3-(((4-amino-2,2-dioxido-1H benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-3-methylbutan-1-one. AB - A toxicological evaluation of two structurally related flavors with modifying properties, 3-((4-amino-2,2-dioxido-1H- benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2,2 dimethyl-N-propylpropanamide (S6973; CAS 1093200-92-0) and (S)-1-(3-(((4-amino 2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-3 methylbutan-1-one (S617; CAS 1469426-64-9), was completed for the purpose of assessing their safety for use in food and beverage applications. Both compounds exhibited minimal oxidative metabolism in vitro, and in rat pharmacokinetic studies, were poorly absorbed and rapidly eliminated. Neither compound exhibited genotoxic concerns. S6973 and S617 were not found to be mutagenic or clastogenic, and did not induce micronuclei in vitro or in vivo. In subchronic oral toxicity studies in rats, the no-observed-adverse-effect-levels (NOAELs) were 20 mg/kg/day and 100 mg/kg/day (highest doses tested) for S6973 and S617, respectively, when administered as a food ad-mix for 90 consecutive days. Furthermore, S617 demonstrated a lack of maternal toxicity, as well as adverse effects on fetal morphology at the highest dose tested, providing a NOAEL of 1000 mg/kg/day for both maternal toxicity and embryo/fetal development when administered orally during gestation to pregnant rats. PMID- 25434310 TI - Alterations in gene expression during sexual differentiation in androgen receptor knockout mice induced by environmental endocrine disruptors. AB - In the present study, we aimed to explore the effect of environmental endocrine disruptors (EEDs) on sexual differentiation in androgen receptor (AR)-/-, AR+/- and AR+/+ male mice. By using a Cre-loxP conditional knockout strategy, we generated AR knockout mice. By mating flox-AR female mice with AR-Cre male mice, the offspring male mice which were produced were examined. Mice not subjected to any type of intervention were used as the controls. Furthermore, male mice of different genotypes were selected and further divided into subgroups as follows: the control group, bisphenol A (BPA) group and the dibutyl phthalate [corrected] (DBP) group. The expression of the Wilms tumor 1 (WT1), lutropin/choriogonadotropin receptor (LHR), 17-beta-hydroxysteroid dehydrogenase type 3 (17betaHSD3) and steroid-5-alpha-reductase, alpha polypeptide 2 (SRD5A2) genes was determined by RT-qPCR and western blot analysis. There was no statistically significant difference in the weight of the mice between the control group and the knockout group (P>0.05). The results revealed that, compared with the control group, in the knockout group, anogenital distance was shortened, and testicular weight and testosterone levels were decreased; estradiol levels were elevated; the differences were statistically significant (P<0.05). In the group of AR+/- male mice exposed to 100 mg/l EEDs, hypospadias was successfully induced, suggesting that EEDs are involved in the embryonic stage of sexual development in male mice. The quantitative detection of WT1, LHR, 17betaHSD3 and SRD5A2 gene expression by RT-qPCR and western blot analysis indicated that these genes were significantly downregulated in the mice in the BPA group. In conclusion, exposure to EEDs induces hypospadias in heterozygous and wild-type male mice offspring during sexual differentiation, but has no effect on homozygous offspring. Therefore, EEDs play an important role during the third stage of sexual differentiation. PMID- 25434311 TI - Saudi gastroenterology association position statement on privilege and credentialing for performing endoscopic retrograde cholangiopancreatography in Saudi Arabia. PMID- 25434312 TI - Hepatitis B management: it is time to change the strategy. PMID- 25434313 TI - Transarterial therapy: an evolving treatment modality of hepatocellular carcinoma. AB - Liver cancer is the fifth most common cancer in men, the seventh most common in women, and the third most common cause of death from cancer worldwide. Only 30 40% of liver cancer patients present early enough to undergo curative treatments such as surgery or liver transplantation. Local treatment with radiofrequency ablation or ethanol injection is often reserved for non-surgical candidates with early stages of disease. Transarterial embolization has become a widely accepted treatment for asymptomatic patients with unresectable lesions. This review discusses in details the three major forms of transarterial therapies: Bland embolization, chemoembolization, and radioembolization. PMID- 25434315 TI - Comparison of the antiviral effects of different nucleos(t)ide analogues in chinese patients with chronic hepatitis B: a head-to-head study. AB - BACKGROUND/AIMS: To assess the antiviral efficacy of lamivudine (LAM), entecavir (ETV), telbivudine (LDT), and lamivudine and adefovir dipivoxil (CLA) combination in previously untreated hepatitis B patients at different time points during a 52 week treatment period. PATIENTS AND METHODS: A total of 164 patients were included in this prospective, open-label, head-to-head study. Serum levels of alanine transaminase (ALT), hepatitis B virus (HBV) DNA, and hepatitis B e antigen (HBeAg) were measured at baseline, and at 12, 24, and 52 weeks of treatment. RESULTS: Median reductions in serum HBV DNA levels at 52 weeks (log 10 copies/mL) were as follows: LAM, 3.98; ETV, 3.89; LDT, 4.11; and CLA, 3.36. The corresponding HBV DNA undetectability rates were 83%, 96%, 91%, and 89%, respectively. These two measures showed no significant intergroup differences. Clinical efficacy appeared related to HBV DNA level reduction after 24 weeks of therapy. Patients were divided into three groups based on HBV DNA levels at week 24: Undetectable (<10(3) copies/mL), detectable but <10(4) copies/mL, and >10(4) copies/mL. Patients with levels below quantitation limit (QL) were analyzed at 52 weeks for HBV DNA undetectability rate (94%), ALT normalization rate (83%), and viral breakthrough rate (0%). The corresponding values in the QL-10(4) copies/mL group were 50%, 75%, and 13%, whereas those in the above 10(4) copies/mL group were 53%, 65%, and 18%. There were significant differences at week 52 for HBV DNA levels and viral breakthrough rate between the three groups. CONCLUSIONS: Different nucleos(t)ide (NUC) analogues tested exhibited no significant differences in effectiveness for Chinese NUC-naive HBV patients during 1-year treatment period. PMID- 25434316 TI - Efficacy and safety of gum chewing in adjunct to high-dose senna for bowel cleansing before colonoscopy: a single-blind randomized controlled trial. AB - BACKGROUND/AIMS: Inadequate bowel cleaning leads to a suboptimal colonoscopic examination. Gum chewing has been reported to have a favorable effect on postoperative bowel functions. We conducted this study to establish if gum chewing added to high-dose senna before colonoscopy promotes bowel cleaning. PATIENTS AND METHODS: In this randomized controlled study, consecutive outpatients scheduled for elective colonoscopy were randomized into two groups. Group 1 patients (n = 65) used senna solution 150 mL (300 mg senna) the night before colonoscopy. The patients also used sennoside tablet 80 mg daily for 3 days before the colonoscopy. Patients in group 2 (n = 64) were additionally advised to chew sugarless gum half an hour three-times daily after meals for these 3 days. The overall quality of colonoscopy cleaning was evaluated using the Aronchick scale by a single endoscopist who was blinded to the intervention. Difficulty of procedure, patients' tolerance, and adverse events were also evaluated. RESULTS: A total 129 patients were enrolled in the study. Superior cleaning was found in gum chewing group when compared with other group particularly in the cecum and ascending colon. Cecal intubation time was significantly shorter in the gum-chewing group (8.6 +/- 5.1 and 7.1 +/- 2.8 min, P = 0.03). Adverse events were more common in group 1 compared to the gum-chewing group. CONCLUSIONS: Gum chewing enhances colonoscopy bowel preparation quality. Moreover, it is a physiologically sound, safe, and an inexpensive part of the colonoscopy bowel preparation. Gum chewing could be advised in addition to high dose senna containing bowel preparation. PMID- 25434317 TI - Which clip? A prospective comparative study of retention rates of endoscopic clips on normal mucosa and ulcers in a porcine model. AB - BACKGROUND/AIM: There are currently no data on the relative retention rates of the Instinct clip, Resolution clip, and QuickClip2Long. Also, it is unknown whether retention rate differs when clips are applied to ulcerated rather than normal mucosa. The aim of this study is to compare the retention rates of three commonly used endoscopic clips. MATERIALS AND METHODS: Six pigs underwent upper endoscopy with placement of one of each of the three types of clips on normal mucosa in the gastric body. Three mucosal resections were also performed to create "ulcers." Each ulcer was closed with placement of one of the three different clips. Repeat endoscopy was performed weekly for up to 4 weeks. RESULTS: Only the Instinct and Resolution clips remained attached for the duration of the study (4 weeks). At each time point, a greater proportion of Instinct clips were retained on normal mucosa, followed by Resolution clips. QuickClip2Long had the lowest retention rate on normal mucosa. Similar retention rates of Instinct clips and Resolution clips were seen on simulated ulcers, although both were superior to QuickClip2Long. However, the difference did not reach statistical significance. All QuickClip2Long clips were dislodged at 4 weeks in both the groups. CONCLUSIONS: The Resolution and Instinct clips have comparable retention rates and both appeared to be better than the QuickClip2Long on normal mucosa-simulated ulcers; however this did not reach statistical significance. Both the Resolution clip and the Instinct clip may be preferred in clinical situations when long-term clip attachment is required, including marking of tumors for radiotherapy and anchoring feeding tubes or stents. Either of the currently available clips may be suitable for closure of iatrogenic mucosal defects without features of chronicity. PMID- 25434314 TI - Overlap syndromes: an emerging diagnostic and therapeutic challenge. AB - Overlap syndrome in hepatology is emerging as a diagnostic and therapeutic challenge, which is further complicated by the present gaps in the information regarding the immunopathogenesis of these diseases. The present review represents a concise review of literature on overlap syndromes with emphasis on prevalence, etiopathogenesis, clinical presentation, diagnosis, and management of true overlap syndromes. PMID- 25434318 TI - Efficacy of spyglass-guided electrohydraulic lithotripsy in difficult bile duct stones. AB - BACKGROUND/AIMS: We aimed to evaluate the efficacy and safety of Spyglass-guided electrohydraulic lithotripsy (EHL) for difficult common bile duct stones (CBD) not amenable to conventional endoscopic therapy. DESIGN: A retrospective study evaluating the efficacy of Spyglass-guided EHL in treating difficult CBD stones, in a single tertiary care center. PATIENTS AND METHODS: All patients who underwent Spyglass-guided EHL from 2012 to 2013 were compared with a historical cohort who had ECSWL. RESULTS: A total number of 13 patients underwent Spyglass guided EHL, 8 (61.5%) of them were males. The mean age was 46.5 +/- 5.6 years. Bile duct clearance was achieved in 13 (100%) of them. Seventy-six percent required only one Endoscopic Retrograde Cholangiopancreatography (ERCP) to clear the CBD, 7.7% required two ERCPs, and 15.4% required three ERCPs. Adverse effects (cholangitis) occurred in one patient (10%), whereas only 30 patients (64.4%) of the ESWL group had complete CBD stone clearance. Thirty-seven percent required one ERCP to clear the CBD, 35.6% required two ERCPs, and 20% required three ERCPs. Adverse effects happened in seven (15.5%) patients, where five (11%) had cholangitis and two (4.4%) had pancreatitis. CONCLUSION: Although a retrospective design with a small sample size, we concluded that Spyglass-guided EHL is an effective procedure in treating difficult CBD stones. PMID- 25434319 TI - Phospholipase C epsilon 1 (PLCE1) haplotypes are associated with increased risk of gastric cancer in Kashmir Valley. AB - BACKGROUND/AIM: Phospholipase C epsilon 1 (PLCE1) plays a crucial role in carcinogenesis and progression of several types of cancers. A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus. The aim of the present study was to investigate the role of three potentially functional SNPs (rs2274223A > G, rs3765524C > T, and rs7922612C > T) of PLCE1 in gastric cancer patients from Kashmir Valley. PATIENTS AND METHODS: The study was conducted in 108 GC cases and 195 healthy controls from Kashmir Valley. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism method. Data were statistically analyzed using c2 test and logistic regression models. A P value of less than 0.05 was regarded as statistically significant. RESULTS: The frequency of PLCE1 A2274223C3765524T7922612, G2274223C3765524T7922612 , and G2274223T3765524C7922612 haplotypes were higher in patients compared with controls, conferred high risk for GC [odds ratio (OR) =6.29; P = 0.001; Pcorr = 0.003], (OR = 3.23; P = 0.011; Pcorr = 0.033), and (OR = 5.14; P = 0.011; Pcorr = 0.033), respectively. Smoking and salted tea are independent risk factors for GC, but we did not find any significant modulation of cancer risk by PLCE1 variants with smoking or excessive consumption of salted tea. CONCLUSION: These results suggest that variation in PLCE1 may be associated with GC risk in Kashmir Valley. PMID- 25434320 TI - Efficacy and safety of drotaverine hydrochloride in irritable bowel syndrome: a randomized double-blind placebo-controlled study. AB - BACKGROUNDS/AIMS: To study the efficacy and safety of drotaverine hydrochloride (HCl) 80 mg tablet given thrice a day in the symptomatic relief of patients with irritable bowel syndrome (IBS). PATIENTS AND METHODS: The study was a multicentric, randomized, double-blind, placebo-controlled parallel group study performed at three centers. The patients who fulfilled Rome II Criteria of IBS were included in the study. A total of 180 patients with IBS were randomized to drotaverine and placebo treatment groups. Abdominal pain and stool frequency were measured every week in both the groups for all the 4 weeks of treatment duration. Subject Global Assessment of Relief (SGA) of IBS symptoms was assessed at the end of the study. Appropriate statistical analysis was done using SPSS software. STATISTICAL ANALYSIS USED: Mann-Whitney U-test (two-tailed), Wilcoxon signed ranks test, and McNemar tests. RESULTS: Pain frequency decreased significantly (P < 0.01) in 22 (25.9%), 51 (60%), and 66 (77.7%) patients in the drotaverine group, at the end of 2nd, 3rd, and 4th weeks, respectively, as compared with 8 (9.4%), 18 (21.2%), and 26 (30.6%) in the placebo group. Pain severity scores also decreased significantly in the drotaverine group 66 (77.7%) as compared with placebo 26 (30.6%) after 4 weeks. Drotaverine HCl was shown to provide significant improvement (P < 0.01) in global relief in abdominal pain as perceived by the patient (85.9% vs 39.5%) and the clinician (82.4% vs 36.5%) in the drotaverine group as compared with placebo. There is significant (P < 0.01) improvement in stool frequency in drotaverine HCl treatment group as compared with placebo. The drug is well tolerated without any major side effects. CONCLUSIONS: A 4-week treatment with drotaverine significantly improves abdominal symptoms in patients with IBS. PMID- 25434321 TI - Pneumomediastinum following anastomotic leakage in colon surgery: a case report and literature review. AB - We are presenting the case of a 62-year-old woman who developed a pneumomediastinum as a complication of anastomotic leakage (AL) following laparoscopic sigmoid resection due to diverticulitis. The patient presented with retroperitoneal air, pneumomediastinum, emphysematous gall bladder, air in the wall of stomach, and proximal small bowel. There were a few tiny air bubbles around the anastomosis. We discuss this unusual clinical presentation of intraperitoneal and extraperitoneal air as a presenting sign of AL. PMID- 25434322 TI - IgG4-related sclerosing mesenteritis in a 7-year-old Saudi girl. AB - Sclerosing mesenteritis (SM) is a rare, benign inflammatory disorder of unknown etiology, affecting the membranes of the digestive tract that involves lymphoplasmacytic inflammation, fat necrosis, and fibrosis of the mesentery. We report a child patient with a history of recurrent abdominal pain and fever who was found to have an intra-abdominal mass suspicious for malignancy. A tissue biopsy revealed the diagnosis of SM associated with IgG4-related systemic disease. The patient is currently maintained on 5 mg prednisone daily and no recurrence of symptoms was noted during the 24-month follow-up period. We emphasize, therefore, that SM can present clinical challenges and the presence of SM should cue clinicians to search for other coexisting autoimmune disorders that can have various outcomes. PMID- 25434323 TI - Reversible chalcogen-atom transfer to a terminal uranium sulfide. AB - The reaction of elemental S or Se with [K(18-crown-6)][U(S)(NR2)3] (1) results in the formation of the new uranium(IV) dichalcogenides [K(18-crown-6)][U(eta(2) S2)(NR2)3] (2) and [K(18-crown-6)][U(eta(2)-SSe)(NR2)3] (5). The further addition of elemental S to 2 results in the formation of [K(18-crown-6)][U(eta(3) S3)(NR2)3] (3). Complexes 2, 3, and 5 can be reconverted into 1 via the addition of R3P (R = Et, Ph), concomitant with the formation of R3P?E (E = S, Se). PMID- 25434324 TI - Manganese, the stress reliever. AB - Convergent evidence has emerged over the past decade to highlight the role of manganese as a key player in the defenses that many organisms are building to fight oxidative stress. For redox processes replacing iron by manganese requires adaptation at different levels. The aim of this perspective is to summarize recent important observations and to analyze the implications of the present knowledge for resolving future issues. PMID- 25434325 TI - Anxiety and Attentional Bias in Preschool-Aged Children: An Eyetracking Study. AB - Extensive research has examined attentional bias for threat in anxious adults and school-aged children but it is unclear when this anxiety-related bias is first established. This study uses eyetracking technology to assess attentional bias in a sample of 83 children aged 3 or 4 years. Of these, 37 (19 female) met criteria for an anxiety disorder and 46 (30 female) did not. Gaze was recorded during a free-viewing task with angry-neutral face pairs presented for 1250 ms. There was no indication of between-group differences in threat bias, with both anxious and non-anxious groups showing vigilance for angry faces as well as longer dwell times to angry over neutral faces. Importantly, however, the anxious participants spent significantly less time looking at the faces overall, when compared to the non-anxious group. The results suggest that both anxious and non-anxious preschool-aged children preferentially attend to threat but that anxious children may be more avoidant of faces than non-anxious children. PMID- 25434327 TI - Early intrahepatic recurrence of hepatocellular carcinoma after hepatectomy treated with re-hepatectomy, ablation or chemoembolization: a prospective cohort study. AB - AIMS: To observe the outcomes of various treatments for patients with early intrahepatic recurrent hepatocellular carcinoma (HCC) after partial hepatectomy. METHODS: A total of 629 patients with intrahepatic recurrent HCC within Milan criteria following hepatectomy were prospectively collected between November 2004 and May 2010. Overall survival (OS) and recurrence to death survival (RTDS) were analyzed by the Kaplan-Meier method and log-rank test. Cox regression analysis was used for multivariate analyses. RESULTS: The 5-year OS and RTDS rates were 64.5%, 43.0%; 37.0%, 26.7%; 27.7% and 8.3% for patients who received re hepatectomy (n = 128), percutaneous radiofrequency ablation (PRFA, n = 162) and transarterial chemoembolization (TACE, n = 339) (re-hepatectomy vs. TACE, P < 0.001, <0.001; vs. PRFA, P = 0.005, 0.008; PRFA vs. TACE, P < 0.001, <0.001). The independent predictors of OS and RTDS were tumor number (hazard ratio: 1.54, 95% confidence interval: 1.18-2.00; 1.57, 1.21-2.04), alpha fetoprotein >20 ng/mL (1.64, 1.24-2.17; 1.66, 1.26-2.20), presence of varices (1.69, 1.28-2.22; 1.61, 1.23-2.10) and Edmondson-Steiner grade III-IV (1.66, 1.17-2.35; 1.70, 1.20-2.40) at the initial stage; and tumor number (1.34, 1.04-1.73; 1.32, 1.03-1.70), time to recurrence (TTR) (3.46, 2.58-4.65; 1.59, 1.19-2.14) and treatment for recurrence (TACE: 3.18, 2.16-4.66; 2.95, 2.02-4.31; PRFA: 1.49, 0.97-2.29; 1.44, 0.94-2.19). CONCLUSIONS: For early intrahepatic recurrent HCC, re-hepatectomy achieved best outcome. It produced similar result as PRFA for patients with more invasive primary tumors and underlying cirrhosis/varices. TACE had worst prognosis which was only suitable for multifocal recurrence and TTR <=1 year. PMID- 25434328 TI - Expression and clinical value of peroxiredoxin-1 in patients with pancreatic cancer. AB - BACKGROUND: Peroxiredoxin-1 (Prx-1) is an important protector for redox damage and its abnormal expression is continually reported in various tumors. This study aims to investigate the expression status of Prx-1 and evaluate its clinical value in pancreatic cancer. METHODOLOGY: Immunohistochemistry was used to detect Prx-1 expression in pancreatic cancer tissues and para-cancerous tissues. Enzyme linked immunosorbent assay (ELISA) method was applied to detect the serum Prx-1 levels. RESULTS: The immunohistochemical results indicated that positive rate of Prx-1 was (p < 0.05) higher in pancreatic cancer tissues (74.4%) than in para cancerous tissues (37.2%). Prx-1 expression was positively correlated with vascular endothelial growth factor (VEGF) and microvessel density (MVD) in cancer tissues. The ELISA results showed that patients with pancreatic cancer had a higher serum Prx-1 level than healthy subjects (31.2 +/- 13.5 vs. 13.2 +/- 11.9 ng/ml, p < 0.001). Prx-1 expression was correlated with aggressive clinicopathological parameter. The combination of serum Prx-1 and CA19-9, the area under the curve (AUC) was significantly higher than Prx-1 separate. Positive Prx-1 expression was correlated with disappointing overall survival (OS) (p = 0.002) and disease-free survival (DFS) (p < 0.001). Multivariate analysis showed that Prx-1 staining as an independent biomarker of poor OS (p = 0.035) and DFS (p < 0.001). CONCLUSION: These findings suggest that the levels of Prx-1 expression are significantly increased in pancreatic cancer. The up-regulated Prx-1 is closely related to tumor angiogenesis and acts as a promising tumor marker for diagnosis and prognosis of pancreatic cancer. PMID- 25434326 TI - Local delivery of VEGF and SDF enhances endothelial progenitor cell recruitment and resultant recovery from ischemia. AB - Biomaterials may improve outcomes of endothelial progenitor-based therapies for the treatment of ischemic cardiovascular disease, due to their ability to direct cell behavior. We hypothesized that local, sustained delivery of exogenous vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF) from alginate hydrogels could increase recruitment of systemically infused endothelial progenitors to ischemic tissue, and subsequent neovascularization. VEGF and SDF were found to enhance in vitro adhesion and migration of outgrowth endothelial cells (OECs) and circulating angiogenic cells (CACs), two populations of endothelial progenitors, by twofold to sixfold, and nearly doubled recruitment to both ischemic and nonischemic muscle tissue in vivo. Local delivery of VEGF and SDF to ischemic hind-limbs in combination with systemic CAC delivery significantly improved functional perfusion recovery over OEC delivery, or either treatment alone. Compared with OECs, CACs were more responsive to VEGF and SDF treatment, promoted in vitro endothelial sprout formation in a paracrine manner more potently, and demonstrated greater influence on infiltrating inflammatory cells in vivo. These studies demonstrate that accumulation of infused endothelial progenitors can be enriched using biomaterial-based delivery of VEGF and SDF, and emphasize the therapeutic benefit of using CACs for the treatment of ischemia. PMID- 25434331 TI - Cation-pi interactions in iminium ion activation: correlating quadrupole moment & enantioselectivity. AB - A linear correlation between quadrupole moment (Qzz) and enantioselectivity (es) advocates the notion that a cation-pi interaction is a contributing factor in the addition of uncharged nucleophiles to iminium salts derived from MacMillan's 1st generation catalyst. The quadrupole moment of the aryl shielding group is a useful qualitative parameter for predicting selectivity (Qzz < 0 -> high es). PMID- 25434329 TI - The arterial supply of the tendon of the long head of the biceps brachii in the human: a combined anatomical and radiological study. AB - PURPOSE: Arthroscopic repair of superior labral anterior to posterior (SLAP) lesions is often associated with a prolonged period of pain during the rehabilitation process. This might possibly be due to hypoxia in the biceps tendon anchor caused by sutures. The purpose of the study was to investigate the arterial supply of the long head of the biceps brachii tendon (LHBT) that may be impaired by surgery in the region of the biceps tendon anchor. METHODS: On 20 human formalin-fixed bodies, the anterior circumflex humeral artery (ACHA) was located and followed into the intertubercular groove until it reached the LHBT. On 10 fresh-frozen anatomic specimens of the upper extremities, contrast medium was injected into the axillary artery, a 3D scan was performed, and multiplanar reconstructed (MPR) slices were generated. A set of maximum intensity projection (MIP) reconstructions from 10 computed tomography angiographies (CTA) of the upper extremities was used to confirm the findings of the 3D scan. RESULTS: All anatomical dissections and radiological investigations revealed that the proximal portion of the LHBT was consistently supplied by an ascending branch of the ACHA. No artery was found to supply the biceps tendon anchor from the proximal aspect. CONCLUSIONS: As the arterial supply of the LHBT is mainly provided by the ACHA, which enters the glenohumeral joint from the distal aspect, surgery at the bony origin of the LHBT may not interfere with this specific vessel. PMID- 25434333 TI - Milk fatty acid composition, rumen microbial population, and animal performances in response to diets rich in linoleic acid supplemented with chestnut or quebracho tannins in dairy ewes. AB - The aim of the study was to evaluate milk fatty acid (FA) profile, animal performance, and rumen microbial population in response to diets containing soybean oil supplemented or not with chestnut and quebracho tannins in dairy ewes. Eighteen Comisana ewes at 122+/-6 d in milking were allotted into 3 experimental groups. Diets were characterized by chopped grass hay administered ad libitum and by 800 g/head and day of 3 experimental concentrates containing 84.5 g of soybean oil/kg of dry matter (DM) and 52.8 g/kg of DM of bentonite (control diet), chestnut tannin extract (CHT diet), or quebracho tannin extract (QUE diet). The trial lasted 4 wk. Milk yield was recorded daily, and milk composition and blood parameters were analyzed weekly. At the end of the experiment, samples of rumen fluid were collected to analyze pH, volatile fatty acid profile, and the relative proportions of Butyrivibrio fibrisolvens and Butyrivibrio proteoclasticus in the rumen microbial population. Hepatic functionality, milk yield, and gross composition were not affected by tannin extracts, whereas milk FA composition was characterized by significant changes in the concentration of linoleic acid (CHT +2.77% and QUE +9.23%), vaccenic acid (CHT +7.07% and QUE +13.88%), rumenic acid (CHT -1.88% and QUE +24.24%), stearic acid (CHT + 8.71% and QUE -11.45%), and saturated fatty acids (CHT -0.47% and QUE -3.38%). These differences were probably due to the ability of condensed versus hydrolyzable tannins to interfere with rumen microbial metabolism, as indirectly confirmed by changes in the relative proportions of B. fibrisolvens and B. proteoclasticus populations and by changes in the molar proportions of volatile fatty acids. The effect of the CHT diet on the milk FA profile and microbial species considered in this trial was intermediate between that of QUE and the control diet, suggesting a differential effect of condensed and hydrolyzable tannins on rumen microbes. Compared with control animals, the presence of B. fibrisolvens increased about 3 times in ewes fed CHT and about 5 times in animals fed QUE. In contrast, the abundance of B. proteoclasticus decreased about 5- and 15-fold in rumen liquor of ewes fed CHT and QUE diets, respectively. The use of soybean oil and a practical dose of QUE or CHT extract in the diet of dairy ewes can be an efficient strategy to improve the nutritional quality of milk. PMID- 25434332 TI - Across-country test-day model evaluations for Holstein, Nordic Red Cattle, and Jersey. AB - Three random regression models were developed for routine genetic evaluation of Danish, Finnish, and Swedish dairy cattle. Data included over 169 million test day records with milk, protein, and fat yield observations from over 8.7 million dairy cows of all breeds. Variance component analyses showed significant differences in estimates between Holstein, Nordic Red Cattle, and Jersey, but only small to moderate differences within a breed across countries. The obtained variance component estimates were used to build, for each breed, their own set of covariance functions. The covariance functions describe the animal effects on milk, protein, and fat yields of the first 3 lactations as 9 different traits, assuming the same heritabilities and a genetic correlation of unity across countries. Only 15, 27, and 7 eigenfunctions with the largest eigenvalues were used to describe additive genetic animal effects and nonhereditary animal effects across lactations and within later lactations, respectively. These reduced-rank covariance functions explained 99.0 to 99.9% of the original variances but reduced the number of animal equations to be solved by 44%. Moderate rank reduction for nonhereditary animal effects and use of one-third-smaller measurement error correlations than obtained from variance component estimation made the models more robust against extreme observations. Estimation of the genetic levels of the countries' subpopulations within a breed was found sensitive to the way the breed effects were modeled, especially for the genetically heterogeneous Nordic Red Cattle. Means to ensure that only additive genetic effects entered the estimated breeding values were to describe the crossbreeding effects by fixed and random cofactors and the calving age effect by an age * breed proportion interaction, and to model phantom parent groups as random effects. To ensure that genetic variances were the same across the 3 countries in breeding value estimation, as suggested by the variance component estimates, the applied multiplicative heterogeneous variance adjustment method had to be tailored using country-specific reference measurement error variances. Results showed the feasibility of across-country genetic evaluation of cows and sires based on original test-day phenotypes. Nevertheless, applying a thorough model validation procedure is essential throughout the model building process to obtain reliable breeding values. PMID- 25434334 TI - Effect of 2-hydroxy-4-methylthio-butanoic acid on ruminal fermentation, bacterial distribution, digestibility, and performance of lactating dairy cows. AB - The objective of this experiment was to test the effect of a Met analog, 2 hydroxy-4-methylthio-butanoic acid (HMTBa), on ruminal fermentation and microbial protein synthesis, nutrient digestibility, urinary N losses, and performance of dairy cows. Eight multiparous lactating Holstein dairy cows were assigned to 4 levels of HMTBa [0 (control), 0.05, 0.10, and 0.15% (dry matter basis)] in a replicated 4*4 Latin square trial. Experimental periods were 28 d, including 21 d for adaptation. Ruminal ammonia and microbial N were labeled through a 6-d intraruminal infusion of (15)NH4Cl, and microbial protein synthesis in the rumen was estimated using the reticular sampling technique. Treatment had no effect on dry matter intake (28.4 to 29.8kg/d), milk yield (44.1 to 45.3kg/d), feed efficiency, and milk composition. Total-tract apparent digestibility of nutrients was generally not affected by treatment, except digestibility of crude protein and starch decreased quadratically with HMTBa supplementation. Fecal, but not urinary, and total excreta N losses were increased quadratically by HMTBa. Ruminal pH, ammonia concentration, protozoal counts, and the major volatile fatty acids were not affected by treatment. Microbial N outflow from the rumen was linearly increased by HMTBa. 2-Hydroxy-4-methylthio-butanoic acid linearly increased the proportion of Fecalibacterium and quadratically decreased the proportion of Eubacterium in ruminal contents. Of the individual bacterial species, HMTBa increased or tended to increase Prevotella loescheii and Prevotella oralis. 2-Hydroxy-4-methylthio-butanoic acid linearly increased the concentration (and yield) of 15:0 in milk fat. In the conditions of this crossover experiment, HMTBa had no effect on feed intake and performance of dairy cows, decreased dietary crude protein digestibility, and increased microbial N outflow from the rumen. PMID- 25434335 TI - Perceptions and practices of Finnish dairy producers on disbudding pain in calves. AB - Disbudding causes pain-related distress and behavioral changes in calves. Local anesthesia and non-steroidal anti-inflammatory drugs are effective for treating disbudding-related pain. Dairy producers play a key role in whether or not calves to be disbudded are properly medicated. Pain and distress related to disbudding of calves often remains untreated. Thus, we conducted this study to characterize perceptions and practices of dairy producers on disbudding and disbudding-related pain management. A questionnaire was sent to 1,000 randomly selected Finnish dairy producers (response rate: 45%). Our aim was to investigate producer perceptions about disbudding-related pain, the perceived need for pain alleviation before disbudding, and how these perceptions affect the valuing and use of pain alleviation before disbudding. More than 70% of Finnish dairy farms disbud their calves. Producers who ranked disbudding-related pain and need for pain alleviation higher called a veterinarian to medicate calves before disbudding more often than producers who ranked disbudding pain and need for pain alleviation lower. Among respondents who disbudded calves on their farms, 69% stated that disbudding caused severe pain, 63% stated that pain alleviation during disbudding is important, and 45% always had a veterinarian medicate their calves before disbudding. Producers with a herd healthcare agreement with their veterinarian estimated disbudding-related pain to be higher and had a veterinarian medicate calves more often than producers without such an agreement. Producers with tiestall systems and producers who did not use disbudding valued pain alleviation prior to disbudding higher than producers with freestalls and producers who used disbudding. PMID- 25434336 TI - Short communication: determination of potential 5-hydroxymethyl-2-furaldehyde and 2-furaldehyde compounds in follow-on milks and infant formulas using the high performance liquid chromatography method. AB - The aim of present study was to determine the levels of potential 5-hydroxymethyl 2-furaldehyde (HMF) and 2-furaldehyde (F) in 109 baby food samples (60 follow-on milks, 49 cereal- and milk-based infant formulas) obtained from different markets in Ankara (Turkey). Potential HMF and F compounds were determined by HPLC. Mean levels (+/- standard error) of HMF and F of follow-on milk samples were found to be 237.85+/-18.25 and 9.44+/-0.39 ug/100mL, respectively. Regarding the infant formulas, mean levels of HMF and F were found to be 905.41+/-91.94 and 13.22+/ 1.21 ug/100g. As a result, potential HMF was determined in all of the samples; potential F was determined in all the samples except 1. The mean levels of potential HMF and F of infant formulas were higher than mean levels of potential HMF and F of follow-on milks. In addition, HMF and F values of some samples with an imminent expiration date were found to be higher than HMF and F values of the other samples. At present, no limits have been established in the Turkish Food Codex (TFC) for furfural compounds concentrations in infant formula and milks. Establishing limits related to these compounds would be important for protecting the quality of infant foods. PMID- 25434337 TI - Activity and milk compositional changes following experimentally induced Streptococcus uberis bovine mastitis. AB - Milk constituents and physical activity of cows experimentally infected with Streptococcus uberis mastitis were compared with those of uninfected cows. Twelve late-lactation Holsteins cows were paired based on milk production and parity. One cow in each pair was experimentally infected in the right front mammary gland with Strep. uberis. The remaining cow in each pair served as an uninfected control. Real-time analyses of milk constituents provided fat, protein, and lactose percentages at each milking. Pedometers were placed on the left front leg of all cows and activity was measured. Intramammary infections with Strep. uberis reduced milk yield in experimental cows by approximately 1.6kg/d in the first week after challenge compared with control cows. Lactose percentage in milk was reduced on d 3, 4, 5, and 6 after challenge in treatment cows compared with controls. Percentages of fat and protein in milk did not differ between infected and uninfected cows the week after infections were induced. Total steps per day were reduced and minutes resting per day were increased the week after experimental challenge in infected cows compared with control cows. The number of resting bouts did not differ between infected and uninfected cows. Changes in percentage of lactose in milk and animal activity caused by experimentally induced Strep. uberis mastitis were detected by the automated milk analyzer and pedometer systems. PMID- 25434338 TI - Effect of pregnancy and embryonic mortality on milk production in dromedary camels (Camelus dromedarius). AB - The main objective of the present study was to compare milk production in pregnant versus nonpregnant dromedary camels. In addition, we described the effect of embryonic mortality on lactation and measured serum progesterone levels until d 60 to 90 of gestation. Twenty-five multiparous camels were selected in midlactation for 2 studies in consecutive years. Camels were mated naturally when the size of the dominant follicle reached 1.2 to 1.5cm. Pregnancy was diagnosed by ultrasonography and progesterone determination. In the first experiment (Exp 1), 8 of 11 animals conceived at 284+/-21.5d postpartum. Three pregnant dromedaries were given PGF2alpha to induce luteolysis and pregnancy loss on d 62 and spontaneous embryonic loss was detected in 2 camels (on d 27 and 60). Animals were allotted to 3 groups retrospectively: nonpregnant camels (group 1, n=4), pregnant camels (group 2; n=3), and camels with embryonic loss after d 55 (group 3; n=4). In the second study (Exp 2), 14 dromedaries were mated during midlactation. Seven of them failed to conceive (group 1) and 7 became pregnant (group 2). No embryonic loss was detected in Exp 2. Turning points in milk production were identified by change point analysis. In nonpregnant dromedaries (group 1), milk decreased slowly over time without significant change point. In pregnant camels (group 2), a gradual decline until 4 wk after mating was followed by a sudden drop, and the change point model resulted in one breakpoint at d 28+/ 7 and 35+/-3 of gestation in Exp 1 and Exp 2, respectively. In camels with embryonic mortality (group 3, Exp 1), milk yield started to decline similarly as in pregnant animals, but milk production increased gradually after embryonic loss and reached similar levels as in their nonpregnant herdmates. Change point analysis for group 3 resulted in 2 turning points at 30+/-4 and 48+/-4d after conception. Mean length of lactation was shorter by 230 (34.2%) and by 249d (37.6%) and mean total lactation production was decreased by 1,532 (31.6%) and 2,151 kg (44.3%) in pregnant compared with nonpregnant camels in Exp 1 and Exp 2, respectively. We concluded that the calving interval can be shortened by mating during midlactation. However, pregnancy has a strong negative effect on milk production as dromedaries stop lactating by the fourth month of gestation. Following embryonic mortality within 3mo of conception, milk production is restored. PMID- 25434339 TI - Effect of adding a gonadotropin-releasing-hormone treatment at the beginning and a second prostaglandin F2alpha treatment at the end of an estradiol-based protocol for timed artificial insemination in lactating dairy cows during cool or hot seasons of the year. AB - Our hypothesis was that fertility could be increased in a timed artificial insemination (TAI) protocol based on estradiol (E2) and progesterone (P4) by combining GnRH with E2-benzoate at the start of the protocol to increase circulating P4 during preovulatory follicle development and by using 2 prostaglandin F2alpha (PGF) treatments at the end to decrease P4 near TAI. Lactating Holstein cows (n=1,808) were randomly assigned during the cool or hot season of the year to receive TAI (d 0) following 1 of 3 treatments: (1) control: controlled internal drug-release insert + 2mg of E2-benzoate on d -11, PGF on d 4, controlled internal drug-release insert withdrawal + 1.0mg of E2-cypionate on d -2, and TAI on d 0; (2) 2PGF: identical to control protocol with addition of a second PGF treatment on d -2; (3) GnRH: identical to 2PGF protocol with addition of a 100-MUg GnRH treatment on d -11. Pregnancy diagnoses were performed on d 32 and 60 after TAI. Season had major effects on many reproductive measures, with cool season greater than hot season in percentage of cows with corpus luteum (CL) at PGF (62.9 vs. 56.2%), ovulatory follicle diameter (15.7 vs. 14.8mm), expression of estrus (86.7 vs. 79.9%), ovulation following the protocol (89.7 vs. 84.3%), and pregnancies per artificial insemination (P/AI; 45.4 vs. 21.4%). The GnRH protocol increased percentage of cows with CL (control=56.9%; 2PGF=55.8%; GnRH=70.5%) and P4 at PGF (control=3.28+/-0.22; 2PGF=3.35+/-0.22; GnRH=3.70+/ 0.21ng/mL), compared with control and 2PGF protocols. The GnRH protocol increased P/AI at the pregnancy diagnosis at 32d [37.3% (219/595)] and 60d [31% (179/595)] after TAI, compared with control [30.0% (177/604); 25.1% (145/604)], with intermediate results with 2PGF protocol [33.2% (196/609); 28.0% (164/609)]. The positive effects of GnRH treatment on P/AI were only detected during the cool season (GnRH=50.9%; 2PGF=44.2%; control=41.0%) and not during the hot season. In addition, the effect of GnRH was only observed in cows with low P4 (<3ng/mL) at the start of the protocol and not in cows that began the protocol with high P4. Furthermore, presence of CL at PGF interacted with follicle diameter such that cows with a CL at PGF had greater P/AI if they ovulated larger rather than smaller follicles near TAI. Thus, fertility to TAI can be improved by inducing ovulation at the beginning of an E2/P4-based protocol using GnRH treatment, particularly during the cool season of the year and in cows with low P4 at the start of the protocol. PMID- 25434340 TI - Allometric comparison of Georgia dairy heifers on farms and at youth shows. AB - Studies were conducted to determine the relationship between allometric measures of growth of Holstein dairy heifers and placing in the show ring, and to compare differences in growth between Holstein heifers that are shown and not shown. In the first study, 494 Holstein show heifers were evaluated at the 2012 and 2013 Georgia Junior National Livestock Shows. Measurements were obtained for weight, head length, withers height, hip height, thurl width, and tail length. Heifer mass index (HMI), average daily gain (ADG), and age were calculated. In total, 72.5% of Holstein show heifers were underweight. Average ADG was 0.63 kg/d, which is below the industry recommendation of 0.7 to 0.8 kg/d. Variables were ranked and converted to percentages to account for differences in class size. Withers height, head length, and HMI were most indicative of show placing. In the second study, we compared differences between growth patterns of show heifers and non show heifers. An additional 293 non-show Holstein heifers were evaluated on 3 Georgia dairy farms during the same period as the show. In total, 43.3% of non show heifers were underweight. Average ADG for non-show heifers was 0.71 kg/d, which is within the industry recommendation of 0.7 to 0.8 kg/d. Show heifers weighed less for their age than non-show heifers and tended to be taller at the withers than non-show heifers. The HMI scores were similar for younger show and non-show heifers, but older show heifers had lower HMI scores than non-show heifers of the same age. Show heifers had HMI scores that were lower than values calculated from standard growth data. As show heifers matured, ADG decreased, whereas as non-show heifers matured, ADG increased. Youth, leaders, and parents need to be aware of the importance of growing replacement heifers correctly so that heifers calve at 22 to 24 mo of age at an acceptable size and scale and become profitable members of the milking herd. PMID- 25434341 TI - Genetic and environmental effects on early growth and performance in purebred Holstein, Jersey, and reciprocal crossbred calves. AB - For this designed experiment, Holstein * Holstein (n=28), Jersey * Jersey (n=10), Holstein * Jersey (n=15), and Jersey * Holstein (n=15) bull and heifer calves were compared for body weight (BW), dry matter intake, feed efficiency, hip height, BW gain to 42 and 56 d, and days to weaning from birth to 8 wk. All traits were examined for purebred, maternal, and heterotic genetic effects. Purebred genetic effects significantly favored the Holstein breed for BW, dry matter intake, hip height, and BW gain to 42 and 56 d. Heterotic genetic effects were present for dry matter intake and hip height. Calf sex affected BW and BW gain to 56 d. Our results indicate that early calf growth is influenced primarily by purebred effects favoring the Holstein breed and to a lesser extent heterosis. PMID- 25434342 TI - The effect of citrus-derived oil on bovine blood neutrophil function and gene expression in vitro. AB - Research on the use of natural products to treat or prevent microbial invasion as alternatives to antibiotic use is growing. Polymorphonuclear leukocytes (PMNL) play a vital role with regard to the innate immune response that affects severity or duration of mastitis. To our knowledge, effect of cold-pressed terpeneless Valencia orange oil (TCO) on bovine PMNL function has not been elucidated. Therefore, the objective of this study was to investigate the effect of TCO on bovine blood PMNL chemotaxis and phagocytosis capabilities and the expression of genes involved in inflammatory response in vitro. Polymorphonuclear leukocytes were isolated from jugular blood of 12 Holstein cows in mid-lactation and were incubated with 0.0 or 0.01% TCO for 120min at 37 degrees C and 5% CO2, and phagocytosis (2*10(6) PMNL) and chemotaxis (6*10(6) PMNL) assays were then performed in vitro. For gene expression, RNA was extracted from incubated PMNL (6*10(6) PMNL), and gene expression was analyzed using quantitative PCR. The supernatant was stored at -80 degrees C for analysis of tumor necrosis factor alpha. Data were analyzed using a general linear mixed model with cow and treatment (i.e., control or TCO) in the model statement. In vitro supplementation of 0.01% of TCO increased the chemotactic ability to IL-8 by 47%; however, migration of PMNL to complement 5a was not altered. Treatment did not affect the production of tumor necrosis factor-alpha by PMNL. Expression of proinflammatory genes (i.e., SELL, TLR4, IRAK1, TRAF6, and LYZ) coding for proteins was not altered by incubation of PMNL with TCO. However, downregulation of TLR2 [fold change (FC=treatment/control)=-2.14], NFKBIA (FC=1.82), IL1B (FC=-2.16), TNFA (FC=-9.43), and SOD2 (FC=-1.57) was observed for PMNL incubated with TCO when compared with controls. Interestingly, expression of IL10, a well-known antiinflammatory cytokine, was also downregulated (FC=-3.78), whereas expression of IL8 (FC=1.93), a gene coding for the cytokine IL-8 known for its chemotactic function, tended to be upregulated in PMNL incubated with TCO. Incubation of PMNL with TCO enhanced PMNL chemotaxis in vitro. The expression of genes involved in the inflammatory response was primarily downregulated. Results showed that 0.01% TCO did not impair the function of PMNL in vitro. Future studies investigating the use of TCO as an alternative therapy for treatment of mastitis, including dose and duration, for cows during lactation are warranted. PMID- 25434343 TI - A multiarm randomized field trial evaluating strategies for udder health improvement in Swiss dairy herds. AB - The aims of this study were to quantify the effectiveness of specialist advice about udder health in Swiss dairy herds and to compare 3 different udder health improvement strategies against a negative control group. In 2010, 100 Swiss dairy herds with a high (between 200,000 and 300,000 cells/mL) yield-corrected bulk milk somatic cell count (YCBMSCC) were recruited for a 1-yr multiarm randomized field trial. The herds were visited between September and December 2011 to evaluate udder health-management practices and then randomly allocated into 1 of 4 study arms containing 25 herds each. The negative control study arm received neither recommendations for improving udder health nor any active support. The remaining 75 farmers received a herd-specific report with recommendations to improve udder health management. The positive control study arm received no further active support during 2012. The veterinarian study arm received additional support in the form of monthly visits by their herd veterinarian. Finally, the study group study arm received support in the form of bimonthly study group meetings where different topics concerning udder health were discussed. One year later, implementation of recommendations and changes in udder health were assessed. Of the recommendations given, 44.3% were completely implemented, 23.1% partially, and 32.6% were not implemented. No differences in implementation of recommendations were noted between the 3 study arms. At study enrollment, farmers were asked for the study arm of their preference but were subsequently randomly assigned to 1 of the 4 study arms. Farmers that were assigned to the study arm of their preference implemented more recommendations than farmers assigned to a study arm not of their preference. No decrease in the within-herd prevalence of cows that had a high (>=200,000 cells/mL) composite somatic cell count was observed in herds that had a YCBMSCC >=200,000 cells/mL at the start of intervention. However, the 3 study arms with intervention (positive control, the veterinarian, and the study groups) prevented an increase in the within-herd prevalence of cows that had a high somatic cell count in herds with a low YCBMSCC at the start of the intervention compared with the negative control study arm. In the year after sending the report, herds assigned to the study group study arm had a reduced incidence rate of treated mastitis cases in comparison with the year before sending the report. PMID- 25434344 TI - Short communication: 3-phenyllactic acid production in milk by Pediococcus pentosaceus SK25 during laboratory fermentation process. AB - 3-Phenyllactic acid (PLA) is a broad-spectrum antimicrobial compound, produced by a wide range of lactic acid bacteria. A novel lactic acid bacteria strain with high PLA-producing ability, Pediococcus pentosaceus SK25, was isolated from traditional Chinese pickles. When grown in de Man, Rogosa, Sharpe broth at 30 degrees C for 36h, this strain produced 135.6mg/L of PLA. Using this strain as starter for milk fermentation, 47.2mg/L of PLA was produced after fermentation for 12h. The PLA production was significantly improved by phenylalanine supplement, but was completely inhibited by tyrosine supplement. PMID- 25434345 TI - [Invasive infection diseases by filamentous fungi]. PMID- 25434346 TI - [Invasive mould disease in haematological patients]. AB - Invasive mould infections (IMI) are a persistent problem with high morbidity and mortality rates among patients receiving chemotherapy for hematological malignancies and hematopoietic stem cell transplant recipients. Management of IMI in this setting has become increasingly complex with the advent of new antifungal agents and diagnostic tests, which have resulted in different therapeutic strategies (prophylactic, empirical, pre-emptive, and directed). A proper assessment of the individual risk for IMI appears to be critical in order to use the best prophylactic and therapeutic approach and increase the survival rates. Among the available antifungal drugs, the most frequently used in the hematologic patient are fluconazole, mould-active azoles (itraconazole, posaconazole and voriconazole), candins (anidulafungin, caspofungin and micafungin), and lipid formulations of amphotericin B. Specific recommendations for their use, and criteria for selecting the antifungal agents are discussed in this paper. PMID- 25434347 TI - Jeffreys's Nursing Universal Retention and Success model: overview and action ideas for optimizing outcomes A-Z. AB - BACKGROUND: Nursing student persistence, retention, and success are universally desired outcomes yet remain elusive and challenging worldwide. OBJECTIVES: The aim of this study is to provide nurse educators with an organizing framework and action ideas for optimizing student outcomes. CONCEPTUAL MODEL: Jeffreys's Nursing Universal Retention and Success (NURS) model presents a globally applicable framework for examining the multidimensional factors that affect undergraduate and graduate nursing student retention and success in order to make a positive difference. DISCUSSION: This article presents a brief overview of the empirically-based NURS model and indicates that retention decisions, persistence, and optimal outcomes will be based on the interaction of student profile characteristics, student affective factors, academic factors, environmental factors, academic outcomes, psychological outcomes, outside surrounding factors, and professional integration factors. CONCLUSION: An A-Z list of action ideas provides nurse educators with a springboard for further developing ideas tailored to individual program and student needs. Recommendations for global collaborative partnerships and networks are presented. PMID- 25434348 TI - From rice bran to high energy density supercapacitors: a new route to control porous structure of 3D carbon. AB - Controlled micro/mesopores interconnected structures of three-dimensional (3D) carbon with high specific surface areas (SSA) are successfully prepared by carbonization and activation of biomass (raw rice brans) through KOH. The highest SSA of 2475 m(2) g(-1) with optimized pore volume of 1.21 cm(3) g(-1) (40% for mesopores) is achieved for KOH/RBC = 4 mass ratio, than others. The as-prepared 3D porous carbon-based electrode materials for supercapacitors exhibit high specific capacitance specifically at large current densities of 10 A g(-1) and 100 A g(-1) i.e., 265 F g(-1) and 182 F g(-1) in 6 M KOH electrolyte, respectively. Moreover, a high power density ca. 1223 W kg(-1) (550 W L(-1)) and energy density 70 W h kg(-1) (32 W h L(-1)) are achieved on the base of active material loading (~10 mg cm(2)) in the ionic liquid. The findings can open a new avenue to use abundant agricultural by-products as ideal materials with promising applications in high-performance energy-storage devices. PMID- 25434349 TI - The impact of epileptiform abnormalities and hippocampal lesions on retention of recent autobiographical experiences: Adding insult to injury? AB - Accelerated long term forgetting (ALF), whereby information is rapidly lost over days or weeks has been noted in patients with epileptic conditions. The present study sought to determine which clinical factors underlie such consolidation failure for recent autobiographical experiences in patients with focal epilepsy. We enrolled 21 patients with temporal lobe epilepsy (TLE), with and without hippocampal lesions (TLE(+)=12; TLE(-)=9, respectively), 11 patients with extratemporal epilepsy (ETE) and 29 controls (NC). Recall and recognition were tested at different delays (i.e., 30min, 24h and 4 days). During the study interval, most of the patients underwent concurrent ambulatory EEG monitoring. Analyses of variance indicated Group*Delay interval interactions for recall. The TLE(+) group showed significant decline in recall by 24h delay. On recognition Group by Delay interval was not detected but main effect for Group revealed that the ETE group demonstrated ALF on recognition questions over the interval between 24h and 4 days. Regression analyses confirmed that a hippocampal lesion was particularly disruptive to consolidation over the first 24h, and that seizures were associated with memory decline over longer delays. Our findings show that the retention of autobiographical experiences involves multiple mechanisms, which operate over different timeframes. PMID- 25434351 TI - Electrophysiological characteristics of permanent atrial fibrillation: insights from research models of cardiac remodeling. AB - Atrial fibrillation (AF) results in a remodeling of the electrical and structural characteristics of the cardiac tissue which dramatically reduces the efficacy of pharmacological and catheter-based ablation therapies. Recent experimental and clinical results have demonstrated that the complexity of the fibrillatory process significantly differs in paroxysmal versus persistent AF; however, the lack of appropriate research models of remodeled atrial tissue precludes the elucidation of the underlying AF mechanisms and the identification of appropriated therapeutic targets. Here, we summarize the different research models used to date, highlighting the lessons learned from them and pointing to the new doors that should be open for the development of innovative treatments for AF. PMID- 25434352 TI - The antimitotic potential of PARP inhibitors, an unexplored therapeutic alternative. AB - ADP-ribosylation or PARsylation is one of the most abundant modifications of proteins and DNA. Although the usual context for PARsylation involves the detection and repair of DNA damage in the cell, poly(ADP-ribose) polymerases are known to regulate a number of biological processes besides maintaining genome integrity. One of these processes is the assembly and maintenance of the mitotic spindle where the presence of PARP-1 and tankyrase 1 (TNKS1), two of the best characterized members of the PARP superfamily, is of critical importance. Here, we recapitulate the biological implications of the absence of poly(ADP-ribose) polymerases and depletion of PARsylation occurrence in mitosis in order to better understand the antimitotic effects of PARP inhibitors. In this regard, we also present an overview of the existing and more relevant molecules, with a special attention to the historical development of their pharmacological properties and structures, as well as a brief summary of clinical trials involving PARP inhibitors. PMID- 25434354 TI - KSP inhibitors as antimitotic agents. AB - There is a strong need for new antimitotic drugs that overcome the limitations of the currently used antitubulin compounds, mainly neurotoxicity and the development of resistance. One of the most promising new targets is kinesin spindle protein (KSP, also known as Eg5), which contributes to the formation of mitotic spindle during cell division and has not been reported to play any other cellular role so far. This review covers KSP inhibitors binding at the allosteric, induced-fit L5 site reported between 2008 and December 2013. Among them, main groups include dihydropyrimidines, STLC derivatives, quinazoline-based compounds and pyrrole/ pyrazole and related agents. Structure-activity relationships are described, as well as the synthesis of representative compounds. They are remarkably selective for KSP and produce G2/M mitotic arrest accompanied by a characteristic monoastral cellular phenotype. Some of them have entered clinical trials, the most advanced being in Phase II. Therefore, KSP inhibitors show great potential as future clinical antimitotic agents, especially due to their activity in taxane-resistant tumors. PMID- 25434355 TI - Natural products as antimitotic agents. AB - Natural products still play an important role in the medicinal chemistry, especially in some therapeutic areas. As example more than 60% of currently-used anticancer agents are derives from natural sources including plants, marine organisms or micro-organism. Thus natural products (NP) are an high-impact source of new "lead compounds" or new potential therapeutic agents despite the large development of biotechnology and combinatorial chemistry in the drug discovery and development. Many examples of anticancer drugs as paclitaxel, combretastatin, bryostatin and discodermolide have shown the importance of NP in the anticancer chemotherapy through many years. Many organisms have been studied as sources of drugs namely plants, micro-organisms and marine organisms and the obtained NP can be considered a group of "privileged chemical structures" evolved in nature to interact with other organisms. For this reason NP are a good starting points for pharmaceutical research and also for library design. Tubulin and microtubules are one of the most studied targets for the search of anticancer compounds. Microtubule targeting agents (MTA) also named antimitotic agents are compounds that are able to perturb mitosis but are also able to arrest cell growing during interphase. The anticancer drugs, taxanes and vinca alkaloids have established tubulin as important target in cancer therapy. More recently the vascular disrupting agents (VDA) combretastatin analogues were studied for their antimitotics properties. This review will consider the anti mitotic NP and their potential impact in the development of new therapeutic agents. PMID- 25434353 TI - Epothilones: From discovery to clinical trials. AB - Epothilones are natural compounds isolated from a myxobacterium at the beginning of the 1990s, and showed a remarkable anti-neoplastic activity. They act through the same mechanism of action of paclitaxel, by stabilizing microtubules and inducing apoptosis. Although, their chemical structure, simpler than taxanes, makes them more suitable for derivatization. Their interesting pharmacokinetic and bioavailabilty profiles, and the activity against paclitaxel-resistant cell lines make them interesting therapeutic agents. Here a brief historical perspective of epothilones is presented, since their isolation, the identification of their mechanism of action and activity, to the recent clinical trials. PMID- 25434356 TI - Target driven preclinical screening for new antimitotic chemotherapy agents. AB - Currently approved antimitotic therapies used in chemotherapy are microtubule targeting agents (MTAs). Despite they achieved some level of success, they have limited efficacy as single agents, with issues of slippages and resistance, and cause significant side effects. The advances in the identification of other mitosis-related targets led to the development of new mitotic regulators aimed to perturb mitosis without interfering with microtubule dynamics in non-dividing cells trying to reduce side effects in patients. Some of these compounds like those targeted to entry and mitotic kinases, mitotic kinesins/motor proteins, and multiprotein complexes have been evaluated in vitro and in animal models, and some of them have reached clinical trials. Despite promising preclinical results, in many cases, the efficacy demonstrated by these new antimitotics was not better than current microtubule inhibitors. In this paper we review present and future strategies on the search for new antimitotic compounds based on identification of new protein targets and development of multifunctional inhibitors of mitosis in cancer cells. PMID- 25434358 TI - New ligands of the tubulin colchicine site based on X-ray structures. AB - Colchicine site ligands have proved to be potent inhibitors of tubulin polymerization, which leads them not only to display cytotoxic effects but also vascular disrupting effects on tumour neovasculature. In recent years, many compounds have been designed, synthesized and evaluated in order to improve the potency, stability and physicochemical properties of these agents with the aim of developing an agent that could reach the clinical assay level. Here we analyze the eleven X-ray structures of tubulin in complex with ligands at the colchicine site by dividing it into four different zones of interaction, we review the new compounds that have appeared in the literature since 2008 and that were designed based on any of these X-ray structures and, finally, we describe our latest results in the design of new potent antimitotic indole derivatives that have confirmed the flexibility of one of the zones described for the colchicine site. PMID- 25434357 TI - QSAR and 3D-QSAR models in the field of tubulin inhibitors as anticancer agents. AB - Microtubules are high dynamic protein filaments fundamental for cells growth and proliferation. Hence, tubulin inhibitors are useful anticancer compounds. Three major binding site have been identified in tubulin, on the basis of known ligands: the vinca domain, the colchicine domain and the taxane domain. Several compounds able to bind the colchicine and the taxane domains have been to date synthesized and evaluated. In this review we give a description of the developed QSAR and 3D-QSAR models, giving particular attention to those studies that give structural insight in the binding modes of compounds with the target. PMID- 25434359 TI - Structure-based drug design and combinatorial chemistry in the search of antimitotic agents). PMID- 25434360 TI - Udder characteristics and effects of pulsation rate on milking machine efficiency in donkeys. AB - Very little is known about the udder characteristics, partitioning of milk in the mammary gland and efficiency of machine milking in donkeys. This study aimed to evaluate the characteristics of the udder and teats, milk yield in relation to pulsation rates (90, 120 and 150 cycles/min), milk partitioning in the mammary gland, composition of the spontaneously removed and residual milk fractions and milking efficiency. Forty-one healthy Martina Franca jennies in the third month of lactation and routinely milked twice daily were used in three studies. Udder characteristics were evaluated by direct measurements and ultrasonographic scanning. Residual milk was obtained by milking after an oxytocin administration (40 IU i.m.). The prevalent shapes were 'bowl' for udders and 'conical' for teats. After milking the udder characteristics decreased within a range from 11.6% (udder depth) to -25.7% (diameter of teat at the base). The internal structures of the udder resulted as several pockets of ducts empting directly into the teat. The pulsation rate of 120 cycles/min improved (P<0.05) the milk yield in comparison to the 90 and 150 cycles/min, reduced the residual milk fraction, thus improved (P<0.05) milking efficiency. Residual milk composition had higher (P<0.05) fat content and somatic cell count than the spontaneously removed milk fraction. The udders revealed several pockets of ducts empting into the teat instead of a single cisternal cavity and showed a certain compliance. The use of 120 cycles/min pulsation rate improved milking efficiency. PMID- 25434362 TI - The molecular mechanisms and therapeutic potential of microRNA-7 in cancer. AB - INTRODUCTION: Increasing evidence supports that microRNAs (miRNAs) play crucial roles in cancer through post-transcriptional gene silencing of their target genes, therefore, more and more effort has been devoted to develop miRNA targeting therapeutics in cancer. MicroRNA-7 (miR-7) has been characterized as a potential tumor suppressor and regulates diverse fundamental biological processes of cancer cells including initiation, proliferation, migration, invasion, survival and death by targeting a number of oncogenic signaling pathways. AREAS COVERED: This review examines evidence of the biological responses of miR-7 in cancer, with an emphasis on its regulation of the vital oncogenic signaling pathways. It also discusses the rationale, strategies and challenges of miR-7 as a potential therapeutic target for cancer. EXPERT OPINION: With the increasing understanding of molecular mechanisms of miR-7-mediated regulatory networks and the advancement of miRNA-based therapeutics, targeting miR-7 may be a potential and promising strategy for cancer therapy. PMID- 25434361 TI - Non-invasive ventilation with bubble CPAP is feasible and improves respiratory physiology in hospitalised Malawian children with acute respiratory failure. AB - BACKGROUND: In low-income countries and those with a high prevalence of HIV, respiratory failure is a common cause of death in children. However, the role of non-invasive ventilation with bubble continuous positive airway pressure (bCPAP) in these patients is not well established. METHODS: A prospective observational study of bCPAP was undertaken between July and September 2012 in 77 Malawian children aged 1 week to 14 years with progressive acute respiratory failure despite oxygen and antimicrobial therapy. RESULTS: Forty-one (53%) patients survived following bCPAP treatment, and an HIV-uninfected single-organ disease subgroup demonstrated bCPAP success in 14 of 17 (82%). Compared with children aged ?60 months, infants of 0-2 months had a 93% lower odds of bCPAP failure (odds ratio 0.07, 95% confidence interval 0.004-1.02, P = 0.05). Following commencement of bCPAP, respiratory physiology improved, the average respiratory rate decreased from 61 to 49 breaths/minute (P = 0.0006), and mean oxygen saturation increased from 92.1% to 96.1% (P = 0.02). CONCLUSIONS: bCPAP was well accepted by caregivers and patients and can be feasibly implemented into a tertiary African hospital with high-risk patients and limited resources. PMID- 25434363 TI - Fish erythrocytes as biomarkers for the toxicity of sublethal doses of an azo dye, Basic Violet-1 (CI: 42535). AB - The aim of the present study was to investigate poikilocytosis in Labeo rohita (an important food fish) as an early indicator of stress due to an azo dye, Basic Violet-1 (CI: 42535). This dye was observed to be very toxic to test fish (96 h LC50 as0.45 mg/L dye). Fish were given short-term (96 h) and subchronic (150 days) exposures to the dye, and poikilocytosis was recorded under light and scanning electron microscopy (SEM). Light microscopy helped in identification of micronuclei along with irregularities, notches, blebs, lobes, crenation, clumps, chains, spherocytes, vacuolation, and necrosis in erythrocytes. However, SEM indicated shrinkage, oozing of cytoplasm, and several new abnormal shapes including marginal foldings, discocytes, keratocytes, dacrocytes, degmacytes, acanthocytes, echinocytes, protuberances, stomatocytes, drepanocytes, holes in the membrane, stippling/spicules, crescent-shaped cells, triangular cells, and pentagonal cells. Earlier studies speculated changes in the membrane to be responsible for clumping and chaining of erythrocytes, whereas the present SEM study clearly indicates that oozing out of cytoplasm is also responsible for the formation of chains and clumps. This study also shows that erythrocytes exhibit pathological symptoms before the appearance of other external symptoms such as abnormal behavior or mortality of fish. There was a dose- and duration-dependent increase; therefore, poikilocytosis, especially echinocytes, spherocytes, and clumps, can act as a biomarker for the stress caused by azo dyes. PMID- 25434365 TI - Multi-dose parecoxib provides an immunoprotective effect by balancing T helper 1 (Th1), Th2, Th17 and regulatory T cytokines following laparoscopy in patients with cervical cancer. AB - Analgesic treatment with anti-inflammatory drugs may aid the prevention of postoperative pain and the attenuation of the postoperative immune inflammatory response. The current study presents a randomized, double-blind controlled study, which was performed to investigate the levels of Th1, Th2, Th17 and Treg cytokines, including interleukin (IL)-2, interferon (IFN)-gamma, IL-4, IL-10, IL 17, IL-23 and transforming growth factor (TGF)-beta in the peripheral blood of patients with cervical cancer following laparoscopy. The effects of perioperative multi-dose parecoxib on postoperative immune function was evaluated. A total of 80 patients with cervical cancer (stage IB/IIA, ASA I-III, aged 18-65 years) that were scheduled for laparoscopy were randomly assigned into either the parecoxib (I; n=40) or control (II; n=40) groups. Group I received 40 mg parecoxib 30 min prior to surgery and then every 12 h subsequent to surgery for 60 h, and group II received normal saline at the corresponding time points. Intravenous tramadol (100 mg) was prescribed for pain relief as required. The mRNA and protein expression levels of cytokines in the peripheral blood were detected by quantitative polymerase chain reaction and ELISA. Pain visual analog scales (VAS) and incidence, analgesic relief, adverse events and the length of hospital stay were recorded. It was demonstrated that the mRNA and protein levels of IL-2, IFN gamma and IL-17 in the two groups were reduced subsequent to surgery, while mRNA and protein expression levels of IL-4, IL-10 and TGF-beta were enhanced. Administration of multi-dose parecoxib may diminish the increase in postoperative IL-2, IFN-gamma and IL-17 levels, and suppress the excessive production of IL-4, IL-10 and TGF-beta. This effect is accompanied by lower VAS scores, pain incidence, postoperative nausea/vomiting and infections. In conclusion, perioperative multi-dose parecoxib was able to alleviate postoperative pain and ameliorate surgery-induced immune suppression by balancing Th1, Th2, Th17 and Treg cytokines following laparoscopy in patients with cervical cancer. The current study provides support to the hypothesis that parecoxib may be a more effective therapeutic strategy than the currently available options, for postoperative pain and immune function management of patients with cancer. PMID- 25434364 TI - Antiphospholipid antibodies correlate with stroke severity and outcome in patients with antiphospholipid syndrome. AB - BACKGROUND: Our goal was to analyze the association of the level of antiphospholipid antibodies (aPLs) with stroke severity and outcome in patients with antiphospholipid syndrome (APS). METHODS: Observational study included consecutive patients with ischemic stroke younger than 55 years (2007-2012). We analyzed serum levels of aPLs, including anticardiolipin (aCL) antibodies, anti beta2-glycoprotein I antibodies (anti-beta2GPI) and antiprothrombin antibodies (aPS/PT) within the first 48 h after admission, and again, in the case of a positive result, at least 12 weeks after the first measurement. Stroke severity was measured by the National Institutes of Health Stroke Scale (NIHSS), and the three-month stroke outcome by the modified Rankin Scale (mRS). Multiple linear regression models were used to analyze the correlation between the aPLs and stroke severity and outcome. RESULTS: Overall 255 stroke patients were included, 22 (8.6%) with APS. Among them, a positive correlation was found between immunoglobulin M (IgM) aCL levels within 48 h and NIHSS (rho = 0.471; p = 0.027), as well as a tendency toward a positive correlation between immunoglobulin G (IgG) anti-beta2GPI levels within 48 h and three-month mRS (rho = 0.364; p = 0.096). Multiple linear regression analyses showed a positive correlation between levels of IgM aCL < 48 h and the NIHSS (beta-coefficient [standard error; SE] = 0.127 [0.044]), as well as the levels of IgG anti-beta2GPIwithin 48 h and the three-month mRS (beta-coefficient [SE] = 0.034 [0.011]). CONCLUSIONS: In young stroke patients with APS, serum levels of IgM aCL within 48 h are correlated with stroke severity and levels of IgG anti-beta2GPI within 48 h are correlated with three-month outcomes. PMID- 25434366 TI - Isoquercitrin inhibits the progression of pancreatic cancer in vivo and in vitro by regulating opioid receptors and the mitogen-activated protein kinase signalling pathway. AB - Pancreatic cancer is a common malignant tumour that affects individuals worldwide. In recent years, the incidence and mortality rates of pancreatic cancer have continuously increased. Currently, the primary clinical treatment methods for pancreatic cancer include surgical resection, chemotherapy and radiotherapy. However, these treatment methods rarely produce satisfactory therapeutic outcomes. Extensive research has also proven that the effective components of several traditional Chinese medicines, particularly flavonoids extracted from plants, have significant antitumour effects. Isoquercitrin, which is one of the flavonoids found in Bidens pilosa extracts, has a significant antitumour effect. However, the antitumour effect of isoquercitrin and its mechanism of action remain unclear. The objective of the present study was to investigate the effect of isoquercitrin on the progression of pancreatic cancer and to further understand the biological characteristics of the participation of isoquercitrin in the progression of pancreatic cancer. In vitro, we found that a therapeutic dose of isoquercitrin significantly inhibited proliferation, promoted apoptosis and induced cell cycle arrest within the G1 phase in pancreatic cancer cells. Isoquercitrin activated caspase-3, -8 and -9 and reduced the mitochondrial membrane potential. In addition, isoquercitrin inhibited the expression level of the delta opioid receptor; however, isoquercitrin had no effect on the kappa and u opioid receptors. Furthermore, isoquercitrin inhibited extracellular signal regulated kinase (ERK) phosphorylation and promoted c-Jun N-terminal kinase (JNK) phosphorylation. In vivo, we found that a therapeutic dose of isoquercitrin significantly inhibited xenograft growth in nude mice. In summary, the present study demonstrated that isoquercitrin inhibits human pancreatic cancer progression in vivo and in vitro and that its molecular mechanism may be closely related to opioid receptors and to the activation of the mitogen-activated protein kinase (MAPK) signalling pathway. PMID- 25434367 TI - Circulating microRNA profiles and the identification of miR-593 and miR-511 which directly target the PROP1 gene in children with combined pituitary hormone deficiency. AB - Since the tissue of children with combined pituitary hormone deficiency (CPHD) is not readily accessible, a new focus in children with CPHD is the blood-based expression profiling of non-protein coding genes, such as microRNAs (miRNAs or miRs), which regulate gene expression by inhibiting the translation of mRNAs. In this study, to address this, we identified potential miRNA signatures for CPHD by comparing genome-wide miRNA expression profiles in the serum of children with CPHD vs. normal (healthy) controls. Human embryonic kidney 293T cells were transfected with miR-593 or miR-511 oligonucleotides. Potential target gene expression was validated by western blot analysis for proteins and by miR-593 or miR-511 reporter assay using PROP1 gene 3'-untranslated region (3'-UTR) reporter. The miR-593 and miR-511 levels in the serum of 103 children with CPHD were assessed using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) method. We found 23 upregulated and 19 downregulated miRNAs with abnormal expression in children with CPHD compared with the normal controls using miRNA microarray analysis and RT-qPCR. miR-593 and miR-511 targeted the 3'-UTR of the PROP1 gene and attenuated the expression of PROP1. The levels of miR-593 and miR-511 in the serum of children with CPHD were increased compared with those in the control subjects. According to Youden's index, the sensitivity was 82.54 and 84.86%, and the specificity was 98.15 and 91.36% for miR-593 and miR-511, respectively. The various levels of specific miRNAs, particularly miR-593 and miR 511 whose direct target is the PROP1 gene, may serve as a non-invasive diagnostic biomarkers for children with CPHD. PMID- 25434368 TI - Efficient delivery of docetaxel for the treatment of brain tumors by cyclic RGD tagged polymeric micelles. AB - The treatment of glioblastoma, and other types of brain cancer, is limited due to the poor transport of drugs across the blood brain barrier and poor penetration of the blood-brain-tumor barrier. In the present study, cyclic Arginine-Glycine Aspartic acid-D-Tyrosine-Lysine [c(RGDyK)], that has a high binding affinity to integrin alphavbeta3 receptors, that are overexpressed in glioblastoma cancers, was employed as a novel approach to target cancer by delivering therapeutic molecules intracellularly. The c(RGDyK)/docetaxel polylactic acid-polyethylene glycol (DTX-PLA-PEG) micelle was prepared and characterized for various in vitro and in vivo parameters. The specific binding affinity of the Arginine-Glycine Aspartic acid (RGD) micelles, to the integrin receptor, enhanced the intracellular accumulation of DTX, and markedly increased its cytotoxic efficacy. The effect of microtubule stabilization was evident in the inhibition of glioma spheroid volume. Upon intravenous administration, c(RGDyK)/DTX-PLA-PEG showed enhanced accumulation in brain tumor tissues through active internalization, whereas non-targeted micelles showed limited transport ability. Furthermore, RGD linked micelles showed marked anti-glioma activity in U87MG malignant glioma tumor xenografts, and significantly suppressed the growth of tumors without signs of systemic toxicity. In conclusion, the results of the present study suggest that ligand-mediated drug delivery may improve the efficacy of brain cancer chemotherapy. PMID- 25434369 TI - The evaluation of endometrial sulfate glycosaminoglycans in women with polycystic ovary syndrome. AB - The aim of this study was to quantify the sulfated glycosaminoglycans in the endometria of women with polycystic ovary syndrome (PCOS). Of the 18 patients recruited for this study, 10 patients with PCOS comprised the PCOS group (PCOSG), and eight patients with regular and ovulatory menstrual cycles comprised the control group (CG). The clinical, biochemical, morphological and endometrial data from both groups were analyzed. Biopsies were performed during the proliferative phase of the menstrual cycle for the CG and during the persistent proliferative phase for the PCOSG (all women were amenorrheic). In the PCOSG, there was a significant increase in the endometrial concentration levels of heparan sulfate (p = 0.03), but no difference in the concentrations of chondroitin sulfate was determined between the two groups (p = 0.77). Period of time without menstruation (p = 0.001) and body mass index (BMI) (p = 0.04) correlated directly and positively with heparan sulfate concentration. There was no association between heparan sulfate levels and basal insulin values (p = 0.08). High levels of endometrial heparan sulfate in women with PCOS indicate an interference with maternal-fetal recognition, which contributes to infertility; thus, endometrial heparan sulfate may be a predictive marker of future neoplasia risk. PMID- 25434370 TI - Parental characteristics have a larger effect on children's health behaviour than their body weight. AB - OBJECTIVE: Parents take an important role in a child's development, but there is currently limited information on parental correlates with children's health behaviour. The purpose of this study, therefore, was to examine whether parental characteristics, such as body weight, TV consumption and sport participation, affect children's body weight and health behaviour. METHODS: To examine the effects of parental characteristics on children's body weight and health behaviour, baseline data of 1,118 elementary school children (7.6 +/- 0.4 years) participating in a school-based intervention in southwest Germany was used. Children's height and weight were measured and parent as well as child behaviour was assessed via questionnaire. RESULTS: BMI percentiles of children were positively associated with parental BMI (r = 0.2, p <0.01). Further, high parental TV time increased the odds for high TV time in children (OR mother= 2.2, OR father = 2.3) and parental club sport participation increased the odds for club sport participation in children (OR mother = 1.9, OR father = 1.7). The relationship between parental and child behaviour was stronger than the relationship between parental BMI and BMI percentiles of the child. CONCLUSION: These results suggest that parental behaviour and role modeling provide an important contribution to childrens' health behaviour, especially at younger ages. PMID- 25434372 TI - Analysis of wind-blown sand movement over transverse dunes. AB - Wind-blown sand movement often occurs in a very complicated desert environment where sand dunes and ripples are the basic forms. However, most current studies on the theoretic and numerical models of wind-blown sand movement only consider ideal conditions such as steady wind velocity, flat sand surface, etc. In fact, the windward slope gradient plays a great role in the lift-off and sand particle saltation. In this paper, we propose a numerical model for the coupling effect between wind flow and saltating sand particles to simulate wind-blown sand movement over the slope surface and use the SIMPLE algorithm to calculate wind flow and simulate sands transport by tracking sand particle trajectories. We furthermore compare the result of numerical simulation with wind tunnel experiments. These results prove that sand particles have obvious effect on wind flow, especially that over the leeward slope. This study is a preliminary study on windblown sand movement in a complex terrain, and is of significance in the control of dust storms and land desertification. PMID- 25434374 TI - Erratum: On the differentiation between trait and state food craving: Half-year retest-reliability of the Food Cravings Questionnaire-Trait-reduced (FCQ-T-r) and the Food Cravings Questionnaire-State (FCQ-S). AB - [This corrects the article DOI: 10.1186/s40337-014-0025-z.]. PMID- 25434375 TI - Parity independence of the zero-bias conductance peak in a nanowire based topological superconductor-quantum dot hybrid device. AB - We explore the signatures of Majorana fermions in a nanowire based topological superconductor-quantum dot-topological superconductor hybrid device by charge transport measurements. At zero magnetic field, well-defined Coulomb diamonds and the Kondo effect are observed. Under the application of a finite, sufficiently strong magnetic field, a zero-bias conductance peak structure is observed. It is found that the zero-bias conductance peak is present in many consecutive Coulomb diamonds, irrespective of the even-odd parity of the quasi-particle occupation number in the quantum dot. In addition, we find that the zero-bias conductance peak is in most cases accompanied by two differential conductance peaks, forming a triple-peak structure, and the separation between the two side peaks in bias voltage shows oscillations closely correlated to the background Coulomb conductance oscillations of the device. The observed zero-bias conductance peak and the associated triple-peak structure are in line with Majorana fermion physics in such a hybrid topological system. PMID- 25434376 TI - Population-based approaches for reducing stroke risk. AB - The global burden of stroke is particularly substantial in low- and middle-income countries. There are several risk factors or determinants of stroke and other cardiovascular diseases that are modifiable and have been shown to reduce the risk of stroke in at-risk persons. The high-risk or individual approach to prevention uses screening to identify such persons and medication is then usually required; however, to affect change in risk in a community, a population or mass approach is required to shift the community population to a lower risk profile. The community approach is usually accomplished through legislation, health education and wider economic means. In this review, the authors discuss the population approach to primary stroke prevention. PMID- 25434371 TI - Corneal tissue engineering: recent advances and future perspectives. AB - To address the growing need for corneal transplants two main approaches are being pursued: allogenic and synthetic materials. Allogenic tissue from human donors is currently the preferred choice; however, there is a worldwide shortage in donated corneal tissue. In addition, tissue rejection often limits the long-term success of this approach. Alternatively, synthetic homologs to donor corneal grafts are primarily considered temporary replacements until suitable donor tissue becomes available, as they result in a high incidence of graft failure. Tissue engineered cornea analogs would provide effective cornea tissue substitutes and alternatives to address the need to reduce animal testing of commercial products. Recent progress toward these needs is reviewed here, along with future perspectives. PMID- 25434377 TI - The effect of long term under- and over-feeding on the expression of genes related to lipid metabolism in mammary tissue of sheep. AB - Milk fatty acid (FA) synthesis by the mammary gland involves expression of a large number of genes whose nutritional regulation remains poorly defined. In this study, we examined the effect of long-term under- and over-feeding on the expression of genes (acetyl Co A carboxylase, ACC; fatty acid synthetase, FAS; lipoprotein lipase, LPL; stearoyl Co A desaturase, SCD; peroxisome proliferator activated receptor gamma2, PPARgamma2; sterol regulatory element binding protein 1, SREBP-1c; and hormone sensitive lipase, HSL) related to FA metabolism in sheep mammary tissue (MT). Twenty-four lactating sheep were divided into three homogenous sub-groups and fed the same ration in quantities covering 70% (underfeeding), 100% (control) and 130% (overfeeding) of their energy and crude protein requirements. The results showed a significant reduction of mRNA of ACC, FAS, LPL and SCD in the MT of underfed sheep, and a significant increase on the mRNA of LPL and SREBP-1c in the MT of overfed compared with the control respectively. In conclusion, the negative, compared to positive, energy balance in sheep down-regulates ACC, FAS, LPL, SCD, SREBP-1c and PPARgamma2 expression in their MT which indicates that the decrease in nutrient availability may lead to lower rates of lipid synthesis. PMID- 25434378 TI - Stereotactic laser ablation of high-grade gliomas. AB - Evolving research has demonstrated that surgical cytoreduction of a high-grade glial neoplasm is an important factor in improving the prognosis of these difficult tumors. Recent advances in intraoperative imaging have spurred the use of stereotactic laser ablation (laser interstitial thermal therapy [LITT]) for intracranial lesions. Among other targets, laser ablation has been used in the focal treatment of high-grade gliomas (HGGs). The revived application of laser ablation for gliomas parallels major advancements in intraoperative adjuvants and groundbreaking molecular advances in neuro-oncology. The authors review the research on stereotactic LITT for the treatment of HGGs and provide a potential management algorithm for HGGs that incorporates LITT in clinical practice. PMID- 25434379 TI - Targeting MET for glioma therapy. AB - Glioblastoma multiforme is the most common and most lethal of all primary brain tumors. Even with the standard therapy, life expectancy is still poor, with an average survival of approximately 14 months following initial diagnosis. Hence, there is an urgent need for novel treatment strategies that inhibit proliferation and angiogenesis in high-grade gliomas. One such strategy consists of inhibiting receptor tyrosine kinases, including MET and/or its ligand hepatocyte growth factor (HGF). Because of their widespread involvement in human cancer, HGF and MET have emerged as promising therapeutic targets, and some inhibitory agents that target them have already entered clinical trials. In this paper, the authors highlight recent evidence implicating HGF/MET pathway deregulation in glioblastoma multiforme, discuss therapeutic approaches to inhibit HGF/MET signaling, and summarize ongoing clinical trials targeting this pathway. PMID- 25434380 TI - Molecular and cellular heterogeneity: the hallmark of glioblastoma. AB - There has been increasing awareness that glioblastoma, which may seem histopathologically similar across many tumors, actually represents a group of molecularly distinct tumors. Emerging evidence suggests that cells even within the same tumor exhibit wide-ranging molecular diversity. Parallel to the discoveries of molecular heterogeneity among tumors and their individual cells, intense investigation of the cellular biology of glioblastoma has revealed that not all cancer cells within a given tumor behave the same. The identification of a subpopulation of brain tumor cells termed "glioblastoma cancer stem cells" or "tumor-initiating cells" has implications for the management of glioblastoma. This focused review will therefore summarize emerging concepts on the molecular and cellular heterogeneity of glioblastoma and emphasize that we should begin to consider each individual glioblastoma to be an ensemble of molecularly distinct subclones that reflect a spectrum of dynamic cell states. PMID- 25434381 TI - Chloroquine enhances temozolomide cytotoxicity in malignant gliomas by blocking autophagy. AB - OBJECT: In a recent clinical trial, patients with newly diagnosed glioblastoma multiforme benefited from chloroquine (CQ) in combination with conventional therapy (resection, temozolomide [TMZ], and radiation therapy). In the present study, the authors report the mechanism by which CQ enhances the therapeutic efficacy of TMZ to aid future studies aimed at improving this therapeutic regimen. METHODS: Using in vitro and in vivo experiments, the authors determined the mechanism by which CQ enhances TMZ cytotoxicity. They focused on the inhibition-of-autophagy mechanism of CQ by knockdown of the autophagy-associated proteins or treatment with autophagy inhibitors. This mechanism was tested using an in vivo model with subcutaneously implanted U87MG tumors from mice treated with CQ in combination with TMZ. RESULTS: Knockdown of the autophagy-associated proteins (GRP78 and Beclin) or treatment with the autophagy inhibitor, 3-methyl adenine (3-MA), blocked autophagosome formation and reduced CQ cytotoxicity, suggesting that autophagosome accumulation precedes CQ-induced cell death. In contrast, blocking autophagosome formation with knockdown of GRP78 or treatment with 3-MA enhanced TMZ cytotoxicity, suggesting that the autophagy pathway protects from TMZ-induced cytotoxicity. CQ in combination with TMZ significantly increased the amounts of LC3B-II (a marker for autophagosome levels), CHOP/GADD 153, and cleaved PARP (a marker for apoptosis) over those with untreated or individual drug-treated glioma cells. These molecular mechanisms seemed to take place in vivo as well. Subcutaneously implanted U87MG tumors from mice treated with CQ in combination with TMZ displayed higher levels of CHOP/GADD-153 than did untreated or individual drug-treated tumors. CONCLUSIONS: Taken together, these results demonstrate that CQ blocks autophagy and triggers endoplasmic reticulum stress, thereby increasing the chemosensitivity of glioma cells to TMZ. PMID- 25434382 TI - Isocitrate dehydrogenase status and molecular subclasses of glioma and glioblastoma. AB - Diffuse gliomas and secondary glioblastomas (GBMs) that develop from low-grade gliomas are a common and incurable class of brain tumor. Mutations in the metabolic enzyme glioblastomas (IDH1) represent a distinguishing feature of low grade gliomas and secondary GBMs. IDH1 mutations are one of the most common and earliest detectable genetic alterations in low-grade diffuse gliomas, and evidence supports this mutation as a driver of gliomagenesis. Here, the authors highlight the biological consequences of IDH1 mutations in gliomas, the clinical and therapeutic/diagnostic implications, and the molecular subtypes of these tumors. They also explore, in brief, the non-IDH1-mutated gliomas, including primary GBMs, and the molecular subtypes and drivers of these tumors. A fundamental understanding of the diversity of GBMs and lower-grade gliomas will ultimately allow for more effective treatments and predictors of survival. PMID- 25434383 TI - Wilms tumor 1 gene, CD97, and the emerging biogenetic profile of glioblastoma. AB - Glioblastoma multiforme (GBM) is the most common type of primary brain tumor, and current treatment regimens are only marginally effective. One of the most vexing and malignant aspects of GBM is its pervasive infiltration into surrounding brain tissue. This review describes the role of the Wilms tumor 1 gene (WT1) and its relationship to GBM. WT1 has several alternative splicing products, one of which, the KTS(+) variant, has been demonstrated to be involved in the transcriptional activation of a variety of oncogenes as well as the inhibition of tumor suppressor genes. Further, this paper will examine the relationship of WT1 with CD97, a gene that codes for an epidermal growth factor receptor family member, an adhesion G-protein-coupled receptor, thought to promote tumor invasiveness and migration. The authors suggest that further research into WT1 and CD97 will allow clinicians to begin to deal more effectively with the infiltrative behavior displayed by GBM and design new therapies that target this deadly disease. PMID- 25434385 TI - Intraoperative monopolar mapping during 5-ALA-guided resections of glioblastomas adjacent to motor eloquent areas: evaluation of resection rates and neurological outcome. AB - OBJECT: Resection of glioblastoma adjacent to motor cortex or subcortical motor pathways carries a high risk of both incomplete resection and postoperative motor deficits. Although the strategy of maximum safe resection is widely accepted, the rates of complete resection of enhancing tumor (CRET) and the exact causes for motor deficits (mechanical vs vascular) are not always known. The authors report the results of their concept of combining monopolar mapping and 5-aminolevulinic acid (5-ALA)-guided surgery in patients with glioblastoma adjacent to eloquent tissue. METHODS: The authors prospectively studied 72 consecutive patients who underwent 5-ALA-guided surgery for a glioblastoma adjacent to the corticospinal tract (CST; < 10 mm) with continuous dynamic monopolar motor mapping (short-train interstimulus interval 4.0 msec, pulse duration 500 MUsec) coupled to an acoustic motor evoked potential (MEP) alarm. The extent of resection was determined based on early (< 48 hours) postoperative MRI findings. Motor function was assessed 1 day after surgery, at discharge, and at 3 months. RESULTS: Five patients were excluded because of nonadherence to protocol; thus, 67 patients were evaluated. The lowest motor threshold reached during individual surgery was as follows (motor threshold, number of patients): > 20 mA, n = 8; 11-20 mA, n = 13; 6-10 mA, n = 10; 4-5 mA, n = 13; and 1-3 mA, n = 23. Motor deterioration at postsurgical Day 1 and at discharge occurred in 30% (n = 20) and 10% (n = 7) of patients, respectively. At 3 months, 3 patients (4%) had a persisting postoperative motor deficit, 2 caused by vascular injury and 1 by mechanical injury. The rates of intra- and postoperative seizures were 1% and 0%, respectively. Complete resection of enhancing tumor was achieved in 73% of patients (49/67) despite proximity to the CST. CONCLUSIONS: A rather high rate of CRET can be achieved in glioblastomas in motor eloquent areas via a combination of 5-ALA for tumor identification and intraoperative mapping for distinguishing between presumed and actual motor eloquent tissues. Continuous dynamic mapping was found to be a very ergonomic technique that localizes the motor tissue early and reliably. PMID- 25434387 TI - Editorial: laser interstitial thermal therapy: an effective treatment for focally recurrent high grade glioma. PMID- 25434384 TI - Molecularly targeted therapies for recurrent glioblastoma: current and future targets. AB - OBJECT: Glioblastoma is the most aggressive and diffusely infiltrative primary brain tumor. Recurrence is expected and is extremely difficult to treat. Over the past decade, the accumulation of knowledge regarding the molecular and genetic profile of glioblastoma has led to numerous molecularly targeted therapies. This article aims to review the literature and highlight the mechanisms and efficacies of molecularly targeted therapies for recurrent glioblastoma. METHODS: A systematic search was performed with the phrase "(name of particular agent) and glioblastoma" as a search term in PubMed to identify all articles published up until 2014 that included this phrase in the title and/or abstract. The references of systematic reviews were also reviewed for additional sources. The review included clinical studies that comprised at least 20 patients and reported results for the treatment of recurrent glioblastoma with molecular targeted therapies. RESULTS: A total of 42 articles were included in this review. In the treatment of recurrent glioblastoma, various targeted therapies have been tested over the past 10-15 years. The targets of interest include epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, Ras pathway, protein kinase C, mammalian target of rapamycin, histone acetylation, and integrins. Unfortunately, the clinical responses to most available targeted therapies are modest at best. Radiographic responses generally range in the realm of 5%-20%. Progression-free survival at 6 months and overall survival were also modest with the majority of studies reporting a 10%-20% 6-month progression-free survival and 5- to 8-month overall survival. There have been several clinical trials evaluating the use of combination therapy for molecularly targeted treatments. In general, the outcomes for combination therapy tend to be superior to single-agent therapy, regardless of the specific agent studied. CONCLUSIONS: Recurrent glioblastoma remains very difficult to treat, even with molecular targeted therapies and anticancer agents. The currently available targeted therapy regimens have poor to modest activity against recurrent glioblastoma. As newer agents are actively being developed, combination regimens have provided the most promising results for improving outcomes. Targeted therapies matched to molecular profiles of individual tumors are predicted to be a critical component necessary for improving efficacy in future trials. PMID- 25434386 TI - Phosphorylation of NMDA 2B at S1303 in human glioma peritumoral tissue: implications for glioma epileptogenesis. AB - OBJECT: Peritumoral seizures are an early symptom of a glioma. To gain a better understanding of the molecular mechanism underlying tumor-induced epileptogenesis, the authors studied modulation of the N-methyl-d-aspartate (NMDA) receptor in peritumoral tissue. METHODS: To study the possible etiology of peritumoral seizures, NMDA receptor expression, posttranslational modification, and function were analyzed in an orthotopic mouse model of human gliomas and primary patient glioma tissue in which the peritumoral border (tumor-brain interface) was preserved in a tissue block during surgery. RESULTS: The authors found that the NMDA receptor containing the 2B subunit (NR2B), a predominantly extrasynaptic receptor, is highly phosphorylated at S1013 in the neurons located in the periglioma area of the mouse brain. NR2B is also highly phosphorylated at S1013 in the neurons located in the peritumoral area from human brain tissue containing a glioma. The phosphorylation of the extrasynaptic NMDA receptor increases its permeability for Ca(2+) influx and subsequently mediates neuronal overexcitation and seizure activity. CONCLUSIONS: These data suggest that overexcitation of the extrasynaptic NMDA receptors in the peritumoral neurons may contribute to the development of peritumoral seizures and that the phosphorylated NR2B may be a therapeutic target for blocking primary brain tumor-induced peritumoral seizures. PMID- 25434388 TI - Time window for postoperative reactive enhancement after resection of brain tumors: less than 72 hours. AB - OBJECT: Early postoperative MRI within 72 hours after brain tumor surgery is commonly used to assess residual contrast-enhancing tumor. The 72-hour window is commonly accepted because previous 1.5-T MRI studies have not found confounding postoperative reactive contrast enhancement in this time frame. The sensitivity to detect contrast enhancement increases with the field strengths. Therefore, the authors aimed to assess whether the 72-hour window is also appropriate for the MRI scanner with a field strength of 3 T. METHODS: The authors retrospectively analyzed findings on early postsurgical MR images acquired in 46 patients treated for high-grade gliomas. They performed 3-T MRI within 7 days before surgery and within 72 hours thereafter. The appearance of enhancement was categorized as postoperative reactive enhancement or tumoral enhancement by comparison with the pattern and location of presurgical enhancing tumor. RESULTS: Postoperative reactive enhancement was present in 15 patients (32.6%). This enhancement, not seen on presurgical MRI, had a marginal or leptomeningeal/dural pattern. In 13 patients (28.3%) postsurgical enhancement was found within the first 72 postoperative hours, with the earliest seen 22:57 hours after surgery. Subsequent MR scans in patients with postoperative reactive enhancement did not reveal tumor recurrence in these regions. CONCLUSIONS: Postoperative reactive enhancement earlier than 72 hours after brain tumor surgery can be expected in about one third of the cases in which a 3-T scanner is used. This might be due to the higher enhancement-to-brain contrast at higher field strengths. Therefore, the time window of 72 hours does not prevent reactive enhancement, which, however, can be recognized as such comparing it with presurgical enhancing tumor. PMID- 25434389 TI - Long-term therapy with temozolomide is a feasible option for newly diagnosed glioblastoma: a single-institution experience with as many as 101 temozolomide cycles. AB - OBJECT: The objective of this study was to report the authors' experience with the long-term administration of temozolomide (TMZ; > 6 cycles, up to 101) in patients with newly diagnosed glioblastoma and to analyze its feasibility and safety as well as its impact on survival. The authors also compared data obtained from the group of patients undergoing long-term TMZ treatment with data from patients treated with a standard TMZ protocol. METHODS: A retrospective analysis was conducted of 37 patients who underwent operations for glioblastoma between 2004 and 2012. Volumetric analysis of postoperative Gd-enhanced MR images, obtained within 48 hours, confirmed tumor gross-total resection (GTR) in all but 2 patients. All patients received the first cycle of TMZ at a dosage of 150 mg/m(2) starting on the second or third postsurgical day. Afterward, patients received concomitant radiochemotherapy according to the Stupp protocol. With regard to adjuvant TMZ therapy, the 19 patients in Group A, aged 30-72 years (mean 56.1 years), received 150 mg/m(2) for 5 days every 28 days for more than 6 cycles (range 7-101 cycles). The 18 patients in Group B, aged 46-82 years (mean 64.8 years), received the same dose, but for no more than 6 cycles. O(6) methylguanine-DNA methyltransferase (MGMT) promoter methylation status was analyzed for both groups and correlated with overall survival (OS) and progression-free survival (PFS). The impact of age, sex, Karnofsky Performance Scale score, and Ki 67 staining were also considered. RESULTS: All patients but 1 in Group A survived at least 18 months (range 18-101 months), and patients in Group B survived no more than 17 months (range 2-17 months). The long-term survivors (Group A), defined as patients who survived at least 12 months after diagnosis, were 51.3% of the total (19/37). Kaplan-Meier curve analysis showed that patients treated with more than 6 TMZ cycles had OS and PFS that was significantly longer than patients receiving standard treatment (median OS 28 months vs 8 months, respectively; p = 0.0001; median PFS 20 months vs 4 months, respectively; p = 0.0002). By univariate and multivariate Cox proportional hazard regression analysis, MGMT methylation status and number of TMZ cycles appeared to be survival prognostic factors in patients with glioblastoma. After controlling for MGMT status, highly significant differences related to OS and PFS between patients with standard and long-term TMZ treatment were still detected. Furthermore, in Group A and B, the statistical correlation of MGMT status to the number of TMZ cycles showed a significant difference only in Group A patients, suggesting that MGMT promoter methylation was predictive of response for long term TMZ treatment. Prolonged therapy did not confer hematological toxicity or opportunistic infections in either patient group. CONCLUSIONS: This study describes the longest experience so far reported with TMZ in patients with newly diagnosed glioblastomas, with as many as 101 cycles, who were treated using GTR. Statistically significant data confirm that median survival correlates with MGMT promoter methylation status as well as with the number of TMZ cycles administered. Long-term TMZ therapy appears feasible and safe. PMID- 25434390 TI - Home palliative care and end of life issues in glioblastoma multiforme: results and comments from a homogeneous cohort of patients. AB - OBJECT: Glioblastoma multiforme (GBM) is a rare tumor whose prognosis has remained poor over the years despite innovative radio- and chemotherapies, and important technical advances in neurosurgery such as intraoperative imaging, fluorescence, Cavitron ultrasonic surgical aspirator, and neuronavigation. Particular attention has been dedicated in the last years to the end of life (EOL) period in cancer patients for both ethical and socioeconomic issues. Good palliative care at home avoids improper and expensive hospitalizations, and helps and trains families, caregivers, and patients in facing a difficult situation. METHODS: In 2012-2013 the authors' group cared for 197 patients with brain tumors. Of these there were 122 with GBMs: 64 died and 58 are still receiving assistance. The clinical conditions are periodically evaluated with the following scales: Barthel Index, Karnofsky Performance Scale, and Mini-Mental State Examination. Home care staff includes 2 neurologists, 5 nurses, 2 psychologists, 3 rehabilitation therapists, and 1 social worker. The intensity of care changes at the different stages of disease, ranging from low to medium levels of intensity at the progression stage (more than 1 access weekly) to high levels of intensity at the EOL stage (at least 3 accesses weekly). Control MRI studies are obtained every 3 months before terminal progression. RESULTS: Overall in this sample of patients there were 2838 home visits and 11,714 days of assistance. Thirty-four patients (14 female and 20 male) died at home (53.1%); 22 (13 female and 9 male) at the hospice (34.4%); and 8 (4 female and 4 male) at the hospital (12.5%). A positive impact on caregivers for home assistance was recorded in 97% of cases, for nursing in 95%, communication in 90%, rehabilitation at home in 92%, and social work help in 85%. Also, 72% had an improvement in their quality of life scores due to rehabilitation. End of life palliative sedation with midazolam was necessary in 11% of cases to obtain good control of symptoms such as uncontrolled delirium, agitation, death rattle, or refractory seizures. Intramuscular phenobarbital is the authors' drug of choice for the severe seizures that occurred in 30% of cases. The reduction of steroid dosage is also used to decrease wakefulness. Steroids were withdrawn in 45% of patients dying at home, mild hydration was done in 87%, and tube feeding in 13%. The decision making process at the EOL stage is time consuming, but the degree of distress of the family is inversely proportional to the extent of the preparatory period. CONCLUSIONS: A previous paper showed the positive cost-effectiveness of home assistance for a larger group of patients dealing with any kind of malignant brain tumors. The same is enhanced for patients with GBM. This requires a well trained neuro-oncology team that manages neurological deterioration, clinical complications, rehabilitation, and psychosocial problems with a multidisciplinary approach. PMID- 25434392 TI - Introduction: Glioblastoma: an update on pathophysiology and management strategies. PMID- 25434391 TI - The role of cancer stem cells in glioblastoma. AB - Recurrence in glioblastoma is nearly universal, and its prognosis remains dismal despite significant advances in treatment over the past decade. Glioblastoma demonstrates considerable intratumoral phenotypic and molecular heterogeneity and contains a population of cancer stem cells that contributes to tumor propagation, maintenance, and treatment resistance. Cancer stem cells are functionally defined by their ability to self-renew and to differentiate, and they constitute the diverse hierarchy of cells composing a tumor. When xenografted into an appropriate host, they are capable of tumorigenesis. Given the critical role of cancer stem cells in the pathogenesis of glioblastoma, research into their molecular and phenotypic characteristics is a therapeutic priority. In this review, the authors discuss the evolution of the cancer stem cell model of tumorigenesis and describe the specific role of cancer stem cells in the pathogenesis of glioblastoma and their molecular and microenvironmental characteristics. They also discuss recent clinical investigations into targeted therapies against cancer stem cells in the treatment of glioblastoma. PMID- 25434393 TI - Morphological and chemical comparative analysis of the human and bovine dentin adhesive layer. AB - Micro energy-dispersive X-ray fluorescence spectrometry (u-EDXRF) and scanning electron microscopy (SEM) were used to evaluate dentin treated with an etch and rinse adhesive (ER) and a self-etch adhesive (SE). Ten human molars (H) and ten bovine anterior teeth (B) were prepared (exposure of dentin and divided in the middle) and allocated into two different adhesion strategy groups per substrate (n=40). u-EDXRF data and SEM images were obtained before and after treatment. Untreated dentin of both substrates did not differ in terms of Ca (p<0.1503), P (p<0.2986) or Ca/P ratio (p<0.1400). H-SE and B-SE specimens showed reduced P content (p<0.0001; p<0.0002), while H-ER and B-ER specimens showed reduced Ca and P content (p<0.0001; p<0.0001) when compared with untreated specimens. The Ca/P ratio was significantly higher in H-ER and B-ER specimens than in H-SE and B-SE specimens (p<0.0001; p<0.0080). Untreated dentin showed a homogeneous elemental distribution. However, after adhesive treatments, the surface of the dentin showed an irregular demineralization pattern. The resin tags and adhesive layer were shorter in bovine specimens than in human specimens due to morphological differences. PMID- 25434394 TI - Disparate results between proliferation rates of surgically excised prostate tumors and an in vitro bioassay using sera from a positive randomized controlled trial. AB - In vitro bioassay has been used extensively to test the effects of culturing cancer cells in sera from humans participating in dietary interventions, i.e, studies of modified intake of nutrients for the purpose of reducing cancer risk or progression. It has been hypothesized that cell proliferation rates determined by the in vitro bioassay indicate whether modification of dietary intake could decrease cancer cell growth in vivo. It has been suggested, however, that the in vitro bioassay may not correlate with tumor cell proliferation rates in prostate cancer. We investigated the concordance of cell proliferation rates from surgically excised prostate tumor tissue with the in vitro bioassay using sera from matched patients. We used samples from an earlier randomized clinical trial that showed that supplementation with flaxseed significantly inhibited prostate cancer cell proliferation rates in vivo as indicated by Ki67 staining in tumor specimens. Proliferation rates of LNCaP, DU145 and PC3 cell lines cultured in 10% human sera from participants in the flaxseed trial were determined using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Spearman's Rho correlation coefficients (rho) indicated no association between Ki67 staining in prostate tumors and the in vitro bioassay for the three cell lines. These disparate findings suggest that the in vitro bioassay may not provide an accurate assessment of the environment in vivo. PMID- 25434395 TI - Alteration of serum and cardiac tissue adropin, copeptin, irisin and TRPM2 expressions in DOX treated male rats. AB - Doxorubicin (DOX) cardiotoxicity is a significant side effect in cancer survivors. DOX and its metabolites alter cardiac gene expression and affect metabolic energy-related peptides. Adropin, copeptin, irisin and TRPM2 are produced locally in the heart and play a role in energy homeostasis. We investigated the fates of adropin, copeptin, irisin and TRPM2 in serum and cardiac tissues of DOX treated rats. Animals were divided into three groups of six: 1) untreated controls, 2) DOX treated and 3) saline treated. The rats were fed a standard diet ad libitum for 14 days then were sacrificed and heart and serum samples were taken. Adropin, copeptin, irisin levels in tissue homogenates and serum were measured using ELISA. Immunoreactivity of heart tissue adropin, copeptin, irisin and TRPM2 also were investigated. The peptides increased in both serum and cardiac tissue homogenates in animals treated with DOX compared to the other groups. DOX increased adropin in endocardial and myocardial cells, but it decreased expression of copeptin. DOX did not affect endocardial irisin and TRPM2 expressions, but myocardial irisin and TRPM2 expressions were increased. Serum adropin, irisin and copeptin were increased in DOX treated rats. Cardiac adropin, copeptin, irisin and TRPM2 are affected by DOX and may play a role in DOX cardiotoxicity. PMID- 25434396 TI - Pathologic diagnosis, immunohistochemistry, multigene assays and breast cancer treatment: progress toward "precision" cancer therapy. AB - Clinical decisions regarding the suitability of adjuvant systemic therapy for individual patients with breast cancer depends on comprehensive assessment of the underlying biology of each patient's tumor. The previous clinical-pathologic paradigm for treatment, which had been used for decades, now has been augmented by significant advances in molecular analysis of breast tumor tissue samples. Molecular testing has the potential to understand better both tumor biology and clinical behavior, which enables more appropriate therapy choices to be made. We review the rapid evolution in profiling breast cancer tissues, and discuss the current evidence for clinical use of this information and how the emerging molecular paradigm can be integrated into the clinical-pathologic context as we progress toward "precision" therapy for patients with breast cancer and other solid tumors. PMID- 25434397 TI - Deoxycholic acid inhibits the growth of BGC-823 gastric carcinoma cells via a p53 mediated pathway. AB - The aim of the present study was to investigate the effects of deoxycholic acid (DCA) on BGC-823 human gastric carcinoma cells and to explore the possible mechanisms underlying any such effects. Cell proliferation was detected using a 3 (4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, cell morphology was observed by inverted microscopy, and cell cycle progression and the mitochondrial membrane potential were analyzed using flow cytometry. The expression of Bcl-2, Bax, p53, Cyclin D1 and cyclin-dependent kinase (CDK)2 proteins in BGC-823 cells was analyzed with western blotting. The results demonstrated that DCA significantly inhibited cell growth, and that the cell cycle was arrested at the G1 phase. DCA was also shown to induce BGC-823 cell apoptosis, which was associated with the collapse of the mitochondrial membrane potential. The mitochondria-dependent pathway was activated via an increase in the ratio of Bax:Bcl-2 in BGC-823 cells. In addition, the expression of p53, cyclin D1 and CDK2 was altered following DCA treatment. These results suggest that DCA induces apoptosis in gastric carcinoma cells through activation of an intrinsic mitochondrial-dependent pathway, in which p53 is involved. PMID- 25434398 TI - The influences of aconitine, an active/toxic alkaloid from aconitum, on the oral pharmacokinetics of CYP3A probe drug buspirone in rats. AB - Aconitine (AC), an active/toxic alkaloid from Aconitum species, is commonly present in Traditional Chinese Medicine (TCM) prescriptions because of the great effectiveness of Aconitum for the treatment of rheumatoid arthritis, cardiovascular diseases, and tumors in clinic. Buspirone (BP) is a sensitive CYP3A probe drug that is administered through oral/intravenous routes as recommended by the U.S. Food and Drug Administration. This study aims to investigate the influences of AC (0.125 mg/kg, oral) on first-pass (intestinal and hepatic) CYP3A activity by using oral BP as the probe in rats. The pharmacokinetics of oral buspirone hydrochloride at different doses (12.5, 25, and 50 mg/kg) were conducted. The pharmacokinetics of oral BP in rats pretreated with single dose or multiple doses (7-day) of AC were investigated. The plasma concentrations of BP and its major metabolites [1-(2-pyrimidinyl)piperazine (1 PP) and 6'-hydroxybuspirone (6'-OH-BP)] were determined. The formation ratios of 1-PP and 6'-OH-BP from BP (AUC0-infinity of 1-PP/AUC0-infinity of BP and AUC0 infinity of 6'-OH-BP/AUC0-infinity of BP values) showed no alternation when the dose of BP changed. Single dose of AC decreased the AUC0-infinity of BP by 53% but increased the formation ratio of 6'-OH-BP by 74% (P<0.05). Multiple AC exposure increased the AUC0-infinity of BP by 110%, and the formation ratios of 1 PP and 6'-OH-BP from BP were increased by 229% and decreased by 95%, respectively (P<0.05). Conclusively, single/multiple AC exposure did not alter the first-pass CYP3A activity when using oral BP as probe in rats. Nevertheless, multiple AC exposure had markedly changed the production of BP metabolites. PMID- 25434399 TI - 17beta-estradiol-containing liposomes as a novel delivery system for the antisense therapy of ER-positive breast cancer: An in vitro study on the MCF-7 cell line. AB - The present study suggests and describes the application of a delivery system for antisense oligonucleotides against mRNA encoding estrogen receptor proteins alpha and beta. The delivery system is composed of a cationic liposome envelope containing 17beta-estradiol (E2) in its structure. Cationic liposomes protect cargo against the extracellular matrix, and E2 can increase its shuttling efficiency into cells. Using MCF-7 cells derived from estrogen receptor-positive ductal carcinoma, treatment with liposomes against ERalpha was found to decrease MCF-7 proliferation, and importantly the application of both the antisense against ERalpha and beta exhibited an antiproliferative effect expressed as cell viability. Using qRT-PCR, it was shown that MT1A, NF-kappaB1 and K-ras genes, but not TFF1, were downregulated using E2-based liposomes (evaluated at P=0.05). Further indicators of oxidative stress were employed to assess the effect on treatment efficiency. Glutathione (GSH/GSSG redox ratio), metallothionein (MT) and malondialdehyde (MDA) confirmed a positive effect of antisense therapy resulting in their decreased levels in the MCF-7 cells. Based on these data, we suggest that E2-based liposomes offer sufficient transfer efficiency and moreover, due to the effect on NF-kappaB1, MT and GSH, tumor cells can be chemosensitized to increase treatment effectiveness. PMID- 25434402 TI - Perception of the influence of environmental factors in the use of electronic planning devices in adults with cognitive disabilities. AB - BACKGROUND: Adults with cognitive disabilities often have difficulties in dealing with the complexity of everyday life. With cognitive assistive technology (e.g. electronic planning devices [EPDs] and individual support), they can bring order to their often chaotic life. Assumptions are that environmental factors influence with non-use of EPDs. OBJECTIVE: To explore how adults with cognitive disabilities perceive the influence of environmental factors in the use of EPDs. METHODS: A reference group with experience of use of EPDs assisted the researchers. Twelve adults with cognitive disabilities and experience of using EPDs participated. An interview guide was implemented covering environmental factors according to the International Classification of Functioning, Disability and Health. Qualitative content analysis was applied in the analyses. RESULTS: Five categories and two themes emerged, which were integrated into a model of facilitating factors influencing the use of EPDs. Measures to prevent or eliminate negative influences of the device use are important to be taken. CONCLUSIONS: Professionals need more knowledge about EPDs, while users need individual adaption of the EPDs. EPDs need to be user-friendly, manageable and work in any seasons. Implications for Rehabilitation The users should have access to specially trained prescribers. There is a need for development of user friendly and manageable products to function in any climate. Knowledge is lacking on how to implement the users in all stages of the prescribing process. Prescribers should increase knowledge in the use of EPDs to influence the attitudes of the social environment. PMID- 25434403 TI - One-step ultrasonic synthesis of graphene quantum dots with high quantum yield and their application in sensing alkaline phosphatase. AB - With only graphene oxide and KMnO4, the luminescent graphene quantum dots (GQDs) in high quantum yield were prepared by one-step synthesis using ultrasonication, and applied in the label-free, simple and fast fluorescence assay of alkaline phosphatase (ALP). PMID- 25434400 TI - Dynamic changes and functions of macrophages and M1/M2 subpopulations during ulcerative colitis-associated carcinogenesis in an AOM/DSS mouse model. AB - The high risk of developing colorectal carcinoma (CRC), from ulcerative colitis (UC), is well known. Macrophages are widely distributed immune cells that have an indispensable role in UC, as well as in CRC. However, little is currently known about the dynamic changes that occur in macrophage and M1/M2 macrophage subpopulations, during UC-associated carcinogenesis. The aim of the present study was to investigate the alteration of colorectal macrophages and M1/M2 macrophage subpopulations during UC-associated carcinogenesis. Both expression level alterations and functional changes were determined during UC-associated carcinogenesis in an azoxymethane/dextran sodium sulfate-induced chemically colitis-associated carcinoma mouse model of Crj:CD-1 (ICR) mice. Notable evidence from immunohistochemistry, flow cytometry, cytokine detection, and gene expression analyses demonstrated that M2 macrophages have a critical role in CRC initiation, promotion, and metastasis. M2 macrophages are associated with unbalanced pro-inflammatory and anti-inflammatory axes and aberrant enhancement of migration/invasion-associated factors. Functional changes, similar to M2 polarized macrophages, were shown to occur in the M1 macrophages, without phenotypical changes, during the development of carcinoma and metastasis. The results of the present study suggest that M2 macrophages have a pro-tumor role during UC-associated carcinogenesis. Furthermore, similar functional changes occurred in the M1 macrophages, without polarization alterations, during carcinogenesis and metastasis. PMID- 25434404 TI - Exact solution for first-order synchronization transition in a generalized Kuramoto model. AB - First-order, or discontinuous, synchronization transition, i.e. an abrupt and irreversible phase transition with hysteresis to the synchronized state of coupled oscillators, has attracted much attention along the past years. We here report the analytical solution of a generalized Kuramoto model, and derive a series of exact results for the first-order synchronization transition, including i) the exact, generic, solutions for the critical coupling strengths for both the forward and backward transitions, ii) the closed form of the forward transition point and the linear stability analysis for the incoherent state (for a Lorentzian frequency distribution), and iii) the closed forms for both the stable and unstable coherent states (and their stabilities) for the backward transition. Our results, together with elucidating the first-order nature of the transition, provide insights on the mechanisms at the basis of such a synchronization phenomenon. PMID- 25434405 TI - Phosphine-catalyzed dearomatizing [3+2] annulations of isoquinolinium methylides with allenes. AB - A phosphine-catalyzed dearomatizing [3+2] annulation of isoquinolinium methylides with allenoates or allenones yields highly functionalized pyrroloisoquinolines with high regioselectivity and in viable yields. PMID- 25434406 TI - Gene expression profile for predicting survival of patients with meningioma. AB - Current staging methods are inadequate for predicting the overall survival of meningioma. DNA microarray technologies improve the understanding of tumour progression. We analysed genome wide expression profiles of 119 meningioma samples from two previous published DNA microarray studies. The Cox proportional hazards regression models were applied to identify overall survival related gene signature. A total of 449 genes (109 upregulated and 340 downregulated) were identified as differentially expressed in meningioma. Among these differentially expressed genes, 37 genes were identified to be related to meningioma overall survival. Our 37-gene signature is closely associated with overall survival among patients with meningioma. This gene expression profile could provide an optimization of the clinical management and development of new therapeutic strategies for meningioma. PMID- 25434407 TI - Genetics of bovine respiratory disease in cattle: can breeding programs reduce the problem? AB - Genetics is responsible for approximately half the observed change in performance internationally in well-structured cattle breeding programs. Almost all, if not all, individual characteristics, including animal health, have a genetic basis. Once genetic variation exists then breeding for improvement is possible. Although the heritability of most health traits is low to moderate, considerable exploitable genetic variation does exist. From the limited studies undertaken, and mostly from limited datasets, the direct heritability of susceptibility to BRD varied from 0.07 to 0.22 and the maternal heritability (where estimated) varied from 0.05 to 0.07. Nonetheless, considerable genetic variation clearly exists; the genetic standard deviation for the direct component (binary trait), although differing across populations, varied from 0.08 to 0.20 while the genetic standard deviation for the maternal component varied from 0.04 to 0.07. Little is known about the genetic correlation between genetic predisposition to BRD and animal performance; the estimation of these correlations should be prioritized. (Long-term) Breeding strategies to reduce the incidence of BRD in cattle should be incorporated into national BRD eradication or control strategies. PMID- 25434408 TI - Evaluation of benzaldehyde derivatives from Morinda officinalis as anti-mite agents with dual function as acaricide and mite indicator. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by SFTS virus with 12-30% fatality rate. Despite severity of the disease, any medication or treatment for SFTS has not developed yet. One approach to prevent SFTS spreading is to control the arthropod vector carrying SFTS virus. We report that 2-methylbenzaldehyde analogues from M. officinalis have a dual function as acaricide against Dermatophagoides spp. and Haemaphysalis longicornis and indicator (color change) against Dermatophagoides spp. Based on the LD50 values, 2,4,5-trimethylbenzaldehyde (0.21, 0.19, and 0.68 MUg/cm(3)) had the highest fumigant activity against D. farinae, D. pteronyssinus, and H. longicornis, followed by 2,3-dimethylbenzaldehyde (0.46, 0.44, and 0.79 MUg/cm(3)), 2,4-dimethylbenzaldehyde (0.66, 0.59, and 0.95 MUg/cm(3)), 2,5 dimethylbenzaldehyde (0.65, 0.68, and 0.88 MUg/cm(3)), 2-methylbenzaldehyde (0.95, 0.87, and 1.28 MUg/cm(3)), 3-methylbenzaldehyde (0.99, 0.93, and 1.38 MUg/cm(3)), 4-methylbenzaldehyde (1.17, 1.15, and 3.67 MUg/cm(3)), and M. officinalis oil (7.05, 7.00, and 19.70 MUg/cm(3)). Furthermore, color alteration of Dermatophagoides spp. was shown to be induced, from colorless to dark brown, by the treatment of 2,3-dihydroxybenzaldehyde. These finding indicated that 2 methylbenzaldehyde analogues could be developed as functional agent associated with the arthropod vector of SFTS virus and allergen. PMID- 25434409 TI - Exercise intervention and health checks for middle-aged men with elevated cardiovascular risk: a randomized controlled trial. AB - OBJECTIVE: To study the effects of a health check by a nurse alone or combined with an exercise intervention in middle-aged men at increased cardiovascular risk. DESIGN: A randomized controlled trial. SETTING AND INTERVENTION: Primary care in Kirkkonummi municipality with 36 000 inhabitants. A health check by a nurse alone or combined with an exercise intervention to controls with no intervention was compared. SUBJECTS: A total of 168 men aged 35 to 45 years with at least two cardiovascular risk factors and physical activity (PA) frequency < 3 times a week. MAIN OUTCOME MEASURES: Metabolic syndrome (MetS) as defined by International Diabetes Federation/American Heart Association and self-reported PA frequency. RESULTS: Overall, focusing on health increased physical activity frequency in middle-aged men. After one year, 19% had increased PA to >= 3 times a week (95% CI 12-26). All study groups increased PA to >= 3 times: 26% of men in the exercise intervention group, 15% of men in the health check group, and 16% of controls. The differences between the groups were not statistically significant. The intervention did not have any meaningful impact on MetS or other cardiovascular outcomes at one-year follow up. CONCLUSIONS: Physical activity increased in all study groups of middle-aged men in this health-promotion trial. The interventions had no effect on metabolic syndrome or other cardiovascular outcomes in the participants. The trial increased awareness and collaboration in physical activity promotion among municipal health care and exercise services. PMID- 25434411 TI - A question of reproducibility. PMID- 25434410 TI - Cost consequences of point-of-care troponin T testing in a Swedish primary health care setting. AB - OBJECTIVE: To evaluate the safety and cost-effectiveness of point-of-care troponin T testing (POCT-TnT) for the management of patients with chest pain in primary care. DESIGN: Prospective observational study with follow-up. SETTING: Three primary health care (PHC) centres using POCT-TnT and four PHC centres not using POCT-TnT in south-east Sweden. PATIENTS: All patients >= 35 years of age, contacting one of the PHC centres for chest pain, dyspnoea on exertion, unexplained weakness and/or fatigue, with no other probable cause than cardiac, were included. Symptoms must have commenced or worsened during the previous seven days. MAIN OUTCOME MEASURES: Emergency referral rates, diagnoses of acute myocardial infarction (AMI) or unstable angina (UA), and costs were collected for 30 days after the patient sought care at the PHC centre. RESULTS: A total of 196 patients with chest pain were included: 128 in PHC centres with POCT-TnT and 68 in PHC centres without POCT-TnT. Fewer patients from the PHC centres with POCT TnT (n = 32, 25%) were emergently referred to hospital than from centres without POCT-TnT (n = 29, 43%; p = 0.011). Eight patients (6.2%) from PHC centres with POCT-TnT were diagnosed with AMI or UA compared with six patients (8.8%) from centres without POCT-TnT (p = 0.565). Two patients with AMI or UA were classified as missed cases from PHC centres with POCT-TnT and there were no missed cases from PHC centres without POCT-TnT. SKr290 000 was saved per missed case of AMI or UA. CONCLUSION: The use of POCT-TnT in primary care may be cost saving but at the expense of missed cases. PMID- 25434416 TI - Correction to Local massive venous invasion in colorectal cancer: CT-pathological correlation and its clinical implication. PMID- 25434417 TI - Expression of beta-nerve growth factor and homeobox A10 in experimental cryptorchidism treated with exogenous nerve growth factor. AB - With the exception of standard inguinal orchidopexy, treatment of cryptorchidism with human chorionic gonadotropin has been performed for several years; however, its side effects have limited its application. The beta-nerve growth factor (NGF) and homeobox A10 (HoxA10) genes are closely associated with the development of the testes. To the best of our knowledge, whether exogenous NGF alters the endogenous levels of NGF and HoxA10 in cryptorchidism in rats remains to be elucidated. The aim of the present study was to evaluate the gene and protein expression of NGF and HoxA10 in experimental cryptorchidism following treatment with exogenous NGF. A unilateral mechanical cryptorchidism model in Sprague Dawley rats was established and different concentrations of exogenous NGF were administered to observe the effects of NGF on cryptorchidism. Changes in the gene and protein expression levels of NGF and HoxA10 in the cryptorchid tissues of each group were identified using one step reverse transcription-quantitative polymerase chain reaction, in situ hybridization with digoxigenin-labeled-beta NGF RNA probes, immunofluorescence and immunohistochemistry, respectively. The expression levels of NGF and HoxA10 were markedly higher in the group treated with a high dose of exogenous NGF compared with the group treated with a low dose of exogenous NGF and the group treated with human chorionic gonadotropin. These results confirmed the potential therapeutic effect of exogenous NGF in human cryptorchidism. PMID- 25434418 TI - Three new polyunsaturated lipids from a Guangxi marine sponge Haliclona sp. AB - Three new polyunsaturated lipids, (6Z,9Z,12Z,15Z)-octadeca-6,9,12,15-tetraen-3 one (1), (6Z,9Z,12Z,15Z)-1-bromooctadeca-6,9,12,15-tetraen-3-one (2), and (Z) ethyl docos-5-enoate (3), together with two known polyunsaturated lipids, 4(Z),7(Z),10(Z)-tridecatrienoic acid (4) and (6Z,9Z,12Z,15Z)-octadeca-1,6,9,12,15 pentaen-3-one (5), were isolated from the marine sponge Haliclona sp., which was collected from Guangxi, using HSCCC and HPLC methods. Chemical structures of the five compounds were elucidated by spectroscopic techniques. PMID- 25434419 TI - Stem cells in the management of heart failure: what have we learned from clinical trials? AB - Research shows that various types of stem cells (SCs) have the ability to rebuild damaged heart tissue. The TIME and Late TIME human trials shed light on the optimum timing of SC therapy administration after myocardial damage. The FOCUS study failed to show a substantial positive effect of bone marrow-derived mononuclear cells in patients suffering from ischemic heart failure; however, some completed human trials do show promise, with improvement in cardiac function. Recent clinical trials have identified a subset of marrow cells that was able to stimulate endogenous adult cardiac SCs where cardiac SCs administration showed promise in the SCIPIO trial. This review addresses some of the lessons learned from clinical trials with SC therapy in ischemic heart failure. PMID- 25434420 TI - The association between improved quality diabetes indicators, health outcomes and costs: towards constructing a "business case" for quality of diabetes care--a time series study. AB - BACKGROUND: In primary health care systems where member's turnover is relatively low, the question, whether investment in quality of care improvement can make a business case, or is cost effective, has not been fully answered.The objectives of this study were: (1) to investigate the relationship between improvement in selected measures of diabetes (type 2) care and patients' health outcomes; and (2) to estimate the association between improvement in performance and direct medical costs. METHODS: A time series study with three quality indicators - Hemoglobin A1c (HbA1c) testing, HbA1C and LDL- cholesterol (LDL-C) control - which were analyzed in patients with diabetes, insured by a large health fund. Health outcomes measures used: hospitalization days, Emergency Department (ED) visits and mortality. Poisson, GEE and Cox regression models were employed. Covariates: age, gender and socio-economic rank. RESULTS: 96,553 adult (age >18) patients with diabetes were analyzed. The performance of the study indicators, significantly and steadily improved during the study period (2003-2009). Poor HbA1C (>9%) and inappropriate LDL-C control (>100 mg/dl) were significantly associated with number of hospitalization days. ED visits did not achieve statistical significance. Improvement in HbA1C control was associated with an annual average of 2% reduction in hospitalization days, leading to substantial reduction in tertiary costs. The Hazard ratio for mortality, associated with poor HbA1C and LDL-C, control was 1.78 and 1.17, respectively. CONCLUSION: Our study demonstrates the effect of continuous improvement in quality care indicators, on health outcomes and resource utilization, among patients with diabetes. These findings support the business case for quality, especially in healthcare systems with relatively low enrollee turnover, where providers, in the long term, could "harvest" their investments in improving quality. PMID- 25434422 TI - Directed assembly of living Pseudomonas aeruginosa bacteria on PEI patterns generated by nanoxerography for statistical AFM bioexperiments. AB - Immobilization of living micro-organisms on predefined areas of substrates is a prerequisite for their characterizations by atomic force microscopy (AFM) in culture media. It remains challenging since micro-organisms should not be denatured but attached strongly enough to be scanned with an AFM tip, in a liquid phase. In this work, a novel approach is proposed to electrostatically assemble biological objects of interest on 2 nm thick polyethylenimine (PEI) patterns fabricated by nanoxerography. This nanoxerography process involves electrostatic trapping of PEI chains on negatively charged patterns written on electret thin films by AFM or electrical microcontact printing. The capability of this approach is demonstrated using a common biological system, Pseudomonas aeruginosa bacteria. These negatively charged bacteria are selectively assembled on large scale arrays of PEI patterns. In contrast to other PEI continuous films commonly used for cell anchoring, these ultrathin PEI patterns strongly attached on the surface do not cause any denaturation of the assembled Pseudomonas aeruginosa bacteria. AFM characterizations of large populations of individual living bacteria in culture media can thus be easily performed through this approach, providing the opportunity to perform representative statistical data analysis. Interestingly, this process may be extended to any negatively charged micro organism in solution. PMID- 25434421 TI - NCR1+ cells in dogs show phenotypic characteristics of natural killer cells. AB - No specific markers for natural killer (NK) cells in dogs have currently been described. NCR1 (NKp46, CD355) has been considered a pan species NK cell marker and is expressed on most or all NK cells in all species investigated except for the pig which has both a NCR1(+) and a NCR1(-) population. In this study peripheral blood mononuclear cells (PBMC) from 14 healthy dogs, 37 dogs with a clinical diagnosis, including a dog diagnosed with LGL leukemia, and tissue samples from 8 dogs were evaluated for NCR1(+) expression by a cross reacting anti bovine NCR1 antibody. CD3(-)NCR1(+) cells were found in the blood of 93 % of healthy dogs and comprised up to 2.5 % of lymphocytes in PBMC. In a selection of healthy dogs, sampling and immunophenotyping were repeated throughout a period of 1 year revealing a substantial variation in the percentage of CD3(-)NCR1(+) over time. Dogs allocated to 8 disease groups had comparable amounts of CD3(-)NCR1(+) cells in PBMC to the healthy individuals. All organs examined including liver, spleen and lymph nodes contained CD3(-)NCR1(+) cells. Circulating CD3(-)NCR1(+) cells were further characterized as CD56(-)GranzymeB(+)CD8(-). A CD3(+)NCR1(+) population was observed in PBMC in 79 % of the healthy dogs examined representing at the most 4.8 % of the lymphocyte population. In canine samples examined for CD56 expression, CD56(+) cells were all CD3(+) and NCR1(-). To our knowledge, this is the first examination of NCR1 expression in the dog. The study shows that this NK cell associated receptor is expressed both on populations of CD3(+) and CD3(-) blood lymphocytes in dogs and the receptor is found on a CD3(+) GranzymeB(+) CD8(+) leukemia. Our results support that CD56 is expressed only on CD3(+) cells in dogs and shows that NCR1 defines a different CD3(+) lymphocyte population than CD56(+)CD3(+) cells in this species. CD3(-)NCR1(+) cells may represent canine NK cells. PMID- 25434424 TI - Hybrid uranium-transition-metal oxide cage clusters. AB - Transition-metal based polyoxometalate clusters have been known for decades, whereas those built from uranyl peroxide polyhedra have more recently emerged as a family of complex clusters. Here we report the synthesis and structures of six nanoscale uranyl peroxide cage clusters that contain either tungstate or molybdate polyhedra as part of the cage, as well as phosphate tetrahedra. These transition-metal-uranium hybrid clusters exhibit unique polyhedral connectivities and topologies that include 6-, 7-, 8-, 10-, and 12-membered rings of uranyl polyhedra and uranyl ions coordinated by bidentate peroxide in both trans and cis configurations. The transition-metal polyhedra appear to stabilize unusual units built of uranyl polyhedra, rather than templating their formation. PMID- 25434423 TI - Sister chromatid exchange: A possible approach to characterize familial breast cancer patients. AB - Sister chromatid exchange (SCE) frequency is widely used as an indicator of spontaneous chromosome instability. We investigated SCE frequency in the peripheral blood lymphocytes of familial and sporadic breast cancer (BC) patients from the Apulian Caucasian Population. Eighty-one patients were enrolled: 22 with familial history and 59 sporadic patients. Eleven familial patients had an 'increased risk' of BRCA gene mutation (BRCAPro >= 10%) and were candidates for BRCA1 and BRCA2 mutation analysis. For these reasons, we stratified the 22 familial BC patients in two group: 'low-risk' (n=11) and 'high-risk' (n=11) patients for BRCA gene mutations. Two of these 11 'high-risk' patients (18%) had pathogenic mutations in the BRCA2 gene. The subjects were not cigarette smokers or alcohol or drug users, and had no genetic disorders or chronic diseases affecting the family. Our results showed a significant increase in SCE frequency in the familial (5.305 +/- 1.088/metaphase) (P<0.0001) and the sporadic patients (3.943 +/- 0.552) (P<0.0001) compared to the controls (3.197 +/- 0.649). We found that the SCE frequency was always significantly higher in familial than in sporadic patients, regardless of their clinicopathological characteristics. Moreover, we observed that the frequency of SCE in BRCA2 mutation carrier patients was higher compared to patients without mutations in BRCA1/2 genes. These findings highlight an intrinsic genomic instability in familial patients, and we suggest that SCE frequency may be used as a biomarker to better characterize familial BC. PMID- 25434425 TI - Protein extracts of Crassostrea gigas alleviate CCl4-induced hepatic fibrosis in rats by reducing the expression of CTGF, TGF-beta1 and NF-kappaB in liver tissues. AB - Hepatic fibrosis may contribute to liver carcinoma and the mortality of patients with hepatic fibrosis is gradually increasing. However, no definitive treatment has been established for hepatic fibrosis. The hepatic fibrotic process is reversible and can be controlled; therefore, the creation of novel and effective therapeutic methods to prevent or reverse the disease is required. The aim of the present study was to identify whether protein extracts from Pacific oysters (PEPO) could alleviate the hepatic fibrosis induced by CCl4 and to examine the mechanisms involved. A total of sixty rats were randomly divided into the following experimental groups: The normal control group; the hepatic fibrosis model group; the high-dose; medium-dose; and low-dose PEPO groups; and the colchicine group. The results indicated that compared with those of the model group, PEPO treatment significantly decreased the serum levels of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, alkaline phosphatase, hyaluronic acid, laminin, collagen type IV and procollagen III in rats with hepatic fibrosis. The hematoxylin and eosin staining demonstrated that PEPO markedly alleviated hepatic fibrosis. The experiments using immunohistochemistry, western blotting and quantitative PCR indicated that protein and mRNA expression levels of connective tissue growth factor (CTGF), transforming growth factor beta1 (TGFbeta-1) and nuclear factor kappaB (NF kappaB) in the liver tissues were significantly reduced by PEPO treatment. Therefore, it was concluded that PEPO successfully alleviated hepatic fibrosis induced by CCl4 and reversed the effects of hepatotoxicity by regulating the serum levels of enzymes and decreasing the expression levels of CTGF, TGF-beta1 and NF-kappaB in liver tissues. These findings may provide a novel treatment option for patients with hepatic fibrosis in the future. PMID- 25434427 TI - Firefly luciferase inhibition: a widely neglected problem. PMID- 25434428 TI - Utility of the Vivosonic IntegrityTM auditory brainstem response system as a hearing screening device for difficult-to-test children. AB - OBJECTIVE: Inability to complete a behavioral hearing screening is a challenge for children with developmental disorders or who are otherwise difficult to test, defined here as unable or unwilling to complete a behavioral screening. The study compared referral rates from screenings that used behavioral methods alone, with screenings that added a screen with the Vivosonic IntegrityTM auditory brainstem response (ABR) device. DESIGN: Behavioral screening was performed first. Those children who failed were re-screened with the Vivosonic Integrity ABR device. Changes in referral and screening completion rates after the second screening were calculated and analysed. STUDY SAMPLE: The participant population (n = 43) consisted of children with diagnosed developmental disorders. RESULTS: Adding the Vivosonic Integrity to the screening protocol significantly increased the proportion of children who completed the screening, from 57% after behavioral screening to 81% after behavioral and ABR screening. The addition of the ABR screen did not change that overall pass/refer rate, in part because four participants who did not complete the behavioral screen received a 'Refer' outcome on the ABR screen. CONCLUSIONS: The results indicate that the Vivosonic Integrity device could be a useful tool for hearing screening of children who are difficult to screen using behavioral procedures. PMID- 25434429 TI - Evaluation of new technology for intraoperative evoked compound action potential threshold measurements. AB - OBJECTIVE: To determine whether new technology for intraoperative evoked compound action potential (ECAP) threshold measurements-the CR120 Intraoperative Remote Assistant device-is comparable to the existing Custom Sound((r)) clinical system, as well as assess test-retest accuracy of the systems. DESIGN: Within subject, repeated measures comparative design. STUDY SAMPLE: ECAP data were collected from 81 pediatric subjects (41 females and 40 males). RESULTS: The average ECAP threshold measurement time for the Custom Sound system was 6.2 minutes (SD = 1.0) versus 4.8 minutes (SD = 0.7) for the CR120 device. ECAP thresholds measured with Custom Sound and the CR120 device had an average Pearson product-moment correlation coefficient for all electrodes (N = 1724) of 0.92, p < 0.01; an average mean absolute difference of 6 CLs (SD = 6); and a 95% confidence interval of - 1 to 1 CLs. The test-retest results for Custom Sound and the CR120 device are also included. CONCLUSION: A significant reduction in the measurement time for ECAP thresholds was noted with the CR120 device. Furthermore, ECAP thresholds measured with the CR120 device are equivalent to Custom Sound within a clinically acceptable range. PMID- 25434430 TI - Plasmonic metal scattering immunoassay by total internal reflection scattering microscopy with nanoscale lateral resolution. AB - Immunoassays on nanopatterned chips through TIRS detection based on reconstructing the three dimensional position provided a nanoscale accuracy of the lateral resolution by using the z-stage controller in the spatial range up to 10 nm. This method offers highly accurate and sensitive quantification with the zeptomolar (~10(-21) M) detection of proteins. PMID- 25434432 TI - Multiplex plasmonic anti-counterfeiting security labels based on surface-enhanced Raman scattering. AB - We demonstrate a multiplex plasmonic anti-counterfeiting platform by embedding multiple molecules on a single substrate with superior nanometer scale spectral and spatial resolution. The encoded specific molecular information can be read out only using Raman spectroscopy. Multiplexing increases the complexity of these plasmonic security labels without compromising the spectral resolution. PMID- 25434431 TI - Correlation between micrometer-scale ripple alignment and atomic-scale crystallographic orientation of monolayer graphene. AB - Deformation normal to the surface is intrinsic in two-dimensional materials due to phononic thermal fluctuations at finite temperatures. Graphene's negative thermal expansion coefficient is generally explained by such an intrinsic property. Recently, friction measurements on graphene exfoliated on a silicon oxide surface revealed an anomalous anisotropy whose origin was believed to be the formation of ripple domains. Here, we uncover the atomistic origin of the observed friction domains using a cantilever torsion microscopy in conjunction with angle-resolved photoemission spectroscopy. We experimentally demonstrate that ripples on graphene are formed along the zigzag direction of the hexagonal lattice. The formation of zigzag directional ripple is consistent with our theoretical model that takes account of the atomic-scale bending stiffness of carbon-carbon bonds and the interaction of graphene with the substrate. The correlation between micrometer-scale ripple alignment and atomic-scale arrangement of exfoliated monolayer graphene is first discovered and suggests a practical tool for measuring lattice orientation of graphene. PMID- 25434433 TI - [Problems of and solutions of the Japanese general rules of cancer handling]. AB - More than 27 series of the Japanese general rules of cancer handling, which comprise the basic foundations of cancer diagnosis and treatment, are currently used for routine clinical management in Japan. However, important concerns such as compatibility with the Union for International Cancer Control (UICC) tumor node-metastasis (TNM) classification, the lack of unity of revised time, and unsuitable term definitions during consensus have emerged following medical globalization, advances in medical treatment, and legislation regarding cancer registration in hospital, which will begin 2015. To efficiently employ the strong points of the Japanese general rules of cancer handling and conquer the problems associated with cancer treatment globalization in Japan, immediate unification of the current Japanese general rules of cancer handling is thought to be required. In this paper, I would like to propose a method for solving these problems henceforth by clarifying the problems associated with the Japanese general rules of cancer handling and establishing future relationships between the Japanese general rules of cancer handling and the UICC-TNM and American Joint Committee on Cancer (AJCC). More than 27 series of the Japanese general rules of cancer handling, which comprise the basic foundations of cancer diagnosis and treatment, are currently used for routine clinical management in Japan. However, important concerns such as compatibility with the Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) classification, the lack of unity of revised time, and unsuitable term definitions during consensus have emerged following medical globalization, advances in medical treatment, and legislation regarding cancer registration in hospital, which will begin 2015. To efficiently employ the strong points of the Japanese general rules of cancer handling and conquer the problems associated with cancer treatment globalization in Japan, immediate unification of the current Japanese general rules of cancer handling is thought to be required. In this paper, I would like to propose a method for solving these problems henceforth by clarifying the problems associated with the Japanese general rules of cancer handling and establishing future relationships between the Japanese general rules of cancer handling and the UICC-TNM and American Joint Committee on Cancer (AJCC). PMID- 25434434 TI - [Current clinical issues and recent trends in hereditary breast and ovarian cancer in Japan-genetic testing for HBOC and risk-reducing surgery]. AB - The recognition of hereditary breast and ovarian cancer (HBOC) is gradually spreading in Japan after a famous American actress made it public that she underwent risk-reducing mastectomy (RRM) based on mutation of BRCA1. HBOC is a cancer susceptibility syndrome involving breast, ovarian, or prostate cancers due to germline mutation of BRCA1 or BRCA2. Although the frequency is low, genomic rearrangement is also found in Japan; therefore, in addition to PCR-direct sequencing, multiplex ligation-dependent probe amplification (MLPA) should be performed in genetic testing for HBOC. Recently, candidate genes other than BRCA1/2, such as RAD51C, PALB2, and BRIP1, have been identified for hereditary breast cancers. Variants of uncertain significance are seen in approximately 4-6% of all genetic testing reports for BRCA1/2. ACMG recommends the use of the term"variant"in addition to a modifier such as pathogenic, benign, and so on, instead of terms such as mutation or polymorphism. The incidence of ovarian cancer is not increased in women from breast cancer-only families that test negative for BRCA1/2 mutations. Therefore, intensive gynecological surveillance may not be needed for these clients. Basic data such as penetrance and cumulative risks of HBOC in Japanese populations are insufficient for risk assessment in genetic counseling. The Japanese HBOC consortium was established, and as one of the activities of the consortium, the registration project will start to provide essential genetic information in clinical practice. In Japan risk-reducing surgeries are, albeit gradually, increasingly being performed to potentially protect mutation carriers against HBOC. Risk-reducing salpingo-oophorectomy (RRSO) is effective in the reduction of the incidence of breast cancer, as well as of ovarian cancer. Furthermore, RRSO is associated with improved overall survival in BRCA1/2 mutation carriers. RRM also reduces the risk of breast cancer by more than 90%, but the survival benefit remains unknown. Recently, contralateral RRM has shown improved overall survival in a prospective analysis. Pathological examination of resected surgical specimens from RRSO revealed that some serous ovarian carcinomas originated from fimbriae of the uterine tube, showing focal p53 overexpression (p53 signature) in the tubal epithelium. Therefore, initial bilateral salpingectomy followed by a delayed oophorectomy may be a proposed alternative to RRSO, but there is no prospective evidence on the efficacy of bilateral salpingectomy. PMID- 25434435 TI - [Robot-assisted surgery-the current state of radical prostatectomy]. AB - Minimally invasive surgeries such as laparoscopic surgery and robot-assisted surgery have become validated treatment modalities and hold a prominent position in clinical practice. Robot-assisted radical prostatectomy(RARP)is a relatively new procedure. Because this technique does not require the urologist to overcome a steep and long learning curve, a dramatic increase in the number of RARP surgeries was observed in recent years and RARP has rapidly gained acceptance in the Japanese urological community after its introduction in Japan in 2006. Robot assisted surgery that combines optical magnification, three-dimensional vision, and instruments with 7 degrees of freedom allows surgeons to perform meticulous, precise, and accurate movements. In summary, for the previously mentioned reasons, RARP is considered to be an effective procedure for improving intraoperative blood loss, the transfusion and complication rates, as well as the recovery of urinary continence and potency rates. In this article, we briefly describe the evolution of this minimally invasive technique. In addition, we present the current state of RARP and a critical evaluation of the learning curves associated with performing RARP as well as published oncological, continence, and potency outcomes. PMID- 25434436 TI - [Current status and future prospects of robotic surgery for lung cancer]. AB - As the use of robotic surgery has widely spread, its usefulness in the field of general thoracic surgery needs to be verified. The biggest advantage of robotic surgery is the remarkably free movement of joint-equipped robotic forceps under 3 dimensional high vision. An accurate operation makes complex procedures straightforward and may overcome the disadvantages of previous thoracoscopic surgery. Robotic surgery for lung cancer has been safely introduced, and the initial results have been favorable. While still at the stage of clinical research, it is expected to be useful in hilar exposure, lymph node dissection, and suturing of lung parenchyma or bronchus. We considered robotic surgery for lung cancer surgery because of its ability to facilitate both thoracotomy and minimally invasive video-assisted thoracic surgery. Robotic thoracic surgery has not been sufficiently examined for its usefulness, and other major issues such as safety management, education, and significant cost need to be addressed. However, it may become an extension of thoracoscopic surgery, and studies showing its usefulness for primary lung cancer have been increasing. Two urgent issues are its use in advanced medical care and national heal th insurance coverage. PMID- 25434437 TI - [Uterine cancer]. AB - It is thought that robotic surgery is highly useful for uterine malignant tumor such as endometrial cancer and cervical cancer. It is nothing but that robotic surgery enables us the correct and delicate movement of forceps, which is necessary for operative procedures at the deep and narrow space in the pelvic cavity and the perivascular lymphadenectomy. By our experience, significant reduction of blood loss and shortening of the hospital stay were accepted in the cases of endometrial cancer and cervical cancer. At present the robotic surgery in uterine cancer in Japan lags far behind the USA In order not to miss the trend in the world, it is required for the robotic surgery of uterine cancer to spread widely in Japan from now on. For this purpose, it is necessary to accumulate cases on the assumption that advanced medical care and also insurance adaptation. PMID- 25434438 TI - [Current status of robotic surgery for gastric cancer]. AB - Robotic surgery was launched in Japan in 2000.In particular, the development of the da Vinci S Surgical System was a major breakthrough. It was introduced in Japan for the first time through our hospital in January 2009. Since then, the number of surgical robots used has been dramatically increasing, with up to approximately 160 robots all over the country. To date, we have performed more than 500 robotic surgeries, including 180 gastrectomies, at our hospital. Our data suggest that compared with the conventional laparoscopic approach, the use of the da Vinci Surgical System in minimally invasive gastrectomy for gastric cancer might improve short-term outcomes, particularly in terms of preventing postoperative local complications. Thus, we believe that use of surgical robots become increasingly beneficial for more extensive resections and operations that require more advanced skills, even though a couple of issues remain to be solved, such as long operative time, high cost, and limited experience and evidence. In this article, the current status and future perspectives regarding robotic gastrectomy for gastric cancer are presented based on our experience and a review of the literature. PMID- 25434439 TI - [Colorectal cancer]. AB - Since the da Vinci(r)surgical system was adopted, the use of robotic surgery has become widespread. The safety and feasibility of colorectal cancer surgery have been described, comparing laparoscopic surgery with robotic surgery. For rectal cancer surgery, it is important to achieve a good balance between radical cure of the rectal cancer and functional preservation, based on progression of the rectal cancer. Advantages of robotic surgery include 1) stable control of the camera and surgical field by the surgeon; 2) flexibility within the narrow cavity of the pelvis, facilitated by complicated manipulation of forceps; and 3) rendering of poorly operative and technical difficult surgeries in the deep cavity of the pelvis easy through intuitive operation.Because of these advantages, robotic surgery is expected to provide both curability of rectal cancer and preservation of urogenital function via nerve sparing. There is also less blood loss compared to laparotomy and laparoscopic surgery.In order to provide more patients with robotic surgery under health insurance coverage, further evidence on safety and efficacy needs to be established. PMID- 25434440 TI - [Treatment algorithm for oxaliplatin-induced peripheral neuropathy]. AB - Oxaliplatin (L-OHP) is a key drug in the treatment of colorectal cancer; however, L-OHP-induced peripheral neuropathy becomes a dose-limiting factor for which withdrawal is the only effective option. In the present study, we attempted to treat L-OHP-induced peripheral neuropathy using the algorithm consisting of pregabalin, duloxetine, and oxycodone at Iwate Medical University Hospital. The first, second, and third stages of the algorithm consist of pregabalin, duloxetine, and oxycodone, respectively. We examined the usefulness and safety of the treatment algorithm for 27 patients with colorectal cancer by evaluating the side effects and degree of improvement of subjective symptoms. When discontinuation was necessary due to adverse events or invalid treatment during the 4-week study period, the patient was transitioned to the next stage. The response rates of the first, second, and third stages of the algorithm were 33% (9/27), 33% (6/18), and 17% (1/6), respectively, whereas the overall response rate was 59% (16/27). The side effect rates of the first, second, and third stages were 37% (10/27), 33% (6/18), and 83% (5/6), respectively. Somnolence was the most common side effect of these drugs. Thus, our treatment algorithm appears to be useful for L-OHP-induced peripheral neuropathy. However, pregabalin, duloxetine, and oxycodone should be administered with specific attention on the potential side effects. PMID- 25434441 TI - [Denosumab for bone metastasis of thoracic tumors-preparation of a practice manual and evaluation of its effectiveness]. AB - The anti-receptor activator of nuclear factor-kB ligand (RANKL) antibody denosumab is thought to be useful in the improvement of the quality of life of patients with bone metastasis from thoracic tumors, given the ease of its subcutaneous administration. However, attention has to paid to the onset of hypocalcemia when determining the optimal dosage, especially since data and methods on its prevention are limited. Our project team monitored serum calcium levels in patients receiving denosumab treatment, evaluated methods to supplement calcium and vitamin D in cases of hypocalcemia, and developed an evidence-based common manual. Subsequently, denosumab administration and hypocalcemia were evaluated as per the manual. Grade 3 hypocalcemia was observed in 2 cases before the preparation, with no new cases seen since adopting the new protocol in the manual. We conclude that the development of severe hypocalcemia associated with denosumab treatment can be avoided by prompt management of this condition in the early stages and by adopting measures listed in the practice manual. PMID- 25434442 TI - [A study of 31 terminally ill cancer patients who received pure oxycodone injections at home]. AB - Since the launch of pure oxycodone injections in May 2012, it has been possible to use oxycodone without opioid rotation. Although an extremely important step showing progress, very few studies regarding the use of pure oxycodone injections have been performed. In this study, we evaluated the safety and efficacy of pure oxycodone injections in 31 terminally ill cancer patients receiving home care. The difficulty in oral oxycodone intake was the main reason for changing to pure oxycodone injections. The mean administered period of subcutaneous pure oxycodone was 5.6 +/- 6.7 days. One out of 5 patients receiving pure oxycodone injections complained of worsening sleepiness. However, other symptoms improved. In addition, in cases wherein pure oxycodone injection was the initiating opioid, 1 out of 6 patients showed no improvement of respiratory discomfort, while other symptoms improved. It was difficult to evaluate more patients because of the short period for administration. Although 5 patients experienced skin problems, they were successfully managed by changing the injection site. Of these 5 patients, 2 patients had sensitive skin, with a previous history of alcohol rash. In conclusion, our study suggests that pure oxycodone injections are beneficial over oral oxycodone treatment for terminally ill cancer patients. However, further evaluation of skin problems associated with pure oxycodone injections is required by performing larger studies. PMID- 25434443 TI - [Efficacy and safety of transdermal fentanyl patches for opioid initiation in patients with gastrointestinal obstruction]. AB - The transdermal fentanyl patch (TDF) can be used when switching from other opioids; therefore, little is known about the efficacy and safety of TDF patches applied for opioid initiation. However, TDF patches have been applied for opioid initiation in gastrointestinal cancer patients with gastrointestinal obstruction. In this study, we retrospectively investigated 12 gastrointestinal cancer patients to evaluate the efficacy and frequency of adverse effects of TDF patches compared to oral oxycodone (OXY) for opioid initiation. The frequency of adverse effects such as nausea, somnolence, and constipation in the TDF patch group was 25%, 41.7%, and 8.3%, respectively. No severe adverse effects were observed, and there was no significant difference between the TDF patch and OXY groups. Moreover, according to the numerical pain rating scale(ranging from 0 [no pain] to 10 [worst possible pain]), the pain intensity in the TDF patch group decreased from 5.42 on the first day to 3.33 after 3 days (p=0.0377), and 2.67 after 7 days (p=0.0089), with no significant difference between groups. Our study results suggest that TDF patches applied for opioid initiation may be useful for gastrointestinal cancer patients with gastrointestinal obstruction. PMID- 25434444 TI - [Therapeutic effect of rebamipide for oral mucositis associated with FEC therapy for breast cancer]. AB - No guidelines for supportive drug therapy have been established for oral mucositis occurring during cancer chemotherapy. We retrospectively examined the progression of oral mucositis in 91 patients with breast cancer who received the 5-fluorouracil, epirubicin, and cyclophosphamide (FEC)-100 regimen between September 2007 and August 2008. Daily rebamipide was administered to patients with oral mucositis as per hospital protocol to evaluate the hypothesized preventive and mucosal protective effects of rebamipide(Mucosta(r)). Oral mucositis was observed in 43 patients (47%)during 4 courses of FEC. The median age of the patients was 55 years(range, 32-76 years). Of the 91 patients, 49 patients who did not receive rebamipide during the 4 FEC courses were classified as group A, 14 patients who received rebamipide before the start of FEC were classified as group B, and 28 patients who received rebamipide after developing oral mucositis were classified as group C. The incidence of oral mucositis at the start of FEC with or without rebamipide administration was observed in 5 patients in group B (36%) and 38 patients in groups A and C (49%) (p=0.3472). The mucositis grade was G1 in 4 patients and G2 in 1 patient in group B, and G1 in 20 patients and G2 plus G3 in 18 patients in groups A and C (p=0.2467). In group C, the grade decreased in 25 patients (89%) and did not occur (G0) in 17 patients (61%) during the next course, and 15 patients (54%) continued to the final course without any occurrence of mucositis. These results suggest that rebamipide is effective for the treatment of oral mucositis. Although significant differences were not observed in the groups, rebamipide has the potential to prevent development of oral mucositis and alleviate its symptoms, and seems promising as a new supportive drug therapy. We hope to verify the preventive and protective effects of rebamipide by conducting a prospective, randomized trial while treating oral mucositis with basic oral care and appropriate interventions provided by a multidisciplinary team. PMID- 25434445 TI - [Effect of lidocaine gargling on taste perception]. AB - Because stomatitis is a painful condition, gargling with lidocaine is often prescribed before meals. However, because lidocaine inhibits nerve conduction, lidocaine gargling may affect taste perception. Therefore, we studied the effects of lidocaine gargle on taste. We prepared samples of the 5 basic tastes at equivalent concentration levels in terms of the taste quotient. We conducted sensory tests to judge whether the samples could be tasted, and the threshold concentrations (50% taste rate) were estimated from the taste rates. The sensory test was repeated after the subjects gargled with lidocaine, and the efficacy ratio was calculated by comparing the threshold concentrations. Although no interaction was observed between the lidocaine gargle and the threshold concentration levels in the logistic regression analysis, significant differences were observed in the primary effects of each standard, such as the concentration levels, flavor, and bitterness. When the efficacy ratios based on the threshold values were calculated, increases in the thresholds for flavor and bitterness were observed. The results of this study suggested that gargling with lidocaine before a meal increases the thresholds for the appreciation of flavor and bitterness. This increase in the threshold values due to lidocaine was associated not with the pharmacological effect of the drug but with its strong bitterness. PMID- 25434446 TI - [Long-term disease-free survival by S-1 therapy in a case of gastric cancer with peritoneal dissemination]. AB - The patient was a 77-year-old woman who underwent gastrectomy for gastric cancer. Since the patient had positive peritoneal washing cytology and positive peritoneal dissemination, she was started on oral S-1 therapy post-surgery for 4 weeks, followed by a 2-week rest period. During the first course of therapy, her white blood cell count decreased; therefore, the regimen was changed to a 1-week administration, followed by a 1-week rest period. No subsequent adverse events were noted. The patient has experienced no relapse in the four years she has been followed up after surgery in our outpatient clinic. We report our experience with an elderly patient for whom S-1 monotherapy was effective in the treatment of gastric cancer with peritoneal dissemination. PMID- 25434447 TI - [Gastric cancer with liver metastasis and peritoneal dissemination treated with conversion surgery to achieve r0 resection after capecitabine, cisplatin, and trastuzumab chemotherapy-a case report]. AB - Herein, we present a case report suggesting the importance of conversion surgery and the effectiveness of adjuvant chemotherapy with trastuzumab. A 77-year-old woman was diagnosed with gastric cancer complicated by multiple liver metastases and peritoneal dissemination. Owing to a HER2 immunohistochemistry (IHC) tumor score of 3+, we initiated capecitabine plus cisplatin (CDDP) plus trastuzumab chemotherapy. Subsequently, the liver metastases and peritoneal dissemination were absent on computed tomography images, and no new metastatic lesions developed during chemotherapy. After 10 chemotherapy courses, the patient underwent distal gastrectomy and 2 partial liver resection procedures. The liver metastasis remained, and it received a score of 2+ on the HER2 IHC test. We have continued to administer postoperative capecitabine plus trastuzumab chemotherapy because no metastatic lesions have appeared. PMID- 25434449 TI - [A case of cStage III B non-squamous non-small-cell lung cancer completely resected after downstaging with chemotherapy]. AB - A 64-year-old man was diagnosed with a gastric ulcer, and a tumor shadow was observed in the right lower lung field on a chest radiograph. Chest computed tomography (CT) revealed the tumor shadow to be 33 * 25 mm in the right lower lobe; it also revealed a 7-mm nodule in the right S3, and lymph node swelling in the upper and lower mediastinum. Positron emission tomography (PET)-CT revealed an SUVmax of 12.8, 1.2, 7.6, and 10.0 for the right lower lobe tumor, right S3 nodule, and the No. 4 and No. 7 lymph nodes, respectively. The right lower lobe tumor was diagnosed as an adenocarcinoma via transbronchiall ung biopsy. The patient was diagnosed with cT4N2M0, cStage III B cancer. Four courses of carboplatin, pemetrexed, and bevacizumab were administered. After the fourth course, chest CT revealed that the right lower lobe tumor and the right S3 nodule significantly reduced to 14 * 7 mm and 5mm respectively, and the mediastinal lymph node swelling was nearly eliminated. Subsequent PET-CT examination revealed an SUVmax of 1.3 and 0.8 in the right lower lobe tumor and right S3 nodule, respectively. The patient was diagnosed with ycT4N0M0, ycStage III A cancer, and he underwent right lower lobe resection, right S3 partial resection, and lymph node. Postoperative pathological analysis was used to make a diagnosis of mixed type adenocarcinoma for the right lower lobe tumor, and a diagnosis of papillary adenocarcinoma for the right S3 nodule. Both tumors were diagnosed as primary lung cancers. There were no metastatic cancer cells in the dissected lymph nodes. PMID- 25434448 TI - [A case of cecum colon cancer with lymph node metastasis successfully treated with XELOX plus bevacizumab]. AB - A 65-year-old woman with a history of constipation presented at our hospital and was subsequently diagnosed with advanced cecum cancer. We performed laparoscopic right hemicolectomy in January 2009, with pathological findings reveal- ing the presence of Stage III b (pT3, pN3, cM0, Cur A) disease. The patient was treated with a uracil/tegafur plus Leucovorin (UFT/LV) adjuvant chemotherapy regimen for six months. In June 2010, bold examination indicated an elevated level of tumor marker CA19-9. Computed tomography (CT) and positron emission tomography (PET)/CT revealed Virchow's and para-aortic lymph node metastasis. Therapy with XELOX and bevacizumab (Bmab) was administered and continued for 10 cycles. Capecitabine+Bmab treatment was also administered for 11 courses due to an adverse event of peripheral neuropathy. Follow-up revealed both the Virchow's and para-aortic lymph node metastasis had disappeared upon completion of treatment. In November, 2011 the patient was considered to have achieved a clinical complete response (CR) and continues to be followed with no further disease progression. PMID- 25434450 TI - [A case of stage IV breast cancer successfully treated over 1 year with eribulin as fourth-line systemic chemotherapy]. AB - A 59-year-old woman with an exudative, reddish bilateral breast tumor and dyspnea visited our hospital. She was diagnosed as having scirrhous carcinoma with metastasis to the liver and pleural effusion, designated as Stage IV, hormone receptor positive, and human epidermal growth factor receptor-2 (HER2) negative. Systemic chemotherapy (3 regimens) and endocrine therapy (5 regimens) were administered for a total of 5 years 7 months. Eribulin was administered as fourth line systemic chemotherapy. The pleural effusion reduced and dyspnea improved. Her status was maintained for 1 year 3 months. This case suggests that eribulin may provide long-term survival and maintenance of quality of life (QOL) in metastatic breast cancer patients. PMID- 25434451 TI - [A case of platinum-resistant, recurrent ovarian clear cell adenocarcinoma successfully treated with irinotecan (CPT-11) and paclitaxel (PTX) chemotherapy]. AB - A 40-year-old woman presented to a local clinic with abdominal distension. She was referred to our hospital for suspected ovarian cancer. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed an ovarian tumor with mural nodules, ascites, pleural effusion, and peritoneal dissemination. Laparotomy revealed a 20-cm right ovarian tumor with strong adhesion to the uterus and rectum. Bilateral salpingo-oophorectomy was performed as a primary surgery. The histopathological diagnosis was stage IVovarian clear cell adenocarcinoma, and 6 cycles of postoperative chemotherapy with a combination of TC (paclitaxel [PTX] and carboplatin) and the mTOR inhibitor temsirolimus was administered. During maintenance treatment with temsirolimus, the lesion recurred, and progressive disease was confirmed. Because relapse occurred after 5 months from the last TC treatment, the disease was considered platinum-resistant ovarian cancer, and second-line chemotherapy with 6 cycles of irinotecan (CPT-11 ) and PTX was administered. Partial response was observed after 2 cycles, and the response period was 7 months. We suggest that chemotherapy with CPT-11/PTX could be a treatment option for platinum resistant recurrent ovarian clear cell adenocarcinoma. PMID- 25434452 TI - [A case of multiple myeloma in a young adult, discovered on the basis of an abnormal finding on a chest X-ray film]. AB - A 35-year-old woman was referred to our hospital because of an abnormal finding on a chest X-ray film. Chest and abdominal computed tomography (CT) revealed a 25 * 5-mm tumor in the anterior right third rib as well as punched-out lesions in the vertebral bodies and iliac bones. Positron emission tomography (PET)/CT revealed accumulation in the right third rib and lumbar vertebral bodies. From these imaging findings and the lumbar magnetic resonance imaging (MRI) findings, we suspected a case of multiple myeloma. We performed histological bone marrow examination, serum protein electrophoresis, and urine immunoelectrophoresis. The patient was finally diagnosed with a Bence-Jones-type multiple myeloma. To our knowledge, this is a rare case of multiple myeloma in a young adult, discovered on the basis of an abnormal finding on a chest X-ray film. PMID- 25434453 TI - [A case of mFOLFOX6-induced lactic acidosis in a patient with colon cancer]. AB - Leucovorin calcium, 5-fluorouracil, and oxaliplatin (FOLFOX) therapy is a standard chemotherapy regimen used to treat colorectal cancer. Peripheral nerve disorder and myelosuppression are frequently reported treatment-related adverse events. With modified FOLFOX6 (mFOLFOX6) therapy, adverse events of an altered mental state with reversible posterior leukoencephalopathy and hypoammonemia have been reported, while lactic acidosis is uncommon. We describe a case of mFOLFOX6 induced lactic acidosis in a 64-year-old man with colorectal cancer who underwent pelvic exenteration following chemotherapy. Postoperative histopathological analysis revealed residual cancer. Following the commencement of mFOLFOX6 therapy, the patient experienced emesis, hiccupping, and an altered mental state. Laboratory testing revealed only severe lactic acidosis, while diagnostic imaging was unrevealing. All symptoms quickly improved upon the administration of intravenous infusion of sodium bicarbonate. PMID- 25434454 TI - Value congruence in health care priority setting: social values, institutions and decisions in three countries. AB - Most developed democracies have faced the challenge of priority setting in health care by setting up specialized agencies to take decisions on which medical services to include in public health baskets. Under the influence of Daniels and Sabin's seminal work on the topic, agencies increasingly aim to fulfil criteria of procedural justice, such as accountability and transparency. We assume, however, that the institutional design of agencies also and necessarily reflects substantial value judgments on the respective weight of distributive principles such as efficiency, need and equality. The public acceptance of prioritization decisions, and eventually of the health care system at large, will ultimately depend not only on considerations of procedural fairness, but also on the congruence between a society's values and its institutions. We study social values, institutions and decisions in three countries (France, Germany and the United Kingdom) in order to assess such congruence and formulate expectations on its effects. PMID- 25434455 TI - Overview of protein and peptide letters volumes 19-21. PMID- 25434456 TI - Expression profile of apoptotic and proliferative proteins in hypoxic HUVEC treated with statins. AB - Vascular endothelial hyperproliferation is involved in the pathophysiological process of angiogenesis, which is indispensable for tumor growth and spread in hypoxic adaptation. There is increasing evidence indicating that statins have potential anti-angiogenesis benefits. However, the intracellular signaling mechanism underlying the effect of statins in vascular endothelial cells is undefined. The present study was conducted to investigate the effect of fluvastatin on cell proliferation and apoptosis in normoxic and hypoxic human umbilical vein endothelial cells (HUVEC). Flow cytometric analyses revealed that statins reversed hypoxia-induced cell proliferation by slowing down G1 to S transition and inducing cell apoptosis. To get further insights into the downstream effects of statins, we measured the expression of various apoptosis associated proteins in hypoxic HUVEC using human apoptosis antibody array. The results suggested that cell apoptosis was accompanied by upregulation of caspase 3, p27, IGFBP-6 and a decrease of bcl-2, survivin levels. Subsequent studies confirmed the results of array and demonstrated that fluvastatin activated mitochondrial apoptosis through enhancing bax/bcl-2 ratio, releasing cytochrome c, in turn activating caspase-9 and caspase-3, and eventually cleaving PARP. Further experiments showed that inhibition of cell proliferation by fluvastatin was associated with elevated IGFBP-6, p27, p53 levels and reduced survivin, cyclin B1, cyclin D1 and VEGF expression. Taken together, fluvastatin suppressed cell proliferation and induced apoptosis of HUVEC in hypoxia via multiple signaling pathways, providing a theoretical basis for statins in the therapy of cancer. PMID- 25434457 TI - Development of the microsporidian parasite, Loma salmonae, in a rainbow trout gill epithelial cell line (RTG-1): evidence of xenoma development in vitro. AB - Growth and propagation of fish-infecting microsporidians within cell culture has been more difficult to achieve than for insect- and human-infecting microsporidians. Fish microsporidia tend to elicit xenoma development rather than diffuse growth in vivo, and this process likely increases host specificity. We present evidence that the fish microsporidian, Loma salmonae, has the capacity to develop xenomas within a rainbow trout gill epithelial cell line (RTG-1). Spore numbers increased over a 4 weeks period within cell culture flasks. Xenoma-like structures were observed using phase contrast microscopy, and then confirmed using transmission electron microscopy. Optimization of the L. salmonae-RTG-1 cell model has important implications in elucidating the process of xenoma development induced by microsporidian parasites. PMID- 25434458 TI - Quantum correlation exists in any non-product state. AB - Simultaneous existence of correlation in complementary bases is a fundamental feature of quantum correlation, and we show that this characteristic is present in any non-product bipartite state. We propose a measure via mutually unbiased bases to study this feature of quantum correlation, and compare it with other measures of quantum correlation for several families of bipartite states. PMID- 25434459 TI - Eating Disorder Inventory-3, validation in Swedish patients with eating disorders, psychiatric outpatients and a normal control sample. AB - BACKGROUND: The Eating Disorder Inventory-3 (EDI-3) is designed to assess eating disorder psychopathology and the associated psychological symptoms. The instrument has been revised and has not yet been validated for Swedish conditions in its current form. AIMS: The aim of this study was to investigate the validity and reliability of this inventory and present national norms for Swedish females. METHODS: Data from patients with eating disorders (n = 292), psychiatric outpatients (n = 140) and normal controls (n = 648), all females, were used to study the internal consistency, the discriminative ability, and the sensitivity and specificity of the inventory using preliminary cut-offs for each subscale and diagnosis separately. Swedish norms were compared with those from Denmark, USA, Canada, Europe and Australian samples. RESULTS: The reliability was acceptable for all subscales except Asceticism among normal controls. Analysis of variance showed that the EDI-3 discriminates significantly between eating disorders and normal controls. Anorexia nervosa was significantly discriminated from bulimia nervosa and eating disorder not otherwise specified on the Eating Disorder Risk Scales. Swedish patients scored significantly lower than patients from other countries on the majority of the subscales. Drive for Thinness is the second best predictor for an eating disorder. The best predictor for anorexia nervosa was Interoceptive Deficits and Bulimia for the other diagnoses. Conclusions/clinical implications: The EDI-3 is valid for use with Swedish patients as a clinical assessment tool for the treatment planning and evaluation of patients with eating related problems. However, it still exist some uncertainty regarding its use as a screening tool. PMID- 25434460 TI - Childhood trauma in the lives of substance-dependent patients: The relationship between depression, anxiety and self-esteem. AB - BACKGROUND: High levels of childhood traumatic experiences have been observed among substance abusers. There has been insufficient study of the effects of childhood trauma in adulthood. OBJECTIVE: The aim of this study is to research the relationship between childhood trauma, self-esteem, and levels of depression and anxiety in substance-dependent (SD) people. METHOD: This study took place between March 2012 and April 2013, at Balikli Rum Hospital (Istanbul) substance dependency clinic. It included 50 patients diagnosed as substance dependent according to the criteria of DSM-IV as compared with 45 healthy controls. The Structured Clinical Interview for DSM-IV Diagnosis (SCID-I) was used to identify Axis I disorders. All other data was collected using a semi-structured socio demographic questionnaire, the Childhood Trauma Questionnaire (CTQ), the Rosenberg Self Esteem Scale (RSES), the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI). FINDINGS: The total scores of the SD group on the CTQ and on its Emotional Abuse/Emotional Neglect (EA/EN), Physical Abuse (PA) and Sexual Abuse (SA) subscales were statistically significant. In relation to the healthy controls, the SD group scored higher on the RSES, BDI and BAI. A correlation was observed between the total scores of SD individuals on the CTQ and their scores on the RSES, BDI and BAI. CONCLUSION: This study showed high levels of childhood traumatic experiences for SD people and indicates that there may be a relationship between these experiences and their levels of self-esteem, depression and anxiety. PMID- 25434461 TI - Fabrication of shape-controlled reduced graphene oxide nanorings by Au@Pt nanoring lithography. AB - We fabricated a variety of reduced graphene oxide (RGO) nanoring arrays using Au@Pt nanoplates as a pattern mask. RGO nanoflakes were assembled into a 2 dimensional assembly at the water-oil interface, and then various shapes of Au@Pt nanoplates were utilized as a pattern mask in order to convert the RGO into circular, triangular, and hexagonal RGO nanorings. PMID- 25434463 TI - Gut endoderm takes flight from the wings of mesoderm. AB - The endoderm layer destined to be primitive gut is a mosaic of earlier visceral endoderm and definitive endoderm that arises later, during gastrulation. Live imaging now reveals that in mouse embryos, definitive endoderm cells egress from underlying mesoderm and intercalate into the overlying cell layer. This process requires SOX17-mediated control of basement membrane organization. PMID- 25434464 TI - Rsp5/Nedd4 clears cells of heat-damaged proteins. AB - Protein quality control systems protect cells from proteotoxicity caused by the accumulation of aberrantly folded polypeptides. The Rsp5 ubiquitin ligase (mammalian homologue Nedd4) is now identified as a major constituent of a clearance pathway that degrades misfolded cytosolic proteins after exposure to heat. PMID- 25434465 TI - Sugar modification inhibits autophagosome-lysosome fusion. AB - Autophagy is an intracellular degradation system that is mediated by orchestrated functions of membranes and proteins. A genetic screen in Caenorhabditis elegans revealed that O-linked N-acetylglucosamine modification of the SNARE protein SNAP 29 negatively regulates SNARE-dependent fusion between autophagosomes and lysosomes. This regulatory mechanism is conserved in mammals. PMID- 25434466 TI - Hepatocellular adenoma management: call for shared guidelines and multidisciplinary approach. AB - Hepatocellular adenomas are rare benign nodules developed mainly in women taking oral contraceptives. They are solitary or multiple. Their size is highly variable. There is no consensus in the literature for their management except that once their size exceeds 5 cm nodules are taken out to prevent 2 major complications: bleeding and malignant transformation. There are exceptions particularly in men where it is recommended to remove smaller nodules. Since the beginning of this century, major scientific contributions have unveiled the heterogeneity of the disease. HCA are composed of four major subtypes. HNF1A (coding for hepatocyte nuclear factor 1a) inactivating mutations (H-HCA); inflammatory adenomas (IHCA); the beta-catenin-mutated HCAs (beta-HCA) and unclassified HCA (UHCA) occurring in 30-40%, 40-50%, 10-15% and 10% of all HCA, respectively. Half of beta-HCAs are also inflammatory (beta-IHCA). Importantly, beta-catenin mutations are associated with a high risk of malignant transformation. HCA subtypes can be identified on liver tissue, including biopsies using specific immunomarkers with a good correspondence with molecular data. Recent data has shown that TERT promoter mutation was a late event in the malignant transformation of beta-HCA, beta-IHCA. Furthermore, in addition to beta catenin exon 3 mutations, other mutations do exist (exon 7 and 8) with a lower risk of malignant transformation. With these new scientific informations, we have the tools to better know the natural history of the different subtypes, in terms of growth, disappearance, bleeding, malignant transformation and to investigate HCA in diseased livers (vascular diseases, alcoholic cirrhosis). A better knowledge of HCA should lead to a more rational management of HCA. This can be done only if the different subspecialties, including hepatologists, liver pathologists, radiologists and surgeons work altogether in close relationship with molecular biologists. It is a long way to go. PMID- 25434467 TI - Hydrogen-bonding interactions in hard segments of shape memory polyurethane: toluene diisocyanates and 1,6-hexamethylene diisocyanate. A theoretical and comparative study. AB - In this study, the hydrogen-bonding interactions of three widely used diisocyanate-based hard-segment (HS) models in polyurethane, 2,4 toluenediisocyanate-methanol (2,4-TDI-MeOH), 2,6-toluenediisocyanate-methanol (2,6-TDI-MeOH), and 1,6-hexamethylenediisocyanate-methanol (HDI-MeOH), were investigated theoretically by density functional theory (DFT). The B3LYP/6-31G* method was used to calculate the equilibrium structures, Mulliken charges, hydrogen-bonding energies, and infrared (IR) spectra, in good agreement with previous experimental data. The HS models with benzene ring have much longer hydrogen bonds (HB), due to steric hindrance of benzene ring, whereas the aliphatic model forms much shorter hydrogen bonds. Different positions of the methyl group on the benzene ring for 2,4-TDI-MeOH and 2,6-TDI-MeOH result in different types of hydrogen bonds with various strengths. The style of hydrogen bonding for HDI-MeOH is more flexible due to simple aliphatic chemical structure without the benzene ring. The charge transfer on atoms N, H, and O involved in hydrogen bonding occurs with the forming of a hydrogen bond. The hydrogen bonding of 2,4-TDI-MeOH is much stronger than the others, and 2,6-TDI-MeOH froms the weakest hydrogen bonds. This study can supply guidance for the selection of a hard segment in the design of polyurethane and in-depth understanding of the hydrogen-bonding mechanism in the hard segments of polyurethane. PMID- 25434468 TI - Analysis of the protein-protein interaction networks of differentially expressed genes in pulmonary embolism. AB - The aim of the present study was to explore the function and interaction of differentially expressed genes (DEGs) in pulmonary embolism (PE). The gene expression profile GSE13535, was downloaded from the Gene Expression Omnibus database. The DEGs 2 and 18 h post-PE initiation were identified using the affy package in R software. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the DEGs were analyzed using Database for Annotation Visualization and Integrated Discovery (DAVID) online analytical tools. In addition, protein protein interaction (PPI) networks of the DEGs were constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins. The PPI network at 18 h was modularized using Clusterone, and a functional enrichment analysis of the DEGs in the top three modules was performed with DAVID. Overall, 80 and 346 DEGs were identified 2 and 18 h after PE initiation, respectively. The KEGG pathways, including chemokine signaling and toll-like receptor signaling, were shown to be significantly enriched. The five highest degree nodes in the PPI networks at 2 or 18 h were screened. The module analysis of the PPI network at 18 h revealed 11 hub nodes. A Gene Ontology terms analysis demonstrated that the DEGs in the top three modules were associated with the inflammatory, defense and immune responses. The results of the present study suggest that the DEGs identified, including chemokine-related genes TFPI2 and TNF, may be potential target genes for the treatment of PE. The chemokine signaling pathway, inflammatory response and immune response were explored, and it may be suggested that these pathways have important roles in PE. PMID- 25434469 TI - Polyanthumin, a novel cyclobutane chalcone trimmer from Memecylon polyanthum. AB - A novel unusual trimmer chalcone, polyanthumin (1), together with five known compounds myricetin 3-O-(3"-O-galloyl)-alpha-l-rhamnopyranoside (2), sulfuretin (3), fustin (4), gallic acid (5), and ethyl gallate (6), was isolated from the dry stems of Memecylon polyanthum H.L. Li. Among them, compound 1 is a new chalcone trimmer with a novel cyclobutane skeleton in nature. Compounds 3 and 4 are flavonoids carrying a single 7-OH in A ring, which provided the first example of these class flavonoids from the family Melastomataceae. In addition, the antitumor activities for 2-4 were reported for the first time in this study. The antitumor effects of the isolated compounds 1-6 in vitro were assayed by the SRB method using human cancer K562 cells, with the inhibition rates ranging from 39.4% to 54.5% at 100 MUg/ml. The IC50 values of compounds 1 and 3 for the inhibition of K562 cell proliferation were determined to be 45.4 and 30.5 MUg/ml, respectively. To the best of our knowledge, compound 1 was the second sample as chalcone trimer. In addition, the antitumor activities for 2-4 were reported for the first time in this study. PMID- 25434470 TI - Investigating the use of oil platform marine fouling invertebrates as monitors of oil exposure in the Northern Gulf of Mexico. AB - The concentration of 51 parent and alkylated PAHs was examined in oysters, Ostrea equestris, and corals, Tubastrea coccinea, collected from oil-rig structures off the coast of Louisiana during April and May 2011 to investigate their potential use as monitors for offshore contamination events. Corals and oysters collected from both sampling trips had lower PAH accumulation than most bivalves collected in previous studies near the shoreline of Louisiana and elsewhere in the Gulf of Mexico. In April, total PAH (TPAH) concentrations ranged from 8.73 to 15.17 ng g( 1) in corals and 2.52 to 22.04 ng g(-1) in oysters. In May, corals and oysters had elevated concentrations of TPAH ranging from 24.28 to 79.23 ng g(-1) and 7.18 to 95.55 ng g(-1), respectively. This increase could be a result of Mississippi River flooding that occurred during that time, as evidenced by the high perylene concentrations (3.92-41.49 ng g(-1)) measured in May oysters. Oysters and corals collected in May from MC21B, the closest rig to the Mississippi River Delta, had the highest TPAH concentrations observed among all locations and the only rig to have predominantly petrogenic source inputs. Overall, given the low baseline of PAHs demonstrated in this study and the rapid accumulation of diagnostic chemicals in response to a possible contamination event (i.e. sediment plume from May flooding), oil-rig invertebrates could make excellent monitoring tools to examine the exposure to and recovery from oil (and oil-spill response options) in the offshore Northern Gulf of Mexico. Pre-spill baseline data of chemical and biological biomarkers of contamination is key to better estimating the impacts and recovery of oil exposure. Therefore, this screen of PAH accumulation represents a crucial first step in determining baseline contaminant levels in order to utilize these unique resources as monitors for offshore oil exposure in the Northern Gulf of Mexico. PMID- 25434471 TI - Probing effects of polymer adsorption in colloidal particle suspensions by light scattering as relevant for the aquatic environment: An overview. AB - Modification of particle surfaces by adsorption of polymers is a process that governs particle behavior in aqueous environmental systems. The present article briefly reviews the current understanding of the adsorption mechanisms and the properties of the resulting layers, and it discusses two environmentally relevant cases of particle modification by polymers. In particular, the discussion focuses on the usefulness of methods based on light scattering to probe such adsorbed layers together with the resulting properties of the particle suspensions, and it highlights advantages and disadvantages of these techniques. Measurement of the electrophoretic mobility allows to follow the development of the adsorption layer and to characterize the charge of the modified particles. At saturation, the surface charge is governed by the charge of the adsorbed film. Dynamic light scattering provides information on the film thickness and on the behavior of the modified suspensions. The charge and the structure of the adsorbed layer influence the stability of the particles, as well as the applicability of the classical theory of Derjaguin, Landau, Verwey, and Overbeek (DLVO). This fundamental knowledge is presented in the light of environmental systems and its significance for applied systems is underlined. In particular, the article discusses two examples of environmental processes involving adsorption of polymers, namely, the modification of particles by natural adsorption of humic substances and the tailoring of surface properties of iron-based particles used to remediate contaminated aquifers. PMID- 25434472 TI - The fate of silver nanoparticles in soil solution--Sorption of solutes and aggregation. AB - Nanoparticles enter soils through various pathways. In the soil, they undergo various interactions with the solution and the solid phase. We tested the following hypotheses using batch experiments: i) the colloidal stability of Ag NP increases through sorption of soil-borne dissolved organic matter (DOM) and thus inhibits aggregation; ii) the presence of DOM suppresses Ag oxidation; iii) the surface charge of Ag NP governs sorption onto soil particles. Citrate-stabilized and bare Ag NPs were equilibrated with (colloid-free) soil solution extracted from a floodplain soil for 24h. Nanoparticles were removed through centrifugation. Concentrations of free Ag ions and DOC, the specific UV absorbance at a wavelength of 254 nm, and the absorption ratio alpha254/alpha410 were determined in the supernatant. Nanoparticle aggregation was studied using time-resolved dynamic light scattering (DLS) measurement following the addition of soil solution and 1.5mM Ca(2+) solution. To study the effect of surface charge on the adsorption of Ag NP onto soil particles, bare and citrate-stabilized Ag NP, differing in the zeta potential, were equilibrated with silt at a solid-to solution ratio of 1:10 and an initial Ag concentration range of 30 to 320 MUg/L. Results showed that bare Ag NPs sorb organic matter, with short-chained organic matter being preferentially adsorbed over long-chained, aromatic organic matter. Stabilizing effects of organic matter only come into play at higher Ag NP concentrations. Soil solution inhibits the release of Ag(+) ions, presumably due to organic matter coatings. Sorption to silt particles was very similar for the two particle types, suggesting that the surface charge does not control Ag NP sorption. Besides, sorption was much lower than in comparable studies with sand and glass surfaces. PMID- 25434473 TI - Urban rivers as conveyors of hydrocarbons to sediments of estuarine areas: source characterization, flow rates and mass accumulation. AB - Aliphatic (n-C12-n-C40, unresolved complex mixture, resolved peaks) and aromatic hydrocarbons (46 PAH) were investigated in suspended particulate matter (SPM) sampled over eleven months in six of the major rivers and two channels of the Guanabara Bay Basin. PAH flow rates of the most contaminated rivers, the contribution to the PAH sediment load of the receiving bay, and the main sources of hydrocarbons were determined. PAH (38) ranged from 28 ng L(-1) to 11,514 ng L( 1). Hydrocarbon typology and statistical evaluation demonstrated contribution of distinct sources in different regions and allowed quantification of these contributions. Total flow rate for the five major rivers amounts to 3 t year(-1) and responds for 30% of the total PAH annual input into the northern area of the Guanabara Bay. For the first time PAH mass deposited in the bay sediments has been estimated and shall serve as base for decision making and source abatement. PMID- 25434474 TI - Azelnidipine and glucose tolerance: possible indications and treatment selection for hypertensive patients with metabolic disorders. AB - Azelnidipine is a unique dihydropyridine calcium channel blocker with selectivity for L-type calcium channels that has been launched for the treatment of hypertension. Azelnidipine exhibits long-acting blood pressure-lowering effects without increasing heart rate. High blood pressure is associated with many metabolic disorders, including glucose intolerance and insulin resistance. Antihypertensive medications that interfere with various steps in the renin angiotensin system improve glucose tolerance and insulin resistance; however, the effects of calcium channel blockers on glucose metabolism and insulin resistance remain controversial. Recent studies have demonstrated that azelnidipine could improve insulin resistance and glucose tolerance by potentially inhibiting sympathetic nerve activity. In addition, azelnidipine exhibits anti-inflammatory and anti-oxidative effects, suggesting that it is a beneficial antihypertensive agent with anti-atherogenic and cardioprotective effects for the treatment of not only hypertensive patients with glucose intolerance, but also those with metabolic disorders. PMID- 25434475 TI - A rare case of 3C disease: Ritscher-Schinzel syndrome presenting with recurrent talipes equinovarus. AB - INTRODUCTION: Club foot (CF) is characterized by multiple deformities such as varus, adductus and internal rotation of the forefoot. It is well-known and a frequent congenital disorder. CF can concurrently be seen with several diseases but it can rarely manifest as a component of any other syndrome. Ritscher Schinzel syndrome, or cranio-cerebello-cardiac syndrome, is rarely seen and has autosomal recessive inheritance. It is characterized by cranio-facial, cerebellar and cardiac abnormalities. We report a case diagnosed as Ritscher-Schinzel syndrome concurrent with persistent CF. PRESENTATION OF CASE: A two-year-old boy with persistent CF and concurrent congenital hip dysplasia. Despite successful serial casting and subsequent achilloplasty a clinical relapse was observed in our patient. After a detailed phenotypic evaluation, genetical tests and imaging technique the patient was diagnosed 3C Ritscher-Schinzel syndrome. DISCUSSION: A comprehensive literature review did not show any reports about concurrent hip dysplasia and clubfoot in Ritscher-Schinzel syndrome. We report that CF may be associated with rare genetical abnormalities. CONCLUSION: With this report we would like to raise awareness about the possible association of persistent CF with this rare genetical disorder, Ritscher-Schinzel syndrome. It should be included in differential diagnosis of patients with persistent CF. PMID- 25434476 TI - Cataplexy and sleep disorders in Niemann-Pick type C disease. AB - Niemann-Pick disease type C (NP-C) is a rare and progressive autosomal recessive disease leading to disabling neurological manifestation and premature death. The disease is prone to underdiagnosis because of its highly heterogeneous presentation. NP-C is characterized by visceral, neurological, and psychiatric manifestation, and its clinical picture varies according to age at onset. Although cataplexy is one of its characteristic symptoms, particularly in the late infantile and juvenile form, sleep disturbances are described only exceptionally. A combination of splenomegaly, vertical supranuclear gaze palsy, and cataplexy creates a most useful suspicion index tool for the disease. In adolescent and adult patients, when intellectual deterioration progresses and emotional reactions become flat, cataplexy usually disappears. Pathological findings in the brainstem in NP-C mouse model are compatible with the patients' symptoms including cataplexy. The authors observed cataplexy in 5 (3 with late infantile and 2 with juvenile form) out of 22 NP-C cases followed up in the past 20 years. PMID- 25434477 TI - Radioembolization in patients with progressive gastrointestinal stromal tumor liver metastases undergoing treatment with tyrosine kinase inhibitors. AB - PURPOSE: Gastrointestinal stromal tumors (GISTs) spread frequently to the peritoneum and the liver. If metastasectomy or tyrosine kinase inhibitors (TKIs) fail, interventional ablation techniques are considered. The purpose of this study is to assess the progression-free interval (PFI) of GIST liver metastases after radioembolization (RE). MATERIALS AND METHODS: Eleven patients with progressive GIST liver metastases undergoing TKI therapy were referred for RE; one was excluded because of a large hepatopulmonary shunt, and one was lost to follow-up. Depending on intrahepatic tumor distribution, one or both liver lobes were treated with RE. Contrast-enhanced magnetic resonance imaging, contrast enhanced computed tomography (CT), and [(18)F]fluorodeoxyglucose positron emission tomography/CT were used for follow-up. RESULTS: In all, 16 liver lobes were treated with a mean activity of 1.06 GBq +/- 0.37 (range, 0.55-1.88) per lobe. Three patients showed complete response, five showed partial response, and one showed stable disease. No patient showed progressive disease after RE. Median PFI was 15.9 months (range, 4-29 mo). Median survival was 29.8 months (range, 10 72 mo). No radiation-induced liver disease developed; however, one patient required surgery for persistent stomach ulcer. CONCLUSIONS: RE offers a safe and effective treatment for patients with GIST liver metastases who do not show a response to TKIs. RE could be an option for earlier phases of therapy in patients with mutational status. The results might also challenge the notion that GISTs are resistant to radiation therapy. PMID- 25434479 TI - Protective effect of resveratrol against cisplatin-induced ototoxicity in HEI-OC1 auditory cells. AB - OBJECTIVES: Cisplatin is an effective chemotherapeutic drug, but it generates reactive oxygen species (ROS) that induce severe adverse effects such as ototoxicity. Resveratrol reportedly prevents oxidative stress-induced cell death. Thus, we hypothesized that the anti-oxidative effect of resveratrol could protect against cisplatin-induced ototoxicity. The present study examined the protective effect of resveratrol against cisplatin-induced ototoxicity in HEI-OC1 auditory cells. METHODS: HEI-OC1 cells were pretreated with resveratrol at 1MUM for 24h and then exposed to 15MUM cisplatin for 48h. Resulting cytotoxicity was measured by the MTT method, and intracellular ROS was measured using flow cytometry. Protective effect of resveratrol was compared with other anti-oxidants. RESULTS: Pretreatment with resveratrol 1MUM protected HEI-OC1 auditory cells against cisplatin-induced cytotoxicity and significantly reduced a cisplatin-induced increase in ROS. Resveratrol provided significant protection against 15MUM cisplatin applied for 48h (50.8% cell viability in the cisplatin group vs. 57.6% in the cisplatin-plus-resveratrol group), and there was a 9% decrease in cisplatin-induced ROS associated with resveratrol. CONCLUSIONS: This is the study investigating the protective effects of resveratrol against cisplatin-induced ototoxicity in an auditory cell line. Resveratrol significantly reduced a cisplatin-induced increase in ROS and thereby inhibited cisplatin-induced cytotoxicity. PMID- 25434481 TI - Is nocturnal desaturation a trigger for neuronal damage in chronic obstructive pulmonary disease? AB - Patients with chronic obstructive pulmonary disease (COPD) present many neurological disorders of unknown origin. Although hypoxemia has long been thought to be responsible, several studies have shown evidence of neuronal damage and dysfunction even in non-hypoxemic patients with COPD. Adaptive mechanisms protect the brain from hypoxia: when arterial oxygen tension (PaO2) decreases, the cerebral blood flow (CBF) increases, ensuring continuously adequate oxygen delivery to the brain. However, this mechanism is abolished during non-rapid eye movement (NREM) sleep. Any drop in PaO2 during NREM sleep is therefore not compensated by increased CBF, causing decreased cerebral oxygen delivery with subsequent brain hypoxia. Patients with may therefore be exposed to neuronal damage during this critical time. This mechanism is of vital importance for patients with COPD because of the potentially deleterious cortical effects. Nocturnal desaturation is quite frequent in COPD and affects approximately one out of two patients who are not hypoxemic during wakefulness. Although the prevalence of NREM sleep desaturation has never been specifically assessed in COPD, current data suggest that at least half of the nocturnal desaturation in desaturating patients occurs during NREM sleep. This review presents the rationale for the hypothesis that nocturnal desaturation during NREM sleep promotes neuronal damage and dysfunction in COPD. PMID- 25434480 TI - Early auditory preverbal skills development in Mandarin speaking children with cochlear implants. AB - OBJECTIVE: The purpose of this study was to investigate the development of auditory preverbal skills in Mandarin speaking infants/toddlers with cochlear implants (CIs). METHODS: Participants were recruited from the Pediatric Audiology Center of Beijing Children's Hospital, Capital Medical University. A total of 33 children with severe-to-profound hearing loss who received CIs participated in the study. The evaluation tools were LittlEARS((r)) Auditory Questionnaire (LEAQ) and self-designed demographic information questionnaire. Evaluations were administrated immediately after the CI was switched on (0-month), and at 1, 3, 6, 9, 12, 18, and 24-month intervals of CI use. RESULTS: The mean total scores of the LEAQ in 0, 1, 3, 6, 9, 12, 18, and 24-month were 1, 5, 10, 15, 21, 24, 30, and 33 points, respectively. The developmental trajectory of early auditory preverbal skills in the CI children was consistent with the published norm data of the LEAQ, and the expected value even slightly higher than the norms. Analysis showed that the parents' level of education and age of implantation influenced the final LEAQ score significantly (ANOVA, p<0.0001). CONCLUSIONS: Auditory preverbal skills improved dramatically after cochlear implantation in the first 2 years of implant use. Early implanted children exhibited a steeper and faster improvement in auditory preverbal developmental compared to the later implanted peers. This study described the developmental trajectories of preverbal auditory skills and confirmed the effectiveness of early implantation on the development of auditory preverbal skills. The results could provide guidance for auditory/speech rehabilitation in Mandarin speaking infants/toddlers who received CIs in their early age. PMID- 25434482 TI - Widespread depolarization during expiration: a source of respiratory drive? AB - Respiration influences various pacemakers and rhythms of the body during inspiration and expiration but the underlying mechanisms are relatively unknown. Understanding this phenomenon is important, as breathing disorders, breath holding, and hyperventilation can lead to significant medical conditions. We discuss the physiological modulation of heart rhythm, blood pressure, sympathetic nerve activity, EEG, and other changes observed during inspiration and expiration. We also correlate the intracellular mitochondrial respiratory metabolic processes with real-time breathing and correlate membrane potential changes with inspiration and expiration. We propose that widespread minor hyperpolarization occurs during inspiration and widespread minor depolarization occurs during expiration. This depolarization is likely a source of respiratory drive. Further knowledge of intracellular and extracellular ionic changes associated with respiration will enhance ourunderstanding of respiration and its role as a modulator of cellular membrane potential. This could expand treatment options for a wide range of health conditions, such as breathing disorders, stress-related disorders, and further our understanding of the Hering-Breuer reflex and respiratory sinus arrhythmia. PMID- 25434483 TI - The immunosuppressive effect of Siglecs on tendon-bone healing after ACL reconstruction. AB - The quality of the bone-tendon healing is very important to the surgery outcome after anterior cruciate ligament reconstruction. The necrosis of autograft and local new blood vessels occur after the surgery. The fibroblasts and mesenchymal cells presenting in the tendon-bone interface as well as the infiltrated of neutrophils and macrophages improve the biomechanical properties of the healing. We hypothesize that immunosuppressive effect of Siglecs which present on the surface of neutrophils and macrophages play the important roles to regulate acute local inflammatory reaction, maintain the physiological environment and induce the differentiation of the pluripotent cells to form the accepted histologic structure healing of the tendon-bone interface. It might be helpful to understand the mechanism of tendon-bone healing. PMID- 25434484 TI - Differences in stress-induced changes in extinction and prefrontal plasticity in postweanling and adult animals. AB - BACKGROUND: Postweaning is a critical developmental stage during which the medial prefrontal cortex (mPFC) undergoes major changes and the brain is vulnerable to the effects of stress. Surprisingly, the engagement of the mPFC in extinction of fear was reported to be identical in postweanling (PW) and adult animals. Here, we examined whether the effect of stress on extinction and mPFC plasticity would be similar in PW and adult animals. METHODS: PW and adult animals were fear conditioned and exposed to the elevated platform stress paradigm, and extinction and long-term potentiation were examined. The dependency of stress-induced modulation of extinction and plasticity on N-methyl-D-aspartate receptors was examined as well. RESULTS: We show that exposure to stress is associated with reduction of fear and enhanced induction of long-term potentiation (LTP) in PW pups, in contrast to its effects in adult animals. Furthermore, we report opposite effects in the occlusion of LTP following the enhanced or impaired extinction in the two age groups and that the reversal of the effects of stress is independent of N-methyl-D-aspartate receptor activation in PW animals. CONCLUSIONS: Our results show that qualitatively different mechanisms control the modulatory effects of stress on extinction and plasticity in postweanling pups compared with adult rats. Our results point to significant differences between young and adult brains, which may have potential implications for the treatment of anxiety and stress disorders across development. PMID- 25434485 TI - Influenza-associated MOG antibody-positive longitudinally extensive transverse myelitis: a case report. AB - BACKGROUND: Myelin-oligodendrocyte glycoprotein antibody (MOG antibodies) was found in various demyelinated diseases. This is the first report of a patient with longitudinally extensive transverse myelitis with an extremely high titer of MOG antibodies after an influenza infection. This case supports the view that MOG antibodies are linked to longitudinally extensive transverse myelitis and that influenza infection might trigger the MOG antibodies. CASE PRESENTATION: A 32 year-old healthy male developed high fever, dysesthesia and paraesthesia below the C2 area, muscle weakness of the bilateral lower extremities, and urinary retention ten days after an influenza type A infection. Magnetic resonance imaging revealed a longitudinal lesion in the spinal cord extending from C2 to the spinal conus. There were no lesions in the brain or optic nerves. Established cell-based immunoassays revealed that he was positive for MOG antibodies (titer = 65,536) and negative for anti-aquaporin 4 antibodies (AQP4 antibodies). He fully recovered after steroid pulse therapy followed by 60 mg prednisolone. CONCLUSION: This is the first report of influenza A-associated longitudinally extensive transverse myelitis with a high titer anti-MOG antibodies. Our case report supports a relationship between anti-MOG antibodies and longitudinally extensive transverse myelitis, which was triggered by influenza infection. Further studies are needed to establish the clinical significance of anti-MOG antibodies for diagnosis, treatment, and prognosis. PMID- 25434486 TI - Diosgenin induces G2/M cell cycle arrest and apoptosis in human hepatocellular carcinoma cells. AB - Diosgenin is a major compound of Dioscoreaceae plants such as yam, which is used as a drug in Traditional Chinese Medicine, and a common vegetable worldwide. The anticancer effect of diosgenin has been reported in various tumor cells, including leukemia, gastric, colorectal, and breast cancer. However, the activity of diosgenin on hepatocellular carcinoma (HCC) and the underlying mechanism have not been completely investigated. Therefore, we investigated the efficacy and associated mechanisms of diosgenin in HCC cells. Flow cytometric analysis was performed to determine the presence of cell cycle arrest and apopotic cells. Diosgenin significantly inhibited the growth of Bel-7402, SMMC-7721 and HepG2 HCC cells in a concentration-dependent manner. Diosgenin treatment for 24 h induced G2/M cell cycle arrest and apoptosis of hepatoma cells. Diosgenin inhibited Akt phosphorylation and upregulated p21 and p27 expression, but did not alter the expression of p53, suggesting diosgenin-induced upregulation of p21 and p57 is p53-independent in HCC cells. Diosgenin induced HCC cell apoptosis by activating caspase cascades -3, -8 and -9. However, diosgenin did not affect Bcl-2 and Bax levels. In conclusion, results of the present study suggest that diosgenin may be an active anti-HCC agent obtained from natural plants and provide new insights in understanding the mechanisms of diosgenin. PMID- 25434487 TI - Activation of mGlu3 metabotropic glutamate receptors enhances GDNF and GLT-1 formation in the spinal cord and rescues motor neurons in the SOD-1 mouse model of amyotrophic lateral sclerosis. AB - Enhancement of glial-derived neurotrophic factor (GDNF) is an established therapeutic target for amyotrophic lateral sclerosis (ALS). Activation of group II metabotropic glutamate (mGlu) receptors with the orthosteric agonist, LY379268, enhanced GDNF levels in cultured spinal cord astrocytes from wild-type mice and mGlu2(-/-) mice, but not in astrocytes from mGlu3(-/-) mice. LY379268 protected Sternberger monoclonal incorporated antibody-32 (SMI-32)(+) motor neurons against excitotoxic death in mixed cultures of spinal cord cells, and its action was abrogated by anti-GDNF antibodies. Acute systemic injection of LY379268 (0.5, 1 or 5mg/kg, i.p.) enhanced spinal cord GDNF levels in wild-type and mGlu2(-/-) mice, but not in mGlu3(-/-) mice. No tolerance developed to the GDNF-enhancing effect of LY379268 when the drug was continuously delivered for 28days by means of s.c. osmotic minipumps (0.5-5mg/day). Double fluorescent immunostaining showed a co-localization of GDNF with the astrocyte marker, GFAP, but not with the neuronal marker, Neuronal Nuclear Antigen (NeuN), or with SMI 32. Continuous infusion of LY379268 also enhanced the expression of the glutamate transporter GLT-1, in the spinal cord. These data laid the groundwork for the study of LY379268 in ALS mice. Continuous treatment with 1 or 5mg/kg/day with LY379268 had a beneficial effect on neurological disability in SOD1G93A mice. At day 40 of treatment, LY379268 enhanced spinal cord levels of GDNF and GLT-1, and rescued spinal cord motor neurons, as assessed by stereologic counting of SMI 32(+) cells. LY379268 had no significant effect on the mortality rate of SODG93A. These findings encourage the development of selective mGlu3 receptor agonists/enhancers as neuroprotective agents in ALS. PMID- 25434488 TI - Pyruvate prevents the development of age-dependent cognitive deficits in a mouse model of Alzheimer's disease without reducing amyloid and tau pathology. AB - Amyloid-beta (Abeta) deposition and tau-dependent pathology are key features of Alzheimer's disease (AD). However, to date, approaches aimed at counteracting these two pathogenic factors have produced only modest therapeutic outcomes. More effective therapies should therefore consider additional pathogenic factors like energy production failure, hyperexcitability and excitotoxicity, oxidative stress, deregulation of metal ion homeostasis, and neuroinflammation. Pyruvate is an energy substrate associated with neuroprotective properties. In this study, we evaluated protective effects of long-term administration of pyruvate in 3xTg-AD mice, a preclinical AD model that develops amyloid-beta- and tau-dependent pathology. Chronic (9 months) treatment with pyruvate inhibited short and long term memory deficits in 6 and 12 months old 3xTg-AD mice as assessed with the Morris water maze test. Pyruvate had no effects on intraneuronal amyloid-beta accumulation and, surprisingly, the molecule increased deposition of phosphorylated tau. Pyruvate did not change aerobic or anaerobic metabolisms but decreased lipid peroxidation, counteracted neuronal hyperexcitability, decreased baseline levels of oxidative stress, and also reduced reactive oxygen species driven elevations of intraneuronal Zn(2+) as well as glutamate receptor-mediated deregulation of intraneuronal Ca(2+). Thus, pyruvate promotes beneficial cognitive effects without affecting Abeta and tau pathology. The molecule mainly promotes a reduction of hyperexcitability, oxidative stress while favors the regulation of intraneuronal Ca(2+) and Zn(2+) homeostasis rather than acting as energy substrate. Pyruvate can be therefore a valuable, safe, and affordable pharmacological tool to be associated with classical anti-Abeta and tau drugs to counteract the development and progression of AD-related cognitive deficits and neuronal loss. PMID- 25434489 TI - Immunoproteomic analysis reveals a convergent humoral response signature in the Sporothrix schenckii complex. AB - Sporotrichosis is a polymorphic disease that affects both humans and animals worldwide. The fungus gains entry into a warm-blooded host through minor trauma to the skin, typically by contaminated vegetation or by scratches and bites from a diseased cat. Cellular and humoral responses triggered upon pathogen introduction play important roles in the development and severity of the disease. We investigated molecules expressed during the host-parasite interplay that elicit the humoral response in human sporotrichosis. For antigenic profiling, Sporothrix yeast cell extracts were separated by two-dimensional (2D) gel electrophoresis and probed with pooled sera from individuals with fixed cutaneous and lymphocutaneous sporotrichosis. Thirty-five IgG-seroreactive spots were identified as eight specific proteins by MALDI-ToF/MS. Remarkable cross reactivity among Sporothrix brasiliensis, Sporothrix schenckii, and Sporothrix globosa was noted and antibodies strongly reacted with the 70-kDa protein (gp70), irrespective of clinical manifestation. Gp70 was successfully identified in multiple spots as 3-carboxymuconate cyclase. In addition, 2D-DIGE characterization suggested that the major antigen of sporotrichosis undergoes post-translational modifications involving glycosylation and amino acid substitution, resulting in at least six isoforms and glycoforms that were present in the pathogenic species but absent in the ancestral non-virulent Sporothrix mexicana. Although a primary environmental function related to the benzoate degradation pathway of aromatic polymers has been attributed to orthologs of this molecule, our findings support the hypothesis that gp70 is important for pathogenesis and invasion in human sporotrichosis. We propose a diverse panel of new putative candidate molecules for diagnostic tests and vaccine development. BIOLOGICAL SIGNIFICANCE: Outbreaks due to Sporothrix spp. have emerged over time, affecting thousands of patients worldwide. A sophisticated host-pathogen interplay drives the manifestation and severity of infection, involving immune responses elicited upon traumatic exposure of the skin barrier to the pathogen followed by immune evasion. Using an immunoproteomic approach we characterized proteins of potential significance in pathogenesis and invasion that trigger the humoral response during human sporotrichosis. We found gp70 to be a cross immunogenic protein shared among pathogenic Sporothrix spp. but absent in the ancestral environmental S. mexicana, supporting the hypothesis that gp70 plays key roles in pathogenicity. For the first time, we demonstrate with 2D-DIGE that post-translational modifications putatively involve glycosylation and amino acid substitution, resulting in at least six isoforms and glycoforms, all of them IgG reactive. These findings of a convergent humoral response highlight gp70 as an important target serological diagnosis and for vaccine development among phylogenetically related agents of sporotrichosis. PMID- 25434490 TI - Partially isobaric peptide termini labeling assisted proteome quantitation based on MS and MS/MS signals. AB - Isotopic labeling and isobaric labeling are two kinds of the typical quantification method that have been widely used in proteomics analysis. Herein, a novel quantitative strategy, partially isobaric peptide termini labeling (PITL), was developed to overcome the drawbacks of each above-mentioned labeling strategy, by simultaneously collecting the quantitative information from both MS and MS/MS spectrum. PITL is based on the site-selective N-terminus dimethylation labeling of peptide alpha-N-termini and the free epsilon-amino group of lysines, resulting in the partially isobaric labeling of peptides. The relative quantification can then be achieved by comparing the intensities of precursor ions in MS spectra and a, b and y ions in MS/MS spectra. The quantitative analysis of differently labeled yeast digests pooled with various ratios indicated the good quantitative accuracy, reproducibility, coverage and wide dynamic range of PITL strategy. Furthermore, PITL was applied to the quantitative proteome analysis of two mouse hepatocarcinoma ascites syngeneic cell lines with low and high lymph node metastasis rates (Hca-F and Hca-P). Given its low cost, simple operation and good accuracy, PITL might have great potential in the quantitative proteome analysis of biological samples. BIOLOGICAL SIGNIFICANCE: The partially isobaric peptide termini labeling (PITL) method enabled to simultaneously obtain the quantitative information from MS and MS/MS spectrum, which combined the advantages of these two strategies. Relative quantification could be achieved by comparing the intensities of parent ions in MS spectra and a, b, y ions in the MS/MS spectra. The quantitative analysis for differently labeled yeast digests mixed at various ratios indicated the good accuracy, reproducibility, quantitative coverage and wide dynamic range of the PITL strategy. Finally, we found 84 differentially expressed proteins in mouse hepatocarcinoma ascites syngeneic cell lines with low and high lymph node metastasis rates with PITL strategy and 77 proteins of them were consistently quantified in our previous studies. PMID- 25434491 TI - The S. cerevisiae SUMO stress response is a conjugation-deconjugation cycle that targets the transcription machinery. AB - The small ubiquitin-related modifier (SUMO) "stress response" (SSR) is a poorly understood evolutionarily conserved phenomenon in which steady-state SUMO conjugate levels are dramatically increased in response to environmental stresses. Here we characterize Saccharomyces cerevisiae SSR kinetics in response to several different types of stress, demonstrate that SSR activation and inactivation do not require protein synthesis or proteasome-dependent degradation, and establish that the SSR is effected primarily by the Siz1 E3 ligase and inactivated by the SUMO-specific protease Ulp2. Affinity purification coupled with mass spectrometry identifies the primary hyperosmotic SSR targets as components of the TFIID and mediator complexes, Pol II-associated mRNA maturation factors, chromatin remodeling proteins, and the transcriptional co-repressor Tup1 Cyc8. Consistent with these findings, our data also suggest that ongoing transcription (but not translation) is required to activate the SSR. The SSR thus does not appear to be directly linked to the stress itself, but likely represents a synchronized wave of sumoylation that occurs as a consequence of the large scale, coordinated changes in the transcriptional program in response to environmental stress. BIOLOGICAL SIGNIFICANCE: SUMO is a ubiquitin-like protein with a number of important biological functions. Increased levels of sumoylation are associated with a number of human diseases, and previous reports have described an evolutionarily conserved "SUMO stress response" (SSR), in which SUMO conjugate levels are markedly increased in response to environmental stresses. However, the connection between cellular stress and sumoylation has remained poorly understood. Here we conduct the first in-depth characterization of the S. cerevisiae SSR. The SUMO system components required to effect it are identified, and SSR kinetics in response to different types of environmental stresses are established. Using mass spectrometry, we identify the principle osmotic shock associated SSR targets as components of the basal transcription machinery, transcriptional regulators and chromatin remodeling complexes. Consistent with these data, we also observe that the sumoylation of SSR targets is dependent upon, and thus appears to be coupled with, transcription. Together, our data suggest that the SSR is not responsive to environmental stress per se, but more likely reflects a synchronized, transcription-coupled wave of sumoylation that accompanies the rapid, global re-programming of transcription in response to stress. This article is part of a Special Issue entitled: Protein dynamics in health and disease. Guest Editors: Pierre Thibault and Anne-Claude Gingras. PMID- 25434492 TI - Growth hormone deficiency in treated acromegaly. AB - Growth hormone deficiency (GHD) of the adult is characterized by reduced quality of life (QoL) and physical fitness, skeletal fragility, and increased weight and cardiovascular risk. Hypopituitarism may develop in patients after definitive treatment of acromegaly, but an exact prevalence of GHD in this population is still uncertain owing to limited awareness and the scarce and conflicting data available on this topic. Because acromegaly and GHD may yield adverse consequences on similar target systems, the final outcomes of some complications of acromegaly may be further affected by the occurrence of GHD. However, it is still largely unknown whether patients with post-acromegaly GHD may benefit from GH replacement. We review the diagnostic, clinical, and therapeutic aspects of GHD in adult patients treated for acromegaly. PMID- 25434493 TI - Double skin perforator flaps for aesthetic resurfacing of extensive limb defects. PMID- 25434494 TI - Novel liver findings in ornithine transcarbamylase deficiency due to Xp11.4-p21.1 microdeletion. AB - Ornithine transcarbamylase deficiency (OTCD, OMIM 311250), the most common urea cycle disorder, results in impaired synthesis of citrulline from carbamoyl phosphate and ornithine. Individuals have been identified with OTCD due to a contiguous gene deletion at Xp11.4-p21.1 and unique clinical features, described as the "extended OTCD phenotype". We present a male with neonatal-lethal OTCD due to a 1.87Mb microdeletion at Xp11.4-p21.1 (37126841-38998991 hg18). Autopsy revealed a novel histological finding of hepatocyte globular and granular inclusions. Such inclusions have not been described in OTCD or other metabolic disorders and are not an associated finding in neonatal liver failure due to other causes. The deleted region includes the gene SYTL5, potentially involved in RAB27A-dependent membrane trafficking in the liver and placenta. We propose that the contiguous gene deletion could contribute to the severity of the clinical presentation here and hypothesize that deletion of SYTL5 could contribute to the liver findings. PMID- 25434496 TI - Genetic variants at 1q32.1, 10q11.2 and 19q13.41 are associated with prostate specific antigen for prostate cancer screening in two Korean population-based cohort studies. AB - Prostate-specific antigen (PSA) levels are affected by non-cancerous conditions such as benign prostatic hyperplasia, inflammations, and inherited factors. To search for genetic variants associated with PSA levels, we conducted a genome wide association study (GWAS) using a two-stage design. A total of 554 men from the Korean Cancer Prevention Study-II were used as a discovery stage and 1575 men collected by the Korean Genome Epidemiology Study were used as a replication stage. Analysis by Genome-wide Human single-nucleotide polymorphism (SNP) array 5.0 was performed by using DNAs derived from venous blood. We analyzed the association between genetic variants and PSA levels using multivariate linear regression models, including age as a covariate. We detected 12 genome-wide significant signals on chromosome 1q32.1, 10q11.2, and 19q13.41 between PSA levels and SNPs. The top SNP associated with log PSA levels was rs2153904 in SLC45A3 (p values, 5.24*10(-9) to 2.00*10(-6)). We also investigated GWAS using 754 subjects from KCPS-II cohort whether our genome-wide significant loci were associated with a risk of prostate cancer (PCa) (200 PCa cases and 554 controls). Three of the SNPs on 10q11.2, rs7077830, rs2611489, and rs4631830, were associated with a risk of PCa. However, two loci, 1q32.1 and 19q13, were not significantly associated with a PCa risk. We suggest that our results for some but not all PCa risk SNPs to be associated with PSA levels could be used as an evidence for the advance of individual PCa screening strategies, such as applying a personalized cutoff value for PSA. PMID- 25434495 TI - Gene expression pattern of KIFC3 during spermatogenesis of the skink Eumeces chinensis. AB - Kinesin superfamily is a class of microtubule-dependent motors that play crucial roles in acrosome biogenesis, nuclear reshaping and flagellum formation during spermiogenesis. We have cloned kinesin-like gene kifc3 (termed ec-kifc3) from the total RNA of the testis of the skink Eumeces chinensis. The cDNA sequence of ec kifc3 had a full-length of 3033bp, including a 260bp 5'-untranslated region (5'UTR), a 445bp 3'-untranslated region (3'UTR) and an open reading frame that encoded a 775-amino-acid protein. Additionally, the calculated molecular weight of the putative ec-KIFC3 was 87kDa and its estimated isoelectric point was 6.18. Structurally, the putative ec-KIFC3 had three domains: head domain, neck domain and tail domain. Protein alignment demonstrated that ec-KIFC3 had 47.2%, 67.8%, 68.8%, 69.3% and 76.8% identity with its homologues in Xenopus laevis, Mus musculus, Cricetulus griseus, Homo sapiens, and Gallus gallus. The phylogenetic analysis showed that ec-KIFC3 was more related to KIFC3 in vertebrates than invertebrates. Tissue expression results showed the presence of ec-KIFC3 in various tissues with its highest expression in the testis. In situ hybridization demonstrated that ec-KIFC3 mRNA was distributed around the nucleus in early and middle stage spermatids and expressed in the nucleus in the elongating spermatids during spermiogenesis. Besides, the ec-KIFC3 mRNA was expressed in the acrosome of the developmental spermatids. From the results of in situ hybridization and previous researches, we speculated that ec-KIFC3 may play a role in nuclear morphogenesis and acrosome formation during spermiogenesis of E. chinensis. PMID- 25434497 TI - Interleukin-6 is associated with obesity, central fat distribution, and disease severity in patients with acute pancreatitis. AB - BACKGROUND/OBJECTIVE: Acute pancreatitis (AP) is a systemic inflammatory disease, and cytokines are suggested to be related to the course of AP. Obesity and central fat distribution are considered to have been associated with severe AP. This study investigated the profile of inflammatory cytokines in AP to determine how they are related to obesity, central fat distribution, and AP severity. METHODS: Fifty-nine patients with AP were prospectively enrolled in the study. Body mass index and waist circumference were obtained at admission. Serum levels of inflammatory cytokines, IL-Ibeta, IL-1ra, IL-6, TNF-alpha, sTNFR-I, and sTNFR II, were measured on day 1 and 2 of AP. RESULTS: Of the patients included in the study, 19 (32%) were overweight, 23 (39%) had central fat distribution, and 23 (39%) had moderate AP. IL-1ra and IL-6 were significantly higher in overweight patients compared with non-overweight patients. IL-1ra, IL-6, TNF-alpha, and sTNFR-I were significantly higher in patients with central fat distribution compared with patients with non-central fat distribution. IL-6, sTNFR-I, and sTNFR-II were significantly higher in patients with moderate pancreatitis compared to those with mild pancreatitis. Among the six cytokines, IL-6 was commonly elevated in patients with central fat distribution, overweight, and moderate AP. The areas under the receiver operating characteristic curves of IL-6 for predicting the association with overweight, central fat distribution, and AP severity were 0.678, 0.716, and 0.801, respectively (P < 0.05). CONCLUSIONS: IL-6 is a good marker for AP severity and is associated with obesity and central fat distribution in AP patients. PMID- 25434498 TI - The influence of chronic pain on the daily lives of underprivileged South Africans. AB - Chronic pain is a major public health problem that changes lives and has devastating consequences for the person experiencing the pain, the family, and society. Living with chronic pain is not easy, especially in South Africa where the public health care system, serving 80% of the population, fails people suffering from chronic pain. The purpose of the study was to explore how experiencing chronic pain influenced the daily lives of underprivileged patients receiving nursing care at the palliative care clinic serving a resource-poor community in Tshwane, South Africa. A qualitative descriptive phenomenologic design was selected for the study. Nine purposively selected community members, registered as patients at the palliative care clinic and who suffered chronic pain, participated in the study. In-depth interviews were conducted and Tesch's coding process was used to analyze the data. Data gathering and analysis were done concurrently to determine data saturation. Four themes arose from the data: pain as a multidimensional experience, the influence of pain on physical activities, the psychosocial influence of pain, and the influence of pain on spirituality. Participants' experience of pain tells of severe suffering that hindered them in performing activities of daily living. Participants were confronted with total pain and were caught in a vicious circle where pain was responsible for severe suffering and their suffering added to their pain. However, strong religious beliefs improved pain and gave hope for the future. PMID- 25434499 TI - Effect of hospice nonprofessional caregiver barriers to pain management on adherence to analgesic administration recommendations and patient outcomes. AB - Nonprofessional caregivers frequently experience barriers to using analgesics for pain in patients in home hospice settings, and patients in pain may suffer needlessly. For example, caregiver adherence to the administration of analgesics is lower for as-needed (PRN) regimens than for standard around-the-clock regimens. But little is known about the barriers caregivers experience and the effects of those barriers. Accordingly, we determined caregiver barriers to using analgesics to manage the pain of patients in the home hospice care setting, and how such barriers affected caregiver adherence and patient quality of life. To this end, we measured barriers, caregiver adherence to PRN analgesic regimens, and patient health outcomes (pain, depression, quality of life [QoL]). A 3-day longitudinal design was used. We recruited 46 hospice nonprofessional caregiver patient dyads from a local community hospice agency. Barriers were measured with the Barrier Questionnaire II. Adherence to the PRN analgesic regimen was obtained with a 3-day pain and medication diary. Patient outcome measures included pain intensity, the Hospital Depression Scale, and the Brief Hospice Inventory for QoL. Barrier scores were moderate to low. Caregivers adhered to PRN analgesic regimens approximately 51% of the time. Higher caregiver adherence to PRN analgesic regimens was associated with lower patient pain intensity and higher patient QoL, but not, surprisingly, with barriers to pain management. Longitudinal studies are now needed to identify factors besides caregiver barriers that may unduly lower caregiver adherence to PRN analgesic regimens. PMID- 25434500 TI - Comparison of analgesic efficacy of paracetamol and tramadol for pain relief in active labor. AB - STUDY OBJECTIVE: To evaluate the efficacy and safety profile of paracetamol in comparison with tramadol for pain relief during active labor. DESIGN: Prospective, randomized, double-blind study. SETTING: Maternity Wing of the Postgraduate Institute of Medical Education and Research, Chandigarh. PATIENT: Sixty laboring, primiparous, full-term parturients with uncomplicated, singleton pregnancy in spontaneous labor and cervical dilatation of 3-5 cm. INTERVENTION: Parturients were randomized into 2 groups to receive either 1 mg/kg of tramadol intramuscularly (group T; n = 29) or 1 g of paracetamol intravenously (group P; n = 30). Same doses of the drugs were repeated after 4 hours of initial dose. MEASUREMENT: Primary outcome of the study was to assess the analgesic efficacy of the 2 drugs as measured by visual analog scale (VAS) score. Secondary outcome recorded was duration of labor, presence of any maternal, or fetal adverse events during the study. RESULTS: Both the groups showed comparable VAS scores at all times of observation. Lower mean VAS scores were reported in both the groups till 120 minutes only. The duration of first stage of labor was shorter in group P (248.00 +/- 98.171 vs 340.63 +/- 111.592 minutes; P = .003). The duration of second stage of labor was comparable between the 2 groups. Higher incidence of maternal side effects such as nausea/vomiting and sedation was associated with the use of tramadol. Neonatal outcome was comparable. CONCLUSION: Intravenous paracetamol provides comparable analgesia as intramuscular tramadol during active labor. PMID- 25434502 TI - Angioedema in the neurointerventional suite. AB - A 68-year-old woman with acute ischemic stroke presented for mechanical thrombectomy, after failed thrombolysis with intravenous recombinant tissue plasminogen activator. The procedure was completed successfully with dexmedetomidine infusion. However, she developed acute angioedema toward the end of the procedure requiring emergent fiberoptic-guided endotracheal intubation. Angioedema has been reported to occur after administering intravenous recombinant tissue plasminogen activator with an incidence of 1.3%-5.1% in patients with acute stroke. PMID- 25434501 TI - Landiolol in the treatment of the intraoperative supraventricular tachycardia: a multicenter, randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Supraventricular tachycardia during the induction of anesthesia may carry a higher risk. STUDY OBJECTIVE: The aim of this study was to evaluate efficacy and safety of intravenous landiolol in Chinese patients with intraoperative supraventricular tachycardia during anesthesia. DESIGN: A randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase 2 study. SETTING: Eight sites of Chinese hospitals. PATIENTS: Men and women aged 18 to 70 years with the intraoperative supraventricular tachycardia (heart rate [HR], >=100 beats/min) or the supraventricular tachycardia outside of the sinus tachycardia lasting more than 1 minute. INTERVENTIONS: Patients received landiolol or placebo-0.125 mg kg(-1) min(-1) (1 minute) loading->0.04 mg kg(-1) min(-1) (10 minutes) continuous. MEASUREMENTS: The proportion of patients receiving rescue medication (esmolol) when the reduction of HR did not exceed 10% after intravenous landiolol for 5 minutes. Other secondary efficacy end points include HR, blood pressure, rate pressure product, and electrocardiogram; the improvement of supraventricular tachycardia; the time it takes for the decrease of the HR to reach more than 10%; and the time it takes for the HR to reach <100 beats/min. MAIN RESULTS: Efficacy and safety were evaluated for 240 patients who received study drug. Lower proportions of patients received rescue medication in the landiolol group (7.63%) compared with that in the placebo group (80.33%) (P < .0001). Suppression of HR and rate pressure product was generally more potent(P < .0001), and higher proportions of patients improved supraventricular tachycardia (P < .0001) in the landiolol group. The most frequent adverse event was hypotension. CONCLUSION: Intravenous landiolol (loading dose of 0.125 mg/kg) may effectively control intraoperative supraventricular tachycardia during anesthesia. It inhibited the increases in HR during the induction of anesthesia. The effect of landiolol on blood pressure was minimal without decreasing diastolic blood pressure and with the minor reduction of systolic blood pressure (ClinicalTrials.gov number, ChiCTR-TRC-12003021). PMID- 25434503 TI - Young age, male sex, and end-stage renal disease with secondary hyperparathyroidism as risk factors for intraoperative hyperkalemia during parathyroidectomy. AB - STUDY OBJECTIVE: The aim of this study was to investigate the risk factors of intraoperative hyperkalemia in end-stage renal disease patients undergoing parathyroidectomy (PTx) with autotransplantation (AT). DESIGN: Prospective observational study. SETTING: Operating room of a tertiary care medical center. PATIENTS: Thirty-two adult, American Society of Anesthesiologists physical status 2 and 3 patients with secondary hyperparathyroidism aged between 31 and 72 years scheduled for PTx with AT. MEASUREMENTS: Laboratory chemistries (intact parathyroid hormone, Na, K, Ca, P, arterial blood gas) were obtained before surgery and at 2 time points during surgery. The first chemistry levels during surgery were checked after the first 2 parathyroid glands had been removed, and the second levels were checked after wound closure. Statistical analysis was performed using t test, Fisher exact test, the receiver operating characteristic curve method, as appropriate. MAIN RESULTS: Eight patients (25%) developed hyperkalemia during surgery. The hyperkalemia patients had younger age (42+/ 11.44 years vs 52.58+/-11.83 years, P=.044) and a male dominance (odds ratio, 11.4; P=.01; 95% confidence interval, 1.74-74.65). The cutoff for age was 40.5 years, according to the highest value for sensitivity plus specificity of the receiver operating characteristic curve. There was a higher incidence of intraoperative hyperkalemia in younger patients than in older patients (odds ratio, 8.33; P=.023; 95% confidence interval, 1.39-49.87) as well as a significant increase in potassium level during surgery in younger male patients (P=.005 and .002, respectively). CONCLUSIONS: The anesthesiologist should be aware of the complications of intraoperative hyperkalemia during PTx with AT, especially in male end-stage renal disease patients younger than 40 years. PMID- 25434504 TI - Reductive silylation of the uranyl ion with Ph3SiOTf. AB - The reaction of 2 equiv of Ph3SiOTf with UO2(dbm)2(THF) (dbm = OC(Ph)CHC(Ph)O) and UO2((Ar)acnac)2 ((Ar)acnac = ArNC(Ph)CHC(Ph)O; Ar = 3,5-(t)Bu2C6H3) results in the formation of U(OSiPh3)2(dbm)2(OTf) (1) and [U(OSiPh3)2((Ar)acnac)2][OTf] (2), respectively, in good yield. PMID- 25434505 TI - Inositol-requiring enzyme 1-mediated endoplasmic reticulum stress triggers apoptosis and fibrosis formation in liver cirrhosis rat models. AB - Long-term and advanced cirrhosis is usually irreversible and often coincides with variceal hemorrhage or development of hepatocellular carcinoma; therefore, liver cirrhosis is a major cause of morbidity and mortality globally. The aim of the present study was to investigate the specific mechanism behind the formation of fibrosis or cirrhosis using rat models of hepatic fibrosis. The cirrhosis model was established by intraperitoneally administering dimethylnitrosamine to the rats. Hematoxylin and eosin staining was performed on the hepatic tissues of the rats to observe the fibrosis or cirrhosis, and western blot analysis was employed to detect alpha-smooth muscle actin and desmin protein expression. Flow cytometric analysis was used to examine early and late apoptosis, and the protein and mRNA expression of endoplasmic reticulum (ER) stress-associated unfolded protein response (UPR) pathway proteins and apoptotic proteins [C/EBP homologous protein (CHOP) and caspase-12] was detected by western blotting and the reverse transcription polymerase chain reaction, respectively. The results indicated that the cirrhosis model was established successfully and that fibrosis was significantly increased in the cirrhosis model group compared with that in the normal control group. Flow cytometric analysis showed that early and late apoptosis in the cirrhosis model was significantly higher compared with that in the control group. The expression of the UPR pathway protein inositol-requiring enzyme (IRE) 1, as well as the expression of CHOP, was increased significantly in the cirrhotic rat tissues compared with that in the control group tissues (P<0.05). In conclusion, apoptosis was clearly observed in the hepatic tissue of cirrhotic rats, and the apoptosis was caused by activation of the ER stress mediated IRE1 and CHOP. PMID- 25434506 TI - Professor Hector Maldonado. PMID- 25434508 TI - Endocrine changes in histiocytosis of the hypothalamic-pituitary axis. AB - Histiocytosis is characterized by proliferation of cells from the mononuclear phagocyte system, and may be divided into Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (including Erdheim-Chester disease [ECD]). While diabetes insipidus (DI) is the most common hypothalamic-pituitary consequence, anterior pituitary deficiencies are less known. This study analyzed the frequency and progression of pituitary hormone deficiencies and the radiographic findings in 9 patients (7 with LCH and 2 with ECD) with hypothalamic pituitary (HP) axis. Eighty-nine percent of patients had DI (62% at diagnosis), and 78% had one or more anterior pituitary deficiencies (71% at diagnosis). HP involvement is relatively common in patients diagnosed with histiocytosis and hormone deficiencies may be present at diagnosis or appear gradually during the course of disease. Regular monitoring of these patients is recommended. PMID- 25434509 TI - Cytochrome P1B1 (CYP1B1) polymorphisms and cancer risk: a meta-analysis of 52 studies. AB - CYP1B1 plays a critical role in the oxidative metabolism of a variety of exogenous compounds, including carcinogenic compounds, which may be activated during metabolism. There are only a few studies that have examined the association between the two polymorphisms and cancer, and that these studies have been inconclusive. Hence, the aim of the present meta-analysis was to evaluate the relationship between polymorphisms in CYP1B1 G119T and A453G and cancer risk. We performed a detailed search using the PubMed and EMBASE libraries to obtain all relevant published reports on the relationship between the G119T and A453G polymorphisms in CYP1B1 and cancer risk. Combined odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated by Stata version 11.2. We conducted stratified analyses based on cancer types, ethnicity, source of controls, and quality assessments. We also made assessments of heterogeneity tests, sensitivity analyses, and publication bias. There were a total of 25 articles with 15,376 cases and 18,382 controls concerning CYP1B1 G119T and 40 articles with 27,983 cases and 35,839 controls concerning A453G polymorphisms. Regarding G119T, the combined results indicate that the variant genotypes were significantly associated with a slightly increased cancer risk in comparison to the homozygote (TT versus GG: p=0.006, OR=1.231, 95% CI: 1.061-1.428), especially for breast cancer and prostate cancer. Moreover, significantly increased associations with cancer risk were demonstrated in Asians in all genetic models. The combined results indicated no association of A453G with cancer risk; however, an association was observed specifically for prostate cancer. This meta-analysis suggests that the CYP1B1 G119T polymorphism may confer to genetic susceptibility to cancer in Asians, especially to breast cancer and prostate cancer. The A453G polymorphism was found to modify the risk of prostate cancer. PMID- 25434511 TI - What money can buy: family income and childhood obesity. AB - This paper investigates the relationship between family income and childhood obesity. Using the Early Childhood Longitudinal Study, Kindergarten Class of 1998 99 (ECLS-K), I report three new findings. First, family income and childhood obesity are generally negatively correlated, but for children in very low-income families, they are positively correlated. Second, the negative association between family income and Body Mass Index (BMI) is especially strong and significant among high-BMI children. Third, the difference in obesity rates between children from low- and high-income families increases as children age. This study further investigates potential factors that might contribute to a rapid increase in the obesity rate among low-income children. I find that their faster weight gain, rather than slower height growth, is a greater contributor to the rapid increase in their BMI over time. On the other hand, I also find that the faster weight gain by low-income children cannot be attributed to any single factor, such as participation in school meal programs, parental characteristics, or individual characteristics. These findings add to the current obesity debate by demonstrating that the key to curbing childhood obesity may lie in factors generating different obesity rates across income levels. PMID- 25434510 TI - [Treatment of tuberculosis]. AB - The aim of this article is to give practicing physicians a practical approach to the treatment of latent and active tuberculosis. Most patients follow TB standard treatment recommended by WHO that depend on category of patient. It is a combination of four essential tuberculosis drugs of the first group: isoniazid, rifampicin, pyrazinamid and ethambutol; in some cases streptomycin can replace ethambutol. This initial phase of intensive treatment is followed by a consolidation phase. Drugs should be administered in the morning on an empty stomach one hour before meals. Treatment of latent tuberculosis (TB) infection is an important component of TB control programs. Preventive treatment can reduce the risk of developing active TB. PMID- 25434512 TI - Breastfeeding and child disability: a comparison of siblings from the United States. AB - Little is known about whether breastfeeding may prevent disabilities throughout childhood. We evaluate the effects of breastfeeding on child disability using data from the National Survey of Family Growth merged to the National Health Interview Survey for a large nationally representative sample of children aged 1 18 years from the U.S. including over 3000 siblings who are discordant on breastfeeding status/duration. We focus on a mother fixed effect model that compares siblings in order to account for family-level unobservable confounders and employ multiple specifications including a dynamic model that accounts for disability status of the prior child. Breastfeeding the child for a longer duration is associated with a lower risk of child disability, by about 0.2 percentage-points per month of breastfeeding. This effect is only observed on the intensive margin among breastfed children, as any breastfeeding has no effect on the extensive margin. We conclude that very short breastfeeding durations are unlikely to have an effect on reducing disability risk. PMID- 25434513 TI - Decomposing race and gender differences in underweight and obesity in South Africa. AB - Using data from the National Income Dynamics Study, we document differentials in both underweight and obesity across race and gender in post-Apartheid South Africa. Using a nonlinear decomposition method, we decompose these differences across gender within race and then across race within gender. Less than one third of the differences in obesity and underweight across gender are explained by differences in covariates. In contrast, at least 70% of the obesity differences across race are explained by differences in covariates. Behavioral variables such as smoking and exercise explain the largest part of the bodyweight differentials across gender. For bodyweight differentials across race within gender, however, socioeconomic status and background variables have the largest explanatory power for obesity differentials, while background variables play the key role in explaining the underweight differentials. These results indicate that eradicating obesity and underweight differentials will require targeting policies to specific groups. PMID- 25434514 TI - [Frailty syndrome: an old new friend]. AB - Frailty syndrome is defined as extreme stress vulnerability and decreased potential to adapt. The elderly and chronically ill patients are affected mostly. This condition increases the risk of adverse health outcomes as infections, falls, delirium, institutionalization, progression of comorbidities and mortality. The pathophysiological mechanism is a complex immune and neuroendocrine dysregulation. According to the phenotype model, frailty presents when three of the followings occur: weakness, exhaustion, slowness, weight loss and decreased activity, while cumulative model counts the number of health deficits. Aging, frailty, dementia and depression are independent clinical entities; they may present separately but may also potentiate each other. Hence most of the frailty scales assess the physical, mental and social dimensions as well. Mild or moderate frailty is potentially reversible with an individualised caring plan. Given short, easy-to-use screening tools, risk groups can be identified in the primary care and referred to a specialised team for further treatment. Here the authors summarise the literature of a re-discovered, current clinical phenomena, frailty syndrome, focusing on the practical issues in primary care. PMID- 25434515 TI - [Percutaneous coronary intervention in stable coronary artery disease]. AB - Percutaneous coronary intervention is a well-established symptomatic therapy of stable coronary artery disease. Using a literature search with special emphasis on the newly-published FAME 2 trial data, the author wanted to explore why percutaneous coronary intervention fails to reduce mortality and myocardial infarction in stable coronary artery disease, as opposed to surgical revascularisation. In the FAME 2 trial, fractional flow reserve-guided percutaneous coronary intervention with second generation drug eluting stents showed a significant reduction in the primary composite endpoint of 2-year mortality, myocardial infarction and unplanned hospitalization with urgent revascularisation as compared to medical therapy alone. In addition, landmark analysis showed that after 8 days, mortality and myocardial infarction were significantly reduced. The author concludes that percutaneous coronary intervention involving fractional flow reserve guidance and modern stents offers symptomatic, as well as prognostic benefit. PMID- 25434516 TI - [Current approaches for early detection and treatment of medication-related osteonecrosis of jaw]. AB - Owing to the increased life expectancy, the incidence of rheumatoid disorders and oncologic cases with bone metastasis has dramatically increased. Despite the beneficial effects of the applied antiresorptive and antiangiogenic drugs (e.g. bisphosphonates), serious side effects such as jaw osteonecrosis may also develop. The aim of the authors was to summarize present knowledge about the possibilities of prevention and treatment in medication-related osteonecrosis of the jaw. Based on literature data, currently used detection methods for medication-related osteonecrosis of the jaw (including their advantages and limitations) are summarized. In addition, novel trends of surgical and adjuvant therapeutic approaches are also reviewed. The authors conclude that possibilities of prevention and efficacy of therapeutic interventions in this disorder are still limited possibly due to an incomplete knowledge of the underlying pathomechanism. An interdisciplinary cooperation for prevention and attentive monitoring in order to decrease the incidence of iatrogenic oral and maxillofacial complications seems to be particularly important. PMID- 25434517 TI - [Relationship between early maladaptive schemas, attachment quality and fear of darkness]. AB - INTRODUCTION: Although fear of darkness is most common in childhood, it is also a remarkable phenomenon in young adulthood. AIM: To examine the relationship between fear of darkness, early maladaptive schemas and attachment quality in young adults and assess fear related sex differences. METHOD: A self-developed scale was used to measure fear of darkness' intensity and frequency. Young Schema Questionnaire - Short Form and two scales that measure attachment dimensions were also applied. 120 university students (68 women, 52 men) filled in the tests. RESULTS: Fear of darkness' frequency correlated with avoidant attachment, and intensity with independent and anxious attachment. Fear of darkness variables correlated with several early maladaptive schemas. Women reported more frequent and intensive fear of darkness than men. CONCLUSIONS: These results indicated that the elevated level of fear of darkness is related to specific cognitive style and attachment quality. This highlights the potential clinical relevance of fear of darkness. PMID- 25434518 TI - Associations among four polymorphisms (BsmI, FokI, TaqI and ApaI) of vitamin D receptor gene and end-stage renal disease: a meta-analysis. AB - BACKGROUND AND AIMS: To evaluate the association between vitamin D receptor (VDR) BsmI, FokI, TaqI and ApaI gene polymorphisms and the risk of end-stage renal disease (ESRD). METHODS: All eligible studies were included in our meta-analysis of a search of the PubMed, Cochrane and China National Knowledge Infrastructure (CNKI) databases according to predefined criteria. The fixed-effects or random effects models were used to calculate the pooled odds ratio (OR) and corresponding 95% confidence interval (CI). RESULTS: Thirteen studies including 1510 patients and 1812 controls were recruited for the analysis of the association between the VDR BsmI, FokI, TaqI and ApaI gene polymorphisms and the risk of ESRD.VDR BsmI B allele, BB genotype and bb genotype, FokI F allele, FF genotype and ff genotype, TaqI T allele, TT genotype and tt genotype, ApaI A allele, AA genotype and aa genotype were not associated with ESRD susceptibility for overall populations, Asians and Caucasians. CONCLUSIONS: Results from the current study suggest that VDR BsmI, FokI, TaqI and ApaI gene polymorphisms are not associated with the risk of ESRD in the overall populations, Asians and Caucasians. However, more studies should be performed in the future. PMID- 25434520 TI - Consideration on bipolar manio-depressive disease and the effect of Lithium. A neurophysiological view on mental disorders. PMID- 25434519 TI - Mitochondrial dynamics regulates hypoxia-induced migration and antineoplastic activity of cisplatin in breast cancer cells. AB - Mitochondria are high dynamic organelles with frequent fission and fusion. Here, we found hypoxia stimulated Drp1 expression, mitochondrial fission and migration in metastatic MDA-MB-231 cells, but not in non-metastatic MCF-7 cells. Inhibition of Drp1-dependent mitochondrial fission by Mdivi-1 or silencing Drp1 attenuated hypoxia-induced mitochondrial fission and migration in MDA-MB-231 cells. On the other hand, cisplatin induced significant apoptosis and mitochondrial fission in MDA-MB-231 cells, but not in MCF-7 cells. Mdivi-1 and silencing Drp1 also efficiently prevented cisplatin-induced MMP decrease, ROS production and apoptosis in MDA-MB-231 cells. Our data suggest that Drp1-dependent mitochondrial fission not only regulates hypoxia-induced migration of breast cancer cells, but also facilitates its sensitivity to chemotherapeutic agents. Thus, targeting Drp1 dependent mitochondrial dynamics may provide a novel strategy to suppress breast cancer metastasis and improve the chemotherapeutic effect in the future. PMID- 25434521 TI - Letter to the editor: The effect of ECT on sleep--a comment to Winkler et al. AB - Recent publications in this journal have suggested that successful electroconvulsive therapy (ECT) in depressed patients is associated with a phase advance, similar to what has been reported with antidepressant medications. Herein we review the effects of ECT on polysomnographic (PSG) sleep, and we conclude with the observation that ECT reliably increases PSG total sleep time and probably has a suppressive effect on rapid eye movement (REM) sleep. Remarkably, there is less information available on the topic of the effect of ECT on the patient's perception of their sleep. PMID- 25434522 TI - Reliability of transthoracic echocardiogram interpretation in potential adult heart transplant donors. PMID- 25434523 TI - Venous thromboembolism in heart transplant recipients: incidence, recurrence and predisposing factors. AB - BACKGROUND: A high frequency of venous thromboembolism (VTE) has been observed after lung, kidney, and liver transplantation. However, data about the incidence of this complication among heart transplant (HT) recipients are lacking. METHODS: We analyzed the incidence, recurrence, and predisposing factors of VTE in a single-center cohort of 635 patients who underwent HT from April 1991 to April 2013. Deep venous thrombosis (DVT) and pulmonary embolism (PE) were considered as VTE episodes. RESULTS: During a median post-transplant follow-up of 8.4 years, 62 VTE episodes occurred in 54 patients (8.5%). Incidence rates of VTE, DVT, and PE were, respectively, 12.7 (95% confidence interval [CI], 9.7-16.3), 8.4 (95% CI, 6.0-11.4), and 7.0 (95% CI 4.8-9.7) episodes per 1,000 patient-years. Incidence rates of VTE during the first post-transplant year and beyond were, respectively, 45.1 (95% CI, 28.9-67.1) and 8.7 (95% CI 6.2-11.2) episodes per 1,000 patient years. The incidence rate of VTE recurrence after a first VTE episode was 30.5 (95% CI, 13.2-60.2) episodes per 1,000 patient-years. By means of multivariable Cox regression, chronic renal dysfunction, older age, obesity, and the use of mammalian target of rapamycin inhibitors were identified as independent risk factors for VTE among HT recipients. CONCLUSIONS: VTE is a frequent complication after HT, mainly during the first post-operative year. In view of a high recurrence rate, long-term anti-coagulation should be considered in HT recipients who experience a first VTE episode. PMID- 25434524 TI - Repetitive HeartMate II pump stoppage induced by transitioning from battery to main power source: the short-to-shield phenomenon. PMID- 25434525 TI - Effect of incorporating sugar beet pulp in the finisher diet on performance of geese. AB - The aim of this work was to study the effects of incorporating sugar beet pulp (SBP) into the diet on the development of the crop and performance of geese. A total of 480 1-day-old ganders were divided into three groups differing in the composition and mode of distribution of the diet offered from day 56 to 89. The following two diets were used: a standard diet (nitrogen-corrected apparent metabolizable energy, AMEn 11.44 MJ/kg; 160 g/kg CP) or a diet containing 10% of SBP (SBP diet; AMEn 11.47 MJ/kg; 160 g/kg CP). The swelling capacity (SC) hydration was higher for SBP than for the standard diet (3.62 v. 2.72 ml of H2O/g of dry matter at 60 min; P<0.05). In the Control group, birds were fed with a controlled time of access to a standard diet. Other birds were fed the SBP diet with a controlled time of access (SBPt group) or a controlled quantity offered (SBPq). From day 90 to 104, 88 birds/group were overfed with a mixture containing mainly corn. Body traits including volume of the crop were measured at day 89. Fatty liver weight and commercial grading were measured at d 104. Feed intake from day 56 to 89 was higher in the Control group than in the SBPt group (8097 v. 7545 g; P<0.05), feed intake in the SBPq group being intermediate (7801 g); however, live weights (LW) of the birds were similar in the three groups measured at day 89 (5746 g; P>0.05). At day 89, the volume of the crop tended to be higher in the SBPt compared with the Control group (52.8 v. 48.8 ml/kg of LW; P=0.101). After overfeeding, feed intake (12 922 g), weight gain (2412 g), LW (8170 g), fatty liver weight (875 g) and commercial grading of the fatty liver were similar (P>0.1) for all the three groups. Therefore, SBP could help adapt the digestive tract of waterfowl to high feed intake through an increase in the crop volume, but its method of use - that is, level of incorporation and mode of distribution should continue to be investigated. PMID- 25434527 TI - A novel method for synthetic vaccine construction based on protein assembly. AB - In the history of vaccine development, the synthetic vaccine is a milestone that is in stark contrast with traditional vaccines based on live-attenuated or inactivated microorganisms. Synthetic vaccines not only are safer than attenuated or inactivated microorganisms but also provide the opportunity for vaccine design for specific purposes. The first generation of synthetic vaccines has been largely based on DNA recombination technology and genetic manipulation. This de novo generation is occasionally time consuming and costly, especially in the era of genomics and when facing pandemic outbreaks of infectious diseases. To accelerate and simplify the R&D process for vaccines, we developed an improved method of synthetic vaccine construction based on protein assembly. We optimized and employed the recently developed SpyTag/SpyCatcher technique to establish a protein assembly system for vaccine generation from pre-prepared subunit proteins. As proof of principle, we chose a dendritic cell (DC)-targeting molecule and specific model antigens to generate desired vaccines. The results demonstrated that a new vaccine generated in this way does not hamper the individual function of different vaccine components and is efficient in inducing both T and B cell responses. This protein assembly strategy may be especially useful for high-throughput antigen screening or rapid vaccine generation. PMID- 25434528 TI - Coronary artery disease in giant cell arteritis: a systematic review and meta analysis. AB - OBJECTIVE: To investigate the association between giant cell arteritis (GCA) and risk of coronary artery disease (CAD). METHODS: We conducted a systematic review and meta-analysis of observational studies that reported relative risks, hazard ratios, or standardized incidence ratios with 95% confidence interval comparing CAD risk in patients with GCA versus non-GCA controls. Pooled risk ratios and 95% confidence intervals were calculated using a random-effect, generic inverse variance of DerSimonian and Laird. RESULT: Six studies with 10,868 patients with GCA and 245,323 controls were identified and included in our data analysis. The pooled risk ratio of CAD in patients with GCA was 1.51 and did not achieve statistical significance (95% CI: 0.88-2.61). The statistical heterogeneity was high with an I(2) of 97%. CONCLUSION: In contrast to other chronic systemic inflammatory disorders, our meta-analysis did not show any statistically significant increased risk of CAD among patients with GCA. PMID- 25434529 TI - From a typical focal nodular hyperplasia to a fibrotic band with capsular retraction: a case report. PMID- 25434531 TI - Suicidal ideation and its determinants in Korean adults: The role of physical activity and functional limitations. AB - The recognition of suicide as a major public health problem has suggested the need to identify risk factors that have implications for preventive intervention. In the suicidal process, suicidal ideation is a key stage in the pathway leading to eventual suicide. This study investigated the influence of physical activity and functional limitations on suicidal ideation among young and middle-aged adults in a high suicidal society. Data for the current study were obtained from the Fourth Korea National Health and Nutrition Examination Survey 2007-2009 (KNHANES), a cross-sectional study conducted by the Korea Centers for Disease Control and Prevention. The survey conducted face-to-face interviews with young adults (n = 2326) and middle-aged adults (n = 3396). Using multivariate logistic regression analysis, the relationship of physical activity and functional limitations with suicidal ideation in young and middle-aged adults was assessed. A notable outcome was that the absence of a regular walking was correlated with increased suicidal ideation in middle-aged women. The other major finding was that young women and middle-aged adults with functional limitations had a high rate of suicidal thoughts. Multiple intervention approaches, including informational, social and behavioural approaches, are needed to promote regular walking in middle-aged women. For instance, mass media campaigns, community walking groups and individually adapted health behaviour modification may provide opportunities for positive intervention. Additionally, another important public health implication from these findings is the need for a suicide-intervention support system that includes screening for suicide risk in healthcare settings, especially among young women with physical limitations. PMID- 25434530 TI - [Prevalence of genital anomalies in young football players]. AB - The purpose of genital examination (GE) during the Pre-participation Physical Examination (PPE) is to identify the state of maturity, and rule out any genital pathology. To describe genital anomalies (GA) and estimate the awareness of GE in young football players. A descriptive, cross-sectional study was conducted in 280 elite football players from the results of PPE over two seasons. There was a detection rate of 5.4% GA, with varicocele being 3.2%, and of which only 13% were aware of their condition. Although this study shows a low incidence of genital abnormality in the study population, only 13% were aware of the GE prior to assessment. These findings demonstrate a low incidence of GA in this population. While GE is recommended during PPE, it is not a routine practice performed by family doctors or sports medicine specialists. This article attempts to raise awareness of the importance of GE in PPE as a preventive health strategy. PMID- 25434532 TI - Baicalin, a flavonoid, affects the activity of human dermal papilla cells and promotes anagen induction in mice. AB - Baicalin, a flavonoid isolated from Scutellaria baicalensis, is known to have multiple biological functions. Recent studies have demonstrated that baicalin treatment increases alkaline phosphatase activity (ALP) and osteoprotegerin secretion by osteoblasts. Furthermore, baicalin induces the differentiation of cultured osteoblasts via the activation of the Wnt/beta-catenin signaling pathway. In this study, we evaluated the hair growth-promoting effects of baicalin in human follicular dermal papilla (DP) cells. A reporter assay and Western blotting were used to assess the effect of baicalin on beta-catenin signaling in DP cells. ALP activity and messenger RNA (mRNA) expression were examined by ALP staining and real-time polymerase chain reaction (PCR), respectively. Growth factor expression levels were also evaluated using real-time PCR. Finally, the effect of baicalin on hair growth in vivo was examined by topical application of baicalin on the shaved dorsal skin of C57BL/6 mice. Our results indicate that baicalin activates Wnt/beta-catenin signaling in a dose dependent manner in human DP cells. ALP mRNA expression and activity were significantly induced in the presence of baicalin. In addition, treatment with baicalin induced the mRNA expression of growth factors, such as insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF). Moreover, compared to vehicle treatment, baicalin treatment induced an earlier conversion from telogen to anagen. Our results strongly suggest that baicalin promotes hair growth by regulating the activity of DP cells. PMID- 25434533 TI - 5'-Nucleotidase from Vipera lebetina venom. AB - 5'-Nucleotidase (5'-NT) is widely represented in animal tissues (CD73) as well as in almost all snake venoms. In the present study, a 5'-NT isoform has been isolated from Vipera lebetina venom. The homodimeric isoform consists of monomers with molecular masses of 60 kDa. The enzyme is thermolabile and has pH optimum at 7.5. The 5'-NT activity is inhibited by metal ions Fe(3+), Cu(2+) and Zn(2+), enhanced by Mn(2+) while Mg(2+) and Ca(2+) have no remarkable effect. In addition to 120-kDa protein there are higher molecular forms of 5'-NT present in the V. lebetina venom. The cloning and sequencing of the 5'-NT coding cDNA resulted in 5'-truncated construct. MALDI-TOF and Orbitrap mass-spectrometry of the tryptic peptides confirmed the translated N-terminally truncated protein sequence concordance to the 5'-NT isolated from the venom. The isolated protein strongly inhibited ADP- or collagen-induced platelet aggregation. PMID- 25434535 TI - [Study of aspiration therapy for primary spontaneous pneumothorax]. AB - The 2003 British Thoracic Society guidelines recommend aspiration for treating primary spontaneous pneumothorax. This procedure allows the patient management on an outpatient basis, and is highly significant in terms of medical cost and quality of life (QOL). The safety and success rate of aspiration was studied in 23 patients who received this treatment. The success rate was at 69.6%, and the patients were safely managed without emergency drainage due to dyspnea. Aspiration is a possible choice for the 1st-line treatment for primary spontaneous pneumothorax. PMID- 25434534 TI - First crotoxin-like phospholipase A(2) complex from a New World non-rattlesnake species: nigroviriditoxin, from the arboreal Neotropical snake Bothriechis nigroviridis. AB - Bothriechis nigroviridis is an arboreal Neotropical pitviper found in Costa Rica and Panama. A previous proteomic profiling of its venom revealed the presence of proteins with homology to the A and B subunits of crotoxin/Mojave toxin, a heterodimeric phospholipase A2 (PLA2) complex only described in rattlesnake venoms (genera Crotalus and Sistrurus). The native crotoxin-like heterodimer, named nigroviriditoxin, and its A and B subunits were isolated in the present work, and the complete amino acid sequence of the B subunit was determined. The purified A and B components were demonstrated to form a complex when reconstituted under native conditions. Nigroviriditoxin presents features similar to crotoxin, albeit displaying lower toxicity: the A component decreases the PLA2 activity of the B component, and increases its lethal potency in mice. Also in similarity to crotoxin B, nigroviriditoxin B induces myonecrosis. Its 122 amino acid sequence presents 81% identity with crotoxin B. Accordingly, nigroviriditoxin B was cross-recognized by equine antibodies from a Crotalus durissus terrificus antivenom. Phylogenetic analysis shows that the novel PLA2 from B. nigroviridis venom is basal to the branch including all the homologous PLA2 enzymes described in rattlesnakes, and more distant from PLA2s from Bothriechis species. Nigroviriditoxin is the first heterodimeric PLA2 complex found in a non-rattlesnake, Neotropical viperid venom, which displays structural, functional, and immunochemical similarities to crotoxin. The present findings are compatible with the existence of the particular structural trait of crotoxin-like molecules in New World pitvipers before the split of the Meso-South American and the Nearctic clades. PMID- 25434536 TI - [Construction of a heart team using network attached storage]. AB - There has been recent emphasis on the importance of an interdisciplinary heart team to allow active communication between physicians and surgeons regarding the management of cardiovascular diseases. Construction of a heart team requires a system that enables doctors to rapidly review patients' data when exchanging opinions. We tried to build up a heart team by sharing patients' data via network attached storage( NAS). We installed a server at the Information Technology Center of the University of Toyama with a high-security firewall and online storage software( Proself) for receipt and transfer of data. Accounts and passwords allowing connection to the file server were allocated to cardiovascular physicians at 18 core hospitals without cardiovascular surgery departments, and they were grouped in Proself for security. All communications are encrypted and file transfer is automatically notified to an internet protocol (IP) address via e-mail when data are uploaded or downloaded. Thus, the hospital sending the data and the type of data can be identified immediately, making it possible to refer to the corresponding image files. Sharing of data via NAS allows cardiovascular physicians and surgeons to communicate safely and effectively, leading to successful building of a heart team. PMID- 25434537 TI - [Heparin-induced thrombocytopenia developed during the acute phase after left upper lobectomy for lung cancer]. AB - Heparin-induced thrombocytopenia (HIT) is a serious adverse effect of heparin administration. This must not be rarely encountered but is not often reported in Japan compared to Western countries. A 68-year-old woman underwent left upper lobectomy for lung cancer. Low-dose unfractionated heparin was administrated to prevent thromboembolism after the operation. Two days later, sudden dyspnea appeared and ultracardiosonography showing an extensive thromboembolus from the main trunk to both main branches of pulmonary artery indicated pulmonary embolization. After the establishment of percutaneous cardiopulmonary support (PCPS) support, the embolus was removed by emergent open heart surgery. However, despite further unfractionated heparin administration following embolization surgery, other thrombus was identified in both the bi-lateral internal jagular veins and inferior vena cava by ultrasonography and contrast computed tomography( CT). Her platelet count was decreased gradually despite platelet transfusion. Plate factor 4( PF4) antibody against heparin in her blood examination was found, and HIT II was diagnosed. Discontinuation of unfractionated heparin and administration of antithrombin agent improved platelet count, and no additional embolization was identified. PMID- 25434538 TI - [Repair of a huge Bochdalek hernia by direct suture and mesh reconstruction]. AB - A 72-year-old man presented with complaints of sudden abdominal pain and vomiting. After a thorough examination, the patient was diagnosed with a left sided Bochdalek hernia with strangulation of the stomach and spleen. The impaction was cleared by drainage of the stomach contents by a nasogastric tube;then, surgical repair through thoracic approach was performed. The herinia port size was large, and the defect of diaphragm was successfully repaired by both direct closure and mesh reconstruction. PMID- 25434539 TI - [Tricuspid valve plasty using autologous pericardium in a patient with infective endocarditis]. AB - A 67-year-old woman was diagnosed with infective endocarditis. She had no history of any cardiac event or dental treatment. Echocardiography showed a large vegetation attached to the anterior leaflet of the tricuspid valve with severe tricuspid regurgitation. Surgery consisted of removal of the vegetation and tricuspid valve plasty with a glutaraldehyde-treated autologous pericardial patch and artificial chordae of the anterior leaflet. Her postoperative course was uneventful. Five years after surgery, neither recurrence of infection nor worsening of tricuspid regurgitation was noted. PMID- 25434540 TI - [Successful endovascular treatment under cardiopulmonary resuscitation for spontaneous rupture of the thoracic aorta]. AB - The patient was a 67-year-old man. He was admitted to a local hospital with severe back pain, and left hydrothorax was noted by a chest X-ray. Then, he went into shock and was transferred to our hospital. Enhanced computed tomography (CT) showed massive liquid retention of the left thorax, but no aortic dissection or aneurysms. He was diagnosed with spontaneous aortic rupture, and endovascular treatment was chosen because of his unstable hemodynamics. He fell into cardiac arrest 10 minutes after the operation started, and we implanted 2 stent-grafts while giving cardiac massage. After 23 minutes cardiac massage, he was resuscitated. He was discharged without any complication. Even if no signs of aortic aneurysms or aortic dissection were detected, the possibility of spontaneous aortic rupture should be suspected. Endovascular treatment is a reliable option in the case of unstable hemodynamics. PMID- 25434541 TI - [Surgery for spontaneous pneumothorax in a 102-year-old woman]. AB - We report a 102-year-old female who underwent surgery for spontaneous pneumothorax. As leakage did not disappear for over one month, she was referred to our hospital for surgery. Video-assisted thoracoscopic surgery was performed. Multiple small bullae were observed, and one of which was the cause of leakage. She was successfully treated by pleural covering with polyglycolic acid sheet and fibrin glue. Patients of such advanced age can be good candidates for surgical treatment of spontaneous pneumothorax, when they have no severe underlying diseases. PMID- 25434542 TI - [Expression of bone morphogenetic protein 2 in lung adenocarcinoma with ossification]. AB - We report a case of primary lung cancer with ossification. A 69-year-old woman was referred to our hospital due to an abnormal shadow on a chest roentgenogram. Chest computed tomography demonstrated an irregular mass with scattered high density areas in the left lower lung. Excisional biopsy of the mass revealed lung adenocarcinoma, and we performed left lower lobectomy. Histologic examination revealed the tumor to be a papillary adenocarcinoma with ossification. We confirmed that bone morphogenetic protein(BMP)-2 developed from the tumor by a western blot analysis. PMID- 25434543 TI - [Cardiac tamponade due to ruptured coronary artery aneurysm associated with coronary-pulmonary artery fistula; report of a case]. AB - We report a successful operative treatment of ruptured coronary artery aneurysm associated with coronary-pulmonary artery fistula. A 67-year-old woman was diagnosed with coronary artery fistula previously but observed without any treatment. She had medical examination at a previous hospital because of sudden onset of dyspnea, and transported to our institution with a diagnosis of cardiac tamponade. Multi-detector computed tomography (MDCT) showed massive pericardial effusion, coronary-pulmonary artery fistula and giant coronary artery aneurysm. We performed emergency operation. Under cardiopulmonary bypass, coronary artery fistula and aneurysm was resected. Postoperative MDCT showed almost complete exclusion of coronary artery fistula. Postoperative course was uneventful. PMID- 25434544 TI - [Chronic type A aortic dissection associated with Turner syndrome; report of a case]. AB - Aortic dissection is a critical but rare complication of Turner syndrome. This report describes a case of chronic aortic dissection in a patient with Turner syndrome. A 54-year-old woman, suffering from mild back pain for 1 month, was referred to our hospital with a diagnosis of Stanford type A chronic aortic dissection and a bicuspid aortic valve with moderate regurgitation. Computed tomography revealed aortic dissection, involving all arch branches, extending from the ascending to the abdominal aorta. The true lumen of the brachial artery was nearly obstructed by the thrombosed false lumen. Elective aortic arch repair and aortic valve replacement were successfully performed. The patient was diagnosed with 45, XO Turner syndrome after surgery. Taking aortopathy of Turner syndrome into consideration, surveillance of the residual aorta was performed. No rapidly progressive dilatation of the residual aorta was detected during the 6 years' follow-up. PMID- 25434545 TI - [Severe aortic valve stenosis combined with a large brain tumor; report of a case]. AB - We report a case of severe aortic valve stenosis with a large benign brain tumor (meningioma), which was successfully treated with simple replacement with a mechanical valve under extracorporeal circulation (ECC). A large meningioma is considered as a risk in an operation under ECC because it may increase intracranial pressure and cause bleeding. In this case we chose a simple method of aortic valve replacement for the purpose of shortening the ECC time. Under warfarin control, the patient is in a stable condition with good cardiac function and without any neurological symptom at 8 years after the operation. PMID- 25434546 TI - [Left atrium thrombus after mitral valve replacement presented with syncope; report of a case]. AB - Left atrial free ball thrombus (LABT) after mitral valve replacement (MVR) is very rare, and sudden death may occur by thrombus impaction to the mitral valve orifice. A 81-year-old woman who underwent MVR and tricuspid annuloplasty ten years ago presented with syncope. She was admitted to a hospital, and echocardiography revealed a LABT. When she took sitting position, she fainted. The free ball thrombus possibly impacted mitral valve orifice. She was transferred to our hospital and an emergent operation was performed. There was a LABT of 4 cm in diameter, which was removed. Postoperative course was uneventful. There are 12case reports which described LABT after MVR, and anticoagulant therapy was insufficient in most of those cases. Strict anticoagulant therapy is important to prevent left atrial thrombus after MVR. PMID- 25434547 TI - [Calcified amorphous tumor of the right atrium after open heart surgery; report of a case]. AB - A 37-year-old woman, who had undergone surgery of atrial septal defect (ASD) at 12-year-old, developed bradycardia and referred to our hospital. Transthoracic echocardiography revealed high echoic tumor in the right atrium. The image of the tumor was of low intensity by T2 weighted magnetic resonance imaging (MRI) and floating mass with a stalk to the right atrium in cine MRI. She underwent tumor resection under cardiopulmonary bypass. Histopathologilal examination of the tumor was calcified amorphous tumor. The postoperative course was uneventful. PMID- 25434548 TI - [Penetrating injury of the right ventricle by nail gun; report of a case]. AB - A 43-year-old man accidentally shot himself with a nail gun. He was seen in the other hospital. Chest computed tomography showed nail penetrating the thorax, and a small amount of pericardial effusion. He was transferred to our hospital and underwent an operation on emergency. After sternotomy and pericardiotomy, the nail was found to reach the right ventricle, and was almost pulled out. The nail was removed and the right ventricle was repaired with felt 4-0 mattress sutures. His postoperative course was uneventful and discharged 7 days after the accident. Because penetrating cardiac injuries often cause cardiac tamponade, prompt diagnosis and emergency surgical repair are required. We report a case of nail penetration injury of the right ventricle with a review of the pertinent literature. PMID- 25434549 TI - [Left atrial giant myxoma incidentally discovered during endoscopic ultrasonography; report of a case]. AB - A 49-year-old female patient with a symptom of dysphagia underwent endoscopic ultrasonography (EUS) of the upper gastrointestinal tract, which incidentally revealed a tumor compressing the esophagus from outside. Transthoracic echocardiography performed after EUS showed a giant tumor in the left atrium. The tumor, measuring 75*68*43 mm, weighing 105 g was successfully removed, and pathologically diagnosed as myxoma. Her symptom disappeared completely. When performing clinical studies, it is important to pay every attention not to miss any abnormal findings beyond the scope of targeted areas. We also mentioned an ambiguity of the term," giant" regarding the size and weight of myxoma. PMID- 25434550 TI - [Excision of a left atrial myxoma through right minithoracotomy in a patient with multiple myeloma; report of a case]. AB - We present a case of a 63-year-old female who underwent an excision of a left atrial myxoma. Previously, she had been diagnosed with multiple myelomas and received radiation therapy and chemotherapy. A left atrial myxoma was found at an annual medical check-up. The myxoma was removed via a right minithoracotomy with peripheral cannulation to minimize bleeding complications and surgical site infection. She was transferred to the referring hospital on postoperative day 7 due to recurrence of multiple myelomas. She was doing well 14 months after the operation. Right minithoracotomy is a useful approach to minimizing the risks of bleeding and infection in patients with multiple myelomas. PMID- 25434551 TI - [Resection of double bronchogenic cysts within the anterior mediastinum; report of a case]. AB - We reported a case of surgically resected double bronchogenic cysts within the anterior mediastinum. An anterior mediastinal tumor had been found at medical examination 6 years ago in a 66-year-old man, but has been followed up without treatment. After the treatment of another disease, he was referred to our hospital for evaluation of the mediastinal tumor. A chest computed tomography showed 2 anterior mediastinal nodules. Nodules in the thymus were resected with video-assisted thoracic surgery. The tumors were both pathologically diagnosed as bronchogenic cysts. PMID- 25434552 TI - [Synovial cyst of chest wall; report of a case]. AB - A 55-year-old male taxi driver visited our hospital because of a left dorsal tumor. The tumor was palpated at the inferior angle of the left scapula with tenderness. Computed tomography (CT) revealed a homogeneous 5-cm mass with capsule between the latissimus dorsi muscle and rib. T2-weighted magnetic resonance imaging( MRI) demonstrated the tumor with high intensity. The latissimus dorsi muscle was divided and separated off from the tumor and the lower layer;then, an applied wound retractor (Alexis) was placed under the lower layer of the latissimus dorsi muscle and the operative field was developed. Next, the anterior serratus and greater rhomboid muscles were separated off from the tumor and the lower layer, the Alexis was placed under the lower layer of those muscles. All muscles were preserved and the tumor was removed. The tumor was 56*32 mm in size. The histological diagnosis was synovial cyst. PMID- 25434553 TI - [Thymoma with extensive coagulative necrosis and high serum level of CYFRA 21-1; report of a case]. AB - A 73-year-old woman complained of right chest discomfort. Chest X-ray during the follow-up for rheumatoid arthritis showed a mediastinal tumor. Chest computed tomography (CT) and magnetic resonance imaging (MRI) showed a 65-mm tumor in the right anterior mediastinum. A blood test showed high serum levels of CYFRA 21 1(29.8 ng/ml), white blood cells( WBC 10,800/ul), and C-reactive protein(CRP 16.1 mg/dl). Subsequently, inflammatory reactions improved, and the thymic tumor was resected. Histopathologically, the tumor was a type B2 thymoma with extensive coagulative necrosis. After resection, the serum CYFRA 21-1 level returned to the normal range. PMID- 25434554 TI - Anti-angiogenic effects of Siegesbeckia glabrescens are mediated by suppression of the Akt and p70S6K-dependent signaling pathways. AB - Siegesbeckia glabrescens (SG) Makino (Compositae) has been used as a traditional medicine for the treatment of allergic and inflammatory diseases. In the present study, we report the effects and molecular mechanism of an ethanolic extract of SG on cell proliferation, migration and tube formation in vascular endothelial growth factor-A (VEGF-A)-treated human umbilical vein endothelial cells. SG treatment inhibited VEGF-A-stimulated endothelial cell proliferation through downregulation of cyclin D and upregulation of cyclin-dependent kinase inhibitors such as p27Kip1 and p21WAF1/Cip1. In addition, SG inhibited VEGF-A-stimulated endothelial cell migration and tube formation. These anti-angiogenic activities of SG were mediated by inactivation of the Akt- and p70S6K-dependent signaling pathways. Collectively, our findings demonstrate the pharmacological roles and molecular mechanism of SG in regulating angiogenic responses and support further evaluation and development of SG as a potential therapeutic agent for the treatment and prevention of angiogenesis-related diseases including cancer. PMID- 25434555 TI - Guest editors' introduction to the Proceedings of the 9th International Symposium on Biomedical Research and Applications. PMID- 25434556 TI - Key local and surgical factors related to implant failure. AB - The concept of osseointegration has revolutionized the treatment options for the replacement of missing teeth in both partially and completely edentulous patients. Dental implants are widely used because clinical practice and studies have documented its successful outcomes. However, implants can occasionally fail, and such failures can be classified as early or late. Measures that can aid in the early recognition of failing osseointegrated implants are needed, as are measures that can facilitate appropriate treatment methods aimed at saving failing implants by determining the probable etiologic factors. This article summarizes our current understanding of the local factors that can be linked to implant failure. PMID- 25434557 TI - Key systemic and environmental risk factors for implant failure. AB - Dental implants are an important treatment option for patients interested in replacing lost or missing teeth. Although a robust body of literature has reviewed risk factors for tooth loss, the evidence for risk factors associated with dental implants is less well defined. This article focuses on key systemic risk factors relating to dental implant failure, as well as on perimucositis and peri-implantitis. PMID- 25434558 TI - Use of cone-beam computed tomography in early detection of implant failure. AB - Preimplant planning with complex imaging techniques has long been a recommended practice for assessing the quality and quantity of alveolar bone before dental implant placement. When maxillofacial imaging is necessary, static film or digital images lack the depth and dimension offered by computed tomography. Cone beam computed tomography (CBCT) offers the dentist not only a radiographic volumetric view of alveolar bone but also a 3-dimensional reconstruction. This article reviews the use of CBCT for assessing implant placement and early detection of failure, and compares the performance of CBCT with that of other imaging modalities in the early detection of implant failure. PMID- 25434559 TI - Surgical complications after implant placement. AB - Placement of dental implants in the maxillofacial region is routine and considered safe. However, as with any surgical procedure, complications occur. Many issues that arise at surgery can be traced to the preoperative evaluation of the patient and assessment of the underlying anatomy. In this article, the authors review some common and uncommon complications that can occur during and shortly after implant placement. The emphasis of each section is on the management and prevention of complications that may occur during implant placement. PMID- 25434560 TI - Immediate implant placement: surgical techniques for prevention and management of complications. AB - Loss of soft and hard tissue is common after tooth extraction. Substantial resorption of alveolar bone compromises esthetics and may result in prosthetic and surgical limitations. Immediate implant placement at the time of tooth extraction is used to maintain alveolar ridge dimensions. Clinical studies support the successful outcome of immediate placement of dental implants in fresh extraction sockets; comparative clinical studies have found that implant survival rates after immediate placement are similar to those after delayed placement. This article addresses surgical techniques for immediate implant placement and the prevention and the management of complications associated with this procedure. PMID- 25434561 TI - Complications when augmenting the posterior maxilla. AB - The maxillary posterior edentulous region presents a challenge when planning for restoring missing teeth with a dental implant. The available bone in such cases is often not dense and not adequate for the placement of a properly sized implant because of maxillary sinus pneumatization and alveolar bone loss. Maxillary sinus lift is a predictable procedure to provide adequate bone height for the purpose of implant placement. However, complications are encountered during or after the execution of the sinus lift procedure. In this article, the prevention and management of maxillary sinus complications are discussed. PMID- 25434562 TI - Persistent pain and neurosensory disturbance after dental implant surgery: pathophysiology, etiology, and diagnosis. AB - Many studies have documented the successful outcomes of dental implants, but have also reported the association of sensory disturbances with the surgical implant procedure. Postsurgical pain is a normal response to tissue injury, and usually resolves after the tissue heals. However, some patients who receive dental implants experience persistent pain even after normal healing. This article describes the basic anatomy and pathophysiology associated with nerve injury. The incidence and diagnosis of these problems, in addition to factors that result in the development of chronic persistent neuropathic pain and sensory disturbances associated with surgical implant placement, are discussed. PMID- 25434563 TI - Persistent pain and neurosensory disturbance after dental implant surgery: prevention and treatment. AB - Nerve trauma caused by dental implant placement is associated with altered sensation and chronic pain. Complete or partial loss of sensation is often reported by patients who have experienced nerve trauma during implant surgery. Some patients report persistent pain and neurosurgery disturbance long after the normal healing time has passed. In addition, neuropathic pain is reported after implant surgery. Practitioners who place dental implants must be familiar with the differential diagnosis, prevention, and management of neuropathic pain. This article provides insights into the prevention and management of neurosensory deficits and chronic persistent neuropathic pain and considerations for patient referral. PMID- 25434564 TI - Peri-implant diseases: a review of treatment interventions. AB - The ideal management of peri-implant diseases focuses on infection control, detoxification of implant surfaces, regeneration of lost tissues, and plaque control regimens via mechanical debridement (with or without raising a surgical flap). However, a variety of other therapeutic modalities also have been proposed for the management of peri-implantitis. These treatment strategies encompass use of antiseptics and/or antibiotics, laser therapy, guided bone regeneration, and photodynamic therapy. The aim of this article was to review indexed literature with reference to the various therapeutic interventions proposed for the management of peri-implant diseases. PMID- 25434565 TI - Biologic markers of failing implants. AB - Implants are exposed to a diverse oral environment and host responses that contribute to health or disease. For the last few decades, clinicians have relied on standard clinical and radiographic findings to assess the health of implants. However, recent studies involving the pathogenesis of peri-implantitis have identified microbial species and several putative biomarkers that could aid clinicians in this diagnostic process in the near future. This article provides an overview of the microbial species involved in implant health and disease and biomarkers found in oral fluids that relate to the underlying biological phases of a failing implant. PMID- 25434566 TI - Prosthetic failure in implant dentistry. AB - Although osseointegrated dental implants have become a predictable and effective modality for the treatment of single or multiple missing teeth, their use is associated with clinical complications. Such complications can be biologic, technical, mechanical, or esthetic and may compromise implant outcomes to various degrees. This article presents prosthetic complications accompanied with implant supported single and partial fixed dental prostheses. PMID- 25434567 TI - Complications associated with implant-retained removable prostheses. AB - Implant-supported removable prostheses improve patients' satisfaction with treatment and quality of life. Improvements in the implant's surface and in attachment elements have made this treatment method very successful. However, some biological and mechanical complications remain. Mechanical complications associated with implant-supported overdentures and implant-supported removable partial dentures are loss of retention of attachment systems, the need to replace retention elements and to reline or repair the resin portion of the denture, and implant fracture. Despite their success, implant-supported removable prostheses require periodic maintenance. PMID- 25434568 TI - Esthetic failure in implant dentistry. AB - The definition of failure for dental implants has evolved from lack of osseointegration to increased concern for other aspects, such as esthetics. However, esthetic failure in implant dentistry has not been well defined. Although multiple esthetic indices have been validated for objectively evaluating clinical outcomes, including failure of an implant-supported crown, only one author has determined a failure threshold. On the basis of objective indices, esthetic failures in implant dentistry can be categorized as pink-tissue failures and white-tissue failures. This article discusses esthetic failures, the factors involved in these failures, and their prevention and treatment. PMID- 25434569 TI - Complications in implant dentistry. PMID- 25434570 TI - Silver-loaded nitrogen-doped yolk-shell mesoporous TiO2 hollow microspheres with enhanced visible light photocatalytic activity. AB - Silver-loaded nitrogen-doped yolk-shell mesoporous TiO2 hollow microspheres (Ag-N TiO2-YSM) were prepared by employing acetic acid as the hollowing controller and triethanolamine as the N source for the first time. Ag nanoparticles (NPs) were uniformly deposited by a simple in situ photo-reduction method, which can prevent the aggregation of Ag NPs. The efficiency of the as-prepared samples was investigated by monitoring the degradation of rhodamine B and ciprofloxacin under visible light irradiation. The experimental results indicate that N-doped yolk shell mesoporous TiO2 hollow microspheres show higher photocatalytic activity than P25 TiO2 under visible light irradiation because of N doping and the unique yolk-shell structure. In addition, Ag-N-TiO2-YSM shows enhanced activity compared with N-TiO2-YSM due to the SPR absorption of silver NPs and the fast generation, separation and transportation of the photogenerated carriers. Moreover, the Ag contents can affect the photocatalytic activity of the Ag-N-TiO2-YSM composite. A suitable amount of Ag deposition gives the highest photocatalytic activity. A higher loading does not improve the photocatalytic activity of N-TiO2-YSM further. The active species generated in the photocatalytic system were also investigated. Based on our experimental results, a possible photocatalytic mechanism was proposed. The strategy presented here gives a promising route towards the development of delicate metal@hollow semiconductor composites for many applications in photocatalysis. PMID- 25434571 TI - Prevalence of Toxoplasma gondii in localized populations of Apodemus sylvaticus is linked to population genotype not to population location. AB - Toxoplasma gondii is a globally distributed parasite infecting humans and warm blooded animals. Although many surveys have been conducted for T. gondii infection in mammals, little is known about the detailed distribution in localized natural populations. In this study, host genotype and spatial location were investigated in relation to T. gondii infection. Wood mice (Apodemus sylvaticus) were collected from 4 sampling sites within a localized peri-aquatic woodland ecosystem. Mice were genotyped using standard A. sylvaticus microsatellite markers and T. gondii was detected using 4 specific PCR-based markers: SAG1, SAG2, SAG3 and GRA6 directly from infected tissue. Of 126 wood mice collected, 44 samples were positive giving an infection rate of 34.92% (95% CI: 27.14-43.59%). Juvenile, young adults and adults were infected at a similar prevalence, respectively, 7/17 (41.18%), 27/65 (41.54%) and 10/44 (22.72%) with no significant age-prevalence effect (P = 0.23). Results of genetic analysis of the mice showed that the collection consists of 4 genetically distinct populations. There was a significant difference in T. gondii prevalence in the different genotypically derived mouse populations (P = 0.035) but not between geographically defined populations (P = 0.29). These data point to either a host genetic/family influence on parasite infection or to parasite vertical transmission. PMID- 25434572 TI - Neuromuscular electrical stimulation of the median nerve facilitates low motor cortex excitability in patients with spinocerebellar ataxia. AB - The neuromodulation of motor excitability has been shown to improve functional movement in people with central nervous system damage. This study aimed to investigate the mechanism of peripheral neuromuscular electrical stimulation (NMES) in motor excitability and its effects in people with spinocerebellar ataxia (SCA). This single-blind case-control study was conducted on young control (n=9), age-matched control (n=9), and SCA participants (n=9; 7 SCAIII and 2 sporadic). All participants received an accumulated 30 min of NMES (25 Hz, 800 ms on/800 ms off) of the median nerve. The central motor excitability, measured by motor evoked potential (MEP) and silent period, and the peripheral motor excitability, measured by the H-reflex and M-wave, were recorded in flexor carpi radialis (FCR) muscle before, during, and after the NMES was applied. The results showed that NMES significantly enhanced the MEP in all 3 groups. The silent period, H-reflex and maximum M-wave were not changed by NMES. We conclude that NMES enhances low motor excitability in patients with SCA and that the mechanism of the neuromodulation was supra-segmental. These findings are potentially relevant to the utilization of NMES for preparation of motor excitability. The protocol was registered at Clinicaltrials.gov (NCT02103075). PMID- 25434573 TI - Empirical modelling of the dynamic response of fatigue during intermittent submaximal contractions of human forearm and calf muscles. AB - Maximum force (Fmax) declines during intermittent submaximal contractions, but the linearity of this fatigue response and number of underlying phases is not clear. Healthy men were studied during two experiments (n=10 each). Experiment 1 involved single bouts of intermittent forearm contractions (50% Fmax) to failure using both limbs assigned as Armcontrol or Armtraining. Experiment 2 involved five bouts of intermittent calf contractions (60% Fmax) to failure using the same limb where data from the longest single trial (Calfsingle) or averaged across five bouts (Calfaveraged) were analysed. Fmax was assessed at 25-30s intervals during exercise and fitted to ten mono- and biphasic functions consisting of linear and/or nonlinear terms. For each fatigue response, the function which provided the best fit was determined on statistical grounds. Biphasic functions provided the majority of best fits during Armcontrol (9/10), Armtraining (10/10), Calfsingle (7/10) and Calfaveraged (9/10). For each condition, linear functions provided the best fit in 4-5 out of 10 responses. Two biphasic functions differentiated only by their first term (linear versus exponential) provided the best fit for 29/40 fatigue responses. These outcomes suggest that fatigue during intermittent contractions exhibits a biphasic response characterised by nonlinear and linear behaviour. PMID- 25434574 TI - Increases in plasma 25(OH)D levels are related to improvements in body composition and blood pressure in middle-aged subjects after a weight loss intervention: Longitudinal study. AB - BACKGROUND & AIMS: The aim of this study is to further clarify the role of plasma 25(OH)D concentration after a weight-lowering nutritional intervention on body composition, blood pressure and inflammatory biomarkers in overweight/obese middle-aged subjects. METHODS: This longitudinal research encompassed a total of 50 subjects [57.26 (5.24) year], who were under a 15% energy restricted diet for 4 weeks. Anthropometric and body composition variables, blood routine, inflammatory markers as well as 25(OH)D were analysed. RESULTS: Circulating 25(OH)D levels [12.13(+/-17.61%)] increased while anthropometric, body composition, routine blood markers as well as the concentration of TNF-alpha, C reactive protein and Lp-PLA2 were significantly reduced after the intervention. Multiple linear regression analyses evidenced that Delta25(OH)D increase was linked to the decrease in weight, adiposity, SBP and IL-6 levels. Moreover, a relationship was found between Delta25(OH)D, Deltafat mass (r = -0.405; p = 0.007), DeltaSBP (r = -0.355; p = 0.021) and DeltaIL-6 (r = -0.386; p = 0.014). On the other hand, a higher increase in 25(OH)D was accompanied by reductions in weight, BMI, SBP, IL-6 and an increase in bone mineral concentration (p < 0.05). Interestingly, higher levels of 25(OH)D at the endpoint, showed a significantly higher decrease in weight, BMI and total fat mass. CONCLUSIONS: The increase in plasma 25(OH)D level is linked with the decrease in SBP and adiposity in middle aged subjects after a weight-loss intervention. Therefore, 25(OH)D assessment is a potential marker to be accounted in metabolic measures related to blood pressure, adiposity and inflammation in obesity management. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01596309). PMID- 25434575 TI - Long-term outcome of patients with systemic sclerosis requiring home parenteral nutrition. AB - BACKGROUND & AIMS: Patients with systemic sclerosis may develop intestinal failure requiring home parenteral nutrition. However, few outcome data have been reported. This study aimed to review the outcome of patients with systemic sclerosis receiving home parenteral nutrition. METHODS: Records of all patients with systemic sclerosis who commenced home parenteral nutrition, at a national intestinal failure unit were retrospectively reviewed. Disease characteristics, survival and outcome data were evaluated. RESULTS: Twenty five patients (20% male; median age: 55 years) were included over a 22-year period (37,200 central venous catheter days). All patients had small intestinal involvement. Prior to home parenteral nutrition, 16 failed enteral feeding. Nine patients were trained to self-administer their home parenteral nutrition; carers/relatives were trained for the remainder. Cumulative survivals on home parenteral nutrition at 2, 5 and 10 years were 75%, 37%, and 23%. Sixteen patients died from causes unrelated to home parenteral nutrition. Two patients were weaned off home parenteral nutrition. Seven patients survive on home parenteral nutrition (median: 41 months; range 9-178). Central venous catheter-related complications were low; these included occlusion (0.70 episodes per 1000 central venous catheter days), sepsis (0.19 episodes per 1000 central venous catheter days) and central venous thrombosis (0.11 episodes per 1000 central venous catheter days). CONCLUSIONS: This is the longest, largest reported series of patients with systemic sclerosis receiving home parenteral nutrition. It shows that home parenteral nutrition can be used safely and effectively in patients with very severe systemic sclerosis related gastrointestinal involvement. PMID- 25434576 TI - Malnutrition is a prognostic factor in patients with hepatocellular carcinoma (HCC). AB - BACKGROUND & AIMS: Malnutrition is a common, hence frequently underdiagnosed condition in patients with liver cirrhosis as well as in patients with cancer and has been shown to have a negative impact on survival in these patients. Frequently applied screening tools including anthropometric measurements or laboratory parameters to screen for malnutrition are not suitable for patients with liver cirrhosis with additional pathophysiological mechanisms leading to hypoalbuminemia and edema. Prospective data on the prevalence and prognostic impact of malnutrition in patients with HCC are scarce. METHODS: Fifty-one consecutive patients with hepatocellular carcinoma were prospectively enrolled into this study and screened for malnutrition by anthropometric measurements, the MNA score, the NRS score, laboratory work-up, and BIA measurement. The results of the different screening tools were compared to each other and with the BIA assessment and correlated with the outcome of patients. RESULTS: The calculation of a body mass index (BMI) was not suitable to identify malnourished patients with HCC. The MNA identified 19, the NRS score 17 patients at a risk for malnutrition. BIA revealed a reduction in relative body cell mass in 12 patients. Univariate Cox regression analyses identified tumor stage, MNA score, and phase angle obtained by BIA as significant factors with influence on survival. Multivariate analyses confirmed the phase angle at a cut-off of 4.8 to be an independent factor. CONCLUSIONS: A significant proportion of patients with HCC is malnourished or at risk for malnutrition. Screening questionnaires and BIA measurement are superior to pure anthropometric measurements to identify the condition that negatively influences survival. The phase angle derived from body impedance analysis is an independent prognostic factor in patients with HCC. PMID- 25434577 TI - A soybean and fish oil mixture with different n-6/n-3 PUFA ratios modulates the inflammatory reaction in mice with dextran sulfate sodium-induced acute colitis. AB - BACKGROUND & AIMS: Inflammatory bowel disease is a recurrent disease of the gastrointestinal tract. n-3 polyunsaturated fatty acids (PUFAs) are proved to have anti-inflammatory and immunomodulatory properties. This study evaluated the effects of different dietary n-6/n-3 PUFA ratios on the mechanism of alleviating the inflammatory response in mice with dextran sulfate sodium (DSS)-induced colitis. METHODS: Mice were randomly assigned to 6 groups including 3 non-colitis groups (C, LF, and HF) and 3 colitis groups (DC, DLF, and DHF). Mice in the C and DC groups were fed a common semipurified diet with soybean oil as the fat source. The other groups received an identical component except that part of the soybean oil was replaced by different amounts of fish oil. The n-6/n-3 PUFA ratio of the LF and DLF groups was 4:1, the ratio of the HF and DHF groups was 2:1. After feeding the respective diets for 2 weeks, the colitis groups were given distilled water containing 2% DSS, while the non-colitis groups were given distilled water for 5 days. After that, all mice were sacrificed at the recovery phase after drinking distilled water for another 5 days. RESULTS: Colitis resulted in higher expressions of colonic inflammatory mediators in colon tissues and colon lavage fluid. Also, colonic peroxisome proliferator-activated receptor (PPAR)-gamma and the IkappaBalpha/nuclear factor (NF)-kappaB p65 ratio were lower than those of the non-colitis groups. Compared to the DC group, fish oil-enriched colitis groups had lower inflammatory mediator expressions and higher PPAR-gamma protein levels and IkappaBalpha/NF-kappaB p65 ratios in colon tissues. The DHF group had even lower colonic inflammatory gene and higher PPAR-gamma protein expressions than did the DLF group. CONCLUSIONS: These findings suggest that diets enriched with fish oil upregulated PPAR-gamma and decreased NF-kappaB activation that may consequently have reduced luminal inflammatory mediator production. Compared to a n-6/n-3 PUFA ratio 4:1, a ratio of 2:1 was more effective in reducing inflammatory reactions in DSS-induced colitis. PMID- 25434578 TI - Symptomatic dermatographism treated with narrowband UVB phototherapy. AB - Dermatographism occurs when there is an exaggerated response to physical stimulus. There are both simple and symptomatic forms. Symptomatic dermatographsim can be exceedingly difficult to treat. Treatment modalities include H1 and H2 antagonists, leukotriene antagonists, cyclosporine and oral steroids. In a few small case series and studies, phototherapy has been used. We report a further two patients who were treated successfully with TL01 UVB narrowband (NB) phototherapy. PMID- 25434579 TI - Introduction from the editor. PMID- 25434580 TI - Recurrent copy number alterations in prostate cancer: an in silico meta-analysis of publicly available genomic data. AB - We present a meta-analysis of somatic copy number alterations (CNAs) from 11 publications that examined 662 prostate cancer patient samples, which were derived from 546 primary and 116 advanced tumors. Normalization, segmentation, and identification of corresponding CNAs for meta-analysis was achieved using established commercial software. Unsupervised analysis identified five genomic subgroups in which approximately 90% of the samples were characterized by abnormal profiles with gains of 8q. The most common loss was 8p (NKX3.1). The CNA distribution in other genomic subgroups was characterized by losses at 2q, 3p, 5q, 6q, 13q, 16q, 17p, 18q, and PTEN (10q), and acquisition of 21q deletions associated with the TMPRSS2-ERG fusion rearrangement. Parallel analysis of advanced and primary tumors in the cohort indicated that genomic deletions of PTEN and the gene fusion were enriched in advanced disease. A supervised analysis of the PTEN deletion and the fusion gene showed that PTEN deletion was sufficient to impose higher levels of CNA. Moreover, the overall percentage of the genome altered was significantly higher when PTEN was deleted, suggesting that this important genomic subgroup was likely characterized by intrinsic chromosomal instability. Predicted alterations in expression levels of candidate genes in each of the recurrent CNA regions characteristic of each subgroup showed that signaling networks associated with cancer progression and genome stability were likely to be perturbed at the highest level in the PTEN deleted genomic subgroup. PMID- 25434582 TI - Soft epitaxy of nanocrystal superlattices. AB - Epitaxial heterostructures with precise registry between crystal layers play a key role in electronics and optoelectronics. In a close analogy, performance of nanocrystal (NC) based devices depends on the perfection of interfaces formed between NC layers. Here we systematically study the epitaxial growth of NC layers for the first time to enable the fabrication of coherent NC layers. NC epitaxy reveals an exceptional strain tolerance. It follows a universal island size scaling behaviour and shows a strain-driven transition from layer-by-layer to Stranski-Krastanov growth with non-trivial island height statistics. Kinetic bottlenecks play an important role in NC epitaxy, especially in the transition from sub-monolayer to multilayer coverage and the epitaxy of NCs with anisotropic shape. These findings provide a foundation for the rational design of epitaxial structures in a fundamentally and practically important size regime between atomic and microscopic systems. PMID- 25434581 TI - Sedative load and frailty among community-dwelling population aged >=65 years. AB - OBJECTIVE: To explore the association between use of sedative drugs and frailty. DESIGN: Cross-sectional study. SETTING: First wave of The Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort of the community dwelling population aged 50 years or older in Ireland. PARTICIPANTS: Participants were 1642 men and 1804 women aged 65 years or older. MEASUREMENTS: Regular use of sedative drugs determined according to the sedative load (SL) model, frailty phenotype status, and frailty deficit index (FI) score assessed using validated, established protocols. RESULTS: Overall, 19% of the participants took sedative drugs, most frequently hypnotics and antidepressants. Sedative drug use was at 46% for frail, 23% for prefrail, and 9% for nonfrail participants. After adjustment for covariates, SL was positively associated with being prefrail (odds ratio [OR] 1.27; 95% confidence interval [CI] 1.11-1.46) and frail (OR 1.30; 95% CI 1.02-1.64). Advancing age but not sex remained significant (P < .001). After adjustment for covariates, the association between SL and the FI was also significant at P <= .001 (beta = 1.77; 95% CI 1.13-2.42). CONCLUSION: Higher SL was positively associated with phenotype frailty and the FI. This suggests that careful consideration must be given when prescribing sedatives to frail older adults, who are most vulnerable to adverse drug reactions and adverse health outcomes. PMID- 25434583 TI - Fluorosis induces endoplasmic reticulum stress and apoptosis in osteoblasts in vivo. AB - The present study investigated the effects of fluoride on endoplasmic reticulum (ER) stress (ERS) and osteoblast apoptosis in vivo. Forty-eight Wistar rats were randomly divided into four groups (12/group) and exposed to 0, 50, 100, and 150 mg/L of fluoride in drinking water for 8 weeks, respectively. Peripheral blood samples and bilateral femurs were used to monitor the progression of fluorosis in the animals. Hematoxylin and eosin (H&E) staining of the bone tissues was used to determine the severity of osteofluorosis. The expression of ERS chaperones (glucose-regulated protein 78 (GRP78), X-box binding protein l (XBP1), cysteine aspartate specific protease-12 (caspase-12), and growth arrest and DNA damage inducible gene 153 (Gadd153/CHOP) was analyzed by immunohistochemistry staining, and osteoblast apoptosis was determined by TUNEL staining and flow cytometry. Accumulation of fluoride in bone was associated with the severity of osteofluorosis. The expression of GRP78, XBP1, caspase-12, and CHOP was increased in a dose-dependent manner. Fluoride-induced apoptosis in osteoblasts was also dose-dependent. High concentrations of fluoride induced ERS and osteoblast apoptosis in vivo. The increased expression of GRP78 and XBP1 increased the adaptation of osteoblasts to ERS to a certain extent. Caspase-12 and CHOP activation was associated with ERS and osteoblast apoptosis. PMID- 25434584 TI - Anticancer agent icaritin induces apoptosis through caspase-dependent pathways in human hepatocellular carcinoma cells. AB - Icaritin is an active ingredient derived from the plant Herba epimedium, which exhibits various pharmacological and biological activities. However, the function, and the underlying mechanisms of icaritin on the growth of SMMC-7721 human hepatoma cells have yet to be elucidated. The present study aimed to investigate the function and underlying mechanisms of icaritin in the growth of SMMC-7721 cells. The cells were treated with varying concentrations of icaritin for 12, 24 and 48 h, respectively, prior to cytotoxic analysis. Apoptosis of SMMC 7721 cells following treatment with icaritin was measured using flow cytometry. The gene expression of mitochondria- and Fas-mediated caspase-dependent pathways was detected by reverse transcription-quantitative polymerase chain reaction and western blotting. Statistical analysis was performed by Student's t-test and one way analysis or variance. The present study demonstrated that treatment with icaritin significantly inhibited growth, and induced apoptosis of SMMC-7721 cells, in a time- and dose-dependent manner. In addition, icaritin triggered the mitochondrial/caspase apoptotic pathway, by decreasing the Bcl-2/Bax protein ratio and increasing activation of caspase-3. Icaritin also activated the Fas mediated apoptosis pathway, as was evident by the increased expression levels of Fas and activation of caspase-8. These data suggest that icaritin may be a potent growth inhibitor and induce apoptosis of SMMC-7721 cells through the mitochondria and Fas-mediated caspase-dependent pathways. The present study may provide experimental evidence for preclinical and clinical evaluations of icaritin for HCC therapy. PMID- 25434586 TI - Prevention of head and neck squamous cell carcinoma: removing the "chemo" from "chemoprevention". AB - The concept of chemoprevention whereby the use of a systemic agent is intended to halt the carcinogenesis process has been an attractive topic in head and neck squamous cell carcinoma (HNSCC). Yet, despite the significant efforts over the past decades and the substantial gain in knowledge of the biology of pre malignant lesions of the head and neck, no tangible indications for chemoprevention have emerged for this disease. The negative results observed in the earlier larger studies using retinoids did not encourage further trials with these agents. Attention has been more recently focused on epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) as well as cyclo-oxygenase 2 (COX 2) inhibitors with early studies showing encouraging responses but rather poor tolerance to therapy. Natural compounds have gained more interest recently given preclinical evidence of activity as well as a low side effect profile. We herein offer a comprehensive overview of the field of chemoprevention in HNSCC with an in depth analysis of the challenges we face and discuss a road map for future directions. PMID- 25434585 TI - Update report of T4 classification nasopharyngeal carcinoma after intensity modulated radiotherapy: an analysis of survival and treatment toxicities. AB - OBJECTIVE: To evaluate the long-term survival outcomes and toxicity of a larger series of patients with non-metastatic T4 classification nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: From March 2004 to June 2011, 335 non-metastatic T4 classification NPC patients treated by IMRT were analyzed retrospectively. Treatment induced toxicities were scored according to the Common Terminology Criteria for Adverse Events version 3.0. RESULTS: With a median follow-up time of 53.6 months (range, 2.8-114.9 months), the 5-year local failure-free survival (LFFS), regional failure free survival (RFFS), distant failure-free survival (DFFS), and overall survival (OS) were 84.1%, 92.2%, 74.1%, and 63.0%, respectively. At their last follow-up visit, 118 patients (35.2%) had developed treatment failure. Distant metastasis was the major failure pattern after treatment. The most common toxicities were mainly in grade 1 or 2. Concurrent chemotherapy failed to improve survival rates for patients with T4 classification NPC. CONCLUSION: The results of T4 classification NPC treated by IMRT were excellent, and distant metastasis was the most commonly failure pattern. Treatment-related toxicities were well tolerable. The role of concurrent chemotherapy for T4 classification NPC needs to be further investigated in the era of IMRT. PMID- 25434587 TI - Creutzfeldt-Jakob disease mimicking autoimmune encephalitis with CASPR2 antibodies. AB - BACKGROUND: Differential diagnosis of severe progressive dementia includes a wide spectrum of inflammatory and neurodegenerative diseases. Particularly challenging is the differentiation of potentially treatable autoimmune encephalitis and Creutzfeldt-Jakob disease. Such a coincidence may indeed complicate the correct diagnosis and influence subsequent treatment. CASE PRESENTATION: A 75-year-old woman was admitted due to rapid progressive cognitive impairment. Her husband observed a temporal disorientation and confusion. The initial neurological examination and an extensive neuropsychological evaluation showed significant impairments in almost all tested cognitive domains. All other neurological functions including motor, sensory and coordinative function were intact. Initial diagnostics included EEG, MRI and lumbar puncture with unspecific results. Complementary blood testing revealed a positive result for antineural antibodies to Contactin-associated protein 2 (CASPR2) and the patient received treatment for CASPR2 autoimmune encephalitis. Further symptoms and results, including 14-3-3 proteins, led to suspected Creutzfeldt-Jakob disease. The postmortem examination supported the diagnosis of a definitive Creutzfeldt-Jakob disease. CONCLUSION: One could argue that global screening for antineural antibodies may lead to a false diagnosis triggering intense and potentially dangerous procedures. We believe, however, that potentially treatable causes of dementia should aggressively sought out and subsequently treated in an attempt to curtail the course of disease and ultimately reduce the rate of mortality. PMID- 25434588 TI - Fast self-healing of graphene oxide-hectorite clay-poly(N,N-dimethylacrylamide) hybrid hydrogels realized by near-infrared irradiation. AB - Self-healing hydrogels were proposed to be used as biomaterials, because of the capability of spontaneously healing injury, but most of the reported self-healing hydrogels do not possess high mechanical strength and fast self-healing at the same time. Herein, we prepared graphene oxide (GO)-hectorite clay-poly(N,N dimethylacrylamide) (PDMAA) hybrid hydrogels with enhanced mechanical properties and fast self-healing capability realized by near-infrared (NIR) irradiation. The physical cross-linking between clay sheets and PDMAA chains provided the hydrogel with mechanical strength to maintain its stability in shape and architecture. GO sheets in the hybrid hydrogels acted as not only a collaborative cross-linking agent but also as a NIR absorber to absorb the NIR irradiation energy and transform it to thermal energy rapidly and efficiently, resulting in a rapid temperature increase of the GO containing gels. The chain mutual diffusion and the reformation of physical cross-linking occurred more quickly at higher temperature; consequently, the damaged hydrogel was almost completely recovered in a few minutes upon irradiation. We also demonstrated a potential application of the hybrid hydrogel as a self-healing surgical dressing. PMID- 25434589 TI - PC1, a non-peptide PKR1-preferring antagonist, reduces pain behavior and spinal neuronal sensitization in neuropathic mice. AB - Peripheral neuropathy is characterized by abnormal pain responses triggered by the release of several mediators and neuronal hyperexcitability at the spinal cord level. Emerging evidence indicates that the enhanced activity of dorsal horn neurons requires communication with glia and microglia, cells that are physiologically involved in neuronal wellbeing. Prokineticins (PKs), which include PK1 and PK2, represent a novel family of chemokines characterized by a unique structural motif comprising five disulfide bonds. They are expressed in the peripheral and central nervous system. PKs bind two G protein coupled receptors, PKR1 and PKR2, and participate in the regulation of several biological processes, including pain sensation. This study aimed to investigate the anti nociceptive effect of PC1, a non-peptide PKR1-preferring antagonist, in a mouse model of neuropathic pain. To do this, we assessed the activity of spinal cord nociceptive neurons as well as astrocyte and microglia phenotypes after repeated administration of PC1 in vivo. PC1 treatment strongly delayed the development of thermal hyperalgesia and tactile and mechanical allodynia. It also reduced spinal microglial and glial activation 8 days post injury in spared nerve injury (SNI) mice. Neuropathic mice showed an increased level of PK2 protein in the spinal cord, mostly in astrocytes. PC1 treatment completely reversed the increased responsiveness to mechanical stimuli, the decreased threshold of neuronal activation, and the increased spontaneous activity that were observed in nociceptive specific (NS) neurons of SNI mice. PMID- 25434590 TI - Signal-on electrochemiluminescent aptasensors based on target controlled permeable films. AB - A novel permeability gate-based electrochemiluminescent (ECL) aptasensor has been constructed by utilizing target-responsive polyelectrolyte-aptamer film deposited on the solid-state ECL electrode to control the rate of diffusion of a coreactant that triggers the ECL. PMID- 25434591 TI - Fine granules showing sustained drug release prepared by high-shear melt granulation using triglycerin full behenate and milled microcrystalline cellulose. AB - This study aimed to prepare fine granules with a diameter less than 200MUm and sustained drug release properties by melt granulation. Triglycerin full behenate (TR-FB) was examined as a new meltable binder (MB) by comparison of its properties with those of glycerin monostearate (GM), widely used as MB. The effect of milling microcrystalline cellulose (MCC), an excipient for melt granulation, on the granule properties was also investigated. TR-FB was more stable during heating and storage than GM, and produced smaller granules with narrower particle size distribution, larger yield in the 106-200MUm range, uniform roundness and better sustained drug release profile than those prepared with GM. Granules prepared with milled MCC had almost the same physicochemical properties as those produced with intact MCC. However, milled MCC produced granules with a more rigid structure and smaller void space than intact MCC. Consequently, the granules produced with milled MCC showed better sustained drug release behavior than those prepared with intact MCC. We successfully prepared fine granules with sustained drug release properties and diameter of less than 200MUm using TR-FB and milled MCC. PMID- 25434592 TI - Matrix tablets for sustained release of repaglinide: Preparation, pharmacokinetics and hypoglycemic activity in beagle dogs. AB - Repaglinide (RG) is an efficient antihyperglycemic drug; however, due to its short half-life, patients are required to take the marketed products several times a day, which compromises the therapeutic effects. The present study was conducted to develop a hydrophilic sustained release matrix tablet for RG with the aims of prolonging its action time, reducing the required administration times and side effects and improving patient adherence. The matrix tablets were fabricated by a direct compression method, the optimized formulation for which was obtained by screening the factors that affected the drug release. Moreover, studies of the pharmacokinetics and hypoglycemic activity as measured by glucose assay kits were performed in dogs. Sustained drug releases profiles over 10h and a reduced influence of medium pHs on release were achieved with the optimized formulation; moreover, the in vivo performance of extended release formulation was also examined, and better absorption, a one-fold decrease in Cmax, a two-fold increase of Tmax and a prolonged hypoglycemic effect compared to the marketed product were observed. In conclusion, sustained RG release and prolonged action were observed with present matrix tablets, which therefore provide a promising formulation for T2D patients who require long-term treatment. PMID- 25434594 TI - A new class of luminescent Cu(I) complexes with tripodal ligands - TADF emitters for the yellow to red color range. AB - A new class of emissive and neutral Cu(I) compounds with tripodal ligands is presented. The complexes were characterized chemically, computationally, and photophysically. Under ambient conditions, the powders of the compounds exhibit yellow to red emission with quantum yields ranging from about 5% to 35%. The emission represents a thermally activated delayed fluorescence (TADF) combined with a short-lived phosphorescence which represents a rare situation and is a consequence of high spin-orbit coupling (SOC). In the series of the investigated compounds the non-radiative rates increase with decreasing emission energy according to the energy gap law while the radiative rate is almost constant. Furthermore, a well-fit linear dependence between the experimental emission energies and the transition energies calculated by DFT and TD-DFT methods could be established, thus supporting the applicability of these computational methods also to Cu(I) complexes. PMID- 25434595 TI - Pharmacological treatment of obesity in Europe: waiting for the arrival of the white blackbird. PMID- 25434593 TI - Intravoxel incoherent motion diffusion-weighted MR imaging of gliomas: efficacy in preoperative grading. AB - The preoperative grading of gliomas, which is critical for guiding therapeutic strategies, remains unsatisfactory. We aimed to retrospectively assess the efficacy of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) in the grading of gliomas. Forty-two newly diagnosed glioma patients underwent conventional MR imaging, DWI, and contrast-enhanced MR imaging. Parameters of apparent diffusion coefficient (ADC), slow diffusion coefficient (D), fast diffusion coefficient (D*), and fraction of fast ADC (f) were generated. They were tested for differences between low- and high-grade gliomas based on one-way ANOVA. Receiver-operating characteristic (ROC) analyses were conducted to determine the optimal thresholds as well as the sensitivity and specificity for grading. ADC, D, and f were higher in the low-grade gliomas, whereas D* tended to be lower (all P<0.05). The AUC, sensitivity, specificity and the cutoff value, respectively, for differentiating low- from high-grade gliomas for ADC, D and f, and differentiating high- from low-grade gliomas for D* were as follows: ADC, 0.926, 100%, 82.8%, and 0.7 * 10(-3) mm(2)/sec; D, 0.942, 92.3%, 86.2%, and 0.623 * 10(-3) mm(2)/sec; f, 0.902, 92.3%, 86.2%, and 35.3%; D*, 0.798, 79.3%, 84.6%, and 0.303 * 10(-3) mm(2)/sec. The IVIM DWI demonstrates efficacy in differentiating the low- from high-grade gliomas. PMID- 25434596 TI - Paralogous cAMP receptor proteins in Mycobacterium smegmatis show biochemical and functional divergence. AB - The cyclic AMP receptor protein (CRP) family of transcription factors consists of global regulators of bacterial gene expression. Here, we identify two paralogous CRPs in the genome of Mycobacterium smegmatis that have 78% identical sequences and characterize them biochemically and functionally. The two proteins (MSMEG_0539 and MSMEG_6189) show differences in cAMP binding affinity, trypsin sensitivity, and binding to a CRP site that we have identified upstream of the msmeg_3781 gene. MSMEG_6189 binds to the CRP site readily in the absence of cAMP, while MSMEG_0539 binds in the presence of cAMP, albeit weakly. msmeg_6189 appears to be an essential gene, while the Deltamsmeg_0539 strain was readily obtained. Using promoter-reporter constructs, we show that msmeg_3781 is regulated by CRP binding, and its transcription is repressed by MSMEG_6189. Our results are the first to characterize two paralogous and functional CRPs in a single bacterial genome. This gene duplication event has subsequently led to the evolution of two proteins whose biochemical differences translate to differential gene regulation, thus catering to the specific needs of the organism. PMID- 25434597 TI - Role of grafted alkoxybenzylidene ligand in silica-supported Hoveyda-Grubbs-type catalysts. AB - Using both circulating flow and batch reaction systems, we explored the role of immobilized alkoxybenzylidene ligands in capturing and stabilizing active ruthenium species. The bidentate ligands turned out to considerably affect reaction rate, catalyst decomposition, leaching and recycling. It was also observed that the dynamic release-return catalytic pathway worked more efficiently in a batch system leading to less catalyst decomposition and leaching. PMID- 25434598 TI - Antithrombotic therapy after left atrial appendage closure. AB - It is important to prevent on-device thrombus formation without increasing the risk for bleeding complications after successful interventional left atrial appendage closure. Therefore, choosing the optimal antithrombotic therapy poses a challenging task. While major clinical studies investigated patients eligible for oral anticoagulation using vitamin K antagonists, the vast majority of implants in 'real life' are performed in patients with contraindications to oral anticoagulation after serious bleeding events. In this patient population, strategies using dual antiplatelet therapy were found to be a sound alternative; however, the optimal duration of antithrombotic therapy remains unclear. Future studies will have to investigate the role of direct anticoagulants for post implant thrombus formation and address the question of whether left atrial appendage closure obviates the need for long-term aspirin therapy. PMID- 25434599 TI - [Resistance to flow of uncoated urinary catheters. Experimental study with bladder model]. AB - OBJECTIVES: Evaluate the flow resistance caused by uncoated urinary catheter put during night. MATERIAL: Experimental synthetic bladder in vitro study measuring the flow of uncoated urinary catheter most frequently observed in the continuous nocturnal drainage with data charier and pressure (for catheters 10, 12 and 14 Ch diameter and 20, 40 and 60 cmH2O pressure). For each pressure/charier relationship, five catheters of the same type were used. RESULTS: We observed that for the median flow (Qmax), two catheters with identical charier and pressure, which differed only by their brand, was not significantly different. For example, Peters((r)) and Coloplast((r)) Ch 14 probes and 20 cmH2O pressure (P value=0.915). Faced with the nomogram of Abrams-Griffiths (Lim and Abrams, 1995 [7]), uncoated catheters prove obstructive or partially obstructive at a higher pressure of 20 cmH2O for all those charier studied. CONCLUSION: Uncoated urinary catheter put during the night is obstructive under some data charier. Increasing charier of uncoated catheter decreases resistance to flow. It seems that not difference in drainage flow between different brands with data charier and pressure. PMID- 25434600 TI - The Shigella flexneri OspB effector: an early immunomodulator. AB - Through the action of the type three secretion system (T3SS) Shigella flexneri delivers several effectors into host cells to promote cellular invasion, multiplication and to exploit host-cell signaling pathways to modulate the host innate immune response. Although much progress has been made in the understanding of many type III effectors, the molecular and cellular mechanism of the OspB effector is still poorly characterized. In this study we present new evidence that better elucidates the role of OspB as pro-inflammatory factor at very early stages of infection. Indeed, we demonstrate that, during the first hour of infection, OspB is required for full activation of ERK1/2 and p38 MAPKs and the cytosolic phospholipase A(2) (cPLA(2)). Activation of cPLA(2) ultimately leads to the production and secretion of PMN chemoattractant metabolite(s) uncoupled with release of IL-8. Moreover, we also present evidence that OspB is required for the development of the full and promptly inflammatory reaction characteristic of S. flexneri wild-type infection in vivo. Based on OspB and OspF similarity (both effectors share similar transcription regulation, temporal secretion into host cells and nuclear localization) we hypothesized that OspB and OspF effectors may form a pair aimed at modulating the host cell response throughout the infection process, with opposite effects. A model is presented to illustrate how OspB activity would promote S. flexneri invasion and bacterial dissemination at early critical phases of infection. PMID- 25434601 TI - Effect of temperature acclimation on red blood cell oxygen affinity in Pacific bluefin tuna (Thunnus orientalis) and yellowfin tuna (Thunnus albacares). AB - Hemoglobin-oxygen (Hb-O2) binding properties are central to aerobic physiology, and must be optimized for an animal's aerobic requirements and environmental conditions, both of which can vary widely with seasonal changes or acutely with diving. In the case of tunas, the matter is further complicated by large regional temperature differences between tissues within the same animal. This study investigates the effects of thermal acclimation on red blood cell Hb-O2 binding in Pacific bluefin tuna (T. orientalis) and yellowfin tuna (T. albacares) maintained in captive tanks at acclimation temperatures of 17 degrees , 20 degrees and 24 degrees C. Oxygen binding properties of acclimated tuna isolated red blood cells were examined under varying experimental temperatures (15 degrees -35 degrees C) and CO2 levels (0%, 0.5% and 1.5%). Results for Pacific bluefin tuna produced temperature-independence at 17 degrees C- and 20 degrees C acclimation temperatures and significant reverse temperature-dependence at 24 degrees C-acclimation in the absence of CO2, with instances of reverse temperature-dependence in 17 degrees C- and 24 degrees C-acclimations at 0.5% and 1.5% CO2. In contrast, yellowfin tuna produced normal temperature-dependence at each acclimation temperature at 0% CO2, temperature-independence at 0.5% and 1.5% CO2, and significant reverse temperature-dependence at 17 degrees C acclimation and 0.5% CO2. Thermal acclimation of Pacific bluefin tuna increased O2 binding affinity of the 17 degrees C-acclimation group, and produced a significantly steeper oxygen equilibrium curve slope (nH) at 24 degrees C acclimation compared to the other acclimation temperatures. We discuss the potential implications of these findings below. PMID- 25434603 TI - Causes of in-hospital cardiac arrest - incidences and rate of recognition. AB - BACKGROUND AND METHODS: Do emergency teams (ETs) consider the underlying causes of in-hospital cardiac arrest (IHCA) during advanced life support (ALS)? In a 4.5 year prospective observational study, an aetiology study group examined 302 episodes of IHCA. The purpose was to investigate the causes and cause-related survival and to evaluate whether these causes were recognised by the ETs. RESULTS: In 258 (85%) episodes, the cause of IHCA was reliably determined. The cause was correctly recognised by the ET in 198 of 302 episodes (66%). In the majority of episodes, cardiac causes (156, 60%) or hypoxic causes (51, 20%) were present. The cause-related survival was 30% for cardiac aetiology and 37% for hypoxic aetiology. The initial cardiac rhythm was pulseless electrical activity (PEA) in 144 episodes (48%) followed by asystole in 70 episodes (23%) and combined ventricular fibrillation/ventricular tachycardia (VF/VT) in 83 episodes (27%). Seventy-one patients (25%) survived to hospital discharge. The median delay to cardiopulmonary resuscitation (CPR) was 1min (inter-quartile range 0 1min). CONCLUSIONS: Various cardiac and hypoxic aetiologies dominated. In two thirds of IHCA episodes, the underlying cause was correctly identified by the ET, i.e. according to the findings of the aetiology study group. PMID- 25434602 TI - Is the deep-sea crab Chaceon affinis able to induce a thermal stress response? AB - Fluctuations in the stress level of an organism are expressed in behavioural and molecular changes that can affect its ecology and survival. Our knowledge of thermal adaptations in deep-sea organisms is very limited, and this study investigates the critical thermal maximum (CTmax) and the heat-shock response (HSR) in the deep-sea crab Chaceon affinis commonly found in waters of the North East Atlantic. A mild but significant HSR in C. affinis was noted and one of the lowest CTmax known amongst Crustacea was revealed (27.5 degrees C at 0.1 MPa; 28.5 degrees C at 10 MPa). The thermal sensitivity of this species appears to be reduced at in situ pressure (10 MPa), given the slightly higher CTmax and the significant 3-fold induction of stress genes hsp70 form 1 and hsp70 form 2. Although C. affinis deep-sea habitat is characterized by overall low temperature this species appears to have retained its ability to induce a HSR. This capability may be linked with C. affinis' occasional exploitation of warmer and thermally instable hydrothermal vent fields, where it has been found foraging for food. PMID- 25434604 TI - Histological characteristics of collagen denaturation and injuries in bipolar radiofrequency-induced colonic anastomoses. AB - Bipolar radiofrequency-induced thermo-fusion has been explored as an advanced surgical method for intestinal anastomoses; however, the histological characteristics of collagen denaturation and injuries arising from this process remain unclear. The aim of this study was to investigate the microcosmic changes and tissue damage of fusion regions with various parameters of injury. Ex vivo colons of pigs were fused serosa-serosa on two carrier rings, which were installed on a homemade anastomotic device. Five levels of compressive pressure from 171 to 313 kPa were applied for 5s to fuse the colons under radiofrequency power of 160 W, and then the collagen denaturation of the fused region was examined by transmission electron microscopy. Light microscopy was utilized to observe histological slices that were stained with picrosirius red in order to visualize the tissue injuries under two levels of radiofrequency power (120 vs. 140 W) and operation time (5 vs. 10s). Transmission electron micrographs showed that increased compressive pressure led to thicker denatured collagen fibrils and wider gaps between each collagen fibril. Serosa adhesion regions appeared abundant in collagen. No histological differences were observed when 120 W of power was applied for 5 and 10s. Significant muscle cracking occurred when colons were fused using 140 W for 5s. When the operation time was extended to 10s, 140 W led to tight fusion and less splitting on muscles. These results suggest that higher compressive pressure results in more severe collagen unfolding and also reduces collagen crosslinking in fused colons. Improved radiofrequency power along with operation time could avoid tissue injury upon radiofrequency-induced colonic anastomoses. PMID- 25434605 TI - Hodgkin-like peripheral T-cell lymphoma (PTCL) with preserved Hodgkin-like lesions at autopsy: a case report with an interesting clinical course. AB - The presence of the so-called Hodgkin and Reed-Sternberg (H-RS) like cells may occur in T-cell non-Hodgkin lymphoma. Reported herein is the autopsy case of Hodgkin-like peripheral T-cell lymphoma (PTCL) in a 77-year-old male with gradual submandibular lymph node enlargement. The first biopsy showed Hodgkin-like PTCL, initially misdiagnosed as classical Hodgkin lymphoma. Although he was treated with a regimen of ABVD, his disease recurred with cervical lymph node enlargement. A second biopsy showed angioimmunoblastic T-cell lymphoma (AITL) and H-RS like cells became obscure. Despite treatment with the CHOP regimen, he died. An autopsy confirmed that only Hodgkin-like lesions preserved while the AITL component had disappeared. This clinical course is very interesting in that only the Hodgkin-like lesions were systematically exacerbated and became the main cause of death. There are no reports of Hodgkin-like PTCL following AITL and finally preserved Hodgkin-like lesions in autopsy. PMID- 25434606 TI - Developing situation awareness amongst nursing and paramedicine students utilizing eye tracking technology and video debriefing techniques: a proof of concept paper. AB - OBJECTIVE: The aims of this quasi-experimental before-and-after study were to first determine whether the use of eye tracking technology combined with video debriefing techniques has the potential to improve the quality of feedback and enhance situation awareness (SA) in simulated settings and second to determine students' satisfaction towards simulated learning. METHODS: Nursing and paramedicine students from three universities participated in three 8-minute simulation scenarios of acutely deteriorating patients. Eye tracking glasses video recorded the scenarios and tracked right eye movement. On completion, participants were questioned using the Situation Awareness Global Assessment Technique, completed the Satisfaction with Simulation Experience Scale (SSES), and provided textual feedback and received video-based verbal feedback. RESULTS: Participants lacked awareness of presenting medical conditions and patient environments and had poor recall of patient vital signs. Significant improvements in SA scores were demonstrated between the first and third scenarios (P = 0.04). Participants reported greater insight into their performance and were satisfied with simulated learning. CONCLUSIONS: Use of visual field review techniques appears to enhance the use of realistic simulated practice as a means of addressing significant performance deficits. Eye tracking and point of view recording techniques are feasible and with applicable debriefing techniques could enhance clinical and situated performance. PMID- 25434607 TI - New triterpenoid saponins from the aerial parts of Comastomapedunculatum. AB - Three new saikosaponin analogs, comastomasaponins I-K (1-3), were isolated from the aerial portions of Comastomapedunculatum. The structures of these compounds were elucidated on the basis of spectroscopic data analysis, and their nitric oxide production inhibitory activity was evaluated invitro. PMID- 25434608 TI - Anti-inflammatory effects and pharmacokinetics study of geniposide on rats with adjuvant arthritis. AB - The aim of this study was to explore the anti-inflammatory effects of Geniposide (GE), an iridoid glycoside compound extracted from Gardenia jasminoides Ellis (GJ) fruit in adjuvant-induced arthritis (AA) rats and its pharmacokinetic (PK) basis. AA was induced by injecting with Freund's complete adjuvant (FCA). Male SD rats were subjected to treatment with GE (30, 60 and 120mg/kg) from day 17 to 24 after immunization. Fibroblast-like synoviocyte (FLS) proliferation was assessed by MTT. Interleukin (IL)-1, IL-6, TNF-alpha and IL-10 were determined using double-sandwich enzyme-linked immunosorbent assay (ELISA). Expression of p38 mitogen-activated protein kinases (p38MAPKs) related proteins in FLS was detected by Western blotting. PK profiles were simultaneously detected by ultra performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) in AA rat plasma after oral administration of GE on day 17 after immunization. As a result, GE promoted the recovery of arthritis and inhibited the colonic inflammation damage in AA rats by decreasing the expression level of TNF-alpha, IL-1 and IL-6, increasing the production of IL-10 and inhibiting the expression of phospho-p38 (p-p38) related proteins in FLS. PK parameters (AUC, Cmax and t1/2) tended to be associated with dosage-related decreasing of efficacy index. PMID- 25434609 TI - Changing the stability conditions in a back squat: the effect on maximum load lifted and erector spinae muscle activity. AB - The aim of this study was to identify how changes in the stability conditions of a back squat affect maximal loads lifted and erector spinae muscle activity. Fourteen male participants performed a Smith Machine (SM) squat, the most stable condition, a barbell back (BB) squat, and Tendo-destabilizing bar (TBB) squat, the least stable condition. A one repetition max (1-RM) was established in each squat condition, before electromyography (EMG) activity of the erector spinae was measured at 85% of 1-RM. Results indicated that the SM squat 1-RM load was significantly (p = 0.006) greater (10.9%) than the BB squat, but not greater than the TBB squat. EMG results indicated significantly greater (p < 0.05) muscle activation in the TBB condition compared to other conditions. The BB squat produced significantly greater (p = 0.036) EMG activity compared to the SM squat. A greater stability challenge applied to the torso seems to increase muscle activation. The maximum loads lifted in the most stable and unstable squats were similar. However, the lift with greater stability challenge required greatest muscle activation. The implications of this study may be important for training programmes; if coaches wish to challenge trunk stability, while their athletes lift maximal loads designed to increase strength. PMID- 25434610 TI - Mid-Term Results of 121 Periprosthetic Femoral Fractures: Increased Failure and Mortality Within but not After One Postoperative Year. AB - Periprosthetic femoral fractures are associated with high failure rates and mortality, particularly within one postoperative year. However, mid-term results related to this issue are lacking. Thus, we performed a retrospective follow-up evaluation. Between 2007 and 2012, we treated a total of 121 consecutive patients for periprosthetic femoral fractures. After a mean of 57.2 postoperative months, we documented a total surgical revision rate of 16.5% within the first year, and the one-year mortality rate was 13.2%. Between one year and up to 7.3 postoperative years, only one surgical revision was necessary, and the mortality rate also decreased. No significant factors related to surgical revisions were detected. However, the initial hip fracture, older age, higher ASA score and dementia were associated with a higher mortality rate. PMID- 25434611 TI - Effects of tachyplesin I on human U251 glioma stem cells. AB - Glioblastoma, is one of the most malignant types of intracranial tumor with complex progressive cellular and underlying molecular events. The use of glioma stem cells (GSCs) offers a promising strategy for tumor therapy in the future. Tachyplesin I has been demonstrated to have potential anticancer activity and was first observed in leukocytes. In the present study, the GSC subset was isolated from U251 glioma cells and tachyplesin I was assessed for antitumor activity. As a result, the U251 cells exhibited certain GSC phenotypes, including the expression of stem cell biomarkers CD133 and nestin, when transferred into stem cell culture conditions. The GSCs were grown in an adherent manner in a medium containing serum, while the U251 glioma cells were suspended and cultured in serum-free medium. Tachyplesin I damaged the structure of GSC and inhibited the culture of GSC spheres in a time and dose-dependent manner. When tachyplesin I was administered at a concentration of 10-40 ug/ml, GSC differentiation was induced. GSCs treated with a low dose of tachyplesin I disrupted the plasma membrane and led to a loss of cytoplasmic organelles. These findings indicated that tachyplesin I had an effect on inhibiting tumor stem cells and demonstrated that tachyplesin I inhibited GSCs by disrupting the plasma membranes and inducing GSC differentiation. PMID- 25434613 TI - John West: life at the summit of pulmonary physiology. PMID- 25434612 TI - Imaging of CAIX-expressing xenografts in vivo using 99mTc-HEHEHE-ZCAIX:1 affibody molecule. AB - Carbonic anhydrase IX (CAIX) is a transmembrane enzyme involved in regulation of tissue pH balance. In cancer, CAIX expression is associated with tumor hypoxia. CAIX is also overexpressed in renal cell carcinoma and is a molecular target for the therapeutic antibody cG250 (girentuximab). Radionuclide imaging of CAIX expression might be used for identification of patients who may benefit from cG250 therapy and from treatment strategies for hypoxic tumors. Affibody molecules are small (7 kDa) scaffold proteins having a high potential as probes for radionuclide molecular imaging. The aim of the present study was to evaluate feasibility of in vivo imaging of CAIX-expression using radiolabeled Affibody molecules. A histidine-glutamate-histidine-glutamate-histidine-glutamate (HE)3 tag-containing CAIX-binding Affibody molecule (HE)3-ZCAIX:1 was labeled with [(99m)Tc(CO)3](+). Its binding properties were evaluated in vitro using CAIX expressing SK-RC-52 renal carcinoma cells. (99m)Tc-(HE)3-ZCAIX:1 was evaluated in NMRI nu/nu mice bearing SK-RC-52 xenografts. The in vivo specificity test confirmed CAIX-mediated tumor targeting. (99m)Tc-(HE)3-ZCAIX:1 cleared rapidly from blood and normal tissues except for kidneys. At optimal time-point (4 h p.i.), the tumor uptake was 9.7 +/- 0.7% ID/g, and tumor-to-blood ratio was 53 +/ 10. Experimental imaging of CAIX-expressing SK-RC-52 xenografts at 4 h p.i. provided high contrast images. The use of radioiodine label for ZCAIX:1 enabled the reduction of renal uptake, but resulted in significantly lower tumor uptake and tumor-to-blood ratio. Results of the present study suggest that radiolabeled Affibody molecules are promising probes for imaging of CAIX-expression in vivo. PMID- 25434614 TI - Cognitive decline after sepsis. AB - The modern era of sepsis management is characterised by a growing number of patients who survive in the short term and are discharged from hospital. Increasing evidence suggests that these survivors exhibit long-term neurological sequelae, particularly substantial declines in cognitive function. The exact prevalence and outcomes of these neuropsychological sequelae are unclear. The mechanisms by which sepsis induces cognitive dysfunction probably include vascular injuries and neuroinflammation that are mediated by systemic metabolism disorders and overwhelming inflammation, a disrupted blood-brain barrier, oxidative stress, and severe microglial activation, particularly within the limbic system. Interventions targeting the blood-brain barrier, glial activation, and oxidative stress have shown promise in prevention of cognitive dysfunction in various experimental models of sepsis. The next step should be to translate these favourable effects into positive clinical results. PMID- 25434616 TI - Field experience with surgical castration with anaesthesia, analgesia, immunocastration and production of entire male pigs: performance, carcass traits and boar taint prevalence. AB - Male piglets are castrated to reduce boar taint and also to reduce aggressive and sexual behaviour. However, the procedure as traditionally performed is painful and negatively affects performance. Large-scale results about the consequences of implementing alternatives on farms are lacking. We, therefore, investigated the practical applicability of the following five alternatives that can be implemented in the short term: surgical castration (1) without pain relief (CONT, control group), (2) with analgesia (MET, Metacam, 0.2 ml, 10 to 15 min before castration), (3) with general anaesthesia (CO2, inhalation, 100% CO2, 25 s, 3 l/min), (4) vaccination against boar taint (IM, two injections with Improvac) and (5) production of entire males (EM). The study consisted of the following two trials: (1) an experimental farm trial with 18 animals/treatment and (2) a large field trial on 20 farms with ~120 male pigs/farm per treatment and all treatments performed on each farm. Performance results as well as data on carcass traits, boar taint (hot-iron method) and testes development and weight were collected in both trials. Neither castration nor administration of analgesia or anaesthesia had an effect on daily gain of the piglets in the farrowing crates (P>0.05). Farmer records indicated that mortality in the farrowing crates (1.1%), nursery pens (1.8%) and fattening stable (2.2%) was not influenced by MET or CO2 compared with EM, IM or CONT (P>0.05). No significant differences were found for daily gain (P>0.05) nor slaughter age (P>0.05). Immunocastrates and EM had a better gain-to-feed ratio (P<0.05) compared with the groups of barrows (CONT, MET and CO2). Lean meat percentage was higher for EM compared with the barrows, and intermediate for IM (P<0.05). Carcass yield was lowest for IM (P<0.05). The hot iron method indicated that boar taint was eliminated in barrows and IM compared with EM (P<0.001). Average prevalence of strong boar taint was 3% for EM, but varied from 0% to 14% between farms. As the effect of treatment on performance as well as the level of boar taint of EM was farm dependent, farmers should be encouraged to pre-test the different alternatives in order to make a well considered choice for the best practical and profitable alternative for their farm. PMID- 25434617 TI - Staying relevant with the times--the changing face of an asylum. PMID- 25434615 TI - Gene polymorphisms of stress hormone and cytokine receptors associate with immunomodulatory profile and psychological measurement. AB - OBJECTIVE: We sought to identify whether stable single nucleotide polymorphisms (SNPs) of various endocrine and immune molecules could be used as biomarkers associated with specific immune alterations and chronic stress measures in normal humans. METHODS: A total of 207 volunteer participants answered stress questionnaire and gave peripheral blood cells for identification of SNPs in genes coding for glucocorticoid receptor (GR), beta 2 adrenergic receptor (B2AR), interferon-gamma receptors (IFNGR1, IFNGR2), and interleukin-4 receptor (IL4R). Immunoregulatory profiles were measured by flow cytometry and genotyping assays were performed by allelic discrimination real-time PCR. RESULTS: Several significant differences were revealed in associations between stress marker and immune indicators based on SNP categories. For instance, Th1 levels of the minor alleles of GR TthIIII (AA) and IFNGR2 Q64R (Arg/Arg) groups were positively associated with chronic stress (PSS) (p = 0.024 and 0.005, respectively) compared with wild type (WT) and negatively associated with PSS in the heterozygous genotypes of GR BclI and IL4R Ile50Val (p = 0.040 and p = 0.052, respectively). Treg levels of the minor alleles of BclI (GG) and IFNGR1 T-56C (CC) groups were positively associated with PSS (p = 0.045 and p = 0.010, respectively) and negatively associated in the minor allele (Val/Val) of IL4R Ile50Va and the heterozygous genotype of IL4R Q576R (p = 0.041 and p = 0.017, respectively) compared to WT. CONCLUSION: The data support the notion that gene polymorphisms from various components of the psychoneuroendocrine-immune network may be useful as biomarkers to categorize individual stress-associated immune responses. PMID- 25434619 TI - Changes in mechanical, structural integrity and microbiological properties following cryopreservation of human cadaveric iliac arteries. AB - INTRODUCTION: The study seeks to investigate how the duration of storage of cryopreserved human cadaveric iliac arteries impacts their mechanical, structural and microbiological properties as compared to their fresh sample. MATERIALS AND METHODS: Iliac arteries were harvested from 12 human cadavers and divided into 2 groups. One group underwent mechanical stress-strain assessment immediately and another was cryopreserved for a pre-determined time-period (range, 29 to 364 days). Mechanical functionality was assessed with a customised clamping mechanism. The arteries' microbiological properties were studied pre- and post cryopreservation. The post-thawed arteries were also assessed histologically for structural integrity. RESULTS: Of the 12 pairs, only 7 (58, 119, 150, 252, 300, 332 and 364 days) iliac arteries were included in the final analysis. The other 5 pairs (29, 90, 188, 205 and 270 days) had abundant local calcification and their stress-strain curves could not be characterised. From the curves, pre- and post cryopreserved arteries had the most similar mechanical properties when stored for 119 days. A trend of increasing relative stiffness with increased duration of storage was noted. The post-thawed arteries demonstrated minimal fragmentation except in atherosclerotic areas. Majority of the arteries were not contaminated by bacterial or fungal infection pre- and post-cryopreservation. Also, 2 arteries (364 and 332 days) which had initial bacterial colonisation showed no bacterial growth on their post-thawed sample. CONCLUSION: Mechanically, non-atherosclerotic cryopreserved arteries can be a good substitute to their corresponding fresh arterial graft. However, the length of cryopreservation has an effect on the relative stiffness of the pre- and post-cryopreserved arteries. Histological and microbiological findings suggest that cryopreservation have little impact on an artery structural integrity and may possibly have a role in maintaining sterility and sterilising the arteries. PMID- 25434618 TI - Assessment of the American Joint Committee on Cancer 7th edition staging for localised prostate cancer in Asia treated with external beam radiotherapy. AB - INTRODUCTION: Most international clinical practice guidelines for prostate cancer (PCa) are driven by data derived in a Western setting. However, tumour biology and clinical disease progression are likely to differ in the Asian population. We compare the performance of the revised American Joint Committee on Cancer (AJCC) prognostic groups with the commonly used D'Amico Risk Classification and conventional predictors for PCa, in a large cohort of Asian patients. MATERIALS AND METHODS: We retrospectively reviewed data for 404 consecutive Singaporean patients receiving definitive radiotherapy at our centre between December 1996 and October 2006. The primary outcome was biochemical relapse-free survival (BRFS), defined using the Phoenix definition. The secondary outcome was overall survival (OS). Prognostic risk groups were defined using AJCC 7th edition (AJCC7) and 6th edition (AJCC6). Univariate analysis (UVA) and multivariate analysis (MVA) were performed for the following putative risk factors: age, Gleason score, prognostic grouping, tumour classification, radiation delivery technique, radiotherapy dose, hormonal therapy and initial PSA value. RESULTS: For the cohort, median age was 69 years. Median follow-up was 66.3 months. Five-year BRFS rate was 84.3% with 71 biochemical relapses and 5-year OS rate was 89.1% with 54 deaths. The concordance-indices for BRFS prediction were 0.588, 0.550 and 0.567 for AJCC7, AJCC6 and D'Amico respectively. Initial PSA, T-stage and AJCC7 were prognostic for BRFS on UVA. Comparison of AJCC7 vs. D'Amico showed no statistical additional value of either classification system although D'Amico was superior when compared to AJCC6 in predicting BRFS. T-stage >=3 and D'Amico were significant prognostic factors for BRFS on MVA. CONCLUSION: In our local, predominantly Chinese population, neither AJCC6 nor AJCC7 demonstrated a high predictive accuracy for BRFS although AJCC7 has a slightly better predictive ability than AJCC6. PMID- 25434620 TI - Biological reconstruction for children with osteosarcoma around the knee. AB - INTRODUCTION: Limb salvage in children with primary malignant bone tumours around the knee is challenging, with considerations such as shortening, bone and joint remodeling and high functional demands of active children. The ultimate aim for reconstruction is restoring a stable, painless and mobile joint. With improved survival rates from chemotherapy, reconstructive techniques should ideally last the child's lifespan. We adopted a biological approach by preserving the patients' native joint, with bony defects bridged by fibula grafts supplemented by autoclaved bone grafts infused with bone marrow. We conducted this retrospective review to determine if we were able to meet our objectives of reconstruction. MATERIALS AND METHODS: A retrospective review of children with osteogenic sarcoma involving the distal femur or proximal tibia treated at our institution was done. Patients aged 13 years and below at the time of surgery who had undergone a limb salvage procedure that preserved the knee joint were included. RESULTS: Nine patients were identified, 3 males and 6 females. The average age was 10.0 years (range, 7 to 13 years) at the time of surgery. Seven had tumours involving the distal femur while 2 had tumours involving the proximal tibia. There were no cases of local recurrence. Four of the 9 patients died from metastatic disease, the 5 surviving patients have no evidence of disease, and the average follow-up for survivors was 13.2 years. The average active range of motion for the knee joint was 96 degrees (range, 50 degrees to 130 degrees ). The average Musculoskeletal Tumour Society (MSTS) score was 26.3 (range, 23 to 30). CONCLUSION: We have observed this technique of limb salvage offers satisfactory limb function with long-term follow-up. PMID- 25434621 TI - Natural history and comorbidities of subjects with subclinical hyperthyroidism: analysis at a tertiary hospital setting. AB - INTRODUCTION: Subclinical hyperthyroidism (SH, grade 1, thyrotropin (TSH) >=0.1 mU/L and grade 2, TSH <0.1 mU/L) is a common disorder with increased prevalence in older subjects. There is evidence for increased morbidities in SH, such as atrial fibrillation and osteoporosis. We aim to study the natural history and comorbidities of SH from patients referred to a tertiary endocrine clinic in Singapore as they are currently unknown. MATERIALS AND METHODS: Retrospective evaluation of SH subjects for natural progression and comorbidities. RESULTS: One hundred and thirteen SH subjects (male/female: 24/89, mean age: 67.2 years, grade 1/grade 2: 60/53) were identified from the endocrine clinic. The aetiology of SH include 52 multinodular goitre, 15 Graves' disease, 7 toxic adenoma and 39 unclassified. A minority of SH patients (5.3 %) progressed to overt hyperthyroidism while 13% remitted to euthyroid state (1 to 3 years with a mean follow-up of 18 months) in the total cohort. Most of the patients remained in SH state during follow-up (50/60 in grade 1 SH and 42/53 in grade SH). However, no single predictive factor could be identified for progression or remission of SH. The prevalence of morbidities in SH subjects include ischaemic heart disease (16.8%), heart failure (8.9%), tachyarrhythmias (13.3%), any cardiovascular disease (28%), cerebrovascular disease (28%), osteoporosis (28%), and any fracture (15.9%). CONCLUSION: Most of SH cases in our cohort remain in subclinical state with very few progressing to overt hyperthyroidism. Significant proportion of SH subjects have vascular disease, but this association needs to be confirmed in prospective controlled studies. PMID- 25434622 TI - A Double-Blind, Randomised, Placebo-Controlled Trial of EMLA(r) Cream (Eutectic Lidocaine/Prilocaine Cream) for Analgesia Prior to Cryotherapy of Plantar Warts in Adults. AB - INTRODUCTION: Cryotherapy with liquid nitrogen is an effective, safe and convenient form of treatment for plantar warts. EMLA(r) cream (eutectic mixture of lidocaine 2.5% and prilocaine 2.5%) is a topical local anaesthetic agent that has proven to be effective and well tolerated in the relief of pain associated with various minor interventions in numerous clinical settings. MATERIALS AND METHODS: In a single-centre, double-blind, randomised placebo-controlled study, 64 subjects were randomised into 2 groups. The subjects had a thick layer of EMLA(r) cream or placebo cream applied to pared plantar wart(s) and onto the surrounding margin of 1 mm to 2 mm under occlusion for 60 minutes prior to receiving cryotherapy. The pain of cryotherapy was evaluated by the subjects using a self-administered Visual Analogue Scale (VAS) immediately after the cryotherapy. RESULTS: There was no statistical difference between the mean VAS score for EMLA(r) cream (47.0 +/- 21.4 mm) and placebo (48.9 +/- 22.0 mm). Those with more than 1 wart had a significantly higher VAS score than those with only 1 wart (59.1 +/- 21.8 vs. 44.3 +/- 20.4, P <0.05) but this did not affect the therapeutic effect of EMLA(r) cream prior to cryotherapy. CONCLUSION: We conclude that the application of EMLA(r) cream prior to cryotherapy does not reduce the pain associated with cryotherapy. PMID- 25434624 TI - Does patient education and recommendation result in increased uptake of colorectal cancer screening using the fecal occult blood test? PMID- 25434623 TI - Open reduction and internal fixation of displaced intra-articular calcaneal fractures with Norian Skeletal Repair System (SRS) bone cement: surgical technique, clinical and radiographical results. PMID- 25434625 TI - Not all that wheezes is asthma. PMID- 25434627 TI - WITHDRAWN: Polymyositis of bilateral upper legs seen on FDG-PET/CT in a patient with rheumatoid arthritis. AB - This article has been withdrawn at the request of the author and editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25434628 TI - Structured metal thin film as an asymmetric color filter: the forward and reverse plasmonic halos. AB - We observe asymmetric color filtering under unpolarized incidence in a structured metallic (Ag) film, where the center of an optically thick circular Ag disk surrounded by a step gap appears dark when observed from one side, and bright from the other. The latter situation corresponds to abnormally high optical transmission through the optically thick film. We explain this by a three-step process: coupling of photons to surface plasmon polaritons (SPPs), wave interference of SPPs forming resonant cavity modes, and out-coupling from SPPs to photons. Full wave electromagnetic simulations based on the finite element method support our findings. These results may have potential applications in areas such as optical color filtering and biosensing via dielectric detection within the step gap plasmonic cavity. PMID- 25434626 TI - Mn(II) complexes of scorpiand-like ligands. A model for the MnSOD active centre with high in vitro and in vivo activity. AB - Manganese complexes of polyamines consisting of an aza-pyridinophane macrocyclic core functionalised with side chains containing quinoline or pyridine units have been characterised by a variety of solution techniques and single crystal x-ray diffraction. Some of these compounds have proved to display interesting antioxidant capabilities in vitro and in vivo in prokaryotic (bacteria) and eukaryotic (yeast and fish embryo) organisms. In particular, the Mn complex of the ligand containing a 4-quinoline group in its side arm which, as it happens in the MnSOD enzymes, has a water molecule coordinated to the metal ion that shows the lowest toxicity and highest functional efficiency both in vitro and in vivo. PMID- 25434629 TI - Incidence of symptomatic venous thromboembolism in patients with hemophilia undergoing joint replacement surgery: a retrospective study. AB - INTRODUCTION: Venous thromboembolism (VTE) is a recognized complication after joint replacement surgery, and prophylaxis is routinely used in patients without bleeding disorders. However, for patients with hemophilia, pharmacologic prophylaxis is highly variable and controversial because of the inherent bleeding risk. AIM: To review our institutional experience with outcomes of total knee or hip arthroplasty with regard to symptomatic VTE and use of VTE prophylaxis in patients with hemophilia and without inhibitors. METHODS: We reviewed records of 42 consecutive patients with hemophilia A or B who underwent 71 hip or knee replacements over a 39-year period. We also reviewed the literature to estimate the incidence of VTE after arthroplasty in the hemophilia population. RESULTS: All patients used compression stockings for up to 6weeks after surgery; additionally, 6 cases (10.5%; 57 with available data) used sequential intermittent compression devices and 2 (2.8%) postoperatively received low molecular-weight heparin. One patient (1.4%) who received low-molecular-weight heparin had a symptomatic, lower-extremity, deep venous thrombosis 10days after hip replacement for traumatic fracture. None of the other 70 surgical cases had symptomatic VTE within 3months after the procedure. Analysis of pooled data from published series of hemophilia patients undergoing arthroplasty showed an estimated incidence of symptomatic VTE of 0.5%. CONCLUSION: Our study suggests that in patients with hemophilia, joint replacement surgery can be performed safely without routine pharmacologic VTE prophylaxis and without increasing risk of thromboembolic events. Pharmacologic VTE prophylaxis may be considered in select patients with known additional risk factors for VTE. PMID- 25434630 TI - No evidence for increased platelet activation in patients with hepatitis B- or C related cirrhosis and hepatocellular carcinoma. AB - INTRODUCTION: Cancer is a major risk factor for developing venous thromboembolism (VTE). Plasma hypercoagulability is an established risk factor for cancer-related VTE. In addition, thrombocytosis and hyperreactive platelets have been implicated in VTE and cancer progression. Cirrhosis is associated with changes in platelet number and function. The platelet activation status of patients with cirrhosis and hepatocellular carcinoma has not yet been established. Here we assessed the platelet activation status in patients with hepatitis-related cirrhosis in presence or absence of HCC. MATERIALS AND METHODS: We performed a cross-sectional study including thirty-eight consecutive patients with hepatitis B- or C- related liver cirrhosis in presence or absence of HCC. We studied basal and agonist induced platelet activation using flow cytometry. In addition, we studied the plasma levels of von Willebrand factor (VWF) and the VWF-cleaving protease ADAMTS13. Twenty healthy volunteers served as controls. RESULTS: We found no evidence of basal platelet activation in patients with cirrhosis compared to controls. However, we found reduced agonist-induced platelet activation in patients. No differences in the basal and agonist-induced platelets activation status between patients with or without HCC were detected. Plasma levels of VWF were increased and the levels of ADAMTS13 activity were decreased in patients compared to controls. No differences between the levels of VWF and ADAMTS13 in patients with or without HCC were detected. CONCLUSIONS: HCC development or recurrence in patients with hepatitis B- or C-related cirrhosis does not appear to be associated with platelet activation and changes in pivotal proteins in primary hemostasis. PMID- 25434631 TI - Diabetes is associated with increased risk of venous thromboembolism: a systematic review and meta-analysis. AB - AIMS: Increasing evidence suggests an association between diabetes and risk of venous thromboembolism (VTE); however, the results are inconsistent. We conducted a systematic review and meta-analysis of all epidemiological evidence to clarify association of diabetes with risk of VTE. METHODS: We searched MEDLINE and EMBASE to retrieve all relevant articles. Pooled effect estimates were calculated through a random-effects model. RESULTS: Sixteen articles involving 803,627,121 participants and 10,429,227 VTE patients were included. Pooled analysis of all evidence suggested that diabetes was associated with increased risk of VTE (HR, 1.35; 95%CI, 1.17-1.55; p=2.92*10(-5)), with evidence of small-study effect (p=0.024) and heterogeneity (I(2)=87.1%, p<0.001). However, when analysis was restricted to high quality cohort studies, the association remained significantly (HR, 1.36; 95%CI 1.11-1.68; p=0.004), with no evidence of publication bias (p=0.192) and heterogeneity (I(2)=23.2%, p=0.245). CONCLUSIONS: Diabetes is associated with increased risk of VTE, which may have implications for the primary and secondary prevention of VTE. PMID- 25434632 TI - MALDI imaging mass spectrometry of N-linked glycans on formalin-fixed paraffin embedded murine kidney. AB - Recent developments in spatial proteomics have paved the way for retrospective in situ mass spectrometry (MS) analyses of formalin-fixed paraffin-embedded clinical tissue samples. This type of analysis is commonly referred to as matrix-assisted laser desorption/ionization (MALDI) imaging. Recently, formalin-fixed paraffin embedded MALDI imaging analyses were augmented to allow in situ analyses of tissue-specific N-glycosylation profiles. In the present study, we outline an improved automated sample preparation method for N-glycan MALDI imaging, which uses in situ PNGase F-mediated release and measurement of N-linked glycans from sections of formalin-fixed murine kidney. The sum of the presented data indicated that N-glycans can be cleaved from proteins within formalin-fixed tissue and characterized using three strategies: (i) extraction and composition analysis through on-target MALDI MS and liquid chromatography coupled to electrospray ionization ion trap MS; (ii) MALDI profiling, where N-glycans are released and measured from large droplet arrays in situ; and (iii) MALDI imaging, which maps the tissue specificity of N-glycans at a higher resolution. Thus, we present a complete, straightforward method that combines MALDI imaging and characterization of tissue-specific N-glycans and complements existing strategies. PMID- 25434633 TI - Management of symptomatic ascites and post-operative lymphocysts with an easy-to use, patient-controlled, vascular catheter. AB - OBJECTIVE: Malignant ascites (MA) can be managed with paracentesis, diuretics, shunt-systems, chemotherapy, and targeted therapies. Some treatments are ineffective; others are associated with complications, involve inpatient procedures, or are not cost-effective. Postoperative lymphocysts (LCs) are managed with inpatient drainage and sclerotherapy or surgery. We tested the use of a vascular catheter in the management of symptomatic MA and LC. METHODS: Fifty five patients with primary or recurrent cancers with ascites or LCs were managed for symptom relief. A central venous 14-Ga 16-cm catheter (Arrow) was inserted into the abdominal cavity or LC, followed by drainage. RESULTS: The catheter was safely inserted with ultrasound guidance in 43 patients with MA (39 with ovarian cancer: 9 before primary cytoreduction, 30 with recurrence; 4 non-gynecological cancers), and 12 patients with LCs (10 retroperitoneal, 2 bilateral inguinal). All procedures were performed in the outpatient department under local anesthesia, without insertion-related complications. Within a mean of 30 days after catheter placement (range: 7-90 days), no grade 3 infection, peri-drain leakage, or self-removal was noted. In three patients with recurrent ovarian mucinous ascites and one patient with an inguinal LC, some drain obstruction was noted. In cases before primary cytoreduction for ovarian cancer, drainage enabled better nutritional and anesthiological outcomes. Patients with chronic ascites were able to self-monitor the amount of evacuated fluid. Twelve patients whose ascites were drained had chemotherapy at the time, and they reported better well being, and we estimated better performance status. LC drainage followed by sclerotherapy enabled symptom control and LC radical treatment. CONCLUSION: The use of the vascular catheter is safe, easy, and cost-effective in the management of symptomatic MA and LC. PMID- 25434634 TI - A critical appraisal of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced and recurrent ovarian cancer. AB - OBJECTIVE: Our objective was to review the published experiences of the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced and recurrent ovarian cancer with a focus on survival outcomes. METHODS: A search of the PubMed database (2008-2014) for articles specifically addressing the topic "HIPEC and ovarian cancer" was performed. We found a total of 22 publications that included 1450 patients. A final group of eleven studies (248 patients with advanced ovarian cancer) and eight publications (499 patients with recurrent sensitive ovarian cancer) that included information about survival were reviewed. RESULTS: Among patients with primary ovarian cancer who were treated with primary debulking and HIPEC, the weighted median overall survival was 37.3 months (range 27-78), the median disease-free survival was 14.4 months (range 12-30), and the 5 yr-survival rate was 40% (range 28-72). In the recurrent cohort, the overall survival after HIPEC was 36.5 months (range 23-62), and the median disease-free survival was 20.2 months (range 11-29). The rates of severe morbidity were 25 and 19% in the primary and recurrent groups, respectively. CONCLUSION: Although randomized trials are ongoing, the recently published retrospective data regarding the use of HIPEC for primary advanced and for recurrent ovarian cancer do not indicate any apparent advantage of this treatment in terms of the survival outcomes in these patients. Therefore, HIPEC cannot be considered a standard treatment and should not be offered outside of clinical trials. PMID- 25434635 TI - Progression-free survival by local investigator versus independent central review: comparative analysis of the AGO-OVAR16 Trial. AB - BACKGROUND: Analysis of progression-free survival (PFS) as the primary endpoint in advanced epithelial ovarian, fallopian tube, and primary peritoneal cancer (AEOC) trials may be confounded by the difficulty of radiologic evaluation of disease progression and the potential for discrepancy between investigator and blinded independent central assessments. PFS as assessed by local investigator (INV) was the primary endpoint of AGO-OVAR16, a randomized, double-blind trial of pazopanib maintenance therapy in AEOC. To confirm the robustness of the primary analysis, PFS was also evaluated by blinded independent central review (BICR). METHODS: Patients with histologically confirmed AEOC (N = 940) were randomized 1:1 to receive pazopanib 800 mg/day or placebo for up to 24 months. Tumor response in the intent-to-treat population was evaluated by CT/MRI every 6 months and analyzed per RECIST 1.0. RESULTS: Pazopanib prolonged PFS versus placebo by INV (median 17.9 vs 12.3 months; hazard ratio [HR] = 0.766, 95% confidence interval [CI]: 0.643-0.911; P = 0.0021). Results for PFS by BICR were similar (median 15.4 vs 11.8 months; HR = 0.802, 95% CI: 0.678-0.949; P = 0.0084). Progression events were recorded later by INV in 23% of pazopanib-treated patients and 17% of placebo-treated patients. The overall concordance between INV and BICR assessments was 84% and 86% in the pazopanib and placebo arms, respectively. CONCLUSIONS: By INV and BICR assessments, maintenance therapy with pazopanib in AEOC provided a significantly longer PFS than placebo. The good overall concordance between INV and BICR assessments, as well as HR and P value consistency, supports the reliability of investigator-assessed PFS as the primary endpoint in AGO-OVAR16. PMID- 25434636 TI - Invasion of uterine cervical squamous cell carcinoma cells is facilitated by locoregional interaction with cancer-associated fibroblasts via activating transforming growth factor-beta. AB - OBJECTIVE: Local invasion is a common pattern of spread in uterine cervical squamous cell carcinoma (CSCC). Although transforming growth factor-beta (TGF beta) facilitates invasion of various types of cancer cells, the role of the TGF beta pathway in CSCC is unclear. In this study, we analyzed the role of TGF-beta signaling in the progression of CSCC. METHODS: Immunohistochemistry was used to examine the expression of TGF-beta pathway molecules in 67 CSCC samples with clinicopathological data. Activation of the TGF-beta pathway was investigated following co-culture of CSCC cells and cervical cancer-associated fibroblasts (CCAFs). RESULTS: Clinicopathological analysis of CSCC samples revealed that prominent expression of TGF-beta receptor-2 was more frequent in CSCC with lymphovascular space invasion (LVSI) than without LVSI (p < 0.01). Lymph node metastasis was more frequent in cases in which phosphorylated SMAD3 (pSMAD3) was localized exclusively at the boundary of tumor clusters (n = 9, p < 0.05). Recombinant TGF-beta1 increased pSMAD3 expression and enhanced cellular invasion (p < 0.005) in CSCC cells, which was attenuated by an inhibitor of the TGF-beta receptor (p < 0.005). Enhanced pSMAD3 expression and invasion was also observed when conditioned media from CSCC cells co-cultured with CCAFs were administered. Luciferase assays showed that this medium contained a large amount of active TGF beta. Along with TGF-beta activation, thrombospondin-1 was upregulated in both CSCC cells and CCAFs, while thrombospondin-1 silencing in either CSCC cells or CCAFs repressed the activity of TGF-beta. Thrombospondin-1 was prominently expressed in cases with pSMAD3 boundary staining (p < 0.05). CONCLUSIONS: These results suggest that interaction between CSCC cells and surrounding CCAFs activates TGF-beta via thrombospondin-1 secretion to facilitate CSCC invasion. PMID- 25434637 TI - An investigation into the relationship between persistent pain, psychological distress and emotional connectedness. AB - Previous research into the social consequences of persistent pain has shown that relationship difficulties and marital distress are major factors that contribute to negative outcomes for sufferers. Furthermore, psychological distress is often co-morbid with persistent pain. This study explored the relationship between persistent pain, psychological distress and emotional connectedness. It involved a cross-sectional design utilising an online survey of 388 Australian women with persistent pain. Self-report measures of pain severity, psychological distress and emotional connectedness were administered. Results confirmed that many women in persistent pain experience relationship and emotional connectedness difficulties which they attribute to the experience of persistent pain. Additionally, psychological distress significantly mediated the relationship between pain severity and emotional connectedness. It was concluded that, in this sample of persistent pain sufferers, pain severity and psychological distress had significant impact on a women's ability to connect emotionally to those closest to them. The implications of these findings for intervening with women who suffer with persistent pain are discussed. PMID- 25434639 TI - Palladium-catalyzed oxidative cross-coupling of azole-4-carboxylates with indoles: an approach to the synthesis of pimprinine. AB - An efficient and straightforward method for the production of 5-(3-indolyl)azoles incorporating the privileged structures indoles and azoles via palladium catalyzed double C-H bond cleavage under mild conditions was disclosed. As expected, this protocol provided an easy method for the synthesis of indole alkaloids pimprinine and WS-30581 A in moderate yields. PMID- 25434638 TI - Chemokine receptor 7 promotes tumor migration and invasiveness via the RhoA/ROCK pathway in metastatic squamous cell carcinoma of the head and neck. AB - Metastatic squamous cell carcinoma of the head and neck (SCCHN) has been shown to express chemokine receptor 7 (CCR7), which can activate signaling pathways to promote invasion and survival of SCCHN cells. We hypothesized that the RhoA/Rho associated kinase (ROCK) pathway is involved in the CCR7-induced invasion and migration of metastatic SCCHN cells. Thus, using migration, matrigel invasion and scrape wound-healing assays, we elucidated the role of RhoA in mediating CCR7 associated cellular mobility. Pull-down assays and western blotting were used to measure RhoA and its downstream expression. Immunohistochemical staining and analysis were useful in identifying the correlation between CCR7 and RhoA expression and clinicopathological factors. The results showed that inhibition of RhoA/ROCK reduced the tumor cell migration and invasiveness induced by CCL19. Activated RhoA, proline-rich tyrosine kinase-2 (Pyk2) and cofilin induced by CCL19 were elevated, and increased RhoA, Pyk2 and cofilin activity was eliminated by CCR7mAb, RhoA/ROCK and Pyk2 inhibitors, indicating involvement of the RhoA/ROCK-Pyk2-cofilin cascade. In summary, CCR7 via RhoA/ROCK-Pyk2 cofilin pathway promotes invasion and migration of metastatic SCCHN cells. PMID- 25434640 TI - Effect of nanosize micelles of ionic and neutral surfactants on the photophysics of protonated 6-methoxyquinoline: time-resolved fluorescence study. AB - The excited state dynamic studies have been carried out to investigate the effects of micellar surface charge on the photophysics of protonated 6 methoxyquinoline (6MQ(+)) in anionic, sodium dodecylsulphate (SDS), cationic, cetyltrimethylammonium bromide (CTAB) and neutral, triton X-100 (TX100) surfactant at premicellar, micellar and postmicellar concentrations in aqueous phase at room temperature. At premicellar concentrations of SDS, there is a slight decrease in emission intensity and at micellar and postmicellar concentrations, increase in emission intensity and blue shift of spectrum has been observed. The blue shift in fluorescence spectrum and slight increase in quantum yield are attributed to incorporation of solute molecule to the micelles. Edge excitation red shift (EERS) in fluorescence maximum of 6MQ(+) has been observed in all the surfactant solutions studied. The EERS has been ascribed in terms of solvent relaxation process. In SDS surfactant system, due to heterogeneous restricted motion of solvent molecules, the solvent viscosity increases which results in an increase in net magnitude of EERS. The fluorescence decay components of 6MQ(+) fit with multi exponential functions in all the micellar systems studied. The location of the probe molecule in micellar systems is justified by a variety of spectral parameters such as refractive index, dielectric constant, ET (30), EERS, average fluorescence decay time, radiative and non radiative rate constants, and rotational relaxation time. PMID- 25434641 TI - Halochromism, ionochromism, solvatochromism and density functional study of a synthesized copper(II) complex containing hemilabile amide derivative ligand. AB - This study investigates chromotropism of newly synthesized 3,3'-(ethane-1,2 diylbis(benzylazanediyl))dipropanamide copper(II) perchlorate complex. The compound was structurally characterized by physico-chemical and spectroscopic methods. X-ray crystallography of the complex showed that the copper atom achieved a distorted square pyramidal environment through coordination of two amine N atoms and two O atoms of the amide moieties. The pH effect on the visible absorption spectrum of the complex was studied which functions as pH-induced "off on-off" switches through protonation and deprotonation of amide moieties along with the CuO to CuN bond rearrangement at room temperature. The complex was also observed to show solvatochromism and ionochromism. The distinct solution color changes mainly associated with hemilability of the amide groups. The solvatochromism of the complex was investigated with different solvent parameter models using stepwise multiple linear regression method. The results suggested that the basicity power of the solvent has a dominant contribution to the shift of the d-d absorption band of the complex. Density functional theory, DFT calculations were performed in order to study the electronic structure of the complex, the relative stabilities of the CuN/CuO isomers, and to understand the nature of the halochromism processes taking place. DFT computational results buttressed the experimental observations indicating that in the natural pH (5.8) the CuO isomer is more stable than its linkage isomer and conversely in alkaline aqueous solution. PMID- 25434642 TI - Zn2TiO4:Eu(3+) nanophosphor: self explosive route and its near UV excited photoluminescence properties for WLEDs. AB - A simple and low-cost solution combustion method was used to prepare Eu(3+) (1 11mol%) doped Zn2TiO4 nanophosphors at 500 degrees C using zinc nitrates as precursors and oxalyl di-hydrazide (ODH) as fuel. The final product was calcined at 1100 degrees C for 3h and then characterized by powder X-ray diffraction (PXRD), fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and UV-visible absorption (UV-Vis). The PXRD patterns of the sample calcined at 1100 degrees C show pure cubic phase. The crystallite size was estimated using Scherrer's method and found to be in the range 20-25nm and the same was confirmed by TEM studies. Effects of Eu(3+) (1-11mol%) cations on the luminescence properties of Zn2TiO4 nanoparticles were studied. The samples exhibit intense red emission upon 395nm near ultra violet (NUV) excitation. The characteristic emission peaks recorded at ~578, 592, 613 and 654nm may be attributed to the 4f-4f intra shell transitions ((5)D0->(7)Fj=0,1,2,3) of Eu(3+) cations. The CIE chromaticity co-ordinates and CCT were calculated from emission spectra and the values (x, y) were very close to NTSC standard values for red emission and CCT was close to Plankian locus. Therefore, the present phosphor may be highly useful for display applications. PMID- 25434643 TI - RiboFSM: frequent subgraph mining for the discovery of RNA structures and interactions. AB - Frequent subgraph mining is a useful method for extracting meaningful patterns from a set of graphs or a single large graph. Here, the graph represents all possible RNA structures and interactions. Patterns that are significantly more frequent in this graph over a random graph are extracted. We hypothesize that these patterns are most likely to represent biological mechanisms. The graph representation used is a directed dual graph, extended to handle intermolecular interactions. The graph is sampled for subgraphs, which are labeled using a canonical labeling method and counted. The resulting patterns are compared to those created from a randomized dataset and scored. The algorithm was applied to the mitochondrial genome of the kinetoplastid species Trypanosoma brucei, which has a unique RNA editing mechanism. The most significant patterns contain two stem-loops, indicative of gRNA, and represent interactions of these structures with target mRNA. PMID- 25434644 TI - Grey-scale and colour Doppler ultrasound versus magnetic resonance imaging for the prenatal diagnosis of placenta accreta. AB - OBJECTIVE: To assess the effectiveness of grey-scale and colour Doppler ultrasound (US) versus magnetic resonance imaging (MRI) for the prenatal diagnosis of placenta accreta. METHODS: A prospective observational study including a total of 74 patients with placenta previa and previous uterine scar (n = 74). Grey-scale and colour Doppler US was done followed by MRI by different observers to diagnose adherent placenta. Test validity of US and MRI were calculated. Maternal morbidity and mortality were also assessed. RESULTS: A total of 53 patients confirmed to have placenta accreta at operation. The overall sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of US was 94.34, 91.67, 96.15 and 88% compared to 96.08, 87.50, 94.23 and 91.3% for MRI, respectively. The most relevant US sign was turbulent blood flow by colour Doppler, while dark intra-placental band was the most sensitive MRI sign. Venous thromboembolism (1.3%), bladder injury (29.7%), ureteric injury (18.9%), postoperative fever (10.8%), admission to ICU (50%) and re-operation (31.1%). CONCLUSION: Placenta accreta can be successfully diagnosed by grey-scale and colour Doppler US. MRI would be more likely suggested for either posteriorly or laterally situated placenta previa in order to exclude placental invasion. PMID- 25434645 TI - Chlorhexidine - a novel intervention to decrease the nursery stay and antibiotic exposure duration - randomized trial. AB - OBJECTIVE: To study the effect of chlorhexidine (CHD) application on umbilical cord and evaluate its impact on duration of NICU stay and antibiotic exposure days. METHOD: We enrolled 140 newborns in our study (70 in intervention group and 70 in control group), and their data were collected. Newborns in control group were given routine umbilical cord care, and intervention group received CHD spray on umbilical cord three times a day and for the next three days of cord fall. In this study, swabs were sent from umbilical cord at the age of three and seven days of life for culture. Data regarding culture-proven sepsis, duration of NICU stay and antibiotic days were recorded in the proforma for data collection. RESULTS: This is a secondary analysis of the data of the randomized control trial. A significant reduction in duration of nursery stay was seen in CHD group in comparison with control group (12.4 +/- 5.38 d versus 14.7 +/- 6.62 d, p = 0.04, significant). Significant reduction was also seen in days of antibiotic exposure in the intervention group (9.74 +/- 6.88 d versus 12.1 +/- 7.78 d, p = 0.04, significant). CONCLUSION: Application of CHD to umbilical cord shortens duration of nursery stay and antibiotic days during nursery admission. This simple intervention may be used as mode in places where nursery facilities are limited, as aid in early discharge and shortening the exposure to antibiotic, which may help in reducing the prevalence of multidrug-resistance microbes. This cheap intervention may also be effective in reducing the economical burden on the health infrastructure of the country and parents. PMID- 25434646 TI - Small calcifying fibrous pseudotumor of the heart confined to the epicardium. AB - A calcifying fibrous pseudotumor (CFPT) is a rare benign lesion that often presents in the upper and lower extremities of children and young adults. In the present report, we describe a case of a small CFPT arising from the epicardium (visceral pericardium) in a 32-year-old woman. The tumor presented as a 25-mm polypoid mass protruding into the pericardial cavity, without extending into the myocardium. A complete resection was performed, and the patient has not experienced any relapse for more than 2 years. On histological examination, the lesion contained densely hyalinized collagen with psammomatous and dystrophic calcifications, as well as patchy chronic inflammatory infiltrate. The localization in the epicardium with no involvement of the myocardium was confirmed by the elastic stain. Amyloid was negative by the Congo red stain. On immunohistochemical analysis, the lesional cells indicated diffuse positive staining for vimentin and factor XIIIa and focal positive staining for CD34, but did not indicate positive staining for other pertinent antigens such as cytokeratins, calretinin, desmin, alpha-smooth muscle actin, ALK, and estrogen and progesterone receptors as well as IgG4 in plasma cells. To our knowledge, only three cases of CFPT in the heart have been reported in the literature, all of which developed in young females as a large mass involving the epicardium; the lesion also extended to the parietal pericardium in two cases. Moreover, all cases presented with few symptoms, despite the large lesion. In the present case, the CFPT developed also in a young woman, but the lesion was much smaller than those previously published and was localized in the visceral serous membrane of the heart. The findings of this case suggest a potential preferable site of origin of CFPTs of the heart. PMID- 25434647 TI - Chest wall hypoplasia--principles and treatment. AB - The chest is a dynamic structure. For normal movement it relies on a coordinated movement of the multiple bones, joints and muscles of the respiratory system. While muscle weakness can have clear impact on respiration by decreasing respiratory motion, so can conditions that cause chest wall hypoplasia and produce an immobile chest wall. These conditions, such as Jarcho-Levin and Jeune syndrome, present significantly different challenges than those faced with early onset scoliosis in which chest wall mechanics and thoracic volume may be much closer to normal. Because of this difference more aggressive approaches to clinical and surgical management are necessary. PMID- 25434648 TI - Scoliosis and the impact in neuromuscular disease. AB - Scoliosis can alter respiratory mechanics by changing the orientation of the muscles and joints of the respiratory system and in severe forms can put a patient at risk of severe respiratory morbidity or respiratory failure. However, perhaps the most important factor in determining the pulmonary morbidity in scoliosis is the balance between the "load" or altered respiratory mechanics and the "pump" or the respiratory muscle strength. Therefore, scoliosis in patients with neuromuscular disease will both lead to increased "load" and a weakened "pump", an exceptionally unfortunate combination. While progressive neuromuscular disease by its nature does not respond favorably to attempts to improve respiratory muscle strength, the natural approach of early proactive management of the "load" and in the case of scoliosis a variety of different strategies have been tried with variable short term and long term results. Figuring this out requires both an understanding of the underlying pathophysiology of a particular neuromuscular condition and the available options for and timing of surgical intervention. PMID- 25434649 TI - Oligodendrocyte ablation triggers central pain independently of innate or adaptive immune responses in mice. AB - Mechanisms underlying central neuropathic pain are poorly understood. Although glial dysfunction has been functionally linked with neuropathic pain, very little is known about modulation of pain by oligodendrocytes. Here we report that genetic ablation of oligodendrocytes rapidly triggers a pattern of sensory changes that closely resemble central neuropathic pain, which are manifest before overt demyelination. Primary oligodendrocyte loss is not associated with autoreactive T- and B-cell infiltration in the spinal cord and neither activation of microglia nor reactive astrogliosis contribute functionally to central pain evoked by ablation of oligodendrocytes. Instead, light and electron microscopic analyses reveal axonal pathology in the spinal dorsal horn and spinothalamic tract concurrent with the induction and maintenance of nociceptive hypersensitivity. These data reveal a role for oligodendrocytes in modulating pain and suggest that perturbation of oligodendrocyte functions that maintain axonal integrity can lead to central neuropathic pain independent of immune contributions. PMID- 25434652 TI - Managing CAP patients at risk of clinical failure. AB - Community-acquired pneumonia (CAP) is a curable disease. Both the European and American clinical practice guidelines provide algorithms how to manage patients with CAP. However, as populations worldwide are ageing and bacteria are becoming multidrug resistant, it is necessary to address the major factors that put patients at risk of poor outcome. These may include age, comorbidities, the settings where pneumonia was acquired or treated, the need for hospitalisation or ICU admission, likely causative pathogen (bacteria or virus) in a certain region and their local susceptibility pattern. One complicating fact is the lack of definite causative pathogen in approximately 50% of patients making it difficult to choose the most appropriate antibiotic treatment. When risk factors are present simultaneously in patients, fewer treatment options could be rather challenging for physicians. For example, the presence of comorbidities (renal, cardiac, hepatic) may exclude certain antibiotics due to potential adverse events. Assessing the severity of the disease and monitoring biomarkers, however, could help physicians to estimate patient prognosis once diagnosis is confirmed and treatment has been initiated. This review article addresses the most important risk factors of poor outcome in CAP patients. PMID- 25434650 TI - ERAP1 in the pathogenesis of ankylosing spondylitis. AB - The endoplasmic reticulum aminopeptidase 1 (ERAP1) performs a major role in antigen processing, trimming N-terminally extended peptides to the final epitope for presentation by major histocompatibility complex class I molecules. Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) within ERAP1 as being associated with disease, in particular ankylosing spondylitis (AS). AS is a polygenic chronic inflammatory disease with a strong genetic link to HLA-B27 known for over 40 years. The association of ERAP1 SNPs with AS susceptibility is only observed in HLA-B27-positive individuals, which intersect on the antigen processing pathway. Recent evidence examining the trimming activity of polymorphic ERAP1 highlights its role in generating peptides for loading onto and stabilizing HLA-B27, and the consequent alterations in the interaction of specific NK cell receptors, and the activation of the unfolded protein response as important in the mechanism of disease pathogenesis. Here, we discuss the recent genetic association findings linking ERAP1 SNPs with AS disease susceptibility and the effect of these variants on ERAP1 function, highlighting mechanisms by which AS may arise. The identification of these functional variants of ERAP1 may lead to better stratification of AS patients by providing a diagnostic tool and a potential therapeutic target. PMID- 25434651 TI - Decreased delta sleep ratio and elevated alpha power predict vulnerability to depression during interferon-alpha treatment. AB - OBJECTIVE: Although poor sleep accompanies depression, it is unknown which specific sleep abnormalities precede depression. This is similarly the case for depression developing during interferon-alpha (IFN-alpha) therapy. Because vulnerability becomes evident in those who slept poorly before IFN-alpha, we prospectively determined which specific aspect of sleep could predict subsequent depression. METHODS: Two nights of polysomnography with quantitative electroencephalogram (EEG) were obtained in 24 adult, euthymic subjects--all subsequently treated with IFN-alpha for hepatitis C. Every 2 weeks, a Beck Depression Inventory-II (BDI-II) score was obtained, and the maximal increase in BDI-II from pre-treatment baseline--excluding the sleep question--was determined. RESULTS: The delta sleep ratio (DSR; an index of early-night restorative delta power) was inversely associated with BDI-II increases (p<0.01), as was elevated alpha power (8-12 Hz; p<0.001). Both delta (0.5-4 Hz) and alpha power exhibited high between-night correlations (r=0.83 and 0.92, respectively). In mixed-effect repeated-measure analyses, there was an interaction between alpha power and DSR (p<0.001)--subjects with low alpha power and elevated DSR were resilient to developing depression. Most other sleep parameters--including total sleep time and percentage of time in slow wave sleep--were not associated with subsequent changes in depression. CONCLUSIONS: Both high DSR and low alpha power may be specific indices of resilience. As most other aspects of sleep were not associated with resilience or vulnerability, sleep interventions to prevent depression may need to specifically target these specific sleep parameters. PMID- 25434653 TI - The relationship between chronic obstructive pulmonary disease and comorbidities: a cross-sectional study using data from KNHANES 2010-2012. AB - BACKGROUND: Multiple comorbidities related to chronic obstructive pulmonary disease (COPD) make it a difficult disease to treat. The relationship between these comorbidities and COPD has not been fully investigated. We aimed to determine whether COPD was independently associated with various comorbidities. METHODS: This was a cross-sectional study, which used data from the Korean National Health and Nutrition Examination Survey (KNHANES) V conducted between 2010 and 2012. Survey design analysis was employed to determine the association between COPD and 15 comorbidities. A COPD patient was defined as a smoker with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 0.7 and comorbidities were defined based on objective laboratory findings and questionnaires. RESULTS: Of a total of 9488 patient who underwent spirometry, 744 (7.84%) COPD cases and 3313 non-COPD controls were included in the analyses. Although the prevalence rates of the majority of the comorbidities were high among the COPD patients, only hypertension (adjusted odds ratio [aOR], 1.63; 95% CI, 1.13-2.33 in Stage 1 COPD group; aOR, 1.92; 95% CI, 1.36-2.72 in Stage 2-4 COPD group) and a history of pulmonary tuberculosis (aOR, 3.38; 95% CI, 1.90-5.99 in Stage 2-4 COPD group) were independently associated with COPD after adjustment for age, smoking status, and confounders. CONCLUSIONS: Only hypertension and a history of pulmonary tuberculosis were independently associated with COPD after adjustment for confounders among 15 comorbidities. The results suggest that majority of COPD patients might have similar risk factors with its comorbidities, including age and smoking status. PMID- 25434654 TI - EUS-guided tissue acquisition: an evidence-based approach (with videos). PMID- 25434655 TI - Recently highlighted non-neoplastic pathologic entities of the upper GI tract and their clinical significance. PMID- 25434656 TI - Turn, Turn, Turn-it's time to turn over the reins at GIE. PMID- 25434657 TI - FISH then grill? Using biomarkers to predict response to ablation. PMID- 25434659 TI - RFA: THE treatment option in esophageal squamous cell carcinoma? PMID- 25434660 TI - Prediction of colorectal polyp pathologic lesions with image-enhanced endoscopy: What will it take to make it matter? PMID- 25434661 TI - Nonsteroidal anti-inflammatory and antiplatelet drugs and risk of GI bleeding: don't forget the colon. PMID- 25434658 TI - Is it justified to ablate flat-type esophageal squamous cancer? An analysis of endoscopic submucosal dissection specimens of lesions meeting the selection criteria of radiofrequency studies. AB - BACKGROUND: Endoscopic radiofrequency ablation (RFA) appears to be a safe and effective treatment for flat-type noninvasive squamous neoplasia of the esophagus. However, if RFA is applied to lesions containing invasive cancer (esophageal squamous cell carcinoma [ESCC]), histological features associated with lymph node metastases may remain undetected. In addition, extension of neoplasia down the ducts of esophageal submucosal glands (SMGs) may create a sheltered "niche" beyond the reach of ablation. OBJECTIVE: To determine the RFA eligibility of flat-type ESCC. DESIGN: Retrospective analysis of prospectively collected data of ESCC patients. SETTING: National Cancer Center Hospital, Tokyo, Japan. PATIENTS: Patients with flat-type ESCC larger than 3 cm removed by endoscopic submucosal dissection (ESD). INTERVENTIONS: Three endoscopists involved in RFA studies in China reviewed endoscopic images to select lesions eligible for RFA. Corresponding ESD resection specimens were histologically examined. MAIN OUTCOME MEASUREMENTS: The presence of poor histological features (ie, invasion in m3 or deeper, poor tumor differentiation, or lymphovascular invasion) and the number of involved esophageal SMGs and ducts. RESULTS: Sixty five lesions were included, 17 (26%) of which qualified as RFA eligible by RFA endoscopists. Interobserver agreement for this assessment was poor (kappa = 0.09). Six of the 17 specimens (35%) showed relevant disease: 4 lesions invaded in the muscularis mucosae, 1 of which also showed lymphovascular invasion; 2 lesions showed extension of neoplasia into SMGs. LIMITATIONS: Limited number of cases. RFA eligibility status was based on analysis of still images. CONCLUSIONS: One third of flat-type ESCC, deemed eligible for RFA, demonstrated histological features that are considered (relative) contraindications to endoscopic treatment. Because it appears difficult for endoscopists to identify low-risk ESCC, conservative use of RFA for flat-type ESCC is advocated until long-term follow-up data are available. PMID- 25434662 TI - Impact of the relative value unit-based system on academic centers. PMID- 25434663 TI - Establishing a clinical and molecular diagnosis for hereditary colorectal cancer syndromes: Present tense, future perfect? PMID- 25434664 TI - Chronic vomiting from esophageal stenosis due to a congenital, ectopic, tracheobronchial ring within the esophagus: endoscopic and endoscopic ultrasound findings. PMID- 25434665 TI - Simultaneous dual-endoscope rendezvous procedure for complete esophageal stricture. PMID- 25434666 TI - Intraductal papillary mucinous neoplasm causing recurrent acute pancreatitis, necrotizing pancreatitis, and multifocal adenocarcinoma. PMID- 25434667 TI - Submucosal fecalith in the ileocecal valve. PMID- 25434668 TI - Not all of Barrett's esophagus surveillance protocols are created equal: the dangers of retrospective outcome research in the treatment of Barrett's esophagus. PMID- 25434669 TI - Darkest before dawn: esophageal melanocytosis mimicking primary esophageal melanoma. PMID- 25434670 TI - Endoscopic repair of gastric perforation with an over-the-scope clip after endoscopic mucosal resection. PMID- 25434671 TI - Control of the treatment device for endoscopy by the left hand: two-fingers method. PMID- 25434672 TI - Retrograde transpyloric hemostatic powder intervention of a concealed prepyloric antral ulcer. PMID- 25434673 TI - Control of tip deflection by right pinkie shaft grip: right pinkie maneuver. PMID- 25434675 TI - Reversible catalysis for the reaction between methyl orange and NaBH4 by silver nanoparticles. AB - The reaction between MO and NaBH4 catalyzed by Ag NPs has been studied. Ag NPs catalyzed the reduction of MO rapidly, while adding CTAB into the solution caused the regeneration of MO. Thus, reversible catalysis for the reaction between MO and NaBH4 by Ag NPs was discovered for the first time. PMID- 25434674 TI - Identification of suitable reference genes for investigating gene expression in human gallbladder carcinoma using reverse transcription quantitative polymerase chain reaction. AB - Reverse transcription quantitative polymerase chain reaction (RT-qPCR) has become a frequently used strategy in gene expression studies. The relative quantification method is an important and commonly used method for the evaluation of RT-qPCR data. The key aim of this method is to identify an applicable internal reference gene, however, there are currently no suitable reference genes for gene analysis in gallbladder carcinoma. In the present study, screening was performed using 12 common reference genes, which were selected in order to provide an experimental basis for the investigation of gene expression in gallbladder carcinoma. A total of 16 tissue samples of gallbladder carcinoma and their matched normal gallbladder tissues were used. The gene expression stability and applicability of the 12 reference gene candidates were determined using the geNorm, NormFinder and BestKeeper software programs. Following comparison of the results of the three software programs, HPRT1 was identified as the most stably expressed reference gene. In the normal gallbladder group, the relative stably expressed reference gene was PPIA and in the entire sample group, the relatively stably expressed reference gene was PPIA. The present study also demonstrated that the combination of the three reference genes was the most appropriate. The recommended combinations were PPIA + PUM1 + ACTB for the total sample group, GAPDH + PBGD + ALAS1 for the gallbladder carcinoma group and PPIA + PUM1 + TBP for the paired normal gallbladder group. PMID- 25434676 TI - Surface protein imprinted core-shell particles for high selective lysozyme recognition prepared by reversible addition-fragmentation chain transfer strategy. AB - A novel kind of lysozyme (Lys) surface imprinted core-shell particles was synthesized by reversible addition-fragmentation chain transfer (RAFT) strategy. With controllable polymer shell chain length, such particles showed obviously improved selectivity for protein recognition. After the RAFT initial agent and template protein was absorbed on silica particles, the prepolymerization solution, with methacrylic acid and 2-hydroxyethyl methacrylate as the monomers, and N,N'-methylenebis(acrylamide) as the cross-linker, was mixed with the silica particles, and the polymerization was performed at 40 degrees C in aqueous phase through the oxidation-reduction initiation. Ater polymerization, with the template protein removal and destroying dithioester groups with hexylamine, the surface Lyz imprinted particles were obtained with controllable polymer chain length. The binding capacity of the Lys imprinted particles could reach 5.6 mg protein/g material, with the imprinting factor (IF) as 3.7, whereas the IF of the control material prepared without RAFT strategy was only 1.6. The absorption equilibrium could be achieved within 60 min. Moreover, Lys could be selectively recognized by the imprinted particles from both a four-proteins mixture and egg white sample. All these results demonstrated that these particles prepared by RAFT strategy are promising to achieve the protein recognition with high selectivity. PMID- 25434677 TI - Amino acid derived CuII compounds as catalysts for asymmetric oxidative coupling of 2-naphthol. AB - We report the synthesis and characterization of several novel aminopyridine - L amino acid derived Cu(II)-complexes. The ligands are prepared by a one-pot reductive alkylation of the L-amino acid scaffold and the respective aminopyridine Cu(II)-complexes were obtained by reaction with CuCl2 or Cu(acetato)2. All compounds were characterized by spectroscopic techniques, as well as ESI-MS. Two of the Cu(II)-complexes were characterized by single-crystal X-ray diffraction, one of them, [Cu(II)(L)(CH3COO)] (HL = (S)-3-phenyl-2-(pyridin 2-ylmethylamino)propanoic acid), being the first ever reported aminopyridine class Cu(II) complex bearing a tridentate N,N,O donor set and a monodentate acetato ligand. The complexes are tested as catalysts in the oxidative coupling of 2-naphthol in organic solvent-water mixtures using dioxygen as the terminal oxidant. The effect of variables such as ligand denticity and substituents, as well as solvent, temperature and oxidant intake, on the overall performance is studied. In general, moderate to low conversions of 2-naphthol to 1,1'-bi-2 naphthol (BINOL) are obtained. The catalysts also showed moderate to low enantioselectivity. Some aspects of the reaction mechanism were elucidated by spectroscopy, electrochemical and theoretical studies. It was found that basic additives are important for activity, but these also increase the formation of secondary oxidation products. The addition of peroxide scavengers such as KI resulted in an increase of conversion, the yield of BINOL and enantioselectivity. PMID- 25434678 TI - Transition from linear- to nonlinear-focusing regime in filamentation. AB - Laser filamentation in gases is often carried out in the laboratory with focusing optics to better stabilize the filament, whereas real-world applications of filaments frequently involve collimated or near-collimated beams. It is well documented that geometrical focusing can alter the properties of laser filaments and, consequently, a transition between a collimated and a strongly focused filament is expected. Nevertheless, this transition point has not been identified. Here, we propose an analytical method to determine the transition, and show that it corresponds to an actual shift in the balance of physical mechanisms governing filamentation. In high-NA conditions, filamentation is primarily governed by geometrical focusing and plasma effects, while the Kerr nonlinearity plays a more significant role as NA decreases. We find the transition between the two regimes to be relatively insensitive to the intrinsic laser parameters, and our analysis agrees well with a wide range of parameters found in published literature. PMID- 25434679 TI - Piloting a computer assisted telephone interview: the FUCHSIA Women's Study. AB - BACKGROUND: Loss of fertility has been reported as an important concern of reproductive age women diagnosed with cancer. The Furthering Understanding of Cancer, Health, and Survivorship In Adult (FUCHSIA) Women's Study examines how cancer treatment affects the fertility of cancer survivors who were diagnosed during their reproductive years. In this paper we discuss the process of developing and pilot testing the FUCHSIA computer assisted telephone interview (CATI). METHODS: The CATI was developed in several phases and pilot tested twice to evaluate several aspects of the instrument including question sequencing, understandability of the questions, and women's comfort with certain questions. Participants were recruited from cancer and infertility support groups and study team contacts. RESULTS: Fifty-two women were recruited and participated in the first pilot. The participants had a mean age of 31.5 years, 17.3% had cancer, and 38.5% experienced a period of infertility. Twenty-four women participated in the second pilot with similar representation. CONCLUSIONS: The collection of detailed information on reproductive outcomes with the CATI may improve the understanding of how cancer treatment during the reproductive years affects female fertility. The pilot studies provided important information to improve the CATI before the full study. Our comprehensive recruitment strategy allowed us to interview a diverse group of women to ensure that questions and answer choices were easily interpreted, check complicated skip patterns and the flow of questions, and evaluate the length of the interview. This experience can be used to help inform others in what steps can be useful for developing telephone interviews for research studies. PMID- 25434680 TI - Immunity genes and susceptibility to otitis media: a comprehensive review. AB - Otitis media (OM) is a middle ear infection associated with inflammation and pain. This disease frequently afflicts humans and is the major cause of hearing loss worldwide. OM continues to be one of the most challenging diseases in the medical field due to its diverse host targets and wide range of clinical manifestations. Substantial morbidity associated with OM is further exacerbated by high frequency of recurrent infections leading to chronic suppurative otitis media (CSOM). Children have greater susceptibility to, and thus, suffer most frequently from OM, which can cause significant deterioration in quality of life. Genetic factors have been demonstrated, in large part by twin and family studies, to be key determinants of OM susceptibility. In this review, we summarize the current knowledge on immunity genes and selected variants that have been associated with predisposition to OM. In particular, polymorphisms in innate immunity and cytokine genes have been strongly linked with the risk of developing OM. Future studies employing state-of-the-art technologies, including next generation sequencing (NGS), will aid in the identification of novel genes associated with susceptibility to OM. This, in turn, will open up avenues for identifying high-risk individuals and designing novel therapeutic strategies based on precise targeting of these genes. PMID- 25434681 TI - Induction of clusterin expression by neuronal cell death in Zebrafish. AB - Clusterin, a protein associated with multiple functions, is expressed in a wide variety of mammalian tissues. Although clusterin is known to be involved in neurodegenerative diseases, ageing, and tumorigenesis, a detailed analysis of the consequences of gain- or loss-of-function approaches has yet to be performed to understand the underlying mechanisms of clusterin functions. Since clusterin levels change in neurological diseases, it is likely that clusterin contributes to cell death and degeneration in general. Zebrafish was investigated as a model system to study human diseases. During development, zebrafish clusterin was expressed in the notochord and nervous system. Embryonic overexpression of clusterin by mRNA microinjection did not affect axis formation, whereas its knock down by anti-sense morpholino treatment resulted in neuronal cell death. To analyze the function of clusterin in neurodegeneration, a transgenic zebrafish was investigated, in which nitroreductase expression is regulated under the control of a neuron-specific huC promoter which is active between the stages of early neuronal precursors and mature neurons. Nitroreductase turns metronidazole into a cytotoxic agent that induces cell death within 12 h. After metronidazole treatment, transgenic zebrafish showed neuron-specific cell death. Interestingly, we also observed a dramatic induction of clusterin expression in the brain and spinal cord in these fish, suggesting a direct or indirect role of clusterin in neuronal cell death and thus, more generally, in neurodegeneration. PMID- 25434682 TI - Molecular cytogenetic characterization and stem rust resistance of five wheat Thinopyrum ponticum partial amphiploids. AB - Partial amphiploids created by crossing common wheat (Triticum aestivum L.) and Thinopyrum ponticum (Podp.) Barkworth & D. R. Dewey are important intermediates in wheat breeding because of their resistance to major wheat diseases. In this study, we examined the chromosome compositions of five Xiaoyan-series wheat-Th. ponticum partial amphiploids (Xiaoyan 68, Xiaoyan 693, Xiaoyan 784, Xiaoyan 7430, and Xiaoyan 7631) using GISH, multicolor-GISH, and multicolor-FISH. We found several chromosome changes in these lines. For example, wheat chromosomes 1B and 2B were added in Xiaoyan 68 and Xiaoyan 7430, respectively, while wheat chromosome 6B was eliminated from Xiaoyan 693 and Xiaoyan 7631. Chromosome rearrangements were also detected in these amphiploids, including an interspecific translocation involving chromosome 4D and some intergenomic translocations, such as A-B and A-D translocations, among wheat genomes. Analysis of the Th. ponticum chromosomes in the amphiploids showed that some lines shared the same alien chromosomes. We also evaluated these partial amphiploids for resistance to nine races of stem rust, including TTKSK (commonly known as Ug99). Three lines, Xiaoyan 68, Xiaoyan 784, and Xiaoyan 7430, exhibited excellent resistance to all nine races, and could therefore be valuable sources of stem rust resistance in wheat breeding. PMID- 25434683 TI - Concurrent deficiency of gibberellins and abscisic acid causes plant male sterility. PMID- 25434685 TI - Natural variation in the sequence of SNAC1 and its expression level polymorphism in rice Germplasms under drought stress. PMID- 25434684 TI - The Strigolactone-related mutants have enhanced lamina joint inclination phenotype at the seedling stage. PMID- 25434687 TI - High-level expression and characterization of a thermostable xylanase mutant from Trichoderma reesei in Pichia pastoris. AB - A gene encoding xylanase 2 mutant from Trichoderma reesei (T2C/T28C, named mxyn2) was cloned into the Pichia pastoris X33 strain using the vector pPICZalphaA. Recombinant Mxyn2p was functionally expressed in P. pastoris X33 and secreted into the supernatant. Real time qPCR demonstrated that an increase in gene copy number correlated with higher levels of expression. Supernatant from methanol induced cells was concentrated by ultrafiltration with a 10kDa cut off membrane, and purified with ion exchange chromatography using SP Sepharose Fast Flow chromatography. Recombinant Mxyn2p protein had the highest activity at 75 degrees C, while recombinant protein encoded by the "wild type" xylanase gene xyn2, also expressed in Pichia, was 20 degrees C lower. The Mxyn2p enzyme retained more than 70% of its activity after incubation at 80 degrees C for 10min. The effects of the optimal pH and temperature for higher expression levels in P. pastoris were also determined, 6.0 and 22 degrees C, respectively. The maximum xylanase activity of Mxyn2p was 13,000nkat/mg (9.88g/l) in fed-batch cultivation after 168h induction with methanol in a 50l bioreactor. PMID- 25434686 TI - A prenyltransferase gene confirmed to be a carotenogenic CRTE gene from sweetpotato. PMID- 25434688 TI - The evolution of our understanding of macrophages and translation of findings toward the clinic. AB - 'There is at bottom only one genuinely scientific treatment for all diseases, and that is to stimulate the phagocytes,' so declaimed Sir Ralph Bloomfield Bonington in The Doctor's Dilemma, Act 1, by George Bernard Shaw (1906). More often nowadays, the need is to calm the phagocytes, given their role in inflammation and tissue damage. In spite of the growth of cellular and molecular information gained from studies in macrophage cell culture, mouse models and, to a lesser extent, human investigations, and the importance of macrophages in pathogenesis in a wide range of chronic disease processes, there is still a substantial shortfall in terms of clinical applications. In this review, we summarize concepts derived from macrophage studies and suggest possible properties suitable for diagnosis, prognosis and selective targeting of macrophage pathogenic functions. PMID- 25434689 TI - Developing a national framework for safe drinking water--case study from Iceland. AB - Safe drinking water is one of the fundaments of society and experience has shown that a holistic national framework is needed for its effective provision. A national framework should include legal requirements on water protection, surveillance on drinking water quality and performance of the water supply system, and systematic preventive management. Iceland has implemented these requirements into legislation. This case study analyzes the success and challenges encountered in implementing the legislation and provide recommendations on the main shortcomings identified through the Icelandic experience. The results of the analysis show that the national framework for safe drinking water is mostly in place in Iceland. The shortcomings include the need for both improved guidance and control by the central government; and for improved surveillance of the water supply system and implementation of the water safety plan by the Local Competent Authorities. Communication to the public and between stakeholders is also insufficient. There is also a deficiency in the national framework regarding small water supply systems that needs to be addressed. Other elements are largely in place or on track. Most of the lessons learned are transferable to other European countries where the legal system around water safety is built on a common foundation from EU directives. The lessons can also provide valuable insights into how to develop a national framework elsewhere. PMID- 25434690 TI - Observation of a reversible isomorphous phase transition and an interplay of "sigma-holes" and "pi-holes" in Fmoc-Leu-psi[CH2-NCS]. AB - Fmoc-Leu-psi[CH2NCS] undergoes a reversible isomorphous phase transition upon cooling. The crystal structure at 100 K displays a short N=C=S...N=C=S intermolecular interaction, which has been characterized based on experimental charge density analysis, as a stabilizing interaction with both sigma-holes and pi-holes acting cooperatively. PMID- 25434691 TI - Prevalence and factors associated with childhood overweight/obesity of private school children in Nepal. AB - INTRODUCTION: Childhood overweight/obesity is a global health problem because of adverse health and nutrition consequences worldwide. Currently, there is a paucity of information on childhood overweight/obesity in Nepal. Therefore, the objective of this study was to assess the prevalence of, and the factors associated with, childhood overweight/obesity among primary school children. METHODS: A cross-sectional study was conducted in June-December, 2013. We collected data using the structured self-administered questionnaire with parents of children aged 6-13 years in grades 1-6 studying at private schools of the Lalitpur district of Nepal. Height and weight measurements of 986 children were taken, and the corresponding body mass index (BMI)-for-age was calculated. The prevalence of childhood overweight/obesity was reported in proportion. Factors associated with childhood overweight/obesity were examined using the Chi-square tests followed by multiple logistic regression analyses. RESULTS: Of 986 children, 144 (14.6%) were overweight and 111 (11.3%) were obese. Overall, 255 (25.9%) children were found to be overweight/obese. Children from families, having <=2 siblings (adjusted odds ratio (aOR)=1.958, 95% confidence interval (CI): 1.163-3.296), upper class family (aOR=3.672; 95% CI: 1.154-11.690), and advantaged ethnic group (aOR=1.561; 95% CI: 1.00-2.437) and children who were of larger birth weight (>4.0kg) had a greater likelihood of being (aOR=2.557, 95% CI: 1.222-5.349) overweight/obese. CONCLUSIONS: A quarter of children were found to be overweight/obese in private primary schools. Preventive interventions should focus on the advantaged ethnic groups, families with fewer siblings, and upper class families. A greater emphasis ought to be placed on formulation and implementation of policies aimed at addressing the newly emerging problems of childhood overweight/obesity in Nepal. New school health programs are to be launched and strengthened including avoidance of high energy junk food, and promoting outdoor activities. PMID- 25434692 TI - Retrospective analysis of nuclear protein in testis (NUT) midline carcinoma in the upper aerodigestive tract and mediastinum. AB - OBJECTIVE: Nuclear protein in testis (NUT) midline carcinoma (NMC) is a very aggressive tumor with limited survival, recently recognized as a subset of poorly differentiated squamous cell carcinoma. A simple chromosomal translocation results in NUT overexpression and malignant transformation. This study used immunohistochemistry to retrospectively diagnose and characterize NMC cases. STUDY DESIGN: Immunoperoxidase staining was performed according to a standard protocol and interpreted independently by two pathologists. Scores were based on nuclear staining with monoclonal NUT antibody (C52B1) in the tumor cells. RESULTS: Fifty-one poorly differentiated carcinoma cases with material available for testing were retrieved. Average patient age was 54.9 years (range: 16-82), with 20 women and 31 men. A single NMC case (2%) was retrospectively diagnosed in a 26-year-old man with a left maxillary sinus/nasal cavity tumor; he died of his disease 18 months after presentation, despite treatment. CONCLUSIONS: These results support inclusion of NUT antibody in diagnostic immunohistochemical panels for poorly differentiated carcinomas of the upper aerodigestive tract. PMID- 25434693 TI - Ameloblastic carcinoma with features of ghost cell odontogenic carcinoma in a patient with suspected Gardner syndrome. AB - Ameloblastic carcinoma and ghost cell odontogenic carcinoma are rare malignancies arising in odontogenic epithelium within the jaws. Gardner syndrome is a multifaceted autosomal dominant condition, which results in multiple dentofacial anomalies along with premalignant colon polyp formation and tumor formation in the skin and other organs. We report a case of ameloblastic carcinoma with features of ghost cell odontogenic carcinoma and extensive clear cell change and melanin pigmentation in a patient with clinical features of Gardner syndrome. To the best of our knowledge, odontogenic carcinoma arising in a patient with features of Gardner syndrome has not been reported previously. The clinical, radiographic, and histologic features of the case are discussed along with a review of the relevant literature. PMID- 25434694 TI - A new stent with streamlined cross-section can suppress monocyte cell adhesion in the flow disturbance zones of the endovascular stent. AB - We proposed a new stent with streamlined cross-sectional wires, which is different from the clinical coronary stents with square or round cross-sections. We believe the new stent might have better hemodynamic performance than the clinical metal stents. To test the hypothesis, we designed an experimental study to compare the performance of the new stent with the clinical stents in terms of monocyte (U-937 cells) adhesion. The results showed that when compared with the clinical stents, the adhesion of U-937 cells were much less in the new stent. The results also showed that, when Reynolds number increased from 180 (the rest condition for the coronary arteries) to 360 (the strenuous exercise condition for the coronary arteries), the flow disturbance zones in the clinical stents became larger, while they became smaller with the new stent. The present experimental study therefore suggests that the optimization of the cross-sectional shape of stent wires ought to be taken into consideration in the design of endovascular stents. PMID- 25434696 TI - How do we understand the disagreement in the frequency of surgical site infection between the CDC and Clavien-Dindo classifications? AB - To clarify the discrepancy in the incidence and severity of surgical site infections (SSI) for radical cystectomy between reports based on the CDC guideline and those using the Clavien-Dindo classification we evaluated 449 consecutive patients who underwent radical cystectomy for bladder cancer between 1990 and 2012. Of the 115 (25.6%) patients with SSI defined by the CDC guideline, 89 could be analyzed. We compared the SSI rates and severity defined by the CDC guideline and Clavien-Dindo classifications. There were 58 patients with superficial SSI, 16 with deep SSI, and 15 with organ/space SSI according to the CDC guideline. All patients with organ/space SSI were judged as "not having SSI" by the Clavien-Dindo classification. They were classified as having "intestinal prolapse", "intestinal fistula", "abdominal abscess" and "pelvic abscess." There was a significant association between the treatment duration and depth of SSI based on the CDC guideline by Spearman's rank-correlation coefficient (p < 0.001, r = 0.614) and with the grade of complications (p < 0.001, r = 0.632) in the Clavien-Dindo classification. Multivariate analysis showed that patients with grade III SSI in the Clavien-Dindo classification needed a significantly longer treatment duration. It is necessary to be aware that a discrepancy can occur automatically due to the different natures of the definitions. Using the CDC guideline, we can effectively estimate the future treatment period when SSI occurs. With the Clavien-Dindo classification, grade III SSI requires a longer treatment duration. PMID- 25434695 TI - A large-scale cross-sectional study of ALK rearrangements and EGFR mutations in non-small-cell lung cancer in Chinese Han population. AB - The predictive power of age at diagnosis and smoking history for ALK rearrangements and EGFR mutations in non-small-cell lung cancer (NSCLC) remains not fully understood. In this cross-sectional study, 1160 NSCLC patients were prospectively enrolled and genotyped for EML4-ALK rearrangements and EGFR mutations. Multivariate logistic regression analysis was performed to explore the association between clinicopathological features and these two genetic aberrations. Receiver operating characteristic (ROC) curves methodology was applied to evaluate the predictive value. We showed that younger age at diagnosis was the only independent variable associated with EML4-ALK rearrangements (odds ratio (OR) per 5 years' increment, 0.68; p < 0.001), while lower tobacco exposure (OR per 5 pack-years' increment, 0.88; p < 0.001), adenocarcinoma (OR, 6.61; p < 0.001), and moderate to high differentiation (OR, 2.05; p < 0.001) were independently associated with EGFR mutations. Age at diagnosis was a very strong predictor of ALK rearrangements but poorly predicted EGFR mutations, while smoking pack-years may predict the presence of EGFR mutations and ALK rearrangements but with rather limited power. These findings should assist clinicians in assessing the likelihood of EML4-ALK rearrangements and EGFR mutations and understanding their biological implications in NSCLC. PMID- 25434697 TI - Application of robotic manipulability indices to evaluate thumb performance during smartphone touch operations. AB - This study examined whether manipulability during smartphone thumb-based touch operations could be predicted by the following robotic manipulability indices: the volume and direction of the 'manipulability ellipsoid' (MEd), both of which evaluate the influence of kinematics on manipulability. Limits of the thumb's range of motion were considered in the MEd to improve predictability. Thumb postures at 25 key target locations were measured in 16 subjects. Though there was no correlation between subjective evaluation and the volume of the MEd, high correlation was obtained when motion range limits were taken into account. These limits changed the size of the MEd and improved the accuracy of the manipulability evaluation. Movement directions associated with higher performance could also be predicted. In conclusion, robotic manipulability indices with motion range limits were considered to be useful measures for quantitatively evaluating human hand operations. PMID- 25434698 TI - Uterine-derived stem cells reconstitute the bone marrow of irradiated mice. AB - Hematopoietic stem cells (HSCs) can be found in several tissues of mesodermal origin. Uterine tissue contains stem cells and can regenerate during each menstrual cycle with robust new tissue formation. Stem cells may play a role in this regenerative potential. Here, we report that transplantation of cells isolated from murine uterine tissue can rescue lethally irradiated mice and reconstitute the major hematopoietic lineages. Donor cells can be detected in the blood and hematopoietic tissues such as spleen and bone marrow (BM) of recipient mice. Uterine tissue contains a significant percentage of cells that are Sca 1(+), Thy 1.2(+), or CD45(+) cells, and uterine cells (UCs) were able to give rise to hematopoietic colonies in methylcellulose. Using secondary reconstitution, a key test for hematopoietic potential, we found that the UCs exhibited HSC-like reconstitution of BM and formation of splenic nodules. In a sensitive assay for cell fusion, we used a mixture of cells from Cre and loxP mice for reconstitution and demonstrated that hematopoietic reconstitution by UCs is not a function of fusion with donor BM cells. We also showed that the hematopoietic potential of the uterine tissue was not a result of BM stem cells residing in the uterine tissue. In conclusion, our data provide novel evidence that cells isolated from mesodermal tissues such as the uterus can engraft into the hematopoietic system of irradiated recipients and give rise to multiple hematopoietic lineages. Thus, uterine tissue could be considered an important source of stem cells able to support hematopoiesis. PMID- 25434699 TI - Prostaglandin I2 analog suppresses lung metastasis by recruiting pericytes in tumor angiogenesis. AB - Prostaglandin I2 (PGI2) agonist has been reported to reduce tumor metastasis by modifying tumor angiogenesis; however, the mechanisms of how PGI2 affects the endothelial cells or pericytes in tumor vessel maturation are still unclear. The purpose of this study was to clarify the effects of PGI2 on tumor metastasis in a mouse lung metastasis model using Lewis lung carcinoma (LLC) cells. The mice were treated continuously with beraprost sodium (BPS), a PGI2 analog, for 3 weeks and then examined for lung metastases. The number and size of lung metastases were decreased significantly by BPS treatment. In addition, scanning electron microscopy and immunohistochemistry revealed that BPS increased the number of tumor-associated pericytes and improved intratumor hypoxia. Collectively, this study suggests that BPS attenuated vascular functional maturation in metastatic tumors. PMID- 25434700 TI - Evaluation of real-time RT-PCR Rhino&EV/Cc r-gene((r)) (bioMerieux) kit versions 1 and 2 for rhinovirus detection. AB - BACKGROUND: Human rhinoviruses (HRVs) are frequent etiologic agents of tract infections, ranging from benign upper to potentially life-threatening lower respiratory tract infections. Diagnosis is based on molecular methods. 169 HRV types, belonging to species A, B and C, have been identified. This high genetic diversity makes it difficult to accurately detect circulating HRVs and to diagnose severe infection. OBJECTIVES: To comparatively assess the ability to detect HRV clinical isolates of the first version (V1) of the commercial real time RT-PCR Rhino&EV/Cc r-gene((r)) (bioMerieux) kit, of an in-house RT-PCR followed by genotyping, considered as the reference method, and of the second version of this commercial test (V2). STUDY DESIGN: From September 2011 to April 2013, HRVs were prospectively detected in 2525 respiratory specimens, using V1 in combination with the in-house reference RT-PCR. In November 2013, 85 specimens that had given initially false negative results with V1 were retested simultaneously with V1 and V2 and the in-house RT-PCR. In addition, 421 negative specimens with the in-house assay were prospectively tested with V2. RESULTS: Among the 2525 specimens, V1 detected 80.7% (502/622) of in-house RT-PCR positive isolates: 85.3% (220/258) of HRV-A, 84.4% (27/32) of HRV-B and 74.9% (176/235) of HRV-C. Among the 85 respiratory samples tested with V1, V2 and the in-house RT PCR, V2 was more efficient than V1 in detecting 16 HRV isolates: 11/33 (33.3%) of HRV-A and 5/47 (10.6%) of HRV-C tested. The analytical sensitivity of V2 was greater for 8/18 HRV-A genotypes and 2/22 HRV-C genotypes. Relative to the in house assay, the specificity of V2 was 100% (421/421). CONCLUSIONS: This study showed a slightly higher sensitivity of V2. However, diverse genotypes, especially HRV-C, were undetected. PMID- 25434701 TI - Influence of matching solubility parameter of polymer matrix and CNT on electrical conductivity of CNT/rubber composite. AB - We report a general approach to fabricate elastomeric composites possessing high electrical conductivity for applications ranging from wireless charging interfaces to stretchable electronics. By using arbitrary nine kinds of rubbers as matrices, we experimentally demonstrate that the matching the solubility parameter of CNTs and the rubber matrix is important to achieve higher electrical conductivity in CNT/rubber composite, resulting in continuous conductive pathways leading to electrical conductivities as high as 15 S/cm with 10 vol% CNT in fluorinated rubber. Further, using thermodynamic considerations, we demonstrate an approach to mix CNTs to arbitrary rubber matrices regardless of solubility parameter of matrices by adding small amounts of fluorinated rubber as a polymeric-compatibilizer of CNTs. We thereby achieved electrical conductivities ranging from 1.2 to 13.8 S/cm (10 vol% CNTs) using nine varieties of rubber matrices differing in chemical structures and physical properties. Finally, we investigated the components of solubility parameter of CNT by using Hansen solubility parameters, these findings may useful for controlling solubility parameter of CNTs. PMID- 25434702 TI - Estimate of the size and demographic structure of the owned dog and cat population living in Veneto region (north-eastern Italy). AB - The knowledge of the size and demographic structure of animal populations is a necessary prerequisite for any population-based epidemiological study, especially to ascertain and interpret prevalence data, to implement surveillance plans in controlling zoonotic diseases and, moreover, to provide accurate estimates of tumours incidence data obtained by population-based registries. The main purpose of this study was to provide an accurate estimate of the size and structure of the canine population in Veneto region (north-eastern Italy), using the Lincoln Petersen version of the capture-recapture methodology. The Regional Canine Demographic Registry (BAC) and a sample survey of households of Veneto Region were the capture and recapture sources, respectively. The secondary purpose was to estimate the size and structure of the feline population in the same region, using the same survey applied for dog population. A sample of 2465 randomly selected households was drawn and submitted to a questionnaire using the CATI technique, in order to obtain information about the ownership of dogs and cats. If the dog was declared to be identified, owner's information was used to recapture the dog in the BAC. The study was conducted in Veneto Region during 2011, when the dog population recorded in the BAC was 605,537. Overall, 616 households declared to possess at least one dog (25%), with a total of 805 dogs and an average per household of 1.3. The capture-recapture analysis showed that 574 dogs (71.3%, 95% CI: 68.04-74.40%) had been recaptured in both sources, providing a dog population estimate of 849,229 (95% CI: 814,747-889,394), 40% higher than that registered in the BAC. Concerning cats, 455 of 2465 (18%, 95% CI: 17-20%) households declared to possess at least one cat at the time of the telephone interview, with a total of 816 cats. The mean number of cats per household was equal to 1.8, providing an estimate of the cat population in Veneto region equal to 663,433 (95% CI: 626,585-737,159). The estimate of the size and structure of owned canine and feline populations in Veneto region provide useful data to perform epidemiological studies and monitoring plans in this area. PMID- 25434703 TI - Evaluating peripheral nerve function in asymptomatic patients with type 2 diabetes or latent autoimmune diabetes of adults (LADA): results from nerve conduction studies. AB - AIMS: To assess the involvement of peripheral nerve dysfunction in asymptomatic patients with latent autoimmune diabetes of adults (LADA) or type 2 diabetes (T2DM), and compare nerve conduction (NC) parameters between the two groups. METHODS: A total of 1635 patients without symptoms and signs relevant to diabetic polyneuropathy (1275 with T2DM and 360 with LADA) were included and were further categorized into 3 groups according to diabetes duration: <5years, 5-14 years and >=15years. All subjects underwent nerve conduction studies. Abnormal NC was defined as the abnormality of NC parameters in two or more anatomical nerves. RESULTS: In both LADA and T2DM patients, the proportions of abnormal NC increased significantly with increasing durations (both P for trend <0.001). Specifically, abnormal NC was present in 18.5%, 38.8% and 66.7% of LADA patients with duration of <5 years, 5-14 years and >=15 years, respectively. Those numbers were 24.8% (P=0.152, vs. LADA), 25.3% (P=0.023, vs. LADA) and 62.8% (P=0.723, vs. LADA) in T2DM. Regarding NC parameters, T2DM patients had higher composite Z-scores of latency than LADA patients within 5 years of duration (P=0.001). In patients with duration of 5-14years, the latency Z-scores were comparable between the two groups (P=0.164), whereas the Z-scores of amplitude were lower (the lower the worse) in LADA than in T2DM (P=0.035). CONCLUSIONS: Peripheral nerve dysfunction is common in asymptomatic patients with LADA or T2DM. Findings of the study suggest that LADA and T2DM differ in the pattern of peripheral nerve involvement over diabetes duration. PMID- 25434704 TI - Apoptotic effects of 7,8-dihydroxyflavone in human oral squamous cancer cells through suppression of Sp1. AB - 7,8-Dihydroxyflavone (7,8-DHF) is a member of the flavonoid family and has recently been identified as a brain-derived neurotrophic factor mimetic that selectively activates tropomyosin-receptor kinase B with high affinity. The antioxidant and anticancer effects of 7,8-DHF have been reported. However, the pharmacological mechanisms of 7,8-DHF in oral cancer are unclear. Thus, we investigated the mechanisms of the antiproliferative action of 7,8-DHF on HN22 and HSC4 oral squamous cell carcinoma cell lines. We demonstrated that 7,8-DHF decreased cell growth and induced apoptosis in the HN22 and HSC4 cells through regulation of specificity protein 1 (Sp1) using the MTS assay, DAPI staining, Annexin V, propidium iodide staining, reverse transcription-polymerase chain reaction, immunocytochemistry, pull-down assay and western blot analysis. The results showed that the Sp1 protein bound with 7,8-DHF in the HN22 and HSC4 cells. Taken together, the results suggest that 7,8-DHF could modulate Sp1 transactivation and induce apoptotic cell death by regulating the cell cycle and suppressing antiapoptotic proteins. Furthermore, 7,8-DHF may be valuable for cancer prevention and better clinical outcomes. PMID- 25434705 TI - Poly(aspartic acid)-based degradable assemblies for highly efficient gene delivery. AB - Due to its good properties such as low cytotoxicity, degradability, and biocompatibility, poly(aspartic acid) (PAsp) is a good candidate for the development of new drug delivery systems. In this work, a series of new PAsp based degradable supramolecular assemblies were prepared for effective gene therapy via the host-guest interactions between the cyclodextrin (CD)-cored PAsp based polycations and the pendant benzene group-containing PAsp backbones. Such supramolecular assemblies exhibited good degradability, enhanced pDNA condensation ability, and low cytotoxicity. More importantly, the gene transfection efficiencies of supramolecular assemblies were much higher than those of CD-cored PAsp-based counterparts at various N/P ratios. In addition, the effective antitumor ability of assemblies was demonstrated with a suicide gene therapy system. The present study would provide a new means to produce degradable supramolecular drug delivery systems. PMID- 25434706 TI - "The paradigm of surgical treatment of distal rectal cancer: what to remove vs. what to leave behind". PMID- 25434707 TI - Protective and pathological roles of tissue factor in the heart. AB - Tissue factor (TF) is expressed in the heart where it is required for haemostasis. High levels of TF are also expressed in atherosclerotic plaques and likely contribute to atherothrombosis after plaque rupture. Indeed, risk factors for atherothrombosis, such as diabetes, hypercholesterolaemia, smoking and hypertension, are associated with increased TF expression in circulating monocytes, microparticles and plasma. Several therapies that reduce atherothrombosis, such as statins, ACE inhibitors, beta-blockers and anti platelet drugs, are associated with reduced TF expression. In addition to its haemostatic and pro-thrombotic functions, the TF : FVIIa complex and downstream coagulation proteases activate cells by cleavage of protease-activated receptors (PARs). In mice, deficiencies in either PAR-1 or PAR-2 reduce cardiac remodelling and heart failure after ischaemia-reperfusion injury. This suggests that inhibition of coagulation proteases and PARs may be protective in heart attack patients. In contrast, the TF/thrombin/PAR-1 pathway is beneficial in a mouse model of Coxsackievirus B3-induced viral myocarditis. We found that stimulation of PAR-1 increases the innate immune response by enhancing TLR3-dependent IFN beta expression. Therefore, inhibition of the TF/thrombin/PAR-1 pathway in patients with viral myocarditis could have detrimental effects. CONCLUSION: The TF : FVIIa complex has both protective and pathological roles in the heart. PMID- 25434708 TI - Bidirectional/double fascia grafting for simple and semi-dynamic reconstruction of lower lip deformity in facial paralysis. AB - BACKGROUND: For the total aesthetic reconstruction of facial paralysis, treatment of lower lip deformity as "a neglected target in facial reanimation" is important. Although various dynamic reconstruction approaches have been reported for lower lip deformity, these have not been popularly performed due to aggressive surgical invasiveness, long recovery time for reinnervation, and unstable outcomes. To reconstruct the lower lip deformity more simply but semi dynamically, we modified bidirectional/double fascia grafting methods that have been established as simple and minimally invasive treatments for pediatric congenital lower lip paralysis. METHODS: Between 2009 and 2011, nine patients were treated using this procedure alone or with combinations of other procedures of facial reanimation such as one-stage free muscle transfer. For outcome assessment, patients were evaluated using a lower lip paralysis grading system, including the objective aesthetics and functional results of the lower lip at rest (score range, 0-1), during smiling (score range, 0-4), and during mouth opening (score range, 0-2). RESULTS: The mean total scores improved from 1.43 (poor) preoperatively to 5.71 (excellent) postoperatively. In all evaluation items, the postoperative scores improved significantly compared to the preoperative scores (p<0.01) with no severe complications. CONCLUSIONS: The procedure is simply applied to various types of extensive facial paralysis, as well as congenital lower lip paralysis in combination with other static and dynamic reconstruction methods for facial paralysis, and it is suggested that this approach significantly and semi-dynamically improves the aesthetic function of the lower lip at rest, during smiling, and during mouth opening. PMID- 25434709 TI - Satisfaction and complications after lower body lift with autologous gluteal augmentation by island fat flap: 55 case series over 3 years. AB - BACKGROUND: Major weight loss causes body deformities. Lower circumferential dermolipectomy with autologous gluteal augmentation by a fat island flap can restore a part of the body contour, but this procedure is associated with a high incidence of complications. The aim of this study was to analyse the benefit/risk ratio and the patients' satisfaction. METHODS: All patients who underwent this procedure at the Nancy University Hospital over a 3-year period (between January 2010 and 2013) were reviewed; the complications were analysed and the patients' satisfaction rated. RESULTS: A total of 55 patients were included with a mean age of 41.0 years. The average body mass index of the patients was 28.2 kg/m2 with a mean weight of 76.8 kg at the time of the procedure and a mean weight reduction of 49.6 kg. The mean operative time was 4.85 h. The average hospital stay was 6.1 days. The average haemoglobin loss was 3.0 g/dl, and 12 (21.8%) patients required a blood transfusion. Of the total number of patients, 22 (40%) developed at least one complication, including six (10.9%) major complications. Fifty-two patients answered the questionnaire; 49 (94.2%) patients would go through this procedure again. The overall satisfaction was rated as excellent by 29 (55.8%) patients and as pleasing by 22 (42.3%). The outcome was judged as excellent or pleasing for the abdomen by 29 (55.8%) and 20 (38.35%) patients, respectively, and for the buttocks by 17 (32.7%) and 29 (55.8%) patients, respectively. The quality of life was rated better after than before the intervention by 49 (94.2%) patients. CONCLUSION: Despite a high complication rate, the majority of patients confirmed that they would opt for this procedure again, showing an improvement in their quality of life with an aesthetic and functional benefit. LEVEL OF EVIDENCE: III. PMID- 25434710 TI - Expanding neurosurgery. AB - The history of medicine is replete with innovations in neurosurgery that have spurred further developments across the medical spectrum. Surgeons treating pathologies in the head and spine have broken ground with new approaches, techniques, and technologies since ancient times. Neurosurgeons occupy a vital nexus in patient care, interfacing with the clinical symptoms and signs afflicting patients, the pathology at surgery, and imaging studies. No other physicians occupy this role within the nervous system. This power of observation and the ability to intercede place neurosurgeons in a unique position for impacting disease. Yet despite these pioneering achievements, more recently, forces in the workplace may be challenging neurosurgery's opportunities to contribute to the future growth of the neurosciences and medicine. The authors posit that, in the current health care climate, revenue generation by neurosurgical clinical activity is valued by the system more than neurosurgical research and academic output. Without providing the talented stream of new neurosurgeons with the opportunities and, in fact, the directive to achieve beyond simple financial success, the specialty is missing the opportunity to optimize its progress. The authors contend that the key to remaining relevant with the incorporation of new technologies to the treatment of neurosurgical patients will be to be flexible, open-minded, and nimble with the adaptation of new procedures by training and encouraging neurosurgical residents to pursue new or neglected areas of the specialty. Only by doing so can neurosurgery continue to expand. PMID- 25434711 TI - Evaluation of different bovine muscles to be applied in freeze-drying for instant meal. Study of physicochemical and senescence parameters. AB - The aim of the present research was to evaluate bovine muscles to be subjected to freeze-drying for an instant meal. Physicochemical and senescence parameters were evaluated. The experimental part was divided into two steps. In the first step, the Semitendinosus muscle was chosen to establish methodology and experimental conditions. Physicochemical, microstructure and senescence parameters were analysed. In the second step, economic bovine muscles such as Semimembranous and Spinalis dorsi were subjected to the same methodology and conditions as in the first step in order to compare them by analysing the same parameters. L* and a* values were statistically significant (P<0.05) for Semimembranous and Spinalis dorsi muscles, showing differences among condition effects and in muscles. Humidity and water activity showed among the muscles analysed that cooked and rehydrated samples did not exhibit differences. Microstructure of Semitendinosus and Semimembranous were not separated and fragmented as occurred with Spinalis dorsi after freeze-drying. Results allowed us to select among the muscles studied that Semimembranous was suitable and economic to be used in an instant meal. PMID- 25434712 TI - Do human leukocyte antigen E polymorphisms influence graft-versus-leukemia after allogeneic hematopoietic stem cell transplantation? AB - Hematopoietic-stem-cell transplantation (HSCT) is complicated by histocompatibility-dependent immune responses such as graft-versus-host disease, relapse, and graft rejection. The severity of these common adverse effects is directly related to the degree of human leukocyte antigen (HLA) incompatibility. In addition to the key role of classic HLA matching in influencing HSCT outcome, several lines of evidence suggest an important role for nonclassic major histocompatibility complex class I molecule, HLA-E. The interaction of HLA-E with NKG2A, its main receptor on natural killer cells, modulates cell-mediated cytotoxicity and cytokine production, an important role in innate immune responses. In addition, the HLA-E molecule can present peptides to different subtypes of T cells that may either support graft-versus-leukemia effects or be involved in bridging innate and acquired immunity. To date, the role of HLA-E and its polymorphisms in HSCT outcomes such as graft-versus-host disease, transplant related mortality, and improved survival has been published by a number of groups. In addition, these data suggest an association between HLA-E polymorphisms and relapse. Whether the engagement of the HLA-E molecule in the modulation of donor T cells is involved in the graft-versus-leukemia effect, or whether a different mechanism of HLA-E dependent reduction of relapse is involved, requires further investigation. PMID- 25434713 TI - Serum S100B levels may be associated with cerebral infarction: a meta-analysis. AB - OBJECTIVE: The aim of this paper is to explore the potential association of serum human soluble protein-100B protein (S100B) levels with the diagnosis and prognosis of cerebral infarction (CI). METHODS: Potential relevant studies were searched for in PubMed, Springerlink, Wiley, EBSCO, Ovid, Web of Science, Wanfang databases, China National Knowledge Infrastructure (CNKI) databases and VIP databases. Two investigators extracted data and assessed studies independently. Statistical analyses were carried out with the version 12.0 STATA statistical software. RESULTS: A total of 10 case-control studies that assessed the correlation of S100B serum level with CI, including 1211 subjects (patients=773, healthy controls=438) were included. The results showed that S100B serum levels in CI victims were significantly higher compared with those of the control group. According to the subgroup analysis by ethnicity, S100B serum level in CI victims was statistically significant in Asians and the control group, but no statistical significance was found in Caucasians. An additional subgroup analysis was carried out based on sample size, revealing that the S100B serum levels in CI victims in small samples were of statistical significance; however, no statistical significance was discovered in large samples. CONCLUSIONS: Elevator S100B serum levels might be negatively correlated with CI, suggesting that higher serum levels of S100B could lead to more serious condition and worse prognoses for CI patients. Therefore, S100B serum levels could be regarded as a biomarker for CI, and furthermore, S100B could aide in the diagnosis and prognosis of CI. PMID- 25434714 TI - Impact of hyperthermia before and during ischemia-reperfusion on neuronal damage and gliosis in the gerbil hippocampus induced by transient cerebral ischemia. AB - Hyperthermia can exacerbate the brain damage produced by ischemia. In the present study, we investigated the effects of hyperthermia before and during ischemia reperfusion on neuronal damage and glial changes in the gerbil hippocampus following transient cerebral ischemia using cresyl violet staining, NeuN immunohistochemistry and Fluoro-Jade B histofluorescence staining. The animals were randomly assigned to 4 groups: (1) sham-operated animals with normothermia (normothermia + sham group); (2) ischemia-operated animals with normothermia (normothermia + ischemia group); (3) sham-operated animals with hyperthermia (hyperthermia + sham group); and (4) ischemia-operated animals with hyperthermia (hyperthermia + ischemia group). Hyperthermia (39.5 +/- 0.2 degrees C) was induced by exposing the gerbils to a heating pad connected to a rectal thermistor for 30 min before and during ischemia-reperfusion. In the normothermia+ischemia groups, a significant delayed neuronal death was observed in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) 5 days after ischemia reperfusion. In the hyperthermia+ischemia groups, neuronal death in the SP of the CA1 occurred at 1 day post-ischemia, and neuronal death was observed in the SP of the CA2/3 region at 2 days post-ischemia. In addition, we examined activations of astrocytes and microglia using immunohistochemistry for anti-glial fibrillary acidic protein (GFAP) and anti-ionized calcium-binding adapter molecule 1 (Iba 1). GFAP-positive astrocytes and Iba-1-positive microglia in the ischemic hippocampus were activated much earlier and much more accelerated in the hyperthermia+ischemia groups than those in the normothermia+ischemia groups. Based on our findings, we suggest that an experimentally hyperthermic pre condition before cerebral ischemic insult produces more extensive neuronal damage and glial activation in the ischemic hippocampus. PMID- 25434715 TI - Chronic migraine with medication overuse: association between disability and quality of life measures, and impact of disease on patients' lives. AB - Patients with chronic migraine with medication overuse (CM-MO) have decreased quality of life (QoL) and increased disability: the degree to which these outcomes are connected to disease severity and the pattern of MO towards disease severity are unclear. Patients under withdrawal were administered the Migraine Disability Assessment (MIDAS), the WHO Disability Assessment Schedule (WHODAS), and the Migraine-Specific Quality of Life Questionnaire (MSQ). They overused NSAIDs, triptans, NSAIDs and triptans, and other drugs (ergotamine, caffeine, opioids/barbiturates). We calculated the correlations between MIDAS, WHODAS, and MSQ; compared WHODAS to normative scores; compared MIDAS, WHODAS, and MSQ in patients with different CM-MO severity; and run a logistic regression to predict CM-MO severity based on overused drugs. One hundred ninety-four patients were enrolled: correlations between WHODAS, MSQ, and MIDAS were moderate; wide differences on WHODAS against normative were found; and no trend was found across severity groups. Compared to triptans overusers, patients overusing NSAID and other drugs had higher odds of severe CM-MO. Coupling different disability measures with QoL assessment offered different insights on the lived experience of CM-MO. Future studies are needed to clarify the relationship between overused drugs and CM-MO severity: we added evidence that NSAIDs do not have protective effect in high-frequency CM-MO. PMID- 25434716 TI - Effect of hesperidin on neurobehavioral, neuroinflammation, oxidative stress and lipid alteration in intracerebroventricular streptozotocin induced cognitive impairment in mice. AB - Recent attention is given to the influence of dietary supplementation on health and mental well-being. Oxidative stress is associated with many diseases including neurodegenerative disorders. Dietary flavonoids exert chemopreventive and neuroprotective effects and comprise the most common group of plant polyphenols that provide much of the flavour and colour of the vegetables and fruits. Hesperidin is a flavanone glycoside found abundantly in citrus fruits, has been reported to have antioxidant, hypolipidaemic, analgesic and anti hypertensive activity. Pretreatment of hesperidin (100 and 200mg/kg body weight orally once daily for 15 days) to Swiss male albino mice has prevented the cognitive impairment. The cognitive impairment was developed by giving single intracerebroventricular-streptozotocin (ICV-STZ) injection (2.57 mg/kg body weight each side) bilaterally. Hesperidin pretreatment improved memory consolidation process as tested by Morris water maze possibly through modulation of acetylcholine esterase activity (AChE). Moreover, hesperidin attenuated the depleted content of reduced glutathione (GSH) and elevated level of thiobarbituric acid reactive substances (TBARS) and also augmented lipid alteration significantly following ICV-STZ injection. We also demonstrated that the flavonoid hesperidin modulates neuronal cell death by inhibiting the overexpression of inflammatory markers like nuclear factor kappaB, inducible nitric oxide synthase, cyclooxygenase-2 and glial fibrillary acidic protein positive astrocytes. The results from the present study open the possibility of using flavonoids for potential new therapeutic strategies for sporadic dementia of Alzheimer's disease. PMID- 25434718 TI - Diaphragmatic regional displacement assessed by ultrasound and correlated to subphrenic organ movement in the critically ill patients--an observational study. AB - INTRODUCTION: The objectives of the study are to identify the most reliably imaged regions of the diaphragm, to evaluate the correlation of movement between different parts of each hemidiaphragm, and to assess the agreement between liver or spleen displacement and movement of the ipsilateral hemidiaphragm. METHODS: Images of the diaphragm, liver, and spleen were obtained using 2-dimensional ultrasound. Acceptable agreement between regions of the diaphragm, liver, and spleen was defined as an absence of fixed or proportional bias using Deming regression analysis and limits of agreement of 2 SDs of the difference less than 30% of the mean value. RESULTS: We included 90 critically ill patients. The medial (87%) and middle (73%) regions of the right hemidiaphragm, liver (87.7%), and spleen (81%) and medial (71%) and middle regions (51%) of the left hemidiaphragm were most frequently imaged. In nonintubated patients, acceptable agreement was present for comparisons of the left middle and medial, right middle and medial, and left middle regions and spleen displacement. In intubated patients and in all patients when combined, acceptable agreement was only present for comparisons of the left middle and medial and right middle and medial regions of the diaphragm. Acceptable agreement was not present for intubated and all patients for diaphragmatic and solid organ movement. CONCLUSION: The diaphragm medial part is visualized in the majority of studied patients. The medial and middle thirds may be used interchangeably to assess hemidiaphragm movement. Acceptable agreement does not exist for diaphragm and solid organ movement, other than for the left middle region and the spleen. PMID- 25434717 TI - Influence of tumor necrosis factor alpha gene promoter polymorphisms and its serum level on migraine susceptibility in Egyptian patients. AB - BACKGROUND: Migraine is a common chronic neurological disorder with still largely unknown pathogenesis. We aimed to explore the possible role of tumor necrosis factor alpha (TNF-alpha) gene polymorphisms as risk factors of migraine, and whether they influence the TNF-alpha level. MATERIALS AND METHODS: Two hundred patients with migraine and 200 controls were enrolled in this study. Polymorphisms of TNF-alpha gene were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum TNF-alpha level was measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: TNF-alpha-308 GA, AA genotypes and A allele, TNF-alpha-857 CT genotype and T allele were associated with increased risk of migraine, while the TNF-alpha-238 polymorphism was not. TNF-alpha-308 GA, AA genotypes and A allele or AA genotype were associated with increased risk of migraine with aura (MA) and migraine without aura (MO) respectively; this was more significant in female patients with MA than in males. TNF-alpha-857 CT genotype was associated with increased risk of MO, or MA in females or males. While -857T allele was significantly associated with MO or MA in males and with MA only in females. On the other hand, we didn't find any significant associations of TNF-alpha-238 polymorphism with MO, or MA in males or females. TNF-alpha levels were higher in patients with migraine, MA, or MO than in controls (P<0.001). CONCLUSION: TNF-alpha polymorphisms were associated with migraine, MA, or MO in Egyptians. PMID- 25434719 TI - Soft tissue oxygenation and risk of mortality (STORM): an early marker of critical illness? AB - PURPOSE: Tissue oxygen saturation (StO2) is a noninvasive measure that reflects changes in tissue perfusion. Rapid response teams (RRTs) assess sick inpatients to determine need for intensive care unit (ICU) admission. This determination is subjective based on parameters such as systolic blood pressure, heart rate, and pulse oximetry. Our objective was to determine if parameters readily available at RRT bedside assessment (vital signs and StO2) can predict ICU admission and inhospital mortality. MATERIALS AND METHODS: All inpatients assessed by RRT at a tertiary Canadian hospital were consecutively sampled for 3 months. After clinical assessment, the RRT physician (blinded to StO2) made the ultimate ICU admission decision. RESULTS: In 134 included patients, mean age was 65.5 +/- 15.2 years, and 53% (n = 71) were males. There were 49 ICU admissions (36.6%) and 31 mortalities (23.1%). Two multivariable models significantly predicted ICU admission and inhospital mortality. The only independent predictor of ICU admission was pulse oximetry (adjusted odds ratio, 0.88; 95% confidence interval, 0.80-0.96; P = .007). Tissue oxygen saturation did not predict ICU admission but was the only independent predictor of mortality (adjusted odds ratio, 1.06; 95% confidence interval, 1.01-1.12; P = .04). CONCLUSIONS: Tissue oxygen saturation may identify critical illness in patients who would not traditionally meet ICU admission criteria and thus may identify patients who benefit from closer monitoring. PMID- 25434721 TI - Overexpression of CYP3A5 attenuates inducibility and activity of CYP3A4 in HepG2 cells. AB - There have been conflicting reports regarding the catalytic role of cytochrome P450 (CYP)3A5, which range from deeming it irrelevant to suggesting it is equally as important as CYP3A4, the most potent and abundant catalytic cytochrome enzyme in the human liver. This was partially attributed to the fact that CYP3A5 is highly polymorphic. However the importance of other underlying mechanisms remain unclear. The aim of the present study was to investigate the interaction between these enzymes. A human HepG2 hepatocellular line stably overexpressing CYP3A5 was constructed. The results suggested that CYP3A5 does not affect CYP3A4 expression directly. However, overexpression of CYP3A5 attenuated the inducibility of CYP3A4 in response to dexamethasone. A luciferase reporter assay indicated that this attenuation was due to a decrease in CYP3A4 promoter activity. Furthermore, a pharmacokinetic assay using quinidine and amlodipine showed that CYP3A4 enzyme activity per mg of microsomal protein was also decreased in the group overexpressing CYP3A5 compared with the dexamethasone-induced control group. In conclusion, the current study demonstrated that CYP3A5 may affect CYP3A4 at the transcriptional level and may thus modify CYP3A4 expression and activity in the presence of substrates and inducers. The results indicate that CYPs may interact with each other under certain conditions and that this interaction may be a novel mechanism by which drug-drug interactions are mediated. PMID- 25434720 TI - Choice of renal replacement therapy modality in intensive care units: data from a Japanese Nationwide Administrative Claim Database. AB - PURPOSE: This study was undertaken to assess recent trends of the choice of renal replacement therapy (RRT) modalities in Japanese intensive care units (ICUs). MATERIALS AND METHODS: Data were extracted from the Japanese Diagnosis Procedure Combination database for 2011. We identified adult patients without end-stage renal disease who had been admitted to ICUs for 3 days or longer and started continuous RRT (CRRT) or intermittent RRT (IRRT). Logistic regression was used to analyze which factors affected the modality choice. We further evaluated in hospital mortality according to the choice of RRT. RESULTS: Of 7353 eligible patients, 5854 (79.6%) initially received CRRT. The choice of CRRT was independently associated with sex (female), diagnosis of sepsis, hospital type (academic) and volume, vasoactive agents, mechanical ventilation, colloid administration, blood transfusion, intra-aortic balloon pumping, and venoarterial extracorporeal membrane oxygenation. Particularly, the number of vasoactive drugs was strongly associated with the CRRT choice. Overall in-hospital mortality in the CRRT group was higher than that in the IRRT group (50.0% vs 31.1%) and was increased when IRRT was switched to CRRT (59.1%). CONCLUSIONS: Continuous RRT is apparently preferred in actual ICU practice, especially for hemodynamically unstable patients, and subsequent RRT modality switch is associated with mortality. PMID- 25434722 TI - Characterizations of cationic gamma-carbolines binding with double-stranded DNA by spectroscopic methods and AFM imaging. AB - Two cationic gamma-carbolines, 2-methyl-5H-pyrido[4,3-b]indolium iodide (MPII) and 2,5-dimethyl-5H-pyrido[4,3-b]indolium iodide (DPII), were synthesized, and the DNA-binding properties of the cationic gamma-carbolines were elucidated. Through a series of experiments, we proved that the two cationic gamma-carbolines could strongly interact with DNA by intercalative binding. However, DPII, with a methyl group substituting H atom of 5-NH, has shown a stronger intercalative interaction with DNA compared to MPII. The dissociation of H from the 5-NH of MPII resulted in better water solubility and less binding affinity to DNA. Atomic force microscopy (AFM) images of pBR322 showed that both MPII and DPII strongly interacted with DNA and induced conformational changes in DNA. Moreover, the CT DNA circular dichroism (CD) spectra changes and the statistics of the node numbers of pBR322 in AFM images indicated that MPII had more profound effects on DNA conformations compared to DPII. Furthermore, our studies have shown that the interactions between cationic gamma-carbolines and DNA were sensitive to ionic strength. Increased ionic strength in the buffer caused the DNA helix to shrink, and the base stacking would be more compact, which resulted in minimal intercalation of cationic gamma-carbolines into DNA. PMID- 25434724 TI - Margins of oral leukoplakia: autofluorescence and histopathology. AB - Autofluorescence devices are widely used to examine oral lesions. The aim of this study was to see whether there were any signs of dysplasia, parakeratosis, or mucosal inflammation in the borders of homogeneous oral leukoplakia using autofluorescence, and we also compared clinically visible extensions with those detected by autofluorescence. Twenty patients with 26 homogeneous areas of oral leukoplakia were included in the study. After the clinically visible extensions of the lesion had been marked, we took a photograph through the autofluorescence device, which showed both borders in one picture. We then used photo-editing software to measure the size of the area of leukoplakia together with the area with loss of autofluorescence. We took 3 punch biopsy specimens: one from the leukoplakia, one 2.5mm from its marked borders, and one from healthy mucosa. Seventy-eight biopsy specimens were examined by an experienced pathologist, and 95% CI calculated to assess the amount of parakeratosis. Spearman's rank correlation was used to assess the association with mucosal inflammation. Ten areas of leukoplakia were surrounded by normal green autofluorescence, and 16 were consistent with loss of autofluorescence with a mean size of 66%, which exceeded the clinically visible size of the area of leukoplakia. We calculated that there was a strong association between these entities and their surrounding areas, with loss of autofluorescence for parakeratosis. Some leukoplakias showed clinically invisible extensions during histopathological examination and autofluorescence. The technique described enables clinicians to measure the extent of these lesions beyond their visible margins. We found no dysplasia, which emphasises that autofluorescence detects non-dysplastic lesions caused by mucosal inflammation and parakeratosis. PMID- 25434723 TI - Targeted deletion of Tsc1 causes fatal cardiomyocyte hyperplasia independently of afterload. AB - Despite high expression levels, the role of Tsc1 in cardiovascular tissue is ill defined. We launched this study to examine the role of Tsc1 in cardiac physiology and pathology. Mice in which Tsc1 was deleted in cardiac tissue and vascular smooth muscle (Tsc1c/cSM22cre(+/-)), developed progressive cardiomegaly and hypertension and died early. Hearts of Tsc1c/cSM22cre(+/-) mice displayed a progressive increase in cardiomyocyte number, and to a lesser extent, size between the ages of 1 and 6 weeks. In addition, compared to control hearts, proliferation markers (phospho-histone 3 and PCNA) were elevated in Tsc1c/cSM22cre(+/-) cardiomyocytes at 0-4 weeks, suggesting that cardiomyocyte proliferation was the predominant mechanism underlying cardiomegaly in Tsc1c/cSM22cre(+/-) mice. To examine the contribution of Tsc1 deletion in peripheral vascular smooth muscle to the cardiac phenotype, Tsc1c/cSM22cre(+/-) mice were treated with the antihypertensive, hydralazine. Prevention of hypertension had no effect on survival, cardiac size, or cardiomyocyte number in these mice. We furthermore generated mice in which Tsc1 was deleted only in vascular smooth muscle but not in cardiac tissue (Tsc1c/cSMAcre-ER(T2+/-)). The Tsc1c/cSMAcre-ER(T2+/-) mice also developed hypertension. However, their survival was normal and no cardiac abnormalities were observed. Our results suggest that loss of Tsc1 in the heart causes cardiomegaly, which is driven by increased cardiomyocyte proliferation that also appears to confer relative resistance to afterload reduction. These findings support a critical role for the Tsc1 gene as gatekeeper in the protection against uncontrolled cardiac growth. PMID- 25434726 TI - [How are excisional therapies for CIN performed in France? A national audit]. AB - OBJECTIVES: Evaluate how excisional therapies are performed in France and if colposcopy is used for the guidance of excision. MATERIALS AND METHODS: A national survey was performed among French gynecologists using an anonymous online questionnaire. RESULTS: A total of 555 (14.9%) gynecologists participated to the survey, only answers from the 396 (71.3%) who answered practicing excisional therapies for CIN were considered. LLETZ was the most common excisional technique employed (84.9%). Among respondents, 275 (69.3%) answered not using colposcopy at the time of excision, 67 (16.9%) answered performing excisions under naked eye vision immediately after they had performed a colposcopic examination and 52 (13.8%) under direct colposcopic vision. Although initial colposcopic training did not influence the probability to use colposcopy at the time of excision, the probability of performing excisions immediately after a colposcopic examination or under direct colposcopic vision was significantly increased by the monthly practice of 30 or more colposcopic examinations (AOR: 3.34; 95%CI: 1.54-7.26 and AOR: 2.16; 95%CI: 1.08-4.34, respectively) and by the monthly practice of 5 or more excisional therapies (AOR: 3.06; 95%CI: 1.42-6.56 and AOR: 3.03; 95%: 1.54-5.96, respectively). CONCLUSION: Only a minority of French gynecologists uses colposcopy for the guidance of excisional therapies for CIN. Such practice seems to be influenced by the number of colposcopic examinations and of excisions they perform in a month. PMID- 25434727 TI - Regulatory network of differentially expressed genes in metastatic osteosarcoma. AB - The present study aimed to investigate the possible molecular mechanisms underlying the pathogenesis of metastatic osteosarcoma (OS), by examining the microarray expression profiles of normal samples, and metastatic and non metastatic OS samples. The GSE9508 gene expression profile was downloaded from the Gene Expression Omnibus database, which included 11 human metastatic OS samples, seven non-metastatic OS samples and five normal samples. Pretreatment of the data was performed using the BioConductor package in R language, and the differentially expressed genes (DEGs) were identified by a t-test. Furthermore, function and pathway enrichment analyses of the DEGs were conducted using a molecule annotation system. A differential co-expression network was also constructed, and the submodules were screened using MCODE in Cytoscape. A total of 965 genes were identified as DEGs in metastatic OS. The DEGs were shown to participate in the regulation of DNA-dependent transcription, the composition of the nucleus, cytoplasm and membrane, and protein and nucleotide binding. Furthermore, the screened DEGs were significantly associated with the ribosome, axon guidance and the cytokine-cytokine receptor interaction pathway. Certain hub genes were identified in the constructed differential co-expression network, including matrix metalloproteinase 1 (MMP1), smoothened (SMO), ewing sarcoma breakpoint region 1 (EWSR1) and fasciculation and elongation protein zeta-1 (FEZ1). Brain selective kinase 2 (BRSK2) and aldo-keto reductase family 1 member B10 (AKRIB10) were present in the screened submodules. The results of the present study suggest that genes, including MMP1, SMO, EWSR1, FEZ1, BRSK2 and AKRIB10, may be potential targets for the diagnosis and treatment of metastatic OS. PMID- 25434728 TI - Homozygosity mapping of autosomal recessive intellectual disability loci in 11 consanguineous Pakistani families. AB - BACKGROUND: Autosomal recessive intellectual disability (ID) is genetically heterogeneous and most of the genes causing it remain undiscovered. OBJECTIVE: We have ascertained 11 consanguineous families multiplex for IDs in order to identify new loci for autosomal recessive genes for non-syndromic ID, or to aid pinpointing mutations in known causative gene/loci. Methodology Microarray genotyping (Affymatrix 250K) was performed to identify homozygosity-by-descent (HBD) in all affected families. RESULTS: Analysis of genotypes revealed 45 potential HBD regions across the families, although these may be rationalised down to 39. Two families share an overlapping HBD region on 7q11.21. In one family, X-linkage also looks plausible, and a new ID gene near the centromere may be a likely cause. In one family, no HBD region was found, and thus we exclude autosomal recessive mutation as the likely cause in this family. Copy-number variation (CNV) was also performed and revealed no CNVs, homozygous or heterozygous, segregating with the phenotype. CONCLUSION: The homozygous loci identified in this study might harbour candidate genes for ID in these studied families. Therefore, we are proceeding with next-generation sequencing analysis of the families, using whole-exome approaches, and anticipate that this will identify the causative gene/mutation within the identified HBD regions for many of the families studied here. PMID- 25434725 TI - Inhibition of HDAC6 modifies tau inclusion body formation and impairs autophagic clearance. AB - Proteinaceous inclusions in nerve cells and glia are a defining neuropathological hallmark in a variety of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Their occurrence may be related to malfunctions of the proteolytic degradation systems. In cultured oligodendrocytes, proteasomal inhibition leads to protein aggregate formation resembling coiled bodies, which are characteristic for PSP and CBD. Large protein aggregates are excluded from the proteasome and can only be degraded by autophagy, a lysosomal pathway. Autophagy is a highly selective process, which requires a variety of receptor proteins for ubiquitinated proteins, such as p62 and histone deacetylase 6 (HDAC6). HDAC6 is mainly localized in the cytoplasm, and alpha-tubulin is its major substrate. HDAC6 is considered as a sensor of proteasomal stress; it is involved in the autophagosomal pathway and can mediate the retrograde transport of ubiquitinated proteins along the microtubules. As we have shown recently, HDAC6 is present in oligodendrocytes and its inhibition leads to morphological alterations, microtubule bundling, modulation of acetylation, and phosphorylation of the microtubule-associated protein tau. The present study was undertaken to investigate whether HDAC6 is involved in protein aggregate formation in oligodendrocytes and whether its inhibition modifies the consequences of MG-132 induced inhibition of the ubiquitin proteasome system (UPS). The data show that HDAC6 and acetylated tau are recruited to protein aggregates after proteasomal inhibition. Pharmacological inhibition of HDAC6 by the selective inhibitor tubastatin A (TST) and its small hairpin RNA (shRNA)-mediated downregulation alters the assembly of MG-132-induced compact protein aggregates. After TST treatment, they appear more diffusely dispersed throughout the cytoplasm. This is not a protective means but promotes the onset of apoptotic cell death. Furthermore, the heat shock response is altered, and TST suppresses the MG-132 stimulated induction of HSP70. To test whether the alteration of protein aggregate formation is related to the influence of HDAC6 on the autophagic degradation system, an oligodendroglial cell line, i.e., OLN-93 cells stably expressing green fluorescent protein (GFP)-microtubule associated protein light chain 3 (LC3) and tau, was used. During autophagosome formation, endogenous LC3 is processed to LC3-I, which is then converted to LC3-II. An increase of LC3-II is used as a reliable marker for autophagosome formation and abundance. It is demonstrated that inhibition of HDAC6 leads to the accumulation of LC3-positive autophagosomal vacuoles and an increase in LC3-II immunoreactivity, but the autophagic flux is rather impaired. Hence, the inhibition or dysregulation of HDAC6 contributes to stress responses and pathological processes in oligodendrocytes. PMID- 25434729 TI - Refining discordant gene trees. AB - BACKGROUND: Evolutionary studies are complicated by discordance between gene trees and the species tree in which they evolved. Dealing with discordant trees often relies on comparison costs between gene and species trees, including the well-established Robinson-Foulds, gene duplication, and deep coalescence costs. While these costs have provided credible results for binary rooted gene trees, corresponding cost definitions for non-binary unrooted gene trees, which are frequently occurring in practice, are challenged by biological realism. RESULT: We propose a natural extension of the well-established costs for comparing unrooted and non-binary gene trees with rooted binary species trees using a binary refinement model. For the duplication cost we describe an efficient algorithm that is based on a linear time reduction and also computes an optimal rooted binary refinement of the given gene tree. Finally, we show that similar reductions lead to solutions for computing the deep coalescence and the Robinson Foulds costs. CONCLUSION: Our binary refinement of Robinson-Foulds, gene duplication, and deep coalescence costs for unrooted and non-binary gene trees together with the linear time reductions provided here for computing these costs significantly extends the range of trees that can be incorporated into approaches dealing with discordance. PMID- 25434730 TI - Assessment of vascular function of hand allografts. AB - BACKGROUND: Insufficiency of blood vessels supplying a limb allograft may lead to loss of the extremity. Thus, a regular evaluation of perfusion of transplants seems a reasonable approach. The purpose of the present study was assessment of allograft perfusion by means of non-invasive methods. MATERIAL/METHODS: Six hand allografts transplanted in 5 patients were included in the study group. The transplant procedure occurred on average 45 months before. The study group comprised 2 allografts at forearm level, 2 transplants of the arm, and 1 bilateral transplant of the forearm. Parameters of blood flow using Doppler ultrasonography, impedance plethysmography, Doppler measurement of segmental pressures, optical pulse oscillography (OPO), and thermography were performed in all participants. RESULTS: DUS revealed increased resistive index in ulnar arteries of transplant hands compared to native hands and an altered blood supply was confirmed by IP. Flow-mediated dilatation within the transplanted extremity was abnormal in most patients and was inversely correlated with number of episodes of acute rejection. Analysis of oscillographic spectrum revealed flattening of the dicrotic notch in transplant hands. A tendency for lower temperature of the skin of transplanted hands compared to native extremities was also observed. CONCLUSIONS: In asymptomatic patients after limb transplantation, non-invasive methods disclosed discreet abnormalities of graft perfusion. Thus, regular measurement of perfusion parameters using these methods appears to be a promising approach to detect early and potentially reversible disturbances of blood supply. Further observational studies are required to determine its clinical significance. PMID- 25434731 TI - Elderly patients' heart-related conditions: Disclosing health information differs by target. AB - Americans are living longer, and many are managing at least one chronic illness. Having people with whom to disclose health information is a salient component of managing a chronic health condition, such as heart disease. The purpose of this study is to explore differences in elderly patients' health disclosures by target (i.e. disclosing to a partner vs. another person). Elderly patients (>age 60) with a diagnosed heart-related condition (n = 273) completed a survey regarding sharing information about their health condition. Results indicated significant differences between the two groups in perceived support; breadth, depth, and frequency of disclosures; and disclosure of psychological/emotional symptoms, physical symptoms, and talk about heart-healthy behaviors. No significant differences were found between the two groups for relationship quality and efficacy. Patients who reported sharing information with a partner reported significantly more health information disclosures compared to patients who reported sharing information with another person. PMID- 25434732 TI - Psychrophilic dry anaerobic digestion of dairy cow feces: long-term operation. AB - This paper reports experimental results which demonstrate psychrophilic dry anaerobic digestion of cow feces during long-term operation in sequence batch reactor. Cow feces (13-16% total solids) has been anaerobically digested in 12 successive cycles (252 days) at 21 days treatment cycle length (TCL) and temperature of 20 degrees C using psychrotrophic anaerobic mixed culture. An average specific methane yield (SMY) of 184.9 +/- 24.0, 189.9 +/- 27.3, and 222 +/- 27.7 (N)L CH4 kg(-1) of VS fed has been achieved at an organic loading rate of 3.0, 4.0, and 5.0 g TCOD kg(-1) inoculum d(-1) and TCL of 21 days, respectively. The corresponding substrate to inoculum ratio (SIR) was 0.39 +/- 0.06, 0.48 +/- .02, 0.53 +/- 0.05, respectively. Average methane production rate of 10 +/- 1.4(N)L CH4 kg(-1) VS fed d(-1) has been obtained. The low concentration of volatile fatty acids indicated that hydrolysis was the reaction limiting step. PMID- 25434733 TI - Unusual progression and subsequent improvement in cystic lung disease in a child with radiation-induced lung injury. AB - Radiation-induced lung disease is a known complication of therapeutic lung irradiation, but the features have not been well described in children. We report the clinical, radiologic and histologic features of interstitial lung disease (ILD) in a 4-year-old child who had previously received lung irradiation as part of successful treatment for metastatic Wilms tumor. Her radiologic abnormalities and clinical symptoms developed in an indolent manner. Clinical improvement gradually occurred with corticosteroid therapy. However, the observed radiologic progression from interstitial and reticulonodular opacities to diffuse cystic lung disease, with subsequent improvement, is striking and has not been previously described in children. PMID- 25434734 TI - Understanding the real value of youth physical activity promotion. PMID- 25434737 TI - Thiophene-based terpyridine and its zinc halide complexes: third-order nonlinear optical properties in the near-infrared region. AB - A novel 4'-(4-(diphenylamino)thienyl)-2,2':6',2''-terpyridine ligand () based on thiophene and its complexes (X = Cl, Br, I, SCN) was designed, synthesized and characterized by elemental analysis, far-IR, MALDI-TOF-MS, and single crystal X ray diffraction analysis. Structural studies revealed that the central zinc(ii) atom adopted a distorted trigonal bipyramidal coordination model. However, there were different hydrogen bonds and stacking models with different counter anions in the crystals. The absorption properties of the compounds were investigated with the aid of TD-DFT computational methods. Furthermore, the third-order nonlinear optical (NLO) properties were systematically studied via open-aperture Z-scan methods using a tunable wavelength femtosecond laser. The results from photophysical property investigations suggested that the complexation of the thiophene-based terpyridine ligand with zinc halides resulted in strong ICT/LLCT bands of about 450 nm, and the complexes exhibited strong nonlinear optical response in the near-infrared range around 850 nm. Above all, the two-photon absorption (2PA) cross-section values (sigma) were enhanced by coordination with zinc and influenced by halide ions, reaching up to 2583 GM (X = Br). PMID- 25434736 TI - Mothers' perceived proximity to green space is associated with TV viewing time in children: the Growing Up in Scotland study. AB - OBJECTIVE: The aim of this study is to investigate whether mothers' perception of distance from home to green/open spaces is associated with their child's screen time. METHOD: We used mother-reported data from sweep six (2010-2011) of the Growing Up in Scotland study (n=3586 children aged 5.9yrs) to examine associations between walking distance from home to green/open space and screen time (TV viewing time/computer use). Analyses were adjusted for age, sex and other pre-specified covariates, including sport/exercise participation, mental and general health, birth weight, parental socio-economic group (SEG) and smoking status. RESULTS: Children living the furthest distance from green/open spaces (>20minutes' walking distance) displayed over 2h (95% CI, 0.65 to 3.51) more weekly TV time than the reference category (<5minutes' walking distance). Compared to children in the reference category, those in the >20minute category had worse mental health (mean SDQ [Strengths and Difficulties Questionnaire] score+/-SD, 7.0+/-4.6 vs. 8.7+/-6.2) and general health (% fair-poor, 4.6 vs. 8.6), and were more likely to come from lower SEG households. CONCLUSION: Mothers' perceived distance from home to green/open spaces was associated with child's TV time at age 5.9years. PMID- 25434735 TI - Climate change, human health, and epidemiological transition. AB - The health of populations depends on the availability of clean air, water, food, and sanitation, exposure to pathogens, toxins and environmental hazards, and numerous genetic, behavioral and social factors. For many thousands of years, human life expectancy was low, and population growth was slow. The development of technology-based civilizations facilitated what Abdel Omran called "epidemiological transition," with increasing life expectancy and rapid population growth. To a large extent, the spectacular growth of human populations during the past two centuries was made possible by the energy extracted from fossil fuels. We have now learned, however, that greenhouse gases from fossil fuel combustion are warming the planet's surface, causing changes in oceanic and atmospheric systems, and disrupting weather and hydrological patterns. Climate change poses unprecedented threats to human health by impacts on food and water security, heat waves and droughts, violent storms, infectious disease, and rising sea levels. Whether or not humanity can reduce greenhouse gas emissions quickly enough to slow climate change to a rate that will allow societies to successfully adapt is not yet known. This essay reviews the current state of relevant knowledge, and points in a few directions that those interested in human health may wish to consider. PMID- 25434738 TI - Protein-like dynamics of polycarbonate polymers in water. AB - The dynamics of amphiphilic peptide-mimicking polycarbonate polymers are investigated, considering variations in polymer length, monomer sequence, and monomer modification. The polymers are simulated in aqueous solution with atomistic molecular dynamics simulations and an empirical force field. Various structural polymer properties, interaction strengths, and solvation free energies are derived. It is found that water is a less favorable solvent for these polymers than for peptides. Moreover, polymers readily adopt irreversibly a compact state that consists of a variety of distinct compact conformations that are adopted through frequent transitions. Furthermore, the polymers exhibit a strong propensity to form large aggregates. The driving forces for these processes appear to be a hydrophobic effect and more favorable polymer-solvent interactions of aggregates that overcome the otherwise strong mutual repulsion between the positively charged polymers. Replacing hydrophobic residues with polar side chains destabilizes the compact conformations of the polymers. Our results also indicate that the monomer sequence has little effect on the overall solvation properties of the polymer molecule. However, the sequence influences flexibility and compactness of the monomer in solution. Overall, the results of this work confirm the protein-like characteristics of these polymers and elucidate the role of single residues in influencing the structure and aggregation in aqueous solution. PMID- 25434740 TI - Tolerance induction to human stem cell transplants with extension to their differentiated progeny. AB - There is increasing interest in transplantation of human stem cells for therapeutic purposes. It would benefit future application if one could achieve their long-term acceptance and functional differentiation in allogeneic hosts using minimal immunosuppression. Allogeneic stem cell transplants differ from conventional tissue transplants insofar as not all alloantigens are revealed during tolerance induction. This risks that the immune system tolerized to antigens expressed by progenitors may still remain responsive to antigens expressed later during differentiation. Here we show that brief induction with monoclonal antibody-mediated coreceptor and costimulation blockade enables long term engraftment and tolerance towards murine ESCs, hESCs, human induced pluripotent stem cells (iPSCs) and hESC-derived progenitors in outbred murine recipients. Tolerance induced to PSC-derived progenitors extends to their differentiated progenies, and sometimes even to different tissues derived from the same donor. Global gene expression profiling identifies clear features in T cells from tolerized grafts that are distinct from those involved in rejection. PMID- 25434741 TI - Cellular activation, expression analysis and functional characterization of grass carp IkappaBalpha: evidence for its involvement in fish NF-kappaB signaling pathway. AB - IkappaBalpha is a well-known member of the inhibitors of kappa B (IkappaB) family that controls NF-kappaB signaling by blocking NF-kappaB translocation from cytoplasm to nucleus. In the present study, an IkappaBalpha homologue was identified from grass carp (gcIkappaBalpha), showing the structural characteristics of IkappaB family. Moreover, mRNA expression of this molecule in grass carp periphery blood lymphocytes (PBLs) was enhanced significantly by both LPS and PHA in a time- and dose-dependent manner, indicating the involvement of gcIkappaBalpha in fish immune response. Further analysis demonstrated that LPS but not PHA induced gcIkappaBalpha phosphorylation and protein degradation in PBLs, implying different signaling pathways mediated by LPS and PHA in gcIkappaBalpha expression regulation in grass carp PBLs. In particular, the time dependent oscillation of gcIkappaBalpha phosphorylation and total protein levels induced by LPS is in accordance with the characteristics of mammalian IkappaBalpha phosphorylation followed by protein degradation during NF-kappaB activation. In support of this notion, overexpression of gcIkappaBalpha was able to block both basal and LPS-stimulated NF-kappaB activity in grass carp kidney cell line, indicating the negatively regulatory role of gcIkappaBalpha in NF kappaB activity as seen in mammals. Therefore, our results not only reveal a dynamic variation of NF-kappaB activity based on the activation and expression of IkappaBalpha for the first time, but also provide the direct evidence for the involvement of IkappaBalpha in NF-kappaB signaling in fish immune cells. PMID- 25434739 TI - Clinical considerations and key issues in the management of patients with Erdheim Chester Disease: a seven case series. AB - BACKGROUND: Erdheim-Chester Disease (ECD), a non Langerhans' cell histiocytosis of orphan nature and propensity for multi-systemic presentations, comprises an intricate medical challenge in terms of diagnosis, treatment and complication management. OBJECTIVES: The objectives are to report the clinical, radiological and pathological characteristics, as well as cardinal therapeutic approaches to ECD patients and to provide clinical analyses of the medical chronicles of these complex patients. METHODS: Patients with biopsy proven ECD were audited by a multi-disciplinary team of specialists who formed a coherent timeline of all the substantial clinical events in the evolution of their patients' illness. RESULTS: Seven patients (five men, two women) were recruited to the study. The median age at presentation was 53 years (range: 39 to 62 years). The median follow-up time was 36 months (range: 1 to 72 months). Notable ECD involvement sites included the skeleton (seven), pituitary gland (seven), retroperitoneum (five), central nervous system (four), skin (four), lungs and pleura (four), orbits (three), heart and great vessels (three) and retinae (one). Prominent signs and symptoms were fever (seven), polyuria and polydipsia (six), ataxia and dysarthria (four), bone pain (four), exophthalmos (three), renovascular hypertension (one) and dyspnea (one). The V600E BRAF mutation was verified in three of six patients tested. Interferon-alpha treatment was beneficial in three of six patients treated. Vemurafenib yielded dramatic neurological improvement in a BRAF mutated patient. Infliximab facilitated pericardial effusion volume reduction. Cladribine improved cerebral blood flow originally compromised by perivenous lesions. CONCLUSIONS: ECD is a complex, multi-systemic, clonal entity coalescing both neoplastic and inflammatory elements and strongly dependent on impaired RAS/RAF/MEK/ERK signaling. PMID- 25434742 TI - GenePainter v. 2.0 resolves the taxonomic distribution of intron positions. AB - Conserved intron positions in eukaryotic genes can be used to reconstruct phylogenetic trees, to resolve ambiguous subfamily relationships in protein families and to infer the history of gene families. This version of GenePainter facilitates working with large datasets through options to select specific subsets for analysis and visualization, and through providing exhaustive statistics. GenePainter's application in phylogenetic analyses is considerably extended by the newly implemented integration of the exon-intron pattern conservation with phylogenetic trees. AVAILABILITY AND IMPLEMENTATION: The software along with detailed documentation is available at http://www.motorprotein.de/genepainter and as Supplementary Material. CONTACT: mako@nmr.mpibpc.mpg.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25434744 TI - Isoselective 3,4-(co)polymerization of bio-renewable myrcene using NSN-ligated rare-earth metal precursor: an approach to a new elastomer. AB - The polymerization of bio-renewable myrcene (MY), using a cationic beta diimidosulfonate lutetium catalyst in high activity, afforded an unprecedented isotactic 3,4-polymyrcene (PMY) with a low Tg (-42 degrees C). Based on this result, the random and block copolymerization of myrcene and isoprene (IP) resulted in novel elastomers that comprise the amorphous iso-3,4-PMY and iso-3,4 PIP sequences. PMID- 25434745 TI - First 25-hydroxyvitamin D assay for general chemistry analyzers. AB - 25-Hydroxyvitamin D [25(OH)D], the predominant circulating form of vitamin D, is an accurate indicator of the general vitamin D status of an individual. Because vitamin D deficiencies have been linked to several pathologies (including osteoporosis and rickets), accurate monitoring of 25(OH)D levels is becoming increasingly important in clinical settings. Current 25(OH)D assays are either chromatographic or immunoassay-based assays. These assays include HPLC, liquid chromatography-tandem mass spectrometry (LC-MS/MS), enzyme-immunosorbent, immunochemiluminescence, immunofluorescence and radioimmunoassay. All these assays use heterogeneous formats that require phase separation and special instrumentations. In this article, we present an overview of these assays and introduce the first homogeneous assay of 25(OH)D for use on general chemistry analyzers. A special emphasis is put on the unique challenges posed by the 25(OH)D analyte. These challenges include a low detection limit, the dissociation of the analyte from its serum transporter and the inactivation of various binding proteins without phase separation steps. PMID- 25434746 TI - Fetal male lineage determination by analysis of Y-chromosome STR haplotype in maternal plasma. AB - The aim of this study is to determine the fetus Y-STR haplotype in maternal plasma during pregnancy and estimate, non-invasively, if the alleged father and fetus belong to the same male lineage. The study enrolled couples with singleton pregnancies and known paternity. All participants signed informed consent and the local ethics committee approved the study. Peripheral blood was collected in EDTA tubes (mother) and in FTA paper (father). Maternal plasma DNA was extracted by using NucliSens EasyMAG. Fetal gender was determined by qPCR targeting DYS-14 in maternal plasma and it was also confirmed after the delivery. From all included volunteers, the first consecutive 20 mothers bearing male fetuses and 10 mothers bearing female fetuses were selected for the Y-STR analysis. The median gestational age was 12 weeks (range 12-36). All DNA samples were subjected to PCR amplification by PowerPlex Y23, ampFLSTR Yfiler, and two in-house multiplexes, which together accounts for 27 different Y-STR. The PCR products were detected with 3500 Genetic Analyzer and they were analyzed using GeneMapper-IDX. Fetuses' haplotypes (Yfiler format) were compared to other 5328 Brazilian haplotypes available on Y-chromosome haplotypes reference database (YHRD). As a result, between 22 and 27 loci were successfully amplified from maternal plasma in all 20 cases of male fetuses. None of the women bearing female fetuses had a falsely amplified Y-STR haplotype. The haplotype detected in maternal plasma completely matched the alleged father haplotype in 16 out of the 20 cases. Four cases showed single mismatches and they did not configure exclusions; 1 case showed a mutation in the DYS 458 locus due to the loss of one repeat unit and 3 cases showed one DYS 385I/II locus dropout. All mismatches were confirmed after the delivery. Seventeen fetuses' haplotypes were not found in YHRD and one of them had a mutation, which corresponded to the paternity probability of 99.9812% and 95.7028%, respectively. Three fetuses' haplotypes occurred twice in YHRD, which corresponded to paternity probability of 99.9437%. In conclusion, high discriminatory fetal Y-STR haplotype could be determined from maternal plasma during pregnancy starting at 12 weeks of gestation. All male fetuses could be attributed to the alleged father male lineage early in pregnancy. The high probability of paternity associated with each case suggests that the relationship is not random and this strategy can be use as an alternative for male fetal kinship analysis. PMID- 25434743 TI - Sphingolipids in the DNA damage response. AB - Recently, sphingolipid metabolizing enzymes have emerged as important targets of many chemotherapeutics and DNA damaging agents and therefore play significant roles in mediating the physiological response of the cell to DNA damage. In this review we will highlight points of connection between the DNA damage response (DDR) and sphingolipid metabolism; specifically how certain sphingolipid enzymes are regulated in response to DNA damage and how the bioactive lipids produced by these enzymes affect cell fate. PMID- 25434747 TI - Large area growth and electrical properties of p-type WSe2 atomic layers. AB - Transition metal dichacogenides represent a unique class of two-dimensional layered materials that can be exfoliated into single or few atomic layers. Tungsten diselenide (WSe(2)) is one typical example with p-type semiconductor characteristics. Bulk WSe(2) has an indirect band gap (~ 1.2 eV), which transits into a direct band gap (~ 1.65 eV) in monolayers. Monolayer WSe(2), therefore, is of considerable interest as a new electronic material for functional electronics and optoelectronics. However, the controllable synthesis of large-area WSe(2) atomic layers remains a challenge. The studies on WSe(2) are largely limited by relatively small lateral size of exfoliated flakes and poor yield, which has significantly restricted the large-scale applications of the WSe(2) atomic layers. Here, we report a systematic study of chemical vapor deposition approach for large area growth of atomically thin WSe(2) film with the lateral dimensions up to ~ 1 cm(2). Microphotoluminescence mapping indicates distinct layer dependent efficiency. The monolayer area exhibits much stronger light emission than bilayer or multilayers, consistent with the expected transition to direct band gap in the monolayer limit. The transmission electron microscopy studies demonstrate excellent crystalline quality of the atomically thin WSe(2). Electrical transport studies further show that the p-type WSe(2) field-effect transistors exhibit excellent electronic characteristics with effective hole carrier mobility up to 100 cm(2) V(-1) s(-1) for monolayer and up to 350 cm(2) V( 1) s(-1) for few-layer materials at room temperature, comparable or well above that of previously reported mobility values for the synthetic WSe(2) and comparable to the best exfoliated materials. PMID- 25434748 TI - Genetic diversity and association mapping of iron and zinc concentrations in chickpea (Cicer arietinum L.). AB - Chickpea (Cicer arietinum L.) is the world's second most important pulse crop after common bean. Chickpea has historically been an important daily staple in the diet of millions of people, especially in the developing countries. Current chickpea breeding programs have mainly been directed toward high yield, biotic and abiotic stress resilience that has increased global production, but less attention has been directed toward improving micronutrient concentrations in seeds. In an effort to develop micronutrient-dense chickpea lines, a study to examine the variability and to identify SNP alleles associated with seed iron and zinc concentrations was conducted using 94 diverse accessions of chickpea. The results indicated that there is substantial variability present in chickpea germplasm for seed iron and zinc concentrations. In the current set of germplasm, zinc is negatively correlated with grain yield across all locations and years; whereas the negative correlation between iron and grain yield was only significant at the Elrose locality. Eight SNP loci associated with iron and (or) zinc concentrations in chickpea seeds were identified. One SNP located on chromosome 1 (chr1) is associated with both iron and zinc concentrations. On chr4, three SNPs associated with zinc concentration and two SNPs for iron concentration were identified. Two additional SNP loci, one on chr6 and the other on chr7, were also found to be associated with iron and zinc concentrations, respectively. The results show potential opportunity for molecular breeding for improvement of seed iron and zinc concentrations in chickpea. PMID- 25434749 TI - Undermining the hippocratic oath: the Medical Innovation Bill. PMID- 25434751 TI - Improved efficiency of brewer's spent grain arabinoxylans by ultrasound-assisted extraction. AB - Arabinoxylan (AX) rich extracts from brewer's spent grain (BSG) were produced by the application of ultrasound-assisted extraction (UAE) and conventional alkaline extraction (AKE). UAE and AKE were optimised for the production of the highest yield of ethanol insoluble material using response surface methodology (RSM). The efficiency of UAE was established by the significant reduction of time (7h to 25 min) and energy when compared to AKE, to recover similar amounts of AX (60%) from BSG, leading to the production of starch-free AX-rich extracts. PMID- 25434750 TI - Effects of ephrinB2 gene siRNA on the biological behavior of human colorectal cancer cells. AB - Colorectal cancer (CRC) is a common gastrointestinal malignancy worldwide and is a lethal and aggressive malignancy with a dismal prognosis. EphrinB2 is a membrane-bound ligand and has an intracellular domain that also possesses an intrinsic signaling capacity called 'reverse signaling'. In the present study, CRC cell lines were screened for high expression of ephrinB2. Small interfering RNA (siRNA) knockdown of ephrinB2 was performed in human SW480 CRC cells. The levels of expression of ephrinB2, VEGF, CD105 and matrix metalloproteinase 9 (MMP9) protein were measured by western blotting, and messenger RNA (mRNA) levels were measured using real-time PCR. Apoptosis and cell cycle distribution were determined using flow cytometry. Cell proliferation was measured by a methyl thiazole tetrazolium (MTT) test and a scratch healing experiment was used to measure the extent of cell migration. A Transwell assay was used to detect the extent of cell invasion. The results showed that RNA interference (RNAi) of ephrinB2 effectively silenced the ephrinB2 gene at both the mRNA and protein levels in SW480 cells and inhibited the proliferation, invasion, migration and angiogenesis and induced apoptosis in SW480 cells. These effects may be attributed to VEGF and MMP9 regulation. PMID- 25434752 TI - Effect of ultrasound and stabilizers on nucleation kinetics of curcumin during liquid antisolvent precipitation. AB - Nucleation kinetics of liquid antisolvent precipitation of a poorly water soluble drug curcumin in presence of ultrasound and surfactants have been estimated. Ultrasound and stabilizers were found to have opposing effects on induction time (tau ind), metastable zone width (MSZW) and nucleation rates (J) of curcumin during antisolvent precipitation. The use of ultrasound (in presence or absence of stabilizers) was found to decrease tau ind and MSZW drastically while the values of nucleation rates were found to increase. In contrast to these observations, use of stabilizers (in presence or absence of ultrasound) were found to increase MSZW, increase tau ind and lower the nucleation rates (J) of curcumin. The solid-liquid interfacial energies (gammaSL) for curcumin in aqueous ethanolic solutions (with and without stabilizers) have also been calculated using experimentally estimated induction time (tau ind) and supersaturation data. The values of solid-liquid interfacial energies were found to be in the range of 1.5-3.5 mJ/m(2). In comparison to these values, the values of gammaSL predicted by Mersmann equation and equation proposed by Bennema and Sohnel were found to be significantly higher and were in the range of 10-30 mJ/m(2). PMID- 25434753 TI - Inter-expert and intra-expert reliability in sleep spindle scoring. AB - OBJECTIVES: To measure the inter-expert and intra-expert agreement in sleep spindle scoring, and to quantify how many experts are needed to build a reliable dataset of sleep spindle scorings. METHODS: The EEG dataset was comprised of 400 randomly selected 115s segments of stage 2 sleep from 110 sleeping subjects in the general population (57+/-8, range: 42-72 years). To assess expert agreement, a total of 24 Registered Polysomnographic Technologists (RPSGTs) scored spindles in a subset of the EEG dataset at a single electrode location (C3-M2). Intra expert and inter-expert agreements were calculated as F1-scores, Cohen's kappa (kappa), and intra-class correlation coefficient (ICC). RESULTS: We found an average intra-expert F1-score agreement of 72+/-7% (kappa: 0.66+/-0.07). The average inter-expert agreement was 61+/-6% (kappa: 0.52+/-0.07). Amplitude and frequency of discrete spindles were calculated with higher reliability than the estimation of spindle duration. Reliability of sleep spindle scoring can be improved by using qualitative confidence scores, rather than a dichotomous yes/no scoring system. CONCLUSIONS: We estimate that 2-3 experts are needed to build a spindle scoring dataset with 'substantial' reliability (kappa: 0.61-0.8), and 4 or more experts are needed to build a dataset with 'almost perfect' reliability (kappa: 0.81-1). SIGNIFICANCE: Spindle scoring is a critical part of sleep staging, and spindles are believed to play an important role in development, aging, and diseases of the nervous system. PMID- 25434756 TI - Immunological and histopathological responses of the kidney of common carp (Cyprinus carpio L.) sublethally exposed to glyphosate. AB - Glyphosate is a broad-spectrum herbicide frequently used world widely in agricultural and non-agricultural areas to control unwanted plants. Health risk of chronic and subchronic exposure of glyphosate on animals and humans has received increasing attention in recent years. The aim of this study was to evaluate the effects of glyphosate on the immunoglobulin M (IgM), complement C3 (C3), and lysozyme (LYZ) in the kidney of common carp exposed to 52.08 or 104.15mgL(-1) of glyphosate for 168h. The results showed that the transcriptions of IgM, C3, or LYZ were altered due to glyphosate-exposure, for example, IgM and C3 initially increased at 24h later it decreased (except for a increase of C3 in higher dose group at 24h) while the expression of G-type LYZ were not affected at 24h, then increased at 72h, but decreased at the end of test, however C-type LYZ expression was initially up-regulated (24-72h) but down-regulated at the end of exposure (168h). However, glyphosate-exposure generally decreased the contents of IgM and C3 or inhibited LYZ activity in the kidney of common carp. In addition, glyphosate-exposure also caused remarkable histopathological damage, mainly including vacuolization of the renal parenchyma and intumescence of the renal tubule in fish kidney. The results of this study indicate that glyphosate causes immunotoxicity on common carp via suppressing the expressions of IgM, C3, and LYZ and also via damaging the fish kidney. PMID- 25434754 TI - The role of dapoxetine hydrochloride on-demand for the treatment of men with premature ejaculation. AB - Premature ejaculation (PE) is the most common male sexual dysfunction. Dapoxetine hydrochloride, belonging to a class of drugs known as selective serotonin reuptake inhibitors or, was the first drug originally approved for the on-demand treatment of men with PE. We aimed to compare the intravaginal ejaculatory latency time (IELT), patient-reported global impression of change (PGIC), and adverse effect (AE) incidence associated with the use of dapoxetine (30 mg and 60 mg) versus placebo, and evaluate the differences in administering 60 mg versus 30 mg as on-demand medical oral therapy for the treatment of PE via a literature review and meta-analysis. Relevant randomized controlled trials (RCTs) were identified from PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (Cochrane Library) databases. Ultimately, a total of seven RCTs with 8039 patients were included. Our meta-analysis demonstrated that dapoxetine (in the 30 mg and 60 mg subgroup) resulted in significantly higher IELT, PGIC, and AE incidence relative to the placebo, with higher proportions observed for 60 mg versus 30 mg of dapoxetine administration. The most common AEs were mild and tolerable. We conclude that dapoxetine (particularly the 60 mg dosage) may be considered a safe and effective drug for patients with PE. PMID- 25434755 TI - Excision repair cross complementation group 1 is a chemotherapy-tolerating gene in cisplatin-based treatment for non-small cell lung cancer. AB - This study aimed to evaluate the biological functions of excision repair cross complementation goup 1 (ERCC1) in cell proliferation, cell cycle, invasion and cisplatin response of non-small cell lung cancer (NSCLC) cells. Firstly, ERCC1 gene was successfully transfected into H1299 cells by gene cloning and transfection techniques. Then, cell proliferation was determined with the cell growth curve and colony-forming assays. Flow cytometry (FCM) was employed to investigate the cell cycle distribution. The ability of cell invasion was estimated by means of Matrigel invasion assays. Response of NSCLC cells to cisplatin was detected utilizing MTT assays, and the intracellular drug concentrations were determined by the high performance liquid chromatography (HPLC) analysis. Expression of the two cell membrane proteins, P-glycoprotein (P gp) and multidrug resistance-associated protein (MRP), was also evaluated utilizing FCM technique. By contrast, ERCC1 expression in the NSCLC A549 cells was silenced by small interfering RNA (siRNA) through RNAi technique. In addition, the cytotoxic effect of cisplatin on A549 cells was detected by MTT assays. In the present study, the results demonstrated that ERCC1 had no effect on cell proliferation, cell cycle and the ability of invasion, but showed significant impact on cisplatin response of the NSCLC H1299 cells. Furthermore, siRNA-induced suppression of ERCC1 evidently enhanced sensitivity to cisplatin of NSCLC A549 cells. Therefore, it is confirmed that ERCC1 is a chemotherapy tolerating gene and a promising predictor in tailoring chemotherapy of NSCLC. PMID- 25434757 TI - Exposure to a low dose of bisphenol A impairs pituitary-ovarian axis in prepubertal rats: effects on early folliculogenesis. AB - The research work studies the effect of providing a low dose of bisphenol A (BPA), on the reproductive axis of prepubertal female rats. Wistar mated rats were treated with either 0.1% ethanol or BPA in their drinking water until their offspring were weaned on the 21 day of birth. The estimated average dose of exposure to dams was approximately 3MUg/kg/day. The pups were sacrificed at the 30th day of life. Body weight at the moment of the sacrifice was significantly higher in the group exposed to BPA; ovarian weight and its relative weight were not modified. LH and estradiol levels increased significantly, meanwhile FSH ones showed no significant changes. The number of primary, secondary and atretic follicles increased and antral ones was decreased. Our results demonstrated that early exposure to a low dose of BPA disrupts the normal function of the reproductive axis in prepubertal female rats. PMID- 25434758 TI - Molecular mechanisms involved in lead induced disruption of hepatic and pancreatic glucose metabolism. AB - Lead (Pb) is a toxic heavy metal known to be associated with pathology of various human chronic diseases. This study has focused on the effect of lead on glucose homeostasis with regard to metabolic function of pancreas and liver. Islets of Langerhans were isolated from the pancreas of rats and exposed to lead for 24h, then insulin release along with markers of ER stress and oxidative stress were evaluated. In another part, lead was administered to rats for 32 days and after evaluating criteria of diabetes, the activity of gluconeogenesis and glycogenolysis enzymes, and markers of oxidative stress and inflammation were measured in the liver. Lead disrupted insulin secretory function of islets through activating GSK-3beta and ER stress, and increased activity of gluconeogenic enzymes in the liver featured by glucose intolerance. Chronic exposure to lead can disrupt glucose homeostasis by affecting pancreas and liver mainly through induction of insulin resistance. PMID- 25434759 TI - Anti-inflammatory effects of calcium citrate in RAW 264.7cells via suppression of NF-kappaB activation. AB - Here we aimed to investigate the anti-inflammatory effects of calcium citrate in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The anti-inflammatory effects of calcium citrate were investigated by assessing pro-inflammatory factors (NO, ROS, NF-kappaB, iNOS, and COX-2) and pro-inflammatory cytokines (IL 1beta, IL-6, and TNF-alpha). Treatment of cells with calcium citrate (10-100MUM) significantly reduced the generation of intracellular reactive oxygen species and increased the activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase in LPS-stimulated macrophages. Calcium citrate was further shown to inhibit NO production in LPS-stimulated RAW 264.7cells. The expression levels of iNOS, COX-2, and NF-kappaB were also suppressed by treatment with calcium citrate. Calcium citrate was furthermore found to significantly inhibit the production of IL-1beta, IL-6, and TNF-alpha in response to LPS-stimulation. These findings demonstrate that calcium citrate may be an effective anti-inflammatory agent. PMID- 25434760 TI - Temporal changes in urinary levels of cadmium, N-acetyl-beta-d-glucosaminidase and beta2-microglobulin in individuals in a cadmium-contaminated area. AB - Cadmium (Cd) is a metal that is toxic to renal tubules. If renal tubules are damaged by Cd, urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) and beta 2-microglobulin (beta2-MG) increases. The aim of this study was to describe the changing patterns of urinary Cd, NAG, and beta2-MG levels over a 3-year period in individuals living in a Cd-contaminated area. This follow-up study included 191 residents (65.6+/-9.3 years) who were living in the vicinity of a copper refinery. Urinary levels of Cd, NAG activity, and beta2-MG levels were measured, and their determinants and changing patterns were analyzed statistically. The natural logarithm of urinary Cd levels decreased significantly over time. Sex and intake of locally cultivated rice were significant determinants of urinary Cd concentration. Urinary NAG activity decreased over time. Age and urinary Cd concentration were significant determinants of urinary NAG activity in subjects with urinary Cd concentrations >5MUg/g creatinine. In subjects whose urinary Cd concentrations were >2MUg/g creatinine, diabetes was found to be a significant risk factor for high urinary NAG activity. The slope for temporal changes in urinary beta2-MG levels was negative in subjects whose urinary Cd levels were <2MUg/g creatinine but was positive in those whose urinary Cd levels were 2-5MUg/g creatinine or >5MUg/g creatinine. The urinary beta2-MG levels found in individuals whose urinary Cd levels were >2MUg/g creatinine suggest that previous Cd-induced renal tubular damage had occurred. PMID- 25434761 TI - Human exposure to arsenic in groundwater from Lahore district, Pakistan. AB - In the present study we determined As concentrations in healthy volunteers from three different age groups (children, adults and old age) residing in Lahore, Pakistan to gain insight into arsenic exposure to humans via drinking water. The results revealed that the concentrations of As were significantly (p<0.05) different among different sites, while non significant trends were observed among different age classes. As concentrations in blood and nails samples showed a significant (p<0.05) positive correlation. The mean concentrations of As were higher in nails samples (1.43MUg/g) followed by blood samples (1.15MUg/L); urine samples (0.82MUg/l) and hair samples (0.74MUg/g) based on all sites. The antioxidants enzyme activities in blood samples showed a significant (p<0.01) decrease with the increase in As concentrations. The result suggests that urgent action is needed to prevent further human exposure to As. PMID- 25434762 TI - Pharmacological and safety evaluation of fibrous root of Rhizoma Coptidis. AB - The aim of this study was to investigated the pharmacological activities and safety of fibrous root of Rhizoma Coptidis (FRC). FRC not only protected Kunming mice from the minimal lethal dose of Escherichia coli, but also protected rabbits from hyperpyrexia induced by lipopolysaccharid (LPS). The acute toxicity study showed that oral medial lethal dose (LD50) of FRC was greater than 7000mg/kg body weight in Kunming mice. The sub-chronic toxicity study showed that the no observed-adverse effect level (NOAEL) of FRC was 1.88g/kg body weight in Sprague Dawley rats, whereas FRC at higher dose (3.76g/kg body weight) resulted in damage to liver and lung. Negative results were present in Ames test, mouse micronucleus test and mouse sperm abnormality test. These finding support the use of FRC in veterinary medicine. PMID- 25434764 TI - A qualitative study exploring male cancer patients' experiences with percutaneous nephrostomy. AB - OBJECTIVE: Obstructive uropathy due to advanced cancer can be efficiently treated with a percutaneous nephrostomy. The treatment is associated with complications and frequent readmissions. How the patients' quality of life is affected by a nephrostomy remains uncertain. The aim of this study was to describe how a nephrostomy is perceived by patients and its effects on their everyday lives. MATERIAL AND METHODS: Semi-structured interviews were conducted in the patients' home using a mind map. The inclusion criteria were locally advanced or metastatic urological cancer treated with a nephrostomy for a minimum of 1 month. All interviews were audio recorded, transcribed and analysed using a grounded theory approach. Ten male patients were interviewed, eight with prostate cancer and two with bladder cancer. RESULTS: Treatment with nephrostomy influenced the physical activity level and restricted normal social activities. Readmissions had a negative influence on mood. However, the patients who experienced symptom improvement were thankful for having had the nephrostomy, despite the inconveniences. Communicating about the hazards and benefits helped patients to adjust their expectations of a nephrostomy. CONCLUSIONS: The study describes how nephrostomy is a burdensome intervention accompanied by a plethora of complex physical and psychosocial issues. Having a nephrostomy on a palliative indication has extensive implications for the patients, which should not be neglected or underestimated. Individual assessment of each patient, together with excellent communication regarding the procedure and outcome, is essential. Most patients had frequent contact with the healthcare system and additional support could be offered by a palliative care service. PMID- 25434763 TI - Coverage intervals for trace elements in human scalp hair are site specific. AB - Coverage intervals for trace elements in human scalp hair commonly provide the basis for interpreting laboratory results and also in comparative decision-making processes regarding exposure risk assessment. This short communication documents, by some examples, that those computed for human hair are to be considered site specific, as they reflect local environmental conditions; also each geographic area has a typical profile of hair elemental composition of its inhabitants. Therefore, the levels of trace elements in hair are not strictly comparable between different areas of the world. This issue is particularly relevant when identification of anomalous environmental exposures are requested or even in detecting physiological disorders. PMID- 25434765 TI - The immunopathogenesis of birdshot chorioretinopathy; a bird of many feathers. AB - Birdshot chorioretinopathy (BSCR) is a bilateral chronic intraocular inflammation or posterior uveitis that preferentially affects middle-aged Caucasians. BSCR is characterized by distinctive multiple choroidal hypopigmented lesions in combination with retinal vasculitis and vitritis, and the extraordinary feature that virtually all patients are HLA-A29 positive. Its pathophysiology is still poorly understood. BSCR is the strongest documented association between HLA and disease in humans, which makes it an excellent model for studying the underlying immuno-genetic mechanisms of HLA class I-associated diseases. Although the association with HLA-A29 suggests that it is directly involved in the presentation of peptide antigens to T cells, the exact contribution of HLA-A29 to the pathophysiology of BSCR remains enigmatic. This article revisits the HLA-A29 peptidome using insights from recent studies and discusses why HLA-A29 can be considered a canonical antigen presenting molecule. The first genome-wide association study facilitated novel concepts into a disease mechanism beyond HLA A29 that includes strong genetic predisposition for the ERAP2 gene that affects antigen processing for HLA class I. Furthermore, patients manifest with pro inflammatory cytokine profiles and pathogenic T cell subsets that are associated with IL-17-linked inflammation. We are beginning to understand that the underlying biology of BSCR comprises various pathologic aspects branched into multiple molecular pathways. We propose to employ Systems Medicine to reveal their dynamic interplay for a holistic view of the immunopathology of this intriguing archetypal HLA class I-associated disease. PMID- 25434766 TI - Spatial dosimetric sensitivity of contouring uncertainties in gynecological 3D based brachytherapy. AB - BACKGROUND AND PURPOSE: This study aims to analyze subsections of the target volume that are sensitive to delineation uncertainties with respect to underdosage (spatial dosimetric uncertainty) in MRI-based brachytherapy of cervical cancer. MATERIAL AND METHODS: A methodology was developed to simulate delineation uncertainties by shifting an angular segment of the contour perpendicular to the original HR-CTV. For shifts of 3, 6 and 9mm resulting D90 and D98 were calculated for the modified contour. The sensitivity of the dose plan to the locally introduced error was estimated by linear regression of D90 or D98 against the magnitude of the shift. The methodology was employed on 20 patients treated with tandem ring brachytherapy. RESULTS: Topographic maps resulting from the dosimetric sensitivity analysis showed both large spatial variations and substantial inter-patient variations. For all plans included the spatial sensitivity in D90 ranged from 0.0 to -1.6%/mm, correspondingly sensitivity in D98 ranged from 0 to -4.6%/mm. A significantly increased dosimetric sensitivity was found in anterior direction and the cranial part of the tumor (p<0.05). CONCLUSIONS: The developed methodology identifies specific tumor regions and patients with increased risk of underdosage from delineation uncertainties in brachytherapy of cervical cancer. PMID- 25434767 TI - Potential role of hypoxia imaging using (18)F-FAZA PET to guide hypoxia-driven interventions (carbogen breathing or dose escalation) in radiation therapy. AB - BACKGROUND AND PURPOSE: Hypoxia-driven intervention (oxygen manipulation or dose escalation) could overcome radiation resistance linked to tumor hypoxia. Here, we evaluated the value of hypoxia imaging using (18)F-FAZA PET to predict the outcome and guide hypoxia-driven interventions. MATERIAL AND METHODS: Two hypoxic rat tumor models were used: rhabdomyosarcoma and 9L-glioma. For the irradiated groups, the animals were divided into two subgroups: breathing either room air or carbogen. (18)F-FAZA PET images were obtained just before the irradiation to monitor the hypoxic level of each tumor. Absolute pO2 were also measured using EPR oximetry. Dose escalation was used in Rhabdomyosarcomas. RESULTS: For 9L gliomas, a significant correlation between (18)F-FAZA T/B ratio and tumor growth delay was found; additionally, carbogen breathing dramatically improved the tumor response to irradiation. On the contrary, Rhabdomyosarcomas were less responsive to hyperoxic challenge. For that model, an increase in growth delay was observed using dose escalation, but not when combining irradiation with carbogen. CONCLUSIONS: (18)F-FAZA uptake may be prognostic of outcome following radiotherapy and could assess the response of tumor to carbogen breathing. (18)F FAZA PET may help to guide the hypoxia-driven intervention with irradiation: carbogen breathing in responsive tumors or dose escalation in tumors non responsive to carbogen. PMID- 25434768 TI - Dynamics of tumor hypoxia assessed by 18F-FAZA PET/CT in head and neck and lung cancer patients during chemoradiation: possible implications for radiotherapy treatment planning strategies. AB - INTRODUCTION: To define the optimal time point for the integration of hypoxia (18)F-FAZA-PET/CT information into radiotherapy treatment planning to benefit from hypoxia modification or dose escalation treatment. Therefore, we performed a prospective cohort study, using serial hypoxic imaging ((18)F-FAZA-PET/CT) prior to and at several time-points during (chemo)radiotherapy (CHRT) in six head and neck squamous cell (HNSCC) and six non-small cell lung cancer (NSCLC) patients. METHODS: The spatio-temporal dynamics of tumor hypoxia and fractional hypoxic volumes (FHV) were evaluated using a voxel-by-voxel analysis based on a (18)F FAZA-T/B ratio of 1.4 at four time points in HNSCC patients, at baseline (FAZA BL), at week one (FAZA-W1), two (FAZA-W2), and four (FAZA-W4) during CHRT and at three time points in NSCLC patients (baseline; W2, W4). RESULTS: Ten out of twelve patients showed a substantial pre-treatment tumor hypoxia representing a FHV?1.4 assessed by (18)F-FAZA-PET/CT. The median FHV was 38% (FAZA-BL), 15% (FAZA-W1), 17% (FAZA-W2) and 1.5% (FAZA-W4) in HNSCC patients, and 34% (FAZA-BL), 26% (FAZA-W2) and 26% (FAZA-W4) in NSCLC patients, respectively. Stable tumor hypoxia was observed in three HNSCC patients and two NSCLC patients at FAZA-W2. In three HNSCC patients and two NSCLC patients FHVs declined to non-detectable hypoxia levels at FAZA-W4 during CHRT, while two NSCLC patients, showed increasing FHVs. CONCLUSION: Our results indicate that, instead of using the FAZA BL scan as the basis for the dose escalation, FAZA-W2 of CHRT is most suitable and might provide a more reliable basis for the integration of (18)F-FAZA-PET/CT information into radiotherapy treatment planning for hypoxia-directed dose escalation strategies. PMID- 25434769 TI - Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. AB - Conjugation of small interfering RNA (siRNA) to an asialoglycoprotein receptor ligand derived from N-acetylgalactosamine (GalNAc) facilitates targeted delivery of the siRNA to hepatocytes in vitro and in vivo. The ligands derived from GalNAc are compatible with solid-phase oligonucleotide synthesis and deprotection conditions, with synthesis yields comparable to those of standard oligonucleotides. Subcutaneous (SC) administration of siRNA-GalNAc conjugates resulted in robust RNAi-mediated gene silencing in liver. Refinement of the siRNA chemistry achieved a 5-fold improvement in efficacy over the parent design in vivo with a median effective dose (ED50) of 1 mg/kg following a single dose. This enabled the SC administration of siRNA-GalNAc conjugates at therapeutically relevant doses and, importantly, at dose volumes of <=1 mL. Chronic weekly dosing resulted in sustained dose-dependent gene silencing for over 9 months with no adverse effects in rodents. The optimally chemically modified siRNA-GalNAc conjugates are hepatotropic and long-acting and have the potential to treat a wide range of diseases involving liver-expressed genes. PMID- 25434771 TI - Re: Use of Osirix in developing a digital radiology teaching library. PMID- 25434772 TI - Re: Use of Osirix in developing a digital radiology teaching library. A reply. PMID- 25434770 TI - Axial plane optical microscopy. AB - We present axial plane optical microscopy (APOM) that can, in contrast to conventional microscopy, directly image a sample's cross-section parallel to the optical axis of an objective lens without scanning. APOM combined with conventional microscopy simultaneously provides two orthogonal images of a 3D sample. More importantly, APOM uses only a single lens near the sample to achieve selective-plane illumination microscopy, as we demonstrated by three-dimensional (3D) imaging of fluorescent pollens and brain slices. This technique allows fast, high-contrast, and convenient 3D imaging of structures that are hundreds of microns beneath the surfaces of large biological tissues. PMID- 25434774 TI - Effect of knockout serum replacement supplementation to culture medium on porcine blastocyst development and piglet production. AB - We have previously developed chemically defined media suitable for in vitro production (IVP) of porcine embryos and subsequently generated piglets by nonsurgical embryo transfer. In this study, to further improve the culture conditions for IVP of porcine embryos, we evaluated the effect of knockout serum replacement (KSR), a substitute for serum or albumin, on the viability and development of porcine blastocysts. The addition of 5% (v:v) KSR to porcine blastocyst medium (PBM) on Day 5 (Day 0 = IVF) significantly increased the survival and hatching rates of blastocysts and the total cell number of Day-7 blastocysts compared with those in cultures without KSR or addition of 10% fetal bovine serum. Furthermore, the number of cells in the trophectoderm of Day-6 blastocysts and the ATP content of Day-7 blastocysts cultured with 5% KSR were significantly higher than those of blastocysts cultured without KSR. The mRNA expression of a rate-limiting enzyme in beta-oxidation, carnitine palmitoyltransferase 1, in Day-6 blastocysts, and a serine proteinase, urokinase type plasminogen activator, in Day-7 blastocysts cultured in 5% KSR-PBM was significantly higher than that of blastocysts cultured in PBM alone. Four of eight recipients (50%), in which Day-5 blastocysts treated with 5% KSR were transferred nonsurgically, became pregnant. However, the efficiency of piglet production (percentage of piglets born based on the number of embryos transferred) was similar to recipients with transferred blastocysts treated without KSR. The present study demonstrated that the addition of KSR to PBM enhanced the in vitro viability of porcine blastocysts. In addition, our data suggest that KSR improved development to the hatching stage and blastocyst quality by increasing ATP content and hatching-related mRNA expression of blastocysts. PMID- 25434773 TI - Standardization and validation of a novel and simple method to assess lumbar dural sac size. AB - AIM: To develop and validate a simple, reproducible method to assess dural sac size using standard imaging technology. MATERIALS AND METHODS: This study was institutional review board-approved. Two readers, blinded to the diagnoses, measured anterior-posterior (AP) and transverse (TR) dural sac diameter (DSD), and AP vertebral body diameter (VBD) of the lumbar vertebrae using MRI images from 53 control patients with pre-existing MRI examinations, 19 prospectively MRI imaged healthy controls, and 24 patients with Marfan syndrome with prior MRI or CT lumbar spine imaging. Statistical analysis utilized linear and logistic regression, Pearson correlation, and receiver operating characteristic (ROC) curves. RESULTS: AP-DSD and TR-DSD measurements were reproducible between two readers (r = 0.91 and 0.87, respectively). DSD (L1-L5) was not different between male and female controls in the AP or TR plane (p = 0.43; p = 0.40, respectively), and did not vary by age (p = 0.62; p = 0.25) or height (p = 0.64; p = 0.32). AP-VBD was greater in males versus females (p = 1.5 * 10(-8)), resulting in a smaller dural sac ratio (DSR) (DSD/VBD) in males (p = 5.8 * 10( 6)). Marfan patients had larger AP-DSDs and TR-DSDs than controls (p = 5.9 * 10( 9); p = 6.5 * 10(-9), respectively). Compared to DSR, AP-DSD and TR-DSD better discriminate Marfan from control subjects based on area under the curve (AUC) values from unadjusted ROCs (AP-DSD p < 0.01; TR-DSD p = 0.04). CONCLUSION: Individual vertebrae and L1-L5 (average) AP-DSD and TR-DSD measurements are simple, reliable, and reproducible for quantitating dural sac size without needing to control for gender, age, or height. PMID- 25434775 TI - Seminal plasma and serum fertility biomarkers in dromedary camels (Camelus dromedarius). AB - Eight healthy fertile (control) and 11 infertile male dromedaries were used to investigate whether specific seminal plasma and serum fertility biomarkers could be related to their in vivo fertility. Eight fertility biomarkers and testosterone were determined in both seminal plasma and serum of all studied camels during the rutting season using commercial kits. Results revealed a significant (P < 0.01) difference in semen parameters between the control and infertile camels. There was a significant (P < 0.01) difference between the control and infertile dromedaries in seminal plasma glutathione peroxidase (GPx) activity (15.04 +/- 1.14 vs. 4.55 +/- 0.96 nmol/min/mL, respectively) and both phospholipase A2 (sPLA2; 50.66 +/- 6.28 vs. 23.56 +/- 4.29 pg/mL, respectively) and testosterone concentrations (732.14 +/- 57.12 vs. 396.36 +/- 79.34 pg/mL, respectively). A significant (P < 0.05) difference was found between the control and infertile camels in seminal plasma concentrations of osteopontin, cysteine rich secretory protein 3 (CRISP3), and prostaglandin D synthase (lipocalcin type). There was a significant (P < 0.01) difference between the fertile and infertile camels in serum GPx activity 67.81 +/- 12.41 vs. 21.31 +/- 4.63 nmol/min/mL, respectively) and both testosterone (599.57 +/- 110.90 vs. 176.09 +/ 24.05 pg/mL, respectively) and clusterin concentrations (137.29 +/- 14.15 vs. 253.00 +/- 17.14 ng/mL, respectively). A significant (P < 0.05) difference existed between the control and infertile male dromedaries in serum concentrations of sPLA2, CRISP3, malonialdehyde, and insulinlike growth factor 1. In conclusion, CRISP3, sPLA2, GPx, and testosterone are fertility-associated biomarkers in both seminal plasma and serum of dromedary camels. Seminal plasma osteopontin is positively correlated and prostaglandin D synthase (lipocalcin type) is negatively correlated with camels' fertility. Serum malonialdehyde, insulinlike growth factor 1, and clusterin are negatively correlated with fertility of male dromedary camels. PMID- 25434776 TI - Low-dose natural prostaglandin F2alpha (dinoprost) at timed insemination improves conception rate in dairy cattle. AB - The primary objective was to determine if low doses of PGF2alpha (dinoprost) given intramuscularly (im) concurrent with timed artificial insemination (TAI) would improve conception rates in dairy cattle. A secondary objective was to determine if body condition score (BCS) and parity would influence conception rates, either independently or in interaction with PGF2alpha treatment. In experiment I, 307 lactating Holstein cows were randomly assigned to receive either 5-mg PGF2alpha im (PGF2alpha treated, n = 154) or 0-mg PGF2alpha (control, n = 153) at TAI (Day 0). Blood samples were obtained on Days -10, -3, 0, and 7 to determine plasma progesterone (P4) concentrations. Pregnancy was confirmed 30 to 32 days after insemination by transrectal ultrasonography. In experiment II, 451 cows were randomly assigned to receive either 10-mg PGF2alpha im (PGF2alpha treated, n = 226) or 0-mg PGF2alpha (control, n = 225) at TAI, and pregnancy was confirmed 45 to 50 days after TAI by palpation per rectum. Pregnancy data were analyzed by CATMOD (SAS). In experiment I, PGF2alpha treatment, BCS, and parity did not affect conception rate (35.7% vs. 37.0% for PGF2alpha treated vs. control; P > 0.05). However, in experiment II, conception rates were higher in cows given 10-mg PGF2alpha than those in control cows (45.8% vs. 36.0%; P < 0.05), in cows with high BCS than in cows with low BCS (52.1% vs. 30.4%; P < 0.01), and in primiparous than in multiparous cows (47.6% vs. 34.4%; P < 0.01), but their interaction with PGF2alpha treatment did not affect conception rates. In summary, 5 mg of PGF2alpha given im concurrent with TAI failed to enhance conception rate in lactating dairy cows, whereas 10 mg of PGF2alpha significantly increased conception rate. PMID- 25434777 TI - Effect of horizontal pick and place locations on shoulder kinematics. AB - In this study the effects of horizontal bin locations in an order picking workstation on upper arm elevation, trunk inclination and hand use were investigated. Eight subjects moved (self-paced) light or heavy products (0.2 and 3.0 kg) from a central product bin to an inner or outer order bin (at 60 or 150 cm) on the left or right side of the workstation, while movements were recorded. The outer compared to inner bin location resulted in more upper arm elevation and trunk inclination per work cycle, both in terms of number of peak values and in terms of time integrals of angles (which is a dose measure over time). Considering the peak values and time integrals per minute (instead of per work cycle), these effects are reduced, due to the higher cycle times for outer bins. Hand use (left, right or both) was not affected by order bin locations. PMID- 25434778 TI - Sustained immobilization of growth factor proteins based on functionalized parylenes. AB - Protein molecules immobilized on biomaterial surfaces are performed based on oriented conjugation or replaced mimicking peptides. The sustainable immobilization of growth factor proteins using functionalized parylene coatings is demonstrated in this study. Site-specific and nonspecific immobilization approaches are realized to conjugate bone morphogenetic protein (BMP-2). The binding affinities and conformational changes of BMP-2 are confirmed by QCM and SPR characterizations. Osteoinduction of stem cells is examined by ALP activity on the BMP-2 modified surfaces. Finally, immobilizations and equally sustained biological functions of vascular endothelial growth factor (VEGF) and a mimicking peptide of KLTWQELYQLKYKG (QK) are also examined and confirmed. PMID- 25434779 TI - Commentary: Treatment of periodontitis: effectively managing mucogingival defects. PMID- 25434780 TI - Commentary: Periodontitis severity and progression are modified by various host and environmental factors. PMID- 25434782 TI - Contributing factors to errors in Swedish emergency departments. AB - OBJECTIVE: The Emergency Department (ED) is a complex and dynamic environment, often resulting in a somewhat uncontrolled and unpredictable workload. Contributing factors to errors in health care and in the ED are largely related to communication breakdowns. Moreover, the ED work environment is predisposed to multitasking, overcrowding and interruptions. These factors are assumed to have a negative impact on patient safety. Reported errors from care providers are mainly related to diagnostic procedures in Swedish EDs. However, there is a lack of knowledge and national oversight regarding contributing factors. The aim of this study was therefore to describe contributing factors in regards to errors occurring in Swedish EDs. METHOD: Descriptive design based on registry data from the Lex Maria database of the Swedish National Board of Health and Welfare. RESULTS: The results indicate that factors contributing to errors in Swedish EDs are multifactorial in nature. The most common contributing factor was human error followed by factors in the local ED environment and teamwork failure. CONCLUSION: Factors contributing to ED errors were multifactorial and included both organizational and teamwork failure in which human error was implicated. To reduce errors, further research is needed to develop methods that disclose latent working conditions such as high workload and interruptions. Patient safety research needs to include understanding of human behaviour in complex organizational systems and the impact of working conditions on patient safety and quality of care. PMID- 25434783 TI - Biomechanical evaluation of internal fixation techniques for unstable meso-type os acromiale. AB - BACKGROUND: Several internal fixation surgical techniques have been described for the treatment of symptomatic os acromiale. The purpose of this study was to compare the biomechanical characteristics of different internal fixation techniques for the operative treatment of unstable meso-type os acromiale in a cadaveric model. METHODS: Testing was performed on 12 matched pairs of cadaveric acromia with simulated meso-type os acromiale. Twelve specimens were prepared with 2 cannulated 4.0-mm screws only (SO group), inserted in the anterior posterior direction. Contralateral specimens were repaired with screws and a tension band (TB group). An inferiorly directed load to the anterior acromion was applied at a rate of 60 mm/min until failure. Ultimate failure load, stiffness, and fracture pattern were recorded and analyzed. RESULTS: Ultimate failure load was significantly higher for the TB group (mean, 336 N +/- 126 N; range, 166-623 N; P = .01) than for the SO group (mean, 242 N +/- 57 N; range, 186-365 N). In contrast, no significant difference in stiffness was found between the SO group (mean, 22.1 N/mm +/- 4.7 N/mm; range, 13.0-33.3 N/mm; P = .94)) and the TB group (mean, 22.2 N/mm +/- 2.9 N/mm; range, 18.2-26.6 N/mm). CONCLUSION: Surgical repair of simulated unstable meso-type os acromiale by a combination of cannulated screws with a tension band leads to significantly higher repair strength at time zero in a cadaveric model compared with cannulated screws alone. PMID- 25434785 TI - Combination of Unmix and PMF receptor model to apportion the potential sources and contributions of PAHs in wetland soils from Jiaozhou Bay, China. AB - 16 PAHs in Jiaozhou Bay wetland soils were analyzed by GC/MS. The potential sources and contributions were apportioned by Unmix and PMF models. The total concentrations of PAHs ranged from 176.1 to 563.3 ng/g with a mean of 345.3 ng/g. 2- and 3- rings PAHs were the dominant species accounting for 34.7-87.3% of the total PAHs. The similarities and differences of sources and contributions estimated by Unmix and PMF models were discussed. Three common sources (petrogenic source, coking oven and coal combustion) identified by two models, contributed 43.2%, 39.2% and 12.6% by Unmix and 33.5%, 29.1% and 16.0% by PMF to the total PAHs, respectively. In addition, diesel emission source (5.0%) by Unmix and a mixed source of diesel emission and natural gas burning (21.4%) by PMF were also extracted. It is essential to apply multiple source apportionment techniques to estimate potential source and contributions in further study. PMID- 25434784 TI - Analysis of underlying causes of inter-expert disagreement in retinopathy of prematurity diagnosis. Application of machine learning principles. AB - OBJECTIVE: Inter-expert variability in image-based clinical diagnosis has been demonstrated in many diseases including retinopathy of prematurity (ROP), which is a disease affecting low birth weight infants and is a major cause of childhood blindness. In order to better understand the underlying causes of variability among experts, we propose a method to quantify the variability of expert decisions and analyze the relationship between expert diagnoses and features computed from the images. Identification of these features is relevant for development of computer-based decision support systems and educational systems in ROP, and these methods may be applicable to other diseases where inter-expert variability is observed. METHODS: The experiments were carried out on a dataset of 34 retinal images, each with diagnoses provided independently by 22 experts. Analysis was performed using concepts of Mutual Information (MI) and Kernel Density Estimation. A large set of structural features (a total of 66) were extracted from retinal images. Feature selection was utilized to identify the most important features that correlated to actual clinical decisions by the 22 study experts. The best three features for each observer were selected by an exhaustive search on all possible feature subsets and considering joint MI as a relevance criterion. We also compared our results with the results of Cohen's Kappa [36] as an inter-rater reliability measure. RESULTS: The results demonstrate that a group of observers (17 among 22) decide consistently with each other. Mean and second central moment of arteriolar tortuosity is among the reasons of disagreement between this group and the rest of the observers, meaning that the group of experts consider amount of tortuosity as well as the variation of tortuosity in the image. CONCLUSION: Given a set of image-based features, the proposed analysis method can identify critical image-based features that lead to expert agreement and disagreement in diagnosis of ROP. Although tree-based features and various statistics such as central moment are not popular in the literature, our results suggest that they are important for diagnosis. PMID- 25434786 TI - People's experiences of using outdoor gym equipment in parks. PMID- 25434787 TI - Ubiquitously expressed transcript is a novel interacting protein of protein inhibitor of activated signal transducer and activator of transcription 2. AB - Protein inhibitor of activated signal transducer and activator of transcription 2 (PIAS2) is a member of the PIAS protein family. This protein family modulates the activity of several transcription factors and acts as an E3 ubiquitin ligase in the sumoylation pathway. To improve understanding of the physiological roles of PIAS2, the current study used a yeast two-hybrid system to screen mouse stem cell cDNA libraries for proteins that interact with PIAS2. The screening identified an interaction between PIAS2 and ubiquitously expressed transcript (UXT). UXT, also termed androgen receptor trapped clone-27, is an alpha-class prefoldin-type chaperone that acts as a coregulator for various transcription factors, including nuclear factor-kappaB and androgen receptor (AR). A direct interaction between PIAS2 and UXT was confirmed by direct yeast two-hybrid analysis. In vitro evidence of the association of UXT with PIAS2 was obtained by co immunoprecipitation. Colocalization between PIAS2 and UXT was identified in the nucleus and cytoplasm of HEK 293T and human cervical carcinoma HeLa cells. The results of the current study suggested that UXT is a binding protein of PIAS2, and interaction between PIAS2 and UXT may be important for the transcriptional activation of AR. PMID- 25434788 TI - Ruthenium-catalyzed direct C3 alkylation of indoles with alpha,beta-unsaturated ketones. AB - In this paper, a simple and highly efficient ruthenium-catalyzed direct C3 alkylation of indoles with various alpha,beta-unsaturated ketones without chelation assistance has been developed. This novel C-H activation methodology exhibits a broad substrate scope such as different substituted indoles, pyrroles, and other azoles. Further synthetic applications of the alkylation products can lead to more attractive 3,4-fused tricyclic indoles. PMID- 25434789 TI - Comparison between preoperative digital planning and postoperative outcomes in 197 hip endoprosthesis cases using short stem prostheses. AB - BACKGROUND: Preservation of hip geometry is important for treatment success in endoprosthesis implantation. Digital planning can be used to estimate postoperative hip geometry. This study examined whether digital planning accurately predicts surgical outcomes for two femoral neck resecting short stem implants, Mayo(r) (Zimmer) and Metha(r) (Aesculap). METHODS: Preoperative digital planning of the short stem and acetabular cup was performed for 191 patients (197 endoprostheses) with hip osteoarthritis. Digital planning was done with mediCAD II (Hectec) to evaluate types of prosthesis stems and sizes, leg lengthening and offset, and angle of stem inclination within the femur. The predicted values for these parameters were compared to the postoperative measurements. A double coordinate system was developed to measure pelvic and femoral distances separately. Individual scale factors were applied to minimize measurement bias. FINDINGS: Implantation of the planned short stem prostheses resulted in a mean femoro-acetabular leg lengthening of 4.2mm (SD 5.8mm) and a mean femoro acetabular offset-reduction of 4.2mm (SD 5.9mm) in comparison with preoperative planning. Implantation of both stems resulted in increased valgization compared to planning (Metha(r), mean 5.4 degrees (SD 3.7 degrees ); Mayo(r), mean -3.2 degrees (SD 3.4 degrees )). INTERPRETATION: Differences between preoperative planning and postoperative outcomes were greater for femoro-acetabular than for cup-related leg length and offset. On average, leg length was longer than predicted and there was loss of femoro-acetabular offset. Compared with the planning, valgization of the implanted stems was frequently observed. PMID- 25434790 TI - Assembly of metal-organic polyhedra into highly porous frameworks for ethene delivery. AB - Two new mesoporous metal-organic frameworks (DUT-75 and DUT-76) with exceptional ethene uptake were obtained using carbazole dicarboxylate based metal-organic polyhedra as supermolecular building blocks. The compounds have a total pore volume of 1.84 and 3.25 cm(3) g(-1) and a specific BET surface area of 4081 and 6344 m(2) g(-1), respectively, and high gas uptake at room temperature and high pressure. PMID- 25434791 TI - Health related quality of life in patients with bladder cancer: a cross-sectional survey and validation study of the Hungarian version of the Bladder Cancer Index. AB - Health-related quality of life (HRQoL) is an important outcome in oncology care although an underexplored area in bladder cancer (BC). Our aims were to assess HRQoL of patients with BC, analyse relationships between diverse HRQoL measures and validate the Hungarian version of the Bladder Cancer Index (BCI) questionnaire. A cross-sectional survey was performed among patients with BC (N = 151). Validated Hungarian versions of the FACT-Bl, SF-36 and EQ-5D were applied and SF-6D was derived. Psychometric analysis of the Hungarian BCI was performed. Pearson correlations between the five measures were analysed. Deterioration in SF 36 Physical Functioning was detected among patients aged 45-64 years. The EQ-5D score did not differ significantly from the age-matched population norm. Correlations between the FACT-Bl, EQ-5D and SF-6D utility measures were strong (r > 0.6). Cronbach alpha coefficients of the Hungarian BCI ranged from 0.75 to 0.97 and factor analysis confirmed that data fit to the six predefined subdomains. Test-retest correlations (reliability, N = 50) ranged from 0.67 to 0.87 and interscale correlations between urinary, bowel and sexual BCI domains were weak or moderate (r = 0.29 to 0.49). Convergent validity revealed a stronger correlation with FACT-Bl (r = 0.126 to 0.719) than with generic health state scores (r = 0.096 to 0.584). Results of divergent validity of the Hungarian BCI by treatment groups by Kruskal Wallis test were promising although limited by low sample sizes in cystectomy subgroups. Generic health state measures have limited capacity to capture HRQoL impact of BC. Validity tests yielded favourable results for the Hungarian BCI. Mapping studies to estimate utility scores from FACT-Bl are encouraged but less recommendable with the BCI. PMID- 25434792 TI - Factors associated with HPV awareness among mothers of low-income ethnic minority adolescent girls in Los Angeles. AB - Among caregivers of adolescent girls, awareness of human papillomavirus (HPV) is strongly associated with vaccine uptake. Little is known, however, about the predictors of HPV awareness among low-income ethnic minority groups in the U.S. The purpose of this study is to understand demographic factors associated with HPV awareness among low-income, ethnic minority mothers in Los Angeles County. We conducted a cross-sectional study of caregivers of adolescent girls through the Los Angeles County Department of Public Health Office of Women's Health's hotline. The majority of the participants were foreign-born (88%), one quarter lacked a usual source of care, and one quarter lacked public or private health insurance for their daughter. We found that one in three participants had never heard of HPV or the vaccine. Mothers that were unaware of HPV were significantly more likely to conduct the interview in a language other than English and to lack health insurance for their daughters. HPV vaccine awareness was much lower in our caregiver sample (61%) than in a simultaneous national survey of caregivers (85%). The associations between lack of awareness and use of a language other than English, as well as lack of health insurance for their daughter indicate the need for HPV vaccine outreach efforts tailored to ethnic minority communities in the U.S. PMID- 25434793 TI - [Characteristics of ocular involvement in Behcet disease in Tunisia: Monocentric study and review of literature]. AB - BACKGROUND: Behcet's disease is a multisystemic inflammatory disease characterized by recurrent oral and genital ulcers, skin lesions and uveitis. The diagnosis of Behcet's disease is based on clinical criteria. The etiology of the disease is unknown but the wide variations of ethnic prevalence and of the prevalence in the same ethnic group in different geographic areas indicate environmental triggering of a genetically determined disorder. PATIENTS AND METHODS: A retrospective analysis of the medical charts of 150 Behcet's disease patients seen in our internal medicine department between 1995 and 2010 was undertaken. Patients with confirmed ocular involvement were analyzed and compared with those without ocular involvement. RESULTS: Among the 150 medical charts studied, 85 patients were included in the study. Thirty-three patients (38.5%) had ocular involvement. Mean age at ocular BD diagnosis onset were 35.3. Male to female ratio was 5.6. Ocular involvement was bilateral in 26 patients (78.8%). Uveitis was the most common ocular lesion (n=31 patients, 93.9%). Panuveitis was the most common anatomical location (n=21, 63.6%). The comparison of patients treated for BD with or without ocular involvement showed a statistically significant association between ocular and neurological manifestations (p=0.03). All patients with ocular involvement were treated with corticosteroids. Immunosuppressive (IS) treatments were used in 28 patients (84.8%). Cyclophosphamide was the most used as first-line treatment (71.4%). Cyclophosphamide relayed by azathioprine was the most adopted protocol (28.5%). In case of resistance or relapse and depending on the other manifestations of the BD, the IS used in first intention was replaced by another one. Seven of the 33 patients had received treatment with infliximab (IFX) after failure of other therapeutic lines. CONCLUSION: Ocular prognosis in the BD can be improved by early treatment and regular monitoring. It is important to adjust the therapeutic protocol to the anatomic form, to the severity of uveitis and to the extra-ocular manifestations associated. PMID- 25434794 TI - [Applications of MALDI-TOF technology in clinical microbiology]. AB - Until now, the identification of micro-organisms has been based on the cultural and biochemical characteristics of bacterial and fungal species. Recently, Mass Spectrometry type Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF MS) was developed in clinical microbiology laboratories. This new technology allows identification of micro-organisms directly from colonies of bacteria and fungi within few minutes. In addition, it can be used to identify germs directly from positive blood culture bottles or directly from urine samples. Other ways are being explored to expand the use of MALDI-TOF in clinical microbiology laboratories. Indeed, some studies propose to detect bacterial antibiotic resistance while others compare strains within species for faster strain typing. The main objective of this review is to update data from the recent literature for different applications of MALDI-TOF technique in microbiological diagnostic routine. PMID- 25434795 TI - The positive is inside the negative: HER2-negative tumors can express the HER2 intracellular domain and present a HER2-positive phenotype. AB - Overexpression of human epithelial growth factor receptor 2 (HER2) is a poor prognostic factor in breast cancer. HER2 is a transmembrane receptor comprising an extracellular domain (ECD), a single transmembrane domain, and an intracellular domain (ICD) with tyrosine-kinase activity. Receptor dimerization triggers pivotal effector pathways in cancer, such as phosphatidylinositol 3 kinase (PI3K) signaling. Currently, screening of HER2 in breast tumors for prognostic and therapeutic purposes involves immunohistochemical (IHC) phenotyping for the ECD, in which tumors with IHC scores below 2+ are reported as HER2-negative. We used a label-free liquid chromatography-mass spectrometry (LC MS) proteomic approach to compare plasma samples from patients with HER2-positive breast tumors and patients with HER2-negative tumors. Patients with HER2-negative tumors expressed higher circulating levels of calpain-10 than patients with HER2 positive tumors. Calpains cleave HER2, releasing its ECD and transforming phenotypically positive tumors into phenotypically negative tumors. Therefore, we investigated the expression of the ICD in HER2-negative samples that overexpressed calpain-10. We found that 16% of HER2-negative tumors were positive for HER2-ICD, which was associated with circulating HER2-ECD. HER2 gene amplification was also observed in some HER2-negative tumors. Positive staining for the PI3K pathway was observed in the HER2-negative, ICD-positive tumors, similar to the HER2-positive cohort. Microarray analysis revealed that HER2 negative, ICD-positive samples clustered between HER2-positive tumors and triple negative tumors. Survival analysis revealed that outcome in women with HER2 negative, ICD-positive tumors was better than in women bearing HER2-negative, ICD negative (triple negative) tumors but was quite similar to HER2-positive tumors and worse than women with luminal A tumors. Moreover, in vitro analyses revealed that MDA-MB 231, a triple negative cell line, possesses calpain-10 and HER2-p-ICD up-regulation and blockage of calpain-10 activity promoted an increase in HER2-p ICD and p-AKT levels, suggesting an increase in these pathways signaling. These data indicate that HER2-negative tumors with HER2-ICD positivity exhibit clinical behavior closer to that of HER2-positive tumors. This indicates a need for HER2 ICD screening when determining the molecular profile of breast tumors. These findings further indicate that lapatinib should be investigated as a target therapy for HER2-ICD-positive breast tumors. PMID- 25434796 TI - ICAT inhibits glioblastoma cell proliferation by suppressing Wnt/beta-catenin activity. AB - Inhibitor of beta-catenin and T-cell factor (ICAT) is a key component of Wnt/beta catenin signaling. ICAT blocks the formation of the beta-catenin/TCF complex and has been demonstrated to be involved in embryonic development and carcinogenesis. As an inhibitor of canonical Wnt signaling, ICAT was presumed to be a tumor suppressor gene. However, the ICAT functions in human glioma remain unknown. In this study, we evaluated the expression of ICAT in 305 human glioma tissues and found that negative ICAT expression correlated with higher grade glioma and poor survival in patients with glioma. Then we transfected glioma cells with ICAT plasmid. Western blotting showed an increased ICAT protein expression level in glioma cells. MTT assay, flow cytometry and cell invasion assay were used to detect cell proliferation, cell cycle distribution, apoptosis and invasion. Our studies confirmed that ICAT inhibits glioma cell proliferation and invasion, and it induces cell apoptosis and cell cycle progression arrest. Besides, ICAT slowed down tumor growth in a glioblastoma xenograft model. Therefore, our study demonstrates that ICAT may serve as a tumor-suppressor in human glioma suggesting a promising direction for targeting therapy in glioma. PMID- 25434797 TI - RETRACTED: Silencing EGFR/HER3 signaling with a novel anti-EGFR domain II/IV antibody. AB - Dysfunction of the epidermal growth factor receptor (EGFR) family, is the key process in tumorigenesis, and anti-EGFR therapeutic strategies such as cetuximab therapy now are used in the treatment of cancer. However, resistance to cetuximab is commonly reported. Comprehensive blockade of EGFR signaling using different antibodies might be critical to treat cancer effectively and limit drug resistance with potent novel mechanisms. Here, we launch a screen of a phage display library to isolate a novel anti-EGFR antibody, YAH627. YAH627 exhibits superior efficacy in inhibiting EGFR activation, particularly by blocking EGF/HRG induced EGFR/HER3 heterodimerization and signaling, verifying it as an impressive candidate for clinical translation as a therapeutic antibody. Moreover, we use epitope analysis validates that the epitope of this antibody is within domains II and IV of EGFR and traps EGFR in a silent conformation. Moreover, combining YAH627 with cetuximab produces synergistic antitumor activity in vitro and in vivo. Taken together, our report establishes that YAH627 possesses a novel mechanism of action that, in combination with cetuximab, may achieve clinical efficacy in EGFR-driven cancers. PMID- 25434798 TI - An EGF receptor targeting Ranpirnase-diabody fusion protein mediates potent antitumour activity in vitro and in vivo. AB - Cytotoxic ribonucleases such as the leopard frog derivative Ranpirnase (Onconase((r))) have emerged as a valuable new class of cancer therapeutics. Clinical trials employing single agent Ranpirnase in cancer patients have demonstrated significant clinical activity and surprisingly low immunogenicity. However, dose-limiting toxicity due to unspecific uptake of the RNase into non cancerous cells is reached at relatively low concentrations of > 1 mg/m(2). We have in the present study generated a dimeric anti-EGFR Ranpirnase-diabody fusion protein capable to deliver two Ranpirnase moieties per molecule to EGFR-positive tumour cells. We show that this compound mediated far superior efficacy for killing EGFR-positive tumour cells than a monomeric counterpart. Most importantly, cell killing was restricted to EGFR-positive target cells and no dose-limiting toxicity of Ranpirnase-diabody was observed in mice. These data indicate that by targeted delivery of Ranpirnase non-selective toxicity can be abolished and suggests Ranpirnase-diabody as a promising new drug for therapeutic interventions in EGFR-positive cancers. PMID- 25434800 TI - Alantolactone selectively suppresses STAT3 activation and exhibits potent anticancer activity in MDA-MB-231 cells. AB - The important goal of cancer drug discovery is to develop therapeutic agents that are effective, safe, and affordable. In the present study, we demonstrated that alantolactone, which is a sesquiterpene lactone, has potential activity against triple-negative breast cancer MDA-MB-231 cells by suppressing the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Alantolactone effectively suppressed both constitutive and inducible STAT3 activation at tyrosine 705. Alantolactone decreased STAT3 translocation to the nucleus, its DNA-binding, and STAT3 target gene expression. Alantolactone significantly inhibits STAT3 activation with a marginal effect on MAPKs and on NF kappaB transcription; however, this effect is not mediated by inhibiting STAT3 upstream kinases. Although SHP-1, SHP-2, and PTEN, which are protein tyrosine phosphatases (PTPs), were not affected by alantolactone, the treatment with a PTP inhibitor reversed the alantolactone-induced suppression of STAT3 activation, indicating that PTP plays an important role in the action of alantolactone. Finally, alantolactone treatment resulted in the inhibition of migration, invasion, adhesion, and colony formation. The in vivo administration of alantolactone inhibited the growth of human breast xenograft tumors. These results provide preclinical evidence to continue the development of alantolactone as a STAT3 inhibitor and as a potential therapeutic agent against breast cancer. PMID- 25434799 TI - miR-26a suppresses tumour proliferation and metastasis by targeting metadherin in triple negative breast cancer. AB - It has been reported that miR-26a plays an important role in various cancers. In this study, we found that miR-26a was downregulated in triple-negative breast cancer (TNBC), and its expression levels were associated with lymph node metastasis and overall survival in TNBC. We also found that the ectopic expression of miR-26a inhibited TNBC cell proliferation and metastasis in vitro and in vivo by downregulating MTDH (a miR-26a' target gene) mRNA and protein and that the overexpression of MTDH could partially abrogate miR-26a-mediated suppression. Our data suggest that miR-26a functions as a tumour suppressor in TNBC development and serves as a prognostic marker for breast cancer. PMID- 25434801 TI - Differential microRNA expression profiles in HCT116 colorectal cancer cell lines located in the lung and colon. AB - Colorectal cancer (CRC) is one of the most common types of cancer worldwide. The majority of mortalities caused by colorectal cancer are due to metastatic disease. As numerous CRC patients experience metastasis to the liver or lung and fail to respond to curative therapies, intensive research efforts have sought to identify the molecular changes or regulatory mechanisms underlying CRC metastasis. In the present study, a stable CRC cell line, HCT16, overexpressing firefly luciferase was constructed and an in vivo metastasis model was established via intravenous injection of this cell line. Using an imaging system, tumor tissue located in the lung and colon was separated and cells were prepared. The microRNA (miRNA) expression profiles of these lung homing or colon homing cells were assessed and compared. A total of 38 differentially expressed miRNAs were selected and confirmed our previous results; several of these have been reported to be involved in the regulation of cancer progression. However, the remaining miRNAs require further investigation. The present profiling may be the first step toward delineating the differential expression of miRNAs in the CRC cells located in the colon and the lung, enabling the elucidation of the regulation associated with miRNAs in colorectal lung metastases. These miRNAs require further validation and functional analysis to evaluate whether they are important in the pathogenesis of colorectal lung metastases or are adopted as markers to predict colorectal metastasis. PMID- 25434802 TI - Feature selection and classifier performance on diverse bio- logical datasets. AB - BACKGROUND: There is an ever-expanding range of technologies that generate very large numbers of biomarkers for research and clinical applications. Choosing the most informative biomarkers from a high-dimensional data set, combined with identifying the most reliable and accurate classification algorithms to use with that biomarker set, can be a daunting task. Existing surveys of feature selection and classification algorithms typically focus on a single data type, such as gene expression microarrays, and rarely explore the model's performance across multiple biological data types. RESULTS: This paper presents the results of a large scale empirical study whereby a large number of popular feature selection and classification algorithms are used to identify the tissue of origin for the NCI-60 cancer cell lines. A computational pipeline was implemented to maximize predictive accuracy of all models at all parameters on five different data types available for the NCI-60 cell lines. A validation experiment was conducted using external data in order to demonstrate robustness. CONCLUSIONS: As expected, the data type and number of biomarkers have a significant effect on the performance of the predictive models. Although no model or data type uniformly outperforms the others across the entire range of tested numbers of markers, several clear trends are visible. At low numbers of biomarkers gene and protein expression data types are able to differentiate between cancer cell lines significantly better than the other three data types, namely SNP, array comparative genome hybridization (aCGH), and microRNA data. PMID- 25434803 TI - Insights into the interactions between enzyme and co-solvents: stability and activity of stem bromelain. AB - In present study, an attempt is made to elucidate the effects of various naturally occurring osmolytes and denaturants on BM at pH 7.0. The effects of the varying concentrations of glycerol, sorbitol, sucrose, trehalose, urea and guanidinium chloride (GdnHCl) on structure, stability and activity of BM are explored by fluorescence spectroscopy, circular dichroism (CD), UV-vis spectroscopy and sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS PAGE). Our experimental observations reveal that glycerol and sorbitol are acting as stabilizers at all concentrations while sucrose and trehalose are found to be destabilizers at lower concentrations, however, acted as stabilizers at higher concentrations. On the other hand, urea and GdnHCl are denaturants except at lower concentrations. There is a direct relationship between activity and conformational stability as the activity data are found to be in accordance with conformational stability parameters (DeltaGu, Tm, DeltaCp) and BM profile on SDS PAGE. PMID- 25434804 TI - Targeting chemical and thermal stability of ovalbumin by simulated honey sugar cocktail. AB - Effect of simulated honey sugar cocktail (SHSC) on chemical and thermal stability of ovalbumin (OVA) was investigated using multiple-spectroscopic techniques. Urea induced denaturation of OVA produced a transition, characterized by the start-, the mid- and the end-points at 3.2 M, 5.9/5.6 M and 8.5/8.0 M urea, respectively, when studied by MRE222nm and tryptophan fluorescence measurements. Presence of 10% or 20% (w/v) SHSC in the incubation mixture shifted the transition curve towards higher urea concentration in a concentration dependent manner. A comparison of far- and near-UV CD, UV-difference, ANS fluorescence and 3-D fluorescence spectral results of native OVA and 5.9 M urea-denatured OVA (U-OVA), obtained in the absence and the presence of 20% (w/v) SHSC suggested SHSC-induced stabilization of U-OVA. Furthermore, a significant shift towards higher denaturant concentration was also noticed in the GdnHCl and thermal transition curves of OVA in the presence of 20% (w/v) SHSC. Taken together, all these results suggested stabilization of OVA against chemical and thermal denaturations by SHSC. PMID- 25434805 TI - Structural and anti-inflammatory characterization of a novel neutral polysaccharide from North American ginseng (Panax quinquefolius). AB - Neutral polysaccharides are one of the active components in the American ginseng roots. Recently, the studies about American ginseng polysaccharides are mainly centered on acidic polysaccharides, while there is relatively limited research that explores neutral polysaccharides. In this study a novel neutral polysaccharide (PPQN) was isolated from American ginseng roots and its structure and anti-inflammatory activity were investigated. The average molecular weight (Mw) of PPQN was 3.1 kDa. Monosaccharide components' analysis indicated that PPQN was composed of glucose (Glc) and galactose (Gal) in a molar ratio of 1:1.15. Secretions of nitric oxide (NO), TNF-alpha, IL-6, and IL-1beta after lipopolysaccharide (LPS) stimulation were detected in PPQN pre-treatment RAW264.7 macrophages. PPQN (150 MUg/mL) exhibited more effective inhibition of TNF-alpha, IL-1beta, and IL-6 secretions, followed by NO production with respective values of 40.5%, 41.1%, 34.4%, and 11.1% suppression. These results indicated that PPQN may have therapeutic implications in treatment of inflammation and inflammatory related diseases. PMID- 25434806 TI - Prevalence and behavioural risk factors of Staphylococcus aureus nasal colonization in community-based injection drug users. AB - The aims of this study were to identify Staphylococcus aureus nasal colonization prevalence, behavioural risk factors, and to determine staphylococcal protein A (spa) types in community-based injection drug users (IDUs). Nasal swabs were collected and methicillin susceptibility testing and spa/SCCmec typing were performed on S. aureus isolates. Generalized estimating equations were used to report adjusted odds ratios and 95% confidence intervals. Of the 440 participants, 24.1% were colonized and 5.7% had methicillin-resistant S. aureus (MRSA). Colonization was associated with age, employment/marital status, and the presence of scabs but not with sexually transmitted disease co-infection, HIV status, antibiotic use, hospitalization, or drug treatment programme participation. The USA300 MRSA clone spa types were most common, but 15/49 spa types were new to one of the international databases. Community-based IDUs appear to have different risk factors compared to IDUs from clinical studies. In addition, the number of newly identified spa types indicates a diverse, understudied population. PMID- 25434807 TI - Role of the sympathetic nervous system and spleen in experimental stroke-induced immunodepression. AB - BACKGROUND: The mechanism of stroke-induced immunodepression syndrome (SIDS) remains uncertain. Some studies suggest that hyperactivation of the sympathetic nervous system (SNS) may be the key factor underlying SIDS. Catecholamines impair early lymphocyte response, which can increase the risk of stroke-associated infection (SAI). MATERIAL/METHODS: Our study focused on dynamic changes of metanephrine (MN), normetanephrine (NMN), cytokines, and spleen volume in the rat middle cerebral artery occlusion (MCAO) model. RESULTS: After MCAO, there is hyperactivation of SNS and pro-/anti-inflammatory imbalance, indicating systemic immunodepression. In addition, rat spleen size was reduced. Correlation analysis indicated that MCAO-induced spleen size reduction correlated with the changes in MN, NMN, and cytokines. Blocking SNS with propranolol can partly reverse the immunodepression and the reduction in spleen volume. CONCLUSIONS: Taken together, these findings suggest that acute ischemic stroke induces over-activation of the SNS, which lowers the threshold of infection and increases the risk of infection. PMID- 25434808 TI - Evaluations of secondary cancer risk in spine radiotherapy using 3DCRT, IMRT, and VMAT: A phantom study. AB - This study evaluated the secondary cancer risk from volumetric-modulated arc therapy (VMAT) for spine radiotherapy compared with intensity-modulated radiotherapy (IMRT) and 3-dimensional conformal radiotherapy (3DCRT). Computed tomography images of an Radiological Physics Center spine anthropomorphic phantom were exported to a treatment planning system (Pinnacle(3), version 9.4). Radiation treatment plans for spine were prepared using VMAT (dual-arc), 7-field IMRT (beam angles: 110 degrees , 130 degrees , 150 degrees , 180 degrees , 210 degrees , 230 degrees , and 250 degrees ), and 4-field 3DCRT technique. The mean and maximum doses, dose-volume histograms, and volumes receiving more than 2 and 4Gy to organs at risk (OARs) were calculated and compared. The lifetime risk for secondary cancers was estimated according to the National Cancer Registry Programme Report 116. VMAT delivered the lowest maximum dose to the esophagus (4.03Gy), bone (8.11Gy), heart (2.11Gy), spinal cord (6.45Gy), and whole lung (5.66Gy) as compared with other techniques (IMRT and 3DCRT). The volumes of OAR (esophagus) receiving more than 4Gy were 0% for VMAT, 27.06% for IMRT, and up to 32.35% for 3DCRT. The estimated risk for secondary cancer in the respective OAR is considerably lower in VMAT compared with other techniques. The results of maximum doses and volumes of OARs suggest that the risk of secondary cancer induction for the spine in VMAT is lower than IMRT and 3DCRT, whereas VMAT has the best target coverage compared with the other techniques. PMID- 25434809 TI - Theoretical evidence of metal-induced structural distortions in a series of bipyrimidine-based ligands. AB - Herein, we report theoretical evidence of the geometric changes occurring upon complexation, for a series of octupolar bipyrimidine-based ligands incorporating the NPh2 terminal donor group. It is shown that ligands 1 and 2 (4,4',6,6' tetrakis(N,N-diphenylaminostyryl)-[2,2']bipyrimidine and 4,4',6,6'-tetrakis((N,N diphenyl)-9,9'-dioctyl-9H-fluorene-2-amine)-2,2'-bipyrimidine) exhibit a non planar geometry with a torsion angle between both pyrimidine moieties of ~25 degrees and 50 degrees respectively. 1a (complex of 1) becomes planar upon addition of ZnCl2 to the bipyrimidine moiety whereas 2a remains distorted. Furthermore, an assignment of the absorption bands for all compounds is presented. PMID- 25434810 TI - Simultaneous gene inactivation and promoter reporting in cyanobacteria. AB - Determining spatiotemporal gene expression and analyzing knockout mutant phenotypes have become powerful tools in elucidating the function of genes; however, genetic approaches for simultaneously inactivating a gene and monitoring its expression have not been reported in the literature. In this study, we designed a dual-functional gene knockout vector pZR606 that contains a multiple cloning site (MCS) for inserting the internal fragment of a target gene, with a gfp gene as its transcriptional marker located immediately downstream of the MCS. By using this gene knockout system, we inactivated ava_2679 from Anabaena variabilis ATCC 29413, as well as all2508, alr2887, alr3608, and all4388 from Anabaena sp. strain PCC 7120. The ava_2679 knockout mutant fails to grow diazotrophically. Morphological analysis of ava_2679 knockout mutant after nitrogen step-down revealed defective junctions between heterocysts and adjacent vegetative cells, and the heterocyst was 1.53-fold longer compared to wild-type heterocysts. The alr2887, all4388, and alr3608 mutant colonies turned yellow and showed lack of protracted growth when deprived of fixed nitrogen, consistent with the previous reports that alr2887, all4388, and alr3608 are Fox genes. The all2508 encodes a GTP-binding elongation factor (EF4/LepA), and its knockout mutant exhibited reduced diazotrophic growth. The heterocyst development of all2508 knockout was significantly delayed, and only about 4.0 % of vegetative cells differentiated to heterocysts after nitrogen deprivation for 72 h, decreased 49.6 % compared to wild-type. Thus, we discovered that All2508 may regulate heterocyst development spatiotemporally. Concurrently, the GFP reporter revealed that all five target gene expressions were up-regulated in response to nitrogen deprivation. We demonstrated that the pZR606-based specific gene knockout approach worked effectively for the five selected genes, including four previously identified Fox genes or Fox gene homolog, and a previously unknown function of gene all2508. Thus, gene expression and phenotypic analysis of mutants can be achieved simultaneously by targeted gene inactivation using the pZR606-based system. This combined approach for targeted gene inactivation and its promoter reporting with GFP may be broadly applicable to the study of gene function in other prokaryotic organisms. PMID- 25434811 TI - L-Serine overproduction with minimization of by-product synthesis by engineered Corynebacterium glutamicum. AB - The direct fermentative production of L-serine by Corynebacterium glutamicum from sugars is attractive. However, superfluous by-product accumulation and low L serine productivity limit its industrial production on large scale. This study aimed to investigate metabolic and bioprocess engineering strategies towards eliminating by-products as well as increasing L-serine productivity. Deletion of alaT and avtA encoding the transaminases and introduction of an attenuated mutant of acetohydroxyacid synthase (AHAS) increased both L-serine production level (26.23 g/L) and its productivity (0.27 g/L/h). Compared to the parent strain, the by-products L-alanine and L-valine accumulation in the resulting strain were reduced by 87 % (from 9.80 to 1.23 g/L) and 60 % (from 6.54 to 2.63 g/L), respectively. The modification decreased the metabolic flow towards the branched chain amino acids (BCAAs) and induced to shift it towards L-serine production. Meanwhile, it was found that corn steep liquor (CSL) could stimulate cell growth and increase sucrose consumption rate as well as L-serine productivity. With addition of 2 g/L CSL, the resulting strain showed a significant improvement in the sucrose consumption rate (72 %) and the L-serine productivity (67 %). In fed batch fermentation, 42.62 g/L of L-serine accumulation was achieved with a productivity of 0.44 g/L/h and yield of 0.21 g/g sucrose, which was the highest production of L-serine from sugars to date. The results demonstrated that combined metabolic and bioprocess engineering strategies could minimize by product accumulation and improve L-serine productivity. PMID- 25434812 TI - Thermostability enhancement of an endo-1,4-beta-galactanase from Talaromyces stipitatus by site-directed mutagenesis. AB - Enzymatic conversion of pectinaceous biomasses such as potato and sugar beet pulp at high temperatures is advantageous as it gives rise to lower substrate viscosity, easier mixing, and increased substrate solubility and lowers the risk of contamination. Such high-temperature processing requires development of thermostable enzymes. Talaromyces stipitatus was found to secrete endo-1,4-beta galactanase when grown on sugar beet pectin as sole carbon source. The mature protein contained 353 AA and the MW was estimated to 36.5 kDa. It was subjected to codon optimization and produced in Pichia pastoris in 2 l scale yielding 5.3 g. The optimal reaction condition for the endo-1,4-beta-galactanase was determined to be 46 degrees C at pH 4.5 at which the specific activity was estimated to be 6.93 MUmol/min/mg enzyme with half-lives of 13 and 2 min at 55 and 60 degrees C, respectively. For enhancement of the half-life of TSGAL, nine single amino acid residues were selected for site-directed mutagenesis on the basis of semi-rational design. Of these nine mutants, G305A showed half-lives of 114 min at 55 degrees C and 15 min at 60 degrees C, respectively. This is 8.6 fold higher than that of the TSGAL at 55 degrees C, whereas the other mutants displayed moderate positive to negative changes in their half-lives. PMID- 25434813 TI - The influence of oxygen limitation for the production of succinic acid with recombinant strains of Yarrowia lipolytica. AB - The yeast Yarrowia lipolytica is able to produce high amounts of several organic acids such as pyruvic, citric, isocitric, alpha-ketoglutaric, and succinic acid. Here we report on the influence of the reduced activity of succinate dehydrogenase in Y. lipolytica on its ability to produce succinate. The recombinant strains Y. lipolytica H222-AZ1 and H222-AZ2 were created by exchange of the native promoter of the succinate dehydrogenase subunit 2 encoding gene by inducible promoters. During the cultivation of the strain Y. lipolytica H222-AZ1 in shaking flask experiments, it was found that the promoter exchange resulted in an increase in succinic acid (SA) production. Moreover, it was found that the production of SA depends on an additional limitation of oxygen. Fed-batch cultivations in 1-l bioreactors confirmed this fundamental finding. Y. lipolytica H222-AZ1 produced 2 g l(-1) of SA with oxygen supply and 9.2 g l(-1) under the limitation of oxygen after 165 h. By using a less active promoter in Y. lipolytica H222-AZ2, the production of SA was increased to 25 g l(-1) with a productivity of 0.152 g (l*h)(-1) and a selectivity of 67 % after 165 h. Yields of 2.39 g SA per gram biomass and 0.26 g SA per gram glycerol were found. PMID- 25434814 TI - Letter in response to "The Vitamin B12 analog cobinamide is an effective hydrogen sulfide antidote in a lethal rabbit model". PMID- 25434815 TI - Network-based approach for analyzing intra- and interfluid metabolite associations in human blood, urine, and saliva. AB - Most studies investigating human metabolomics measurements are limited to a single biofluid, most often blood or urine. An organism's biochemical pool, however, comprises complex transboundary relationships, which can only be understood by investigating metabolic interactions and physiological processes spanning multiple parts of the human body. Therefore, we here propose a data driven network-based approach to generate an integrated picture of metabolomics associations over multiple fluids. We performed an analysis of 2251 metabolites measured in plasma, urine, and saliva, from 374 participants of the Qatar Metabolomics Study on Diabetes (QMDiab). Gaussian graphical models (GGMs) were used to estimate metabolite-metabolite interactions on different subsets of the data set. First, we compared similarities and differences of the metabolome and the association networks between the three fluids. Second, we investigated the cross-talk between the fluids by analyzing correlations occurring between them. Third, we propose a framework for the analysis of medically relevant phenotypes by integrating type 2 diabetes, sex, age, and body mass index into our networks. In conclusion, we present a generic, data-driven network-based approach for structuring and visualizing metabolite correlations within and between multiple body fluids, enabling unbiased interpretation of metabolomics multifluid data. PMID- 25434816 TI - Intravenous immunoglobulin for severe sepsis and septic shock: clinical effectiveness, cost-effectiveness and value of a further randomised controlled trial. AB - INTRODUCTION: Prior to investing in a large, multicentre randomised controlled trial (RCT), the National Institute for Health Research in the UK called for an evaluation of the feasibility and value for money of undertaking a trial on intravenous immunoglobulin (IVIG) as an adjuvant therapy for severe sepsis/septic shock. METHODS: In response to this call, this study assessed the clinical and cost-effectiveness of IVIG (using a decision model), and evaluated the value of conducting an RCT (using expected value of information (EVI) analysis). The evidence informing such assessments was obtained through a series of systematic reviews and meta-analyses. Further primary data analyses were also undertaken using the Intensive Care National Audit & Research Centre Case Mix Programme Database, and a Scottish Intensive Care Society research study. RESULTS: We found a large degree of statistical heterogeneity in the clinical evidence on treatment effect, and the source of such heterogeneity was unclear. The incremental cost effectiveness ratio of IVIG is within the borderline region of estimates considered to represent value for money, but results appear highly sensitive to the choice of model used for clinical effectiveness. This was also the case with EVI estimates, with maximum payoffs from conducting a further clinical trial between L 137 and L 1,011 million. CONCLUSIONS: Our analyses suggest that there is a need for a further RCT. Results on the value of conducting such research, however, were sensitive to the clinical effectiveness model used, reflecting the high level of heterogeneity in the evidence base. PMID- 25434818 TI - Age-dependent effects of environmental enrichment on spatial memory and neurochemistry. AB - Although aging and environmental stimulation are well-known to affect cognitive abilities, the question of whether aging effects can be distinguished in already mature adult rats has not been fully addressed. In the present study, therefore, young and mature adult rats were housed in either enriched or standard conditions (EE or SC) for three months. Open-field (OFT) and radial-maze (RM) behavior, and ex-vivo contents of GABA and glutamate in hippocampus, and of dopamine and DOPAC in ventral striatum (VS) were analyzed and compared between the four groups. In OFT, young rats were more active than mature adults irrespective of the housing condition. Surprisingly, in the RM test, mature adults outperformed young counterparts except for the young-enriched rats, which showed a progressive improvement in RM performance. At the neurochemical level, young EE rats showed higher hippocampal glutamate and GABA concentrations, and DA turnover in VS, which correlated with RM performance. Altogether, the behavioral and cognitive strategies underlying habituation learning and spatial memory seem to be qualitatively different between the two ages analyzed. These results challenge the assumption that mature adult animals are always worse in learning and memory tasks. However, young rats benefited more from the social and physical stimulation provided by the enrichment than mature adult counterparts. The latter effect was evident not just on behavior, but also on brain neurochemistry. PMID- 25434817 TI - Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis. AB - Ras pathway mutation is frequent in carcinomas where it induces expression of the transcriptional repressor ZEB1. Although ZEB1 is classically linked to epithelial mesenchymal transition and tumour metastasis, it has an emerging second role in generation of cancer-initiating cells. Here we show that Ras induction of ZEB1 is required for tumour initiation in a lung cancer model, and we link this function to repression Pten, whose loss is critical for emergence of cancer-initiating cells. These two roles for ZEB1 in tumour progression can be distinguished by their requirement for different levels of ZEB1. A lower threshold of ZEB1 is sufficient for cancer initiation, whereas further induction is necessary for tumour metastasis. PMID- 25434819 TI - Zeta inhibitory peptide (ZIP) erases long-term memories in a cockroach. AB - Recent efforts to identify the molecules that are involved in the maintenance of long-term memories in mammals have focused attention on atypical isoforms of protein kinase C (PKC). Inhibition of these kinases by either the general PKC inhibitor, chelerythrine, or the more specific inhibitor, zeta inhibitory peptide (ZIP), can abolish both long-term potentiation in the hippocampus and as well as spatial, fear, appetitive, and sensorimotor memories. These inhibitors can also abolish long-term facilitation and long-term sensitization in the mollusk Aplysia californica. We have extended these results to an insect, the cockroach Leucophaea maderae. We show that systemic injections of either chelerythrine or ZIP erase long-term olfactory memories in the cockroach, but have no effect on memory acquisition during conditioning. We also show that inhibition of either protein kinase A (PKA) or protein synthesis can block memory acquisition but neither has an effect on the memory once it is formed. The results suggest that sustaining memories in insects requires the persistent activity of one or more isoforms of PKC and point to a strong evolutionary conservation of the molecular mechanisms that underlie the persistence of long-term memories in the central nervous system. PMID- 25434820 TI - Early depletion of primordial germ cells in zebrafish promotes testis formation. AB - As complete absence of germ cells leads to sterile males in zebrafish, we explored the relationship between primordial germ cell (PGC) number and sexual development. Our results revealed dimorphic proliferation of PGCs in the early zebrafish larvae, marking the beginning of sexual differentiation. We applied morpholino-based gene knockdown and cell transplantation strategies to demonstrate that a threshold number of PGCs is required for the stability of ovarian fate. Using histology and transcriptomic analyses, we determined that zebrafish gonads are in a meiotic ovarian stage at 14 days postfertilization and identified signaling pathways supporting meiotic oocyte differentiation and eventual female fate. The development of PGC-depleted gonads appears to be restrained and delayed, suggesting that PGC number may directly regulate the variability and length of gonadal transformation and testicular differentiation in zebrafish. We propose that gonadal transformation may function as a developmental buffering mechanism to ensure the reproductive outcome. PMID- 25434821 TI - Tracing dynamics and clonal heterogeneity of Cbx7-induced leukemic stem cells by cellular barcoding. AB - Accurate monitoring of tumor dynamics and leukemic stem cell (LSC) heterogeneity is important for the development of personalized cancer therapies. In this study, we experimentally induced distinct types of leukemia in mice by enforced expression of Cbx7. Simultaneous cellular barcoding allowed for thorough analysis of leukemias at the clonal level and revealed high and unpredictable tumor complexity. Multiple LSC clones with distinct leukemic properties coexisted. Some of these clones remained dormant but bore leukemic potential, as they progressed to full-blown leukemia after challenge. LSC clones could retain multilineage differentiation capacities, where one clone induced phenotypically distinct leukemias. Beyond a detailed insight into CBX7-driven leukemic biology, our model is of general relevance for the understanding of tumor dynamics and clonal evolution. PMID- 25434822 TI - Precise correction of the dystrophin gene in duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9. AB - Duchenne muscular dystrophy (DMD) is a severe muscle-degenerative disease caused by a mutation in the dystrophin gene. Genetic correction of patient-derived induced pluripotent stem cells (iPSCs) by TALENs or CRISPR-Cas9 holds promise for DMD gene therapy; however, the safety of such nuclease treatment must be determined. Using a unique k-mer database, we systematically identified a unique target region that reduces off-target sites. To restore the dystrophin protein, we performed three correction methods (exon skipping, frameshifting, and exon knockin) in DMD-patient-derived iPSCs, and found that exon knockin was the most effective approach. We further investigated the genomic integrity by karyotyping, copy number variation array, and exome sequencing to identify clones with a minimal mutation load. Finally, we differentiated the corrected iPSCs toward skeletal muscle cells and successfully detected the expression of full-length dystrophin protein. These results provide an important framework for developing iPSC-based gene therapy for genetic disorders using programmable nucleases. PMID- 25434824 TI - A tale of two forces: simultaneous chemical and acoustic propulsion of bimetallic micromotors. AB - Bimetallic gold-ruthenium microrods are propelled in opposite directions in water by ultrasound and by catalytic decomposition of hydrogen peroxide. This property was used to effect reversible swarming, to stall and reverse autonomous axial propulsion, and to study the chemically powered movement of acoustically levitated microrods. PMID- 25434825 TI - A simulation model to estimate cost-offsets for a disease-management program for chronic kidney disease. AB - AIM: The aim of this paper is to develop a simulation model that analyzes cost offsets of a hypothetical disease management program (DMP) for patients with chronic kidney disease (CKD) in Germany compared to no such program. METHODS: A lifetime Markov model with simulated 65-year-old patients with CKD was developed using published data on costs and health status and simulating the progression to end-stage renal disease (ESRD), cardiovascular disease and death. A statutory health insurance perspective was adopted. RESULTS: This modeling study shows considerable potential for cost-offsets from a DMP for patients with CKD. The potential for cost-offsets increases with relative risk reduction by the DMP and baseline glomerular filtration rate. Results are most sensitive to the cost of dialysis treatment. CONCLUSION: This paper presents a general 'prototype' simulation model for the prevention of ESRD. The model allows for further modification and adaptation in future applications. PMID- 25434823 TI - Oxymetholone therapy of fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling. AB - Androgens are widely used for treating Fanconi anemia (FA) and other human bone marrow failure syndromes, but their mode of action remains incompletely understood. Aged Fancd2(-/-) mice were used to assess the therapeutic efficacy of oxymetholone (OXM) and its mechanism of action. Eighteen-month-old Fancd2(-/-) mice recapitulated key human FA phenotypes, including reduced bone marrow cellularity, red cell macrocytosis, and peripheral pancytopenia. As in humans, chronic OXM treatment significantly improved these hematological parameters and stimulated the proliferation of hematopoietic stem and progenitor cells. RNA-Seq analysis implicated downregulation of osteopontin as an important potential mechanism for the drug's action. Consistent with the increased stem cell proliferation, competitive repopulation assays demonstrated that chronic OXM therapy eventually resulted in stem cell exhaustion. These results expand our knowledge of the regulation of hematopoietic stem cell proliferation and have direct clinical implications for the treatment of bone marrow failure. PMID- 25434826 TI - Unravelling orientation distribution and merging behavior of monolayer MoS2 domains on sapphire. AB - Monolayer MoS2 prepared by chemical vapor deposition (CVD) has a highly polycrystalline nature largely because of the coalescence of misoriented domains, which severely hinders its future applications. Identifying and even controlling the orientations of individual domains and understanding their merging behavior therefore hold fundamental significance. In this work, by using single crystalline sapphire (0001) substrates, we designed the CVD growth of monolayer MoS2 triangles and their polycrystalline aggregates for such purposes. The obtained triangular MoS2 domains on sapphire were found to distributively align in two directions, which, as supported by density functional theory calculations, should be attributed to the relatively small fluctuations of the interface binding energy around the two primary orientations. Using dark-field transmission electron microscopy, we further imaged the grain boundaries of the aggregating domains and determined their prevalent armchair crystallographic orientations with respect to the adjacent MoS2 lattice. The coalescence of individual triangular flakes governed by unique kinetic processes is proposed for the polycrystal formation. These findings are expected to shed light on the controlled MoS2 growth toward predefined domain orientation and large domain size, thus enabling its versatile applications in next-generation nanoelectronics and optoelectronics. PMID- 25434827 TI - Combination therapy with alpha-galactosylceramide and a Toll-like receptor agonist exerts an augmented suppressive effect on lung tumor metastasis in a mouse model. AB - alpha-galactosylceramide (GalCer), which is a natural killer T (NKT) cell ligand, has been reported to exert therapeutic effects against cancer in humans and mice. Toll-like receptor (TLR) agonists systemically or locally boost antitumor efficacy in mouse cancer models. In our previous study, the co-administration of GalCer and a TLR agonist synergistically enhanced interferon-gamma (IFN-gamma) production in mouse splenocytes in vitro and in vivo. The increased IFN-gamma production promoted a tumor antigen-specific Th1 response. Therefore, co treatment with GalCer and a TLR agonist is expected to exert an enhanced antitumor effect. In the present study, we examined the effect of GalCer and lipopolysaccharide (LPS) combination therapy in a mouse lung-metastasis model. GalCer and LPS combination therapy markedly decreased the number of lung metastatic tumor nodes. Co-treatment with GalCer and LPS enhanced the mRNA expression of CXCL9 and CXCL10 in mediastinal lymph nodes (MLNs) and increased the number of CD8+ cells in the MLNs. Furthermore, the depletion of CD8+ T cells canceled the antitumor effect of GalCer and LPS combination therapy. Thus, GalCer and LPS combination therapy significantly enhanced tumor antigen-specific immune responses and suppressed tumor growth in a mouse lung-metastasis model. PMID- 25434828 TI - Enzyme mediated-transesterification of verbascoside and evaluation of antifungal activity of synthesised compounds. AB - Enzymatic acylation of verbascoside, a polyhydroxylated natural product, has been reported in this study using five different commercial lipases and taking p nitrophenyl alkanoates as acyl donors. Out of these enzymes, the immobilised Candida antarctica lipase B was found as the enzyme of choice. Mono- and di acylated products were formed, with mono as major product indicating high regioselective nature of such transformations. A series of acyl esters of verbascoside have been synthesised by this enzymatic transesterification methodology. The lipophilicity of the synthesised analogues was also checked. The analogues were further subjected to synergistic antifungal activity with amphotericin B (AmB) against Candida albicans. Fourfold reduction in minimum inhibitory concentration of AmB was observed with few synthesised analogues such as verbascoside 4"-octanoate (3b), verbascoside 4"-palmitate (3d) and verbascoside 4",4'-dipalmitate (4d) at a concentration of 0.5 MUg/mL. PMID- 25434829 TI - Antinociceptive effects of sinomenine in a rat model of neuropathic pain. AB - Sinomenine is a principal ingredient of traditional Chinese medicine, Sinomenium Acutum, which has been reported to have various pharmacological effects including anti-rheumatism and immunomodulation. This study examined the effects of sinomenine in rats that received chronic constriction injury (CCI), a model of peripheral neuropathic pain. CCI injury on the right sciatic nerve led to long lasting mechanical hyperalgesia. Acute sinomenine treatment (10-40 mg/kg, i.p.) significantly and dose-dependently reversed mechanical hyperalgesia. In addition, the antinociceptive effects of sinomenine remained stable during repeated daily treatment for up to 2 weeks. Although sinomenine did not alter the duration of immobility in the forced swimming test in healthy animals, it dose-dependently reversed the increased immobility time in rats receiving CCI, suggesting that sinomenine attenuated chronic pain-induced depressive-like behavior. The antinociceptive effects of sinomenine were blocked by the GABAa receptor antagonist bicuculine. The doses of sinomenine studied here did not significantly alter the spontaneous locomotor activity. Together, these results suggested that sinomenine exerts significant antinociceptive effects for neuropathic pain via GABAa-mediated mechanism, which suggests that sinomenine may be useful for the management of chronic painful conditions such as neuropathic pain. PMID- 25434830 TI - The use of video conferencing to develop a community of practice for preceptors located in rural and non traditional placement settings: an evaluation study. AB - Support for nursing students in rural and non-traditional health environments within Tasmania is predominately undertaken by preceptors. It is recognised that preceptors who work within these environments, require support in their role and opportunities to communicate with academic staff within universities. Multiple methods of information distribution support and networking opportunities provide preceptors with flexible options to keep them abreast of the student learning process. This paper presents survey findings from preceptors in rural and non traditional professional experience placement environments taken from a pilot project regarding the implementation of video conferencing forums for education and peer networking in Tasmania. The purpose of the evaluation was to establish whether video conferencing met the requirements of preceptors' understanding of learning and teaching requirements during students' professional experience placement. The findings reveal preceptors' workload pressures and the need for organisational support were key barriers that prevented preceptor participation. PMID- 25434831 TI - Nurse Competence Scale--psychometric testing in a Norwegian context. AB - The aim was to test the construct validity of the Nurse Competence Scale. The Nurse Competence Scale has been used in hospital settings for various purposes in several countries. Despite this, confirmatory factor analyses are scarcely reported. The present study is based on re-analyses of data from 2007 (i.e. psychometric testing) and 593 newly graduated nurses working in various contexts were included. Confirmatory as well as exploratory factor analyses (Principal Component Analysis) were carried out. The original 7-factor model of the Nurse Competence Scale (73 items) was not confirmed. The exploratory factor analyses resulted in a Norwegian Nurse Competence Scale consisting of 46 items in the following competence categories: Planning and delivery of care, Teaching functions, Professional leadership, Research utilization and nursing values and Professional awareness. The results underline the needs for psychometric testing of an instrument after translation processes. The instrument is suitable for describing and comparing nurse competence for various reasons. It may also be helpful in creating competence development programs at an individual as well as at an organizational level. Further studies with a broader sample are recommended. PMID- 25434832 TI - The HMGB1 protein sensitizes colon carcinoma cells to cell death triggered by pro apoptotic agents. AB - The HMGB1 protein has multiple functions in tumor biology and can act both as a transcription factor and as a cytokine. HMGB1 is released during cell death, and in our previous studies we demonstrated that HMGB1 induces a distinct, necrosis like cell death in glioblastoma. In epithelial malignant tumors such as colorectal cancer (CRC), the HMGB1-dependent effects show cross-talk with apoptotic signal transduction. Treatment of CRC cells with low concentrations of recombinant HMGB1 results in dose-dependent cytotoxicity which is morphologically characterized by the formation of giant mitochondria and does not share features of apoptosis. HMGB1-triggered cell death is associated with intracellular ROS release, and overexpression of Bcl-2 blocks both the increase of ROS as well as HMGB1-dependent cell death. Importantly, treatment with recombinant HMGB1 or overexpression of endogenous HMGB1 strongly sensitizes CRC cells to the cytotoxic activity of the pro-apoptotic death ligand TRAIL as well as the small molecule Bcl-2 family inhibitor ABT-737. Moreover, treatment of CRC cells with TRAIL or ABT-737 induces a release of endogenous HMGB1 into the extracellular space, and preincubation with glycyrrhizin, an HMGB1 inhibitor, significantly inhibits induction of cell death by TRAIL and ABT-737, suggesting that HMGB1 functionally contributes to the execution of cell death triggered by pro-apoptotic agents. Finally, we investigated the expression of HMGB1 in human CRC tumor samples and found that loss of HMGB1 expression is associated with a more aggressive phenotype and a more advanced stage of disease in patients with CRC. Altogether, our findings demonstrate a functional link between cytotoxic signaling cascades triggered by HMGB1 and pro-apoptotic agents leading to an HMGB1-dependent sensitization to CRC cell death. Thus, a further evaluation of recombinant HMGB1 as part of an experimental combination treatment of CRC seems warranted. PMID- 25434833 TI - Crystal structure of streptavidin mutant with low immunogenicity. AB - We previously created a low-immunogenic core streptavidin mutant No. 314 (LISA 314) by replacing six amino-acid residues for use as a delivery tool for an antibody multistep pre-targeting process (Yumura et al., Protein Sci., 22, 213 221, 2013). Here, we performed high-resolution X-ray structural analyses of LISA 314 and wild-type streptavidin to investigate the effect of substitutions on the protein function and the three-dimensional structure. LISA-314 forms a tetramer in the same manner as wild-type streptavidin. The binding mode of d-biotin in LISA-314 is also completely identical to that in wild-type streptavidin, and conformational changes were observed mostly at the side chains of substituted sites. Any large conformational changes corresponding to the reduction of B factors around the substituted sites were not observed. These results demonstrated the LISA-314 acquired low immunogenicity without losing structural properties of original wild-type streptavidin. PMID- 25434834 TI - Reply: To PMID 24704063. PMID- 25434835 TI - Development of children born to mothers with cancer during pregnancy: comparing in utero chemotherapy-exposed children with nonexposed controls. AB - OBJECTIVE: Cancer is diagnosed in approximately 1 per 1000 pregnant women. Lifesaving cancer therapy given to the mother during pregnancy appears in conflict with the interest of the developing fetus. Often, termination of pregnancy is suggested but has not been proven in any type of cancer to improve maternal prognosis, while very few studies have documented the long-term effects of in utero chemotherapy exposure on child outcome. To counsel patients about the risk of continuing a pregnancy while undergoing cancer treatment, we performed developmental testing to provide more detailed follow-up on children exposed in utero to chemotherapy. STUDY DESIGN: Mother-infant pairs, enrolled in the Cancer and Pregnancy Registry, were offered developmental testing for children who were >=18 months of age. Based on age, the Bayley Scales of Infant Development-Third Edition, the Wechsler Preschool and Primary Scale of Intelligence-Revised, the Wechsler Intelligence Scale for Children, Third Edition, or the Wechsler Individual Achievement Test was administered. All parents or primary caregivers completed the Child Behavior Checklist, a parent questionnaire to assess behavior and emotional issues. Results of children exposed to chemotherapy before delivery were compared with children whose mothers were also diagnosed with cancer during pregnancy but did not receive chemotherapy before delivery. RESULTS: No significant differences were noted in cognitive skills, academic achievement, or behavioral competence between the chemotherapy-exposed group and the unexposed children. Of children, 95% scored within normal limits on cognitive assessments; 71% and 79% of children demonstrated at or above age equivalency in mathematics and reading scores, respectively; and 79% of children scored within normal limits on measures of behavior. Older children had significantly higher rates of internalizing behavior problems. CONCLUSION: We could not demonstrate a significant difference in cognitive ability, school performance, or behavioral competence for children exposed to chemotherapy in utero compared with nonexposed controls. The majority of these children scored within normal limits on all developmental measures. Premature birth was more prevalent in the chemotherapy exposed group yet did not predict developmental outcome. Older children in the sample demonstrated higher rates of internalizing behavior problems. PMID- 25434836 TI - A system for storing, retrieving, and comparing gene expression information of patients with endometriosis. PMID- 25434837 TI - Assessment of voiding after sling: a randomized trial of 2 methods of postoperative catheter management after midurethral sling surgery for stress urinary incontinence in women. AB - OBJECTIVE: The objective of this study was to compare the backfill standard voiding trial (SVT) that relies on the assessment of voided volume to subjective patients' evaluation of their voiding based on the assessment of the force of stream (FOS) after an outpatient midurethral sling surgery. STUDY DESIGN: This double-blinded randomized trial included patients undergoing an outpatient midurethral sling surgery without any other concomitant surgery. Participants were randomized to either the SVT group or to the FOS group. The primary outcome was the rate of catheterization any time up to 6 weeks after surgery. Both groups underwent the same backfill voiding trial protocol postoperatively. Measurements of the voided amount, postvoid residual, and the response to the FOS visual analog scale were collected. The criteria for passing the voiding trial in the SVT group was voiding at least two-thirds of the instilled amount; while the criteria for passing the trial in the FOS group was assessment of FOS at least 50% of the baseline, regardless of the voided volume. Participants were interviewed preoperatively and 2-4 days, 7-9 days, and 6 weeks postoperatively. All postoperative interviews included assessments of pain, tolerance of physical activity, urinary FOS, as well as satisfaction with the surgery. Validated questionnaires (Incontinence Severity Index and Urinary Distress Inventory, short form) before the surgery and 6 weeks after were used to evaluate urinary symptoms. RESULTS: A total of 108 patients were enrolled and randomized, and 6 week follow-up data were available for 102 participants (FOS 50, SVT 52). The 2 groups were similar with respect to demographic characteristics and urinary symptoms. The incidence of catheterization was also similar between the groups (FOS 13 [26%], SVT 13 [25.5%]; P=.95). Amount voided had a moderate correlation with FOS assessment (Spearman rho 0.5; P<.001). There was no significant difference in mean catheter days, pain scores, Incontinence Severity Index, and Urinary Distress Inventory, short form scores between the 2 groups. Of the patients who were discharged home without a catheter in either group none required catheter reinsertion within 6 weeks after the surgery. CONCLUSION: Patient's subjective assessment of the urinary FOS correlated well with the measured voided amount and no difference in catheterization days was noted between the subjective and objective assessment of voiding. Thus subjective evaluation of the FOS is a reliable and safe method to use after outpatient midurethral surgery. PMID- 25434838 TI - Incidence of adverse events after uterosacral colpopexy for uterovaginal and posthysterectomy vault prolapse. AB - OBJECTIVE: We sought to describe perioperative and postoperative adverse events associated with uterosacral colpopexy, to describe the rate of recurrent pelvic organ prolapse (POP) associated with uterosacral colpopexy, and to determine whether surgeon technique and suture choice are associated with these rates. STUDY DESIGN: This was a retrospective chart review of women who underwent uterosacral colpopexy for POP from January 2006 through December 2011 at a single tertiary care center. The electronic medical record was queried for demographic, intraoperative, and postoperative data. Strict definitions were used for all clinically relevant adverse events. Recurrent POP was defined as the following: symptomatic vaginal bulge, prolapse to or beyond the hymen, or any retreatment for POP. RESULTS: In all, 983 subjects met study inclusion criteria. The overall adverse event rate was 31.2% (95% confidence interval [CI], 29.2-38.6), which included 20.3% (95% CI, 17.9-23.6) of subjects with postoperative urinary tract infections. Of all adverse events, 3.4% were attributed to a preexisting medical condition, while all other events were ascribed to the surgical intervention. Vaginal hysterectomy, age, and operative time were not significantly associated with any adverse event. The intraoperative bladder injury rate was 1% (95% CI, 0.6-1.9) and there were no intraoperative ureteral injuries; 4.5% (95% CI, 3.4 6.0) of cases were complicated by ureteral kinking requiring suture removal. The rates of pulmonary and cardiac complications were 2.3% (95% CI, 1.6-3.5) and 0.8% (95% CI, 0.4-1.6); and the rates of postoperative ileus and small bowel obstruction were 0.1% (95% CI, 0.02-0.6) and 0.8% (95% CI, 0.4-1.6). The composite recurrent POP rate was 14.4% (95% CI, 12.4-16.8): 10.6% (95% CI, 8.8 12.7) of patients experienced vaginal bulge symptoms, 11% (95% CI, 9.2-13.1) presented with prolapse to or beyond the hymen, and 3.4% (95% CI, 2.4-4.7) required retreatment. Number and type of suture used were not associated with a higher rate of recurrence. Of the subjects who required unilateral removal of sutures to resolve ureteral kinking, 63.6% did not undergo suture replacement; this was not associated with a higher rate of POP recurrence. CONCLUSION: Perioperative and postoperative complication rates associated with severe morbidity after uterosacral colpopexy appear to be low. Uterosacral colpopexy remains a safe option for the treatment of vaginal vault prolapse. PMID- 25434841 TI - Primum non nocere: stillbirth rate in intrahepatic cholestasis of pregnancy. PMID- 25434840 TI - Maternal circulating angiogenic factors in twin and singleton pregnancies. AB - OBJECTIVE: The purpose of this study was to compare longitudinally sampled maternal angiogenic proteins between singleton and twin pregnancies. STUDY DESIGN: Placental growth factor (PlGF), soluble feline McDonough sarcoma (fms) like tyrosine kinase (sFlt)-1, and soluble endoglin from healthy pregnant women were quantified at 10, 18, 26, and 35 weeks' gestation (n=91), and during the third trimester (31-39 weeks) and at delivery (33-41 weeks; n=41). Geometric means and 95% confidence intervals were calculated for gestational age-adjusted angiogenic protein concentrations and compared between matched twin and singleton pregnancies. RESULTS: Maternal sFlt-1 concentrations and the sFlt-1/PlGF ratio were higher in twins than singletons across pregnancy and at delivery, with the greatest differences at week 35 (sFlt-1: 36,916 vs 10,151 pg/mL; P<.0001; sFlt 1/PlGF: 168.4 vs 29.0; P<.0001). Maternal concentrations of soluble endoglin also were higher in the third trimester and delivery. Maternal PlGF concentrations were lower in twin than singleton pregnancies at week 35 only (219.2 vs 350.2 pg/mL; P<.0001). Placental weight appeared to be inversely correlated with maternal sFlt-1/PlGF ratio at the end of pregnancy in both twins and singletons. CONCLUSION: Higher maternal antiangiogenic proteins in twin than singleton pregnancies does not appear to be due to greater placental mass in the former, and may be one explanation for the increased risk of preeclampsia in women carrying multiple gestations. Determining whether women with a history of multiple gestations have an altered cardiovascular disease and breast cancer risk, like those with a history of preeclampsia, is warranted. PMID- 25434842 TI - Japan's failure to vaccinate girls against human papillomavirus. PMID- 25434843 TI - Stretchable electronics based on Ag-PDMS composites. AB - Patterned structures of flexible, stretchable, electrically conductive materials on soft substrates could lead to novel electronic devices with unique mechanical properties allowing them to bend, fold, stretch or conform to their environment. For the last decade, research on improving the stretchability of circuits on elastomeric substrates has made significant progresses but designing printed circuit assemblies on elastomers remains challenging. Here we present a simple, cost-effective, cleanroom-free process to produce large scale soft electronic hardware where standard surface-mounted electrical components were directly bonded onto all-elastomeric printed circuit boards, or soft PCBs. Ag-PDMS tracks were stencil printed onto a PDMS substrate and soft PCBs were made by bonding the top and bottom layers together and filling punched holes with Ag-PDMS to create vias. Silver epoxy was used to bond commercial electrical components and no mechanical failure was observed after hundreds of stretching cycles. We also demonstrate the fabrication of a stretchable clock generator. PMID- 25434844 TI - Compositional changes in cell wall polysaccharides from five sweet cherry (Prunus avium L.) cultivars during on-tree ripening. AB - Excessive softening is a major cause of postharvest deterioration during transportation and storage of fresh cherries. In continuing our studies to identify the factors determining the textural differences between sweet cherry fruit genotypes, we evaluated the solubilization, depolymerization, and monosaccharide composition of pectin and hemicelluloses from five sweet cherry cultivars ('Chelan', 'Sumele', 'Brooks', 'Sunburst', and 'Regina') with contrasting firmness and cracking susceptibility at two developmental stages (immature and ripe). In contrast to what is usually shown in most fruits, cherry softening could occur is some cultivars without marked increases in water-soluble pectin. Although polyuronide and hemicellulose depolymerization was observed in the water-soluble and dilute-alkali-soluble fractions, only moderate association occurs between initial polymer size and cultivar firmness. In all the genotypes the Na2CO3-soluble polysaccharides (NSF) represented the most abundant and dynamic wall fraction during ripening. Firm cultivars showed upon ripening a lower neutral sugars/uronic acid ratio in the NSF, suggesting that they have a lower proportion of highly branched polyuronides. The similar molar ratios of arabinose plus galactose to rhamnose [(Ara+Gal)/Rha] suggest that the cultivars differed in their relative proportion of homogalacturonan (HG) and rhamnogalacturonan I (RG-I) rather than in the size of the RG side chains; with greater proportions of HG in firmer cherries. Ultraviolet matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was useful to identify the depolymerization patterns of weakly bound pectins, but gave less accurate results on ionically bound pectins, and was unable to find any pattern on covalently bound pectins. PMID- 25434839 TI - Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling. AB - Maternal diabetes-induced birth defects occur in 6-10% of babies born to mothers with pregestational diabetes, representing a significant maternal-fetal health problem. Currently, these congenital malformations represent a significant maternal-fetal medicine issue, but are likely to create an even greater public health threat as 3 million women of reproductive age (19-44 years) have diabetes in the United States alone, and this number is expected to double by 2030. Neural tube defects (NTDs) and congenital heart defects are the most common types of birth defects associated with maternal diabetes. Animal studies have revealed that embryos under hyperglycemic conditions exhibit high levels of oxidative stress resulting from enhanced production of reactive oxygen species and impaired antioxidant capability. Oxidative stress activates a set of proapoptotic kinase signaling intermediates leading to abnormal cell death in the embryonic neural tube, which causes NTD formation. Work in animal models also has revealed that maternal diabetes triggers a series of signaling intermediates: protein kinase C (PKC) isoforms, PKCalpha, betaII and delta; apoptosis signal-regulating kinase 1; c-Jun-N-terminal kinase (JNK)1/2; caspase; and apoptosis. Specifically, maternal diabetes in rodent models activates the proapoptotic unfolded protein response and endoplasmic reticulum (ER) stress. A reciprocal causation between JNK1/2 activation and ER stress exists in diabetic embryopathy. Molecular studies further demonstrate that deletion of the genes for Prkc, Ask1, Jnk1, or Jnk2 abolishes maternal diabetes-induced neural progenitor apoptosis and ameliorates NTD formation. Similar preventive effects are also observed when apoptosis signal regulating kinase 1, JNK1/2, or ER stress is inhibited. Cell membrane stabilizers and antioxidant supplements are also effective in prevention of diabetes-induced birth defects. Mechanistic studies have revealed important insights into our understanding the cause of diabetic embryopathy and have provided a basis for future interventions against birth defects or other pregnancy complications associated with maternal diabetes. The knowledge of a molecular pathway map identified in animal studies has created unique opportunities to identify molecular targets for therapeutic intervention. PMID- 25434845 TI - Emotional awareness and delusions in schizophrenia and schizoaffective disorder. AB - BACKGROUND AND OBJECTIVES: Emotion plays a significant role in schizophrenia. Emotional awareness (i.e., attention to and clarity of emotions) is associated with a wide range of outcomes. Given that individuals with schizophrenia and schizoaffective disorder differ in the significance of their mood symptoms, the present research examined whether the association between emotional awareness and delusions differs for these two groups of patients. METHODS: Emotional awareness (i.e., attention to and clarity of emotions) was measured with self-report in a sample of 44 individuals diagnosed with either schizophrenia or schizoaffective disorder. Clinical ratings of delusions were made using the Scale for the Assessment of Positive Symptoms. RESULTS: For the sample as a whole, individuals with higher levels of attention to emotion tended to have more severe delusions. In addition, diagnostic group significantly moderated the relation between emotional clarity and delusions. LIMITATIONS: Conclusions regarding causality cannot be drawn due to the cross-sectional design. Replication is particularly important given the small sample sizes. CONCLUSIONS: The present research indicates that emotional awareness is associated with delusions. The results raise the possibility that the emotional factors that contribute to delusional beliefs among individuals with schizophrenia differ in at least some ways from the emotional factors that contribute to delusional beliefs among individuals with schizoaffective disorder. PMID- 25434846 TI - Pathological gambling: understanding relapses and dropouts. AB - There is little available information on the factors that influence relapses and dropouts during therapy for pathological gambling (PG). The aim of this study was to determine socio-demographic, clinical, personality, and psychopathological predictors of relapse and dropout in a sample of pathological gamblers seeking treatment. A total of 566 consecutive outpatients diagnosed with PG according to DSM-IV-TR criteria were included. All patients underwent an individualized cognitive-behavioral treatment program. We analyzed predictors of relapse during 6months of treatment and during the subsequent 6months of follow-up, and predictors of dropout over the entire therapeutic program. Eighty patients (14.1%) experienced at least one relapse during the entire follow-up of the study: 50 (8.8%) within the treatment period and 12 (2.1%) during the subsequent 6-month follow-up period. The main predictors of relapse were single marital status, spending less than 100euros/week on gambling, active gambling behavior at treatment inclusion, and high scores on the TCI-R Harm Avoidance personality dimension. One hundred fifty-seven patients (27.8%) missed 3 or more therapeutic sessions over the entire therapeutic program. The main predictors of dropout were single marital status, younger age, and high scores on the TCI-R Novelty Seeking personality dimension. The presence of these factors at inclusion should be taken into account by physicians dealing with PG patients. PMID- 25434847 TI - Laundry detergent pod ingestion in 2 pediatric patients. PMID- 25434848 TI - Ni(2+) affects dopamine uptake which limits suitability as inhibitor of T-type voltage-gated Ca(2+) channels. AB - Neuronal T-type voltage-gated Ca(2+) channels are reported to have physiological roles that include regulation of burst firing, Ca(2+) oscillations, and neurotransmitter release. These roles are often exposed experimentally by blocking T-type channels with micromolar Ni(2+). We used Ni(2+) to explore the role of axonal T-type channels in dopamine (DA) release in mouse striatum, but identified significant off-target effects on DA uptake. Ni(2+) (100 MUM) reversibly increased electrically evoked DA release and markedly extended its extracellular lifetime, detected using fast-scan cyclic voltammetry. Prior inhibition of the DA transporter (DAT) by cocaine (5 MUM) occluded the facilitatory action of Ni(2+) on DA release and conversely, allowed Ni(2+) to inhibit release, presumably through T-channel inhibition. Ni(2+) further prolonged the timecourse of DA clearance suggesting further inhibition of DA uptake. In summary, Ni(2+) has major effects on DA transmission besides those due to T-channels that likely involve inhibition of the DAT. PMID- 25434849 TI - Microalgal biofilms on common yew needles in relation to anthropogenic air pollution in urban Prague, Czech Republic. AB - Excessive occurrence of microalgae on needles of gymnosperms was reported for the first time in the 1980s from the Scandinavian countries. Since then, it has been repeatedly encountered on needles from various European forest habitats. The abundance of these biofilms has been related to the climatic conditions, such as temperature and precipitation, as well as to the air pollution by nitrogen and sulfur oxides. Urban areas typically have relatively homogenous climates and profound variation in levels of air pollution. Therefore, variation in the occurrence of biofilms in localities within an urban area may be related to local anthropogenic air pollution. We investigated the abundance of biofilms occurring on needles of the common yew (Taxus baccata) in the city of Prague, Czech Republic. The biofilms were composed of algae, fungi and particulate matter. The cover area of the biofilms was marginally explained by a positive influence of short-term maximum atmospheric levels of nitrogen dioxide (NO2). The amounts of the microalgae were also positively influenced by short-term maximum NO2 levels. In addition, high atmospheric levels of particulate matter (PM10) were related to low abundance of algae. The microbial biofilms growing on widely cultivated conifers, such as the common yew, form one of the few commonly occurring natural communities in highly urbanized central areas of temperate European cities. Consequently, we propose that microscopic analysis of biofilms may be used as a rapid and cheap method to collect ecological data. Such data may be used in biomonitoring schemes illustrating the effects of anthropogenic air pollution on natural microcommunities in urban areas. PMID- 25434851 TI - Return to Sport: When to Resume Full Activity After an ACL Surgery. AB - Although surgery to fix a torn anterior cruciate ligament (ACL) is common, knowing when it is safe to return to activities and sports after ACL reconstruction is not always clear. As part of their rehabilitation, patients often fill out surveys, such as the International Knee Documentation Committee survey, that ask questions about how patients think they are recovering. It is not clear, though, how well these surveys truly predict an athlete's readiness to get back to activities and sports. A study published in the December 2014 issue of JOSPT provides new insight and evidence-based tools to help answer this question. PMID- 25434852 TI - Stress reaction of the humerus in a high school baseball player. AB - The patient was an 18-year-old high school baseball pitcher with a chief complaint of right (dominant) arm pain in the region of his right distal humerus that began 8 weeks earlier. Conventional radiographs were obtained, which were interpreted as normal. As a result, magnetic resonance imaging was obtained, which showed a hyperintense bone marrow signal in the distal humerus on fluid sensitive sequences, which was consistent with a stress reaction of the distal humerus. PMID- 25434856 TI - [Metabolic syndrome in patients with systemic lupus erythematosus: causes and consequences]. PMID- 25434857 TI - Multidisciplinary approach to fused maxillary central incisors: a case report. AB - INTRODUCTION: The fusion of permanent teeth is a development anomaly of dental hard tissue. It may require a hard multidisciplinary approach with orthodontics, endodontics, surgery and prosthetics to solve aesthetic and functional problems. CASE PRESENTATION: A 20-year-old Caucasian man presented to our Department to solve a dental anomaly of his upper central incisors. An oral investigation revealed the fusion of his maxillary central incisors and dyschromia of right central incisor. Vitality pulp tests were negative for lateral upper incisors and left central incisor. Radiographic examinations showed a fused tooth with two separate pulp chambers, two distinct roots and two separate root canals. There were also periapical lesions of central incisors and right lateral incisor, so he underwent endodontic treatment. Six months later, OPT examination revealed persistence of the periapical radiolucency, so endodontic surgery was performed, which included exeresis of the lesion, an apicoectomy and retrograde obturation with a reinforced zinc oxide-eugenol cement (SuperEBA) Complete healing of the lesion was obtained six months postoperatively. Fused teeth crowns were separated and orthodontic appliances were put in place. When correct teeth position was achieved (after nine months), the anterior teeth were prosthetically rehabilitated. CONCLUSION: Many treatment options have been proposed in the literature to solve cases of dental fusion. The best treatment plan depends on the nature of the anomaly, its location, the morphology of the pulp chamber and root canal system, the subgingival extent of the separation line, and the patient compliance. Following an analysis of radiographical and clinical data, it was possible to solve our patient's dental anomaly with a multidisciplinary approach. PMID- 25434858 TI - The spectroscopic (FT-IR, FT-Raman, (l3)C, (1)H NMR and UV) and NBO analyses of 4 bromo-1-(ethoxycarbonyl)piperidine-4-carboxylic acid. AB - In this work, we will report a combined experimental and theoretical study on molecular and vibrational structure of 4-bromo-1-(ethoxycarbonyl)piperidine-4 carboxylic acid (BEPA). BEPA has been characterized by FT-IR, FT-Raman, (1)H NMR, (13)C NMR and UV spectroscopy. The FT-IR and FT-Raman spectra of BEPA were recorded in the solid phase. The optimized geometry was calculated by B3LYP and M06-2X methods using 6-311G(d,p) basis set. The FT-IR and FT-Raman spectra of BEPA were calculated at the same level and were interpreted in terms of Potential Energy Distribution (PED) analysis. The scaled theoretical wavenumber showed very good agreement with the experimental values. The (1)H and (l3)C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by the Gauge Independent Atomic Orbital (GIAO) method. Stability of the molecule arising from hyperconjugative interactions and charge delocalization has been analyzed using Natural Bond Orbital (NBO) analysis. Density plots over the highest occupied molecular orbitals (HOMO) and lowest unoccupied molecular orbitals (LUMO) energy surface directly identifies the donor and acceptor atoms in the molecule. It also provides information about the charge transfer within the molecule. To obtain chemical reactivity of the molecule, the molecular electrostatic potential (MEP) surface map is plotted over the optimized geometry of the molecule. PMID- 25434859 TI - Rhodium-catalysed arylative annulation of 1,4-enynes with arylboronic acids. AB - The rhodium(I)-catalysed arylative annulation of 1,4-enynes with arylboronic acids was investigated. The reaction was found to proceed via an addition-1,4 rhodium migration-addition sequence, affording the corresponding 1,1 disubstituted 3-(arylmethylene)indanes. PMID- 25434860 TI - Building partnerships for healthy environments: research, leadership and education. AB - As populations across the globe face an increasing health burden from rising rates of obesity, diabetes and other lifestyle-related diseases, health professionals are collaborating with urban planners to influence city design that supports healthy ways of living. This paper details the establishment and operation of an innovative, interdisciplinary collaboration that brings together urban planning and health. Situated in a built environment faculty at one of Australia's most prestigious universities, the Healthy Built Environments Program (HBEP) partners planning academics, a health non-government organisation, local councils and private planning consultants in a state government health department funded consortium. The HBEP focuses on three strategic areas: research, workforce development and education, and leadership and advocacy. Interdisciplinary research includes a comprehensive literature review that establishes Australian based evidence to support the development, prioritisation and implementation of healthy built environment policies and practices. Another ongoing study examines the design features, social interventions and locational qualities that positively benefit human health. Formal courses, workshops, public lectures and e learning develop professional capacity, as well as skills in interdisciplinary practice to support productive collaborations between health professionals and planners. The third area involves working with government and non-government agencies, and the private sector and the community, to advocate closer links between health and the built environment. Our paper presents an overview of the HBEP's major achievements. We conclude with a critical review of the challenges, revealing lessons in bringing health and planning closer together to create health-supportive cities for the 21st century. PMID- 25434861 TI - Compassion fatigue among registered nurses: connecting theory and research. AB - Unresolved compassion fatigue often causes physical and emotional exhaustion, and can significantly impair job performance. It is also known to cause increased absenteeism and even turnover among health care providers such as registered nurses. Often those experiencing compassion fatigue attempt to self-medicate in order to numb the intense emotions, and distance themselves from patients, colleagues, friends, and even family. This article describes the challenges of applying one widely used conceptual model to research among nurses who are at risk for experiencing this important and debilitating phenomenon. Through two qualitative studies that explored compassion fatigue among registered nurses, symptoms were identified that fit within the conceptual model. Several additional elements were not adequately captured by the conceptual model, and the term was perceived as being stigmatizing. PMID- 25434863 TI - Spatio-temporal variations in biomass and mercury concentrations of epiphytic biofilms and their host in a large river wetland (Lake St. Pierre, Qc, Canada). AB - Within wetlands, epiphytes and macrophytes play an important role in storage and transfer of metals, through the food web. However, there is a lack of information about spatial and temporal changes in their metal levels, including those of mercury (Hg), a key priority contaminant of aquatic systems. We assessed total mercury (THg) and methylmercury (MeHg) concentrations of epiphyte/macrophyte complexes in Lake St. Pierre, a large fluvial lake of the St. Lawrence River (Quebec, Canada). THg and MeHg concentrations were ten fold higher in epiphytes than in macrophytes. THg concentrations in epiphytes linearly decreased as a function of the autotrophic index, suggesting a role of algae in epiphyte Hg accumulation, and % of MeHg in epiphytes reached values as high as 74%. Spatio temporal variability in THg and MeHg concentrations in epiphytes and macrophytes were influenced by water temperature, available light, host species, water level, dissolved organic carbon and dissolved oxygen. PMID- 25434862 TI - A novel long non-coding RNA, hypoxia-inducible factor-2alpha promoter upstream transcript, functions as an inhibitor of osteosarcoma stem cells in vitro. AB - Long non-coding RNAs (lncRNAs) have recently been identified as novel modulators of malignant tumors. However, the function of lncRNAs in cancer stem cells (CSCs) remains to be elucidated. The present study aimed to investigate the regulating role of a novel lncRNA, hypoxia-inducible factor-2alpha (HIF-2alpha) promoter upstream transcript (HIF2PUT), in osteosarcoma stem cells. The expression levels of HIF2PUT were assessed by quantitative polymerase chain reaction in 17 osteosarcoma tissue specimens, and the correlation between the expression of HIF2PUT and its host transcript-HIF-2alpha was determined. In functional experiments, HIF2PUT expression was knocked down by small interfering RNAs, or overexpressed by transfection with pcDNA-HIF2PUT, in order to evaluate the effects of HIF2PUT on cell proliferation, migration, expression rate of osteosarcoma stem cell marker CD133, and stem sphere-forming ability in MG63 cells. HIF2PUT expression levels were positively correlated with HIF-2alpha in osteosarcoma tissues. Overexpression of HIF2PUT markedly inhibited cell proliferation and migration, decreased the percentage of CD133 expressing cells, and impaired the osteosarcoma stem sphere-forming ability of the MG63 cells. Whereas, knockdown of HIF2PUT expression had the opposite effect. Furthermore, altering the expression of HIF2PUT resulted in a concomitant change to HIF-2alpha mRNA expression. These results indicate that the lncRNA HIF2PUT may be a novel regulatory factor of osteosarcoma stem cells, which may exert its function partly by controlling HIF-2alpha expression. Further studies regarding HIF2PUT may provide a novel therapeutic target of osteosarcoma in the future. PMID- 25434864 TI - Nitrogen and carbon export from urban areas through removal and export of litterfall. AB - We found that up to 52 +/- 17% of residential litterfall carbon (C) and nitrogen (N; 390.6 kg C and 6.5 kg N ha(-1) yr(-1)) is exported through yard waste removed from the City of Boston, which is equivalent to more than half of annual N outputs as gas loss (i.e. denitrification) or leaching. Our results show that removing yard waste results in a substantial decrease in N inputs to urban areas, which may offset excess N inputs from atmospheric deposition, fertilizer application and pet waste. However, export of C and N via yard waste removal may create nutrient limitation for some vegetation due to diminished recycling of nutrients. Removal of leaf litter from residential areas disrupts nutrient cycling and residential yard management practices are an important modification to urban biogeochemical cycling, which could contribute to spatial heterogeneity of ecosystems that are either N limited or saturated within urban ecosystems. PMID- 25434865 TI - Chromate and phosphate inhibited each other's uptake and translocation in arsenic hyperaccumulator Pteris vittata L. AB - We investigated the effects of chromate (CrVI) and phosphate (P) on their uptake and translocation in As-hyperaccumulator Pteris vittata (PV). Plants were exposed to 1) 0.10 mM CrVI and 0, 0.25, 1.25, or 2.50 mM P or 2) 0.25 mM P and 0, 0.50, 2.5 or 5.0 mM CrVI for 24 h in hydroponics. PV accumulated 2919 mg/kg Cr in the roots at CrVI0.10, and 5100 and 3500 mg/kg P in the fronds and roots at P0.25. When co-present, CrVI and P inhibited each other's uptake in PV. Increasing P concentrations reduced Cr root concentrations by 62-82% whereas increasing CrVI concentrations reduced frond P concentrations by 52-59% but increased root P concentrations by 11-15%. Chromate reduced P transport, with more P being accumulated in PV roots. Though CrVI was supplied, 64-78% and 92-93% CrIII were in PV fronds and roots. Based on X-ray diffraction, Cr2O3 was detected in the roots confirming CrVI reduction to CrIII by PV. In short, CrVI and P inhibited each other in uptake and translocation by PV, and CrVI reduction to CrIII in PV roots served as its detoxification mechanism. The finding helps to understand the interactions of P and Cr during their uptake in PV. PMID- 25434866 TI - Effects of cyanobacterial extracellular polymeric substances on the stability of ZnO nanoparticles in eutrophic shallow lakes. AB - Extracellular polymeric substances (EPS) from bloom-forming cyanobacteria exist ubiquitously in eutrophic waters, while their effects on the aggregation/stabilization of nanoparticles remain unknown. In this study, the stability of ZnO nanoparticles (ZNPs) upon adsorption of cyanobacterial EPS was investigated by using two dimensional ATR-FTIR correlation spectroscopy, XPS and DLVO theory. Results showed that the adsorption process followed the Langmuir isotherm and pseudo-second-order kinetics both for the total organic contents as well as the individual parallel factor-derived components. The physicochemical and spectroscopic techniques revealed the mechanism of both electrostatic attraction and surface complexation in EPS adsorption. Further analysis showed increased absorbance and turbidity of ZNPs solutions with EPS addition, demonstrating the enhanced colloidal stability. The DLVO theory explained that the increased energy barriers and values of second energy maximum were responsible for the stability enhancement. This study facilitates a deeper insight into the environmental behavior of nanoparticles in eutrophic algae-rich waters. PMID- 25434867 TI - Functional and clinical assessment of two ankle arthrodesis techniques. AB - Isolated tibiotalar fusion is the preferred choice for isolated end-stage arthritis, joint destruction after infection, talar avascular necrosis, Charcot neuroarthropathy, and joint replacement failure. Combined tibiotalar and subtalar joint fusion with an intramedullary nail can achieve better alignment and save patients from prolonged non-weightbearing. The purpose of the present study was to functionally assess using instrumental gait analysis and clinically assess the effect of these 2 surgical techniques. Twelve patients with a mean follow-up duration of 70 (range 55 to 89) months after successful ankle fusion were analyzed, 6 isolated and 6 combined. The main outcome measure was the functional assessment performed using a stereophotogrammetric system and an established multisegment foot kinematics protocol. Standard clinical, imaging, and score systems were also assessed in the 2 groups, including radiographic-based classification of arthritic degeneration at the neighboring foot joints. No significant differences were found between the 2 groups using the scoring systems. Severe arthritic degeneration was found at the subtalar joint in the isolated fusion group and at the talonavicular and Lisfranc joints in the combined fusion group. From the gait analysis, no differences were found in the time-distance parameters; however, significant differences were observed in several joint rotations and planar angles. Isolated tibiotalar fusion allows for motion, however small, at the subtalar joint but can result in severe degeneration. Good clinical and functional results can also be obtained with combined tibiotalar and subtalar fusion, although this can result in degeneration of the adjacent joints of the foot. PMID- 25434868 TI - Metal controlled regioselectivity in the cyclometallation of 2-(1-naphthyl) pyridine. AB - Cyclometallation of 2-(1-naphthyl)-pyridine is described. While cyclopalladation results in a five-membered metallacycle, cycloauration displays a completely orthogonal regioselectivity, resulting in the six-membered ring analogue. Bromination of the gold metallacycle results in the new C-H functionalisation product 2-(8-bromonaphth-1-yl)pyridine. PMID- 25434869 TI - Long-term increases in BK potassium channel underlie increased action potential firing in dentate granule neurons following pilocarpine-induced status epilepticus in rats. AB - Temporal lobe epilepsy (TLE) is the most common form of acquired epilepsy in adult. Since dentate gyrus granule cells (GCs) play a critical role in hippocampal seizure generation, it is, therefore, important to understand changes in intrinsic properties of GCs in TLE. In this study, the electrophysiological properties of GCs obtained from epileptic rates were compared with the control group using whole cell patch-clamp recording. Results indicated a significant increase in the number of action potentials (APs) in depolarizing currents of 150 pA, 200 pA, and 250 pA. In addition, there was a significant decrease in AP half width of GCs. The amplitude of fast afterhyperpolarization (fAHP) in epileptic group significantly decreased compared to control group. Blockade of large conductance calcium activated potassium channel (BK), channels with paxilline and iberiotoxin reversed pilocarpine-induced changes in electrophysiological properties of GCs in epileptic group. These results suggest that the BK channel blockers by reversing the firing properties of GCs might have beneficial preventative effects on pilocarpine-induced electrophysiological changes. PMID- 25434870 TI - Intramuscular injection of bone marrow mesenchymal stem cells with small gap neurorrhaphy for peripheral nerve repair. AB - We had previously reported that small gap neurorrhaphy by scissoring and sleeve jointing epineurium could enhance the rate and quality of peripheral nerve regeneration. To date, local implantation and systemic delivery of bone marrow mesenchymal stem cells (BMSCs) have been routinely used in nerve tissue engineering, but they each have some intrinsic limitations. We hypothesised that targeted muscular administration of BMSCs capable of reaching the damaged nerve would be advisable. Here, we investigated the therapeutic efficacy of transplantation of BMSCs through targeted muscular injection with small gap neurorrhaphy by scissoring and sleeve-jointing epineurium on repairing peripheral nerve injury in a rat model. One week after a rat model of peripheral nerve injury was established by small gap neurorrhaphy, thirty-six Sprague-Dawley rats were randomly divided into three groups (n=12): the intramuscular injection of BMSCs group (IM), the intravenous injection of BMSCs group (IV) and the intramuscular injection of phosphate-buffered solution group (PBS). The process of the nerve regeneration was assayed functionally and morphologically. The results indicated that compared to the IV-treated and PBS-treated groups, the targeted muscular injection therapy resulted in much more beneficial effects, as evidenced by increases in the sciatic function index, nerve conduction velocity, myelin sheath thickness and restoration rate of gastrocnemius muscle wet weight. In conclusion, the combination therapy of small gap neurorrhaphy and BMSC transplantation through targeted muscular injection can significantly promote the regeneration of peripheral nerve and improve the nerve's functional recovery, which may help establish a reliable approach for repairing peripheral nerve injury. PMID- 25434871 TI - Dynamic properties of sensory stimulation evoked responses in mouse cerebellar granule cell layer and molecular layer. AB - Sensory information coming from climbing fiber and mossy fiber-granule cell pathways, generates motor-related outputs according to internal rules of integration and computation in the cerebellar cortex. However, the dynamic properties of sensory information processing in mouse cerebellar cortex are less understood. Here, we studied the dynamic properties of sensory stimulation-evoked responses in the cerebellar granule cell layer (GCL) and molecular layer (ML) by electrophysiological recordings method. Our data showed that air-puff stimulation (5-10 ms in duration) of the ipsilateral whisker pad evoked single-peak responses in the GCL and ML; whereas a duration of stimulation >=30 ms in GCL and >=60 ms in ML, evoked double-peak responses that corresponded with stimulation-on and off responses via mossy fiber pathway. The highest frequency of stimulation train for evoking GCL responses was 33 Hz. In contrast, the highest frequency of stimulation train for evoking ML responses was 4 Hz. These results indicate that the cerebellar granule cells transfer the high-fidelity sensory information from mossy fibers, which is cut-off by molecular layer interneurons (MLIs). Our results suggest that the MLIs network acts as a low-pass filter during the processing of high-frequency sensory information. PMID- 25434872 TI - Phase advance of circadian rhythms in Smith-Magenis syndrome: a case study in an adult man. AB - Melatonin secretion is usually increased during the daytime and decreased at night in Smith-Magenis syndrome (SMS) and consequently is not a pertinent marker of the circadian phase of the clock in these cases. No data on temperature rhythm is available in SMS, another reliable marker of circadian clock activity. For this reason, we assessed the 24h profiles of core temperature, sleep-wake cycle, hormones (plasma cortisol and melatonin) and plasma and urine 6sulfatoxy melatonin, the main hepatic melatonin metabolism in a 31-year-old man diagnosed with a SMS. All circadian rhythms, especially temperature rhythm showed a phase advance, associated with reverse melatonin secretion. Plasma and urine 6sulfatoxy melatonin profiles showed normal melatonin catabolism and confirmed the reversed melatonin secretion. Taking in consideration the reverse melatonin secretion and the phase-advanced temperature rhythm, which is driven by the suprachiasmatic nucleus, we hypothesize that the central clock is more sensitive to afternoon than to morning melatonin. This different responsiveness to melatonin according to the time of the day (i.e. chronaesthesia) corroborates the phase response curve of melatonin secretion to exogenous melatonin. PMID- 25434874 TI - Another way to skin a cath. PMID- 25434873 TI - Carbon monoxide offers neuroprotection from hippocampal cell damage induced by recurrent febrile seizures through the PERK-activated ER stress pathway. AB - Carbon monoxide (CO) is neuroprotective in various models of brain injury, but the precise mechanisms for this are yet to be established. In the present study, using a rat model of recurrent febrile seizures (FSs), we found an increase in plasma CO, evidence of neuronal damage and apoptosis, an increase in the expression of the endoplasmic reticulum stress (ERS) marker glucose-regulated protein 78 (GRP78) and C/EBP homologous binding protein (CHOP), and an increase in phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p PERK)/eukaryotic translation initiation factor 2 alpha (p-eIF2alpha) in the hippocampus after 10 FSs. Administration of Hemin (a CO donor) in FS rats alleviated the neuronal damage, reduced neuronal apoptosis, upregulated GRP78 expression, decreased CHOP, and increased p-PERK and p-eIF2alpha expression in the hippocampus, compared to FS control rats. In contrast, treating FS rats with ZnPP-IX (a CO synthase inhibitor) aggravated the neuronal damage, enhanced neuronal apoptosis, downregulated GRP78 expression, increased CHOP, and decreased p-PERK and p-eIF2alpha expression, compared to FS control rats. These results suggest that endogenous CO limits the neuronal damage induced by recurrent FSs, through the PERK-activated ERS pathway. PMID- 25434875 TI - Investigation of the role of 8-OHdG and oxidative stress in papillary thyroid carcinoma. AB - The aim of this study was to determine levels of serum 8-hydroxy-2' deoxyguanosine (8-OHdG) as an indicator of oxidant-induced DNA damage and oxidant status in patients with papillary thyroid carcinoma before and after surgery. This study included 25 patients with papillary thyroid carcinoma and age-matched 27 healthy controls. Total antioxidant status (TAS), total oxidant status (TOS), lipid hydroperoxide (LOOH), and 8-OHdG levels were measured. 8-OHdG levels were significantly higher in the preoperative papillary thyroid carcinoma (PTC) group compared with the healthy control group (p < 0.001) and were significantly lower after operation in patients with papillary thyroid carcinoma (p = 0.004). Oxidative stress index (OSI) levels were significantly higher in both preoperative and postoperative PTC patients compared with the healthy control group (p < 0.001 and p < 0.001, respectively). TOS levels were higher in the preoperative and postoperative PTC groups compared to the healthy control group (p < 0.001 and p < 0.001, respectively). TAS levels was lower in the preoperative PTC groups compared to the healthy control group (p = 0.011). Serum LOOH levels were higher in both preoperative and postoperative PTC groups compared to the healthy control group (p < 0.001 and p < 0.001, respectively). Correlation analysis yielded that serum 8-OHdG levels were positively correlated with OSI and LOOH levels in patients with PTC before surgery (r = 0.668, p < 0.001; r = 0.446, p = 0.025, respectively) and had a negative correlation with TAS levels (r = 0.616, p = 0.001). We have shown severe oxidative DNA damage and impaired antioxidant status in papillary thyroid carcinoma. PMID- 25434876 TI - Proteasome inhibitor-induced autophagy in PC12 cells overexpressing A53T mutant alpha-synuclein. AB - The aim of the present study was to examine the effects of proteasome inhibitor (PI)-induced autophagy on PC12 cells overexpressing A53T mutant alpha-synuclein (alpha-syn) by detecting alterations in the levels of microtubule-associated protein 1A/1B light chain (LC3)+ autophagosomes and the lysotracker-positive autolysosomes using immunofluorescence, the expression of LC3-II using western blot analysis and the morphology of PC12 cells using transmission electron microscopy. It was found that the addition of MG132 (500 nmol/l) significantly increased the number of autophagosomes and autolysosomes and upregulated the expression of LC3-II. The autophagy inhibitor 3-methyladenine (3-MA) completely inhibited the autophagy induced by MG132 (500 nmol/l). The autophagy enhancer trehalose significantly increased the number of autophagosomes and autolysosomes and improved the protein level of LC3-II induced by MG132. To examine the effect of PI-induced autophagy on the degradation of A53T mutant alpha-syn, the expression of alpha-syn was detected by western blot analysis. It was revealed that MG132 increased the expression of A53T alpha-syn and trehalose counteracted the increase of A53T alpha-syn induced by MG132. Combined inhibition of 3-MA and PI significantly increased the accumulation of A53T alpha-syn as compared with treatment using either single agent. In addition, combination of MG132 (500 nmol/l) with trehalose (50 mmol/l) or 3-MA (2 mmol/l) markedly decreased the cell viability as compared with treatment using either single agent individually as demonstrated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. These results suggest that the PI, MG132, could induce autophagy in PC12 cells overexpressing A53T mutant alpha-syn and this autophagy could be completely inhibited by 3-MA, indicating that PI-induced autophagy is mediated by the upregulation of the macroautophagy class III PI3K pathway. PI-induced autophagy may act as a compensatory degradation system for degradation of A53T alpha-syn when the ubiquitin-proteasome system is impaired. Autophagy activation may directly contribute to the survival of PC12 cells treated with proteasome inhibitors. The present study may assist in illuminating the association between PI and autophagy in the pathogenesis of Parkinson's disease. PMID- 25434878 TI - 3D Co(II) coordination polymer with ferrimagnetic-like layers based on azide and tetrazolate bridges showing slow magnetic dynamics. AB - A novel 3D Co(II) coordination polymer, [Co6(4-ptz)6(N3)6]n (1) (4-ptz = 4 (pyridinyl)tetrazole), was synthesized by in situ hydrothermal reaction and characterized magnetically. Compound 1 consists of ferrimagnetic-like Co(II) layers with the title heterobridges and exhibits the spin-glass slow dynamics. The study on spin-glass behavior in mixed azide and tetrazolate bridged compounds is the first example. PMID- 25434877 TI - The sensitivity and significance analysis of parameters in the model of pH regulation on lactic acid production by Lactobacillus bulgaricus. AB - BACKGROUND: The excessive production of lactic acid by L. bulgaricus during yogurt storage is a phenomenon we are always tried to prevent. The methods used in industry either control the post-acidification inefficiently or kill the probiotics in yogurt. Genetic methods of changing the activity of one enzyme related to lactic acid metabolism make the bacteria short of energy to growth, although they are efficient ways in controlling lactic acid production. RESULTS: A model of pH-induced promoter regulation on the production of lactic acid by L. bulgaricus was built. The modelled lactic acid metabolism without pH-induced promoter regulation fitted well with wild type L. bulgaricus (R2LAC = 0.943, R2LA = 0.942). Both the local sensitivity analysis and Sobol sensitivity analysis indicated parameters Tmax, GR, KLR, S, V0, V1 and dLR were sensitive. In order to guide the future biology experiments, three adjustable parameters, KLR, V0 and V1, were chosen for further simulations. V0 had little effect on lactic acid production if the pH-induced promoter could be well induced when pH decreased to its threshold. KLR and V1 both exhibited great influence on the producing of lactic acid. CONCLUSIONS: The proposed method of introducing a pH-induced promoter to regulate a repressor gene could restrain the synthesis of lactic acid if an appropriate strength of promoter and/or an appropriate strength of ribosome binding sequence (RBS) in lacR gene has been designed. PMID- 25434879 TI - Water driven adsorption of amino acids on the (101) anatase TiO2 surface: an ab initio study. AB - Arg, Lys and Asp amino acids are known to play a critical role in the adhesion of the RKLPDA engineered peptide on the (101) surface of the titania anatase phase. To understand their contribution to peptide adhesion, we have considered the relevant charge states due to protonation (Arg and Lys) or deprotonation (Asp) occurring in neutral water solution, and studied their adsorption on the (101) anatase TiO2 surface by ab initio total energy calculations based on density functional theory. The adsorption configurations on the hydrated surface are compared to those on the dry surface considering also the presence of the hydration shell around amino acid side-chains. This study explains how water molecules mediate the adsorption of charged amino acids showing that protonated amino acids are chemically adsorbed much more strongly than de-protonated Asp. Moreover it is shown that the polar screening of the hydration shell reduces the adsorption energy of the protonated amino acids to a small extent, thus evidencing that both Arg and Lys strongly adhere on the (101) anatase TiO2 surface in neutral water solution and that they play a major role in the adhesion of the RKLPDA peptide. PMID- 25434880 TI - Functional magnetic resonance imaging of mild traumatic brain injury. AB - Functional magnetic resonance imaging (fMRI) offers great promise for elucidating the neuropathology associated with a single or repetitive mild traumatic brain injury (mTBI). The current review discusses the physiological underpinnings of the blood-oxygen level dependent response and how trauma affects the signal. Methodological challenges associated with fMRI data analyses are considered next, followed by a review of current mTBI findings. The majority of evoked studies have examined working memory and attentional functioning, with results suggesting a complex relationship between cognitive load/attentional demand and neuronal activation. Researchers have more recently investigated how brain trauma affects functional connectivity, and the benefits/drawbacks of evoked and functional connectivity studies are also discussed. The review concludes by discussing the major clinical challenges associated with fMRI studies of brain-injured patients, including patient heterogeneity and variations in scan-time post-injury. We conclude that the fMRI signal represents a complex filter through which researchers can measure the physiological correlates of concussive symptoms, an important goal for the burgeoning field of mTBI research. PMID- 25434881 TI - The role of progesterone in memory: an overview of three decades. AB - Memory comprises acquisition, consolidation and retrieval of information. Many substances can influence these different phases. It is well demonstrated that sex hormones, mainly estrogen, impact cognitive function. More recently, progesterone has also been documented as playing an important role in cognition, since it influences brain regions involved in memory. Currently, many women are under hormone treatment, which contain progesterone to decrease the risk of development of endometrial cancer. This affords the opportunity to study the real effects of this hormonal replacement on cognition. There are many contradictory results regarding the role of progesterone in memory. Therefore, the aim of this review was to synthesize these studies using the new perspective of the influence of hormone replacement on cognition in women. PMID- 25434882 TI - Sincerity and freedom in psychoanalysis. Introduction. PMID- 25434883 TI - "Coming from afar" and "temporarily becoming the patient without knowing it": two necessary analytic conditions according to Ferenczi's later thought. AB - In this paper the author discusses two points regarding Ferenczi's views of psychoanalysis. The first concerns the fact that analysts, like their patients, "come from afar" (a concept of Borgogno, 2011). The second, closely linked to the first, has to do with Ferenczi's belief that psychoanalytical knowledge is not intellectual but visceral, seeing that if analysts are to truly understand their patients they must first "take on" their suffering in such a way as to "become the patient." The author follows Ferenczi's progression along these two points through his whole oeuvre, from his first psychoanalytical writings to the Clinical Diary (1932a) of the last year of his life. PMID- 25434884 TI - The return of dissociation as absence within absence. AB - My aim is to translate Ferenczi's central concepts of the intrapsychic impact and imprint of early developmental trauma into both revived and contemporary conceptualizations. The concept of dissociation was renounced by Freud, yet it is returning as a cornerstone of recent trauma theories. Ferenczi used the concept of "repression," but used it in the sense of an intrapsychic imprint of early external trauma that fragments consciousness, that is, as dissociation. Furthermore, early trauma is double: an absence of protection that threatens existence of the self, combined with an absence of attachment and of recognition of this threat and terror; thus it is an absence-within-absence. This contemporary conceptualization entails a widening of the intrapsychic realm to include an intersubjective one, and regards dissociation as a unique and complex intrapsychic absence, which is a negative of the external absence-within-absence in the early environment. PMID- 25434885 TI - The environment of Ferenczi's Clinical Diary. AB - The author evokes the tragic death of Ferenczi's colleague and analysand Dr. Elisabeth Rado-Revesz in 1923. She died of pernicious anemia, the same illness that ended the life of Ferenczi 10 years later, at age 59. Can this be a tragic coincidence? Following notes in Ferenczi's Clinical Diary, the author considers the deep disappointments both Ferenczi and Rado-Revesz had experienced and explores some of the Tragic Man qualities of Ferenczi. PMID- 25434887 TI - Challenges of honesty. AB - The analytic method builds on honesty, specifically in the moment-to-moment events of the micro-process. Ferenczi was a researcher who experimented with the limits (including the limits of honesty) of the method to its extremes. Honesty is a moral virtue, and from that perspective all events and phenomena of the moment have an ethical aspect. Self-analysis-a prerequisite and an important component of the analytic stance-puts on trial the analyst's capacity and willingness to be honest. This paper examines these ethical aspects in the micro process and the unavoidable dilemmas connected with it. The important settings where self-analysis is used are: being in analysis, conducting analysis and in supervision. The limits of honesty in these settings are also discussed. Recently, case discussion groups have been playing an increasingly important role in analytic conferences and also in training. The risks and limits of honesty in case discussion groups deserve to be studied. PMID- 25434886 TI - Empathy, tact and the freedom to be natural. AB - This paper explores the concepts of tact and empathy in the context of the Freud Ferenczi correspondence around Ferenczi's "The Elasticity of Psycho-Analytic Technique" paper. It goes on to explore the problems that they encounter in the neighborhood of reconciling science and subjectivity, in relation to the work on personal knowledge of the Hungarian philosopher Michael Polanyi and concludes with some implications for psychoanalytic training. PMID- 25434888 TI - Ferenczi's ethics for our time: the possibility of being alongside. AB - Ferenczi's practice and therapeutic ethics as exemplified in the Clinical Diary reveal a profound sensitivity to the questions of authority and freedom. This paper will engage with the ways in which these questions have been taken up elsewhere and have become central to post-war extensions of the psychoanalytic field, such as group analysis. A particular comparison will be made with group analytic notions of leadership and horizontal ways of relating, that is, how to be alongside one another. It will be suggested that the translatability of Ferenczi for our time reveals the adaptability of psychoanalysis to different and changing socio-political contexts. PMID- 25434889 TI - Surviving deadness in the analytic experience. AB - The transference/countertransference (third space) analysis is considered to be central in the therapeutic effectiveness of the analytic process. Less emphasis has been placed on the actual experiences of analyst and analysand in the conflictual reenactment of third space experience and its resolution. This paper recounts the shared experience of a patient who was silent throughout most of the analysis, and my reaction, in fantasy and enactment, to this disturbing experience-both for him and for myself. I argue that it is the affective re experiencing of past repressed trauma in the analytic space that has a therapeutic impact, leading to growth in the patient and also the therapist. I contrast Freud's emphasis on insight, making the unconscious conscious, with Ferenczi's suggestion that the therapeutic impact lies in the repetition of past traumatic experience in the analysis but with the possibility of a different outcome with a more benign object, leading to symbolic representation of repressed trauma. Re-experiencing and symbolization, in the third space, of past traumatic experience can be an exit point from the endless repetition of trauma in internal and external object relations, leading to a new beginning in the patient's life. Immersed in the experience of deadness in the analysis, which had become a dead womb, the struggle to remain alive and thinking led to a rupture out of the dead womb, like the Caesura of birth, into aliveness and the ability to mentalize what had previously remained unmentalized. PMID- 25434890 TI - Freedom and authority in the Clinical Diary. AB - The paper discusses some philosophical, ethical and political-philosophical implications of Ferenczi's Clinical Diary, with special regard to the concepts of freedom and authority. These topics are already present in Ferenczi's early writings that explicitly deal with social and political issues, the central concept of which is "individual socialism". The paper also discusses (and publishes in Appendix) two short manuscripts by Ferenczi, written probably in 1920, which attempts to parallel psychoanalysis with Marxism, and with liberal socialism, respectively. It is shown that in 1932, the last year of his life, Ferenczi avoids using political and ideological concepts directly in his Diary, but, in the spirit of his earlier writings, he proposes a balance between "ruthless capitalism and fanciful egalitarianism". Finally, the significance of Utopia in Ferenczi's thinking is discussed. PMID- 25434905 TI - Psychoanalytic pluralism through the lens of envy and narcissism. PMID- 25434906 TI - Gender variations in waist circumference levels between Aboriginal and non Aboriginal Australian populations: a systematic review. AB - OBJECTIVES: To compare gender-specific waist circumference (WC) levels of Aboriginal Australians with non-Aboriginal Australians. METHODS: A systematic search on Medline, PubMed, EMBASE and Google Scholar databases was conducted to identify papers that reported gender-specific waist circumference (WC) estimates of participants from the age of 15 years and above among Aboriginal and non Aboriginal Australians. Means and their 95% confidence intervals of gender differences in WC, height and weight were recorded or calculated where they were not provided. Gender-specific WC, height and weight mean estimates were pooled and the I(2) statistic was used to test heterogeneity among Aboriginal and non Aboriginal Australians. RESULTS: Of 17 selected cross-sectional studies, 9 focused on Aboriginal and 8 on non-Aboriginal Australians. Seven studies reported significantly higher WC estimates among indigenous females than males. On the other hand, non-indigenous males had significantly higher WC levels than females. Males had greater height and weight estimates than females in both groups. CONCLUSION: Although indigenous women were shorter and had lower weight estimates, they had greater WC levels than indigenous men. This is the first systematic review to assess the gender-specific differences between Aboriginal and non-Aboriginal Australians. The findings of this review warrant more efforts to understand and reduce the high prevalence of central obesity and related chronic diseases among Aboriginal women. PMID- 25434907 TI - Health benefits of conjugated linoleic acid (CLA). AB - Conjugated linoleic acid (CLA) is a group of positional and geometric (cis or trans) isomers of linoleic acid with a conjugated double bond. The most representative CLA isomers are 9c,11t-18:2 and 10t,12c-18:2. CLA has been shown to exert various potent physiological functions such as anticarcinogenic, antiobese, antidiabetic and antihypertensive properties. This means CLA can be effective to prevent lifestyle diseases or metabolic syndromes. Also, reports suggest that physiological effects of CLA are different between the isomers, for example the 10t,12c isomer is anticarcinogenic, antiobese and antidiabetic, whereas the 9c,11t isomer is mainly anticarcinogenic. We describe here the physiological properties of CLA including the possible mechanism and the possibility to benefit human health. PMID- 25434908 TI - Dietary factors evoke thermogenesis in adipose tissues. AB - In dietary factors, energetic food constituents and the "non-energetic food constituents" such as smell and taste through sensory nerve stimulation have been found to be linked intrinsically with the accelerated expression of diet-induced thermogenesis that accompanies the burning of fat within brown adipose tissues (BAT). The compounds are responsible for BAT and uncoupling protein-1 (UCP1) activation or induction caused by food components. Many of these activate and strengthen BAT activation through the following pathway: sensory stimulations induce sympathetic nerve activation through central phase. In the fight against obesity, the development of food compounds and pharmaceuticals that activate or induce BAT and UCP1 is expected. In this review, we discuss that how dietary compounds effect thermogenesis through BAT and UCP1. PMID- 25434909 TI - Mechanisms of heart failure in obesity. AB - Heart failure is a leading cause of morbidity and mortality and its prevalence continues to rise. Because obesity has been linked with heart failure, the increasing prevalence of obesity may presage further rise in heart failure in the future. Obesity-related factors are estimated to cause 11% of heart failure cases in men and 14% in women. Obesity may result in heart failure by inducing haemodynamic and myocardial changes that lead to cardiac dysfunction, or due to an increased predisposition to other heart failure risk factors. Direct cardiac lipotoxicity has been described where lipid accumulation in the heart results in cardiac dysfunction inexplicable of other heart failure risk factors. In this overview, we discussed various pathophysiological mechanisms that could lead to heart failure in obesity, including the molecular mechanisms underlying cardiac lipotoxicity. We defined the obesity paradox and enumerated various premises for the paradoxical associations observed in the relationship between obesity and heart failure. PMID- 25434911 TI - Prevalence of overweight/obesity and central obesity and its associated factors among a sample of university students in India. AB - BACKGROUND: Obesity and the lifestyle characteristic of Indian society lead young people to conditions of potential cardiovascular risk. The purpose of this study was to assess the prevalence of overweight/obesity and central obesity and its associated factors in a sample of Indian university students. METHODS: In a cross sectional survey assessed anthropometric measurements and a self-administered questionnaire among a sample of randomly selected university students. The sample included 800 university students from non health (mainly sciences) courses Gitam University in India. The students were 541 (67.6%) males and 259 (32.4%) females in the age range of 17-20 years (M age 18.2 years, SD=1.0). RESULTS: 37.5% were overweight or obese, 26.8% overweight (>=23-27.4 BMI) and 10.7% obese (>=27.5 kg/m(2)), 11.7% underweight (<18.5 kg/m(2)) and 16.4% central obesity (WC >=90 cm for men and >=80 cm for women). In multivariate analysis among men lack of non organised religious activity (odds ratio=OR 0.85, confidence interval=CI 0.77 0.95), lower dietary risk knowledge (OR=0.64, CI=0.41-0.99), tobacco use (OR=2.23, CI=1.14-4.38), and suffering from depression (OR=1.59, CI=1.00-2.47) were associated with overweight/obesity, and younger age (OR=0.32, CI=0.12-0.90), lives away from parents or guardians (OR=1.79, CI=1.04-3.07), healthy dietary practices (OR=1.95, CI=1.02-3.72) and 9 or more hours sleep duration (OR=0.28, CI=0.09-0.96) were associated with central obesity. In bivariate analysis among women, lack of social support, lower dietary risk knowledge, tobacco use, and 9 or more hours sleep duration were associated with overweight/obesity and lives away from parents or guardians and abstinence from alcohol associated with central obesity. CONCLUSIONS: The study found a high prevalence of overweight/obesity and central obesity. Several gender specific health risk practices were identified including lack of dietary risk knowledge, shorter sleep duration, living away from parents or guardians, tobacco use and lack of social support and religiousness that can be utilised in health promotion programmes. PMID- 25434910 TI - Body mass index gain between ages 20 and 40 years and lifestyle characteristics of men at ages 40-60 years: the Adventist Health Study-2. AB - BACKGROUND: Obesity increases risk of premature disease, and may be associated with unfavorable lifestyle changes that add to risk. This study analyzed the association of midlife BMI change with current lifestyle patterns among multiethnic men. METHODS: Men aged 40-60 years (n=9864) retrospectively reported body weight between ages 20-40 years and current dietary, TV, physical activity and sleep practices in the Adventist Health Study II, a study of church-goers in the US and Canada. In multivariate logistic regression analysis, odds ratios for BMI gain were calculated for each lifestyle practice controlling for sociodemographic and other lifestyle factors and current BMI. RESULTS: Men with median or higher BMI gain (2.79 kg/m(2)) between ages 20-40 years were more likely to consume a non-vegetarian diet, and engage in excessive TV watching and little physical activity and had a shorter sleep duration compared to men with BMI gain below the median (all p<0.001). In multivariate logistic analysis current BMI was significantly associated with all lifestyle factors (all p<=0.005). BMI gain was associated with lower odds of vegetarian diet (odds ratio [OR] 0.939; 95% confidence interval [CI] 0.921-0.957) and of physical activity >=150 min/week (OR 0.979, 95% CI 0.960-0.999). CONCLUSIONS: These findings imply that diet and less physical activity are associated with both gained and attained BMI, while inactivity (TV watching) and short sleep duration correlated only with attained BMI. Unhealthy lifestyle may add risk to that associated with BMI. Longitudinal and intervention studies are needed to infer causal relationships. PMID- 25434912 TI - Antiobesity drugs in early pregnancy and congenital malformations in the offspring. AB - Little information exists on the possible teratogenic effect of modern antiobesity drugs. The present study refers to orlistat, sibutramine, and rimonabant. Data in the Swedish Medical Birth Register were utilised. During the years 1998-2011, among 392,126 infants born, 509 had been exposed to antiobesity drugs in early pregnancy: 248 to orlistat, 242 to sibutramine, 12 to rimonabant, 13 to unspecified antiobesity drugs. Simultaneous use of orlistat and sibutramine occurred in six cases. No increase in major malformation risk was seen after orlistat (relative risk=0.42, 95% confidence interval 0.11-1.07) but a significantly high risk was seen after sibutramine (relative risk=1.81, 95% confidence interval 1.02-2.99). The latter effect, which seemed to be mainly due to an increased risk for a cardiovascular defects, may be related to the capacity of the drug to prolong QT-time. Sibutramine has been withdrawn in Europe but is still available on the Internet and is a component in some slimming preparations. Among the 12 infants exposed to rimonabant, two which were in a twin pair were malformed. PMID- 25434913 TI - Behaviours of overweight and obese women during pregnancy who achieve and exceed recommended gestational weight gain. AB - BACKGROUND: Excessive gestational weight gain (GWG) is associated with increased risk of pregnancy-related complications, postpartum weight retention, and long term obesity. Little is known about the behavioural habits of pregnant women who achieve and exceed recommended GWG. METHOD: In 2011, qualitative interviews were conducted in Pennsylvania with postpartum women who were overweight or obese prior to pregnancy to ascertain their behaviours and attitudes regarding dietary habits, physical activity, and self-monitoring during pregnancy. Thematic analysis identified the habits of women who achieved and exceeded recommended GWG guidelines. RESULTS: Of the 29 women interviewed, 11 had appropriate GWG and 18 had excessive GWG. Women achieving appropriate GWG reported modest increases in caloric intake if at all, with deliberate meal and snack planning, while women with excessive GWG described "eating-for-two." Nearly all women with excessive GWG reported exercising less during pregnancy (or remaining sedentary), while women with appropriate GWG largely increased or maintained pre-pregnancy physical activity levels. About half of the sample reported self-monitoring weight gain during pregnancy, but women achieving recommended GWG tied their weight monitoring with GWG goals consistent with recommended guidelines. CONCLUSIONS: Women who achieved appropriate GWG reported deliberate dietary habits and physical activity planning, with appropriate GWG goals during pregnancy. Women exceeding recommended GWG described "eating-for-two," were sedentary, and either had no goals for GWG or intended to gain more weight than recommended. PMID- 25434915 TI - Metabolic monitoring of obese children born small for gestational age. AB - INTRODUCTION: The "catch-up growth" phenomenon in children born small for gestational age (SGA) has been linked to early onset obesity with the subsequent emergence of metabolic syndrome (MetS) or its components. It has been postulated that the prevalence of MetS and its components increases strongly with age. MATERIALS AND METHODS: A retrospective study was carried out over a 5 year period (2007-2011) to determine long-term metabolic complications in obese children born with normal weight for gestational age (appropriate for gestational age: AGA) and SGA. 517 patients were qualified into the study. According to birth weight and gestational age they were first divided into SGA (107 patients--20%) and AGA (410 patients--80%) and then by age into three subgroups: prepubertary group, pubertary group and adolescents. Blood pressure, lipids and glucose were measured. Oral glucose tolerance tests (oGTT) were performed in all subjects. RESULTS: Prepubertary patients showed no significant differences between SGA and AGA; 4.8% met the framing criteria (according to Weiss) for MetS. Pubertary patients showed a slightly increased prevalence of MetS among SGA patients 10.8%, compared to AGA patients 7.3%. MetS prevalence was significantly higher in obese adolescents born SGA 26.3% compared to AGA 15.7%. CONCLUSION: MetS or its components develop progressively with age. Increased prevalence of MetS in SGA patients indicates that being born SGA appears to be an additional risk factor in the development of MetS starting with puberty. PMID- 25434917 TI - Comment on "The impacts of sarcopenia and obesity on physical performance in the elderly". PMID- 25434916 TI - The influence of plaintiff's body weight on judgments of responsibility: the role of weight bias. AB - PROBLEM: The current study investigated the influence of a plaintiff's weight and the location of an accident on a simulated jury's perceptions of plaintiff's personal responsibility for an accident. METHODS: Participants were 185 lean and overweight male and female adults (mean self-reported body mass index: 24.87+/ 5.45) who read one of three vignettes describing an accident that occurred while leaving one of three different establishments (fast food burger restaurant; fitness gym; department store) while viewing one of two silhouettes of the alleged plaintiff (a lean female; an obese female). RESULTS: Participants were significantly more likely to report the plaintiff's weight entered into their perceptions of personal responsibility when they viewed the overweight plaintiff compared to the thin plaintiff. As respondent's self-reported weight bias increased, participants were more likely to hold the plaintiff responsible and more likely to blame plaintiff characteristics for the accident. CONCLUSION: The weight of a plaintiff may affect juror perceptions of personal responsibility particularly if the juror possesses self-reported weight bias. PMID- 25434914 TI - Glucose, insulin, and insulin resistance in normal-weight, overweight and obese children with obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with components of metabolic syndrome. Both body weight and OSA independently influence metabolic measurements. The goal of this study was to determine whether OSA in normal weight, overweight or obese children, compared to matched control groups, was associated with increased levels of glucose, insulin and insulin resistance (IR). METHODS: Age- and gender-specific body mass index (BMI) percentiles were determined and used to categorize subjects into normal-weight (BMI<85%) and overweight-obese (BMI>=85%) groups. In addition, subjects were divided into normal-weight (BMI<85%), overweight (BMI>=85% and <95%) and obese (BMI>=95%) groups. Polysomnography was conducted and morning levels of glucose and insulin were measured and IR was determined from the blood samples collected early in the morning after overnight fast. Results were compared between the subject groups. Effects of severity of OSA defined by apnea hypopnea index (AHI) and oxygen desaturation index (ODI) on glucose, insulin, and HOMA-IR were analyzed. RESULTS: Glucose, insulin, and HOMA-IR in OSA and matched control groups were not significantly different for normal-weight, overweight and obese subjects. The ODI was significantly associated with elevated levels of glucose and HOMA-IR after adjustment for age, gender, race, and BMI Z-score. CONCLUSIONS: IR levels between OSA and control for both normal-weight, overweight and obese subjects were not significantly different. The ODI was associated with increased IR in children with OSA. OSA-induced hypoxic events during sleep may be a potential mechanism of increased IR in children with OSA, independent of body weight. PMID- 25434918 TI - Response to the letter entitled "Comment on the impacts of sarcopenia and obesity on physical performance in the elderly". PMID- 25434919 TI - Corrigendum: Probing auditory scene analysis. AB - [This corrects the article on p. 293 in vol. 8, PMID: 25309314.]. PMID- 25434920 TI - Arrhythmias in the paediatric intensive care unit: a prospective study of the rates and predictors of arrhythmias in children without underlying cardiac disease. AB - OBJECTIVE: Arrhythmias are common in patients admitted to the paediatric intensive care unit. We sought to identify the rates of occurrence and types of arrhythmias, and determine whether an arrhythmia was associated with illness severity and paediatric intensive care unit length of stay. DESIGN: This is a prospective, observational study of all patients admitted to the paediatric intensive care unit at the Children's Hospital at Montefiore from March to June 2012. Patients with cardiac disease or admitted for the treatment of primary arrhythmias were excluded. Clinical and laboratory data were collected and telemetry was reviewed daily. Tachyarrhythmias were identified as supraventricular tachycardia, ventricular tachycardia, and arrhythmias causing haemodynamic compromise or for which an intervention was performed. RESULTS: A total of 278 patients met the inclusion criteria and were analysed. There were 97 incidences of arrhythmia in 53 patients (19%) and six tachyarrhythmias (2%). The most common types of arrhythmias were junctional rhythm (38%), premature atrial contractions (24%), and premature ventricular contractions (22%). Tachyarrhythmias included three supraventricular tachycardia (50%) and three ventricular tachycardia (50%). Of the six tachyarrhythmias, four were related to placement or migration of central venous lines and two occurred during aminophylline infusion. Patients with an arrhythmia had longer duration of mechanical ventilation and paediatric intensive care unit stay (p<0.001). In multivariate analysis, central venous lines (odds ratio 3.1; 95% confidence interval 1.3-7.2, p=0.009) and aminophylline use (odds ratio 5.1; 95% confidence interval 1.7-14.9, p=0.003) were independent predictors for arrhythmias. CONCLUSIONS: Arrhythmias were common in paediatric intensive care unit patients (19%), although tachyarrhythmias occurred rarely (2%). Central venous lines and use of aminophylline were identified as two clinical factors that may be associated with development of an arrhythmia. PMID- 25434921 TI - Large-scale production and characterization of biocompatible colloidal nanoalumina. AB - The rapid uptake of nanomaterials in life sciences calls for the development of universal, high-yield techniques for their production and interfacing with biomolecules. Top-down methods take advantage of the existing variety of bulk and thin-film solid-state materials for improved prediction and control of the resultant nanomaterial properties. We demonstrate the power of this approach using high-energy ball milling (HEBM) of alumina (Al2O3). Nanoalumina particles with a mean size of 25 nm in their most stable alpha-crystallographic phase were produced in gram quantities, suitable for biological and biomedical applications. Nanomaterial contamination from zirconia balls used in HEBM was reduced from 19 to 2% using a selective acid etching procedure. The biocompatibility of the milled nanomaterial was demonstrated by forming stable colloids in water and physiological buffers, corroborated by zeta potentials of +40 mV and -40 mV and characterized by in vitro cytotoxicity assays. Finally, the feasibility of a milled nanoalumina surface in anchoring a host of functional groups and biomolecules was demonstrated by the functionalization of their surface using facile silane chemistry, resulting in the decoration of the nanoparticle surface with amino groups suitable for further conjugation of biomolecules. PMID- 25434922 TI - Management of sporadic desmoid-type fibromatosis: a European consensus approach based on patients' and professionals' expertise - a sarcoma patients EuroNet and European Organisation for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group initiative. AB - Desmoid-type fibromatosis (DF) is a rare monoclonal, fibroblastic proliferation characterised by a variable and often unpredictable clinical course. It may affect nearly all parts of the body including extremities, trunk and abdomen. Considering the variable clinical presentations, anatomic locations and biological behaviours, an individualised treatment approach is required. No established or evidence-based approach for the treatment of this neoplasm is available as of today. Therefore, we propose a consensus treatment algorithm based on a round table meeting bringing together sarcoma experts from the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) with patient advocates from Sarcoma Patients EuroNet (SPAEN). The aim of the meeting was to develop - for the first time ever a consensus approach based on professionals' AND patients' expertise. As a fundamental prerequisite, all patients should be discussed in a multidisciplinary setting in centres or professional networks with a specific expertise in the disease. PMID- 25434923 TI - Phase 1 dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours. AB - BACKGROUND: S-222611 is a reversible inhibitor of EGFR, HER2 and HER4 with preclinical activity in models expressing these proteins. We have performed a Phase 1 study to determine safety, maximum tolerated dose (MTD), pharmacokinetic profile (PK) and efficacy in patients with solid tumours expressing EGFR or HER2. PATIENTS AND METHODS: Subjects had advanced tumours not suitable for standard treatment, expressing EGFR or HER2, and/or with amplified HER2. Daily oral doses of S-222611 were escalated from 100mg to 1600 mg. Full plasma concentration profiles for drug and metabolites were obtained. RESULTS: 33 patients received S 222611. It was well tolerated, and the most common toxicities, almost all mild (grade 1 or 2), were diarrhoea, fatigue, rash and nausea. Only two dose-limiting toxicities occurred (diarrhoea and rash), which resolved on interruption. MTD was not reached. Plasma exposure increased with dose up to 800 mg, exceeding levels eliciting pre-clinical responses. The plasma terminal half-life was more than 24h, supporting once daily dosing. Responses were seen over a wide range of doses in oesophageal, breast and renal tumours, including a complete clinical response in a patient with HER2-positive breast carcinoma previously treated with lapatinib and trastuzumab. Four patients have remained on treatment for more than 12 months. Downregulation of pHER3 was seen in paired tumour biopsies from a responding patient. CONCLUSIONS: Continuous daily oral S-222611 is well tolerated, modulates oncogenic signalling, and has significant antitumour activity. The recommended Phase 2 dose, based on PK and efficacy, is 800 mg/day. PMID- 25434924 TI - Creating a unique, multi-stakeholder Paediatric Oncology Platform to improve drug development for children and adolescents with cancer. AB - Seven years after the launch of the European Paediatric Medicine Regulation, limited progress in paediatric oncology drug development remains a major concern amongst stakeholders - academics, industry, regulatory authorities, parents, patients and caregivers. Restricted increases in early phase paediatric oncology trials, legal requirements and regulatory pressure to propose early Paediatric Investigation Plans (PIPs), missed opportunities to explore new drugs potentially relevant for paediatric malignancies, lack of innovative trial designs and no new incentives to develop drugs against specific paediatric targets are some unmet needs. Better access to new anti-cancer drugs for paediatric clinical studies and improved collaboration between stakeholders are essential. The Cancer Drug Development Forum (CDDF), previously Biotherapy Development Association (BDA), with Innovative Therapy for Children with Cancer Consortium (ITCC), European Society for Paediatric Oncology (SIOPE) and European Network for Cancer Research in Children and Adolescents (ENCCA) has created a unique Paediatric Oncology Platform, involving multiple stakeholders and the European Union (EU) Commission, with an urgent remit to improve paediatric oncology drug development. The Paediatric Oncology Platform proposes to recommend immediate changes in the implementation of the Regulation and set the framework for its 2017 revision; initiatives to incentivise drug development against specific paediatric oncology targets, and repositioning of drugs not developed in adults. Underpinning these changes is a strategy for mechanism of action and biology driven selection and prioritisation of potential paediatric indications rather than the current process based on adult cancer indications. Pre-competitive research and drug prioritisation, early portfolio evaluation, cross-industry cooperation and multi compound/sponsor trials are being explored, from which guidance for innovative trial designs will be provided. PMID- 25434925 TI - Protective effects of tetrandrine on brain cells in phenobarbital-dependent and withdrawn rats. AB - The aim of this study was to investigate the effects of tetrandrine (Tet) on the brain cells of phenobarbital-dependant and -withdrawn rats, and to explore the underlying mechanisms. A total of 100 rats were randomly divided into five groups: The control group, the phenobarbital-dependent model group, and Tet treated groups of low-, mid- and high-dosages. Following drug withdrawl, the morphological changes of the frontal lobe cells were examined by hematoxylin and eosin (H&E) staining. Immunohistochemical staining was applied to detect the expression of apoptosis-related proteins Bcl-2 and Bax. Reverse transcription polymerase chain reaction (RT-PCR) and western blotting methods were applied to detect the mRNA and protein expression levels of Bcl-2 and Bax, respectively, in the frontal lobe. The results indicated that Tet effectively reduced the withdrawal symptoms, particularly the weight loss, in phenobarbital-dependent and -withdrawn rats. H&E staining revealed that Tet significantly restored the histopathological changes in the addicted rats in a dose-dependent manner. The immunohistochemical, RT-PCR, and western blot analyses indicated that Tet treatment significantly increased the Bcl-2+ brain cells and the mRNA and protein expression levels of Bcl-2, and decreased the Bax+ cells and the mRNA and protein expression levels of Bax, as well as elevated the ratio of Bcl-2/Bax, in phenobarbital-dependent and -withdrawn rats. Tet may inhibit apoptosis in these addicted rats, in a dose-dependent manner. Tet alleviates the phenobarbital withdrawal symptoms and protects the brain cells against apoptosis, which may be a result of the regulation of the mRNA and protein expression levels of Bcl-2 and Bax. PMID- 25434926 TI - Fungicidal mechanisms of the antimicrobial peptide Bac8c. AB - Bac8c (RIWVIWRR-NH2) is an analogue peptide derived through complete substitution analysis of the linear bovine host defense peptide variant Bac2A. In the present study, the antifungal mechanism of Bac8c against pathogenic fungi was investigated, with a particular focus on the effects of Bac8c on the cytoplasmic membrane. We used bis-(1,3-dibutylbarbituric acid) trimethine oxonol [DiBAC4(3)] staining and 3,3'-dipropylthiacarbocyanine iodide [DiSC3(5)] assays to show that Bac8c induced disturbances in the membrane potential of Candida albicans. An increase in membrane permeability and suppression of cell wall regeneration were also observed in Bac8c-treated C. albicans. We studied the effects of Bac8c treatment on model membranes to elucidate its antifungal mechanism. Using calcein and FITC-labeled dextran leakage assays from Bac8c-treated large unilamellar vesicles (LUVs) and giant unilamellar vesicles (GUVs), we found that Bac8c has a pore-forming action on fungal membranes, with an estimated pore radius of between 2.3 and 3.3 nm. A membrane-targeted mechanism of action was also supported by the observation of potassium release from the cytosol of Bac8c-treated C. albicans. These results indicate that Bac8c is considered as a potential candidate to develop a novel antimicrobial agent because of its low-cost production characteristics and high antimicrobial activity via its ability to induce membrane perturbations in fungi. PMID- 25434927 TI - Quantitative measurement of cell membrane receptor internalization by the nanoluciferase reporter: Using the G protein-coupled receptor RXFP3 as a model. AB - Nanoluciferase (NanoLuc) is a newly developed small luciferase reporter with the brightest bioluminescence to date. In the present work, we developed NanoLuc as a sensitive bioluminescent reporter to measure quantitatively the internalization of cell membrane receptors, based on the pH dependence of the reporter activity. The G protein-coupled receptor RXFP3, the cognate receptor of relaxin-3/INSL7, was used as a model receptor. We first generated stable HEK293T cells that inducibly coexpressed a C-terminally NanoLuc-tagged human RXFP3 and a C terminally enhanced green fluorescent protein (EGFP)-tagged human RXFP3. The C terminal EGFP-tag and NanoLuc-tag had no detrimental effects on the ligand binding potency and intracellular trafficking of RXFP3. Based on the fluorescence of the tagged EGFP reporter, the ligand-induced RXFP3 internalization was visualized directly under a fluorescence microscope. Based on the bioluminescence of the tagged NanoLuc reporter, the ligand-induced RXFP3 internalization was measured quantitatively by a convenient bioluminescent assay. Coexpression of an EGFP-tagged inactive [E141R]RXFP3 had no detrimental effect on the ligand-binding potency and ligand-induced internalization of the NanoLuc-tagged wild-type RXFP3, suggesting that the mutant RXFP3 and wild-type RXFP3 worked independently. The present bioluminescent internalization assay could be extended to other G protein coupled receptors and other cell membrane receptors to study ligand-receptor and receptor-receptor interactions. PMID- 25434928 TI - Reactivation of dormant "non-culturable" Mycobacterium tuberculosis developed in vitro after injection in mice: both the dormancy depth and host genetics influence the outcome. AB - Three stocks of Mycobacterium tuberculosis H37Rv were cultured in vitro under prolonged hypoxic or acidified conditions until partial or complete loss of the capacity to form colonies on agar medium was achieved. Such dormant "non culturable" mycobacteria were assessed for the growth resuscitation after intra tracheal injection into mice of the two inbred strains with different genetic susceptibility to M. tuberculosis-triggered disease: hyper-susceptible I/St and relatively resistant B6. The results indicate that bacteria which are able to resuscitate spontaneously in liquid medium in vitro started to multiply in organs of infected mice, and that the outcome of such infection strongly depended upon the level of genetic TB susceptibility. However, dormant bacteria required inducers for resuscitation in vitro lost the capacity to multiply even in genetically susceptible mice. The established model of dormancy/reactivation is suitable for the studying host-pathogen interactions and testing vaccine and drug candidates specifically targeting latent TB. PMID- 25434929 TI - Genotypic and phenotypic characterization of Pseudomonas aeruginosa isolates from post-cataract endophthalmitis patients. AB - Endophthalmitis caused by Pseudomonas aeruginosa is associated with rapid disease progression and poor visual outcome due to high virulence of the organism. Our aim was to characterize the virulence determinants of P. aeruginosa causing post operative endophthalmitis. Repetitive sequence analysis (ERIC PCR) was done to study the clonal relatedness of the 17 P. aeruginosa isolates. Type 3 secretion system (T3SS) genotypes were determined and the isolates were further classified as invasive or cytotoxic based on gentamicin survival, trypan blue dye exclusion and MTT assays. Phenotypically, the strains were characterized based on bacterial motility patterns, biofilm formation, phospholipase production and antibiotic susceptibility patterns. Most of our ocular isolates were invasive in nature and nearly half of them were multi-drug resistant. 47% of the isolates formed a strong biofilm, whereas the rest formed moderate to weak biofilms, which may account for an increased colonization and antibiotic resistance. Although the T3SS genotypes correlated well with the invasive/cytotoxic nature of the strains, none of the genotypes were associated with any particular phenotypic trait. To the best of our knowledge, this is the first report on the phenotypic characteristics of P. aeruginosa strains causing post-operative endophthalmitis. Our findings demonstrate that these strains have higher invasive potential and an ability to form biofilm which possibly contributes to an increased ocular virulence. PMID- 25434930 TI - Corrigendum. PMID- 25434932 TI - Giving it your best shot. PMID- 25434931 TI - Altered microbiota associated with abnormal humoral immune responses to commensal organisms in enthesitis-related arthritis. AB - INTRODUCTION: Prior studies have established altered microbiota and immunologic reactivity to enteric commensal organisms in inflammatory bowel disease (IBD). Since intestinal inflammation is present in a subset of patients with both pediatric and adult spondyloarthritis (SpA), we hypothesized that SpA patients may also have altered microbiota and immune responsiveness to enteric organisms. METHODS: Stool and blood specimens were collected from children with enthesitis related arthritis (ERA) and non-inflammatory controls. DNA purified from stool was subject to PCR amplification and sequencing of the variable IV region from the 16S rDNA gene. IgA and IgG Enzyme-linked Immunosorbent Assays (ELISAs) were performed on select species of bacteria in most subjects. RESULTS: Twenty-five children with ERA and 13 controls were included. The ERA patients had less Faecalibacterium prausnitzii (3.8% versus 10%, P = 0.008) and lachnospiraceae family (12 versus 7.0%, P = 0.020), a statistically significant increase in bifidobacterium (1.8% versus 0%, P = 0.032) and a non-statistically significant increase in Bacteroides (21% versus 11%, P = 0.150). Akkermansia muciniphila was abundant (>2%) in 7/27 ERA patients but none of the controls (P = 0.072.) Cluster analysis revealed two clusters of ERA patients: Cluster one (n = 8) was characterized by high levels of Bacteroides genus, while a second (n = 15) cluster had similar levels as the controls. Seven of 17 (41%) of the ERA subjects in Cluster 2 compared to 0/8 of the subjects in Cluster 1 had abundant Akkermansia muciniphila (P = 0.057). Serum IgA and IgG antibody levels against F. prausnitzii and B. fragilis were similar between patients and controls, whereas the two groups showed divergent responses when the fecal relative abundances of F. prausnitzii and Bacteroides were compared individually against IgA antibody levels recognizing F. prausnitzii and B. fragilis, respectively. CONCLUSION: The abundance of F. prausnitzii in the stool among patients with ERA is reduced compared to controls, and Bacteroides and A. muciniphila are identified as associative agents in subsets of ERA patients. Differences in the humoral responses to these bacteria may contribute to disease. PMID- 25434933 TI - Stereotactic radiosurgery for patients with multiple brain metastases: a case matched study comparing treatment results for patients with 2-9 versus 10 or more tumors. AB - OBJECT: Although stereotactic radiosurgery (SRS) alone is not a standard treatment for patients with 4-5 tumors or more, a recent trend has been for patients with 5 or more, or even 10 or more, tumors to undergo SRS alone. The aim of this study was to reappraise whether the treatment results for SRS alone for patients with 10 or more tumors differ from those for patients with 2-9 tumors. METHODS: This was an institutional review board-approved, retrospective cohort study that gathered data from the Katsuta Hospital Mito GammaHouse prospectively accumulated database. Data were collected for 2553 patients who consecutively had undergone Gamma Knife SRS alone, without whole-brain radiotherapy (WBRT), for newly diagnosed (mostly) or recurrent (uncommonly) brain metastases during 1998 2011. Of these 2553 patients, 739 (28.9%) with a single tumor were excluded, leaving 1814 with multiple metastases in the study. These 1814 patients were divided into 2 groups: those with 2-9 tumors (Group A, 1254 patients) and those with 10 or more tumors (Group B, 560 patients). Because of considerable bias in pre-SRS clinical factors between groups A and B, a case-matched study, which used the propensity score matching method, was conducted for clinical factors (i.e., age, sex, primary tumor state, extracerebral metastases, Karnofsky Performance Status, neurological symptoms, prior procedures [surgery and WBRT], volume of the largest tumor, and peripheral doses). Ultimately, 720 patients (360 in each group) were selected. The standard Kaplan-Meier method was used to determine post SRS survival times and post-SRS neurological death-free survival times. Competing risk analysis was applied to estimate cumulative incidence for local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-induced complications. RESULTS: Post-SRS median survival times did not differ significantly between the 2 groups (6.8 months for Group A vs 6.0 months for Group B; hazard ratio [HR] 1.133, 95% CI 0.974-1.319, p = 0.10). Furthermore, rates of neurological death were very similar: 10.0% for group A and 9.4% for group B (p = 0.89); neurological death-free survival times did not differ significantly between the 2 groups (HR 1.073, 95% CI 0.649-1.771, p = 0.78). The cumulative incidence of local recurrence (HR 0.425, 95% CI 0.0.181-0.990, p = 0.04) and repeat SRS for new lesions (HR 0.732, 95% CI 0.554-0.870, p = 0.03) were significantly lower for Group B than for Group A patients. No significant differences between the groups were found for cumulative incidence for neurological deterioration (HR 0.994, 95% CI 0.607-1.469, p = 0.80) or SRS related complications (HR 0.541, 95% CI 0.138-2.112, p = 0.38). CONCLUSIONS: Post SRS treatment results (i.e., median survival time; neurological death-free survival times; and cumulative incidence for local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-related complications) were not inferior (neither less effective nor less safe) for patients in Group B than for those in Group A. We conclude that carefully selected patients with 10 or more tumors are not unfavorable candidates for SRS alone. A randomized controlled trial should be conducted to test this hypothesis. PMID- 25434934 TI - Stereotactic radiosurgery for intraventricular brain metastases. AB - OBJECT: The authors' institution previously reported a 69% rate of crude local control for surgical management of lateral ventricle metastases at the University of Texas MD Anderson Cancer Center. For comparison, the authors here report their institutional experience with use of stereotactic radiosurgery (SRS) to treat intraventricular metastases. METHODS: To identify patients with intraventricular metastases for this retrospective review, the authors queried an institutional SRS database containing the medical records of 1962 patients with 5800 brain metastases who consecutively underwent SRS from June 2009 through October 2013. End points assessed were local control (crude and locoregional), distant failure free survival, progression-free survival, and overall survival. RESULTS: Of the 1962 records examined, those for 25 (1.3%) patients with 30 (0.52%) intraventricular metastases were identified. Median patient age at SRS was 55.8 years. The most common primary malignancy was renal cell carcinoma (n = 13), followed by melanoma (n = 7) and breast adenocarcinoma (n = 5). Median tumor volume was 0.75 cm(3) (range 0.01-5.6 cm(3)). Most lesions were located in the lateral ventricles (n = 25, 83.3%) and were treated to a median dose of 20 Gy (range 14-20 Gy). A total of 12 (48%) patients received whole-brain radiation therapy, most (n = 10) before SRS. With a median follow-up of 11.4 months (range 1.6-39.2 months), the rate of crude local control was 93.3%, and the rates of 6 month and 1-year actuarial locoregional control were 85.2% and 56.2%, respectively. The median overall survival time after SRS was 11.6 months (range 1.3-38.9 months), and the 6-month and 1-year actuarial rates were 87.1% and 46.7%, respectively. Disease dissemination developed in 7 (28%) patients as a second intraventricular metastatic lesion (n = 3, 12%), leptomeningeal disease (n = 3, 12%), or both (n = 1, 4%). Radiographic changes developed in 5 (20%) patients and included necrosis (n = 2, 8%) and hemorrhage (n = 3, 12%). A primary diagnosis of renal cell carcinoma was associated with an improved rate of distant failure-free survival (p = 0.05) and progression-free survival (p = 0.08). CONCLUSIONS: SRS provides excellent local control for intraventricular metastases, with acceptable treatment-related toxicity, thereby supporting nonsurgical treatment for these lesions. The propensity for intraventricular dissemination among intraventricular metastases seems to be histologically dependent. PMID- 25434935 TI - A new grading system focusing on neurological outcomes for brain metastases treated with stereotactic radiosurgery: the modified Basic Score for Brain Metastases. AB - OBJECT: The Basic Score for Brain Metastases (BSBM) proposed by Lorenzoni and colleagues is one of the best grading systems for predicting survival periods after stereotactic radiosurgery (SRS) for brain metastases. However, it includes no brain factors and cannot predict neurological outcomes, such as preservation of neurological function and prevention of neurological death. Herein, the authors propose a modified BSBM, adding 4 brain factors to the original BSBM, enabling prediction of neurological outcomes, as well as of overall survival, in patients undergoing SRS. METHODS: To serve as neurological prognostic scores (NPSs), the authors scored 4 significant brain factors for both preservation of neurological function (qualitative survival) and prevention of neurological death (neurological survival) as 0 or 1 as described in the following: > 10 brain tumors = 0 or <= 10 = 1, total tumor volume > 15 cm(3) = 0 or <= 15 cm(3) = 1, MRI findings of localized meningeal dissemination (yes = 0 or no = 1), and neurological symptoms (yes = 0 or no = 1). According to the sum of NPSs, patients were classified into 2 subgroups: Subgroup A with a total NPS of 3 or 4 and Subgroup B with an NPS of 0, 1, or 2. The authors defined the modified BSBM according to the NPS subgroup classification applied to the original BSBM groups. The validity of this modified BSBM in 2838 consecutive patients with brain metastases treated with SRS was verified. RESULTS: Patients included 1868 with cancer of the lung (including 1604 with non-small cell lung cancer), 355 of the gastrointestinal tract, 305 of the breast, 176 of the urogenital tract, and 134 with other cancers. Subgroup A had 2089 patients and Subgroup B 749. Median overall survival times were 2.6 months in BSBM 0 (382 patients), 5.7 in BSBM 1 (1143), 11.4 in BSBM 2 (1011) and 21.7 in BSBM 3 (302), and pairwise differences between the BSBM groups were statistically significant (all p < 0.0001). One-year qualitative survival rates were 64.6% (modified BSBM 0A, 204 patients), 45.0% (0B, 178), 82.5% (1A, 825), 63.3% (1B, 318), 86.4% (2A, 792), 73.7% (2B, 219), 91.4% (3A, 268), and 73.5% (3B, 34). One-year neurological survival rates were 82.6% (0A), 52.4% (0B), 90.5% (1A), 78.1% (1B), 91.1% (2A), 83.2% (2B), 93.9% (3A), and 76.3% (3B), where A and B identify the subgroup. Statistically significant differences in both qualitative and neurological survivals between Subgroups A and B were detected in all BSBM groups. CONCLUSIONS: The authors' new index, the modified BSBM, was found to be excellent for predicting neurological outcomes, independently of life expectancy, in SRS-treated patients with brain metastases. PMID- 25434936 TI - Quantifying and improving the efficiency of Gamma Knife treatment plans for brain metastases: results of a 1-year audit. AB - OBJECT: A method for quantifying the efficiency of Gamma Knife treatment plans for metastases was previously implemented by the authors to retrospectively identify the least efficient plans and has provided insights into improved planning strategies. The aim of the current work was to ascertain whether those insights led to improved treatment plans. METHODS: Following completion of the initial study, a 1-year audit of metastasis plans created at St. James's Institute of Oncology was carried out. Audited recent plans were compared with the earlier plans of the initial study, in terms of their efficiency and dosimetric quality. The statistical significance of any differences between relevant plan parameters was quantified by Mann-Whitney U-tests. Comparisons were made between all plans and repeated for a reduced set of plans from which the smallest lesions treated with a single 4-mm shot were excluded. The plan parameters compared were a plan efficiency index (PEI), the number of shots, Paddick conformity index (PCI), gradient index (GI), and percent coverage (of the lesion by the prescription isodose). RESULTS: A total of 157 metastatic lesions were included in the audit and were compared with 241 in the initial study. In a comparison of all cases, the audited plans achieved a higher median PEI score than did the earlier plans from the initial study (1.08 vs 1.02), indicating improved efficiency of the audited plans. When the smallest lesions (for which there was little scope for varying plan strategy) were discounted, the improvement in median PEI score was greater (1.23 vs 1.03, p < 0.001). This improvement in efficiency corresponds to an estimated mean (maximum) time saving of 15% (66%) per lesion (11 minutes [64 minutes] on the day of treatment). The modified planning strategy yielding these efficiency improvements did not rely on the use of significantly fewer shots (median 11 vs 11 shots, p = 0.924), nor did it result in significant detriment to dosimetric quality (median coverage 99% vs 99%, median PCI 0.84 vs 0.83, p = 0.449, and median GI 2.72 vs 2.67, p = 0.701, audited plans vs initial plans, respectively). CONCLUSIONS: Choice of planning strategy can substantially affect plan efficiency and thus strongly influence treatment time. Through increased emphasis on efficiency, resulting from the introduction of PEI combined with a modified planning strategy informed by previous work, it has been possible to reduce times for metastatic plans without compromising their dosimetric quality. Although the average time savings achieved per lesion are moderate, the potential benefits per patient are greater for those with multiple metastases. Reducing treatment times has clear benefits with regard to patient comfort and throughput. In addition, optimization of plan efficiency may potentially affect the biologically effective dose from Gamma Knife treatments and offers opportunity for further work. PMID- 25434937 TI - Comparison of radiation dose spillage from the Gamma Knife Perfexion with that from volumetric modulated arc radiosurgery during treatment of multiple brain metastases in a single fraction. AB - OBJECT: The objective of this study was to examine radiation dose distributions created by 2 competing radiosurgery modalities for treating multiple brain metastases: single-isocenter volumetric modulated arc radiosurgery (VMAS) and Gamma Knife Perfexion (GKP). In addition, the effectiveness of multiple radiosurgery quality metrics was evaluated and compared between these advanced treatment modalities. METHODS: Seven anonymized MRI data sets, each showing 2-5 metastases, were used to create plans on each system. The GammaPlan (version 10.1) program was used for planning of GKP. A neurosurgeon contoured the volumes to be treated, and no planning target volume expansion was used. A prescription dose coverage of >= 99% was achieved for each tumor volume. The Philips Pinnacle (version 9.2) program was used for planning of VMAS, using the SmartArc optimization algorithm for delivery on a Varian iX linear accelerator. Contours were transferred from GammaPlan, and again no planning target volume expansion was used. Between 2 and 5 arcs with table angles of 90 degrees -270 degrees were used. Again, a V100% of >= 99% was achieved for each tumor volume. After planning, the MRI scans, tumor volumes, and dose information from each plan were exported according to the Digital Imaging and Communications in Medicine standard to the VelocityAI program for analysis. Brain dose-volume histograms (DVHs) for normal brain tissues were generated, and the volume of these tissues receiving 20%-90% of the prescription dose was tabulated. Finally, the prescription isodose to tumor volume ratio (PITV; Shaw et al., 1993), conformity index (CI; Paddick, 2000), gradient index (GI, Paddick and Lippitz, 2006), and conformity/gradient index (CGI, Wagner et al. 2003) were calculated for each plan. Both the PITV and CI have ideal values of 1, while the GI and CGI have ideal values of lowest and highest achievable, respectively. RESULTS: The DVHs consistently showed that with VMAS a higher amount of normal brain tissues received each dose level than with GKP. These increases were largest for lower isodose levels, with the volumes of normal brain that received 20%-50% and 60%-90% of the prescription dose showing average increases of 403% and 227%, respectively. Prescription isodose conformality showed only minor differences between the 2 modalities. Radiosurgery quality metrics including measures of the dose gradient (GI and CGI) indicated that the GKP plan was superior in each case, with respective average GI and CGI values of 3.04 and 57.75 for GKP and of 10.22 and 10.85 for VMAS. Metrics evaluating prescription isodose conformality alone differed only slightly between the modalities. Average respective PITV and CI values were 2.13 and 0.53 for GKP and 2.27 and 0.51 for VMAS. CONCLUSIONS: Stereotactic radiosurgery plans for the treatment of multiple metastases with VMAS delivered significantly more dose to the normal brain tissues than plans for GKP. Radiosurgery quality metrics including a measure of the dose gradient are better suited to providing contrast between modern radiosurgery treatment platforms. PMID- 25434938 TI - Biological implications of whole-brain radiotherapy versus stereotactic radiosurgery of multiple brain metastases. AB - OBJECT: The efficacy and safety of treatment with whole-brain radiotherapy (WBRT) or with stereotactic radiosurgery (SRS) for multiple brain metastases (> 10) are topics of ongoing debate. This study presents detailed dosimetric and biological information to investigate the possible clinical outcomes of these 2 modalities. METHODS: Five patients with multiple brain metastases (n = 11-23) underwent SRS. Whole-brain radiotherapy plans were retrospectively designed with the same MR image set and the same structure set for each patient, using the standard opposing lateral beams and fractionation (3 Gy * 10). Physical radiation doses and biologically effective doses (BEDs) in WBRT and SRS were calculated for each lesion target and for the normal brain tissues for comparison of the 2 modalities in the context of clinical efficacy and published toxicities. RESULTS: The BEDs targeted to the tumor were higher in SRS than in WBRT by factors ranging from 2.4 to 3.0- fold for the mean dose and from 3.2- to 5.3-fold for the maximum dose. In the 5 patients, mean BEDs in SRS (calculated as percentages of BEDs in WBRT) were 1.3%-34.3% for normal brain tissue, 0.7%-31.6% for the brainstem, 0.5%-5.7% for the chiasm, 0.2%-5.7% for optic nerves, and 0.6%-18.1% for the hippocampus. CONCLUSIONS: The dose-volume metrics presented in this study were essential to understanding the safety and efficacy of WBRT and SRS for multiple brain metastases. Whole-brain radiotherapy results in a higher incidence of radiation related toxicities than SRS. Even in patients with > 10 brain metastases, the normal CNS tissues receive significantly lower doses in SRS. The mean normal brain dose in SRS correlated with the total volume of the lesions rather than with the number of lesions treated. PMID- 25434939 TI - Early Gamma Knife stereotactic radiosurgery to the tumor bed of resected brain metastasis for improved local control. AB - OBJECT: Optimal case management after surgical removal of brain metastasis remains controversial. Although postoperative whole-brain radiation therapy (WBRT) has been shown to prevent local recurrence and decrease deaths, this modality can substantially decrease neurocognitive function and quality of life. Stereotactic radiosurgery (SRS) can theoretically achieve the same level of local control with fewer side effects, although studies conclusively demonstrating such outcomes are lacking. To assess the effectiveness and safety profile of tumor bed SRS after resection of brain metastasis, the authors performed a retrospective analysis of 110 patients who had received such treatment at the Centre Hospitalier Universitaire de Sherbrooke. They designed the study to identify risk factors for local recurrence and placed special emphasis on factors that could potentially be addressed. METHODS: Patients who had received treatment from 2004 through 2013 were included if they had undergone surgical removal of 1 or more brain metastases and if the tumor bed was treated by SRS regardless of the extent of resection or prior WBRT. All cases were retrospectively analyzed for patient and tumor-specific factors, treatment protocol, adverse outcomes, cavity outcomes, and survival for as long as follow-up was available. Univariate and multivariate Cox regression analyses were performed to identify risk factors for local recurrence and predictors of increased survival times. RESULTS: Median patient age at first SRS treatment was 58 years (range 37-84 years). The most frequently diagnosed primary tumor was non-small cell lung cancer. The rate of gross-total resection was 81%. The median Karnofsky Performance Scale score was 90%. Tumor bed SRS was performed at a median of 3 weeks after surgery. Median follow-up and survival times were 10 and 11 months, respectively. Actuarial local control of the cavity at 12 months was 73%; median time to recurrence was 6 months. According to multivariate analysis, risk factors for recurrence were a longer surgery-to-SRS delay (HR 1.625, p = 0.003) and a lower maximum radiation dose delivered to the cavity (HR 0.817, p = 0.006). Factors not associated with increased recurrence were subtotal or piecemeal resections, prior WBRT, histology of the primary tumor, and larger cavity volume. No factors predictive of survival were identified. Symptomatic radiation-induced enhancement occurred in 6% of patients and leptomeningeal dissemination in 11%. Pathologically confirmed radiation-induced necrosis occurred in 1 (0.9%) patient. CONCLUSIONS: Adjuvant tumor bed SRS after the resection of brain metastasis is a valuable alternative to adjuvant WBRT. Risk factors for local recurrence are lower maximum radiation dose and a surgery-to-SRS delay longer than 3 weeks. Outcomes were not worse for patients who had undergone prior WBRT and subtotal or piecemeal resections. Pending the results of prospective randomized controlled trials, the authors' study supports the safety and efficacy of adjuvant SRS after resection of brain metastasis. SRS should be performed as early as possible, ideally within 3 weeks of the surgery. PMID- 25434940 TI - Stereotactic radiosurgery to the resection bed for intracranial metastases and risk of leptomeningeal carcinomatosis. AB - OBJECT: Following resection of a brain metastasis, stereotactic radiosurgery (SRS) to the cavity is an emerging alternative to postoperative whole-brain radiation therapy (WBRT). This approach attempts to achieve local control without the neurocognitive risks associated with WBRT. The authors aimed to report the outcomes of a large patient cohort treated with this strategy. METHODS: A retrospective review identified 91 patients without a history of WBRT who received Gamma Knife (GK) SRS to 96 metastasis resection cavities between 2007 and 2013. Patterns of intracranial control were examined in the 86 cases with post-GK imaging. Survival, local failure, and distant failure were estimated by the Kaplan-Meier method. Prognostic factors were tested by univariate (log-rank test) and multivariate (Cox proportional hazards model) analyses. RESULTS: Common primary tumors were non-small cell lung (43%), melanoma (14%), and breast (13%). The cases were predominantly recursive partitioning analysis Class I (25%) or II (70%). Median preoperative metastasis diameter was 2.8 cm, and 82% of patients underwent gross-total resection. A median dose of 16 Gy was delivered to the 50% isodose line, encompassing a median treatment volume of 9.2 cm(3). Synchronous intact metastases were treated in addition to the resection bed in 43% of cases. Patients survived a median of 22.3 months from the time of GK. Local failure developed in 16 cavities, for a crude rate of 18% and 1-year actuarial local control of 81%. Preoperative metastasis diameter >= 3 cm and residual or recurrent tumor at the time of GK were associated with local failure (p = 0.04 and 0.008, respectively). Distant intracranial failure occurred in 55 cases (64%) at a median of 7.3 months from GK. Salvage therapies included WBRT and additional SRS in 33% and 31% of patients, respectively. Leptomeningeal carcinomatosis developed in 12 cases (14%) and was associated with breast histology and infratentorial cavities (p = 0.024 and 0.012, respectively). CONCLUSIONS: This study bolsters the existing evidence for SRS to the resection bed. Local control rates are high, but patients with larger preoperative metastases or residual/recurrent tumor at the time of SRS are more likely to fail at the cavity. While most patients develop distant intracranial failure, an SRS approach spared or delayed WBRT in the majority of cases. The risk of leptomeningeal carcinomatosis does not appear to be elevated with this strategy. PMID- 25434941 TI - Cost-effectiveness of stereotactic radiosurgery with and without whole-brain radiotherapy for the treatment of newly diagnosed brain metastases. AB - OBJECT: Stereotactic radiosurgery (SRS) alone is increasingly used in patients with newly diagnosed brain metastases. Stereotactic radiosurgery used together with whole-brain radiotherapy (WBRT) reduces intracranial failure rates, but this combination also causes greater neurocognitive toxicity and does not improve survival. Critics of SRS alone contend that deferring WBRT results in an increased need for salvage therapy and in higher costs. The authors compared the cost-effectiveness of treatment with SRS alone, SRS and WBRT (SRS+WBRT), and surgery followed by SRS (S+SRS) at the authors' institution. METHODS: The authors retrospectively reviewed the medical records of 289 patients in whom brain metastases were newly diagnosed and who were treated between May 2001 and December 2007. Overall survival curves were plotted using the Kaplan-Meier method. Multivariate proportional hazards analysis (MVA) was used to identify factors associated with overall survival. Survival data were complete for 96.2% of patients, and comprehensive data on the resource use for imaging, hospitalizations, and salvage therapies were available from the medical records. Treatment costs included the cost of initial and all salvage therapies for brain metastases, hospitalizations, management of complications, and imaging. They were computed on the basis of the 2007 Medicare fee schedule from a payer perspective. Average treatment cost and average cost per month of median survival were compared. Sensitivity analysis was performed to examine the impact of variations in key cost variables. RESULTS: No significant differences in overall survival were observed among patients treated with SRS alone, SRS+WBRT, or S+SRS with respective median survival of 9.8, 7.4, and 10.6 months. The MVA detected a significant association of overall survival with female sex, Karnofsky Performance Scale (KPS) score, primary tumor control, absence of extracranial metastases, and number of brain metastases. Salvage therapy was required in 43% of SRS-alone and 26% of SRS+WBRT patients (p < 0.009). Despite an increased need for salvage therapy, the average cost per month of median survival was $2412 per month for SRS alone, $3220 per month for SRS+WBRT, and $4360 per month for S+SRS (p < 0.03). Compared with SRS+WBRT, SRS alone had an average incremental cost savings of $110 per patient. Sensitivity analysis confirmed that the average treatment cost of SRS alone remained less than or was comparable to SRS+WBRT over a wide range of costs and treatment efficacies. CONCLUSIONS: Despite an increased need for salvage therapy, patients with newly diagnosed brain metastases treated with SRS alone have similar overall survival and receive more cost-effective care than those treated with SRS+WBRT. Compared with SRS+WBRT, initial management with SRS alone does not result in a higher average cost. PMID- 25434942 TI - Calvarial and skull base metastases: expanding the clinical utility of Gamma Knife surgery. AB - OBJECT: Traditionally, the treatment of choice for patients with metastases to the calvaria or skull base has been conventional radiation therapy. Because patients with systemic malignancies are also at risk for intracranial metastases, the utility of Gamma Knife surgery (GKS) for these patients has been explored to reduce excess radiation exposure to the perilesional brain parenchyma. The purpose of this study was to report the efficacy of GKS for the treatment of calvarial metastases and skull base lesions. METHODS: The authors performed a retrospective chart review of 21 patients with at least 1 calvarial or skull base metastatic lesion treated with GKS during 2001-2013. For 7 calvarial lesions, a novel technique, in which a bolus was placed over the treatment site, was used. For determination of local control or disease progression, radiation therapy data were examined and posttreatment MR images and oncology records were reviewed. Survival times from the date of procedure were estimated by using Kaplan-Meier analyses. RESULTS: The median patient age at treatment was 57 years (range 29-84 years). A total of 19 (90%) patients received treatment for single lesions, 1 patient received treatment for 3 lesions, and 1 patient received treatment for 4 lesions. The most common primary tumor was breast cancer (24% of patients). Per lesion, the median clinical and radiographic follow-up times were 10.3 months (range 0-71.9 months) and 7.1 months (range 0-61.3 months), respectively. Of the 26 lesions analyzed, 14 (54%) were located in calvarial bones and 12 (46%) were located in the skull base. The median lesion volume was 5.3 cm(3) (range 0.3-55.6 cm(3)), and the median prescription margin dose was 15 Gy (range 13-24 Gy). The median overall survival time for all patients was 35.9 months, and the 1-year local control rate was 88.9% (95% CI 74.4%-100%). Local control rates did not differ between lesions treated with the bolus technique and those treated with traditional methods or between calvarial lesions and skull base lesions (p > 0.05). Of the 3 patients for whom local treatment failed, 1 patient received no further treatment and 2 patients responded to salvage chemotherapy. Subsequent brain parenchymal metastases developed in 2 patients, who then underwent GKS. CONCLUSIONS: GKS is an effective treatment modality for patients with metastases to the calvarial bones or skull base. For patients with superficial calvarial lesions, a novel approach with bolus application resulted in excellent rates of local control. GKS provides an effective therapeutic alternative to conventional radiation therapy and should be considered for patients at risk for calvarial metastases and brain parenchymal metastases. PMID- 25434943 TI - Gamma Knife surgery for treating brain metastases arising from hepatocellular carcinomas. AB - OBJECT: Brain metastases from hepatocellular carcinoma (HCC) are rare, and the evidence of the effectiveness of Gamma Knife surgery (GKS) in this disease is lacking. The authors report their institutional experience with GKS in patients with brain metastases from HCCs. METHODS: The authors retrospectively reviewed the medical records of 73 consecutive patients who had a combined total of 141 brain metastases arising from HCCs and were treated with GKS. Sixty-four (87.7%) patients were male, and the mean age of the patients was 52.5 years (range 30-79 years). The mean tumor volume was 7.35 cm(3) (range 0.19-33.7 cm(3)). The median margin dose prescribed was 23 Gy (range 15-32 Gy). Univariate and multivariate survival analyses were performed to identify possible prognostic factors of outcomes. RESULTS: The estimated rate of local tumor control was 79.6% at 3 months after GKS. The median overall survival time after GKS was 16 weeks. The actuarial survival rates were 76.7%, 58.9%, and 26.0% at 4, 12, and 24 weeks after GKS, respectively. In the univariate analysis, an age of <= 65 years, Child Pugh Class A (pertaining to liver function), high Karnofsky Performance Scale score (>= 70), and low Radiation Therapy Oncology Group recursive partitioning analysis class (I or II) were positively associated with the survival times of patients. No statistically significant variable was identified in the multivariate analysis. CONCLUSIONS: Although survival was extremely poor in patients with brain metastases from HCCs, GKS showed acceptable local tumor control at 3 months after the treatment. The authors suggest that GKS represents a noninvasive approach that may provide a valuable option for treating patients with brain metastases from HCCs. PMID- 25434944 TI - To fractionate or not to fractionate? That is the question for the radiosurgery of hypoxic tumors. AB - OBJECT: This study aimed to investigate the impact of tumor hypoxia on treatment outcome for metastases commonly treated with radiosurgery using 1 fraction of radiation and the potential gain from reoxygenation if the treatment is delivered in a few radiation fractions. METHODS: In silico metastasis-like radiosurgery targets were modeled with respect to size, density of clonogenic cells, and oxygenation. Treatment plans were produced for the targets using Leksell GammaPlan, delivering clinically relevant doses and evaluating the tumor control probability (TCP) that could be expected in each case. Fractionated schedules with 3, 4, and 5 fractions resulting in similar biological effective doses were also considered for the larger target, and TCP was determined under the assumption that local reoxygenation takes place between fractions. RESULTS: The results showed that well-oxygenated small- and medium-size metastases are well controlled by radiosurgery treatments delivering 20 or 22 Gy at the periphery, with TCPs ranging from 90% to 100%. If they are moderately hypoxic, the TCP could decrease to 60%. For large metastases, the TCPs from single-fraction treatments ranged from 0% to 19%, depending on tumor oxygenation. However, for fractionated treatments, the TCP for hypoxic tumors could significantly increase up to 51%, if reoxygenation occurs between fractions. CONCLUSIONS: This study shows that hypoxia worsens the response to single-fraction radiosurgery, especially for large tumors. However, fractionated therapy for large hypoxic tumors might considerably improve the TCP and might constitute a simple way to improve the outcome of radiosurgery for patients with hypoxic tumors. PMID- 25434945 TI - Gamma Knife surgery for facial nerve schwannomas. AB - OBJECT: The aim of this study was to evaluate the tumor control rate and functional outcomes after Gamma Knife surgery (GKS) among patients with a facial nerve schwannoma. METHODS: The authors reviewed the radiological data and clinical records for 14 patients who had consecutively undergone GKS for a facial nerve schwannoma. Before GKS, 12 patients had facial palsy, 7 patients had hearing disturbance, and 5 patients had undergone partial or subtotal tumor resection. The mean and median tumor volumes were 3707 mm(3) and 3000 mm(3), respectively (range 117-10,100 mm(3)). The mean tumor margin dose was 13.2 Gy (range 12-15 Gy), and the mean maximum tumor dose was 26.4 Gy (range 24-30 Gy). The mean follow-up period was 80.7 months (range 2-170 months). RESULTS: Control of tumor growth was achieved in all 12 (100%) patients who were followed up for longer than 2 years. After GKS, facial nerve function improved in 2 patients, remained unchanged in 9 patients, and worsened in 3 patients. All patients who had had serviceable hearing at the preliminary examination maintained their hearing at a useful level after GKS. Other than mild tinnitus reported by 3 patients, no other major complications developed. CONCLUSIONS: GKS for facial nerve schwannomas resulted in excellent tumor control rates and functional outcomes. GKS might be a good primary treatment option for patients with a small- to medium-sized facial nerve schwannoma when facial nerve function and hearing are relatively preserved. PMID- 25434946 TI - Gamma Knife radiosurgery for vestibular schwannoma: clinical results at long-term follow-up in a series of 379 patients. AB - OBJECT: Since the 1990 s, Gamma Knife radiosurgery (GKRS) has become the first line treatment option for small- to medium-size vestibular schwannomas (VSs), especially in patients without mass effect-related symptoms and with functional hearing. The aim of this study was to assess the safety and efficacy of GKRS, in terms of tumor control, hearing preservation, and complications, in a series of 379 consecutive patients treated for VS. METHODS: Of 523 patients treated at the authors' institution for VS between 2001 and 2010, the authors included 379 who underwent GKRS as the primary treatment. These patients were not affected by Type 2 neurofibromatosis and had clinical follow-up of at least 36 months. Clinical follow-up (mean and median 75.7 and 69.5 months, respectively) was performed for all patients, whereas audiometric and quantitative radiological follow-up examinations were obtained for only 153 and 219 patients, respectively. The patients' ages ranged from 23 to 85 years (mean 59 years). The mean tumor volume was 1.94 +/- 2.2 cm(3) (median 1.2 cm(3), range 0.013-14.3 cm(3)), and the median margin dose was 13 Gy (range 11-15 Gy). Parameters considered as determinants of the clinical outcome were long-term tumor control, hearing preservation, and complications. A statistical analysis was performed to correlate clinical outcomes with the radiological features of the tumor, dose-planning parameters, and patient characteristics. RESULTS: Control of the tumor with GKRS was achieved in 97.1% of the patients. In 82.7% of the patients, the tumor volume had decreased at the last follow-up, with a mean relative reduction of 34.1%. The rate of complications was very low, with most consisting of a transient worsening of preexisting symptoms. Patients who had vertigo, balance disorders, or facial or trigeminal impairment usually experienced a complete or at least significant symptom relief after treatment. However, no significant improvement was observed in patients previously reporting tinnitus. The overall rate of preservation of functional hearing at the long-term follow-up was 49%; in patients with hearing classified as Gardner-Robertson (GR) Class I, this value was 71% and reached 93% among cases of GR Class I hearing in patients younger than 55 years. CONCLUSIONS: Gamma Knife radiosurgery is a safe and effective treatment for VS, achieving tumor control in 97.1% of cases and resulting in a very low morbidity rate. Younger GR Class I patients had a significantly higher probability of retaining functional hearing even at the 10-year follow-up; for this reason, the time between symptom onset, diagnosis, and treatment should be shortened to achieve better outcomes in functional hearing preservation. PMID- 25434947 TI - Long-term follow-up studies of Gamma Knife surgery for patients with neurofibromatosis Type 2. AB - OBJECT: The aim of this study was to evaluate long-term clinical outcomes after Gamma Knife surgery (GKS) for patients with neurofibromatosis Type 2 (NF2) and the role of GKS in the management of NF2. METHODS: From December 1994 through December 2008, a total of 46 patients (21 male, 25 female) with NF2 underwent GKS and follow-up evaluation for at least 5 years at the Gamma Knife Center of the Beijing Neurosurgical Institute. GKS was performed using the Leksell Gamma Knife Models B and C. The mean age of the patients was 30 years (range 13-59 years). A family history of NF2 was found for 9 (20%) patients. The NF2 phenotype was thought to be Wishart for 20 (44%) and Feiling-Gardner for 26 (56%) patients. Among these 46 patients, GKS was performed to treat 195 tumors (73 vestibular schwannomas and 122 other tumors including other schwannomas and meningiomas). For vestibular schwannomas, the mean volume was 5.1 cm(3) (median 3.6 cm(3), range 0.3-27.3 cm(3)), the mean margin dose was 12.9 Gy (range 10-14 Gy), and the mean maximum dose was 27.3 Gy (range 16.2-40 Gy). For other tumors, the mean volume was 1.7 cm(3) (range 0.3-5.5 cm(3)), the mean margin dose was 13.3 Gy (range 11-14 Gy), and the mean maximum dose was 26.0 Gy (range 18.0-30.4 Gy). The median duration of follow-up was 109 months (range 8-195 months). RESULTS: For the 73 vestibular schwannomas that underwent GKS, the latest follow-up MR images demonstrated regression of 30 (41%) tumors, stable size for 31 (43%) tumors, and enlargement of 12 (16%) tumors. The total rate of tumor control for bilateral vestibular schwannomas in patients with NF2 was 84%. Of the 122 other types of tumors that underwent GKS, 103 (85%) showed no tumor enlargement. The rate of serviceable hearing preservation after GKS was 31.9% (15/47). The actuarial rates for hearing preservation at 3 years, 5 years, 10 years, and 15 years were 98%, 93%, 44%, and 17%, respectively. Of the 46 patients, 22 (48%) became completely bilaterally deaf, 17 (37%) retained unilateral serviceable hearing, and 7 (15%) retained bilateral serviceable hearing. The mean history of the disease course was 12 years (range 5-38 years). CONCLUSIONS: GKS was confirmed to provide long term local tumor control for small- to medium-sized vestibular schwannomas and other types of tumors, although vestibular schwannomas in patients with NF2 responded less well than did unilateral sporadic vestibular schwannomas. Phenotype is the most strongly predictive factor of final outcome after GKS for patients with NF2. The risk for loss of hearing is high, whereas the risk for other cranial nerve complications is low. PMID- 25434948 TI - Microsurgery for vestibular schwannoma after Gamma Knife surgery: challenges and treatment strategies. AB - OBJECT: Resection of vestibular schwannoma (VS) after Gamma Knife surgery (GKS) is infrequently performed. The goals of this study were to analyze and discuss the neurological outcomes and technical challenges of VS resection and to explore strategies for treating tumors that progress after GKS. METHODS: In total, 708 patients with VS underwent GKS between 1993 and 2012 at Taipei Veterans General Hospital. The post-GKS clinical courses, neurological presentations, and radiological changes in these patients were analyzed. Six hundred patients with imaging follow-up of at least 1 year after GKS treatment were included in this study. RESULTS: Thirteen patients (2.2%) underwent microsurgery on average 36.8 months (range 3-107 months) after GKS. The indications for the surgery included symptomatic adverse radiation effects (in 4 patients), tumor progression (in 6), and cyst development (in 3). No morbidity or death as a result of the surgery was observed. At the last follow-up evaluation, all patients, except 1 patient with a malignant tumor, had stable or near-normal facial function. CONCLUSIONS: For the few VS cases that require resection after radiosurgery, maximal tumor resection can be achieved with modern skull-based techniques and refined neuromonitoring without affecting facial nerve function. PMID- 25434949 TI - Malignant transformation in vestibular schwannoma: report of a single case, literature search, and debate. AB - OBJECT: The significance of radiation in the induction of malignancy in vestibular schwannomas (VSs) after radiosurgery is unclear despite an increasing number of case reports. The authors describe a new case of verified malignant transformation in a vestibular schwannoma (MTVS) and provide a new evaluation of such cases previously reported in the literature. METHODS: A 46-year-old woman underwent subtotal resection of a right-sided VS in 2004. The histological characteristics of the lesion were typical and benign. In early 2007 Gamma Knife surgery (GKS) was performed to treat a residual enlarging remnant. The radiosurgery parameters included the following: target volume 3.5 cm(3), prescription dose 12 Gy, prescription isodose 45%, maximum dose 26.7 Gy, and coverage 97%. At 2 years' follow-up the lesion was enlarged to 5.2 cm(3), but by 5 years it had decreased to 2.3 cm(3). Six months later the lesion was 8.4 cm(3). Repeated surgery was performed, and a histological analysis revealed a malignant peripheral nerve sheath tumor. The case was further managed with repeated GKS performed in the spring of 2013. At that time, the radiosurgery parameters included the following: target volume 3.5 cm(3), prescription dose 16 Gy, prescription isodose 45%, maximum dose 35.6 Gy, and coverage 91%. This Gamma Knife Department has treated a total of 205 patients with VS (local incidence of MTVS 0.49%). A search of the literature published up to and including 2013 was performed using PubMed as well as more informal search methods. RESULTS: This patient is the 29th reported case of MTVS after radiation therapy. Of these cases, 40.7% were patients with neurofibromatosis (NF). In those cases in which histology showed tumors with previously benign characteristics, totally conforming to the criteria for MTVS, the mean delay to malignant expression was 68 months (median delay 72 months). The authors also retrieved papers reporting 30 cases of malignant VS in patients who had not undergone radiation treatment. Five of those cases were malignant transformation of a benign entity, and in 4 of them histology had verified that the initial disease was benign. In those 4 cases, there was a mean delay to malignant expression of 7.2 months (median delay 8 months). CONCLUSIONS: Despite more frequent reports of MTVS after radiation treatment recently, there has been no accurate quantification of the risk, except in patients with NF, in whom the incidence of malignancy is high in relation to the numbers treated. The present analysis indicates that the risk of malignancy over 20 years in cases in which no radiation treatment has occurred is 1.32-2.08 per 100,000, and this risk decreases to 1.09-1.74 per 100,000 if cases of NF are excluded. After radiation treatment, the overall risk over 20 years is 25.1 per 100,000, and this risk decreases to 15.6 per 100,000 if cases of NF are excluded. Radiation treatment increases the risk by approximately 10 times in non-NF cases. PMID- 25434950 TI - Gamma Knife surgery for craniopharyngioma: report on a 20-year experience. AB - OBJECT: Although craniopharyngiomas are benign intracranial tumors, their high recurrence rates and intimate associations with surrounding neurovascular structures make gross tumor resection challenging. Stereotactic radiosurgery has been introduced as a valuable adjuvant therapy for recurrent or residual craniopharyngiomas. However, studies with large patient populations documenting long-term survival and progression-free survival rates are rare in the literature. The current study aims to report the long-term radiosurgical results and to define the prognostic factors in a large cohort of patients with a craniopharyngioma. METHODS: A total of 137 consecutive patients who underwent 162 sessions of Gamma Knife surgery (GKS) treatments at the Taipei Veterans General Hospital between 1993 and 2012 were analyzed. The patients' median age was 30.1 years (range 1.5-84.9 years), and the median tumor volume was 5.5 ml (range 0.2 28.4 ml). There were 23 solid (16.8%), 23 cystic (16.8%), and 91 mixed solid and cystic (66.4%) craniopharyngiomas. GKS was indicated for residual or recurrent craniopharyngiomas. The median radiation dose was 12 Gy (range 9.5-16.0 Gy) at a median isodose line of 55% (range 50%-78%). RESULTS: At a median imaging follow up of 45.7 months after GKS, the rates of tumor control were 72.7%, 73.9%, and 66.3% for the solid, cystic, and mixed tumors, respectively. The actuarial progression-free survival rates plotted by the Kaplan-Meier method were 70.0% and 43.8% at 5 and 10 years after radiosurgery, respectively. After repeated GKS, the actuarial progression-free survival rates were increased to 77.3% and 61.2% at 5 and 10 years, respectively. The overall survival rates were 91.5% and 83.9% at the 5- and 10-year follow-ups, respectively. Successful GKS treatment can be predicted by tumor volume (p = 0.011). Among the 137 patients who had clinical follow-up, new-onset or worsened pituitary deficiencies were detected in 11 patients (8.0%). Two patients without tumor growth had a worsened visual field, and 1 patient had a new onset of third cranial nerve palsy. CONCLUSIONS: The current study suggests that GKS is a relatively safe modality for the treatment of recurrent or residual craniopharyngiomas, and it is associated with improved tumor control and reduced in-field recurrence rates. Acceptable rates of complications occurred. PMID- 25434951 TI - Clinical and pathological analysis of benign brain tumors resected after Gamma Knife surgery. AB - OBJECT: The goal of this study was to assess the clinical and pathological features of benign brain tumors that had been treated with Gamma Knife surgery (GKS) followed by resection. METHODS: In this retrospective chart review, the authors identified 61 patients with intracranial benign tumors who had undergone neurosurgical intervention after GKS. Of these 61 patients, 27 were male and 34 were female; mean age was 49.1 years (range 19-73 years). There were 24 meningiomas, 18 schwannomas, 14 pituitary adenomas, 3 hemangioblastomas, and 2 craniopharyngiomas. The interval between GKS and craniotomy was 2-168 months, with a median of 24 months; for 7 patients, the interval was 10 years or longer. For 21 patients, a craniotomy was performed before and after GKS; in 9 patients, pathological specimens were obtained before and after GKS. A total of 29 patients underwent GKS at the Beijing Tiantan Hospital. All specimens obtained by surgical intervention underwent histopathological examination. RESULTS: Most patients underwent craniotomy because of tumor recurrence and/or exacerbation of clinical signs and symptoms. Neuroimaging analyses indicated tumor growth in 42 patients, hydrocephalus in 10 patients with vestibular schwannoma, cystic formation with mass effect in 7 patients, and tumor hemorrhage in 13 patients, of whom 10 had pituitary adenoma. Pathological examination demonstrated that, regardless of the type of tumor, GKS mainly induced coagulative necrosis of tumor parenchyma and stroma with some apoptosis and, ultimately, scar formation. In addition, irradiation induced vasculature stenosis and occlusion and tumor degeneration as a result of reduced blood supply. GKS-induced vasculature reaction was rarely observed in patients with pituitary adenoma. Pathological analysis of tumor specimens obtained before and after GKS did not indicate increased tumor proliferation after GKS. CONCLUSIONS: Radiosurgery is effective for intracranial benign tumors of small size and deep location and for tumor recurrence after surgical intervention; it is not effective for intracranial tumors with symptomatic mass effect. The radiobiological effects of stereotactic radiosurgery on the benign tumors are mainly caused by cellular and vascular mechanisms. Among the patients in this study, high-dose irradiation did not increase tumor proliferation. GKS can induce primary and secondary effects in tumors, which could last more than 10 years, thereby warranting long-term follow-up after GKS. PMID- 25434952 TI - Gamma Knife surgery for intracranial chordoma and chondrosarcoma: radiosurgical perspectives and treatment outcomes. AB - OBJECT: Intracranial chordomas and chondrosarcomas are histologically low-grade, locally invasive tumors that are reported to be similar in terms of anatomical location, clinical presentation, and radiological findings but different in terms of behavior and outcomes. The purpose of this study was to investigate and compare clinical outcomes after Gamma Knife surgery (GKS) for the treatment of intracranial chordoma and chondrosarcoma. METHODS: The authors conducted a retrospective review of the results of radiosurgical treatment of intracranial chordomas and chondrosarcomas. They enrolled patients who had undergone GKS for intracranial chordoma or chondrosarcoma at the Yonsei Gamma Knife Center, Yonsei University College of Medicine, from October 2000 through June 2007. Analyses included only patients for whom the disease was pathologically diagnosed before GKS and for whom more than 5 years of follow-up data after GKS were available. Rates of progression-free survival and overall survival were analyzed and compared according to tumor pathology. Moreover, the association between tumor control and the margin radiation dose to the tumor was analyzed, and the rate of tumor volume change after GKS was quantified. RESULTS: A total of 10 patients were enrolled in this study. Of these, 5 patients underwent a total of 8 sessions of GKS for chordoma, and the other 5 patients underwent a total of 7 sessions of GKS for chondrosarcoma. The 2- and 5-year progression-free survival rates for patients in the chordoma group were 70% and 35%, respectively, and rates for patients in the chondrosarcoma group were 100% and 80%, respectively (log-rank test, p = 0.04). The 2- and 5-year overall survival rates after GKS for patients in the chordoma group were 87.5% and 72.9%, respectively, and rates for patients in the chondrosarcoma group were 100% and 100%, respectively (log-rank test, p = 0.03). The mean rates of tumor volume change 2 years after radiosurgery were 79.64% and 39.91% for chordoma and chondrosarcoma, respectively (p = 0.05). No tumor progression was observed when margin doses greater than 16 Gy for chordoma and 14 Gy for chondrosarcoma were prescribed. CONCLUSIONS: Outcomes after GKS were more favorable for patients with chondrosarcoma than for those with chordoma. The data also indicated that at 2 years after GKS, the rate of volume change is significantly higher for chordomas than for chondrosarcomas. The authors conclude that radiosurgery with a margin dose of more than 16 Gy for chordomas and more than 14 Gy for chondrosarcomas seems to enhance local tumor control with relatively few complications. Further studies are needed to determine the optimal dose of GKS for patients with intracranial chordoma or chondrosarcoma. PMID- 25434953 TI - Leksell Gamma Knife radiosurgery of the jugulotympanic glomus tumor: long-term results. AB - OBJECT: Glomus tumors usually display indolent behavior, and the effectiveness of radiation in stopping their growth can be assessed after long-term follow-up. Currently only midterm results of radiosurgery are available, so the authors included patients treated by Gamma Knife at least 10 years ago in this study to obtain a perspective of long-term results. METHODS: During the period from 1992 to 2003, the Gamma Knife was used to treat 46 patients with glomus tumors. The age of the patients ranged from 21 to 79 years (median 56 years). Gamma Knife radiosurgery was the primary treatment in 17 patients (37%). Open surgery preceded radiosurgery in 46% of cases, embolization in 17%, and fractionated radiotherapy in 4%. The volume of the tumor ranged from 0.2 to 24.3 cm(3) (median 3.6 cm(3)). The minimal dose to the tumor margin ranged between 10 and 30 Gy (median 20 Gy). RESULTS: One patient was lost for follow-up after radiosurgery. Clinical follow-up was available in 45 patients and 44 patients were followed with MRI in a follow-up period that ranged from 12 to 217 months (median 118 months). Neurological deficits improved in 19 (42%) of 45 patients and deteriorated in 2 patients (4%). Tumor size decreased in 34 (77%) of 44 patients with imaging follow-up, while an increase in volume was observed in 1 patient (2%) 182 months after radiosurgery and Gamma Knife treatment was repeated. One patient underwent another Gamma Knife treatment for secondary induced meningioma close to the glomus tumor 98 months after initial radiosurgical treatment. Seven patients died 22-96 months after radiosurgery (median 48 months), all for unrelated reasons. CONCLUSIONS: Radiosurgery has proved to be a safe treatment with a low morbidity rate and a reliable long-term antiproliferative effect. PMID- 25434954 TI - Radiosurgery target location and individual anatomical variation in trigeminal nerves. AB - OBJECT: The authors evaluated individual anatomical variations in the trigeminal nerves of patients with medically intractable trigeminal neuralgia and clarified the relationships among the variations, radiosurgical target locations, and the clinical outcomes after high-dose Gamma Knife surgery (GKS). METHODS: From 2006 through 2011, the authors conducted a retrospective review of 106 cases of primary or secondary trigeminal neuralgia consecutively treated with GKS targeting the dorsal root entry zone (DREZ) for which a maximal dose of 90 Gy and a 20% isodose line to the brainstem were used. A questionnaire was used to evaluate patients' pre- and post-GKS clinical conditions. To evaluate individual anatomical variations among trigeminal nerves, the authors used 3 parameters: the length of the trigeminal nerve in the cistern (nerve length), the length of the target between the radiation shot and the brainstem (targeting length), and the ratio between nerve length and targeting length (targeting ratio). RESULTS: The median length of the trigeminal nerves in the 106 patients was 9.6 mm (range 6.04 20.74 mm), the median targeting length was 3.8 mm (range 1.81-10.84 mm), and the median targeting ratio was 38% (range 13%- 80%). No statistically significant differences in pain relief and pain recurrence were detected among patients with these various nerve characteristics. However, radiation-induced facial hypesthesia correlated with nerve length and targeting ratio (p < 0.05) but not with absolute distance from the brainstem (targeting length). CONCLUSIONS: In trigeminal neuralgia patients who received DREZ-targeted GKS, the rate of pain relief did not differ according to anatomical nerve variations. However, the frequency of facial hypesthesia was higher among patients in whom the nerve was longer (> 11 mm) or the targeting ratio was lower (< 36%). Adjusting the target according to the targeting ratio, especially for patients with longer nerves, can reduce facial hypesthesia and enable maintenance of effective pain control. PMID- 25434955 TI - Repeat Gamma Knife surgery for recurrent trigeminal neuralgia: long-term outcomes and systematic review. AB - OBJECT: The purpose of this study was to establish the safety and efficacy of repeat Gamma Knife surgery (GKS) for recurrent trigeminal neuralgia (TN). METHODS: Using the prospective database of TN patients treated with GKS in Timone University Hospital (Marseille, France), data were analyzed for 737 patients undergoing GKS for TN Type 1 from July 1992 to November 2010. Among the 497 patients with initial pain cessation, 34.4% (157/456 with >= 1-year follow-up) experienced at least 1 recurrence. Thirteen patients (1.8%) were considered for a second GKS, proposed only if the patients had good and prolonged initial pain cessation after the first GKS, with no other treatment alternative at the moment of recurrence. As for the first GKS, a single 4-mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 7.6 mm (range 4-14 mm) anterior to the emergence of the nerve (retrogasserian target). A median maximum dose of 90 Gy (range 70-90 Gy) was delivered. Data for 9 patients with at least 1-year followup were analyzed. A systematic review of literature was also performed, and results are compared with those of the Marseille study. RESULTS: The median time to retreatment in the Marseille study was 72 months (range 12-125 months) and in the literature it was 17 months (range 3-146 months). In the Marseille study, the median follow-up period was 33.9 months (range 12-96 months), and 8 of 9 patients (88.9%) had initial pain cessation with a median of 6.5 days (range 1-180 days). The actuarial rate for new hypesthesia was 33.3% at 6 months and 50% at 1 year, which remained stable for 7 years. The actuarial probabilities of maintaining pain relief without medication at 6 months and 1 year were 100% and 75%, respectively, and remained stable for 7 years. The systematic review analyzed 20 peer-reviewed studies reporting outcomes for repeat GKS for recurrent TN, with a total of 626 patients. Both the selection of the cases for retreatment and the way of reporting outcomes vary widely among studies, with a median rate for initial pain cessation of 88% (range 60%-100%) and for new hypesthesia of 33% (range 11%-80%). CONCLUSIONS: Results from the Marseille study raise the question of surgical alternatives after failed GKS for TN. The rates of initial pain cessation and recurrence seem comparable to, or even better than, those of the first GKS, according to different studies, but toxicity is much higher, both in the Marseille study and in the published data. Neither the Marseille study data nor literature data answer the 3 cardinal questions regarding repeat radiosurgery in recurrent TN: which patients to retreat, which target is optimal, and which dose to use. PMID- 25434956 TI - Glossopharyngeal neuralgia and radiosurgery. AB - OBJECT: Glossopharyngeal neuralgia is difficult to treat. On the basis of results obtained by using Gamma Knife surgery (GKS) to treat trigeminal neuralgia, the authors have used GKS to treat glossopharyngeal neuralgia in a series of patients since 2007. Their objectives with this study were to demonstrate the usefulness and safety of GKS for treating glossopharyngeal neuralgia and to describe a simple treatment method. METHODS: From 2007 through 2013, the authors treated glossopharyngeal neuralgia in 5 patients (4 women and 1 man), who ranged in age from 36 to 74 years. One patient had previously undergone treatment for trigeminal neuralgia at the Ruber International Hospital, Department of Functional Neurosurgery and Gamma Knife Radiosurgery. For all patients, before GKS, medical management did not control the pain. Three patients had previously undergone surgery (2 microvascular decompression and 1 rhizotomy) without improvement. For the GKS procedure, the nerve was localized by MRI and CT under stereotactic conditions and the target was located at the level of the glossopharyngeal meatus of the jugular foramen. For 1 patient, a maximum dose of 80 Gy was administrated with a 4-mm collimator, and for the others, the maximum dose was 90 Gy. The nerves located near the glossopharyngeal nerve received between 63 and 10 Gy, and the brainstem received less than 10 Gy. The mean follow up time was 43 months (range 14-83 months). RESULTS: All patients improved within 3-6 months after undergoing GKS. All 5 are without pain; 3 patients take no medication, but the other 2 patients continue to take medication. No neurological deficits after GKS were observed. CONCLUSIONS: GKS is useful and safe for treating glossopharyngeal neuralgia, even for patients who have previously undergone surgery. GKS should be considered as the initial therapy for glossopharyngeal neuralgia. PMID- 25434957 TI - Hemorrhage during pregnancy in the latency interval after stereotactic radiosurgery for arteriovenous malformations. AB - OBJECT: The presentation for patients with arteriovenous malformations (AVMs) is often intracranial hemorrhage; for women, this frequently occurs during the prime childbearing years. Although previous studies have addressed the risk for AVM hemorrhage during pregnancy, such studies have not assessed the risk for hemorrhage among women who become pregnant during the latency interval between stereotactic radiosurgery (SRS) and documented obliteration of the lesion. The authors sought to evaluate the risk for hemorrhage in patients who become pregnant during the latency interval after SRS. METHODS: This single-institution retrospective analysis reviewed the authors' experience with Gamma Knife SRS during 1987-2012. During this time, 253 women of childbearing age (median age 30 years, range 15-40 years) underwent SRS for intracranial AVM. The median target volume was 3.9 cm(3) (range 0.1-27.1 cm(3)), and the median marginal dose was 20 Gy (range 14-38 Gy). For all patients, the date of AVM obliteration was recorded and the latency interval was calculated. Information about subsequent pregnancies and/or bleeding events during the latency interval was retrieved from the medical records and supplemented by telephone contact. RESULTS: AVM obliteration was confirmed by MRI or angiography at a median follow-up time of 39.3 months (range 10-174 months). There were 828.7 patient-years of follow-up within the latency interval between SRS and the date of confirmed AVM obliteration. Among nonpregnant women, 20 hemorrhages occurred before AVM obliteration, yielding an annual hemorrhage rate of 2.5% for nonpregnant women during the latency interval. Among women who became pregnant during the latency interval, 2 hemorrhages occurred over the course of 18 pregnancies, yielding an annual hemorrhage rate of 11.1% for women who become pregnant during the latency interval. For the 2 pregnant patients who experienced hemorrhage, the bleeding occurred during the first trimester of pregnancy. CONCLUSIONS: The authors present the first series of data for women with intracranial AVMs who became pregnant during the latency interval after SRS. Hemorrhage during the latency interval occurred at an annual rate of 2.5% for nonpregnant women and 11.1% for pregnant women. The data suggest that pregnancy might be a risk factor for AVM hemorrhage during the interval between SRS and AVM obliteration. However, this suggestion is not statistically significant because only 18 patients in the study population became pregnant during the latency interval. To mitigate any increased risk for hemorrhage, patients should consider deferring pregnancy until treatment conclusion and AVM obliteration. PMID- 25434958 TI - Minimally invasive techniques for epilepsy surgery: stereotactic radiosurgery and other technologies. AB - Minimally invasive surgical techniques for the treatment of medically intractable epilepsy, which have been developed by neurosurgeons and epileptologists almost simultaneously with standard open epilepsy surgery, provide benefits in the traditional realms of safety and efficacy and the more recently appreciated realms of patient acceptance and costs. In this review, the authors discuss the shortcomings of the gold standard of open epilepsy surgery and summarize the techniques developed to provide minimally invasive alternatives. These minimally invasive techniques include stereotactic radiosurgery using the Gamma Knife, stereotactic radiofrequency thermocoagulation, laser-induced thermal therapy, and MRI-guided focused ultrasound ablation. PMID- 25434959 TI - Personal thermal management by metallic nanowire-coated textile. AB - Heating consumes large amount of energy and is a primary source of greenhouse gas emission. Although energy-efficient buildings are developing quickly based on improving insulation and design, a large portion of energy continues to be wasted on heating empty space and nonhuman objects. Here, we demonstrate a system of personal thermal management using metallic nanowire-embedded cloth that can reduce this waste. The metallic nanowires form a conductive network that not only is highly thermal insulating because it reflects human body infrared radiation but also allows Joule heating to complement the passive insulation. The breathability and durability of the original cloth is not sacrificed because of the nanowires' porous structure. This nanowire cloth can efficiently warm human bodies and save hundreds of watts per person as compared to traditional indoor heaters. PMID- 25434960 TI - LuxS signaling in Porphyromonas gingivalis-host interactions. AB - Dental plaque is a multispecies biofilm in the oral cavity that significantly influences oral health. The presence of the oral anaerobic pathogen Porphyromonas gingivalis is an important determinant in the development of periodontitis. Direct and indirect interactions between P. gingivalis and the host play a major role in disease development. Transcriptome analysis recently revealed that P. gingivalis gene-expression is regulated by LuxS in both an AI-2-dependent and an AI-2 independent manner. However, little is known about the role of LuxS signaling in P. gingivalis-host interactions. Here, we investigated the effect of a luxS mutation on the ability of P. gingivalis to induce an inflammatory response in human oral cells in vitro. Primary periodontal ligament (PDL) fibroblasts were challenged with P. gingivalis DeltaluxS or the wild-type parental strain and gene-expression of pro-inflammatory mediators IL-1beta, IL-6 and MCP-1 was determined by real-time PCR. The ability of P. gingivalis DeltaluxS to induce an inflammatory response was severely impaired in PDL-fibroblasts. This phenotype could be restored by providing of LuxS in trans, but not by addition of the AI-2 precursor DPD. A similar phenomenon was observed in a previous transcriptome study showing that expression of PGN_0482 was reduced in the luxS mutant independently of AI-2. We therefore also analyzed the effect of a mutation in PGN_0482, which encodes an immuno-reactive, putative outer-membrane protein. Similar to P. gingivalis DeltaluxS, the P. gingivalis Delta0482 mutant had an impaired ability to induce an inflammatory response in PDL fibroblasts. LuxS thus appears to influence the pro-inflammatory responses of host cells to P. gingivalis, likely through regulation of PGN_0482. PMID- 25434961 TI - [Acute myocardial infarction: What the coronariography doesn't see]. PMID- 25434962 TI - Screening and identification of potential predictive biomarkers for Down's syndrome from second trimester maternal serum. AB - OBJECTIVE: In this study, we aimed to search for noninvasive predictive biomarkers for prenatal diagnosis of Down's syndrome (DS). METHODS: Maternal serum samples from five DS-affected pregnant women and five DS-unaffected women were analyzed by 2D gel electrophoresis and MALDI-TOF mass spectrometry to screen for potential predictive biomarkers of DS. Then, differential levels of dGTPase, beta2-glycoprotein I (beta2-GPI), complement factor H-related protein 1 precursor (CFHR1) and kininogen 1 isoform 2 were further verified by western blotting tests in another independent group. RESULTS: Statistical analysis results revealed 29 protein spots whose levels differed significantly in the DS-affected pregnancies group. Of these, the eight most differentially expressed in DP were identified successfully. Among these, levels of dGTPase, CFHR1 and kininogen 1 were elevated significantly, whereas beta2-GPI was reduced in DP. DISCUSSION: These preliminarily verified proteins might serve as potential predictive biomarkers for DS-affected pregnancies. PMID- 25434963 TI - Inhibition of PGC-1alpha after chemotherapy-mediated insult confines multiple myeloma cell survival by affecting ROS accumulation. AB - Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) is a key regulator of reactive oxygen species (ROS). However, whether it has the same role in multiple myeloma (MM), especially after treatement with chemotherapy, remains unclear. After treating cells with bortezomib or dexamethasone, the expression of PGC-1alpha, superoxide dismutase 2 (SOD-2) and catalase (CAT) was examined by RT-PCR. PGC-1alpha expression was also analyzed by western blotting. Small-interference RNA (siRNA) was applied to inhibit the expression of PGC-1alpha after chemotherapy. Changes of cellular ROS and apoptosis were detected by flow cytometric analysis. Cell proliferation was assessed by MTT assay. The expression of PGC-1alpha and SOD-2 following chemotherapy were upregulated, but accompanied by increased ROS. Following suppression of PGC-1alpha, ROS levels, as well as the pro-apoptotic effect of bortezomib were further increased. These findings suggested that PGC-1alpha regulates ROS in MM, and that inhibition of elevated PGC-1alpha following stimulation by chemotherapy leads to a higher level of ROS by downregulating antioxidant factors, eventually enhancing the antitumor effect of bortezomib. PMID- 25434964 TI - Surgical Treatment of Giant Candida albicans Vegetation of Tricuspid Valve Endocarditis in a Preterm Baby. PMID- 25434966 TI - When you come to a fork in the road, take it! PMID- 25434965 TI - DNA consensus sequence motif for binding response regulator PhoP, a virulence regulator of Mycobacterium tuberculosis. AB - Tuberculosis has reemerged as a serious threat to human health because of the increasing prevalence of drug-resistant strains and synergetic infection with HIV, prompting an urgent need for new and more efficient treatments. The PhoP PhoR two-component system of Mycobacterium tuberculosis plays an important role in the virulence of the pathogen and thus represents a potential drug target. To study the mechanism of gene transcription regulation by response regulator PhoP, we identified a high-affinity DNA sequence for PhoP binding using systematic evolution of ligands by exponential enrichment. The sequence contains a direct repeat of two 7 bp motifs separated by a 4 bp spacer, TCACAGC(N4)TCACAGC. The specificity of the direct-repeat sequence for PhoP binding was confirmed by isothermal titration calorimetry and electrophoretic mobility shift assays. PhoP binds to the direct repeat as a dimer in a highly cooperative manner. We found many genes previously identified to be regulated by PhoP that contain the direct repeat motif in their promoter sequences. Synthetic DNA fragments at the putative promoter-binding sites bind PhoP with variable affinity, which is related to the number of mismatches in the 7 bp motifs, the positions of the mismatches, and the spacer and flanking sequences. Phosphorylation of PhoP increases the affinity but does not change the specificity of DNA binding. Overall, our results confirm the direct-repeat sequence as the consensus motif for PhoP binding and thus pave the way for identification of PhoP directly regulated genes in different mycobacterial genomes. PMID- 25434967 TI - Comparison of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy for glycaemic control in patients with type 1 diabetes: an open-label randomised controlled crossover trial. AB - BACKGROUND: The artificial pancreas is an emerging technology for the treatment of type 1 diabetes and two configurations have been proposed: single-hormone (insulin alone) and dual-hormone (insulin and glucagon). We aimed to delineate the usefulness of glucagon in the artificial pancreas system. METHODS: We did a randomised crossover trial of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy (continuous subcutaneous insulin infusion) in participants aged 12 years or older with type 1 diabetes. Participants were assigned in a 1:1:1:1:1:1 ratio with blocked randomisation to the three interventions and attended a research facility for three 24-h study visits. During visits when the patient used the single-hormone artificial pancreas, insulin was delivered based on glucose sensor readings and a predictive dosing algorithm. During dual-hormone artificial pancreas visits, glucagon was also delivered during low or falling glucose. During conventional insulin pump therapy visits, patients received continuous subcutaneous insulin infusion. The study was not masked. The primary outcome was the time for which plasma glucose concentrations were in the target range (4.0-10.0 mmol/L for 2 h postprandially and 4.0-8.0 mmol/L otherwise). Hypoglycaemic events were defined as plasma glucose concentration of less than 3.3 mmol/L with symptoms or less than 3.0 mmol/L irrespective of symptoms. Analysis was by modified intention to treat, in which we included data for all patients who completed at least two visits. A p value of less than 0.0167 (0.05/3) was regarded as significant. This trial is registered with ClinicalTrials.gov, number NCT01754337. FINDINGS: The mean proportion of time spent in the plasma glucose target range over 24 h was 62% (SD 18), 63% (18), and 51% (19) with single-hormone artificial pancreas, dual hormone artificial pancreas, and conventional insulin pump therapy, respectively. The mean difference in time spent in the target range between single-hormone artificial pancreas and conventional insulin pump therapy was 11% (17; p=0.002) and between dual-hormone artificial pancreas and conventional insulin pump therapy was 12% (21; p=0.00011). There was no difference (15; p=0.75) in the proportion of time spent in the target range between the single-hormone and dual hormone artificial pancreas systems. There were 52 hypoglycaemic events with conventional insulin pump therapy (12 of which were symptomatic), 13 with the single-hormone artificial pancreas (five of which were symptomatic), and nine with the dual-hormone artificial pancreas (0 of which were symptomatic); the number of nocturnal hypoglycaemic events was 13 (0 symptomatic), 0, and 0, respectively. INTERPRETATION: Single-hormone and dual-hormone artificial pancreas systems both provided better glycaemic control than did conventional insulin pump therapy. The single-hormone artificial pancreas might be sufficient for hypoglycaemia-free overnight glycaemic control. FUNDING: Canadian Diabetes Association; Fondation J A De Seve; Juvenile Diabetes Research Foundation; and Medtronic. PMID- 25434968 TI - Cooperative protofilament switching emerges from inter-motor interference in multiple-motor transport. AB - Within living cells, the transport of cargo is accomplished by groups of molecular motors. Such collective transport could utilize mechanisms which emerge from inter-motor interactions in ways that are yet to be fully understood. Here we combined experimental measurements of two-kinesin transport with a theoretical framework to investigate the functional ramifications of inter-motor interactions on individual motor function and collective cargo transport. In contrast to kinesin's low sidestepping frequency when present as a single motor, with exactly two kinesins per cargo, we observed substantial motion perpendicular to the microtubule. Our model captures a surface-associated mode of kinesin, which is only accessible via inter-motor interference in groups, in which kinesin diffuses along the microtubule surface and rapidly "hops" between protofilaments without dissociating from the microtubule. Critically, each kinesin transitions dynamically between the active stepping mode and this weak surface-associated mode enhancing local exploration of the microtubule surface, possibly enabling cellular cargos to overcome macromolecular crowding and to navigate obstacles along microtubule tracks without sacrificing overall travel distance. PMID- 25434969 TI - Drug transporter expression during in vitro differentiation of first-trimester and term human villous trophoblasts. AB - Drug transporters interfere with drug disposition during pregnancy by actively transporting drugs from mother to fetus, and vice versa. Data on their placental expression are scarce, especially during the first trimester of pregnancy. The aim of our study was to assess mRNA expression of more than 80 drug transporters by using an RT-qPCR array in primary cytotrophoblastic cells isolated from first trimester and term human placentas and cultured for 72 h to form syncytiotrophoblasts. This original expression panel of human placental drug transporters should help to understand transplacental drug transfer and to ensure more rational drug use during pregnancy. PMID- 25434970 TI - Endoplasmic reticulum stress is induced in the human placenta during labour. AB - Placental endoplasmic reticulum (ER) stress has been postulated in the pathophysiology of pre-eclampsia (PE) and intrauterine growth restriction (IUGR), but its activation remains elusive. Oxidative stress induced by ischaemia/hypoxia reoxygenation activates ER stress in vitro. Here, we explored whether exposure to labour represents an in vivo model for the study of acute placental ER stress. ER stress markers, GRP78, P-eIF2alpha and XBP-1, were significantly higher in laboured placentas than in Caesarean-delivered controls localised mainly in the syncytiotrophoblast. The similarities to changes observed in PE/IUGR placentas suggest exposure to labour can be used to investigate induction of ER stress in pathological placentas. PMID- 25434971 TI - Evolutionary innovation and conservation in the embryonic derivation of the vertebrate skull. AB - Development of the vertebrate skull has been studied intensively for more than 150 years, yet many essential features remain unresolved. One such feature is the extent to which embryonic derivation of individual bones is evolutionarily conserved or labile. We perform long-term fate mapping using GFP-transgenic axolotl and Xenopus laevis to document the contribution of individual cranial neural crest streams to the osteocranium in these amphibians. Here we show that the axolotl pattern is strikingly similar to that in amniotes; it likely represents the ancestral condition for tetrapods. Unexpectedly, the pattern in Xenopus is much different; it may constitute a unique condition that evolved after anurans diverged from other amphibians. Such changes reveal an unappreciated relation between life history evolution and cranial development and exemplify 'developmental system drift', in which interspecific divergence in developmental processes that underlie homologous characters occurs with little or no concomitant change in the adult phenotype. PMID- 25434973 TI - The CROWN Initiative: journal editors invite researchers to develop core outcomes in women's health. PMID- 25434974 TI - Rapid lead discovery through iterative screening of one bead one compound libraries. AB - Primary hits that arise from screening one bead one compound (OBOC) libraries against a target of interest rarely have high potency. However, there has been little work focused on the development of an efficient workflow for primary hit improvement. In this study, we show that by characterizing the binding constants for all of the hits that arise from a screen, structure-activity relationship (SAR) data can be obtained to inform the design of "derivative libraries" of a primary hit that can then be screened under more demanding conditions to obtain improved compounds. Here, we demonstrate the rapid improvement of a primary hit against matrix metalloproteinase-14 using this approach. PMID- 25434975 TI - Painful ankle swelling. PMID- 25434972 TI - Neuropsychological performance in LRRK2 G2019S carriers with Parkinson's disease. AB - BACKGROUND: Ashkenazi Jewish (AJ) LRRK2 carriers are more likely to manifest the postural instability gait difficulty (PIGD) motor phenotype than non-carriers but perform similarly to non-carriers on cognitive screening tests. OBJECTIVE: To compare the cognitive profiles of AJ with Parkinson's disease (PD) with and without LRRK2 G2019S mutations using a comprehensive neuropsychological battery. METHODS: We administered a neuropsychological battery to PD participants in the Michael J. Fox Foundation AJ consortium. Participants (n = 236) from Beth Israel Medical Center, NY, Columbia University Medical Center, NY and Tel Aviv Medical Center, Israel included 116 LRRK2 G2019S carriers and 120 non-carriers. Glucocerbrosidase mutation carriers were excluded. We compared performance on each neuropsychological test between carriers and non-carriers. Participants in New York (n = 112) were evaluated with the entire battery. Tel Aviv participants (n = 124) were evaluated on attention, executive function and psychomotor speed tasks. The association between G2019S mutation status (predictor) and each neuropsychological test (outcome) was assessed using linear regression models adjusted for PIGD motor phenotype, site, sex, age, disease duration, education, Unified Parkinson's Disease Rating Scale (UPDRS) Part III, levodopa equivalent dose, and Geriatric Depression Score (GDS). RESULTS: Carriers had longer disease duration (p < 0.001) and were more likely to manifest the PIGD phenotype (p = 0.024). In adjusted regression models, carriers performed better than non carriers in Stroop Word Reading (p < 0.001), Stroop Interference (p = 0.011) and Category Fluency (p = 0.026). CONCLUSION: In AJ-PD, G2019S mutation status is associated with better attention (Stroop Word Reading), executive function (Stroop Interference) and language (Category Fluency) after adjustment for PIGD motor phenotype. PMID- 25434978 TI - Ultra-performance liquid chromatography coupled with high-resolution quadrupole time-of-flight mass spectrometry analysis of the impact of bran-processing on the chemical profile of Radix Paeoniae Alba (Baishao). AB - In this study, a rapid and versatile ultra-performance liquid chromatography coupled with high-resolution quadrupole time-of-flight mass spectrometry-based chemical profiling approach was applied to evaluate chemical constitution of crude and processed Radix Paeoniae Alba (RPA) samples. A total of 44 compounds were identified, among which the contents of 9 compounds in processed samples were obviously decreased and 8 compounds were increased. Furthermore, compound 28 was not found in RPA sample after stir-frying with wheat bran. The proposed method provided a chemical basis for exploring the processed mechanism of herbal medicine. PMID- 25434977 TI - Are cases of Methicillin-resistant Staphylococcus aureus clonal complex (CC) 398 among humans still livestock-associated? AB - Methicillin-resistant Staphylococcus aureus (MRSA) of clonal complex (CC) 398 are widespread among pigs, cattle and poultry as well as among humans who have contact to these livestock animals. However, there is limited data on livestock independent dissemination of MRSA CC398 in the general population. METHODS: In this case-control study MRSA isolates derived (between July 2013 and June 2014) from patients of four hospitals located in a livestock-dense region were S. aureus protein A (spa) typed and risk factors for MRSA acquisition were assessed from patients colonized or infected with MRSA CC398 vs. other MRSA molecular types (MRSA non-CC398). RESULTS: Of 384 patients, 21% were colonized with MRSA CC398. Contact with livestock (Odds Ratio (OR) 46.03) and residence directly on a pig farm (OR 12.82) were associated with MRSA CC398. Of 55 patients with MRSA CC398, 21 (38%) did not report direct livestock contact. Among the latter we identified several risk factors that could have facilitated indirect transmission, such as living on farms (without being farmer), private contact with known MRSA carriers or previous hospitalization. DISCUSSION: This study suggests that MRSA CC398 is still mostly disseminated via direct contact to livestock. However, a substantial proportion of patients seem to acquire MRSA CC398 via other pathways. PMID- 25434979 TI - Precise quantitative addition of multiple reagents into droplets in sequence using glass fiber-induced droplet coalescence. AB - Precise quantitative addition of multiple reagents into droplets in sequence is still a bottleneck in droplet-based analysis. To address this issue, we presented a simple and robust glass fiber-induced droplet coalescence method. The hydrophilic glass fiber embedded in the microchannels can induce the deformation of droplets and trigger the coalescence. Serial addition of reagents with controlled volumes was performed by this method without the requirement for an external power source. PMID- 25434980 TI - [Presence of intramammary lymph nodes in the preoperative lymphoscintigraphy to locate the sentinel lymph node. Clinical significance]. AB - OBJECTIVE: The routes of lymphatic drainage from a breast cancer are the axilla (the most frequent) and the extra axillary regions. Among the latter, there are the so-called intrammamary lymph nodes (IMLN). This study has aimed to assess the incidence of IMLNs in our patients and study the evolution of these cases with IMLN in the lymphoscintigraphy. MATERIAL AND METHODS: Thirty-eight patients (out of 1725) with IMLN in the pre-operative lymphoscintigraphy were assessed. During the surgical procedure, using a gamma probe, IMLNs were located and excised. After their harvesting, a meticulous surgical field scan was performed. When the axillary sentinel node was positive for metastasis, a complete axillary lymphadenectomy was performed. In those where the axillary sentinel node was negative and IMLN was positive (IMLN+), axillary lymphadenectomy was also performed, except for one case. RESULTS: Thirty-four out of the 38 IMLNs were obtained (89.5%), because no lymphatic tissue was found in pathology analysis in three cases (8%) and in one patient (3%) IMLN was not found during surgery. Ten (26%) metastatic IMLNs were located and the remaining 24 IMLNs cases (63%) were metastasis-free. During the clinical follow-up, one patient with IMLN+ developed hepatic metastases. The remaining 33 patients did not present any recurrence. No follow-up data were available for three patients. CONCLUSIONS: IMLN and axillary sentinel node biopsy are recommended when both are depicted in preoperative lymphoscintigraphy. The axilla treatment will only depend on the axillary sentinel node status. Based on the data from other authors and our own experience, avoiding the axillary lymphadenectomy when a metastatic IMLN without axillary involvement seems reasonable. PMID- 25434976 TI - Spirotetronate polyketides as leads in drug discovery. AB - The discovery of chlorothricin (1) defined a new family of microbial metabolites with potent antitumor antibiotic properties collectively referred to as spirotetronate polyketides. These microbial metabolites are structurally distinguished by the presence of a spirotetronate motif embedded within a macrocyclic core. Glycosylation at the periphery of this core contributes to the structural complexity and bioactivity of this motif. The spirotetronate family displays impressive chemical structures, potent bioactivities, and significant pharmacological potential. This review groups the family members based on structural and biosynthetic considerations and summarizes synthetic and biological studies that aim to elucidate their mode of action and explore their pharmacological potential. PMID- 25434981 TI - Outcomes of gastric cancer resections performed in a high volume community cancer center. AB - BACKGROUND: Large University Hospitals are usually the referral centers for complex surgical procedures. However, the majority of cancer care takes place in the community hospital. The aim of this study was to analyze the morbidity, mortality and long-term survival of gastric cancer patients after the establishment of a multidisciplinary gastric cancer team in an academic community hospital. METHODS: A retrospective review of medical records was performed for patients who presented with gastric cancer from 2005 to 2013. Thirty-day morbidity and mortality were assessed for patients who underwent gastrectomy with curative intent. Long-term survival was determined by Kaplan-Meier analysis. RESULTS: Ninety-one patients underwent curative resection over an 8-year period. Eighty-seven patients (96%) had an R0 resection. Mean lymph node recovery was 20. Serious morbidity rate was reported in 10/91 (11%). Mortality in the series was 3/91 (3%). Five-year survival by stage was similar to AJCC reported survival. CONCLUSION: Complex surgical resections for gastric cancer can be safely performed at a high volume community cancer center with minimal morbidity and mortality. PMID- 25434983 TI - Corrigendum: Relationships between chemical structures and functions of triterpene glycosides isolated from sea cucumbers. AB - [This corrects the article on p. 77 in vol. 2, PMID: 25250309.]. PMID- 25434982 TI - Lentinan reduces tumor progression by enhancing gemcitabine chemotherapy in urothelial bladder cancer. AB - It has been shown that chemotherapy has limited antitumor activity against advanced urothelial bladder cancer (UBC). Consequently, there is an urgent need to develop effective therapeutic methods for patients with advanced UBC. In the present study, the inhibitory effects of lentinan alone, gemcitabine alone, or lentinan combined with gemcitabine on the proliferation of the UBC cell line, T24, were investigated. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, annexin V fluorescein isothiocyanate/propidium iodide staining, and flow cytometry were used to determine the proliferation and apoptosis of T24 cells in each treatment group. Survival-related protein expression was analyzed by western blotting. Increased concentrations of lentinan, or lentinan combined with gemcitabine, positively correlated with decreased T24 cell proliferation. Lentinan combined with gemcitabine chemotherapy significantly inhibited UBC cell proliferation. Gemcitabine has the ability to induce T24 cell apoptosis, and this effect is enhanced when it is combined with lentinan. PMID- 25434985 TI - One world, one health? Social science engagements with the one health agenda. PMID- 25434986 TI - Comparison of photoelectrochemical water oxidation activity of a synthetic photocatalyst system with photosystem II. AB - This discussion describes a direct comparison of photoelectrochemical (PEC) water oxidation activity between a photosystem II (PSII)-functionalised photoanode and a synthetic nanocomposite photoanode. The semi-biological photoanode is composed of PSII from the thermophilic cyanobacterium Thermosynechococcus elongatus on a mesoporous indium tin oxide electrode (mesoITO|PSII). PSII embeds all of the required functionalities for light absorption, charge separation and water oxidation and ITO serves solely as the electron collector. The synthetic photoanode consists of a TiO(2) and NiO(x) coated nanosheet-structured WO(3) electrode (nanoWO(3)|TiO(2)|NiO(x)). The composite structure of the synthetic electrode allows mimicry of the functional key features in PSII: visible light is absorbed by WO(3), TiO(2) serves as a protection and charge separation layer and NiO(x) serves as the water oxidation electrocatalyst. MesoITO|PSII uses low energy red light, whereas nanoWO(3)|TiO(2)|NiO(x) requires high energy photons of blue-end visible and UV regions to oxidise water. The electrodes have a comparable onset potential at approximately 0.6 V vs. reversible hydrogen electrode (RHE). MesoITO|PSII reaches its saturation photocurrent at 0.84 V vs. RHE, whereas nanoWO(3)|TiO(2)NiO(x) requires more than 1.34 V vs. RHE. This suggests that mesoITO|PSII suffers from fewer limitations from charge recombination and slow water oxidation catalysis than the synthetic electrode. MesoITO|PSII displays a higher 'per active' site activity, but is less photostable and displays a much lower photocurrent per geometrical surface area and incident photon to current conversion efficiency (IPCE) than nanoWO(3)|TiO(2)|NiO(x_. PMID- 25434987 TI - Towards limiting QT interval prolongation and arrhythmia risk in citalopram use. PMID- 25434988 TI - Oral delivery of capsaicin using MPEG-PCL nanoparticles. AB - AIM: To prepare a biodegradable polymeric carrier for oral delivery of a water insoluble drug capsaicin (CAP) and evaluate its quality. METHODS: CAP-loaded methoxy poly (ethylene glycol)-poly(epsilon-caprolactone) nanoparticles (CAP/NPs) were prepared using a modified emulsification solvent diffusion technique. The quality of CAP/NPs were evaluated using transmission electron microscopy, powder X-ray diffraction, differential scanning calorimetry and Fourier transform infrared techniques. A dialysis method was used to analyze the in vitro release profile of CAP from the CAP/NPs. Adult male rats were orally administered CAP/NPs (35 mg/kg), and the plasma concentrations of CAP were measured with a validated HPLC method. The morphology of rat gastric mucosa was studied with HE staining. RESULTS: CAP/NPs had an average diameter of 82.54 +/- 0.51 nm, high drug-loading capacity of 14.0% +/- 0.13% and high stability. CAP/NPs showed a biphasic release profile in vitro: the burst release was less than 25% of the loaded drug within 12 h followed by a more sustained release for 60 h. The pharmacokinetics study showed that the mean maximum plasma concentration was observed 4 h after oral administered of CAP/NPs, and approximately 90 ng/mL of CAP was detected in serum after 36 h. The area under the curve for the CAP/NPs group was approximately 6 fold higher than that for raw CAP suspension. Histological studies showed that CAP/NPs markedly reduced CAP-caused gastric mucosa irritation. CONCLUSION: CAP/NPs significantly enhance the bioavailability of CAP and markedly reduce gastric mucosa irritation in rats. PMID- 25434989 TI - beta, beta-Dimethylacrylshikonin induces mitochondria-dependent apoptosis of human lung adenocarcinoma cells in vitro via p38 pathway activation. AB - AIM: beta, beta-Dimethylacrylshikonin (DMAS) is an anticancer compound extracted from the roots of Lithospermum erythrorhizon. In the present study, we investigated the effects of DMAS on human lung adenocarcinoma cells in vitro and explored the mechanisms of its anti-cancer action. METHODS: Human lung adenocarcinoma A549 cells were tested. Cell viability was assessed using an MTT assay, and cell apoptosis was evaluated with flow cytometry and DAPI staining. The expression of the related proteins was detected using Western blotting. The mitochondrial membrane potential was measured using a JC-1 kit, and subcellular distribution of cytochrome c was analyzed using immunofluorescence staining. RESULTS: Treatment of A549 cells with DMAS suppressed the cell viability in dose- and time-dependent manners (the IC50 value was 14.22 and 10.61 MUmol/L, respectively, at 24 and 48 h). DMAS (7.5, 10, and 15 MUmol/L) dose-dependently induced apoptosis, down-regulated cIAP-2 and XIAP expression, and up-regulated Bax and Bak expression in the cells. Furthermore, DMAS resulted in loss of mitochondrial membrane potential and release of cytochrome c in the cells, and activated caspase-9, caspase-8, and caspase-3, and subsequently cleaved PARP, which was abolished by pretreatment with Z-VAD-FMK, a pan-caspase inhibitor. DMAS induced sustained p38 phosphorylation in the cells, while pretreatment with SB203580, a specific p38 inhibitor, blocked DMAS-induced p38 activation and apoptosis. CONCLUSION: DMAS inhibits the growth of human lung adenocarcinoma A549 cells in vitro via activation of p38 signaling pathway. PMID- 25434991 TI - Antitumor and apoptotic activities of the chemical constituents from the ethyl acetate extract of Artemisia indica. AB - Cancer is one of the most eminent diseases of modern times and numerous natural products derived from medicinal plants have been identified as potential sources of antitumor drugs. A successful anticancer drug must target or inhibit tumor cells whilst causing minimal damage to healthy cells. The present study aimed to investigate the antitumor efficacy of ethyl acetate extract, and other isolated compounds from Artemisia indica, on MCF-7, BHY, Miapaca-2, Colo-205 and A-549 cell lines. The apoptotic activity of the compounds was studied using flow cytometry. The different cancer cell lines were treated with the ethyl acetate extract and varying concentrations of compounds (denoted a-g) isolated from the A. indica. The cytotoxicity was evaluated by MTT assay and the apoptotic properties of the compounds and the extract were assessed using flow cytometry. In MCF-7 cells, the effect on mitochondrial membrane potential loss (LambdaPsim) induced by compounds b and d was also studied. Bioassay-guided fractionation of the ethyl acetate extract from the shoot and root parts of A. indica led to the identification of the compounds a-g as: 5-hydroxy-3,7,4'-trimethoxyflavone; ludartin; maackiain; lupeol; cis-matricaria ester; trans-matricaria ester; and 6 methoxy-7,8-methylenedioxy coumarin, respectively. All the compounds exhibited mild to potent inhibition of cell proliferation in all the cell lines, with the half maximal inhibitory concentration values ranging from 25.18-88.12 uM. Ludartin and lupeol were observed to have the most potent inhibitory effects. Based on the initially identified antiproliferative effects, these two compounds were evaluated for their effects on cell cycle phase distribution, DNA damage and their effects on mitochondrial membrane potential loss (LambdaPsim). The two compounds induced DNA damage and mitochondrial membrane potential loss in MCF-7 cells. The results of the current study suggest that lupeol and ludartin, isolated from A. indica, produce anticancer effects by inducing DNA damage and a reduction of mitochondrial membrane potential, and may be used as potent anticancer agents, subsequent to further study. PMID- 25434992 TI - Elevation of circulating LOX-1 ligand levels in Zucker obese and diabetic rats. AB - LOX-1 ligands containing apolipoprotein B (LAB) reflect ligand activity of LOX-1, which is a key molecule for initiation of atherosclerosis. The Zucker rat is a well-known model used for research on obesity and diabetes. Blood levels of LAB were compared among Zucker fatty (ZF), Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats. Log-transformed LAB was significantly higher in ZF and ZDF rats than in control ZL rats, while no significant difference was found in log transformed LAB of ZF and ZDF rats. This study for the first time demonstrated that circulating LOX-1 ligands were elevated in obesity and diabetes model rats. PMID- 25434993 TI - Equilibrium adsorption of hexahistidine on pH-responsive hydrogel nanofilms. AB - We present a molecular theory to study the adsorption of different species within pH-sensitive hydrogel nanofilms. The theoretical framework allows for a molecular level description of all the components of the system, and it explicitly accounts for the acid-base equilibrium. We concentrate on the adsorption of hexahistidine, one of the most widely used tags in bio-related systems, particularly in chromatography of proteins. The adsorption of hexahistidine within a grafted polyacid hydrogel film shows a nonmonotonic dependence on the solution pH. Depending on the salt concentration, the density of the polymer network, and the bulk concentration of peptide, substantial adsorption is predicted in the intermediate pH range where both the network and the amino acids are charged. To enhance the electrostatic attractions, the acid-base equilibrium of adsorbed hexahistidine is shifted significantly, increasing the degree of charge of the residues as compared to the bulk solution. Such a shift depends critically on the conditions of the environment at the nanoscale. At the same time, the degree of dissociation of the network becomes that of the isolated acid group in a dilute solution, which means that the network is considerably more charged than when there is no adsorbate molecules. This work provides fundamental information on the physical chemistry behind the adsorption behavior and the response of the hydrogel film. This information can be useful in designing new materials for the purification or separation/immobilization of histidine-tagged proteins. PMID- 25434990 TI - Regulation of the nongenomic actions of retinoid X receptor-alpha by targeting the coregulator-binding sites. AB - Retinoid X receptor-alpha (RXRalpha), a unique member of the nuclear receptor superfamily, represents an intriguing and unusual target for pharmacologic interventions and therapeutic applications in cancer, metabolic disorders and neurodegenerative diseases. Despite the fact that the RXR-based drug Targretin (bexarotene) is currently used for treating human cutaneous T-cell lymphoma and the fact that RXRalpha ligands (rexinoids) show beneficial effects in the treatment of cancer and diseases, the therapeutic potential of RXRalpha remains unexplored. In addition to its conventional transcription regulation activity in the nucleus, RXRalpha can act in the cytoplasm to modulate important biological processes, such as mitochondria-dependent apoptosis, inflammation, and phosphatidylinositol 3-kinase (PI3K)/AKT-mediated cell survival. Recently, new small-molecule-binding sites on the surface of RXRalpha have been identified, which mediate the regulation of the nongenomic actions of RXRalpha by a class of small molecules derived from the nonsteroidal anti-inflammatory drug (NSAID) Sulindac. This review discusses the emerging roles of the nongenomic actions of RXRalpha in the RXRalpha signaling network, and their possible implications in cancer, metabolic and neurodegenerative disorders, as well as our current understanding of RXRalpha regulation by targeting alternate binding sites on its surface. PMID- 25434994 TI - Whole mitochondrial genome sequence of a rat colorectal cancer MCA38 cell line. AB - Colorectal cancer (CRC) is the second most fatal and the third most diagnosed type of cancer worldwide. We sequenced a complete mitochondrial genome sequence of a rat CRC cell line MCA38 for the first time. The total length of the mitogenome was 16,305 bp and coding 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes. This mitochondrial genome sequence will provide new genetic resource into Colon cancer disease. PMID- 25434995 TI - Effect of booster shot and investigation of vaccination efficacy period against herpesviral haematopoietic necrosis (HVHN) in goldfish Carassius auratus. AB - In this study, the efficacy period of an intraperitoneal vaccination and effect of a booster shot of vaccine against herpesviral haematopoietic necrosis (HVHN) in goldfish Carassius auratus were investigated. Cell culture supernatant of cyprinid herpesvirus 2 (CyHV-2), causative agent of HVHN, propagated in goldfish fin (GFF) cells was inactivated with formalin (0.1%, v/v) for 2 days at 4 degrees C. Three groups of the variety Ryukin were individually intraperitoneally injected with the vaccine and each group was separately maintained in replicate tanks. After 4 weeks (Vaccinated-4w-1 and 2) and 8 weeks (Vaccinated-8w-1 and 2) from the first vaccination, the fish were CyHV-2-challenged by the immersion route (10 TCID50 l(-1)). In addition, the other vaccinated group of fish were injected with a booster vaccine 4 weeks after the first vaccination as the Vaccinated-booster groups, then the fish of these groups were CyHV-2-challenged by the immersion route (10 TCID50 l(-1)) after 8 weeks from the first vaccination. The mean of the relative percentage survival (RPS) values of the Vaccinated-4w and 8w groups showed 42.5% and 57.6%, respectively. In addition, the mean RPS value of Vaccinated-booster groups showed 63.6%. Statistical analysis showed significantly higher survival rates in all the vaccinated groups than those of the respective negative control groups using Fisher's exact test. Moreover, the survival rates of vaccinated-booster groups were significantly higher (p=0.036) compared with the respective control groups by Student's t test. The present study shows the efficacy period of the vaccine is at least 8 weeks and a booster shot showed a tendency to enhance the protection against HVHN in goldfish. PMID- 25434996 TI - Influence of membrane cholesterol in the molecular evolution and functional regulation of TRPV4. AB - TRPV4 is involved in several physiological and sensory functions as well as with several diseases and genetic disorders, though the molecular mechanisms for these are unclear. In this work we have analyzed molecular evolution and structure function relationship of TRPV4 using sequences from different species. TRPV4 has evolved during early vertebrate origin (450million years). Synteny analysis confirms that TRPV4 has coevolved with two enzymes involved in sterol biosynthesis, namely MVK and GLTP. Cholesterol-recognizing motifs are present within highly conserved TM4-Loop4-TM5 region of TRPV4. TRPV4 is present in lipid raft where it co-localizes with Caveolin1 and Filipin. TM4-Loop4-TM5 region as well as Loop4 alone can physically interact with cholesterol, its precursor mevalonate and derivatives such as stigmasterol and aldosterone. Mobility of TRPV4-GFP depends on membrane cholesterol level. Molecular evolution of TRPV4 shared striking parallelism with the cholesterol bio-synthesis pathways at the genetic, molecular and metabolic levels. We conclude that interaction with sterols and cholesterol-dependent membrane dynamics have influence on TRPV4 function. These results may have importance on TRPV4-medaited cellular functions and pathophysiology. PMID- 25434998 TI - Psychosocial determinants of physicians' acceptance of recommendations by antibiotic computerised decision support systems: A mixed methods study. AB - Antibiotic computerised decision support systems (CDSSs) were developed to facilitate optimal prescribing, but acceptance of their recommendations has remained low. We aimed to evaluate physicians' perceptions and attitudes toward antibiotic CDSSs and determine psychosocial factors associated with acceptance of CDSS recommendations for empirical therapy. A mixed methods study was conducted in an adult tertiary-care hospital in Singapore, with its in-house antibiotic CDSS that integrates antimicrobial stewardship with electronic prescribing. Focus group discussions were conducted among purposively sampled physicians and data were analysed using the framework approach. Emerging themes were included in the questionnaire with newly developed scales for the subsequent cross-sectional survey involving all physicians. Principal components analysis was performed to derive the latent factor structure that was later applied in multivariate analyses. Physicians expressed confidence in the credibility of CDSS recommendations. Junior physicians accepted CDSS recommendations most of the time, whilst senior physicians acknowledged overriding recommendations in complex patients with multiple infections or allergies. Willingness to consult the CDSS for common and complex infections (OR=1.68, 95% CI 1.16-2.44) and preference for personal or team decision (OR=0.61, 95% CI 0.43-0.85) were associated with acceptance of CDSS recommendations. Cronbach's alpha for scales measuring physicians' attitudes and perceptions towards acceptance of CDSS recommendations ranged from 0.64 to 0.88. Physicians' willingness to consult an antibiotic CDSS determined acceptance of its recommendations. Physicians would choose to exercise their own or clinical team's decision over CDSS recommendations in complex patient situations when the antibiotic prescribing needs were not met. PMID- 25434997 TI - Trichostatin A, a histone deacetylase inhibitor, reverses epithelial-mesenchymal transition in colorectal cancer SW480 and prostate cancer PC3 cells. AB - Trichostatin A (TSA) is a kind of classical histone deacetylase (HDAC) inhibitor. In this study, we reported the reversal effects of TSA on EMT and investigated the possible involved molecular mechanisms in SW480 and PC3 cells. Firstly, we observed that TSA induced the reversal process of epithelial-mesenchymal transition (EMT) in SW480 and PC3 cells, resulting in attenuated cell invasion and migration abilities. TSA-induced EMT reversal was characterized by up regulation of E-cadherin and down-regulation of Vimentin. Then, treatment with TSA also decreased the expression of transcription factor Slug. Furthermore, over expression of Slug significantly caused down-regulation of E-cadherin and up regulation of Vimentin. Meanwhile, TSA treatment in Slug-expressing cells could prevent these changes. These findings suggested that Slug played a crucial role in TSA-induced EMT reversal. Additionally, the study showed that TSA could induce the increase of HDAC1 and HDAC2 on the Slug gene promoter, which might be responsible for the suppression of Slug. Overall, TSA could reverse EMT in SW480 and PC3 cells and TSA-mediated down-regulation of Slug was involved in the reversal process. PMID- 25434999 TI - Nitride surface passivation of GaAs nanowires: impact on surface state density. AB - Surface nitridation by hydrazine-sulfide solution, which is known to produce surface passivation of GaAs crystals, was applied to GaAs nanowires (NWs). We studied the effect of nitridation on conductivity and microphotoluminescence (MU PL) of individual GaAs NWs using conductive atomic force microscopy (CAFM) and confocal luminescent microscopy (CLM), respectively. Nitridation is found to produce an essential increase in the NW conductivity and the MU-PL intensity as well evidence of surface passivation. Estimations show that the nitride passivation reduces the surface state density by a factor of 6, which is of the same order as that found for GaAs/AlGaAs nanowires. The effects of the nitride passivation are also stable under atmospheric ambient conditions for six months. PMID- 25435001 TI - The topical use of non-thermal dielectric barrier discharge (DBD): nitric oxide related effects on human skin. AB - Dielectric barrier discharge (DBD) devices generate air plasma above the skin containing active and reactive species including nitric oxide (NO). Since NO plays an essential role in skin physiology, a topical application of NO by plasma may be useful in the treatment of skin infections, impaired microcirculation and wound healing. Thus, after safety assessments of plasma treatment using human skin specimen and substitutes, NO-penetration through the epidermis, the loading of skin tissue with NO-derivates in vitro and the effects on human skin in vivo were determined. After the plasma treatment (0-60 min) of skin specimen or reconstructed epidermis no damaging effects were found (TUNEL/MTT). By Franz diffusion cell experiments plasma-induced NO penetration through epidermis and dermal enrichment with NO related species (nitrite 6-fold, nitrate 7-fold, nitrosothiols 30-fold) were observed. Furthermore, skin surface was acidified (~pH 2.7) by plasma treatment (90 s). Plasma application on the forearms of volunteers increased microcirculation fourfold in 1-2 mm and twofold in 6-8 mm depth in the treated skin areas. Regarding the NO-loading effects, skin acidification and increase in dermal microcirculation, plasma devices represent promising tools against chronic/infected wounds. However, efficacy of plasma treatment needs to be quantified in further studies and clinical trials. PMID- 25435002 TI - Network-based modular latent structure analysis. AB - BACKGROUND: High-throughput expression data, such as gene expression and metabolomics data, exhibit modular structures. Groups of features in each module follow a latent factor model, while between modules, the latent factors are quasi independent. Recovering the latent factors can shed light on the hidden regulation patterns of the expression. The difficulty in detecting such modules and recovering the latent factors lies in the high dimensionality of the data, and the lack of knowledge in module membership. METHODS: Here we describe a method based on community detection in the co-expression network. It consists of inference-based network construction, module detection, and interacting latent factor detection from modules. RESULTS: In simulations, the method outperformed projection-based modular latent factor discovery when the input signals were not Gaussian. We also demonstrate the method's value in real data analysis. CONCLUSIONS: The new method nMLSA (network-based modular latent structure analysis) is effective in detecting latent structures, and is easy to extend to non-linear cases. The method is available as R code at http://web1.sph.emory.edu/users/tyu8/nMLSA/. PMID- 25435003 TI - Analytics for vaccine economics and pricing: insights and observations. AB - Pediatric immunization programs in the USA are a successful and cost-effective public health endeavor, profoundly reducing mortalities caused by infectious diseases. Two important issues relate to the success of the immunization programs, the selection of cost-effective vaccines and the appropriate pricing of vaccines. The recommended childhood immunization schedule, published annually by the CDC, continues to expand with respect to the number of injections required and the number of vaccines available for selection. The advent of new vaccines to meet the growing requirements of the schedule results: in a large, combinatorial number of possible vaccine formularies. The expansion of the schedule and the increase in the number of available vaccines constitutes a challenge for state health departments, large city immunization programs, private practices and other vaccine purchasers, as a cost-effective vaccine formulary must be selected from an increasingly large set of possible vaccine combinations to satisfy the schedule. The pediatric vaccine industry consists of a relatively small number of pharmaceutical firms engaged in the research, development, manufacture and distribution of pediatric vaccines. The number of vaccine manufacturers has dramatically decreased in the past few decades for a myriad of reasons, most notably due to low profitability. The contraction of the industry negatively impacts the reliable provision of pediatric vaccines. The determination of appropriate vaccine prices is an important issue and influences a vaccine manufacturer's decision to remain in the market. Operations research is a discipline that applies advanced analytical methods to improve decision making; analytics is the application of operations research to a particular problem using pertinent data to provide a practical result. Analytics provides a mechanism to resolve the challenges facing stakeholders in the vaccine development and delivery system, in particular, the selection of cost-effective vaccines and the appropriate pricing of vaccines. A review of applicable analytics papers is provided. PMID- 25435000 TI - Obesity-induced increases in sympathetic nerve activity: sex matters. AB - Abundant evidence obtained largely from male human and animal subjects indicates that obesity increases sympathetic nerve activity (SNA), which contributes to hypertension development. However, recent studies that included women reported that the strong relationships between muscle SNA and waist circumference or body mass index (BMI) found in men are not present in overweight and obese women. A similar sex difference in the association between adiposity and hypertension development has been identified in animal models of obesity. In this brief review, we consider two possible mechanisms for this sex difference. First, visceral adiposity, leptin, insulin, and angiotensin II have been identified as potential culprits in obesity-induced sympathoexcitation in males. We explore if these factors wield the same impact in females. Second, we consider if sex differences in vascular reactivity to sympathetic activation contribute. Our survey of the literature suggests that premenopausal females may be able to resist obesity-induced sympathoexcitation and hypertension in part due to differences in adipose disposition as well as its muted inflammatory response and reduced production of pressor versus depressor components of the renin angiotensin system. In addition, vascular responsiveness to increased SNA may be reduced. However, more importantly, we identify the urgent need for further study, not only of sex differences per se, but also of the mechanisms that may mediate these differences. This information is required not only to refine treatment options for obese premenopausal women but also to potentially reveal new therapeutic avenues in obese men and women. PMID- 25435004 TI - Hogan's framework for the study of behavior as applied to personality psychology. AB - Hogan's framework for the study of behavior can be used as a guide to the study of personality, considered here as interindividual differences in typical behavioral tendency. For any given dimension of personality variation, one can examine its development, its causal biological bases, its genetic and environmental origins, and its function and evolutionary history. These topics are discussed after a brief introduction to personality assessment and structure, and are followed by a brief review of personality research on non-human animals. This article is part of a Special Issue entitled: In Honor of Jerry Hogan. PMID- 25435005 TI - Therapeutic effect of human umbilical cord mesenchymal stem cells modified by angiotensin-converting enzyme 2 gene on bleomycin-induced lung fibrosis injury. AB - The aim of the present study was to evaluate the therapeutic effects of human umbilical cord mesenchymal stem cells (uMSCs) in the presence of angiotensin converting enzyme 2 gene (ACE2; ACE2-uMSCs) on bleomycin (BLM)-induced lung injury and pulmonary fibrosis in mice. A total of 100 male C57BL/6 mice were divided at random into five groups (n=20) as follows: Control group, BLM group, ACE2 group, uMSC group and ACE2-uMSC group. At 7, 14 and 28 days post-treatment, the following parameters were evaluated in lung tissue: Oxidation indexes [malondialedehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and oxidized glutathione (GSSG)]; fibrosis factors [tumor necrosis factor (TNF) alpha, interferon (IFN)-gamma and transforming growth factor (TGF)-beta]; inflammatory cytokines [Interleukin (IL)-1, IL-2, IL-6 and IL-10]; ACE2 gene expression; hydroxyproline and collagen type 1 messenger RNA (mRNA) concentration; as well as matrix metalloproteinase (MMPs; 2 and 9) and tissue inhibitor of metalloproteinase (TIMP)1-4 expression. ACE2-uMSC injection following bleomycin pretreatment significantly alleviated lung injury in mice. In addition, treatment with ACE2-uMSCs demonstrated a stronger therapeutic effect than ACE2- or uMSC treatment alone, indicated by decreased expression of MDA, GSSG, TNF-alpha, IFN-gamma, TGF-beta, IL-1, IL-2, IL-6, collagen type 1 mRNA, MMPs and TIMPs as well as hydroxyproline concentration, and upregulation of SOD, GSH and ACE2 and IL-10. In conclusion, the results of the present study demonstrated that ACE2 and uMSCs had a synergistic therapeutic effect on bleomycin-induced acute lung injury. PMID- 25435006 TI - Acute Compartment Syndrome After Gastrocnemius Rupture (Tennis Leg) in a Nonathlete Without Trauma. AB - Acute compartment syndrome is a serious emergency that warrants urgent decompression, and tennis leg (i.e., rupture of the medial head of the gastrocnemius) is a known clinical condition that is usually treated symptomatically, with good results overall. In rare cases, acute compartment syndrome is associated with tennis leg after severe direct muscle trauma or severe exercise in athletes or physically active individuals. We present an unusual case of acute compartment syndrome secondary to tennis leg after the patient, a nonathlete, had disembarked from a truck without any trauma. Clinicians should have a high index of suspicion for atraumatic compartment syndrome, and timely surgical fasciotomy must be undertaken to avoid complications resulting from delayed diagnosis and treatment. PMID- 25435007 TI - Early results of a posterolateral polyaxial angle-stable plate for tibiotalocalcaneal arthrodesis. AB - Tibiotalocalcaneal arthrodesis is still considered the reference standard therapy for salvage of severe osteoarthritic deformities of the ankle and hindfoot. Because of the unique anatomy and biomechanics of the ankle, even minor injuries can progress to end-stage osteoarthritis over time. This can be debilitating to patients' general health and physiologic ambulation. Arthrodesis aims to correct the misalignment and should comply with Glissan's principles (i.e., maintenance of permanent stability and sound compression between the fused elements). Several different surgical techniques have been described in the international medical literature. Intramedullary nails can create and maintain a stable condition but lack the necessary compression. Screw fixation can generate compression but might not yield enough stability until sound union has been achieved. In the present study, we report the early results of an innovative posterolateral polyaxial angle-stable plate that combines the features that address all the principles of arthrodesis in 1 device. PMID- 25435008 TI - Effects of Right Lower Limb Orthopedic Immobilization on Braking Function: An On The-Road Experimental Study With Healthy Volunteers. AB - Little is known about how immobilization of the right lower limb might affect driving. The purpose of the present study was to evaluate the effect of 2 types of immobilization on the emergency braking time of healthy subjects during actual driving conditions. The emergency braking times of 14 healthy volunteers were assessed in a closed circuit under 3 conditions: wearing running shoes, wearing an Aircast Walker((r)), or wearing a walking cast on their right lower limb. An instrumented car was used to measure the emergency braking times during braking tests with and without a distractor. The foot movement times were significantly increased with both immobilization devices compared with the running shoe (p < .01). The median total braking time with the running shoe during emergency braking without a distractor was 0.452 (interquartile range, 25th to 75th [IQR], 0.413 to 0.472) second. The results obtained with the Aircast Walker((r)) or the walking cast were significantly longer (p < .01), at 0.480 (IQR, 0.431 to 0.537) second and 0.512 (IQR, 0.451 to 0.535) second, respectively. When a distractor was added, the total braking time with the running shoe, Aircast Walker((r)), and walking cast was 0.489 (IQR, 0.429 to 0.575), 0.516 (IQR, 0.459 to 0.586), and 0.510 (IQR, 0.469 to 0.570) second, respectively, with no statistically significant differences among these 3 conditions. Wearing an immobilization device on the right lower limb minimally lengthens the emergency braking time in healthy drivers under actual driving conditions. Clinicians must nonetheless exercise caution when advising a driver wearing an orthopedic immobilization, because driving a motor vehicle is a complex psychomotor task that goes well beyond the emergency braking time. PMID- 25435009 TI - A retrospective study of 63 hallux valgus corrections using the osteodesis procedure. AB - Osteotomy procedures have been the most popular approach to hallux valgus deformity correction. Soft tissue approaches have, in general, been regarded as ineffective for moderate and severe hallux valgus deformities. Osteodesis is a soft tissue technique that has been shown to be effective in the past but is still seldom practiced. In the present report, we describe a retrospective study of 63 hallux valgus feet in 36 patients who had undergone the osteodesis procedure. Their mean age was 46 +/- 12 years, and the mean follow-up period was 25.4 +/- 9.6 months. The surgical technique consisted of metatarsus primus varus deformity correction by intermetatarsal cerclage sutures and hallux valgus deformity correction by rebalancing the ligaments. The first metatarsophalangeal angle improved from a mean of 32.5 degrees +/- 7.6 degrees preoperatively to 18.4 degrees +/- 7 degrees postoperatively, the first intermetatarsal angle improved from 14.6 degrees +/- 2.6 degrees to 6.8 degrees +/- 1.8 degrees , and the American Orthopaedic Foot and Ankle Society score improved from 59 +/- 14 to 93 +/- 8 points. The rate of patient satisfaction after surgery was 92% (33 of 36 patients, 59 of 63 feet). The complications included a second metatarsal stress fracture in 3 feet (5%), metatarsophalangeal joint medial subluxation in 3 feet (5%), and metatarsophalangeal joint stiffness in 5 feet (8%). This soft tissue, nonosteotomy procedure was a safe technique that effectively corrected hallux valgus and metatarsus primus varus deformities of various severities without osteotomy or fusion. PMID- 25435010 TI - Unicameral Bone Cyst in the Calcaneus of Mirror Image Twins. AB - Unicameral bone cysts (UBCs) are benign tumor-like lesions that commonly occur in the diaphyseal or metaphyseal region of the long bones within the first 2 decades of life. Until today, the pathogenesis of UBC has been unclear, but mechanisms such as vascular occlusion or a response to trauma have been supposed. During the past decade, in particular, the genetic aspects of the development of this rare lesion have been discussed. We present the first case of mirror image monozygotic twins with a mirror image UBC of the calcaneus. Our findings reinforce the importance of additional studies to understand the significance of cytogenetic factors in the etiology of UBC. PMID- 25435012 TI - Introduction of the exotic tick Hyalomma truncatum on a human with travel to Ethiopia: a case report. AB - An Oregon resident returned from a photography trip to Ethiopia with a male Hyalomma truncatum tick attached to the skin on his lower back. The tick was identified morphologically and deposited in the U.S. National Tick Collection housed at Georgia Southern University, Statesboro, Georgia. The public health importance of Hyalomma species of ticks and diagnostic dilemmas with identifying exotic ticks imported into the U.S. are discussed. PMID- 25435011 TI - Interspinous bursitis is common in polymyalgia rheumatica, but is not associated with spinal pain. AB - INTRODUCTION: Polymyalgia rheumatica (PMR) is a common inflammatory disease in older people characterized by shoulder and/or pelvic girdle, and cervical and, occasionally, lumbar pain. Interspinous bursitis has been suggested as a potential cause of spinal symptoms. We evaluated, by 18 F-fluorodeoxyglucose (FDG) positron emission tomography integrated with computed tomography (PET/CT), the vertebral structures involved in PMR in a cohort of consecutive, untreated patients. METHODS: Sixty-five consecutive patients with PMR were studied. After a standardized physical examination, which included evaluation of pain and tenderness in the vertebral column, they underwent FDG-PET/CT. Sites of increased uptake and their correlation with spontaneous and provoked pain were recorded. For comparison, FDG-PET/CT was performed also in 65 age- and sex-matched controls and in 10 rheumatoid arthritis (RA) patients. RESULTS: The most frequent site of spontaneous and provoked pain was the cervical portion. FDG uptake was more frequent in the lumbar portion than at any other location, and in the cervical rather than in the thoracic portion (P <0.0001). No correlation was found between uptake and spontaneous or provoked pain. There was an association between presence of cervical and lumbar bursitis (r = 0.34, P = 0.007). None of the control patients and one out of ten RA patients showed interspinous bursitis. CONCLUSIONS: Interspinous bursitis is a frequent finding in the lumbar spine of patients with PMR. However, it is not associated with clinical symptoms and can hardly explain the spinal pain reported by the patients. Cervical pain is more frequent than lumbar pain in PMR patients and may be caused by shoulder girdle involvement. PMID- 25435014 TI - Chromium deposition and poisoning at La0.6Sr0.4Co0.2Fe0.8O(3-delta) oxygen electrodes of solid oxide electrolysis cells. AB - The degradation of solid oxide electrolysis cells (SOECs) is an issue of both scientific and technical importance. In this study, chromium deposition and poisoning at the La0.6Sr0.4Co0.2Fe0.8O(3-delta) (LSCF) anode or the oxygen electrode of SOECs are studied for the first time under a current density of 200 mA cm(-2) at 900 and 800 degrees C. After polarization in the presence of the Fe Cr interconnect at 900 degrees C for 20 h, electrode polarization resistance and overpotential of the O2 evolution reaction (OER) on the LSCF electrode are 0.413 Omega cm(-2) and 127 mV, respectively, which is nearly 7 and 18 times the initial values of the electrode before the polarization. Significant performance degradation was also observed for the reaction at 800 degrees C in the presence of the Fe-Cr alloy. XRD and XPS analyses clearly identified the deposition of SrCrO4, CrO2.5 and Cr2O3 phases on the surface of LSCF oxygen electrodes and their formation is closely related to the increased segregation of the SrO species under anodic polarization conditions. Sr segregation leads to Sr deficiency at the A-site, thus deteriorating the electrocatalytic activity of the LSCF oxygen electrodes for OER. The results indicate that Cr deposition is essentially a chemical reaction and is initiated by the nucleation reaction between the gaseous Cr species and segregated SrO on the surface region of the LSCF oxygen electrode. PMID- 25435013 TI - Protein-bound polysaccharide K suppresses tumor fibrosis in gastric cancer by inhibiting the TGF-beta signaling pathway. AB - Peritoneal carcinomatosis (PC) is the most frequent metastatic pattern of gastric cancer and its prognosis is extremely poor. PC is characterized by rich fibrosis and the development of obstructive disorders such as ileus, jaundice and hydronephrosis. Epithelial-mesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor beta (TGF-beta) has a pivotal function in the progression of EMT. Protein-bound polysaccharide K (PSK) is a biological response modifier that can modulate the TGF-beta/Smad signaling pathway in vitro. In the present study, we established a fibrotic tumor model using human peritoneal mesothelial cells (HPMCs) and a human gastric cancer cell line to evaluate whether PSK attenuates tumor fibrosis. HPMCs exposed to PSK did not undergo the morphological change from a cobblestone-like pattern to a spindle shape pattern normally induced by treatment with TGF-beta. Immunofluorescence further demonstrated that PSK suppressed TGF-beta-induced overexpression of alpha SMA in the HPMCs. We further showed that HPMCs contributed to the proliferation of tumor fibrosis by using a mouse xenograft model. Additionally, PSK treatment of these mice significantly reduced the area of observable tumor fibrosis. These results suggest that seeded cancer cells transformed HPMCs into myofibroblast like cells through their release of TGF-beta in the microenvironment, facilitating the development of fibrous tumors in organs covered with HPMCs. Therefore, our study indicates that PSK has potential utility as an anti-fibrotic agent in the treatment of gastric cancer patients with PC. PMID- 25435015 TI - Baicalein prevents human prion protein-induced neuronal cell death by regulating JNK activation. AB - Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal isoform of the protease-insensitive isoform (PrPSc) of prion protein. Human prion protein fragment 106-126 [PrP (106-126)] contains most of the pathological characteristics associated with PrPSc. Although a number of compounds have been identified to inhibit PrP accumulation or dissolve fibrils and aggregates in vitro, there is currenlty no treatment available for these progressive neurodegenerative diseases. Baicalein, the dried root of Scutellaria baicalensis (S. baicalensis) Georgi (known as Huang-qin in traditional Chinese medicine) has been reported to exert neuroprotective effects on neurodegenerative diseases. In the present study, we investigated the effects of baicalein on the development of prion diseases using SH-SY5Y and SK-N-SH cells in vitro. We found that baicalein protected the cells against PrP-induced neuronal cell death by inhibiting the production of reactive oxygen species (ROS) and mitochondrial dysfunction using ROS detection assay and MTP assay. We demonstrated that baicalein treatment regulated the phosphorylation of c-Jun N-terminal kinase (JNK) by using western blot analysis and Annexin V assay. Our data suggest that baicalein has potential for use as a therapeutic drug for the treatment of various neurodegenerative diseases, including prion diseases. PMID- 25435017 TI - Breast-feeding support in Ireland: a qualitative study of health-care professionals' and women's views. AB - OBJECTIVE: To examine women's experience of professional support for breast feeding and health-care professionals' experience of providing support. DESIGN: We conducted semi-structured qualitative interviews among women with experience of breast-feeding and health-care professionals with infant feeding roles. Interviews with women were designed to explore their experience of support for breast-feeding antenatally, in hospital and postnatally. Interviews with health care professionals were designed to explore their views on their role and experience in providing breast-feeding support. Interview transcripts were analysed using content analysis and aspects of Grounded Theory. Overarching themes and categories within the two sets were identified. SETTING: Urban and suburban areas of North Dublin, Ireland. SUBJECTS: Twenty-two women all of whom had experience of breast-feeding and fifty-eight health-care professionals. RESULTS: Two overarching themes emerged and in each of these a number of categories were developed: theme 1, facilitators to breast-feeding support, within which being facilitated to breast-feed, having the right person at the right time, being discerning and breast-feeding support groups were discussed; and theme 2, barriers to breast-feeding support, within which time, conflicting information, medicalisation of breast-feeding and the role of health-care professionals in providing support for breast-feeding were discussed. CONCLUSIONS: Breast-feeding is being placed within a medical model of care in Ireland which is dependent on health-care professionals. There is a need for training around breast-feeding for all health-care professionals; however, they are limited in their support due to external barriers such as lack of time. Alternative support such as peer support workers should be provided. PMID- 25435018 TI - Modulation of P-glycoprotein efflux pump: induction and activation as a therapeutic strategy. AB - P-glycoprotein (P-gp) is an ATP-dependent efflux pump encoded by the MDR1 gene in humans, known to mediate multidrug resistance of neoplastic cells to cancer therapy. For several decades, P-gp inhibition has drawn many significant research efforts in an attempt to overcome this phenomenon. However, P-gp is also constitutively expressed in normal human epithelial tissues and, due to its broad substrate specificity, to its cellular polarized expression in many excretory and barrier tissues, and to its great efflux capacity, it can play a crucial role in limiting the absorption and distribution of harmful xenobiotics, by decreasing their intracellular accumulation. Such a defense mechanism can be of particular relevance at the intestinal level, by significantly reducing the intestinal absorption of the xenobiotic and, consequently, avoiding its access to the target organs. In this review, the current knowledge on this important efflux pump is summarized, and a new focus is brought on the therapeutic interest of inducing and/or activating P-gp for limiting the toxicity caused by its substrates. Several in vivo and in vitro studies validating the use of such a therapeutic strategy are discussed. An extensive literature search for reported P-gp inducers/activators and for the experimental models used in their characterization was conducted. Those studies demonstrate that effective antidotal pathways can be achieved by efficiently promoting the P-gp-mediated efflux of deleterious xenobiotics, resulting in a significant reduction in their intracellular levels and, consequently, in a significant reduction of their toxicity. PMID- 25435020 TI - "Disease modifying nutricals" for multiple sclerosis. AB - The association between vitamin D and multiple sclerosis has (re)-opened new interest in nutrition and natural compounds in the prevention and treatment of this neuroinflammatory disease. The dietary amount and type of fat, probiotics and biologicals, salmon proteoglycans, phytoestrogens and protease inhibitor of soy, sodium chloride and trace elements, and fat soluble vitamins including D, A and E were all considered as disease-modifying nutraceuticals. Studies in experimental autoimmune encephalomyelitis mice suggest that poly-unsaturated fatty acids and their 'inflammation-resolving' metabolites and the gut microflora may reduce auto-aggressive immune cells and reduce progression or risk of relapse, and infection with whipworm eggs may positively change the gut-brain communication. Encouraged by the recent interest in multiple sclerosis-nutrition nature's pharmacy has been searched for novel compounds with anti-inflammatory, immune-modifying and antioxidative properties, the most interesting being the scorpion toxins that inhibit specific potassium channels of T cells and antioxidative compounds including the green tea flavonoid epigallocatechin-3 gallate, curcumin and the mustard oil glycoside from e.g. broccoli and sulforaphane. They mostly also inhibit pro-inflammatory signaling through NF kappaB or toll-like receptors and stabilize the blood brain barrier. Disease modifying functions may also complement analgesic and anti-spastic effects of cannabis, its constituents, and of 'endocannabinoid enhancing' drugs or nutricals like inhibitors of fatty acid amide hydrolase. Nutricals will not solve multiple sclerosis therapeutic challenges but possibly support pharmacological interventions or unearth novel structures. PMID- 25435021 TI - Symbiotic adaptations in the fungal cultivar of leaf-cutting ants. AB - Centuries of artificial selection have dramatically improved the yield of human agriculture; however, strong directional selection also occurs in natural symbiotic interactions. Fungus-growing attine ants cultivate basidiomycete fungi for food. One cultivar lineage has evolved inflated hyphal tips (gongylidia) that grow in bundles called staphylae, to specifically feed the ants. Here we show extensive regulation and molecular signals of adaptive evolution in gene trancripts associated with gongylidia biosynthesis, morphogenesis and enzymatic plant cell wall degradation in the leaf-cutting ant cultivar Leucoagaricus gongylophorus. Comparative analysis of staphylae growth morphology and transcriptome-wide expressional and nucleotide divergence indicate that gongylidia provide leaf-cutting ants with essential amino acids and plant degrading enzymes, and that they may have done so for 20-25 million years without much evolutionary change. These molecular traits and signatures of selection imply that staphylae are highly advanced coevolutionary organs that play pivotal roles in the mutualism between leaf-cutting ants and their fungal cultivars. PMID- 25435022 TI - Artificial light at night: a neglected population health concern of the built environment. PMID- 25435024 TI - P22 virus-like particles constructed Au/CdS plasmonic photocatalytic nanostructures for enhanced photoactivity. AB - Plasmonic photocatalytic nanostructures have been fabricated under mild conditions (room temperature aqueous solution) using genetically engineered bacteriophage P22 virus-like particles (VLP) as a nano-platform. The photodegradation of methylene blue by CdS photocatalyst confined inside VLP can be significantly enhanced by the controlled deposition of gold nanoparticles on the outer shell of VLP-CdS. PMID- 25435023 TI - Effect of fibroblast growth factor 9 on the osteogenic differentiation of bone marrow stromal stem cells and dental pulp stem cells. AB - The role of fibroblast growth factor 9 (FGF9) in bone formation may depend on gene dosage, developmental stage, cell type or interactions with other cytokines. In the present study bone marrow stromal stem cells (BMSCs) and dental pulp stem cells (DPSCs) were cultured and osteogenically induced in vitro, treated with exogenous FGF9 at varying concentrations. Alkaline phosphatase staining, alizarin red S staining, reverse transcription quantitative polymerase chain reaction and western blot analyses were performed in order to investigate the gene expression levels of osteogenic markers. The results of the present study demonstrated that FGF9 enhanced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) during osteogenic induction in BMSCs and DPSCs, which are derived from different tissues. FGF9 also inhibited the osteogenic differentiation of BMSCs and DPSCs through the activation of ERK1/2. These findings suggested that FGF9 may be an inhibitor of osteogenesis in mesenchymal stem cells in vitro and its application in vivo requires investigation in the future. PMID- 25435026 TI - Aplastic Anemia & MDS International Foundation (AA&MDSIF): Bone Marrow Failure Disease Scientific Symposium 2014. AB - Bone marrow failure syndromes (BMFS) are characterized by a failure of the hematopoietic stem cells to produce adequate blood cells, resulting in either cytopenia (defect in one or more blood cell lineages) or pancytopenia (defect in all blood cell lineages). BMFS can be inherited or acquired. The pathogenesis of these diseases is very heterogeneous. Research efforts have been made all over the world to improve the basic knowledge of these diseases. The Aplastic Anemia and MDS International Foundation (AA&MDSIF) is an independent nonprofit organization whose mission is to help patients and family members cope with BMFS. Here, we summarize novel scientific discoveries in several BMFS that were presented at the 4th International Bone Marrow Failure Disease Scientific Symposium 2014 that AA&MDSIF sponsored on March 27-28, 2014, in Rockville, MD. PMID- 25435025 TI - A genome scan revealed significant associations of growth traits with a major QTL and GHR2 in tilapia. AB - Growth is an important trait in animal breeding. However, the genetic effects underpinning fish growth variability are still poorly understood. QTL mapping and analysis of candidate genes are effective methods to address this issue. We conducted a genome-wide QTL analysis for growth in tilapia. A total of 10, 7 and 8 significant QTLs were identified for body weight, total length and standard length at 140 dph, respectively. The majority of these QTLs were sex-specific. One major QTL for growth traits was identified in the sex-determining locus in LG1, explaining 71.7%, 67.2% and 64.9% of the phenotypic variation (PV) of body weight, total length and standard length, respectively. In addition, a candidate gene GHR2 in a QTL was significantly associated with body weight, explaining 13.1% of PV. Real-time qPCR revealed that different genotypes at the GHR2 locus influenced the IGF-1 expression level. The markers located in the major QTL for growth traits could be used in marker-assisted selection of tilapia. The associations between GHR2 variants and growth traits suggest that the GHR2 gene should be an important gene that explains the difference in growth among tilapia species. PMID- 25435029 TI - Anion binding and transport properties of cyclic 2,6-bis(1,2,3-triazol-1 yl)pyridines. AB - A series of cyclic 2,6-bis-(1,2,3-triazolyl)-pyridine anion receptors with thiourea functionalities were synthesized by click reaction of 2,6 diazidopyridine with protected propargylamine followed by condensation of a bisthiocyanate derivative with a series of diamines. Their chloride binding affinities as well as their transport properties in POPC bilayers were examined. These receptors were found to function as anion carriers, which can mediate both Cl(-)/NO3(-) antiport and H(+)/Cl(-) symport, and the transport activity of these hosts were dominated by their lipophilicity. PMID- 25435028 TI - Non transferrin bound iron (NTBI) in acute leukemias throughout conventional intensive chemotherapy: kinetics of its appearance and potential predictive role in infectious complications. AB - We analyzed appearance of non transferrin bound iron (NTBI) in 30 transplant eligible patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) during conventional chemotherapy treatment program and evaluated possible relationship with transfusional body iron intake, iron parameters and clinical complications. For each course, serum samples for NTBI detection were taken prior to chemotherapy, during treatment and during subsequent bone marrow myelosuppression: NTBI was assessed by HPLC. Appearance of NTBI was observed from the start of induction treatment and was still detectable during bone marrow myelosuppression; the recovery of the bone marrow function coincided with the disappearance of NTBI. This kinetic was observed in all subsequent high doses chemotherapy courses, independently from confounding variables such as transfusional iron intake and transferrin saturation. NTBI seems to be a consequence of chemotherapy induced lysis of bone marrow cells and, partly, of hepatocytes after cytotoxic injury. The subsequent persistence of NTBI throughout bone marrow myelosuppression is related to the transient suspension of erythropoietic activity. Moreover, NTBI levels >2MUM at the beginning of iatrogenic myelosuppression were associated with higher risk of sepsis caused by Gram negative Bacilli (RR 2.571), also compared with other infectious complications (RR 1.954). PMID- 25435027 TI - Isolated +15 in bone marrow: disease-associated or a benign finding? AB - It has been controversial if trisomy 15 (+15) as an isolated clonal cytogenetic abnormality in bone marrow (BM) is disease-associated or a benign finding. To answer this question, we retrospectively reviewed our cytogenetic archives and identified 31 patients with isolated +15. Four patients presented with acute myeloid leukemia (AML), +15 was the major clone (56-95% of interphases) in BM and the clonal size of +15 was correlated with blast burden and disease status. For the remaining 27 patients, +15 was a minor clone (3-24% of interphases) in BM. Eighteen patients had a history of cytotoxic therapies and developed +15 after a median latency interval of 34 months. Six patients had BM involvement by lymphoma or myeloma, and +15 was exclusively detected in myeloid and erythroid cells, not in lymphoma or myeloma cells. With a median follow-up of 28 months, none of these 27 patients had clinical or morphological evidence of myelodysplastic syndromes. We conclude that +15 can be associated with AML, but more often isolated +15 presents as a minor clone in BM, and may not be disease associated. Clinical follow-up rather than an immediate therapeutic intervention seems most appropriate for non-leukemic patients with isolated +15. PMID- 25435019 TI - Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. AB - Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3alpha and GSK3beta. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders. PMID- 25435030 TI - Periarticular regional analgesia in total knee arthroplasty: a review of the neuroanatomy and injection technique. AB - Postoperative pain control after total knee arthroplasty may be insufficient, resulting in insomnia, antalgic ambulation, and difficulty with rehabilitation. Current strategies, including the use of femoral nerve catheters, may control pain but have been associated with falls, motor blockade, and quadriceps inhibition. Periarticular infiltration using the appropriate technique and knowledge of intraarticular knee anatomy may increase pain control and maximize rehabilitation. PMID- 25435031 TI - Deformity correction in Haiti with the Taylor Spatial Frame. AB - The Taylor Spatial Frame (TSF) is an external-fixator that corrects deformities in 6 axes, and can successfully manage disorders involving multiplanar deformities. In the developing-world, orthopaedic surgeons are often faced with deformities from neglected trauma and birth defects more severe than those typically seen in developed-countries. This article evaluates the applicability of TSF in the challenging medical environment of Haiti. At Haiti Adventist Hospital, the authors treated 80 cases using the TSF with a minimum follow-up of 1-year. Good results were observed in 99% of the cases (79 out of 80), approaching similar outcomes than those described in literature. PMID- 25435032 TI - Contemporary management of subtrochanteric fractures. AB - Cephalomedullary interlocking nails that allow for trochanteric entry and minimally invasive fixation have revolutionized the contemporary management of subtrochanteric fractures with improved union rates and decreased incidence of fixation failure. The most successful alternative to intramedullary fixation remains the angled blade plate. Despite biomechanical superiority of contemporary intramedullary implants to previous intramedullary devices, the importance of achieving and maintaining satisfactory fracture reduction prior to and during hardware insertion cannot be overemphasized. In comminuted and more challenging fractures, additional techniques, such as limited open reduction with clamps and/or cables, can allow for canal restoration and more anatomic reductions prior to and/or during nail insertion. PMID- 25435033 TI - Blount disease: an update. AB - Blount disease is a developmental disorder associated with childhood obesity. Based on whether the deformity is first noted before or after 4 years of age, early-onset and late-onset forms of Blount disease have been described. Besides physeal abnormalities of the proximal tibia, compensatory changes in the intra articular morphology of the medial compartment of the affected knee are often noted on MRI scan. Both guided growth and acute and gradual correction via a proximal tibial osteotomy have roles in the surgical management of these patients. In order to optimize clinical outcome, frequent follow-up until skeletal maturity is recommended. PMID- 25435034 TI - Surgical exposure for reverse total shoulder arthroplasty: differences in approaches and outcomes. AB - Reverse shoulder arthroplasty can relieve pain and restore function in properly selected patients. The procedure is commonly performed through one of 2 surgical approaches: deltopectoral or anterosuperior. This article describes the surgical approaches, discusses advantages and disadvantages of each approach, reviews the current literature, and presents data from our clinical experience. PMID- 25435035 TI - Management of acromioclavicular joint injuries. AB - Although recent advances have been made in the treatment of acromioclavicular (AC) joint injuries, they are still challenging for shoulder surgeons. There is a consensus that type I and II injuries should be treated nonoperatively, whereas acute type IV, V, and VI injuries should be treated surgically. There is no algorithm for correctly diagnosing and treating type III injuries, but the current trend is toward nonoperative treatment except for those with persistent symptoms and functional limitations after a course of conservative management. If surgery is indicated, newer anatomic techniques of reconstructing the coracoclavicular (CC) and AC ligaments are recommended. PMID- 25435036 TI - Flexor tendon injury, repair and rehabilitation. AB - Injuries to the flexor tendons remain among the most difficult problems in hand surgery. Historically, lacerations to the intrasynovial portion of the flexor tendons were thought to be unsuitable for primary repair. Despite continuing advances in our knowledge of flexor tendon biology, repair, and rehabilitation, good results following primary repair of flexor tendons remain challenging to achieve. PMID- 25435037 TI - Novel applications of osseointegration in orthopedic limb salvage surgery. AB - Osseointegration is a biologic process vital to modern endoprosthetic fixation in orthopedic surgery. Numerous engineering advancements have improved the utilization of this technology in orthopedics; however, issues such as stress shielding, aseptic loosening, and bone loss remain an ongoing challenge. These host responses are especially problematic in limb salvage surgery. Novel applications of osseointegration have been developed to address some of these fixation issues with massive tumor endoprostheses. This articles reviews osseointegration and emerging novel applications of this technology in limb salvage surgery and future prosthetics for amputees. PMID- 25435038 TI - Shoulder instability with concomitant bone loss in the athlete. AB - Thorough evaluation of the athlete with persistent shoulder instability and appropriate use of imaging modalities, such as 3-dimensional computed tomography, can help quantify the severity of bony deficiency. Based on obtained imaging and examination, surgical and nonsurgical methods can be considered. In many situations both the humeral- and glenoid-sided bone loss must be addressed. Depending on the extent of bone loss, athletic demands, and surgeon experience, arthroscopic or open surgical options can provide shoulder stability and return athletes to their prior level of activity. PMID- 25435039 TI - The Latarjet-Patte procedure for recurrent anterior shoulder instability in contact athletes. AB - Recurrent anterior shoulder instability is common in contact athletes and the high-energy injuries seen in this group make them more prone to bone loss. Athletes with recurrent instability and associated bone loss have high failure rates when treated with a soft tissue reconstruction procedure. Therefore it is preferred to manage recurrent instability in contact athletes with the Latarjet Patte procedure. In this article, the authors describe their technique. They have found this procedure to be safe and effective, with very low recurrence and early return to sport. A meticulous surgical technique is important to avoid intraoperative and postoperative complications. PMID- 25435040 TI - Mobile-bearing unicondylar knee arthroplasty: the Oxford experience. AB - With the recent increase in medial unicompartmental arthroplasty, this article reviews the design history, indications, results, and modern technique for the implantation of the Oxford mobile-bearing unicompartmental arthroplasty. The article also discusses how the indications for the Oxford differ from the historical indications for medial unicompartmental arthroplasty and supports this paradigm shift with review of the recent data. A detailed series of surgical pearls is also presented to help surgeons with the surgical nuances of the Oxford partial knee. PMID- 25435041 TI - Robotic-assisted unicompartmental knee arthroplasty: the MAKO experience. AB - Since its introduction, unicompartmental knee arthroplasty has been controversial because of poor early clinical outcomes due to implant design, bony fixation, surgical instrumentation, and technique. Improvements in surgical technique and implant design have resulted in improved results and greater survivorship. The ability to obtain accurate implant placement includes avoiding surgeon decisions leading to potential errors. These errors include alignment in the sagittal, coronal, and axial planes on each prepared condyle as well as the preservation of the joint line and the resulting overall limb alignment as something critical to obtaining a successful outcome. PMID- 25435042 TI - A review of arthroscopic classification systems for osteochondritis dissecans of the knee. AB - Multiple systems for classifying osteochondritis dissecans (OCD) of the knee have been reported. These existing classification systems have some similar characteristics, such as stable lesion/intact articular cartilage and presence of a loose body. However, variations are found in the number of stages and specific lesion characteristics assessed. Currently, no system has been universally accepted. A future classification system should be developed that reconciles the discrepancies among the current systems and provides a clear, consistent, and reliable method for classifying OCD lesions of the knee during arthroscopy. PMID- 25435043 TI - Treatment algorithm for osteochondritis dissecans of the knee. AB - The authors' preferred treatment algorithm for osteochondritis dissecans (OCD) of the knee is based on skeletal maturity, OCD lesion stability, and OCD lesion salvageability. For unstable yet salvageable OCD lesions, the senior author's preferred treatment is fixation with bone grafting. For unstable and unsalvageable OCD lesions, the senior author's preferred treatment is autologous chondrocyte implantation with bone grafting. PMID- 25435044 TI - Patellar instability. AB - Patellar instability is a common injury that can result in significant limitations of activity and long-term arthritis. There is a high risk of recurrence in patients and operative management is often indicated. Advances in the understanding of patellofemoral anatomy, such as knowledge about the medial patellofemoral ligament, tibial tubercle-trochlear groove distance, and trochlear dysplasia may allow improved surgical management of patellar instability. However, techniques such as MPFL reconstruction are technically demanding and may result in significant complication. The role of trochleoplasty remains unclear. PMID- 25435048 TI - Adult reconstruction. PMID- 25435045 TI - MPFL reconstruction: technique and results. AB - Patellar instability is a common problem, and medial patellofemoral ligament (MPFL) injury is inherent with traumatic patellar dislocations. Initial nonoperative management is focused on reconditioning and strengthening the dynamic stabilizers of the patella. For those patients who progress to recurrent instability, further investigation into the predisposing factors is required. MPFL reconstruction is indicated in patients with recurrent instability and insufficient medial restraint due to MPFL injury. A technique of MPFL reconstruction is outlined. This procedure may also be performed in combination with other realignment procedures. PMID- 25435049 TI - Pediatric orthopaedics. PMID- 25435050 TI - Upper extremity. PMID- 25435051 TI - Oncology. PMID- 25435052 TI - Sports medicine. PMID- 25435053 TI - HPV transmission in adolescent men who have sex with men. PMID- 25435054 TI - Dose regimen of favipiravir for Ebola virus disease. PMID- 25435056 TI - Autologous stem cell transplantation in multiple myeloma is not dead but alive and well. AB - In multiple myeloma (MM), the use of high-dose chemotherapy with autologous stem cell transplantation (ASCT) led to incremental advances in patient management in the 1990s. The clinical results for patients dramatically improved further in the 2000s with the introduction of immunomodulatory drugs and proteasome inhibitors. In the 'modern' era for MM treatment, transplant trials strongly support the use of upfront ASCT in the context of novel agents, and until proven otherwise, the old ASCT remains the standard of care for eligible patients. Nevertheless, some issues remain unresolved and this editorial aims to highlight the concerns to be addressed in the future. PMID- 25435055 TI - Site-specific human papillomavirus infection in adolescent men who have sex with men (HYPER): an observational cohort study. AB - BACKGROUND: Men who have sex with men (MSM) have an increased risk of anogenital human papilomavirus (HPV) infection, which can lead to HPV-related anogenital lesions such as warts, anal intraepithelial neoplasia, and anal cancer. Some of these HPV types are preventable with vaccines. We aimed to describe the incidence of anal, penile, and oral HPV infection, and to estimate the site-specific transmission probability per partner, for teenage MSM. METHODS: In our observational cohort study, we enrolled teenage MSM (aged 16-20 years) with low sexual exposure and a low prevalence of HPV in Melbourne (VIC, Australia). At baseline, 3, 6, and 12 months, we took a swab from the anal canal, and participants self-collected a swab from the penis and an oral rinse. Our primary outcome was definite and probable incident HPV infection of the anus, penis, or mouth at any time in the 12 months from baseline, assessed through the presence of HPV DNA. We defined definite incident HPV infection as the same HPV type detected more than once from the same site in men who had a negative HPV test at baseline. We defined probable incident HPV infection as only one positive test. We estimated the probability of HPV transmission per partner using HPV prevalence in MSM with a similar age to partners of men in our cohort. This study is registered at the Australian New Zealand Clinical Trials Registry and ClinicalTrials.gov, numbers ACTRN12611000857909 and NCT01422356. FINDINGS: We enrolled 200 MSM aged 16-20 years (median 19 years [IRQ 18-20; range 16-20]) between Sept 20, 2010, and Aug 24, 2012. Over the 12 month follow-up period, we detected 48 definite (107 possible) HPV infections in the anus, ten definite (34 possible) HPV infections on the penis, and no definite (six possible) infections in the mouth. Definite incidence rate per 100 person-years for any anal HPV infection was 57 (95% CI 46-68), and for any anal HPV type in the quadrivalent vaccine was 33 (23-44). Definite incidence rate per 100 person-years for any penile HPV was 12 (6-21) and for any HPV type in the quadrivalent vaccine was 5 (1-12). Estimated probabilities of HPV transmission from the penis to the anus were significantly higher than were those from the anus to the penis (p<0.05 for all HPV types in the quadrivalent vaccine). INTERPRETATION: High incidence rates suggest that the vaccination coverage in MSM will need to be high. The transmission estimates will inform HPV modelling. FUNDING: Merck. PMID- 25435057 TI - The role of natural environments within women's everyday health and wellbeing in Copenhagen, Denmark. AB - Urbanisation has been linked with sedentary lifestyles and poor mental health outcomes amongst women. The potential for natural environments to enhance physical activity and mental wellbeing in urban areas is now well recognised. However, little is known about the ways that women use natural spaces for health and wellbeing within the context of their everyday lives. This paper draws on ideas developed in the therapeutic landscapes literature to examine how experiences in different types of green and blue space provide important health and wellbeing benefits for women in Copenhagen, Denmark. As well as facilitating physical exercise, such spaces were found to enable a range of more subtle benefits that helped to restore mental wellbeing through stress and anxiety alleviation, the facilitation of emotional perspective, clarity and reassurance, and through the maintenance of positive family dynamics. However, amongst some women who were overweight, the socio-political associations they made with natural environments deterred use of such spaces. Such findings challenge dominant planning and policy assumptions that equate open public access to natural spaces with universal benefit. PMID- 25435058 TI - Admixture and genetic relationships of Mexican Mestizos regarding Latin American and Caribbean populations based on 13 CODIS-STRs. AB - Short tandem repeats (STRs) of the combined DNA index system (CODIS) are probably the most employed markers for human identification purposes. STR databases generated to interpret DNA profiles are also helpful for anthropological purposes. In this work, we report admixture, population structure, and genetic relationships of Mexican Mestizos with respect to Latin American and Caribbean populations based on 13 CODIS-STRs. In addition, new STR population data were included from Tijuana, Baja California (Northwest, Mexico), which represents an interesting case of elevated genetic flow as a bordering city with the USA. Inter population analyses included CODIS-STR data from 11 Mexican Mestizo, 12 Latin American and four Caribbean populations, in addition to European, Amerindian, and African genetic pools as ancestral references. We report allele frequencies and statistical parameters of forensic interest (PD, PE, Het, PIC, typical PI), for 15 STRs in Tijuana, Baja California. This Mexican border city was peculiar by the increase of African ancestry, and by presenting three STRs in Hardy-Weinberg disequilibrium, probably explained by recurrent gene flow. The Amerindian ancestry in Central and Southeast of Mexico was the greatest in Latin America (50.9-68.6%), only comparable with the North of Central America and Ecuador (48.8 56.4%), whereas the European ancestry was prevalent in South America (66.7-75%). The African ancestry in Mexico was the smallest (2.2-6.3%) in Latin America (>= 2.6%), particularly regarding Brazil (21%), Honduras (62%), and the Caribbean (43.2-65.2%). CODIS-STRs allowed detecting significant population structure in Latin America based on greater presence of European, Amerindian, and African ancestries in Central/South America, Mexican Mestizos, and the Caribbean, respectively. PMID- 25435059 TI - Nanomimics of host cell membranes block invasion and expose invasive malaria parasites. AB - The fight against most infectious diseases, including malaria, is often hampered by the emergence of drug resistance and lack or limited efficacies of vaccines. Therefore, new drugs, vaccines, or other strategies to control these diseases are needed. Here, we present an innovative nanotechnological strategy in which the nanostructure itself represents the active substance with no necessity to release compounds to attain therapeutic effect and which might act in a drug- and vaccine like dual function. Invasion of Plasmodium falciparum parasites into red blood cells was selected as a biological model for the initial validation of this approach. Stable nanomimics-polymersomes presenting receptors required for parasite attachment to host cells-were designed to efficiently interrupt the life cycle of the parasite by inhibiting invasion. A simple way to build nanomimics without postformation modifications was established. First, a block copolymer of the receptor with a hydrophobic polymer was synthesized and then mixed with a polymersome-forming block copolymer. The resulting nanomimics bound parasite derived ligands involved in the initial attachment to host cells and they efficiently blocked reinvasion of malaria parasites after their egress from host cells in vitro. They exhibited efficacies of more than 2 orders of magnitude higher than the soluble form of the receptor, which can be explained by multivalent interactions of several receptors on one nanomimic with multiple ligands on the infective parasite. In the future, our strategy might offer interesting treatment options for severe malaria or a way to modulate the immune response. PMID- 25435061 TI - Sir Robert Jones: orthopaedic surgeon and war hero. AB - The First World War was a very harsh conflict and statistics recorded a great number of victims, both soldiers and civilians. One hundred years later, the whole world is commemorating the Great War by celebrating people and events that contributed to shaping the XX century. Beyond remembering political figures, war heroes or even famous battles, it is also important to underline the contribution of those who devoted their efforts to improve the living conditions during war campaigns. This is the case of Sir Robert Jones, one of the fathers of XX century orthopaedics, who contributed to re-organize the military medical assistance during war times and whose teachings, coming directly from his "on the field" experience, inspired an entire generation of European surgeons. PMID- 25435060 TI - Associations between urinary phenol and paraben concentrations and markers of oxidative stress and inflammation among pregnant women in Puerto Rico. AB - Phenols and parabens are used in a multitude of consumer products resulting in ubiquitous human exposure. Animal and in vitro studies suggest that exposure to these compounds may be related to a number of adverse health outcomes, as well as potential mediators such as oxidative stress and inflammation. We examined urinary phenol (bisphenol A (BPA), triclosan (TCS), benzophenone-3 (BP-3), 2,4 dichlorophenol (24-DCP), 2,5-dichlorophenol (25-DCP)) and paraben (butyl paraben (B-PB), methyl paraben (M-PB), propyl paraben (P-PB)) concentrations measured three times during pregnancy in relation to markers of oxidative stress and inflammation among participants in the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) project. Serum markers of inflammation (c reactive protein (CRP), IL-1beta, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-alpha)) were measured twice during pregnancy (n=105 subjects, 187 measurements) and urinary markers of oxidative stress (8-hydroxydeoxyguanosine (OHdG) and isoprostane) were measured three times during pregnancy (n=54 subjects, 146 measurements). We used linear mixed models to assess relationships between natural log-transformed exposure and outcome biomarkers while accounting for within individual correlation across study visits. After adjustment for urinary specific gravity, study visit, maternal pre-pregnancy BMI, and maternal education, an interquartile range (IQR) increase in urinary BPA was associated with 21% higher OHdG (p=0.001) and 29% higher isoprostane (p=0.0002), indicating increased oxidative stress. The adjusted increase in isoprostane per IQR increase in marker of exposure was 17% for BP-3, 27% for B-PB, and 20% for P-PB (all p<0.05). An IQR increase in triclosan (TCS) was associated with 31% higher serum concentrations of IL-6 (p=0.007), a pro-inflammatory cytokine. In contrast, IQR increases in BP-3 and B-PB were significantly associated with 16% and 18% lower CRP, a measure of systemic inflammation. Our findings suggest that exposure to BPA, select parabens, and TCS during pregnancy may be related to oxidative stress and inflammation, potential mechanisms by which exposure to these compounds may influence birth outcomes and other adverse health effects, but additional research is needed. PMID- 25435062 TI - Placental extracts induce the expression of antioxidant enzyme genes and suppress melanogenesis in B16 melanoma cells. AB - One of the activities of placental extracts (PEs) is skin-whitening effect, but the physiological and genetic mechanism for this effect has not yet been clarified. Here, we focus on PE as a regulator of antioxidant enzyme genes. Porcine PE was prepared, and its activity was investigated in B16 melanoma cells. PE treatment decreased the melanin content of UV-irradiated B16 cells in a dose dependent manner. PE directly reduced the enzyme activity of tyrosinase in a cell free assay. In addition, PE treatment increased the gene expression of cytosolic superoxide dismutase (SOD-1), extracellular SOD (SOD-3) and catalase but did not affect the expression of tyrosinase. Moreover, PE protected the B16 cells from H2O2-induced cell death. Taken together, our data suggest that PEs could play a role not only as a suppressor of melanin synthesis but also as a regulator of antioxidant genes and might protect the skin against oxidative stress. PMID- 25435063 TI - Pseudoxanthoma elasticum-like papillary dermal elastolysis. PMID- 25435064 TI - Ultrasonic cavitation for disruption of microalgae. AB - Challenges with mid-stream fractionation steps in proposed microalgae biofuel pathways arise from the typically dilute cell density in growth media, micron scale cell sizes, and often durable cell walls. For microalgae to be a sustainable source of biofuels and co-products, efficient fractionation by some method will be necessary. This study evaluates ultrasonic cell disruption as a processing step that fractionates microalgae. A range of species types with different sizes and cell wall compositions were treated. The initial seconds of sonication offered the most significant disruption, even for the more durable Nannochloropsis cells. Following this initial period, diminishing effectiveness was attributed, by acoustic measurements, to attenuation of the ultrasound in the ensuing cloud of cavitating bubbles. At longer exposure times, differences between species were more pronounced. Processing higher concentrations of Isochrysis slowed cell disintegration only marginally, making the expenditure of energy more worthwhile. PMID- 25435065 TI - In vitro engineering of microbial enzymes with multifarious applications: prospects and perspectives. AB - The discovery of a novel enzyme from a microbial source takes anywhere between months to years, and therefore, there has been an immense interest in modifying the existing microbial enzymes to suit the present day needs of the industry. The redesigning of industrially useful enzymes for improving their performance has become a challenge because bioinformatics databases have been revealing new facts on a day-to-day basis. Modification of the existing enzymes has become a trend for fine tuning of biocatalysts in the biotech industry. Hydrolases are employed in pharmaceutical, biofuel, detergent, food and feed industries that significantly contribute to the global annual revenue, and therefore, the emphasis has been on engineering them. Although a large data is accumulating on making alterations in microbial enzymes, there is a lack of definite information on redesigning industrial enzymes. This review focuses on the recent developments in improving the characteristics of various biotechnologically important enzymes. PMID- 25435066 TI - Effects of pyrolysis temperature and heating time on biochar obtained from the pyrolysis of straw and lignosulfonate. AB - In this study, the effects of pyrolysis temperature and heating time on the yield and physicochemical and morphological properties of biochar obtained from straw and lignosulfonate were investigated. As pyrolysis temperature increased, pH, ash content, carbon stability, and total content of carbon increased while biochar yield, volatile matter, total content of hydrogen, oxygen, nitrogen and sulfur decreased. The data from scanning electron microscope image and nuclear magnetic resonance spectra indicated an increase in porosity and aromaticity of biochar produced at a high temperature. The results showed that feedstock types could also influence characteristics of the biochar with absence of significant effect on properties of biochar for heating time. PMID- 25435067 TI - Isolation and screening of heterocystous cyanobacterial strains for biodiesel production by evaluating the fuel properties from fatty acid methyl ester (FAME) profiles. AB - This study reports on the biodiesel quality parameters of eleven heterocystous cyanobacterial strains based on fatty acid methyl esters (FAME) profiles. The biomass productivity of the tested cyanobacterial strains ranged from 9.33 to 20.67 mg L(-1) d(-1) while the lipid productivity varied between 0.65 and 2.358 mg L(-1) d(-1). The highest biomass and lipid productivity was observed for Calothrix sp. MBDU 013 but its lipid content is only 11.221 in terms of percent dry weight, next to the Anabaena sphaerica MBDU 105, whose lipid content is high. To identify the most competent isolate, a multi-criteria decision analyses (MCDA) was performed by including the key chemical and physical parameters of biodiesel calculated from FAME profiles. The isolate A.sphaerica MBDU 105 is the most promising biodiesel feed stock based on decision vector through Preference Ranking Organisation Method for Enrichment Evaluation (PROMETHEE) and Graphical Analysis for Interactive Assistance (GAIA) analysis. PMID- 25435068 TI - Energy evaluation of algal cell disruption by high pressure homogenisation. AB - The energy consumption of high pressure homogenisation (HPH) was analysed to determine the feasibility of rupturing algal cells for biodiesel production. Experimentally, the processing capacity (i.e. flow rate), power draw and cell disruption efficiency of HPH were independent of feed concentration (for Nannochloropsis sp. up to 25%w/w solids). Depending on the homogenisation pressure (60-150 MPa), the solids concentration (0.25-25%w/w), and triacylglyceride (TAG) content of the harvested algal biomass (10-30%), the energy consumed by HPH represented between 6% and 110-times the energy density of the resulting biodiesel. Provided the right species (weak cell wall and high TAG content) is selected and the biomass is processed at a sufficiently high solids concentration, HPH can consume a small fraction of the energy content of the biodiesel produced. This study demonstrates the feasibility of process-scale algal cell disruption by HPH based on its energy requirement. PMID- 25435069 TI - Structural variation of eucalyptus lignin in a combination of hydrothermal and alkali treatments. AB - In this work, the structural features of the lignin isolated with 2% NaOH at 90 degrees C for 2.5h from the hydrothermally pretreated eucalyptus fibers at different temperatures (100-200 degrees C) for different times (15-60min) were thoroughly investigated. Results showed that the hydrothermal pretreatment facilitated the separation of alkali lignin from the pretreated fibers. It was found that the linkages of beta-O-4, beta-beta, and beta-5 decreased gradually with the increase of hydrothermal severity. Furthermore, decreased molecular weights (1630-510g/mol), associated carbohydrates contents (1.99-0.05%) and aliphatic OH contents (3.37-0.65mmol/g), and increased phenolic OH contents (0.71 2.98mmol/g) and thermal stability of the alkali lignins were observed with the increase of the hydrothermal severity. PMID- 25435070 TI - [Buttocks enhancement using silicone implants: a national practices assessement about 538 patients]. AB - Buttock enhancement using gluteal silicone implants is known as a high risk of complications procedure. However, few studies have attempted to quantify the rate of overall complications. The aim of this work is to analyze the rates and types of complications encountered by French plastic surgeons practicing this procedure, and to review their technical choices about incisional access, implant plane, implant type, postoperative instructions, and drain use. We also tried to assess patients global satisfaction rate. MATERIAL AND METHODS: A survey of 17 questions was emailed to French Plastic Surgeons (sent through the channel tamtam@plasticiens.com and emails), the criterias studied included information about number of cases performed, surgical approach used, implant placement plane and implant type, drainage, postoperative instructions, complications experienced and patients satisfaction. RESULTS: Thirteen participants provided data on 538 patients, 84.6% of surgeons used a single incision, 100% favored the intramuscular dissection plane over the subfascial plane, 38% have experienced complications (all types included). The main complications encountered were wound separation (4,4%), seroma (2.2%), infections requiring explantation (1.4%), caspular retraction (1.3%) and asymmetry (3.3%). The global patients satisfaction rate was 8/10. CONCLUSION: Our results show that this procedure remains reliable, and serious complications are rare. It also helps providing an assessment of French plastic surgeons practices with the aim of popularizing this procedure. PMID- 25435071 TI - Memory T Cells in Transplantation. AB - Following infections and environmental exposures, memory T cells are generated that provide long-term protective immunity. Compared to their naive T cell counterparts, memory T cells possess unique characteristics that endow them with the ability to quickly and robustly respond to foreign antigens. While such memory T cells are beneficial in protecting their hosts from recurrent infection, memory cells reactive to donor antigens pose a major barrier to successful transplantation and tolerance induction. Significant progress has been made over the past several decades contributing to our understanding of memory T cell generation, their distinct biology, and their detrimental impact in clinical and animal models of transplantation. This review focuses on the unique features which make memory T cells relevant to the transplant community and discusses potential therapies targeting memory T cells which may ameliorate allograft rejection. PMID- 25435073 TI - Droplet actuation in an electrified microfluidic network. AB - This work demonstrates that liquid droplet emulsions in a microchannel can be deformed, decelerated and/or pinned by applying a suitable electrical potential. By concentrating a potential gradient at the corners, we show that different droplets can be passively binned by size and on demand in a branched microfluidic device. The deformation, deceleration, squeezing and release of droplets in a three-dimensional numerical simulation are qualitatively verified by experiments in a PDMS microfluidic device. The forces required for pinning or binning a droplet provide a delicate balance between hydrodynamics and the electric field, and are obtained using appropriate non-dimensional parameters. PMID- 25435072 TI - Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a. AB - Dimethyl fumarate (DMF) is a new drug used to treat multiple sclerosis (MS) patients. Here, we examined the effects of DMF and the DMF metabolite monomethyl fumarate (MMF) on various activities of natural killer (NK) cells. We demonstrated that MMF augments the primary CD56(+), but not CD56(-), NK cell lysis of K562 and RAJI tumor cells. MMF induced NKp46 expression on the surface of CD56(+), but not CD56(-), NK cells after incubation for 24 h. This effect was closely correlated with the upregulation of CD107a expression on the surface of CD56(+) NK cells and the induction of Granzyme B release from these cells through this metabolite. An anti-NKp46 antibody inhibited the MMF-induced upregulation of CD107a and the lysis of tumor cells through CD56(+) NK cells. Thus, these results are the first to show that MMF augments CD56(+) NK cell lysis of tumor target cells, an effect mediated through NKp46. This novel effect suggests the use of MMF for therapeutic and/or preventive protocols in cancer. PMID- 25435074 TI - Breastfeeding practices in women with type 1 diabetes: a discussion of the psychosocial factors and policies in Sweden and Australia. AB - BACKGROUND: Women with type 1 diabetes (T1DM) face many challenges during their pregnancy, birth and in the postnatal period, including breastfeeding initiation and continuation while maintaining stable glycaemic control. In both Sweden and Australia the rates of breastfeeding initiation are high. However, overall there is limited information about the breastfeeding practices of women with T1DM and the factors affecting them. Similarities in demographics, birth rates and health systems create bases for discussion. AIM: The aim of this paper is to discuss psychosocial factors, policies and practices that impact on the breastfeeding practices of women with T1DM. FINDINGS: Swedish research indicates that the overall breastfeeding rate in women with T1DM remains significantly lower than in women without diabetes in the first 2 and 6 months after childbirth with no differences in exclusive breastfeeding. Breastfeeding initiation and continuation among women with T1DM in Sweden has been shown to be influenced by health services delivery, supportive breastfeeding policies and socio-economic factors, particular perceived support from social networks and health professionals. CONCLUSION: There is limited research on the impact of attitudes towards breastfeeding, emotional and social well-being and diabetes-related stress on the decision of women with T1DM to initiate and continue to breastfeed for at least 6 months. A more comprehensive understanding of the breastfeeding practices and psychosocial factors operating during the first 6 months after birth for women with T1DM will be instrumental in the future design of interventions promoting initiation and continuation of breastfeeding in Sweden, Australia and elsewhere. PMID- 25435075 TI - Langmuir monolayers and thin films of amphifilic thiacalix[4]arenes. Properties and matrix for the immobilization of cytochrome c. AB - Formation and properties of Langmuir films of thiacalix[4]arene (TCA) derivatives containing N-donor groups on the lower rim (Y?O(CH2)3CN; OCH2CN; NH2; OCH2ArCN-p) in 1,3-alternate conformation on aqueous subphase and solid substrates have been studied. Only tetra-cyanopropoxy-p-tert-butylthiacalix[4]arene 1 forms a typical monomolecular layer with perpendicular orientation of the macrocycle relative to the water-air interface that is able to immobilize cytochrome c in the entire range of the surface pressure. Obtained monolayers were transferred by Langmuir Schaefer technique onto quartz, indium-tin oxide (ITO), and silicon. It was demonstrated that protein activity is retained after immobilization on the substrate. PMID- 25435076 TI - beta-catenin induces A549 alveolar epithelial cell mesenchymal transition during pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by expansion of the fibroblast and myofibroblast population and extracellular matrix deposition. Although the pathogenic mechanisms of IPF remain to be fully elucidated, there is emerging evidence that fibroblasts and myofibroblasts may be derived partially from alveolar epithelial cells by epithelial-mesenchymal transition (EMT). In the present study, A549 cells were treated with different concentrations of Wnt1 and the results indicated that the mRNA and protein expression levels of vimentin, alpha-smooth muscle actin (alpha-SMA) and collagen I gradully increased and those of E-cadherin gradully decreased in a concentration-dependent manner. Furthermore, the A549 cells were transfected with beta-catenin plasmid cells, revealing phenotypic changes in the cells from a pebble to a fusiform shape. The mRNA and protein expression levels of of vimentin, alpha-SMA and collagen I increased significantly, whereas those of E cadherin decreased significantly. The present study examined the roles of alveolar epithelial cell injury and profibrogenic cytokine release in EMT and their association with the Wnt/beta-catenin signaling pathway in a mouse model of bleomycin-induced pulmonary fibrosis. Bronchoalveolar fluid was obtained 7 days after treatment with bleomycin and the A549 cells were incubated for 48 h. An increase in the expression levels of the mesenchymal markers, alpha-SMA, vimentin and collagen I, and a concomitant decrease in the expression of the epithelial marker, E-cadherin were observed. This corresponded with an increased expression of beta-catenin. When the A549 cells were infected with a lentivirus expressing beta-catenin shRNA, no significant increase was observed in the expression of the mesenchymal cell markers and the expression of E-cadherin did not decrease. These findings demonstrated that activation of the Wnt signaling pathway was capable of inducing an EMT program in the lung epithelial cells through beta-catenin and that injured alveolar epithelium activated the Wnt/beta-catenin signaling pathway, thereby inducing the expansion of the fibroblast/myofibroblast population through EMT. These results suggested that beta-catenin was involved in the formation of lung fibrosis and may provide a theoretical basis for the treatment of IPF. PMID- 25435077 TI - Machine learning algorithms and forced oscillation measurements to categorise the airway obstruction severity in chronic obstructive pulmonary disease. AB - The purpose of this study was to develop automatic classifiers to simplify the clinical use and increase the accuracy of the forced oscillation technique (FOT) in the categorisation of airway obstruction level in patients with chronic obstructive pulmonary disease (COPD). The data consisted of FOT parameters obtained from 168 volunteers (42 healthy and 126 COPD subjects with four different levels of obstruction). The first part of this study showed that FOT parameters do not provide adequate accuracy in identifying COPD subjects in the first levels of obstruction, as well as in discriminating between close levels of obstruction. In the second part of this study, different supervised machine learning (ML) techniques were investigated, including k-nearest neighbour (KNN), random forest (RF) and support vector machines with linear (SVML) and radial basis function kernels (SVMR). These algorithms were applied only in situations where high categorisation accuracy [area under the Receiver Operating Characteristic curve (AUC)>=0.9] was not achieved with the FOT parameter alone. It was observed that KNN and RF classifiers improved categorisation accuracy. Notably, in four of the six cases studied, an AUC>=0.9 was achieved. Even in situations where an AUC>=0.9 was not achieved, there was a significant improvement in categorisation performance (AUC>=0.83). In conclusion, machine learning classifiers can help in the categorisation of COPD airway obstruction. They can assist clinicians in tracking disease progression, evaluating the risk of future disease exacerbations and guiding therapy. PMID- 25435078 TI - The KIT is a putative marker for differentiating spermatogonia in stallions. AB - Putative markers have been discovered and are used to identify and separate certain lineage of spermatogonia. The KIT is a marker for differentiating spermatogonial stem cells in several species including mice and goats. The objectives of this study were (1) to investigate reproductive stage-dependent KIT expression patterns in stallions and (2) to identify spermatogonia subpopulations expressing KIT in stallion testes. To achieve these objectives, testicular samples were obtained during routine field castration of stallions. The reproductive stage of the stallions was classified as pre-pubertal (<1 year, n=3), pubertal (1-1.5 year, n=4), post-pubertal (2-3 year, n=6), or adult (4-8 year, n=6). For immunohistochemistry, KIT was used at a dilution of 1:200. In the pre-pubertal and pubertal stage, most germ cells were immunolabeled with KIT. In the post-pubertal and adult stages, immunolabeling of KIT was evident in the germ cells attached to the basement membrane of the seminiferous tubules with exception of some spermatogonia. Co-immunolabeling with KIT and deleted in azoospermia like (DAZL) showed different co-staining patterns, including KIT only, both KIT and DAZL), or DAZL positive germ cell populations alone. The KIT was not immunolabeled in Sertoli or Leydig cells at any reproductive stages. The result of Western blot analysis verified the cross-activity of the KIT antibody with horse testes tissue. In conclusion, KIT appears to be expressed in differentiating spermatogonia, and may be used to identify and isolate differentiating germ cells from stallions. PMID- 25435079 TI - Irreversible multitargeted ErbB family inhibitors for therapy of lung and breast cancer. AB - Overactivation of the ErbB protein family, which is comprised of 4 receptor tyrosine kinase members (ErbB1/epidermal growth factor receptor [EGFR]/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4), can drive the development and progression of a wide variety of malignancies, including colorectal, head and neck, and certain non-small cell lung cancers (NSCLCs). As a result, agents that target a specific member of the ErbB family have been developed for the treatment of cancer. These agents include the reversible EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib; the EGFR-targeting monoclonal antibodies cetuximab and panitumumab; and the HER2-targeting monoclonal antibody trastuzumab. Lapatinib is a dual TKI that targets both EGFR and HER2. In addition, TKIs that inhibit multiple members of the ErbB family and also bind their targets irreversibly are under evaluation for the treatment of cancer. Three such compounds have progressed into clinical studies: the EGFR, HER2, and HER4 inhibitors afatinib, dacomitinib, and neratinib. Phase I studies of these agents have shown clinical activity in NSCLC, breast cancer, and other malignancies. Currently, afatinib is approved for EGFR mutation-positive NSCLC and is in development for squamous NSCLC, and dacomitinib is in phase III of clinical development for NSCLC, neratinib is in phase III of clinical development for the treatment of breast cancer, and afatinib is also in phase III development in head and neck cancer. Final results from clinical trials may lead to the potential approval of these agents in a variety of solid tumor malignancies. PMID- 25435081 TI - Musculoskeletal physiotherapists' use of psychological interventions: a systematic review of therapists' perceptions and practice. AB - BACKGROUND: Research has demonstrated that incorporating psychological interventions within physiotherapy practice has numerous potential benefits. Despite this physiotherapists have reported feeling inadequately trained to confidently use such interventions in their day-to-day practice. OBJECTIVE: To systematically review musculoskeletal physiotherapists' perceptions regarding the use of psychological interventions within physiotherapy practice. DATA SOURCES: Eligible studies were identified through a rigorous search of AMED, CINAHL, EMBASE, MEDLINE and PsychINFO from January 2002 until August 2013. STUDY ELIGIBILITY CRITERIA: Full text qualitative, quantitative and mixed methodology studies published in English language investigating musculoskeletal physiotherapists' perceptions regarding their use of psychological interventions within physiotherapy practice. STUDY SYNTHESIS AND APPRAISAL: Included studies were appraised for risk of bias using the Critical Appraisal Skills Programme qualitative checklist. Meta-analysis was not possible due to study heterogeneity. RESULTS: Six studies, all with a low risk of bias, met the inclusion criteria. These studies highlighted that physiotherapists appreciate the importance of using psychological interventions within their practice, but report inadequate understanding and consequent underutilisation of these interventions. LIMITATIONS: These results should be noted with some degree of caution due to various limitations associated with the included studies and with this review, including the use of a qualitative appraisal tool for mixed methodology/quantitative studies. CONCLUSION: These findings suggest that musculoskeletal physiotherapists are aware of the potential benefits of incorporating psychological interventions within their practice but feel insufficiently trained to optimise their use of such interventions; hence highlighting a need for further research in this area and a review of physiotherapist training. PMID- 25435082 TI - III-V nanowire synthesis by use of electrodeposited gold particles. AB - Semiconductor nanowires are great candidates for building novel electronic devices. Considering the cost of fabricating such devices, substrate reuse and gold consumption are the main concerns. Here we report on implementation of high throughput gold electrodeposition for selective deposition of metal seed particles in arrays defined by lithography for nanowire synthesis. By use of this method, a reduction in gold consumption by a factor of at least 300 was achieved, as compared to conventional thermal evaporation for the same pattern. Because this method also facilitates substrate reuse, a significantly reduced cost of the final device is expected. We investigate the morphology, crystallography, and optical properties of InP and GaAs nanowires grown from electrodeposited gold seed particles and compare them with the properties of nanowires grown from seed particles defined by thermal evaporation of gold. We find that nanowire synthesis, as well as the material properties of the grown nanowires are comparable and quite independent of the gold deposition technique. On the basis of these results, electrodeposition is proposed as a key technology for large scale fabrication of nanowire-based devices. PMID- 25435080 TI - Involvement of the strychnine-sensitive glycine receptor in the anxiolytic effects of GlyT1 inhibitors on maternal separation-induced ultrasonic vocalization in rat pups. AB - Several studies have shown that glycine transporter 1 (GlyT1) inhibitors have anxiolytic actions. There are two types of glycine receptor: the strychnine sensitive glycine receptor (GlyA) and the strychnine-insensitive glycine receptor (GlyB); however, which receptor is the main contributor to the anxiolytic actions of GlyT1 inhibitors is yet to be determined. Here, we clarified which glycine receptor is the main contributor to the anxiolytic effects of GlyT1 inhibitors by using maternal separation-induced ultrasonic vocalization (USV) by rat pups as an index of anxiety. We confirmed that administration of the benzodiazepine diazepam or the selective serotonin reuptake inhibitor escitaloplam, which are both clinically proven anxiolytics, or the GlyT1 inhibitor SSR504734 (2-chloro-N-[(S) phenyl[(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide), decreases USV in rat pups. In addition, we showed that another GlyT1 inhibitor, ALX5407 ((R)-N [3-(4'-fluorophenyl)-3(4'-phenylphenoxy)propyl]sarcosine) also decreases USV in rat pups. SSR504734- or ALX5407-induced decreases in USV were dose-dependently reversed by administration of the GlyA antagonist strychnine, whereas the diazepam- or escitalopram-induced decreases in USV were not. Furthermore, GlyT1 induced decreases in USV were not reversed by administration of the GlyB antagonist L-687,414. Together, these results suggest that GlyA activation is the main contributor to the anxiolytic actions of GlyT1 inhibitors and that the anxiolytic actions of diazepam and escitalopram cannot be attributed to GlyA activation. Our findings provide new insights into the importance of the activation of GlyA in the anxiolytic effects of GlyT1 inhibitors. PMID- 25435083 TI - Neurobiological basis of motivational deficits in psychopathology. AB - In recent years, there has been increasing emphasis on the importance of motivational symptoms in depression, schizophrenia and other disorders. The present review discusses the conceptual background related to the construct of motivation, and provides a framework that for research on both physiological and pathological aspects of motivation. Particular emphasis is placed on what is known about the neurobiological basis of activational aspects of motivation, including studies from animal models. The role of limbic/prefrontal/striatal circuitry in behavioral activation and effort-related functions is examined, and the utility of behavioral tasks of effort-based decision making as models of motivational symptoms is discussed. We also review the neurobiology of motivational symptoms in relation to psychopathology, and issues related to the language used to characterize motivational dysfunctions are considered. The literature suggests that research on the neurobiology of motivational dysfunction in psychopathology, at both clinical and preclinical levels, could inform the development of novel and more effective treatments for a range of CNS disorders. PMID- 25435084 TI - Normalisation of frontal theta activity following methylphenidate treatment in adult attention-deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is associated with cognitive performance and functional brain changes that are sensitive to task conditions, indicating a role for dynamic impairments rather than stable cognitive deficits. Prominent hypotheses consistent with this observation are a failure to optimise brain arousal or activation states. Here we investigate cortical activation during different conditions. Using a sample of 41 non-comorbid adults with ADHD and 48 controls, we examine quantitative EEG activity during a resting state, a cued continuous performance test with flankers (CPT-OX) and the sustained attention to response task (SART). We further investigate the effects of methylphenidate in a subsample of 21 ADHD cases. Control participants showed a task-related increase in theta activity when engaged in cognitive tasks, primarily in frontal and parietal regions, which was absent in participants with ADHD. Treatment with methylphenidate resulted in normalisation of the resting state to task activation pattern. These findings suggest that ADHD in adults is associated with insufficient allocation of neuronal resources required for normal cortical activation commensurate with task demands. Further work is required to clarify the causal role of the deficit in cortical activation and provide a clearer understanding of the mechanisms involved. PMID- 25435085 TI - Sociodemographic, neuropsychiatric and cognitive characteristics of pathological gambling and impulse control disorders NOS in Parkinson's disease. AB - Despite of previous evidence supporting the association between impulse control disorder (ICD) and several demographic, clinical and therapeutic features in Parkinson's disease (PD), the relationships between pathological gambling (PG) or other variants of ICD (ICD-NOS) and specific neuropsychiatric or cognitive domains are not entirely defined. In this study, 155 PD patients without dementia or cognitive impairment underwent: i. the ICD diagnoses, using the Questionnaire for Impulsive-Compulsive Disorders, ii. the mood and anxiety disorders diagnoses, according to the DSM-IV-TR criteria, and iii. a comprehensive battery for measuring severity of psychopathology and neuropsychology domains. Patients were divided in those with pathological gambling (PG), ICDs not otherwise specified (ICD-NOS), or the lack of ICD (No-ICD). There was a progression in age and age at onset from the younger PG subjects throughout ICD-NOS to No-ICD. PG and ICD-NOS subjects had longer disease duration and were taking significantly higher dosages of antiparkinsonian drugs than No-ICD ones. PG subjects had significantly higher severity of depressive and anxious symptoms with respect to the other 2 groups. Both PG and ICD-NOS subjects suffer from increased severity of psychotic symptoms than No-ICD ones. The 3 groups did not differ in any cognitive measure. Our results support the concept that the different sociodemographic and neuropsychiatric profiles of PD patients are associated with different ICDs. Moreover, we clearly demonstrate the lack of relationship between ICD and cognitive performances in undemented PD patients. PMID- 25435086 TI - Effects of the static and ELF magnetic fields on the neuronal population activity in Morimus funereus (Coleoptera, Cerambycidae) antennal lobe revealed by wavelet analysis. AB - To study the influence of a static magnetic field (SMF, 2 mT) and extremely low frequency magnetic field (ELF MF, 50 Hz, 2 mT) on the neuronal population activity, the experiments were performed on adult longhorn beetles Morimus funereus (Coleoptera, Cerambycidae). Based on a wavelet analysis of the local field potentials (LFPs), our study showed for the first time that the effects of prolonged and repeated exposure to the ELF MF on the LFPs were irreversible within investigated time frame. The relative wavelet energy (RWE) of 4-8 Hz frequency band was significantly increased after sine ELF MF (SnMF)/square ELF MF (SqMF) in comparison to the control value. The RWE of slower oscillations (1-2Hz) was significantly decreased after the repeated exposures to either SnMF or SqMF. The SqMF induced decreasing of the faster waves in the range of 64-128 Hz. However, we did not prove with presented methods that exposure to the SMF for 5 min produces any effects on the neuronal population activity. This study has proved the wavelet transform as a valuable tool for measuring the effects of SMF and ELF MF on the neuronal population activity in M. funereus antennal lobe. PMID- 25435088 TI - HotSpotter: efficient visualization of driver mutations. AB - BACKGROUND: Driver mutations are positively selected during the evolution of cancers. The relative frequency of a particular mutation within a gene is typically used as a criterion for identifying a driver mutation. However, driver mutations may occur with relative infrequency at a particular site, but cluster within a region of the gene. When analyzing across different cancers, particular mutation sites or mutations within a particular region of the gene may be of relatively low frequency in some cancers, but still provide selective growth advantage. RESULTS: This paper presents a method that allows rapid and easy visualization of mutation data sets and identification of potential gene mutation hotspot sites and/or regions. As an example, we identified hotspot regions in the NFE2L2 gene that are potentially functionally relevant in endometrial cancer, but would be missed using other analyses. CONCLUSIONS: HotSpotter is a quick, easy-to use visualization tool that delivers gene identities with associated mutation locations and frequencies overlaid upon a large cancer mutation reference set. This allows the user to identify potential driver mutations that are less frequent in a cancer or are localized in a hotspot region of relatively infrequent mutations. PMID- 25435087 TI - Community acquired Panton-Valentine Leukocidin (PVL) positive Methicilin Resistant Staphylococcal aureus cerebral abscess in an 11-month old boy: a case study. AB - BACKGROUND: Brain abscess are uncommon childhood infection. Brain abscess caused by Panton-Valentine Leukocidin positive Community acquired Methicillin Resistant Staphylococcal aureus have never been reported in the United Kingdom. CASE PRESENTATION: We report a case of a previously well 11-month old boy of Indian origin who developed a parietal lobe abscess from PVL positive CA-MRSA. CONCLUSION: This case is one of the few described cases of brain abscess caused by PVL CA-MRSA in children. The unusual (insidious) presentation, the absence of a clear staphylococcal focus and the unexpected finding of a CA-MRSA in this patient highlight the challenges of managing such cases in clinical settings and the potential future risk to public health. PMID- 25435089 TI - A twenty-year review of diagnosing and treating children with diffuse intrinsic pontine glioma in The Netherlands. AB - INTRODUCTION: Children with diffuse intrinsic pontine glioma (DIPG) face a dismal prognosis, with a median overall survival of 9 months. Our aims are to determine the incidence of DIPG in the Netherlands and to identify points for improvement in clinical research, a prerequisite for increasing the chance to find a cure. METHODS: We performed a population-based retrospective cohort study by evaluating all children diagnosed with DIPG in the Netherlands between 1990 and 2010. RESULTS: The incidence of DIPG in the Netherlands corresponds with international literature. Between 1990 and 2010, a large heterogeneity of treatment schedules was applied and only a minority of patients was included in clinical trials. DISCUSSION: Given the rarity of DIPG, we emphasize the need for (inter-)national trials to facilitate the identification of potentially effective therapeutics in the future. This can be supported by the recent development of a European DIPG registry enabling international study collaborations. PMID- 25435090 TI - Upregulation of the miR-212/132 cluster suppresses proliferation of human lung cancer cells. AB - Lung cancer is the leading cause of cancer-related mortality worldwide. microRNAs (miRNAs) are small post-transcriptional regulatory non-coding RNAs that function as oncogenes or tumor suppressors in human cancers. Emerging evidence reveals that deregulation of miRNAs contributes to the progression of human lung cancer, which is the leading cause of cancer-related deaths worldwide. In the present study, we found that upregulation of the miR-212/132 cluster significantly suppressed the growth and focus formation of A549 and H1299 cells. Moreover, forced expression of this cluster conferred radiosensitivity and inhibited the migration of lung cancer cells, whereas downregulation of miR-212/132 reversed the above effects. Furthermore, miR-212/132 overexpression induced cell cycle arrest at the G1/S phase transition of the lung cancer cells, and inhibition of miR-132 and miR-212 abrogated this arrest. In addition, miR-212/132 overexpression increased the percentage of cells undergoing apoptosis. Cells transfected with the miR-212/132 cluster exhibited upregulated p21 expression and reduced cyclin D1 expression. Conversely, cells transfected with the miR-212/132 inhibitor showed reduced expression of p21 and upregulated expression of cyclin D1, suggesting that miR-212/132 may mediate proliferation and cell cycle arrest through p21 and cyclin D1. Our study provides insight into the biological function of the miR-212/132 cluster in lung cancer. The present study may provide a potential therapeutic target for the treatment of lung cancer. PMID- 25435091 TI - A new mutation in the ryanodine receptor 2 gene (RYR2 C2277R) as a cause catecholaminergic polymorphic ventricular tachycardia. PMID- 25435092 TI - Optical Coherence Tomography in Thromboembolic Pulmonary Hypertension. PMID- 25435093 TI - Safety of Outpatient Implantation of the Implantable Cardioverter-defibrillator. AB - INTRODUCTION AND OBJECTIVES: Strategies are needed to reduce health care costs and improve patient care. The objective of our study was to analyze the safety of outpatient implantation of cardioverter-defibrillators. METHODS: A retrospective study was conducted in 401 consecutive patients who received an implantable cardioverter-defibrillator between 2007 and 2012. The rate of intervention related complications was compared between 232 patients (58%) whose implantation was performed in the outpatient setting and 169 patients (42%) whose intervention was performed in the inpatient setting. RESULTS: The mean age (standard deviation) of the patients was 62 (14) years; 336 (84%) were male. Outpatients had lower left ventricular ejection fraction and a higher percentage had an indication for primary prevention of sudden death, compared to inpatients. Only 21 outpatients (9%) required subsequent hospitalization. The rate of complications until the third month postimplantation was similar for outpatients (6.0%) and inpatients (5.3%); P = .763. In multivariate analysis, only previous anticoagulant therapy was related to the presence of complications (odds ratio = 3.2; 95% confidence interval, 1.4-7.4; P < .01), mainly due to an increased rate of pocket hematomas. Each outpatient implantation saved approximately ?735. CONCLUSIONS: Outpatient implantation of implantable cardioverter-defibrillators is safe and reduces costs. Close observation is recommended for patients receiving chronic anticoagulation therapy due to an increased risk of complications. PMID- 25435095 TI - Nutrieconomic model can facilitate healthy and low-cost food choices. AB - OBJECTIVE: Promotion of healthy eating can no longer be postponed as a priority, given the alarming growth rate of chronic degenerative diseases in Western countries. We elaborated a nutrieconomic model to assess and identify the most nutritious and affordable food choices. DESIGN: Seventy-one food items representing the main food categories were included and their nationally representative prices monitored. Food composition was determined using CRA-NUT (Centro di Ricerca per gli Alimenti e la Nutrizione) and IEO (Istituto Europeo di Oncologia) databases. To define food nutritional quality, the mean adequacy ratio and mean excess ratio were combined. Both prices and nutritional quality were normalised for the edible food content and for the recommended serving sizes for the Italian adult population. SETTING: Stores located in different provinces throughout Italy. SUBJECTS: Not applicable. RESULTS: Cereals and legumes presented very similar nutritional qualities and prices per serving. Seasonal fruits and vegetables presented differentiated nutritional qualities and almost equal prices. Products of animal origin showed similar nutritional qualities and varied prices: the best nutrieconomic choices were milk, oily fish and poultry for the dairy products, fish and meat groups, respectively. CONCLUSIONS: Analysing two balanced weekly menus, our nutrieconomic model was able to note a significant decrease in cost of approximately 30 % by varying animal-protein sources without affecting nutritional quality. Healthy eating does not necessarily imply spending large amounts of money but rather being able to make nutritionally optimal choices. The nutrieconomic model is an innovative and practical way to help consumers make correct food choices and nutritionists increase the compliance of their patients. PMID- 25435094 TI - Gene expression microarray analysis of the sciatic nerve of mice with diabetic neuropathy. AB - The present study aimed to explore novel target genes that regulate the development of diabetic neuropathy (DN) by analyzing gene expression profiles in the sciatic nerve of infected mice. The GSE11343 microarray dataset, which was downloaded from Gene Expression Omnibus, included data on 4 control samples and 5 samples from mice with diabetes induced by streptozotocin (STZ), 5 samples from normal mice treated with rosiglitazone (Rosi) and 5 samples from mice with diabetes induced by STZ and treated with Rosi. Differentially expressed genes (DEGs) between the different groups were identified using the substitution augmentation modification redefinition (SAMR) model. The Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Regulatory and protein-protein interaction networks were searched using BioCarta and STRING, respectively. The protein structures of potential regulatory genes were predicted using the SYBYL program. Compared with the controls, 1,384 DEGs were identified in the mice with STZ-induced diabetes and 7 DEGs were identified in the mice treated with Rosi. There were 518 DEGs identified between the mice in the STZ + Rosi and STZ groups. We identified 45 GO items, and the calmodulin nerve phosphatase and chemokine signaling pathways were identified as the main pathways. Three genes [myristoylated alanine-rich protein kinase C substrate (Marcks), GLI pathogenesis-related 2 (Glipr2) and centrosomal protein 170 kDa (Cep170)] were found to be co-regulated by both STZ and Rosi, the protein structure of which was predicted and certain binding activity to Rosi was docked. Our study demonstrates that the Marcks, Glipr2 and Cep170 genes may be underlying drug targets in the treatment of DN. PMID- 25435096 TI - Polymer scaffolds with preferential parallel grooves enhance nerve regeneration. AB - We have modified the surface topography of poly E-caprolactone (PCL) and polylactic acid (PLA) blended films to improve cell proliferation and to guide the regeneration of peripheral nerves. Films with differing shaped grooves were made using patterned silicon templates, sloped walls (SL), V-shaped (V), and square-shaped (SQ), and compared with nongrooved surfaces with micropits. The solvent cast films were tested in vitro using adult adipose-derived stem cells differentiated to Schwann cell-like cells. Cell attachment, proliferation, and cell orientation were all improved on the grooved surfaces, with SL grooves giving the best results. We present in vivo data on Sprague-Dawley rat sciatic nerve injury with a 10-mm gap, evaluating nerve regeneration at 3 weeks across a polymer nerve conduit modified with intraluminal grooves (SL, V, and SQ) and differing wall thicknesses (70, 100, 120, and 210 MUm). The SL-grooved nerve conduit showed a significant improvement over the other topographical-shaped grooves, while increasing the conduit wall thickness saw no positive effect on the biological response of the regenerating nerve. Furthermore, the preferred SL grooved conduit (C) with 70 MUm wall thickness was compared with the current clinical gold standard of autologous nerve graft (Ag) in the rat 10-mm sciatic nerve gap model. At 3 weeks postsurgery, all nerve gaps across both groups were bridged with regenerated nerve fibers. At 16 weeks, features of regenerated axons were comparable between the autograft (Ag) and conduit (C) groups. End organ assessments of muscle weight, electromyography, and skin reinnervation were also similar between the groups. The comparable experimental outcome between conduit and autograft, suggests that the PCL/PLA conduit with inner lumen microstructured grooves could be used as a potential alternative treatment for peripheral nerve repair. PMID- 25435097 TI - Evolutionary aspects of lipoxygenases and genetic diversity of human leukotriene signaling. AB - Leukotrienes are pro-inflammatory lipid mediators, which are biosynthesized via the lipoxygenase pathway of the arachidonic acid cascade. Lipoxygenases form a family of lipid peroxidizing enzymes and human lipoxygenase isoforms have been implicated in the pathogenesis of inflammatory, hyperproliferative (cancer) and neurodegenerative diseases. Lipoxygenases are not restricted to humans but also occur in a large number of pro- and eucaryotic organisms. Lipoxygenase-like sequences have been identified in the three domains of life (bacteria, archaea, eucarya) but because of lacking functional data the occurrence of catalytically active lipoxygenases in archaea still remains an open question. Although the physiological and/or pathophysiological functions of various lipoxygenase isoforms have been studied throughout the last three decades there is no unifying concept for the biological importance of these enzymes. In this review we are summarizing the current knowledge on the distribution of lipoxygenases in living single and multicellular organisms with particular emphasis to higher vertebrates and will also focus on the genetic diversity of enzymes and receptors involved in human leukotriene signaling. PMID- 25435098 TI - Incidental physical activity in Melbourne, Australia: health and economic impacts of mode of transport and suburban location. AB - ISSUE ADDRESSED: Using the known health impacts of physical activity (PA), levels of incidental PA in Melbourne were analysed, and after determining key behavioural associations, economic modelling estimated potential long-term health and economic benefits of changes in active transport (AT) patterns. METHODS: A cross-sectional survey (VISTA07-08) obtained daily travel data from 29840 individuals of all ages in Melbourne evenly spread over 364 days of the year. Correlates of adequate PA were analysed. The health and economic impact of changes in AT from postulated changes in (1) mode of transport, and (2) transport use by urban sub-region, were modelled. RESULTS: 15.1% of individuals had adequate incidental PA. Private vehicle users averaged 10.0min PA, public transport users 35.2min and walkers/cyclists 38.3min daily. Distance from city centre was strongly inversely correlated with adequate PA. Conservative modelling of postulated changes in AT patterns found annual savings of 34-272 deaths, 114 903 new cases of disease and 442-3511 DALYs. Lifetime savings accounted for 17300 70100 days of home-based/leisure time production, and savings of $1.5-12.2million in the health sector and $2.9-22.9million in production. CONCLUSIONS: Public transport users, walkers, cyclists and those living closer to the city centre were more likely to gain travel-related PA sufficient for health benefits. Both transport mode and urban location were associated with levels of travel-related PA that have significant health and financial impacts. SO WHAT?: Improving population levels of incidental PA may improve health and economic outcomes. This may require changes in urban and transport infrastructure. PMID- 25435099 TI - A chemo-centric view of human health and disease. AB - Efforts to compile the phenotypic effects of drugs and environmental chemicals offer the opportunity to adopt a chemo-centric view of human health that does not require detailed mechanistic information. Here we consider thousands of chemicals and analyse the relationship of their structures with adverse and therapeutic responses. Our study includes molecules related to the aetiology of 934 health threatening conditions and used to treat 835 diseases. We first identify chemical moieties that could be independently associated with each phenotypic effect. Using these fragments, we build accurate predictors for approximately 400 clinical phenotypes, finding many privileged and liable structures. Finally, we connect two diseases if they relate to similar chemical structures. The resulting networks of human conditions are able to predict disease comorbidities, as well as identifying potential drug side effects and opportunities for drug repositioning, and show a remarkable coincidence with clinical observations. PMID- 25435101 TI - ESR spectroscopy for monitoring the photochemical and thermal degradation of conjugated polymers used as electron donor materials in organic bulk heterojunction solar cells. AB - It was shown that ESR spectroscopy is a very useful technique for monitoring the photochemical and thermal degradation of conjugated polymers commonly used in organic solar cells. The relative stability of materials can be quantified by comparing the rates of trap accumulation (dC(R)/dt) estimated from their ESR profiles. PMID- 25435100 TI - Cold ischemia-induced autophagy in rat lung tissue. AB - Autophagy is a highly conserved pathway that permits recycling of nutrients within the cell and is rapidly upregulated during starvation or cell stress. Autophagy has been implicated in the pathophysiological process of warm ischemia reperfusion injury in the rat lung. Cold ischemia (CI) preservation for lung transplantation also exhibits cell stress and nutrient deprivation, however, little is known with regard to the involvement of autophagy in this process. In the present study, CI preservation-induced autophagy and apoptosis was investigated in the lungs of Sprague Dawley rats. Sprague Dawley rat lungs were flushed and preserved at 4C (i.e. CI) for various durations (0, 3, 6, 12 and 24 h). The levels of autophagy, autophagic cell death and apoptosis were measured at each time point following CI. The results revealed that autophagy was induced by CI preservation, which was initiated at 3 h, peaked at 6 h after CI and declined thereafter. Additionally, a coexistence of autophagic cell death and apoptosis was observed in rat lung tissues following prolonged CI. These findings demonstrate that autophagy is involved in the pathophysiological process of lung CI. Furthermore, autophagic cell death in addition to necrosis and apoptosis occurs following CI in the lung. CI preservation may therefore be a potential mechanism of lung injury during organ preservation prior to lung transplantation. PMID- 25435102 TI - Ultrasensitive and fast detection of denaturation of milk by coherent backscattering of light. AB - In this work, Coherence backscattering (CBS) of light has been used to detect the onset of denaturation of milk. The CBS cone shape and its enhancement factor are found to be highly sensitive to the physical state of the milk particles. The onset of denaturing of milk not visible to the naked eye, can be easily detected from changes in the CBS cone shape. The onset of denaturation is confirmed by spectral changes in Raman spectra from these milk samples. Further, the possibility to estimate the dilution of milk by water as an adulterant is demonstrated. The method reported has a broad scope in industry for making an inline ultrafast cost effective sensor for milk quality monitoring during production and before consumption. PMID- 25435103 TI - Tunneling in tocopherol-mediated peroxidation of 7-dehydrocholesterol. AB - The peroxidation of 7-dehydrocholesterol (7-DHC), a biosynthetic precursor to vitamin D3 and cholesterol, has been linked to the pathophysiology of Smith-Lemli Optiz syndrome (SLOS), a devastating human disorder. In SLOS, 7-DHC plasma and tissue levels are elevated because of defects in the enzyme that convert it to cholesterol. alpha-Tocopherol can mediate the peroxidation of 7-DHC under certain circumstances and this prompted us to investigate the kinetic isotope effect (KIE) during this process. Thus, 9,14-d2-7-DHC was synthesized using a photochemical cyclization of deuterium-reinforced previtamin D3 (retro to its biosynthesis). Subsequently, we carried out co-oxidation of 9,14-h2 25,26,26,26,27,27,27-d7- and 9,14-d2-7-DHC in the presence of alpha-tocopherol under conditions that favor TMP. By monitoring the products formed from each precursor using mass spectrometry, the KIE for the hydrogen (deuterium) atom removal at C9 was found to be 21 +/- 1. This large KIE value indicates that tunneling plays a role in the hydrogen atom transfer step in the tocopherol mediated peroxidation of 7-DHC. PMID- 25435105 TI - Punishment for bedwetting is associated with child depression and reduced quality of life. AB - This study assessed the relationship between parental punishment and depression as well as quality of life in children with primary monosymptomatic nocturnal enuresis (PMNE). A consecutive sample of 65 children (7-13 years) with PMNE and 40 healthy children, selected as controls (Group III), were included in the study. The children with PMNE were further sub-classified into two groups: Group I, which included children who received parental punishment for enuresis and Group II, which comprised children who were not punished for bedwetting. Depression and health-related quality of life (HRQL) were assessed among the three groups. The number of wet nights per week was significantly increased in Group I compared with Group II (P<.001). In addition, the severity of depressive symptoms increased in Group I as compared to the other two groups (P<.001). Similarly, the psychosocial HRQL lower in Group compared to the control group (Group III) (P<.001). Prior parental discipline, including corporal punishment (B=0.55, P=.008), as well as the frequency (B=0.73, P<.001) and duration of punishment (B=0.33, P=.02) were strong predictors of increased depressive symptom severity. It was also found that prior punishment (B=-0.42, P=.01) and the frequency (B=-0.62, P<.001) and duration of punishment (B=-0.34, P=.02) were strong predictors for poor psychosocial HRQL. Overall, parental punishment has a poor outcome in children with PMNE. PMID- 25435104 TI - Maternal intimate partner violence exposure, child cortisol reactivity and child asthma. AB - Psychosocial stressors like intimate partner violence (IPV) exposure are associated with increased risk of childhood asthma. Longitudinal studies have not investigated the role of hypothalamic-pituitary-adrenal (HPA) axis reactivity (and associated alterations in cortisol release) in the child IPV exposure-asthma association. We sought to investigate this association, and to assess whether this relationship differs by child HPA reactivity. This secondary analysis used longitudinal cohort data from the Family Life Project. Participants included 1,292 low-income children and mothers; maternal interview and child biomarker data, including maternal report of IPV and child asthma, and child salivary cortisol obtained with validated stress reactivity paradigms, were collected when the child was 7, 15, 24, 35, and 48 months. Using structural equation modeling, maternal IPV when the child was 7 months of age predicted subsequent reports of childhood asthma (B=0.18, p=.002). This association differed according to the child's HPA reactivity status, with IPV exposed children who were HPA reactors at 7 and 15 months of age--defined as a >=10% increase in cortisol level twenty minutes post peak arousal during the challenge tasks and a raw increase of at least .02MUg/dl--being significantly at risk for asthma (7 months: B=0.17, p=.02; 15 months: B=0.17, p=.02). Our findings provide support that children who are physiologically reactive are the most vulnerable to adverse health outcomes when faced with environmental stressors. PMID- 25435106 TI - Avoidant and compulsive sexual behaviors in male and female survivors of childhood sexual abuse. AB - The main objectives of this study were to test a theory-based mediation model in which the relation between childhood sexual abuse (CSA) and dyadic adjustment is mediated through adult sexual avoidance and sexual compulsivity and to examine the gender-invariance of this model. A sample of 686 adults currently involved in a close relationship completed online self-report computerized questionnaires. Prevalence of CSA was 20% in women and 19% in men. In line with our hypotheses, path analyses and structural equation analyses showed that, for both women and men, CSA was associated with more sexual avoidance and sexual compulsivity, which, in turn, predicted lower couple adjustment. Overall, these findings suggest that both avoidant and compulsive sexuality are relevant intervention targets with couples in which one or both partners are CSA survivors. PMID- 25435107 TI - Non-Suicidal Self-Injury--Does social support make a difference? An epidemiological investigation of a Danish national sample. AB - Teenagers and young adults who had experienced child maltreatment, being bullied in school and other serious life events have an increased risk of Non-Suicidal Self-Injury (NSSI), but some individuals manage to escape serious stressful life events. The research question is: does social support make a difference? A national representative sample of 4,718 persons born in 1984 were selected for an interview about their childhood, maltreatment, serious life events and social support in order to test if social support during childhood is a statistical mediator between childhood disadvantages and NSSI. The survey obtained a 67% response rate (N=2,980). The incidence rate of NSSI among this sample was estimated at 2.7% among young adult respondents. Participants with a history of child maltreatment, being bullied in school or other traumatic life events reported a rate of NSSI 6 times greater than participants without this history (odds ratio: 6.0). The correlation between traumatic life events during adolescence and NSSI is reduced when low social support is accounted for in the statistical model (p<0.01). The results indicate that social support is a partial mediator for NSSI. The reported low self-esteem indicates the importance of treating adolescents who are engaged in NSSI with respect and dignity when they are treated in the health care system. Results further imply that increasing social support may reduce the likelihood of NSSI. PMID- 25435108 TI - Evolution of modern treatment of childhood acute leukemia and cancer: adventures and battles in the 1970s and 1980s. AB - This article summarizes the adventures and explorations in the 1970s and 1980s in the treatment of children with leukemia and cancer that paved the way for the current success in childhood cancers. Indeed, these were adventures and bold steps into unchartered waters. Because childhood leukemia the most common of the childhood cancers, success in childhood leukemia was pivotal in the push toward cure of all childhood cancers. The success in childhood leukemia illustrates how treatment programs were designed using clinical- and biology-based risk factors seen in the patients. PMID- 25435110 TI - Supportive care in pediatric oncology: oncologic emergencies and management of fever and neutropenia. AB - Advancements in the care of children with cancer have, in part, been achieved through improvements in supportive care. Situations that require prompt care can occur at the time of presentation as well as during treatment. This article discusses the approach to children with fever and neutropenia, a complication encountered daily by care providers, as well as oncologic emergencies that can be seen at the time of a child's initial diagnosis: hyperleukocytosis, tumor lysis syndrome, superior vena cava syndrome, and spinal cord compression. PMID- 25435109 TI - Genetic and nongenetic risk factors for childhood cancer. AB - The causes of childhood cancer have been systematically studied for decades, but apart from high-dose radiation and prior chemotherapy there are few strong external risk factors. However, inherent risk factors including birth weight, parental age, and congenital anomalies are consistently associated with most types of pediatric cancer. Recently the contribution of common genetic variation to etiology has come into focus through genome-wide association studies. These have highlighted genes not previously implicated in childhood cancers and have suggested that common variation explains a larger proportion of childhood cancers than adult. Rare variation and nonmendelian inheritance may also contribute to childhood cancer risk but have not been widely examined. PMID- 25435111 TI - Biology of childhood acute lymphoblastic leukemia. AB - Giant strides have been made in the management of childhood acute lymphoblastic leukemia (ALL) over previous decades. Extensive collaborative efforts internationally have played a vital role in the remarkable progress made in not only improving therapeutic outcomes but also deciphering the complex biology of childhood ALL. This review summarizes various insights gained from biological studies of childhood ALL, with a focus on recent studies, and also discusses genomic lesions and epigenetic regulatory mechanisms associated with leukemic transformation. The importance of studying the biology of the host so as to understand additional heterogeneity in treatment response and toxicities is highlighted. PMID- 25435113 TI - Pediatric acute myeloid leukemia: biology and therapeutic implications of genomic variants. AB - Acute myeloid leukemia (AML) is a molecularly heterogeneous disease and age associated molecular alterations result in younger children harboring a distinct signature from older children and adolescents. Pediatric AML has a genetic and epigenetic profile with significant differences compared to adult AML. Somatic and epigenetic alterations contribute to myeloid leukemogenesis and can evolve from diagnosis to relapse. Cytogenetic alterations, somatic mutations and response to induction therapy are important in informing risk stratification and appropriate therapy allocation. Next-generation sequencing technologies are providing novel insights into the biology of AML and have the ability to identify potential targets for therapeutic intervention. PMID- 25435112 TI - Treatment of pediatric acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most common pediatric oncologic diagnosis, and advances in its treatment have led to progressive improvements in survival. The 4 main components of therapy are remission induction, consolidation, maintenance, and central nervous system-directed therapy, and usually last 2 to 3 years. Treatment intensity based on risk-based stratification is the cornerstone of treatment. Patients with features of more favorable disease are spared the more toxic effects of chemotherapy, whereas more aggressive regimens are reserved for those with higher-risk disease. Prognosis of relapsed pediatric ALL depends primarily on duration of remission and site of relapse. PMID- 25435114 TI - Juvenile myelomonocytic leukemia. AB - Juvenile myelomonocytic leukemia (JMML), a rare myeloid malignancy that occurs in young children, is considered a clonal disease originating in pluripotent stem cells of the hematopoietic system. The pathogenesis of JMML involves disruption of signal transduction through the RAS pathway, with resultant selective hypersensitivity of JMML cells to granulocyte-macrophage colony-stimulating factor. Progress has been made in understanding aspects of the molecular basis of JMML. How these molecular mechanisms may lead to targeted therapeutics and improved outcomes remains to be elucidated. Allogeneic hematopoietic stem cell transplant is the only curative option for children with JMML, and it is fraught with frequent relapse and significant toxicity. PMID- 25435115 TI - Chronic myeloid leukemia in children: clinical findings, management, and unanswered questions. AB - Chronic myelogenous leukemia (CML) is a rare disease in children. There is little evidence of biological differences between CML in children and adults, although host factors are different. Children develop distinct morbidities related to the off-target effects of tyrosine kinase inhibitors. The goal of treatment in children should be cure rather than suppression of disease, which can be the treatment goal for many older adults. This article reviews data from the literature on the treatment of CML, discusses the issues that are unique to CML in children, and recommends management that takes these issues into consideration. PMID- 25435116 TI - Down syndrome preleukemia and leukemia. AB - Children with Down syndrome (DS) and acute leukemias acute have unique biological, cytogenetic, and intrinsic factors that affect their treatment and outcome. Myeloid leukemia of Down syndrome (ML-DS) is associated with high event free survival (EFS) rates and frequently preceded by a preleukemia condition, the transient abnormal hematopoiesis (TAM) present at birth. For acute lymphoblastic leukemia (ALL), their EFS and overall survival are poorer than non-DS ALL, it is important to enroll them on therapeutic trials, including relapse trials; investigate new agents that could potentially improve their leukemia-free survival; and strive to maximize the supportive care these patients need. PMID- 25435118 TI - Brain tumors. AB - The past 2 decades have witnessed a revolution in the management of childhood brain tumors, with the establishment of multidisciplinary teams and national and international consortiums that led to significant improvements in the outcomes of children with brain tumors. Unprecedented cooperation within the pediatric neuro oncology community and sophisticated rapidly evolving technology have led to advances that are likely to revolutionize treatment strategies and improve outcomes. PMID- 25435119 TI - Sarcomas. AB - Malignant bone tumors (osteosarcoma, Ewing sarcoma) and soft-tissue sarcomas (rhabdomyosarcoma, nonrhabdomyosarcoma) account for approximately 14% of childhood malignancies. Successful treatment of patients with sarcoma depends on a multidisciplinary approach to therapy, including oncology, surgery, radiation oncology, radiology, pathology, and physiatry. By combining systemic treatment with chemotherapy and primary tumor control using surgery and/or radiation, survival rates for localized disease range from 70% to 75%. However, children with metastatic or recurrent disease continue to have dismal outcomes. A better understanding of the biology underlying both bone and soft-tissue sarcomas is required to further improve outcomes for children with these tumors. PMID- 25435117 TI - Pediatric lymphomas and histiocytic disorders of childhood. AB - Although there have been dramatic improvements in the treatment of children with non-hodgkin lymphoma, hodgkin lymphoma and histiocytic disorders over the past 3 decades, many still relapse or are refractory to primary therapy. In addition, late effects such as 2nd malignancies, cardiomyopathy and infertility remain a major concern. Thus, this review focuses on the current state of the science and, in particular, novel treatment strategies that are aimed at improving outcomes for all pediatric patients with lymphoma and histiocytic disorders while reducing treatment related morbidity. PMID- 25435120 TI - Retinoblastoma. AB - Retinoblastoma is the most common neoplasm of the eye in childhood, and represents 3% of all childhood malignancies. Retinoblastoma is a cancer of the very young; two-thirds are diagnosed before 2 years of age and 95% before 5 years. Retinoblastoma presents in 2 distinct clinical forms: (1) a bilateral or multifocal, heritable form (25% of all cases), characterized by the presence of germline mutations of the RB1 gene; and (2) a unilateral or unifocal form (75% of all cases), 90% of which are nonhereditary. The treatment of retinoblastoma is multidisciplinary and is designed primarily to save life and preserve vision. PMID- 25435121 TI - Neuroblastoma: paradigm for precision medicine. AB - Neuroblastoma (NB) is the third most common pediatric cancer. Although NB accounts for 7% of pediatric malignancies, it is responsible for more than 10% of childhood cancer-related mortality. Prognosis and treatment are determined by clinical and biological risk factors. Estimated 5-year survival rates for patients with non-high-risk and high-risk NB are more than 90% and less than 50%, respectively. Recent clinical trials have continued to reduce therapy for patients with non-high-risk NB, including the most favorable subsets who are often followed with observation approaches. In contrast, high-risk patients are treated aggressively with chemotherapy, radiation, surgery, and myeloablative and immunotherapies. PMID- 25435122 TI - Hematopoietic cell transplantation and cellular therapeutics in the treatment of childhood malignancies. AB - Hematopoietic cell transplantation (HCT) represents the most common and effective form of immunotherapy for childhood malignancies. The role of the graft-versus leukemia effect in allogeneic HCT has been well established in childhood malignancies, but is also associated with short-term and long-term morbidity. HCT may be ineffective in some settings at obtaining control of the malignancy, and as such, cannot be used as a universal cancer immunotherapy. Novel therapies using dendritic cell vaccinations, tumor-infiltrating lymphocytes, and chimeric antigen receptor T cells are being evaluated as potential adjuvants to HCT. PMID- 25435123 TI - Late effects of childhood cancer and its treatment. AB - Treatment for childhood cancer with chemotherapy, radiation and/or hematopoietic cell transplant can result in adverse sequelae that may not become evident for many years. A clear understanding of the association between therapeutic exposures and specific long-term complications, and an understanding of the magnitude of the burden of morbidity borne by childhood cancer survivors, has led to the development of guidelines to support lifelong risk-based follow up for this population. It is important to develop interventions to reduce the impact of treatment-related late effects on morbidity and mortality and to continue research regarding the etiopathogenesis of therapy-related cancers and other late effects. PMID- 25435126 TI - Childhood leukemia and cancer. Foreword. PMID- 25435127 TI - Childhood leukemia and cancer. Preface. PMID- 25435124 TI - Remaining challenges in childhood cancer and newer targeted therapeutics. AB - Despite the enormously important and gratifying advances in cancer treatment outcomes for children with cancer, cancer remains the biggest cause of death from disease in children. Because the etiology and biology of cancers that occur in children differ dramatically from those that occur in adults, the immediate extrapolation of efficacy and safety of new cancer drugs to childhood cancer indications is not possible. We discuss factors that will play key roles in guiding pediatric oncologists as they select lines of research to pursue in their quest for more effective treatments for children with cancer. PMID- 25435128 TI - Analysis of adverse events following the treatment of autologous cytokine-induced killer cells for adoptive immunotherapy in malignant tumour sufferers. AB - BACKGROUND: Adoptive immune cell transfer such as cytokine-induced killer (CIK) cells has become an important adjuvant approach in patients with tumours. OBJECTIVES: The aim of this study was to analyse the adverse events (AEs) that occur during the transfusion of autologous CIK cells and to identify the risk factors associated with these AEs. METHODS: Cell infusion-associated AEs were evaluated according to National Cancer Institute Common Terminology Criteria. Analysis was performed from a single-centre data on 893 malignant tumour patients who received a total of 4088 transfusions from March 2008 to October 2013. RESULTS: A total of 215/4088 (5.26%) transfusion cases from 893 patients presented with AEs (Grade 1 - 4); 204/215 (94.88%) were Grade 1 - 2, and 156/215 (72.56%) occurred within 24 h. The most common AEs were fever (0.88%), chills (0.56%) and fatigue (0.49%). The rare but severe AEs included anaphylactoid purpura, tumour lysis syndrome, anaphylactic shock, arthralgia. No transfusion associated death was noticed. The mainly relative risk factors for AEs included transfer cycles and clinical stages. CONCLUSION: This study is a large-sample AEs research, to our knowledge, relative to immune cell transfusion from a single centre data analysis, revealing that autologous CIK cell therapy represents a fairly safe and well-tolerated treatment modality for malignant tumour patients, even rare severe, but not lethal AEs were observed in few patients. PMID- 25435130 TI - Covering all the bases to improve acute stroke care. PMID- 25435129 TI - Thrombolysis and clinical outcome in patients with stroke after implementation of the Tyrol Stroke Pathway: a retrospective observational study. AB - BACKGROUND: Intravenous thrombolysis for ischaemic stroke remains underused worldwide. We aimed to assess whether our statewide comprehensive stroke management programme would improve thrombolysis use and clinical outcome in patients. METHODS: In 2008-09, we designed the Tyrol Stroke Pathway, which provided information campaigns for the public and standardised the entire treatment pathway from stroke onset to outpatient rehabilitation. It was commenced in Tyrol, Austria, as a long-term routine-care programme and aimed to include all patients with stroke in the survey area. We focused on thrombolysis use and outcome in the first full 4 years of implementation (2010-13). FINDINGS: We enrolled 4947 (99%) of 4992 patients with ischaemic stroke who were admitted to hospitals in Tyrol; 675 (14%) of the enrollees were treated with alteplase. Thrombolysis administration in Tyrol increased after programme implementation, from 160 of 1238 patients (12.9%, 95% CI 11.1-14.9) in 2010 to 213 of 1266 patients (16.8%, 14.8-19.0) in 2013 (ptrend 2010-13<0.0001). Differences in use of thrombolysis in the nine counties of Tyrol in 2010 (range, 2.2-22.6%) were reduced by 2013 (12.1-22.5%). Median statewide door-to-needle time decreased from 49 min (IQR 35-60) in 2010 to 44 min (29-60) in 2013; symptomatic post thrombolysis intracerebral haemorrhages occurred in 28 of 675 patients (4.1%, 95% CI 2.8-5.9) during 2010-13. In four Austrian states without similar stroke programmes, thrombolysis administration remained stable or declined between 2010 and 2013 (mean reduction 14.4%, 95% CI 10.9-17.9). Although the 3-month mortality was not affected by our programme (137 [13%] of 1060 patients in 2010 vs 143 [13%] of 1069 patients in 2013), 3-month functional outcome significantly improved (modified Rankin Scale score 0-1 in 375 [40%] of 944 patients in 2010 vs 493 [53%] of 939 in 2013; score 0-2 in 531 [56%] patients in 2010 and 615 [65%] in 2013; ptrend 2010-13<0.0001). INTERPRETATION: During the period of implementation of our comprehensive stroke management programme, thrombolysis administration increased and clinical outcome significantly improved, although mortality did not change. We hope that these results will guide health authorities and stroke physicians elsewhere when implementing similar programmes for patients with stroke. FUNDING: Reformpool of the Tyrolean Health Care Fund. PMID- 25435131 TI - Comprehensive classification test of scapular dyskinesis: A reliability study. AB - BACKGROUND: Assessment of scapular dyskinesis (SD) is of clinical interest, as SD is believed to be related to shoulder pathology. However, no clinical assessment with sufficient reliability to identify SD and provide treatment strategies is available. OBJECTIVES: The purpose of this study was to investigate the reliability of the comprehensive SD classification method. DESIGN: Cross sectional reliability study. METHOD: Sixty subjects with unilateral shoulder pain were evaluated by two independent physiotherapists with a visual-based palpation method. SD was classified as single abnormal scapular pattern [inferior angle (pattern I), medial border (pattern II), superior border of scapula prominence or abnormal scapulohumeral rhythm (pattern III)], a mixture of the above abnormal scapular patterns, or normal pattern (pattern IV). The assessment of SD was evaluated as subjects performed bilateral arm raising/lowering movements with a weighted load in the scapular plane. Percentage of agreement and kappa coefficients were calculated to determine reliability. RESULTS: Agreement between the 2 independent physiotherapists was 83% (50/60, 6 subjects as pattern III and 44 subjects as pattern IV) in the raising phase and 68% (41/60, 5 subjects as pattern I, 12 subjects as pattern II, 12 subjects as pattern IV, 12 subjects as mixed patterns I and II) in the lowering phase. The kappa coefficients were 0.49 0.64. CONCLUSIONS: We concluded that the visual-based palpation classification method for SD had moderate to substantial inter-rater reliability. The appearance of different types of SD was more pronounced in the lowering phase than in the raising phase of arm movements. PMID- 25435132 TI - Nanocasting hierarchical carbide-derived carbons in nanostructured opal assemblies for high-performance cathodes in lithium-sulfur batteries. AB - Silica nanospheres are used as templates for the generation of carbide-derived carbons with monodisperse spherical mesopores (d=20-40 nm) and microporous walls. The nanocasting approach with a polycarbosilane precursor and subsequent pyrolysis, followed by silica template removal and chlorine treatment, results in carbide-derived carbons DUT-86 (DUT=Dresden University of Technology) with remarkable textural characteristics, monodisperse, spherical mesopores tunable in diameter, and very high pore volumes up to 5.0 cm3 g(-1). Morphology replication allows these nanopores to be arranged in a nanostructured inverse opal-like structure. Specific surface areas are very high (2450 m2 g(-1)) due to the simultaneous presence of micropores. Testing DUT-86 samples as cathode materials in Li-S batteries reveals excellent performance, and tailoring of the pore size allows optimization of cell performance, especially the active center accessibility and sulfur utilization. The outstanding pore volumes allow sulfur loadings of 80 wt %, a value seldom achieved in composite cathodes, and initial capacities of 1165 mAh gsulfur(-1) are reached. After 100 cycle capacities of 860 mAh gsulfur(-1) are retained, rendering DUT-86 a high-performance sulfur host material. PMID- 25435133 TI - Utilisation of a Helicopter Emergency Medical Service (HEMS) for equestrian accidents in a regional major trauma network in the United Kingdom. AB - INTRODUCTION: The utilisation of Helicopter Emergency Medical Services (HEMS) in response to equestrian accidents has been an integral part of operations for many years throughout the UK. The recent establishment of major trauma networks in the UK has placed great emphasis on the appropriate tasking of HEMS units to cases where added benefit can be provided and the incidence of time critical injury in cases of equestrian accidents has been shown to be low. This study assesses the impact made on the utilisation of the different HEMS resources for cases of equestrian accidents within the West Midlands following the launch of the regional trauma network. METHODS: We present a retrospective analysis of all equestrian accidents attended by Midlands Air Ambulance (MAA) between 1 April 2012 and 1 April 2013. Data were abstracted from the MAA operational database relating to mission activations/scene attendances; team configuration (physician led and Critical Care Paramedic (CCP) led); on-scene interventions; mission timings and patient conveyance by helicopter. RESULTS: A total of 114 activations involved equestrian accidents (6% of overall workload). The contribution of equestrian accidents to overall workload was similar for physician led and CCP led (69/1069) platforms (5% vs. 6%, p=0.50). Only three patients (3%) required pre-hospital RSI during the period analysed and there were no recorded cases of ketamine administration for analgesia/conscious sedation. In approximately half of all scene attendances patients did not require any medication to be administered by the HEMS team. The vast majority of incidents occurred in rural locations with over 80% of patients conveyed to hospital by helicopter. The average mission time for scene attendances resulting in conveyance by helicopter was in excess of 90 min on both types of platform. CONCLUSIONS: There is a clear requirement for the design and implementation of informed and intelligent tasking models to respond to the need for assistance in equestrian accidents. Such models may include preferential deployment of non-physician led HEMS resources to equestrian accidents or the utilisation of other local or regional resources, such as those with specially adapted vehicles with off road capability, to offer alternative solutions to access/egress challenges posed in such cases. PMID- 25435134 TI - A preliminary RCT of a mind body skills based intervention addressing mood and coping strategies in patients with acute orthopaedic trauma. AB - OBJECTIVE: To test the acceptability and feasibility of a mind body skills-based intervention (RRCB) and estimate its preliminary effect in reducing disability and pain intensity as compared to standard care (SC) in patients with acute musculoskeletal trauma. DESIGN: Randomised controlled trial. SETTING: Level I trauma centre. PATIENTS: Adult patients with acute fractures at risk for chronic pain and disability based on scores on two coping with pain measures who presented to an orthopedic trauma center and met inclusion and exclusion criteria. INTERVENTION: Participants were randomied to either RRCB with SC or SC alone. MAIN OUTCOME MEASUREMENT: Disability (short musculoskeletal functional assessment, SMFA) and pain (Numerical Analogue Scale). SECONDARY OUTCOME MEASURES: coping strategies (Pain Catastrophizing Scale, PCS and Pain Anxiety Scale, PAS) and mood (CESD Depression and PTSD checklist). RESULTS: Among the 50 patients consented, two did not complete the initial assessment. Of these, the first four received the intervention as part of an open pilot and the next 44 were randomised (24 RRCBT and 20 UC) and completed initial assessment. We combined the patients who received RRCB into one group, N=28. Of the entire sample, 34 completed time two assessments (24 RRCBT and 10 SC). The RRCB proved to be feasible and accepted (86% retention, 28 out of 24 completers). Analyses of covariance ANCOVA showed a significant (p<05) improvement and large effect sizes for all time two main study variables (.2-.5) except pain with activity where the effect size was medium (.08). Improvement for pain at rest was not significantly higher in the RRCB as compared to the control, for a small effect size (.03). CONCLUSION: The RRCB is feasible, acceptable and potentially efficacious. LEVEL OF EVIDENCE: Level 1 prognostic. PMID- 25435135 TI - Solving the etiology of dental caries. AB - For decades, the sugar-fermenting, acidogenic species Streptococcus mutans has been considered the main causative agent of dental caries and most diagnostic and therapeutic strategies have been targeted toward this microorganism. However, recent DNA- and RNA-based studies from carious lesions have uncovered an extraordinarily diverse ecosystem where S. mutans accounts only a tiny fraction of the bacterial community. This supports the concept that consortia formed by multiple microorganisms act collectively, probably synergistically, to initiate and expand the cavity. Thus, antimicrobial therapies are not expected to be effective in the treatment of caries and other polymicrobial diseases that do not follow classical Koch's postulates. PMID- 25435136 TI - Why doesn't Mycobacterium tuberculosis spread in animals? PMID- 25435137 TI - A computational algorithm to predict shRNA potency. AB - The strength of conclusions drawn from RNAi-based studies is heavily influenced by the quality of tools used to elicit knockdown. Prior studies have developed algorithms to design siRNAs. However, to date, no established method has emerged to identify effective shRNAs, which have lower intracellular abundance than transfected siRNAs and undergo additional processing steps. We recently developed a multiplexed assay for identifying potent shRNAs and used this method to generate ~250,000 shRNA efficacy data points. Using these data, we developed shERWOOD, an algorithm capable of predicting, for any shRNA, the likelihood that it will elicit potent target knockdown. Combined with additional shRNA design strategies, shERWOOD allows the ab initio identification of potent shRNAs that specifically target the majority of each gene's multiple transcripts. We validated the performance of our shRNA designs using several orthogonal strategies and constructed genome-wide collections of shRNAs for humans and mice based on our approach. PMID- 25435139 TI - Cytokine-induced GAPDH sulfhydration affects PSD95 degradation and memory. AB - Induction of a proinflammatory cytokine, interleukin-1beta (IL-1beta) plays a role in memory impairment associated with various neurological disorders and brain injury. Here we show that IL-1beta-induced memory impairment in brain is mediated by hydrogen sulfide (H2S) synthesized by cystathionine beta-synthase (CBS). H2S modifies GAPDH essentially via sulfhydration in dendrites, which promotes its binding to the E3 ligase protein, Siah. Then Siah binds to a critical synaptic scaffolding molecule, PSD95, and leads it to degradation via ubiquitination. In CBS heterozygous mice (cbs(+/-)) and primary neurons depleted with either CBS or IL-1R, IL-1beta-induced loss of PSD95 was rescued along with a decrease in the level of GAPDH sulfhydration. Moreover, decrease in the loss of PSD95 in cbs(+/-) mice results in improvement of IL-1beta-induced cognitive deficits and neurobehavioral outcomes. Thus, our findings reveal a mechanism where GAPDH sulfhydration appears to be a physiologic determinant of cytokine induced memory impairment in brain. PMID- 25435141 TI - Bowel function and lower urinary tract symptoms in males with low anorectal malformations: an update of controlled, long-term outcomes. AB - PURPOSE: This study aimed to define the controlled outcomes into adulthood for bowel function and lower urinary tract symptoms (LUTS) for males treated for low ARMs with individualized, minimally invasive approaches that preserve the native continence mechanisms as far as possible. METHODS: This is a single-institution, cross-sectional study. All males treated for low ARMs with cutback anoplasty, incision of anocutaneous membrane or dilatations based on the exact type of each malformation between 1983 and 2006 were invited to answer a detailed questionnaire on bowel function and LUTS. Each patient was matched to three controls representing the normal population. Ethical approval was obtained. RESULTS: Amongst 46 respondents (67%; median age 12.3 (5-29) years), overall fecal control was comparable to controls (p = NS). All patients had voluntary bowel movements; 98% of patients and 97% of controls were socially continent (p = NS); 67% of patients and 64% of controls were totally continent (p = NS). Constipation amongst patients (33 vs 3% in controls; p < 0.0001) declined significantly with age. Outcomes by bowel function score were good in 85%, satisfactory in 15% and poor in 0%. Prevalence of LUTS and age at completion of toilet training were comparable to controls (p = NS). CONCLUSIONS: Our results support the adequacy and appropriateness of treating males with low ARMs with individualized, minimally invasive perineal procedures. Long-term functional outcomes comparable to controls are achieved in the majority, provided that constipation is effectively addressed. PMID- 25435138 TI - HCoDES reveals chromosomal DNA end structures with single-nucleotide resolution. AB - The structure of broken DNA ends is a critical determinant of the pathway used for DNA double-strand break (DSB) repair. Here, we develop an approach involving the hairpin capture of DNA end structures (HCoDES), which elucidates chromosomal DNA end structures at single-nucleotide resolution. HCoDES defines structures of physiologic DSBs generated by the RAG endonuclease, as well as those generated by nucleases widely used for genome editing. Analysis of G1 phase cells deficient in H2AX or 53BP1 reveals DNA ends that are frequently resected to form long single stranded overhangs that can be repaired by mutagenic pathways. In addition to 3' overhangs, many of these DNA ends unexpectedly form long 5' single-stranded overhangs. The divergence in DNA end structures resolved by HCoDES suggests that H2AX and 53BP1 may have distinct activities in end protection. Thus, the high resolution end structures obtained by HCoDES identify features of DNA end processing during DSB repair. PMID- 25435140 TI - Transcription-coupled nucleotide excision repair factors promote R-loop-induced genome instability. AB - R-loops, consisting of an RNA-DNA hybrid and displaced single-stranded DNA, are physiological structures that regulate various cellular processes occurring on chromatin. Intriguingly, changes in R-loop dynamics have also been associated with DNA damage accumulation and genome instability; however, the mechanisms underlying R-loop-induced DNA damage remain unknown. Here we demonstrate in human cells that R-loops induced by the absence of diverse RNA processing factors, including the RNA/DNA helicases Aquarius (AQR) and Senataxin (SETX), or by the inhibition of topoisomerase I, are actively processed into DNA double-strand breaks (DSBs) by the nucleotide excision repair endonucleases XPF and XPG. Surprisingly, DSB formation requires the transcription-coupled nucleotide excision repair (TC-NER) factor Cockayne syndrome group B (CSB), but not the global genome repair protein XPC. These findings reveal an unexpected and potentially deleterious role for TC-NER factors in driving R-loop-induced DNA damage and genome instability. PMID- 25435142 TI - Rectal adenocarcinoma in prolapsed rectal stump following Hartmann's procedure. PMID- 25435143 TI - Erratum to "15-Deoxy-gamma12,14-prostaglandin J2 Reduces Liver Impairment in a Model of ConA-Induced Acute Hepatic Inflammation by Activation of PPARgamma and Reduction in NF-kappaB Activity". AB - [This corrects the article DOI: 10.1155/2014/215631.]. PMID- 25435144 TI - Angry pathogens, how to get rid of them: introducing microfluidics for waterborne pathogen separation to children. AB - The purpose of this paper is to present a new approach for introducing to a non scientific audience a major public health issue: access to safe drinking water. Access to safe drinking water is a privilege in developed countries and an urgent need in the third world, which implies always more efficient and reliable engineering tools to be developed. As a major global challenge it is important to make children aware of this problem for understanding (i) what safe drinking water is, (ii) how ingenious techniques are developed for this purpose and (iii) the role of microfluidics in this area. This paper focuses on different microfluidic-based techniques to separate and detect pathogens in drinking water that have been adapted to be performed by a young audience in a simplified, recreational and interactive way. PMID- 25435145 TI - 2-Substituted Ngamma-glutamylanilides as novel probes of ASCT2 with improved potency. AB - Herein, we report the discovery and structure-activity relationships (SAR) of 2 substituted glutamylanilides as novel probes of the steric environment comprising the amino acid binding domain of alanine-serine-cysteine transporter subtype 2 (ASCT2). Focused library development led to three novel, highly potent ASCT2 inhibitors, with N-(2-(morpholinomethyl)phenyl)-L-glutamine exhibiting the greatest potency in a live-cell glutamine uptake assay. This level of potency represents a three-fold improvement over the most potent, previously reported inhibitor in this series, GPNA. Furthermore, this and other compounds in the series exhibit tractable chemical properties for further development as potential therapeutic leads. PMID- 25435146 TI - A potent antimicrobial compound isolated from Clathria cervicornis. AB - The sponge of Clathria cervicornis is commonly used in traditional medicine. This study aims to identify the active compound in C. cervicornis and to evaluate its antimicrobial activity. The purified active compound was determined to be crambescidin 800 and was found to be highly active against Acinetobacter baumannii (minimal inhibitory concentration, MIC=2 MUg/ml), Klebsiella pneumoniae (MIC=1 MUg/ml) and Pseudomonas aeruginosa (MIC=1 MUg/ml). A potent antimicrobial compound, crambescidin 800, was isolated in Clathria cervicornis. It is extremely active against three common pathogenic bacteria. PMID- 25435147 TI - N-Aryl azacycles as novel sodium channel blockers. AB - We have identified a new series of N-aryl azacycles as sodium channel blockers, which showed good potency on Nav1.7 in FLIPR-based and electrophysiological functional assays. Analogs from this series possessed selectivity over hERG, reasonable oral exposure in rat PK studies and are predicted to have limited CNS penetration. PMID- 25435148 TI - One-pot multicomponent synthesis of indole incorporated thiazolylcoumarins and their antibacterial, anticancer and DNA cleavage studies. AB - A series of indole incorporated thiazolylcoumarins (7a-q) have been synthesized and evaluated for their antibacterial, anticancer and DNA cleavage studies. Analysis of antibacterial studies indicated that all the synthesized compounds possess promising activity towards the screened bacterial strains. In vitro anticancerous action was studied for compound 7a (NSC: 768621/1) against the full panel of 60 human tumor cell lines. The five dose level activity results revealed that, the compound 7a was active against all the cell lines among them it has shown potent activity against Leukemia: CCRF-CEM (GI50: 0.33 MUM), Non-Small Cell Lung Cancer: NCI-H522 (GI50: 1.03 MUM), Colon Cancer: HCT-116 (GI50: 1.60 MUM), CNS Cancer: SF-539 (GI50: 1.58 MUM), Melanoma MALME-3M (GI50: 1.59 MUM), Ovarian Cancer: OVCAR-3 (GI50: 1.16 MUM), Renal Cancer: UO-31 (GI50: 0.76 MUM), Prostate Cancer: PC-3 (GI50: 0.82 MUM) and Breast Cancer: BT-549 (GI50: 1.13 MUM). DNA cleavage studies revealed that even at 50 MUg/mL concentration complete DNA digestion was observed for all the compounds, except for compound (7o) where partial DNA digestion was observed even at 100 MUg/mL. PMID- 25435149 TI - Facile and diastereoselective synthesis of 3,2'-spiropyrrolidine-oxindoles derivatives, their molecular docking and antiproliferative activities. AB - In the present study, a series of novel highly functionalized spiropyrrolidine oxindoles have been synthesized through 1,3-dipolar cycloaddition of an azomethine ylide formed from isatin and various amino acids such as sarcosine, proline and thioproline with the dipolarophile (E)-3-(1,3-diphenyl-1H-pyrazol-4 yl)-2-(1H-indole-3-carbonyl)acrylonitrile under optimized conditions. All the synthesized compounds were evaluated for their antimicrobial activity and shown significant activity. PMID- 25435150 TI - Discovery and SAR of muscarinic receptor subtype 1 (M1) allosteric activators from a molecular libraries high throughput screen. Part 1: 2,5-dibenzyl-2H pyrazolo[4,3-c]quinolin-3(5H)-ones as positive allosteric modulators. AB - Results from a 2012 high-throughput screen of the NIH Molecular Libraries Small Molecule Repository (MLSMR) against the human muscarinic receptor subtype 1 (M1) for positive allosteric modulators is reported. A content-rich screen utilizing an intracellular calcium mobilization triple-addition protocol allowed for assessment of all three modes of pharmacology at M1, including agonist, positive allosteric modulator, and antagonist activities in a single screening platform. We disclose a dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-one hit (DBPQ, CID 915409) and examine N-benzyl pharmacophore/SAR relationships versus previously reported quinolin-3(5H)-ones and isatins, including ML137. SAR and consideration of recently reported crystal structures, homology modeling, and structure function relationships using point mutations suggests a shared binding mode orientation at the putative common allosteric binding site directed by the pendant N-benzyl substructure. PMID- 25435151 TI - Liver X receptor (LXR) partial agonists: biaryl pyrazoles and imidazoles displaying a preference for LXRbeta. AB - A series of biaryl pyrazole and imidazole Liver X Receptor (LXR) partial agonists has been synthesized displaying LXRbeta selectivity. The LXRbeta selective partial agonist 18 was identified with potent induction of ATP binding transporters ABCA1 and ABCG1 in human whole blood (EC50=1.2MUM, 55% efficacy). In mice 18 displayed peripheral induction of ABCA1 at 3 and 10mpk doses with no significant elevation of plasma or hepatic triglycerides at these doses, showing an improved profile compared to a full pan-agonist. PMID- 25435152 TI - New trisubstituted 1,2,4-triazoles as ghrelin receptor antagonists. AB - Ghrelin receptor ligands based on a trisubstituted 1,2,4-triazole scaffold were recently synthesized and evaluated for their in vitro affinity for the GHS-R1a receptor and their biological activity. In this study, replacement of the alpha aminoisobutyryl (Aib) moiety (a common feature present in numerous growth hormone secretagogues described in the literature) by aromatic and heteroaromatic groups was explored. We found potent antagonists incorporating the picolinic moiety in place of the Aib moiety. In an attempt to increase affinity and activity of our lead compound 2, we explored the modulation of the pyridine ring. Herein we report the design and the structure-activity relationships study of these new ghrelin receptor ligands. PMID- 25435153 TI - Astragalus and Paeoniae Radix Rubra extract (APE) inhibits hepatic stellate cell activation by modulating transforming growth factor-beta/Smad pathway. AB - Previous studies have shown that Astragalus and Paeoniae Radix Rubra extract (APE) is capable of protecting against liver fibrosis in rats. The hypothesis of the present study was that APE exerts its anti-fibrotic effect by mediating the transforming growth factor beta (TGF-beta)/Smad signaling pathway. In order to investigate this hypothesis, a series of assays were designed to detect the effects of APE on cell proliferation, cell invasion and the activation of hepatic stellate cells (HSCs). In addition, the effects of APE on the TGF-beta/Smad signaling pathway were explored, with the aim of elucidating the underlying mechanisms. HSCs were initially isolated from normal rat liver. A number of assays were then employed in order to evaluate the effects of APE on the function of these cells. Cell proliferation was investigated using an MTT assay and cell invasion was observed with the use of transwell invasion chambers. Collagen synthesis was measured with a 3H-proline incorporation assay and expression of alpha-smooth muscle actin was used to determine the extent of HSC activation. Protein expression induced by TGF-beta1 in HSCs was investigated by western blot and immunofluorescence analyses. Plasminogen activator inhibitor type1 (PAI-1) and urokinase-type plasminogen activator (uPA) transcriptional activity was measured using reverse transcription polymerase chain reaction. The results demonstrated that APE (5-80 ug/ml) significantly inhibited fetal bovine serum induced cell proliferation in a dose-dependent manner. Cell invasion and activation of HSCs induced by TGF-beta1 were disrupted by treatment with APE in a dose-dependent manner. TGF-beta1 was observed to increase the phosphorylation of Smad2/3, while APE administered at higher doses produced inhibitory effects on Smad2/3 phosphorylation. In addition, administration of APE abrogated the TGF beta1-induced reduction in Smad-7 expression in a dose-dependent manner. The results further indicated that APE treatment not only reduced PAI-1 expression, but also increased uPA expression in a dose-dependent manner. In conclusion, APE exerted inhibitory effects on cell proliferation, invasion and activation of HSCs, and the mechanisms underlying these effects may involve the TGF-beta1/Smad pathway. PMID- 25435154 TI - Estimating inter-annual diversity of seasonal agricultural area using multi temporal resourcesat data. AB - The present study aims at analysis of spatial and temporal variability in agricultural land cover during 2005-6 and 2011-12 from an ongoing program of annual land use mapping using multidate Advanced Wide Field Sensor (AWiFS) data aboard Resourcesat-1 and 2. About 640-690 multi-temporal AWiFS quadrant data products per year (depending on cloud cover) were co-registered and radiometrically normalized to prepare state (administrative unit) mosaics. An 18 fold classification was adopted in this project. Rule-based techniques along with maximum-likelihood algorithm were employed to deriving land cover information as well as changes within agricultural land cover classes. The agricultural land cover classes include - kharif (June-October), rabi (November-April), zaid (April June), area sown more than once, fallow lands and plantation crops. Mean kappa accuracy of these estimates varied from 0.87 to 0.96 for various classes. Standard error of estimate has been computed for each class annually and the area estimates were corrected using standard error of estimate. The corrected estimates range between 99 and 116 Mha for kharif and 77-91 Mha for rabi. The kharif, rabi and net sown area were aggregated at 10 km * 10 km grid on annual basis for entire India and CV was computed at each grid cell using temporal spatially-aggregated area as input. This spatial variability of agricultural land cover classes was analyzed across meteorological zones, irrigated command areas and administrative boundaries. The results indicate that out of various states/meteorological zones, Punjab was consistently cropped during kharif as well as rabi seasons. Out of all irrigated commands, Tawa irrigated command was consistently cropped during rabi season. PMID- 25435155 TI - Insights into the origin of rare haplogroup C3* Y chromosomes in South America from high-density autosomal SNP genotyping. AB - The colonization of Americas is thought to have occurred 15-20 thousand years ago (Kya), with little or no subsequent migration into South America until the European expansions beginning 0.5 Kya. Recently, however, haplogroup C3* Y chromosomes were discovered in two nearby Native American populations from Ecuador. Since this haplogroup is otherwise nearly absent from the Americas but is common in East Asia, and an archaeological link between Ecuador and Japan is known from 6 Kya, an additional migration 6 Kya was suggested. Here, we have generated high-density autosomal SNP genotypes from the Ecuadorian populations and compared them with genotypes from East Asia and elsewhere to evaluate three hypotheses: a recent migration from Japan, a single pulse of migration from Japan 6 Kya, and no migration after the First Americans. First, using forward-time simulations and an appropriate demographic model, we investigated our power to detect both ancient and recent gene flow at different levels. Second, we analyzed 207,321 single nucleotide polymorphisms from 16 Ecuadorian individuals, comparing them with populations from the HGDP panel using descriptive and formal tests for admixture. Our simulations revealed good power to detect recent admixture, and that >= 5% admixture 6 Kya ago could be detected. However, in the experimental data we saw no evidence of gene flow from Japan to Ecuador. In summary, we can exclude recent migration and probably admixture 6 Kya as the source of the C3* Y chromosomes in Ecuador, and thus suggest that they represent a rare founding lineage lost by drift elsewhere. PMID- 25435156 TI - Expanding X-chromosomal forensic haplotype frequencies database: Italian population data of four linkage groups. AB - Requests for solving complex kinship casework involving at least one female are increasing and in these circumstances the analysis of X-chromosomal STR markers plays a relevant role. Actually, it is well known the superior statistical power of X-STRs compared to autosomal markers in solving relationship when two sisters or half-sisters are involved and none of parents is available, in maternity testing or in cases involving close relatives as alternative putative fathers. In addition, the possibility to amplify more loci simultaneously and the strategy based on the analysis of four linkage groups to obtain the X-haplotype provide a powerful and validated tool. Nevertheless, haplotypes frequency distribution in different populations is still needed for calculation of probabilities in relationship testing. Published haplotype frequencies from German population data are available, but in different caseworks we found unreported X-haplotypes. To enlarge the forensic X-chromosome database, we present haplotype frequencies and other parameter of forensic interest obtained from 200 anonymous DNA samples of unrelated Italian males for the four linkage groups included in the Investigator Argus X-12 kit. From the comparison of the Italian sample haplotype frequencies with other populations, significant genetic distances were found with Asian and African populations, but not with Europeans. Finally, casework examples of complex kinship analysis are presented. PMID- 25435158 TI - Simultaneous control over both molecular order and long-range alignment in films of the donor-acceptor copolymer. AB - Control over both molecular order and long-range alignment order in films of the donor-acceptor copolymer of 3,6-bis(thiophen-2-yl)-N,N'-bis(2-octyl-1-dodecyl) 1,4-dioxo-pyrrolo[3,4-c]pyrrole and thieno[3,2-b]thiophene (PDBT-TT) was demonstrated via off-center spin-coating (OCSC) from its blend solution with polystyrene (PS). It was found that the dichroic ratio (DR) of OCSC blend films was dependent on both the physical process of spin-coating and the effect of PS chains. The highest DR of 2.75 was obtained via OCSC from the blend solution in oDCB at 1500 rpm. Meanwhile, both the intrachain and interchain molecular order were improved in blend films compared with neat ones, which were indicated by the red-shift of the max absorption, enhanced J-aggregation absorption, and smaller pi-pi stacking distance (from 3.77 to 3.70 A). According to the results of the investigation into the macro anisotropy, micro morphology, solution rheology properties, and photophysics features of films, an overall mechanism of simultaneous control over molecular and long-range order of D-A copolymer films was proposed. On the one hand, a larger viscosity and the pseudoplastic nature of the solution tuned by choosing good solvents with high boiling points and adding PS resulted in a better chain disentanglement, better shear transfer, and a slower contact line receding velocity to induce an enhanced alignment of chains and thus fibrillar aggregates. Also, the critical contact line receding velocity for alignment dominated by the solvent evaporation rate accounted for the variation of DR with OCSC rates. A vertical phase separation accompanying the formation of aligned fibrils during OCSC was also confirmed due to the friction shear between air and solution surface. On the other hand, the negligible dependence of the blend OCSC film's photophysical and morphological features on the solvent suggested the critical role of PS in determining the better intrachain conjugation in blend films, which was attributed to multiple reasons, like limited phase separation room, a coil-toward conformation promotion, and a high surface energy. Furthermore, the enhanced pi-attraction and smaller steric hindrance induced by improved intrachain conjugation accounted for the smaller pi pi stacking distance in the blend films than that in the neat ones. PMID- 25435157 TI - Non-lamellar lipid liquid crystalline structures at interfaces. AB - The self-assembly of lipids leads to the formation of a rich variety of nano structures, not only restricted to lipid bilayers, but also encompassing non lamellar liquid crystalline structures, such as cubic, hexagonal, and sponge phases. These non-lamellar phases have been increasingly recognized as important for living systems, both in terms of providing compartmentalization and as regulators of biological activity. Consequently, they are of great interest for their potential as delivery systems in pharmaceutical, food and cosmetic applications. The compartmentalizing nature of these phases features mono- or bicontinuous networks of both hydrophilic and hydrophobic domains. To utilize these non-lamellar liquid crystalline structures in biomedical devices for analyses and drug delivery, it is crucial to understand how they interact with and respond to different types of interfaces. Such non-lamellar interfacial layers can be used to entrap functional biomolecules that respond to lipid curvature as well as the confinement. It is also important to understand the structural changes of deposited lipid in relation to the corresponding bulk dispersions. They can be controlled by changing the lipid composition or by introducing components that can alter the curvature or by deposition on nano structured surface, e.g. vertical nano-wire arrays. Progress in the area of liquid crystalline lipid based nanoparticles opens up new possibilities for the preparation of well-defined surface films with well-defined nano-structures. This review will focus on recent progress in the formation of non-lamellar dispersions and their interfacial properties at the solid/liquid and biologically relevant interfaces. PMID- 25435159 TI - Antiadhesive effect of polyurethane foam packing in the guinea pig middle ear. AB - CONCLUSIONS: No significant subepithelial healing differences were found between Gelfoam and polyurethane foam (PUF). However, levels of hyperplasia of the mucosal lining and inflammation were lower with PUF packing. PUF packing is not feasible as a middle ear packing material for abraded mucosa. Further studies are required before clinical application. OBJECTIVE: To date, there have been few reports on the antiadhesive effect of PUF as a middle ear packing. The purpose of this study was to investigate the antiadhesive effect of PUF soaked with saline in an animal model of mucosal trauma. METHODS: Bioresorbable PUF soaked with saline was placed over abraded mucosa in the experimental group (n = 7), and compressed Gelfoam soaked with saline was placed in the control group (n = 7). After measurement of auditory brainstem responses (ABRs), the animals were sacrificed 3 weeks after packing placement for histological observation. RESULTS: The ABR results at postoperative week 3 showed no statistically significant difference between the preoperative and post-packing values. An adhesion pattern with subepithelial thickening was observed in the control group. Adhesion was not observed in the experimental group; however, subepithelial fibrous thickening was noted. PMID- 25435160 TI - Clinical characteristics and outcomes of delayed facial palsy after tympanoplasty. AB - CONCLUSION: Delayed facial palsy after tympanoplasty had no predisposition for gender or side. It seemed that prednisolone alone without antiviral drugs was enough for the treatment of delayed facial palsy after tympanoplasty. OBJECTIVE: To analyze the clinical characteristics and prognosis of delayed facial palsy after tympanoplasty. METHODS: The cases with delayed facial palsy after tympanoplasty treated from January 2005 to January 2014 at our hospital were included in the study, and their clinical characteristics and outcomes were analyzed. RESULTS: The incidence of delayed facial palsy after tympanoplasty was 1.1% (16/1420 cases). Facial palsy occurred between 5 and 14 days (average 7.4 +/ 1.8 days) after surgery. The incidence of delayed facial palsy was not different between males and females (p > 0.05). Also there was no significant difference between left and right side (p > 0.05). All patients were treated by prednisolone alone, and their facial nerve recovered to HB grade I after 3 weeks to 2 months without any sequelae. PMID- 25435161 TI - Can mano-videoendoscopy substitute for videofluorography in evaluation of upper esophageal sphincter function? AB - CONCLUSIONS: Mano-videoendoscopy (MVE), a manometry technique with endoscopic confirmation of the pressure catheter, can supplement the information on upper esophageal sphincter (UES) function, and overcomes the drawbacks of videoendoscopic swallowing study (VESS). OBJECTIVES: This study aimed to investigate the possibility of replacing videofluorographic swallowing study (VFSS) with MVE, as a test to precisely evaluate UES function. METHODS: Data from 52 patients with dysphagia were retrospectively reviewed. All patients underwent both MVE and VFSS for evaluation of dysphagia. The manometry was performed with a transnasally inserted catheter (2.6 mm outer diameter and four pressure sensors) under endoscopic observation. The sensors were kept at the tongue base, upper pyriform sinus, apex of pyriform sinus, and UES. We statistically compared the manometric parameters of UES relaxation with fluorographic UES opening. RESULTS: Fluorographic UES opening was diagnosed as good in 34 patients and poor in 18 patients. The nadir pressure, pressure drop, and pressure rise in the UES had significant correlation on the fluorographic UES opening. Stepwise logistic regression test revealed that pressure drop, the gap between the resting pressure and the nadir of UES pressure, was a robust parameter for predicting fluorographic UES opening, and the cut-off level to anticipate good fluorographic opening was >= 33.5 mmHg (specificity, 0.853; sensitivity, 0.759). PMID- 25435162 TI - A new strategy for development of transducers for middle ear implants. AB - CONCLUSION: The new strategy was efficient in designing and fabricating a new transducer for middle ear implants. The transducer could overcome important limitations (implantability of transducers, functional needs) of practical application of currently existing implants. The strategy uncovers the potential of translational research in this area of audiology. OBJECTIVES: To present an overview of research and development (R&D) strategic aspects and its practical implementation through one example of transducer development based on micro electro-mechanical systems (MEMS) technology. METHODS: (a) Rationale of technology in relation to the anatomical and functional features of the middle ear and implant requirements, (b) description and explanation of the different stages and decision-making process for the R&D of a MEMS transducer based on published pieces with their own experimental methods. RESULTS: This R&D strategy focuses on achieving minute-size transducers by using MEMS technology. The process allows a designing-simulation-testing circle to be accomplished on the bench by special software, before fabrication and in vivo testing. The strategy, consequently, saves animal experiments, empowers the design capabilities and allows the fabrication of customized transducers for special problems. The developed prototypes are in the range of millimetres, fit the requirements of new implants and can be fabricated on a large scale and at low cost. PMID- 25435163 TI - Endonasal flap suture-dacryocystorhinostomy (eFS-DCR): a new surgical technique for nasolacrimal duct obstruction (NLDO). AB - CONCLUSION: Endonasal flap suture-dacryocystorhinostomy (eFS- DCR) is a new and valuable technique for the treatment of nasolacrimal duct obstruction (NLDO). This technique could improve the success rate of endonasal DCR in comparison to external DCR. OBJECTIVE: The standard procedure for NLDO is DCR. DCR can be performed via either an external or endonasal approach. External DCR is now regarded as the gold standard in the treatment of NLDO because of its higher success rate. However, we report a new endonasal surgical technique, eFS-DCR, and assess its efficacy by comparison with the standard endonasal DCR. METHODS: We prospectively investigated a series of 62 consecutive patients with NLDO undergoing endonasal DCR. There were two surgical intervention groups: group 1 (24 patients, 28 sites) undergoing endonasal DCR without eFS; and group 2 (38 patients, 47 sites) undergoing eFS-DCR. Study end points were success rate, the ostium diameter (OD) of the lacrimal sac after DCR, and the duration of stent placement. We compared the two groups on these three points. RESULTS: The success rate was 78.6% (22 of 28 sites) for group 1 (DCR without eFS) and 97.9% (46 of 47 sites) for group 2 (eFS-DCR). The ostium size in patients in group 2 was larger than that in group 1. The median time for the duration of stent placement was 42.5 days for group 1 and 31.5 days for group 2. There was a statistical difference (p < 0.01) in all these parameters between the two groups. PMID- 25435164 TI - Gene co-expression network and function modules in three types of glioma. AB - The aim of the present study was to identify the disease-associated genes and their functions involved in the development of three types of glioma (astrocytoma, glioblastoma and oligodendroglioma) with DNA microarray technology, and to analyze their differences and correlations. First, the gene expression profile GSE4290 was downloaded from the Gene Expression Omnibus database, then the probe-level data were pre-processed and the differentially expressed genes (DEGs) were identified with limma package in R language. Gene functions of the selected DEGs were further analyzed with the Database for Annotation, Visualization and Integrated Discovery. After the co-expression network of DEGs was constructed by Cytoscape, the functional modules were mined and enrichment analysis was performed, and then the similarities and differences between any two types of glioma were compared. A total of 1151 genes between normal and astrocytoma tissues, 684 genes between normal and malignant glioma tissues, and 551 genes between normal and oligodendroglioma tissues were filtered as DEGs, respectively. By constructing co-expression networks of DEGs, a total of 77232, 455 and 987 interactions were involved in the differentially co-expressed networks of astrocytoma, oligodendroglioma and glioblastoma, respectively. The functions of DEGs were consistent with the modules in astrocytoma, glioblastoma and oligodendroglioma, which were mainly enriched in neuron signal transmission, immune responses and synthesis of organic acids, respectively. Model functions of astrocytoma and glioblastoma were similar (mainly related with immune response), while the model functions of oligodendroglioma differed markedly from that of the other two types. The identification of the associations among these three types of glioma has potential clinical utility for improving the diagnosis of different types of glioma in the future. In addition, these results have marked significance in studying the underlying mechanisms, distinguishing between normal and cancer tissues, and examining novel therapeutic strategies for patients with glioma. PMID- 25435165 TI - Thermogelling polymer-platinum(IV) conjugates for long-term delivery of cisplatin. AB - In this study, we suggest a novel strategy of constituting an in situ-formed hydrogel composed of polymer-platinum(IV) conjugate to realize a long-term delivery of cisplatin. A unique conjugate was designed and synthesized by covalent linking of Pt(IV) complex to the hydrophobic end of two methoxyl poly(ethylene glycol)-b-poly(d,l-lactide) (mPEG-PLA) copolymer chains, resulting in the formation of Bi(mPEG-PLA)-Pt(IV). The conjugate could self-assemble into micelles in water, and its concentrated solution exhibited a thermoreversible sol gel transition and formed a semisolid thermogel at body temperature. The incorporation of the cisplatin analogue Pt(IV) prodrug into the conjugate had a significant influence on its thermogelling properties and the conjugate thermogelation was attributed to the micellar aggregation. In vitro release experiments of Pt(IV)-conjugated thermogel showed that the platinum release lasted as long as two months. Furthermore, we demonstrated that the Pt(IV) prodrug was released mainly in the form of micelles and micellar aggregates from the gel depot. Compared with free cisplatin, the formation of conjugate micelles led to the enhanced in vitro cytotoxicity against cancer cells due to the effective accumulation into cells via endocytosis. PMID- 25435166 TI - Reinterpretation of the expected electronic density of states of semiconductor nanowires. AB - One-dimensional semiconductor nanowires hold the promise for various optoelectronic applications since they combine the advantages of quantized in plane energy levels (as in zero-dimensional quantum dots) with a continuous energy spectrum along the growth direction (as in three-dimensional bulk materials). This dual characteristic is reflected in the density of states (DOS), which is thus the key quantity describing the electronic structures of nanowires, central to the analysis of electronic transport and spectroscopy. By comparing the DOS derived from the widely used "standard model", the effective mass approximation (EMA) in single parabolic band mode, with that from direct atomistic pseudopotential theory calculations for GaAs and InAs nanowires, we uncover significant qualitative and quantitative shortcomings of the standard description. In the EMA description the nanowire DOS is rendered as a series of sharply rising peaks having slowly decaying tails, with characteristic peak height and spacing, all being classifiable in the language of atomic orbital momenta 1S, 1P, 1D, etc. Herein we find in the thinner nanowires that the picture changes significantly in that not only does the profile of each DOS peak lose its pronounced asymmetry, with significant changes in peak width, height, and spacing, but also the origin of the high-energy peaks changes fundamentally: below some critical diameter, the region of atomic orbital momentum classified states is occupied by a new set of DOS peaks folded-in from other non-Gamma valleys. We describe explicitly how distinct physical effects beyond the conventional EMA model contribute to these realistic DOS features. These results represent a significant step toward understanding the intriguing electronic structure of nanowires reflecting the coexistence of discrete and continuum states. Experimental examinations of the predicted novel DOS features are called for. PMID- 25435167 TI - [The association of fibromyalgia and systemic lupus erythematosus change the presentation and severity of both diseases?]. AB - INTRODUCTION: The association of fibromyalgia (FM) and systemic lupus erythematosus (SLE) have been investigated, with conflicting results regarding the impact of a condition on the other. OBJECTIVES: To determine the frequency of FM in a sample of patients with SLE treated at the Hospital Complex of Sorocaba (CHS) and the impact of FM in SLE activity and quality of life, as well as of SLE in FM. MATERIAL AND METHODS: Descriptive and correlational study. Patients who met the American College of Rheumatology (ACR) criteria for SLE and/or FM were included. The total sample was divided into three groups: FM/SLE (patients with association of SLE and FM), SLE (SLE patients only) and FM (FM patients only). The following variables were used: Fibromyalgia Impact Questionnaire (FIQ), activity index of SLE (SLEDAI), Indices of Diagnostic Criteria for Fibromyalgia 2010 (SSI end GPI) and SF-36. RESULTS: The prevalence of patients with FM among SLE patients was 12%. FIQ showed no difference between groups, indicating that SLE did not affect the impact caused by FM alone. The presence of FM in SLE patients did not influence the clinical activity of this disease. A strong impact of FM on the quality of life in patients with SLE was observed; the opposite was not observed. CONCLUSIONS: The prevalence of FM observed in SLE patients is 12%. The presence of FM adversely affects the quality of life of patients with SLE. PMID- 25435168 TI - [Analysis of conditions for the diagnosis of rheumatic diseases in primary health care in the city of Sorocaba-SP]. AB - OBJECTIVES: The study had as main goal to define the profile of the attending professional working at the primary healthcare sector in the city of Sorocaba, and to analyze the environment in which this professional is inserted, trying to identify if there are conditions for the care of low-complexity rheumatic diseases and possible reasons that would lead to a high degree of referral to specialists. METHODS: A quantitative study was performed in which physicians of primary health care were invited to answer a questionnaire that addressed personal aspects, besides the technical aspects of four rheumatic diseases: osteoarthritis, gout, fibromyalgia and osteoporosis, which served as the basis for evaluating the care for low-complexity diseases in UBSs. RESULTS: It was observed that the professional is part integral of an organizational system that hinders his/her performance; moreover, certain personal difficulty techniques were realized. Together, these conditions turned out to be the factors that determine a quality of care that falls short of that expected. CONCLUSION: There must be a review of how medical education is offered, in order to seek a more qualified training, focused on the basic needs of the health system, as well as a restructuring of the entire health system in terms of its organization and management, in order to attain a suitable condition for the development of a good medical practice, and thus, for providing a good service to the community. PMID- 25435170 TI - Preparation, characterization and utilization of starch nanoparticles. AB - Starch is one of the most abundant biopolymers in nature and is typically isolated from plants in the form of micro-scale granules. Recent studies reported that nano-scale starch particles could be readily prepared from starch granules, which have unique physical properties. Because starch is environmentally friendly, starch nanoparticles are suggested as one of the promising biomaterials for novel utilization in foods, cosmetics, medicines as well as various composites. An overview of the most up-to-date information regarding the starch nanoparticles including the preparation processes and physicochemical characterization will be presented in this review. Additionally, the prospects and outlooks for the industrial utilization of starch nanoparticles will be discussed. PMID- 25435172 TI - Antibacterial compounds from Salvia adenophora Fernald (Lamiaceae). AB - From the aerial parts of Salvia adenophora Fernald four derivatives of 12-oxo phytodienoic acid (1-4) together with five clerodane diterpenoids (5, 6, 8-10), and one known diterpene (7) have been isolated. Compounds 1-6 and 8-10 are described for the first time. The structures were established by extensive 1D, 2D NMR and HRESI-TOFMS spectroscopic methods. Finally, the absolute configuration has been established by comparing of experimental and quantum chemical calculation of ECD spectra. Despite a total lack of antimicrobial activity of the plant extract, hinting to the existence of antagonistic interactions in the crude material, three oxylipins (2-4) displayed a promising inhibition on Gram-positive multidrug-resistant clinical strains including Staphylococcus aureus, Streptococcus agalactiae and, particularly, Staphylococcus epidermidis, while the compounds 9 and 10 revealed a specific and strain-dependent activity against S. epidermidis. Interestingly, the inhibition provided by these compounds was independent of the resistance patterns of these pathogens to classic antibiotics. No action was reported on Gram-negative strains nor on Candida albicans. These results confirm that clerodanes and, particularly, prostaglandin-like compounds can be considered as interesting antimicrobial agents deserving further study. PMID- 25435171 TI - c-di-AMP recognition by Staphylococcus aureus PstA. AB - Cyclic-di-AMP (c-di-AMP) is a bacterial secondary messenger involved in various processes, including sensing of DNA-integrity, cell wall metabolism and potassium transport. A number of c-di-AMP receptor proteins have recently been identified in Staphylococcus aureus. One of them - PstA - possesses a ferredoxin-like fold and is structurally related to the class of PII signal-transduction proteins. PII proteins are involved in a large number of pathways, most of them associated with nitrogen metabolism. In this study we describe the mode of c-di-AMP binding and subsequent structural changes of S. aureus PstA. An altered architecture in PstA compared to canonical PII proteins results in differences in ligand coordination. PMID- 25435173 TI - Failed PCR of Ganoderma type specimens affects nomenclature. AB - The nomenclature of Ganoderma used as a Chinese medicine is debated. A group of researchers could not amplify the DNA of type specimens and concluded the DNA was degraded irreparably. New topotypes were used as the type specimens which was premature. The use of internal amplification controls is recommended to determine if other factors were involved as alternative explanations. PMID- 25435174 TI - Withanolides from three species of the genus Deprea (Solanaceae). Chemotaxonomical considerations. AB - Nine withanolides were isolated from the aerial parts of Deprea bitteriana, Depreacuyacensis, and Depreazamorae. D.bitteriana yielded two withaphysalins, D. cuyacensis gave two 13,14-seco withaphysalins, while D. zamorae yielded five physangulidines. The compounds were fully characterized by a combination of spectroscopic methods (1D and 2D NMR and MS). All compounds isolated from D.bitteriana and D. cuyacensis were obtained as epimeric mixtures at C-18. The structure of physangulidine D was confirmed by X-ray diffraction analysis. The skeletons found in this research support the chemotaxonomical position of the genus Deprea in the tribe Physalideae. PMID- 25435175 TI - Collagenase as a useful tool for the analysis of plant cellular peripheries. AB - A technique for the selective loosening of the cell wall structure and the isolation of proteins permanently knotted in the cell walls was elaborated. Following treatment with collagenase, some proteins, such as calreticulin (CRT) and auxin binding protein 1 (ABP1) were released from purified cell walls, most probably through destruction of respective interacting proteins. The results were confirmed by the immunolocalization of the ABP1 and CRT with confocal and electron microscopy. On the other hand, potential substrates of collagenase, among them annexin 1 have been recognized. Mass spectra of annexin 1 obtained after collagenase digestion and results from analysis of potential cleavage sites suggested that the mechanism of enzyme cleavage might not depend on the amino acid sequence. Summarizing, collagenase was found to be a very useful tool for exploring molecules involved in the functioning of cellular peripheries. PMID- 25435176 TI - Deteriorating patients and time pressures. PMID- 25435178 TI - Disseminated fusariosis. PMID- 25435179 TI - Sirtuin modulators: an updated patent review (2012 - 2014). AB - INTRODUCTION: Since 2000 sirtuins (SIRT1-7) have gained growing attention for their connections with many biological processes such as cellular metabolism regulation, neuroprotection, apoptosis, inflammation, and cancer progression. In particular, SIRT1 has been the most studied isoform, not only for its role during caloric restriction but also as target in prevention of aging-related diseases. SIRT inhibition can be useful for treating cancer, HIV infection or muscular diseases, SIRT activation can exert positive effects in aging-related disorders such as metabolism, cardiovascular, and neurodegenerative diseases. AREAS COVERED: This review includes the patents about sirtuin modulation released during the 2012 - 2014 period, and covers the potential therapeutic uses of known sirtuin modulators as well as new related small molecules in various disease contexts. EXPERT OPINION: The effective role of sirtuins in cancer is still controversial, because some of them seem to have tumor-promoter as well as tumor suppressor properties. Thus, few patents describing SIRT inhibitors have been found in 2012 - 2014 period. Despite the still active debate on their role as direct or indirect activators of SIRT1, sirtuin-activating compounds are actually subjected to intense research for the ability to treat neurodegenerative diseases, metabolic disorders, inflammation, vascular system injuries, wound healing and endothelial dysfunctions. A great number of clinical trials are reported with either SIRT inhibitors or activators, thus it is possible that in the foreseeable future one or more of them will enter in the clinical arena. PMID- 25435177 TI - Genetic characterisation of influenza B viruses detected in Singapore, 2004 to 2009. AB - BACKGROUND: Influenza B viruses are classified into two main lineages: Yamagata like and Victoria-like, which differ antigenically and phylogenetically. To understand the evolution of influenza B viruses in South East Asia as well as to determine the vaccine efficacy, we genetically characterised gene segments 4, 6 and 8 from non-tissue culture adapted influenza B viruses detected in Singapore from 2004 to 2009. METHODS: vRNA were extracted from the nasopharyngeal swabs or nasal washes of SAF servicemen displaying febrile and respiratory symptoms, and subjected to PCR assay to test for the presence of influenza B virus. The PCR positive specimens were next subjected to sequencing of the full gene segments 4 (HA), 6 (NA/NB) and 8 (NS1/NEP). The nucleotide sequences were aligned together with that of other specimens isolated from South East Asia as well as the vaccine strains. Phylogenetic trees of each gene segment were constructed and the amino acid alignments were analysed. RESULTS: A majority of the Singaporean specimens analysed in this study, from 2004-2009, had gene segment 4 from the Victoria-like lineage and gene segment 6 from Yamagata-like lineage. Some of these specimens had both gene segments from the Yamagata lineage and this resulted in several vaccine mismatches. Gene segment 8 from majority of these specimens clustered separately from both the Yamagata and Victoria strains. The HA protein of most of the Singaporean specimens isolated post 2000 contained a glycosylation site at position 211, which was not dominant prior to 2000. No amino acid substitution conferring drug-resistance was found in either the HA or NA proteins. CONCLUSIONS: The presence of both lineages co-circulating post 2000, suggests that a trivalent vaccine is not enough to confer immunity to the general public, strongly endorsing the inclusion of both lineages in the vaccine. Several amino acid substitutions were observed, prompting in depth functional analyses. PMID- 25435181 TI - The unique enzymatic and mechanistic properties of plant myosins. AB - Myosins are molecular motors that move along actin-filament tracks. Plants express two main classes of myosins, myosin VIII and myosin XI. Along with their relatively conserved sequence and functions, plant myosins have acquired some unique features. Myosin VIII has the enzymatic characteristics of a tension sensor and/or a tension generator, similar to functions found in other eukaryotes. Interestingly, class XI plant myosins have gained a novel function that consists of propelling the exceptionally rapid cytoplasmic streaming. This specific class includes the fastest known translocating molecular motors, which can reach an extremely high velocity of about 60MUms(-1). However, the enzymatic properties and mechanistic basis for these remarkable manifestations are not yet fully understood. Here we review recent progress in understanding the uniqueness of plant myosins, while emphasizing the unanswered questions. PMID- 25435180 TI - Impact of analytic provenance in genome analysis. AB - BACKGROUND: Many computational methods are available for assembly and annotation of newly sequenced microbial genomes. However, when new genomes are reported in the literature, there is frequently very little critical analysis of choices made during the sequence assembly and gene annotation stages. These choices have a direct impact on the biologically relevant products of a genomic analysis--for instance identification of common and differentiating regions among genomes in a comparison, or identification of enriched gene functional categories in a specific strain. Here, we examine the outcomes of different assembly and analysis steps in typical workflows in a comparison among strains of Vibrio vulnificus. RESULTS: Using six recently sequenced strains of V. vulnificus, we demonstrate the "alternate realities" of comparative genomics, and how they depend on the choice of a robust assembly method and accurate ab initio annotation. We apply several popular assemblers for paired-end Illumina data, and three well-regarded ab initio genefinders. We demonstrate significant differences in detected gene overlap among comparative genomics workflows that depend on these two steps. The divergence between workflows, even those using widely adopted methods, is obvious both at the single genome level and when a comparison is performed. In a typical example where multiple workflows are applied to the strain V. vulnificus CECT 4606, a workflow that uses the Velvet assembler and Glimmer gene finder identifies 3275 gene features, while a workflow that uses the Velvet assembler and the RAST annotation system identifies 5011 gene features. Only 3171 genes are identical between both workflows. When we examine 9 assembly/annotation workflow scenarios as input to a three-way genome comparison, differentiating genes and even differentially represented functional categories change significantly from scenario to scenario. CONCLUSIONS: Inconsistencies in genomic analysis can arise depending on the choices that are made during the assembly and annotation stages. These inconsistencies can have a significant impact on the interpretation of an individual genome's content. The impact is multiplied when comparison of content and function among multiple genomes is the goal. Tracking the analysis history of the data--its analytic provenance--is critical for reproducible analysis of genome data. PMID- 25435182 TI - Evaluation of the coat quality of sustained release pellets by individual pellet dissolution methodology. AB - This study explored the application of 400-DS dissolution apparatus 7 for individual pellet dissolution methodology by a design of experiment approach and compared its capability with that of the USP dissolution apparatus 1 and 2 for differentiating the coat quality of sustained release pellets. Drug loaded pellets were prepared by extrusion-spheronization from powder blends comprising 50%, w/w metformin, 25%, w/w microcrystalline cellulose and 25%, w/w lactose, and then coated with ethyl cellulose to produce sustained release pellets with 8% and 10%, w/w coat weight gains. Various pellet properties were investigated, including cumulative drug release behaviours of ensemble and individual pellets. When USP dissolution apparatus 1 and 2 were used for drug release study of the sustained release pellets prepared, floating and clumping of pellets were observed and confounded the release profiles of the ensemble pellets. Hence, the release profiles obtained did not characterize the actual drug release from individual pellet and the applicability of USP dissolution apparatus 1 and 2 to evaluate the coat quality of sustained release pellets was limited. The cumulative release profile of individual pellet using the 400-DS dissolution apparatus 7 was found to be more precise at distinguishing differences in the applied coat quality. The dip speed and dip interval of the reciprocating holder were critical operational parameters of 400-DS dissolution apparatus 7 that affected the drug release rate of a sustained release pellet during the individual dissolution study. The individual dissolution methodology using the 400-DS dissolution apparatus 7 is a promising technique to evaluate the individual pellet coat quality without the influence of confounding factors such as pellet floating and clumping observed during drug release test with dissolution apparatus 1 and 2, as well as to facilitate the elucidation of the actual drug release mechanism conferred by the applied sustained release coat onto the pellets. PMID- 25435183 TI - Pediatric brain tumor consortium multisite assessment of apparent diffusion coefficient z-axis variation assessed with an ice-water phantom. AB - RATIONALE AND OBJECTIVES: Magnetic resonance diffusion imaging can characterize physiologic characteristics of pediatric brain tumors used to assess therapy response. The purpose of this study was to assess the variability of the apparent diffusion coefficient (ADC) along z-axis of scanners in the multicenter Pediatric Brain Tumor Consortium (PBTC). MATERIALS AND METHODS: Ice-water diffusion phantoms for each PBTC site were distributed with a specific diffusion imaging protocol. The phantom was scanned four successive times to 1) confirm water in the tube reached thermal equilibrium and 2) allow for assessment of intra examination ADC repeatability. ADC profiles across slice positions for each vendor and institution combination were characterized using linear regression modeling with a quadratic fit. RESULTS: Eleven sites collected data with a high degree of compliance to the diffusion protocol for each scanner. The mean ADC value at slice position zero for vendor A was 1.123 * 10(-3) mm(2)/s, vendor B was 1.0964 * 10(-3) mm(2)/s, and vendor C was 1.110 * 10(-3) mm(2)/s. The percentage coefficient of variation across all sites was 0.309% (standard deviation = 0.322). The ADC values conformed well to a second-order polynomial along the z-axis, (ie, following a linear model pattern with quadratic fit) for vendor-institution combinations and across vendor-institution combinations as shown in the longitudinal model. CONCLUSIONS: Assessment of the variability of diffusion metrics is essential for establishing the validity of using these quantitative metrics in multicenter trials. The low variability in ADC values across vendors and institutions and validates the use of ADC as a quantitative tumor marker in pediatric multicenter trials. PMID- 25435184 TI - Fast inner-volume imaging of the lumbar spine with a spatially focused excitation using a 3D-TSE sequence. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to evaluate the feasibility and technical quality of a zoomed three-dimensional (3D) turbo spin echo (TSE) sampling perfection with application optimized contrasts using different flip-angle evolutions (SPACE) sequence of the lumbar spine. MATERIALS AND METHODS: In this prospective feasibility study, nine volunteers underwent a 3 T magnetic resonance examination of the lumbar spine including 1) a conventional 3D T2-weighted (T2w) SPACE sequence with generalized autocalibrating partially parallel acquisition technique acceleration factor 2 and 2) a zoomed 3D T2w SPACE sequence with a reduced field of view (reduction factor 2). Images were evaluated with regard to image sharpness, signal homogeneity, and the presence of artifacts by two experienced radiologists. For quantitative analysis, signal-to-noise ratio (SNR) values were calculated. RESULTS: Image sharpness of anatomic structures was statistically significantly greater with zoomed SPACE (P < .0001), whereas the signal homogeneity was statistically significantly greater with conventional SPACE (cSPACE; P = .0003). There were no statistically significant differences in extent of artifacts. Acquisition times were 8:20 minutes for cSPACE and 6:30 minutes for zoomed SPACE. Readers 1 and 2 selected zSPACE as the preferred sequence in five of nine cases. In two of nine cases, both sequences were rated as equally preferred by both the readers. SNR values were statistically significantly greater with cSPACE. CONCLUSIONS: In comparison to a cSPACE sequences, zoomed SPACE imaging of the lumbar spine provides sharper images in conjunction with a 25% reduction in acquisition time. PMID- 25435185 TI - The influence of mammographic technologists on radiologists' ability to interpret screening mammograms in community practice. AB - RATIONALE AND OBJECTIVES: To determine whether the mammographic technologist has an effect on the radiologists' interpretative performance of screening mammography in community practice. MATERIALS AND METHODS: In this institutional review board-approved retrospective cohort study, we included Carolina Mammography Registry data from 372 radiologists and 356 mammographic technologists from 1994 to 2009 who performed 1,003,276 screening mammograms. Measures of interpretative performance (recall rate, sensitivity, specificity, positive predictive value [PPV1], and cancer detection rate [CDR]) were ascertained prospectively with cancer outcomes collected from the state cancer registry and pathology reports. To determine if the mammographic technologist influenced the radiologists' performance, we used mixed effects logistic regression models, including a radiologist-specific random effect and taking into account the clustering of examinations across women, separately for screen-film mammography (SFM) and full-field digital mammography (FFDM). RESULTS: Of the 356 mammographic technologists included, 343 performed 889,347 SFM examinations, 51 performed 113,929 FFDM examinations, and 38 performed both SFM and FFDM examinations. A total of 4328 cancers were reported for SFM and 564 cancers for FFDM. The technologists had a statistically significant effect on the radiologists' recall rate, sensitivity, specificity, and CDR for both SFM and FFDM (P values <.01). For PPV1, variability by technologist was observed for SFM (P value <.0001) but not for FFDM (P value = .088). CONCLUSIONS: The interpretative performance of radiologists in screening mammography varies substantially by the technologist performing the examination. Additional studies should aim to identify technologist characteristics that may explain this variation. PMID- 25435186 TI - MR imaging near metallic implants using MAVRIC SL: initial clinical experience at 3T. AB - RATIONALE AND OBJECTIVES: To compare the effectiveness of multiacquisition with variable resonance image combination selective (MAVRIC SL) with conventional two dimensional fast spin-echo (2D-FSE) magnetic resonance (MR) techniques at 3T in imaging patients with a variety of metallic implants. MATERIALS AND METHODS: Twenty-one 3T MR studies were obtained in 19 patients with different types of metal implants. Paired MAVRIC SL and 2D-FSE sequences were reviewed by two radiologists and compared for in-plane and through-plane metal artifact, visualization of the bone implant interface and surrounding soft tissues, blurring, and overall image quality using a two-tailed Wilcoxon signed rank test. The area of artifact on paired images was measured and compared using a paired Wilcoxon signed rank test. Changes in patient management resulting from MAVRIC SL imaging were documented. RESULTS: Significantly less in-plane and through-plane artifact was seen with MAVRIC SL, with improved visualization of the bone-implant interface and surrounding soft tissues, and superior overall image quality (P = .0001). Increased blurring was seen with MAVRIC SL (P = .0016). MAVRIC SL significantly decreased the image artifact compared to 2D-FSE (P = .0001). Inclusion of MAVRIC SL to the imaging protocol determined the need for surgery or type of surgery in five patients and ruled out the need for surgery in 13 patients. In three patients, the area of interest was well seen on both MAVRIC SL and 2D-FSE images, so the addition of MAVRIC had no effect on patient management. CONCLUSIONS: Imaging around metal implants with MAVRIC SL at 3T significantly improved image quality and decreased image artifact compared to conventional 2D FSE imaging techniques and directly impacted patient management. PMID- 25435187 TI - Comparison of CT colonography with conventional colonoscopy in patients with ulcerative colitis. AB - RATIONALE AND OBJECTIVE: Patients with ulcerative colitis require recurrent conventional colonoscopy (CC) to define the extent of the disease. Computed tomography (CT) colonography (CTC) can be used as an alternative technique for studying the colon in these patients. The purpose of the study was to compare the findings of CTC to CC in patients with ulcerative colitis. MATERIALS AND METHODS: Twenty patients proven to have ulcerative colitis on biopsy and in clinical remission state were enrolled in the study. They underwent CTC and CC within 1 week of each test. The investigators performing CTC and CC were blinded to the findings of each other. The chi-square test, kappa test, sensitivity, and specificity were used to compare the findings on CTC and CC. In addition, patient acceptance for both the procedures was compared. RESULTS: Sensitivity and specificity on CTC for detecting granular appearance were 81.0% and 73.8%, respectively, and for pseudopolyps were 82.1% and 84.5%, respectively. Good correlation was seen between CTC and CC for detection of granular appearance and pseudopolyps. Loss of haustral folds, wall thickening, pericolonic vascularity, and pericolonic lymph nodes seen on CTC were found to correlate with intraluminal findings seen on CC. Patient acceptance for CTC was better than that for CC. CONCLUSIONS: CTC can be used for evaluating patients with ulcerative colitis who are in remission. PMID- 25435189 TI - Epithelial-mesenchymal transition-associated microRNAs in colorectal cancer and drug-targeted therapies (Review). AB - Colorectal cancer (CRC) is one of the most common malignancies, and the third leading cause of cancer-associated mortality worldwide. Therefore, the identification of effective targets at the early stages of cancer invasion and metastasis, and new tumor markers for early diagnosis and individualized treatment is imperative for CRC. Epithelial-mesenchymal transition (EMT) refers to the phenomenon of the transformation of epithelial cells to mesenchymal cells in specific physiological and/or pathological circumstances. Evidence suggests that EMT plays an important role in in situ infiltration and distant metastasis of many types of cancer, including CRC. Recent findings showed that microRNA expression is important in regulating the EMT process. This review aimed to summarize EMT-associated specific miRNA molecules in CRC, with particular emphasis on clinical targets for effective treatment of this lethal disease. PMID- 25435188 TI - Color vision in attention-deficit/hyperactivity disorder: a pilot visual evoked potential study. AB - BACKGROUND: Individuals with attention-deficit/hyperactivity disorder (ADHD) are reported to manifest visual problems (including ophthalmological and color perception, particularly for blue-yellow stimuli), but findings are inconsistent. Accordingly, this study investigated visual function and color perception in adolescents with ADHD using color Visual Evoked Potentials (cVEP), which provides an objective measure of color perception. METHOD: Thirty-one adolescents (aged 13 18), 16 with a confirmed diagnosis of ADHD, and 15 healthy peers, matched for age, gender, and IQ participated in the study. All underwent an ophthalmological exam, as well as electrophysiological testing color Visual Evoked Potentials (cVEP), which measured the latency and amplitude of the neural P1 response to chromatic (blue-yellow, red-green) and achromatic stimuli. RESULT: No intergroup differences were found in the ophthalmological exam. However, significantly larger P1 amplitude was found for blue and yellow stimuli, but not red/green or achromatic stimuli, in the ADHD group (particularly in the medicated group) compared to controls. CONCLUSION: Larger amplitude in the P1 component for blue yellow in the ADHD group compared to controls may account for the lack of difference in color perception tasks. We speculate that the larger amplitude for blue-yellow stimuli in early sensory processing (P1) might reflect a compensatory strategy for underlying problems including compromised retinal input of s-cones due to hypo-dopaminergic tone. PMID- 25435190 TI - Centipedegrass extract induces apoptosis through the activation of caspases and the downregulation of PI3K/Akt and MAPK phosphorylation in leukemia cells. AB - Acute lymphoblastic leukemia (ALL), which involves the blood and bone marrow, is the most common type of cancer in children younger than 5 years of age. Previous studies have investigated the effects of centipedegrass extract (CGE), which is mainly composed of maysin and its derivatives, and have demonstrated that it has various biological activities, including antioxidant and anti-inflammatory activities, pancreatic lipase inhibitory activity, anti-adipogenic activity and insecticidal activity. To the best of our knowledge, this study is the first to investigate the anticancer effects of CGE in ALL cell lines and to elucidate the mechanisms underlying these effects. Cell viability was measured by thiazolyl blue tetrazolium blue (MTT) assay. Apoptosis, cell cycle progression and mitochondrial membrane potential (?Psim) were determined by flow cytometry. The effects of CGE on the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and mitogen-activated protein kinases (MAPKs) were assessed by immunoblotting. PI3K, MAPK and caspase inhibitors were used to further confirm the molecular mechanisms involved. Our results clearly demonstrated that the proliferation of the ALL cells was significantly inhibited by CGE in a dose-dependent manner. Apoptosis was accompanied by the induction of significant G1 cell cycle arrest. The resulting alteration of the ?Psim increased the activity of caspase-3/7. The induction of apoptosis was enhanced by the combined treatment of CGE with a PI3K inhibitor or an extracellular signal-regulated kinase (ERK) inhibitor, whereas the CGE-induced apoptosis was inhibited in the presence of caspase inhibitors, such as z-VAD-fmk and z-IETD-fmk. Furthermore, CGE inhibited PI3K activity by decreasing the levels of phosphorylated (p-)Akt, p-BAD, and Bcl-2 together with the levels of MAPKs, including p-ERK and p-JNK, but demonstrated no effects on p38 MAPK. Thus, our data suggest that CGE may be a novel natural compound with potential for use as an antitumor agent in ALL. PMID- 25435191 TI - The impact of conventional dietary intake data coding methods on foods typically consumed by low-income African-American and White urban populations. AB - OBJECTIVE: Analysing dietary data to capture how individuals typically consume foods is dependent on the coding variables used. Individual foods consumed simultaneously, like coffee with milk, are given codes to identify these combinations. Our literature review revealed a lack of discussion about using combination codes in analysis. The present study identified foods consumed at mealtimes and by race when combination codes were or were not utilized. DESIGN: Duplicate analysis methods were performed on separate data sets. The original data set consisted of all foods reported; each food was coded as if it was consumed individually. The revised data set was derived from the original data set by first isolating coded foods consumed as individual items from those foods consumed simultaneously and assigning a code to designate a combination. Foods assigned a combination code, like pancakes with syrup, were aggregated and associated with a food group, defined by the major food component (i.e. pancakes), and then appended to the isolated coded foods. SETTING: Healthy Aging in Neighborhoods of Diversity across the Life Span study. SUBJECTS: African American and White adults with two dietary recalls (n 2177). RESULTS: Differences existed in lists of foods most frequently consumed by mealtime and race when comparing results based on original and revised data sets. African Americans reported consumption of sausage/luncheon meat and poultry, while ready-to-eat cereals and cakes/doughnuts/pastries were reported by Whites on recalls. CONCLUSIONS: Use of combination codes provided more accurate representation of how foods were consumed by populations. This information is beneficial when creating interventions and exploring diet-health relationships. PMID- 25435192 TI - Income inequality and Neisseria gonorrhoeae notifications in females: a country level analysis. AB - Background Patterns of population susceptibility to sexually transmissible infections may be influenced by various social determinants of health, however these receive relatively little attention. Income inequality is one such determinant that has been linked to a number of poor health outcomes. The objective of this analysis was to determine whether there is an association between income inequality and Neisseria gonorrhoeae notification rates when measured at the country level. METHODS: Gini coefficients, gonorrhoea notification rates among women, per capita gross domestic product and approximate size of female population were obtained for 11 countries of the OECD. Linear regression was used to measure the association between income inequality and gonorrhoea notification rates, using generalised estimation equations (GEE) to control for the non-independence of repeat measures from particular countries. RESULTS: A total of 36 observations from 11 countries were included. Gini coefficients ranged from 0.21 to 0.38 and gonorrhoea notifications from 0.7 to 153 per 100000 females. Significant associations were found between country-level income inequality and gonorrhoea notification rates among women (b=17.79 (95% CI: 10.64, 24.94, P<0.01). CONCLUSIONS: Significant associations were found, highlighting the importance of acknowledging and accounting for social determinants of sexual health and suggesting that further research in this arena may be fruitful. PMID- 25435193 TI - Body mass index, self-esteem and weight contentment from adolescence to young adulthood and women's risk for sexually transmitted disease. AB - Background Women's risk for sexually transmitted diseases (STDs) were examined in terms of adolescent and young adult weight status, self-esteem trajectories and weight contentment using two waves of a nationally representative dataset. METHODS: Using Waves 1 and 3 of the National Longitudinal Study of Adolescent Health, body mass index (BMI), self-esteem and weight contentment were examined during adolescence and young adulthood to assess the likelihood of STDs among 4000 young adult single women. RESULTS: Change in BMI, specifically weight loss between adolescence and young adulthood, significantly increased women's risk for STDs. Continuously low self-esteem during adolescence and young adulthood significantly increased women's risk for STDs. When women's contentment with their weight decreased from adolescence to young adulthood, women's risk for STDs was greater. Regardless of other variables, Black women were more likely to have an STD. CONCLUSIONS: RESULTS suggest that women's self-perception is important in reducing sexual risk; specifically, patterns of self-esteem, BMI and weight contentment across developmental periods should be a critical focus of research and practice related to adolescent and young adult sexual health. There are many known benefits to fostering self-esteem during adolescence and findings from this study add STD prevention among young women to this list. RESULTS emphasise the needed prevention during adolescence to address self-perspective and self-esteem for the long-term sexual well-being of young women. PMID- 25435194 TI - Comparative performance of the Kalon and HerpeSelect enzyme-linked immunosorbant assays to determine the prevalence of herpes simplex virus type 2 in Papua New Guinea. AB - Background Infection with herpes simplex virus type 2 (HSV-2) is common worldwide and an important risk factor for HIV infection. Aetiological diagnosis of HSV-2 is typically determined with the use of commercially available type-specific enzyme-linked immunosorbent assays (ELISAs). This study aimed to determine the prevalence of HSV-2 among people attending sexual health clinics in the Highlands of Papua New Guinea. The study also aimed to compare the performance of two type specific ELISA assays, the Kalon and HerpeSelect glycoprotein G2 assays, in this context. METHODS: Participants were recruited as part of a longitudinal sexual health study. Participants attended four appointments over a 12-month period and had blood taken for HSV-2 serology at each time point. Both the Kalon and HerpeSelect assays were performed as per manufacturer's instructions. RESULTS: A total of 132 participants were tested for HSV-2 using the Kalon and HerpeSelect ELISAs. HSV-2 prevalence was 52% (95% CI, 43-60) and 61% (95% CI, 52-69) with Kalon and HerpeSelect assays respectively. There was high concordance (87%, ?=0.75, P<0.001, n=115) between the two assays at the manufacturer recommended index value cut-offs. For participants with discordant results at baseline, (n=16), three sero-conversions were observed over the 12-month period when sequential sera was tested. CONCLUSIONS: A high HSV-2 prevalence was observed in this clinic-based population. Our longitudinal data indicate the higher prevalence of HSV-2 detected with the HerpeSelect ELISA was likely due to false positives rather than a higher sensitivity in the early stages of infection. PMID- 25435195 TI - C-reactive protein as a predictor of cardiovascular risk in HIV-infected individuals. AB - Background In some studies HIV infection confers approximately two-fold higher risk of cardiac events compared with the general population. C-reactive protein (CRP) is a well-characterised biomarker of cardiac events in the general population and is also elevated in patients with HIV infection. The aim of this study was to determine the predictive value of CRP for cardiac events in HIV infected individuals. METHODS: We retrospectively analysed CRP levels in stored plasma samples from HIV-infected patients who did or did not experience a coronary event in a case-controlled manner. All CRP measurements were performed using a high-sensitivity assay (hs-CRP). RESULTS: Of the study participants with samples available, we found slightly elevated hs-CRP levels in the cardiac cases (median 3.5, IQR 1.6-14.4, n=23) compared with controls (median 2.6, IQR1.2-8.3, n=49) which were shown to not be statistically significant P=0.20. Analysis of CRP as a binary variable (>=5mgL(-1)) was also not statistically significant (OR: 1.32, 95% CI 0.48-3.63). CONCLUSIONS: CRP levels may indicate elevated risk of future cardiac events, however this must be interpreted with caution due to the generalised elevation of CRP during HIV infection. CRP has no predictive value for atherosclerosis, and further research is required to improve early prediction of cardiovascular disease in HIV infection. PMID- 25435196 TI - Short message service broadcasting to improve the uptake of influenza vaccination in HIV-positive patients at a metropolitan sexual health clinic. AB - A trial of using Short Message Service (SMS) broadcasting at a metropolitan sexual health clinic in 2013 to promote the awareness and uptake of influenza vaccinations in HIV-positive patients resulted in a significant increase in the number of patients contacted (35% vs 81% P<0.0001) and vaccinated by the clinic (26% vs 47% P<0.001) compared with 2012, when individual telephone calls were made to patients. Additional benefits were less staff time used promoting influenza vaccination and the resultant lower staff cost. SMS broadcasting is an efficient and inexpensive method of communicating health messages to large numbers of patients. PMID- 25435197 TI - Lower sexually transmissible infection prevalence among lifetime exclusive women who have sex with women compared with women who have sex with women and men. AB - Background Sexually transmissible infection (STI) history, prevalence and seroprevalence among lifetime exclusive women who have sex with women (WSW) and an age-matched group of women who have sex with women and men (WSWM) was evaluated. METHODS: Participants completed a study questionnaire and had genital specimens and sera collected for STI testing. RESULTS: Twenty-one lifetime exclusive WSW and 42 WSWM were included. WSWM were more likely to report a history of prior STIs and be seropositive for chlamydia and HSV-2. Prevalent STIs were less common among WSW. CONCLUSIONS: While lifetime exclusive WSW are at risk of contracting STIs, WSWM are disproportionally affected. Healthcare providers should consider routine STI screening among WSW. PMID- 25435199 TI - Akt regulates beta-catenin in a rat model of focal cerebral ischemia-reperfusion injury. AB - The present study aimed to investigate the effects of the phosphoinositide 3 kinase (PI3K)/Akt signaling pathway on the Wnt/beta-catenin signaling pathway in rats with focal cerebral ischemia-reperfusion injury. A total of 96 rat focal cerebral ischemia-reperfusion models, established according to a modified version of Longa's method, were randomly divided into four groups: Sham-operated (S), cerebral ischemia-reperfusion injury (I), cerebral ischemia-reperfusion + basic fibroblast growth factor (bFGF) post-processing and, finally, cerebral ischemia reperfusion + bFGF post-processing + PI3K inhibitor LY294002 (LY). Each group consisted of 24 rats and each group was divided into four subgroups according to the indicated reperfusion times of 12, 24, 48 and 72 h. The morphological changes of the cortical tissue and the cellular apoptosis were determined using hematoxylin and eosin staining and the terminal deoxynucleotidyl transferase dUTP nick end labeling method, respectively. The expression levels of phosphorylated (p-)Akt, glycogen synthase kinase-3beta (GSK-3beta) mRNA and beta-catenin in the cortical tissue were detected at different time-points. The number of apoptotic cells and the expression levels of p-Akt, GSK-3beta mRNA and beta-catenin in the I and LY groups were significantly higher compared with those in the S group (P<0.05). In the bFGF group, the number of apoptotic cells and the mRNA expression levels of GSK-3beta were significantly decreased, whereas the expression levels of p-Akt and beta-catenin were significantly increased compared with those in the I and LY groups (P<0.05). In cerebral ischemia-reperfusion injury, the PI3K/Akt signaling pathway regulated beta-catenin, the main member of the Wnt signaling pathway, via GSK-3beta, providing information to assist in further investigation of the mechanism of beta-catenin in ischemia-reperfusion injury. PMID- 25435201 TI - A unifying framework for measuring weighted rich clubs. AB - Network analysis can help uncover meaningful regularities in the organization of complex systems. Among these, rich clubs are a functionally important property of a variety of social, technological and biological networks. Rich clubs emerge when nodes that are somehow prominent or 'rich' (e.g., highly connected) interact preferentially with one another. The identification of rich clubs is non-trivial, especially in weighted networks, and to this end multiple distinct metrics have been proposed. Here we describe a unifying framework for detecting rich clubs which intuitively generalizes various metrics into a single integrated method. This generalization rests upon the explicit incorporation of randomized control networks into the measurement process. We apply this framework to real-life examples, and show that, depending on the selection of randomized controls, different kinds of rich-club structures can be detected, such as topological and weighted rich clubs. PMID- 25435200 TI - Evaluation of small intestine submucosa and poly(caprolactone-co-lactide) conduits for peripheral nerve regeneration. AB - The present study employed nerve guidance conduits (NGCs) only, which were made of small intestine submucosa (SIS) and poly(caprolactone-co-lactide) (PCLA) to promote nerve regeneration in a peripheral nerve injury (PNI) model with nerve defects of 15 mm. The SIS- and PCLA-NGCs were easily prepared by rolling of a SIS sheet and a bioplotter using PCLA, respectively. The prepared SIS- and PCLA-NGCs fulfilled the general requirement for use as artificial peripheral NGCs such as easy fabrication, reproducibility for mass production, suturability, sterilizability, wettability, and proper mechanical properties to resist collapsing when applied to in vivo implantation. The SIS- and PCLA-NGCs appeared to be well integrated into the host sciatic nerve without causing dislocations and serious inflammation. All NGCs stably maintained their NGC shape for 8 weeks without collapsing, which matched well with the nerve regeneration rate. Staining of the NGCs in the longitudinal direction showed that the regenerated nerves grew successfully from the SIS- and PCLA-NGCs through the sciatic nerve-injured gap and connected from the proximal to distal direction along the NGC axis. SIS-NGCs exhibited a higher nerve regeneration rate than PCLA-NGCs. Collectively, our results indicate that SIS- and PCLA-NGCs induced nerve regeneration in a PNI model, a finding that has significant implications in the future with regard to the feasibility of clinical nerve regeneration with SIS- and PCLA-NGCs prepared through an easy fabrication method using promising biomaterials. PMID- 25435202 TI - Sulfide synthesis through copper-catalyzed C-S bond formation under biomolecule compatible conditions. AB - We report here an efficient and mild method for constructing C-S bonds. The reactions were carried out with Na2S2O3 as a sulfurating reagent, CuSO4 as a catalyst, and water as solvent without any surfactant. The products were achieved in moderate to excellent yields at room temperature under air. Notably, this reaction is compatible with various biomolecules including amino acids, oligosaccharides, nucleosides, proteins, and cell lysates. PMID- 25435204 TI - Breakthrough programme turns two. PMID- 25435205 TI - Drug discoverers chart path to tackling data irreproducibility. PMID- 25435203 TI - Securing the future of drug discovery for central nervous system disorders. AB - Innovative partnerships among researchers, patients, regulators, payors and industry are needed to reinvigorate drug discovery for central nervous system disorders. Here, we summarize plans of the Collegium Internationale Neuro Psychopharmacologicum (CINP) to achieve this goal. PMID- 25435209 TI - Deal watch: Genentech dives deeper into the next wave of cancer immunotherapies. PMID- 25435210 TI - Doug williams. PMID- 25435211 TI - Sepsis: PCSK9 blockade helps clear pathogenic lipids. PMID- 25435212 TI - Neurodegenerative disease: New dimensions in Alzheimer's modelling. PMID- 25435213 TI - Cancer: New delivery platform targets antimirs to tumours. PMID- 25435215 TI - Overexpression of circadian clock protein cryptochrome (CRY) 1 alleviates sleep deprivation-induced vascular inflammation in a mouse model. AB - Disturbance of the circadian clock by sleep deprivation has been proposed to be involved in the regulation of inflammation. However, the underlying mechanism of circadian oscillator components in regulating the pro-inflammatory process during sleep deprivation remains poorly understood. Using a sleep deprivation mouse model, we showed here that sleep deprivation increased the expression of pro inflammatory cytokines expression and decreased the expression of cryptochrome 1 (CRY1) in vascular endothelial cells. Furthermore, the adhesion molecules including intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin were elevated in vascular endothelial cells and the monocytes binding to vascular endothelial cells were also increased by sleep deprivation. Interestingly, overexpression of CRY1 in a mouse model by adenovirus vector significantly inhibited the expression of inflammatory cytokines and adhesion molecules, and NF-kappaB signal pathway activation, as well as the binding of monocytes to vascular endothelial cells. Using a luciferase reporter assay, we found that CRY1 could repress the transcriptional activity of nuclear factor (NF) kappaB in vitro. Subsequently, we demonstrated that overexpression of CRY1 inhibited the basal concentration of cyclic adenosine monophosphate (cAMP), leading to decreased protein kinase A activity, which resulted in decreased phosphorylation of p65. Taken together, these results suggested that the overexpression of CRY1 inhibited sleep deprivation-induced vascular inflammation that might be associated with NF-kappaB and cAMP/PKA pathways. PMID- 25435216 TI - Solar ultraviolet radiation and ozone depletion-driven climate change: effects on terrestrial ecosystems. AB - In this assessment we summarise advances in our knowledge of how UV-B radiation (280-315 nm), together with other climate change factors, influence terrestrial organisms and ecosystems. We identify key uncertainties and knowledge gaps that limit our ability to fully evaluate the interactive effects of ozone depletion and climate change on these systems. We also evaluate the biological consequences of the way in which stratospheric ozone depletion has contributed to climate change in the Southern Hemisphere. Since the last assessment, several new findings or insights have emerged or been strengthened. These include: (1) the increasing recognition that UV-B radiation has specific regulatory roles in plant growth and development that in turn can have beneficial consequences for plant productivity via effects on plant hardiness, enhanced plant resistance to herbivores and pathogens, and improved quality of agricultural products with subsequent implications for food security; (2) UV-B radiation together with UV-A (315-400 nm) and visible (400-700 nm) radiation are significant drivers of decomposition of plant litter in globally important arid and semi-arid ecosystems, such as grasslands and deserts. This occurs through the process of photodegradation, which has implications for nutrient cycling and carbon storage, although considerable uncertainty exists in quantifying its regional and global biogeochemical significance; (3) UV radiation can contribute to climate change via its stimulation of volatile organic compounds from plants, plant litter and soils, although the magnitude, rates and spatial patterns of these emissions remain highly uncertain at present. UV-induced release of carbon from plant litter and soils may also contribute to global warming; and (4) depletion of ozone in the Southern Hemisphere modifies climate directly via effects on seasonal weather patterns (precipitation and wind) and these in turn have been linked to changes in the growth of plants across the Southern Hemisphere. Such research has broadened our understanding of the linkages that exist between the effects of ozone depletion, UV-B radiation and climate change on terrestrial ecosystems. PMID- 25435214 TI - Targeting RAS-ERK signalling in cancer: promises and challenges. AB - The RAS-RAF-MEK-ERK signalling pathway is hyperactivated in a high percentage of tumours, most frequently owing to activating mutations of the KRAS, NRAS and BRAF genes. Recently, the use of compounds targeting components of ERK signalling, such as RAF or MEK inhibitors, has led to substantial improvement in clinical outcome in metastatic melanoma and has shown promising clinical activity in additional tumour types. However, response rates are highly variable and the efficacy of these drugs is primarily limited by the development of resistance. Both intrinsic and acquired resistance to RAF and MEK inhibitors are frequently associated with the persistence of ERK signalling in the presence of the drug, implying the need for more innovative approaches to target the pathway. PMID- 25435217 TI - Safety of intravitreal ocriplasmin for focal vitreomacular adhesion in patients with exudative age-related macular degeneration. AB - PURPOSE: The evaluation of the safety and preliminary efficacy of 125 MUg ocriplasmin intravitreal injection in patients with focal vitreomacular adhesion (VMA) and exudative age-related macular degeneration (AMD). DESIGN: Randomized, sham-injection controlled, double-masked, multicenter, phase II trial. PARTICIPANTS: A total of 100 patients with VMA and wet AMD were randomized 3:1 to receive 125 MUg ocriplasmin intravitreal injection or sham injection. METHODS: Study treatment was administered in the mid-vitreous cavity by injection. Post treatment safety and efficacy assessments were made at baseline and on days 7, 14, and 28 and months 3, 6, and 12 after injection. Secondary efficacy end points were exploratory in nature. MAIN OUTCOME MEASURES: The safety and tolerability of ocriplasmin were evaluated. The primary efficacy end point was the proportion of patients with VMA release at day 28 after injection. Secondary end points reported included VMA release over time, total posterior vitreous detachment (PVD), change in visual acuity from baseline, and number of anti-vascular endothelial growth factor (VEGF) injections. RESULTS: The safety of ocriplasmin in patients with VMA and wet AMD was shown to be comparable to the known safety profile, with the majority of adverse events in the study eye occurring in the first 7 days after study treatment. A greater proportion of patients achieved VMA resolution and total PVD at month 12 with ocriplasmin compared with sham treatment. There was a decrease in the number of anti-VEGF injections with ocriplasmin at month 12 compared with the sham group, although no differences in visual acuity were observed. CONCLUSIONS: Ocriplasmin treatment in this population seems to be generally safe and well tolerated and resulted in more patients achieving VMA resolution and PVD with less anti-VEGF use compared with sham treatment. PMID- 25435218 TI - Standard addition flow method for potentiometric measurements at low concentration levels: application to the determination of fluoride in food samples. AB - A standard addition method was implemented by using a flow manifold able to perform automatically multiple standard additions and in-line sample treatment. This analytical strategy was based on the in-line mixing of sample and standard addition solutions, using a merging zone approach. The flow system aimed to exploit the standard addition method to quantify the target analyte particularly in cases where the analyte concentration in the matrix is below the lower limit of linear response of the detector. The feasibility of the proposed flow configuration was assessed through the potentiometric determination of fluoride in sea salts of different origins and different types of coffee infusions. The limit of quantification of the proposed manifold was 5*10(-6) mol L(-1), 10-fold lower than the lower limit of linear response of the potentiometric detector used. A determination rate of 8 samples h(-1) was achieved considering an experimental procedure based on three standard additions per sample. The main advantage of the proposed strategy is the simple approach to perform multiple standard additions, which can be implemented with other ion selective electrodes, especially in cases when the primary ion is below the lower limit of linear response of the detector. PMID- 25435219 TI - Iodine speciation in coastal and inland bathing waters and seaweeds extracts using a sequential injection standard addition flow-batch method. AB - The present work describes the development of a sequential injection standard addition method for iodine speciation in bathing waters and seaweeds extracts without prior sample treatment. Iodine speciation was obtained by assessing the iodide and iodate content, the two inorganic forms of iodine in waters. For the determination of iodide, an iodide ion selective electrode (ISE) was used. The indirect determination of iodate was based on the spectrophotometric determination of nitrite (Griess reaction). For the iodate measurement, a mixing chamber was employed (flow batch approach) to explore the inherent efficient mixing, essential for the indirect determination of iodate. The application of the standard addition method enabled detection limits of 0.14 uM for iodide and 0.02 uM for iodate, together with the direct introduction of the target water samples, coastal and inland bathing waters. The results obtained were in agreement with those obtained by ICP-MS and a colorimetric reference procedure. Recovery tests also confirmed the accuracy of the developed method which was effectively applied to bathing waters and seaweed extracts. PMID- 25435220 TI - Iron speciation by microsequential injection solid phase spectrometry using 3 hydroxy-1(H)-2-methyl-4-pyridinone as chromogenic reagent. AB - The speciation of iron using the newly synthesized 3-hydroxy-1(H)-2-methyl-4 pyridinone by solid phase spectrophotometry in a microsequential injection lab-on valve (uSI-LOV-SPS) methodology is described. Iron was retained in a reusable column, Nitrilotriacetic Acid Superflow (NTA) resin, and the ligand was used as both chromogenic and eluting reagent. This approach, analyte retention and matrix removal, enabled the assessment of iron (III) and total iron content in fresh waters and high salinity coastal waters with direct sample introduction, in the range of 20.0-100 ug/L. with a LOD of 9 ug/L. The overall effluent production was 2 mL, corresponding to the consumption of 0.48 ug of 2-metil-3-hydroxy-4 pyridinone, 0.34 mg of NaHCO3, 16 mg of HNO3, 4.4 ug H2O2 and 400uL of sample. Four reference samples were analyzed and a relative deviation<10% was obtained; furthermore, several bathing waters (?13) were analyzed using the developed method and the results were comparable to those obtained by atomic absorption spectrophotometry (relative deviations<6%). PMID- 25435221 TI - Solenoid micropump-based flow system for generalized calibration strategy. AB - Generalized calibration strategy (GCS) is one of the innovative approaches aimed at verification and improvement of accuracy of analytical determinations. It combines in a single procedure the interpolative and the extrapolative calibration approaches along with stepwise dilution of a sample with the use of a dedicated flow system. In the paper a simple solenoid micropump-based flow system designed for implementation of GCS has been described. The manifold consists of several modules fully operated by a computer and connected with each other in a properly designed network. Its performance and usefulness were tested on determination of calcium by FAAS in synthetic and natural samples containing strong interferents. It was shown how GCS can serve for detection, examination and elimination of the interference effects. It was demonstrated that the designed manifold enabled to perform GCS procedure with very good precision, in short time and with very low standard, sample and reagent consumption. PMID- 25435222 TI - Visual detection and sequential injection determination of aluminium using a cinnamoyl derivative. AB - A cinnamoyl derivative, 3-[4-(dimethylamino)cinnamoyl]-4-hydroxy-6-methyl-3,4-2H pyran-2-one, was used as a ligand for the determination of aluminium. Upon the addition of an acetonitrile solution of the ligand to an aqueous solution containing Al(III) and a buffer solution at pH 8, a marked change in colour from yellow to orange is observed. The colour intensity is proportional to the concentration of Al(III); thus, the 'naked-eye' detection of aluminium is possible. The reaction is also applied for sequential injection determination of aluminium. Beer's law is obeyed in the range from 0.055 to 0.66 mg L(-1) of Al(III). The limit of detection, calculated as three times the standard deviation of the blank test (n=10), was found to be 4 MUg L(-1) for Al(III). The method was applied for the determination of aluminium in spiked water samples and pharmaceutical preparations. PMID- 25435223 TI - Automated procedure for determination of ammonia in concrete with headspace single-drop micro-extraction by stepwise injection spectrophotometric analysis. AB - A novel automatic stepwise injection headspace single-drop micro-extraction system is proposed as a versatile approach for automated determination of volatile compounds. The system application is demonstrated for ammonia determination in concrete samples. An ammonia gas was produced from ammonium ions and extracted on-line into 5 MUL 0.1M H3PO4 to eliminate the interference effect of concrete species on the ammonia stepwise injection spectrophotometric determination. The linear range was 0.1-1 mg kg(-1) with LOD 30 ug kg(-1). The sample throughput was 4 h(-1). This system has been successfully applied for the determination of ammonia in concretes. PMID- 25435224 TI - Determination of polyphenolic compounds in Cirsium palustre (L.) extracts by high performance liquid chromatography with chemiluminescence detection. AB - The first method for the simultaneous determination of polyphenolic antioxidants in extracts from leaves of Cirsium palustre based on high performance liquid chromatography combined with flow injection chemiluminescence detection (HPLC-FI CL) has been developed. The extracts were prepared by using methanol as extraction medium and two types of extraction methods (reflux and ultrasound assisted extraction). The post-column CL determination of polyphenols was based on their enhancing effect on the chemiluminescence intensity generated in manganese(IV)-hexametaphosphate-formaldehyde system in a phosphoric acid medium. Main antioxidants determined in C. palustre leaves were eriodictyol-7-O glucoside, luteolin-7-O-glucoside and 6-hydroxyluteolin-7-O-glucoside belonging to flavonoids, and chlorogenic acid belonging to phenolic acids. Chromatographic separation was carried out on a C18 column with gradient elution by using a mobile phase containing 0.25% (v/v) phosphoric acid in water (solvent A) and 100% methanol (solvent B). Under the optimized conditions of chromatographic separation and CL detection the validation of the method was performed. The calibration curves showed good linearity in the concentration range from 0.5 to 40 ug mL(-1). The HPLC-FI-CL method was successfully applied to the determination of four polyphenolic compounds in methanolic extracts from leaves of C. palustre. The accuracy of the developed method was confirmed by the comparison of the results with those obtained by an HPLC-PDA method. The relative error of determination does not exceed 6.1%. However, the HPLC-FI-CL method is characterized by 40-65 times higher sensitivity compared to the HPLC-PDA method. PMID- 25435225 TI - Sequential injection technique as a tool for the automatic synthesis of silver nanoparticles in a greener way. AB - This paper presents a new way to the synthesis of uniform and size-controlled silver nanoparticles by means of microreaction technology. It complies with the philosophy of green chemistry by developing a process that prevents pollution at source-by automation of the manipulations using microtubes manifolds and with the use of benign reagents and photochemistry to enhance the reaction of synthesis of Ag nanoparticles. Effect of hydrodynamic parameters (reagent volumes and volume flow rate) and concentrations (reducer and stabilizer), temperature, pH and UV irradiation time on morphology and size of nanoparticles was studied. The silver nanoparticles has been characterized by transmission electronic microscopy (TEM), electron diffraction X-ray spectroscopy (EDS), UV-vis spectra analysis, dynamic light scattering (DLS) and zeta potential measurements. Particles are mostly spherical in shape and have average sizes between 7 and 20 nm. The particle size can be controlled by changing not only the flow rate and UV light time exposition but also the reducer/AgNO3 concentration ratio. This is a sustainable and cost saving methodology that guarantees not only reproducible synthesis, but also the changing of NPs characteristics at time by simple control of the fluid transport. PMID- 25435226 TI - Tandem measurements of iron and creatinine by cross injection analysis with application to urine from thalassemic patients. AB - This work presents development of a method for the dual determination of Fe(III) and creatinine using cross injection analysis (CIA). Two CIA platforms connected in series accommodated sample and reagents plugs aspirated via y-direction channels while water was pumped through the x-direction channel toward a flow through cell of a diode array UV-vis. detector. Iron was detected from the colorimetric reaction between Fe(II) and 2-(5-bromo-2-pyridylazo)-5-(N-propyl-N (3-sulfopropyl)amino) aniline (5-Br-PSAA), with prior reduction of Fe(III) to Fe(II) by ascorbic acid. The Jaffe's reaction was employed for the detection of creatinine. Under the optimal conditions, good linearity ranges were achieved for iron in the range 0.5 to 7 mg L(-1) and creatinine in the range 50 to 800 mg L( 1). The CIA system was applied to spot urine samples from thalassemic patients undergoing iron chelation therapy, and was successfully validated with ICP-OES and batchwise Jaffe's method. Normalization of urinary iron excretion with creatinine is useful for correcting the iron concentration between urine samples due to variation of the collected urine volume. PMID- 25435227 TI - Hybrid flow system integrating a miniaturized optoelectronic detector for on-line dynamic fractionation and fluorometric determination of bioaccessible orthophosphate in soils. AB - An integrated Sequential Injection (SI)/Flow Injection (FI) system furnished with a miniaturized LED-based fluorometric detector is presented in this work for expedient bioaccessibility tests of orthophosphate in soils. Equipped with a microcolumn of conical shape containing 50 mg of soil, the hybrid flow system was resorted to on-line dynamic leaching and real-time quantification of pools of mobilizable orthophosphate using a bi-directional syringe pump and multiposition valve. The flexibility of the flow manifold was harnessed to explore both bi directional and uni-directional flow extraction modes with the added degree of freedom of on-line dilution of extracts whenever needed. Bioaccessible orthophosphate was split in three fractions, the so-called NH4Cl fraction containing labile exchangeable phosphates, the alkaline fraction with Fe and Al bound phosphates and the acidic fraction containing Ca-bound phosphates. The prevailing molybdenum blue photometric detection method is replaced by spectrofluorometric detection based on the ion pair formation between the phosphomolybdate heteropolyacid and rhodamine B with the subsequent quenching of the dye fluorescence. The dedicated optoelectronic detector was integrated in a secondary FI manifold and operated according to the fluorometric paired emitter detector diode (FPEDD) principle involving two light emitting diodes as fluorescence inductors and one as detector of LED-induced fluorescence. Demonstrated with the analysis of a standard reference material (SRM 2711) and a real agricultural soil, the developed FI/SI fractionation system with FPEDD detection is proven reliable against the standard molybdenum blue method (p>0.05), and useful for investigation of the leaching kinetics of orthophosphate in bioaccessibility tests through in-line recording of the extraction profiles. PMID- 25435228 TI - Determination of antipyrine in saliva using the dispersive liquid-liquid microextraction based on a stepwise injection system. AB - A fully automated stepwise injection spectrophotometric method for determination of antipyrine in saliva (agent for non-invasive assessment of the activity of the drug metabolizing system in hepatocytes) has been developed. The method is based on the antipyrine derivatization by nitrite-ion dispersive liquid-liquid microextraction (DLLME) of formed 4-nitrosoantipyrine with subsequent UV-vis spectrophotometric detection. Under optimal experimental conditions (0.5 M sulfuric acid, 6*10(-3) M sodium nitrite, time 6 min) the absorbance of the colored extract at the 345 nm obeys Beer's law in the range of 3-200 MUM of antipyrine in saliva. The LOD, calculated from a blank test, based on 3sigma, found to be 1 MUM. The relative standard deviation for the determination of 50 MUM antipyrine was 4.5% (n=10). The proposed method was successfully applied to the determination of antipyrine in saliva and the analytical results agreed fairly well with the results obtained by reference HPLC method. PMID- 25435229 TI - Successive determination of urinary bilirubin and creatinine employing simultaneous injection effective mixing flow analysis. AB - A novel four-channel simultaneous injection effective mixing flow analysis (SIEMA) system has been assembled for successive determination of bilirubin and creatinine in urinary samples. The chemical variables and physical parameters in the flow system were optimized for the enhancement of successive analytical performances. The interferences from urine matrices on the determination of bilirubin and creatinine were eliminated to dilute urine samples. The calibration graphs with the optimum conditions were achieved to be in 0.024-5.0 mg L(-1) for bilirubin and 2-100 mg L(-1) for creatinine. The relative standard deviations (RSDs) at 3 mg L(-1) of bilirubin and at 50 mg L(-1) of creatinine for 11 runs were 1.5 and 1.0%, respectively. The limits of detections (3sigma of blank) for bilirubin and creatinine were 7 ug L(-1) and 0.6 mg L(-1), respectively. The sample throughput for stepwise detection was 22 h(-1). The proposed method was applied to the successive determination of bilirubin and creatinine in urine samples. PMID- 25435230 TI - An automatic countercurrent liquid-liquid micro-extraction system coupled with atomic absorption spectrometry for metal determination. AB - A novel and versatile automatic sequential injection countercurrent liquid-liquid microextraction (SI-CC-LLME) system coupled with atomic absorption spectrometry (FAAS) is presented for metal determination. The extraction procedure was based on the countercurrent flow of aqueous and organic phases which takes place into a newly designed lab made microextraction chamber. A noteworthy feature of the extraction chamber is that it can be utilized for organic solvents heavier or lighter than water. The proposed method was successfully demonstrated for on-line lead determination and applied in environmental water samples using an amount of 120 MUL of chloroform as extractant and ammonium diethyldithiophosphate as chelating reagent. The effect of the major experimental parameters including the volume of extractant, as well as the flow rate of aqueous and organic phases were studied and optimized. Under the optimum conditions for 6 mL sample consumption an enhancement factor of 130 was obtained. The detection limit was 1.5 MUg L(-1) and the precision of the method, expressed as relative standard deviation (RSD) was 2.7% at 40.0 MUg L(-1) Pb(II) concentration level. The proposed method was evaluated by analyzing certified reference materials and spiked environmental water samples. PMID- 25435231 TI - Multicommutated stepwise injection determination of ascorbic acid in medicinal plants and food samples by capillary zone electrophoresis ultraviolet detection. AB - An automation of the extraction of analytes from solid samples into the aqueous phase based on multicommutated stepwise injection analysis concept has been suggested. The feasibility of the approach has been demonstrated by determination of ascorbic acid as model analyte. The method includes automated extraction of ascorbic acid from solid sample into borate buffer solution pH 8 in mixing chamber during vigorous mixing by nitrogen stream, and subsequent detection by capillary zone electrophoresis at 254 nm. The method has a linear range of 0.1 5.0 mg g(-1) for ascorbic acid with the LOD of 0.03 mg g(-1). The sample throughput was 7 h(-1). This method was applied for determination of ascorbic acid in various medicinal plants and food samples. PMID- 25435233 TI - A multisyringe flow-based system for kinetic-catalytic determination of cobalt(II). AB - A kinetic-catalytic method for cobalt determination based on the catalytic effect of cobalt(II) on the oxidative coupling of 1,2-dihydroxyanthraquinone (alizarin) was automated exploiting multisyringe flow injection analysis (MSFIA). The proposed method was performed at pH 9.2, resulting in a discoloration process in the presence of hydrogen peroxide. The fixed-time approach was employed for analytical signal measurement. The spectrophotometric detection was used exploiting a liquid waveguide capillary cell (LWCC), of 1m optical length at 465 nm. The optimization was carried out by a multivariate approach, reaching critical values of 124 umol L(-1) and 0.22 mol L(-1) for alizarin and hydrogen peroxide, respectively, and 67 degrees C of reagent temperature. A sample volume of 150 uL was used allowing a sampling rate of 30h(-1). Under optimal conditions, calibration curve was linear in the range of 1-200 ug L(-1) Co, achieving a DL of 0.3 ug L(-1) Co. The repeatability, expressed as relative standard deviation (RSD) was lower than 1%. The proposed analytical procedure was applied to the determination of cobalt in cobalt gluconate and different forms of vitamin B12, cyanocobalamin and hydroxicobalamin with successful results showing recoveries around 95%. PMID- 25435232 TI - Automation of 99Tc extraction by LOV prior ICP-MS detection: application to environmental samples. AB - A new, fast, automated and inexpensive sample pre-treatment method for (99)Tc determination by inductively coupled plasma-mass spectrometry (ICP-MS) detection is presented. The miniaturized approach is based on a lab-on-valve (LOV) system, allowing automatic separation and preconcentration of (99)Tc. Selectivity is provided by the solid phase extraction system used (TEVA resin) which retains selectively pertechnetate ion in diluted nitric acid solution. The proposed system has some advantages such as minimization of sample handling, reduction of reagents volume, improvement of intermediate precision and sample throughput, offering a significant decrease of both time and cost per analysis in comparison to other flow techniques and batch methods. The proposed LOV system has been successfully applied to different samples of environmental interest (water and soil) with satisfactory recoveries, between 94% and 98%. The detection limit (LOD) of the developed method is 0.005 ng. The high durability of the resin and its low amount (32 mg), its good intermediate precision (RSD 3.8%) and repeatability (RSD 2%) and its high extraction frequency (up to 5 h(-1)) makes this method an inexpensive, high precision and fast tool for monitoring (99)Tc in environmental samples. PMID- 25435234 TI - Automated chemiluminescence immunoassay for a nonionic surfactant using a recycled spinning-pausing controlled washing procedure on a compact disc-type microfluidic platform. AB - A fully automated and integrated chemiluminescence immunoassay, carried out on a compact disc (CD)-type microfluidic platform, for the detection of alkylphenol polyethoxylates (APnEOs) is described. The pattern of the CD-type microchip was designed so as to permit the sequential solution delivery of the sample solution, the washing solution and the luminol solution, which are required in the chemiluminescence immunoassay process, along with a designed rotation program for spinning the CD-type microchip. The procedure for flowing the washing solution, the volume of which was limited on the CD-type microchip, was optimized by using a recycled spinning-pausing rotation program to overcome the non-specific adsorption of the horseradish peroxidase labeled APnEOs at the detection area. The detection limit of the immunoassay is about 10 ppb. PMID- 25435235 TI - Towards chemiluminescence detection in micro-sequential injection lab-on-valve format: a proof of concept based on the reaction between Fe(II) and luminol in seawater. AB - Micro-sequential injection lab-on-valve (uSI-LOV) is a well-established analytical platform for absorbance and fluorescence based assays but its applicability to chemiluminescence detection remains largely unexplored. In this work, we describe a novel fluidic protocol and two distinct strategies for photon collection that enable chemiluminescence detection using uSI-LOV for the first time. To illustrate this proof of concept, we selected the reaction between Fe(II) and luminol and developed a preliminary protocol for Fe(II) determinations in acidified seawater. The optimized fluidic strategy consists of holding 100 uL of the luminol reagent in a confined zone of the LOV and then displacing it with 50 uL of sample while monitoring the chemiluminescent product. Detection is achieved using two strategies: one based on a bifurcated optical fiber and the other based on a customized detection window created by mounting a photomultiplier tube atop of the LOV device. We show that detection is possible using both strategies but that the window strategy yields significantly enhanced sensitivity (355*) due to the larger detection area. In our final experimental conditions and using window detection, it was possible to achieve a limit of detection (LOD) of 1 nmol L(-1) and to quantify Fe(II) in acidified seawater samples up to 20.00 nmol L(-1) with high precision (RSD<6%). These analytical features combined with the long-term stability of luminol solution and the full automation and low reagent consumption make this approach a promising analytical tool for shipboard analysis of Fe(II). The intrinsic capacity of the LOV to operate at a low microliter level and to handle solid phases also opens up a new avenue for chemiluminescence applications. Moreover, this contribution shows that LOV can be a universal platform for optical detection, capable of absorbance, fluorescence and luminescence measurements in a single instrument setup. PMID- 25435236 TI - Direct-injection chemiluminescence detector. Properties and potential applications in flow analysis. AB - We present a novel chemiluminescence detector, with a cone-shaped detection chamber where the analytical reaction takes place. The sample and appropriate reagents are injected directly into the chamber in countercurrent using solenoid operated pulse micro-pumps. The proposed detector allows for fast measurement of the chemiluminescence signal in stop-flow conditions from the moment of reagents mixing. To evaluate potential applications of the detector the Fenton-like reaction with a luminol-H2O2 system and several transition metal ions (Co(2+), Cu(2+), Cr(3+), Fe(3+)) as a catalyst were investigated. The results demonstrate suitability of the proposed detector for quantitative analysis and for investigations of reaction kinetics, particularly rapid reactions. A multi pumping flow system was designed and optimized. The developed methodology demonstrated that the shape of the analytical signals strongly depends on the type and concentration of the metal ions. The application of the detector in quantitative analysis was assessed for determination of Fe(III). The direct injection chemiluminescence detector allows for a sensitive and repeatable (R.S.D. 2%) determination. The intensity of chemiluminescence increased linearly in the range from about 0.5 to 10 mg L(-1) Fe(III) with the detection limit of 0.025 mg L(-1). The time of analysis depended mainly on reaction kinetics. It is possible to achieve the high sampling rate of 144 samples per hour. PMID- 25435237 TI - High-throughput automatic flow method for determination of trace concentrations of aluminum in dialysis concentrate solutions using salicylaldehyde picolinoylhydrazone as a turn-on fluorescent probe. AB - A simple and expedient flow-based assembly capitalizing on programmable flow is herein proposed for reliable determination of trace level concentrations of aluminum as a potential contaminant in dialysis concentrate solutions without any prior sample clean-up/preconcentration procedure. Using salicylaldehyde picolinoylhydrazone in weakly acidic media as a turn-on fluorescent probe, the manifold is devised to handle three samples concurrently in stopped-flow reaction mode for simultaneous improvement of the analytical sensitivity and sample throughput. Analytical parameters influencing the sensitivity and repeatability of the assays, namely, probe concentration, reaction temperature and reaction time were investigated using a multivariate optimization protocol composed of a full factorial screening design followed by a Doehlert matrix model. The analysis of the Pareto chart and surface response revealed that the reaction time and amount of fluorescent probe were critical parameters for reliable assays of aluminum at the low ng mL(-1) level. Under the optimized chemical and physical variables, a detection limit of 1.1ngmL(-1) Al(III) at the 3s(blank) level, relative standard deviations better than 1.0%, a dynamic linear range of 5.0-80 ng mL(-1) and a sample throughput up to 25 h(-1) were obtained with no need for either sample preconcentration or the use of organized supramolecular systems. Demonstrated with the analysis of hemodialysis and peritoneal concentrate solutions, and dialysis waters, the flow-through method copes with the requirements of regulatory bodies (e.g., European Pharmacopeia) for quality control of aluminum in high salinity containing dialysis concentrates. PMID- 25435238 TI - An automatic, vigorous-injection assisted dispersive liquid-liquid microextraction technique for stopped-flow spectrophotometric detection of boron. AB - A novel automatic vigorous-injection assisted dispersive liquid-liquid microextraction procedure based on the use of a modified single-valve sequential injection manifold (SV-SIA) was developed and applied for determination of boron in water samples. The major novelties in the procedure are the achieving of efficient dispersive liquid-liquid microextraction by means of single vigorous injection (250 uL, 900 uL s(-1)) of the extraction solvent (n-amylacetate) into aqueous phase resulting in the effective dispersive mixing without using dispersive solvent and after self-separation of the phases, as well as forwarding of the extraction phase directly to a Z-flow cell (10 mm) without the use of a holding coil for stopped-flow spectrophotometric detection. The calibration working range was linear up to 2.43 mg L(-1) of boron at 426nm wavelength. The limit of detection, calculated as 3s of a blank test (n=10), was found to be 0.003 mg L(-1), and the relative standard deviation, measured as ten replicable concentrations at 0.41 mg L(-1) of boron was determined to be 5.6%. The validation of the method was tested using certified reference material. PMID- 25435239 TI - Simple flow injection for determination of sulfite by amperometric detection using glassy carbon electrode modified with carbon nanotubes-PDDA-gold nanoparticles. AB - A new approach is presented for sensitive and selective measurement of sulfite (SO3(2-)) in beverages based on a simple flow injection system with amperometric detection. In this work, the sulfite sensor was a glassy carbon electrode modified with multiwall carbon nanotubes-poly(diallyldimethylammonium chloride) gold nanoparticles composites (CNTs-PDDA-AuNPs/GC). Electrochemical oxidation of sulfite with this electrode was first studied in 0.1M phosphate buffer (pH 7.0) using cyclic voltammetry. The results indicated that the CNTs-PDDA-AuNPs/GC electrode possesses electrocatalytic activity for the oxidation of sulfite with high sensitivity and selectivity. Sulfite was quantified using amperometric measurement with the new sensor at +0.4V vs Ag/AgCl in conjunction with flow injection. The linear working range for the quantitation of sulfite was 2-200 mg L(-1) (r(2)=0.998) with a detection limit of 0.03 mg L(-1) (3sigma of blank) and an estimated precision of 1.5%.The proposed method was successfully applied to the determination of sulfite in fruit juices and wines with a sample throughput of 23 samples per hour. PMID- 25435240 TI - On-line hyphenation of solid-phase extraction to chromatographic separation of sulfonamides with fused-core columns in sequential injection chromatography. AB - On-line sample pretreatment (clean-up and analyte preconcentration) is for the first time coupled to sequential injection chromatography. The approach combines anion-exchange solid-phase extraction and the highly effective pentafluorophenylpropyl (F5) fused-core particle column for separation of eight sulfonamide antibiotics with similar structures (sulfathiazole, sulfanilamide, sulfacetamide, sulfadiazine, sulfamerazine, sulfadimidine, sulfamethoxazole and sulfadimethoxine). The stationary phase was selected after a critical comparison of the performance achieved by three fused-core reversed phase columns (Ascentis((r)) Express RP-Amide, Phenyl-Hexyl, and F5) and two monolithic columns (Chromolith((r)) High Resolution RP-18 and CN). Acetonitrile and acetate buffer pH 5.0 at 0.60 mL min(-1) were used as mobile phase to perform the separations before spectrophotometric detection. The first mobile phase was successfully used as eluent from SPE column ensuring transfer of a narrow zone to the chromatographic column. Enrichment factors up to 39.2 were achieved with a 500 uL sample volume. The developed procedure showed analysis time <10.5 min, resolutions >1.83 with peak symmetry <=1.52, LODs between 4.9 and 27 ug L(-1), linear response ranges from 30.0 to 1000.0 ug L(-1) (r(2)>0.996) and RSDs of peak heights <2.9% (n=6) at a 100 ug L(-1) level and enabled the screening control of freshwater samples contaminated at the 100 ug L(-1) level. The proposed approach expanded the analytical potentiality of SIC and avoided the time-consuming batch sample pretreatment step, thus minimizing risks of sample contamination and analyte losses. PMID- 25435241 TI - Simultaneous spectrophotometric flow injection determination of phosphate and silicate. AB - A method for the simultaneous determination of phosphate and silicate based on spectrophotometric measurement at 385 nm of a single peak using a flow injection system with two component calibration is described. In the system, a stream of sample containing both analytes is merged with a stream of ammonium molybdate to form (at 16 months was associated with lower FM (FM z score: -0.17 (-0.28 to -0.05), P=0.005) and lower FFM (FFM z score: -0.13 (-0.23 to -0.03), P=0.015), as was the introduction of complementary feeding >6 months (FM z score: -0.22 (-0.38 to -0.07), P=0.004), compared with <4 months. CONCLUSIONS: Faster infant weight gain is associated with a healthier childhood body composition when it is caused by faster linear growth. Full breastfeeding >6 months and introduction of complementary feeding >6 months are associated with lower childhood FM. PMID- 25435258 TI - Rheometry-on-a-chip: measuring the relaxation time of a viscoelastic liquid through particle migration in microchannel flows. AB - A novel method to estimate the relaxation time of viscoelastic fluids, down to milliseconds, is here proposed. The adopted technique is based on the particle migration phenomenon occurring when the suspending viscoelastic fluid flows in microfluidic channels. The method is applied to measure the fluid relaxation times of two water-glycerol polymer solutions in an ample range of concentrations. A remarkable improvement in the accuracy of the measure of the relaxation time is found, as compared with experimental data obtained from shear or elongational experiments available in the literature. Good agreement with available theoretical predictions is also found. The proposed method is reliable, handy and does not need a calibration curve, opening an effective way to measure relaxation times of viscoelastic fluids otherwise not easily detectable by conventional techniques. PMID- 25435257 TI - Neutropenia in childhood: a 5-year experience at a tertiary center. AB - Clinical characteristics corroborated by laboratory investigations are essential to determine the etiology in cases of childhood neutropenia and the level of future health-care needs. Here the presentation, findings, and need of interventions in different types of neutropenia in children followed at our center from 2007 to 2012 were investigated retrospectively. Children with congenital and autoimmune neutropenia presented at a significantly younger age and with lower absolute neutrophil granulocyte counts than those with other types of neutropenia (p < 0.01-0.05). The duration of neutropenia, in case of remission, was shorter in post-infection and drug-induced cases compared to autoimmune and chronic idiopathic neutropenias (p = 0.001). Least affected from infections were children with ethnic and post-infection neutropenias compared to the others (p = 0.01-0.05). With the exception of congenital and autoimmune neutropenias, neutropenic children had few clinical infections and few hospital admissions even though the outpatient visit frequency was similar among the groups. A vast majority of the patients received no antibiotic prophylaxis. CONCLUSION: The majority of patients with pediatric neutropenia, apart from congenital types, display a benign clinical course. Our data suggest that most neutropenic children need neither antibiotic prophylaxis nor extensive medical attention. PMID- 25435259 TI - Salinomycin inhibits the tumor growth of glioma stem cells by selectively suppressing glioma-initiating cells. AB - Glioma-initiating cells are a small population of cells that have the ability to undergo self-renewal and initiate tumorigenesis. In the present study, the potential role of salinomycin, a polyether antibiotic, on the suppression of glioma cell growth was investigated. GL261 glioma cells were maintained in a stem cell-like status [GL261 neurospheres (GL261-NS)] or induced for differentiation [GL261 adherent cells (GL261-AC)]. It was demonstrated that salinomycin significantly reduced the cell viability of GL261-NS and GL261-AC cells in a dose dependent manner, with a more substantial inhibition of GL261-NS proliferation (P<0.05). The inhibitory effect of salinomycin on cell growth was more effective than that of 1-(4-amino-2-methyl-5-pyrimid l)-methyl-3-(2-chloroethyl)-3 nitrosourea hydrochloride and vincristine (P<0.05). Salinomycin depleted GL261-NS from tumorspheres and induced cell apoptosis. In addition, salinomycin prolonged the median survival time of glioma-bearing mice (P<0.05). Therefore, the present study indicated that salinomycin may preferentially inhibit glioma-initiated cell growth by inducing apoptosis, suggesting that salinomycin may provide a valuable therapeutic strategy for the treatment of malignant glioma. PMID- 25435260 TI - [Differences in health-related quality of Life between men and women with sleep disordered breathing]. AB - INTRODUCTION: Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS) increases cardiovascular risk and has a negative impact on neurocognitive functioning. Health Related Quality of Life (HRQL) is impaired in OSAHS patients, differently in men and women, but its evaluation is difficult by primary care providers. OBJECTIVE: To screen for OSAHS in patients with cardiovascular disease or cardiovascular risk factors, under the hypothesis of gender differences in HRQL. METHODOLOGY: Cross-sectional study including 75 consecutive patients (39 male, 36 female) with cardiovascular disease or cardiovascular risk factors, without acute disease. Anthropometric, demographic, and laboratory data were collected. The STOP-BANG questionnaire, for the screening of OSASH, and the COOP/WONCA charts for HRQL evaluation, were administered at the primary care setting. RESULTS: Women with clinical finding evocative of OSAHS had lower HRQL than men with the same condition, as indicated by higher summation scores for COOP/WONCA charts (P=.002) and for dimensions of Physical Fitness (P<.001), Daily Activities (P=.040) and Change in health (P=.004), with a trend to a be into a lower social class. Summation scores for COOP/WONCA correlates with social class (P=.008) pointing out to a parallel improvement of HRQL with social status. CONCLUSIONS: OSAHS screening along with HRQL measurement is feasible at the primary care level, revealing a distinctive feature in women with sleep-disordered breathing, a lower HRQL, undetectable by the instrumental sleep study. PMID- 25435261 TI - [Cardiovascular risk and income]. PMID- 25435262 TI - [Delayed thromboembolism diagnosis and its consequences]. PMID- 25435264 TI - Becoming a back-up carer: parenting sons with Duchenne muscular dystrophy transitioning into adulthood. AB - The population of adults with Duchenne muscular dystrophy is increasing rapidly. However, information for individuals with DMD and their parents about the transition to adulthood is lacking; young adult sons and their parents may struggle to maintain smooth family functioning and well-being during this period. This study examined the process of change in parental behaviors during their son's transition. The participants were 18 parents with sons aged 15-30 years. Data were obtained from semi-structured interviews and analyzed using a grounded theory approach. Eleven categories of behaviors were identified across three domains: emotional, physical, and determination. The changes made by parents were directed toward becoming a back-up carer: letting go of some control but still being active participants in their sons' lives. We identified several issues important for well-being in the transition period: psychological support, the aging of the parents (the primary caregivers) and the concomitant emergency and specialized care needs, and parents' intervention in the self-determination of adult sons with DMD. The findings of this study may provide a rationale to advocate for policies to improve support for parents of sons with DMD transitioning to adulthood and provide information to help parents in their role as primary care providers. PMID- 25435263 TI - [Centralization of health services in primary care in summer: Patients and professionals view during two consecutive years]. AB - The Spanish primary health care, gateway and pillar of the Health Care System has his resources increasingly constrained by current crisis. OBJECTIVE: To know the opinion of users and professionals on two primary care centers which centralized in August 2011 and 2012 the attendance of seven primary care centers. METHODS: Two questionnaires were designed: a telephone survey of a random sample of users and a self-completed questionnaire for health care professionals. The variables were scored on a scale of 1-10 (low to high). RESULTS: Cronbach's coefficient alpha>0,84. 1293 people responded (836 users and 357 professionals). Users rated, in 2011, the satisfaction with 6.7 points in August and 7.3 points the rest of the year (P<.001). And, in 2012, with 7.7 points in August and 8.1 points the rest of the year (P<.001). Health care professionals, rated their satisfaction with 6.8 points in 2011 and 7.3 points in 2012. The waiting time was the only variable best scores in August that the rest of the year. The perception of the solution given in consultation did not change. Satisfaction, marking, care and treatment were highest rated in the regular center than in the reference center (P<.001). CONCLUSIONS: The centralization of primary health care during periods of reduced demand could reduce costs while maintaining quality. The experience of centralizing primary care services during August was perceived as acceptable and improved over time. Users showed a slight, but significant, preference for their usual primary care center. PMID- 25435265 TI - Lower-pole stones: do we finally have more answers than questions? PMID- 25435267 TI - Genetic rescue to the rescue. AB - Genetic rescue can increase the fitness of small, imperiled populations via immigration. A suite of studies from the past decade highlights the value of genetic rescue in increasing population fitness. Nonetheless, genetic rescue has not been widely applied to conserve many of the threatened populations that it could benefit. In this review, we highlight recent studies of genetic rescue and place it in the larger context of theoretical and empirical developments in evolutionary and conservation biology. We also propose directions to help shape future research on genetic rescue. Genetic rescue is a tool that can stem biodiversity loss more than has been appreciated, provides population resilience, and will become increasingly useful if integrated with molecular advances in population genomics. PMID- 25435266 TI - Active surveillance for low-risk prostate cancer: developments to date. PMID- 25435268 TI - Memory for emotional words: The role of semantic relatedness, encoding task and affective valence. AB - Emotional stimuli have been repeatedly demonstrated to be better remembered than neutral ones. The aim of the present study was to test whether this advantage in memory is mainly produced by the affective content of the stimuli or it can be rather accounted for by factors such as semantic relatedness or type of encoding task. The valence of the stimuli (positive, negative and neutral words that could be either semantically related or unrelated) as well as the type of encoding task (focused on either familiarity or emotionality) was manipulated. The results revealed an advantage in memory for emotional words (either positive or negative) regardless of semantic relatedness. Importantly, this advantage was modulated by the encoding task, as it was reliable only in the task which focused on emotionality. These findings suggest that congruity with the dimension attended at encoding might contribute to the superiority in memory for emotional words, thus offering us a more complex picture of the underlying mechanisms behind the advantage for emotional information in memory. PMID- 25435269 TI - Cadmium depletes cellular iron availability through enhancing ferroportin translation via iron responsive element. AB - Cadmium (Cd) is a heavy metal that has detrimental effects on various organs. The widespread contamination of Cd in the environment, crops and food sources poses a severe threat to human health. Acute toxicities of Cd have been extensively investigated; however, the health impact of chronic low-dose exposure to Cd, particularly exposure under non-toxic concentrations, has yet to be elucidated. Furthermore, the toxic threshold of Cd is currently unknown. Ferroportin is the only known iron exporter in vertebrate cells, and it has an essential role in controlling iron egress from cells. To the best of our knowledge, the present study is the first to verify the regulation of ferroportin by Cd. Treatment with low-dose Cd (i.e. at sublethal concentrations, without undermining cell viability) increased the protein expression of ferroportin in macrophages, and this was associated with depleted cellular iron levels. Mechanistic investigations revealed that Cd modulated the ferroportin concentration at the translational level, via the iron responsive element located at the 5' untranslated region of ferroportin. In conclusion, these data provide evidence for the molecular basis by which Cd alters cellular iron availability through elevating concentrations of ferroportin. PMID- 25435270 TI - PET-CT offers accurate assessment of tumour length in oesophageal malignancy. AB - INTRODUCTION: Radiotherapy is increasingly used for both curative and palliative treatment of oesophageal malignancy. Accurate treatment depends on determining tumour location and length. This study assessed the value of PET-CT versus other staging modalities in determining tumour length. MATERIALS AND METHODS: Oesophageal cancer patients who underwent staging with PET/CT and endoscopic ultrasound (EUS) in addition to their diagnostic upper GI endoscopy and subsequent surgical resection were assessed. PET/CT length was obtained retrospectively by using Hermes Hybrid ViewerTM with a 1-5 Standardised Uptake Value grey scale. An SUV of 5 was used as the cut off for determining length. Direct measurement by EUS and OGD were determined. RESULTS: 53 patients underwent PET-CT, EUS, OGD and surgical resection for oesophageal cancer. Overall the correlation between PET-CT and histopathological length was strongest (Pearson r=0.5977, 95% CI 0.390-0.747) versus EUS (Pearson R=0.5365, 95% CI 0.311-0.705) and OGD (Pearson r=0.1574, 95% CI -0.118 to 0.410). After excluding tumours with a significant chemotherapy response, PET-CT length correlated significantly with histopathological length (R=0.5651, p=0.0005). In comparison, the correlation between histological length and EUS (R=0.4637, p=0.0057) measurement was less significant and this did not correlate with OGD (R=-0.1084, p=0.5417). CONCLUSION: Tumour length estimated by PET-CT correlated most strongly with histopathological length of oesophageal malignancy and is the most accurate determinant of tumour length of all the staging modalities. This suggests a potential role for PET-CT in the planning of radiotherapy and resection, particularly when considering the practical limitations of EUS. PMID- 25435271 TI - [Pseudotumoral soft tissue masses in children and adolescents]. AB - INTRODUCTION: Pseudotumoral soft tissue masses in children and adolescents are a frequent reason for consultation and a diagnostic dilemma. Soft tissue malignancies are relatively uncommon, unlike the large number of benign lesions that may be seen in the superficial tissue and that can be diagnosed with clinical characteristics. MATERIALS AND METHODS: This retrospective study concerns 161 children and adolescents less than 20 years old, referred for a soft tissue mass between 2007 and 2011. It describes their epidemiology, clinical characteristics, and course of care to validate a diagnostic strategy for such masses. RESULTS: Final diagnoses were malignant tumors (44%), benign tumors (32%), and pseudotumoral lesions (24%). Clinical features were similar between these three groups except for age and tumor location, with more benign thoracic masses in younger children. Clinical and radiological association led to an accurate diagnosis for 50% of benign masses and with cytological analysis contribution in 79% of benign tumors and 86% of pseudotumoral lesions. Malignant tumors were suspected in only 39% of cases with radiological exams and in 89% after fine-needle aspiration, an essential additional diagnostic tool. Final diagnoses were formally established through simple standard clinical and radiological evaluation in 19 patients (11.8%; benign tumors, seven patients; malformations, eight patients; post-traumatic lesions, two patients; infection and inflammation, one patient each); ultrasound exam in five patients (3.1%; hemangioendotheliomas, two patients, fascial dehiscence, hemangioma, and vascular malformation, one patient each); MRI in four patients (2.5%; three vascular malformations and one lipoma); CT in two cases (1.2%; vascular malformation and myositis ossificans), and radiological examinations associated with cell aspiration in 15 cases (9.3%; ten benign tumors and five malignant tumors). CONCLUSIONS: A multidisciplinary approach should be requested from oncological, radiological, and pathologic experts to optimize soft tissue mass management as soon as initial investigations start. The authors advise a diagnostic strategy for children with pseudotumoral soft tissue masses. PMID- 25435272 TI - [Recent prevalence of child and adolescent overweight and obesity in France and abroad]. AB - During the 2000s, surveillance of child overweight and obesity experienced a large expansion and provided an opportunity to document such a public health issue using standardized procedures in France and abroad. Nowadays, in France, it has been estimated that just less than one child out of five is overweight and among them, 3 to 4 % are obese. Like in other developed countries, these frequencies have reached a plateau during the 2000s and set France belonging to a group of countries in which the situation looks as fairly favorable. Nevertheless, they also hide huge disparities across social groups and the number of concerned children remains too high, while care possibilities are rather inconclusive. Therefore, prevention actions are still needed. PMID- 25435273 TI - [Embolization of pulmonary arteriovenous malformation causing hypoxemia in a 7 year-old child]. AB - Pulmonary arteriovenous fistulas are abnormal vessels joining the right pulmonary artery to the pulmonary veins. They lead to an extracardiac right-to-left shunt with refractory hypoxemia. We report the case of a 7-year-old girl with a large pulmonary arteriovenous fistula discovered with refractory hypoxemia diagnosed during general anesthesia for adenoidectomy. Radio-opacity was observed on the upper lobe of the right lung. The diagnosis was made using thoracic angiotomography. The proximal arterial vessel arose from the lobar pulmonary artery. The fistula had developed in the entire right upper lobe and drained into two veins flowing into the right superior pulmonary artery. Given the marked hypoxemia, the potential risks of pulmonary hemorrhage and pulmonary infection, an occlusion of the fistula was indicated. After discussion between surgeons and interventional cardiologists, catheterization was indicated. The occlusion of the fistula was successful at the second attempt after release of a vascular plug in the main proximal vessel. This case illustrates the clinical circumstances of diagnosis of arteriovenous fistula, the diagnostic algorithm for refractory hypoxemia and the therapeutic options, with discussion of the benefits and drawbacks of a catheterization procedure. PMID- 25435274 TI - [Incontinentia pigmenti with subcortical band heterotopias]. PMID- 25435275 TI - [Klippel-Trenaunay syndrome associated with hemimegalencephaly]. AB - Klippel-Trenaunay syndrome (KTS) is a rare, complex congenital vascular malformation. This neurocutaneous syndrome can be associated with brain malformations. We report a case involving Klippel-Trenaunay syndrome and hemimegalencephaly in a 3-year-old child revealed by epileptic encephalopathy. We discuss the clinical features and the contribution of imaging in this association. PMID- 25435277 TI - Gastric sarcoidosis: rare presentation of a rare disease. AB - Gastrointestinal sarcoidosis is a rare form of extrapulmonary sarcoidosis. Most of the cases are represented by gastric involvement. We describe a patient with previous systemic sarcoidosis who presented with non-specific abdominal complaints. The workup showed the unusual combination of isolated active gastric sarcoidosis and quiescent activity of the disease elsewhere. We briefly review the clinical, diagnostic and therapeutic aspects of gastric sarcoidosis. We hope to increase awareness about this rare disease. PMID- 25435278 TI - Co-storage and secretion of growth hormone and secretoneurin in retinal ganglion cells. AB - It is well established that growth hormone (GH) and granins are co-stored and co secreted from pituitary somatotrophs. In this work we demonstrate for the first time that GH- and secretoneurin (SN) immunoreactivity (the secretogranin II (SgII) fragment) are similarly present in retinal ganglion cells (RGCs), which is an extrapituitary site of GH expression, and in quail QNR/D cells, which provide an experimental RGC model. The expression of SgII and chromogranin A in the pituitary gland, neuroretina and QNR/D cells was confirmed by RT-PCR analysis. Western blotting also showed that the SN-immunoreactivity in somatotrophs and QNR/D cells was associated with multiple protein bands (24, 35, 48, 72, 78, 93 and 148kDa) of which the 72kDa and 148kDa bands were most abundant. Secretoneurin was constitutively secreted from QNR/D cells as 35kDa and 37kDa proteins and unlike GH, was not increased by exogenous GH-releasing hormone (GHRH). Intracellular analysis by EM showed co-localization of GH and SN in cell bodies and neurites in QNR/D cells. This co-localization was associated with small dark bodies in the neurites. In addition, co-localization of GH and SNAP-25 in the cell surface of QNR/D's plasma membranes suggests GH-release involves specific vesicle-membrane recognition in QNR/D cells. As SN is a marker for secretory granules, GH secretion from RGCs is thus likely to be in secretory granules, as in somatotrophs. PMID- 25435279 TI - Androgens directly stimulate spermatogonial differentiation in juvenile Atlantic salmon (Salmo salar). AB - We studied the effects of androgens on early stages of spermatogenesis along with androgen receptor binding characteristics and the expression of selected testicular and pituitary genes. To this end, immature Atlantic salmon postsmolts received testosterone (T), adrenosterone (OA, which is converted in vivo into 11 ketotestosterone, 11-KT) or a combination of the two androgens (T+OA). Treatment with OA and T elevated the plasma levels of 11-KT and T, respectively, and co injection of OA with T lead to high 11-KT levels but prevented plasma T levels to reach the levels observed after injecting T alone. Clear stimulatory effects were recorded as regards pituitary lhb and gnrhr4 transcript levels in fish receiving T, and to a lesser extent in fish receiving OA (but for the lhb transcript only). The two androgen receptors (Ara1 and Ara2) we cloned bound T and 11-KT and responded to these androgens in a similar way. Both androgens down-regulated testicular amh and increased igf3 transcript levels after 1 week of treatment, but effects on growth factor gene expression required sustained androgen stimulation and faded out in the groups with the decreasing T plasma levels. In fish exhibiting a sustained elevation of 11-KT plasma levels (OA and T+OA groups) for 2 weeks, the number of differentiating spermatogonia had increased while the number of undifferentiated spermatogonia decreased. Previous work showed that circulating gonadotropin levels did not increase following androgen treatments of gonad-intact immature male salmonids. Taken together, androgen treatment of immature males modulated testicular growth factor expression that, when sustained for 2 weeks, stimulated differentiation, but not self-renewal, of undifferentiated type A spermatogonia. PMID- 25435280 TI - HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer. AB - Resistance to HER2-targeted therapies remains a major obstacle in the treatment of HER2-overexpressing breast cancer. Understanding the molecular pathways that contribute to the development of drug resistance is needed to improve the clinical utility of novel agents, and to predict the success of targeted personalized therapy based on tumor-specific mutations. Little is known about the clinical significance of HER family mutations in breast cancer. Because mutations within HER1/EGFR are predictive of response to tyrosine kinase inhibitors (TKI) in lung cancer, we investigated whether mutations in HER family kinase domains are predictive of response to targeted therapy in HER2-overexpressing breast cancer. We sequenced the HER family kinase domains from 76 HER2-overexpressing invasive carcinomas and identified 12 missense variants. Patients whose tumors carried any of these mutations did not respond to HER2 directed therapy in the metastatic setting. We developed mutant cell lines and used structural analyses to determine whether changes in protein conformation could explain the lack of response to therapy. We also functionally studied all HER2 mutants and showed that they conferred an aggressive phenotype and altered effects of the TKI lapatinib. Our data demonstrate that mutations in the finely tuned HER kinase domains play a critical function in breast cancer progression and may serve as prognostic and predictive markers. PMID- 25435282 TI - Comparison of insertion/deletion calling algorithms on human next-generation sequencing data. AB - BACKGROUND: Insertions/deletions (indels) are the second most common type of genomic variant and the most common type of structural variant. Identification of indels in next generation sequencing data is a challenge, and algorithms commonly used for indel detection have not been compared on a research cohort of human subject genomic data. Guidelines for the optimal detection of biologically significant indels are limited. We analyzed three sets of human next generation sequencing data (48 samples of a 200 gene target exon sequencing, 45 samples of whole exome sequencing, and 2 samples of whole genome sequencing) using three algorithms for indel detection (Pindel, Genome Analysis Tool Kit's UnifiedGenotyper and HaplotypeCaller). RESULTS: We observed variation in indel calls across the three algorithms. The intersection of the three tools comprised only 5.70% of targeted exon, 19.52% of whole exome, and 14.25% of whole genome indel calls. The majority of the discordant indels were of lower read depth and likely to be false positives. When software parameters were kept consistent across the three targets, HaplotypeCaller produced the most reliable results. Pindel results did not validate well without adjustments to parameters to account for varied read depth and number of samples per run. Adjustments to Pindel's M (minimum support for event) parameter improved both concordance and validation rates. Pindel was able to identify large deletions that surpassed the length capabilities of the GATK algorithms. CONCLUSIONS: Despite the observed variability in indel identification, we discerned strengths among the individual algorithms on specific data sets. This allowed us to suggest best practices for indel calling. Pindel's low validation rate of indel calls made in targeted exon sequencing suggests that HaplotypeCaller is better suited for short indels and multi-sample runs in targets with very high read depth. Pindel allows for optimization of minimum support for events and is best used for detection of larger indels at lower read depths. PMID- 25435281 TI - Myc and Ras oncogenes engage different energy metabolism programs and evoke distinct patterns of oxidative and DNA replication stress. AB - Both Myc and Ras oncogenes impact cellular metabolism, deregulate redox homeostasis and trigger DNA replication stress (RS) that compromises genomic integrity. However, how are such oncogene-induced effects evoked and temporally related, to what extent are these kinetic parameters shared by Myc and Ras, and how are these cellular changes linked with oncogene-induced cellular senescence in different cell context(s) remain poorly understood. Here, we addressed the above-mentioned open questions by multifaceted comparative analyses of human cellular models with inducible expression of c-Myc and H-RasV12 (Ras), two commonly deregulated oncoproteins operating in a functionally connected signaling network. Our study of DNA replication parameters using the DNA fiber approach and time-course assessment of perturbations in glycolytic flux, oxygen consumption and production of reactive oxygen species (ROS) revealed the following results. First, overabundance of nuclear Myc triggered RS promptly, already after one day of Myc induction, causing slow replication fork progression and fork asymmetry, even before any metabolic changes occurred. In contrast, Ras overexpression initially induced a burst of cell proliferation and increased the speed of replication fork progression. However, after several days of induction Ras caused bioenergetic metabolic changes that correlated with slower DNA replication fork progression and the ensuing cell cycle arrest, gradually leading to senescence. Second, the observed oncogene-induced RS and metabolic alterations were cell type/context dependent, as shown by comparative analyses of normal human BJ fibroblasts versus U2-OS sarcoma cells. Third, the energy metabolic reprogramming triggered by Ras was more robust compared to impact of Myc. Fourth, the detected oncogene-induced oxidative stress was due to ROS (superoxide) of non mitochondrial origin and mitochondrial OXPHOS was reduced (Crabtree effect). Overall, our study provides novel insights into oncogene-evoked metabolic reprogramming, replication and oxidative stress, with implications for mechanisms of tumorigenesis and potential targeting of oncogene addiction. PMID- 25435284 TI - Bootstrap-based differential gene expression analysis for RNA-Seq data with and without replicates. AB - A major application of RNA-Seq is to perform differential gene expression analysis. Many tools exist to analyze differentially expressed genes in the presence of biological replicates. Frequently, however, RNA-Seq experiments have no or very few biological replicates and development of methods for detecting differentially expressed genes in these scenarios is still an active research area. In this paper we introduce a novel method, called IsoDE, for differential gene expression analysis based on bootstrapping. We compared IsoDE against four existing methods (Fisher's exact test, GFOLD, edgeR and Cuffdiff) on RNA-Seq datasets generated using three different sequencing technologies, both with and without replicates. Experiments on MAQC RNA-Seq datasets without replicates show that IsoDE has consistently high accuracy as defined by the qPCR ground truth, frequently higher than that of the compared methods, particularly for low coverage data and at lower fold change thresholds. In experiments on RNA-Seq datasets with up to 7 replicates, IsoDE has also achieved high accuracy. Furthermore, unlike GFOLD and edgeR, IsoDE accuracy varies smoothly with the number of replicates, and is relatively uniform across the entire range of gene expression levels. The proposed non-parametric method based on bootstrapping has practical running time, and achieves robust performance over a broad range of technologies, number of replicates, sequencing depths, and minimum fold change thresholds. PMID- 25435283 TI - Maintenance of picobirnavirus (PBV) infection in an adult orangutan (Pongo pygmaeus) and genetic diversity of excreted viral strains during a three-year period. AB - The present work provide data about the maintenance of picobirnavirus (PBV) infection during adulthood in a mammalian host. For this purpose PBV infection was studied in an adult orangutan (Pongo pygmaeus) by PAGE/SS, RT-PCR and nucleotide sequencing. PBV infection in the animal was asymptomatic and was characterized by interspaced silent and high/ low active viral excretion periods. The PBV strains excreted by the studied individual were identified as genogroup I and revealed a nucleotide identity among them of 64-81%. The results obtained allowed to arrive to a deeper understanding of the natural history of PBV infection, which seems to be characterized by new-born, juvenile and adult asymptomatic hosts which persistently excrete closely related strains in their feces. Consequently, picobirnaviruses could be considered frequent inhabitants of the gastrointestinal tract, leaving the question open about the molecular mechanisms governing persistent and asymptomatic coexistence within the host and the potential host suitability to maintain this relationship. PMID- 25435285 TI - Novel metabotropic glutamate receptor 2/3 antagonists and their therapeutic applications: a patent review (2005 - present). AB - INTRODUCTION: This review focuses on the medicinal chemistry efforts directed toward the identification of competitive and noncompetitive antagonists of glutamate at group II metabotropic glutamate receptors (mGluRII: mGlu2/3 and mGlu2). This class of compounds holds promise for the treatment of CNS disorders such as major depression, cognitive deficits and sleep-wake disorders, and several pharmaceutical companies are advancing mGluRII antagonists from discovery research into clinical development. AREA COVERED: This review article covers for the first time the patent applications that were published on mGlu2/3 orthosteric and allosteric antagonists between January 2005 and September 2014, with support from the primary literature, posters and oral communications from international congresses. Patent applications published prior to 2005 for which compositions of matter were largely described in peer review articles are briefly discussed with main findings. EXPERT OPINION: Recent advances in the prodrug approach of novel mGlu2/3 orthosteric antagonists combined with the design of novel mGlu2/3 and mGlu2 negative allosteric modulators provide new therapeutic opportunities for neurologic and psychiatric disorders. PMID- 25435286 TI - Danzhi Xiaoyao San ameliorates depressive-like behavior by shifting toward serotonin via the downregulation of hippocampal indoleamine 2,3-dioxygenase. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Danzhi Xiaoyao San (DXS) is a canonical Chinese medicine formula from Principles of Internal Medicine, which was written during the Ming dynasty. This formula is approved and commercialized for use in the prevention and treatment of affective disorders. This study is aimed to investigate the hypothesis that DXS treats depressive-like behavior by shifting the balance of the kynurenine (Kyn)/serotonin (5-HT) pathway toward the 5-HT pathway through the downregulation of hippocampal indoleamine 2,3-dioxygenase (IDO). MATERIALS AND METHODS: Chemical fingerprints of gardenoside, paeoniflorin, ferulic acid, paeonol, and ligustilide in standard extraction were used as the material bases of DXS. Rats with depressive-like behavior induced by chronic unpredictable mild stress (CUMS) were randomly divided into four groups, namely the control, model, DXS, and fluoxetine groups. Cytokines, IDO, and tryptophan (Trp) catabolites were analyzed by enzyme-linked immunosorbent assay, western blot, and liquid chromatography-electrospray ionization tandem mass spectrometry, respectively. RESULTS: DXS significantly increased crossing grid numbers, sucrose consumption, and body weight. This treatment significantly decreased the serum levels of tumor necrosis factor-alpha and interleukin 6 (IL-6). However, DXS elicited no significant effects on IL-1beta, IL-2, and interferon gamma. DXS downregulated the activity of IDO and subsequent production of Kyn in the hippocampus. This treatment upregulated the hippocampal contents of Trp and 5-HT but did not influence 5-HT turnover. CONCLUSIONS: DXS exhibited antidepressant like effects on rats exposed to CUMS. DXS reduced IDO activity to shift the balance of the Kyn/5-HT pathway toward the 5-HT pathway. PMID- 25435287 TI - An inventory of plants commonly used in the treatment of some disease conditions in Ogbomoso, South West, Nigeria. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This study was designed to take an inventory of medicinal plants, recipes and methods commonly used traditionally to treat some cardiovascular and inflammatory diseases in five local government areas in Ogbomoso, Oyo State, Nigeria. MATERIAL AND METHODS: First-hand field survey through semi-structured questionnaire was employed in the 5 months study. RESULTS: A total of 101 plant species (medicinal plants (80.90%), spices (17.5%) and vegetables (1.53%)) belonging to 51 different families were mentioned for the treatment of various types of cardiovascular and inflammatory diseases. The survey revealed that 51.5% of the plants mentioned are used for the management of inflammatory diseases, 34.7% for the treatment of cardiovascular diseases and 11.9% of the plants are used for the treatment of both diseases. Euphorbiaceae (7.9%) are the most frequently used families of plants for the treatment of the various types of diseases mentioned, followed by Caesalpiaceae, (4.9%), Apocynoceae (4.9%) and Poaceae (4.9%). Fifty-nine recipes are usually prepared for the treatment of the six types of inflammatory diseases while twenty-three recipes are reportedly used for the treatment of the four types of cardiovascular diseases mentioned in this study. The recipes covered in the survey were mostly prepared from leaves (37.6%) and roots (23.8%) decoction or infusions. Medications are mostly administered orally with few numbers of the recipes showing side effect. CONCLUSION: The study has documented indigenous plants in Ogbomoso as a potential source for the development of new drugs for the treatment of cardiovascular and inflammatory diseases. PMID- 25435288 TI - Lipidomic profiling reveals significant alterations in lipid biochemistry in hypothyroid rat cerebellum and the therapeutic effects of Sini decoction. AB - Hypothyroidism is known to be closely associated with lipid metabolism. Although our previous serum and urine metabonomics studies have provided some clues about the molecular mechanism of hypothyroidism at the metabolic level, the precise mechanism underlying the pathogenesis of hypothyroidism remains elusive, especially from the aspect of lipid metabolism. In the present study, we applied an ultra high performance liquid chromatography/time-of-flight mass spectrometry (UHPLC/TOF-MS)-based lipidomics method to analyze the global lipid profiles of hypothyroidism in rat cerebellum. Using unsupervised analysis and multivariate statistical analysis, we separated the Sham and hypothyroid groups clearly and screened out 23 potential lipid biomarkers related to hypothyroidism that were primarily involved in sphingolipid metabolism, glycerophospholipid metabolism and beta-oxidation of fatty acid. Subsequently, we conducted computational analysis to build and simulate the lipid network of hypothyroidism, knowing that it would be useful to elucidate the pathological mechanism of hypothyroidism. Based on the selected 23 lipid biomarkers, we systematically evaluated the therapeutic effects of Sini decoction (SND) and the positive drug T4. The results showed that both SND and T4 can to some extent convert the pathological status of hypothyroidism through different pathways. Overall, this investigation illustrates that lipidomic profiling approach is powerful in giving a complementary view to the pathophysiology of hypothyroidism and offers a valuable tool for systematic study of the therapeutic effects of SND on hypothyroidism at lipid level. PMID- 25435290 TI - Commentary on 'External Validation of Models Predicting Survival After Ruptured Abdominal Aortic Aneurysm Repair'. PMID- 25435291 TI - Re: "Spontaneous Delayed Sealing in Selected Patients With a Primary Type Ia Endoleak After Endovascular Aneurysm Repair.' Does Correcting the Picture Save the Life?'. PMID- 25435289 TI - Khat use and appetite: an overview and comparison of amphetamine, khat and cathinone. AB - ETHNOPHARMACOLOGICAL RELEVANCE: To understand the role of khat (Catha edulis) use on the aberrations in appetite and weight which are common comorbidities for khat and other amphetamine users. MATERIALS AND METHODS: We provide a comprehensive overview and conceptual summary of the historical cultural use of khat as a natural stimulant and describe the similarities and differences between cathinone (the main psychoactive constituent of khat) and amphetamine highlighting the limited literature on the neurophysiology of appetite and subsequent weight effects of khat. RESULTS: Animal and some human studies indicate that khat produces appetite suppression, although little is known about mechanisms of this effect. Both direct and indirect effects of khat stem from multiple factors including behavioral, chemical and neurophysiological effects on appetite and metabolism. Classic and newly identified appetite hormones have not been explored sufficiently in the study of appetite and khat use. Unique methodological challenges and opportunities are encountered when examining effects of khat and cathinone including khat-specific medical comorbidities, unique route of administration, differential patterns of behavioral effects relative to amphetamines and the nascent state of our understanding of the neurobiology of this drug. CONCLUSION: A considerable amount of work remains in the study of the appetite effects of khat chewing and outline a program of research that could inform our understanding of this natural amphetamine's appetite effects and help prepare health care workers for the unique health effects of this drug. PMID- 25435292 TI - Reverse shoulder arthroplasty due to glenoid bone defects. AB - OBJECTIVE: Reverse shoulder arthroplasty is becoming a useful tool for many diseases of the shoulder. Any severe glenoid bone defect may affect the fixing of the glenoid component. The aim of this paper is to evaluate the medium-term outcomes of reverse shoulder arthroplasty associated with a glenoplasty. MATERIALS AND METHODS: A retrospective study was conducted on 5 patients from our hospital, selected due to glenoid defects of different etiology. All of them where treated with reverse shoulder arthroplasty associated with glenoplasty with bone graft. RESULTS: The minimum follow-up was one year (mean 30.4 months). All grafts were radiologically integrated, with no signs of resorption or necrosis being observed. At 12 months, the Constant score was 66.75 and the mean EVA score was 1. DISCUSSION: Glenoplasty surgery is technically demanding for restoring original bone size in patients with glenoid structural defects, enabling a reverse shoulder arthroplasty to be implanted. Thus improving both the function and clinical outcomes in selected patients with glenohumeral pathology and providing them with a solution. PMID- 25435293 TI - SECOT-GEDOS consensus on pre-surgical pain management in knee and hip arthrosis. AB - OBJECTIVE: To develop recommendations, based on best evidence and experience, on pain management in patients undertaking total knee or hip replacement. METHODS: Nominal group methodology was followed. A group of experts was selected (5 orthopedics, 1 anesthesiologist), who defined the scope, users, topics, preliminary recommendations, and 3 systematic reviews: efficacy and safety of pre surgical analgesia regarding to post-surgical pain, efficacy and safety of pre emptive analgesia and pre-operative factors of post-operative pain. The level of evidence and grade of recommendation was established using the Oxford Centre for Evidence Based Medicine, and the level of agreement with the Delphi technique (2 rounds). The Delphi was extended to 39 orthopedics and anesthesiologists. The whole document was reviewed by all the experts. RESULTS: A total of 21 recommendations were produced. They include specific pharmacological treatment, as well as the evaluation and monitoring of patients on this treatment, and post operative pre-emptive treatment. Agreement above 70% was reached in 19 recommendations. CONCLUSIONS: In patients undergoing total knee or hip replacement, a proper evaluation, follow-up, pharmacological and non pharmacological treatment of predictors of poor surgical outcomes should be performed, especially those related to pre-operative pain. This can improve post operative pain and surgery outcomes. PMID- 25435294 TI - Level of response to telematic questionnaires on Health Related Quality of Life on total knee replacement. AB - Questionnaires measuring health-related quality of life are difficult to perform and obtain for patients and professionals. Computerised tools are now available to collect this information. The objective of this study was to assess the ability of patients undergoing total knee replacement to fill in health-related quality-of-life questionnaires using a telematic platform. MATERIAL AND METHODS: Ninety eight consecutive patients undergoing total knee arthroplasty were included. Participants were given an access code to enter the website where they had to respond to 2 questionnaires (SF8 and the reduced WOMAC), and 3 additional questions about the difficulty in completing the questionnaires. RESULTS: A total of 98 patients agreed to participate: 45 males and 53 females (mean age 72.7 years). Fourteen did not agree to participate due to lack of internet access. Of the final 84 participants, 50% entered the website, and only 36 answered all questions correctly. Of the patients who answered the questionnaire, 80% were helped by a relative or friend, and 22% reported difficulty accessing internet. CONCLUSION: The use of telematic systems to respond to health-related quality of life questionnaires should be used cautiously, especially in elderly population. It is likely that the population they are directed at is not prepared to use this type of technology. Therefore, before designing telematics questionnaires it must be ensured that they are completed properly. PMID- 25435296 TI - Association between household food access insecurity and nutritional status indicators among children aged <5 years in Nepal: results from a national, cross sectional household survey. AB - OBJECTIVE: To examine the association between household food insecurity score and Z-scores of childhood nutritional status indicators. DESIGN: Population-based, cross-sectional survey, Nepal Demographic and Health Survey 2011. SETTING: A nationally representative sample of 11 085 households selected by a two-stage, stratified cluster sampling design to interview eligible men and women. SUBJECTS: Children (n 2591) aged 0-60 months in a sub-sample of households selected for men's interview. RESULTS: Prevalence of moderate and severe household food insecurity was 23.2% and 19.0%, respectively, for children aged 0-60 months. Weighted prevalence rates for stunting (height-for-age Z-score (HAZ) <-2), wasting (weight-for-height Z-score (WHZ) <-2) and underweight (weight-for-age Z score (WAZ) <-2) were 41.6% (95% CI 38.9, 44.3%), 11.5% (95% CI 9.8, 13.2%) and 30.1% (95% CI 27.5, 32.8%), respectively. Prevalences of stunting, severe stunting (HAZ<-3) and underweight by level of household food insecurity were statistically significant (P<0.001). By multiple linear regression analyses and after adjustment for sociodemographic, child and environmental factors, household food access insecurity score was associated with HAZ (beta=-0.02, P=0.01) and WAZ (beta=-0.01, P=0.01) but was not associated with WHZ and BMI-for-age Z-score. A 10-point increase in household food access insecurity score was associated with a decrease in HAZ of 0.2 (95% CI 0.05, 0.39) and decrease in WAZ of 0.1 (95% CI 0.03, 0.27). CONCLUSIONS: Our results from a nationally representative sample confirm the previously reported association of household food insecurity with stunting and underweight. Community nutrition interventions may use household food insecurity scales for identifying those households where children may be at risk of growth faltering. PMID- 25435295 TI - Cyanidin-3-glucoside isolated from mulberry fruit protects pancreatic beta-cells against oxidative stress-induced apoptosis. AB - The extract obtained from berries contains high amounts of anthocyanins, and this extract is used as a phytotherapeutic agent for different types of diseases. In this study, we examined the cytoprotective effects of cyanidin-3-glucoside (C3G) isolated from mulberry fruit against pancreatic beta-cell apoptosis caused by hydrogen peroxide (H2O2)-induced oxidative stress. The MIN6 pancreatic beta-cells were used to investigate the cytoprotective effects of C3G on the oxidative stress-induced apoptosis of cells. Cell viability was examined by MTT assay and lipid peroxidation was assayed by thiobarbituric acid (TBA) reaction. Immunofluorescence staining, flow cytometry and western blot analysis were also used to determine apoptosis and the expression of proteins associated with apoptosis. Our results revealed that H2O2 increased the rate of apoptosis by stimulating various pro-apoptotic processes, such as the generation of intracellular reactive oxygen species (ROS), lipid peroxidation, DNA fragmentation and caspase-3 activation. However, C3G reduced the H2O2-induced cell death in the MIN6N pancreatic beta-cells. In addition, we confirmed that H2O2 activated mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK) and p38 MAPK. C3G inhibited the phosphorylation of ERK and p38 without inducing the phosphorylation of JNK. Furthermore, C3G regulated the intrinsic apoptotic pathway-associated proteins, such as proteins belonging to the Bcl-2 family, cytochrome c and caspase-3. Taken together, our results suggest that C3G isolated from mulberry fruit has potential for use as a phytotherapeutic agent for the prevention of diabetes by preventing oxidative stress-induced beta-cell apoptosis. PMID- 25435298 TI - Is laparoscopic sleeve gastrectomy a lower risk bariatric procedure compared with laparoscopic Roux-en-Y gastric bypass? A meta-analysis. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is the current "gold standard" bariatric procedure in the United States. Laparoscopic sleeve gastrectomy (LSG) has recently become a commonly performed procedure for many reasons, including patients' perception that LSG has less complexity and invasiveness, and lower risk. Our objective was to review the literature and compare the leak rates, morbidity, and mortality for LRYGB versus LSG. METHODS: Publications from 2002 to 2012 with n greater than or equal to 25 and postoperative leak rate reported were included. Statistical analysis included chi square according to patient number. RESULTS: Twenty-eight (10,906 patients) LRYGB and 33 (4,816 patients) LSG articles were evaluated. Leak rates after LRYGB versus LSG were 1.9% (n = 206) versus 2.3% (n = 110), respectively (P = .077). Mortality rates were .4% (27/7,117) for LRYGB and .2% (7/3,594) for LSG (P = .110). Timing from surgery to leak ranged from 1 to 12 days for LRYGB versus 1 to 35 days for LSG. CONCLUSIONS: Leak and mortality rates after LRYGB and LSG were comparable. The appropriate procedure should be tailored based on patient factors, comorbidities, patient and surgeon comfort level, surgeon experience, and institutional outcomes. PMID- 25435297 TI - Innovation and the difficult gallbladder: tread lightly. AB - Innovation has advanced the treatment of biliary disease significantly, but further progress is needed to improve safety. An uncommonly used technique is described, which could potentially prevent serious complications for the difficult gallbladder. PMID- 25435299 TI - Should clopidogrel be discontinued before laparoscopic cholecystectomy? AB - BACKGROUND: The perioperative management of clopidogrel remains an area of controversy. METHODS: An institutional review board-approved retrospective review of patients undergoing a laparoscopic cholecystectomy while on clopidogrel from 2008 to 2012 was performed. These patients were then matched with a nonclopidogrel cohort based on American Society of Anesthesiologists score and emergent or elective surgery. Intraoperative estimated blood loss, operative time, length of stay, and 30-day morbidity were compared. RESULTS: Thirty-six clopidogrel and 36 control patient records were analyzed. There were no significant differences in age, body mass index, sex, or incidence of coronary artery disease, diabetes, hyperlipidemia, and congestive heart failure. Estimated blood loss averaged 50 mL in the clopidogrel group and 47 mL in the control group (P = nonsignificant). There were no significant differences in operative time, 30 day morbidity, or length of stay between the 2 groups. CONCLUSIONS: Laparoscopic cholecystectomy performed on patients maintained on clopidogrel during the perioperative period did not produce an increase in blood loss, operative time, 30-day morbidity, or length of stay. PMID- 25435300 TI - Preoperative dosing of low-molecular-weight heparin in hepatopancreatobiliary surgery. AB - BACKGROUND: Venous thromboembolism is a common cause of morbidity. Guidelines recommend perioperative thromboprophylaxis, but clinicians remain cautious of bleeding after major oncologic resections. METHODS: Retrospective analysis of a single institution's prospective hepatopancreatobiliary database was performed for patients undergoing surgery between January 2010 and February 2013. A total of 223 patients received postoperative thromboprophylaxis and 93 patients were dosed with low-molecular-weight heparin (LMWH) preoperatively. RESULTS: Two hundred twenty-three patients were analyzed; 50.6% underwent pancreatic and 49.3% underwent liver resection. There were no differences in previous venous thromboembolism (3.8% vs 3.3%; P = .56) or preoperative venous thromboembolism scores (5.74 vs 5.67; P = .82). Estimated blood loss (537 mL vs 592 mL; P = .54), transfusions (25.4% vs 30.4%; P = .25), and complications (52.3% vs 43.5%; P = .12) were equivalent. Incidence of thromboembolic events was lower (6.1% vs 1.1%; P = .05); however, bleeding requiring intervention was increased in the preoperative LMWH group (10.9% vs 3.1%; P = .026). CONCLUSIONS: Caution must be exercised when using LMWH, as bleeding remains a concern for oncologic hepatopancreatobiliary surgery. PMID- 25435301 TI - Piperlongumine attenuates collagen-induced arthritis via expansion of myeloid derived suppressor cells and inhibition of the activation of fibroblast-like synoviocytes. AB - Piperlonguminine (PL), a key compound from the Piper longum fruit, is known to exhibit anti-tumor and anti-inflammatory activities. However, little is known about its effects on collagen-induced arthritis (CIA). Fibroblast-like synoviocytes (FLS) have a pivotal role in the development of rheumatoid arthritis (RA). Myeloid-derived suppressor cells (MDSCs) are able to suppress T cell responses and have important roles in the regulation of autoimmune arthritis. The current study investigated whether PL alters the progression of RA. It was determined that PL reduces the arthritis score and histopathologic lesions in a mouse model of CIA. PL also reduces the expression levels of serum anti-collagen II antibodies (anti-CII), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-23 and IL-17 in CIA mice. In draining lymph nodes (DLNs), MDSCs were significantly expanded, however, the number of Th17 cells was markedly decreased by PL treatment. Additionally, PL reduced secretion of IL-1beta, IL-23 and IL-17 by TNF-alpha-stimulated human RA FLS. PL significantly inhibited the migration and invasion of TNF-alpha-stimulated human RA FLS. These results indicate that PL may be a candidate therapeutic agent for the treatment of RA, via the expansion of MDSCs and the inhibition of the Th17 response and activation of FLS. PMID- 25435302 TI - Matrix-specific anchors: a new concept for targeted delivery and retention of therapeutic cells. AB - Biomedical strategies for tissue engineering and repair utilize specific cells, scaffolds, and growth factors to reconstruct elements of damaged tissue. The cellular element of these strategies is limited, however, by poor efficiency of delivery and retention of therapeutic cells in target sites. We propose that the presence of a cellular anchor that is able to specifically bind a defined element of target tissue will facilitate efficient binding and retention of therapeutic cells, thereby promoting repair of the target site. To do so, we engineered an artificial collagen-specific anchor (ACSA) that is able to specifically bind collagen I. The ACSA was engineered by creating a construct comprising rationally designed consecutive domains. The binding specificity of the ACSA was achieved by employing variable regions of a monoclonal antibody that recognizes a unique epitope present in human collagen I. Meanwhile, cell membrane localization of the ACSA was provided by the presence of a transmembrane domain. We determined that the ACSA was localized within cell membranes and interacted with its intended target, that is, collagen I. We have demonstrated that, in comparison to the control, the cells expressing the ACSA attached better to collagen I and exhibited improved retention in sites of seeding. We have also demonstrated that the presence of the ACSA did not interfere with cell proliferation, the biosynthesis of endogenous collagen I, or the biological functions of native collagen receptors. Since the presented cell delivery system utilizes a common characteristic of major connective tissues, namely the presence of collagen I, the findings described here could have a broad positive impact for improving the repair processes of tendon, ligament, bone, intervertebral disc, skin, and other collagen I-rich connective tissues. If successful, the ACSA approach to deliver cells will serve as an outline for developing cell delivery methods that target other elements of extracellular matrices, including other collagen types, laminins, and fibronectins. PMID- 25435303 TI - Natural killer T cells play a necessary role in modulating of immune-mediated liver injury by gut microbiota. AB - Gut microbiota are implicated in many liver diseases. Concanavalin A (ConA) induced hepatitis is a well-characterized murine model of fulminant immunological hepatic injury. Oral administration of pathogenic bacteria or gentamycin to the mice before ConA injection, liver injury and lymphocyte distribution in liver and intestine were assessed. Our data show that administration of pathogenic bacteria exacerbated the liver damage. There was more downregulation of activation-induced natural killer T (NKT) cells in the liver of pathogenic bacteria-treated ConA groups. Also, there was a negative correlation between the numbers of hepatic NKT cells and liver injury in our experiments. Moreover, intestinal dendritic cells (DCs) were increased in pathogenic bacteria-treated ConA groups. The activation of DCs in Peyer's patches and the liver was similar to the intestine. However, depletion of gut gram-negative bacteria alleviated ConA-induced liver injury, through suppressed hepatic NKT cells activation and DCs homing in liver and intestine. In vitro experiments revealed that DCs promoted NKT cell cytotoxicity against hepatocyte following stimulation with pathogenic bacteria. Our study suggests that increased intestinal pathogenic bacteria facilitate immune-mediated liver injury, which may be due to the activation of NKT cells that mediated by intestinal bacterial antigens activated DCs. PMID- 25435304 TI - Oxidative regioselective amination of chromones exposes potent inhibitors of the hedgehog signaling pathway. AB - A transition metal-free, oxidative, regioselective cross-coupling between non functionalized azoles and chromones at C2-position was developed. A broad reaction scope and further transformation of products were demonstrated. The biological evaluation of products revealed a novel class of hedgehog signaling pathway inhibitors. PMID- 25435310 TI - Microbiome: A viral understudy for commensal bacteria. PMID- 25435307 TI - Prochlorococcus: the structure and function of collective diversity. AB - The marine cyanobacterium Prochlorococcus is the smallest and most abundant photosynthetic organism on Earth. In this Review, we summarize our understanding of the diversity of this remarkable phototroph and describe its role in ocean ecosystems. We discuss the importance of interactions of Prochlorococcus with the physical environment, with phages and with heterotrophs in shaping the ecology and evolution of this group. In light of recent studies, we have come to view Prochlorococcus as a 'federation' of diverse cells that sustains its broad distribution, stability and abundance in the oceans via extensive genomic and phenotypic diversity. Thus, it is proving to be a useful model system for elucidating the forces that shape microbial populations and ecosystems. PMID- 25435311 TI - Bacterial pathogenesis: Food for cholera. PMID- 25435312 TI - Smectite clay--inorganic nanoparticle mixed suspensions: phase behaviour and rheology. AB - Smectite clay minerals and their suspensions have long been of both great scientific and applications interest and continue to display a remarkable range of new and interesting behaviour. Recently there has been an increasing interest in the properties of mixed suspensions of such clays with nanoparticles of different size, shape and charge. This review aims to summarize the current status of research in this area focusing on phase behaviour and rheological properties. We will emphasize the rich range of data that has emerged for these systems and the challenges they present for future investigations. The review starts with a brief overview of the behaviour and current understanding of pure smectite clays and their suspensions. We then cover the work on smectite clay inorganic nanoparticle mixed suspensions according to the shape and charge of the nanoparticles - spheres, rods and plates either positively or negatively charged. We conclude with a summary of the overarching trends that emerge from these studies and indicate where gaps in our understanding need further research for better understanding the underlying chemistry and physics. PMID- 25435309 TI - Molecular mechanisms of antibiotic resistance. AB - Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics. PMID- 25435313 TI - A comparison of brain volume and cortical thickness in excoriation (skin picking) disorder and trichotillomania (hair pulling disorder) in women. AB - Skin picking disorder (SPD) and trichotillomania (hair pulling disorder, or HPD) significantly overlap in terms of clinical features. However, few studies have directly compared structural brain data in these disorders. The aim of this study was to compare volumes of brain structures and cortical thickness in patients with SPD and HPD, and determine involvement of fronto-striatal pathways. Seventeen female SPD, 17 HPD and 15 healthy age-matched controls underwent clinical assessment and structural MRI imaging. Group differences were determined in brain volume and cortical thickness, controlling for illness severity. Participants with SPD had greater volume of the ventral striatum bilaterally; and reduced cortical thickness in right hemisphere frontal areas, and greater thickness of the cuneus bilaterally compared to HPD and control participants. HPD participants demonstrated reduced thickness of the right parahippocampal gyrus compared to SPD and control participants. The findings here are partially consistent with previous structural work in SPD, and suggest some differences in the neurobiology of SPD and HPD. The more extensive involvement of the ventral striatum in SPD may suggest greater involvement of the reward system, while the more extensive involvement of the parahippocampal gyrus in HPD may be consistent with the dissociative symptoms often seen in these patients. PMID- 25435314 TI - Dopamine bioavailability in the mPFC modulates operant learning performance in rats: an experimental study with a computational interpretation. AB - Dopamine encodes reward and its prediction in reinforcement learning. Catechol-O methyltransferase (COMT) activity in the medial prefrontal cortex (mPFC) has been shown to influence cognitive abilities by modifying dopamine clearance. Nevertheless, it is unknown how COMT in the mPFC influences operant learning. Systemic entacapone (50mg/kg), as well as local entacapone (3 pg) and recombinant COMT (17 MUg) in the mPFC were administered to male Long Evans rats prior to training in an operant conditioning task. We found that systemic and local administration of the COMT inhibitor entacapone significantly improves learning performance. Conversely, recombinant COMT administration totally impaired learning. These data have been interpreted through a computational model where the phasic firing of dopaminergic neurons was computed by means of a temporal difference algorithm and dopamine bioavailability in the mPFC was simulated with a gating window. The duration of this window was selected to simulate the effects of inhibited or enhanced COMT activity (by entacapone or recombinant COMT respectively). The model accounts for an improved performance reproducing the entacapone effects, and a detrimental impact on learning when the clearance is increased reproducing the recombinant COMT effects. The experimental and computational results show that learning performance can be deeply influenced by COMT manipulations in the mPFC. PMID- 25435315 TI - Environmental heat stress enhances mental fatigue during sustained attention task performing: evidence from an ASL perfusion study. AB - This study was to investigate the potential enhancing effect of heat stress on mental fatigue progression during sustained attention task using arterial spin labeling (ASL) imaging. Twenty participants underwent two thermal exposures in an environmental chamber: normothermic (NT) condition (25 degrees C, 1h) and hyperthermic (HT) condition (50 degrees C, 1h). After thermal exposure, they performed a twenty-minute psychomotor vigilance test (PVT) in the scanner. Behavioral analysis revealed progressively increasing subjective fatigue ratings and reaction time as PVT progressed. Moreover, heat stress caused worse performance. Perfusion imaging analyses showed significant resting-state cerebral blood flow (CBF) alterations after heat exposure. Specifically, increased CBF mainly gathered in thalamic-brainstem area while decreased CBF predominantly located in fronto-parietal areas, anterior cingulate cortex, posterior cingulate cortex, and medial frontal cortex. More importantly, diverse CBF distributions and trend of changes between both conditions were observed as the fatigue level progressed during subsequent PVT task. Specifically, higher CBF and enhanced rising trend were presented in superior parietal lobe, precuneus, posterior cingulate cortex and anterior cingulate cortex, while lower CBF or inhibited rising trend was found in dorsolateral frontal cortex, medial frontal cortex, inferior parietal lobe and thalamic-brainstem areas. Furthermore, the decrease of post-heat resting-state CBF in fronto-parietal cortex was correlated with subsequent slower reaction time, suggesting prior disturbed resting-state CBF might be indicator of performance potential and fatigue level in following task. These findings may provide proof for such a view: heat stress has a potential fatigue-enhancing effect when individual is performing highly cognition-demanding attention task. PMID- 25435317 TI - Theory of mind and decision-making processes are impaired in Parkinson's disease. AB - Prefrontal cortex plays a vital role in the theory of mind (ToM) and decision making, as shown in functional brain imaging and lesion studies. Considering the primary neuropathology of Parkinson's disease (PD) involving the frontal lobe system, patients with PD are expected to exhibit deficits in ToM and social decision making. The aim of this study was to investigate affective ToM and decision making in patients with PD and healthy controls (HC) in a task assessing affective ToM (Reading the Mind in the Eyes, RME) and two decision-making tasks (Iowa Gambling Task, IGT; Game of Dice Task, GDT). Consistent with previous findings, patients with PD were impaired in the affective ToM task, and when making decisions under ambiguity and in risk situations. The score of emotion recognition in the RME task was negatively correlated with the severity of the disease and positively correlated with the total number of advantageous cards chosen in the IGT. However, the final capital in the GDT was correlated with memory impairment. The present study implies that affective ToM and decision making under ambiguity may share similar neural mechanisms, while decision making under ambiguity and decision making under risk may involve processing within different neural networks. PMID- 25435316 TI - Mouse genetic differences in voluntary wheel running, adult hippocampal neurogenesis and learning on the multi-strain-adapted plus water maze. AB - Moderate levels of aerobic exercise broadly enhance cognition throughout the lifespan. One hypothesized contributing mechanism is increased adult hippocampal neurogenesis. Recently, we measured the effects of voluntary wheel running on adult hippocampal neurogenesis in 12 different mouse strains, and found increased neurogenesis in all strains, ranging from 2- to 5-fold depending on the strain. The purpose of this study was to determine the extent to which increased neurogenesis from wheel running is associated with enhanced performance on the water maze for 5 of the 12 strains, chosen based on their levels of neurogenesis observed in the previous study (C57BL/6 J, 129S1/SvImJ, B6129SF1/J, DBA/2 J, and B6D2F1/J). Mice were housed with or without a running wheels for 30 days then tested for learning and memory on the plus water maze, adapted for multiple strains, and rotarod test of motor performance. The first 10 days, animals were injected with BrdU to label dividing cells. After behavioral testing animals were euthanized to measure adult hippocampal neurogenesis using standard methods. Levels of neurogenesis depended on strain but all mice had a similar increase in neurogenesis in response to exercise. All mice acquired the water maze but performance depended on strain. Exercise improved water maze performance in all strains to a similar degree. Rotarod performance depended on strain. Exercise improved rotarod performance only in DBA/2 J and B6D2F1/J mice. Taken together, results demonstrate that despite different levels of neurogenesis, memory performance and motor coordination in these mouse strains, all strains have the capacity to increase neurogenesis and improve learning on the water maze through voluntary wheel running. PMID- 25435318 TI - The therapeutic armamentarium in migraine is quite elderly. AB - Global Burden of Disease 2010 study considers migraine as one of the most important noncommunicable diseases in the world, classifying it third in terms of global prevalence (14.70%): it sums up the 54.19% of all the years of life lived with disabilities caused by the rest of all neurological disorders. This Editorial provides an historical excursus of old and new-entry molecules in migraine therapeutic area. Drugs for acute treatment such as triptans date back to the early 1990s with the appearance of sumatriptan and the following six triptans in the years immediately after (zolmitriptan, rizatriptan, naratriptan, eletriptan, almotriptan, frovatriptan). Prophylaxis drugs, dedicated to patients with medium/high frequency of crises, show as last entries topiramate and botulinum toxin type A. The use of this preventative group, with its intrinsic limits, is mandatory to reduce the risk of migraine chronification, a highly harmful clinical phenomenon that produces as its natural consequence the medication overuse headache. The development of new acute and preventative compounds, such as 5HT (serotonin) 1F receptor (5-HT1F) agonist lasmiditan, calcitonin gene related peptide (CGRP) peptide receptor antagonists, anti-CGRP monoclonal antibodies (LY2951742, ALD403, LBR101) and anti-CGRP-r monoclonal antibody (AMG334), is warranted and might be soon completed in order to offer new opportunities to migraine patients. PMID- 25435319 TI - Identification of the target binding site of ethanolamine-binding aptamers and its exploitation for ethanolamine detection. AB - Aptamers are promising recognition elements for sensitive and specific detection of small molecules. We have previously selected ssDNA aptamers for ethanolamine, one of the smallest aptamer targets so far. The work presented here focuses on the determination of the binding region within the aptamer structure and its exploitation for the development of an aptamer-based assay for detection of ethanolamine. Sequence analysis of the aptamers resulted in the identification of a G-rich consensus sequence, which was able to fold in a typical two- or three layered G-quartet structure. Experiments with stepwise truncated variants of the aptamers revealed that the consensus sequence is responsible and sufficient for binding to the target. On the basis of the knowledge of the aptamers binding site, we developed an aptamer-based microarray assay relying on competition between ethanolamine and an oligonucleotide complementary to the consensus sequence. Competitive binding of ethanolamine and fluorescently labeled complementary oligonucleotides resulted in fluorescence intensities dependent on ethanolamine concentration with a limit of detection of 10 pM. This method enables detection of small molecules without any labeling of analytes. The competitive assay could potentially be transferred to other aptamers and thus provides a promising system for aptamer-based detection of diverse small molecules. PMID- 25435320 TI - Plasticity of specialized metabolism as mediated by dynamic metabolons. AB - The formation of specialized metabolites enables plants to respond to biotic and abiotic stresses, but requires the sequential action of multiple enzymes. To facilitate swift production and to avoid leakage of potentially toxic and labile intermediates, many of the biosynthetic pathways are thought to organize in multienzyme clusters termed metabolons. Dynamic assembly and disassembly enable the plant to rapidly switch the product profile and thereby prioritize its resources. The lifetime of metabolons is largely unknown mainly due to technological limitations. This review focuses on the factors that facilitate and stimulate the dynamic assembly of metabolons, including microenvironments, noncatalytic proteins, and allosteric regulation. Understanding how plants organize carbon fluxes within their metabolic grids would enable targeted bioengineering of high-value specialized metabolites. PMID- 25435321 TI - Blood transfusion practice: a survey in Sichuan, China. AB - OBJECTIVE: To get full knowledge of current conditions and development in the past seven years of clinical transfusion practice in Sichuan, China. STUDY DESIGN AND METHODS: This survey was performed by means of a questionnaire which consisted of three parts of questions including basic conditions of blood banks in the hospitals, procedures for clinical blood transfusion and the utilization of different types of blood products. Thirty-five representative hospitals from different geographic locations in Sichuan province participated in this survey. RESULTS: All of the 35 hospitals returned the questionnaires and 33 hospitals (94.3%) answered the questions completely. The blood bank information system began to be used by more hospitals from 2006 (21.21%, 7/33) to 2012 (48.48%, 16/33). Automated grouping and cross-matching systems have not been used in level 2 hospitals and only 3 level 3 hospitals used automated systems in 2012. Still less common were procedures for evaluation of blood order forms for appropriateness (2/33, 6.06%) and evaluation of appropriateness and effect of blood component transfusion (8/33, 24.2%), and all the hospitals having these procedures are level 3 hospitals. The percentage of whole blood usage in the volume of all types of blood products used decreased a lot from 7.45% in 2006 to 0.16% in 2010. Technological instruments for bedside checking are not used by any of the hospitals. CONCLUSIONS: The transfusion service degree of the hospitals in Sichuan, China, has developed a lot in the past seven years; however, there are still some problems including whole blood still being used, albeit decreasing; lack of independent blood banks within the hospitals; lack of dedicated personnel for the transfusion services; lack of education; lack of blood bank information systems and automation; lack of screening for appropriateness for blood orders. Thus, the quality control center of clinical blood transfusion (QCCCBT) of Sichuan province should help the transfusion departments to attract more investment in staffing, equipment and information system from the hospitals, enhance the training of transfusion department staffs, and emphasize the supervision of transfusion department's work on directing clinical blood utilization and evaluating clinical transfusion appropriateness. PMID- 25435322 TI - Acute and long-term psychiatric side effects of mefloquine: a follow-up on Danish adverse event reports. AB - BACKGROUND: The aim of the study was to explore the profile of acute and long term psychiatric side effects associated with mefloquine. METHODS: Subjects (n = 73) reported to a Danish national register during five consecutive years for mefloquine associated side effects were included. Acute psychiatric side effects were retrospectively assessed using the SCL-90-R and questions based on Present State Examination (PSE). Subjects reporting suspected psychotic states were contacted for a personal PSE interview. Electronic records of psychiatric hospitalizations and diagnoses were cross-checked. Long-term effects were evaluated with SF-36. SCL-90-R and SF-36 data were compared to age- and gender matched controls. RESULTS: In the SCL-90-R, clinically significant scores for anxiety, phobic anxiety and depression were found in 55%, 51%, and 44% of the mefloquine group. Substantial acute phase psychotic symptoms were found in 15% and were time-limited. Illusions/hallucinations were more frequently observed among women. Cases of hypomania/mania in the acute phase were 5.5%. Significant long-term mental health effects were demonstrated for the SF-36 subscales mental health (MH), role emotional (RE), and vitality (VT) in the mefloquine group compared to matched controls. CONCLUSION: The most frequent acute psychiatric problems were anxiety, depression, and psychotic symptoms. Data indicated that subjects experiencing acute mefloquine adverse side effects may develop long-term mental health problems with a decreased sense of global quality of life with lack of energy, nervousness, and depression. PMID- 25435323 TI - A label-free and sensitive fluorescent method for the detection of uracil-DNA glycosylase activity. AB - The activity of uracil-DNA glycosylase (UDG), an enzyme in the base excision repair, is detected at a high sensitivity by a DNA substrate containing only one uracil through a label-free fluorescent approach, which is also successfully applied for the measurement of UDG inhibitors. PMID- 25435324 TI - Structural mechanism of nuclear transport mediated by importin beta and flexible amphiphilic proteins. AB - Karyopherin beta family proteins mediate the nuclear/cytoplasmic transport of various proteins through the nuclear pore complex (NPC), although they are substantially larger than the size limit of the NPC.To elucidate the molecular mechanism underlying this paradoxical function, we focused on the unique structures called HEAT repeats, which consist of repetitive amphiphilic alpha helices. An in vitro transport assay and FRAP analyses demonstrated that not only karyopherin beta family proteins but also other proteins with HEAT repeats could pass through the NPC by themselves, and serve as transport mediators for their binding partners. Biochemical and spectroscopic analyses and molecular dynamics simulations of purified HEAT-rich proteins revealed that they interact with hydrophobic groups, including phenyl and alkyl groups, and undergo reversible conformational changes in tertiary structures, but not in secondary structures. These results show that conformational changes in the flexible amphiphilic motifs play a critical role in translocation through the NPC. PMID- 25435325 TI - Crystal structure of the human, FIC-domain containing protein HYPE and implications for its functions. AB - Protein AMPylation, the transfer of AMP from ATP to protein targets, has been recognized as a new mechanism of host-cell disruption by some bacterial effectors that typically contain a FIC-domain. Eukaryotic genomes also encode one FIC domain protein,HYPE, which has remained poorly characterized.Here we describe the structure of human HYPE, solved by X-ray crystallography, representing the first structure of a eukaryotic FIC-domain protein. We demonstrate that HYPE forms stable dimers with structurally and functionally integrated FIC-domains and with TPR-motifs exposed for protein-protein interactions. As HYPE also uniquely possesses a transmembrane helix, dimerization is likely to affect its positioning and function in the membrane vicinity. The low rate of auto AMPylation of the wild-type HYPE could be due to autoinhibition, consistent with the mechanism proposed for a number of putative FIC AMPylators. Our findings also provide a basis to further consider possible alternative cofactors of HYPE and distinct modes of target-recognition. PMID- 25435326 TI - Molecular mechanisms of phospholipase C beta3 autoinhibition. AB - Phospholipase C beta (PLCbeta) enzymes are dramatically activated by heterotrimeric G proteins. Central to this response is the robust autoinhibition of PLCbeta by the X-Y linker region within its catalytic core and by the Halpha2' helix in the C-terminal extension of the enzyme. The molecular mechanism of each and their mutual dependence are poorly understood. Herein, it is shown that distinct regions within the X-Y linker have specific roles in regulating activity. Most important,an acidic stretch within the linker stabilizes a lid that occludes the active site, consistent with crystal structures of variants lacking this region. Inhibition by the Halpha2' helix is independent of the X-Y linker and likely regulates activity by limiting membrane interaction of the catalytic core. Full activation of PLCbeta thus requires multiple independent molecular events induced by membrane association of the catalytic core and by the binding of regulatory proteins. PMID- 25435327 TI - Structural Principles of CRISPR RNA Processing. AB - The Cas6 superfamily, the Cas5d subclass, and the host RNase III endoribonucleases are responsible for producing small RNAs (crRNA) that function in the CRISPR-Cas immunity. The three enzymes may also interact with the crRNA associated nucleic acid interference complexes. Recent development in structural biology of Cas6 and Cas5d and their complexes with RNA substrates has lent new insights on principles of crRNA processing and the structural basis for linking crRNA processing to interference. Both Cas6 and Cas5d are characterized by the presence of the ferredoxin-like fold, but each has unique domain arrangement and insertion elements. Cas6 proteins often interact strongly with stable RNA stem loop structures but can also fold unstructured RNA into stem-loop structures for their cleavage. The extraordinarily simple fold, the wide range of substrates, and kinetic properties of Cas6/Cas5d make them excellent candidates for exploring molecular evolution, protein-RNA interaction, and biotechnology applications. PMID- 25435328 TI - Homolog of allograft inflammatory factor-1 induces macrophage migration during innate immune response in leech. AB - Allograft inflammatory factor-1 (AIF-1) is a 17-kDa cytokine-inducible calcium binding protein that, in vertebrates, plays an important role in the allograft immune response. Its expression is mostly limited to the monocyte/macrophage lineage. Until recently, AIF-1 was assumed to be a novel molecule involved in inflammatory responses. To clarify this aspect, we have investigated the expression of AIF-1 after bacterial challenge and its potential role in regulating the innate immune response in an invertebrate model, the medicinal leech (Hirudo medicinalis). Analysis of an expressed sequence tag library from the central nervous system of Hirudo revealed the presence of the gene Hmaif 1/alias Hmiba1, showing high homology with vertebrate aif-1. Immunohistochemistry with an anti-HmAIF-1 polyclonal antibody revealed the constitutive presence of this protein in spread CD68(+) macrophage-like cells. A few hours after pathogen (bacterial) injection into the body wall, the amount of these immunopositive cells co-expressing HmAIF-1 and the common leucocyte marker CD45 increased at the injected site. Moreover, the recombinant protein HmAIF-1 induced massive angiogenesis and was a potent chemoattractant for macrophages. Following rHmAIF-1 stimulation, macrophage-like cells co-expressed the macrophage marker CD68 and the surface glycoprotein CD45, which, in vertebrates, seems to have a role in the integrin-mediated adhesion of macrophages and in the regulation of the functional responsiveness of cells to chemoattractants. CD45 is therefore probably involved in leech macrophage-like cell activation and migration towards an inflammation site. We have also examined its potential effect on HmAIF-1-induced signalling. PMID- 25435329 TI - Chemometric design to explore pharmacophore features of BACE inhibitors for controlling Alzheimer's disease. AB - The beta-amyloid precursor protein cleavage enzyme (BACE) has been conceived to be an attractive therapeutic target to control Alzheimer's disease (AD). Validated ligand-based pharmacophore mapping was combined with 3D QSAR modeling approaches that include CoMFA, CoMSIA and HQSAR techniques to identify structural and physico-chemical requirements for a potential BACE inhibitor using a database containing 980 structurally diverse compounds, assembled from different reports. A structure-based docking technique was also used to validate the features obtained from the ligand-based models, which were further used to screen the database of compounds designed by a de novo approach. Contour maps of 3D QSAR models, CoMFA (R(2) = 0.880, se = 0.402, Q(2) = 0.596, Rpred(2) = 0.713,) and CoMSIA (R(2) = 0.903, se = 0.362, Q(2) = 0.578, Rpred(2) = 0.715), and a pharmacophore space model (R(2) = 0.833, rmsd = 1.578, Q(2) = 0.845, Rpred(2) = 0. 764) depict that the models are robust and provide an explanation of the important features such as steric, electrostatic, hydrophobic, positive ionization, hydrogen bond acceptor and donor properties, which play important roles for interaction with the receptor site cavity. The HQSAR study (R(2) = 0.823, se = 0.488, Q(2) = 0.823, Rpred(2) = 0.768) and de novo design, which generate new fragments, illustrated the important molecular fingerprints for inhibition. The docking study elucidated the important interactions between the amino acid residues (Gly11, Thr72, Asp228, Gly230, Thr231, Arg235) at the catalytic site of the receptor and the ligand, indicating the structural requirements of the inhibitors. The de novo designed molecules were further screened for ADMET properties, and ligand-receptor interactions of the top hits were analysed by molecular docking to explore pharmacophore features of BACE inhibitors. PMID- 25435330 TI - Effect of OLIG1 on the development of oligodendrocytes and myelination in a neonatal rat PVL model induced by hypoxia-ischemia. AB - OLIG1 is an oligodendrocyte (OL) transcription factor, which can contribute to the proliferation and differentiation of OLs, and the maturation of myelin. The aim of this study was to clarify the role of OLIG1 in neonatal Sprague Dawley rats with periventricular leukomalacia (PVL), induced by hypoxia-ischemia (HI). Newborn rats in the HI group were subjected to ligation of the right carotid artery, followed by 8% oxygen delivery for 2 h, while rats in the normoxia group were only subjected to isolation of the right carotid artery, without exposure to hypoxia. Samples of brain tissue from rats in both groups were collected at 1, 3, 7, 14 and 21 days. In the HI group, observation by transmission electron microscopy (TEM) revealed OLs with a damaged nuclear membrane, cellular atrophy, deformation and necrosis, and cells in myelin with a high number of small vacuoles. A double-label immunofluorescence assay revealed the translocation of OLIG1 from the cytoplasm to the nucleus, while western blot and reverse transcription-quantitative polymerase chain reaction assays showed that there is a significant decrease, followed by an increase, in the gene and protein expression levels of OLIG1 and myelin basic protein (MBP). Despite the increase at the late stages of HI, the final levels of these proteins remained lower than the corresponding levels in the normoxia group. In conclusion, the decreased protein expression of OLIG1 following HI plays an important role in inhibiting the development and maturation of OLs and myelin. Although OLIG1 may, via its nuclear translocation, promote the growth and development of myelin to a certain extent, this factor fails to fully repair injured myelin. PMID- 25435331 TI - Nationwide survey of mother-to-child infections in Japan. AB - OBJECTIVES: The aim of this survey study was to evaluate a state of mother-to child infections in Japan. METHODS: A nationwide survey on 2714 obstetric facilities where regular maternity checkups were carried out was conducted. A primary questionnaire assessed numbers of pregnancies including induced abortion, spontaneous abortion, still-birth as well as live-birth, which were affected by congenital infections of 6 pathogens during a year of 2011. The secondary questionnaire assessed clinical information, diagnostic modality, and the outcome for each case. The clinical features and diagnostic problems were evaluated. RESULTS: The high reply rates for the primary (73.7%) and the secondary questionnaire (100%) were achieved. The presence of congenital infections for 34 cases with cytomegalovirus (CMV), 1 with Toxoplasma gondii, 4 with rubella virus, 5 with Treponema pallidum, 8 with herpes simplex virus, and 69 with parvovirus B19 was confirmed after questionnaire assessment. The incidence of fetal demise among pregnancies with congenital parvovirus B19 infection was up to 71.0%. Eleven mothers with hydrops fetalis received prenatal fetal therapies involving fetal blood transfusion and immunoglobulin administration, whereas only three pregnancies (27.3%) ended in live-births. CONCLUSIONS: This survey study for the first time revealed the annual frequency of pregnancies with mother-to-child infections of 6 pathogens in Japan. The results involve important information and are helpful for clinical practitioners. The majority of neonates with congenital infection of CMV or T. gondii might be undiagnosed in obstetric facilities. PMID- 25435332 TI - Management of central breast tumours with immediate reconstruction of the nipple areola complex; a suggested guide. AB - BACKGROUND: Breast conserving surgery (BCS) for central breast tumours with immediate reconstruction of the nipple-areola complex (NAC) is a relatively new addition to the surgical palette of the oncoplastic surgeon. Most oncoplastic techniques presented to date have only been suitable for women with large breasts. METHODS: From 2012 to 2013, a series of eligible women with central breast cancers were treated with BCS and NAC reconstruction. According to breast size and shape, three different procedures were performed. RESULTS: 20 women were operated, 13 by breast reduction techniques and 7 by anterior intercostal perforator flaps (AICAP flaps). Overall cosmetic results were good to excellent for breast shape, symmetry and neo-nipple projection. CONCLUSION: We present a guideline for selecting the best available surgical technique for immediate NAC reconstruction in women with any breast type, size or shape and describe a new replacement technique using a local perforator flap. PMID- 25435333 TI - Can doubt attenuate access to internal states? Implications for obsessive compulsive disorder. AB - BACKGROUND AND OBJECTIVES: We have previously reported that obsessive-compulsive individuals perform more poorly on tasks that require accurate perception of internal states. As these individuals are also characterized by elevated levels of doubt regarding internal states, the causal relationship between doubt and accurate perception remained unclear. The presented study examines whether undermining participants' confidence in their ability to accurately produce a specific internal state would affect their performance on a task that requires accurate perception of this state. METHODS: Participants were trained to produce specific levels of forearm muscle tension and then required to produce various tension levels in four experimental phases. The first three alternated in terms of whether the participants viewed a biofeedback monitor while the fourth offered participants several times the choice to view the monitor. Prior to the task, half of the participants received instructions that undermined their confidence in their ability to accurately assess their own muscle tension. We measured participants' accuracy in producing the required muscle tension levels and the number of times they requested to view the monitor in the final phase. RESULTS: Undermined confidence participants were less accurate in producing the required muscle tension levels in the absence of biofeedback, and were also more likely to request the monitor in the final phase. CONCLUSIONS: Doubt can affect performance on tasks that require perceiving and experiencing internal states. This finding supports the possibility that access to internal states in OCD is attenuated due to elevated levels of doubt regarding these states. PMID- 25435334 TI - Phosphorylated silk fibroin matrix for methotrexate release. AB - Silk-based matrix was produced for delivery of a model anticancer drug, methotrexate (MTX). The calculation of net charge of silk fibroin and MTX was performed to better understand the electrostatic interactions during matrix formation upon casting. Silk fibroin films were cast at pH 7.2 and pH 3.5. Protein kinase A was used to prepare phosphorylated silk fibroin. The phosphorylation content of matrix was controlled by mixing at specific ratios the phosphorylated and unphosphorylated solutions. In vitro release profiling data suggest that the observed interactions are mainly structural and not electrostatical. The release of MTX is facilitated by use of proteolytic enzymes and higher pHs. The elevated beta-sheet content and crystallinity of the acidified-cast fibroin solution seem not to favor drug retention. All the acquired data underline the prevalence of structural interactions over electrostatical interactions between methotrexate and silk fibroin. PMID- 25435335 TI - The dangerous turn of "brain eating amoeba" in Sindh, Pakistan. PMID- 25435336 TI - Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer's type. AB - Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1-42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline. PMID- 25435338 TI - Repertoires of emotion regulation: A person-centered approach to assessing emotion regulation strategies and links to psychopathology. AB - Despite growing research on emotion regulation (ER) strategies and psychopathology, research has primarily focused on identifying one-to-one associations between ER strategies and symptoms. Thus, little is known about how patterns in the repertoires of ER strategies are associated with different mental disorders. We utilised latent class analysis to identify distinct repertoires of ER strategies, and their links with various psychopathology domains (i.e., anxiety, depression, disordered eating, borderline personality). Participants (N = 531) reported on their use of seven ER strategies in six recalled stressful contexts, as well as on their symptoms of psychopathology. We identified five classes of ER strategies: Low Regulators (n = 168), High Regulators (n = 140), Adaptive Regulators (n = 99), Worriers/Ruminators (n = 96) and Avoiders (n = 28). Generally, High Regulators and Worriers/Ruminators endorsed greater levels of psychopathology, relative to Low and Adaptive Regulators. Our findings underscore the importance of characterising the dynamics of ER repertoires when seeking to understand links between ER strategies and psychopathology. PMID- 25435337 TI - Plasma levels of progranulin and interleukin-6 in frontotemporal lobar degeneration. AB - We have measured plasma progranulin and interleukin-6 in 230 patients with frontotemporal lobar degeneration (FTLD), 104 patients with Alzheimer's disease, and 161 control subjects. We have replicated previous findings of decreased levels of progranulin protein in FTLD because of mutations in GRN and show this is not observed in FTLD cases because of other causes. interleukin-6 levels were increased in FTLD overall, but these did not discriminate between clinical and genetic subtypes. PMID- 25435339 TI - Synergism between asymmetric dimethylarginine (ADMA) and a genetic marker of uric acid in CKD progression. AB - BACKGROUND & AIMS: We have recently reported that a polymorphism (rs734553) in a major urate transporter gene (GLUT9) is a strong predictor of incident renal events in stage 2-5 CKD patients implying that life-time exposure to high uric acid levels may be causally implicated in CKD progression. Since disturbed NO bioavailability is a major pathway whereby high uric may cause renal damage, we tested the interaction between the major endogenous inhibitor of NO synthase, asymmetric-dimethylargine (ADMA), and the rs734553 polymorphism for CKD progression in the same cohort. METHODS & RESULTS: Over a 29 +/- 11 months follow up the risk for incident renal events was higher in patients harboring the risk allele of the polymorphism (T) as compared to those without the risk allele (HR: 2.35, 95% CI: 1.25-4.42, P = 0.008) (p = 0.01). Similarly, patients with ADMA > median value had an increased risk for the same outcome (HR: 1.37, 95% CI: 1.06 1.76, P = 0.016). Interaction analysis showed a strong amplification by ADMA of the risk for renal events associated to the T allele because in adjusted (P = 0.016) and bootstrapping validated (P = 0.020) analyses the risk excess associated to this allele was progressively higher across increasing ADMA levels. CONCLUSIONS: The rs734553 polymorphism, the strongest genetic marker of uric acid levels discovered so far, interacts with ADMA in determining the risk for CKD progression in CKD patients. This synergic interaction conforms to biological knowledge indicating that disturbed NO bio-availability is a critical pathway whereby life time exposure to high uric acid may engender renal damage. PMID- 25435341 TI - Understanding the complexity of antigen retrieval of DNA methylation for immunofluorescence-based measurement and an approach to challenge. AB - Cytosine methylation (5-methylcytosine, 5meC) in the CpG-rich regions of the mammalian genome is an important epigenetic mechanism playing roles in transcription regulation and genomic stability. The abnormalities in DNA methylation can occur in various types of cancer and some genetic diseases. The measurement of DNA methylation is therefore important and there is a range of methodologies used to detect DNA methylation. Many methods based on bisulfite treatment appeared with a lack of specificity after recent discoveries of various modifications of methylated cytosine, however there are new treatments developed to overcome this limitation. Immunofluorescence is currently known to be able to specifically detect DNA methylation as it uses different antibodies against 5meC and its derivatives, but it is a semi-quantitative method. Immunofluorescence protocols commonly include fixation of cells followed by permeabilisation, antigen retrieval, and treatments with antibodies. Establishing the strategy for antigen retrieval of immunofluorescence is important to unmask epitopes (i.e. 5meC) from other proteins, and therefore to access the antigen of interest. There are many approaches used for antigen retrieval induced by acid, enzyme and/or heat. The selection of antigen retrieval method can depend on a variety of such antigen-based or cell-based conditions, since the dynamic structure of DNA and chromatin accounts for the complexity of involved proteins to mask the epitope. This review aims to specifically focus on the complexity of in situ detection of DNA methylation by immunofluorescence-based methods using antigen retrieval with the current understanding of DNA methylation mechanism, and suggests conditions for antigenic retrieval of 5meC epitope. PMID- 25435340 TI - Short Communication: Viral Suppression Is Associated with Increased Likelihood of Colorectal Cancer Screening Among Persons Living with HIV/AIDS. AB - With improved survival and aging, more persons living with HIV/AIDS (PLWHA) are at risk for colorectal cancer (CRC). This retrospective longitudinal study evaluated patient characteristics associated with CRC screening in our HIV cohort. Patients were followed beginning at age 50 years during a study period from January 1, 2003 to December 31, 2010 (n=265). During a median follow-up time of 1.7 years, only 30% of patients underwent CRC screening. The majority of screened patients received endoscopic screening (colonoscopy, 86%; sigmoidoscopy, 8%); among these patients, results were available for 68/75, and adenomatous polyps were found in 13%. No cases of CRC were reported. Among unscreened patients, only 23% had an external primary care provider, indicating an HIV provider was the expected source for CRC screening referral in the majority. Patients with time-varying suppressed HIV viral load were more likely to receive screening (HRadjusted=1.74; 95% CI: 1.05-2.87), independent of CD4 count. Our findings suggest HIV providers are more likely to address non-HIV-related healthcare maintenance when HIV is controlled. In addition, a significant number of neoplastic lesions are likely being missed in PLWHA who have not been screened for CRC. Provision of evidence-based preventive care in addition to HIV care is required for the aging population of PLWHA. PMID- 25435342 TI - Antiviral activity of lambda-carrageenan prepared from red seaweed (Gigartina skottsbergii) against BoHV-1 and SuHV-1. AB - The antiviral effect of polysaccharides has been known for many years. Carrageenans are considered a good alternative for the prevention of a wide range of diseases, mainly caused by enveloped viruses. The advantages lie on their high availability, low cost and low induction of resistance. The aim of this study was to evaluate the sensitivity of two viral pathogens of veterinary interest to the presence of lambda-carrageenan. This is the first report of a lambda-carrageenan having antiviral activity against animal viruses belonging to the Alphaherpesvirinae subfamily, BoHV-1 (bovine herpesvirus type 1) strain Cooper and SuHV-1 (suid herpesvirus type 1) strain Bartha. Lambda-carrageenan was able to reduce infectivity of both viruses with a more pronounced effect against BoHV 1. These results proved, as previously shown for human herpes virus type 1, that these compounds could be used as potential antiviral agents in the veterinary field. PMID- 25435343 TI - [The intra-thyroid thyroglossal cyst in the differential diagnosis of the solitary thyroid nodule: A presentation of 2 cases]. PMID- 25435344 TI - [Vestibular impairment in CHARGE syndrome. To see the invisible]. PMID- 25435345 TI - [What can I do? I am unable to comb my daughter's hair]. PMID- 25435346 TI - Association of circulating cytochrome c with clinical manifestations of antiretroviral-induced toxicity. AB - Diagnosis of antiretroviral therapy (ART) toxicity is complicated. Apoptosis has been implicated in ART toxicity. Cytochrome c (Cyt-C) is a mitochondrial protein found in plasma during pro-apoptotic states. We conducted a study of HIV-infected individuals on ART with (cases, n=21) and without (controls, n=21) clinical evidence of toxicity to determine if elevated plasma Cyt-C is associated with ART toxicity. When corrected for CD4 count, viral load, and duration of HIV infection, cases are 7.86 times more likely than controls to have plasma Cyt C>0.216 ng/mL. Cyt-C could be a useful clinical tool to guide treatment decisions in this population. PMID- 25435347 TI - High dimensional biological data retrieval optimization with NoSQL technology. AB - BACKGROUND: High-throughput transcriptomic data generated by microarray experiments is the most abundant and frequently stored kind of data currently used in translational medicine studies. Although microarray data is supported in data warehouses such as tranSMART, when querying relational databases for hundreds of different patient gene expression records queries are slow due to poor performance. Non-relational data models, such as the key-value model implemented in NoSQL databases, hold promise to be more performant solutions. Our motivation is to improve the performance of the tranSMART data warehouse with a view to supporting Next Generation Sequencing data. RESULTS: In this paper we introduce a new data model better suited for high-dimensional data storage and querying, optimized for database scalability and performance. We have designed a key-value pair data model to support faster queries over large-scale microarray data and implemented the model using HBase, an implementation of Google's BigTable storage system. An experimental performance comparison was carried out against the traditional relational data model implemented in both MySQL Cluster and MongoDB, using a large publicly available transcriptomic data set taken from NCBI GEO concerning Multiple Myeloma. Our new key-value data model implemented on HBase exhibits an average 5.24-fold increase in high-dimensional biological data query performance compared to the relational model implemented on MySQL Cluster, and an average 6.47-fold increase on query performance on MongoDB. CONCLUSIONS: The performance evaluation found that the new key-value data model, in particular its implementation in HBase, outperforms the relational model currently implemented in tranSMART. We propose that NoSQL technology holds great promise for large-scale data management, in particular for high-dimensional biological data such as that demonstrated in the performance evaluation described in this paper. We aim to use this new data model as a basis for migrating tranSMART's implementation to a more scalable solution for Big Data. PMID- 25435348 TI - Targeting microglia for the treatment of Alzheimer's disease. AB - INTRODUCTION: Activated microglia are associated with the progression of Alzheimer's disease (AD), as well as many other neurodegenerative diseases of aging. Microglia are therefore key targets for therapeutic intervention. AREAS COVERED: beta-amyloid (Abeta) deposits activate the complement system, which, in turn, stimulates microglia to release neurotoxic materials. Research has focused primarily on anti-inflammatory agents to temper this toxic effect. More recently there has been a focus on converting microglia from this M1 state to an M2 state in which the toxic effects are reduced and their phagocytic activity toward Abeta enhanced. Studies in transgenic mice have suggested a number of possible anti inflammatory approaches but they may not always be a good model. An example is vaccination with antibodies to Abeta, which is effective in mouse models, but has repeatedly failed in clinical trials. Biomarker studies indicate that AD commences many years prior to clinical onset. EXPERT OPINION: A hopeful approach to a disease-modifying treatment of AD is to administer agents that inhibit the inflammatory stimulation of microglia or successfully convert them to an M2 state. However, any such treatment must be started early in the disease. PMID- 25435349 TI - Mt Everest Base Camp Medical Clinic "Everest ER": epidemiology of medical events during the first 10 years of operation. AB - OBJECTIVES: As the highest peak on the planet, Mt Everest provides a truly austere environment in which to practice medicine. We examined records of all visits to the Everest Base Camp Medical Clinic (Everest ER) to characterize the medical problems that occur in these patients. METHODS: A retrospective analysis of medical records from the first 10 years of operation (2003 to 2012) was performed. RESULTS: Medical reasons accounted for 85.3% (3045) of diagnoses, whereas 14.0% (500) were for trauma. The most common medical diagnoses were pulmonary causes such as high altitude cough and upper respiratory infection, comprising more than 38% of medical diagnoses. For traumatic diagnoses, 56% were for dermatologic causes, most commonly for frostbite and lacerations. Pulmonary and dermatologic diagnoses were also the most frequent causes for evacuation from Everest Base Camp, most commonly for high altitude pulmonary edema and frostbite, respectively. CONCLUSIONS: Medical professionals treating patients at extreme altitude should have a broad scope of practice and be well prepared to deal with serious trauma from falls, cold exposure injuries, and altitude illness. PMID- 25435350 TI - Effects of barley beta-glucan on radiation damage in the human hepatoma cell line HepG2. AB - Damage to normal tissue is an obstacle to radiotherapy of cancer. We have tested whether barley beta-glucan can enhance radioprotection in the human hepatoma cell line HepG2. The cytotoxicity of beta-glucan was determined by the 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. A clonogenic assay was used to study the sensitivity of cells to beta-glucan, ionizing radiation (2-8Gy), and the combination of both treatments. Acridine Orange/ethidium bromide staining was used to examine induction of apoptosis by beta-glucan, radiation (6Gy), and the combination. DNA strand breaks were assessed by the comet assay. The MTT assay showed that treatment with beta-glucan was not cytotoxic. Indeed, a slight increase in cell viability was observed. Pre treatment with beta-glucan, 1MUg/ml, for 72h protected HepG2 cells against radiation, as indicated by increased surviving fraction, reduced apoptosis, and fewer DNA strand breaks. These results show that barley beta-glucan is a radioprotective agent. PMID- 25435351 TI - Genotoxicity assessment of cerium oxide nanoparticles in female Wistar rats after acute oral exposure. AB - Cerium oxide nanoparticles (CeO2 NPs; nanoceria) have demonstrated excellent potential for commercial use in various arenas, such as in biomedical industry in cosmetics and as a fuel additive. However, limited knowledge exists regarding their potential toxicity. In this study, acute oral toxicity of CeO2 NPs and their microparticles (MPs; bulk) was carried out in female albino Wistar rats. The CeO2 NPs and CeO2 MPs were characterized utilizing transmission electron microscopy (TEM), dynamic light scattering (DLS) and laser Doppler velocimetry (LDV) for the size, distribution and surface charge respectively. The genotoxicity studies were conducted using micronucleus test (MNT), comet and chromosomal aberration (CA) assays. Results revealed that at high dose (1000mg/kg bw) CeO2 NPs induced significant DNA damage in peripheral blood leukocytes (PBL) and liver cells, micronucleus formation in bone marrow and blood cells and total cytogenetic changes in bone marrow. However, significant genotoxicity was not observed at 500 and 100mg/kg bw of CeO2 NPs. The findings from biochemical assays depicted significant alterations in ALP and LDH activity in serum and GSH content in liver, kidneys and brain only at the high dose of CeO2 NPs. Tissue biodistribution of both particles was analyzed by inductively coupled plasma optical emission spectrometer (ICP-OES). Bioaccumulation of nanoceria in all tissues was significant and dose-, time- and organ-dependent. Moreover, CeO2 NPs exhibited higher tissue distribution along with greater clearance in large fractions through urine and feces than CeO2 bulk, whereas, maximum amount of micro-sized CeO2 got excreted in feces. The histopathological examination documented alterations in the liver due to exposure with CeO2 NPs only. Hence, the results suggest that bioaccumulation of CeO2 NPs may induce genotoxic effects. However, further research on long term fate and adverse effects of CeO2 NPs is warranted. PMID- 25435352 TI - Genotoxicity of freshwater ecosystem shows DNA damage in preponderant fish as validated by in vivo micronucleus induction in gill and kidney erythrocytes. AB - Genotoxicity of Anambra River was studied by micronucleus (MN) assay of preponderant fish species in the river. The micronucleus indices obtained were used as biomarker to estimate and predict pollution profile and possible danger of feeding on the aquatic species. Micronuclei profile of the fish was measured from gill and kidney erythrocytes using microscopic technique. Season, species and location effects on micronuclei, together with their interactions were also determined. Two major seasons (rainy and dry) and preponderant fish species in the river (Synodontis clarias, Linnaeus, 1758 and Tilapia nilotica, Linnaeus, 1757) were studied at five distinct locations that displayed differential environmental stresses. The study showed that the micronucleus index of fish is an excellent biomarker for measuring pollution level and genotoxicity of freshwater habitat. Season, species of fish and location affect micronuclei profile of the fish species sampled in the river. Disease outbreak among rural dwellers depending on the river for domestic and other uses is imminent and they lack knowledge on its health implication. Moreover, the study maintained that the micronuclei in fish could be measured from either the gill or kidney; however, gill is more efficient as it enables collection of several samples from the same individuals without sacrificing it, and Synodontis clarias fish species appeared to be more vulnerable to the genotoxic damage than Tilapia nilotica. Consequently, the study recommended regular monitoring (micronucleus tests) of edible aquatic life such as Synodontis clarias in order to eliminate the danger of people feeding on toxic metals, some of which are carcinogenic. PMID- 25435353 TI - An evaluation of genotoxicity in human neuronal-type cells subjected to oxidative stress under an extremely low frequency pulsed magnetic field. AB - The possible genotoxicity of extremely low frequency magnetic field (ELF-MF) exposure is still a controversial topic. The most of the reported data suggests that it alone does not affect DNA integrity, but several recent reports have suggested that sinusoidal ELF-MF may increase the effect of known genotoxic agents. Only a few studies deal with non sinusoidal ELF-MF, including pulsed magnetic field (PMF), which are produced by several devices. The aim of this study is to investigate whether PMF exposure can interfere with DNA damage and repair in the presence of a genotoxic oxidative agent in neuronal type cells. To this purpose gamma-H2AX foci formation, which is a sensitive marker of DNA double strand breaks (DSB), was investigated at different points of time (1, 24, 48, 72h) after the H2O2 treatment (300MUM for 1h) under PMF exposure (1mT, 50Hz) in human neuroblastoma BE(2)C cells. Moreover, cytotoxicity evaluation, by MTT assay and cell cycle analysis, was performed at various points of time after the treatment. Taken together, results suggest that PMF exposure does not interfere with genotoxicity and cytotoxicity induced by oxidative stress. PMID- 25435354 TI - Cadmium-induced genotoxicity in human osteoblast-like cells. AB - Cadmium (Cd) is a widespread heavy metal used in numerous industrial processes. Cd exerts toxicological effects mostly in kidney and liver. Bone is also an important target of Cd, however, the cellular mechanisms of Cd toxicological effects in the bone cells are still poorly understood. Therefore, the present work aimed to investigate the putative cytotoxic and genotoxic effects of Cd to human bone cells. For that, the osteoblast-like MG-63 cells were exposed to 20 and 50MUM Cd for 24 and 48h. Results showed a dose-dependent increase in Cd accumulation in cells and a decrease in cell viability, especially after 48h. Cell cycle analysis showed a delay at S phase concomitant with a decrease in cells at G0/G1 phase. After 24h, Cd treatment downregulated the expression of CHEK1, CHEK2 and CDK2 genes and upregulated the expression of CCNE1 gene. After 48h, the expression of ATM and CCNB1 genes were downregulated. Also, a 3.3 fold increase on the expression of gene CCNE1 was detected. Both Cd doses induced DNA fragmentation at 48h, while an increase in micronuclei (MN) and nucleoplasmic bridges (NPBs) together with an increase in the percentage of apoptotic/necrotic cells was detected for both time periods. Overall, our results demonstrate the cytotoxicity and genotoxicity of Cd in human bone cells. Also, the cytokinesis block micronucleus (CBMN) assay parameters (MN, NPBs and the percentage of cells under apoptosis or necrosis) together with the cell cycle appear as the most sensitive to Cd cyto- and genotoxicity, being early affected even with the lowest Cd dose. Therefore, these cyto-/genotoxic techniques may be selected for early detection of Cd-induced toxicity. PMID- 25435355 TI - Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. AB - Genetic mutations are known to drive cancer progression and certain tumors have mutation signatures that reflect exposures to environmental carcinogens. Benzo[a]pyrene (BaP) has a known mutation signature and has proven capable of inducing changes to DNA sequence that drives normal pre-stasis human mammary epithelial cells (HMEC) past a first tumor suppressor barrier (stasis) and toward immortality. We analyzed normal, pre-stasis HMEC, three independent BaP-derived post-stasis HMEC strains (184Aa, 184Be, 184Ce) and two of their immortal derivatives(184A1 and 184BE1) by whole exome sequencing. The independent post stasis strains exhibited between 93 and 233 BaP-induced mutations in exons. Seventy percent of the mutations were C:G>A:T transversions, consistent with the known mutation spectrum of BaP. Mutations predicted to impact protein function occurred in several known and putative cancer drivers including p16, PLCG1, MED12, TAF1 in 184Aa; PIK3CG, HSP90AB1, WHSC1L1, LCP1 in 184Be and FANCA, LPP in 184Ce. Biological processes that typically harbor cancer driver mutations such as cell cycle, regulation of cell death and proliferation, RNA processing, chromatin modification and DNA repair were found to have mutations predicted to impact function in each of the post-stasis strains. Spontaneously immortalized HMEC lines derived from two of the BaP-derived post-stasis strains shared greater than 95% of their BaP-induced mutations with their precursor cells. These immortal HMEC had 10 or fewer additional point mutations relative to their post-stasis precursors, but acquired chromosomal anomalies during immortalization that arose independent of BaP. The results of this study indicate that acute exposures of HMEC to high dose BaP recapitulate mutation patterns of human tumors and can induce mutations in a number of cancer driver genes. PMID- 25435356 TI - Can in vitro mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or in vivo genotoxic activity? I. Reports of individual databases presented at an EURL ECVAM Workshop. AB - Positive results in the Ames test correlate well with carcinogenic potential in rodents. This correlation is not perfect because mutations are only one of many stages in tumour development. Also, situations can be envisaged where the mutagenic response may be specific to the bacteria or the test protocol, e.g., bacterial-specific metabolism, exceeding a detoxification threshold, or the induction of oxidative damage to which bacteria may be more sensitive than mammalian cells in vitro or tissues in vivo. Since most chemicals are also tested for genotoxicity in mammalian cells, the pattern of mammalian cell results may help identify whether Ames-positive results predict carcinogenic or in vivo mutagenic activity. A workshop was therefore organised and sponsored by the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) to investigate this further. Participants presented results from other genotoxicity tests with Ames-positive compounds. Data came from published, regulatory agency, and industry sources. The question was posed whether negative results in mammalian cell tests were associated with absence of carcinogenic or in vivo genotoxic activity despite a positive Ames test. In the limited time available, the presented data were combined and an initial analysis suggested that the association of negative in vitro mammalian cell test results with lack of in vivo genotoxic or carcinogenic activity could have some significance. Possible reasons why a positive Ames test may not be associated with in vivo activity and what additional investigations/tests might contribute to a more robust evaluation were discussed. Because a considerable overlap was identified among the different databases presented, it was recommended that a consolidated database be built, with overlapping chemicals removed, so that a more robust analysis of the predictive capacity for potential carcinogenic and in vivo genotoxic activity could be derived from the patterns of mammalian cell test results obtained for Ames-positive compounds. PMID- 25435357 TI - Can in vitro mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or in vivo genotoxic activity? II. Construction and analysis of a consolidated database. AB - A Workshop sponsored by EURL ECVAM was held in Ispra, Italy in 2013 to consider whether the in vitro mammalian cell genotoxicity test results could complement and mitigate the implications of a positive Ames test response for the prediction of in vivo genotoxicity and carcinogenicity, and if patterns of results could be identified. Databases of Ames-positive chemicals that were tested for in vivo genotoxicity and/or carcinogenicity were collected from different sources and analysed individually (Kirkland et al., in this issue). Because there were overlaps and inconsistent test results among chemicals in the different databases, a combined database which eliminated the overlaps and evaluated the inconsistencies was considered preferable for addressing the above question. A database of >700 Ames-positive chemicals also tested in vivo was compiled, and the results in in vitro mammalian cell tests were analysed. Because the database was limited to Ames-positive chemicals, the majority (>85%) of carcinogens (103/119) and in vivo genotoxins (83/88) were positive when tested in both in vitro gene mutation and aneugenicity/clastogenicity tests. However, about half (>45%) of chemicals that were not carcinogenic (19/28) or genotoxic in vivo (33/73) also gave the same patterns of positive mammalian cell results. Although the different frequencies were statistically significant, positive results in 2 in vitro mammalian cell tests did not, per se, add to the predictivity of the positive Ames test. By contrast, negative results for both in vitro mammalian cell endpoints were rare for Ames-positive carcinogens (3/119) and in vivo genotoxins (2/88) but, were significantly more frequent for Ames-positive chemicals that are not carcinogenic (4/28) or genotoxic in vivo (14/73). Thus, in the case of an Ames-positive chemical, negative results in 2 in vitro mammalian cell tests covering both mutation and clastogenicity/aneugenicity endpoints should be considered as indicative of absence of in vivo genotoxic or carcinogenic potential. PMID- 25435358 TI - Performance and data interpretation of the in vivo comet assay in pharmaceutical industry: EFPIA survey results. AB - In genotoxicity testing of pharmaceuticals the rodent alkaline comet assay is being increasingly used as a second in vivo assay in addition to the in vivo micronucleus assay to mitigate in vitro positive results as recommended by the ICH S2(R1) guideline. This paper summarizes a survey suggested by the Safety Working Party of European Medicines Agency (EMA), and conducted by the European Federation of Pharmaceutical Industries and Associations (EFPIA) to investigate the experience among European pharmaceutical companies by conducting the in vivo comet assay for regulatory purpose. A special focus was given on the typology of the obtained results and to identify potential difficulties encountered with the interpretation of study data. The participating companies reported a total of 147 studies (conducted in-house or outsourced) and shared the conclusion on the comet assay response for 136 studies. Most of the studies were negative (118/136). Only about 10% (14/136 studies) of the comet assays showed a positive response. None of the positive comet assay results were clearly associated with organ toxicity indicating that the positive responses are not due to cytotoxic effects of the compound in the tissue examined. The number of comet assays with an equivocal or inconclusive response was rare, respectively <1% (1/147 studies) and 2% (3/147 studies). In case additional information (e.g. repeat assay, organ toxicity, metabolism, tissue exposure) would have been available for evaluation, a final conclusion could most probably have been drawn for most or all of these studies. All (46) negative in vivo comet assays submitted alongside with a negative in vivo micronucleus assay were accepted by the regulatory authorities to mitigate a positive in vitro mammalian cell assay following the current ICH S2 guidance. The survey results demonstrate the robustness of the comet assay and the regulatory acceptance of the current ICH S2 guidance. PMID- 25435359 TI - Genotoxic effects of CdS quantum dots and Ag2S nanoparticles in fish cell lines (RTG-2). AB - The increasing use of nanotechnologies will lead to significant releases of engineered nanoparticles into the aquatic environment, where their impact is still poorly characterized. In the present paper, the genotoxic and cytotoxic properties of CdS quantum dots (QDs) and silver sulphide (Ag2S) coated with methyl polyethylene glycol (M-PEG) were investigated in a rainbow trout cell line (RTG-2). The results showed that CdS QDs were highly cytotoxic at high concentrations (10 and 50MUg/ml), and exhibited a concentration-dependent genotoxicity in the sub-toxic range (0.01-1MUg/ml) after 24h exposure. Ag2S showed neither genotoxic nor cytotoxic effects. PMID- 25435360 TI - Evaluation of in vivo mutagenicity of hydroquinone in MutaTM mice. AB - Hydroquinone (HQ) is used in skin bleaching agents, hair dyes, and finger nail treatments. Many skin-lightening cosmetics that contain HQ are currently marketed in Japan. Concerns have been expressed regarding health risks to the general population because the carcinogenicity of HQ was previously suggested in animal studies. HQ induced hepatocellular adenomas and forestomach hyperplasias in mice and renal tubular cell adenomas in male rats. In the present study, the lacZ transgenic mutation assay was conducted according to OECD test guideline 488 to determine whether mutagenic mechanisms were involved in HQ-induced carcinogenesis. Male MutaTM mice were repeatedly administered HQ orally at dosages of 0, 25, 50, 100, or 200mg/kg bw/day for 28 days. Body weight gain was decreased in all treatment groups. No significant differences were observed in mutant frequencies in the liver, stomach, lung, or kidney between HQ-treated mice and the concurrent negative controls, whereas the significant induction of mutations was noted in the positive control, N-ethyl-N-nitrosourea. These results suggest that a mutagenic mechanism is not responsible for HQ-induced carcinogenesis. PMID- 25435361 TI - Infection-associated biomarkers of inflammation in atherosclerosis. AB - Atherosclerosis is a systemic inflammatory disease leading to lipid-laden inflammatory lesions in the arterial walls that may destabilize and rupture. It is becoming clear that addressing the "classical" risk factors for atherosclerosis does not entirely reduce the risk of cardiovascular events. Novel biomarkers to be used in highthroughput assays are necessary for diagnosis, for determination of the residual risk and for monitoring the effects of the therapy. Since inflammation is a hallmark of atherosclerosis, tests for pro-inflammatory biomarkers have been introduced such as for hsCRP, fibrinogen and IL-6, with many more at different stages of development. There has been a dearth of novel approaches for the diagnosis and management of atherosclerosis, reflected in a continuous reliance on LDL cholesterol as a proven target of investigations. To bring another perspective, here we briefly overview the accumulated epidemiological and sero-epidemiological evidence suggesting systemic infections as a component of atherosclerotic inflammations. We have shown that different individuals' plaques are colonized with different bacterial species (atherosclerosis microbiota). Most of the time the pathogens are likely in an intracellular state, shielded from the host immune responses. There are controlled clinical trials and metaanalyses that corroborate the infections, specifically periodontal disease as a contributing risk factor of atherosclerosis. Infection-related markers, including transcriptome signatures, may identify latent infection patients with sub-clinical disease. Thus, the emerging infection- associated markers of inflammation could complement the existing ones and their use as companion diagnostics for atherosclerosis should stimulate the growing field of personalized medicine within cardiovascular diseases. PMID- 25435362 TI - Differential gene expression profiling of Actinobacillus pleuropneumoniae during induction of primary alveolar macrophage apoptosis in piglets. AB - Actinobacillus pleuropneumoniae (A. pleuropneumoniae) is the causative agent of porcine pleuropneumonia, a disease that causes serious problems for the swine industry. Successful infection by this bacterium requires breaking the first line of defence in the lungs, the primary alveolar macrophages (PAMs). Therefore, exploring A. pleuropneumoniae-PAM interactions will provide vital groundwork for the scientific control of this infectious disease, which has been little studied up to now. In this work, PAMs were isolated from piglets and co-incubated with A. pleuropneumoniae serovar 5b strain L20 in vitro, and their interaction, PAM cell death, and differential gene expression of A. pleuropneumoniae in response to PAM cell death were observed and analysed using confocal microscopy, electron microscopy, RT-PCR, Western blot, flow cytometry and the use of a gene expression profile chip. A. pleuropneumoniae quickly adhered to and invaded PAMs, inducing apoptosis, which was confirmed using transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The highest percentage of apoptosis in cells was confirmed using flow cytometry when the cells were infected at a multiplicity of infection (MOI) of 10 and incubated for 5 h, with higher expression of activated caspase-3 as measured by Western blot. Using microarray gene chips with 2868 probes containing nearly all of the genomic sequence of A. pleuropneumoniae serotype 5b strain L20, a total of 185 bacterial genes were found to be differentially expressed (including 92 up-regulated and 93 down-regulated genes) and involved in the process of apoptosis, as compared with the expression of control bacteria cultured without PAMs in BHI medium (mean expression ratios >1.5 fold, p < 0.05). The up-regulated genes are involved in energy metabolism, gene transcription and translation, virulence related gene such as LPS, Trimeric Autotransporter Adhesin, RTX and similar genes. The down-regulated genes are involved in amino acid, cofactor, and vitamin metabolism, and also include ABC transporters. These data demonstrate that A. pleuropneumoniae induces apoptosis of PAMs and undergoes complex changes in gene transcription, including expression changes in known and potential virulence factors. Some potentially novel virulence targets have been identified, suggesting new strategies for the development of vaccines and medicines for both preventive and clinical use. PMID- 25435363 TI - The Spanish Burden of Disease 2010: Neurological, mental and substance use disorders. AB - INTRODUCTION: We used data from the Global Burden of Disease, Injuries, and Risk Factors Study 2010 to report on the burden of neuropsychiatric disorders in Spain. MATERIALS AND METHODS: The summary measure of burden used in the study was the disability-adjusted life-year (DALY), which sums of the years of life lost due to premature mortality (YLLs) and the years lived with disability (YLDs). DALYs were adjusted for comorbidity and estimated with 95% uncertainty intervals. RESULTS: The burden of neuropsychiatric disorders accounted for 18.4% of total all-cause DALYs generated in Spain for 2010. Within this group, the top five leading causes of DALYs were: depressive disorders, Alzheimer's disease, migraine, substance-use disorders, and anxiety disorder, which accounted for 70.9% of all DALYs due to neuropsychiatric disorders. Neurological disorders represented 5.03% of total all cause YLLs, whereas mental and substance-use disorders accounted for 0.8%. Mental and substance-use disorders accounted for 22.4% of total YLDs, with depression being the most disabling disorder. Neurological disorders represented 8.3% of total YLDs. CONCLUSIONS: Neuropsychiatric disorders were one of the leading causes of disability in 2010. This finding contributes to our understanding of the burden of neuropsychiatric disorders in the Spanish population and highlights the importance of prioritising neuropsychiatric disorders in the Spanish public health system. PMID- 25435364 TI - USP7 modulates UV-induced PCNA monoubiquitination by regulating DNA polymerase eta stability. AB - DNA polymerase eta (Poleta) has unique and pivotal functions in several DNA damage-tolerance pathways. Steady-state level of this short-lived protein is tightly controlled by multiple mechanisms including proteolysis. Here, we have identified the deubiquitinating enzyme (DUB), ubiquitin-specific protease 7 (USP7), as a novel regulator of Poleta stability. USP7 regulates Poleta stability through both indirect and direct mechanisms. Knockout of USP7 increased the steady-state level of Poleta and slowed down the turnover of both Poleta and p53 proteins through destabilizing their E3 ligase murine double minute 2 (Mdm2). Also, USP7 physically binds Poleta in vitro and in vivo. Overexpression of wild type USP7 but not its catalytically-defective mutants deubiquitinates Poleta and increases its cellular steady-state level. Thus, USP7 directly serves as a specific DUB for Poleta. Furthermore, ectopic expression of USP7 promoted the UV induced proliferating cell nuclear antigen (PCNA) monoubiquitination in Poleta proficient but not in Poleta-deficient XPV (Xeroderma pigmentosum variant) cells, suggesting that USP7 facilitates UV-induced PCNA monoubiquitination by stabilizing Poleta. Taken together, our findings reveal a modulatory role of USP7 in PCNA ubiquitination-mediated stress-tolerance pathways by fine-tuning Poleta turnover. PMID- 25435365 TI - Polycomb-dependent repression of the potassium channel-encoding gene KCNA5 promotes cancer cell survival under conditions of stress. AB - Relapse after clinical remission remains a leading cause of cancer-associated death. Although the mechanisms of tumor relapse are complex, the ability of cancer cells to survive physiological stress is a prerequisite for recurrence. Ewing sarcoma (ES) and neuroblastoma (NB) are aggressive cancers that frequently relapse after initial remission. In addition, both tumors overexpress the polycomb group (PcG) proteins BMI-1 and EZH2, which contribute to tumorigenicity. We have discovered that ES and NB resist hypoxic stress-induced death and that survival depends on PcG function. Epigenetic repression of developmental programs is the most well-established cancer-associated function of PcG proteins. However, we noted that voltage-gated potassium (Kv) channel genes are also targets of PcG regulation in stem cells. Given the role of potassium in regulating apoptosis, we reasoned that repression of Kv channel genes might have a role in cancer cell survival. Here we describe our novel finding that PcG-dependent repression of the Kv1.5 channel gene KCNA5 contributes to cancer cell survival under conditions of stress. We show that survival of cancer cells in stress is dependent upon suppression of Kv1.5 channel function. The KCNA5 promoter is marked in cancer cells with PcG-dependent chromatin repressive modifications that increase in hypoxia. Genetic and pharmacological inhibition of BMI-1 and EZH2, respectively, restore KCNA5 expression, which sensitizes cells to stress-induced death. In addition, ectopic expression of the Kv1.5 channel induces apoptotic cell death under conditions of hypoxia. These findings identify a novel role for PcG proteins in promoting cancer cell survival via repression of KCNA5. PMID- 25435366 TI - CHIP buffers heterogeneous Bcl-2 expression levels to prevent augmentation of anticancer drug-resistant cell population. AB - Many types of cancer display heterogeneity in various features, including gene expression and malignant potential. This heterogeneity is associated with drug resistance and cancer progression. Recent studies have shown that the expression of a major protein quality control ubiquitin ligase, carboxyl terminus of Hsc70 interacting protein (CHIP), is negatively correlated with breast cancer clinicopathological stages and poor overall survival. Here we show that CHIP acts as a capacitor of heterogeneous Bcl-2 expression levels and prevents an increase in the anticancer drug-resistant population in breast cancer cells. CHIP knockdown in breast cancer cells increased variation in Bcl-2 expression levels, an antiapoptotic protein, among the cells. Our results also showed that CHIP knockdown increased the proportion of anticancer drug-resistant cells. These findings suggest that CHIP buffers variation in gene expression levels, affecting resistance to anticancer drugs. In single-cell clones derived from breast cancer cell lines, CHIP knockdown did not alter the variation in Bcl-2 expression levels and the proportion of anticancer drug-resistant cells. In contrast, when clonal cells were treated with a mutagen, the variation in Bcl-2 expression levels and proportion of anticancer drug-resistant cells were altered by CHIP knockdown. These results suggest that CHIP masks genetic variations to suppress heterogeneous Bcl-2 expression levels and prevents augmentation of the anticancer drug-resistant population of breast cancer cells. Because genetic variation is a major driver of heterogeneity, our results suggest that the degree of heterogeneity in expression levels is decided by a balance between genetic variation and the buffering capacity of CHIP. PMID- 25435367 TI - Mortalin (GRP75/HSPA9) upregulation promotes survival and proliferation of medullary thyroid carcinoma cells. AB - Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the rearranged during transfection (RET) proto-oncogene. For therapy of advanced MTC, the Food and Drug Administration recently approved vandetanib and cabozantinib, the tyrosine kinase inhibitors targeting RET, vascular endothelial growth factor receptor, epidermal growth factor receptor and/or c MET. Nevertheless, not all patients respond to these drugs, demanding additional therapeutic strategies. We found that mortalin (HSPA9/GRP75), a member of HSP70 family, is upregulated in human MTC tissues and that its depletion robustly induces cell death and growth arrest in MTC cell lines in culture and in mouse xenografts. These effects were accompanied by substantial downregulation of RET, induction of the tumor-suppressor TP53 and altered expression of cell cycle regulatory machinery and apoptosis markers, including E2F-1, p21(CIP1), p27(KIP1) and Bcl-2 family proteins. Our investigation of the molecular mechanisms underlying these effects revealed that mortalin depletion induces transient MEK/ERK (extracellular signal-regulated kinase) activation and altered mitochondrial bioenergetics in MTC cells, as indicated by depolarized mitochondrial membrane, decreased oxygen consumption and extracellular acidification and increased oxidative stress. Intriguingly, mortalin depletion induced growth arrest partly via the MEK/ERK pathway, whereas it induced cell death by causing mitochondrial dysfunction in a Bcl-2-dependent manner. However, TP53 was not necessary for these effects except for p21(CIP1) induction. Moreover, mortalin depletion downregulated RET expression independently of MEK/ERK and TP53. These data demonstrate that mortalin is a key regulator of multiple signaling and metabolic pathways pivotal to MTC cell survival and proliferation, proposing mortalin as a novel therapeutic target for MTC. PMID- 25435368 TI - Impact of the Mdm2(SNP309-G) allele on a murine model of colorectal cancer. AB - A single-nucleotide polymorphism (SNP) in the promoter of the Mdm2 gene (Mdm2(SNP309-G)) results in an increased Mdm2 expression, partial attenuation of the p53 pathway and accelerated tumor development. Clinical case-control studies indicate the Mdm2(SNP309-)(G) allele associates with a significant increase in colorectal cancer (CRC) risk that is heightened in women, but the biological significance of this polymorphism has never been directly evaluated. To examine whether the Mdm2(SNP309-)(G) allele contributes to colorectal cancer, we generated cohorts of mice harboring either the G (minor allelic variant) or T (major allelic variant) allele and treated them with azoxymethane (AOM), a carcinogen that induces sporadic colorectal cancer. Mdm2(SNP309-G/G) mice displayed a significant reduction in survival following AOM treatment with more colonic lesions in a wider distribution throughout the lower and upper colon and an attenuated apoptotic response following exposure. AOM did not significantly induce stabilization of wild-type p53 or activate p53 downstream targets following AOM treatment, regardless of the genotype. Instead, Mdm2(SNP309-G/G) colons had significant changes in the expression of genes that regulate Mdm2 transcription (ERalpha and Sp1) as well as downstream targets of Mdm2. Together these results suggest the Mdm2(SNP309-)(G) allele significantly impacts CRC through mechanisms outside the p53 pathway. PMID- 25435369 TI - The activation loop tyrosine 823 is essential for the transforming capacity of the c-Kit oncogenic mutant D816V. AB - Oncogenic c-Kit mutations have been shown to display ligand-independent receptor activation and cell proliferation. A substitution of aspartate to valine at amino acid 816 (D816V) is one of the most commonly found oncogenic c-Kit mutations and is found in >90% of cases of mastocytosis and less commonly in germ-cell tumors, core-binding factor acute myeloid leukemia and mucosal melanomas. The mechanisms by which this mutation leads to constitutive activation and transformation are not fully understood. Previous studies have shown that the D816V mutation causes a structural change in the activation loop (A-loop), resulting in weaker binding of the A-loop to the juxtamembrane domain. In this paper, we have investigated the role of Y823, the only tyrosine residue in the A-loop, and its role in oncogenic transformation by c-Kit/D816V by introducing the Y823F mutation. Although dispensable for the kinase activity of c-Kit/D816V, the presence of Y823 was crucial for cell proliferation and survival. Furthermore, mutation of Y823 selectively downregulates the Ras/Erk and Akt pathways as well as the phosphorylation of STAT5 and reduces the transforming capacity of the D816V/c-Kit in vitro. We further show that mice injected with cells expressing c Kit/D816V/Y823F display significantly reduced tumor size as well as tumor weight compared with controls. Finally, microarray analysis, comparing Y823F/D816V cells with cells expressing c-Kit/D816V, demonstrate that mutation of Y823 causes upregulation of proapoptotic genes, whereas genes of survival pathways are downregulated. Thus, phosphorylation of Y823 is not necessary for kinase activation, but essential for the transforming ability of the c-Kit/D816V mutant. PMID- 25435370 TI - Fluid shear promotes chondrosarcoma cell invasion by activating matrix metalloproteinase 12 via IGF-2 and VEGF signaling pathways. AB - Interstitial fluid flow in and around the tumor tissue is a physiologically relevant mechanical signal that regulates intracellular signaling pathways throughout the tumor. Yet, the effects of interstitial flow and associated fluid shear stress on the tumor cell function have been largely overlooked. Using in vitro bioengineering models in conjunction with molecular cell biology tools, we found that fluid shear (2 dyn/cm(2)) markedly upregulates matrix metalloproteinase 12 (MMP-12) expression and its activity in human chondrosarcoma cells. MMP-12 expression is induced in human chondrocytes during malignant transformation. However, the signaling pathway regulating MMP-12 expression and its potential role in human chondrosarcoma cell invasion and metastasis have yet to be delineated. We discovered that fluid shear stress induces the synthesis of insulin growth factor-2 (IGF-2) and vascular endothelial growth factor (VEGF) B and D, which in turn transactivate MMP-12 via PI3-K, p38 and JNK signaling pathways. IGF-2-, VEGF-B- or VEGF-D-stimulated chondrosarcoma cells display markedly higher migratory and invasive potentials in vitro, which are blocked by inhibiting MMP-12, PI3-K, p38 or JNK activity. Moreover, recombinant human MMP-12 or MMP-12 overexpression can potentiate chondrosarcoma cell invasion in vitro and the lung colonization in vivo. By reconstructing and delineating the signaling pathway regulating MMP-12 activation, potential therapeutic strategies that interfere with chondrosarcoma cell invasion may be identified. PMID- 25435371 TI - Epigenetic changes in gastroenteropancreatic neuroendocrine tumours. AB - An understanding of epigenetic drivers of tumorigenesis has developed rapidly during the last years. The identification of these changes including DNA methylation and histone modifications in gastroenteropancreatic neuroendocrine tumours (GEP-NETs) is a step forward in trying to define underlying biologic processes in this heterogeneous disease. The reversible nature of these changes represents a potential therapeutic target. We present an overview of the current knowledge of epigenetic alterations related to GEP-NETs, focusing on the influence and impact these changes have on pathogenesis and prognosis. The potential role of demethylating agents in the management of this patient population is discussed. PMID- 25435372 TI - LRH-1 controls proliferation in breast tumor cells by regulating CDKN1A gene expression. AB - Liver receptor homolog-1 (LRH-1, NR5A2) is an orphan nuclear receptor that has an essential role in cancer progression, notably in breast cancer. Although its role in promoting cancer cell proliferation and migration is well documented, the molecular basis is not completely established. Here, we report that LRH-1 inhibition affects two- and three-dimensional cell proliferation of different types of breast cancer cells, including estrogen receptor alpha (ERalpha) positive and triple-negative cells. This phenotype is accompanied by the upregulation of the cyclin-dependent kinase inhibitor CDKN1A (aka p21(CIP1/WAF1)) in a p53-independent manner. Chromatin immunoprecipitation analysis shows that LRH-1 cooperates with FOXA1 and binds directly to CDKN1A promoter and a distal regulatory region found at -62 kb from its transcriptional start sites, allowing repression of CDKN1A transcription. LRH-1 or FOXA1 depletion induces CDKN1A upregulation by removing histone deacetylase 2 from the promoter and distal regulatory elements and permitting histone acetylation in these regions. Analysis of breast cancer samples reveals that a high LRH-1 level is inversely correlated with CDKN1A expression in breast cancer patients and is associated with poor prognosis. This study reveals a novel mechanism of control of cell proliferation by LRH-1 regulating CDKN1A transcription in breast cancer cells, independent of ERalpha and p53 status. Targeting LRH-1 may provide an attractive prospect for treatment of tumors that are resistant to hormonal and targeted therapy. PMID- 25435373 TI - A small subunit processome protein promotes cancer by altering translation. AB - Dysregulation of ribosome biogenesis or translation can promote cancer, but the underlying mechanisms remain unclear. UTP18 is a component of the small subunit processome, a nucleolar multi-protein complex whose only known function is to cleave pre-ribosomal RNA to yield the 18S ribosomal RNA component of 40S ribosomal subunits. Here, we show that UTP18 also alters translation to promote stress resistance and growth, and that UTP18 is frequently gained and overexpressed in cancer. We observed that UTP18 localizes to the cytoplasm in a subset of cells, and that serum withdrawal increases cytoplasmic UTP18 localization. Cytoplasmic UTP18 associates with the translation complex and Hsp90 to upregulate the translation of IRES-containing transcripts such as HIF1a, Myc and VEGF, thereby inducing stress resistance. Hsp90 inhibition decreases cytoplasmic UTP18 and UTP18-induced increases in translation. Importantly, elevated UTP18 expression correlates with increased aggressiveness and decreased survival in numerous cancers. Enforced UTP18 overexpression promotes transformation and tumorigenesis, whereas UTP18 knockdown inhibits these processes. This stress adaptation mechanism is thus co-opted for growth by cancers, and its inhibition may represent a promising new therapeutic target. PMID- 25435375 TI - A selenophenyl bridged perylene diimide dimer as an efficient solution processable small molecule acceptor. AB - We report herein a new solution-processable small molecule acceptor, a selenophenyl bridged perylene diimide dimer, that gives 4.0% efficiency when employing PBDTTT-C-T as the polymer donor and a conventional cell structure. PMID- 25435374 TI - SOX30, a novel epigenetic silenced tumor suppressor, promotes tumor cell apoptosis by transcriptional activating p53 in lung cancer. AB - Although members of SOX family have been well documented for their essential roles in embryonic development, cell proliferation and disease, the functional role and molecular mechanism of SOX30 in cancer are largely unexplored. Here, we first identified SRY-box containing gene 30 (SOX30) as a novel preferentially methylated gene using genome-wide methylation screening. SOX30 hypermethylation was detected in 100% of lung cancer cell lines (9/9) and 70.83% (85/120) of primary lung tumor tissues compared with none (0/20) of normal and 8.0% (2/25) of peri-tumoral lung tissues (P<0.01). SOX30 was expressed in normal and peri tumoral lung tissues in which SOX30 was unmethylated, but was silenced or downregulated in lung cancer cell lines and primary lung tumor tissues harboring a hypermethylated SOX30. De-methylation experiments further confirmed that silence of SOX30 was regulated by its hypermethylation. Ectopic expression of SOX30 induces cancer cell apoptosis with inhibiting proliferation in vitro and represses tumor formation in vivo, whereas knockdown of SOX30 demonstrates a reversed effect both in vitro and in vivo. At the molecular level, the antitumorigenic effect of SOX30 is mediated by directly binding to CACTTTG (+115 to +121) of p53 promoter region and activating p53 transcription, suggesting that SOX30 is a novel transcriptional activating factor of p53. Indeed, blockade of p53 attenuates the tumor inhibition of SOX30. Overall, these findings demonstrate that SOX30 is a novel epigenetic silenced tumor suppressor acting through direct regulation of p53 transcription and expression. This study provides novel insights on the mechanism of tumorigenesis in lung cancer. PMID- 25435377 TI - Defect structures mediate the isotropic-nematic transition in strongly confined liquid crystals. AB - Using Monte Carlo simulations, we study rod-like lyotropic liquid crystals confined to a square slab-like geometry with lateral dimensions comparable to the length of the particles. We observe that this system develops linear defect structures upon entering the planar nematic phase. These defect structures flank a lens-shaped nematic region oriented along a diagonal of the square box. We interpret these structures as a compromise between the 2-fold order of the bulk nematic phase and the 4-fold order imposed by the lateral boundaries. A simple Onsager-type theory that effectively implements these competing tendencies is used to model the phase behavior in the center of the box and shows that the free energy cost of forming the defect structures strongly offsets the transition inducing effects of both the transverse and lateral confinement. PMID- 25435376 TI - The thymoquinone-induced production of reactive oxygen species promotes dedifferentiation through the ERK pathway and inflammation through the p38 and PI3K pathways in rabbit articular chondrocytes. AB - Dedifferentiation and inflammation are major features of cartilage degeneration during the pathogenesis of osteoarthritis (OA). Thymoquinone (TQ) is the major compound of black seed oil isolated from Nigella sativa with various beneficial or harmful effects on several diseases; however, its effects on the dedifferentiation and inflammation of chondrocytes have not yet been characterized. In the present study, we investigated whether TQ regulates the dedifferentiation and inflammation of rabbit articular chondrocytes, focusing on the production of reactive oxygen species (ROS) in rabbit articular chondrocytes. TQ induced the generation of ROS in a dose-dependent manner, as shown by staining with the fluorescent probe, 2'-7'-dichlorofluorescein diacetate. We confirmed that TQ induced dedifferentiation by measuring the loss of type II collagen and the reduction in chondroitin sulfate proteoglycan levels. TQ also caused inflammation by inducing the expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). The antioxidant, N-acetyl cysteine (NAC), prevented the dedifferentiation and inflammation which was generated by the TQ-induced production of ROS. Furthermore, TQ caused a dose-dependent increase in p38, phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphoinositide 3-kinase (PI3K) expression. NAC abrogated this effect and attenuated the dedifferentiation and inflammation which was generated by the TQ-induced production of ROS. To identify the ROS-regulated pathways, we treated the chondrocytes with the p38 inhibitor, SB203580, the MEK inhibitor, PD98059, and the PI3K inhibitor, LY294002. PD98059 inhibited the TQ-induced dedifferentiation and SB203580 and LY294002 prevented the TQ-induced inflammation. These findings suggest that the TQ-induced production of ROS causes dedifferentiation through the ERK pathway and inflammation through the PI3K and p38 pathways in rabbit articular chondrocytes. PMID- 25435378 TI - Enhanced hexose fermentation by Saccharomyces cerevisiae through integration of stoichiometric modeling and genetic screening. AB - In order to determine beneficial gene deletions for ethanol production by the yeast Saccharomyces cerevisiae, we performed an in silico gene deletion experiment based on a genome-scale metabolic model. Genes coding for two oxidative phosphorylation reactions (cytochrome c oxidase and ubiquinol cytochrome c reductase) were identified by the model-based simulation as potential deletion targets for enhancing ethanol production and maintaining acceptable overall growth rate in oxygen-limited conditions. Since the two target enzymes are composed of multiple subunits, we conducted a genetic screening study to evaluate the in silico results and compare the effect of deleting various portions of the respiratory enzyme complexes. Over two-thirds of the knockout mutants identified by the in silico study did exhibit experimental behavior in qualitative agreement with model predictions, but the exceptions illustrate the limitation of using a purely stoichiometric model-based approach. Furthermore, there was a substantial quantitative variation in phenotype among the various respiration-deficient mutants that were screened in this study, and three genes encoding respiratory enzyme subunits were identified as the best knockout targets for improving hexose fermentation in microaerobic conditions. Specifically, deletion of either COX9 or QCR9 resulted in higher ethanol production rates than the parental strain by 37% and 27%, respectively, with slight growth disadvantages. Also, deletion of QCR6 led to improved ethanol production rate by 24% with no growth disadvantage. The beneficial effects of these gene deletions were consistently demonstrated in different strain backgrounds and with four common hexoses. The combination of stoichiometric modeling and genetic screening using a systematic knockout collection was useful for narrowing a large set of gene targets and identifying targets of interest. PMID- 25435379 TI - A 3D tension bioreactor platform to study the interplay between ECM stiffness and tumor phenotype. AB - Extracellular matrix (ECM) structure, composition, and stiffness have profound effects on tissue development and pathologies such as cardiovascular disease and cancer. Accordingly, a variety of synthetic hydrogel systems have been designed to study the impact of ECM composition, density, mechanics, and topography on cell and tissue phenotype. However, these synthetic systems fail to accurately recapitulate the biological properties and structure of the native tissue ECM. Natural three dimensional (3D) ECM hydrogels, such as collagen or hyaluronic acid, feature many of the chemical and physical properties of tissue, yet, these systems have limitations including the inability to independently control biophysical properties such as stiffness and pore size. Here, we present a 3D tension bioreactor system that permits precise mechanical tuning of collagen hydrogel stiffness, while maintaining consistent composition and pore size. We achieve this by mechanically loading collagen hydrogels covalently-conjugated to a polydimethylsiloxane (PDMS) membrane to induce hydrogel stiffening. We validated the biological application of this system with oncogenically transformed mammary epithelial cell organoids embedded in a 3D collagen I hydrogel, either uniformly stiffened or calibrated to create a gradient of ECM stiffening, to visually demonstrate the impact of ECM stiffening on transformation and tumor cell invasion. As such, this bioreactor presents the first tunable 3D natural hydrogel system that is capable of independently assessing the role of ECM stiffness on tissue phenotype. PMID- 25435380 TI - Transcriptional profiles of Haloferax mediterranei based on nitrogen availability. AB - The haloarchaeon Haloferax mediterranei is able to grow in the presence of different inorganic and organic nitrogen sources by means of the assimilatory pathway under aerobic conditions. In order to identify genes of potential importance in nitrogen metabolism and its regulation in the halophilic microorganism, we have analysed its global gene expression in three culture media with different nitrogen sources: (a) cells were grown stationary and exponentially in ammonium, (b) cells were grown exponentially in nitrate, and (c) cells were shifted to nitrogen starvation conditions. The main differences in the transcriptional profiles have been identified between the cultures with ammonium as nitrogen source and the cultures with nitrate or nitrogen starvation, supporting previous results which indicate the absence of ammonium as the factor responsible for the expression of genes involved in nitrate assimilation pathway. The results have also permitted the identification of transcriptional regulators and changes in metabolic pathways related to the catabolism and anabolism of amino acids or nucleotides. The microarray data was validated by real-time quantitative PCR on 4 selected genes involved in nitrogen metabolism. This work represents the first transcriptional profiles study related to nitrogen assimilation metabolism in extreme halophilic microorganisms using microarray technology. PMID- 25435381 TI - Severe microbial keratitis and associated perforation after corneal crosslinking for keratoconus. AB - PURPOSE: To report two cases of microbial keratitis with subsequent corneal perforation immediately following corneal collagen crosslinking (CXL). METHODS: Retrospective case note review. RESULTS: First case was a 19 year old female presented with staphylococcal corneal abscess 3 days post CXL procedure. Corneal perforation occurred during hospital admission and was successfully treated with corneal gluing. Microbial keratitis eventually resolved, with both topical and systemic antibiotics therapy, resulting in a vascularized corneal scar. Second case was an 18 year old male whom developed Methicillin Resistant Staphylococcus aureus (MRSA) corneal abscess 5 days after CXL procedure for progressive keratoconus. Corneal perforation occurred 48 h after presentation and patient underwent uneventful corneal gluing. Although infective keratitis was successfully treated with topical therapy, patient had visual outcome of count fingers due to scarring. CONCLUSIONS: CXL has been widely used in the treatment of corneal ectatic conditions and complications, such as infective keratitis, are uncommon post procedure. We present two cases of severe microbial keratitis with subsequent corneal perforation within 7 days of CXL. The exact mechanism for the accelerated keratolysis process is unclear. Nonetheless, patients should be well informed of such potentially devastating complication. PMID- 25435382 TI - Selective tracking of lysosomal Cu2+ ions using simultaneous target- and location activated fluorescent nanoprobes. AB - Levels of lysosomal copper are tightly regulated in the human body. However, few methods for monitoring dynamic changes in copper pools are available, thus limiting the ability to diagnostically assess the influence of copper accumulation on health status. We herein report the development of a dual target and location-activated rhodamine-spiropyran probe, termed Rhod-SP, activated by the presence of lysosomal Cu(2+). Rhod-SP contains a proton recognition unit of spiropyran, which provides molecular switching capability, and a latent rhodamine fluorophore for signal transduction. Upon activation by lysosomal acidic pH, Rhod SP binds with Cu(2+) by spiropyran-based proton activation, promoting, in turn, rhodamine ring opening, which shows a "switched on" fluorescence signal. However, to protect Rhod-SP from degradation and interference by the physiological environment, it is engineered on mesoporous silica nanoparticles (MSNs), and the surface of Rhod-SP@MSNs is further anchored with beta-cyclodextrin (beta-CD) to enhance the solubility and bioavailability of Rhod-SP@MSN-CD. Next, to enhance cell specificity, a guiding unit of c(RGDyK) peptide conjugated adamantane (Ad RGD) as prototypical system, is incorporated on the surface of Rhod-SP@MSN-CD to target integrin alphavbeta3 and alphavbeta5 overexpressed on cancer cells. Fluorescence imaging showed that both Rhod-SP@MSN-CD and Rhod-SP@MSN-CD-RGD were suitable for visualizing exogenous and endogenous Cu(2+) in lysosomes of living cells. This strategy addresses some common challenges of chemical probes in biosensing, such as spatial resolution in cell imaging, the solubility and stability in biological system, and the interference from intracellular species. The newly designed nanoprobe, which allows one to track, on a location-specific basis, and visualize lysosomal Cu(2+), offers a potentially rich opportunity to examine copper physiology in both healthy and diseased states. PMID- 25435383 TI - Effects of pressure on the shear modulus, mass and thickness of the perfused porcine kidney. AB - Eleven fresh ex vivo porcine kidneys were perfused in the artery, vein and ureter with degassed Dulbecco's Modified Eagle Medium (DMEM). The effect of perfusion pressure was evaluated using ten different pressures combinations. The shear modulus of the tissues was estimated during perfusion using shear wave elastography. The organ weight change was measured by a digital scale and cameras were used to follow the changes of the dimensions after each pressure combination. The effect of perfusion on the weight and the thickness was non reversible, whereas the effect on the shear modulus was reversible. Pressure was found to increase the average shear modulus in the cortex by as much as 73%. A pressure of 80 mmHg was needed to observe tissues shear modulus in the same range as in vivo tests (Gcortex=9.1 kPa, Gmedulla=8.5 kPa ex vivo versus Gcortex=9.1 kPa, Gmedulla=8.7 kPa in vivo in Gennisson et al., 2012). PMID- 25435384 TI - Biomechanical influence of crown-to-implant ratio on stress distribution over internal hexagon short implant: 3-D finite element analysis with statistical test. AB - The study of short implants is relevant to the biomechanics of dental implants, and research on crown increase has implications for the daily clinic. The aim of this study was to analyze the biomechanical interactions of a singular implant supported prosthesis of different crown heights under vertical and oblique force, using the 3-D finite element method. Six 3-D models were designed with Invesalius 3.0, Rhinoceros 3D 4.0, and Solidworks 2010 software. Each model was constructed with a mandibular segment of bone block, including an implant supporting a screwed metal-ceramic crown. The crown height was set at 10, 12.5, and 15 mm. The applied force was 200 N (axial) and 100 N (oblique). We performed an ANOVA statistical test and Tukey tests; p<0.05 was considered statistically significant. The increase of crown height did not influence the stress distribution on screw prosthetic (p>0.05) under axial load. However, crown heights of 12.5 and 15 mm caused statistically significant damage to the stress distribution of screws and to the cortical bone (p<0.001) under oblique load. High crown to implant (C/I) ratio harmed microstrain distribution on bone tissue under axial and oblique loads (p<0.001). Crown increase was a possible deleterious factor to the screws and to the different regions of bone tissue. PMID- 25435385 TI - Finite element analysis of the biomechanical effects of PEEK dental implants on the peri-implant bone. AB - Dental implants are mostly fabricated of titanium. Potential problems associated with these implants are discussed in the literature, for example, overloading of the jawbone during mastication due to the significant difference in the elastic moduli of titanium (110 GPa) and bone (~1-30 GPa). Therefore poly-ether-ether ketone (PEEK) could represent an alternative biomaterial (elastic modulus 3-4 GPa). Endolign((r)) represents an implantable carbon fiber reinforced (CFR)-PEEK including parallel oriented endless carbon fibers. According to the manufacturer it has an elastic modulus of 150 GPa. PEEK compounds filled with powders show an elastic modulus around 4 GPa. The aim of the present finite element analysis was to point out the differences in the biomechanical behavior of a dental implant of Endolign((r)) and a commercial powder-filled PEEK. Titanium served as control. These three materials were used for a platform-switched dental implant-abutment assembly, whereas Type 1 completely consisted of titanium, Type 2 of a powder filled PEEK and Type 3 of Endolign((r)). A force of 100 N was applied vertically and of 30 degrees to the implant axis. All types showed a minimum safety factor regarding the yield strength of cortical bone. However, within the limits of this study the Type 2 implant showed higher stresses within the adjacent cortical bone than Type 1 and Type 3. These implant assemblies showed similar stress distributions. Endless carbon fibers give PEEK a high stability. Further investigations are necessary to evaluate whether there is a distinct amount of endless carbon fibers causing an optimal stress distribution behavior of CFR PEEK. PMID- 25435386 TI - High-bandwidth AFM-based rheology is a sensitive indicator of early cartilage aggrecan degradation relevant to mouse models of osteoarthritis. AB - Murine models of osteoarthritis (OA) and post-traumatic OA have been widely used to study the development and progression of these diseases using genetically engineered mouse strains along with surgical or biochemical interventions. However, due to the small size and thickness of murine cartilage, the relationship between mechanical properties, molecular structure and cartilage composition has not been well studied. We adapted a recently developed AFM-based nano-rheology system to probe the dynamic nanomechanical properties of murine cartilage over a wide frequency range of 1 Hz to 10 kHz, and studied the role of glycosaminoglycan (GAG) on the dynamic modulus and poroelastic properties of murine femoral cartilage. We showed that poroelastic properties, highlighting fluid-solid interactions, are more sensitive indicators of loss of mechanical function compared to equilibrium properties in which fluid flow is negligible. These fluid-flow-dependent properties include the hydraulic permeability (an indicator of the resistance of matrix to fluid flow) and the high frequency modulus, obtained at high rates of loading relevant to jumping and impact injury in vivo. Utilizing a fibril-reinforced finite element model, we estimated the poroelastic properties of mouse cartilage over a wide range of loading rates for the first time, and show that the hydraulic permeability increased by a factor ~16 from knormal=7.80*10(-16)+/-1.3*10(-16) m(4)/N s to kGAG-depleted=1.26*10( 14)+/-6.73*10(-15) m(4)/N s after GAG depletion. The high-frequency modulus, which is related to fluid pressurization and the fibrillar network, decreased significantly after GAG depletion. In contrast, the equilibrium modulus, which is fluid-flow independent, did not show a statistically significant alteration following GAG depletion. PMID- 25435388 TI - In pursuit of prodromal Parkinson's disease. PMID- 25435387 TI - Prediagnostic presentations of Parkinson's disease in primary care: a case control study. AB - BACKGROUND: Parkinson's disease has an insidious onset and is diagnosed when typical motor features occur. Several motor and non-motor features can occur before diagnosis, early in the disease process. We aimed to assess the association between first presentation of several prediagnostic features in primary care and a subsequent diagnosis of Parkinson's disease, and to chart the timeline of these first presentations before diagnosis. METHODS: We identified individuals with a first diagnosis of Parkinson's disease and those without Parkinson's disease from Jan 1, 1996, to Dec 31, 2012, from The Health Improvement Network UK primary care database. Codes were extracted for a range of possible prediagnostic or early symptoms, comprising motor features (tremor, rigidity, balance impairments, neck pain or stiffness, and shoulder pain or stiffness), autonomic features (constipation, hypotension, erectile dysfunction, urinary dysfunction, and dizziness), neuropsychiatric disturbances (memory problems, late-onset anxiety or depression, cognitive decline, and apathy), and additional features (fatigue, insomnia, anosmia, hypersalivation and rapid-eye movement sleep behaviour disorder) in the years before diagnosis. We report the incidence of symptoms recorded in more than 1% of cases per 1000 person-years and incidence risk ratios (RRs) for individuals with and without Parkinson's disease at 2, 5, and 10 years before diagnosis. FINDINGS: 8166 individuals with and 46,755 individuals without Parkinson's disease were included in the study. Apathy, REM sleep behaviour disorder, anosmia, hypersalivation, and cognitive decline were all reported in less than 1% of people per 1000 person-years and were excluded from further analyses. At 2 years before Parkinson's disease diagnosis, the incidence of all studied prediagnostic features except neck pain or stiffness was higher in patients who went on to develop Parkinson's disease (n=7232) than in controls (n=40,541). At 5 years before diagnosis, compared with controls (n=25,544), patients who went on to develop Parkinson's disease (n=4769) had a higher incidence of tremor (RR 13.70, 95% CI 7.82-24.31), balance impairments (2.19, 1.09-4.16), constipation (2.24, 2.04-2.46), hypotension (3.23, 1.85-5.52), erectile dysfunction (1.30, 1.11-1.51), urinary dysfunction (1.96, 1.34-2.80), dizziness (1.99, 1.67-2.37), fatigue (1.56, 1.27-1.91), depression (1.76, 1.41-2.17), and anxiety (1.41, 1.09-1.79). At 10 years before diagnosis of Parkinson's disease, the incidence of tremor (RR 7.59, 95% CI 1.11-44.83) and constipation (2.01, 1.62-2.49) was higher in those who went on to develop Parkinson's disease (n=1680) than in controls (n=8305). INTERPRETATION: A range of prediagnostic features can be detected several years before diagnosis of Parkinson's disease in primary care. These data can be incorporated into ongoing efforts to identify individuals at the earliest stages of the disease for inclusion in future trials and to help understand progression in the earliest phase of Parkinson's disease. FUNDING: Parkinson's UK. PMID- 25435389 TI - Preface. PMID- 25435390 TI - Non-communicable diseases in maternal fetal medicine: volume I. Preface issue 29.1. PMID- 25435391 TI - Polymer supported ZIF-8 membranes prepared via an interfacial synthesis method. AB - Porous polymer supported continuous ZIF-8 membranes were prepared via an interfacial synthesis method. Membranes with only one synthesis cycle showed excellent performance in the nanofiltration range. PMID- 25435392 TI - [French guidelines on electroencephalogram]. AB - Electroencephalography allows the functional analysis of electrical brain cortical activity and is the gold standard for analyzing electrophysiological processes involved in epilepsy but also in several other dysfunctions of the central nervous system. Morphological imaging yields complementary data, yet it cannot replace the essential functional analysis tool that is EEG. Furthermore, EEG has the great advantage of being non-invasive, easy to perform and allows control tests when follow-up is necessary, even at the patient's bedside. Faced with the advances in knowledge, techniques and indications, the Societe de Neurophysiologie Clinique de Langue Francaise (SNCLF) and the Ligue Francaise Contre l'Epilepsie (LFCE) found it necessary to provide an update on EEG recommendations. This article will review the methodology applied to this work, refine the various topics detailed in the following chapters. It will go over the summary of recommendations for each of these chapters and underline proposals for writing an EEG report. Some questions could not be answered by the review of the literature; in those cases, an expert advice was given by the working and reading groups in addition to the guidelines. PMID- 25435393 TI - Reconstruction of the anterior skull base after major trauma or extensive tumour resection. AB - BACKGROUND: The authors describe their experience with the reconstruction of complex anterior skull base defects after trauma or tumour resection using a "sandwich" technique with pericranial flap, titanium mesh and TachoSil. METHODS: Description of surgical anatomy, surgical technique, indications, limitations, complications, specific perioperative considerations and specific information to give to the patient about surgery and potential risks. A summary of ten key points is given. CONCLUSIONS: After a bifrontal craniotomy and a subfrontal approach, it is possible to achieve a reliable reconstruction of the anterior skull base in a watertight manner by fixing a pericranial flap or a fascia lata graft to the orbital roofs and planum sphenoidale with an individually tailored titanium mesh and closing the frontobasal dura leasion with TachoSil. PMID- 25435394 TI - Is duration of surgery a risk factor for extracranial complications and surgical site infections after intracranial tumor operations? AB - BACKGROUND: Duration of surgery has not been much explored as a possible risk factor for complications in neurosurgery. OBJECTIVE: To explore the possible impact of duration of surgery on the risk of developing extracranial complications and surgical site infections following intracranial tumor surgery. METHODS: Retrospective review of 1,000 consecutive patients who underwent planned surgery for intracranial tumors at a single institution. Complications within 30 days of surgery were registered. RESULTS: Of all patients, 18.6 % acquired extracranial complications, and they were seen in 14.3, 17.7, 22.1 and 37.4 % after operations lasting <2, 2-4, 4-6 and >=6 h (p = 0.025). In multivariate analyses, duration of surgery per hour [OR 1.14 (1.04-1.25)], ASA 3-4 [OR 1.37 (1.14-1.63)] and acquired neurological deficits [OR 1.47 (1.02-2.11)] were associated with extracranial complications. For surgical site infections, there was a significant association between increased risk and increased duration of surgery (p < 0.001). CONCLUSION: Duration of surgery together with comorbidity and acquired neurological deficits is an independent risk factor for extracranial complications after brain tumor surgery. Duration of surgery is also associated with surgical site infections. Knowledge about the potential harm of slow surgery should be of interest to neurosurgeons when deciding on various surgical approaches, surgical tools or providing training. Also if acquiring ethical approval or informed consent in technical research projects, the risks associated with prolonging brain surgery should be considered. Special consideration should be warranted in patients with significant comorbidity, planned long surgery and higher risk of acquiring neurological deficits after surgery. PMID- 25435395 TI - Computational characterization of parallel dimeric and trimeric coiled-coils using effective amino acid indices. AB - The coiled-coil, which consists of two or more alpha-helices winding around each other, is a ubiquitous and the most frequently observed protein-protein interaction motif in nature. The coiled-coil is known for its straightforward heptad repeat pattern and can be readily recognized based on protein primary sequences, exhibiting a variety of oligomer states and topologies. Due to the stable interaction formed between their alpha-helices, coiled-coils have been under close scrutiny to design novel protein structures for potential applications in the fields of material science, synthetic biology and medicine. However, their broader application requires an in-depth and systematic analysis of the sequence-to-structure relationship of coiled-coil folding and oligomeric formation. In this article, we propose a new oligomerization state predictor, termed as RFCoil, which exploits the most useful and non-redundant amino acid indices combined with the machine learning algorithm - random forest (RF) - to predict the oligomeric states of coiled-coil regions. Benchmarking experiments show that RFCoil achieves an AUC (area under the ROC curve) of 0.849 on the 10 fold cross-validation test using the training dataset and 0.855 on the independent test using the validation dataset, respectively. Performance comparison results indicate that RFCoil outperforms the four existing predictors LOGICOIL, PrOCoil, SCORER 2.0 and Multicoil2. Furthermore, we extract a number of predominant rules from the trained RF model that underlie the oligomeric formation. We also present two case studies to illustrate the applicability of the extracted rules to the prediction of coiled-coil oligomerization state. The RFCoil web server, source codes and datasets are freely available for academic users at http://protein.cau.edu.cn/RFCoil/. PMID- 25435396 TI - MLLT10 and IL3 rearrangement together with a complex four-way translocation and trisomy 4 in a patient with early T-cell precursor acute lymphoblastic leukemia: A case report. AB - Cytogenetic classification of acute lymphoblastic leukemia (ALL) is primarily based on numerical and structural chromosomal abnormalities. In T-cell ALL (T ALL), chromosomal rearrangements are identified in up to 70% of the patients while the remaining patients show a normal karyotype. In the present study, a 16 year-old male was diagnosed with T-precursor cell ALL and a normal karyotype after standard GTG-banding, was studied retrospectively (>10 years after diagnosis) in frame of a research project by molecular approaches. In addition to molecular cytogenetics, multiplex ligation-dependent probe amplification (MLPA) and high resolution array-comparative genomic hybridization (aCGH) were also applied. Thus, the following yet unrecognized balanced chromosomal aberrations were detected: der(3)t(3;5)(p23;q31.1), der(5)t(3;5)(p23;q35.3), der(5)t(5;10)(q31.1;p12.3) and der(10)t(5;10)(q35.3;p12.3). The oncogene MLLT10 was involved in this rearrangement as was the IL3 gene; in addition, trisomy 4 was present. All of these clonal aberrations were found in 40% of the cells. Even if this complex karyotype would have been identified at the time of diagnosis, most likely no other protocol of anticancer therapy (ALL-BFM 95) would have been applied. Three months after the end of a successful 2-year treatment, the patient suffered from isolated bone marrow relapse and died of sepsis during ALL-REZ-BFM protocol treatment. PMID- 25435397 TI - Influence of ultrasound power on acoustic streaming and micro-bubbles formations in a low frequency sono-reactor: mathematical and 3D computational simulation. AB - This paper aims at investigating the influence of ultrasound power amplitude on liquid behaviour in a low-frequency (24 kHz) sono-reactor. Three types of analysis were employed: (i) mechanical analysis of micro-bubbles formation and their activities/characteristics using mathematical modelling. (ii) Numerical analysis of acoustic streaming, fluid flow pattern, volume fraction of micro bubbles and turbulence using 3D CFD simulation. (iii) Practical analysis of fluid flow pattern and acoustic streaming under ultrasound irradiation using Particle Image Velocimetry (PIV). In mathematical modelling, a lone micro bubble generated under power ultrasound irradiation was mechanistically analysed. Its characteristics were illustrated as a function of bubble radius, internal temperature and pressure (hot spot conditions) and oscillation (pulsation) velocity. The results showed that ultrasound power significantly affected the conditions of hotspots and bubbles oscillation velocity. From the CFD results, it was observed that the total volume of the micro-bubbles increased by about 4.95% with each 100 W-increase in power amplitude. Furthermore, velocity of acoustic streaming increased from 29 to 119 cm/s as power increased, which was in good agreement with the PIV analysis. PMID- 25435398 TI - Bio-refinery of orange peels waste: a new concept based on integrated green and solvent free extraction processes using ultrasound and microwave techniques to obtain essential oil, polyphenols and pectin. AB - In this study, extraction of essential oil, polyphenols and pectin from orange peel has been optimized using microwave and ultrasound technology without adding any solvent but only "in situ" water which was recycled and used as solvent. The essential oil extraction performed by Microwave Hydrodiffusion and Gravity (MHG) was optimized and compared to steam distillation extraction (SD). No significant changes in yield were noticed: 4.22 +/- 0.03% and 4.16 +/- 0.05% for MHG and SD, respectively. After extraction of essential oil, residual water of plant obtained after MHG extraction was used as solvent for polyphenols and pectin extraction from MHG residues. Polyphenols extraction was performed by ultrasound-assisted extraction (UAE) and conventional extraction (CE). Response surface methodology (RSM) using central composite designs (CCD) approach was launched to investigate the influence of process variables on the ultrasound-assisted extraction (UAE). The statistical analysis revealed that the optimized conditions of ultrasound power and temperature were 0.956 W/cm(2) and 59.83 degrees C giving a polyphenol yield of 50.02 mgGA/100 g dm. Compared with the conventional extraction (CE), the UAE gave an increase of 30% in TPC yield. Pectin was extracted by conventional and microwave assisted extraction. This technique gives a maximal yield of 24.2% for microwave power of 500 W in only 3 min whereas conventional extraction gives 18.32% in 120 min. Combination of microwave, ultrasound and the recycled "in situ" water of citrus peels allow us to obtain high added values compounds in shorter time and managed to make a closed loop using only natural resources provided by the plant which makes the whole process intensified in term of time and energy saving, cleanliness and reduced waste water. PMID- 25435399 TI - cCMP and cUMP: emerging second messengers. AB - The cyclic purine nucleotides cAMP and cGMP are established second messengers. By contrast, the existence of the cyclic pyrimidine nucleotides cytidine 3',5' cyclic monophosphate (cCMP) and uridine 3',5'-cyclic monophosphate (cUMP) has been controversial for decades. The recent development of highly sensitive mass spectrometry (MS) methods allowed precise quantitation and unequivocal identification of cCMP and cUMP in cells. Importantly, cCMP and cUMP generators, effectors, cleaving enzymes, and transporters have now been identified. Here, I discuss evidence in support of cCMP and cUMP as bona fide second messengers, the emerging therapeutic implications of cCMP and cUMP signaling, and important unresolved questions for this field. PMID- 25435401 TI - Mining diverse small RNA species in the deep transcriptome. AB - Transcriptomes of many species are proving to be exquisitely diverse, and many investigators are now using high-throughput sequencing to quantify non-protein coding RNAs, namely small RNAs (sRNA). Unfortunately, most studies are focused solely on microRNA changes, and many investigators are not analyzing the full compendium of sRNA species present in their large datasets. We provide here a rationale to include all types of sRNAs in sRNA sequencing analyses, which will aid in the discovery of their biological functions and physiological relevance. PMID- 25435400 TI - Nuclear receptor full-length architectures: confronting myth and illusion with high resolution. AB - The crystal structures of three nuclear receptor (NR) complexes have emerged to reveal their multidomain architectures on DNA. These pictures provide unprecedented views of interfacial couplings between the DNA-binding domains (DBDs) and ligand-binding domains (LBDs). The detailed pictures contrast with previous interpretations of low-resolution electron microscopy (EM) and small angle X-ray scattering (SAXS) data, which had suggested a common architecture with noninteracting DBDs and LBDs. Revisiting both historical and recent interpretations of NR architecture, we invoke new principles underlying higher order quaternary organization and the allosteric transmission of signals between domains. We also discuss how NR architectures are being probed in living cells to understand dimerization and DNA-binding events in real time. PMID- 25435402 TI - Understanding the impact of socioeconomic differences in breast cancer survival in England and Wales: avoidable deaths and potential gain in expectation of life. AB - BACKGROUND: Socioeconomic differences in cancer patient survival are known to exist for women diagnosed with breast cancer. Standard metrics tend not to place great emphasis on evaluating the actual impact of these differences. METHODS: We used two alternative, but related, methods of reporting the impact of socioeconomic differences for breast cancer patients in England and Wales. We calculated the average gain in life years for each patient should socioeconomic differences in relative survival be removed and show how this is related to the number of all-cause deaths that could be postponed by removing socioeconomic differences in cancer patient survival. RESULTS: Our results indicate that deprivation differences for women with breast cancer exist and result in women from more deprived areas losing a larger proportion of their life due to a diagnosis of cancer. We also estimate that on average 1.1 years could be gained for a 60 year old breast cancer patient in the most deprived group by improving their relative survival to match the least deprived group. However, our results also show that deprivation differences in general survival have a large impact on life expectancy; showing that over two-thirds of the gap in differential life expectancy is explained by differences in other-cause survival. CONCLUSION: Socioeconomic differences in relative survival have an impact on life expectancy for patients and result in higher early mortality for more deprived patients. However, differences in general survival across socioeconomic groups explain a larger proportion of the deprivation gap in life expectancy for breast cancer patients. PMID- 25435403 TI - Comparison between retrograde intrarenal surgery and extracorporeal shock wave lithotripsy in the treatment of lower pole kidney stones up to 15 mm. Prospective, randomized study. AB - INTRODUCTION: Extracorporeal Shock Wave Lithotripsy (ESWL) is currently the recommended treatment for intra-renal calculi smaller than 2 cm. However the low Stone Free Rate (SFR) in lower pole calculi gives rise to new techniques, such us retrograde intrarenal surgery (RIRS), for improve the surgery outcomes. OBJECTIVE: To compare the efficacy of a treatment with ESWL with RIRS, in terms of SFR after surgery, in patients with kidney stones up to 15 mm in the lower pole. MATERIAL AND METHODS: A prospective study was carried out in order to assess the results of ESWL and RIRS in patients with lower pole stones less than 15 mm. Among a total of 55 patients, 31 were underwent to ESWL (Group 1) and the remaining 24 to RIRS (Group 2). Clinical data recorded, including general characteristics of each patient, were: calculi size, side, operative time, complications according to Clavien scale, SFR and the presence of residual fragments at 2 months post-treatment assessed by a CT scan. STATA 11 was used to perform the statistical analysis. RESULTS: There were no differences for general descriptors among groups with the exception of a significantly longer operative time for RIRS. The rates of SFR and residual fragments lesser than 3 mm. were lower in the RIRS group than in ESWL ones. RIRS also showed a lower rate of clinically significant fragments (0% vs 42.3%. P < .05). In the subgroup of patients with stones between 10/15 mm RIRS showed higher SFR (75% vs. 41.2%) and a lower rate of stones>3 mm (0% vs. 58.8%), being statistically significant (P < .05). Clavien III or higher complications were not reported in any of the groups. CONCLUSIONS: In the treatment of lower pole stone RIRS has the same results than ESWL in terms of SFR. Regarding absence of a clinically significant residual fragment, RIRS was superior to ESWL. A bigger sample size is required in order to confirm this results. PMID- 25435405 TI - Low-valent chemistry: an alternative approach to phosphorus-containing oligomers. AB - A convenient preparative approach to low-valent phosphorus-rich oligomers is presented. Ligand substitution reactions involving anionic diphosphine ligands of the form [(PR2)2N](-) and [(PPh2)2C5H3](-) and a triphosphenium bromide P(I) precursor result in the formation of phosphorus(I)-containing heterocycles, several of which are of types that have never been prepared before. The methodology described also allows for the preparation of the known heterocycle cyclo-[P(PPh2)N(PPh2)]2 in better yields and purity than the synthetic approach reported previously. Preliminary reactivity studies demonstrate the viability of such zwitterionic oligomers as multidentate ligands for transition metals. PMID- 25435404 TI - Looking with different eyes: The psychological meaning of categorisation goals moderates facial reactivity to facial expressions. AB - In the present research we examined whether the psychological meaning of people's categorisation goals affects facial muscle activity in response to facial expressions of emotion. We had participants associate eye colour (blue, brown) with either a personality trait (extraversion) or a physical trait (light frequency) and asked them to use these associations in a speeded categorisation task of angry, disgusted, happy and neutral faces while assessing participants' response times and facial muscle activity. We predicted that participants would respond differentially to the emotional faces when the categorisation criteria allowed for inferences about a target's thoughts, feelings or behaviour (i.e., when categorising extraversion), but not when these lacked any social meaning (i.e., when categorising light frequency). Indeed, emotional faces triggered facial reactions to facial expressions when participants categorised extraversion, but not when they categorised light frequency. In line with this, only when categorising extraversion did participants' response times indicate a negativity bias replicating previous results. Together, these findings provide further evidence for the contextual nature of people's selective responses to the emotions expressed by others. PMID- 25435406 TI - Endotracheal tube-assisted orogastric tube insertion in intubated patients in an ED. AB - BACKGROUND AND AIMS: Inserting a nasogastric tube (NGT) in intubated patients may be difficult because they cannot follow swallowing instructions, resulting in a high rate of first-attempt failure. We introduce a simple technique for inserting an orogastric tube in an emergency department (ED). METHODS: Fifty-six patients in the ED, who were intubated and required NGT insertion, were randomly allocated to 2 groups. We inserted the NGT using a conventional technique from the nostril (control group) and an endotracheal tube (ET)-assisted technique from the mouth (ET group). The procedures' success rate, insertion duration, and complications were compared between the groups. RESULTS: There was a significantly higher overall success rate in the ET group than the control group (100% vs 64%, P<.001). Endotracheal tube group showed 100% first-attempt success rate, but 50% of the control group failed at first attempt. Mean duration of the first trial was not significantly different between the ET and control groups (58.0+/-16.9 vs 57.3+/-29.5 seconds, P=.903), but total time for successful insertion was longer in the control group than the ET group (58.0+/-16.9 vs 111.7+/-74.5 seconds, P<.001). There was less NGT kinking and more mucosal bleeding in the ET group than in the control group (0% vs 16%, P=.019; 16% vs 7%, P=.225, respectively). CONCLUSION: Endotracheal tube-assisted orogastric tube insertion technique showed a higher rate of successful insertion and shorter total duration. With this result, ET-assisted orogastric tube insertion would be useful in ED. PMID- 25435407 TI - The LOOP technique: a novel incision and drainage technique in the treatment of skin abscesses in a pediatric ED. AB - OBJECTIVE: This study assesses outcome in pediatric patients with skin abscess using the LOOP compared to the standard incision and drainage (I&D) with packing method. METHODS: This retrospective study used ICD-9 codes to identify pediatric patients aged 0 to 17 years with a skin abscess presenting to a level I pediatric trauma emergency department (ED). Patients requiring surgical debridement were excluded; as were patients with abscesses on the face, scalp, hands or feet. The primary outcome was failure rate, defined as those requiring admission, intravenous antibiotics, or repeat drainage. RESULTS: Over a 1-year period there were 233 pediatric abscesses identified: 79 cases (34%) treated with the LOOP technique and 154 cases with standard I&D (66%). The overall mean age of patients was 6.2 yrs: children in the LOOP group were younger than those in the standard group, 4.4 vs 7.1 years respectively (P=.001). Abscess location also differed between the two groups; however they had a similar gender distribution and mean temperature. Of the cases identified by chart review, clinical outcome could be assessed in 143 patients (61%): 52 (36%) patients with LOOP vs 91 (64%) with I&D. Failure rate was 1.4% in the LOOP group and 10.5% in the standard I&D (P<.030). CONCLUSION: There was a significant difference in failure rate between the LOOP and the standard I&D groups. A prospective randomized trial is needed to confirm these results, but this novel technique shows promise as an alternative to I&D with packing in the management of skin abscesses in pediatric ED patients. PMID- 25435408 TI - Development and evaluation of a sublingual film of the antiemetic granisetron hydrochloride. AB - The objective of this study was to develop an oral transmucosal formulation of an antiemetic drug that can not only serve in the active form but also provide a controlled release profile. In this study, sublingual films based on the biodegradable and water-soluble polymers, that is HPMCK-4M and PVPK-30, were developed by the solvent casting method, and were loaded with the antiemetic drug granisetron hydrochloride (granisetron HCl). The entrapment efficiency of the developed formulation was found to be 86%. The in vitro profile showed an instant release of the drug from the sublingual film, in a pattern following the first order kinetics array. The in vivo studies showed that granisetron HCl was delivered in its active state and showed effective results, as compared to its activity in the marketed formulation. PMID- 25435409 TI - Current methods for synthesis of magnetic nanoparticles. AB - The synthesis of different kinds of magnetic nanoparticles (MNPs) has attracted much attention. During the last few years, a large portion of the articles published about MNPs have described efficient routes to attain shape-controlled and highly stable MNPs with narrow size distribution. In this review, we have reported several popular methods including co-precipitation, microemulsion, thermal decomposition, solvothermal, sonochemical, microwave-assisted, chemical vapor deposition, combustion, carbon arc, and laser pyrolysis, for the synthesis of magnetic nanoparticles. PMID- 25435410 TI - A comparison of the inhibitory effect of nano-encapsulated helenalin and free helenalin on telomerase gene expression in the breast cancer cell line, by real time PCR. AB - BACKGROUND: The up-regulation of telomerase gene expression occurs in numerous cancers such as breast cancer. A recent study used the PLGA-PEG-helenalin complex, and free helenalin, to inhibit the expression of telomerase in the breast cancer cell line. The purpose of this study was to examine whether nano encapsulating helenalin improves the anti-cancer effect of free helenalin in the T47D breast cancer cell line. METHOD: The breast cancer cell line (T47D) was grown in the RPMI 1640 medium, supplemented with 10% FBS. The helenalin was encapsulated by the double emulsion method. Then, the drug loading was calculated and its morphology identified by SEM. Other properties of this copolymer were characterized by Fourier transform infrared (FTIR) spectroscopy and H nuclear magnetic resonance (H NMR) spectroscopy. The assessment of drug cytotoxicity on the growth of the breast cancer cell line was carried out through MTT assay. After treating the cells with a given amount of drug, RNA was extracted and cDNA was synthesized. In order to assess the amount of telomerase gene expression, real-time PCR was performed. RESULTS: With regard to the amount of the drug loaded, IC50 value was significantly decreased in nanocapsulated (NC) helenalin, in comparison with that of free helenalin. This finding has been proved through the decrease of telomerase gene expression by real-time PCR. CONCLUSION: In this study, we demonstrated that the NC-helenalin complex is more effective than free helenalin in inhibiting the growth of breast cancer cells. PMID- 25435411 TI - The role of short term memory and conduction velocity restitution in alternans formation. AB - Alternans is the periodic beat-to-beat short-long alternation in action potential duration (APD), which is considered to be a precursor of ventricular arrhythmias and sudden cardiac death. In extended cardiac tissue, electrical alternans can be either spatially concordant (SCA, all cells oscillate in phase) or spatially discordant (SDA, cells in different regions oscillate out of phase). SDA gives rise to an increase in the spatial dispersion of repolarization, which is thought to be proarrhythmic. In this paper, we investigated the effect of two aspects of short term memory (STM) (alpha, tau) and their interplay with conduction velocity (CV) restitution on alternans formation using numerical simulations of a mapping model with two beats of memory. Here, alpha quantifies the dependence of APD restitution on pacing history and tau characterizes APD accommodation, which is an exponential change of APD over time once basic cycle length (BCL) changes. Our main findings are as follows: In both single cell and spatially coupled homogeneous cable, the interplay between alpha and tau affects the dynamical behaviors of the system. For the case of large APD accommodation (tau >= 290 ms), increase in alpha leads to suppression of alternans. However, if APD accommodation is small (tau <= 250 ms), increase in alpha leads to appearance of additional alternans region. On the other hand, the slope of CV restitution does not change the regions of alternans in the cable. However, steep CV restitution leads to more complicated dynamical behaviors of the system. Specifically, SDA instead of SCA are observed. In addition, for steep CV restitution and sufficiently large tau, we observed formations of type II conduction block (CB2), transition from type I conduction block (CB1) to CB2, and unstable nodes. PMID- 25435412 TI - Control exponential growth of tumor cells with slow spread of oncolytic virus. AB - Great attention has been paid to cancer therapy by means of oncolytic viruses, but the fast virus-spread, which eliminates all tumor cells, cannot be applied to solid tumors. As slow virus-spread is applied, solid tumors are expected to be controlled but complicated dynamical behaviors appear. In this paper we investigate bifurcations of equilibria in the oncolytic virus dynamics model with exponential growth of tumor cells and slow virus-spread. We find conditions of parameters for saddle-node bifurcation, Hopf bifurcation and Bogdanov-Takens bifurcation. Those conditions give thresholds for slow virus-spread to control the population of tumor cells within an appropriate range. PMID- 25435413 TI - [Bilateral parotitis in a patient under continuous positive airway pressure treatment]. AB - BACKGROUND AND OBJECTIVES: Many conditions such as bacterial and viral infectious diseases, mechanical obstruction due to air and calculi and drugs can cause parotitis. We present a case of unusual bilateral parotitis in a patient under non-invasive continuous positive airway pressure (CPAP) therapy for chronic obstructive pulmonary disease exacerbation in intensive care unit. CASE REPORT: A 36-year-old patient was admitted to intensive care unit with the diagnosis of chronic obstructive pulmonary disease exacerbation. Antibiotherapy, bronchodilator therapy and non-invasive positive pressure ventilation were applied as treatment regimen. Painless swellings developed on the 3rd day of admission on the right and a day after this on the left parotid glands. Amylase levels were increased and ultrasonographic evaluation revealed bilateral parotitis. No intervention was made and the therapy was continued. The patient was discharged on the 6th day with clinical improvement and regression of parotid swellings without any complications. CONCLUSIONS: Parotitis may have occurred after retrograde air flow in the Stensen duct during CPAP application. After the exclusion of possible viral and bacteriological etiologies and possible drug reactions we can focus on this diagnosis. PMID- 25435414 TI - [Frequency of colonization and isolated bacteria from the tip of the epidural catheter implanted for postoperative analgesia]. AB - BACKGROUND AND OBJECTIVE: The increased use of epidural analgesia with catheter leads to the need to demonstrate the safety of this method and know the incidence of catheter colonization, inserted postoperatively for epidural analgesia, and the bacteria responsible for this colonization. METHODS: From November 2011 to April 2012, patients electively operated and maintained under epidural catheter for postoperative analgesia were evaluated. The catheter tip was collected for semiquantitative and qualitative microbiological analysis. RESULTS: Of 68 cultured catheters, six tips (8.8%) had positive cultures. No patient had superficial or deep infection. The mean duration of catheter use was 43.45hours (18-118) (p=0.0894). The type of surgery (contaminated or uncontaminated), physical status of patients, and surgical time showed no relation with the colonization of catheters. Microorganisms isolated from the catheter tip were Staphylococcus aureus, Pseudomonas aeruginosa and Sphingomonas paucimobilis. CONCLUSION: Postoperative epidural catheter analgesia, under this study conditions, was found to be low risk for bacterial colonization in patients at surgical wards. PMID- 25435415 TI - [Predictive value of preoperative tests in estimating difficult intubation in patients who underwent direct laryngoscopy in ear, nose, and throat surgery]. AB - BACKGROUND AND OBJECTIVES: Predictive value of preoperative tests in estimating difficult intubation may differ in the laryngeal pathologies. Patients who had undergone direct laryngoscopy (DL) were reviewed, and predictive value of preoperative tests in estimating difficult intubation was investigated. METHODS: Preoperative, and intraoperative anesthesia record forms, and computerized system of the hospital were screened. RESULTS: A total of 2611 patients were assessed. In 7.4% of the patients, difficult intubations were detected. Difficult intubations were encountered in some of the patients with Mallampati scoring (MS) system Class 4 (50%), Cormack-Lehane classification (CLS) Grade 4 (95.7%), previous knowledge of difficult airway (86.2%), restricted neck movements (cervical ROM) (75.8%), short thyromental distance (TMD) (81.6%), vocal cord mass (49.5%) as indicated in parentheses (p<0.0001). MS had a low sensitivity, while restricted cervical ROM, presence of a vocal cord mass, short thyromental distance, and MS each had a relatively higher positive predictive value. Incidence of difficult intubations increased 6.159 and 1.736-fold with each level of increase in CLS grade and MS class, respectively. When all tests were considered in combination difficult intubation could be classified accurately in 96.3% of the cases. CONCLUSION: Test results predicting difficult intubations in cases with DL had observedly overlapped with the results provided in the literature for the patient populations in general. Differences in some test results when compared with those of the general population might stem from the concomitant underlying laryngeal pathological conditions in patient populations with difficult intubation. PMID- 25435416 TI - [Evaluation of brachial plexus fascicles involvement on infraclavicular block: unfixed cadaver study]. AB - BACKGROUND AND OBJECTIVES: This study shows how occurs the diffusion of the anesthetic into the sheath through the axiliary infraclavicular space and hence prove the efficacy of the anesthetic block of the brachial plexus, and may thereby allow a consolidation of this pathway, with fewer complications, previously attached to the anesthesia. MATERIALS AND METHODS: 33 armpits of adult cadavers were analyzed and unfixed. We injected a solution of neoprene with latex dye in the infraclavicular space, based on the technique advocated by Gusmao et al., and put the corpses in refrigerators for three weeks. Subsequently, the specimens were thawed and dissected, exposing the axillary sheath along its entire length. RESULTS AND DISCUSSION: Was demonstrated involvement of all fasciculus of the plexus in 51.46%. In partial involvement was 30.30%, and 18.24% of cases the acrylic was located outside the auxiliary sheath involving no issue. CONCLUSIONS: The results allow us to establish the infraclavicular as an effective and easy way to access plexus brachial, because the solution involved the fascicles in 81.76% partially or totally, when was injected inside the axillary sheath. We believe that only the use of this pathway access in practice it may demonstrate the efficiency. PMID- 25435417 TI - [Anesthesia in pregnant women with HELLP syndrome: case report]. AB - BACKGROUND AND OBJECTIVES: HELLP syndrome, characterized by hemolysis, high levels of liver enzyme, and low platelet count, is an advanced clinical stage of pre-eclampsia, progressing to high maternal (24%) and perinatal (up 40%) mortality, despite childbirth care in a timely manner. The goal is to describe the anesthetic management of a case with indication to emergency caesarean. CASE REPORT: Female patient, 36 years old, gestational age of 24 weeks, with hypertensive crisis (BP 180/100 mmHg) and severe headache, was admitted to the operating room for a cesarean section after diagnosis of HELLP syndrome. Indicated for general anesthesia, we opted for total intravenous with intubation after rapid sequence induction with propofol and remifentanil in continuous target-controlled infusion, and rocuronium at a dose of 1.2 mg/kg. Maintenance was achieved with propofol and remifentanil. The surgical procedure was uneventful, the child was born with APGAR 1/5 and transferred to the NICU. At the end of surgery, the patient was extubated in the operating room and taken to the ICU. The postoperative period was uneventful with no changes worthy of note and the patient was discharged on the sixth postoperative day. CONCLUSION: When general anesthesia is the choice in parturient with HELLP syndrome, tracheal intubation with rapid sequence induction due to possible difficult airway, as well as the use of drugs to control the hemodynamic response can minimize the complications associated with the procedure, as occurred in this case. PMID- 25435418 TI - [Non-invasive mechanical ventilation and epidural anesthesia for an emergency open cholecystectomy]. AB - Non-invasive ventilation is an accepted treatment modality in both acute exacerbations of respiratory diseases and chronic obstructive lung disease. It is commonly utilized in the intensive care units, or for postoperative respiratory support in post-anesthesia care units. This report describes intraoperative support in non-invasive ventilation to neuroaxial anesthesia for an emergency upper abdominal surgery. PMID- 25435419 TI - [Effect of nitrous oxide on fentanyl consumption in burned patients undergoing dressing change]. AB - BACKGROUND AND OBJECTIVES: Thermal injuries and injured areas management are important causes of pain in burned patients, requiring that these patients are constantly undergoing general anesthesia for dressing change. Nitrous oxide (N2O) has analgesic and sedative properties; it is easy to use and widely available. Thus, the aim of this study was to evaluate the analgesic effect of N2O combined with fentanyl in burned patients during dressing change. METHOD: After approval by the institutional Ethics Committee, 15 adult burned patients requiring daily dressing change were evaluated. Patient analgesia was controlled with fentanyl 0.0005% administered by intravenous pump infusion on-demand. Randomly, in one of the days a mixture of 65% N2O in oxygen (O2) was associated via mask, with a flow of 10 L/min (N2O group) and on the other day only O2 under the same flow (control group). RESULTS: No significant pain reduction was seen in N2O group compared to control group. VAS score before dressing change was 4.07 and 3.4, respectively, in N2O and control groups. Regarding pain at the end of the dressing, patients in N2O group reported pain severity of 2.8; while the control group reported 2.87. There was no significant difference in fentanyl consumption in both groups. CONCLUSIONS: The association of N2O was not effective in reducing opioid consumption during dressing changes. PMID- 25435420 TI - Behcet's syndrome patients exhibit specific microbiome signature. AB - BACKGROUND AND AIMS: Behcet syndrome is a systemic inflammatory condition characterized by muco-cutaneous and ocular manifestations, with central nervous system, vascular and/or gastro-intestinal involvement. The association of microbiota with Behcet syndrome has not been shown yet. Our work was aimed to compare the gut microbiota structure and the profiles of short-chain fatty acids production in Behcet syndrome patients and healthy control relatives. METHODS: Here, we compared the fecal microbiota of 22 patients with Behcet syndrome and that of 16 healthy co-habiting controls, sharing the same diet and lifestyle by pyrosequencing of the V3-V4 hypervariable regions of the 16 rDNA gene and biochemical analyses. RESULTS: Our analyses showed significant differences in gut microbiota between Behcet patients and healthy cohabitants. In particular we found that Behcet's patients were significantly depleted in the genera Roseburia and Subdoligranulum. Roseburia showed a relative abundance value of 10.45+/-6.01% in healthy relatives and 4.97+/-5.09% in Behcet's patients, and Subdoligranulum, which reached a relative abundance of 3.28+/-2.20% in healthy controls, was only at 1.93+/-1.75% of abundance in Behcet's patients. Here we report, for the first time, that a peculiar dysbiosis of the gut microbiota is present in patients with Behcet syndrome and this corresponds to specific changes in microbiome profile. A significant decrease of butyrate production (P=0.0033) in Behcet's patients was demonstrated. Butyrate is able to promote differentiation of T-regulatory cells, and consequently the results obtained prompt us to speculate that a defect of butyrate production might lead to both reduced T-reg responses and activation of immuno-pathological T-effector responses. CONCLUSIONS: Altogether, our results indicate that both a peculiar dysbiosis of the gut microbiota and a significant decrease of butyrate production are present in patients with Behcet syndrome. PMID- 25435421 TI - Association between ratio of measured extracellular volume to expected body fluid volume and renal outcomes in patients with chronic kidney disease: a retrospective single-center cohort study. AB - BACKGROUND: Excess extracellular volume is a major clinical problem in patients with chronic kidney disease (CKD). However, whether the extracellular volume status is associated with disease progression is unclear. We investigated the association between the extracellular volume status and renal outcomes. METHODS: We performed a retrospective cohort study of 149 patients with CKD who underwent bioelectrical impedance analysis (BIA) from 2005 to 2009. Patients were categorized according to tertiles of extracellular volume status. The extracellular volume status was assessed by examining the ratio of extracellular water measured by BIA (ECWBIA) to the total body water calculated using the Watson formula (TBWWatson). The main outcomes were adverse renal outcomes as defined by a decline of >=50% from the baseline glomerular filtration rate or initiation of renal replacement therapy. RESULTS: A higher %ECWBIA/TBWWatson ratio tended to be associated with older age, male sex, diabetes mellitus, resistant hypertension, lower renal function, lower serum albumin levels, higher proteinuria levels, and a higher frequency of furosemide use. In the multivariate analysis, proteinuria remained independently associated with the %ECWBIA/TBWWatson ratio. Both the intracellular and extracellular water volumes decreased with age (correlation between ICW and age, r=-0.30, P<0.001; correlation between ECW and age, r=-0.17, P=0.03). Consequently, the %ECWBIA in the body fluid composition increased with age. During a median follow-up of 4.9 years, patients in the highest tertile of the %ECWBIA/TBWWatson ratio were at greater risk of adverse renal outcomes (16.6 per 100.0 patient years) than were those in the lowest tertile (8.1 per 100.0 patient years) or second tertile (5.6 per 100.0 patient years) (log-rank P=0.005). After adjustment for covariates, the %ECWBIA/TBWWatson ratio was significantly associated with adverse renal outcomes (hazard ratio, 1.21; 95 % confidence interval, 1.10-1.34; P<0.001). CONCLUSIONS: The ECWBIA/TBWWatson ratio was independently associated with adverse renal outcomes. Proteinuria was independently associated with the extracellular volume status. The balance between ICW and ECW changes with age in that the percentage of ECW content in the body fluid composition increases. Elderly patients with CKD may thus be susceptible to volume overload. PMID- 25435422 TI - Evolving P450pyr monooxygenase for highly regioselective terminal hydroxylation of n-butanol to 1,4-butanediol. AB - Directed evolution of P450pyr created I83M/I82T mutant for highly regioselective terminal hydroxylation of n-butanol to 1,4-butanediol, representing the first achievement of this hydroxylation reaction by chemical or enzymatic methods and an unique example of evolving a hydroxylase to switch the substrate acceptance from a hydrophobic to hydrophilic compound. PMID- 25435423 TI - ErbB2 signaling activates the Hedgehog pathway via PI3K-Akt in human esophageal adenocarcinoma: identification of novel targets for concerted therapy concepts. AB - The Hedgehog pathway plays an important role in the pathogenesis of several tumor types, including esophageal cancer. In our study, we show an expression of the ligand Indian hedgehog (Ihh) and its downstream mediator Gli-1 in primary resected adenocarcinoma tissue by immunohistochemistry and quantitative PCR in fifty percent of the cases, while matching healthy esophagus mucosa was negative for both proteins. Moreover, a functionally important regulation of Gli-1 by ErbB2-PI3K-mTORC signaling as well as a Gli-1-dependent regulation of Ihh in the ErbB2 amplified esophageal adenocarcinoma cell line OE19 was observed. Treatment of OE19 cells with the Her2 antibody trastuzumab, the PI3K-mTORC1 inhibitor NVP BEZ235 (BEZ235) or the knockdown of Akt1 resulted in a downregulation of Gli-1 and Ihh as well as in a reduction of viable OE19 cells in vitro. Interestingly, the Hedgehog receptor Smo, which acts upstream of Gli-1, was not expressed in OE19 cells and in the majority of primary human esophageal adenocarcinoma, suggesting a non-canonical upregulation of Gli-1 expression by the ErbB2-PI3K axis. To translate our findings into a therapeutic concept, we targeted ErbB2 PI3K-mTORC1 by trastuzumab and BEZ235, combining both compounds with the Gli-1/2 inhibitor GANT61. The triple combination led to significantly stronger reduction of tumor cell viability than cisplatinum or each biological alone. Therefore, concomitant blockage of the ErbB2-PI3K pathway and the Hedgehog downstream mediator Gli-1 may provide a new therapeutic strategy for esophageal cancer. PMID- 25435424 TI - Inhibition of protein phosphatase-1 and -2A decreases the chemosensitivity of leukemic cells to chemotherapeutic drugs. AB - The phosphorylation of key proteins balanced by protein kinases and phosphatases are implicated in the regulation of cell cycle and apoptosis of malignant cells and influences anticancer drug actions. The efficacy of daunorubicin (DNR) in suppression of leukemic cell survival was investigated in the presence of tautomycin (TM) and calyculin A (CLA), specific membrane permeable inhibitors of protein phosphatase-1 (PP1) and -2A (PP2A), respectively. CLA (50 nM) or TM (1MUM) suppressed viability of THP-1 and KG-1 myeloid leukemia cell lines to moderate extents; however, they significantly increased survival upon DNR-induced cell death. CLA increased the phosphorylation level of Erk1/2 and PKB/Akt kinases, the retinoblastoma protein (pRb), decreased caspase-3 activation by DNR and increased the phosphorylation level of the inhibitory sites (Thr696 and Thr853) in the myosin phosphatase (MP) target subunit (MYPT1) as well as in a 25kDa kinase-enhanced phosphatase inhibitor (KEPI)-like protein. TM induced enhanced phosphorylation of pRb only, suggesting that this event may be a common factor upon CLA-induced PP2A and TM-induced PP1 inhibitory influences on cell survival. Silencing PP1 by siRNA in HeLa cells, or overexpression of Flag-KEPI in MCF-7 cells coupled with inducing its phosphorylation by PMA or CLA, resulted in increased phosphorylation of pRb. Our results indicate that PP1 directly dephosphorylates pRb, while PP2A might have an indirect influence via mediating the phosphorylation level of PP1 inhibitory proteins. These data imply the importance of PP1 inhibitory proteins in controlling the phosphorylation state of key proteins and regulating drug sensitivity and apoptosis in leukemic cells. PMID- 25435426 TI - Effect of Cdc42 domains on filopodia sensing, cell orientation, and haptotaxis. AB - Filopodia are sensors which, along with microtubules, regulate the persistence of locomotion. To determine whether protrusions were involved in sensing adhesion, epithelial cells were cultured on platinum and tantalum gradients. Protrusions were defined by an unbiased statistical method of classification as factors 4 (filopodia), 5 (mass distribution), and 7 (nascent neurites). When the prevalence of protrusions was measured in zones of high (H), middle (M), and low (L) adhesiveness, the main differences were in factor 4. Its values were highest at H and declined at M and L regardless of the gradient composition. The significance of the differences was enhanced when T (top/adhesive end) and B (bottom/nonadhesive end) sides of cells were analyzed separately. Since information about sidedness increased the statistical power of the test, this result suggested that cells pointed more filopodia toward the adhesive end. Trends occurred in factors 5 and 7 only when conditions allowed for a marked trend in factor 4. The data showed that gradient sensing is proportional to the prevalence of filopodia, and filopodia are the only protrusions engaged in comparing adhesiveness across a cell. The probability (P) of the significance of a trend was then used to determine how cells sense the gradient. Binding peptides (BPs) were introduced representing sequences critical for Cdc42 docking on a specific partner. BPs for IQGAP (IQ(calmodulin-binding domain)-containing GTPase activating protein) and ACK (Cdc42-associated kinase) reduced factor 4 values and prevented cell orientation on the gradient. Micrographs showed attenuated or stubby filopodia. These effectors may be implicated in gradient sensing. Another IQGAP BP increased filopodia prevalence and enhanced orientation on the gradient (P<0.00015). A Wiskott-Aldrich syndrome protein (WASP) BP had no effect. When sensing and orientation were abolished, they both failed at the level of filopodia, indicating that filopodia are both sensors and implementers of signals transduced by adhesion. PMID- 25435425 TI - In vitro and in silico analysis of an inhibitory mechanism of osteoclastogenesis by salubrinal and guanabenz. AB - Inactivating bone-resorbing osteoclasts is a prime therapeutic strategy for the prevention of bone loss in patients with osteopenia and osteoporosis. Synthetic agents such as salubrinal and guanabenz, which attenuate stress to the endoplasmic reticulum, are reported to inhibit development of osteoclasts. However, the mechanism of their inhibitory action on osteoclasts is largely unknown. Using genome-wide expression profiles, we predicted key transcription factors that downregulated nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a master transcription factor for osteoclastogenesis. Principal component analysis (PCA) predicted a list of transcription factors that were potentially responsible for reversing receptor activator of nuclear factor kappa B ligand (RANKL)-driven stimulation of osteoclastogenesis. A partial silencing of NFATc1 allowed a selection of transcription factors that were likely to be located upstream of NFATc1. We validated the predicted transcription factors by focusing on two AP-1 transcription factors (c-Fos and JunB) using RAW264.7 pre osteoclasts as well as primary bone marrow cells. As predicted, their mRNA and protein levels were elevated by RANKL, and the elevation was suppressed by salubrinal and guanabenz. A partial silencing of c-Fos or JunB by RNA interference decreased NFATc1 as well as tartrate-resistant acid phosphatase (TRAP) mRNA. Collectively, a systems-biology approach allows the prediction of a RANKL-salubrinal/guanabenz-NFATc1 regulatory axis, and in vitro assays validate an involvement of AP-1 transcription factors in suppression of osteoclastogenesis. PMID- 25435428 TI - Sirtuin 7 in cell proliferation, stress and disease: Rise of the Seventh Sirtuin! AB - Sirtuin 7 is a member of the sirtuin family of proteins. Sirtuins were originally discovered in yeast for its role in prolonging replicative lifespan. Until recently SIRT7 happened to be the least studied sirtuin of the seven mammalian sirtuins. However, a number of recent breakthrough reports have provided significant clarity to SIRT7 biology. SIRT7 is now seen as a vital regulator of rRNA and protein synthesis for maintenance of normal cellular homeostasis. Proteins like p53, H3K18, PAF53, NPM1 and GABP-beta1 are the known substrates for the deacetylase activity of SIRT7, thereby making it a key mediator of many cellular activities. Studies using in vitro based assays and also knockout mice have revealed a role of SIRT7 in certain disease pathologies as well. High expression of SIRT7 has been reported in few cancer types and is steadily propelling SIRT7 towards an oncogene status. The role of SIRT7 as a pro-survival adaptor molecule in conditions of cellular stress has recently emerged in view of the fact that SIRT7 can regulate molecules like HIF and IRE1alpha. Additionally, SIRT7 plays a key role in maintenance of the epigenome as it caused the deacetylation of histone (H3K18) and global proteomics studies have shown its interaction with many chromatin remodelling complexes such as B-WICH and other proteins. Lately, the role of SIRT7 in hepatic lipid metabolism has been debated. This review attempts to summarize these recent findings and present the role of SIRT7 as an important cellular regulator. PMID- 25435427 TI - The autophagy pathway maintained signaling crosstalk with the Keap1-Nrf2 system through p62 in auditory cells under oxidative stress. AB - The main purposes of our study were to consider the effect of autophagy on auditory cells under oxidative stress, and the function of possible crosstalk among p62, Keap1 and Nrf2 in autophagy-deficient auditory cells. First, we described how cell death was induced in auditory cell line (HEI-OC1) exposed to H2O2. We found that the decision for the cell death of auditory cells under oxidative stress depends on the balance between autophagy and necrosis due to ATP depletion, and autophagy plays a cytoprotective function in oxidative stress induced necrosis. Our data clearly suggested that autophagy was a cell survival mechanism in H2O2-induced cell death, based on the observation that suppression of autophagy by knockdown of Atg7 sensitized, whereas activation of autophagy by rapamycin protected against H2O2-induced cell death. Next, our results regarding the relationship among p62, Nrf2 and Keap1 by siRNA paradoxically showed that p62 creates a positive feedback loop in the Keap1/Nrf2 pathway. Autophagy impaired by Atg7 knockdown degrades Keap1 in a p62-dependent manner, whereas Nrf2 is activated. As a result, the cell death induced by H2O2 was promoted in auditory cells. Taken together, these results suggested that the autophagy pathway maintained signaling crosstalk with the Keap1-Nrf2 system through p62 in auditory cells under oxidative stress. PMID- 25435429 TI - Active heat shock transcription factor 1 supports migration of the melanoma cells via vinculin down-regulation. AB - Heat shock transcription factor 1 (HSF1), the major regulator of stress response, is frequently activated in cancer and has an apparent role in malignant transformation. Here we analyzed the influence of the over-expression of a constitutively active transcriptionally-competent HSF1 mutant form on phenotypes of mouse and human melanoma cells. We observed that the expression of active HSF1 supported anchorage-independent growth in vitro, and metastatic spread in the animal model in vivo, although the proliferation rate of cancer cells was not affected. Furthermore, active HSF1 enhanced cell motility, reduced the adherence of cells to a fibronectin-coated surface, and affected the actin cytoskeleton. We found that although the expression of active HSF1 did not affect levels of epithelial-to-mesenchymal transition markers, it caused transcriptional down regulation of vinculin, protein involved in cell motility, and adherence. Functional HSF1-binding sites were found in mouse and human Vcl/VCL genes, indicating a direct role of HSF1 in the regulation of this gene. An apparent association between HSF1-induced down-regulation of vinculin, increased motility, and a reduced adherence of cells suggests a possible mechanism of HSF1-mediated enhancement of the metastatic potential of cancer cells. PMID- 25435430 TI - MiR-16 targets Bcl-2 in paclitaxel-resistant lung cancer cells and overexpression of miR-16 along with miR-17 causes unprecedented sensitivity by simultaneously modulating autophagy and apoptosis. AB - Non-small cell lung cancer is one of the most aggressive cancers as per as the mortality and occurrence is concerned. Paclitaxel based chemotherapeutic regimes are now used as an important option for the treatment of lung cancer. However, resistance of lung cancer cells to paclitaxel continues to be a major clinical problem nowadays. Despite impressive initial clinical response, most of the patients eventually develop some degree of paclitaxel resistance in the course of treatment. Previously, utilizing miRNA arrays we reported that downregulation of miR-17 is at least partly involved in the development of paclitaxel resistance in lung cancer cells by modulating Beclin-1 expression [1]. In this study, we showed that miR-16 was also significantly downregulated in paclitaxel resistant lung cancer cells. We demonstrated that anti-apoptotic protein Bcl-2 was directly targeted miR-16 in paclitaxel resistant lung cancer cells. Moreover, in this report we showed that the combined overexpression of miR-16 and miR-17 and subsequent paclitaxel treatment greatly sensitized paclitaxel resistant lung cancer cells to paclitaxel by inducing apoptosis via caspase-3 mediated pathway. Combined overexpression of miR-16 and miR-17 greatly reduced Beclin-1 and Bcl-2 expressions respectively. Our results indicated that though miR-17 and miR-16 had no common target, both miR-16 and miR-17 jointly played roles in the development of paclitaxel resistance in lung cancer. miR-17 overexpression reduced cytoprotective autophagy by targeting Beclin-1, whereas overexpression of miR-16 potentiated paclitaxel induced apoptotic cell death by inhibiting anti-apoptotic protein Bcl-2. PMID- 25435431 TI - Alternative splicing of KAI1 abrogates its tumor-suppressive effects on integrin alphavbeta3-mediated ovarian cancer biology. AB - Loss or downregulation of the tumor-suppressor KAI1 correlates with poor cancer patient prognosis. KAI1 functions by interacting with other proteins, including integrin cell adhesion and signaling receptors. We previously showed that KAI1 physically and functionally crosstalks with the tumor-biologically relevant integrin alphavbeta3, thereby suppressing ovarian cancer cell migration and proliferation. Interestingly, in metastases, a KAI1 splice variant had been identified, indicating poor patient prognosis. Thus, we here characterized differential effects of the two KAI1 proteins upon their cellular restoration. Opposite to KAI1, KAI1-splice reduced alphavbeta3-mediated cell adhesion, thereby inducing cell migration. This was accompanied by elevated alphavbeta3 levels and drastically elevated focal adhesion kinase activation, however, without any obvious colocalization with alphavbeta3, as observed for KAI1. Moreover, codistribution of KAI1 with the cell/cell-adhesion molecule E-cadherin was abrogated in KAI1-splice. Whereas KAI1 diminished cell proliferative activity, KAI1-splice prominently enhanced cell proliferation concomitant with elevated transcription and cell-surface expression of the epidermal growth factor receptor. Thus KAI1-splice does not only counteract the tumor-suppressive actions of KAI1, but - beyond that - promotes alphavbeta3-mediated biological functions in favor of tumor progression and metastasis. PMID- 25435432 TI - Stress-induced NF-kappaB activation differentiates promyelocytic leukemia cells to macrophages in response to all-trans-retinoic acid. AB - All-trans-retinoic acid (ATRA) has been known as a choice of treatment for inducing differentiation of promyelocytic leukemia cells to granulocytes. NF kappaB plays a crucial role in inflammation and immunity and its activation is an important event for macrophage differentiation both in vivo and in vitro. We report here that NF-kappaB activation is critical for determining ATRA-induced lineage specific differentiation of myeloid leukemia cells. Our data revealed that ATRA treatment to HL-60 cells enhanced IkappaBalpha degradation and NF kappaB nuclear translocation and the activated NF-kappaB potentiated the ability of ATRA for differentiation and switched differentiation to macrophages instead of granulocytes. Serum withdrawal and LPS treatment dampened IkappaBalpha expression via MAPK activation and reactive oxygen species generation leading to NF-kappaB nuclear translocation and ATRA treatment further corroborated these effects in myeloid leukemia cells. Activated NF-kappaB enhanced the degree of ATRA-induced differentiation of HL-60 cells to macrophages, rather than granulocytes, as assessed by morphologic examination and expressions of differentiation markers such as CD11b, CD38, CD68, MMP9 and Btg2. Employing LLnL or dominant negative IkappaBalpha attenuated NF-kappaB associated enhanced cell maturation and differentiation switch thus suggesting NF-kappaB as one of the factors that determines ATRA induced lineage specificity of myeloid leukemia cells. Furthermore, MAPK activation was observed to be central both for the differentiation of promyelocytic cells to macrophages or granulocytes regulating NF-kappaB or C/EBPalpha expressions, respectively; however, MAPK-mediated signals are modulated under various conditions affecting lineage specificity. In summary, our present data demonstrate that activation of NF-kappaB directly affects differentiation program of promyelocytes to macrophages, rather than granulocyte, in response to ATRA treatment. PMID- 25435433 TI - MicroRNA-29b regulates migration in oral squamous cell carcinoma and its clinical significance. AB - OBJECTIVES: MicroRNA (miRNA) machinery regulates cancer cell behavior, and has been implicated in patients' clinical status and prognosis. We found that microRNA-29b (miR-29b) increased significantly in advanced migratory cells. However, miR-29b controls the migration ability, and its regulatory mechanism in oral squamous cell carcinoma (OSCC) remains unknown. MATERIALS AND METHODS: We triggered miR-29b expression in OSCC patients and cell lines by conducting real time quantitative PCR. We determined the functions of miR-29b in the migration of OSCC cells by using gain- and loss-of-function approaches. We elevated the target genes of miR29b through software predictions and a luciferase report assay. We used an orthotopic OSCC animal model to investigate the effects of miR29b on OSCC cell metastasis in vivo. RESULTS: The clinical data revealed that miR-29b expression was correlated with lymph node metastasis and an advanced tumor stage in 98 OSCC patients. Furthermore, multivariate analysis revealed that miR-29b expression was significantly correlated with recurrence, and indicated poor survival. MiR-29b promoted OSCC cell migration and downregulated CX3CL1, a cell cell adhesion regulator, which plays an essential role in miR-29b-regulated OSCC cell migration machinery. Furthermore, we found that CX3CL1 expression was correlated with lymph node metastasis and an early tumor stage in OSCC patients, and negatively correlated with miR-29b expression. CONCLUSION: MiR-29b acts as an oncomir, promoting cell migration through CX3CL1 suppression, and could be a potential therapeutic target for preventing OSCC progression. PMID- 25435434 TI - Recurrence in regional lymph nodes after total thyroidectomy and neck dissection in patients with papillary thyroid cancer. AB - BACKGROUND: We investigated the risk factors of the regional lymph node (LN) recurrence in papillary thyroid cancer (PTC) patients underwent thyroidectomy and neck dissection according to the clinicopathologic features, preoperative clinical nodal status and the recurrence in previously dissected or undissected compartment of the neck. METHODS: A retrospective analysis was performed on 297 patients who underwent total thyroidectomy and LN dissection between 2004 and 2010. Patients with and without regional recurrence were compared by the various clinicopathological factors. Recurrence-free survival rates were estimated by the Kaplan-Meier and Cox regression method. RESULTS: With a median follow-up of 53 months, 22 (7.4%) patients developed regional LN recurrence. Initial LN metastasis and tumor size ?1 cm were independent predictive factors for regional recurrence. In patients without preoperative clinical LN, Tumor size ?1 cm and extrathyroidal extension were significant risk factors for regional recurrence. In cases with preoperative clinical LN, there was no specific significant factor for recurrence. Tumor size ?1 cm, capsular invasion, extrathyroidal extension, and lymphovascular invasion were significant risk factors of regional recurrence in previously dissected compartments. Tumor size ?1 cm and extrathyroidal extension were significant predictive factors of regional recurrence in previously undissected compartments. CONCLUSIONS: Tumor size and LN metastasis were independent predictors of regional LN recurrence in PTC patients after total thyroidectomy and central neck dissection. Patients with tumor size >1 cm or extrathyroidal extension were more likely to have tumor recur both within the previously dissected field as well as the un-dissected compartments. PMID- 25435435 TI - Autophagy and senescence in fibrosing cholangiopathies. AB - Fibrosing cholangiopathy such as primary sclerosing cholangitis (PSC) and biliary atresia (BA) is characterized by biliary epithelial injuries and concentric fibrous obliteration of the biliary tree together with inflammatory cell infiltration. In these diseases, inappropriate innate immunity is reported to contribute more to bile duct pathology as compared with various aspects of "classical" autoimmune diseases. Primary biliary cirrhosis (PBC) is characterized by chronic cholangitis with bile duct loss and classical autoimmune features. Cellular senescence of cholangiocytes and a senescence-associated secretory phenotype lead to the production of proinflammatory cytokines and chemokines that may modify the milieu of the bile duct and then trigger fibroinflammatory responses in PSC and PBC. Furthermore, deregulated autophagy might be involved in cholangiocyte senescence and possibly in the autoimmune process in PBC, and the deregulated innate immunity against enteric microbes or their products that is associated with cholangiocyte senescence might result in the fibrosing cholangitis that develops in PBC and PSC. In BA, innate immunity against double stranded RNA viruses might be involved in cholangiocyte apoptosis and also in the development of the epithelial-mesenchymal transition of cholangiocytes that results in fibrous obliteration of bile ducts. These recent advances in the understanding of immune-mediated biliary diseases represent a paradigm shift: the cholangiocyte is no longer viewed merely as a passive victim of injury; it is now also considered to function as a potential effector in bile duct pathology. PMID- 25435436 TI - Human cathelicidin antimicrobial protein 18 (hCAP18/LL-37) is increased in foetal membranes and myometrium after spontaneous labour and delivery. AB - Infection and/or inflammation are most commonly associated with preterm birth. Studies have shown that antimicrobial peptides can modulate the inflammatory response in non-gestational tissues; the human cathelicidin hCAP18 (and its active component LL-37) has such anti-microbial and immunomodulatory properties. The aim of this study was to determine the effect of human labour on hCAP18 expression in foetal membranes and myometrium, and to determine the effect of the synthetic LL-37 peptide on pro-inflammatory and pro-labour mediators in foetal membranes and myometrium. The localisation and expression of hCAP18 in non labouring and labouring tissues was determined by immunohistochemistry and Western blot, respectively. Tissue explants were used to determine the effect of LL-37 on pro-labour mediators. hCAP18 was localised to the amnion epithelium, cytotrophoblasts and decidua in the foetal membranes, and in the longitudinal and transverse muscle fibres of the myometrium. Additional hCAP18 staining was present in leukocytes. In foetal membranes and myometrium, human labour was associated with significantly higher hCAP18 protein expression. Treatment of foetal membranes and myometrium with LL-37 significantly induced the expression and secretion of the pro-inflammatory cytokines IL-6 and TNF-alpha, and the chemokines IL-8 and MCP-1. LL-37 also induced expression of MMP-9 mRNA and pro MMP-9 expression in foetal membranes. Co-treatment with BAY 11-7082 was associated with a decrease in LL-37-induced pro-inflammatory cytokine expression. Moreover, inhibition of MyD88 in myometrial cells decreased LL-37-induced pro inflammatory cytokine expression and release. LL-37 also significantly increased NF-kappaB transcriptional activity. In conclusion, hCAP18/LL-37 induces pro inflammatory and pro-labour mediators, via the MyD88/NF-kappaB pathway. PMID- 25435437 TI - The health of India: a future that must be devoid of caste. PMID- 25435438 TI - Migrants' health in China. PMID- 25435439 TI - Tackling liver disease in the UK: a Lancet Commission. PMID- 25435440 TI - A new network to promote evidence-based research. PMID- 25435442 TI - Anatoli Kamali: spearheading HIV prevention in Africa. PMID- 25435443 TI - Child mortality in the UK. PMID- 25435444 TI - Child mortality in the UK. PMID- 25435445 TI - Child mortality in the UK - Authors' reply. PMID- 25435447 TI - Dietary patterns need emphasising. PMID- 25435446 TI - Learning objectives for sustainable health care. PMID- 25435448 TI - Obesity stigmatisation from obesity researchers. PMID- 25435449 TI - Iran: the health cost of a political order. PMID- 25435450 TI - Ageing in iran. PMID- 25435451 TI - Alcohol consumption in Iran. PMID- 25435452 TI - The three facets of the patient's history. PMID- 25435453 TI - Prosopometamorphopsia and facial hallucinations. PMID- 25435454 TI - AIDS: transforming global health. PMID- 25435455 TI - Connecting short and long time dynamics in hard-sphere-like colloidal glasses. AB - Glass-forming materials are characterized by an intermittent motion at the microscopic scale. Particles spend most of their time rattling within the cages formed by their neighbors, and seldom jump to a different cage. In molecular glass formers the temperature dependence of the jump features, such as the average caging time and jump length, characterizes the relaxation processes and allows for a short-time prediction of the diffusivity. Here we experimentally investigate the cage-jump motion of a two-dimensional hard-sphere-like colloidal suspension, where the volume fraction is the relevant parameter controlling the slowing down of the dynamics. We characterize the volume fraction dependence of the cage-jump features and show that, as in molecular systems, they allow for a short time prediction of the diffusivity. PMID- 25435456 TI - Enrichment of circulating tumor cells using a centrifugal affinity plate system. AB - Circulating tumor cells (CTCs) are defined as cells that have detached from a primary tumor and are circulating in the bloodstream. Their isolation and quantification is of great value for cancer prognoses and drug testing. Here, the development of a centrifugal affinity plate (CAP) system is described, in which centrifugal force and antibody-based capture are exploited to enrich CTCs on one plate and hematological cells on the other. The CAP is rotated to exert centrifugal force on the cells in a blood sample, quickly transporting them to the anti-epithelial adhesion molecule (EpCAM)-coated and anti-CD45-coated surface of the CAP to shorten the reaction time and increase the adhesion force between the tumor and blood cells and each antibody. The effect of a rotating process on cell capture was investigated, and the capture efficiency was demonstrated using blood samples from healthy donors spiked with human non-small cell lung cancer (NCI-H1650) and breast cancer (MCF-7) cells. The CAP system was capable of rapid isolation and identification of CTCs without the requirement for pretreatment of blood samples. Finally, the CAP system was tested to evaluate the detection efficiency of CTCs in the blood samples of breast cancer patients. The number of captured CTCs in only 1ml of blood varied from 6 to 10. PMID- 25435457 TI - Response to "Velocity gradients in static chromatography always broaden the peaks". PMID- 25435458 TI - Comparative evaluation of eight software programs for alignment of gas chromatography-mass spectrometry chromatograms in metabolomics experiments. AB - Since retention times of compounds in GC-MS chromatograms always vary slightly from chromatogram to chromatogram, it is necessary to align chromatograms before comparing them in metabolomics experiments. Several software programs have been developed to automate this process. Here we report a comparative evaluation of the performance of eight programs using prepared samples of mixtures of chemicals, and an extract of tomato vines spiked with three concentrations of a mixture of alkanes. The programs included in the comparison were SpectConnect, MetaboliteDetector 2.01a, MetAlign 041012, MZmine 2.0, TagFinder 04, XCMS Online 1.21.01, MeltDB and GAVIN. Samples were analyzed by GC-MS, chromatograms were aligned using the selected programs, and the resulting data matrices were preprocessed and submitted to principal components analysis. In the first trial, SpectConnect, MetAlign and MetaboliteDetector correctly identified >=90% of the true positives. In the second trial, MetAlign and MetaboliteDetector correctly identified 87% and 81% of the true positives, respectively. In addition, in both trials >90% of the peaks identified by MetAlign and MetaboliteDetector were true positives. PMID- 25435460 TI - In-syringe dispersive solid-phase extraction using dissolvable layered double oxide hollow spheres as sorbent followed by high-performance liquid chromatography for determination of 11 phenols in river water. AB - Layered double oxide hollow spheres (LDO-HSs) were synthesized and employed as a dissolvable sorbent in dispersive solid-phase extraction (DSPE) to extract eleven United States Environmental Protection Agency's priority phenols from aqueous samples. With their higher specific surface area, LDO-HSs showed much higher extraction efficiency than normal layered double hydroxides and layered double oxides. The entire extraction process was accomplished in a syringe. After DSPE, the sorbent with the analytes was isolated conveniently by directly expelling the spent sample solution out of the syringe. The analyte-enriched sorbent was then subsequently dissolved by withdrawing an acidic solution into the syringe. The final extract was analyzed by high-performance liquid chromatography with ultraviolet detection. The results showed that this method provided low limits of detection for the phenols (0.005-0.153 MUg/L), good linearity (r(2)>= 0.9956) and relative standard deviations of <= 6.7%. The optimized method was applied to water samples from 3 rivers. This simple extraction procedure was demonstrated to be a fast, efficient and convenient DSPE approach. PMID- 25435459 TI - A sensitive quantification of the peptide apidaecin 1 isoforms in single bee tissues using a weak cation exchange pre-separation and nanocapillary liquid chromatography coupled with mass spectrometry. AB - Apidaecins represent an important group of antimicrobial peptides occurring in honey bee hemolymph, where they play an important role as key components of humoral immunity. The present study demonstrates the development of a highly sensitive assay for apidaecin 1 isoforms quantification in the hemolymph or body parts from honey bee individuals. The analytical protocol comprises apidaecins 1 purification and enrichment steps by weak cation-exchange chromatography (WCX) in laboratory-made WCX-Tip microcolumns combined with a desalting step on a reversed phase sorbent (C8) carried in StageTips. Apidaecin-enriched fraction was analyzed by a reversed-phase based nanoliquid chromatography (C4) separation coupled with high-resolution mass spectrometry. The method performance was validated in its specificity, linearity (0-5pmol), recovery (~45%), precision (<10% at 0.1pmol), limit of detection (~50fmol), limit of quantification (0.1pmol) and sample stability. The method was successfully applied to analyze the content of apidaecin 1 isoforms in the following samples: hemolymph - 13.0ng/MUL (95% confidence interval of 7.5-18.6ng/MUL), thoraxes - 36.2ng/unit (95% CI of 18.9 53.6ng/unit) and heads - 12.9ng/unit (95% CI of 9.1-16.7ng/unit). Freshly emerged bees had apidaecin 1 isoforms levels below the limit of detection. Thus it was possible to use them as a competitive matrix for calibration standards to prevent losses of highly basic apidaecins. This new protocol for apidaecin 1 isoforms quantification represents a promising tool to study the role of apidaecins in honey bee immunity and can be considered as a proof-of-concept for the development of sensitive quantification methods for basic antimicrobial peptides in various organisms. PMID- 25435461 TI - Mechanism of protein desorption from 4-mercaptoethylpyridine resins by arginine solutions. AB - A multimodal chromatography column containing 4-mercaptoethylpyridine (4-MEP) as a resin ligand is capable of binding antibodies. Arginine has been proven effective for eluting bound antibodies from the 4-MEP resin column. In this study, the effect of arginine on the binding of antibodies to 4-MEP resin was examined through equilibrium adsorption experiments using bovine gamma-globulin (BGG). Arginine was found to efficiently reduce antibody adsorption onto 4-MEP resin more than solvents containing guanidine, urea and NaCl. Organic solvents, including ethylene glycol and glycerol, were also found to be effective for antibody desorption. These results suggest that the attraction between BGG and 4 MEP is based on hydrophobic interactions that can be weakened by arginine or the organic solvents. The use of arginine yielded similar results with globular proteins. Molecular dynamics simulations used to illuminate the mechanism of binding of an arginine molecule to a 4-MEP resin ligand molecule showed that the alkyl chain of the arginine side chain primarily interacts with the pyridine ring of the 4-MEP resin ligand through hydrophobic interactions. Interaction of the backbone or guanidinium group of arginine with the pyridine ring of the 4-MEP resin ligand played an insignificant role in their bindings. The hydrophobic interaction of the arginine side chain with the pyridine ring reduces the attraction between the antibodies and 4-MEP, leading to the efficient dissociation of the antibodies from the 4-MEP resin in the presence of arginine containing solutions. Thus, utilization of arginine as an eluent can improve antibody purification by multimodal column chromatography. PMID- 25435462 TI - Systematic evaluation of commercially available ultra-high performance liquid chromatography columns for drug metabolite profiling: optimization of chromatographic peak capacity. AB - The present study investigated the practical use of modern ultra-high performance liquid chromatography (UHPLC) separation techniques for drug metabolite profiling, aiming to develop a widely applicable, high-throughput, easy-to-use chromatographic method, with a high chromatographic resolution to accommodate simultaneous qualitative and quantitative analysis of small-molecule drugs and metabolites in biological matrices. To this end, first the UHPLC system volume and variance were evaluated. Then, a mixture of 17 drugs and various metabolites (molecular mass of 151-749Da, logP of -1.04 to 6.7), was injected on six sub-2MUm particle columns. Five newest generation core shell technology columns were compared and tested against one column packed with porous particles. Two aqueous (pH 2.7 and 6.8) and two organic mobile phases were evaluated, first with the same flow and temperature and subsequently at each column's individual limit of temperature and pressure. The results demonstrated that pre-column dead volume had negligible influence on the peak capacity and shape. In contrast, a decrease in post-column volume of 57% resulted in a substantial (47%) increase in median peak capacity and significantly improved peak shape. When the various combinations of stationary and mobile phases were used at the same flow rate (0.5mL/min) and temperature (45 degrees C), limited differences were observed between the median peak capacities, with a maximum of 26%. At higher flow though (up to 0.9mL/min), a maximum difference of almost 40% in median peak capacity was found between columns. The finally selected combination of solid-core particle column and mobile phase composition was chosen for its selectivity, peak capacity, wide applicability and peak shape. The developed method was applied to rat hepatocyte samples incubated with the drug buspirone and demonstrated to provide a similar chromatographic resolution, but a 6 times higher signal-to noise ratio than a more traditional UHPLC metabolite profiling method using a fully porous particle packed column, within one third of the analysis time. In conclusion, a widely applicable, selective and fast chromatographic method was developed that can be applied to perform drug metabolite profiling in the timeframe of a quantitative analysis. It is envisioned that this method will in future be used for simultaneous qualitative and quantitative analysis and can therefore be considered a first important step in the Quan/Qual workflow. PMID- 25435463 TI - Moving thermal gradients in gas chromatography. AB - This paper examines the separation effects of a moving thermal gradient on a chromatographic column in gas chromatography. This movement of the gradient has a focusing effect on the analyte bands, limiting band broadening in the column. Here we examine the relationship between the slope of this gradient, the velocity of the gradient and the resulting band width. Additionally we examine how transport of analytes along the column at their analyte specific constant temperatures, determined by the gradient slope and velocity, affects resolution. This examination is based primarily on a theoretical model of partitioning and transport of analyte under low concentration conditions. Preliminary predictions indicate that analytes reach near constant temperatures, relative positions and resolutions in less than 100cm of column transport. Use of longer columns produces very little improvement in resolution for any fixed slope. Properties of the thermal gradient determine a fixed solute band width for each analyte. These widths are nearly reached within the first 40-70cm, after which little broadening or narrowing of the bands occur. The focusing effect of the thermal gradient corrects for broad injections, reduces effects of irregular stationary phase coatings and can be used with short columns for fast analysis. Thermal gradient gas chromatographic instrumentation was constructed and used to illustrate some characteristics predicted from the theoretical results. PMID- 25435465 TI - Validation of a rapid method of analysis using ultrahigh-performance liquid chromatography - tandem mass spectrometry for nitrogen-rich adulterants in nutritional food ingredients. AB - A method for the rapid quantification of 9 potential nitrogen-rich economic adulterants (dicyandiamide, urea, biuret, cyromazine, amidinourea, ammeline, amidinourea, melamine, and cyanuric acid) in five milk and soy derived nutritional ingredients, i.e. whole milk powder, nonfat dry milk, milk protein concentrate, sodium caseinate, and soy protein isolate has been developed and validated for routine use. The samples were diluted tenfold with water followed by treatment with 2% formic acid and acetonitrile to precipitate proteins. Sample extracts were analyzed using hydrophilic interaction chromatography and tandem mass spectrometry (HILIC-MS/MS) under both positive and negative modes. Stable isotope labeled internal standards were used to ensure accurate quantification. In multi-day validation experiments, the average accuracies, relative standard deviations (RSD), and method detection limits (MDL) for all analytes in whole milk powder were 82-101%, 6-13%, and 0.1mg/kg-7 mg/kg, respectively. The retention times of the analytes in matrix spiked controls were within +/- 0.06 min of the average retention times of the corresponding analytes in calibration standards. The validated method was proven to be rugged for routine use to quantify the presence of 9 nitrogen-rich compounds in milk and soy derived ingredients and to provide a defense from economically motivated adulteration. PMID- 25435464 TI - Application of beta-cyclodextrin-modified, carbon nanotube-reinforced hollow fiber to solid-phase microextraction of plant hormones. AB - A new, efficient, and environmental friendly solid-phase microextraction (SPME) medium based on beta-cyclodextrin (beta-CD)-modified carbon nanotubes (CNTs) and a hollow fiber (HF) was prepared. Functionalized beta-CD was covalently linked to the surface of the carboxylic CNTs and then the obtained nanocomposite was immobilized into the wall pores of HFs under ultrasonic-assisted effect. The scanning electron microscope was used to inspect surface characteristics of fibers, demonstrating the presence of nanocomposites in their wall pores. The reinforced HF was employed in SPME, and its extraction performance was evaluated by analyzing 1-naphthaleneacetic acid (NAA) and 2-naphthoxyacetic acid (2-NOA) in vegetables. Without any tedious clean-up procedure, analytes were extracted from the sample to the adsorbent and organic solvent immobilized in HFs and then desorbed in acetonitrile prior to chromatographic analysis. Under the optimized extraction conditions, the method provided 275- and 283-fold enrichment factors of NAA and 2-NOA, low limits of detection and quantification (at an ngg(-1) level), satisfactory spiked recoveries, good inter-fiber repeatability, and batch to-batch reproducibility. The selectivity of the developed fiber was investigated to three structurally similar compounds and two reference compounds with recognition coefficients up to 3.18. The obtained results indicate that the newly developed fiber is a feasible, selective, green, and cost-effective microextraction medium and could be successfully applied for extraction and determination of naphthalene-derived plant hormones in complex matrices. PMID- 25435466 TI - A theoretical study on trivalent europium: from the free ion to the water complex. AB - The energy levels within the (7)F and (5)D manifolds of trivalent europium were computed for the free ion and in the crystal field of 6-9 water molecules. Fully relativistic Kramers pairs configuration interaction (KRCI) calculations were performed with different correlation spaces for the free ion, and with the complete open-shell configuration interaction (COSCI) method including the 4f electrons in the active space for the water clusters. The best agreement with experimental data was found with the KRCI method or when including the spin-other orbit effect in the COSCI calculations. For the free ion, the (7)F6 multiplet is found only 162 cm(-1) higher compared to experiment, while the (5)D(0-3) multiplets are approximately 3100 cm(-1) too high. In the crystal field of six water molecules, the multiplets with J > 0 split by 48-123 cm(-1). The energy separation (7)F0-(5)D0 of the unsplit multiplets is computed within 255 cm( 1)/247 cm(-1) compared to the experimental data for the free ion/in water. It has been found that the effect of higher coordination number or lower symmetry is small, increasing the transition energies by only about 40 cm(-1) by lowering the (7)F(J) states by the same amount. The hypersensitive transition (5)D0-(7)F2 is computed at 17079 cm(-1) with the KRCI method as compared to the experimental value of 16267 cm(-1). PMID- 25435467 TI - Discotic liquid crystals as novel corrosion-resistant coatings. AB - A discotic liquid crystal (DLC), HBC-C12, coating was successfully applied to improve the corrosion resistance of an iron surface. The iron surface with the DLC-coating exhibited improved corrosion resistance in various environments, including exposure to air and solutions with different pH values. To the best of our knowledge, studies regarding corrosion protection using DLCs have never been reported. PMID- 25435468 TI - Changes in immunity parameters and blood cytokine concentrations after chronic nitrile acrylate intoxication. AB - Experiments on outbred albino rats showed that chronic nitrile acrylate intoxication (60 days, 0.05 LD50 per day subcutaneously) led to reduction of T dependent humoral immune response (T-independent humoral immune response was less affected); parameters cell immunity were suppressed to a greater extent than parameters of humoral immune reactions. Equal attenuation of the functions of Th1 and Th2 lymphocytes, decrease of the blood levels of immunoregulatory, pro- and anti-inflammatory cytokines (IFN-gamma, IL-2, IL-4, IL-6, IL-10, IL-13), and decrease of acetyl cholinesterase activity in thymic and splenic T lymphocytes were observed. PMID- 25435469 TI - Addressing sleep problems and cognitive dysfunctions in comprehensive rehabilitation for chronic musculoskeletal pain. PMID- 25435470 TI - Clinimetric properties of illness perception questionnaire revised (IPQ-R) and brief illness perception questionnaire (Brief IPQ) in patients with musculoskeletal disorders: A systematic review. AB - Several questionnaires are available to evaluate illness perceptions in patients, such as the illness perception questionnaire revised (IPQ-R) and the brief version (Brief IPQ). This study aims to systematically review the literature concerning the clinimetric properties of the IPQ-R and the Brief IPQ in patients with musculoskeletal pain. The electronic databases Web of Sciences and PubMed were searched. Studies were included when the clinimetric properties of the IPQ-R or Brief IPQ were assessed in adults with musculoskeletal pain. Methodological quality was determined using the COSMIN checklist. Eight articles were included and evaluated. The methodological quality was good for 3 COSMIN boxes, fair for 11 and poor for 3 boxes. None of the articles obtained an excellent methodological score. The results of this review suggest that the IPQ-R is a reliable questionnaire, except for illness coherence. Internal consistency is good, except for the causal domain. The IPQ-R has good construct validity, but the factor structure is unstable. Hence, the IPQ-R appears to be a useful instrument for assessing illness perceptions, but care must be taken when generalizing the results of adapted versions of the questionnaires. The Brief IPQ shows moderate overall test-retest reliability. No articles examining the validity of the Brief IPQ were found. Further research should therefore focus on the content and criterion validity of the IPQ-R and the clinimetric properties of the Brief IPQ. PMID- 25435471 TI - Norbornane-based nucleoside and nucleotide analogues locked in North conformation. AB - We report on the synthesis of novel conformationally locked nucleoside and nucleotide derivatives, which are structurally closely related to clinically used antivirals such as didanosine and abacavir. As a suitable conformationally rigid substitute of the sugar/pseudosugar ring allowing a permanent stabilization of the nucleoside in North conformation we employed bicyclo[2.2.1]heptane (norbornane) substituted in the bridgehead position with a hydroxymethyl group and in the C-3 position with a nucleobase. Prepared nucleoside derivatives were also converted into appropriate phosphoramidate prodrugs (ProTides) in order to increase delivery of the compounds in the cells. All target compounds were evaluated in a broad antiviral and cytostatic assay panel. PMID- 25435472 TI - [Population needs, a call for changes in Primary Care]. PMID- 25435473 TI - [Communication skills in the curriculum of Medical students from Spain (1990 2014): From the Primary Health Care to the Bologna Plan. A descriptive study]. AB - OBJECTIVES: Analyse the currently situation of teaching in communication skills in the Spanish Medical Schools (MS) and the grade of implementation from the recommended by the National Agency of Evaluation of the Quality and Accreditation. DESIGN: Descriptive-comparative, transversal and quantitative qualitative study. SITUATION: University teaching field. SAMPLE: The whole population of MS in Spain. INCLUSION CRITERIA: teaching during the academic year 2013-2014 the Degree in Medicine homologated by the National Agency of Evaluation of the Quality and Accreditation and offering information of their educational plans and teaching guides (online, telephonic or e-mail). VARIABLES: 1) Existence of courses about communication skills; 2) type of teaching; 3) format of the course; 4) credits; 5) length, and 6) grade. They were analysed with descriptive parameters and the Cohen's coefficient (d). RESULTS: Forty-two MS: 10 privates and 32 publics. Thirty MS (71.43%) presented at least one course of communication skills. The 78.12% of the public MS contained this kind of teaching as an entire course versus the 50.00% of the private MS. The national average by MS was 2.77 (sigma=2.41), lower than the 5.0 credits recommended by the the National Agency of Evaluation of the Quality and Accreditation (relevant difference: d=1.63>>0,8). The 63.63% contained this teaching over the second cycle (mode: second degree). CONCLUSIONS: The course loads in terms of credits destined to this skills has increased considerably from 1990 to 2014 (d= 1,43>>0,8). However, it has not been completely established yet the recommendations about this aspect in most of the Spanish MS. The public universities seem to be more aware of this teaching. Furthermore, it would be interesting strengthen this skills in the sixth grade. PMID- 25435474 TI - Low-fidelity hybrid sexual assault simulation training's effect on the comfort and competency of resident physicians. AB - BACKGROUND: Alternative training methods are needed for resident physicians to ensure that care is not compromised should they practice in settings without well established Sexual Assault Nurse Examiner (SANE) programs. OBJECTIVE: The purpose of this study is to determine the effectiveness of a simulation-based sexual assault response course for resident physicians at an institution without an on site SANE program. METHODS: Educational intervention study of 12 emergency medicine residents using a low-fidelity hybrid simulation model. The study was comprised of eight male and four female physicians at a military medical center in San Diego, CA. Assessment occurred using three separate metrics. The first was a written knowledge test. The second was a simulated interview and evidentiary examination. These metrics were given 1 month before and 3 months after an 8-h training course. The final metric was Likert-scale questionnaires surveying pre- and post-course feelings of competency and comfort. RESULTS: The emergency medicine residents showed a 13% improvement (95% confidence interval [CI] 7-20%) in written examination scores pre and post intervention. Post-course interview and examinations reflected a 44% improvement (95% CI 24-64%) in critical action completion. Pre-course comfort and competency questionnaires were a median of 2 (interquartile range [IQR] 1-3) on a Likert Scale. Post-course survey responses were a median of 4 (IQR 2-5). CONCLUSIONS: Low-fidelity hybrid simulation is a useful tool to train inexperienced physicians to perform evidentiary examinations and interviews without sacrificing the privacy and direct care of sexual assault victims. PMID- 25435475 TI - Spontaneous bilateral avulsion fracture of the tuberositas tibiae in a New Zealand White rabbit - a counterpart to Osgood-Schlatter disease in humans? AB - The first reported case describing a spontaneous bilateral avulsion fracture of the tuberositas tibiae in a New Zealand White rabbit is presented. So far in animals, this condition has been only described in dogs and horses. In humans, this condition is also called Osgood-Schlatter disease (OSD) or syndrome, traction apophysitis of the tibial tubercle (ATT) or patellar tendon enthesopathy of the tibial tuberosity respectively. It is mainly seen in young adolescents coinciding with periods of growth spurts. In humans, its pathogenesis is believed to be caused by repetitive tendon/muscle strain at the insertion of the patellar tendon to the immature tibial tuberosity, which has its own secondary ossification center. Morphologically this case is characterized by bilateral chronic avulsion with incomplete separation of the tuberositas tibae, and proximal dislocation of the patella (patella alta). Despite these marked pathological changes, the animal was clinically without findings. Nevertheless, this case emphasizes the need for thorough clinical and radiological examination of rabbits intended for preclinical research studies prior to study begin, especially in orthopedic research. PMID- 25435477 TI - Minimally invasive monitoring. AB - Although use of the classic pulmonary artery catheter has declined, several techniques have emerged to estimate cardiac output. Arterial pressure waveform analysis computes cardiac output from the arterial pressure curve. The method of estimating cardiac output for these devices depends on whether they need to be calibrated by an independent measure of cardiac output. Some newer devices have been developed to estimate cardiac output from an arterial curve obtained noninvasively with photoplethysmography, allowing a noninvasive beat-by-beat estimation of cardiac output. This article describes the different devices that perform pressure waveform analysis. PMID- 25435478 TI - Bedside ultrasonography for the intensivist. AB - Critical care ultrasonography is a bedside technique performed by the frontline clinician at the point of care. Point-of-care ultrasonography is conceptually related to physical examination. The intensivist uses visual assessment, auscultation, and palpation on an ongoing basis to monitor the patient. Ultrasonography adds to traditional physical examination by allowing the intensivist to visualize the anatomy and function of the body in real time. Initial, repeated, and goal-directed ultrasonography is an extension of the physical examination that allows the intensivist to establish a diagnosis and monitor the condition of the patient on a regular basis. PMID- 25435479 TI - Invasive hemodynamic monitoring. AB - Although invasive hemodynamic monitoring requires considerable skill, studies have shown a striking lack of knowledge of the measurements obtained with the pulmonary artery catheter (PAC). This article reviews monitoring using a PAC. Issues addressed include basic physiology that determines cardiac output and blood pressure; methodology in the measurement of data obtained from a PAC; use of the PAC in making a diagnosis and for patient management, with emphasis on a responsive approach to management; and uses of the PAC that are not indications by themselves for placing the catheter, but can provide useful information when a PAC is in place. PMID- 25435476 TI - The interface between monitoring and physiology at the bedside. AB - Hemodynamic instability as a clinical state represents either a perfusion failure with clinical manifestations of circulatory shock or heart failure or 1 or more out-of-threshold hemodynamic monitoring values, which may not necessarily be pathologic. Different types of causes of circulatory shock require different types of treatment modalities, making these distinctions important. Diagnostic approaches or therapies based on data derived from hemodynamic monitoring assume that specific patterns of derangements reflect specific disease processes, which respond to appropriate interventions. Hemodynamic monitoring at the bedside improves patient outcomes when used to make treatment decisions at the right time for patients experiencing hemodynamic instability. PMID- 25435481 TI - Defining goals of resuscitation in the critically ill patient. AB - There is still no "universal" consensus on an optimal endpoint for goal directed therapy (GDT) in the critically ill patient. As in other areas of medicine, this should help providers to focus on a more "individualized approach" rather than a protocolized approach to ensure proper patient care. Hemodynamic optimization needs more than simply blood pressure, heart rate, central venous pressure and urine output monitoring. It is essential to also monitor flow variables (cardiac output/stroke volume) and dynamic parameters of fluid responsiveness whenever available. This article will provide a review of current and trending approaches of the goals of resuscitation in the critically ill patient. PMID- 25435483 TI - Organizational approaches to improving resuscitation effectiveness. AB - Hemodynamic instability and shock are important causes of mortality worldwide. Improving outcomes for these patients through effective resuscitation is a key priority for the health system. This article discusses several organizational approaches to improving resuscitation effectiveness and outlines key areas for future research and development. The discussion is rooted in a conceptual model of effective resuscitation based on three domains: monitoring systems, response teams, and feedback mechanisms. Targeting each of these domains in a unified approach helps clinicians effectively treat deteriorating patients, ultimately improving outcomes for this high-risk patient group. PMID- 25435480 TI - Functional hemodynamic monitoring. AB - Functional hemodynamic monitoring is the assessment of the dynamic interactions of hemodynamic variables in response to a defined perturbation. Recent interest in functional hemodynamic monitoring for the bedside assessment of cardiovascular insufficiency has heightened with the documentation of its accuracy in predicting volume responsiveness using a wide variety of monitoring devices, both invasive and noninvasive, and across multiple patient groups and clinical conditions. However, volume responsiveness, though important, reflects only part of the overall spectrum of functional physiologic variables that can be measured to define the physiologic state and monitor response to therapy. PMID- 25435484 TI - Advances in hemodynamic monitoring. PMID- 25435485 TI - p38 Mitogen-activated protein kinase and c-Jun NH2-terminal protein kinase regulate the accumulation of a tight junction protein, ZO-1, in cell-cell contacts in HaCaT cells. AB - To investigate the involvement of stress-activated protein kinases, JNK and p38 MAPK, in the assembly of tight junctions in keratinocytes, we treated HaCaT cells with various combinations of SP600125 (an inhibitor of JNK), SB202190 (an inhibitor of p38 MAPK) and anisomycin (an activator of both JNK and p38 MAPK) and examined the localization of ZO-1, an undercoat constitutive protein of the tight junction. Short-term (8h) incubation with SP600125, SB202190 or anisomycin induced the accumulation of ZO-1 in the cell-cell contacts, with reduced ZO-1 staining in the cytoplasm, while only long-term (24h) incubation with SP600125 induced the accumulation of ZO-1. SP600125, SB202190 or SP600125 plus SB202190 treatment induced thin linear staining for ZO-1 in the cell-cell contacts. Anisomycin treatment induced thick and irregular linear staining for ZO-1, while anisomycin plus SP600125 treatment induced zipper-like staining for ZO-1. Anisomycin plus SB202190 treatment or anisomycin plus both SP600125 and SB202190 treatment for 8h failed to lead to the accumulation of ZO-1 in cell-cell contacts, but induced thin linear staining with several gaps 16 h after removal of these agents. These results suggest that the localization of ZO-1 in cell-cell contacts is differently regulated by activation and inhibition of JNK and/or p38 MAPK depending on the incubation period. PMID- 25435486 TI - Commentary on "spectral characterization of the binding and conformational changes of serum albumins upon interaction with an anticancer drug, anastrozole". AB - The manuscript by R. Punith and J. Seetharamappa (http://dx.doi.org/10.1016/j.saa.201202.038) presents the interaction between serum albumin from human (HAS) and from bovine (BSA) with a drug called Anastrozole (AZ). The drug is on the market for treating patients with breast cancer after surgery and for metastasis in women. The study utilizes various spectroscopic techniques such as; fluorescence, synchronous fluorescence, 3D fluorescence measurements, FTIR, CD and UV. Although there are some relatively minor comments on the paper, the main point that needs to be reviewed by the authors is the result of FTIR measurements. Based on the data provided in the text (there is no figure), the protein sample is not in its native state, which makes the data inconvenient to be used in drawing conclusions. Authors are kindly requested to take another look at the FTIR experiments. PMID- 25435482 TI - Using what you get: dynamic physiologic signatures of critical illness. AB - The development and resolution of cardiopulmonary instability take time to become clinically apparent, and the treatments provided take time to have an impact. The characterization of dynamic changes in hemodynamic and metabolic variables is implicit in physiologic signatures. When primary variables are collected with high enough frequency to derive new variables, this data hierarchy can be used to develop physiologic signatures. The creation of physiologic signatures requires no new information; additional knowledge is extracted from data that already exist. It is possible to create physiologic signatures for each stage in the process of clinical decompensation and recovery to improve outcomes. PMID- 25435487 TI - Comparison of ultrasonic with stirrer performance for removal of sunset yellow (SY) by activated carbon prepared from wood of orange tree: artificial neural network modeling. AB - The present work focused on the removal of sunset yellow (SY) dye from aqueous solution by ultrasound-assisted adsorption and stirrer by activated carbon prepared from wood of an orange tree. Also, the artificial neural network (ANN) model was used for predicting removal (%) of SY dye based on experimental data. In this study a green approach was described for the synthesis of activated carbon prepared from wood of an orange tree and usability of it for the removal of sunset yellow. This material was characterized using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The impact of variables, including initial dye concentration (mg/L), pH, adsorbent dosage (g), sonication time (min) and temperature ( degrees C) on SY removal were studied. Fitting the experimental equilibrium data of different isotherm models such as Langmuir, Freundlich, Temkin and Dubinin-Radushkevich models display the suitability and applicability of the Langmuir model. Analysis of experimental adsorption data by different kinetic models including pseudo-first and second order, Elovich and intraparticle diffusion models indicate the applicability of the second-order equation model. The adsorbent (0.5g) is applicable for successful removal of SY (>98%) in short time (10min) under ultrasound condition. PMID- 25435488 TI - Clothing-related burns in New South Wales, Australia: impact of legislation on a continuing problem. AB - To combat the risk of nightwear burns a mandatory standard regulating the design, flammability and labelling requirements of children's nightwear was introduced in Australia in 1987. This population-based study examined the trends, characteristics and causes of clothing-related burns to inform a review of the current standard, and to facilitate the development of targeted prevention strategies. Clothing-related burns for 1998-2013 were identified from hospitalisation data for all hospitals in NSW and detailed information regarding circumstance of injury from a burn data registry. To investigate percentage annual change (PAC) in trends negative binomial regression analysis was performed. There were 541 hospitalisations for clothing-related burns, 18% were nightwear-related and 82% were for other clothing. All clothing burns decreased by an estimated 4% per year (95% CI -6.2 to -2.1). Nightwear-related burns decreased by a significantly higher rate (PAC -7.4%; 95% CI -12.5 to -2.1) than other clothing (PAC -2.5%; 95%CI -4.7 to -0.1). Exposure to open heat source (campfire/bonfire) was the most common cause, followed by cooking. Of factors known to be associated with clothing burns, accelerant use was reported in 27% of cases, cigarettes 17%, loose skirt or dress 8%, and angle grinders in 6% of cases. Hospitalisations for clothing burns are relatively uncommon in NSW and rates, particularly of nightwear burns, have decreased over the last 15 years. Strategies for continued reduction of these injuries include increasing the scope of the current clothing standard or developing new standards to include all children's clothing and adult nightwear, and increasing community awareness of the risk associated with open heat sources, accelerant use and loose clothing. PMID- 25435489 TI - Seasonal dynamics of agonistic displays in territorial and non-territorial males of goitered gazelle. AB - Aggression serves a great variety of social functions, one of which is protection of individual territories from intruders. Territorial males of many antelope species show aggressive noncontact displays, and only rarely fight. It has been suggested that ungulate males tend to have more frequent and longer aggressive interactions with rivals of similar age or social status than with males of dissimilar status. In the present paper, we test whether territorial and non territorial males behave in a similar manner and avoid fights, and whether or not they preferentially direct aggressive and longer agonistic interactions towards males of similar age or social status, rather than towards other classes of males. We found that territorial males usually avoided straight fights with peers, and instead mainly used noncontact displays in aggressive interactions. In contrast, non-territorial males used fights considerably more often, especially during the onset of territoriality in April to May, when these males had their most frequent aggressive interactions. Territorial bucks aggressively interacted most frequently with non-territorial males and significantly less often with other territorial males, but agonistic noncontact displays between territorial males lasted the longest. In contrast, non-territorial males addressed their aggressive noncontact displays and fights most often to peers and less frequently to sub-adults. Asymmetry in the social status of territorial vs. non-territorial males was likely responsible for the distinctively different agonistic behaviors shown by the two types of males, which in turn are likely due to the different costs and benefits each male can accrue from these aggressive interactions. PMID- 25435491 TI - Modeling and design of challenge tests: Inflammatory and metabolic biomarker study examples. AB - Given the complexity of pharmacological challenge experiments, it is perhaps not surprising that design and analysis, and in turn interpretation and communication of results from a quantitative point of view, is often suboptimal. Here we report an inventory of common designs sampled from anti-inflammatory, respiratory and metabolic disease drug discovery studies, all of which are based on animal models of disease involving pharmacological and/or patho/physiological interaction challenges. The corresponding data are modeled and analyzed quantitatively, the merits of the respective approach discussed and inferences made with respect to future design improvements. Although our analysis is limited to these disease model examples, the challenge approach is generally applicable to the vast majority of pharmacological intervention studies. In the present five Case Studies results from pharmacodynamic effect models from different therapeutic areas were explored and analyzed according to five typical designs. Plasma exposures of test compounds were assayed by either liquid chromatography/mass spectrometry or ligand binding assays. To describe how drug intervention can regulate diverse processes, turnover models of test compound-challenger interaction, transduction processes, and biophase time courses were applied for biomarker response in eosinophil count, IL6 response, paw-swelling, TNFalpha response and glucose turnover in vivo. Case Study 1 shows results from intratracheal administration of Sephadex, which is a glucocorticoid-sensitive model of airway inflammation in rats. Eosinophils in bronchoalveolar fluid were obtained at different time points via destructive sampling and then regressed by the mixed-effects modeling. A biophase function of the Sephadex time course was inferred from the modeled eosinophil time courses. In Case Study 2, a mouse model showed that the time course of cytokine-induced IL1beta challenge was altered with or without drug intervention. Anakinra reversed the IL1beta induced cytokine IL6 response in a dose-dependent manner. This Case Study contained time courses of test compound (drug), challenger (IL1beta) and cytokine response (IL6), which resulted in high parameter precision. Case Study 3 illustrates collagen-induced arthritis progression in the rat. Swelling scores (based on severity of hind paw swelling) were used to describe arthritis progression after the challenge and the inhibitory effect of two doses of an orally administered test compound. In Case Study 4, a cynomolgus monkey model for lipopolysaccharide LPS-induced TNFalpha synthesis and/or release was investigated. This model provides integrated information on pharmacokinetics and in vivo potency of the test compounds. Case Study 5 contains data from an oral glucose tolerance test in rats, where the challenger is the same as the pharmacodynamic response biomarker (glucose). It is therefore convenient to model the extra input of glucose simultaneously with baseline data and during intervention of a glucose-lowering compound at different dose levels. Typically time-series analyses of challenger- and biomarker-time data are necessary if an accurate and precise estimate of the pharmacodynamic properties of a test compound is sought. Erosion of data, resulting in the single point assessment of drug action after a challenge test, should generally be avoided. This is particularly relevant for situations where one expects time curve shifts, tolerance/rebound, impact of disease, or hormetic concentration response relationships to occur. PMID- 25435493 TI - The comparison of ultrasonic effects in different metal melts. AB - The effect of ultrasonic treatment of the melts is mainly ultrasonic streaming and cavitation. In this paper, the ultrasonic streaming in water, aluminum and steel melts was numerically simulated and compared. And the simulated results of streaming in water were validated by experimental results. In the experiment, the ultrasonic booster was immersed vertically into water, the ultrasonic streaming phenomenon was observed by high-speed CCD (Charge-coupled Device) system, then the streaming velocity and streamlines were obtained. The cavitation area and threshold in aluminum and steel melts were compared. The results show that the effective streaming and cavitation area in steel melt is smaller than that in aluminum melt, and far smaller than that in water. A symmetrical vortex forms both in water and aluminum melt by the drive of downward ultrasonic streaming caused by the booster tip. However, in steel melt, a double-vortex structure, including a vortex in the upper part and a vortex with reverse cycling in the lower part appears in the flow field. As a result, inclusions and air bubbles may be trapped in steel melt. The density and viscosity of the fluids are the main factors influencing ultrasonic streaming and cavitation. The results provide references for the application of ultrasonic treatment in metal melts. PMID- 25435490 TI - Attentional bias to food cues in youth with loss of control eating. AB - Emerging data indicate that adults with binge eating may exhibit an attentional bias toward highly palatable foods, which may promote obesogenic eating patterns and excess weight gain. However, it is unknown to what extent youth with loss of control (LOC) eating display a similar bias. We therefore studied 76 youth (14.5 +/- 2.3 years; 86.8% female; BMI-z 1.7 +/- .73) with (n = 47) and without (n = 29) reported LOC eating. Following a breakfast to reduce hunger, youth participated in a computerized visual probe task of sustained attention that assessed reaction time to pairs of pictures consisting of high palatable foods, low palatable foods, and neutral household objects. Although sustained attentional bias did not differ by LOC eating presence and was unrelated to body weight, a two-way interaction between BMI-z and LOC eating was observed (p = .01), such that only among youth with LOC eating, attentional bias toward high palatable foods versus neutral objects was positively associated with BMI-z. These findings suggest that LOC eating and body weight interact in their association with attentional bias to highly palatable foods cues, and may partially explain the mixed literature linking attentional bias to food cues with excess body weight. PMID- 25435494 TI - A plasmonic SAW transducer. AB - In this work, an acoustic-optical transducer that is based on the utilization of plasmons is proposed to optically detect SAW of wavelength (<400 nm) smaller than the optical wavelength (800 nm). Although grating based coupling of plasmons is well known, it has not been applied in the detection of ultrasound. In this work, designs utilizing this operating principle are proposed which can achieve higher changes in reflectivity than those achievable by traditional methods, thus overcoming the traditional difficulties in the detection of very high frequency (10 GHz range) SAWs. The proposed device can be fabricated on surfaces at low cost and be used to detect remotely. PMID- 25435492 TI - Correlation of ghrelin concentration and ghrelin, ghrelin-O-acetyltransferase (GOAT) and growth hormone secretagogue receptor 1a mRNAs expression in the proventriculus and brain of the growing chicken. AB - To determine mechanisms for age-related decrease of GHS-R1a expression in the chicken proventriculus, changes in mRNA expression of ghrelin and ghrelin-O acetyltransferase (GOAT) as well as ghrelin concentrations in the proventriculus and plasma were examined in growing chickens. Changes in expression levels of ghrelin, GOAT and GHS-R1a mRNAs were also examined in different brain regions (pituitary, hypothalamus, thalamus, cerebellum, cerebral cortex, olfactory bulb, midbrain and medulla oblongata). Ghrelin concentrations in the proventriculus and plasma increased with aging and reached plateaus at 30-50 days after hatching. High level of ghrelin mRNA decreased at 3 days after hatching, and it became stable at half of the initial level. Expression levels of GHS-R1a and GOAT decreased 3 or 5 days after hatching and became stable at low levels. Significant negative correlations were found between plasma ghrelin and mRNA levels of GOAT and GHS-R1a. Expression levels of ghrelin mRNA were different in the brain regions, but a significant change was not seen with aging. GHS-R1a expression was detected in all brain regions, and age-dependent changes were observed in the pituitary and cerebellum. Different from the proventriculus, the expression of GOAT in the brain increased or did not change with aging. These results suggest that decreased GHS-R1a and GOAT mRNA expression in the proventriculus is due to endogenous ghrelin-induced down-regulation. Expression levels of ghrelin, GOAT and GHS-R1a in the brain were independently regulated from that in the proventriculus, and age-related and region-dependent regulation pattern suggests a local effect of ghrelin system in chicken brain. PMID- 25435495 TI - Venous occlusion after transvenous pacemaker implantation--is there a role for new oral anticoagulants? PMID- 25435496 TI - Warning: climate change is dangerous to your health (in case you were not sure). PMID- 25435497 TI - Moxibustion for asthma, acupuncture for epilepsy, psychological therapies for irritable bowel syndrome, exercise training for multiple sclerosis, and comfrey root for acute back pain. PMID- 25435498 TI - An enzyme-free and amplified colorimetric detection strategy via target-aptamer binding triggered catalyzed hairpin assembly. AB - Here we introduce an enzyme-free and colorimetric detection strategy for small molecule adenosine. The approach is based on the adenosine-aptamer binding triggered liberation of an initiator strand that consecutively catalyzes DNA hairpins hybridized from singles to couples. These couples induce gold nanoparticles assembled via crosslinking, which could be visualized by a color change. PMID- 25435499 TI - Establishment of a melanogenesis regulation assay system using a fluorescent protein reporter combined with the promoters for the melanogenesis-related genes in human melanoma cells. AB - There are two established depigmenting agent assays currently in use. However, these methods are unreliable and time-consuming. Therefore, it will be valuable to establish a better assay system for depigmenting agent analysis. In this study, we established a melanogenesis regulation assay system using a fluorescent protein reporter combined with the promoters for the microphthalmia-associated transcription factor (MITF), tyrosinase (Tyr) and dopachrome tautomerase (Dct) genes in MeWo human melanoma cells. We used several melanogenesis regulators, including theophylline, hesperetin, arbutin and rottlerin, to confirm the function of this assay system. The established MeWo/pMITF-EGFP, MeWo/pTyr-EGFP and MeWo/pDct-EGFP stable cells integrated the pMITF-EGFP, pTyr-EGFP and pDct EGFP plasmids into their genomic DNA. These stably transfected cells were used to examine alterations in the expression of the MITF, Tyr and Dct genes. All of the tested compounds, including theophylline, hesperetin, arbutin and rottlerin, could be analyzed in the stable cells, producing reliable results. Therefore, we believe that this melanogenesis regulation assay system can be used as a rapid and reliable assay system to analyze the regulation of melanogenesis by many known or unknown compounds. PMID- 25435500 TI - Multi-functional glycoside hydrolase: Blon_0625 from Bifidobacterium longum subsp. infantis ATCC 15697. AB - We here describe a unique beta-D-glucosidase (BGL; Blon_0625) derived from Bifidobacterium longum subsp. infantis ATCC 15697. The Blon_0625 gene was expressed by recombinant Escherichia coli. Purified recombinant Blon_0625 retains hydrolyzing activity against both p-nitrophenyl-beta-D-glucopyranoside (pNPG; 17.3+/-0.24Umg(-1)) and p-nitrophenyl-beta-D-xylopyranoside (pNPX; 16.7+/ 0.32Umg(-1)) at pH 6.0, 30 degrees C. To best of our knowledge, no previously described BGL retains the same level of both pNPGase and pNPXase activity. Furthermore, Blon_0625 also retains the activity against 4-nitrophenyl-alpha-l arabinofranoside (pNPAf; 5.6+/-0.09Umg(-1)). In addition, the results of the degradation of phosphoric acid swollen cellulose (PASC) or xylan using endoglucanase from Thermobifida fusca YX (Tfu_0901) or xylanase from Kitasatospora setae KM-6054 (KSE_59480) show that Blon_0625 acts as a BGL and as a beta-D-xylosidase (XYL) for hydrolyzing oligosaccharides. These results clearly indicate that Blon_0625 is a multi-functional glycoside hydrolase which retains the activity of BGL, XYL, and also alpha-l-arabinofuranosidase. Therefore, the utilization of multi-functional Blon_0625 may contribute to facilitating the efficient degradation of lignocellulosic materials and help enhance bioconversion processes. PMID- 25435501 TI - Fabricating polystyrene fiber-dehydrogenase assemble as a functional biocatalyst. AB - Immobilization of the enzymes on nano-structured materials is a promising approach to enhance enzyme stabilization, activation and reusability. This study aimed to develop polystyrene fiber-enzyme assembles to catalyze model formaldehyde to methanol dehydrogenation reaction, which is an essential step for bioconversion of CO2 to a renewable bioenergy. We fabricated and modified electrospun polystyrene fibers, which showed high capability to immobilize dehydrogenase for the fiber-enzyme assembles. Results from evaluation of biochemical activities of the fiber-enzyme assemble showed that nitriation with the nitric/sulfuric acid ratio (v/v, 10:1) and silanization treatment delivered desirable enzyme activity and long-term storage stability, showing great promising toward future large-scale applications. PMID- 25435503 TI - Multivariate modular engineering of the protein secretory pathway for production of heterologous glucose oxidase in Pichia pastoris. AB - Limitations in protein production and secretion have been attributed to the inefficient folding rate of overexpressed proteins and the cellular response to the presence of overexpressed proteins in the endoplasmic reticulum (ER). In this study, we improved the yield of glucose oxidase (GOD) by manipulating genes involved in protein folding machinery and abnormal folding stress responses. First, genes with folding and secretion functions were used to modulate the folding rate of GOD in the ER and its secretion level in the cytoplasm. Next, the potential benefits of the ERAD elements were determined. Cellular resistance to ER derived stress was then strengthened by overexpressing the stress response gene GCN4. Furthermore, a module combination strategy, which co-expressed the SEC53, CNE1 and GCN4 genes, was employed to construct the Pichia pastoris strain S17. This increased the yield of GOD to 21.81g/L, with an activity of 1972.9U/mL, which were 2.53- and 5.11-fold higher, respectively, than the control strain. The work described here improved GOD production significantly, and the strategies employed in this study provide novel information for the large-scale production of heterologous proteins. PMID- 25435504 TI - Expression, characterization and mutagenesis of an FAD-dependent glucose dehydrogenase from Aspergillus terreus. AB - An FAD-dependent glucose dehydrogenase (FAD-GDH) from Aspergillus terreus NIH2624 was expressed in Escherichia coli with a yield of 228+/-16U/L of culture. Co expression with chaperones DnaK/DnaJ/GrpE and osmotic stress induced by simple carbon sources enhanced productivity significantly, improving the yield to 23883+/-563U/L after optimization. FAD-GDH was purified in two steps with the specific activity of 604U/mg. Using d-glucose as substrate, the optimal pH and temperature for FAD-GDH were determined to be 7.5 and 50 degrees C, respectively. Activity was stable across the pH range 3.5-9.0, and the half-life was 52min at 42 degrees C. Km and Vmax were calculated as 86.7+/-5.3mM and 928+/-35U/mg, and the molecular weight was approximately 65.6kDa based on size exclusion chromatography, indicating a monomeric structure. The 3D structure of FAD-GDH was simulated by homology modelling using the structure of A. niger glucose oxidase (GOD) as template. From the model, His551, His508, Asn506 and Arg504 were identified as key residues, and their importance was verified by site-directed mutagenesis. Furthermore, three additional mutants (Arg84Ala, Tyr340Phe and Tyr406Phe) were generated and all exhibited a higher degree of substrate specificity than the native enzyme. These results extend our understanding of the structure and function of FAD-GDH, and could assist potential commercial applications. PMID- 25435502 TI - The effect of mutations near the T1 copper site on the biochemical characteristics of the small laccase from Streptomyces coelicolor A3(2). AB - Bacterial laccases show low activities but can be of biotechnological interest due to industrially suitable characteristics such as thermostability and tolerance to alkaline pH. In this study, three separate mutations (M298F, V290N and V290A) were introduced at or near the T1 copper site of the small laccase (SLAC) from Streptomyces coelicolor A3(2) and biochemical properties were assessed in comparison with the native enzyme. The mutation, V290N showed approximately double the activity of SLAC when ABTS was used as substrate while the specific activity of SLAC-M298F was 4-5 times higher than that of SLAC when the assays were performed at >=70 degrees C. There was no significant difference in activity with 2,6-dimethoxyphenol (2,6-DMP); however, there was a significant shift in the optimal pH from pH 9.5 (SLAC) to 7.5 (SLAC-V290N). Optimal temperature for activity was not significantly altered but thermostability was reduced in all three mutants. The substrate range of the mutant variants remained largely unchanged, with the exception of SLAC-M298F which was unable to oxidise veratryl alcohol. Interestingly, the "typical" laccase inhibitor, sodium azide, had no significant inhibitory effect on the activity of SLAC-M298F, which also exhibited increased resistance to inhibition by sulfhydryl compounds. SLAC-V290N showed higher catalytic efficiency for 2,6-DMP (kcat/Km=2.226mM(-1)s(-1)) and ABTS (kcat/Km=1.874mM(-1)s(-1)) compared to SLAC (kcat/Km=1.615mM(-1)s(-1) for 2,6-DMP and kcat/Km=1.611mM(-1)s(-1) for ABTS). This study has shown that three ligands that are closely associated with the T1 copper in SLAC play a key role in maintaining enzymatic activity. Whilst the introduction of mutations at these sites negated favourable characteristics such as thermostability, several favourable effects were observed. This study has also extended the knowledge base on the biochemical characteristics of SLAC, and its suitability as a template for engineering with the aim of widening its potential range of industrial applications. PMID- 25435505 TI - Geranyl diphosphate synthase: an important regulation point in balancing a recombinant monoterpene pathway in Escherichia coli. AB - The expression level of geranyl diphosphate synthase (GPPS) was suspected to play a key role for geraniol production in recombinant Escherichia coli harboring an entire mevalonate pathway operon and a geraniol synthesis operon. The expression of GPPS was optimized by using ribosomal binding sites (RBSs) designed to have different translation initiation rates (TIRs). The RBS strength in TIR window of 500 arbitrary unit (au)-1400 au for GPPS appears to be suitable for balancing the geraniol biosynthesis pathway in this study. With the TIR of 500 au, the highest production titer of geraniol was obtained at a level of 1119mg/L, which represented a 6-fold increase in comparison with the previous titer of 183mg/L. The TIRs of GPPS locating out of range of the optimal window (500-1400 au) caused significant decreases of cell growth and geraniol production. It was suspected to result from metabolic imbalance and plasmid instability in geraniol production by inappropriate expression level of GPP synthase. Our results collectively indicated GPPS as an important regulation point in balancing a recombinant geraniol synthesis pathway. The GPPS-based regulation approach could be applicable for optimizing microbial production of other monoterpenes. PMID- 25435506 TI - Identification of lipase encoding genes from Antarctic seawater bacteria using degenerate primers: expression of a cold-active lipase with high specific activity. AB - Cold-active enzymes are valuable catalysts showing high activity at low and moderate temperatures and low thermostability. Among cold-active enzymes, lipases offer a great potential in detergent, cosmetic, biofuel and food or feed industries. In this paper we describe the identification of novel lipase coding genes and the expression of a lipase with high activity at low temperatures. The genomic DNA from Antarctic seawater bacteria showing lipolytic activity at 4 degrees C was used to amplify five DNA fragments that partially encode novel lipases using specifically designed COnsensus-DEgenerate Hybrid Oligonucleotide Primers (CODEHOP). All the fragments were found to have a high identity with an alpha/beta-hydrolase domain-containing protein identified by the sequencing of the complete genome of Shewanella frigidimarina NCIMB 400. The complete sequence of one of the lipase-coding gene fragments, lipE13, was obtained by genome walking. Considering that the other fragments had a high identity to the putative lipase from S. frigidimarina NCIMB 400, the complete lipase genes were amplified using oligonucleotide primers designed based on the 5' and 3' regions of the coding sequence of the related protein. This strategy allowed the amplification of 3 lipase-encoding genes of which one was expressed in the periplasm using the Escherichia coli BL21(DE3)/pET-22b(+) expression system. The recombinant protein was obtained with activity toward p-nitrophenyl caproate showing a high specific activity between 15 and 25 degrees C. PMID- 25435507 TI - Competitive inhibition of cellobiohydrolase I by manno-oligosaccharides. AB - In the hydrolysis of softwood, significant amounts of manno-oligosaccharides (MOS) are released from mannan, the major hemicelluloses in softwood. However, the impact of MOS on the performance of cellulases is not yet clear. In this work, the effect of mannan and MOS in cellulose hydrolysis by cellulases, especially cellobiohydrolase I (CBHI) from Thermoascus aurantiacus (Ta Cel7A), was studied. The glucose yield of Avicel decreased with an increasing amount of added mannan. Commercial cellulases contained mannan hydrolysing enzymes, and beta-glucosidase played an important role in mannan hydrolysis. Addition of 10mg/ml mannan reduced the glucose yield of Avicel (at 20g/l) from 40.1 to 24.3%. No inhibition of beta-glucosidase by mannan was observed. The negative effects of mannan and MOS on the hydrolytic action of cellulases indicated that the inhibitory effect was at least partly attributed to the inhibition of Ta Cel7A (CBHI), but not on beta-glucosidase. Kinetic experiments showed that MOS were competitive inhibitors of the CBHI from T. aurantiacus, and mannobiose had a stronger inhibitory effect on CBHI than mannotriose or mannotetraose. For efficient hydrolysis of softwood, it was necessary to add supplementary enzymes to hydrolyze both mannan and MOS to less inhibitory product, mannose. PMID- 25435508 TI - Development of glucose biosensor based on reconstitution of glucose oxidase onto polymeric redox mediator coated pencil graphite electrodes. AB - In this study, a novel glucose biosensor was fabricated by reconstitutional immobilization of glucose oxidase (GOx) onto a poly(glycidyl methacrylate-co vinylferrocene) (poly(GMA-co-VFc)) film coated pencil graphite electrode (PGE). The amperometric current response of poly(GMA-co-VFc)-GOx to glucose is linear in the concentration range between 1 and 16mM (correlation coefficient of 0.9998) with a detection limit of 2.7MUM (S/N=3). Experimental parameters were studied in detail and optimized, including the pH and temperature governing the analytical performance of the biosensor. The stability and reusability of the biosensor as well as its kinetic parameters have also been studied. PMID- 25435510 TI - Influence of breed and genotype on the onset and distribution of infectivity and disease-associated prion protein in sheep following oral infection with the bovine spongiform encephalopathy agent. AB - The onset and distribution of infectivity and disease-specific prion protein (PrP(d)) accumulation was studied in Romney and Suffolk sheep of the ARQ/ARQ, ARQ/ARR and ARR/ARR prion protein gene (Prnp) genotypes (where A stands for alanine, R for arginine and Q for glutamine at codons 136, 154 and 171 of PrP), following experimental oral infection with cattle-derived bovine spongiform encephalopathy (BSE) agent. Groups of sheep were killed at regular intervals and a wide range of tissues taken for mouse bioassay or immunohistochemistry (IHC), or both. Bioassay results for infectivity were mostly coincident with those of PrP(d) detection by IHC both in terms of tissues and time post infection. Neither PrP(d) nor infectivity was detected in any tissues of BSE-dosed ARQ/ARR or ARR/ARR sheep or of undosed controls. Moreover, four ARQ/ARQ Suffolk sheep, which were methionine (M)/threonine heterozygous at codon 112 of the Prnp gene, did not show any biological or immunohistochemical evidence of infection, while those homozygous for methionine (MARQ/MARQ) did. In MARQ/MARQ sheep of both breeds, initial PrP(d) accumulation was identified in lymphoreticular system (LRS) tissues followed by the central nervous system (CNS) and enteric nervous system (ENS) and finally by the autonomic nervous system and peripheral nervous system and other organs. Detection of infectivity closely mimicked this sequence. No PrP(d) was observed in the ENS prior to its accumulation in the CNS, suggesting that ENS involvement occurred simultaneously to that of, or followed centrifugal spread from, the CNS. The distribution of PrP(d) within the ENS further suggested a progressive spread from the ileal plexus to other ENS segments via neuronal connections of the gut wall. Differences between the two breeds were noted in terms of involvement of LRS and ENS tissues, with Romney sheep showing a more delayed and less consistent PrP(d) accumulation than Suffolk sheep in such tissues. Whether this accounted for the slight delay (~5 months) in the appearance of clinical signs in Romney sheep is debatable since by the last scheduled kill before animals reached clinical end point, both breeds showed widespread accumulation and similar magnitudes of PrP(d) accumulation in the brain. PMID- 25435511 TI - Absence of canine papillomavirus sequences in canine mammary tumours. AB - Human papillomaviruses (PVs) are found in human breast cancer tissue; however, it remains controversial as to whether these viruses play a role in the aetiology of this tumour. There has been minimal study of whether PVs are found in normal or abnormal mammary glands of animals. The present study investigated whether a PV sequence could be found in the mammary glands of 33 female dogs by rolling circle amplification and polymerase chain reaction. No PV DNA was found in normal or neoplastic canine mammary tissues, suggesting that canine PVs are probably not involved in the pathogenesis of canine mammary neoplasia. PMID- 25435509 TI - The clinical management of Type 2 Gaucher disease. AB - Gaucher disease, the inherited deficiency of the enzyme glucocerebrosidase, is the most common of the lysosomal storage disorders. Type 2 Gaucher disease, the most severe and progressive form, manifests either prenatally or in the first months of life, followed by death within the first years of life. The rarity of the many lysosomal storage disorders makes their diagnosis a challenge, especially in the newborn period when the focus is often on more prevalent illnesses. Thus, a heightened awareness of the presentation of these rare diseases is necessary to ensure their timely consideration. This review, designed to serve as a guide to physicians treating newborns and infants with Gaucher disease, discusses the presenting manifestations of Type 2 Gaucher disease, the diagnostic work-up, associated genotypes and suggestions for management. We also address the ethical concerns that may arise with this progressive and lethal disorder, since currently available treatments may prolong life, but do not impact the neurological manifestations of the disease. PMID- 25435512 TI - Acute tracheal oedema and haemorrhage with fibrinonecrotic tracheitis in pigs--a porcine counterpart of bovine honker syndrome? AB - Cases of acute tracheal oedema and haemorrhage with fibrinonecrotic tracheitis have been described in Hungarian pig herds. Clinical signs and gross and microscopical tracheal lesions bore resemblance to those of bovine 'honker syndrome'. Diagnostic examination of affected tracheas and corresponding lungs revealed the presence of a variety of agents; however, in some cases tracheal lesions developed without detectable pathogens or associated pulmonary pathology. In line with the bovine condition, this suggests the possibility of cough-induced tracheal damage as an initiating factor for this tracheal change in swine. PMID- 25435513 TI - Comparative pathology of canine soft tissue sarcomas: possible models of human non-rhabdomyosarcoma soft tissue sarcomas. AB - Comparative analyses of canine and human soft tissue sarcomas (STSs) are lacking. This study compared the histological and immunohistochemical (labelling for desmin, smooth muscle actin [SMA], CD31, pancytokeratin, S100 and CD34) appearance of 32 archived, formalin-fixed, paraffin wax-embedded canine STS tumour specimens by board-certified veterinary and medical pathologists, both blinded to the other's interpretations. Comparison between the veterinary and human diagnoses revealed a generally consistent pattern of interpretation with few notable variations. Most tumours (13/32) were judged to display similar histomorphological appearance to human low-grade spindle cell sarcomas, appearing non-distinctive and morphologically of a fibroblastic/myofibroblastic type. Five canine cases resembled human liposarcoma, but with atypical desmin-positive epithelioid cells present. Five canine cases resembled human spindle cell sarcoma with myxoid features and two additional cases resembled human myxofibrosarcoma. Seven canine cases were noted to resemble human undifferentiated sarcoma. Findings in the present study demonstrate that canine STSs display histological and immunohistochemical features similar to their human equivalents. Because of these cross-species similarities, a particular opportunity exists to understand the biology and treatment of human STS by potentially including dogs as clinical models. PMID- 25435514 TI - Tic related local field potentials in the thalamus and the effect of deep brain stimulation in Tourette syndrome: Report of three cases. AB - OBJECTIVE: Three patients with intractable Tourette syndrome (TS) underwent thalamic deep brain stimulation (DBS). To investigate the role of thalamic electrical activity in tic generation, local field potentials (LFP), EEG and EMG simultaneously were recorded. METHODS: Event related potentials and event related spectral perturbations of EEG and LFP, event related cross-coherences between EEG/LFP and LFP/LFP were analyzed. As time locking events, the tic onsets were used. Spontaneous tics were compared to voluntary tic mimicking. The effect of tic suppression and DBS on thalamic LFPs was evaluated. RESULTS: All three patients showed time-locked and prior to onset of spontaneous motor tics thalamic synchronization and thalamo-cortical cross-coherence. Also in three patients, not time-locked to motor tics, increased intra-thalamic coherences in the 1-8Hz frequency band were found. In one patient it was demonstrated that voluntary mimicked tics were preceded by premotor cortical and thalamic potentials. In this patient unilateral thalamic DBS contralaterally decreased the background thalamic activity. CONCLUSIONS: The present study in three cases with TS shows that spontaneous tics in TS are preceded by repetitive coherent thalamo-cortical discharges, indicating that preceding a tic the basal ganglia circuits are "charged up", ultimately leading to a motor tic. SIGNIFICANCE: Thalamic LFP recording may lead to more insight in underlying pathophysiological mechanisms in TS. PMID- 25435515 TI - Evaluation of the different sleep-disordered breathing patterns of the compressed tracheal sound. AB - OBJECTIVE: Suitability of the compressed tracheal sound signal for screening different sleep-disordered breathing patterns was evaluated. The previous results suggest that the plain pattern in the compressed sound signal represents mostly normal, unobstructed breathing, the thick pattern consists of periodic apneas/hypopneas and during the thin pattern, flow limitation in the nasal cannula signal is abundant. METHODS: Twenty-seven patients underwent a polysomnography with a tracheal sound and oesophageal pressure monitoring. The tracheal sound data was compressed and scored visually into three different breathing patterns. The percentage of oesophageal pressure values under -8cm H2O, the minimum pressure value and the average duration of the breathing cycles were extracted from 10-min episodes of those plain, thick and thin patterns. In addition, the spectral contents of the tracheal sound during the different breathing patterns were evaluated. RESULTS: The percentage of time when the oesophageal pressure negativity increased was highest during the thin pattern and lowest during the plain pattern. In addition, the thin pattern presented most high frequency components in the 1001-2000Hz frequency band of the tracheal sound. CONCLUSIONS: The results confirmed our previous findings that both the thick and thin patterns seem to consist of obstructed breathing, whereas during the plain pattern the breathing is normal, unobstructed. SIGNIFICANCE: Most screening methods for sleep-disordered breathing reveal only periodic apneas/hypopneas, but with the compressed sound signal the sustained partial obstruction can be estimated as well. PMID- 25435516 TI - Patient perceptions of proactive medication discontinuation. AB - OBJECTIVE: While many patients prefer fewer medications, decisions about medication discontinuation involve collaboration between patients and providers. We sought to identify patient perspectives on intentional medication discontinuation in order to optimize medication use. METHODS: We conducted 20 interviews and two focus groups with a convenience sample of patients (22 men, 5 women; mean age 66 years) at two US Veterans Affairs Medical Centers. We queried patients' experiences with and attitudes toward taking multiple medications, preferences about taking fewer medications, and communication with their providers about stopping a medicine. Transcripts were analyzed qualitatively. RESULTS: Three main themes emerged to create a conceptual model of medication discontinuation from the patient perspective: (1) conflicting views of medication, encompassing the sub-themes of desire for fewer medications, adherence, and specific versus general; (2) importance of patient-provider relationships, encompassing the sub-themes of trust, relying on expertise, shared decision making, and balancing multiple providers; and (3) limited experience with medication discontinuation. CONCLUSION: Many patients who have a preference to take fewer medicines do not share their beliefs with providers and recall few instances of provider-initiated medication discontinuation. PRACTICE IMPLICATIONS: Strengthening patient-provider relationships and eliciting patient attitudes about taking fewer medications may enable appropriate discontinuation of unnecessary medications. PMID- 25435517 TI - Pharmacist-led nonpharmacological intervention in cancer chemotherapy. PMID- 25435518 TI - Expanding horizons of TWA testing. PMID- 25435519 TI - 2013 ACC/AHA cholesterol treatment guideline: Paradigm shifts in managing atherosclerotic cardiovascular disease risk. AB - The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults represents a major shift from prior cholesterol management guidelines. The new guidelines include data from individual randomized trials as well as the most comprehensive meta-analyses, and introduce several major paradigm shifts, which include: aiming for ASCVD risk reduction as opposed to targeting LDL-C levels, advocating for the use of evidence-based doses of statins as first line therapy, and utilizing a new risk calculator and risk cut point to guide initiation of statin therapy. These major changes have created controversy and confusion among the medical community, with some clinicians hesitant to embrace the shift. We review the evidence that forms the basis for these major changes, compare them to other major lipid guidelines, and recommend an integrated approach to managing dyslipidemia to decrease atherosclerotic cardiovascular disease risk. PMID- 25435521 TI - Management of pulmonary embolism: recent evidence and the new European guidelines. PMID- 25435520 TI - Vascular calcification: Mechanisms of vascular smooth muscle cell calcification. AB - Vascular calcification is highly prevalent and, when present, is associated with major adverse cardiovascular events. Vascular smooth muscle cells play an integral role in mediating vessel calcification by undergoing differentiation to osteoblast-like cells and generating matrix vesicles that serve as a nidus for calcium-phosphate deposition in the vessel wall. Once believed to be a passive process, it is now recognized that vascular calcification is a complex and highly regulated process that involves activation of cellular signaling pathways, circulating inhibitors of calcification, genetic factors, and hormones. This review will examine several of the key mechanisms linking vascular smooth muscle cells to vessel calcification that may be targeted to reduce vessel wall mineralization and, thereby, reduce cardiovascular risk. PMID- 25435522 TI - What to use INSTEAD of inhaled corticosteroids in COPD? PMID- 25435523 TI - A sum greater than its parts. PMID- 25435524 TI - Symptomatic, frail, elderly patients: the urgent need for comprehensive assessment and management. PMID- 25435525 TI - Chronic thromboembolic pulmonary hypertension: do we need a new definition? PMID- 25435527 TI - Drug resistance and tuberculosis elimination in low-incidence countries. PMID- 25435526 TI - Goal-oriented therapy in paediatric pulmonary arterial hypertension: are we ready? PMID- 25435528 TI - Ensuring rational introduction and responsible use of new TB tools: outcome of an ERS multisector consultation. PMID- 25435529 TI - Diagnosis of primary ciliary dyskinesia: searching for a gold standard. PMID- 25435530 TI - Abraham ("Abe") Guz: a life devoted to breathing and breathlessness. PMID- 25435534 TI - The bit in the middle: a synthesis of global health literature on policy formulation and adoption. AB - Policy formulation and adoption are poorly understood phases of the health policy process. We conducted a narrative synthesis of 28 articles on health policy in low- and middle-income countries to provide insight on what kinds of activities take place in these phases, the actors crafting policies and the institutions in which policy making occurs. The narrative synthesis involved an inductive process to identify relevant articles, extract relevant data from text and reach new understandings. We find that actors exercising decision-making power include not just various governmental entities, but also civil society, commissioners, nongovernmental organizations and even clergy. We also find that most articles identified two or more distinct institutions in which policy formulation and adoption occurred. Finally, we identify seven distinct activities inherent in policy formulation and adoption: generation of policy alternatives, deliberation and/or consultation, advocacy of specific policy alternatives, lobbying for specific alternatives, negotiation of policy decisions, drafting or enacting policy and guidance/influence on implementation development. Health policy researchers can draw on these categories to deepen their understanding of how policy formulation and adoption unfolds. PMID- 25435535 TI - Mapping the existing body of health policy implementation research in lower income settings: what is covered and what are the gaps? AB - This article uses 85 peer-reviewed articles published between 1994 and 2009 to characterize and synthesize aspects of the health policy analysis literature focusing on policy implementation in low- and middle-income countries (LMICs). It seeks to contribute, first, to strengthening the field of LMIC health policy analysis by highlighting gaps in the literature and generating ideas for a future research agenda and, second, to thinking about the value and applicability of qualitative synthesis approaches to the health policy analysis field. Overall, the article considers the disciplinary perspectives from which LMIC health policy implementation is studied and the extent to which the focus is on systems or programme issues. It then works with the more specific themes of the key thrusts of the reviewed articles, the implementation outcomes studied, implementation improvement recommendations made and the theories used in the reviewed articles. With respect to these more specific themes, the article includes explorations of patterns within the themes themselves, the contributions of specific disciplinary perspectives and differences between systems and programme articles. It concludes, among other things, that the literature remains small, fragmented, of limited depth and quite diverse, reflecting a wide spectrum of health system dimensions studied and many different suggestions for improving policy implementation. However, a range of issues beyond traditional 'hardware' health system concerns, such as funding and organizational structure, are understood to influence policy implementation, including many 'software' issues such as the understandings of policy actors and the need for better communication and actor relationships. Looking to the future, there is a need, given the fragmentation in the literature, to consolidate the existing body of work where possible and, given the often broad nature of the work and its limited depth, to draw more explicitly on theoretical frames and concepts to deepen work by sharpening and focusing concerns and questions. PMID- 25435536 TI - Practice and power: a review and interpretive synthesis focused on the exercise of discretionary power in policy implementation by front-line providers and managers. AB - Tackling the implementation gap is a health policy concern in low- and middle income countries (LMICs). Limited attention has so far been paid to the influence of power relations over this gap. This article presents, therefore, an interpretive synthesis of qualitative health policy articles addressing the question: how do actors at the front line of health policy implementation exercise discretionary power, with what consequences and why? The article also demonstrates the particular approach of thematic synthesis and contributes to discussion of how such work can inform future health policy research. The synthesis drew from a broader review of published research on any aspect of policy implementation in LMICs for the period 1994-2009. From an initial set of 50 articles identified as relevant to the specific review question, a sample of 16 articles were included in this review. Nine report experience around decentralization, a system-level change, and seven present experience of implementing a range of reproductive health (RH) policies (new forms of service delivery). Three reviewers were involved in a systematic process of data extraction, coding, analysis, synthesis and article writing. The review findings identify: the practices of power exercised by front-line health workers and their managers; their consequences for policy implementation and health system performance; the sources of this power and health workers' reasons for exercising power. These findings also provide the basis for an overarching synthesis of experience, highlighting the importance of actors, power relations and multiple, embedded contextual elements as dimensions of health system complexity. The significance of this synthesis lies in its insights about: the micropractices of power exercised by front-line providers; how to manage this power through local level strategies both to influence and empower providers to act in support of policy goals; and the focus and nature of future research on these issues. PMID- 25435537 TI - Can frameworks inform knowledge about health policy processes? Reviewing health policy papers on agenda setting and testing them against a specific priority setting framework. AB - This article systematically reviews a set of health policy papers on agenda setting and tests them against a specific priority-setting framework. The article applies the Shiffman and Smith framework in extracting and synthesizing data from an existing set of papers, purposively identified for their relevance and systematically reviewed. Its primary aim is to assess how far the component parts of the framework help to identify the factors that influence the agenda setting stage of the policy process at global and national levels. It seeks to advance the field and inform the development of theory in health policy by examining the extent to which the framework offers a useful approach for organizing and analysing data. Applying the framework retrospectively to the selected set of papers, it aims to explore influences on priority setting and to assess how far the framework might gain from further refinement or adaptation, if used prospectively. In pursuing its primary aim, the article also demonstrates how the approach of framework synthesis can be used in health policy analysis research. PMID- 25435538 TI - The use of street-level bureaucracy theory in health policy analysis in low- and middle-income countries: a meta-ethnographic synthesis. AB - This article presents a synthesis of studies that explicitly use the theory of street-level bureaucracy to illuminate health policy implementation in low- and middle-income countries. Street-level bureaucrats are frontline workers in bureaucracies, e.g. nurses, who regularly interact directly with citizens in discharging their policy implementation duties and who have some discretion over which services are offered, how services are offered and the benefits and sanctions allocated to citizens. This synthesis seeks to achieve the dual objectives of, first, reflecting on how street-level bureaucracy theory has been used in the literature and, second, providing an example of the application of the synthesis methodology of meta-ethnography to the health policy analysis literature. The article begins by outlining meta-ethnography and providing more information on the papers on which the synthesis is based. This is followed by a detailed account of how the synthesis was achieved and by an articulation of the synthesis. It then concludes with thoughts and questions on the value and relevance of the synthesis, the experience of conducting the synthesis and the partial way in which street-level bureaucracy theory has been used in the literature examined. PMID- 25435539 TI - [Acute hepatitis C in the HIV-infected homosexual male: a second wave of HIV/HCV coinfection?]. PMID- 25435540 TI - [Suggestions on post-mortem microbiological molecular analysis. Authors reply]. PMID- 25435541 TI - Population testing for cancer predisposing BRCA1/BRCA2 mutations in the Ashkenazi Jewish community: a randomized controlled trial. AB - BACKGROUND: Technological advances raise the possibility of systematic population based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)-based testing. METHODS: In a randomized controlled trial of BRCA1/2 gene mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the population screening (PS) arm with testing those fulfilling standard FH-based clinical criteria (FH arm). Following a targeted community campaign, AJ participants older than 18 years were recruited by self-referral after pretest genetic counseling. The effects of BRCA1/2 genetic testing on acceptability, psychological impact, and quality-of-life measures were assessed by random effects regression analysis. All statistical tests were two-sided. RESULTS: One thousand, one hundred sixty-eight AJ individuals were counseled, 1042 consented, 1034 were randomly assigned (691 women, 343 men), and 1017 were eligible for analysis. Mean age was 54.3 (SD = 14.66) years. Thirteen BRCA1/2 carriers were identified in the PS arm, nine in the FH arm. Five more carriers were detected among FH-negative FH-arm participants following study completion. There were no statistically significant differences between the FH and PS arms at seven days or three months on measures of anxiety, depression, health anxiety, distress, uncertainty, and quality-of-life. Contrast tests indicated that overall anxiety (P = .0001) and uncertainty (P = .005) associated with genetic testing decreased; positive experience scores increased (P = .0001); quality-of-life and health anxiety did not change with time. Overall, 56% of carriers did not fulfill clinical criteria for genetic testing, and the BRCA1/2 prevalence was 2.45%. CONCLUSION: Compared with FH-based testing, population-based genetic testing in Ashkenazi Jews doesn't adversely affect short-term psychological/quality-of-life outcomes and may detect 56% additional BRCA carriers. PMID- 25435543 TI - Preprocessing significantly improves the peptide/protein identification sensitivity of high-resolution isobarically labeled tandem mass spectrometry data. AB - Isobaric labeling techniques coupled with high-resolution mass spectrometry have been widely employed in proteomic workflows requiring relative quantification. For each high-resolution tandem mass spectrum (MS/MS), isobaric labeling techniques can be used not only to quantify the peptide from different samples by reporter ions, but also to identify the peptide it is derived from. Because the ions related to isobaric labeling may act as noise in database searching, the MS/MS spectrum should be preprocessed before peptide or protein identification. In this article, we demonstrate that there are a lot of high-frequency, high abundance isobaric related ions in the MS/MS spectrum, and removing isobaric related ions combined with deisotoping and deconvolution in MS/MS preprocessing procedures significantly improves the peptide/protein identification sensitivity. The user-friendly software package TurboRaw2MGF (v2.0) has been implemented for converting raw TIC data files to mascot generic format files and can be downloaded for free from https://github.com/shengqh/RCPA.Tools/releases as part of the software suite ProteomicsTools. The data have been deposited to the ProteomeXchange with identifier PXD000994. PMID- 25435544 TI - Efficient programmable gene silencing by Cascade. AB - Methods that permit controlled changes in the expression of genes are important tools for biological and medical research, and for biotechnological applications. Conventional methods are directed at individually changing each gene, its regulatory elements or its mRNA's translation rate. We demonstrate that the CRISPR-associated DNA-binding Cascade complex can be used for efficient, long lasting and programmable gene silencing. When Cascade is targeted to a promoter sequence the transcription of the downstream gene is inhibited, resulting in dramatically reduced expression. The specificity of Cascade binding is provided by the integral crRNA component, which is easily designed to target virtually any stretch of DNA. Cascade targeted to the ORF sequence of the gene can also silence expression, albeit at lower efficiency. The system can be used to silence plasmid and chromosome targets, simultaneously target several genes and is active in different bacterial species and strains. The findings described here are an addition to the expanding range of CRISPR-based technologies and may be adapted to additional organisms and cell systems. PMID- 25435545 TI - Friends or foes: new insights in jasmonate and ethylene co-actions. AB - One strategy for sessile plants to adapt to their surrounding environment involves the modulation of their various internal phytohormone signaling and distributions when the plants sense environmental change. There are currently dozens of identified phytohormones in plant cells and they act in concert to regulate plant growth, development, metabolism and defense. It has been determined that phytohormones often act together to achieve certain physiological functions. Thus, the study of hormone-hormone interactions is becoming a competitive research field for deciphering the underlying regulatory mechanisms. Among phytohormones, jasmonate and ethylene present a fascinating case of synergism and antagonism. They are commonly recognized as defense hormones that act synergistically. Plants impaired in jasmonate and/or ethylene signaling are susceptible to infections by necrotrophic fungi, suggesting that these two hormones are both required for defense. Moreover, jasmonate and ethylene also act antagonistically, such as in the regulation of apical hook development and wounding responses. Here, we highlight the recent breakthroughs in the understanding of jasmonate-ethylene co-actions and point out the potential power of studying protein-protein interactions for systematically exploring signal cross-talk. PMID- 25435542 TI - Cost-effectiveness of population screening for BRCA mutations in Ashkenazi jewish women compared with family history-based testing. AB - BACKGROUND: Population-based testing for BRCA1/2 mutations detects the high proportion of carriers not identified by cancer family history (FH)-based testing. We compared the cost-effectiveness of population-based BRCA testing with the standard FH-based approach in Ashkenazi Jewish (AJ) women. METHODS: A decision-analytic model was developed to compare lifetime costs and effects amongst AJ women in the UK of BRCA founder-mutation testing amongst: 1) all women in the population age 30 years or older and 2) just those with a strong FH (>=10% mutation risk). The model assumes that BRCA carriers are offered risk-reducing salpingo-oophorectomy and annual MRI/mammography screening or risk-reducing mastectomy. Model probabilities utilize the Genetic Cancer Prediction through Population Screening trial/published literature to estimate total costs, effects in terms of quality-adjusted life-years (QALYs), cancer incidence, incremental cost-effectiveness ratio (ICER), and population impact. Costs are reported at 2010 prices. Costs/outcomes were discounted at 3.5%. We used deterministic/probabilistic sensitivity analysis (PSA) to evaluate model uncertainty. RESULTS: Compared with FH-based testing, population-screening saved 0.090 more life-years and 0.101 more QALYs resulting in 33 days' gain in life expectancy. Population screening was found to be cost saving with a baseline discounted ICER of -L2079/QALY. Population-based screening lowered ovarian and breast cancer incidence by 0.34% and 0.62%. Assuming 71% testing uptake, this leads to 276 fewer ovarian and 508 fewer breast cancer cases. Overall, reduction in treatment costs led to a discounted cost savings of L3.7 million. Deterministic sensitivity analysis and 94% of simulations on PSA (threshold L20000) indicated that population screening is cost-effective, compared with current NHS policy. CONCLUSION: Population-based screening for BRCA mutations is highly cost-effective compared with an FH-based approach in AJ women age 30 years and older. PMID- 25435547 TI - MPIC: a mitochondrial protein import components database for plant and non-plant species. AB - In the 2 billion years since the endosymbiotic event that gave rise to mitochondria, variations in mitochondrial protein import have evolved across different species. With the genomes of an increasing number of plant species sequenced, it is possible to gain novel insights into mitochondrial protein import pathways. We have generated the Mitochondrial Protein Import Components (MPIC) Database (DB; http://www.plantenergy.uwa.edu.au/applications/mpic) providing searchable information on the protein import apparatus of plant and non plant mitochondria. An in silico analysis was carried out, comparing the mitochondrial protein import apparatus from 24 species representing various lineages from Saccharomyces cerevisiae (yeast) and algae to Homo sapiens (human) and higher plants, including Arabidopsis thaliana (Arabidopsis), Oryza sativa (rice) and other more recently sequenced plant species. Each of these species was extensively searched and manually assembled for analysis in the MPIC DB. The database presents an interactive diagram in a user-friendly manner, allowing users to select their import component of interest. The MPIC DB presents an extensive resource facilitating detailed investigation of the mitochondrial protein import machinery and allowing patterns of conservation and divergence to be recognized that would otherwise have been missed. To demonstrate the usefulness of the MPIC DB, we present a comparative analysis of the mitochondrial protein import machinery in plants and non-plant species, revealing plant specific features that have evolved. PMID- 25435548 TI - Increased risk of lung cancer among patients with bronchiectasis: a nationwide cohort study. AB - BACKGROUND: We conducted a longitudinal nationwide cohort study in Taiwan to determine whether patients with bronchiectasis are at an increased risk of developing lung cancer. METHODS: This study investigated the incidence and risk for lung cancer in 57 576 patients newly hospitalized with bronchiectasis between 1998 and 2010 from the Taiwan National Health Insurance Research Database. The comparison cohort comprised 230 304 individuals from the general population without bronchiectasis. The follow-up period was from the time of the initial hospitalization for bronchiectasis to the date of a lung cancer diagnosis, censoring, or 31 December 2011. We used Cox proportional hazard regression models to analyse the risk of lung cancer by including the variables of sex, age and comorbidities. RESULTS: The incidence of lung cancer was higher in patients with bronchiectasis than in the comparison cohort (4.58 vs. 2.02 per 1000 person years). The bronchiectasis patients exhibited a 2.36-fold increased risk of lung cancer compared with the comparison cohort after adjustment for age, sex and comorbidities (adjusted hazard ratio [aHR] = 2.36, 95% confidence interval [CI] = 2.19-2.55). The sex-specific bronchiectasis cohort to comparison cohort revealed that the aHR was 2.41 (95% CI = 2.11-2.76) for the women and 2.33 (95% CI = 2.12 2.56) for the men. The incidence rate of lung cancer increased as age increased in both cohorts. CONCLUSION: This nationwide study determined that the patients with bronchiectasis exhibited an increased risk of lung cancer compared with the general population. PMID- 25435546 TI - Plant-PrAS: a database of physicochemical and structural properties and novel functional regions in plant proteomes. AB - Arabidopsis thaliana is an important model species for studies of plant gene functions. Research on Arabidopsis has resulted in the generation of high-quality genome sequences, annotations and related post-genomic studies. The amount of annotation, such as gene-coding regions and structures, is steadily growing in the field of plant research. In contrast to the genomics resource of animals and microorganisms, there are still some difficulties with characterization of some gene functions in plant genomics studies. The acquisition of information on protein structure can help elucidate the corresponding gene function because proteins encoded in the genome possess highly specific structures and functions. In this study, we calculated multiple physicochemical and secondary structural parameters of protein sequences, including length, hydrophobicity, the amount of secondary structure, the number of intrinsically disordered regions (IDRs) and the predicted presence of transmembrane helices and signal peptides, using a total of 208,333 protein sequences from the genomes of six representative plant species, Arabidopsis thaliana, Glycine max (soybean), Populus trichocarpa (poplar), Oryza sativa (rice), Physcomitrella patens (moss) and Cyanidioschyzon merolae (alga). Using the PASS tool and the Rosetta Stone method, we annotated the presence of novel functional regions in 1,732 protein sequences that included unannotated sequences from the Arabidopsis and rice proteomes. These results were organized into the Plant Protein Annotation Suite database (Plant-PrAS), which can be freely accessed online at http://plant-pras.riken.jp/. PMID- 25435554 TI - Tobacco control recommendations identified by LGBT Atlantans in a community-based participatory research project. AB - BACKGROUND: Lesbian, gay, bisexual, and transgender (LGBT) people are increasingly aware that disproportionately high smoking rates severely impact the health of their communities. Motivated to make a change, a group of LGBT community members, policymakers, and researchers from Atlanta carried out a community-based participatory research (CBPR) project. OBJECTIVES: This formative research study sought to identify recommendations for culturally relevant smoking prevention and cessation interventions that could improve the health of Atlanta's LGBT communities. METHODS: Data presented here come from four focus groups with 36 participants and a community meeting with 30 participants. RESULTS: Among study participants, the most favored interventions were providing LGBT-specific cessation programs, raising awareness about LGBT smoking rates, and getting community venues to go smoke-free. Participants also suggested providing reduced cost cessation products for low-income individuals, using LGBT "role models" to promote cessation, and ensuring that interventions reach all parts of the community. CONCLUSIONS: Findings reinforce insights from community-based research with other marginalized groups. Similarities include the importance of tailoring cessation programs for specific communities, the need to acknowledge differences within communities, and the significance of community spaces in shaping discussions of cessation. Further, this study highlights the need for heightened awareness. The Atlanta LGBT community is largely unaware that high smoking rates affect its health, and is unlikely to take collective action to address this problem until it is understood. PMID- 25435555 TI - Community-based research in action: tales from the Ktunaxa community learning centres project. AB - BACKGROUND: Rural communities, particularly Aboriginal communities, often have limited access to health information, a situation that can have significant negative consequences. To address the lack of culturally and geographically relevant health information, a community-university partnership was formed to develop, implement, and evaluate Aboriginal Community Learning Centres (CLCs). OBJECTIVES: The objective of this paper is to evaluate the community-based research process used in the development of the CLCs. It focuses on the process of building relationships among partners and the CLC's value and sustainability. METHODS: Semistructured interviews were conducted with key stakeholders, including principal investigators, community research leads, and supervisors. The interview transcripts were analyzed using an open-coding process to identify themes. RESULTS: Key challenges included enacting shared project governance, negotiating different working styles, and hiring practices based on commitment to project objectives rather than skill set. Technological access provided by the CLCs increased capacity for learning and collective community initiatives, as well as building community leads' skills, knowledge, and self-efficacy. An important lesson was to meet all partners "where they are" in building trusting relationships and adapting research methods to fit the project's context and strengths. CONCLUSIONS: Successful results were dependent upon persistence and patience in working through differences, and breaking the project into achievable goals, which collectively contributed to trust and capacity building. The process of building these partnerships resulted in increased capacity of communities to facilitate learning and change initiatives, and the capacity of the university to engage in successful research partnerships with Aboriginal communities in the future. PMID- 25435556 TI - Towards participatory air pollution exposure assessment in a goods movement community. AB - BACKGROUND: Air pollution from diesel truck traffic travelling to and from port facilities is a major environmental health concern in areas of Philadelphia such as the Port Richmond neighborhood. Ambient monitoring has limited capability to assess neighborhood- or personal-level exposures to this pollution. OBJECTIVES: We sought to conduct a pilot study using a community-based participatory research (CBPR) approach to assess community environmental health concerns, and measure residents' exposure to airborne traffic-related pollutants (fine particles [PM2.5]). METHODS: The research team established relationships with neighborhood schools and organizations, conducted 24 semistructured interviews, 2 community meetings, and 1 Photovoice exercise. Nine community researchers wore personal monitors that collected PM2.5 in the personal breathing zone for 1 to 3 days over a 6-day period in December 2011. RESULTS: Air pollution and safety hazards from truck traffic, environmental hazards posed by nearby industry, related community health problems, and environmental assets were four major themes emerging from interviews and discussions. Personal monitoring revealed that smoking and smoke exposure had the most pronounced effect on PM2.5 concentrations, and that personal PM2.5 exposure levels were not related to ambient PM2.5 concentrations reported from stationary monitoring stations in Philadelphia. CONCLUSIONS: Participation in personal air pollution monitoring and Photovoice exercises helped to increase awareness of pervasive mobile- and point-source diesel emissions throughout the neighborhood and develop priorities for action. Monitoring indicated the negative effects of cigarette smoke exposure, and disconnect between ambient- and personal-level PM2.5 concentrations that emphasized the need for more personal- and local-level monitoring. In addition, participatory methods are appropriate to involve lay persons in personal air pollution monitoring. PMID- 25435557 TI - Capacity building among african american faith leaders to promote HIV prevention and vaccine research. AB - BACKGROUND: In light of the increasing rates of HIV infection in African Americans, it is essential that black faith leaders become more proactive in the fight against the epidemic. The study aim was to engage faith leaders in a sustainable partnership to increase community participation in preventive HIV vaccine clinical research while improving their access to and utilization of HIV/AIDS prevention services. METHOD: Leadership Development Seminars were adapted for faith leaders in Rochester, NY, with topics ranging from the importance of preventive HIV vaccine research to social issues surrounding HIV/AIDs within a theological framework. Seminars were taught by field-specific experts from the black community and included the development of action plans to institute HIV preventive ministries. To assess the outcome of the Seminars, baseline and post-training surveys were administered and analyzed through paired sample t Tests and informal interviews. RESULTS: 19 faith leaders completed the intervention. In general, the majority of clergy felt that their understanding of HIV vaccine research and its goals had increased postintervention. A critical outcome was the subsequent formation of the Rochester Faith Collaborative by participating clergy seeking to sustain the collaborative and address the implementation of community action plans. CONCLUSION: Providing scientific HIV/AIDS knowledge within the context of clergy members' belief structure was an effective method for engaging black Church leaders in Rochester, NY. Collaborative efforts with various local institutions and community-based organizations were essential in building trust with the faith leaders, thereby building bridges for better understanding of HIV/AIDS prevention efforts, including HIV vaccine research. PMID- 25435558 TI - Health in my community: conducting and evaluating PhotoVoice as a tool to promote environmental health and leadership among Latino/a youth. AB - BACKGROUND: The PhotoVoice method has shown substantial promise for work with youth in metropolitan areas, yet its potential for use with Latino youth from agricultural areas has not been well documented. OBJECTIVES: This project was designed to teach environmental health to 15 high school youth while building their individual and community capacity for studying and addressing shared environmental concerns. The project also aimed to test the utility of PhotoVoice with Latino agricultural youth. METHODS: Fifteen members of the Youth Community Council (YCC), part of a 15-year project with farmworker families in Salinas, CA, took part in a 12-week PhotoVoice project. Their pictures captured the assets and strengths of their community related to environmental health, and were then analyzed by participants. A multi-pronged evaluation was conducted. RESULTS: YCC members identified concerns such as poor access to affordable, healthy foods and lack of safe physical spaces in which to play, as well as assets, including caring adults and organizations, and open spaces in surrounding areas. Participants presented their findings on radio, television, at local community events, and to key policy makers. The youth also developed two action plans, a successful 5K run/walk and a school recycling project, still in progress. Evaluation results included significant changes in such areas as perceived ability to make presentations, leadership, and self-confidence, as well as challenges including transportation, group dynamics, and gaining access to people in power. CONCLUSION: The PhotoVoice method shows promise for environmental health education and youth development in farmworker communities. PMID- 25435559 TI - Lessons learned: cultural and linguistic enhancement of surveys through community based participatory research. PMID- 25435560 TI - Evolution of a community-based participatory approach in a rural and remote dementia care research program. AB - BACKGROUND: Community-based participatory research (CBPR) approaches are valuable strategies for addressing complex health and social problems and powerful tools to support effective transformation of social and health policy to better meet the needs of diverse stakeholders. OBJECTIVES: Since 1997, our team has utilized CBPR approaches to improve health service delivery for persons with dementia and their caregivers in rural and remote settings. We describe the evolution of our approach, including benefits, challenges, and lessons learned over the last 15 years. METHODS: A multistage approach initiated an ongoing CBPR research program in rural dementia care and shaped its direction based on stakeholders' recommendation to prioritize both community and facility-based care. Strategies to develop and foster collaborative partnerships have included travel to rural and remote regions, province-wide community meetings, stakeholder workshops, creation of a Decision-Maker Advisory Council to provide ongoing direction to the overall program, development of diverse project-specific advisory groups, and a highly successful and much anticipated annual knowledge exchange and team building event. LESSONS LEARNED: Partnering with stakeholders in the full research process has enhanced the research quality, relevance, application, and sustainability. These benefits have supported the team's evolution from a relatively traditional focus to an integrated approach guiding all aspects of our research. CONCLUSIONS: Developing and sustaining the full range of stakeholder and decision-maker partnerships is resource-and time-intensive, but our experience shows that community-based participatory strategies are highly suited to health services research that is designed to support sustainable service delivery improvements. PMID- 25435562 TI - "We make the path by walking it": building an academic community partnership with Boston Chinatown. AB - BACKGROUND: The potential for academic community partnerships are challenged in places where there is a history of conflict and mistrust. Addressing Disparities in Asian Populations through Translational Research (ADAPT) represents an academic community partnership between researchers and clinicians from Tufts Medical Center and Tufts University and community partners from Boston Chinatown. Based in principles of community-based participatory research and partnership research, this partnership is seeking to build a trusting relationship between Tufts and Boston Chinatown. OBJECTIVES: This case study aims to provides a narrative story of the development and formation of ADAPT as well as discuss challenges to its future viability. METHODS: Using case study research tools, this study draws upon a variety of data sources including interviews, program evaluation data and documents. RESULTS: Several contextual factors laid the foundation for ADAPT. Weaving these factors together helped to create synergy and led to ADAPT's formation. In its first year, ADAPT has conducted formative research, piloted an educational program for community partners and held stakeholder forums to build a broad base of support. CONCLUSIONS: ADAPT recognizes that long term sustainability requires bringing multiple stakeholders to the table even before a funding opportunity is released and attempting to build a diversified funding base. PMID- 25435563 TI - Building community capacity: sustaining the effects of multiple, two-year community-based participatory research projects. AB - BACKGROUND: The time-limited nature of health and public health research fellowships poses a challenge to trainees' and community partners' efforts to sustain effective, collaborative, community-based participatory research (CBPR) relationships. OBJECTIVES: This paper presents CBPR case studies of partnerships between health services research trainees and community organization leaders in a medium-sized city to describe how participation in the partnership altered community partners' understanding and willingness to conduct research and to engage with research-derived data. METHODS: Trainees and faculty used participatory methods with community leaders to identify research questions, and conduct and disseminate research. Throughout the process, trainees and faculty included research capacity building of community partners as a targeted outcome. Community partners were asked to reflect retrospectively on community research capacity building in the context of CBPR projects. Reflections were discussed and categorized by the authorship team, who grouped observations into topics that may serve as a foundation for development of future prospective analyses. RESULTS: Important ideas shared include that trainee participation in CBPR may have an enduring impact on the community by increasing the capacity of community partners and agencies to engage in research beyond that which they are conducting with the current trainee. CONCLUSION: We posit that CBPR with research trainees may have an additive effect on community research capacity when it is conducted in collaboration with community leaders and focuses on a single region. More research is needed to characterize this potential outcome. PMID- 25435564 TI - Community grand rounds: re-engineering community and academic partnerships in health education-a partnership and programmatic evaluation. AB - BACKGROUND: Community participation in population health improvement can assist university researchers in targeting intervention resources more effectively and efficiently, leading to more effective implementation of interventions, because of joint ownership of both process and product. Two academic health centers partnered with community based organizations to develop a bidirectional educational seminar series called "Community Grand Rounds" (CGR), which identified health concerns of Chicago's South Side residents and provided information regarding university and community resources that addressed community health concerns. OBJECTIVES: We evaluated the community consultants' perceptions of the quality and effectiveness of the planning and implementation of the seminars that resulted from the partnership. METHODS: We conducted one-on-one interviews and focus groups with community consultants to assess their perceptions of the partnership using a tailored version of a previously developed individual and focus group interview instrument. Analysis of the interview text was conducted using grounded theory where themes were coded as they emerged. CONCLUSIONS: CGR is an effective mechanism for providing needed community health information in an easily accessible format. Additional work is needed to determine whether this format represents a sustainable community-university partnership. PMID- 25435565 TI - Partnering with American Indian communities in health using methods of strategic collaboration. AB - BACKGROUND: The Association for Prevention Teaching and Research (APTR) sponsored six regional workshops in 2010 on community engagement and community-engaged research. One of the six workshops was a collaborative effort between the Great Plains Tribal Chairman's Health Board (GPTCHB)-Northern Plains Tribal Epidemiology Center and the College of Public Health at the University of Nebraska Medical Center (UNMC-COPH). OBJECTIVES: To create a meaningful and dynamic forum for the exchange of ideas and co-learning between researchers from urban, tribal and nontribal communities and to build the groundwork for development of sustainable partnerships between researchers and American Indian (AI) communities to eliminate health disparities. METHODS: To enhance meaningful community engagement, we utilized methods of Strategic Collaboration using the Appreciative Inquiry, 4D Change Process Model and designed several interactive group activities including Collaborative Learning and Understanding Exercises (CLUE) and the Research Cafe. RESULTS: The key themes that emerged from the interactive sessions stressed the importance of building relationships and trust; mutual use and sharing of data; and acquiring knowledge, skills, and abilities to enable sustainable research partnerships with AI communitiesConclusions: Innovative, dynamic, and strategic collaborative methods of Appreciative Inquiry and the World Cafe can served to engage people in a constructive dialogue to create a shared vision and plan for more meaningful research partnerships based on principles of equity and social justice, essential for the elimination of health disparities. These collaborative methods can be replicated and adapted in diverse communities, locally, nationally, and globally. PMID- 25435567 TI - What is ...?: a research ethics jeopardy" game to help community partners understand human subjects protections and their importance. PMID- 25435566 TI - A three-decade evolution to transdisciplinary research: community health research in California-Mexico border communities. AB - BACKGROUND: The Institute for Behavioral and Community Health (IBACH) is a transdisciplinary organization with a team-oriented approach to the translation of research to practice and policy within the context of behavioral medicine. OBJECTIVES: This paper tracks the growth of IBACH in the context of evolving, multi-university transdisciplinary research efforts from a behavioral medicine research focus to community approaches to disease prevention and control, ultimately specializing in Latino health research and practice. We describe how this growth was informed by our partnerships with community members and organizations, and training a diverse array of students and young professionals. METHODS: Since 1982, IBACH's research has evolved to address a greater breadth of factors associated with health and well-being. This was driven by our strong community focus and emphasis on collaborations, the diversity of our investigative teams, and our emphasis on training. Although behavioral science still forms the core of IBACH's scientific orientation, research efforts extend beyond those traditionally examined. CONCLUSIONS: IBACH's "team science" successes have been fueled by a specific population emphasis, making IBACH one of the nation's leaders in Latino health behavior research. PMID- 25435568 TI - Pancreatic extracts for painful chronic pancreatitis: micronutrient antioxidant therapy by proxy. PMID- 25435569 TI - Prevention and management of post-ERCP pancreatitis. AB - Pancreatitis remains as one of the most frequent and serious complications of ERCP. Research has identified several patient-related and procedural risk factors, which help guide the endoscopist in prophylaxis and management of pancreatitis. Recent studies have had a major impact on both procedural techniques and pharmacological methods for prophylaxis of post-ERCP pancreatitis. The purpose of this article is to review the relevant literature and describe the most recent and effective approaches in prevention and management of post-ERCP pancreatitis. PMID- 25435570 TI - Chronic metabolic acidosis destroys pancreas. AB - One primary reason for the current epidemic of digestive disorders might be chronic metabolic acidosis, which is extremely common in the modern population. Chronic metabolic acidosis primarily affects two alkaline digestive glands, the liver, and the pancreas, which produce alkaline bile and pancreatic juice with a large amount of bicarbonate. Even small acidic alterations in the bile and pancreatic juice pH can lead to serious biochemical/biomechanical changes. The pancreatic digestive enzymes require an alkaline milieu for proper function, and lowering the pH disables their activity. It can be the primary cause of indigestion. Acidification of the pancreatic juice decreases its antimicrobial activity, which can lead to intestinal dysbiosis. Lowering the pH of the pancreatic juice can cause premature activation of the proteases inside the pancreas with the potential development of pancreatitis. The acidification of bile causes precipitation of the bile acids, which irritate the entire biliary system and create bile stone formation. Aggressive mixture of the acidic bile and the pancreatic juice can cause erratic contractions of the duodenum's walls and subsequent bile reflux into the stomach and the esophagus. Normal exocrine pancreatic function is the core of proper digestion. Currently, there is no effective and safe treatment for enhancing the exocrine pancreatic function. Restoring normal acid-base homeostasis can be a useful tool for pathophysiological therapeutic approaches for various gastrointestinal disorders. There is strong research and practical evidence that restoring the HCO3(-) capacity in the blood can improve digestion. PMID- 25435571 TI - Risk factors associated with recurrence in patients with solid pseudopapillary tumors of the pancreas. AB - CONTEXT: Solid pseudopapillary tumors (SPT) are rare, generally low grade pancreatic neoplasms that occasionally display malignant behavior. OBJECTIVE: To analyze the clinical and pathological features associated with increased risk of recurrence of SPT. METHODS: Cohort study of patients with SPT who underwent resection of the primary tumor and in selected cases resection of metastatic disease from 1999-2013 at a single tertiary care Hepatopancreatobiliary center. Risk factors for recurrence were statistically analyzed. RESULTS: There were 32 patients. The mean age was 35.65 years (standard deviation: 12.26), 26/32, 81.25% were female. Median size of resected tumors was 4.7 cm (1.1-14.5). Most were solid and cystic (22/32, 68.75%), encapsulated (27/32, 84.4%) and located in the pancreatic body or tail (22/32, 68.75%). All displayed strong beta-catenin, cyclin D1, CD56, and progesterone receptor staining with loss of E-cadherin. Most stained positive for vimentin (15/16, 93.75%) and CD10 (17/18, 94.4%). Median follow-up was 43 months (range: 3-207); 3/32, 9.38% recurred (all after 5-years from curative resection) and 1 died by the end of the study period, 11 years after diagnosis. Patients who developed recurrences (n=3) more commonly had synchronous metastases at presentation (P=0.006), lymphovascular invasion (P=0.04) and invasion of tumor capsule (P=0.08) compared to those who did not have disease recurrence. CONCLUSIONS: Lymphovascular invasion, synchronous metastases and local invasion of tumor capsule are associated with aggressive behavior. Since recurrences may occur >5 years from resection, this high-risk group should undergo extended follow-up. Progression and recurrence is slow, therefore, resection of liver metastases can offer long-term survival. PMID- 25435572 TI - The Modified Early Warning Score (MEWS): an instant physiological prognostic indicator of poor outcome in acute pancreatitis. AB - CONTEXT: The Modified Early Warning Score (MEWS) is a bedside scoring system that is non-invasive, simple and repeatable to reflect dynamic changes in physiological state. OBJECTIVE: This study aims to assess accuracy of MEWS and determine an optimal MEWS value in predicting severity in acute pancreatitis (AP). METHODS: A prospective database of consecutive admissions with AP to a single institution was analysed to determine value of MEWS in identifying severe acute pancreatitis (SAP) and predicting poor outcome. Receiver operator curves (ROC) were used to determine optimal accuracy. Sensitivity, specificity, negative predictive value (NPV), and positive predictive values (PPV) were calculated for the optimal MEWS values obtained. RESULTS: One-hundred and 42 patients with AP were included. The optimal highest MEWS per 24 hours period (hMEWS) and mean MEWS per 24 hour period (mMEWS) in predicting SAP as determined by ROC were 2.5 and 1.625 respectively; with hMEWS >=3 and mMEWS >1 utilised in this cohort as MEWS scores are whole numbers. On admission, sensitivity, specificity, NPV, PPV, and accuracy of hMEWS >=3 was 95.5%, 90.8%, 99.0%, 65.6% and 92.0%; and for mMWES >1 was 95.5%, 87.5%, 99.0%, 58.3% and 88.7%, both superior than the Imrie score: 31.5%, 92.1%, 88.9%, 40.0% and 83.5%. The accuracy of hMEWS >=3 and mMEWS >1 increased over the subsequent 72 hours (days 0-2) from 92 to 96%, and 89% to 94%, respectively. CONCLUSIONS: MEWS provides a novel, easy, instant, repeatable, reliable prognostic score that may be superior to existing scoring systems. A larger cohort is required to validate these findings. PMID- 25435573 TI - The usefulness of a multidisciplinary team approach in decision making for pancreatic serous cystic neoplasms. AB - CONTEXT: Serous cystic neoplasms of the pancreas are regarded as benign entities with rare malignant potential and are frequently resected. OBJECTIVE: The purpose of the study was to evaluate the usefulness of a multidisciplinary team (MDT) approach in decision making regarding the diagnosis and management of pancreatic serous cystic neoplasms. METHODS: A retrospective study of a prospective database involving 43 patients with serous cystic neoplasms was carried out. Patients who underwent multidisciplinary team evaluation (Group 1) were compared with patients who did not (Group 2) as regards demographic, clinical, radiological, surgical and pathological data. Uni-multivariate analyses were carried out. RESULTS: Uni multivariate analysis showed that a multidisciplinary team approach was significantly related to the type of management, suggesting that MDT evaluation independently reduced the odds of surgery (odds ratio (OR) 0.1; 95% confidence interval (CI) 0.02-0.8; P=0.027). Age, second level imaging techniques, latero lateral diameter, cranio-caudal diameter and Wirsung duct size differed between the two groups; however, the differences were not statistically significant. CONCLUSIONS: A multidisciplinary team approach seems to be useful in proper decision making regarding the diagnosis and management of pancreatic serous cystic neoplasms. PMID- 25435574 TI - Differential expression of GNAS and KRAS mutations in pancreatic cysts. AB - CONTEXT: KRAS mutations play an important role in pancreatic cancer. GNAS mutations were discovered in intraductal papillary mucinous neoplasms (IPMN). OBJECTIVES: Our aim was to identify the frequency of KRAS and GNAS mutations in pancreatic cystic neoplasms and pancreatic ductal adenocarcinoma (PDAC). METHODS: Sixty-eight surgically resected formalin fixed, paraffin embedded pancreatic specimens were analyzed, including: 1) benign (20 serous cystadenoma (SCA)), 2) pre-malignant (10 mucinous cystic neoplasm (MCN), 10 branch duct intraductal papillary mucinous neoplasm (BD-IPMN), 9 main duct IPMN (MD-IPMN)), 3) malignant (19 PDAC). Total nucleic acid extraction was performed. KRAS codon 12/13 and GNAS codon 201 mutations were interrogated via targeted sequencing using the Ion Torrent's Personal Genome Machine (PGM). RESULTS: Mean age of 68 patients was 61.9+/-8.4 with 72% female. KRAS and GNAS mutations were more common in PDAC and IPMN. KRAS mutations predominated in PDAC compared to pancreatic cysts (16/19, 84% versus 10/49, 20%; P<0.001). GNAS mutations were more common in IPMN compared to non-IPMN lesions (8/19, 42% versus 2/49, 4%; P=0.0003). No GNAS mutations were detected in PDAC and MCN while 2 SCA carried GNAS mutations. Double mutations with KRAS and GNAS were only present in IPMN (5/19 versus 0/30 SCA and MCN, P=0.006). CONCLUSIONS: KRAS and GNAS mutations were more common in PDAC and IPMN with KRAS mutations primarily in PDAC and GNAS mutations more frequent in IPMN. No GNAS mutations occurred in MCN and double mutations were only present in IPMN. PMID- 25435575 TI - Endoscopic snare excision of adenoma of the papilla of Vater without prophylactic pancreatic-duct stent. AB - CONTEXT: The endoscopic excision of adenomas of the papilla of Vater has gained increased popularity in the recent years. Temporary pancreatic drainage has been advised to accompany snare papillectomy in order to prevent ductal obstruction and serious pancreatitis. OBJECTIVES: We evaluated treatment outcome of patients who had undergone endoscopic papillectomy without pancreatic drainage. METHODS: Three consecutive adult patients with adenomas of the papilla of Vater presented with jaundice and pain were treated by endoscopic snare excision between October 2013 and February 2014 in a single center. ERCP procedures revealed papillary tumors and endoscopic biopsy specimens revealed tubular adenoma the papilla of Vater. Adenomas were treated by snare papillectomy method and a biliary stent was inserted as a prophylactic procedure immediately after excision of the adenoma in each case. In addition to physical examination, laboratory tests were repeated in the follow-up period after papillectomy in order to document if there is any complication particularly pancreatitis. RESULTS: None of the patients experienced an immediate complication, including pancreatitis after papillectomy. Also neither patient experienced abnormal fluctuations of laboratory tests during the follow-up. Histopathologic evaluation of the resection specimens revealed a tubular adenoma with low grade dysplasia in the first two patients and a tubular adenoma with high-grade dysplasia in the third one. Endoscopy and pathologic evaluation revealed no recurrent/residual disease during the follow-up period of these patients. CONCLUSION: Endoscopic snare resection of adenoma of the major papilla of the duodenum is a safe and minimal invasive alternative to surgical therapy. Biliary stent is sufficient to prevent biliary ductal patency and pancreatic stenting might not be necessary to prevent pancreatitis. PMID- 25435576 TI - Trophic actions of oral vanadium and improved glycemia on the pancreatic beta cell ultrastructure of streptozotocin-induced diabetic rats. AB - CONTEXT: Oral vanadyl sulfate (vanadium) has potent hypoglycemic effects in diabetes animals, but data about its actions on pancreatic beta-cells (BC) ultrastructure is limited. OBJECTIVE: Partial diabetic rats were treated with vanadium and insulin injection and their effects on BC ultrastructure are studied. METHODS: Male rats were made diabetic with intravenous streptozotocin injection (STZ, 40 mg/kg). Animals were randomly divided to control (CD), vanadium-treated (1 mg/mL VOSO4 + 5H2O in base solution, VTD) and insulin-treated (80 U/kg/day NPH insulin injection, ITD) diabetic groups. Treatments started 10 days after STZ injection and terminated after 2 months. Intermittent tail blood samples were taken for measurements of blood glucose (BG) and plasma insulin (PI). Finally animals were sacrificed and pancreata prepared for assessments of BC ultrastructure, islets histology and insulin immunoreactivity (IIR). RESULTS: Vanadium decreased BG (P<0.0001), elevated the reduced PI (P<0.001), prevented islet atrophy and restored BC ultrastructure. Low BG seen during treatment in VTD and ITD only persisted in VTD after vanadium withdrawal. Hyperglycemia worsened in CD and repaired in ITD shortly after insulin withdrawal. CD islets were atrophied, had scattered IIR spots. BC had pyknotic nuclei, vacuolated cytoplasm and few tiny insulin secretory granules. VTD islets looked normal with compact centered IIR spots. BC had well-developed endoplasmic reticulum, many insulin secretory granules and mitochondria. ITD islet structure was slightly better than CD and BC had some immature insulin secretory granules. CONCLUSION: The trophic actions of vanadium in diabetic rats effectively renovated beta cell ultrastructure and prevented pancreatic islets atrophy, whereas the relief of glucotoxicity seen with insulin treatment could repair some beta cells and partially prevented islet atrophy. PMID- 25435578 TI - Mixed periampullary adenocarcinoma and somatostatinoma with small bowel gastrointestinal stromal tumour in neurofibromatosis type 1. AB - CONTEXT: Gastrointestinal (GI) involvement is present in about one quarter of cases of neurofibromatosis type 1 (NF1). Adenocarcinomas have been reported in several organs. Gastrointestinal stromal tumors are the most common GI lesion seen in NFI. GISTs in combination with ampullary neuroendocrine tumors in NF-1 have been reported rarely. CASE REPORT: We present the case of a 44-year-old man who presented with a history of obstructive jaundice and weight loss. Investigations revealed a pancreatic tumor associated with a common bile duct (CBD) stricture. At operation, an ampullary adenocarcinoma that infiltrated into the head of pancreas with an adjacent somatostatinoma was found. In addition, a small bowel GIST was present. CONCLUSIONS: Mixed periampullary adenocarcinoma and somatostatinoma in a patient with NF1 has only been previously reported once. The current case highlights the spectrum of associated tumor types which can be seen in association with NF1. Patients with NF1 who present with jaundice and weight loss should be investigated in the usual manner with increased suspicion for duodenal and ampullary tumors. PMID- 25435577 TI - The use of LigaSureTM Does not Affect Histologic Margin Assessment in Pancreatoduodenectomy (PD) specimens. AB - CONTEXT: LigaSureTM is considered safe in performing pancreaticoduodenectomy (PD). However, no data are available regarding the possible damage of tissues at the resection margins and the impact thereof on histologic margin assessment. OBJECTIVE: This study compares the degree of histologic damage to the resection margins when using LigaSureTM (Group 1) or traditional ligature (Group 2). METHODS: Both groups included 8 consecutive patients who underwent PD at Karolinska Institute in December 2013 (Group 1) or earlier (Group 2) by the same surgeon (M.D.C.). The quality of tissues at the circumferential margins was compared between both groups by scoring for three different kinds of damage: tissue fragmentation, hemorrhage, and cell damage. RESULTS: The mean score for fragmentation was 1.3 (Group 1) versus 1.7 (Group 2; P=0.1). For hemorrhage the mean score was 0.8 (Group 1) versus 1.5 (Group 2; P=0.04). The mean score for cell damage was 1.4 (Group 1) compared to 1.2 (Group 2; P=0.1). CONCLUSIONS: LigaSureTM does not cause tissue damage that could affect histologic margin assessment in PD specimens. PMID- 25435579 TI - "Vascular lock" causing splenic perfusion defects during irreversible electroporation of a locally advanced pancreatic tumor. AB - CONTEXT: There is little reported experience of irreversible electroporation (IRE) of locally advanced pancreatic tumors (LAP). In literature, few data reported complications. In particular vascular vasoconstriction miming splenic infarcts in humans has never been found. CASE REPORT: This report describes the onset of asymptomatic multiple little splenic perfusion defects after the treatment of a LAP localized in the boby-tail portion of the pancreas with the application of five percutaneous probes for IRE, in a 79 year-old man. Splenic artery was regularly patent but entirely trapped in the tumor. CONCLUSION: To the best of our knowledge, until now, no experience concerning percutaneous IRE of pancreatic cancer described that phenomenon. The cause could not be established with certainty and "vascular lock" may be a valid hypothesis. Additional studies are necessary to evaluate its frequency and its exact pathophysiological cause in humans. PMID- 25435580 TI - Dangerous course and atypical termination of the splenic vein in relation to pancreas--a case report. AB - CONTEXT: Knowledge of variations of the vessels closely related to the pancreas adds greatly to the success of pancreatic surgery. Splenic vein is one of the vessels that are closely related to the pancreas. Its variations might not only change the haemodynamics in the vein but also cause unexpected bleeding during pancreatic surgery. CASE REPORT: During our dissection classes, we noted the variations in the course and termination of the splenic vein. After emerging from the spleen, it coursed upward and to the right, embedded in a groove on the anterior surface of body of pancreas. After reaching the upper border, it turned downwards and entered the body of the pancreas. After having a downward course in the body of pancreas, it emerged out and united with the superior mesenteric vein at an angle of about 160 degrees to form the portal vein. CONCLUSION: This peculiar course of the vein might predispose it for thrombosis in case of pancreatitis. It can also lead to iatrogenic injuries during pancreatic or splenic surgeries. PMID- 25435581 TI - High-dose corticosteroid therapy for erlotinib-induced interstitial lung disease in Japanese patient with advanced pancreatic cancer. AB - CONTEXT: Erlotinib is a selective epidermal growth factor receptor tyrosine kinase inhibitor used as a target therapy against non-small lung cancer and advanced pancreatic cancer. A regimen of erlotinib plus gemcitabine has been proven to prolong overall survival in the patient with advanced pancreatic cancer. In addition to common adverse effects, such as diarrhea, mucositis and skin rash (acne form eruptions), acute interstitial lung disease (ILD) has been reported as an infrequent but potentially fatal complication. We here report a case of a Japanese patient with erlotinib-induced ILD in whom high-dose corticosteroid therapy was successful. CASE REPORT: A fifty-five-year-old male with cancer of the head of the pancreas with multiple liver metastases started treatment with gemcitabine plus erlotinib. On the 13th day of erlotinib treatment, he had high fever. Chest computed tomography (CT) scan showed a diffuse ground-glass like infiltration of both lungs. He was diagnosed with ILD, and high-dose corticosteroid therapy was started. Two weeks after the introduction of steroid therapy, the reticular shadow faded away on CT. He was successfully treated with corticosteroid for erlotinib-induced acute ILD although he died 6 months after the initiation of chemotherapy owing to disease progression. CONCLUSION: we showed a case of a successfully treated Japanese patient of erlotinib-induced ILD. Because erlotinib-induced ILD would frequently occur in Japanese patients, closer attention to ILD should be paid for Japanese patients than in Western populations. If erlotinib-induced ILD occurs, a high dose corticosteroid therapy would be a useful option of treatment. PMID- 25435582 TI - Ciliated foregut cyst of the pancreas: another differential in the diagnosis of cystic pancreatic lesions. AB - CONTEXT: With the more frequent use of cross sectional imaging, the detection of cystic pancreatic incidentalomas has become a relatively common entity. The commonest cystic incidentalomas are neoplastic. Pseudocysts are the most single common pathological entity. Foregut cystic lesions as a pathological entity are rare but mostly observed in the mediastinum. Ciliated foregut cysts of the pancreas are very rare and an extremely uncommon cause of a cystic lesion within the pancreas. CASE REPORT: We present herewith an uncommon case of a large cystic lesion, confirmed as a ciliated foregut cyst on final histology arising from the body and tail of the pancreas. The lesion was very effectively treated with a laparoscopic distal pancreatectomy and splenectomy. CONCLUSION: The rarity of the lesion makes the case worth reporting. PMID- 25435583 TI - Pancreatic desmoplastic small round cell tumour--a rare presentation of painful obstructive jaundice. AB - CONTEXT: Pancreatic desmoplastic small round cell tumour (DSRCT) is an extremely rare malignancy of which very few reports exist. It follows an aggressive course and has a dismal prognosis. CASE REPORT: A twenty-four-year-old male presented with a one-month history of rapidly progressive obstructive jaundice associated with abdominal pain suggestive of a biliary colic. Contrast-enhanced CT (CECT) of the abdomen revealed a pancreatic head mass. He underwent a pancreaticoduodenectomy and adjuvant chemotherapy and is disease free one year after surgery. CONCLUSION: This is the first reported case of a pancreatic head DSRCT, discovered in a young male investigated for a short history of painful obstructive jaundice. PMID- 25435584 TI - Non-functioning pancreatic neuroendocrine tumor accompanied with multiple liver metastases: remorseful case and literature review. AB - CONTEXT: Pancreatic neuroendocrine tumor (P-NET) is a rare and slow-growing tumor. Unfortunately, there is no clear consensus on the role and timing of surgery for primary tumor and liver metastases, although current reports refer to liver surgery including LT for unresectable liver metastases. CASE REPORT: A thirty-nine-year-old man was diagnosed with nonfunctioning pancreatic neuroendocrine tumor (P-NET) in the pancreatic head, with multiple liver metastases. The tumor was 2.5 cm in diameter and he was asymptomatic. Small but multiple metastases were detected in the liver, and no extrahepatic metastases were observed. We initially intended to control the liver metastases before resection of the primary tumor. To begin with, transarterial chemoembolization (TACE) and transcatheter arterial infusion (TAI) were repeated. Thereafter, systemic chemotherapy and biotherapy were introduced according to follow-up assessments. Unfortunately, imaging assessment at about 10 months later revealed that liver metastases were partially enlarged, although some were successfully treated. Therefore, these therapies were switched to other regimens, and TACE/TAI, systemic chemotherapies and biotherapies were repeated. Although liver metastases seemed to be stable for a while, the primary tumor was enlarged even after therapy. At 3.5 years after initial diagnosis, the primary tumor became symptomatic (pain and jaundice). Liver metastases enlarged and massive swelling of the para-aortic lymph nodes was observed. Thereafter, palliative therapy was the main course of action. He died at 4.3 years after initial diagnosis. CONCLUSION: Our young patient could have been a candidate for initial surgery for primary tumor and might have had a chance of subsequent liver transplantation for unresectable metastases. Surgeons still face questions in deciding the best surgical scenario in patients with P-NET with liver metastases. PMID- 25435585 TI - Relationship between body mass index and pancreas volume in Japanese people. AB - CONTEXT: The volume of the pancreas increases with obesity. OBJECTIVE: This study was aimed to explore the relationship between body mass index (BMI) and pancreas volume in Japanese. METHODS: The pancreas volume was examined in a total of 103 (60 men and 43 women) Japanese adults who had undergone abdominal computed tomography (CT) scan. The pancreas was outlined by hand in each CT image and the pancreas volume was computed by summing the product of pancreas area of each image and the CT section thickness. RESULTS: There was a significant positive correlation between BMI and pancreas volume (r = 0.41, P <0.001). This relationship was expressed by the following equation: y = 23.8 + 2.48x, where y is pancreas volume (cm3) and x is BMI. CONCLUSIONS: There is a positive correlation between BMI and pancreas volume in Japanese and this relationship is similar to that in Caucasians. This information will be useful to estimate the impact of obesity on pancreas volume in Japanese and for comparison among different ethnicities. PMID- 25435586 TI - Spontaneous intra-gastric walled-off pancreatic necrosis rupture. PMID- 25435588 TI - Concomitant pancreas divisum and double pylorus: a case report. PMID- 25435587 TI - Squamous cell carcinoma of the pancreas. PMID- 25435589 TI - Using Structural Equation Modeling to Assess Functional Connectivity in the Brain: Power and Sample Size Considerations. AB - The present study assessed the impact of sample size on the power and fit of structural equation modeling applied to functional brain connectivity hypotheses. The data consisted of time-constrained minimum norm estimates of regional brain activity during performance of a reading task obtained with magnetoencephalography. Power analysis was first conducted for an autoregressive model with 5 latent variables (brain regions), each defined by 3 indicators (successive activity time bins). A series of simulations were then run by generating data from an existing pool of 51 typical readers (aged 7.5-12.5 years). Sample sizes ranged between 20 and 1,000 participants and for each sample size 1,000 replications were run. Results were evaluated using chi-square Type I errors, model convergence, mean RMSEA (root mean square error of approximation) values, confidence intervals of the RMSEA, structural path stability, and D-Fit index values. Results suggested that 70 to 80 participants were adequate to model relationships reflecting close to not so close fit as per MacCallum et al.'s recommendations. Sample sizes of 50 participants were associated with satisfactory fit. It is concluded that structural equation modeling is a viable methodology to model complex regional interdependencies in brain activation in pediatric populations. PMID- 25435590 TI - Improvements in the Synthesis and Understanding of the Iodo-bridged Intermediate en Route to the Pt(IV) Prodrug Satraplatin. AB - Mixed amine/ammine motifs are important features in newer generation platinum anticancer agents, including the Pt(IV) prodrug satraplatin. One synthetic route that can be used to access platinum molecules with such structures exploits the trans effect during NH3-mediated cleavage of iodo-bridged platinum(II) dimers of the form [Pt(Am)I(MU-I)]2, where Am is an amine. A clear picture of the nature of these dimers that is consistent with the reactivity they exhibit has remained elusive. Moreover, technical aspects of this chemistry have impeded its more widespread use. We present here an improved strategy that permits isolation and use of [Pt(Am)I(MU-I)]2, where Am is cyclohexylamine, within minutes as opposed to weeks, as previously reported. A detailed spectroscopic, crystallographic, and chromatographic investigation of this intermediate in the synthesis of satraplatin is also presented with a discussion of the ability of both cis and trans isomers of the dimer to produce exclusively cis-[Pt(NH2C6H11)(NH3)I2] upon treatment with NH3. PMID- 25435591 TI - Coexistence and relative abundance in plant communities are determined by feedbacks when the scale of feedback and dispersal is local. AB - 1. Negative plant-soil feedback occurs when the presence of an individual of a particular species at a particular site decreases the relative success of individuals of the same species compared to those other species at that site. This effect favors heterospecifics thereby facilitating coexistence and maintaining diversity. Empirical work has demonstrated that the average strengths of these feedbacks correlate with the relative abundance of species within a community, suggesting that feedbacks are an important driver of plant community composition. Understanding what factors contribute to the generation of this relationship is necessary for diagnosing the dynamic forces that maintain diversity in plant communities. 2. We used a spatially explicit, individual-based computer simulation to test the effects of dispersal distance, the size of feedback neighbourhoods, the strength of pairwise feedbacks and community wide variation of feedbacks, community richness, as well as life-history differences on the dependence of relative abundance on strength of feedback. 3. We found a positive dependence of relative abundance of a species on its average feedback for local scale dispersal and feedback. However, we found that the strength of this dependence decreased as either the spatial scale of dispersal and/or the spatial scale of feedback increased. We also found that for spatially local (i.e. relatively small) scale interaction and dispersal, as the mean strength of feedbacks in the community becomes less negative, the greater the increase in abundance produced by a comparable increase in species-specific average feedback. We found that life-history differences such as mortality rate did not generate a pattern with abundance, nor did they affect the relationship between abundance and average feedback. 4.Synthesis. Our results support the claim that empirical observations of a positive correlation between relative abundance and strength of average feedback serves as evidence that local scale negative feedbacks play a prominent role in structuring plant communities. We also identify that this relationship depends upon local scale plant dispersal and feedback which generates clumping and magnifies the negative feedbacks. PMID- 25435592 TI - Montessori Public School Pre-K Programs and the School Readiness of Low-Income Black and Latino Children. AB - Within the United States, there are a variety of early education models and curricula aimed at promoting young children's pre-academic, social, and behavioral skills. This study, using data from the Miami School Readiness Project (MSRP; Winsler et al., 2008, 2012), examined the school readiness gains of low income Latino (n = 7,045) and Black children (n = 6,700) enrolled in two different types of Title-1 public school pre-K programs: those in programs using the Montessori curricula and those in more conventional programs using the High/Scope curricula with a literacy supplement. Parents and teachers reported on children's socio-emotional and behavioral skills with the Devereux Early Childhood Assessment (DECA), while children's pre-academic skills (cognitive, motor, and language) were assessed directly with the Learning Accomplishment Profile Diagnostic (LAP-D) at the beginning and end of their four-year-old pre-K year. All children, regardless of curricula, demonstrated gains across pre academic, socio-emotional, and behavioral skills throughout the pre-K year; however, all children did not benefit equally from Montessori programs. Latino children in Montessori programs began the year at most risk in pre-academic and behavioral skills, yet exhibited the greatest gains across these domains and ended the year scoring above national averages. Conversely, Black children exhibited healthy gains in Montessori, but demonstrated slightly greater gains when attending more conventional pre-K programs. Findings have implications for tailoring early childhood education programs for Latino and Black children from low-income communities. PMID- 25435593 TI - Growth rates are related to production efficiencies in juveniles of the sea urchin Lytechinus variegatus. AB - Growth rates of newly-metamorphosed urchins from a single spawning event (three males and three females) were highly variable, despite being held en masse under identical environmental and nutritional conditions. As individuals reached ~5 mm diameter (0.07-0.10 g wet weight), they were placed in growth trials (23 dietary treatments containing various nutrient profiles). Elapsed time from the first individual entering the growth trials to the last individual entering was 121 days (N = 170 individuals). During the five-week growth trials, urchins were held individually and proffered a limiting ration to evaluate growth rate and production efficiency. Growth rates among individuals within each dietary treatment remained highly variable. Across all dietary treatments, individuals with an initially high growth rate (entering the study first) continued to grow at a faster rate than those with an initially low growth rate (entering the study at a later date), regardless of feed intake. Wet weight gain (ranging from 0.13 3.19 g, P < 0.0001, R2 = 0.5801) and dry matter production efficiency (ranging from 25.2-180.5%, P = 0.0003, R2 = 0.6162) were negatively correlated with stocking date, regardless of dietary treatment. Although canalization of growth rate during en masse early post-metamorphic growth is possible, we hypothesize that intrinsic differences in growth rates are, in part, the result of differences (possibly genetic) in production efficiencies of individual Lytechinus variegatus. That is, some sea urchins are more efficient in converting feed to biomass. We further hypothesize that this variation may have evolved as an adaptive response to selective pressure related to food availability. PMID- 25435594 TI - ADVANTAGES OF MCNPX-BASED LATTICE TALLY OVER MESH TALLY IN HIGH-SPEED MONTE CARLO DOSE RECONSTRUCTION FOR PROTON RADIOTHERAPY. AB - Monte Carlo simulations are increasingly used to reconstruct dose distributions in radiotherapy research studies. Many studies have used the MCNPX Monte Carlo code with a mesh tally for dose reconstructions. However, when the number of voxels in the simulated patient anatomy is large, the computation time for a mesh tally can become prohibitively long. The purpose of this work was to test the feasibility of using lattice tally instead of mesh tally for whole-body dose reconstructions. We did this by comparing the dosimetric accuracy and computation time of lattice tallies with those of mesh tallies for craniospinal proton irradiation. The two tally methods generated nearly identical dosimetric results, within 1% in dose and within 1 mm distance-to-agreement for 99% of the voxels. For a typical craniospinal proton treatment field, simulation speed was 4 to 17 times faster using the lattice tally than using the mesh tally, depending on the numbers of proton histories and voxels. We conclude that the lattice tally is an acceptable substitute for the mesh tally in dose reconstruction, making it a suitable potential candidate for clinical treatment planning. PMID- 25435595 TI - Mushrooms-Biologically Distinct and Nutritionally Unique: Exploring a "Third Food Kingdom" AB - Mushrooms are fungi, biologically distinct from plant- and animal-derived foods (fruits, vegetables, grains, dairy, protein [meat, fish, poultry, legumes, nuts, and seeds]) that comprise the US Department of Agriculture food patterns operationalized by consumer-focused MyPlate messages. Although mushrooms provide nutrients found in these food groups, they also have a unique nutrient profile. Classified into food grouping systems by their use as a vegetable, mushrooms' increasing use in main entrees in plant-based diets is growing, supporting consumers' efforts to follow dietary guidance recommendations. Mushrooms' nutrient and culinary characteristics suggest it may be time to reevaluate food groupings and health benefits in the context of 3 separate food kingdoms: plants/botany, animals/zoology, and fungi/mycology. PMID- 25435596 TI - Generalized Identity Matching to Sample after Multiple-Exemplar Training in Capuchin Monkeys. AB - A multiple-exemplar identity matching-to-sample baseline was established to encourage development of generalized IDMTS performances in three adult male capuchins. Mask (blank comparison) or Shuffled S- procedures were used to promote select (sample-S+) control in baseline relations and to assess stimulus control relations in generalized IDMTS tests. The IDMTS baseline comprised eight 3 stimulus sets or four 4-stimulus sets. Probe trials with new stimulus sets were substituted for baseline sets in successive testing sessions and subsequently converted to new baseline relations. All monkeys exhibited high accuracy on generalized IDMTS tests. A monkey who was given the Mask procedure in training and tests showed generalized IDMTS with select relations predominating. Two monkeys who were given training and testing with the Shuffled S- procedure performed somewhat better on Shuffled S- IDMTS test trials than on test trials that contained non-shuffled test IDMTS trials thus suggesting that exclusion of familiar nonmatching comparison stimuli from baseline in Shuffled S-test trials contributed to the higher accuracy scores with the former procedures. Development of select relations appeared to be a positive predictor of development of generalized IDMTS. PMID- 25435597 TI - Practicing What is Preached: The Relationship between Congregational Support and HIV Prevention Behaviors among Black Women. AB - Through the current analysis, we aimed to better understand the relationship between congregational support and HIV prevention behaviors among a sample of high risk, HIV negative Black women. Participants were 434 Black women who were at high risk for contracting HIV through heterosexual sex. They were recruited from a city in the Mid Atlantic Region. Data were collected through face-to-face interviews and Audio-Computer-Assisted Self-Interviews (ACASI). Results revealed three congregational characteristics were important for Black women's comfort level discussing HIV and their likelihood of returning for their HIV test results: feeling loved by their congregation, having ministries that helped people with their problems and feeling listened to by their congregation. Thus, religious congregational support was a significant correlate of Black women's comfort discussing HIV prevention and treatment as well as their motivation to return to get their HIV test results. PMID- 25435598 TI - Spatially Varying Coefficient Model for Neuroimaging Data with Jump Discontinuities. AB - Motivated by recent work on studying massive imaging data in various neuroimaging studies, we propose a novel spatially varying coefficient model (SVCM) to capture the varying association between imaging measures in a three-dimensional (3D) volume (or 2D surface) with a set of covariates. Two stylized features of neuorimaging data are the presence of multiple piecewise smooth regions with unknown edges and jumps and substantial spatial correlations. To specifically account for these two features, SVCM includes a measurement model with multiple varying coefficient functions, a jumping surface model for each varying coefficient function, and a functional principal component model. We develop a three-stage estimation procedure to simultaneously estimate the varying coefficient functions and the spatial correlations. The estimation procedure includes a fast multiscale adaptive estimation and testing procedure to independently estimate each varying coefficient function, while preserving its edges among different piecewise-smooth regions. We systematically investigate the asymptotic properties (e.g., consistency and asymptotic normality) of the multiscale adaptive parameter estimates. We also establish the uniform convergence rate of the estimated spatial covariance function and its associated eigenvalues and eigenfunctions. Our Monte Carlo simulation and real data analysis have confirmed the excellent performance of SVCM. PMID- 25435599 TI - Inference for longitudinal data with nonignorable nonmonotone missing responses. AB - For the analysis of longitudinal data with nonignorable and nonmonotone missing responses, a full likelihood method often requires intensive computation, especially when there are many follow-up times. The authors propose and explore a Monte Carlo method, based on importance sampling, for approximating the maximum likelihood estimators. The finite-sample properties of the proposed estimators are studied using simulations. An application of the proposed method is also provided using longitudinal data on peptide intensities obtained from a proteomics experiment of trauma patients. PMID- 25435600 TI - Imaging, Spectroscopic, Mechanical and Biocompatibility Studies of Electrospun Tecoflex(r) EG 80A Nanofibers and Composites Thereof Containing Multiwalled Carbon Nanotubes. AB - The present study discusses the design, development and characterization of electrospun Tecoflex(r) EG 80A class of polyurethane nanofibers and the incorporation of multiwalled carbon nanotubes (MWCNTs) to these materials. Scanning electron microscopy results confirmed the presence of polymer nanofibers, which showed a decrease in fiber diameter at 0.5% wt. and 1% wt. MWCNTs loadings, while transmission electron microscopy showed evidence of the MWCNTs embedded within the polymer matrix. The fourier transform infrared spectroscopy and Raman spectroscopy were used to elucidate the polymer-MWCNTs intermolecular interactions, indicating that the C-N and N-H bonds in polyurethanes are responsible for the interactions with MWCNTs. Furthermore, tensile testing indicated an increase in the Young's modulus of the nanofibers as the MWCNTs concentration was increased. Finally, NIH 3T3 fibroblasts were seeded on the obtained nanofibers, demonstrating cell biocompatibility and proliferation. Therefore, the results indicate the successful formation of polyurethane nanofibers with enhanced mechanical properties, and demonstrate their biocompatibility, suggesting their potential application in biomedical areas. PMID- 25435601 TI - Effect of chronic administration of hexane extract of Byrsonima crassifolia seed on B-cell and pancreatic oxidative parameters in streptozotocin-induced diabetic rat. AB - BACKGROUND: In Mexican traditional medicine, the seeds of Byrsonima crassifolia have been used in the treatment of diabetes, rheumatism and for wound healing. The aim was to evaluate the effect of seeds of B. crassifolia on insulin release from the pancreatic beta cells in streptozotocininduced diabetic rats. MATERIALS AND METHODS: In the present study, we evaluated the beneficial effect of seeds B. crassifolia streptozotocin-induced type 1 diabetic rats. Insulin level; insulin sensitivity index, insulin content in pancreas, malonaldehyde, nitric oxide contents, oxidative stress parameters were assayed. Serum glucose levels were determined by the glucose oxidase method. To determine the insulin releasing activity, after extract treatment, the pancreas was excised. Pancreatic sections were processed for examination of insulin-releasing activity using an imunocytochemistry kit. RESULTS: Administration of the hexane extract (200 and 400 mg/kg), exhibited a significant reduction in serum glucose. Administration of streptozotocin decreased the number of beta cells with insulin secretory activity in comparison with intact rats; but treatment with the B. crassifolia seed extract increased significantly the activity of the beta cells in comparison with the diabetic control rats. The extract decreased serum glucose in streptozotocin induced diabetic rats and increased insulin release from the beta cells of the pancreas. CONCLUSION: These finding suggest that B. crassifolia seed has beneficial effect for diabetes through decreasing blood glucose and lipid levels, increasing insulin sensitivity index and insulin content, up-regulating antioxidant enzyme activity and decreasing lipid peroxidation. PMID- 25435603 TI - Extraction and isolation of alkaloids of Sophora alopecuroides and their anti tumor effects in H22 tumor-bearing mice. AB - BACKGROUND: Alkaloids of Sophora alopecuroides have good biological activity, and are widely used in clinical settings, which not only have pharmacological activities of anti-cancer, cancer suppression, as well as the inhibition, and killing of various microorganisms; but also possess extensive pharmacological effects on immune system, nervous system and cardiovascular system. The objective of this paper was to extract and isolate total alkaloids of Sophora alopecuroides (TASA), and to study their anti-tumor effects in H22 tumor-bearing mice. MATERIALS AND METHODS: TASA were extracted and isolated using thin-layer chromatography, and column chromatography; and the isolated compounds were analyzed using nuclear magnetic resonance. The inhibitory effects of TASA on tumor in H22-bearing mice were determined by MTT assay. RESULTS: Three compounds were isolated from Sophora alopecuroides L., which were matrine, oxymatrine and sophoridine, respectively. Meanwhile, mouse H22 sarcoma model was established and different doses of TASA apparently inhibited solid H22-tumor in mice; it inhibited the thymus, and spleen to some extent; the degree of inhibition was more obvious for the spleen. CONCLUSION: TASA has an anti-tumor effect in H22 tumor-bearing mice. PMID- 25435602 TI - Hepatoprotective properties of aqueous leaf extract of Persea Americana, Mill (Lauraceae) 'avocado' against CCL4-induced damage in rats. AB - BACKGROUND: Natural products from plants have received considerable attention in recent years due to their diverse pharmacological properties, including antioxidants and hepatoprotective activities. The protective effects of aqueous extract of Persea americana (AEPA) against carbon tetrachloride (CCl4)-induced hepatotoxicity in male albino rats was investigated. MATERIALS AND METHODS: Liver damage was induced in rats by administering a 1:1 (v/v) mixture of CCl4 and olive oil [3 ml/kg, subcutaneously (sc)] after pre-treatment for 7 days with AEPA. Hepatoprotective effects of AEPA was evaluated by estimating the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and levels of total bilirubin (TBL). The effects of AEPA on biomarkers of oxidative damage (lipid peroxidation) and antioxidant enzymes namely, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione S-transferase (GST) were measured in liver post mitochondrial fraction. RESULTS: AEPA and Reducdyn(r) showed significant (p<0.05) hepatoprotective activity by decreasing the activities of ALT, AST, ALP and reducing the levels of TBL. The activities of antioxidant enzymes, levels of malondialdehyde and protein carbonyls were also decreased dose-dependently in the AEPA-treated rats. Pre-treatment with AEPA also decreased the serum levels of glutathione significantly. CONCLUSION: These data revealed that AEPA possesses significant hepatoprotective effects against CCl4-induced toxicity attributable to its constituent phytochemicals. The mechanism of hepatoprotection seems to be through modulation of antioxidant enzyme system. PMID- 25435604 TI - Anti-hyperglycemic and anti-hyperlipidemic potential of a polyherbal preparation "Diabegon" in metabolic syndrome subject with type 2 diabetes. AB - BACKGROUND: In the present study, "Diabegon" a poly-herbal preparation, with hypoglycemic activity, was evaluated for its preventive effect in metabolic syndrome subjects with type 2 diabetes and also to reveal its side effects, on liver and kidney. MATERIALS AND METHODS: Type 2 diabetic subjects with metabolic syndrome (N=58) were categorized on the basis of age and fasting blood glucose. The grouping was as follows: Group I (35-50 yrs), Group II (51-65 yrs), Group III >65 yrs, Group IV FBS<145.9, Group V FBS>145. Each group was administered 4 gm of diabegon daily. Blood glucose levels, lipid profile, liver and kidney function of the subjects were regularly monitored within 3 months of interval to 18 months. RESULTS: The reduction in fasting blood glucose level ranged from 12.3% (P<0.05) to 42% (P<0.001) after 18 month of therapy whereas in postprandial blood glucose, the decrease ranged from 28% (P<0.05) to 32% (P<0.05) after 18 month of therapy. Overall reductions in the individual parameters of the metabolic syndrome subjects were significantly higher in Group I. Cholesterol level decreased from 11% to 27.2% (P<0.001), triglyceride levels decreased from 24% to 55%, VLDL and LDL levels reduced by 60% & 54% respectively after 18 months of therapy. The HDL C level increased in all groups. Moreover, diabegon administration for 1.5 years exhibited no alteration in liver and kidney function tests, which indicate its non-toxicity. CONCLUSION: Our study suggests that diabegon could be included as a preventive treatment in metabolic syndrome subjects with type 2 diabetes especially for long term treatment as it efficiently shows anti-hyperglycemic and anti-lipidemic effects with no adverse impacts on the liver and kidney. PMID- 25435606 TI - Comparison of physicochemical and functional properties of flour and starch extract in different methods from Africa locust bean (Parkia biglobosa) seeds. AB - BACKGROUND: African locust bean tree is an important food tree for both human and livestock such as husks and pods. It plays a very vital role in the rural areas. The aim of this study was to evaluate some physicochemical, mineral characteristics and functional properties of flour and starch extract produced from Parkia biglobosa seeds, using different methods. MATERIALS AND METHODS: Three different methods were used for starch extraction in other to get the Starch yield (%),composition analysis for; moisture, protein, fat, ash and fiber contents of flour and starch extracts from Parkia biglobosa were determined on dry basis (db), by AACC method, color and PH value measurements was carried out using color flex spectrocolorimeter, and the official method of AOAC respectively. Pasting properties was determined and X-ray powder starch diffraction was used to examine the crystalline property of flour and starch extract. Gelatinization characteristics and in vitro starch digestibility were also determined, test results were processed using one-way analysis of variance (ANOVA). RESULTS: Flour showed higher (P < 0.05), moisture content, fat, carbohydrate, amylopectine, and protein content than starch, while amylose content of this starch was higher (P<0.05). Phosphorus, sodium, magnesium, and potassium minerals content were higher in flour than starch. Pasting properties, gelatinisation, color, pH values, water and oil absorption capacity content of the flour were found to be higher than that of starch. The pasting characteristics showed a decrease of viscosity, final viscosity, set back value, breakdown, and pasting temperature of flour when compared to that of starch. CONCLUSION: From our results, we speculate that flour from native Parkia biglobosa grown in Guinea under controlled environmental conditions could be considered as an ideal RS material, whereas the extract Parkia starch could be an ideal SDS material. Therefore, these may offer an interesting alternative for food developers, depending on their characteristics and functional properties. PMID- 25435605 TI - Antidiarrheal mechanism and ionic profile of Carpolobia lutea ethanolic stem-bark extract in rats. AB - BACKGROUND: The stem-bark extract of Carpolobia lutea (Polygalaceae), used in ethno-medicine as anti-diarrhea was pharmacologically evaluated. This was the first report of assessment of the ethanolic stem extract (ESE), of C. lutea as anti-diarrhoeal agent in rats. The anti-diarrhoeal effects, acute toxicity and ionic profile are investigated and reported. MATERIALS AND METHODS: The acute toxicity was established using Lock's method. The anti-diarrhoeal effects were demonstrated using castor oil-induced diarrheal and fluid accumulation and its effect on normal intestinal transit. The mechanism elucidated using yohimbine, isosorbide dinitrate, and diphenoxylate. The elemental and ionic profile of ESE was established using inductively coupled argon-plasma emission spectrometer and potentiometric titration respectively. The finger print of ESE was revealed by Jasco (Tokyo, Japan), HPLC and active compounds by phytochemical screening using standard procedure. RESULTS: The LD50 obtained is 866.025 mg/kg (i.p). The doses of 43.3, 86.6, and 173.2 mg/kg of ESE showed inhibition of castor oil-induced diarrheal (p<0.05 -0.001). The most abundant cations in the extract are potassium and phosphorus (1.00 +/-0.01 and 0.80 +/- 0.030 mg/g respectively); while the most abundant anions are phosphate and sulphate (33.50+/-7.09 and 7.19+/-3.29 mg/g respectively). The HPLC fingerprint of ESE revealed UV spectra of biomolecules. Phytochemical screening revealed presence of saponins, polyphenols and glycosides. CONCLUSION: These investigations indicate presence of bioactive and elemental substances which could play major role in diarrheal management. This investigation justifies the use of stem-bark of C. lutea in illicit gin (akpatashi), among the Effiks in Nigeria as antidiarrheal. PMID- 25435607 TI - Study on the anti-depressant effect of Chaihu Guizhi decoction and its mechinisims of actions. AB - BACKGROUND: Chaihu Guizhi has the effects of treating exogenous wind-cold; alternating episodes of chills and fever; noisy nose and retching; strong headache; chest and rib-side pain, and fullness, in clinical practice, it can also be used for the treatment of depression. The objective of this paper was to study the anti-depressant effect of Chaihu Guizhi decoction and its mechanism. MATERIALS AND METHODS: The anti-depressant effect of Chaihu Guizhi decoction was investigated by forced swimming test, tail suspension test and antagonism of reserpine hypothermia test in mice. RESULTS: Chaihu Guizhi decoction could significantly shorten immobility time of mice in the forced swimming test, and dose-dependence significantly shorten immobility time of mice in the tail suspension test, after administration of 50, 100, and 200mg/kg, Chaihu Guizhi decoction, a significant dose-dependent antagonism of reserpine-induced hypothermia was observed in mice of each treatment group. CONCLUSION: Chaihu Guizhi decoction has an antidepressant effect. PMID- 25435608 TI - Evaluation of the essential oil of Foeniculum vulgare Mill (fennel) fruits extracted by three different extraction methods by GC/MS. AB - BACKGROUND: Hydrodistillation (HD) and steam-distillation, or solvent extraction methods of essential oils have some disadvantages like thermal decomposition of extracts, its contamination with solvent or solvent residues and the pollution of residual vegetal material with solvent which can be also an environmental problem. Thus, new green techniques, such as supercritical fluid extraction and microwave assisted techniques, are potential solutions to overcome these disadvantages. MATERIALS AND METHODS: The aim of this study was to evaluate the essential oil of Foeniculum vulgare subsp. Piperitum fruits extracted by three different extraction methods viz. Supercritical fluid extraction (SFE) using CO2, microwave-assisted extraction (MAE) and hydro-distillation (HD) using gas chromatography-mass spectrometry (GC/MS). RESULTS: The results revealed that both MAE and SFE enhanced the extraction efficiency of the interested components. MAE gave the highest yield of oil as well as higher percentage of Fenchone (28%), whereas SFE gave the highest percentage of anethol (72%). CONCLUSION: Microwave assisted extraction (MAE) and supercritical fluid extraction (SFE) not only enhanced the essential oil extraction but also saved time, reduced the solvents use and produced, ecologically, green technologies. PMID- 25435609 TI - Pharmacological experimental study of the anti-depressant effect of total saikosaponins. AB - BACKGROUND: Chai Hu has the hepato-protective, choleretic, anti-tussive, analgesic, anti-inflammatory, anti-viral, hypotensive, hypolipidemic, and anti tumor pharmacological effects. In this study, the objective of this paper was to study the anti-depressant effect of total saikosaponins. MATERIALS AND METHODS: Total saikosaponins were extracted by reflux method, and were identified by thin layer chromatography (TLC). The anti-depressant effect of total saikosaponins was investigated in vitro by tail suspension test, forced swimming test, and reserpine antagonism test in mice. RESULTS: Two times of reflux extraction, temperature of 70 degrees C, and extraction time of 4hrs, for each extraction could improve the yield of saikosaponins. Each treatment group (100, 200, and 300 mg/kg), could significantly shorten the immobility time of mice in the tail suspension test in a somewhat dose-dependent manner. The total saikosaponins antagonized the reserpine-induced akinesia, and ptosis in mice. CONCLUSION: Total saikosaponins have an anti-depressant effect. PMID- 25435610 TI - Effects of Ficus thonningii extracts on the gastrointestinal tract and clinical biochemistry of suckling rats. AB - BACKGROUND: Ficus thonningii is commonly used in traditional medicine across the African continent. We investigated the effects of crude Ficus thonningii extracts on growth, morphology and morphometry of the abdominal viscera and clinical biochemistry of neonatal rats. MATERIALS AND METHODS: Forty, 6-day old Sprague Dawley rat pups were orally gavaged once daily with either low (50 mg.kg(-1) b.w) or high (500 mg.kg(-1) b.w) doses of aqueous or methanolic F. thonningii leaf extracts while the control received distilled water. After 7 days of treatment, the pups were euthanased and gross morphometric measurements of the abdominal visceral organs were recorded. Samples of the liver, caecum and proximal small intestine were processed for histology. Plasma biochemical parameters were analysed colorimetrically. RESULTS: High methanolic doses of F. thonningii extracts exhibited trophic effects on the stomach while both aqueous and methanolic extracts had trophic effects on the ceacal mucosa of rats. No significant growth-promoting effects were observed in other visceral organs. Histological analysis revealed no mucosal damage or necrosis. Clinical biochemistry parameters were not abnormally altered. There was a significant decrease (p<0.05, ANOVA) in the plasma concentration of non-fasting glucose in the high methanolic group but triglycerides and cholesterol were unaltered. CONCLUSION: The findings suggest that at low doses, F. thonningii extracts can be safely used without the risk of any disruption in the structural integrity of the neonatal rat GIT and function of the liver and kidneys. PMID- 25435611 TI - Investigation on antidiarrhoeal activity of Aristolochia indica Linn. Root extracts in mice. AB - BACKGROUND: The present study aimed at investigating the effect of ethanolic extract (EtAI), and aqueous extract (AqAI) of Aristolochia indica Linn roots on castor oil-induced diarrhoea and study on small intestinal transit. Phytochemical analysis of extracts was performed as per standard procedure. MATERIALS AND METHODS: The oral toxicity study using Swiss albino mice was performed in accordance with OECD guidelines. The EtAI and AqAI extracts of Aristolochia indica Linn were studied for antidiarrhoeal property using castor oil-induced diarrhoeal model and charcoal-induced gastrointestinal motility test in Swiss albino mice. RESULTS: Among the tested doses of 200 and 400 mg/kg body weight, the extracts reduced the frequency and severity of diarrhoea in test animals throughout the study period. At the same doses, the extract delayed the intestinal transit of charcoal meal in test animals as compared to the control and the results were statistically significant. CONCLUSION: Experimental findings showed that ethanol extract of Aristolochia indica Linn root possess significant antidiarrheal activity and may be a potent source of anti-diarrhoeal drug in future. PMID- 25435612 TI - The use of alternative methods in reducing menopausal complaints in Turkey. AB - BACKGROUND: Millions of women experience menopause every year, therefore the aim of this study is to determine the rates of application of alternative methods applied by women in order to reduce their complaints caused by menopause and alternative application methods. MATERIALS AND METHODS: This study was carried out on 246 women in their menopausal period. The data was obtained by the researcher through face to face interviews during the home visits. During the collection of data, a questionnaire form by the researcher that was developed in accordance with the literature information was applied. RESULTS: 37.4% of women were determined to use alternative methods to reduce their menopausal symptoms. In the consequence of statistical analysis, a significant relation was found between the menopausal complaints such as hot flashes, night sweats and sleeping problem and the use of alternative methods in order to reduce their menopausal complaints (p<0.05). CONCLUSION: It was determined that the women at their menopausal ages experienced vasomotor complaints and sleeping problems and they used alternative methods to reduce those problems. PMID- 25435613 TI - An assessment of traditional Uighur medicine in current Xinjiang region (China). AB - BACKGROUND: The main objectives of this study were to assess the current research and development of traditional Uighur medicine in Xinjiang (China), and to evaluate the promising pharmacological products of traditional Uighur medicine for further studies. MATERIALS AND METHODS: Traditional Uighur medicine data of medicine registry, patent, and academic publications was collected and analyzed. RESULTS: Data showed that, among the registered and studied traditional Uighur medicine, the main therapeutic areas of traditional Uighur medicine focused on skin disease, urogenital disease, rheumatism and digestive system disease. The representative traditional Uighur patent medicine included the following: BaixuanXiatare Tablets, Kaliziran Tincture and Vernoniaanthelmintica Injection (Psoriasis and vitiligo); Xi-payimazibiziLiquid (prostatitis); KursiKaknaq (urinary tract infection); Tongzhisurunjiang Capsules (anti-rheumatism medicine); HuganBuzure Granules (digestive system disease). Moreover, ten Uighur herbs were widely used, including: ResinaScammoniae, Folium FumicisDentati, HerbaDracocephali, Semen AmygdaliDulcis, HerbaChamomillae, FructusPimpinellaeanisi, Cortex Foeniculi, FructusVernoniae, FructusApii, and Radix AnacycliPyrethri. CONCLUSION: This study concluded by indicating that traditional Uighur medicine with excellent curative effect should be screened in details for their phytochemical properties and pharmacological activity to discover new bioactive constituents. PMID- 25435614 TI - In-vitro screening of Malaysian honey from different floral sources for antibacterial activity on human pathogenic bacteria. AB - BACKGROUND: Different researches on therapeutic effects of honey have been conducted in different regions; however the study on the potential antibacterial activity of Malaysian honey is still limited. In this study, antibacterial activities of different monofloral honey samples were tested against several common human pathogenic bacteria. MATERIALS AND METHODS: The well-diffusion method, minimum inhibitory concentrations (MIC) and minimum bactericidal concentration (MBC) techniques were employed to investigate the putative antibacterial activity of Malaysian monofloral honey from Koompassia excelsa (Becc.) Taub (Tualang), Melaleuca cajuputi Powell (Gelam) and Durio zibethinus Murr. (Durian). Honey samples were tested against Staphylococcus aureus ATCC6518 and ATCC25923, Staphylococcus epidermidis ATCC12228, Enterococcus faecium LMG16192, Enterococcus faecalis LMG16216 and ATCC29212, Escherichia coli ATCC25922, Salmonella enterica serovar Typhimurium ATCC14028 and Klebsiella pneumoniae ATCC13883. RESULTS: Marked variations were observed in the antibacterial activity of these honey samples. Durian honey failed to produce substantial antibacterial activity, whereas Tualang and Gelam honey showed a spectrum of antibacterial activity with their growth inhibitory effects against all of the tested bacterial species including vancomycin-resistant enterococci (VRE). CONCLUSION: Present findings suggested Gelam honey possesses highest antibacterial effect among the tested Malaysian honey samples. PMID- 25435615 TI - A new bioactive thiophenolic glycoside from the leaf of Massularia acuminata (g. Don Bullock) ex Hoyle (Rubiaceae). AB - BACKGROUND: Massularia acuminata is a small tree or shrub of tropical rainforest. The leaves are used in Nigerian ethno-medicine for the treatment of microbial infections and pharmacological report suggested the leaf extract as possessing antioxidant activity. This study was therefore carried out to determine the most antioxidant and antimicrobial active fraction(s) of Massularia acuminata leaf and the constituent(s) responsible for the activities. MATHERIALS AND METHODS: The leaf of Massularia acuminata was investigated for in vitro antioxidant and antimicrobial activities, using a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and agar dilution method respectively. RESULTS: The ethyl acetate fraction demonstrated the best activities among the partitioned fractions tested. Bioassay guided purification of the most active ethyl acetate fraction led to isolation of a new thiophenolic glycoside, characterized as 4-(3',3' dihydroxy-1-mercaptopropyl)phenyl glycosylpyranoside. CONCLUSION: The isolated compound from the leaf of Massularia acuminata demonstrated antioxidant and antimicrobial activities and may be responsible for the activities of leaf extract and its ethyl acetate fraction, hence this may justify its ethnomedicinal use. PMID- 25435616 TI - Cytotoxicity of three South African medicinal plants using the Chang liver cell line. AB - BACKGROUND: Arctotis arctotoides, Gasteria bicolor and Pittosporum viridiflorum are commonly used in the Eastern Cape, South Africa by traditional healers for the treatment of opportunistic fungal infections in HIV/AIDS patients. Unfortunately, there is a dearth of published data regarding the toxicity of the selected plants, despite the fact that experimental screening of toxicity is crucial to guarantee the safety of the users. MATERIALS AND METHODS: Therefore, it was decided to evaluate the cytotoxicity of the hexane and acetone extracts of the medicinal plants against the Chang Liver cell line using the in vitro MTT assay. Different concentrations of the extracts were added into 24-hour cultured cells and incubated for 72 hours under specific condition (37 degrees C, 5% CO2). Cell survival was evaluated using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) assay. RESULTS: Depending on the dosage and duration of treatment, the cytotoxic effects of Gasteria bicolor and Pittosporum viridiflorum were considered relatively weak (but not entirely absent) and less of a toxicity risk. Arctotis arctotoides extracts were the most toxic both in terms of IC50 values as well as the steeper slope of the dose response curve. The IC50 values for the acetone and hexane extracts of this plant were 17.4 and 12.4 ug/ml respectively. CONCLUSION: These relatively low values raise concern for potential hepatotoxic effects and deserve further investigation or at least a warning to potential users. PMID- 25435617 TI - GA3-mediated dormancy alleviation in the reputed African potato, Hypoxis hemerocallidea. AB - BACKGROUND: Hypoxis hemerocallidea, arguably the most well-known medicinal species in South Africa, has been the subject of intensive harvesting from the wild leading to recent conservation concerns. The seeds of this species do not propagate easily and can lie dormant for up to twelve months. MATERIALS AND METHODS: In the in vitro germination experiments water, acid and chemical pre sowing treatments were performed to determine the germination response of this species in both light and dark conditions. In the ex vitro experiment, intact seeds were sown and left to germinate in a potting soil mix under greenhouse conditions. RESULTS: Highest levels of germination (36.7-60.0% in the light and 36.7-46.7% in the dark) were achieved by treating mechanically scarified seeds with GA3 at various concentrations for 24 h. This was followed by scarified seeds soaked in water (26.7% in the light and 23.3% in the dark). Similar results (23.3 and 26.7%) were obtained in the 1% and 4% KNO3 treatments, respectively, under light conditions only. The fastest time to germinate was two days and was obtained in the 1200 ppm GA3 treatment in both light and dark conditions. Ex vitro germination of H. hemerocallidea seeds under greenhouse conditions was unsuccessful. CONCLUSION: H. hemerocallidea displays physical and non-deep physiological dormancy where pre-sowing treatments are required before the seeds will germinate. PMID- 25435618 TI - Studies on the identification of constituents in ethanol extract of Radix Glycyrrhizae and their anticancer activity. AB - BACKGROUND: The main functions of Radix Glycyrrhizae include regulating middle warmer, moistening lung, relieving toxicity, harmonizing property of drugs which is a traditional Chinese medicine widely used in clinical settings. The objective of the paper is to isolate and identify the constituents in ethanol extract of Radix Glycyrrhizae, and to study their anticancer activity. MATERIALS AND METHODS: Column chromatography, ODS column chromatography, preparative thin layer chromatography and NMR spectroscopy techniques were used to isolate compounds from ethanol extract of Radix Glycyrrhizae; optical microscopy and flow cytometry were used to determine the anticancer effect of Radix Glycyrrhizae extract. RESULTS: Four compounds were isolated from the ethanol extract of Radix Glycyrrhizae, namely oleanolic acid, isoliquiritin, glycyrrhetinic acid and licochalcone A. Optical microscopic observation showed that the growth of gastric cancer cell line SGC-7901 was inhibited in the experimental groups, and apoptotic morphological changes were observed in adherent cells; flow cytometry with PI staining showed that Radix Glycyrrhizae extract could induce SGC-7901 cell apoptosis within a concentration range of 0.5-1.5 mg/mL, compared with the control group, the apoptosis was positively correlated with the drug concentration, which exhibited an apparent dose-dependence. CONCLUSION: We conclude Ethanol extract of Radix Glycyrrhizae has an anti-proliferative activity on SGC-7901 cells. PMID- 25435619 TI - Iron deficiency anaemia in reproductive age women attending obstetrics and gynecology outpatient of university health centre in Al-Ahsa, Saudi Arabia. AB - BACKGROUND: Iron deficiency is the most common nutritional disorder in the world. The aim of this questionnaire based survey study was to determine the prevalence of iron deficiency anemia in reproductive age women, and their relation to variables such as age, marital status, education with those attending obstetrics and gynecology outpatient of King Faisal University Health Centre in Al-Ahsa in eastern region of Kingdom of Saudi Arabia. MATERIALS AND METHODS: This study was conducted for the period of 6 month staring from September 2012 to February 2013. The questionnaire had three sections on personal information: their educational indicators, gynecological clinical history, and hematological indices. RESULTS: The average age was 25.97+/-7.17 years. According to the gynecological clinical history of the respondents, 15 (48.4%) respondents were pregnant while 16 (51.6%) were not pregnant. There was significant effect of pregnancy status on Hb level. Majority of the anemic respondents 15/17 were married. Moreover 14/17 anemic women were experiencing severe menstrual bleeding, 11/17 respondents were pregnant. 54.8% of respondents were hemoglobin deficient while 77.4% were found to have low Hct. In 87.1 % of the respondents, transferrin saturation was found to be abnormal. CONCLUSION: In this study iron deficiency anemia is quite prevalent in the university community especially among pregnant women. The fetus's and newborn infant's iron status depends on the iron status of the pregnant woman and therefore, iron deficiency in the mother-to-be means that growing fetus probably will be iron deficient as well. Thus iron deficiency anemia during pregnancy in well-educated set up needs more attention by the concerned authorities. PMID- 25435620 TI - Use of Chinese medicine among colorectal cancer patients: a nationwide population based study. AB - BACKGROUND: Traditional Chinese medicine (CM) appears to be used worldwide, especially by cancer patients. The aim of the present study was to explore CM uses and CM non-users by patients with colorectal cancer (CRC). MATERIALS AND METHODS: A retrospective study was conducted using registration and claims data sets for 2007 from the National Health Insurance Research Database. Patients with colorectal cancer were identified from the Registry for Catastrophic illness Patients. Binary logistic regression was used to estimate odds ratios as the measure of association with the use of CM. RESULTS: A total of 61,211 CRC patients diagnosed in 2007 were analysis. Most CM users preferred to visit private clinics (46.9%) with 306,599 visits. In contrast, the majority of CM non users preferred to visit private hospitals (42.2%) with 538,769 visits. Among all 176,707 cancer-specific CM visit, there were 66.6% visits to CM outpatient department (OPD) of private hospitals, while in 477,612 non-cancer-specific CM visits, 62.0% was for private clinics. The proportion of expenses for diagnostic fees for CM user in CM visits was much less than that for WM visits and CM non users (US$4.6 vs. 29.3 vs. 33.5). The average cost for CM user in CM was less than that for WM visits and CM non-users (US$6.3 vs. 25.9 vs. 30.3). Female patients, younger age, and patients not living in the northern region, with higher EC or more comorbidities were more likely to receive CM treatment. CONCLUSION: The prevalence and costs of insurance-covered CM among CRC patients were low. Further longer longitudinal study is needed to follow up this trend. PMID- 25435621 TI - The foliar anatomy and micromorphology of Aloe ferox Mill. (Asphodelaceae). AB - BACKGROUND: The genus Aloe has been the subject of several chemotaxonomic and phytochemical investigations. Aloe ferox is an important source of biologically active compounds like anthrones, chromones, pyrones, and flavonoids. It is a plant used extensively in traditional medicine. Despite the myriad of studies on the pharmacological profile of the plant, there still exists a dearth of scientific literature on the anatomical and morphological attributes of this important medicinal plant. MATERIALS AND METHODS: Hence, the objective of this study was to examine the foliar anatomy and micromorphological characteristics of A. ferox using light microscope and scanning electron microscope and to determine the elemental composition of the leaf sections by energy dispersive x-ray spectroscopy. RESULTS: Epidermal cells varied from round, square to hexagonal, with distinctive anticlinal walls and sunken stomata, equally distributed on both the adaxial and abaxial surfaces were observed. There were vertically elongated palisade cells with numerous chloroplasts in the palisade mesophyll layer. The EDXS analysis revealed Ca, K, S, Al, Mg, and Si as the major constituents of crystals present in the mesophyll. CONCLUSION: Information on the foliar anatomy and micromorphology can further enlightened our perceptions on the inherent interrelationships between structure and function as regards the synthesis and secretion of bioactive secondary metabolites by plants. PMID- 25435622 TI - Study on the extraction process of total anthraquinones in Radix et Rhizoma Rhei and their antilipemic effects. AB - BACKGROUND: Radix et Rhizoma Rhei has a gastric mucosal protective effect, major anti-gastritis and anti-peptic ulcer active constituents were emodin, aloe emodin, chrysophanol, rhein, etc. The objective of the study was the extraction process of total anthraquinones in Radix et Rhizoma rhei and their antilipemic effects. MATERIALS AND METHODS: Orthogonal experiment, UV spectrophotometry and conventional antilipemic effect determination method were used to optimize the extraction process, and to determine the total anthraquinone content, as well as blood levels of total cholesterol, triglycerides, HDL and LDL. RESULTS: Ethanol concentration, extraction time and ethanol amount had significant influences on the extraction of total Radix et Rhizoma rhei anthraquinones, total Radix et Rhizoma rhei anthraquinones could significantly reduce blood levels of total cholesterol, triglycerides, HDL and LDL. CONCLUSION: The optimum extraction process was two times extraction of Radix et Rhizoma rhei with 70% ethanol, the amounts of solvent of 8 folds and 5 folds, successively, and the extraction time of 60 min each. In addition, this extract has an antilipemic effect in mice. PMID- 25435623 TI - Analysis and study on 47 cases of adverse reactions of Chinese medicine injection. AB - BACKGROUND: Along with efficacy, Chinese medicine is increasingly being known to people, Chinese medicine and its preparations are increasingly widespread in clinical use. People generally believe that Chinese medicine has few side effects and is safe, especially Chinese medicine injections. Due to the direct injection in blood, rapid onset and good efficacy, they are welcomed by people. However, with increased use, adverse reactions are increasing, even causing serious consequences. The objective is to learn about the characteristics and laws of the adverse effects of Chinese medicine injections, provide references for the clinical safe drug use, and reduce the incidence of adverse reactions. MATERIALS AND METHODS: The method was established to analyze the data of 47 cases of adverse reactions caused by Chinese medicine injections in our hospital from the year, 2009 to 2010. RESULTS: The organs / systems involved in the 47 cases of adverse reactions are primarily skin and its accessories and secondly systemic damage, involving a total of eight varieties of drugs. CONCLUSION: The adverse reactions of Chinese medicine injections are mostly in Chinese patent drugs, which should be paid attention to, to find out the problems and laws, use the drugs rationally, and reduce the incidence of the adverse reactions. PMID- 25435625 TI - Market survey on traditional medicine of the third month fair in Dali Prefecture in Yunnan Province, South West China. AB - BACKGROUND: The Third Month Fair in Dali is a historical festival and fair. The market of traditional medicine (TM) is one of the main parts in the fair, which has important influence on local and peripheral people. MATERIALS AND METHODS: In this study, approaches of ethnobotany, pharmacognosy, and participatory rural appraisal were used in market survey. Twenty-six druggists were selected randomly as informants and their TMs were recorded. RESULTS: As a result, 427 TMs were recorded including 362 plant medicines, 33 animal medicines, 13 mineral medicines and 19 unidentified medicines. Xinyi, Shanza and Gancao were the most popular medicines due to their popular usages, whereas Sanqi, Tianma and Renshen were relatively fewer in this investigation probably owing to high price and limited output. The plant medicines were from medicinal plants of 117 families belonged to Angiosperm, Gymnospermae, Pteridophyta, Bryophyta, Lichenes and Fungi. Asteraceae, Apiaceae and Fabaceae provided the maximum numbers of TMs successively. Moreover, these TMs were mainly from the cultivated especially familiar TMs, which reflected significant progress in utilization and conservation of medicinal resource in China. CONCLUSION: Medicinal market in the Third Month Fair is the most important traditional bazaar in Yunnan province. This study systematically surveyed TMs in the fair for the first time, analyzing and revealing resource compositions and current market situations. These newly gathered data provided precious information for development of medicine cultivation, resource protection and market management as well as further pharmacognostical, pharmacological and clinical researches. PMID- 25435624 TI - Genes underlying positive influence of prenatal environmental enrichment and negative influence of prenatal earthquake simulation and corrective influence of Chinese herbal medicine on rat offspring: Irf7 and Ninj2. AB - BACKGROUND: Prenatal environmental enrichment (EE) has been proven to positively affect but prenatal stress negatively influence the physiological and psychological processes in animals, whose trans-generational genetic mechanism remains unclearly defined. We aimed to investigate and find out key genes underlying the positive-negative effects derived from prenatal interventions. MATERIALS AND METHODS: Pregnant rats were randomized into EE group (EEG), earthquake simulation group (ESG), herbal group (HG) received herbal supplements in feed after earthquake simulation, and control group (CG). RESULTS: Light Box Defecation Test (LBDT) showed EEG offspring presented less fecal pellets than CG offspring, ESG's more than CG's, and HG's less than ESG (p's<0.05). Open-field Test (OFT) score of EEG was higher than CG offspring, of ESG's was lower than CG's, and HG's higher than ESG's. Irf7 and Ninj were screened, which were up regulated in EEG, down-regulated in ESG (FC<0.5), and were neutralized in HG. Prenatal EE could positively promote the nervous system development, prenatal earthquake simulation could retard the nervous system development and Chinese herbal remedy (JKSQW) which could correct the retardation. CONCLUSION: The negative-positive prenatal effect could contribute to altered gene expression of Irf7 and Ninj2 which also could play a key role in the improving function of JKSQW for the kidneys. PMID- 25435626 TI - Evaluation of the anti-arthritic activity of the hydroethanolic leaf extract of Alchornea cordifolia in rats. AB - BACKGROUND: Different decoctions of Alchornea cordifolia leaves are used by Yoruba herbalists (Southwest Nigeria) for the local treatment of ulcers, rheumatic pains, febrile convulsions, and for enhancing physical performance. MATERIALS AND METHODS: In this study, the anti-arthritic effect of 100 - 400 mg/kg/day of the hydroethanolic leaf extract of Alchornea cordifolia (HEAC) was investigated in Complete Freund's Adjuvant (CFA)-induced arthritic rats as a way of evaluating its efficacy in the local management of arthritis. In addition, the effects of HEAC on liver and renal function parameters as well as its effect on the antioxidant enzyme system were investigated. Arthritis was induced using 0.1 ml of 10 mg/ml of Complete Freund's Adjuvant (CFA) following 1 h oral pretreatment and 8(th) day post-arthritic induction with 100, 200 and 400 mg/kg/day of HEAC and 3 mg/kg/day of celecoxib as the reference drug. The anti arthritic activity of HEAC was assessed based on the ability of HEAC to alter the paw edema diameter, body weight, full blood count, renal and liver function markers, glycoprotein, lysosomal enzymes and possible antioxidant potential in the arthritic rats. RESULTS: Oral pretreatment with 100, 200, and 400 mg/kg/day of HEAC produced significant (p<0.001, p<0.05 and p<0.01) reductions in the paw edema diameter in a non-dose dependent fashion in ACF-induced arthritic rats with the 100 mg/kg/day of HEAC producing the most significant anti-arthritic effect. Similarly, HEAC increased hepatic GSH levels, CAT and SOD activities suggesting possible antioxidant mechanism for its anti-arthritic effect. CONCLUSION: Overall, results of this study lend credence to the folkloric use of water decoction of Alchornea cordifolia leaves against rheumatoid arthritis. However, further pharmacological investigations would be required at isolating and determining the active anti-arthritic molecule(s) in HEAC in the nearest future. PMID- 25435627 TI - Experimental study on the optimization of extraction process of garlic oil and its antibacterial effects. AB - BACKGROUND: Garlic oil which is the main active constituent of garlic has a wide range of pharmacological activities, and a broad antibacterial spectrum. It also has a strong anti-cancer activity, and can significantly inhibit a variety of tumors such as liver cancer, gastric cancer and colon cancer. The objective is to study the extraction process of garlic oil and its antibacterial effects. MATERIALS AND METHODS: CO2 Supercritical extraction was used to investigate the optimal processing conditions for garlic oil extraction; filter paper test and suspension dilution test were applied to determine the bacteriostatic action of garlic oil. RESULTS: In the CO2 supercritical extraction experiment, factors influencing the yield of garlic oil were: extraction pressure > extraction temperature > extraction time in descending order. Range analysis showed that the optimal experimental conditions for CO2 supercritical extraction of garlic oil were extraction pressure of 15 Mpa, temperature of 40 degrees C, and duration of 1 h. Different concentrations of garlic oil could all inhibit the growth of Staphylococcus aureus, Escherichia coli and Bacillus subtilis, suggesting that garlic oil has an antibacterial effect. CONCLUSION: The optimal experimental conditions for CO2 supercritical extraction of garlic oil were: extraction pressure of 15 Mpa, temperature of 40 degrees C, and duration of 1 h; garlic oil has an antibacterial effect. PMID- 25435628 TI - Protopine inhibits heterotypic cell adhesion in MDA-MB-231 cells through down regulation of multi-adhesive factors. AB - BACKGROUND: A Chinese herb Corydalis yanhusuo W.T. Wang that showed anticancer and anti-angiogenesis effects in our previous studies was presented for further studies. In the present study, we studied the anticancer proliferation and adhesion effects of five alkaloids which were isolated from Corydalis yanhusuo. MATERIALS AND METHODS: MTT dose response curves, cell migration assay, cell invasion assay, as well as three types of cell adhesive assay were performed on MDA-MB-231 human breast cancer cells. The mechanism of the compounds on inhibiting heterotypic cell adhesion were further explored by determining the expression of epidermal growth factor receptor (EGFR), Intercellular adhesion molecule 1 (ICAM-1), alphav-integrin, beta1-integrin and beta5-integrin by western blotting assay. RESULTS: In five tested alkaloids, only protopine exhibited anti-adhesive and anti-invasion effects in MDA-MB-231 cells, which contributed to the anti-metastasis effect of Corydalis yanhusuo. The results showed that after treatment with protopine for 90 min, the expression of EGFR, ICAM-1, alphav-integrin, beta1-integrin and beta5-integrin were remarkably reduced. CONCLUSION: The present results suggest that protopine seems to inhibit the heterotypic cell adhesion between MDA-MB-231 cells, and human umbilical vein endothelial cells by changing the expression of adhesive factors. PMID- 25435629 TI - Contribution of plants and traditional medicines to the disparities and similarities in acute poisoning incidents in Botswana, South Africa and Uganda. AB - BACKGROUND: Acute poisoning incidents are one of the leading causes of morbidity and hospitalization in several countries. The purpose of this analysis was to compare the patterns of acute poisoning in three countries namely, Botswana, South Africa and Uganda; and examine the similarities and disparities in the patterns of occurrence of acute poisoning based on the sociodemographic factors of the victims, the toxic agents involved, the circumstances surrounding the incidents and their outcomes. MATERIALS AND METHODS: This paper is based on the re-analysis of data that were collected from January to June 2005 by some Master of Public Health students using a similar data collection tool. A single dataset made of the original individual datasheets was constituted and analysed. RESULTS: Overall, it was found that the mean age of victims of acute poisoning was 20.9 +/ 14.5 years; the youngest victim was a 3 months old boy from South Africa; and the oldest was a 75 years old man from Uganda. In descending order, the most common toxic agents involved in poisoning incidents were household products (46.1%), agrochemicals (18.8%), pharmaceuticals (14.0%), animal and insect bites (13.0%), food poisoning (4.5%), as well as plants and traditional medicines (3.6%). Across the three countries, acute poisoning occurred mainly by accident, but the contextual factors of each country led to a pattern of acute poisoning that showed some similarities with regard to the distribution of deliberate self poisoning among females, teenagers, and young adult victims. There were disparities related to the differential access to toxic agents, based on the age and gender of the victims. Of the 17 deaths reported, 2 (11.7%) were due to traditional medicines; household products were implicated in fatal outcomes in all three countries, though the extent of their involvement varied from country to country. CONCLUSION: Although plant and traditional medicines caused fewer cases of acute poisoning incidents, they contributed considerably to fatal outcomes. PMID- 25435630 TI - Improved growth and colchicine concentration in Gloriosa superba on mycorrhizal inoculation supplemented with phosphorus-fertilizer. AB - BACKGROUND: Gloriosa superba produces an array of alkaloids including colchicine, a compound of interest in the treatment of various diseases. The tuber of Gloriosa superba is a rich source of colchicine which has shown anti-gout, anti inflammatory, and anti-tumor activity. However, this promising compound remains expensive and Gloriosa superba is such a good source in global scale. Increase in yield of naturally occurring colchicine is an important area of investigation. MATERIALS AND METHODS: The effects of inoculation by four arbuscular mycorrhizal (AM), fungi, Glomus mossae, Glomus fasciculatum, Gigaspora margarita and Gigaspora gilmorei either alone or supplemented with P-fertilizer, on colchicine concentration in Gloriosa superba were studied. The concentration of colchicine was determined by high-performance thin layer chromatography. RESULTS: The four fungi significantly increased concentration of colchicine in the herb. Although there was significant increase in concentration of colchicine in non-mycorrhizal P-fertilized plants as compared to control, the extent of the increase was less compared to mycorrhizal plants grown with or without P-fertilization. This suggests that the increase in colchicine concentration may not be entirely attributed to enhanced P-nutrition and improved growth. Among the four AM fungi Glomus mossae was found to be best. The total colchicine content of plant (mg / plant) was significantly high in plants inoculated with Glomus mossae and 25 mg kg(-1)phosphorus fertilizer (348.9 mg /plant) while the control contain least colchicine (177.87 mg / plant). CONCLUSION: The study suggests a potential role of AM fungi in improving the concentration of colchicine in Gloriosa superba tuber. PMID- 25435631 TI - Hepatoprotective effect of Cymbopogon citratus aqueous extract against hydrogen peroxide-induced liver injury in male rats. AB - BACKGROUND: Cymbopogon citratus (Poaceae) a tropical perennial herb plant that is widely cultivated to be eaten either fresh with food or dried in tea or soft drink has been reported to possess a number of medicinal and aromatic properties. This study aimed at evaluating the protective effects of C. citratus aqueous extract against liver injury induced by hydrogen peroxide (H2O2), in male rats. MATERIALS AND METHODS: Twenty-five rats were randomly divided into five different groups of five animals in each group; (1) Control. (2) Received H2O2 (0.5%) with drinking water. (3), and (4) received H2O2 and C. citratus (100 mg.kg(-1) b wt), vitamin C (250 mg.kg(-1) b wt) respectively. (5), was given C. citratus alone. The treatments were administered for 30 days. Blood samples were collected and serum was used for biochemical assay including liver enzymes activities, total protein, total bilirubin and malonaldehyde, glutathione in serum and liver homogenates. Liver was excised and routinely processed for histological examinations. RESULTS: C. citratus attenuated liver damage due to H2O2 administration as indicated by the significant reduction (p<0.05), in the elevated levels of ALT, AST, ALP, LDH, TB, and MDA in serum and liver homogenates; increase in TP and GSH levels in serum and liver homogenates; and improvement of liver histo-pathological changes. These effects of the extract were similar to that of vitamin C which used as antioxidant reference. CONCLUSION: C. citratus could effectively ameliorate H2O2-induced oxidative stress and prevent liver injury in male rats. PMID- 25435632 TI - Antimicrobial and anti-inflammatory activities of Pleurostylia capensis Turcz (Loes) (celastraceae). AB - BACKGROUND: Pleurostylia capensis is a large tree that can reach the maximum height of 20 m long, and it have been traditionally used as cosmetic, for steam bath, ritual body wash, and as a purgative to treat symptoms of witchcraft. Using ethanol, chloroform, dichloromethane (DCM), ethyl acetate (EA), and water extracts, leaves, bark and roots of Pleurostylia capensis were investigated scientifically for their effectiveness in antimicrobial, antioxidant and anti inflammatory activities using standard methods. MATERIALS AND METHODS: The extracts were evaluated for antimicrobial activity against Gram positive (Staphylococcus aureus, Bacillus cereus, and Mycobacterium smegmatis), Gram negative (Escherichia coli, Klebsiella pneumonia, Klebsiella oxytoca, Streptococcus pyogenes, Pseudomonas aeruginosa and Salmonella typhimurium), and Candida albicans. The antioxidant activity was investigated using 2, 2-diphenlyl 1-picrylhadrazyl (DPPH), free radical scavenging assay. The anti-inflammatory activity of P. capensis extracts was evaluated against both cyclooxygenase enzymes (COX 1 and 2). RESULTS: The ethyl acetate extracts of P. capensis showed a strong antimicrobial activity against B. cereus, K. pneumonia, S. pyogenes, and M. smegmatis with MIC value of 0.39 and 0.78 mg/ml. While the ethanol bark extract was most active against M. smegmatis with MIC value of 0.78 mg/ml; the least potent activity was observed with dichloromethane, chloroform and water extracts, with an MIC value ranging from 1.56 mg/ml to 50.0 mg/ml. The plant extracts proved to be good antioxidant agent, whereas extracts of ethanol were the most active, with IC50 ranging from 1.00 to 1.74 ug/ml, which is lower, and in close range to Vitamin C (1.40 ug/ml). CONCLUSIONS: Its moderation to potent inhibitory activity was observed in all extracts. Ethanol and dichloromethane extracts were among the most potent when compared to water and petroleum ether extracts. The water extracts showed to be nontoxic on the Hek cell line with an IC50 value of 204.0, and 207.3 ug/ml (roots and bark) respectively. The dichloromethane, ethyl acetate, chloroform and ethanol extracts showed to be toxic on the Hek cell, with IC50 range from 5.94 to 42.91ug/ml. The results obtained indicate the effectiveness of these plants. PMID- 25435634 TI - Study on the antibacterial activity of Bergenia purpurascens extract. AB - BACKGROUND: Bergenia purpurascens has tonic, haemostatic and anti-tussive actions. Anti-inflammatory and anti-bacterial activities of Bergenia purpurascens have not been reported so far. The objective of this paper is to provide experimental basis for the clinical application of Bergenia purpurascens through the pharmacodynamic study on its anti-inflammatory and anti-bacterial effects. METHODS: Experimental models of xylene-induced ear edema in mice, cotton pellet granuloma in rats, and acetic acid-induced peritoneal capillary permeability in mice were used to investigate the anti-inflammatory effect of Bergenia purpurascens; bacteriostatic and bactericidal effects of Bergenia purpurascens extract on Staphylococcus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), and beta-lactamase positive Staphylococcus aureus (ESBLs-SA), were observed in vitro. RESULTS: The results show that Bergenia purpurascens extract could markedly inhibit xylene-induced mouse ear edema, cotton pellet granulation tissue hyperplasia, and increased capillary permeability. Bergenia purpurascens extract has an inhibitory effect on SA, MRSA and ESBLs-SA. CONCLUSION: We conclude that Bergenia purpurascens extract has certain anti-inflammatory and anti-bacterial effects. PMID- 25435635 TI - Electroacupuncturing at Zusanli point (ST36) attenuates pro-inflammatory cytokine release and organ dysfunction by activating cholinergic anti-inflammatory pathway in rat with endotoxin challenge. AB - BACKGROUND: It is considered that the pathogenesis is closely related to an excessive production of pro-inflammatory cytokines caused by bacterial toxins and an imbalance between pro-inflammatory and anti-inflammatory mediators. MATERIALS AND METHODS: This work investigates the effect of electro-acupuncturing (EA), at Zusanli point (ST36) on plasma cytokine release and organ dysfunction and their mechanism in conscious rats with endotoxin challenge. RESULTS: EA at Zusanli points obviously lowered the elevated levels of plasma TNF-alpha, and attenuated changes in parameters relevant to various organ functions at 2 h after LPS challenge. alpha-BGT injection or bilateral cervical vagotomy could weaken or eliminate the effects of EA, and further aggravated the elevated levels of pro inflammatory cytokines and organ dysfunction. CONCLUSION: The results suggested that EA at Zusanli points significantly reduced the release of pro-inflammatory cytokines and organ dysfunction after LPS challenge by activating cholinergic anti-inflammatory pathway. PMID- 25435633 TI - Restoration of glutamine synthetase activity, nitric oxide levels and amelioration of oxidative stress by propolis in kainic acid mediated excitotoxicity. AB - BACKGROUND: Propolis has been proposed to be protective on neurodegenerative disorders. To understand the neuroprotective effects of honeybee propolis, glutamine synthetase (GS) activity, nitric oxide (NO), thiobarbituric acid reactive substances (TBARS) and total antioxidant status (TAS) were studied in different brain regions-cerebral cortex (CC), cerebellum (CB) and brain stem (BS) of rats supplemented with propolis and subjected to kainic acid (KA) mediated excitotoxicity. MATERIALS AND METHODS: Male Sprague-Dawley rats were divided into four groups; Control group and KA group received vehicle and saline. Propolis group and propolis + KA group were orally administered with propolis (150mg/kg body weight), five times every 12 hours. KA group and propolis + KA group were injected subcutaneously with kainic acid (15mg/kg body weight) and were sacrificed after 2 hrs and CC, CB and BS were separated homogenized and used for estimation of GS activity, NO, TBARS, and TAS concentrations by colorimetric methods. Results were analyzed by one-way ANOVA, reported as mean + SD from 6 animals, and p<0.05 considered statistically significant. RESULTS: NO was increased (p< 0.001) and GS activity was decreased (p< 0.001) in KA treated group compared to control group as well as propolis + KA treated group. TBARS was decreased and TAS was increased (p< 0.001) in propolis + KA treated group compared KA treated group. CONCLUSION: This study clearly demonstrated the restoration of GS activity, NO levels and decreased oxidative stress by propolis in kainic acid mediated excitotoxicity. Hence the propolis can be a possible potential candidate (protective agent) against excitotoxicity and neurodegenerative disorders. PMID- 25435636 TI - Studies on resin purification process optimization of Eucommia ulmoides Oliver and its antihypertensive effect mechanism. AB - BACKGROUND: Through research it is found that the barks, stems, fruits and flowers of Eucommia ulmoides contain various compositions, such as lignin, cycloalkane and phenylpropanoids. The modern pharmacological research shows that Eucommia ulmoides has many functions, such as anti-aging, antitumor and bone cell proliferation. This paper studied the resin purification process optimization conditions and antihypertensive effect of Eucommia ulmoides Oliver. MATERIALS AND METHODS: The orthogonal experiment method was adopted to determine the purification effect of various macro-porous resins for eucommia ulmoides Oliver, and the SHR model was used to determine antihypertensive level of eucommia ulmoides Oliver. RESULTS: The optimal process of resin extraction and purification of Eucommia ulmoides Oliver was verified through the loading liquid concentration at 6 mg/ml, 20% ethanol used as the eluent; the flow rate control was 3.0, column volume per hour and the diameter-height ratio of adsorption column was 1:6; the extracts of Eucommia ulmoides Oliver can reduce SHR blood pressure, its antihypertensive effect is relatively stable and has no significant impact on HR, but the antihypertensive effect is lower than that of control medicine captopril. Also, the extracts of eucommia ulmoides Oliver can significantly increase the content of serum NO and reduce the content of ET. CONCLUSION: The Eucommia ulmoides Oliver can relax blood vessels, reduce the peripheral resistance, reduce the returned blood volume, and eventually achieve the antihypertensive effect. PMID- 25435637 TI - Investigation of antioxidant potentials of solvent extracts from different anatomical parts of Asphodeline anatolica E. Tuzlaci: an endemic plant to Turkey. AB - BACKGROUND: The genus Asphodeline (Liliaceae) is represented in Turkey by 20 taxa, which are traditionally used for medicinal purposes in Anatolia. MATERIALS AND METHODS: In this study, we tested the phytochemical content and antioxidant effect of different solvent extracts obtained from different anatomical parts of Asphodeline anatolica. The different extracts of each plant parts were tested for antioxidant activity using different chemical assays. The total antioxidant components were also calculated. RESULTS: Generally, acetone extracts produced the seed and root exhibited significantly higher antioxidant activity with high antioxidant components. Total phenolic content of extracts were significantly correlated with antioxidant potentials (except for, metal chelating activity). CONCLUSION: On the basis of the results obtained, A. anatolica extracts should be regarded as a valuable source of natural antioxidants for food and therapeutic applications. PMID- 25435639 TI - Preparing the Next Generation for Electoral Engagement: Social Studies and the School Context. PMID- 25435638 TI - Obsequies - late Prof. Marian Ewurama Addy. PMID- 25435640 TI - Analytically Derived Neighborhoods in a Rapidly Growing West African City: The Case of Accra, Ghana. AB - Large numbers of people are currently migrating from the poor, inland areas of West Coast Africa to the major cities of Lagos, Accra, Abidjan, and other budding metropolises (Figures 1 and 2). The infrastructure of the Sub-Saharan African cities is inadequate to service their burgeoning populations. An argument is presented for using scientifically derived neighborhoods as the building blocks for current African urban understanding and planning. In this paper, I will explore the neighborhood concept and use available data and new heterogeneity statistics to derive homogeneous neighborhoods. The statistics are explained and maps of Accra neighborhoods are given. PMID- 25435641 TI - Bound by Children: Intermittent Cohabitation and Living Together Apart. AB - In this article, we examine variations in low-income mothers' patterns of intermittent cohabitation and the voluntary and involuntary nature of these unions. Intermittent cohabitation involves couples living together and separating in repeating cycles. Using Three-City Study ethnographic data, we identified 45 low-income mothers involved in these arrangements, 18 of whom resided with their children's fathers occasionally while saying that they were not in a cohabiting relationship. We term such relationships living together apart (LTA). Data analysis revealed that distinct patterns of voluntary and involuntary separations and reunifications characterized intermittent cohabitation and LTA and that these relationships were shaped by the bonds that shared parenting created and the economic needs of both parents. We argue that these dimensions may explain some disparate accounts of cohabitation status in low-income populations. They also demonstrate previously unexplored diversity in cohabiting relationships and suggest further questioning contemporary definitions of families. PMID- 25435642 TI - Commentary on "Mediation analysis without sequential ignorability: Using baseline covariates interacted with random assignment as instrumental variables" by Dylan Small. AB - I applaud Dr. Small for advancing causal mediation analysis and thank the editors for the opportunity to comment on this valuable article. Small's project was to relax and test the assumptions on which a previously proposed model relies; in the second half of this discussion I will assess those assumptions and others on which the model hinges. But first I will review the various schools of mediation analysis and situate the estimand considered by Small within the somewhat esoteric domain of mediation estimands. PMID- 25435643 TI - Longitudinal Imaging and Deterioration in Word Comprehension in Primary Progressive Aphasia: Potential Clinical Significance. AB - BACKGROUND: Three variants of primary progressive aphasia (PPA), distinguished by language performance and supportive patterns of atrophy on imaging, have different clinical courses and the prognoses for specific functions. For example, semantic variant PPA alone is distinguished by impaired word comprehension. However, sometimes individuals with high education show normal performance on word comprehension tests early on, making classification difficult. Furthermore, as the condition progresses, individuals with other variants develop word comprehension deficits and other behavioral symptoms, making distinctions between variants less clear. Longitudinal brain imaging allows identification of specific areas of atrophy in individual patients, which identifies the location of disease in each patient. AIMS: We hypothesized that the areas of atrophy in individual PPA participants would be closely correlated with decline in word comprehension over time. We propose that areas where tissue volume is correlated with word comprehension are areas that: (1) are essential for word comprehension, (2) compensate for word comprehension in some individuals with semantic variant PPA early in the course; and (3) show atrophy in individuals with logopenic and nonfluent variant PPA only late in the course. METHODS AND PROCEDURES: Fifteen participants with PPA (5 logopenic variant PPA; 8 semantic variant PPA; 2 nonfluent/agrammatic variant PPA; mean age 67.8), underwent high resolution MRI and cognitive tests at least 9 months apart. The correlations between change in regional volumes and change in auditory word comprehension scores were investigated using Spearman test. OUTCOMES & RESULTS: While scores on auditory word comprehension at Time 1 were correlated with volume loss in right and left temporal pole and left inferior temporal cortex (areas of atrophy associated with semantic variant PPA), deterioration in auditory word comprehension from Time 1 to Time 2 was associated with individual atrophy in left middle temporal cortex, left angular gyrus, and right inferior and middle temporal cortex. CONCLUSIONS: Progressive atrophy in focal areas surrounding left temporal pole and left inferior temporal cortex, and right homologous area is closely related to progressive decline in auditory word comprehension. These correlations likely reflect areas that help support auditory word comprehension, effectively compensating for subtle deficits in some individuals early in the course of semantic variant PPA, as well as areas that are critical for auditory word comprehension that eventually atrophy in individuals with other variants of PPA. Individual patterns of atrophy also help us understand and predict the clinical course of individuals, such as associated behavioral or motor deficits. PMID- 25435644 TI - Organometallic Titanocene-Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties. AB - Early-late transition metal TiAu2 compounds [(eta-C5H5)2Ti{OC(O)CH2PPh2AuCl}2] (3) and new [(eta-C5H5)2Ti{OC(O)-4-C6H4PPh2AuCl}2] (5) were evaluated as potential anticancer agents in vitro against renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and gold(I) [{HOC(O)RPPh2}AuCl] (R = -CH2- 6, -4-C6H4- 7) derivatives in renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on renal cancer cell lines (for 5 in the nanomolar range) was considerably higher than that of cisplatin and highly active titanocene Y. Initial mechanistic studies in Caki-1 cells in vitro coupled with studies of their inhibitory properties on a panel of 35 kinases of oncological interest indicate that these compounds inhibit protein kinases of the AKT and MAPKAPK families with a higher selectivity toward MAPKAPK3 (IC503 = 91 nM, IC505 = 117 nM). The selectivity of the compounds in vitro against renal cancer cell lines when compared to a nontumorigenic human embryonic kidney cell line (HEK-293T) and the favorable preliminary toxicity profile on C57black6 mice indicate that these compounds (especially 5) are excellent candidates for further development as potential renal cancer chemotherapeutics. PMID- 25435645 TI - Synthesis, Structure, and Conformational Dynamics of Rhodium and Iridium Complexes of Dimethylbis(2-pyridyl)borate. AB - Rhodium(I) and Iridium(I) borate complexes of the structure [Me2B(2-py)2]ML2 (L2 = (tBuNC)2, (CO)2, (C2H4)2, cod, dppe) were prepared and structurally characterized (cod = 1,5-cyclooctadiene; dppe = 1,2-diphenylphosphinoethane). Each contains a boat-configured chelate ring that participates in a boat-to-boat ring flip. Computational evidence shows that the ring flip proceeds through a transition state that is near planarity about the chelate ring. We observe an empirical, quantitative correlation between the barrier of this ring flip and the pi acceptor ability of the ancillary ligand groups on the metal. The ring flip barrier correlates weakly to the Tolman and Lever ligand parameterization schemes, apparently because these combine both sigma and pi effects while we propose that the ring flip barrier is dominated by pi bonding. This observation is consistent with metal-ligand pi interactions becoming temporarily available only in the near-planar transition state of the chelate ring flip and not the boat-configured ground state. Thus, this is a first-of-class observation of metal ligand pi bonding governing conformational dynamics. PMID- 25435646 TI - O2-Promoted Allylic Acetoxylation of Alkenes: Assessment of "Push" vs. "Pull" Mechanisms and Comparison between O2 and Benzoquinone. AB - Palladium-catalyzed acetoxylation of allylic C-H bonds has been the subject of extensive study. These reactions proceed via allyl-palladium(II) intermediates that react with acetate to afford the allyl acetate product. Benzoquinone and molecular oxygen are two common oxidants for these reactions. Benzoquinone has been shown to promote allyl acetate formation from well-defined pi-allyl palladium(II) complexes. Here, we assess the ability of O2 to promote similar reactions with a series of "unligated" pi-allyl palladium(II) complexes (i.e., in the absence of ancillary phosphorus, nitrogen or related donor ligands). Stoichiometric and catalytic allyl acetate formation is observed under aerobic conditions with several different alkenes. Mechanistic studies are most consistent with a "pull" mechanism in which O2 traps the Pd0 intermediate following reversible C-O bond-formation from an allyl-palladium(II) species. A "push" mechanism, involving oxidatively induced C-O bond formation, does not appear to participate. These results and conclusions are compared with benzoquinone-promoted allylic acetoxylation, in which a "push" mechanism seems to be operative. PMID- 25435647 TI - Electrocatalysis in DNA Sensors. AB - Electrocatalysis is often thought of solely in the inorganic realm, most often applied to energy conversion in fuel cells. However, the ever-growing field of bioelectrocatalysis has made great strides in advancing technology for both biofuel cells as well as biological detection platforms. Within the context of bioelectrocatalytic detection systems, DNA-based platforms are especially prevalent. One subset of these platforms, the one we have developed, takes advantage of the inherent charge transport properties of DNA. Electrocatalysis coupled with DNA-mediated charge transport has enabled specific and sensitive detection of lesions, mismatches and DNA-binding proteins. Even greater signal amplification from these platforms is now being achieved through the incorporation of a secondary electrode to the platform both for patterning DNA arrays and for detection. Here, we describe the evolution of this new DNA sensor technology. PMID- 25435648 TI - Global biogeography of scaly tree ferns (Cyatheaceae): evidence for Gondwanan vicariance and limited transoceanic dispersal. AB - AIM: Scaly tree ferns, Cyatheaceae, are a well-supported group of mostly tree forming ferns found throughout the tropics, the subtropics and the south temperate zone. Fossil evidence shows that the lineage originated in the Late Jurassic period. We reconstructed large-scale historical biogeographical patterns of Cyatheaceae and tested the hypothesis that some of the observed distribution patterns are in fact compatible, in time and space, with a vicariance scenario related to the break-up of Gondwana. LOCATION: Tropics, subtropics and south temperate areas of the world. METHODS: The historical biogeography of Cyatheaceae was analysed in a maximum likelihood framework using Lagrange. The 78 ingroup taxa are representative of the geographical distribution of the entire family. The phylogenies that served as a basis for the analyses were obtained by Bayesian inference analyses of mainly previously published DNA sequence data using MrBayes. Lineage divergence dates were estimated in a Bayesian Markov chain Monte Carlo framework using beast. RESULTS: Cyatheaceae originated in the Late Jurassic in either South America or Australasia. Following a range expansion, the ancestral distribution of the marginate-scaled clade included both these areas, whereas Sphaeropteris is reconstructed as having its origin only in Australasia. Within the marginate-scaled clade, reconstructions of early divergences are hampered by the unresolved relationships among the Alsophila, Cyathea and Gymnosphaera lineages. Nevertheless, it is clear that the occurrence of the Cyathea and Sphaeropteris lineages in South America may be related to vicariance, whereas transoceanic dispersal needs to be inferred for the range shifts seen in Alsophila and Gymnosphaera. MAIN CONCLUSIONS: The evolutionary history of Cyatheaceae involves both Gondwanan vicariance scenarios as well as long-distance dispersal events. The number of transoceanic dispersals reconstructed for the family is rather few when compared with other fern lineages. We suggest that a causal relationship between reproductive mode (outcrossing) and dispersal limitations is the most plausible explanation for the pattern observed. PMID- 25435649 TI - Genetic structure of pike (Esox lucius) reveals a complex and previously unrecognized colonization history of Ireland. AB - AIM: We investigated genetic variation of Irish pike populations and their relationship with European outgroups, in order to elucidate the origin of this species to the island, which is largely assumed to have occurred as a human mediated introduction over the past few hundred years. We aimed thereby to provide new insights into population structure to improve fisheries and biodiversity management in Irish freshwaters. LOCATION: Ireland, Britain and continental Europe. METHODS: A total of 752 pike (Esox lucius) were sampled from 15 locations around Ireland, and 9 continental European sites, and genotyped at six polymorphic microsatellite loci. Patterns and mechanisms of population genetic structure were assessed through a diverse array of methods, including Bayesian clustering, hierarchical analysis of molecular variance, and approximate Bayesian computation. RESULTS: Varying levels of genetic diversity and a high degree of population genetic differentiation were detected. Clear substructure within Ireland was identified, with two main groups being evident. One of the Irish populations showed high similarity with British populations. The other, more widespread, Irish strain did not group with any European population examined. Approximate Bayesian computation suggested that this widespread Irish strain is older, and may have colonized Ireland independently of humans. MAIN CONCLUSIONS: Population genetic substructure in Irish pike is high and comparable to the levels observed elsewhere in Europe. A comparison of evolutionary scenarios upholds the possibility that pike may have colonized Ireland in two 'waves', the first of which, being independent of human colonization, would represent the first evidence for natural colonization of a non-anadromous freshwater fish to the island of Ireland. Although further investigations using comprehensive genomic techniques will be necessary to confirm this, the present results warrant a reappraisal of current management strategies for this species. PMID- 25435651 TI - IR Across the Pond-and Elsewhere. PMID- 25435650 TI - Personality and depressive symptoms: Stress generation and cognitive vulnerabilities to depression in a prospective daily diary study. AB - Personality and psychopathology have long been associated, however the mechanisms that account for this link are less understood. Stress generation was examined as a potential mechanism to explain the association between personality traits, especially negative emotionality, and depressive symptoms. In addition, the moderating influence of cognitive vulnerabilities to potentiate the relation between stressors and depressive symptoms was investigated. These hypothesized processes were evaluated in a prospective daily diary study in which young adults (N=210) completed baseline measures of personality, dysfunctional attitudes, negative cognitive style, and depressive symptoms. The participants then recorded their levels of depressive symptoms and the occurrence of stressors daily for 35 days. Negative Emotionality-Stress Reaction (NEM-SR) predicted initial levels and trajectories of depressive symptoms and stressors over time. Daily stressors partially mediated the longitudinal association between baseline NEM-SR and trajectories of daily depressive symptoms. Both dysfunctional attitudes and negative cognitive style interacted with these additional stressors to predict prospective fluctuations of daily depressive symptoms. PMID- 25435653 TI - Clinical assessment of patients with peripheral arterial disease. AB - Peripheral arterial disease (PAD) describes the clinical manifestations of atherosclerosis affecting the circulation in the legs. The severity of PAD is classified according to symptom severity, time course, and anatomical distribution. The signs and symptoms of PAD reflect the degree of circulatory compromise and whether there has been a gradual reduction in the circulation or an abrupt, uncompensated decrease. Accurate clinical assessment underpins decisions on management strategy and should objectively assess the severity of the ischemia and need for revascularization. Clinical history should discriminate symptoms of PAD from other conditions presenting with leg pain, elucidate cardiovascular risk factors and the effect of symptoms on the patient's quality of life. Clinical examination includes signs of general cardiovascular disease and associated conditions before assessing the circulation and viability of the limb. Palpation of peripheral pulses must be augmented by determination of the ankle brachial pressure index using hand held Doppler. A whole patient approach to management is required and must include modification of cardiovascular risk status as well as dealing with the local circulatory manifestation of PAD. PMID- 25435652 TI - Conditions presenting with symptoms of peripheral arterial disease. AB - Peripheral artery disease (PAD) is estimated to affect more than 20% of people older than 65 years. The vast majority of patients with symptoms suggestive of PAD have atherosclerosis often associated with conventional vascular risk factors such as smoking, diabetes, dyslipidemia, and inflammation. A minority of people presenting with symptoms suggesting PAD have an alternative etiology. These groups of disorders are often underdiagnosed, and if diagnosed correctly the diagnosis may be delayed. Understanding these pathologies well is important, as they can be very debilitating and optimal treatment may vary significantly. Inappropriate treatment of these disorders can lead to worsening morbidity and mortality. This article discusses the underlying causes of nonatherosclerotic PAD, including the diagnosis and treatment of these disorders. PMID- 25435654 TI - Contemporary treatment for critical ischemia: the evidence for interventional radiology or surgery. AB - This article is a review of the evidence regarding the management of patients with critical limb ischemia. The aim of the study is to discuss the definition, incidence, and clinical importance of critical limb ischemia, as well as the aims of treatment in terms of quality of life and limb salvage. Endovascular and surgical treatments should not be viewed as competing therapies. In fact, these are complementary techniques each with strengths and weaknesses. The authors will propose a strategy based on the available evidence for deciding the optimal approach to management of patients with critical limb ischemia. PMID- 25435655 TI - The diabetic foot: the importance of coordinated care. AB - Because of the severe morbidity and mortality associated with diabetes, diabetic foot care is an essential component of a peripheral vascular service. The goal of this article is to describe the vascular diabetic foot care pathway and how the coordinated foot care service for diabetic patients is delivered at King's College Hospital, London. PMID- 25435656 TI - Treating calf and pedal vessel disease: the extremes of intervention. AB - Recent developments in catheter, balloon, and guidewire technology have increased the scope for endovascular treatments in the management of complex and challenging disease in the calf and foot. The antegrade femoral approach remains the starting point for most interventions, but there is a growing role for procedures performed from unconventional access such as the pedal arteries. This article reviews the indications for intervention, atypical access, and the choice of equipment for these extreme interventions. PMID- 25435657 TI - Vascular imaging: the evolving role of the multidisciplinary team meeting in peripheral vascular disease. AB - This article reviews the importance of preinterventional cross-sectional imaging in the evaluation of peripheral arterial disease, as well as discussing the pros and cons of each imaging modality. The importance of a multidisciplinary team approach is emphasized. PMID- 25435659 TI - Iliac arteries: how registries can help improve outcomes. AB - There are many publications reporting excellent short and long-term results with endovascular techniques. Patients included in trials are often highly selected and may not represent real world practice. Registries are important to interventional radiologists for several reasons; they reflect prevailing practice and can be used to establish real world standards of care and safety profiles. This information allows individuals and centers to evaluate their outcomes compared with national norms. The British Iliac Angioplasty and Stenting (BIAS) registry is an example of a mature registry that has been collecting data since 2000 and has been reporting outcomes since 2001. This article discusses the evidence to support both endovascular and surgical intervention for aortoiliac occlusive disease, the role of registries, and optimal techniques for aortoiliac intervention. PMID- 25435658 TI - Pharmacology in peripheral arterial disease: what the interventional radiologist needs to know. AB - Peripheral arterial disease (PAD) is a progressive disease with significant morbidity and mortality. Risk factor control, using diet and lifestyle modification, exercise, and pharmacological methods, improves symptoms and reduces associated cardiovascular events in these patients. Antiplatelet agents and anticoagulants may be used to reduce the incidence of acute events related to thrombosis. The armamentarium available for symptom relief and disease modification is discussed. Novel treatments such as therapeutic angiogenesis are in their evolutionary phase with promising preclinical data. PMID- 25435660 TI - Treating femoropopliteal disease: established and emerging technologies. AB - The femoropopliteal artery is the most common site of disease in patients with peripheral arterial disease and presents some of the greatest challenges for interventional radiology. Many patients can be managed with medical treatment combined with supervised exercise alone. However, a significant proportion, especially those suffering from severe intermittent claudication or critical limb ischemia, will require some form of endovascular or surgical revascularization procedure. During the past few years an endovascular-first approach has gained support from all vascular specialties. Today, even complex lesions can be treated successfully with an endovascular approach. Unfortunately, the unique bio mechanical properties of this vascular segment have limited long-term patency rates and clinical value of the endovascular options. In this review, the authors discuss the methods and techniques for treatment of femoropopliteal lesions and review the current evidence for commercially available devices on patency outcomes following successful recanalization. PMID- 25435662 TI - Complications and great escapes: equipment and techniques. AB - All endovascular procedures have the potential for complications. The primary aims should always be avoidance of preventable complications and to minimize the impact of any complication. The core principles of an effective preventive strategy are: involving the interventional and clinical teams in a clear outline of the procedure and its potential adverse outcomes; ensuring an adequate inventory of required and backup equipment; the use of "time-out" to minimize wrong patient/wrong side adverse events; and an active audit program to identify areas of improvement. In the event of an adverse outcome there are many strategies that can be employed to rectify the situation or minimize the iatrogenic injury. This article provides a case-based discussion highlighting some of these techniques and how they can be used in a clinical setting. PMID- 25435661 TI - Access and hemostasis: femoral and popliteal approaches and closure devices-why, what, when, and how? AB - This article reviews the arterial access sites used in the treatment of peripheral arterial disease, including common femoral, superficial femoral, and popliteal arterial puncture. The optimal approach and techniques for arterial puncture will be described and technical tips and tricks will be discussed. An overview of the currently available vascular closure devices will also be presented. Indications, contraindications, and complications will be discussed. Results of the use of vascular closure devices compared with manual compression will be presented. PMID- 25435663 TI - Treatment of infrapopliteal arterial occlusive disease in critical limb ischemia. PMID- 25435664 TI - Systemic Air Embolism following Percutaneous Lung Biopsy. PMID- 25435665 TI - Overview of classification systems in peripheral artery disease. AB - Peripheral artery disease (PAD), secondary to atherosclerotic disease, is currently the leading cause of morbidity and mortality in the western world. While PAD is common, it is estimated that the majority of patients with PAD are undiagnosed and undertreated. The challenge to the treatment of PAD is to accurately diagnose the symptoms and determine treatment for each patient. The varied presentations of peripheral vascular disease have led to numerous classification schemes throughout the literature. Consistent grading of patients leads to both objective criteria for treating patients and a baseline for clinical follow-up. Reproducible classification systems are also important in clinical trials and when comparing medical, surgical, and endovascular treatment paradigms. This article reviews the various classification systems for PAD and advantages to each system. PMID- 25435666 TI - Gene doping in sport - perspectives and risks. AB - In the past few years considerable progress regarding the knowledge of the human genome map has been achieved. As a result, attempts to use gene therapy in patients' management are more and more often undertaken. The aim of gene therapy is to replace defective genes in vivo and/or to promote the long-term endogenous synthesis of deficient protein. In vitro studies improve the production of human recombinant proteins, such as insulin (INS), growth hormone (GH), insulin-like growth factor-1 (IGF-1) and erythropoietin (EPO), which could have therapeutic application. Unfortunately, genetic methods developed for therapeutic purposes are increasingly being used in competitive sports. Some new substances (e.g., antibodies against myostatin or myostatin blockers) might be used in gene doping in athletes. The use of these substances may cause an increase of body weight and muscle mass and a significant improvement of muscle strength. Although it is proven that uncontrolled manipulation of genetic material and/or the introduction of recombinant proteins may be associated with health risks, athletes are increasingly turning to banned gene doping. At the same time, anti-doping research is undertaken in many laboratories around the world to try to develop and refine ever newer techniques for gene doping detection in sport. Thanks to the World Anti-Doping Agency (WADA) and other sports organizations there is a hope for real protection of athletes from adverse health effects of gene doping, which at the same time gives a chance to sustain the idea of fair play in sport. PMID- 25435667 TI - THE GSTP1 c.313A>G POLYMORPHISM MODULATES THE CARDIORESPIRATORY RESPONSE TO AEROBIC TRAINING. AB - The GSTP1 c.313A>G polymorphism is a candidate to explain some of the individual differences in cardiorespiratory fitness phenotypes' responses to aerobic exercise training. We aim to explore the association between the GSTP1 c.313A>G polymorphism and the response to low-high impact aerobic exercise training. Sixty six Polish Caucasian women were genotyped for the GSTP1 c.313A>G polymorphism; 62 of them completed 12-week aerobic (50-75% HRmax) exercise training and were measured for selected somatic features (body mass and BMI) and cardiorespiratory fitness indices - maximal oxygen uptake (VO2max, maximum heart rate (HRmax), maximum ventilation (VEmax) and anaerobic threshold (AT) - before and after the training period. Two-factor analysis of variance revealed a main training effect for body mass reduction (p=0.007) and BMI reduction (p=0.013), improvements of absolute and relative VO2max (both p<0.001), and increased VEmax (p=0.005), but not for changes in fat-free mass (FFM) (p=0.162). However, a significant training x GSTP1 c.313A>G interaction was found only for FFM (p=0.042), absolute and relative VO2max (p=0.029 and p=0.026), and VEmax (p=0.005). As the result of training, significantly greater improvements in VO2max, VEmax and FFM were gained by the GG+GA group compared to the AA genotype group. The results support the hypothesis that heterogeneity in individual response to training stimuli is at least in part determined by genetics, and GSTP1 c.313A>G may be considered as one (of what appear to be many) target polymorphisms to influence these changes. PMID- 25435669 TI - Delayed uric Acid accumulation in plasma provides additional anti-oxidant protection against iron-triggered oxidative stress after a wingate test. AB - Reactive oxygen species are produced during anaerobic exercise mostly by Fe ions released into plasma and endothelial/muscle xanthine oxidase activation that generates uric acid (UA) as the endpoint metabolite. Paradoxically, UA is considered a major antioxidant by virtue of being able to chelate pro-oxidative iron ions. This work aimed to evaluate the relationship between UA and plasma markers of oxidative stress following the exhaustive Wingate test. Plasma samples of 17 male undergraduate students were collected before, 5 and 60 min after maximal anaerobic effort for the measurement of total iron, haem iron, UA, ferric reducing antioxidant activity in plasma (FRAP), and malondialdehyde (MDA, biomarker of lipoperoxidation). Iron and FRAP showed similar kinetics in plasma, demonstrating an adequate pro-/antioxidant balance immediately after exercise and during the recovery period (5-60 min). Slight variations of haem iron concentrations did not support a relevant contribution of rhabdomyolysis or haemolysis for iron overload following exercise. UA concentration did not vary immediately after exercise but rather increased 29% during the recovery period. Unaltered MDA levels were concomitantly measured. We propose that delayed UA accumulation in plasma is an auxiliary antioxidant response to post-exercise (iron-mediated) oxidative stress, and the high correlation between total UA and FRAP in plasma (R-Square = 0.636; p = 0.00582) supports this hypothesis. PMID- 25435668 TI - Heritability of aerobic power of individuals in northeast Brazil. AB - The objective of this study was to evaluate the genetic and environmental contribution to variation in aerobic power in monozygotic (MZ) and dizygotic (DZ) twins. The sample consisted of 20 MZ individuals (12 females and 8 males) and 16 DZ individuals (12 females and 4 males), aged from 8 to 26 years, residents in Natal, Rio Grande do Norte. The twins were assessed by a multistage fitness test. The rate of heritability found for aerobic power was 77%. Based on the results, the estimated heritability was largely responsible for the differences in aerobic power. This implies that such measures are under strong genetic influence. PMID- 25435670 TI - Acute effects of a resisted dynamic warm-up protocol on jumping performance. AB - This study aimed to investigate the kinematic and kinetic changes when resistance is applied in horizontal and vertical directions, produced by using different percentages of body weight, caused by jumping movements during a dynamic warm-up. The group of subjects consisted of 35 voluntary male athletes (19 basketball and 16 volleyball players; age: 23.4 +/- 1.4 years, training experience: 9.6 +/- 2.7 years; height: 177.2 +/- 5.7 cm, body weight: 69.9 +/- 6.9 kg) studying Physical Education, who had a jump training background and who were training for 2 hours, on 4 days in a week. A dynamic warm-up protocol containing seven specific resistance movements with specific resistance corresponding to different percentages of body weight (2%, 4%, 6%, 8%, 10%) was applied randomly on non consecutive days. Effects of different warm-up protocols were assessed by pre /post- exercise changes in jump height in the countermovement jump (CMJ) and the squat jump (SJ) measured using a force platform and changes in hip and knee joint angles at the end of the eccentric phase measured using a video camera. A significant increase in jump height was observed in the dynamic resistance warm up conducted with different percentages of body weight (p < 0.05). On the other hand, no significant difference in different percentages of body weight states was observed (p > 0.05). In jump movements before and after the warm-up, while no significant difference between the vertical ground reaction forces applied by athletes was observed (p > 0.05), in some cases of resistance, a significant reduction was observed in hip and knee joint angles (p < 0.05). The dynamic resistance warm-up method was found to cause changes in the kinematics of jumping movements, as well as an increase in jump height values. As a result, dynamic warm-up exercises could be applicable in cases of resistance corresponding to 6 10% of body weight applied in horizontal and vertical directions in order to increase the jump performance acutely. PMID- 25435672 TI - Iatrogenic biliary injuries: multidisciplinary management in a major tertiary referral center. AB - Background. Iatrogenic biliary injuries are considered as the most serious complications during cholecystectomy. Better outcomes of such injuries have been shown in cases managed in a specialized center. Objective. To evaluate biliary injuries management in major referral hepatobiliary center. Patients & Methods. Four hundred seventy-two consecutive patients with postcholecystectomy biliary injuries were managed with multidisciplinary team (hepatobiliary surgeon, gastroenterologist, and radiologist) at major Hepatobiliary Center in Egypt over 10-year period using endoscopy in 232 patients, percutaneous techniques in 42 patients, and surgery in 198 patients. Results. Endoscopy was very successful initial treatment of 232 patients (49%) with mild/moderate biliary leakage (68%) and biliary stricture (47%) with increased success by addition of percutaneous (Rendezvous technique) in 18 patients (3.8%). However, surgery was needed in 198 patients (42%) for major duct transection, ligation, major leakage, and massive stricture. Surgery was urgent in 62 patients and elective in 136 patients. Hepaticojejunostomy was done in most of cases with transanastomotic stents. There was one mortality after surgery due to biliary sepsis and postoperative stricture in 3 cases (1.5%) treated with percutaneous dilation and stenting. Conclusion. Management of biliary injuries was much better with multidisciplinary care team with initial minimal invasive technique to major surgery in major complex injury encouraging early referral to highly specialized hepatobiliary center. PMID- 25435671 TI - A pilot study on how do elite surfski padllers manage their effort and hydration pattern in the heat. AB - To investigate thermal response, hydration behaviour and performance over flatwater kayaking races in tropical conditions (36.8 degrees C and 68% rh). Five internationally-ranked subjects participated in the 2012 Surfski Ocean Racing World Cup in Guadeloupe to the "Ze Caribbean Race 2012" [i.e., a 35-km downwind race]. Core temperature (T degrees C) and heart rate (HR) were measured using portable telemetry units whereas water intake was deduced from backpacks absorption. The kayakers were asked to rate both their comfort sensation and thermal sensation on a scale before and after the race. The performance was related to an increase in T degrees C, high HR and low water intake (WI); and (2) high values of final T degrees C were related to high pre T degrees C and greater increases in T degrees C being obtained with low pre T degrees C and (3) WI being related to high pre T degrees C. The present study demonstrated that the fastest kayakers were those able to paddle at the highest intensities, increasing their T degrees C and drinking little water without any interference from thermal sensations. Water intake was positively related to pre-race T degrees C, which reinforces the importance of beginning surfski races with a low T degrees C. This study demonstrated that well-trained kayakers drinking ad libitum were able to anticipate their intensity/heat storage ratio to prevent heat illness and severe dehydration and maintain high performance. PMID- 25435673 TI - The effect of exercise using a sliding rehabilitation machine on the gait function of children with cerebral palsy. AB - [Purpose] The purpose of the present study was to examine the effect of strength training using a sliding rehabilitation machine (SRM) on the gait function of cerebral palsy children. [Subjects and Methods] Thirteen children aged 6-18 years participated in the SRM training for 8 weeks (30 min/day, 2 times/week). The SRM is designed for the performance of a closed-kinetic chain exercise in which a tilt table is moved up and down using wheels on the table. Participants began in a position of flexion of the 3 lower joints (hips, knees, and ankles) on the SRM. In each exercise session, they extended and flexed the 3 joints. The level of exercise was set by changing the inclination of the tilt table. Functional gait ability was measured with the 6-minute walk test (6MWT), 10-m walk test (10MWT), and timed up-and-go test (TUG) before and after the training. Muscle strength was also measured using an isokinetic dynamometer. [Results] Nine of the thirteen children completed the entire study. The peak torques of the knee extensor and flexor group muscles significantly improved after training with the SRM. The total distance of the 6 MWT significantly increased after training. The times of the 10 MWT and the TUG significantly improved after training. The changes in muscle tone were also investigated using the MAS (Modified Ashworth Scale) and Tardieu scale, but no significant changes were found in muscle tone between the pre- and post-test measurements. [Conclusion] The findings demonstrate the effect of the SRM intervention which resulted in improved muscle strength and functional gait. PMID- 25435674 TI - Characteristics of sway in the center of gravity of badminton players. AB - [Purpose] To clarify the characteristics of fluctuations in the center of gravity (CoG) of badminton players by comparing them between those with high and low performance levels. [Subjects] Eight male badminton players belonging to teams ranked among the top 3 at the All Japan Badminton Championships (high-level group) and 8 playing badminton for recreation in university clubs (low-level group) were studied. [Methods] CoG sway during two- and one (dominant and non dominant)-leg standing with the eyes open and closed were recorded for 30 seconds, using a stabilometer. [Results] With their eyes open, the CoG was maintained near the center by the high-level group, while it was displaced in the direction of the dominant leg by the low-level group, with a significant difference between the two groups. In contrast, with the eyes closed, the trace length, sway area, and X- and Y-axis sway amplitudes were greater in the low- than in high-level group, with significant differences between the two groups. [Conclusion] These results support the usefulness of standing on the non-dominant leg with the eyes closed for the evaluation of badminton players' balance ability. PMID- 25435675 TI - Effects of exercise therapy on blood lipids of obese women. AB - [Purpose] The aim of this study was to examine the effects of exercise therapy on blood lipids of obese women. [Subjects] The subjects were 24 clinically obese women. [Methods] The subjects were divided into an exercise group (n=12), and a control group (n=12). The exercise group performed exercise for 10 weeks with diet restriction. We investigated how this type of exercise influenced blood lipids. Blood was taken before and after the intervention. The collected blood was centrifuged at 3,000 rpm for 10 minutes; and plasma was preserved at -73 degrees C. For hemanalysis, a medical laboratory was asked to analyze total cholesterol and triglyceride. The exercise was performed 5 times per week, and an exercise was performed every two days, and exercise program was composed of warm up, main exercise and cool down. [Results] There were significant differences between the two groups in blood lipid levels after the intervention. The differences between the two groups in TC and TG were significant. [Conclusion] TC and TG significantly inproved in the experimental group showing that the exercise was effective at improveing blood lipid levels. PMID- 25435676 TI - Relationship among Ocular Diseases, Developmental Levels, and Clinical Characteristics of Children with Diplegic Cerebral Palsy. AB - [Purpose] The aim of this study was to evaluate the relationships among vision problems, developmental levels, upper extremity functions, and qualities of life of children with cerebral palsy (CP). [Subjects] The study included 32 children, aged 4-15 years, diagnosed with diplegic type CP. [Methods] Hand function was evaluated using the Manual Ability Classification System (MACS) and the Bimanual Fine Motor Function (BFMF) scale, and the severity of CP was assessed using the Gross Motor Function Classification System (GMFCS). The developmental and mental capabilities of the children were evaluated using the Ankara Developmental Screening Inventory (ADSI) or the WISC-R test. An oculomotor examination was conducted for all patients. [Results] Positive correlations were found between GMFCS and BFMF, GMFCS and MACS, and MACS and BFMF scores (r=0.636; r=0.553; r=0.718, respectively). Significant correlations were found between upper extremity function, the severity of CP, the quality of life, and the general developmental level. There was no significant correlation between ocular disorders and clinical characteristics. [Conclusion] GMFCS, MACS, and BFMF may be useful for defining the functional status of children with CP, as they are easy, practical, and simple classification scales that conform to each other. PMID- 25435677 TI - A Study on the Differences of Quadriceps Femoris Activities by Knee Alignment during Isometric Contraction. AB - [Purpose] This study attempted to identify how genu varum or valgum affects the electromyographic activities of the vastus medialis, vastus lateralis, and rectus femoris during knee isometric contraction. [Subjects] Fifty-two healthy young adults were enrolled in this study. They were enrolled and classified into three groups by knee alignment conditions: the genu varum, genu valgum, and control groups. [Methods] The electromyographic activity ratio of the vastus medialis to the vastus lateralis and rectus femoris were calculated using the percentage of maximum voluntary contraction. The participants contracted their quadriceps during isometric contraction at 30 and 60 degrees of knee flexion. [Results] The genu varum group had more activity in the vastus medialis than in the vastus lateralis and rectus femoris, whereas the genu valgum group had more activity in the vastus lateralis and rectus femoris than in the vastus medialis. There was a significant difference in the muscle activity ratio between the vastus medialis and vastus lateralis by angle of knee flexion degree only in the genu valgum. There were no significant differences in any of the three groups in terms of the muscle activity ratio of the vastus medialis to the rectus femoris by angle of knee flexion. [Conclusion] The quadriceps femoris was used for different strategies according to knee alignment during isometric contraction at 30 and 60 degrees . This study suggests that rehabilitation training programs used to strengthen the quadriceps should consider the knee alignment conditions of the target subjects. PMID- 25435678 TI - Effect of unstable surface training on walking ability in stroke patients. AB - [Purpose] The purpose of this study was to determine the effects of unstable surface training (UST) on walking ability in chronic stroke patients. [Subjects] The subjects were 12 stroke patients who were randomly divided into experimental (n1=6) and control (n2=6) groups. [Methods] The Subjects in both groups performed treadmill training for 30 minutes. The Subjects in the experimental group also performed UST after treadmill training, with the UST being performed for 10 minutes, five times per week, for four weeks. All subjects were evaluated with a 10-meter walk test, Timed Up and Go test and 6-minute walk test. The pared t-test was performed to test the significant differences between before and after the intervention. The independent t-test was conducted to test the significant differences between groups. [Results] Following the intervention, the experimental group showed significant differences in the Timed Up and Go test and 6-minute walk test. [Conclusion] The results of the study suggest that UST is an effective method for improvement of walking ability in chronic stroke patients. PMID- 25435679 TI - Effects of a Task-specific Exercise Program on Balance, Mobility, and Muscle Strength in the Elderly. AB - [Purpose] The aim of this study was to investigate the effects of a task-specific exercise program based on motor learning on balance ability and strength of the lower extremity in the elderly with/without falling experiences. [Subjects and Methods] Individuals who had experiences of falling over 2 times within the past 6 months were included in the falling group. The task-specific exercise program consisted of 3 stages (weeks 1-2, 3-4, and 5-6) and was conducted according to the level of difficulty in this study. [Results] The scores of the Korean version of the Activities-Specific Balance Confidence Scale and Performance-Oriented Mobility Assessment were significantly changed in both the falling group and non falling group after the task-specific exercise program. In comparisons between the falling group and non-falling group, there were also significant differences in the Korean version of the Activities-Specific Balance Confidence Scale and muscle strength of the semitendinosus and gastrocnemius. [Conclusion] The task specific exercise program has a positive effect on balance ability and muscle strength related to falls in the elderly. PMID- 25435680 TI - Analysis of Core Stability Exercise Effect on the Physical and Psychological Function of Elderly Women Vulnerable to Falls during Obstacle Negotiation. AB - [Purpose] The aim of the present study was to investigate the effects of core stability exercise (CSE) on the physical and psychological functions of elderly women while negotiating general obstacles. [Subjects and Methods] After allocating 10 elderly women each to the core stability training group and the control group, we carried out Performance-Oriented Mobility Assessment (POMA) and measured crossing velocity (CV), maximum vertical heel clearance (MVHC), and knee flexion angle for assessing physical performances. We evaluated depression and fear of falling for assessing psychological functions. [Results] Relative to the control group, the core stability training group showed statistically significant overall changes after the training session: an increase in POMA scores, faster CV, lower MVHC, and a decrease in knee flexion angle. Furthermore, depression and fear of falling decreased significantly. [Conclusion] CSE can have a positive effect on the improvement of physical and psychological performances of older women who are vulnerable to falls as they negotiate everyday obstacles. PMID- 25435681 TI - Effects of home exercise on physical function and activity in home care patients with Parkinson's disease. AB - [Purpose] The aim of this study was to clarify the effects of guidance in home exercise on physical function and the amount of activity in home care patients with Parkinson's disease (PD). [Subjects and Methods] A 2-month home exercise intervention consisting of self-administered exercise by patients (self-exercise) and home visit exercise therapy guided by a physical therapist (home visit exercise) was conducted in 10 home care patients with PD to compare changes in physical function, activities of daily living, and postural status between before and after the intervention. [Results] A decreased number of chief complaints and alleviation of fear of falling were observed after the intervention. In terms of physical function, a significant increase in flexibility and muscle strength were observed, although no significant changes were found in activities of daily living, gait, and balance. Although there was no significant change in the total amount of daily physical activity, the analysis of daily posture changes revealed a significant reduction in the percentage of time spent lying down and a significant increase in the percentage of time spent sitting after the intervention. [Conclusion] Guidance in home exercise in home care patients with PD can be effective in making self-exercise a habit, improving range of motion and muscle strength, and reducing the time spent in a supine position. PMID- 25435682 TI - Isometric contraction of an upper extremity and its effects on the contralateral lower extremity. AB - [Purpose] The aim of this study was to examine effects of the isometric contraction of an upper limb in a supine position on the muscle activity of a healthy adult in the contralateral lower limb. [Subjects] The subjects were 40 healthy adults (35 males and 5 females). [Methods] The muscle activity of the rectus femoris (RF), biceps femoris, anterior tibialis, and medial gastrocnemius (MG) of the contralateral lower limb was measured using electromyography while the subjects flexed, extended, abducted, and adducted the shoulder joint of an upper limb. [Results] The muscle activity of the RF of the contralateral lower limb was significantly high when the subject flexed the shoulder joint of an upper limb, and the muscle activity of the MG of the contralateral lower limb was significantly high when the subject adducted the shoulder joint of an upper limb. [Conclusion] The isometric contraction that results from flexion and adduction of the shoulder joint of an upper limb in a supine position is considered to selectively affect the RF and MG activity of the contralateral lower limb. PMID- 25435683 TI - Effects of thoracic mobilization and manipulation on function and mental state in chronic lower back pain. AB - [Purpose] The aim of this study was to evaluate the changes in function and mental state after thoracic mobilization and manipulation in patients with chronic lower back pain (LBP). [Subjects and Methods] Thirty-six subjects were randomly divided into mobilization group (group A), manipulation group (group B) and control group (group C). The Oswestry disability index (ODI) was used to measure the functional impairment of patients with LBP. A multiple spinal diagnosis was used to measure the range of motion (ROM) of vertebra segments. The Fear-avoidance beliefs questionnaire (FABQ) was used to investigate the mental state of LBP patients. [Results] Group A and group B were significantly different from group C in terms of the ODI. Between groups, there was no difference in ROM during trunk flexion. Group A and group B were also significantly different from the control group in extension ROM. The FABQ of group B was significantly different from that of group A. [Conclusion] Application of mobilization or manipulation to thoracic lumbar vertebrae has a positive effect on function, mental state, and ROM in patients with lower back pain. PMID- 25435684 TI - The Effects of Wearing High Heels while Pressing a Car Accelerator Pedal on Lower Extremity Muscle Activation. AB - [Purpose] The purpose of this study was to determine the effects of wearing high heels while driving on lower extremity muscle activation. [Subjects] The subjects of this experimental study were 14 healthy women in their 20s who normally wear shoes with high heels. [Methods] The subjects were asked to place their shoes on an accelerator pedal with the heel touching the floor and then asked to press the pedal with as much pressure as possible for 3 seconds before removing their feet from the pedal. A total of 3 measurements were taken for each heel height (flat, 5 cm, 7 cm), and the heel height was randomly selected. [Results] The levels of muscle activity, indicated as the percentage of reference voluntary contraction, for gastrocnemius muscle in the flat, 5 cm, and 7 cm shoes were 180.8+/-61.8%, 285.4+/-122.3%, and 366.2+/-193.7%, respectively, and there were significant differences between groups. Those for the soleus muscle were 477.3+/-209.2%, 718.8+/-380.5%, and 882.4+/-509.9%, and there were significant differences between groups. [Conclusion] To summarize the results of this study, it was found that female drivers require greater lower extremity muscle activation when wearing high heels than when wearing low heels. Furthermore, instability and muscle fatigue of the ankle joint, which results from wearing high heels on a daily basis, could also occur while driving. PMID- 25435685 TI - The efficiency of the sideways stepping test in detecting unilateral vestibular hypofunction. AB - [Purpose] This study investigated to determine whether the Sideways Stepping Test (SST) is a useful test to detect unilateral vestibular hypofunction (UVH). [Subjects and Methods] Twenty-eight subjects including both male and females between the ages of 25 and 55 who had been diagnosed with UVH were recruited for the study. All the subjects were tested with the SST and followed by the head shaking nystagmus (HSN) test using video electronystagmography (VENG) to confirm the presence of UVH. The results of both tests were then compared with each other to determine the correlation, sensitivity, and specificity. [Results] The results showed that the SST is strongly correlated with the gold standard HSN test using VENG and is highly sensitive and specific. [Conclusion] The present study showed that the SST is a highly valid test that can be used as an alternative method to the gold standard HSN test using VENG in detecting UVH. PMID- 25435686 TI - Effect of Walking Exercise on Changes in Cardiorespiratory Fitness, Metabolic Syndrome Markers, and High-molecular-weight Adiponectin in Obese Middle-aged Women. AB - [Purpose] The purpose of this study was to assess the effect of a 24-week exercise intervention on cardiorespiratory fitness, metabolic syndrome markers, and high-molecular-weight (HMW) adiponectin among obese middle-aged women. [Subjects] The subjects were 14 obese middle-aged women. [Methods] The exercise program involved walking at 50-60% of the maximum oxygen consumption, 3 times a week, for 24 weeks. Body composition analysis, blood pressure measurements, and blood analysis were performed before the exercise program and at weeks 6, 12, 18, and 24. [Results] The results showed that after 24 weeks in the exercise program, the obesity indices and metabolic risk factors, namely, weight, body fat, body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, and triglycerides decreased significantly, whereas HDLC, a metabolic improvement factor, increased significantly. Additionally, VO2max increased significantly, together with the level of total and HMW adiponectins. Correlation analysis of the changes in measured variables (? score) during resulting from the 24-week exercise program showed that body fat had a significant negative correlation and VO2max had a significant positive correlation with HMW adiponectin. [Conclusion] Among obese middle-aged women, regular exercise increases cardiorespiratory fitness and HMW adiponectin expression and therefore can be effective in the prevention and treatment of obesity and metabolic syndrome. PMID- 25435687 TI - The Reference Values for the Chair Stand Test in Healthy Japanese Older People: Determination by Meta-analysis. AB - [Purpose] The aim of this study was to determine the reference values for the chair stand test (CST) in healthy older Japanese people. [Methods] Relevant research articles for the 5-repetition chair stand test (CS-5) and the 30-second chair stand test (CS-30) were identified by electronic database and manual searching. Research articles involving healthy Japanese people aged 60 years and older were included in a meta-analysis. Weighted means of the CS-5 and CS-30 were estimated by the random effect model as the reference values for the CST. Further, the effects of age and sex on the reference values were analyzed by a meta-regression analysis. [Results] Seven articles (21 data) and three articles (14 data) were included in the meta-analyses for the CS-5 and CS-30, respectively. The reference value for the CS-5 was estimated as 8.50 sec [95% confidence interval (CI): 7.93-9.07]; age and sex were not associated with this reference value. The reference value for the CS-30 was estimated as 17.26 times [95%CI: 15.98-18.55], and age was significantly associated with this value. [Conclusion] When the CS-5 and CS-30 are used to evaluate elderly Japanese people, the reference values for the CS-5 and CS-30 determined in this study would be useful indices. PMID- 25435688 TI - The effects of tai chi on the renal and cardiac functions of patients with chronic kidney and cardiovascular diseases. AB - [Purpose] To assess the effects of Tai Chi on the renal and cardiac functions of patients with chronic kidney disease (CKD) and cardiovascular disease (CVD). [Subjects and Methods] Twenty-one patients with CKD and CVD were randomly divided into control and exercise groups. The exercise group performed Tai Chi training for 30 minutes three to five times a week for 12 weeks, while the control group did not. All patients' renal and cardiac functions and blood lipid parameters were measured at baseline and after 12 weeks. [Results] The 12 weeks Tai Chi intervention improved the estimated glomerular filtration rate (eGFR), left ventricular ejection fraction (LVEF), and the high density lipoprotein (HDL) level, and decreased the serum creatintine (Scr) level, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and the total cholesterol (CH), triglyceride (TG) and low density lipoprotein (LDL) levels. The change in eGFR correlated negatively with the changes in CH, TG and LDL, and positively with the change in HDL. In addition, the change in SBP correlated positively with the changes in CH, TG and LDL, and negatively with the change in HDL. [Conclusion] Tai Chi training might improve the renal and cardiac functions of CKD and CVD patients via improved regulation of lipid metabolism. PMID- 25435689 TI - Effect of the Push-up Plus (PUP) Exercise at Different Shoulder Rotation Angles on Shoulder Muscle Activities. AB - [Purpose] Although the Push-Up Plus is a useful exercise method for shoulder stabilization, few studies have examined its effects at different angles of shoulder rotation. Therefore, the present study investigated the most effective exercise method for shoulder stabilization by analyzing muscle activities of the rotator cuff muscles at different angles of shoulder rotation. [Subjects] Fifteen healthy university students in their 20s were the subjects of this study. [Methods] Changes in muscle EMG related to shoulder stabilization were analyzed by performing the Push-Up Plus in shoulder positions of neutral, internal and external rotation. [Results] The highest muscle activity was found in external rotation, and in internal rotation the pectoralis major and levator scapula showed significantly lower activities than the other positions. [Conclusion] Selectively changing the rotation angle of the shoulder for different purposes of the shoulder exercise would be an effective exercise method. PMID- 25435690 TI - Characteristics of cervical position sense in subjects with forward head posture. AB - [Purpose] The purpose of this study was to investigate the effect of forward head posture (FHP) on proprioception by determining the cervical position-reposition error. [Subjects and Methods] A sample population was divided into two groups in accordance with the craniovertebral angle: the FHP group and the control group. We measured the craniovertebral angle, which is defined as the angle between a horizontal line passing through C7 and a line extending from the tragus of the ear to C7. The error value of the cervical position sense after cervical flexion, extension, and rotation was evaluated using the head repositioning accuracy test. [Results] There were significant differences in the error value of the joint position sense (cervical flexion, extension, and rotation) between the FHP and control groups. In addition, there was an inverse correlation between the craniovertebral angle and error value of the joint position sense. [Conclusion] FHP is associated with reduced proprioception. This result implies that the change in the muscle length caused by FHP decreases the joint position sense. Also, proprioception becomes worse as FHP becomes more severe. PMID- 25435691 TI - A reliability of the prototype trunk training system for sitting balance. AB - [Purpose] Cerebral palsy is a disorder that affects balance in the sitting position. Cerebral palsy patients need trunk muscle strengthening and balance training. In order to improve trunk control sensory-motor control training is carried out on an unstable surface. We have developed a Trunk Training System (TTS) that can provide visual feedback using a tilt sensor for balance training in the sitting position. Before using the TTS for training children with cerebral palsy experiments were conducted with healthy adult subjects and the TTS to gather basic data for its improvement. [Subjects] The subjects were 11 healthy men (n=3) and women (n=8). [Methods] Subjects trained at two levels (5 degrees , 10 degrees ), in four different directions (anterior, posterior, left, right), three times each. TTS outcome indices (stability index, performance time) were measured. [Results] The stability index and performance time showed high correlation (-0.6 1.0 * 10(9)/L). Response was evaluated by bone marrow examination on day 30 post chemotherapy. Patients included were refractory acute lymphoblastic leukemia (ALL) (five patients), relapsed ALL (four patients), refractory acute myeloid leukemia (AML) (eight patients), relapsed AML (three patients). Complete remission (CR) was achieved in nine (45 %) patients, while three (15 %) patients got partial remission. Three (15 %) patients died because of post chemotherapy complications and five (25 %) patient failed to achieve remission. Major complications encountered were: anemia, fever, bleeding, mucositis and bacterial infections. FLAG protocol is well tolerated and effective regimen in relapsed/refractory acute leukemias. The toxicity is acceptable, enabling most patients to receive further treatment, including transplantation procedures. PMID- 25435720 TI - Second primary malignancies in chronic myeloid leukemia. AB - Survival of patients with chronic myeloid leukemia (CML) has improved with the use of imatinib and other tyrosine kinase inhibitors. There is limited data on second primary malignancies (SPM) in CML. We analyzed the SPMs rates among CML patients reported to Surveillance, Epidemiology, and End Results (SEER) database during pre-(1992-2000) and post-(2002-2009) era. We used SEER Multiple Primary Standardized Incidence Ratio session to calculate standardized incidence ratios (SIRs). Among 8,511 adult CML patients, 446 patients developed 473 SPMs. The SIR for SPMs in CML patients was significantly higher with observed/expected ratio:1.27, P < 0.05 and absolute excess risk of 32.09 per 10,000 person years compared to general population. The rate of SPMs for cancers of all sites in post imatinib era were significantly higher compared to pre-imatinib era with observed/expected ratio of 1.48 versus 1.06, P = 0.03. This study showed that risk of SPMs is higher among CML patients. The risk of SPMs is significantly higher in post-imatinib era compared to pre-imatinib era. PMID- 25435721 TI - Location of the BCR/ABL Fusion Genes on Both Chromosomes 9 in Ph Negative Young CML Patients: An Indian Experience. AB - The BCR/ABL gene rearrangement is cytogenetically visualized in most chronic myeloid leukemia (CML) cases. About 5-10 % of CML patients lack its cytogenetic evidence, however, shows BCR/ABL fusion by molecular methods. We describe two CML patients with Philadelphia (Ph) negative (-ve) and BCR/ABL positive by fluorescence in situ hybridization (FISH). Both the cases were in chronic phase at diagnosis. Conventional cytogenetics and different FISH assays were adopted using BCR/ABL probes. Home-brew FISH assay using bacterial artificial clone (BAC) for BAC-CTA/bk 299D3 for chromosomal region 22q13.31-q13.32 was performed in case 1. Both the patients were Ph-ve. In first case, dual color dual fusion (DCDF) FISH studies revealed 1 Red (R) 2 Green (G) 1 Fusion (F) signal pattern in 80 % of cells indicating BCR/ABL fusion signals on chromosomes 9 instead of Ph and 2G2F signal pattern in 20 % of cells indicating two BCR/ABL fusions on both chromosomes 9q34 on presentation. In second case, FISH studies revealed the 1R1G1F signal pattern indicating BCR/ABL fusion signals on chromosomes 9 instead of Ph in 100 % of cells at presentation. During follow-up, both the patients exhibited 2G2F signal pattern indicating two BCR/ABL fusions on both chromosomes 9q34, which indicated a clonal evolution in 100 % cells. Both the patients did not achieve therapeutic response. Relocation of BCR/ABL fusion sequence on sites other than 22q11 represents a rare type of variant Ph, the present study highlights the hot spots involved in CML pathogenesis and signifies their implications in Ph-ve BCR/ABL positive CML. This study demonstrated the genetic heterogeneity of this subgroup of CML and strongly emphasized the role of metaphase FISH, especially in Ph-ve CML cases, as it detects variations of the classical t(9;22). PMID- 25435722 TI - Assessment of interleukin 1beta serum level in different responder groups and stages of chronic myeloid leukemia patients on imatinb mesylate therapy. AB - Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of an acquired mutation which affects the hematopoietic stem cell, leading to a striking overproduction of immature granulocytes. The first important clue to its pathogenesis the Philadelphia chromosome created by a reciprocal translocation between chromosomes 9 and 22 (t [9; 22] [q34; q11]). The development of the BCR-ABL-targeted imatinib mesylate represents a paradigm shift in the treatment of CML. Imatinib displays inhibitory activity against other kinase(s) that play a role in monocyte/macrophage development. Accordingly many studies revealed the role of cytokines in pathophysiology of myeloid neoplasia including participation of IL-1beta in the pathogenesis of CML. This study designed to assess the behavior of IL-1beta through newly diagnosed patients, different responders groups (optimal, suboptimal and failure cytogenetic response) and advanced stages (acceleration and crisis groups) of CML Iraqi patients whom receiving Imatinib mesylate (tyrosine kinase inhibitor), trying to elucidate the role of immunity in pathophysiology of CML disease development and treatments. In this study 96 Iraqi CML patients under imatinib mesylate treatment categorized by complete blood picture and fluorescent in situ hybridization analysis into different response groups and stages, then used an enzyme linked immunosorbent assay technique to assess serum level of IL-1beta in each response group and advance stage (acceleration and transformed) of CML patients, in comparison to level in 32 healthy control subjects and 32 newly diagnosed CML. Out of 128 patients the mean serum of interleukin 1beta level (pg/ml) for the newly diagnosed, optimal responded, suboptimal responded, failure cytogenetic and advance stage of CML were 6.53 +/- 3.81, 18.47 +/- 4.29, 18.69 +/- 3.03, 5.73 +/- 2.44, and 18.10 +/- 3.10, respectively. While healthy was 12.17 +/- 3.44. The measurement of IL-1beta before and during treatment of CML patients may contribute to the early identification of responder and non responder patients, and help in the earlier choice and/or design of alternative therapeutic strategies. PMID- 25435724 TI - Arsenic Trioxide Combined with VCMP or VAD Chemotherapy in Patients with Refractory or Relapsed Multiple Myeloma in a Single Institution of China. AB - Arsenic trioxide (ATO) combined with dexamethasone, melphalan or other cytostatic agents had been used to treat refractory or relapsed multiple myeloma (MM) patients. We assessed the safety and efficacy of ATO combined with vindesine/cyclophosphamide/melphalan/prednisone (VCMP) or vindesine/doxorubicin/dexamethsone (VAD) chemotherapy for MM patients who failed more than two different prior regimens. All patients received ATO (0.25 mg/kg day) for 10 days/cycle combined with VCMP or VAD in 30-day cycles. Vindesine (1.4 mg/m(2)) was given intravenously on day 1, cyclophosphamide (400 mg/m(2) day) was given intravenously on days 2, 4, 6, 8, 10, melphalan (6 mg/day) and prednisone (1 mg/kg day) were given orally day 1 to day 10 for VCMP regimen. VAD regimen consisted of vindesine 1 mg/day and doxorubicin 10 mg/day intravenously drip for 4 days with oral dexamethasone 40 mg/day for days 1-4, 9-12, 17-20. Patients who completed at least one cycle were evaluated for response to treatment. Objective responses occurred in 35 of 63 (56 %) patients, including seven complete, 14 partial and 14 minor responses. Median progression-free survival and overall survival were 6 and 23 months respectively. 12 patients had elevated serum creatinine levels (SCr) at baseline, and 9 of 12 (75 %) showed decreased SCr levels during treatment. Frequent Grade 3/4 non-hematological adverse events included arrhythmia, hypertension, fatigue and neuropathy. These results indicate that ATO combined with VCMP or VAD was effective and well tolerated as a new therapeutic option for patients with relapsed or refractory MM. PMID- 25435723 TI - Amplification of 1q21 and other abnormalities in multiple myeloma patients from a tertiary hospital in singapore. AB - Much effort has been made to stratify multiple myeloma patients for targeted therapy. However, responses have been varied and improved patient stratifications are needed. Forty-five diagnostic samples from multiple myeloma patients (median age 65 years) were stratified cytogenetically as 15 having non-hyperdiploidy, 20 having hyperdiploidy and 10 having a normal karyotype. Fluorescence in situ hybridization (FISH) assays with FGFR3/IGH, CCND1/IGH, IGH/MAF, RB1 and TP53 probes on bone marrow samples showed that IGH rearrangements were the most common abnormality in the non-hyperdiploid group but these were also found among hyperdiploid patients and patients with normal cytogenetics. Of these, FGFR3/IGH rearrangements were most frequent. Deletion of RB1/monosomy 13 was the most common genetic abnormality across the three groups and was significantly higher among non-hyperdiploid compared to hyperdiploid patients. On the other hand, the study recorded a low incidence of TP53 deletion/monosomy 17. The FGFR3/IGH fusion was frequently seen with RB1 deletion/monosomy 13. FISH with 1p36/1q21 and 6q21/15q22 probes showed that amplification of 15q22 was seen in all of the hyperdiploid patients while amplification of 1q21, Amp(1q21), characterized non hyperdiploid patients. In contrast, deletions of 1p36 and 6q21 were very rare events. Amp(1q21), FGFR3/IGH fusion, RB1 deletion/monosomy 13, and even TP53 deletion/monosomy 17 were seen in some hyperdiploid patients, suggesting that they have a less than favorable prognosis and require closer monitoring. PMID- 25435725 TI - Modified Irinotecan Plus Cisplatin and Dexamethasone (ICD) Combination Chemotherapy as Salvage Chemotherapy for Patients with Relapsed/Refractory Diffuse Large Cell Lymphoma. AB - About 50 % of patients with diffuse large cell lymphoma are candidate for salvage chemotherapy followed by bone marrow transplantation in the selected patients. In the current study we evaluated modified ICD (Irinotecan, Cisplatin, and Dexamethasone with G-CSF support) as salvage chemotherapy in the patients previously treated with R-CHOP or CHOP. In a retrospective study we evaluated 16 patients treated with modified ICD: irinotecan 65 mg/m(2) (max 100 mg)/day plus cisplatin 30 mg/m(2) (max 50 mg)/day and dexamethasone 40 mg/day on days 1 and 8. Prednisolone 200 mg divided in 2 doses was given orally on days 2 and 9. G-CSF (PDgrastim) was administered at 300 MUg/day subcutaneously on days 4-6 and 11-13. pre- and post-hydration was given according to our hospital protocol. Overall response rate was 75 % for all of the patients and 90 % for the patients treated as first line salvage. The median overall survival was 23 +/- 12 months. There was no grade 3/4 of neutropenia and no cycles of chemotherapy were delayed due to leucopenia. Modified ICD might be an effective salvage regimen for refractory/relapsed lymphoma patients. Unlike original ICD, leucopenia does not seem to be a limiting factor. So we conclude that modified ICD shall be considered as a safe and effective regimen for salvage chemotherapy in refractory/relapsed patients. PMID- 25435726 TI - Switching to BCL-6 Negativity in Relapsed Diffuse Large B Cell Lymphoma Correlated with More Aggressive Disease Course. AB - Diffuse large B-cell lymphoma (DLBCL) is the most frequent, complex and heterogeneous lymphoma of adulthood. Heterogeneity is expressed at clinical, genetic, and molecular levels. It is known that BCL-6 expression is a favorable prognostic factor in DLBCL. However, the underlying mechanisms of BCL-6 expression in DLBCL relapse are not yet elucidated. Here, we present so far undescribed clinical phenomenon of switching BCL-6(+) protein expression into BCL 6(-) expression in 19 of 41 relapsed DLBCL patients. The switch in relapsed DLBCL was associated with more aggressive clinical course of the disease. Bone marrow infiltration and high IPI risk were more often present in BCL-6(-) patients. Significantly increased biochemical parameters, such as LDH, beta-2 macroglobulin, CRP, and ferritin have been found, as well as significantly decreased serum Fe, TIBC, and hemoglobin. A Ki-67 proliferation marker was considerably high in relapsed DLBCL, but without significant differences between BCL-6(+) and BCL-6(-) groups of patients. Thus, switching of the positive into negative BCL-6 expression during DLBCL relapse could be used as a prognostic factor and a valuable criterion for treatment decision. PMID- 25435727 TI - Ocular manifestations in egyptian children and young adults with sickle cell disease. AB - In sickle cell disease (SCD), ocular lesions result from stasis and occlusion of small eye vessels by sickled erythrocytes. Vaso-occlusive disease of the retina can be responsible for nonproliferative (NPR) and proliferative retinopathy (PR). Patients are often asymptomatic until serious complications arise as, vitreous hemorrhage and retinal detachment. This work aimed to study the frequency and pattern of ocular manifestations in Egyptian children and young adults with SCD. In this cross-sectional study, 40 steady state patients (80 eyes) aged 2-28 years (30 children and 10 young adults) with established diagnosis of SCD (26 with homozygous SS and 14 with S/beta thalassemia underwent complete ophthalmic examination with dilated fundoscopy. Fluorescein angiography was performed for patients >=12 years old. The overall frequency of retinal lesions was 47.5 % (46.2 and 50 % of SS and S/beta patients respectively). PR and NPR were evident in 32.5 and 27.5 % of all enrolled patients respectively (five patients having both). Peripheral retinal occlusion was a frequent ocular finding in both groups; the youngest patient showing PR was 15 years old. Older age, longer disease duration and splenectomy were significantly more prevalent among patients with PR. Despite lack of visual symptoms, children and young adults are at risk of PR. Frequency of retinal lesions was comparable in SS and S/beta patients. Periodic ophthalmologic examination starting at the age of 12 years is recommended for timely-identification of retinal lesions thus minimizing the risk of sight threatening retinopathy. PMID- 25435728 TI - Serum ferritin in thalassemia intermedia. AB - Serum ferritin is a useful monitoring tool for iron overload in thalassemia major. In resource poor settings access to modalities for assessment of iron overload are limited. This study was undertaken to assess the efficiency and usefulness of serum ferritin level in thalassemia intermedia (TI) patients. This was a cross sectional observational study. Seventy seven TI patients attending the pediatric hematology clinic were included. Fasting blood sample was taken from each patient in iron free vials for iron studies. Serum ferritin was estimated by immunometric enzyme immunoassay using Orgentec GmbH kits. Mean age of patients evaluated was 10.9 +/- 5.03 (3-26) years. The mean age at diagnosis was 4.21 +/- 2.3 (0.8-11) years. Mean serum ferritin was 486.54 +/- 640.0 ng/ml (15-4,554). Thirty two (41.5 %) patients had a ferritin value of >=500 ng/ml. Nine patients had a serum ferritin of >=1,000 ng/ml. Three of the subjects with a ferritin >1,000 ng/ml had never received a blood transfusion (BT) and in the other six, the number of BTs ranged from 1 to 8. Serum ferritin did not correlate with age, total number of BTs splenectomy status or BT in last one year (p > 0.05). In 41.5 % of TI patients, serum ferritin was >=500 ng/ml. Age, BT and splenectomized status did not affect ferritin level. We postulate interplay of other biological factors like HFE gene mutation, ferroportin, etc. to contribute to ferritin level and hence iron load in TI patients. Ferritin can possibly be used as screening and monitoring tool for iron load in TI patients when other modalities to assess iron overload are not easily available. PMID- 25435729 TI - Influence of Xmn 1(G)gamma (HBG2 c.-211 C -> T) Globin Gene Polymorphism on Phenotype of Thalassemia Patients of North India. AB - Beta (beta) thalassemia is the most common single gene disorder in India. It has been reported that in patients with beta-thalassemia in the presence of Xmn 1(G)gamma polymorphic site the level of fetal hemoglobin (HbF) is increased thereby reducing the severity of disease. To determine the prevalence of Xmn 1(G)gamma polymorphic site and its effect on the clinical phenotype and HbF level in 39 beta-thalassemia major and 62 thalassemia intermedia patients, along with response to hydroxyurea therapy in thalassemia intermedia cases. Status of Xmn 1(G)gamma polymorphism was determined by polymerase chain reaction-restricted fragment length polymorphism procedure. The HbF level was determined using high performance liquid chromatography. Genotypes and allele frequencies of the Xmn 1(G)gamma polymorphism did not vary significantly between the various thalassemia groups. HbF levels were observed to be significantly increased and age at presentation was significantly greater in presence of Xmn 1(G)gamma polymorphic site on both alleles as compared to its absence in thalassemia major but not in thalassemia intermedia cases. The response of hydroxyurea in thalassemia intermedia was found only in a few patients irrespective of their Xmn 1(G)gamma status. Xmn 1(G)gamma polymorphisms appear to significantly influence HbF levels and age at presentation in thalassemia major but not in thalassemia intermedia patients. Small numbers precluded a definitive correlation of the polymorphism with response to hydroxyurea therapy. PMID- 25435730 TI - Detection and identification of red cell alloantibodies in multiply transfused thalassemia major patients: a prospective study. AB - Life long red blood transfusion remains the main treatment for beta thalassemia major patients. The development of alloantibodies complicates transfusion therapy in thalassemia patients. Alloimmunization to red cell antigens is one of the most important immunological transfusion reaction and causes delayed type of transfusion reaction. A prospective study was conducted from January 2007 to January 2010. This was a cohorts of 115 patients were selected from regular transfusion group and they were followed for two and half year. They were followed up for the effect of transfusion during study period. There was a decline in patient number from 115 to 96 due to mortality and transfer of patient. A total of 96 multiply transfused thalassemia patients were prospectively included in this study and three consecutive samples collected after every 6 months and investigated for the development of alloantibody to red cell antigens. Tests for antibody screening and identification were performed on preserved sample to investigate prevalence and development of red cell alloimmunization by standardized laboratory techniques by same person at Prathama Blood Centre. A total of 96 patients were included in the study. 63 patients were males and 33 females. A total of five single alloantibodies were formed in five patients out of them four (80 %) belonged to Kell blood group system and one (20 %) from Rh system. It was observed that two (1.92 %) of new thalassemia patients developed red cell alloantibodies during study period. Red cell alloimmunization should be kept in mind in the patients receiving multiple transfusions. In present study, alloimmunization rate was 5.21 %. Mean transfusion duration in these patients was 23.90 days, probably due to presence of alloantibody. RBC alloantibody detection on regular interval and corresponding antigen negative blood transfusion is strongly recommended in transfusion dependent thalassemia patients. PMID- 25435731 TI - Thalassemia major and intermedia in jammu and kashmir, India: a regional transfusion centre experience. AB - Data on status of thalassemia and hemoglobinopathies from the extreme northern part of India is scarce. We investigated socio-demographic characteristics and management issues related to beta-thalassemia in Jammu and Kashmir, India. Data from 96 thalassemia major and intermedia patients visiting the department of transfusion medicine for their transfusion needs was collected. Parameters recorded included age group, age at diagnosis, gender, religion, districts of the state they belonged to, family history of thalassemia, blood group, type of thalassemia (major/intermedia), total number of transfusions received and chelation therapy status. Thalassemia major patients comprised 92 (95.8 %) and intermedia 4 (4.2 %) of the cohort. Most cases were diagnosed in infancy or early childhood. The districts of Jammu and Rajouri together contributed 53 % of the cases. Most patients were Hindu (76/96, 79.2 %). A positive family history was most often obtained from Muslim patients (8/18, 44.4 %). Only 50 % cases were on iron chelation therapy. There is a need to come up with a national/local policy to manage disease in endemic areas and a policy formulated to help families and patients. Data such as ours may help in health management planning for thalassemic patients in this region. PMID- 25435732 TI - Red blood cell antibodies in thalassemia patients in northern India: risk factors and literature review. AB - Study of the factors responsible for red cell alloimmunization can help in adopting appropriate strategy to minimize alloimmunization. However data for thalassemia patients from our region is limited. Therefore, a study was conducted to find out the frequency and the factors associated with red cell allo and autoimmunization in thalassemia patients at our center so as to enable us to take appropriate action to reduce alloimmunization. Clinical, demographic, allo and autoantibody and transfusion records of 280 thalassemia patients at our hospital were studied. Patients with and without alloantibodies were compared to find significant differences for age, gender, race, age at start of regular transfusions and splenectomy. Red cell antigen frequencies in thalassemia patients and published antigen frequencies in blood donors from the same center were compared to look antigen differences as a risk factor for alloimmunization. Twenty four thalassemia patients (8.6 %) developed 28 clinically significant alloantibodies. 18 (65 %) of the alloantibodies were of Rh system. The three most common antibodies detected was anti E (11, 39.3 %) followed by anti K (6, 21.4 %) and anti c (10.8 %). Five (1.8 %) of the 280 patients developed autoantibodies. Patient age was found to be significantly higher in alloimmunized patients than in non alloimmunized patients. Red cell antigen frequencies between blood donor and recipient populations were found to be homogenous for most of the relevant RBC antigens. The frequency of red cell alloimmunization in thalassemia patients from our center is moderate. In this setting of red cell phenotype concordant donor-recipient population requirement of extended phenotype matched transfusions may not be cost effective. PMID- 25435734 TI - Pulse cyclophosphamide therapy in refractory warm autoimmune hemolytic anemia: a new perspective. AB - Treatment of steroid refractory autoimmune hemolytic anemia (AIHA) is challenging especially with no evidence based consensus guide lines and limited resources. The aim of this study was to evaluate the efficacy of pulse cyclophosphamide therapy in patients with severe refractory warm AIHA. The prospective study was designed to evaluate the efficacy of pulse cyclophosphamide-1 g/month for four consecutive months-in 17 patients (10 males and 7 females) with severe refractory warm AIHA [13 primary AIHA and 4 (females) secondary to SLE], all studied patients failed to respond to high dose of steroid therapy +/- azathioprine +/- intravenous immunoglobulin +/- oral cyclophosphamide. Mean hemoglobin level, reticulocytic count and direct antiglobulin test were assessed before and after cyclophosphamide treatment every month. After the 4th cycle of cyclophosphamide (82 %, 14 patients) achieved partial response while the remaining (17 %, 3 patients) showed no response, while after 6 months follow up 47 % (8 patients) show complete response, while 53 % (9 patients) showed partial response. The mean hemoglobin levels were significantly increased after the 1st, 2nd, 3rd and 4th months of pulse cyclophosphamide therapy when compared to before treatment (P < 0.01, P < 0.001, P < 0.001 and P < 0.001) respectively, and the mean reticulocyte (%) were significantly decreased after the 2nd, 3rd and 4th months (P < 0.05, P < 0.01 and P < 0.001) respectively. We conclude that pulse cyclophosphamide therapy is well tolerated and induces good response in patients with severe refractory warm AIHA. PMID- 25435733 TI - Prevalence of Alloimmunization to Human Platelet Antigen Glycoproteins and Human Leucocyte Antigen Class I in beta Thalassemia Major Patients in Western India. AB - Present management of beta thalassemia major by regular packed red blood cell (PRBC) transfusions poses risk of alloimmunization not only to red blood cell antigens, but also to human platelet antigens (HPA) and Human leucocyte antigens class I (HLA I). However data in this context is very limited in Indian population. The aim of the study was to determine the prevalence of alloimmunization to HPA and HLA I in beta thalassemia major patients who have received multiple PRBC transfusions over the years. A cross sectional study was performed at our tertiary care blood bank. beta thalassemia major patients of more than 6 years of age were included who were receiving fresh, leucoreduced and irradiated PRBC units regularly with annual requirement of more than ten PRBC transfusions. A total of 9 out of 80 (11.25 %) patients were found to be alloimmunized for HPA antigens of various specificity and 24 out of 80 (30 %) developed antibodies to HLA I. The awareness of development of alloimmunization to HPA and HLA antigens in multi PRBC transfused thalassemics, despite use of leucofilters will prompt us, to look for improvement in our current PRBC preparations to minimise platelet alloimmunisation. Further studies are required to validate the findings and build the base line data in this regard. This is of importance, especially in view of providing suitable cross-matched platelets when required in future especially when considering future haematopoietic stem cell transplantation (HSCT). PMID- 25435735 TI - A prospective study to determine the frequency of bacterial contamination of platelets. AB - Bacterial contamination of transfusion products is a long standing problem which includes donor bacteremia, contamination during the whole blood collection procedure, contamination of the collection pack and contamination during the blood processing procedure. The purpose of this study is to know the incidence of bacterial contamination of platelets and how to overcome it. During January 2009 to December 2010, 5,000 units of platelets concentrate were collected and 5 ml of platelet concentrate was sent for sterility test. A total of 8 units were reported as bacterially contaminated. Bacterial contamination can be reduced by better skin disinfection, collection of blood with a diversion pouch set, testing for bacteria and potentially the use of safe & effective pathogen reduction technologies and when available. PMID- 25435736 TI - Evaluation of a red cell leukofilter performance and effect of buffy coat removal on filtration efficiency and post filtration storage. AB - Prestorage leukoreduction of red cells is effective in reducing the incidence of HLA alloimmunization and improving the quality of stored packed red blood cells (PRBC). This study was conducted to evaluate the effectiveness of Imugard III-RC 4P in removing the leukocyte from packed red cells and the storage effects thereafter. The effects of buffy coat removal on the efficiency of leukofiltration, storage parameters of leukofiltered packed red blood cells and feasibility of prestorage leukofiltration were also assessed. Sixteen units each of buffy coat-depleted (LP) and nondepleted (NLP) PRBC were taken. Every unit was divided into two equal halves, one leukofiltered and other, non-leukofiltered. Cell counts, volume, hematocrit and hemoglobin were measured before and after filtration. Levels of K(+), lactate dehydrogenase (LDH) and hemolysis were assessed in all the units weekly, post leukofiltration. Post leukofiltration, red cell and volume loss was within the specified limit in all the units. Residual leukocytes were significantly lesser in LP- PRBC compared to NLPPRBC. K(+), LDH and hemolysis were significantly elevated in NLP- PRBC. Leukofiltered PRBC showed lesser elevation of K(+), LDH and hemolysis towards the end of the storage period as compared to their unfiltered counterparts. Leukofilter is capable of performing ~4 log reduction. Buffy coat removal prior to filtration improves the efficiency of leukofilter and aids in improving the storage of red cells in terms of hemolysis. PMID- 25435737 TI - An audit of fresh frozen plasma usage in a tertiary trauma care centre in north India. AB - Fresh frozen plasma (FFP) transfusion is a crucial part of management of trauma patients. There is a paucity of literature about the audit of appropriateness of FFP use in trauma patients. To evaluate and analyze the appropriateness of FFP transfusion practices for trauma patients. Prospectively compiled blood bank records of FFP transfusion practices over a period of 4 months from Augusts'08 through Deember'08 were retrospectively analyzed for 207 patients. The number of FFP units used in all these trauma patients were evaluated a propos the cause of injury, departments, type of surgery, presence of coagulopathy, bleeding, massive transfusion, length of hospital stay and patient outcome. Trauma scores such as Glasgow coma score and injury severity score were also calculated to estimate the severity of injury. The appropriateness of FFP transfusion was assessed according to the guidelines drafted by the College of American Pathologists. FFP transfusion for patients experiencing active bleeding, micro vascular bleeding, coagulopathy and/or massive transfusion, was deemed appropriate. Patients receiving FFP were categorized and individually correlated with the outcome. The influences of other variables which affect patient outcome were excluded using stepwise multivariate logistic regression analysis. p value < 0.05 were considered to be statistically significant. A total of 207 trauma patients were included in the study, 183 (88.4 %) males and 24 (11.6 %) females. The FFP use among neurosurgery patients was 46.9 %, general surgery patients 40.6 % and orthopedics 12.6 %. Appropriate use of FFP was 49.5 % according to the CAP guidelines. Trauma patients who required FFP as a part of treatment were categorized as; Patients who had bleeding alone (n = 40), bleeding with coagulopathy (n = 16), and coagulopathy alone (n = 43), and further correlated with the outcome and were found statistically insignificant. The prevalence of appropriate use of FFP at trauma centre was 49.5 %. The FFP use by neurosurgery:orthopedics:general surgery was 5:1:4. The highest appropriate FFP use was by Neurosurgery department (50.5 %). Assessing the pattern of usage and rate of misuse of FFP units, allows us to establish required strategies to improve the state of affairs. PMID- 25435738 TI - Activation of coagulation and fibrinolysis during coronary artery bypass grafting: a comparison between on-pump and off-pump techniques. AB - Coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) is associated with intense activation of hemostatic mechanisms. But the precise knowledge of the effects of eliminating CPB in patients undergoing off-pump coronary artery bypass grafting (CABG) are not well established. The present study was carried out to compare and document the changes in selected coagulation and fibrinolysis variables in patients undergoing on-pump and off-pump CABG (OPCAB). A total of 42 patients of on-pump and 31 patients of off-pump CABG were selected for the study. Platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), Fibrinogen and D-dimer levels were measured immediately, 24 h and 7 days after operation and compared with the baseline preoperative values. Statistical analysis was done by mixed ANOVA for repeated measures and Post-hoc tests using the Bonferroni correction, Chi square and unpaired t test. All the parameters were significantly changed (P < 0.05) with the time. Platelet counts, fibrinogen and D-dimer levels were significantly different between on-pump and off-pump CABG patients on immediate and 24 h postoperative period and attained almost same level after 7 days of operation. Fibrinogen level and platelet counts were increased after a sharp fall in the immediate post-operative period whereas D-dimer levels were persistently increased with a sharp peak of rise in the immediate post-operative period in on pump group. On-pump surgery was associated with excessive fibrinolytic activity immediately after operation. The off-pump group demonstrated less activation of coagulation and fibrinolysis and delayed postoperative response that became almost equal to the on-pump group in the later postoperative period. PMID- 25435739 TI - Diagnosis and management of atypical hemolytic uremic syndrome in children: single centre experience. AB - Atypical hemolytic uremic syndrome (aHUS) although rare is the commonest cause of acute renal failure (ARF) in children and has poor prognosis. We present single centre experience of aHUS. Thirty six children (29 males, 7 females) with mean age, 7.9 years presented with ARF, 2 children also had tonic-clonic type convulsions. Their hematology examination revealed hemolytic anemia with s. creatinine (SCr), 5.54 mg/dl. Acute HUS was observed in 75 %, acute on chronic HUS in 19.4 % and patchy cortical necrosis (PCN) in 5.6 % biopsies. Mean 5.4 plasma exchanges (PE) were carried out. Supportive management of anti hypertensives and prednisone was also given. Recovery end points were establishment of urine output, improvement of SCr and hematological profile. Hematology and renal function profile improved variably in all children, 5.6 % died, relapse was observed in 80.5 % over mean 70 days; 13.9 % children are doing well over mean follow-up of 268.8 days. Thus poor prognosis was observed in 86.1 % children. Children with acute on chronic HUS and PCN did not recover. Six children who recovered had acute HUS. aHUS in Indian children occurs at an older age of around 8 years and chronic/irreversible changes on histopathology examination are harbingers of poor prognosis. PE is life-saving however further research for developing strategies to improve long-term survival is needed. PMID- 25435740 TI - Routine coagulation testing: do we need a discard tube? AB - When coagulation tests are performed, the recommended guideline is that a discard tube be used and the coagulation testing should be done only on the second tube. This guideline is however inconsistently enforced and most laboratories follow a single tube draw for routine coagulation testing. Few studies have however, challenged this guideline and have shown that comparable results can be obtained in both tubes when a two tube draw is used. This prospective study was done over a 3 months period in the hematology laboratory under the Clinical Hematology unit of a tertiary care teaching institution in North India. Fifty-six paired specimens were drawn from healthy volunteers following the prescribed "two tube draw" method. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were performed within 1 h of sample collection on a fully automated photo optical coagulation instrument (Ceveron-Alpha). Paired results for PT and APTT were compared using Bland-Altman plots for method comparison. There was good correlation between the PT, INR and APTT of the first and second tubes with bias of 0.09, -0.05 and 0.3 respectively). Bland-Altman plots showed acceptable agreement between the two values with 95 % confidence interval ranging from -0.62 to 0.79 for PT, -0.05 to 0.06 for INR and -3.9 to 4.6 for APTT. Our study has shown no significant difference between PT and APTT values for the first and second tubes. Hence the use of a discard tube is not required. PMID- 25435741 TI - Bone mineral density in hemophilia patients. AB - Patients with hemophilia suffer from low bone mineral density (BMD) due to several risk factors including arthropathy and resulting immobility. Recent studies have shown variable frequency of low BMD in this group of patients. This study attempts to assess the prevalence of low BMD (osteoporosis and osteopenia) and the associated risk factors in a group of Iranian hemophilia patients. Patients with moderate or severe hemophilia underwent BMD measurement by dual energy X-ray absorptiometry. The results were correlated with other variables including physical activity, calcium intake and demographic data. Forty two patients with the mean age of 31 years (range 18-72) completed the study. The prevalence of osteoporosis in the spine and the left femoral neck was 23.8 and 14.6 %, respectively, and osteopenia in the spine and femoral neck was seen in 45.2 and 31.7 % of the patients, respectively based on the WHO T-score criteria. We found only cigarette smoking to be significantly related to low BMD (P < 0.001). There were two cases of pathologic fracture at femoral neck and forearm (4.8 %). Low BMD is very common in patients with hemophilia. Appropriate assessment of BMD and control of predisposing factors such as prophylactic factor replacement (to prevent hemarthrosis) and cessation of cigarette smoking are warranted. PMID- 25435742 TI - The Epidemiology of FVIII Inhibitors in Indian Haemophilia A Patients. AB - A serious complication of replacement therapy in patients with bleeding disorders is the development of 'inhibitors', particularly FVIII inhibitors in haemophilia A patients. This leads to an increase in the management cost, morbidity and mortality, especially post-operatively. The mechanism of FVIII inhibitor development is quite complex and it is difficult to predict inhibitor development, but a prompt and accurate diagnosis is critical as early therapy can save lives. The aim of this study was to screen patients with bleeding disorders in India for inhibitors, and to analyse and compare the prevalence of inhibitors in different regions in India. Patient details were recorded and blood samples were collected in sodium citrate vacutainers from 1,505 patients with bleeding disorders, in different cities in India. Coagulation and inhibitor screening assays were performed, followed by the Bethesda assay in inhibitor positive samples to quantify the FVIII inhibitor titre. Out of the 1,505 samples analysed, 1,285 were Haemophilia A patients, out of which 78 (6.07 %) were positive for 'FVIII Inhibitors'. The highest incidence of FVIII Inhibitors was seen in South India (13.04 %). The highest incidence of 20.99 % was observed in Chennai, followed by Hyderabad (13.33 %), Jammu (9.90 %) and Guwahati (8.51 %), respectively, with respect to the samples analysed. The other regions showed an inhibitor incidence <8 %. The incidence of inhibitors in haemophilia A patients is different in different regions of India; this may be due to the intensity of treatment, type of product or the genetic characteristics of these patients. PMID- 25435743 TI - Activated protein C resistance and antiphospholipid antibodies in recurrent fetal loss: experience of a single referral center in northern iraq. AB - The current study was initiated to determine the prevalence of activated protein C (APC) resistance, factor V Leiden and antiphospholipid antibodies (APA) in Iraqi women with recurrent fetal loss (RFL), and evaluate the outcome of intervention in those with such states. For this purpose a total of 103 Iraqi women referred to a major teaching hospital in Northern Iraq with two or more consecutive fetal losses, as well as 100 age matched women with no history of fetal loss and at least one live birth were enrolled. After appropriate clinical evaluation, the enrolled subjects were tested for APA as well as APC resistance. Subjects who were APC resistant were further tested for factor V Leiden mutation using a polymerase chain reaction and reverse hybridization. Patients with documented APA and/or with APC resistance, were put on low dose aspirin with or without low molecular weight heparin during pregnancy, and followed for a minimum of 5 years. The results revealed that among patients' group, APA were detected in 19.4 % compared to 1.0 % of the controls (OR 23.9, p = 0.00005). On the other hand, APC resistance was documented in 9.7 % compared to 1.0 % of the controls (OR 10.6, p = 0.01). Factor V Leiden was detected in 3.9 % of patients and 1 % of the controls (p = 0.38). Among 17 patients with APA available for follow up, there were 24 pregnancies, 18 of which ended with live births (75 %). While among the ten patients who had factor V Leiden or were APC resistant non-carriers, there were 13 pregnancies, 12 ended with live births (92.3 %). In conclusion, this study has demonstrated that among the enrolled Iraqi women, APA and APCR and not factor V Leiden were significantly associated with RFL, and that treatment with aspirin (with or without low molecular weight heparin) had lead to live births in 80.6 % of pregnancies. PMID- 25435744 TI - Levator resection in the management of myopathic ptosis. AB - PURPOSE: To evaluate the results of levator resection in patients with myopathic ptosis. METHODS: The medical records of consecutive patients who underwent levator resection surgery performed for myopathic ptosis between October 2009 and March 2013 were reviewed. Indications for surgery were ptosis obscuring the visual axis and margin-reflex distance <= 2 mm. Surgical success was defined as clear pupillary axis when the patient voluntarily opened his eye and margin reflex distance >= 3 mm. We analyzed the effect of levator function and Bell's phenomenon on the rates of success and corneal complication. RESULTS: This series included six male and six female patients. Levator function was between 4 and 12 mm. We performed bilateral levator resection surgery in all patients. The mean follow-up time was 14.8 months (range, 6 to 36 months). No patient was overcorrected. Adequate lid elevation was achieved after the operation in 20 eyes. Ptosis recurred in three out of 20 eyes after adequate lid elevation was achieved. Our overall success rate was 70.8%. In three eyes with poor Bell's phenomenon, corneal irritation and punctate epitheliopathy that required artificial eye drops and ointments developed in the early postoperative period, although symptoms resolved completely within 2 months of the resection surgery. No patients required levator recession or any other revision surgery for lagophthalmos or corneal exposure after levator resection. CONCLUSIONS: Levator resection seems to be a safe and effective procedure in myopathic patients with moderate or good Bell's phenomenon and levator function greater than 5 mm. PMID- 25435745 TI - Prevalence and spatial concordance of visual field deterioration in fellow eyes of glaucoma patients. AB - PURPOSE: To examine the prevalence of visual field deterioration in contralateral eyes of patients with worsening open-angle glaucoma and to evaluate the spatial concordance of visual field deterioration between both eyes. METHODS: One hundred sixteen open-angle glaucoma patients who underwent 8 or more visual field examinations over >= 6 years of follow-up were included. The rates of the fast and slow components of visual field decay for each of 52 visual field test locations were calculated with point-wise exponential regression analysis. The spatial concordance of visual field deterioration in contralateral eyes was evaluated with a concordance ratio (calculated as the number of overlapping locations divided by the total number of deteriorating locations) and by comparing the rate of decay in corresponding modified glaucoma hemifield test clusters. RESULTS: The average visual field mean deviation (+/- standard deviation [SD]) was -8.5 (+/- 6.4) dB and the mean (+/- SD) follow-up time was 9.0 (+/- 1.6) years. Sixty-three patients had mild damage, 23 had moderate damage, and 30 had severe damage. The mean concordance ratio (+/- SD) was 0.46 (+/- 0.32) for the mild group, 0.33 (+/- 0.27) for the moderate group, and 0.35 (+/- 0.21) for the severe group. Thirty-one patients (27%) had deterioration in concordant locations (p < 0.05). Visual field deterioration was greater in the superior hemifield than the inferior hemifield (p < 0.05) when evaluated with both the concordance ratio and modified glaucoma hemifield test cluster analysis methods. CONCLUSIONS: There is only fair spatial concordance with regard to visual field deterioration between the both eyes of an individual. We conclude that testing algorithms taking advantage of inter-eye spatial concordance would not be particularly advantageous in the early detection of glaucomatous deterioration. PMID- 25435746 TI - Accuracy of biometry for intraocular lens implantation using the new partial coherence interferometer, AL-scan. AB - PURPOSE: To compare the refractive results of cataract surgery measured by applanation ultrasound and the new partial coherence interferometer, AL-scan. METHODS: Medical records of 76 patients and 104 eyes who underwent cataract surgery from January 2013 to June 2013 were retrospectively reviewed. Biometries were measured using ultrasound and AL-scan and intraocular lens power was calculated using the SRK-T formula. Automatic refraction examination was done 1 month after the operation, and differences between the ultrasound group and AL scan group were compared and analyzed by mean absolute error. RESULTS: Mean axial length measured preoperatively by the ultrasound method was 23.53 +/- 1.17 mm while the lengths measured using the AL-scan were 0.03 mm longer than that of the ultrasound group (23.56 +/- 1.15 mm). However, there was not a significant difference in this finding (p = 0.638). Mean absolute error was 0.34 +/- 0.27 diopters in the ultrasound group and 0.36 +/- 0.31 diopters in AL-scan group, which showed no significant difference (p = 0.946) in precision of predicting postoperative refraction. CONCLUSIONS: Although the difference was not statistically significant, intraocular lens calculations done by the AL-scan were nearly similar in predicting postoperative refraction compared to those of applanation ultrasound, however more precise measurements may be obtained if the axial length is longer than 24.4 mm. Except in the case of opacity in the media, which makes obtaining measurements with the AL-scan difficult, AL-scan could be a useful biometry in cataract surgery. PMID- 25435748 TI - Elevated plasma pentraxin 3 and its association with retinal vein occlusion. AB - PURPOSE: To evaluate plasma pentraxin 3 (PTX3) in patients with retinal vein occlusion (RVO), and investigate the possibility of its role as a predictive biomarker. METHODS: Nested case-control study. The study included 57 patients with RVO and 45 age- and gender-matched subjects without RVO as controls. Plasma PTX3 and C-reactive protein concentration were measured in both groups a posteriori from frozen samples by using an enzyme-linked immunosorbent assay kit. RESULTS: The measured PTX3 value for the RVO group was 1,508 +/- 1,183 pg/mL (mean +/- standard deviation) and 833 +/- 422 pg/mL for the controls (p < 0.001). There was no significant difference in PTX3 levels between patients with central retinal vein occlusion and branched retinal vein occlusion (1,468 +/- 1,300 vs. 1,533 +/- 1,121 pg/mL; p = 0.818). CONCLUSIONS: Our data seems to support the role of chronic inflammation and ischemia in the development of RVO. It is possible that PTX3 can be used as a diagnostic biomarker of RVO. PMID- 25435749 TI - Intravitreal anti-vascular endothelial growth factor for typical exudative age related macular degeneration in eyes with good baseline visual acuity. AB - PURPOSE: To investigate 12-month treatment outcomes of anti-vascular endothelial growth factor therapy in eyes with typical exudative age-related macular degeneration with good baseline visual acuity. METHODS: This retrospective observational case series included 18 eyes (18 patients) with typical exudative age-related macular degeneration with a baseline best-corrected visual acuity of 20 / 25 or better. Patients were treated with anti-vascular endothelial growth factor monotherapy during the 12-month follow-up period. Baseline visual acuity and central foveal thickness were compared to the values at 12 months. RESULTS: Patients received an average of 4.4 +/- 1.3 intravitreal anti-vascular endothelial growth factor injections. The mean logarithm of minimum angle of resolution visual acuity was 0.08 +/- 0.04, 0.08 +/- 0.07, 0.12 +/- 0.09, and 0.16 +/- 0.11 at baseline, three months, six months, and 12 months, respectively. Visual acuity at 12 months was significantly worse than the baseline value at diagnosis (p = 0.017), and the mean central foveal thickness at the defined time points was 270.2 +/- 55.6, 204.4 +/- 25.4, 230.1 +/- 56.3, and 216.8 +/- 48.7 um, respectively. The central foveal thickness at 12 months was significantly less than the baseline value at diagnosis (p = 0.042). CONCLUSIONS: Deterioration in visual acuity was noted in eyes with typical exudative age-related macular degeneration with good baseline visual acuity, suggesting the need for close patient monitoring and prompt treatment even in patients with good baseline visual acuity. PMID- 25435747 TI - Changing trends in surgery for retinal detachment in Korea. AB - PURPOSE: To analyze trends in rhegmatogenous retinal detachment (RRD) surgery among the members of the Korean Retina Society from 2001 to 2013. METHODS: In 2013, surveys were conducted by email and post to investigate the current practice patterns regarding RRD treatment. Questions included how surgeons would manage six cases of hypothetical RRD. Results were compared to those reported in 2001. RESULTS: A total of 133 members (60.7%) in 2013 and 46 members(79.3%) in 2001 responded to the survey. Preference for pneumatic retinopexy has decreased in uncomplicated primary RRD (p = 0.004). More respondents in 2013 selected vitrectomy as the primary procedure when mild vitreous hemorrhage (p = 0.001), myopia (p = 0.044) and history of successful scleral buckling on the fellow eye (p = 0.044) were added to the primary scenario. Vitrectomy was over twice as popular in cases of pseudophakic, macula-off RRD with posterior capsular opacity (p = 0.001). CONCLUSIONS: For RRD with myopia, pseudophakia and media opacity, surgical interventions over the last decade have drastically shifted from scleral buckling and pneumatic retinopexy to vitrectomy. PMID- 25435750 TI - Comparison of the thickness of the lamina cribrosa and vascular factors in early normal-tension glaucoma with low and high intraocular pressures. AB - PURPOSE: To compare the thickness of the lamina cribrosa (LC) and vascular factors of early normal-tension glaucoma (NTG) patients with high and low intraocular pressure (IOP) that are expected to be associated with the development of glaucoma. METHODS: Seventy-one Korean NTG patients with low IOP (the highest IOP <15 mmHg, 40 patients) and high IOP (the lowest IOP >15 mmHg, 31 patients) were included in this study. The thickness of LC and vascular factors were compared. The thickness of the LC was measured using the enhanced depth imaging method with spectral domain optical coherence tomography (Heidelberg Spectralis). RESULTS: The mean thickness of the central LC was 190.0 +/- 19.2 um in the low IOP group and 197.8 +/- 23.6 um in the high IOP group, but there was no statistical significant difference between the two groups (p > 0.05). The prevalence of self-reported Raynaud phenomenon was significantly higher in the low IOP group (33.0%) than the high IOP group (10.3%, p = 0.04). CONCLUSIONS: The laminar thickness did not significantly differ between the high and low IOP groups. However, the prevalence of Raynaud phenomenon was higher in the low IOP groups. These results suggest that the development of glaucoma with low IOP patients may be more influenced by peripheral vasospasm, such as Raynaud phenomenon, rather than laminar thickness in NTG. PMID- 25435752 TI - Introduction of lens-angle reconstruction surgery in rabbit eyes. AB - PURPOSE: In this study, we examined the stability of the lens-angle supporter (LAS) for accommodation restoration by comparing intraocular lens (IOL) location, after-cataract and ciliary body damage after cataract surgery in rabbits. METHODS: Eight rabbits were divided into experimental and control groups of four rabbits each. Phacoemulsification and irrigation and aspiration were performed in all rabbits. This was followed by an LAS and IOL insertion in the four experimental rabbits. In the four control rabbits, only an IOL insertion was performed. Six months after the surgery, the location of the IOL, the conditions of the lens capsule and ciliary body were evaluated using a slitl-amp examination and Miyake-Apple view. RESULTS: For the experimental group, the ultrasound biomicroscope results showed normal LAS and IOL positioning in all four cases. According to the slitlamp examination and Miyake-Apple view, the IOL was positioned at the center, with less after-cataract and damage to the ciliary body. For the control group, ultrasound biomicroscope results indicated a higher IOL position than normal, as well as a single case of IOL decentering. According to the slit-lamp examination and Miyake-Apple view, the IOL was decentered with more severe after-cataract and ciliary body damage. CONCLUSIONS: The LAS has the potential to maintain a stable IOL position while producing less after-cataract when used in lens-angle reconstruction for correction of presbyopia. Moreover, LAS implantation incurs less damage to the ciliary body. PMID- 25435753 TI - A case of paradoxical reaction after treatment of eyelid tuberculosis. PMID- 25435751 TI - Congenital aniridia: long-term clinical course, visual outcome, and prognostic factors. AB - PURPOSE: To describe the clinical course of congenital aniridia and to evaluate prognostic factors for visual outcome after long-term follow-up. METHODS: The medical records of 120 eyes from 60 patients with congenital aniridia were retrospectively reviewed. The prevalence and clinical course of ophthalmic characteristics, systemic disease, refractive errors, and visual acuity were assessed. Prognostic factors for final visual outcomes were analyzed. RESULTS: Aniridic keratopathy developed in 82 (69%) of 119 eyes. Macular hypoplasia was observed in 70 eyes of 35 patients (91%). Cataract was observed in 63 of 120 eyes (53%). Nystagmus was present in 41 patients (68% of 60 patients) at the initial visit but decreased in five patients (8% of 60 patients). Ocular hypertension was detected in 19 eyes (20% of 93 eyes), six (32% of 19 eyes) of which developed secondarily after cataract surgery. The mean changes in spherical equivalent and astigmatism during the follow-up period were -1.10 and 1.53 diopter, respectively. The mean final visual acuity was 1.028 logarithm of minimal angle of resolution. Nystagmus and ocular hypertension were identified as prognostic factors for poor visual outcome. CONCLUSIONS: Identification of nystagmus and ocular hypertension was important to predict final visual outcome. Based on the high rate of secondary ocular hypertension after cataract surgery, careful management is needed. PMID- 25435754 TI - Orbital dirofilariasis. PMID- 25435755 TI - A case of syphilitic outer retinitis mimicking acute zonal occult outer retinopathy. PMID- 25435756 TI - Bilateral free floating vitreous cysts with posterior embryotoxon. PMID- 25435757 TI - "GWM looking for sex-SERIOUS ONLY": The interplay of sexual ad placement frequency and success on the sexual health of "men seeking men" on Craigslist. AB - Over the past few years, researchers have begun to explore the use of the personals section on Craigslist.org as it applies to the sexual behaviors and partner accrual of men who have sex with men (MSM). Yet, the exact ramification of such a free sexual advertisement service on MSM's sexual health and sexual risk-taking behaviors are just being documented. As such, we surveyed 535 men by responding to their sexual ads placed on Craigslist.org to assess their sexual health and sexual health behaviors. Using Self-Efficacy Theory as our foundation, we posited that MSM who placed more ads and reported more success from these ads would also report more negative health behaviors (e.g., lowered condom use) and sexually transmitted diseases. Testing confirmed this hypothesis. There were two important implications. The behavior of Internet cruising, on its own, insufficiently impacted MSM health. It was the interaction of number of ads (self efficacy) and the success of those ads (outcome-efficacy) that ultimately contributed to negative health behaviors. Second, MSM may have had different intentions for cruising. The anti-theoretical tendency for some men to continually place high numbers of ads while also reporting very low success suggested that the outcome of merely placing the ads might be sufficiently erotic for some men. PMID- 25435758 TI - Estimation and Testing of Gene Expression Heterosis. AB - Heterosis, also known as the hybrid vigor, occurs when the mean phenotype of hybrid off-spring is superior to that of its two inbred parents. The heterosis phenomenon is extensively utilized in agriculture though the molecular basis is still unknown. In an effort to understand phenotypic heterosis at the molecular level, researchers have begun to compare expression levels of thousands of genes between parental inbred lines and their hybrid offspring to search for evidence of gene expression heterosis. Standard statistical approaches for separately analyzing expression data for each gene can produce biased and highly variable estimates and unreliable tests of heterosis. To address these shortcomings, we develop a hierarchical model to borrow information across genes. Using our modeling framework, we derive empirical Bayes estimators and an inference strategy to identify gene expression heterosis. Simulation results show that our proposed method outperforms the more traditional strategy used to detect gene expression heterosis. This article has supplementary material online. PMID- 25435759 TI - Phonemic awareness is a more important predictor of orthographic processing than rapid serial naming: Evidence from Russian. AB - We studied the relationship between rapid serial naming (RSN) and orthographic processing in Russian, an asymmetrically transparent orthography. Ninety-six students (mean age = 13.73) completed tests of word and pseudoword reading fluency, spelling, orthographic choice, phonological choice, PA and RSN. PA was a better predictor of orthographic skills and pseudoword reading accuracy than RSN, which accounted for more variance in word and pseudoword reading fluency. Controlling for pseudoword reading fluency washed out RSN's contribution to word reading fluency. These results extend previous findings questioning the role of RSN as an index of orthographic processing skills and support the idea that RSN taps into automaticity/efficiency of processing print-sound mappings. PMID- 25435760 TI - How Gendered Attitudes Relate to Women's and Men's Sexual Behaviors and Beliefs. AB - This study examines associations between endorsement of a sexual double standard, gender role attitudes, and sexual behaviors and beliefs. First year university students in the northeastern United States (N = 434; 52 % female; 33 % Black, 29 % Latino, 39 % White; ages 17-19) participated during their first year of college. Endorsement of a sexual double standard was associated with more conventionally gender-stereotyped sexual behaviors and beliefs, specifically, more sexual partners and fewer perceived barriers to condom use for young men, and more perceived barriers to condom use for young women. Women who were more conventional about men's roles in society tended to use condoms less, whereas women who were more conventional about women's roles tended to use condoms more. Men who were more conventional about men's roles tended to have fewer sexual partners. Findings suggest the importance of examining gender's role in sexual behaviors and beliefs by assessing multiple gendered attitudes, rather than simply considering biological sex. PMID- 25435762 TI - The Effect of Fatigue on Electromyographic Characteristics during Obstacle Crossing of Different Heights in Young Adults. AB - The aim of this study was to investigate the effect of fatigue on electromyographic (EMG) parameters of healthy young adults during obstacle crossing of two different heights. Twelve untrained male adults (23 +/- 5 years of age) were fatigued running on a treadmill with increasing speed and inclination and walked over an obstacle with a height set at 10% and 20% of each individual's lower limb length. Maximal plantar flexor torque and EMG of the medial gastrocnemius, soleus, and tibialis anterior muscles of the trailing limb were assessed during obstacle crossing. Data were captured before, immediately after and 5 minutes after a fatigue session. Fatigue induced significant reduction on the plantar flexor torque output immediately after and 5 minutes after exhaustion. After fatigue gait speed was not affected, the minimum distance between the obstacle and the trailing or leading foot remained unchanged, and the trailing foot contacted the ground closer to the obstacle immediately after fatigue. Regarding the EMG, medial gastrocnemius became after fatigue more active during swing phase when increasing the obstacle height, whereas this was not the case before or 5 minutes after fatigue. No other significant difference was observed for any of the examined muscles. It is concluded that the assessed fatigue protocol induced only minimal changes in the EMG activity of the examined muscles during obstacle crossing. Therefore, it is suggested that the neuromuscular system of healthy young individuals is able to respond to the decreased force capacity after fatigue during obstacle crossing of heights up to the 20% of the limb length. Key PointsExhaustion after running on a treadmill induces significant reduction in plantar flexion strength and changes in the positioning of the feet relative to the obstacle during obstacle crossing.EMG activity of the calf muscles of the trailing limb does not change significantly after fatigue during the stance phaseDuring swing phase, medial gastrocnemius EMG activity of the trailing limb increases after fatigue when obstacle height increases.These minor changes in EMG after fatigue, reveals that untrained, healthy, young subjects may compensate the deficit in muscular force due to fatigue when performing obstacle crossing. PMID- 25435763 TI - Shuttle-run sprint training in hypoxia for youth elite soccer players: a pilot study. AB - The purposes of the present study were to investigate if a) shuttle-run sprint training performed in a normobaric hypoxia chamber of limited size (4.75x2.25m) is feasible, in terms of producing the same absolute training load, when compared to training in normoxia, and b) if such training improves the repeated sprint ability (RSA) and the Yo-Yo intermittent recovery (YYIR) test outcome in young elite soccer players. Players of an elite soccer training Centre (age: 15.3 +/- 0.5 years, height: 1.73 +/- 0.07 m, body mass: 62.6 +/- 6.6 kg) were randomly assigned to a hypoxia or a normoxia training group. Within a 5-week period, players, who were not informed about the hypoxia intervention, performed at least 7 sessions of identical shuttle-run sprint training either in a normal training room (FiO2 = 20.95%) or in a hypoxic chamber (FiO2 = 14.8%; approximately 3300m), both equipped with the same floor. Each training session comprised 3 series of 5x10s back and forth sprints (4.5m) performed at maximal intensity. Recovery time between repetitions was 20s and between series 5min. Before and after the training period the RSA (6 x 40m shuttle sprint with 20 s rest between shuttles) and the YYIR test were performed. The size of the chamber did not restrict the training intensity of the sprint training (both groups performed approximately 8 shuttles during 10s). Training in hypoxia resulted in a lower fatigue slope which indicates better running speed maintenance during the RSA test (p = 0.024). YYIR performance increased over time (p = 0.045) without differences between groups (p > 0.05). This study showed that training intensity of the shuttle-run sprint training was not restricted in a hypoxic chamber of limited size which indicates that such training is feasible. Furthermore, hypoxia compared to normoxia training reduced the fatigue slope during the RSA test in youth soccer players. Key PointsShuttle-run sprint training is feasible in hypoxic chambers of limited size (i.e., 4.75x2.25m).Hypoxia sprint training (RSH), in comparison to normoxia training, might lead to better running speed maintenance during the repeated sprint ability test. PMID- 25435764 TI - Knowledge of repetitions range affects force production in trained females. AB - Most studies have examined pacing strategies with cyclical activities (running and cycling). It has been demonstrated that males employ different pacing strategies during repeated maximal voluntary contractions (MVCs) dependent upon a known endpoint. Since different fatiguing mechanisms have been identified between the genders, it is not known if females use comparable pacing strategies. The purpose of this study was to examine if informing female subjects regarding the number of MVCs to perform would affect force and electromyography (EMG). Twenty well-trained females completed 3 fatiguing protocols in a randomized order. In the control condition participants were informed they would perform twelve MVCs and then actually completed twelve. In the unknown condition they were not told how many MVCs to perform but were stopped after twelve. In the deception condition they were initially informed to perform 6 MVCs, but after the 6(th) MVC they were asked to perform a few more MVCs and were stopped after twelve. During the first 6 MVCs, forces in the deception condition were greater compared to the unknown (p = 0.021, ES = 0.65, 5%) and control (p = 0.022, ES = 0.42, 3%) conditions. No differences were found between conditions in the last 6 MVCs. A main effect for repetitions showed force deficits during the first 6 MVCs (p = 0.000, ES = 1.81, 13%) and last 6 MVCs (p = 0.05, ES = 0.34, 3%). No differences were found between conditions in biceps and triceps EMG. However, EMG decreased during the first 6 MVCs for biceps (p = 0.001, ES = 1.0, 14%) and triceps (p = 0.001, ES = 0.76, 14%) across conditions. No differences were found in the last 6 MVCs. The anticipation of performing fewer MVCs led to increased force, whereas no endpoint led to decreased force production. Key pointsPacing strategies occur during repeated (fatiguing) MVCs as a function of end point expectations.Females use similar pacing strategies as previously published results with males.Without a known end point, females will tend to pace themselves by decreasing force output even when asked to perform maximal contractions. PMID- 25435761 TI - Sex difference in irritable bowel syndrome: do gonadal hormones play a role? AB - Sex and gender effects in irritable bowel syndrome (IBS) have been reported in epidemiological, physiological, and clinical treatment studies. The potential role of gonadal hormones is discussed based on the female predominance in IBS and the correlation between IBS symptoms and hormonal status. Several different models have been proposed to examine the role of sex hormones in gastrointestinal (GI) function, including changes in GI symptoms during the menstrual cycle and differences in symptom expression in pre- and post-menopausal women as well as changes during pregnancy, hormonal treatment, or after ovariectomy. Gonadal hormones, in particular estrogens, can significantly modulate various clinical manifestations of IBS, including alterations in GI motility and visceral hypersensitivity. Additionally, sex differences in the stress response of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system are considered to be contributing factors in the pathogenesis of functional bowel disorders. The modulatory effects of estrogens on visceral pain may result from interactions with numerous neurotransmitters at different levels of the brain-gut axis, with a pivotal role of estrogens' interactions with the serotonin and corticotropin-releasing factor (CRF) signaling systems. Estrogens can also modulate neuroimmune interactions triggered by stress via the brain-gut axis. Sex differences in the biological actions, pharmacokinetics, and treatment efficacy of serotonergic medications clearly suggest sex differences in pain pathways that have to be taken into consideration in therapeutic interventions. PMID- 25435765 TI - Kinematic and Kinetic Profiles of Trunk and Lower Limbs during Baseball Pitching in Collegiate Pitchers. AB - The purpose of this study was to clarify differences in the kinematic and kinetic profiles of the trunk and lower extremities during baseball pitching in collegiate baseball pitchers, in relation to differences in the pitched ball velocity. The subjects were 30 collegiate baseball pitchers aged 18 to 22 yrs, who were assigned to high- (HG, 37.4 +/- 0.8 m.s(-1)) and low-pitched-ball velocity groups (LG, 33.3 +/- 0.8 m.s(-1)). Three-dimensional motion analysis with a comprehensive lower-extremity model was used to evaluate kinematic and kinetic parameters during baseball pitching. The ground-reaction forces (GRF) of the pivot and stride legs during pitching were determined using two multicomponent force plates. The joint torques of hip, knee, and ankle were calculated using inverse-dynamics computation of a musculoskeletal human model. To eliminate any effect of variation in body size, kinetic and GRF data were normalized by dividing them by body mass. The maxima and minima of GRF (Fy, Fz, and resultant forces) on the pivot and stride leg were significantly greater in the HG than in the LG (p < 0.05). Furthermore, Fy, Fz, and resultant forces on the stride leg at maximum shoulder external rotation and ball release were significantly greater in the HG than in the LG (p < 0.05). The hip abduction, hip internal rotation and knee extension torques of the pivot leg and the hip adduction torque of the stride leg when it contacted the ground were significantly greater in the HG than in the LG (p < 0.05). These results indicate that, compared with low-ball-velocity pitchers, high-ball-velocity pitchers can generate greater momentum of the lower limbs during baseball pitching. Key pointsHigh-ball-velocity pitchers are characterized by greater momentum of the lower limbs during pitching motion.For high-pitched-ball velocity, stabilizing lower limbs during pitching plays an important role in order to increase the rotation and forward motion of the trunk.Computation of the lower-extremity kinetics and measurement of lower-extremity strength may help clarify the role of muscle strength in determining knee and hip function in baseball pitching. PMID- 25435766 TI - A boxing-oriented exercise intervention for obese adolescent males: findings from a pilot study. AB - In New Zealand, obese Maori and Pasifika adolescents are at risk of numerous cardio-metabolic conditions with raising physical activity levels being proposed as a useful intervention. The present study used a mixed method design to explore the effects of a non-contact boxing-oriented training programme designed in terms of improvements to cardio-metabolic variables. Traditional recruitment strategies (media, referrals) were employed, with limited success leading to 3 adolescent boys (14-15 y) participating in the pilot intervention. Exercise sessions included 30 minutes of non-contact boxing training, followed by 30 minutes of progressive resistance training. Participants attended three 1h training sessions each week, for a total of 12 weeks. Physiological variables included anthropometric indices, visceral fat thickness, central blood pressures, central arterial stiffness (augmentation index: AIx), and carotid arterial stiffness (beta). Results revealed that there was no trend for change in body weight (125.5 +/- 12.1 kg vs. 126.5 +/- 11.0 kg) or BMI (39.3 +/- 4.1 kg.m(-2) vs. 39.0 +/- 4.6 kg.m(-2)). However, there was a moderate decrease in visceral fat thickness (4.34 +/- 2.51 cm vs 3.65 +/- 1.11 cm, d = 0.36). There was no change in central pulse pressure (38.7 +/- 7.3 mmHg vs. 38.3 +/- 5.0 mmHg), however, there was a small improvement in beta (3.01 +/- 0.73 vs. 2.87 +/- 0.84, d = 0.18). Focus group interview data with participants and their parents were used to explore issues related to motivation to participation. Results revealed participants commented on how the programme has led to new friendships, changes to their physical appearance, and increased physical fitness. Parents commented on increased self confidence, better performance in school, and a willingness to take part in new activities. In conclusion, it appears participating in the boxing oriented training programme was motivating to participants who engaged and had some physiological benefits in obese adolescent boys of Maori and Pasifika descent. However, despite these positive attributes, poor recruitment rates suggest that future work should focus on identifying the barriers to engagement. Key pointsA boxing-oriented intervention was developed for use with Maori and Pasifika adolescents to improve cardiometabolic risk factors.While results indicate positive benefits of participation in the 60-minute boxing-orientated programme, only three participants were recruited despite intense promotion.Future research should investigate the efficacy of strategies designed to raise intentions to exercise. PMID- 25435767 TI - Construct and concurrent validation of a new resistance intensity scale for exercise with thera-band(r) elastic bands. AB - The construct and concurrent validity of the Thera-Band Perceived Exertion Scale for Resistance Exercise with elastic bands (EB) was examined. Twenty subjects performed two separate sets of 15 repetitions of both frontal and lateral raise exercise over two sessions. The criterion variables were myoelectric activity and heart rate. One set was performed with an elastic band grip width that permitted 15 maximum repetitions in the selected exercise, and another set was performed with a grip width 50% more than the 15RM grip. Following the final repetition of each set, active muscle (AM) and overall body (O) ratings of perceived exertion (RPE) were collected from the Thera-Band(r) resistance exercise scale and the OMNI-Resistance Exercise Scale of perceived exertion with Thera-Band(r) resistance bands (OMNI-RES EB). Construct validity was established by correlating the RPE from the OMNI-RES EB with the Thera-Band RPE scale using regression analysis. The results showed significant differences (p <= 0.05) in myoelectric activity, heart rate, and RPE scores between the low- and high-intensity sets. The intraclass correlation coefficient for active muscles and overall RPE scale scores was 0.67 and 0.58, respectively. There was a positive linear relationship between the RPE from the OMNI-RES EB and the Thera-Band scale. Validity coefficients for the RPE AM were r(2) = 0.87 and ranged from r(2) = 0.76 to 0.85 for the RPE O. Therefore, the Thera-Band Perceived Exertion Scale for Resistance Exercise can be used for monitoring elastic band exercise intensity. This would allow the training dosage to be better controlled within and between sessions. Moreover, the construct and concurrent validity indicates that the OMNI-RES EB measures similar properties of exertion as the Thera-Band RPE scale during elastic resistance exercise. Key pointsThis new resistance intensity scale is an appropriate and valid tool for assessing perceived exertion during strength training with elastic bands.This scale can be used without reducing the accuracy of the dosage prescribed during training/rehabilitation sessions and while carrying out medium and/or long-term periodization programs or therapeutic interventions.Populations with specific physical or physiological needs could have access to an easy-to-use resource that allows them to carry out their training/rehabilitation programs with greater efficacy and without any risk to health. PMID- 25435768 TI - Motor Learning as Young Gymnast's Talent Indicator. AB - Talent identification plans are designed to select young athletes with the ability to achieve future success in sports. The aim of the study was to verify the predictive value of coordination and precision in skill acquisition during motor learning, as indicators of talent. One hundred gymnasts, both cadets (aged 11.5 +/- 0.5 yr.) and juniors (aged 13.3 +/- 0.5 years), competing at the national level, were enrolled in the study. The assessment of motor coordination involved three tests of the validated Hirtz's battery (1985), and motor skill learning involved four technical tests, specific of rhythmic gymnastics. All the tests were correlated with ranking and performance scores reached by each gymnast in the 2011, 2012, and 2013 National Championships. Coordination tests were significantly correlated to 2013 Championships scores (p < 0.01) and ranking (p < 0.05) of elite cadet athletes. Precision, in skill acquisition test results, was positively and significantly associated with scores in 2013 (adj. R(2) = 0.26, p < 0.01). Gymnasts with the best results in coordination and motor learning tests went on to achieve better competition results in three- year time. Key pointsIn talent identification and selection procedures it is better to include the evaluation of coordination and motor learning ability.Motor learning assessment concerns performance improvement and the ability to develop it, rather than evaluating the athlete's current performance.In this manner talent identification processes should be focused on the future performance capabilities of athletes. PMID- 25435769 TI - Influence of acute normobaric hypoxia on physiological variables and lactate turn point determination in trained men. AB - The goal of this study is to evaluate the response of physiological variables to acute normobaric hypoxia compared to normoxia and its influence on the lactate turn point determination according to the three-phase model of energy supply (Phase I: metabolically balanced at muscular level; Phase II: metabolically balanced at systemic level; Phase III: not metabolically balanced) during maximal incremental exercise. Ten physically active (VO2max 3.9 [0.49] l.min(-1)), healthy men (mean age [SD]: 25.3 [4.6] yrs.), participated in the study. All participants performed two maximal cycle ergometric exercise tests under normoxic as well as hypoxic conditions (FiO2 = 14%). Blood lactate concentration, heart rate, gas exchange data, and power output at maximum and the first and the second lactate turn point (LTP1, LTP2), the heart rate turn point (HRTP) and the first and the second ventilatory turn point (VETP1, VETP2) were determined. Since in normobaric hypoxia absolute power output (P) was reduced at all reference points (max: 314 / 274 W; LTP2: 218 / 184 W; LTP1: 110 / 96 W), as well as VO2max (max: 3.90 / 3.23 l.min(-1); LTP2: 2.90 / 2.43 l.min(-1); LTP1: 1.66 / 1.52 l.min(-1)), percentages of Pmax at LTP1, LTP2, HRTP and VETP1, VETP2 were almost identical for hypoxic as well as normoxic conditions. Heart rate was significantly reduced at Pmax in hypoxia (max: 190 / 185 bpm), but no significant differences were found at submaximal control points. Blood lactate concentration was not different at maximum, and all reference points in both conditions. Respiratory exchange ratio (RER) (max: 1.28 / 1.08; LTP2: 1.13 / 0.98) and ventilatory equivalents for O2 (max: 43.4 / 34.0; LTP2: 32.1 / 25.4) and CO2 (max: 34.1 / 31.6; LTP2: 29.1 / 26.1) were significantly higher at some reference points in hypoxia. Significant correlations were found between LTP1 and VETP1 (r = 0.778; p < 0.01), LTP2 and HRTP (r = 0.828; p < 0.01) and VETP2 (r = 0.948; p < 0.01) for power output for both conditions. We conclude that the lactate turn point determination according to the three-phase-model of energy supply is valid in normobaric, normoxic as well as hypoxic conditions. The turn points for La, HR, and VE were reproducible among both conditions, but shifted left to lower workloads. The lactate turn point determination may therefore be used for the prescription of exercise performance in both environments. Key PointsThe lactate turn point concept can be used for performance testing in normoxic and hypoxic conditionsThe better the performance of the athletes the higher is the effect of hypoxiaThe HRTP and LTP2 are strongly correlated that allows a simple performance testing using heart rate measures only. PMID- 25435770 TI - Effect of different attentional instructions on the acquisition of a serial movement task. AB - Recent research in attentional focus of instruction has predominantly over emphasized the investigation of discrete and continuous skills rather than serial skills. The purpose of this study was therefore to examine the effect of different attentional focus instructions on learning a serial skill task (i.e., taekwondo routine) in novice learners. It was predicted that the use of movement outcome instructions could enhance the learning of a serial skill as previously supported in studies examining the acquisition of discrete and continuous skills. Thirteen female participants were recruited for this study and were assigned to either movement form condition - control group (n = 7) or movement outcome condition - treatment group (n = 6). All participants underwent 12 practice sessions over an 8-week period with their respective instructional conditions with each session lasting 30 minutes. Video recording of the serial skill tasks (hand techniques, kicking techniques and 10-step routine) were captured at "the twelfth-training session", "after 1-week", and "after 1-month". It was found that more participants in the treatment group obtained a higher score in all three serial skill tasks, especially in Mastery component of 'Kicking' techniques at 'after 1-week' (p < 0.05, r = 0.57). This study suggested that movement outcome instructions have positive medium effect on balance control for serial skill task, especially in kicking actions. Key PointsMovement outcome (MO) instructions have a positive impact on learning a serial task, especially in kicking actions.More functional coordination during movement executions for MO participants.Benefits for MO instructions may be individual specific. PMID- 25435771 TI - Muscle Synergies of Untrained Subjects during 6 min Maximal Rowing on Slides and Fixed Ergometer. AB - The slides ergometer (SE) was an improvisation from fixed ergometer (FE) to bridge the gap of mechanics between ergometer rowing and on-water rowing. The specific mechanical constraints of these two types of ergometers may affect the pattern of muscle recruitment, coordination and adaptation. The main purpose of this study was to evaluate the muscle synergy during 6 minutes maximal rowing on slides (SE) and fixed ergometers (FE). The laterality of muscle synergy was also examined. Surface electromyography activity, power output, heart rate, stroke length and stroke rate were analyzed from nine physically active subjects to assess the rowing performance. Physically active subjects, who were not specifically trained in rowing, were chosen to exclude the training effect on muscle synergy. Principal component analysis (PCA) with varimax rotation was applied to extract muscle synergy. Three muscle synergies were sufficient to explain the majority of variance in SE (94.4 +/- 2.2 %) and FE (92.8 +/- 1.7 %). Subjects covered more rowing distance, exerted greater power output and attained higher maximal heart rate during rowing on SE than on FE. The results proved the flexibility of muscle synergy to adapt to the mechanical constraints. Rowing on SE emphasized on bi-articular muscles contrary to rowing on FE which relied on cumulative effect of trunk and upper limb muscles during propulsive phase. Key pointsThree muscle synergies were extracted during maximal rowing on both fixed and slides ergometerUntrained subjects emphasized leg muscles while rowing on SEUntrained subjects focused on back muscles during FE rowing. PMID- 25435772 TI - Psychometric Properties of the "Sport Motivation Scale (SMS)" Adapted to Physical Education. AB - The aim of this study was to investigate the factor structure of a Spanish version of the Sport Motivation Scale adapted to physical education. A second aim was to test which one of three hypothesized models (three, five and seven-factor) provided best model fit. 758 Spanish high school students completed the Sport Motivation Scale adapted for Physical Education and also completed the Learning and Performance Orientation in Physical Education Classes Questionnaire. We examined the factor structure of each model using confirmatory factor analysis and also assessed internal consistency and convergent validity. The results showed that all three models in Spanish produce good indicators of fitness, but we suggest using the seven-factor model (chi(2)/gl = 2.73; ECVI = 1.38) as it produces better values when adapted to physical education, that five-factor model (chi(2)/gl = 2.82; ECVI = 1.44) and three-factor model (chi(2)/gl = 3.02; ECVI = 1.53). Key PointsPhysical education research conducted in Spain has used the version of SMS designed to assess motivation in sport, but validity reliability and validity results in physical education have not been reported.Results of the present study lend support to the factorial validity and internal reliability of three alternative factor structures (3, 5, and 7 factors) of SMS adapted to Physical Education in Spanish.Although all three models in Spanish produce good indicators of fitness, but we suggest using the seven-factor model. PMID- 25435774 TI - Hydration Status and Fluid Balance of Elite European Youth Soccer Players during Consecutive Training Sessions. AB - The objective of the study was to investigate the hydration status and fluid balance of elite European youth soccer players during three consecutive training sessions. Fourteen males (age 16.9 +/- 0.8 years, height 1.79 +/- 0.06 m, body mass (BM) 70.6 +/- 5.0 kg) had their hydration status assessed from first morning urine samples (baseline) and pre- and post-training using urine specific gravity (USG) measures, and their fluid balance calculated from pre- to post-training BM change, corrected for fluid intake and urine output. Most participants were hypohydrated upon waking (USG >1.020; 77% on days 1 and 3, and 62% on day 2). There was no significant difference between first morning and pre-training USG (p = 0.11) and no influence of training session (p = 0.34) or time (pre- vs. post training; p = 0.16) on USG. Significant BM loss occurred in sessions 1-3 (0.69 +/ 0.22, 0.42 +/- 0.25, and 0.38 +/- 0.30 kg respectively, p < 0.05). Mean fluid intake in sessions 1-3 was 425 +/- 185, 355 +/- 161, and 247 +/- 157 ml, respectively (p < 0.05). Participants replaced on average 71.3 +/- 64.1% (range 0 363.6%) of fluid losses across the three sessions. Body mass loss, fluid intake, and USG measures showed large inter-individual variation. Elite young European soccer players likely wake and present for training hypohydrated, when a USG threshold of 1.020 is applied. When training in a cool environment with ad libitum access to fluid, replacing ~71% of sweat losses results in minimal hypohydration (<1% BM). Consumption of fluid ad libitum throughout training appears to prevent excessive (>=2% BM) dehydration, as advised by current fluid intake guidelines. Current fluid intake guidelines appear applicable for elite European youth soccer players training in a cool environment. Key PointsThe paper demonstrates a notable inter-participant variation in first morning, pre- and post-training hydration status and fluid balance of elite young European soccer players.On average, elite young European soccer players are hypohydrated upon waking and remain hypohydrated before and after training.Elite young European soccer players display varied fluid intake volumes during training, but on average do not consume sufficient fluid to offset fluid losses.Consecutive training sessions do not significantly impair hydration status, suggesting that elite young European soccer players consume sufficient fluid between training to maintain a stable hydration status and prevent excessive (>=2% body mass) dehydrationCurrent fluid intake guidelines appear applicable to this population when training in a cool environment. PMID- 25435773 TI - Individual and team performance in team-handball: a review. AB - Team handball is a complex sport game that is determined by the individual performance of each player as well as tactical components and interaction of the team. The aim of this review was to specify the elements of team-handball performance based on scientific studies and practical experience, and to convey perspectives for practical implication. Scientific studies were identified via data bases of PubMed, Web of Knowledge, SPORT Discus, Google Scholar, and Hercules. A total of 56 articles met the inclusion criteria. In addition, we supplemented the review with 13 additional articles, proceedings and book sections. It was found that the specific characteristics of team-handball with frequent intensity changes, team-handball techniques, hard body confrontations, mental skills and social factors specify the determinants of coordination, endurance, strength and cognition. Although we found comprehensive studies examining individual performance in team-handball players of different experience level, sex or age, there is a lack of studies, particularly for team-handball specific training, as well as cognition and social factors. Key PointsThe specific characteristics of team-handball with frequent intensity changes, specific skills, hard body confrontations, mental skills and social factors define the determinants of coordination, endurance, strength and cognition.To increase individual and team performance in team-handball specific training based on these determinants have been suggested.Although there are comprehensive studies examining individual performance in team-handball players of different experience level, sex, or age are published, there is a lack of training studies, particularly for team-handball specific techniques and endurance, as well as cognition and social factors. PMID- 25435775 TI - Does achilles tendon cross sectional area differ after downhill, level and uphill running in trained runners? AB - In this study we examined how hill running affects the Achilles tendon, a common location for injuries in runners. Twenty females ran for 10 min on each of three randomly ordered grades (-6%, 0 and +6%) at speeds selected to match the metabolic rates. Achilles tendon (AT) cross-sectional area (CSA) was imaged using Doppler ultrasound and peak vertical forces were analyzed using an instrumented treadmill. A metabolic cart and gas analyzer ensured a similar metabolic cost across grades. Data were analyzed using a forward selection regression. Results showed similar decreases in AT CSA from pre- to post-run for all three conditions of ~5 to 7% (p = 0.0001). Active peak vertical forces were different across grades (p = 0.0001) with the largest occurring during downhill running and smallest during uphill running. Since changes in AT CSA were not different between grades, each form of running appears equal and acceptable in regards to how the Achilles tendon reacts. That is, the results suggest that the Achilles tendon is affected by downhill, level, and uphill running and a decrease in CSA appears to be a normal response. Key PointsDownhill (- 6%), level and uphill (+ 6%) running at different speeds each caused a statistically significant decrease in the Achilles tendon cross-sectional area in healthy, trained runners.The magnitude of change in Achilles tendon cross-sectional area did not differ between grades when metabolic cost of running was matched.Downhill running resulted in the largest peak vertical force, while uphill running resulted in the smallest. PMID- 25435776 TI - The effect of structured exercise intervention on intensity and volume of total physical activity. AB - This study aimed to investigate the effects of a 12-week structured exercise intervention on total physical activity and its subcategories. Twenty-three overweight or obese middle aged men with impaired glucose regulation were randomized into a 12-week Nordic walking group, a power-type resistance training group, and a non-exercise control group. Physical activity was measured with questionnaires before the intervention (1-4 weeks) and during the intervention (1 12 weeks) and was expressed in metabolic equivalents of task. No significant change in the volume of total physical activity between or within the groups was observed (p > 0.050). The volume of total leisure-time physical activity (structured exercises + non-structured leisure-time physical activity) increased significantly in the Nordic walking group (p < 0.050) but not in the resistance training group (p > 0.050) compared to the control group. In both exercise groups increase in the weekly volume of total leisure-time physical activity was inversely associated with the volume of non-leisure-time physical activities. In conclusion, structured exercise intervention did not increase the volume of total physical activity. Albeit, endurance training can increase the volume of high intensity physical activities, however it is associated with compensatory decrease in lower intensity physical activities. To achieve effective personalized exercise program, individuality in compensatory behavior should be recognised. Key PointsStructured NW or RT training does not increase the volume of total physical activity.NW intervention can increase the volume of higher intensity activities.The increased in volume of LTPA induced by the structured NW and RT interventions was associated with the decreased volume of NLTPA. PMID- 25435778 TI - Review of the status of learning in research on sport education: future research and practice. AB - Research concerning Sport Education's educational impact has shown unequivocal results according to students' personal and social development. Nevertheless, research is still sparse with respect to the model's impact on student learning outcomes. The goal of the present review is to therefore scrutinize what is currently known regarding students' learning during their participation in Sport Education. This research spans a variety of studies, cross various countries, school grades, the sports studied, as well as the methods applied and dimensions of student learning analyzed. While research on the impact of Sport Education on students' learning, as well as teachers' and students' perceptions about student learning has shown students' improvements during the participation in Sport Education seasons, there is still considerable variance in these results. For example, some studies report superior learning opportunities to boys and higher skill-level students while other studies have identified superior learning opportunities for girls and lower skill-level students. These inconsistent results can be explained by factors not considered in the Sport Education research, such as the effect of time on students' learning and the control of the teaching-learning process within Sport Education units. In this review directions for future research and practice are also described. Future research should define, implement, and evaluate protocols for student-coaches' preparation in order to understand the influence of this issue on students' learning as well as consider the implementation of hybrid approaches. Moreover, future studies should consider the interaction of gender and skill level and a retention test in the analysis of students' learning improvements in order to obtain a more realist and complete portrait of the impact of Sport Education. Finally, in order to reach an entirely understanding of the teaching-learning process, it is necessary to use research designs that attend to the complexity of this process. Key PointsDespite research regarding has showed students' improvements during the participation in Sport Education seasons, it remains somewhat equivocal.The studies included in this review show students' improvements on skill, knowledge and tactical development, as we as game play, during the participation in Sport Education units.Some studies report superior learning opportunities to boys and higher skill-level students while other studies exposed superior learning opportunities to girls and lower skill-level students.The effect of time on students' learning and the control of the teaching-learning process within Sport Education units can explain these equivocal results.Future research is encouraged to consider the implementation of protocols for student-coaches' preparation, hybrid models, a retention test, the interaction of gender and skill level, and use research designs that attend to the complexity of the teaching-learning process. PMID- 25435777 TI - Effect of differing intensities of fatiguing dynamic contractions on contralateral homologous muscle performance. AB - The purpose of this study was to investigate different intensities of unilateral fatiguing dynamic quadriceps contractions on non-exercised, contralateral quadriceps performance. In a randomized crossover study design with 12 recreationally trained male (1.78 +/- 0.05 m, 84.5 +/- 7.6 kg, 30.0 +/- 8.5 yrs) participants, maximal voluntary contraction (MVC) force, force developed in the first 100 ms (F100), and electromyography of the non-exercised contralateral knee extensors were measured before and after fatiguing protocols performed by ipsilateral knee extensors. Non-exercised knee extensors' endurance was also measured post-intervention. The fatigue protocols consisted of four sets of dynamic knee extensions each to task failure with 40% and 70% MVC on separate days. Both the 40% (p = 0.009, Effect Size [ES] = 0.72) and 70% (p = 0.001, ES = 2.03) conditions exhibited 23.7% and 34.6% decreases in F100 respectively with the non-exercised contralateral knee extensors. A significant time effect (p = 0.002) demonstrated that both the 40% (and 70% (conditions exhibited 4.4% (ES = 0.29) and 7.1% (ES = 0.53) force decreases from pre- to post-intervention, respectively. However, the condition * time interaction only showed a trend (p = 0.09) with moderate (40%: ES = 0.62) to large (70%: ES = 0.82) effect sizes for decreased contralateral limb force compared with control session. The 40% (p = 0.09, ES = 0.65) and 70% (p = 0.07, ES = 0.79) protocols had a tendency to induce greater contralateral force variation during sustained submaximal isometric contraction compared with control. In conclusion, this study highlighted that unilateral lower limb fatigue induced by low intensity as well as high intensity dynamic knee extensions provided some evidence of crossover fatigue with the contralateral non-exercised limb. Key PointsThere was a pattern of crossover fatigue effects with significant impairments in F100, near significant, moderate to large magnitude decrements in MVC force and moderate magnitude increases in submaximal force variability in the contralateral knee extensors.Although both contraction intensities resulted in significant and near significant F100 and force decrements respectively, higher intensity (70%) fatiguing contractions manifested moderate to large magnitude effects (force and F100 respectively) compared to small to moderate magnitude effects (F100 and force respectively) for the lower intensity (40%) fatiguing contractions. PMID- 25435779 TI - Kinetic constrained optimization of the golf swing hub path. AB - This study details an optimization of the golf swing, where the hand path and club angular trajectories are manipulated. The optimization goal was to maximize club head velocity at impact within the interaction kinetic limitations (force, torque, work, and power) of the golfer as determined through the analysis of a typical swing using a two-dimensional dynamic model. The study was applied to four subjects with diverse swing capabilities and styles. It was determined that it is possible for all subjects to increase their club head velocity at impact within their respective kinetic limitations through combined modifications to their respective hand path and club angular trajectories. The manner of the modifications, the degree of velocity improvement, the amount of kinetic reduction, and the associated kinetic limitation quantities were subject dependent. By artificially minimizing selected kinetic inputs within the optimization algorithm, it was possible to identify swing trajectory characteristics that indicated relative kinetic weaknesses of a subject. Practical implications are offered based upon the findings of the study. Key PointsThe hand path trajectory is an important characteristic of the golf swing and greatly affects club head velocity and golfer/club energy transfer.It is possible to increase the energy transfer from the golfer to the club by modifying the hand path and swing trajectories without increasing the kinetic output demands on the golfer.It is possible to identify relative kinetic output strengths and weakness of a golfer through assessment of the hand path and swing trajectories.Increasing any one of the kinetic outputs of the golfer can potentially increase the club head velocity at impact.The hand path trajectory has important influences over the club swing trajectory. PMID- 25435780 TI - Three-dimensional analysis of a ballet dancer with ischial tuberosity apophysitis. A case study. AB - The purpose of this case study was to describe the three-dimensional biomechanics of common ballet exercises in a ballet dancer with ischial tuberosity apophysitis. This was achieved by comparing kinematics between the symptomatic (i.e. ischial apophyseal symptoms) and contralateral lower limbs, as well as via reported pain. Results suggest consistent differences in movement patterns in this dancer. These differences included: 1) decreased external rotation of contralateral hip, hence a decreased hip contribution to 'turn out'; 2) increased contralateral knee adduction and internal rotation; 3) an apparent synchronicity in the contralateral lower limb of the decreased hip external rotation and increased knee adduction; and 4) minimal use of ankle plantar/dorsiflexion movement for symptomatic side. Pain related to the left ischial apophysitis was associated with reduced amplitudes especially in fast ballet movements that required large range of motion in flexion and adduction in the left hip joint. These findings suggest that ischial apophysitis may limit dancer's ballet technique and performance. Key PointsThe pain related to the left ischial apophysitis was associated with reduced amplitudes especially in fast ballet movements that require large range of motion. This may affect to the lower limbs kinematics, and limit dancer's technique and performance.Compensatory strategies in the kinetic chain, differences in the joint angles between the lower limbs, traction forces, velocity and amplitude demands should be taken in consideration while training and rehabilitation of the ischial apophyseal injury within classical ballet. PMID- 25435781 TI - Effects of Synchronization between Cardiac and Locomotor Rhythms on Oxygen Pulse during Walking. AB - The oObjective of the study was to investigate whether the occurrence of cardiac locomotor synchronization (CLS) affects oxygen pulse (O2 pulse, mL/beat) during walking. Twelve healthy men were studied under two treadmill protocols. The CLS protocol involved subjects walking at a frequency of their heart rate (HR) to induce CLS. The free protocol (reference) involved subjects walking at a self selected cadence. The treadmill load was equal between the two protocols and was adjusted so that the subject's HR was maintained at approximately 120 bpm. Electrocardiographic signals, foot switch signals, and oxygen consumption (VO2) were measured continuously for 10 min after the heart rate reached a steady state. VO2, O2 pulse, and mean HR were calculated. VO2 and O2 pulse were significantly higher in subjects in the CLS protocol compared to those in the free protocol. However, mean HR was not different between the two groups. The synchronization strength was significantly related to the increase in O2 pulse in subjects in the CLS protocol compared with those in the free protocol. These results suggest that the occurrence of CLS enhances O2 pulse by increasing the strength of CLS during walking. Key PointsTwelve healthy men walked at a frequency of their heart rate (CLS protocol) and at a self-selected cadence (free protocol).Walking at the frequency of heart rate would induce the CLS by entrainment.Oxygen pulse was significantly higher in subjects in the CLS protocol compared to those in the free protocol.The occurrence of CLS enhances oxygen pulse by increasing the strength of CLS during walking. PMID- 25435782 TI - Physical Activity and Suicide Attempt of South Korean Adolescents - Evidence from the Eight Korea Youth Risk Behaviors Web-based Survey. AB - Suicide is the leading cause of death among South Korean adolescents. The purpose of this study was to examine the relationship between suicidal thoughts (ST) and suicidal attempts (SA) with the level of physical activity (PA) among South Korean adolescents. Based on data from the eighth Korea Youth Risk Behaviors Web Based Survey, 74,186 South Korean adolescents were evaluated in terms of their relationship between meeting guidelines for vigorous PA (VPA), moderate PA (MPA), and low PA (LPA) and in respect of ST and SA status. The adjusted odds ratio in adolescents who thought about suicide increased significantly with PA levels (1.02 in males, 1.21 in females with VPA, 1.10 in males, 1.18 in females with MPA, and 1.16 in males, 1.20 in females with LPA) compared to participants who did not think about suicide. In addition, the AOR in adolescents who attempted suicide increased significantly with PA levels (1.16 in males, 1.36 in females with VPA, 1.13 in males, 1.15 in females with MPA, and 1.26 in males, 1.15 in females with LPA) compared to participants who did not attempt suicide. These results show that VPA, MPA, and LPA are positively associated with ST and SA prevention in South Korean adolescents. Therefore, to prevent suicide of South Korean adolescents, we support public health program including PA participation. Key PointsSouth Korean male adolescents, compared to female adolescents, showed relatively high values for physical activity-related variables such as vigorous, moderate, and low PA.Regardless of gender, more physical activity participation is positively associated with prevention of suicidal thought and attempts of South Korean adolescents.To prevent suicide of South Korean adolescents, we support public health program including meeting guidelines for vigorous, moderate, and low physical activity. PMID- 25435783 TI - Heavy resistance training and peri-exercise ingestion of a multi-ingredient ergogenic nutritional supplement in males: effects on body composition, muscle performance and markers of muscle protein synthesis. AB - This study determined the effects of heavy resistance training and peri-exercise ergogenic multi-ingredient nutritional supplement ingestion on blood and skeletal markers of muscle protein synthesis (MPS), body composition, and muscle performance. Twenty-four college-age males were randomly assigned to either a multi-ingredient SizeOn Maximum Performance (SIZE) or protein/carbohydrate/creatine (PCC) comparator supplement group in a double-blind fashion. Body composition and muscle performance were assessed, and venous blood samples and muscle biopsies were obtained before and after 6 weeks of resistance training and supplementation. Data were analyzed by 2-way ANOVA (p <= 0.05). Total body mass, body water, and fat mass were not differentially affected (p > 0.05). However, fat-free mass was significantly increased in both groups in response to resistance training (p = 0.037). Lower-body muscle strength (p = 0.029) and endurance (p = 0.027) were significantly increased with resistance training, but not supplementation (p > 0.05). Serum insulin, IGF-1, GH, and cortisol were not differentially affected (p > 0.05). Muscle creatine content was significantly increased in both groups from supplementation (p = 0.044). Total muscle protein (p = 0.038), MHC 1 (p = 0.041), MHC 2A, (p = 0.029), total IRS- (p = 0.041), and total Akt (p = 0.011) were increased from resistance training, but not supplementation. In response to heavy resistance training when compared to PCC, the peri-exercise ingestion of SIZE did not preferentially improve body composition, muscle performance, and markers indicative of MPS. Key pointsIn response to 42 days of heavy resistance training and either SizeOn Maximum Performance or protein/carbohydrate/creatine supplementation, similar increases in muscle mass and strength in both groups occurred; however, the increases were not different between supplement groups.The supplementation of SizeOn Maximum Performance had no preferential effect on augmenting serum insulin, IGF-1, and GH, or in decreasing cortisol.While resistance training was effective in increasing total creatine content in skeletal muscle, myofibrillar protein, and the content of total IRS-1 and Akt, it was not preferentially due to SizeOn Maximum Performance supplementation.At the daily dose of 50 g, SizeOn Maximum Performance supplementation for 42 days combined with resistance training does not increases muscle mass and strength due to its ability to elevate serum hormones and growth factors or in its ability to augment skeletal muscle signaling pathway markers indicative of muscle protein synthesis when compared to an equivalent daily dose of protein/carbohydrate/creatine. PMID- 25435784 TI - Influence of gender and muscle architecture asymmetry on jump and sprint performance. AB - Muscle architecture is a determinant for sprinting speed and jumping power, which may be related to anaerobic sports performance. In the present investigation, the relationships between peak (PVJP) and mean (MVJP) vertical jump power, 30m maximal sprinting speed (30M), and muscle architecture were examined in 28 college-aged, recreationally-active men (n = 14; 24.3 +/- 2.2y; 89.1 +/- 9.3kg; 1.80 +/- 0.07 m) and women (n = 14; 21.5 +/- 1.7y; 65.2 +/- 12.4kg; 1.63 +/- 0.08 m). Ultrasound measures of muscle thickness (MT), pennation angle (PNG), cross sectional area (CSA), and echo intensity (ECHO) were collected from the rectus femoris (RF) and vastus lateralis (VL) of both legs; fascicle length (FL) was estimated from MT and PNG. Men possessed lower ECHO, greater muscle size (MT & CSA), were faster, and were more powerful (PVJP & MVJP) than women. Stepwise regression indicated that muscle size and quality influenced speed and power in men. In women, vastus lateralis asymmetry negatively affected PVJP (MT: r = 0.73; FL: r = -0.60) and MVJP (MT: r = -0.76; FL: r = -0.64), while asymmetrical ECHO (VL) and FL (RF) positively influenced MVJP (r = 0.55) and 30M (r = 0.57), respectively. Thigh muscle architecture appears to influence jumping power and sprinting speed, though the effect may vary by gender in recreationally-active adults. Appropriate assessment of these ultrasound variables in men and women prior to training may provide a more specific exercise prescription. Key pointsThe manner in which thigh muscle architecture affects jumping power and sprinting speed varies by gender.In men, performance is influenced by the magnitude of muscle size and architecture.In women, asymmetrical muscle size and architectural asymmetry significantly influence performance.To develop effective and precise exercise prescription for the improvement of jumping power and/or sprinting speed, muscle architecture assessment prior to the onset of a training program is advised. PMID- 25435787 TI - High Training Volumes are Associated with a Low Number of Self-Reported Sick Days in Elite Endurance Athletes. AB - It has been proposed that high exercise loads increase the risk of infection, most frequently reported as upper respiratory tract infections, by suppressing the immune system. Most athletes will not train when experiencing sickness due to the fear of health complications. However, high training volumes are incompatible with high rates of non-training days, regardless of the cause. The purpose of this observational study was to examine the relationship between self-reported, exercise-constraining days of sickness (days when the athlete decided not to train due to symptoms of disease, either self-reported or by a physician) and the volumes of exercise training in elite endurance athletes by analyzing data from training logs kept for several years. The subjects included 11 elite endurance athletes (8 male, 3 female) competing at national and international levels in cross-country skiing, biathlon and long-distance running. Training logs available from these 11 subjects added to a total of 61 training years. The number of training hours per year (462, 79-856; median, range) was significantly and negatively correlated to the reported number of days not training due to sickness (15, 0-164) by a 3(rd) degree polynomial regression (R(2) = 0.48, F ratio = 18, p < 0.0001). We conclude that elite endurance athletes can achieve high training volumes only if they also experience few sick-days. Key pointsTop level performance demands high training volumes and intensities, which may compromise immune function.Elite athletes must have an immune system capable of intact function also when under sever physiological and psychological stress.Elite performance, especially in endurance sports, is therefore incompatible with a high rate of infections.A negative correlation between infections and exercise training load among elite athletes is consequently observed - the less sick you are the more you can train. PMID- 25435785 TI - The effects of hypobaric hypoxia on erythropoiesis, maximal oxygen uptake and energy cost of exercise under normoxia in elite biathletes. AB - The aim of the present study was to evaluate the effects of 3 weeks altitude training according to the HiHiLo (live high-base train high-interval train low) procedure as described by Chapman et al. (1998), on erythropoiesis, maximal oxygen uptake and energy cost of exercise under normoxia in elite biathletes. Fifteen male elite biathletes randomly divided into an experimental (H) group (n = 7; age 27.1 +/- 4.6 years; maximal oxygen uptake (VO2max) 66.9 +/- 3.3 ml.kg( 1).min(-1); body height (BH) 1.81 +/- 0.06 m; body mass (BM) 73.1 +/- 5.4kg), and a control (C) group (n = 8; age 23.2 +/- 0.9 years; VO2max 68.2 +/- 4.1 ml.kg( 1).min(-1); BH 1.75 +/- 0.03 m; BM 63.1 +/- 1.5 kg) took part in the study. The H group stayed for 3 weeks at an altitude of 2015 m and performed endurance training on skis four times per week at 3000 m. Additionally, the training protocol included three high-intensity interval sessions at an altitude of 1000 m. The C group followed the same training protocol with skirollers in normoxia at an altitude of 600 m. The HiHiLo protocol applied in our study did not change VO2max or maximal workload (WRmax) significantly during the incremental treadmill test in group H. However, the energy cost for selected submaximal workloads in group H was significantly (p < 0.01) reduced compared to group C (-5.7%, -4.4%, 6% vs. -3.5%, -2.1%, -2.4%). Also a significant (p < 0.001) increase in serum EPO levels during the first two weeks of HiHiLo training at 2015 m was observed, associated with a significant (p < 0.05) increase in hemoglobin mass, number of erythrocytes, hematocrit value and percent of reticulocytes compared with initial values (by 6.4%, 5%, 4.6% and 16,6%, respectively). In group C, changes in these variables were not observed. These positive changes observed in our study led to a conclusion that the HiHiLo training method could improve endurance in normoxia, since most of the biathlon competitions are performed at submaximal intensities. Key pointsThe observed results suggests that the 3-weeks HiHiLo protocol is an effective training means for improving energy cost during submaximal exercise at sea level.The 3-weeks HiHiLo protocol increased the rate of erythropoiesis and improved most haematological variables.However, the positive changes in the athletes haematological variables after the HiHiLo protocol did not contribute to the improvement of VO2max values. PMID- 25435786 TI - Frowning and jaw clenching muscle activity reflects the perception of effort during incremental workload cycling. AB - The present study aimed to investigate whether facial electromyography (EMG) recordings reflect the perception of effort and primary active lower limb muscle activity during incremental workload cycling. The effects of exercise intensity on EMG activity of the corrugator supercilii (CS), masseter and vastus lateralis (VL) muscles, heart rate (HR) and the rating of perceived exertion (RPE) were investigated, and the correlations among these parameters were determined. Eighteen males and 15 females performed continuous incremental workload cycling exercise until exhaustion. CS, masseter and VL muscle activities were continuously recorded using EMG during exercise. HR was also continuously monitored during the test. During the final 30 s of each stage of cycle ergometer exercise, participants were asked to report their feeling of exertion on the adult OMNI-Cycle RPE. HR and EMG activity of the facial muscles and the primary active lower limb muscle were strongly correlated with RPE; they increased with power output. Furthermore, facial muscle activity increased significantly during high-intensity exercise. Masseter muscle activity was strongly and positively correlated with HR, RPE and VL activity. The present investigation supports the view that facial EMG activity reflects the perception of effort. The jaw clenching facial expression can be considered an important factor for improving the reporting of perceived effort during high-intensity exercise in males and females. Key pointsFrowning and jaw clenching muscle activity reflects the perception of effort during incremental workload cycling.EMG activity of the masseter muscle was strongly and positively correlated with RPE, HR and lower limb EMG activity during incremental workload cycling.The jaw clenching facial expression can be considered an important factor for estimating the intensity of effort. PMID- 25435788 TI - Calcineurin-NFAT Signaling and Neurotrophins Control Transformation of Myosin Heavy Chain Isoforms in Rat Soleus Muscle in Response to Aerobic Treadmill Training. AB - This study elucidated the role of CaN-NFAT signaling and neurotrophins on the transformation of myosin heavy chain isoforms in the rat soleus muscle fiber following aerobic exercise training. To do so, we examined the content and distribution of myosin heavy chain (MyHC) isoforms in the rat soleus muscle fiber, the activity of CaN and expression of NFATc1 in these fibers, and changes in the expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neutrophin-3 (NT-3) in the soleus and striatum following high-and medium-intensity aerobic treadmill training. Specific pathogen-free 2 month old male Sprague-Dawley (SD) rats were randomly divided into three groups: Control group (Con, n = 8), moderate-intensity aerobic exercise group (M-Ex, n = 8) and high-intensity aerobic exercise group (H-Ex, n = 8). We used ATPase staining to identify the muscle fiber type I and II, SDS-PAGE to separate and analyze the isoforms MyHCI, MyHCIIA, MyHCIIB and MyHCIIx, and performed western blots to determine the expression of NFATc1, NGF, BDNF and NT-3. CaN activity was measured using a colorimetric assay. In the soleus muscle, 8 weeks of moderate-intensity exercise can induce transformation of MyHC IIA and MyHC IIB to MyHC IIX and MyHC I (p < 0.01), while high-intensity treadmill exercise can induce transform MyHC IIx to MyHC IIB, MyHC IIA and MyHC I (p < 0.01). In comparison to the control group, CaN activity and NFATcl protein level were significantly increased in both the M-Ex and H-Ex groups (p < 0.05, p < 0.01), with a more pronounced upregulation in the M-Ex group (p < 0.05). Eight weeks of moderate- and high intensity aerobic exercise induced the expression of NGF, BDNF and NT-3 in the soleus muscle and the striatum (p < 0.01), with the most significant increase in the H-Ex group (p < 0.01). In the rat soleus muscle, (1) CaN-NFATcl signaling contributes to the conversion of MyHC I isoform in response to moderate-intensity exercise; (2) Neurotrophins NGF, BDNF and NT-3 might play a role in the conversion of MyHC II isoform in response to high-intensity treadmill exercise. Key pointsEight weeks of moderate-intensity treadmill training induces the transformation MyHC IIA and MyHC IIB to MyHC IIX and MyHC I in the soleus muscles, while high-intensity exercise leads to transformation of MyHC IIX to MyHC IIA, MyHC IIB and MyHC I.MyHC I conversion in response to moderate-intensity aerobic exercise is mediated by calcineurin-NFATcl signaling.Eight weeks of moderate- and high-ntensity aerobic exercise induces the expression of NGF, BDNF and NT-3 in expression noted in rats subjected to high-intensity training. NGF and NT-3 expression in the striatum is lower than in the soleus muscle, while BDNF levels are similar. Neurotrophins may be involved in mediating MyHC II conversion in response to high-intensity aerobic exercise. PMID- 25435789 TI - Upper limb static-stretching protocol decreases maximal concentric jump performance. AB - The purpose of the present study was to evaluate the acute effects of an upper limb static-stretching (SS) protocol on the maximal concentric jump performance. We recruited 25 young healthy, male, resistance trained individuals (stretched group, n = 15 and control group, n = 10) in this study. The randomized between group experimental protocol consisted of a three trials of maximal concentric jump task, before and after a SS of the upper limb. Vertical ground reaction forces (vGRF) and surface electromyography (sEMG) of both gastrocnemius lateralis (GL) and vastus lateralis (VL) were acquired. An extensive SS was employed consisting of ten stretches of 30 seconds, with 15 seconds of rest, and 70-90% of the point of discomfort (POD). ANOVA (2x2) (group x condition) was used for shoulder joint range of motion (ROM), vGRF and sEMG. A significant interaction for passive ROM of the shoulder joint revealed significant increases between pre- and post-SS protocol (p < 0.001). A significant interaction demonstrated decreased peak force and an increased peak propulsion duration between pre- and post-stretching only for stretch group (p = 0.021, and p = 0.024, respectively. There was a significant main effect between groups (stretch and control) for peak force for control group (p = 0.045). Regarding sEMG variables, there were no significant differences between groups (control versus stretched) or condition (pre-stretching versus post-stretching) for the peak amplitude of RMS and IEMG for both muscles (VL and GL). In conclusion, an acute extensive SS can increase the shoulder ROM, and negatively affect both the propulsion duration and peak force of the maximal concentric jump, without providing significant changes in muscle activation. Key pointsThe jump performance can be affected negatively by an intense extensive static-stretching protocol.An intense acute extensive SS protocol can affect positively the shoulder ROM.The intense acute extensive SS protocol does not change the level of muscle activation for vastus lateralis and gastrocnemius lateralis. PMID- 25435790 TI - Asymmetry between the Dominant and Non-Dominant Legs in the Kinematics of the Lower Extremities during a Running Single Leg Jump in Collegiate Basketball Players. AB - The present study aimed to clarify the asymmetry between the dominant (DL) and non-dominant takeoff legs (NDL) in terms of lower limb behavior during running single leg jumps (RSJ) in collegiate male basketball players in relation to that of the jump height. Twenty-seven players performed maximal RSJ with a 6 m approach. Three-dimensional kinematics data during RSJ was collected using a 12 Raptor camera infrared motion analysis system (MAC 3D system) at a sampling frequency of 500 Hz. The symmetry index in the jump heights and the kinematics variables were calculated as {2 * (DL - NDL) / (DL + NDL)} * 100. The run-up velocity was similar between the two legs, but the jump height was significantly higher in the DL than in the NDL. During the takeoff phase, the joint angles of the ankle and knee were significantly larger in the DL than the NDL. In addition, the contact time for the DL was significantly shorter than that for the NDL. The symmetry index of the kinematics for the ankle joint was positively correlated with that of jump height, but that for the knee joint was not. The current results indicate that, for collegiate basketball players, the asymmetry in the height of a RSJ can be attributed to that in the joint kinematics of the ankle during the takeoff phase, which may be associated with the ability to effectively transmit run-up velocity to jump height. Key pointsAsymmetry of height during running single leg jump between two legs is due to the behavior of the ankle joint (i.e. stiffer the ankle joint and explosive bounding).The dominant leg can transmit run-up velocity into the vertical velocity at takeoff phase to jump high compared with the non-dominant leg.Basketball players who have a greater asymmetry of the RSJ at the collegiate level could be assessed as non-regulars judging by the magnitude of asymmetry. PMID- 25435791 TI - Effects of in-water passive recovery on sprint swimming performance and heart rate in adolescent swimmers. AB - The aim of the present study is to test the hypothesis that sprint swimming performance is enhanced by in-water passive recovery (IN) after sprint swimming bouts in well-trained adolescent swimmers. Using a randomized crossover study design, twelve well-trained adolescent swimmers performed two tests at the swimming pool after preliminary testing. They performed 5 bouts of 100m all-out swimming separated by 5 minutes of passive rest. Their individual in- or out-of water passive recovery condition was randomized on the first day. In their second visit to the swimming pool the opposite recovery condition was indicated. More than 60% of the subjects which rested in-water were faster in the 5th bout when compared to the OUT group. However, no significant differences were found in blood lactate when IN and OUT were compared. After the first bout peak heart rate (HR peak) was lower in subsequent bouts for IN recovery when compared with OUT (p < 0.001). Thus, coaches and researchers should take into account that IN passive recovery may decrease loss of performance and diminish HR peak during sprint swimming bouts. This is particularly important given the use that many coaches give to HR as a tool in daily training. Key pointsIn-water passive recovery minimizes the loss of performance during high intensity swimmingMaximal HR is significantly reduced by in-water recoveryCoaches should take this information into account when using HR to control swimming intensityFuture research should study long-term effects induced by in-water passive recovery. PMID- 25435792 TI - Seasonal Variation in Objectively Assessed Physical Activity among Young Norwegian Talented Soccer Players: A Description of Daily Physical Activity Level. AB - 'Practise makes perfect' is a well-known expression in most sports, including top level soccer. However, a high training and match load increases the risk for injury, overtraining and burnout. With the use of accelerometers and a self report questionnaire, the aim of this study was to describe talented players' physical activity (PA) level. Data were collected three times during the 2011 Norwegian Football season (March, June and October). The accelerometer output, counts.min(-1) (counts per unit time registered), reports the daily PA-level for young talented soccer players. Results showed a stable PA-level across the season (March: 901.2 counts.min(-1), June: 854.9 counts.min(-1), October: 861.5 counts.min(-1)). Furthermore, comparison of five different training sessions across the season showed that the PA-level ranged from 2435.8 to 3745.4 counts.min(-1). A one-way ANOVA showed no significant differences between the three measured weeks during the soccer season (p<=0.814). However, the training sessions in January had a significantly higher PA-level than those in June and October (p<=0.001). Based on these results, we discuss how potential implications of PA-level affect factors such as risk of injury, overtraining and burnout. We argue that player development must be seen as part of an overall picture in which club training and match load should be regarded as one of many variables influencing players' PA-level. Key pointsIt is well established that to achieve a high performance level in sport, one must implement a high training and match load in childhood and youth.With the use of accelerometers and a self-reported questionnaire, the aim of this study was to describe talented players' total physical activity (PA) load.These results indicate that young talented soccer players must overcome large doses of PA on a weekly basis, exposing them to a high risk of injury, overtraining and burnout. PMID- 25435793 TI - The precocity-longevity hypothesis re-examined: does career start age in canadian national hockey league players influence length of lifespan? PMID- 25435794 TI - Item Response Theory Approaches to Harmonization and Research Synthesis. AB - The need to harmonize different outcome metrics is a common problem in research synthesis and economic evaluation of health interventions and technology. The purpose of this paper is to describe the use of multidimensional item response theory (IRT) to equate different scales which purport to measure the same construct at the item level. We provide an overview of multidimensional item response theory in general and the bi-factor model which is particularly relevant for applications in this area. We show how both the underlying true scores of two or more scales that are intended to measure the same latent variable can be equated and how the item responses from one scale can be used to predict the item responses for a scale that was not administered but are necessary for the purpose of economic evaluations. As an example, we show that a multidimensional IRT model predicts well both the EQ-5D descriptive system and the EQ-5D preference index from SF-12 data which cannot be directly used to perform an economic evaluation. Results based on multidimensional IRT performed well compared to traditional regression methods in this area. A general framework for harmonization of research instruments based on multidimensional IRT is described. PMID- 25435795 TI - Genomic applications to various biological questions. PMID- 25435797 TI - Cloning and Characterisation of Two H+ Translocating Organic Pyrophos-phatase Genes in Salix and Their Expression Differences in Two Willow Varieties with Different Salt Tolerances. AB - Willows are one of the most important tree species for landscaping, biofuel and raw timber. Screening salt-tolerant willow varieties is an effective approach to balance wood supply and demand. However, more salt-tolerant willow varieties are required and little is known regarding the mechanism of salt tolerance at the gene expression level. In this paper, two willow varieties were studies in terms of their differences in salt-tolerances and mechanism of salt tolerance at the level of VP1 gene expression. The results showed that Salix L0911 (L0911) had higher biomass than Salix matsudana (SM), and salt injuries were less severe in L0911 than in SM. The activities of peroxidase and superoxide dismutase, as well as the contents of soluble protein and proline, were higher in L0911 than in SM, whereas the contents of Na(+) and K(+), as well as the Na(+)/K(+) ratio, were lower in L0911 than in SM. Two VP1 genes (VP1.1 and VP1.2) cloned in L0911 and SM had similar sequences and structures. VP1.1 and VP1.2 belonged to different subgroups. Total expression levels of the VP1.1 gene in both roots and leaves of L0911 were higher than that in SM under normal conditions. Under salt stress, expression of VP1 in SM roots initially increased and then decreased, whereas the expression of VP1 in leaves of L0911 and SM, as well as in roots of L0911, decreased with increasing salt concentrations. This study increased our understanding of the salt-tolerance mechanism of willow and may facilitate the selection of salt-tolerant willow resources. PMID- 25435796 TI - Transcriptome Profiles of Populus euphratica upon Heat Shock stress. AB - Heat stress, which strongly affects plant performance and often results in reduced vegetative growth and yields depression, has become an increasingly serious global problem. Populus euphratica Oliv. which has been considered as a tree model for the study of plant response to abiotic stresses, could be resistant to an extremely wide environmental temperature range (-40 degrees C to 45 degrees C). Previous study is mainly focused on its gene regulation upon drought and salt stress. However, little is known about gene regulation at the global transcriptome level upon heat stress. To understand the gene network controlling heat stress in P. euphratica, a transcriptome sequencing using Illumina Hiseq 2000 was performed to generate a 10 gigabases depth for each sample in the tissue of leaf. 119,573 unigeneswere generated with an average length of 474 bp. Approximately 49,605 (41.49%) unigenes exhibited significantly different expressions between two libraries. Among these unigenes, 11,165 (9.34%) were upregulated and 38,440 (32.15%) were down regulated. Heat shock proteins classified as molecular chaperones showed a significant percentage (1.13%) in the up regulated group. Heat responsive genes, such as polyubiquitins, were over expressed in heat treated sample. GO enrichment analysis revealed that the Go terms for differentially expressed unigenes were significantly enriched in hormone-mediated signal, biological process regulation and metabolic process regulation. Our data revealed a global transcriptome picture of P. euphratica in response to heat shock. The identified potential heat stress-related transcripts can be used to infer the gene regulation networks underlying the molecular mechanisms of heat response in P. euphratica. PMID- 25435798 TI - Modeling Expression Plasticity of Genes that Differentiate Drug-sensitive from Drug-resistant Cells to Chemotherapeutic Treatment. AB - By measuring gene expression at an unprecedented resolution and throughput, RNA seq has played a pivotal role in studying biological functions. Its typical application in clinical medicine is to identify the discrepancies of gene expression between two different types of cancer cells, sensitive and resistant to chemotherapeutic treatment, in a hope to predict drug response. Here we modified and used a mechanistic model to identify distinct patterns of gene expression in response of different types of breast cancer cell lines to chemotherapeutic treatment. This model was founded on a mixture likelihood of Poisson-distributed transcript read data, with each mixture component specified by the Skellam function. By estimating and comparing the amount of gene expression in each environment, the model can test how genes alter their expression in response to environment and how different genes interact with each other in the responsive process. Using the modified model, we identified the alternations of gene expression between two cell lines of breast cancer, resistant and sensitive to tamoxifen, which allows us to interpret the expression mechanism of how genes respond to metabolic differences between the two cell types. The model can have a general implication for studying the plastic pattern of gene expression across different environments measured by RNA-seq. PMID- 25435799 TI - Development of SSR Markers in Hickory (Carya cathayensis Sarg.) and Their Transferability to Other Species of Carya. AB - Hickory (Carya cathayensis Sarg.), an important nut-producing species in Southeastern China, has high economic value, but so far there has been no cultivar bred under species although it is mostly propagated by seeding and some elite individuals have been found. It has been found recently that this species has a certain rate of apomixis and poor knowledge of its genetic background has influenced development of a feasible breeding strategy. Here in this paper we first release SSR (Simple sequence repeat) markers developed in this species and their transferability to other three species of the same genus, Carya. A total of 311 pairs of SSR primers in hickory were developed based on sequenced cDNAs of a fruit development-associated cDNA library and RNA-seq data of developing female floral buds and could be used to distinguish hickory, C. hunanensis Cheng et R. H. Chang ex R. H. Chang et Lu, C. illinoensis K. Koch (pecan) and C. dabieshanensis M. C. Liu et Z. J. Li, but they were monomorphic in both hickory and C. hunanensis although multi-alleles have been identified in all the four species. There is a transferability rate of 63.02% observed between hickory and pecan and the markers can be applied to study genetic diversity of accessions in pecan. When used in C. dabieshanensis, it was revealed that C. dabieshanensis had the number of alleles per locus ranging from 2 to 4, observed heterozygosity from 0 to 0.6667 and expected heterozygosity from 0.333 to 0.8667, respectively, which supports the existence of C. dabieshanensis as a separate species different from hickory and indicates that there is potential for selection and breeding in this species. PMID- 25435800 TI - A graphical weighted power improving multiplicity correction approach for SNP selections. AB - Controlling for the multiplicity effect is an essential part of determining statistical significance in large-scale single-locus association genome scans on Single Nucleotide Polymorphisms (SNPs). Bonferroni adjustment is a commonly used approach due to its simplicity, but is conservative and has low power for large scale tests. The permutation test, which is a powerful and popular tool, is computationally expensive and may mislead in the presence of family structure. We propose a computationally efficient and powerful multiple testing correction approach for Linkage Disequilibrium (LD) based Quantitative Trait Loci (QTL) mapping on the basis of graphical weighted-Bonferroni methods. The proposed multiplicity adjustment method synthesizes weighted Bonferroni-based closed testing procedures into a powerful and versatile graphical approach. By tailoring different priorities for the two hypothesis tests involved in LD based QTL mapping, we are able to increase power and maintain computational efficiency and conceptual simplicity. The proposed approach enables strong control of the familywise error rate (FWER). The performance of the proposed approach as compared to the standard Bonferroni correction is illustrated by simulation and real data. We observe a consistent and moderate increase in power under all simulated circumstances, among different sample sizes, heritabilities, and number of SNPs. We also applied the proposed method to a real outbred mouse HDL cholesterol QTL mapping project where we detected the significant QTLs that were highlighted in the literature, while still ensuring strong control of the FWER. PMID- 25435802 TI - Algorithm for the Construction of a Global Enzymatic Network to be Used for Gene Network Reconstruction. AB - Relationships between genes are best represented using networks constructed from information of different types, with metabolic information being the most valuable and widely used for genetic network reconstruction. Other types of information are usually also available, and it would be desirable to systematically include them in algorithms for network reconstruction. Here, we present an algorithm to construct a global metabolic network that uses all available enzymatic and metabolic information about the organism. We construct a global enzymatic network (GEN) with a total of 4226 nodes (EC numbers) and 42723 edges representing all known metabolic reactions. As an example we use microarray data for Arabidopsis thaliana and combine it with the metabolic network constructing a final gene interaction network for this organism with 8212 nodes (genes) and 4606,901 edges. All scripts are available to be used for any organism for which genomic data is available. PMID- 25435803 TI - Analysis of Genome-scale Expression Network in Four Major Bacterial Residents of Cystic Fibrosis Lung. AB - In polymicrobial communities where several species co-exist in a certain niche and consequently the possibility of interactions among species is very high, gene expression data sources can give better insights in to underlying adaptation mechanisms assumed by bacteria. Furthermore, several possible synergistic or antagonistic interactions among species can be investigated through gene expression comparisons. Lung is one of the habitats harboring several distinct pathogens during severe pulmonary disorders such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Expression data analysis of these lung residents can help to gain a better understanding on how these species interact with each other within the host cells. The first part of this paper deals with introducing available data sources for the major bacteria responsible for causing lung diseases and their genomic relations. In the second part, the main focus is on the studies concerning gene expression analyses of these species. PMID- 25435801 TI - Congenital heart disease: the crossroads of genetics, epigenetics and environment. AB - Congenital heart diseases (CHDs) are recognized as the most common type of birth malformations. Although recent advances in pre- and neonatal diagnosis as well as in surgical procedures have reduced the morbidity and mortality for many CHD, the etiology for CHD remains undefined. In non-syndromic and isolated (without a familial history or a Mendelian inheritance) forms of CHDs, a multifactorial pathogenesis with interplay between inherited and non-inherited causes is recognized. In this paper, we discuss the current knowledge of the potential molecular mechanisms, mediating abnormal cardiac development in non-syndromic and isolated CHD, including mutations in cardiac transcription factors, the role of somatic mutations and epigenetic alterations as well as the influence of gene environment interactions. In the near future, the advent of high-throughput genomic technologies with the integration of system biology will expand our understanding of isolated, non-syndromic CHDs for their prevention, early diagnosis and therapy. PMID- 25435804 TI - Self Realization and Meaning Making in the Face of Adversity: A Eudaimonic Approach to Human Resilience. AB - This article considers a eudaimonic approach to psychological well-being built on the integration of developmental, existential and humanistic formulations as well as distant writings of Aristotle. Eudaimonia emphasizes meaning-making, self realization and growth, quality connections to others, self-knowledge, managing life, and marching to one's own drummer. These qualities may be of particular importance in the confrontation with significant life challenges. Prior formulations of resilience are reviewed to underscore the unique features of a eudaimonic approach. Empirical findings on meaning making and self realization are then reviewed to document the capacity of some to maintain high well-being in the face of socioeconomic inequality, the challenges of aging, and in dealing with specific challenges (child abuse, cancer, loss of spouse). Moreover, those who sustain or deepen their well-being as they deal with adversity, show better health profiles, thereby underscoring broader benefits of eudaimonia. How meaning is made and personal capacities realized in the confrontation with challenge is revealed by narrative accounts. Thus, the latter half of the article illustrates human resilience in action via the personal stories of three individuals (Mark Mathabane, Ben Mattlin, Victor Frankl) who endured unimaginable hardship, but prevailed and grew in the face of it. The essential roles of strong social ties and the capacity to derive meaning and realize personal growth in grappling with adversity are unmistakable in all three cases. PMID- 25435805 TI - Language Experience Changes Language and Cognitive Ability. AB - The sustained use of two languages by bilinguals has been shown to induce broad changes in language and cognitive abilities across the lifespan. The largest changes are seen as advantages in executive control, a set of processes responsible for controlled attention, inhibition, and shifting. Moreover, there is evidence that these executive control advantages mitigate cognitive decline in older age and contribute to cognitive reserve. In this paper, we examine some of the evidence for these findings and explain their relation to bilingual language use. These effects are considered in terms of their implications for our understanding of cognitive and brain plasticity. Some implications for social policy are discussed. PMID- 25435806 TI - Techniques for the insertion of the ProSeal laryngeal mask airway: comparison of the Foley airway stylet tool with the introducer tool in a prospective, randomized study. AB - BACKGROUND: Many tools have been developed to facilitate the insertion of the ProSeal laryngeal mask airway (LMA) insertion, which can be impeded by folding of its soft cuff. The aim of this study was to compare the efficiency of ProSeal LMA insertion guided by a soft, direct optical Foley Airway Stylet Tool (FAST) with the standard introducer tool (IT). METHODS: One hundred sixty patients undergoing general anesthesia using the ProSeal LMA as an airway management device were randomly allocated to either FAST-guided or IT-assisted groups. Following ProSeal LMA insertion, the glottic and esophageal openings were identified using a fiberoptic bronchoscope introduced through the airway and the drain tube. The primary outcomes were time taken to insert the ProSeal LMA and the success rate at the first attempt. Secondary end points included ease of insertion, hemodynamic response to insertion, and postoperative adverse events recorded in the recovery room and on the first postoperative morning. RESULTS: One hundred forty patients were included in the final analysis: 66 in the FAST-guided group and 74 in the IT-assisted group. The success rate of FAST device-guided ProSeal LMA insertion (95.7%) was broadly comparable with IT-assisted insertion (98.7%). However, the time taken to insert the ProSeal LMA was significantly longer when the FAST technique was used (p <0.001). The incidence of correct alignment of the airway tube and the drain tube did not differ significantly between the groups. There were no significant differences in ease of insertion or hemodynamic responses to insertion, except that the incidence of postoperative sore throat was significantly higher in the FAST group on the first postoperative day (22.2% compared with 6.8% in the IT group; p = 0.035). CONCLUSION: Both FAST-guided and IT-assisted techniques achieved correct ProSeal LMA positioning, but the IT technique was significantly quicker and less likely to cause a sore throat. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02048657. PMID- 25435807 TI - Corticosteroids in palliative care - perspectives of clinicians involved in prescribing: a qualitative study. AB - BACKGROUND: Corticosteroids are commonly prescribed in palliative care for alleviation of both specific and non-specific symptoms, but relatively little is known of the perspectives of clinicians and what influences their prescribing in this context. The aim of this study was to explore the experiences and perspectives of those involved in the prescribing of corticosteroids in palliative care. METHODS: Semi-structured interviews were undertaken with 12 medical practitioners and six senior nurses from a sample of six New Zealand hospices to identify their experiences and attitudes regarding the prescribing of corticosteroids. A general inductive approach was used to thematically analyse data. RESULTS: Five broad themes were identified: the role of corticosteroids in palliative care; indications for corticosteroids; influences on prescribing; use of guidelines; and perceptions of previous study data on prescribing patterns for their hospice. Interviewees regarded these agents as having an important place in in palliative care but expressed a degree of uncertainty about certain aspects of their use. They were concerned about issues such as prescribing for non-specific indications, methods of stopping, and lack of monitoring and reviewing. Guidelines were used routinely by only one of the sample hospices. Corticosteroids tended to be prescribed experientially or by habit, rather than based on evidence-based guidelines. CONCLUSIONS: This study has highlighted differences in the understanding of the place of corticosteroids in palliative care by the clinicians interviewed in this study and different practices, particularly in the treatment of non-specific symptoms and in the use of guidelines. These findings suggest a need for further research and discussion about the role of corticosteroids in palliative care and the development of evidence-based guidelines to assist prescribers. PMID- 25435808 TI - Use of chemotherapy at the end of life in Turkey. AB - BACKGROUND: An increasing number of patients receive palliative chemotherapy near the end of life. The aim of this study is to evaluate the aggressiveness of chemotherapy in Turkish individuals near the end of life. METHODS: Patients diagnosed with solid tumors and died from 2010 to 2011 in the medical oncology department of Akdeniz University were included in the study. Data about the diagnosis, treatment details and imaging procedures were collected. RESULTS: Three hundred and seventy-three people with stage IV solid tumors died from 2010 to 2011 in our clinic. Eighty-nine patients (23.9%) patients underwent chemotherapy in the last month of life while 39 patients (10.5%) received chemotherapy in the last 14 days. The probability of undergoing chemotherapy in the last month of life was influenced by: age, 'newly diagnosed' patients, and performance status. There was no significant association of chemotherapy in the last month of life with gender and tumor type. Having a PET-CT scan did not alter the chemotherapy decision. CONCLUSION: In conclusion, chemotherapy used in the last month of life in a tertiary care center of Turkey is high. Increasing quality of life should be a priority near the end of life and physicians should consider ceasing chemotherapy and direct the patient to early palliative care. PMID- 25435809 TI - Patient safety subcultures among registered nurses and nurse assistants in Swedish hospital care: a qualitative study. AB - BACKGROUND: Patient safety culture emerges from the shared assumptions, values and norms of members of a health care organization, unit, team or other group with regard to practices that directly or indirectly influence patient safety. It has been argued that organizational culture is an amalgamation of many cultures, and that subcultures should be studied to develop a deeper understanding of an organization's culture. The aim of this study was to explore subcultures among registered nurses and nurse assistants in Sweden in terms of their assumptions, values and norms with regard to practices associated with patient safety. METHODS: The study employed an exploratory design using a qualitative method, and was conducted at two hospitals in southeast Sweden. Seven focus group interviews and two individual interviews were conducted with registered nurses and seven focus group interviews and one individual interview were conducted with nurse assistants. Manifest content analysis was used for the analysis. RESULTS: Seven patient safety culture domains (i.e. categories of assumptions, values and norms) that included practices associated with patient safety were found: responsibility, competence, cooperation, communication, work environment, management and routines. The domains corresponded with three system levels: individual, interpersonal and organizational levels. The seven domains consisted of 16 subcategories that expressed different aspects of the registered nurses and assistants nurses' patient safety culture. Half of these subcategories were shared. CONCLUSIONS: Registered nurses and nurse assistants in Sweden differ considerably with regard to patient safety subcultures. The results imply that, in order to improve patient safety culture, efforts must be tailored to both registered nurses' and nurse assistants' patient safety-related assumptions, values and norms. Such efforts must also take into account different system levels. The results of the present study could be useful to facilitate discussions about patient safety within and between different professional groups. PMID- 25435811 TI - Expression of undifferentiated embryonic cell transcription factor-1 (UTF1) in breast cancers and their matched normal tissues. AB - OBJECTIVES: Undifferentiated embryonic cell transcription factor-1 (UTF1) plays a critical role in the developmental timing during embryonic development. However, there is little paper dealing with UTF1 expressed in adult tissues. In the present study, we evaluate the expression of UTF1 in breast cancer and its correlation with clinicopathological parameters. METHODS: Real-time polymerase chain reaction (real-time PCR) was applied to detect the expression of UTF1 mRNA in the 55 pairs of samples of breast cancer tissues and match normal tissues. ??CT method was used to evaluate the relative quantity of target mRNA expression. RESULTS: Among the 55 pairs of samples of breast cancer tissues and match normal tissues adjacent to the tumor, the UTF1 mRNA levels in normal tissues were significantly higher than those observed in breast cancer tissues (p < 0.001). UTF1 mRNA levels expression correlated with lymph node metastasis (p = 0.002) and tumor size (p < 0.001). CONCLUSIONS: Expression of UTF1 in breast cancer tissues were confirmed in this study. Decreased expression of UTF1 mRNA in breast cancer tissues was maybe one of the factors impact on tumorigenes in breast cancer patients. PMID- 25435810 TI - The journey with dementia from the perspective of bereaved family caregivers: a qualitative descriptive study. AB - BACKGROUND: With increasing rates of dementia among older adults, many people will be affected by this disease; either by having the disease or by caring for a relative with dementia. Due to a shift toward home and community-based care there will be an increase in the number of family caregivers caring for persons with dementia. The caregiving experience in the dementia journey is influenced by many factors. Currently there is a paucity of research that examines the dementia caregiving experience from the perspective of bereaved caregivers or that presents the complete caregiving journey. The purpose of this study was to describe the dementia caregiving journey as revealed by bereaved family caregivers. METHODS: This study utilized qualitative description to describe the overall dementia caregiving journey as told by 11 bereaved caregivers. Open-ended interviews resulted in rich detailed descriptions of the caregiving journey from before a dementia diagnosis and into bereavement. RESULTS: Findings are discussed based on the following caregiving themes: (a) getting a diagnosis; (b) managing at home; (c) transition to long-term care; (d) end of life; and (e) grief in bereavement. Subthemes reflect the dementia caregiving journey using the words of the participants. Participants spoke of grieving throughout the caregiving experience. CONCLUSIONS: Bereaved caregivers have similar experiences to active caregivers over comparable points in the journey with dementia. Findings from this work contribute new understanding to the literature around the unique perspective of bereaved caregivers, while presenting the overall dementia caregiving journey. PMID- 25435812 TI - Role of BC040587 as a predictor of poor outcome in breast cancer. AB - BACKGROUND: Accumulating studies have focused on the oncogenic and tumor suppressive roles of the newly identified lncRNAs. A novel lncRNA BC040587 in 3q13.31 locus which exists frequent copy number alterations was found to be associated with poor survival of osteosarcoma patients. However, its role in breast cancer (BC) remains unknown. The aim of this study was to examine the expression pattern of BC040587 in BC and to evaluate its biological role and clinical significance in prediction of prognosis. METHODS: Expression of BC040587 was analyzed in 20 pairs of BC cancer tissues and adjacent noncancerous tissues (ANCT), also in 151 BC tissues, 9 BC cell lines and one normal breast cell line by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Differences between groups were tested for significance using Student's t-test (two-tailed). Then we analyzed the potential relationship between BC040587 expression and clinic pathological features of BC patients. The correlation was analyzed by SPSS software. RESULTS: It showed that BC040587 expression was down regulated both in BC samples and in BC cell lines compared with corresponding normal control. BC040587 expression was correlated with menopausal status (p = 0.040) and tumor differentiation (p = 0.035). The Kaplan-Meier survival curves indicated that the overall survival (OS) was significantly poor in low BC040587 expression BC patients (p = 0.023). Furthermore, expression of BC040587 was significantly associated with worse prognosis and was shown to be an independent prognostic marker breast cancer (p = 0.032). Our studies indicate that BC040587 may represent a new marker of prognosis in breast cancer. CONCLUSION: Our studies indicate that BC040587 is significantly down-regulated in BC tissues and BC cell lines. BC040587 may represent a new marker of prognosis in breast cancer. PMID- 25435813 TI - Proteomic analysis of rat cartilage: the identification of differentially expressed proteins in the early stages of osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is a chronic degenerative disease of the articular cartilage, and its diagnosis is based on symptoms and radiological signs that are only present in the late stages of the disease. Due to the limitations in diagnosing OA before the onset of symptoms, such as pain, little is known about the molecular mechanisms involved in the pathogenesis of OA. Experimental OA models are often used to study the kinetics of the progression of this disease. In this report, we conducted a proteomic study of osteoarthritic cartilage during the early stages of OA using an experimental rat model. RESULTS: Ten proteins that are differentially expressed under early OA conditions were identified by 2-DE and MALDI-TOF/MS. These proteins mediated many processes, such as glycolysis and energy production (Nme2 and Pnp), cartilage matrix (Col2a1), transcription and protein synthesis (Eef1a1 and DJ-1), signal transduction (CaM and Pebp1), transport (Alb and Hba1), and latexin (Lxn). In addition, changes in Lxn expression in early OA were observed and validated by western blot and immunofluorescence analysis. CONCLUSIONS: The proteins that we identified indicate that energy metabolism, cartilage matrix remodelling, and protective cellular mechanisms are associated with early OA. In addition, latexin expression during the early stages of OA could be implicated in cartilage repair. PMID- 25435814 TI - Improving disease incidence estimates in primary care surveillance systems. AB - BACKGROUND: In primary care surveillance systems based on voluntary participation, biased results may arise from the lack of representativeness of the monitored population and uncertainty regarding the population denominator, especially in health systems where patient registration is not required. METHODS: Based on the observation of a positive association between number of cases reported and number of consultations by the participating general practitioners (GPs), we define several weighted incidence estimators using external information on consultation volume in GPs. These estimators are applied to data reported in a French primary care surveillance system based on voluntary GPs (the Sentinelles network) for comparison. RESULTS: Depending on hypotheses for weight computations, relative changes in weekly national-level incidence estimates up to 3% for influenza, 6% for diarrhea, and 11% for varicella were observed. The use of consultation-weighted estimates led to bias reduction in the estimates. At the regional level (NUTS2 level - Nomenclature of Statistical Territorial Units Level 2), relative changes were even larger between incidence estimates, with changes between -40% and +55%. Using bias-reduced weights decreased variation in incidence between regions and increased spatial autocorrelation. CONCLUSIONS: Post-stratification using external administrative data may improve incidence estimates in surveillance systems based on voluntary participation. PMID- 25435815 TI - A methodological framework for the improved use of routine health system data to evaluate national malaria control programs: evidence from Zambia. AB - BACKGROUND: Due to challenges in laboratory confirmation, reporting completeness, timeliness, and health access, routine incidence data from health management information systems (HMIS) have rarely been used for the rigorous evaluation of malaria control program scale-up in Africa. METHODS: We used data from the Zambia HMIS for 2009-2011, a period of rapid diagnostic and reporting scale-up, to evaluate the association between insecticide-treated net (ITN) program intensity and district-level monthly confirmed outpatient malaria incidence using a dose response national platform approach with district-time units as the unit of analysis. A Bayesian geostatistical model was employed to estimate longitudinal district-level ITN coverage from household survey and programmatic data, and a conditional autoregressive model (CAR) was used to impute missing HMIS data. The association between confirmed malaria case incidence and ITN program intensity was modeled while controlling for known confounding factors, including climate variability, reporting, testing, treatment-seeking, and access to health care, and additionally accounting for spatial and temporal autocorrelation. RESULTS: An increase in district level ITN coverage of one ITN per household was associated with an estimated 27% reduction in confirmed case incidence overall (incidence rate ratio (IRR): 0 . 73, 95% Bayesian Credible Interval (BCI): 0 . 65-0 . 81), and a 41% reduction in areas of lower malaria burden. CONCLUSIONS: When improved through comprehensive parasitologically confirmed case reporting, HMIS data can become a valuable tool for evaluating malaria program scale-up. Using this approach we provide further evidence that increased ITN coverage is associated with decreased malaria morbidity and use of health services for malaria illness in Zambia. These methods and results are broadly relevant for malaria program evaluations currently ongoing in sub-Saharan Africa, especially as routine confirmed case data improve. PMID- 25435817 TI - Modeling Pathological Speech Perception From Data With Similarity Labels. AB - The current state of the art in judging pathological speech intelligibility is subjective assessment performed by trained speech pathologists (SLP). These tests, however, are inconsistent, costly and, oftentimes suffer from poor intra- and inter-judge reliability. As such, consistent, reliable, and perceptually relevant objective evaluations of pathological speech are critical. Here, we propose a data-driven approach to this problem. We propose new cost functions for examining data from a series of experiments, whereby we ask certified SLPs to rate pathological speech along the perceptual dimensions that contribute to decreased intelligibility. We consider qualitative feedback from SLPs in the form of comparisons similar to statements "Is Speaker A's rhythm more similar to Speaker B or Speaker C?" Data of this form is common in behavioral research, but is different from the traditional data structures expected in supervised (data matrix + class labels) or unsupervised (data matrix) machine learning. The proposed method identifies relevant acoustic features that correlate with the ordinal data collected during the experiment. Using these features, we show that we are able to develop objective measures of the speech signal degradation that correlate well with SLP responses. PMID- 25435816 TI - VALIDATION OF ACOUSTIC MODELS OF AUDITORY NEURAL PROSTHESES. AB - Acoustic models have been used in numerous studies over the past thirty years to simulate the percepts elicited by auditory neural prostheses. In these acoustic models, incoming signals are processed the same way as in a cochlear implant speech processor. The percepts that would be caused by electrical stimulation in a real cochlear implant are simulated by modulating the amplitude of either noise bands or sinusoids. Despite their practical usefulness these acoustic models have never been convincingly validated. This study presents a tool to conduct such validation using subjects who have a cochlear implant in one ear and have near perfect hearing in the other ear, allowing for the first time a direct perceptual comparison of the output of acoustic models to the stimulation provided by a cochlear implant. PMID- 25435818 TI - Distributions of reproductive and somatic cell numbers in diverse Volvox (Chlorophyta) species. AB - BACKGROUND: Volvox (Chlorophyta) asexual colonies consist of two kinds of cells: a large number of small somatic cells and a few large reproductive cells. The numbers of reproductive and somatic cells correspond directly to the major components of fitness - fecundity and viability, respectively. Volvox species display diverse patterns of development that give rise to the two cell types. QUESTIONS: For Volvox species under fixed conditions, do species differ with respect to the distribution of somatic and reproductive cell numbers in a population of asexual clones? Specifically, do they differ with respect to the dispersion of the distribution, i.e. with respect to their intrinsic variability? If so, are these differences related to major among-species developmental differences? DATA DESCRIPTION: For each of five Volvox species, we estimate the number of somatic and reproductive cells for 40 colonies and the number of reproductive cells for an additional 200 colonies. We sampled all colonies from growing, low-density, asexual populations under standard conditions. SEARCH METHOD: We compare the distribution of reproductive cell numbers to a Poisson distribution. We also compare the overall dispersion of reproductive cell number among species by calculating the coefficient of variation (CV). We compare the bivariate (reproductive and somatic cell) dataset to simulated datasets produced from a simple model of cell-type specification with intrinsic variability and colony size variation. This allows us to roughly estimate the level of intrinsic variability that is most consistent with our observed bivariate data (given an unknown level of size variation). CONCLUSIONS: The overall variability (CV) in reproductive cell number is high in Volvox compared with more complex organisms. Volvox species show differences in reproductive cell number CV that were not clearly related to development, as currently understood. If we used the bivariate data and tried to account for the effects of colony size variation, we found that the species that have fast embryonic divisions and asymmetric divisions have substantially higher intrinsic variability than the species that have slow divisions and no asymmetric divisions. Under our culture conditions, the Poisson distribution is a good description of intrinsic variability in reproductive cell number for some but not all Volvox species. PMID- 25435819 TI - Eric K. Johnson, MD, FACS, FASCRS. PMID- 25435820 TI - Biologics in colon and rectal surgery. PMID- 25435822 TI - Biomaterials: so many choices, so little time. What are the differences? AB - The use of biologic mesh has increased greatly in recent years in response to the need for a solution in managing contaminated hernias. Multiple different meshes are commercially available, and are derived from a variety of sources, including human dermis as well as animal sources. For a mesh to be effective, it must be resistant to infection, have adequate tensile strength for hernia repair, and be well tolerated by the host. To achieve this end, biologic meshes go through an intense processing that varies from one product to the next. In this article, the authors review the types of mesh available, how they are processed, and examine these characteristics in terms of their strengths and weaknesses in application to surgical technique. PMID- 25435821 TI - A primer on wound healing in colorectal surgery in the age of bioprosthetic materials. AB - Wound healing is a complex, dynamic process that is vital for closure of cutaneous injuries, restoration of abdominal wall integrity after laparotomy closure, and to prevent anastomotic dehiscence after bowel surgery. Derangements in healing have been described in multiple processes including diabetes mellitus, corticosteroid use, irradiation for malignancy, and inflammatory bowel disease. A thorough understanding of the process of healing is necessary for clinical decision making and knowledge of the current state of the science may lead future researchers in developing methods to enable our ability to modulate healing, ultimately improving outcomes. An exciting example of this ability is the use of bioprosthetic materials used for abdominal wall surgery (hernia repair/reconstruction). These bioprosthetic meshes are able to regenerate and remodel from an allograft or xenograft collagen matrix into site-specific tissue; ultimately being degraded and minimizing the risk of long-term complications seen with synthetic materials. The purpose of this article is to review healing as it relates to cutaneous and intestinal trauma and surgery, factors that impact wound healing, and wound healing as it pertains to bioprosthetic materials. PMID- 25435823 TI - Incisional reinforcement in high-risk patients. AB - Hernia formation after surgical procedures continues to be an important cause of surgical morbidity. Incisional reinforcement at the time of the initial operation has been used in some patient populations to reduce the risk of subsequent hernia formation. In this article, reinforcement techniques in different surgical wounds are examined to identify situations in which hernia formation may be prevented. Mesh use for midline closure, pelvic floor reconstruction, and stoma site reinforcement is discussed. Additionally, the use of retention sutures, closure of the open abdomen, and reinforcement after component separation are examined using current literature. Although existing studies do not support the routine use of mesh reinforcement for all surgical incisions, certain patient populations appear to benefit from reinforcement with lower rates of subsequent hernia formation. The identification and characterization of these groups will guide the future use of mesh reinforcement in surgical incisions. PMID- 25435824 TI - Staple line/anastomotic reinforcement and other adjuncts: do they make a difference? AB - Since the development of the stapled intestinal anastomosis, efforts have been aimed at reducing complications and standardizing methods. The main complications associated with stapled anastomoses include bleeding, device failure, and anastomotic failure (leaks and strictures). These complications are associated with increased cost of care, increase in cancer recurrence, decreased overall survival, poor quality of life, and in some cases the need for further procedures including a diverting ostomy. Reducing these complications therefore has important implications. To this end, techniques to reduce the incidence of anastomotic complications have been the focus of many investigators. In this review, we summarize the current staple line reinforcement technology as well as other adjunctive measures, and specifically discuss the role of biologic materials in this realm. PMID- 25435825 TI - Parastomal hernia repair and reinforcement: the role of biologic and synthetic materials. AB - Parastomal hernia is a prevalent problem and treatment can pose difficulties due to significant rates of recurrence and morbidities of the repair. The current standard of care is to perform parastomal hernia repair with mesh whenever possible. There exist multiple options for mesh reinforcement (biologic and synthetic) as well as surgical techniques, to include type of repair (keyhole and Sugarbaker) and position of mesh placement (onlay, sublay, or intraperitoneal). The sublay and intraperitoneal positions have been shown to be superior with a lower incidence of recurrence. This procedure may be performed open or laparoscopically, both having similar recurrence and morbidity results. Prophylactic mesh placement at the time of stoma formation has been shown to significantly decrease the rates of parastomal hernia formation. PMID- 25435826 TI - Biomaterials in the treatment of anal fistula: hope or hype? AB - Anal fistula (AF) presents a chronic problem for patients and colorectal surgeons alike. Surgical treatment may result in impairment of continence and long-term risk of recurrence. Treatment options for AFs vary according to their location and complexity. The ideal approach should result in low recurrence rates and minimal impact on continence. New technical approaches involving biologically derived products such as biological mesh, fibrin glue, fistula plug, and stem cells have been applied in the treatment of AF to improve outcomes and decrease recurrence rates and the risk of fecal incontinence. In this review, we will highlight the current evidence and describe our personal experience with these novel approaches. PMID- 25435828 TI - The Changing Landscape of Love and Marriage. PMID- 25435827 TI - The role of synthetic and biologic materials in the treatment of pelvic organ prolapse. AB - Pelvic organ prolapse is a significant medical problem that poses a diagnostic and management dilemma. These diseases cause serious morbidity in those affected and treatment is sought for relief of pelvic pain, rectal bleeding, chronic constipation, obstructed defecation, and fecal incontinence. Numerous procedures have been proposed to treat these conditions; however, the search continues as colorectal surgeons attempt to find the procedure that would optimally treat these conditions. The use of prosthetics in the repair of pelvic organ prolapse has become prevalent as the benefits of their use are realized. While advances in biologic mesh and new surgical techniques promise improved functional outcomes with decreased complication rates without de novo symptoms, the debate concerning the best prosthetic material, synthetic or biologic, remains controversial. Furthermore, laparoscopic ventral mesh rectopexy has emerged as a procedure that could potentially fill this role and is rapidly becoming the procedure of choice for the surgical treatment of pelvic organ prolapse. PMID- 25435829 TI - Needle Steering in 3-D Via Rapid Replanning. AB - Steerable needles have the potential to improve the effectiveness of needle-based clinical procedures such as biopsy and drug delivery by improving targeting accuracy and reaching previously inaccessible targets that are behind sensitive or impenetrable anatomical regions. We present a new needle steering system capable of automatically reaching targets in 3-D environments while avoiding obstacles and compensating for real-world uncertainties. Given a specification of anatomical obstacles and a clinical target (e.g., from preoperative medical images), our system plans and controls needle motion in a closed-loop fashion under sensory feedback to optimize a clinical metric. We unify planning and control using a new fast algorithm that continuously replans the needle motion. Our rapid replanning approach is enabled by an efficient sampling-based rapidly exploring random tree (RRT) planner that achieves orders-of-magnitude reduction in computation time compared with prior 3-D approaches by incorporating variable curvature kinematics and a novel distance metric for planning. Our system uses an electromagnetic tracking system to sense the state of the needle tip during the procedure. We experimentally evaluate our needle steering system using tissue phantoms and animal tissue ex vivo. We demonstrate that our rapid replanning strategy successfully guides the needle around obstacles to desired 3-D targets with an average error of less than 3 mm. PMID- 25435830 TI - Formation of nanostructured silicon surfaces by stain etching. AB - In this work, we report the fabrication of ordered silicon structures by chemical etching of silicon in vanadium oxide (V2O5)/hydrofluoric acid (HF) solution. The effects of the different etching parameters including the solution concentration, temperature, and the presence of metal catalyst film deposition (Pd) on the morphologies and reflective properties of the etched Si surfaces were studied. Scanning electron microscopy (SEM) was carried out to explore the morphologies of the etched surfaces with and without the presence of catalyst. In this case, the attack on the surfaces with a palladium deposit begins by creating uniform circular pores on silicon in which we distinguish the formation of pyramidal structures of silicon. Fourier transform infrared spectroscopy (FTIR) demonstrates that the surfaces are H-terminated. A UV-Vis-NIR spectrophotometer was used to study the reflectance of the structures obtained. A reflectance of 2.21% from the etched Si surfaces in the wavelength range of 400 to 1,000 nm was obtained after 120 min of etching while it is of 4.33% from the Pd/Si surfaces etched for 15 min. PMID- 25435831 TI - Lysozyme-coated silver nanoparticles for differentiating bacterial strains on the basis of antibacterial activity. AB - Lysozyme, an antibacterial enzyme, was used as a stabilizing ligand for the synthesis of fairly uniform silver nanoparticles adopting various strategies. The synthesized particles were characterized using UV-visible spectroscopy, FTIR, dynamic light scattering (DLS), and TEM to observe their morphology and surface chemistry. The silver nanoparticles were evaluated for their antimicrobial activity against several bacterial species and various bacterial strains within the same species. The cationic silver nanoparticles were found to be more effective against Pseudomonas aeruginosa 3 compared to other bacterial species/strains investigated. Some of the bacterial strains of the same species showed variable antibacterial activity. The difference in antimicrobial activity of these particles has led to the conclusion that antimicrobial products formed from silver nanoparticles may not be equally effective against all the bacteria. This difference in the antibacterial activity of silver nanoparticles for different bacterial strains from the same species may be due to the genome islands that are acquired through horizontal gene transfer (HGT). These genome islands are expected to possess some genes that may encode enzymes to resist the antimicrobial activity of silver nanoparticles. These silver nanoparticles may thus also be used to differentiate some bacterial strains within the same species due to variable silver resistance of these variants, which may not possible by simple biochemical tests. PMID- 25435832 TI - Dual active layer a-IGZO TFT via homogeneous conductive layer formation by photochemical H-doping. AB - In this study, InGaZnO (IGZO) thin film transistors (TFTs) with a dual active layer (DAL) structure are fabricated by inserting a homogeneous embedded conductive layer (HECL) in an amorphous IGZO (a-IGZO) channel with the aim of enhancing the electrical characteristics of conventional bottom-gate-structure TFTs. A highly conductive HECL (carrier concentration at 1.6 * 10(13) cm(-2), resistivity at 4.6 * 10(-3) Omega?cm, and Hall mobility at 14.6 cm(2)/Vs at room temperature) is fabricated using photochemical H-doping by irradiating UV light on an a-IGZO film. The electrical properties of the fabricated DAL TFTs are evaluated by varying the HECL length. The results reveal that carrier mobility increased proportionally with the HECL length. Further, a DAL TFT with a 60-MUm long HECL embedded in an 80-MUm-long channel exhibits comprehensive and outstanding improvements in its electrical properties: a saturation mobility of 60.2 cm(2)/Vs, threshold voltage of 2.7 V, and subthreshold slope of 0.25 V/decade against the initial values of 19.9 cm(2)/Vs, 4.7 V, and 0.45 V/decade, respectively, for a TFT without HECL. This result confirms that the photochemically H-doped HECL significantly improves the electrical properties of DAL IGZO TFTs. PMID- 25435833 TI - Comparative study of absorption in tilted silicon nanowire arrays for photovoltaics. AB - Silicon nanowire arrays have been shown to demonstrate light trapping properties and promising potential for next-generation photovoltaics. In this paper, we show that the absorption enhancement in vertical nanowire arrays on a perfectly electric conductor can be further improved through tilting. Vertical nanowire arrays have a 66.2% improvement in ultimate efficiency over an ideal double-pass thin film of the equivalent amount of material. Tilted nanowire arrays, with the same amount of material, exhibit improved performance over vertical nanowire arrays across a broad range of tilt angles (from 38 degrees to 72 degrees ). The optimum tilt of 53 degrees has an improvement of 8.6% over that of vertical nanowire arrays and 80.4% over that of the ideal double-pass thin film. Tilted nanowire arrays exhibit improved absorption over the solar spectrum compared with vertical nanowires since the tilt allows for the excitation of additional modes besides the HE 1m modes that are excited at normal incidence. We also observed that tilted nanowire arrays have improved performance over vertical nanowire arrays for a large range of incidence angles (under about 60 degrees ). PMID- 25435834 TI - Ferromagnetic ordering in Mn-doped ZnO nanoparticles. AB - Zn1 - x Mn x O nanoparticles have been synthesized by hydrothermal technique. The doping concentration of Mn can reach up to 9 at% without precipitation or secondary phase, confirmed by electron spin resonance (ESR) and synchrotron X-ray diffraction (XRD). Room-temperature ferromagnetism is observed in the as-prepared nanoparticles. However, the room-temperature ferromagnetism disappears after post annealing in either argon or air atmosphere, indicating the importance of post treatment for nanostructured magnetic semiconductors. PMID- 25435835 TI - The ergogenic effect of elastic therapeutic tape on stride and step length in fatigued runners. AB - OBJECTIVE: The purpose of this study was to determine if elastic therapeutic tape placed on anterior lower limbs would affect stride and step length in fatigued runners' gait. METHODS: Forty-two healthy participants were equally divided into a kinesiology tape group (Rocktape) and a no-tape control group. Participants in both groups underwent a baseline running gait test at 6 mph without tape. After this, participants engaged in an exhaustive lower body fatigue protocol until they reached maximal volitional exhaustion. Participants were then randomized to 1 of 2 interventions: (1) Experimental group, which had kinesiology tape placed under tension on the anterior aspect of their lower limbs bilaterally from the upper thigh to just below the patella, or (2) Control group, which did not receive taping. All participants then engaged in a similar 6-mph running gait postanalysis. Participant's gait was analyzed for 90 seconds during each test iteration. Researchers used a 2-way repeated-measures analysis of variance considering fatigue (prefatigue, postfatigue) and group (tape, no-tape) as subject factors. RESULTS: After the fatigue protocol, the no-tape group demonstrated a significant decrease in step length of 14.2 mm (P = .041) and stride length of 29.4 mm (P = .043). The kinesiology tape group did not demonstrate a significant decline in these gait parameters. CONCLUSIONS: In this preliminary study, placing elastic therapeutic tape over the anterior lower limbs demonstrated short-term preservation of runner step length and stride length in a fatigued state. PMID- 25435836 TI - Effect of lumbar spine manipulation on asymptomatic cyclist sprint performance and hip flexibility. AB - OBJECTIVE: The purpose of this study was to measure the impact of midlumbar spinal manipulation on asymptomatic cyclist sprint performance and hip flexibility. METHODS: Twelve cyclists were equally randomized into an AB:BA crossover study design after baseline testing. Six participants were in the AB group, and 6 were in the BA group. The study involved 1 week of rest in between each of the 3 tested conditions: baseline testing (no intervention prior to testing), condition A (bilateral midlumbar spine manipulation prior to testing), and condition B (sham acupuncture prior to testing, as a control). Testing was blinded and involved a sit-and-reach test followed by a 0.5-km cycle ergometer sprint test against 4-kp resistance. Outcome measures were sit-and-reach distance, time to complete 0.5 km, maximum heart rate, and rating of perceived exertion. An additional 8 cyclists were recruited and used as a second set of controls that engaged in 3 testing sessions without any intervention to track test acclimation. An analysis of variance was used to compare dependent variables under each of the 3 conditions for the experimental group and control group #1, and a repeated-measures analysis of variance was used to analyze test acclimation in control group #2. RESULTS: Lumbar spine manipulation did not demonstrate statistically significant between-group changes in sit-and-reach (P = .765), 0.5 km sprint performance time (P = .877), maximum exercise heart rate (P = .944), or rating of perceived exertion (P = .875). CONCLUSIONS: The findings of this preliminary study showed that midlumbar spinal manipulation did not improve hip flexibility or cyclist power output of asymptomatic participants compared with an acupuncture sham and no-treatment control groups. PMID- 25435838 TI - Exploratory evaluation of the effect of axial rotation, focal film distance and measurement methods on the magnitude of projected lumbar retrolisthesis on plain film radiographs. AB - OBJECTIVE: The purpose of this exploratory study was to evaluate the amount of error in retrolisthesis measurement due to measurement methods or projection factors inherent in spinal radiography. In addition, this study compared how accurately these methods determine positions of the lumbar vertebrae being studied and the expected projected size of the retrolisthesis. METHODS: Vertebral models were situated in a retrolisthesis position. Radiographs of the models were obtained in positive and negative y-axis rotations at 40- and 84-in focal film distances. The projected retrolisthesis was measured using the Gohl, Iguchi, and Lopes methods. RESULTS: At the 40-in focal film distance, the Iguchi method and Lopes methods were significantly more accurate than the Gohl method. At the 84-in focal film distance, the Lopes method was significantly more accurate than the Gohl method. Almost all measurements overestimated both the actual amount of retrolisthesis as well as the amount of trigonometrically calculated retrolisthesis that should have been present on the radiographs. Findings suggest that measurements were less accurate with vertebrae rotated more than 10 degrees . CONCLUSIONS: This study demonstrated that lumbar vertebral rotation, focal film distance, and measurement methods are potential sources of error in retrolisthesis measurement. PMID- 25435837 TI - Analysis of the charge exchange between the human body and ground: evaluation of "earthing" from an electrical perspective. AB - OBJECTIVE: The purpose of this study was to investigate "earthing" from an electrical perspective through measurement and analysis of the naturally occurring electron flow between the human body or a control and ground as this relates to the magnitude of the charge exchange, the relationship between the charge exchange and body functions (respiration and heart rate), and the detection of other information that might be contained in the charge exchange. METHODS: Sensitive, low-noise instrumentation was designed and fabricated to measure low-level current flow at low frequencies. This instrumentation was used to record current flow between human subjects or a control and ground, and these measurements were performed approximately 40 times under varied circumstances. The results of these measurements were analyzed to determine if information was contained in the current exchange. RESULTS: The currents flowing between the human body and ground were small (nanoamperes), and they correlated with subject motion. There did not appear to be any information contained in this exchange except for information about subject motion. CONCLUSIONS: This study showed that currents flow between the environment (earth) and a grounded human body; however, these currents are small (nanoamperes) and do not appear to contain information other than information about subject motion. PMID- 25435839 TI - Chiropractic care of a patient with neurogenic heterotopic ossification of the anterior longitudinal ligament after traumatic brain injury: a case report. AB - OBJECTIVE: The purpose of this case report is to describe the use of chiropractic care for a patient with neurogenic heterotopic ossification of the anterior longitudinal ligament in the cervical spine and soft tissues of the right hip after a traumatic brain injury and right femur fracture. CLINICAL FEATURES: A 25 year-old military officer was referred to a hospital-based chiropractic clinic with complaints of pain and stiffness of the neck and back along with reduced respiratory excursions that began several months after a motor vehicle accident in which he had a traumatic brain injury. The patient had a fractured right femur from the accident, which had since been treated surgically, but had complications of heterotopic ossification in the soft tissues of the hip. His overall pain level was 3 of 10 on a verbal pain scale during use of oxycodone HCL/acetaminophen. Chest excursion was initially measured at .5 cm. INTERVENTION AND OUTCOME: With the intent to restore respiratory chest motion and to reduce the patient's back and neck pain, the patient was placed on a program of chiropractic and myofascial manipulation, exercise therapy, and respiratory therapy. After a year of care, the patient rated overall pain at 3 of 10 verbal pain scale level but was no longer taking medications for pain and an increase in respiratory chest excursions measured at 3.5 cm. CONCLUSION: This case demonstrated that chiropractic treatment provided benefit to a patient with heterotopic ossification concurrent with musculoskeletal pain. PMID- 25435840 TI - Distal embolic brain infarction due to recanalization of asymptomatic vertebral artery occlusion resulting from cervical spine injury: a case report. AB - OBJECTIVE: The purpose of this case report is to describe a patient with brain infarction due to recanalization of an occluded vertebral artery (VA) following closed reduction and open fixation of cervical spinal dislocation and to discuss the management of asymptomatic VA injuries associated with spine trauma. CLINICAL FEATURES: A 41-year-old Asian man experienced a C4-5 distractive-flexion injury manifesting with quadriplegia and anesthesia below the C3 cord level (including phrenic nerve paralysis), and bowel and bladder dysfunction. Magnetic resonance angiography and computed tomography angiography showed left extracranial VA (V2) occlusion and a patent contralateral VA. INTERVENTION AND OUTCOME: The patient was observed without antiplatelet and/or anticoagulation therapy and underwent open reduction and internal fusion of C4/5 and tracheostomy 8 hours after the injury. After surgery, supraspinal symptoms such as left horizontal nystagmus and left homonymous hemianopsia led to cranial computed tomography and magnetic resonance imaging, which showed left-side cerebellar infarction in the posterior inferior cerebellar artery territory and right-side posterior cerebral artery infarction. Magnetic resonance angiography and computed tomography angiography demonstrated patent bilateral VA (but hypoplastic right VA) and occluded right posterior cerebral artery. The injured VA was treated conservatively, and there were no other ischemic complications. CONCLUSION: The management of asymptomatic VA injury is controversial, with several treatment options available, including observation alone, antiplatelet therapy, anticoagulation therapy, or invasive intervention. Although there are some reports described where management with observation alone seems safe, serious attention should be given to the VA injury caused by cervical spine trauma. PMID- 25435841 TI - Chiropractic care of acute low back pain and incidental spina bifida occulta: a case report. AB - OBJECTIVE: The purpose of this case report is to describe chiropractic care of an adolescent with acute low back pain and incidental finding of spina bifida occulta managed with high-velocity low-amplitude manipulation. CLINICAL FEATURES: A 10-year-old boy was referred for chiropractic care by his pediatrician for the management of low back pain after a fall 3 days prior. Examination and medical records revealed the patient also had spina bifida occulta at the level of L5. INTERVENTION AND OUTCOME: High-velocity low-amplitude treatment for lower back pain showed resolution of patient's pain after 6 visits. No adverse effects were reported. CONCLUSION: An adolescent patient with lower back pain and incidental finding of spina bifida occulta improved with a course of care that included with high-velocity low-amplitude manipulation therapy. PMID- 25435843 TI - Chiropractic management of a 24-year-old woman with idiopathic, intermittent right-sided hemiparesthesia. AB - OBJECTIVE: The purpose of this case report is to describe the chiropractic management of a patient with idiopathic, intermittent right-sided hemiparesthesia. CLINICAL FEATURES: A 24-year-old woman presented with a 2-year history of intermittent idiopathic right arm paresthesia. She also had a 3-month history of intermittent idiopathic right leg/face paresthesia. These symptoms were strongest at night and caused insomnia and worsened over time. She rated her discomfort at 5/10 on a numeric scale. INTERVENTION AND OUTCOME: Care included vibration stimulation therapy, spinal manipulation and cold laser therapy. She had a noticeable reduction in her paresthesia both subjectively and objectively. She showed improvement in paresthesia on the right side of her body after the first visit. The following week, after 2 visits she returned and stated that she was symptom free with 0/10 discomfort on a numeric scale. CONCLUSION: This patient's symptoms of idiopathic, intermittent right-sided hemi-paresthesia seemed to improve with a short course of chiropractic care using manipulation, vibration therapy and cold laser therapy. PMID- 25435842 TI - Late complication of surgically treated atlantoaxial instability: occipital bone erosion induced by protruded fixed titanium rod: a case report. AB - OBJECTIVE: Polyaxial screw-rod fixation of C1-C2 is a relatively new technique to treat atlantoaxial instability, and there have been few reports in the literature outlining all possible complications. The purpose of this case report is to present the occurrence and management of occipital bone erosion induced by the protruded rostral part of a posterior atlantoaxial screw-rod construct causing headache. CLINICAL FEATURES: A 70-year-old Asian man with rheumatoid arthritis initially presented to our institution with atlantoaxial instability causing progressive quadraparesis and neck pain. INTERVENTION AND OUTCOME: Posterior atlantoaxial instrumented fixation using C1 lateral mass screws in conjunction with C2 pedicle screws was performed to stabilize these segments. Postoperatively, the patient regained the ability to independently walk and had no radiographic evidence of instrumentation hardware failure and excellent sagittal alignment. However, despite a well-stabilized fusion, the patient began to complain of headache during neck extension. Follow-up imaging studies revealed left occipital bone erosion induced by a protruded titanium rod fixed with setscrews. During revision surgery, the rod protrusion was modified and the headaches diminished. CONCLUSION: This case demonstrates that occipital bone erosion after posterior atlantoaxial fixation causing headache may occur. The principal cause of bone erosion in this case was rod protrusion. Although posterior atlantoaxial fixation using the screw-rod system was selected to manage atlantoaxial instability because it has less complications than other procedures, surgeons should pay attention that the length of the rod protrusion should not exceed 2 mm. PMID- 25435844 TI - How handshape type can distinguish between nouns and verbs in homesign. AB - All established languages, spoken or signed, make a distinction between nouns and verbs. Even a young sign language emerging within a family of deaf individuals has been found to mark the noun-verb distinction, and to use handshape type to do so. Here we ask whether handshape type is used to mark the noun-verb distinction in a gesture system invented by a deaf child who does not have access to a usable model of either spoken or signed language. The child produces homesigns that have linguistic structure, but receives from his hearing parents co-speech gestures that are structured differently from his own gestures. Thus, unlike users of established and emerging languages, the homesigner is a producer of his system but does not receive it from others. Nevertheless, we found that the child used handshape type to mark the distinction between nouns and verbs at the early stages of development. The noun-verb distinction is thus so fundamental to language that it can arise in a homesign system not shared with others. We also found that the child abandoned handshape type as a device for distinguishing nouns from verbs at just the moment when he developed a combinatorial system of handshape and motion components that marked the distinction. The way the noun verb distinction is marked thus depends on the full array of linguistic devices available within the system. PMID- 25435845 TI - Accuracy of (18)F-flurodeoxyglucose-positron emission tomography/computed tomography in the staging of newly diagnosed nasopharyngeal carcinoma: a systematic review and meta-analysis. AB - BACKGROUND: The specific role of 18F-flurodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in staging of nasopharyngeal carcinoma (NPC) remains to be validated. A systematic review and meta-analysis were performed to assess the accuracy of staging FDG-PET/CT for newly diagnosed NPC. METHODS: We searched various biomedical databases and conference proceedings for relevant studies. We determined the pooled sensitivities and specificities, diagnostic odds ratios (DOR) and constructed summary receiver operating characteristic (SROC) curves using the hierarchical regression model. RESULTS: 15 relevant studies including 851 patients were identified. Five addressed primary tumor (T), nine addressed regional lymph nodes (N) and seven addressed distant metastasis (M). The combined sensitivity estimate for FDG-PET/CT in T classification was 0.77 (95% confidence interval [CI] 0.59-0.95). For N classification, combined sensitivity was 0.84 (95% CI 0.76-0.91), specificity was 0.90 (95% CI 0.83-0.97), DOR was 82.4 (23.2-292.6) and Q*-index was 0.90. For M classification, the combined sensitivity estimate was 0.87 (95% CI 0.74-1.00), specificity was 0.98 (95% CI 0.96-1.00), DOR was 120.9 (43.0-340.0) and Q*-index was 0.89. CONCLUSION: FDG-PET/CT showed good accuracy in N and M but not T classification for newly diagnosed NPC. FDG-PET/CT, together with Magnetic resonance imaging (MRI) of the nasopharynx, should be part of the routine staging investigations. PMID- 25435846 TI - Searching for primaries in patients with neuroendocrine tumors (NET) of unknown primary and clinically suspected NET: Evaluation of Ga-68 DOTATOC PET/CT and In 111 DTPA octreotide SPECT/CT. AB - BACKGROUND: To evaluate the clinical efficacy of In-111 DTPA octreotide SPECT/CT and Ga-68 DOTATOC PET/CT for detection of primary tumors in patients with either neuroendocrine tumor of unknown primary (NETUP) or clinically suspected primary NET (SNET). PATIENTS AND METHODS: A total of 123 patients were included from 2006 to 2009, 52 received Ga-68 DOTATOC PET/CT (NETUP, 33; SNET, 19) and 71 underwent In-111 DTPA octreotide SPECT/CT (50; 21). The standard of reference included histopathology or clinical verification based on follow-up examinations. RESULTS: In the NETUP group Ga-68 DOTATOC detected primaries in 15 patients (45.5%) and In 111 DTPA octreotide in 4 patients (8%) (p < 0.001); in the SNET group, only 2 primaries could be detected, all by Ga-68 DOTATOC. In patients with NETUP, primary tumors could be found significantly more often than in patients with SNET (p = 0.01). Out of these 21 patients 14 patients were operated. CONCLUSION: Ga-68 DOTATOC PET/CT is preferable to In-111 DTPA octreotide SPECT/CT when searching for primary NETs in patients with NETUP but should be used with caution in patients with SNET. PMID- 25435847 TI - The role of elastosonography, gray-scale and colour flow Doppler sonography in prediction of malignancy in thyroid nodules. AB - BACKGROUND: Ultrasound is as a noninvasive method commonly used in the work-up of thyroid nodules. This study aimed to evaluate the usefulness of sonographic and elastosonographic parameters in the discrimination of malignancy. PATIENTS AND METHODS: 150 thyroid nodules were evaluated by gray-scale, Doppler and elastosonography. The cytological analysis revealed that 141 nodules were benign and 9 were malignant. RESULTS: Orientation of the nodule was the only sonographic parameter associated with malignancy (p = 0.003). In the strain ratio analysis the best cut-off point was 1.935 to discriminate malignancy (p = 0.000), with 100% sensitivity, 76% specificity, 100% negative predictive value, 78.5% positive predictive value and 78% accuracy rate. There was a statistically significant correlation between the elasticity score and malignancy (p = 0.001). Most of the benign nodules had score 2 and 3, none of them displayed score 5. On the other hand, none of the malignant nodules had score 1 and 2, most of them displaying score 5. CONCLUSIONS: A change in the diagnostic algorithm of the thyroid nodules should be considered integrating the elastosonographic analysis. PMID- 25435848 TI - Differential S-phase progression after irradiation of p53 functional versus non functional tumour cells. AB - BACKGROUND: Many pathways seem to be involved in the regulation of the intra-S phase checkpoint after exposure to ionizing radiation, but the role of p53 has proven to be rather elusive. Here we have a closer look at the progression of irradiated cells through S-phase in dependence of their p53 status. MATERIALS AND METHODS: Three pairs of tumour cell lines were used, each consisting of one p53 functional and one p53 non-functional line. Cells were labelled with bromodeoxyuridine(BrdU) immediately after irradiation, they were then incubated in label-free medium, and at different times afterwards their position within the S-phase was determined by means of flow cytometry. RESULTS: While in the p53 deficient cells progression through S-phase was slowed significantly over at least a few hours, it was halted for just about an hour in the p53 proficient cells and then proceeded without further delay or even at a slightly accelerated pace. CONCLUSIONS: It is clear from the experiments presented here that p53 does play a role for the progress of cells through the S-phase after X-ray exposure, but the exact mechanisms by which replicon initiation and elongation is controlled in irradiated cells remain to be elucidated. PMID- 25435849 TI - Intercalated chemotherapy and erlotinib for advanced NSCLC: high proportion of complete remissions and prolonged progression-free survival among patients with EGFR activating mutations. AB - BACKGROUND: Pharmaco-dynamic separation of cytotoxic and targeted drugs might avoid their mutual antagonistic effect in the treatment of advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients were treatment naive with stage IIIB or IV NSCLC. In addition, inclusion was limited to never smokers or light smokers or, after 2010, to patients with activating epidermal growth-factor receptor (EGFR) mutations. Treatment started with 3-weekly cycles of gemcitabine and cisplatin on days 1, 2 and 4 and erlotinib on days 5 to 15. After 4 to 6 cycles, patients continued with erlotinib maintenance. RESULTS: Fifty-three patients were recruited into the trial: 24 prior to 2010 (of whom 9 were later found to be positive for EGFR mutations), and 29 EGFR mutation positive patients recruited later. Unfavourable prognostic factors included stage IV disease (51 patients - 96%), performance status 2-3 (11 patients - 21%) and brain metastases (15 patients -28%). Grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. The 15 EGFR negative patients had 33% objective response rate, median progression-free survival (PFS) 6.0 months and median survival 7.6 months. Among 38 EGFR positive patients, complete response (CR) or partial response (PR) were seen in 16 (42.1%) and 17 (44.7%) cases, respectively. PET-CT scanning was performed in 30 patients and confirmed CR and PR in 16 (53.3%) and 9 (30.0%) cases, respectively. Median PFS for EGFR mutated patients was 21.2 months and median survival was 32.5 months. CONCLUSIONS: While patients with EGFR negative tumors do not benefit from addition of erlotinib, the intercalated schedule appears most promising for those with EGFR activating mutations. PMID- 25435850 TI - Induction gemcitabine in standard dose or prolonged low-dose with cisplatin followed by concurrent radiochemotherapy in locally advanced non-small cell lung cancer: a randomized phase II clinical trial. AB - BACKGROUND: The optimal combination of chemotherapy with radiation therapy for treatment locally advanced non-small cell lung cancer (NSCLC) remains an open issue. This randomized phase II study compared gemcitabine in two different schedules and cisplatin - as induction chemotherapy, followed by radiation therapy concurrent with cisplatin and etoposid. PATIENTS AND METHODS: Eligible patients had microscopically confirmed inoperable non-metastatic non-small cell lung cancer; fulfilled the standard criteria for platin-based chemotherapy; and signed informed consent. Patients were treated with 3 cycles of induction chemotherapy with gemcitabine and cisplatin. Two different aplications of gemcitabine were compared: patients in arm A received gemcitabine at 1250 mg/m(2) in a standard half hour i.v. infusion on days 1 and 8; patients in arm B received gemcitabine at 250 mg/m(2) in prolonged 6-hours i.v. infusion on days 1 and 8. In both arms, cisplatin 75 mg/m(2) on day 2 was administered. All patients continued treatment with radiation therapy with 60-66 Gy concurrent with cisplatin 50 mg/m(2) on days 1, 8, 29 and 36 and etoposid 50 mg/m(2) on days 1-5 and 29-33. The primary endpoint was response rate (RR) after induction chemotherapy; secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). RESULTS: From September 2005 to November 2010, 106 patients were recruited to this study. No statistically signifficant differences were found in RR after induction chemotherapy between the two arms (48.1% and 57.4%, p = 0.34). Toxicity profile was comparable and mild with grade 3/4 neutropenia as primary toxicity in both arms. One patient in arm B suffered from acute peripheral ischemia grade 4 and an amputation of lower limb was needed. With a median follow up of 69.3 months, progression-free survival and median survival in arm A were 15.7 and 24.8 months compared to 18.9 and 28.6 months in arm B. The figures for 1 and 3-year overall survival were 73.1% and 30.8% in arm A, and 81.5 % and 44.4% in arm B, respectively. CONCLUSIONS: Among the two cisplatin-based doublets of induction chemotherapy for inoperable NSCLC, both schedules of gemcitabine have a comparable toxicity profile. Figures for RR, PFS and OS are among the best reported in current literature. While there is a trend towards better efficacy of the treament with prolonged infusion of gemcitabine, the difference between the two arms did not reach statistical significance. PMID- 25435851 TI - Survival of patients treated with radiation therapy for anaplastic astrocytoma. AB - BACKGROUND: Anaplastic astrocytoma (AA) represents 7% of primary brain tumors in adults. Patient-, tumor-, and treatment-related factors are thought to be predictive of survival. We retrospectively assessed the association of patient-, tumor-, and treatment-related factors with survival in AA treated with radiotherapy (RT) at our institution. PATIENTS AND METHODS: Medical records of patients with AA treated with RT between 1987 and 2007 were reviewed. Patient-, tumor-, and treatment-related variables were recorded and used to assign patients to a Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) classification. First use of chemotherapy was recorded. Log-rank tests and Cox regression models were used to assess for an association of patient-, tumor- and treatment-related factors with survival. RESULTS: One-hundred twenty-six patients were eligible for study. Median age, Karnofsky performance status, and duration of symptoms were 43 years, 90, and 8 weeks. Median radiation dose was 59.4 Gy; 61% of patients underwent tumor resection, and 17% and 41% of patients received temozolomide during and after RT. Median survival was 31 months, and 2-year survival was 58%. RTOG RPA class was associated with survival (p < 0.001), but use of temozolomide during or after RT was not (p > 0.05). CONCLUSIONS: In this retrospective study with inherent limitations, RTOG RPA classification was associated with survival. Further studies are necessary to confirm or refute this finding. PMID- 25435852 TI - Identification of three anatomical patterns of the spinal accessory nerve in the neck by neurophysiological mapping. AB - BACKGROUND: In spite of preservation of the accessory nerve there is still considerable proportion of patients with partial nerve damage during modified radical neck dissection (MRND). METHODS: The nerve was identified during the surgery and its branches for the trapezius muscle mapped with nerve monitor. RESULTS: The accessory nerve was mapped during 74 hemineck dissections and three patterns were identified. In type 1 nerve exits at the posterior end of the sternocleidomastoid muscle (SCm) and then it enters the level V (66%). In type 2 the nerve for trapezius muscle branches off before entering the SCm (22%). In type 3 the nerve exits at the posterior part of the SCm and it joins to the cervical plexus (12%). The nerve than exits this junction more medially as a single trapezius branch. CONCLUSIONS: The description of three anatomical patterns in level II and V could help preserving the trapezius branch during MRND. PMID- 25435853 TI - Distant metastasis of rectal adenocarcinoma in a temporary tracheostoma. AB - BACKGROUND: The temporary tracheostoma's metastases of head and neck cancer had already been reported in the literature. So far, they had been considered as regional dissemination of the malignant disease. We report a case of temporary tracheostoma's metastasis of carcinoma from non-head-and-neck primary site, what has not been reported in the literature, yet. Therefore, it is the first reported case of the systemic dissemination of malignant tumour into temporary tracheostoma. CASE REPORT: Fifty-four-year-old female patient, previously treated for a rectal adenocarcinoma, reported in our office with exophytic pink tissue masses around the temporary tracheostoma. The biopsy and immunohistochemistry findings were consistent with temporary tracheostoma's metastasis of the rectal adenocarcinoma. The patient received palliative radiotherapy and died of systemic progression of the disease. CONCLUSIONS: The patients with history of primary cancer of any origin and exophytic proliferating changes around the tracheostoma require an appropriate diagnostic work-up including a biopsy. The type of treatment depends on the extent of the disease, previous therapy and general condition of the patient. PMID- 25435854 TI - Mediastinal teratoma with hydrops fetalis in a newborn and development of chronic respiratory insufficiency. AB - BACKGROUND: Mediastinal fetal teratoma can be detected as a mass in the chest during a routine prenatal ultra-sound screening. Because of the pressure on mediastinal structures it can be the cause of non-immune hydrops fetalis and polyhydramnion. The development of hydrops fetalis leads to fetal death or premature delivery in most reported cases. Early surgical removal is important, but, the result of treatment depends on the stage of development of mediastinal organs and complications in the postoperative period. CASE REPORT: A 31-year-old gravida carrying twins, with spontaneous membrane rupture at 32 weeks gestation underwent urgent caesarean section after antenatal ultrasound revealed severe polyhydramnion and hydrops fetalis in geminus A. The child was intubated immediately after birth due to severe respiratory distress. Ultrasound and X-ray revealed a tumour mass in the right hemithorax. Tumour resection was performed at the age of 7 days. Histology examination revealed an encapsulated immature teratoma. The postoperative course was complicated with respiratory insufficiency which turned into chronic at the age of eight months. CONCLUSION: This is the fifth reported child with fetal mediastinal teratoma and severe hydrops fetalis that survived the neonatal period. Additional diagnostic search revealed abnormal course of both pulmonary arteries, which was probably one of the main causes of respiratory insufficiency. PMID- 25435855 TI - Effectiveness of adjuvant trastuzumab in daily clinical practice. AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER2) positive breast cancer is an entity with aggressive behaviour. One year of adjuvant trastuzumab significantly improves the disease free survival in the range of 40-50% and reduces the risk of dying from HER2 positive breast cancer by one third. Adjuvant treatment with trastuzumab became available in Slovenia in 2005 and the aim of this study is to explore, if the exceptional results reported in adjuvant clinical trials are achieved also in daily clinical practice. PATIENTS AND METHODS: An analysis of tumour and patient characteristics, type of treatment and outcome (relapse free and overall survival) of 313 patients (median age 52 years) treated at the Institute of Oncology Ljubljana in years 2005-2009 was performed. RESULTS: Median follow-up was 4.4 years. Sixty-one patients relapsed and 24 died. Three and four years relapse free survival was 84.2% and 80.8% and the overall survival was 94.4% and 92.5%, respectively. Independent prognostic factors for relapse were tumour grade (HR 2.10; 95% CI 1.07-4.14; p = 0.031) and nodal stage (HR 1.35; 1.16-1.56; p < 0.0001) and for the overall survival nodal stage only (HR 1.36; 1.05-1.78; p = 0.021). CONCLUSIONS: The outcome in patients with adjuvant trastuzumab in daily clinical practice, treated by medical oncologists, is comparable to results obtained in international adjuvant studies. PMID- 25435856 TI - A method for generating large datasets of organ geometries for radiotherapy treatment planning studies. AB - BACKGROUND: With the rapidly increasing application of adaptive radiotherapy, large datasets of organ geometries based on the patient's anatomy are desired to support clinical application or research work, such as image segmentation, re planning, and organ deformation analysis. Sometimes only limited datasets are available in clinical practice. In this study, we propose a new method to generate large datasets of organ geometries to be utilized in adaptive radiotherapy. METHODS: Given a training dataset of organ shapes derived from daily cone-beam CT, we align them into a common coordinate frame and select one of the training surfaces as reference surface. A statistical shape model of organs was constructed, based on the establishment of point correspondence between surfaces and non-uniform rational B-spline (NURBS) representation. A principal component analysis is performed on the sampled surface points to capture the major variation modes of each organ. RESULTS: A set of principal components and their respective coefficients, which represent organ surface deformation, were obtained, and a statistical analysis of the coefficients was performed. New sets of statistically equivalent coefficients can be constructed and assigned to the principal components, resulting in a larger geometry dataset for the patient's organs. CONCLUSIONS: These generated organ geometries are realistic and statistically representative. PMID- 25435857 TI - Slovenian experience from diagnostic angiography to interventional radiology. AB - BACKGROUND: The purpose of writing this article is to document the important events and people in the first 50 years of diagnostic angiography and interventional radiology in Slovenia. During this period not only did the name of the institutions and departments change, but also its governance. CONCLUSIONS: This depicted the important roles different people played at various times in the cardiovascular divisions inside and outside of the diagnostic and interventional radiology. Historical data show that Slovenian radiology has relatively immediately introduced the new methods of interventional radiology in clinical practice. PMID- 25435859 TI - Application of temperature-dependent fluorescent dyes to the measurement of millimeter wave absorption in water applied to biomedical experiments. AB - Temperature sensitivity of the fluorescence intensity of the organic dyes solutions was used for noncontact measurement of the electromagnetic millimeter wave absorption in water. By using two different dyes with opposite temperature effects, local temperature increase in the capillary that is placed inside a rectangular waveguide in which millimeter waves propagate was defined. The application of this noncontact temperature sensing is a simple and novel method to detect temperature change in small biological objects. PMID- 25435860 TI - Real-time evaluation of breast self-examination using computer vision. AB - Breast cancer is the most common cancer among women worldwide and breast self examination (BSE) is considered as the most cost-effective approach for early breast cancer detection. The general objective of this paper is to design and develop a computer vision algorithm to evaluate the BSE performance in real-time. The first stage of the algorithm presents a method for detecting and tracking the nipples in frames while a woman performs BSE; the second stage presents a method for localizing the breast region and blocks of pixels related to palpation of the breast, and the third stage focuses on detecting the palpated blocks in the breast region. The palpated blocks are highlighted at the time of BSE performance. In a correct BSE performance, all blocks must be palpated, checked, and highlighted, respectively. If any abnormality, such as masses, is detected, then this must be reported to a doctor to confirm the presence of this abnormality and proceed to perform other confirmatory tests. The experimental results have shown that the BSE evaluation algorithm presented in this paper provides robust performance. PMID- 25435858 TI - Characteristics of hemolytic activity induced by the aqueous extract of the Mexican fire coral Millepora complanata. AB - BACKGROUND: Millepora complanata is a plate-like fire coral common throughout the Caribbean. Contact with this species usually provokes burning pain, erythema and urticariform lesions. Our previous study suggested that the aqueous extract of M. complanata contains non-protein hemolysins that are soluble in water and ethanol. In general, the local damage induced by cnidarian venoms has been associated with hemolysins. The characterization of the effects of these components is important for the understanding of the defense mechanisms of fire corals. In addition, this information could lead to better care for victims of envenomation accidents. METHODS: An ethanolic extract from the lyophilized aqueous extract was prepared and its hemolytic activity was compared with the hemolysis induced by the denatured aqueous extract. Based on the finding that ethanol failed to induce nematocyst discharge, ethanolic extracts were prepared from artificially bleached and normal M. complanata fragments and their hemolytic activity was tested in order to obtain information about the source of the heat-stable hemolysins. RESULTS: Rodent erythrocytes were more susceptible to the aqueous extract than chicken and human erythrocytes. Hemolytic activity started at ten minutes of incubation and was relatively stable within the range of 28-50 degrees C. When the aqueous extract was preincubated at temperatures over 60 degrees C, hemolytic activity was significantly reduced. The denatured extract induced a slow hemolytic activity (HU50 = 1,050.00 +/- 45.85 MUg/mL), detectable four hours after incubation, which was similar to that induced by the ethanolic extract prepared from the aqueous extract (HU50 = 1,167.00 +/- 54.95 MUg/mL). No significant differences were observed between hemolysis induced by ethanolic extracts from bleached and normal fragments, although both activities were more potent than hemolysis induced by the denatured extract. CONCLUSIONS: The results showed that the aqueous extract of M. complanata possesses one or more powerful heat-labile hemolytic proteins that are slightly more resistant to temperature than jellyfish venoms. This extract also contains slow thermostable hemolysins highly soluble in ethanol that are probably derived from the body tissues of the hydrozoan. PMID- 25435862 TI - A novel artificial immune algorithm for spatial clustering with obstacle constraint and its applications. AB - An important component of a spatial clustering algorithm is the distance measure between sample points in object space. In this paper, the traditional Euclidean distance measure is replaced with innovative obstacle distance measure for spatial clustering under obstacle constraints. Firstly, we present a path searching algorithm to approximate the obstacle distance between two points for dealing with obstacles and facilitators. Taking obstacle distance as similarity metric, we subsequently propose the artificial immune clustering with obstacle entity (AICOE) algorithm for clustering spatial point data in the presence of obstacles and facilitators. Finally, the paper presents a comparative analysis of AICOE algorithm and the classical clustering algorithms. Our clustering model based on artificial immune system is also applied to the case of public facility location problem in order to establish the practical applicability of our approach. By using the clone selection principle and updating the cluster centers based on the elite antibodies, the AICOE algorithm is able to achieve the global optimum and better clustering effect. PMID- 25435861 TI - Microwave radar imaging of heterogeneous breast tissue integrating a priori information. AB - Conventional radar-based image reconstruction techniques fail when they are applied to heterogeneous breast tissue, since the underlying in-breast relative permittivity is unknown or assumed to be constant. This results in a systematic error during the process of image formation. A recent trend in microwave biomedical imaging is to extract the relative permittivity from the object under test to improve the image reconstruction quality and thereby to enhance the diagnostic assessment. In this paper, we present a novel radar-based methodology for microwave breast cancer detection in heterogeneous breast tissue integrating a 3D map of relative permittivity as a priori information. This leads to a novel image reconstruction formulation where the delay-and-sum focusing takes place in time rather than range domain. Results are shown for a heterogeneous dense (class 4) and a scattered fibroglandular (class-2) numerical breast phantom using Bristol's 31-element array configuration. PMID- 25435863 TI - Numerical simulation of nonperiodic rail operation diagram characteristics. AB - This paper succeeded in utilizing cellular automata (CA) model to simulate the process of the train operation under the four-aspect color light system and getting the nonperiodic diagram of the mixed passenger and freight tracks. Generally speaking, the concerned models could simulate well the situation of wagon in preventing trains from colliding when parking and restarting and of the real-time changes the situation of train speeds and displacement and get hold of the current train states in their departures and arrivals. Finally the model gets the train diagram that simulates the train operation in different ratios of the van and analyzes some parameter characters in the process of train running, such as time, speed, through capacity, interval departing time, and departing numbers. PMID- 25435865 TI - A framework for spatial interaction analysis based on large-scale mobile phone data. AB - The overall understanding of spatial interaction and the exact knowledge of its dynamic evolution are required in the urban planning and transportation planning. This study aimed to analyze the spatial interaction based on the large-scale mobile phone data. The newly arisen mass dataset required a new methodology which was compatible with its peculiar characteristics. A three-stage framework was proposed in this paper, including data preprocessing, critical activity identification, and spatial interaction measurement. The proposed framework introduced the frequent pattern mining and measured the spatial interaction by the obtained association. A case study of three communities in Shanghai was carried out as verification of proposed method and demonstration of its practical application. The spatial interaction patterns and the representative features proved the rationality of the proposed framework. PMID- 25435864 TI - Modeling the commuting travel activities within historic districts in Chinese cities. AB - The primary objective of this study is to analyze the characteristics of commuting activities within the historical districts in cities of China. The impacts of various explanatory variables on commuters' travels are evaluated using the structural equation modeling (SEM) approach. The household survey was conducted in the historical districts in Yangzhou, China. Based on the data, various individual and household attributes were considered exogenous variables, while the subsistence activity characteristics, travel times, numbers of three typical home-based trip chains, trip chains, and travel mode were considered as the endogenous variables. Commuters in our study were classified into two main groups according to their working location, which were the commuters in the historic district and those out of the district. The modeling results show that several individual and household attributes of commuters in historic district have significant impacts on the characteristics of travel activities. Additionally, the characteristics of travel activities within the two groups are quite different, and the contributing factors related to commuting travels are different as well. PMID- 25435866 TI - High speed railway environment safety evaluation based on measurement attribute recognition model. AB - In order to rationally evaluate the high speed railway operation safety level, the environmental safety evaluation index system of high speed railway should be well established by means of analyzing the impact mechanism of severe weather such as raining, thundering, lightning, earthquake, winding, and snowing. In addition to that, the attribute recognition will be identified to determine the similarity between samples and their corresponding attribute classes on the multidimensional space, which is on the basis of the Mahalanobis distance measurement function in terms of Mahalanobis distance with the characteristics of noncorrelation and nondimensionless influence. On top of the assumption, the high speed railway of China environment safety situation will be well elaborated by the suggested methods. The results from the detailed analysis show that the evaluation is basically matched up with the actual situation and could lay a scientific foundation for the high speed railway operation safety. PMID- 25435867 TI - Robust optimization model and algorithm for railway freight center location problem in uncertain environment. AB - Railway freight center location problem is an important issue in railway freight transport programming. This paper focuses on the railway freight center location problem in uncertain environment. Seeing that the expected value model ignores the negative influence of disadvantageous scenarios, a robust optimization model was proposed. The robust optimization model takes expected cost and deviation value of the scenarios as the objective. A cloud adaptive clonal selection algorithm (C-ACSA) was presented. It combines adaptive clonal selection algorithm with Cloud Model which can improve the convergence rate. Design of the code and progress of the algorithm were proposed. Result of the example demonstrates the model and algorithm are effective. Compared with the expected value cases, the amount of disadvantageous scenarios in robust model reduces from 163 to 21, which prove the result of robust model is more reliable. PMID- 25435868 TI - A new cellular automaton model for urban two-way road networks. AB - A new cellular automaton (CA) model is proposed to simulate traffic dynamics in urban two-way road network systems. The NaSch rule is adopted to represent vehicle movements on road sections. Two novel rules are proposed to move the vehicles in intersection areas, and an additional rule is developed to avoid the "gridlock" phenomenon. Simulation results show that the network fundamental diagram is very similar to that of road traffic flow. We found that the randomization probability and the maximum vehicle speed have significant impact on network traffic mobility for free-flow state. Their effect may be weak when the network is congested. PMID- 25435869 TI - Study of track irregularity time series calibration and variation pattern at unit section. AB - Focusing on problems existing in track irregularity time series data quality, this paper first presents abnormal data identification, data offset correction algorithm, local outlier data identification, and noise cancellation algorithms. And then proposes track irregularity time series decomposition and reconstruction through the wavelet decomposition and reconstruction approach. Finally, the patterns and features of track irregularity standard deviation data sequence in unit sections are studied, and the changing trend of track irregularity time series is discovered and described. PMID- 25435871 TI - Optimization of the design of pre-signal system using improved cellular automaton. AB - The pre-signal system can improve the efficiency of intersection approach under rational design. One of the main obstacles in optimizing the design of pre-signal system is that driving behaviors in the sorting area cannot be well evaluated. The NaSch model was modified by considering slow probability, turning deceleration rules, and lane changing rules. It was calibrated with field observed data to explore the interactions among design parameters. The simulation results of the proposed model indicate that the length of sorting area, traffic demand, signal timing, and lane allocation are the most important influence factors. The recommendations of these design parameters are demonstrated. The findings of this paper can be foundations for the design of pre-signal system and show promising improvement in traffic mobility. PMID- 25435870 TI - A red-light running prevention system based on artificial neural network and vehicle trajectory data. AB - The high frequency of red-light running and complex driving behaviors at the yellow onset at intersections cannot be explained solely by the dilemma zone and vehicle kinematics. In this paper, the author presented a red-light running prevention system which was based on artificial neural networks (ANNs) to approximate the complex driver behaviors during yellow and all-red clearance and serve as the basis of an innovative red-light running prevention system. The artificial neural network and vehicle trajectory are applied to identify the potential red-light runners. The ANN training time was also acceptable and its predicting accurate rate was over 80%. Lastly, a prototype red-light running prevention system with the trained ANN model was described. This new system can be directly retrofitted into the existing traffic signal systems. PMID- 25435872 TI - Understanding attitudes towards proenvironmental travel: an empirical study from Tangshan City in China. AB - Understanding people's attitudes towards proenvironmental travel will help to encourage people to adopt proenvironmental travel behavior. Revealed preference theory assumes that the consumption preference of consumers can be revealed by their consumption behavior. In order to investigate the influences on citizens' travel decision and analyze the difficulties of promoting proenvironmental travel behavior in medium-sized cities in China, based on revealed preference theory, this paper uses the RP survey method and disaggregate model to analyze how individual characteristics, situational factors, and trip features influence the travel mode choice. The field investigation was conducted in Tangshan City to obtain the RP data. An MNL model was built to deal with the travel mode choice. SPSS software was used to calibrate the model parameters. The goodness-of-fit tests and the predicted outcome demonstrate the validation of the parameter setting. The results show that gender, occupation, trip purpose, and distance have an obvious influence on the travel mode choice. In particular, the male gender, high income, and business travel show a high correlation with carbon intensive travel, while the female gender and a medium income scored higher in terms of proenvironmental travel modes, such as walking, cycling, and public transport. PMID- 25435873 TI - Aberrant Expression of MicroRNA-15a and MicroRNA-16 Synergistically Associates with Tumor Progression and Prognosis in Patients with Colorectal Cancer. AB - The aim of this study was to reveal the associations of microRNA miR-15a and miR 16 dysregulation with clinicopathological characteristics and prognosis in patients with colorectal cancer. As a result, we found that miR-15a and miR-16 expression, detected by quantitative real time-PCR, were both significantly downregulated in colorectal cancer tissues compared with adjacent colorectal mucosa (both P < 0.001). Particularly, the expression levels of miR-15a in colorectal cancer tissues were positively correlated with those of miR-16 significantly (Spearman correlation coefficient r = 0.652, P < 0.001). In addition, miR-15a and/or miR-16 downregulation were all significantly associated with advanced TNM stage (all P < 0.05), poorly histological grade (all P < 0.05), and positive lymph node metastasis (all P < 0.05). Moreover, the survival analysis identified miR-15a expression, miR-16 expression, and miR-15a/miR-16 combination as independent predictors of both unfavorable overall survival and disease-free survival. Interestingly, the prognostic value of miR-15a/miR-16 combination was more significant than miR-15a or miR-16 expression alone. Collectively, the aberrant expression of miR-15a and miR-16 could be used to stratify patients with aggressive tumor progression of colorectal cancer. The combined pattern of miR-15a and miR-16 downregulation has a significant value for distinguishing patients with a worse prognosis of colorectal cancer after surgery. PMID- 25435875 TI - In vitro reporter assays for screening of chemicals that disrupt androgen signaling. AB - Endocrine disruptive chemicals (EDCs) modulate hormone signaling and cause developmental and reproductive anomalies. Today, there is a global concern regarding endocrine disruption effects, particularly those mediated by the androgen receptor (AR). Androgen or male hormones are critical for the development and maintenance of male characteristics and numerous EDCs exist in the environment with the potential to disrupt androgen action. The threat is more during critical developmental windows when there is increased sensitivity to these compounds. Timely screening and detection of the EDCs is essential to minimize deleterious effects produced by these toxic chemicals. As a first line of screening, in vitro transcription assays are very useful due to their speed, convenience, and cost effectiveness. In this paper, recent in vitro reporter assays for detecting androgenic or antiandrogenic activity of EDCs have been reviewed. Two important cell systems used for this purpose, namely, the mammalian or yeast cell systems, have been discussed. Use of reporter genes such as bacterial luciferase (lux) and green fluorescent protein (gfp) has significantly improved speed and sensitivity of detection. Also, many of the current reporter assay systems can be used in a high throughput format allowing speedy evaluation of multiple potential EDCs at a lower price. PMID- 25435874 TI - Xylazine as a drug of abuse and its effects on the generation of reactive species and DNA damage on human umbilical vein endothelial cells. AB - Human xylazine (XYL) abuse among addicts has received great interest due to its potential toxic effects upon addicts and the need to understand the mechanism of action associated with the potential health effects. XYL is an alpha-2 agonist restricted to veterinarian applications, without human medical applications. Our previous work demonstrated that XYL and its combination with cocaine (COC) and/or 6-monoacetylmorphine (6-MAM) induce cell death through an apoptotic mechanism. The aim of this study was to determine the effect of xylazine on the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as well as DNA damage on endothelial cell. Human umbilical vein endothelial cells (HUVEC) were treated with XYL (60 MUM), COC (160 MUM), 6-MAM (160 MUM), camptothecin (positive control, 50 MUM), XYL/COC (50 MUM), XYL/6-MAM (50 MUM), and XYL/COC/6 MAM (40 MUM) for a period of 24 hours. Generation of intracellular ROS, RNS, and DNA fragmentation were analyzed using a fluorometric assay. Results reveal that XYL and 6-MAM increase levels of ROS; no induction of RNS production was observed. The combination of these drugs shows significant increase in DNA fragmentation in G2/M phase, while XYL, COC, and 6-MAM, without combination, present higher DNA fragmentation in G0/G1 phase. These findings support that these drugs and their combination alter important biochemical events aligned with an apoptotic mechanism of action in HUVEC. PMID- 25435876 TI - Evaluating the Effect of Ramadan Fasting on Muslim Patients with Diabetes in relation to Use of Medication and Lifestyle Patterns: A Prospective Study. AB - Objectives. This study aimed to examine the effect of Ramadan fasting on HbA1c in Muslim patients with type 2 diabetes. The incidence of hypoglycemia and glycemic changes in relation to the adjustment of doses of antidiabetic agents, diet, and physical activity during Ramadan was also evaluated. Methods. This was a prospective study conducted in an outpatient endocrine clinic. A set of questionnaires was administered to Muslim patients with diabetes who fasted for >=10 days. Those who were hospitalized for diabetic ketoacidosis or severe hypoglycemia a month prior to Ramadan or were given short-term corticosteroid therapy were excluded. The patients' responses and clinical outcomes from the clinic database were collected before, during, and after Ramadan. Results. A total of 153 participants completed the study. The mean HbA1c improved from 8.9% before Ramadan to 8.6% during Ramadan (P < 0.05). Although diet and physical activity did not contribute to changes in glycemia, a significant improvement in HbA1c was observed in patients who had adjustments made to their doses of antidiabetic agents during Ramadan (P < 0.001). In addition, their rate of hypoglycemia was minimal. Conclusions. Ramadan fasting appeared to improve glycemic control, especially in those whose doses of antidiabetic agents were adjusted during Ramadan. PMID- 25435877 TI - Determinants of Vitamin D Levels in Italian Children and Adolescents: A Longitudinal Evaluation of Cholecalciferol Supplementation versus the Improvement of Factors Influencing 25(OH)D Status. AB - Objective. This paper aims to assess 25(OH)D levels in Italian children and adolescents identifying risk factors for 25(OH)D deficiency and to evaluate whether a normal 25(OH)D value can be restored in 25(OH)D-deficient patients. Methods. We evaluated 25(OH)D levels in 679 Italian children and adolescents (<=10, 11-20, 21-30, and >30 ng/mL were defined as severe deficiency, deficiency, insufficiency, and sufficiency, resp.). Of these, 365 25(OH)D-deficient were followed up for 1 year; 205 were treated with cholecalciferol (Arm A: 400 I.U.) and 160 by improving the environmental variables influencing 25(OH)D levels (Arm B). Results. At cross-sectional evaluation, 11.3% showed sufficiency, 30.0% insufficiency, and 58.7% 25(OH)D deficiency. Mean 25(OH)D was 19.08 +/- 8.44 ng/mL. At the enrollment time (T 0), no difference was found between Arms A and B with respect to distribution and 25(OH)D levels. At end time (T 1) 26.0% (29.7% in Arm A versus 20.6% in Arm B) showed sufficiency, 38.4% (42.0% versus 34.4%) insufficiency, and 35.6% (28.3% versus 45.0%) 25(OH)D deficiency. Mean 25(OH)D level was 23.71 +/- 6.83 ng/mL. Conclusions. Neither changes of lifestyle nor 400 I.U. cholecalciferol supplementation alone appears to be sufficient to restore adequate 25(OH)D levels. PMID- 25435878 TI - The Protective Effect of Beraprost Sodium on Diabetic Cardiomyopathy through the Inhibition of the p38 MAPK Signaling Pathway in High-Fat-Induced SD Rats. AB - Objective. To investigate the effect of beraprost sodium (BPS) on diabetic cardiomyopathy and the underlying mechanism. Methods. A total of 40 Sprague Dawley rats were randomly divided into the normal control group (N = 10) and the model group (N = 30). The model group was fed a high-fat diet followed by a one time dose of streptozotocin (STZ) to establish the diabetes mellitus model. After that, rats were randomly divided into two groups with or without BPS intervention. After 8 weeks, we explored the role of the p38 MAPK signaling pathway in inflammation, oxidative stress, cardiac morphology, and myocardial apoptosis. Results. Compared with control, the ratio of heart-weight to body weight and the serum levels of SOD and GSH in the BPS group significantly increased, the expression of p38 MAPK, the serum levels of MDA, TGF-beta1, TNF alpha, HIF-1alpha, MMP-9, caspase-3, BNP, ANP, and heart Bax expression significantly decreased, and heart Bcl-2 expression significantly increased. H&E staining in diabetic rats showed the cardiac muscle fibers derangement, the widening gap, the pyknotic and fragmented nuclei, and more apoptosis. Conclusions. BPS effectively showed protective effects on diabetic myocardial cells, possibly through the inhibition of p38 MAPK signaling pathway. PMID- 25435880 TI - A Case with Repeated Recurrent Acute Coronary Syndrome due to Pseudoephedrine Use: Kounis Syndrome. AB - Allergic reaction-associated acute coronary syndrome picture is defined as Kounis syndrome. Although drug use is the most common cause of allergic reaction, foods and environmental factors may also play a role in the etiology. Herein, a case with acute coronary syndrome that developed two times at 8-month interval due to pseudoephedrine use for upper respiratory tract infection is presented. PMID- 25435879 TI - Are There Clinical Differences in Limited Systemic Sclerosis according to Extension of Skin Involvement? AB - Objectives. To examine the characteristics of our patients with limited systemic sclerosis (lSSc) for differences between Barnett Type 1 (sclerodactyly only) and Type 2 or intermediate (acrosclerosis-distal but may reach up to elbows and/or knees plus face) subsets. Methods. Records of patients between January 1, 2000, and December 31, 2011, with SSc or those with anti-Scl-70, anticentromere, or antinucleolar antibodies were reviewed. Only cases fulfilling ACR 1980 criteria were included and classified as diffuse or limited according to LeRoy's criteria. Limited SSc was separated into sclerodactyly and acrosclerosis (Barnett's Types 1 and 2). Results. 234 SSc patients (216 females) fulfilled criteria. Female/male ratio was 12 : 1; 24% had dSSc and 76% lSSC (64% Type 1 and 12% Type 2). Total follow-up was 688 patient-years. Within lSSC, the Type 2 group had significantly shorter duration of Raynaud's and more anti-Scl-70 and less anticentromere antibodies. In particular, interstitial lung disease (ILD) was significantly more prevalent in Type 2 group and similar to Type 3. Conclusions. These results appear to confirm that extension of skin involvement within limited SSc may identify two different subsets with clinical and serologic characteristics. PMID- 25435881 TI - Nontuberculous mycobacteria immune reconstitution syndrome. AB - The prevalence of nontuberculous mycobacteria infection (NTM) in Sub-Saharan Africa is estimated to be less than 1%. NTM is often underdiagnosed or misdiagnosed as tuberculosis in patients who present with immune reconstitution syndrome (IRS) following initiation of antiretroviral treatment (ART). Immune reconstitution syndrome is common in patients who start ART with low CD4 counts and high HIV viral load. Furthermore, Mycobacterium avium complex (MAC) commonly infects those with CD4 counts less than 50 cells/mm(3). Three patients, with low baseline CD4 counts, presenting with NTM following the initiation of antiretroviral treatment are described in this case series. The first patient presented with disseminated NTM two weeks after commencing antiretroviral treatment. Acid fast bacilli were found in the liver, duodenum, and bone marrow and were suggestive of MAC microscopically. The second developed cervical lymphadenitis following the initiation of ART. Lymph node aspirate culture grew NTM. The last patient developed pancytopenia after 3 months of ART. AFB was seen on bone marrow biopsy. Culture of the bone marrow aspirate was suggestive of NTM. All three patients improved on ethambutol, clarithromycin, and rifampicin. NTM may be underdiagnosed in areas with a high TB prevalence and should be actively excluded by culture. PMID- 25435882 TI - Delayed Facial Paralysis following Uneventful KTP Laser Stapedotomy: Two Case Reports and a Review of the Literature. AB - Facial palsy that occurs immediately after middle ear surgery (stapedectomy, stapedotomy, and tympanoplasty) can be a consequence of the local anesthetics and it regresses completely within a few hours. In the case of delayed facial palsy, the alarming symptom occurs several days or even weeks after uneventful surgery. The mechanism of the neural dysfunction is not readily defined. Surgical stress, intraoperative trauma, or laceration of the chorda tympani nerve with a resultant retrograde facial nerve edema can all be provoking etiological factors. A dehiscent bony facial canal or a multiple microporotic fallopian canal (microtrauma or laser effect) can also contribute to the development of this rare phenomenon. The most popular theory related to the explanation of delayed facial palsy at present is the reactivation of dormant viruses. Both the thermal effect of the laser and the elevation of the tympanomeatal flap can reactivate viruses resting inside the ganglion geniculi, facial nerve, or facial nuclei. The authors report the case histories of a 55-year-old female, and a 45-year-old male who presented with a delayed facial palsy following laser stapedotomy. The clinical characteristics, the therapeutic options, and the possibility of prevention are discussed. PMID- 25435883 TI - What Parents Think about Giving Nonnutritive Sweeteners to Their Children: A Pilot Study. AB - Objective. To evaluate parental attitudes toward providing foods and beverages with nonnutritive sweeteners (NNS) to their children and to explore parental ability to recognize NNS in packaged foods and beverages. Methods. 120 parents of children >= 1 and <=18 years of age completed brief questionnaires upon entering or exiting a grocery store. Parental attitudes toward NNS were assessed using an interviewer-assisted survey. Parental selection of packaged food and beverages (with and without NNS) was evaluated during a shopping simulation activity. Parental ability to identify products with NNS was tested with a NNS recognition test. Results. Most parents (72%) disagreed with the statement "NNS are safe for my child to consume." This was not reflected during the shopping simulation activity because about one-quarter of items selected by parents contained NNS. Parents correctly identified only 23% of NNS-containing items presented as foods or beverages which were sweetened with NNS. Conclusions. The negative parental attitudes toward providing NNS to their children raise the question whether parents are willing to replace added sugars with NNS in an effort to reduce their child's calorie intake. Our findings also suggest that food labeling should be revised in order for consumers to more easily identify NNS in foods and beverages. PMID- 25435885 TI - Problem-solving and mental health outcomes of women and children in the wake of intimate partner violence. AB - The environmental stress of intimate partner violence is common and often results in mental health problems of depression, anxiety, and PTSD for women and behavioral dysfunctions for their children. Problem-solving skills can serve to mitigate or accentuate the environmental stress of violence and associated impact on mental health. To better understand the relationship between problem-solving skills and mental health of abused women with children, a cross-sectional predictive analysis of 285 abused women who used justice or shelter services was completed. The women were asked about social problem-solving, and mental health symptoms of depression, anxiety, and PTSD as well as behavioral functioning of their children. Higher negative problem-solving scores were associated with significantly (P < 0.001) greater odds of having clinically significant levels of PTSD, anxiety, depression, and somatization for the woman and significantly (P < 0.001) greater odds of her child having borderline or clinically significant levels of both internalizing and externalizing behaviors. A predominately negative problem-solving approach was strongly associated with poorer outcomes for both mothers and children in the aftermath of the environmental stress of abuse. Interventions addressing problem-solving ability may be beneficial in increasing abused women's abilities to navigate the daily stressors of life following abuse. PMID- 25435884 TI - Epithelial antimicrobial peptides: guardian of the oral cavity. AB - Gingival epithelium provides first line of defence from the microorganisms present in dental plaque. It not only provides a mechanical barrier but also has an active immune function too. Gingival epithelial cells participate in innate immunity by producing a range of antimicrobial peptides to protect the host against oral pathogens. These epithelial antimicrobial peptides (EAPs) include the beta-defensin family, cathelicidin (LL-37), calprotectin, and adrenomedullin. While some are constitutively expressed in gingival epithelial cells, others are induced upon exposure to microbial insults. It is likely that these EAPs have a role in determining the initiation and progression of oral diseases. EAPs are broad spectrum antimicrobials with a different but overlapping range of activity. Apart from antimicrobial activity, they participate in several other crucial roles in host tissues. Some of these, for instance, beta-defensins, are chemotactic to immune cells. Others, such as calprotectin are important for wound healing and cell proliferation. Adrenomedullin, a multifunctional peptide, has its biological action in a wide range of tissues. Not only is it a potent vasodilator but also it has several endocrine effects. Knowing in detail the various bioactions of these EAPs may provide us with useful information regarding their utility as therapeutic agents. PMID- 25435887 TI - IMPACT OF AGE AND AUTOANTIBODY STATUS ON THE GENE EXPRESSION OF SCLERODERMA FIBROBLASTS IN RESPONSE TO SILICA STIMULATION. AB - Environmental factors are believed to play an important role in the pathogenesis of systemic sclerosis (SSc). Silica exposure has been implicated as potentially hazardous in epidemiological studies of SSc. It can activate fibroblasts to express profibrotic genes at certain conditions. The aim of this study is to examine whether the fibroblasts of SSc patients respond to silica particles with specific gene expressions differentially from normal control fibroblasts. The fibroblasts obtained from skin biopsies of 96 SSc patients and 104 controls were examined. Silica particles were used to perturb the cultures of the fibroblasts in time-course and dose-response assays. The transcript levels of COL1A2, COL3A1, MIVIP1, MMP3, TIMP3 and CTGF genes of the fibroblasts were measured with quantitative RT-PCR. The results showed that the expressions of all six genes in SSc fibroblasts under silica perturbation appeared significantly different from normal control fibroblasts. In age stratified analysis, compared to control fibroblasts, SSc fibroblasts from patients at age 30-40 years and 50-60 years displayed significantly decreased expressions of MMP1 gene in all dosage assays and increased expression of COL3A1 genes started at low dosages perturbation of silica particles, respectively. In autoantibody stratified analysis, specific gene expression patterns were significantly associated with autoantibody subgroups of fibroblasts. A common feature of SSc fibroblasts was unstable and a wide range of gene expression changes in response to silica perturbation. Our studies may suggest an altered intrinsic dynamic control in SSc fibroblasts. In addition, sensitivity and specificity of SSc fibroblasts to potentially hazardous environmental trigger is age and autoantibody-subgroup-dependent. The fibroblasts of SSc patients at age 30-60 years may be more sensitive to silica perturbation toward a profibrotic gene expression. PMID- 25435888 TI - Effect of Gloriosa superba and Catharanthus roseus Extracts on IFN-gamma-Induced Keratin 17 Expression in HaCaT Human Keratinocytes. AB - Gloriosa superba and Catharanthus roseus are useful in traditional medicine for treatment of various skin diseases and cancer. However, their molecular effect on psoriasis has not been investigated. In this study, the effect of ethanol extracts derived from G. superba leaves and C. roseus stems on the expression of psoriatic marker, keratin 17 (K17), was investigated in human keratinocytes using biochemical and molecular experimental approaches. Both extracts could reduce the expression of K17 in a dose-dependent manner through JAK/STAT pathway as demonstrated by an observation of reduced phosphorylation of STAT3 (p-STAT3). The inhibitory activity of G. superba extract was more potent than that of C. roseus. The Pearson's correlation between K17 and cell viability was shown positive. Taken together, the extracts of G. superba and C. roseus may be developed as alternative therapies for psoriasis. PMID- 25435886 TI - Effects of recombinant human growth hormone (rhGH) administration on body composition and cardiovascular risk factors in obese adolescent girls. AB - BACKGROUND: Obesity is associated with a relative deficiency of growth hormone, which is predictive of greater visceral fat and markers of cardiovascular risk. The study's purpose was to use recombinant human growth hormone (rhGH) as a physiologic probe to assess the effects of reversing obesity-related GH deficiency on body composition, cardiovascular risk markers, and insulin resistance. METHODS: 22 obese girls 13-21 years old were followed for a randomized 6-month trial of rhGH vs. placebo/no treatment. At baseline and 6 months, DXA was performed for body composition, MRI to measure visceral, subcutaneous and total adipose tissue (VAT, SAT and TAT), and fasting blood drawn for IGF-1, inflammatory cardiovascular risk markers [soluble intercellular adhesion molecule (sICAM), high sensitivity CRP], lipids and HbA1C. An oral glucose tolerance test (OGTT) was performed. Twelve girls completed the 6-month visit. Baseline and mean 6-month change were compared between the groups using the Student t-test and the relationship between variables was determined through multiple regression analysis. RESULTS: After 6-months, the rhGH group maintained IGF-1 levels, and had decreases in total cholesterol (p = 0.03), sICAM-1 (p = 0.04) and HbA1C (p = 0.03) compared to placebo/no treatment. The rhGH group trended towards greater decreases in LDL and 2-hour OGTT glucose. Glucose tolerance did not worsen with rhGH administration. CONCLUSIONS: Administering rhGH in small doses is able to stabilize IGF-1 levels in obesity. We have also shown that rhGH administration leads to an improvement in some markers of cardiovacular risk with without adversely affecting glucose tolerance. TRIAL REGISTRATION: CLINICAL TRIAL REGISTRATION NUMBER: NCT01169103. PMID- 25435889 TI - The molecular mechanism of rhein in diabetic nephropathy. AB - Diabetic nephropathy (DN) is characterized by unclear pathogenesis. Recent medical data shows that the incidence of DN rises year by year. Rhein is the main compositions of rhubarb, a traditional Chinese medicinal plant, which plays an active role in kidney protection. The prophylaxis and phytotherapeutic effects of rhein are due to its anti-inflammatory and antifibrosis properties. Here, we shed light on the renal protective role of rhein in diabetes mellitus (DM) with a particular focus on the molecular basis of this effect. PMID- 25435890 TI - Adverse events of auricular therapy: a systematic review. AB - The aim of this study was to systematically evaluate the literature on adverse events associated with auricular therapy (AT). Case reports, case series, surveys, and all types of clinical trials reporting adverse events of AT were included. Relevant articles were mainly retrieved from 13 electronic databases and seven Chinese journals on complementary medicine. AT-related adverse events were reported in 32 randomized controlled trials, five uncontrolled clinical trials, four case reports, and two controlled clinical trials. For auricular acupuncture, the most frequently reported adverse events were tenderness or pain at insertion, dizziness, local discomfort, minor bleeding and nausea, and so forth. For auricular acupressure, local skin irritation and discomfort, mild tenderness or pain, and dizziness were commonly reported. Skin irritation, local discomfort, and pain were detected in auricular electroacupuncture, and minor infection was identified in auricular bloodletting therapy. Most of these events were transient, mild, and tolerable, and no serious adverse events were identified. Our findings provide preliminary evidence that AT is a relatively safe approach. Considering the patient's safety, prospective or retrospective surveys are needed in future research to gather practitioner-reported and patient reported adverse events on AT, and the quality of adverse events reporting in future AT trials should be improved. PMID- 25435891 TI - Crotonis Fructus and Its Constituent, Croton Oil, Stimulate Lipolysis in OP9 Adipocytes. AB - Introduction. Crotonis fructus (CF) is the mature fruit of Croton tiglium L. and has been used for the treatment of gastrointestinal disturbance in Asia. It is well known that the main component of CF is croton oil (CO). The present study is to investigate the effects of CF extracts (CFE) and CO on lipolysis in OP9 adipocytes. Methods. Glycerol release to the culture supernatants was used as a marker of adipocyte lipolysis. Results. Treatment with various concentrations of CFE and CO stimulates glycerol release in a dose-dependent manner. The increase in glycerol release by CFE is more potent than isoproterenol, which is a beta adrenergic agonist as a positive control in our system. The increased lipolysis by CFE and CO was accompanied by an increase of phosphorylated hormone sensitive lipase (pHSL) but not nonphosphorylated HSL protein and mRNA. Pretreatment with H89, which is a protein kinase A inhibitor, significantly abolished the CFE- and CO-induced glycerol release in OP9 adipocytes. These results suggest that CFE and CO may be a candidate for the development of a lipolysis-stimulating agent in adipocytes. PMID- 25435892 TI - Evidence-based novel changes in prevalence and symptom characteristics of spleen deficiency syndrome in persons of varied health status and different ages: a cross-sectional observational study. AB - Deficiency of the organs is a vital pathophysiologic characteristic in the elderly. A core TCM aging theory is known as aging caused by spleen deficiency syndrome (SDS) that can be found in ancient and modern literature. The key objectives of this study were to establish a full-scale trial to evaluate the prevalence, symptom severity, frequency, and distribution of SDS in different age groups as related to health status (healthy, subhealthy, and chronic disease) to elucidate the role of spleen deficiency in the aging process and deterioration of health status. This cross-sectional observational study was conducted in 4 hospitals in China. 1390 participants aged 20-79 were interviewed by investigators who completed questionnaires recording prevalence, severity, and frequency of symptoms as well as other relevant information. The results revealed that prevalence and symptom characteristics of SDS showed regularities with increasing age and deteriorating health status. It supports the TCM concept that spleen deficiency is an important mechanism of aging, subhealth, and chronic diseases. Early recognition of the warning signs and symptoms of SDS may lead to intervention and even prevention strategies for subhealth and chronic diseases as well as promotion of healthy aging. PMID- 25435893 TI - Anti-Inflammatory and Antihyperalgesic Activities of Ethanolic Extract and Fruticulin A from Salvia lachnostachys Leaves in Mice. AB - The anti-inflammatory and analgesic effects of the ethanolic extract (SLEE) and fruticulin A from the leaves of Salvia lachnostachys were evaluated in mice, using experimental models of inflammation (paw oedema and pleurisy induced by carrageenan injection) and hyperalgesia (electronic Von Frey). Oral administration of SLEE (30, 100, and 300 mg/kg) and fruticulin A (0.3 and 3.0 mg/kg) decreased the total leucocytes number in pleural lavage, protein extravasation, and paw oedema. SLEE (100 mg/kg) and fruticulin A (3 mg/kg) also exhibited antihyperalgesic activity in carrageenan induced mechanical hyperalgesia. In addition, fruticulin A (3 mg/kg) prevented mechanical hyperalgesia, inhibiting TNF but not L-DOPA-induced mechanical hyperalgesia. In conclusion, SLEE and fruticulin A display anti-inflammatory and analgesic properties. Therefore, fruticulin A is at least partially responsible for the activity observed in the ethanolic extract of Salvia lachnostachys. PMID- 25435895 TI - Potential mechanisms of an antiadenomyosis chinese herbal formula shaoyao-gancao decoction in primary cell culture model. AB - Background. Shaoyao-Gancao Decoction (SGD), a well-known traditional Chinese medicine prescription, has been widely used to treat adenomyosis, dysmenorrhea, abdominal pain, and inflammation in Asia. However, the mechanism underlying the effectiveness of SGD in the treatment of adenomyosis still remains elusive. The present study aimed to investigate the bioactivity of SGD and its underlying molecular mechanisms using cultured human adenomyosis-derived cells. Methods. Human adenomyosis-derived cells were treated with SGD and its major constituents (paeoniflorin and liquiritin) in vitro. Effects of SGD, paeoniflorin, and liquiritin on cell proliferation and apoptosis were examined by MTT assay and flow cytometry analyses. The effects of SGD, paeoniflorin, and liquiritin on the production of PGE2 and PGF2alpha were assayed using ELISA. ER-alpha and OTR mRNA expression levels were also evaluated by real-time qRT-PCR. Results. SGD, paeoniflorin, and liquiritin inhibited proliferation and induced apoptosis of human adenomyosis-derived cells in a dose-dependent manner. SGD and paeoniflorin significantly reduced the PGE2 and PGF2alpha production. Furthermore, they remarkably decreased the mRNA levels of ER-alpha and OTR. Conclusions. The results of this study provide possible mechanisms for the bioactivity of SGD for treating adenomyosis and contribute to the ethnopharmacological knowledge about this prescription. PMID- 25435894 TI - Phytochemical Constituents and Toxicity of Duguetia furfuracea Hydroalcoholic Extract in Drosophila melanogaster. AB - Duguetia furfuracea is frequently used as a medicinal plant in Brazil. However, studies have evidenced its cytotoxic, bactericide, and antitumor activities. In the present study we aimed to evaluate the potential toxicity of hydroalcoholic leaves extracts of D. furfuracea (HEDF) in a Drosophila melanogaster model. Toxicity was assessed as changes in locomotor performance, mitochondrial activity, oxidative stress, MAPKs phosphorylation, and apoptosis induction after exposure to HEDF concentrations (1-50 mg/mL) for 7 days. The phytoconstituents of the plant were screened for the presence of alkaloids, tannins, xanthones, chalcones, flavonoids, aurones, and phenolic acids. Exposure of adult flies to HEDF caused mitochondrial dysfunction, overproduction of ROS, and alterations in the activity of detoxifying enzymes GST, SOD and CAT. Induction of ERK phosphorylation and PARP cleavage was also observed, indicating occurrence of HEDF-induced cell stress and apoptotic cell death. In parallel, alterations in cholinesterase activity and impairments in negative geotaxis behavior were observed. Our study draws attention to the indiscriminate use of this plant by population and suggests oxidative stress as a major mechanism underlying its toxicity. PMID- 25435898 TI - LEAF-E: a tool to analyze grass leaf growth using function fitting. AB - In grasses, leaf growth is often monitored to gain insights in growth processes, biomass accumulation, regrowth after cutting, etc. To study the growth dynamics of the grass leaf, its length is measured at regular time intervals to derive the leaf elongation rate (LER) profile over time. From the LER profile, parameters such as maximal LER and leaf elongation duration (LED), which are essential for detecting inter-genotype growth differences and/or quantifying plant growth responses to changing environmental conditions, can be determined. As growth is influenced by the circadian clock and, especially in grasses, changes in environmental conditions such as temperature and evaporative demand, the LER profiles show considerable experimental variation and thus often do not follow a smooth curve. Hence it is difficult to quantify the duration and timing of growth. For these reasons, the measured data points should be fitted using a suitable mathematical function, such as the beta sigmoid function for leaf elongation. In the context of high-throughput phenotyping, we implemented the fitting of leaf growth measurements into a user-friendly Microsoft Excel-based macro, a tool called LEAF-E. LEAF-E allows to perform non-linear regression modeling of leaf length measurements suitable for robust and automated extraction of leaf growth parameters such as LER and LED from large datasets. LEAF-E is particularly useful to quantify the timing of leaf growth, which forms an important added value for detecting differences in leaf growth development. We illustrate the broad application range of LEAF-E using published and unpublished data sets of maize, Miscanthus spp. and Brachypodium distachyon, generated in independent experiments and for different purposes. In addition, we show that LEAF-E could also be used to fit datasets of other growth-related processes that follow the sigmoidal profile, such as cell length measurements along the leaf axis. Given its user-friendliness, ability to quantify duration and timing of leaf growth and broad application range, LEAF-E is a tool that could be routinely used to study growth processes following the sigmoidal profile. PMID- 25435897 TI - Psychopathological symptoms of patients with heroin addiction entering opioid agonist or therapeutic community treatment. AB - BACKGROUND: The relationship between substance use disorders and psychiatric pathology is still an open question. The main aim of the present study was to verify whether the five psychopathological dimensions identified through the SCL 90 tool in a previous study carried out on patients with heroin addiction entering an outpatient opioid agonist treatment (OAT) were also observable in those entering a residential treatment community (TC). Further aims were to look at differences in the psychopathological profiles of patients entering a TC versus an OAT treatment and at the correlation between gender and the observed psychopathology. METHODS: A confirmatory factor analysis was performed on the results of SCL-90 filled by 1,195 patients with heroin dependence entering TC treatment. It replicates the extraction method previously used on 1,055 OAT patients with heroin addiction by using a principal component factor analysis (PCA). The association between the kind of treatment received (TC or OAT), gender, and the psychopathological dimensions was assessed through logistic regression and general linear model (GLM) analysis. RESULTS: The PCA carried out on the SCL-90 results of patients entering a TC yielded a five-factor solution, confirming the same dimensions observed in patients entering an OAT: 'worthlessness and being trapped', 'somatization', 'sensitivity-psychoticism', 'panic anxiety', and 'violence-suicide'. The logistic regression analysis showed a statistically significant association between 'somatization' and 'violence suicide' severity score and OAT. GLM analysis showed that psychopathological factorial scores for 'worthlessness-being trapped', 'somatic symptoms', and 'panic anxiety' dimensions were more severe in OAT vs TC male patients and in TC vs OAT female ones. 'Violence suicide' followed the same severity pattern for males, but did not differ in TC vs OAT females, while 'sensitivity-psychoticism' did not differ in OAT vs TC patients. The five dimensions did not differ in OAT males vs females. CONCLUSIONS: Our research appears to confirm the existence of a specific aggregation of psychological/psychiatric features within the category of individuals with heroin addiction. It also shows a correlation between the dominant psychopathological subgroup and the assignment to TC versus OAT. Further research is needed to clarify the differences between the five psychopathological subgroups and their determinants. PMID- 25435899 TI - Advances in statistical medicine. PMID- 25435900 TI - Pin-Align: a new dynamic programming approach to align protein-protein interaction networks. AB - To date, few tools for aligning protein-protein interaction networks have been suggested. These tools typically find conserved interaction patterns using various local or global alignment algorithms. However, the improvement of the speed, scalability, simplification, and accuracy of network alignment tools is still the target of new researches. In this paper, we introduce Pin-Align, a new tool for local alignment of protein-protein interaction networks. Pin-Align accuracy is tested on protein interaction networks from IntAct, DIP, and the Stanford Network Database and the results are compared with other well-known algorithms. It is shown that Pin-Align has higher sensitivity and specificity in terms of KEGG Ortholog groups. PMID- 25435901 TI - Anthraquinonyl glycoside facilitates the standardization of graphene electrodes for the impedance detection of lectins. AB - BACKGROUND: Construction of electrochemical impedance sensors by the self assembly technique has become a promising strategy for the 'label-free' detection of protein-ligand interactions. However, previous impedance sensors are devoid of an inherent electrochemical signal, which limits the standardization of the sensors for protein recognition in a reproducible manner. RESULTS: We designed and synthesized an anthraquinonyl glycoside (AG) where the anthraquinone (AQ) moiety can bind to the surface of a graphene-based working electrode while the glycoside serving as a ligand for lectin. By measuring the inherent voltammetric signal of AQ, the glycosides decorated on the working electrode could be simply quantified to obtain electrodes with a unified signal window. Subsequently, impedance analysis showed that the 'standardized' electrodes gave a reproducible electrochemical response to a selective lectin with no signal variation in the presence of unselective proteins. CONCLUSION: Anthraquinone-modified ligands could be used to facilitate the standardization of electrochemical impedance sensors for the reproducible, selective analysis of ligand-protein interactions. PMID- 25435896 TI - Pharmacological potential of tocotrienols: a review. AB - Tocotrienols, members of the vitamin E family, are natural compounds found in a number of vegetable oils, wheat germ, barley, and certain types of nuts and grains. Like tocopherols, tocotrienols are also of four types viz. alpha, beta, gamma and delta. Unlike tocopherols, tocotrienols are unsaturated and possess an isoprenoid side chain. Tocopherols are lipophilic in nature and are found in association with lipoproteins, fat deposits and cellular membranes and protect the polyunsaturated fatty acids from peroxidation reactions. The unsaturated chain of tocotrienol allows an efficient penetration into tissues that have saturated fatty layers such as the brain and liver. Recent mechanistic studies indicate that other forms of vitamin E, such as gamma-tocopherol, delta tocopherol, and gamma-tocotrienol, have unique antioxidant and anti-inflammatory properties that are superior to those of alpha-tocopherol against chronic diseases. These forms scavenge reactive nitrogen species, inhibit cyclooxygenase- and 5-lipoxygenase-catalyzed eicosanoids and suppress proinflammatory signalling, such as NF-kappaB and STAT. The animal and human studies show tocotrienols may be useful against inflammation-associated diseases. Many of the functions of tocotrienols are related to its antioxidant properties and its varied effects are due to it behaving as a signalling molecule. Tocotrienols exhibit biological activities that are also exhibited by tocopherols, such as neuroprotective, anti cancer, anti-inflammatory and cholesterol lowering properties. Hence, effort has been made to compile the different functions and properties of tocotrienols in experimental model systems and humans. This article constitutes an in-depth review of the pharmacology, metabolism, toxicology and biosafety aspects of tocotrienols. Tocotrienols are detectable at appreciable levels in the plasma after supplementations. However, there is inadequate data on the plasma concentrations of tocotrienols that are sufficient to demonstrate significant physiological effect and biodistribution studies show their accumulation in vital organs of the body. Considering the wide range of benefits that tocotrienols possesses against some common human ailments and having a promising potential, the experimental analysis accounts for about a small fraction of all vitamin E research. The current state of knowledge deserves further investigation into this lesser known form of vitamin E. PMID- 25435902 TI - Excess cost of non-remission among outpatients with major depressive disorder. AB - BACKGROUND: The purpose of this study was to assess the economic benefit of achieving remission among outpatients with major depressive disorder (MDD) who are currently employed in Korea. METHODS: Cross-sectional observational study. A total of 337 outpatients with MDD with paid jobs were recruited from 14 psychiatric clinics in Korea and were then divided into three groups as follows: new visit group (n = 128), remitted group (n = 100) and non-remitted group (n = 109). The 17-item Hamilton Depression Rating Scale (HAM-D) was used to decide whether a patient should be assigned to the remitted or non-remitted group. Direct medical and non-medical costs were measured via interview with the subjects. The World Health Organization Health and Work Performance Questionnaire (HPQ) were applied in order to measure the lost productive time (LPT) and related productivity costs. RESULTS: The three groups did not show a significant difference in direct medical cost. However, the difference between the remitted group and non-remitted group was statistically significant (25.49 +/- 52.99 vs. 44.79 +/- 126.55, chi (2) = 12.99, p = 0.0015). The remitted group demonstrated a significant improvement in productivity (particularly presenteeism) when compared with the new visit group (Z = -3.29, p = 0.001). Although the non-remitted group received treatment at psychiatric clinics similar to the remitted group, it lost 33 more working hours per month, which is compatible to $332 per month. CONCLUSION: These results suggest the economic importance of achieving remission in treating depression. PMID- 25435903 TI - Acute stress responses in Chinese soldiers performing various military tasks. AB - BACKGROUND: To examine Chinese soldiers' acute stress responses, we did this study. METHODS: The soldiers completed the Acute Stress Response Scale (ASRS) when engaged in major tasks, such as earthquake rescue in Wenchuan, Sichuan, and maintaining social stability in Urumchi, Xinjiang. The ASRS has good reliability and validity. The study enrolled 1,832 male soldiers. RESULTS: The results showed significant differences among five dimensions and the overall response index when comparing four diverse military tasks. Further analysis found that reduced work efficiency and 24 symptom clusters were significantly positively correlated. CONCLUSIONS: The acute stress response of soldiers performing various tasks was influenced by many factors, including the task characteristics and external factors. In addition, the acute stress response affected their work efficiency. PMID- 25435904 TI - Perfusion CT is a valuable diagnostic method for prostate cancer: a prospective study of 94 patients. AB - PURPOSE: The aim of this study is to assess the usefulness of perfusion computer tomography (pCT) in prostate cancer (PCa) diagnostics. MATERIALS AND METHODS: 94 patients with biopsy-proven PCa were enrolled in the study. Dynamic pCT of the prostate gland was performed for 50 seconds after an intravenous injection of contrast medium. Blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability surface area product (PS) were computed in the suspected PCa area and in normal prostatic tissue. RESULTS: PCa was visible in pCT in 90 of the 94 examined patients as a focal peripheral CT enhancement. When PCa was located in the peripheral zone (PZ), it was visible on perfusion maps, mostly showing an early peak followed by wash-out. The average values of all perfusion parameters were higher for tumour than for normal prostate tissue (p < 0.000). BV and BF were dependent on tumour grade expressed by the Gleason score (GS). All PCa cases were divided into groups, according to histological grade, as low (GS <= 6), medium (GS = 7), and high (GS > 7). In high-grade PCa, the mean BF value was significantly higher (p = 0.001) than the mean value of BF low- and medium-grade PCa (p = 0.011). Similar results were obtained regarding the mean values of BV; the more aggressive the cancer grade, the higher the mean BV value (p = 0.04). CONCLUSION: CT quantitative perfusion imaging allows PCa to be distinguished from normal prostate tissue. The highest values for BF and BV were observed in the most aggressive PCa grade. PMID- 25435905 TI - lnvasive cystic hypersecretory carcinoma of the breast associated with papillary pattern: a rare and poorly recognised variant of ductal carcinoma of the breast. AB - Cystic hypersecretory pattern is a rare and poorly recognised variant of invasive ductal carcinoma of the breast. Cystic hypersecretory lesions of the breast have a spectrum of morphological features ranging from clearly benign cystic hypersecretory hyperplasia (CHH), CHH with atypia, cystic hypersecretory carcinoma (CHC) to invasive CHC. Until now, no case of invasive CHC has been reported in India, to the best of our knowledge. We report a case of a 57-year old female with a history of a lump in the inferomedial quadrant of the right breast for three years, gradually increasing in size. A mammography showed a well defined, lobulated radio-opacity. A modified radical mastectomy was done. Gross examination showed multiple cystic spaces filled with thick gelatinous material and solid areas. On histopathology, cystic hypersecretory variant of invasive ductal breast carcinoma with focal papillary pattern was diagnosed. Cystic hypersecretory ductal carcinoma behaves in a low-grade fashion for many years but has a potential for invasiveness and metastasis, so regular follow-up of such cases is crucial. PMID- 25435907 TI - Dramatic response to dabrafenib and trametinib combination in a BRAF V600E mutated cholangiocarcinoma: implementation of a molecular tumour board and next generation sequencing for personalized medicine. AB - This is the case of a 47-year-old woman diagnosed with chemotherapy and radiation refractory BRAF V600E mutant, poorly differentiated intrahepatic cholangiocarcinoma (ICC), with multiple metastatic lesions within the liver, lungs, pleura, and bone, stage IV. Discussion of her malignancy's next-generation sequencing genomic information at a multidisciplinary molecular tumour board took place. The patient was considered a suitable candidate for dual BRAF and MEK inhibition, with the intent to prolong her survival and optimize the quality of life. We report her excellent tolerance and exceptional response to dual therapy with dabrafenib and trametinib, including symptomatic and sustained near-complete radiological improvement. We also briefly review the current knowledge of the genomics of cholangiocarcinoma with a focus on BRAF mutations, and make a point of the importance of the establishment of a molecular tumour board for personalized genomic medicine approaches. To our knowledge, this is the first reported case of the use of personalized genomic information for the successful management of a patient with ICC, and it is also the first description of dual BRAF and MEK targeted therapy in this malignancy, leading to what is considered an exceptional response. PMID- 25435906 TI - Childhood leukaemia and lymphoma: African experience supports a role for environmental factors in leukaemogenesis. AB - Major differences exist in the nature of leukaemia and lymphoma in low-income African children compared to those in the high-income countries. These include the absence of the peak incidence of acute lymphoblastic leukaemia (ALL) in under five-year olds that characterizes the disease in high-income countries. Conversely, chloroma association with acute myelogenous leukaemia (CA-AML/AMML) and Burkitt's lymphoma (BL) are rare in the high-income countries. This report describes clinical and laboratory as well as epidemiological features of childhood leukaemia and lymphoma reported betwen 1982 and 1984 in the city of Ibadan, Nigeria. The observed pattern of distribution of childhood haematological malignancies in the city is more consistent with the observations of Ludwik Gross's experiments on environmental influences, such as malnutrition and infections, animal leukaemogenesis, and mirroring the consequences of the primordial pressures that have shaped human genetics and pathophysiology. PMID- 25435908 TI - Metastasis occurring eleven years after diagnosis of human papilloma virus related oropharyngeal squamous cell carcinoma. AB - Human papilloma virus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favourable prognosis, although approximately 20-25% of patients ultimately develop recurrent cancer. Most disease recurrence events appear within 3 years; however, long-term follow-up of reported studies are limited, and the risk of late recurrence is unknown. We present a case report of a patient who developed distant metastases of HPV-related SCC 11 years after initial diagnosis and treatment of HPV-related OPSCC. Late disease recurrence may occur after initial diagnosis of HPV-related OPSCC. This observation has implications on the appropriate duration of follow-up and surveillance of these patients. PMID- 25435909 TI - Report on the 9th EONS Congress, Istanbul, Turkey, 18-19 September 2014: nursing highlights. AB - The European Oncology Nursing Society (EONS), in partnership with the Oncology Nursing Association of Turkey (TONA), organised the 9th EONS Congress in Istanbul, Turkey, 18-19 September 2014. The Congress venue was in Harbiye Cultural Centre and Istanbul Military Museum and offered two days of unprecedented scientific, educational, and networking opportunities for all stakeholders active in the field of oncology nursing around the world. EONS is a pan-European organisation dedicated to the support and development of cancer nurses. Through individual members and national societies EONS engages in projects to help nurses develop their skills, network with each other, and raise the profile of cancer nursing across Europe. This biennial Congress brings together cancer nurses across the globe from many fields of expertise to 'Celebrate Excellence in Cancer Nursing' through interactive sessions, lectures, and collegial networking. The format was specifically designed to meet the needs of nurses working in the field of cancer care, education, and research. PMID- 25435911 TI - Comprehensive chronic lymphocytic leukemia diagnostics by combined multiplex ligation dependent probe amplification (MLPA) and interphase fluorescence in situ hybridization (iFISH). AB - BACKGROUND: Banding-karyotyping and metaphase-directed-fluorescence-in situhybridization (FISH) may be hampered by low mitotic index in leukemia. Interphase FISH (iFISH) is a way out here, however, testing many probes at the same time is protracted and expensive. Here multiplex-ligation-dependent-probe amplification (MLPA) was used retrospectively in chronic lymphocytic leukemia (CLL) samples initially studied by banding cytogenetics and iFISH. Detection rates of iFISH and MLPA were compared and thus a cost-efficient scheme for routine diagnostics is proposed. RESULTS: Banding cytogenetics was done successfully in 67/85 samples. DNA was extracted from all 85 CLL samples. A commercially available MLPA probe set directed against 37 loci prone to be affected in hematological malignancies was applied. Besides, routine iFISH was done by commercially available probes for following regions: 11q22.3, 12p11.2 q11.1, 13q14.3, 13q34, 14q32.33 and 17p13.1. MLPA results were substantiated by iFISH using corresponding locus-specific probes. Aberrations were detected in 67 of 85 samples (~79%) applying banding cytogenetics, iFISH and MLPA. A maximum of 8 aberrations was detected per sample; however, one aberration per sample was found most frequently. Overall 163 aberrations were identified. 15 of those (~9%) were exclusively detected by banding cytogenetics, 95 were found by MLPA (~58%) and 100 (~61%) by routine iFISH. MLPA was not able to distinguish reliably between mono- and biallelic del(13)(q14.3q14.3), which could be easily identified as well as quantified by routine iFISH. Also iFISH was superior to MLPA in samples with low tumor cell load. On the other hand MLPA detected additional aberrations in 22 samples, two of them being without any findings after routine iFISH. CONCLUSIONS: Both MLPA and routine iFISH have comparable detection rates for aberrations being typically present in CLL. As MLPA can detect also rare chromosomal aberrations it should be used as an initial test if routine cytogenetics is not possible or non-informative. Still iFISH should be used additionally to distinguish mono- from biallelic deletions and also to determine rate of mosaicism for 13q14.2 to 13q14.3. In case MLPA is negative the corresponding CLL samples should be tested at least by iFISH using the standard probe set to. PMID- 25435910 TI - Leveraging transcription factors to speed cellobiose fermentation by Saccharomyces cerevisiae. AB - BACKGROUND: Saccharomyces cerevisiae, a key organism used for the manufacture of renewable fuels and chemicals, has been engineered to utilize non-native sugars derived from plant cell walls, such as cellobiose and xylose. However, the rates and efficiencies of these non-native sugar fermentations pale in comparison with those of glucose. Systems biology methods, used to understand biological networks, hold promise for rational microbial strain development in metabolic engineering. Here, we present a systematic strategy for optimizing non-native sugar fermentation by recombinant S. cerevisiae, using cellobiose as a model. RESULTS: Differences in gene expression between cellobiose and glucose metabolism revealed by RNA deep sequencing indicated that cellobiose metabolism induces mitochondrial activation and reduces amino acid biosynthesis under fermentation conditions. Furthermore, glucose-sensing and signaling pathways and their target genes, including the cAMP-dependent protein kinase A pathway controlling the majority of glucose-induced changes, the Snf3-Rgt2-Rgt1 pathway regulating hexose transport, and the Snf1-Mig1 glucose repression pathway, were at most only partially activated under cellobiose conditions. To separate correlations from causative effects, the expression levels of 19 transcription factors perturbed under cellobiose conditions were modulated, and the three strongest promoters under cellobiose conditions were applied to fine-tune expression of the heterologous cellobiose-utilizing pathway. Of the changes in these 19 transcription factors, only overexpression of SUT1 or deletion of HAP4 consistently improved cellobiose fermentation. SUT1 overexpression and HAP4 deletion were not synergistic, suggesting that SUT1 and HAP4 may regulate overlapping genes important for improved cellobiose fermentation. Transcription factor modulation coupled with rational tuning of the cellobiose consumption pathway significantly improved cellobiose fermentation. CONCLUSIONS: We used systems-level input to reveal the regulatory mechanisms underlying suboptimal metabolism of the non-glucose sugar cellobiose. By identifying key transcription factors that cause suboptimal cellobiose fermentation in engineered S. cerevisiae, and by fine-tuning the expression of a heterologous cellobiose consumption pathway, we were able to greatly improve cellobiose fermentation by engineered S. cerevisiae. Our results demonstrate a powerful strategy for applying systems biology methods to rapidly identify metabolic engineering targets and overcome bottlenecks in performance of engineered strains. PMID- 25435912 TI - Large cryptic genomic rearrangements with apparently normal karyotypes detected by array-CGH. AB - BACKGROUND: Conventional karyotyping (550 bands resolution) is able to identify chromosomal aberrations >5-10 Mb, which represent a known cause of intellectual disability/developmental delay (ID/DD) and/or multiple congenital anomalies (MCA). Array-Comparative Genomic Hybridization (array-CGH) has increased the diagnostic yield of 15-20%. RESULTS: In a cohort of 700 ID/DD cases with or without MCA, including 15 prenatal diagnoses, we identified a subgroup of seven patients with a normal karyotype and a large complex rearrangement detected by array-CGH (at least 6, and up to 18 Mb). FISH analysis could be performed on six cases and showed that rearrangements were translocation derivatives, indistinguishable from a normal karyotype as they involved a similar band pattern and size. Five were inherited from a parent with a balanced translocation, whereas two were apparently de novo. Genes spanning the rearrangements could be associated with some phenotypic features in three cases (case 3: DOCK8; case 4: GATA3, AKR1C4; case 6: AS/PWS deletion, CHRNA7), and in two, likely disease genes were present (case 5: NR2F2, TP63, IGF1R; case 7: CDON). Three of our cases were prenatal diagnoses with an apparently normal karyotype. CONCLUSIONS: Large complex rearrangements of up to 18 Mb, involving chromosomal regions with similar size and band appearance may be overlooked by conventional karyotyping. Array-CGH allows a precise chromosomal diagnosis and recurrence risk definition, further confirming this analysis as a first tier approach to clarify molecular bases of ID/DD and/or MCA. In prenatal tests, array-CGH is confirmed as an important tool to avoid false negative results due to karyotype intrinsic limit of detection. PMID- 25435913 TI - Deletions and duplications of the 22q11.2 region in spermatozoa from DiGeorge/velocardiofacial fathers. AB - BACKGROUND: DiGeorge/velocardiofacial syndrome (DGS/VCFS) is the most common deletion syndrome in humans. Low copy repeats flanking the 22q11.2 region confer a substrate for non-allelic homologous recombination (NAHR) events leading to rearrangements. This study sought to identify DGS/VCFS fathers with increased susceptibility to deletions and duplications at the 22q11.2 region in spermatozoa and to assess the particular contribution of intra-chromatid and/or inter chromatid NAHR. Semen samples from nine DGS/VCFS fathers were analyzed by triple color FISH using a probe combination that discriminated between normal, deleted and duplicated genotypes. Microsatellite analysis were performed in the parents and the affected children to determine the parental origin of the deleted chromosome 22. RESULTS: A significant increase in 22q11.2 deletions was observed in the sperm of two out of nine DGS/VCFS fathers (odds ratio 2.03-fold, P < 0.01), and in both cases the deletion in the offspring was transmitted by the father. Patients with significant increases in sperm anomalies presented a disturbed deletion:duplication 1:1 ratio (P < 0.01). CONCLUSIONS: Altogether, results support that intra-chromatid NAHR is the mechanism responsible for the higher rate of sperm deletions, which is directly related to the transmission of the deleted chromosome 22 to offspring. Accordingly, the screening of sperm anomalies in the 22q11.2 region should be taken into account in the genetic counseling of DGS/VCFS families. PMID- 25435914 TI - Selection criteria for initiation and renewal of luteinizing hormone-releasing hormone agonist therapy in patients with prostate cancer: a French prospective observational study. AB - OBJECTIVES: To define the profile of patients with prostate cancer (PCa) receiving a 3-month or 6-month formulation of luteinizing hormone-releasing hormone (LHRH) agonist in France and the reasons for choosing between formulations. METHODS: This prospective 1-year observational study included patients with PCa starting LHRH agonist therapy in everyday practice. Reasons for prescription and patient preference were recorded at inclusion, 3 or 6 months, and 12 months. The percentage of patients with a renewed initial prescription was recorded during follow up. RESULTS: A total of 1438 patients with PCa were included. Hormonotherapy was initiated more frequently with a 6-month (n = 903; 62.8%) than with a 3-month formulation (n = 535; 37.2%). The initial prescription was renewed in most patients after 3 or 6 months (86.1%) and 12 months (71%); 170 patients switched from a 3-month to a 6-month formulation during follow up. Presence of metastases influenced initial prescription (odds ratio 0.439; 95% confidence interval 1.095-1.892), with a 3-month formulation more often prescribed than a 6-month formulation to men with metastatic PCa at diagnosis (21.3% versus 15.8%, respectively). The most frequent reasons given by physicians for choosing the 6-month formulation were 'simplification of therapeutic regimen' (86.9%) or 'fewer unnecessary visits' (46.8%). Similar reasons were given for switching from a 3-month to a 6-month formulation during follow up. The most frequent reasons given by physicians to initiate therapy with a 3-month formulation were 'usual practice/habit' (55.5%) or 'closer patient management' (46.2%). 'Closer patient management' and 'reassuring effect upon patient' were the main reasons for switching from a 6-month to a 3-month formulation during follow up. Approximately 80% of patients were satisfied with the formulation they were prescribed and patients' reasons for preferring one formulation over another were similar to the physicians' reasons for prescribing these formulations. CONCLUSIONS: Slow-release formulations of LHRH agonists are useful therapies for physicians treating patients with PCa and there may be a preference for the 6 month formulation. PMID- 25435915 TI - Randomized controlled trial of cyclic and continuous therapy with trospium and solifenacin combination for severe overactive bladder in elderly patients with regard to patient compliance. AB - OBJECTIVES: The aim of the study was to increase the efficiency of treatment for severe symptoms of overactive bladder (OAB) with antimuscarinic drugs in elderly men and women. METHODS: A total of 341 patients over 65 years of age (average age 69.9; 186 women and 155 men) with severe symptoms of OAB (frequency of incontinence episodes [IEs] >= 3/day) underwent examination. Patients were distributed into three main groups: A (n = 58; trospium 60 mg/day + solifenacin 20): three cycles, each cycle 8 weeks, with an 8-week interval; B (n = 55; trospium 30 mg/day + solifenacin 10), regimen was the same as in group A; C (n = 62; trospium 30 mg/day + solifenacin 10) daily during 1 year. RESULTS: The most successful treatment for the clinical and urodynamic symptoms of OAB was observed in group A, without an increase in the quantity or intensity of side effects (IEs = 4.8 (0.9) -> 1.4 (0.8); p <= 0.01). Groups B and C also demonstrated positive effects for most of the markers for lower urinary tract state with statistical significance p <= 0.01. Nonparametric correlation between decrease in IEs and relative number of patients who accurately fulfilled prescriptions was in group A, r = 0.53, p <= 0.05; in group B, r = 0.61; p <= 0.05; in group C, r = 0.55, p <= 0.05. CONCLUSIONS: Cyclic therapy with two different spectrum antimuscarinics appears to be effective for controlling severe OAB in elderly patients. One-year cyclic therapy with a trospium and solifenacin combination provides a high compliance level (76-84%). However, continuous therapy with standard doses of trospium and solifenacin results in low adherence and high rates of treatment withdrawals (>= 66%) despite satisfactory clinical and urodynamic results. PMID- 25435916 TI - Altered perineal microbiome is associated with vulvovaginitis and urinary tract infection in preadolescent girls. AB - BACKGROUND: Vulvovaginitis has a known association with urinary tract infections (UTIs) in girls. We hypothesize that vulvovaginitis is a major contributor to UTIs in prepubertal girls by increasing periurethral colonization with uropathogens. METHODS: Periurethral swabs and urine specimens were obtained from a total of 101 girls (58 with vulvovaginitis and 43 without vulvovaginitis). Specimens were cultured for bacterial growth. The dominant organism in the periurethral swabs and urine cultures was recorded and antibiotic sensitivity profiles were compared. RESULTS: Periurethral swabs from children with vulvovaginitis were associated with a statistically significant increase in uropathogenic bacteria (79% Enterococcus species or Escherichia coli) as the dominant culture compared with swabs from girls without vaginitis (18%) (p < 0.05). In children with vulvovaginitis, 52% of the urine cultures were positive for UTIs, and the dominant organism in the urine cultures matched the species and antibiotic sensitivity profile of the corresponding periurethral swab. Only 11% of the urine cultures from girls without vulvovaginitis were positive for UTIs. CONCLUSIONS: Vulvovaginitis may cause UTIs by altering the perineal biome such that there is increased colonization of uropathogens. PMID- 25435917 TI - Management of priapism: an update for clinicians. AB - Priapism is a prolonged erection that persists beyond or is unrelated to sexual stimulation. It is associated with significant morbidity: psychological, socioeconomic, and physical, including pain and potentially irreversible compromise of erectile function. There are three major types of priapism: ischemic, nonischemic, and stuttering. Establishing the type of priapism is paramount to safely and effectively treating these episodes. Ischemic priapism represents a urological emergency. Its treatment may involve aspiration/irrigation with sympathomimetic injections, surgical shunts, and as a last resort, penile prosthesis implantation. Nonischemic priapism results from continuous flow of arterial blood into the penis, most commonly related to penile trauma. This is not an emergency and may be managed conservatively initially, as most of these episodes are self-limiting. Stuttering priapism involves recurrent self-limiting episodes of ischemic priapism. The primary goal of therapy is prevention, but acute episodes should be managed in accordance with guidelines for ischemic priapism. In this paper we review the diagnosis and treatment of the three priapism variants, as well as discuss future targets of therapy and novel targets on the horizon. PMID- 25435918 TI - Potential utility of cancer-specific biomarkers for assessing response to hormonal treatments in metastatic prostate cancer. AB - Prostate cancer is the second leading cause of cancer death in men and there is an urgent clinical need to improve its detection and treatment. The introduction of prostate-specific antigen (PSA) as a biomarker for prostate cancer several decades ago represented an important step forward in our ability to diagnose this disease and offers the potential for earlier and more effective treatment. PSA measurements are now routinely conducted alongside digital rectal examination, with raised PSA levels leading to biopsy. PSA is also used to monitor disease and assess therapeutic response. However, there are some important limitations to its use, not least its lack of specificity for prostate cancer, and increased PSA screening may have resulted in overdiagnosis and overtreatment of early, low-risk prostate cancer. Therefore, there is a need for more specific and sensitive biomarkers for the diagnosis and monitoring of prostate cancer and treatment response; in particular, biomarkers of response to hormonal treatments in prostate cancer and predictive biomarkers to identify who is most likely to respond to these treatments. Here we review the current utilization of PSA and data on potentially more specific and sensitive biomarkers for the diagnosis and monitoring of prostate cancer: prostate cancer antigen 3 (PCA3) and the TMPRSS2 ERG fusion gene. A description of the design of an ongoing study of the 6-month extended release formulation of leuprorelin acetate (Eligard((r)) 45 mg) will provide preliminary data on the potential utility of these new biomarkers for detecting therapeutic response after hormonal therapy. PMID- 25435920 TI - Predictors for pregnancy outcomes in Romanian women with Type 1 Diabetes Mellitus: a prospective study. AB - BACKGROUND: Type 1 diabetes mellitus in pregnant women is associated with an increased risk of congenital malformations, obstetric complications, neonatal morbidity, and mortality. Our aim was to evaluate which factors from the first trimester of pregnancy have a significant impact on the pregnancy outcomes of women with type 1 diabetes. METHODS: We included 94 pregnant women with type 1 diabetes in this study. In these patients, we analyzed the influence of several diabetes-related parameters on the pregnancy outcome. We compared the parameters between two cohorts: those with successful pregnancies and those with adverse pregnancy outcomes, defined as spontaneous abortion or congenital malformations. The influence of several factors on the pregnancy outcome was assessed using multivariate and univariate logistic regressions. RESULTS: The prevalence of adverse pregnancy outcomes was 28.7%, and was associated with poorer glycemic control (p <0.001), lower frequency of daily self-monitoring tests (p <0.001), smoking status (p <0.001), alcohol consumption (p <0.001), increased prevalence of chronic complications of diabetes, and the presence of ketosis. However, the adverse outcomes were not significantly associated with age, duration of diabetes, presence of thyroid disease, or body mass index. Furthermore, planned pregnancy was found to be a significant protective factor (odds ratio, 0.15; p <0.001). CONCLUSION: These results indicate that by carefully planning the pregnancy, ensuring optimal glycemic control, and eliminating habitual risk factors, the fetal risk in pregnancies among women with type 1 diabetes may decrease to a value similar to that noted in women without diabetes. PMID- 25435921 TI - Cerebral inflammation is an underlying mechanism of early death in Alzheimer's disease: a 13-year cause-specific multivariate mortality study. AB - INTRODUCTION: Although Alzheimer's disease (AD) is associated with early death, its life expectancy differs greatly between patients. A better understanding of this heterogeneity may reveal important disease mechanisms underlying the malignancy of AD. The aim of this study was to examine the relation between AD pathologies and early death in AD caused by dementia. METHODS: At a memory clinic, 247 referred consecutive patients with AD were monitored during 12.6 +/- 1.6 years. Multivariate Cox regression analyses were performed with baseline measures of amyloid beta (Abeta) pathology (APOE genotype, cerebrospinal fluid (CSF) Abeta42) tau pathology (CSF phosphorylated tau and total tau), cerebrovascular pathology (white-matter lesions and CSF/serum albumin ratio), neuroinflammatory pathology (CSF soluble vascular cell adhesion molecule-1, sVCAM 1), frontal, temporal, and central brain atrophies, global cognition, sex, and age. Comorbidities and medications also were analyzed. All continuous variables were transformed to z scores to compare hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: At follow-up, 89% of the patients had died. The mean survival time was 6.4 +/- 3.0 years. The AD pathology that independently predicted an early death caused by dementia was cerebral inflammation (sVCAM-1; HR, 1.32; 95% CI, 1.07-1.64). Other independent predictors were lower global cognition (HR, 0.51; 95% CI, 0.43-0.61), frontal atrophy (HR, 1.38; 95% CI, 1.12 1.70), and medial temporal atrophy (HR, 1.23; 95% CI, 1.02-1.49). When examining death caused by dementia and related causes (vascular diseases and infections), age (HR, 1.23; 95% CI, 1.04-1.46) and cerebrovascular pathology (white-matter lesions: HR, 1.17; 95% CI, 1.01-1.36; and CSF/serum albumin ratio: HR, 1.16; 95% CI, 1.001-1.34) were also significant risk factors in addition to the previous variables. No comorbidity or medication was significant in the specific-cause models. CONCLUSIONS: This is the first study to link neuroinflammation independently to early death in AD and, hence, a rapidly progressing disease. Frontal and medial temporal atrophies and low cognition were also significant predictors. These are probably downstream biomarkers that reflect neuronal degeneration and late-stage disease. Our results suggest that inflammation, and not amyloid or tau pathology, is an independent underlying mechanism in the malignancy of AD. PMID- 25435919 TI - Two ways to fold the genome during the cell cycle: insights obtained with chromosome conformation capture. AB - Genetic and epigenetic inheritance through mitosis is critical for dividing cells to maintain their state. This process occurs in the context of large-scale re organization of chromosome conformation during prophase leading to the formation of mitotic chromosomes, and during the reformation of the interphase nucleus during telophase and early G1. This review highlights how recent studies over the last 5 years employing chromosome conformation capture combined with classical models of chromosome organization based on decades of microscopic observations, are providing new insights into the three-dimensional organization of chromatin inside the interphase nucleus and within mitotic chromosomes. One striking observation is that interphase genome organization displays cell type-specific features that are related to cell type-specific gene expression, whereas mitotic chromosome folding appears universal and tissue invariant. This raises the question of whether or not there is a need for an epigenetic memory for genome folding. Herein, the two different folding states of mammalian genomes are reviewed and then models are discussed wherein instructions for cell type specific genome folding are locally encoded in the linear genome and transmitted through mitosis, e.g., as open chromatin sites with or without continuous binding of transcription factors. In the next cell cycle these instructions are used to re-assemble protein complexes on regulatory elements which then drive three dimensional folding of the genome from the bottom up through local action and self-assembly into higher order levels of cell type-specific organization. In this model, no explicit epigenetic memory for cell type-specific chromosome folding is required. PMID- 25435923 TI - Biological drugs for the treatment of rheumatoid arthritis by the subcutaneous route: interpreting efficacy data to assess statistical equivalence. AB - BACKGROUND: No equivalence analysis has yet been conducted on the effectiveness of biologics in rheumatoid arthritis. Equivalence testing has a specific scientific interest, but can also be useful for deciding whether acquisition tenders are feasible for the pharmacological agents being compared. METHODS: Our search covered the literature up to August 2014. Our methodology was a combination of standard pairwise meta-analysis, Bayesian network meta-analysis and equivalence testing. The agents examined for their potential equivalence were etanercept, adalimumab, golimumab, certolizumab, and tocilizumab, each in combination with methotrexate (MTX). The reference treatment was MTX monotherapy. The endpoint was ACR50 achievement at 12 months. Odds ratio was the outcome measure. The equivalence margins were established by analyzing the statistical power data of the trials. RESULTS: Our search identified seven randomized controlled trials (2846 patients). No study was retrieved for tocilizumab, and so only four biologics were evaluable. The equivalence range was set at odds ratio from 0.56 to 1.78. There were 10 head-to-head comparisons (4 direct, 6 indirect). Bayesian network meta-analysis estimated the odds ratio (with 90% credible intervals) for each of these comparisons. Between-trial heterogeneity was marked. According to our results, all credible intervals of the 10 comparisons were wide and none of them satisfied the equivalence criterion. A superiority finding was confirmed for the treatment with MTX plus adalimumab or certolizumab in comparison with MTX monotherapy, but not for the other two biologics. CONCLUSION: Our results indicate that these four biologics improved the rates of ACR50 achievement, but there was an evident between-study heterogeneity. The head-to head indirect comparisons between individual biologics showed no significant difference, but failed to demonstrate the proof of no difference (i.e. equivalence). This body of evidence presently precludes any option of undertaking competitive tenderings for the procurement of these agents. PMID- 25435922 TI - Quantitative neuropathological assessment to investigate cerebral multi morbidity. AB - The aging brain is characterized by the simultaneous presence of multiple pathologies, and the prevalence of cerebral multi-morbidity increases with age. To understand the impact of each subtype of pathology and the combined effects of cerebral multi-morbidity on clinical signs and symptoms, large clinico pathological correlative studies have been performed. However, such studies are often based on semi-quantitative assessment of neuropathological hallmark lesions. Here, we discuss some of the new methods for high-throughput quantitative neuropathological assessment. These methods combine increased quantitative rigor with the added technical capacity of computers and networked analyses. There are abundant new opportunities - with specific techniques that include slide scanners, automated microscopes, and tissue microarrays - and also potential pitfalls. We conclude that quantitative and digital neuropathologic approaches will be key resources to further elucidate cerebral multi-morbidity in the aged brain and also hold the potential for changing routine neuropathologic diagnoses. PMID- 25435924 TI - New strategies for osteoporosis patients previously managed with strontium ranelate. AB - The aim of this article is to describe potential alternatives to patients no longer eligible for management with strontium ranelate for osteoporosis according to the recommendations by the European Medicines Agency. A systematic search of Pubmed was done for papers on fracture efficacy of various treatments for osteoporosis, and potential harms especially in terms of cardiovascular events and stroke. The results showed that drugs more efficacious in terms of relative risk reduction of fractures than strontium ranelate were alendronate, risedronate, zoledronate, and denosumab. Raloxifene, as for strontium, may be associated with an increased risk of deep venous thromboembolism and fatal stroke. In terms of cardiovascular events special attention may be given to calcium supplements. Thus, patients at risk of stroke and ischemic cardiac events such as acute myocardial infarction should not use strontium ranelate. Ideally more efficacious drugs in terms of fracture reduction should be used such as alendronate, risedronate, zoledronate or denosumab. Raloxifene may pose a special problem as this too may be associated with an increased risk of fatal strokes. Other less-potent drugs in terms of fracture reduction should only be used if no alternatives are available (ibandronate, pamidronate, clodronate). Parathyroid hormone or analogs may be used for a limited time interval in specially selected patients and needs to be followed up with antiresorptive treatment to prevent loss of the bone gained. However, it should be remembered that no head-to-head comparison studies exist. PMID- 25435925 TI - Therapy gloves for patients with rheumatoid arthritis: a review. AB - Rheumatoid arthritis is a chronic inflammatory disease that causes pain, joint stiffness and swelling leading to impaired hand function and difficulty with daily activities. Wearing therapy gloves has been recommended by occupational therapists as one of the alternative treatment methods for rheumatoid arthritis. This study aims to review the available literature on the effects of wearing therapy gloves on patients' hand function and symptoms as well as to discuss the attributes of gloves that might influence the glove performance. An electronic databases search of MEDLINE, Physiotherapy Evidence Database, Occupational Therapy Systematic Evaluation of Evidence, Wiley Online Library, ScienceDirect and Cochrane Central Register of Controlled Trial was performed. Eight articles met the inclusion criteria, and covered seven clinical trials and one case study. Seven outcome measures were identified from the included studies and were then classified into two categories: hand function and hand symptoms. The hand symptoms such as pain, stiffness and swelling improve substantially when the therapy gloves are used. However, marginal or no improvement in hand function (with the exception of grip strength) linked to the use of therapy gloves is being reported. Further research is needed to quantify the effectiveness of therapy gloves, especially in improvement of hand function and in patients' interest in wearing therapy gloves. Furthermore, future studies should include parameters which might influence therapy gloves' performance, such as duration of trials, interface pressure generated by the gloves on the underlying skin and tissue, glove fit and construction, as well as thermophysiological comfort. PMID- 25435927 TI - Dosimetric absorption of intensity-modulated radiotherapy compared with conventional radiotherapy in breast-conserving surgery. AB - The aim of this study was to investigate the dosimetric benefits between intensity-modulated radiotherapy (IMRT) and conventional radiotherapy (CR) among patients receiving breast-conserving surgery. A dosimetric comparison of IMRT and CR was evaluated in 20 patients with early-stage breast cancer using a three dimensional treatment planning system. The prescribed mammary gland dose was completed in 25 fractions with a total dose of 5,000 cGy. Homogeneity of the planning target volume (PTV), irradiation dose and volume of organs at risk (OARs) were evaluated through a dose-volume histogram. For the homogeneity of PTV, the average volume receiving 95% of the prescribed dose in the IMRT plan was similar to that in the CR plan (97 vs. 96%, respectively). With regard to normal tissue sparing in OARs, the ipsilateral lung V20 in the IMRT and CR plans was 27.8 and 20.8%, respectively. The mean dose and V30 of the heart for five patients were 598.4 versus 348.3 cGy and 10.06 versus 5.3%, respectively. The mean dose sparing the heart or lung was markedly reduced in the IMRT plan compared with the CR plan. The results of the current study demonstrated that whole breast IMRT improves PTV dose distribution and improves normal tissue sparing in OARs. PMID- 25435926 TI - Diagnostic and prognostic serum marker of cholangiocarcinoma (Review). AB - Cholangiocarcinoma (CCA) is a fatal disease that is typically diagnosed late and treated ineffectively. As the morbidity and mortality rates for CCA rise markedly, patietns with CCA currently have a poor prognosis. However, if it were possible to diagnose CCA early while effective treat methods are available, CCA patients would achieve a better quality of life. Therefore, preventing the process of CCA in the early stages is an urgent problem to solve. An accurate, quick and safe method to diagnose early-stage CCA is required. The present review discusses the risk factors, status of research and certain serum markers of CCA. The sensitivity and specificity of these markers differ from each other. To explore the more accurate serum markers may be a novel direction and method for the diagnosis of CCA in laboratory medicine in the future. PMID- 25435928 TI - Raf kinase inhibitor protein inhibits cholangiocarcinoma cell metastasis by downregulating matrix metalloproteinase 9 and upregulating tissue inhibitor of metalloproteinase 4 expression. AB - Cholangiocarcinoma cells originate in the biliary epithelium. The cells easily metastasize and cause relapse. The effect of Raf kinase inhibitor protein (RKIP) on the biological behavior of cholangiocarcinoma cells is not yet clear. In the present study, RKIP and cytokeratin 19 expression was detected in the extrahepatic tissues of cholangiocarcinoma patients by immunohistochemistry. RKIP small interfering (si)RNA or an RKIP-overexpressing adenoviral vector were used to infect the human cholangiocarcinoma RBE cell line. RKIP protein or gene expression was analyzed by western blotting or reverse transcription-quantitative polymerase chain reaction (RT-qPCR), respectively. The cells were assayed for proliferation, apoptosis, invasion and migration. Matrix metalloproteinase 9 (MMP 9) and tissue inhibitor of metalloproteinase 4 (TIMP-4) mRNA was assayed by RT qPCR. RKIP expression was reduced in the extrahepatic cholangiocarcinoma tumor compared with the adjacent uninvolved peritumoral tissues. The current study revealed that RKIP expression was positively correlated with cell differentiation, but negatively correlated with lymph node or distant metastasis (P<0.05). RKIP siRNA treatment promoted RBE cell invasion, but RKIP overexpression prevented cell invasion. In the pDC316-siRNA recombinant vector group, the cells migrated more quickly compared with the siRNA-negative control group, and in the RKIP-expressing adenoviral vector group, the cells migrated more slowly compared with the adenoviral negative control group. RKIP inhibited the invasive and metastatic ability of the cholangiocarcinoma cell line, RBE, by downregulating MMP-9 and upregulating TIMP-4 mRNA expression. RKIP is negatively associated with cholangiocarcinoma distant metastasis and prevents cholangiocarcinoma cell metastasis through downregulating MMP-9 expression and upregulating TIMP-4 expression. PMID- 25435929 TI - Complications in the treatment of oropharyngeal carcinoma in patients with systemic sclerosis: A case report. AB - Systemic sclerosis is a chronic, progressive disease with an extremely poor prognosis. The incidence of malignant tumors in patients with systemic sclerosis is increased when compared with that of the general population. In certain malignancies, systemic sclerosis presents as a paraneoplastic process. The symptoms of sclerosis in the organs of the head and neck often overlap with symptoms of malignant diseases, which may increase the difficulty of a differential diagnosis. Additionally, the presence of sclerosis may complicate standard examination procedures, due to poor access to the oral cavity and oropharynx. When considering treatment options, it is important to evaluate the surgical and oncological risks to soft tissues of the head and neck with regard to both diseases, as well as the relatively poor prognosis for systemic sclerosis and oropharyngeal cancer. The low incidence of patients with systemic sclerosis and oropharyngeal carcinoma together presents a clear case for a casuistic approach. Based upon our own experience, we can attest to the difficulty of treating such patients. However, we have no evidence to indicate that these patients have reduced tolerance to surgical treatments. The current study presents the case of a 47-year-old female with systemic sclerosis, who was diagnosed with oropharyngeal carcinoma. The patient initially tolerated radiotherapy treatment well, however post-radiotherapy complications occurred. Despite many enigmatic indications to the contrary, it appears that the complications in this instance may be due to late toxicity from radiotherapy. PMID- 25435930 TI - Melanotic neuroectodermal tumor of infancy: A case report and review of the surgical treatment. AB - Melanotic neuroectodermal tumor of infancy (MNTI) is a rare, fast-growing, benign tumor originating from the neural crest. The tumor most often occurs during the first year of life. The predilection site of MNTI is the anterior maxilla, whereas lesions of the mandible are uncommon and account for only 6% of all cases. At present, the most common treatment for MNTI is surgical resection, however, tumor recurrence arises in 10-60% of cases. The optimal extent of surgical resection is a matter of debate; rapid growth and the possibilities of malignant transformation and metastasis indicate aggressive surgical resection. However, extensive resection may interfere with post-operative growth and development. The procedure should therefore preserve as much of the surrounding tissue as possible. The present case study examines a rare case of right-sided mandibular MNTI in a two-month-old female. The association between the tumor and the surrounding sclerotin, affected dental germ and the condition of the inferior alveolar nerve, were observed during the operative and post-operative periods. In addition, previous cases of MNTI were reviewed to evaluate the optimal scope of surgical resection. PMID- 25435931 TI - Alterations in the basal ganglia in patients with brain tumours may be due to excessive iron deposition. AB - The accumulation of iron in the brain is a common physiological process. However, alterations in the deposition of iron or other paramagnetic substances are associated with various diseases. In the present study, the deposition of paramagnetic substances in patients with brain tumours was evaluated using T2 relaxometry. A total of 23 patients with untreated tumours or with recurrent tumours following treatment, together with a group of 19 age-matched healthy controls, were examined using T2 relaxometry at 3T. The relaxation times in the basal ganglia, thalamus and white matter were evaluated. Significantly lower T2 relaxation times were identified in the basal ganglia and thalamus of the patients with tumours, as compared with those of the controls (P<0.05). No statistically significant difference was identified between patients with untreated or recurrent brain tumours. The reduction in T2 relaxation times in the brain tumour patients was possibly caused by the accumulation of iron, since iron homeostasis is known to be altered in patients with tumours. We propose that increased iron deposition is a consequence of a higher risk of oxidative stress caused by an increased iron concentration in the plasma or cerebrospinal fluid. PMID- 25435932 TI - Isolation, cultivation and identification of human lung adenocarcinoma stem cells. AB - Recently, an increasing number of studies have demonstrated that lung cancer is a stem cell disease. However, ideal cell surface markers for isolating stem cells in lung cancer are yet to be identified. In the present study, a cell population with a cluster of differentiation (CD)133+ phenotype was successfully isolated from a single cell suspension of lung adenocarcinoma tissue using magnetic activated cell sorting (MACS) and enriched in a serum-free culture. In comparison to CD133- cells, the CD133+ cells exhibited an enhanced capacity for self-renewal and differentiation, and a greater potential for in vivo tumor formation, in non obese diabetic/severe combined immunodeficient (NOD/SCID) mice. Tumors could be induced in NOD/SCID mice by the transplantation of 102 stem-like cells per mouse. The results of the present study demonstrated that CD133 may serve as a specific cell surface marker for lung adenocarcinoma stem cells, and that MACS combined with serum-free culture is an effective method for isolating and enriching lung cancer stem cells. PMID- 25435933 TI - Optimization of lentiviral vector production using polyethylenimine-mediated transfection. AB - The aim of the present study was to optimize the polyethylenimine (PEI)-mediated transfection method in order to simplify the efficient production of lentiviral vectors (LvVs), and to compare the CaPO4- and PEI-mediated transfection methods for producing LvVs. Different titration methods of LvV stocks, as well as different culture media, culture durations, cell densities and DNA quantities were compared to obtain an optimized procedure for the production of LvVs. Optimization of the production method for LvVs was achieved using PEI-mediated transient transfections. Serum-free Opti-MEM(r) was used to directly produce LvVs that could be harvested 48 h after transfection. Furthermore, a cell density of 15*106 cells/10-cm plate and a DNA concentration of 1X were selected for the optimum production of LvVs. The optimized LvV titration method was simple and direct; it involved LvVs carrying fluorescent reporters, which proved to be faster than the standard methods but equally as sensitive. In conclusion, a scalable process for production of LvVs by PEI-mediated transfection was established and optimized. The optimized PEI-mediated transfection method was easy to use, as well as providing greater reliability with a higher degree of reproducibility and consistency. Despite using less DNA, the PEI-mediated transfection method resulted in viral titers that were the same as those achieved using the CaPO4-mediated method. PMID- 25435934 TI - Refractory peptic ulceration following radiation therapy in primary gastric lymphoma: A report of two cases. AB - The optimal prognosis for primary gastric lymphoma (PGL) is observed in those patients exhibiting PGL with minimal infiltration and who are eligible for radical resection. The initial treatment strategy for high-grade PGL (stages I/II) is chemotherapy followed by radiotherapy, however, subsequent to chemotherapy and/or radiotherapy for PGL, there is a risk of gastric bleeding and perforation. The present study reports two cases of PGL with refractory peptic ulcers that were negative for Helicobacter pylori following radiotherapy. Although the two patients received regular treatment for their ulcers and symptoms, the position and size of the ulcers remained unchanged for a number of years. PMID- 25435935 TI - A phase I clinical trial of dose escalation of lobaplatin in combination with fixed-dose docetaxel for the treatment of human solid tumours that had progressed following chemotherapy. AB - In this study, the maximum tolerated dose (MTD) of lobaplatin (LBP) when it was combined with docetaxel (TXT) for the treatment of solid tumours that had progressed following chemotherapy was determined, and toxicities to this regimen were evaluated. A modified Fibonacci method was used for the dose escalation of LBP. The patients received TXT (at a fixed dose of 60 mg/m2) on day one (d1) and LBP (at an initial tested dose of 30 mg/m2) on day two (d2) of a treatment cycle that was repeated every 21 days. Each dose group consisted of at least three cases. In the absence of dose-limiting toxicity (DLT), we proceeded to the next dose group, with a dose increment of 5 mg/m2 between groups, until DLT occurred. The dose immediately below the dose that produced DLT was regarded as the MTD. The 17 patients examined in this study completed a total of 58 cycles of chemotherapy, and a total of three dose-escalation groups (30 mg/m2 LBP, 35 mg/m2 LBP, and 40 mg/m2 LBP) were established. The main adverse event that was observed was myelosuppression. DLT occurred in four patients, including three patients in the 40 mg/m2 LBP group and one patient in the 35 mg/m2 LBP group. In total, three out of the four patients in the 40 mg/m2 LBP group exhibited DLT. We determined that the treatment administered to the 35 mg/m2 LBP group represented the MTD. Thus, our phase I trial revealed that the MTD for the tested LBP combination regimen was 35 mg/m2 LBP and 60 mg/m2 TXT. This regimen resulted in mild adverse reactions and favourable patient tolerance. Therefore, we recommend the use of these dosages in phase II clinical trials. PMID- 25435936 TI - Craniopharyngioma: Survivin expression and ultrastructure. AB - The aim of the present study was to investigate the significance of survivin protein expression levels in craniopharyngioma. Tumor samples and clinical data were obtained from 50 patients with craniopharyngioma who were admitted to the West China Hospital of Sichuan University (Chengdu, China). The morphology of the craniopharyngioma samples was observed using optical and electron microscopes, and survivin expression was investigated in the samples by immunohistochemical analysis. The immunohistochemical results revealed survivin expression in all of the craniopharyngioma samples, but not in the healthy brain tissue samples. It was identified that survivin was expressed at a higher level in cases of the adamantinomatous type compared with those of the squamous-papillary type, in male patients compared with female patients, in children compared with adults and in recurrent cases compared with non-recurrent cases. Furthermore, no significant difference was detected in survivin expression levels among the tumors of different subtypes and different disease stages. The results of the present study indicate that survivin is significant in the development of craniopharyngioma, and that survivin protein expression levels are a meaningful indicator for assessing craniopharyngioma recurrence. PMID- 25435937 TI - Suppression of wingless-type MMTV integration site family, member 1 expression by small interfering RNA inhibits U251 glioma cell growth in vitro. AB - A Wingless-type MMTV integration site family, member 1 (Wnt-1) RNA interference expression vector was constructed during the present study, which was used to transfect the glioma U251 cell line and investigate its effect on glioma. Two 21 base oligonucleotides complementary to the coding sequence that was flanking the loop sequence were designed to form a DNA hairpin template for the target small interfering RNA (siRNA). The siRNA templates were cloned into the siRNA expression vector, pGPU6/green fluorescent protein (GFP)/Neo and the sequence was confirmed by DNA sequencing. The pGPU6/GFP/Neo-short hairpin RNA (shRNA)-Wnt-1 vector was subsequently transfected into U251 cells, and reverse transcription polymerase chain reaction and western blot analysis were used to evaluate the Wnt 1 gene silencing effect on U251 cell growth by MTT assay and flow cytometry. The Wnt-1 protein expression was significantly reduced following transfection with the recombinant plasmid, as determined by western blot analysis of the transfected U251 cells. This transfection exhibited a significantly higher death rate, as shown by MTT. Thus, the present study demonstrated that the pGPU6/GFP/Neo-shRNA-Wnt-1 vector inhibited Wnt-1 protein expression. However, further investigations regarding the Wnt signaling pathway in glioma pathogenesis are required. PMID- 25435938 TI - Intramedullary neurocytomas in the craniocervical spinal cord: A report of two cases and a literature review. AB - Central neurocytoma is a relatively rare tumor of the central nervous system. Young adults are most commonly affected, with a similar incidence in males and females. The tumor is predominantly occurs in the ventricular system of the brain. The tumor is benign and exhibits a good response to surgical resection and radiation therapy. The typical central neurocytoma occurs in the supratentorial ventricular system in young adults. Extraventricular neurocytomas are rare in the spinal cord. In the present study, two cases of craniocervical neurocytomas and the clinical presentation, magnetic resonance imaging observations, pathological features and two-year follow-up results are reported. The first case presents a 26 year old male with an intramedullary mass extending from the medualla oblongata to the T4 segement of the spine. The second case presents the case of a 48 year old female with an intramedullary mass extending from the oblongata to the T2 segement of the spine. The two patients underwent subtotal resection of the masses and post-operative radiotherapy was administered for three months. Post-operative magentic resoance imaging revealed no tumor recurrence in the two cases, two years after resection. The relevant literature is also discussed. PMID- 25435939 TI - Small cell carcinoma of the uterine cervix in pregnancy: A case report and review of the literature. AB - The occurrence of cervical cancer during pregnancy is extremely rare, particularly small cell carcinoma. Small cell cervical carcinoma (SCCC) is a neuroendocrine tumor with a poor prognosis. This study presents the case of an 18 year-old female with stage IB2 SCCC complicated by pregnancy, who was treated with chemotherapy and radiotherapy. The patient was diagnosed shortly after giving birth, and is the youngest female case to be reported in the world. The patient was treated with cisplatin and etoposide chemotherapy and radiotherapy. Complete remission was achieved following neoadjuvant chemotherapy and radiotherapy, and the patient remains in clinical remission eight months following treatment. Cytological screening, colposcopy and if necessary, biopsy, and selective conization at 14-20 weeks should be considered in the patient evaluation. PMID- 25435940 TI - miR-29a activates Hes1 by targeting Nfia in esophageal carcinoma cell line TE-1. AB - MicroRNA (miR)-29a has been associated with carcinogenesis in humans; however, its functional significance in esophageal squamous cell carcinoma (ESCC) is yet to be determined. In the present study, the expression of miR-29a was markedly downregulated in ESCC tissue and the ESCC TE-1 cell line, compared with normal esophageal tissue and cells. Furthermore, the present study identified that the forced expression of miR-29a in TE-1 cells significantly reduced cell proliferation and migration. miR-29a overexpression did not affect the expression of Notch1, however, it did increase the gene expression levels of hairy and enhancer of split 1 (Hes1), which is the key effector of the Notch signaling pathway. Direct targeting by miR-29a resulted in the downregulation of nuclear factor 1 A (Nfia), which represses the transcriptional activity of the Hes1 promoter. Furthermore, knockdown of Nfia increased Hes1 expression and inhibited cell growth in TE-1 cells. These results indicate that a low level of miR-29a expression is involved in ESCC tumorigenesis, and exogenous expression of miR-29a may repress cancer cell growth by downregulating Nfia and activating the Notch signaling pathway. PMID- 25435941 TI - Risk factor analysis for central nodal metastasis in papillary thyroid carcinoma. AB - Lymph node involvement is associated with recurrence in papillary thyroid carcinoma (PTC). The central neck compartment (level VI) lymph nodes are at the greatest risk of metastases from PTC, but the role of central neck dissection (CND) remains controversial, particularly in PTC without clinical cervical lymph node metastasis (cN0). The present study aimed to identify risk factors of central cervical nodal metastasis and the safety of CND in patients with cN0 PTC. The current study retrospectively investigated 389 patients who had been followed up for 12.0-25.5 months after surgery, and were divided into positive or negative lymph node involvement groups according to the pathological results subsequent to this surgery. Univariate and multivariate analyses were used to study the risk factor of central node involvement. The mean tumor size was 0.71+/-0.35 cm (range, 0.1-2.0 cm). There was no significant difference in the rate of central lymph node involvement based on age (<45 or >=45 years) or tumor focality (unifocal or multifocal). However, there were significant differences based on gender, extra-thyroid invasion and tumor size (P<0.05). The incidence of transient hypoparathyroidism and transient vocal cord paralysis following CND was 12.34 and 4.11%, respectively. No patient experienced permanent hypoparathyroidism or vocal cord paralysis. One patient (1/389; 0.23%) experienced disease recurrence during the follow-up. A larger tumor size and the male gender were significantly associated with the central nodal metastasis rate for cN0 PTC with a tumor size of <2.0 cm. CND for cN0 PTC patients was safe and the tumor-associated recurrence rate following CND plus total thyroidectomy was low. The present study suggests that CND should be conducted for male cN0 PTC patients with a larger tumor size (>=0.5 cm). PMID- 25435942 TI - Peripheral primitive neuroectodermal tumor of the kidney in a 51-year-old female following breast cancer: A case report and review of the literature. AB - Peripheral primitive neuroectodermal tumor/Ewing's sarcoma (pPNET/EWS) is an aggressive type of sarcoma that is rarely observed in the kidney. pPNET of the kidney principally occurs in young patients (<50 years old) and is very rare in older patients (>=50 years old). Additionally, only six cases of pPNET of the kidney have been reported in the literature in older patients (>=50 years old), and pPNET as a secondary primary tumor has rarely been reported. The current study presents a case of renal pPNET in a 51-year-old female who had been surgically treated for breast carcinoma and administered with adjuvant chemotherapy five years prior to hospitalization for pPNET. A computed tomography scan identified a tumor in the lower pole of the right kidney, which was treated by nephrectomy. Immunohistochemistry demonstrated diffuse, strong membranous positivity for cluster of differentiation (CD)99, positive nuclear staining for friend leukemia integration 1, and negative staining for Wilms' tumor 1 and other markers. Fluorescence in situ hybridization (FISH) analysis of the EWS breakpoint region 1 (EWSR1) demonstrated the characteristic EWSR1 translocation. The patient declined chemotherapy or radiotherapy but accepted traditional Chinese medicine. No evidence of recurrence was observed eight months after diagnosis. Only two cases of renal pPNET with a history of an earlier or synchronous primary cancer were reported in the literature from the USA and Germany, respectively. To the best of our knowledge, the present case is the first FISH-confirmed renal pPNET in an older patient following breast adenocarcinoma. PMID- 25435943 TI - p53, MDM2, eIF4E and EGFR expression in nasopharyngeal carcinoma and their correlation with clinicopathological characteristics and prognosis: A retrospective study. AB - In the present study, the expression of p53, mouse double minute 2 homolog (MDM2), eukaryotic translation initiation factor 4E (eIF4E), and epidermal growth factor receptor (EGFR) were investigated in nasopharyngeal carcinoma (NPC), and the correlation between their expression and clinicopathological characteristics and prognosis was analyzed. The medical records of 96 NPC patients who had undergone biopsy prior to radical radiotherapy and chemotherapy between 2005 and 2009 were reviewed, retrospectively. All patients received intensity-modulated radiotherapy with concurrent platinum-based chemotherapy. Patients were followed up for three years. Streptavidin-peroxidase immunohistochemistry was used to evaluate the expression of p53, MDM2, eIF4E and EGFR in NPC biopsy specimens, and the association between their expression and clinical parameters and survival was analyzed. The p53, MDM2, eIF4E and EGFR expression rates were 65.6% (63/96), 79.16% (76/96), 77.08% (74/96) and 89.5% (86/96), respectively. p53 (chi2,20.322; P=0.001) and EGFR (chi2,8.337; P=0.005) expression were found to correlate with T stage, whereas MDM2 (chi2,16.361; P=0.001) expression was found to correlate with lymph node metastasis. p53 expression was found to inversely correlate with MDM2 expression (r, -3.24; P<0.05). Three-year survival rates were lower in p53 positive (76.2%) patients when compared with p53-negative (93.9%) patients. In addition, three-year survival rates were lower in EGFR-positive (75.8%) patients than in EGFR-negative patients (91.2%). The Cox proportional-hazards regression model revealed that p53 (beta,-0.455; chi2,5.491; P=0.019) and EGFR (beta, 3.93; chi2, 11.95; P=0.001) expression were independent prognostic factors. Thus, it was hypothesized that p53 and EGFR expression present potential unfavorable prognostic markers for patients with NPC. PMID- 25435945 TI - Tumor necrosis is a strong predictor for recurrence in patients with pathological T1a renal cell carcinoma. AB - Patients with pT1aN0M0 renal cell carcinoma (RCC) generally have good prognosis, and recurrence is rare. However, metastasis develops postoperatively in a small number of patients with pT1aN0M0 RCC. The present study was undertaken to identify predictors for recurrence in patients with pT1aN0M0 RCC. We reviewed the clinicopathological factors of 133 patients with pT1aN0M0 RCC who underwent radical or partial nephrectomy at the Department of Urology, National Defense Medical College (Saitama, Japan). Clinicopathological factors, including age, gender, tumor size, histological subtype, tumor grade, microvascular invasion, histological tumor necrosis, C-reactive protein levels and performance status were reviewed. These factors were compared between patients with and without postoperative recurrence. Recurrence-free survival (RFS) and cause-specific survival (CSS) rates were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to determine independent factors predicting recurrence in patients with pT1aN0M0 RCC. The 5-year RFS and CSS rates were 97.2 and 99.1%, respectively. When clinicopathological factors were compared between patients with and without recurrence, tumor size (P=0.0390) and percentage of tumor necrosis (P<0.0001) were significantly different between groups. All patients with recurrence had primary lesions >=3 cm. By univariate analysis, tumor size (P=0.0379) and the presence of tumor necrosis (P=0.0319) were significant predictors for recurrence; tumor necrosis was also an independent predictor for recurrence (P=0.0143). In patients with pT1b tumors <=5 cm (recurrence rate, 16.8%; n=48), the percentage of tumor necrosis was significantly higher in patients with recurrence compared with those without (P=0.0261). This suggests that tumor necrosis may be an important predictor for recurrence in small RCCs. Although recurrence is rare in pT1a RCC, the presence of tumor necrosis may be an important predictor for recurrence. Particularly, patients presenting with pT1a RCC with histological tumor necrosis should undergo careful follow-up. PMID- 25435944 TI - Comparison between the antiemetic effects of palonosetron and granisetron in breast cancer patients treated with anthracycline-based regimens. AB - Chemotherapy-induced nausea and vomiting is a serious adverse side-effect of anthracycline-based chemotherapy regimens, in patients with breast cancer. A combination of three drugs, 5-hydroxytryptamine (5-HT3) receptor antagonist, aprepitant and dexamethasone, is recommended for antiemetic therapy. Palonosetron (PALO), a novel 5-HT3 receptor antagonist has been identified to be effective against delayed nausea and vomiting. In this study, the results of PALO for patients who received anthracycline-based chemotherapy were compared with that of granisetron (GRA) using a crossover study design. This study evaluated the efficacy of antiemetics in the first cycle of chemotherapy, as well as the second and third cycles. A total of 21 patients and 19 patients were assigned to PALO and GRA treatment groups during the first cycle of chemotherapy, respectively. The patients switched to the other antiemetic drug for the second chemotherapy cycle (PALO followed by GRA or GRA followed by PALO). The patients could select PALO or GRA antiemetics for the third cycle, according to their preference. A total of 21 patients selected PALO and 18 patients selected GRA in the third cycle, and one patient was withdrawn from the study as their third cycle questionnaire was not obtained. No significant differences between PALO and GRA were identified in first and second cycles. However, during the third cycle, a significant difference was observed in acute-phase complete control of emetic events between the PALO and GRA groups, which was defined as no emetic episode, no additional antiemetic treatment and no more than mild nausea, between PALO and GRA. These results demonstrated that changing antiemetics may affect the efficacy of antiemetics. This study indicates that alteration of antiemetic regimens, including drug combination and order, may improve the efficacy of antiemetic treatment. PMID- 25435946 TI - Primary intraosseous squamous cell carcinoma of the maxilla possibly arising from an infected residual cyst: A case report. AB - Primary intraosseous squamous cell carcinoma (PIOSCC) is a rare type of odontogenic carcinoma arising from the jawbone. Odontogenic cysts are true cysts that arise from the dental epithelium, which is associated with tooth formation. The epithelial lining of odontogenic cysts has the potential to transform into various types of odontogenic tumor; however, this transformation from an odontogenic cyst to a malignant tumor is rare. The definitive diagnosis for PIOSCC generally requires the observation of either features of squamous cell carcinoma (SCC) within the jawbone that are distinct from direct invasion from the surface oral epithelium, or evidence of SCC arising from odontogenic epithelium and from tumors that have metastasized to the jawbone from distant sites. In the present study, a case of PIOSCC of the maxilla is presented, which, based on the results of computed tomography and the clinical course, was hypothesized to have originated from an infected residual cyst. PMID- 25435947 TI - Anticancer effects of CKD-602 (Camtobell(r)) via G2/M phase arrest in oral squamous cell carcinoma cell lines. AB - CKD-602 (7-[2-(N-isopropylamino) ethyl]-(20S)-camptothecin, belotecan) is a synthetic water-soluble camptothecin derivative and topoisomerase I inhibitor that has been shown to exert a clinical anticancer effect on various types of tumor. In the present study, the anticancer effects of CKD-602 on the following three human oral squamous cell carcinoma (OSCC) cell lines originating from Korean cancer patients: YD-8 (tongue), YD-9 (buccal mucosa) and YD-38 (lower gingiva) were analyzed. The apoptotic proportion of the cells and cell cycle position were analyzed using flow cytometry. The expression of cell cycle regulatory proteins was detected by western blot analysis. CKD-602 was demonstrated to exert a time- and dose-dependent antiproliferative effect in all cell lines in vitro, however, susceptibility to CKD-602 at 72 h following treatment varied among the three cell lines, with 50% inhibition of cell viability at concentrations of 2.4 MUg/ml for YD-8, 0.18 MUg/ml for YD-9 and 0.05 MUg/ml for YD-38. To investigate the underlying mechanism of the CKD-602 antiproliferative effect, a cell cycle-analysis was conducted in the three OSCC cell lines and CKD-602 treatment was observed to induce G2/M phase arrest. Furthermore, western blot analysis revealed that the expression levels of phospho cdc2 (Tyr 15), cyclin A2 and cyclin B1 were increased in a time-dependent manner, following the administration of CKD-602. In the fluorescence-activated cell sorting analysis, the number of apoptotic cells was also increased in a dose dependent manner following CKD-602 treatment of the OSCC cell lines. The results suggest that CKD-602 may inhibit the proliferation of OSCC oral cancer cells derived from samples from Korean patients by apoptosis and by G2/M phase arrest. PMID- 25435948 TI - Insulin-like growth factor-I induces epithelial to mesenchymal transition via GSK 3beta and ZEB2 in the BGC-823 gastric cancer cell line. AB - Metastasis is the most common cause of mortality in patients with gastric cancer. Epithelial-to-mesenchymal transition (EMT), which may be stimulated by insulin like growth factor-I (IGF-I) is involved in the metastasis of numerous tumors; however, the molecular mechanism by which IGF-I may induce tumor cell EMT remains to be elucidated in gastric cancer. The present study aimed to investigate the induction of EMT in BGC-823 gastric cancer cells. It was identified that IGF-I induced EMT by upregulating the levels of ZEB2 transcription factor, and this was dependent on the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in these cells. In addition, glycogen synthase kinase 3beta (GSK-3beta), an intracellular downstream effector of PI3K/Akt, sustained the epithelial phenotype by repressing ZEB2 expression and the subsequent inhibition of EMT induced by IGF-I, suggesting the involvement of a potential PI3K/Akt-GSK-3beta-ZEB2 signaling pathway in IGF-I induced EMT in gastric cancer BGC-823 cells. Overall, the results of the present study suggest that IGF-I induced EMT by the activation of a PI3K/Akt-GSK-3beta ZEB2 signaling pathway in gastric cancer BGC-823 cells. Therefore, this study may provide more useful information regarding the mechanism of gastric cancer metastasis. PMID- 25435949 TI - Ki67 as a predictor of poor prognosis in patients with triple-negative breast cancer. AB - The aim of the current study was to investigate the expression of the proliferation antigen, Ki67, in triple-negative breast cancer (TNBC) and its correlation with clinicopathological factors. The expression of Ki67 and other biological indicators in 24 cases of TNBC tissues and 178 cases of non-TNBC tissues were detected using immunohistochemistry. Their correlation with the clinicopathological factors were also analyzed using the chi2 test. The positive rate of Ki67 expression in TNBC tissues was 83.3%, exhibiting a statistically significant difference when compared with that in non-TNBC tissues (73.0%) (P<0.05). The expression of Ki67 in breast cancer tissue significantly correlated with the tumor size and lymph node metastases; however, no correlation was observed with the age and the clinical stage. Ki67 may be an indicator of poor prognosis in TNBC patients. PMID- 25435950 TI - Rare incidence of primary adrenocortical carcinosarcoma: A case report and literature review. AB - Adrenocortical carcinoma (ACC) is a rare, but highly aggressive type of tumor with an incidence of one to two per million annually. Adrenocortical carcinosarcoma is an exceptional variant of ACC, which is characterized by the presence of histological regions of carcinoma and sarcoma. To date, to the best of our knowledge, there have only been 12 reported cases of adrenocortical carcinosarcoma. In the present study, a case of primary, non-functional adrenocortical carcinosarcoma is described, as well as a review of the literature to raise awareness of this particularly rare type of malignant neoplasm that is associated with a worse diagnosis and prognosis than adrenocortical carcinoma. In the present study, the patient underwent a laparoscopic left adrenalectomy and the tumor was dissected without complication from the left kidney. Microscopic observations showed the tumor comprised of epithelial and spindle cell components. The patient did not exhibit signs of tumor recurrence at the one month follow-up. The potential diagnosis of adrenocortical carcinosarcoma must be considered when diagnosing adrenal malignancies in adults. In addition, comphrensive imunohistochemical staining may be required to identify possible sarcomatous patterns. To the best of our knowledge, the present case is the first to report an incidence of adrenocortical carcinosarcoma in China. Details of the patient are presented and the pathology of adrenocortical carcinosarcoma is discussed. PMID- 25435951 TI - Reactivation of HIC-1 gene by saRNA inhibits clonogenicity and invasiveness in breast cancer cells. AB - Hypermethylated in cancer 1 (HIC-1) is a tumor suppressor gene, which is epigenetically silenced in breast cancer. It is known that the loss of HIC-1, caused by promoter hypermethylation, is associated with tumor aggression and poor survival in breast carcinoma. It has been shown that small activating RNA (saRNA) targeting promoter sequences may induce gene re-expression. In the current study, saRNA was used to restore HIC-1 expression, and the effects on colony formation, invasiveness and the cell cycle in breast cancer cells were explored. dsHIC1 2998, an saRNA, exhibited activating efficacy on MCF-7 and MDA-MB-231 cancer cell lines. A clonogenicity assay showed that evident colony inhibition was induced via saRNA-mediated re-expression of HIC-1 in the two cancer cell lines. Reactivation of HIC-1 significantly inhibited cell migration and invasion, resulting in G0/G1 cell cycle arrest in these cell lines. These findings suggest that HIC-1 may be a potential target in gene therapy for the treatment of breast cancer. saRNA may function as a therapeutic option for upregulating tumor suppressor genes in breast cancer. PMID- 25435952 TI - Synchronous occurrence of gastrointestinal stromal tumor and intrahepatic cholangiocarcinoma: A case report. AB - Various cases of gastrointestinal stromal tumor (GIST) coinciding with other gastrointestinal malignancies have been reported to date, however, the synchronous occurrence of GIST and intrahepatic cholangiocarcinoma (ICC) is exceptionally rare and, to the best of our knowledge, has only been reported once. The coinciding malignancy has usually been encountered incidentally during surgical exploration. Thus, this is the first report where a targeted biopsy of the clinically suspicious lesion was used to determine the diagnosis of ICC concurrent with GIST. The liver is the most frequent metastatic site of GIST, therefore, additional hepatic masses may be mistakenly diagnosed as metastatic disease, rather than the presentation of multiple primary tumors. This subsequently delays the accurate diagnosis and complicates the performance of a curable resection. The current study reports a case of advanced synchronous GIST and ICC, which was operable at initial presentation, but progressed to become surgically unresectable. PMID- 25435953 TI - Long intergenic non-coding RNA induced by X-ray irradiation regulates DNA damage response signaling in the human bronchial epithelial BEAS-2B cell line. AB - Long non-coding RNAs (lncRNAs) have been regarded as the primary genetic regulators of several important biological processes. However, the biological functions of lncRNAs in radiation-induced lung damage remain largely unknown. The present study aimed to investigate the potential effects of lncRNAs on radiation induced lung injury (RILI). Female C57BL/6 mice were exposed to 12 Gy single doses of total body irradiation (TBI). LncRNA microarray screening was conducted at 24 h post-irradiation (IR) to investigate the differentially-expressed lncRNAs during RILI. Following the subsequent bioinformatics analysis and reverse transcription-polymerase chain reaction (RT-PCR) validation, one of the verified differentially-expressed long intergenic radiation-responsive ncRNAs (LIRRs), LIRR1, was selected for further functional study. The normal human bronchial epithelial BEAS-2B cell line was used as the cell model. The recombinant eukaryotic expression vector for the lncRNA was designed, constructed and transfected using lipofectamine. RT-PCR, clonogenic and flow cytometry assays, immunofluorescence detection and western blot analysis were performed to reveal the role of the lncRNA in the radiosensitivity regulation of the RILI target cells. In lung tissues 24 h after 12 Gy TBI, six of the identified differentially expressed LIRRs near the coding genes were validated using quantitative (q)PCR. The upregulation of two LIRRs was observed and confirmed using qPCR. LIRR1 was chosen for further functional study. Following the stable transfection of LIRR1, identified through G418 screening, increased radiosensitivity, evident cell cycle G1 phase arrest and increased gamma-H2AX foci formation were observed in the bronchial epithelial BEAS-2B cell line subsequent to IR. LIRR1 overexpression also led to decreased expression of the KU70, KU80 and RAD50 DNA repair proteins, marked activation of p53, decreased mouse double minute 2 homolog (MDM2) expression, and substantially induced p21 and suppressed cyclin-dependent kinase 2 in BEAS-2B following IR. Subsequent to the use of Pifithrin-alpha, a specific inhibitor of p53 activation, increased MDM2 expression was observed in the LIRR1 overexpressing cells, suggesting that LIRR1 could mediate the DNA damage response (DDR) signaling in a p53-dependent manner. The present study provides a novel mechanism for RILI, using the concept of lncRNAs. PMID- 25435954 TI - Expression of P-gp in acute myeloid leukemia and the reversal function of As2O3 on drug resistance. AB - To study the expression of P-glycoprotein (P-gp) and the reversal function of As2O3, the active ingredient of arsenic, on drug resistance in acute myeloid leukemia (AML) patients, P-gp and cluster of differentiation 34 (CD34) were examined in primary mononuclear and resistant cells, with or without As2O3. In addition, multidrug resistance gene 1 (MDR1) mRNA expression was investigated in K562/D cells and AML patients. In total, 28.6% of newly-treated (NT) patients and 59.1% of relapsed/refractory (RR) patients were P-gpfunction+, and 31.7% of NT patients and 59.1% of RR patients were CD34+. The positivity rate of P-gpfunction and CD34+ expression in the RR group were significantly higher compared with that in the NT group (P<0.05). In addition, higher CD34+, P-gpexpression+ and P gpfunction+ values were observed in older patients compared with younger patients. MDR1 expression was downregulated in certain patients following treatment with AS2O3. In the present study, the overexpression of P-gp was the primary cause of drug resistance in the AML patients, and MDR1 expression was downregulated by As2O3 in primary leukemia and drug-resistant cells. PMID- 25435955 TI - A novel c. 204 Ile68Met germline variant in exon 2 of the mutL homolog 1 gene in a colorectal cancer patient. AB - Mutations in the mutL homolog 1 (MLH1) gene are frequent in patients with hereditary non-polyposis colorectal cancer (CRC). The MLH1 gene was screened for mutations in patients with sporadic CRC. The nucleotide sequences for all 19 exons of MLH1 were analyzed by high resolution melting and sequenced in a group of 104 sporadic CRC patients, and the results were verified in a replication group of 1,095 patients and 1,469 controls. Different melting profiles for exon 2 of the MLH1 gene were observed in the germline DNA of one patient. Sequencing of the patient's DNA resulted in the identification of a heterozygous C>G variant at c.204, which resulted in an Ile68Met change in the amino acid. A detailed search of the National Center for Biotechnology Information and the 1000 Genomes databases indicated that the detected variant was unique. According to the SIFT and PolyPhen-2 algorithms, the substitution of Ile to Met was predicted to decrease the activity of the MLH1 protein. The newly identified, functional germline variant was not present in any other CRC patient or control. Thus, a novel germline variant in the MLH1 gene was identified, representing a rare event in sporadic CRC. The occurrence and relevance of this mutation in other types of cancer requires additional investigation. PMID- 25435956 TI - Small intestine metastasis from cervical cancer with acute abdomen: A case report. AB - Cervical cancer metastasis to the small intestine is a rare occurrence that is easily misdiagnosed as a small bowel obstruction. The present study reports the case of a 46-year-old cervical cancer patient with metastasis to the small intestine, which presented as an acute abdomen due to intestinal obstruction. Enteroscopy revealed no primary intestinal tumors. The patient underwent exploratory laparotomy and resection of the tumor of the small intestine. Pathology revealed the mass to be squamous cell carcinoma, limited to the outer muscular layer and serosa. This case demonstrates that small intestine seeding must be considered in the differential diagnosis of acute abdomen in patients with cervical cancer. PMID- 25435957 TI - Solitary plasmacytoma of the sternum with a spiculated periosteal reaction: A case report. AB - Solitary plasmacytomas (SPs) represent <=5% of all plasma cell neoplasms and mostly occur in the spine, pelvis, ribs and pectoral girdle, while rarely occurring in the sternum. The tumors typically appear as osteolytic lesions. In rare cases, SPs can manifest as bony spicules on the surface of the bone. The present study reports the case of a 74 year-old female with an osteolytic tumor localized in the sternum. The tumor displayed extensive bony destruction, with a large quantity of thick straight spicules on the surface of the bone, resembling a sunray in appearance. The imaging, laboratory and pathological examinations of the patient met the diagnostic criteria of SP. The patient was initially treated with radiotherapy at a dose of 45 Gy. Six months later, chemotherapy consisting of vindesine, Adriamycin and dexamethasone was administered. Vindesine and Adriamycin were administered at a dose of 2 and 15 mg/day, respectively on days 1 4 in a 20-day cycle. Dexamethasone was administered at a dose of 20 mg/day on days 1-4, 9-12 and 17-20 in the 20-day cycle. In total, the patient underwent 6 cycles of chemotherapy, with a total duration of 7 months. The patient was followed-up for two years after beginning therapy. At present, the patient is well, without any evidence of progressive disease or multiple myeloma. To the best of our knowledge, this is the first case in the English literature of SP in the sternum, with an unusual sunray periosteal reaction on radiological imaging. The sites of bony spiculation in the lesions that have previously been described in the literature are the mandible, orbit, vertebral body and skull vault. To the best of our knowledge, the current study presents the first case of a SP of the sternum with a unusual spiculated periosteal reaction on radiological imaging to be reported in the English literature. PMID- 25435958 TI - The regulatory loop of COMP1 and HNF-4-miR-150-p27 in various signaling pathways. AB - MicroRNAs (miRNAs) are short regulatory RNAs that negatively modulate protein expression at the post-transcriptional level. Additionally, they have been associated with the pathogenesis of a number of types of cancer. In the current study, two target sites for miR-150 were determined within the 3'-untranslated region of p27Kip1 (hereafter referred to as p27) mRNA, and it was determined that ectopic overexpression of miR-150 led directly to p27 downregulation in cancer cells. These findings indicate that miR-150 may be a novel regulator of p27 expression. In the databases of the University of California, Santa Cruz (UCSC) and Match online, two common transcription factors were identified for miR-150 and p27: Cooperates with myogenic proteins 1 (COMP1) and hepatocyte nuclear factor-4 (HNF-4). Using the Database for Annotation, Visualization, and Integrated Discovery (DAVID), it was determined that p27 is involved in pathways regulated by the target genes of miR-150. Therefore, these results suggest that there may be a regulatory loop between COMP1 and HNF-4-miR-150-p27. Additional functional studies are required to understand the molecular basis for the formation of this circuit loop, and provide an insight into the development of innovative therapies targeting specific tumor markers. PMID- 25435959 TI - Extragastrointestinal stromal tumors: Computed tomography and magnetic resonance imaging findings. AB - Extragastrointestinal stromal tumors (EGISTs) are rare mesenchymal tumors that originate outside the gastrointestinal tract. The aim of the present study was to investigate the computed tomography (CT) and magnetic resonance imaging (MRI) features of EGISTs and analyze the correlations between radiological findings and pathological features. CT and MRI images of 24 patients with EGISTs were reviewed retrospectively. Patient demographics and tumor characteristics, including localization, size, contours, borders, cystic-necrotic components, calcification, hemorrhage, tumor vessels, attenuation and intensity, degree and pattern of enhancement, ascites, tumor invasion, lymphadenopathy and distant metastasis were recorded. Statistical analyses to compare the radiological characteristics of low and high-grade EGISTs were performed with chi2 or Fisher's exact tests. The mean patient age at the time of presentation was 53 years. A total of 24 EGISTs were detected, originating in the omentum (n=4), mesentery (n=19) and retroperitoneum (n=1), respectively. The EGISTs displayed a predominantly spindle cell subtype (87.5%; 21/24). The majority of the EGISTs appeared as large (>10 cm; 70.8%; 17/24), round or oval (66.7%; 16/24), cystic-solid (87.5%; 21/24) and ill-defined (66.7%; 16/24) soft-tissue masses. The EGISTs were hypodense (69.6%; 16/23) or isodense (30.4%; 7/23) on CT images, hypointense (50%; 3/6), isointense (33.3%; 2/6) or hyperintense (16.7%; 1/6) on T1-weighted imaging (T1WI), and hyperintense on T2WI (100%; 6/6) and diffusion-WI (DWI; 100%; 6/6). A total of 54.2% (13/24) of the EGISTs displayed tumor vessels. Overall, 95.8% (23/24) of the masses showed marked enhancement and 87.5% (21/24) demonstrated heterogeneous enhancement. Calcification, hemorrhage, ascites and lymphadenopathy were rare characteristics in the EGISTs. Distant metastases were present in 10 patients (41.7%). The size, borders, tumor vessels and distant metastasis correlated with high-grade EGISTs [>5 mitoses/50 high-power fields (HPFs)] (P<0.05). The results of the present study indicated that clinical and radiological features, including advanced age, a large tumor size, cystic-necrotic components, rare lymphadenopathy, a heterogeneous enhancement pattern and hepatic metastasis may aid in the diagnosis of EGISTs. Radiological characteristics, such as a large size (>10 cm), ill-defined borders, tumor vessels and distant metastasis, can provide useful information in identifying the malignant behavior of EGISTs. PMID- 25435960 TI - Hemangioendothelioma arising from the spleen: A case report and literature review. AB - Primary hemangioendotheliomas (HEs) of the spleen are rare, low-grade borderline malignant vascular tumors. To date, only a few splenic HE cases have been reported in adults. In infants, one 9-year-old male patient has previously been reported, and the patient succumbed to the disease shortly following surgery. Currently, the clinical treatment and prognosis of the disease remains challenging to define, due to the extremely low number of cases reported. The current report presents the case of a 9-year-old pediatric patient with splenic HE, who survived with no recurrence or complications following a partial splenectomy. Additionally, a literature review was conducted to analyze the treatment and prognosis of the disease. PMID- 25435961 TI - MicroRNA let-7g and let-7i inhibit hepatoma cell growth concurrently via downregulation of the anti-apoptotic protein B-cell lymphoma-extra large. AB - Let-7 family members have been identified as tumor-suppressing microRNAs, which are important in human hepatocellular carcinoma (HCC). These family members may function differently as a result of different base sequences at the 3'end. The aim of this study was to determine the antitumor effects of miR-let-7g/i (let 7g/i) on HCC cells and to investigate whether let-7g and let-7i have a combinatorial effect on HCC. The expression levels of let-7g/i in hepatoma cells were determined by quantitative reverse transcription polymerase chain reaction. In addition, a 5-ethynyl-2'-deoxyuridine retention assay and flow cytometry analysis were used to detect the effect of let-7g/i on the proliferation and apoptosis of BEL-7402 cells, respectively. The expression of anti-apoptotic protein B-cell lymphoma-extra large (Bcl-xL) was analyzed using western blot analysis. The results revealed that the expression levels of let-7g/i were significantly decreased in HCC cell lines when compared with L-02 cells. Furthermore, the overexpression of let-7g/i significantly suppressed DNA replication, inhibited cell proliferation and promoted apoptosis of BEL-7402 hepatoma cells. The expression of the anti-apoptotic protein, Bcl-xL, was inhibited by the combined role of let-7g and let-7i. We hypothesize that let-7g and let-7i exhibit a concurrent effect to regulate cell proliferation and the apoptosis of hepatoma cells, and this function is mediated by the Bcl-xL protein. PMID- 25435962 TI - Computed tomography findings of a solitary extramedullary plasmacytoma of the spleen: A case report and literature review. AB - Solitary extramedullary plasmacytoma (EMP) of the spleen is a rare condition. The present study describes the case of a 23-year-old female with an extremely rare solitary EMP of the spleen. Upon examination, the tumor demonstrated unusual and notable multiple-phase spiral computed tomography (CT) findings. The lesion was a solitary, well-defined mass, with areas of variable splenic necrosis and cystic degeneration. Contrast-enhanced CT revealed progressive enhancement of the lesion in the cystic wall, internal septa and solid portion, a finding that has not previously been described. The patient underwent a splenectomy and recovered without complications. No evidence of tumor recurrence has occurred during the past two years of follow-up. To the best of our knowledge, this is the first study to examine the CT findings of a solitary EMP of the spleen. The study aimed to investigate the imaging features of solitary EMP, in particular the multiple phase spiral CT findings, and raise awareness of the disease to reduce misdiagnoses. PMID- 25435963 TI - Role of high-field intraoperative magnetic resonance imaging on a multi-image fusion-guided stereotactic biopsy of the basal ganglia: A case report. AB - The aim of the present case study was to investigate the advantages of intraoperative magnetic resonance imaging (iMRI) on the real-time guidance and monitoring of a stereotactic biopsy. The study describes a patient with intracranial lesions, which were examined by conventional MRI and diffusion tensor imaging using a 1.5T intraoperative MRI system. The digital and pre operative positron emission/computed tomography image data were transferred to a BrainLAB planning workstation, and a variety of images were automatically fused. The BrainLAB software was then used to reconstruct the corticospinal tract (CST) and create a three-dimensional display of the anatomical association between the CST and the brain lesions. A Leksell surgical planning workstation was used to identify the ideal target site and a reasonable needle track for the biopsy. The 1.5T iMRI was used to effectively monitor the intracranial condition during the brain biopsy procedure. Post-operatively, the original symptoms of the patient were not aggravated and no further neurological deficits were apparent. The histopathological diagnosis of non-Hodgkin's B-cell lymphoma was made. Using high field iMRI, the multi-image fusion-guided stereotactic brain biopsy allows for a higher positive rate of biopsy and a lower incidence of complications. The approach of combining multi-image fusion images with the frame-based stereotactic biopsy may be clinically useful for intracranial lesions of deep functional areas. PMID- 25435964 TI - Role of ultrasound evaluation for the diagnosis and monitoring of thyroid tuberculosis: A case report and review of the literature. AB - Thyroid tuberculosis (TT) is an extremely rare condition, with acute abscess formation being the most uncommon form of presentation. Mycobacterium tuberculosis may affect the thyroid gland through hematogenous spread from an extra-thyroid focus of disease or by direct extension from adjacent cervical lymph nodes. Due to the non-specific imaging findings and the variable clinical manifestations, TT is rarely diagnosed promptly prior to percutaneous biopsy or surgery. The present study reports the dynamic monitoring of the sonographic features of a case with thyroid tuberculosis that was diagnosed by a thyroid ultrasound (US) scan, confirmed by a US-guided core-needle biopsy and followed-up sonographically during the whole course of treatment. PMID- 25435965 TI - Peripheral T-cell lymphoma with hypercalcemic crisis as a primary symptom accompanied by polymyositis: A case report and review of the literature. AB - The present study reports the case of a 61-year-old male with polymyositis who presented with exacerbated weakness in the lower limbs and a recurrent fever that had persisted for one month. Positron emission tomography/computed tomography scans revealed multiple regions of elevated fluorodeoxyglucose metabolism in the lymph nodes, lungs, liver, spleen and bones. While symptoms of nonchalance and confusion were identified on admission, the patient's serum calcium level was high at 3.87 mmol/l, so a hypercalcemic crisis was confirmed. A biopsy of the right lingual lymph node revealed peripheral T-cell lymphoma, not otherwise specified. The serum calcium level was restored to within the normal range following emergency measures, such as saline rehydration, diuretics, calcitonin and glucocorticoids, and partial remission was achieved following two courses of chemotherapy. The study may improve our present understanding of the diagnosis and treatment of cancer-associated myositis (CAM) and malignancy-associated hypercalcemia. PMID- 25435966 TI - The expression of Wnt-1 inducible signaling pathway protein-2 in astrocytoma: Correlation between pathological grade and clinical outcome. AB - Wnt-1 inducible signaling pathway protein-2 (WISP-2) is a member of the CCN family, which is critical for the control of cell morphology, motion, adhesion and other processes involved in tumorigenesis. The expression pattern and clinical significance of WISP-2 in astrocytomas remains unclear. In this study, reverse transcription-polymerase chain reaction was performed to systematically investigate the expression of WISP-2 in 47 astrocytoma tissues of different pathological grades and 10 normal brain tissues. The mRNA expression levels of WISP-2 in the astrocytoma tissues were observed to be significantly higher than those in the normal brain tissues. Furthermore, the upregulation of WISP-2 was found to be associated with astrocytomas of higher pathological grades. Subsequently, 154 astrocytoma and 15 normal brain tissues were analyzed using immunohistochemistry and similar results were obtained. Univariate and multivariate survival analyses were used to determine the correlations between WISP-2 expression and overall survival (OS) and progression-free survival (PFS). The results indicated that the expression of WISP-2 was found to negatively correlate with patient PFS and OS. These results demonstrated that the WISP-2 protein is involved in the pathogenesis and progression of human astrocytomas and may serve as a malignant biomarker of this disease. PMID- 25435967 TI - Expression and significance of DOK2 in colorectal cancer. AB - A reduction in the levels of docking protein 2 (DOK2) expression has previously been reported in lung adenocarcinoma and gastric cancer, indicating that this protein acts as a tumor suppressor in solid tumors. The aim of the current study was to determine the significance of DOK2 in colorectal cancer. The study consisted of 102 patients who underwent curative surgery for colorectal cancer. Histopathological and immunohistochemical analysis of DOK2 protein expression levels was performed in issue samples, and univariate and multivariate analyses were used to investigate the correlation between prognosis and the clinicopathological parameters. DOK2 expression was confirmed in the normal colorectal mucosa tissues, which is consistent with the literature, whereas 34 out of 102 (33.3%) tumor specimens were negative. The results revealed that recurrence was more likely to develop in DOK2(-) patients compared with DOK2(+) patients. The DOK2(-) patients also exhibited a poorer five-year overall survival rate (59.1%) compared with the DOK2(+) group (76.4%; P=0.0328). These results indicate that DOK2 may potentially be used as a marker of poor prognosis in patients with colorectal cancer following curative resection. PMID- 25435968 TI - Prognostic factors of second primary contralateral breast cancer in early-stage breast cancer. AB - The aim of the present study was to investigate the therapeutic outcome of early stage breast cancer (pT1aN0M0) and to identify prognostic factors for secondary primary contralateral breast cancer (CBC). A total of 85 patients with mammary carcinomas were included. All patients had undergone breast surgery and adjuvant treatment between January 2001 and December 2008 at the Central Hospital of Grenoble University (Grenoble, France). The primary end-points were disease-free survival and secondary CBC, and the potential prognostic factors were investigated. During a median follow-up of 60 months, 10 of the 85 patients presented with secondary primary cancer, of which six suffered with CBC. No patient mortalities were reported. The rates of CBC were 2.35, 3.53 and 7.06% at one, two and five years, respectively. The cumulative univariate analysis showed that microinvasion and family history are potential risk factors for newly CBC. The current study also demonstrated that secondary CBC was more likely to occur in patients with microinvasion or a family history of hte dise. In addition, the systematic treatment of secondary CBC should include hormone therapy. PMID- 25435969 TI - Predictive value of thymidylate synthase for the prognosis and survival of lung adenocarcinoma patients. AB - Chemotherapy represents an important treatment modality for lung adenocarcinoma. Thymidylate synthase (TS) is an essential enzyme in DNA synthesis, and its overexpression has been associated with reduced sensitivity to antifolate agents. The aim of the current study was to investigate the expression of TS and the effect on prognosis in lung adenocarcinoma patients. Adenocarcinoma and adjacent carcinoma tissues were resected from 100 patients with lung adenocarcinoma and the TS levels were detected by immunohistochemical analysis. The values for overall survival (OS) and disease-free survival (DFS) were determined using the Kaplan-Meier analysis. The results indicated that the TS protein was expressed predominantly in adenocarcinoma tissues, which exhibited higher TS expression compared with the adjacent tissues (P<0.001). The statistical analysis indicated that TS expression was associated with the clinical stage and history of smoking (P<0.05). The Kaplan-Meier analysis results indicated that the DFS and OS in patients with high TS expression levels were significantly shorter compared with those with low expression levels (P<0.05). In conclusion, the results from this study suggested that TS may serve as an independent predictive factor for survival rate, which may indicate the prognosis of lung adenocarcinoma patients. PMID- 25435970 TI - Clinical significance of gefitinib antitumor activity in patients with lung adenocarcinoma. AB - Non-small cell lung cancer is a subtype of adenocarcinoma, which has previously shown positive responses to gefitinib. The aim of the current study was to determine a clinical profile of gefitinib-induced disease controls for patients with lung adenocarcinoma. Retrospective evaluation of the clinical characteristics of 52 lung adenocarcinoma patients, enrolled at the Zhejiang Cancer Hospital (Hangzhou, China) between October 2004 and August 2008, was undertaken. All patients received gefitinib (250 mg/day orally) until disease progression or until an unacceptable toxicity was observed. Of the 52 patients, complete response (CR) and partial response (PR) rates were 23.1% (12/52) and 57.7% (30/52), respectively. An additional 19.2% (10/52) of patients demonstrated stable disease (SD) after three months of treatment with gefitinib. Disease control was observed in the primary lesion, and tumor metastasis to the lungs, brain, adrenal glands, pleura, peritoneum, pericardium, bone and lymph nodes was identified. The one-year progression-free survival (PFS) and overall survival (OS) rates were 74.8 and 78.0%, respectively. Multivariate analysis revealed that female patients were associated with significantly longer survival times when compared with males (hazard ratio, 0.077; 95% confidence interval [CI], 0.007 0.083; P=0.035). One-year PFS and OS rates in CR, PR and SD patients were 77.8, 73.9 and 33.3%, and 89.2, 79.8 and 33.7%, respectively, although neither difference was identified to be statistically significant. In addition, the median OS of SD patients was 12 months (95% CI, 7.2-16.8 months). Brain metastasis was the major site of disease progression (23.1%). Gefitinib treatment for patients with lung adenocarcinoma showed a marked long-term survival benefit, even in SD patients. However, further studies are required to analyze the efficacy of gefitinib in penetrating the blood-brain barrier in order to prolong PFS in patients with lung adenocarcinoma. PMID- 25435971 TI - Characteristic waffle-like appearance of gastric linitis plastica: A case report. AB - Linitis plastica is a gastric cancer of diffuse histotype that presents in the fundic gland area, and is characterized by thickening of the stomach wall and deformation of the stomach, resulting in a leather bottle-like appearance. A 66 year-old female was admitted to Kagawa University Hospital (Kagawa, Japan) with epigastric pain. X-ray examination revealed reduced gastric distension and deformation of the stomach, which exhibited a leather bottle-like appearance. Endoscopy indicated a depressed lesion in the gastric antrum, and abnormal folds, which crossed to form a waffle-like appearance in the upper gastric body. Analysis of biopsy specimens from the depressed lesion revealed a poorly differentiated adenocarcinoma. Morphological changes in the gastric folds indicated that the tumor had invaded the upper gastric body, therefore, a total gastrectomy was performed. Subsequent pathological findings demonstrated that the tumor had spread from the primary lesion to the upper gastric body. Therefore, the present report recommends that the diagnosis of the spread of linitis plastica-type gastric cancer should include assessments of the primary lesion, as well as evaluation of morphological changes in the gastric folds. PMID- 25435972 TI - Nuclear translocation of telomerase reverse transcriptase is a critical process in lymphatic metastasis of nasopharyngeal carcinoma. AB - Telomerase reverse transcriptase (TERT) is the predominant functional unit of telomerase and maintains the telomere length and the stability of chromosomes. Recently, TERT has been shown to be a critical factor in a number of other biological processes, including cell proliferation and cancer metastasis. In addition, although numerous studies have been conducted, the subcellular localization of the TERT protein and the association of such with cancer metastasis remains unclear. To investigate the involvement of TERT in in vivo metastasis, quantum dots-based immunofluorescence and western blot analysis were conducted to detect changes in the subcellular localization of TERT in human nasopharyngeal carcinoma (NPC) tissues and metastatic lymph nodes. To further investigate, metastatic and non-metastatic models of NPC were generated using 5 8F (high metastasis capability) and 6-10B (low metastasis capability) cell lines, respectively. It was found that TERT protein was overexpressed in NPC tissue samples and metastatic lymph nodes and TERT was predominantly located in the cytoplasm of primary NPC tissues, while TERT was predominantly located in the nucleus of the metastatic lymph nodes. The ratio of cytoplasmic TERT/nuclear TERT for the primary tumor of the 6-10B cell line was almost six-fold higher than that of the metastatic lymph nodes of the 5-8F cell line. TERT translocation from the cytoplasm to nucleus may present a critical step in the lymphatic metastasis of NPC. Thus, TERT translocation may be more useful than TERT expression level and telomerase activity for predicting the metastasis of NPC. PMID- 25435974 TI - Nasopharyngeal carcinoma metastasis to the mammary gland: A case report. AB - Nasopharyngeal carcinoma is the second most common type of malignancy in Southern China. Metastatic sites are usually multifocal and involve the bones, lungs and distant lymph nodes. To date, there have been no studies with regard to nasopharyngeal carcinoma metastasis to the mammary gland. In the current study, the case of a 56-year-old female with nasal obstruction, epitaxis and a bilateral neck mass is presented. Following a series of examinations, the patient was diagnosed with nasopharyngeal carcinoma (cT3N3M0). Subsequently, the patient received radical radiation therapy. After three months, a mass was identified in the left breast, together with enlargement of multiple lymph nodes in the left axilla. The patient underwent a mastectomy and pathological examination revealed that the breast mass and axillary lymph node tissues were derived from the nasopharynx. To the best of our knowledge, this is the first report of a nasopharyngeal carcinoma that metastasized to the mammary gland. PMID- 25435975 TI - Polyamine analog TBP inhibits proliferation of human K562 chronic myelogenous leukemia cells by induced apoptosis. AB - The aim of the present study was to investigate the effects of the novel polyamine analog tetrabutyl propanediamine (TBP) on the growth of K562 chronic myelogenous leukemia (CML) cells and the underlying mechanism of these effects. MTT was used for the analysis of cell proliferation and flow cytometry was performed to analyze cell cycle distribution. DNA fragmentation analysis and Annexin V/propidium iodide double staining were used to identify apoptotic cells. The activity of the key enzymes in polyamine catabolism was detected using chemiluminescence. TBP can induce apoptosis and significantly inhibit K562 cell proliferation in a time- and dose-dependent manner. TBP treatment significantly induced the enzyme activity of spermine oxidase and acetylpolyamine oxidase in K562 cells, and also enhanced the inhibitory effect of the antitumor drug doxorubicin on K562 cell proliferation. As a novel polyamine analog, TBP significantly inhibited proliferation and induced apoptosis in K562 cells by upregulating the activity of the key enzymes in the polyamine catabolic pathways. TBP also increased the sensitivity of the K562 cells to the antitumor drug doxorubicin. These data indicate an important potential value of TBP for clinical therapy of human CML. PMID- 25435973 TI - Bisdemethoxycurcumin attenuates gastric adenocarcinoma growth by inducing mitochondrial dysfunction. AB - Bisdemethoxycurcumin (BDMC) is a demethoxy derivative of curcumin. In this study, a human gastric adenocarcinoma xenograft model was generated in vivo using nude mice and BDMC was observed to suppress the growth and activity of tumors, in addition to improving the physical and mental capacity of the mice. An increased number of apoptotic cells, decreased ratio of B-cell lymphoma 2 (Bcl-2)/Bcl-2 associated X protein and increased caspase-3 expression was also observed following treatment with BDMC, indicating that BDMC may promote apoptosis in tumors via mitochondrial modulation. The growth of SGC 7901 gastric cancer cells was inhibited and arrested at G1 phase. Specific indicators of mitochondrial dysfunction, a reduction in adenosine triphosphate generation, the inner mitochondrial membrane potential, augmentation of reactive oxygen species production and cytochrome c were also detected in the mitochondria following treatment with BDMC. These results indicate that BDMC attenuates gastric adenocarcinoma growth by inducing mitochondrial dysfunction. PMID- 25435976 TI - Analysis of plasma metabolic biomarkers in the development of 4-nitroquinoline-1 oxide-induced oral carcinogenesis in rats. AB - The aim of the present study was to identify time-dependent changes in the expression of metabolic biomarkers during the various stages of oral carcinogenesis to provide an insight into the sequential mechanism of oral cancer development. An 1H nuclear magnetic resonance (NMR)-based metabolomics approach was used to analyze the blood plasma samples of Sprague-Dawley rats exhibiting various oral lesions induced by the administration of 4-nitroquinoline-1-oxide (4NQO) in drinking water. The 1H NMR spectra were processed by principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) to determine the metabolic differences between the three developmental stages of oral mucosa cancer (health, oral leukoplakia [OLK] and oral squamous cell carcinoma [OSCC]). The variable importance in projection (VIP) score derived from the PLS-DA model was used to screen for important metabolites, whose significance was further verified through analysis of variance (ANOVA). Data from the present study indicated that 4NQO-induced rat oral carcinogenesis produced oral pre neoplastic and neoplastic lesions and provided an effective model for analyzing sequential changes in the 1H NMR spectra of rat blood plasma. The 1H NMR-based metabolomics approach clearly differentiates between healthy, OLK and OSSC rats in the PCA and PLS-DA models. Furthermore, lactic acid, choline, glucose, proline, valine, isoleucine, aspartic acid and 2-hydroxybutyric acid demonstrated VIP>1 in the PLS-D model and P<0.05 with ANOVA. It was also identified that increases in lactic acid, choline and glucose, and decreases in proline, valine, isoleucine, aspartic acid and 2-hydroxybutyric acid may be relative to the characteristic mechanisms of oral carcinogenesis. Therefore, these plasma metabolites may serve as metabolic biomarkers in oral carcinogenesis and assist in the early diagnosis and preventive treatment of oral cancer. PMID- 25435978 TI - Synergistic effects of curcumin and bevacizumab on cell signaling pathways in hepatocellular carcinoma. AB - The aim of the present study was to explore the effects of curcumin in combination with bevacizumab on the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)/K-ras pathway in hepatocellular carcinoma. A total of 30 Sprague Dawley (SD) rats were randomly divided into five groups: Control, model, curcumin, VEGF blocker, and curcumin + VEGF blocker groups. The mRNA levels of VEGF and VEGFR in all groups were subsequently measured by quantitative reverse transcriptase-polymerase chain reaction and the protein expression of K ras was detected by western blot analysis. Compared with the control group, the mRNA levels of VEGF and VEGFR were revealed to be significantly increased in the model, curcumin and VEGF blocker groups. The VEGF mRNA levels in the curcumin, VEGF blocker and curcumin + VEGF blocker groups were all decreased when compared with the model group. In addition, the VEGF mRNA levels in the curcumin + VEGF blocker group were significantly lower compared with the curcumin group (P<0.05). The VEGF mRNA levels in the curcumin, VEGF blocker and curcumin + VEGF blocker groups were decreased when compared with the model group (P=0.0001). No significant differences in VEGF mRNA levels were identified between the VEGF blocker and curcumin groups (P=0.863), whereas the VEGF mRNA levels in the curcumin + VEGF blocker group were significantly lower than that of the curcumin group (P=0.025). Curcumin and the VEGF blocker are each capable of inhibiting hepatocellular carcinoma progression by regulating the VEGF/VEGFR/K-ras pathway. The combination of the two compounds has a synergistic effect on the inhibition of the effects of the VEGF signaling pathways in hepatocellular carcinoma progression. PMID- 25435977 TI - 14-3-3sigma is an independent prognostic biomarker for gastric cancer and is associated with apoptosis and proliferation in gastric cancer. AB - 14-3-3 proteins participate in various cellular processes, including apoptosis, proliferation and malignant transformation. 14-3-3sigma, a member of the 14-3-3 protein family, is important in several types of cancer; however, little is known about the clinical significance and biological roles of 14-3-3sigma in gastric cancer. The present study analyzed the expression pattern of 14-3-3sigma in gastric cancer and investigated its correlation with the prognosis of gastric cancer patients. Furthermore, the association of 14-3-3sigma with Ki-67, Bcl-2 and Bax was evaluated. 14-3-3sigma was expressed at higher level in gastric cancer tissue compared with healthy gastric tissue, and 14-3-3sigma expression was significantly correlated with tumor size and tumor node metastasis stage (P<0.05). To the best of our knowledge, the present study data are the first to suggest that 14-3-3sigma expression has been significantly associated with poor prognosis in gastric cancer. Additionally, 14-3-3sigma overexpression was positively correlated with Ki-67 and Bcl-2 expression levels. Thus, 14-3-3sigma is a potential prognostic marker for gastric cancer patients, and may be involved in regulating the apoptosis and proliferation of gastric cancer cells. PMID- 25435979 TI - Lesion human leukocyte antigen-F expression is associated with a poor prognosis in patients with hepatocellular carcinoma. AB - Human leukocyte antigen (HLA)-F, a non-classical HLA-class I molecule, has attracted attention as an important immunosuppressive molecule in recent years, although the clinical relevance of HLA-F expression in cancer patients remains unclear. In the present study, HLA-F expression in 90 primary hepatocellular carcinoma (HCC) lesions and 55 corresponding adjacent normal liver tissues was analyzed by immunohistochemistry, and the associations between HLA-F expression and clinicopathological parameters and patient survival times were analyzed. Positive HLA-F expression was observed in 47.8% (43/90) of the HCC lesions and in 10.9% (6/55) of the normal liver tissues. HLA-F expression in HCC lesions was significantly correlated with patient gender (P=0.02), and venous or lymphatic invasion (P=0.02). Patients who were HLA-F-positive had worse survival times than those who were HLA-F-negative (P=0.04). The mean overall survival times for HLA-F negative and -positive patients were 44.2 months [95% confidence interval (CI), 37.7-50.7] and 33.0 months (95% CI, 25.1-40.8), respectively. Multivariate analysis revealed that HLA-F was an independent prognostic factor for HCC patients with a hazard ratio of 2.1 (95% CI, 1.0-4.4). In conclusion, the present study demonstrated that HLA-F expression was associated with poor survival in HCC patients, and is correlated with tumor cell invasion and metastasis. PMID- 25435980 TI - IL-32 promotes breast cancer cell growth and invasiveness. AB - Interleukin (IL)-32 is a newly identified cytokine in humans and primates. It has been established that IL-32 may antagonize cancer growth. However, to the best of our knowledge, the direct effect of IL-32 on breast cancer cell growth has not yet been investigated. In addition, rodents lack the expression of IL-32; hence, the effects of IL-32 on breast cancer xenografts in nude mice have not been studied. The present study aimed to examine the potential regulatory effects of IL-32 on breast cancer cells in nude mice. The effects of IL-32 on tumor cell growth in cell cuture and a tumor xenograft model were investigated, as well as the effects of IL-32 on apoptosis. The effects of IL-32 on cell proliferation and apoptosis were investigated by MTT assay and TUNEL staining, respectively. The results revealed that IL-32 increases the proliferation rate of cancer cells and decreases the rate of apoptosis, In addition, IL-32 was found to enhance the growth of tumor xenografts in vivo. In summary, IL-32 may represent a useful therapeutic target for human breast cancer. PMID- 25435981 TI - Paratesticular sarcomas: A report of seven cases. AB - Primary tumors of the paratesticular region are rare, with paratesticular sarcomas constituting a major proportion of these tumors, particularly in the elderly. The paratesticular region consists of mesothelial, various epithelial and mesenchymal cells and may therefore give rise to a number of tumors with various behaviors. Defining the association between the paratesticular mass and the testicle, and differentiation between benign and malignant masses using radiology is challenging, therefore the mass is usually considered to be malignant and radical orchiectomy with high ligation is performed. The present study reports the cases of seven patients with tumors of the paratesticular region and presents the clinical and significant histological features of the tumors. In total, two patients suffered from dedifferentiated liposarcoma (DDLS), two exhibited leiomyosarcoma, two exhibited low-grade fibromyxoid sarcoma and one case of undifferentiated pleomorphic sarcoma was identified. Radical orchiectomy with high ligation was performed in five cases; simple orchiectomy was performed in one case and excisional biopsy was performed in the remaining case. A leiomyosarcomatous and epithelial membrane antigen (EMA) positive whorl pattern was observed during microscopy in the two DDLS cases. Additionally, one of the low-grade fibromyxoid sarcoma patients exhibited pleomorphism and mitosis in focal areas. To the best of our knowledge, the present study is the second time low-grade fibromyxoid sarcoma cases with paratesticular localization have been reported in the literature. Of the seven cases, four patients succumbed to the disease, one patient is living with the disorder and the two cases of DDLS are living without the disease. Paratesticular sarcomas are often aggressive and a multidisciplinary approach is required for the diagnosis and treatment of these tumors. PMID- 25435982 TI - Myoepithelial cells from pleomorphic adenoma are not influenced by tumor conditioned media from breast ductal adenocarcinoma and melanoma cells: An in vitro study. AB - Myoepithelial cells have been implicated in the regulation of the transition from in situ to invasive neoplasia in salivary gland tumors. Considering the importance of the microenvironment of the tumor, the present in vitro study therefore analyzed the morphological and phenotypic changes undergone by benign myoepithelial cells from pleomorphic adenoma (PA) stimulated by tumor-conditioned medium. The benign myoepithelial cells were obtained from PA and were cultured with fibronectin extracellular matrix protein, supplemented with tumor conditioned medium, which was harvested from breast ductal adenocarcinoma AU-565 and melanoma Hs 852.T cells. The morphological alterations were assessed by immunofluorescence analysis using vimentin antibody. The alpha-smooth muscle actin (alpha-SMA) and fibroblast growth factor (FGF)-2 proteins were analyzed by indirect immunofluorescence and quantitative polymerase chain reaction (qPCR). No morphological changes were observed in the myoepithelial cells cultured in fibronectin protein under stimulation from either tumor-conditioned medium. The immunofluorescence results, which were supported by qPCR analysis, revealed that only alpha-SMA was upregulated in the fibronectin substratum, with or without tumor-conditioned medium obtained from breast ductal adenocarcinoma and melanoma cells. No significant difference in FGF-2 mRNA expression was detected when the cells were cultured either in the tumor-conditioned medium or in the fibronectin substratum. The tumor-conditioned medium harvested from breast ductal adenocarcinoma and melanoma did not affect myoepithelial cell differentiation and function, which was reflected by the fact that there was no observed increase in alpha-SMA and FGF-2 expression, respectively. PMID- 25435983 TI - Long-term survival following total pancreatectomy and superior mesenteric-portal vein resection for pancreatic ductal adenocarcinoma: A case report. AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with few therapeutic options. At present, surgical resection remains the only potential curative treatment for PDAC. However, only 15-20% of patients with PDAC are eligible for lesion resection. Total pancreatectomy (TP) and superior mesenteric portal vein resection (SMPVR) may increase the rate of resection of PDCA, but the effect of this approach on improving long-term patient outcomes remains controversial. The present study investigated a case of PDAC in the pancreatic neck of a male patient. The patient underwent a TP, combined with SMPVR, for a margin-negative resection. Following an uneventful post-operative recovery, the patient received adjuvant chemoradiotherapy. The patient is currently alive at six years post-surgery, with a high quality of life. Given the clinical outcome of this patient, TP combined with SMPVR may provide PDAC patients with an opportunity for long-term survival. Therefore, patients with PDAC that is believed to be unresectable based on pre-operative assessment, may benefit from TP and SMPVR. PMID- 25435984 TI - Pure primary ovarian squamous cell carcinoma: A case report and review of the literature. AB - Pure primary ovarian squamous cell carcinoma (SCC) is a rare lesion that usually arises from the malignant transformation of an existing ovarian dermoid cyst. The de novo occurrence of an ovarian SCC in the absence of a prior ovarian dermoid cyst, Brenner tumor or endometriosis is extremely rare. At present, no effective therapy exists for treating pure primary ovarian SCC. The present case study describes a patient that presented with progressive coughing, who was diagnosed with an International Federation of Gynecology and Obstetrics stage IV pure primary ovarian SCC with lung metastases. The patient received postoperative chemotherapy, however, the patient succumbed to the disease. The current study also presents a review of the literature. PMID- 25435986 TI - An unusual presentation of an inflammatory fibroid polyp of the ileum: A case report. AB - Inflammatory fibroid polyps (IFP) are rare, benign lesions of the gastrointestinal tract. Recent molecular studies of IFPs identified platelet derived growth factor receptor alpha (PDGFRA)-activating mutations, suggesting possible neoplastic qualities to IFPs. IFPs originate from the submucosa and often extend into the overlying mucosa. Although certain IFPs infiltrate the muscularis propria focally, disruption of the muscularis propria and penetration into the subserosa is extremely rare. The current study presents an unusual case of an ileal IFP. A 48-year-old female visited the Department of Surgery, Chonbuk National University Hospital (Jeonju, Republic of Korea) due to abdominal pain. Radiological study demonstrated an ileocecal-type intussusception due to a luminal polypoid mass of the ileum. The excised tumor consisted of haphazardly arranged epithelioid and spindled cells in a fibromyxoid stroma, with an abundant vascular network, accompanied by an inflammatory reaction predominantly composed of eosinophilic infiltrates. The infiltrating tumor cells disrupted the muscularis mucosa above the tumor cells and the muscularis propria below the tumor cells, and extended into the subserosa. Immunohistochemically, the tumor cells were positive for vimentin and cluster of differentiation 34, while they were negative for keratin, PDGFRA, smooth muscle actin, desmin, S-100 protein, DOG-1 and c-kit. Sequencing analysis of c-kit exons 9, 11, 13 and 17, and PDGFRA exons 12 and 18 indicated a wild-type status. The patient has remained well for 12 months after surgery without further treatment, with no recurrence of the tumor. Although spread of IFP under the muscularis propria is rare, identification of similar cases and further study will enhance our understanding of the nature of this tumor. PMID- 25435985 TI - Primary hepatic non-Hodgkin's lymphoma with rectal cancer: A case report. AB - Primary hepatic non-Hodgkin's lymphoma (NHL) is an extremely rare disease that is commonly neglected as a possible diagnosis. The present study reports the case of a middle-aged male with chronic hepatitis B in which primary hepatic NHL and rectal cancer occurred simultaneously. A large solitary tumor in the left lobe of the liver was incidentally detected on routine examination prior to the laparoscopic resection of the rectal cancer. Laparoscopic resection of the rectal cancer and a liver biopsy were performed simultaneously. The pathology revealed that the hepatic tumor was NHL and that the rectal cancer was adenocarcinoma. Systemic staging revealed no evidence of nodal or bone marrow involvement, therefore, primary hepatic lymphoma (PHL) was diagnosed. PHL associated with rectal adenocarcinoma is extremely rare and to the best of our knowledge, has never been reported. At present, the cause and most effective therapy for the condition remain unclear. PMID- 25435987 TI - Alternative splicing isoform in succinate dehydrogenase complex, subunit C causes downregulation of succinate-coenzyme Q oxidoreductase activity in mitochondria. AB - Mitochondrial succinate dehydrogenase (SDH) is localized to the inner mitochondrial membrane and is responsible for the redox of succinic acid. SDH is a tetrameric iron-sulfur flavoprotein of the tricarboxylic acid cycle and respiratory chain. The SDH complex, subunit C (SDHC) transcript has deletion-type alternative splicing sites. Generally, alternative splicing produces variant proteins and expression patterns, as products of different genes. In certain cases, specific alternative splicing variants (ASVs) have been associated with human disease. Due to a frameshift mutation causing loss of the heme binding region, the SDHC Delta5 isoform (lacking exon 5) exhibits no SDHC activity. To investigate whether the SDHC splicing variants can function as dominant-negative inhibitors, SDHC ASVs were overexpressed in HCT-15 human colorectal cancer cells. Using real-time reverse transcription-polymerase chain reaction, a dominant negative effect of the Delta5 isoform on SDHC mRNA was shown. In addition, Delta5 overexpression increased the levels of reactive oxygen species. Furthermore, in the Delta5 isoform-overexpressing cells, SDH activity was reduced. SDHC activation is a significant event during the electron transport chain, and the function of the SDHC Delta5 variant may be significant for the differentiation of tumor cells. PMID- 25435988 TI - Nordamnacanthal potentiates the cytotoxic effects of tamoxifen in human breast cancer cells. AB - Tamoxifen (TAM) is the mainline drug treatment for breast cancer, despite its side effects and the development of resistance. As an alternative approach, in the present study a novel combination therapy was established through combining TAM with nordamnacanthal (NDAM) in order to investigate the additive effect of these drugs in MCF-7 human breast cancer cells. A significant dose-dependent reduction in cell viability and an increase in apoptosis were observed in the MCF 7 cells cotreated with TAM and NDAM compared with the untreated control cells or the cells treated with TAM and NDAM alone (P<0.05). The cytotoxic influence of the combination of TAM and NDAM was found to be two-fold that of the individual agents. Annexin V/propidium iodide double-staining revealed the typical nuclear features of apoptosis. Furthermore, an increase in the proportion of apoptotic, Annexin V-positive cells was observed with the combination therapy. Moreover, this apoptotic induction was associated with a collapse of the mitochondrial membrane potential and the generation of reactive oxygen species. To the best of our knowledge, the findings of the present study are the first to suggest that combining TAM with NDAM may be a potential combination therapy for the treatment of breast cancer and may have the potential to minimize or eliminate the side effects associated with high doses of TAM. PMID- 25435989 TI - PRDI-BF1-RIZ domain of retinoblastoma protein-interacting zinc finger gene 1 induces apoptosis and exerts anticancer activity in esophageal squamous cell carcinoma cells. AB - The present study examined the role of the PRDI-BF1-RIZ (PR) domain of tumor suppressor retinoblastoma protein-interacting zinc finger gene 1 (RIZ1) as an anticancer domain and its ability to induce apoptosis in esophageal squamous cell carcinoma (ESCC) cells. The TE13 ESCC cell line was transfected with pcDNA3.1(+) eukaryotic expression vectors bearing the open reading frames of either the human RIZ1 gene or the PR domain, and the mRNA and protein expression levels were then detected using quantitative reverse transcription polymerase chain reaction and western blotting, respectively. The rate of apoptosis was determined by flow cytometry and the cell invasion ability was determined by an invasion assay. RIZ1 and the PR domain induced apoptosis and reduced the cell invasion ability (P<0.01). These findings indicate that the RIZ1 gene possesses anticancer activity in the PR domain, which may be important in inhibiting the development of ESCC. PMID- 25435990 TI - Characterization of uncommon portosystemic collateral circulations in patients with hepatic cirrhosis. AB - The purpose of the present study was to characterize uncommon portosystemic collateral circulation in hepatic cirrhosis. Portosystemic uncommon collateral circulation (UCC) was detected, characterized and evaluated by a combination of spiral computed tomography angiography, three-dimensional imaging angiography and electronic gastroscopy in patients diagnosed with hepatic cirrhosis. In total, 118 cases with UCC were detected from a pool of 700 hepatic cirrhosis patients with portal hypertension. The incidence was 16.86% and included cases with splenic-renal, gastro-renal, paravertebral, retroperitoneal, gastric-splenic and cardio-phrenic angle vein shunts. The occurrence rate of UCC formation increased with the Child-Pugh grade. Compared with common collateral circulations, the incidence of severe esophageal or gastric fundus varicose veins, severe portal hypertensive gastropathy and the incidence of a large quantity of ascites was much lower in the patients with UCC (P<0.01), whereas the incidence of hepatic encephalopathy and chronic elevated blood ammonia levels was significantly higher (P<0.01). The incidence of uncommon portosystemic collateral circulation is extremely common in patients with liver cirrhosis and is associated with the Child-Pugh grades of hepatic function. UCC can aid in the relief of the complications derived from portal hypertension, but it may increase the incidence of hepatic encephalopathy and chronic elevated blood ammonia levels. PMID- 25435991 TI - Synchronous primary cancers of the thyroid and breast: A case report and review of the literature. AB - The current report presents the case of a 41-year-old female exhibiting synchronous primary cancers of the thyroid and breast. Pathological examination of a tissue sample following biopsy identified papillary carcinoma of the thyroid and invasive ductal carcinoma of the breast to provide a definitive diagnosis of synchronous primary tumors. The patient underwent a modified radical mastectomy and total thyroidectomy. Following regular adjuvant chemotherapy with cyclophosphamide (800 mg), doxorubicin (100 mg) and paclitaxel (120 mg), once every three weeks for 3.5 months, oral levothyroxine and endocrinotherapy was recommended. Two years after the initial diagnosis, the patient was healthy with no disease recurrence. To the best of our knowledge, no association has been identified between the etiology and diagnoses of the two synchronous primary tumors. Thus, the aim of the current report was to improve the understanding of synchronous primary tumors of the thyroid and breast by presenting a review of the associated literature regarding breast and thyroid cancer. The mechanisms of synchronous neoplasms have only recently been elucidated, however, misdiagnosis is common. Clinicians are, therefore, advised to carefully examine patients with thyroid or breast cancer to avoid an incorrect or misdiagnosis. Furthermore, the present report aims to provide a reference for the cancer database, since the majority of analyses of rare diseases are derived from case reports. To improve the understanding of synchronous primary cancers of the thyroid and breast, an analysis of recent studies regarding the underlying mechanisms of synchronous primary cancers was also undertaken. PMID- 25435992 TI - Survival analysis of pelvic lymphadenectomy alone versus combined pelvic and para aortic lymphadenectomy in patients exhibiting endometrioid type endometrial cancer. AB - The therapeutic benefit of lymphadenectomy in patients exhibiting endometrial cancer (EC) remains controversial. The aim of the present study was to determine whether the addition of para-aortic lymphadenectomy to pelvic lymphadenectomy (PLND) improves survival in patients with endometrioid type EC. A single tertiary center, retrospective analysis was conducted in a total of 186 patients who were surgically treated with either PLND alone (n=97) or combined pelvic and para aortic lymphadenectomy (PPaLND; n=89). Adjuvant treatments were assigned according to the Gynecologic Oncology Group (GOG) risk of recurrence analysis. The primary endpoint of the present study was progression-free survival (PFS). The median follow-up time was 38 months (95% confidence interval, 36.47-42.90) for all patients. No statistically significant differences were identified between the two groups in terms of overall survival (OS), PFS or time to progression (TTP). Kaplan-Meier estimates of three-year OS, PFS and TTP for patients with low or low-intermediate risk were as follows: PLND, 100, 98.7 and 98.7%, respectively; and PPaLND, all 100%. The estimated three-year OS, PFS and TTP for patients with high or high-intermediate risk were as follows: PLND, 92.3, 81.3 and 81.3%; and PPaLND, 90.7, 77.1 and 80.9%, respectively. No statistically significant differences were detected in the three-year OS, PFS and TTP between the lymphadenectomy groups, regardless of the GOG risk of recurrence (PLND, 98.4, 95.3 and 95.3%; and PPaLND, 94.9, 87.1 and 89.4%). Therefore, the combination treatment, PPaLND did not provide any survival advantage over pelvic lymphadenectomy alone. PMID- 25435993 TI - Upregulation of Toll-like receptor 2 expression in colorectal cancer infected by human cytomegalovirus. AB - The aim of the present study was to investigate the association between Toll-like receptor 2 (TLR2) expression and human cytomegalovirus (HCMV) in colorectal carcinoma by detecting the expression of IE1-72, TLR2, TLR4 and tumor necrosis factor (TNF)-alpha in colorectal carcinoma and colon adenoma samples, as well as by analyzing the mRNA levels of the proteins in colon cancer cell lines, following HCMV infection. For this study, 56 colorectal cancer and 36 colon adenoma samples were collected, and normal mucosal tissue adjacent to the tumor was used as the control. The expression of the IE1-72, TLR2, TLR4, nuclear factor (NF)-kappaB and TNF-alpha protein was detected by immunohistochemistry. Cells from the SW480 human colon carcinoma cell line were infected with HCMV. The expression of IE1-72, TLR2, TLR4, NF-kappaB and TNF-alpha mRNA was quantified at different time points prior to and following infection. The positive expression rate of IE1-72 was 44.6% (25/56) in colorectal cancer and 41.7% (15/36) in colon adenoma. These rates were significantly higher when compared with the 12.5% (7/56) observed in the normal tissues adjacent to the cancer tissues (P<0.05). The expression levels of TLR2, TLR4, NF-kappaB and TNF-alpha in colorectal cancer and adenoma were also higher than those in the control tissues. Furthermore, the expression of IE1-72 in colorectal cancer tissues was found to correlate with TLR2 and TLR4, and the correlation coefficients were 0.515 and 0.462, respectively. Following the infection of SW480 cells, the mRNA levels of TLR2 and TNF-alpha increased gradually from 6 h, peaked at 48 h, and then decreased gradually. No significant differences in TLR4 and NF-kappaB expression were identified. The results of the present study indicated that there is a specific association between HCMV and the occurrence and development of colorectal cancer, which may be facilitated by the TLR2 signaling pathway. PMID- 25435994 TI - Salivary duct carcinoma of the parotid gland: A case report and review of the literature. AB - Salivary duct carcinoma (SDC) is a rare and aggressive parotid malignancy that most commonly affects males in the fifth and sixth decades of life. Histopathology specimens obtained from SDC patients demonstrate a resemblance to ductal carcinoma of the breast. Therefore, to distinguish SDC from breast ductal carcinoma, several immunohistochemical markers exist that may enable surgeons to make an accurate diagnosis. In this study, the case of a 54-year-old male with salivary duct carcinoma of the right parotid gland is presented. The results of the present case study revealed that the SDC sample was positive for the expression of human epidermal growth factor 2 (Her-2), cytokeratin (CK) 8/CK 18, p63, high molecular weight CK and calponin, and negative for expression of the estrogen receptor and progesterone receptor. Based on the result, an ipsilateral selective neck dissection followed by adjuvant post-operative radiation therapy was suitable at the primary treatment stage. At one year of follow-up, the patient was alive and free of recurrence. In advanced cases of SDC, treatment with anti-HER-2 monoclonal antibodies, such as trastuzumab, is recommended. PMID- 25435995 TI - CT-guided 125I brachytherapy on pulmonary metastases after resection of colorectal cancer: A report of six cases. AB - Colorectal cancer (CRC) is one of the most common malignancies in the world and distant metastasis is the main cause of cancer-related mortality. Percutaneous computed tomography (CT) guided radioactive 125I seed implantation (CTRISI) is a minimally invasive technique used to treat pulmonary metastases in CRC patients. In the present study, following colorectal cancer resection, six patients with pulmonary metastases were treated with computed tomography (CT)-guided percutaneous implantation of radioactive 125I seeds. At six months following seed implantation, CT examination was performed and compared with the images captured prior to the treatment. Of the total 13 lesions, four had disappeared, eight were reduced by >50% and one was enlarged, indicating that the local control rate was 92.3% (12/13). Overall, two patients developed intraoperative pneumothorax and one experienced hemoptysis subsequent to the procedure. Following a median follow up period of 31 months, no local recurrence was observed in 12 of the metastatic lesions. The mean survival time was 32.7 months and the median survival time was 31 months. PMID- 25435996 TI - Tumor size predicts prognosis of head and neck synovial cell sarcoma. AB - Head and neck synoviosarcoma (HNSS) is uncommon. To the best of our knowledge, the specific clinicopathological characteristics, treatment outcome and prognostic factors of HNSS were uninvestigated at the time of writing, so a meta analysis was performed. An online data collection was carried out using PubMed and Google Scholar. Studies that reported primary HNSS and the treatment, follow up time and outcome were chosen for the present study. In total, 93 cases from 26 studies were included for analysis. The study sample consisted of 55 males and 38 females and the median age was 32.1 years (range, 4-76 years). The median follow up period was 62.1 months (range, 1-373 months). The tumor size was correlated with local recurrence and metastasis of HNSS, as well as with mortality (P=0.001, P<0.0001 and P<0.0001, respectively). The three-year, five-year and 10-year survival rates were 82.1, 80.4 and 78.2% for treatment with surgery alone, and 88.5, 85.5 and 82% for treatment with surgery plus radiotherapy, respectively. A significant tumor size-dependent difference was found between the overall survival (OS) rates (P<0.0001), as tumors that were >5.0 cm in diameter were associated with a worse OS rate (hazard ratio, 6.460; 95% confidence interval, 206-18.917; P=0.001). The tumor size was found to be an independent adverse prognostic factor for the OS of HNSS patients. In conclusion, surgical excision is a mainstream treatment of HNSS and post-operative adjuvant radiotherapy improves the OS rate of HNSS patients. PMID- 25435997 TI - Subcutaneous nephrovesical bypass: Treatment for ureteral obstruction in advanced metastatic disease. AB - The aim of the present study was to explore the value of subcutaneous nephrovesical bypass (SNVB) for the treatment of ureteral obstruction due to pelvic metastatic disease. SNVB stents (n=30) were implanted in 24 patients with advanced metastatic disease between January 2008 and December 2012. Urinalysis, serum creatinine (SCr), glomerular filtration rate (GFR), quality of life (QoL) scores, and renal ultrasonography were evaluated at follow-up. The SNVB procedures were successful in all 24 patients. Patient follow-ups occurred at an average of 10.6 months. Preoperative hydronephrosis was eliminated in 16 cases (53.3%) and reduced in the remaining patients. Following surgery, SCr levels reduced significantly from 256+/-46 to 124+/-23 MUmol/l (P<0.001). GFRs increased from 25+/-4.8 to 45+/-5.3 ml/min (P<0.01). The mean QoL scores were 3.4+/-1.4 preoperatively and 7.6+/-1.0 postoperatively (P<0.001). The results showed that SNVB is a minimally invasive, effective and safe procedure for patients with ureteral obstruction resulting from advanced malignant disease. As an alternative procedure to percutaneous nephrostomy, SNVB offers patients a better QoL. PMID- 25435998 TI - Extranodal follicular dendritic cell sarcoma: A clinicopathological report of four cases and a literature review. AB - The aim of the present study was to characterize the clinicopathological features of follicular dendritic cell sarcoma (FDCS), and to report the experience of the Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine (Shanghai, China) with this entity. The clinicopathological findings of four cases that had recently been encountered and 142 previously reported cases in the English literature were evaluated. The current tumors were found in two male and two female patients, aged 49-76 years old, who exhibited a mean tumor size of 8.7 cm. Three of the four cases were misdiagnosed during the initial diagnosis and one experienced intra-abdominal recurrence six months after the first diagnosis. Assessment of all 142 cases in the literature revealed a mild female predominance. The tumors exhibited a mean tumor size of ~7.0 cm. Histologically, the tumors were composed of plump spindle- or oval-shaped cells that exhibited eosinophilic cytoplasm and were arranged in sheets, storiform patterns or whorls. Immunohistochemically, the neoplastic cells expressed at least one of the FDC markers. Among the 130 cases with follow-up data, the overall recurrence, metastasis and mortality rates were 49.2% (64 cases), 21.5% (28 cases), and 13.8% (18 cases), respectively. FDCS can appear deceptively similar to other soft tissue tumors, even poorly-differentiated carcinomas. A correct diagnosis requires a high degree of suspicion and immunohistochemical evaluation. PMID- 25435999 TI - Methylation analysis of the DAPK1 gene in imatinib-resistant chronic myeloid leukemia patients. AB - Death-associated protein kinase-1 (DAPK1) is a pro-apoptotic gene that induces cellular apoptosis in response to internal and external apoptotic stimulants. The silencing of DAPK1 can result in uncontrolled cell proliferation, indicating that it may have a role in tumor suppression. DAPK1 activity can be inhibited by the cytosine methylation that occurs in its promoter region. These methylation changes in the promoter region of DAPK1 have been reported in a range of solid and hematological malignancies. In the present study, DAPK1 methylation was investigated in chronic myeloid leukemia patients (n=43) using bisulfite conversion followed by methylation-specific polymerase chain reaction. The present study included a number of patients who were identified to be resistant to the common chemotherapeutic agent imatinib (STI571, Gleevec(r), Glivec(r)), exhibiting at least one mutation in the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) gene. Thus, the patients in the present study were divided into two groups according to their response to imatinib therapy: Non-resistant (n=26) and resistant (n=17) to imatinib. Resistant patients were characterized by the presence of single or multiple mutations of the BCR-ABL gene: i) T315I, ii) M351T, iii) E255K, iv) T315I and M351T or v) T315I, M351T and E255K. The present study identified that: i) The incidence of DAPK1 methylation was significantly higher in the resistant patients compared with the non-resistant patients; ii) the extent of resistance varied between mutation types; and iii) there was no DAPK1 methylation in any of the healthy controls. These findings indicate that DAPK1 methylation may be associated with a signaling pathway for imatinib resistance in chronic myeloid leukemia. PMID- 25436000 TI - Multiple regulatory mechanisms of hepatocyte growth factor expression in malignant cells with a short poly(dA) sequence in the HGF gene promoter. AB - Hepatocyte growth factor (HGF) expression is a poor prognostic factor in various types of cancer. Expression levels of HGF have been reported to be regulated by shorter poly(dA) sequences in the promoter region. In the present study, the poly(dA) mononucleotide tract in various types of human cancer cell lines was examined and compared with the HGF expression levels in those cells. Short deoxyadenosine repeat sequences were detected in five of the 55 cell lines used in the present study. The H69, IM95, CCK-81, Sui73 and H28 cells exhibited a truncated poly(dA) sequence in which the number of poly(dA) repeats was reduced by >=5 bp. Two of the cell lines exhibited high HGF expression, determined by reverse transcription quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The CCK-81, Sui73 and H28 cells with shorter poly(dA) sequences exhibited low HGF expression. The cause of the suppression of HGF expression in the CCK-81, Sui73 and H28 cells was clarified by two approaches, suppression by methylation and single nucleotide polymorphisms in the HGF gene. Exposure to 5-Aza-dC, an inhibitor of DNA methyltransferase 1, induced an increased expression of HGF in the CCK-81 cells, but not in the other cells. Single-nucleotide polymorphism (SNP) rs72525097 in intron 1 was detected in the Sui73 and H28 cells. Taken together, it was found that the defect of poly(dA) in the HGF promoter was present in various types of cancer, including lung, stomach, colorectal, pancreas and mesothelioma. The present study proposes the negative regulation mechanisms by methylation and SNP in intron 1 of HGF for HGF expression in cancer cells with short poly(dA). PMID- 25436001 TI - PDCD5 transfection increases cisplatin sensitivity and decreases invasion in hepatic cancer cells. AB - Low expression levels of the programmed cell death 5 (PDCD5) gene have been reported in numerous human cancers, however, PDCD5 expression has not been investigated in hepatic cancer. The present study aims to investigate the biological behavior of PDCD5 overexpression in hepatocellular carcinoma (HCC) cells. The PDCD5 gene was stably transfected into the HepG2 HCC cell line (HepG2 PDCD5), and the expression levels of PDCD5 were examined by quantitative polymerase chain reaction and western blotting. An MTT assay was used to assess the cellular proliferating ability, and propidium iodide (PI) staining was used to evaluate the cell cycle by flow cytometry. The cells were incubated with 2 ng/ml transforming growth factor (TGF)-beta for 7 days in order to induce invasion and epithelial-mesenchymal transition (EMT). Apoptosis was measured by Annexin V-fluorescein isothiocyanate and PI double labeling. A Boyden chamber invasion assay was carried out to detect tumor invasion. Western blotting was performed to detect the protein expression levels of PDCD5, insulin-like growth factor (IGF)-1 and the EMT marker, Snail. The results showed that the HepG2-PDCD5 cells exhibited slower proliferation rates and high G2/M cell numbers compared with those of the HepG2 and HepG2-Neo controls (P<0.05). The PDCD5 transfected cells showed higher sensitivity to cisplatin treatment than the HepG2-Neo cells, with a higher p53 protein expression level. PDCD5 overexpression can attenuate tumor invasion, EMT and the level of IGF-1 protein induced by TGF-beta treatment. In conclusion, stable transfection of the PDCD5 gene can inhibit growth and induce cell cycle arrest in HepG2 cells, and its also notably improves the apoptosis-inducing effects of cisplatin, and reverses invasion and EMT induced by TGF-beta. The use of PDCD5 is a novel strategy for improving the chemotherapeutic effects on HCC. PMID- 25436002 TI - OVSCORE - a validated score to identify ovarian cancer patients not suitable for primary surgery. AB - Following primary debulking surgery, the presence of a residual tumor mass is one of the most important prognostic factors in ovarian cancer. In a previous study, we established the OVSCORE, an algorithm to predict surgical outcome, based on the clinical factors of nuclear grading and ascitic fluid volume, plus the cancer biomarkers, kallikrein-related peptidases (KLKs), KLK6 and KLK13. In the present study, OVSCORE performance was tested in an independent ovarian cancer patient cohort consisting of 87 patients. The impact of KLKs, KLK5, 6, 7 and 13 and other clinical factors on patient prognosis and outcome was also evaluated. The OVSCORE proved to be a strong and statistically significant predictor of surgical success in terms of area under the receiver operating characteristic curve (ROC AUC, 0.777), as well as positive and negative predictive value in this independent study group. KLK6 and 13 individually did not show clinical relevance in this cohort, but two other KLKs, KLK5 and KLK7, were associated with advanced FIGO stage, higher nuclear grade and positive lymph node status. In the multivariate Cox regression analysis for overall survival (OS), KLK7 had a protective impact on OS. This study confirms the role of KLKs in ovarian cancer for surgical success and survival, and validates the novel OVSCORE algorithm in an independent collective. As a key clinical application, the OVSCORE could aid gynecological oncologists in identifying those ovarian cancer patients unlikely to benefit from radical surgery who could be candidates for alternative therapeutic approaches. PMID- 25436003 TI - Pre-operative granulocyte/lymphocyte ratio as a predictive marker of post operative complications in patients with colorectal cancer. AB - The aim of the present study was to assess the clinical relevance of the pre operative granulocyte/lymphocyte (G/L) ratio as a predictive marker of post operative complications in patients with colorectal cancer. In total, 85 patients (59 males and 26 females; mean age, 68.9 years) underwent surgery for colorectal cancer at the Department of Surgery, Ibraki Medical Center, Tokyo Medical University (Ami, Japan), and were divided into post-operative complication and non-complication groups. Clinical data, including age, gender, body mass index, tumor localization, tumor pathological type, cancer staging, surgery time, volume of surgical bleeding, pre-operative G/L ratio and further pre-operative laboratory data, including levels of albumin and C-reactive protein, Glasgow Prognostic Score, white blood cell count and levels of hemoglobin, creatine kinase, lactate dehydrogenase, carcinoembryonic antigen and carbohydrate antigen 19-9 were analyzed between these groups. The total post-operative complication rate was 18.8%. On univariate analysis, the amount of surgical bleeding and the pre-operative G/L ratio were significantly higher in the complication group than in the non-complication group (299.8+/-361.7 vs. 155.6+/-268.6 ml, P<0.05; and 6.73+/-10.38 vs. 3.49+/-2.78, P<0.05, respectively). Multivariate logistic regression analysis for the risk factors of post-operative complications, determined using univariate analysis, demonstrated that the amount of surgical bleeding and the pre-operative G/L ratio were independent risk factors of post operative complications in patients with colorectal cancer. In conclusion, the G/L ratio may be a clinically relevant pre-operative predictive marker for post operative complications. PMID- 25436004 TI - Expression characteristics of FHIT, p53, BRCA2 and MLH1 in families with a history of oesophageal cancer in a region with a high incidence of oesophageal cancer. AB - The aim of the present study was to determine the changes to the expression levels of fragile histidine triad (FHIT), breast cancer type 2 susceptibility protein (BRCA2), MutL homolog 1 (MLH1) and tumour protein 53 (p53) exhibited by families with a history of oesophageal cancer in a region that has a high incidence of oesophageal cancer, and to determine the association of these changes with the cancer history of the families. Immunohistochemistry was used to detect the protein expression of FHIT, p53, BRCA2, and MLH1 in the excised specimens of cancer tissues from 74 oesophageal cancer patients (positive family history of oesophageal cancer [OCFH +], n=33; negative family history of oesophageal cancer [OCFH -], n=41) from a region with a high incidence of oesophageal cancer. The positive expression rates of FHIT (61%; 45/74), BRCA2 (50%; 37/74) and MLH1 (27%; 9/33) in the oesophageal cancer tissues were significantly lower than those in the healthy tissues adjacent to the cancer (97% [29/30], 87% [26/30] and 73% [25/41], respectively). A significant difference was identified between the positive expression rates (P<0.01). However, FHIT, p53, BRCA2 and MLH1 expression demonstrated no significant affect on clinicopathological changes, such as oesophageal cancerous tissue differentiation, the degree of infiltration and cancer cell metastasis. The FHIT, BRCA2 and MLH1 expression levels were identified to be significantly lower in the cancer tissues from OCFH + patients. This result indicates that the expression levels of FHIT, BRCA2, and MLH1 are important molecular indices of genetic susceptibility to oesophageal cancer. PMID- 25436005 TI - Sulfur inhibits the growth of androgen-independent prostate cancer in vivo. AB - Sulfur is a bright yellow crystalline solid at room temperature. The aim of the present study was to investigate the inhibitory effect of sulfur on prostate cancer (PCa) in vivo. Prostate tumors were developed by injecting 22Rv1 or DU-145 PCa cells into sulfur-treated or untreated nude mice. The weight and volume of the tumors were measured. The cancer cells were separated from the tumors, and analyzed for their growth rate and clonogenicity in culture. The expression of PCa-targeted genes was also assessed using real-time polymerase chain reaction. The rate of growth of 22Rv1 tumors in sulfur-treated nude mice gradually decreased, and was reduced by 41.99% (P<0.01) after 22 days when compared with that of the control group. In addition, the growth of DU-145 tumors was also suppressed by 75.16% (P<0.05) after 11 weeks. The clonogenicity of the sulfur treated tumor cells decreased by 36.7% when compared with that of the control cells. However, no significant difference in cell growth was identified. mRNA levels of the androgen-receptor, prostate specific antigen and human Hox (NKX3.1) genes were significantly decreased by 32.8, 48.2 and 42.2% in sulfur-treated tumors, respectively. Additionally, it was found that the hydrogen sulfide concentration in the serum of sulfur-treated mice was increased by 4.73% (P<0.05). Sulfur significantly suppressed the growth of PCa in vivo. Since sulfur is a known ingredient used in traditional Chinese medicine, it may be used clinically for the treatment of PCa, independently or in combination with other medicine. PMID- 25436006 TI - CCND1 gene polymorphic variants in patients with differentiated thyroid carcinoma. AB - Alterations in the CCND1 gene affect the cell cycle and are frequently observed in a variety of cancers. While the most frequent mutations that occur in thyroid tumor tissue have been characterized, the genetic factors that predispose individuals to differentiated thyroid cancer (DTC) remain to be elucidated. The present study examined whether the CCND1 c.723G>A (rs9344; p.Pro241=) and c.669C>T (rs3862792; p.Phe223=) variants have an impact on DTC susceptibility. A cohort consisting of 652 patients diagnosed with DTC were analyzed and comapred with a reference group of 799 subjects from the general population. Pyrosequencing was used as the genotyping technique. In order to determine the statistical significance of differences observed in the genotypic and allelic frequencies between the compared groups, GraphPad Prism 4 was used. At the rs9344 locus in the DTC patients, a higher frequency of allele A [P=0.032; odds ratio (OR), 1.18; 95% confidence interval (CI), 1.014-1.361] and the AA homozygous genotype (P=0.028; OR, 1.41; 95% CI, 1.059-1.989) was observed compared with the control population group. The differences were stronger for papillary carcinomas (OR 1.45; 95% CI, 1.059-1.989), but were not significant in follicular tumors. No statistically significant differences were noted in the frequency of genotypes or alleles at the rs3862792 locus in the examined groups. The present findings indicate that the c.723A variant of the CCDN1 gene may be a susceptibility low penetrance allele in the development of papillary thyroid cancer in the population studied, however it does not impact on multifocality, metastatic ability or age at diagnosis. A cumulative effect of the analyzed CCND1 gene variants was also excluded. PMID- 25436007 TI - P2X7 mRNA expression in non-small cell lung cancer: MicroRNA regulation and prognostic value. AB - The human P2X7 receptor is significant and exhibits several functions in neoplasia. At present, little is known with regard to its regulation. P2X7 expression may be regulated post-transcriptionally and putative microRNA (miRNA) binding sites are considered to be involved. The aim of this study was to determine whether miRNAs (miR-21, let-7 g and miR-205) regulate P2X7 mRNA stability. In addition, the impact of P2X7 expression in patients with non-small cell lung cancer (NSCLC) was investigated. P2X7 mRNA and mature Let-7 g, miR-21, and miR-205 expression levels were quantified in 96 NSCLC cases using quantitative reverse transcription polymerase chain reaction. In all samples, epidermal growth factor receptor and K-Ras mutational analysis was also performed. Samples with low P2X7 expression were found to exhibit a higher fold change in miR-21 expression when compared with samples exhibiting high P2X7 expression. Significantly higher miR-21 expression was observed in the tumors of NSCLC patients with a K-Ras mutation when compared with patients who had K-Ras wild-type tumors (P=0.003). Additionally, to evaluate the association between P2X7 expression and prognosis in NSCLC patients, survival analysis was performed using the Kaplan-Meier method. A significant difference in the progression-free survival and overall survival in the NSCLC patients with high P2X7 expression was identified, when compared with that of patients with low expression (P=0.03 and P=0.02, respetively). Therefore, we hypothesized that high levels of miR-21 expression in NSCLC patients with K-Ras mutations may be regulated by a complex circuit, including P2X7 downregulation and together these processes may promote tumor progression. PMID- 25436008 TI - Long-fragment DNA as a potential marker for stool-based detection of colorectal cancer. AB - Neoplastic cells that are exfoliated from the colorectal epithelium exhibit dysfunctional apoptotic mechanisms, and thus it is possible to identify high molecular-weight DNA fragments (long DNA) in feces. In the present study, the sensitivity and specificity of fecal-based long DNA assays were evaluated for the detection of colorectal cancer (CRC). Feces were collected from 54 healthy volunteers and 130 patients with CRC prior to surgical treatment. The presence of long DNA of the adenomatosis polyposis coli, Kirsten rat sarcoma viral oncogene homolog (KRAS), B-raf proto-oncogene, serine/threonine kinase and p53 genes was assessed by polymerase chain reaction followed by electrophoresis. The identification of long DNA in feces was found to exhibit a sensitivity of 56.2% and specificity of 96.3% for CRC detection. In addition, long DNA was identified in the feces of 58/90 (64.4%) patients with distal CRC and 15/40 (37.5%) patients with proximal CRC. This study indicates the potential of the fecal long DNA assay as a non-invasive and easily performed method for the detection of individuals with CRC. PMID- 25436009 TI - Primary ameloblastic carcinoma of the maxilla: A case report and literature review. AB - Ameloblastic carcinoma (AC) is a rare malignant odontogenic neoplasm that tends to occur in the mandible rather than in the maxilla. This malignancy is classified as a tumor that combines the morphological features of ameloblastoma and carcinoma, regardless of the presence or absence of metastasis. In addition, AC has been classified into two types, primary and secondary. The former develops de novo and the latter develops by malignant transformation of a pre-existing benign ameloblastoma. The present study describes the case of a 22-year-old patient with primary AC of the maxilla. A review of the literature focusing on the clinical details, treatment results and histopathological and phenotypic information available for ameloblastic carcinoma of the maxilla from a 60-year period was also performed. As a result, it was found that primary AC is dominant in the maxilla and does not exhibit an aggressive phenotype compared with secondary AC. In addition, the presence of recurrence was found to correlate with mortality, indicating that early, aggressive and complete removal of the tumor is the best treatment for survival. PMID- 25436010 TI - Malignant melanoma and papillary thyroid carcinoma that were diagnosed concurrently and treated simultaneously: A case report. AB - Malignant melanoma can be successfully treated when it is identified in its early stages, but the disease is associated with a poor prognosis when it is detected in an advanced stage. Papillary thyroid carcinoma is a thyroid cancer that has a good prognosis. The present study reports a rare case of malignant melanoma and papillary thyroid carcinoma that were diagnosed concurrently and treated simultaneously. The present patient was a 37-year-old male, in whom examination of a skin biopsy that was obtained from a lesion in the right retroauricular region revealed the lesion to be consistent with malignant melanoma. The patient underwent radical neck dissection upon the detection of malignant melanoma metastasis to the sentinel lymph node. Metastases of papillary thyroid carcinoma were detected in four out of 38 lymph nodes. The patient was then diagnosed with papillary thyroid carcinoma and underwent total thyroidectomy. The patient was administered with high-dose followed by moderate-dose interferon-alpha therapy for the treatment of malignant melanoma. The patient also received concurrent radioactive iodine therapy for the treatment of papillary thyroid carcinoma, at the same time as the interferon therapy. The two primary tumors of the patient were treated successfully. During therapy, no serious side-effects were observed, with the exception of fever caused by high-dose interferon therapy. Malignant melanoma and papillary thyroid carcinoma may occur concurrently, although this is rarely observed. The present study reports a rare case that demonstrates that the two tumors can be successfully treated simultaneously. PMID- 25436011 TI - MicroRNA-27a directly targets KRAS to inhibit cell proliferation in esophageal squamous cell carcinoma. AB - MicroRNAs (miRNAs) are a type of small non-coding RNA that negatively regulate gene expression levels by binding to the 3'-untranslated region of specific target mRNAs. To investigate the role of miR-27a in esophageal squamous cell carcinoma (ESCC), TargetScan software was used to predict the target gene of miR 27a. Kirsten rat sarcoma viral oncogene homolog (KRAS), which has been implicated as a regulator of cell proliferation, differentiation and transformation, was identified as a potential target gene of miR-27a and, thus, was the focus of the present study. Luciferase activity in cells transfected with miR-27a mimics was 48% lower when compared with that of the miRNA-negative control. Furthermore, expression levels of the K-ras protein were reduced by <=50% in cells cotransfected with an expression vector containing miR-27a and miR-27a binding sequences, when compared with the control. The expression level of miR-27a was significantly lower in ESCC cell lines and tissues when compared with healthy esophageal epithelial cells and tissues. However, the expression level of the target gene, KRAS was upregulated and ESCC cell proliferation was significantly inhibited following miR-27a mimic or small interfering K-ras transfection. In conclusion, the present study demonstrated that the expression level of miR-27a was low in ESCC and that miR-27a directly targets the KRAS gene, resulting in inhibited cell proliferation in esophageal cancer. PMID- 25436012 TI - E6-associated transcription patterns in human papilloma virus 16-positive cervical tissues. AB - The change in transcription pattern induced by post-transcriptional RNA splicing is an important mechanism in the regulation of the early gene expression of human papilloma virus (HPV). The present study was conducted to establish a method to specifically amplify HPV-16 E6-associated transcripts. The E6-related transcripts from 63 HPV-16-positive cervical tumor tissue samples were amplified, consisting of eight cases of low-risk intraepithelial lesions, 38 cases of high-risk intraepithelial lesions and 17 cases of cervical cancer (CxCa). The appropriate amplified segments were recovered following agarose gel electrophoresis, and subjected to further sequencing and sequence alignment analysis. Six groups of E6 transcription patterns were identified from HPV-16-positive cervical tumor tissue, including five newly-discovered transcripts. Different HPV-16 E6 associated transcription patterns were detected during the development of CxCa. Over the course of the progression of the low-grade squamous intraepithelial lesions to CxCa, the specific HPV-16 E6-associated transcription patterns and the dominant transcripts were all different. As indicated by this study, the transcription pattern of the E6 early gene of HPV-16 was closely associated with the stages of cervical carcinogenesis, and may also be involved in the development of CxCa. PMID- 25436013 TI - Effect of Cnidii Rhizoma on nitric oxide production and invasion of human colorectal adenocarcinoma HT-29 cells. AB - Colorectal adenocarcinoma is the most common type of gastrointestinal cancer. Colon adenocarcinoma is a major health problem worldwide due to the high prevalence and mortality rates associated with the disease. The majority of colorectal carcinomas are adenocarcinomas, which originate from the epithelial cells of the colorectal mucosa. HT-29 cells, which originate from human colon adenocarcinoma, are used as an in vitro model to investigate the effect of malignant transformation on the expression of cellular constituents and functions of the intestinal epithelium. Nitric oxide (NO) is a signaling molecule, which is involved in inflammation and carcinogenesis. It has been reported that enhanced inducible NO synthase (iNOS) activity and the resulting NO concentrations in human colon carcinoma contribute to tumor progression and vascular invasion. The present study investigates the effect of pro-inflammatory cytokine-induced nitric oxide (NO) production and iNOS expression on the invasion of human colorectal adenocarcinoma HT-29 cells, and the effect of extract from Cnidii Rhizoma on NO production and the invasiveness of HT-29 cells. Treatment of HT-29 cells with cytokines, 100 U/ml interferon gamma, 10 ng/ml interleukin-1 alpha and 25 ng/ml tumor necrosis factor alpha was found to increase NO production. Pretreatment of the cells with Cnidii Rhizoma (0.1-5 mg/ml) resulted in an inhibition of cytokine induced NO production and iNOS expression. The invasiveness of HT-29 cells through Matrigel was significantly increased by treatment with cytokines. Cnidii Rhizoma inhibited the invasiveness of cytokine-treated HT-29 cells through the Matrigel-coated membrane in a concentration-dependent manner. Matrix metalloproteinase (MMP) activity in HT-29 cells increased following the treatment with cytokines, and pretreatment of the cells with Cnidii Rhizoma inhibited cytokine-induced MMP-2 activity. These results provide sufficient information for the further development of Cnidii Rhizoma as an antitumor metastatic agent for the treatment of colon cancer. PMID- 25436014 TI - Small cell carcinoma of the urinary bladder: A case report and review of the literature. AB - Small cell carcinoma of the urinary bladder (SCBC) is a type of rare malignant tumor of the urinary tract. As it does not have specific symptoms and its epidemiological features are similar to transitional cell carcinoma of the bladder, it is often misdiagnosed. SCBC is highly aggressive, metastasizes very early and has a poor prognosis, and consequently, it has become a focus for urological surgeons and oncologists. An 82-year-old male visited the Department of Urinary Surgery, in the Affiliated Hospital of Guangdong Medical College (Zhanjiang, China), due to gross hematuria that had persisted for one week. Abdominal computed tomography showed a neoplasm of ~6*6*7 cm on the anterior wall of the bladder. The initial diagnosis was of uroepithelial cell carcinoma of the bladder and surgery was performed to remove the tumor. However, the subsequent pathological examination suggested that the tumor was an SCBC. Small cell carcinoma is a highly malignant disease, with a high mortality rate, and it rarely occurs in the bladder. Upon review of a large number of studies, SCBC was not found to present with specific symptoms, making the early diagnosis of the disease difficult, however, commonly occurring symptoms included dysuria, painless gross hematuria and urinary tract obstruction. PMID- 25436015 TI - DCF intraperitoneal and intravenous dual chemotherapy regimen for advanced gastric cancer: A feasibility study. AB - Gastric cancer is the fourth most common type of cancer globally and accounts for the second highest cancer-associated mortality rate in the world. Current treatment strategies for gastric cancer include surgery, radiotherapy, chemotherapy and targeted therapy. Intraperitoneal (IP) chemotherapy may increase the IP concentrations of chemotherapy drugs and reduce the systemic toxicity. At present, IP chemotherapy is used to treat patients with advanced gastric cancer, which has a high rate of peritoneal recurrence. The present study evaluated the feasibility of using docetaxel, cisplatin and fluorouracil (DCF) in an IP and intravenous (IV) dual chemotherapy regimen for the treatment of advanced gastric cancer. The treatment-associated adverse reactions and preliminary efficacy were reported. The first dose level utilized the full dose of DCF: Docetaxel, day one, 45 mg/m2 (IP) and day eight, 30 mg/m2 (IV); cisplatin (DDP), day one, 75 mg/m2 (IP); and fluorouracil (FU), days one to five, 750 mg/m2 (continuous IV). A total of six patients were treated at this level and two patients withdrew due to serious adverse reactions. Taking into account that the the tolerated doses used in combination regimens for Eastern populations are lower than that of the corresponding doses for Western populations, the dosages of the three drugs were all reduced by 20% in the application of the second dose level: Docetaxel, day one, 30 mg/m2 (IP) and day eight, 30 mg/m2 (IV); DDP, day two, 60 mg/m2 (IP); and FU, days one to five, 600 mg/m2 (continuous IV). A total of 26 patients were treated at this level. The main adverse reaction was bone marrow suppression, with grade III/IV neutropenia, leukopenia and febrile neutropenia accounting for 61.5, 53.8 and 19.2% of reactions, respectively, and grade III/IV anemia and thrombocytopenia accounting for 19.2 and 15.4% of reactions, respectively. Gastrointestinal adverse reactions primarily consisted of abdominal pain, with grade III/IV abdominal pain accounting for 30.8% of reactions. Only 7.7% of the patients withdrew from the treatment. The median time to progression (TTP) was five months [95% confidence interval (CI), 1.0-9.0 months], and the median overall survival (OS) was nine months (95% CI, 7.4-10.6 months). It was concluded that the DCF regimen with reduced dosage should be applied. IP and IV dual chemotherapy for the treatment of unresectable advanced gastric cancer is tolerated and demonstrated a good initial efficacy. Strategies for mitigating and reducing the adverse gastrointestinal reactions, particularly abdominal pain, may be the focus of future studies. PMID- 25436016 TI - The network of microRNAs, transcription factors, target genes and host genes in human renal cell carcinoma. AB - At present, scientists have performed numerous studies investigating the morbidity of renal cell carcinoma (RCC) in the genetic and microRNA (miRNA) fields, obtaining a substantial amount of knowledge. However, the experimentally validated data of genes, miRNA and transcription factors (TFs) cannot be found in a unified form, which makes it challenging to decipher the regulatory mechanisms. In the present study, the genes, miRNAs and TFs involved in RCC are regarded as elements in the regulatory network, and the present study therefore focuses on the association between each entity. Three regulatory networks were constructed hierarchically to indicate the regulatory association between the genes, miRNAs and TFs clearly, including the differentially expressed, associated and global networks. All the elements were macroscopically investigated in these networks, instead of only investigating one or several of them. The present study not only compared and analyzed the similarities and the differences between the three networks, but also systematically expounded the pathogenesis of RCC and supplied theoretical foundations for future gene therapy investigations. Following the construction of the three networks, certain important pathways were highlighted. The upstream and downstream element table of differentially expressed genes and miRNAs was listed, in which self-adaption associations and circle-regulations were identified. In future studies, the identified genes and miRNAs should be granted more attention. PMID- 25436017 TI - Nuclear deformability constitutes a rate-limiting step during cell migration in 3 D environments. AB - Cell motility plays a critical role in many physiological and pathological settings, ranging from wound healing to cancer metastasis. While cell migration on 2-dimensional (2-D) substrates has been studied for decades, the physical challenges cells face when moving in 3-D environments are only now emerging. In particular, the cell nucleus, which occupies a large fraction of the cell volume and is normally substantially stiffer than the surrounding cytoplasm, may impose a major obstacle when cells encounter narrow constrictions in the interstitial space, the extracellular matrix, or small capillaries. Using novel microfluidic devices that allow observation of cells moving through precisely defined geometries at high spatial and temporal resolution, we determined nuclear deformability as a critical factor in the cells' ability to pass through constrictions smaller than the size of the nucleus. Furthermore, we found that cells with reduced levels of the nuclear envelope proteins lamins A/C, which are the main determinants of nuclear stiffness, passed significantly faster through narrow constrictions during active migration and passive perfusion. Given recent reports that many human cancers have altered lamin expression, our findings suggest a novel biophysical mechanism by which changes in nuclear structure and composition may promote cancer cell invasion and metastasis. PMID- 25436019 TI - An anthropologist in unexpected places: An Interview with Philippe Bourgois. AB - Much contemporary anthropology has turned away from exclusive focus on so-called "primitive" tribes in far-away places. The study of urban people has become more prominent, and some researchers have also turned their gaze towards marginalized minorities in their communities. Philippe Bourgois is an example of this. He is well known for studying crack dealers in East Harlem, New York ( In Search of Respect) and homeless heroin addicts in San Francisco (Righteous Dopefiend). Kula Kula was lucky enough to catch him in his office, and had a chat via skype. PMID- 25436018 TI - A Story Mapping Intervention to Improve Narrative Comprehension Deficits in Adolescents with ADHD. AB - The current study examined the effects of an 8-week Story Mapping Intervention (SMI) to improve narrative comprehension in adolescents with ADHD. Thirty 12 - 16 year-old adolescents with ADHD who were participating in a summer treatment program for adolescents with ADHD received the SMI instruction ten times and completed SMI homework ten times in a structured environment with teacher feedback. Recall of fables and story creation were assessed before and after the SMI. At post-test, fable recalls included more of the most important events, were more coherent, and included a greater number of plausible inferences than pre test fable recalls. SMI homework scores accounted for increases in recall of important events and plausible inferences, suggesting that consistent practice and feedback with story mapping could contribute to important recall gains. In contrast, the inclusion of goal-based events and the rated coherence of created stories did not improve, suggesting that more explicit instruction in applying story mapping to story creation may be required. PMID- 25436020 TI - Left ventricular mass: correlation with fatness, hemodynamics and renal morphology. AB - BACKGROUND: Left ventricular mass (LVM) is correlated with body composition and central hemodynamics as well as kidney function. Recently, fat-free mass has been considered to be more strongly correlated with LVM in comparison to other descriptors of fatness. We therefore address the question of whether comprehensive descriptors of fatness, central hemodynamics and renal characteristics demonstrate the association with left ventricular mass in healthy non-obese population. MATERIAL/METHODS: 119 healthy non-obese subjects (53 females, 66 males, mean age 50 yrs) were evaluated. Central hemodynamics was measured by Pulse Wave Analysis, left ventricular mass was assessed by echocardiography, fatness was evaluated by anthropometry, bioimpedance, and ultrasound. RESULTS: Left ventricular mass index (LVMI) correlated to the same extent with central and peripheral blood pressure but not with descriptors of wave reflection. Fat-free mass as well as intraabdominal fat correlated to a similar extent with LVMI. Kidney morphological characteristics indexed to body surface area were associated inversely and independently with LVMI. CONCLUSIONS: Comprehensive assessment of fatness reinforced the concept that intraabdominal fat compartment is strongly correlated with left ventricular mass. Descriptors of wave reflection are not associated with left ventricular mass. The interrelationsh between kidney morphology and LVMI indicates that such associations may be a biologically plausible phenomenon. PMID- 25436021 TI - Odontogenic inflammatory processes of head and neck in computed tomography examinations. AB - BACKGROUND: Infections of odontogenic origin are the most common cause of inflammatory disease of head and neck region. Computed tomography allows for defining localization and extent of inflammatory lesions, visualizes soft tissue involvement, presence of an abscess or an osteolytic lesion around causative tooth. THE AIM OF THIS STUDY WAS TO ASSESS PATHWAYS, BY WHICH ODONTOGENIC INFECTIONS SPREAD INTO RESPECTIVE DEEP HEAD AND NECK STRUCTURES IN COMPUTED TOMOGRAPHY EXAMINATION, TAKING INTO ACCOUNT THE FOLLOWING CRITERIA: frequency of involvement of respective deep cervical spaces, possibility to determine a probable causative tooth and concordance with the results of clinical examination. MATERIAL/METHODS: Thirty-eight patients cervicofacial inflammatory disease had undergone CT examination of head and neck region with a 64-slice CT scanner after intravenous contrast administration. RESULTS: Abscess was reported in 30 (79%) cases, while inflammatory infiltration was diagnosed in remaining 8 (21%) patients. There was full concordance between radiological report and intraoperative report In 33 cases (87%). The most commonly involved cervical space was masticator space - 31 patients (82%), followed by submandibular space - 27 patients (71%). Dental examination was impossible in 29 patient because of trismus. During analysis of CT studies we evaluated maxillary and mandibular alveolar processes for presence of osteolytic bone lesions around causative teeth roots and we found them in 30 cases (79%). In 32 cases (84%) cervicofacial infection were of mandibular odontogenic origin. CONCLUSIONS: In most cases CT study in patients suspected of odontogenic craniofacial infection revealed presence of an abscess, needing urgent surgery. Inflammatory infiltration of dental origin most frequently involves masticator space, followed by submandibular space. In most cases CT scanning allows for identification of causative teeth, especially when trismus makes detailed clinical examination impossible. PMID- 25436022 TI - Implementation of continuous capnography is associated with a decreased utilization of blood gases. AB - BACKGROUND: Capnography provides a continuous, non-invasive monitoring of the CO2 to assess adequacy of ventilation and provide added safety features in mechanically ventilated patients by allowing for quick identification of unplanned extubation. These monitors may allow for decreased utilization of blood gases. The objective was to determine if implementation of continuous capnography monitoring decreases the utilization of blood gases resulting in decreased charges. METHODS: This is a retrospective review of a quality improvement project that compares the utilization of blood gases before and after the implementation of standard continuous capnography. The time period of April 2010 to September 2010 was compared to April 2011 to September 2011. Parameters collected included total number of blood gases analyzed, cost of blood gas analysis, ventilator and patient days. RESULTS: The total number of blood gases after the institution of end tidal CO2 monitoring decreased from 12,937 in 2009 and 13,171 in 2010 to 8,070 in 2011. The average number of blood gases per encounter decreased from 20.8 in 2009 and 21.6 in 2010 to 13.8 post intervention. The blood gases per ventilator day decreased from 4.94 in 2009 and 4.76 in 2010 to 3.30 post intervention. The total charge savings over a 6-month period was $880,496. CONCLUSIONS: Continuous capnography resulted in a significant savings over a 6 month period by decreasing the utilization of blood gas measurements. PMID- 25436023 TI - Potent Anticancer Effects of Bioactive Mushroom Extracts (Phellinus linteus) on a Variety of Human Cancer Cells. AB - BACKGROUND: Although several therapeutic options are currently available for patients with various cancers, the outcomes are often disappointing and a more effective modality needs to be promptly established. We have been exploring an alternative approach using natural agents and two bioactive mushroom extracts isolated from Phellinus linteus (PL), namely PL-ES and PL-I-ES, were of our interest. As anticancer effects of similar extracts have been reported in several cancers, we investigated whether PL-ES and PL-I-ES might have such anticancer activities on a variety of human cancer cells in vitro. METHODS: Ten different types of human cancer cell lines, including three metastatic prostate, bladder, kidney, lung, breast, stomach, liver, and brain cancer cells, were employed and tested with PL-ES or PL-I-ES. Cell growth/viability, exertion of oxidative stress, and induction of apoptosis were assessed by MTT (3-[4,5-dimethylthiazol-2 yl]-2,5-diphenyl-tetrazolium bromide) assay, lipid peroxidation (LPO) assay, and specific enzymatic assay, respectively. RESULTS: PL-ES (100 ug/mL) exhibited potent anticancer activity, resulting in a significant (40-80%) growth reduction in all 10 cancer cells at 72 hours. PL-I-ES (100 ug/mL) was effective on only four cancer cells but its higher concentration at 250 ug/mL led to a significant (25-90%) growth reduction in seven cancer cells. LPO assays indicated that such a significant growth reduction by PL-ES (100 ug/mL) or PL-I-ES (100 or 250 ug/mL) could result from cell death due to a cytotoxic effect of oxidative stress (through free radicals). Moreover, enzymatic assays for caspase-3 (Csp-3) and caspase-9 (Csp-9), the pro-apoptotic regulators, showed that both enzymes were significantly activated by PL-ES or PL-I-ES, indicating that cell death due to oxidative stress was more likely associated with apoptosis. CONCLUSIONS: The present study shows that both PL-ES and PL-I-ES indeed have anticancer effects on a variety of cancer cells, although PL-ES appears to be more potent than PL-I-ES. Such an anticancer effect is presumably attributed to oxidative stress, which will ultimately lead to apoptosis. Therefore, these two bioactive mushroom extracts may have clinical implications in a more effective therapeutic option for a variety of human malignancies. PMID- 25436024 TI - Variations in respiratory excretion of carbon dioxide can be used to calculate pulmonary blood flow. AB - BACKGROUND: A non-invasive means of measuring pulmonary blood flow (PBF) would have numerous benefits in medicine. Traditionally, respiratory-based methods require breathing maneuvers, partial rebreathing, or foreign gas mixing because exhaled CO2 volume on a per-breath basis does not accurately represent alveolar exchange of CO2. We hypothesized that if the dilutional effect of the functional residual capacity was accounted for, the relationship between the calculated volume of CO2 removed per breath and the alveolar partial pressure of CO2 would be reversely linear. METHODS: A computer model was developed that uses variable tidal breathing to calculate CO2 removal per breath at the level of the alveoli. We iterated estimates for functional residual capacity to create the best linear fit of alveolar CO2 pressure and CO2 elimination for 10 minutes of breathing and incorporated the volume of CO2 elimination into the Fick equation to calculate PBF. RESULTS: The relationship between alveolar pressure of CO2 and CO2 elimination produced an R(2) = 0.83. The optimal functional residual capacity differed from the "actual" capacity by 0.25 L (8.3%). The repeatability coefficient leveled at 0.09 at 10 breaths and the difference between the PBF calculated by the model and the preset blood flow was 0.62 +/- 0.53 L/minute. CONCLUSIONS: With variations in tidal breathing, a linear relationship exists between alveolar CO2 pressure and CO2 elimination. Existing technology may be used to calculate CO2 elimination during quiet breathing and might therefore be used to accurately calculate PBF in humans with healthy lungs. PMID- 25436025 TI - Trends in the epidemiological aspects and mortality of alcoholic liver disease in Korea in the decade between 2000 and 2009. AB - BACKGROUND: Alcohol consumption and related alcohol liver disease (ALD) have substantially increased in Korea during the last decade. The objective of this study was to evaluate the trends in the epidemiological aspects and mortality rate (MR) of Korea in the decade between 2000 and 2009. METHODS: The raw data analyzed in this study were obtained from the website of "the ALD" managed by Korea Center for Disease Control and Prevention (KCDC), Korea Public Health Association (KPHA), and statistics website of Statistics Korea. The data analyses were performed using Excel 2007 statistical software (Microsoft Corp., USA). RESULTS: The amount of alcohol-consumption-per-capita-per-year (ACCY) in Korea was 8.38 L in 2000 and 8.54 L in 2009. The most taken alcoholic beverage was soju, followed by beer. There were a total of 1,403 case-fatalities (CF) with an MR of 2.98 per 100,000 populations of ALD in 2000, while a total of 3,588 CF with an MR of 7.21 in 2009 (P < 0.01). The CF and MR of ALD in males were significantly higher than those in females (P < 0.01). In over 40-year-old age groups, the CF and MR were significantly increased (P < 0.01). Moreover, occupational classification revealed that the mistress/students/jobless (MSJ) were the most risky group. The comparison of overall CF and MR of ALD by six key classifications (International Classification of Diseases (ICD)) showed that alcoholic cirrhosis (229 CF and 16.3%) in 2000 tended to be increased in 2009 (2,803 CF and 78.1%), while alcoholic fibrosis and sclerosis (607 CF and 43.3%) in 2000 significantly decreased in 2009 (120 CF and 3.3%), respectively. CONCLUSION: ALD is one of the most severe diseases in Korea, as indicated by its high CF and MR in this study. As over-consumption of alcoholic beverages is relatively common in Korea, more efforts should be made toward prevention of ALD by raising awareness of the risk factors of ALD by public health education. PMID- 25436026 TI - Effect of maternal age on pregnancy outcome and cesarean delivery rate. AB - BACKGROUND: The aims of this retrospective study were to evaluate the maternal and prenatal outcomes between 35 years and older pregnancies and younger pregnancies, and the effects of the age of pregnancy, mother and newborn. METHODS: Pregnant women who gave birth in Vakif Gureba Training and Research Hospital, Clinic of Obstetrics and Gynecology in 2006 were retrospectively screened. Pregnant women aged 35 years and over were included in this study and the pregnant women between age range of 30 - 34 years were included in the control group. RESULTS: Pregnancy rate was found as 7.1% in 35 years and older women in all the deliveries, cesarean delivery rate was found as 46.1% in this group at 1 year period. However, cesarean delivery rate was 40.9% in the control group. Cesarean delivery rate was found as 31.6% in all the deliveries. The most common cause of cesarean section indication was fetal distress in advanced maternal age (AMA) (11.7%), whereas previous cesarean section was found as the most common cause in the control group (15.1%). CONCLUSION: No significant difference was found between AMA group and normal pregnancies in terms of preterm labor, caesarian section, morbidity, mortality and chronic diseases such as hypertension and diabetes mellitus. PMID- 25436027 TI - Seroepidemiology of hepatitis e virus infection in mennonites in Mexico. AB - BACKGROUND: The seroepidemiology of hepatitis E virus (HEV) infection in Mennonites has not been studied. We aimed to determine the seroprevalence of anti HEV IgG antibodies in Mennonites in Durango, Mexico, and to compare it with the seroprevalence in general population in rural Durango. The socio-demographic, clinical and behavioral characteristics of Mennonites associated with HEV seropositivity were also investigated. METHODS: We performed a case-control study to determine the frequency of anti-HEV IgG antibodies in 150 Mennonites (mean age 38.40 +/- 15.53 years old) and 150 age- and gender-matched non-Mennonites controls using an enzyme-linked immunoassay. We used a standardized questionnaire to obtain the socio-demographic, clinical and behavioral characteristics of the Mennonites. RESULTS: Anti-HEV IgG antibodies were detected in 10 (6.7%) of 150 Mennonites and in 61 (40.7%) of 150 controls. Seroprevalence of anti-HEV IgG antibodies was significantly lower in Mennonites than in controls (odds ratio (OR) = 0.009; 95% confidence interval (CI): 0.0006 - 0.15; P < 0.000001). Logistic regression of socio-demographic and behavioral characteristics of Mennonites showed that HEV seropositivity was only associated with increasing age (OR = 1.05; 95% CI: 1.00 - 1.09; P = 0.03). While sex, birth place, residence, educational level, socio-economic status, occupation, animal contacts, foreign travel, frequency of eating away from home, consumption of raw or undercooked meat, type of meat consumed, consumption of unpasteurized milk or untreated water, and consumption of unwashed raw vegetables or fruits were not associated with HEV seropositivity. None of the Mennonites suffered from clinical hepatitis. CONCLUSIONS: RESULTS DEMONSTRATE: 1) serological evidence of HEV exposure in Mennonites; however, Mennonites have a lower seroprevalence of HEV antibodies than controls from the rural general population; 2) seroprevalence in Mennonites increased with age. Further studies with a larger sample size to determine more contributing factors for HEV infection in Mennonites are needed. PMID- 25436029 TI - Preventing "a bridge too far": promoting earlier identification of dislodged dental appliances during the perioperative period. AB - The presence of fixed partial dentures presents a unique threat to the perioperative safety of patients that require orotracheal intubation or placement of instruments into the gastrointestinal (GI) tract. There are many chances for the displacement of a fixed partial denture: instrumentation of the airway for intubation, or introduction of temporary devices, such as gastroscopes or transesophageal echo probes. If dislodged, the fixed partial dentures can enter the hypopharynx, esophagus or lungs and cause perforations with their sharp tines. Oral or esophageal perforation can lead to potentially fatal mediastinitis. We describe a case of a patient with a fixed partial denture who underwent cardiac surgery with intubation and transesophageal echocardiography (TEE). His partial denture was intact after the procedure. After extubation, he reported that his teeth were missing. Multiple procedures were required to remove his dislodged partial dentures. In sign-out reports, verbal descriptions of the patient's partial dentures were not adequate in this case. A picture of the patient's denture and oral pharynx pre-operatively would have provided a more accurate template for the post-operative team to refer to when caring for the patient. This may have avoided the multiple potentially risky procedures the patient had to undergo. We describe a suggested protocol utilizing a pre operative photo to reduce the incidence of unrecognized partial denture dislodgement in the perioperative period. Because the population is aging, this will become a more frequent issue confronting practitioners. This protocol could mitigate this complication. PMID- 25436028 TI - Utilization of emergency service of obstetrics and gynecology: a cross-sectional analysis of a training hospital. AB - BACKGROUND: Overutilization and inappropriate use of emergency departments (EDs) by patients with non-urgent health problems has become a major concern worldwide. This study aims to describe the characteristics of obstetric and gynecologic patients admitted to the Department of Emergency Obstetric and Gynecology. METHODS: A retrospective and cross-sectional study was designed at our Emergency Service of Obstetrics and Gynecology of Kayseri Education and Research Hospital of Medicine between January 1 and December 31, 2013. A total of 30,853 patients applying to emergency service were retrospectively analyzed from the admission charts, patient files and hospital automation system. Patients were assessed in terms of demographic features, presentation times, complaints, admission type (with own facilities, with consultation or with ambulance), diagnoses (urgent or non-ergent), discharge rates, clinical admission, rejection rate of examination, and rejection rate of hospitalization. RESULTS: A total of 30,853 patients were analyzed retrospectively. The mean age of patients was 27.69 +/- 8.44 years; 51% of patients were between 20 and 29 years old. The categories of patients in urgent and non-urgent were 69% and 31% respectively. Most common presentation time period was between 19:00 and 21:00. Labor pain, pain and bleeding during pregnency, routine antenatal control, pelvic pain and menstrual irregularity were the most common complaints. Labor pain with the rate of 21% was the most common cause of ED admission. All patients who presented with labor pain were hospitalized. Patients hospitalized for labor constituted 56% of all hospitalized patients. Among patients, 62% were treated on an outpatient basis and 38% were hospitalized. Of patients, 3.54% refused to hospitalization. The cases using the ambulance to admission constituted 1.07% of all ED patients. Of these patients who have used ambulance 3.65% refused to the patient examination. CONCLUSIONS: To improve the obstetric and gynecologic emergency medical care in Turkey, demographic properties and other characteristics of patients should be analyzed in detail. Detailed analysis of the data contributes to the further design and perspective of the EDs. PMID- 25436030 TI - The first case of biological therapy discontinuation after a complete remission induced by maintenance therapy with adalimumab for refractory ulcerative colitis. AB - A 43-year-old woman, diagnosed with ulcerative colitis (UC) at age of 30, received outpatient treatment with corticosteroids. However, flare-up occurred, and adalimumab (ADA) treatment commenced in July 2009. A complete remission with mucosal healing was achieved by 32 weeks after initiation of ADA therapy. Because of progressive skin eruptions, ADA maintenance was discontinued at 124 weeks. Regardless, complete remission with mucosal healing was maintained until 176 weeks. We concluded that ADA is an effective therapy to achieve a complete remission in a patient with steroid-refractory UC, and that long-term complete remission may be an important indication to discontinue biological therapy. PMID- 25436031 TI - Successful surgical treatment of mature teratoma arising from the sella. AB - Mature teratoma of the pituitary-hypothalamic region is rarely reported in the literature. In this article, we present a 13-year-old girl with clinical and radiological findings that were initially considered as germinoma. However, histological examinations disclosed a mature teratoma. This case highlights that the radiation-induced cerebral edema caused acute hydrocephalus. The mature teratoma is not radiosensitive, and the most appropriate treatment is direct surgery. PMID- 25436032 TI - Artery of percheron occlusion in an elderly male: a case report. AB - Acute bilateral paramedian thalamic and mesencephalic infarcts are uncommon. Occlusion of the artery of Percheron (AOP) is presumed to cause this specific stroke syndrome. However, occlusion of the AOP is rare and early diagnosis is challenging. Here we described a 70-year-old male patient who presented with acute disturbance of consciousness due to acute bilateral paramedian thalamo mesencephalic infarction secondary to AOP occlusion. Anticoagulant therapy was administered, and his consciousness gradually improved. PMID- 25436033 TI - Vertical open patella fracture, treatment, rehabilitation and the moment to fixation. AB - Patella fracture is relatively uncommon and the vertical trace fracture represents almost 12-17%. The open patella fracture expresses 6-30%. The association of these two uncommon conditions was the aim of this case report even as the treatment and the moment of fixation (definitive surgical treatment). A 27 year-old man after a motorcycle accident showed an open patella fracture classified as a Gustilo and Anderson type IIIA lesion. The patient was immediately treated with precocious surgery fixation with a modified tension band which consists of two parallel K-wires positioned orthogonal to the fracture line and a cerclage wire shaped anteriorly at patella as an eight. The premature fixation benefited the infection prevention and provided earlier joint motion, which increased the nutrition of articular cartilage. Six months postoperatively, the patient had a satisfactory joint motion with full extension and 116 degrees of joint flexion and returned to his daily life activities without restriction. Twelve months postoperatively, the patient had full extension and 120 degrees of knee flexion without pain, joint effusion and instability. Muscle strength force was considered normal at grade V. In conclusion, early chirurgic treatment and precocious articular mobilization improve prognosis, suggesting that the employment of these practices should be adopted whenever possible in most of the open fractures. PMID- 25436034 TI - Suicide Intervention Skills: Graduate Training and Exposure to Suicide among Psychology Trainees. PMID- 25436035 TI - Surface Structure of Aerobically Oxidized Diamond Nanocrystals. AB - We investigate the aerobic oxidation of high-pressure, high-temperature nanodiamonds (5-50 nm dimensions) using a combination of carbon and oxygen K-edge X-ray absorption, wavelength-dependent X-ray photoelectron, and vibrational spectroscopies. Oxidation at 575 degrees C for 2 h eliminates graphitic carbon contamination (>98%) and produces nanocrystals with hydroxyl functionalized surfaces as well as a minor component (<5%) of carboxylic anhydrides. The low graphitic carbon content and the high crystallinity of HPHT are evident from Raman spectra acquired using visible wavelength excitation (lambdaexcit = 633 nm) as well as carbon K-edge X-ray absorption spectra where the signature of a core hole exciton is observed. Both spectroscopic features are similar to those of chemical vapor deposited (CVD) diamond but differ significantly from the spectra of detonation nanodiamond. The importance of these findings to the functionalization of nanodiamond surfaces for biological labeling applications is discussed. PMID- 25436036 TI - CAT, GPX1, MnSOD, GSTM1, GSTT1, and GSTP1 genetic polymorphisms in chronic myeloid leukemia: a case-control study. AB - Oxidative damage at the DNA level may be promoted by high levels of reactive oxygen species (ROS), leading to genomic instability and increased neoplastic risk. Superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) enzymes are implicated in the prevention of DNA damage by ROS. The aim of the study was to investigate the relationships between CAT C262T, GPX1 Pro198Leu, MnSOD Ala16Val, GSTM1, GSTT1, and GSTP1 Ile105Val polymorphisms and the risk of CML. No association was observed between CML and variant genotypes of GPX1, MnSOD, GSTM1, and GSTT1 polymorphisms in any of the investigated cases. Our study suggests that the homozygous variant genotype of the GSTP1 Ile105Val gene polymorphisms may be associated with the risk of developing CML (OR = 2.5; 95% CI = 1.08-5.7; P value = 0.02), while the heterozygous genotype of the CAT C262T polymorphism seems to have a protective effect against CML (OR = 0.59, 95% CI = 0.39-0.89, P value = 0.01). In most cases, no association was found between laboratory parameters and prognostic factors and the variant genotype of investigated gene polymorphisms. We concluded that CAT, GPX, MnSOD, GSTM1, and GSTT1 gene polymorphisms are not associated with the risk of CML. Variant genotype of the GSTP1 Ile105Val gene polymorphisms may contribute to the risk of developing CML. PMID- 25436038 TI - Early Retirement Incentives and Student Achievement. AB - Early retirement incentives (ERIs) are increasingly prevalent in education as districts seek to close budget gaps by replacing expensive experienced teachers with lower-cost newer teachers. Combined with the aging of the teacher workforce, these ERIs are likely to change the composition of teachers dramatically in the coming years. We use exogenous variation from an ERI program in Illinois in the mid-1990s to provide the first evidence in the literature of the effects of large scale teacher retirements on student achievement. We find the program did not reduce test scores; likely, it increased them, with positive effects most pronounced in lower-SES schools. PMID- 25436037 TI - The Role of Peers in the Relation between Hurricane Exposure and Ataques de Nervios among Puerto Rican Adolescents. AB - Although a relation between disaster exposure and ataques de nervios (ataques) has been established in adult samples, little is known about this among youth, including factors that may moderate this relation. This study examined the role of the peer context in the relation between exposure to Hurricane Georges and experiencing a past year and lifetime ataques among a representative community sample of 905 youth (N = 476 boys and 429 girls; ages 11-18) residing in Puerto Rico. Data were gathered from 1999-2000 in Puerto Rico, 12-27 months following Hurricane Georges. Logistic regression analyses found that peer violence significantly predicted experiencing an ataque in the past year. Hurricane exposure and peer violence were both significant predictors of a lifetime experience of an ataque. An interaction was found between hurricane exposure and peer violence, indicating that hurricane exposure was significantly related to a lifetime experience of an ataque among adolescents who do not report associating with violent peers. For participants reporting high levels of peer violence, hurricane exposure did not add additional risk for a lifetime experience of an ataque. Understanding the influence of peers in the relation between hurricane exposure and experiencing an ataque may assist in planning developmentally and culturally sensitive response plans. PMID- 25436039 TI - AIRWAY LABELING USING A HIDDEN MARKOV TREE MODEL. AB - We present a novel airway labeling algorithm based on a Hidden Markov Tree Model (HMTM). We obtain a collection of discrete points along the segmented airway tree using particles sampling [1] and establish topology using Kruskal's minimum spanning tree algorithm. Following this, our HMTM algorithm probabilistically assigns labels to each point. While alternative methods label airway branches out to the segmental level, we describe a general method and demonstrate its performance out to the subsubsegmental level (two generations further than previously published approaches). We present results on a collection of 25 computed tomography (CT) datasets taken from a Chronic Obstructive Pulmonary Disease (COPD) study. PMID- 25436041 TI - The influence of incudostapedial joint separation on the middle ear transfer function. AB - OBJECTIVES: One of the risks in middle ear surgery is high frequency hearing loss. It is believed that manipulations on the middle ear ossicles with the instruments may cause overstimulation of the inner ear and damage of the hear cells. Controversy arises whether temporary separation of the ossicles has any impact on middle ear transfer function and hearing threshold after surgery. The aim of the study is to evaluate the influence of incudostapedial joint (ISJ) separation on middle ear function in an experimental model. METHODS: With the use of single point laser Doppler vibrometer (LDV) stapes velocity in the intact chain and after ISJ separation was measured in 5 fresh human cadaver temporal bones. RESULTS: In all cases there was a decrease in stapes velocity after ISJ separation. Mead stapes velocity was reduced for 1 dB in 800 Hz to 9 dB in frequencies above 1,000 Hz. The decrease of velocity was greater in higher frequencies. CONCLUSION: Separation of the ISJ does not reduce significantly the middle ear function. PMID- 25436040 TI - Sublingual immunotherapy in allergic rhinitis: efficacy, safety, adherence and guidelines. AB - Allergic rhinitis (AR) is a globally increasing health problem affecting the quality of life. Specific immunotherapy is an available causal treatment changing the basic allergic mechanisms of the disease. Over one hundred years, subcutaneous immunotherapy (SCIT) was developed and proved its efficacy but many adverse effects were recorded including anaphylaxis. In 1986, sublingual immunotherapy (SLIT) was introduced as an alternative solution to solve this problem. Our study aims to discuss SLIT from the points of efficacy, safety, adherence and guidelines developed. A literature search was conducted in Medline/PubMed and the Cochrane Library in January 2013 using the keywords "allergic rhinitis, sublingual immunotherapy, efficacy, safety, compliance, adherence, guidelines." All types of publications were included. We augmented our study by searching the reference lists of identified reviews. SLIT has been established in many guidelines as an evidence-based effective treatment in AR with safer profile than SCIT. The meta-analyses confirmed its efficacy and showed a significant reduction in both symptoms and medication scores. The most common recorded adverse effects were minor local effects in the mouth, gastrointestinal reactions with few cases of anaphylaxis and no fatality. Adherence is more favorable for SLIT mainly because it is safe, noninvasive and easily taken at home. We support the call to conduct large multi-centric studies to gain more statistical power and overcome the problem of heterogeneity observed in the meta analyses. PMID- 25436042 TI - Weighting of static and transition cues in voiceless fricatives and stops in children wearing cochlear implants. AB - OBJECTIVES: To determine how normal-hearing adults (NHA), normal-hearing children (NHC) and children wearing cochlear implants (CI) differ in the perceptual weight given cues for fricative consonants (having a comparatively long static cue and short transition cue) versus stop consonants (having a comparatively short static cue and long transition cue). METHODS: Ten NHA, eleven 5- to 8-year-old NHC and eight 5- to 8-year-old children wearing CI were participated. Fricative /su/-/?u/ and stop /pu/-/tu/continua were constructed by varying the fricative/burst cue and the F2 onset transition cue. A quantitative method of analysis (analysis of variance model) was used to determine cue weighting and measure cue interaction within groups. RESULTS: For the fricative consonant, all groups gave more weight to the frication spectral cue than to the formant transition. For the voiceless stop consonant, all groups gave more weight to the transition cue than to the burst cue. The CI group showed similar cue weighting strategies to age-matched NHC, but integration of cues by the CI group was not significant. CONCLUSION: All groups favored the longer-duration cue in both continua to make phonemic judgments. Additionally, developmental patterns across groups were evident. Results of the current study may be used to guide development of CI devices and in efforts to improve speech and language of children wearing CIs. PMID- 25436043 TI - Is hearing loss in infants associated with risk factors? Evaluation of the frequency of risk factors. AB - OBJECTIVES: To evaluate the frequency of risk factors and their influence on the evoked otoacoustic emission (OAE) of infants. METHODS: All newborns between November 2009 and June 2012 in Haydarpasa Numune Education and Research Hospital were tested on distortion evoked OAE screening test. Total of 2,284 infants were examined. Sex, maternal infectious disease, birth type (vaginal birth or caesarean sectio), birth weight, familial hearing loss, intermarriage of parents, hyperbilirubinemia, intensive care were analyzed as risk factors. RESULTS: Total of 2,284 neonates were screened (1,220 males and 1,064 females) for the presence of OAE in both ears. Vaginal delivery, maternal infections during pregnancy, intermarriage of parents relative, low birth weight(<1,500 g) are related risk factors to failure of screening with OAE in our study. There was no statistically significant difference in sex ratios, birth weight, familial hearing loss, hyperbilirubinemia, and intensive care stay. CONCLUSION: Risk factors are only as useful as their predictive power. Not enough is known about which risk factors are relevant, which babies have the risk factors, or which babies will fail to attend follow-up, the effectiveness of targeted hearing loss testing is questionable at this point in time. A system needs to be developed to clarify which risk factors are discoverable, predictive and useful. PMID- 25436044 TI - Hearing and facial function after surgical removal of cholesteatomas involving petrous bone. AB - OBJECTIVES: The purpose of this study was to inspect the clinical characteristics, surgical approaches, functional preservation, and complications of petrous bone cholesteatoma and to propose appropriate surgical approaches based on long-term follow-up cases and previous reports in the literature. METHODS: The medical records of 31 patients who underwent surgery for petrous bone cholesteatoma between 1990 and 2011 at two tertiary referral hospitals were retrospectively analyzed with regard to the classification, type of surgical approach, preservation of facial and auditory function, and recurrence. RESULTS: Of 31 cases, 16 were supralabyrinthine (class I), 1 was infralabyrinthine-apical (class III), 13 were massive (class IV), and 1 was apical (class V). Facial nerve palsy was found in 35.5% of the cases (11 cases). Hearing was preserved in 11 of 22 patients who had better than a 50-dB hearing level of bone conduction pure tone average preoperatively. Preoperative hearing was preserved in only four of the patients in class I (supralabyrinthine). Facial function was preserved or improved in 29 patients (93.5%). CONCLUSION: Complete removal of cholesteatoma of petrous bone can be achieved by choosing the appropriate approach based on location and extent. Facial function was preserved postoperatively in most reviewed cases. Auditory function could not be preserved postoperatively in some cases, but preserving residual hearing levels can be accomplished mostly in supralabyrinthine cholesteatomas with the appropriate surgical approach. PMID- 25436045 TI - The Expression of AGO2 and DGCR8 in Idiopathic Sudden Sensorineural Hearing Loss. AB - OBJECTIVES: The microRNAs have been implicated in the development and function of the inner ear, especially in contribution to hearing. However, the impact of idiopathic sudden sensorineural hearing loss (SSNHL) on expression of miRNA biogenesis-related components has not been established. To investigate the regulations of microRNA (miRNA) biogenesis-related components, argonaute 2 (AGO2) and DiGeorge syndrome critical region gene 8 (DGCR8) mRNA expression in SSNHL and to evaluate the value of clinical parameters on their expression. METHODS: Thirty seven patients diagnosed with SSNHL and fifty-one healthy volunteers were included in this study. We measured mRNA expression levels of AGO2 and DGCR8 in whole blood cells but erythrocytes of patients with SSNHL and controls, using reverse transcription and real-time polymerase chain reaction analysis. RESULTS: The mRNA expression level of AGO2 is upregulated in SSNHL. The expression level of AGO2 was significantly correlated with that of DGCR8 in both patients with SSNHL and controls. Expression level of AGO2 in SSNHL was correlated with white blood cell counts. CONCLUSION: This study demonstrated for the first time that the AGO2 mRNA expression level was upregulated in SSNHL, suggesting its important role in pathobiology of SSNHL development. PMID- 25436046 TI - Dexmedetomidine preconditioning attenuates Cisplatin-induced ototoxicity in zebrafish. AB - OBJECTIVES: Utilisation of high-frequency drills is known to increase noise induced hearing loss due to increasing the damages of inner ear cells. This study aimed to investigate whether preconditioning by using dexmedetomidine (DEX) decreased the occurrence of ischemia in inner cells of the ear. METHODS: We utilised a transgenic zebrafish line Brn3C, and the embryos were collected from breeding adult zebrafish. Five-day-old larvae were cultured at the density of 50 embryos, and the larvae were classified into 4 groups: control, cisplatin group, DEX group, and DEX+yohimbine; adrenoreceptor blocker group. The DEX group was categorised into 3 subgroups by dosage; 0.1, 1, and 10 uM. Preconditioning was performed for 150 minutes and then exposed to cisplatin for 6 hours. The experiment was performed in 7 replicates for each group and the number of hair cells in 3 parts of the neuromasts of each fish was determined. RESULTS: Hair cell apoptosis by cisplatin was attenuated more significantly in the DEX preconditioning group than in the control group. However, the preconditioning effects were not blocked by yohimbine. CONCLUSION: The results of this study suggest that hearing loss caused by vibration-induced noise could be reduced by using DEX and may occur through other mechanisms rather than adreno-receptors. PMID- 25436047 TI - Isosorbide concentration in perilymph of the Guinea pig after oral administration versus that after round window perfusion. AB - OBJECTIVES: The aims of this study were to investigate the feasibility of isosorbide delivery into perilymph through the round window membrane (RWM), and to compare the intracochlear isosorbide concentration in perilymph after oral administration (PO) versus that after round window perfusion (RWP). METHODS: Sixteen male guinea pigs (32 ears) were used. Isosorbide, an osmotic diuretic, was administered via RWP or PO. First, to investigate the optimal perfusion time, perilymph sampling of scala tympani from the RWM was performed after RWP for 15, 30, or 60 minutes. Second, to compare the drug concentration after RWP versus that after PO, perilymph was aspirated at 3 and 6 hours after administration. Intracochlear concentration of isosorbide was analyzed by high-performance liquid chromatography coupled to refractive index detection. RESULTS: Isosorbide passed through the RWM into perilymph after RWP. After RWP for 15, 30, and 60 minutes, mean isosorbide concentrations in perilymph were 116.27+/-44.65, 245.48+/-112.84, and 279.78+/-186.32 mM, respectively. The intracochlear concentration after RWP for 30 minutes was higher than that after RWP for 15 minutes (P=0.043). At 3 and 6 hours after PO, isosorbide concentrations in perilymph were 28.88+/-4.69 and 12.67+/-2.28 mM, respectively. In contrast, the corresponding concentrations after RWP were 117.91+/-17.70 and 75.03+/-14.82 mM at 3 and 6 hours, respectively. Isosorbide concentrations in perilymph following RWP were significantly higher than those following PO at both 3 and 6 hours (P=0.025 and P=0.034, respectively). CONCLUSION: Isosorbide can rapidly pass through the RWM after RWP in guinea pigs, and 30 minutes of perfusion is considered to be appropriate. In addition, over a 6-hour period, RWP can deliver higher concentrations of isosorbide into perilymph than those achieved with PO. PMID- 25436048 TI - Protective effect of metformin on gentamicin-induced vestibulotoxicity in rat primary cell culture. AB - OBJECTIVES: One of the antidiabetic drugs, metformin, have shown that it prevented oxidative stress-induced death in several cell types through a mechanism involving the opening of the permeability transition pore and cytochrome c release. Thus, it is possible that the antioxidative effect of metformin can also serve as protection against gentamicin-induced cytotoxicity related to reactive oxygen species (ROS). The aim of this study was to examine the protective effect of metformin on gentamicin-induced vestibulotoxicity in primary cell culture derived from rat utricle. METHODS: For vestibular primary cell culture, rat utricles were dissected and incubated. Gentamicin-induced cytotoxicity was measured in both the auditory and vestibular cells. To examine the effects of metformin on gentamicin-induced cytotoxicity in the primary cell culture, the cells were pretreated with metformin at a concentration of 1 mM for 24 hours, and then exposed to 2.5 mM gentamicin for 48 hours. The intracellular ROS level was measured using a fluorescent dye, and also measured using a FACScan flow cytometer. Intracellular calcium levels in the vestibular cells were measured with calcium imaging using Fura-2 AM. RESULTS: Vestibular cells were more sensitive to gentamicin-induced cytotoxicity than auditory hair cells. Metformin protects against gentamicin-induced cytotoxicity in vestibular cells. Metformin significantly reduced a gentamicin-induced increase in ROS, and also reduced an increase in intracellular calcium concentrations in gentamicin-induced cytotoxicity. CONCLUSION: Metformin significantly reduced a gentamicin-induced increase in ROS, stabilized the intracellular calcium concentration, and inhibited gentamicin-induced apoptosis. Thus, Metformin showed protective effect on gentamicin-induced cytotoxicity in vestibular primary cell culture. PMID- 25436049 TI - Role of caffeic Acid on collagen production in nasal polyp-derived fibroblasts. AB - OBJECTIVES: Caffeic acids are known to have anti-oxidant, anti-inflammatory, immunomodulatory, and tissue reparative effects. The purposes of this study were to determine the effect of caffeic acid on transforming growth factor (TGF) beta1 induced myofibroblast differentiation and collagen production, and to determine whether caffeic acid is involved in the antioxidant effect in nasal polyp-derived fibroblasts (NPDFs). METHODS: NPDFs were pretreated with caffeic acid (1-10 uM) for 2 hours and stimulated with TGF-beta1 (5 ng/mL) for 24 hours. The expression of alpha-smooth muscle actin (SMA), collagen types I and III, and Nox4 mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of alpha-SMA protein was determined by actin ned by immunofluorescence microscopy. The amount of total soluble collagen production was analyzed by the Sircol collagen dye-binding assay. The reactive oxygen species (ROS) generated by NPDFs were determined using 2',7'-dichlorfluorescein-diacetate. siNox4 was used to determine the effect of Nox4. RESULTS: The expression of alpha-SMA and production of collagen were significantly increased following TGF-beta1 treatment. In contrast, the level of expression of alpha-SMA and the level of production of collagen were decreased by pretreatment with caffeic acid. The activation of Nox4 and the subsequent production of ROS were also reduced by pretreatment with caffeic acid. The expression of alpha-SMA was prevented by inhibition of ROS generation with siNox4. CONCLUSION: Caffeic acid may inhibit TGF-beta1-induced differentiation of fibroblasts into myofibroblasts and collagen production by regulating ROS. PMID- 25436050 TI - Surgical management of rhinosinusitis in onco-hematological patients. AB - OBJECTIVES: In onco-hematological diseases, the incidence of paranasal sinuses infection dramatically increase and requires a combination of medical and surgical therapy. Balloon dilatation surgery (DS) is a minimally invasive, tissue preserving procedure. The study evaluates the results of DS for rhinosinusitis in immunocompromised patients. METHODS: A retrospective chart review was conducted in 110 hematologic patients with rhinosinusitis. Twenty-five patients were treated with DS technique and 85 patients with endoscopic sinus surgery (ESS). We considered the type of anesthesia and the extent of intra- and postoperative bleeding. Patients underwent Sino-Nasal Outcome Test (SNOT-20) to evaluate changes in subjective symptoms and global patient assessment (GPA) questionnaire to value patient satisfaction. RESULTS: Local anesthesia was employed in 8 cases of DS and in 15 of ESS. In 50 ESS patients, an anterior nasal packing was placed and in 12 cases a repacking was necessary. In the DS group, nasal packing was required in 8 cases and in 2 cases a repacking was placed (P=0.019 and P=0.422, respectively). The SNOT-20 change score showed significant improvement of health status in both groups. However the DS group showed a major improvement in 3 voices: need to blow nose, runny nose, and facial pain/pressure. The 3-month follow-up GPA questionnaire showed an higher satisfaction of DS group. CONCLUSION: Balloon DS represents a potentially low aggressive treatment and appears to be relatively safe and effective in onco-hematologic patients. All these remarks may lead the surgeon to consider a larger number of candidates for surgical procedure. PMID- 25436051 TI - Comparison of clonidine and midazolam premedication before endoscopic sinus surgery: results of clinical trial. AB - OBJECTIVES: Premedication with clonidine has been found to reduce the bleeding during endoscopic sinus surgery (ESS), therefore lowering the risk of surgical complications. Premedication is an essential part of pre-surgical care and can potentially affect magnitude of systemic stress response to a surgical procedure. The aim of this study was to compare the efficacy of premedication with clonidine and midazolam in patients undergoing sinus surgery. METHODS: Forty-four patients undergoing ESS for chronic sinusitis and polyp removal were enrolled and randomly assigned to receive either oral clonidine or midazolam as a premedication before receiving propofol/remifentanil total intravenous anesthesia. The effect of this premedication choice on anesthetic requirements, intraoperative hemodynamic profile, preoperative anxiety and sedation as well as postoperative pain and shivering were examined in each premedication group. RESULTS: Total intraoperative remifentanil requirement was lower in the clonidine group as compared to the midazolam group 503.2+/-147.0 ug vs. 784.5+/-283.8 ug, respectively (P<0.001). There was no difference between groups in required induction dose of propofol, level of preoperative anxiety, level of sedation and postoperative shivering. Intraoperative systemic blood pressure and heart rate response had a more favorable profile in patients premedicated with clonidine. Postoperative pain assessed by visual analogue scale for pain was lower in the clonidine group compared with to the midazolam premedication group. CONCLUSION: Premedication with clonidine provides better attenuation of hemodynamic response and reduction of intraoperative remifentanil requirements in patients undergoing ESS. Postoperative pain seems to be better controlled after clonidine premedication as well. PMID- 25436052 TI - Preoperative subclinical hyperthyroidism in patients with papillary thyroid carcinoma. AB - OBJECTIVES: Numerous studies have reported the effects of subclinical hyperthyroidism on the cardiovascular system, osteoporosis, and metabolic syndrome. However, there are few studies examining the relationships between subclinical hyperthyroidism and thyroid cancer. The aim of this study was to investigate the relationships between preoperative subclinical hyperthyroidism and clinicopathological characteristics in patients with papillary thyroid carcinoma (PTC) in terms of thyroid-stimulating hormone (TSH) levels and TSH receptor antibody (TRAb) values. METHODS: Between January 2001 and December 2007, 462 patients were eligible for analysis in our study; we compared the clinicopathological characteristics of 39 preoperative subclinical hyperthyroidism patients with those of 423 euthyroid patients. RESULTS: There were no statistical differences between the 2 groups with respect to age, male to female ratio, primary tumor size, extrathyroidal extension (ETE), multifocality, lymph node metastasis, TNM and AMES stages, recurrence, and survival, despite significant difference in TSH concentrations between the 2 groups. In the evaluation for TRAb, primary tumor size was significantly larger in patients with normal TRAb than in patients with elevated TRAb. When the patients were subdivided into 4 categories according to TRAb values (<5.0%; 5.0%-10.0%; 10.1% 15.0%; >15.0%), tumor size and ETE were significantly different. However, we could not find linear relationships in the increase or decrease of TRAb values. CONCLUSION: The results of our study suggest that subclinical hyperthyroidism is not independently associated with tumor aggressiveness and prognosis in PTC in spite of reduced TSH levels and increased TRAb values as compared with euthyroid patients. PMID- 25436053 TI - Mapping regional laryngopharyngeal mechanoreceptor response. AB - OBJECTIVES: To map mechanoreceptor response in various regions of the laryngopharynx. METHODS: Five patients with suspected laryngopharyngeal reflux and six healthy control subjects underwent stimulation of mechanoreceptors in the hypopharynx, interarytenoid area, arytenoids, aryepiglottic folds, and pyriform sinuses. The threshold stimuli evoking sensation and eliciting laryngeal adductor reflex were recorded. RESULTS: In controls, an air pulse with 2 mmHg pressure evoked mechanoreceptor response in all regions, except bilateral aryepiglottic folds of one control. In patients, stimulus intensity to elicit mechanoreceptor response ranged between 2 mmHg and 10 mmHg and varied among the regions. Air pulse intensity differed between right and left sides of laryngopharyngeal regions in the majority of patients. CONCLUSION: Laryngopharyngeal mechanoreceptor response was uniform among regions and subjects in the healthy group. Patients with suspected laryngopharyngeal reflux showed inter- and intra regional variations in mechanoreceptor response. Laryngopharyngeal sensory deficit in patients with suspected laryngopharyngeal reflux is not limited to aryepiglottic folds. PMID- 25436054 TI - Long-term results of endoscopic dilatation for tracheal and subglottic stenosis. AB - OBJECTIVES: The purpose of this study was to assess the long-term results of endoscopic dilatation of airway stenosis and to evaluate predictive factors for favorable results. METHODS: Fifty-four patients with tracheal and subglottic stenosis who underwent endoscopic dilatation with at least 12 months follow-up were enrolled in this study. We evaluated predictive factors for final treatment outcome such as stenosis length, location, characteristics, procedure type, and the severity of stenosis. RESULTS: The final outcome of endoscopic dilatation showed a cure rate of 40.7%, improvement rate of 46.3%, and failure rate of 13.0%. Patients with mild stenosis or a shorter stenotic segment and those who underwent a touch-up procedure following tracheal resection with end-to-end anastomosis showed better outcomes. The cure rate of endoscopic dilatation for patients with shorter mild stenosis was 72.2%. CONCLUSION: Endoscopic dilatation may be a primary treatment modality for patients with airway stenosis characterized by mild severity and a short stenotic segment. PMID- 25436055 TI - Real-time video-assisted retrieval of airway foreign body in very young pediatric patients. AB - OBJECTIVES: Advancements in medical endoscopy and techniques of rigid bronchoscopy for foreign body removal have enabled higher diagnostic accuracy, reduced morbidity and precise manipulation. However, in pediatric patients, endoscope-combined forceps may be too big to fit into the small sized airway. Here we present our method of endoscope assisted rigid bronchoscopy in pediatric patients and compare the clinical benefits with conventional naked-eye rigid bronchoscopy. METHODS: We used a 2.7 mm, 0 degrees straight endoscope and small caliber grasping forceps with 3.0 to 4.5 mm sized rigid bronchoscopy for very young (<3 years of age) patients of foreign body aspiration. As an assistant held the rigid bronchoscope in situ, the operator could manipulate the endoscope and forceps bimanually. With endoscopic guidance, the foreign body retrieval was performed carefully. The clinical advantages were compared between our endoscope assisted method (n=29) and the conventional bronchoscopy method (n=33) in terms of operation time and recovery (hospital stay). RESULTS: Bimanual endoscope assisted rigid bronchoscopy method was technically feasible and safe. The operation time was less, compared to the conventional technique and the patients recovered more quickly. In all cases, our method completely removed the foreign body without need of a second bronchoscopy procedure. CONCLUSION: Bimanual endoscope-assisted retrieval of airway foreign body in very young age pediatric patients was superior to the conventional naked-eye method concerning accurate manipulation and safety. PMID- 25436056 TI - Vegetable or pulse granuloma in the nasal cavity. AB - Vegetable granuloma or pulse granuloma results from the implantation of food particles of vegetable origin. Pulse granulomas have mainly been reported in association with lung aspirations, the oral cavity with a history of oral procedures and less frequently in gastrointestinal tracks. We report a 31-year old woman who presented with right nasal obstruction and was found to have a firm mass in the right nasal cavity. Paranasal sinus computerized tomography scans identified a calcified ring lesion in her right nasal cavity. Endoscopic sinus surgery was performed, and pathology examination revealed a lesion consistent with a pulse granuloma that contains starch granules with cellulose envelopes appearing as hyaline rings surrounded by inflammation cells and concentrically arranged delicate connective tissue. Pulse granuloma is a well described entity with distinct histopathology. However, pulse granulomas are rare, and especially extraoral pulse granulomas are extremely rare. We found that pulse granuloma can be occurred in the nasal cavity through regurgitation. PMID- 25436057 TI - Endoscopic-Assisted Total Thyroidectomy via Lateral Keloid Scar Incision. AB - Thyroidectomy is traditionally performed by the transcervical approach. To avoid or reduce visible scarring, diverse innovative surgical trials have been reported. Here we report a patient who underwent endoscopic thyroidectomy via a lateral keloid scar due to a previous traffic accident. A 30-year-old woman presented with a papillary thyroid carcinoma. Total thyroidectomy was performed via a keloid scar incision. The keloid scar was then revised. The total thyroidectomy was successful, resulting in no acute complications, such as neural injury, hematoma, or seroma formation. The keloid scar healed with excellent cosmetic results and the patient remains free of disease 12 months after excision. Endoscopic total thyroidectomy via a lateral keloid scar incision healed not only the physical disease but also the mental disease. PMID- 25436058 TI - Complications of medial unicompartmental knee arthroplasty. AB - BACKGROUND: We report intra- and postoperative complications of unicompartmental knee arthroplasty (UKA). METHODS: This study was conducted on 246 cases of UKA which were performed for degenerative osteoarthritis confined to the medial compartment, from May 2002 to May 2010, for which follow-up periods longer than one year were available. Complications were divided into intra- and postoperative complications. Pre- and postoperative clinical scores, the range of motion, and radiologic findings were analyzed. RESULTS: Complications developed in a total of 24 cases (9.8%, 24/246). Among them, 6 cases had intraoperative complications while 18 had postoperative complications. Among the 6 intraoperative complications, one fracture of the medial tibial condyle, two fractures of the intercondylar eminence, one rupture of the medial collateral ligament, one widening of the peg hole leading to femoral component malposition and late failure, and one total knee arthroplasty (TKA) conversion of a large bony defect of tibial avascular necrosis were observed. Among the 18 postoperative complications, four cases of aseptic loosening of the femoral component, one soft tissue impingement due to malalignment, nine cases of polyethylene bearing dislocation, one case of suprapatellar bursitis, one periprosthetic fracture, one TKA conversion due to medial component overhanging, and one TKA conversion due to pain of unexplained cause were observed. CONCLUSIONS: The mid-term clinical outcomes of UKA were excellent in our study. However, the incidence of complications was very high (9.8%). To prevent intra- and postoperative complications, proper selection of the patients and accurate surgical techniques are required. PMID- 25436059 TI - Patella resurfacing during total knee arthroplasty: have we got the issue covered? AB - BACKGROUND: Management of the patella during total knee arthroplasty (TKA) is controversial. Multiple studies have examined mechanical and clinical results of TKA with native and resurfaced patellae with no clear consensus. METHODS: We surveyed a large cohort of consultant surgeons in a questionnaire based study in order to assess the indications for patella resurfacing and to correlate practice with degree of specialization, experience and volume of procedures performed. RESULTS: Six hundred and nineteen surgeons were included. The main indication for patella resurfacing was patellofemoral arthritis. The ratio of those who always:sometimes:never resurfaced was 1:2:1 irrespective of experience or volume performed. There was no difference between knee specialists and non-specialists (p = 0.977) or between high and lower volume surgeons (p = 0.826). Senior and high volume surgeons tended to always resurface. CONCLUSIONS: The majority of surgeons only sometimes resurfaced the patella. The number who always and never resurfaced were similar. There was a tendency for more experienced and high volume surgeons to always resurface. PMID- 25436060 TI - Association of COL2A1 gene polymorphism with degenerative lumbar scoliosis. AB - BACKGROUND: Degenerative lumbar scoliosis (DLS) progresses with aging after 50-60 years, and the genetic association of DLS remains largely unclear. In this study, the genetic association between collagen type II alpha 1 (COL2A1) gene and DLS was investigated. METHODS: COL2A1 gene polymorphism was investigated in DLS subjects compared to healthy controls to investigate the possibility of its association with COL2A1 gene. Based on a single nucleotide polymorphism (SNP) database, SNP (rs2276454) in COL2A1 were selected and genotyped using direct sequencing in 51 patients with DLS and 235 healthy controls. The SNP effects were analyzed using three models of codominant, dominant, and recessive. Logistic regression models were calculated for odds ratios (ORs) with 95% confidence intervals (CIs) and corresponding p-values, controlling age and gender as co variables. RESULTS: SNP (rs2276454) in COL2A1 was significantly associated with the degenerative lumbar scoliosis in the codominant (OR, 1.90; 95% CI, 1.17 to 3.10; p = 0.008) and dominant models (OR, 3.58; 95% CI, 1.59 to 9.29; p = 0.001). CONCLUSIONS: The results suggest that COL2A1 is associated with the risk of DLS in Korean population. PMID- 25436062 TI - The factors affecting pain pattern after arthroscopic rotator cuff repair. AB - BACKGROUND: We evaluated the factors that affect pain pattern after arthroscopic rotator cuff repair. METHODS: From June 2009 to October 2010, 210 patients underwent arthroscopic rotator cuff repair operations. Of them, 84 patients were enrolled as subjects of the present study. The evaluation of postoperative pain was conducted by visual analog scale (VAS) scores during postoperative outpatient interviews at 6 weeks, 3 months, 6 months, and 12 months. The factors that were thought to affect postoperative pain were evaluated by dividing into three categories: preoperative, operative, and postoperative. RESULTS: Pain after arthroscopic rotator cuff repair surgery showed a strictly decreasing pain pattern. In single analysis and multiple regression tests for factors influencing the strictly decreasing pain pattern, initial VAS and pain onset were shown to be statistically significant factors (p = 0.012, 0.012, 0.044 and 0.028, respectively). With regard to the factors influencing lower than average intensity pain pattern for each period, the stiffness of internal rotation at 3 months postoperatively was shown to be a statistically significant factor in single and multiple regression tests (p = 0.017 and p = 0.004, respectively). CONCLUSIONS: High initial VAS scores and the acute onset of pain affected the strictly decreasing postoperative pain pattern. Additionally, stiffness of internal rotation at postoperative 3 months affected the higher than average intensity pain pattern for each period after arthroscopic rotator cuff repair. PMID- 25436063 TI - Arthrodesis of distal interphalangeal joints in the hand with interosseous wiring and intramedullary K-wire fixation. AB - BACKGROUND: To evaluate the efficacy of intramedullary K-wire fixation and interosseous wiring in the arthrodesis of the distal interphalangeal (DIP) joint with description of surgical procedure. METHODS: We retrospectively analyzed 9 cases (7 women and 2 men) of DIP joint arthrodesis. The average age of patients was 44.2 years (range, 21 to 71 years) and the mean follow-up period was 19.6 months. Joint union was evaluated on the follow-up radiographs together with postoperative complications. RESULTS: All cases achieved radiologic union of the arthrodesis site. There was no surgical complication except for one case of skin irritation by the interosseous wire knot which was removed during the follow-up period. CONCLUSIONS: Intramedullary K-wire fixation and interosseous wiring could be an alternative procedure of arthrodesis in the DIP joint. PMID- 25436061 TI - The prevalence of lumbar spine facet joint osteoarthritis and its association with low back pain in selected Korean populations. AB - BACKGROUND: This study was to evaluate the association of lumbar spine facet joint osteoarthritis (LSFJOA) identified by multi-detector computed tomography (MDCT) with age and low back pain (LBP) in an adult community-based population in Korea. METHODS: A sample of 472 participants (age range, 20 to 84 years) who underwent MDCT imaging for abdominal or urological lesions, not for chief complaints of LBP, were included in this study. LSFJOA based on MDCT findings was characterized using four grades of osteoarthritis of the facet joints. The prevalence of LSFJOA according to age group (below 40 years, 40-49 years, 50-59 years, 60-69 years, and above 70 years), gender, and spinal level was analyzed using chi-square tests and the association between LBP and LSFJOA adjusting for age, gender, and spine level was analyzed using multiple binary logistic regression test. RESULTS: Eighty-three study subjects (17.58%) had LSFJOA (grade >= 2). The prevalence of LSFJOA was not associated with gender (p = 0.092). The prevalence of LSFJOA increased with age (p = 0.015). The highest prevalence of LSFJOA was observed at L4-5 in men (p = 0.001) and at L5-S1 in women (p = 0.003), and at L5-S1 in the overall population (p = 0.000). LSFJOA was not associated with LBP in men (p = 0.093) but was associated with LBP in women (p = 0.003), especially at L3-4 (p = 0.018) and L5-S1 (p = 0.026). CONCLUSIONS: The prevalence of LSFJOA based on the computed tomography imaging was 17.58% in the adult community Korean population. The prevalence of LSFJOA increased with age, and the highest prevalence was noted at L5-S1. LSFJOA was not associated with LBP at any spinal level and age except at L3-4 and L5-S1 in women. PMID- 25436064 TI - Surgical release of the first extensor compartment for refractory de Quervain's tenosynovitis: surgical findings and functional evaluation using DASH scores. AB - BACKGROUND: Few studies have evaluated surgical outcomes in patients with refractory de Quervain's disease using validated outcome measures. We assessed the clinical outcomes of dorsal release of the first extensor compartment for the treatment of de Quervain's disease using the disabilities of the arm, shoulder and hand (DASH) score. METHODS: From October 2003 to May 2009, we retrospectively evaluated 33 patients (3 men and 30 women) who underwent surgical treatment for de Quervain's disease. All patients had a positive Finkelstein test and localized tenderness over the first dorsal compartment. All operations were performed under local anesthesia. A 2-cm-long transverse skin incision was made over the first extensor compartment and the dorsal retinaculum covering the extensor pollicis brevis was incised longitudinally. Preoperative and postoperative clinical evaluation included the use of DASH score, Finkelstein test, and visual analogue scale (VAS) score. RESULTS: In 18 patients (55%), the extensor pollicis brevis tendon compartment was separated from the abductor pollicis longus compartment. Eight patients had intracompartmental ganglia in the extensor pollicis brevis subcompartment. All patients except one had negative sign on Finkelstein test at the last follow-up. The average VAS score decreased from 7.42 preoperatively to 1.33 postoperatively (p < 0.05), and DASH score was improved from 53.2 to 3.45 (p < 0.05). There were no postoperative complications such as subluxation of the tendon of the first dorsal compartment or injury to the sensory branch of the radial nerve. CONCLUSIONS: Intracompartment ganglia and the separate septum of extensor pollicis brevis are often related to de Quervain's disease. The release of the first extensor compartment for refractory de Quervain's disease resulted in good clinical outcomes with minimal morbidity. PMID- 25436065 TI - Salient features of the Maasai foot: analysis of 1,096 Maasai subjects. AB - BACKGROUND: The Maasai are the most widely known African ethnic group located in Kenya and northern Tanzania. Most spend their days either barefoot or in their traditional shoes made of car tires. Although they walk long distances of up to sixty kilometers a day, they do not suffer from any foot ailments. Little is known about their foot structure and gait. The goal of this investigation was to characterize various aspects of Maasai foot in standing and walking. METHODS: Foot length, calf circumference, hindfoot alignment, step length, cadence, and walking velocity were obtained from 1,096 adult Maasai people (545 males and 551 females; mean age, 40.28 +/- 14.69 years; age range, 16 to 65 years). All included subjects were from rural areas, where the primary terrain was sandy soil, who spend most of their lifetime barefoot, walking. They all denied any medical history or previous symptoms related to foot problems. A trained clinician scanned all feet for deformities. Static (standing) and dynamic (walking) Harris mat footprints were taken to determine the distribution of forefoot pressure patterns during walking. RESULTS: The average foot length was 250.14 +/- 18.12 mm (range, 210 to 295 mm) and calf circumference was 32.50 +/- 3.22 cm (range, 25 to 41 cm). The mean hindfoot alignment was 6.21 degrees +/- 1.55 degrees of valgus. Sixty-four subjects (5.84%) had bilateral flat-shaped feet with a low medial longitudinal arch that exactly matched the broad pattern of their static footprints. Step length, cadence, and walking velocity were 426.45 +/- 88.73 cm (range, 200 to 690 cm), 94.35 steps/min (range, 72 to 111 steps/min), and 40.16 +/- 8.36 m/min (range, 18.20 to 63.36 m/min), respectively. A total of 83.39% subjects showed unilateral or bilateral deformities of multiple toes regardless of age. The most frequent deformity was clawing (98.79%) of which the highest incidence occurred with the fifth toe (93.23%). Dynamic footprints showed even pressure patterns throughout the forefoot (64.87%), followed by lateral forefoot pressure concentration patterns (21.81%). CONCLUSIONS: Our study shows the distinct parameters that provide more insight into the Maasai foot. PMID- 25436066 TI - The relationship between osteoarthritis of the knee and bone mineral density of proximal femur: a cross-sectional study from a Korean population in women. AB - BACKGROUND: The relationship between osteoarthritis (OA) and osteoporosis (OP) is complicated and it may differ according to the site or stage of disease. The purpose of this cross-sectional study is to examine the relationship between the severity of radiological knee OA and the degree of OP in the ipsilateral proximal femur as denoted by bone mineral density (BMD) in a Korean population, especially among women. METHODS: One hundred ninety-five female patients who had knee pain and radiological knee OA were investigated with respect to the relationship of knee OA severity with BMD. The BMD of the proximal femur and spine was measured by dual energy X-ray absorptiometry, and the severity of knee OA was evaluated based on Kellgren-Lawrence (K-L) radiographic criteria, joint space narrowing (JSN) and mechanical axis of knee alignment. Partial correlation analysis and ANCOVA adjusted for confounding factors (age and body mass index) were performed to assess the relationship. RESULTS: There was a statistically significant relationship between the BMD of the proximal femur and JSN, and the BMD of the proximal femur was positively associated with increased joint space width. There was a lack of association between the spine BMD and JSN. The BMD of the proximal femur was also significantly lower in patients who had a higher K-L grade. CONCLUSIONS: The radiographic finding of severe OA in the knee is associated with decreased BMD of the ipsilateral proximal femur including the femoral neck, trochanter, intertrochanter, and region of the entire hip (neck, trochanter, and Ward's triangle). PMID- 25436068 TI - Pattern of fractures in non-accidental injuries in the pediatric population in Singapore. AB - BACKGROUND: Fractures as a result of non-accidental injuries (NAI) are not uncommon among children. The purpose of our study was to describe the incidence, demographic characteristics, and associated risk factors in patients with NAI in a multiethnic Asian cohort. METHODS: A retrospective record review of patients admitted to our hospital between September 2007 and 2009 with the diagnosis of NAI was conducted. RESULTS: A total of 978 children were reported with suspicion of NAI. Among them, 570 patients (58.28%) were diagnosed with NAI. Fractures were observed in 35 children (6.14%). NAI fractures were highest among female infants (73.3%). The biological father was the most common known perpetrator of NAI (n = 155, 29.0%). The most common perpetrator sadly remained unknown (n = 14, 40%). All NAI fractures were closed (n = 35, 6.14%), and the most commonly affected bone was the humeral shaft (n = 10, 28.57%) with an oblique configuration. Age < 1 year and parental divorce were significant risk factors associated with these fractures. CONCLUSIONS: The skeletal injury pattern and risk factors highlighted in our study will help treating physicians identify patients susceptible to NAI, as many of these patients are young and vulnerable. Protective measures can be initiated early by recognizing these injuries and preventing further physical and psychological harm to the child. PMID- 25436067 TI - Anterior knee pain in patients with cerebral palsy. AB - BACKGROUND: The aim of this study was to identify the risk factors for anterior knee pain in patients with cerebral palsy. METHODS: This prospective study investigated the risk factors for anterior knee pain in 127 ambulatory patients with spastic cerebral palsy in terms of walking pain, resting pain, and provocative pain. Demographic data analysis and physical examination for measuring the knee flexion contracture and unilateral and bilateral popliteal angles were performed. Patellar height was measured on radiographs, and patella alta was identified. The risk factors for anterior knee pain were analyzed using multivariate analysis with a generalized estimating equation. RESULTS: Seventy seven patients were found to have patella alta based on the radiographic measurements (60.6%). Overall, sixteen patients (12.6%) had either unilateral or bilateral anterior knee pain. Of these, 6 patients showed a visual analogue scale (VAS) <= 3, 9 patients showed 3 < VAS <= 7, and one patient showed a VAS > 7. Age was found to be a significant risk factor for walking pain and resting pain with odds ratios (ORs) of 1.08 (95% confidence interval [CI], 1.02 to 1.14) and 1.09 (95% CI, 1.03 to 1.15), respectively. In the multivariate analysis, knee flexion contracture was a significant protective factor with an OR of 0.92 (95% CI, 0.85 to 0.98). CONCLUSIONS: Approximately 12.6% of ambulatory patients with spastic cerebral palsy were found to have anterior knee pain in our hospital-based cohort study. Age was found to be a significant risk factor for anterior knee pain while walking and resting. PMID- 25436069 TI - The analysis of treatment of aggressive fibromatosis using oral methotrexate chemotherapy. AB - BACKGROUND: Aggressive fibromatosis is a rare but invasive tumor infiltrating widely between fascia and muscle fibers. It has a high tendency to be locally recurrent despite complete resection. Effectiveness of adjuvant treatment for aggressive fibromatosis including radiotherapy, pharmacological agents, hormonal treatments, and chemotherapy have been previously reported. The purpose of this article was to collect and analyze all information regarding the effectiveness and side effects of oral methotrexate in aggressive fibromatosis. METHODS: From 2005 to 2011, eleven patients with aggressive fibromatosis treated with oral methotrexate at our institution were analyzed in this study. Oral methotrexate was administered once per week at 10 mg per week. Authors collected information about effectiveness concerning cases of local recurrence and metastasis. RESULTS: Eleven patients had remission, two patients had local recurrence. Fatal complications or toxicity were not observed. CONCLUSIONS: Oral methotrexate given at this dose and schedule was considered as a useful treatment in primary inoperable fibromatosis and recurrent fibromatosis. PMID- 25436071 TI - The effect of poloxamer 407-based hydrogel on the osteoinductivity of demineralized bone matrix. AB - BACKGROUND: Demineralized bone matrix (DBM) is used for bone healing due to its osteoinductivity, but it requires a carrier for clinical application. Here, we report the effects on the osteoinductivity of DBM by use of a poloxamer 407-based hydrogel as the carrier, compared to sterile water. METHODS: DBM-W and DBM-H represent 27 wt% of DBM with sterile water and DBM with a poloxamer 407-based hydrogel, respectively. Both of the compositions were applied to human mesenchymal stem cell (MSC) cultures, and monitored for alkaline phosphatase (ALP) staining and ALP activity. Six 10-week-old athymic nude rats were used for abdominal muscle grafting with either DBM-W or DBM-H, and were tested by plane radiography, microfocus X-ray computed tomography (CT), and decalcified histology to evaluate ectopic bone formation. RESULTS: The DBM-W group showed stronger ALP staining at 7, 14, and 21 days of treatment, and significantly higher ALP activity at 7 and 14 days of treatment, compared to the DBM-H group. Plane radiography could not confirm the radio-opaque lesions in the rat ectopic bone formulation model. However, ectopic bone formation was observed in both groups by micro-CT. Compared to the DBM-H group, the DBM-W group showed higher bone volume, percent bone volume and trabecular number, and the difference in percent bone volume was statistically significant. Decalcified histology found bony tissue with lamellation in both groups. CONCLUSIONS: Our results suggest that poloxamer 407-based hydrogel has efficacy as a DBM carrier since it shows ectopic bone formation, but its effects on the quality and quantity of osteoblastic differentiation in rat abdominal ectopic bone and MSC are considered negative. PMID- 25436072 TI - Robotic and navigation systems in orthopaedic surgery: how much do our patients understand? AB - BACKGROUND: Technology in orthopaedic surgery has become more widespread in the past 20 years, with emerging evidence of its benefits in arthroplasty. Although patients are aware of benefits of conventional joint replacement, little is known on patients' knowledge of the prevalence, benefits or drawbacks of surgery involving navigation or robotic systems. METHODS: In an outpatient arthroplasty clinic, 100 consecutive patients were approached and given questionnaires to assess their knowledge of navigation and robotics in orthopaedic surgery. Participation in the survey was voluntary. RESULTS: Ninety-eight patients volunteered to participate in the survey, mean age 56.2 years (range, 19 to 88 years; 52 female, 46 male). Forty percent of patients thought more than 30% of National Health Service (NHS) orthopaedic operations involved navigation or robotics; 80% believed this was the same level or less than the private sector. One-third believed most of an operation could be performed independently by a robotic/navigation system. Amongst perceived benefits of navigation/robotic surgery was more accurate surgery (47%), quicker surgery (50%), and making the surgeon's job easier (52%). Sixty-nine percent believed navigation/robotics was more expensive and 20% believed it held no benefit against conventional surgery, with only 9% believing it led to longer surgery. Almost 50% would not mind at least some of their operation being performed with use of robotics/navigation. CONCLUSIONS: Although few patients were familiar with this new technology, there appeared to be a strong consensus it was quicker and more accurate than conventional surgery. Many patients appear to believe navigation and robotics in orthopaedic surgery is largely the preserve of the private sector. This study demonstrates public knowledge of such new technologies is limited and a need to inform patients of the relative merits and drawbacks of such surgery prior to their more widespread implementation. PMID- 25436070 TI - Role of matrix metalloproteinase (MMP) 2 and MMP-9 in soft tissue sarcoma. AB - BACKGROUND: We investigated the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in malignant fibrous histiocytoma (MFH), and determined whether these could be useful as prognostic factors. METHODS: Among patients treated from 1993 to 2007, 30 cases of MFH were evaluated. Immunohistochemical staining was performed for MMP-2, MMP-9, TIMP-1, and TIMP-2 using paraffin wax-embedded blocks of MFH tissues. Reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot and zymography were performed using fresh tissues obtained from 17 of the 30 cases. The levels of MMP and TIMP expression were compared between the MFH and normal control groups, and between non-metastatic and metastatic MFH groups. RESULTS: Expression levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 were higher in the MFH group than the control group by RT-PCR, Western blotting, and zymography. Immunohistochemical staining revealed that MMP-2 and MMP-9 protein expression was higher in the metastatic than in the non-metastatic group. The expression levels of MMP-2 and TIMP-1 were significantly higher in the metastatic than in the non-metastatic group (p < 0.05) by RT-PCR. By Western blot analysis, the expression levels of MMP-2, TIMP-1, and TIMP-2 were higher in the metastatic group (p < 0.05), but MMP 9 showed only a slight increase in the metastatic group compared with the non metastatic group (p > 0.05). Finally, gelatin zymography analysis showed that the expression levels of the pro- and active forms of MMP-2 were significantly higher in the metastatic group (p < 0.05), but the expression of the pro- and active forms of MMP-9 showed a slight decrease in the metastatic group (p > 0.05). CONCLUSIONS: These results suggest that MMP-2, MMP-9, TIMP-1, and TIMP-2 may have important roles in the development and progression of MFH, and that the degree of expression of these metalloproteinases and their inhibitors, especially MMP-2, could be useful as prognostic factors related to metastasis in MFH. PMID- 25436074 TI - Total knee arthroplasty in patients with ipsilateral fused hip: a technical note. AB - We report the surgical technique used to perform posterior-stabilized total knee arthroplasty (TKA) in two patients with a well positioned and functional hip arthrodesis. Intraoperatively, the operating table was placed in an increased Trendelenburg position. Episodically, we flexed the foot of the table by 90 degrees to allow maximal knee flexion to facilitate exposure and bone cuts. We opted to resect the patella and tibia first to enable exposure, given the stiffness of the arthritic knee. One patient's medical condition prohibited complex conversion total hip arthroplasty (THA) prior to the TKA. The other patient's scarred soft tissues around the hip, due to chronic infection and multiple operations, made THA risky. The final outcome provided satisfactory results at a minimum of 2 years postoperatively. TKA can be successfully performed with adjustments of table position and modification of the sequence of surgical steps in patients with ipsilateral hip fusion. PMID- 25436073 TI - Comparison of clinical and physiological efficacies of different intermittent sequential pneumatic compression devices in preventing deep vein thrombosis: a prospective randomized study. AB - BACKGROUND: There are few comparative studies about the optimal method of pneumatic compression to prevent deep vein thrombosis (DVT). The aim of this prospective randomized study was to compare venous hemodynamic changes and their clinical influences between two graded sequential compression groups (an alternate sequential compression device [ASCD] vs. a simultaneous sequential compression device [SSCD]). METHODS: In total, 34 patients (68 limbs) undergoing knee and spine operations were prospectively randomized into two device groups (ASCD vs. SSCD groups). Duplex ultrasonography examinations were performed on the 4th and 7th postoperative days for the detection of DVT and the evaluation of venous hemodynamics. Continuous data for the two groups were analyzed using a two tailed, unpaired t-test. Relative frequencies of unpaired samples were compared using Fisher exact test. Mixed effects models that might be viewed as ANCOVA models were also considered. RESULTS: DVT developed in 7 patients (20.6%), all of whom were asymptomatic for isolated calf DVTs. Two of these patients were from the ASCD group (11.8%) and the other five were from the SSCD group (29.4%), but there was no significant difference (p = 0.331). Baseline peak velocity, mean velocity, peak volume flow, and total volume flow were enhanced significantly in both device groups (p < 0.001). However, the degrees of flow and velocity enhancement did not differ significantly between the groups. The accumulated expelled volumes for an hour were in favor of the ASCD group. CONCLUSIONS: Both graded sequential compression devices showed similar results both in clinical and physiological efficacies. Further studies are required to investigate the optimal intermittent pneumatic compression method for enhanced hemodynamic efficacy and better thromboprophylaxis. PMID- 25436075 TI - Myositis ossificans traumatica causing ankylosis of the elbow. AB - Myositis ossificans traumatica is an unusual complication following a muscle contusion injury. A significantly large myositic mass causing ankylosis of the elbow is even rarer. We report a 13-year-old boy who presented with a 14-month history of a fixed elbow with no movement and a palpable bony mass in the anterior aspect of the elbow. He had sustained significant trauma to the affected limb 1 month prior to onset of symptoms, which was managed by native massage and bandaging for 4 weeks. The clinicoradiological diagnosis was suggestive of myositis ossificans, and the myositic mass was completely excised. Histopathology revealed lamellar bone. The 2-year follow-up showed full function of the affected limb and no signs of recurrence. We report this case of clinical interest due to the unusually large myositic mass. PMID- 25436076 TI - Autosomal dominant type I osteopetrosis is related with iatrogenic fractures in arthroplasty. AB - Autosomal dominant osteopetrosis (ADO) is a sclerotic bone disorder due to failure of osteoclasts. ADO poses difficulties during arthroplasty because of the increased chance for iatrogenic fractures due to sclerotic bone. ADO is divided into two types based on radiological findings, fracture risk, and osteoclast activity. These differences suggest less brittle bone in patients with ADO I compared to that of patients with ADO II, which suggests a smaller chance of preoperative fractures during cementless arthroplasty in ADO I compared with that in ADO II. A case of cementless total knee arthroplasty in a patient with ADO I is presented. Total hip arthroplasty was performed during follow-up, and known major problems related to ADO II were experienced. Therefore, the differences between ADO I and ADO II may not be clinically relevant for an iatrogenic fracture during arthroplasty in patients with ADO. PMID- 25436077 TI - Sustainable development of cognitive science and technology ecosystem; an overview to the "human brain project" as a functioning sample. PMID- 25436078 TI - Antidepressant activity of methanolic extract of amaranthus spinosus. AB - INTRODUCTION: Depressive disorder is a prevalent psychiatric disorder, which affects 21% of the world population. The presently using drugs can impose a variety of side-effects including cardiac toxicity, hypopiesia, sexual dysfunction, body weight gain, and sleep disorder. During the last decade, there is a growing interest in the therapeutic effects of natural products on mental disorders. Amaranthus spinosus was investigation for antidepressant activity. METHODS: Antidepressant activity of methanolic extract of Amaranthus spinosus (MEAS) was investigated by using Forced swimming test (FST) and Tail suspension test (TST) models. Escitalopram and Imipramine were used as reference standards. RESULTS: It has been observed from our study that both the MEAS at higher concentration showed significant (p<0.01) reduction in immobility in tail suspension and forced swim model of depression comparable to Escitalopram and Imipramine. DISCUSSION: However further study is needed to understand mechanism of action and to identify active component responsible for antidepressant like activity. PMID- 25436080 TI - Real Time Driver's Drowsiness Detection by Processing the EEG Signals Stimulated with External Flickering Light. AB - The objective of this study is development of driver's sleepiness using Visually Evoked Potentials (VEP). VEP computed from EEG signals from the visual cortex. We use the Steady State VEPs (SSVEPs) that are one of the most important EEG signals used in human computer interface systems. SSVEP is a response to visual stimuli presented. We present a classification method to discriminate between closed eyes and opened eyes. Fourier transforms and power spectrum density features extracted from signals and Multilayer perceptron and radial basis function neural networks used for classification. The experimental results show an accuracy of 97% for test data. PMID- 25436079 TI - Mu opioid receptor gene: new point mutations in opioid addicts. AB - INTRODUCTION: Association between single-nucleotide polymorphisms (SNPs) in mu opioid receptor gene and drug addiction has been shown in various studies. Here, we have evaluated the existence of polymorphisms in exon 3 of this gene in Iranian population and investigated the possible association between these mutations and opioid addiction. METHODS: 79 opioid-dependent subjects (55 males, 24 females) and 134 non-addict or control individuals (74 males, 60 females) participated in the study. Genomic DNA was extracted from volunteers' peripheral blood and exon 3 of the mu opioid receptor gene was amplified by polymerase chain reaction (PCR) whose products were then sequenced. RESULTS: Three different heterozygote polymorphisms were observed in 3 male individuals: 759T > C and 877G > A mutations were found in 2 control volunteers and 1043G > C substitution was observed in an opioid-addicted subject. Association between genotype and opioid addiction for each mutation was not statistically significant. DISCUSSION: It seems that the sample size used in our study is not enough to confirm or reject any association between 759T > C, 877G > A and 1043G > C substitutions in exon 3 of the mu opioid receptor gene and opioid addiction susceptibility in Iranian population. PMID- 25436081 TI - Prevalence of cognitive impairment in community-dwelling older adults. AB - INTRODUCTION: Mild cognitive impairment can be considered as an intermediate clinical state between normal cognitive aging and mild dementia. Elderly people with this impairment represent an at-risk group for the development of dementia. The aim of this study was to investigate the prevalence of cognitive impairment in community-dwelling older adults by Mini-Mental State Examination (MMSE) and its relationship with socio-demographic variables. METHODS: In this analytical descriptive study, 212 subjects admitted to Hamadan's day care centers were selected through simple random sampling method. To gather the data, MMSE was used as well as a questionnaire containing demographic variables. Data analysis was completed through SPSS-16. RESULTS: The sample consisted of 17.9% male, 59.4% of whom were married. According to the results, 96 cases (45.3%) suffered from mild (MMSE>=22), 110 cases (51.9%) from moderate (11<=MMSE<=21) and 6 cases (2.8%) from severe cognitive disorder (MMSE<=10). As findings revealed, factors such as age (Pv = 0.005, r = -0.491) and schooling (Pv < 0.001) are of significant relationship with MMSE score. DISCUSSION: Prevalence of cognitive decline in community-dwelling older adults was of normal range. Hence, familial relations and social support can decrease mental status disorder. PMID- 25436083 TI - Naloxone induces frequent jumping after chronic morphine and methamphetamine co administration in rats. AB - Combined use of an opioid with a psychostimulant is popular among drug abusers. Such "polydrug use" may increase drug effects or attenuate adverse effects of either drug alone. We proposed that a combination of methamphetamine (meth) and morphine may change physical opioid withdrawal symptoms. Adult male rats were chronically injected with cumulative subcutaneous (s.c.) doses of morphine, meth or a combination of both drugs within five days. On day six, a challenge dose of the same drug was injected. Two hours later, precipitated withdrawal symptoms were scored within 30 minutes after naloxone (1mg/kg, i.p.) injection. Both frequency and incidence of jumping significantly increased in combined treated animals (P<0.05). The sole emergent symptom in combined treated animals was digging which we consider as another escaping behavior in addition to jumping. Our findings imply that combined use of meth and morphine may exacerbate averseness of morphine withdrawal which may cause more intense opioid dependence. PMID- 25436082 TI - The Effect of Acute Intra Locus Coeruleus (LC) Microinfusion of Bupropion on Formalin-Induced Pain Behavior in Rat. AB - INTRODUCTION: Inflammatory pain is a common sign of chronic diseases. Some brain regions such as locus coeruleus (LC) of the brainstem nor-epinephrine (NE) system have a key role in The mechanisms of the pain modulation and dependence. Bupropion synthesized as an antidepressant, but it is using for smoke cessation. It can change morphine withdrawal signs such as pain related behaviors. This study tested the acute effect of intra-LC microinfusion of bupropion on the formalin-induced pain behavior in rats. METHODS: Wistar male rats were divided into 6 groups (control-naive, control-operated, shamoperated, and 3 treated groups with 10(-2), 10(-3), 10(-4) mol/ul intra-LC of bupropion). The injection guide cannulae were implanted into LC nuclei bilaterally by stereotaxic coordinated surgery under sterile condition. The sham group received normal saline as drug vehicle but control groups had no intra-LC injections. Formalin (50 ul, 2.5%) was injected subcutaneously in plantar region of the right hindpaw in all animals (30 min after drug administration in treated animals). Nociceptive signs were observed continuously and registered on-line each minute. Common pain scoring was used for pain assessment. RESULTS: The analysis of data by one-way ANOVA showed that bupropion can reduce pain behavior scores significantly. Bupropion reduced total pain score in the phase 01 (60%) and phase 02 (52%) of maximal behavior compared to the sham group, dose dependently and significantly. The pain scores of controls and sham groups had no significant difference. DISCUSSION: The results showed that bupropion has analgesic effects on LC neurons and can alter the neurochemical involvement of LC in pain process. Bupropion has different and significant effect on early and late phases of formalin test. PMID- 25436084 TI - Termination of Nociceptive Bahaviour at the End of Phase 2 of Formalin Test is Attributable to Endogenous Inhibitory Mechanisms, but not by Opioid Receptors Activation. AB - INTRODUCTION: Formalin injection induces nociceptive bahaviour in phase I and II, with a quiescent phase between them. While active inhibitory mechanisms are proposed to be responsible for initiation of interphase, the exact mechanisms which lead to termination of nociceptive response in phase II are not clear yet. Phase II is a consequence of peripheral and central sensitization processes, which can lead to termination of the noxious stimuli responses; 45-60 minutes after formalin injection via possible recruitment of active inhibitory mechanisms which we have investigated in this study. METHODS: To test our hypothesis, in the first set of experiments, we evaluated nociceptive response after two consecutive injection of formalin (50uL, 2%), with intervals of 5 or 60 minutes. In the next set, formalin tests were carried out in companion with injection of Naloxone Hydrochloride, a non-selective antagonist of opioid receptors, pre-formalin injection and 30 and 45 minutes post formalin injection. RESULTS: While normal nociceptive behaviour was observed in the group receiving one injection of formalin, a diminished response was observed in phases I and II of those receiving consequent injection of formalin, 60 minute after first injection. While second injection of formalin, 5 minute after first injection, had no effect. Administration of naloxone (1mg/kg) decreased nociception in phase 2A; but had no effect on delayed termination of formalin test. DISCUSSION: The results of this study suggest the existence of an active inhibitory mechanism, other than the endogenous opioids, that is responsible for termination of nociceptive behaviour at the end of formalin test. PMID- 25436085 TI - Using eye movement analysis to study auditory effects on visual memory recall. AB - Recent studies in affective computing are focused on sensing human cognitive context using biosignals. In this study, electrooculography (EOG) was utilized to investigate memory recall accessibility via eye movement patterns. 12 subjects were participated in our experiment wherein pictures from four categories were presented. Each category contained nine pictures of which three were presented twice and the rest were presented once only. Each picture presentation took five seconds with an adjoining three seconds interval. Similarly, this task was performed with new pictures together with related sounds. The task was free viewing and participants were not informed about the task's purpose. Using pattern recognition techniques, participants' EOG signals in response to repeated and non-repeated pictures were classified for with and without sound stages. The method was validated with eight different participants. Recognition rate in "with sound" stage was significantly reduced as compared with "without sound" stage. The result demonstrated that the familiarity of visual-auditory stimuli can be detected from EOG signals and the auditory input potentially improves the visual recall process. PMID- 25436086 TI - Unilateral Hypothalamus Inactivation Prevents PTZ Kindling Development through Hippocampal Orexin Receptor 1 Modulation. AB - INTRODUCTION: Epilepsy is a neural disorder in which abnormal plastic changes during short and long term periods lead to increased excitability of brain tissue. Kindling is an animal model of epileptogenesis which results in changes of synaptic plasticity due to repetitive electrical or chemical sub-convulsive stimulations of the brain. Lateral hypothalamus, as the main niche of orexin neurons with extensive projections, is involved in sleep and wakefulness and so it affects the excitability of the brain. Therefore, we investigated whether lateral hypothalamic area (LHA) inactivation or orexin-A receptor blocking could change convulsive behavior of acute and kindled PTZ treated animals and if glutamate has a role in this regard. METHODS: Kindling was induced by 40 mg/kg PTZ, every 48 hours up to 13 injections to each rat. Three consecutive stages 4 or 5 of convulsive behavior were used to ensure kindling. Lidocaine was injected stereotaxically to inactivate LHA, unilaterally. SB334867 used for orexin receptor 1 (OX1R) blocking administered in CSF. RESULTS: We demonstrated that LHA inactivation prevented PTZ kindling and hence, excitability evolution. Hippocampal glutamate content was decreased due to LHA inactivation, OX1R antagonist infusion, lidocaine injection and kindled groups. In accordance, OX1R antagonist (SB334867) and lidocaine injection decreased PTZ single dose induced convulsive behavior. While orexin-A i.c.v. infusion increased hippocampal glutamate content, it did not change PTZ induced convulsive intensity. DISCUSSION: It is concluded that LHA inactivation prevented kindling development probably through orexin receptor antagonism. CSF orexin probably acts as an inhibitory step on convulsive intensity through another unknown process. PMID- 25436087 TI - Fluoxetin upregulates connexin 43 expression in astrocyte. AB - INTRODUCTION: Recent studies have shown that astrocytes play major roles in normal and disease condition of the central nervous system including multiple sclerosis (MS). Molecular target therapy studies in MS have revealed that connexin-43 (Cx43) and Aquaporin-4 (AQP4) contents of astrocytes undergo expression alteration. Fluoxetine had some effects in MS patients unrelated to its known antidepressant effects. Some of fluoxetine effects were attributed to its capability of cAMP signaling pathway stimulation. This study aimed to investigate possible acute effects of fluoxetine on Cx43 and AQP4 expression in astrocyte. METHODS: Astrocytoma cells were treated for 24 hours with fluoxetine (10 and 20 ug/ml) with or without adenyl cyclase (AC) and protein kinase A (PKA) inhibition. Cx43 expression at both mRNA and protein levels and AQP4 expression at mRNA level were evaluated. RESULTS: Acquired results showed that fluoxetine with and without AC and PKA inhibition resulted in Cx43 up-regulation both in mRNA and protein levels, whereas AQP4 expression have not changed. DISCUSSION: In conclusion, data showed that fluoxetine alone and in the absence of serotonin acutely up-regulated Cx43 expression in astrocytes that can be assumed in molecular target therapy of MS patients. It seems that cAMP involvement in fluoxetine effects need more researches. PMID- 25436088 TI - Interaction between Analgesic Effect of Nano and Conventional size of Zinc Oxide and Opioidergic System Activity in Animal Model of Acute Pain. AB - INTRODUCTION: Today Nano-medicine tries to produce new drugs to reduce the dosage and side effects of their conventional forms. According to the interaction between zinc and opioidergic system activity, this study has investigated the effect of new kind of zinc supplement, nano zinc oxide (nZnO), in compared to its conventional form (cZnO), in presence and absence of opioidergic system activity on acute pain. METHODS: Adult male Wistar rats (weighting 200+/-20gr) divided into groups: control (receiving saline %0.9), nZnO (1, 5, 10, 20 mg/kg), cZnO (1, 5, 10, 20 mg/kg), naloxone 1mg/kg, morphine 6 mg/kg, and co-injected groups of morphine and/or naloxone with nZnO (5mg/kg) and/or cZnO 10 mg/kg. Hot plate assay was used to evaluation of nociception and post injected latencies were recorded every 30 min for 90 min after I.P. injections of drugs. In co-injected groups latency time recorded after 60 minutes. RESULTS: Data indicated that both of ZnO supplements reduced latency time in dose and time dependent on the effect of nZnO was higher than cZnO. Also these components could improve anti-nociception effect of morphine and naloxone could not change the effect of these supplements. DISCUSSION: It seems that nZnO has more efficacy than its conventional form to showing analgesic effect that probably is related to the physicochemical properties of nZnO. Also may be these supplements have interaction with opioideric system in body. PMID- 25436089 TI - Detection of interleukin-19 mRNA in C57BL/6 mice astroglial cells and brain cortex. AB - INTRODUCTION: Astrocytes are the most abundant glial cell type. In addition to their neurological roles, astrocytes also have immune functions. They have been involved in antigen presentation in the central nervous system (CNS). Activated astrocytes express adhesion molecules, chemokines and release several inflammatory mediators, pro-inflammatory cytokines, neurotrophic and neuroprotective factors, thus these cells have a dual role within the CNS: neuroinflammation and repair processes. IL-19, IL-20, IL-22, IL-24, IL-26, IL 28A, IL-28B, and IL-29 are members of the IL-10 family of cytokines. These cytokines have different biological functions in spite of partial amino acid sequences homology. Signal transduction of the IL-10 family of cytokines is through R1-type and R2-type receptors. METHODS: No information has been available about the expression and regulation of IL-19 in mice astrocytes and brain. To investigate the expression of IL-19, we examined its expression in C57BL/6 mice astroglial cells in response to lipopolysaccharide (LPS), using reverse transcription polymerase chain reaction (RT-PCR) method. RESULTS: We provide for the first time, evidence that astrocytes can express IL-19 mRNA following LPS stimulation. Furthermore, we have found the expression of IL-19 mRNA in the cortex of adult C57BL/6 mice following intraperitoneal (i.p.) administration of LPS. DISCUSSION: This finding will contribute to current knowledge on the function and behavior of cells and mediators during inflammatory conditions in the brain. PMID- 25436090 TI - New view on treatment of drug dependence. AB - In the 1960s, discovery of pleasure system (defined as reward system) in the brain that may underlie drug reward and addiction encouraged many scientists to investigate the mechanisms by which drug abuse affects central nervous system function. In this regard, investigators developed several drugs targeting the brain reward system for drug dependence therapy. However, no positive results obtained in drug addiction treatment. It seems that more brain systems other than brain reward system must be considered in this regard. PMID- 25436091 TI - Immunogenetics of non celiac gluten sensitivity. PMID- 25436092 TI - Gastrointestinal disorders in Down syndrome. PMID- 25436093 TI - Potential treatment of inflammatory bowel disease: a review of helminths therapy. AB - An inflammatory bowel disease (IBD) is most common in highly industrialized Western countries but uncommon in less developed areas of the world where helminths are frequent. The hygiene hypothesis proposes that the recent increase in allergic and autoimmune diseases is due to modern highly hygienic life styles and medical conditions. Loss of routine exposure to parasitic helminths, as a result of increasing lifestyle-associated factors, may be one factor leading to the increased disease prevalence. In animal models and clinical trials of IBD, gastrointestinal nematodes colonization suppresses intestinal inflammation through multiple mechanisms including induction of innate and adaptive regulatory circuits. Studies using helminths like Trichuris suis or Necator americanus showed that these helminths are safe and may be effective therapeutic approaches for the control of IBD and other immune diseases. The aim of present review was to exploring the therapeutic use of helminths for the control of IBD. PMID- 25436095 TI - Neo-adjuvant chemoradiotherapy; an opportunity in sphincter preserving procedure for rectal cancer. AB - AIM: The present study was designed to assess the impact of neo-adjuvant chemoradiotherapy on the possibility of utilizing sphincter preserving techniques in rectal cancer surgery. BACKGROUND: For both patients and surgeons anal sphincter preserving surgery serves as the ideal procedure to treat rectal cancer. PATIENTS AND METHODS: Patients with rectal cancer who were admitted to Shohadaye Tajrish hospital between 2001 and 2011 and underwent sphincter preserving or non-preserving surgery were identified. They were divided into those who had received neo-adjuvant chemo-radiotherapy prior to surgery and those who didn't, and the type of surgical procedure they underwent was compared between the two arms. Data regarding tumor pathology, tumor size and distance from anal verge before and after neo-adjuvant therapy, together with the duration of chemo-radiotherapy were also assessed. RESULTS: 103 patients with documented rectal cancer were included in our analysis. Among 47 patients who had not received neo-adjuvant therapy, 26 (55%) underwent APR while 15(32%) and 6(13%) patients were treated with LAR and VLAR respectively. Of the 56 patients who had gone through chemo-radiotherapy prior to surgery, 30 (53%) underwent APR while 14 (25%) and 10 (18%) patients were treated with LAR and VLAR respectively. 2 patients had unresectable tumor. Tumor staging before and after neo-adjuvant therapy showed a statistically significant difference (p=0.0001). CONCLUSION: Neo adjuvant chemo-radiotherpy can decrease tumor size, increase the distance between the tumor and anal verge, and downgrade the staging. However, it does not necessarily increase the possibility of performing sphincter preserving surgery on patients suffering from low-lying tumors. PMID- 25436096 TI - Isolation of Enteropathogenic Escherichia coli from lettuce samples in Tehran. AB - AIM: The purpose of this study was to find the isolation rate of enteropathogenic Escherichia coli (EPEC) from lettuce samples collected in Tehran. BACKGROUND: During the last decade, the prevalence of infectious diarrheal diseases due to consumption of contaminated food especially raw vegetable has been increasingly reported. Enteropathogenic Escherichia coli strains are an important group of diarrheagenic E. coli that can cause infant diarrhea especially in the developing world. MATERIAL AND METHODS: One hundred lettuce samples collected in Tehran were transported to the laboratory, homogenized by a stomacher in EC broth containing cefixime, and cultured on MacConkey agar plates. Bacterial DNA was extracted by boiling method and PCR was performed using three pairs of primers targeting stx 1, stx 2 and eaeA genes. RESULTS: Screening of 100 lettuce samples by PCR showed four samples were positive for the presence of EPEC. CONCLUSION: This study suggests contamination of the lettuce by the EPEC and its possible role as the source of infection in this region. PMID- 25436094 TI - Protein-protein interaction networks (PPI) and complex diseases. AB - The physical interaction of proteins which lead to compiling them into large densely connected networks is a noticeable subject to investigation. Protein interaction networks are useful because of making basic scientific abstraction and improving biological and biomedical applications. Based on principle roles of proteins in biological function, their interactions determine molecular and cellular mechanisms, which control healthy and diseased states in organisms. Therefore, such networks facilitate the understanding of pathogenic (and physiologic) mechanisms that trigger the onset and progression of diseases. Consequently, this knowledge can be translated into effective diagnostic and therapeutic strategies. Furthermore, the results of several studies have proved that the structure and dynamics of protein networks are disturbed in complex diseases such as cancer and autoimmune disorders. Based on such relationship, a novel paradigm is suggested in order to confirm that the protein interaction networks can be the target of therapy for treatment of complex multi-genic diseases rather than individual molecules with disrespect the network. PMID- 25436097 TI - Inhibiting the oncogenic mir-221 by microRNA sponge: toward microRNA-based therapeutics for hepatocellular carcinoma. AB - AIM: We evaluated the capability of "microRNA sponges" in sequestering and inhibiting the over-expressed miR-221 in HCC cell lines. BACKGROUND: Advanced hepatocellular carcinoma (HCC) is a serious public health problem, with no effective cure at present. It has been demonstrated that the deregulation of microRNAs expression contributes to tumorigenesis. In HCC, miR-221 was shown to be up-regulated in more than 70% of the cases and was associated with higher tumor stage, metastasis and a shorter time to recurrence after surgery, suggesting an important pathogenic role. A tumor promoting function of miR-221 was proved in a transgenic mouse model, which was predisposed to the development of liver cancers. These findings suggested that miR-221 could represent a potential target for anti-tumor approaches. MATERIAL AND METHODS: Novel adeno and adeno-associated viral vectors (AAVs) were developed: they were genetically modified to drive the expression of multiple binding sites for miR-221, the "miR 221 sponge", which was designed to sequester miR-221 cellular molecules. RESULTS: Analysis of viral vectors activity in HCC cells revealed their capability to reduce miR-221 endogenous levels, which was accompanied by the increase in CDKN1B/ p27 protein, a known target of miR-221. An increase in apoptosis was also measured in Hep3B cells after infection with any of the two viral vectors in comparison with control vectors, with stronger effects induced by adenovirus compared to AAV vectors. CONCLUSION: The depletion of oncogenic microRNAs represents a potential anti-cancer approach that needs to be tested for safety and efficacy. Here, we describe the development of novel "miR-221 sponge" vectors, which can reduce miR-221 activity in vitro and may be used for in vivo delivery. PMID- 25436098 TI - Effect of non-alcoholic fatty liver disease on carotid artery intima-media thickness as a risk factor for atherosclerosis. AB - AIM: This study aimed to evaluate the effect of NAFLD on CIMT as a risk factor for atherosclerosis. BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide due to rise of obesity and diabetes mellitus (DM) prevalence. Non-invasive assessment of carotid intima-media thickness (CIMT) by high-resolution carotid B-mode ultrasonography is widely used for determining the atherosclerosis. PATIENTS AND METHODS: In this case-control setting, 151 subjects were categorized in three groups: group I including 49 patients with NAFLD and DM; group II including 50 non-diabetic NAFLD patients; and the control including 52 normal subjects as group III. The right and left CIMTs and its maximum reading (CIMTmax) were measured by a skilled sonographist blind to the groups. The sonographic grading of the NAFLD was determined in group I and II. RESULTS: Median CIMTmax was significantly higher in group I comparing with group II and control group (p<0.001). This difference between group I and group II was not significant after adjusting for age and history of hypertension and hyperlipidemia (p=0.089). After controlling the confounders, there was statistical significant between group I and group II with the control group (p<0.05). There was no significant difference in median maximal thickness of intima-media in the carotid of group I compare to group II in patients with and without elevated liver enzymes (in both groups, 0.6 mm, p= 0.402). CONCLUSION: Based on our findings, there is a significant association between the presence of NAFLD and atherosclerosis. This association was independent to the DM presence. The grade of NAFLD and elevated liver function tests had no effect on severity of atherosclerosis. PMID- 25436099 TI - Association of Helicobacter pylori with central serous chorioretinopathy in Iranian patients. AB - AIM: This study was conducted to investigate a possible association between H. pylori infection and CSR. BACKGROUND: Helicobacter pylori infection is one of the most common infections worldwide. Central Serous Chorioretinopathy (CSR) is a serious macular detachment that usually affects young people. The etiopathogenesis of the disease is still not completely understood. PATIENTS AND METHODS: A prospective study was performed and we evaluated a total of 35 CSR patients and control group of138 patients who referred to gastroenterology research center of Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Central serous chorioretinopathy was diagnosed on the basis of findings in ophthalmic examinations and confirmed by fluoresce in angiogram. All patients underwent a 13C-urea breath test (UBT) to detect H. pylori infection. Patients were defined as H. pylori infected, if breath test was positive. RESULTS: The mean duration of symptoms before diagnosis was8.3+/- 2.5 days. Overall, no statistically significant difference was found between left and right eyes, bilateral CSR was observed in 5 patients (14.2%).The incidence of H. pylori infection was 85.7% in CSR patients and 55.1% in control subjects (p=0.001). Odd's ratio was 4.895. CONCLUSION: These results indicate that the prevalence of H. pylori infection is significantly higher in patients with CSR than in controls. No effect of age or sex was seen on H.pylori test results. Further multiple centers, randomized, case control trials are necessary to confirm the potential contributory role of the H. pylori infection in the pathogenesis of CSR as a possible association between infectious agents and endothelial dysfunction. PMID- 25436100 TI - Mirizzi's syndrome in a cystic duct variation. AB - Mirizzi's syndrome is a rare complication of gallstone disease, that gallbladder lumen can lie alongside the common hepatic duct, resulting in inflammation and resultant bile duct stricture. Most cases are not identified preoperatively. Variations of the cystic duct and its point of union with the common hepatic duct are surgically important. Here, we present an unusual case of type I Mirizzi's syndrome with an uncommon anomalous cystic duct that long cystic duct joins common hepatic duct behind the duodenum. Also, there is a high bilirubin level due to gallstone and bile duct stone. PMID- 25436101 TI - Benign duodenocolic fistula as a complication of peptic ulcer disease. AB - A 44-year-old man with upper abdominal pain, diarrhea and 25 kg weight loss since 3 months ago was admitted. He had a history of dyspepsia and peptic ulcer disease 4 months before admission. Gastroduodenal endoscopy and upper gastrointestinal series with barium study were done. Biopsies and CT-scan ruled out malignancies. Endoscopy and radiology studies revealed a duodenocolic fistula. He underwent right hemicolectomy, fistula en bloc excision, and distal gastrectomy surgery with gastrojejunostomy and ileocolic anastomosis. Radiologic modalities are necessary before surgery. Surgery is the only curative treatment in benign cases and reconstruction method is dependent on patient's situation. PMID- 25436102 TI - Short cut. PMID- 25436103 TI - The importance of dynamic ultrasound in the diagnosis of tibialis anterior muscle herniation. AB - Tibialis anterior muscle hernia is a challenging diagnosis. Ultrasound findings generally are negative because patients come to ultrasound study from home when they are at rest. When the operator of ultrasound suspects a muscle hernia, he has to scan the affected limb or the affected organ dynamically at rest and after stressing the limb. Here, we present a case of a 19-year-old dancer with anterior leg mass with negative ultrasonographic findings at rest but was diagnosed with tibialis anterior hernia after stress dynamic ultrasound. PMID- 25436104 TI - Patients' perspectives regarding long-term warfarin therapy and the potential transition to new oral anticoagulant therapy. AB - OBJECTIVES: To examine patients' perspectives regarding long-term vitamin K antagonist (VKA) therapy and the potential transition to new oral anticoagulants (NOACs) such as dabigatran and rivaroxaban, and to determine if factors such as residential location affect these opinions. DESIGN SETTING AND PARTICIPANTS: Patients on VKA therapy for at least 12 weeks completed a questionnaire specifically designed for the study. They were recruited while attending point-of care international normalized ratio (INR) testing at six South Australian general practice clinics during the period July-September 2013. MAIN OUTCOME MEASURES: Opinions of current VKA therapy, level of awareness of NOACs, and ratings of potential benefits and deterrents of transition to NOACs were sought. RESULTS: Data from 290 participants were available for analysis (response rate 95.4%). The majority of the sample (79.5%, 229/288) were either satisfied or very satisfied with current VKA therapy. The mean score for the potential benefits of transition to NOACs was 7.6 (+/-4.2) out of a possible 20, which was significantly lower than the mean score 10.9 (+/-4.5) for the perceived deterrents to transition (p < 0.001). Rural patients (82.0%, 82/100) were significantly more likely (p = 0.001) to have not heard of NOACs than metropolitan patients (50.3%, 95/189) and also perceived significant less benefits in a transition to NOACs (p = 0.001). CONCLUSION: When considering potential transition from VKAs to NOACs it is important for prescribers to consider that some patients, in particular those from a rural location, may not perceive a significant benefit in transitioning or may have particular concerns in this area. PMID- 25436105 TI - Antimicrobial resistance: risk associated with antibiotic overuse and initiatives to reduce the problem. AB - Antimicrobial resistance is a global public health challenge, which has accelerated by the overuse of antibiotics worldwide. Increased antimicrobial resistance is the cause of severe infections, complications, longer hospital stays and increased mortality. Overprescribing of antibiotics is associated with an increased risk of adverse effects, more frequent re-attendance and increased medicalization of self-limiting conditions. Antibiotic overprescribing is a particular problem in primary care, where viruses cause most infections. About 90% of all antibiotic prescriptions are issued by general practitioners, and respiratory tract infections are the leading reason for prescribing. Multifaceted interventions to reduce overuse of antibiotics have been found to be effective and better than single initiatives. Interventions should encompass the enforcement of the policy of prohibiting the over-the-counter sale of antibiotics, the use of antimicrobial stewardship programmes, the active participation of clinicians in audits, the utilization of valid rapid point-of care tests, the promotion of delayed antibiotic prescribing strategies, the enhancement of communication skills with patients with the aid of information brochures and the performance of more pragmatic studies in primary care with outcomes that are of clinicians' interest, such as complications and clinical outcomes. PMID- 25436106 TI - Dapagliflozin efficacy and safety: a perspective review. AB - Type 2 diabetes mellitus is a prevalent, progressive disease with a need for innovative therapeutic agents to continue to advance disease management. Dapagliflozin is the second agent in a new class of oral antihyperglycemic drugs: sodium-glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 is responsible for the majority of renal glucose reuptake; inhibition of the cotransporter allows for increased renal glucose excretion that consequently leads to reduced plasma glucose levels. Because this mechanism does not require the action of insulin, dapagliflozin rarely causes hypoglycemia and is effective in patients both early and late in the course of their disease. Studies of dapagliflozin have demonstrated efficacy both as monotherapy and in combination with oral antihyperglycemic agents and insulin. Dapagliflozin has been shown to decrease hemoglobin A1c (HbA1c) values 6 mmol/mol (0.5%) to 8 mmol/mol (0.7%). The most common adverse reactions observed with dapagliflozin in clinical trials were female genital mycotic infections, urinary tract infections, and nasopharyngitis. Dapagliflozin is a new oral agent for type 2 diabetes with short-term efficacy similar to dipeptidyl peptidase 4 inhibitors; its long-term safety and efficacy are unknown. PMID- 25436107 TI - How retellings shape younger and older adults' memories. AB - The way a story is retold influences the way it is later remembered; after retelling an event in a biased manner people subsequently remember the event in line with their distorted retelling. This study tested the hypothesis that this should be especially true for older adults. To test this, older and younger adults retold a story to be entertaining, to be accurate, or did not complete an initial retelling. Later, all participants recalled the story as accurately as possible. On this final test younger adults were unaffected by how they had previously retold the story. In contrast, older adults had better memory for the story's content and structure if they had previously retold the story accurately. Furthermore, for older adults, greater usage of storytelling language during the retelling was associated with lower subsequent recall. In summary, retellings exerted a greater effect on memory in older, compared with younger, adults. PMID- 25436108 TI - Do mitochondria donate membrane to form autophagosomes or undergo remodeling to form mitochondrial spheroids? PMID- 25436110 TI - Ruling in or out a source of gastrointestinal bleeding. AB - BACKGROUND AND AIMS: The search for a source of gastrointestinal bleeding is associated with two distinct approaches of trying to rule in a specific diagnosis or rule out any potential source of bleeding. The study aim was to understand the conceptual differences underlying the two searches. METHODS: The performance of endoscopy as diagnostic test is analyzed in terms of Bayes' formula. RESULTS: The performance of gastrointestinal endoscopy to rule in a suspected lesion is mostly influenced by its underlying specificity. Because the specificity of endoscopy is less likely to be affected by procedural exigencies, the demands on pre procedural prep and general quality can be more relaxed. In contradistinction, the performance of endoscopy to rule out a suspected bleeding site is mostly influenced by its sensitivity, which can easily be compromised by suboptimal procedural conditions. CONCLUSIONS: Paradoxically, the more urgent, focused, and important search (to rule in a bleeding site), carries less stringent criteria for its execution than the more general and aimless search (to rule out a bleeding site) that frequently ends up just empty handed. PMID- 25436112 TI - UEG Week Vienna 2014 award winners. PMID- 25436111 TI - Survey of digestive health across Europe: Final report. Part 2: The economic impact and burden of digestive disorders. PMID- 25436109 TI - Cytokines from the pig conceptus: roles in conceptus development in pigs. AB - Establishment of pregnancy in pigs involves maintaining progesterone secretion from the corpora lutea in addition to regulating a sensitive interplay between the maternal immune system and attachment of the rapidly expanding trophoblast for nutrient absorption. The peri-implantation period of rapid trophoblastic elongation followed by attachment to the maternal uterine endometrium is critical for establishing a sufficient placental-uterine interface for subsequent nutrient transport for fetal survival to term, but is also marked by the required conceptus release of factors involved with stimulating uterine secretion of histotroph and modulation of the maternal immune system. Many endometrial genes activated by the conceptus secretory factors stimulate a tightly controlled proinflammatory response within the uterus. A number of the cytokines released by the elongating conceptuses stimulate inducible transcription factors such as nuclear factor kappa B (NFKB) potentially regulating the maternal uterine proinflammatory and immune response. This review will establish the current knowledge for the role of conceptus cytokine production and release in early development and establishment of pregnancy in the pig. PMID- 25436116 TI - How to reduce costs in transcatheter aortic valve implantation. PMID- 25436115 TI - Mental symptoms in patients with cardiac symptoms and normal coronary arteries. AB - OBJECTIVES: Patients with chest pain and normal coronary arteries often suffer from physical and psychological symptoms. Therefore, this study aimed to examine the incidence of mental symptoms in patients with angiographic exclusion of a coronary heart disease. DESIGN: In 253 patients with angiographic exclusion of a coronary heart disease the type and intensity of their symptoms were evaluated before and after coronary angiography. In addition, the incidence of psychopathological symptoms was quantified by standardised questionnaires such as general anxiety and depression (HADS), heart-focused anxiety (CAQ), hypochondria (Whiteley Index) and somatoform disorder (SOMS) and quality of life (SF-12). Finally, the incidence of psychological symptoms in these patients was compared to the incidence in the normal population. RESULTS: Despite the absence of a coronary artery disease, 70% of patients continue to suffer from cardiac symptoms. The incidence of general anxiety was increased by 37% in women and by 22% in men in comparison to the normal population. Heart-focused anxiety was raised by 27%. Somatoform disorder appeared 120% more often in patients after cardiac catheterisation in comparison to the normal population. In addition, the incidence of hypochondria was elevated by 68% in patients after coronary angiography compared to normal population. This increased appearance of psychological symptoms was reflected in a significantly lower quality of life (SF 12) in patients with inconspicuous coronary angiography. CONCLUSIONS: Patients with cardiac symptoms and normal coronary arteries more often suffer from mental symptoms in comparison to the healthy population. PMID- 25436113 TI - Detailed characterization of tumor infiltrating lymphocytes in two distinct human solid malignancies show phenotypic similarities. AB - BACKGROUND: We examined the phenotype and function of lymphocytes collected from the peripheral blood (PBL) and tumor (TIL) of patients with two different solid malignancies: colorectal cancer liver metastases (CRLM) and ovarian cancer (OVC). METHODS: Tumor and corresponding peripheral blood were collected from 16 CRLM and 22 OVC patients; immediately following resection they were processed and analyzed using a multi-color flow cytometry panel. Cytokine mRNA from purified PBL and TIL CD4(+) T cells were also analyzed by qPCR. RESULTS: Overall, we found similar changes in the phenotypic and cytokine profiles when the TIL were compared to PBL from patients with two different malignancies. The percentage of Treg (CD4(+)/CD25(+)/FoxP3(+)) in PBL and TIL was similar: 8.1% versus 10.2%, respectively in CRLM patients. However, the frequency of Treg in primary OVC TIL was higher than PBL: 19.2% versus 4.5% (p <0.0001). A subpopulation of Treg expressing HLA-DR was markedly increased in TIL compared to PBL in both tumor types, CRLM: 69.0% versus 31.7% (p = 0.0002) and OVC 74.6% versus 37.0% (p <0.0001), which suggested preferential Treg activation within the tumor. The cytokine mRNA profile showed that IL-6, a cytokine known for its immunosuppressive properties through STAT3 upregulation, was increased in TIL samples in patients with OVC and CRLM. Both TIL populations also contained a significantly higher proportion of activated CD8(+) T cells (HLA-DR(+)/CD38(+)) compared to PBL (CRLM: 30.2% vs 7.7%, (p = 0.0012), OVC: 57.1% vs 12.0%, (p <0.0001)). CONCLUSION: This study demonstrates that multi-color flow cytometry of freshly digested tumor samples reveals phenotypic differences in TIL vs PBL T cell sub-populations. The TIL composition in primary and metastatic tumors from two distinct histologies were remarkably similar, showing a greater proportion of activated/suppressive Treg (HLA-DR(+), CD39(+), CTLA-4(+) and Helios(+)) and activated cytotoxic T cells (CD8(+)/HLA-DR(+)/CD38(+)) when compared to PBL and an increase in IL-6 mRNA from CD4 TIL. PMID- 25436114 TI - Biodegradation of polycyclic aromatic hydrocarbons by a bacterial consortium enriched from mangrove sediments. AB - Polycyclic aromatic hydrocarbons (PAHs) biodegradation in contaminated sediment is an attractive remediation technique and its success depends on the optimal condition for the PAH-degrading isolates. The aims of the current study was to isolate and identify PAHs-degrading bacteria from surface sediments of Nayband Bay and to evaluate the efficiency of statistically based experimental design for the optimization of phenanthrene (Phe) and Fluorene (Flu) biodegradation performed by enriched consortium. PAHs degrading bacteria were isolated from surface sediments. Purified strains were then identified by 16S rDNA gene sequence analysis. Taguchi L16 (4(5)) was employed to evaluate the optimum biodegradation of Phe and Flu by the enriched consortium. Total of six gram negative bacterial strains including Marinobacter hydrocarbonoclasticus, Roseovarius pacificus, Pseudidiomarina sediminum and 3 unidentified strains were isolated from enrichment consortium, using Fluorene (Flu) and phenanthrene (Phe) as the sole carbon and energy source. The enriched consortium showed highest degradation abilities (64.0% Flu and 58.4% Phe degraded in 7 days) in comparison to a single strain cultures or mixtures. Maximum biodegradation efficiency was occur at temperature = 35 degrees C; pH = 8; inoculum size = 0. 4 OD600nm; salinity = 40 ppt; C/N ratio = 100:10. In conclusion our results showed that, indigenous bacteria from mangrove surface sediments of Nayband Bay have high potential to degrade Flu and Phe with the best results achieved when enriched consortium was used. PMID- 25436117 TI - Incidence and prognostic impact of high-risk HPV tumor infection in cervical esophageal carcinoma. AB - BACKGROUND: Cervical esophageal carcinoma (CEC) is an uncommon malignancy. Limited data supports the use of definitive chemoradiotherapy (CRT) as primary treatment. Furthermore, the role of human papillomavirus (HPV) tumor infection in CEC remains unknown. This study retrospectively analyzes both outcomes of CEC patients treated with CRT and the incidence and potential role of HPV tumor infection in CEC lesions. METHODS: A total of 37 CEC patients were treated with definitive CRT at our institution between 1987 and 2013. Of these, 19 had tumor samples available for high-risk HPV (types 16 and 18) pathological analysis. RESULTS: For all patients (n=37), 5-year overall survival (OS), disease-free survival (DFS), and loco-regional control (LRC) rates were 34.1%, 40.2%, and 65.6%, respectively. On pathological analysis, 1/19 (5.3%) patients had an HPV positive lesion. CONCLUSIONS: Definitive CRT provides disease-related outcomes comparable to surgery. Moreover, HPV tumor infection in CEC is uncommon and its prognostic role is unclear. Our data contribute to the construction of an anatomical map of HPV tumor infection in squamous cell carcinomas (SCC) of the upper aerodigestive tract, and suggest a steep drop in viral infection rates at sites distal to the oropharynx, including the cervical esophagus. PMID- 25436118 TI - Second-line systemic treatment for advanced cholangiocarcinoma. AB - BACKGROUND: Gemcitabine plus platinum (GEM-P) combination chemotherapy is standard treatment for first-line advanced cholangiocarcinoma (aCC). GEM-P first line therapy reports a progression-free survival (PFS) of 8 months and overall survival (OS) of 11.7 months. Treatment in the second-line setting is less clear. Five-year survival for aCC remains dismal at 5-10%. The purpose of this study was to describe the outcomes with second-line systemic treatment at our institution. METHODS: This study was a single institution retrospective chart review of aCC patients who initiated second-line systemic treatment during 1/1/2009 to 12/31/2012. The primary objective was to evaluate PFS with second-line systemic treatment. Secondary objectives were OS and disease control rate. Second-line systemic regimens were classified into four treatment groups: GEM-P, gemcitabine + fluoropyrimidine (GEM-FU), other FU combination (FU-combo), and others. RESULTS: Fifty-six patients were included and the majority had intrahepatic aCC. A total of 80% received first-line gemcitabine-based therapy. Second-line therapy consisted of GEM-P (19.6%), GEM-FU (28.6%), FU-combo (37.5%), and others (14.3%). Median PFS was 2.7-month (95% CI, 2.3-3.8 months) with a median OS of 13.8 months (95% CI, 12-19.3 months) and a disease control rate of 50%. No significant difference in survival was identified between the four treatment groups. CONCLUSIONS: This study revealed a 2.7-month PFS, 50% disease control rate, and potential survival benefit with second-line treatment. Options for second-line systemic therapy include GEM-FU, FU-combo, GEM-P if not given in the first-line setting. Targeted therapy with erlotinib or bevacizumab could be considered in addition to chemotherapy. PMID- 25436119 TI - Outcomes of rectal cancer with liver oligometastases. AB - PURPOSE: In patients with oligometastatic colorectal cancer to the liver, long term survival is possible and a multi-modality treatment approach may be considered. This is a report of a single institution experience of oligometastatic rectal cancer patients after treatment of the primary tumor and pelvic lymph nodes with extended course chemoradiation therapy. METHODS: Between 2004 and 2013, 26 oligometastatic rectal cancer patients with liver metastases were treated with extended course chemoradiation at our institution followed by total mesorectal excision (TME). Amongst these there were 17 men and 9 women. The mean age at the time of diagnosis was 59.8 years, with a range from 36 to 87 years of age. Eleven patients had metastases in other sites in addition to liver, and one patient in our cohort had lung metastasis with no liver metastasis. Kaplan-Meier method was used to generate overall survival (OS), progression free survival (PFS), distant metastases (DM) and local control (LC). RESULTS: OS rates were 95%, and 70% at 12 and 24 months respectively, with a mean survival time of 40.5 months. PFS rates were 91% and 36% at 12 and 24 months respectively, with a mean PFS time of 23.1 months. LC rates were 91% and 66% at 12 and 24 months respectively. DM rates were 0% and 61% at 12 and 24 months respectively. Finally, when censoring deaths, progression of liver metastases and distant progression, Kaplan-Meier analysis demonstrated five events of local failure. CONCLUSIONS: This series demonstrated an OS of 70% at 24 months, with a mean survival of 40.5 months. Significantly, LC was only 66% despite the use of extended course chemoradiation and TME. This data suggests that many patients with oligometastatic rectal cancer will survive past 2 years, and that a substantial number will fail locally as well as distantly. Therefore, a multimodality approach is reasonable. Recent data suggests that a hypofractionated radiation regiment of 25 Gy in 5 Gy fractions allows an equivalent LC compared to extended course chemoradiation with 50.4 Gy in 1.8 Gy fractions. A short course of radiation may be more consistent with the goals of care of the oligometastatic rectal cancer patient who is at high risk of recurrence. PMID- 25436120 TI - Patterns of failure for stage I ampulla of Vater adenocarcinoma: a single institutional experience. AB - BACKGROUND: Ampullary adenocarcinoma is a rare malignancy associated with a relatively favorable prognosis. Given high survival rates in stage I patients reported in small series with surgery alone, adjuvant chemoradiotherapy (CRT) has traditionally been recommended only for patients with high risk disease. Recent population-based data have demonstrated inferior outcomes to previous series. We examined disease-related outcomes for stage I tumors treated with pancreaticoduodenectomy, with and without CRT. METHODS: All patients with stage I ampullary adenocarcinoma treated from 1976 to 2011 at Duke University were reviewed. Disease-related endpoints including local control (LC), metastasis-free survival (MFS), disease-free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. RESULTS: Forty-four patients were included in this study. Thirty-one patients underwent surgery alone, while 13 also received adjuvant CRT. Five-year LC, MFS, DFS and OS for patients treated with surgery only and surgery with CRT were 56% and 83% (P=0.13), 67% and 83% (P=0.31), 56% and 83% (P=0.13), and 53% and 68% (P=0.09), respectively. CONCLUSIONS: The prognosis for patients diagnosed with stage I ampullary adenocarcinoma may not be as favorable as previously described. Our data suggests a possible benefit of adjuvant CRT delivery. PMID- 25436121 TI - A population based analysis of prognostic factors in advanced biliary tract cancer. AB - BACKGROUND: Data regarding prognostic factors in advanced biliary tract cancer (BTC) remains scarce. The aim of this study was to review our institutional experience with cisplatin and gemcitabine in advanced BTC as well as to evaluate potential prognostic factors for overall survival (OS). MATERIAL AND METHODS: Consecutive patients with advanced BTC who initiated palliative chemotherapy with cisplatin and gemcitabine from 2009 to 2012 at the BC Cancer Agency were identified using the pharmacy database. Clinicopathologic variables and treatment outcome were retrospectively collected. Potential prognostic factors were assessed by univariate and multivariate analyses. RESULTS: A total of 106 patients were included in the analysis. Median OS was 8.5 months (95% CI: 6.5 10.5). On univariate analysis, poor ECOG performance status (ECOG PS) at diagnosis, primary tumor location (extra-hepatic cholangiocarcinoma, and unknown biliary cancer), and sites of advanced disease (extra-hepatic metastasis) were significantly associated with worse OS (P<0.001, 0.036 and 0.034, respectively). Age, gender, CA19-9, CEA, hemoglobin, neutrophil count, and prior stent were not significantly associated with OS. On multivariate analysis, ECOG PS 2/3 was the only predictor of poor OS (P<0.001), while primary location (P=0.089) and sites of advanced disease (P=0.079) had a non-significant trend towards prognostic significance. CONCLUSIONS: In this population based analysis, a poorer performance status was significantly prognostic of worse OS. Although not significant in our analysis, primary tumor location and sites of advanced disease may also have prognostic relevance. PMID- 25436122 TI - Quality-of-life (QoL) as a predictive biomarker in patients with advanced pancreatic cancer (APC) receiving chemotherapy: results from a prospective multicenter phase 2 trial. AB - PURPOSE: Pancreatic cancer is rapidly fatal with median survival of only 6 months (mo). Quality-of-life (QoL) was analyzed prospectively in a phase 2 study of gemcitabine (G), capecitabine (C) and bevacizumab (B) in APC patients. METHODS: A total of 50 patients with APC received B 15 mg/kg, C 1,300 mg/m(2) daily for 2 weeks and G 1,000 mg/m(2) weekly 2 times; cycles were repeated every 21 days. ENDPOINTS: progression free survival (PFS), overall survival (OS) and assessment of QoL prior to each cycle using the European organization for research and treatment of cancer (EORTC) PAN-26 QoL questionnaire. An exact 95% confidence interval (CI) (Clopper-Pearson method) was used to assess rate of improved QoL (defined as >5% decrease in two consecutive scores compared with baseline). RESULTS: Patient characteristics- Stage IIB/III/IV: 3/5/42; Sex: 28 M/22 F; Median age: 64 years. QoL in patients- improved: 56%, no improvement: 24%; unevaluable: 20%. Median PFS: 5.8 mo, OS: 9.8 mo. QoL improvement rate: 28/40=0.7 (95% CI: 0.53-0.83) in evaluable patients. Using QoL improvement rate, no significant difference was seen in patients with OS >=6 mo compared to OS <6 mo. However QoL scores at 3 and 6 weeks from start of treatment correlated strongly with >=6 mo survival (P value 0.0092 and 0.0081, respectively). CONCLUSIONS: Baseline score and change in QoL scores of patients on G, C and B were not predictive of survival >=6 mo. Post treatment scores at 3 and 6 weeks from start of therapy however, were predictive of survival >=6 mo suggesting the potential predictive value of this tool for use in future studies. PMID- 25436123 TI - Association between nonalcoholic fatty liver disease and colorectal adenoma: a systemic review and meta-analysis. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is considered to be a hepatic manifestation of metabolic syndrome (MetS) and the most common chronic liver disease worldwide. The association between NAFLD and colorectal adenoma has been investigated in multiples studies but the results have been conflicting. We performed a systematic review and meta-analysis to evaluate this in asymptomatic patients who underwent screening colonoscopy. METHODS: We searched the literatures of all languages from PubMed, EMBASE and the Cochrane library from January 1, 1980 through July 15, 2014. Combined and subgroup analyses stratified by study designs, study locations, characteristics of adenoma (location, size, number, and advanced adenoma) were performed. RESULTS: Four cross-sectional and one cohort studies with a total of 6,263 subjects were included in the meta analysis. NAFLD was significantly associated with colorectal adenoma [pooled odds ratio (OR) 1.74, 95% confidence interval (CI): 1.53-1.97]. The association was more significant in Asian population (pooled OR =1.77, 95% CI: 1.52-2.05, n=3 studies), compared to European/North American population (pooled OR =1.42, 95% CI: 0.75-2.67, n=2 studies). NAFLD was significantly associated with the number of colorectal adenoma (pooled OR =1.78, 95% CI: 1.10-2.86, n=2 studies), but not the location, size, or presence of advanced adenoma. CONCLUSIONS: Our results suggest NAFLD is significantly associated with the presence of colorectal adenoma in asymptomatic patients undergoing screening colonoscopy. This finding provides additional risk stratifications for applying colorectal cancer (CRC) screening strategies. However, more studies of western population are needed to further investigate the ethnic disparity. PMID- 25436124 TI - CD133-positive tumor cell content is a predictor of early recurrence in colorectal cancer. AB - BACKGROUND: The aims of this study were to demonstrate the tumorigenicity of CD133+ colon cancer cells in vitro, analyze the correlations between spheroid formation and clinicopathologic variables, and screen for overexpressed genes in CD133+ colon cancer stem cells. Moreover, the aim of this study was to establish a living tumor tissue bank using surgically resected specimens. METHODS: Using LoVo cell line, we isolated CD133+ cells and performed clonogenic assay and animal experiment to test tumorigenicity of CD133+ cells. Twenty-nine surgical samples were freshly collected from 27 patients who received curative or palliative surgery, and the samples were mechanically and enzymatically dissociated into single cells. RESULTS: We confirmed the enhanced tumorigenicity of CD133+ cells isolated from LoVo cell line both in vitro and in vivo. Of these 29 samples, 8 (28%) contained >3% CD133+ cells. Sphere formation was significantly higher in samples from patients with lymphatic invasion than in those without lymphatic invasion [54.5% (6/11) vs. 12.5% (2/16); P=0.033] and in samples containing >3% of CD133+ cells than in those containing <=3% of CD133+ cells [36.4% (4/11) vs. 0% (0/16); P=0.019]. CONCLUSIONS: These findings indicate that CD133 is a valid marker for identifying cancer stem cells from fresh surgically resected colorectal cancer tissues. Furthermore, we successfully established a living tumor tissue bank using surgically resected colorectal tissues with a viability of >70%. PMID- 25436125 TI - The role of chemotherapy and/or octreotide in patients with metastatic gastroenteropancreatic and hepatobiliary neuroendocrine carcinoma. AB - BACKGROUND: Neuroendocrine carcinomas (NECs) of the gastro-entero-pancreatic (GEP) and hepatobiliary (HB) tract are rare and a heterogenous group of malignancies. Octreotide showed the anti-tumor activity in functional and nonfunctional well differentiated metastatic midgut neuroendocrine tumors (NETs). However, the effect of octreotide on survival has not been evaluated. PATIENTS AND METHODS: We analyzed 17 patients (6 HB- and 11 GEP- tract) with metastatic NEC diagnosed between January 2009 and June 2012. All patients had one or more cytotoxic chemotherapy and nine patients had received octreotide as single agent (n=3) or combination of cytotoxic chemotherapy (n=6). RESULTS: The median age was 68 years (range, 23-79 years) and median Eastern Cooperative Oncology Group performance status (ECOG PS) was 1. Sixteen of all patients (n=17) received cytotoxic chemotherapy with or without octreotide as the first line therapy and 10 of 16 patients who experienced disease progression to the first line therapy received the second line therapy. Overall response rates (RR) and disease control rates (DCR) to the 1(st) line therapy were 41.2% and 76.5%, respectively. The median overall survival (OS) was 16 months [95% confidence interval (CI), 12.8 19.2] and the median OS in patients receiving octreotide during treatment was 40.2 months. In univariate analysis, any clinico-pathologic features including sex, the location of primary tumor, the number of metastatic sites, the debulking operation and the liver metastasis did not have prognostic value regarding OS. However, the use of octreotide offered favorable trend for OS (P=0.091). CONCLUSIONS: The use of octreotide may benefit for patients with GEP- and HB- NECs as a single agent or a combination therapy. PMID- 25436126 TI - The association of H. pylori and colorectal adenoma: does it exist in the US Hispanic population? AB - BACKGROUND: Although data on the association between colorectal adenomas and Helicobacter pylori (H. pylori) exists in White and Black patients, there is no data on this association in a US Hispanic population. Our aim was to study the association of adenoma detection and biopsy proven H. pylori infection in a cohort of US Hispanics. METHODS: Data were collected from Nassau University Medical Center, a 530-bed tertiary care teaching hospital in East Meadow, New York. Patients who underwent both an esophagogastroduodenoscopy (EGD) and colonoscopy from July 2009 to March 2011 were pulled from an electronic database. A total of 1,737 patients completed colonoscopies during this time with 95 excluded: 17 inflammatory bowel disease, 12 malignancy, 22 prior history of colorectal adenoma, and 44 incomplete. Among the colonoscopies, 799 patients had EGD's performed prior to colonoscopies that were eligible for our study. RESULTS: H. pylori prevalence was highest in Hispanics 40.9%, followed by Blacks 29.1% (OR 0.59, 95% CI: 0.42-0.84), then Whites 7.9% (OR 0.12, 95% CI: 0.06-0.24). The adenoma detection rate was significantly higher in Whites 23.2% and Blacks 21.8% compared to Hispanics 14.5%, P=0.0002 respectively. Smoking and alcohol were lower in the H. pylori group, 18.6% (n=44) vs. 26.1% (n=147) for smoking (P=0.02) and 14.4% (n=34) vs. 19% (n=107) for alcohol (P=0.12), respectively. There was no evidence in the Hispanics for an association between adenoma detection and H. pylori infection. Furthermore size, location, and multiple polyps did not differ between the two groups. CONCLUSIONS: While data has shown an association between H. pylori and colorectal adenomas, we did not find this in our Hispanic population. With the growing population of Hispanics in the U.S, large scale studies are needed to conclusively characterize the role of H. pylori infection in colorectal adenoma and adenocarcinoma in this group of patients. PMID- 25436127 TI - The localisation of cancer in the sigmoid, rectum or rectosigmoid junction using endoscopy or radiology-What is the most accurate method? AB - INTRODUCTION: There is a difference in approach between colon and rectal cancer. AIM: EVALUATE THE METHODS OF LOCALISATION: endoscopy and radiology. MATERIALS AND METHODS: Patients with cancer in the sigmoid or rectum diagnosed with endoscopy, were included. Patients underwent additional radiological examinations. The resection specimen served as the gold standard. A tumour surrounded by serosa was considered a sigmoid cancer, surrounded by perirectal fat, than it was rectal cancer. If the frontal edge of the tumour showed serosa and the dorsal plane perirectal fat than the tumour was located in the "rectosigmoid". RESULTS: A total of 182 cancers were diagnosed. Of the 128 cancers with gold standard, endoscopy had the correct localisation in 112 (87.5%), and radiology in 114 (90.5%) cases. Concordance between both techniques was present in 80%. In 28 cases there was discordance. Radiology located 10 sigmoidal cancers wrongly in the rectum. One rectal cancer was placed in the sigmoid. In 16 cases the endoscopic localisation wrongly was the sigmoid. Sensitivity and specificity for endoscopy in sigmoidal cancer is 100% and 77% respectively, for rectal cancer 77% and 100%. Sensitivity of radiology for cancer in the sigmoid and rectum are 80% and 98% respectively. Specificity for both cancers is 98% and 80% respectively. CONCLUSIONS: The endoscopist and the radiologist should not be too overconfident with localisation of the tumour in cases of high rectal or low sigmoidal cancer. PMID- 25436128 TI - Intestinal metaplasia and anastomotic recurrence of gastric carcinoma. AB - Intestinal metaplasia (IM) of the stomach has been shown to increase the relative risk of gastric cancer. Endoscopic surveillance has been proposed and advocated for populations at risk. Those patients who had undergone surgery for gastric malignancy exhibited precancerous lesions such as atrophic gastritis and IM, and the possibility of anastomotic recurrence is higher than for the patients who had undergone benign gastric surgery. At present, there are no other recognized good markers of gastric dysplasia or cancer. We reviewed the literature on IM of the stomach to ascertain whether residual premalignant (type III) IM may predispose to anastomotic recurrence of gastric cancer. PMID- 25436130 TI - Muscular metastasis from gastric cancer. AB - The association between gastric cancer and muscle metastasis is extremely rare. Few cases have been reported in the literature. We report a case of a 68-year-old man, with a diagnosis of gastric adenocarcinoma by endoscopy and biopsy. A painful nodule on the right thigh became noticeable during chemotherapy sessions, where positron emission tomography and percutaneous biopsy diagnosed a muscle metastasis of gastric adenocarcinoma. This report demonstrates the importance of further investigation of muscle lesion in patients with gastrointestinal cancer and how we can diagnose and treat these lesions. PMID- 25436129 TI - The early diagnosis of pancreatic cancer and diabetes: what's the relationship? AB - Pancreatic cancer (PC) has a dismal prognosis as cancer-specific symptoms occur only at an advanced stage. If the cancer is to be discovered early, it will have to be done in asymptomatic individuals. Since the incidence of PC is low, screening for asymptomatic cancer in the general population will not be feasible. Screening will have to be restricted to subjects at high risk for PC. The proportion of PC patients who also have hyperglycemia or diabetes has previously been under appreciated; new data show that up to 80% are either hyperglycemic or diabetic and this can be evident in the pre-symptomatic phase. Diabetes improves following PC resection suggesting that diabetes is caused by the cancer. Conversely, older subjects with new-onset diabetes have an approximately eight fold higher risk of having PC compared to the general population. Recognition of new-onset diabetes as an early manifestation of PC could lead to diagnosis of asymptomatic, early stage PC. However, primary type 2 diabetes is common and PC is relatively uncommon in the general population and the two forms of diabetes are clinically indistinguishable. The success of the strategy to use new-onset hyperglycemia and diabetes as a screening tool to identify subjects with a high likelihood of having asymptomatic PC will depend largely on our ability to differentiate PC-associated diabetes from the more common type 2 diabetes using a (serologic) biomarker. PMID- 25436131 TI - HER2-positive, trastuzumab-resistant metastatic esophageal cancer presenting with brain metastasis after durable response to dual HER2 blockade: a case report. AB - We here report a case of a patient diagnosed with human epithelial growth factor receptor 2 (HER2)-amplified esophageal adenocarcinoma. The patient responded well to trastuzumab-based chemotherapy initially, but progressed with liver metastases. Her treatment was then switched to dual HER2 blockade with both trastuzumab and lapatinib in combination with capecitabine. She tolerated therapy and responded remarkably well with radiographic resolution of liver metastases. Unfortunately, she developed multiple brain metastases in the absence of extracranial progression. Discordant negative expression of HER2 and subclonal mutations in brain lesions were discovered, which, at least in part, explained her brain metastases in the presence of capecitabine and lapatinib, as both agents are known to be able to cross the blood brain barrier. The potential mechanism for dual HER2 blockade is discussed in the context of HER2-positive, trastuzumab-resistant, advanced esophageal cancer. The incidence of brain metastasis in advanced gastro-esophageal cancer has been reported to be extremely low, but is expected to increase with more effective systemic therapy. The intratumoral heterogeneity between the metastases, local recurrences and the primary tumor is definitely noteworthy. PMID- 25436132 TI - Bilateral above knee amputations after prolonged exposure to sorafenib and trebananib. AB - Sorafenib is an oral tyrosine kinase inhibitor (TKI) that acts on many targets including RAF kinases, vascular endothelial growth factor (VEGF) 1, 2, 3, platelet derived growth factor and c-kit receptor and is currently FDA approved for unresectable hepatocellular carcinoma (HCC). Trebananib (AMG 386) is an angiopoietin 1/2 antagonist and acts as anti-angiogenic agent and may possess synergistic effects with sorafenib. Here we report a case of a 66-year-old male with a history of Hepatitis C, and a 22 pack year (PY) smoking history with unresectable multifocal HCC who was placed on both therapies for an extended period of time with an excellent clinical response but ended up developing bilateral critical limb ischemia requiring above knee amputations. PMID- 25436133 TI - Bone marrow infiltration as the initial presentation of gastric signet ring cell adenocarcinoma. AB - This case report describes a 52-year-old African American man who initially presented with worsening back pain. The patient was found to have lytic lucencies in the T5 and T9 vertebral bodies and a subsequent bone marrow biopsy revealed an extensive infiltrate of signet ring cells. These findings prompted a workup for a gastrointestinal malignancy, and upper endoscopy revealed a mass in the gastric pylorus. A biopsy of this mass was positive for signet ring cell adenocarcinoma. This case is significant for two reasons. First, it highlights the importance of a broad differential diagnosis when approaching a patient with lytic bone lesions. Second, bone marrow involvement is more common in patients with diffuse type gastric cancer and occurs in particularly young patients. The increasing incidence of diffuse type gastric adenocarcinoma means bone marrow metastases will likely play a greater role in the presentation and management of gastric cancer. PMID- 25436134 TI - A curious discourse of Krukenberg tumor: a case report. AB - Krukenberg tumor is usually but not always a bilateral involvement of ovaries from metastatic deposit from adenocarcinoma of stomach and rarely from other gastrointestinal (GI) and non GI organs. The route of metastatsis of this rare condition is still not proven. It is still uncertain whether surgical resection of ovarian metastases and/or primary tumor could improve the outcome. We report even a rare presentation of this rare disease entity. PMID- 25436135 TI - A case of necrotizing vasculitis with panniculitis, during sorafenib treatment for hepatocellular carcinoma, appeared in disease progression. AB - Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and is the third most common cause of death from cancer. Sorafenib is the only drug which improves survival in first line advanced HCC. Sorafenib has been associated with several dermatologic toxicities and toxic effects have been related to a better treatment response. We report the case of a well-circumscribed panniculitis and necrotizing vasculitis due to sorafenib, appeared in disease progression in a man affected by advanced HCC. PMID- 25436136 TI - A journey into insidious world of MALT lymphoma of the ileum: from the beginning to the end. AB - INTRODUCTION: Lymphoma of the mucosa-associated lymphoid tissue (MALT) has been used to describe a marginal zone B-cell lymphoma derived from gastrointestinal lymphoid tissue. mucosa-associated lymphoid tissue lymphoma (MALToma) of the ileum are extremely rare and only few reports with endoscopic features have been reported. CASE STUDY: We present a 55-year-old male patient with history of abdominal pain and loss of appetite since 21/2 years. Abdomino-pelvic ultrasonography was normal, but computed tomography (CT) scan of the abdomen showed, dilated segment of ileum containing both contrast and debris. He underwent segmental resection of ileum associated with stricture site, histopathology of which revealed MALToma of ileum. Patient was subsequently treated with low dose chemotherapy and strictly followed up. DISCUSSION: Primary treatment possibility should be considered as the treatment of H. pylori infection while surgical resection for superficial lesions followed by low dose chemotherapy is recommended. The present case report explore MALToma of the GI tract, its diagnostic criterions, role of radiological and pathological tools, various investigative techniques and role of surgery and chemotherapy in such cases. PMID- 25436137 TI - Regorafenib-induced transverse myelopathy after stereotactic body radiation therapy. AB - Stereotactic body radiation therapy (SBRT) delivers large doses of radiation with great accuracy, but is known to have deleterious effects on the vascular compartment of irradiated tissues. Combining SBRT with targeted anti-angiogenesis agents, while able to increase therapeutic efficacy, may unexpectedly precipitate vascular-based toxicities. In this report, we describe a patient with colon cancer who developed transverse myelopathy from regorafenib 2 years after receiving SBRT for three metastatic liver lesions. Regorafenib (Stivarga), formerly BAY 73-4506, (Bayer HealthCare Pharmaceuticals, Montville, NJ) is a multiple receptor tyrosine kinase inhibitor with anti-angiogenic effects used in metastatic colon cancer. Its most common side effects are fatigue, diarrhea and hypertension. However, severe neurologic toxicity has not been previously recognized. Here, we illustrate a case in which the patient developed hyperalgesia and radicular pain 2 weeks after starting regorafenib. Several studies report an increased neurological toxicity when angiogenesis inhibitors are given after radiation therapy, and we postulate that the angioinhibitory effects of regorafenib accelerated subclinical microvascular injury from SBRT. This unexpected toxicity may be clinically relevant when giving targeted angiogenesis inhibitors after SBRT. PMID- 25436139 TI - A case of periampullary adenocarcinoma in neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF-1) is an autosomal dominant genetic disorder with a known predisposition to gastrointestinal neoplasms such as stromal tumors and carcinoids. Adenocarcinomas (ACs) of the gastrointestinal tract are relatively rare in patients with NF-1, especially those found in the periampullary region. We present a case report of periampullary adenocarcinoma in a 56-year-old woman with NF-1 who presented with abdominal pain and obstructive jaundice. PMID- 25436138 TI - A patient with cholangiocarcinoma demonstrating pathologic complete response to chemotherapy: exploring the role of neoadjuvant therapy in biliary tract cancer. AB - The role of neoadjuvant chemotherapy and/or radiation for localized or potentially resectable cholangiocarcinoma (CCA) has not been well established. We present here the case of a patient with an extrahepatic CCA who achieved a pathologic complete response after undergoing preoperative gemcitabine-based chemotherapy, without sequential or concurrent use of radiation. Further evaluation of neoadjuvant strategies in CCA, including not only combined-modality therapy but also the use of chemotherapy exclusively, is warranted in prospective study design. PMID- 25436140 TI - Ocular surface temperature in age-related macular degeneration. AB - Background. The aim of this study is to investigate the ocular thermographic profiles in age-related macular degeneration (AMD) eyes and age-matched controls to detect possible hemodynamic abnormalities, which could be involved in the pathogenesis of the disease. Methods. 32 eyes with early AMD, 37 eyes with atrophic AMD, 30 eyes affected by untreated neovascular AMD, and 43 eyes with fibrotic AMD were included. The control group consisted of 44 healthy eyes. Exclusion criteria were represented by any other ocular diseases other than AMD, tear film abnormalities, systemic cardiovascular abnormalities, diabetes mellitus, and a body temperature higher than 37.5 degrees C. A total of 186 eyes without pupil dilation were investigated by infrared thermography (FLIR A320). The ocular surface temperature (OST) of three ocular points was calculated by means of an image processing technique from the infrared images. Two-sample t test and one-way analysis of variance (ANOVA) test were used for statistical analyses. Results. ANOVA analyses showed no significant differences among AMD groups (P value >0.272). OST in AMD patients was significantly lower than in controls (P > 0.05). Conclusions. Considering the possible relationship between ocular blood flow and OST, these findings might support the central role of ischemia in the pathogenesis of AMD. PMID- 25436142 TI - Psychophysiology of refractive accommodative esotropia. AB - Purpose. To investigate the psychophysiologic aspects of refractive accommodative esotropia (RAE). Methods. I prospectively recruited patients aged 3-6 years with more than 3.0 diopters of hyperopia who presented at Kim's Eye Hospital from January 2011 to March 2013. I compared Korean Child Behavior Checklist (K-CBCL) which consists of internalizing factors (social withdrawal, somatic complaints, anxiety, and depression) and externalizing factors (social problems, thought problems, attention problems, delinquent behavior, and aggressive behavior) between RAE group and control group. Results. Two out of three internalizing indexes were significantly different between groups (somatic complaints: RAE children 50.1 +/- 4.6 and controls 46.6 +/- 5.8, P = 0.026; depression/anxiety: RAE children 48.8 +/- 7.9 and controls 43.9 +/- 6.8, P = 0.024). Although there was no significant difference, RAE children scored slightly higher on the externalizing behavior index. In the RAE group, the far angle of esodeviation showed a moderate correlation with withdrawn behaviors. Conclusion. Hypermetropic children with high scores on the somatic complaint and depression/anxiety subscales of the CBCL could be at high risk for developing RAE. Psychosocial problems might be related to the pathogenesis of refractive accommodative esotropia. PMID- 25436141 TI - The Relationship between Visual Field Global Indices and Retinal Nerve Fiber Layer Thickness in Healthy Myopes. AB - The aim of the current study was to investigate the association between the thickness of the retinal nerve fiber layer (RNFL) and central visual field indices in otherwise healthy myopes. In total, 57 otherwise healthy subjects were cross-sectionally studied. General ophthalmic examinations, refractive measurements, RNFL thickness by spectral domain optical coherence tomography (OCT), and central visual fields were examined. Linear models were used to assess the associations. In this young and mid-aged population, the mean spherical equivalent was -4.79 (SD 1.66) and -4.59 (SD 1.88) diopters in the right and left eyes, respectively. Approximately 7% to 14% of the eyes showed the average RNFL thickness out of the normal range. The temporal RNFL was remarkably thicker, whereas the nasal RNFL was thinner. The higher the refractive error, the thinner the RNFL thickness. A thicker overall RNFL was significantly associated with decreased mean sensitivity and increased mean defect, and further adjustments for age, sex, refractive error, optic disk area, or ocular magnification did not change the association. Although nonpathologic myopia does not significantly affect central visual field global indices, its effects on the RNFL may be linked with performance on the central visual field test. PMID- 25436143 TI - Variations in aging, gender, menopause, and obesity and their effects on hypertension in taiwan. AB - Aim. We assessed obesity, sex, menopause, and gender differences on hypertension in a Hakka-majority Taiwanese sample. Methods. 9621 subjects aged 20 and over participated in this community-based study. Trained nurses collected blood pressure (BP) measurements and anthropometric indices, including weight, height, hip circumference (HC), waist circumference (WC), body mass index (BMI), waist to height ratio (WHtR), and waist to hip ratio (WHR). Results. Levels of systolic and diastolic BP significantly increased at a dose-dependent relationship based on four anthropometric indices (BMI, WC, WHR, and WHtR); the slopes for SBP and DBP differed. After controlling for other covariates using multivariate logistic regression, we found the adjusted odds ratios (OR) of hypertension to be significantly related to the four anthropometric indices. Notably, the effect of obesity on the ORs for hypertension was considerably higher in premenopausal women, but we found no such phenomenon among men. BMI, WC, WHR, and WHtR had significant linear associations with BP. Conclusion. Obesity indices are significantly correlated with the risk of hypertension across gender and age, with BMI having the highest relative potency. The effect of obesity on the risk of hypertension is especially high in premenopausal women, implying a relationship between hormones and hypertension. PMID- 25436144 TI - Body composition and Basal metabolic rate in women with type 2 diabetes mellitus. AB - Objective. The aim of this study was to determine which of the seven selected equations used to predict basal metabolic rate most accurately estimated the measured basal metabolic rate. Methods. Twenty-eight adult women with type 2 diabetes mellitus participated in this cross-sectional study. Anthropometric and biochemical variables were measured as well as body composition (by absorptiometry dual X-ray emission) and basal metabolic rate (by indirect calorimetry); basal metabolic rate was also estimated by prediction equations. Results. There was a significant difference between the measured and the estimated basal metabolic rate determined by the FAO/WHO/UNU (P value < 0.021) and Huang et al. (P value <= 0.005) equations. Conclusion. The calculations using Owen et al's. equation were the closest to the measured basal metabolic rate. PMID- 25436145 TI - Validity of Palmar Pallor for Diagnosis of Anemia among Children Aged 6-59 Months in North India. AB - Introduction. The Integrated Management of Childhood and Neonatal Illness (IMNCI) recommends the use palmar pallor to diagnose anaemia. Earlier studies to validate palmar pallor as clinical sign for anaemia were largely done in African context. There was a need to test validity of palmar pallor to detect anemia in different settings. Objective. To study the validity and interobserver agreement of palmar pallor examination to diagnose anemia in children under 5 years of age in India. Methods. In a village in Northern India, hemoglobin estimation was done for 80 children using cyanomethemoglobin method. Two examiners, a physician and a health worker, trained in IMNCI evaluated children for palmar pallor. Sensitivity and specificity and Kappa statistics were calculated. Results. Health worker diagnosed palmar pallor with sensitivity of 30.8-42.8% and specificity of 70-89%. Similar figures for doctor were 40-47% and 60-66%, respectively. Kappa agreement between a health worker and a physician was 0.48 (95% CI = 0.298-0.666) and then increased to 0.51 when categories of severe pallor and mild pallor were merged. Conclusion. While using palmar pallor as clinical sign for anaemia, children with no pallor should also be followed up closely for possible detection of missed cases during follow-up. PMID- 25436146 TI - Close margins in oral cancers: implication of close margin status in recurrence and survival of pT1N0 and pT2N0 oral cancers. AB - INTRODUCTION: Among all prognostic factors, "margin status" is the only factor under clinician's control. Current guidelines describe histopathologic margin of >5 mm as "clear margin" and 1-5 mm as "close margin." Ambiguous description of positive margin in the published data resulted in comparison of microscopically "involved margin" and "close margin" together with "clear margin" in many publications. Authors attempted to compare the outcome of close and clear margins of stage I and stage II squamous cell carcinoma of oral cavity to investigate the efficacy of description of margin status. PATIENTS AND METHODS: Historical cohorts of patients treated between January 2010 and December 2011 at tertiary cancer hospital were investigated and filtered for stage I and stage II primary squamous cell carcinomas of oral cavity. Patients with margin status of tumor at margin or within 1mm from cut margin were excluded and analyzed in multivariate logistic regression model for locoregional recurrences and Cox regression for overall survival. RESULTS: A total of 104 patients fulfilled the abovementioned criteria, of whom 36 were "clear margin" and 68 were "close margin" with median period of follow-up of 39 months. There was no significant difference in locoregional recurrence (P value: 0.0.810) and survival (P value: 0.0.851) among "close margin" and "clear margin" patients. PMID- 25436147 TI - Comparison of (99m)tc-tetrofosmin and (99m)tc-sestamibi uptake in glioma cell lines: the role of p-glycoprotein expression. AB - (99m)Tc-Tetrofosmin ((99m)Tc-TF) and (99m)Tc-Sestamibi ((99m)Tc-MIBI) are SPECT tracers that have been used for brain tumor imaging. Tumor's multidrug resistance phenotype, namely, P-glycoprotein (p-gp), and the multidrug resistance related proteins (MRPs) expression have been suggested to influence both tracers' uptake. In the present study we set out to compare (99m)Tc-TF and (99m)Tc-MIBI uptake in high-grade glioma cell lines and to investigate the influence of gliomas p-gp expression on both tracers' uptake. We used four glioma cell lines (U251MG, A172, U87MG, and T98G). The expression of p-gp protein was evaluated by flow cytometry. Twenty MUCi (7.4.10(5) Bq) of (99m)Tc-TF and (99m)Tc-MIBI were used. The radioactivity in the cellular lysate was measured with a dose calibrator. P-gp was significantly expressed only in the U251MG cell line (P < 0.001). In all gliomas cell lines (U251MG, U87MG, A172, and T98G) the (99m)Tc-TF uptake was significantly higher than (99m)Tc-sestamibi. The U251MG cell line, in which significant p-gp expression was documented, exhibited the strongest uptake difference. (99m)Tc-TF uptake was higher than (99m)Tc-MIBI in all studied high grade glioma cell lines. Thus, (99m)Tc-TF may be superior to (99m)Tc-MIBI for glioma imaging in vivo. PMID- 25436149 TI - Low back pain in primary care: a description of 1250 patients with low back pain in danish general and chiropractic practice. AB - Study Design. Baseline description of a multicenter cohort study. Objective. To describe patients with low back pain (LBP) in both chiropractic and general practice in Denmark. Background. To optimize standards of care in the primary healthcare sector, detailed knowledge of the patient populations in different settings is needed. In Denmark, most LBP-patients access primary healthcare through chiropractic or general practice. Methods. Chiropractors and general practitioners recruited adult patients seeking care for LBP. Extensive baseline questionnaires were obtained and descriptive analyses presented separately for general and chiropractic practice patients, Mann-Whitney rank sum test and Pearson's chi-square test, were used to test for differences between the two populations. Results. Questionnaires were returned from 934 patients in chiropractic practice and 319 patients from general practice. Four out of five patients had had previous episodes, one-fourth were on sick leave, and the LBP considerably limited daily activities. The general practice patients were slightly older and less educated, more often females, and generally worse on all disease-related parameters than chiropractic patients. All differences were statistically significant. Conclusions. LBP in primary care was recurrent, causing sick leave and activity limitations. There were clear differences between the chiropractic and general practice populations in this study. PMID- 25436150 TI - A web-based survey of residents' views on advocating with patients for a healthy built environment in Canada. AB - Purpose. To determine family medicine residents' perceived knowledge and attitudes towards the built environment and their responsibility for health advocacy and to identify their perceived educational needs and barriers to patient education and advocacy. Methods. A web-based survey was conducted in Canada with University of Toronto family medicine residents. Data were analyzed descriptively. Results. 93% agreed or strongly agreed that built environment significantly impacts health. 64% thought educating patients on built environment is effective disease prevention; 52% considered this a role of family physicians. 78% reported that advocacy for built environment is effective disease prevention; 56% perceived this to be the family physician's role. 59% reported being knowledgeable to discuss how a patient's environment may affect his/her health; 35% reported being knowledgeable to participate in community discussions on built environment. 78% thought education would help with integration into practice. Inadequate time (92%), knowledge (73%), and remuneration (54%) were barriers. Conclusions. While residents perceived value in education and advocacy as disease prevention strategies and acknowledged the importance of a healthy built environment, they did not consider advocacy towards this the family physician's role. Barrier reduction and medical education may contribute to improved advocacy, ultimately improving physical activity levels and patient health outcomes. PMID- 25436151 TI - Development of Small Molecular Proteasome Inhibitors Using a Caenorhabditis elegans Screen. AB - We have developed a screening protocol to identify compounds with characteristics of small molecule proteasome inhibitors using the real-time analysis of the Caenorhabditis elegans germ line. This screen is able to identify compounds that induce germ line phenotypes characteristic of a reduction in proteasome function such as changes in polarity, aberrant nuclear morphology, and stimulation of apoptosis. This basic protocol is amenable to a high throughput (96-well) format and has been used successfully to identify multiple compounds for further analysis based on structural elements from the naturally occurring compounds lactacystin and the beta-lactone homologs omuralide and salinosporamide A. The further development of this assay system should allow for the generation of novel small molecule proteasome inhibitors in a genetically tractable whole animal amenable to biochemical analysis. PMID- 25436152 TI - Protective Effect of Selected Medicinal Plants against Hydrogen Peroxide Induced Oxidative Damage on Biological Substrates. AB - Oxidative stress is developed due to susceptibility of biological substrates to oxidation by generation of free radicals. In degenerative diseases, oxidative stress level can be reduced by antioxidants which neutralize free radicals. Primary objective of this work was to screen four medicinal plants, namely, Andrographis paniculata, Costus speciosus, Canthium parviflorum, and Abrus precatorius, for their antioxidant property using two biological substrates-RBC and microsomes. The antioxidative ability of three solvent extracts, methanol (100% and 80%) and aqueous leaf extracts, was studied at different concentrations by thiobarbituric acid reactive substances method using Fenton's reagent to induce oxidation in the substrates. The polyphenol and flavonoid content were analyzed to relate with the observed antioxidant effect of the extracts. The phytochemical screening indicated the presence of flavonoids, polyphenols, tannins, and beta-carotene in the samples. In microsomes, 80% methanol extract of Canthium and Costus and, in RBC, 80% methanol extract of Costus showed highest inhibition of oxidation and correlated well with the polyphenol and flavonoid content. From the results it can be concluded that antioxidants from medicinal plants are capable of inhibiting oxidation in biological systems, suggesting scope for their use as nutraceuticals. PMID- 25436148 TI - Signaling pathways involved in renal oxidative injury: role of the vasoactive peptides and the renal dopaminergic system. AB - The physiological hydroelectrolytic balance and the redox steady state in the kidney are accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Angiotensin II, atrial natriuretic peptide and intrarenal dopamine play a pivotal role in this interactive network. The balance between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide, by one side, and the prooxidant effect of the renin angiotensin system, by the other side, contributes to ensuring the normal function of the kidney. Different pathological scenarios, as nephrotic syndrome and hypertension, where renal sodium excretion is altered, are associated with an impaired interaction between two natriuretic systems as the renal dopaminergic system and atrial natriuretic peptide that may be involved in the pathogenesis of renal diseases. The aim of this review is to update and comment the most recent evidences about the intracellular pathways involved in the relationship between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide and the prooxidant effect of the renin angiotensin system in the pathogenesis of renal inflammation. PMID- 25436153 TI - Factor XII (Hageman) levels in women with recurrent pregnancy loss. AB - OBJECTIVE: To evaluate factor XII levels in women with recurrent pregnancy loss (RPL) in a tertiary referral hospital. METHODS: Women who were referred to our hospital for two consecutive abortions or three abortions in between 2007 and 2013 were included in this retrospective observational study. Women were further grouped according to factor XII levels, as <60% and >= 60%. RESULTS: Mean factor XII level was 109.1 +/- 35.7% (range: 9-200). Ninety-three (7.4%) women had factor XII levels < 60%. Mean factor XII level was 44.8 +/- 13.1, and levels ranged between 9 and 60 in this group. Only one woman had factor XII level < 10 %. Remaining 1164 (92.6%) women had factor XII levels >= 60%. Mean factor XII level was 114.3 +/- 31.7, and levels ranged between 60.3 and 200 in this group, while 1015 (72.4%) women had factor XII levels within the normal range (60%-150% [100% = 30 MUg/mL]). CONCLUSION: Decreased activity of F-XII was diagnosed in 7.4% of women with RPL. We concluded factor XII deficiency that might be a rare but significant factor for RPL, and should be evaluated in women who are investigated for recurrent pregnancy loss. PMID- 25436154 TI - Dermoglandular rotation flaps for breast-conserving therapy: aesthetic results, patient satisfaction, and morbidity in comparison to standard segmentectomy. AB - We compared a dermoglandular rotation flap (DGR) in the upper inner, lower inner, and upper outer quadrant regarding similar aesthetic results, patient satisfaction, and comfort after breast-conserving therapy with standard segmentectomy (SE). Between 2003 and 2011, 69 patients were treated with breast conserving surgery using DGR for cancers with high tumor-to-breast volume ratios or skin resection in the three above mentioned quadrants; 161 patients with tumors in the same quadrants were treated with SE. The outcome of the procedures was assessed at least 7 months after completed radiation therapy using a patient and breast surgeon questionnaire and the BCCT.core software. Symmetry, visibility of the scars, the position of the nipple-areola complex, and the appearance of the treated breast were each assessed on a scale from 1 to 4 by an expert panel and by the patients. Univariate and multivariate analysis were used to evaluate the relationship between patient-, tumor-, and treatment-dependent factors and patient satisfaction. 94.2% of the patients with rotation flaps and 83.5% of the patients with lumpectomy were very satisfied with the cosmetic appearance of their breast. Younger patient age was significantly associated with a lower degree of satisfaction. DGR provides good cosmetic results compared with SE and shows high patient satisfaction despite longer scarring and higher median resection volume. PMID- 25436155 TI - Activation of the prefrontal cortex while performing a task at preferred slow pace and metronome slow pace: a functional near-infrared spectroscopy study. AB - Individuals have a preferred pace at which they perform voluntary repetitive movements. Previous studies have reported that greater activation of the prefrontal cortex was observed during self-initiated movements than during externally triggered movements. The purpose of the present study is to compare the activation of the prefrontal cortex induced when the subjects performed a peg board task at their preferred slow pace (PSP, the self-initiated condition) with that induced when they performed the same task at metronome slow pace (MSP, the externally triggered condition) using functional near-infrared spectroscopy. Healthy subjects performed the task while sitting in a chair. By assessing the activated channels individually, we confirmed that all of the prefrontal regions of interest were activated by both tasks. In the second-level analyses, we found that the activation detected in the frontopolar cortex (FPPFC; Brodmann area 10) was higher during the PSP task than during the MSP task. The FPPFC is known to be at the top of prefrontal hierarchy, and specifically involved in evaluating self generated information. In addition, the FPPFC plays a role in coordinating lateral prefrontal cortex. In the present study, the subjects evaluated and managed the internally generated PSP by coordinating the activity of other lower level prefrontal regions. PMID- 25436156 TI - Management of a large internal resorption lesion with metal reinforced glass ionomer cement. AB - Mineral trioxide aggregate is the mainstay of treatment of large internal resorption defects. But its cost may be a deterrent to its use in some patients. The present case report describes the successful endodontic management of an extensive internal resorptive lesion in a mandibular molar with metal reinforced glass ionomer cement. PMID- 25436157 TI - Impact of orthodontic decompensation on bone insertion. AB - There has always been concern in determining the relationship between orthodontic tooth movement and the consequent biological costs to the periodontium and tooth root. The possibility of evaluating the tooth and bone morphology by CBCT allows more accurate analysis of qualitative and quantitative aspects of these processes. This paper presents a case report of a 20-year-old male patient with Class III malocclusion and hyperdivergent facial pattern, who was surgically treated. A significant amount of labial movement of mandibular incisors was performed during orthodontic treatment before surgery. CBCT was used for evaluation of buccal and lingual bone plates before and after tooth decompensation. The changes in the bone insertion level of maxillary and mandibular incisors in the present case encourage a reflection on the treatment protocol in individuals with dentoskeletal discrepancies. PMID- 25436158 TI - Tufted angioma in children: report of two cases and a review of the literature. AB - Tufted angioma (TA) is a benign vascular tumor with endothelial origin. It is extremely rare in oral mucosa; only seven cases have been reported in the literature so far. Here, we describe two cases of tufted angioma observed in children and we also present a review of the literature about this pathology, concerning the differential diagnosis and management of this lesion in children. PMID- 25436159 TI - Self-administered ethanol enema causing accidental death. AB - Excessive ethanol consumption is a leading preventable cause of death in the United States. Much of the harm from ethanol comes from those who engage in excessive or hazardous drinking. Rectal absorption of ethanol bypasses the first pass metabolic effect, allowing for a higher concentration of blood ethanol to occur for a given volume of solution and, consequently, greater potential for central nervous system depression. However, accidental death is extremely rare with rectal administration. This case report describes an individual with klismaphilia whose death resulted from acute ethanol intoxication by rectal absorption of a wine enema. PMID- 25436160 TI - Psychiatric Symptoms due to Thyroid Disease in a Female Adolescent. AB - The hypothalamic-pituitary-thyroid axis is involved in the production of thyroid hormone which is needed to maintain the normal functioning of various organs and systems, including the central nervous system. This study reports a case of hypothyroidism in a fifteen-year-old female adolescent who was attended for psychiatric symptoms. This case reveals the importance of evaluating thyroid function in children and adolescents with neuropsychiatric symptoms. PMID- 25436161 TI - A Case of Acute Myeloid Leukemia with a Previously Unreported Translocation (14; 15) (q32; q13). AB - Background. We hereby describe what we believe to be the first reported case of t (14; 15) (q32; q13) associated with acute myeloid leukemia (AML). Methods. PubMed, Embase, and OVID search engines were used to review the related literature and similar published cases. Case. A47-year-old female presented in December 2011 with AML (acute myelomonocytic leukemia) with normal cytogenetics; molecular testing revealed FLT-3 internal tandem duplication (ITD) mutation, while no mutations involving FLT3 D385/I836, NPM1 exon 12, or KIT exons 8 and 17 were detected. She was induced with 7 + 3 (cytarabine + idarubicin) and achieved complete remission after a second induction with high-dose cytarabine (HiDAC) followed by uneventful consolidation. She presented 19 months after diagnosis with relapsed disease. Of note, at relapse cytogenetic analysis revealed t (14; 15) (q32; q13), while FLT-3 analysis showed a codon D835 mutation (no ITD mutation was detected). She proved refractory to the initial clofarabine-based regimen, so FLAG-idarubicin then was used. She continued to have persistent disease, and she was discharged on best supportive care. Conclusion. Based on this single case of AML with t (14; 15) (q32; q13), this newly reported translocation may be associated with refractory disease. PMID- 25436162 TI - Retained intra-abdominal surgical clamp complicating emergency laparotomy: incidental finding on hysterosalpingogram for evaluation of tubal infertility. AB - The finding of intraperitoneal foreign body complicating surgical intervention broadly remains as an issue of safety in the operative room, a source of emotive concern for the patient, and an upsetting but equally embarrassing situation to the surgeon and the team. However, in the media world, it is a source of sumptuous and captivating headline on the newspaper and to the legal profession, an attractive case to prosecute. A middle age teacher presented with secondary infertility. She had emergency laparotomy fifteen years ago for ruptured tubal ectopic pregnancy in a private hospital and postoperative period was uneventful. Amongst other investigations to find out the cause of infertility, she had hysterosalpingography and a radio-opaque clamp was visualized on the films. She was counselled and had laparotomy. A pair of surgical Kocher clamps was retrieved buried in the mesentery. PMID- 25436163 TI - Delayed spontaneous bleeding in the blind eye of a type a hemophilic patient. AB - A 40-year-old man was complaining of severe left ocular pain and headache for the past 2 months. His left eye was traumatized and rendered blind about 20 years ago. He had no other medical problems and his preoperative laboratory tests were nonspecific. Evisceration of the left eye was performed for pain control and cosmetic improvement. However, postoperative progressive and prolonged eyelid swelling, bruising, and wound bleeding recurred. This patient was diagnosed with moderate factor VIII deficiency with a coagulation time within the normal range. PMID- 25436165 TI - Sanjad-sakati syndrome and its association with superior mesenteric artery syndrome. AB - Sanjad-Sakati syndrome (SSS) is an autosomal recessive disorder found exclusively in people of Arabian origin. It was first reported in the Kingdom of Saudi Arabia in 1988 and confirmed by a definitive report in 1991. The syndrome comprises of congenital hypoparathyroidism, seizures, severe growth and developmental retardation, low IQ, and atypical facial features. Supportive treatment in the form of vitamin D and growth hormone supplementation is often offered to patients suffering from SSS. This case study focuses on the steps taken to help a patient who was found to have very unusual symptoms and was later found to have superior mesenteric artery syndrome. PMID- 25436164 TI - A Case Report of Herpetic Whitlow with Positive Kanavel's Cardinal Signs: A Diagnostic and Treatment Difficulty. AB - Herpetic whitlow is an acute viral infection of the hand caused by either herpes simplex virus (HSV) 1 or 2. Its characteristic findings are significant pain and erythema with overlying nonpurulent vesicles. The differential diagnosis includes flexor tenosynovitis. We present a case of recurrent infection of the middle finger in an immunocompetent 19-year-old girl. Multiple painful pustules with tracking cellulitis were partially treated by oral antibiotics. A recurrence with positive Kanavel's signs suggested flexor tenosynovitis at seven months. Her symptoms improved transiently following emergent surgical open flexor sheath exploration and washout however, she required two further washouts; at eleven and thirteen months to improve symptoms. Viral cultures were obtained from the third washout as HSV infection was disclosed from further history taking. These were positive for HSV2. Treatment with acyclovir at thirteen months after presentation led to a complete resolution of her symptoms with no further recurrences to date. This rare case highlights the similarity in presentation between flexor sheath infection and herpetic whitlow which can lead to diagnostic confusion and mismanagement. We emphasise the importance of careful past medical history taking as well as considering herpetic whitlow as a differential diagnosis despite the presence of strongly positive Kanavel's signs. PMID- 25436166 TI - Primary squamous cell carcinoma of lung leading to metastatic jaw tumor. AB - Metastatic tumors to the orofacial region are unusual and they may occur in the oral soft tissues or jaw bones. Owing to their clinical variability the diagnosis of such tumors is often a dilemma. We report a unique case of mandibular metastasis which became the first evidence of an occult primary in the lung. PMID- 25436167 TI - Effectiveness and safety of infliximab in two cases of severe chondrocalcinosis: nine years of follow-up. AB - Objectives. To investigate the efficacy of infliximab in the treatment of severe calcium pyrophosphate deposition diseases (CPPD). Methods. Two patients with severe CPPD and diffuse idiopathic skeletal hyperostosis- (DISH-) like phenotype are described. Both patients were resistant to therapy with nonsteroidal anti inflammatory drugs (NSAIDs). Both patients were treated with infliximab, a TNF alpha receptor antagonist, for nine years. Results. Treatment with infliximab resulted in major clinical and laboratory improvements without relevant side effects. Conclusions. These results suggest that infliximab may be an effective treatment of severe CPDD. PMID- 25436168 TI - Pulmonary Nodules as an Initial Manifestation of Behcet's Disease. AB - Behcet's disease (BD) is a systemic vasculopathy, characterized by recurrent oral aphthae, genital ulcers, uveitis, and skin lesions. Although vascular involvement, including venous and arteries of any size, is a usual manifestation, cases with pulmonary thrombosis as the initial symptom are not common in the absence of pulmonary artery aneurysm (PAA). This report describes a 36-year-old man with recurrent fever, nonmassive hemoptysis, and persistent cough with lung nodules in CT scan who had undergone open lung biopsy. On the basis of morphological findings, BD was suggested and more precise evaluation confirmed the diagnosis. PMID- 25436169 TI - Intraneobladder Hem-o-Lok Migration with Stone Formation after Orthotopic Neobladder Cystectomy. AB - Introduction. Laparoscopic and robot-assisted laparoscopic surgery are widely performed in urology field, so Hem-o-Lok clips are thus extensively used in the laparoscopic procedures. We describe the first case of Hem-o-Lok clip which migrated into the neobladder with calculus formation 26 months after laparoscopic orthotopic neobladder cystectomy, which causes symptoms of gross hematuria and frequent urination. Case Presentation. A 57-year-old man with T2a muscle invasive bladder cancer underwent laparoscopic orthotopic sigmoid neobladder reconstruction after cystectomy which was complicated by intestinal anastomosis leak and peritoneal abscess requiring transverse colostomy and drainage 15 days postoperatively. Twenty-six months after cystectomy, he complained of gross hematuria and frequent urination. Computerized tomography and plain pelvic X-ray revealed a stone measuring approximately 2.8 cm in diameter in the neobladder. During cystoscopy, a closed whitish Hem-o-Lok clip was seen in the center of the calculi. No anastomotic leak or neoplasm was found during cystoscopy. Conclusion. Hem-o-Lok clip migration into the bladder after laparoscopic orthotopic neobladder cystectomy is a rare complication; the first reported case in the literature. To prevent Hem-o-Lok clip migration, it is recommended to avoid extensive use of Hem-o-Lok clip close to anastomosis site, and any loose Hem-o Lok clip should be retrieved before closure. PMID- 25436170 TI - The therapeutic effectiveness of the coadministration of weekly risedronate and proton pump inhibitor in osteoporosis treatment. AB - This trial was conducted to investigate the long-term effects of proton pump inhibitor (PPI) coadministration on the efficacy of weekly risedronate treatment for osteoporosis. Ninety-six women over 50 years old with low bone mineral density (BMD) participated in this trial. Subjects were randomly divided into 2 groups: a 17.5 mg dose of sodium risedronate was administered weekly, with or without a daily 10 mg dose of sodium rabeprazole (n = 49 and 47 in the BP + PPI and BP groups, resp.). The following biomarkers were measured at the baseline and every 3 months: bone-specific alkaline phosphatase, N-terminal telopeptide of type I collagen corrected for creatinine, parathyroid hormone, BMD of the lumbar spine, and physical parameters evaluated according to the SF-36v2 Health Survey. Statistical comparisons of these parameters were performed after 6, 12, 18, and 24 months. The Delta values of improvement in physical functioning after 12 months and bodily pain after 6 and 12 months in the BP + PPI group were significantly larger than those in the BP group. These results suggest that PPI does not adversely affect bone metabolism. Alternatively, approved bone formation by concomitant PPI treatment may have had favorable effects on the improvement of bodily pain and physical functions. PMID- 25436171 TI - Parathyroid gland involvement by thyroid cancer: results from a large series of thyroidectomies performed in two italian university hospitals and review of the literature. AB - Objectives.Parathyroid involvement by thyroid cancer (TC) has not been frequently investigated in thyroidectomy-based studies. We aimed to detect cases of parathyroid invasion by TC in a large series of thyroidectomies and to review the literature on this topic. Study Design. A 10-yr period database research was made from the files of the Section of Pathology of two Italian University Hospitals. Out of 22,310 thyroidectomies, 10 patients with parathyroid involvement by TC were found. Results. The 10 patients, 7 females and 3 males, aged 55 +/- 14 years (range 34-76, median 56) had papillary thyroid carcinoma and accounted for 0.4% of subjects affected by all TCs and submitted to thyroidectomy. The tumor invaded perithyroid soft tissues in 6 patients and central neck (level VI) lymph nodes in 3. Parathyroid involvement by TC occurred by infiltration in 6 cases, extension through an intervening pseudocapsule in 1, and both patterns in 3. All patients are alive and disease free at 5.6 +/- 3-yr follow-up. Conclusion. Limited to thyroidectomy series, our results and literature data suggest that parathyroid involvement by TC has a 0.4-3.9% incidence rate; mainly affects women in their sixth-seventh decade of life; is associated to a good prognosis, unless massive extrathyroid extension of TC occurs. PMID- 25436172 TI - Peritoneal reactivity evaluation in horses subjected to experimental small colon enterotomy and treated with subcutaneous heparin. AB - Heparin is routinely administered in postoperative abdominal surgery aiming to prevent adhesions formation; however, there is no consensus indicating its effectiveness. This study evaluated the effect of heparin on peritoneal reactivity after abdominal surgery, through the association between peritoneal fluid features and ultrasonographic and laparoscopic examination. Ten adult horses were used: control group (CG) and treated group (TG). Both groups underwent laparotomy and small colon enterotomy. TG received subcutaneous heparin at 150 IU/kg every 12 hours for 5 days. The animals underwent ultrasonography and peritoneal fluid examination prior to enterotomy (M0) 12 hours (M1), 1 day (M2), 2 days (M3), 4 days (M4), 6 days (M5), 10 days (M6), and 14 days after enterotomy (M7) with laparoscopic examination being performed on the fifth postoperative day. Peritoneal inflammatory response was observed in both groups. The peritoneal fluid of TG animals showed higher echogenicity during heparin therapy. No inflammatory difference was observed between groups through peritoneal fluid features, except for the higher D-dimer concentration in CG. On laparoscopy, slightly diffuse peritoneal reactivity for both groups was observed, being higher for TG. Laparoscopy and ultrasonography association allowed detailed access to the abdominal cavity. Ultrasonography assessed the diffuse peritoneal inflammation, and laparoscopy allowed the detailed analysis of the segments. No gross beneficial reactions resulting from the use of heparin on peritoneal reactivity were observed; however, it was observed by D-dimer evaluation that the TG had less fibrin deposition, which is directly related to a lower rate of abdominal adhesions formation. PMID- 25436173 TI - A Modified o-Phthalaldehyde Fluorometric Analytical Method for Ultratrace Ammonium in Natural Waters Using EDTA-NaOH as Buffer. AB - In the existence of appropriate amount of disodium ethylenediaminetetraacetate (EDTA), precipitation would not occur in seawater and other natural waters even if the sample solution was adjusted to strong basicity, and the NH3-OPA-sulfite reaction at the optimal pH range could be used to determine ammonium in natural waters. Based on this, a modified o-phthalaldehyde fluorometric analytical method has been established to determine ultratrace ammonium in natural waters. Experimental parameters, including reagent concentration, pH, reaction time, and effect of EDTA, were optimized throughout the experiments based on univariate experimental design. The results showed that the optimal pH range was between 10.80 and 11.70. EDTA did not obviously affect the fluorometric intensity. The linearity range of the proposed method was 0.032-0.500 umol/L, 0.250-3.00 umol/L, and 1.00-20.0 umol/L at the excitation/emission slit of 3 nm/5 nm, 3 nm/3 nm, and 1.5 nm/1.5 nm, respectively. The method detection limit was 0.0099 umol/L. Compared to the classical OPA method, the proposed method had the advantage of being more sensitive and could quantify ultratrace ammonium without enrichment. PMID- 25436174 TI - Simultaneous determination of uric Acid and xanthine using a poly(methylene blue) and electrochemically reduced graphene oxide composite film modified electrode. AB - Poly(methylene blue) and electrochemically reduced graphene oxide composite film modified electrode (PMB-ERGO/GCE) was successfully fabricated by electropolymerization and was used for simultaneous determination of uric acid (UA) and xanthine (Xa). Based on the excellent electrocatalytic activity of PMB ERGO/GCE, the electrochemical behaviors of UA and Xa were studied by cyclic voltammetry (CV) and square wave voltammetry (SWV). Two anodic sensitive peaks at 0.630 V (versus Ag/AgCl) for UA and 1.006 V (versus Ag/AgCl) for Xa were given by CV in pH 3.0 phosphate buffer. The calibration curves for UA and Xa were obtained in the range of 8.00 * 10(-8)~4.00 * 10(-4) M and 1.00 * 10(-7)~4.00 * 10(-4) M, respectively, by SWV. The detection limits for UA and Xa were 3.00 * 10(-8) M and 5.00 * 10(-8) M, respectively. Finally, the proposed method was applied to simultaneously determine UA and Xa in human urine with good selectivity and high sensitivity. PMID- 25436176 TI - Interactive-rate Motion Planning for Concentric Tube Robots. AB - Concentric tube robots may enable new, safer minimally invasive surgical procedures by moving along curved paths to reach difficult-to-reach sites in a patient's anatomy. Operating these devices is challenging due to their complex, unintuitive kinematics and the need to avoid sensitive structures in the anatomy. In this paper, we present a motion planning method that computes collision-free motion plans for concentric tube robots at interactive rates. Our method's high speed enables a user to continuously and freely move the robot's tip while the motion planner ensures that the robot's shaft does not collide with any anatomical obstacles. Our approach uses a highly accurate mechanical model of tube interactions, which is important since small movements of the tip position may require large changes in the shape of the device's shaft. Our motion planner achieves its high speed and accuracy by combining offline precomputation of a collision-free roadmap with online position control. We demonstrate our interactive planner in a simulated neurosurgical scenario where a user guides the robot's tip through the environment while the robot automatically avoids collisions with the anatomical obstacles. PMID- 25436175 TI - Assessing Acceptability of Short Message Service Based Interventions towards Becoming Future Voluntary Blood Donors. AB - All blood bank services, especially those of developing countries, face a major shortfall of blood donations due to lack of voluntary blood donors. Our study aims to evaluate the acceptability of Short Message Service based interventions towards becoming voluntary blood donors among medical university students of Karachi, Pakistan. Methods. A total of 350 medical students were approached in medical universities of Karachi, Pakistan, using a nonprobability convenient sampling technique. Data collectors administered a self-made questionnaire to each participant using an interview based format. All data was recorded and analyzed on SPSS 16. Results. 350 participants, having a mean age of 21.47 +/- 1.36, were included in our study with 30.6% (107/350) being males and 69.4% (243/350) being females. 93.4% (327/350) of participants agreed that donating blood was healthy, but only 26% had donated blood in the past with 79.1% donating voluntarily. 65.7% (230/350) of the participants agreed to take part in Short Message Service based behavioral interventions to become voluntary blood donors with 69.7% (244/350) also agreeing that Short Message Service reminders will promote them to donate blood more often. Conclusion. With university students willing to become voluntary blood donors, Pakistani blood banks can carry out Short Message Service based interventions to encourage them to donate blood. PMID- 25436177 TI - Is Insecurity Worse for Well-Being in Turbulent Times? Mental Health in Context. AB - Using General Social Survey data, we examine whether any association between job insecurity and well-being is contingent on economic climate (comparing those interviewed in turbulent 2010 vs. pre-recessionary 2006), as well as income and gender. We find respondents with higher levels of job insecurity in 2010 reported lower levels of happiness compared to those similarly insecure in 2006. The positive relationship between job insecurity and days of poor mental health becomes more pronounced for those in the 3rd quartile of personal income in 2010, suggesting middle-class vulnerability during the economic downturn. Men (but not women) with higher insecurity report more days of poor mental health in both 2006 and 2010. These findings reinforce a "cycles of control" theoretical approach, given the mental health-job insecurity relationship is heightened for workers in turbulent times. PMID- 25436178 TI - Driving after traumatic brain injury: evaluation and rehabilitation interventions. AB - The ability to return to driving is a common goal for individuals who have sustained a traumatic brain injury. However, specific and empirically validated guidelines for clinicians who make the return-to-drive decision are sparse. In this article, we attempt to integrate previous findings on driving after brain injury and detail the cognitive, motor, and sensory factors necessary for safe driving that may be affected by brain injury. Various forms of evaluation (both in clinic and behind-the-wheel) are discussed, as well as driver retraining and modifications that may be necessary. PMID- 25436179 TI - Maternal Familismo and early childhood functioning in Mexican and Dominican immigrant families. AB - A large theoretical and empirical literature documents the central role of familismo (i.e., a strong emphasis on family) in the functioning of Latino youth. Few studies, however, have examined its association with early childhood functioning. The present study explored the potential risk and protective effects of maternal familismo on the adaptive and mental health functioning of 4 - 5 year old Latino children. A sample of 205 Mexican and 147 Dominican immigrant families was recruited from New York City. Mothers reported on their level of familismo, and acculturative status. Mothers and teachers rated child adaptive behavior and internalizing and externalizing problems. Findings suggest that maternal familismo is not uniformly associated with positive or negative early developmental outcomes but that its effects are moderated by child gender, family poverty and cultural (e.g., maternal ethnic and US American identity) characteristics. In addition, different mechanisms were identified for each ethnic group. Familismo was associated both positively (for boys) and negatively (for poor children) with adaptive behavior in the Mexican American sample. In the Dominican American sample, familismo showed a wide range of positive, albeit moderated, effects. Prevention efforts that help parents critically evaluate the impact of familismo on family processes, and preserve those manifestations of familismo that are protective, may best promote Latino child well-being. PMID- 25436180 TI - Interference Mitigation for Cyber-Physical Wireless Body Area Network System Using Social Networks. AB - Wireless body area networks (WBANs) are cyber-physical systems (CPS) that have emerged as a key technology to provide real-time health monitoring and ubiquitous healthcare services. WBANs could operate in dense environments such as in a hospital and lead to a high mutual communication interference in many application scenarios. The excessive interferences will significantly degrade the network performance including depleting the energy of WBAN nodes more quickly, and even eventually jeopardize people's lives due to unreliable (caused by the interference) healthcare data collections. Therefore, It is critical to mitigate the interference among WBANs to increase the reliability of the WBAN system while minimizing the system power consumption. Many existing approaches can deal with communication interference mitigation in general wireless networks but are not suitable for WBANs due to their ignoring the social nature of WBANs. Unlike the previous research, we for the first time propose a power game based approach to mitigate the communication interferences for WBANs based on the people's social interaction information. Our major contributions include: (1) model the inter WBANs interference, and determine the distance distribution of the interference through both theoretical analysis and Monte Carlo simulations; (2) develop social interaction detection and prediction algorithms for people carrying WBANs; (3) develop a power control game based on the social interaction information to maximize the system's utility while minimize the energy consumption of WBANs system. The extensive simulation results show the effectiveness of the power control game for inter-WBAN interference mitigation using social interaction information. Our research opens a new research vista of WBANs using social networks. PMID- 25436182 TI - Progress in research on Tourette syndrome. AB - Tourette syndrome (TS) is a heritable neuropsychiatric disorder commonly complicated by obsessions and compulsions, but defined by frequent unwanted movements (motor tics) and vocalizations (phonic tics) that develop in childhood or adolescence. In recent years, research on TS has progressed rapidly on several fronts. Inspired by the Fifth International Scientific Symposium on Tourette Syndrome, the articles in this special issue review advances in the phenomenology, epidemiology, genetics, pathophysiology, and treatment of TS. PMID- 25436183 TI - The Prevalence of Tic Disorders and Clinical Characteristics in Children. AB - BACKGROUND: Prevalence is a simple statement about the frequency of a disease in the population. For many medical conditions, including Tourette syndrome, there are true cases that have not been previously diagnosed due to problems of access to appropriate clinical services. Therefore, to obtain a trustworthy estimate of prevalence, it is necessary to go beyond cases identified in clinical settings and evaluate community samples. METHOD: We reviewed 11 community surveys in children with Tourette syndrome (TS) published since 2000. We also examined the frequency of co-occurring psychiatric conditions in community samples and large clinically-ascertained samples. RESULTS: Transient tics are relatively common affecting as many as 20% of school-age children. The 11 studies reviewed here offer a wide range of estimates from 2.6 to 38 per 1000 children for TS. Six studies provide estimates in a narrower range from 4.3 to 7.6 per 1000, but the confidence interval around this narrower range remains wide. Six studies provided results on chronic tic disorders ranging from 3 to 50 per 1000 for Chronic Motor Tic Disorder and 2.5 to 9.4 per 1000 for Chronic Vocal Tic Disorder. Community samples and large clinically-ascertained samples consistently show high rates of ADHD, disruptive behavior and anxiety disorders in children with TS. CONCLUSIONS: The wide range of prevalence estimates for TS and chronic tic disorders is likely due to differences in sample size and assessment methods. The best estimate of prevalence for TS in school-age children is likely to fall between 4 and 8 cases per 1000. Clinical assessment of children with chronic tic disorders warrants examination of other problems such as ADHD, disruptive behavior and anxiety. PMID- 25436184 TI - Molecular recognition of live methicillin-resistant staphylococcus aureus cells using DNA aptamers. AB - AIM: To generate DNA-aptamers binding to Methicillin-resistant Staphylococcus aureus (MRSA). METHODS: The Cell-Systematic Evolution of Ligands by Exponential Enrichment (SELEX) technology was used to run the selection against MRSA bacteria and develop target-specific aptamers. MRSA bacteria were targeted while Enterococcus faecalis bacteria were used for counter selection during that process. Binding assays to determine the right aptamer candidates as well as binding assays on clinical samples were performed through flow cytometry and analyzed using the FlowJo software. The characterization of the aptamers was done by determination of their Kd values and determined by analysis of flow data at different aptamer concentration using SigmaPlot. Finally, the recognition of the complex Gold-nanoparticle-aptamer to the bacteria cells was observed using transmission electron microscopy (TEM). RESULTS: During the cell-SELEX selection process, 17 rounds were necessary to generate enrichment of the pool. While the selection was run using fixed cells, it was shown that the binding of the pools with live cells was giving similar results. After sequencing and analysis of the two last pools, four sequences were identified to be aptamer candidates. The characterization of those aptamers showed that based on their Kd values, DTMRSA4 presented the best binding with a Kd value of 94.61 +/- 18.82 nmol/L. A total of ten clinical samples of MRSA , S. aureus and Enterococcus faecalis were obtained to test those aptamers and determine their binding on a panel of samples. DTMRSA1 and DTMRSA3 showed the best results regarding their specificity to MRSA , DTMRSA1 being the most specific of all. Finally, those aptamers were coupled with gold nanoparticle and their binding to MRSA cells was visualized through TEM showing that adduction of nanoparticles on the aptamers did not change their binding property. CONCLUSION: A total of four aptamers that bind to MRSA were obtained with Kd values ranking from 94 to 200 nmol/L. PMID- 25436181 TI - Molecular Advances Leading to Treatment Implications for Fragile X Premutation Carriers. AB - Fragile X syndrome (FXS) is the most common single gene cause of intellectual disability and it is characterized by a CGG expansion of more than 200 repeats in the FMR1 gene, leading to methylation of the promoter and gene silencing. The fragile X premutation, characterized by a 55 to 200 CGG repeat expansion, causes health problems and developmental difficulties in some, but not all, carriers. The premutation causes primary ovarian insufficiency in approximately 20% of females, psychiatric problems (including depression and/or anxiety) in approximately 50% of carriers and a neurodegenerative disorder, the fragile X associated tremor ataxia syndrome (FXTAS), in approximately 40% of males and 16% of females later in life. Recent clinical studies in premutation carriers have expanded the health problems that may be seen. Advances in the molecular pathogenesis of the premutation have shown significant mitochondrial dysfunction and oxidative stress in neurons which may be amenable to treatment. Here we review the clinical problems of carriers and treatment recommendations. PMID- 25436186 TI - Expression and purification of functional human vascular endothelial growth factor-a121; the most important angiogenesis factor. AB - PURPOSE: Angiogenesis or formation of new blood vessels is an essential process for tumor growth, invasion and metastasis. Vascular Endothelial Growth Factor (VEGF) and its receptors play an important role in angiogenesis-dependent tumors. VEGF-A is the most important factor in angiogenesis process. Human VEGF-A gene consists of eight exons that undergoes alternative exon splicing and produce five different proteins consisting of 121, 145, 165, 189 and 206 amino acids (named VEGF121, VEGF145, VEGF165, VEGF189, and VEGF206). METHODS: In this study, VEGF121 gene synthesized and cloned into the pET-26b plasmid. The recombinant plasmid was transferred into appropriate expression strain of BL-21. Expression of VEGF121 induced by IPTG (Isopropyl beta-D-1-thiogalactopyranoside) and confirmed by SDS PAGE and Western-Blotting. Recombinant VEGF121 was purified by nickel affinity chromatography. HUVECs (Human Umbilical Vein Endothelia Cells) cells were isolated from umbilical vein and the effect of VEGF121 on tube formation of endothelial cells was investigated. RESULTS: SDS-PAGE and Western-Blotting results verified the purification of VEGF121. The final yield of recombinant protein was about 5mg per liter. Endothelial cell tube formation assay results showed that VEGF121 leads to tube formation of endothelial cell on matrix and induces angiogenesis in vitro. CONCLUSION: Recombinant VEGF121 is important factor in tube formation of endothelial cell, so it could be used in different cancer researches and angiogenesis assay. PMID- 25436185 TI - RNA interference and its role in cancer therapy. AB - In todays' environment, it is becoming increasingly difficult to ignore the role of cancer in social health. Although a huge budget is allocated on cancer research every year, cancer remains the second global cause of death. And, exclusively, less than 50% of patients afflicted with advanced cancer live one year subsequent to standard cancer treatments. RNA interference (RNAi) is a mechanism for gene silencing. Such mechanism possesses uncanny ability in targeting cancer-related genes. A majority of gene products involved in tumorigenesis have recently been utilized as targets in RNAi based therapy. The evidence from these studies indicates that RNAi application for targeting functional carcinogenic molecules, tumor resistance to chemotherapy and radiotherapy is required in today's cancer treatment. Knock downing of gene products by RNAi technology exerts antiproliferative and proapoptotic effects upon cell culture systems, animal models and in clinical trials in the most studies. The recognition of RNAi mechanism and the progress in this field leaded several new RNAi-based drugs to Clinical Trial phases. This has also developed genome based personalized cancer therapeutics. Hopefully, this type of treatment will work as one of the efficient one for cancer patients. PMID- 25436187 TI - Effects of formulation variables and storage conditions on light protected vitamin B12 mixed parenteral formulations. AB - PURPOSE: In this research the effect of vitamin B1 and B6 on cyanocobalamin stability in commercial light protected parenteral formulations and upon adding stabilizing agents will be investigated and best formulation composition and proper storage condition will be introduced. METHODS: In this research some additives such as co solvents and tonicity adjusters, surfactants, antioxidants and chelating agents as well as buffer solutions, were used to improve the stability of the parenteral mixed formulations of B12 in the presence of other B vitamins (B1 and B6). Screening tests and accelerated stability tests were performed according to ICH guidelines Q1A (R2). RESULTS: Shelf life evaluation revealed the best formulation and the proper storage condition. The results indicated the first kinetic models for all tested formulations and the optimum pH value was determined to be 5.8. There was no evidence of B12 loss when mixed with B1 and B6 in a medical syringe at room temperature for maximum of 8 hours. CONCLUSION: It is necessary to formulate vitamin B12 mixed parenteral solutions using proper phosphate buffers (pH=5.8) and to indicate "Store in refrigerator" on the mixed parenteral formulations of vitamin B12 with other B vitamins, which has not been expressed on the label of tested Brand formulations at the time of this study. PMID- 25436188 TI - Ghrelin increases lymphocytes in chronic normobaric hypoxia. AB - PURPOSE: Hypoxia is a condition of decreased availability of oxygen. To adapt hypoxia, some changes in blood cells occur in the body. The aim of this study was to evaluate the effect of ghrelin on different types of blood cell in normobaric hypoxia situation. METHODS: Thirty-two animals were divided in 4 groups (n=8): control (C), ghrelin (G), hypoxia (H), and hypoxic animals that received ghrelin (H+G). Hypoxia (11%) was induced by an Environmental Chamber System GO2 Altitude. Animals in ghrelin groups received a subcutaneous injection of ghrelin (150 μg/kg/day) for 14 days. RESULTS: Our results show that ghrelin significantly (p<0.05) increased RBC and Hct levels, whereas it significantly (p<0.05) decreased lymphocytes in the blood. RBC, Hct, Hb concentration, platelet and MCV increased significantly (p<0.05) in hypoxic conditions but lymphocytes, monocytes and Polymorphonuclears did not show any significant changes. Platelets had a significant (p<0.05) decrease in hypoxic conditions and ghrelin administration in hypoxic conditions could increase lymphocyte levels significantly (p<0.05). CONCLUSION: Effect of ghrelin on blood cells could be related to blood oxygen level. Ghrelin in normal oxygen conditions increases RBC and Hct levels but decreases lymphocytes, whereas in hypoxic conditions, ghrelin increases blood lymphocytes. PMID- 25436189 TI - The preventive effect of atorvastatin on paraquat-induced pulmonary fibrosis in the rats. AB - PURPOSE: Pulmonary fibrosis is a potentially lethal inflammatory disease and there has been no effective medication for this progressive disease up to now. As a model, different therapeutic approaches have been applied for paraquat-induced pulmonary injury and fibrosis. Atorvastatin besides cholesterol-lowering effects possesses anti-inflammatory and anti-oxidant properties. The current study was designed to investigate the preventive anti-fibrotic effects of atorvastatin on paraquat-induced pulmonary fibrosis in rats. METHODS: The rats were randomly divided into five experimental groups. Group I, control group (saline), group II received a single oral dose of 20 mg/kg paraquat with no treatment and III, IV and V groups received atorvastatin at the doses of 10, 20, and 40 mg/kg/day orally one week before and three weeks after paraquat administration, respectively. The rats were sacrificed 21 days after paraquat. Lung hydroxyproline and serum levels of malondialdehyde (MDA) were determined and lung indices and semi-quantitative histopathological changes were evaluated. RESULTS: Paraquat could significantly increase the serum MDA and lung hydroxyproline levels. Elevated content of tissue hydroxyproline and serum levels of malondialdehyde induced by paraquat, attenuated by atorvastatin at the doses of 10, 20 and 40 mg/kg. Furthermore, histopathological findings and the amount of lung indices showed the beneficial preventive role of atorvastatin in rat pulmonary fibrosis induced by paraquat. CONCLUSION: In conclusion, the present data show that atorvastatin alleviate the toxic effects of paraquat under the experimental circumstances and may be a useful agent in cases who are in contact or poisoned with paraquat. PMID- 25436190 TI - High-performance liquid chromatographic determination of propofol in human plasma: comparison of different heteroscedastic calibration curve models. AB - PURPOSE: The aim of this study was to select the best calibration model for determination of propofol plasma concentration by high-performance liquid chromatography method. METHODS: Determination of propofol in plasma after deproteinization with acetonitrile containing thymol (as internal standard) was carried out on a C18 column with a mixture of acetonitrile and trifluoroacetic acid 0.1% (60:40) as mobile phase which delivered at the flow rate of 1.2 mL/minute . Fluorescence detection was done at the excitation and emission wavelengths of 276 and 310 nm, respectively. After fitting different equations to the calibration data using weighted regression, the adequacy of models were assessed by lack-of-fit test, significance of all model parameters, adjusted coefficient of determination (R(2) adjusted) and by measuring the predictive performance with median relative prediction error and median absolute relative prediction error of the validation data set. RESULTS: The best model was a linear equation without intercept with median relative prediction error and median absolute relative prediction error of 4.0 and 9.4%, respectively in the range of 10-5000 ng/mL. The method showed good accuracy and precision. CONCLUSION: The presented statistical framework could be used to choose the best model for heteroscedastic calibration data for analytes like propofol with wide range of expected concentration. PMID- 25436191 TI - Amino Acid profile as a feasible tool for determination of the authenticity of fruit juices. AB - PURPOSE: Fruit juice is a nutrient rich food product with a direct connection to public health. The purpose of this research was to determine the amino acid profile of juices and provide a quick and accurate indicator for determining their authenticity. METHODS: The method of analysis was HPLC with fluorescence detector and pre-column derivatization by orthophtaldialdehyde (OPA). Sixty-six samples of fruit juices were analyzed, and fourteen amino acids were identified and determined in the sampled fruit juices. The fruit samples used for this analysis were apples, oranges, cherry, pineapple, mango, apricot, pomegranate, peach and grapes. RESULTS: The results showed that 32% of samples tested in this study had a lower concentrate percentage as compared to that of their labels and/or other possible authenticity problems in the manufacturing process. The following samples showed probable adulteration: four cherry juice samples, two pomegranate juice samples, one mango, three grape, four peach, seven orange, two apple and one apricot juice samples. CONCLUSION: In general, determining the amount of amino acids and comparing sample amino acids profiles with the standard values seems to be an indicator for quality control. This method can provide the regulatory agencies with a tool, to help produce a healthier juice. The aim of this study is the analytical control of the fruit juice composition is becoming an important issue, and HPLC can provide an important and essential tool for more accurate research as well as for routine analysis. PMID- 25436192 TI - Effects of preoperative non-steroidal anti-inflammatory drugs on pain mitigation and patients' shoulder performance following rotator cuff repair. AB - PURPOSE: Pain is one of the most important factors adversely affecting clinical outcomes of operated patients. The present study aims at evaluating effects of preoperative COX2 non-steroidal anti-inflammatory inhibitors on pain mitigation and performance of patients with shoulder rotator cuff tear. METHODS: This case control study was conducted on 60 patients suffering from rotator cuff injury candidate for arthroscopic repair. The patients were classified in two parallel and matched groups. One group (case group) was treated using Celecoxib (200mg/12h) started 48 hours before surgery and continued for 10 days after operation. In the control group, the placebo was prescribed in the same way. Postoperative pain, side effects, sleep disturbance, and short-term outcomes were compared between two groups using DASH questionnaire. RESULTS: Postoperative pain in the Celecoxib group significantly decreased in comparison with the control one. The difference was statistically meaningful (P<0.001). Well motion ability was seen in 80% of patients of the Celecoxib group. It was 26.6% in the placebo group since pain inhibited them from exercising more motions. In this regard, there was a statistically meaningful difference between these two groups (P=0.02). Sleep disturbance was meaningfully at higher levels in the placebo group (P=0.001). Following up the patients for three months, it was made clear that performance of the Celecoxib group was better than that of the placebo one. CONCLUSION: COX2 inhibitors are well efficient in patients' pain management after arthroscopic rotator cuff repair surgery. It results in less life complications, less sleep disturbances, improvement of patients' short-term clinical outcome, and more quick recovery. PMID- 25436193 TI - Development and physicochemical characterization of sirolimus solid dispersions prepared by solvent evaporation method. AB - PURPOSE: The aim of the present investigation was preparation and characterization of sirolimus solid dispersions by solvent evaporation technique to improve its dissolution properties. METHODS: Polyvinylpyrrolidone (PVP), Poloxamer 188 and Cremophore RH40 were used to prepare the solid dispersions of sirolimus. In vitro dissolution study using USP type I apparatus, were performed in distilled water (containing SLS 0.4%) for pure sirolimus, physical mixtures, Rapamune and prepared solid dispersions. The characterization of solid dispersions was performed using Fourier Transform Infrared (FTIR) Spectroscopy and Differential Scanning Calorimetry (DSC). RESULTS: More than 75% of sirolimus was released within 30 minutes from all prepared solid dispersions. The dissolution rate of all prepared solid dispersion powders were more than physical mixtures. The absence of sirolimus peak in the DSC spectrum of solid dispersions indicated the conversion of crystalline form of sirolimus into amorphous form. The results from FT-IR spectroscopy showed that there was no significant change in the FT-IR spectrum of solid dispersions indicating absence of well-defined interaction between drug and carriers. CONCLUSION: It was concluded that solid dispersion method, using PVP, Poloxamer 188 and Cremophore RH40 can improve dissolution rate of sirolimus. PMID- 25436194 TI - Effect of adding oral calcium dobesilate to laser photocoagulation on the macular thickness in patients with diabetic macular edema: a randomized clinical trial. AB - PURPOSE: To evaluate the effect of oral calcium dobesilate (Doxium) on macular thickness in clinically significant macular edema (CSME). METHODS: Overall, 71 eyes of 40 patients with non-proliferative diabetic retinopathy and clinically significant macular edema were included. All patients were received laser treatment for macular edema. Coherence optical tomography was used to determine the retinal thickness. Patients were randomized into two groups: group A received three Doxium capsule daily and group B received three placebo capsule daily for six months. RESULTS: The mean macular thickness before and after treatment in the group A was 340 and 257 micrometers respectively (24.5% reduced), and in the group B was 336 micrometers and 263 micrometers respectively (21.5% reduced). Macular thickness significantly decreased after treatment in both groups and the reduction in group A is higher but the difference of reduction between the two groups was not statistically significant (P>0.05). CONCLUSION: In respect to the effect of adding oral Doxium to Laser Photocoagulation on the macular thickness in patients with diabetic macular edema, this study showed no statistically significant difference between Doxium and placebo. PMID- 25436195 TI - Interaction of palmitic Acid with metoprolol succinate at the binding sites of bovine serum albumin. AB - PURPOSE: The aim of this study was to characterize the binding profile as well as to notify the interaction of palmitic acid with metoprolol succinate at its binding site on albumin. METHODS: The binding of metoprolol succinate to bovine serum albumin (BSA) was studied by equilibrium dialysis method (ED) at 27 degrees C and pH 7.4, in order to have an insight in the binding chemistry of the drug to BSA in presence and absence of palmitic acid. The study was carried out using ranitidine as site-1 and diazepam as site-2 specific probe. RESULTS: Different analysis of binding of metoprolol succinate to bovine serum albumin suggested two sets of association constants: high affinity association constant (k1 = 11.0 x 10(5) M(-1)) with low capacity (n1 = 2) and low affinity association (k2 = 4.0*10(5) M(-1)) constant with high capacity (n2 = 8) at pH 7.4 and 27 degrees C. During concurrent administration of palmitic acid and metoprolol succinate in presence or absence of ranitidine or diazepam, it was found that palmitic acid displaced metoprolol succinate from its binding site on BSA resulting reduced binding of metoprolol succinate to BSA. The increment in free fraction of metoprolol succinate was from 26.27% to 55.08% upon the addition of increased concentration of palmitic acid at a concentration of 0*10(-5) M to 16*10(-5) M. In presence of ranitidine and diazepam, palmitic acid further increases the free fraction of metoprolol succinate from 33.05% to 66.95% and 40.68% to 72.88%, respectively. CONCLUSION: This data provided the evidence of interaction at higher concentration of palmitic acid at the binding sites on BSA, which might change the pharmacokinetic properties of metoprolol succinate. PMID- 25436196 TI - Formulation and characterization of cetylpyridinium chloride bioadhesive tablets. AB - PURPOSE: Bioadhesive polymers play an important role in biomedical and drug delivery applications. The aim of this study is to develop a sustained- release tablet for local application of Cetylpyridinium Chloride (CPC). This delivery system would supply the drug at an effective level for a long period of time, and thereby overcome the problem of the short retention time of CPC and could be used for buccal delivery as a topical anti-infective agent. METHODS: CPC bioadhesive tablets were directly prepared using 7 mm flat-faced punches on a hydraulic press. The materials for each tablet were weighted, introduced into the die and compacted at constant compression pressure. The dissolution tests were performed to the rotation paddle method and the bioadhesive strength of the tablets were measured. RESULTS: The results showed that as the concentration of polymer increased, the drug release rate was decreased. Also the type and ratio of polymers altered the release kinetic of Cetylpyridinium Chloride from investigated tablets. The bioadhesion strength increased with increasing the concentration of polymer and maximum bioadhesion strength was observed with HPMC K100M. CONCLUSION: The selected formulation of CPC bioadhesive tablet can be used as a suitable preparation for continuous release of CPC with appropriate bioadhesion strength. PMID- 25436197 TI - Development and characterization of solid dispersion for dissolution improvement of furosemide by cogrinding method. AB - PURPOSE: The purpose of this study was to prepare and characterize solid dispersion formulation of furosemide to enhance dissolution rate. METHODS: Solid dispersions with different drug: carrier ratios were prepared by cogrinding method using crospovidone and microcrystalline cellulose as carrier. The physical state and interactions between the drug and carrier were characterized by Fourier transform infrared spectroscopic (FT-IR) and X ray diffraction (XRD). RESULTS: Solid dispersions (especially with drug: Carrier ratio of 1:2) showed a higher dissolution rate than their respective physical mixture and pure furosemide. Dissolution rate in pH 5.8 was also higher than pH 1.2. The XRD analysis showed that crystalline form was changed to the amorphous state in the solid dispersions. FT-IR analysis did not show any physicochemical interactions in the solid dispersion formulations. Release kinetic of formulations were fitted best to the Weibull and Wagner log probability (linear kinetic) as well as suggested 2 and Gompertz (non-linear kinetic) models. CONCLUSION: The dissolution properties of furosemide were improved with the use of hydrophilic carriers in solid dispersions due to change in the crystalline form of the drug and more intimate contact between drug and carriers which was dependent on the type and ratio of carrier as well as dissolution medium pH. PMID- 25436198 TI - Mefenamic Acid induced nephrotoxicity: an animal model. AB - PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are used for the treatment of many joint disorders, inflammation and to control pain. Numerous reports have indicated that NSAIDs are capable of producing nephrotoxicity in human. Therefore, the objective of this study was to evaluate mefenamic acid, a NSAID nephrotoxicity in an animal model. METHODS: Mice were dosed intraperitoneally with mefenamic acid either as a single dose (100 or 200 mg/kg in 10% Dimethyl sulfoxide/Palm oil) or as single daily doses for 14 days (50 or 100 mg/kg in 10% Dimethyl sulfoxide/Palm oil per day). Venous blood samples from mice during the dosing period were taken prior to and 14 days post-dosing from cardiac puncture into heparinized vials. Plasma blood urea nitrogen (BUN) and creatinine activities were measured. RESULTS: Single dose of mefenamic acid induced mild alteration of kidney histology mainly mild glomerular necrosis and tubular atrophy. Interestingly, chronic doses induced a dose dependent glomerular necrosis, massive degeneration, inflammation and tubular atrophy. Plasma blood urea nitrogen was statistically elevated in mice treated with mefenamic acid for 14 days similar to plasma creatinine. CONCLUSION: RESULTS from this study suggest that mefenamic acid as with other NSAIDs capable of producing nephrotoxicity. Therefore, the study of the exact mechanism of mefenamic acid induced severe nephrotoxicity can be done in this animal model. PMID- 25436199 TI - Stability indicating liquid chromatographic method for the simultaneous determination of rosuvastatin and ezetimibe in pharmaceutical formulations. AB - PURPOSE: A simple stability indicating reverse phase liquid chromatographic method was developed for the simultaneous determination of rosuvastatin and ezetimibe in pharmaceutical formulations. METHODS: Best chromatographic response was achieved with C18 column (250 X 4.6 mm, 5um) with photo diode array (PDA) detector. The mobile phase was composed of a mixture of sodium acetate buffer (pH 4.0) and acetonitrile (30:70, %v/v) with a flow rate of 1.2 mL/min. (UV detection at 254 nm). Rosuvastatin and ezetimibe were subjected to stress conditions of degradation and the method was validated as per ICH guidelines. RESULTS: The method shows linearity over a concentration range of 0.5-250 ug/ml for both rosuvastatin (r2 = 0.9993) and ezetimibe (r2 = 0.9996). Both the drugs are highly sensitive towards alkaline conditions in comparison to other stress conditions. CONCLUSION: The proposed method can be successfully applied to perform long-term and accelerated stability studies for the simultaneous determination of rosuvastatin and ezetimibe in pharmaceutical formulations. PMID- 25436201 TI - Inhibition of mitochondrial permeability transition pore restores the cardioprotection by postconditioning in diabetic hearts. AB - BACKGROUND: Cardiovascular risk factors, including diabetes mellitus may attenuate the cardioprotection by postconditioning. This study aimed to investigate the cardioprotective effect of ischemic-postconditioning (IPostC) against ischemia/reperfusion injury in normal and chronically type-1 diabetic rats and the effect of mitochondrial permeability transition pore (mPTP) inhibition in this field. METHODS: Diabetes was induced by a single intra peritoneal injection of streptozotocin (50 mg/kg) in Wistar male rats (250-300 g). After 8 weeks, the hearts of control and diabetic animals were isolated and mounted on a constant-pressure Langendorff apparatus. All hearts were subjected to 30 min regional ischemia followed by 45 min reperfusion (by occluding and re opening of LAD coronary artery, respectively). At the end of ischemia, the hearts received IPostC, cyclosporine-A, or both or none of them. Myocardial creatine kinase (CK) release as an index of tissue injury was measured spectrophotometery in coronary effluent in reperfusion phase. Infarct size was identified by triphenyltetrazolium chloride staining. Heart rate, left ventricular end diastolic pressure (LVEDP), LV systolic pressure (LVSP), rate-pressure product (RPP) and coronary flow were recorded throughout the experiment. RESULTS: IPostC, applied at the onset of reperfusion, failed to improve myocardial LVEDP and RPP, or reduce tissue damage indicated by infarct size and CK release in diabetic hearts, while it significantly recovered these parameters toward the pre-ischemic values in control hearts (P < 0.05). In contrast, with simultaneous inhibition of mPTP using cyclosporine-A, the cardioprotective effects of IPostC on myocardial hemodynamics, infarct size and CK release were significantly restored in diabetic hearts (P < 0.05). CONCLUSIONS: The loss of cardioprotection by IPostC in diabetic state can be overcome by increasing the potency of protective IPostC through its co-application with mPTP inhibition. PMID- 25436203 TI - Walking in intensive care unit while recovering from heart transplantation. PMID- 25436202 TI - Impact of family support improvement behaviors on anti diabetic medication adherence and cognition in type 2 diabetic patients. AB - BACKGROUND: Glycaemic control is the main goal of treatment for type 2 diabetic patients. Hyperglycaemia may result in cognitive decline. More family support may increase medication adherence and decrease glycaemic level. The purpose of this study was to determine the impact of family support improvement behavior on anti diabetic medication adherence and cognition in type 2 diabetic patients. METHOD: The randomized control trial study was conducted on 91 patients from an outpatient diabetes clinic. They were randomly divided to intervention (n = 45) and control (n = 46) group. Data on the patients' demographic information and their family gathered using a questionnaire, For two groups Morisky Medication Adherence Scale (MMAS), drug administration part of Diabetes Social Support Questionnaire - family version (DSSQ), Number Connection Test (NCT) were applied and hemoglobin A1C was measured two times in the onset of study and three months later for control group and before and after intervention for intervention group. The key family members of the intervention group were taught according to their educational needs in small groups. RESULT: In intervention group mean of NCT score was significantly decreased after intervention (P = 0.006) however in the control group there was no significant difference after three months. In intervention group a significant correlation was noted between DSSQ scores and MMAS scores after intervention(r =0.67, P < 0.001) but, there was no significant correlation in the control group. CONCLUSION: Family support instruction based on the educational needs of family members, may improve medication adherence through direct effect and cognitive status with indirect effect. PMID- 25436204 TI - Anesthesia for cardiac catheterization procedures. AB - Anesthesiologist's involvement for the purpose of diagnostic and interventional procedures in cardiac catheterization laboratory has been evolving particularly since last two decades. Catheterization laboratory environment poses certain challenges for the anesthesiologist including unfamiliar remote location, exposure to radiation, limited help from colleagues and communication with cardiologists. Anesthesiologists working in catheterization laboratory are required to have adequate knowledge of the environment, personnel, fluoroscope, echocardiography and type of radio contrast dye during the procedure. Anyone who is exposed to radiation environment is expected to protect himself from the exposure and must also wear a dosimeter for cumulative exposure tracing. There is no ideal anesthetic technique and the decision about sedation, general anesthesia or regional anesthesia for the procedure has to be made by attending anesthesiologists in consultation with cardiologists. Anesthesiologists should always try to minimize the effects of anesthesia on cardiovascular system. In addition, oxygenation and ventilatory management should be done according to the diagnostic procedure as it can also influence the diagnosis particularly in pediatric cath procedures. Since more complex procedures are being done in cardiac catheterization laboratory, it is the responsibility of anesthesia department to train and assign dedicated anesthesiologists for new challenges. Role of anesthetist should be well defined so that there is no confrontation during patient management. Sedation in cardiac catheterization laboratory by non anesthetists is also an issue, which can be sorted out by making policies and protocol in consultation with cardiologists. PMID- 25436205 TI - Network meta-analysis on the comparative effectiveness and safety of transcatheter aortic valve implantation with CoreValve or Sapien devices versus surgical replacement. AB - INTRODUCTION: Surgical replacement for aortic stenosis is fraught with complications in high-risk patients. Transcatheter techniques may offer a minimally invasive solution, but their comparative effectiveness and safety is uncertain. We performed a network meta-analysis on this topic. METHODS: Randomized trials on transcatheter aortic valve replacement vs surgery were searched. The primary outcome was all cause death. Risk estimates were obtained with Bayesian network meta-analytic methods. RESULTS: Four trials with 1,805 patients were included. After a median of 8 months, risk of death and myocardial infarction was not different when comparing surgery versus transcatheter procedures, irrespective of device or access. Conversely, surgery was associated with higher rates of major bleeding (odds ratio vs CoreValve=3.03 [95% credible interval: 2.23-4.17]; odds ratio vs transfemoral Sapien =1.82 [1.21-2.70]; odds ratio vs transapical Sapien =2.08 [1.20-3.70]), and acute kidney injury (odds ratio vs CoreValve =2.08 [1.33-3.32]; odds ratio vs transapical Sapien =2.78 [2.21-99.80]), but lower rates of pacemaker implantation (odds ratio vs CoreValve =0.41 [0.28-0.59]), and moderate or severe aortic regurgitation (odds ratio vs CoreValve =0.06 [0.02-0.27]; odds ratio vs Sapien=0.17 [0.02-0.76]). Strokes were less frequent with CoreValve than with transfemoral Sapien (odds ratio =0.32 [0.13-0.73]) or transapical Sapien (odds ratio =0.33 [0.10-0.93]), whereas pacemaker implantation was more common with CoreValve (odds ratio vs surgery =2.46 [1.69-3.61]; odds ratio vs transfemoral Sapien =2.22 [1.27-3.85]). CONCLUSIONS: Survival after transcatheter or surgical aortic valve replacement is similar, but there might be differences in the individual safety and effectiveness profile between the treatment strategies and the individual devices used in transcatheter aortic valve implantation. PMID- 25436206 TI - The effect of prior percutaneous coronary intervention on the immediate and late outcome after coronary artery bypass grafting: systematic review and meta analysis. AB - INTRODUCTION: A number of studies reported on a possible increased risk of morbidity and mortality after coronary artery bypass grafting in patients with prior percutaneous coronary intervention. METHODS: A systematic review and meta analysis of studies comparing the outcome of patients undergoing coronary surgery with or without prior percutaneous coronary intervention was performed. Only studies reporting results of adjusted analysis and excluding acute percutaneous coronary intervention failures were included in this meta-analysis. RESULTS: Literature search yielded nine studies reporting on 68,645 patients who underwent coronary surgery. Of them, 8,358 (12.2%) had a prior percutaneous coronary intervention. Patients without prior percutaneous coronary intervention were significantly older (p=0.002), had significantly higher prevalence of left main stenosis (p=0.005) and three-vessel disease (p<0.0001). Prior percutaneous coronary intervention was associated with higher risk of resternotomy for bleeding (p=0.04) and dialysis (p=0.003). Thirty-day/in-hospital mortality was significantly higher in patients with prior percutaneous coronary intervention (pooled rate: 2.7% vs 2.0%, risk ratio 1.39, 95% confidence interval 1.06-1.84, p=0.02) as confirmed also by generic inverse variance analysis (risk ratio 1.47, 95% confidence interval 1.12-1.93, p=0.005). Prior percutaneous coronary intervention did not affect late outcome (five studies included, risk ratio 1.07, 95% confidence interval 0.90-1.28, p=0.43). CONCLUSIONS: Prior percutaneous coronary intervention seems to be associated with an increased risk of immediate postoperative morbidity and mortality after coronary surgery, but does not affect late mortality. These results are not conclusive and need to be confirmed by studies of better quality evaluating the impact of indication, timing, type of stents, amount of treated vessels and number of previous percutaneous coronary interventions. PMID- 25436207 TI - Effects of transcatheter aortic valve implantation on left ventricular mass and global longitudinal strain: tissue Doppler and strain evaluation. AB - INTRODUCTION: Transcatheter aortic valve implantation is the option of choice for high surgical risk patients suffering from symptomatic aortic stenosis. We aimed to evaluate the influence of baseline global longitudinal strain on left ventricular mass regression after the procedure. METHODS: We enrolled 23 patients with pure symptomatic severe aortic stenosis who underwent CoreValve prosthesis (Medtronic, Minneapolis, MN) implantation. Everyone had echocardiography registration before the procedure and after six months in order to analyze two-, three-, and four-chamber peak longitudinal strain and global longitudinal strain. RESULTS: After the procedure New York Heart Association class, peak and mean aortic valve gradients (p<0.001 for all) improved. Interventricular septum and posterior wall thicknesses decreased (p<0.001 for both). Moreover, left ventricular mass index for body surface area changed from 190+/-44 to 143+/-30 g/m(2), (p<0.001). Finally, global longitudinal strain significantly increased (from 9.4+/-0.9 to 11.5+/-0.8%; p<0.001), as well as its components. Baseline global longitudinal strain correlated with left ventricular mass regression (r=0.560; p=0.005; 2-sided) and predicted it at linear regression analysis (B=23.707; p=0.005; adjusted R(2)=0.281). CONCLUSIONS: Global longitudinal strain and its components improved six months after the procedure. Moreover, baseline global longitudinal strain seemed to predict left ventricular mass regression in patients with pure aortic stenosis undergoing transcatheter aortic valve implantation. This finding could be related to the extent of myocardial fibrosis which is also responsible for lack of left ventricular mass regression and poorer prognosis. PMID- 25436208 TI - Mobile ECMO team for inter-hospital transportation of patients with ARDS: a retrospective case series. AB - INTRODUCTION: Transport of patients undergoing extracorporeal membrane oxygenation is currently available in 5 referral centers in our country. METHODS: Retrospective case series of patients managed by our mobile extracorporeal membrane oxygenation team and transferred to San Gerardo University Hospital from December 2004 to December 2012. RESULTS: 42 patients were transported. The mean age was 42.11 (standard deviation +/-18.11) years, with a range between 2 years and 70. 14 patients were females (33%) and 28 males (67%). The average transport distance was 121.69 km (+/-183.08) with a range between 9 km and 1044 Km. The mission's mean time was equal to 508 minutes (+/-185) with range of 120-960 minutes. 29 patients (69%) were transported with extracorporeal membrane oxygenation support, while 13 patients (31%) were transported with conventional ventilation. In 28 patients (97%) a veno-venous bypass was utilized, while in one case (3%) a Veno-Arterial cannulation was performed. 32 patients survived (76%) and have been discharged alive from hospital. No major clinical or technical issues were observed during the transport. CONCLUSIONS: According to our data, we conclude that a dedicated mobile team allowed safe ground transportation of patients with severe acute lung injury to our tertiary care institution. PMID- 25436209 TI - Isoproterenol infusion and microcirculation in septic shock. AB - INTRODUCTION: Our study primarily aimed at investigating the effect of isoproterenol infusion on tissue oxygen saturation in patients with septic shock. The secondary aim was to assess the relation between cardiac index, central venous oxygen saturation and tissue oxygen saturation. METHODS: This retrospective study was conducted from December 2010 to March 2012. We included 14 consecutive patients with septic shock treated with isoproterenol. All patients were monitored by cardiac index and tissue oxygen saturation. From medical charts, routine hemodynamic data were extracted one hour before and six hours after the onset of isoproterenol infusion. RESULTS: From baseline to H6, tissue oxygen saturation levels rise from 78 [72-82]% to 85 [78-88]% (p = 0.03). Isoproterenol infusion was associated with an increase of central venous oxygen saturation (from 67 [65-74]% to 84 [77-86]%, p = 0.02) and cardiac index (from 2.9 [2.7-3.1] L/min/m2 to 3.9 [3.0-4.4] L/min/m2, p = 0.006). Tissue oxygen saturation was correlated neither to cardiac index (p = 0.14, R(2) = 0.08) nor to central venous oxygen saturation (p = 0.19, R(2) = 0.10). CONCLUSIONS: Use of isoproterenol was associated with an increase of tissue oxygen saturation. This increase was not correlated to cardiac index, suggesting a decoupling between macrocirculation and microcirculation. PMID- 25436210 TI - A case of isolated left ventricle diverticulum. PMID- 25436211 TI - Mechanisms of blood flow and hypoxia production in rat 9L-epigastric tumors. AB - Classical descriptions of tumor physiology suggest two origins for tumor hypoxia; steady-state (diffusion-limited) hypoxia and cycling (perfusion-modulated) hypoxia. Both origins, primarily studied and characterized in murine models, predict relatively small, isolated foci or thin shells of hypoxic tissue interspersed with contrasting oxic tissue. These foci or shells would not be expected to scale with overall tumor size since the oxygen diffusion distance (determined by oxygen permeability and tissue oxygen consumption rate) is not known to vary dramatically from tumor to tumor. We have identified much larger (macroscopic) regions of hypoxia in rat gliosarcoma tumors and in larger human tumors (notably sarcomas and high-grade glial tumors), as indicated by biochemical binding of the hypoxia marker, EF5. Thus, we considered an alternative cause of tumor hypoxia related to a phenomenon first observed in window-chamber tumor models: namely longitudinal arteriole gradients. Although longitudinal arteriole gradients, as originally described, are also microscopic in nature, it is possible for them to scale with tumor size if tumor blood flow is organized in an appropriate manner. In this organization, inflowing blood would arise from relatively well-oxygenated sources and would branch and then coalesce to poorly-oxygenated outflowing blood over distances much larger than the length of conventional arterioles (multi-millimeter scale). This novel concept differs from the common characterization of tumor blood flow as disorganized and/or chaotic. The organization of blood flow to produce extended longitudinal gradients and macroscopic regional hypoxia has many important implications for the imaging, therapy and biological properties of tumors. Herein, we report the first experimental evidence for such blood flow, using rat 9L gliosarcoma tumors grown on the epigastric artery/vein pair. PMID- 25436212 TI - Periodontal ligament mesenchymal stromal cells increase proliferation and glycosaminoglycans formation of temporomandibular joint derived fibrochondrocytes. AB - OBJECTIVES: Temporomandibular joint (TMJ) disorders are common disease in maxillofacial surgery. The aim of this study is to regenerate fibrocartilage with a mixture of TMJ fibrochondrocytes and periodontal ligament derived mesenchymal stem cells (PD-MSCs). MATERIALS AND METHODS: Fibrochondrocytes and PD-MSC were cocultured (ratio 1 : 1) for 3 weeks. Histology and glycosaminoglycans (GAGs) assay were performed to examine the deposition of GAG. Green florescent protein (GFP) was used to track PD-MSC. Conditioned medium of PD-MSCs was collected to study the soluble factors. Gene expression of fibrochondrocytes cultured in conditioned medium was tested by quantitative PCR (qPCR). RESULTS: Increased proliferation of TMJ-CH was observed in coculture pellets when compared to monoculture. Enhanced GAG production in cocultures was shown by histology and GAG quantification. Tracing of GFP revealed the fact that PD-MSC disappears after coculture with TMJ-CH for 3 weeks. In addition, conditioned medium of PD-MSC was also shown to increase the proliferation and GAG deposition of TMJ-CH. Meanwhile, results of qPCR demonstrated that conditioned medium enhanced the expression levels of matrix-related genes in TMJ-CH. CONCLUSIONS: Results from this study support the mechanism of MSC-chondrocyte interaction, in which MSCs act as secretor of soluble factors that stimulate proliferation and extracellular matrix deposition of chondrocytes. PMID- 25436213 TI - Long-term effects and prognosis in acute heart failure treated with tolvaptan: the AVCMA trial. AB - BACKGROUND: Diuresis is a major therapy for the reduction of congestive symptoms in acute decompensated heart failure (ADHF) patients. We previously reported the efficacy and safety of tolvaptan compared to carperitide in hospitalized patients with ADHF. There were some reports of cardio- and renal-protective effects in carperitide; therefore, the purpose of this study was to compare the long-term effects of tolvaptan and carperitide on cardiorenal function and prognosis. METHODS AND RESULTS: One hundred and five ADHF patients treated with either tolvaptan or carperitide were followed after hospital discharge. Levels of plasma B-type natriuretic peptide, serum sodium, potassium, creatinine, and estimated glomerular filtration rate were measured before administration of tolvaptan or carperitide at baseline, the time of discharge, and one year after discharge. These data between tolvaptan and carperitide groups were not different one year after discharge. Kaplan-Meier survival curves demonstrated that the event-free rate regarding all events, cardiac events, all cause deaths, and rehospitalization due to worsening heart failure was not significantly different between tolvaptan and carperitide groups. CONCLUSIONS: We demonstrated that tolvaptan had similar effects on cardiac and renal function and led to a similar prognosis in the long term, compared to carperitide. PMID- 25436216 TI - Social History Matters-The Impact of Illicit Drug Use on tPA Use and In-Hospital Mortality in Acute Ischemic Stroke. AB - AIMS: The objective of this descriptive study was to compare time to medical evaluation, intravenous tissue plasminogen activator (IV tPA) use, and short-term outcomes in illicit drug users compared to non-users presenting with acute ischemic stroke (AIS). STUDY DESIGN: This is a retrospective study performed from our stroke registry using deidentified patient information. PLACE AND DURATION OF STUDY: Tulane Medical Center Primary Stroke Center (PSC). Consecutive AIS patients presenting to our PSC from July 2008 to December of 2010 were identified from our prospectively collected stroke registry. METHODOLOGY: Patients were categorized as toxicology positive (TP) or toxicology negative (TN). We compared baseline characteristics, clinical presentation, tPA use, and short-term outcomes in TP and TN patients. RESULTS: Two hundred and sixty-three patients met inclusion criteria (median age 63, 35.4% female, 66.5% Black). Nearly 40% of toxicology screens were positive. Stroke severity was similar with the median National Institute of Health Stroke Scale (NIHSS) of 6 in both groups; however, a higher proportion of TN patients were treated with IV tPA (32.1% vs. 21.2%). After adjustment for time from last seen normal to emergency department arrival (LSN-to-ED arrival), the odds of being treated with tPA for TP patients were similar to TN patients (OR 0.69, 95% CI 0.36-1.31, p=0.255). After adjustment for age, NIHSS, glucose, and tPA, the odds of in-hospital mortality in TP patients was 3 times that of TN patients (OR 3.17, 95% CI 1.07-9.43, p=0.038). CONCLUSION: We found that the disparities observed in tPA use were attenuated after adjustment for time from LSN-to-ED arrival, suggesting an area for future intervention. Additionally, we found that TP patients may be at higher risk for in-hospital mortality. Further study on the role of substance abuse in time to ED arrival, tPA use, and outcome in AIS patients is warranted. PMID- 25436217 TI - Effect of sound similarity and word position on lexical selection. AB - Spoken word production research has shown that phonological information influences lexical selection. It remains unclear, however, whether this phonological information is specified for its phonological environment (e.g., word position) or its phonetic (allophonic) realization. To examine this, two definition naming experiments were performed during which subjects produced lexical targets (e.g., "balcony") in response to the targets' definitions ("deck higher than a building's first floor") after naming a series of phonologically related or unrelated primes. Subjects produced target responses significantly more often when the primes were phonologically related to the target, regardless of whether the phonologically related primes matched the target's word position or did not. For example, subjects were equally primed to produce the target "balcony" after the prime "ballast" or "unbalanced" relative to unrelated primes. Moreover, equal priming occurred irrespective of phonological environment or phonetic realization. The results support models of spoken word production which include context-independent phonological representations. PMID- 25436214 TI - TNFalpha promotes Th17 cell differentiation through IL-6 and IL-1beta produced by monocytes in rheumatoid arthritis. AB - TNFalpha plays an important role in autoimmune pathogenesis and is the main therapeutic target of rheumatoid arthritis. However, its underlying mechanism is not completely understood. In this study, we described that Th17 cells were accumulated in synovial fluid, which was attributable to TNFalpha aberrantly produced in rheumatoid synovium. Interestingly, TNFalpha cannot induce IL-17 production of CD4(+) T cells directly, but through the monocytes high levels of IL-1beta and IL-6 in a TNFRI and TNFRII dependent manner from the active RA patients are produced. TNFalpha was shown to enhance the phosphorylation level of STAT3 and the expression level of transcription factor RORC of CD4(+) T cells when cultured with CD14(+) monocytes. Treatment with an approved TNFalpha blocking antibody showed marked reduction in the levels of IL-6, IL-1beta, and IL 17 and the expression level of STAT3 phosphorylation in relation to Th17 cell differentiation in patients with rheumatoid arthritis. The study provides new evidence supporting the critical role of TNFalpha in the pathogenic Th17 cell differentiation in rheumatoid arthritis. PMID- 25436215 TI - A circulating subpopulation of monocytic myeloid-derived suppressor cells as an independent prognostic/predictive factor in untreated non-small lung cancer patients. AB - Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of cells with immunosuppressive properties and might confer to worse prognosis in cancer patients. The presence of phenotypically newly described subpopulations of MDSCs and their association with the clinical outcome were investigated in non small cell lung cancer (NSCLC) patients. The percentages and correlation between MDSCs and distinct immune cells in the peripheral blood of 110 chemotherapy-naive patients before treatment and healthy controls were investigated using flow cytometry. Two monocytic [CD14(+)CD15(-)CD11b(+)CD33(+)HLA-DR(-)Lin(-) and CD14(+)CD15(+)CD11b(+)CD33(+)HLA-DR(-)Lin(-)] and a granulocytic [CD14( )CD15(+)CD11b(+)CD33(+)HLA-DR(-)Lin(-)] subpopulations of MDSCs were identified, expressing inducible nitric oxide synthase, and reactive oxygen species, respectively. Increased percentages of both monocytic-MDSCs' subpopulations were inversely correlated to dendritic/monocyte levels (P <= 0.04), while granulocytic MDSCs were inversely correlated to CD4(+) T cells (P = 0.006). Increased percentages of monocytic-MDSCs were associated with worse response to treatment (P = 0.02) and patients with normal levels of CD14(+)CD15(+)CD11b(+)CD33(+)HLA DR(-)Lin(-) had longer overall survival and progression free-survival compared to those with high levels (P = 0.008 and P = 0.005, resp.). Multivariate analysis revealed that the increased percentages of CD14(+)CD15(+)CD11b(+)CD33(+)HLA-DR( )Lin(-) MDSCs were independently associated with decreased progression free survival and overall survival. The data provide evidence that increased percentages of new monocytic-MDSCs' subpopulations in advanced NSCLC patients are associated with an unfavourable clinical outcome. PMID- 25436218 TI - Frequency and regularity effects in reading are task dependent: Evidence from ERPs. AB - Many theories of visual word processing assume obligatory semantic access and phonological recoding whenever a written word is encountered. However, the relative importance of different reading processes depends on task. The current study uses event related potentials (ERPs) to investigate whether - and, if so, when and how - effects of task modulate how visually-presented words are processed. Participants were presented written words in the context of two tasks, delayed reading aloud and proper name detection. Stimuli varied factorially on lexical frequency and on spellingto-sound regularity, while controlling for other lexical variables. Effects of both lexical frequency and regularity were modulated by task. Lexical frequency modulated N400 amplitude, but only in the reading aloud task, whereas spellingto-sound regularity interacted with frequency to modulate the LPC, again only in the reading aloud task. Taken together, these results demonstrate that task demands affect how meaning and sound are generated from written words. PMID- 25436219 TI - Control of Working Memory in Rhesus Monkeys (Macaca mulatta). AB - Cognitive control is critical for efficiently using the limited resources in working memory. It is well established that humans use rehearsal to increase the probability of remembering needed information, but little is known in nonhumans, with some studies reporting the absence of active control and others subject to alternative explanations. We trained monkeys in a visual matching-to-sample paradigm with a post-sample memory cue. Monkeys either saw a remember cue that predicted the occurrence of a matching test that required memory for the sample, or a forget cue that predicted a discrimination test that did not require memory of the sample. Infrequent probe trials on which monkeys were given tests of the type not cued on that trial were used to assess whether memory was under cognitive control. Our procedures controlled for reward expectation and for the surprising nature of the probes. Monkeys matched less accurately after forget cues, while discrimination accuracy was equivalent in the two cue conditions. We also tested monkeys with lists of two consecutive sample images that shared the same cue. Again, memory for expected memory tests was superior to that on unexpected tests. Together these results show that monkeys cognitively control their working memory. PMID- 25436220 TI - Stochastic variations of migration speed between cells in clonal populations. AB - We combined microfluidic tools and molecular probes to monitor the migration speed of successive generations of cancer cells. We found that the migratory speed of individual cells changes stochastically from parent cells to their descendants, while the average speed of successive generations of cells remains constant. Further studies of the interrelations between cell migration and division processes may help identify the molecular determinants of cell speed and lead to new therapies to slow the invasion of cancer cells and delay metastases. PMID- 25436221 TI - Tabriz nephro-educational courses; A global scientific vision with local vigilance. PMID- 25436223 TI - Overexpression of bacterial mtlD gene in peanut improves drought tolerance through accumulation of mannitol. AB - In the changing global environmental scenarios, water scarcity and recurrent drought impose huge reductions to the peanut (Arachis hypogaea L.) crop yield. In plants, osmotic adjustments associated with efficient free radical scavenging ability during abiotic stress are important components of stress tolerance mechanisms. Mannitol, a compatible solute, is known to scavenge hydroxyl radicals generated during various abiotic stresses, thereby conferring tolerance to water deficit stress in many plant species. However, peanut plant is not known to synthesize mannitol. Therefore, bacterial mtlD gene coding for mannitol 1 phosphate dehydrogenase under the control of constitutive promoter CaMV35S was introduced and overexpressed in the peanut cv. GG 20 using Agrobacterium tumefaciens-mediated transformation. A total of eight independent transgenic events were confirmed at molecular level by PCR, Southern blotting, and RT-PCR. Transgenic lines had increased amount of mannitol and exhibited enhanced tolerance in response to water-deficit stress. Improved performance of the mtlD transgenics was indicated by excised-leaf water loss assay and relative water content under water-deficit stress. Better performance of transgenics was due to the ability of the plants to synthesize mannitol. However, regulation of mtlD gene expression in transgenic plants remains to be elucidated. PMID- 25436224 TI - The approach for action recognition based on the reconstructed phase spaces. AB - This paper presents a novel method of human action recognition, which is based on the reconstructed phase space. Firstly, the human body is divided into 15 key points, whose trajectory represents the human body behavior, and the modified particle filter is used to track these key points for self-occlusion. Secondly, we reconstruct the phase spaces for extracting more useful information from human action trajectories. Finally, we apply the semisupervised probability model and Bayes classified method for classification. Experiments are performed on the Weizmann, KTH, UCF sports, and our action dataset to test and evaluate the proposed method. The compare experiment results showed that the proposed method can achieve was more effective than compare methods. PMID- 25436222 TI - The Effects of Stress Exposure on Prefrontal Cortex: Translating Basic Research into Successful Treatments for Post-Traumatic Stress Disorder. AB - Research on the neurobiology of the stress response in animals has led to successful new treatments for Post-Traumatic Stress Disorder (PTSD) in humans. Basic research has found that high levels of catecholamine release during stress rapidly impair the top-down cognitive functions of the prefrontal cortex (PFC), while strengthening the emotional and habitual responses of the amygdala and basal ganglia. Chronic stress exposure leads to dendritic atrophy in PFC, dendritic extension in the amygdala, and strengthening of the noradrenergic (NE) system. High levels of NE release during stress engage low affinity alpha-1 adrenoceptors, (and likely beta-1 adrenoceptors), which rapidly reduce the firing of PFC neurons, but strengthen amygdala function. In contrast, moderate levels of NE release during nonstress conditions engage higher affinity alpha-2A receptors, which strengthen PFC, weaken amygdala, and regulate NE cell firing. Thus, either alpha-1 receptor blockade or alpha-2A receptor stimulation can protect PFC function during stress. Patients with PTSD have signs of PFC dysfunction. Clinical studies have found that blocking alpha-1 receptors with prazosin, or stimulating alpha-2A receptors with guanfacine or clonidine can be useful in reducing the symptoms of PTSD. Placebo-controlled trials have shown that prazosin is helpful in veterans, active duty soldiers and civilians with PTSD, including improvement of PFC symptoms such as impaired concentration and impulse control. Open label studies suggest that guanfacine may be especially helpful in treating children and adolescents who have experienced trauma. Thus, understanding the neurobiology of the stress response has begun to help patients with stress disorders. PMID- 25436225 TI - Does scoliosis-specific exercise treatment in adolescence alter adult quality of life? AB - OBJECTIVE: Health-related quality of life in adults, who in adolescence participated in a scoliosis-specific exercise program, was not previously studied. Design. Cross-sectional study, with retrospective data collection. MATERIAL AND METHODS: Homogenous groups of 68 persons (43 women) aged 30.10 (25 39) years, with mild or moderate scoliosis, and 76 (38 women) able-bodied persons, aged 30.11 (24-38) years, who 16.5 (12-26) years earlier had completed scoliosis-specific exercise or observation regimes, participated. Their respiratory characteristics did not differ from predicted values. The WHOQOL-BREF questionnaire, Oswestry Disability Questionnaire, and pain scale (VAS) were applied. RESULTS: The transformed WHOQOL-BREF scores ranged from 54.6 +/- 11.19 in the physical domain in the mild scoliotic subgroup to 77.1 +/- 16.05 in the social domain in the able-bodied subgroup. The ODQ values did not generally exceed 5.3 +/- 7.53. Inter- and intragroup differences were nonsignificant. Age, marital status, education, and gender were significantly associated with the ODQ scores. Significant association between the ODQ and WHOQOL-BREF social relationships domain scores with the participation in exercise treatment was found. CONCLUSIONS: Participants with the history of exercise treatment generally did not differ significantly from their peers who were only under observation. This study cannot conclude that scoliosis-specific exercise treatment in adolescence alters quality of life in adulthood. PMID- 25436226 TI - Acaricidal activity of petroleum ether extract of leaves of Tetrastigma leucostaphylum (Dennst.) Alston against Rhipicephalus (Boophilus) annulatus. AB - The acaricidal activity of the petroleum ether extract of leaves of Tetrastigma leucostaphylum (Dennst.) Alston (family: Vitaceae) against Rhipicephalus (Boophilus) annulatus was assessed using adult immersion test (AIT). The per cent of adult mortality, inhibition of fecundity, and blocking of hatching of eggs were studied at different concentrations. The extract at 10% concentration showed 88.96% inhibition of fecundity, 58.32% of adult tick mortality, and 50% inhibition of hatching. Peak mortality rate was observed after day 5 of treatment. Mortality of engorged female ticks, inhibition of fecundity, and hatching of eggs were concentration dependent. The LC50 value of the extract against R. (B.) annulatus was 10.46%. The HPTLC profiling of the petroleum ether extract revealed the presence of at least seven polyvalent components. In the petroleum ether extract, nicotine was identified as one of the components up to a concentration of 5.4%. However, nicotine did not reveal any acaricidal activity up to 20000 ppm (2%). Coconut oil, used as diluent for dissolving the extract, did not reveal any acaricidal effects. The results are indicative of the involvement of synergistic or additive action of the bioactive components in the tick mortality and inhibition of the oviposition. PMID- 25436227 TI - Utility of AD8 for cognitive impairment in a Chinese physical examination population: a preliminary study. AB - OBJECTIVE: To investigate the utility of AD8 for cognitive impairment in a Chinese physical examination population. METHODS: Military cadres who took routine physical examination in Chinese PLA General Hospital from Jan 1, 2013, to Dec 31, 2013, were subjected to AD8 scale. Individual information such as age, gender, and education was also collected. All data were analyzed by SPSS 19.0. RESULTS: 1544 subjects were enrolled in this study with mean age 75.4 +/- 10.6 years. The subjects who scored 0 to 8 of AD8 scale were 1015, 269, 120, 60, 30, 14, 19, 8, and 9, respectively. Corresponding proportions were 65.7%, 17.4%, 7.8%, 3.9%, 2.0%, 0.9%, 1.2%, 0.5%, and 0.6%, respectively. The endorsement prevalence of 8 questions was 5.6%, 9.2%, 6.6%, 9.2%, 4.8%, 4.5%, 8.9%, and 24.1%, respectively. The endorsement prevalence of question 8 was significantly higher than others (P < 0.05). 260 subjects were scored equal to or greater than 2. The abnormal rate was 16.9%. All the participants were stratified into 9 groups by age; the prevalence of dementia was highly correlated with age (P < 0.01). CONCLUSION: AD8 scale is a convenient and effective tool for cognitive screening in routine physical examination population. PMID- 25436228 TI - Genetic diversity and genetic structure of different types of natural populations in Osmanthus fragrans Lour. and the relationships with sex ratio, population structure, and geographic isolation. AB - Osmanthus fragrans Lour., an evergreen small tree, has the rare sexual system of androdioecy (coexistence of males and hermaphrodites), once with wide-spread natural distribution in the areas of the South Yangzi river basin. However, due to excessive human utilization, natural distribution became fragmented and the number and size of natural populations reduced sharply. With four different types of natural populations from the same region as research object, we aim to provide a comparative analysis on the relationships among genetic diversity, sexual system, population structure and size, and geographic isolation by ISSR. In genetic parameters of N e , H e , and I, the LQGC population had the highest value and the LQZGQ population had the lowest value. These indicated that LQGC population showed the highest genetic diversity, followed by QDH and JN population, and LQZGQ population exhibited the lowest genetic diversity. Genetic diversity in populations is closely related to population structure, reproduction mode, and sex ratio. However, there seems to be no obvious correlation between genetic diversity and population size. The results of AMOVA showed that genetic variations mostly occurred within populations. It indicates that no significant genetic differentiation among populations occurs, and geographic isolation has no significant effect on genetic diversity. PMID- 25436229 TI - Three-dimensional aspects of the lingual papillae and their connective tissue cores in the tongue of rats: a scanning electron microscope study. AB - The aim of the present study was to describe the tridimensional morphological characteristics of the lingual papillae and their connective tissue cores (CTCs) in Sprague Dawley rats. Four types of papillae were reported on the dorsal surface. Filiform papillae were distributed on the tongue surface and after epithelial maceration a conic and multifilamentary shape of the CTCs was revealed. Fungiform papillae were reported on the rostral and middle regions covered by a squamous epithelium. After the removal of the epithelium, the shape of a volcano with the taste orifice at its top was noted. Foliate papillae were composed of five pairs of epithelial folds situated on the lateral-caudal margin of the tongue. After the removal of the epithelium, they were shown to be limited by thin laminar projections. The vallate papilla with an oval shape was present in the caudal region and delimited by an incomplete groove. The morphological characteristics of the lingual papillae of Sprague Dowley rats, three-dimensional SEM images, and the types of papillae on the dorsal surface were similar to those reported previously in other rodent mammals. The maceration technique revealed the details of extracellular matrix with varied shapes form of connective tissue cores. PMID- 25436230 TI - Platelet rich concentrate promotes early cellular proliferation and multiple lineage differentiation of human mesenchymal stromal cells in vitro. AB - Platelet rich concentrate (PRC) is a natural adjuvant that aids in human mesenchymal stromal cell (hMSC) proliferation in vitro; however, its role requires further exploration. This study was conducted to determine the optimal concentration of PRC required for achieving the maximal proliferation, and the need for activating the platelets to achieve this effect, and if PRC could independently induce early differentiation of hMSC. The gene expression of markers for osteocytes (ALP, RUNX2), chondrocytes (SOX9, COL2A1), and adipocytes (PPAR-gamma) was determined at each time point in hMSC treated with 15% activated and nonactivated PRC since maximal proliferative effect was achieved at this concentration. The isolated PRC had approximately fourfold higher platelet count than whole blood. There was no significant difference in hMSC proliferation between the activated and nonactivated PRC. Only RUNX2 and SOX9 genes were upregulated throughout the 8 days. However, protein expression study showed formation of oil globules from day 4, significant increase in ALP at days 6 and 8 (P <= 0.05), and increased glycosaminoglycan levels at all time points (P < 0.05), suggesting the early differentiation of hMSC into osteogenic and adipogenic lineages. This study demonstrates that the use of PRC increased hMSC proliferation and induced early differentiation of hMSC into multiple mesenchymal lineages, without preactivation or addition of differentiation medium. PMID- 25436231 TI - Role of Ulva lactuca extract in alleviation of salinity stress on wheat seedlings. AB - Seaweeds are potentially excellent sources of highly bioactive materials that could represent useful leads in the alleviation of salinity stress. The effects of presoaking wheat grains in water extract of Ulva lactuca on growth, some enzymatic activities, and protein pattern of salinized plants were investigated in this study. Algal presoaking of grains demonstrated a highly significant enhancement in the percentage of seed germination and growth parameters. The activity of superoxide dismutase (SOD) and catalase (CAT) increased with increasing the algal extract concentration while activity of ascorbate peroxidase (APX) and glutathione reductase (GR) was decreased with increasing concentration of algal extract more than 1% (w/v). The protein pattern of wheat seedling showed 12 newly formed bands as result of algal extract treatments compared with control. The bioactive components in U. lactuca extract such as ascorbic acid, betaine, glutathione, and proline could potentially participate in the alleviation of salinity stress. Therefore, algal presoaking is proved to be an effective technique to improve the growth of wheat seedlings under salt stress conditions. PMID- 25436232 TI - On the multiuser diversity of relay-aided downlink systems using reduced feedback. AB - We introduce an efficient multiuser scheduling method using amplify-and-forward relaying in relay-aided downlink systems, consisting of one base station (BS), one relay station, and multiple mobile stations (MSs). In our scheme, the BS opportunistically selects both the transmission mode, that is, either one- or two hop transmission, and the desired user (i.e., the desired MS). Closed-form expressions for the average achievable rates are derived for the two transmission modes with multiuser scheduling, and its asymptotic solutions are also analyzed in the limit of large number of MSs. Based on the analysis, we propose a feedback efficient two-step multiuser scheduling algorithm: the transmission mode selection followed by the user selection that only needs a partial feedback for instantaneous signal-to-noise ratios (SNRs) to the BS. We also analyze the average SNR condition such that the multiuser diversity gain is fully exploited for two-hop transmission. The proposed two-step scheduling algorithm exhibits the quite comparable achievable rates to those of the optimal one using full feedback information, while its required feedback information is reduced by half of the optimal one. PMID- 25436234 TI - Renal replacement therapy in children in the developing world: challenges and outcome in a tertiary hospital in southeast Nigeria. AB - A 5-year observational, retrospective study was conducted to evaluate the indications, the availability, the accessibility, the sustainability, and the outcome of children managed for acute kidney injury (AKI) and end stage kidney disease (ESKD) who required renal replacement therapy RRT in Enugu, southeast Nigeria. A total of 64 patients aged 5 months to 16 years required RRT, of which only 25 underwent RRT, giving an RRT accessibility rate of 39.1%. Eleven (44%) patients required chronic dialysis program/ renal transplant, of which only 1 (9.1%) accessed and sustained chronic hemodialysis, giving a dialysis acceptance rate of 9.1%. Fifty (78%) of the patients belonged to the low socioeconomic class. Thirty-three (51.5%) could not access RRT because of financial constraints and discharge against medical advice (DAMA); 6 (9.4%) died on admission while sourcing for funds to access the therapy; 5 (7.8%) died while on RRT; 9 (14.1%) improved and were discharged for follow-up; 1 (1.6%) improved and was discharged to be on chronic dialysis program while awaiting renal transplantation outside the country/clinic follow-up, while the remaining 10 (15.6%) were unable to sustain chronic dialysis program or access renal transplantation and were lost to follow-up. We conclude that RRT remains unaffordable within the subregion. PMID- 25436233 TI - Is there a role for probiotics in liver disease? AB - Intestinal microbiota plays an important role in health and disease. Alteration in its healthy homeostasis may result in the development of numerous liver disorders including complications of liver cirrhosis. On the other hand, restoration and modulation of intestinal flora through the use of probiotics is potentially an emerging therapeutic strategy. There is mounting evidence that probiotics are effective in the treatment of covert and overt hepatic encephalopathy, as well as in the prevention of recurrence of encephalopathy. The beneficial effect of probiotics also extends to liver function in cirrhosis, nonalcoholic fatty liver disease, and alcoholic liver disease. On the other hand, data associating probiotics and portal hypertension is scanty and conflicting. Probiotic therapy has also not been shown to prevent primary or secondary spontaneous bacterial peritonitis. Larger clinical studies are required before probiotics can be recommended as a treatment modality in liver diseases. PMID- 25436235 TI - Zinc oxide nanoparticles for revolutionizing agriculture: synthesis and applications. AB - Nanotechnology is the most innovative field of 21st century. Extensive research is going on for commercializing nanoproducts throughout the world. Due to their unique properties, nanoparticles have gained considerable importance compared to bulk counterparts. Among other metal nanoparticles, zinc oxide nanoparticles are very much important due to their utilization in gas sensors, biosensors, cosmetics, drug-delivery systems, and so forth. Zinc oxide nanoparticles (ZnO NPs) also have remarkable optical, physical, and antimicrobial properties and therefore have great potential to enhance agriculture. As far as method of formation is concerned, ZnO NPs can be synthesized by several chemical methods such as precipitation method, vapor transport method, and hydrothermal process. The biogenic synthesis of ZnO NPs by using different plant extracts is also common nowadays. This green synthesis is quite safe and ecofriendly compared to chemical synthesis. This paper elaborates the synthesis, properties, and applications of zinc oxide nanoparticles. PMID- 25436236 TI - Global genome comparative analysis reveals insights of resistome and life-style adaptation of Pseudomonas putida strain T2-2 in oral cavity. AB - Most Pseudomonas putida strains are environmental microorganisms exhibiting a wide range of metabolic capability but certain strains have been reported as rare opportunistic pathogens and some emerged as multidrug resistant P. putida. This study aimed to assess the drug resistance profile of, via whole genome analysis, P. putida strain T2-2 isolated from oral cavity. At the same time, we also compared the nonenvironmental strain with environmentally isolated P. putida. In silico comparative genome analysis with available reference strains of P. putida shows that T2-2 has lesser gene counts on carbohydrate and aromatic compounds metabolisms, which suggested its little versatility. The detection of its edd gene also suggested T2-2's catabolism of glucose via ED pathway instead of EMP pathway. On the other hand, its drug resistance profile was observed via in silico gene prediction and most of the genes found were in agreement with drug susceptibility testing in laboratory by automated VITEK 2. In addition, the finding of putative genes of multidrug resistance efflux pump and ATP-binding cassette transporters in this strain suggests a multidrug resistant phenotype. In summary, it is believed that multiple metabolic characteristics and drug resistance in P. putida strain T2-2 helped in its survival in human oral cavity. PMID- 25436237 TI - Synthesis and thermal degradation studies of melamine formaldehyde resins. AB - Melamine formaldehyde (MF) resins have been synthesized at different reaction temperature and pH values. Different molar ratios of melamine and formaldehyde were used to synthesize the corresponding resins. The prepared resin samples were characterized by using molecular weight determination viscometry and thermogravimetric analysis (TGA). The maximum percentage of solid content (69.7%) was obtained at pH 8.5 and 75 degrees C temperature. The molecular weight of MF resin was increased with an increase of melamine monomer concentration. The highest residual weight 14.125 wt.% was obtained with sample 10. PMID- 25436239 TI - Sorption of hydrophilic dyes on anodic aluminium oxide films and application to pH sensing. AB - The sorption of selected hydrophilic pH-sensitive dyes (bromophenol blue, bromothymol blue, bromocresol purple, alizarin red, methyl orange, congo red, rhodamine 6G) on films of anodized aluminium oxide (AAO) was investigated in this study. Depth and pore structure of the AAO channels were adjusted by changing electrolysis time and current density during treatment of aluminium foil in oxalic acid, sulfosalycilic acid and sulfuric acid at concentration levels between 0.2 and 0.6 M. The dyes were immobilized on the AAO surface by direct saturation of the films in dye solutions. It was shown by scanning electron microscopy and X-ray spectral analysis that the dyes penetrated into the AAO channels by more than 1.5 MUm, even at static saturation conditions. The anionic dyes linked to the porous AAO surface exhibited differential shifts of the UV absorption bands in their acidic/basic forms. By combining several dyes, the films have an application range between pH = 0.5-9 in aqueous media. The dye modified AAO film was a simple, portable, inexpensive and reusable pH sensor with very fast response time and clear colour transitions. PMID- 25436238 TI - Analysis of metal contents in Portland Type V and MTA-based cements. AB - The aim of this study was to determine, by Atomic Absorption Spectrometry (AAS), the concentration levels of 11 metals in Type V gray and structural white PC, ProRoot MTA, and MTA Bio. Samples, containing one gram of each tested cement, were prepared and transferred to a 100 mL Teflon tube with a mixture of 7.0 mL of nitric acid and 21 mL of hydrochloric acid. After the reaction, the mixture was filtered and then volumed to 50 mL of distilled water. For each metal, specific patterns were determined from universal standards. Arsenic quantification was performed by hydride generator. The analysis was performed five times and the data were statistically analyzed at 5% level of significance. Only the cadmium presented concentration levels of values lower than the quantification limit of the device. The AAS analysis showed increased levels of calcium, nickel, and zinc in structural white PC. Type V PC presented the greatest concentration levels of arsenic, chromium, copper, iron, lead, and manganese (P < 0.05). Bismuth was found in all cements, and the lowest concentration levels were observed in Portland cements, while the highest were observed in ProRoot MTA. Both PC and MTA based cements showed evidence of metals inclusion. PMID- 25436240 TI - Effect of pore diameter in nanoporous anodic alumina optical biosensors. AB - The influence of pore diameter over the optical response of nanoporous anodic alumina (NAA) films is analyzed by reflectance interference spectroscopy. NAA films manufactured by a two-step anodization procedure in oxalic acid exhibiting three well-defined pore diameter distributions with pores of 32 +/- 4, 50 +/- 3, and 73 +/- 2 nm are studied. The optical detection of biomolecules is investigated by serially dosing protein A, human IgG and anti-human IgG into a nanoporous matrix using a custom-made flow cell. The results demonstrate that the transduction signal, the variation of effective optical thickness upon IgG binding to protein A (DeltaEOT), depends on the nanopore diameter: for small pore diameter (32 nm) no significant differences in signals are observed for different protein concentrations whereas for larger pore diameters (50 nm and 73 nm) the signals increase for increasing concentrations from 10 to 100 MUg mL(-1). Our experiments also show that this signal can be further enhanced by amplification with anti-human IgG due to the multiple binding events between the antigen and the antibody. These results will enable the development of more sensitive interferometric biosensors based on NAA. PMID- 25436241 TI - CDC report indicates slight rise in attempted suicide among U.S. high school students. PMID- 25436242 TI - HHS announces new grants to improve mental health services for youth and adolescents. PMID- 25436244 TI - Women in leadership: Goldilocks syndrome. PMID- 25436243 TI - Reply: To PMID 23903366. PMID- 25436245 TI - 2014 annual congress of the European Respiratory Society. PMID- 25436246 TI - Outbreaks of enterovirus D68 continue across the USA. PMID- 25436247 TI - Mining and tuberculosis: we need to dig deeper. PMID- 25436248 TI - Corrigendum to "The unimodal model for the classification of ordinal data" [Neural Netw. 21 (2008) 78-79]. PMID- 25436250 TI - Sibship structure and risk of infectious mononucleosis: a population-based cohort study. AB - BACKGROUND: Present understanding of increased risk of Epstein-Barr virus (EBV) related infectious mononucleosis among children of low birth order or small sibships is mainly based on old and indirect evidence. Societal changes and methodological limitations of previous studies call for new data. METHODS: We used data from the Danish Civil Registration System and the Danish National Hospital Discharge Register to study incidence rates of inpatient hospitalizations for infectious mononucleosis before the age of 20 years in a cohort of 2,543,225 Danes born between 1971 and 2008, taking individual sibship structure into account. RESULTS: A total of 12,872 cases of infectious mononucleosis were observed during 35.3 million person-years of follow-up. Statistical modelling showed that increasing sibship size was associated with a reduced risk of infectious mononucleosis and that younger siblings conferred more protection from infectious mononucleosis than older siblings. In addition to this general association with younger and older siblings, children aged less than 4 years transiently increased their siblings' infectious mononucleosis risk. Our results were confirmed in an independent sample of blood donors followed up retrospectively for self-reported infectious mononucleosis. CONCLUSIONS: Younger siblings, and to a lesser degree older siblings, seem to be important in the transmission of EBV within families. Apparently the dogma of low birth order in a sibship as being at the highest risk of infectious mononucleosis is no longer valid. PMID- 25436251 TI - [Anoxygenic phototrophic bacteria of the Kislo-Sladkoe Stratified Lake (White Sea, Kandalaksha Bay)]. AB - The community of anoxygenic phototrophic bacteria (APB) in the water column of the Kislo-Sladkoe stratified lake recently isolated from the sea (White Sea, Kandalaksha Bay) was investigated in September 2010. The water of the sulfide rich zone was greenish-brown due to intense development of green sulfur bacteria (GSB). Nine APB strains were isolated from the water samples: three belonging to GSB, five, to purple sulfur bacteria (PSB), and one, to purple nonsulfur bacteria (PNB). GSB predominated in the phototrophic community of the chemocline. Unexpectedly, two morphologically different green-colored GSB strains were found to be phylogenetically identical and related to the brown-colored @Chlorobium phaeovibrioides (99% similarity according to the 16S rRNA gene sequencing). Homology to the closest green-colored species (Chlorobium luteolum) was 98%. Two morphologically and physiologically similar PSB strains (TcrPS10 and AmPS10) had rounded cells containing okenonokenonee and gas vesicles. According to the 16S rRNA gene sequencing, these strains were most closely related (99%) to two different Thiocapsa species: Tca. marina (containing okenonokenonee and no gas vesicles) and Tca. rosea (containing spirilloxanthin and gas vesicles). The remaining isolates of purple bacteria were similar to the already described APB species. PMID- 25436252 TI - [Culturable psychrotolerant methanotrophic bacteria in landfill cover soil]. AB - Methanotrophs closely related to psychrotolerant members of the genera Methylobacter and Methylocella were identified in cultures enriched at 10@C from landfill cover soil samples collected in the period from April to November. Mesophilic methanotrophs of the genera Methylobacter and Methylosinus were found in cultures enriched at 20 degrees C from the same cover soil samples. A thermotolerant methanotroph related to Methylocaldum gracile was identified in the culture enriched at 40 degrees C from a sample collected in May (the temperature of the cover soil was 11.5-12.5 degrees C). In addition to methanotrophs, methylobacteria of the genera Methylotenera and Methylovorus and members of the genera Verrucomicrobium, Pseudomonas, Pseudoxanthomonas, Dokdonella, Candidatus Protochlamydia, and Thiorhodospira were also identified in the enrichment cultures. A methanotroph closely related to the psychrotolerant species Methylobacter tundripaludum (98% sequence identity of 16S r-RNA genes with the type strain SV96(T)) was isolated in pure culture. The introduction of a mixture of the methanotrophic enrichments, grown at 15 degrees C, into the landfill cover soil resulted in a decrease in methane emission from the landfill surface in autumn (October, November). The inoculum used was demonstrated to contain methanotrophs closely related to Methylobacter tundripaludum SV96. PMID- 25436254 TI - Patient Education: the story of edema. PMID- 25436253 TI - Association between dog guardianship and HIV clinical outcomes. AB - Despite numerous potential health outcomes of dog guardianship, their value has not been examined in the HIV-positive population. The study objective was to examine the relationship between dog guardianship and HIV clinical outcomes (antiretroviral adherence [>95% versus <95%], HIV viral load [> or =48 versus <48 copies/mL], and CD4 count) among HIV-positive individuals. The authors conducted a secondary analysis of baseline data of 370 HIV-positive men on antiretroviral regimen enrolled in the Duo Project. Generalized estimating equations were used for inferential regression analyses, while controlling for the focal dog guar- dianship variable and nonfocal covariates. Current dog guardianship was reported in 28.7% of participants. Dog guardianship may be associated with higher CD4 (coefficient = 60.6, P = .052) and adherence >95% (odds ratio [OR] = 1.80, P = .048); however, having a detectable viral load was not related to dog guardianship (OR = 0.94, P = .85). Further clinical research with detailed dog guardianship data is needed to further examine the association between dog guardianship and HIV clinical outcomes. PMID- 25436255 TI - Managing pacemaker-related complications and malfunctions in the emergency department. AB - The use of implanted pacemaker devices is increasing worldwide, owing to technological advances, new indications, and an aging population. Despite greater experience in implantation and improved device sophistication, patients continue to face complications associated with hardware implantation and device malfunction. This review summarizes current indications for permanent pacing, reviews epidemiologic data relevant to implant complications, and describes a clinical approach to the patient with potential pacing malfunction. The electrocardiographic diagnosis of hyperkalemia and acute myocardial infarction in paced rhythms is also discussed. Potential sources of electromagnetic interference and special considerations pertaining to the cardiac resuscitation of patients with implanted cardiac devices are reviewed. Finally, a basic approach to implanted cardioverter-defibrillator devices (which often accompany pacemaker devices) is presented. PMID- 25436257 TI - New potential target for chronic pain identified. PMID- 25436258 TI - New study suggests a better pain control option for orthopedic patients. PMID- 25436259 TI - New cancer pain therapy may be on the horizon. PMID- 25436260 TI - Coexistent BCR-ABL1 and JAK2 V617F: converting CML dwarves to ET staghorns with imatinib therapy. PMID- 25436256 TI - Pathways to self-harmful behaviors in young women with and without ADHD: a longitudinal examination of mediating factors. AB - BACKGROUND: Rates of suicide attempts and nonsuicidal self-injury [(NSSI); e.g., cutting, burning] peak in adolescence and early adulthood; females and individuals with psychiatric symptoms and diagnoses appear to beat particular risk. Hinshaw et al. [Journal of Consulting and Clinical Psychology, (2012), 80, 1041] reported that young women with histories of childhood ADHD diagnoses reported higher rates of suicide attempts and NSSI than nondiagnosed, comparison women. METHODS: Via analyses of an ongoing longitudinal investigation, our aims are to examine, with respect to both aspects of self-harmful behavior, (a) ADHD subtype differences and effects of diagnostic persistence (vs. transient and nondiagnosed classifications) and (b) potential mediating effects of impulsivity and comorbid psychopathology, ascertained during adolescence. RESULTS: Young adult women with a childhood diagnosis of ADHD-Combined type were at highest risk for suicide attempts as well as the most varied and severe forms of NSSI compared with those with ADHD-Inattentive type and those in the comparison group; participants with a persistent ADHD diagnosis were at higher risk than those with a transient diagnosis or those never meeting criteria for ADHD. Mediator analyses revealed that, during adolescence, an objective measure of impulsivity plus comorbid externalizing symptoms were simultaneous, partial mediators of the childhood ADHD-young adult NSSI linkage.Adolescent internalizing symptoms emerged as a partial mediator of the childhood ADHD-young adult suicide attempt linkage. CONCLUSIONs: ADHD in females, especially when featuring childhood impulsivity and especially with persistent symptomatology, carries high risk for self-harm. Psychiatric comorbidity and response inhibition are important mediators of this clinically important longitudinal association. We discuss limitations and implications for prevention and intervention. PMID- 25436261 TI - Basophilic blast phase of chronic myelogenous leukemia. PMID- 25436262 TI - Epidermoid carcinoma of the prepuce. PMID- 25436263 TI - Microbladder after the BCG therapy. PMID- 25436264 TI - Drug rehab. PMID- 25436265 TI - When the going gets tough: scientists' personal challenges. PMID- 25436266 TI - Stephen F. Heinemann: 1939-2014. PMID- 25436267 TI - Sodium and cardiovascular disease. PMID- 25436268 TI - Retraction notice to Significant variations in afferent conduction and axonal morphology of aortic depressive nerve imply broader baroreflex function of myelinated Ah-type baroreceptor neurons in female rats. PMID- 25436269 TI - Mechanism of stylet-facilitated nasotracheal intubation. Reply. PMID- 25436270 TI - Strengthening the peer review process for the International Journal of Toxicology. PMID- 25436271 TI - The law and politics of workplace wellness. Editor's note. PMID- 25436272 TI - Mouse undifferentiated spermatogonial stem cells cultured as aggregates under simulated microgravity. AB - Dynamic simulated microgravity (SMG) culture systems provide environments that stimulate stem cell proliferation and differentiation. However, the effect of SMG on spermatogonial stem cells (SSCs) remains unclear. Here, we used a rotating cell culture system (RCCS) to determine its effect on mouse SSC proliferation and differentiation. SSCs were enriched from mouse pub testis and cocultured with Sertoli cell feeders pre-treated with mitomycin C on fibrin scaffolds in a rotary bioreactor for 14 days. Our results show that mouse SSCs cultured in a rotary bioreactor exhibited enhanced proliferation surpassing those cultured in static conditions, although SSC cultures in SMG underwent a growth lag at initial 3 days. After 14 days, mouse SSCs and feeders grew into cell aggregates with average diameters of 242.63 +/- 16.53 MUm compared with those in conventional static culture (49.51 +/- 15.64 MUm). Related detection revealed that proliferating SSCs in SMG remained undifferentiated, maintained clone-forming capacity and were capable of differentiation into round spermatids with flagella. The growth characteristics of mouse SSCs in RCCS suggest that the resulting aggregates are similar to native in vivo cells. Rotary bioreactors that create SMG environments may be an alternative to conventional systems for the clinical application of SSCs. PMID- 25436273 TI - Stress management and sexual health of young adults: a pilot randomised controlled trial. AB - Young people often experience excessive stress that definitely undermines their sexual life and leads them to adopt risky sexual behaviours. As such, the design and application of a stress management programme in this particular age group is, undoubtedly, a crucial matter. In this parallel randomised controlled trial, 60 psychology students of the Panteion University of Athens, aged 18-20, were randomly assigned to undergo either an 8-week stress management programme (n = 30; diaphragmatic breathing-progressive muscle relaxation and guided imagery, twice a day) or not (n = 30). Self-reported validated measures were used to evaluate stress, stressful life events, health locus of control, general health status, sexual behaviours, sexual desire, satisfaction from sexual life and interpersonal relationships. Between-group analyses revealed statistically significant differences in internal health locus of control and general health evaluation. Within the intervention group analyses showed reductions in BMI, stress, the 'chance' subscale of multidimensional health locus of control (MHLC) and greater satisfaction from sexual life. No other significant change was reported. We deem that our results should encourage relevant future studies. PMID- 25436274 TI - [Middle ear surgery - detailed risk information necessary]. PMID- 25436275 TI - [Subglottic stenosis - stent compared with two-stage laryngotracheoplasty]. PMID- 25436276 TI - Retrospective analysis of venograms of hepatic and portal veins: clinical implications for transjugular intrahepatic portosystemic shunt placement. AB - AIMS: This study was aimed to provide safety guidance of needle passes into the portal vein during transjugular intrahepatic portosystemic shunt (TIPS) placement. METHODOLOGY: On anteroposterior venograms, the orifice of right hepatic trunk (RHT), furcation position, and branching of portal trunk in 128 patients underwent TIPS were mapped in relation to the vertebrae and intervertebral space. Impact of clinical factors on these parameters was determined. RESULTS: The orifices of RHTs were all above the furcation position of portal trunk, RHTs were posterior and superior to portal branch. Of the 128 patients, 84.4% had the orifice positioned between 9th and 10th thoracic (T) vertebrae, 58.6% positioned to T10. Portal trunks were furcated between T11 and T12 in 80.5% patients. Portal trunks were bifurcated at right hepatic portal in 91.4% patients into left and right veins, and trifurcated into right posterior, right anterior and left branches in 8.6% patients. Statistical analysis indicated that these parameters were not affected by cause of disease, gender, age and Child-Pugh score. CONCLUSIONS: The puncture site for portal vein located at or beyond imaged trunk furcation would be safe for most of the patients. PMID- 25436277 TI - Prognostic significance of hypokalemia in hepatic encephalopathy. AB - BACKGROUND/AIMS: The aim of this study was to investigate whether hypokalemia prognosticates outcomes in hepatic encephalopathy. We also examined other potential prognostic variables such as serum pH, systemic vascular resistance (SVR) and serum ammonia levels. METHODOLOGY: Patients with cirrhosis who were admitted for overt hepatic encephalopathy were included in the study and divided into two groups: Group-I consisted of patients with serum Potassium level < 4.0 mEq/L and Group-II consisted of patients with serum Potassium level > 4.0 mEq/L. We collected the baseline demographic data for both the groups including age, gender, ethnicity and calculated the Model for End Stage Liver Disease scores for both the groups at the time of admission. We analyzed the correlation between serum potassium levels and outcome variables including 30- day mortality rate, length of Intensive Care Unit (ICU)/ hospital stay, mechanical ventilation rate and 30-day readmission rate. RESULTS: A total of 447 patients with diagnosis of cirrhosis were admitted to the hospital with overt hepatic encephalopathy between January 2008 and December 2012. 157 patients with low Potassium level (< 4.0 mEq/L) were included in Group-I while 290 patients with normal Potassium level (> 4.0 mEq/L) and were included in Group-II. Total length of stay in the hospital (P Value= 0.0001) and ICU length of stay (P Value= 0.0003) were significantly longer among the patients with serum potassium level of <4mEq/L. CONCLUSIONS: We observed statistically significant correlation between serum potassium level and length of stay in hospital and ICU. PMID- 25436278 TI - Cost utility analysis of endoscopic biliary stent in unresectable hilar cholangiocarcinoma: decision analytic modeling approach. AB - BACKGROUND/AIMS: Endoscopic biliary drainage using metal and plastic stent in unresectable hilar cholangiocarcinoma (HCA) is widely used but little is known about their cost-effectiveness. This study evaluated the cost-utility of endoscopic metal and plastic stent drainage in unresectable complex, Bismuth type II-IV, HCA patients. METHODOLOGY: Decision analytic model, Markov model, was used to evaluate cost and quality-adjusted life year (QALY) of endoscopic biliary drainage in unresectable HCA. Costs of treatment and utilities of each Markov state were retrieved from hospital charges and unresectable HCA patients from tertiary care hospital in Thailand, respectively. Transition probabilities were derived from international literature. Base case analyses and sensitivity analyses were performed. RESULTS: Under the base-case analysis, metal stent is more effective but more expensive than plastic stent. An incremental cost per additional QALY gained is 192,650 baht (US$ 6,318). From probabilistic sensitivity analysis, at the willingness to pay threshold of one and three times GDP per capita or 158,000 baht (US$ 5,182) and 474,000 baht (US$ 15,546), the probability of metal stent being cost-effective is 26.4% and 99.8%, respectively. CONCLUSIONS: Based on the WHO recommendation regarding the cost-effectiveness threshold criteria, endoscopic metal stent drainage is cost-effective compared to plastic stent in unresectable complex HCA. PMID- 25436279 TI - Mirizzi Syndrome: How it could be a challenge. AB - BACKGROUND/AIMS: Mirizzi syndrome (MS) is a rare complication of cholelithiasis. This entity should be considered in the differential diagnosis of all patients with obstructive jaundice. Failure to recognize this condition preoperatively can result in a major bile duct injury. In this study, our aim is to describe the clinical presentations, investigations, operative details, endoscopic management and the complications of both procedures. METHODOLOGY: We performed a retrospective analysis on the records of 65 patients with MS. All patients had a cholangiogram; either magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). We used a McSherry classification to divide patients with MS into type I MS and type II MS. Those patients had undergone different types of management either ERCP and/or surgery. RESULTS: The incidence of MS was 0.98% from a total of 4600 patients who had undergone cholecystectomy. From 65 patients with MS, 20 patients underwent ERCP where it was the sole treatment (18 of which had stent while 2 had the stone extracted). The overall surgically treated patients were 45 (23 patients with preliminary ERCP with stent and 22 patients with primary surgical treatment), 18 patients had MS type I while 27 patients had MS type II. Patients with different types of MS underwent different types of surgical procedures. PMID- 25436280 TI - Intensification of treatment with pegylated interferon alfa in patients coinfected with HIV and HBV genotype H or G being treated with a tenofovir/emtricitabine-containing regimen. AB - BACKGROUND/AIMS: The most common HBV genotypes in HIV-coinfected patients in Mexico are H and G; the response to treatment for these genotypes is unknown. The aim of the study was to examine the effectiveness of intensification with pegylated interferon (PEG-IFN) alfa-2a or alfa-2b in HBV/HIV-coinfected patients treated with a tenofovir/emtricitabine (TDF/FTC) backbone in an HIV clinic in Mexico City. METHODOLOGY: We performed a single-arm open-label trial involving HBV/HIV-coinfected patients. Patients with chronic hepatitis B who were HBeAg positive were treated with TDF/FTC-containing regimen. Treatment was intensified by addition of PEG-IFN alfa-2b or alfa-2a for 24 weeks. The primary endpoint of effectiveness, assessed after 24 weeks, was suppression of HBV DNA to <60 IU/mL. RESULTS: We enrolled 29 patients; 27 (93%) were men. HBV genotypes were F in 2 (6.9%), A in 2 (6.9%), G in 10 (34.5%), and H in 15 (51.7%). The primary endpoint was present in 17 (58%) patients (95% CI 29.7%-70.8%). CONCLUSIONS: Intensification with PEG-IFN alfa-2a or alfa-2b is effective and well tolerated in patients with chronic hepatitis B who are HBeAg positive, have genotype H or G, and are coinfected with HIV while they are being treated with TDF/FTC containing regimen. PMID- 25436281 TI - Surgical treatment of giant aneurysm of hepatic artery: report of three cases. AB - BACKGROUND/AIMS: To explore the surgical way of treating giant hepatic artery aneurysm(HAA). METHODOLOGY: Three hepatic artery aneurysm patients who were performed aneurysm resection without revascularization of the hepatic artery were reviewed. After surgery, the values of liver function and enhanced CT scan of the patients were followed. RESULTS: All the three patients were recovered well postoperatively and only several values of biochemistry marks of liver function as ALT, AST, TBIL and DB in one case with liver cirrhosis were elevated and decreased to normal ranges in a few days postoperatively. The values of biochemistry marks of liver function in other two cases were within normal limits. The enhanced CT scan also showed arteries in the liver after hepatic artery aneurysm resection. CONCLUSIONS: Giant HAA may be safely removed without revascularization of the hepatic artery. PMID- 25436282 TI - Evaluation of the relationship between serum ghrelin, C-reactive protein and interleukin-6 levels, and disease activity in inflammatory bowel diseases. AB - BACKGROUND/AIMS: Ghrelin is a 28 aminoasid peptide hormone, have generally focused upon this peptide's role upon growth and energy metabolism. Recently, studies investigating ghrelin's effect upon inflammation and immune response have gained importance. We aimed to compare the effectiveness of ghrelin levels, Creactive protein and interleukin-6 levels in establishing disease activity. METHODOLOGY: 52 cases with ulcerative colitis and 33 with Crohn's disease, total 85 patients, were included in this study. The serum ghrelin levels of the patients in remission and of those with active disease were compared. RESULTS: The mean serum ghrelin level in active patients (1243 +/- 648 pg/ml), was found to be higher than those in remission (466 +/- 214 pg/ml) (p<0.001). In establishing the disease activity, CRP is a the most effective marker compared to the other two inflammatory markers. AUC values were established as; CRP: 0.947 (95% CI,0.903-0.992),ghrelin:0.934(95% CI, 0.884-0.984) and interleukin-6: 0.756 (95% CI, 0.648- 0.864). DISCUSSION: Serum ghrelin level can be used with CRP as an important marker in establishing the mucosal damage in inflammatory bowel diseases. PMID- 25436283 TI - Acute pancreatitis as an early indicator of pancreatic head carcinoma. AB - BACKGROUND: The purpose of this study was to determine if AP is an indicator of pancreatic head carcinoma, and if it is associated with disease stage. METHODS: A retrospective review of the medical records of 154 patients with pancreatic head cancer who were treated from January 2006 to December 2011 was conducted. Patients were divided into 2 groups: those with AP and those without. Data extracted and compared including age, gender, the presence of AP, and laboratory results. RESULTS: This study included 103 males (67.8%) and 49 females (32.9%), with an age range of 38-83 years. The frequency of main pancreatic duct dilation (MPD) was higher in patients without pancreatitis than in patients with AP (P = 0.018). There were 18, 14, 4, and 2 patients in the AP group, and 34, 26, 31, and 23 patients in nonpancreatitis group with stage I, II, III, and IV disease, respectively, (P = 0.007). The median length of tumors in AP group was 3.41 cm, and that in the non-pancreatitis group was 4.15 cm (P = 0.028).No correlation was found between disease stage and the presence of MPD dilatation (P = 0.646). The area under the receiver operating characteristic curve (AUC) of 0.66 (P = 0.003; 95% confidence interval [CI] 0.568-0.753) indicated that AP itself was insufficient for predicting disease stage. CONCLUSIONS: AP is an early manifestation of pancreatic head carcinoma, although the presence of AP is insufficient to predict disease stage. PMID- 25436284 TI - The accuracy of computed tomography in the pretreatment staging of colorectal cancer. AB - Colorectal cancer (CRC) is one of the most frequent cancers around the world. Multimodality therapies are used for CRC including surgery, chemotherapy, radiotherapy and targeted therapy. Correct treatment plan depends greatly on the accurate pretreatment staging. Computed tomography (CT) is a widely used detection and staging modality for CRC patients in clinical practice. The role of CT in assessing the patients with CRC has been well established, but the accuracy of pretreatment staging by CT varies in different reports. With the development of CT techniques, some reformations such as multi-detector CT (MDCT), CT with water enema or air insufflations, multiple planner reconstruction (MPR) help to give us higher resolution images in shorter time. The accuracy of CT for N staging was still not so ideal, but CT played an important role in chest and liver staging. Magnetic resonance imaging (MRI) and endorectal ultrasound (ERUS) may provide more precise images and evaluation of local T and N staging for rectal cancer. And positron emission tomography (PET) or PET/CT is recommended as a complement of CT, only for cases suspected of residual or recurrent colorectal carcinoma or before metastasectomy, not for routine use. PMID- 25436285 TI - Thoracic epidural analgesia (TEA) vs. patient controlled analgesia (PCA) in laparoscopic colectomy: a meta-analysis. AB - BACKGROUND/AIMS: Use of thoracic epidural analgesia (TEA) in laparoscopic colorectal surgery is still controversial. Previous clinical trials have conflicting findings in terms of bowel function return, length of hospital stay and postoperative complications. This meta-analysis aims to assess the effect of TEA on clinical outcomes of laparoscopic colorectal surgery compared with patient controlled analgesia (PCA). METHODOLOGY: Randomized, controlled trials (RCTs) compared the effect of thoracic epidural analgesia (TEA) and patient controlled analgesia (PCA) on outcomes of laparoscopic colorectal surgery was searched. The effects on pain relief, bowel function return, length of hospital stay and post operative complications were compared. RESULTS: Seven RCTs were included in this meta-analysis. Compared with PEA, TEA contributed significantly lower visual analog scale (VAS) or verbal rate scale (VRS) pain score during the initial period after surgery. No significant difference was observed in time to return of bowel function and length of hospital stay between the two groups. TEA group was associated with lower risk in nausea and vomiting, but with similar risk in urinary retention, urinary tract infection, wound infection, ileus and anastomotic leakage compared with PCA group. CONCLUSIONS: Use of epidural analgesia in laparoscopic colorectal surgery helps to provide better pain alleviation during the initial period after operation. This benefit is not at the expense of increased risks of any major complications, or significantly longer hospital stay. No significant benefits in return of bowel function were observed. PMID- 25436286 TI - Incidence and risk factors for incisional hernia after open surgery for colorectal cancer. AB - BACKGROUND/AIMS: To confirm the incidence and risk factors of incisional hernia after colorectal cancer surgery, we analyzed the clinical data including the surveillance computed tomography (CT) examination. METHODOLOGY: One hundred sixty seven patients with open abdominal surgery for colorectal cancer were analyzed retrospectively. RESULTS: Incisional hernia was recognized in 27 cases (16.2%), and occurred at median 7 (1-21) months after surgery. Multivariate analysis showed the risk factors for incisional hernia were female (p=0.0014), distal colon and rectal cancer (p=0.0038), high body mass index (p=0.0055) and lower serum albumin (p=0.0081). CONCLUSIONS: Obesity, lower median incision and malnutrition might seem to relate to the incisional hernia after colorectal cancer surgery. PMID- 25436287 TI - Repeated screening with fecal immunochemical tests reduced the incidence of colorectal cancers in Saga, Japan. AB - BACKGROUND/AIMS: Screening with fecal occult blood test has reduced mortality from colorectal cancer (CRC), with fecal immunochemical tests (FIT) widely utilized for CRC screening in Japan. To evaluate the importance of repeated FIT screening, the incidence of CRC was compared in patients undergoing initial and repeated screening. METHODOLOGY: Participants aged >=40 years in Saga, Japan, were invited to undergo a 2-day FIT. FIT positive subjects were verified by colonoscopy to evaluate the CRC incidence rates. RESULTS: From 2005 to 2007, 55,595 individuals were invited to undergo CRC screening, including 47,168 undergoing repeated and 8,427 undergoing initial screening. Of the 5,832 FIT positive subjects, 4,615 were assessed by colonoscopy, with 114 diagnosed as having CRC. Of these 114 patients, 67 had early and 47 had advanced CRC. The risk of CRC was 63% lower in the repeated than in the initial screening group (p<0.0001). Of the 67 patients with early CRC, 42 underwent endoscopic resection, with the rate significantly higher in the repeated than in the initial screening group (p = 0.01). Overall survival was longer in screened subjects than in those who visited hospitals with clinical symptoms. CONCLUSIONS: Repeated CRC screening with FIT reduced the incidence of CRC in Saga, Japan. PMID- 25436288 TI - Licochalcone-A sensitizes human esophageal carcinoma cells to TRAIL-mediated apoptosis by proteasomal degradation of XIAP. AB - BACKGROUND/AIMS: Esophageal carcinoma is one of the most aggressive human cancers, and novel treatment modality is required. Although expressing adequate levels of functional tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4/DR5, significant proportion of esophageal cancer cells exhibit resistance to the cytotoxic effect of this ligand. Licochalcone-A (LA), a flavonoid present in a variety of edible plants, exhibits a wide spectrum of pharmacologic properties such as anticancer, antioxidant, and anti-inflammatory activities. METHODOLOGY: Eca109 and TE1 cells were cultured and transfected, then their viability was detected using MTT assay. Immunoprecipitation and immunoblotting analysis and RT-PCR analysis were also performed. RESULTS: In this study, we found that LA synergistically caused the TRAIL-induced apoptosis in Eca109 and TE1 cells. Such potentiation was achieved through inhibiting Akt activation and promoting proteasomal degradation of X-linked Inhibitor of Apoptosis Protein (XIAP) which mediated the survival signals and allow the cells to escape from apoptosis in various human cancers. CONCLUSIONS: The combination of TRAIL and LA might be a novel therapeutic strategy for esophageal carcinoma patients who fail to respond to standard chemotherapy. PMID- 25436289 TI - Intranodal cytokeratin particles is a predictive marker of efficacy for neoadjuvant therapies in patients with squamous cell carcinoma of the esophagus. AB - BACKGROUND/AIMS: Lymph node metastasis is one of the most important prognostic factors in patients with esophageal squamous cell carcinoma (ESCC). Neoadjuvant treatment can reduce micrometastasis in lymph nodes to enable curative resection by down staging. The aim of this study was to evaluate the histological effect of neoadjuvant therapy on lymph node metastasis of ESCC by performing immunohistochemistry for cytokeratin staining. METHODOLOGY: A total of 3061 lymph nodes were examined from 62 patients who received neoadjuvant treatment followed by esophagectomy with lymphadenectomy. RESULTS: We observed positive staining for cytokeratin in 276 (9.0%) lymph nodes, which included overt metastasis, micrometastasis and hyalinized cytokeratin particles (HCP). Patients with HCPs in lymph nodes had better outcomes than patients without HCPs in lymph node. A significant prognostic difference between the patients with HCPs and without HCPs was observed in a subgroup of patients with nodal metastasis. CONCLUSIONS: Our findings suggest that HCP might reflect a degenerative change of cancer cells in lymph nodes and can predict the response to neoadjuvant therapy. PMID- 25436290 TI - Endoscopic follow-up and management of Barrett's esophagus in relation to its preneoplastic potential. AB - Barrett's esophagus is an acquired clinical condition in which the squamous epithelium of the distal esophagus is replaced by a columnar epithelium. The diagnosis requires histological confirmation of specialized intestinal metaplasia, in which goblet cells must be present. Barrett's esophagus is a risk factor for the development of esophageal adenocarcinoma, a tumor with an incidence and mortality have increased alarmingly in recent years in the western world. It has been estimated that the annual incidence of cancer in patients with Barrett's esophagus has increased from 0.2-2%. Once diagnosed, Barrett's esophagus is estimated to have an annual neoplastic transformation rate of 0.5% per patient. The highlights of the endoscopic diagnosis and treatment are reviewed here, as well as the screening and monitoring of this process. PMID- 25436291 TI - Esophagectomy and pancreatoduodenectomy in the same patient: tactical and technical considerations. AB - Esophagectomy (EE) and pancreatoduodenectomy (PDE) are considered the most invasive and technically demanding surgical procedures performed on the digestive organs. These surgical interventions significantly change the normal anatomic relationships in the upper abdomen. Any additional digestive surgeries, especially resectional procedures, performed after a prior EE or PDE can be extremely difficult. The cases of simultaneous or metachronous EE and PDE in the same patient are very interesting from both a scientific and a practical viewpoint. We collected and analyzed the existing literature data on EE and PDE in the same patient. There were 60 cases: 3 cases of EE after PDE, 22 cases of PDE after EE, and 35 cases of simultaneous EE and PDE. The technical and tactical features of the surgery in a different sequence of stages or in a simultaneous procedure are discussed in a review. PMID- 25436293 TI - Nomogram to predict anastomotic leakage after laparoscopic anterior resection with intracorporeal rectal transection and double-stapling technique anastomosis for rectal cancer. AB - BACKGROUND/AIMS: Laparoscopic rectal cancer surgery involving rectal division with intracorporeal stapling devices is technically difficult. This study aimed to identify risk factors for anastomotic leakage associated with laparoscopic anterior resection for rectal cancer. METHODOLOGY: 476 patients who underwent laparoscopic anterior resection with intracorporeal rectal transection and double stapling technique (DST) anastomosis for rectal cancer between July 2007 and February 2013 were retrospectively studied. All clinical variables were examined by univariate and multivariate analyses. A nomogram was developed to predict postoperative anastomotic leakage, given associated risk factors, and bootstrap validation was performed. The outcome of interest was clinical anastomotic leakage. RESULTS: In multivariate analysis, tumor location (p=0.001), operation time (p=0.001) and preservation of the left colic artery (p=0.037) were independently and significantly associated with anastomotic leakage. The resulting nomogram demonstrated good accuracy in predicting long-term complication, with a bootstrapcorrected concordance index 0.835. CONCLUSIONS: Our results suggest that we found that tumor localization, preservation of the left colic artery and operation time are predictive factors for clinical anastomotic leakage in laparoscopic anterior resection with intracorporeal rectal transection and double-stapling technique (DST) anastomosis for rectal cancer. PMID- 25436292 TI - Cure and prevention strategy for postoperative gastrointestinal fistula after esophageal and gastric cardiac cancer surgery. AB - Gastrointestinal fistula is the most serious complication of esophageal and gastric cardiac cancer surgery. According to occurrence of organ, gastrointestinal fistula can be divided into anastomotic fistula, gastric fistula; According to occurrence site, fistula can be divided into cervical fistula, thoracic fistula; According to time of occurrence, can be divided into early, middle and late fistula. There are special types of fistula including 'thoracic cavity'-stomach-bronchial fistula, 'thoracic cavity'-stomach-aortic fistula. Early diagnosis needs familiarity with various types of clinical gastrointestinal fistulas. However, Prevention of gastrointestinal fistula is better than cure, including perioperative nutritional support, respiratory tract management, and acid suppression, positive treatment of complications, antibiotic prophylaxis, and gastrointestinal decompression and eating timing. Prevention can effectively reduce the incidence of postoperative gastrointestinal fistula. Collectively, early diagnosis and treatment, nutritional supports are key to reducing mortality of gastrointestinal fistula. PMID- 25436294 TI - Postoperative surveillance and prognostic factors in patients with esophageal cancer. AB - BACKGROUND/AIMS: Here we investigated postoperative prognostic factors and surveillance in patients with esophageal cancer. METHODOLOGY Prognostic factors were evaluated at several different postoperative stages in 257 patients with curative (R0) esophagectomy. Cause of death and pattern of tumor recurrence were also analyzed. RESULTS: There was a significant difference in the distribution of cause of death according to the time after surgery (p<0.001). The pattern of recurrence also differed according to the time after surgery, although this was not statistically significant. A Cox proportional regression hazard model for disease-specific survival revealed that Tumor-Node-Metastasis (TNM) stage was an independent prognostic factor only from the time of initial surgery until the third postoperative year, and no postoperative prognostic factors were detected after the fourth and fifth years. There were significant differences in disease specific survival among pathological TNM stages between the time of initial surgery and postoperative year five, but not between stages I and II at postoperative years two, three, or four. There were no significant differences between the stages at postoperative year five. Relapse-free survival differed between stages II and III at postoperative year five, although the other results were similar to those for disease-specific survival. CONCLUSIONS: Prognostic factors for esophageal cancer alter during the postoperative period. Although the pathological stage at the time of initial surgery has less prognostic power after 3 years, it remains important to monitor treatments for esophageal cancer continuously, as well as concomitant diseases and other malignancies. PMID- 25436295 TI - Prognostic value of SOX2 in digestive tumors: a meta-analysis. AB - BACKGROUND/AIMS: Sex determine region Y-box 2 (SOX2) is involved in tumor onset and progress. However its prognostic value for survival in patients with digestive tumors remains controversial. METHODOLOGY: Publications related to the prognostic significance of SOX2 in digestive tumors were included up to 1 Oct 2013. We computed the pooled hazard ratio and subgroup stratification analysis for overall survival (OS) by software Stata. RESULTS: A total of eight studies met the inclusion criteria. The pooled results showed that high SOX2 level was not significantly associated with OS in digestive tumors with significant heterogeneity. We then performed a subgroup analysis according to tumor types and patients' numbers. SOX2 over-expression was associated with a poor OS in hepatocellular carcinoma (HR, 2.56; 95%CI, 1.77-3.71; P=0.000) with no heterogeneity. While in gastric carcinoma, SOX2 over-expression was not associated with OS (HR, 0.83; 95%CI, 0.23-3.03; P=0.773) with obvious heterogeneity. In addition, the sample size affected the pooled results. CONCLUSIONS: Taken together, our findings suggested that SOX2 expression was associated with a poor prognosis in patients with hepatocellular carcinoma, while not for gastric carcinoma. The prognosis role for SOX2 in digestive tumors might vary from different tumor type and different pathology stage. Further large scale multicenter studies need to confirm these results. PMID- 25436296 TI - Effects of ramosetron oral disintegrating tablets on gastric emptying: crossover study using the 13C-acetic acid breath test. AB - BACKGROUND/AIMS: Ramosetron is a new selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist that reportedly has more potent antiemetic effects than other 5-HT3 receptor antagonists. The aim of this study was to determine the effect of ramosetron pretreatment on gastric emptying using the 13C-acetic acid breath test. METHODOLOGY: Ten healthy male and female volunteers participated in this randomized, twoway crossover study. After they had fasted overnight, the subjects were randomly assigned to receive 0.1 mg ramosetron 1 hour before ingestion of a test meal (200 kcal per 200 mL, containing 100 mg 13C acetate) or to receive the test meal alone. Under both conditions, breath samples were collected for 150 min following ingestion of the meal. Statistical comparison of the parameters between the two test conditions was performed. RESULTS: No significant differences in the calculated parameters, including T 1/2, T lag, GEC or beta and kappa, were observed between the two test conditions. CONCLUSIONS: The present study revealed that 0.1 mg ramosetron had no significant effect on the rate of gastric emptying. Thus, our results suggest that ramosetron can be administered safely, without gastrointestinal adverse effects, even to terminal cancer patients with delayed or accelerated gastric emptying abnormality. PMID- 25436297 TI - Is annual endoscopic surveillance necessary for the early detection of gastric remnant cancer in Korea? A retrospective multi-center study. AB - BACKGROUND/AIMS: This study investigated the clinical characteristics, survival outcomes of the patients with gastric remnant cancers (GRC) diagnosed after gastric cancer surgery and the need of annual endoscopic surveillance after gastric resection for early detection of GRC. METHODOLOGY: We reviewed the medical records of 30 patients who underwent endoscopy and diagnosed with GRC between 1999 and 2009. We analyzed the clinical features, tumor characteristics, regular endoscopic surveillance, treatment, and survival outcomes. RESULTS: The median time interval between first operation and diagnosis of GRC was 36 months. Fifteen patients (50%) had GRC at non-anastomotic sites. Seventeen patients (56.7%) underwent annual endoscopic surveillance and nine patients (30%) had no symptom at the time of diagnosis of GRC. GRC were detected earlier in patients with annual endoscopic surveillance than those without surveillance (p=0.0014). The median overall survival (OS) after the diagnosis of GRC for all patients was 35.9 months. The median OS of patients with curative resection including endoscopic resection for early gastric cancer was longer than those without resectability (46.3 vs. 13.6 months, p=0.0026). CONCLUSIONS: These results suggest that annual endoscopic surveillance program after gastric partial resection would be helpful to detect early cancer of remnant stomach for curative resection. PMID- 25436298 TI - Retrograde long intestinal tube splinting: a safe and effective treatment for preventing recurrent adhesive small bowel obstruction. AB - BACKGROUND/AIMS: Long intestinal tube splinting (LITS) is a strategy that helps to reduce the recurrence of adhesive small bowel obstruction (ASBO) by fixing the bowel to ensure a favorable lie. Even though anterograde LITS is favored by most surgeons, its postoperative complications are noteworthy. Retrograde LITS was hardly reported in previous studies. METHODOLOGY: A retrospective analysis was performed on all patients who had retrograde LITS for postoperative ASBO between December 2001 and 2008 at our unit. Medical records were reviewed. Patients were followed up by telephone to identify recurrent ASBO. RESULTS: There were 162 patients received retrograde LITS. The overall complication rate was 8%, and the tube splinting complication rate was 0.6%. The average length of follow-up was 75+/-28.1 months (from 5 to 131 months). The incidence of recurrent ASBO was 5.4%. CONCLUSIONS: The results show that retrograde LITS is an effective method for preventing recurrent ASBO. Its overall complication rate and tube splinting rate are lower than anterograde LITS. PMID- 25436299 TI - Clinical usefulness of double balloon enteroscopy in suspected Crohn's disease: the KASID multi-center trial. AB - BACKGROUND/AIMS: The recently developed double balloon enteroscopy (DBE) may be useful to evaluate small bowel lesions in patients with suspected Crohn's disease (CD). We investigated the findings of DBE, small bowel follow-through and abdominal CT in patients with suspected CD who could not be diagnosed with CD using conventional colonoscopy. METHODOLOGY: Thirty patients (27 males, mean age 32.7+/-9.27 years) with suspected CD were consecutively enrolled in this study. The main symptoms were abdominal pain, chronic diarrhea, weight loss, obscure bleeding, or anemia. These patients were enrolled from May 2006 to January 2007 at 10 tertiary medical centers participating in the Korean Association for the Study of Intestinal Diseases. RESULTS: The DBE demonstrated definite CD in 24 patients (80.0%) and suspected findings of CD in six patients. The pathology results obtained by endoscopic biopsies revealed a granuloma in six patients (23.1%). The DBE identified additional findings not detected by radiology studies in 24 patients (80%) although the small bowel followthrough and the abdominal CT revealed the abnormal findings (73.1% and 64%). CONCLUSIONS: DBE may be a promising alternative and useful technique for patients with suspected CD. DBE provides biopsy sampling and more detailed information than radiology studies. PMID- 25436300 TI - Giant hemangiomas: effects of size and type of surgical procedure on postoperative outcome. AB - BACKGROUND/AIMS: Controversies still exist regarding the management of giant hemangiomas. The purpose of this study was to evaluate in a retrospective manner the effects of size and type of surgical procedures on early postoperative results. METHODOLOGY: Between January 2000 and January 2011, a total of 82 patients underwent surgery. Patients were divided into 2 groups; according to size (Group 1 >10cm and Group 2 <=10cm) and the selected operative procedure. RESULTS: When the patients were compared according to size of the lesions, the operation time was significantly longer (p=0.01) and the amount of blood loss was significantly higher (p=0.04) in hemangiomas >10cm. If the patients were compared according to type of the surgical procedure, hepatic resection was more frequently preferred in bilobar and left lobe localized lesions, whereas enucleation was significantly more chosen in lesions localized to the right lobe (p=0.01). CONCLUSIONS: Size of the hemangioma did not alter selection of the surgical procedure in this series. Larger hemangiomas are associated with longer operation time and more blood loss. Surgical results after enucleation and resection are similar. Although enucleation seems preferable, it is not an easy procedure, and may result in severe bleeding. PMID- 25436301 TI - MicroRNA-206, down-regulated in hepatocellular carcinoma, suppresses cell proliferation and promotes apoptosis. AB - BACKGROUND/AIMS: MicroRNA-206 has been proven down-regulated in many human malignancies and correlated with tumor progression. However, the expression and functions of miR-206 in hepatocellular carcinoma (HCC) are still unclear. The aim of this study was to explore the effects of miR-206 in HCC tumorigenesis and development. METHODOLOGY: The expression levels of miR-206 were quantified by qRT PCR in 147 surgically resected HCC and matched adjacent non-cancerous tissues, and correlated with clinicopathological factors. MTT, flow cytometric assay, and Transwell invasion and migration assays were used to test the proliferation, apoptosis, invasion, and migration of HepG2 HCC cells transfected with miR-206 mimics or negative control (NC) RNA-oligonucleotides. RESULTS: MiR-206 expression was significantly downregulated in HCC compared with matched non-cancerous liver tissues. Low level of miR-206 was associated with poor tumor differentiation, multiple tumor nodes, lymph node metastasis, and advanced TNM stage. In addition, transfection of miR-206 mimics in HepG2 cells was able to reduce cell proliferation, invasion, and migration, and promote cell apoptosis. CONCLUSIONS: These findings demonstrate that miRNA-206 could not only be useful as a novel biomarker but also serve as a potential target for gene therapy of HCC. PMID- 25436302 TI - Improvement in the nutritional status and clinical conditions of patients with liver failure using a liver diet combined with a branched chain amino acids enriched elemental diet. AB - BACKGROUND/AIMS: This study was performed to evaluate any improvement in the nutritional state and clinical symptoms in patients with liver failure and advanced cirrhosis after consumption of a liver diet with restricted energy and protein, in combination with a branched chain amino acids (BCAA)-enriched elemental diet. METHODOLOGY: A BCAA-enriched elemental diet, in combination with a liver diet, characterized by restricted energy and protein, was administered in divided meals to 20 patients with liver failure associated with ascites or hepatic encephalopathy for 4 weeks. RESULTS: The symptom of ascites abated as a result of increased total serum protein and albumin levels after the nutritional intervention in comparison with baseline levels. Ammonia levels were slightly increased without exacerbating hepatic encephalopathy, and the protein nutrition state consequently improved. CONCLUSIONS: Divided meals of a BCAA-enriched elemental diet combined with a liver diet improved the nutritional state and clinical symptoms of patients with liver failure. PMID- 25436303 TI - Low postoperative platelet count is associated with negative outcome after liver resection for hepatocellular carcinoma. AB - BACKGROUND/AIMS: Hepatocellular carcinoma is one of the most common malignancies worldwide. The only curative treatment is surgery. As hepatocellular carcinoma is often associated with liver cirrhosis, patients are at risk for postoperative liver failure. In the recent years, platelets are thought to play an important role in liver regeneration.The aim of this study was to discover the relevance of postoperative platelet counts after liver resection for hepatocellular carcinoma. METHODOLOGY: Data of 68 patients who underwent liver resection for hepatocellular carcinoma between July 2007 and July 2012 in a single centre were analysed. Postoperative morbidity and mortality were evaluated in regard to postoperative platelet counts. Comparative analysis between patients with platelet counts <=100 2x109/ l and >100 x109/ l at d1 was performed in regard to postoperative outcome. RESULTS: Within this cohort, 43 patients (63%) suffered from histologically proven liver cirrhosis. Postoperative mortality was statistically significant associated with postoperative reduced platelet counts. Comparative analysis showed significantly elevated postoperative bilirubin levels and lower prothrombin time in patients with platelet counts <= 100 1x109/ l at d1. CONCLUSIONS: Postoperative low platelet counts are associated with poor outcome after hepatic resection for hepatocellular carcinoma. PMID- 25436304 TI - Decreased expression of liver-type fatty acid-binding protein is associated with poor prognosis in hepatocellular carcinoma. AB - BACKGROUND/AIMS: The purpose of this study was to assess liver-type fatty acid binding protein (L-FABP) expression and its association with clinicopathological features in hepatocellular carcinoma (HCC). METHODOLOGY: L-FABP mRNA expression in 57 samples of HCC and corresponding adjacent liver tissue and 8 normal liver tissue samples were examined by real-time reverse transcriptase (RT)-PCR analyses. Tissue microarray technique and immunohistochemistry (IHC) were used to detect the expression of L-FABP in 163 HCCs. The association between L-FABP expression and the clinicopathological factors and prognosis was analyzed. RESULTS: The average expression of L-FABP mRNA was 0.233 in the HCC tissues, 1.407 in the peri-carcinoma tissues, and 1.0 in the normal liver tissues. IHC analysis showed that there were 47% (76/163) HCCs exhibited weak or even no immunoreactivity of L-FABP. The L-FABP expression in HCC showed significant associations with preoperative levels of AFP (p=0.039), tumor size (p=0.026), histological grade (p=0.000), differential degree (p=0.000), vascular invasion (p=0.016), capsular invasion (p=0.029) and recurrence (p=0.004). Patients with L FABP high-expression showed better prognosis than patients with L-FABP low expression (p=0.008). CONCLUSIONS: L-FABP was downregulated in HCC and could be served as a promising prognostic marker for HCC patients. PMID- 25436305 TI - Influence of the time of hepatocyte infusion on liver transplantation outcome. AB - BACKGROUND/AIMS: Donor-derived hepatocytes infused into recipient rats before liver transplantation can improve the results of liver transplantation in rats. However, the appropriate time when the hepatocytes were infused before transplantation is needed to be explored. METHODOLOGY: All the rats were randomly divided into five groups, the recipient rats were infused with donor-derived hepatocytes at different points of time before transplantation (Group A received the injection one week prior to the transplantation; group B, two weeks prior to the transplantation; group C, three weeks; and group D, four weeks; the control group did not receive hepatocytes infusion). The alanine aminotransferase (ALT), alkaline phosphatase (ALP), and albumin (ALB) levels were tested and the survival time was recorded. RESULTS: The survival times of recipient rats in group B was the longest among the five groups. The level of serum ALT and ALP in group B were the lowest and the level of ALB was the highest among the five groups. CONCLUSIONS: In order to achieve the best result following liver transplantation, infusion of hepatocytes two weeks before liver transplantation was determined to be the optimal time. PMID- 25436306 TI - C-reactive protein as a prognostic factor for mortality in pneumonia patients with liver cirrhosis. AB - BACKGROUND/AIMS: C-reactive protein (CRP) is considered a useful predictor of mortality from community- acquired pneumonia (CAP). Serum CRP concentration reflects its production in the liver, and impaired liver function may affect CRP level. The purpose of this study was to evaluate whether the initial CRP level is a prognostic factor for mortality from CAP in patients with liver cirrhosis (LC). METHODOLOGY: CAP patients with LC admitted to two tertiary referral hospitals from January 2005 to June 2009 were included in this study. The associations between the initial clinical findings including CRP level and mortality were analyzed. RESULTS: Sixty-one men and 15 women were included. Seventeen patients (22.4%) died while in the hospital. Univariate analysis showed that an initial CRP level above the median value of 6.93 mg/dL was related to a lower risk of mortality (P=0.048). Multivariate Cox regression analysis showed that the significance of the relationship between the initial CRP level and mortality risk in CAP patients with LC was sustained after adjusting for the CURB-65 score, presence of malignancy, MELD score, and underlying lung condition. CONCLUSIONS: Higher initial serum CRP level is associated with lower mortality risk in CAP patients with LC. PMID- 25436308 TI - High levels of procalcitonin in the early phase after pediatric liver transplantation indicate poor postoperative outcome. AB - BACKGROUND/AIMS: To date, no data is available about procalcitonin (PCT) levels and its relevance to morbidity and graft function in the early phase after pediatric liver transplantation (pLTx). The aim of this study was to analyse the prognostic relevance of early postoperative PCT elevations in pediatric liver recipients. METHODOLOGY: Thirty pediatric patients who underwent 32 liver transplantations were included into this observational single-center study. RESULTS: Patients with high PCT levels on postoperative day (POD) 2 had higher International Normalized Ratio values on POD 5 (p<0.05) and suffered more often from primary graft non-function (p<0.05). They also had a longer stay in the pediatric intensive care unit (p<0.01) and on mechanical ventilation (p=0.001). There was no correlation between PCT elevation and systemic infection. However, PCT levels were correlated with peak serum lactate levels immediately after graft reperfusion and elevation of serum aminotransferases on POD 1 (r2=0.61, p<0.001). CONCLUSIONS: High levels of PCT after pLTx are an early indicator of poor postoperative outcome and may reflect ischemia induced liver cell injury within the context of an ischemia- reperfusion injury. PMID- 25436307 TI - Gemcitabine transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma. AB - BACKGROUND/AIMS: Transcatheter arterial chemoembolization (TACE) has been shown to increase survival in patients with unresectable hepatocellular carcinoma (HCC), however toxicity from commonly used agents limits its use in unresectable disease. Gemcitabine is a well tolerated chemotherapeutic agent with a high first pass clearance. In this study we evaluated a cohort of patients with unresectable HCC treated with gemcitabine-TACE alone. METHODOLOGY: A review of all patients that underwent gemcitabine-TACE for unresectable HCC from 2002 to 2006 was performed. No patients were eligible for resection, liver transplantation or ablation. All patients received gemcitabine-TACE alone. The primary outcome measure was survival from first treatment. Secondary outcome measures included radiological response and toxicity. RESULTS: 55 patients underwent a total of 172 gemcitabine-TACE treatments for unresectable HCC. Median age was 64.7 years. All patients had Barcelona-Clinic Liver Cancer (BCLC) stage B (44%) or C (56%) disease. Median survival following gemcitabine-TACE was 8.8 months. 22% demonstrated a partial response and 61% had stable disease. 6% experienced grade 3/4 adverse events. There was 1 treatment related death. CONCLUSIONS: Gemcitabine TACE is well tolerated and appears to provide an alternative agent for patients with unresectable HCC undergoing chemoembolization. PMID- 25436309 TI - Central hepatic resection under hypothermic total vascular exclusion using ante situm techniques while maintaining liver blood supply. AB - Ante-situm liver resection under hypothermic total vascular exclusion is used to resect large tumours that involve the hepatic veins close to the vena cava or the cava itself. This procedure traditionally requires venovenous bypass when it is necessary to clamp the cava, or portocaval shunt when caval continuity is maintained by piggyback dissection of the liver. We present a technique of ante situm liver resection, operating on one side of the liver at a time while maintaining prograde portal flow through the opposite side of the liver, thereby avoiding venovenous bypass, portacaval shunt and portal vein reconstruction. PMID- 25436310 TI - Assessment of treatment success and short-term effectiveness using C-arm CT immediately after hepatic chemoembolization of HCC. AB - BACKGROUND/AIMS: To investigate semiquantitative analyses based on amount and morphology of iodized oil uptake about non-enhanced C-arm cone-beam CT(C-arm CT) immediately following hepatic chemoembolization of HCC. METHODOLOGY: We retrospectively reviewed 40 C-arm CT images taken immediately following chemoembolization in 29 consecutive patients who underwent hepatic chemoembolization for HCC lesions(n=97). Two radiologists scored iodized oil uptake in the index tumours from Grade 0(complete) to 4(invisible). To describe the morphologic characteristics of uptake, the lesions scored as Grade 1 to 3 were subclassified as 'defective' and 'not-defective' with respect to uptake. To evaluate the performance of this modality, we performed a receiver operating characteristic curve analysis. RESULTS: All treated lesions were classified into 'complete treatment'(n=50) and 'viable HCC'(n=47). Thirty-one lesions were evaluated as Grade 0, two as Grade 4, and the rest (n=64) as between Grades 1 and 3, and the lesions of Grade 3 or 4 were all viable. Of the defective uptake lesions(n=35), 28 lesions were also viable. The areas under the curves of the lesions were 0.827 to 0.860. CONCLUSIONS: The analysis of C-arm CT based on the amount and morphologic characteristics of iodized oil uptake may be useful to predict the effectiveness of the hepatic chemoembolization of HCC. PMID- 25436311 TI - Combined evaluation of the Glasgow prognostic score and carcinoembryonic antigen concentration prior to hepatectomy predicts postoperative outcomes in patients with liver metastasis from colorectal cancer. AB - BACKGROUND/AIMS: Little is known about the ability of the inflammation-based Glasgow prognostic score (GPS). METHODOLOGY: 106 patients who underwent curative resection for colorectal liver metastasis (CRLM) were analyzed. Patients with an elevated Creactive protein concentration (>10 mg/L) and hypoalbuminemia (<35 g/L) at admission were assigned a GPS 2, those with only 1 of these biochemical abnormalities were assigned a GPS 1, and those without either abnormality were assigned a GPS 0. RESULTS: Multivariate analysis showed that 2 variables, carcinoembryonic antigen (CEA) concentration > 30 ng/mL and a GPS 1 or 2, were independently prognostic of survival. Patients were classified into 3 groups on the basis of these 2 variables. Patients with GPS 1 or 2 and CEA concentration > 30 ng/mL were assigned a new score of 2, those with either 1 factor were assigned a new score of 1, and those with neither factors were assigned a new score of 0. The 5-year overall survival rates of new scores of 0, 1, 2 were 71.5%, 31.6%, and 0%, respectively (P < 0.0001). CONCLUSIONS: This simple staging system may be able to identify a subgroup of patients who are eligible for curative resection but show poor prognosis. PMID- 25436312 TI - Synchronous splenectomy and hepatectomy in patients with hepatocellular carcinoma, hypersplenism and liver cirrhosis. AB - BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) mainly arises from underlying liver disease. Complicated liver cirrhosis and secondary hypersplenism are the most risk factors preventing surgical treatment of patients with HCC. The present study aimed at investigating the safety and long term outcome of patients with HCC and liver cirrhosis undergoing synchronous hepatectomy and splenectomy. METHODOLOGY: The clinical data of 306 cases of patients with HCC and liver cirrhosis undergoing curative hepatectomy were reviewed. 18 cases underwent synchronous hepatectomy and splenectomy. The rest 288 cases of HCC with hepatectomy only were compared in aspects of clinicopathological and surgical variables and surgical outcomes. RESULTS: Preoperative hemoglobin and platelet count were significantly lower in splenectomy than non-splenectomy group (p<0.01, respectively). Patients undergoing combined splenectomy and hepatectomy needed longer surgery time and hospital stay time, and transfused much more blood intraoperatively (p=0.07, 0.03, and 0.02), and also experienced more portal vein thrombosis (p<0.01). The level of hemoglobin and platelet increased after splenectomy and finally to normal level one month postoperatively. There was no statistical difference of overall and disease-free survival of patients in splenectomy and non-splenectomy groups (p>0.05). CONCLUSIONS: With strict selection, patients with HCC and hypersplenism could undergo combined splenectomy and hepatectomy safely. PMID- 25436314 TI - Radical resection of noncolorectal liver metastases: is cure possible? PMID- 25436313 TI - Impact of 3-D glucan during liver transplantation. AB - BACKGROUND/AIMS: beta-D glucan in the portal vein blood is processed by the hepatic reticuloendothelial system, and therefore, it is possible that the beta-D glucan kinetics of the peripheral vein blood may be useful as a biological index. In this study, the beta-D glucan levels in the peripheral and portal vein blood during liver transplantation were measured in order to study the clinical significance of the molecule. METHODOLOGY: The subjects comprised 20 patients who underwent living donor liver transplantation. In the perioperative period, the beta-D glucan levels were measured before liver transplantation, during surgical procedure, then on postoperative days 5, 14 and 21. RESULTS: The portal vein blood showed a significantly higher level of beta-D glucan than the peripheral blood (p<0.001). A significant difference of beta-D glucan levels was observed between the pre-liver transplantation and postoperative days 5 (p=0.048). There was a significant positive correlation between the preoperative beta-D glucan level and the period of postoperative hospitalization (p<0.001). The patients with fungal infections (35.0%) had a significantly longer period of hospitalization (p=0.019). CONCLUSIONS: The beta-D glucan kinetics accurately reflects the liver function and fungal infections. The beta-D glucan level before liver transplantation can be used to PMID- 25436315 TI - Changes in left portal vein diameter in live liver donors after right hemihepatectomy for living donor liver transplantation. AB - BACKGROUND/AIMS: To evaluate changes in left portal vein(LPV) diameter and its effect on changes of remnant liver volume(RLV) and splenic volume(SV) in live liver donors after right hemihepatectomy. METHODOLOGY: From November 2008 to May 2009, 92 live liver donors were included. On preoperative, postoperative 1-week and 1-month CT, we measured LPV diameters(LPVB, LPV1W, LPV1M), RLVs(RLVB, RLV1W, RLV1M) and SVs(SVB, SV1W, SV1M). Percentage-intervalchanges were analyzed. The relationships between %LPV1W-B and other parameters were evaluated by univariate regression analyses. RESULTS: On postoperative 1-week, LPV1W invariably decreased. However, RLV1W and SV1W increased. %RLVB and %RLV1W-B were significantly associated with %LPV1W-B(P=.016,.011). On postoperative 1-month, mean %LPV1M-1W, %LPV1M-B, %SV1M-1W and %SV1M-B were 108.1+/-9.8%, 82.9+/-11.8%, 99.3+/-11.4% and 146.9+/-23.0%. Although %RLV1M-B or %RLV1M-1W were not related with %LPV1W-B(P=.034,.401), there were negative correlations between %LPV1W-B and %SV1M-1W or %SV1M-B(P=.004,.007). CONCLUSIONS: LPV diameter mostly decreases following right hemihepatectomy and improves spontaneously. Besides extent of hepatectomy, %LPV1W-B may be another indicator predicting splenic enlargement. PMID- 25436316 TI - Transcatheter arterial chemoembolization with an interventional-CT system for recurrent hepatocellular carcinoma after living donor liver transplantation. AB - BACKGROUND/AIMS: The aim of this retrospective study was to evaluate the feasibility and treatment effects of transcatheter arterial chemoembolization (TACE) for recurrent intrahepatic hepatocellular carcinoma (HCC) after liver transplantation. METHODOLOGY: Between March 2007 and December 2012, we treated 8 patients (6 men and 2 women; mean age, 54 years) with recurrent HCC after living donor liver transplantation by TACE using an interventional-CT system. We retrospectively investigated treatment outcomes, complications, and the prognosis in these patients. RESULTS: Overall, 17 sessions of TACE were performed. A single TACE session was performed in 4 patients while multiple TACE sessions were performed in 4 patients. Anticancer drugs and embolic agents were selectively infused from the right hepatic artery (n=7), left hepatic artery (n=1), A3 (n=1), A5 (n=1), A6 (n=1), A7 (n=2), anterior branch (n=1), posterior branch (n=3), intercostal artery (n=1), and right inferior phrenic artery (n=5). There were no procedure-related complications. Response rate was 50%. The median overall survival from the initial TACE for recurrence of HCC was 12.9 months (95% confidence interval, 5 to 21). The 1-year survival rate was 42.9%. CONCLUSION: TACE with an interventional-CT system could play an important role in the treatment of recurrent HCC after liver transplantation. PMID- 25436317 TI - Apoptosis and cell proliferation: correlation with BCL-2 and P53 oncoprotein expression in human hepatocellular carcinoma. AB - BACKGROUND/AIM: Occurrence and biological characteristics of tumors are related not only to over-proliferation of carcinoma cells but also to decrease of apoptosis. The present study was suggested to evaluate the correlation between P53 and Bcl-2 oncoprotein expression with apoptosis and cell proliferative activity in HCC patients. METHODOLOGY: P53 and Bcl-2 protein expression were estimated in the sera and in liver tissues of 45 HCC cases using ELISA and immunohistochemistry. Apoptosis was estimated as apoptotic index (AI) and cell proliferative activity was detected using AgNORs. RESULTS: Serum p53 antigen in HCC patients (0.46+/-0.331ng/ml) showed significant elevation than healthy individuals (0.24+/-0.11ng/ml, p<0.05). P53 protein was immunostained in 41% of HCC; 37.5% of these positive cases were in diffuse pattern representing the mutant p53. Serum Bcl-2 was elevated in HCC cases (50.28+/-25.83u/ ml) than healthy individuals (26.65+/-8.63u/ml, p<0.05). Bcl-2 was immunohistochemically localized in 35.9% of HCC and the positivity was inversely proportional with the histological grade (47.4%, 25%, 25% in grade I,II,III respectively). Bcl-2 showed a positive linear correlation with p53 in the sera of carcinoma patients (p<0.05). CONCLUSION: Bcl-2 may play a role in hepatocarcinogenesis as an inhibitor of apoptosis. However, a positive linear correlation was found between bcl-2 and p53 suggesting that bcl-2/p53 co-expression pattern may be of value in the development of more effective medical therapies in HCC. PMID- 25436318 TI - To Pringle or not to pringle: is Pedicle clamping a necessity in liver resection? AB - A single center prospective study was done to evaluate the role of hepatic portal pedicle clamping (PC) during right hepatectomy (RH) in patients with primary and secondary liver tumors. Cirrhotics were excluded. Two groups were compared for preoperative demographics including diagnosis, tumor size, portal vein embolization and liver enzymes, pre and postoperative hemoglobin levels, percentage of residual liver mass, morbidity and mortality, pedicle clamp time, intensive care unit stay, length of hospital stay and blood loss. We observed no significant difference in the analysis of the post-operative hemoglobin, liver enzymes, residual liver size, size of tumor resected, need for postoperative monitoring in ICU stay, length of hospital stay and blood loss. Mortality and morbidity were the same. None of the patients were transfused during surgery. Our findings show that pedicle clamping was beneficial 15% of the time when uncontrolled intra-operative bleeding was encountered or in a subset of patients with peliosis, steatohepatitis, Jehovah Witness patient, and post-chemotherapy patients. However, its advantage has to be weighed against the disadvantages. PMID- 25436319 TI - Hepatic arterial infusion chemotherapy reduced hepatic metastases from pancreatic cancer after pancreatectomy. AB - BACKGROUND/AIMS: This study aims to investigate the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) on liver metastases from pancreatic cancer after pancreatectomy. METHODOLOGY: We randomly assigned 106 patients with pancreatic cancer after pancreatectomy between 2005 and 2010 to receive 2 cycles of HAIC plus 4 cycles of systemic chemotherapy (Combined Therapy) or 6 cycles of systemic chemotherapy alone (Monotherapy). Both the HAIC and systemic chemotherapy regimen consisted of a 5-hour infusion of 5-fluorouracil 1000 mg/m2 on day 1 followed by gemcitabine 800 mg/m2 as an over 30-min infusion on day 1 and day 8. The treatment was started on an average of 21.2 days after surgery and repeated every 4 weeks. The disease-free survival, overall survival and liver metastases-free survival were compared. RESULTS: There was no significant difference in adverse effects between two groups. Significant differences were found in 3-year overall survival (Combined Therapy, 23.08 %; Monotherapy, 14.81%; P=0.0473) and liver metastases-free survival (Combined Therapy, 80.77%; Monotherapy, 55.56%; P=0.0014). CONCLUSIONS: HAIC effectively and safely prevents liver metastases and improves the prognosis of patients with pancreatic cancer after pancreatectomy. PMID- 25436320 TI - The effect of modified pancreaticojejunostomy for reducing the pancreatic fistula after pancreaticoduodenectomy. AB - BACKGROUND/AIMS: Pancreatic fistula (PF) has traditionally been a source of significant morbidity and mortality after pancreaticoduodenectomy (PD). External drainage of pancreatic duct with stent and Blumgart anastomosis had reduced PF after PD in some studies. We applied compounding described two methods for pancreaticojejunostomy (PJ) during PD, and investigated the effectiveness of this modified PJ technique to prevent PF. METHODOLOGY: Between March 2002, and March 2013, 90 patients who underwent PD were enrolled. The patients were divided into 2 groups according to pancreatienterostomy method. Group 1 contain patients who did not undergo modified PJ (n=70) compared with group 2 (n=20) those who did undergo the modified PJ technique. We compared clinical data between two groups. RESULTS: No differences were noted in the demographics and operation-related factors, between the 2 groups. A PF occurred in 38 of 70 patients in group 1 (54.3%) and in 2 of 20 in group 2 (10.0%). Group 2 had a significantly lower incidence of PF (P=.0016), and these fistulas were classified as being grade A using the International Study Group on Pancreatic Fistula Definition. Mortality in group 1 was 10.0% and no mortality in group 2. CONCLUSIONS: External drainage with Blumgart method of PJ showed reducing high grade PF after PD. PMID- 25436321 TI - Prognostic factors affecting survival after pancreaticoduodenectomy for pancreatic adenocarcinoma (single center experience). AB - BACKGROUND: Pancreatic cancer is considered to have the worst prognosis of the periampullary carcinomas. This retrospective study was to determine prognostic factors for survival after pancreaticoduodenectomy in patients had pancreatic carcinoma. METHODS: We retrospectively studied all patients who underwent PD for pancreatic adenocarcinoma originating from the head, neck or uncinate process from January 1996 to January 2011 in our center. Preoperative variables, intraoperative variables and postoperative variables were collected. RESULTS: The study included 480 patients (282 males and 198 females with a median age of 53 years. At the time of analysis, 180 (37.5%) patients were still alive. The median survival was 19 months. This corresponded to a 1-, 3-, and 5-year actuarial survival of 44 %, 20%, and 15% respectively. Mass size less than 2 cm (P=0.0001), lymph node ratio (P=0.0001), safety margin (P=0.0001), perineural, perivascular infiltration, age above 60 years (P=0.03), gender, preoperative bilirubin, SGPT, liver status, pre and postoperative CEA, CA19- 9 (P=0.0001) were significant predictors of survival. CONCLUSION: Mass size less than 2 cm, lymph node ratio, safety margin, perineural, perivascular infiltration, age above 60 years, gender, liver status, pre and postoperative CEA, CA19-9 are important predictors of survival in patients undergoing PD for pancreatic cancer. PMID- 25436322 TI - Clinical benefit of surgical management for gastric cancer with synchronous liver metastasis. AB - BACKGROUND/AIMS: The aim of this study was to evaluate the benefit of resection for liver metastasis from gastric cancer. METHODOLOGY: Consecutive 74 patients of gastric cancer who undergone the gastrectomy for primary gastric cancer and simultaneous hepatic resection for synchronous liver metastasis were enrolled. The clinicopathological factors were retrospectively compared to the prognosis. RESULTS: The median survival time and 5-year overall survival rate in 53 patients who accomplished microscopically negative margin resection was 27.4 months and 18.6%, respectively. In the multivariate survival analysis, the number of liver metastasis was identified as an independent prognostic factor (HR;2.232, 95%CI;1.036-4.808, p=0.04). When the patients undergone curative resection were subdivided into solitary and multiple liver metastasis, the median survival time and 5-year overall survival rate in a subgroup with solitary liver metastasis was 24.2 months and 27.2%, which was superior to the corresponding values of 12.6 months and 5.5% in another group with multiple liver metastasis (p=0.02). CONCLUSIONS: The resection for liver metastasis might offer a chance for long term survival in a carefully selected group of patients. The number of liver metastasis was a reliable criterion to discriminate the subgroup of patients who are most likely to benefit from hepatic resection. PMID- 25436323 TI - Risk factors for duodenal stump leakage after gastrectomy for gastric cancer and management technique of stump leakage. AB - BACKGROUND/AIMS: The goal of this study was to elucidate the risk factors for duodenal stump leakage after gastrectomy for gastric cancer. In addition, the management of duodenal stump leakage is reviewed. METHODOLOGY: From January 2002 through December 2012, 1,195 patients with gastric cancer who underwent gastric R0 resection were enrolled in this study. The clinicopathologic features, postoperative outcomes (i.e., operation time, hospital stay, surgical procedures, method of duodenal stump closure, retrieved lymph nodes), and the risk factors of duodenal stump leakage were analyzed. RESULTS: Of the 1,195 patients, 13 patients (1.1%) suffered duodenal stump leakage. Most of the patients with duodenal stump leakage were male (92.3%). Nine patients underwent a subtotal gastrectomy with Billroth- II or Roux-en-Y anastomosis; the other four patients underwent a total gastrectomy with a Roux-en-Y anastomosis. There were two mortalities. With univariate and multivariate analysis, age was the most predictable factor for duodenal stump leakage (p= 0.034, p=0.044) CONCLUSIONS: Duodenal stump leakage was affected by the age. For older patients who undergo a radical gastrectomy for gastric cancer, the surgeon must pay meticulous attention to the transection and mobilization of the duodenum in order to prevent duodenal stump leakage. PMID- 25436324 TI - Yields of dual therapy containing high-dose proton pump inhibitor in eradication of H. pylori positive dyspeptic patients. AB - BACKGROUND/AIMs: H. pylori eradication has been recommended for dyspeptic patients in high prevalance regions. Triple therapies are still prescribed mostly because culture and antibiotic susceptibility tests aren't widely available in the world. Dual therapy with high-dose proton pump inhibitors reported to have higher eradication rates. Our objective was to determine eradication success and cost-effectivity of dual therapy in dyspeptic patients. METHODOLOGY: Patients were treated orally with either dual (n:74,omeprazole 20mg q.i.d and amoxicillin 1g b.i.d) or triple therapy (n:116,omeprazole 20mg b.i.d and amoxicillin 1g b.i.d and clarithromycin 500mg b.i.d) for 14 days. HpSA was requested 3 months later. The results were evaluated statistically, p values ?0,05 were considered significant. RESULTS: Patients (n:190) were included the study((80 female,110 male, mean age: 35.6+/-11year(p<0.001)). Alcohol/smoking, endoscopic findings and H. pylori rates with pathological examinations were not significantly different between groups whereas there was a significant difference in HpFast tests(p<0.01). When examined with HpSA tests 3 months after the treatment, eradication rate was 81.1% in the dual therapy group versus 63.8% in the triple therapy group (p:0.011). Dual therapy was economic than triple therapy (144USDvs.107USD,p<0.001). CONCLUSIONS: Dual therapy seems more successful, cost effective and is less risky in terms of side effects compared to standard triple therapy in patients with dyspepsia. PMID- 25436325 TI - Up-regulation of SALL4 associated with poor prognosis in gastric cancer. . AB - BACKGROUND/AIMS: SALL4 [encoding the Sal-Like 4 (Drosophila) protein, also known as spalt-like transcription factor 4] plays crucial roles in the development of different cancers, as well as vital embryogenic roles. However, knowledge of its relationship to gastric cancer is limited, and its association with prognosis in gastric cancer has not yet been reported. METHODOLOGY: comprehensive bioinformatics analyses including mRNA expression, gene occurrence, protein/gene interaction, pathway enrichment and biological processes annotation were performed. RESULTS: we indicated that the expression of SALL4 was up-regulated at least 2.2-fold in 103 cases of gastric cancers, compared with its expression in 65 normal controls. Further analysis indicated that SALL4 was co-occurred and interacted with 23 proteins/genes which all were associated with a poor gastric cancer prognosis. It also associated with 14 biological processes and Wnt signaling pathway, which have been proven to be closely related to gastric cancer and its prognosis. CONCLUSIONS: for the first time, we have shown that the up regulation of SALL4 in gastric cancers should serve as a worthwhile biological marker of poor prognosis in gastric cancer therapies, via the strong interactions with a number of proteins, genes, biological processes and pathways which all were associated with poor prognosis in gastric and other cancer. PMID- 25436327 TI - Postoperative chemoradiotherapy for advanced gastric cancer after D2 gastrectomy. AB - BACKGROUND/AIMS: The purpose of this study is to investigate the role of postoperative chemoradiotherapy with paclitaxel and cisplatin in the multimodality treatment of locally advanced gastric cancer after D2 gastrectomy. METHODOLOGY: Sixty-five patients underwent D2 gastrectomy with stage IB-IV (M0) gastric cancers were enrolled. A postoperative radiotherapy dose of 46 Gy in 23 fractions with concurrent chemotherapy of paclitaxel and cisplatin were delivered to the patients. Chemotherapy was administrated with paclitaxel 135mg/ m2 at day 1 and 21, cisplantin 20mg/ m2 at day 1-3 and day 29-31 during the radiotherapy course. Sixty-three out off 65 eligible patients were irradiated to a total dose of 46Gy and completed two cycles of full-dose chemotherapy. Thirty-three patients died at the time of analysis. RESULTS: The median follow-up was 68.0 months (range 1.9-119.1). The 3-year overall survival (OS) and disease-free survival (DFS) were 78.5% and 73.2%, respectively. The 5-year OS and DFS were 57.4% and 54.8%, respectively. Toxicity was tolerant. The main toxicities were gastrointestinal disorder, hematologic toxicity and hair loss. CONCLUSION: This novel postoperative chemoradiotherapy regimen for patients with gastric cancer after D2 gastrectomy had a tolerable toxicity, however, it did not decrease the local recurrence rate. PMID- 25436326 TI - Endoscopic surveillance can increase the chance of resectability and endoscopic treatment in gastric cancer. AB - BACKGROUND/AIMS: Little is known about the effects of periodic endoscopic screening before detection of primary gastric cancer. We compared clinical outcomes in patients who did and did not undergo endoscopy before diagnosis. METHODS: Between January 2009 and November 2011, 769 patients were referred to Asan Medical Center after diagnosis of gastric cancer. Clinical outcomes were compared in patients who had (n=512) and had not (n=257) undergone endoscopic screening before diagnosis of gastric cancer. Factors about resectability and possibility of endoscopic resection were analyzed. RESULTS: In the nonexamined group, 225 patients (87.5%) had resectable gastric cancers and were treated surgically (n=151, 67.1%) or by endoscopic resection (n=74, 32.9%). In the examined group, 493 (96.3%) had resectability and were resected surgically (n=243, 49.3%) or endoscopically (n=250, 50.7%). Multivariate analysis showed that symptoms, no endoscopic screening, and lower serum albumin were associated with unresectability. Of the 718 resectable tumors, 394 underwent surgery and 324 underwent endoscopic resection. Multivariate analysis showed that older age, no symptoms, <=1 year interval endoscopy, and higher serum albumin were associated with endoscopic resection. CONCLUSIONS: Previous endoscopy can increase gastric cancer resectability. Moreover, a <=1 year interval from endoscopic examination can increase the possibility of endoscopic resection. PMID- 25436329 TI - Perioperative management after pancreaticoduodenectomy. AB - Recent advances in surgical techniques and perioperative management have markedly reduced operative mortality after pancreaticoduodenectomy. However, some issues remain regarding to perioperative management of pancreaticoduodenectomy. These issues are reviewed to standarize management following a good outcome. PMID- 25436328 TI - Increased expression of pleiotrophin is a prognostic marker for patients with gastric cancer. AB - BACKGROUND/AIMs: Pleiotrophin (PTN) have been demonstrated to play an important role in the development of human gastric cancer. However, the prognostic value remains unclear. The aim of this study was to investigate whether expression of PTN has prognostic relevance in human gastric cancer. METHODOLOGY: Immunohistochemistry was used to investigate the expression of PTN proteins in 178 patients with gastric cancer. The level of PTN mRNA in gastric cancer tissues and paratumor tissues were evaluated in 52 paired cases by quantitative real-time polymerase chainreaction(qRT-PCR). Survival analysis by the Kaplan-Meier method was performed to assess prognostic significance. RESULTS: The expression level of PTN in gastric cancer tissues was significantly higher (P<0.001) than those in paratumor tissues according to the immunohistochemistry analysis, which was confirmed by qRT-PCR analysis. Additionally, the overexpression of PTN was significantly associated with the tumor site (P=0.001), Lauren's classification (P<0.001),histologic differentiation(P=0.014),depth of invasion(P<0.001), TNM stage (P=0.003),and lymph node metastasis (P=0.002). Moreover, the Cox proportional- hazards regression analysis revealed that the increased expression of PTN was an independent prognostic factor for poor recurrence-free survival(RFS) and overall survival(OS)(both P<0.001). CONCLUSIONS: These findings indicated that the expression of PTN is significantly correlated with prognosis in gastric cancer patients, suggesting that the expression of PTN may be used as an independent prognostic marker. PMID- 25436330 TI - Hybrid laparoscopic complete untinatectomy of pancreas by Shuriken shaped umbilicoplasty with sliding windows method. AB - In this study, we demonstrated the complete resection of untinate process that was performed by the hybrid laparoscopic surgery using our original new technique of Shuriken shaped umbilicoplasty with sliding window's method. A 70-year-old weman was hospitalized for surgery of intraductal papillary mucinous neoplasm located in the uncinate process of pancreas. Under general anesthesia, a Shuriken shaped umbilical skin incision was made by 7 cm in horizontal and 4cm longitudinal width with 3cm round skin incision. The intermediate skin between outside and inside skin incision was removed. Subcutaneous tissue around the umbilicus and the upper abdominal subcutaneous region was dissected, and the 8cm of upper abdominal minilaparotomy was performed. The complete resection of untinate process was performed by hybrid laparoscopic procedure with the hand assisted or the laparo-assisted manner. The umbilicoplasty of only 3cm round skin wound was made by the reefing of subcutaneous suture with 5-0 absorbable suture. The patient suffered from pancreas leakage from pancreas stump, however it was recovered spontaneously. Our new procedure could be used for PD, DP, and Major hepatectomy with the hybrid laparoscopic procedure. It might be considered that our method is good for both cosmetic and safety benefits in HPB surgery. PMID- 25436331 TI - Timing of laparoscopic cholecystectomy for mild and moderate acute cholecystitis. AB - BACKGROUND/AIMS: The timing of a laparoscopic cholecystectomy (LC) for acute cholecystitis (AC) remains controversial. Traditionally, LC for AC is performed within 3 days. We designed this study so that the cut-off time of LC for AC was within 7 days of admission, based on severity. METHODOLOGY: A total of 103 patients were divided into 2 groups: patients undergoing LC within 7 days of admission [early LC (ELC), n = 41] and patients undergoing LC between 8 days and 5 weeks of admission [delayed LC (DLC), n = 62]. The outcomes compared were complication rate, conversion rate, postoperative hospital days, and operation time. Statistical analyses were performed in mild, moderate and all AC cases. Results: Of all AC cases, successful LC was performed in 93 patients, and no significant difference was observed between the 2 groups. In DLC for moderate AC, percutaneous cholecystectomy (PC) with or without endoscopic nasal bile drainage (ENBD) was performed more frequently than ELC. CONCLUSIONS: DLC had no advantage over ELC. ELC for AC is preferable in cost-effect. Even if the operation cannot be scheduled early, proper initial treatment, including percutaneous cholecystectomy with or without endoscopic nasal bile drainage for moderate AC, enables DLC a safe option. PMID- 25436332 TI - Clinicopathologic correlation of autophagy-related Beclin-1 expression in gallbladder cancer. AB - BACKGROUND/AIMS: Autophagy plays critical roles in both cell survival and cell death. Beclin-1, a key modulator of autophagy function, is considered a haploinsufficient tumor suppressor. The role of Beclin-1 expression in cancer is still controversial. Some studies favor the idea that autophagy suppresses tumor development, whereas other researchers suggest that autophagy enhances tumorigenesis. The expression and function of Beclin-1 in gallbladder cancer (GBCA) remain largely unknown. METHODOLOGY: Methodology: We performed immunohistochemical staining for Beclin-1 in 119 GBCA cases, and investigated whether Beclin-1 expression correlated with clinicopathologic characteristics and prognosis of patients. RESULTS: Beclin-1 was expressed in the cytoplasm of cancer cells with occasional nuclear staining in 53 (44.5%) of the 119 cases of GBCA with no expression in adjacent normal epithelial cells. Increased expression of Beclin-1 was significantly associated with longer survival rate of patients with GBCA in univariate (p=0.006) and multivariate analyses (p=0.005). There is no association between Beclin-1 expression and clinicopathologic characteristics. CONCLUSIONS: Beclin-1 was highly expressed in GBCA, and positive expression in cancer cells was significantly related with favorable prognosis in GBCA patients. Our results suggest that the expression of Beclin-1 may be an independent predictive marker of favorable prognosis in GBCA. PMID- 25436333 TI - Safety of early laparoscopic cholecystectomy for patients with acute cholecystitis undergoing antiplatelet or anticoagulation therapy: a single institution experience. AB - BACKGROUND/AIMS: Early cholecystectomy is recommended for patients with acute cholecystitis, particularly when less than 72 hours have passed since symptom onset. The safety of early laparoscopic cholecystectomy for patients receiving anticoagulants or antiplatelet agents is unclear. We retrospectively analyzed the safety of early laparoscopic cholecystectomy for patients with acute cholecystitis undergoing antiplatelet or anticoagulation therapy. METHODOLOGY: Between 2005 and 2012, a total of 239 patients were diagnosed with acute cholecystitis, 183 of whom underwent early laparoscopic cholecystectomy. We compared the clinical features and surgical outcomes of 21 patients undergoing antiplatelet or anticoagulation therapy with those of 162 patients not undergoing antiplatelet or anticoagulation therapy. RESULTS: Of the 21 patients, 15 patients took aspirin and four took clopidogrel sulfate. Three patients received dual therapy with two agents. The distributions of the severity of acute cholecystitis, a past history of abdominal operations, body mass index, blood test results, operation time, and blood loss were not significant between the two groups. Neither conversion to open surgery nor bleeding-related complications occurred in the patients undergoing antiplatelet and anticoagulation therapy. CONCLUSIONS: Early laparoscopic cholecystectomy for selected patients with acute cholecystitis undergoing antiplatelet and anticoagulation therapy is feasible and safe. PMID- 25436334 TI - Endoscopic treatment of postoperative benign bile duct stricture compared with malignant bile duct stricture. AB - BACKGROUND/AIMS: Endoscopic treatment for postoperative benign bile duct stricture (BBS) is a therapeutic challenge. No previous studies have compared endoscopic treatments for BBS and malignant bile duct stricture (MBS). The aim of this study was to compare endoscopic treatments for postoperative BBS and MBS. METHODOLOGY: This study enrolled 22 consecutive patients with a diagnosis of postoperative BBS and 110 patients diagnosed with MBS. Cases involving digestive tract reconstruction were excluded. We compared the length of the bile duct strictures, the success rate of endoscopic treatment, and the incidence of complications. RESULTS: The following results were obtained for the postoperative BBS and MBS groups, respectively: length of bile duct stricture, 6.50 mm vs. 24.3 mm (P<0.0001); success rate of endoscopic treatment, 90.9% vs. 93.6% (P=0.6551). Post-ERCP pancreatitis occurred after 11 sessions (10.7%) vs. 7 sessions (1.83%) (P=0.0002), and post-ERCP cholangitis occurred after 7 sessions (6.80%) vs. 4 sessions (1.04%) (P=0.0021). BBS was a significant risk factor for post-ERCP pancreatitis and cholangitis based on a multivariate analysis (OR, 10.732; P=0.0022; OR, 6.443; P=0.0260). CONCLUSIONS: Post-ERCP-related complications were more frequent after postoperative BBS than after MBS. The need for careful endoscopic treatment may be greater for postoperative BBS cases than for MBS cases. PMID- 25436335 TI - Combined T/Y biliary stent placement for the treatment of biliary obstruction caused by Bismuth-Corlett type IV hilar cholangiocarcinoma. AB - BACKGROUND/AIMS: To assess the feasibility and efficacy of combined T/Y biliary stent for the bilateral drainage of biliary obstruction caused by Bismuth-Corlett type IV hilar cholangiocarcinoma. METHODOLOGY: Eleven patients with unresectable malignant hilar biliary obstruction of Bismuth-Corlett type IV underwent placement of combined T/Y biliary stent. After unilateral or bilateral percutaneous transhepatic cholangiography, "T" or "Y" type combined biliary metal stents were placed based on the intersection angle of the left and right intrahepatic bile ducts. RESULTS: Technical success of stent placement was achieved for all 11 cases. Eight patients had "T" type and three cases had "Y" type stents placement. Internal drainage achieved with no major complications developed, except for minor hemorrhage occurred for two patients (18.2%). The survival time, liver function including bilirubin concentration and degree of dilation of the bile duct improved. CONCLUSIONS: The combined T/Y biliary stent may be feasible and effective for bilaterally drainage of malignant hilar biliary obstruction, this operation is easy to perform, less invasive and shows a good effect of biliary drainage. PMID- 25436336 TI - Hepatocellular carcinoma recurrence is an independent risk factor for HB recurrence after liver transplantation. AB - BACKGROUND/AIMS: To confirm the relationship between hepatitis B recurrence and Hepatocellular carcinoma recurrence. METHODOLOGY: Data from 340 patients undergoing liver transplantation for HBV-related liver disease were retrospectively evaluated. Clinically relevant variables were analyzed using univariate models. Significant variables were subjected to multivariate logistic regression analysis to identify the independent predictors for HBV recurrence. Fifteen samples removed from HCC recurrence patients were stained for HBsAg and HBcAg. RESULTS: The analyzed population included 283 male and 57 female patients. The mean age was 48.5+/-9.33 years and median follow-up was 47 months. Hepatitis B relapsed in 16 patients (4.7%). Univariate analysis indicated that HCC (P=0.022) and HCC recurrence (P=0.000) were associated to post transplantation HB. Multivariate analysis identified HCC recurrence as an independent risk factor for HB recurrence (hazard ratio: 23.262 (95% CI: 3.752, 144.216); P <0.001). Three of 15 metastatic lesions were positive for HBsAg and 1 lesion was positive for HBcAg. Conclusion: HCC recurrence is an independent risk factor for post transplantation recurrence of hepatitis. PMID- 25436337 TI - Yttrium-90 radioembolization in patients with unresectable liver metastases: determining the factors that lead to treatment efficacy. AB - INTRODUCTION: Locoregional treatments, such as radioembolization, can be used to treat patients with unresectable liver metastases. We aimed to determine the progression-free survival and factors that predict survival of patients with liver metastases whose response to selective internal radiation therapy (SIRT) with Y-90 was assessed by positron emission tomography-computed tomography (PET CT). PATIENTS: Our study included 78 liver cancer patients who were treated with Y-90 radioembolization. RESULTS: The post-treatment response rates were as follows: 7 patients (9%) had stable disease (SD), 26 patients (33.3%) had a partial response (PR), 4 patients (5.1%) had a complete response (CR). The median hepatic progression-free survival (HPFS) was 4.4 months while median overall survival was 10.1 months. Univariate analysis revealed that HPFS is significantly affected by international normalized ratio (INR) levels and age (Hazard Ratio(HR)=0.54 (95%CI:0.30-096), P=0.034, HR=1.03(95%CI:1.00-1.05), P=0.051). However, only INR levels retained significance with multivariate analysis (HR=0.53 (95%CI:0.30-0.93), P=0.028), while age had limited significance (HR =1.02 (95% CI:1.00-1.05), P=0.051). CONCLUSIONS: We determined that Y-90 radioembolization is effective as a salvage therapy in patients with predominant liver metastases. For the first time, we showed that age and INR values reflecting the functional hepatic reserve can be used as positive predictive factors for HPFS. PMID- 25436338 TI - Modified technique of laparoendoscopic rendezvous ERCP during laparoscopic cholecystectomy for concomitant gallstone and common bile ductal stone. AB - Laparoendoscopic rendezvous ERCP and laparoscopic cholecystectomy (LC+ERCP/LERV) is considered an optimal approach for concomitant gallstone and common bile duct stone, but this procedure could be failed due to some technical challenges. We describe a modified technique which was adopted in 32 consecutive cases and yielded good results. A Dormia basket is inserted through cystic duct to enter duodenum and grasp the guide wire which is introduced with sphincterotome through endoscope. After pulling the basket catheter and guide wire into bile duct, the selective bile duct cannulation could be achieved by advancing sphinterotome over guide wire. An atraumatic clamp is also used to temporarily occlude proximal jejunum preventing diffuse bowel distention by air insufflation. The procedure was successfully performed in 31 cases(96.8%) , the mean operative time and endoscopic time were 82.6+/-19.6 min and 26.5+/-5.99min, respectively. This modified technique is safe, feasible and associated with short operative time. PMID- 25436339 TI - Factors influencing delayed gastric emptying after pancreaticoduodenectomy - a meta-analysis. AB - BACKGROUND/AIMS: Delayed gastric emptying (DGE) is the most frequent postoperative complication after pancreaticoduodenectomy. Not only does it contribute considerably to prolonged hospitalization, but it is also associated with increased postoperative morbidity and mortality. We performed a meta analysis to assess factors influencing the development of DGE after pancreaticoduodenectomy. METHODOLOGY: We systematically searched for studies that assessed association between peri-operative factors and DGE. We reviewed separately each of the factors, including preservation of pylorus, methods of gastrointestinal reconstruction, postoperative enteral feeding and postoperative complications. We identified 1035 studies published between May 1, 1988 and May 1, 2008. RESULTS: Compared with control subjects, the risk of DGE was 2.35 for preservation of pylorus (95% CI, 0.72 to 7.61), 6.14 for postoperative complications (95% CI, 3.47 to 10.85). There was no significant association between the occurrence of DGE with either PD or PPPD. CONCLUSIONS: Postoperative enteral feeding did not show any advantages in preventing DGE. Postoperative complications were the most important factor associated with DGE's occurrence. Antecolic and BII type gastrojejunostomy seems to suggest an improvement in the incidence of DGE. PMID- 25436341 TI - Predictive factors of portal vein thrombus following splenectomy in patients with severe cirrhosis. AB - BACKGROUND/AIMS: Splenectomy is performed in patients with severe cirrhosis who have a low platelet count. A portal vein thrombus (PVT) is one of the complications associated with splenectomy. This study aimed to identify predictive factors of postoperative PVT following splenectomy. METHODOLOGY: Twentyeight patients who underwent splenectomy between April 2003 and March 2013 were retrospectively analyzed. Patients were divided into two groups: the PVT(+) group comprising 11 patients who developed postoperative PVT, and the PVT(-) group comprising 17 patients who did not develop postoperative PVT. The patient characteristics of the 2 groups were analyzed. Results: In univariate analysis, the platelet count, rate of simultaneous treatment of hepatocellular carcinoma, and preoperative spleen volume were significantly different between the groups (p < 0.05). In multivariate analysis, preoperative spleen volume alone was an independent factor associated with the development of PVT (p = 0.007). At a preoperative spleen volume cutoff of 450 mL, the sensitivity and specificity were 90% and 73%, respectively. CONCLUSIONS: In patients with severe cirrhosis scheduled to undergo splenectomy, if the preoperative spleen volume is >450 mL, as measured by enhanced computed tomography, preventive administration of anticoagulant therapy is recommended to reduce the risk of PVT development. PMID- 25436340 TI - Effect of landiolol hydrochloride on tachyarrhythmia after esophagectomy. AB - BACKGROUND/AIMS: The objective of this study was to evaluate the efficacy and safety of landiolol hydrochloride, a newly developed ultra-short-acting beta1 selective blocker, for postoperative tachyarrhythmia after esophagectomy. METHODOLOGY: In total 231 patients underwent transthoracic esophagectomy at the Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine from 2007 to 2012. Twenty-four patients who were treated with either landiolol hydrochloride (n = 11) or conventional agents (combination of calcium channel blocker and digitalis preparation; control group, n = 13) for postoperative tachyarrhythmia after transthoracic esophagectomy were retrospectively analyzed. Tachyarrhythmia was defined as a heart rate of >120 bpm or atrial fibrillation. Hemodynamic changes, conversion rates, and adverse events were evaluated. RESULTS: The reduction in the heart rate at 1 h after medication was seen significantly more frequent in the landiolol group than in the control group. The time to conversion to sinus rhythm was also significantly shorter in the landiolol group. There were no significant differences between the two groups in blood pressure either before or after the medication. One patient in the landiolol group showed hypotension and bradycardia, without serious consequences. CONCLUSIONS: Landiolol hydrochloride can be effectively and safely used in patients who develop tachyarrhythmia after esophagectomy. PMID- 25436342 TI - Management complicated hepatolithiasis with operative rigid choledochoscope guided by computed tomography (CT)-based 3D reconstruction technique. AB - BACKGROUND: Treatment of complicated hepatolithiasis is complex and difficult. In this report, we present a novel approach to manage complicated hepatolithiasis using the rigid choledochoscope guided by CT-based 3D reconstruction technique with or without hepatectomy. METHODS: Between February 2012 to December 2013, 25 patients with complicated hepatolithiasis underwent rigid choledochoscope guided by CT-based 3D reconstruction technique combined with or without hepatectomy. 27 patients with complicated hepatolithiasis underwent a traditional operation (traditional method group) from June 2011 to January 2012. All operations were performed by the authors. RESULTS: The final stone clearance rate of the rigid choledochoscope group was 96%, whereas that of the traditional method group was 74.1% (P=0.032). There was no patient died of postoperative mortality in two groups. Moreover, the operative time in the traditional method group was significantly longer than that in the rigid choledochoscope group (P=0.010). Recurrent intrahepatic bile duct stones were not found during the follow-up period in the two groups. CONCLUSIONS: Operative rigid choledochoscope guided by CT-based 3D reconstruction technique combined with or without hepatectomy may be an effective and safe treatment for complicated hepatolithiasis. PMID- 25436343 TI - CD133 expression is correlated with poor prognosis in colorectal cancer. AB - BACKGROUND/AIMS: Cancer stem cells (CSC) was reported to play an important role in various kinds of cancer. CD133 is one of the cancer stem cell markers in solid cancers. However, the correlation between CD133 expression and the clinicopathological factors in colorectal cancer (CRC) remains unclear. METHODOLOGY: Forty patients with CRC who underwent operations were enrolled. Expression of CD133 was investigated by immunohistochemistry (IHC). The staining was observed in the cytoplasm of cancer cells and the patients who have the staining were defined as CD133-positive cases. The patients were divided into two groups: the CD133-positive group (n = 22) and negative group (n = 18). Clinicopathological factors were compared between the two groups. The prognostic factors were investigated by multivariate analysis. RESULTS: In the CD133 positive group, the incidence of lymph node and liver metastasis, lymphatic and venous invasion, as well as the progression of stage of cancer were higher than that in the CD133-negative group. The 5-year survival rate and the disease-free survival rate in the CD133-positive group were lower than that in the CD133 negative group. The multivariate analysis revealed that CD133 expression tended to be an independent prognostic factor. CONCLUSIONS: CD133 expression is correlated with poor prognosis in CRC. PMID- 25436344 TI - Treatment and multivariate analysis of colorectal cancer with liver metastasis. AB - BACKGROUND/AIMS: The aim of this study was to identify the influencing factors related to outcome of patients of colorectal cancer with liver metastasis. METHODOLOGY: From January 1999 to January 2009, 293 cases of colorectal cancer with liver metastasis undergoing surgery were analysised retrospectively. Relationships between survival and clinicopathological factors including patient demographics and tumor characteristics were evaluated using univariate and multivariate analysis. Results: The 1-, 3- and 5-year survival rates of patients after resection were 58.3%, 26.4%, and 11.3%, respectively. Univariate analysis showed that preoperative CEA level, degree of primary tumor differentiation, resection margin, number of liver metastases, resection of liver metastases were prognostic impacts. The difference was statistically significant (p<0.05). Cox multivariate analysis showed that preoperative CEA level, number of liver metastases, and resection of liver metastases are three separate prognostic factors. CONCLUSIONS: Racical resection is the key to improve the long-term survival rate of colorectal cancer with liver metastasis. Important predictive factors related to poor survival are preoperative CEA level and number of liver metastases. PMID- 25436345 TI - The Impact of pelvimetry on anastomotic leakage in a consecutive series of open, laparoscopic and robotic low anterior resections with total mesorectal excision for rectal cancer. . AB - BACKGROUND/AIMS: Recently, pelvic anatomy has been taken into consideration and related to surgical outcome indicators after low anterior resection (LAR). Several pelvimetric parameters have been matched with conversion rate, postoperative complications and duration of surgery in laparoscopic series, and with the quality of specimen and pathologic outcomes in further open surgical series. METHODOLOGY: In 97 consecutive patients submitted to sphincter-saving LAR with total mesorectal excision (TME) five pelvic dimensions were measured by abdominal computed tomography scan: anteroposterior and transverse diameters in the pelvic inlet (IAP and ITRA), anteroposterior and transverse diameters in the pelvic outlet (OAP and OTRA), and the pelvic depth. The endpoint evaluated was anastomotic leakage (AL) rate. RESULTS: There were 51 open, 12 laparoscopic and 34 robotic LARs. The sum of IAP OAP and OTRA (Pelvic Index) significantly predicted AL showing that starting from the cut-point of 290 mm down to a PI of 278 mm the odds-ratio of having an AL increased from 2.63 (95% CI: 1.10,5.47) to 5.07 (95% CI: 1.35,8.02). CONCLUSIONS: The sum of the 3 pelvic dimensions which we termed "Pelvic Index" was associated to AL following sphinctersaving LAR. This may be considered in planning the surgical strategy for rectal cancer patients. PMID- 25436346 TI - Efficacy of perioperative chemotherapy in patients with colorectal cancer undergoing hepatectomy for resectable synchronous liver metastasis. AB - BACKGROUND/AIMS: Although aggressive resection is recommended for the treatment of resectable liver metastasis of colorectal cancer, recurrences often develop in the remaining liver. In our department, perioperative chemotherapy was introduced for the treatment of colorectal cancer associated with resectable synchronous liver metastasis. The results of this treatment are reported herein. The study population was 20 patients (9 men, 11 women) with colorectal cancer associated with resectable synchronous liver metastasis whose data were collected between April 2009 and September 2012. METHODOLOGY: The patients received chemotherapy (mFOLFOX6 or XELOX + bevacizumab) for 3 months each before and after hepatectomy following resection of the primary lesion. RESULTS: Preoperative chemotherapy yielded a response rate of 66.7%, and no serious postoperative complications were noted. Although recurrence was found in 9 patients after treatment, 4 have so far remained cancer-free after re-resection. Thus, re-resection of the recurrent lesion resulted in patients maintaining cancer-free status for a prolonged period. CONCLUSIONS: The use of perioperative chemotherapy in patients with colorectal cancer associated with resectable synchronous liver metastasis may improve outcomes after hepatectomy. PMID- 25436347 TI - Association of hyper-LDL cholesterolemia with increased risk of colorectal adenoma. AB - BACKGROUND/AIMS: Previous studies on the association between dyslipidemia and the presence of colorectal adenoma showed conflicting results, and were limited due to small sample sizes, inconsistent definitions of dyslipidemia, or a lack of data on full lipid profiles. The aim of this study was to determine the association between colorectal adenomas and dyslipidemia according to the definition by the National Cholesterol Education Program- Adult Treatment Panel III. METHODOLOGY: We conducted a retrospective, cross-sectional study in subjects who underwent screening colonoscopy and blood tests for full lipid profiles. Serum dyslipidemia profiles were compared between the adenoma group and the control group, and multivariate analysis was performed to identify independent predictors of the presence of colorectal adenomas. RESULTS: Patients with hyper LDL cholesterolemia were more frequently included in the adenoma group than the control group (46.7% vs. 32.1%, respectively, p=0.023), and hyper-LDL cholesterolemia (OR = 1.954, 95% CI=0.981-3.893, p=0.057) showed a statistical trend for the positive association with the presence of colorectal adenomas by multivariate analysis. Furthermore, proximal colorectal adenomas were more prevalent in the hyper-LDL cholesterolemia group than in the normal LDL cholesterolemia group (p=0.026). CONCLUSIONS: Hyper-LDL cholesterolemia was associated with the presence of colorectal adenomas, especially in the proximal colon. PMID- 25436348 TI - Protective effect of lactoferrin on acute acid reflux-induced esophageal mucosal damage. AB - BACKGROUND/AIMS: The natural immunomodulator lactoferrin is known to possess anti inflammatory effects. However, there have been no studies examining the mode of action of lactoferrin in protecting the esophageal mucosa against damage. We investigated the effect of lactoferrin on gastric acid secretion and in protecting against acute acid reflux-induced esophagitis in rats. METHODOLOGY: Male Wistar rats aged 8 weeks, weighing 210-240 g, were used for all the experiments. A gastric perfusion system was installed using the method of Ghosh et al. Lactoferrin was administered once via the caudate vein, starting 24 hours before an acute acid reflux (treatment mode), or saline (control). Statistical comparison of the parameters between the two test conditions was performed. RESULTS: No significant differences in basal or stimulated gastric acid secretion, or in the serum gastrin level were observed between the two test conditions. Esophageal damage was attenuated by lactoferrin in a dose-dependent manner, as reflected by the improvement in the esophageal tissue weight and macroscopic scores. Significant reductions in the histological scores, myeloperoxidase activity and the levels of proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta were also observed following lactoferrin administration. CONCLUSIONS: We concluded that lactoferrin exerts a protective effect against acute acid reflux-induced esophageal damage in rats. PMID- 25436349 TI - Endoscopic transesophageal biopsy in the posterior mediastinum using submucosal tunneling technology and novel homemade instruments. AB - BACKGROUND/AIMS: This animal study was performed to evaluate the feasibility and safety of endoscopic transesophageal biopsy by using submucosal tunneling technology novel homemade instruments in the posterior mediastinum. METHODOLOGY: In six survival pigs, a mid-esophageal mucosal incision and a 10-cm submucosal tunnel was created. The endoscope attached to homemade decompression tube was passed through the muscular layers into the posterior mediastinal space. The mediastinal compartment, lung, descending thoracic aorta, vertebra, and exterior surface of the esophagus will be identified, and mediastinal living tissue as lymph node biopsy will also be accomplished. During two survival weeks, blood test and temperature monitoring and chest radiograph and endoscopic examination were performed. RESULTS: The procedure was successfully completed in all six pigs. Mediastinal structures could be identified without difficulty by the transesophageal tunneling approach. Tissue as lymph nodes and pleural biopsy under direct visualization were easily accomplished. One pig died after operation due to an unexplained pneumothorax. At necropsy, apparent atelectasis was noted in the right lobe. After applying homemade drainage tube attached to the syringe, one pig with pneumothorax soon had restoration. There were no apparent ill effects in the survival pigs. CONCLUSIONS: Endoscopic transesophageal biopsy in the posterior mediastinum using a novel tunneling technology can provide excellent visualization of mediastinal structures. These procedures could be performed safely in pigs with short-term survival. Further study about immediate complications will be needed with a larger sample size and longer survival time. PMID- 25436350 TI - Comparative study of the QUEST questionnaire and GerdQ questionnaire for Japanese students. AB - BACKGROUND/AIMS: The aim of this study was to comparatively examine the convenience of use of the QUEST and GerdQ questionnaires as self-administered diagnostic instruments. METHODOLOGY: This was a two-way crossover study conducted from December 2011 to April 2012. The subjects were 70 third-year nursing students of Yokohama Soei University in Yokohama, Japan. They were randomly assigned to fill in either of the study questionnaires first, and then the other on a later. RESULTS: A significant difference was observed in the questionnaire completion time between the QUEST and GerdQ questionnaires (125.5 vs. 44 seconds, P < 0.0001) and also in the number of subjects asking questions while completing the questionnaires (26 vs. 1 subject, respectively: P < 0.0001). To detect GERD based on a QUEST score of >=4, ROC analysis revealed an area under the curve for the GerdQ score of 0.616. The optimal cutoff value of the GerdQ score was 6, and the sensitivity and specificity calculated using this cutoff value were 0.842 and 0.312, respectively. CONCLUSIONS: This study revealed that Japanese subjects may find it easier to complete the GerdQ than the QUEST questionnaire. PMID- 25436351 TI - Diagnosis and treatment of achalasia patients: a ten-year review of the clinical features. AB - BACKGROUND/AIMS: To study the clinical features, the diagnosis and treatment efficacy with pneumatic balloon dilatation in patients with achalasia in a teaching hospital in Eastern Saudi Arabia. METHODOLOGY: Clinical records of patients with the diagnosis of achalasia during the period from 2001 to 2012 were reviewed. Their presentation, radiologic, monometric and endoscopic findings as well as treatment outcome with pneumatic dilatation were reviewed. RESULTS Results: Thirty-one new patients were diagnosed with achalasia during the study period. The mean age at the diagnosis was 36 years, ranging from 14 to 85 years of age. Male to female ratio was 1.4: 1.7. Five patients while waiting received 20mg of long acting calcium channel blockers (Nifedipine) for four months without any impressive result and asked for pneumatic dilation. Pneumatic dilation in one year follow-up revealed 91% satisfaction and long term follow-up of 5 to 10 years showed 83% satisfaction of patients. During procedure and follow-up, no significant complication was noted. CONCLUSIONSAchalasia effects all ages in both sexes. Graded Pneumatic Balloon Dilation (PBD) is a safe and effective form of symptomatic treatment of achalasia without significant complication in the hands of experts. PMID- 25436352 TI - Radiochemotherapy for esophageal squamous cell carcinoma in elderly patients. AB - BACKGROUND/AIMS: The goal of this retrospective study was to investigate the efficacy and safety of curative radiochemotherapy (CRT) in elderly patients with esophageal squamous cell cancer (SCC). METHODOLOGY: Between 1986 and 2011, 38 consecutive patients aged over 75 years with esophageal SCC were initially treated with a CRT regimen comprising radiation therapy at a dose of 60 Gy and two cycles of chemotherapy with 5-fluorouracil/cisplatin. RESULTS: Fourteen patients were aged over 80 and 24 under 79 years. Complete treatment compliance was obtained in 30 (78.9%) of the patients. Chemotherapy was terminated and the dose of radiation reduced in 7 and 1 patients, respectively. The overall incidence of CRT-related complications was 86.8% (33 patients). Grade 3 leukocytopenia was observed in 6 (15.8%) patients, all of whom recovered promptly. A complete response was observed in 17 patients (44.7%). The overall 3 year survival rate was 32.0%. CONCLUSIONS: Curative CRT is safe and may improve overall and progression-free 3-year survival rates in elderly patients aged more than 75 years with esophageal SCC. PMID- 25436353 TI - GERD is becoming a challenge for the medical profession: is there any remedy? AB - Gastroesophageal reflux disease is becoming a common and serious problem. Proton pump inhibitors are considered as drugs of choice however, long term use leads to complications. Transient lower esophageal sphincter relaxation inhibitors, i.e., gamma-aminobutyric acid B receptor agonists, baclofen, and metabotropic glutamate receptor 5 antagonists, ADX10059, were tried in resistant cases, but caused central nervous and hepatic side effects, respectively. Irregular dietary habits possess the strongest association with GERD, because intake of food in between meals aggravates gastric distention in upper stomach and generates TLESRs, triggering reflux. During fasting, migrating myoelectrical complex clears stomach of food. Considering relationship between irregular dietary habits and GERD pathophysiology, it is suggested that two regular meals a day with only fluids in between will reduce reflux and lead to healing of inflammation caused by repeated refluxes. Initially, the suggested regimen eliminated symptoms of GERD in 4 cases in 10 days. Later, in a pilot study on 20 patients of endoscopically diagnosed GERD, it benefitted 15 cases; 100% of Los Angles grade 'a', 66% of grade 'b' and 33% of grade 'c'. Long term studies are proposed to confirm usefulness of this dietary regimen for management of GERD, alone and in combination with drugs. PMID- 25436354 TI - Prospective evaluation of a transnasal endoscopy utilizing flexible spectral imaging color enhancement (FICE) with the Valsalva maneuver for detecting pharyngeal and esophageal cancer. AB - BACKGROUND/AIMS: This study evaluated the efficacy and safety of transnasal endoscopy (TNE) with flexible spectral imaging color enhancement (FICE) for detection of superficial cancer in the pharyngeal and esophageal regions for high risk populations. METHODOLOGY: Patients who previously had head and neck or esophageal squamous cell carcinoma were enrolled. Screening was conducted using TNE with conventional white-light endoscopy (WLE) followed by FICE chromoendoscopy. For observation of the pharyngeal region, the Valsalva maneuver was employed. RESULTS: 99 patients were eligible. Six esophageal cancers were detected in four patients (4.0%). The sensitivity, specificity, and accuracy for the detection of cancer were 25.0% (95% CI, 3.4- 71.0), 97.8% (95% CI, 92.1 99.8), and 94.9 % (95% CI, 88.4-98.1), respectively for WLE; 100% (95% CI, 45.4%- 100%), 96.8% (95% CI, 90.7%-99.3%), and 96.9% (95% CI, 89.3%-99.1%), respectively for FICE chromoendoscopy. Pain in the nose and nasal hemorrhage were observed in 3 (3.0%) and 2 patients (2.0%), respectively. Following the Valsalva maneuver, endoscopic scores significantly increased from a mean of 1.1 (0.8-1.4) to 2.0 (1.3-2.6) (p<0.05). CONCLUSIONS: TNE with the Valsalva maneuver is a promising screening method for the pharyngeal and esophageal regions. TNE with FICE chromoendoscopy for detecting pharyngeal and esophageal cancer was more sensitive than WLE. PMID- 25436355 TI - Balloon-assisted enteroscopy in portal hypertensive enteropathy. AB - BACKGROUND/AIMS: Balloon-assisted enteroscopy (BAE) provides higher-resolution of imaging and allows both diagnosis and treatment in the small intestine. However, the role of BAE in portal hypertensive enteropathy (PHE) is not clear. The purpose of this study is to define BAE findings and its utility in patients with PHE. METHODOLOGY: This study included 20 cirrhotic patients with PHE and 20 control patients, matched by age and gender, who underwent BAE. The indications were to investigate the cause of obscure gastrointestinal bleeding and to achieve a diagnosis in patients with abnormal video capsule endoscopy and/ or abnormal radiological imaging. We evaluated the diagnostic yield and safety of BAE in PHE. RESULTS: BAE revealed significantly abnormal small bowel mucosa including angiodysplasia-like lesions, friability, edema, erythema, and punctate hemorrhage in PHE. There was a significantly higher prevalence of small bowel angiodysplasia like lesions (65%) in the cirrhotic patients as compared with that (10%) in the controls (p = 0.01). Among the patients with small bowel angiodysplasialike lesions (65%), seven patients (35%) exhibited a diffuse pattern, which was not found in the control group (p = 0.008). CONCLUSIONS: Our study has shown that small bowel angiodysplasia-like lesion, particularly, the diffuse form of the lesion, is the dominant mucosal abnormality in PHE. PMID- 25436356 TI - Pre-medication to improve esophagogastroduodenoscopic visibility: a meta-analysis and systemic review. AB - BACKGROUND/AIMS: The use of pre-medication to improve visibility in gastrointestinal endoscopy has not been well addressed and remains controversial. The aim is to evaluate the effects of current pre-medication on endoscopic visualization. METHODOLOGY: We made the overall strategies to search the different databases and assessed the quality of included studies according to the included and excluded standard. 1541 patients were treated with pre-medication. RESULT: Ten prospective studies involving 1541 patients were included. There was improved visibility in patients treated with Simethicone (weighted mean difference -4.3; 95% confidence interval (CI), -4.94 to -3.67), compared to those who did not use Simethicone. In the Simethicone based regiment, administration of Pronase was noted with significantly improved visibility in the location of antrum and fundus, compared to those who did not use; however, administration of N-acetyl-L-cysteine could not lead to significantly improved visibility. Simethicone offered better visibility than N-acetyl-L-cysteine and Pronase alone. CONCLUSIONS: There is improved visibility with pre-medication using Simethicone before esophagogastroduodenoscopy. In the Simethicone based regimen, administration of Pronase or N-acetyl-Lcysteine may be of little use in improving visibility. Based on the literature review, Simethicone dissolved in the water with the acceptably lowest ratio of 0.7 can still offer the good visibility but 30 mL of water should be avoided. PMID- 25436357 TI - Neutrophil-to-lymphocyte ratio: could it be used in the clinic as prognostic marker for gastrointestinal stromal tumor? AB - BACKGROUND/AIMS: The association between systemic inflammatory response and tumor biology has been well documented over the last decade. The aim of this study is to investigate the prognostic role of neutrophilto- lymphocyte ratio (NLR) in gastrointestinal stromal tumors (GISTs). METHODOLOGY: A prospectively recorded database of 67 patients who underwent surgical resection for GIST was reviewed. High and low NLR were defined with respect to the sample median, which was 1.92. Demographical, clinicopathological, and surgical characteristics were analyzed as well as disease free survival (DFS) rates according to NLR classification. RESULTS: We observed better disease free survival rates in patients with low NLR compared to patients with high NLR (85.7% and 69%, respectively; p=0.037). Estimated five-year overall and disease free survival rates were 95.1% and 78.7%, respectively. In univariate analysis synchronous sarcomatosis, tumor size, mitotic rate, presence of necrosis, lymph node metastasis, surgical margin status, risk category and NLR were associated with DFS. On multivariate analysis sarcomatosis (HR: 30.455), surgical margin status (HR: 4.228) and necrosis (HR: 4.415) were found as independent prognostic factors for DFS. CONCLUSIONS: NLR can give information about inflammatory status, tumor aggressivity and prognosis in GIST patients. It could be a new prognostic factor for GIST patients. PMID- 25436358 TI - Patients' assessment of adalimumab self-injection for Crohn's disease: a multicenter questionnaire survey (The PEARL Survey). AB - BACKGROUND/AIMS: Adalimumab (ADA) is a self-injectable anti-tumor necrosis factor alpha antibody used for treating Crohn's disease (CD). Although self-injecting ADA may be convenient for patients, few reports have assessed patients receiving ADA self-injection therapy. METHODOLOGY: We conducted a questionnaire survey involving outpatients on ADA self-injection therapy at four university hospitals. We analyzed the degree of satisfaction with and adherence to the self-injection therapy and performed sub-analyses. RESULTS: Responses were obtained from 124 patients. Before treatment initiation, 38% patients replied that they were unwilling to accept the self-injection therapy. However, after treatment initiation, 75% patients were satisfied with the treatment. 66 patients previously treated with infliximab (IFX), the degree of treatment satisfaction was significantly higher in patients who felt burdened to the time required for IFX infusion than in those who had not felt burdened (P < 0.05). Patient adherence to ADA was high (85%). Multivariate analysis regarding adherence revealed that duration of disease (OR, 0.99), degree of treatment efficacy satisfaction (OR, 13.42), and schedule registration (OR, 7.95) were significant. Safety assessment results were within the range of those already reported. CONCLUSIONS: ADA self-injection was thought to have good adherence and a safe administration method according to patients' assessments. PMID- 25436359 TI - Gut microbiota in cirrhotic liver transplant candidates. AB - BACKGROUND/AIMS: The purpose of this study was to evaluate the gut microflora of liver transplant candidates. METHODOLOGY: Fecal microflora of 20 cirrhotic liver transplant candidates was analyzed basing on prospectively collected stool samples. The results were compared with those of 20 non-cirrhotic patients with liver disease and/or abnormal liver function tests, 20 patients with Crohn's disease, and 20 patients without any gastrointestinal disease. Moreover, correlations between particular counts of microbiota, as well as between microbial counts and stool pH were examined. RESULTS: The pattern of fecal microbiota of liver transplant candidates was characterized by increased counts of lactobacilli (p=0.001), including hydrogen peroxide producing strains (p=0.008). In these patients, lactobacilli were positively correlated to enterococci (p=0.006) and bifidobacteria (p=0.004). No correlations other than those observed for lactobacilli in general were observed between hydrogen peroxide producing lactobacilli and the remaining microbiota. Increased yeast and Escherichia coli counts were associated with a tendency towards lower (p=0.095) and higher (p=0.072) stool pH, respectively. CONCLUSIONS: Surprisingly, gut microflora of liver transplant candidates with cirrhosis is particularly enriched with lactobacilli, including hydrogen peroxide producing strains. Thus, the use of other potentially beneficial microorganisms, such as particular yeast strains, might be more appropriate for these patients. PMID- 25436360 TI - Beneficial effect of low caloric intake in the early period after orthotopic liver transplantation: a new concept using graft weight. AB - BACKGROUND/AIMS: Although various factors are correlated with early graft function after orthotopic liver transplantation (OLT), caloric supplementation is not considered in postoperative period. This retrospective study investigated the correlation between caloric intake and early graft function and compared calorie/ body weight ratio (CBWR) and calorie/graft weight ratio (CGWR) as standards for nutritional provision. METHODOLOGY: Patients were divided into the low caloric group (<18 kcal/kg/day) and eucaloric group (>=18 kcal/kg/day) according to caloric intake until 48 hours post-OLT. Graft function was assessed according to aminotransferase level, bilirubin level, and international normalised ratio (INR) on postoperative days (POD) 0, 2, and 7. The variables associated with caloric intake were compared to identify the superiority between CBWR and CGWR. RESULTS: There were 32 and 8 patients in the low caloric and eucaloric groups. INR on POD 2 was significantly lower in the low caloric group (p = 0.018). CGWR was more strongly correlated with INR than CBWR on POD 2 (r = 0.08, p = 0.63 vs. r = 0.36, p = 0.024). CONCLUSIONS: Low caloric intake has a beneficial effect on the restoration of early graft function. CGWR is superior to CBWR as a standard for nutritional supplementation. PMID- 25436361 TI - The effect of hepatocellular carcinoma bile duct tumor thrombi in liver transplantation. AB - BACKGROUND/AIMS: The presence of bile duct tumor thrombi (BDTT) of hepatocellular carcinoma (HCC) in explant liver is considered to be a poor prognostic factor. However, studies about HCC BDTT in liver transplant recipients are rare. We compared the characteristics of liver transplant recipients with HCC BDTT in their pathology with those of recipients who had portal vein tumor thrombi (PVTT) of HCC in their pathology. METHODOLOGY: The medical records of patients who underwent liver transplantation from 2002 to 2008 at Samsung Medical Center were reviewed. HCC recurrence was considered as an end-point. RESULTS: Eight patients were identified as having HCC BDTT in explant liver. The disease-free survival rates at 1-year and 5-year were 37.5% and 25.0%, respectively. Patients whose HCC did not recur had lower alpha-fetoprotein (AFP) levels than others (P=0.046). Patients with HCC BDTT were compared with recipients who had PVTT in their pathology, and there was no statistically significant difference between the two groups (P=0.750). CONCLUSIONS: HCC BDTT of explant liver has been considered to be a poor prognostic factor, like PVTT of HCC. However, we found that patients with low AFP levels before transplantation could be expected to have a longer disease-free survival. PMID- 25436362 TI - A novel technique for resection of huge right lobe hepatocellular carcinoma extending to the right atrium: in-situ cold perfusion of liver. AB - BACKGROUND/AIMS: Surgery for advanced hepatocellular carcinoma with inferior vena cava or right atrium extension represents challenging procedures for hepatobiliary surgeons. Regardless of the surgical approach chosen, the liver parenchyma inevitably has to suffer from ischemia during the total hepatic vascular exclusion period. METHODOLOGY: We report our novel technique for resection of a huge hepatocellular carcinoma extending to the right atrium. During the total hepatic vascular exclusion period, in-situ cold perfusion of the liver was performed in order to minimize the ischemic insults. RESULTS: The 53 year-old male patient with chronic hepatitis B was diagnosed to have a huge right lobe hepatocellular carcinoma, besides which the tumor had invaded the right hepatic vein and right atrium. With the help of cardio-pulmonary bypass and in situ cold perfusion of the liver, the tumor was removed en-bloc. The operating time was 458 minutes. The cold ischemia time of the liver was 53 minutes 30 seconds. The cardio-pulmonary bypass time was 61 minutes. The estimated blood loss was about 7000 ml. The patient was discharged under stable condition on postoperative day 35. CONCLUSIONS: In selected patients, when the expected tumor resection time is long, the in-situ cold perfusion of the liver could be considered an option. PMID- 25436363 TI - Factors related to shift from hepatic borderline lesion to overt HCC diagnosed by CT. AB - BACKGROUND/AIMS: Factors contributing to the shift from the hepatic borderline lesion to overt hepatocellular carcinoma (HCC) were investigated. METHODOLOGY: Ninety-five borderline nodules from 69 patients were followed-up for 6-55 (median 24) months. The borderline lesion was diagnosed when the CT image demonstrated low density in the portal phase and lacked enhancement in the arterial phase. RESULTS: The shift to overt HCC was seen in 32 nodules from 27 patients. Using multivariate analysis, only size was a significant factor contributing to the shift to overt HCC (p = 0.009). The cumulative incidence of the shift to overt HCC was higher in nodules of >=13 mm in size than in those of < 13 mm (p = 0.034). Among nodules of >=13 mm, nodules showing iso density in the arterial phase and low density in the portal phase had a higher cumulative incidence of the shift to overt HCC than those showing low density in the arterial and portal phases on CT (p=0.007). CONCLUSIONS: In hepatic borderline nodules diagnosed by CT, greater size, and iso density in the arterial phase and low density in the portal phase may be risk factors associated with the shift to overt HCC. PMID- 25436364 TI - Serum P53 Abs in HCC patients with viral hepatitis - type C. AB - BACKGROUND/AIMS: P53 gene mutations have a higher malignant potential and often leads to the production of p53 Abs. This study was conducted to evaluate the clinical implications of p53Abs in HCV-related HCC and its diagnostic capacity as a new biomarker in HCC. METHODOLOGY: 83 patients with HCV-chronic liver disease (25 with LC and 58 with HCC) were enrolled in this study. Ten healthy individuals (HI) served as control group. The studied group was subjected to clinical examination, imaging radiology, laboratory investigation and liver biopsy. Serum p53 Abs was assessed by (ELISA). RESULTS: Serum p53 Abs in HCC (0.5567+/-0.227) was significantly elevated (p<0.0001) than LC (0.252+/-0.0099) and HI (0.214+/ 0.068) (p=0.001). Serum P53 Abs was significantly (p=0.01) increased with the progression of child score but there was no significant difference with regard to age, sex, tumor size or serum liver profile. However, serum p53 Abs showed no significant positive correlation with AFP in HCV-related HCC (r=0.09, p value= 0.6) but serum p53 Abs in combination with AFP showed higher diagnostic sensitivity (82.2%) of HCC than either alone. CONCLUSIONS: P53 Abs could be regarded as a specific biomarker for cancer process and its use in combination with AFP may increase the diagnostic sensitivity of HCC. PMID- 25436365 TI - Risk factors of microvascular invasion, portal vein tumor thrombosis and poor post-resectional survival in HBV-related hepatocellular carcinoma. AB - BACKGROUND/AIMS: Microvascular invasion (MVI) and portal vein tumor thrombosis (PVTT) associated factors in hepatocellular carcinoma (HCC) were previously shown. However, those for HBV-related HCC remain unknown. This study aimed to investigate the risk factors of MVI, PVTT and poor prognosis in this type of HCC. METHODOLOGY: Consecutive 130 patients with HBV-related HCC were enrolled. The impact of variables on MVI, PVTT and post-resectional survival was determined by uni- and multi-variate analyses. RESULTS: By Chi-square analysis, Edmondson Steiner grade and tumor size were related to MVI, whereas Edmondson-Steiner grade and MVI were associated with PVTT. Logistic regression identified Edmondson Steiner grade as the sole independent determinant of MVI, but none is significant for PVTT. Tumor size carried high sensitivity and negative predictive value in prediction of MVI. Survival estimation revealed that Edmondson-Steiner grade, tumor size, PVTT, MVI, satellite nodule, TNM stage and AFP level were prognostic for overall and disease-free survival, but only Edmondson-Steiner grade was of independent implication for both. Besides, tumor size independently predicted overall survival. CONCLUSIONS: In HBV-related HCC, differentiation degree might play an important role in vascular involvement, tumor size might be helpful in primary screening of MVI, differentiation and tumor size might be particularly significant as prognostic markers. PMID- 25436366 TI - Hepatitis B virus reactivation during anti-cancer chemotherapy in patients with past hepatitis B virus infection. AB - BACKGROUND/AIMS: The necessity of preemptive antiviral therapy in patients with past HBV infection is uncertain. We evaluated the incidence and risk factors of HBV reactivation in cancer patients with past HBV infection who received anti cancer chemotherapy. METHODOLOGY: Between Jan. 2009 and Dec. 2011, we reviewed 675 HBsAg negative and anti-HBc positive patients who had solid cancers or hematologic malignancies that were treated with intravenous cytotoxic chemotherapy. RESULTS: Among 675 patients, 321 (47.6%) patients had solid cancer and 354 (52.4%) had hematologic malignancy. HBV reactivation was observed in 13 patients (1.9%). In solid cancer patients, 1 (0.3%) patient had HBV reactivation, whereas 12 out of 365 (3.3%) patients with hematologic malignancy experienced HBV reactivation. Among the 12 HBV-reactivated patients with hematologic malignancy, 11 patients had lymphoma. Lymphoma carried a significantly higher risk for HBV reactivation than solid cancer in patients with past HBV infection (OR, 24.134; 95% CI, 3.027-192.406; P = 0.003). Among HBV-reactivated lymphoma patients, 2 patients experienced fulminant liver failure. The absence of anti- HBs was identified as a risk factor for HBV reactivation (OR, 22.446; 95% CI, 4.816 104.609; P < 0.001). CONCLUSIONS: Preemptive antiviral therapy should be considered in lymphoma patients with past HBV infection before starting anti cancer chemotherapy PMID- 25436367 TI - Residual right portal branch flow after first-step ALPPS: artifact or homeostatic response? AB - BACKGROUND/AIMS: Mutual interactions between portal vein and hepatic artery can be documented during hepatobiliary surgery. Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) is a recently introduced surgical technique which can also represent a unique living human model to investigate intrahepatic blood circulation. We report three consecutive cases in which a residual right portal branch flow was clearly detectable after first-step ALPPS, and try to further investigate this unexpected finding with intraoperative clamping tests. METHODOLOGY: Every patient was evaluated with CT scan 7 days after first-step ALPPS and Intraoperative Doppler Ultrasonography (IOUS) at both steps of the procedure. RESULTS: In every patient, CT scan and second-step IOUS demonstrated a clear hepatopetal flow distally to the divided right portal branch. The flow was present after right biliary duct clamping and stopped after right total hilar clamping as well as after right hepatic artery occlusion. CONCLUSIONS: Neither cross-portal circulation between the two hemilivers nor trans-sinusoidal backflow from the hepatic veins can explain these findings, which are rather consistent with a refilling of the occluded portal branch through the opening of intrahepatic arterioportal shunts (APS). APS could represent the simplest homeostatic mechanism that regulate intrahepatic blood flow. PMID- 25436368 TI - Endoscopic ultrasound guided radiofrequency ablation in pancreas. AB - Radiofrequency ablation of the pancreas represents a more effective tumor destruction method compared to other ablation techniques. The endoscopic ultrasound guided radiofrequency ablation is indicated for locally advanced, non metastatic pancreatic adenocarcinoma, without the need of general anesthesia and fast recovery. The main limitations are the encasement of the mesenteric vessels or of the common bile duct in the head pancreatic tumours. The technique is feasible, effective and relatively safe in porcine models, with minimal evidence of fat necrosis in intra-pancreatic and/or extra-pancreatic adipose tissue. It has been successfully applied on insulinomas and pancreatic adenocarcinoma in humans, with few complications, such as duodenal bleeding or mild abdominal pain. Other side effects as biliary fistula, pancreatic fistula or acute pancreatitis seen in intraoperative settings of radiofrequency ablation, have not been reported in endoscopic ultrasound guided radiofrequency ablation. PMID- 25436369 TI - Radiofrequency ablation vs. surgical resection on the treatment of patients with small hepatocellular carcinoma: a system review and meta-analysis of five randomized controlled trials. AB - BACKGROUND/AIMS: To investigate the meta-analysis of randomized controlled trials(RCTs) of the efficacy and safety between radiofrequency ablation (RFA ) and surgical resection (SR) in treating small hepatocellular carcinoma (SHCC). METHODOLOGY: RCTs comparing RFA with SR for SHCC were collected from PubMed/Medline, Cochrane Library, EMBASE and CNKI data base. Odds ratios and 95% confidence intervals were calculated. RESULTS: Five RCTs with a total of 776 patients were included in this analysis. The 1-, 3-year overall survival rate and 1-year recurrence-free survival rate were of no difference between the RFA and SR . However, SR was shown to be superior to the RFA with the analysis of 5-year overall rate and 3-, 5-year recurrence-free survival rate. The 1-year recurrence rate was similar between the SR and RFA . However, the 2-, 3-year recurrence rate of RFA is significantly higher than SR . In addition, the SR presented a high complication rate. CONCLUSIONS: SR treatment led to a higher long-term survival rate and a lower long-term recurrence rate, while RFA led to a lower complication rate than SR. However, Further research was needed to investigate the efficacy of RFA because of the inadequate research data and the heterogeneity among the included studies. PMID- 25436370 TI - The epidemiology and distribution of pathogens and risk factors for mortality in liver transplant recipients with Gram negative bacteremia. AB - BACKGROUND/AIMS: More data on the epidemiology and distribution of pathogens and the risk factors for mortality in liver transplant recipients with Gram negative bacteremia are needed. METHODs: Among a cohort of 228 liver transplant recipients, we identified 35 patients with initial episodes of Gram negative bacteremia after operation. The association between the risk factors and Gram negative bacteremia related mortality was assessed. RESULTS: Forty-seven episodes of Gram negative bacteremia occurred in 15.4% of liver transplant recipients. The mean age for these 35 patients was 46.1 years. Among patients with Gram negative bacteremia, 51.4% had an intra-abdominal/biliary source of infection and Escherichia coli was the most common microorganism. There were 18 deaths with a mortality rate of 51.4%. Multivariate logistic regression showed that the independent risk factors for mortality are serum albumin level < 3.0 mg/ dL (odds ratio[OR] = 17.6, 95% confidence interval[CI] = 1.4-224.6, P = 0.027) and septic shock (OR = 37.5, 95% CI = 3.6-386.7, P = 0.002). CONCLUSIONS: The risk factors significantly associated with increased mortality due to Gram negative bacteremia in liver transplant recipients are decreased serum albumin level and septic shock. PMID- 25436371 TI - A new simple navigation for anatomic liver resection under intraoperative real time ultrasound guidance. AB - Anatomic liver resection is indispensable for liver surgeons. However, recognition of the precise intrahepatic resectional plane is difficult because intrahepatic Glissonean branches cannot be visualized. We have devised a new surgical procedure to accurately determine the resectional plane of deep parts of the liver. After dividing the surrounding ligaments, the echo probe is placed on the back of liver and the monitor image is reversed, right to left and up to down. This provides images almost the same as those from the usual position of the echo probe. This method enables the targeted Glissonean pedicle to be approached without losing the intrahepatic resectional plane. Because both the excision side and preserved side are depicted, injury to the hepatic vein and Glissonean branch on the preserved side is readily avoided. Real-time ultrasonographic guidance contributes to not only safe and precise hepatectomy, but also the education of inexperienced liver surgeons. PMID- 25436372 TI - Clinicopathological parameters associated with surgical site infections in patients who underwent pancreatic resection. AB - BACKGROUND/AIMS: To clarify parameters associated with postoperative surgical site infection (SSI) after pancreatectomy, we examined clinicopathological and surgical records in 186 patients who underwent pancreatectomy at a single academic institute. METHODOLOGY: Patient demographics, liver functional parameters, histological findings, surgical records and post-hepatectomy outcomes during hospitalization were compared between the non-SSI and SSI group, in which SSIs included superficial and deep SSIs. RESULTS: The prevalence of SSI (29-35%) has not changed over an 18-year period. With respect to patient demographics and laboratory data, no parameters were associated with postoperative SSI. In surgical records, the operating time in the SSI group tended to be longer in comparison with that in the non- SSI group (618 vs. 553 minutes, respectively) but not significantly different (p=0.070). With respect to postoperative outcomes, time to oral intake in the SSI group was significantly longer than that in the non-SSI group (21.2 vs. 13.7 days, respectively) (p<0.01). Incidences of pancreatic fistula, postoperative bleeding, long-term ascites and re-operation were significantly more frequent in the SSI group in comparison with the non-SSI group (p<0.05). Decrease of body weight after surgery in the SSI group was significantly greater than that in the non- SSI group (-4.1 vs. -2.7kg, respectively) (p<0.05). Period of hospital stay in the SSI group was significantly longer than that in the non-SSI group (37 vs. 25 days) (p<0.05). Multivariate analysis showed that only postoperative pancreatic fistula was significantly associated with SSI (p<0.01). CONCLUSIONS: SSI is an important risk factor of longer hospital stay after pancreatectomy and prevention of pancreatic fistula through the future improvement of surgical procedures is necessary to decrease SSI rates. PMID- 25436373 TI - Minimally invasive image analysis of biliary-pancreatic structure for preoperative simulation. AB - For preoperative assessment of the pancreatic tumors, we developed minimally invasive method to extract the pancreatic duct from multidetector row computed tomography (MD-CT) images and to visualize the biliarypancreatic structures, tumor and adjacent organs simultaneously using an image workstation. PMID- 25436374 TI - Comparative study between uncinate process carcinoma and pancreatic head carcinoma after pancreaticodudenectomy (clincopathological features and surgical outcomes). AB - BACKGROUND/AIMS: Pancreatic head cancer is considered to have the worst prognosis of the periampullary carcinomas. The clinicopathological features of uncinate process pancreatic cancer are poorly published. METHODOLOGY: We retrospectively studied patients who underwent pancreaticodudenectomy (PD) for pancreatic head adenocarcinoma. This study included three groups of patients. Group A patients with pure pancreatic head carcinoma (PPHC), group B patients with combined head and uncinate process carcinoma (CPHUC) and group C patients with pure uncinate process carcinoma (PUPC). Preoperative, intraoperative and postoperative variables were collected. RESULTS: The study included 157 patients. Jaundice was the most common presenting symptoms in PPHC and CPHUC. Abdominal pain was the most common presenting symptoms in PUPC. The mean common bile duct (CBD) and pancreatic duct diameters were significantly smallest in PUPC group (P=0.0001). The venous invasion was significantly observed more in PUPC group and vascular resection was done in 50% of cases. The number of patients with microscopically residual tumor was significantly highest in PUPC group after PD than in other two groups (P=0.001). Recurrence rate occurred in 54.2% in PUPC group, 34.8% in CPHUC group and 22.7% in PPUC group after PD (P=0.007). The median survival was 19 months in PPHC groups, 16 months in CPHUC group, 14 months in PUPC group (P= 0.02). CONCLUSIONS: PUPC presented with abdominal pain with more vascular infiltration. The recurrence rate was common after PD for uncinate process carcinoma especially locoregional recurrence and the overall survival rate was found to be lower for PUPC. PMID- 25436375 TI - Pattern of first recurrent lesions in pancreatic cancer: hepatic relapse is associated with dismal prognosis and portal vein invasion. AB - BACKGROUND/AIMS: The aim of this study was to evaluate patterns of the initial recurrence after pancreatectomy for pancreatic cancer and risk factors in each pattern. METHODOLOGY: This study included 209 pancreatic cancer patients who underwent pancreatectomy and of whom the detailed information on the first recurrent lesions detected by imaging during postoperative followup were available. Relapse patterns were classified into 4 groups: liver, peritoneal, local and extra-abdominal recurrences. We evaluated their associations with prognosis and various clinicopathological factors to identify relevant risk factors. RESULTS: Cumulative numbers of patients with liver, peritoneal, local, and extra-abdominal recurrences were 81, 70, 98 and 22, respectively, for the first recurrences. Hepatic relapse was associated with significantly shorter overall survival than other sites (p<0.001) and was an independent prognostic factor in multivariate analysis (p<0.001). Pathological portal vein invasion was the only independent risk factor for hepatic relapse (p=0.045). There was no significant correlation between the depth of invasion and prevalence of hepatic relapse. CONCLUSIONS: Hepatic relapse was associated with a dismal prognosis and with pathological portal vein invasion. Novel therapeutic strategies are therefore required to reduce the incidence of hepatic relapse, especially in patients with portal vein invasion. PMID- 25436376 TI - Clinical outcomes after pancreaticoduodenectomy in elderly patients at middle volume center. AB - BACKGROUND/AIMS: It has been reported that age and hospital volume are risk factors after pancreaticoduodenectomy (PD), however the mortality rate after PD at middle volume center is decreasing by surgical advances and recently PD in the elderly patients is safely performed. The aim of this study is to evaluate the safety and feasibility of PD in the patients over 80 years of age at middle volume center. METHODOLOGY: 60 patients who underwent PD between 2004 and 2012 were divided into two groups (>=80 and <80years). The clinical outcomes of the two groups were retrospectively analyzed. RESULTS: There were no statistical differences in terms of preoperative parameters, co-morbidity, perioperative data, morbidity, mortality and postoperative hospital stay. We achieved zero mortality in patients over 80 years of age and 40% of them are alive without recurrence. CONCLUSIONS: Clinical outcomes after PD in the elderly patients at middle-volume center are acceptable. Age and hospital volume are not necessarily risk factors after PD. PMID- 25436377 TI - Clinical significance of vessel-sealing device usage for pancreatectomy: a retrospective cohort study. AB - BACKGROUND/AIMS: We compared each vessel-sealing device to evaluate safety and efficacy for controlling surgical results in 200 patients undergoing pancreatectomy. METHODOLOGY: Sixty-seven patients applied the hemostatic devices (VS group) consisted of LigaSureTM (LS) or the Harmonic ultrasonic dissector (USD). Results were compared with that of a historical control group (n=134). RESULTS: In pancreaticoduodenectomy, the prevalence of lymph node dissection was high in the VS group. Blood transfusion was significantly less frequent in the VS group than in the control group (p<0.01). The prevalence of surgical site infection and systemic complications was significantly lower in the VS group than in the control group (p<0.05). The duration of hospitalization was significantly shorter in the VS group than in the control group (p<0.01). In distal pancreatectomy, the prevalence of cutting stapler usage for transection was low in the VS group. Postoperative weight loss and the prevalence of surgical site infections was higher in the VS group than in the control group but were more frequently observed in the USD group than in the LS group. CONCLUSIONS: Use of energy sealing devices improves surgical results and avoids pancreatectomy related complications. These devices are safe and effective for use in pancreatic surgery. PMID- 25436378 TI - The efficacy and safety of single-session endoscopic ultrasound-guided fine needle aspiration and endoscopic retrograde cholangiopancreatography for evaluation of pancreatic masses. AB - BACKGROUND/AIMS: There have been limited studies evaluating single-session EUS FNA and ERCP for evaluation of pancreatic masses. The aim of this study was to determine the safety of single-session EUS-FNA and ERCP, and to compare the diagnostic accuracies of cytodiagnosis by EUS-FNA, ERCP, and their combination. METHODOLOGY: A total of 100 patients with pancreatic masses were prospectively enrolled. All patients underwent single-session EUS-FNA and ERCP. The main outcome measurement was frequency of post-procedural complications. Another measurement was diagnostic accuracy of cytodiagnosis by EUS-FNA, ERCP, and their combination. RESULTS: Procedure-related pancreatitis occurred in 10 patients, but all patients were conservatively managed. Cytodiagnosis by EUS-FNA was significantly superior to ERCP in accuracy. In patients with a pancreatic head mass, 3 cases of false negative EUS-FNA were positive on ERCP. The combination procedures improved accuracy compared with EUS-FNA alone. By contrast, in the subgroup of the pancreatic body or tail mass, the combination of EUS-FNA and ERCP did not improve cytodiagnosis compared to that with EUS-FNA alone. CONCLUSIONS: Single-session EUS-FNA and ERCP appears to be as safe as performing each procedure separately. EUS-FNA should be considered the principal procedure for cytodiagnosis. ERCP has only a complementary role in patients with pancreatic head mass. PMID- 25436379 TI - Surgical outcomes for solid pseudopapillary neoplasm of the pancreas. AB - BACKGROUND/AIMS: Solid pseudopapillary neoplasm (SPN) is a rare exocrine tumor of the pancreas with low malignant potential. This study was designed to evaluate surgical outcome of solid pseudopapillary neoplasm (SPN). METHODOLOGY: From Between January 1994 to November 2013, 41 patients were diagnosed with SPN of the pancreas at Ajou University Medical Center and underwent surgical resection. RESULTS: Of the 41 patients, 33(80.5%) were female and 8(19.5%) were male with a mean age of 34.5 years (range, 12-63 years). The most common location of SPN was the tail (43.9%). Mean diameters of SPN was 5.5 cm (range, 1.2- 14.5 cm). Nineteen patients (46.3%) had non-specific abdominal symptoms that had been investigated. Surgical treatment included distal pancreatectomy in 21, pancreaticoduodenectomy in 11, segmental resection of pancreas in 4, enucleation in 2, excision in 2 and surgical biopsy in 1. Thirty-nine of the 41 patients were disease-free at a median follow-up of 59 months (range, 1-125 months). CONCLUSIONS: Patients diagnosed as SPN should receive surgical resection because of the excellent prognosis. Closed follow-up is recommended after surgery, even in patients without pathological malignant potential. For metastasis or recurrence, an aggressive surgical treatment is necessary because of the good possibility of long-term survival. PMID- 25436380 TI - Comparison of gastric cancer surgery between patients aged >80 years and <79 years: complications and multivariate analysis of prognostic factors. AB - BACKGROUND/AIMS: To evaluate the clinicopathological features and results of surgery for gastric cancer in elderly patients aged ?80 years relative to those aged ?79 years, and to recommend the appropriate surgical treatment for elderly patients. METHODOLOGY: A total of 332 patients with gastric cancer who underwent gastrectomy in our department between 2002 and 2012 were evaluated. Of these, 81 were aged ?80 years (Group A) and 251 were aged ?79 years (Group B). We compared surgical outcomes and survival in these two groups. RESULTS; Postopeartive complications were associated with preoperative cormorbid disease(p<0.01). D2 and R0 resection was common in GroupB (p<0.01). Respiratory complications and hospital deaths were higher in Group A than in Group B. Overall survival (OS) was significantly lower in Group A than in Group B. Regarding Stage I disease, OS was significantly lower in Group A; however, cause-specific survival was similar between the two groups. Multivariate analysis showed that radicality and postoperative complications were independent prognostic factors for OS in elderly gastric cancer patients. CONCLUSIONS: These results indicate that postoperative respiratory complications and other causes of death worsened the prognosis of elderly. Preoperative accurate judgment of co-morbid disease, meticulous postoperative management and follow up might be improved survival of gastric cancer in elderly. PMID- 25436381 TI - Risk factors for delayed gastric emptying caused by anastomosis edema after subtotal gastrectomy for gastric cancer. AB - BACKGROUND/AIMS: Delayed gastric emptying (DGE) is one of the most troublesome complications after subtotal gastrectomy for gastric cancer. We evaluated operative and perioperative variables to assess for independent risk factors of DGE caused by anastomosis edema. METHODOLOGY: The study retrospectively reviewed clinical data of 382 consecutive patients who underwent subtotal gastrectomy for gastric cancer between 2009 and 2011 at a single institution. RESULTS: Delayed gastric emptying had occurred in twelve patients (3.1%). Univariate analysis revealed high body mass index (>25kg/m2), open gastrectomy, and Billroth II or Roux-en Y reconstructions to be significant factors for delayed gastric emptying. Multivariate analysis identified high body mass index and open gastrectomy as predictors of delayed gastric emptying. CONCLUSIONS: To avoid delayed gastric emptying, surgeons should take care in creating the gastrointestinal anastomosis, particularly in patients with high BMI or in cases of open gastrectomy. PMID- 25436382 TI - Safety and survival benefit of surgical management for elderly gastric cancer patients. AB - OBJECTIVE: To study the safety and survival outcome of surgical management for elderly gastric cancer patients. Methods: Patients proven of gastric cancer who aged >=80 years during November 2002 to July 2011 were retrospectively analyzed. The detailed information of patients' characteristics and surgical management was retrieved. Follow-up of overall survival status was performed to analyze the surgical effectiveness. RESULTS: Totally, 92 (48 in surgery and 44 in non-surgery group) out of 187 eligible patients recorded adequate information and analyzed finally. There were 34 patients undergone radical gastrectomy, 6 palliative gastrectomy, 1 gastrojejunostomy and 7 exploratory laparotomy. Median follow-up durations were 25 (9-111) and 28 (8-114) months in surgery and non-surgery groups, respectively (p=0.797). Clinical-pathological T stage and node status were comparable. Clinical-pathological distal metastasis status was 15 and 26 M1 cases for surgery and nonsurgery, respectively (p=0.006). Incidence of postoperative complications and hospital mortality were 25.0% and 2.1%, respectively. The 2-year survival rates of M0 subgroups were 35.7% and 0% for surgery and nonesurgery, respectively (HR=3.98, p=0.022). CONCLUSIONS: The safety of surgery for well-selected >= 80-year elderly gastric cancer patients was potentially acceptable and the patients of early or locally advanced diseases could obtain survival benefits by surgery. PMID- 25436383 TI - Usefulness of CT volumetry for gastric varix before balloon-occluded retrograde transvenous obliteration. AB - BACKGROUND/AIMS: To evaluate the feasibility of gastric variceal (GV) volumetry using computed tomography (CT) images taken before balloon-occluded retrograde transvenous obliteration (B-RTO) and to assess its correlation with the actual amount of 5% ethanolamine oleate and iodinated contrast medium (EOI) injected in B-RTO. METHODOLOGY: Forty-seven consecutive patients with GV underwent B-RTO of the gastrorenal shunt. GV volume was measured with preoperative CT images by three radiologists. Statistical significance was examined by intraclass correlation coefficient (ICC) for concordance among three radiologists and by Pearson correlation test for correlation between GV volume and the amount of 5% EOI injected. RESULTS: GV volumes measured by three radiologists significantly correlated with each other (ICC=0.959). Combining all patients and all measurements, the mean GV volume and the mean amount of 5% EOI were 27.02+/ 16.67cm3 and 28.72+/-17.72mL, respectively. There was a significant correlation between GV volume, calculated as a mean of the three values measured by the three radiologists, and the amount of EOI (r2=0.706, p<0.001). CONCLUSIONS: GV volume measured on CT showed a significant correlation with the amount of 5% EOI injected. CT volumetry of GV has the potential to determine an amount of the sclerosing agent to be injected in B-RTO. PMID- 25436384 TI - Clinical investigation of combined Billroth II with Braun anastomosis for patients with gastric cancer. AB - BACKGROUND/AIMS: This study gives insight into the effect of combined Billroth II with Braun anastomosis for patients with gastric cancer. METHODOLOGY: The clinical data of 720 patients with gastric cancer who underwent surgical treatment in our hospital from 1997 to 2011 were reviewed retrospectively. The results of different operative approaches were analyzed. RESULTS: Combined Billroth II with Braun anastomosis was performed in 378 cases, and Billroth II in 342 cases. The Gastrointestinal Quality of Life Index (GIQLI) was used to evaluate postoperative quality of life. CONCLUSIONS: If the indications for combined Billroth II with Braun anastomosis are strictly controlled, and more attention is paid to perioperatively support, combined Billroth II with Braun anastomosis can prolong the life span of the patients with gastric cancer rather than increase the surgical complications and the mortality. PMID- 25436385 TI - Immunohistochemical HER2 expression not associated with clinicopathological characteristics of stage I-III gastric cancer patients. AB - BACKGROUND/AIMS: The aim of this study was to investigate the association of human epidermal growth factor receptor 2 (HER2) expression with clinicopathological characteristics of resectable gastric cancer patients. METHODOLOGY: A total of 394 stage I-III surgical gastric cancer patients who were detected of immunohistochemical (IHC) HER2 expression postoperatively were included in this retrospective study. Association of IHC HER2 over-expression (3+) rate with clinicopathological characteristics was tested by univariate and multivariate analyses. RESULTS: IHC HER2 over-expression rate was 5.1% (95% CI 3.1%-7.7%). By univariate analyses, none of the clinicopathological characteristics was associated with the IHC HER2 over-expression compared to negative expression (0/1+) (p>0.05), with the exception of a higher rate (12.2%) of IHC HER2 (3+) in moderate differentiation subset (p=0.02). However, the multivariate analyses didn't selected any characteristic as an independent risk factor of IHC HER2 over-expression or the combination of IHC HER2 (2/3+). CONCLUSIONS: IHC HER2 over-expression rate is relatively low among stage I-III gastric cancer patients, and might be generally not associated with clinicopathological characteristics. PMID- 25436386 TI - Comparative proteomics in gastric cancer cell line BGC823 after ZNF139 gene inhibited with RNA interference. AB - BACKGROUND/AIMS: Zinc finger protein 139 (ZNF139) gene is proved play an important role in gastric cancer. Aim of this study is to identify changes of proteins after ZNF139 gene was inhibited in gastric cancer cell line BGC823. METHODS: siRNA-specific ZNF139 was synthesized and transfected into BGC823; 2-D fluorescence difference gel electrophoresis (2-D DIGE) and liquid chromatography mass spectrometry (LC-MS) were applied to screen, identify differentially expressed proteins, and function of these proteins was analyzed; Western blot method was applied to verify the identified proteins. RESULTS: ZNF139 expression in siRNA transfected cancer cell BGC823 decreased significantly. Results of 2-D DIGE showed eight differential protein spots, of which seven were identified with LC-MS, including switches associated protein 70, far upstream element binding protein 1, heat shock protein 60, annexin A7, small ubiquitin-like modifier 1 activating enzyme, chaperonin-containing tail-less complex protein 1 and annexin A2. These proteins were found to be associated with proliferation, apoptosis, invasion, metastasis, adhesion of gastric cancer cells with bioinformatic analysis. Western blot analysis confirmed that expressions of these proteins in BGC823 were consistent with the proteomic results. CONCLUSIONS: ZNF139 gene may influence the biological behavior of gastric cancer cells in many ways by regulating multiple proteins. PMID- 25436387 TI - Metabolic effects of gastrectomy with or without omentectomy in gastric cancer. AB - BACKGROUND/AIMS: The metabolic effects of gastrectomy and the reduction of visceral adiposity through omentectomy for gastric cancer are unknown. METHODOLOGY: We retrospectively reviewed of prospectively collected data of 67 patients over one year who underwent radical gastrectomy with either a complete or partial omentectomy for gastric cancer. The change in Body mass index (BMI), triglyceride, low density lipoprotein, high density lipoprotein, and hematological profile were evaluated. RESULTS: In the group of 67 patients changes were observed after 1 year follow-up for BMI (23.7+/-3.1 versus 21.3+/ 2.5kg/m2; p<0.001), triglyceride (155.2+/-136.1 versus 89.7+/-41.2mg/dL, p=0.011), low density lipoprotein (107.4+/-45.4 versus 95.8+/-27.5mg/dL, p=0.020), vitamin B12 (681.4+/-297.4 versus 558.1+/-338.6pg/mL, p=0.076). High density lipoprotein (41.4+/-12.6 versus 52.8+/-10.5mg/dL) increased after surgery (p<0.001). There were no changes between the complete and partial omentectomy groups for BMI, albumin, triglyceride, lipoprotein, and hemoglobin. CONCLUSIONS: Gastrectomy with or without omentectomy induced a decrease of BMI and improvements in metabolic parameters such as triglyceride, low density lipoprotein, high density lipoprotein. Omentectomy had no significant impact on any measured parameter in this group. PMID- 25436388 TI - Systematic analysis of gene expression and molecular interactions in cardiac and non-cardiac gastric carcinomas. AB - BACKGROUND/AIMS: : This study aims to comparing the gene expression profiles and molecular interactions among gastric cardiac adenocarcinomas (GCA), gastric noncardiac adenocarcinomas (GNCA) and their adjacent normal tissues. METHODOLOGY: Gene expression profile of GSE29272 was downloaded from Gene expression omnibus. Differentially expressed genes (DEGs) were identified at the cut-off of p-value <= 0.01. Gene ontology (GO) enrichment analysis was further performed for the DEGs, and then the binding sites of the transcriptional factors and the specific protein-protein interactions were analyzed. RESULTS: Total 1024 DEGs were screened, including 741 up-regulated genes and 283 down-regulated genes. VSNL1 (visinin-like protein-1) is expressed relatively higher in the GNCA and could be its molecular biomarker, as KRT14 (cytokeratin 14) in the GCA. GO analysis showed that the analogous cancer-relevant factors network appears in these two cancer subgroups. The DEGs in the GCA tend to be bound by SPIB and ZNF354C. FN1 lies in the center of the protein-protein interaction networks of the two cancer subgroups. CONCLUSIONS: We found out the RNA expression level of the two gastric cancers varied greatly from the normal tissues while gene expression profile of them were very similar, however, the different biomarker and transcriptional factors indicate the differences of two mechanisms. PMID- 25436389 TI - Single port intra-gastric full thickness resection: Using "Rotation and Revolution Single Instrument Tie (RRSIT)". AB - BACKGROUND/AIMS: Recently, minimize incisions has led to a reduction in the number of ports, and has led to transumbilical single-port surgery. We evaluated the treatment result of single-port, intragastric, full thickness resections for gastric SMTs. In addition, we introduce a novel intracorporeal knot tying method. METHODOLOGY: From August 2010 to March 2011, five patients underwent single-port intragastric, full thickness gastric wedge resections. After performing a gastrostomy, a single port was inserted into the stomach. After full thickness resection, the defect in the gastric wall was sutured by full thickness interrupted suture and a new knot tying technique. RESULTS: The mean operative time was 129 +/- 21.0 min and the mean mass size was 3.0+/-0.6 cm. There were two very low-risk GISTs, 2 leiomyomas, and 1 carcinoid. The post-operative course was uneventful in all patients. The mean hospital stay was 7.2+/-1.2 days. CONCLUSIONS: Single-port intra-gastric full thickness resection with novel intracorporeal knot tying method is feasible and safe. novel intracorporeal knot tying method is a very useful knot tying method. We expect the application of novel intracorporeal knot tying method to be diverse and broad. PMID- 25436390 TI - Differential abundance of egg white proteins in laying hens treated with corticosterone. AB - Stressful environments can affect not only egg production and quality but also gene and protein abundance in the ovary and oviduct in laying hens. The oviductal magnum of laying hens is the organ responsible for the synthesis and secretion of egg white proteins. The objective of this study was to investigate the effects of dietary corticosterone as a stress model on the abundance of proteins in the egg white and of mRNA and proteins in the magnum in laying hens. After a 14-day acclimation, 40 laying hens were divided into two groups which were provided for the next 14 days with either control (Control) or corticosterone (Stress) diet containing at 30 mg/kg. Corticosterone treatment resulted in increased feed intake (P <= 0.05) and decreased egg production. Two-dimensional electrophoresis (2DE) with MALDI-TOF/TOF MS/MS using eggs obtained on days 0 and 5 revealed differential abundance of egg white proteins by Stress: transiently expressed in neural precursors (TENP), hemopexin (HPX), IgY-Fcupsilon3-4, and extracellular fatty acid-binding protein (Ex-FABP) were decreased while ovoinhibitor and ovalbumin-related protein X (OVAX) were increased on days 5 vs 0 (P <= 0.05). Expression of mRNAs and proteins was also significantly modulated in the magnum of hens in Stress on day 14 (P <= 0.05). In conclusion, the current study provides the first evidence showing that dietary corticosterone modulates protein abundance in the egg white in laying hens, and it suggests that environmental stress can differentially modify expression of egg white proteins in laying hens. PMID- 25436391 TI - Serum cytokine profiles in Takayasu's arteritis: search for biomarkers. AB - OBJECTIVES: Assessment of disease activity is one of the major difficulties in patients with Takayasu arteritis (TAK) during follow-up. To date, no biomarker is universally accepted to be a surrogate for active disease in TAK. In this study, we aimed to investigate levels of various pro-and anti-inflammatory molecules including serum granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, IL-8, IL-10, IL-18 and IL-23 in patients with TAK. METHODS: The study included 51 patients (age: 40.6+/-12.2 years, F/M: 45/6) with TAK and 42 age- and sex-matched healthy controls (age: 38.1+/-7.4 years, F/M: 38/4). All patients fulfilled the criteria of the American College of Rheumatology (ACR). TAK patients were evaluated by physician's global assessment (PGA; active/inactive) and ITAS2010 (Indian Takayasu Arteritis Clinical Activity Score) in terms of clinical activity in baseline and follow-up visits. Commercial enzyme linked immuno-sorbent assay (ELISA) kits were used for measurements of serum cytokine levels. RESULTS: At baseline, 21 (41.2%) patients were active according to PGA and 8 (15.7%) according to ITAS2010. Serum IL-6, IL-8 and IL-18 levels were significantly higher in patients with TAK, whereas GM-CSF, IL-10, IL-23 levels were similar to healthy controls. IL-8 significantly decreased in the follow-up, associated with a decrease of clinical activity, whereas IL-23 level significantly increased. When assessed by ITAS2010 active patients had significantly higher IL-18 levels. CONCLUSIONS: We found significantly increased IL-6, IL-8 and IL-18 levels in patients with TAK compared to healthy controls. Only IL-18 level was significantly higher in active patients assessed by ITAS2010. IL-18 was also the only cytokine in our study that correlated with CRP. These findings suggest that cytokines associated with neutrophilic, pro inflammatory responses such as IL-6, IL-8 and IL-18 can be potential biomarkers for the assessment of disease activity in TAK and warrant further studies in larger series. PMID- 25436393 TI - Self-expandable metal stents for obstructing colonic and extracolonic cancer: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. PMID- 25436394 TI - Is it time to consider other options for Barrett's esophagus screening? PMID- 25436396 TI - Why it's time for updated U.S. colorectal cancer prevention guidelines in inflammatory bowel disease. PMID- 25436395 TI - Endoscopic palliation of advanced cholangiocarcinoma: can we go beyond stenting? PMID- 25436397 TI - Colorectal cancer screening and the "menu of options". PMID- 25436398 TI - The case for ablating nondysplastic Barrett's esophagus. PMID- 25436399 TI - Radiofrequency ablation for nondysplastic Barrett's esophagus: certainly not for all. PMID- 25436400 TI - Hot avulsion: a modification of an existing technique for the management of nonlifting areas of a polyp. Will it give us the lift we need? PMID- 25436401 TI - Gastric malakoplakia. PMID- 25436402 TI - Pyobilia seen during small-bowel capsule endoscopy (with video). PMID- 25436403 TI - Position change during colonoscope withdrawal: is it worth the effort? PMID- 25436404 TI - Informed consent should not be obtained under duress. PMID- 25436405 TI - Response. PMID- 25436406 TI - Response. PMID- 25436407 TI - Buried bumper syndrome treated with HybridKnife endoscopic submucosal dissection. PMID- 25436408 TI - Overtube-assisted endoscopic application of oxidized cellulose to achieve hemostasis in anastomotic ulcer bleeding. PMID- 25436409 TI - Advanced thinking: potable reuse strategies gain traction. PMID- 25436413 TI - The E3 ubiquitin ligase Itch and Yap1 have antagonistic roles in the regulation of ASPP2 protein stability. AB - ASPP2 is an important tumor suppressor protein promoting p53-dependent and independent apoptosis. However, it has been unclear how ASPP2 protein is regulated. Here, we identified Itch as the E3 ubiquitin ligase for ASPP2. Itch interacts with ASPP2 and mediates its degradation and ubiquitination in vivo. The PPXY motif of ASPP2 interacts with the WW domains of Itch. Yap1 competes with Itch for binding to ASPP2, and prevents Itch-mediated degradation and ubiquitination of ASPP2. Together, these observations reveal that Itch and Yap1 have antagonistic roles in the regulation of ASPP2 protein stability through competing post-translational regulatory mechanism of ASPP2. PMID- 25436414 TI - A potential function for neuronal exosomes: sequestering intracerebral amyloid beta peptide. AB - Elevated amyloid-beta peptide (Abeta) in brain contributes to Alzheimer's disease (AD) pathogenesis. We demonstrated the presence of exosome-associated Abeta in the cerebrospinal fluid (CSF) of cynomolgus monkeys and APP transgenic mice. The levels of exosome-associated Abeta notably decreased in the CSF of aging animals. We also determined that neuronal exosomes, but not glial exosomes, had abundant glycosphingolipids and could capture Abeta. Infusion of neuronal exosomes into brains of APP transgenic mice decreased Abeta and amyloid depositions, similarly to what reported previously on neuroblastoma-derived exosomes. These findings highlight the role of neuronal exosomes in Abeta clearance, and suggest that their downregulation might relate to Abeta accumulation and, ultimately, the development of AD pathology. PMID- 25436415 TI - Pathogenic uromodulin mutations result in premature intracellular polymerization. AB - Several renal diseases involve mutations in the gene encoding uromodulin, the predominant protein in urine. We investigated the intracellular processing of wild-type uromodulin, and three mutants: p.V93_G97del/ins AASC; C155R; and C150S. A renal biopsy from a patient harboring the C155R mutation revealed intracellular protein accumulation. Wild-type uromodulin was efficiently trafficked to the cell surface in transfected tsA 201 cells, whereas the mutants were partially retained within the cell, and incompletely processed. Atomic force microscopy imaging revealed that the intracellular mutant proteins contained fibrillar structures similar to urinary uromodulin. We suggest that premature intracellular polymerization underlies the pathology of uromodulin diseases. PMID- 25436416 TI - Exploring NAG-thiazoline and its derivatives as inhibitors of chitinolytic beta acetylglucosaminidases. AB - NAG-thiazoline (NGT) and its derivatives are well-known inhibitors against most beta-acetylglucosaminidases (beta-GlcNAcases) except for insect and bacterial chitinolytic beta-GlcNAcases, including the molting-indispensable OfHex1 from the insect Ostrinia furnacalis. Here, we report the co-crystal structure of OfHex1 in complex with NGT. This structure reveals a large active pocket in OfHex1 that may account for the poor inhibitory activity of NGT. To test this hypothesis, a bulky substituent was designed and synthesized on the thiazoline ring of NGT. The resulting compound (NMAGT) was determined to be a submicromolar inhibitor of OfHex1 with a Ki value of 0.13 MUM, which is 600-fold lower than Ki value of NGT. Molecular dynamics simulation analysis supported the good fit of NMAGT to the active pocket. PMID- 25436417 TI - Making an impact: FEBS Open Bio celebrates its 3rd anniversary. PMID- 25436418 TI - Thermally-induced structural changes in an armadillo repeat protein suggest a novel thermosensor mechanism in a molecular chaperone. AB - Molecular chaperones are commonly identified by their ability to suppress heat induced protein aggregation. The muscle-specific molecular chaperone UNC-45B is known to be involved in myosin folding and is trafficked to the sarcomeres A-band during thermal stress. Here, we identify temperature-dependent structural changes in the UCS chaperone domain of UNC-45B that occur within a physiologically relevant heat-shock range. We show that distinct changes to the armadillo repeat protein topology result in exposure of hydrophobic patches, and increased flexibility of the molecule. These rearrangements suggest the existence of a novel thermosensor within the chaperone domain of UNC-45B. We propose that these changes may function to suppress aggregation under stress by allowing binding to a wide variety of aggregation prone loops on its client. PMID- 25436419 TI - Structural and biochemical characterization of a carbohydrate acetylesterase from Sinorhizobium meliloti 1021. AB - In many microorganisms, carbohydrate acetylesterases remove the acetyl groups from various types of carbohydrates. Sm23 from Sinorhizobium meliloti is a putative member of carbohydrate esterase family 3 (CE3) in the CAZy classification system. Here, we determined the crystal structure of Sm23 at 1.75 A resolution and investigated functional properties using biochemical methods. Furthermore, immobilized Sm23 exhibited improved stability compared with soluble Sm23, which can be used for the design of plant cell wall degrading-systems. PMID- 25436420 TI - The green tea polyphenol (-)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios. AB - The accumulation of amyloid-beta (Abeta) and tau aggregates is a pathological hallmark of Alzheimer's disease. Both polypeptides form fibrillar deposits, but several lines of evidence indicate that Abeta and tau form toxic oligomeric aggregation intermediates. Depleting such structures could thus be a powerful therapeutic strategy. We generated a fragment of tau (His-K18DeltaK280) that forms stable, toxic, oligomeric tau aggregates in vitro. We show that (-) epigallocatechin gallate (EGCG), a green tea polyphenol that was previously found to reduce Abeta aggregation, inhibits the aggregation of tau K18DeltaK280 into toxic oligomers at ten- to hundred-fold substoichiometric concentrations, thereby rescuing toxicity in neuronal model cells. PMID- 25436421 TI - MicroRNA-520g induces epithelial-mesenchymal transition and promotes metastasis of hepatocellular carcinoma by targeting SMAD7. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Aberrant expression of miRNAs contributes to HCC development. Here, we observed elevated miR-520g expression in tumor samples from HCC patients with relapse and metastasis, and this high miR-520g expression was correlated with poor survival. Through gain- and loss-of-function studies, miR-520g was demonstrated to facilitate HCC cell migration, invasion and epithelial mesenchymal transition (EMT). SMAD7 was identified as a direct target of miR 520g. Accordingly, we conclude that high miR-520g expression promotes HCC cell mobility and EMT by targeting SMAD7, and this is correlated with reduced survival in HCC patients. PMID- 25436422 TI - Induction of DKK1 by ox-LDL negatively regulates intracellular lipid accumulation in macrophages. AB - Dickkopf1 (DKK1), a canonical Wnt/beta-catenin pathway antagonist, is closely associated with cardiovascular disease and adipogenesis. We performed an in vitro study to determine whether oxidized low-density lipoprotein (ox-LDL) increased the expression of DKK1 in macrophages and whether beta-catenin and liver X receptor alpha (LXRalpha) were involved in this regulation. Induction of DKK1 expression by ox-LDL decreased the level of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) via a Wnt/beta-catenin pathway and increased ATP binding cassette transporter A/G1 (ABCA/G1) levels via a signal transducer and activator of transcription 3 (STAT3) pathway. Lower LOX-1 and higher ABCA/G1 levels inhibited cholesterol loading in macrophages. In conclusion, ox-LDL may induce DKK1 expression in macrophages to inhibit the accumulation of lipids through a mechanism that involves downregulation of LOX-1-mediated lipid uptake and upregulation of ABCA/G1-dependent cholesterol efflux. PMID- 25436423 TI - Intrinsically disordered proteins as crucial constituents of cellular aqueous two phase systems and coacervates. AB - Here, we hypothesize that intrinsically disordered proteins (IDPs) serve as important drivers of the intracellular liquid-liquid phase separations that generate various membrane-less organelles. This hypothesis is supported by the overwhelming abundance of IDPs in these organelles. Assembly and disassembly of these organelles are controlled by changes in the concentrations of IDPs, their posttranslational modifications, binding of specific partners, and changes in the pH and/or temperature of the solution. Each resulting phase provides a distinct solvent environment for other solutes leading to their unequal distribution within phases. The specificity and efficiency of such partitioning is determined by the nature of the IDP(s) and defines "targeted" enrichment of specific molecules in the resulting membrane-less organelles that determines their specific activities. PMID- 25436426 TI - Incidence of Amblyopia and Its Risk Factors in Children With Isolated Metopic Craniosynostosis. AB - OBJECTIVE: Ophthalmic abnormalities in children with syndromic craniosynostosis have been reported previously, and referral of these children to a pediatric ophthalmologist is recommended. However, it is not as clear whether a child with nonsyndromic synostosis needs to be referred to a pediatric ophthalmologist. The aim of this study is to report the incidence of amblyopia and its risk factors in children with isolated metopic craniosynostosis. DESIGN: An institutional review board-approved, retrospective review was performed on 91 children diagnosed with isolated metopic craniosynostosis. Ophthalmologic records were reviewed for diagnoses of amblyopia, strabismus, and refractive error. RESULTS: Of the 91 children, 19 (20.9%) had astigmatism, eight (8.8 %) had amblyopia, eight (8.8%) had strabismus, five had myopia (5.5%), five had hyperopia (5.5%), and five had anisometropia (5.5%). The incidence of amblyopia and its risk factors found in our study are higher than the rate found in the clinically normal pediatric population. CONCLUSIONS: In our patient population, children with isolated metopic craniosynostosis demonstrate an increased rate of amblyopia and its risk factors. Amblyopia is best treated early in life to achieve a successful outcome. A referral to a pediatric ophthalmologist for a formal eye exam and potential treatment is therefore recommended for children with isolated metopic craniosynostosis. PMID- 25436425 TI - Evolution of Postoperative Edema in Alveolar Graft Performed With Bone Morphogenetic Protein (rhBMP-2). AB - OBJECTIVE: To evaluate the evolution of facial edema in the postoperative period after alveolar graft surgeries performed with collagen membrane soaked with recombinant human bone morphogenetic protein-2 (rhBMP-2) in individuals with cleft lip and palate. DESIGN: Longitudinal prospective. SETTING: Tertiary craniofacial center. PARTICIPANTS: One hundred fifty individuals submitted to alveolar graft. INTERVENTIONS: In the preoperative consultation and 4 days after surgery, the individuals were assessed as to age, professional performing the surgery, duration of the procedure, type of cleft, measurement of facial edema, mouth opening, and global evaluation of the postoperative period. MAIN OUTCOME MEASURES: Statistical analysis was performed to compare the facial edema and different variables, at a significance level of .05. RESULTS: The maximum facial edema occurred between 3 and 4 days postoperatively, was inversely proportional to age and mouth opening, greater for female patients compared with male patients, for incomplete unilateral cleft lip and palate compared with other types of clefts, and for surgeon 1 compared with the other surgeons at some moment postoperatively. The surgeries were longer for complete unilateral and bilateral clefts. The difference was statistically significant for these variables. CONCLUSIONS: The facial edema was influenced by the rhBMP-2 used in alveolar graft, and trismus was proportional to the intensity of facial edema. PMID- 25436427 TI - Minimally Invasive Surgical Approaches for Esthetic Implant Dentistry: A Case Report. PMID- 25436424 TI - ApoE and pulse pressure interactively influence level and change in the aging of episodic memory: Protective effects among epsilon2 carriers. AB - OBJECTIVE: We tested independent and interactive effects of Apolipoprotein E (ApoE) and pulse pressure (PP) concurrently and longitudinally across 9 years (3 waves) of episodic (EM) and semantic memory (SM) data from the Victoria Longitudinal Study. METHOD: We assembled a sample of older adults (n = 570, baseline M age = 71, age range = 53-95) and used latent growth modeling to test 4 research goals. RESULTS: First, the best fitting memory model was 2 single latent variables for EM and SM, each exhibiting configural, metric, and partial scalar invariance. This model was analyzed as a parallel process model. Second, baseline level of PP predicted EM performance at centering age (75) and rate of 9-year EM change. Third, we observed no main effects of ApoE on EM or SM. Fourth, EM was affected by higher PP but differentially less so for carriers of the ApoE epsilon2 allele than the epsilon3 or epsilon4 alleles. CONCLUSIONS: PP is confirmed as a risk factor for concurrent and changing cognitive health in aging, but the effects operate differently across risk and protective allelic distribution of the ApoE gene. PMID- 25436428 TI - Sensitive troponin assay and the classification of myocardial infarction. AB - BACKGROUND: Lowering the diagnostic threshold for troponin is controversial because it may disproportionately increase the diagnosis of myocardial infarction in patients without acute coronary syndrome. We assessed the impact of lowering the diagnostic threshold of troponin on the incidence, management, and outcome of patients with type 2 myocardial infarction or myocardial injury. METHODS: Consecutive patients with elevated plasma troponin I concentrations (>=50 ng/L; n = 2929) were classified with type 1 (50%) myocardial infarction, type 2 myocardial infarction or myocardial injury (48%), and type 3 to 5 myocardial infarction (2%) before and after lowering the diagnostic threshold from 200 to 50 ng/L with a sensitive assay. Event-free survival from death and recurrent myocardial infarction was recorded at 1 year. RESULTS: Lowering the threshold increased the diagnosis of type 2 myocardial infarction or myocardial injury more than type 1 myocardial infarction (672 vs 257 additional patients, P < .001). Patients with myocardial injury or type 2 myocardial infarction were at higher risk of death compared with those with type 1 myocardial infarction (37% vs 16%; relative risk [RR], 2.31; 95% confidence interval [CI], 1.98-2.69) but had fewer recurrent myocardial infarctions (4% vs 12%; RR, 0.35; 95% CI, 0.26-0.49). In patients with troponin concentrations 50 to 199 ng/L, lowering the diagnostic threshold was associated with increased healthcare resource use (P < .05) that reduced recurrent myocardial infarction and death for patients with type 1 myocardial infarction (31% vs 20%; RR, 0.64; 95% CI, 0.41-0.99), but not type 2 myocardial infarction or myocardial injury (36% vs 33%; RR, 0.93; 95% CI, 0.75 1.15). CONCLUSIONS: After implementation of a sensitive troponin assay, the incidence of type 2 myocardial infarction or myocardial injury disproportionately increased and is now as frequent as type 1 myocardial infarction. Outcomes of patients with type 2 myocardial infarction or myocardial injury are poor and do not seem to be modifiable after reclassification despite substantial increases in healthcare resource use. PMID- 25436429 TI - Trans-Golgi protein p230/golgin-245 is involved in phagophore formation. AB - p230/golgin-245 is a trans-Golgi coiled-coil protein that is known to participate in regulatory transport from the trans-Golgi network (TGN) to the cell surface. We investigated the role of p230 and its interacting protein, microtubule actin crosslinking protein 1 (MACF1), in amino acid starvation-induced membrane transport. p230 or MACF1 knock-down (KD) cells failed to increase the autophagic flow rate and the number of microtubule-associated protein 1 light chain 3 (LC3) positive puncta under starvation conditions. Loss of p230 or MACF1 impaired mAtg9 recruitment to peripheral phagophores from the TGN, which was observed in the early step of autophagosome formation. Overexpression of the p230-binding domain of MACF1 resulted in the inhibition of mAtg9 trafficking in starvation conditions as in p230-KD or MACF1-KD cells. These results indicate that p230 and MACF1 cooperatively play an important role in the formation of phagophore through starvation-induced transport of mAtg9-containing membranes from the TGN. In addition, p230 itself was detected in autophagosomes/autolysosome with p62 or LC3 during autophagosome biogenesis. Thus, p230 is an important molecule in phagophore formation, although it remains unclear whether p230 has any role in late steps of autophagy. PMID- 25436431 TI - Direct determination of the redox status of cysteine residues in proteins in vivo. AB - The redox states of proteins in cells are key factors in many cellular processes. To determine the redox status of cysteinyl thiol groups in proteins in vivo, we developed a new maleimide reagent, a photocleavable maleimide-conjugated single stranded DNA (DNA-PCMal). The DNA moiety of DNA-PCMal is easily removed by UV irradiation, allowing DNA-PCMal to be used in Western blotting applications. Thereby the state of thiol groups in intracellular proteins can be directly evaluated. This new maleimide compound can provide information concerning redox proteins in vivo, which is important for our understanding of redox networks in the cell. PMID- 25436430 TI - The planar cell polarity effector protein Wdpcp (Fritz) controls epithelial cell cortex dynamics via septins and actomyosin. AB - Planar cell polarity (PCP) signaling controls polarized behaviors in diverse tissues, including the collective cell movements of gastrulation and the planar polarized beating of motile cilia. A major question in PCP signaling concerns the mechanisms linking this signaling cascade with more general cytoskeletal elements to drive polarized behavior. Previously, we reported that the PCP effector protein Wdpcp (formerly known as Fritz) interacts with septins and is critical for collective cell migration and cilia formation. Here, we report that Wdpcp is broadly involved in maintaining cortical tension in epithelial cells. In vivo 3D time-lapse imaging revealed that Wdpcp is necessary for basolateral plasma membrane stability in epithelial tissues, and we further show that Wdpcp controls cortical septin localization to maintain cortical rigidity in mucociliary epithelial cells. Finally, we show that Wdpcp acts via actomyosin to maintain balanced cortical tension in the epithelium. These data suggest that, in addition to its role in controlling plasma membrane dynamics in collective mesenchymal cell movements, Wdpcp is also essential for normal cell cortex stability during epithelial homeostasis. PMID- 25436432 TI - Analytical method for determining relative chaperone activity using an ovalbumin conjugated column. AB - Investigating the relative efficiencies of molecular chaperones is important for understanding protein biosynthesis inside a cell. We developed an analytical method for estimating relative chaperone activity under physiological, multi chaperone conditions using a protein-conjugated column. A chaperone mixture was subjected to chromatography on a column conjugated with denatured ovalbumin, and the elution positions of target chaperones were compared using western blotting to determine the relative affinity of each chaperone for the denatured protein. Because molecular chaperones should be eluted according to their strength of association with the denatured ovalbumin in the column, the elution position must accord with the chaperone activity and can be used as an indicator of relative chaperone activity. We found that the column procedure was effective in an assay of a mixture of calreticulin and BiP, the molecular chaperones in the endoplasmic reticulum; the assay showed that calreticulin associated with denatured ovalbumin more strongly than BiP. PMID- 25436434 TI - Rh(III)-Catalyzed Oxidative Coupling of Benzoic Acids with Geminal-Substituted Vinyl Acetates: Synthesis of 3-Substituted Isocoumarins. AB - The Rh(III)-catalyzed C-H activation initiated cyclization of benzoic acids with electron-rich geminal-substituted vinyl acetates was described. The reaction was employed to prepare a range of 3-aryl and 3-alkyl substituted isocoumarins selectively. PMID- 25436433 TI - The omega-3 fatty acid docosahexaenoic acid attenuates organic dust-induced airway inflammation. AB - Workers exposed to organic dusts from concentrated animal feeding operations (CAFOs) are at risk for developing airway inflammatory diseases. Available preventative and therapeutic measures for alleviating dust-induced lung disease are inadequate. Because omega-3 fatty acids can mitigate inflammatory processes, we aimed to determine whether nutritional supplementation with the omega-3 fatty acid docosahexaenoic acid (DHA) could reduce the airway inflammatory consequences of exposures to organic dust. Aqueous extracts of organic dusts from swine CAFOs (ODE) were utilized. In DHA-pretreated human bronchial epithelial cells, lung fibroblasts, monocyte cell cultures, and precision-cut murine lung slices, we found that DHA pretreatment dose-dependently decreased ODE-induced inflammatory cytokine production. To determine the in vivo significance of DHA, C57BL/6 mice were orally administered DHA for seven days prior to treatment with intranasal ODE or saline inhalations. Animals treated with 2 mg DHA demonstrated significant reductions in ODE-induced bronchial alveolar lavage neutrophil influx and pro inflammatory cytokine/chemokine production compared to mice exposed to ODE alone. Collectively, these data demonstrate that DHA affects several lung cells to reduce the airway inflammatory response to organic dust exposures. Dietary supplementation with DHA may be an effective therapeutic strategy to reduce the airway inflammatory consequences in individuals exposed to agriculture dust environments. PMID- 25436435 TI - Molecular Dynamics Simulations of Family 7 Cellobiohydrolase Mutants Aimed at Reducing Product Inhibition. AB - Enzymatic conversion of lignocellulosic biomass into biofuels and chemicals constitutes a potential route for sustainable development. Cellobiohydrolases are key enzymes used in industrial cocktails for depolymerization of crystalline cellulose, and their mechanism of action has been intensely studied in the past several years. Provided with a tunnel-like substrate-binding cavity, cellobiohydrolases possess the ability to processively hydrolyze glycosidic bonds of crystalline cellulose, yielding one molecule of cellobiose per catalytic cycle. As such, cellobiose expulsion from the product binding site is a necessary step in order to allow for the processive hydrolysis mechanism. However, the high affinity binding of cellobiose to the enzyme impairs the process and causes activity inhibition due to reaction products. Here, we use molecular dynamics simulations to study the binding of cellobiose to the Trichoderma reesei Cel7A (TrCel7A) cellobiohydrolase and the effects of mutations that reduce cellobiose binding, without affecting the structural and dynamical integrities of the enzyme. We observe that the product binding site exhibits an intrinsic flexibility that can sterically hinder cellobiose release. Several point mutations in the product binding site reduce cellobiose-enzyme interactions, but not all modifications are able to maintain the structural integrity of the enzyme. In particular, mutation of charged residues in the TrCel7A product binding site causes perturbations that affect the structure of the loops that form the substrate-binding tunnel of the enzyme and, hence, may affect TrCel7A function in other steps of the hydrolysis mechanism. Our results suggest there is a trade-off between product inhibition and catalytic efficiency, and they provide directions for cellulases engineering. PMID- 25436436 TI - Transcendental meditation for the primary prevention of cardiovascular disease. AB - BACKGROUND: A major determinant in cardiovascular disease (CVD) is stress. As transcendental meditation (TM) is thought to help in lowering negative stress indicators, it may be a beneficial strategy for the primary prevention of CVD. OBJECTIVES: To determine the effectiveness of TM for the primary prevention of CVD. SEARCH METHODS: We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 10); MEDLINE (Ovid) (1946 to week three November 2013); EMBASE Classic and EMBASE (Ovid) (1947 to week 48 2013); ISI Web of Science (1970 to 28 November 2013); and Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment Database and Health Economics Evaluations Database (November 2013). We also searched the Allied and complementary Medicine Database (AMED) (inception to January 2014) and IndMed (inception to January 2014). We handsearched trial registers and reference lists of reviews and articles and contacted experts in the field. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of at least three months' duration involving healthy adults or adults at high risk of CVD. Trials examined TM only and the comparison group was no intervention or minimal intervention. We excluded trials that involved multi factorial interventions. Outcomes of interest were clinical CVD events (cardiovascular mortality, all-cause mortality and non-fatal events) and major CVD risk factors (e.g. blood pressure and blood lipids, occurrence of type 2 diabetes, quality of life, adverse events and costs). DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion, extracted data and assessed the risk of bias. MAIN RESULTS: We identified four trials (four papers) (430 participants) for inclusion in this review. We identified no ongoing studies. The included trials were small, short term (three months) and at risk of bias. In all studies, TM was practised for 15 to 20 minutes twice a day.None of the included studies reported all-cause mortality, cardiovascular mortality or non-fatal endpoints as trials were short term, but one study reported survival rate three years after the trial was completed. In view of the considerable statistical heterogeneity between the results of the studies for the only outcomes reported, systolic blood pressure (I(2) = 72%) and diastolic blood pressure (I(2) = 66%), we decided not to undertake a meta-analysis. None of the four trials reported blood lipids, occurrence of type 2 diabetes, adverse events, costs or quality of life. AUTHORS' CONCLUSIONS: Currently, there are few trials with limited outcomes examining the effectiveness of TM for the primary prevention of CVD. Due to the limited evidence to date, we could draw no conclusions as to the effectiveness of TM for the primary prevention of CVD. There was considerable heterogeneity between trials and the included studies were small, short term and at overall serious risk of bias. More and larger long-term, high-quality trials are needed. PMID- 25436437 TI - Subsurface nanoimaging by broadband terahertz pulse near-field microscopy. AB - Combined with terahertz (THz) time-domain spectroscopy, THz near-field microscopy based on an atomic force microscope is a technique that, while challenging to implement, is invaluable for probing low-energy light-matter interactions of solid-state and biomolecular nanostructures, which are usually embedded in background media. Here, we experimentally demonstrate a broadband THz pulse near field microscope that provides subsurface nanoimaging of a metallic grating embedded in a dielectric film. The THz near-field microscope can obtain broadband nanoimaging of the subsurface grating with a nearly frequency-independent lateral resolution of 90 nm, corresponding to ~ lambda/3300, at 1 THz, while the AFM only provides a flat surface topography. PMID- 25436438 TI - Unplanned health care tourism. AB - Health care tourism is often a preplanned event carefully laying out all the details. Sometimes, when one least expects it, medical care is needed outside of the mainland. This Editorial speaks to an unplanned experience. PMID- 25436439 TI - Exploring indicators of use of costly health services in community-dwelling adults with multiple chronic conditions. AB - Although experts recognize that including patient functional and social variables would improve models predicting risk of using costly health services, these self reported variables are not widely used. PURPOSE OF STUDY: Explore differences in predisposing characteristics, enabling resources, patient-perceived need for care and professionally evaluated need for care variables between patients receiving primary care within a Health Care Home who did and did not use hospital, emergency department, or skilled nursing facility services in a 3-month period of time. PRIMARY PRACTICE SETTING(S): Primary care. METHODOLOGY AND SAMPLE: Guided by the Behavioral Model of Health Service Use, a secondary analysis was conducted on data from a study that included 57 community-dwelling older adults receiving primary care in a Health Care Home. Because of the exploratory nature of the study, group differences in the use of costly care services were compared at the 0.10 level of statistical significance. RESULTS: Seventeen patients (29.8%) experienced costly care services. The greatest number of differences in variables between groups was in the category of patient-perceived need for care (functional impairments, dependencies, difficulties). IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Targeting case management services using evidence-based decision support tools such as prediction models enhances the opportunity to maximize outcomes and minimize waste of resources. Patient-perceived and clinician evaluated need for care may need to be combined to fully describe the contextual needs that drive the use of health services. Difficulty with Activities with Daily Living and Instrumental Activities of Daily Living should be considered in future studies as candidate predictor variables for need for case management services in primary care settings. PMID- 25436441 TI - Exploring the effect of at-risk case management compensation on hospital pay-for performance outcomes: tools for change. AB - PURPOSE/OBJECTIVES: Acute care nurse case managers are charged with compliance oversight, managing throughput, and ensuring safe care transitions. Leveraging the roles of nurse case managers and social workers during care transitions translates into improved fiscal performance under the Affordable Care Act. This article aims to equip leaders in the field of case management with tools to facilitate the alignment of case management systems with hospital pay-for performance measures. A quality improvement project was implemented at a hospital in south Alabama to examine the question: for acute care case managers, what is the effect of key performance indictors using an at-risk compensation model in comparison to past nonincentive models on hospital readmissions, lengths of stay, and patient satisfaction surrounding the discharge process. PRIMARY PRACTICE SETTING(S): Inpatient acute care hospital. FINDINGS/CONCLUSIONS: The implementation of an at-risk compensation model using key performance indicators, Lean Six Sigma methodology, and Creative Health Care Management's Relationship Based Care framework demonstrated reduced length of stay, hospital readmissions, and improved patient experiences. IMPLICATIONS FOR CASE MANAGEMENT: Regulatory changes and new models of reimbursement in the acute care environment have created the perfect storm for case management leaders. Hospital fiscal performance is dependent on effective case management processes and the ability to optimize scarce resources. The quality improvement project aimed to further align case management systems and structures with hospital pay-for-performance measures. Tools for change were presented to assist leaders with the change acceleration process. PMID- 25436443 TI - A qualitative study of case management of children with asthma. AB - PURPOSE: The purpose of this study was to describe the process of case management delivered to Head-off Environmental Asthma in Louisiana (HEAL) study participants. PRIMARY PRACTICE SETTING: Participants' homes; community facilities (clinic and library meeting rooms, schools) in a post-Katrina environment. METHODOLOGY AND SAMPLE: A qualitative descriptive study consisted of analysis of existing data that describe the case management provided by HEAL asthma counselors to 151 children, aged 4-12 years, with moderate-severe asthma, and their families. The HEAL study (2006-09) was conducted in the New Orleans area after Hurricane Katrina. FINDINGS/CONCLUSIONS: Case management was intensive and comprehensive and consisted of asthma education, symptom management, addressing caretaker/participant/family issues, consistent follow-up, referrals, and goal setting. Several factors impacted the case management process, including caretaker beliefs, accessibility, and posthurricane issues. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Health care providers must recognize the complexity of case management in a postdisaster environment, consider the influence of social determinants and one's health literacy on asthma treatment adherence and outcomes, and develop models of case management to effectively manage children with asthma and their families. PMID- 25436444 TI - I have questions ... Do you have answers? PMID- 25436445 TI - Strategies for reducing hospitalization costs and improving health care access for veterans: the nurse practitioner-case manager collaboration. PMID- 25436446 TI - Taking a multidisciplinary approach to workers' compensation case management. PMID- 25436447 TI - Posttraumatic stress disorder in the combat veteran. PMID- 25436449 TI - Naked-eye detection and thermochromic properties of Cu(II)-3,3'-thiodipropionate complexes with benzimidazole. AB - Two new coordination complexes, namely, [Cu(tdp)(H2O)(bim)3].4H2O (1) and {[Cu(MU2-tdp)(bim)2].4H2O}n (2) (tdp = 3,3'-thiodipropionate, bim = benzimidazole), having naked-eye sensor properties and thermochromic behaviors, were synthesized and structurally characterized using elemental analysis, IR and UV spectra, and single-crystal X-ray diffraction, powder X-ray diffraction (PXRD) and thermal analyses (TG, DTA and DTG) techniques. Complex 1 changed color from blue to dark and light green in methanol and DMF solvents, respectively, while complex 2 changed color from light blue to light green only in DMF solvent. Moreover, complex 1 can be used to detect as little as 10 percent methanol in ethanol by the naked eye. The thermochromic properties of the complexes showed that complexes 1 and 2 changed color from blue and light blue to light and dark green at 65 degrees C, respectively. PMID- 25436448 TI - Intervention effects on diurnal cortisol rhythms of Child Protective Services referred infants in early childhood: preschool follow-up results of a randomized clinical trial. AB - IMPORTANCE: A number of interventions for at-risk children have shown benefits for children's hypothalamic-pituitary-adrenal axis activity immediately after treatment. It is critical to examine whether such changes are maintained over time, given that physiological regulation is implicated in later mental and physical health outcomes. OBJECTIVE: To examine whether differences in diurnal cortisol production between children receiving the active parenting intervention and children in the control group persisted at a preschool follow-up (approximately 3 years following intervention). DESIGN, SETTING, AND PARTICIPANTS: Between-subject comparison of cortisol patterns among 2 groups of children (experimental and control groups) involved with Child Protective Services following allegations of neglect. The participants included 115 children (43.5% female) between 46.5 and 69.6 months of age (mean [SD], 50.73 [4.98] months) who had been previously randomly assigned to either the Attachment and Biobehavioral Catch-up (ABC) intervention (n = 54) or the control intervention (n = 61). INTERVENTIONS: The experimental ABC intervention focused on 3 aims: increasing parental nurturance to child distress, increasing synchronous interactions, and decreasing frightening parental behavior. The control intervention provided educational information about child development to parents. Both interventions were manualized and involved 10 sessions implemented by a trained parent coach in the families' homes or other places of residence. MAIN OUTCOMES AND MEASURES: Salivary cortisol samples collected at waking and bedtime for children on 3 separate days. RESULTS: Analyses revealed significant differences in cortisol production at the preschool follow-up, such that children in the ABC intervention group showed more typical patterns of cortisol production than children in the control intervention group. Specifically, children in the ABC group exhibited higher mean (SD) log-transformed morning levels than children in the control group (-0.87 [0.45] vs -1.05 [0.43] MUg/dL, respectively [to convert to nanomoles per liter, multiply by 27.588]; beta = 0.18; P = .03). Bedtime cortisol levels did not differ significantly between the ABC and DEF groups (mean [SD], -1.19 [0.49] vs -1.17 [0.48] MUg/dL, respectively; beta01 = 0.01; P = .87). Those in the ABC group showed a steeper decline in cortisol across the day (mean, -0.31 MUg/dL) than those in the control group, who showed a blunted cortisol rhythm (mean, -0.12 MUg/dL) (beta = -0.19; P = .02). CONCLUSIONS AND RELEVANCE: Differences in cortisol production between the experimental and control groups persisted at the preschool follow-up and resembled differences initially observed 3 months following intervention. This is encouraging evidence that the ABC intervention for Child Protective Services-referred children may have long-lasting effects on a physiological stress system critical for health and adjustment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02093052. PMID- 25436450 TI - Potential of Live Spirulina platensis on Biosorption of Hexavalent Chromium and Its Conversion to Trivalent Chromium. AB - Microalga biomass has been described worldwide according their capacity to realize biosorption of toxic metals. Chromium is one of the most toxic metals that could contaminate superficial and underground water. Considering the importance of Spirulina biomass in production of supplements for humans and for animal feed we assessed the biosorption of hexavalent chromium by living Spirulina platensis and its capacity to convert hexavalent chromium to trivalent chromium, less toxic, through its metabolism during growth. The active biomass was grown in Zarrouk medium diluted to 50% with distilled water, keeping the experiments under controlled conditions of aeration, temperature of 30 degrees C and lighting of 1,800 lux. Hexavalent chromium was added using a potassium dichromate solution in fed-batch mode with the aim of evaluate the effect of several additions contaminant in the kinetic parameters of the culture. Cell growth was affected by the presence of chromium added at the beginning of cultures, and the best growth rates were obtained at lower metal concentrations in the medium. The biomass removed until 65.2% of hexavalent chromium added to the media, being 90.4% converted into trivalent chromium in the media and 9.6% retained in the biomass as trivalent chromium (0.931 mg.g(-1)). PMID- 25436451 TI - New instruments for lenticule extraction in small incision lenticule extraction (SMILE). AB - Small incision lenticule extraction (SMILE) is an alternative to Laser-Assisted in situ Keratomileusis (LASIK) for correction of myopia. In cases where surgeons inadvertently dissect the posterior surface first, identification of the anterior surface and subsequent removal become difficult since the anterior surface of the lenticule is compacted against the anterior stromal surface. This may result in incomplete lenticule removal, and a remnant of intrastromal lenticule in SMILE may lead to visual sequelae. In order to aid surgeons in lenticule removal, we have designed and developed 5 novel SMILE lenticule strippers to locate and extract the lenticules more easily. The aim of this study was to investigate and compare the efficacy and quality of these lenticule strippers in assisting SMILE. Thirty porcine eyes were used. The ease of extraction and removal of the lenticule with different strippers was graded by an experienced SMILE surgeon, the extracted lenticule circularity was evaluated by calculating the lenticule circularity, and the intactness of the extracted lenticule edge was assessed using scanning electron microscopy. We found these novel strippers can be of great help to improve the safety and quality of SMILE surgery, particularly in those cases of difficult lenticule extraction. PMID- 25436454 TI - Remotely monitoring change in vegetation cover on the Montebello Islands, Western Australia, in response to introduced rodent eradication. AB - The Montebello archipelago consists of 218 islands; 80 km from the north-west coast of Western Australia. Before 1912 the islands had a diverse terrestrial fauna. By 1952 several species were locally extinct. Between 1996 and 2011 rodents and cats were eradicated, and 5 mammal and 2 bird species were translocated to the islands. Monitoring of the broader terrestrial ecosystem over time has been limited. We used 20 dry-season Landsat images from 1988 to 2013 and estimation of green fraction cover in nadir photographs taken at 27 sites within the Montebello islands and six sites on Thevenard Island to assess change in vegetation density over time. Analysis of data averaged across the 26-year period suggests that 719 ha out of 2169 ha have increased in vegetation cover by up to 32%, 955 ha have remained stable and 0.6 ha have declined in vegetation cover. Over 492 ha (22%) had no vegetation cover at any time during the period analysed. Chronological clustering analysis identified two breakpoints in the average vegetation cover data occurring in 1997 and 2003, near the beginning and end of the rodent eradication activities. On many islands vegetation cover was declining prior to 1996 but increased after rodents were eradicated from the islands. Data for North West and Trimouille islands were analysed independently because of the potential confounding effect of native fauna being introduced to these islands. Mala (Lagorchestes hirsutus) and Shark Bay mice (Pseudomys fieldi) both appear to suppress native plant recruitment but not to the same degree as introduced rodents. Future research should assess whether the increase in vegetation cover on the Montebello islands is due to an increase in native or introduced plants. PMID- 25436452 TI - Resveratrol enhances palmitate-induced ER stress and apoptosis in cancer cells. AB - BACKGROUND: Palmitate, a saturated fatty acid (FA), is known to induce toxicity and cell death in various types of cells. Resveratrol (RSV) is able to prevent pathogenesis and/or decelerate the progression of a variety of diseases. Several in vitro and in vivo studies have also shown a protective effect of RSV on fat accumulation induced by FAs. Additionally, endoplasmic reticulum (ER) stress has recently been linked to cellular adipogenic responses. To address the hypothesis that the RSV effect on excessive fat accumulation promoted by elevated saturated FAs could be partially mediated by a reduction of ER stress, we studied the RSV action on experimentally induced ER stress using palmitate in several cancer cell lines. PRINCIPAL FINDINGS: We show that, unexpectedly, RSV promotes an amplification of palmitate toxicity and cell death and that this mechanism is likely due to a perturbation of palmitate accumulation in the triglyceride form and to a less important membrane fluidity variation. Additionally, RSV decreases radical oxygen species (ROS) generation in palmitate-treated cells but leads to enhanced X-box binding protein-1 (XBP1) splicing and C/EBP homologous protein (CHOP) expression. These molecular effects are induced simultaneously to caspase 3 cleavage, suggesting that RSV promotes palmitate lipoapoptosis primarily through an ER stress-dependent mechanism. Moreover, the lipotoxicity reversion induced by eicosapentaenoic acid (EPA) or by a liver X receptor (LXR) agonist reinforces the hypothesis that RSV-mediated inhibition of palmitate channeling into triglyceride pools could be a key factor in the aggravation of palmitate induced cytotoxicity. CONCLUSIONS: Our results suggest that RSV exerts its cytotoxic role in cancer cells exposed to a saturated FA context primarily by triglyceride accumulation inhibition, probably leading to an intracellular palmitate accumulation that triggers a lipid-mediated cell death. Additionally, this cell death is promoted by ER stress through a CHOP-mediated apoptotic process and may represent a potential anticancer strategy. PMID- 25436453 TI - P21-activated kinase 7 mediates cisplatin-resistance of esophageal squamous carcinoma cells with Aurora-A overexpression. AB - Aurora-A overexpression is common in various types of cancers and has been shown to be involved in tumorigenesis through different signaling pathways, yet how the deregulation affects cancer therapeutics remains elusive. Here we showed that overexpression of Aurora-A rendered esophageal cancer cells resistance to cisplatin (CDDP) by inhibiting apoptosis. By using an apoptosis array, we identified a downstream gene, p21-activated kinase 7 (PAK7). PAK7 was upregulated by Aurora-A overexpression at both mRNA and protein levels. Importantly, the expression levels of Aurora-A and PAK7 were correlated in ESCC primary samples. Chromatin immunoprecipitation (ChIP) assay revealed that binding of E2F1 to the promoter of PAK7 was significantly enhanced upon Aurora-A activation, and knockdown of transcription factor E2F1 decreased PAK7 expression, suggesting that Aurora-A regulated PAK7 through E2F1. Furthermore, we demonstrated that PAK7 knockdown led to increased apoptosis, and Aurora-A-induced resistance to CDDP was reversed by downregulation of PAK7, suggesting PAK7 was a downstream player of Aurora-A that mediated chemoresistance of ESCC cells to CDDP. Our data suggest that PAK7 may serve as an attractive candidate for therapeutics in ESCC patients with Aurora-A abnormality. PMID- 25436455 TI - Douglas-fir seedlings exhibit metabolic responses to increased temperature and atmospheric drought. AB - In the future, periods of strongly increased temperature in concert with drought (heat waves) will have potentially detrimental effects on trees and forests in Central Europe. Norway spruce might be at risk in the future climate of Central Europe. However, Douglas-fir is often discussed as an alternative for the drought and heat sensitive Norway spruce, because some provenances are considered to be well adapted to drier and warmer conditions. In this study, we identified the physiological and growth responses of seedlings from two different Douglas-fir provenances to increased temperature and atmospheric drought during a period of 92 days. We analysed (i) plant biomass, (ii) carbon stable isotope composition as an indicator for time integrated intrinsic water use efficiency, (iii) apparent respiratory carbon isotope fractionation as well as (iv) the profile of polar low molecular metabolites. Plant biomass was only slightly affected by increased temperatures and atmospheric drought but the more negative apparent respiratory fractionation indicated a temperature-dependent decrease in the commitment of substrate to the tricarboxylic acid cycle. The metabolite profile revealed that the simulated heat wave induced a switch in stress protecting compounds from proline to polyols. We conclude that metabolic acclimation successfully contributes to maintain functioning and physiological activity in seedlings of both Douglas-fir provenances under conditions that are expected during heat waves (i.e. elevated temperatures and atmospheric drought). Douglas-fir might be a potentially important tree species for forestry in Central Europe under changing climatic conditions. PMID- 25436456 TI - Recommendations for the regionalizing of coffee cultivation in Colombia: a methodological proposal based on agro-climatic indices. AB - The Colombian National Federation of Coffee Growers (FNC) conducted an agro ecological zoning study based on climate, soil, and terrain of the Colombian coffee-growing regions (CCGR) located in the tropics, between 1 degrees and 11.5 degrees N, in areas of complex topography. To support this study, a climate baseline was constructed at a spatial resolution of 5 km. Twenty-one bioclimatic indicators were drawn from this baseline data and from yield data for different coffee genotypes evaluated under conditions at eight experimental stations (ESs) belonging to the National Center for Coffee Research (CENICAFE). Three topographic indicators were obtained from a digital elevation model (DEM). Zoning at a national level resulted in the differentiation of 12 agro-climatic zones. Altitude notably influenced zone differentiation, however other factors such as large air currents, low-pressure atmospheric systems, valleys of the great rivers, and physiography also played an important role. The strategy of zoning according to coffee-growing conditions will enable areas with the greatest potential for the development of coffee cultivation to be identified, criteria for future research to be generated, and the level of technology implementation to be assessed. PMID- 25436457 TI - Free thyroxine level as an independent predictor of infection-related mortality in patients on peritoneal dialysis: a prospective multicenter cohort study. AB - BACKGROUND: Previous studies have reported the relationship between thyroid hormone levels and mortality in dialysis patients. However, little is known about the association of free thyroxine (fT4) and mortality in patients on peritoneal dialysis (PD). This study investigated the association between basal and annual variation in fT4 level and mortality in PD patients. METHODS: Patients on maintenance PD were enrolled from a prospective multicenter cohort study in Korea; their serum triiodothyronine, fT4, and thyroid-stimulating hormone levels were measured 12 months apart. Patients with overt thyroid disease and those receiving thyroid hormone replacement therapy were excluded from the analysis. Patients were divided into two groups based on the median levels of fT4. The differences of all-cause, infection-related, and cardiovascular mortalities were analyzed between the two groups. The association of basal levels and annual variation with mortality was investigated with Kaplan-Meier curves and Cox proportional hazard models. RESULTS: Among 235 PD patients, 31 (13.2%) deaths occurred during the mean follow-up period of 24 months. Infection (38.7%) was the most common cause of death. Lower basal fT4 levels were an independent predictor of all-cause and infection-related death (hazard ratio [HR] = 2.74, 95% confidence interval [CI] 1.27-5.90, P = 0.01, and HR = 6.33, 95% CI 1.16-34.64, P = 0.03, respectively). Longitudinally, patients with persistently lower fT4 levels during the 12-month period had significantly higher all-cause mortality than those with persistently higher levels (HR = 3.30, 95% CI 1.15-9.41, P = 0.03). The area under the receiver operating characteristic curve of fT4 for predicting all-cause and infection-related mortality was 0.60 and 0.68, respectively. CONCLUSIONS: fT4 level is an independent predictor of mortality and is especially attributable to infection in PD patients. This predictor was consistent when considering both baseline measurements and annual variation patterns. Close attention to infection in PD patients with relatively lower fT4 levels should be considered. PMID- 25436458 TI - Decreases in molecular diffusion, perfusion fraction and perfusion-related diffusion in fibrotic livers: a prospective clinical intravoxel incoherent motion MR imaging study. AB - PURPOSE: This study was aimed to determine whether pure molecular-based diffusion coefficient (D) and perfusion-related diffusion parameters (perfusion fraction f, perfusion-related diffusion coefficient D*) differ in healthy livers and fibrotic livers through intra-voxel incoherent motion (IVIM) MR imaging. MATERIAL AND METHODS: 17 healthy volunteers and 34 patients with histopathologically confirmed liver fibrosis patients (stage 1 = 14, stage 2 = 8, stage 3 & 4 = 12, METAVIR grading) were included. Liver MR imaging was performed at 1.5-T. IVIM diffusion weighted imaging sequence was based on standard single-shot DW spin echo-planar imaging, with ten b values of 10, 20, 40, 60, 80, 100, 150, 200, 400, 800 sec/mm2 respectively. Pixel-wise realization and regions-of-interest based quantification of IVIM parameters were performed. RESULTS: D, f, and D* in healthy volunteer livers and patient livers were 1.096+/-0.155 vs 0.917+/-0.152 (10(-3) mm2/s, p = 0.0015), 0.164+/-0.021 vs 0.123+/-0.029 (p<0.0001), and 13.085+/-2.943 vs 9.423+/ 1.737 (10(-3) mm2/s, p<0.0001) respectively, all significantly lower in fibrotic livers. As the fibrosis severity progressed, D, f, and D* values decreased, with a trend significant for f and D*. CONCLUSION: Fibrotic liver is associated with lower pure molecular diffusion, lower perfusion volume fraction, and lower perfusion-related diffusion. The decrease of f and D* in the liver is significantly associated liver fibrosis severity. PMID- 25436459 TI - Environmental lead exposure among preschool children in Shanghai, China: blood lead levels and risk factors. AB - OBJECTIVE: To determine blood lead levels and to identify related risk factors among children in Shanghai; to explore the lead change trend of children after industrial transformation and to provide data for policy development to control environmental lead pollution in Shanghai. METHODS: A stratified-clustered-random sampling method was used. A tungsten atomizer absorption spectrophotometer was employed to determine blood lead levels. RESULTS: The arithmetic mean, geometric mean and median of blood lead levels of 0- to 6-year-old children from Shanghai were 22.49 ug/L, 19.65 ug/L and 19.5 ug/L, including 0.26% (6/2291) with concentrations >=100 ug/L and 2.7% (61/2291) with concentrations >=50 ug/L. Boys' levels (23.57 ug/L) were greater than those of girls (21.2 ug/L). The blood lead levels increased with age. This survey showed that the Chongming district was the highest and Yangpu district was the lowest, this result is completely opposite with the earlier survey in Shanghai. Risk factors for lead contamination included housing environment, parents' education levels, social status, hobbies, and children's nutritional status. CONCLUSIONS: The blood lead levels of children in Shanghai were lower than the earlier data of Shanghai and those of published studies in China, but higher than the blood lead levels of developed countries. The blood lead levels of urban districts are higher than the central districts with the industrial transformation. Society and the government should take an active interest in childhood lead poisoning of urban areas. PMID- 25436460 TI - Reliability of pseudotyped influenza viral particles in neutralizing antibody detection. AB - BACKGROUND: Current influenza control strategies require an active surveillance system. Pseudotyped viral particles (pp) together with the evaluation of pre existing immunity in a population might satisfy this requirement. However, the reliability of using pp in neutralizing antibody (nAb) detection are undefined. METHODOLOGY/PRINCIPAL FINDINGS: Pseudotyped particles of A(H1N1)pmd09 (A/California/7/2009) and HPAI H5N1 (A/Anhui/1/2005), as well as their reassortants, were generated. The reliability of using these pp in nAb detection were compared concurrently with the corresponding viruses by a hemagglutination inhibition test, as well as ELISA-, cytopathic effect-, and fluorescence-based microneutralization assays. In the qualitative detection on nAbs, the pp and their corresponding viruses were in complete agreement, with an R2 value equal to or near 1 in two different populations. In the quantitative detection on nAbs, although the geometric mean titers (95% confidence interval) differed between the pp and viruses, no significant difference was observed. Furthermore, humoral immunity against the reassortants was evaluated; our results indicated strong consistency between the nAbs against reassortant pp and those against naive pp harboring the same hemagglutinin. CONCLUSION/SIGNIFICANCE: The pp displayed high reliability in influenza virus nAb detection. The use of reassortant pp is a safe and convenient strategy for characterizing emerging influenza viruses and surveying the disease burden. PMID- 25436461 TI - Coexpression of IQ-domain GTPase-activating protein 1 (IQGAP1) and Dishevelled (Dvl) is correlated with poor prognosis in non-small cell lung cancer. AB - BACKGROUND: IQ-domain GTPase-activating protein 1 (IQGAP1) binds to Dishevelled (Dvl) and functions as a modulator of Dvl nuclear localization in Xenopus embryos. However, the relationship between IQGAP1 and Dvl in tumor tissues is unclear. MATERIALS AND METHODS: We used immunohistochemistry to assess the expressions of IQGAP1 and Dvl in a cohort of 111 non-small cell lung cancer (NSCLC) patients. Association of their localization expressions with clinicopathological factors was also analyzed. RESULTS: The positive rate of IQGAP1 in primary tumors was 48.6% (54/111) for its cytoplamic expression, 9.0% (10/111) for nuclear expression and 31.5% (35/111) for membranous expression; the positive rate of Dvl was 65.8% (73/111) for cytoplamic expression, 9.9% (11/111) for nuclear expression and 10.8% (12/111) for membranous expression. Coexpression rate of IQGAP1 and Dvl was 77.8% (42/54) in the cytoplasm, 80.0% (8/10) in the nucleus and 8.6% (3/35) in the membrane. Coexpression of IQGAP1 and Dvl in the cytoplasm and nucleus were significantly correlated (P<0.05), but not in the membrane (P>0.05). The positive expression rates of cyclin D1 and c-myc were significantly higher in the group of IQGAP1 and Dvl coexpression in the nucleus than that in the cytoplasm. Coexpression rate of IQGAP1 and Dvl in the cytoplasm and nucleus was significantly higher in lymph nodal metastases (63.3%, 19/30) than in primary growths (38.3%, 31/81), correlating with poor prognosis. Five year survival time after resection in the group with their coexpression in the cytoplasm and nucleus was significantly lower than that with no coexpression (44.705+/-3.355 vs 58.403+/-2.543 months, p<0.05). CONCLUSIONS: Coexpression of IQGAP1 and Dvl in the cytoplasm and nucleus was correlated with the lymph nodal metastase and poor prognosis of NSCLC, and coexpression in nucleus might play a critical role in the activation of canonical Wnt pathway. PMID- 25436463 TI - Synthesis and specific fluoride binding properties of expanded dithiacalixphyrins. AB - Expanded dithiacalixphyrins with the N(2)S(2) core containing two sp(3) and three sp(2) meso-carbons have been prepared by condensation of one equivalent of butene 2,3-diyl-bisthiophene-2,5-diyl-bis(p-methoxyphenylmethanol) with one equivalent of 5,5'-dialkyldipyrromethane under mild acid catalyzed conditions in decent yields. The expanded dithiacalixphyrins were characterized by HR-MS, 1D and 2D NMR techniques and the structure of one of the expanded dithiacalixphyrin macrocycles was solved by X-ray crystallography. The crystal structure analysis indicated that the macrocycle is highly distorted and attains a boat shaped structure. The expanded thiacalixphyrins showed a specific sensing ability for F( ) ions over other anions as judged from absorption, NMR and mass spectral studies. PMID- 25436462 TI - The lonely mouse - single housing affects serotonergic signaling integrity measured by 8-OH-DPAT-induced hypothermia in male mice. AB - Male BALB/c mice single-housed for a period of three weeks were found to respond with a more marked hypothermia to a challenge with a selective serotonergic agonist (8-OH-DPAT) than their group-housed counterparts. This effect of single housing was verified by screening a genetically heterogeneous population of male mice on a C57BL/6 background from a breeding colony. Enhanced activity of the implicated receptor (5-HT1A) leading to an amplified hypothermic effect is strongly associated with depressive states. We therefore suggest that the 8-OH DPAT challenge can be used to demonstrate a negative emotional state brought on by e.g. long-term single housing in male laboratory mice. The study emphasizes the importance of social housing, and demonstrates that male mice deprived of social contact respond with altered serotonergic signaling activity. Male mice not only choose social contact when given the option, as has previously been shown, but will also, when it is deprived, be negatively affected by its absence. We propose that the 8-OH-DPAT challenge constitutes a simple, but powerful, tool capable of manifesting the effect of social deprivation in laboratory mice. It potentially allows not only for an unbiased, biochemical evaluation of psychological stressors, but may also allow for determining whether the effect of these can be counteracted. PMID- 25436464 TI - Combinatorialization of fungal polyketide synthase-peptide synthetase hybrid proteins. AB - The programming of the fungal polyketide synthase (PKS) is quite complex, with a simple domain architecture leading to elaborate products. An additional level of complexity has been found within PKS-based pathways where the PKS is fused to a single module nonribosomal peptide synthetase (NRPS) to synthesize polyketides conjugated to amino acids. Here, we sought to understand the communication between these modules that enable correct formation of polyketide-peptide hybrid products. To do so, we fused together the genes that are responsible for forming five highly chemically diverse fungal natural products in a total of 57 different combinations, comprising 34 distinct module swaps. Gene fusions were formed with the idea of testing the connection and compatibility of the PKS and NRPS modules mediated by the acyl carrier protein (ACP), condensation (C) and ketoreductase (KR) domains. The resulting recombinant gene fusions were analyzed in a high yielding expression platform to avail six new compounds, including the first successful fusion between a PKS and NRPS that make highly divergent products, and four previously reported molecules. Our results show that C domains are highly selective for a subset of substrates. We discovered that within the highly reducing (hr) PKS class, noncognate ACPs of closely related members complement PKS function. We intercepted a pre-Diels-Alder intermediate in lovastatin synthesis for the first time, shedding light on this canonical fungal biochemical reaction. The results of these experiments provide a set of ground rules for the successful engineering of hr-PKS and PKS-NRPS products in fungi. PMID- 25436465 TI - Prevalence and determinants of direct and generative modes of production of episodic future thoughts in the word cueing paradigm. AB - Recent research suggests that episodic future thoughts can be formed through the same dual mechanisms, direct and generative, as autobiographical memories. However, the prevalence and determinants of the direct production of future event representations remain unclear. Here, we addressed this issue by collecting self reports of production modes, response times (RTs), and verbal protocols for the production past and future events in the word cueing paradigm. Across three experiments, we found that both past and future events were frequently reported to come directly to mind in response to the cue, and RTs confirmed that events were produced faster for direct than for generative responses. When looking at the determinants of direct responses, we found that most past and future events that were directly produced had already been thought of on a previous occasion, and the frequency of previous thoughts predicted the occurrence of direct access. The direct production of autobiographical thoughts was also more frequent for past and future events that were judged important and emotionally intense. Collectively, these findings provide novel evidence that the direct production of episodic future thoughts is frequent in the word cueing paradigm and often involves the activation of personally significant "memories of the future." PMID- 25436466 TI - Metabolic pathway analysis approach: identification of novel therapeutic target against methicillin resistant Staphylococcus aureus. AB - Multiple Drug Resistant (MDR) bacteria are no more inhibited by the front line antibiotics due to extreme resistance. Methicillin Resistant Staphylococcus aureus (MRSA) is one of the MDR pathogens notorious for its widespread infection around the world. The high resistance acquired by MRSA needs a serious concern and efforts should be carried out for the discovery of better therapeutics. With this aim, we designed a comparison of the metabolic pathways of the pathogen, MRSA strain 252 (MRSA252) with the human host (i.e., Homo sapiens) by using well established in silico methods. We identified several metabolic pathways unique to MRSA (i.e., absent in the human host). Furthermore, a subtractive genomics analysis approach was applied for retrieval of proteins only from the unique metabolic pathways. Subsequently, proteins of unique MRSA pathways were compared with the host proteins. As a result, we have shortlisted few unique and essential proteins that could act as drug targets against MRSA. We further assessed the druggability potential of the shortlisted targets by comparing them with the DrugBank Database (DBD). The identified drug targets could be useful for an effective drug discovery phase. We also searched the sequences of unique as well as essential enzymes from MRSA in Protein Data Bank (PDB). We shortlisted at least 12 enzymes for which there was no corresponding deposition in PDB, reflecting that their crystal structures are yet to be solved! We selected Glutamate synthase out of those 12 enzymes owing to its participation in significant metabolic pathways of the pathogen e.g., Alanine, Aspartate, Glutamate and Nitrogen metabolism and its evident suitability as drug target among other MDR bacteria e.g., Mycobacteria. Due to the unavailability of any crystal structure of Glutamate synthase in PDB, we generated the 3D structure by homology modeling. The modeled structure was validated by multiple analysis tools. The active site of Glutamate synthase was identified by not only superimposing the template structure (PDB ID: 1E0A) over each other but also by the Parallel-ProBiS algorithm. The identified active site was further validated by cross-docking the co-crystallized ligand (2-oxoglutaric acid; AKG) of PDB ID: 1LLW. It was concluded that the comparative metabolic in silico analysis together with structure-based methods provides an effective approach for the identification of novel antibiotic targets against MRSA. PMID- 25436469 TI - Double [4 + 2] cycloaddition reaction to approach a large acene with even-number linearly fused benzene rings: 6,9,16,19-tetraphenyl-1.20,4.5,10.11,14.15 tetrabenzooctatwistacene. AB - It is more challenging to synthesize acenes with even-number fused benzene rings (AWEB) than acenes with odd-number fused benzene rings (AWOB) because AWEB are either synthetically asymmetric or the precursors to prepare AWEB are very difficult to obtain or to prepare from commercially available sources. In this work, we employed 2,6-naphthodiyne precursor (2) as an effective synthon to prepare a large AWEB, 6,9,16,19-tetraphenyl-1.20,4.5,10.11,14.15 tetrabenzooctatwistacene (1), through a simple, one-step, double [4 + 2] cycloaddition reaction. The physical properties of as-prepared octatwistacene (1) have been carefully studied, and the OLED performance of compound 1 was also investigated. PMID- 25436468 TI - Consensus review of the treatment of cardiovascular disease in people with hemophilia A and B. AB - With advances in care, increasing numbers of people with hemophilia (PWH) achieve near-normal life expectancies and present with typical age-related cardiovascular conditions. Evidence-based guidelines for medical or surgical management of cardiovascular conditions in individuals with hemophilia are limited. Published recommendations exist for the management of some common cardiovascular conditions (eg, ischemic heart disease, atrial fibrillation), but identifying optimal strategies for anticoagulant or antithrombotic therapy constitutes the primary challenge of managing nonoperative cardiovascular disease (CVD) in PWH. In general, as long as factor concentrates or other hemostatic therapies maintain adequate hemostasis, the recommended medical and surgical management of CVD in PWH parallels that in individuals without hemophilia. The presence of factor inhibitors complicates hemophilia management. Published outcomes of CVD treatment in PWH are similar to those in the general population. Specific knowledge about factor replacement, factor inhibitors, and disease-specific treatment distinguishes the cardiovascular care of PWH from similar care of individuals without this rare bleeding disorder. Furthermore, a multidisciplinary approach incorporating a hematologist with an onsite coagulation laboratory, ideally associated with a hemophilia treatment center, is integral to the management of CVD in PWH. PMID- 25436470 TI - External ventricular drain placement in the intensive care unit versus operating room: evaluation of complications and accuracy. AB - OBJECTIVE: External ventricular drain (EVD) placement is a common neurosurgical procedure performed in both the intensive care unit (ICU) and operating room (OR). The optimal setting for EVD placement in regard to safety and accuracy of placement is poorly defined. METHODS: A retrospective chart review was performed on 150 consecutive patients who underwent EVD placement at a tertiary care center from January of 2013 to February of 2014. Clinical and radiographic data were obtained and used to compare safety and accuracy of placement between EVDs placed in the ICU versus OR. RESULTS: One hundred and thirty eight patients were evaluated. Complications (hemorrhage, infection, non-functional drain) occurred in 21.5% of ICU placements and 6.7% of OR placements (p = 0.028). Grade 1, 2, and 3 placements occurred in 67.7%, 25.8%, and 6.5% of ICU placements, respectively, versus 55.6%, 42.2%, and 2.2% of OR placements (p = 0.258). No patient who received pre-placement antibiotics suffered a ventriculostomy associated infection (VAI). CONCLUSION: Patients who underwent ventriculostomy placement in the ICU differed in important ways (i.e. indication for placement and the administration of pre-procedure prophylactic antibiotics) from patients treated in the OR. However, the available data suggests that complications of hemorrhage, infection, and non-functional drains may be mitigated by ventriculostomy placement in the OR. PMID- 25436471 TI - Postoperative initial single fungal discitis progressively spreading to adjacent multiple segments after lumbar discectomy. AB - OBJECTIVE: To report multiple cases and investigate etiology of initially single fungal spondylodiscitis that progressively spread to adjacent segments following lumbar discectomy, resulting in multiple spinal involvements. METHODS: From January 2005 to May 2013, ten adult patients were admitted or referred to our institution with postoperative discitis. Fungal infections were confirmed by microbiologic and pathologic examinations. The clinical appearance, radiographic features, and treatments of this pathology were investigated. RESULTS: All the patients were previously healthy. The average interval between the occurrence of symptoms and primary lumbar discectomy was 61 days (range, 15-120 days). All the patients were treated with anterior surgical debridement, interbody fusion, and prolonged antifungal therapy. Three patients additionally received combined posterior instrumented fusion. Despite aggressive surgical debridement and antifungal therapy, spread of the infections to adjacent multiple discs was observed. No deaths, severe neurologic deficits, or deterioration of neurologic status were noted. The infections were completely resolved in all cases with spontaneous fusion within an average follow-up of 32.4 months. CONCLUSION: Fungal spondylodiscitis after surgery represents an intractable and troublesome complication, and surgical debridement may not impede the progression of the infection in cases where an insufficient course of antifungal treatment is administered. Such cases may require prolonged antifungal treatment with regular consultation by an infectious disease specialist. PMID- 25436472 TI - Epidemiology of cancers in Serbia and possible connection with cyanobacterial blooms. AB - Cyanobacteria produce toxic metabolites known as cyanotoxins. These bioactive compounds can cause acute poisoning, and some of them may promote cancer through chronic exposure. Direct ingestion of and contact with contaminated water is one of the many exposure routes to cyanotoxins. The aim of this article was to review the incidence of 13 cancers during a 10-year period in Serbia and to assess whether there is a correlation between the cancer incidences and cyanobacterial bloom occurrence in reservoirs for drinking water supply. The types of cancers were chosen and subjected to epidemiological analyses utilizing previously published data. Based on the epidemiological and statistical analysis, the group of districts in which the incidences of cancers are significant, and may be considered as critical, include Nisavski, Toplicki, and Sumadijski district. A significantly higher incidence of ten cancers was observed in the three critical districts as compared to the remaining 14 districts in Central Serbia. These elevated incidences of cancer include: brain cancer, heart, mediastinum and pleura cancer, ovary cancer, testicular cancer, gastric cancer, colorectal cancer, retroperitoneum and peritoneum cancer, leukemia, malignant melanoma of skin, and primary liver cancer. In addition, the mean incidence of five chosen cancers was the highest in the three critical regions, then in the rest of Central Serbia, while the lowest values were recorded in Vojvodina. Persistent and recurrent cyanobacterial blooms occur during summer months in reservoirs supplying water to waterworks in the three critical districts. People in Central Serbia mainly use surface water as water supply (but not all the water bodies are blooming) while in Vojvodina region (control region in this study) only groundwater is used. Among the 14 "noncritical" districts, reservoirs used for drinking water supply have been affected by recurrent cyanobacterial blooms in two districts (Rasinski and Zajecarski), but the waterworks in these districts have been performing ozonation for more than 30 years. We propose that the established statistical differences of cancer incidences in Serbia could be related to drinking water quality, which is affected by cyanobacterial blooms in drinking water reservoirs in certain districts. However, more detailed research is needed regarding cyanobacterial secondary metabolites as risk factors in tumor promotion and cancerogenesis in general. PMID- 25436473 TI - Chemoprevention against arsenic-induced mutagenic DNA breakage and apoptotic liver damage in rat via antioxidant and SOD1 upregulation by green tea (Camellia sinensis) which recovers broken DNA resulted from arsenic-H2O2 related in vitro oxidant stress. AB - Green tea (Camellia sinensis; CS) strongly reverses/prevents arsenic-induced apoptotic hepatic degeneration/micronecrosis and mutagenic DNA damage in in vitro oxidant stress model and in rat as shown by comet assay and histoarchitecture (HE and PAS staining) results. Earlier, we demonstrated a link between carcinogenesis and impaired antioxidant system-associated mutagenic DNA damage in arsenic exposed human. In this study, arsenic-induced (0.6 ppm/100 g body weight/day for 28 days) impairment of cytosolic superoxide-dismutase (SOD1), catalase, xanthine oxidase, thiol, and urate activities/levels led to increase in tissue levels of damaging malondialdehyde, conjugated dienes, serum necrotic-marker lactate dehydrogenase, and metabolic inflammatory-marker c-reactive protein suggesting dysregulation at the transcriptional/signal-transduction level. These are decisively restrained by CS-extract (>=10 mg/ml aqueous) with a restoration of DNA/tissue structure. The structural/functional impairment of dialyzed and centrifugally concentrated (6-8 kd cutoff) hepatic SOD1 via its important Cys modifications by H2O2/arsenite redox-stress and that protection by CS/2 mercaptoethanol are shown in in vitro/in situ studies paralleling the present Swiss-Model-generated rSOD1 structural data. Here, arsenite(3+) incubation (>=10( 8) MUM + 10 mM H2O2, 2 hr) is shown for the first time with this low concentration to initiate breakage in rat hepatic-DNA in vitro whereas, arsenite/H2O2/UV-radiation does not affect DNA separately. Arsenic initiates Fe and Cu ion-associated free-radical reaction cascade in vivo. Here, 10 MUM of Cu(2+)/Fe(3+)/As(3+) +H2O2-induced in vitro DNA fragmentation is prevented by CS (>=1 mg/ml), greater than the prevention of ascorbate or tocopherol or DMSO or their combination. Moreover, CS incubation for various time with differentially and already degraded DNA resulted from pre-incubation in 10 MUM As(3+)-H2O2 system markedly recovers broken DNA. Present results decisively suggest for the first time that CS and its mixed polyphenols have potent SOD1 protecting, diverse radical-scavenging and antimutagenic activities furthering to DNA protection/therapy in arsenic-induced tissue necrosis/apoptosis. PMID- 25436476 TI - A high-temperature dielectric process as a probe of large-scale silica filler structure in simplified industrial nanocomposites. AB - The existence of two independent filler-dependent high-temperature Maxwell-Wagner Sillars (MWS) dielectric processes is demonstrated and characterized in detail in silica-filled styrene-butadiene (SB) industrial nanocomposites of simplified composition using Broadband Dielectric Spectroscopy (BDS). The uncrosslinked samples are made with 140 kg mol(-1) SB-chains, half of which carry a single graftable end-function (50% D3), and Zeosil 1165 MP silica incorporated by solid phase mixing. While one high-temperature process is known to exist in other systems, the dielectric properties of a new silica-related process - strength, relaxation time, and activation energy - have been evidenced and described as a function of silica volume fraction and temperature. In particular, it is shown that its strength follows a percolation behavior as observed with the ionic conductivity and rheology. Moreover, activation energies show the role of polymer layers separating aggregates even when they are percolated. Apart from simultaneous characterization over a broad frequency range up to local polymer and silanol dynamics, it is believed that such high-temperature BDS-measurements can thus be used to detect reorganizations in structurally-complex silica nanocomposites. Moreover, they should contribute to a better identification of dynamical processes via the described sensitivity to structure in such systems. PMID- 25436474 TI - Metabolic activation of pyrrolizidine alkaloids leading to phototoxicity and photogenotoxicity in human HaCaT keratinocytes. AB - Pyrrolizidine alkaloids, produced by a large number of poisonous plants with wide global distribution, are associated with genotoxicity, tumorigenicity, and hepatotoxicity in animals and humans. Mammalian metabolism converts pyrrolizidine alkaloids to reactive pyrrolic metabolites (dehydropyrrolizidine alkaloids) that form covalent protein and DNA adducts. Although a mechanistic understanding is currently unclear, pyrrolizidine alkaloids can cause secondary (hepatogenous) photosensitization and induce skin cancer. In this study, the phototoxicity of monocrotaline, riddelliine, dehydromonocrotaline, dehydroriddelliine, and dehydroretronecine (DHR) in human HaCaT keratinocytes under ultraviolet A (UVA) irradiation was determined. UVA irradiation of HaCaT cells treated with dehydromonocrotaline, dehydroriddelline, and DHR resulted in increased release of lactate dehydrogenase and enhanced photocytotoxicity proportional to the UVA doses. UVA-induced photochemical DNA damage also increased proportionally with dehydromonocrotaline and dehydroriddelline. UVA treatment potentiated the formation of 8-hydroxy-2'-deoxyguanosine DNA adducts induced by dehydromonocrotaline in HaCaT skin keratinocytes. Using electron spin resistance trapping, we found that UVA irradiation of dehydromonocrotaline and dehydroriddelliine generates reactive oxygen species (ROS), including hydroxyl radical, singlet oxygen, and superoxide, and electron transfer reactions, indicating that cytotoxicity and genotoxicity of these compounds could be mediated by ROS. Our results suggest that dehydropyrrolizidine alkaloids formed or delivered to the skin cause pyrrolizidine alkaloid-induced secondary photosensitization and possible skin cancer. PMID- 25436477 TI - Photocatalytic and photoelectrocatalytic degradation of the antibacterial agent ciprofloxacin. AB - Photocatalytic and photoelectrocatalytic degradation of the antibacterial fluoroquinolone drug, ciprofloxacin, has been studied in the presence of nanocrystalline titania films supported on glass slides or transparent electrodes. The degradation has been examined either in pure water or in the presence of NaOH or NaCl. Titania films can photocatalytically or photoelectrocatalytically degrade ciprofloxacin. In the presence of NaOH, the degradation rate was lower than in pure water and this is explained by the fact that at high pH values attraction of ciprofloxacin to the titania surface is discouraged. In the presence of NaCl, the degradation rate was the highest, thanks to Cl-based radicals which can be photocatalytically created by interacting with photogenerated holes. Application of a forward (anodic) bias increased the photodegradation rate in the presence of both electrolytes while a reverse (cathodic) bias decreased the photodegradation rate. Electrocatalytic effects, i.e. degradation of ciprofloxacin in the dark or in the absence of a photocatalyst under an applied bias of up to +/-1.0 V vs. Ag/AgCl, were not detected in the case of NaOH and were of limited importance in the case of NaCl. PMID- 25436479 TI - A comparison of two methods to assess the usage of mobile hand-held communication devices. AB - The purposes of this study were to: 1) examine agreement between self-reported measures of mobile device use and direct measures of use, and 2) understand how respondents thought about their device use when they provided self-reports. Self reports of six categories of device use were obtained using a previously developed questionnaire, and direct measures of use were collected using a custom logging application (n = 47). Bland-Altman analyses were used to examine agreement between the two measurement approaches. Interviews targeted participants' experiences completing the device use section of the questionnaire. Self-reports of use on a typical day last week overestimated logged use. Overestimates tended to be low at low average usage times, and became more variable as usage time increased. Self-reports of use yesterday also exceeded logged use, however the degree of overestimation was less than for a typical day last week. Six themes were identified from interviews, including the thought process used by participants to arrive at usage and the ease of reporting usage. It is challenging for respondents of this questionnaire to provide accurate self reports of use. The source of this challenge may be attributed to the intrinsic difficulty of estimating use, partly due to the multiple functions of the devices as well as the variability of use both within a day and a week. Research investigating the relationship between device use and health outcomes should include a logging application to examine exposure simultaneously with self reports to better understand the sources of hazardous exposures. PMID- 25436478 TI - How is the serial order of a spatial sequence represented? Insights from transposition latencies. AB - How is the serial order of a spatial sequence represented in short-term memory (STM)? Previous research by Farrell and Lewandowsky (Farrell & Lewandowsky, 2004; Lewandowsky & Farrell, 2008) has shown that 5 alternative mechanisms for the representation of serial order can be distinguished on the basis of their predictions concerning the response times accompanying transposition errors. We report 3 experiments involving the output-timed serial recall of sequences of seen spatial locations that tested these predictions. The results of all 3 experiments revealed that transposition latencies are a negative function of transposition displacement, but with a reduction in the slope of the function for postponement, compared with anticipation errors. This empirical pattern is consistent with that observed in serial recall of verbal sequences reported by Farrell and Lewandowsky (2004), and with the predictions of a competitive queuing mechanism, within which serial order is represented via a primacy gradient of activations over items combined with associations between items and positional markers, and with suppression of items following recall. The results provide the first clear evidence that spatial and verbal STM rely on some common mechanisms and principles for the representation of serial order. PMID- 25436480 TI - Simple bone cysts: better with age? AB - PURPOSE: The purpose of this study was to evaluate whether simple bone cysts (SBC) resolve with age. METHODS: Twenty four subjects with SBC who participated in a prior randomized clinical trial but had not healed at trial conclusion were evaluated for cyst healing. The following clinical and radiographic data were evaluated: age, sex, pain (Visual Analogue Scale), functional health (Short Form 36), subsequent fracture, involved bone, cyst area (cm), distance from physis (cm), endosteal thickening (yes/no), scalloping (no new scalloping/new scalloping), opacity/radiolucency (as is), loculation (yes/no), trabeculation (yes/no), tubulation (yes/no), transition zone (sharp/wide), geographic borders (geographic nonpermeative/nongeographic permeative), radiodense rim (>50%/no rim), and growth plate status (open/closed). Cyst healing was graded as: 1-cyst clearly visible; 2-cyst visible but multilocular and opaque; 3-sclerosis around or within a partially visible cyst; or 4-complete healing with obliteration of cyst. Healing was defined as grade 4. RESULTS: Of 24 subjects, 15 (63%) were male, 18 (75%) cysts were located in the humerus, and 4 (25%) in the femur. Patients were followed for 7.0+/-1.0 years following initial treatment with a mean age at follow-up of 17.2+/-3.2 years and 14 (87%) of growth plates were closed. Pain was minimal (0.6/10), function was high (91/100), and none of the patients had experienced subsequent fractures. Although distance from physeal scar had increased (P<0.0001), cyst area reduction (P<0.1) and overall cyst healing (P<0.2) had not changed. Of the 24 subjects, none were graded as healed at time of follow-up. Of the remaining radiographic variables, only decreased loculation (P<0.02) and increased endosteal thickening (P<0.04) showed significant changes. CONCLUSION: Despite the assumption that most SBC will resolve with skeletal maturity, this study indicates that none of the cysts were graded as completely healed although 87% of growth plates were closed. SIGNIFICANCE: Growth plate closure may not signify healing of SBC and although symptoms and fractures are rare, further studies are needed to follow patients with SBC through early adulthood. PMID- 25436481 TI - The Factors Influencing the Refracture of Pediatric Forearms. AB - PURPOSE: Pediatric forearm fractures are common and usually heal uneventfully. The purpose of this study was to review the refracture rate and to identify trends and risk factors that may lead to a refracture. METHODS: Using current procedure terminology code and subsequent chart review we retrospectively identified 2590 patients who sustained forearm fractures over the past 10 years (2000 to 2010) and were treated at a single, large pediatric orthopaedic practice. RESULTS: We identified 37 patients who met our search criterion which yielded a refracture rate of 1.4%. Average length of immobilization was 72.2 days for initial fractures and 98.2 days for refractures. Average time to refracture after declared healing of initial injury was 128.7 days with 36% of refractures occurring within 6 weeks of clinical clearance. Fractures with >= 15 degrees angulation refractured earlier (mean 40 d). Seventy-one percent (71%) of patients with refractures had >= 10 degrees residual angulation at the time of union of the initial fracture. There was complete radiographic healing in 72% of patients that subsequently refractured. Forearm fractures that refractured most commonly occurred in the middle third (72%), with 24% in the proximal third and 4% in the distal third. Only 2 of 28 patients required surgical instrumentation of the forearm to achieve union of the refracture. We identified a trend toward longer immobilization and time to clinical clearance following a refracture, 76.4 versus 104.2 days. CONCLUSIONS: Over the past 10 years, our clinical data identifies a 1.4% refracture rate, which is significantly less than the previously published rate of 5%. Fractures with greater residual angulation (> 15 degrees) showed a tendency toward earlier refracture and may warrant longer immobilization. Forearm refractures united in most instances with closed treatment. Our treatment with cast or protective brace immobilization and limitation of activity until complete radiographic union likely influences our improved refracture rates. PMID- 25436482 TI - Kyphoplasty for Intractable Pain Due to Glucocorticosteroid-induced Osteoporotic Vertebra Fracture of a 9-Year-Old Patient With Systemic Lupus Erythematosus: 8 Year Follow-up. AB - BACKGROUND CONTEXT: The incidence of glucocorticoid-induced osteoporosis is approximately 50% in patients treated for >6 months, and in the long-term usage fracture risk is approximately 34%. The awareness of pediatric vertebral fractures due to glucocorticoid-induced osteoporosis is increasing. Although most of these fractures are asymptomatic, a small number of children may have severe pain. PURPOSE: In this case report we are presenting long-term result of a 9-year old patient with intractable pain due to glucocorticoid-induced osteoporotic vertebral fracture managed by kyphoplasty. STUDY DESIGN: Case report. PATIENT SAMPLE: Case report of a 9-year-old girl who had L3 vertebral fracture due to glucocorticoid-induced osteoporosis treated by kyphoplasty. METHODS: The patient was a 9-year-old girl with severe back pain, and lupus nephritis. Glucocorticoid induced L3 vertebral fracture was detected and the case was resistant to conservative treatment. Seeing this, we have performed balloon kyphoplasty procedure to L3 vertebrae. RESULTS: No complication and pain was observed after the operation although L3 vertebral height could not restored. On the 8-year control, L3 vertebral height was almost totally restored with a compression index of 10% without any clinical problem. CONCLUSIONS: To the best of the authors' knowledge, the patient sample of this case report is the first and the youngest patient who was treated with kyphoplasty for vertebral compression fracture intractable pain due to glucocorticoid-induced osteoporosis, mentioned in literature. During the 8-year follow-up, no adverse effect was reported that was related to kyphoplasty procedure. This case report indicates that kyphoplasty can be an alternative method for selective pediatric intractable painful vertebral glucocorticoid-induced osteoporotic fractures, but it should be performed after careful consideration in pediatric group. We do not advise routine usage of kyphoplasty for pediatric vertebral fractures. PMID- 25436483 TI - A quantitiative LC-MS/MS method for the measurement of arachidonic acid, prostanoids, endocannabinoids, N-acylethanolamines and steroids in human plasma. AB - Free arachidonic acid is functionally interlinked with different lipid signaling networks including those involving prostanoid pathways, the endocannabinoid system, N-acylethanolamines, as well as steroids. A sensitive and specific LC MS/MS method for the quantification of arachidonic acid, prostaglandin E2, thromboxane B2, anandamide, 2-arachidonoylglycerol, noladin ether, lineoyl ethanolamide, oleoyl ethanolamide, palmitoyl ethanolamide, steroyl ethanolamide, aldosterone, cortisol, dehydroepiandrosterone, progesterone, and testosterone in human plasma was developed and validated. Analytes were extracted using acetonitrile precipitation followed by solid phase extraction. Separations were performed by UFLC using a C18 column and analyzed on a triple quadrupole MS with electron spray ionization. Analytes were run first in negative mode and, subsequently, in positive mode in two independent LC-MS/MS runs. For each analyte, two MRM transitions were collected in order to confirm identity. All analytes showed good linearity over the investigated concentration range (r>0.98). Validated LLOQs ranged from 0.1 to 190ng/mL and LODs ranged from 0.04 to 12.3ng/mL. Our data show that this LC-MS/MS method is suitable for the quantification of a diverse set of bioactive lipids in plasma from human donors (n=32). The determined plasma levels are in agreement with the literature, thus providing a versatile method to explore pathophysiological processes in which changes of these lipids are implicated. PMID- 25436484 TI - A novel method for the simultaneous analysis of seven biothiols in rice (Oryza sativa L.) using hydrophilic interaction chromatography coupled with electrospray tandem mass spectrometry. AB - Analysis of biothiols is still problematic, due to their high polarity, oxidation sensitivity and time-consuming sample preparation. In this paper, a direct, rapid and sensitive method was developed for simultaneous quantification of unbound cysteine (Cys), glutathione (GSH) and phytochelatins (PCs) in rice leaf, stem and root samples by hydrophilic interaction chromatography coupled with electrospray tandem mass spectrometry (HILIC-MS/MS). Homogenized samples were extracted with water containing 50mM dithiothreitol, without derivatization and further clean up, and the extracts were injected directly onto an Xbridge Amide-HILIC column (3.5MUm, 150mm*2.1mm i.d.). The best chromatographic separation and MS sensitivity was achieved using a linear gradient elution with 10mM aqueous ammonium formate and acetonitrile as the mobile phase. In MS/MS mode the detection limit (S/N>=3) of seven biothiols was 3-105nM. Good linearities were observed (r>0.995) with linear dynamic range at least over three orders of magnitude. Recoveries for most analytes were within the range of 77-128%, with relative standard deviations less than 18.2%. The intra-day precision (n=7) was 6.1-11.7%, and the inter-day precision over 15 d (n=15) was 8.5-16.3% for all biothiols. The optimized HILIC-MS/MS method was applied to study the influence of different cadmium (Cd) concentrations (0, 1 and 50MUM) on contents of Cys, GSH and PC2-6 in rice tissue. With increasing Cd concentrations in nutrient solutions, contents of PC2-4 in rice roots increased but contents of Cys and GSH decreased. Contents of PC2-4 in both rice leafs and stems increased markedly at high dose Cd (50MUM) treatment compared with controls, compared with low Cd concentrations (1MUM). However, both PC5 and PC6 were not detected throughout the stress experiment. PMID- 25436485 TI - Global exponential stability of delayed Markovian jump fuzzy cellular neural networks with generally incomplete transition probability. AB - The problem of global exponential stability in mean square of delayed Markovian jump fuzzy cellular neural networks (DMJFCNNs) with generally uncertain transition rates (GUTRs) is investigated in this paper. In this GUTR neural network model, each transition rate can be completely unknown or only its estimate value is known. This new uncertain model is more general than the existing ones. By constructing suitable Lyapunov functionals, several sufficient conditions on the exponential stability in mean square of its equilibrium solution are derived in terms of linear matrix inequalities (LMIs). Finally, a numerical example is presented to illustrate the effectiveness and efficiency of our results. PMID- 25436486 TI - Robust sequential learning of feedforward neural networks in the presence of heavy-tailed noise. AB - Feedforward neural networks (FFNN) are among the most used neural networks for modeling of various nonlinear problems in engineering. In sequential and especially real time processing all neural networks models fail when faced with outliers. Outliers are found across a wide range of engineering problems. Recent research results in the field have shown that to avoid overfitting or divergence of the model, new approach is needed especially if FFNN is to run sequentially or in real time. To accommodate limitations of FFNN when training data contains a certain number of outliers, this paper presents new learning algorithm based on improvement of conventional extended Kalman filter (EKF). Extended Kalman filter robust to outliers (EKF-OR) is probabilistic generative model in which measurement noise covariance is not constant; the sequence of noise measurement covariance is modeled as stochastic process over the set of symmetric positive definite matrices in which prior is modeled as inverse Wishart distribution. In each iteration EKF-OR simultaneously estimates noise estimates and current best estimate of FFNN parameters. Bayesian framework enables one to mathematically derive expressions, while analytical intractability of the Bayes' update step is solved by using structured variational approximation. All mathematical expressions in the paper are derived using the first principles. Extensive experimental study shows that FFNN trained with developed learning algorithm, achieves low prediction error and good generalization quality regardless of outliers' presence in training data. PMID- 25436487 TI - Nanotextured stainless steel for improved corrosion resistance and biological response in coronary stenting. AB - Nanosurface engineering of metallic substrates for improved cellular response is a persistent theme in biomaterials research. The need to improve the long term prognosis of commercially available stents has led us to adopt a 'polymer-free' approach which is cost effective and industrially scalable. In this study, 316L stainless steel substrates were surface modified by hydrothermal treatment in alkaline pH, with and without the addition of a chromium precursor, to generate a well adherent uniform nanotopography. The modified surfaces showed improved hemocompatibility and augmented endothelialization, while hindering the proliferation of smooth muscle cells. Moreover, they also exhibited superior material properties like corrosion resistance, surface integrity and reduced metal ion leaching. The combination of improved corrosion resistance and selective vascular cell viability provided by nanomodification can be successfully utilized to offer a cell-friendly solution to the inherent limitations pertinent to bare metallic stents. PMID- 25436489 TI - Ophthalmic oncology: how to search, appraise, and report evidence. PMID- 25436488 TI - Changes in cognition and continence as predictors of rehabilitation outcomes in individuals with severe traumatic brain injury. AB - The study objective was to examine postacute changes in bowel and bladder continence and cognition after severe traumatic brain injury (TBI) in persons with long-term functional recovery to full independence. This case series included nine patients initially admitted to inpatient rehabilitation (IR) with severe TBI who had returned to prior responsibilities and functional independence by 8 to 15 mo. Patients had initial Glasgow Coma Scale scores of 3 to 6, posttraumatic amnesia durations of 18 to 70 d, time-to-follow-commands of 16 to 56 d, initial abnormal brain computed tomography scans, and initial pupil abnormalities. IR Functional Independence Measure (FIM) cognitive and sphincter score improvements were compared with national TBI FIM data from Uniform Data Systems for Medical Rehabilitation (UDSMR) for 2010 (n = 16,368). All patients had IR improvements in cognitive and sphincter FIM scores approximately twice the national UDSMR data for 2010. All patients had combined IR discharge sphincter FIM scores that were 12 or greater, indicating independence to modified independence with bowel and bladder function with no incontinence. Five participants (55%) were admitted to IR with sphincter FIM scores of 11 to 12, indicating recovery of continence during acute care. These findings suggest potential usefulness of IR cognitive FIM score changes and of the recovery of bowel and bladder continence for predicting favorable functional outcomes following severe TBI. PMID- 25436490 TI - Ocular surface squamous neoplasia: evidence for topical chemotherapy. PMID- 25436491 TI - Uveal melanoma: evidence for efficacy of therapy. PMID- 25436492 TI - Uveal melanoma: evidence for adjuvant therapy. PMID- 25436493 TI - Radiation chorioretinopathy: evidence for effective therapy. PMID- 25436494 TI - Retinoblastoma: evidence for stage-based chemotherapy. PMID- 25436495 TI - Retinoblastoma: evidence for postenucleation adjuvant chemotherapy. PMID- 25436496 TI - Ocular adnexal lymphoma: evidence-based treatment approach. PMID- 25436497 TI - Primary central nervous system lymphoma. PMID- 25436500 TI - Preface. PMID- 25436501 TI - Facile synthesis, metastable phase induced morphological evolution and crystal ripening, and structure-dependent photocatalytic properties of 3D hierarchical anatase superstructures. AB - Unique 3D hierarchical anatase TiO2 superstructures with evolvable morphologies and tunable sizes were successfully fabricated through a facile solvothermal route without using any structure-directing additives. A complex assembly process involving nucleation of nascent nanoparticles, agglomeration and ordered attachment of tiny nanocrystals, and regrowth induced by metastable crystal phase was put forward for the formation and morphology evolution of the anatase superstructures. It was revealed the crystalline phase experienced a ripening process from semicrystal to mesocrystal status accompanying the morphologies evolving from peony-like to chrysanthemum-like and eventually to spherical structures. The obtained 3D hierarchical anatase TiO2 superstructures exhibited superior photocatalytic activities for organic pollutant degradation, which could be largely attributed to the more efficient light-harvesting ability and the high specific surface area of the unique structures. PMID- 25436498 TI - Sentinel lymph node biopsy for eyelid and conjunctival tumors: what is the evidence? PMID- 25436502 TI - Coupled protein diffusion and folding in the cell. AB - When a protein unfolds in the cell, its diffusion coefficient is affected by its increased hydrodynamic radius and by interactions of exposed hydrophobic residues with the cytoplasmic matrix, including chaperones. We characterize protein diffusion by photobleaching whole cells at a single point, and imaging the concentration change of fluorescent-labeled protein throughout the cell as a function of time. As a folded reference protein we use green fluorescent protein. The resulting region-dependent anomalous diffusion is well characterized by 2-D or 3-D diffusion equations coupled to a clustering algorithm that accounts for position-dependent diffusion. Then we study diffusion of a destabilized mutant of the enzyme phosphoglycerate kinase (PGK) and of its stable control inside the cell. Unlike the green fluorescent protein control's diffusion coefficient, PGK's diffusion coefficient is a non-monotonic function of temperature, signaling 'sticking' of the protein in the cytosol as it begins to unfold. The temperature dependent increase and subsequent decrease of the PGK diffusion coefficient in the cytosol is greater than a simple size-scaling model suggests. Chaperone binding of the unfolding protein inside the cell is one plausible candidate for even slower diffusion of PGK, and we test the plausibility of this hypothesis experimentally, although we do not rule out other candidates. PMID- 25436503 TI - How to conduct a proper sensitivity analysis in life cycle assessment: taking into account correlations within LCI data and interactions within the LCA calculation model. AB - Sensitivity analysis (SA) is a significant tool for studying the robustness of results and their sensitivity to uncertainty factors in life cycle assessment (LCA). It highlights the most important set of model parameters to determine whether data quality needs to be improved, and to enhance interpretation of results. Interactions within the LCA calculation model and correlations within Life Cycle Inventory (LCI) input parameters are two main issues among the LCA calculation process. Here we propose a methodology for conducting a proper SA which takes into account the effects of these two issues. This study first presents the SA in an uncorrelated case, comparing local and independent global sensitivity analysis. Independent global sensitivity analysis aims to analyze the variability of results because of the variation of input parameters over the whole domain of uncertainty, together with interactions among input parameters. We then apply a dependent global sensitivity approach that makes minor modifications to traditional Sobol indices to address the correlation issue. Finally, we propose some guidelines for choosing the appropriate SA method depending on the characteristics of the model and the goals of the study. Our results clearly show that the choice of sensitivity methods should be made according to the magnitude of uncertainty and the degree of correlation. PMID- 25436506 TI - Serum Survival of Vibrio vulnificus: Role of Genotype, Capsule, Complement, Clinical Origin, and in Situ Incubation. AB - Virulence of the human pathogen, V. vulnificus, is associated with encapsulation, serum complement resistance, and genotype. The C-genotype of this bacterium is correlated (>90%) with virulence and with isolation source (clinical settings). E genotype strains are highly correlated with environmental isolation (93%) but appear less virulent. In this study, we characterized the importance of genotype, encapsulation, serum complement, and in situ exposure to estuarine water on the survival of the two genotypes in human serum. Results confirmed the superior ability of C-genotype strains to survive exposure to human serum, as well as the significance of complement, and revealed that lack of capsule allowed serum killing of both C- and E-genotypes. Cells incubated in situ responded similarly to cells incubated in vitro with the exception of E-environmental strains. Interestingly, our studies found that those cells of the E-genotype, typically considered non-pathogenic, which were isolated from wound infections demonstrated serum survival similar to that of virulent, C-genotype, strains. PMID- 25436505 TI - Evolution of antimicrobial peptides to self-assembled peptides for biomaterial applications. AB - Biomaterial-related infections are a persistent burden on patient health, recovery, mortality and healthcare budgets. Self-assembled antimicrobial peptides have evolved from the area of antimicrobial peptides. Peptides serve as important weapons in nature, and increasingly medicine, for combating microbial infection and biofilms. Self-assembled peptides harness a "bottom-up" approach, whereby the primary peptide sequence may be modified with natural and unnatural amino acids to produce an inherently antimicrobial hydrogel. Gelation may be tailored to occur in the presence of physiological and infective indicators (e.g. pH, enzymes) and therefore allow local, targeted antimicrobial therapy at the site of infection. Peptides demonstrate inherent biocompatibility, antimicrobial activity, biodegradability and numerous functional groups. They are therefore prime candidates for the production of polymeric molecules that have the potential to be conjugated to biomaterials with precision. Non-native chemistries and functional groups are easily incorporated into the peptide backbone allowing peptide hydrogels to be tailored to specific functional requirements. This article reviews an area of increasing interest, namely self-assembled peptides and their potential therapeutic applications as innovative hydrogels and biomaterials in the prevention of biofilm-related infection. PMID- 25436507 TI - Exploring PFGE for Detecting Large Plasmids in Campylobacter jejuni and Campylobacter coli Isolated from Various Retail Meats. AB - Campylobacter spp. is one of the most prevalent bacterial pathogens in retail meat, particularly poultry, and is a leading cause of diarrhea in humans. Studies related to Campylobacter large plasmids are limited in the literature possibly due to difficulty in isolating them using available alkaline lysis methods. The objectives of this study were to determine the prevalence of plasmids, particularly large ones, in Campylobacter spp. isolated from various Oklahoma retail meats, and to explore PFGE (Pulsed Field Gel Electrophoresis) as a tool in facilitating the detection of these plasmids. One hundred and eighty nine strains (94 Campylobacter jejuni and 95 Campylobacter coli) were screened for the presence of plasmids using both alkaline lysis and PFGE. Plasmids were detected in 119/189 (63%) using both methods. Most of the plasmids detected by alkaline lysis were smaller than 90 kb and only three were larger than 90 kb. Plasmids over 70 kb in size were detected in 33 more strains by PFGE of which 11 strains contained larger than 90 kb plasmids. Plasmids were more prevalent in Campylobacter coli (73.5%) than in Campylobacter jejuni (52%). BglII restriction analysis of plasmids isolated from 102 isolates revealed 42 different restriction patterns. In conclusion, PFGE was able to detect large plasmids up to 180 Kb in Campylobacter spp. which might have been missed if the alkaline lysis method was solely used. Campylobacter spp. isolated from retail meats harbor a diverse population of plasmids with variable sizes. To our knowledge, this is the first study to use PFGE to detect large plasmids in Campylobacter. PMID- 25436510 TI - First trimester cervical length is associated with mid-trimester loss. AB - OBJECTIVE: To study the value of the cervical length (CL) measurement at 11-14 weeks in predicting second trimester miscarriage occurring at 16-24 weeks. METHODS: Prospective study in routine obstetric population using transvaginal ultrasound examination to measure the length of the endocervical canal at 11-14 weeks. RESULTS: The study group consisted of 2836 singleton pregnancies. Eleven (0.0038%) women miscarried between 16 and 24 weeks whereas 2825 delivered after 34 weeks. CL was significantly shorter (Mann-Whitney U test, p = 0.001), in women that had a second trimester miscarriage in comparison to those who delivered after 34 weeks (median CL 28 mm versus 32 mm, respectively). First trimester CL was predictive of a late miscarriage (OR = 0.7093304, R(2 )= 0.1211, AUC = 0.7838, p < 0.001). The detection rate was 63.64% for 20% screen positive rate. CONCLUSIONS: First trimester endocervix is significantly shorter in women destined to miscarry between 16 and 24 weeks. In low risk singleton pregnancies, first trimester CL can be useful in predicting second trimester miscarriage. PMID- 25436511 TI - Copper-catalyzed/promoted cross-coupling of gem-diborylalkanes with nonactivated primary alkyl halides: an alternative route to alkylboronic esters. AB - The first copper-catalyzed/promoted sp(3)-C Suzuki-Miyaura coupling reaction of gem-diborylalkanes with nonactivated electrophilic reagents is reported. Not only 1, 1-diborylalkanes but also some other gem-diborylalkanes can be coupled with nonactivated primary alkyl halides, offering a new method for sp(3)C-sp(3)C bond formation and, simultaneously, providing a new strategy for the synthesis of alkylboronic esters. PMID- 25436512 TI - Assessment of colloid response by nonlinear optical microscopy after preoperative radiochemotherapy for rectal carcinoma. AB - Colloid response is a type of tumor response that occurs after preoperative radiochemotherapy for rectal carcinoma. Given its important influence on survival, the colloid response should be considered when estimating histopathological reactions. Here, multiphoton microscopy (MPM) was applied to evaluate the colloid response ex vivo. This study demonstrated that MPM has the capability to visualize the colloid response in the absence of labels and can, in particular, identify rare residual carcinomatous cells in mucin pools. These results highlight the potential of this nonlinear optical technique as a diagnostic tool for tumor response after neoadjuvant treatment. PMID- 25436508 TI - Animal models for influenza viruses: implications for universal vaccine development. AB - Influenza virus infections are a significant cause of morbidity and mortality in the human population. Depending on the virulence of the influenza virus strain, as well as the immunological status of the infected individual, the severity of the respiratory disease may range from sub-clinical or mild symptoms to severe pneumonia that can sometimes lead to death. Vaccines remain the primary public health measure in reducing the influenza burden. Though the first influenza vaccine preparation was licensed more than 60 years ago, current research efforts seek to develop novel vaccination strategies with improved immunogenicity, effectiveness, and breadth of protection. Animal models of influenza have been essential in facilitating studies aimed at understanding viral factors that affect pathogenesis and contribute to disease or transmission. Among others, mice, ferrets, pigs, and nonhuman primates have been used to study influenza virus infection in vivo, as well as to do pre-clinical testing of novel vaccine approaches. Here we discuss and compare the unique advantages and limitations of each model. PMID- 25436509 TI - Comparison of potato and asian citrus psyllid adult and nymph transcriptomes identified vector transcripts with potential involvement in circulative, propagative liberibacter transmission. AB - The potato psyllid (PoP) Bactericera cockerelli (Sulc) and Asian citrus psyllid (ACP) Diaphorina citri Kuwayama are the insect vectors of the fastidious plant pathogen, Candidatus Liberibacter solanacearum (CLso) and Ca. L. asiaticus (CLas), respectively. CLso causes Zebra chip disease of potato and vein-greening in solanaceous species, whereas, CLas causes citrus greening disease. The reliance on insecticides for vector management to reduce pathogen transmission has increased interest in alternative approaches, including RNA interference to abate expression of genes essential for psyllid-mediated Ca. Liberibacter transmission. To identify genes with significantly altered expression at different life stages and conditions of CLso/CLas infection, cDNA libraries were constructed for CLso-infected and -uninfected PoP adults and nymphal instars. Illumina sequencing produced 199,081,451 reads that were assembled into 82,224 unique transcripts. PoP and the analogous transcripts from ACP adult and nymphs reported elsewhere were annotated, organized into functional gene groups using the Gene Ontology classification system, and analyzed for differential in silico expression. Expression profiles revealed vector life stage differences and differential gene expression associated with Liberibacter infection of the psyllid host, including invasion, immune system modulation, nutrition, and development. PMID- 25436513 TI - Cationic poly(2-aminoethylmethacrylate) and poly(N-(2-aminoethylmethacrylamide) modified cellulose nanocrystals: synthesis, characterization, and cytotoxicity. AB - Cellulose nanocrystals (CNCs) continue to gain increasing attention in the materials community as sustainable nanoparticles with unique chemical and mechanical properties. Their nanoscale dimensions, biocompatibility, biodegradability, large surface area, and low toxicity make them promising materials for biomedical applications. Here, we disclose a facile synthesis of poly(2-aminoethylmethacrylate) (poly(AEM)) and poly(N-(2 aminoethylmethacrylamide) (poly(AEMA)) CNC brushes via the surface-initiated single-electron-transfer living radical polymerization technique. The resulting modified CNCs were characterized for their chemical and morphological features using a combination of analytical, spectroscopic, and microscopic techniques. Zeta potential measurements indicated a positive surface charge, and further proof of the cationic nature was confirmed by gold deposition as evidenced by electron microscopy. The cytotoxicity of these cationic modified CNCs was evaluated utilizing a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two different cell lines, J774A1 (mouse monocyte cells) and MCF-7 (human breast adenocarcinoma cells). The results indicated that none of the cationic modified CNCs decreased cell viability at low concentrations, which could be suitable for biomedical applications. PMID- 25436514 TI - Ritual risk: incense use and cardiovascular mortality. PMID- 25436515 TI - Prevalence and determinants of cardiovascular disease risk factors among the residents of urban community housing projects in Malaysia. AB - OBJECTIVES: The objectives are to assess the prevalence and determinants of cardiovascular disease (CVD) risk factors among the residents of Community Housing Projects in metropolitan Kuala Lumpur, Malaysia. METHOD: By using simple random sampling, we selected and surveyed 833 households which comprised of 3,722 individuals. Out of the 2,360 adults, 50.5% participated in blood sampling and anthropometric measurement sessions. Uni and bivariate data analysis and multivariate binary logistic regression were applied to identify demographic and socioeconomic determinants of the existence of having at least one CVD risk factor. RESULTS: As a Result, while obesity (54.8%), hypercholesterolemia (51.5%), and hypertension (39.3%) were the most common CVD risk factors among the low-income respondents, smoking (16.3%), diabetes mellitus (7.8%) and alcohol consumption (1.4%) were the least prevalent. Finally, the results from the multivariate binary logistic model illustrated that compared to the Malays, the Indians were 41% less likely to have at least one of the CVD risk factors (OR = 0.59; 95% CI: 0.37 - 0.93). CONCLUSION: In Conclusion, the low-income individuals were at higher risk of developing CVDs. Prospective policies addressing preventive actions and increased awareness focusing on low-income communities are highly recommended and to consider age, gender, ethnic backgrounds, and occupation classes. PMID- 25436516 TI - Women's health and fertility, family planning and pregnancy in immune-mediated rheumatic diseases: a report from a south-eastern European Expert Meeting. AB - With current advances in medical treatment, reproductive issues have become more important for women with chronic immune-mediated diseases. Most, if not all, patients report that their disease affects their personal relationships, their decision to have children, and the size of their family. These decisions are multi-factorial, influenced mainly by concerns over the effect of pregnancy on the rheumatic disease, the impact of disease activity during pregnancy on foetal health, the patient's ability to care for the child, and the possible harmful effects medication could have on the child, both pre- and post-natally during breastfeeding. Apart from that, women's health issues tend to be overlooked in favour of the management of the underlying rheumatic disease. To this end, we convened an expert panel to review the published literature on women's health and reproductive issues and provide evidence- and eminence-based points to consider for the treating physicians. We conclude that there is a need for a change in mind-set from one which 'cautions against pregnancy' to one which 'embraces pregnancy' through the practice of individualised, pre- and post-conceptual, multi-disciplinary care. PMID- 25436517 TI - Underlying substance abuse problems in drunk drivers. AB - OBJECTIVES: The aim of this study was to investigate polydrug use in drunk drivers. METHODS: The experimental study was conducted on 2,072 drunk drivers undergoing a driving license reissue protocol at the Department of Legal Medicine of Padova University Hospital in the period between January 2011 and December 2012. The study protocol involved anamnesis, clinical examination, toxicological history, and toxicological analyses on multiple biological samples. RESULTS: One thousand eight hundred seventy-seven subjects (90.6%) were assessed as fit to drive, and 195 (9.5%) were declared unfit. Among those unfit, 32 subjects (1.6%) were declared unfit due to recent use of an illicit drug (time span < 6 months), 23 (1.1%) spontaneously interrupted the protocol before its end, and 140 (6.8%) completed the assessment. Ineligibility to drive after completeness of the protocol was established in 1.2% of cases for alcohol disorders and in 5.7% of cases for illicit drug abuse; only one subject was included in both subgroups. Cocaine was the most widely used substance, followed by cannabis, opiates, and psychotropic pharmaceutical drugs. CONCLUSIONS: The application of the protocol presented in this study allowed the identification of underlying polydrug use in drunk drivers. The study led to the identification of 6.8% unfit subjects on the basis of alcohol disorders and/or drug abuse, compared to 1.2% of identifiable unfitness if the protocol were limited to the mere assessment of alcohol consumption. The frequent association of alcohol and cocaine is different from other patterns of use in North Europe countries. PMID- 25436520 TI - Memory impairment induced by amphetamine derivatives in laboratory animals and in humans: a review. AB - Abstract The 20th century brought with it the so-called club drugs (the most notorious being amphetamine derivatives), which are used by young adults at all night dance parties. Methamphet-amine and 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) are synthetic drugs with stimulant and psychoactive properties that belong to the amphetamine family. Here, we have reviewed the literature about the cognitive impairment induced by these two amphetamine derivatives and the preclinical and clinical outcomes. Although there is controversial evidence about the effect of methamphetamine and MDMA on learning and memory in laboratory animals, results from published papers demonstrate that amphetamines cause long term impairment of cognitive functions. A large number of pharmacological receptors have been studied and screened as targets of amphetamine-induced cognitive dysfunction, and extensive research efforts have been invested to provide evidence about the molecular mechanisms behind these cognitive deficits. In humans, there is a considerable body of evidence indicating that methamphetamine and MDMA seriously disrupt memory and learning processes. Although an association between the impairments of memory performance and a history of recreational amphetamine ingestion has also been corroborated, a number of methodological difficulties continue to hamper research in this field, the most important being the concomitant use of other illicit drugs. PMID- 25436521 TI - Shaping the CD4+ memory immune response against tuberculosis: the role of antigen persistence, location and multi-functionality. AB - Abstract Effective vaccination against intracellular pathogens, such as tuberculosis (TB), relies on the generation and maintenance of CD4 memory T cells. An incomplete understanding of the memory immune response has hindered the rational design of a new, more effective TB vaccine. This review discusses how the persistence of antigen, the location of memory cells, and their multifunctional ability shape the CD4 memory T cell response against TB. PMID- 25436518 TI - Selective inhibitors of the FK506-binding protein 51 by induced fit. AB - The FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is an established risk factor for stress-related psychiatric disorders such as major depression. Drug discovery for FKBP51 has been hampered by the inability to pharmacologically differentiate against the structurally similar but functional opposing homolog FKBP52, and all known FKBP ligands are unselective. Here, we report the discovery of the potent and highly selective inhibitors of FKBP51, SAFit1 and SAFit2. This new class of ligands achieves selectivity for FKBP51 by an induced-fit mechanism that is much less favorable for FKBP52. By using these ligands, we demonstrate that selective inhibition of FKBP51 enhances neurite elongation in neuronal cultures and improves neuroendocrine feedback and stress coping behavior in mice. Our findings provide the structural and functional basis for the development of mechanistically new antidepressants. PMID- 25436522 TI - Are synonymous codons indeed synonymous? AB - Abstract It has long been known that the distribution and frequency of occurence of synonymous codons can vary greatly among different species, and that the abundance of isoaccepting tRNA species could also be very different. The interaction of these two factors may influence the rate and efficiency of protein synthesis and therefore synonymous mutations might influence the fitness of the organism and cannot be treated generally as 'neutral' in an evolutionary sense. These general effects of synonymous mutations, and their possible role in evolution, have been discussed in several recent papers. This review, however, will only deal with the influence of synonymous codon replacements on the expression of individual genes. It will describe the possible mechanisms of such effects and will present examples demonstrating the existence and effects of each of these mechanisms. PMID- 25436519 TI - Intrinsic disorder drives N-terminal ubiquitination by Ube2w. AB - Ubiquitination of the alphaN-terminus of protein substrates has been reported sporadically since the early 1980s. However, the identity of an enzyme responsible for this unique ubiquitin (Ub) modification has only recently been elucidated. We show the Ub-conjugating enzyme (E2) Ube2w uses a unique mechanism to facilitate the specific ubiquitination of the alpha-amino group of its substrates that involves recognition of backbone atoms of intrinsically disordered N termini. We present the NMR-based solution ensemble of full-length Ube2w that reveals a structural architecture unlike that of any other E2 in which its C terminus is partly disordered and flexible to accommodate variable substrate N termini. Flexibility of the substrate is critical for recognition by Ube2w, and either point mutations in or the removal of the flexible C terminus of Ube2w inhibits substrate binding and modification. Mechanistic insights reported here provide guiding principles for future efforts to define the N-terminal ubiquitome in cells. PMID- 25436523 TI - MicroRNA-mediated gene silencing: are we close to a unifying model? AB - Abstract MicroRNAs (miRNAs) comprise a group of small non-coding RNA -21 nucleotides in length. They act as post-transcriptional regulators of gene expression by forming base pairing interactions with target messenger RNA (mRNA). At least 1000 miRNAs are predicted to be expressed in humans and are encoded for in the genome of almost all organisms. Functional studies indicate that every cellular process studied thus far is regulated at some level by miRNAs. Given this expansive role, it is not surprising that disruption of this crucial pathway underlies the initiation of, or in the least, contributes to the development and progression of numerous human diseases and physiological disorders. This review will focus on the latest developments in uncovering the mechanism(s) of miRNA mediated silencing with specific reference to the function of terminal effector proteins, how translation of target mRNA is inhibited and whether we are moving towards understanding this fundamental gene silencing paradigm. PMID- 25436524 TI - From head to toe of the norovirus 3C-like protease. AB - Abstract Noroviruses are major causative agents of viral gastroenteritis in humans. Currently, there are no therapeutic medications to treat noroviral infections, nor are there effective vaccines against these pathogens. The viral 3C-like protease is solely responsible for the maturation of viral protein components. The crystal structures of the proteases were resolved at high atomic resolution. The protease was also explored by means of mutagenesis. These studies revealed the active-site amino acid residues and factors determining and affecting substrate specificity as well as the principle of architecting the protease molecule. The possible mechanism of proteolysis was also suggested. Consideration of the data accumulated thus far will be useful for development of therapeutic drugs targeting the viral protease. PMID- 25436525 TI - Regulation of protein function by interfering protein species. AB - Abstract Most proteins do not function alone but act in protein complexes. For several transcriptional regulators, it is known that they have to homo- or heterodimerize prior to DNA binding. These protein interactions occur through defined protein-protein-interaction (PPI) domains. More than two decades ago, inhibitor of DNA binding (ID), a small protein containing a single helix-loop helix (HLH) motif was identified. ID is able to interact with the larger DNA binding basic helix-loop-helix (bHLH) transcription factors, but due to the lack of the basic domain required for DNA binding, ID traps bHLH proteins in non functional complexes. Work in plants has, in the recent years, identified more small proteins acting in analogy to ID. A hallmark of these small negative acting proteins is the presence of a protein-interaction domain and the absence of other functional domains required for transcriptional activation or DNA binding. Because these proteins are often very small and function in analogy to microRNAs (meaning in a dominant-negative manner), we propose to refer to these protein species as 'microProteins' (miPs). miPs can be encoded in the genome as individual transcription units but can also be produced by alternative splicing. Other negatively acting proteins, consisting of more than one domain, have also been identified, and we propose to call these proteins 'interfering proteins' (iPs). The aim of this review is to state more precisely how to discriminate miPs from iPs. Therefore, we will highlight recent findings on both protein species and describe their mode of action. Furthermore, miPs have the ability to regulate proteins of diverse functions, emphasizing their value as biotechnological tools. PMID- 25436526 TI - The universe of Hsp90. AB - Abstract Molecular chaperones are key components in the maintenance of cellular homeostasis and survival, not only during stress but also under optimal growth conditions. Among the ATP-dependent chaperones, heat shock proteins (Hsp90) proteins play a special role. While Hsp90s can interact with unfolded and misfolded proteins, their main (and in eukaryotic cells essential) function appears to involve interactions with a limited number of protein clients at late steps of maturation or in "alter-native" conformations for regulating their stability and activity. Because Hsp90 clients are hubs of diverse signaling networks and participate in nearly every cellular function, Hsp90s interconnect many regulatory circuits and link them to environmental impacts. The availability and activity of Hsp90 may thus influence complex physiological and pathophysiological processes, such as differentiation, development, aging, cancer, neurodegeneration, and infectious diseases. Furthermore, through homeostatic effects on differentiation and development, Hsp90s act as capacitors of phenotypic evolution. In this review, we discuss recent insights in the structure and chaperone cycle of Hsp90s, the mechanisms underlying Hsp90 binding to clients, and potential reasons why client proteins specifically require the assistance of Hsp90s. Moreover, the current views on Hsp90-cochaperone interactions and regulation of Hsp90 proteins via posttranslational modifications are summarized. The second half of this article is devoted to the role of Hsp90 proteins in health and disease, aging, and evolution. PMID- 25436527 TI - Stem cells for cardiac regeneration and possible roles of the transforming growth factor-beta superfamily. AB - Abstract Heart failure is a leading cause of death worldwide. Studies of stem cell biology are essential for developing efficient treatments. Recently, we established and characterized c-kit-positive cardiac stem cells from the adult rat heart. Using a MethoCult culture system with a methyl-cellulose-based medium, stem-like left-atrium-derived pluripotent cells could be regulated to differentiate into skeletal/cardiac myocytes or adipocytes with almost 100% purity. Microarray and pathway analyses of these cells showed that transforming growth factor-beta1 (TGF-beta1) and noggin were significantly involved in the differentiation switch. Furthermore, TGF-beta1 may act as a regulator for this switch because it simultaneously inhibits adipogenesis and activates myogenesis in a dose-dependent manner. However, the effect of TGF-beta varies with developmental stage, dosage, and timing of treatment. In the present review, the findings of recent studies, in particular the use of c-kit-positive cardiac stem cells, are discussed. The effects of the TGF-beta superfamily on differentiation, especially on adipogenesis and/or myogenesis, have important implications for future regenerative medicine. PMID- 25436528 TI - Structural diversity in the recognition between reduced thioredoxin and its oxidized enzyme partners. AB - Abstract Thioredoxins (Trx) are ubiquitous proteins that are conserved in all living organisms from archaea to humans. These small proteins display various cellular roles, including functioning as reductases in redox processes. All Trxs share a similar, characteristic three-dimensional fold with the Cys-Pro-Gly-Cys motif that contains both the catalytic and the resolving cysteine (Cys) on the surface of the protein. Reaction of reduced Trx with its oxidized protein partners leads to formation of a transient interdisulfide intermediate. However, the short lifetime of this species hinders the characterization of the stabilizing interactions that occur between the partners. In this short review, the three-dimensional structures of four artificial covalent Trx-protein partner complexes are analyzed. The data show that interprotein stabilization is mainly due to hydrophobic contacts and main-chain hydrogen bonds but that no common recognition motif between Trx and its protein partners can be identified. In two cases, formation of the Trx-partner complex is accompanied by a significant conformational change of the protein target, although in no case does the conformation of Trx change significantly. The absence of a common recognition motif supports the idea that it is difficult to predict with confidence putative oxidized protein substrates of Trx using only soft docking and molecular simulation methods. Instead, biochemical methods including proteomic approaches remain the primary tools to identify novel protein substrates of Trx. The generality and relevance of methods used to identify which of the two Cys of the disulfide-oxidized protein partner forms the transient interdisulfide intermediate with Trx are also discussed. PMID- 25436529 TI - Challenges in nutrition-related DNA methylation studies. AB - Abstract The rapid progress in nutritional epigenetics allowed for a much better understanding of the mechanisms involved in gene-nutrient interactions and the roles that nutrition has in transgenerational inheritance of acquired epigenetic traits. Studies indicated that a considerable number of nutrients or diet types are capable of inducing epimutations. In parallel, the rapid development of genome-wide DNA methylation detection methods allowed for a broader image on how nutrition impacts the epigenetic status in human and animal models. But this increased complexity in the epigenetic field and also brought important challenges that need resolution, or it suggests that some of the initial epigenetic paradigms have to be revisited or reconsidered. The aim of this review is to discuss the inherent challenges that need to be resolved, from both practical and theoretical aspects, stemming from the rapid progress in the field of nutritional epigenetics, with a focus on DNA methylation. Because such challenges are present at every stage of study development, the review systematically discusses the most common issues relevant to DNA methylation in a nutritional context. Various types of challenges and potential bias generators are discussed within study design, sample quality, detection methods, data processing, and statistical and bioinformatic analysis. Additional aspects to be considered include epigenetic heterogeneity of treatment groups, the role of genomic variability in introducing measurement bias and errors in interpretation of changes, and issues related to the final interpretation of results and in assigning functional significance. It is also posited that all these issues will be largely resolved within the next decade. PMID- 25436530 TI - Keratin function and regulation in tissue homeostasis and pathogenesis. AB - Abstract Epithelial tissues act as hubs in metabolism and communication and protect the organism against dehydration, infections, pharmacological and physical stress. Keratin intermediate filament proteins are well established as major cytoskeletal players in maintaining epithelial integrity. More recently, an involvement of keratins in growth control and organelle functions has emerged. Disruption of the keratin cytoskeleton by mutations or its reorganization following posttranslational modifications can render epithelia susceptible to tissue damage and various stresses, while loss of keratin expression is a hallmark of epithelial-mesenchymal transition (EMT). To understand the molecular mechanisms by which keratins perform their functions remains a formidable challenge. Based on selected examples, we will discuss how cell-specific expression of keratin isotypes affects cytoarchitecture and cell behavior. Further, we ask how posttranslational modifications alter keratin organization and interactions during signaling. Next, we discuss pathomechanisms of epidermal keratin disorders in the light of novel data. Finally, we raise open questions and point out future directives. PMID- 25436531 TI - Peptide-based rotaxanes and catenanes: an emerging class of supramolecular chemistry systems. AB - Abstract [2]Rotaxanes are interlocked molecular systems in which the cavity of a macrocycle (wheel) is threaded by a linear compound (axle). The axle is held in place principally by a sterically demanding moiety (stopper) at each end. If the two ends of a rotaxane are covalently linked together, then an assembly of two intertwined macrocycles (termed [2]catenane) is generated. Although rotaxanes and catenanes have been extensively investigated by several research groups, only a limited amount of studies has been devoted to these systems when a peptide molecule characterizes either the axle or the wheel(s) (or both). The purpose of this short conceptual overview is to summarize recent findings on synthetic and naturally occurring peptide-based [2]rotaxanes, [3]rotaxanes, and [2]catenanes and discuss future prospects for the research in this emerging area of supramolecular chemistry. PMID- 25436532 TI - Optogenetic electrophysiology: a new approach to combine cellular and systems physiology. AB - Abstract Optogenetics is the latest new subdiscipline in brain sciences that merges optical imaging, protein engineering and genetic dissection of neuronal circuits to optically monitor and control brain activity with high spatial and temporal precision. In this review, the conceptual framework that fueled the development of this methodology is first introduced and the central tools utilized in monitoring and controlling of neuronal circuit elements using light are described. How this innovative approach fosters our understanding of both physiological and pathophysiological properties of brain networks is then discussed. Finally, the potential clinical application of optogenetic approaches is outlined. PMID- 25436533 TI - The immortal strand hypothesis: still non-randomly segregating opinions. AB - Abstract Cairns first suggested a mechanism for protecting the genomes of stem cells (SCs) from replicative errors some 40 years ago when he proposed the immortal strand hypothesis, which argued for the inheritance of a so-called immortal strand by an SC following asymmetric SC divisions. To date, the existence of immortal strands remains contentious with published evidence arguing in favour of and against the retention of an immortal strand by asymmetrically dividing SCs. The conflicting evidence is derived from a diverse array of studies on adult SC types and is predominantly based on following the fate of labelled DNA strands during asymmetric cell division events. Here, we review current data, highlighting limitations of such labelling techniques, and suggest how interpretation of such data may be improved in the future. PMID- 25436534 TI - Endothelial senescence and microRNA. AB - Abstract Cellular senescence occurs when cells lose the ability to divide and proliferate. Endothelial cell senescence is associated with vascular diseases, such as atherosclerosis. In this review, I discuss the factors affecting endothelial cell senescence. Then I describe the role of microRNAs (miRNAs) in endothelial cell senescence. Understanding miRNA pathways in endothelial senescence may lead to new treatments for endothelial dysfunction and atherosclerosis. PMID- 25436535 TI - Focal adhesion kinase-regulated signaling events in human cancer. AB - Abstract Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that is highly expressed or activated in many human cancers. Under specific scenarios, FAK can regulate cell proliferation, cell survival, cell migration and invasion, and has been implicated in the control of tumorigenesis and metastasis. FAK has both catalytic and scaffolding activity, and triggers downstream signals by activation of a number of pathways, including the Ras/mitogen-activated protein kinase pathway, the phosphatidylinositol 3'-kinase/Akt pathway, and Rho family GTPases. Recent evidence also suggests novel signaling interactions between FAK and p53. These signaling events were defined primarily from studies on cells in culture, and elucidating which of these signaling pathways are pathologically relevant downstream of FAK in human cancer remains an important goal in determining the molecular mechanisms of tumorigenesis and metastasis. This review discusses select evidence of these signaling pathways with an emphasis on studies linking these to animal models of cancer and human disease. The role of FAK in the process of epithelial-to-mesenchymal transition and in cancer stem cells and recent therapeutic advances targeting FAK are also discussed. PMID- 25436536 TI - Molecular mechanisms of the glucocorticoid receptor in steroid therapy - lessons from transgenic mice. AB - Abstract Glucocorticoids (GCs) are potent anti-inflammatory agents that are used to treat chronic inflammatory diseases, allergic conditions, and some cancers. However, their therapeutic effects are hampered by severe side effects, such as muscle weakness, insulin resistance, fat redistribution, and osteoporosis. GCs act on many cell types that express the GC receptor (GR) via several modes of action. One of them includes GR homodimers recognizing binding sequences in the DNA of gene promoters. Another mode involves the modulation of other DNA-bound transcription factors via dimer-independent mechanisms. To what extent these mechanisms contribute to GC-mediated effects is currently being elucidated from analyses of mice with conditional and function-selective mutations of the GR and is summarized in this review. Whether GR homodimerization or its monomer activity is decisive in the therapeutic effectiveness and associated side effects of GCs for the treatment of inflammatory conditions depends on the type of the pathological condition. Thus, the classic criterion for selective GR modulators, discrimination between GR dimer- and GR monomer-dependent protein-protein interaction, will not help in any condition to avoid side effects and maintain anti-inflammatory activity. Rather, novel criteria for selective GR modulators have to be defined that take into consideration the tissue-specific mechanisms of the GR to achieve optimized anti-inflammatory therapies with reduced side effects. In the case of avoiding osteoporosis as a side effect, a first example of such optimized compounds can be provided. PMID- 25436537 TI - Peptide-nucleic acid nanostructures for transfection. AB - Abstract To use nucleic acids in biomedical research and medical applications, these highly hydrophilic macromolecules have to be transported through the organism, targeted to specific cell surfaces, and have to cross cellular barriers. To this end, nanosized transfection complexes have been designed and several of them have been successfully tested. Here, the different steps of the transfection process and the particular optimization protocols are reviewed, including the physicochemical properties of such vectors (size, charge, composition), protection in serum, cellular uptake, endosomal escape, and intracellular targeting. The transfection process has been subdivided into separate steps and here special emphasis is given to peptides that have been designed to optimize these steps individually. Finally, complex devices encompassing a multitude of beneficial functionalities for transfection have been developed. PMID- 25436538 TI - Pat1 proteins: regulating mRNAs from birth to death? AB - Abstract The Pat1 protein family has been the subject of several recent extensive investigations of diverse model systems ranging from yeast, flies and worms to man, using a variety of experimental approaches. Although some contradictions remain, the emerging consensus view is that these RNA-binding proteins act in mRNA decay by physically linking deadenylation with decapping and by regulating gene expression as translational repressors. These multiple functions are present in the single invertebrate Pat1 proteins, whereas, in vertebrates, one Pat1 variant represses translation in early development, while a somatic version synthesised in embrogenesis and in adults acts in mRNA decay. At steady state, Pat1 proteins are found enriched in cytoplasmic P(rocessing)-bodies, and related mRNP complexes and granules. Evidence recently obtained from mammalian tissue culture cells shows that Pat1 shuttles in and out of the nucleus, where it localises to nuclear speckles, PML bodies and nucleolar caps, which suggests RNA related nuclear functions. Less well understood, Pat1 proteins may play additional roles in miRNA silencing and/or biogenesis, as well in the regulation of viral gene expression. Due to the relatively low level of sequence conservation between Pat1 proteins from different species and lacking any discernable motifs, determining their functional domains has proved difficult, as is obtaining a simple unified view of the location of the binding sites of their interacting proteins in all examined species. Questions that remain to be addressed include the following: 1) What are their roles in the nucleus? 2) What is the link, if one exists, between their cytoplasmic and nuclear roles? 3) Do they have specific mRNA targets? 4) Which signalling pathways regulate their P body localisation in mammalian cells, which may affect quiescent cell survival? PMID- 25436539 TI - Small GTPase Ran and Ran-binding proteins. AB - Abstract Like many other small GTPases, Ran functions in eukaryotic cells as a molecular switch that cycles between GTP- and GDP-bound forms. Through the proper modulation of the GTP/GDP cycle, Ran functions with a number of Ran-binding proteins to control a broad array of fundamental cellular functions, including nucleocytoplasmic transport, mitotic spindle assembly, and nuclear envelope and nuclear pore complex formation. Recent studies have revealed that 'Ran and Ran binding proteins' are involved in a variety of functions involving cell fate determination, including cell death, cell proliferation, cell differentiation, and malignant transformation. In this review, we discuss recent progress on the functional link between the Ran system and tumorigenesis, which give clues to the molecular understanding of cancer biology. PMID- 25436540 TI - Multidrug resistance-associated ABC transporters - too much of one thing, good for nothing. AB - Abstract Overexpression of ATP-binding cassette (ABC) transporters in cancer cells results in multidrug resistance (MDR) which leads to unsuccessful chemotherapy. The most important MDR-associated members of ABC superfamily are ABC B1/P-glycoprotein/MDR1, ABC C1/multidrug resistance associated protein 1 (MRP1), and ABC G2/BCRP. This study is not only focused on function, substrates, and localization of these popular proteins but also on other ABC C family members such as ABC C2-6/MRP2-6 and ABC C7/CFTR. Current research is mainly oriented on the cancer-promoting role of these proteins, but important lessons could also be learned from the physiological roles of these proteins or from polymorphisms affecting their function. Thorough knowledge of structure and detailed mechanism of efflux can aid in the discovery of new chemotherapy targets in the future. Although the best way on how to deal with MDR would be to prevent its development, we describe some new promising strategies on how to conquer both inherited and induced MDRs. PMID- 25436541 TI - Role of extracellular matrix in regulating embryonic epithelial-mesenchymal transition. AB - Abstract Embryogenesis and morphogenesis are characterized by complex cell rearrangements and movements which require appropriate interactions of cells with the surrounding extracellular matrix (ECM) by means of specific membrane receptors. Interest in the identification and purification of ECM components, as well as in conducting functional studies of them, including their ligands and other molecules involved in cell-matrix adhesion, has intensified in recent years, increasing our knowledge of developmental machinery. Cellular movements play an important role during the epithelial-mesenchymal transition (EMT) events, which are key processes in normal embryogenesis as well as in pathological conditions, such as fibrotic diseases and cancer. Thus, to more fully understand mechanisms underlying the EMT process, and for better knowledge of the embryonic defects related to this process, it would be useful to study the substrates on which EMT cells move during embryo development. This review focuses on a few different embryonic systems, taking into account the cell migration that occurs during EMT and highlighting, in particular, studies describing the direct involvement of ECM molecules. PMID- 25436542 TI - Genomic and non-genomic actions of estrogen: recent developments. AB - Abstract Estrogen affects transcriptional status by activating its corresponding nuclear receptor, the estrogen receptor (ER). It can also induce rapid cellular reactions within a few minutes, and this feature cannot be explained by the transcription-mediated effects of estrogen. The latter mechanisms are called 'non genomic actions' of estrogen. In contrast, the former classic modes of action came to be called 'genomic actions'. One of the recent developments of research on estrogen was the substantiation of the non-genomic actions of estrogen; these were initially observed and reported as intriguing phenomena more than 40 years ago. The interacting molecules as well as the biological significance of non genomic actions have now been shown. In the field of genomic actions, invention and spread of new technologies, including high-throughput sequencers, promoted a comprehensive view of estrogen-mediated transcriptional regulation. PMID- 25436543 TI - Scavenger receptors: a key player in cardiovascular diseases. AB - Abstract The scavenger receptor (SR) super family consists of integral membrane glycoproteins that are involved in recognition of polyanionic structures of either endogenous (e.g., oxidized low-density lipoprotein) or exogenous (e.g., bacterial lipopolysaccharides) origin. SRs are structurally diverse and can be classified into seven different classes (A-G) based on the multidomain structure of the individual members. SRs are present on various types of tissues, such as vascular, adipose, and steroidogenic tissues. In addition to modified lipoprotein uptake, these proteins are also known to regulate apoptotic cell clearance, initiate signal transduction, and serve as pattern recognition receptors for pathogens. Different SRs are involved in many physiological and pathological processes; more importantly, the function of SRs is highly implicated in the initiation and progression of atherosclerotic plaque. Targeting the SR gene products that mediate the response to and uptake of modified lipids holds great promise in the prevention of cardiovascular diseases. Inhibition of SR expression using a combined gene therapy and RNA interference strategy also appears to be an option for long-term therapy. The present review focuses on the involvement of SRs in atherosclerosis, thrombosis, and other cardiovascular diseases. Moreover, the role of SRs is not restricted to vascular lesions; it is also implicated in a number of different cellular functions. PMID- 25436544 TI - Long telomeres: too much of a good thing. AB - Abstract Telomeres, the physical ends of linear eukaryotic chromosomes, protect chromosome ends from end fusions and degradation. Telomere length is tightly regulated to ensure that telomeres are neither too short nor too long. Short telomeres are preferentially elongated by the enzyme telomerase. In the absence of telomerase, telomeres progressively shorten with each round of cell division. Critically shortened telomeres lose their ability to protect chromosome ends, inducing cell cycle arrest and senescence. While the consequences and cellular response to short telomeres are frequently explored, long telomeres also pose problems and cells have evolved mechanisms to shorten over-elongated telomeres. These aspects of long telomeres are discussed in this short conceptual overview. PMID- 25436545 TI - Tet proteins: on track towards DNA demethylation? AB - Abstract Dynamic DNA methylation is a prerequisite for many developmental processes and maintenance of cellular integrity. In mammals however, mechanisms of active DNA demethylation have for long been elusive. The discovery of the ten eleven translocation (Tet) family of enzymes that oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) or 5-carboxylcytosine (5caC) provided new means by which DNA methylation could actively be reversed. This review focuses on the possible mechanisms of DNA demethylation via Tet proteins and their metabolites 5hmC, 5fC and 5caC. Additionally, it discusses the roles of the three Tet protein family members Tet1, Tet2 and Tet3 as developmental regulators, probably in part independent of their enzymatic activity. By contrast, recent evidence suggests a function of 5hmC as an epigenetic mark on its own, going beyond the expectation of only acting as an intermediate in an active DNA demethylation pathway. PMID- 25436546 TI - RNA regulons and the RNA-protein interaction network. AB - Abstract The development of genome-wide analysis tools has prompted global investigation of the gene expression program, revealing highly coordinated control mechanisms that ensure proper spatiotemporal activity of a cell's macromolecular components. With respect to the regulation of RNA transcripts, the concept of RNA regulons, which - by analogy with DNA regulons in bacteria - refers to the coordinated control of functionally related RNA molecules, has emerged as a unifying theory that describes the logic of regulatory RNA-protein interactions in eukaryotes. Hundreds of RNA-binding proteins and small non-coding RNAs, such as microRNAs, bind to distinct elements in target RNAs, thereby exerting specific and concerted control over posttranscriptional events. In this review, we discuss recent reports committed to systematically explore the RNA protein interaction network and outline some of the principles and recurring features of RNA regulons: the coordination of functionally related mRNAs through RNA-binding proteins or non-coding RNAs, the modular structure of its components, and the dynamic rewiring of RNA-protein interactions upon exposure to internal or external stimuli. We also summarize evidence for robust combinatorial control of mRNAs, which could determine the ultimate fate of each mRNA molecule in a cell. Finally, the compilation and integration of global protein-RNA interaction data has yielded first insights into network structures and provided the hypothesis that RNA regulons may, in part, constitute noise 'buffers' to handle stochasticity in cellular transcription. PMID- 25436547 TI - Paraspeckles: possible nuclear hubs by the RNA for the RNA. AB - Abstract The mammalian cell nucleus is a highly compartmentalized system in which multiple subnuclear structures, called nuclear bodies, exist in the nucleoplasmic spaces. Some of the nuclear bodies contain specific long non-coding RNAs (ncRNAs) as their components, and may serve as sites for long ncRNA functions that remain largely enigmatic. A paraspeckle is a nuclear body that is almost ubiquitously observed in mammalian cultured cells but is cell population-specific in adult mouse tissue. The paraspeckle structure is RNase-sensitive. Long ncRNAs, termed MENepsilon/beta ncRNAs (also referred to as NEAT1 ncRNAs), have been identified as the RNA components of the paraspeckles. Specific elimination has revealed that MENepsilon/beta ncRNAs are essential components for the formation of the intact paraspeckle structure. Paraspeckle formation requires the continual MENepsilon/beta ncRNA biogenesis process, including ongoing transcription, alternative 3'-end processing, and stabilization. Some paraspeckle-localized RNA binding proteins (p54/nrb and PSF) direct paraspeckle formation through the selective stabilization of MENbeta ncRNA. Both MENepsilon/beta ncRNA expression and their subsequent interactions with paraspeckle proteins can be regulated under environmental and developmental conditions, which are reflected in the size and number of the paraspeckles. However, how paraspeckles function remains largely unsolved. Paraspeckles appear to serve as the site of nuclear retention of specific mRNAs that are selectively transported to the cytoplasm upon certain signals. Alternatively, MENepsilon/beta ncRNAs may sequester paraspeckle proteins that function outside the paraspeckles. This review focuses on known aspects of paraspeckles and provides a model of their structure and function. PMID- 25436549 TI - Recent progress in orexin/hypocretin physiology and pharmacology. AB - Abstract Orexin peptides and their cognate receptors were discovered 14 years ago. They soon took a very central position in the regulation of sleep and wakefulness. Active studies have further elucidated these functions as well as the role of orexins in, for instance, appetite, metabolism, analgesia, addiction, and stress response. This review summarizes all the important fields but especially aims at focusing on novel findings and future directions. PMID- 25436550 TI - Starting at the end: telomeres and telomerase in arthropods. AB - Abstract Telomere composition and structure have been studied in several arthropods allowing us to better understand the evolution of such an important portion of the eukaryotic chromosomes. Genes coding for telomerase reverse transcriptase (TERT) have been sequenced and studied in few arthropod species only, where they resulted highly transcribed also in somatic tissues suggesting a different TERT regulation in respect to vertebrates. Contrary to the strict conservation of telomeres, subtelomeric regions were more polymorphic and heterogeneous in composition and frequently contained retrotransposable elements that strongly influenced subtelomere evolution. PMID- 25436551 TI - The intracellular phospholipase A1 protein family. AB - Abstract Phospholipase A1 is an enzyme that hydrolyzes phospholipids, producing 2 acyl-lysophospholipids and fatty acids. The intracellular phospholipase A1 (iPLA1) protein family is a relatively recently discovered lipid-metabolizing enzyme family. Lower eukaryotes, such as yeasts and nematodes, and plants have only one iPLA1 protein, whereas mammals have three iPLA1 family proteins (PA PLA1/DDHD1/iPLA1alpha, p125/Sec23IP/iPLA1beta and KIAA0725p/DDHD2/iPLA1gamma). Mammalian iPLA1 proteins are localized in different cellular compartments, and two of them, p125 and KIAA0725p, have been implicated in membrane trafficking events. Recent gene targeting studies on several organisms showed that iPLA1 family proteins are involved in various physiological functions, including plant shoot gravitropism, epithelial stem cell differentiation and spermiogenesis. In this review, we describe the features of iPLA1 family proteins and recent progress regarding our understanding of their physiological functions. PMID- 25436552 TI - Memory immune response: a major challenge in vaccination. AB - Abstract A crucial challenge for vaccine development is to design vaccines that induce a long-lasting protective immune response, i.e., immune memory. The persistence of antigen-specific antibody titers over a protective threshold, and the ability to exibit a 'recall response' to a subsequent encounter with an antigen have long been the only measurable correlates of vaccine take and immune memory development, suffering from the disadvantage of relying on long-term monitoring of the immune response. In the last few years, advances in the technologies for the identification and characterization of the cell subsets and molecular pathways involved in the immune response to vaccination have allowed innovative approaches to the identification of early correlates of immune memory. In this review, we discuss recent data and hypotheses on early correlates of the development of immune memory, with special emphasis on the gene expression signatures that underlie the self-renewal ability of some lymphocyte subsets, and their similarities with gene expression signatures in stem cells. PMID- 25436548 TI - Transforming growth factor-beta superfamily, implications in development and differentiation of stem cells. AB - Abstract Transforming growth factor-beta (TGF-beta) family members, including TGF betas and bone morphogenetic proteins (BMPs), play important roles in directing the fate of stem cells. In embryonic stem cells, the TGF-beta superfamily participates in almost all stages of cell development, such as cell maintenance, lineage selection, and progression of differentiation. In adult mesenchymal stem cells (MSCs), TGF-betas can provide competence for early stages of chondroblastic and osteoblastic differentiation, but they inhibit myogenesis, adipogenesis, and late-stage osteoblast differentiation. BMPs also inhibit adipogenesis and myogenesis, but they strongly promote osteoblast differentiation. The TGF-beta superfamily members signal via specific serine/threonine kinase receptors and their nuclear effectors termed Smad proteins as well as through non-Smad pathways, which explain their pleiotropic effects in self-renewal and differentiation of stem cells. This review summarizes the current knowledge on the pleiotropic effects of the TGF-beta superfamily of growth factors on the fate of stem cells and also discusses the mechanisms by which the TGF-beta superfamily members control embryonic and MSCs differentiation. PMID- 25436554 TI - The influence of glucocorticoids on neuronal survival and synaptic function. AB - Abstract Glucocorticoids, recognized as stress-related steroid hormones secreted from adrenal glands, have multiple roles in brain function. The concentration of glucocorticoids is regulated by the hypothalamic-pituitary-adrenal axis, and chronically elevated levels of glucocorticoids are putatively involved in the pathophysiology of mental disorders, such as depression. As corticosteroids are also widely used as medical drugs (e.g., for chronic lung disease in infants), the developmental influence of glucocorticoids on neuronal survival and synaptic plasticity is a critical concern. Although many reports suggest a biological effect of glucocorticoids on neuronal populations of the central nervous system (CNS), some reports suggest a possibility that glial responses (including regulation of neurotrophic factor expression) to glucocorticoids are different from that of neurons. In the present review, we show an overview of the current knowledge concerning the impact of glucocorticoids on behavior in animal models of depression, and on cell survival and function in the CNS. PMID- 25436560 TI - Paradoxical inhibition of cellular protein expression by proteasome inhibitors. AB - Abstract Proteasome inhibitors are used as anticancer drugs, however, the precise mechanisms of their selective activity against cancer cells are not understood well. While proteasome inhibitors stabilize the majority of cellular proteins through inhibition of proteasome activity, they also paradoxically downregulate several other proteins. We recently discovered that proteasome inhibitors suppress mRNA and protein expression of FOXM1, NPM, and ARF proteins that are involved in cancer. We postulated that proteasome inhibitors preferentially stabilize negative regulators of transcription of these genes, which overrides their protein stabilization. These data suggest a presence of multiple secondary mechanisms that may regulate transcription, degradation, or localization of cellular proteins after treatment with proteasome inhibitors. Future experiments will identify these mechanisms and additional proteins suppressed by proteasome inhibitors, and will help explain the role of protein suppression by proteasome inhibitors in their anticancer activity. PMID- 25436556 TI - Mismatch repair in recombination of bacteriophage T4. AB - Abstract The review focuses on the mechanism of mismatch repair in bacteriophage T4. It was first observed in T4 as an extra recombination mechanism, which contributed to the general recombination only when particular rII mutations were used as genetic markers (high-recombination markers), whereas it was inactive toward other rII mutations (low-recombination markers). This marker-dependent recombination pathway was identified as a repair of mismatches in recombinational heteroduplexes. Comparison of the structure of markers enabled us to make several specific conclusions on the nature of the marker discrimination by the mismatch repair system operating during T4 crosses. First, heteroduplexes with one mismatched base pair (either of transition or of transversion type) as well as single-nucleotide mismatches of indel type are not efficiently repaired. Second, among the repairable mismatches, those with two or more contiguous mismatched nucleotides are the most effectively repaired, whereas insertion of one correct pair between two mismatched ones reduces the repairability. Third, heteroduplexes containing insertion mutations are repaired asymmetrically, the longer strand being preferentially removed. Fourth, the sequence environment is an important factor. Inspection of the sequences flanking mismatches shows that runs of A:T pairs directly neighboring the mismatches greatly promote repair. The mismatch is recognized by T4 endonuclease VII and nicked on the 3' side. The nonpaired 3' terminus is attacked by the proofreading 3'->5' exonuclease of T4 DNA polymerase that removes the mismatched nucleotides along with several (~25) complementary nucleotides (the repair tract) and then switches to polymerization. The residual nick is ligated by DNA ligase (gp30). Most probably, the T4 system repairs replication and other mismatches as well; however, it might not discriminate old and new DNA strands and so does not seem to be aimed at repair of replication errors, in contrast to the most commonly studied examples of mismatch repair. PMID- 25436555 TI - Apicobasal polarity and its role in cancer progression. AB - Abstract Appropriate establishment and maintenance of cell polarity is essential for normal development and homeostasis. The vast majority of human cancers originate from epithelial tissues and tumour cell invasion and metastasis are the major cause of mortality in human cancers. Invading cells demonstrate loss of cell polarity, loss of epithelial cell-cell adhesions and tissue disorganisation. We examine the growing evidence linking loss of apicobasal polarity with tumour progression. PMID- 25436558 TI - From transcription to translation: new insights in the structure and function of Argonaute protein. AB - Abstract Argonaute proteins play a central role in gene silencing pathways mediated by small RNA molecules. The ancestral function of small RNA-dependent silencing is related to genome protection against parasitic nucleic acids, such as transposons and viruses. However, new classes of small RNAs are continuously being uncovered in all higher eukaryotes in which they play important functions in processes ranging from embryonic development to differentiation to cell proliferation and metabolism. Small RNAs have variegated biogenesis pathways and accomplish distinct functions. Nevertheless, it appears that all small RNAs work merely as guides in recognizing the target RNAs invariably relying on the interaction with Argonaute proteins and associated factors for their biological function. Here, we discuss recent findings on the structure and regulation of mammalian Argonaute proteins and overview the various roles that these versatile proteins play in regulating gene expression. PMID- 25436557 TI - Cyclin A2: a genuine cell cycle regulator? AB - Abstract Cyclin A2 belongs to the core cell cycle regulators and participates in the control of both S phase and mitosis. However, several observations suggest that it is also endowed with other functions, and our recent data shed light on its involvement in cytoskeleton dynamic and cell motility. From the transcription of its gene to its posttranslational modifications, cyclin A2 regulation reveals the complexity of the regulatory network shaping cell cycle progression. We summarize our current knowledge on this cell cycle regulator and discuss recent findings raising the possibility that cyclin A2 might play a much broader role in epithelial tissues homeostasis. PMID- 25436553 TI - Epigenetic control of cell invasion - the trophoblast model. AB - Abstract Trophoblast implantation and placentation allow the survival of the young embryo and its normal development inside the uterus. In order for these processes to function properly, the trophoblast has to undergo a series of characteristic changes that lead to its adhesion and invasion of the uterus. This is achieved, among other mechanisms, by inactivation of specific tumor suppressor genes, commonly by methylation of their promoters. Cell adhesion and tissue invasion are also characteristics of malignant tumors and patterns of methylation similar to that seen in trophoblast are found in various tumor types. Another important mechanism that aids trophoblast cells invasion is their transition from epithelial to mesenchymal phenotype. Such a transition is also a common characteristic of invading malignant cells. Thus, studying tissue invasion and its control mechanisms can benefit the understanding of both the trophoblast and malignant cells behavior. PMID- 25436559 TI - Diverse roles for the p24 family of proteins in eukaryotic cells. AB - Abstract Members of the p24 protein family form a highly conserved family of type I transmembrane proteins that are abundant components of the early secretory pathway. Topologically, the proteins have a large luminal domain and a short cytoplasmic domain that allows for targeting to both coat protein complex II and coat protein complex I vesicles, and thus these proteins cycle between the endoplasmic reticulum and Golgi compartments. Several functions have been proposed for these proteins including a role in coat protein complex I vesicle biogenesis, cargo protein selection, organization of intracellular membranes, and protein quality control. Recent studies have added to the list of potential cargo substrates for which p24 function is required for normal transport in the secretory pathway. This review focuses on recent developments in the study of p24 proteins and their requirement for secretory and membrane protein transport in eukaryotic cells. PMID- 25436561 TI - Epigenetic regulation of memory: implications in human cognitive disorders. AB - Epigenetic modification of chromatin structure is an important mechanism in the regulation of gene expression. Recent studies have shown that dynamic regulation of chromatin structure occurs in response to neuronal stimulation associated with learning and memory. Learning-induced chromatin modifications include DNA methylation, histone acetylation, histone phosphorylation and histone methylation. Studies in animal models have used genetic and pharmacological methods to manipulate the epigenetic machinery in the brain during learning and memory formation. In general, these studies suggest that epigenetic regulation of chromatin structure is essential for long term memory (LTM) consolidation, which is known to require new gene transcription. Analysis of animal models has also implicated epigenetic mechanisms in impaired cognition associated with aging, neurodegenerative disease, and intellectual disability (ID). Recently, it has been shown that a subset of ID disorders and autism are caused by disruption of specific chromatin modification complexes that are involved in nuclear hormone receptor mediated transcriptional regulation. This review provides an overview of chromatin modifications that are implicated in learning and memory and discusses the role of chromatin modifying proteins in learning-induced transcriptional regulation and human cognitive disorders. PMID- 25436562 TI - The emerging roles for histone demethylases in the modulation of signaling pathways. AB - Since their discovery in 2004, histone demethylases have emerged as key regulators of chromatin. Recent studies have started to reveal the interconnections between histone demethylases and signaling pathways, suggesting that this interplay drives fundamental biological processes. Here, we summarize the different families and subfamilies of histone demethylases and the insights into the biological roles of these enzymes that have been provided by the analysis of mutant animals. We then review recent work linking demethylases and signaling pathways. These studies suggest that demethylase activities are a component of the critical connections that enable environmental signals to modulate the epigenetic landscape of a cell. A greater mechanistic understanding of the network of signals that control chromatin states during normal cellular processes, together with a better understanding of the ways that epigenetic alterations lead to uncontrolled cell proliferation, might help in the design of effective tools for cancer therapy. PMID- 25436564 TI - RNAi and retroviruses: are they in RISC? AB - RNA interference (RNAi) is a potent cellular system against viruses in various organisms. Although common traits are observed in plants, insects, and nematodes, the situation observed in mammals appears more complex. In mammalian somatic cells, RNAi is implicated in endonucleolytic cleavage mediated by artificially delivered small interfering RNAs (siRNAs) as well as in translation repression mediated by microRNAs (miRNAs). Because siRNAs and miRNAs recognize viral mRNAs, RNAi inherently limits virus production and participates in antiviral defense. However, several observations made in the cases of hepatitis C virus and retroviruses (including the human immunodeficiency virus and the primate foamy virus) bring evidence that this relationship is much more complex and that certain components of the RNAi effector complex [called the RNA-induced silencing complex (RISC)], such as AGO2, are also required for viral replication. Here, we summarize recent discoveries that have revealed this dual implication in virus biology. We further discuss their potential implications for the functions of RNAi-related proteins, with special emphasis on retrotransposition and genome stability. PMID- 25436566 TI - Elastin peptides in aging and pathological conditions. AB - Elastin is the protein responsible for the resilience of vertebrate tissue. It is an extremely stable protein deposited during the early stages of life and experiencing almost no renewal. As a consequence, it can be considered that each individual has an elastin capital for life. Despite its extreme stability, elastin can be degraded by several enzymes termed elastases. Elastases are among the most aggressive proteases, and their presence is increased with age. As a consequence, elastin fragmentation resulting in the generation of elastin peptides is one of the hallmarks of aging. This review will examine their nature and further expose our current understanding of the role played by these peptides in aging and their contribution to tissue homeostasis and several pathologies. PMID- 25436565 TI - Contributions of peroxisome proliferator-activated receptor beta/delta to skin health and disease. AB - Among the three peroxisome proliferator-activated receptor (PPAR) transcription factors, PPARbeta/delta is the isotype with the broadest expression pattern. In fact, the expression of PPARbeta/delta is ubiquitous, albeit at levels that are tightly regulated. Herein, we reviewed its multiple functions in skin health and disease. PPARbeta/delta has pro-differentiating effects in keratinocytes, regulates sebocyte differentiation, and promotes hair follicle growth in healthy skin. Furthermore, we reviewed novel insights into the roles of PPARbeta/delta in skin wound healing, especially in inhibiting apoptosis and in modulating keratinocyte proliferation and migration. Therefore, PPARbeta/delta represents a research target for the understanding and treatment of inflammatory skin diseases, such as psoriasis and acne vulgaris. In addition, PPARbeta/delta is a tumor growth modifier. Epidemiological studies have established that tumor progression may be exacerbated by chronic low-grade inflammation, a condition promoting the production of the lipids that act as modulators of PPARbeta/delta activity. The action of PPARbeta/delta in skin cancer is ambivalent, which might be explained by this receptor's putative highly context-specific behavior, which depends on a combination of factors ranging from receptor expression levels to co regulator distribution, diversity and activity of the ligands produced, and other tissue-specific conditions. Given its diverse and crucial roles in many tissues and organs, PPARbeta/delta will remain a major focus of future research. PMID- 25436567 TI - The meaning of aluminium exposure on human health and aluminium-related diseases. AB - The aim of this review is to attempt to answer extremely important questions related to aluminium-related diseases. Starting from an overview on the main sources of aluminium exposure in everyday life, the principal aspects of aluminium metabolism in humans have been taken into consideration in an attempt to enlighten the main metabolic pathways utilised by trivalent metal ions in different organs. The second part of this review is focused on the available evidence concerning the pathogenetic consequences of aluminium overload in human health, with particular attention to its putative role in bone and neurodegenerative human diseases. PMID- 25436568 TI - Tropomodulins and tropomyosins - organizers of cellular microcompartments. AB - Eukaryotic cells show a remarkable compartmentalization into compartments such as the cell nucleus, the Golgi apparatus, the endoplasmic reticulum, and endosomes. However, organelle structures are not the only means by which specialized compartments are formed. Recent research shows a critical role for diverse actin filament populations in defining functional compartments, here referred to as microcompartments, in a wide range of cells. These microcompartments are involved in regulating fundamental cellular functions including cell motility, plasma membrane organization, and cellular morphogenesis. In this overview, the importance of two multigene families of actin-associated proteins, tropomodulins and tropomyosins, their interactions with each other, and a large number of other proteins will be discussed in the context of generating specialized actin-based microcompartments. PMID- 25436570 TI - TCP transcription factors: architectures of plant form. AB - After its initial definition in 1999, the TCP family of transcription factors has become the focus of a multiplicity of studies related with plant development at the cellular, organ, and tissue levels. Evidence has accumulated indicating that TCP transcription factors are the main regulators of plant form and architecture and constitute a tool through which evolution shapes plant diversity. The TCP transcription factors act in a multiplicity of pathways related with cell proliferation and hormone responses. In recent years, the molecular pathways of TCP protein action and biochemical studies on their mode of interaction with DNA have begun to shed light on their mechanism of action. However, the available information is fragmented and a unifying view of TCP protein action is lacking, as well as detailed structural studies of the TCP-DNA complex. Also important, the possible role of TCP proteins as integrators of plant developmental responses to the environment has deserved little attention. In this review, we summarize the current knowledge about the structure and functions of TCP transcription factors and analyze future perspectives for the study of the role of these proteins and their use to modify plant development. PMID- 25436569 TI - Y RNAs: recent developments. AB - Non-coding RNAs have emerged as key regulators in diverse cellular processes. Y RNAs are ~100-nucleotide-long non-coding RNAs that show high conservation in metazoans. Human Y RNAs are known to bind to the Ro60 and La proteins to form the Ro ribonucleoprotein complex. Their main biological function appears to be in mediating the initiation of chromosomal DNA replication, regulating the autoimmune protein Ro60, and generating smaller RNA fragments following cellular stress, although the precise molecular mechanisms underlying these functions remain elusive. Here, we aim to review the most recent literature on Y RNAs and gain insight into the function of these intriguing molecules. PMID- 25436563 TI - Neurosteroids and GABAergic signaling in health and disease. AB - Endogenous neurosteroids such as allopregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol are synthesized either de novo in the brain from cholesterol or are generated from the local metabolism of peripherally derived progesterone or corticosterone. Fluctuations in neurosteroid concentrations are important in the regulation of a number of physiological responses including anxiety and stress, reproductive, and sexual behaviors. These effects are mediated in part by the direct binding of neurosteroids to gamma aminobutyric acid type-A receptors (GABAARs), resulting in the potentiation of GABAAR-mediated currents. Extrasynaptic GABAARs containing the delta subunit, which contribute to the tonic conductance, are particularly sensitive to low nanomolar concentrations of neurosteroids and are likely their preferential target. Considering the large charge transfer generated by these persistently open channels, even subtle changes in neurosteroid concentrations can have a major impact on neuronal excitability. Consequently, aberrant levels of neurosteroids have been implicated in numerous disorders, including, but not limited to, anxiety, neurodegenerative diseases, alcohol abuse, epilepsy, and depression. Here we review the modulation of GABAAR by neurosteroids and the consequences for health and disease. PMID- 25436571 TI - The Src family kinases: distinct functions of c-Src, Yes, and Fyn in the liver. AB - The Src family kinases Yes, Fyn, and c-Src play a pivotal role in regulating diverse liver functions such as bile flow, proteolysis, apoptosis, and proliferation and are regulated by anisoosmotic cell volume changes, death receptor ligands, and bile acids. For example, cell swelling leads to an integrin sensed and focal adhesion kinase-mediated activation of c-Src-triggering choleresis, proteolysis inhibition, regulatory volume decrease via p38MAPK and proliferation via the activation of the epidermal growth factor receptor and extracellular regulated kinases 1 and 2. In contrast, hepatocyte shrinkage generates an almost instantaneous oxidative stress response that triggers the activation of c-Jun N-terminal kinase and the Src family kinases Fyn and Yes. Whereas Fyn activation mediates cholestasis, Yes triggers CD95 activation and apoptosis. This review will discuss the role of Src family kinases in the regulation of liver function with emphasis on their role in osmo-signaling and bile acid signaling. PMID- 25436572 TI - Metallothionein-protein interactions. AB - Metallothioneins (MTs) are a family of universal, small proteins, sharing a high cysteine content and an optimal capacity for metal ion coordination. They take part in a plethora of metal ion-related events (from detoxification to homeostasis, storage, and delivery), in a wide range of stress responses, and in different pathological processes (tumorigenesis, neurodegeneration, and inflammation). The information on both intracellular and extracellular interactions of MTs with other proteins is here comprehensively reviewed. In mammalian kidney, MT1/MT2 interact with megalin and related receptors, and with the transporter transthyretin. Most of the mammalian MT partners identified concern interactions with central nervous system (mainly brain) proteins, both through physical contact or metal exchange reactions. Physical interactions mainly involve neuronal secretion multimers. Regarding metal swap events, brain MT3 appears to control the metal ion load in peptides whose aggregation leads to neurodegenerative disorders, such as Abeta peptide, alpha-synuclein, and prion proteins (Alzheimer's and Parkinson's diseases, and spongiform encephalopathies, respectively). Interaction with ferritin and bovine serum albumin are also documented. The intercourse of MTs with zinc-dependent enzymes and transcription factors is capable to activate/deactivate them, thus conferring MTs the role of metabolic and gene expression regulators. As some of these proteins are involved in cell cycle and proliferation control (p53, nuclear factor kappaB, and PKCMU), they are considered in the context of oncogenesis and tumor progression. Only one non-mammalian MT interaction, involving Drosophila MtnA and MtnB major isoforms and peroxiredoxins, has been reported. The prospective use for biomedical applications of the MT-interaction information is finally discussed. PMID- 25436574 TI - Elastin biology and tissue engineering with adult cells. AB - The inability of adult cells to produce well-organized, robust elastic fibers has long been a barrier to the successful engineering of certain tissues. In this review, we focus primarily on elastin with respect to tissue-engineered vascular substitutes. To understand elastin regulation during normal development, we describe the role of various elastic fiber accessory proteins. Biochemical pathways regulating expression of the elastin gene are addressed, with particular focus on tissue-engineering research using adult-derived cells. PMID- 25436573 TI - Inhibitor of apoptosis proteins as E3 ligases for ubiquitin and NEDD8. AB - The inhibitors of apoptosis proteins (IAPs) are endogenous inhibitors for apoptosis. Apoptosis is carried out by caspases, which are the family of cystein proteases. IAPs regulate caspases through two conserved regions, the baculovirus IAP repeats (BIRs) and the really interesting new gene (RING) domains. Although the BIRs are responsible for binding to caspases, the RING domain can act as a ubiquitin-E3 ligase, leading to ubiquitylation of IAPs themselves and their pro apoptotic IAP counterparts such as caspases. Recently, it is reported that another ubiquitin-like protein, neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8), is also involved in the regulation of apoptosis through neddylation of caspases mediated by IAPs. On the contrary, the results against the function of IAPs as a NEDD8-E3 ligase are also suggested. This review presents the summary of IAPs, caspases, and the ubiquitin-proteasome system and how their interactions influence the regulation of apoptosis. PMID- 25436575 TI - Role of nuclear IkappaBs in inflammation regulation. AB - A wide variety of environmental cues, including inflammatory cytokines, ligands for pattern recognition receptors and endogenous danger signals, activate the inducible transcription factor nuclear factor-kappaB (NF-kappaB), which is a central regulator of inflammatory and immune responses. Excessive activation of NF-kappaB results in the development of severe diseases, such as chronic inflammatory disorders, autoimmune diseases and cancer. Therefore, the transcriptional activity of NF-kappaB is tightly regulated at multiple steps. One mechanism is mediated by the inhibitor of kappaB (IkappaB), a well-defined regulator of NF-kappaB that resides in the cytoplasm and prevents NF-kappaB from nuclear entry by sequestration. Recently, several atypical IkappaBs that reside in the nucleus were identified: Bcl-3, IkappaBzeta, IkappaBNS and IkappaBeta. In contrast to conventional IkappaBs, these atypical IkappaBs positively and negatively modulate NF-kappaB-mediated transcription. The function of atypical IkappaBs is independent of the prevention of NF-kappaB nuclear entry. Therefore, atypical IkappaBs are considered distinct from conventional IkappaBs and have been termed 'nuclear IkappaBs.' In addition to these members, our recent study indicated that IkappaBL, originally reported as a susceptibility gene for rheumatoid arthritis, also serves as a nuclear IkappaB. Biological and genetic studies strongly suggest that nuclear IkappaBs play important roles in the pathogenesis of inflammatory and autoimmune diseases via the regulation of both innate and adaptive immunity. In this review, we discuss the recent advances in our understanding of nuclear IkappaBs in the context of NF-kappaB-mediated transcriptional regulation and inflammatory responses. PMID- 25436576 TI - Transport of substrates into peroxisomes: the paradigm of beta-lactam biosynthetic intermediates. AB - Peroxisomes are ubiquitous organelles that enclose catalases, fatty acid oxidizing enzymes, and a variety of proteins involved in different cellular processes. Interestingly, the late enzymes involved in penicillin biosynthesis, and the isopenicillin N epimerization enzymes involved in cephalosporin biosynthesis are located inside peroxisomes in the producer fungi Penicillium chrysogenum and Acremonium chrysogenum. Peroxisome proteins are targeted to those organelles by peroxisomal targeting signals located at the C-terminus (PTS1) or near the N-terminal end (PTS2) of those proteins. Peroxisomal membrane proteins (PMPs) are largely recruited by the interaction with specific sequences in the Pex19 protein. The compartmentalization into peroxisomes of several steps of the biosynthesis of penicillin, cephalosporin, and other secondary metabolites raises the question of how the precursors and/or intermediates of the biosynthesis of beta-lactam antibiotics are transported into peroxisomes and the mechanisms of secretion of the final products (penicillin or cephalosporin) from peroxisomes to the extracellular medium. Recent advances in peroxisome proteomics, immunoelectron microscopy, and fluorescence labeling have shown that the transport of these intermediates is mediated by membrane proteins of the major facilitator superfamily class (drug/H+ antiporters) containing 12 transmembrane spanning domains (TMS). In some cases, the transport of the substrates (e.g., fatty acids) or intermediates may be mediated by ATP-binding cassette (ABC) transporters. Knowledge on the transport and secretion mechanisms is of paramount importance to understand the complex mechanisms of cell differentiation and their crosstalk with the biosynthesis of different secondary metabolites that act as biochemical signals between the producer cells and also as communication signals with competing microorganisms (e.g., antimicrobial agents or plant elicitors). PMID- 25436577 TI - Free radical-mediated cytosine C-5 methylation triggers epigenetic changes during carcinogenesis. AB - The methylation of the C-5 position of deoxycytidine (dC) in the promoter regions of tumor suppressor genes is often observed in cancer cells. We found that various environmental agents, as well as endogenous compounds such as methionine sulfoxide (MetO), generate methyl radicals and modify dC to form 5-methyl-dC in DNA in vitro. We confirmed that both DNA methylation and cancer incidence in the liver were increased by the administration of MetO to oxidatively stressed mice. In this review, we summarize previous reports on methyl radical generation in vitro and in vivo and DNA modifications by methyl radicals, including our discoveries, as well as our recent experimental evidence suggesting that free radical-mediated dC methylation triggers epigenetic changes. PMID- 25436578 TI - Neurokinin receptors in the gastrointestinal muscle wall: cell distribution and possible roles. AB - The neurokinin receptors are G-protein-linked receptors; three distinct molecules, called neurokinin-1, neurokinin-2, and neurokinin-3 receptors, have been identified. Their physiological ligands are the tachykinins, which, in the mammalian gut, correspond to substance P, neurokinin A, and neurokinin B. In this apparatus, the main source of tachykinins is represented by intrinsic neurons located either in the myenteric plexus and projecting mainly to the muscle coat, or in the submucous plexus and projecting to the mucosa and submucosal blood vessels. The availability of specific antibodies has allowed identifying the sites of distribution of the neurokinin receptors in the gut, and important differences have been found among cell types and animal species. The complexity of the receptor distribution, either intraspecies or interspecies, is in agreement with the variegated picture coming out from physiological and pharmacological experiments. Interestingly, most of the knowledge on the tachykinin systems has been obtained from pathological conditions. Here, we tried to collect the main information available on the cellular distribution of the neurokinin receptors in the gut wall in the attempt to correlate their cell location with the several roles the tachykinins seem to play in the gastrointestinal apparatus. PMID- 25436579 TI - Programmed cell death with a necrotic-like phenotype. AB - Programmed cell death is the process by which an individual cell in a multicellular organism commits cellular 'suicide' to provide a long-term benefit to the organism. Thus, programmed cell death is important for physiological processes such as development, cellular homeostasis, and immunity. Importantly, in this process, the cell is not eliminated in response to random events but in response to an intricate and genetically defined set of internal cellular molecular events or 'program'. Although the apoptotic process is generally very well understood, programmed cell death that occurs with a necrotic-like phenotype has been much less studied, and it is only within the past few years that the necrotic program has begun to be elucidated. Originally, programmed necrosis was somewhat dismissed as a nonphysiological phenomenon that occurs in vitro. Recent in vivo studies, however, suggest that regulated necrosis is an authentic classification of cell death that is important in mammalian development and other physiological processes, and programmed necrosis is now considered a significant therapeutic target in major pathological processes as well. Although the RIP1 RIP3-dependent necrosome complex is recognized as being essential for the execution of many instances of programmed necrosis, other downstream and related necrotic molecules and pathways are now being characterized. One of the current challenges is understanding how and under what conditions these pathways are linked together. PMID- 25436581 TI - Papain-like peptidases: structure, function, and evolution. AB - Papain-like cysteine peptidases are a diverse family of peptidases found in most known organisms. In eukaryotes, they are divided into multiple evolutionary groups, which can be clearly distinguished on the basis of the structural characteristics of the proenzymes. Most of them are endopeptidases; some, however, evolved into exopeptidases by obtaining additional structural elements that restrict the binding of substrate into the active site. In humans, papain like peptidases, also called cysteine cathepsins, act both as non-specific hydrolases and as specific processing enzymes. They are involved in numerous physiological processes, such as antigen presentation, extracellular matrix remodeling, and hormone processing. Their activity is tightly regulated and dysregulation of one or more cysteine cathepsins can result in severe pathological conditions, such as cardiovascular diseases and cancer. Other organisms can utilize papain-like peptidases for different purposes and they are often part of host-pathogen interactions. Numerous parasites, such as Plasmodium and flukes, utilize papain-like peptidases for host invasion, whereas plants, in contrast, use these enzymes for host defense. This review presents a state-of-the art description of the structure and phylogeny of papain-like peptidases as well as an overview of their physiological and pathological functions in humans and in other organisms. PMID- 25436582 TI - Alternative genetic code for amino acids and transfer RNA revisited. AB - The genetic code is highly conserved among all organisms and its evolution is thought to be strictly limited. However, an increasing number of studies have reported non-standard codes in prokaryotic and eukaryotic genomes. Most of these deviations from the standard code are attributable to tRNA changes relating to, for example, codon/anticodon base pairing and tRNA/aminoacyl-tRNA synthetase recognition. In this review, we focus on tRNA, a key molecule in the translation of the genetic code, and summarize the most recently published information on the evolutionary divergence of the tRNAs. Surprisingly, although higher eukaryotes, such as the nematode (worm), utilize the standard genetic code, newly identified nematode-specific tRNAs (nev-tRNAs) translate nucleotides in a manner that transgresses the code. Furthermore, a variety of additional functions of tRNAs, beyond their translation of the genetic code, have emerged rapidly. We also review these intriguing new aspects of tRNA, which have potential impacts on translational control, RNA silencing, antibiotic resistance, RNA biosynthesis, and transcriptional regulation. PMID- 25436580 TI - The nucleolus: a raft adrift in the nuclear sea or the keystone in nuclear structure? AB - The nucleolus is a prominent nuclear structure that is the site of ribosomal RNA (rRNA) transcription, and hence ribosome biogenesis. Cellular demand for ribosomes, and hence rRNA, is tightly linked to cell growth and the rRNA makes up the majority of all the RNA within a cell. To fulfill the cellular demand for rRNA, the ribosomal RNA (rDNA) genes are amplified to high copy number and transcribed at very high rates. As such, understanding the rDNA has profound consequences for our comprehension of genome and transcriptional organization in cells. In this review, we address the question of whether the nucleolus is a raft adrift the sea of nuclear DNA, or actively contributes to genome organization. We present evidence supporting the idea that the nucleolus, and the rDNA contained therein, play more roles in the biology of the cell than simply ribosome biogenesis. We propose that the nucleolus and the rDNA are central factors in the spatial organization of the genome, and that rapid alterations in nucleolar structure in response to changing conditions manifest themselves in altered genomic structures that have functional consequences. Finally, we discuss some predictions that result from the nucleolus having a central role in nuclear organization. PMID- 25436583 TI - Human neuronal cells: epigenetic aspects. AB - Histone acetyltransferases (HATs) and histone deacetylases (HDACs) promote histone posttranslational modifications, which lead to an epigenetic alteration in gene expression. Aberrant regulation of HATs and HDACs in neuronal cells results in pathological consequences such as neurodegeneration. Alzheimer's disease is the most common neurodegenerative disease of the brain, which has devastating effects on patients and loved ones. The use of pan-HDAC inhibitors has shown great therapeutic promise in ameliorating neurodegenerative ailments. Recent evidence has emerged suggesting that certain deacetylases mediate neurotoxicity, whereas others provide neuroprotection. Therefore, the inhibition of certain isoforms to alleviate neurodegenerative manifestations has now become the focus of studies. In this review, we aimed to discuss and summarize some of the most recent and promising findings of HAT and HDAC functions in neurodegenerative diseases. PMID- 25436584 TI - Endothelin systems in the brain: involvement in pathophysiological responses of damaged nerve tissues. AB - In addition to their potent vasoconstriction effects, endothelins (ETs) show multiple actions in various tissues including the brain. The brain contains high levels of ETs, and their production is stimulated in many brain disorders. Accumulating evidence indicates that activation of brain ET receptors is involved in several pathophysiological responses in damaged brains. In this article, the roles of brain ET systems in relation to brain disorders are reviewed. In the acute phase of stroke, prolonged vasospasm of cerebral arteries and brain edema occur, both of which aggravate brain damage. Studies using ET antagonists show that activation of ETA receptors in the brain vascular smooth muscle induces vasospasm after stroke. Brain edema is induced by increased activity of vascular permeability factors, such as vascular endothelial growth factor and matrix metalloproteinases. Activation of ETB receptors stimulates astrocytic production of these permeability factors. Increases in reactive astrocytes are observed in neurodegenerative diseases and in the chronic phase of stroke, where they facilitate the repair of damaged nerve tissues by releasing neurotrophic factors. ETs promote the induction of reactive astrocytes through ETB receptors. ETs also stimulate the production of astrocytic neurotrophic factors. Recent studies have shown high expression of ETB receptors in neural progenitors. Activation of ETB receptors in neural progenitors promotes their proliferation and migration, suggesting roles for ETB receptors in neurogenesis. Much effort has been invested in the pursuit of novel drugs to induce protection or repair of damaged nerve tissues. From these studies, the pharmacological significance of brain ET systems as a possible target of neuroprotective drugs is anticipated. PMID- 25436586 TI - MicroRNA biogenesis and variability. AB - MicroRNAs (miRNAs) are cell-endogenous small noncoding RNAs that, through RNA interference, are involved in the posttranscriptional regulation of mRNAs. The biogenesis and function of miRNAs entail multiple elements with different alternative pathways. These confer a high versatility of regulation and a high variability to generate different miRNAs and hence possess a broad potential to regulate gene expression. Here we review the different mechanisms, both canonical and noncanonical, that generate miRNAs in animals. The 'miRNome' panorama enhances our knowledge regarding the fine regulation of gene expression and provides new insights concerning normal, as opposed to pathological, cell differentiation and development. PMID- 25436587 TI - Progress in mitochondrial epigenetics. AB - Mitochondria, intracellular organelles with their own genome, have been shown capable of interacting with epigenetic mechanisms in at least four different ways. First, epigenetic mechanisms that regulate the expression of nuclear genome influence mitochondria by modulating the expression of nuclear-encoded mitochondrial genes. Second, a cell-specific mitochondrial DNA content (copy number) and mitochondrial activity determine the methylation pattern of nuclear genes. Third, mitochondrial DNA variants influence the nuclear gene expression patterns and the nuclear DNA (ncDNA) methylation levels. Fourth and most recent line of evidence indicates that mitochondrial DNA similar to ncDNA also is subject to epigenetic modifications, particularly by the 5-methylcytosine and 5 hydroxymethylcytosine marks. The latter interaction of mitochondria with epigenetics has been termed 'mitochondrial epigenetics'. Here we summarize recent developments in this particular area of epigenetic research. Furthermore, we propose the term 'mitoepigenetics' to include all four above-noted types of interactions between mitochondria and epigenetics, and we suggest a more restricted usage of the term 'mitochondrial epigenetics' for molecular events dealing solely with the intra-mitochondrial epigenetics and the modifications of mitochondrial genome. PMID- 25436588 TI - Raf kinases in signal transduction and interaction with translation machinery. AB - In recent years, a large amount of evidence has given a central role to translational control in diseases such as cancer, tissue hypertrophy and neurodegeneration. Its deregulation can directly modulate cell cycling, transformation and survival response. The aim of this review is to describe the interaction between Raf activation and the main characters of the translational machinery, such as the elongation factor 1A (eEF1A), which has been recognized in recent years as one of the most interesting putative oncogenes. A particular emphasis is given to an intriguing non-canonical role that eEF1A can play in the relationship between the Ras->Raf-1->MEK1->ERK-1/2 and PI3K->Akt signaling pathways. Recently, our group has described a C-Raf kinase-mediated phosphorylation of eEF1A triggered by a survival pathway induced upon interferon alpha (IFNalpha) treatment in the human epidermoid cancer cell line (H1355). This phosphorylation seems to be the center of the survival pathway that counteracts the well-known pro-apoptotic function of IFNalpha. Furthermore, we have identified two new phosphorylation sites on eEF1A (Ser21 and Thr88) that are substrates for Raf kinases in vitro and, likely, in vivo as well. These residues seem to have a significant functional role in the control of cellular processes, such as cell proliferation and survival. In fact, overexpression of eEF1A2 in gemcitabine-treated cancer cells caused the upregulation of phosphoAkt and an increase in cell viability, thereby suggesting that eEF1A2 could exert its oncogenic behavior by participating in the regulation of PI3K pathway. PMID- 25436589 TI - Deoxyadenosine family: improved synthesis, DNA damage and repair, analogs as drugs. AB - Improved synthesis of 2'-deoxyadenosine using Escherichia coli overexpressing some enzymes and gram-scale chemical synthesis of 2'-deoxynucleoside 5' triphosphates reported recently are described in this review. Other topics include DNA damage induced by chromium(VI), Fenton chemistry, photoinduction with lumazine, or by ultrasound in neutral solution; 8,5'-cyclo-2'-deoxyadenosine isomers as potential biomarkers; and a recapitulation of purine 5',8 cyclonucleoside studies. The mutagenicities of some products generated by oxidizing 2'-deoxyadenosine 5'-triphosphate, nucleotide pool sanitization, and translesion synthesis are also reviewed. Characterizing cross-linking between nucleosides in opposite strands of DNA and endonuclease V-mediated deoxyinosine excision repair are discussed. The use of purine nucleoside analogs in the treatment of rarer chronic lymphoid leukemias is reviewed. Some analogs at the C8 position induced delayed polymerization arrest during HIV-1 reverse transcription. The susceptibility of clinically metronidazole-resistant Trichomonas vaginalis to two analogs, toyocamycin and 2-fluoro-2'-deoxyadenosine, were tested in vitro. GS-9148, a dAMP analog, was translocated to the priming site in a complex with reverse transcriptase and double-stranded DNA to gain insight into the mechanism of reverse transcriptase inhibition. PMID- 25436585 TI - The molecular biology of selenocysteine. AB - Selenium is an essential trace element that is incorporated into 25 human proteins as the amino acid selenocysteine (Sec). The incorporation of this amino acid turns out to be a fascinating problem in molecular biology because Sec is encoded by a stop codon, UGA. Layered on top of the canonical translation elongation machinery is a set of factors that exist solely to incorporate this important amino acid. The mechanism by which this process occurs, put into the context of selenoprotein biology, is the focus of this review. PMID- 25436590 TI - Long antisense non-coding RNAs and the epigenetic regulation of gene expression. AB - Shortly after the completion of the human genome project in 2003, the Encode project was launched. The project was set out to identify the functional elements in the human genome, and unexpectedly it was found that >80% of the genome is transcribed. The Encode project identified those transcribed regions of the genome to be encoded by non-coding RNAs (ncRNAs). With only 2% of the genome carrying gene-encoding proteins, the conundrum was then, what is the function, if any, of these non-coding regions of the genome? These ncRNAs included both short and long RNAs. The focus of this review will be on antisense long non-coding RNAs (lncRNAs), as these transcripts have been observed to play a role in gene expression of protein-coding genes. Some lncRNAs have been found to regulate protein-coding gene transcription at the epigenetic level, whereby they suppress transcription through the recruitment of protein complexes to target loci in the genome. Conversely, there are lncRNAs that have a positive role in gene expression with less known about mechanism, and some lncRNAs have been shown to be involved in post-transcriptional processes. Additionally, lncRNAs have been observed to regulate their own expression in a positive feedback loop by functioning as a decoy. The biological significance of lncRNAs is only just now becoming evident, with many lncRNAs found to play a significant role in several human diseases. PMID- 25436591 TI - New insights into the activation of sterol regulatory element-binding proteins by proteolytic processing. AB - Abstract Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate a wide variety of genes involved in cholesterol and fatty acid synthesis. After transcription, SREBPs are controlled at multiple post transcriptional levels, including proteolytic processing and post-translational modification. Among these, proteolytic processing is a crucial regulatory step that activates SREBPs, which are synthesized as inactive endoplasmic reticulum membrane proteins. In this review, we focus on recent progress with regard to signaling pathways and small molecules that affect activation of SREBPs by proteolytic processing. PMID- 25436592 TI - Amyloid-like fibrils labeled with magnetic nanoparticles. AB - A number of human diseases are associated with the formation of insoluble protein aggregates commonly known as amyloid fibrils or amyloid plaques. Similar materials can be prepared in vitro resulting in so-called amyloid-like fibrils. Herein is discussed how to prepare such fibrils labeled with magnetic nanoparticles. Such materials have the potential to be used as magnetic probes for magnetic resonance imaging applications. PMID- 25436593 TI - The anti-catabolic role of bovine lactoferricin in cartilage. AB - Bovine lactoferricin (LfcinB) is a multifunctional peptide derived from bovine lactoferrin that demonstrates antibacterial, antifungal, antiviral, antitumor, and immunomodulatory activities. Recently, studies have focused on the anti catabolic and anti-inflammatory potential of LfcinB. LfcinB is able to modulate the effects cytokines such as IL-1 and fibroblast growth factor 2 as well as promote specific cartilage anabolic factors. These properties are particularly important in maintaining cartilage homeostasis and preventing a catabolic state, which leads to clinical pathology. This review focuses on the recent literature elucidating the role of LfcinB in preventing cartilage degradation. PMID- 25436594 TI - The CAP protein superfamily: function in sterol export and fungal virulence. AB - CAP superfamily proteins, also known as sperm-coating proteins, are found in all kingdoms of life and have been implicated in a variety of physiological contexts, including immune defense in plants and mammals, sperm maturation and fertilization, fungal virulence, and toxicity of insect and reptile venoms as well as prostate and brain cancer. CAP family members are mostly secreted glycoproteins that are highly stable in the extracellular fluid. All members of the superfamily share a common CAP domain of approximately 150 amino acids, which adopts a unique alpha-beta-alpha sandwich fold. The conserved structure suggests that CAP proteins exert fundamentally similar functions. However, the molecular mode of action of this protein family has remained enigmatic. The budding yeast Saccharomyces cerevisiae has three CAP family members designated Pry (pathogen related in yeast), and recent evidence indicates that they act as sterol-binding and export proteins. Expression of the mammalian CAP protein CRISP2, which binds sterols in vitro, complements the sterol export defect of a yeast pry mutant, suggesting that sterol binding and export is conserved among different CAP family members. Collectively, these observations suggest that CAP family members constitute a novel class of secreted extracellular sterol-binding proteins. A ligand-binding activity of the CAP domain could explain many of the biological activities attributed to these proteins. For example, the strong induction of plant pathogenesis-related 1 protein upon exposure to pathogens may serve to inhibit pathogen proliferation by extracting sterols from the pathogen membrane. Similarly, the presence of these proteins in the venom of toxic insects and reptiles or in the secretome of pathogenic fungi might inflict damage by sequestering sterols or related small hydrophobic compounds from the host tissue. PMID- 25436595 TI - Plant phospholipase A: advances in molecular biology, biochemistry, and cellular function. AB - Plant phospholipase As (PLAs) are a complex group of enzymes that catalyze the release of free fatty acids from phospholipids. Plant PLAs can be grouped into three families, PLA1, PLA2, and patatin-like PLA, that catalyze the hydrolysis of acyl groups from the sn-1 and/or sn-2 position. Each family is composed of multiple isoforms of phospholipases that differ in structural, catalytic, and physiological characteristics. In this review, recently acquired information on molecular, biochemical, and functional aspects of plant PLAs will be discussed. PMID- 25436596 TI - How colonization factors are linked to outbreaks of methicillin-resistant Staphylococcus aureus: the roles of SasX and ACME. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is the most frequent cause of hospital-associated morbidity and mortality. One reason why MRSA has remained a serious threat to public health is that new clones of MRSA constantly keep re emerging. These new clones are better adapted to thrive in the hospital environment or even the community than their predecessors because they have developed increased and diversified antibiotic resistance and/or enhanced virulence. In addition, non-symptomatic colonization has been identified as a risk factor for subsequent MRSA infection; therefore, acquisition of factors promoting colonization has gained increased attention regarding the surge of MRSA outbreak clones. Two specific genes or genetic loci, namely sasX and the arginine catabolic mobile element (ACME), could recently be linked to the epidemiological success of MRSA clones, supporting the notion that colonization factors play a crucial role in MRSA outbreaks. SasX is a surface protein that enhances nasal colonization. ACME contains an arc arginine deiminase gene cluster promoting the survival of MRSA in the acidic skin environment, in addition to a polyamine resistance gene that deals with the increased production of toxic polyamines by the host that is prompted by arc. Notably, a better understanding of MRSA colonization on the molecular level may lead to eradication strategies based on vaccination or bacterial interference, with great promise to decrease MRSA infection rates. PMID- 25436598 TI - Does positive affect change in old age? Results from a 22-year longitudinal study. AB - The authors examined longitudinal change in positive affect (PA), a component of subjective well-being. Positive affect was assessed with the PA subscale of the Center for Epidemiologic Studies-Depression Scale (Radloff, 1977) in a sample of individuals from the PAQUID cohort (n = 3,777; age 62-101 years, M = 75.46, SD = 6.91 at Wave 1) over a period of 22 years (10 waves of data). Latent growth curve modeling was used to assess change in PA. A quadratic latent growth curve was found to characterize the latent growth pattern of PA in our sample, indicating linear change before a decline phase. These results were discussed with reference to the well-being paradox. PMID- 25436597 TI - Position paper of Italian rheumatologists on the use of biosimilar drugs. AB - The recent availability of biosimilars as a result of the expiry of the patents of first-generation biotechnological drugs may theoretically reduce the direct costs of such treatments, making their use accessible to a larger number of patients. However, the currently available clinical data refer to a relatively small number of patients, and do not provide sufficient information concerning long-term efficacy and safety or the frequency of rare adverse events. Given the importance of the introduction of biosimilar drugs and the limitations of our current knowledge of their efficacy and safety profiles, we believe it is mandatory to draw up a position paper for Italian Rheumatologists. Moreover, in order to guarantee their safety, it is mandatory to indicate behavioural rules for the involved specialists and competent authorities, and perform ad hoc clinical trials and appropriate drug surveillance. PMID- 25436599 TI - Nice to meet you--adult age differences in empathic accuracy for strangers. AB - Empathic accuracy is the ability to correctly identify others' thoughts and feelings. Based on evidence from past laboratory experiments, researchers concluded that this ability decreases throughout adulthood. This conclusion, however, was mostly based on evidence regarding isolated components of the ability to read others' thoughts and feelings (e.g., inferring thoughts or feelings from facial expressions presented without context). In contrast, empathic accuracy involves the integration of a multitude of such inferences from diverse sources of information that are available in everyday interactions (e.g., facial and bodily expressions, prosody, communication content, situational context, etc.). To strengthen empirical evidence on age differences in this integrative ability, we assessed empathic accuracy in dyadic interactions between 102 younger (20-31 years) and 106 older (69-80 years) women, paired in same-age or mixed-age dyads. In these interactions, older women were only less empathically accurate than younger women when judging their interaction partner's negative feelings and when judging thoughts that accompanied experiences of negative affect. In contrast, there were no age differences in empathic accuracy for positive feelings and for thoughts accompanying experiences of positive affect. These results were independent of the age of the interaction partner. The current study thus provides further evidence that age differences in empathic accuracy (a) may be qualified by situational properties, such as valence of inferred content, and (b) can be less pronounced when integration of multiple sources of information is possible than research investigating isolated information channels has thus far suggested. PMID- 25436600 TI - Pathogens: a new open access journal serving all those interested in infectious disease. AB - Infection ranks alongside cardiovascular disease as the major cause of human death across the world. Word Health Organization data for 2002 shows that 26% of all deaths, almost 15 million in number, were due to infectious disease with HIV/AIDS, TB and malaria being the top three responsible infections. A significant proportion of these deaths were due to lower respiratory infections and diarrheal diseases in children. The worldwide morbidity associated with infectious disease is incalculable. When considered along with the consequences of infection in animals, it is hard to imagine any other disease that has such a significant impact on our lives-on health systems, on agriculture and on world economics. Our understanding of the agents responsible for infections-bacteria, fungi, parasites, prions and viruses-has an interesting history that heralds the great developments in modern biology and demonstrates how an understanding of disease pathogenesis can lead to successful prophylactic and therapeutic interventions. Van Leeuwenhoek's first observation of bacteria under the light microscope, John Snow's investigations tracing the source of a cholera epidemic in Victorian London's Soho and Pasteur's vaccines for rabies and anthrax contributed to an acceptance of the germ theory of disease and to the rational, scientific application of this knowledge to develop innovative disease control measures ranging from hygienic practices to antibiotics. [...]. PMID- 25436601 TI - Interaction of phenol-soluble modulins with phosphatidylcholine vesicles. AB - Several members of the staphylococcal phenol-soluble modulin (PSM) peptide family exhibit pronounced capacities to lyse eukaryotic cells, such as neutrophils, monocytes, and erythrocytes. This is commonly assumed to be due to the amphipathic, alpha-helical structure of PSMs, giving PSMs detergent-like characteristics and allowing for a relatively non-specific destruction of biological membranes. However, the capacities of PSMs to lyse synthetic phospholipid vesicles have not been investigated. Here, we analyzed lysis of synthetic phosphatidylcholine (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, POPC) vesicles by all Staphylococcus aureus and S. epidermidis PSMs. In addition, we investigated the lytic capacities of culture filtrates obtained from different S. aureus PSM deletion mutants toward POPC vesicles. Our results show that all staphylococcal PSMs have phospholipid vesicle-lysing activity and the capacity of S. aureus culture filtrate to lyse POPC vesicles is exclusively dependent on PSMs. Notably, we observed largely differing capacities among PSM peptides to lyse POPC vesicles. Interestingly, POPC vesicle-lytic capacities did not correlate with those previously seen for the lysis of eukaryotic cells. For example, the beta-type PSMs were strongly lytic for POPC vesicles, but are known to exhibit only very low lytic capacities toward neutrophils and erythrocytes. Thus our results also suggest that the interaction between PSMs and eukaryotic membranes is more specific than previously assumed, potentially depending on additional structural features of those membranes, such as phospholipid composition or yet unidentified docking molecules. PMID- 25436602 TI - Evaluation of the Cobas 4800 HPV Test for Detecting High-Risk Human Papilloma Virus in Cervical Cytology Specimens. AB - As new platforms for high-risk strains of human papillomavirus (HR HPV) testing are introduced into the clinical laboratory, it is important to verify their performance and agreement. In this validation study, post-aliquot cervical cytopathology specimens (n = 226) were used to analyze agreement between the Invader HPV ASR assay (Hologic) and the recently FDA-approved Cobas 4800 high risk HPV assay (Roche). Residual sample from 92 Invader positive and 134 Invader negative samples were analyzed with the Cobas 4800 test. Discordant results were further analyzed by Linear Array HPV genotype testing (Roche). To assess intra- and inter-run precision, 31 Invader positive samples were run in duplicate on the Cobas 4800 by different operators over multiple days and purchased HR HPV DNA control was run in ten replicates. Cross-contamination during cytology processing was evaluated by spiking 6 Invader negative samples with different volumes of Acrometrix HPV High Risk Positive Control and analyzed on the Cobas with 4 negative samples in between. There was significant discordance between the assays (p < 0.001; exact McNemar X2 test), with overall agreement of 82%. Of the 92 Invader positive samples, 58 (63%) were positive with the Cobas assay, while 34 (37%) were negative. Of the 134 Invader negative samples, 6 (4%) were positive with the Cobas while 128 (96%) were negative. The observed discordance may be attributed to the previously described false positive rate of the Invader ASR assay. The Cobas 4800 high-risk HPV assay is a viable new tool for use in the clinical setting to identify high-risk HPV. PMID- 25436605 TI - Risk and protective factors for falls from furniture in young children: multicenter case-control study. AB - IMPORTANCE: Falls from furniture are common in young children but there is little evidence on protective factors for these falls. OBJECTIVE: To estimate associations for risk and protective factors for falls from furniture in children aged 0 to 4 years. DESIGN, SETTING, AND PARTICIPANTS: Multicenter case-control study at hospitals, minor injury units, and general practices in and around 4 UK study centers. Recruitment commenced June 14, 2010, and ended April 27, 2012. Participants included 672 children with falls from furniture and 2648 control participants matched on age, sex, calendar time, and study center. Thirty-five percent of cases and 33% of control individuals agreed to participate. The mean age was 1.74 years for cases and 1.91 years for control participants. Fifty-four percent of cases and 56% of control participants were male. Exposures included safety practices, safety equipment use, and home hazards. MAIN OUTCOMES AND MEASURES: Falls from furniture occurring at the child's home resulting in attendance at an emergency department, minor injury unit, or hospital admission. RESULTS: Compared with parents of control participants, parents of cases were significantly more likely not to use safety gates in the home (adjusted odds ratio [AOR], 1.65; 95% CI, 1.29-2.12) and not to have taught their children rules about climbing on kitchen objects (AOR, 1.58; 95% CI, 1.16-2.15). Cases aged 0 to 12 months were significantly more likely to have been left on raised surfaces (AOR, 5.62; 95% CI, 3.62-8.72), had their diapers changed on raised surfaces (AOR, 1.89; 95% CI, 1.24-2.88), and been put in car/bouncing seats on raised surfaces (AOR, 2.05; 95% CI, 1.29-3.27). Cases 3 years and older were significantly more likely to have played or climbed on furniture (AOR, 9.25; 95% CI, 1.22-70.07). Cases were significantly less likely to have played or climbed on garden furniture (AOR, 0.74; 95% CI, 0.56-0.97). CONCLUSIONS AND RELEVANCE: If estimated associations are causal, some falls from furniture may be prevented by incorporating advice into child health contacts, personal child health records, and home safety assessments about use of safety gates; not leaving children, changing diapers, or putting children in car/bouncing seats on raised surfaces; allowing children to play or climb on furniture; and teaching children safety rules about climbing on objects. PMID- 25436604 TI - Arginine Methyltransferases Are Regulated by Epstein-Barr Virus in B Cells and Are Differentially Expressed in Hodgkin's Lymphoma. AB - Although there is increasing evidence that aberrant expression of those enzymes which control protein arginine methylation contribute to carcinogenesis, their de regulation by oncogenic viruses in primary cells has yet to be reported. We first show that the protein arginine methyltransferases, CARM1, PRMT1 and PRMT5 are strongly expressed in Hodgkin Reed-Sternberg (HRS) cells, and up-regulated in Hodgkin's lymphoma (HL) cell lines. Given that Epstein-Barr virus (EBV) can be detected in approximately 50% of primary HL, we next examined how EBV infection of germinal centre (GC) B cells, the presumptive precursors of HRS cells, modulated the expression of these proteins. EBV infection of GC B cells was followed by the up-regulation of CARM1, PRMT1 and PRMT5, and by the down regulation of the arginine deiminase, PADI4. Latent membrane protein 1 (LMP1), the major EBV transforming gene was shown to induce PRMT1 in GC B cells and in a stably transfected B cell line. The recent development of compounds which inhibit PRMT-mediated reactions provides a compelling case for continuing to dissect the contribution of virus induced changes in these proteins to lymphomagenesis. PMID- 25436603 TI - Similarities between the Epstein-Barr Virus (EBV) Nuclear Protein EBNA1 and the Pioneer Transcription Factor FoxA: Is EBNA1 a "Bookmarking" Oncoprotein that Alters the Host Cell Epigenotype? AB - EBNA1, a nuclear protein expressed in all EBV-associated neoplasms is indispensable for the maintenance of the viral episomes in latently infected cells. EBNA1 may induce genetic alterations by upregulating cellular recombinases, production of reactive oxygen species (ROS) and affecting p53 levels and function. All these changes may contribute to tumorigenesis. In this overview we focus, however, on the epigenetic alterations elicited by EBNA1 by drawing a parallel between EBNA1 and the FoxA family of pioneer transcription factors. Both EBNA1 and FoxA induce local DNA demethylation, nucleosome destabilization and bind to mitotic chromosomes. Local DNA demethylation and nucleosome rearrangement mark active promoters and enhancers. In addition, EBNA1 and FoxA, when associated with mitotic chromatin may "bookmark" active genes and ensure their reactivation in postmitotic cells (epigenetic memory). We speculate that DNA looping induced by EBNA1-EBNA1 interactions may reorganize the cellular genome. Such chromatin loops, sustained in mitotic chromatin similarly to the long-distance interactions mediated by the insulator protein CTCF, may also mediate the epigenetic inheritance of gene expression patterns. We suggest that EBNA1 has the potential to induce patho-epigenetic alterations contributing to tumorigenesis. PMID- 25436606 TI - Distinct behaviour of sorafenib in experimental cachexia-inducing tumours: the role of STAT3. AB - The presence of a tumour is very often associated with wasting in the host, affecting both skeletal muscle and adipose tissue. In the present study we used sorafenib, a multi-kinase inhibitor with anti-tumour activity, in order to investigate the effects of chemotherapy on wasting. Three different experimental mouse tumour models were included: C26 colon carcinoma, B16 melanoma and Lewis lung carcinoma (LLC). The results obtained clearly show that sorafenib was effective in reducing tumour growth in LLC and B16 models, while it had no effect on C26. Interestingly, sorafenib treatment reduced the signs of muscle wasting and improved the physical activity in the LLC model and also in the C26, despite the absence of antineoplastic action in the latter. Our results discard a role for IL-6 in the action of sorafenib since the drug did not affect the levels of this cytokine. Conversely, sorafenib seems to act by influencing both STAT3 and ERK activity at muscle level, leading to reduced accumulation of Pax7 and atrogin 1. Sorafenib may interfere with muscle wasting by decreasing the activation of these signal transduction pathways. PMID- 25436607 TI - Myeloid zinc finger 1 (Mzf1) differentially modulates murine cardiogenesis by interacting with an Nkx2.5 cardiac enhancer. AB - Vertebrate heart development is strictly regulated by temporal and spatial expression of growth and transcription factors (TFs). We analyzed nine TFs, selected by in silico analysis of an Nkx2.5 enhancer, for their ability to transactivate the respective enhancer element that drives, specifically, expression of genes in cardiac progenitor cells (CPCs). Mzf1 showed significant activity in reporter assays and bound directly to the Nkx2.5 cardiac enhancer (Nkx2.5 CE) during murine ES cell differentiation. While Mzf1 is established as a hematopoietic TF, its ability to regulate cardiogenesis is completely unknown. Mzf1 expression was significantly enriched in CPCs from in vitro differentiated ES cells and in mouse embryonic hearts. To examine the effect of Mzf1 overexpression on CPC formation, we generated a double transgenic, inducible, tetOMzf1-Nkx2.5 CE eGFP ES line. During in vitro differentiation an early and continuous Mzf1 overexpression inhibited CPC formation and cardiac gene expression. A late Mzf1 overexpression, coincident with a second physiological peak of Mzf1 expression, resulted in enhanced cardiogenesis. These findings implicate a novel, temporal-specific role of Mzf1 in embryonic heart development. Thereby we add another piece of puzzle in understanding the complex mechanisms of vertebrate cardiac development and progenitor cell differentiation. Consequently, this knowledge will be of critical importance to guide efficient cardiac regenerative strategies and to gain further insights into the molecular basis of congenital heart malformations. PMID- 25436608 TI - Characterisation of translation elongation factor eEF1B subunit expression in mammalian cells and tissues and co-localisation with eEF1A2. AB - Translation elongation is the stage of protein synthesis in which the translation factor eEF1A plays a pivotal role that is dependent on GTP exchange. In vertebrates, eEF1A can exist as two separately encoded tissue-specific isoforms, eEF1A1, which is almost ubiquitously expressed, and eEF1A2, which is confined to neurons and muscle. The GTP exchange factor for eEF1A1 is a complex called eEF1B made up of subunits eEF1Balpha, eEF1Bdelta and eEF1Bgamma. Previous studies have cast doubt on the ability of eEF1B to interact with eEF1A2, suggesting that this isoform might use a different GTP exchange factor. We show that eEF1B subunits are all widely expressed to varying degrees in different cell lines and tissues, and at different stages of development. We show that ablation of any of the subunits in human cell lines has a small but significant impact on cell viability and cycling. Finally, we show that both eEF1A1 and eEF1A2 colocalise with all eEF1B subunits, in such close proximity that they are highly likely to be in a complex. PMID- 25436610 TI - A machine reading system for assembling synthetic paleontological databases. AB - Many aspects of macroevolutionary theory and our understanding of biotic responses to global environmental change derive from literature-based compilations of paleontological data. Existing manually assembled databases are, however, incomplete and difficult to assess and enhance with new data types. Here, we develop and validate the quality of a machine reading system, PaleoDeepDive, that automatically locates and extracts data from heterogeneous text, tables, and figures in publications. PaleoDeepDive performs comparably to humans in several complex data extraction and inference tasks and generates congruent synthetic results that describe the geological history of taxonomic diversity and genus-level rates of origination and extinction. Unlike traditional databases, PaleoDeepDive produces a probabilistic database that systematically improves as information is added. We show that the system can readily accommodate sophisticated data types, such as morphological data in biological illustrations and associated textual descriptions. Our machine reading approach to scientific data integration and synthesis brings within reach many questions that are currently underdetermined and does so in ways that may stimulate entirely new modes of inquiry. PMID- 25436609 TI - TP53 Pro72 allele is enriched in oral tongue cancer and frequently mutated in esophageal cancer in India. AB - PURPOSE: The tumor suppressor p53 is known to be inactivated frequently in various cancers. In addition, germline polymorphisms in TP53 are known to affect protein function and influence risk of developing different types of cancers. In this study, we analyzed the association of TP53 Pro72Arg polymorphism with squamous cell carcinoma of oral tongue (SCCOT) and esophagus (ESCC) in India. METHODS: We assessed the distribution of TP53 Pro72Arg polymorphism in one hundred and fifteen and eighty two SCCOT and ESCC patients, respectively, with respect to one hundred and ten healthy controls from the same population. In addition, we analyzed association of the polymorphism with several clinico pathological and molecular parameters. RESULTS: Pro72 allele was significantly enriched in SCCOT patients compared to the healthy control group but neither allele was enriched in ESCC. Interestingly, Pro72 allele was preferentially mutated in ESCC which was confirmed by analysis of samples heterozygous for Pro72Arg. CONCLUSIONS: Our study revealed the association of Pro72 allele with SCCOT suggesting the effect of this polymorphism on SCCOT risk. Preferential mutation of Pro72 allele exclusively in ESCC indicates the need for further studies to understand the tissue specific effect of p53 polymorphism. PMID- 25436611 TI - Seed-mediated gene flow promotes genetic diversity of weedy rice within populations: implications for weed management. AB - Increased infestation of weedy rice-a noxious agricultural pest has caused significant reduction of grain yield of cultivated rice (Oryza sativa) worldwide. Knowledge on genetic diversity and structure of weedy rice populations will facilitate the design of effective methods to control this weed by tracing its origins and dispersal patterns in a given region. To generate such knowledge, we studied genetic diversity and structure of 21 weedy rice populations from Sri Lanka based on 23 selected microsatellite (SSR) loci. Results indicated an exceptionally high level of within-population genetic diversity (He = 0.62) and limited among-population differentiation (Fst = 0.17) for this predominantly self pollinating weed. UPGMA analysis showed a loose genetic affinity of the weedy rice populations in relation to their geographical locations, and no obvious genetic structure among populations across the country. This phenomenon was associated with the considerable amount of gene flow between populations. Limited admixture from STRUCTURE analyses suggested a very low level of hybridization (pollen-mediated gene flow) between populations. The abundant within-population genetic diversity coupled with limited population genetic structure and differentiation is likely caused by the considerable seed-mediated gene flow of weedy rice along with the long-distance exchange of farmer-saved rice seeds between weedy-rice contaminated regions in Sri Lanka. In addition to other effective weed management strategies, promoting the application of certified rice seeds with no weedy rice contamination should be the immediate action to significantly reduce the proliferation and infestation of this weed in rice ecosystems in countries with similar rice farming styles as in Sri Lanka. PMID- 25436612 TI - Self-reported body fat change in HIV-infected men is a marker of decline in physical health-related quality of life with aging, independent of co-morbidity. AB - OBJECTIVE: Self-perception of changes in body fat among HIV+ persons is associated with decreased health related quality of life in cross-sectional studies. The longitudinal impact of body fat changes on health related quality of life, while accounting for comorbidity and anatomic location or severity of body fat changes, is unknown. DESIGN: This was a longitudinal analysis of HIV+ and HIV Multicenter AIDS Cohort Study (MACS) participants who completed questionnaires assessing self-perceived body fat changes (baseline visit) and a health related quality of life (Short Form-36) at baseline and then >=5 years later. METHODS: Relationships between body fat changes and change in Short Form-36 Physical and Mental Component Summary scores were investigated using mixed-model regression. RESULTS: We studied 270 HIV+ and 247 HIV- men. At baseline, >=50% of HIV+ men reported body fat changes; physical component but not mental component summary scores were lower among HIV+ men who reported moderate/severe leg or abdominal fat changes (p<0.05). At follow-up, physical component summary scores were significantly lower among men with face, leg, or abdominal fat changes compared to men without perceived fat changes (p<0.05). No significant changes were seen in mental component scores by fat change location or severity. In the final model, body fat changes at any site or severity were significant predictors of a decline in physical component summary score (p<0.05), independent of demographics or comorbidities. Mental component summary score was not associated with body fat changes, but higher mental component summary score was associated with increasing age and time. CONCLUSIONS: Negative self-perceived body fat changes were associated with decline in physical health related quality of life, independent of comorbidities, and may be a marker of an increased risk for physical function decline with aging. PMID- 25436613 TI - Impact of diabetes mellitus on the prognosis of patients with hepatocellular carcinoma after curative hepatectomy. AB - BACKGROUND: The influence of diabetes mellitus (DM) on the prognosis of patients with hepatocellular carcinoma (HCC) remains controversial. Here we investigated the impact of DM on the prognosis of such patients after curative hepatectomy. METHODS: A consecutive cohort of 505 patients with HCC (134 with DM, 371 without) underwent curative hepatectomy were retrospectively evaluated. Postoperative morbidity and mortality, overall survival (OS) and disease-free survival (DFS) were compared between patients with or without DM. Independent prognostic predictors were identified using the Cox proportional hazards model. RESULTS: Patients with or without DM showed similar morbidity and 30- and 90- day mortality after curative hepatectomy (all P>0.05), as well as similar DFS at 1, 3, 5 years (P = 0.781). However, the group of patients with DM showed significantly lower OS at 1, 3, 5 years than the group without DM (P = 0.038). Similar results were obtained in the propensity-matched cohort. Cox multivariate analysis identified DM as an independent predictor of poor OS, but not of poor DFS. We repeat compared OS and DFS for DM and non-DM subgroups defined according to the presence or absence of hepatitis B virus infection and cirrhosis. Similar results were obtained in all subgroups except the non-cirrhotic subgroup which showed patients with and without DM had similar OS. CONCLUSIONS: DM does not significantly affect the postoperative morbidity or mortality or the DFS of patients with HCC after curative hepatectomy. It is, however, associated with significantly lower OS, especially in patients with cirrhosis. PMID- 25436614 TI - Efficacy and safety of fixed-dose artesunate-amodiaquine vs. artemether lumefantrine for repeated treatment of uncomplicated malaria in Ugandan children. AB - The safety and efficacy of the two most widely used fixed-dose artemisinin-based combination therapies (ACT), artesunate-amodiaquine (ASAQ) and artemether lumefantrine (AL) are well established for single episodes of uncomplicated Plasmodium falciparum malaria, but the effects of repeated, long-term use are not well documented. We conducted a 2-year randomized, open-label, longitudinal, phase IV clinical trial comparing the efficacy and safety of fixed-dose ASAQ and AL for repeated treatment of uncomplicated malaria in children under 5 years at Nagongera Health Centre, Uganda. Participants were randomized to ASAQ or AL and all subsequent malaria episodes were treated with the same regimen. 413 children were enrolled and experienced a total of 6027 malaria episodes (mean 15; range, 1 26). For the first malaria episode, the PCR-corrected-cure rate for ASAQ (97.5%) was non-inferior to that for AL (97.0%; 95% CI [-0.028; 0.037]). PCR-corrected cure rates for subsequent malaria episodes that had over 100 cases (episodes 2 18), ranged from 88.1% to 98.9% per episode, with no clear difference between the treatment arms. Parasites were completely cleared by day 3 for all malaria episodes and gametocyte carriage was less than 1% by day 21. Fever clearance was faster in the ASAQ group for the first episode. Treatment compliance for subsequent episodes (only first dose administration observed) was close to 100%. Adverse events though common were similar between treatment arms and mostly related to the disease. Serious adverse events were uncommon, comparable between treatment arms and resolved spontaneously. Anemia and neutropenia occurred in <0.5% of cases per episode, abnormal liver function tests occurred in 0.3% to 1.4% of cases. Both regimens were safe and effective for repeated treatment of malaria. TRIAL REGISTRATION: Current Controlled Trials NCT00699920. PMID- 25436615 TI - The proapoptotic protein BNIP3 interacts with VDAC to induce mitochondrial release of endonuclease G. AB - BNIP3 is a proapoptotic protein that induces cell death through a mitochondria mediated pathway. We reported previously that mitochondrial localization of BNIP3 and translocation of EndoG from mitochondria to the nucleus are critical steps of the BNIP3 pathway. It is not clear, however, that how BNIP3 interacts with mitochondria. Here we show that expression of BNIP3 resulted in mitochondrial release and nuclear translocation of EndoG. Incubation of a recombinant GST-BNIP3 protein with freshly isolated mitochondria led to the integration of BNIP3 into mitochondria, reduction in the levels of EndoG in mitochondria and the presence of EndoG in the supernatant that was able to cleave chromatin DNA. Co immunoprecipitation and mass spectrometry analysis reveals that BNIP3 interacted with the voltage-dependent anion channel (VDAC) to increase opening probabilities of mitochondrial permeability transition (PT) pores and induce mitochondrial release of EndoG. Blocking VDAC with a VDAC antibody largely abolished mitochondrial localization of BNIP3 and prevented EndoG release. Together, the data identify VDAC as an interacting partner of BNIP3 and support endonuclease G as a mediator of the BNIP3 pathway. PMID- 25436617 TI - Application of an importance-performance analysis approach to evaluate an acupuncture treatment information system. AB - Acupuncture treatment has become increasingly popular worldwide, but it is not without risk to the patient. Most physicians in Taiwan have adopted a computerized physician order entry system for traditional Chinese medicine. Use of such a system can prevent some adverse events related to a paper-based system but increases other unexpected risks. This study is the first to introduce a patient safety-based acupuncture treatment information system that integrates advanced healthcare devices to reduce the risks associated with acupuncture treatment using a computerized physician order entry system for traditional Chinese medicine. The acupuncture treatment information system considerably improved patient safety and increased clinicians' workflow efficiency. The importance-performance analysis indicated that improvement in the vital sign measurement function was of the highest priority. In conclusion, acupuncture treatment--the demand for which is increasing--can be performed more safely using an acupuncture treatment information system. PMID- 25436616 TI - Fibromyalgia is associated with coronary heart disease: a population-based cohort study. AB - BACKGROUND AND OBJECTIVES: We examined whether patients with a diagnosis of fibromyalgia have an increased risk of coronary heart disease (CHD), compared with age- and sex-matched control patients. We hypothesized that patients diagnosed with fibromyalgia are at increased risk of adverse coronary events. METHODS: Using a matched-cohort study design, we analyzed data retrieved from the Longitudinal Health Insurance Database 2000 released by the National Health Research Institute, Taiwan. The Longitudinal Health Insurance Database 2000 includes medical claims data and registration files for 1 million enrollees randomly selected from the 2000 Registry for Beneficiaries (n = 23.72 million) of the National Health Insurance program. Patients treated for fibromyalgia at least once a month for 3 consecutive months following their initial diagnosis were enrolled in our study. The primary end point was the composite of CHD events, including percutaneous coronary interventions and coronary artery bypass grafting procedures. A propensity score was estimated by a logistic regression method, in which the fibromyalgia status was regressed on baseline prognostic factors. The hazard ratios and the 95% confidence intervals were estimated using multivariate Cox proportional-hazards regression models while adjusting for the propensity score. RESULTS: After adjusting for the propensity score, the patients with fibromyalgia showed a significantly higher subsequent risk of a CHD event (hazard ratio, 2.11; 95% confidence interval, 1.46-3.05; P < 0.001) than the patients without fibromyalgia. CONCLUSIONS: An association between fibromyalgia and CHD appears to exist. PMID- 25436618 TI - Sodium magnetic resonance imaging of ankle joint in cadaver specimens, volunteers, and patients after different cartilage repair techniques at 7 T: initial results. AB - OBJECTIVES: The goal of cartilage repair techniques such as microfracture (MFX) or matrix-associated autologous chondrocyte transplantation (MACT) is to produce repair tissue (RT) with sufficient glycosaminoglycan (GAG) content. Sodium magnetic resonance imaging (MRI) offers a direct and noninvasive evaluation of the GAG content in native cartilage and RT. In the femoral cartilage, this method was able to distinguish between RTs produced by MFX and MACT having different GAG contents. However, it needs to be clarified whether sodium MRI can be useful for evaluating RT in thin ankle cartilage. Thus, the aims of this 7-T study were (1) to validate our sodium MRI protocol in cadaver ankle samples, (2) to evaluate the sodium corrected signal intensities (cSI) in cartilage of volunteers, (3) and to compare sodium values in RT between patients after MFX and MACT treatment. MATERIALS AND METHODS: Five human cadaver ankle samples as well as ankles of 9 asymptomatic volunteers, 6 MFX patients and 6 MACT patients were measured in this 7-T study. Sodium values from the ankle samples were compared with histochemically evaluated GAG content. In the volunteers, sodium cSI values were calculated in the cartilages of ankle and subtalar joint. In the patients, sodium cSI in RT and reference cartilage were measured, morphological appearance of RT was evaluated using the magnetic resonance observation of cartilage repair tissue (MOCART) scoring system, and clinical outcome before and after surgery was assessed using the American Orthopaedic Foot and Ankle Society score and Modified Cincinnati Knee Scale. All regions of interest were defined on morphological images and subsequently transferred to the corresponding sodium images. Analysis of variance, t tests, and Pearson correlation coefficients were evaluated. RESULTS: In the patients, significantly lower sodium cSI values were found in RT than in reference cartilage for the MFX (P = 0.007) and MACT patients (P = 0.008). Sodium cSI and MOCART scores in RT did not differ between the MFX and MACT patients (P = 0.185). No significant difference in sodium cSI was found between reference cartilage of the volunteers and the patients (P = 0.355). The patients showed significantly higher American Orthopaedic Foot and Ankle Society and Modified Cincinnati scores after treatment than they did before treatment. In the volunteers, sodium cSI was significantly higher in the tibial cartilage than in the talar cartilage of ankle joint (P = 0.002) and in the talar cartilage than in the calcaneal cartilage of subtalar joint (P < 0.001). Data from the cadaver ankle samples showed a strong linear relationship between the sodium values and the histochemically determined GAG content (r = 0.800; P < 0.001; R = 0.639). CONCLUSIONS: This study demonstrates the feasibility of in vivo quantification of sodium cSI, which can be used for GAG content evaluation in thin cartilages of ankle and subtalar joints at 7 T. A strong correlation observed between the histochemically evaluated GAG content and the sodium values proved the sufficient sensitivity of sodium MRI to changes in the GAG content of cartilages in the ankle. Both MFX and MACT produced RT with lower sodium cSI and, thus, of lower quality compared with reference cartilage in the patients or in the volunteers. Our results suggest that MFX and MACT produce RT with similar GAG content and similar morphological appearance in patients with similar surgery outcome. Sodium MRI at 7 T allows a quantitative evaluation of RT quality in the ankle and may thus be useful in the noninvasive assessment of new cartilage repair procedures. PMID- 25436619 TI - Depression, posttraumatic stress disorder, and grade point average among student servicemembers and veterans. AB - The current study examined relationships among self-reported depression severity, posttraumatic stress disorder (PTSD) symptom severity, and grade point average (GPA) among student servicemembers and veterans. We asked 422 student servicemembers and veterans (72% male, 86% Caucasian, mean age = 36.29 yr) to complete an anonymous online survey that assessed self-reported GPA, depression severity, PTSD severity, and frequency of academic problems (late assignments, low grades, failed exams, and skipped classes). Female respondents reported a slightly higher GPA than males (3.56 vs 3.41, respectively, p = 0.01). Depression symptoms (beta weight = -0.174, p = 0.03), male sex (beta weight = 0.160, p = 0.01), and younger age (beta weight = 0.155, p = 0.01) were associated with lower GPA but not PTSD symptoms (beta weight = -0.040, p = 0.62), although the interaction of depression and PTSD symptoms showed a nonsignificant inverse relationship with GPA (beta weight = -0.378, p = 0.08). More severe depression was associated with turning in assignments late (beta weight = 0.171, p = 0.03), failed exams (beta weight = 0.188, p = 0.02), and skipped classes (beta weight = 0.254, p = 0.01). The relationship of depression with self-reported GPA was mediated by frequency of failed examns. Results suggest that student servicemembers and veterans with greater emotional distress also report worse academic performance. PMID- 25436620 TI - Influence of number of sets on blood pressure and heart rate variability after a strength training session. AB - The purpose of this study was to compare the acute effects of 1, 3, and 5 sets of strength training (ST), on heart rate variability (HRV) and blood pressure. Eleven male volunteers (age: 26.1 +/- 3.6 years; body mass: 74.1 +/- 8.1 kg; height: 172 +/- 4 cm) with at least 6 months previous experience in ST participated in the study. After determining the 1 repetition maximum (1RM) load for the bench press (BP), lat pull down (LPD), shoulder press (SP), biceps curl (BC), triceps extension (TE), leg press (LP), leg extension (LE), and leg curl (LC), the participants performed 3 different exercise sequences in a random order and 72 hours apart. During the first sequence, subjects performed a single set of 8-10 repetitions, at 70% 1RM, and with 2-minute rest interval between exercises. Exercises were performed in the following order: BP, LPD, SP, BC, TE, LP, LE, and LC. During the second sequence, subjects performed the same exercise sequence, with the same intensity, 2-minute rest interval between sets and exercises, but with 3 consecutive sets of each exercise. During the third sequence, the same protocol was followed but with 5 sets of each exercise. Before and after the training sessions, blood pressure and HRV were measured. The statistical analysis demonstrated a greater duration of postexercise hypotension after the 5-set program vs. the 1 set or 3 sets (p <= 0.05). However, the 5-set program promoted a substantial cardiac stress, as demonstrated by HRV (p <= 0.05). These results indicate that 5 sets of 8-10 repetitions at 70% 1RM load may provide the ideal stimulus for a postexercise hypotensive response. Therefore, ST composed of upper and lower-body exercises and performed with high volumes are capable of producing significant and extended postexercise hypotensive response. In conclusion, strength and conditioning professionals can prescribe 5 sets per exercises if the goal is to reduce blood pressure after training. In addition, these findings may have importance, specifically in the early phase of high blood pressure development, but more research is needed in hypertensive populations to validate this hypothesis. PMID- 25436621 TI - Peak power in the hexagonal barbell jump squat and its relationship to jump performance and acceleration in elite rugby union players. AB - Recent research suggests that jump squats with a loaded hexagonal barbell are superior for peak power production to comparable loads in a traditional barbell loaded jump squat. The aim of this study was to investigate the relationship between relative peak power output during performance of the hexagonal barbell jump squat (HBJS), countermovement jump (CMJ) height, and linear acceleration speed in rugby union players. Seventeen professional rugby union players performed 10- and 20-m sprints, followed by a set of 3 unloaded CMJs and a set of 3 HBJS at a previously determined optimal load corresponding with peak power output. The relationship between HBJS relative peak power output, 10- and 20-m sprint time, and CMJ height was investigated using correlation analysis. The contribution of HBJS relative peak power output and CMJ height to 10- and 20-m sprint time was investigated using standard multiple regression. Strong, significant, inverse correlations were observed between HBJS relative peak power output, 10-m sprint time (r = -0.70, p < 0.01), and 20-m sprint time (r = -0.75, p < 0.01). A strong, significant, positive correlation was observed between HBJS relative peak power output and CMJ height (r = 0.80, p < 0.01). Together, HBJS relative peak power output and CMJ height explained 46% of the variance in 10-m sprint time while explaining 59% of the variance in 20-m sprint time. The findings of the current study demonstrate a significant relationship between relative peak power in the HBJS and athletic performance as quantified by CMJ height and 10- and 20-m sprint time. PMID- 25436622 TI - Correlation between cardiac autonomic modulation in response to orthostatic stress and indicators of quality of life, physical capacity, and physical activity in healthy individuals. AB - Increased heart rate variability (HRV) at rest is frequently associated to maximal oxygen uptake (VO2max), physical activity, and markers of quality of life (QoL). However, the HRV has not been observed during physical exercise or orthostatic (ORT) challenge. This study investigated the associations of HRV changes (DeltaHRV) from rest at supine (SUP) to ORT positions with (VO2max), physical activity level, and QoL in young adults. Cardiac autonomic modulation was assessed by spectral analysis of R-R time series measured from SUP to ORT positions in 15 healthy volunteers (26 +/- 7 years). Questionnaires were applied for evaluation of QoL (SF-36 score), to estimate (VO2max), and to quantify physical activity (Baecke Sport Score). All HRV indices at SUP, but not ORT, strongly correlated to QoL, estimated (VO2max), and physical activity. The DeltaHRV from SUP to ORT showed significant correlations with all questionnaire scores (r = 0.52-0.61 for low frequency and r = -0.61 to -0.65 for high frequency, p <= 0.05). Higher vagal activity at rest and greater changes in adrenergic and parasympathetic modulation from SUP to ORT were detected in the volunteers exhibiting higher scores of QoL, estimated (VO2max), and physical activity. Taken together, the level of neural adaptations from resting SUP position to active standing, and physical activity and QoL questionnaires seem to be a simple approach to understand the physiological and lifestyle adaptations to exercise that may be applied to a large sample of subjects in almost any sports facilities at a low cost. PMID- 25436623 TI - Vertical jump performance of professional male and female volleyball players: effects of playing position and competition level. AB - Vertical jump (VJ) performance is an important element for successful volleyball practice. The aims of the study were (a) to explore the overall VJ performance of elite volleyball players of both sexes, (b) to explore the differences in VJ performance among different competition levels and different playing positions, and (c) to evaluate the sex-related differences in the role of the arm swing and 3-step approach with arm swing on the jump height. We assessed the VJ capacity in 253 volleyball players (113 males and 140 females) from Slovenian first and second Volleyball Division. The height of squat jump (SJ), countermovement jump, block jump, and attack jump was tested using an Optojump system. We observed significant differences (p <= 0.05) in VJ height between different levels of play that were most pronounced in the SJ. Position-related differences in VJ performance were observed in male players between receivers and setters (p <= 0.05), whereas in females, VJ performance across different playing positions seems equal. Finally, we found that male players significantly better use the arm swing during VJ than females (p <= 0.05), whereas the use of eccentric part of the jump and approach before the spike to improve VJ performance seem to be equally mastered activity in both sexes. These results could assist coaches in the development of jumping performance in volleyball players. Furthermore, presented normative data for jump heights of elite male and female volleyball players could be useful in selection and profiling of young volleyball players. PMID- 25436624 TI - Adaptation of local muscle blood flow and surface electromyography to repeated bouts of eccentric exercise. AB - The aim of this randomized controlled crossover study was to investigate the effect of a bout of unaccustomed eccentric exercise (ECC) followed by a consecutive bout of the same intensity on local muscle blood flow, amplitude, and frequency of the electromyographic (EMG) signal from the exercised tibialis anterior muscle. Sixteen healthy male participants (age, 25.7 (0.6) years; body mass index 24.8 (1) kg.m(-2) participated in this study. Two identical bouts of high-intensity ECC were performed on the tibialis anterior muscle 7 days apart. Control sessions involving no exercise were performed 4 weeks either before or after the exercise sessions. Changes in local total blood flow [DeltatHb], EMG root mean square, and median power frequency were recorded during isometric maximum voluntary contraction of ankle dorsiflexion. Measurements were performed before, immediately after, and the day after both ECCs (ECC1 and ECC2). The participants rested quietly in a chair in the control session. Eccentric exercise 1 led to a significant decrease in [DeltatHb] on the day after (p <= 0.05), whereas ECC2 did not. Median power frequency decreased significantly in ECC2 compared with ECC1 (p < 0.01). Root mean square was unchanged in all the instants. The present study showed that adaptation is depicted in the local muscle blood flow and the frequency contents of the EMG after an unaccustomed ECC inducing muscle soreness. These alterations provide a potential mechanism for a rapid adaptation, which decreases susceptibility of the muscle to develop further soreness in the subsequent ECC bout. PMID- 25436625 TI - Division I Hockey Players Generate More Power Than Division III Players During on and Off-Ice Performance Tests. AB - Current research has found anthropometric and physiological characteristics of hockey players that are correlated to performance. These characteristics, however, have never been examined to see whether significant differences exist between on- and off-ice performance markers at different levels of play; Division I, Elite Junior, and Division III. The purpose of this study was to examine the differences that may exist between these characteristics in Division I (24), Elite Junior (10), and Division III hockey (11) players. Forty-five (age: 18-24 years) hockey players completed anthropometric, on-ice, and off-ice tests to ascertain average measures for each division of play. On-ice testing was conducted in full hockey gear and consisted of acceleration, top-speed, and on ice repeated shift test (RST). Off-ice tests included vertical jump, Wingate, grip strength, and a graded exercise test performed on a skating treadmill to ascertain their (Equation is included in full-text article.). Division I players had significantly lower body fat than their Division III peers (p = 0.004). Division I players also scored significantly better on measures of anaerobic power; vertical jump (p = 0.001), Wingate peak power (p = 0.05), grip strength (p = 0.008), top speed (p = 0.001), and fastest RST course time (p = 0.001) than their Division III counterparts. There was no significant difference between Division I and Elite Junior players for any on- or off-ice performance variable. The results of this study indicate that performance differences between Division I and Division III hockey players seem to be primarily because of the rate of force production. PMID- 25436626 TI - A single set of biomechanical variables cannot predict jump performance across various jumping tasks. AB - Vertical jump performance is related to high-level function in athletics. The purpose of this study was to determine whether a single set of biomechanical variables exist that can predict vertical jump height during multiple jumping strategies: single foot jump, drop jump, and countermovement jump. Three dimensional mechanics were collected during the 3 different jumping tasks in 50 recreational male athletes. Three successful trials were analyzed for each jump type. Testing order was randomized to minimize fatigue effects, and the dominant limb was used for analysis. All discrete variables were correlated to jump height and the 10 variables that had the strongest correlation were inserted into a linear regression model to identify what variables predicted maximum jump height. No single set of variables that predicted jump height existed across all 3 jumping tasks. One foot jump height was predicted by peak knee power, peak hip extension moment, peak knee extension velocity, and the percentage of the trial when peak knee flexion velocity occurred (r = 0.58). Countermovement jump height was predicted by peak hip power, ankle range of motion, and knee range of motion (r = 0.65). Drop jump height was predicted by the peak vertical ground reaction force and the percentage of the trial when the peak hip velocity occurred (r = 0.37). A single set of variables was not identified that could predict jump performance across different types of jumping tasks; therefore, additional interventional investigations are needed to better understand how to alter and improve jump performance. PMID- 25436627 TI - Stature and jumping height are required in female volleyball, but motor coordination is a key factor for future elite success. AB - It was hypothesized that differences in anthropometry, physical performance, and motor coordination would be found between Belgian elite and sub-elite level female volleyball players using a retrospective analysis of test results gathered over a 5-year period. The test sample in this study consisted of 21 young female volleyball players (15.3 +/- 1.5 years) who were selected to train at the Flemish Top Sports Academy for Volleyball in 2008. All players (elite, n = 13; sub-elite, n = 8) were included in the same talent development program, and the elite-level athletes were of a high to very high performance levels according to European competition level in 2013. Five multivariate analyses of variance were used. There was no significant effect of playing level on measures of anthropometry (F = 0.455, p = 0.718, (Equation is included in full-text article.)= 0.07), flexibility (F = 1.861, p = 0.188, (Equation is included in full-text article.)= 0.19), strength (F = 1.218, p = 0.355, (Equation is included in full-text article.)= 0.32); and speed and agility (F = 1.176, p = 0.350, (Equation is included in full-text article.)= 0.18). Multivariate analyses of variance revealed significant multivariate effects between playing levels for motor coordination (F = 3.470, p = 0.036, (Equation is included in full-text article.)= 0.59). A Mann-Whitney U test and a sequential discriminant analysis confirmed these results. Previous research revealed that stature and jump height are prerequisites for talent identification in female volleyball. In addition, the results show that motor coordination is an important factor in determining inclusion into the elite level in female volleyball. PMID- 25436628 TI - Comparison of inflammatory responses to a soccer match between elite male and female players. AB - The aim of this study was to compare the inflammatory responses between male and female soccer players for a period of 48 hours after an official match. Blood samples were taken from 83 subjects (22 elite male and 21 elite female soccer players and 20 male and 20 female inactive individuals) in the morning of the game day, immediately after the soccer game and 24 and 48 hours after the match. Average relative exercise intensity during the match was similar in male and female players, as indicated by mean heart rate that was 86.9 +/- 4.3 and 85.6 +/ 2.3% of maximal heart rate (p = 0.23), respectively. Interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) increased 2- to 4-fold above resting values, peaking immediately after the match. C-reactive protein (CRP) and creatine kinase peaked 24 hours after the match. Interleukin 6, CRP, and creatine kinase responses were similar in male and female players, but the peak in TNF alpha was 18% higher in male players. Interleukin 6, TNF-alpha, and CRP at rest were lower in male and female players compared with the control subjects, suggesting a protective effect of regular exercise training regarding the inflammatory profile. The results of this study show that a soccer match induces significant inflammatory responses in both male and female players, with only TNF alpha peak values being lower in females. Because of the effects of inflammatory responses on performance and health of the players, it is suggested that coaches and trainers should adjust exercise training programs after a match to promote recovery and protect the athletes' health. PMID- 25436629 TI - The role of rotational mobility and power on throwing velocity. AB - Sound rotational power and mobility are an integral component in functional performances, such as throwing and striking. The purpose of this study was to examine the role of rotational power and mobility on cricket ball-throwing velocity. Eleven professional cricketers and 10 under-19 club-level cricketers performed the chop and lift, seated and standing cricket ball throw, seated and standing side medicine ball throw, and seated active thoracic rotation range of motion (ROM) and hip rotation ROM on one occasion. Participants were divided into 2 groups (fast and slow) based on their standing cricket ball-throwing velocity. The seated and standing cricket ball throw on the dominant side was significantly different (p < 0.00) between fast and slow throwers (11.03 and 10.7 km.h(-1), respectively). Muscular performance measures, such as bilateral thoracic rotation ROM, hip external rotation ROM on the dominant side, and force and work required in the chop, were significantly different (p <= 0.05) between fast and slow throwers. Faster throwers in this study displayed greater force (18.4%) and work (31.2%) outputs in the chop compared with the slower throwers; however, slower throwers showed significantly greater ROM in the thoracic (13.4-16.8%) and hip regions (11.8%). It was concluded that greater ROM at proximal segments, such as hips and thoracic, may not increase throwing velocity in cricket as reduced ROM at proximal segments can be useful in transferring the momentum from the lower extremity in an explosive task such as throwing. PMID- 25436630 TI - Perceived training intensity and performance changes quantification in judo. AB - The objective of this study was to determine the methods of quantification for training and performance, which would be the most appropriate for modeling the responses to long-term training in cadet and junior judo athletes. For this, 10 young male judo athletes (15.9 +/- 1.3 years, 64.9 +/- 10.3 kg, and 170.8 +/- 5.4 cm) competing at a regional/state level volunteered to take part in this study. Data were collected during a 2-year training period (i.e., 702 days) from January 2011 to December 2012. Their mean training volume was 6.52 +/- 0.43 hours per week during the preparatory periods and 4.75 +/- 0.49 hours per week during the competitive periods. They followed a training program prescribed by the same coach. The training load (TL) was quantified through the session rating of perceived exertion (RPE) and expressed in arbitrary unit (a.u.). Performance was quantified from 5 parameters and divided into 2 categories: performance in competition and performance in training. The evaluation of performance in competition was based on the number of points per level. Performance in training was assessed through 4 different tests. A physical test battery consisting of a standing long jump, 2 judo-specific tests that were the maximal number of dynamic chin-up holding the judogi, and the Special Judo Fitness Test was used. System modeling for describing training adaptations consisted of mathematically relating the TL of the training sessions (system input) to the change in performance (system output). The quality of the fit between TL and performance was similar, whether the TL was computed directly from RPE (R = 0.55 +/- 0.18) or from the session RPE (R = 0.56 +/- 0.18) and was significant in 8 athletes over 10, excluding the standing jump from the computation of the TL, leading to a simplest method. Thus, this study represents a first attempt to model TL effects on judo specific performance and has shown that the best relationships between amounts of training and changes in performance were obtained when training amounts were quantified simply from RPE. PMID- 25436631 TI - The National Football League Scouting Combine from 1999 to 2014: normative reference values and an examination of body mass normalization techniques. AB - The primary purpose of this study was to identify the most appropriate method for normalizing physical performance measures to body mass in American football players. Data were obtained from the population of players (n = 4,603) that completed the vertical jump, broad jump, 40-yd sprint, 20-yd shuttle, 3-cone drill, and bench press at the National Football League Scouting Combine from 1999 to 2014. Correlation coefficients were used to assess relationships between body mass and physical performance measures. For the entire group and each playing position, absolute (i.e., non-normalized) performance measures were significantly (p <= 0.05) correlated with body mass, indicating that normalization is warranted. Ratio scaling, however, was not appropriate for normalizing most performance measures because it merely reversed (and increased in magnitude) the significant correlations between body mass and performance. Allometric scaling with derived allometric parameters was appropriate for normalizing all performance measures because correlations between body mass and performance were near to zero and no longer statistically significant. However, the derived allometric parameters differed by playing position. Thus, when normalizing physical performance measures to body mass, strength and conditioning professionals should use allometric scaling with test- and position-specific allometric parameters. Additionally, in the current study, percentile rankings were generated to provide test- and position-specific normative reference values for the absolute measures. Until body mass normalization techniques are adopted more broadly, strength and conditioning professionals can use these normative references values to compare current players with those who have already participated in the Scouting Combine. PMID- 25436632 TI - Lower-extremity strength ratios of professional soccer players according to field position. AB - Previous investigators have proposed that knee strength, hamstrings to quadriceps, and side-to-side asymmetries may vary according to soccer field positions. However, different results have been found in these variables, and a generalization of this topic could lead to data misinterpretation by coaches and soccer clubs. Thus, the aim of this study was to measure knee strength and asymmetry in soccer players across different field positions. One hundred and two male professional soccer players performed maximal concentric and eccentric isokinetic knee actions on the preferred and nonpreferred legs at a velocity of 60 degrees . s. Players were divided into their field positions for analysis: goalkeepers, side backs, central backs, central defender midfielders, central attacking midfielders, and forwards. Results demonstrated that only goalkeepers (GK) differed from most other field positions on players' characteristics, and concentric peak torque across muscles. Although all players presented functional ratios of the preferred (0.79 +/- 0.14) and nonpreferred (0.75 +/- 0.13) legs below accepted normative values, there were no differences between positions for conventional or functional strength ratios or side-to-side asymmetry. The same comparisons were made only between field players, without inclusion of the GK, and no differences were found between positions. Therefore, the hamstrings to quadriceps and side-to-side asymmetries found here may reflect knee strength functional balance required for soccer skills performance and game demands across field positions. These results also suggest that isokinetic strength profiles should be considered differently in GK compared with other field positions due to their specific physiological and training characteristics. PMID- 25436634 TI - A comparison of reactive strength index-modified between six U.S. Collegiate athletic teams. AB - The purpose of this study was to examine the differences in reactive strength index-modified (RSImod), jump height (JH), and time to takeoff (TTT) between 6 U.S. collegiate sport teams. One hundred six male and female Division I collegiate athletes performed unloaded (<1 kg) and loaded (20 kg) countermovement jumps as part of an ongoing athlete monitoring program. Reactive strength index modified, JH, and TTT values for each team were compared using 1-way analysis of variance. Statistically significant differences in RSImod (p < 0.001), JH (p < 0.001), and TTT (p = 0.003) existed between teams during the unloaded jumping condition. Similarly, statistically significant differences in RSImod (p < 0.001), JH (p < 0.001), and TTT (p = 0.028) existed between teams during the loaded jumping condition. Men's soccer and baseball produced the greatest RSImod values during both the unloaded and loaded jumping conditions followed by women's volleyball, men's tennis, women's soccer, and women's tennis. The greatest JH during unloaded and loaded jumping conditions was produced by men's baseball followed by men's soccer, women's volleyball, men's tennis, women's soccer, and women's tennis. Men's soccer produced shorter TTT compared with men's baseball (12.7%) and women's soccer (13.3%) during the unloaded and loaded jumping conditions, respectively. Collegiate sport teams exhibit varying reactive strength characteristics during unloaded and loaded jumping conditions. Understanding the differences in RSImod between sports may help direct the creation of training and monitoring programs more effectively for various sports. PMID- 25436635 TI - Perceived exertion responses to changing resistance training programming variables. AB - This study examined the influence of intensity (%1 repetition maximum [1RM]), tonnage (sets * repetitions * load), rate of fatigue (percentage decrement in repetitions from set to set), work rate (total tonnage per unit of time), rest interval (time between sets), time under load, and session duration on session rating of perceived exertion (sRPE: Borg's CR-10 scale). Here, participants performed a standardized lifting session of 5 exercises (bench press, leg press, lat pulldown, leg curl, and triceps pushdown) as either: (a) 3 sets * 8 repetitions * 3-minute recovery at 70% 1RM, (b) 3 sets * 14 repetitions * 3 minute recovery at 40% 1RM, (c) 3 sets * MNR (maximum number of repetitions) * 1 minute recovery at 70% 1RM, (d) 3 sets * MNR * 3-minute recovery at 70% 1RM, (e) 3 sets * MNR * 1-minute recovery at 40% 1RM, or (f) 3 sets * MNR * 3-minute recovery at 40% 1RM. The sRPE for session A (4 +/- 1) was significantly higher than session B (2.5 +/- 1), despite matched tonnage. Protocols involving MNR showed no significant difference in sRPE. Work rate was the only variable to significantly relate with sRPE (r = 0.45). Additionally, sRPE at 15-minute postexercise (5 +/- 2) was not different to 30-minute postexercise (5 +/- 2). In resistance training with matched tonnage and rest duration between sets, sRPE increases with intensity. In sets to volitional failure, sRPE is likely to be similar, regardless of intensity or rest duration between sets. PMID- 25436636 TI - In-season effect of a combined repeated sprint and explosive strength training program on elite junior tennis players. AB - The aim of this study was to analyze the effects of a combined explosive strength (ExpS) and repeated sprint (RS)-training program (2 times per week) on performance (sprint, jumping ability, and RS ability [RSA]) in young elite tennis players during a competitive period. Eight competitive internationally ranked male junior tennis players participated in an 8-week training intervention. After training, except for percentage of decrement in the RS test (p = 0.72) and maximal aerobic performance (p = 1.0), all performance variables (i.e., sprint, countermovement jump, and RSA) were significantly improved (p <= 0.05; effect sizes ranging from 0.56 to 1.12). Although one can expect greater effects of ExpS or RS training programs alone than a combined program, the results obtained here show that the inclusion of a combined ExpS and RS training program seems to be an effective training tool to improve neuromuscular performance (i.e., changes in jumping ability and single sprint) as well as RSA in high-level tennis players. PMID- 25436637 TI - Intermediate length C9orf72 expansion in an ALS patient without classical C9orf72 neuropathology. PMID- 25436639 TI - Hypertensive disorders of pregnancy: a systematic review of international clinical practice guidelines. AB - BACKGROUND: Clinical practice guidelines (CPGs) are developed to assist health care providers in decision-making. We systematically reviewed existing CPGs on the HDPs (hypertensive disorders of pregnancy) to inform clinical practice. METHODOLOGY & PRINCIPAL FINDINGS: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessments, and Database of Abstracts of Reviews of Effects (Ovid interface), Grey Matters, Google Scholar, and personal records were searched for CPGs on the HDPs (Jan/03 to Nov/13) in English, French, Dutch, or German. Of 13 CPGs identified, three were multinational and three developed for community/midwifery use. Length varied from 3-1188 pages and three guidelines did not formulate recommendations. Eight different grading systems were identified for assessing evidence quality and recommendation strength. No guideline scored ?80% on every domain of the AGREE II, a tool for assessing guideline methodological quality; two CPGs did so for 5/6 domains. Consistency was seen for (i) definitions of hypertension, proteinuria, chronic and gestational hypertension; (ii) pre-eclampsia prevention for women at increased risk: calcium when intake is low and low-dose aspirin, but not vitamins C and E or diuretics; (iii) antihypertensive treatment of severe hypertension; (iv) MgSO4 for eclampsia and severe pre-eclampsia; (v) antenatal corticosteroids at <34 wks when delivery is probable within 7 days; (vi) delivery for women with severe pre-eclampsia pre-viability or pre-eclampsia at term; and (vii) active management of the third stage of labour with oxytocin. Notable inconsistencies were in: (i) definitions of pre-eclampsia and severe pre eclampsia; (ii) target BP for non-severe hypertension; (iii) timing of delivery for women with pre-eclampsia and severe pre-eclampsia; (iv) MgSO4 for non-severe pre-eclampsia, and (v) postpartum maternal monitoring. CONCLUSIONS: Existing international HDP CPGs have areas of consistency with which clinicians and researchers can work to develop auditable standards, and areas of inconsistency that should be addressed by future research. PMID- 25436638 TI - Genetic variants associated with serum thyroid stimulating hormone (TSH) levels in European Americans and African Americans from the eMERGE Network. AB - Thyroid stimulating hormone (TSH) hormone levels are normally tightly regulated within an individual; thus, relatively small variations may indicate thyroid disease. Genome-wide association studies (GWAS) have identified variants in PDE8B and FOXE1 that are associated with TSH levels. However, prior studies lacked racial/ethnic diversity, limiting the generalization of these findings to individuals of non-European ethnicities. The Electronic Medical Records and Genomics (eMERGE) Network is a collaboration across institutions with biobanks linked to electronic medical records (EMRs). The eMERGE Network uses EMR-derived phenotypes to perform GWAS in diverse populations for a variety of phenotypes. In this report, we identified serum TSH levels from 4,501 European American and 351 African American euthyroid individuals in the eMERGE Network with existing GWAS data. Tests of association were performed using linear regression and adjusted for age, sex, body mass index (BMI), and principal components, assuming an additive genetic model. Our results replicate the known association of PDE8B with serum TSH levels in European Americans (rs2046045 p = 1.85*10-17, beta = 0.09). FOXE1 variants, associated with hypothyroidism, were not genome-wide significant (rs10759944: p = 1.08*10-6, beta = -0.05). No SNPs reached genome-wide significance in African Americans. However, multiple known associations with TSH levels in European ancestry were nominally significant in African Americans, including PDE8B (rs2046045 p = 0.03, beta = -0.09), VEGFA (rs11755845 p = 0.01, beta = -0.13), and NFIA (rs334699 p = 1.50*10-3, beta = -0.17). We found little evidence that SNPs previously associated with other thyroid-related disorders were associated with serum TSH levels in this study. These results support the previously reported association between PDE8B and serum TSH levels in European Americans and emphasize the need for additional genetic studies in more diverse populations. PMID- 25436643 TI - Assessing the impact of aerial pesticide spraying: mancozeb exposures among pregnant women living near banana plantations. PMID- 25436642 TI - Seroprevalence of HCV and HIV infections by year of birth in Spain: impact of US CDC and USPSTF recommendations for HCV and HIV testing. AB - BACKGROUND: The US Centers for Disease Control and Prevention (CDC) recently add the advice of one-time testing of HCV infection in persons born during 1945-1965. Moreover, the US Preventive Services Task Force (USPSTF) newly recommended one time HIV testing for persons aged 15-65. Herein, we evaluate the potential impact of these recommendations in a reference medical area of Spain. METHODS: All assays results entries for HCV and HIV serological markers ordered at a reference lab from primary care and specialized physicians between 2008 and 2012 were recorded in a medical area which covers 501,526 citizens in Northern Spain. The year of birth were also documented. RESULTS: A total of 108,159 anti-HCV-Ab results were generated during the study period. The global rate of anti-HCV-Ab+ was 7.7% (95% CI: 7.6%-7.9%), being more prevalent in men than women (8.6% vs. 4.5%). By year of birth, the highest prevalence was found in persons born between 1955 and 1970. HCV genotype 1 was the most prevalent (59.7%) followed by genotype 3 (22.7%). Regard HIV infection, among 65,279 anti-HIV results generated the prevalence of anti-HIV+ was 1.1% (95% CI: 1.0%-1.2%), being more frequent in men (2% vs 0.5%). The years of birth with highest rates of HIV infection exactly match with those for HCV infection. CONCLUSIONS: The highest rates of HCV and HIV infections are found between 1960 and 1965. Different historical and social circumstances such as the huge intravenous drug use epidemic in the eighties in Spain, might explain it. Therefore, each country needs to determine its own HCV and HIV seroprevalences by year of birth to establish the proper recommendations for the screening of both infections. PMID- 25436644 TI - Effect of Bisphosphonate and Age on Implant Failure as Determined by Patient Reported Outcomes. AB - The aim of the current study was to elucidate whether there is an association between selected risk factors and implant failure, as determined by patient reported outcomes. A trained clinician administered a formal survey questionnaire to 415 patients who had received a total of 963 implants through the University of Kentucky College of Dentistry's implant training program. The questionnaire was designed to obtain information about potential risk factors that may affect implant failure. Patients were also asked to rate their satisfaction with the appearance and function of the implant, their surgical experience, and the levels of pain and mobility associated with the implant(s). Both patient-level and implant-level data were analyzed in this study. Multiple logistic regression analysis at the patient level indicated that the following variables did not contribute to the success or failure of the implants: sex, smoking status, diabetes, osteoporosis, and use of bisphosphonates. When the statistical analyses controlled for these variables, the odds of patient-reported implant failure increased with the patient's age (by 15% every 5 years). The results of implant level analyses adjusted for smoking status, diabetes, and osteoporosis showed that the patient's age (odds of failure increased by 12% every 5 years) and no use of bisphosphonates (odds ratio, 9.22; 95% confidence interval, 1.849, 45.975) were significantly associated with poor implant outcome. Our findings suggest a possible association between implant failure and the patient's age and use of bisphosphonates. PMID- 25436650 TI - RESTful M2M gateway for remote wireless monitoring for district central heating networks. AB - In recent years, the increased interest in energy conservation and environmental protection, combined with the development of modern communication and computer technology, has resulted in the replacement of distributed heating by central heating in urban areas. This paper proposes a Representational State Transfer (REST) Machine-to-Machine (M2M) gateway for wireless remote monitoring for a district central heating network. In particular, we focus on the resource oriented RESTful M2M gateway architecture, and present an uniform devices abstraction approach based on Open Service Gateway Initiative (OSGi) technology, and implement the resource mapping mechanism between resource address mapping mechanism between RESTful resources and the physical sensor devices, and present the buffer queue combined with polling method to implement the data scheduling and Quality of Service (QoS) guarantee, and also give the RESTful M2M gateway open service Application Programming Interface (API) set. The performance has been measured and analyzed. Finally, the conclusions and future work are presented. PMID- 25436651 TI - Face liveness detection using a light field camera. AB - A light field camera is a sensor that can record the directions as well as the colors of incident rays. This camera is widely utilized from 3D reconstruction to face and iris recognition. In this paper, we suggest a novel approach for defending spoofing face attacks, like printed 2D facial photos (hereinafter 2D photos) and HD tablet images, using the light field camera. By viewing the raw light field photograph from a different standpoint, we extract two special features which cannot be obtained from the conventional camera. To verify the performance, we compose light field photograph databases and conduct experiments. Our proposed method achieves at least 94.78% accuracy or up to 99.36% accuracy under different types of spoofing attacks. PMID- 25436652 TI - Long-term activity recognition from wristwatch accelerometer data. AB - With the development of wearable devices that have several embedded sensors, it is possible to collect data that can be analyzed in order to understand the user's needs and provide personalized services. Examples of these types of devices are smartphones, fitness-bracelets, smartwatches, just to mention a few. In the last years, several works have used these devices to recognize simple activities like running, walking, sleeping, and other physical activities. There has also been research on recognizing complex activities like cooking, sporting, and taking medication, but these generally require the installation of external sensors that may become obtrusive to the user. In this work we used acceleration data from a wristwatch in order to identify long-term activities. We compare the use of Hidden Markov Models and Conditional Random Fields for the segmentation task. We also added prior knowledge into the models regarding the duration of the activities by coding them as constraints and sequence patterns were added in the form of feature functions. We also performed subclassing in order to deal with the problem of intra-class fragmentation, which arises when the same label is applied to activities that are conceptually the same but very different from the acceleration point of view. PMID- 25436653 TI - Biomimetic receptors and sensors. AB - In biomimetics, living systems are imitated to develop receptors for ions, molecules and bioparticles. The most pertinent idea is self-organization in analogy to evolution in nature, which created the key-lock principle. Today, modern science has been developing host-guest chemistry, a strategy of supramolecular chemistry for designing interactions of analytes with synthetic receptors. This can be realized, e.g., by self-assembled monolayers (SAMs) or molecular imprinting. The strategies are used for solid phase extraction (SPE), but preferably in developing recognition layers of chemical sensors. PMID- 25436654 TI - Early classification of pathological heartbeats on wireless body sensor nodes. AB - Smart Wireless Body Sensor Nodes (WBSNs) are a novel class of unobtrusive, battery-powered devices allowing the continuous monitoring and real-time interpretation of a subject's bio-signals, such as the electrocardiogram (ECG). These low-power platforms, while able to perform advanced signal processing to extract information on heart conditions, are usually constrained in terms of computational power and transmission bandwidth. It is therefore essential to identify in the early stages which parts of an ECG are critical for the diagnosis and, only in these cases, activate on demand more detailed and computationally intensive analysis algorithms. In this work, we present a comprehensive framework for real-time automatic classification of normal and abnormal heartbeats, targeting embedded and resource-constrained WBSNs. In particular, we provide a comparative analysis of different strategies to reduce the heartbeat representation dimensionality, and therefore the required computational effort. We then combine these techniques with a neuro-fuzzy classification strategy, which effectively discerns normal and pathological heartbeats with a minimal run time and memory overhead. We prove that, by performing a detailed analysis only on the heartbeats that our classifier identifies as abnormal, a WBSN system can drastically reduce its overall energy consumption. Finally, we assess the choice of neuro-fuzzy classification by comparing its performance and workload with respect to other state-of-the-art strategies. Experimental results using the MIT BIH Arrhythmia database show energy savings of as much as 60% in the signal processing stage, and 63% in the subsequent wireless transmission, when a neuro fuzzy classification structure is employed, coupled with a dimensionality reduction technique based on random projections. PMID- 25436656 TI - BCDP: Budget constrained and delay-bounded placement for hybrid roadside units in vehicular ad hoc networks. AB - In vehicular ad hoc networks, roadside units (RSUs) placement has been proposed to improve the the overall network performance in many ITS applications. This paper addresses the budget constrained and delay-bounded placement problem (BCDP) for roadside units in vehicular ad hoc networks. There are two types of RSUs: cable connected RSU (c-RSU) and wireless RSU (w-RSU). c-RSUs are interconnected through wired lines, and they form the backbone of VANETs, while w-RSUs connect to other RSUs through wireless communication and serve as an economical extension of the coverage of c-RSUs. The delay-bounded coverage range and deployment cost of these two cases are totally different. We are given a budget constraint and a delay bound, the problem is how to find the optimal candidate sites with the maximal delay-bounded coverage to place RSUs such that a message from any c-RSU in the region can be disseminated to the more vehicles within the given budget constraint and delay bound. We first prove that the BCDP problem is NP-hard. Then we propose several algorithms to solve the BCDP problem. Simulation results show the heuristic algorithms can significantly improve the coverage range and reduce the total deployment cost, compared with other heuristic methods. PMID- 25436655 TI - Micro-Raman spectroscopy for monitoring changes in periodontal ligaments and gingival crevicular fluid. AB - Micro-Raman Spectroscopy is an efficient method for analyzing biological specimens due to its sensitivity to subtle chemical and structural changes. The aim of this study was to use micro-Raman spectroscopy to analyze chemical and structural changes in periodontal ligament after orthodontic force application and in gingival crevicular fluid in presence of periodontal disease. The biopsy of periodontal ligament samples of premolars extracted for orthodontic reasons and the gingival crevicular fluid samples collected by using absorbent paper cones; were analyzed by micro-Raman spectroscopy. Changes of the secondary protein structure related to different times of orthodontic force application were reported; whereas an increase of carotene was revealed in patients affected by periodontal inflammation. PMID- 25436657 TI - A wireless swing angle measurement scheme using attitude heading reference system sensing units based on microelectromechanical devices. AB - Feasible real-time swing angle measurement is significant to improve the efficiency and safety of industrial crane systems. This paper presents a wireless microelectromechanical system (MEMS)-based swing angle measurement system. The system consists of two attitude heading reference system (AHRS) sensing units with a wireless communication function, which are mounted on the hook (or payload) and the jib (or base) of the crane, respectively. With a combination of a three-axis accelerometer, a three-axis gyroscope and a three-axis magnetometer, the standard extended Kalman filter (EKF) is used to estimate the desired orientation of the payload and the base. Wireless ZigBee communication is employed to transmit the orientation of the payload to the sensing unit mounted on the base, which measures the orientation of the base. Because several physical parameters from the payload to the base can be acquired from the original crane control system, the swing angles of the payload can be calculated based on the two measured orientation parameters together with the known physical parameters. Experiments were performed to show the feasibility and effectiveness of the proposed swing angle measurement system. PMID- 25436658 TI - High accuracy localization of long term evolution based on a new multiple carrier noise model. AB - A high accuracy localization technique using Long Term Evolution (LTE) based on a new and accurate multiple carrier noise model has been developed. In the noise consideration, the LTE multiple carriers phase noise has been incorporated so that a new and accurate noise model is achieved. An experiment was performed to characterize the phase noise of carriers at 2 GHz. The developed noise model was incorporated into LTE localization analysis in a high traffic area in Hong Kong to evaluate the accuracy of localization. The evaluation and analysis reveals that the new localization method achieves an improvement of about 10% accuracy comparing to existing widely adopted schemes. PMID- 25436659 TI - The Integrated System of Phytodepuration of Sile River Natural Park. AB - The water conservation topic is likely to become increasingly important and alternative water resources employment should be considered as one possible response to the challenges of fresh water demand and environmental protection; among alternative water sources, municipal wastewaters represent one of the most profitable source but in order to reuse them they need adequate and advanced depuration techniques, such as the use of Integrated System of Phytodepuration (ISP). Across a 3-year sampling period, the performances of an ISP within the Natural Park of the Sile River in the Northern Italy were evaluated, analyzing raw wastewater and final effluent characteristics according to the recommendations of European and Italian legislation. The investigated ISP represents one of the first attempts designed in Italy to improve the efficiency of an existing wastewater treatment plant, able to serve 8000 equivalent inhabitants. The results obtained during the 3 years of analysis show that the designed ISP is characterized by a general efficiency value higher than 87% for TSS removal, 79% for TN, 91% for BOD5 and 86% for COD; moreover the ISP final effluent is characterized by a quality not only suited for release into surface waters but also for irrigation. PMID- 25436660 TI - Advantages of externally powered prosthesis with feedback system using pseudo cineplasty. AB - Externally powered upper-limb prostheses are difficult to use because of the lack of sensory feedback. Neuroprostheses have recently been developed for people with upper-limb amputation but are complicated, expensive, and still developing. We therefore designed a simple system by combining pseudo-cineplasty with extended physiological proprioception to provide sensory feedback to the body. We penetrated the palmaris longus tendon percutaneously with a metal ring, similar to that used in body piercing, in a nondisabled subject as a pseudo-cineplasty. The tendon and ring were connected to the system, and a sensory feedback experiment was performed. We investigated the ability of the user to determine the size of an object grasped by the prosthetic hand without visual information. The subject could distinguish between large and small objects with 100% accuracy and between small, medium, and large objects with 80% accuracy. In pseudo cineplasty, control and sensory feedback are natural because the prosthetic hand is controlled by muscle contraction. Tension transmitted from the prosthetic hand is sensed via muscle spindles and skin sensors. This technique allows only partial sensory feedback but appears to offer several advantages over other human machine interfaces. PMID- 25436661 TI - A comparison of two podiatric protocols for metatarsalgia in patients with rheumatoid arthritis and osteoarthritis. AB - OBJECTIVES: In rheumatoid arthritis (RA) and osteoarthritis (OA) forefoot involvement causes disability and metatarsalgia. Our objective was to evaluate, in RA and OA patients, the efficacy of two protocols combining insoles in polypropylene terephtalate (PPT) and custom silicone orthoses for toes on disability and metatarsalgia. METHODS: Twenty-four women (13 with OA, 11 with RA) with metatarsalgia were treated with two protocols: group A (protocol A) wore PPT insoles (T1) for 30 days and for another 30 days silicone orthosis for toes were added (T2). Group B (protocol B) wore PPT insoles and silicone orthosis (T1) for 30 days and in the following 30 days only insoles (T2). At T0, T1 and T2, pain, disability and function (Foot Function Index - FFI), pressure (KPA) and plantar contact areas (cm2) (baropodometer), and gait spatial-temporal parameters (GAITRite(r)) were assessed. RESULTS: At T0 versus T2, both protocols reduced FFI pain, -disability and -functional limitation (p<0.05), with better results of protocol A than protocol B (p<0.05) for FFI-pain and -disability. Both protocols reduced baropodometer foot plantar pressures (p<0.001), with better results for protocol A for right foot pressures (p<0.05) and increased foot contact areas (p<0.05), with no difference between them (p=NS). Gait parameters were not significantly changed by both protocols (p=NS). CONCLUSIONS: In patients with RA and OA with metatarsalgia, the synergic action of silicone toe orthosis and PPT insoles improves FFI, reduces foot plantar pressures and increases foot plantar contact areas. Protocol A, using firstly insoles and then adding silicone toe orthoses, is the more efficacious. PMID- 25436662 TI - Reliability and validity of the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF) in evaluations of chronic low back pain patients. AB - The purpose of the current study was to investigate the reliability and concurrent validity of Minnesota Multiphasic Personality Inventory (MMPI)-2 Restructured Form (2-RF) (Ben-Porath & Tellegen, 2008/2011) scores in a sample of 811 chronic low back pain patients (346 males, 529 females) beginning treatment in a short-term interdisciplinary pain rehabilitation program. We calculated internal consistency coefficients, mean-item correlations, and SEM for all substantive scales, as well as zero-order correlations with collateral medical record information and self-report testing. Results indicated reliability and validity for most of the MMPI-2-RF substantive scales. Implications of these findings and limitations of this study are discussed. PMID- 25436663 TI - Using a genetic algorithm to abbreviate the Psychopathic Personality Inventory Revised (PPI-R). AB - Some self-report measures of personality and personality disorders, including the widely used Psychopathic Personality Inventory-Revised (PPI-R), are lengthy and time-intensive. In recent work, we introduced an automated genetic algorithm (GA) based method for abbreviating psychometric measures. In Study 1, we used this approach to generate a short (40-item) version of the PPI-R using 3 large-N German student samples (total N = 1,590). The abbreviated measure displayed high convergent correlations with the original PPI-R, and outperformed an alternative measure constructed using a conventional approach. Study 2 tested the convergent and discriminant validity of this short version in a fourth student sample (N = 206) using sensation-seeking and sensitivity to reward and punishment scales, again demonstrating similar convergent and discriminant validity for the PPI-R-40 compared with the full version. In a fifth community sample of North American participants acquired using Amazon Mechanical Turk, the PPI-R-40 showed similarly high convergent correlations, demonstrating stability across language, culture, and data-collection method. Taken together, these studies suggest that the GA approach is a viable method for abbreviating measures of psychopathy, and perhaps personality measures in general. PMID- 25436664 TI - Behavioral phenotype in children with 22q11DS: agreement between parents and teachers. AB - Patients with the 22q11-deletion syndrome (22q11DS) are at an increased risk of developing schizophrenia. Besides the effects of genetic variation, environmental factors could also be important in modifying the risk of schizophrenia in 22q11DS patients. In particular, previous studies have shown the importance of stress as a precipitating factor of psychosis. An incongruence between the perceived and actual severity of behavioral and cognitive domains could lead caregivers, and even the children themselves, to make demands that are insufficiently adapted to the child's abilities, causing stress and anxiety. Here, we investigate whether such diagnostic discrepancies are indeed present by comparing parent and teacher reports on behavioral concerns in children with 22q11DS. Behavioral questionnaires (CBCL and TRF) were prepared for both parents and teachers of 146 children with 22q11DS. We found that in line with previous reports, internalizing behavior was more frequently reported than externalizing behavior. While the behavioral profiles reported by parents and teachers were remarkably similar, the teachers' ratings were significantly lower (Total problem score p = .002). Age and IQ were not significantly associated with the severity of reported concerns. Our results indicate that indeed a disparity often exists between parents' and teachers' perceptions of the severity of a child's behavioral deficits. This may result in (substantially) different demands and expectations being placed on the child from the two fronts. We speculate that the stress resulting from this lack of cohesion between parents and teachers could precipitate, at least in some 22q11DS children, the emergence of psychosis. PMID- 25436665 TI - Modeling of human viruses on hands and risk of infection in an office workplace using micro-activity data. AB - Although the number of illnesses resulting from indirect viral pathogen transmission could be substantial, it is difficult to estimate the relative risks because of the wide variation and uncertainty in human behavior, variable viral concentrations on fomites, and other exposure factors. The purpose of this study was to evaluate the micro-activity approach for assessment of microbial risk by adapting a mathematical model to estimate probability of viral infection from indirect transmission. To evaluate the model, measurements of phage loading on fomites and hands collected before and after implementation of a Healthy Workplace Project intervention were used. Parameter distributions were developed from these data, as well as for micro-activity rates, contact surface areas, phage transfer efficiencies, and inactivation rates. Following the Monte Carlo simulations (n = 1,000), the estimated phage loading on hands was not significantly different from the loading of phage on hands measured in the experimental trials. The model was then used to demonstrate that the Healthy Workplace Project intervention significantly reduced risk of infection by 77% for rotavirus and rhinovirus. This is the first published study to successfully evaluate a model focused on the indirect transmission of viruses via hand contact with measured data and provide an assessment of the micro-activity approach to microbial risk evaluation. PMID- 25436666 TI - Neuronal encoding of the switch from specific to generalized fear. AB - Fear memories are crucial for survival. However, excessive generalization of such memories, characterized by a failure to discriminate dangerous from safe stimuli, is common in anxiety disorders. Neuronal encoding of the transition from cue specific to generalized fear is poorly understood. We identified distinct neuronal populations in the lateral amygdala (LA) of rats that signaled generalized versus cue-specific associations and determined how their distributions switched during fear generalization. Notably, the same LA neurons that were cue specific before the behavioral shift to generalized fear lost their specificity afterwards, thereby tilting the balance of activity toward a greater proportion of generalizing neurons. Neuronal activity in the LA, but not the auditory cortex, was necessary for fear generalization. Furthermore, targeted activation of cAMP-PKA signaling in the LA increased neuronal excitability of LA neurons and led to generalized fear. These results provide a cellular basis in the amygdala for the alteration of emotional states from normal to pathological fear. PMID- 25436668 TI - Neural Correlates of Fixation Duration during Real-world Scene Viewing: Evidence from Fixation-related (FIRE) fMRI. AB - During active scene perception, our eyes move from one location to another via saccadic eye movements, with the eyes fixating objects and scene elements for varying amounts of time. Much of the variability in fixation duration is accounted for by attentional, perceptual, and cognitive processes associated with scene analysis and comprehension. For this reason, current theories of active scene viewing attempt to account for the influence of attention and cognition on fixation duration. Yet almost nothing is known about the neurocognitive systems associated with variation in fixation duration during scene viewing. We addressed this topic using fixation-related fMRI, which involves coregistering high resolution eye tracking and magnetic resonance scanning to conduct event-related fMRI analysis based on characteristics of eye movements. We observed that activation in visual and prefrontal executive control areas was positively correlated with fixation duration, whereas activation in ventral areas associated with scene encoding and medial superior frontal and paracentral regions associated with changing action plans was negatively correlated with fixation duration. The results suggest that fixation duration in scene viewing is controlled by cognitive processes associated with real-time scene analysis interacting with motor planning, consistent with current computational models of active vision for scene perception. PMID- 25436667 TI - A novel role for visual perspective cues in the neural computation of depth. AB - As we explore a scene, our eye movements add global patterns of motion to the retinal image, complicating visual motion produced by self-motion or moving objects. Conventionally, it has been assumed that extraretinal signals, such as efference copy of smooth pursuit commands, are required to compensate for the visual consequences of eye rotations. We consider an alternative possibility: namely, that the visual system can infer eye rotations from global patterns of image motion. We visually simulated combinations of eye translation and rotation, including perspective distortions that change dynamically over time. We found that incorporating these 'dynamic perspective' cues allowed the visual system to generate selectivity for depth sign from motion parallax in macaque cortical area MT, a computation that was previously thought to require extraretinal signals regarding eye velocity. Our findings suggest neural mechanisms that analyze global patterns of visual motion to perform computations that require knowledge of eye rotations. PMID- 25436669 TI - Brief exposure to aversive stimuli impairs visual selective attention. AB - Although it is well established that stress can disrupt complex cognitive functions, relatively little is known about how it influences visual processing, especially in terms of visual selective attention. In the current study, we used highly aversive images, taken from the International Affective Picture System, to induce acute, low-intensity stress while participants performed a visual discrimination task. Consistent with prior research, we found that anticipation of aversive stimuli increased overall amplitude of the N170, suggesting an increase in early sensory gain. More importantly, we found that stress disrupted visual selective attention. While in no-stress blocks, the amplitude of the face sensitive N170 was higher when participants attended to faces rather than scenes in face-scene overlay images; this effect was absent under stress. This was because of an increase in N170 amplitude in the scene-attend condition under stress. We interpret these findings as suggesting that even low-intensity acute stress can impair participants' ability to filter out task-irrelevant information. We discuss our findings in relation to how even brief exposure to low-intensity stress may adversely impact both healthy and clinical populations. PMID- 25436670 TI - Cortical representations sensitive to the number of perceived auditory objects emerge between 2 and 4 months of age: electrophysiological evidence. AB - Sound waves emitted by two or more simultaneous sources reach the ear as one complex waveform. Auditory scene analysis involves parsing a complex waveform into separate perceptual representations of the sound sources [Bregman, A. S. Auditory scene analysis: The perceptual organization of sounds. London: MIT Press, 1990]. Harmonicity provides an important cue for auditory scene analysis. Normally, harmonics at integer multiples of a fundamental frequency are perceived as one sound with a pitch corresponding to the fundamental frequency. However, when one harmonic in such a complex, pitch-evoking sound is sufficiently mistuned, that harmonic emerges from the complex tone and is perceived as a separate auditory object. Previous work has shown that the percept of two objects is indexed in both children and adults by the object-related negativity component of the ERP derived from EEG recordings [Alain, C., Arnott, S. T., & Picton, T. W. Bottom-up and top-down influences on auditory scene analysis: Evidence from event related brain potentials. Journal of Experimental Psychology: Human Perception and Performance, 27, 1072-1089, 2001]. Here we examine the emergence of object related responses to an 8% harmonic mistuning in infants between 2 and 12 months of age. Two-month-old infants showed no significant object-related response. However, in 4- to 12-month-old infants, a significant frontally positive component was present, and by 8-12 months, a significant frontocentral object related negativity was present, similar to that seen in older children and adults. This is in accordance with previous research demonstrating that infants younger than 4 months of age do not integrate harmonic information to perceive pitch when the fundamental is missing [He, C., Hotson, L., & Trainor, L. J. Maturation of cortical mismatch mismatch responses to occasional pitch change in early infancy: Effects of presentation rate and magnitude of change. Neuropsychologia, 47, 218-229, 2009]. The results indicate that the ability to use harmonic information to segregate simultaneous sounds emerges at the cortical level between 2 and 4 months of age. PMID- 25436671 TI - Working memory delay activity predicts individual differences in cognitive abilities. AB - A great deal of prior research has examined the relation between estimates of working memory and cognitive abilities. Yet, the neural mechanisms that account for these relations are still not very well understood. The current study explored whether individual differences in working memory delay activity would be a significant predictor of cognitive abilities. A large number of participants performed multiple measures of capacity, attention control, long-term memory, working memory span, and fluid intelligence, and latent variable analyses were used to examine the data. During two working memory change detection tasks, we acquired EEG data and examined the contralateral delay activity. The results demonstrated that the contralateral delay activity was significantly related to cognitive abilities, and importantly these relations were because of individual differences in both capacity and attention control. These results suggest that individual differences in working memory delay activity predict individual differences in a broad range of cognitive abilities, and this is because of both differences in the number of items that can be maintained and the ability to control access to working memory. PMID- 25436673 TI - Training-induced Changes in the Dynamics of Attention as Reflected in Pupil Dilation. AB - One of the major topics in attention literature is the attentional blink (AB), which demonstrates a limited ability to identify the second of two targets (T1 and T2) when presented in close temporal succession (200-500 msec). Given that the effect has been thought of as robust and resistant to training for over two decades, one of the most remarkable findings in recent years is that the AB can be eliminated after a 1-hr training with a color-salient T2. However, the underlying mechanism of the training effect as well as the AB itself is as of yet still poorly understood. To elucidate this training effect, we employed a refined version of our recently developed pupil dilation deconvolution method to track any training-induced changes in the amount and onset of attentional processing in response to target stimuli. Behaviorally, we replicated the original training effect with a color-salient T2. However, we showed that training without a salient target, but with a consistent short target interval, is already sufficient to attenuate the AB. Pupil deconvolution did not reveal any posttraining changes in T2-related dilation but instead an earlier onset of dilation around T1. Moreover, normalized pupil dilation was enhanced posttraining compared with pretraining. We conclude that the AB can be eliminated by training without a salient cue. Furthermore, our data point to the existence of temporal expectations at the time points of the trained targets posttraining. Therefore, we tentatively conclude that temporal expectations arise as a result of training. PMID- 25436674 TI - Cytokine receptors and their Stat-mediated mechanisms of action. PMID- 25436675 TI - The versatile regulation of cellular events by Jak-Stat signaling: from transcriptional control to microtubule dynamics and energy metabolism. PMID- 25436672 TI - Grasping with the Press of a Button: Grasp-selective Responses in the Human Anterior Intraparietal Sulcus Depend on Nonarbitrary Causal Relationships between Hand Movements and End-effector Actions. AB - Evidence implicates ventral parieto-premotor cortices in representing the goal of grasping independent of the movements or effectors involved [Umilta, M. A., Escola, L., Intskirveli, I., Grammont, F., Rochat, M., Caruana, F., et al. When pliers become fingers in the monkey motor system. Proceedings of the National Academy of Sciences, U.S.A., 105, 2209-2213, 2008; Tunik, E., Frey, S. H., & Grafton, S. T. Virtual lesions of the anterior intraparietal area disrupt goal dependent on-line adjustments of grasp. Nature Neuroscience, 8, 505-511, 2005]. Modern technologies that enable arbitrary causal relationships between hand movements and tool actions provide a strong test of this hypothesis. We capitalized on this unique opportunity by recording activity with fMRI during tasks in which healthy adults performed goal-directed reach and grasp actions manually or by depressing buttons to initiate these same behaviors in a remotely located robotic arm (arbitrary causal relationship). As shown previously [Binkofski, F., Dohle, C., Posse, S., Stephan, K. M., Hefter, H., Seitz, R. J., et al. Human anterior intraparietal area subserves prehension: A combined lesion and functional MRI activation study. Neurology, 50, 1253-1259, 1998], we detected greater activity in the vicinity of the anterior intraparietal sulcus (aIPS) during manual grasp versus reach. In contrast to prior studies involving tools controlled by nonarbitrarily related hand movements [Gallivan, J. P., McLean, D. A., Valyear, K. F., & Culham, J. C. Decoding the neural mechanisms of human tool use. Elife, 2, e00425, 2013; Jacobs, S., Danielmeier, C., & Frey, S. H. Human anterior intraparietal and ventral premotor cortices support representations of grasping with the hand or a novel tool. Journal of Cognitive Neuroscience, 22, 2594-2608, 2010], however, responses within the aIPS and premotor cortex exhibited no evidence of selectivity for grasp when participants employed the robot. Instead, these regions showed comparable increases in activity during both the reach and grasp conditions. Despite equivalent sensorimotor demands, the right cerebellar hemisphere displayed greater activity when participants initiated the robot's actions versus when they pressed a button known to be nonfunctional and watched the very same actions undertaken autonomously. This supports the hypothesis that the cerebellum predicts the forthcoming sensory consequences of volitional actions [Blakemore, S. J., Frith, C. D., & Wolpert, D. M. The cerebellum is involved in predicting the sensory consequences of action. NeuroReport, 12, 1879-1884, 2001]. We conclude that grasp-selective responses in the human aIPS and premotor cortex depend on the existence of nonarbitrary causal relationships between hand movements and end-effector actions. PMID- 25436676 TI - Genomic and bioinformatics tools to understand the biology of signal transducers and activators of transcription. AB - Abstract The signal transducer and activator of transcription (STAT) family is activated by cytokines and conveys biochemical signals to the genome through binding to specific regulatory sequences, called IFN-gamma-activated sequence (GAS) motifs. As common GAS motifs (TTCnnnGAA) contain only six conserved nucleotides, the mammalian genome harbors hundreds of thousands of copies of this sequence. However, it is not possible to predict which specific GAS motifs bind to STATs and are of functional significance. Here, we apply several layers of statistical, bioinformatics and experimental analyses to narrow down the number of GAS sites that might be of biological relevance. In particular, we determined the number of bona fide GAS motifs by utilizing publically available genome-wide STAT5 ChIP-seq data sets. Less than 10% of GAS motifs within the mouse genome are recognized by STAT5 in vivo and only a small portion of them are shared across different cell types. However, even bona fide STAT5 binding did not predict that the respective gene was under cytokine-STAT control. Therefore, additional bioinformatics, genomic and epigenetic parameters, such as patterns of histone modifications, are required to more reliably predict the behavior of cytokine STAT regulatory networks. PMID- 25436677 TI - The role of Stat3 in mammary gland involution: cell death regulator and modulator of inflammation. AB - Abstract Mammary gland regression post-weaning (involution) is a highly regulated, complicated process in which the transcription factor Stat3 is a key player. Over the last decade, microarray analyses have had a profound impact on our understanding of this role. Studies using mammary epithelial cells in which Stat3 was activated in a ligand-independent manner have allowed direct transcriptional targets of Stat3 to be identified. Additionally, global gene expression changes during involution have been profiled by microarray analyses, which allowed characterization of clusters of genes with distinct expression profiles during the first 4 days of involution. Such expression profiling led to the observation that one of the most strikingly upregulated genes in the absence of Stat3 is the serpin Spi2a. This led to the discovery that mammary epithelial cell lysosomes undergo lysosomal membrane permeablisation and leak cathepsins during involution. Stat3 upregulates the expression of cathepsins B and L within 24 h of weaning and is thus the critical inducer of lysosomal-mediated cell death during this process. In addition to its pivotal role in the control of cell death during involution, microarray-based studies have demonstrated that the expression of acute phase and inflammatory genes is regulated by Stat3 and that mammary epithelial expression of this transcription factor modulates the phenotype of macrophages present in the gland during second phase remodelling. Thus, Stat3 signalling may have effects that are not cell-autonomous, in addition to its cell autonomous role in involution. PMID- 25436678 TI - From tissue invasion to glucose metabolism: the many aspects of signal transducer and activator of transcription 3 pro-oncogenic activities. AB - Abstract Background: The pro-oncogenic transcription factor STAT3 is constitutively active in tumours of many different origins, which often become addicted to its activity. STAT3 is believed to contribute to the initial survival of pre-cancerous cells as well as to hyper-proliferation and, later, metastasis. MATERIALS AND METHODS: To evaluate the contribution of enhanced STAT3 activation in a controlled model system, we generated knock-in mice in which a mutant constitutively active Stat3C allele replaces the endogenous wild-type allele and analysed its contribution to breast tumorigenesis. Moreover, we generated Stat3C/C MEF cells and analysed their gene expression and metabolic profiles. RESULTS: Constitutively active STAT3 could enhance the tumorigenic power of the rat Neu oncogene in MMTV-Neu transgenic mice and trigger the production of earlier onset and more invasive mammary tumours. Tumour-derived cell lines displayed higher migrating, invading and metastatic ability and showed disrupted distribution of cell-cell junction markers. These features were mediated by STAT3 dependent over-expression of the C-terminal tensin-like (Cten) focal adhesion protein. Moreover, STAT3C alone was able to induce aerobic glycolysis and down regulate mitochondrial activity, both in primary fibroblasts and in STAT3 dependent tumour cell lines, acting via both HIF-1alpha-dependent and independent mechanisms. CONCLUSIONS: STAT3 can induce a metabolic switch that predisposes cells to aberrant survival, enhanced proliferation and, finally, tumour transformation. Later, enhanced Cten expression contributes to tissue infiltration and metastasis. While not excluding the contribution of many other tumour-specific STAT3 target genes, our data provide a unifying explanation of several pro-oncogenic STAT3 activities. PMID- 25436679 TI - Transforming growth factor beta signaling regulates the invasiveness of normal mammary epithelial cells and the metastasis formation of tumor cells. AB - Abstract Breast cancer patients with disseminated metastatic disease still have a very unfavorable prognosis. Investigations into the molecular mechanisms that underlie metastasis formation have a high priority and can possibly result in improved therapeutic interventions. The process of oncogenic epithelial to mesenchymal transition (EMT) has recently become a focus in cancer research because it encompasses many of the phenotypic traits characteristic of metastatic cells, e.g., increased motility, invasion, anoikis resistance, immunosuppression, and cancer stem cell potential. A number of central cellular signaling pathways and transcription factors have been implied in the control of EMT and metastasis formation, among them signal originating from the activation of the transforming growth factor beta (TGFbeta), epithelial growth factor, Wnt, Notch, and Hedgehog pathways. We have investigated the contribution of TGFbeta signaling to metastasis-related cellular properties. TGFbeta signaling can have tumor suppressive and -promoting effects depending on the tumor type and the stage of tumor progression. TGFbeta can inhibit the proliferation of mammary epithelial cells (MECs), but it can also induce EMT, invasion, and metastasis, possibly through Smad-independent signaling events. We investigated the effects of TGFbeta pathway inhibition on the proliferation, differentiation, and invasion of both normal and malignant MECs. shRNA-mediated downregulation of the Smad4 protein in non-tumorigenic HC11 and tumorigenic 4T1 cells promotes the invasiveness of both cell lines. Mammary gland reconstitution studies, with primary MECs expressing shSmad4, resulted only in subtle effects on the glandular morphogenesis. Orthotopic transplantation of shSmad4-transduced 4T1 tumor cells caused the accelerated growth of mammary tumors and enhanced colonization and macroscopic lung metastases when compared to control cells. Surprisingly, the expression of Smad4 was restored, and a strong activation of Stat3 was found in the metastatic lesions present in the lungs. These lesions express metastatic factors, such as angiopoietin-like-4 and the inhibitor of DNA binding/differentiation 1. We suggest that the downregulation of Smad4 inhibits the tumor-suppressive effects of TGFbeta signaling and enhances tumor growth. The downregulation, however, was only transient, and the reactivation of Smad4 expression caused the reversal of EMT, mesenchymal to epithelial transition, and thereby promoted metastasis formation in the lungs. PMID- 25436680 TI - Expression of reprogramming factors in breast cancer cell lines and the regulation by activated Stat3. AB - Abstract Distinct gene expression patterns, accompanied by particular epigenetic states, provide the basis for different stages of cellular differentiation. The programming of cells usually proceeds from stem cells to progenitor cells to differentiated progeny. The process, however, is not irreversible, and pluripotency can be reestablished in terminally differentiated cells through the expression of the reprogramming factors (RFs) octamer-binding transcription factor 3/4 (Oct4), sex-determining region Y box 2 (Sox2), Kruppel-like factor 4 (Klf4), and c-Myc. Tumor cell formation is characterized by partial differentiation, epigenetic alterations, and drastic changes in the transcriptional program. As the RF can cause pluripotency through cellular dedifferentiation and epigenetic alterations, it is possible that the activation of their genes might contribute to cellular transformation. The shared capacity for self-renewal between pluripotent stem cells and cancer stem cells is in line with this assumption. The deregulation of RF has been observed in poorly differentiated, high-grade breast cancer and is associated with unfavorable prognosis. Signal transducer and activator of transcription 3 (Stat3) mediates a wide variety of cellular functions including survival, proliferation, and differentiation and is constitutively activated in tumor cells of diverse origins. Stat3 is also accelerates somatic cell reprogramming. We investigated the connection between Stat3 activation and the expression of RF in the breast cancer cell lines MCF-7, SK-BR-3, MDA-MB-231, and MDA-MB-468 and the normal mammary epithelial cell line MCF-10A by real-time quantitative PCR and immunoblot analyses. We detected strong expression of Sox2 and Klf4 messenger RNA (mRNA) in MCF-7 cells and the expression of Oct4 mRNA in all the four cell lines. Immunoblot analyses revealed the strong protein expression of homeobox protein Nanog (Nanog), Oct4, and Sox2 in MCF-7 cells. This cell line only contains a low level of phosphorylated Stat3. We also examined the effect of the Stat3 inhibitor Stattic on the expression of RF and observed that it suppressed mRNA and protein expression of RF in MCF-7 cells. The expression levels of reprogramming proteins can strongly differ from their mRNA expression levels and do not necessarily correspond with the extent of Stat3 activation in the cell lines compared. PMID- 25436681 TI - Toward realization of the promise of regenerative medicine. AB - Abstract Somatic cell nuclear transfer allows the generation of cloned embryonic stem cells (ESC) and cloned mice from natural killer T (NKT) cells, an innate type invariant T cell. The progeny of these cloned mice harboring a rearranged T cell receptor alpha loci specific for NKT cells, Valpha14-Jalpha18, possess an increased number of NKT cells in the primary as well as in the secondary lymphoid organs. NKT cells in these mice are able to produce interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) when stimulated with dendritic cells (DC) pulsed with an NKT cell agonist, alpha-galactosylceramide (alpha-GalCer). The directed differentiation of cloned ESC toward T cells results in quasi-exclusive generation of NKT cells. These NKT cells are functional as evidenced by the production of cytokines such as IFN-gamma, IL-4, IL-10, and IL-13 in response to alpha-GalCer. Furthermore, they mature autonomously in vivo upon adoptive transfer, and exhibit an antigen-specific adjuvant effect, resulting in IFN-gamma production from CD8+ T cells. This effect is evident when the growth of tumors is inhibited in an antigen-dependent manner upon tumor inoculation into the mouse. Unfortunately, in humans, NKT cells are rare, and there is no guarantee that the same technique will be applicable for use in the clinic. We, therefore, exploited a different type of T cells in humans. We established induced pluripotent stem cells (iPSC) from these T cells, and succeeded in directed differentiation of the iPSC into monoclonal T cells. The availability of iPSC-derived monoclonal T cells paves the way for their use in regenerative medicine. In addition, they will be useful for drug screening to target unmet medical needs such as autoimmunity, severe infection, allergy, and cancer. PMID- 25436682 TI - Stat3 inhibition in neural lineage cells. AB - Abstract Deregulation of signal transducer and activator of transcription 3 (Stat3) is attracting attentions in neurological disorders of elderly populations, e.g., Stat3 is inactivated in hippocampal neurons of Alzheimer's disease (AD) brains, whereas it is often constitutively activated in glioblastoma multiforme (GBM), correlating with poor prognosis. Stat3-inhibiting drugs have been intensively developed for chemotherapy based on the fact that GBM, in many cases, are "addicted" to Stat3 activation. Stat3 inhibitors, however, potentially have unfavorable side effects on postmitotic neurons, normal permanent residents in the central nervous system. It is, therefore, of great importance to address detailed cellular responses of neural lineage cells including normal neurons, astrocytes, and neuronal/glial cancer cell lines to several classes of Stat3 inhibitors focusing on their effective concentrations. Here, we picked up five human and mouse cancer cell lines (Neuro-2a and SH-SY5Y neuroblastoma cell lines and Tu-9648, U-87MG, and U-373MG glioblastoma cell lines) and treated with various Stat3 inhibitors. Among them, Stattic, FLLL31, and resveratrol potently suppressed P-Stat3 and cell viability in all the tested cell lines. Stat3 knockdown or expression of dominant-negative Stat3 further sensitized cells to the inhibitors. Expression of familial AD-related mutant amyloid precursor protein sensitized neuronal cells, not glial cells, to Stat3 inhibitors by reducing P-Stat3 levels. Primary neurons and astrocytes also responded to Stat3 inhibitors with similar sensitivities to those observed in cancer cell lines. Thus, Stat3 inhibitors should be carefully targeted to GBM cells to avoid potential neurotoxicity leading to AD-like neuropsychiatric dysfunctions. PMID- 25436683 TI - Stat3 is activated in skin lesions by the local application of imiquimod, a ligand of TLR7, and inhibited by the recombinant peptide aptamer rS3-PA. AB - Abstract Signal transducer and activator of transcription 3 (Stat3) assumes central functions in the regulation of apoptosis, proliferation, angiogenesis, and immune responses in normal cells. It also plays crucial roles in inflammatory and malignant diseases and in the cellular communication in the tissue microenvironment. Signaling interactions among normal endothelial cells, immune cells, and tumor cells, mediated by the release of cytokines, chemokines, and growth factors, often result in the activation of Stat3 and promotion of cancer cell proliferation, invasion, angiogenesis, and immune evasion. Stat3 also causes the differentiation and activation of T helper 17 (Th17) cells, which is involved, e.g., in psoriasis, an inflammatory autoimmune disease of the skin. Here, we describe molecular characteristics of a mouse model triggered by the treatment of mouse skin with the immune modulator imiquimod. The application of this compound causes the local release of proinflammatory cytokines and symptoms that resemble human psoriasis. We show that this process is accompanied by strong Stat3 activation. We also investigated the effects of a membrane-permeable, peptide-based Stat3 inhibitor, recombinant Stat3-specific peptide aptamer (rS3 PA). This molecule specifically interacts with Stat3 and prevents its transactivation potential in cultured cells. rS3-PA is able to penetrate the skin, enter cells, and reduce the level of activated Stat3. The topical applications of rS3-PA to the skin could thus possibly become useful in the treatment of inflammatory skin diseases and skin cancer. PMID- 25436684 TI - Inhibition of Stat3 by peptide aptamer rS3-PA enhances growth suppressive effects of irinotecan on colorectal cancer cells. AB - Abstract Cytotoxic agents, alone or in combination, are being used in the treatment of colorectal cancer. Despite progress in the therapeutic regimes, this common malignancy is still the cause of considerable morbidity and mortality, and further improvements are required. Cancer cells often exhibit intrinsic resistance against chemotherapeutic agents or they develop resistance over the time of treatment. Several mechanisms have been made responsible, e.g., drugs may fail to reach tumor cells or drugs may fail to elicit cytotoxicity. The molecular characterization of drug resistance in cancer cells may lead to strategies to overcome it and enhance the sensitivity to chemotherapy. Irinotecan is one of the main treatments of colorectal cancer; it is converted into its active metabolite SN38 and acts as a topoisomerase I inhibitor. Inhibition of this enzyme prevents DNA relegation following uncoiling. Irinotecan has been used as a chemotherapeutic agent either as a single agent or in combination with 5 fluorouracil and targeted therapies directed against the epidermal growth factor receptor, such as cetuximab. The transcription factor signal transducer and activator of transcription 3 (Stat3) is a member of the signal transducer and activator of transcription protein family. Its persistent activation is found in tumor cells and has been associated with drug and radiation resistance. The treatment of colorectal cancer cells with irinotecan leads to senescence or apoptosis following DNA double-strand break induction. This process is impaired by the activation of Stat3. We have derived a Stat3 specific peptide aptamer [recombinant Stat3 inhibitory peptide aptamer (rS3-PA)] that recognizes the dimerization domain of Stat3 and effectively inhibits its function. The delivery of rS3-PA into colon cancer cells and the resulting inhibition of Stat3 strongly enhanced the cytotoxic action of SN38. These data show that the targeted inhibition of Stat3 decreases drug resistance and enhances SN38-mediated cell death. The combination of these agents has a potent antitumor effect and could become beneficial for the treatment of patients with colorectal cancer. PMID- 25436685 TI - Progress towards direct inhibitors of Stat5 protein. AB - Abstract Molecular approaches to inhibit STAT5 signaling have been hailed as a viable targeted anticancer therapy. In particular, many drugs and drug candidates have been developed to successfully inhibit upstream effectors of STAT5 by indirectly targeting cell surface receptors and protein kinases (FLT-3, JAK2, and BCR-ABL). Indirect strategies have yielded potent agents, such as imatinib, AC2207, and EXEL823 which effectively silence STAT5 activity but which suffer from off-target effects and toxicity. This article will focus on reviewing the current literature pertaining to direct inhibitors of STAT5 protein and assess the prospects for a future STAT5-targeting therapeutic. PMID- 25436686 TI - Steroids and their metabolites in CSF from shunt as potential predictors of further disease progression in patients with hydrocephalus and the importance of 11beta-hydroxysteroid dehydrogenase. AB - Abstract Hydrocephalus is the result of an imbalance between the formation and drainage of cerebrospinal fluid (CSF), characterized by an elevation of the CSF pressure within the brain. A primary method of its treatment is the surgical insertion of a shunt. The patient's condition is usually improved and he or she attends the hospital for periodic controls, at which CSF can be easily and repeatedly collected. Unfortunately, the effect of the operation is not durable and the number of patients in which the improvement of the clinical stage is recorded sinks considerably, and many of them develop dementia. Various biochemical markers in CSF have been searched to assess the response to surgical treatment and the further prognosis. They include classic clinical biochemistry parameters, some proteins occurring in excess in patients with Alzheimer's disease, other biomarkers generally reflecting the overall neuronal injury, and hormones, including steroids. The existing as well as the potential biomarkers enabling to predict the patient's fate after shunt operation are critically reviewed here. Special attention is paid to corticosteroids with respect to their role in influencing electrolyte balance in choroidal cells and consequently CSF and water flow among the ventricles. The importance of the local activity of steroid 11beta-hydroxysteroid dehydrogenase (11beta-HSD) of both types for regulation of the actual corticosteroid concentration is emphasized, and an original method for determination of cortisol/cortisone concentration in CSF is described. Preliminary results showing the changes of 11beta-HSD activity in ten patients with hydrocephalus immediately after shunt introduction and after 1 month are provided. PMID- 25436687 TI - Chemical and biochemical approaches to the production of 7-hydroxylated C19 steroids. AB - Abstract Interest has developed into 7-hydroxylated derivatives of 3beta hydroxylated C19-steroids, such as dehydroepiandrosterone (DHEA) and epiandrosterone because of their effects on inflammation, immune response, and cell repair. These steroids are not currently available from commercial sources, and it is necessary to produce them for relevant studies. We report here the chemical and biochemical approaches that were used for their production. Simplified chemical approaches lead to the production of 7alpha-/7beta-hydroxy DHEA and 7beta-hydroxy-epiandrosterone in gram quantities, which are made available to researchers. Biochemical approaches were used to produce isotope labeled compounds. Thus, 2H-, 3H-, and 14C-labeled 7alpha-/7beta-hydroxy-DHEA and 7beta-hydroxy-epiandrosterone could be produced in quantities sufficient for use in investigations into their mode of action. PMID- 25436688 TI - Balancing steroidal hormone cascade in treatment-resistant veteran soldiers with PTSD using a fermented soy product (FSWW08): a pilot study. AB - Abstract Introduction: A clinical study was conducted to determine steroidal hormone cascade in the blood to relate them to mental performance with the Clinician-Administered PTSD scale (CAPS), serum lipid concentrations, and steroidal hormones, particularly cortisol, testosterone, estradiol, dehydroepiandrosterone (DHEA), and pregnenolone, in treatment-resistant male veterans with combat-related chronic posttraumatic stress disorder (PTSD) before and after consumption of a special fermented soy formulation (FSWW08). Admitted veterans in the study were resistant to conventional psychological and pharmacological therapies. METHOD: Ten treatment-resistant soldiers with combat related PTSD (according to the International Classification of Diseases, 10th Revision code) for <=1.5 years were enrolled in this study. A specially formulated fermented soy product, FSWW08, was given to the veterans for 3 months and then extended to 6 months. CAPS was used to assess the severity of PTSD. Immunologic cytokines, triglycerides, and 16 steroidal hormones were also determined from the blood of the PTSD patients before, during, and after consumption of the FSWW08. RESULTS: FSWW08 increased blood levels of steroids, such as testosterone, estradiol, and particularly the adrenal hormones cortisol and androstenediol. Decreased steroidal hormones from the upper part of the hormone cascade, such as cholesterol, DHEA, and pregnenolone were experienced. The arteriosclerotic risk was reduced (cholesterol, 280+/-35 to 205+/-22 mmol/L, p<0.001; triglycerides, 645+/-267 to 161+/-22 mg/dL, p<0.001; very-low-density lipoprotein cholesterol, 312+/-112 to 151+/-20 mg/dL, p<0.001; homocysteine in serum (i.s.), 26+/-4 to 11.8+/-2.1 MUmol/L, p<0.001). High-density lipoprotein cholesterol concentration was significantly lower after consumption of FSWW08 (51+/-15 to 89+/-7.8 mg/dL, p<0.001). FSWW08 significantly reduced mental symptoms according to CAPS after 7 days throughout the 6-month study. Insomnia (estradiol increased from 53+/-24 to 88+/-41 pg/L), breathing disorders (may be related to increased aldosterone) are hormone dependent and were corrected in those with insomnia. The increase in testosterone and decrease in prolactin was corroborated by an increase in sex drive and improved partner relationships. Common immunity disorders of the veterans, such as increased herpes labialis, flu like syndromes, and stomach pain were resolved in all veterans and was corroborated by significant improvements in immunologic cytokines: tumor necrosis factor alpha was reduced (from 13.5+/-0.4 to 9.0+/-1.4 pg/mL, p<0.001) and interleukin beta (from 7.0+/-0.5 to 4.5+/-1.8 pg/mL) and interferon gamma (from 10.4+/-2.4 to 6.3+/-1.5 pg/mL, p=0.001) were also detected. PTSD is associated with clinically elevated leukocytes and lymphocytes, which are reduced by FSWW08 as well. CONCLUSION: It is the first time that the normalization of the whole steroidal hormone cascade in the blood could be correlated with improvements in mental and physical parameters (especially metabolic and immunologic disorders) in veterans with combat-related and treatment-resistant PTSD. Studies of FSWW08 in larger cohorts and over longer periods of time, as well as dosing effects, have to be conducted to validate these results. PMID- 25436689 TI - Hormones in normal and pathological prostate. PMID- 25436690 TI - Abdominal obesity and intra-abdominal pressure: a new paradigm for the pathogenesis of the hypogonadal-obesity-BPH-LUTS connection. AB - Abstract The pathogenesis of benign prostatic hyperplasia-lower urinary tract symptoms (BPH-LUTS) is complicated, multifactorial, and incompletely understood. A number of recent observations have provided for new insights and offer a better appreciation for, and the understanding of, the pathophysiological and hormonal contributions for the development and progression of prostatic enlargement. A major paradox has been the progressive increase in the prostate size at a time when the peripheral blood testosterone levels are decreasing as men age. This has been associated with the findings of increasing obesity-related states and the manifestation of BPH-LUTS. Several converging and new findings combine the mechanisms that result in an integration of the hypogonadal-obesity-increased intra-abdominal pressure (IAP)-BPH-LUTS connection. The net positive caloric balance results increased the IAP and damaged the one-way valves of the internal spermatic veins. This results in an increased venous back pressure that leads to the reflux of the high testicular testosterone concentrations and venous pressures that are transmitted to the communicating prostatic venous system. Simultaneously, increasing obesity results in an increased aromatase activity, which leads to a reduction of the testosterone levels. Consequently, there is also an increased estradiol production, which inhibits gonadotropin secretion and the production of testosterone. This hypogonadal obesity cycle eventually results in a progressive hypogonadal state, while the prostate continues to enlarge and produce increasing LUTS. PMID- 25436691 TI - Chaperones for proper androgen action - a plethora of assistance to androgen receptor function. AB - Abstract The androgen receptor (AR) plays a major role for normal prostate growth and also promotes the development and progression of prostate cancer (PCa). PCa, an important age-related disease, is one of the most commonly diagnosed cancers and the second leading cause of cancer mortality for men in Western countries. AR function and activity are regulated by molecular chaperones. The AR belongs to the steroid hormone receptor (SHR) family and can be activated by androgens such as dihydrotestosterone. SHRs are ligand-dependent transcription factors that are predominantly localized in the cytoplasm in the absence of their appropriate ligand. Upon hormone binding, translocation to the nucleus occurs as shown for glucocorticoid receptors, mineralocorticoid receptors, or the AR, while others, such as estrogen and progesterone receptors, are mainly nuclear. Importantly, the newly synthesized and unliganded receptors bind stepwise with chaperones then being associated in a dynamic chaperone heterocomplex, including heat shock proteins. It emerges that chaperones are very important, not only in the proper folding of the AR but they are also involved in receptor stability, intracellular localization and androgen-controlled transcription. Accordingly, chaperones may be interesting future targets for PCa treatment. In this review we will summarize the involvement of chaperones controlling AR activity. PMID- 25436692 TI - Testosterone protects the lower urinary tract from metabolic syndrome-induced alterations. AB - Abstract Epidemiological studies document a positive and independent association between metabolic syndrome (MetS) and lower urinary tract symptoms (LUTS). In the male, the pathogenesis of MetS-related LUTS involves a complex interplay among pathophysiological mechanisms mainly affecting the prostate and the bladder. Recently, hypogonadism has been recognized as a key factor bridging MetS and LUTS. Preclinical data have evidenced that MetS-induced hypogonadism is associated with alterations not only of the prostate but also of the bladder, and testosterone supplementation can counteract both. Interestingly, testosterone also shows a marked effect on the bladder, preventing the MetS-related RhoA/ROCK hyperactivation, which drives the pathogenesis of bladder overactivity and LUTS. The precise mechanisms through which testosterone exerts its protective action on the LUT remains to be fully elucidated; however, indirect (through improved cardiometabolic status) and direct (through local androgen receptor-mediated pathways) actions are both likely to play a role. PMID- 25436693 TI - Clinically insignificant improvement of prostate cancer prediction by addition of sex steroid hormones and SHBG serum levels to serum PSA, fPSA%, and age in a screening setting. AB - Abstract Various findings implicate sex hormones in prostate growth and development and also in prostate carcinogenesis. We investigated if addition of sex steroid hormone and sex hormone binding globulin (SHBG) serum levels to standard risk assessment parameters [prostate-specific antigen (PSA), free PSA percentage (fPSA%), and age] improves prostate cancer prediction in a PSA screening setting. Steroid hormones testosterone (T), free testosterone (fT), and estradiol (E2), and binding protein SHBG levels were measured in 762 men undergoing prostate biopsy due to suspect PSA serum levels. Prostate cancer was diagnosed in 286 (37.5%) of these men. Our data confirmed that PSA (mean BE=5.09; mean CA=6.05; p=1.24*10-5), fPSA% (mean BE=22.08; mean CA=18.67; p=1.97*10-7), and age (mean BE=60.64; mean CA=64.5; p=7.05*10-10) differentiate men with cancer (CA) and men with benign disease (BE), such as benign prostate hyperplasia. In addition, SHBG (mean BE=50.3; mean CA=54.9; p=0.008) also differed statistically significantly between these two groups. All hormones except E2 and tumor markers correlated significantly with age (T: rho=-0.09; fT: rho=-0.27; SHBG: rho=0.21; PSA: rho=0.32; and fPSA%: rho=0.22). Furthermore, we found that PSA correlates with E2 (rho=0.08), and fPSA% with SHBG (rho=0.1) and fT (rho=-0.09). Addition of hormones and SHBG to a baseline marker model including PSA, fPSA%, and age improved cancer prediction in three multivariate classification methods; however, the improvement was minimal. The best improvement by 0.8% was obtained in the logistic regression model with the addition of T and SHBG or of E2 and SHBG, or in the support vector machine model with the addition of SHBG and all steroid hormones to the combination of standard markers PSA, fPSA%, and age; however, this additional gain of accuracy is too small to justify the additional efforts and costs. PMID- 25436694 TI - Testosterone replacement in normal and pathologic prostate. AB - Abstract The testosterone replacement therapy (TRT) market has grown rapidly over the past 5 years. Exogenous testosterone in various forms is now the fastest growing medication prescribed in the USA. From 2005 to 2009, spending on testosterone jumped 115.5%, and the number of prescriptions filled increased 64.5%. One of the main reasons for this rapid growth in the TRT market is decreased concern that TRT can lead to prostate cancer. Other reasons are decreased concerns that testosterone can lead to worsening of benign prostatic hyperplasia (BPH) symptoms. In fact, recent studies suggest that TRT may improve BPH symptoms. Although there have been marked increases in the treatment of low testosterone, lingering concerns about prostate cancer have hindered progress. There are many theories, such as the prostate saturation theory, that may help us understand why testosterone may be safely administered in men with hypogonadism with normal and pathologic prostatic disease. PMID- 25436695 TI - Circulating levels of gonadotropins before and after prostate ablation in cancer patients. AB - Abstract Background: The prostate gland synthesizes a host of hormones, prostaglandins and growth factors. It is not clear if such biochemical factors modulate the hypothalamic/pituitary (H-P) gonadal axis. AIM: To determine the influence of the prostate gland on the hypothalamic-pituitary axis feedback system and changes in circulating hormone levels before and after cryoablation of the entire prostate. METHODS: In 37 consecutive patients with localized prostate cancer who underwent total cryoablation we investigated the circulating levels of testosterone, estradiol, progesterone, sex hormone binding globulin (SHBG) luteinizing hormone (LH), follicle stimulating hormone (FSH), dehydroepiandrosterone sulfate (DHEAS), prolactin, insulin-like growth factor 1(IGF-1) and prostatic specific antigen (PSA) from 3 years prior to diagnosis to 3 years after initiating treatment. RESULTS: The levels of LH and FSH were significantly elevated in most patients up to 3 years after surgery. No significant changes were observed for the other hormones, with a decrease in PSA as expected. CONCLUSION: LH and FSH levels rise after ablation of the prostate gland and the levels remain high for up to 3 years after surgery, which suggests that the prostate gland may influence the H-P feedback axis. PMID- 25436696 TI - Hormones: electron emission, communication, mutual interaction, regeneration, metabolites, carcinogenesis and receptor action. AB - Abstract This review discusses the highlights of the recently made discovery about the ability of hormones to eject 'solvated electrons' (eaq-) in water containing media. The resulting consequences for communication with other biological systems by the electron-transfer process, formation of metabolites, the possible initiation of cancer, hormone regeneration and the action of hormone receptor systems are briefly discussed. The molecular structure of the hormones and the environment are hereby found to be the most important determining factors for the yield of ejected eaq-. Furthermore, the hormone transients, which result from emission of eaq-, are reviewed, as well as the formation of metabolites, which can be involved in various biological processes. The hormone-transients can also be regenerated by electron-transfer from a potent electron donor, at least partly, as long as they are in a 'status nascendi state'. The discussion of all these effects is supported by corresponding experimental data and experiments in vitro. This review presents a complete new conception of the action mechanisms of hormones. PMID- 25436697 TI - Co-expression of genes with estrogen receptor-alpha and progesterone receptor in human breast carcinoma tissue. AB - Abstract Background: To detect genes associated with the expression of ESR1 and PGR - as well as of their protein products, estrogen receptor (ER) and progesterone receptor (PR) - 221 de-identified invasive ductal carcinomas of the breast were investigated. Our long-term goal is to decipher relationships between the expression of ER- and PR-associated genes and breast cancer behavior to improve diagnostics and identify new molecular targets for drug design. MATERIALS AND METHODS: Frozen tissue sections were evaluated for structural integrity and pathology after hematoxylin and eosin staining. ER and PR protein levels were quantified by either enzyme immunoassay or radio-ligand binding assay. Total RNA preparations were reverse transcribed for qPCR measurements of ESR1, PGR and 31 gene candidates. RESULTS: Both ESR1 and PGR expression levels were correlated with their cognate receptor protein expression (Pearson correlations of 0.82 and 0.68, p<0.001, respectively), to assess molecular relationships between clinically relevant biomarkers in tissue specimens. Coordinate expression of EVL, NAT1, TBC1D9, SCUBE2, RABEP1, SLC39A6, TCEAL1, FUT8, XBP1, PTP4A2 or GATA3 with either ESR1 or PGR was detected. CONCLUSIONS: Examination of relationships between ESR1 and PGR gene expression and that of other genes of interest indicated: a high degree of correlation between ESR1 levels and expression of NAT1, SCUBE2, XBP1 and GATA3; and a high degree of correlation between PGR expression and that of NAT1, ESR1, SCUBE2 and RABEP1. These results suggest that direct relationships of these genes exist with estrogen and progestin receptor mediated pathways. Pathway analysis software provided additional evidence of gene interactions. PMID- 25436698 TI - Circulating 5alpha-dihydrotestosterone, abdominal obesity and adipocyte characteristics in women. AB - Abstract Background: The association between circulating androgen levels and fat distribution in women has been widely inconsistent among existing studies. OBJECTIVE: We sought to investigate the relation between plasma adrenal and gonadal androgen levels and body fat distribution, as well as abdominal adipocyte characteristics. METHODS: Paired omental and subcutaneous adipose tissue samples were surgically obtained from 60 women (age, 47+/-5 years; body mass index, 26+/ 5 kg/m2) undergoing gynecological surgery. Body composition and fat distribution were measured by dual-energy X-ray absorptiometry and computed tomography, respectively. Adipocyte diameter, basal lipolysis, and heparin-releasable lipoprotein lipase activity were measured. Steroids were quantified using high performance gas chromatography and mass spectrometry. RESULTS: Significant negative associations were found between plasma dihydrotestosterone (DHT) levels and total adiposity (body mass index, r=-0.35, p<0.05; fat mass, r=-0.31, p<0.05) as well as computed tomography assessments of abdominal adiposity (r=-0.30, p<0.05 and r=-0.44, p<0.005 for subcutaneous and visceral adipose tissue area, respectively). The association between DHT levels and visceral adipose tissue area was independent of total body fat mass. A significant negative association was also observed between plasma DHT and omental adipocyte diameter (r=-0.27, p<0.05). When expressed as the omental/subcutaneous ratio, heparin-releasable lipoprotein lipase activity was negatively and significantly related to plasma DHT, androstenedione, and dehydroepiandrosterone (DHEA) levels. CONCLUSION: Abdominally obese women with large, metabolically active omental adipocytes appear to be characterized by reduced endogenous levels of DHT. The assumption that high androgen levels are associated with an android body fat distribution pattern in women should be critically re-examined. PMID- 25436699 TI - Effects of short-term testosterone administration on variables of the metabolic syndrome, in particular aldosterone. AB - Abstract Background: The ATPIII criteria of the metabolic syndrome (MS) comprise impaired fasting glucose (>5.6 nmol/L), waist circumference >102 cm, hypertension (>130/85 mm Hg), high triglycerides (>1.7 nmol/L) and low HDL cholesterol (<=1.03 nmol/L). Aldosterone is currently recognized as a key factor in the pathogenesis of cardiovascular diseases and insulin resistance, linking hypertension to MS and obesity. Further, the MS is related to psychological functioning. MATERIALS AND METHODS: Forty-two men older than 40 years with BMI >30 kg/m2, chronic heart failure (CHF) and serum testosterone (T) <12.0 nmol/L were recruited. Of these 42, 26 consented to T treatment and received two injections with T undecanoate 1000 mg. Biochemical variables relevant for the MS and also serum aldosterone were determined before and after injections; an echocardiography and Aging Males' Symptoms (AMS) scale were also utilized. RESULTS AND CONCLUSIONS: After 24 weeks of testosterone administration, there were significant declines of insulin and homeostatic model assessment and of serum aldosterone, but no changes in blood pressure. Serum glucose declined but not significantly (p=0.073). There was a slight increase in LDL cholesterol and a decrease in triglycerides. Other variables of MS and other biochemical variables did not change. Echocardiographical variables did not change. The AMS showed improvements over the first 3 months after testosterone administration but, although sustained, there was no further improvement. Short-term testosterone administration over 24 weeks led to some improvements of variables of the MS, notably of aldosterone. Longer-term studies are needed to analyze whether the decrease in serum aldosterone will improve blood pressure and glycemic control. PMID- 25436700 TI - The effect of fermented soy (FSWW08) on blood hematology and cachexia in cancer patients. AB - Abstract In cancer patients, appetite and immune status are significantly weakened. Two experimental fermented formulations without (group A, named as FSWW08) and with (group B, FSWW08) an extract from yam root were investigated against a placebo formulation with casein (group C) in a clinical study conducted in six cancer hospitals where cancer patients underwent radio or chemotherapy (patients undergoing radiation therapy n=78, patients undergoing chemotherapy n=184, total 262). IgG and IgA were increased by formulation A in patients despite receiving radio- or chemotherapy. Group A experienced statistically significant increases in lymphocyte transformation rates, whereas group B and group C did not. Formulations A and B either inhibited or lessened statistically significant decreases in white blood counts, whereas the placebo group experienced substantial decreases. Hemoglobin and platelet decreases were inhibited in group A, although not statistically significantly. Patients in group A received no blood transfusions, whereas many patients from the placebo group received blood transfusions. Appetite loss was reduced in group A from 57.9% to 13.3% and in group B from 70% to 35.8%. In the placebo group, an increase in appetite loss was detected under chemo and radiation therapy from 41.8% to 70.9%. PMID- 25436701 TI - Partial agonist, but not pure antiestrogens stimulate doming, a marker of normal differentiation, in the MCF-7 breast cancer cell line. AB - Abstract Background: The mechanisms by which tamoxifen inhibits breast tumor growth are not completely understood. Partial agonist antiestrogens such as tamoxifen may cause the estrogen receptor (ER) to interact with genes different from those activated by ER bound to estradiol. Doming is a property often associated with, and considered a marker of, differentiation in mammary epithelial cells in culture. This study compared the ability of pure and partial agonist antiestrogens to stimulate doming. MATERIALS AND METHODS: MCF-7 cells grown in medium with 10% calf serum were treated with antiestrogens. Domes were counted in three rows (width of the 4* field) across the flask. RESULTS: Three partial agonist antiestrogens [4-hydroxytamoxifen (OHT), H1285 and RU 39,411] caused dome formation. None of the pure antiestrogens tested (ICI 164,384, ICI 182,780 and RU 58,668) caused doming. Doming was stimulated in a dose-dependent manner starting at 1 nM OHT with maximum stimulation at 10-100 nM. Estradiol did not stimulate doming, but blocked doming at 1%-10% of the OHT concentration. Trichostatin A (TSA) reduced the level of estrogen receptor alpha (ERalpha) and adding it 24 h before adding OHT prevented dome formation. CONCLUSIONS: OHT and the other partial agonist antiestrogens appear to act through the ER to stimulate doming. The ability of tamoxifen to induce a marker of differentiation may play a role in its inhibition of breast tumors. If so, then the fact that other partial agonist antiestrogens share this ability, but that pure antiestrogens lack it, may be an important consideration in developing new antiestrogens for breast cancer therapy. PMID- 25436702 TI - The molecular basis of progesterone receptor action in breast carcinogenesis. AB - Abstract Progesterone plays an essential role in the regulation of cell proliferation and differentiation in the mammary gland. In addition, experimental and clinical evidence points to a critical role of progesterone and the nuclear progesterone receptor (PR) in controlling mammary gland tumorigenesis. However, the molecular mechanisms of progesterone action in breast cancer still remain elusive. In its classical mechanism of action, PR acts as a ligand-induced transcription factor (TF) interacting directly with specific progesterone response elements (PREs) in the promoter of target genes. In addition to its transcriptional effects, PR activates signal transduction pathways through a rapid or non-genomic mechanism. Interestingly, progestin induces the expression of key genes involved in breast cancer growth, which lack PREs in their promoters, via a non-classical PR transcriptional mechanism through PR tethering to other TFs. Recent findings on steroid hormone receptor modulation of target genes raise the most exciting possibility that progestin may also induce long range transcriptional control of gene expression via PR binding to cis-regulatory elements (PREs or half PREs) located far upstream or downstream from the trascriptional start site. This review will focus on the involvement and interplay of the different PR actions in breast cancer. PMID- 25436703 TI - Aromatase inhibitors and breast cancer. AB - Abstract Breast cancer is the most prevalent cancer and the second leading cause of death among women worldwide. The advent of hormonal therapy has revolutionized the treatment for breast cancer for a century. In the 1960s, an important advance was the development of the antiestrogen tamoxifen. While this drug has had a major impact on breast cancer treatment, its partial agonist activity is associated with increased risk of stroke and endometrial cancer as well as drug resistance. One of the breakthroughs in breast cancer treatment is the discovery of aromatase inhibitors (AIs) in the early 1970s. AIs have proven to be effective in treating hormone receptor-positive breast cancer and lack the estrogenic effects of tamoxifen. They are now considered to be the standard treatment for postmenopausal women with hormone receptor-positive breast cancer. While AIs are effective in treating hormone receptor-positive breast cancer, resistance to AIs inevitably occurs in metastatic setting after prolonged suppression of estrogen production. This chapter summarizes the evolution of AIs, clinical efficacy of AIs, mechanisms of AI resistance, and the strategies to overcome resistance. PMID- 25436704 TI - Interaction of dietary polyphenols with molecular signaling pathways of antiestrogen resistance: possible role in breast cancer recurrence. AB - Abstract Breast cancer is the most common cancer diagnosed in women and its global incidence is rising rapidly. Adjuvant hormonal therapy, with antiestrogens (AE) such as tamoxifen and fulvestrant, is highly effective in the treatment of estrogen receptor-positive (ER+) breast cancers and is largely responsible for the increase in survival rates seen in the past four decades. However, nearly 50% of women with ER+ cancer display de novo or acquired resistance to AE therapies. Potential molecular mechanisms driving the resistance phenotype are beginning to be elucidated, allowing further development of more effective therapeutic and preventive strategies to reduce the overall mortality due to breast cancer. Over 70% of breast cancer survivors surveyed report increasing their comsumption of fruits, vegetables, and natural product supplements upon diagnosis. These are rich sources of dietary polyphenols (PPs) that can interact with cell-signaling pathways involved in the development of AE resistance. However, research on mechanisms by which these agents may affect AE resistance and whether PP intake can significantly change breast cancer recurrence is limited. We summarize the available data on the effects of PPs on breast cancer recurrence and the interactions of these compounds with some of the signaling pathways hypothesized to drive cell death and survival involved in the development of AE resistance in breast cancer. PMID- 25436705 TI - Mechanisms of resistance to endocrine therapies for breast cancer. AB - Abstract Breast cancer is the most frequently diagnosed cancer in women and 70% of the cases are hormone-dependent. The presence of ERalpha is one of the most important prognostic factors predictive of response to endocrine therapy in human breast cancers. Resistance to endocrine therapies has become a major public health concern and it appears essential to understand the mechanisms underlying this phenomenon. This review provides insights into the molecular mechanisms associated with resistance to endocrine therapies and presents the different strategies currently developed in pre-clinical models to overcome this resistance. PMID- 25436706 TI - Expression of thyroid-stimulating hormone receptor, octamer-binding transcription factor 4, and intracisternal A particle-promoted polypeptide in human breast cancer tissues. AB - Abstract Background: Thyroid-stimulating hormone receptor (TSHR) is one of the members of glycoprotein hormone receptor family; activation of TSHR by thyroid stimulating hormone (TSH) regulates thyroid function, proliferation, and differentiation. The other family members of glycoprotein hormone receptors, such as leutinizing hormone receptor (LHR), human chorionic gonadotropin (hCG), and follicle-stimulating hormone (FSH) are known to be expressed in nonendocrine tissues including human breast cancer and regulate proliferation and differentiation. The involvement of thyroid hormones in the growth and differentiation of normal breast tissue is well documented. However, the presence of TSHR in breast cancer has not been demonstrated. The aim of the present study was to establish the expression pattern of TSHR along with transcription factors, such as octamer 4 (OCT4) and intracisternal A particle-promoted polypeptide (IPP) in human breast tumor. MATERIALS AND METHODS: For this study, patients with stages I-III breast cancers and adjacent noncancerous tissues were prospectively accrued and analyzed. We employed semiquantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis to determine the expression levels of TSHR in normal and human breast cancer tissues. RESULTS: The results indicated that a significant increase in TSHR expression was observed in tumor tissues compared to normal breast tissues. RT-PCR analysis of OCT4 and IPP also revealed a significant increase in breast tumor tissues over the controls. CONCLUSIONS: To our knowledge, this is the first report demonstrating expression of TSHR and IPP in normal breast and breast tumors. The expression of TSHR, IPP, and OCT4 increased in the human breast tumor samples over the noncancer tissues. However, further studies are needed to establish an unequivocal role for TSHR in breast tumor progression. PMID- 25436707 TI - Cytochrome P450-7B1 and 11beta-hydroxysteroid dehydrogenase type 1 distribution in human tissues. AB - Abstract Successive action of cytochrome P450-7B1 (CYP7B1) and 11beta hydroxysteroid dehydrogenase type 1 (11beta-HSD1) on 3beta-hydroxysteroids such as DHEA and epiandrosterone leads to the production of cytoprotective 7beta hydroxylated derivatives. Investigation of the presence of these enzymes in human tissues could be carried out on commercially available human tissue arrays with use of antibodies specific to CYP7B1 and 11beta-HSD1 for immunohistochemistry. Both enzymes were detected mainly in tissues of endodermic and ectodermic origin which are prone to undergo inflammation. As low doses of the 7beta-hydroxylated derivatives of DHEA and epiandrosterone trigger the resolution of inflammation and tissue repair, CYP7B1 and 11beta-HSD1 tissue contents may reflect the tissue ability for reparation after pathological conditions. PMID- 25436708 TI - Steroids in semen, their role in spermatogenesis, and the possible impact of endocrine disruptors. AB - The data on hormonal steroids in the human seminal plasma and their role in spermatogenesis are summarized. The seminal steroid levels need not correlate with the blood plasma levels. The recent reports showed that androgen, especially dihydrotestosterone, and the estrogen levels in the seminal fluid may be used as the markers of spermatogenesis impairment. The estradiol concentration in the seminal plasma was higher than in the blood plasma, and its levels were significantly increased in men with impaired spermatogenesis. A good indicator for predicting the normal spermatogenesis, therefore, seems to be the testosterone/estradiol ratio. The seminal plasma also contains significant amounts of cortisol, which influences the androgen biosynthesis through its receptors in the Leydig cells. The local balance between cortisol and inactive cortisone is regulated by 11beta-hydroxysteroid dehydrogenase, the activity of which may be affected by the environmental chemicals acting as the endocrine disruptors (EDCs). These compounds are believed to participate in worsening the semen quality - the sperm count, motility, and morphology, as witnessed in the recent last decades. As to the steroids' role in the testis, the EDCs may act as antiandrogens by inhibiting the enzymes of testosterone biosynthesis, as the agonists or antagonists through their interaction with the steroid hormone receptors, or at the hypothalamic-pituitary-gonadal axis. Surprisingly, though the EDCs affect the steroid action in the testis, there is no report of a direct association between the concentrations of steroids and the EDCs in the seminal fluid. Therefore, measuring the steroids in the semen, along with the various EDCs, could help us better understand the role of the EDCs in the male reproduction. PMID- 25436710 TI - Dysthyronemia in normal concentrations of thyrotropin--analytical and clinical consequences. AB - This article discusses the conditions that may lead to a phenomenon called dysthyronemia. Here, the thyroid gland has concentration of thyrotropin in circulation within the reference range, but the concentrations of free or total fractions of thyroid hormones are outside the reference range. Normal values of thyrotropin (TSH) and increased values of THs are referred to as hyperthyroxinemia, while normal values of thyrotropin and decreased values of thyroid hormone are hypothyroxinemia. As shown by our observations, it is a relatively frequent situation in the parallel determinations of TSH and free thyroxine, when results verging on hyperthyroxinemia were found in 7% of cases (6.74%, n=259,590), and also in the parallel sets of TSH and total triiodothyronine when hypotriiodothyroninemia reached 8.5% (8.48%, n=73,143). We are assuming that the main cause of hyperthyroxinemia in the free thyroxine and TSH system is the presence of autoantibodies against thyroxine in patients with autoimmune thyroid disease. The reason of hypotriiodothyroninemia in the system of triiodothyronine and TSH is a decreased concentration of thyroid binding globulin in postmenopausal women. Manufacturers of immunoanalytical kits should take into account the potential adverse effects of autoantibodies against thyroid hormones when measuring the results of immunoassay determination of the free fraction of these hormones. PMID- 25436709 TI - Density and distribution of connexin 43 in corpus cavernosum tissue from diabetic and hypogonadal patients with erectile dysfunction. AB - AIM: Altered expression of connexin 43 (Cx43) has been postulated to be involved in the development and progression of various diseases including erectile dysfunction (ED). The aim of this study was to determine whether distribution and density of the gap junction protein Cx43 are altered in human corpus cavernosum (HCC) tissue samples derived from diabetic or hypogonadal patients with ED compared to those from normal subjects. METHODS: HCC tissue sections derived from normal, diabetic and hypogonadal subjects were fixed in 4% formaldehyde, embedded in paraffin and immunostained with a monoclonal mouse anti-rat Cx43 antibody. Cx43 density was expressed as the cumulative number of gap junction plaques per unit area of tissue corrected for number of 4',6-diamidino-2-phenylindole, dihydrochloride-labeled smooth muscle cells (dots per unit area corrected for number of cells). RESULTS: The distribution of Cx43 plaques in smooth muscle was not affected in tissues derived from diabetic or hypogonadal subjects with ED compared with those from normal subjects. However, the number of Cx43 plaques was significantly reduced in HCC tissues derived from diabetic or hypogonadal subjects (73 +/- 8% and 68 +/- 11% of normal, respectively), indicating reduced Cx43 gap junctions in diabetic and hypogonadal subjects with ED. CONCLUSIONS: Cx43 density in the HCC was diminished in tissue samples derived from diabetic or hypogonadal patients with ED compared to tissue samples from normal non-diabetic subjects. This marked decrease in Cx43 gap junction channels may contribute to attenuated gap junction function and to diminished erectile physiology. PMID- 25436711 TI - Hormone replacement therapy: evolution of body mass index, bone mineral density, and lipid profile. AB - One hundred and eighty-five female never-hormone users with a mean age of 50.71 (SD = 5.58) years upon initiation of treatment were studied before instauration and during treatment. The profile of patients subjected to the study included body mass index (BMI), bone mineral density (BMD), and lipid profile (LP). In our population, pretreatment values were within the normal range, which is why a hormone replacement therapy (HRT), conjugated equine estrogen plus medroxyprogesterone acetate, was administered to a healthy population of women for 9.82 +/- 5.42 years and follow-up comprised 1815.84 woman-years. To study the effects of treatment on the investigated clinical subjects, we resorted to comparative analyses of pretreatment and posttreatment mean values: descriptive and comparative hypothesis, followed by a repeated measurements design to investigate the evolution on three levels according to age groups just before the initiation of the treatment and on the other three levels during the treatment with a minimum follow-up of 9 years. On the basis of the numerical results, we were able to conclude that BMD decreased significantly (p = 0.00) well above the values found on curves corresponding to these age groups. The total cholesterol decreased significantly at 2-3 years interval (p = 0.04). The rest of the LP factors remained within a safe margin. Therefore, long-term HRT may be considered initially as a beneficial alternative in the treated study population. PMID- 25436712 TI - Neonatal rat osteoblasts bioconvert testosterone to non-phenolic metabolites with estrogen-like effects on bone cell proliferation and differentiation. AB - Testosterone (T) restores bone mass loss in postmenopausal women and osteoporotic men mainly through its bioconversion to estradiol (E2). In target tissues, T is also biotransformed to the A-ring-reduced metabolites 3alpha,5alpha androstanediol (3alpha,5alpha-diol) and 3beta,5alpha-androstanediol (3beta,5alpha diol), which are potent estrogen receptor (ER) agonists; however, their biological role in bone has not been completely elucidated. To assess if osteoblasts bioconvert T to 3alpha,5alpha-diol and to 3beta,5alpha-diol, we studied in cultured neonatal rat osteoblasts the metabolism of [14C]-labeled T. In addition, the intrinsic estrogenic potency of diols on cell proliferation and differentiation in neonatal calvarial rat osteoblasts was also investigated. Osteoblast function was assessed by determining cell DNA, cell-associated osteocalcin, and calcium content, as well as alkaline phosphatase activity and Alp1 gene expression. The results demonstrated that diols were the major bioconversion products of T, with dihydrotestosterone being an obligatory intermediary, thus demonstrating in the rat osteoblasts the activities of 5alpha steroid reductase and 3alpha- and 3beta-hydroxysteroid dehydrogenases. The most important finding was that 3beta,5alpha- and 3alpha,5alpha-diols induced osteoblast proliferation and differentiation, mimicking the effect of E2. The observation that osteoblast differentiation induced by diols was abolished by the presence of the antiestrogen ICI 182,780, but not by the antiandrogen 2 hydroxyflutamide, suggests that diols effects are mediated through an ER mechanism. The osteoblast capability to bioconvert T into diols with intrinsic estrogen-like potency offers new insights to understand the mechanism of action of T on bone cells and provides new avenues for hormone replacement therapy to maintain bone mass density. PMID- 25436714 TI - Pathophysiology of adipose tissue: effects of steroid hormones. Part A. PMID- 25436713 TI - Megestrol acetate may stimulate the production of insulin-like growth factor 1 in breast tissues of women with breast cancer. AB - BACKGROUND: In women with breast cancer who were treated with either continuous tamoxifen alone or sequential tamoxifen followed by megestrol acetate (MA), we demonstrated significant positive associations between the breast tumor estrogen receptor (ER) and an increase in serum sex hormone-binding globulin (SHBG) during tamoxifen treatment. We interpreted this as "ER uniformity" in different tissues, e.g., breast, liver. No other associations with ER were found. In the same study, the breast tumor progesterone receptor (PR) was determined. Our aim was to see if there were any associations between PR and endocrine changes during MA treatment. METHODS: The breast tumor PR before treatment and serum insulin-like growth factor I (?IGF-1), steroids, steroid-binding proteins, and insulin before and during treatment were measured in 17 postmenopausal women with breast cancer who were treated sequentially with tamoxifen 40 mg/day followed by MA 160 mg/day in alternating 3-month periods. RESULTS: During MA treatment periods, the levels of IGF-1 and insulin increased significantly, whereas the levels of androgens, SHBG, corticosteroid-binding globulin, and cortisol decreased significantly. Significant positive correlations were found between the PR content and increments in ?IGF-1 but not between PR and any other endocrine change. CONCLUSIONS: PR expression in human liver is very weak, but malignant and normal breast tissues secrete considerable amounts of growth hormone and IGF-1 in vitro and in vivo. This activity is stimulated by progestogens. The association between PR and ?IGF-1 may therefore reflect a direct PR-mediated action of MA on malignant and normal human breast tissues in vivo. PMID- 25436715 TI - The role of steroids in mesenchymal stem cell differentiation: molecular and clinical perspectives. AB - Mesenchymal stem cells (MSCs) are multipotent stem cells capable of either self regeneration or differentiation into more mature cell types, depending on the environmental stimuli. MSCs originate from the mesoderm and differentiate readily into mesodermal tissue. The tissues most studied in that respect are bone, fat and cartilage, and the key molecular elements in these three differentiation pathways are RUNX2, PPARgamma and SOX9, respectively. Steroidal molecules play an important role in determining the fate of MSCs, mainly by altering the expression of key cellular molecules. Not all steroids exert the same effects on these cells. This review discusses the effects of sex steroids and glucocorticoids on the proliferative capacity and differentiation patterns of MSCs. With stem-cell based therapy gaining worldwide attention, we explore the role of steroids in modulating MSCs for clinical and therapeutic purposes. The ease with which some MSCs, such as adipose-derived stem cells, can be harvested from the body and manipulated in the laboratory may lead to increased interest in this era of stem cells. PMID- 25436716 TI - Adipose circadian clocks: coordination of metabolic rhythms by clock genes, steroid hormones, and PPARs. AB - A central clock consisting of interconnected positive and negative feedback gene loops operates in the brain, tying rhythmic activity to the 24-h day. The central clock entrains similar feedback loops present in most peripheral tissues to coordinate metabolic gene expression among organs and with feeding activity for more efficient utilization of resources. Recent studies are beginning to elucidate the intricate feedback mechanisms among central and peripheral clocks and their roles in activity and metabolic homeostasis. Adipose tissue serves as a major energy storage organ and releases paracrine and endocrine hormones to signal energy status to other organs. Within the adipose tissue, the transcriptional feedback regulation between clock genes and nuclear hormone receptors, together with direct protein associations among these molecules, ensures the expression of metabolic genes at the appropriate time. This review will summarize the important components and mechanisms of adipose clock entrainment, particularly highlighting instructive studies carried out in mice. This research not only illustrates the intricate connections between clocks and metabolism but also provides potential mechanisms to correct abnormalities induced by disrupted sleep or poor diet. PMID- 25436717 TI - Impact of glucocorticoid hormones on adipokine secretion and human adipose tissue metabolism. AB - The glucocorticoid hormones alter the metabolism of the adipose tissue after an approximately 2-h lag period. The effects are mediated through the nuclear receptors that alter the expression of a wide variety of genes through the mechanisms that are similar to those seen in the other cells. There are many direct metabolic effects of the glucocorticoids on the adipose tissue metabolism, and every year, new effects are added to the list of proteins whose expression is influenced by the glucocorticoids. Furthermore, some enzymatic processes are affected by these hormones only in the presence of the other hormones such as growth hormone (GH) or insulin. Most of the effects of the glucocorticoids are on the gene transcription, and the effects on the mRNA are reflected in the altered levels of the target proteins. The glucocorticoids enhance the leptin release, while reducing that of the inflammatory adipokines and stimulating that of the lipoprotein lipase (LPL) in the presence of insulin. The activity of 11beta hydroxysteroid dehydrogenase type 1 (HSD1) is enhanced by the glucocorticoids along with that of alpha1 glycoprotein 1 and serum amyloid A release by the adipose tissue. In contrast, the tumor necrosis factor alpha (TNF)-stimulated lipolysis in the adipose tissue is blocked by the glucocorticoids. It is still unclear which, if any, of these effects account for the insulin resistance due to the glucocorticoids in the adipose tissue. However, recent work suggests that, at least in mice, the reduction in the osteocalcin release by the osteoblasts in the presence of the glucocorticoids accounts for much of the in vivo insulin resistance. In summary, there are multiple direct effects of the glucocorticoids, both anti-inflammatory and proinflammatory, on the adipose tissue. PMID- 25436718 TI - Role of maternal nutrition in programming adiposity in the offspring: potential implications of glucocorticoids. AB - The epidemiological studies initially indicated that maternal undernutrition leading to a low birth weight may predispose to the long-lasting energy balance disorders. A high birth weight due to maternal obesity or diabetes, inappropriate early postnatal nutrition, and rapid catch-up growth, may also sensitize to an increased risk of obesity. As stated by the developmental origin of health and disease concept, the perinatal perturbation of the fetus/neonate nutrient supply might be a crucial determinant of the individual programming of the body weight set point. The adipose tissue is considered as the main fuel storage unit involved in the maintenance of the energy homeostasis. Several models have demonstrated that this tissue is a prime target of the developmental programming in a gender- and depot-specific manner. In the rodents, the perinatal period of life corresponds largely to the period of adipogenesis. In contrast, this phenomenon essentially takes place before birth in bigger mammals. Despite these different developmental time windows, the altricial and precocial species share several common offspring programming mechanisms. Thus, the adipose tissue of the offspring from malnourished dams exhibited impaired glucose uptake and leptin/insulin resistance with increased proinflammatory markers. It also displayed a modified sympathetic activity, circadian rhythm, fatty acid composition, and thermogenesis. This might lead to the reprogrammed metabolism and distribution of the adipose tissue with enhanced adipogenesis and fat accumulation predisposing to adiposity. The inappropriate glucocorticoid (GC) levels and modified tissue sensitivity might be key actors of perinatal programming and long-lasting altered adipose tissue activity in the offspring. Following maternal malnutrition, the epigenetic mechanisms might also be responsible for the adipose tissue programming. PMID- 25436719 TI - Paracrine and intracrine contributions of androgens and estrogens to adipose tissue biology: physiopathological aspects. AB - In mammals, the male and female hormones androgen and estrogen act as endocrine regulators of energy metabolism. However, adipose tissue is also a site of androgen and estrogen synthesis; androgens convert to estrogens in these tissues, and adipose tissue is also a reservoir of steroids that act locally in a paracrine and intracrine manner. Thus, in adipose tissue, the local output of sex hormones is more complex than would be suggested by routine measurement of serum hormone concentrations. This review integrates studies on the effects of androgens and estrogens in the developmental programming of adipose tissue function in early life and addresses the contributions of local androgen and estrogen metabolism on adipose tissue function in adults. PMID- 25436720 TI - Menopausal status, adipose tissue, and breast cancer risk: impact of estrogen replacement therapy. AB - The seeds of breast cancer are likely sown in the first two or three decades of life. Rapid weight gain and height in infancy predict breast cancer risk in later life. The age at first pregnancy is also a strong predictor for breast cancer; the earlier the first full-term pregnancy, then the lower the risk of breast cancer in later life. It has been postulated that the breast stem cell number may be the factor linking these observations together. Menopause, per se, is associated with an increase in central adiposity, which is reversed by hormone replacement usage. Breast and nonbreast fat both produce estrogens and cytokines that may promote the growth of small breast cancers making them appear earlier. Obesity also is associated with metabolic syndrome, which is a risk factor for breast cancer. The breast cancer stem cells make up only around 1%-2% of the tumor mass and, yet, are the likely driver for much of a breast cancer's behavior. Future research into breast cancer biology, especially into the cancer stem cells is likely to translate into novel methods of treatment and prevention of this common cancer. PMID- 25436721 TI - Effects of DHEA on metabolic and endocrine functions of adipose tissue. AB - Dehydroepiandrosterone (DHEA) and its sulfate ester, DHEAS, are the major circulating adrenal steroids and serve as substrates for sex hormone biosynthesis. DHEA is effectively taken up by adipose tissue, where the concentrations of free DHEA are four to ten times higher than those found in the circulation. DHEA reduces adipose tissue mass and inhibits the proliferation and differentiation of adipocytes; it may also protect against obesity by lowering the activity of stearoyl-CoA desaturase 1 in fat cells. Recent studies demonstrate that DHEA stimulates triacylglycerol hydrolysis in adipose tissue by increasing the expression and activity of adipose triglyceride lipase and hormone sensitive lipase, the key enzymes of lipolysis. DHEA has been shown to modulate insulin signaling pathways, enhance glucose uptake in adipocytes, and increase insulin sensitivity in patients with DHEA deficiency or abnormal glucose tolerance. Additionally, by suppressing the activity of 11beta-hydroxysteroid dehydrogenase 1 in adipocytes, DHEA may promote intra-adipose inactivation of cortisol to cortisone. Several studies have demonstrated that DHEA may also regulate the expression and secretion of adipokines such as leptin, adiponectin, and resistin. The effects of DHEA on adipokine expression in adipose tissue are depot-specific, with visceral fat being the most responsive. The mechanisms underlying DHEA actions in adipose tissue are still unclear; however, they involve nuclear receptors such as androgen receptor and peroxisome proliferator activated receptors gamma and alpha. Because clinical trials investigating the effects of DHEA failed to yield consistent results, further studies are needed to clarify the role of DHEA in the regulation of human adipose tissue physiology. PMID- 25436722 TI - Retinoids and nuclear retinoid receptors in white and brown adipose tissues: physiopathologic aspects. AB - Vitamin A, ingested either as retinol or beta-carotene from animal- or plant derived foods respectively, is a nutrient essential for many biological functions such as embryonic development, vision, immune response, tissue remodeling, and metabolism. Its main active metabolite is all trans-retinoic acid (atRA), which regulates gene expression through the activation of alpha, beta, and gamma isotypes of the nuclear atRA receptor (RAR). More recently, retinol derivatives were also shown to control the RAR activity, enlightening the interplay between vitamin A metabolism and RAR-mediated transcriptional control. The white and brown adipose tissues regulate the energy homeostasis by providing dynamic fatty acid storing and oxidizing capacities to the organism, in connection with the other fatty acid-consuming tissues. This concerted interorgan response to fatty acid fluxes is orchestrated, in part, by the endocrine activity of the adipose tissue depots. The adipose tissues are also sites for synthesizing and storing vitamin A derivatives, which will act as hormonal cues or intracellularly to regulate essential aspects of adipocyte biology. As agents that prevent adipocyte differentiation hence, expected to decrease fat mass, and inducers of uncoupling protein expression, thus, favoring energy expenditure, retinoids have prompted many investigations to decipher their roles in adipose tissue pathophysiology, which are summarized in this review. PMID- 25436723 TI - Nuclear receptor-mediated regulation of lipid droplet-associated protein gene expression in adipose tissue. AB - In adipose tissues, nuclear receptors (NRs) have important metabolic actions on cellular lipid-storing capacity through targeted gene regulation. Lipid droplets (LDs) are the organelles for intracellular triacylglycerol (TAG) storage and are present in all eukaryotic cells. They are small in most cells, but in white adipocytes, they can occupy 90% of the cytoplasm. LDs consist of a TAG core surrounded by a phospholipid monolayer and an array of associated proteins that determine size, stability, inter-droplet interaction, and lipid storage capacity. The genes that encode these proteins are more highly expressed in brown compared with white fat, correlating with the greater LD surface area in multilocular brown adipocytes. Gene expression profiling reveals that most NRs are present in adipose tissues, with some showing greater expression in brown compared with white fat, including peroxisome proliferator-activated receptor (PPAR) alpha, estrogen-related receptor alpha, and NURR1. NR signaling is important for the regulated expression of most genes that encode LD-associated proteins. For example, estradiol signals via estrogen receptor alpha to regulate the levels of PLIN1 and the lipase ATGL controlling LD size and total lipid accumulation. PPARgamma is essential for adipocyte differentiation and function, and analysis of data obtained through chromatin immunoprecipitation followed by high throughput DNA sequencing shows that it binds to the promoters of many genes encoding LD proteins in adipocytes. Of these genes, the greatest PPARgamma binding was to regulatory regions for Plin1, Cidec, and G0s2. NRs represent an important target for controlling LD dynamics in diseases affected by altered fat storage encompassing obesity and lipodystrophy, which are an increasing health problem. PMID- 25436724 TI - Regulation of apoptosis in adipocytes and breast cancer cells by 1,25 dihydroxyvitamin D3: a link between obesity and breast cancer. AB - Modulation of apoptosis is emerging as a promising strategy for prevention and treatment of breast cancer and obesity because removal of mammary cancer cells and mature adipocytes through this process will result in decreasing tumor size and produce long-term reduction in adipose tissue mass. The hormone 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) triggers apoptosis in breast cancer cells and adipocytes via the induction of the apoptotic Ca2+ signal - a sustained increase in concentration of intracellular Ca2+. This signal acts as an apoptotic initiator that directly recruits Ca2+-dependent apoptotic effectors, calpain and caspase 12, in breast cancer cells and adipocytes. Normal mammary epithelial cells are resistant to 1,25(OH)2D3-induced, Ca2+-mediated apoptosis because the mechanisms regulating Ca2+ in these cells do not sustain Ca2+ increase at the apoptosis-inducing level. Induction of apoptosis with 1,25(OH)2D3 in adipose tissue, particularly in the tumor-surrounding adipose tissue involved in tumor progression, can contribute to the anticancer effects of the hormone. The 1,25(OH)2D3-Ca2+ link between obesity and breast cancer supports the rationale to include Ca2+-dependent apoptotic proteases as molecular targets for the discovery of new therapeutic and preventive agents for breast cancer and obesity; it also supports the recommendation to maintain adequate or increased vitamin D and calcium intakes as one of the possible ways to protect against breast cancer and decrease adiposity. PMID- 25436725 TI - The estrogen-related receptors and the adipocyte. AB - The estrogen-related receptors (ERRalpha, beta, and gamma) are orphan members of the nuclear receptor superfamily. ERRalpha and gamma are highly expressed in tissues displaying elevated energy demands and are involved in several aspects of energetic metabolism, which they regulate mostly in association with members of the PGC-1 coactivator family. These activities have mostly been documented in the liver, heart, or skeletal muscle. ERRalpha and gamma are also highly expressed in adipocytes. Their precise roles in this cell type are less documented, although published data indicate that they contribute to cell differentiation as well as functionality. This review describes these activities. PMID- 25436726 TI - Pathophysiology of adipose tissue: effects of steroid hormones. Part B. PMID- 25436727 TI - Steroid hormones and the stroma-vascular cells of the adipose tissue. AB - The stroma-vascular fraction (SVF) of adipose tissue (AT) is a heterogeneous cell fraction composed of progenitor cells, endothelial cells, and immune cells. SVF plays a key role in AT homeostasis and growth as well as in obesity-associated pathologies. The SVF cell composition and phenotype are distinct according to AT location and adiposity. Such discrepancies influence AT function and are involved in obesity-associated disorders such as chronic inflammation. Investigations performed in recent years in rodents and humans provided evidence that the stroma vascular cells contribute to the conversion of steroid hormones in AT and are also steroid targets. This review describes the link between steroids and SVF depending on gender, adiposity, and AT location and highlights the potential role of sex and corticosteroid hormones in adipogenesis, angiogenesis, and their contributions in AT inflammation. PMID- 25436728 TI - Caveolae, lipid droplets, and adipose tissue biology: pathophysiological aspects. AB - Adipocytes are specialized cells that function to store energy in the form of lipids, predominantly triglycerides (TGs), and as a regulatory system contributing to metabolic homoeostasis through the production and secretion of hormones and cytokines. The regulation of lipid homeostasis by adipose tissue is an important aspect of whole-body metabolism. Owing to the central nature of adipose tissue in lipid metabolism, dysregulation has wide-ranging effects, contributing to disorders as diverse as diabetes, cardiovascular disease, cancer, and neurodegeneration. Excess lipids are stored in specialized organelles called lipid droplets (LDs). The surface of the lipid droplet can be considered a highly regulated membrane domain that both protects the contents of the LD from unregulated lipolysis and the cell from the cytotoxic effects of elevated free fatty acids. The surface of the LD is coated with a variety of regulatory proteins, either resident or transiently associated, including enzymes involved in the breakdown of TG, lipid transport proteins, and cofactors. Recent studies have begun to unravel the range of LD-associated proteins and to define their functional significance. Importantly, the involvement of LD proteins in pathophysiological disorders is beginning to be understood. This review will outline recent advances in defining the diversity of LD-associated proteins and their links to metabolic disorders including the integral membrane protein, caveolin-1 (CAV1). Analysis of the role of CAV1 in adipose tissue has highlighted the interconnectedness between the regulation of lipid storage and the function of the adipocyte plasma membrane. PMID- 25436729 TI - Adipose tissue inflammation and metabolic dysfunction: a clinical perspective. AB - Obesity is characterized by a state of chronic low-grade inflammation due to increased immune cells, specifically infiltrated macrophages into adipose tissue, which in turn secrete a range of proinflammatory mediators. This nonselective low grade inflammation of adipose tissue is systemic in nature and can impair insulin signaling pathways, thus, increasing the risk of developing insulin resistance and type 2 diabetes. The aim of this review is to provide an update on clinical studies examining the role of adipose tissue in the development of obesity associated complications in humans. We will discuss adipose tissue inflammation during different scenarios of energy imbalance and metabolic dysfunction including obesity and overfeeding, weight loss by calorie restriction or bariatric surgery, and conditions of insulin resistance (diabetes, polycystic ovarian syndrome). PMID- 25436730 TI - Pregnancy, obesity and insulin resistance: maternal overnutrition and the target windows of fetal development. AB - A substantial body of literature has demonstrated that the nutritional environment an individual experiences before birth or in early infancy is a key determinant of their health outcomes across the life course. This concept, the developmental origins of health and disease (DOHaD) hypothesis, was initially focused on the adverse consequences of exposure to a suboptimal nutrient supply and provided evidence that maternal undernutrition, fetal growth restriction, and low birth weight were associated with heightened risk of central adiposity, insulin resistance, and cardiovascular disease. More recently, the epidemic rise in the incidence of maternal obesity has seen the attention of the DOHaD field turn toward identifying the impact on the offspring of exposure to an excess nutrient supply in early life. The association between maternal obesity and increased risk of obesity in the offspring has been documented in human populations worldwide, and animal models have provided critical insights into the biological mechanisms that drive this relationship. This review will discuss the important roles that programming of the adipocyte and programming of the central neural networks which control appetite and reward play in the early life programming of metabolic disease by maternal overnutrition. It will also highlight the important research gaps and challenges that remain to be addressed and provide a personal perspective on where the field should be heading in the coming 5-10 years. PMID- 25436731 TI - The role and regulation of 11beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome. AB - The cortisol regenerating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) amplifies tissue glucocorticoid levels, particularly in the liver and adipose tissue. The importance of this enzyme in causing metabolic disease was highlighted by transgenic mice which over- or under-expressed 11beta-HSD1; consequently, selective 11beta-HSD1 inhibitors have been widely developed as novel agents to treat obesity and type 2 diabetes mellitus (T2DM). This review focuses on the importance of 11beta-HSD1 in humans which has been more difficult to ascertain. The recent development of a deuterated cortisol tracer has allowed us to quantify in vivo cortisol production by 11beta-HSD1. These results have been surprising, as cortisol production rates by 11beta-HSD1 are at least equivalent to that of the adrenal glands. The vast majority of this production is by the liver (>90%) with a smaller contribution from subcutaneous adipose tissue and possibly skeletal muscle, but with no detectable production from visceral adipose tissue. This tracer has also allowed us to quantify the tissue-specific regulation of 11beta-HSD1 observed in obesity and obesity-associated T2DM, determine the likely basis for this dysregulation, and identify obese patients with T2DM as the group most likely to benefit from selective inhibition of 11beta HSD1. Some of these inhibitors have now reached Phase II clinical development, demonstrating efficacy in the treatment of T2DM. We review these results and discuss whether selective 11beta-HSD1 inhibitors are likely to be an important new therapy for metabolic disease. PMID- 25436732 TI - Obesity and cardiovascular disease: role of adipose tissue, inflammation, and the renin-angiotensin-aldosterone system. AB - Obesity is a leading contributor to morbidity and mortality worldwide. Chronic overnutrition and lack of physical activity result in excess deposition of adipose tissue and insulin resistance, which plays a key role in the pathophysiology of type 2 diabetes mellitus (DM2) and associated cardiovascular disease (CVD). Dysfunctional adipose tissue in obese individuals is characterized by chronic low-grade inflammation that spreads to several tissues as well as systemically and is able to impact the cardiovascular system, resulting in both functional and anatomical abnormalities. Inflammation is characterized by abnormalities in both innate and adaptive immunity including adipose tissue infiltration by CD4+ T lymphocytes, pro-inflammatory (M1) macrophages, and increased production of adipokines. The renin-angiotensin-aldosterone system (RAAS) is inappropriately activated in adipose tissue and contributes to originating and perpetuating inflammation and excessive oxidative stress by increasing production of reactive oxygen species (ROS). In turn, ROS and pro inflammatory adipokines cause resistance to the metabolic actions of insulin in several tissues including cardiovascular and adipose tissue. Insulin resistance in cardiovascular tissues is characterized by impaired vascular reactivity and abnormal cardiac contractility as well as hypertrophy, fibrosis, and remodeling, which ultimately result in CVD. In this context, weight loss through caloric restriction, regular physical activity, and surgery as well as pharmacologic RAAS blockade all play a key role in reducing obesity-related cardiovascular morbidity and mortality. PMID- 25436733 TI - The mineralocorticoid receptor: a new player controlling energy homeostasis. AB - Numerous studies have demonstrated the interaction that exists between adipocyte differentiation, energy balance and factors involved in fluid and electrolyte homeostasis, such as the renin-angiotensin-aldosterone system. More specifically, a potential impact of aldosterone on the function of several organs implicated in the control of energy homeostasis, such as adipose tissue, liver, skeletal muscle or pancreas, has been recently described. In addition, the mineralocorticoid receptor (MR, NR3C2), a transcription factor, was shown to play a crucial role on white and brown adipocyte differentiation and function, mediating the effects of both mineralocorticoid and glucocorticoid hormones on adipose tissues. Transgenic mouse models as well as pharmacological inactivation of MR signaling provided compelling evidence that MR is an important control point for energy homeostasis. Herein, we review recent findings on the involvement of aldosterone but also of MR on energy metabolism and discuss the therapeutic potential of manipulating MR signaling for the management of metabolic disorders in humans. PMID- 25436734 TI - Effects of energy restriction on activity of the hypothalamo-pituitary-adrenal axis in obese humans and rodents: implications for diet-induced changes in body composition. AB - BACKGROUND: Obesity treatments aim to maximize fat loss, particularly abdominal or visceral fat, without compromising lean or bone mass. However, the literature contains numerous examples of obesity treatments that - in addition to fat loss - result in loss of lean mass and/or bone mass. MATERIALS AND METHODS: Because of the known effects of energy restriction to increase activity of the hypothalamo pitutiary adrenal (HPA) axis in lean humans and animals, and because increases in circulating glucocorticoid levels could potentially contribute to adverse body compositional changes with obesity treatments, we conducted a systematic PubMed search to determine whether HPA axis activation also occurs in response to energy restriction in obese humans and animals. RESULTS AND CONCLUSIONS: In most studies in obese humans, short-term severe energy restriction increased circulating cortisol levels, and this response was also seen in two longer-term human studies involving severe or moderate energy restriction. These findings parallel studies on short- or long-term energy restriction in obese rodents, with most studies showing increases in circulating corticosterone concentrations, and no change or actual increases in hypothalamic expression of corticotropin-releasing hormone, urocortin 3 or their receptors. However, a significant proportion of studies involving longer-term severe or moderate energy restriction in obese humans showed no change or decreases in HPA axis function. There was variability among human studies in the duration of energy restriction and timing of the HPA axis investigations (i.e., during energy restriction, or after a period of post restriction weight maintenance). In order to unambiguously determine changes in HPA axis function with energy restriction in obese humans, it will be important to assess HPA axis function at multiple time points during energy restriction, given that obese individuals may spend many weeks or months in severe or moderate energy restriction in order to reduce excess weight, and given that increases in glucocorticoid function can have significant effects on body composition within weeks to months. PMID- 25436735 TI - Implications of estrogen receptor alpha and estrogen receptor beta for adipose tissue functions and cardiometabolic complications. AB - There is growing evidence that estrogen signaling regulates energy metabolism and exerts important functions in maintaining adipose tissue metabolism, including controlling the distribution of body fat. Changes in the physiological functions of adipose tissue, particularly the white adipose tissue, have been strongly connected to obesity and the development of related cardiometabolic complications. In this review, we will focus on discussing the role of estrogen signaling in regulating adipocyte differentiation, metabolism and its endocrine function with a focus on the possible underlying molecular mechanisms mediated by estrogen receptor alpha and estrogen receptor beta. PMID- 25436736 TI - The impact of hyperandrogenism in female obesity and cardiometabolic diseases associated with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a common condition characterized by reproductive and hyperandrogenic features and is often associated with obesity and metabolic dysfunction. Overall, women with PCOS have a substantially greater prevalence of metabolic syndrome than women from the general population. Furthermore, PCOS per se (independent of its frequent association with obesity) often confers cardiometabolic risk (including insulin resistance), and its concurrence with obesity often represents a metabolic "double-whammy" from the adverse effects of PCOS and obesity. The introduction of the Rotterdam diagnostic criteria for PCOS in 2003 has broadened the scope of this condition. The Rotterdam diagnostic criteria have also introduced two new phenotypic subgroups (including normoandrogenemic women with PCOS) that have provided novel insights into a potential role for hyperandrogenism in the development of adverse cardiometabolic risk in women with PCOS. Based on evidence from cross-sectional and interventional studies, hyperandrogenism, obesity, and cardiometabolic risk in women appear to be linked through complex and multidirectional pathways. Furthermore, data from obese women without a formal diagnosis of PCOS also suggest that these interrelationships often exist in female obesity per se (in milder forms than occurs in PCOS). Data from female-to-male transsexuals are particularly informative because these show direct effects of hyperandrogenism (induced through exogenous use of androgenic therapies) on fat distribution and cardiometabolic risk in women. A challenge for the future will be to disentangle and improve our understanding of this complex pathogenic web, thereby facilitating novel and targeted therapies for the hyperandrogenic and adverse cardiometabolic manifestations of PCOS. PMID- 25436737 TI - Adipose tissue and bone: role of PPARgamma in adipogenesis and osteogenesis. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a critical factor for the reciprocal regulation of adipogenesis and osteogenesis. Because of their insulin-sensitizing effect, PPARgamma agonists, the thiazolidinediones (TZDs), have been widely used for the treatment of type 2 diabetes mellitus; however, the use of TZDs has also been revealed to cause bone loss and bone fractures. The nodal point of regulation of skeletal metabolism by PPARgamma activation may reside in its role in cell fate determination of mesenchymal stem cells toward adipogenesis at the expense of osteogenesis. In addition, accumulating evidence demonstrates that PPARgamma possesses a circadian expression profile and plays an important role in the skeletal and adipose metabolism regulated by the circadian clock network. Recently, we have shown that nocturnin, a circadian-regulated gene, enhances PPARgamma activity, resulting in the suppression of osteogenesis and enhancement of adipogenesis, thus providing additional evidence of the link between circadian networks and PPARgamma. In this review, we will focus on the emerging concept of PPARgamma as a regulator for skeletal metabolism and summarize recent findings about one of the mechanisms on how PPARgamma is connected to the circadian-regulatory system, which involves nocturnin. PMID- 25436738 TI - Insulin resistance: cross-talk between adipose tissue and skeletal muscle, through free fatty acids, liver X receptor, and peroxisome proliferator-activated receptor-alpha signaling. AB - Skeletal muscle and adipose tissue play a major role in the regulation of whole body glucose homeostasis. Much of the coordinated regulation of whole-body glucose homeostasis results from the regulation of lipid storage and release by adipose tissue and efficient switching between glucose oxidation and fatty acid oxidation in skeletal muscle. A control point for these biochemical actions center around the regulation of the insulin responsive glucose transporter, GLUT4. This review examines the regulation of GLUT4 in adipose tissue and skeletal muscle, in the context of the steroid nuclear hormone receptor signaling. PMID- 25436739 TI - Vitamin D, adipose tissue, and obesity. AB - Epidemiological studies have shown a link between vitamin D deficiency and numerous pathologies such as cancers, immunity diseases, cardiovascular diseases, hypertension, type 2 diabetes, and obesity. Recent studies in vitro and in animal models demonstrated an impact of vitamin D on adipose tissue and adipocyte biology. Such observations are of particular interest and provide mechanistic explanations on the relationship between vitamin D deficiency and obesity. PMID- 25436740 TI - Special issue on hormones and ageing. PMID- 25436741 TI - Why do we need to age? AB - Abstract A key question remains: why do multicellular organisms have a limited lifespan? The aging process is considered to be a decline of keeping the molecular, cellular and organ structure and interactions upright. It is hypothesized here that an evolutionary force has actively selected for limited lifespan and prior to that there is the process of aging. Many theories exist, including the endocrine theory of aging and reproduction-based aging. Here, a hypothesis is deduced for the driving force of the evolution of aging and lifespan limitation. PMID- 25436743 TI - Skin mirrors human aging. AB - Abstract Aged skin exhibits disturbed lipid barrier, angiogenesis, production of sweat, immune functions, and calcitriol synthesis as well as the tendency towards development of certain benign or malignant diseases. These complex biological processes comprise endogenous and exogenous factors. Ethnicity also markedly influences the phenotype of skin aging. The theories of cellular senescence, telomere shortening and decreased proliferative capacity, mitochondrial DNA single mutations, the inflammation theory, and the free radical theory try to explain the biological background of the global aging process, which is mirrored in the skin. The development of advanced glycation end-products and the declining hormonal levels are major factors influencing intrinsic aging. Chronic photodamage of the skin is the prime factor leading to extrinsic skin aging. The deterioration of important skin functions, due to intrinsic and extrinsic aging, leads to clinical manifestations, which mirror several internal age-associated diseases such as diabetes, arterial hypertension and malignancies. PMID- 25436742 TI - Estrogen receptor beta and its selective ligands: an option for treatment of menopausal vasomotor symptoms? AB - Abstract In the human female, menopause is the permanent end of fertility, defined as occurring 12 months after the last menstrual period. During peri- and postmenopausal stages, the vast majority of women experience moderate-to-severe vasomotor symptoms, such as hot flashes and night sweats, which interfere with sleep and may be severe enough to affect quality of life. The only treatment approved by national health authorities is hormone therapy with estrogen alone or in combination with a progestagen. However, this therapeutic regimen is associated with severe side effects, such as stimulation of growth of breast cancer or cardiovascular events. Thus, there is a demand for efficient and safe alternative treatments for menopausal complaints. After the discovery of estrogen receptor beta in many organs, and confirmation of its presence in the brain, many researchers raised the question of whether ERbeta-specific ligands may be novel therapeutic agents for treatment of menopausal complaints with the desirable effects of estrogen but without increased risk of tumor incidence. This minireview will briefly summarize the relevance of estrogen receptor beta and its specific ligands for the treatment of menopausal symptoms with a focus on vasomotor menopausal symptoms. At present, estrogen receptor beta-selective ligands do not seem to be active in models of prevention or reversal of osteoporosis. However, data from animal experiments suggest that estrogen receptor beta-selective ligands might be safe therapeutics for the treatment of vasomotor menopausal symptoms. PMID- 25436744 TI - Neuropeptides and skin aging. AB - Abstract Neuropeptides (NP) are peptides that are released as chemical messengers from nerve cells. They act either in an endocrine manner, where they reach their target cells via the bloodstream or a paracrine manner, as co-transmitters modulating the function of neurotransmitters. To date approximately 100 different NP have been described in the literature. In recent years, several studies have documented that human skin expresses several functional receptors for NP, such as corticotropin-releasing hormone, melanocortins, beta-endorphin, vasoactive intestinal polypeptide, neuropeptide Y and calcitonin gene-related peptide. These receptors modulate the production of inflammatory cytokines, proliferation, differentiation, lipogenesis and hormone metabolism in human skin cells. In addition, several NP are directly produced by human skin cells, indicating the complexity of understanding the real functions of NPs in human skin. In this review we address the possible effects of neuropeptides on the pathogenesis of aged skin. PMID- 25436745 TI - Plant derived alternatives for hormone replacement therapy (HRT). AB - Abstract Hormone replacement therapy (HRT) has undisputable positive effects on climacteric complaints, in the bone and on body weight but also several undesired side effects. Therefore, plant-derived alternatives are currently promoted. Phytoestrogens - primarily the isoflavones genistein, daidzein and coumestrol, stemming from soy (Glycine max) or red clover (Trifolium pratense) - were suggested to have the desired but not the undesired effects of estrogens. Most recently published placebo-controlled studies question the beneficial effects. When taken at the time of puberty however, phytoestrogens appear to protect against mammary cancer later in life. Extracts from the rhizome of Cimicifuga racemosa (black cohosh) have no estrogenic effects. In a narrow dose range they have beneficial effects on climacteric complaints, which are due to several compounds with dopaminergic, noradrenergic, serotoninergic and GABAergic actions that act together in the hypothalamus. Ecdysone is produced by several plants, including spinach (Spinacia oleracea) and was very early on shown to increase muscle mass. Later it became apparent that spinach extracts containing ecdysone decreased body fat load, thereby reducing secretion of proinflammatory cytokines by visceral adipocytes and oxidative stress. This had beneficial effects on body weight and serum lipids not only in obese postmenopausal but also in premenopausal women and in men. For the above-described plant extracts, solid placebo-controlled clinical trials are available. For other plant extracts claiming beneficial effects on climacteric complaints or postmenopausal diseases, no solid data are available. PMID- 25436746 TI - Beneficial effect of melatonin treatment on age-related insulin resistance and on the development of type 2 diabetes. AB - Abstract This paper will review the effect of aging on glucose metabolism and insulin resistance in pancreas and in peripheral tissues and how melatonin administration could affect these parameters. In SAMP8 mice insulin levels in plasma were found to be increased together with enhanced HOMA-IR values, whereas insulin content in pancreas showed a decrease with aging. Aging in SAMP8 mice was also associated with a significant increase in the relative expression of both protein and mRNA of different pro-inflammatory mediators. Furthermore, aging was associated with a decrease in the expression of Pdx-1, FoxO 1 and FoxO 3A and Sirt 1 in pancreas SAMP8 samples. Melatonin administration was able to reduce these age-related alterations, decreasing plasma insulin levels and increasing its pancreatic content in SAMP8 mice. HOMA-IR was decreased with melatonin treatment in all animals. Conversely, in SAMP8 mice, melatonin treatment decreased the expression of glucagon, GLUT2, somatostatin and insulin. Furthermore it was also able to increase the expression of Sirt 1, Pdx-1 and FoxO 3A. The present study has shown that aging is associated with significant alterations in the relative expression of pancreatic genes involved in both insulin secretion and glucose metabolism and that these are associated with an increase in inflammation and oxidative stress. Melatonin administration was able to reduce oxidative stress and inflammation and thus to improve pancreatic function in old mice. By doing so, insulin resistance is diminished and plasma insulin is reduced, enhancing insulin pancreatic content and reducing plasma glucose levels and HOMA index. PMID- 25436747 TI - Natural products and the aging process. AB - Abstract Literature surveys show that the most of the research that have been conducted on the effect of herbal remedies on many tissue pathologies, including metabolic disturbances, cardiovascular decline, neurodegeneration, cataract, diabetic retinopathy and skin inflammation, all lead to an accelerated aging process. The increased carbonylation of proteins (carbonyl stress) disturbing their function has been indicated as an underlying mechanism of cellular senescence and age-related diseases. Because it is also linked to the carbonyl stress, aging chronic disease and inflammation plays an important role in understanding the clinical implications of cellular stress response and relevant markers. Greater knowledge of the molecular and cellular mechanisms involved in several pathologies associated with aging would provide a better understanding to help us to develop suitable strategies, use specific targets to mitigate the effect of human aging, prevent particularly chronic degenerative diseases and improve quality of life. However, research is lacking on the herbal compounds affecting cellular aging signaling as well as studies regarding the action mechanism(s) of natural products in prevention of the age-related disease. This review provides leads for identifying new medicinal agents or potential phytochemical drugs from plant sources for the prevention or delaying cellular aging processes and the treatment of some disorders related with accelerated body aging. PMID- 25436748 TI - Role of oestrogens on oxidative stress and inflammation in ageing. AB - Abstract Females live longer than males. We have shown that this could be in part due to the higher levels of oestrogens in females, which protect them against ageing, by up-regulating the expression of antioxidant, longevity-related genes. However, the low concentration of oestrogens makes it unlikely that they exhibit significant antioxidant capacity in the organism. Our results show that physiological concentrations of oestrogens activate the expression of manganese superoxide dismutase and glutathione peroxidase by oestrogen receptors and the mitogen-activated protein kinase and nuclear factor kappa B pathway. Moreover, when considering oestrogen replacement therapy, it is of utmost importance to take into account when to start the therapy after menopause. We have shown that only early-onset administration of oestrogen replacement therapy is effective on oestrogen deprivation associated with oxidative and metabolic stress. This is due to a change in oestrogen receptor distribution after oestrogen deprivation. Oestrogens are also involved in inflammatory processes. Their role on inflammation is very complex, because their effects are different depending on the doses and also on the oestrogen receptor distribution. PMID- 25436749 TI - Hormesis and vitagenes in aging and longevity: mitochondrial control and hormonal regulation. AB - Abstract Average life span has increased because of medical and environmental factors, but maximal life span remains unchanged. Understanding the mechanisms of aging will help to reduce age-related morbidity and facilitate healthy aging. Unlike female menopause, which is accompanied by an abrupt and permanent cessation of ovarian function (both folliculogenesis and estradiol production), male aging does not result in either cessation of testosterone production or infertility. Although the circulating serum testosterone concentration does decline with aging, in most men this decrease is small, resulting in levels that are generally within the normal range. Age-related hypogonadism has been referred to as andropause or late-onset hypogonadism (LOH), with LOH considered to be the most suitable term for this condition. Hormone therapy (HT) trials have caused both apprehension and confusion about the overall risks and benefits associated with HT treatment. During aging, a gradual decline in the potency of the heat shock response occurs, and this may prevent the repair of protein damage. Thus, the interest in developing pharmacological agents capable of inducing stress responses is growing within the broad frame of hormesis, which underlie strategies for optimal patient treatment of numerous diseases. Vitagenes encode for heat shock proteins, thioredoxin, and sirtuin protein systems. Nutritional antioxidants have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. Here, we focus on possible signaling mechanisms involved in the activation of vitagenes resulting in enhanced defense against bioenergetic defects leading to degeneration and cell death with consequent impact on longevity processes. PMID- 25436750 TI - Early gender differences in the redox status of the brain mitochondria with age: effects of melatonin therapy. AB - Abstract Mitochondrial dysfunction and oxidative/nitrosative stress are common features of senescence, and they explain some of the pathophysiological events during aging. In different animal models of aging, the existence of oxidative stress, inflammation, and mitochondrial dysfunction has been reported. There is no information, however, regarding the age when these symptoms begin and if they account for gender differences in aging. Here we analyzed oxidative/nitrosative stress markers and bioenergetics in the brain mitochondria of normal mice during the first 10 months of life, looking for early signs of senescence. Male and female mice were treated with vehicle or melatonin during the first 9 months of life, starting at weaning. Mice were sacrificed at 5 and 10 months of life, and pure brain mitochondria were prepared and assayed for respiratory chain activity, ATP production, and oxidative/nitrosative stress status. The results showed that the brain mitochondria from male mice have a better glutathione cycle than female mice, whereas female mice have higher electron transport chain activity and ATP production at 5 months old. Five months later, however, oxidative/nitrosative stress markers increased in both male and female mice, thus eliminating the differences between the genders. More importantly, these changes were prevented by chronic melatonin administration, which also restored the gender differences found in 5-month-old mice. Thus, melatonin administration as a single therapy can maintain the full function of the brain mitochondria during the early events of aging, a finding that has important consequences in the pathophysiology of brain senescence. PMID- 25436751 TI - Melatonin and diet-induced metabolic syndrome in rats: impact on the hypophysial testicular axis. AB - Abstract Combinations of fructose- and fat-rich diets in experimental animals can model the human metabolic syndrome (MS). In rats, the increase in blood pressure (BP) after diet manipulation is sex related and highly dependent on testosterone secretion. However, the extent of the impact of diet on rodent hypophysial testicular axis remains undefined. In the present study, rats drinking a 10% fructose solution or fed a high-fat (35%) diet for 10 weeks had higher plasma levels of luteinizing hormone (LH) and lower plasma levels of testosterone, without significant changes in circulating follicle-stimulating hormone or the weight of most reproductive organs. Diet manipulation brought about a significant increase in body weight, systolic BP, area under the curve (AUC) of glycemia after an intraperitoneal glucose tolerance test (IPGTT), and plasma low-density lipoprotein cholesterol, cholesterol, triglycerides, and uric acid levels. The concomitant administration of melatonin (25 MUg/mL of drinking water) normalized the abnormally high LH levels but did not affect the inhibited testosterone secretion found in fructose- or high-fat-fed rats. Rather, melatonin per se inhibited testosterone secretion. Melatonin significantly blunted the body weight and systolic BP increase, the increase in the AUC of glycemia after an IPGTT, and the changes in circulating lipid profile and uric acid found in both MS models. The results are compatible with a primary inhibition of testicular function in diet-induced MS in rats and with the partial effectiveness of melatonin to counteract the metabolic but not the testicular sequelae of rodent MS. PMID- 25436752 TI - Epigenetic drugs in Alzheimer's disease. AB - Epigenetic processes, such as DNA methylation and histone acetylation, regulate the genome-environment interactions that may play important roles in a wide range of brain disorders, including Alzheimer's disease (AD). Indeed, the role of epigenetic machinery in learning and memory processes is well documented. In this review, we will focus on the most recent literature on tools that target epigenetic mechanisms, particularly on histone acetylation, and we will discuss the use of chemical probes to validate these targets in therapeutic strategies for AD. PMID- 25436753 TI - Notch signaling in the pathologic adult brain. AB - Along the entire lifetime, Notch is actively involved in dynamic changes in the cellular architecture and function of the nervous system. It controls neurogenesis, the growth of axons and dendrites, synaptic plasticity, and ultimately neuronal death. The specific roles of Notch in adult brain plasticity and neurological disorders have begun to be unraveled in recent years, and pieces of experimental evidence suggest that Notch is operative in diverse brain pathologies including tumorigenesis, stroke, and neurological disorders such as Alzheimer's disease, Down syndrome, and multiple sclerosis. In this review, we will cover the recent findings of Notch signaling and neural dysfunction in adult human brain and discuss its relevance in the pathogenesis of diseases of the central nervous system. PMID- 25436754 TI - The CCN family acting throughout the body: recent research developments. AB - The animal body is composed of a variety of cells and extracellular matrices that are organized and orchestrated in a harmonized manner to support life. Therefore, the critical importance of a comprehensive understanding of the molecular network surrounding and integrating the cells is now emphasized. The CCN family is a novel group of matricellular proteins that interact with and orchestrate a number of extracellular signaling and matrix molecules to construct and maintain living tissues. This family comprises six distinct members in mammals, which are characterized by a unique and conserved modular structure. These proteins are not targeted to limited and specific receptors to execute specific missions, but manipulate a vast number of biomolecules in the network by serving as a molecular hub at the center. The unified nomenclature, CCN, originates from a simple acronym of the three classical members, which helps us to avoid having any preconception about their pleiotropic and anonymous functional nature. In this review, after a brief summary of the general molecular concepts regarding the CCN family, new aspects of each member uncovered by recent research are introduced, which represent, nevertheless, only the tip of the iceberg of the profound functionality of these molecules. PMID- 25436755 TI - MurD enzymes: some recent developments. AB - The synthesis of the peptide stem of bacterial peptidoglycan involves four enzymes, the Mur ligases (MurC, D, E and F). Among them, MurD is responsible for the ATP-dependent addition of d-glutamic acid to UDP-MurNAc-l-Ala, a reaction which involves acyl-phosphate and tetrahedral intermediates. Like most enzymes of peptidoglycan biosynthesis, MurD constitutes an attractive target for the design and synthesis of new antibacterial agents. Escherichia coli MurD has been the first Mur ligase for which the tridimensional (3D) structure was solved. Thereafter, several co-crystal structures with different ligands or inhibitors were released. In the present review, we will deal with work performed on substrate specificity, reaction mechanism and 3D structure of E. coli MurD. Then, a part of the review will be devoted to recent work on MurD orthologs from species other than E. coli and to cellular organization of Mur ligases and in vivo regulation of the MurD activity. Finally, we will review the different classes of MurD inhibitors that have been designed and assayed to date with the hope of obtaining new antibacterial compounds. PMID- 25436756 TI - Viroid-induced DNA methylation in plants. AB - In eukaryotes, DNA methylation refers to the addition of a methyl group to the fifth atom in the six-atom ring of cytosine residues. At least in plants, DNA regions that become de novo methylated can be defined by homologous RNA molecules in a process termed RNA-directed DNA methylation (RdDM). RdDM was first discovered in viroid-infected plants. Viroids are pathogenic circular, non coding, single-stranded RNA molecules. Members of the Pospiviroidae family replicate in the nucleus through double-stranded RNA intermediates, attracting the host RNA silencing machinery. The recruitment of this machinery results in the production of viroid-derived small RNAs (vd-sRNAs) that mediate RNA degradation and DNA methylation of cognate sequences. Here, we provide an overview of the cumulative data on the field of viroid-induced RdDM and discuss three possible scenarios concerning the mechanistic details of its establishment. PMID- 25436757 TI - Gene amplification: mechanisms and involvement in cancer. AB - Gene amplification was recognized as a physiological process during the development of Drosophila melanogaster. Intriguingly, mammalian cells use this mechanism to overexpress particular genes for survival under stress, such as during exposure to cytotoxic drugs. One well-known example is the amplification of the dihydrofolate reductase gene observed in methotrexate-resistant cells. Four models have been proposed for the generation of amplifications: extrareplication and recombination, the breakage-fusion-bridge cycle, double rolling-circle replication, and replication fork stalling and template switching. Gene amplification is a typical genetic alteration in cancer, and historically many oncogenes have been identified in the amplified regions. In this regard, novel cancer-associated genes may remain to be identified in the amplified regions. Recent comprehensive approaches have further revealed that co-amplified genes also contribute to tumorigenesis in concert with known oncogenes in the same amplicons. Considering that cancer develops through the alteration of multiple genes, gene amplification is an effective acceleration machinery to promote tumorigenesis. Identification of cancer-associated genes could provide novel and effective therapeutic targets. PMID- 25436758 TI - Small heat shock proteins: recent developments. AB - Small heat shock proteins (sHSPs) are abundantly present in many different organisms at elevated temperatures. Members of the subgroup of alpha crystallin domain (ACD)-type sHSPs belong to the large family of protein chaperones. They bind non-native proteins in an ATP-independent manner, thereby holding the incorporated clients soluble for subsequent refolding by other molecular chaperoning systems. sHSPs do not actively refold incorporated peptides therefore they are sometimes referred to as holdases. Varying numbers of sHSPs have been documented in the different domains of life and dependent on the analyzed organism. Generally, diverse sHSPs possess more sequence similarities in the conserved ACD, whereas the N- and C-terminal extensions are less conserved. Despite their designation as sHSPs, they are not solely present during heat stress. sHSPs presumably help to protect cells under various stresses, but they were also found during development, e.g., in embryonic development of higher plants which is associated with ongoing seed desiccation. The functional and physiological relevance of several different sHSPs in one organism remains still unclear, especially in plants where several highly similar sHSPs are present in the same compartment. The wide range of biotic and abiotic stresses that induce the expression of multiple sHSP genes makes it challenging to define the physiological relevance of each of these versatile proteins. PMID- 25436759 TI - Folding of peptides and proteins: role of disulfide bonds, recent developments. AB - Disulfide-containing proteins are ideal models for studies of protein folding as the folding intermediates can be observed, trapped, and separated by HPLC during the folding reaction. However, regulating or analyzing the structures of folding intermediates of peptides and proteins continues to be a difficult problem. Recently, the development of several techniques in peptide chemistry and biotechnology has resulted in the availability of some powerful tools for studying protein folding in the context of the structural analysis of native, mutant proteins, and folding intermediates. In this review, recent developments in the field of disulfide-coupled peptide and protein folding are discussed, from the viewpoint of chemical and biotechnological methods, such as analytical methods for the detection of disulfide pairings, chemical methods for disulfide bond formation between the defined Cys residues, and applications of diselenide bonds for the regulation of disulfide-coupled peptide and protein folding. PMID- 25436760 TI - The role of chromogranins in the secretory pathway. AB - Chromogranins (Cgs) are acidic proteins implicated in several physiological processes, including the biogenesis and sorting of secretory vesicles, the generation of bioactive peptides, and the accumulation of soluble species inside large dense core vesicles (LDCV). Indeed, Cgs are the main protein component of the vesicular matrix in LDCV, and they are involved in the concentration of soluble species like neurotransmitters and calcium. Experiments using electrochemical techniques such amperometry, patch amperometry, and intracellular electrochemistry have clarified the functional roles of Cgs in the accumulation and release of catecholamines. We have focused this review at a single event of exocytosis of chromaffin cells from three mouse strains lacking Cgs. Accordingly, in this brief review, we will focus on the role of Cgs in maintaining the intravesicular environment of secretory vesicles and in exocytosis, bringing together the most recent findings from studies on adrenal chromaffin cells. PMID- 25436761 TI - Selenomethionine metabolism and its toxicity in yeast. AB - The importance of selenium for organisms can be explained by its existence as selenocysteine in the catalytic centers of glutathione peroxidase and thioredoxin reductase. Another selenoamino acid, selenomethionine, is the major form of selenium in foods, and organisms that require selenium as a nutrient directly metabolize selenomethionine to a reactive form of selenium or store it in general proteins. Selenium is recognized as an essential nutrient for human and animal health; however, its excessive uptake harms mammals and the cytotoxic mechanism of selenium remains unclear. Recent progress in the development of selenium enriched yeast and selenomethionine-resistant mutant to produce selenomethionine containing proteins for X-ray crystallography has provided new insights into the molecular mechanism of selenomethionine toxicity. In this review, we describe the metabolism of seleno-compounds in yeast and discuss the cytotoxicity caused by selenomethionine against yeast from a metabolic viewpoint. PMID- 25436763 TI - Efficacy of generic highly active antiretroviral therapy in HIV-1 infected individuals in Nigeria. AB - CD4 T lymphocyte and plasma HIV RNA parameters have been used to monitor disease progression, and predict clinical course in HIV infection. Initial evaluation of these parameters was conducted in the western countries where accessible ARVs, circulating HIV subtypes and mode of transmission are different from the situation in Nigeria. This study appraised these parameters, and efficacy of generic ARVs. Consenting 106 HIV infected ARV naive patients were enrolled. CD4 T lymphocyte and plasma HIV RNA levels were determined at interval for 24 months. Ninety eight (92.5%) of the patients who completed the follow up in strict adherence to therapy guideline were included in the analysis. Baseline median CD4 T lymphocyte increased from 114 (Range: 6-330) to highest 357 (Range: 15-1036) cells/ MU L at 18 months of therapy, while baseline median plasma viral RNA declined from 4.6 (Range: 2.6-6.0) Log10 copies/mL to undetectable level within three months of therapy. Significant CD4 T-cell restoration and plasma viral RNA decline in the study population demonstrate efficacy of the generic HAART. The importance of combined use of both parameters for evaluation of immunologic and virologic responses to ART was confirmed. PMID- 25436762 TI - Plasma exchange therapy for severe gastrointestinal involvement of Henoch Schonlein purpura in children. AB - OBJECTIVES: The aim of this report is to evaluate the plasma exchange as a choice for the management of life-threating gastrointestinal system (GIS) involvement in Henoch-Schonlein purpura (HSP) when refractory to conventional therapies. METHODS: We retrospectively reviewed the medical records of HSP patients who had plasma exchange therapy due to massive GIS involvement. We reported age, gender, initial HSP presentation, etiological or triggering factors and disease course. Treatment modalities, side effects and their outcomes were noted. RESULTS: We reported 7 cases of childhood HSP with severe gastrointestinal involvement refractory to common immunosuppression with systemic steroid and cytotoxic therapy. All patients gave inadequate response to pulse methyl prednisolone or oral prednisolone therapy with ongoing GIS bleeding and severe abdominal pain. Therefore, pulse cyclophosphamide was added to the treatment. Two patients received additional intravenous immunoglobulin (IVIG) therapy. Gastrointestinal manifestations continued and plasma exchange was performed. All patients improved after plasma exchange treatment. CONCLUSIONS: Treatment of GI involvement in HSP with plasma exchange has been mainly based on case reports. According to our data, we propose that, plasma exchange may be a safe and efficient management choice in paediatric HSP patients with massive GIS involvement that are refractory to other therapies. PMID- 25436764 TI - Addressing the challenges of clinician training for long-acting reversible contraception. PMID- 25436765 TI - Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors. AB - We previously proved that a histone deacetylase inhibitor (valproate, VPA) decreases the number of leukemic cells in bovine leukemia virus (BLV)-infected sheep. Here, we characterize the mechanisms initiated upon interruption of treatment. We observed that VPA treatment is followed by a decrease of the B cell counts and proviral loads (copies per blood volume). However, all sheep eventually relapsed after different periods of time and became refractory to further VPA treatment. Sheep remained persistently infected with BLV. B lymphocytes isolated throughout treatment and relapse were responsive to VPA induced apoptosis in cell culture. B cell proliferation is only marginally affected by VPA ex vivo. Interestingly, in four out of five sheep, ex vivo viral expression was nearly undetectable at the time of relapse. In two sheep, a new tumoral clone arose, most likely revealing a selection process exerted by VPA in vivo. We conclude that the interruption of VPA treatment leads to the resurgence of the leukemia in BLV-infected sheep and hypothesize that resistance to further treatment might be due to the failure of viral expression induction. The development of more potent HDAC inhibitors and/or the combination with other compounds can overcome chemoresistance. These observations in the BLV model may be important for therapies against the related Human T-lymphotropic virus type 1. PMID- 25436766 TI - Hypomethylation and Over-Expression of the Beta Isoform of BLIMP1 is Induced by Epstein-Barr Virus Infection of B Cells; Potential Implications for the Pathogenesis of EBV-Associated Lymphomas. AB - B-lymphocyte-induced maturation protein 1 (BLIMP1) exists as two major isoforms, alpha and beta, which arise from alternate promoters. Inactivation of the full length BLIMP1alpha isoform is thought to contribute to B cell lymphomagenesis by blocking post-germinal centre (GC) B cell differentiation. In contrast, the shorter beta isoform is functionally impaired and over-expressed in several haematological malignancies, including diffuse large B cell lymphomas (DLBCL). We have studied the influence on BLIMP1beta expression of the Epstein-Barr virus (EBV), a human herpesvirus that is implicated in the pathogenesis of several GC derived lymphomas, including a subset of DLBCL and Hodgkin's lymphoma (HL). We show that BLIMP1beta expression is increased following the EBV infection of normal human tonsillar GC B cells. We also show that this change in expression is accompanied by hypomethylation of the BLIMP1beta-specific promoter. Furthermore, we confirmed previous reports that the BLIMP1beta promoter is hypomethylated in DLBCL cell lines and show for the first time that BLIMP1beta is hypomethylated in the Hodgkin/Reed-Sternberg (HRS) cells of HL. Our results provide evidence in support of a role for BLIMP1beta in the pathogenesis of EBV-associated B cell lymphomas. PMID- 25436767 TI - From Exit to Entry: Long-term Survival and Transmission of Salmonella. AB - Salmonella spp. are a leading cause of human infectious disease worldwide and pose a serious health concern. While we have an improving understanding of pathogenesis and the host-pathogen interactions underlying the infection process, comparatively little is known about the survival of pathogenic Salmonella outside their hosts. This review focuses on three areas: (1) in vitro evidence that Salmonella spp. can survive for long periods of time under harsh conditions; (2) observations and conclusions about Salmonella persistence obtained from human outbreaks; and (3) new information revealed by genomic- and population-based studies of Salmonella and related enteric pathogens. We highlight the mechanisms of Salmonella persistence and transmission as an essential part of their lifecycle and a prerequisite for their evolutionary success as human pathogens. PMID- 25436769 TI - Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. AB - OBJECTIVE: Uncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect. In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients. Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study. METHODS: Patients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0-6.5 were randomized to receive IV 1-2*10(6) bone-marrow-derived-MSCs/Kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months. Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures. Immunological tests were explored to assess the immunomodulatory effects. RESULTS: At baseline 9 patients were randomized to receive MSCs (n = 5) or placebo (n = 4). One patient on placebo withdrew after having 3 relapses in the first 5 months. We did not identify any serious adverse events. At 6 months, patients treated with MSCs had a trend to lower mean cumulative number of GEL (3.1, 95% CI = 1.1-8.8 vs 12.3, 95% CI = 4.4-34.5, p = 0.064), and at the end of study to reduced mean GEL (-2.8+/-5.9 vs 3+/-5.4, p = 0.075). No significant treatment differences were detected in the secondary endpoints. We observed a non significant decrease of the frequency of Th1 (CD4+ IFN-gamma+) cells in blood of MSCs treated patients. CONCLUSION: Bone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties. ClinicalTrials.gov NCT01228266. PMID- 25436768 TI - Epstein-barr virus sequence variation-biology and disease. AB - Some key questions in Epstein-Barr virus (EBV) biology center on whether naturally occurring sequence differences in the virus affect infection or EBV associated diseases. Understanding the pattern of EBV sequence variation is also important for possible development of EBV vaccines. At present EBV isolates worldwide can be grouped into Type 1 and Type 2, a classification based on the EBNA2 gene sequence. Type 1 EBV is the most prevalent worldwide but Type 2 is common in parts of Africa. Type 1 transforms human B cells into lymphoblastoid cell lines much more efficiently than Type 2 EBV. Molecular mechanisms that may account for this difference in cell transformation are now becoming clearer. Advances in sequencing technology will greatly increase the amount of whole EBV genome data for EBV isolated from different parts of the world. Study of regional variation of EBV strains independent of the Type 1/Type 2 classification and systematic investigation of the relationship between viral strains, infection and disease will become possible. The recent discovery that specific mutation of the EBV EBNA3B gene may be linked to development of diffuse large B cell lymphoma illustrates the importance that mutations in the virus genome may have in infection and human disease. PMID- 25436770 TI - Hypermethylation of Cox5a promoter is associated with mitochondrial dysfunction in skeletal muscle of high fat diet-induced insulin resistant rats. AB - High-fat diet (HFD) is an environmental factor that contributes to the pathogenesis of obesity and type 2 diabetes. A number of genes influencing oxidative phosphorylation (OXPHOS) were found to be downregulated in skeletal muscle of humans and rats treated with HFD and have been implicated in mitochondrial dysfunction, insulin resistance, and consequent type 2 diabetes. In this study, we hypothesized that DNA methylation plays a crucial role in the regulation of OXPHOS genes in skeletal muscle of rats exposed to HFD. Using whole genome promoter methylation analysis of skeletal muscle followed by qPCR and bisulfite sequencing analysis, we identified hypermethylation of Cox5a in HFD rats. Furthermore, we found that Cox5a hypermethylation was associated with downregulation of Cox5a expression at the mRNA and protein level, and a reduction in mitochondrial complex IV activity and ATP content in HFD-induced insulin resistant rats compared to controls. Moreover, we found that while exposure to palmitate resulted in hypermethylation of the Cox5a promoter in rat myotubes, demethylation with 5-aza-2'-deoxycytidine was associated with preserved Cox5a expression, as well as restoration of complex IV activity and cellular ATP content. These novel observations indicate that Cox5a hypermethylation is associated with mitochondrial dysfunction in skeletal muscle of HFD-induced insulin resistant rats. PMID- 25436771 TI - Effects of hyperbaric oxygen on eye tracking abnormalities in males after mild traumatic brain injury. AB - The effects of hyperbaric oxygen (HBO2) on eye movement abnormalities in 60 military servicemembers with at least one mild traumatic brain injury (TBI) from combat were examined in a single-center, randomized, double-blind, sham controlled, prospective study at the Naval Medicine Operational Training Center. During the 10 wk of the study, each subject was delivered a series of 40, once a day, hyperbaric chamber compressions at a pressure of 2.0 atmospheres absolute (ATA). At each session, subjects breathed one of three preassigned oxygen fractions (10.5%, 75%, or 100%) for 1 h, resulting in an oxygen exposure equivalent to breathing either surface air, 100% oxygen at 1.5 ATA, or 100% oxygen at 2.0 ATA, respectively. Using a standardized, validated, computerized eye tracking protocol, fixation, saccades, and smooth pursuit eye movements were measured just prior to intervention and immediately postintervention. Between and within groups testing of pre- and postintervention means revealed no significant differences on eye movement abnormalities and no significant main effect for HBO2 at either 1.5 ATA or 2.0 ATA equivalent compared with the sham-control. This study demonstrated that neither 1.5 nor 2.0 ATA equivalent HBO2 had an effect on postconcussive eye movement abnormalities after mild TBI when compared with a sham-control. PMID- 25436772 TI - Intergenomic comparisons highlight modularity of the denitrification pathway and underpin the importance of community structure for N2O emissions. AB - Nitrous oxide (N2O) is a potent greenhouse gas and the predominant ozone depleting substance. The only enzyme known to reduce N2O is the nitrous oxide reductase, encoded by the nosZ gene, which is present among bacteria and archaea capable of either complete denitrification or only N2O reduction to di-nitrogen gas. To determine whether the occurrence of nosZ, being a proxy for the trait N2O reduction, differed among taxonomic groups, preferred habitats or organisms having either NirK or NirS nitrite reductases encoded by the nirK and nirS genes, respectively, 652 microbial genomes across 18 phyla were compared. Furthermore, the association of different co-occurrence patterns with enzymes reducing nitric oxide to N2O encoded by nor genes was examined. We observed that co-occurrence patterns of denitrification genes were not randomly distributed across taxa, as specific patterns were found to be more dominant or absent than expected within different taxonomic groups. The nosZ gene had a significantly higher frequency of co-occurrence with nirS than with nirK and the presence or absence of a nor gene largely explained this pattern, as nirS almost always co-occurred with nor. This suggests that nirS type denitrifiers are more likely to be capable of complete denitrification and thus contribute less to N2O emissions than nirK type denitrifiers under favorable environmental conditions. Comparative phylogenetic analysis indicated a greater degree of shared evolutionary history between nosZ and nirS. However 30% of the organisms with nosZ did not possess either nir gene, with several of these also lacking nor, suggesting a potentially important role in N2O reduction. Co-occurrence patterns were also non-randomly distributed amongst preferred habitat categories, with several habitats showing significant differences in the frequencies of nirS and nirK type denitrifiers. These results demonstrate that the denitrification pathway is highly modular, thus underpinning the importance of community structure for N2O emissions. PMID- 25436774 TI - Dimensional analysis using toric ideals: primitive invariants. AB - Classical dimensional analysis in its original form starts by expressing the units for derived quantities, such as force, in terms of power products of basic units [Formula: see text] etc. This suggests the use of toric ideal theory from algebraic geometry. Within this the Graver basis provides a unique primitive basis in a well-defined sense, which typically has more terms than the standard Buckingham approach. Some textbook examples are revisited and the full set of primitive invariants found. First, a worked example based on convection is introduced to recall the Buckingham method, but using computer algebra to obtain an integer [Formula: see text] matrix from the initial integer [Formula: see text] matrix holding the exponents for the derived quantities. The [Formula: see text] matrix defines the dimensionless variables. But, rather than this integer linear algebra approach it is shown how, by staying with the power product representation, the full set of invariants (dimensionless groups) is obtained directly from the toric ideal defined by [Formula: see text]. One candidate for the set of invariants is a simple basis of the toric ideal. This, although larger than the rank of [Formula: see text], is typically not unique. However, the alternative Graver basis is unique and defines a maximal set of invariants, which are primitive in a simple sense. In addition to the running example four examples are taken from: a windmill, convection, electrodynamics and the hydrogen atom. The method reveals some named invariants. A selection of computer algebra packages is used to show the considerable ease with which both a simple basis and a Graver basis can be found. PMID- 25436773 TI - Silica nanoparticles as the adjuvant for the immunisation of mice using hepatitis B core virus-like particles. AB - Advances in nanotechnology and nanomaterials have facilitated the development of silicon dioxide, or Silica, particles as a promising immunological adjuvant for the generation of novel prophylactic and therapeutic vaccines. In the present study, we have compared the adjuvanting potential of commercially available Silica nanoparticles (initial particles size of 10-20 nm) with that of aluminium hydroxide, or Alum, as well as that of complete and incomplete Freund's adjuvants for the immunisation of BALB/c mice with virus-like particles (VLPs) formed by recombinant full-length Hepatitis B virus core (HBc) protein. The induction of B cell and T-cell responses was studied after immunisation. Silica nanoparticles were able to adsorb maximally 40% of the added HBc, whereas the adsorption capacity of Alum exceeded 90% at the same VLPs/adjuvant ratio. Both Silica and Alum formed large complexes with HBc VLPs that sedimented rapidly after formulation, as detected by dynamic light scattering, spectrophotometry, and electron microscopy. Both Silica and Alum augmented the humoral response against HBc VLPs to the high anti-HBc level in the case of intraperitoneal immunisation, whereas in subcutaneous immunisation, the Silica-adjuvanted anti-HBc level even exceeded the level adjuvanted by Alum. The adjuvanting of HBc VLPs by Silica resulted in the same typical IgG2a/IgG1 ratios as in the case of the adjuvanting by Alum. The combination of Silica with monophosphoryl lipid A (MPL) led to the same enhancement of the HBc-specific T-cell induction as in the case of the Alum and MPL combination. These findings demonstrate that Silica is not a weaker putative adjuvant than Alum for induction of B-cell and T-cell responses against recombinant HBc VLPs. This finding may have an essential impact on the development of the set of Silica-adjuvanted vaccines based on a long list of HBc derived virus-like particles as the biological component. PMID- 25436775 TI - Induced autoimmunity against gonadal proteins affects gonadal development in juvenile zebrafish. AB - A method to mitigate or possibly eliminate reproduction in farmed fish is highly demanded. The existing approaches have certain applicative limitations. So far, no immunization strategies affecting gonadal development in juvenile animals have been developed. We hypothesized that autoimmune mechanisms, occurring spontaneously in a number of diseases, could be induced by targeted immunization. We have asked whether the immunization against specific targets in a juvenile zebrafish gonad will produce an autoimmune response, and, consequently, disturbance in gonadal development. Gonadal soma-derived factor (Gsdf), growth differentiation factor (Gdf9), and lymphocyte antigen 75 (Cd205/Ly75), all essential for early gonad development, were targeted with 5 immunization tests. Zebrafish (n = 329) were injected at 6 weeks post fertilization, a booster injection was applied 15 days later, and fish were sampled at 30 days. We localized transcripts encoding targeted proteins by in situ hybridization, quantified expression of immune-, apoptosis-, and gonad-related genes with quantitative real-time PCR, and performed gonadal histology and whole-mount immunohistochemistry for Bcl2-interacting-killer (Bik) pro-apoptotic protein. The treatments resulted in an autoimmune reaction, gonad developmental retardation, intensive apoptosis, cell atresia, and disturbed transcript production. Testes were remarkably underdeveloped after anti-Gsdf treatments. Anti-Gdf9 treatments promoted apoptosis in testes and abnormal development of ovaries. Anti-Cd205 treatment stimulated a strong immune response in both sexes, resulting in oocyte atresia and strong apoptosis in supporting somatic cells. The effect of immunization was FSH-independent. Furthermore, immunization against germ cell proteins disturbed somatic supporting cell development. This is the first report to demonstrate that targeted autoimmunity can disturb gonadal development in a juvenile fish. It shows a straightforward potential to develop auto-immunization based technologies to mitigate fish reproduction before they reach maturation. However, the highly variable results between treatments and individuals suggest significant optimization should be performed to achieve the full potential of this technology. PMID- 25436777 TI - Off-target rewards of augmentation therapy with alpha1-antitrypsin. PMID- 25436778 TI - Goal-directed cardiopulmonary resuscitation for patients in intensive care units. PMID- 25436776 TI - Evaluation of the impact of the cancer therapy everolimus on the central nervous system in mice. AB - Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link between chemotherapy and cognitive dysfunctions was recently validated in animal models. New cancer targeted therapies have become widely used, and their impact on brain functions and quality of life needs to be explored. We evaluated the impact of everolimus, an anticancer agent targeting the mTOR pathway, on cognitive functions, cerebral metabolism, and hippocampal cell proliferation/vascular density in mice. Adult mice received everolimus daily for 2 weeks, and behavioral tests were performed from 1 week after the last treatment. Everolimus-treated mice displayed a marked reduction in weight gain from the last day of the treatment period. Ex vivo analysis showed altered cytochrome oxidase activity in selective cerebral regions involved in energy balance, food intake, reward, learning and memory modulation, sleep/wake cycle regulation, and arousal. Like chemotherapy, everolimus did not alter emotional reactivity, learning and memory performances, but in contrast to chemotherapy, did not affect behavioral flexibility or reactivity to novelty. In vivo hippocampal neural cell proliferation and vascular density were also unchanged after everolimus treatments. In conclusion, two weeks daily everolimus treatment at the clinical dose did not evoke alteration of cognitive performances evaluated in hippocampal- and prefrontal cortex-dependent tasks that would persist at one to four weeks after the end of the treatment completion. However, acute everolimus treatment caused selective CO modifications without altering the mTOR effector P70S6 kinase in cerebral regions involved in feeding behavior and/or the sleep/wake cycle, at least in part under control of the solitary nucleus and the parasubthalamic region of the hypothalamus. Thus, this area may represent a key target for everolimus-mediating peripheral modifications, which has been previously associated with symptoms such as weight loss and fatigue. PMID- 25436779 TI - The infant nose. Introducing the respiratory tract to the world. PMID- 25436780 TI - Keep the airway open and let the brain sleep. PMID- 25436781 TI - Hemoptysis in primary pulmonary amyloidoma treated with intrabronchial arterial coiling. PMID- 25436782 TI - Simulation of blind tracheal intubation during pediatric cardiopulmonary resuscitation. PMID- 25436783 TI - Xpert MTB/RIF false detection of rifampin-resistant tuberculosis from prior infection. PMID- 25436784 TI - Effect of parapharyngeal fat on dynamic obstruction of the upper airway in patients with obstructive sleep apnea. PMID- 25436785 TI - Extracorporeal membrane oxygenation for acute respiratory failure in adults: the need for pulmonary INTERMACS. PMID- 25436786 TI - Reply: Extracorporeal membrane oxygenation for acute respiratory failure in adults: the need for pulmonary INTERMACS. PMID- 25436787 TI - Neonatal caffeine therapy and sleep: important findings to guide new approaches and reduce concerns. PMID- 25436788 TI - Reply: neonatal caffeine therapy and sleep: important findings to guide new approaches and reduce concerns. PMID- 25436789 TI - Subacute onset of pulmonary langerhans cell histiocytosis with resolution after smoking cessation. PMID- 25436790 TI - Critical airway obstruction due to pseudomembranous Aspergillus tracheitis. PMID- 25436791 TI - Carryover of cadmium from feed in growing pigs. AB - Growing male pigs were exposed to cadmium (Cd) at levels around 1 and 10 mg kg( 1) feed for up to 12 weeks, administered as CdCl2 or Cd-cysteine (CdCys). Pigs exposed to 10 mg kg(-1) showed decreased growth during the last 3 weeks. Liver and kidney concentrations of Cd continuously increased over the entire 12-week exposure, exceeding the European Union limits of 1.0 mg kg(-1) (kidney) and 0.5 mg kg(-1) (liver) within 3 weeks at the feed level of 10 mg kg(-1). A switch to clean feed after 3 weeks for 5 or 9 weeks resulted in steadily decreased levels in kidney and liver, which could be completely attributed to organ growth. At the lower feed level, the level in kidney exceeded the limit almost twofold after 12 weeks, but not after 3 weeks. Liver levels remained below the limit. Metallothionein (MT) levels in livers showed a steady decrease in both untreated and treated animals over time. In kidney such a decrease was only observed in control animals, whereas in the highest-dosed animals the MT concentrations steadily increased. The observed carryover of Cd from feed to liver and kidney was modelled by means of a simple transfer model relating levels in feed via MT levels to accumulation of Cd. Using this model, it was shown that the exposure period of growing pigs to feed containing the European Union limit of 0.5 mg kg( 1) feed should be less than 12 weeks in order to prevent Cd levels in the kidneys to exceed the European Union limit. PMID- 25436793 TI - BRAF mutations in non-small-cell lung cancer. PMID- 25436794 TI - Refining the toxicity profile of crizotinib. PMID- 25436795 TI - Intensity-modulated radiotherapy for lung cancer: current status and future developments. AB - Radiotherapy plays an important role in the management of lung cancer, with over 50% of patients receiving this modality at some point during their treatment. Intensity-modulated radiotherapy (IMRT) is a technique that adds fluence modulation to beam shaping, which improves radiotherapy dose conformity around the tumor and spares surrounding normal structures. Treatment with IMRT is becoming more widely available for the treatment of lung cancer, despite the paucity of high level evidence supporting the routine use of this more resource intense and complex technique. In this review article, we have summarized data from planning and clinical studies, discussed challenges in implementing IMRT, and made recommendations on the minimum requirements for safe delivery of IMRT. PMID- 25436797 TI - Patient-reported outcomes and quality of life in PROFILE 1007: a randomized trial of crizotinib compared with chemotherapy in previously treated patients with ALK positive advanced non-small-cell lung cancer. AB - INTRODUCTION: The main objective of the current post hoc analysis was to compare patient-reported outcomes between crizotinib (N = 172) and chemotherapy subgroups (pemetrexed [N = 99] and docetaxel [N = 72]) in previously treated patients with advanced ALK-positive non-small-cell lung cancer, in PROFILE 1007 study (Pfizer; NCT0093283). METHODS: Patient-reported outcomes were assessed at baseline, day 1 of each cycle, and end of treatment. General health status was measured using the EuroQol-5D visual analog scale and health utility index scores were assessed using the EuroQol-5D descriptive system. Functioning, lung cancer symptoms, and global quality of life (QOL) were assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and the QLQ-LC13 lung cancer module. Repeated measures mixed-effects analyses compared overall scores and change from baseline scores, controlling for baseline scores. RESULTS: The overall mean EQ-5D health utility index scores (95% CI) on treatment were significantly greater (p < 0.05) for crizotinib (0.82 [0.79-0.85]) than for chemotherapy (0.73 [0.70-0.77]; 0.74 [0.70-0.79] for pemetrexed and 0.66 [0.58-0.74] for docetaxel). A significantly greater improvement from baseline was observed with crizotinib versus pemetrexed and versus docetaxel treatment groups for general health status, physical functioning, global QOL, dyspnea, fatigue, and pain. Improvement rates for fatigue, cough, pain, dyspnea, and global QOL were significantly greater on crizotinib compared with pemetrexed and docetaxel, respectively. Worsening rates for diarrhea and constipation were higher with crizotinib. CONCLUSION: The benefits of crizotinib in improving symptoms and QOL are demonstrated regardless of whether the comparator is pemetrexed or docetaxel. PMID- 25436799 TI - A common polymorphism within MSLN affects miR-611 binding site and soluble mesothelin levels in healthy people. AB - INTRODUCTION: Soluble mesothelin related peptide (SMRP) was proposed as a promising diagnostic marker for malignant pleural mesothelioma (MPM). In a previous study, we found that rs1057147 within the 3' untranslated region of MSLN gene was associated with SMRP levels. Thus, we aimed to (1) confirm the previous association on a large series of volunteers and (2) test the hypothesis that the SNP could affect microRNA binding sites. METHODS: The association analysis was verified in 759 subjects. Then, in silico predictions highlighted miR-611 and miR 887 as candidate miRNAs binding to the polymorphic site. Thus, chimeric constructs bearing the alternative alleles (G > A) were assayed alone or in cotransfection with the miRNA mimics, with dual luciferase reporter assay in non MPM Met-5A cells. The miRNAs were also assayed by western blot analysis for their ability to down-regulate endogenous mesothelin in the MPM Mero-14 cell line. RESULTS: We confirmed that, among non-MPM volunteers, GG homozygotes have the lowest SMRP levels. When the genotype is taken into account, the specificity of SMRP as biomarker improves from 79.7% to 85.3%. Dual-luciferase assays showed a significantly lower reporter activity when the vector harbored the G allele as compared to A allele. miR-887 mimic caused a reduced reporter activity of vectors harboring A or G alleles, while miR-611 was effective only on the vector harboring the G allele. Transfection of these miRNAs into Mero-14 cells significantly reduced endogenous MSLN protein. CONCLUSION: SMRP performance as diagnostic biomarker improved by considering the genotype rs1057147. This polymorphism most likely affects a binding site for miR-611. PMID- 25436798 TI - Crizotinib effects on creatinine and non-creatinine-based measures of glomerular filtration rate. AB - INTRODUCTION: Rapid reductions in creatinine-based estimates of the glomerular filtration rate (GFR) have recently been reported secondary to crizotinib use. Whether these reflect drug-induced changes in the true GFR or the validity of creatinine as a measure of kidney function in the presence of crizotinib is unknown. METHODS: Two anaplastic lymphoma kinase-rearranged non-small-cell lung cancer patients (one with pre-existing renal impairment) were identified during periods of time on and off crizotinib. Creatinine- and iothalamate-based estimates of renal function were conducted in the presence and absence of crizotinib. RESULTS: Crizotinib is associated with both acute and chronic effects on kidney function. Chronic creatinine changes seem to reflect a true reduction in the GFR. In contrast, acute effects include a reduction in creatinine-based estimates of the GFR without a reduction in non-creatinine-based measurements (consistent with, e.g., an acute effect of crizotinib on creatinine secretion), in addition to some reduction in the true GFR (with this latter effect seeming to be more prominent in the presence of pre-existing renal impairment). CONCLUSION: If crizotinib-associated changes in creatinine-based kidney function suggest a change in dosing with either crizotinib or concomitant medications that are renally excreted, use of a non-creatinine-based assessment of kidney function, such as iothalamate assessments, should be considered before making a final decision. PMID- 25436796 TI - The IASLC lung cancer staging project: the new database to inform the eighth edition of the TNM classification of lung cancer. AB - The analyses of the retrospective database of the International Association for the Study of Lung Cancer (IASLC), consisting of more than 81,000 evaluable patients diagnosed with lung cancer between 1990 and 2000, formed the basis of recommendations to the Union for International Cancer Control and the American Joint Committee on Cancer for the revision of the sixth edition of the tumor, node, and metastasis (TNM) classification of lung cancer. However, despite the large number of patients, not all descriptors could be validated. This prompted a new collection of retrospective and prospective data to overcome the limitations of the original retrospective database. The new IASLC database has information on 94,708 new patients diagnosed of lung cancer between 1999 and 2010. They originated from 35 sources in 16 countries, and 4,667 were submitted via the online electronic data capture system. Europe contributed 46,560 patients, Asia: 41,705, North America: 4,660, Australia: 1,593, and South America: 190. After exclusions, 77,156 (70,967 with nonsmall cell lung cancer and 6,189 with small cell lung cancer) remained for analysis. This database will be analyzed according to established objectives for the T, the N, and the M components to inform the eighth edition of the TNM classification of lung cancer due to be published in 2016. The IASLC hopes for the continuing contribution of our partners around the world to improve the classification of anatomical extent of disease, but also to create prognostic groups in a parallel project of the IASLC Staging and Prognostic Factors Committee. PMID- 25436800 TI - Clinical characteristics and course of 63 patients with BRAF mutant lung cancers. AB - INTRODUCTION: Mutant BRAF is a driver oncogene found in 2% of lung adenocarcinomas and represents a target for therapy. We examined the clinical characteristics and course of patients with lung adenocarcinomas harboring BRAF mutations. METHODS: We identified patients with lung adenocarcinomas harboring BRAF mutations between 2009 and 2013 detected using a mass spectrometry-based polymerase chain reaction genotyping assay of hot-spot mutations involving codons corresponding to amino acids V600, D594, and G469 of BRAF. Patient characteristics and treatment outcomes were analyzed. Overall survival (OS) was compared with stage-matched patients with KRAS and EGFR mutant lung adenocarcinomas. RESULTS: Sixty-three patients were diagnosed with BRAF mutant lung adenocarcinomas between 2009 and 2013 (V600, 36; non-V600, 27). The majority of patients with BRAF mutations were smokers (92%), although patients with V600 mutations were more likely to be light/never-smokers compared with patients with non-V600 mutations (42% versus 11%; p = 0.007). Of the 32 patients with early stage disease, six (19%; 95% confidence interval 7%-36%) developed second primary lung cancers harboring KRAS mutations. Patients with advanced V600 mutant lung adenocarcinomas had a better survival from diagnosis compared with those with non V600 mutant lung adenocarcinomas (3-year OS: 24% versus 0%; p < 0.001). CONCLUSIONS: This is the largest series of patients with BRAF mutant lung cancers described. Most patients were heavy smokers. Nineteen percent of patients with early-stage BRAF mutant lung cancers developed second primary lung cancers harboring KRAS mutations. Patients with advanced lung adenocarcinomas harboring V600 mutations have an improved OS compared with those with non-V600 mutations. PMID- 25436802 TI - Multicenter immunohistochemical ALK-testing of non-small-cell lung cancer shows high concordance after harmonization of techniques and interpretation criteria. AB - INTRODUCTION: Detection of anaplastic lymphoma kinase (ALK)-gene rearrangements in non-small-cell lung cancer (NSCLC) is mainly performed by fluorescence in-situ hybridization (FISH). The question was raised if FISH might be replaced by immunohistochemistry (IHC) in a reliable and reproducible manner across different laboratories. METHODS: After calibration of the staining instruments and training of the observers to binary interpretation (positive versus negative), 15 NSCLC were independently tested for ALK protein expression by IHC only in a multicenter setting (16 institutes). Each laboratory utilized the VENTANA ALK-D5F3 IHC assay. As demonstrated by FISH the samples displayed unequivocal ALK break-positivity (6*) and negativity (7*), as well as ALK positive-"borderline" character (2*), which is challenging for FISH diagnosis and thus was RT-PCR-confirmed. RESULTS: All seven ALK FISH-negative cases were homogenously scored as ALK-IHC negative. All 16 participants scored the two ALK positive-"borderline" samples as unequivocally positive according to their protein expression. Concordant IHC interpretation was also noticed in four of six unequivocal ALK break positive cases. In two of six some observers described a weak/heterogeneous ALK-IHC staining. This would have resulted in a subsequent ALK-testing (FISH/PCR) in a routine diagnostic setting. CONCLUSIONS: This so-called "ALK-Harmonization-Study" shows for the first time that predictive semiquantitative IHC reveals reliable and reproducible results across several labs when methodology and interpretation are strictly defined and the pathologists are uniquely trained. The application of validated ALK IHC assays and its comparison to ALK-FISH is highly needed in future clinical trials. This might answer the question if ALK-IHC cannot only serve as a prescreening tool, but as a stand-alone test at least in cases displaying an unequivocally staining pattern as well as an alternative predictive test in samples with reduced FISH interpretability. PMID- 25436804 TI - Association of EPAS1 gene rs4953354 polymorphism with susceptibility to lung adenocarcinoma in female Japanese non-smokers. AB - INTRODUCTION: Hypoxia-inducible factor-2alpha (also called endothelial periodic acid-Schiff domain protein 1 [EPAS1]) seems to play an important role in some carcinogenesis, though there is no information on the relationship between single nucleotide polymorphism of EPAS1 and lung cancer development. The aim of this study was to explore a possible association of the EPAS1 gene rs4953354 polymorphism with susceptibility to lung cancer. METHODS: A case-control study of 346 patients with non-small-cell lung carcinoma (adenocarcinoma = 249, squamous cell carcinoma = 97) and 247 healthy control subjects was carried out. A/G polymorphism within an intron 2 of the EPAS1 (rs4953354) was determined by direct sequencing. RESULTS: A frequency of lung adenocarcinoma patients with a minor allele G (A/G or G/G genotype) at the rs4953354 was much higher than that of controls (odds ratio, 1.800; 95% confidence interval, 1.161-2.791; p = 0.008). This association was more evident when analyzed using female never-smokers (odds ratio, 3.31; 95% confidence interval, 1.21-9.01; p = 0.017). Mutations in epidermal growth factor receptor tended to be frequent in patients with G allele at the rs4953354, compared with those with other genotypes. CONCLUSION: The EPAS1 rs4953354 may be a potentially susceptible marker for development of lung adenocarcinoma, especially in female never-smokers. PMID- 25436801 TI - Lungscape: resected non-small-cell lung cancer outcome by clinical and pathological parameters. AB - INTRODUCTION: The Lungscape project was designed to address the impact of clinical, pathological, and molecular characteristics on outcome in resected non small- cell lung cancer (NSCLC). MATERIALS AND METHODS: A decentralized biobank with fully annotated tissue samples was established. Selection criteria for participating centers included sufficient number of cases, tissue microarray building capability, and documented ethical approval. Patient selection was based on availability of comprehensive clinical data, radical resection between 2003 and 2009 with adequate follow-up, and adequate quantity and quality of formalin fixed tissue. RESULTS: Fifteen centers contributed 2449 cases. The 5-year overall survival (OS) was 69.6% and 63.6% for stages IA and IB, 51.6% and 47.7% for stages IIA and IIB, and 29.0% and 13.0% for stages IIIA and IIIB, respectively (p < 0.001). Median and 5-year relapse-free survival (RFS) were 52.8 months and 47.3%, respectively. Distant relapse was recorded for 44.4%, local for 26.0%, and both for 16.9% of patients. Based on multivariate analysis for the OS, RFS, and time to relapse, the factors significantly associated with all of them are performance status and pathological stage. CONCLUSION: The aim of this report is to present the results from Lungscape, the first large series reporting on NSCLC surgical outcome measured not only by OS but also by RFS and time to relapse and including multivariate analysis by significant clinical and pathological prognostic parameters. As tissue from all patients is preserved locally and is available for detailed molecular investigations, Lungscape provides an excellent basis to evaluate the influence of molecular parameters on the disease outcome after radical resection, besides providing an overview of the molecular landscape of stage I to III NSCLC. PMID- 25436803 TI - Evaluation of antitumor activity using change in tumor size of the survivin antisense oligonucleotide LY2181308 in combination with docetaxel for second-line treatment of patients with non-small-cell lung cancer: a randomized open-label phase II study. AB - Chemoresistance is mediated, in part, by the inhibition of apoptosis in tumor cells. Survivin is an antiapoptotic protein that blocks chemotherapy-induced apoptosis. To investigate whether blocking survivin expression enhances docetaxel induced apoptosis in patients with non-small-cell lung cancer (NSCLC), we compared the antitumor activity of the survivin inhibitor LY2181308 plus docetaxel with docetaxel alone. We used change in tumor size (CTS) as a primary endpoint to assess its use in early decision-making for this and future studies of novel agents in NSCLC. Patients (N = 162) eligible for second-line NSCLC treatment (stage IIIB/IV) with an Eastern Cooperative Oncology Group performance status of 0 to 1 were randomized 2:1 to receive LY2181308 (750 mg intravenously, weekly) and docetaxel (75 mg/m intravenously, day 1) or docetaxel alone every 21 days. CTS from baseline to the end of cycle 2 was compared between the two treatment arms. The mean (SD) tumor size ratio for LY2181308/docetaxel and docetaxel was 1.05 (0.21) and 1.00 (0.15) (p = 0.200), respectively, suggesting no significant improvement in antitumor activity between the arms. Because there was also no significant difference between the two arms for progression-free survival (PFS) (2.83 months with LY2181308/docetaxel and 3.35 months with docetaxel [p = 0.191]), both arms were combined. Using the combined arms, CTS correlated with PFS (PFS = 4.63 months in patients with decreased CTS compared with 2.66 months in patients with increased CTS), supporting its use in early decision-making in phase II studies. PMID- 25436805 TI - RET-rearranged lung adenocarcinomas with lymphangitic spread, psammoma bodies, and clinical responses to cabozantinib. AB - Oncogenic rearrangements of the RET gene have recently been described in 1% to 2% of lung adenocarcinomas. We report five cases of RET-rearranged lung adenocarcinoma with an unusual constellation of clinical and histologic features that has not previously been described in tumors with this genomic alteration. The age at diagnosis of the five patients (4F, 1M) ranged from 44 to 77 years. All were never-smokers. Radiologically, four tumors showed lymphangitic spread within the lungs at presentation; three of these had multiple bilateral lung nodules. Histology showed psammoma bodies within the tumor in four of five cases. Molecular testing for activating EGFR mutations by standard genotyping and ALK expression by immunohistochemistry was negative in all cases. Additional molecular analysis was prompted by the clinical profile in that all five patients were never-smokers with metastatic, relapsed, and/or refractory disease; and also by unusual histologic findings in two cases. Comprehensive genomic profiling performed by means of a clinical grade cancer gene panel next-generation sequencing assay demonstrated a KIF5B-RET fusion in three; and fluorescence in situ hybridization documented a RET rearrangement in two. Three of the patients were treated with the RET inhibitor cabozantinib. By Response Evaluation Criteria In Solid Tumors (RECIST) criteria, two had a confirmed partial response (at 6 weeks and 4 weeks) and one had stable disease. Our findings suggest that the combination of lymphangitic spread and psammoma bodies may be characteristic of a subset of advanced stage RET-rearranged lung adenocarcinomas. These findings should prompt additional molecular testing for RET translocations, particularly in never-smokers with EGFR- and ALK-negative lung adenocarcinoma. PMID- 25436806 TI - Development of renal cysts after crizotinib treatment in advanced ALK-positive non-small-cell lung cancer. AB - INTRODUCTION: The development of complex renal cysts after crizotinib treatment for non-small-cell lung cancer (NSCLC) is a reported side effect. However, its occurrence and characteristics have not been reported. METHODS: Medical records and computed tomography images of crizotinib-treated patients in three prospective clinical trials were reviewed. The size and Bosniak category of the renal cysts before and after crizotinib treatment were determined. Patients' clinical characteristics, tumor stage, treatment response, renal function, and outcomes were analyzed. RESULTS: During December 2010 to March 2013, we enrolled 32 patients who received crizotinib. There were 23 patients who had renal cysts before crizotinib. The median follow-up time was 493 days. Seven patients (22%, six with baseline renal cyst and one without baseline renal cyst) had significant renal cyst change. Four (13% of all) had new complex renal cysts. The median time from crizotinib treatment to first recognization of significant renal cyst change was 77 days. After stopping crizotinib, complex renal cysts regressed significantly. Patients with significant renal cyst change received more previous anticancer therapy (median, 5 lines versus 3 lines, p = 0.04) and received crizotinib for longer duration (median, 956 days versus 248 days, p = 0.007) compared with those without significant renal cyst change. CONCLUSIONS: Change of renal cysts after crizotinib treatment is not uncommon. Development of complex renal cysts reverses after stopping crizotinib. PMID- 25436808 TI - The case of the missed chest radiograph: bilateral mammary gland metastases mimicking multifocal primary breast cancer as the initial manifestation of non small-cell lung cancer. PMID- 25436807 TI - Successful desensitization of two patients with ALK-positive lung cancer and hypersensitivity to crizotinib. AB - The tyrosine kinase inhibitor crizotinib is an effective therapy for patients with cancers harboring rearrangements of the anaplastic lymphoma kinase (ALK) gene. Here, we describe two patients with advanced ALK-positive lung cancer who developed hypersensitivity to crizotinib, requiring temporary discontinuation of the drug. Both patients were treated with a rapid oral desensitization protocol allowing them to resume crizotinib without further signs or symptoms of hypersensitivity. PMID- 25436809 TI - Vocal cord paralysis after stereotactic body radiation therapy to the left lung apex. PMID- 25436810 TI - First-line chemotherapy treatment of advanced non-small-cell lung cancer: does cisplatin versus carboplatin make a difference? PMID- 25436811 TI - How to minimize harms of lung cancer screening. PMID- 25436812 TI - Young male with fanconi anemia and EGFR-mutant non-small-cell lung cancer. PMID- 25436814 TI - Towards comprehensive women's healthcare in sub-Saharan Africa: addressing intersections between HIV, reproductive and maternal health. AB - This themed supplement to JAIDS: Journal of Acquired Immune Deficiency Syndromes focuses on the critical intersections between HIV, reproductive, and maternal health services in the health systems of sub-Saharan Africa. The epidemiology of HIV among women of reproductive age on the sub-continent demands a holistic conceptualization and comprehensive approaches to ensure that HIV, reproductive, and maternal health are optimally addressed. Yet, in many instances, the national and global responses to these health issues remain siloed. Women's health needs and new global and national guidelines for HIV treatment raise important policy, programmatic, and operational questions regarding service integration, scale-up, and health systems functioning. In June 2013, the Maternal Health Task Force at the Harvard School of Public Health, the United States Agency for International Development, and the United States Centers for Disease Control and Prevention convened an international technical meeting of researchers, policymakers, and practitioners to discuss the existing evidence base about the interconnections between HIV, reproductive, and maternal health and identify the most important knowledge gaps and research priorities. The articles in this special issue deepen and expand on those discussions by (1) providing empirical evidence about challenges, (2) identifying how improving clinical care and models of service delivery, strengthening health systems, and addressing social dynamics can contribute to better outcomes, and (3) mapping future research directions. Together, these articles underscore that new policy frameworks and integrated approaches are necessary but not sufficient to address health system challenges. Addressing the multiple needs of women of reproductive age who are living with HIV or are at risk of acquiring HIV is a complex undertaking that requires improved access to, utilization and quality of comprehensive women's healthcare. Continued evaluation and knowledge generation are needed to ensure that potential health gains are actualized. PMID- 25436815 TI - Supplementation with multivitamins and vitamin A and incidence of malaria among HIV-infected Tanzanian women. AB - INTRODUCTION: HIV and malaria infections occur in the same individuals, particularly in sub-Saharan Africa. We examined whether daily multivitamin supplementation (vitamins B complex, C, and E) or vitamin A supplementation altered malaria incidence in HIV-infected women of reproductive age. METHODS: HIV infected pregnant Tanzanian women recruited into the study were randomly assigned to daily multivitamins (B complex, C, and E), vitamin A alone, both multivitamins and vitamin A, or placebo. Women received malaria prophylaxis during pregnancy and were followed monthly during the prenatal and postpartum periods. Malaria was defined in 2 ways: presumptive diagnosis based on a physician's or nurse's clinical judgment, which in many cases led to laboratory investigations, and periodic examination of blood smears for malaria parasites. RESULTS: Multivitamin supplementation compared with no multivitamins significantly lowered women's risk of presumptively diagnosed clinical malaria (relative risk: 0.78, 95% confidence interval: 0.67 to 0.92), although multivitamins increased their risk of any malaria parasitemia (relative risk: 1.24, 95% confidence interval: 1.02 to 1.50). Vitamin A supplementation did not change malaria incidence during the study. CONCLUSIONS: Multivitamin supplements have been previously shown to reduce HIV disease progression among HIV-infected women, and consistent with that, these supplements protected against development of symptomatic malaria. The clinical significance of increased risk of malaria parasitemia among supplemented women deserves further research, however. Preventive measures for malaria are warranted as part of an integrated approach to the care of HIV-infected individuals exposed to malaria. PMID- 25436817 TI - Lessons learned from early implementation of option B+: the Elizabeth Glaser Pediatric AIDS Foundation experience in 11 African countries. AB - BACKGROUND: "Option B+" is a World Health Organization-recommended approach to prevent mother-to-child HIV transmission whereby all HIV-positive pregnant and lactating women initiate lifelong antiretroviral therapy (ART). This review of early Option B+ implementation experience is intended to inform Ministries of Health and others involved in implementing Option B+. METHODS: This implementation science study analyzed data from 11 African countries supported by the Elizabeth Glaser Pediatric AIDS Foundation (EGPAF) to describe early experience implementing Option B+. Data are from 4 sources: (1) national guidelines for prevention of mother-to-child HIV transmission and Option B+ implementation plans, (2) aggregated service delivery data between January 2013 and March 2014 from EGPAF-supported sites, (3) field visits to Option B+ implementation sites, and (4) relevant EGPAF research, quality improvement, and evaluation studies. RESULTS: Rapid adoption of Option B+ led to large increases in percentage of HIV-positive pregnant women accessing ART in antenatal care. By the end of 2013, most programs reached at least 50% of HIV-positive women in antenatal care with ART, even in countries using a phased approach to implementation. Scaling up Option B+ through integrating ART in maternal and child health settings has required expansion of the workforce, and task shifting to allow nurse-led ART initiation has created staffing pressure on lower-level cadres for counseling and community follow-up. Complex data collection needs may be impairing data quality. DISCUSSION: Early experiences with Option B+ implementation demonstrate promise. Continued program evaluation is needed, as is specific attention to counseling and support around initiation of lifetime ART in the context of pregnancy and lactation. PMID- 25436816 TI - Depression during pregnancy and the postpartum among HIV-infected women on antiretroviral therapy in Uganda. AB - BACKGROUND: Among HIV-infected women, perinatal depression compromises clinical, maternal, and child health outcomes. Antiretroviral therapy (ART) is associated with lower depression symptom severity but the uniformity of effect through pregnancy and postpartum periods is unknown. METHODS: We analyzed prospective data from 447 HIV-infected women (18-49 years) initiating ART in rural Uganda (2005-2012). Participants completed blood work and comprehensive questionnaires quarterly. Pregnancy status was assessed by self-report. Analysis time periods were defined as currently pregnant, postpartum (0-12 months post-pregnancy outcome), or non-pregnancy-related. Depression symptom severity was measured using a modified Hopkins Symptom Checklist 15, with scores ranging from 1 to 4. Probable depression was defined as >1.75. Linear regression with generalized estimating equations was used to compare mean depression scores over the 3 periods. RESULTS: At enrollment, median age was 32 years (interquartile range: 27 37), median CD4 count was 160 cells per cubic millimeter (interquartile range: 95 245), and mean depression score was 1.75 (s = 0.58) (39% with probable depression). Over 4.1 median years of follow-up, 104 women experienced 151 pregnancies. Mean depression scores did not differ across the time periods (P = 0.75). Multivariable models yielded similar findings. Increasing time on ART, viral suppression, better physical health, and "never married" were independently associated with lower mean depression scores. Findings were consistent when assessing probable depression. CONCLUSIONS: Although the lack of association between depression and perinatal periods is reassuring, high depression prevalence at treatment initiation and continued incidence across pregnancy and non-pregnancy-related periods of follow-up highlight the critical need for mental health services for HIV-infected women to optimize both maternal and perinatal health. PMID- 25436818 TI - Community health workers to improve antenatal care and PMTCT uptake in Dar es Salaam, Tanzania: a quantitative performance evaluation. AB - BACKGROUND: Home visits by community health workers (CHW) could be effective in identifying pregnant women in the community before they have presented to the health system. CHW could thus improve the uptake of antenatal care (ANC), HIV testing, and prevention of mother-to-child transmission (PMTCT) services. METHODS: Over a 16-month period, we carried out a quantitative evaluation of the performance of CHW in reaching women early in pregnancy and before they have attended ANC in Dar es Salaam, Tanzania. RESULTS: As part of the intervention, 213 CHW conducted more than 45,000 home visits to about 43,000 pregnant women. More than 75% of the pregnant women identified through home visits had not yet attended ANC at the time of the first contact with a CHW and about 40% of those who had not yet attended ANC were in the first trimester of pregnancy. Over time, the number of pregnant women the CHW identified each month increased, as did the proportion of women who had not yet attended ANC. The median gestational age of pregnant women contacted for the first time by a CHW decreased steadily and significantly over time (from 21/22 to 16 weeks, P-value for test of trend <0.0001). CONCLUSIONS: A large-scale CHW intervention was effective in identifying pregnant women in their homes early in pregnancy and before they had attended ANC. The intervention thus fulfills some of the conditions that are necessary for CHW to improve timely ANC uptake and early HIV testing and PMTCT enrollment in pregnancy. PMID- 25436819 TI - Pregnancy intent among a sample of recently diagnosed HIV-positive women and men practicing unprotected sex in Cape Town, South Africa. AB - BACKGROUND: Sexual and reproductive health (SRH) services for HIV-positive women and men often neglect their fertility desires. We examined factors associated with pregnancy intent among recently diagnosed HIV-positive women (N = 106) and men (N = 91) who reported inconsistent condom use and were enrolled in an SRH intervention conducted in public sector HIV care clinics in Cape Town. METHODS: Participants were recruited when receiving their first CD4 results at the clinic. All reported unprotected sex in the previous 3 months. Logistic regression identified predictors of pregnancy intent for the total sample and by gender. RESULTS: About three fifths of men and one fifth of women reported intent to conceive in the next 6 months. In the full-sample multiple regression analysis, men [adjusted odds ratio (AOR = 6.62)] and those whose main partner shared intent to conceive (AOR = 3.80) had significantly higher odds of pregnancy intent; those with more years of education (AOR = 0.81) and more biological children (AOR = 0.62) had lower odds of intending pregnancy. In gender-specific analyses, partner sharing pregnancy intent was positively associated with intent among both men (AOR = 3.53) and women (AOR = 13.24). Among men, odds were lower among those having more biological children (AOR = 0.71) and those unemployed (AOR = 0.30). Among women, relying on hormonal contraception was negatively associated with intent (AOR = 0.08), and main partner knowing her HIV status (AOR = 5.80) was positively associated with intent to conceive. CONCLUSIONS: Findings underscore the importance of providing integrated SRH services, and we discuss implications for clinical practice and care. PMID- 25436820 TI - Lost opportunities to reduce periconception HIV transmission: safer conception counseling by South African providers addresses perinatal but not sexual HIV transmission. AB - INTRODUCTION: Safer conception strategies create opportunities for HIV serodiscordant couples to realize fertility goals and minimize periconception HIV transmission. Patient-provider communication about fertility goals is the first step in safer conception counseling. METHODS: We explored provider practices of assessing fertility intentions among HIV-infected men and women, attitudes toward people living with HIV (PLWH) having children, and knowledge and provision of safer conception advice. We conducted in-depth interviews (9 counselors, 15 nurses, 5 doctors) and focus group discussions (6 counselors, 7 professional nurses) in eThekwini District, South Africa. Data were translated, transcribed, and analyzed using content analysis with NVivo10 software. RESULTS: Among 42 participants, median age was 41 (range, 28-60) years, 93% (39) were women, and median years worked in the clinic was 7 (range, 1-27). Some providers assessed women's, not men's, plans for having children at antiretroviral therapy initiation, to avoid fetal exposure to efavirenz. When conducted, reproductive counseling included CD4 cell count and HIV viral load assessment, advising mutual HIV status disclosure, and referral to another provider. Barriers to safer conception counseling included provider assumptions of HIV seroconcordance, low knowledge of safer conception strategies, personal feelings toward PLWH having children, and challenges to tailoring safer sex messages. CONCLUSIONS: Providers need information about HIV serodiscordance and safer conception strategies to move beyond discussing only perinatal transmission and maternal health for PLWH who choose to conceive. Safer conception counseling may be more feasible if the message is distilled to delaying conception attempts until the infected partner is on antiretroviral therapy. Designated and motivated nurse providers may be required to provide comprehensive safer conception counseling. PMID- 25436821 TI - Preventing unintended pregnancy and HIV transmission: effects of the HIV treatment cascade on contraceptive use and choice in rural KwaZulu-Natal. AB - BACKGROUND: For women living with HIV, contraception using condoms is recommended because it prevents not only unintended pregnancy but also acquisition of other sexually transmitted infections and onward transmission of HIV. Dual-method dual protection contraception (condoms with other contraceptive methods) is preferable over single-method dual-protection contraception (condoms alone) because of its higher contraceptive effectiveness. We estimate the effect of progression through the HIV treatment cascade on contraceptive use and choice among HIV-infected women in rural South Africa. METHODS: We linked population-based surveillance data on contraception collected by the Wellcome Trust Africa Centre for Health and Population Studies to data from the local antiretroviral treatment (ART) program in Hlabisa subdistrict, KwaZulu-Natal. In bivariate probit regression, we estimated the effects of progressing through the cascade on contraceptive choice among HIV-infected sexually active women aged 15-49 years (N = 3169), controlling for a wide range of potential confounders. FINDINGS: Contraception use increased across the cascade from <40% among HIV-infected women who did not know their status to >70% among women who have been on ART for 4-7 years. Holding other factors equal (1) awareness of HIV status, (2) ART initiation, and (3) being on ART for 4-7 years increased the likelihood of single-method/dual-method dual protection by the following percentage points (pp), compared with women who were unaware of their HIV status: (1) 4.6 pp (P = 0.030)/3.5 pp (P = 0.001), (2) 10.3 pp (P = 0.003)/5.2 pp (P = 0.007), and (3) 21.6 pp (P < 0.001)/11.2 pp (P < 0.001). CONCLUSIONS: Progression through the HIV treatment cascade significantly increased the likelihood of contraception in general and contraception with condoms in particular. ART programs are likely to contribute to HIV prevention through the behavioral pathway of changing contraception use and choice. PMID- 25436822 TI - Disrespect and abuse during childbirth in Tanzania: are women living with HIV more vulnerable? AB - INTRODUCTION: HIV-related stigma and discrimination and disrespect and abuse during childbirth are barriers to use of essential maternal and HIV health services. Greater understanding of the relationship between HIV status and disrespect and abuse during childbirth is required to design interventions to promote women's rights and to increase uptake of and retention in health services; however, few comparative studies of women living with HIV (WLWH) and HIV-negative women exist. METHODS: Mixed methods included interviews with postpartum women (n = 2000), direct observation during childbirth (n = 208), structured questionnaires (n = 50), and in-depth interviews (n = 18) with health care providers. Bivariate and multivariate regressions analyzed associations between HIV status and disrespect and abuse, whereas questionnaires and in-depth interviews provided insight into how provider attitudes and workplace culture influence practice. RESULTS: Of the WLWH and HIV-negative women, 12.2% and 15.0% reported experiencing disrespect and abuse during childbirth (P = 0.37), respectively. In adjusted analyses, no significant differences between WLWH and HIV-negative women's experiences of different types of disrespect and abuse were identified, with the exception of WLWH having greater odds of reporting non consented care (P = 0.03). None of the WLWH reported violations of HIV confidentiality or attributed disrespect and abuse to their HIV status. Provider interviews indicated that training and supervision focused on prevention of vertical HIV transmission had contributed to changing the institutional culture and reducing HIV-related violations. CONCLUSIONS: In general, WLWH were not more likely to report disrespect and abuse during childbirth than HIV-negative women. However, the high overall prevalence of disrespect and abuse measured indicates a serious problem. Similar institutional priority as has been given to training and supervision to reduce HIV-related discrimination during childbirth should be focused on ensuring respectful maternity care for all women. PMID- 25436823 TI - HIV-positive status disclosure and use of essential PMTCT and maternal health services in rural Kenya. AB - BACKGROUND: In sub-Saharan Africa, women's disclosure of HIV-positive status to others may affect their use of services for prevention of mother-to-child transmission of HIV (PMTCT) of HIV and maternal and child health-including antenatal care, antiretroviral drugs (ARVs) for PMTCT, and skilled birth attendance. METHODS: Using data from the Migori and AIDS Stigma Study conducted in rural Nyanza Province, Kenya, we compared the use of PMTCT and maternal health services for all women by HIV status and disclosure category (n = 390). Among HIV infected women (n = 145), associations between disclosure of HIV-positive status and the use of services were further examined with bivariate and multivariate logistic regression analyses. RESULTS: Women living with HIV who had not disclosed to anyone had the lowest levels of maternity and PMTCT service utilization. For example, only 21% of these women gave birth in a health facility, compared with 35% of HIV-negative women and 49% of HIV-positive women who had disclosed (P < 0.001). Among HIV-positive women, the effect of disclosure to anyone on ARV drug use [odds ratio (OR) = 5.8; 95% confidence interval (CI): 1.9 to 17.8] and facility birth (OR = 2.9; 95% CI: 1.4 to 5.7) remained large and significant after adjusting for confounders. Disclosure to a male partner had a particularly strong effect on the use of ARVs for PMTCT (OR = 7.9; 95% CI: 3.7 to 17.1). CONCLUSIONS: HIV-positive status disclosure seems to be a complex yet critical factor for the use of PMTCT and maternal health services in this setting. The design of interventions to promote such disclosure must recognize the impact of HIV-related stigma on disclosure decisions and protect women's rights, autonomy, and safety. PMID- 25436824 TI - Family matters: Co-enrollment of family members into care is associated with improved outcomes for HIV-infected women initiating antiretroviral therapy. AB - BACKGROUND: Although there is widespread interest in understanding how models of care for delivering antiretroviral therapy (ART) may influence patient outcomes, family-focused approaches have received little attention. In particular, there have been few investigations of whether the co-enrollment of HIV-infected family members may improve adult ART outcomes over time. METHODS: We examined the association between co-enrollment of HIV-infected family members into care and outcomes of women initiating ART in 12 HIV care and treatment programs across sub Saharan Africa. Using data from the mother-to-child transmission-(MTCT) Plus Initiative, women starting ART were categorized according to the co-enrollment of an HIV-infected partner and/or HIV-infected child within the same program. Mortality and loss to follow-up were assessed for up to 5 years after women's ART initiation. RESULTS: Of the 2877 women initiating ART included in the analysis, 31% (n = 880) had at least 1 HIV-infected family member enrolled into care at the same program, including 24% (n = 689) who had an HIV-infected male partner, and 10% (n = 295) who had an HIV-infected child co-enrolled. There was no significant difference in the risk of death of women by family co-enrollment status (P = 0.286). However, the risk of loss to follow-up was greatest among women who did not have an HIV-infected family member co-enrolled (19% after 36 months on ART) compared with women who had an HIV-infected family member co-enrolled (3%-8% after 36 months on ART) (P < 0.001). These associations persisted after adjustment for demographic and clinical covariates and were consistent across countries and care programs. DISCUSSION: These data provide novel evidence for the association between adult outcomes on ART and co-enrollment of HIV-infected family members into care at the same program. Interventions that build on women's family contexts warrant further consideration in both research and policies to promote retention in ART services across sub-Saharan Africa. PMID- 25436827 TI - High-risk Prostate Cancer Treated With Dose-escalated RT: An Analysis of Hormonal Therapy Use and Duration, and Prognostic Implications of PSA Nadir <=0.2 to Select Men for Short-term Hormonal Therapy. AB - OBJECTIVES: To determine prognostic factors to select high-risk men receiving dose-escalated radiation therapy (RT) who will have favorable outcomes with short term (ST) or no androgen deprivation therapy (ADT). METHODS: Medical records of 458 men treated with definitive RT for high-risk, nonmetastatic prostate cancer at 3 academic referral centers from 1988 to 2009 were examined. Median dose was 76.4 Gy. Men received no ADT (n=105), STADT (<12 mo, n=194), or long-term ADT (LTADT: >=12 mo, n=160). Univariate and multivariable analysis for freedom from distant metastases (FFDM) and cause-specific survival (CSS) were performed. Median follow-up was 71 months. RESULTS: Seven-year FFDM was 83% and CSS was 91%. Multivariable analysis demonstrated that prostate-specific antigen (PSA) nadir <=0.2 (HR=0.36; 95% CI, 0.20-0.64) and Gleason score (GS) were associated with FFDM and CSS (all P<0.05). ADT duration was not associated (P>0.05). Those with PSA nadir <=0.2 ng/mL had improved outcomes. Men with GS 9 disease did poorly despite a PSA nadir <=0.2 ng/mL and had improved CSS with LTADT (95% vs. 71%, P<0.05). CONCLUSIONS: Select men with high-risk disease treated with dose escalated RT may not require LTADT. In men treated with ADT, PSA nadir <=0.2 is an independent prognostic factor associated with FFDM and CSS. Men without GS 9 may have acceptable outcomes with STADT if PSA nadir is <=0.2 ng/mL. Further investigation is necessary to elucidate the role of PSA nadir in determining the optimal length of adjuvant ADT. PMID- 25436828 TI - Longitudinal DSC-MRI for Distinguishing Tumor Recurrence From Pseudoprogression in Patients With a High-grade Glioma. AB - OBJECTIVE: For patients with high-grade glioma on clinical trials it is important to accurately assess time of disease progression. However, differentiation between pseudoprogression (PsP) and progressive disease (PD) is unreliable with standard magnetic resonance imaging (MRI) techniques. Dynamic susceptibility contrast perfusion MRI (DSC-MRI) can measure relative cerebral blood volume (rCBV) and may help distinguish PsP from PD. METHODS: A subset of patients with high-grade glioma on a phase II clinical trial with temozolomide, paclitaxel poliglumex, and concurrent radiation were assessed. Nine patients (3 grade III, 6 grade IV), with a total of 19 enhancing lesions demonstrating progressive enhancement (>=25% increase from nadir) on postchemoradiation conventional contrast-enhanced MRI, had serial DSC-MRI. Mean leakage-corrected rCBV within enhancing lesions was computed for all postchemoradiation time points. RESULTS: Of the 19 progressively enhancing lesions, 10 were classified as PsP and 9 as PD by biopsy/surgery or serial enhancement patterns during interval follow-up MRI. Mean rCBV at initial progressive enhancement did not differ significantly between PsP and PD (2.35 vs. 2.17; P=0.67). However, change in rCBV at first subsequent follow-up (-0.84 vs. 0.84; P=0.001) and the overall linear trend in rCBV after initial progressive enhancement (negative vs. positive slope; P=0.04) differed significantly between PsP and PD. CONCLUSIONS: Longitudinal trends in rCBV may be more useful than absolute rCBV in distinguishing PsP from PD in chemoradiation treated high-grade gliomas with DSC-MRI. Further studies of DSC-MRI in high-grade glioma as a potential technique for distinguishing PsP from PD are indicated. PMID- 25436826 TI - Health systems integration of sexual and reproductive health and HIV services in sub-Saharan Africa: a scoping study. AB - OBJECTIVE: Both sexual and reproductive health (SRH) services and HIV programs in sub-Saharan Africa are typically delivered vertically, operating parallel to national health systems. The objective of this study was to map the evidence on national and international strategies for integration of SRH and HIV services in sub-Saharan Africa and to develop a research agenda for future health systems integration. METHODS: We examined the literature on national and international strategies to integrate SRH and HIV services using a scoping study methodology. Current policy frameworks, national HIV strategies and research, and gray literature on integration were mapped. Five countries in sub-Saharan Africa with experience of integrating SRH and HIV services were purposively sampled for detailed thematic analysis, according to the health systems functions of governance, policy and planning, financing, health workforce organization, service organization, and monitoring and evaluation. RESULTS: The major international health policies and donor guidance now support integration. Most integration research has focused on linkages of SRH and HIV front-line services. Yet, the common problems with implementation are related to delayed or incomplete integration of higher level health systems functions: lack of coordinated leadership and unified national integration policies; separate financing streams for SRH and HIV services and inadequate health worker training, supervision and retention. CONCLUSIONS: Rigorous health systems research on the integration of SRH and HIV services is urgently needed. Priority research areas include integration impact, performance, and economic evaluation to inform the planning, financing, and coordination of integrated service delivery. PMID- 25436825 TI - Eliminating preventable HIV-related maternal mortality in sub-Saharan Africa: what do we need to know? AB - INTRODUCTION: HIV makes a significant contribution to maternal mortality, and women living in sub-Saharan Africa are most affected. International commitments to eliminate preventable maternal mortality and reduce HIV-related deaths among pregnant and postpartum women by 50% will not be achieved without a better understanding of the links between HIV and poor maternal health outcomes and improved health services for the care of women living with HIV (WLWH) during pregnancy, childbirth, and postpartum. METHODS: This article summarizes priorities for research and evaluation identified through consultation with 30 international researchers and policymakers with experience in maternal health and HIV in sub-Saharan Africa and a review of the published literature. RESULTS: Priorities for improving the evidence about effective interventions to reduce maternal mortality and improve maternal health among WLWH include better quality data about causes of maternal death among WLWH, enhanced and harmonized program monitoring, and research and evaluation that contributes to improving: (1) clinical management of pregnant and postpartum WLWH, including assessment of the impact of expanded antiretroviral therapy on maternal mortality and morbidity, (2) integrated service delivery models, and (3) interventions to create an enabling social environment for women to begin and remain in care. CONCLUSIONS: As the global community evaluates progress and prepares for new maternal mortality and HIV targets, addressing the needs of WLWH must be a priority now and after 2015. Research and evaluation on maternal health and HIV can increase collaboration on these 2 global priorities, strengthen political constituencies and communities of practice, and accelerate progress toward achievement of goals in both areas. PMID- 25436829 TI - Ultrastructural and histological findings on examination of skin in osteogenesis imperfecta: a novel study. AB - Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity for fractures. It is a variable condition with a range of clinical severities. The histological and ultrastructural findings in the skin of patients with OI have not been described in detail in the previously published literature. Although protein analysis of cultured fibroblasts has historically been used in the diagnostic work-up of OI patients, other aspects of skin examination are not routinely performed as part of the diagnostic pathway in patients with OI. The aims of this study were to perform histological and ultrastructural examination of skin biopsies in patients with OI. This was to identify common and distinguishing features in the numerous genetically distinct subtypes of OI and compare the findings with those in patients who did not present with fractures, and to enable the use of the results thus obtained to aid in the diagnostic work up of patients with OI. As part of a larger research study set-up to identify clinical features and natural history in patients with atypical features of OI, skin biopsy and examination (histology and electron microscopy) were undertaken. Genetic analysis and ancillary investigations were also performed to identify similarities within this group and to differentiate this group from the 'normal' population. At the end of this study, we were able to demonstrate that the histological and electron microscopic findings on a skin biopsy may be an indicator of the likelihood of identifying a pathogenic mutation in type 1 collagen genes. This is because patients with specific findings on examination, such as elastic fibre area fraction (on histological analysis), collagen fibril diameter variability, deviation from the expected mean and collagen flowers (on electron microscopy), are more likely to be positive on genetic analyses. This has, in turn, provided more insight into the pathways to direct gene testing and has reinforced the need for accurate phenotyping before undertaking further genetic investigations. The morphometric assessment of elastic fibre area fraction and ultrastructural findings from this study have provided us with a better understanding of OI and insights into the possible mechanism of these changes in the skin. Correlation of skin findings with the clinical phenotype as well as genetic testing has enabled understanding of the molecular pathogenesis and translation of changes at the genomic level to clinical phenotype. PMID- 25436831 TI - CS2 activation at uranium(III) siloxide ate complexes: the effect of a Lewis acidic site. AB - Multimetallic cooperative binding of heteroallenes provides an attractive route to their activation, but the reduction of CS(2) at heterobimetallic sites, associating an electron-rich metal with a main group Lewis acid has not been explored. Here we show that the presence of a heterometallic U, K site plays an important role in the CS(2) reduction by uranium(iii) complexes of the electron rich and the sterically demanding tris(tert-butoxy)siloxide ligand. Specifically, the ion-pair complex [K(18c6)][U(OSi(O(t)Bu)(3))(4)], 1, leads preferentially to the reductive disproportionation of CS(2) to K(2)CS(3) and CS. The crystal structure of the thiocarbonate intermediate complex [U(OSi(O(t)Bu(3)(4) (MU(3) kappa(2):kappa(2):kappa(2-)CS(3))K(2)(18c6)(2)], 2, isolated from the toluene reaction mixture has been determined. In contrast, the heterobimetallic complex [U(OSi(O(t)Bu(3)(4)K], 3, promotes preferentially the reductive dimerization of CS(2) to K(2)C(2)S(4) and K(2)C(3)S(5). The [K(2)C(2)S(4)(DMSO)(3)](n), 5, and [U(OSi(O(t)Bu)(3))(4)K(2)(C(3)S(5))](n), 6, polymeric compounds were isolated from this reaction and structurally characterized. PMID- 25436830 TI - The effectiveness of a life style modification and peer support home blood pressure monitoring in control of hypertension: protocol for a cluster randomized controlled trial. AB - BACKGROUND: Death rates due to hypertension in low and middle income countries are higher compared to high income countries. The present study is designed to combine life style modification and home blood pressure monitoring for control of hypertension in the context of low and middle income countries. METHODS: The study is a two armed, parallel group, un-blinded, cluster randomized controlled trial undertaken within lower income areas in Kuala Lumpur. Two housing complexes will be assigned to the intervention group and the other two housing complexes will be allocated in the control group. Based on power analysis, 320 participants will be recruited. The participants in the intervention group (n = 160) will undergo three main components in the intervention which are the peer support for home blood pressure monitoring, face to face health coaching on healthy diet and demonstration and training for indoor home based exercise activities while the control group will receive a pamphlet containing information on hypertension. The primary outcomes are systolic and diastolic blood pressure. Secondary outcome measures include practice of self-blood pressure monitoring, dietary intake, level of physical activity and physical fitness. DISCUSSION: The present study will evaluate the effect of lifestyle modification and peer support home blood pressure monitoring on blood pressure control, during a 6 month intervention period. Moreover, the study aims to assess whether these effects can be sustainable more than six months after the intervention has ended. PMID- 25436832 TI - A sterically stabilized FeI-FeI semi-rotated conformation of [FeFe] hydrogenase subsite model. AB - The [FeFe] hydrogenase is a highly sophisticated enzyme for the synthesis of hydrogen via a biological route. The rotated state of the H-cluster in the [Fe(I)Fe(I)] form was found to be an indispensable criteria for an effective catalysis. Mimicking the specific rotated geometry of the [FeFe] hydrogenase active site is highly challenging as no protein stabilization is present in model compounds. In order to simulate the sterically demanding environment of the nature's active site, the sterically crowded meso-bis(benzylthio)diphenylsilane (2) was utilized as dithiolate linker in an [2Fe2S] model complex. The reaction of the obtained hexacarbonyl complex 3 with 1,2-bis(dimethylphosphino)ethane (dmpe) results three different products depending on the amount of dmpe used in this reaction: [{Fe2(CO)5{MU-(SCHPh)2SiPh2}}2(MU-dmpe)] (4), [Fe2(CO)5(kappa(2) dmpe){MU-(SCHPh)2SiPh2}] (5) and [Fe2(CO)5(MU-dmpe){MU-(SCHPh)2SiPh2}] (6). Interestingly, the molecular structure of compound 5 shows a [FeFe] subsite comprising a semi-rotated conformation, which was fully characterized as well as the other isomers 4 and 6 by elemental analysis, IR and NMR spectroscopy, X-ray diffraction analysis (XRD) and DFT calculations. The herein reported model complex is the first example so far reported for [Fe(I)Fe(I)] hydrogenase model complex showing a semi-rotated geometry without the need of stabilization via agostic interactions (Fe...H-C). PMID- 25436833 TI - Maximizing antiretroviral therapy in developing countries: the dual challenge of efficiency and quality. PMID- 25436834 TI - PFOA and high cholesterol: basis for the finding of a probable link. PMID- 25436835 TI - Representing the potential-energy surface of protonated water clusters by high dimensional neural network potentials. AB - Investigating the properties of protons in water is essential for understanding many chemical processes in aqueous solution. While important insights can in principle be gained by accurate and well-established methods like ab initio molecular dynamics simulations, the computational costs of these techniques are often very high. This prevents studying large systems on long time scales, which is severely limiting the applicability of computer simulations to address a wide range of interesting phenomena. Developing more efficient potentials enabling the simulation of water including dissociation and recombination events with first principles accuracy is a very challenging task. In particular protonated water clusters have become important model systems to assess the reliability of such potentials, as the presence of the excess proton induces substantial changes in the local hydrogen bond patterns and many energetically similar isomers exist, which are extremely difficult to describe. In recent years it has been demonstrated for a number of systems including neutral water clusters of varying size that neural networks (NNs) can be used to construct potentials with close to first-principles accuracy. Based on density-functional theory (DFT) calculations, here we present a reactive full-dimensional NN potential for protonated water clusters up to the octamer. A detailed investigation of this potential shows that the energetic, structural, and vibrational properties are in excellent agreement with DFT results making the NN approach a very promising candidate for developing a high-quality potential for water. This finding is further supported by first preliminary but very encouraging NN-based simulations of the bulk liquid. PMID- 25436836 TI - Conservative Implant Removal for the Analysis of the Cause, Removal Torque, and Surface Treatment of Failed Nonmobile Dental Implants. AB - This study was performed to study the effect of implant surface treatment on the cause and removal torque of failed nonmobile implants. Implant explantation was achieved by the application of countertorque at the implant-bone interface. The explantation socket was examined carefully and curetted to remove any granulation tissue. Immediate implant placement was accomplished when primary stability could be achieved. Eighty-one patients were treated according to the described treatment protocol for the explantation of 158 nonmobile implants in the maxilla and the mandible. The patient's mean age was 62 +/- 11 years. The main cause of implant explantation was peri-implantitis (131 implants; 82.9%) followed by malpositioning of the implants (22 implants; 13.9%). The explantation of 139 implants at 146 +/- 5 Ncm was performed without the need for trephine bur. However, the use of trephine burs to cut into the first 3 to 4 mm was necessary in 19 explantations, and the removal torque was 161 +/- 13 Ncm. All titanium plasma-sprayed implants were removed due to peri-implantitis at a significantly lower torque when compared to acid-etched, particle-blasted, and oxidized implants. The postoperative recovery of the patients was uneventful and the conservation of the available hard and soft tissues was successfully achieved. The protocol followed in this study could constitute a real alternative to other traumatic technique for the removal of failed implants and advanced stages of peri-implantitis. The type of implant surface treatment could influence the value of removal torque and the occurrence of peri-implantitis. PMID- 25436837 TI - Topical gene silencing by iontophoretic delivery of an antisense oligonucleotide dendrimer nanocomplex: the proof of concept in a skin cancer mouse model. AB - The study was aimed at investigating the feasibility of using a poly (amidoamine) (PAMAM) dendrimer as a carrier for topical iontophoretic delivery of an antisense oligonucleotide (ASO). Bcl-2, an anti-apoptotic protein implicated in skin cancer, was used as the model target protein to demonstrate the topical gene silencing approach. Confocal laser scanning microscopy studies demonstrated that the iontophoretically delivered ASO-dendrimer complex can reach the viable epidermis in porcine skin. In contrast, passively delivered free or dendrimer complexed ASO was mainly localized to the stratum corneum. The cell uptake of ASO was significantly enhanced by the dendrimer complex and the complex suppressed Bcl-2 levels in the cell. In the skin cancer mouse model, the iontophoretically delivered ASO-dendrimer complex reduced the tumor volume by 45% and was consistent with the reduction in Bcl-2 protein levels. The iontophoretically delivered ASO-dendrimer complex caused significant apoptosis in skin tumor. Overall, the findings from this study demonstrate that dendrimers are promising nanocarriers for developing topical gene silencing approaches for skin diseases. PMID- 25436838 TI - Knee joint pain potentially due to bone alterations in a knee osteoarthritis patient. AB - BACKGROUND: Osteoarthritis (OA) is the leading cause of musculoskeletal pain and functional disability worldwide. However, the etiology of this condition is still largely unknown. CASE REPORT: We report the clinical course of an elderly man with knee OA. CONCLUSIONS: Plain radiographs and MRI examinations performed during follow-up suggested that the pathophysiology of the patient's knee OA and joint pain may have been primarily due to bone alterations. PMID- 25436839 TI - Bloodstream infections among children with juvenile idiopathic arthritis: a prospective study from the onset of disease. AB - OBJECTIVES: To describe the incidence and nature of bloodstream infections (BSI) among children with juvenile idiopathic arthritis (JIA) followed-up prospectively from disease onset. METHODS: The Social Insurance Institution's (SII) national register on individuals with reimbursement for medication of chronic diseases was used to identify children with JIA from 2004 through 2011 and their medications. The National Infectious Disease Register (NIDR) collects data of all blood culture positive samples from all microbiology laboratories in Finland. We combined the NIDR and SII registers to identify JIA patients with BSI. Clinical and laboratory data of each JIA-BSI patient were collected from hospital records. RESULTS: There were 1604 JIA patients and 6630 person-years of follow-up. Five patients had BSI. During the first 5 years after diagnosis the cumulative emergence of BSI was 0.38% [95% confidence interval (CI) 0.16% to 0.92%]. The incidence rates were 7.5/10 000 follow-up years for JIA (95% CI 2.4-17.6) and 2.8/10 000 follow-up years for the age-matched general population (95% CI 2.7 2.9). The standardised incidence ratio was 3.0 (95% CI 1.2 to 7.2). The causative bacteria were Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli and Fusobacterium necrophorum. Three patients were on anti-rheumatic drugs, including two on TNF inhibitors. All patients responded rapidly to antimicrobial therapy and recovered uneventfully. CONCLUSIONS: Although BSI is rare among children with JIA, the incidence is 3-fold higher than among the general population. PMID- 25436840 TI - The motivational salience of cigarette-related stimuli among former, never, and current smokers. AB - While smokers are known to find smoking-related stimuli motivationally salient, the extent to which former smokers do so is largely unknown. In this study, we collected event-related potential (ERP) data from former and never smokers and compared them to a sample of current smokers interested in quitting who completed the same ERP paradigm prior to smoking cessation treatment. All participants (n = 180) attended 1 laboratory session where we recorded dense-array ERPs in response to cigarette-related, pleasant, unpleasant, and neutral pictures and where we collected valence and arousal ratings of the pictures. We identified 3 spatial and temporal regions of interest, corresponding to the P1 (120-132 ms), early posterior negativity (EPN; 244-316 ms), and late positive potential (LPP; 384-800 ms) ERP components. We found that all participants produced larger P1 responses to cigarette-related pictures compared to the other picture categories. With the EPN component, we found that, similar to pleasant and unpleasant pictures, cigarette-related pictures attracted early attentional resources, regardless of smoking status. Both former and never smokers produced reduced LPP responses to cigarette-related and pleasant pictures compared to current smokers. Current smokers rated the cigarette-related pictures as being more pleasant and arousing than the former and never smokers. The LPP and picture-rating results suggest that former smokers, like never smokers, do not find cigarette-related stimuli to be as motivationally salient as current smokers. PMID- 25436846 TI - A teenager with fever, rash, and arthralgia. Streptobacillus moniliformis infection. PMID- 25436842 TI - Alcohol and tobacco cue effects on craving in non-daily smokers. AB - Non-daily smokers commonly smoke cigarettes following the consumption of alcohol, yet the reason(s) for this remains poorly understood. The present study examined the impact of alcohol consumption on responses in tobacco salient cues 49 male and 50 female non-daily smokers. After the administration of an alcohol, placebo, or control beverage, participants were exposed to series neutral video clips and tobacco smoking salient video clips, and their subjective states and heart rates were monitored. The timing of the exposure to the tobacco smoking clips was randomly determined to coincide with the timing of either the ascending limb or the descending limb of the blood alcohol concentration (BAC) curve of the alcohol beverage condition. The tobacco smoking clips were found to increase cigarette craving regardless of beverage condition or timing of exposure (p = .002). Alcohol consumption was associated with increased ratings of intoxication (p < .001), increased heart rate across participants (p < .001), and increased cigarette craving in female participants specifically (p = .017). Alcohol did not influence responses to the smoking videos. These results suggest that smoking salient cues and alcohol may impact cigarette craving in non-daily smokers through independent processes. PMID- 25436841 TI - GRIK1 genotype and daily expectations of alcohol's positive effects moderate the reduction of heavy drinking by topiramate. AB - Using retrospective reports obtained during treatment visits in 138 heavy drinkers, we found that topiramate's reduction of heavy drinking was moderated by a polymorphism (rs2832407) in GRIK1, which encodes the GluK1 kainate subunit (Kranzler et al., 2014a). A subsequent analysis of that 12-week topiramate treatment trial showed similar effects of medication and genotype on daily drinking reports obtained via interactive voice response technology (IVR; Kranzler et al., 2014b). Specifically, rs2832407*C-allele homozygotes treated with topiramate reported lower levels of drinking than those receiving placebo. This group also had the largest decreases in the expected positive effects of drinking (i.e., expectancies) and desire to drink. To extend that analysis, which focused on how mean levels of desire and expectancies changed over time with treatment, we used a within-person approach to examine whether daily variation in expectancies and desire to drink interact with topiramate treatment and genotype to predict nighttime drinking levels. In contrast to the previous analysis (Kranzler et al., 2014b), here we focus on whether alcohol expectancies and desire to drink moderate the effects of topiramate on drinking. Results showed a 3-way interaction of daily expectancies with genotype and medication, such that the protective effect of topiramate on nighttime drinking among rs2832407*C allele homozygotes was decreased on days characterized by relatively high levels of anticipated positive effects of alcohol. There was no moderating effect of desire to drink or negative alcohol expectancies. Thus, there is specific moderation of the effects of topiramate by both genotype and cognitive process. PMID- 25436847 TI - Pain terminology. PMID- 25436848 TI - Pain terminology. PMID- 25436849 TI - Surgery and neurodevelopmental impairment: need for time-dependent covariates to correct for confounding by indication. PMID- 25436850 TI - In reply. PMID- 25436851 TI - In reply. PMID- 25436852 TI - JAMA pediatrics patient page. Texting and driving. PMID- 25436853 TI - Missed opportunities for pregnancy prevention among insured adolescents. AB - IMPORTANCE: Birth to a teenaged mother is associated with adverse health and social outcomes. Adolescents at risk for pregnancy may not receive needed reproductive health services at primary care visits. OBJECTIVE: To review services provided at outpatient visits in the year prior to pregnancy among adolescents in a US Midwestern integrated health care delivery system. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of continuously insured adolescents aged 15 to 19 years experiencing pregnancy in a nonprofit Minnesota health care organization. MAIN OUTCOMES AND MEASURES: Primary care visits in the year prior to pregnancy. RESULTS: Adolescents experiencing a pregnancy with stable insurance coverage had an estimated average of 2.7 primary care visits in the 12 months prior to becoming pregnant. Medical record review revealed that 57% did not have documentation of sexual activity and 47% did not have documentation of reproductive health counseling. These rates varied by health care professional type and visit type. Only 35% had contraception prescribed within 12 months of becoming pregnant and only 1 had a long-acting contraceptive prescribed. CONCLUSIONS AND RELEVANCE: Our data highlight the need for primary care professionals to review health behaviors and pregnancy risk at all adolescent encounters. PMID- 25436854 TI - Retinal vessel alterations and cerebral white matter microstructural damage in obese adolescents with metabolic syndrome. AB - IMPORTANCE: Cerebral white matter (WM) damage has been reported in childhood obesity and in metabolic syndrome (MetS) but mechanisms remain unclear. OBJECTIVES: To ascertain whether adolescents with MetS have retinal vessel alterations and if the anticipated reductions in retinal arteriolar diameter are associated with diminished cerebral WM microstructural integrity and to test a model for vascular etiology of the WM abnormalities. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of the brain correlates of obesity and related metabolic disease in youths. This study was conducted at the Brain, Obesity, and Diabetes Laboratory, New York University School of Medicine, New York. Thirty-nine obese adolescents with MetS and 51 matched adolescents without MetS received comprehensive endocrine, neuropsychological, retinal vessel, and diffusion tensor imaging-based cerebral WM evaluations. MAIN OUTCOMES AND MEASURES: Retinal arteriolar diameter, cerebral WM microstructural integrity, waist circumference, and insulin resistance. RESULTS: Obese adolescents with MetS had significant reductions in retinal arteriolar diameter relative to adolescents without MetS (mean [SD] central retinal arteriolar equivalent, 182.35 [16.10] vs. 198.62 [19.03] MUm, respectively; P < .001). The greater the number of MetS criteria present, the greater the reduction was in retinal arteriolar diameter (beta = -8.61; ?r2 = 0.335; ?F1,83 = 70.79; P < .001). We found that abdominal obesity (waist circumference) was the strongest MetS component related to reductions in retinal arteriolar diameter (rp[85] = -0.661; P < .001), and importantly, for the first time to our knowledge, we demonstrated that its effect was partially mediated by comorbid insulin resistance (indirect effect = -0.1355 [95% CI, -0.2471 to -0.0593]; Z = -2.56; P = .01). Consistent with our prior report of nondiabetic adolescents with MetS, we also uncovered cerebral WM microstructural damage. These subtle WM changes were associated with reductions in retinal arteriolar diameter, a proxy for cerebral microvascular health (3150 voxels or 3.15 cm3; P < .001). Importantly, some of the WM regions showing lower microstructural integrity also demonstrated associations with retinal arteriolar diameter, suggesting that the observed WM pathology is likely vascular in nature. CONCLUSIONS AND RELEVANCE: We document, for the first time to our knowledge, the associations between retinal vessel alterations and subclinical WM pathology among obese adolescents with MetS. This suggests that the subtle WM pathology in adolescents with MetS may have a vascular origin. Future work should include direct assessments of cerebral microvascular health. PMID- 25436855 TI - Optical coherence tomography for the diagnosis, monitoring and guiding of treatment for neovascular age-related macular degeneration: a systematic review and economic evaluation. AB - BACKGROUND: Age-related macular degeneration is the most common cause of sight impairment in the UK. In neovascular age-related macular degeneration (nAMD), vision worsens rapidly (over weeks) due to abnormal blood vessels developing that leak fluid and blood at the macula. OBJECTIVES: To determine the optimal role of optical coherence tomography (OCT) in diagnosing people newly presenting with suspected nAMD and monitoring those previously diagnosed with the disease. DATA SOURCES: Databases searched: MEDLINE (1946 to March 2013), MEDLINE In-Process & Other Non-Indexed Citations (March 2013), EMBASE (1988 to March 2013), Biosciences Information Service (1995 to March 2013), Science Citation Index (1995 to March 2013), The Cochrane Library (Issue 2 2013), Database of Abstracts of Reviews of Effects (inception to March 2013), Medion (inception to March 2013), Health Technology Assessment database (inception to March 2013). REVIEW METHODS: Types of studies: direct/indirect studies reporting diagnostic outcomes. INDEX TEST: time domain optical coherence tomography (TD-OCT) or spectral domain optical coherence tomography (SD-OCT). COMPARATORS: clinical evaluation, visual acuity, Amsler grid, colour fundus photographs, infrared reflectance, red-free images/blue reflectance, fundus autofluorescence imaging, indocyanine green angiography, preferential hyperacuity perimetry, microperimetry. Reference standard: fundus fluorescein angiography (FFA). Risk of bias was assessed using quality assessment of diagnostic accuracy studies, version 2. Meta-analysis models were fitted using hierarchical summary receiver operating characteristic curves. A Markov model was developed (65-year-old cohort, nAMD prevalence 70%), with nine strategies for diagnosis and/or monitoring, and cost-utility analysis conducted. NHS and Personal Social Services perspective was adopted. Costs (2011/12 prices) and quality-adjusted life-years (QALYs) were discounted (3.5%). Deterministic and probabilistic sensitivity analyses were performed. RESULTS: In pooled estimates of diagnostic studies (all TD-OCT), sensitivity and specificity [95% confidence interval (CI)] was 88% (46% to 98%) and 78% (64% to 88%) respectively. For monitoring, the pooled sensitivity and specificity (95% CI) was 85% (72% to 93%) and 48% (30% to 67%) respectively. The FFA for diagnosis and nurse-technician-led monitoring strategy had the lowest cost (L 39,769; QALYs 10.473) and dominated all others except FFA for diagnosis and ophthalmologist-led monitoring (L 44,649; QALYs 10.575; incremental cost-effectiveness ratio L 47,768). The least costly strategy had a 46.4% probability of being cost effective at L 30,000 willingness-to-pay threshold. LIMITATIONS: Very few studies provided sufficient information for inclusion in meta-analyses. Only a few studies reported other tests; for some tests no studies were identified. The modelling was hampered by a lack of data on the diagnostic accuracy of strategies involving several tests. CONCLUSIONS: Based on a small body of evidence of variable quality, OCT had high sensitivity and moderate specificity for diagnosis, and relatively high sensitivity but low specificity for monitoring. Strategies involving OCT alone for diagnosis and/or monitoring were unlikely to be cost-effective. Further research is required on (i) the performance of SD-OCT compared with FFA, especially for monitoring but also for diagnosis; (ii) the performance of strategies involving combinations/sequences of tests, for diagnosis and monitoring; (iii) the likelihood of active and inactive nAMD becoming inactive or active respectively; and (iv) assessment of treatment associated utility weights (e.g. decrements), through a preference-based study. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012001930. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 25436856 TI - Metabolomic analysis reveals mechanism of antioxidant butylated hydroxyanisole on lipid accumulation in Crypthecodinium cohnii. AB - The heterotrophic dinoflagellate alga Crypthecodinium cohnii is known to accumulate lipids with a high fraction of docosahexaenoic acid (DHA). In this study, we first evaluated two antioxidant compounds, butylated hydroxyanisole (BHA) and propyl gallate (PG), for their effects on lipid accumulation in C. cohnii. The results showed that antioxidant BHA could increase lipid accumulation in C. cohnii by 8.80% at a final concentration of 30 MUM, while PG had no obvious effect on lipid accumulation at the tested concentrations. To decipher the molecular mechanism responsible for the increased lipid accumulation by BHA, we employed an integrated GC-MS and LC-MS metabolomic approach to determine the time series metabolic profiles with or without BHA, and then subjected the metabolomic data to a principal component analysis (PCA) and a weighted gene coexpression network analysis (WGCNA) network analyses to identify the key metabolic modules and metabolites possibly relevant to the increased lipid accumulation. LC-MS analysis showed that several metabolites, including NADPH, could be important for the stimulation role of BHA on lipid accumulation. Meanwhile GC-MS and network analyses allowed identification of eight metabolic modules and nine hub metabolites possibly relevant to the stimulation role of BHA in C. cohnii. The study provided a metabolomics view of the BHA mode of action on lipid accumulation in C. cohnii, and the information could be valuable for a better understanding of antioxidant effects on lipid accumulation in other microalgae as well. PMID- 25436857 TI - Gene-gene and gene-environment interactions detected by transcriptome sequence analysis in twins. AB - Understanding the genetic architecture of gene expression is an intermediate step in understanding the genetic architecture of complex diseases. RNA sequencing technologies have improved the quantification of gene expression and allow measurement of allele-specific expression (ASE). ASE is hypothesized to result from the direct effect of cis regulatory variants, but a proper estimation of the causes of ASE has not been performed thus far. In this study, we take advantage of a sample of twins to measure the relative contributions of genetic and environmental effects to ASE, and we find substantial effects from gene * gene (G*G) and gene * environment (G*E) interactions. We propose a model where ASE requires genetic variability in cis, a difference in the sequence of both alleles, but where the magnitude of the ASE effect depends on trans genetic and environmental factors that interact with the cis genetic variants. PMID- 25436860 TI - Structural analysis of calmodulin binding by nNOS inhibitory amphibian peptides. AB - Calmodulin (CaM) is a ubiquitous protein in nature and plays a regulatory role in numerous biological processes, including the upregulation of nitric oxide (NO) synthesis in vivo. Several peptides that prevent NO production by interacting with CaM have been isolated in the cutaneous secretions of Australian amphibians, and are thought to serve as a defense mechanism against predators. In this work, we probe the mechanism by which three of these peptides, namely, caerin 1.8, dahlein 5.6, and a synthetic modification of citropin 1.1, interact with CaM to inhibit NO signaling. Isothermal titration calorimetry was used to determine thermodynamic parameters of the binding interactions and revealed that all the peptides bind to CaM in a similar fashion, with the peptide encapsulated between the two lobes of CaM. Ion mobility-mass spectrometry was used to investigate the changes in collision cross section that occur as a result of complexation, providing additional evidence for this binding mode. Finally, nuclear magnetic resonance spectroscopy was used to track chemical shift changes upon binding. The results obtained confirm that these complexes adopt canonical collapsed structures and demonstrate the strength of the interaction between the peptides and CaM. An understanding of these molecular recognition events provides insights into the underlying mechanism of the amphibian host-defense system. PMID- 25436859 TI - Hydrophobic Hydration in Water-tert-Butyl Alcohol Solutions by Extended Depolarized Light Scattering. AB - Molecular dynamics and structural properties of water-tert-butyl alcohol (TBA) mixtures are studied as a function of concentration by extended depolarized light scattering (EDLS) experiments. The wide frequency range, going from fraction to several thousand GHz, explored by EDLS allows distinguishing TBA rotational dynamics from structural relaxation of water and intermolecular vibrational and librational modes of the solution. Contributions to the water relaxation originating from two distinct populations, i.e. hydration and bulk water, are clearly identified. The dynamic retardation factor of hydration water with respect to the bulk, xi ~ 4, almost concentration independent, is one of the smallest found by EDLS among a variety of systems of different nature and complexity. This result, together with the small number of water molecules perturbed by the presence of TBA, supports the idea that hydrophobic simple molecules are less effective than hydrophilic and more complex molecules in perturbing the H-bond network of liquid water. At increasing TBA concentrations the average number of perturbed water molecules shows a pronounced decrease and the characteristic frequency of librational motions reduces significantly, both of which are results consistent with the occurrence of self-aggregation of TBA molecules. PMID- 25436858 TI - The beet Y locus encodes an anthocyanin MYB-like protein that activates the betalain red pigment pathway. AB - Nearly all flowering plants produce red/violet anthocyanin pigments. Caryophyllales is the only order containing families that replace anthocyanins with unrelated red and yellow betalain pigments. Close biological correlation of pigmentation patterns suggested that betalains might be regulated by a conserved anthocyanin-regulating transcription factor complex consisting of a MYB, a bHLH and a WD repeat-containing protein (the MBW complex). Here we show that a previously uncharacterized anthocyanin MYB-like protein, Beta vulgaris MYB1 (BvMYB1), regulates the betalain pathway in beets. Silencing BvMYB1 downregulates betalain biosynthetic genes and pigmentation, and overexpressing BvMYB1 upregulates them. However, unlike anthocyanin MYBs, BvMYB1 will not interact with bHLH members of heterologous anthocyanin MBW complexes because of identified nonconserved residues. BvMYB1 resides at the historic beet pigment-patterning locus, Y, required for red-fleshed beets. We show that Y and y express different levels of BvMYB1 transcripts. The co-option of a transcription factor regulating anthocyanin biosynthesis would be an important evolutionary event allowing betalains to largely functionally replace anthocyanins. PMID- 25436861 TI - Gate-tunable resonant tunneling in double bilayer graphene heterostructures. AB - We demonstrate gate-tunable resonant tunneling and negative differential resistance in the interlayer current-voltage characteristics of rotationally aligned double bilayer graphene heterostructures separated by hexagonal boron nitride (hBN) dielectric. An analysis of the heterostructure band alignment using individual layer densities, along with experimentally determined layer chemical potentials indicates that the resonance occurs when the energy bands of the two bilayer graphene are aligned. We discuss the tunneling resistance dependence on the interlayer hBN thickness, as well as the resonance width dependence on mobility and rotational alignment. PMID- 25436862 TI - Professor Robert Sutherland FAA, AO (1947-2012). PMID- 25436863 TI - Irma h. Russo, MD. PMID- 25436864 TI - Estrogen receptor beta: putting a positive into triple negative breast cancer? AB - Abstract ERbeta was discovered over 15 years ago, yet the initial expectancy that this protein could have therapeutic use has ebbed, because of the complexity surrounding its function and significance in breast cancer. It has become apparent that its functional role and prognostic significance in breast cancer may depend on a number of factors, such as co-expression with ERalpha, presence of various isoforms (ERbeta1, -2 and -5 in breast cancer), post-transcriptional modifications and cellular location. Interestingly, ERbeta1 is often expressed in triple negative breast cancer (TNBC), a more aggressive type of breast cancer with limited treatment options because of the lack of expression of a recognised biological target. Furthermore, clinical data has demonstrated a clear correlation between ERbeta1 positivity and improved disease-free and overall survival in those patients treated with tamoxifen. This suggests ERbeta1 may be worth considering as a potential therapeutic target, particularly in TNBC. PMID- 25436865 TI - Fundamental biological importance of solvated electrons in humans. AB - Abstract In recent years, "solvated electrons" were shown to be emitted by various biological systems in humans such as hormones, enzymes, amino acids, etc., even by vitamins, dyes, and other organic compounds. Based on experimental results and data from the literature, it is hypothesized that most biological systems in humans are capable of emission. Most systems in humans generate as well as consume and transfer them to other moieties, hence enabling intersystem communication via the brain. Emission of is associated with generation of free radicals, which are likewise involved in biological processes in humans. The data presented in this article underline this hypothesis, which offers a completely new concept in the course of biological mechanisms in humans. PMID- 25436866 TI - Ovariectomy lowers urine levels of unconjugated (+)-catechin, (-)-epicatechin, and their methylated metabolites in rats fed grape seed extract. AB - Abstract Steroid hormones modulate expression of enzymes that metabolize xenobiotics, including dietary supplements. Half of the human population undergoes menopause, yet the effect of this age-related loss of ovarian steroid hormones on the metabolism of dietary supplements has yet to be determined. Grape seed extract (GSE) is a dietary supplement comprised of monomeric and oligomeric catechins and has health benefits in models of age-related diseases. We hypothesized that surgically-induced loss of ovarian hormones would increase methylation, glucuronidation, and/or sulfation of the grape seed polyphenols (+) catechin and (-)-epicatechin. Fourteen-week-old spontaneously hypertensive rats (SHRs) were ovariectomized (OVX) or sham-OVX. At 17 weeks of age, SHRs were gavaged with vehicle (water) or GSE (300 mg/kg body weight) once daily for 6 days. Urinary excretion of (+)-catechin, (-)-epicatechin, and their metabolites was analyzed by liquid chromatography-mass spectrometry. Although total urinary output of (+)-catechin, (-)-epicatechin, and their methylated metabolites was unaffected by OVX, the amounts of (+)-catechin, (-)-epicatechin and their methylated metabolites that were not conjugated with glucuronic acid or sulfate were lowered by OVX. Specifically, urine from OVX SHRs administered GSE contained 30% higher proportions (91.8% vs. 62.3%) of glucuronidated (+)-catechin and (-) epicatechin and glucuronidated methyl (+)-catechin and methyl (-)-epicatechin than urine from sham-OVX SHRs. However, there were no differences in urinary levels of total methylated or sulfated catechins in OVX SHRs. This is the first quantitative characterization of metabolites of grape seed polyphenols in a model of menopause; it indicates that ovariectomy causes either an increase in expression and/or activity of select uridine 5'-diphospho glucuronosyltransferase(s). PMID- 25436867 TI - Electrospray ionization time-of-flight mass spectrum analysis method of polyaluminum chloride flocculants. AB - Electrospray mass spectrometry has been reported as a novel technique for Al species identification, but to date, the working mechanism is not clear and no unanimous method exists for spectrum analysis of traditional Al salt flocculants, let alone for analysis of polyaluminum chloride (PAC) flocculants. Therefore, this paper introduces a novel theoretical calculation method to identify Al species from a mass spectrum, based on deducing changes in m/z (mass-to-charge ratio) and molecular formulas of oligomers in five typical PAC flocculants. The use of reference chemical species was specially proposed in the method to guarantee the uniqueness of the assigned species. The charge and mass reduction of the Al cluster was found to proceed by hydrolysis, gasification, and change of hydroxyl on the oxy bridge. The novel method was validated both qualitatively and quantitatively by comparing the results to those obtained with the (27)Al NMR spectrometry. PMID- 25436868 TI - Allele-specific chemical genetics: concept, strategies, and applications. AB - The relationship between DNA and protein sequences is well understood, yet because the members of a protein family/subfamily often carry out the same biochemical reaction, elucidating their individual role in cellular processes presents a challenge. Forward and reverse genetics have traditionally been employed to understand protein functions with considerable success. A fundamentally different approach that has gained widespread application is the use of small organic molecules, known as chemical genetics. However, the slow time-scale of genetics and inherent lack of specificity of small molecules used in chemical genetics have limited the applicability of these methods in deconvoluting the role of individual proteins involved in fast, dynamic biological events. Combining the advantages of both the techniques, the specificity achieved with genetics along with the reversibility and tunability of chemical genetics, has led to the development of a powerful approach to uncover protein functions in complex biological processes. This technique is known as allele-specific chemical genetics and is rapidly becoming an essential toolkit to shed light on proteins and their mechanism of action. The current review attempts to provide a comprehensive description of this approach by discussing the underlying principles, strategies, and successful case studies. Potential future implications of this technology in expanding the frontiers of modern biology are discussed. PMID- 25436870 TI - Squaraines: crystal structures and spectroscopic analysis of hydrated and anhydrous forms of squaric acid-isoniazid species. AB - The crystal structures, synthesis procedure, thermal behavior, and spectroscopic properties of a new squaraine SqINH.H2O and its anhydrous arrangement are described. This squaraine is obtained through an acid-base reaction using squaric acid (H2Sq) and isoniazid (INH) as precursors. Both squaraines crystallize in the monoclinic system, but in different space groups: the hydrated and anhydrous arrangement crystallizes in the P21 and P21/c space group, respectively. The crystallographic data strongly suggest that the structures present an expressive increase in their electronic delocalization all over the molecular structure of both compounds, when compared with the reagents. The bond distances for both structures present an average value intermediate between a single and double character (1.463(3) A for SqINH.H2O and 1.4959(3) A for SqINH). The vibrational and electronic data also corroborate with this proposal, since the band shifts indicate that the conjugation over the system is increased, as indicated by the blue shift observed for the carbonyl stretching bands for both compounds. The presence of the water molecule is responsible for a decrease in fluorescence emission, as determined by the emission spectra recorded for both compounds. PMID- 25436869 TI - The accuracy, feasibility and challenges of sequencing short tandem repeats using next-generation sequencing platforms. AB - To date we have little knowledge of how accurate next-generation sequencing (NGS) technologies are in sequencing repetitive sequences beyond known limitations to accurately sequence homopolymers. Only a handful of previous reports have evaluated the potential of NGS for sequencing short tandem repeats (microsatellites) and no empirical study has compared and evaluated the performance of more than one NGS platform with the same dataset. Here we examined yeast microsatellite variants from both long-read (454-sequencing) and short-read (Illumina) NGS platforms and compared these to data derived through Sanger sequencing. In addition, we investigated any locus-specific biases and differences that might have resulted from variability in microsatellite repeat number, repeat motif or type of mutation. Out of 112 insertion/deletion variants identified among 45 microsatellite amplicons in our study, we found 87.5% agreement between the 454-platform and Sanger sequencing in frequency of variant detection after Benjamini-Hochberg correction for multiple tests. For a subset of 21 microsatellite amplicons derived from Illumina sequencing, the results of short-read platform were highly consistent with the other two platforms, with 100% agreement with 454-sequencing and 93.6% agreement with the Sanger method after Benjamini-Hochberg correction. We found that the microsatellite attributes copy number, repeat motif and type of mutation did not have a significant effect on differences seen between the sequencing platforms. We show that both long-read and short-read NGS platforms can be used to sequence short tandem repeats accurately, which makes it feasible to consider the use of these platforms in high-throughput genotyping. It appears the major requirement for achieving both high accuracy and rare variant detection in microsatellite genotyping is sufficient read depth coverage. This might be a challenge because each platform generates a consistent pattern of non-uniform sequence coverage, which, as our study suggests, may affect some types of tandem repeats more than others. PMID- 25436871 TI - CO desorption from a catalytic surface: elucidation of the role of steps by velocity-selected residence time measurements. AB - Directly measuring the rate of a surface chemical reaction remains a challenging problem. For example, even after more than 30 years of study, there is still no agreement on the kinetic parameters for one of the simplest surface reactions: desorption of CO from Pt(111). We present a new experimental technique for determining rates of surface reactions, the velocity-selected residence time method, and demonstrate it for thermal desorption of CO from Pt(111). We use UV UV double resonance spectroscopy to record surface residence times at selected final velocities of the desorbing CO subsequent to dosing with a pulsed molecular beam. Velocity selection differentiates trapping-desorption from direct scattering and removes influences on the temporal profile arising from the velocity distribution of the desorbing CO. The kinetic data thus obtained are of such high quality that bi-exponential desorption kinetics of CO from Pt(111) can be clearly seen. We assign the faster of the two rate processes to desorption from (111) terraces, and the slower rate process to sequential diffusion from steps to terraces followed by desorption. The influence of steps, whose density may vary from crystal to crystal, accounts for the diversity of previously reported (single exponential) kinetics results. Using transition-state theory, we derive the binding energy of CO to Pt(111) terraces, D(0)(terr) (Pt-CO) = 34 +/- 1 kcal/mol (1.47 +/- 0.04 eV) for the low coverage limit (<=0.03 ML) where adsorbate-adsorbate interactions are negligible. This provides a useful benchmark for electronic structure theory of adsorbates on metal surfaces. PMID- 25436872 TI - A rare cause of radiculomyelitis: dural arteriovenous fistula. AB - IMPORTANCE: Dural arteriovenous fistula is a very rare cause of myelitis that can only be treated interventionally or surgically. OBSERVATIONS: A man in his 30s with paraparesis and urinary incontinence had a long-segment thoracic lesion on spinal magnetic resonance imaging. Transverse myelitis was the initial diagnosis. Although a pulse steroid and intravenous immunoglobulin treatment regimen was given, no definite clinical response was seen. A spinal angiogram was performed in our center demonstrating right T7 to T8 spinal dural arteriovenous fistula. The fistula was occluded with embolization and the patient showed recovery following the endovascular treatment. CONCLUSIONS AND RELEVANCE: Myelitis usually is known to respond well to immunosuppressive treatments. Despite adequate medical treatment, if slow progression is seen in the follow-up clinically and radiologically, dural arteriovenous fistulas should be kept in mind in the etiopathogenesis. PMID- 25436873 TI - Interfacial structure and photocatalytic activity of magnetron sputtered TiO2 on conducting metal substrates. AB - The photocatalytic behavior of magnetron sputtered anatase TiO2 coatings on copper, nickel, and gold was investigated with the aim of understanding the effect of the metallic substrate and coating-substrate interface structure. Stoichiometry and nanoscale structure of the coating were investigated using X ray diffraction, Raman spectroscopy, atomic force microscope, and scanning and transmission electron microscopy. Photocatalytic behavior of the coating was explored by using optical spectrophotometry and electrochemical methods via photovoltage, photocurrent, and scanning kelvin probe microscopy measurements. The nature of the metal substrate and coating-substrate interface had profound influence on the photocatalytic behavior. Less photon energy was required for TiO2 excitation on a nickel substrate, whereas TiO2 coating on copper showed a higher band gap attributed to quantum confinement. However, the TiO2 coating on gold exhibited behavior typical of facile transfer of electrons to and from the CB, therefore requiring only a small amount of photon energy to make the TiO2 coating conductive. PMID- 25436874 TI - Switching of the triplet excited state of rhodamine/naphthaleneimide dyads: an experimental and theoretical study. AB - Rhodamine-bromonaphthaleneimide (RB-NI) and rhodamine-bromonaphthalenediimide (RB NDI) dyads were prepared for switching of the triplet excited states. Bromo-NI or bromo-NDI parts in the dyads are the spin converters, i.e., the triplet state producing modules, whereas the RB unit is the acid-activatable electron donor/energy acceptor. NI and NDI absorb at 359 and 541 nm, and the T1 state energy levels are 2.25 and 1.64 eV, respectively. RB undertakes the reversible spirolactam (RB-c) <-> opened amide (RB-o) transformation. RB-c shows no visible light absorption, and the triplet-state energy level is ET1 = 3.36 eV. Conversely RB-o shows strong absorption at 557 nm, and ET1 is 1.73 eV. Thus, the acid activated fluorescence-resonance-energy-transfer (FRET) competes with the ISC of NI or NDI. No triplet state was observed for the dyads with nanosecond time resolved transient absorption spectroscopy. Upon addition of acid, strong fluorescence and long-living triplet excited states were observed. Thus, the producing of triplet state is acid-activatable. The triplet state of RB-NI is localized on RB-o part, whereas in RB-NDI the triplet state is delocalized on both the NDI and RB-o units. The ISC of spin converter was not outcompeted by RET. These studies are useful for switching of triplet excited state. PMID- 25436875 TI - Transfusion-transmissible infections among U.S. military recipients of emergently transfused blood products, June 2006-December 2012. AB - In austere deployment environments, transfusion of freshly collected blood products from volunteer donors is sometimes necessary to save wounded service members' lives. Because these blood products may have an increased risk of transmitting bloodborne pathogens, recipients are administratively tracked and offered serial serologic testing by the Blood Look Back (BLB) program. This study evaluates the frequency of transfusion-transmissible infections (TTIs) in U.S. service member (SM) recipients of non-FDA-compliant blood products from 1 June 2006 through 31 December 2012. Routine BLB program efforts identified and evaluated 1,127 SM recipients for evidence of seven TTIs for 12 months following transfusion. The Defense Medical Surveillance System was then queried for evidence of provider-diagnosed TTIs and the results were compared. A single, previously reported incident case of human T-lymphotropic virus (rate of 1.3 per 1,000 persons) was the only TTI identified during the study period. Screening of recipients identified two (rate of 1.9 per 1,000 persons) prevalent (pre transfusion) cases of chronic hepatitis B virus (HBV) infection, 16 (rate of 15.5 per 1,000 persons) prevalent cases of naturally acquired immunity to HBV and seven (rate of 6.8 per 1,000 persons) prevalent cases of hepatitis C virus infection. No cases of infection with human immunodeficiency virus, syphilis, Trypanosoma cruzi, or West Nile virus were identified. PMID- 25436876 TI - Evaluation of extragenital screening for gonorrhea and chlamydia in HIV-infected active duty Air Force members. AB - This study evaluated the hypothesis that detection of Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) infections among HIV-infected active duty members of the U.S. Air Force would increase after expanding screening to include extragenital infections. Before and after the start of extragenital screening, urethral screening was positive for GC/CT in 2.9% and 1.9% of HIV-infected service members. Much higher proportions of rectal (11.1%) and pharyngeal (21.9%) specimens were found to be positive for GC or CT after starting extragenital screening. Only 5.9% of the extragenital positive specimens were associated with positive urethra specimens. Circumstances that warrant routine extragenital screening and the potential benefits are discussed. PMID- 25436877 TI - An outbreak of Campylobacter enteritis associated with a community water supply on a U.S. military installation. AB - An outbreak of acute gastroenteritis involving 249 persons, 32% of whom were hospitalized, occurred on a U.S. Army installation in 1990. Campylobacter jejuni was isolated from 81 of 163 (50%) persons cultured. Seventeen isolates of C. jejuni available for serotyping were Lior serotype 5. The outbreak remained restricted to one recruit barracks area and adjacent Junior Reserve Officer Training Corps cadet barracks. Infection of sequential cohorts of recruits over an interval of 3 weeks suggested a continuing or intermittent common source. Contaminated food was not implicated because affected persons ate at separate dining facilities and other facilities with the same food sources had no associated illnesses. There was a strong association between the amount of water consumed by recruits and risk of diarrhea (chi-square test for trend, p<0.001). Samples of drinking water collected in the affected area had no residual chlorine and when cultured yielded greater than 200 colonies of coliform bacteria per 100 mL of water sampled. Although Campylobacter was not isolated from water, living and dead birds were found in an elevated water storage tank providing drinking water to the affected area. This and other similar outbreaks indicate that contamination of water storage tanks can lead to large outbreaks of Campylobacter enteritis. PMID- 25436879 TI - Defensin production by human limbo-corneal fibroblasts infected with mycobacteria. AB - Epithelial cells of the cornea and the conjunctiva constitutively produce antimicrobial peptides; however, the production of defensins by other cell types located around the eye has not been investigated. We analyzed the production of beta-defensins (hBD) and cathelicidin LL-37 during the infection of primary limbo corneal fibroblasts with M. tuberculosis (MTB), M. abscessus (MAB), and M. smegmatis (MSM). The intracellular survival of each mycobacterium, the production of cytokines and the changes on the distribution of the actin filaments during the infection were also analyzed. Fibroblasts produce basal levels of hBD1 and LL 37 and under PMA stimulation they produce hBD2, hBD3 and overexpress hBD1 and LL 37. MAB induced the highest levels of hBD1 and LL-37 and intermediate levels of IL-6; however, MAB was not eliminated. In addition, MAB induced the greatest change to the distribution of the actin filaments. MTB also produced changes in the structure of the cytoskeleton and induced low levels of hBD1 and IL-6, and intermediate levels of LL-37. The balance of these molecules induced by MTB appeared to contribute to the non-replicative state observed in the limbo-corneal cells. MSM induced the lowest levels of hBD1 and LL-37 but the highest levels of IL-6; MSM was eliminated. The results suggest that mycobacterial infections regulate the production of antimicrobial peptides and cytokines, which in conjunction can contribute to the control of the bacilli. PMID- 25436878 TI - Human bocavirus: lessons learned to date. AB - Human bocavirus (HBoV) was identified as the second human parvovirus with pathogenic potential in 2005 in respiratory samples from children suffering from viral respiratory infections of unknown etiology. Since its first description, a large number of clinical studies have been performed that address the clinical significance of HBoV detection and the molecular biology of the virus. This review summarizes the most important steps taken in HBoV research to date and addresses open questions that need to be answered in the future to provide a better understanding of the role of a virus that is difficult to grow in cell culture and is suspected to be a pathogen, although it has not yet fulfilled Koch's postulates. PMID- 25436880 TI - Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance. AB - Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine. PMID- 25436881 TI - Goblet cells and mucins: role in innate defense in enteric infections. AB - Goblet cells reside throughout the gastrointestinal (GI) tract and are responsible for the production and preservation of a protective mucus blanket by synthesizing and secreting high molecular weight glycoproteins known as mucins. The concept of the mucus layer functioning as a dynamic protective barrier is suggested by studies showing changes in mucins in inflammatory conditions of the GI tract, by the altered goblet cell response in germ-free animals, and by the enhanced mucus secretion seen in response to infections. The mucin-containing mucus layer coating the GI epithelium is the front line of innate host defense. Mucins are likely to be the first molecules that invading pathogens interact with at the cell surface and thus, can limit binding to other glycoproteins and neutralize the pathogen. This review will focus on what is known about goblet cell response in various GI infections and the regulatory networks that mediate goblet cell function and mucin production in response to intestinal insults. In addition, we describe the current knowledge on the role of mucins in intestinal innate defense. It is the aim of this review to provide the readers with an update on goblet cell biology and current understanding on the role of mucins in host defense in enteric infections. PMID- 25436883 TI - Heterogeneity of the Abnormal Prion Protein (PrPSc) of the Chandler Scrapie Strain. AB - The pathological prion protein, PrPSc, displays various sizes of aggregates. In this study, we investigated the conformation, aggregation stability and proteinase K (PK)-sensitivity of small and large PrPSc aggregates of mouse adapted prion strains. We showed that small PrPSc aggregates, previously thought to be PK-sensitive, are resistant to PK digestion. Furthermore, we showed that small PrPSc aggregates of the Chandler scrapie strain have greater resistance to PK digestion and aggregation-denaturation than large PrPSc aggregates of this strain. We conclude that this strain consists of heterogeneous PrPSc. PMID- 25436882 TI - Immune evasion, immunopathology and the regulation of the immune system. AB - Costs and benefits of the immune response have attracted considerable attention in the last years among evolutionary biologists. Given the cost of parasitism, natural selection should favor individuals with the most effective immune defenses. Nevertheless, there exists huge variation in the expression of immune effectors among individuals. To explain this apparent paradox, it has been suggested that an over-reactive immune system might be too costly, both in terms of metabolic resources and risks of immune-mediated diseases, setting a limit to the investment into immune defenses. Here, we argue that this view neglects one important aspect of the interaction: the role played by evolving pathogens. We suggest that taking into account the co-evolutionary interactions between the host immune system and the parasitic strategies to overcome the immune response might provide a better picture of the selective pressures that shape the evolution of immune functioning. Integrating parasitic strategies of host exploitation can also contribute to understand the seemingly contradictory results that infection can enhance, but also protect from, autoimmune diseases. In the last decades, the incidence of autoimmune disorders has dramatically increased in wealthy countries of the northern hemisphere with a concomitant decrease of most parasitic infections. Experimental work on model organisms has shown that this pattern may be due to the protective role of certain parasites (i.e., helminths) that rely on the immunosuppression of hosts for their persistence. Interestingly, although parasite-induced immunosuppression can protect against autoimmunity, it can obviously favor the spread of other infections. Therefore, we need to think about the evolution of the immune system using a multidimensional trade-off involving immunoprotection, immunopathology and the parasitic strategies to escape the immune response. PMID- 25436885 TI - Order of Inoculation during Heligmosomoides bakeri and Hymenolepis microstoma Coinfection Alters Parasite Life History and Host Responses. AB - Parasite life history may differ during coinfection compared to single infections, and the order of infection may be an important predictor of life history traits. We subjected laboratory mice (Mus musculus) to single and coinfections with Heligmosomoides bakeri and Hymenolepis microstoma and measured life history traits of worms and also hepatobiliary and morphological responses by the host. We found that fewer H. bakeri larvae established, and adult worms were shorter and produced fewer eggs during a coinfection where H. microstoma occurred first. H. microstoma grew more and released more eggs after simultaneous inoculation of both parasites compared to a single H. microstoma infection, despite similar worm numbers. Mouse small intestine mass, but not length, varied with coinfection and bile duct mass was largest when H. microstoma was given alone or first. Mouse serum alkaline phosphatase levels were greatest for mice infected with H. microstoma only but did not vary with number of scolices; no change in mouse serum alanine transaminase levels was observed. Overall, the order of coinfection influenced life history traits of both H. bakeri and H. microstoma, but changes in survival, growth, and reproduction with order of inoculation were not consistent between the two parasites. PMID- 25436884 TI - The significance of matrix metalloproteinases in parasitic infections involving the central nervous system. AB - Matrix metalloproteinases (MMPs) represent a large family of over twenty different secreted or membrane-bound endopeptidases, involved in many physiological (embryogenesis, precursor or stem cell mobilization, tissue remodeling during wound healing, etc.), as well as pathological (inflammation, tumor progression and metastasis in cancer, vascular pathology, etc.) conditions. For a long time, MMPs were considered only for the ability to degrade extracellular matrix (ECM) molecules (e.g., collagen, laminin, fibronectin) and to release hidden epitopes from the ECM. In the last few years, it has been fully elucidated that these molecules have many other functions, mainly related to the immune response, in consideration of their effects on cytokines, hormones and chemokines. Among others, MMP-2 and MMP-9 are endopeptidases of the MMP family produced by neutrophils, macrophages and monocytes. When infection is associated with leukocyte influx into specific organs, immunopathology and collateral tissue damage may occur. In this review, the involvement of MMPs and, in particular, of gelatinases in both protozoan and helminth infections will be described. In cerebral malaria, for example, MMPs play a role in the pathogenesis of such diseases. Also, trypanosomosis and toxoplasmosis will be considered for protozoan infections, as well as neurocysticercosis and angiostrongyloidosis, as regards helminthiases. All these situations have in common the proteolytic action on the blood brain barrier, mediated by MMPs. PMID- 25436887 TI - Antimicrobial Human beta-Defensins in the Colon and Their Role in Infectious and Non-Infectious Diseases. AB - beta-defensins are small cationic antimicrobial peptides secreted by diverse cell types including colonic epithelial cells. Human beta-defensins form an essential component of the intestinal lumen in innate immunity. The defensive mechanisms of beta-defensins include binding to negatively charged microbial membranes that cause cell death and chemoattraction of immune cells. The antimicrobial activity of beta-defensin is well reported in vitro against several enteric pathogens and in non-infectious processes such as inflammatory bowel diseases, which alters beta-defensin production. However, the role of beta-defensin in vivo in its interaction with other immune components in host defense against bacteria, viruses and parasites with more complex membranes is still not well known. This review focuses on the latest findings regarding the role of beta-defensin in relevant human infectious and non-infectious diseases of the colonic mucosa. In addition, we summarize the most significant aspects of beta-defensin and its antimicrobial role in a variety of disease processes. PMID- 25436886 TI - Humanized mouse models of epstein-barr virus infection and associated diseases. AB - Epstein-Barr virus (EBV) is a ubiquitous herpesvirus infecting more than 90% of the adult population of the world. EBV is associated with a variety of diseases including infectious mononucleosis, lymphoproliferative diseases, malignancies such as Burkitt lymphoma and nasopharyngeal carcinoma, and autoimmune diseases including rheumatoid arthritis (RA). EBV in nature infects only humans, but in an experimental setting, a limited species of new-world monkeys can be infected with the virus. Small animal models, suitable for evaluation of novel therapeutics and vaccines, have not been available. Humanized mice, defined here as mice harboring functioning human immune system components, are easily infected with EBV that targets cells of the hematoimmune system. Furthermore, humanized mice can mount both cellular and humoral immune responses to EBV. Thus, many aspects of human EBV infection, including associated diseases (e.g., lymphoproliferative disease, hemophagocytic lymphohistiocytosis and erosive arthritis resembling RA), latent infection, and T-cell-mediated and humoral immune responses have been successfully reproduced in humanized mice. Here we summarize recent achievements in the field of humanized mouse models of EBV infection and show how they have been utilized to analyze EBV pathogenesis and normal and aberrant human immune responses to the virus. PMID- 25436888 TI - Zebrafish prion protein PrP2 controls collective migration process during lateral line sensory system development. AB - Prion protein is involved in severe neurodegenerative disorders but its physiological role is still in debate due to an absence of major developmental defects in knockout mice. Previous reports in zebrafish indicate that the two prion genes, PrP1 and PrP2, are both involved in several steps of embryonic development thus providing a unique route to discover prion protein function. Here we investigate the role of PrP2 during development of a mechano-sensory system, the posterior lateral line, using morpholino knockdown and PrP2 targeted inactivation. We confirm the efficiency of the translation blocking morpholino at the protein level. Development of the posterior lateral line is altered in PrP2 morphants, including nerve axonal outgrowth and primordium migration defects. Reduced neuromast deposition was observed in PrP2 morphants as well as in PrP2-/- mutants. Rosette formation defects were observed in PrP2 morphants, strongly suggesting an abnormal primordium organization and reflecting loss of cell cohesion during migration of the primordium. In addition, the adherens junction proteins, E-cadherin and beta-catenin, were mis-localized after reduction of PrP2 expression and thus contribute to the primordium disorganization. Consequently, hair cell differentiation and number were affected and this resulted in reduced functional neuromasts. At later developmental stages, myelination of the posterior lateral line nerve was altered. Altogether, our study reports an essential role of PrP2 in collective migration process of the primordium and in neuromast formation, further implicating a role for prion protein in cell adhesion. PMID- 25436889 TI - Nifedipine promotes the proliferation and migration of breast cancer cells. AB - Nifedipine is widely used as a calcium channel blocker (CCB) to treat angina and hypertension,but it is controversial with respect the risk of stimulation of cancers. In this study, we demonstrated that nifedipine promoted the proliferation and migration of breast cancer cells both invivo and invitro. However, verapamil, another calcium channel blocker, didn't exert the similar effects. Nifedipine and high concentration KCl failed to alter the [Ca2+]i in MDA MB-231 cells, suggesting that such nifedipine effect was not related with calcium channel. Moreover, nifedipine decreased miRNA-524-5p, resulting in the up regulation of brain protein I3 (BRI3). Erk pathway was consequently activated and led to the proliferation and migration of breast cancer cells. Silencing BRI3 reversed the promoting effect of nifedipine on the breast cancer. In a summary, nifedipine stimulated the proliferation and migration of breast cancer cells via the axis of miRNA-524-5p-BRI3-Erk pathway independently of its calcium channel blocking activity. Our findings highlight that nifedipine but not verapamil is conducive for breast cancer growth and metastasis, urging that the caution should be taken in clinic to prescribe nifedipine to women who suffering both hypertension and breast cancer, and hypertension with a tendency in breast cancers. PMID- 25436890 TI - Novel mouse model of spinal cord injury-induced heterotopic ossification. AB - Heterotopic ossification (HO) develops in about 20% to 30% of patients with spinal cord injury (SCI) and significantly impairs their rehabilitation. There is no effective prevention or treatment for this condition at this time. Our current understanding of its etiology and pathophysiology is limited partially due to the lack of clinically relevant animal models. In this study, we report a novel mouse model of SCI-induced HO by administering a subthreshold dose of bone morphogenetic protein (BMP)-2 to muscles in mice after SCI. Micro-computed tomography scanning showed that an intramuscular injection of 0.25 micrograms of BMP-2 causes significant HO in mice with SCI but not in control (sham surgery) mice. Our analysis of gene expression showed significantly increased BMP signaling in quadriceps following SCI, suggesting that BMP signaling may play a role in SCI-induced HO. Administering 0.25 micrograms of BMP-2 to the front arms of the mice with SCI also results in the development of significant HO but not in control mice. This suggests that SCI causes a systematic osteogenic effect, which is not limited to paralyzed limbs. This novel mouse model will serve as a powerful tool in exploring the molecular mechanisms of SCI-induced HO, which may lead to novel treatment for this disease. PMID- 25436891 TI - Impaired practice effects following mild traumatic brain injury: an event-related potential investigation. AB - BACKGROUND: The negative effects of mild traumatic brain injury (mTBI) on attention are well established. Effects of practice on neuropsychological test performance have also been long recognized and more recently linked to electrophysiological indices of information processing. OBJECTIVE: The current study examined the behavioural and electrophysiological impact of mTBI on consistent practice of a neuropsychological test of attention. RESEARCH DESIGN: Prospective cohort study. METHODS: Adult participants with a history of mild TBI (n = 10; time since injury > 2 months, mean = 15.2 months) and healthy matched controls (n = 10) completed the Paced Auditory Serial Addition Task (PASAT) at four separate sessions. Event-related potentials (ERPs) were simultaneously recorded. RESULTS: Accuracy of PASAT performance in both groups improved significantly with practice. In healthy controls behavioural improvements were associated with significant attenuation of a frontally distributed ERP component marker of executive attention. These executive attention demands did not appear to ease with consistent practice in the mTBI group, who also endorsed more concussion-related symptoms. CONCLUSIONS: These preliminary results suggest sustained mental effort is required to achieve 'normal' performance levels following mTBI and support the use of practice-related, ERP indices of recovery from mTBI as a sensitive correlate of persistent post-concussion symptoms. PMID- 25436893 TI - Flow characteristics and spillage mechanisms of an inclined quad-vortex range hood subject to influence from draft. AB - The flow and spillage characteristics of an inclined quad-vortex (IQV) range hood subject to the influence of drafts from various directions were studied. The laser-assisted smoke flow visualization technique was used to reveal the flow characteristics, and the tracer-gas (sulfur hexafluoride) concentration detection method was used to indicate the quantitative values of the capture efficiency of the hood. It was found that the leakage mechanisms of the IQV range hood are closely related to the flow characteristics. A critical draft velocity of about 0.5 m/s and a critical face velocity of about 0.25 m/s for the IQV range hood were found. When the IQV range hood was influenced by a draft with a velocity larger than the critical draft velocity, the spillage of pollutants became significant and the pollutant spillage rate increased with increasing draft velocity. At draft velocities less than or equal to the critical value, no containment leakages induced by the turbulence diffusion, reverse flow, or boundary-layer separation were observed, and the capture efficiency was about 100%. The IQV range hood exhibited a high ability to resist the influences of lateral and frontal drafts. The capture efficiency of the IQV range hood operated at the suction flow rate 5 to 9 m(3)/min is higher than that of the conventional range hood operated at 11 to 15 m(3)/min. PMID- 25436892 TI - A mathematical model for eph/ephrin-directed segregation of intermingled cells. AB - Eph receptors, the largest family of receptor tyrosine kinases, control cell-cell adhesion/de-adhesion, cell morphology and cell positioning through interaction with cell surface ephrin ligands. Bi-directional signalling from the Eph and ephrin complexes on interacting cells have a significant role in controlling normal tissue development and oncogenic tissue patterning. Eph-mediated tissue patterning is based on the fine-tuned balance of adhesion and de-adhesion reactions between distinct Eph- and ephrin-expressing cell populations, and adhesion within like populations (expressing either Eph or ephrin). Here we develop a stochastic, Lagrangian model that is based on Eph/ephrin biology: incorporating independent Brownian motion to describe cell movement and a deterministic term (the drift term) to represent repulsive and adhesive interactions between neighbouring cells. Comparison between the experimental and computer simulated Eph/ephrin cell patterning events shows that the model recapitulates the dynamics of cell-cell segregation and cell cluster formation. Moreover, by modulating the term for Eph/ephrin-mediated repulsion, the model can be tuned to match the actual behaviour of cells with different levels of Eph expression or activity. Together the results of our experiments and modelling suggest that the complexity of Eph/ephrin signalling mechanisms that control cell cell interactions can be described well by a mathematical model with a single term balancing adhesion and de-adhesion between interacting cells. This model allows reliable prediction of Eph/ephrin-dependent control of cell patterning behaviour. PMID- 25436894 TI - Comparison of self-reported alcohol consumption to phosphatidylethanol measurement among HIV-infected patients initiating antiretroviral treatment in southwestern Uganda. AB - BACKGROUND: Alcohol consumption among HIV-infected patients may accelerate HIV disease progression or reduce antiretroviral therapy adherence. Self-reported alcohol use is frequently under-reported due to social desirability and recall bias. The aim of this study was to compare self-reported alcohol consumption to phosphatidylethanol (PEth), a biomarker of alcohol consumption, and to estimate the correlation between multiple measures of self-reported alcohol consumption with PEth. METHODS: The Uganda AIDS Rural Treatment Outcomes (UARTO) cohort is located in southwestern Uganda and follows patients on ART to measure treatment outcomes. Patients complete standardized questionnaires quarterly including questions on demographics, health status and alcohol consumption. Baseline dried blood spots (DBS) were collected and retrieved to measure PEth. RESULTS: One hundred fifty samples were tested, and 56 (37.3%) were PEth positive (>=8 ng/mL). Of those, 51.7% did not report alcohol use in the past month. Men were more likely to under-report compared to women, OR 2.9, 95% CI = 1.26, 6.65) and those in the higher economic asset categories were less likely to under-report compared to those in the lowest category (OR = 0.41 95% CI: 0.17, 0.94). Among self reported drinkers (n = 31), PEth was highly correlated with the total number of drinking days in the last 30 (Spearman R = 0.73, p<0.001). CONCLUSIONS: Approximately half of HIV infected patients initiating ART and consuming alcohol under-report their use of alcohol. Given the high prevalence, clinicians should assess all patients for alcohol use with more attention to males and those in lower economic asset categories who deny alcohol use. Among those reporting current drinking, self-reported drinking days is a useful quantitative measure. PMID- 25436898 TI - Management of hydrosalpinx before IVF: a literature review. AB - Hydrosalpinx has a detrimental effect on the outcome of in vitro fertilization (IVF). Surgical intervention such as salpingectomy or tubal occlusion before IVF improves the outcome of IVF, but these procedures are often contraindicated in women with dense pelvic adhesions. Thus, it is worthwhile to search minimally invasive alternative therapies. The main objective of this review is to assess and compare the value of all the therapeutic options for hydrosalpinx before IVF. The results of the following procedures were compared: the laparoscopic treatments (salpingectomy/proximal tubal occlusion), the hysteroscopic insertion of device achieving tubal occlusion, the tuberous sclerosis and the aspiration of hydrosalpingeal fluid at the time of IVF procedure. Laparoscopic surgical treatment should be considered for all women with hydrosalpinx before IVF. Whenever laparoscopy is not recommended, hysteroscopic insertion of device seems the most effective option for management of hydrosalpinx before IVF. PMID- 25436899 TI - Differences in phonologic and prosodic abilities in children with phonological language impairment and phonological-grammatical language impairment assessed with non-word repetition. AB - Prosody can be described as the rhythmic, dynamic, and melodic aspects of language. Swedish has a relatively complex prosodic system compared to, for example, English. A large percentage of Swedish children with language impairment show prosodic problems to some extent. In the present study, non-word repetition was used to assess the phonological and prosodic abilities in children with phonological language impairment and children with phonological-grammatical language impairment. In the study, 10 children with phonological language impairment and 14 children with phonological-grammatical language impairment from 4;3 to 6;2 years of age participated. All children heard the same recorded non words and words. The group with phonological language impairment received higher scores in all variables, compared to the group with phonological-grammatical language impairment. The results showed significant differences between the groups regarding production of vowels correct in words and production of phonemes correct in non-words as well as production of unstressed syllables in non-words and production of correct stress in non-words. Percent correctly produced vowels in words, but not in non-words, correlated significantly with grammatical ability. PMID- 25436896 TI - Wild type RTA and less toxic variants have distinct requirements for Png1 for their depurination activity and toxicity in Saccharomyces cerevisiae. AB - Ricin A chain (RTA) undergoes retrograde trafficking and is postulated to use components of the endoplasmic reticulum (ER) associated degradation (ERAD) pathway to enter the cytosol to depurinate ribosomes. However, it is not known how RTA evades degradation by the proteasome after entry into the cytosol. We observed two distinct trafficking patterns among the precursor forms of wild type RTA and nontoxic variants tagged with enhanced green fluorescent protein (EGFP) at their C-termini in yeast. One group, which included wild type RTA, underwent ER-to-vacuole transport, while another group, which included the G83D variant, formed aggregates in the ER and was not transported to the vacuole. Peptide: N glycanase (Png1), which catalyzes degradation of unfolded glycoproteins in the ERAD pathway affected depurination activity and toxicity of wild type RTA and G83D variant differently. PreG83D variant was deglycosylated by Png1 on the ER membrane, which reduced its depurination activity and toxicity by promoting its degradation. In contrast, wild type preRTA was deglycosylated by the free pool of Png1 in the cytosol, which increased its depurination activity, possibly by preventing its degradation. These results indicate that wild type RTA has a distinct requirement for Png1 compared to the G83D variant and is deglycosylated by Png1 in the cytosol as a possible strategy to avoid degradation by the ERAD pathway to reach the ribosome. PMID- 25436900 TI - Alcohol screening in people with cognitive impairment: an exploratory study. AB - OBJECTIVE: Alcohol misuse can coexist with and/or contribute to the development of cognitive impairment in the older adult population but continues to be underestimated and undetected in older people. This study aimed to examine the feasibility and acceptability of routine screening for alcohol misuse in a small sample of older people with cognitive impairment receiving services in memory clinics. METHODS: This study employed a qualitative and exploratory design, using a convenience sample of individuals attending a memory clinic in England. Ten service users older than 65 with a diagnosis of cognitive impairment (i.e., mild cognitive impairment or dementia) took part in the study. Individuals who met inclusion criteria were invited to take part in an hour-long interview, which included the interviewer administering the alcohol screening tools. Interview transcripts were analyzed using thematic analysis. RESULTS: Participants were able to engage with the screening tools and could, with assistance, complete them in a collaborative and timely manner without distress. All participants reported that these tools were acceptable as part of the clinic assessment. Administering the screening tools was not time-consuming or difficult, making their use feasible within the memory clinic setting. While there were some challenges (e.g., arithmetic, recall, language problems), these challenges could be overcome with the aid of the person administering the screening tool using standardized techniques for assessment administration. CONCLUSIONS: Routine screening for alcohol misuse in older people with cognitive impairment receiving services in memory clinics is feasible and acceptable. The process of completing alcohol screening tools with older adults receiving services at memory clinics may increase awareness of the potential impact of alcohol on cognitive functioning and provide practitioners with an opportunity to educate service users about the ways that their drinking is affecting their memory. Several techniques to facilitate completion of screening tools were identified. Future research should evaluate the reliability and validity of alcohol screening tools with older people through corroborating screening results with other assessment methods. PMID- 25436901 TI - Factors facilitating and constraining the scaling up of an evidence-based strategy of community-based primary care: management perspectives from northern Ghana. AB - From 1994 to 2003, the government of Ghana investigated the child survival and fertility impacts of community-based primary care nurses and volunteer mobilisation efforts. This study, known as the Navrongo Project, demonstrated improved health outcomes and was scaled-up as the Community-based Health Planning and Services (CHPS) Initiative. Studies suggest that scaled-up CHPS services have not fully replicated the impact of the Project. This study investigates implementation challenges that could explain this atrophy by assembling the perspectives of health care managers that have experience with both the Project and CHPS. Data from in-depth interviews of health managers are analysed using deductive content analysis. Respondents exhibited a consistent vision of doorstep services with regard to the Project and CHPS. They shared the perspective that while scale-up has progressed slowly, it has expanded the range of services provided. Respondents felt, however, that the original emphasis on community involvement has atrophied with scale-up and that current operations are managed less rigorously than during the Project. Thus, while the expanded scope of CHPS has increased access to health care, the original focus on community engagement has faded. The original Project leadership strategy merits review for ways to integrate leadership development into scale-up activities. PMID- 25436902 TI - Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. AB - BACKGROUND: The introduction of enteral feeds for very preterm (less than 32 weeks' gestation) or very low birth weight (VLBW; less than 1500 g) infants is often delayed for several days or longer after birth due to concern that early introduction may not be tolerated and may increase the risk of necrotising enterocolitis (NEC). However, delaying enteral feeding could diminish the functional adaptation of the gastrointestinal tract and prolong the need for parenteral nutrition with its attendant infectious and metabolic risks. OBJECTIVES: To determine the effect of delayed introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in very preterm or VLBW infants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2014, Issue 8), MEDLINE (1966 to September 2014), EMBASE (1980 to September 2014), CINAHL (1982 to September 2014), conference proceedings and previous reviews. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials that assessed the effect of delayed (more than four days after birth) versus earlier introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in very preterm or VLBW infants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias and undertook data extraction. We analysed the treatment effects in the individual trials and reported the risk ratio (RR) and risk difference for dichotomous data and mean difference for continuous data, with respective 95% confidence intervals (CI). We used a fixed-effect model in meta-analyses and explored the potential causes of heterogeneity in sensitivity analyses. MAIN RESULTS: We identified nine randomised controlled trials in which 1106 infants participated. Few participants were extremely preterm (less 28 weeks' gestation) or extremely low birth weight (less than 1000 g). The trials defined delayed introduction of progressive enteral feeds as later than four to seven days after birth and early introduction as four days or less after birth. Meta-analyses did not detect statistically significant effects on the risk of NEC (typical RR 0.93, 95% CI 0.64 to 1.34; 8 trials; 1092 infants) or all-cause mortality (typical RR 1.18, 95% CI 0.75 to 1.88; 7 trials; 967 infants). Four of the trials restricted participation to growth-restricted infants with Doppler ultrasound evidence of abnormal fetal circulatory distribution or flow. Planned subgroup analyses of these trials found no statistically significant effects on the risk of NEC or all-cause mortality. Infants who had delayed introduction of enteral feeds took longer to establish full enteral feeding (reported median differences two to four days). AUTHORS' CONCLUSIONS: The evidence available from randomised controlled trials suggested that delaying the introduction of progressive enteral feeds beyond four days after birth did not reduce the risk of developing NEC in very preterm or VLBW infants, including growth-restricted infants. Delaying the introduction of progressive enteral feeds resulted in a few days' delay in establishing full enteral feeds but the clinical importance of this effect was unclear. The applicability of these findings to extremely preterm or extremely low birth weight was uncertain. Further randomised controlled trials in this population may be warranted. PMID- 25436903 TI - A newly developed mouse monoclonal SOX10 antibody is a highly sensitive and specific marker for malignant melanoma, including spindle cell and desmoplastic melanomas. AB - CONTEXT: Recent immunohistochemical studies have demonstrated Sry-related HMG-Box gene 10 (SOX10) expression in malignant melanomas, malignant peripheral nerve sheath tumors, a subset of breast carcinomas, and gliomas. SOX10 has shown important clinical utility in its ability to detect desmoplastic and spindle cell melanomas. To date, most publications have employed a research use-only goat polyclonal SOX10 antibody for immunohistochemical staining. OBJECTIVE: To describe the development of a new mouse monoclonal SOX10 antibody (BC34) and evaluate its immunohistochemical staining profile in a wide range of normal and neoplastic tissues, with an emphasis on melanoma. DESIGN: SOX10 antibody was optimized for staining using a polymer detection system and visualization with diaminobenzidine. RESULTS: In normal tissues, SOX10 was expressed in skin melanocytes and eccrine cells, breast myoepithelial and lobular epithelial cells, salivary gland myoepithelial cells, peripheral nerve Schwann cells, and central nervous system glial cells. SOX10 was expressed in 238 of 257 melanomas (92.6%), including 50 of 51 of both spindle cell and desmoplastic melanomas (98%). SOX10 was expressed in 100% of nevi (20 of 20) and schwannomas (28 of 28). In other neoplasms, SOX10 was expressed in 18 of 109 invasive ductal breast carcinomas (16.5%). All other carcinomas were negative for SOX10. SOX10 was identified in 25 of 52 central nervous system neoplasms, primarily in astrocytomas (22 of 41; 53.7%), and in 4 of 99 various sarcomas examined (4.0%). CONCLUSIONS: The newly developed mouse monoclonal SOX10 antibody BC34 is highly sensitive and specific for malignant melanoma, including desmoplastic and spindle cell variants, and appears highly suitable for clinical use. PMID- 25436904 TI - The Cancer Genomics Resource List 2014. AB - CONTEXT: Genomic sequencing for cancer is offered by commercial for-profit laboratories, independent laboratory networks, and laboratories in academic medical centers and integrated health networks. The variability among the tests has created a complex, confusing environment. OBJECTIVE: To address the complexity, the Personalized Health Care (PHC) Committee of the College of American Pathologists proposed the development of a cancer genomics resource list (CGRL). The goal of this resource was to assist the laboratory pathology and clinical oncology communities. DESIGN: The PHC Committee established a working group in 2012 to address this goal. The group consisted of site-specific experts in cancer genetic sequencing. The group identified current next-generation sequencing (NGS)-based cancer tests and compiled them into a usable resource. The genes were annotated by the working group. The annotation process drew on published knowledge, including public databases and the medical literature. RESULTS: The compiled list includes NGS panels offered by 19 laboratories or vendors, accompanied by annotations. The list has 611 different genes for which NGS-based mutation testing is offered. Surprisingly, of these 611 genes, 0 genes were listed in every panel, 43 genes were listed in 4 panels, and 54 genes were listed in 3 panels. In addition, tests for 393 genes were offered by only 1 or 2 institutions. Table 1 provides an example of gene mutations offered for breast cancer genomic testing with the annotation as it appears in the CGRL 2014. CONCLUSIONS: The final product, referred to as the Cancer Genomics Resource List 2014, is available as supplemental digital content. PMID- 25436905 TI - Human papillomavirus testing and reporting rates in 2012: results of a College of American Pathologists national survey. AB - CONTEXT: College of American Pathologists (CAP) surveys are used to establish national benchmarks for laboratory parameters. OBJECTIVE: To evaluate changes in laboratory human papillomavirus (HPV) testing patterns in laboratories incorporating HPV testing with Papanicolaou tests in 2012. DESIGN: Data were analyzed from the CAP HPV Supplemental Questionnaire distributed to 1771 laboratories participating in either CAP HPV or CAP Papanicolaou proficiency testing in 2013. RESULTS: A total of 1022 laboratories (58%) responded. There were more high-risk (HR) HPV tests performed per institution as compared to previous surveys. There were more HPV tests performed within an institution as compared to previous surveys. Hybrid Capture 2 (HC2) remains the most common method (42.4%, 239 of 564); Cervista and cobas methods are used in 37.2% (210 of 564) and 14.9% (84 of 564) of laboratories, respectively. Human papillomavirus testing is offered as a reflex test after a Papanicolaou test result of atypical squamous cells of undetermined significance (ASC-US) in 89.6% of laboratories (476 of 531); as a cotest for women aged 30 years and older in 60.3% (404 of 531); as reflex testing after atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) in 42.7% (320 of 531); and as reflex testing after atypical glandular cells (AGC) in 27.3% (145 of 531). The HPV positive rates for ASC-US and ASC-H were similar in 2012 and 2006. Cervista (49.2%, 88 of 179) and Roche cobas (27.4%, 49 of 179) are the most common methods used for genotyping. Most laboratories use the CAP Human Papillomavirus for Cytology Program for proficiency testing. CONCLUSIONS: There was an increase in annual volume of HR-HPV testing with a shift toward in-house HR-HPV testing. Genotyping volumes also increased. HC2 and Cervista are most commonly used, with an increasing volume of Roche cobas testing. The most common indication for HPV testing among all laboratories was ASC-US reflex testing, but an increase in HPV cotesting was observed. The data provide an update into persisting and newer trends in HPV testing practices. PMID- 25436906 TI - Implication of TLR- but not of NOD2-signaling pathways in dendritic cell activation by group B Streptococcus serotypes III and V. AB - Group B Streptococcus (GBS) is an important agent of life-threatening invasive infection. It has been previously shown that encapsulated type III GBS is easily internalized by dendritic cells (DCs), and that this internalization had an impact on cytokine production. The receptors underlying these processes are poorly characterized. Knowledge on the mechanisms used by type V GBS to activate DCs is minimal. In this work, we investigated the role of Toll-like receptor (TLR)/MyD88 signaling pathway, the particular involvement of TLR2, and that of the intracellular sensing receptor NOD2 in the activation of DCs by types III and V GBS. The role of capsular polysaccharide (CPS, one of the most important GBS virulence factors) in bacterial-DC interactions was evaluated using non encapsulated mutants. Despite differences in the role of CPS between types III and V GBS in bacterial internalization and intracellular survival, no major differences were observed in their capacity to modulate release of cytokines by DC. For both serotypes, CPS had a minor role in this response. Production of cytokines by DCs was shown to strongly rely on MyD88-dependent signaling pathways, suggesting that DCs recognize GBS and become activated mostly through TLR signaling. Yet, GBS-infected TLR2-/- DCs only showed a partial reduction in the production of IL-6 and CXCL1 compared to control DCs. Surprisingly, CXCL10 release by type III or type V GBS-infected DCs was MyD88-independent. No differences in DC activation were observed between NOD2-/- and control DCs. These results demonstrate the involvement of various receptors and the complexity of the cytokine production pathways activated by GBS upon DC infection. PMID- 25436907 TI - Reversible blockade of complex I or inhibition of PKCbeta reduces activation and mitochondria translocation of p66Shc to preserve cardiac function after ischemia. AB - AIM: Excess mitochondrial reactive oxygen species (mROS) play a vital role in cardiac ischemia reperfusion (IR) injury. P66Shc, a splice variant of the ShcA adaptor protein family, enhances mROS production by oxidizing reduced cytochrome c to yield H2O2. Ablation of p66Shc protects against IR injury, but it is unknown if and when p66Shc is activated during cardiac ischemia and/or reperfusion and if attenuating complex I electron transfer or deactivating PKCbeta alters p66Shc activation during IR is associated with cardioprotection. METHODS: Isolated guinea pig hearts were perfused and subjected to increasing periods of ischemia and reperfusion with or without amobarbital, a complex I blocker, or hispidin, a PKCbeta inhibitor. Phosphorylation of p66Shc at serine 36 and levels of p66Shc in mitochondria and cytosol were measured. Cardiac functional variables and redox states were monitored online before, during and after ischemia. Infarct size was assessed in some hearts after 120 min reperfusion. RESULTS: Phosphorylation of p66Shc and its translocation into mitochondria increased during reperfusion after 20 and 30 min ischemia, but not during ischemia only, or during 5 or 10 min ischemia followed by 20 min reperfusion. Correspondingly, cytosolic p66Shc levels decreased during these ischemia and reperfusion periods. Amobarbital or hispidin reduced phosphorylation of p66Shc and its mitochondrial translocation induced by 30 min ischemia and 20 min reperfusion. Decreased phosphorylation of p66Shc by amobarbital or hispidin led to better functional recovery and less infarction during reperfusion. CONCLUSION: Our results show that IR activates p66Shc and that reversible blockade of electron transfer from complex I, or inhibition of PKCbeta activation, decreases p66Shc activation and translocation and reduces IR damage. These observations support a novel potential therapeutic intervention against cardiac IR injury. PMID- 25436908 TI - Transferable coarse-grained potential for de novo protein folding and design. AB - Protein folding and design are major biophysical problems, the solution of which would lead to important applications especially in medicine. Here we provide evidence of how a novel parametrization of the Caterpillar model may be used for both quantitative protein design and folding. With computer simulations it is shown that, for a large set of real protein structures, the model produces designed sequences with similar physical properties to the corresponding natural occurring sequences. The designed sequences require further experimental testing. For an independent set of proteins, previously used as benchmark, the correct folded structure of both the designed and the natural sequences is also demonstrated. The equilibrium folding properties are characterized by free energy calculations. The resulting free energy profiles not only are consistent among natural and designed proteins, but also show a remarkable precision when the folded structures are compared to the experimentally determined ones. Ultimately, the updated Caterpillar model is unique in the combination of its fundamental three features: its simplicity, its ability to produce natural foldable designed sequences, and its structure prediction precision. It is also remarkable that low frustration sequences can be obtained with such a simple and universal design procedure, and that the folding of natural proteins shows funnelled free energy landscapes without the need of any potentials based on the native structure. PMID- 25436909 TI - Functional characterization of a Nudix hydrolase AtNUDX8 upon pathogen attack indicates a positive role in plant immune responses. AB - Nudix hydrolases comprise a large gene family of twenty nine members in Arabidopsis, each containing a conserved motif capable of hydrolyzing specific substrates like ADP-glucose and NADH. Until now only two members of this family, AtNUDX6 and AtNUDX7, have been shown to be involved in plant immunity. RPP4 is a resistance gene from a multigene family that confers resistance to downy mildew. A time course expression profiling after Hyaloperonospora arabidopsidis inoculation in both wild-type (WT) and the rpp4 mutant was carried out to identify differentially expressed genes in RPP4-mediated resistance. AtNUDX8 was one of several differentially expressed, downregulated genes identified. A T-DNA knockout mutant (KO-nudx8) was obtained from a Salk T-DNA insertion collection, which exhibited abolished AtNUDX8 expression. The KO-nudx8 mutant was infected separately from the oomycete pathogen Hpa and the bacterial pathogen Pseudomonas syringae pv. maculicola ES4326. The mutant displayed a significantly enhanced disease susceptibility to both pathogens when compared with the WT control. We observed a small, stunted phenotype for KO-nudx8 mutant plants when grown over a 12/12 hour photoperiod but not over a 16/8 hour photoperiod. AtNUDX8 expression peaked at 8 hours after the lights were turned on and this expression was significantly repressed four-fold by salicylic acid (SA). The expression of three pathogen-responsive thioredoxins (TRX-h2, TRX-h3 and TRX-h5) were downregulated at specific time points in the KO-nudx8 mutant when compared with the WT. Furthermore, KO-nudx8 plants like the npr1 mutant, displayed SA hypersensitivity. Expression of a key SA biosynthetic gene ICS1 was repressed at specific time points in the KO-nudx8 mutant suggesting that AtNUDX8 is involved in SA signaling in plants. Similarly, NPR1 and PR1 transcript levels were also downregulated at specific time points in the KO-nudx8 mutant. This study shows that AtNUDX8 is involved in plant immunity as a positive regulator of defense in Arabidopsis. PMID- 25436910 TI - Associations between social support and condom use among commercial sex workers in China: a cross-sectional study. AB - OBJECTIVE: The aim of this study was to investigate the association between social support and AIDS high-risk behaviors in commercial sex workers (CSWs) in China. METHODS: A cross-sectional study was performed based on a convenience sample. Data were collected through questionnaire interviews including information about social demographic characteristics, the Social Support Rating Scale (SSRS) and AIDS knowledge. Multiple logistic regression was performed to evaluate the association between social support and AIDS high-risk behaviors, specifically condom use during commercial sex. RESULTS: A total of 581 commercial sex workers from 4 counties in East China participated in the study. The majority of the participants were 15 to 30 years old (79.7%). Sources of individual and family support were mainly provided by their parents (50.3%), relatives and friends (46.3%), spouses (18.4%), respectively. Univariate analysis revealed that marital status, hobbies, smoking habit, individual monthly income and family monthly income were all significantly correlated with current levels of social support being received (P = 0.04, P = 0.00, P = 0.01, P = 0.01, P = 0.01, respectively). Furthermore, Multiple logistic regression analysis indicated that after adjusting for confounding factors, high levels of social support were significantly correlated with increased condom use at the last sexual encounter (P = 0.02, OR = 1.86, 95%CI: 1.10-3.16); and consistently in the past month with clients (P = 0.03, OR = 2.10, 95%CI: 1.09-4.04). CONCLUSION: CSWs with high levels of social support are more likely to use condoms during commercial sex. This suggests that increasing social support can potentially reduce AIDS-related high-risk behaviors and accordingly play an important role in AIDS prevention. PMID- 25436911 TI - Altercentric intrusions from multiple perspectives: beyond dyads. AB - Recent findings suggest that in dyadic contexts observers rapidly and involuntarily process the visual perspective of others and cannot easily resist interference from their viewpoint. To investigate whether spontaneous perspective taking extends beyond dyads, we employed a novel visual perspective task that required participants to select between multiple competing perspectives. Participants were asked to judge their own perspective or the visual perspective of one or two avatars who either looked at the same objects or looked at different objects. Results indicate that when a single avatar was present in the room, participants processed the irrelevant perspective even when it interfered with participants' explicit judgments about the relevant perspective. A similar interference effect was observed when two avatars looked at the same discs, but not when they looked at different discs. Indeed, when the two avatars looked at different discs, the interference from the irrelevant perspective was significantly reduced. This is the first evidence that the number and orientation of agents modulate spontaneous perspective taking in non-dyadic contexts: observers may efficiently compute another's perspective, but in presence of more individuals holding discrepant perspectives, they may not spontaneously track multiple viewpoints. These findings are discussed in relation to the hypothesis that perspective calculation occurs in an effortless and automatic manner. PMID- 25436912 TI - Patient perspectives on post-discharge surgical site infections: towards a patient-centered mobile health solution. AB - BACKGROUND: Post-discharge surgical site infections (SSI) are a major source of morbidity, expense and anxiety for patients. However, patient perceptions about barriers experienced while seeking care for post-discharge SSI have not been assessed in depth. We explored patient experience of SSI and openness to a mobile health (mHealth) wound monitoring "app" as a novel solution to address this problem. METHODS: Mixed method design with semi-structured interviews and surveys. Participants were patients who had post-discharge surgical wound complications after undergoing operations with high risk of SSI, including open colorectal or ventral hernia repair surgery. The study was conducted at two affiliated teaching hospitals, including an academic medical center and a level 1 trauma center. RESULTS: From interviews with 13 patients, we identified 3 major challenges that impact patients' ability to manage post-discharge surgical wound complications, including required knowledge for wound monitoring from discharge teaching, self-efficacy for wound monitoring at home, and accessible communication with their providers about wound concerns. Patients found an mHealth wound monitoring application highly acceptable and articulated its potential to provide more frequent, thorough, and convenient follow-up that could reduce post-discharge anxiety compared to the current practice. Major concerns with mHealth wound monitoring were lack of timely response from providers and inaccessibility due to either lack of an appropriate device or usability challenges. CONCLUSIONS: Our findings reveal gaps and frustrations with post discharge care after surgery which could negatively impact clinical outcomes and quality of life. To address these issues, we are developing mPOWEr, a patient centered mHealth wound monitoring application for patients and providers to collaboratively bridge the care transition between hospital and home. PMID- 25436914 TI - Co-occurring motor, language and emotional-behavioral problems in children 3-6 years of age. AB - PURPOSE: Developmental Coordination Disorder (DCD) has been shown to co-occur with behavioral and language problems in school-aged children, but little is known as to when these problems begin to emerge, or if they are inherent in children with DCD. The purpose of this study was to determine if deficits in language and emotional-behavioral problems are apparent in preschool-aged children with movement difficulties. METHOD: Two hundred and fourteen children (mean age 4years 11months, SD 9.8months, 103 male) performed the Movement Assessment Battery for Children 2nd Edition (MABC-2). Children falling at or below the 16th percentile were classified as being at risk for movement difficulties (MD risk). Auditory comprehension and expressive communication were examined using the Preschool Language Scales 4th Edition (PLS-4). Parent-reported emotional and behavioral problems were assessed using the Child Behavior Checklist (CBCL). RESULTS: Preschool children with diminished motor coordination (n=37) were found to have lower language scores, higher externalizing behaviors in the form of increased aggression, as well as increased withdrawn and other behavior symptoms compared with their typically developing peers. CONCLUSIONS: Motor coordination, language and emotional-behavioral difficulties tend to co occur in young children aged 3-6years. These results highlight the need for early intervention. PMID- 25436913 TI - Assessing sensor accuracy for non-adjunct use of continuous glucose monitoring. AB - BACKGROUND: The level of continuous glucose monitoring (CGM) accuracy needed for insulin dosing using sensor values (i.e., the level of accuracy permitting non adjunct CGM use) is a topic of ongoing debate. Assessment of this level in clinical experiments is virtually impossible because the magnitude of CGM errors cannot be manipulated and related prospectively to clinical outcomes. MATERIALS AND METHODS: A combination of archival data (parallel CGM, insulin pump, self monitoring of blood glucose [SMBG] records, and meals for 56 pump users with type 1 diabetes) and in silico experiments was used to "replay" real-life treatment scenarios and relate sensor error to glycemic outcomes. Nominal blood glucose (BG) traces were extracted using a mathematical model, yielding 2,082 BG segments each initiated by insulin bolus and confirmed by SMBG. These segments were replayed at seven sensor accuracy levels (mean absolute relative differences [MARDs] of 3-22%) testing six scenarios: insulin dosing using sensor values, threshold, and predictive alarms, each without or with considering CGM trend arrows. RESULTS: In all six scenarios, the occurrence of hypoglycemia (frequency of BG levels <=50 mg/dL and BG levels <=39 mg/dL) increased with sensor error, displaying an abrupt slope change at MARD =10%. Similarly, hyperglycemia (frequency of BG levels >=250 mg/dL and BG levels >=400 mg/dL) increased and displayed an abrupt slope change at MARD=10%. When added to insulin dosing decisions, information from CGM trend arrows, threshold, and predictive alarms resulted in improvement in average glycemia by 1.86, 8.17, and 8.88 mg/dL, respectively. CONCLUSIONS: Using CGM for insulin dosing decisions is feasible below a certain level of sensor error, estimated in silico at MARD=10%. In our experiments, further accuracy improvement did not contribute substantively to better glycemic outcomes. PMID- 25436916 TI - Human pelvis motions when walking and when riding a therapeutic horse. AB - A prevailing rationale for equine assisted therapies is that the motion of a horse can provide sensory stimulus and movement patterns that mimic those of natural human activities such as walking. The purpose of this study was to quantitatively measure and compare human pelvis motions when walking to those when riding a horse. Six able-bodied children (inexperienced riders, 8-12years old) participated in over-ground trials of self-paced walking and leader-paced riding on four different horses. Five kinematic measures were extracted from three-dimensional pelvis motion data: anteroposterior, superoinferior, and mediolateral translations, list angle about the anteroposterior axis, and twist angle about the superoinferior axis. There was generally as much or more variability in motion range observed between riding on the different horses as between riding and walking. Pelvis trajectories exhibited many similar features between walking and riding, including distorted lemniscate patterns in the transverse and frontal planes. In the sagittal plane the pelvis trajectory during walking exhibited a somewhat circular pattern whereas during riding it exhibited a more diagonal pattern. This study shows that riding on a horse can generate movement patterns in the human pelvis that emulate many, but not all, characteristics of those during natural walking. PMID- 25436915 TI - Postural sway and integration of proprioceptive signals in subjects with LBP. AB - Patients with non-specific low back pain (LBP) may use postural control strategies that differ from healthy subjects. To study these possible differences, we measured the amount and structure of postural sway, and the response to muscle vibration in a working cohort of 215 subjects. Subjects were standing on a force plate in bipedal stance. In the first trial the eyes were open, no perturbation applied. In the following 6 trials, vision was occluded and subjects stood under various conditions of vibration/no vibration of the lumbar spine or m. Triceps Surae (TSM) on firm surface and on foam surface. We performed a factor analysis to reduce the large amount of variables that are available to quantify all effects. Subjects with LBP showed the same amount of sway as subjects without LBP, but the structure of their sway pattern was less regular with higher frequency content. Subjects with LBP also showed a smaller response to TSM vibration, and a slower balance recovery after cessation of vibration when standing on a solid surface. There was a weak but significant association between smaller responses to TSM vibration and an irregular, high frequency sway pattern, independent from LBP. A model for control of postural sway is proposed. This model suggests that subjects with LBP use more co-contraction and less cognitive control, to maintain a standing balance when compared to subjects without LBP. In addition, a reduced weighting of proprioceptive signals in subjects with LBP is suggested as an explanation for the findings in this study. PMID- 25436917 TI - Downregulation of adipose triglyceride lipase promotes cardiomyocyte hypertrophy by triggering the accumulation of ceramides. AB - Adipose triglyceride lipase (ATGL), the rate-limiting enzyme of triglyceride (TG) hydrolysis, plays an important role in TG metabolism. ATGL knockout mice suffer from TG accumulation and die from heart failure. However, the mechanisms underlying cardiac hypertrophy caused by ATGL dysfunction remain unknown. In this study, we found that ATGL expression declined in pressure overload-induced cardiac hypertrophy in vivo and phenylephrine (PE)-induced cardiomyocyte hypertrophy in vitro. ATGL knockdown led to cardiomyocyte hypertrophy, while ATGL overexpression prevented PE-induced hypertrophy. In addition, ATGL downregulation increased but ATGL overexpression reduced the contents of ceramide, which has been proved to be closely associated with cardiac hypertrophy. Moreover, the accumulation of ceramide was due to elevation of free fatty acids in ATGL knockdown cardiomyocytes, which could be explained by the reduced activity of peroxisome proliferator-activated receptor (PPAR) alpha leading to imbalance of fatty acid uptake and oxidation. These observations suggest that downregulation of ATGL causes the decreased PPARalpha activity which results in the imbalance of FA uptake and oxidation, elevating intracellular FFA contents to promote the accumulation of ceramides, and finally inducing cardiac hypertrophy. Upregulation of ATGL could be a strategy for ameliorating lipotoxic damage in cardiac hypertrophy. PMID- 25436918 TI - Erythrodermic Leukemia Cutis in a Patient With Pre-B-Cell Acute Lymphoblastic Leukemia. AB - The clinical differential diagnosis of erythroderma is extensive and includes both benign and malignant causes. The authors present an exceptional case of erythroderma secondary to pre-B-cell lymphoblastic leukemia cutis, with diagnostic findings on biopsy. PMID- 25436919 TI - Epidermolytic Hyperkeratosis: One More Pattern of Grover Disease. PMID- 25436921 TI - Structural diversity and photocatalytic properties of Cd(II) coordination polymers constructed by a flexible V-shaped bipyridyl benzene ligand and dicarboxylate derivatives. AB - Hydrothermal reactions of Cd(OAc)2.2H2O with a flexible V-shaped bipyridyl benzene ligand and five benzenedicarboxylic acid derivatives gave rise to five new coordination polymers i.e., [Cd(1,4-BDC)(bpmb)(H2O)]n (1), {[Cd(1,3 BDC)(bpmb)].0.125H2O}n (2), [Cd2(5-Me-1,3-BDC)2(bpmb)2]n (3), [Cd(5-NO2-1,3 BDC)(bpmb)(H2O)]n (4) and [Cd(5-OH-1,3-BDC)(bpmb)(H2O)]n (5) (bpmb = 1,3 bis(pyridine-3-ylmethoxy)benzene, 1,4-H2BDC = 1,4-benzenedicarboxylic acid, 1,3 H2BDC = 1,3-benzenedicarboxylic acid, 5-Me-1,3-H2BDC = 5-methyl-1,3 benzenedicarboxylic acid, 5-NO2-1,3-H2BDC = 5-nitro-1,3-benzenedicarboxylic acid, 5-OH-1,3-H2BDC = 5-hydroxy-1,3-benzenedicarboxylic acid). Their structures have been determined by single-crystal X-ray diffraction analyses, elemental analyses, IR spectra, powder X-ray diffraction (PXRD) and thermogravimetric analyses (TGA). Compound 1 is a two-fold interpenetrating network showing the coexistence of polyrotaxane and polycatenane characters. Compounds 2 and 3 exhibit similar 2D (3,5)-connected (4(2).6(7).8)(4(2).6) nets in which the bpmb ligands work as lockers in interlocking 1D [Cd(1,3-BDC/5-Me-1,3-BDC)]n chains. Compound 4 shows a 2D 4-connected (6(6)) sandwich-like structure with differently oriented [Cd(5-NO2 1,3-BDC)]n chains. Compound 5 is a 3D supramolecular pcu net based on a 1D ladder shaped chain. These results suggest that the substituted positions of carboxylate groups and changes in substituted R groups in the 5-position of BDC ligands have significant effect on the final structures. These compounds exhibited relatively good photocatalytic activity towards the degradation of methylene blue (MB) in aqueous solution under UV irradiation. Moreover, solid-state photoluminescence properties of 1-5 were also investigated. PMID- 25436920 TI - Biology of breast cancer in young women. AB - Breast cancer arising at a young age is relatively uncommon, particularly in the developed world. Several studies have demonstrated that younger patients often experience a more aggressive disease course and have poorer outcome compared to older women. Expression of key biomarkers, including endocrine receptors, HER2 and proliferation markers, appears to be different in younger patients and young women are more likely to harbor a genetic predisposition. Despite these differences, little research to date has focused on the biology of these tumors to refine prognosis, and potentially direct treatment strategies, which remain similar to those offered to older patients. Accumulating evidence suggests the differences in breast stroma in younger patients and changes that occur with pregnancy and breastfeeding likely contribute to the different biology of these tumors. Reproductive behaviors appear to impact the biology of tumors developing later in life. In addition, tumors arising during or shortly following pregnancy appear to exhibit unique biological features. In this review, we discuss our emerging understanding of the biology of breast cancer arising at a young age at both the pathologic and the genomic level. We elucidate the potential role of genomic signatures, the impact of pregnancy and breastfeeding on breast cancer biology, and how even current knowledge might advance the clinical management of young breast cancer patients. PMID- 25436924 TI - Important issues in studies dealing with total homocysteine. PMID- 25436923 TI - The need for a standardized informed consent procedure in live donor nephrectomy: a systematic review. AB - BACKGROUND: Informed consent in live donor nephrectomy is a topic of great interest. Safety and transparency are key items increasingly getting more attention from media and healthcare inspection. Because live donors are not patients, but healthy individuals undergoing elective interventions, they justly insist on optimal conditions and guaranteed safety. Although transplant professionals agree that consent should be voluntary, free of coercion, and fully informed, there is no consensus on which information should be provided, and how the donors' comprehension should be ascertained. METHODS: Comprehensive searches were conducted in Embase, Medline OvidSP, Web-of-Science, PubMed, CENTRAL (The Cochrane Library 2014, issue 1) and Google Scholar, evaluating the informed consent procedure for live kidney donation. The methodology was in accordance with the Cochrane Handbook for Interventional Systematic Reviews and written based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: The initial search yielded 1,009 hits from which 21 articles fell within the scope of this study. Procedures vary greatly between centers, and transplant professionals vary in the information they disclose. Although research has demonstrated that donors often make their decision based on moral reasoning rather than balancing risks and benefits, providing them with accurate, uniform information remains crucial because donors report feeling misinformed about or unprepared for donation. Although a standardized procedure may not provide the ultimate solution, it is vital to minimize differences in live donor education between transplant centers. CONCLUSION: There is a definite need for a guideline on how to provide information and obtain informed consent from live kidney donors to assist the transplant community in optimally preparing potential donors. PMID- 25436926 TI - Modified Bethe formula for low-energy electron stopping power without fitting parameters. AB - We propose a modified Bethe formula for low-energy electron stopping power without fitting parameters for a wide range of elements and compounds. This formula maintains the generality of the Bethe formula and gives reasonable agreement in comparing the predicted stopping powers for 15 elements and 6 compounds with the experimental data and those calculated within dielectric theory including the exchange effect. Use of the stopping power obtained from this formula for hydrogen silsesquioxane in Monte Carlo simulation gives the energy deposition distribution in consistent with the experimental data. PMID- 25436925 TI - The authors' reply. PMID- 25436927 TI - Sub-micron resolution selected area electron channeling patterns. AB - Collection of selected area channeling patterns (SACPs) on a high resolution FEG SEM is essential to carry out quantitative electron channeling contrast imaging (ECCI) studies, as it facilitates accurate determination of the crystal plane normal with respect to the incident beam direction and thus allows control the electron channeling conditions. Unfortunately commercial SACP modes developed in the past were limited in spatial resolution and are often no longer offered. In this contribution we present a novel approach for collecting high resolution SACPs (HR-SACPs) developed on a Gemini column. This HR-SACP technique combines the first demonstrated sub-micron spatial resolution with high angular accuracy of about 0.1 degrees , at a convenient working distance of 10mm. This innovative approach integrates the use of aperture alignment coils to rock the beam with a digitally calibrated beam shift procedure to ensure the rocking beam is maintained on a point of interest. Moreover a new methodology to accurately measure SACP spatial resolution is proposed. While column considerations limit the rocking angle to 4 degrees , this range is adequate to index the HR-SACP in conjunction with the pattern simulated from the approximate orientation deduced by EBSD. This new technique facilitates Accurate ECCI (A-ECCI) studies from very fine grained and/or highly strained materials. It offers also new insights for developing HR-SACP modes on new generation high-resolution electron columns. PMID- 25436928 TI - High-speed dynamic atomic force microscopy by using a Q-controlled cantilever eigenmode as an actuator. AB - We present a high-speed operating method with feedback to be used in dynamic atomic force microscope (AFM) systems. In this method we do not use an actuator that has to be employed to move the tip or the sample as in conventional AFM setups. Instead, we utilize a Q-controlled eigenmode of an AFM cantilever to perform the function of the actuator. Simulations show that even with an ordinary tapping-mode cantilever, imaging speed can be increased by about 2 orders of magnitude compared to conventional dynamic AFM imaging. PMID- 25436929 TI - Spectral analysis of the emission current noise exhibited by few layer WS2 nanosheets emitter. AB - Spectral analysis of the field emission (FE) current fluctuations has been carried out at the base pressure ~1*10(-8) mbar. The emission current stability investigated at preset value of 2 uA is characterized by 'step' like fluctuation. The spectral analysis performed on a FFT (Fast Fourier Transform) analyzer revealed that the observed noise is of 1/falpha type, with the value of alpha as ~1.05. The estimated value of alpha implies that the current fluctuations are mainly due the various processes occurring on atomic scale like adsorption, migration, and/or desorption of the residual gas species on the emitter surface. PMID- 25436930 TI - Chirality determination of quartz crystals using electron backscatter diffraction. AB - We demonstrate the determination of crystal chirality using electron backscatter diffraction (EBSD) in the scanning electron microscope. The chirality of alpha quartz as a space-group-dependent property is verified via direct comparison of experimental diffraction features to simulations using the dynamical theory of electron diffraction. PMID- 25436931 TI - Atomic resolution tomography reconstruction of tilt series based on a GPU accelerated hybrid input-output algorithm using polar Fourier transform. AB - Advances in diffraction and transmission electron microscopy (TEM) have greatly improved the prospect of three-dimensional (3D) structure reconstruction from two dimensional (2D) images or diffraction patterns recorded in a tilt series at atomic resolution. Here, we report a new graphics processing unit (GPU) accelerated iterative transformation algorithm (ITA) based on polar fast Fourier transform for reconstructing 3D structure from 2D diffraction patterns. The algorithm also applies to image tilt series by calculating diffraction patterns from the recorded images using the projection-slice theorem. A gold icosahedral nanoparticle of 309 atoms is used as the model to test the feasibility, performance and robustness of the developed algorithm using simulations. Atomic resolution in 3D is achieved for the 309 atoms Au nanoparticle using 75 diffraction patterns covering 150 degrees rotation. The capability demonstrated here provides an opportunity to uncover the 3D structure of small objects of nanometers in size by electron diffraction. PMID- 25436932 TI - Effects of hydrogen sulfide (H2S) on water intake and vasopressin and oxytocin secretion induced by fluid deprivation. AB - During dehydration, responses of endocrine and autonomic control systems are triggered by central and peripheral osmoreceptors and peripheral baroreceptors to stimulate thirst and sodium appetite. Specifically, it is already clear that endocrine system acts by secreting vasopressin (AVP), oxytocin (OT) and angiotensin II (ANG II), and that gaseous molecules, such as nitric oxide (NO) and carbon monoxide (CO), play an important role in modulating the neurohypophyseal secretion as well as ANG II production and thirst. More recently, another gas-hydrogen sulfide (H2S)-has been studied as a neuronal modulator, which is involved in hypothalamic control of blood pressure, heart frequency and temperature. In this study, we aimed to investigate whether H2S and its interaction with NO system could participate in the modulatory responses of thirst and hormonal secretion induced by fluid deprivation. For this purpose, Wistar male rats were deprived of water for 12 and 24h, and the activity of sulfide-generating enzymes was measured. Surprisingly, 24-h water deprivation increased the activity of sulfide-generating enzymes in the medial basal hypothalamus (MBH). Furthermore, the icv injection of sodium sulfide (Na2S, 260nmol), a H2S donor, reduced water intake, increased AVP, OT and CORT plasma concentrations and decreased MBH nitrate/nitrite (NOX) content of 24-h water deprived animals compared to controls. We thus suggest that H2S system has an important role in the modulation of hormonal and behavioral responses induced by 24-h fluid deprivation. PMID- 25436933 TI - Fitness level and body composition indices: cross-sectional study among Malaysian adolescent. AB - BACKGROUND: The importance of fitness level on the well-being of children and adolescent has long been recognised. The aim of this study was to investigate the fitness level of school-going Malaysian adolescent, and its association with body composition indices. METHODS: 1071 healthy secondary school students participated in the fitness assessment for the Malaysian Health and Adolescents Longitudinal Research Team (MyHEART) study. Body composition indices such as body mass index for age, waist circumference and waist height ratio were measured. Fitness level was assessed with Modified Harvard Step Test. Physical Fitness Score was calculated using total time of step test exercise and resting heart rates. Fitness levels were divided into 3 categories - unacceptable, marginally acceptable, and acceptable. Partial correlation analysis was used to determine the association between fitness score and body composition, by controlling age, gender, locality, ethnicity, smoking status and sexual maturation. Multiple regression analysis was conducted to determine which body composition was the strongest predictor for fitness. RESULTS: 43.3% of the participants were categorised into the unacceptable fitness group, 47.1% were considered marginally acceptable, and 9.6% were acceptable. There was a significant moderate inverse association (p < 0.001) between body composition with fitness score (r = -0.360, 0.413 and -0.403 for body mass index for age, waist circumference and waist height ratio, respectively). Waist circumference was the strongest and significant predictor for fitness (beta = -0.318, p = 0.002). CONCLUSION: Only 9.6% of the students were fit. There was also an inverse association between body composition and fitness score among apparently healthy adolescents, with waist circumference indicated as the strongest predictor. The low fitness level among the Malaysian adolescent should necessitate the value of healthy lifestyle starting at a young age. PMID- 25436934 TI - Arsenic trioxide suppresses transcription of hTERT through down-regulation of multiple transcription factors in HL-60 leukemia cells. AB - Acute promyelocytic leukemia (APL) is largely caused by the t(15,17) chromosome translocation, leading to the production of the PML/retinoic acid receptor alpha fusion. All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), as a monotherapy or combination therapy, have been successfully used to treat APL primarily by targeting the degradation of the fusion protein. We previously observed that ATO treatment induced cell death in APL cell line HL-60 accompanied by inhibition of the human telomere reverse transcriptase (hTERT) activity, a critical enzyme responsible for the control of cell replication and transformation in cancer cells. In the present study, we investigated the underlying mechanism by which hTERT activity is inhibited by ATO in HL-60 cells. Our results showed that ATO down-regulated the expression of hTERT at both mRNA and protein levels. Further molecular analysis revealed that the expression of four transcription factors Sp1, c-Myc, NF-kappaB and USF2, which are located in the proximate promoter region (-1126 to -47) of hTERT, was also suppressed by ATO. Notably, we observed that down-regulation of these four factors by their siRNAs potentiates ATO-induced cell growth inhibition and apoptosis. Therefore, our results provide a novel mechanism of action of ATO for the treatment of APL. PMID- 25436935 TI - Toxicity of nanoparticles embedded in paints compared to pristine nanoparticles, in vitro study. AB - The unique physicochemical properties of nanomaterials has led to an increased use in the paint and coating industry. In this study, the in vitro toxicity of three pristine ENPs (TiO2, Ag and SiO2), three aged paints containing ENPs (TiO2, Ag and SiO2) and control paints without ENPs were compared. In a first experiment, cytotoxicity was assessed using a biculture consisting of human bronchial epithelial (16HBE14o-) cells and human monocytic cells (THP-1) to determine subtoxic concentrations. In a second experiment, a new coculture model of the lung-blood barrier consisting of 16HBE14o- cells, THP-1 and human lung microvascular endothelial cells (HLMVEC) was used to study pulmonary and extrapulmonary toxicity. The results show that the pristine TiO2 and Ag ENPs have some cytotoxic effects at relative high dose, while pristine SiO2 ENPs and all aged paints with ENPs and control paints do not. In the complex triculture model of the lung-blood barrier, no considerable changes were observed after exposure to subtoxic concentration of the different pristine ENPs and paint particles. In conclusion, we demonstrated that although pristine ENPs show some toxic effects, no significant toxicological effects were observed when they were embedded in a complex paint matrix. PMID- 25436936 TI - 4-(4-carboxyphenoxy)phthalate-based coordination polymers and their application in sensing nitrobenzene. AB - Under hydro(solvo)thermal conditions, two 4-(4-carboxyphenoxy)phthalate-based three-dimensional (3-D) coordination polymers: [Cd3(cpph)2(bpa)2(H2O)].0.5H2O (cpph = 4-(4-carboxyphenoxy)phthalate, bpa = 1,2-bis(4-pyridyl)ethane) 1, and [H2(bpp)][Mn2(cpph)2(H2O)2] (bpp = 1,2-bis(4-piperidyl)propane) 2 were isolated. In both compounds, the cpph molecules extend the metal ions into a 3-D network: a (4,6)-connected net for 1 and a simple 6-connected net with a pcu topology for 2. The introduced bpa or bpp molecule stabilizes the 3-D metal-cpph architecture in the form of linker or guest molecule. The sensing ability of 1 was investigated, revealing that it can be used as a fluorescence probe to sense nitrobenzene at ppm concentrations. PMID- 25436937 TI - Pressure-enhanced surface interactions between nano-TiO2 and ionic liquid mixtures probed by high pressure IR spectroscopy. AB - The pressure-dependent interactions between the ionic liquid mixture ([MPI][I1.5]) and nano-TiO2 surfaces have been studied up to 2.5 GPa. The results of infrared spectroscopic profiles of [MPI][I1.5] and [MPI][I1.5]-nano-TiO2 indicated that no appreciable changes in the C-H stretching bands with the addition of nano-TiO2 were observed under ambient pressure. As the pressure was elevated to 0.7 GPa, the C-H stretching absorption of [MPI][I1.5] underwent band narrowing and red-shifts in frequency. In contrast to the results of [MPI][I1.5], the spectra of [MPI][I1.5]-nano-TiO2 do not show dramatic changes under high pressures. A possible explanation for this observation is the formation of certain pressure-enhanced C-H...nano-TiO2 interactions around the imidazolium C-H and alkyl C-H groups. As imidazolium C-H...I(-) is replaced by the weaker imidazolium C-H...polyiodide, the splitting of the imidazolium C-H stretching bands was observed. The experimental results indicate that both nano-TiO2 and polyiodides are capable of disturbing the self-assembly of ionic liquids. This study suggests the possibility to tune the efficiency of dye-sensitized solar cells via a high pressure method. PMID- 25436938 TI - Vascular protective effects of statin-related increase in serum 25-hydroxyvitamin D among high-risk cardiac patients. AB - AIM: To investigate the protective effects of statin-related increase in serum 25 hydroxyvitamin D [25(OH)D] on vascular function among high-risk cardiovascular patients. METHODS: We studied 443 high-risk cardiovascular patients (coronary disease 83%, ischemic stroke 21%; mean age 68 +/- 10 years; men 77%). Serum 25(OH)D was measured by ELISA assay. Carotid intima-media thickness (IMT) and brachial flow-mediated dilatation were measured by high-resolution vascular ultrasound. Circulating CD34KDR and CD133KDR endothelial progenitor cells (EPCs) were measured by flow cytometry. RESULTS: Three hundred and twenty-nine (74%) patients were statin users. Serum 25(OH)D was higher among statin users than nonusers (30.2 +/- 12.8 versus 26.8 +/- 8.5 ng/ml; P = 0.009), which remained significant after multivariable adjustment [B = +3.8, 95% confidence interval (CI) 0.6 to 6.9, P = 0.019). Serum 25(OH)D was associated with reduced carotid IMT (R = -0.11, P = 0.026), and increased circulating CD34KDR EPC (R = 0.13, P = 0.030) and CD133KDR EPC (R = 0.15, P = 0.012). Adjusted for potential confounders, serum 25(OH)D remained independently associated with reduced carotid IMT (B = -0.003, 95% CI -0.005 to 0.000, P = 0.017), and increased circulating CD34KDR EPC [B = 0.006, 95% CI 0.002 to 0.009, P = 0.001, log, unit (*10/ml)] and CD133KDR EPC [B = 0.004, 95% CI 0.001 to 0.008, P = 0.016, log, unit (*10/ml)]. Interaction test showed no multiplicative effect between statins and serum 25(OH)D on carotid IMT or EPCs. Serum 25(OH)D was negatively associated with HbA1c (B = -0.010, 95% CI -0.019 to -0.001, P = 0.035). There was no significant association between serum 25(OH)D and brachial flow-mediated dilatation (R = 0.045, P = 0.344). CONCLUSION: In patients with cardiovascular disease, statin use is associated with increased serum 25(OH)D, which is independently associated with reduced carotid atherosclerotic burden, increased circulating EPCs, and improved glycemic control. These may partially explain the pleotrophic effects of statins. PMID- 25436939 TI - Shared decision-making: easy to evoke, challenging to implement. PMID- 25436940 TI - Are odorant constituents of herbal tea transferred into human milk? AB - The present study investigates aroma transfer from commercial nursing tea, consumed in the maternal diet, into human milk by correlating sensory assessments with quantitative analytical data. The target terpenes were quantified in milk (expressed before and after tea consumption) and tea samples via gas chromatography-mass spectrometry (GC-MS) using stable isotope dilution assays (volunteer donors n = 5). Sensory analyses were carried out on different milk samples from a single donor, sampled before (blank) and at different times after tea ingestion. Quantitative analysis revealed that no significant odorant transfer into milk was observed after lactating women drank the tea. The comparative sensorial analysis of milk samples expressed before and after tea consumption confirmed that tea ingestion had no significant influence on the odor profile of human milk. PMID- 25436941 TI - EDCs and estrogen receptor activity: a pathway to safer chemical design? PMID- 25436942 TI - Development of a video-based technique for ambulatory monitoring of foot placement with an instrumented rollator. AB - OBJECTIVE: To develop a video-based system, mounted on a rollator to quantify the step width values of rollator users in the community. SUBJECTS: A total of 5 able bodied young adults, age range 24-28 years. METHODS: A digital video camera system was mounted on the rollator frame to capture the position of the participant's feet during overground walking. A method of estimating step width from the video data was developed and evaluated against the output from a concurrently recording Vicon MX motion capture system. RESULTS: Mean step widths of the rollator and motion capture systems were 14.40 cm (standard deviation (SD) 4.64) and 14.37 cm (SD 4.34), respectively, revealing a strong level of agreement; intra-class correlation coefficient 0.999 (95% confidence interval (95% CI) 0.987-1.000; and root-mean-square difference 0.70 cm. CONCLUSION: The video-based system mounted on a rollator to collect foot placement data enabled accurate measurement of step width during rollator use. The ability to record foot placement measurements outside the laboratory setting, characterizing foot placement patterns occurring in the community, will enable research into how these assistive devices influence mobility during everyday use. PMID- 25436943 TI - Accountable care organizations: an opportunity for gastroenterologists. PMID- 25436944 TI - Thermoregulatory capacities and torpor in the South American marsupial, Dromiciops gliroides. AB - During periods of adverse conditions small endotherms depend on a continuous supply of food and energy to maintain body temperature. Thus, rapid and reversible phenotypic modifications at different organizational levels are key for an efficient use of resources and survival. In this study, we provide a quantitative description of thermoregulatory capacities and energy-saving strategies in the Chilean marsupial Dromiciops gliroides. In particular, we evaluated the effect of thermal acclimation on basal metabolic rate (BMR), thermal conductance (C) and torpor patterns, as well as the presence of non shivering thermogenesis (NST) as a rewarming mechanism in this marsupial. Non significant effects of thermal acclimation were observed in BMR, C and body mass, but cold-acclimated individuals exhibited significantly longer torpor bouts. Also, minimum body temperature during torpor, inter-bout body temperature and arousal rewarming rate were lower in cold-acclimated animals. Furthermore, we found that D. gliroides did not display NST in response to Norepinephrine. Hence, despite the high regulation of torpor of other species, D. gliroides shows low flexibility in the ability to adjust energy expenditure and insulation properties, and (as in other marsupials) NST do not seems to be important as thermoregulatory mechanism. PMID- 25436945 TI - Effect of ambient temperature on female endurance performance. AB - Ambient temperature can affect physical performance, and an ambient temperature range of -4 degrees C to 11 degrees C is optimal for endurance performance in male athletes. The few similar studies of female athletes appear to have found differences in response to cold between the genders. This study investigated whether ambient temperature affects female endurance performance. Nine athletes performed six tests while running on a treadmill in a climatic chamber at different ambient temperatures: 20, 10, 1, -4, -9 and -14 degrees C and a wind speed of 5 m s(-1). The exercise protocol consisted of a 10-min warm-up, followed by four 5-min intervals at increasing intensities at 76%, 81%, 85%, and 89% of maximal oxygen consumption. This was followed by an incremental test to exhaustion. Although peak heart rate, body mass loss, and blood lactate concentration after the incremental test to exhaustion increased as the ambient temperature rose, no changes in time to exhaustion, running economy, running speed at lactate threshold or maximal oxygen consumption were found between the different ambient temperature conditions. Endurance performance during one hour of incremental exercise was not affected by ambient temperature in female endurance athletes. PMID- 25436946 TI - Physiological responses of Corythucha ciliata adults to high temperatures under laboratory and field conditions. AB - Under high temperature conditions, insects can tolerate to survive through various physiological mechanisms, which have been well documented in laboratory studies. However, it is still unclear as to whether these laboratory data can scale up to those in the field. Here we studied dynamics of heat-induced metabolites in Corythucha ciliata adults under both laboratory and field conditions to examine their significance in thermal tolerance of the species. We compared the effects of controlled thermal treatments (2h at 33-43 degrees C at 2 degrees C intervals in the laboratory) and naturally increasing thermal conditions (10:00-14:00 at 2-h intervals (33.5-37.2 degrees C) on a hot summer day in a field in Shanghai, China) on water content and levels of water-soluble protein, triglycerides, mannitol, and sorbitol in the adult bodies. The results showed that water content significantly decreased and all other metabolic parameters significantly increased in response to temperature stresses with similar patterns in both the laboratory and field, although the respective threshold temperatures were different under the two conditions. The close linkage observed in the two conditions suggests that a short period of heat stress induces water loss and accumulation of thermal metabolites in C. ciliata adults. This heat-resistance provides a defense mechanism counteracting thermal damage in C. ciliata. PMID- 25436947 TI - Using pairs of physiological models to estimate temporal variation in amphibian body temperature. AB - Physical models are often used to estimate ectotherm body temperatures, but designing accurate models for amphibians is difficult because they can vary in cutaneous resistance to evaporative water loss. To account for this variability, a recently published technique requires a pair of agar models that mimic amphibians with 0% and 100% resistance to evaporative water loss; the temperatures of these models define the lower and upper boundaries of possible amphibian body temperatures for the location in which they are placed. The goal of our study was to develop a method for using these pairs of models to estimate parameters describing the distributions of body temperatures of frogs under field conditions. We radiotracked green-eyed treefrogs (Litoria serrata) and collected semi-continuous thermal data using both temperature-sensitive radiotransmitters with an automated datalogging receiver, and pairs of agar models placed in frog locations, and we collected discrete thermal data using a non-contact infrared thermometer when frogs were located. We first examined the accuracy of temperature-sensitive transmitters in estimating frog body temperatures by comparing transmitter data with direct temperature measurements taken simultaneously for the same individuals. We then compared parameters (mean, minimum, maximum, standard deviation) characterizing the distributions of temperatures of individual frogs estimated from data collected using each of the three methods. We found strong relationships between thermal parameters estimated from data collected using automated radiotelemetry and both types of thermal models. These relationships were stronger for data collected using automated radiotelemetry and impermeable thermal models, suggesting that in the field, L. serrata has a relatively high resistance to evaporative water loss. Our results demonstrate that placing pairs of thermal models in frog locations can provide accurate estimates of the distributions of temperatures experienced by individual frogs, and that comparing temperatures from model pairs to direct measurements collected simultaneously on frogs can be used to broadly characterize the skin resistance of a species, and to select which model type is most appropriate for estimating temperature distributions for that species. PMID- 25436948 TI - Human males and females body thermoregulation: perfusion effect analysis. AB - Skin temperature is a common physiological parameter that reflects thermal responses. Blood perfusion is an important part of the physiological processes that the human body undergoes in order to maintain homeostasis. This study focuses on the effect of perfusion on the temperature distribution in human males and females body in different thermal environment. The study has been carried out for one dimensional steady cases using finite element method. The input parameter of the model is the blood perfusion or volumetric flow rate within the tissue. The appropriate physical and physiological parameters together with suitable boundary conditions that affect the heat regulations have been incorporated in the model. The study is to have a better understanding that how does thermoregulation change in human males and females skin layered due to perfusion. PMID- 25436949 TI - Simultaneous estimation of controllable parameters in a living tissue during thermal therapy. AB - During hyperthermia, controlling the temperature distribution along the tissue can cause remedial advantages. This can be obtained by proper manipulation of effective parameters in hyperthermia such as the external heat source and the heat transfer coefficient at the skin surface. In this study, these parameters are estimated simultaneously for an arbitrary temperature distribution in a skin tissue. The direct problem is solved by the fully implicit finite volume method to obtain the temperature data. This data is used as additional information to estimate the external heat source and the heat transfer coefficient at the skin surface simultaneously. Both of these parameters are considered as functions of time, and since no information exists about their functional form, the problem is classified as the function estimation approach. Conjugate gradient method is applied as an inverse method. Two test cases are considered and the effect of measurement errors is evaluated. The comparison of estimated results with measurements confirms the accuracy of this method. PMID- 25436950 TI - Graded meshes in bio-thermal problems with transmission-line modeling method. AB - In this study, the transmission-line modeling (TLM) applied to bio-thermal problems was improved by incorporating several novel computational techniques, which include application of graded meshes which resulted in 9 times faster in computational time and uses only a fraction (16%) of the computational resources used by regular meshes in analyzing heat flow through heterogeneous media. Graded meshes, unlike regular meshes, allow heat sources to be modeled in all segments of the mesh. A new boundary condition that considers thermal properties and thus resulting in a more realistic modeling of complex problems is introduced. Also, a new way of calculating an error parameter is introduced. The calculated temperatures between nodes were compared against the results obtained from the literature and agreed within less than 1% difference. It is reasonable, therefore, to conclude that the improved TLM model described herein has great potential in heat transfer of biological systems. PMID- 25436951 TI - Experimental and numerical study of physiological responses in hot environments. AB - This paper proposed a multi-node human thermal model to predict human thermal responses in hot environments. The model was extended based on the Tanabe's work by considering the effects of high temperature on heat production, blood flow rate, and heat exchange coefficients. Five healthy men dressed in shorts were exposed in thermal neutral (29 degrees C) and high temperature (45 degrees C) environments. The rectal temperatures and skin temperatures of seven human body segments were continuously measured during the experiment. Validation of this model was conducted with experimental data. The results showed that the current model could accurately predict the skin and core temperatures in terms of the tendency and absolute values. In the human body segments expect calf and trunk, the temperature differences between the experimental data and the predicted results in high temperature environment were smaller than those in the thermally neutral environment conditions. The extended model was proved to be capable of predicting accurately human physiological responses in hot environments. PMID- 25436952 TI - Effect of temperature on the effectiveness of artificial reproduction of dace [Cyprinidae (Leuciscus leuciscus (L.))] under laboratory and field conditions. AB - This study sought to determine the effect of water temperature on the effectiveness of artificial reproduction of dace brooders under laboratory and field conditions. Three temperatures were tested in the laboratory: 9.5, 12 and 14.5 degrees C (+/- 0.1 degrees C). The water temperature under field conditions was 11.0 +/- 0.3 degrees C (Czarci Jar Fish Farm) and 13.2 +/- 1.4 degrees C (Janowo Fish Farm). The study showed that artificial reproduction of dace is possible in all the temperature ranges under study and an embryo survival rate of over 87% can be achieved. Dace has also been found to be very sensitive to rapid temperature changes, even within the temperature ranges optimal for the species. Such changes have an adverse effect on the outcome of the reproduction process, such as a decrease in the percentage of reproducing females, a decrease in the pseudo-gonado-somatic index (PGSI) and a decrease in the embryo survival rate. PMID- 25436953 TI - Heme oxygenase-1 induction by cobalt protoporphyrin enhances fever and inhibits pyrogenic tolerance to lipopolysaccharide. AB - Heme oxygenase-1 (HO-1) is an enzyme that catalyzes degradation of the heme and regulates its availability for newly synthetized hemeproteins such as cyclooxygenases, NO synthases and cytochrome P450. Moreover, HO-1 activity modulates synthesis of cytokines and prostaglandins. All of these factors are well-defined components of fever and pyrogenic tolerance mechanisms. We examine the effect of HO-1 induction and activation using cobalt protoporphyrin (CoPP) on changes in body temperature (Tb), plasma levels of interleukin-6 (IL-6), prostaglandin E2 (PGE2) and HO-1 protein in the course of these processes. Intraperitoneally (i.p.) pre-treatment of rats with CoPP (5 mg kg(-1)) significantly accelerated and enhanced the early stage of lipopolysaccharide (LPS)-induced fever and shortened a post-fever recovery to normal temperature. Pre-treatment with CoPP significantly potentiated the increase in plasma IL-6, PGE2 and HO-1 levels measured 4h after the LPS administration. Furthermore, induction of HO-1 attenuated the development of pyrogenic tolerance to repeated injections of LPS. Based on these data we conclude that heme oxygenase-1 may act as a physiological regulator of the febrile response intensity to bacterial infections. PMID- 25436954 TI - Whole-body cryostimulation increases parasympathetic outflow and decreases core body temperature. AB - The cardiovascular, autonomic and thermal response to whole-body cryostimulation exposure are not completely known. Thus the aim of this study was to evaluate objectively and noninvasively autonomic and thermal reactions observed after short exposure to very low temperatures. We examined 25 healthy men with mean age 30.1 +/- 3.7 years and comparable anthropomorphical characteristic. Each subject was exposed to cryotherapeutic temperatures in a cryogenic chamber for 3 min (approx. -120 degrees C). The cardiovascular and autonomic parameters were measured noninvasively with Task Force Monitor. The changes in core body temperature were determined with the Vital Sense telemetric measurement system. Results show that 3 min to cryotherapeutic temperatures causes significant changes in autonomic balance which are induced by peripheral and central blood volume changes. Cryostimulation also induced changes in core body temperature, maximum drop of core temperature was observed 50-60 min after the stimulation. Autonomic and thermal reactions to cryostimulation were observed up to 6 h after the exposure and were not harmful for examined subjects. PMID- 25436955 TI - Effects of temperature, density and food quality on larval growth and metamorphosis in the north African green frog Pelophylax saharicus. AB - The ectodermic status of Amphibians explains their heavy dependence at ambient temperatures and thus their sensitivity to global warming. Temperature is likely the main factor regulating their physiology by acting on the endocrine system, with consequences on development, growth and size at metamorphosis. All these parameters control survival in the wild and performances in raniculture. This study is, to our knowledge, the first report on the effects of temperature, density and protein level in food on the rearing of the North African green Frog Pelophylax saharicus. Results show that a temperature of 26 degrees C is optimal for maximum weight gain. The maximum metamorphosis rate is obtained between 24 and 26 degrees C. The highest yields occur at low densities from 1 to 10 tadpolesl(-1). The best survival rate and accelerated metamorphosis are obtained at a level of 35% protein in food whose impact on food intake and weight gain is low. The maximum weight attained by tadpoles at metamorphosis, however, is obtained with a level of 40% protein. These results justify examination of this species in the light of climate change and suggest new techniques for aquaculture. PMID- 25436956 TI - Evaporative heat loss in Bos taurus: do different cattle breeds cope with heat stress in the same way? AB - The aim of this study was to compare two Portuguese (Alentejana and Mertolenga) and two exotic (Frisian and Limousine) cattle breeds in terms of the relationship between the increase in ambient temperature and the responses of the evaporative heat loss pathways and the effects on homeothermy. In the experiment, six heifers of the Alentejana, Frisian, and Mertolenga breeds and four heifers of the Limousine breed were used. The animals were placed in four temperature levels, the first one under thermoneutral conditions and the other ones with increase levels of thermal stress. When submitted to severe heat stress, the Frisian developed high thermal tachypnea (125 mov/min) and moderate sweating rates (117 gm(-2) h(-1)), which did not prevent an increase in the rectal temperature (from 38.4 degrees C to 40.0 degrees C). Moderate increases in rectal temperature were observed in the Alentejana (from 38.8 degrees C to 39.4 degrees C) and Limousine (from 38.6 degrees C to 39.4 degrees C), especially in the period of highest heat stress. The Limousine showed moderate levels of tachypnea (101 mov/min) while showing the lowest sweating rates. The Alentejana showed significant increases in sweating rate (156 gm(-2)h(-1)) that played a major role in homeothermy. The Mertolenga showed a superior stability of body temperature, even in the period of highest heat stress (from 38.5 degrees C to 39.1 degrees C). Uncommonly, the maintenance of homeothermy during moderate heat stress was achieved primarily by intense tachypnea (122 mov/min). The sweating rate remained abnormally low under conditions of moderate heat stress, rising significantly (110 gm(-2)h(-1)) without evidence of stabilization, only when tendency for heat storage occurred. This unusual response of the evaporative heat loss pathways infers a different thermoregulatory strategy, suggesting a different adaptation to semi-arid environment and strong association with water metabolism. PMID- 25436957 TI - A model to predict the thermal reaction norm for the embryo growth rate from field data. AB - The incubation of eggs is strongly influenced by temperature as observed in all species studied to date. For example, incubation duration, sexual phenotype, growth, and performances in many vertebrate hatchlings are affected by incubation temperature. Yet it is very difficult to predict temperature effect based on the temperature within a field nest, as temperature varies throughout incubation. Previous works used egg incubation at constant temperatures in the laboratory to evaluate the dependency of growtProd. Type: FTPh rate on temperature. However, generating such data is time consuming and not always feasible due to logistical and legislative constraints. This paper therefore presents a methodology to extract the thermal reaction norm for the embryo growth rate directly from a time series of incubation temperatures recorded within natural nests. This methodology was successfully applied to the nests of the marine turtle Caretta caretta incubated on Dalyan Beach in Turkey, although it can also be used for any egg laying species, with some of its limitations being discussed in the paper. Knowledge about embryo growth patterns is also important when determining the thermosensitive period for species with temperature-dependent sex determination. Indeed, in this case, sexual phenotype is sensitive to temperature only during this window of embryonic development. PMID- 25436958 TI - Study of thermal behavior of a biological tissue: an equivalence of Pennes bioheat equation and Wulff continuum model. AB - Equivalence of Pennes bioheat equation (PBHE) and Wulff continuum model (WCM) is established for a 1-D planar tissue. The derived condition of equivalence is specific to tissue without metabolic heat generation. Mathematical analysis is carried out to relate blood perfusion rate and local mean blood velocity that are needed in the analysis of WCM. It is found that the local mean blood velocity in a tissue is a direct function of square root of blood perfusion rate. This functional dependence is also established numerically by having same solution obtained from PBHE and WCM. Analysis is also done to check how closely the derived relation can be used for practical cases of breast tissue with and without a tumor. Blood velocity is a very important physiological quantity. Its measurement is a difficult process and requires a state-of-the-art technique. The proposed relation allows its computation merely from the knowledge of blood perfusion rate. PMID- 25436959 TI - Monitoring changes in skin temperature associated with exercise in horses on a water treadmill by use of infrared thermography. AB - Infrared thermography (IRT) was used to assess surface temperature change as an indirect measure of muscle activity and exercise associated changes in blood flow in the working hind limb muscles of horses (n=7) undergoing water treadmill exercise. Three treatments were investigated including the treadmill ran dry (TD), water at the height of the proximal interphalangeal joint (PIP) and water at the height of the carpus (CP). Maximum skin surface temperature was recorded from the region of the semitendinosus muscle during exercise at each water height. There was a significant difference in surface hind limb temperature between exercise on the water treadmill ran dry and with water at the height of the PIP and CP (P<0.0001) with hotter temperatures recorded during the TD treatment. There was a greater increase in surface temperature of the hind limbs from pre exercise to maximum temperature during the PIP and CP treatments when compared to the TD treatment, however, this was not significant (P=0.58). There was no significant difference in surface hind limb temperature found between exercise in water at the height of the PIP and water at the height of the CP. The findings from this study suggest that IRT is able to non-invasively detect muscle activity and associated changes in blood flow whilst horses are exercised on a water treadmill. IRT could potentially be used as an alternative method to assess muscle activity and temperature change in an aquatic environment where existing methods present methodological challenges. PMID- 25436960 TI - The ins and outs of water dynamics in cold tolerant soil invertebrates. AB - Many soil invertebrates have physiological characteristics in common with freshwater animals and represent an evolutionary transition from aquatic to terrestrial life forms. Their high cuticular permeability and ability to tolerate large modifications of internal osmolality are of particular importance for their cold tolerance. A number of cold region species that spend some or most of their life-time in soil are in more or less intimate contact with soil ice during overwintering. Unless such species have effective barriers against cuticular water-transport, they have only two options for survival: tolerate internal freezing or dehydrate. The risk of internal ice formation may be substantial due to inoculative freezing and many species rely on freeze-tolerance for overwintering. If freezing does not occur, the desiccating power of external ice will cause the animal to dehydrate until vapor pressure equilibrium between body fluids and external ice has been reached. This cold tolerance mechanism is termed cryoprotective dehydration (CPD) and requires that the animal must be able to tolerate substantial dehydration. Even though CPD is essentially a freeze avoidance strategy the associated physiological traits are more or less the same as those found in freeze tolerant species. The most well-known are accumulation of compatible osmolytes and molecular chaperones reducing or protecting against the stress caused by cellular dehydration. Environmental moisture levels of the habitat are important for which type of cold tolerance is employed, not only in an evolutionary context, but also within a single population. Some species use CPD under relatively dry conditions, but freeze tolerance when soil moisture is high. PMID- 25436961 TI - Seasonal changes in the composition of storage and membrane lipids in overwintering larvae of the codling moth, Cydia pomonella. AB - The codling moth (Cydia pomonella) is a major insect pest of apples worldwide. It overwinters as a diapausing fifth instar larva. The overwintering is often a critical part of the insect life-cycle in temperate zone. This study brings detailed analysis of seasonal changes in lipid composition and fluidity in overwintering larvae sampled in the field. Fatty acid composition of triacylglycerol (TG) depots in the fat body and relative proportions of phospholipid (PL) molecular species in biological membranes were analyzed. In addition, temperature of melting (Tm) in TG depots was assessed by using differential scanning calorimetry and the conformational order (fluidity) of PL membranes was analyzed by measuring the anisotropy of fluorescence polarization of diphenylhexatriene probe in membrane vesicles. We observed a significant increase of relative proportion of linoleic acid (C18:2n6) at the expense of palmitic acid (C16:0) in TG depots during the larval transition to diapause accompanied with decreasing melting temperature of total lipids, which might increase the accessibility of depot fats for enzymatic breakdown during overwintering. The fluidity of membranes was maintained very high irrespective of developmental mode or seasonally changing acclimation status of larvae. The seasonal changes in PL composition were relatively small. We discuss these results in light of alternative survival strategies of codling moth larvae (supercooling vs. freezing), variability and low predictability of environmental conditions, and other cold tolerance mechanisms such as extending the supercooling capacity and massive accumulation of cryoprotective metabolites. PMID- 25436962 TI - Seasonal heat acclimatization in wildland firefighters. AB - The purpose of this study was to determine changes in physiological markers of heat acclimatization across a 4-month wildland fire season. Wildland firefighters (WLFF) (n=12) and non-WLFF (n=14) were assessed pre- and post-season for body mass, percent body fat, and peak VO2. Both groups completed a 60-min heat stress trial (walking at 50% of peak VO2) in a climate controlled chamber (43.3 degrees C, 33% RH) pre and post-fire season (May through September). During the trials, core (Tc) and skin (Tsk) temperatures, heart rate (HR), physiological strain index (PSI), and rating of perceived exertion (RPE) were measured. There were no differences pre or post-season between the WLFF and non-WLFF groups in body mass, percent body fat, or peak V.O2. During the 73 days where the WLFF were involved in direct wildland fire suppression, daily high temperature for the WLFF was higher compared to the non-WLFF, 30.6 +/- 5.4 degrees C and 26.9 +/- 6.1 degrees C, respectively, p<0.05. Tc was lower at post-season compared to pre season (p<0.05) for the WLFF at 30, 45, and 60 min (pre 30, 45, and 60: 37.9 +/- 0.3, 38.3 +/- 0.3 and 38.5 +/- 0.3 degrees C, respectively; post 30, 45, and 60: 37.8 +/- 0.3, 38.1 +/- 0.3 and 38.2 +/- 0.4 degrees C, respectively). For WLFF, PSI was lower (p<0.05) at 15, 30, 45, and 60 min at post-season compared to pre season (4.2 +/- 0.7, 5.6 +/- 0.9, 6.5 +/- 0.9, and 7.1 +/- 1.1 for 15, 30, 45, and 60 min pre-season, respectively; 3.6 +/- 0.8, 4.9 +/- 1.0, 5.7 +/- 1.2, 6.3 +/- 1.3 for 15, 30, 45, and 60 min post-season, respectively). For WLFF, RPE was lower during the post-season trial at 30, 45, and 60 min (pre 30, 45, and 60: 11.7 +/- 1.4, 12.3 +/- 1.2, and 13.5 +/- 1.4, respectively; post 30, 45, and 60: 10.7 +/- 1.2, 11.3 +/- 1.3, and 11.9 +/- 1.5, respectively), p<0.05. There were no differences between pre and post-season for the non-WLFF for Tc and PSI, but RPE was lower at 15 min during the pre-season trial. WLFFs demonstrated significant decreases in Tc, PSI, and RPE during controlled heat stress after the season. Since an age and fitness-matched control group experienced no indication of heat acclimatization, it is suggested that the long-term occupational heat exposure accrued by the WLFFs was adequate to incur heat acclimatization. PMID- 25436963 TI - Reliability and validity of skin temperature measurement by telemetry thermistors and a thermal camera during exercise in the heat. AB - New technologies afford convenient modalities for skin temperature (TSKIN) measurement, notably involving wireless telemetry and non-contact infrared thermometry. The purpose of this study was to investigate the validity and reliability of skin temperature measurements using a telemetry thermistor system (TT) and thermal camera (TC) during exercise in a hot environment. Each system was compared against a certified thermocouple, measuring the surface temperature of a metal block in a thermostatically controlled waterbath. Fourteen recreational athletes completed two incremental running tests, separated by one week. Skin temperatures were measured simultaneously with TT and TC compared against a hard-wired thermistor system (HW) throughout rest and exercise. Post hoc calibration based on waterbath results displayed good validity for TT (mean bias [MB]=-0.18 degrees C, typical error [TE]=0.18 degrees C) and reliability (MB=-0.05 degrees C, TE=0.31 degrees C) throughout rest and exercise. Poor validity (MB=-1.4 degrees C, TE=0.35 degrees C) and reliability (MB=-0.65 degrees C, TE=0.52 degrees C) was observed for TC, suggesting it may be best suited to controlled, static situations. These findings indicate TT systems provide a convenient, valid and reliable alternative to HW, useful for measurements in the field where traditional methods may be impractical. PMID- 25436964 TI - Black wildebeest seek shade less and use solar orientation behavior more than do blue wildebeest. AB - Many ungulates, including wildebeest, seek shade and orient their bodies relative to incoming solar radiation in order to reduce environmental heat loads. Blue (Connochaetes taurinus) and black wildebeest (Connochaetes gnou), which co-exist artificially in some reserves in South Africa, are thought to adopt different thermoregulatory behaviors to mitigate high environmental heat loads. However, whether or not blue and black wildebeest use different behaviors to reduce heat loads in regions where they co-occur has never previously been examined. We compared the shade seeking and solar orientation behavior of free-ranging blue and black wildebeest in summer at three locations in South Africa where both species co-occur. We found that blue wildebeest exhibited more shade seeking behavior than did black wildebeest at all times of day, at all study sites. Black wildebeest remained in the sun but were more likely than blue wildebeest to orient their bodies parallel to the sun at all study sites, a behavior which reduces the amount of surface area exposed to incoming radiation. Black wildebeest were most likely to employ parallel solar orientation during the hottest times of the day when the sun was not directly overhead (i.e., solar noon +/- 1 hour). We thus demonstrate that co-occurring blue and black wildebeest use different thermoregulatory behaviors to reduce high heat loads. It is possible that the lack of shade in the historical distribution of black wildebeest led to selective pressure for reliance on solar orientation. Differences in thermoregulatory behavior can affect species-specific heat loads, habitat use, body mass, fitness and grazing activity. Such differences may also allow blue and black wildebeest to inhabit separate microclimates within the same habitat, provided there is sufficient heterogeneity in vegetation structure, potentially facilitating reproductive isolation. PMID- 25436965 TI - Influence of water temperature and waterborne cadmium toxicity on growth performance and metallothionein-cadmium distribution in different organs of Nile tilapia, Oreochromis niloticus (L.). AB - Cadmium (Cd) is believed to be one of the most abundant and ubiquitously distributed toxins in the aquatic system. This metal is released to the aquatic environment from both anthropogenic sources, such as industrial, agricultural and urban effluents as well as natural sources, such as rocks and soils. Otherwise, the temperature increase of water bodies, which has been observed due to global climatic changes, has been shown to increase Cd toxicity for several aquatic animal species including fish. In the present study, Nile tilapia, Oreochromis niloticus (L.), (26.0 +/- 0.38 g) were reared at 20, 24, 28, or 32 degrees C and exposed to 0.0 or 0.5mg Cd/L for 8 weeks to investigate effects of water temperature, Cd toxicity and their interaction on fish performance as well as metallothionein (MT) and Cd distribution in different fish organs. It was found that fish reared in Cd-free group at 28 degrees C showed the optimum growth and feed intake, while Cd-exposed fish showed low growth and feed intake irrespective to water temperature. A synergetic relationship between water temperature and Cd toxicity was observed where Cd toxicity increased as water temperature increased and the worse growth was obtained in Cd-exposed fish reared at 32 degrees C. Additionally, the highest Cd residues in different fish organs were detected in Cd-exposed fish reared at 32 degrees C. Similarly, MT concentrations in different fish organs increased as water temperature increased especially in Cd exposed fish groups. A high positive correlation between MT and Cd concentrations in fish organs was detected. The distribution of MT and Cd levels was in the order of liver>kidney>gills>muscles. The present study revealed that the optimum water temperature suitable for Nile tilapia growth is 28 degrees C. Additionally, Cd exposure had a deteriorate effect on the growth and health of Nile tilapia. This hazardous effect increased as water temperature increased. Further, liver and kidney were the prime sites of Cd accumulation, while Cd load in the muscles was the lowest as compared to the other investigated organs. PMID- 25436966 TI - Passive heat loading links lipolysis and regulation of fibroblast growth factor 21 in humans. AB - There is relativley little information on the serum biomarkers of heat stress. Therefore, the goal of this study was to verify the effect of passive heat loading (PHL) on the expression of fibroblast growth factor-21 (FGF21) and free fatty acids (FFAs). Four PHL protocols based on intensity (39 degrees C vs. 43 degrees C, leg immersion, 30 min) and type (leg vs. half immersion, 42 degrees C, 30 min) were used. Each protocol was applied on a 2 day cycle to 12 healthy adult males (age, 22.4 +/- 2.9 years; height, 174.1 +/- 4.6 cm; weight, 71.3 +/- 5.6 kg; body mass index, 23.1 +/- 3.0). The subjects were categorized into two groups according to the study design (randomized, with a parallel trial). Body temperature, FGF21 and FFAs were determined prior to PH L, immediately and 60 min after PHL. Body temperature was significant higher (43 degrees C) than the 39 degrees C measured under identical PHL type (leg immersion). PHL was effective for the expression of FGF21 and for lipolysis. The quantitative levels of FGF21 and FFA increased with increasing temperature (39 degrees C<42 degrees C<43 degrees C). A significant difference in the quantitative levels of FGF21 and FFAs was also evident based on the type of PHL (leg10% are predicted with optimized structures. This approach opens the door to new hot carrier collection devices and detectors based on transparent conducting electrodes. PMID- 25436992 TI - Manipulation of developing juvenile structures in purple sea urchins (Strongylocentrotus purpuratus) by morpholino injection into late stage larvae. AB - Sea urchins have been used as experimental organisms for developmental biology for over a century. Yet, as is the case for many other marine invertebrates, understanding the development of the juveniles and adults has lagged far behind that of their embryos and larvae. The reasons for this are, in large part, due to the difficulty of experimentally manipulating juvenile development. Here we develop and validate a technique for injecting compounds into juvenile rudiments of the purple sea urchin, Strongylocentrotus purpuratus. We first document the distribution of rhodaminated dextran injected into different compartments of the juvenile rudiment of sea urchin larvae. Then, to test the potential of this technique to manipulate development, we injected Vivo-Morpholinos (vMOs) designed to knock down p58b and p16, two proteins involved in the elongation of S. purpuratus larval skeleton. Rudiments injected with these vMOs showed a delay in the growth of some juvenile skeletal elements relative to controls. These data provide the first evidence that vMOs, which are designed to cross cell membranes, can be used to transiently manipulate gene function in later developmental stages in sea urchins. We therefore propose that injection of vMOs into juvenile rudiments, as shown here, is a viable approach to testing hypotheses about gene function during development, including metamorphosis. PMID- 25436993 TI - Investigations on CXCL13 in anti-N-methyl-D-aspartate receptor encephalitis: a potential biomarker of treatment response. AB - IMPORTANCE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe but treatable autoimmune encephalitis affecting mainly young adults and children. The lack of suitable biomarkers of disease activity makes treatment decisions and identification of relapses challenging. OBJECTIVE: To determine the levels of the B-cell-attracting C-X-C motif chemokine 13 (CXCL13) in serum samples and cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis and whether they can be used as biomarkers of treatment response and outcome. DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective cohort study of 167 patients consecutively diagnosed as having anti-NMDAR encephalitis between May 1, 2008, and January 31, 2013. Concentration of CXCL13 was determined with enzyme-linked immunosorbent assay in all available patients' samples (272 CSF and 55 serum samples). Samples from 25 patients with noninflammatory neurological disorders and 9 with neuroborreliosis served as controls. Expression of CXCL13 in the brain biopsy of a patient with anti-NMDAR encephalitis was determined by immunohistochemistry. MAIN OUTCOMES AND MEASURES: Percentage of patients with anti-NMDAR encephalitis and elevated CXCL13 in CSF. RESULTS: Compared with control individuals, 70% of patients with early-stage anti-NMDAR encephalitis had increased CXCL13 in CSF (>7 pg/mL; P < .001) but none in serum samples (>1047 pg/mL; P > .99). High concentration of CSF CXCL13 was associated with the presence of prodromal fever or headache (P = .01), limited response to therapy (P = .003), clinical relapses (P = .03), and intrathecal NMDAR-antibody synthesis (P < .001). Among patients with monophasic disease assessed 2 to 6 months after starting treatment, 10 of 15 with limited treatment response vs 0 of 13 with favorable response had increased CSF CXCL13 (specificity, 100%; 95% CI, 75-100 and sensitivity, 67%; 95% CI, 38-88; P = .02). Six of 12 patients had elevated CSF CXCL13 at relapse including 3 with previously normal levels. In brain, abundant mononuclear cells in perivascular infiltrates and scattered intraparenchymal microglia expressed CXCL13. CONCLUSIONS AND RELEVANCE: Seventy percent of patients with early-stage anti-NMDAR encephalitis had increased CSF CXCL13 concentration that correlated with intrathecal NMDAR-antibody synthesis. Prolonged or secondary elevation of CXCL13 was associated with limited response to treatment and relapses. CXCL13 is a potentially useful biomarker of treatment response and outcome in anti-NMDAR encephalitis. PMID- 25436995 TI - 250 mSv: temporary increase in the emergency exposure dose limit in response to the TEPCO Fukushima Daiichi NPP accident and its decision making process. AB - The Great East Japan Earthquake on March 11, 2011, led to an accident at the Fukushima Daiichi Nuclear Power Plant of the Tokyo Electric Power Company (TEPCO). In response to this accident, on March 14, 2011, the Ministry of Health, Labour, and Welfare (MHLW) of Japan enforced an ordinance that temporarily increased the radiation exposure dose limit allowed to 250 mSv during the emergency. This article explains the processes of a) temporarily increasing emergency dose limits, b) controlling for the combined emergency and normal exposure doses, and c) reducing the limit back to 100 mSv. Major issues addressed when deliberating the reduction of the emergency limits includes the following: a) political initiative, b) a phased reduction of dose limits, and c) transitional measures for workers who were exposed to more than 100 mSv. This article also identifies key challenges that need further deliberation to be resolved. These include: a) establishing a pre-defined protocol for applying pre accident emergency dose limits and/or amending post-accident limits; b) designating the conditions in which to apply or amend emergency dose limits; c) selecting methods of radiation control for individuals who are exposed to more than the normal exposure dose limit during emergency work; and d) designating the conditions under which to terminate or reduce emergency dose limits after the accident. PMID- 25436994 TI - Experimental myocardial infarction induces altered regulatory T cell hemostasis, and adoptive transfer attenuates subsequent remodeling. AB - BACKGROUND: Ischemic cardiac damage is associated with upregulation of cardiac pro-inflammatory cytokines, as well as invasion of lymphocytes into the heart. Regulatory T cells (Tregs) are known to exert a suppressive effect on several immune cell types. We sought to determine whether the Treg pool is influenced by myocardial damage and whether Tregs transfer and deletion affect cardiac remodeling. METHODS AND RESULTS: The number and functional suppressive activity of Tregs were assayed in mice subjected to experimental myocardial infarction. The numbers of splenocyte-derived Tregs in the ischemic mice were significantly higher after the injury than in the controls, and their suppressive properties were significantly compromised. Compared with PBS, adoptive Treg transfer to mice with experimental infarction reduced infarct size and improved LV remodeling and functional performance by echocardiography. Treg deletion with blocking anti-CD25 antibodies did not influence infarct size or echocardiographic features of cardiac remodeling. CONCLUSION: Treg numbers are increased whereas their function is compromised in mice with that underwent experimental infarction. Transfer of exogeneous Tregs results in attenuation of myocardial remodeling whereas their ablation has no effect. Thus, Tregs may serve as interesting potential interventional targets for attenuating left ventricular remodeling. PMID- 25436997 TI - Pseudopericyclic 1,5- versus Pericyclic 1,4- and 1,6-Electrocyclization in Electron-Poor 4-Aryl-2-azabuta-1,3-dienes: Indole Synthesis from 2H-Azirines and Diazo Compounds. AB - Transformations of 2-azabuta-1,3-dienes, formed in Rh2(OAc)4-catalyzed reactions of diazo carbonyl compounds with 2H-azirines, dramatically depend on the nature of substituents. 4,4-Diphenyl-2-azabuta-1,3-dienes with two electron-acceptor substituents at C(1) undergo thermal 1,5-cyclization to give indoles in good yields. The increase in electron-withdrawing ability of C(1)-substituents facilitates the reaction that proceeds via pseudopericyclic 1,5 electrocyclization of 2-azabutadiene into 7aH-indolium ylide followed by prototropic shift. 3,4-Diphenyl-2-azabuta-1,3-dienes, resulting from reaction of 2,3-diphenyl-2H-azirine and diazo compounds, do not produce indoles via 1,5 cyclization due to the trans-configuration of the 4-Ph-group and the nitrogen, but undergo 1,4-cyclization to 2,3-dihydroazetes. 1,6-Cyclization into 2H-1,4 oxazines with participation of the oxygen of ester or amide group at C(1) of corresponding 2-azabuta-1,3-dienes does not take place due to kinetic and thermodynamic reasons. Instead of this, 1,6-electrocyclization with participation of phenyl substituent at C(4) of the 2-azabuta-1,3-dienes, providing isoquinoline derivatives, can occur at elevated temperatures. The DFT-calculations (mPWB1K/6 31+G(d,p)) confirm the dependence of 2-azabuta-1,3-diene transformation type on the nature of substituents. PMID- 25436998 TI - High-precision visual long-term memory in children with high-functioning autism. AB - Domain-general theories of autism rest on evidence that the disorder impacts not only social communication skills but also nonsocial functions such as memory. Yet recognition memory deficits have been inconsistently documented, especially for stimuli other than faces and sentences. Here we tested school-age children with high-functioning autism (ASD) and IQ, and age-matched comparison children on a visual long-term memory task involving more than 100 photographs of objects, faces, cats, houses, and abstract stimuli. Children viewed each photograph for 2 s. After a 10-min filled delay, we assessed recognition memory for object category as well as for specific exemplars. Data supported the presence of a high capacity and high-precision visual memory in children with ASD. Both category memory and exemplar memory accuracies were above 90% for categories for which a single exemplar had been encoded. When more exemplars per category were encoded, category memory improved, but exemplar memory declined. An exception was face memory, which remained highly accurate even after many faces had been encoded. Our study provided no evidence that visual memory in general, and face memory in particular, is impaired in children with ASD. PMID- 25436996 TI - CD100 up-regulation induced by interferon-alpha on B cells is related to hepatitis C virus infection. AB - OBJECTIVES: CD100, also known as Sema4D, is a member of the semaphorin family and has important regulatory functions that promote immune cell activation and responses. The role of CD100 expression on B cells in immune regulation during chronic hepatitis C virus (HCV) infection remains unclear. MATERIALS AND METHODS: We longitudinally investigated the altered expression of CD100, its receptor CD72, and other activation markers CD69 and CD86 on B cells in 20 chronic HCV infected patients before and after treatment with pegylated interferon-alpha (Peg IFN-alpha) and ribavirin (RBV) by flow cytometry. RESULTS: The frequency of CD5+ B cells as well as the expression levels of CD100, CD69 and CD86 was significantly increased in chronic HCV patients and returned to normal in patients with sustained virological response after discontinuation of IFN alpha/RBV therapy. Upon IFN-alpha treatment, CD100 expression on B cells and the two subsets was further up-regulated in patients who achieved early virological response, and this was confirmed by in vitro experiments. Moreover, the increased CD100 expression via IFN-alpha was inversely correlated with the decline of the HCV-RNA titer during early-phase treatment. CONCLUSIONS: Peripheral B cells show an activated phenotype during chronic HCV infection. Moreover, IFN-alpha therapy facilitates the reversion of disrupted B cell homeostasis, and up-regulated expression of CD100 may be indirectly related to HCV clearance. PMID- 25436999 TI - Selection of intracellular single-domain antibodies targeting the HIV-1 Vpr protein by cytoplasmic yeast two-hybrid system. AB - The targeting of HIV-1 using antibodies is of high interest as molecular tools to better understand the biology of the virus or as a first step toward the design of new inhibitors targeting critical viral intracellular proteins. Small and highly stable llama-derived single-domain antibodies can often be functionally expressed as intracellular antibodies in the cytoplasm of eukaryotic cells. Using a selection method based on the Sos Recruitment System, a cytoplasmic yeast two hybrid approach, we have isolated single-domain antibodies able to bind HIV-1 Vpr and Capside proteins in the yeast cytoplasm. One anti-Vpr single domain antibody was able to bind the HIV-1 regulatory Vpr protein in the cytoplasm of eukaryotic cells, leading to its delocalization from the nucleus to the cytoplasm. To our knowledge, this is the first description of a functional single-domain intrabody targeting HIV-1 Vpr, isolated using an in vivo cytoplasmic selection method that alleviates some limitations of the conventional yeast two-hybrid system. PMID- 25437000 TI - Surgical versus medical interventions for chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: Nasal polyps cause nasal obstruction, discharge and reduction in or loss of sense of smell, but their aetiology is unknown. The management of chronic rhinosinusitis with nasal polyps, aimed at improving these symptoms, includes both surgical and medical treatments, but there is no universally accepted management protocol. OBJECTIVES: To assess the effectiveness of endonasal/endoscopic surgery versus medical treatment in chronic rhinosinusitis with nasal polyps. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 20 February 2014. SELECTION CRITERIA: Randomised controlled trials of any surgical intervention (e.g. polypectomy, endoscopic sinus surgery) versus any medical treatment (e.g. intranasal and/or systemic steroids), including placebo, in adult patients with chronic rhinosinusitis with nasal polyps. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. Meta-analysis was not possible due to the heterogeneity of the studies and the selective (incomplete) outcome reporting by the studies. MAIN RESULTS: Four studies (231 participants randomised) are included in the review. No studies were at low risk of bias. The studies compared different types of surgery versus various types and doses of systemic and topical steroids and antibiotics. There were three comparison pairs: (1) endoscopic sinus surgery (ESS) versus systemic steroids (one study, n = 109), (2) polypectomy versus systemic steroids (two studies, n = 87); (3) ESS plus topical steroid versus antibiotics plus high-dose topical steroid (one study, n = 35). All participants also received topical steroids but doses and types were the same between the treatment arms of each study, except for the study using antibiotics. In that study, the medical treatment arm had higher doses than the surgical arm. In two of the studies, the authors failed to report the outcomes of interest. Although there were important differences in the types of treatments and comparisons used in these studies, the results were similar. PRIMARY OUTCOMES: symptom scores and quality of life scores There were no important differences between groups in either the patient-reported disease-specific symptom scores or the health-related quality of life scores. Two studies (one comparing ESS plus topical steroid versus antibiotics plus high-dose topical steroid, the other ESS versus systemic steroids) failed to find a difference in generic health-related quality of life scores. The quality of this evidence is low or very low. Endoscopic scores and other secondary outcomes Two studies reported endoscopic scores. One study (ESS versus systemic steroids) reported a large, significant effect size in the surgical group, with a mean difference (MD) in score of -1.5 (95% confidence interval (CI) -1.78 to -1.22, n = 95) on a scale of 0 to 3 (0 = no polyposis, 3 = severe polyposis). In the other study (ESS plus topical steroid versus antibiotics plus high-dose topical steroid) no difference was found between the groups (MD 2.3%, 95% CI -17.4% to 12.8%, n = 34). None of the included studies reported recurrence rates. No differences were found for any objective measurements or olfactory tests in those studies in which they were measured. Complications Complication rates were not reported in all studies, but rates of up to 21% for medical treatment and 14.3% for surgical treatment are described. Epistaxis was the most commonly reported complication with both medical and surgical treatments, with severe complications reported rarely. AUTHORS' CONCLUSIONS: The evidence relating to the effectiveness of different types of surgery versus medical treatment for adults with chronic rhinosinusitis with nasal polyps is of very low quality. The evidence does not show that one treatment is better than another in terms of patient-reported symptom scores and quality of life measurements. The one positive finding from amongst the several studies examining a number of different comparisons must be treated with appropriate caution, in particular when the clinical significance of the measure is uncertain.As the overall evidence is of very low quality (serious methodological limitations, reporting bias, indirectness and imprecision) and insufficient to draw firm conclusions, further research to investigate this problem, which has significant implications for quality of life and healthcare service usage, is justified. PMID- 25437001 TI - Tissue engineering of rat bladder using marrow-derived mesenchymal stem cells and bladder acellular matrix. AB - Bladder replacement or augmentation is required in congenital malformations or following trauma or cancer. The current surgical solution involves enterocystoplasty but is associated with high complication rates. Strategies for bladder tissue engineering are thus actively sought to address this unmet clinical need. Because of the poor efficacy of synthetic polymers, the use of bladder acellular matrix (BAM) has been proposed. Indeed when cellular components are removed from xenogenic or allogeneic bladders, the extracellular matrix scaffold thus obtained can be used alone or in combination with stem cells. In this study, we propose the use of BAM seeded with marrow-derived mesenchymal stem cells (MSCs) for bladder tissue engineering. We optimized a protocol for decellularization of bladder tissue from different species including rat, rabbit and swine. We demonstrate the use of non-ionic detergents followed by nuclease digestion results in efficient decellularization while preserving the extracellular matrix. When MSCs were seeded on acellular matrix scaffold, they remained viable and proliferative while adopting a cellular phenotype consistent with their microenvironment. Upon transplantation in rats after partial cystectomy, MSC-seeded BAM proved superior to unseeded BAM with animals recovering nearly 100% normal bladder capacity for up to six months. Histological analyses also demonstrated increased muscle regeneration. PMID- 25437003 TI - Growth inhibition of head and neck squamous cell carcinoma cells by sgRNA targeting the cyclin D1 mRNA based on TRUE gene silencing. AB - Head and neck squamous cell carcinoma (HNSCC) exhibits increased expression of cyclin D1 (CCND1). Previous studies have shown a correlation between poor prognosis of HNSCC and cyclin D1 overexpression. tRNase ZL-utilizing efficacious gene silencing (TRUE gene silencing) is one of the RNA-mediated gene expression control technologies that have therapeutic potential. This technology is based on a unique enzymatic property of mammalian tRNase ZL, which is that it can cleave any target RNA at any desired site by recognizing a pre-tRNA-like complex formed between the target RNA and an artificial small guide RNA (sgRNA). In this study, we designed several sgRNAs targeting human cyclin D1 mRNA to examine growth inhibition of HNSCC cells. Transfection of certain sgRNAs decreased levels of cyclin D1 mRNA and protein in HSC-2 and HSC-3 cells, and also inhibited their proliferation. The combination of these sgRNAs and cisplatin showed more than additive inhibition of cancer cell growth. These findings demonstrate that TRUE gene silencing of cyclin D1 leads to inhibition of the growth of HNSCC cells and suggest that these sgRNAs alone or combined with cisplatin may be a useful new therapy for HNSCCs. PMID- 25437004 TI - Macromolecular crowding induces holo alpha-lactalbumin aggregation by converting to its apo form. AB - Macromolecular crowding has been shown to have an exacerbating effect on the aggregation propensity of amyloidogenic proteins; while having an inhibitory effect on the non-amyloidogenic proteins. However, the results concerning aggregation propensity of non-amyloidogenic proteins have not been convincing due to the contrasting effect on holo-LA, which despite being a non-amyloidogenic protein was observed to aggregate under crowded conditions. In the present study, we have extensively characterized the crowding-induced holo-LA aggregates and investigated the possible mechanism responsible for the aggregation process. We discovered that macromolecular crowding reduces the calcium binding affinity of holo-LA resulting in the formation of apo-LA (the calcium-depleted form of holo LA) leading to aggregate formation. Another finding is that calcium acts as a chaperone capable of inhibiting and dissociating crowding-induced holo-LA aggregates. The study has a direct implication to Alzheimer Disease as the results invoke a new mechanism to prevent Abeta fibrillation. PMID- 25437005 TI - A genomic instability score in discriminating nonequivalent outcomes of BRCA1/2 mutations and in predicting outcomes of ovarian cancer treated with platinum based chemotherapy. AB - Detecting mutation in BRCA1/2 is a generally accepted strategy for screening ovarian cancers that have impaired homologous recombination (HR) ability and improved sensitivity to PARP inhibitor. However, a substantial subset of BRCA mutant ovarian cancer patients shows less impaired or unimpaired HR ability, resulting in nonequivalent outcome after ovarian cancer development. We hypothesize that genomic instability provides a lifetime record of DNA repair deficiency and predicts ovarian cancer outcome. Based on the multi-dimensional TCGA ovarian cancer data, we developed a biological rationale-driven genomic instability score integrating somatic mutation and copy number change in a tumor genome. The score successfully divided BRCA-mutant ovarian tumors into cases of significantly improved outcome and cases of unimproved outcome. The score was also capable of discriminating HR-deficiency indicated by BRCA1 epigenetically silencing, EMSY amplification and homozygous deletion of core HR genes. We further found that the score was positively correlated with the complete response rate of chemotherapy and the rate of platinum-sensitivity, and predicted improved outcome of ovarian cancer, regardless of BRCA-mutation status. The score may have important value in outcome prediction and clinical trial design. PMID- 25437007 TI - Force transduction and lipid binding in MscL: a continuum-molecular approach. AB - The bacterial mechanosensitive channel MscL, a small protein mainly activated by membrane tension, is a central model system to study the transduction of mechanical stimuli into chemical signals. Mutagenic studies suggest that MscL gating strongly depends on both intra-protein and interfacial lipid-protein interactions. However, there is a gap between this detailed chemical information and current mechanical models of MscL gating. Here, we investigate the MscL bilayer-protein interface through molecular dynamics simulations, and take a combined continuum-molecular approach to connect chemistry and mechanics. We quantify the effect of membrane tension on the forces acting on the surface of the channel, and identify interactions that may be critical in the force transduction between the membrane and MscL. We find that the local stress distribution on the protein surface is largely asymmetric, particularly under tension, with the cytoplasmic side showing significantly larger and more localized forces, which pull the protein radially outward. The molecular interactions that mediate this behavior arise from hydrogen bonds between the electronegative oxygens in the lipid headgroup and a cluster of positively charged lysine residues on the amphipathic S1 domain and the C-terminal end of the second trans-membrane helix. We take advantage of this strong interaction (estimated to be 10-13 kT per lipid) to actuate the channel (by applying forces on protein-bound lipids) and explore its sensitivity to the pulling magnitude and direction. We conclude by highlighting the simple motif that confers MscL with strong anchoring to the bilayer, and its presence in various integral membrane proteins including the human mechanosensitive channel K2P1 and bovine rhodopsin. PMID- 25437009 TI - Expanding access to HIV viral load testing: a systematic review of RNA stability in EDTA tubes and PPT beyond current time and temperature thresholds. AB - BACKGROUND: HIV viral load (VL) testing is the gold standard for antiretroviral treatment monitoring, but many barriers exist to VL testing in resource-limited settings, including storage and transport limitations for whole blood and plasma. Data from various studies indicate that HIV RNA is stable beyond current recommendations. We conducted a systematic review to assess stability data of HIV RNA in whole blood and plasma across times and temperatures. METHODS AND FINDINGS: Using a pre-defined protocol, five databases were searched for studies where blood samples from HIV patients were stored at time and temperature points that exceeded manufacturer recommendations. RNA stability, the primary outcome, was measured by the difference in means compared to samples stored within established thresholds. RNA stability was defined as <=0.5 log degradation. The search identified 10,716 titles, of which nine full-text articles were included for review. HIV RNA maintained stability in EDTA whole blood and plasma at all measured time points up to 168 hours when stored at 4 degrees C, while stability was detected at 72 hours (95% confidence) in whole blood at 25 degrees C, with data points before and beyond 72 hours suggesting stability but not reaching statistical significance. For EDTA plasma stored at 30 degrees C, stability was maintained up to 48 hours (95% confidence), with OLS linear regression estimates up to 127 hours, suggesting stability. Overall, quality of studies was moderate. Limitations included small sample sizes, few studies meeting inclusion criteria, and no studies examining RNA stability in low viremia (<3,000 copies/mL) environments. CONCLUSIONS: Whole blood and plasma samples in EDTA may remain stable under conditions exceeding current manufacturer recommendations for HIV VL testing. However, given the limited number of studies addressing this question, especially at low levels of viremia, additional evaluations on HIV RNA stability in EDTA tubes and PPT in field conditions are needed. PMID- 25437008 TI - Low serum 25-hydroxyvitamin d concentrations are associated with increased risk for melanoma and unfavourable prognosis. AB - BACKGROUND: Low vitamin D status (serum 25(OH)D concentration) is associated with increased incidence and unfavourable outcome of various types of cancer. However, there are limited data on influence of serum 25(OH)D on risk and prognosis of malignant melanoma. METHODS: Basal serum 25(OH)D concentrations were retrospectively analyzed in a cohort of melanoma patients (n = 324) and healthy controls (n = 141). We tested the hypothesis that serum 25(OH)D concentrations are predictive of melanoma risk, thickness of primary melanomas, and overall survival (OS). RESULTS: Median serum 25(OH)D concentrations were significantly lower (p = 0.004) in melanoma patients (median = 13.6 ng/ml) as compared to controls (median = 15.6 ng/ml). Primary tumors of patients with low serum 25(OH)D concentrations (<10 ng/ml) had significantly (p = 0.006) greater Breslow thickness (median: 1.9 mm) as compared to patients with higher levels (>20 ng/ml; median: 1.00 mm). Patients with 25(OH)D serum concentrations in the lowest quartile had inferior overall survival (median: 80 months) comparing with the highest quartile (median: 195 months; p = 0.049). CONCLUSIONS: Our data support the concept that serum 25(OH)D concentrations are associated with risk and prognosis of melanoma. Whether normalizing serum 25(OH)D concentrations in these patients improves outcomes will require testing in future clinical trials. PMID- 25437010 TI - Experiments in globalisation, food security and land use decision making. AB - The globalisation of trade affects land use, food production and environments around the world. In principle, globalisation can maximise productivity and efficiency if competition prompts specialisation on the basis of productive capacity. In reality, however, such specialisation is often constrained by practical or political barriers, including those intended to ensure national or regional food security. These are likely to produce globally sub-optimal distributions of land uses. Both outcomes are subject to the responses of individual land managers to economic and environmental stimuli, and these responses are known to be variable and often (economically) irrational. We investigate the consequences of stylised food security policies and globalisation of agricultural markets on land use patterns under a variety of modelled forms of land manager behaviour, including variation in production levels, tenacity, land use intensity and multi-functionality. We find that a system entirely dedicated to regional food security is inferior to an entirely globalised system in terms of overall production levels, but that several forms of behaviour limit the difference between the two, and that variations in land use intensity and functionality can substantially increase the provision of food and other ecosystem services in both cases. We also find emergent behaviour that results in the abandonment of productive land, the slowing of rates of land use change and the fragmentation or, conversely, concentration of land uses following changes in demand levels. PMID- 25437013 TI - How Will the "$1,000 Dollar Genome" Meet Reality (and Centers for Medicare & Medicaid Services)? PMID- 25437011 TI - A decline in Wnt3a signaling is necessary for mesenchymal stem cells to proceed to replicative senescence. AB - Umbilical cord blood-derived mesenchymal stem cells are a promising source of cells for regeneration therapy due to their multipotency, high proliferative capacity, relatively noninvasive collection, and ready availability. However, extended cell culture inevitably triggers cellular senescence-the irreversible arrest of cell division-thereby limiting the proliferative lifespan of adult stem cells. Wnt/beta-catenin signaling plays a functional role as a key regulator of self-renewal and differentiation in mesenchymal stem cells (MSCs), and thus Wnt/beta-catenin signaling and cellular senescence might be closely connected. Here, we show that the expression levels of canonical Wnt families decrease as MSCs age during subculture. Activation of the Wnt pathway by treatment with Wnt3a conditioned medium or glycogen synthase kinase 3beta inhibitors, such as SB 216763 and 6-bromoindirubin-3'-oxime, delays the progression of cellular senescence as shown by the decrease in the senescence effectors p53 and pRb, lowered senescence-associated beta-galactosidase activity, and increased telomerase activity. In contrast, suppression of the Wnt pathway by treatment with dickkopf-1 (an antagonist of the Wnt coreceptor) and beta-catenin siRNA transfection promotes senescence in MSCs. Interestingly, the magnitude of the response to enhanced Wnt3a/beta-catenin signaling appears to depend on the senescent state during extended culture, particularly after multiple passages. These results suggest that Wnt3a signaling might be a predominant factor that could be used to overcome senescence in long-term cultured MSCs by directly intervening in the proliferative capacity and MSC senescence. The functional role of Wnt3a/beta-catenin signaling in hedging cellular senescence may allow the development of new approaches for stem cell-based therapies. PMID- 25437012 TI - Effect of the duration between total body irradiation and stem cell infusion on the outcome of allogeneic transplantation with myeloablative conditioning. AB - OBJECTIVES: Limited data are available on the effect of how cyclophosphamide (CY) and total body irradiation (TBI) are administered. We analyzed the effect of the interval from TBI to hematopoietic stem cell transplantation (HSCT) on the outcome of HSCT. METHODS: Adult patients who underwent HSCT using myeloablative conditioning consisting of TBI and CY were retrospectively analyzed. They were divided into three groups according to the duration between the start of TBI and HSCT (Group A: 2-4 days, Group B: 5-8 days, Group C: 9-10 days). RESULTS: Seventy five adult patients were included. The 3-year overall survival rate was 56, 47, and 77% in Groups A, B, and C, respectively (P = 0.14). Similarly, there was no significant difference among the three groups with respect to progression-free survival (57, 47, and 72%, P = 0.17), relapse rate (32, 37, and 16%, P = 0.29), or non-relapse mortality (8, 14, and 12%, P = 0.81). In addition, we observed no significant difference among the three groups with respect to the incidence of grade II-IV acute graft-versus-host disease (GVHD) (31, 47, and 32%, respectively, P = 0.56) and that of chronic GVHD (23, 23, and 22%, respectively, P = 0.97). DISCUSSION AND CONCLUSION: Although recipient immune system at HSCT might be affected by the timing of TBI, the duration between the start of TBI and HSCT did not influence the outcome of HSCT using myeloablative conditioning with TBI and CY. PMID- 25437014 TI - Quantifying the impact of expanded age group campaigns for polio eradication. AB - A priority of the Global Polio Eradication Initiative (GPEI) 2013-2018 strategic plan is to evaluate the potential impact on polio eradication resulting from expanding one or more Supplementary Immunization Activities (SIAs) to children beyond age five-years in polio endemic countries. It has been hypothesized that such expanded age group (EAG) campaigns could accelerate polio eradication by eliminating immunity gaps in older children that may have resulted from past periods of low vaccination coverage. Using an individual-based mathematical model, we quantified the impact of EAG campaigns in terms of probability of elimination, reduction in polio transmission and age stratified immunity levels. The model was specifically calibrated to seroprevalence data from a polio-endemic region: Zaria, Nigeria. We compared the impact of EAG campaigns, which depend only on age, to more targeted interventions which focus on reaching missed populations. We found that EAG campaigns would not significantly improve prospects for polio eradication; the probability of elimination increased by 8% (from 24% at baseline to 32%) when expanding three annual SIAs to 5-14 year old children and by 18% when expanding all six annual SIAs. In contrast, expanding only two of the annual SIAs to target hard-to-reach populations at modest vaccination coverage-representing less than one tenth of additional vaccinations required for the six SIA EAG scenario-increased the probability of elimination by 55%. Implementation of EAG campaigns in polio endemic regions would not improve prospects for eradication. In endemic areas, vaccination campaigns which do not target missed populations will not benefit polio eradication efforts. PMID- 25437015 TI - The Affordable Care Act, technology, and type 1 diabetes mellitus. PMID- 25437016 TI - Treatment of transient neonatal diabetes mellitus: insulin pump or insulin glargine? Our experience. AB - Neonatal diabetes mellitus (NDM) results from impaired insulin secretion, occurring within the first 6 months of life. NDM is classified as transient NDM (TNDM) or permanent NDM. To date there are no universal guidelines regarding its management. Intravenous insulin infusion represents the first and most adequate therapeutic approach for sustained hyperglycemia, but this can provide only a short-term solution. Several factors should be taken into account in the choice of the long-term treatment. We describe our experience with two infants affected by TNDM. The first child was treated with continuous subcutaneous insulin infusion, whereas the second infant was treated with subcutaneous insulin glargine injections. Our experience shows that the two different therapeutic approaches, if properly managed, are equally effective. PMID- 25437017 TI - Comprehensive versus consultative rehabilitation services postacute stroke: Outcomes differ. AB - Comprehensive rehabilitation services postacute stroke have been shown efficacious in European trials; however, their effectiveness in everyday practices in the United States is unknown. We compared outcomes of veteran patients provided with comprehensive rehabilitation with those provided with consultative rehabilitation services postacute stroke using propensity scores. Outcomes included change in patients' physical and cognitive independence after rehabilitation, discharge to home as opposed to other settings, and 1-yr posthospital discharge survival. Of the 2,963 patients in the study, 683 (23.1%) received comprehensive rehabilitation while the remaining patients received consultative services. We found, after propensity adjustment, that those who received comprehensive rehabilitation compared with consultative gained on average 12.8 (95% confidence interval [CI]: 9.1 to 16.5) more points of physical independence on a 78-point scale and gained 1.5 (95% CI: 0.8 to 2.2) more points of cognitive independence on a 30-point scale. The likelihoods of discharge to home from the hospital (odds ratio [OR] = 1.61, 95% CI: 1.07 to 2.44) and 1-yr posthospital discharge survival (OR = 1.79, 95% CI: 1.25 to 2.56) were significantly higher among those who received comprehensive rehabilitation. Among patients hospitalized for acute stroke, comprehensive rehabilitation services are associated with greater recovery of physical and cognitive independence, improved home discharge likelihood, and improved 1-yr survival. PMID- 25437018 TI - Predictors of at-risk intoxication in a university field setting: social anxiety, demographics, and intentions. AB - OBJECTIVE: The determinants of alcohol consumption among university students were investigated in a downtown field setting with blood alcohol content (BAC) as the dependent variable. PARTICIPANTS: In total, 521 participants completed a brief survey and had their BAC assessed during April 2013. METHODS: Between 10:00 pm and 2:00 am, teams of researchers recruited passersby at 3 heavy-drinking locations near a university campus. Before the BAC assessment, participants completed a questionnaire regarding their drinking intentions, drinking group, and social anxiety. RESULTS: The average BAC of drinking students was 0.107 g/dL, which was 0.033 g/dL higher than their intended BAC. Males and members of a Greek life organization consumed significantly more alcohol than their demographic counterparts. A significant positive curvilinear relationship was observed between social anxiety and BAC. CONCLUSIONS: University students achieve high levels of intoxication, often exceeding their intended BAC. Social anxiety may be an informative predictor of alcohol consumption in this setting. PMID- 25437019 TI - The importance of basic science and research training for the next generation of physicians and physician scientists. PMID- 25437022 TI - Is the learning curve of robotic low anterior resection shorter than laparoscopic low anterior resection for rectal cancer?: a comparative analysis of clinicopathologic outcomes between robotic and laparoscopic surgeries. AB - As robotic surgery was developed with ergonomic designs, there are expectations that the technical advantages of robotic surgery can shorten the learning curve. However, there is no comparative study, so far, to evaluate the learning curve between robotic and laparoscopic rectal cancer surgeries. Therefore, the aim of this study is to compare the learning curve of robotic low anterior resection (LAR) with laparoscopic LAR for rectal cancer.Patients who underwent robotic or laparoscopic LAR by a single surgeon were compared retrospectively (robot n = 89 vs laparoscopy n = 89). Cumulative sum (CUSUM) was used to evaluate the learning curve. The patients were divided into phase 1 (initial learning curve period) and phase 2 (post-learning curve period). The perioperative clinicopathologic characteristics were compared by phases and surgical procedures.According to CUSUM, the learning curve of robotic LAR was the 44th case and laparoscopic LAR was the 41st case. The learning phases were divided as follows: phase 1 (cases 1 41) versus phase 2 (cases 42-89) in the laparoscopic group, and phase 1 (cases 1 44) versus phase 2 (cases 45-89) in the robotic group. Comparison between phase 1 and phase 2 in each type of surgery showed no significant difference for the perioperative outcomes. Comparison between robotic and laparoscopic surgeries in each phase showed similar perioperative results. Pathologic outcomes were not significantly different in both procedures and phases.The learning curve of robotic LAR for rectal cancer was similar to laparoscopic LAR, and the clinicopathologic outcomes were similar in both the procedures. PMID- 25437023 TI - Palliative care and prehospital emergency medicine: analysis of a case series. AB - Palliative care, which is intended to keep patients at home as long as possible, is increasingly proposed for patients who live at home, with their family, or in retirement homes. Although their condition is expected to have a lethal evolution, the patients-or more often their families or entourages-are sometimes confronted with sudden situations of respiratory distress, convulsions, hemorrhage, coma, anxiety, or pain. Prehospital emergency services are therefore often confronted with palliative care situations, situations in which medical teams are not skilled and therefore frequently feel awkward.We conducted a retrospective study about cases of palliative care situations that were managed by prehospital emergency physicians (EPs) over a period of 8 months in 2012, in the urban region of Lausanne in the State of Vaud, Switzerland.The prehospital EPs managed 1586 prehospital emergencies during the study period. We report 4 situations of respiratory distress or neurological disorders in advanced cancer patients, highlighting end-of-life and palliative care situations that may be encountered by prehospital emergency services.The similarity of the cases, the reasons leading to the involvement of prehospital EPs, and the ethical dilemma illustrated by these situations are discussed. These situations highlight the need for more formal education in palliative care for EPs and prehospital emergency teams, and the need to fully communicate the planning and implementation of palliative care with patients and patients' family members. PMID- 25437024 TI - How well do patients understand written instructions?: health literacy assessment in rural and urban rheumatology outpatients. AB - The aim of this study was to assess health literacy (word recognition and comprehension) in patients at a rural rheumatology practice and to compare this to health literacy levels in patients from an urban rheumatology practice.Inclusion criteria for this cross-sectional study were as follows: >=18 year-old patients at a rural rheumatology practice (Mid-North Coast Arthritis Clinic, Coffs Harbour, Australia) and an urban Sydney rheumatology practice (Combined Rheumatology Practice, Kogarah, Australia). Exclusion criteria were as follows: ill-health precluding participation; poor vision/hearing, non-English primary language. Word recognition was assessed using the Rapid Estimate of Adult Literacy in Medicine (REALM). Comprehension was assessed using the Test of Functional Health Literacy in Adults (TOFHLA). Practical comprehension and numeracy were assessed by asking patients to follow prescribing instructions for 5 common rheumatology medications.At the rural practice (Mid-North Coast Arthritis Clinic), 124/160 patients agreed to participate (F:M 83:41, mean age 60.3 +/- 12.2) whereas the corresponding number at the urban practice (Combined Rheumatology Practice) was 99/119 (F:M 69:30, mean age 60.7 +/- 17.5). Urban patients were more likely to be born overseas, speak another language at home, and be employed. There was no difference in REALM or TOFHLA scores between the 2 sites, and so data were pooled. REALM scores indicated 15% (33/223) of patients had a reading level <=Grade 8 whereas 8% (18/223) had marginal or inadequate functional health literacy as assessed by the TOFHLA. Dosing instructions for ibuprofen and methotrexate were incorrectly understood by 32% (72/223) and 21% (46/223) of patients, respectively.Up to 15% of rural and urban patients had low health literacy and <1/3 of patients incorrectly followed dosing instructions for common rheumatology drugs.There was no significant difference in word recognition, functional health literacy, and numeracy between rural and urban rheumatology patients. PMID- 25437026 TI - Screening for respiratory syncytial virus and isolation strategies in children hospitalized with acute respiratory tract infection. AB - Nosocomial infection with respiratory syncytial virus (RSV) is an important health risk in pediatric care but is largely preventable by efficient infection control measures. Commonly applied rapid antigen detection tests (RADTs) miss a considerable number of RSV-infected patients. The objective of our analysis was to evaluate whether readily available host parameters are associated with false negative RADT, and to assess how these parameters could be applied in an optimized RSV isolation strategy.We retrospectively analyzed a cohort of 242 children under the age of 2 years hospitalized with acute respiratory tract infection to identify host parameters associated with false-negative RADT test result. We subsequently simulated the outcome of different isolation strategies based on RADT result and host parameters in view of the overall isolation efficacy.Out of 242 hospitalized patients, 134 (55%) patients were found RSV positive by RT-PCR, whereas 108 (45%) patients were tested negative. The performance of the RADT was compared with the result obtained by reverse transcription polymerase chain reaction on the identical nasopharyngeal wash. Overall, we found that 85 patients (35%) were tested true positive, 108 (45%) were tested true negative, whereas a false-negative test result was obtained in 49 patients (20%). Duration of respiratory symptoms for >3 days and a respiratory admission diagnosis are associated with false-negative RADT result. In comparison with RADT alone, consideration of these clinical parameters and RADT result can decrease the rate of nonisolated RSV-infected patients from approximately 24% to 8% (65% RSV pretest probability).Consideration of both RADT and clinical parameters associated with false-negative RADT can result in an optimized RSV infection control policy. PMID- 25437025 TI - Independent influence of overweight and obesity on the regression of left ventricular hypertrophy in hypertensive patients: a meta-analysis. AB - Overweight and obesity are associated with adverse cardiovascular outcomes. However, the role of overweight and obesity in left ventricular hypertrophy (LVH) of hypertensive patients is controversial. The aim of the current meta-analysis was to evaluate the influence of overweight and obesity on LVH regression in the hypertensive population.Twenty-eight randomized controlled trials comprising 2403 hypertensive patients (mean age range: 43.8-66.7 years) were identified. Three groups were divided according to body mass index: normal weight, overweight, and obesity groups.Compared with the normal-weight group, LVH regression in the overweight and obesity groups was more obvious with less reduction of systolic blood pressure after antihypertensive therapies (P < 0.001). The renin angiotensin system inhibitor was the most effective in regressing LVH in overweight and obese hypertensive patients (19.27 g/m, 95% confidence interval [15.25, 23.29], P < 0.001), followed by beta-blockers, calcium channel blockers, and diuretics. In the stratified analysis based on blood pressure measurement methods and age, more significant LVH regression was found in 24-h ambulatory blood pressure monitoring (ABPM) group and in relatively young patients (40-60 years' old) group (P < 0.01).Overweight and obesity are independent risk factors for LVH in hypertensive patients. Intervention at an early age and monitoring by ABPM may facilitate therapy-induced LVH regression in overweight and obese hypertensive patients. PMID- 25437027 TI - Impact of environmental particulate matter and peritoneal dialysis-related infection in patients undergoing peritoneal dialysis. AB - In patients undergoing peritoneal dialysis (PD), PD-related infection is a major cause of PD failure and hospital admission. Good air quality is required when dialysate exchange or exit site wound care is performed. To our knowledge, investigation of air pollution as a factor for PD-related infection in patients undergoing dialysis is limited. This study aimed to assess the effect of environmental particulate matter (PM) and other important risk factors on 1-year PD-related infection in patients undergoing PD.A total of 175 patients undergoing PD were recruited in this 1-year retrospective observational study. Differences in environmental PMs (PM10 and PM2.5) were analyzed with respect to the patients' living areas. The patients undergoing PD were categorized into 2 groups according to PM2.5 exposure: high (n = 61) and low (n = 114). Demographic, hematological, nutritional, inflammatory, biochemical, and dialysis-related data were analyzed. Multivariate binary logistic and multivariate Cox regression analyses were used to analyze 1-year PD-related infection.A total of 175 patients undergoing PD (50 men and 125 women) were enrolled. Thirty-five patients had PD-related infection within 1 year. Multivariate Cox regression analysis showed that high environmental PM2.5 exposure (hazard ratio (HR): 2.0, 95% confidence interval [CI] [1.03-3.91]; P = .04) and female sex (HR: 2.77, 95% CI [1.07-7.19]; P = .03) were risk factors for 1-year PD-related infection.Patients undergoing PD with high environmental PM2.5 exposure had a higher 1-year PD-related infection rate than that in those with low exposure. Therefore, air pollution may be associated with PD-related infection in such patients. PMID- 25437028 TI - Association of the Charlson comorbidity index with renal outcome and all-cause mortality in antineutrophil cytoplasmatic antibody-associated vasculitis. AB - The aim of this study is to determine the effect of comorbidity assessed by the Charlson comorbidity index (CCI) at the time of diagnosis on the outcome of antineutrophil cytoplasmatic antibody (ANCA) associated vasculitis (AAV).This is a longitudinal observational study of 30 consecutive patients with AAV who were diagnosed and followed from January 1996 to December 2011. The degree of comorbidity at diagnosis and last visit was scored according to the age-adjusted Charlson comorbidity index (CCI (a)). The post hoc analysis of increment in CCI during the study period and its predictive value for patient and renal survival were analyzed.Thirty patients with AAV were included in this study. A higher CCI (a) at diagnosis was positively correlated with higher activity score of AAV (P = 0.016), a CCI (a) >5, and with an increased risk for mortality (odds ratio 12; confidence interval 1.8-79.68, P = 0.014). The mean increment (Delta) of CCI (a) during the study period was 1.26 +/- 2.03 (6-5). Correlation was found between lower Delta CCI (a) and chronic kidney disease (P = 0.036) and mortality (P = 0.002).Comorbidity at the time of diagnosis of AAV is associated with reduced patient and renal survival. We suggest including the CCI score in the assessment of patients with AAV at diagnosis and at disease relapse. PMID- 25437029 TI - Survival benefit and safety of no. 10 lymphadenectomy for gastric cancer patients with total gastrectomy. AB - This study was aimed to evaluate the survival benefit and safety of No. 10 lymphadenectomy for gastric cancer patients with total gastrectomy.Splenic hilar lymph nodes (LNs) are required to be dissected in total gastrectomy with D2 lymphadenectomy. However, there has still not been a consensus in aspects of survival and safety on No. 10 LN resection.From January 2006 to December 2011, 453 patients undergoing total gastrectomy for gastric cancer were retrospectively analyzed. Patients were grouped according to No. 10 lymphadenectomy (10D+/10D-). Clinicopathologic characteristics were compared between the 2 groups. These patients had undergone a follow-up until January 2014. The overall survival, morbidity, and mortality rate were analyzed. Subgroup analyses which were stratified by the sex, age, tumor location, lymphadenectomy extent, curative degree, differentiation, tumor size, and TNM staging (ie, stages of tumor) were performed.There were 220 patients in 10D+ group, whereas 233 in 10D- group. In terms of prognosis, the baseline features between the 2 groups were almost comparable. The incidence of No. 10 LN metastasis was 11.82%. There was no difference in morbidity and mortality between the 2 groups. Significantly more LNs were harvested from patients in 10D+ group (P = 0.000). The estimated overall 5-year survival rates were 46.44% and 37.43% in 10D+ group and 10D- group respectively, which is not statistically significant (P = 0.3288). Although no statistical significance was found in the estimated 5-year survival rate, these data were obviously higher in patients with age >60 years, Siewert II/ III tumors, N1 status, or IIIa/IIIc stages when No. 10 lymphadenectomies were performed.Although the differences were obvious, the 5-year survival rates between the 2 groups did not reach statistical significances, which was probably caused by too small patient samples. High-quality studies with larger sample sizes are needed before stronger statement can be done. Until then, the No. 10 LNs' resection might be recommended in total gastrectomy with D2 lymphadenectomy with an acceptable incidence of complications. PMID- 25437030 TI - The efficacy and toxicity of paclitaxel plus S-1 compared with paclitaxel plus 5 FU for advanced gastric cancer: a PRISMA systematic review and meta-analysis of randomized controlled trials. AB - The standard treatment for patients with advanced gastric cancer (AGC) is still a matter of debate. The chemotherapy regimen of paclitaxel (PTX) combined with S-1 has been used to treat AGC or metastatic gastric cancer.We conducted a meta analysis to compare oral S-1 and infusional 5-fluorouracil (5-FU) to determine which agent was more efficacious and less toxic in combination with PTX. A systematic review with a meta-analysis was performed. PubMed, EmBase, the Cochrane Central Register of Controlled Trials, and the China National Knowledge Infrastructure databases were searched to select randomized controlled trials (RCTs) comparing PTX plus S-1 and PTX plus 5-FU in patients with AGC.Three RCTs were eligible and 352 patients were analyzed. PTX plus S-1 increased the disease control rate (risk ratio [RR] = 1.14, 95% confidence interval [CI] = 1.00-1.30, P = 0.04) and reduced the progressive disease rate (RR = 0.62, 95% CI] = 0.39-0.98, P = 0.04) compared with PTX plus 5-FU. There was a significant decrease in nausea (RR = 0.60, 95% CI = 0.43-0.82, P = 0.001) and vomiting (RR = 0.55, 95% CI = 0.33 0.91, P = 0.02) in patients treated with PTX plus S-1.PTX plus S-1 was associated with almost equivalent safety and a lower progressive disease rate compared with PTX plus 5-FU. PTX plus S-1 is a good alternative strategy for patients who cannot tolerate a continuous intravenous infusion. PMID- 25437031 TI - Objective CT-based quantification of lung sequelae in treated patients with paracoccidioidomycosis. AB - This study presents methodology for objectively quantifying the pulmonary region affected by emphysemic and fibrotic sequelae in treated patients with paracoccidioidomycosis. This methodology may also be applied to any other disease that results in these sequelae in the lungs.Pulmonary high-resolution computed tomography examinations of 30 treated paracoccidioidomycosis patients were used in the study. The distribution of voxel attenuation coefficients was analyzed to determine the percentage of lung volume that consisted of emphysemic, fibrotic, and normal tissue. Algorithm outputs were compared with subjective evaluations by radiologists using a scale that is currently used for clinical diagnosis.Affected regions in the patient images were determined by computational analysis and compared with estimates by radiologists, revealing mean (+/- standard deviation) differences in the scores for fibrotic and emphysemic regions of 0.1% +/- 1.2% and -0.2% +/- 1.0%, respectively.The computational results showed a strong correlation with the radiologist estimates, but the computation results were more reproducible, objective, and reliable. PMID- 25437032 TI - Optimization of vitamin suppletion after Roux-en-Y gastric bypass surgery can lower postoperative deficiencies: a randomized controlled trial. AB - Iron, vitamin B12, and folic acid deficiencies are among the most common deficiencies occurring after laparoscopic Roux-en-Y gastric bypass (LRYGB). The present study evaluates the effectiveness of a specially designed multivitamin supplement (WLS Forte, FitForMe, Rotterdam, the Netherlands) specifically developed for LRYGB patients.A triple-blind, randomized, 12-month study was conducted comparing WLS forte with a standard multivitamin supplement (sMVS) containing approximately 100% of the recommended daily allowance (RDA) for iron, vitamin B12, and folic acid. WLS Forte contains vitamin B12 14000% RDA, iron 500% RDA, and folic acid 300% RDA.In total, 148 patients (74 in each group) underwent a LRYGB procedure. Baseline characteristics were similar for both groups. Per protocol analysis demonstrated that sMVS treatment was associated with a decline in ferritin (-24.4 +/- 70.1 MUg/L) and vitamin B12 (-45.9 +/- 150.3 pmol/L) over 12 months, whereas in WLS Forte patients, ferritin remained stable (+3.2 +/- 93.2 MUg/L) and vitamin B12 increased significantly (+55.1 +/- 144.2 pmol/L). The number of patients developing ferritin or vitamin B12 deficiency was significantly lower with WLS Forte compared with sMVS (P < 0.05). Iron deficiency (ID) was reduced by 88% after WLS Forte compared with sMVS. Adverse events related to supplement use did not occur.An optimized multivitamin supplement is safe and reduces the development of iron and vitamin B12 deficiencies after LRYGB. PMID- 25437033 TI - Effect of different antipsychotic drugs on short-term mortality in stroke patients. AB - The safety, tolerability, and efficacy data for antipsychotic drugs used in the acute phase of stroke are limited. The primary aim of this study was to examine the effectiveness and safety of typical and atypical antipsychotics on acute ischemic stroke mortality.This observational study was conducted in a retrospective cohort of patients selected from the 2010-2011 National Health Research Institute database in Taiwan. Patients were tracked for 1 month from the time of their first hospitalization for acute ischemic stroke. A nested case control analysis was used to estimate the odds ratio (OR) of 30-day mortality associated with antipsychotic drug, adjusted for age, gender, disease severity, and comorbidities.The study cohort included 47,225 subjects with ischemic stroke, including 9445 mortality cases and 37,780 matched controls. After adjustment for the covariates, antipsychotics users before ischemic stroke are associated with a 73% decrease in the rate of mortality (OR 0.27; 95% CI 0.23-0.31). After ischemic stroke, the use of antipsychotics is associated with 87% decrease in the rate of mortality (OR 0.13; 95% CI 0.1-0.16). The users of conventional antipsychotics are associated with a 78% decrease in the rate of mortality (OR 0.22; 95% CI 0.18 0.26). The users of atypical antipsychotics are also associated with a 86% decrease in the rate of mortality (OR 0.14; 95% CI 0.12-0.17).We found that 1 month mortality among acute stroke patients treated with antipsychotics is significantly lower. The benefit on lower mortality was found not only among ischemic stroke patients who had received antipsychotics previously but also among patients who start antipsychotics after their stroke. PMID- 25437034 TI - Role of damage control surgery in the treatment of Hinchey III and IV sigmoid diverticulitis: a tailored strategy. AB - Many of the treatment strategies for sigmoid diverticulitis are actually focusing on nonoperative and minimally invasive approaches. The aim of this systematic review was to evaluate the actual role of damage control surgery (DCS) in the treatment of generalized peritonitis caused by perforated sigmoid diverticulitis.A literature search was performed in PubMed and Google Scholar for articles published from 1960 to July 2013. Comparative and noncomparative studies that included patients who underwent DCS for complicated diverticulitis were considered.Acute Physiology and Chronic Health Evaluation score, duration of open abdomen, intensive care unit length of stay, reoperation, bowel resection performed at first operation, fecal diversion, method, and timing of closure of abdominal wall were the main outcomes of interest.According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses algorithm for the literature search and review, 10 studies were included in this systematic review. DCS was exclusively performed in diverticulitis patients with septic shock or requiring vasopressors intraoperatively. Two surgical different approaches were highlighted: limited resection of the diseased colonic segment with or without stoma or reconstruction in situ, and laparoscopic washing and drainage without colonic resection.Despite the heterogeneity of patient groups, clinical settings, and interventions included in this review, DCS appears to be a promising strategy for the treatment of Hinchey III and IV diverticulitis, complicated by septic shock. A tailored approach to each patient seems to be appropriate. PMID- 25437035 TI - Use of a Th1 Stimulator Adjuvant for Vaccination against Neospora caninum Infection in the Pregnant Mouse Model. AB - Vertical transmission from an infected cow to its fetus accounts for the vast majority of new Neospora caninum infections in cattle. A vaccine composed of a chimeric antigen named recNcMIC3-1-R, based on predicted immunogenic domains of the two microneme proteins NcMIC1 and NcMIC3, the rhoptry protein NcROP2, and emulsified in saponin adjuvants, significantly reduced the cerebral infection in non-pregnant BALB/c mice. Protection was associated with a mixed Th1/Th2-type cytokine response. However, the same vaccine formulation elicited a Th2-type immune response in pregnant mice and did not prevent vertical transmission or disease, neither in dams nor in offspring mice. In this study, an alternative vaccine formulation containing recNcMIC3-1-R emulsified in Freund's incomplete adjuvant, a stimulator of the cellular immunity, was investigated. No protection against vertical transmission and cerebral infection in the pregnant mice and a very limited protective effect in the non-pregnant mice were observed. The vaccine induced a Th1-type immune response characterized by high IgG2a titres and strong IFN-gamma expression, which appeared detrimental to pregnancy. PMID- 25437036 TI - Regenerative inflammation: lessons from Drosophila intestinal epithelium in health and disease. AB - Intestinal inflammation is widely recognized as a pivotal player in health and disease. Defined cytologically as the infiltration of leukocytes in the lamina propria layer of the intestine, it can damage the epithelium and, on a chronic basis, induce inflammatory bowel disease and potentially cancer. The current view thus dictates that blood cell infiltration is the instigator of intestinal inflammation and tumor-promoting inflammation. This is based partially on work in humans and mice showing that intestinal damage during microbially mediated inflammation activates phagocytic cells and lymphocytes that secrete inflammatory signals promoting tissue damage and tumorigenesis. Nevertheless, extensive parallel work in the Drosophila midgut shows that intestinal epithelium damage induces inflammatory signals and growth factors acting mainly in a paracrine manner to induce intestinal stem cell proliferation and tumor formation when genetically predisposed. This is accomplished without any apparent need to involve Drosophila hemocytes. Therefore, recent work on Drosophila host defense to infection by expanding its main focus on systemic immunity signaling pathways to include the study of organ homeostasis in health and disease shapes a new notion that epithelially emanating cytokines and growth factors can directly act on the intestinal stem cell niche to promote "regenerative inflammation" and potentially cancer. PMID- 25437037 TI - Henipavirus infections: lessons from animal models. AB - The Henipavirus genus contains two highly lethal viruses, the Hendra and Nipah viruses and one, recently discovered, apparently nonpathogenic member; Cedar virus. These three, negative-sense single-stranded RNA viruses, are hosted by fruit bats and use EphrinB2 receptors for entry into cells. The Hendra and Nipah viruses are zoonotic pathogens that emerged in the middle of 90s and have caused severe, and often fatal, neurologic and/or respiratory diseases in both humans and different animals; including spillover into equine and porcine species. Development of relevant models is critical for a better understanding of viral pathogenesis, generating new diagnostic tools, and assessing anti-viral therapeutics and vaccines. This review summarizes available data on several animal models where natural and/or experimental infection has been demonstrated; including pteroid bats, horses, pigs, cats, hamsters, guinea pigs, ferrets, and nonhuman primates. It recapitulates the principal features of viral pathogenesis in these animals and current knowledge on anti-viral immune responses. Lastly it describes the recently characterized murine animal model, which provides the possibility to use numerous and powerful tools available for mice to further decipher henipaviruses immunopathogenesis, prophylaxis, and treatment. The utility of different models to analyze important aspects of henipaviruses-induced disease in humans, potential routes of transmission, and therapeutic approaches are equally discussed. PMID- 25437039 TI - Presence of Viral Genome in Urine and Development of Hematuria and Pathological Changes in Kidneys in Common Marmoset (Callithrix jacchus) after Inoculation with Dengue Virus. AB - Common marmosets (Callithrix jacchus) developed high levels of viremia, clinical signs including fever, weight loss, a decrease in activity and hematuria upon inoculation with dengue virus (DENV). Presence of DENV genome in urine samples and pathological changes in kidneys were examined in the present study. Levels of DENV genome were determined in 228 urine samples from 20 primary DENV-inoculated marmosets and in 56 urine samples from four secondary DENV-inoculated marmosets. DENV genome was detected in 75% (15/20) of marmosets after primary DENV infection. No DENV genome was detected in urine samples from the marmosets with secondary infection with homologous DENV (0%, 0/4). Two marmosets demonstrated hematuria. Pathological analysis of the kidneys demonstrated non-suppressive interstitial nephritis with renal tubular regeneration. DENV antigen-positive cells were detected in kidneys. In human dengue virus infections, some patients present renal symptoms. The results indicate that marmosets recapitulate some aspects of the involvement of kidneys in human DENV infection, and suggest that marmosets are potentially useful for the studies of the pathogenesis of DENV infection, including kidneys. PMID- 25437040 TI - Animal models of varicella zoster virus infection. AB - Primary infection with varicella zoster virus (VZV) results in varicella (chickenpox) followed by the establishment of latency in sensory ganglia. Declining T cell immunity due to aging or immune suppressive treatments can lead to VZV reactivation and the development of herpes zoster (HZ, shingles). HZ is often associated with significant morbidity and occasionally mortality in elderly and immune compromised patients. There are currently two FDA-approved vaccines for the prevention of VZV: Varivax(r) (for varicella) and Zostavax(r) (for HZ). Both vaccines contain the live-attenuated Oka strain of VZV. Although highly immunogenic, a two-dose regimen is required to achieve a 99% seroconversion rate. Zostavax vaccination reduces the incidence of HZ by 51% within a 3-year period, but a significant reduction in vaccine-induced immunity is observed within the first year after vaccination. Developing more efficacious vaccines and therapeutics requires a better understanding of the host response to VZV. These studies have been hampered by the scarcity of animal models that recapitulate all aspects of VZV infections in humans. In this review, we describe different animal models of VZV infection as well as an alternative animal model that leverages the infection of Old World macaques with the highly related simian varicella virus (SVV) and discuss their contributions to our understanding of pathogenesis and immunity during VZV infection. PMID- 25437043 TI - Pathways of care the first year after moderate and severe traumatic brain injury discharge destinations and outpatient follow-up. AB - PRIMARY OBJECTIVE: To determine the pathways of care within the first year after traumatic brain injury (TBI) and to explore whether provided care is related to residual impairments. RESEARCH DESIGN: Retrospective study of 343 patients with moderate and severe TBI admitted to a Level-1 trauma centre. METHODS AND PROCEDURES: Discharge destinations from hospital to home and frequency of outpatient visits were determined. Outcome was defined 1 year after injury by the Extended Glasgow Outcome Scale and Return to Work. RESULTS: Most (94%) patients had returned home 1-year after injury despite cognitive (76%), behavioural (67%) and physical (55%) impairments. One in four patients was severely disabled and 32% had resumed work on a previous level. Two-thirds of all patients went home as secondary discharge destination and 50% needed inpatient rehabilitation. Almost half of patients needed outpatient care, mostly for behavioural and cognitive impairments. One in 10 patients consulted a psychiatrist, with 55% unfavourable outcome. Of those patients initially discharged to home without follow-up, eventually 10% needed outpatient rehabilitation. CONCLUSIONS: One-year after injury most patients had returned home with residual impairments and frequent medical consultations. This finding warrants further investigation to define appropriate aftercare by various medical specialists aimed at long-term community integration. PMID- 25437042 TI - Can we prevent antimicrobial resistance by using antimicrobials better? AB - Since their development over 60 years ago, antimicrobials have become an integral part of healthcare practice worldwide. Recently, this has been put in jeopardy by the emergence of widespread antimicrobial resistance, which is one of the major problems facing modern medicine. In the past, the development of new antimicrobials kept us one step ahead of the problem of resistance, but only three new classes of antimicrobials have reached the market in the last thirty years. A time is therefore approaching when we may not have effective treatment against bacterial infections, particularly for those that are caused by Gram negative organisms. An important strategy to reduce the development of antimicrobial resistance is to use antimicrobials more appropriately, in ways that will prevent resistance. This involves a consideration of the pharmacokinetic and pharmacodynamics properties of antimicrobials, the possible use of combinations, and more appropriate choice of antimicrobials, which may include rapid diagnostic testing and antimicrobial cycling. Examples given in this review include Mycobacterium tuberculosis, Gram-negative and Gram-positive organisms. We shall summarise the current evidence for these strategies and outline areas for future development. PMID- 25437041 TI - Animal models of tick-borne hemorrhagic Fever viruses. AB - Tick-borne hemorrhagic fever viruses (TBHFV) are detected throughout the African and Eurasian continents and are an emerging or re-emerging threat to many nations. Due to the largely sporadic incidences of these severe diseases, information on human cases and research activities in general have been limited. In the past decade, however, novel TBHFVs have emerged and areas of endemicity have expanded. Therefore, the development of countermeasures is of utmost importance in combating TBHFV as elimination of vectors and interrupting enzootic cycles is all but impossible and ecologically questionable. As in vivo models are the only way to test efficacy and safety of countermeasures, understanding of the available animal models and the development and refinement of animal models is critical in negating the detrimental impact of TBHFVs on public and animal health. PMID- 25437044 TI - An assessment of norepinephrine mediated hypertrophy to apoptosis transition in cardiac cells: a signal for cell death. AB - OBJECTIVES: Heart is an organ which is under a constant work load that generates numerous stress responses. Heart failure is associated with increased plasma norepinephrine (NE) and hypertrophic cell death. Within the current study we try to understand the concentration dependent molecular switch from hypertrophy to apoptosis under stress. METHODS: The effect of increasing concentration of NE on cell death was studied using MTT assay based on which further experimental conditions were decided. Trypan Blue staining and TUNEL assay were done at selected concentrations of NE. Cellular and nuclear morphology at these concentrations was studied using Haematoxylin-Eosin, DAPI and PI stains. The molecular switch between hypertrophy and cell death was studied by expression analysis of beta-MyHC and TNF-alpha. Rhodamine and DCFH-DA staining were done to evaluate the role of mitochondria and ROS under these conditions. Role of caspases under these transitions was also evaluated. RESULT: NE shows steep falls in cell viability at 50 MUM and 100 MUM concentrations. The cellular and nuclear morphology is altered at these concentrations along with alterations at molecular level showing a shift from hypertrophy towards cell death. Altered mitochondrial membrane potential and increase in ROS support this which leads to caspase dependent activation of cell death. CONCLUSION: We show that at 50 MUM NE, there occurs a transition from cellular hypertrophy towards death. This could be beneficial to prevent hypertrophy induced cardiac cell death and evaluating cardio protective therapeutic targets in vitro. PMID- 25437045 TI - The endometrial cancer cell lines Ishikawa and HEC-1A, and the control cell line HIEEC, differ in expression of estrogen biosynthetic and metabolic genes, and in androstenedione and estrone-sulfate metabolism. AB - Estrogens have important roles in the pathogenesis of endometrial cancer. They can have carcinogenic effects through stimulation of cell proliferation or formation of DNA-damaging species. To characterize model cell lines of endometrial cancer, we determined the expression profiles of the estrogen receptors (ERs) ESR1, ESR2 and GPER, and 23 estrogen biosynthetic and metabolic genes, and investigated estrogen biosynthesis in the control HIEEC cell line and the Ishikawa and HEC-1A EC cell lines. HIEEC and Ishikawa expressed all ERs to different extents, while HEC-1A cells lacked expression of ESR1. Considering the estrogen biosynthetic and metabolic enzymes, these cells showed statistically significant different gene expression profiles for SULT2B1, HSD3B2, CYP19A1, AKR1C3, HSD17B1, HSD17B7, HSD17B12, CYP1B1, CYP3A5, COMT, SULT1A1, GSTP1 and NQO2. In these cells, E2 was formed from E1S and E1, while androstenedione was not converted to estrogens. HIEEC and Ishikawa had similar profiles of androstenedione and E1 metabolism, but hydrolysis of E1S to E1 was weaker in Ishikawa cells. HEC-1A cells were less efficient for activation of E1 into the potent E2, but metabolized androstenedione to other androgenic metabolites better than HIEEC and Ishikawa cells. This study reveals that HIEEC, Ishikawa, and HEC 1A cells can all form estrogens only via the sulfatase pathway. HIEEC, Ishikawa, and HEC-1A cells expressed all the major genes in the production of hydroxyestrogens and estrogen quinones, and in their conjugation. Significantly higher CYP1B1 mRNA levels in Ishikawa cells compared to HEC-1A cells, together with lack of UGT2B7 expression, indicate that Ishikawa cells can accumulate more toxic estrogen-3,4-quinones than HEC-1A cells, as also for HIEEC cells. This study provides further characterization of HIEEC, Ishikawa, and HEC-1A cells, and shows that they differ greatly in expression of the genes investigated and in their capacity for E2 formation, and thus they represent different in vitro models. PMID- 25437046 TI - Meeting report: 11th EMBL conference on transcription and chromatin - August 23 26, 2014 - Heidelberg, Germany. PMID- 25437047 TI - Type 2 diabetes mellitus in relation to global LINE-1 DNA methylation in peripheral blood: a cohort study. AB - In the last years, epigenetic processes have emerged as a promising area of complex diseases research. DNA methylation measured in Long Interspersed Nucleotide Element 1 (LINE-1) sequences has been considered a surrogate marker for global genome methylation. New findings have suggested the potential involvement of epigenetic mechanisms in Type 2 diabetes (T2DM) as a crucial interface between the effects of genetic predisposition and environmental influences. Our study evaluated whether global DNA methylation predicted increased risk from T2DM or other carbohydrate metabolism disorders in a cohort study. We used a prospective cohort intervention study and a control group. We collected phenotypic, anthropometric, biochemical, and nutritional information from all subjects. Global LINE-1 DNA methylation was quantified by pyrosequencing technology. Subjects that did not improve their carbohydrate metabolism status showed lower levels of global LINE-1 DNA methylation (63.9 +/- 1.7 vs. 64.7 +/- 2.4) and they practiced less intense physical activity (5.8% vs. 21.5%). Logistic regression analyses showed a significant association between LINE-1 DNA methylation and metabolic status after adjustment for sex, age, BMI, and physical activity. Our study showed that lower LINE-1 DNA methylation levels were associated with a higher risk metabolic status worsening, independent of other classic risk factors. This finding highlights the potential role for epigenetic biomarkers as predictors of T2DM risk or other related metabolic disorders. PMID- 25437048 TI - Non-referenced genome assembly from epigenomic short-read data. AB - Current computational methods used to analyze changes in DNA methylation and chromatin modification rely on sequenced genomes. Here we describe a pipeline for the detection of these changes from short-read sequence data that does not require a reference genome. Open source software packages were used for sequence assembly, alignment, and measurement of differential enrichment. The method was evaluated by comparing results with reference-based results showing a strong correlation between chromatin modification and gene expression. We then used our de novo sequence assembly to build the DNA methylation profile for the non referenced Psammomys obesus genome. The pipeline described uses open source software for fast annotation and visualization of unreferenced genomic regions from short-read data. PMID- 25437038 TI - From in vitro to in vivo Models of Bacterial Biofilm-Related Infections. AB - The influence of microorganisms growing as sessile communities in a large number of human infections has been extensively studied and recognized for 30-40 years, therefore warranting intense scientific and medical research. Nonetheless, mimicking the biofilm-life style of bacteria and biofilm-related infections has been an arduous task. Models used to study biofilms range from simple in vitro to complex in vivo models of tissues or device-related infections. These different models have progressively contributed to the current knowledge of biofilm physiology within the host context. While far from a complete understanding of the multiple elements controlling the dynamic interactions between the host and biofilms, we are nowadays witnessing the emergence of promising preventive or curative strategies to fight biofilm-related infections. This review undertakes a comprehensive analysis of the literature from a historic perspective commenting on the contribution of the different models and discussing future venues and new approaches that can be merged with more traditional techniques in order to model biofilm-infections and efficiently fight them. PMID- 25437049 TI - Genome-wide DNA methylation analysis identifies a metabolic memory profile in patient-derived diabetic foot ulcer fibroblasts. AB - Diabetic foot ulcers (DFUs) are a serious complication of diabetes. Previous exposure to hyperglycemic conditions accelerates a decline in cellular function through metabolic memory despite normalization of glycemic control. Persistent, hyperglycemia-induced epigenetic patterns are considered a central mechanism that activates metabolic memory; however, this has not been investigated in patient derived fibroblasts from DFUs. We generated a cohort of patient-derived lines from DFU fibroblasts (DFUF), and site- and age-matched diabetic foot fibroblasts (DFF) and non-diabetic foot fibroblasts (NFF) to investigate global and genome wide DNA methylation patterns using liquid chromatography/mass spectrometry and the Illumina Infinium HumanMethylation450K array. DFFs and DFUFs demonstrated significantly lower global DNA methylation compared to NFFs (p = 0.03). Hierarchical clustering of differentially methylated probes (DMPs, p = 0.05) showed that DFFs and DFUFs cluster together and separately from NFFs. Twenty-five percent of the same probes were identified as DMPs when individually comparing DFF and DFUF to NFF. Functional annotation identified enrichment of DMPs associated with genes critical to wound repair, including angiogenesis (p = 0.07) and extracellular matrix assembly (p = 0.035). Identification of sustained DNA methylation patterns in patient-derived fibroblasts after prolonged passage in normoglycemic conditions demonstrates persistent metabolic memory. These findings suggest that epigenetic-related metabolic memory may also underlie differences in wound healing phenotypes and can potentially identify therapeutic targets. PMID- 25437050 TI - Cell line differences in replication timing of human glutamate receptor genes and other large genes associated with neural disease. AB - There is considerable current interest in the function of epigenetic mechanisms in neuroplasticity with regard to learning and memory formation and to a range of neural diseases. Previously, we described replication timing on human chromosome 21q in the THP-1 human cell line (2n = 46, XY) and showed that several genes associated with neural diseases, such as the neuronal glutamate receptor subunit GluR-5 (GRIK1) and amyloid precursor protein (APP), were located in regions where replication timing transitioned from early to late S phase. Here, we compared replication timing of all known human glutamate receptor genes (26 genes in total) and APP in 6 different human cell lines including human neuron-related cell lines. Replication timings were obtained by integrating our previously reported data with new data generated here and information from the online database ReplicationDomain. We found that many of the glutamate receptor genes were clearly located in replication timing transition zones in neural precursor cells, but this relationship was less clear in embryonic stem cells before neural differentiation; in the latter, the genes were often located in later replication timing zones that displayed DNA hypermethylation. Analysis of selected large glutamate receptor genes (> 200 kb), and of APP, showed that their precise replication timing patterns differed among the cell lines. We propose that the transition zones of DNA replication timing are altered by epigenetic mechanisms, and that these changes may affect the neuroplasticity that is important to memory and learning, and may also have a role in the development of neural diseases. PMID- 25437051 TI - A comparison of DNA methylation specific droplet digital PCR (ddPCR) and real time qPCR with flow cytometry in characterizing human T cells in peripheral blood. AB - Quantitating the copy number of demethylated CpG promoter sites of the CD3Z gene can be used to estimate the numbers and proportions of T cells in human blood and tissue. Quantitative methylation specific PCR (qPCR) is useful for studying T cells but requires extensive calibration and is imprecise at low copy numbers. Here we compared the performance of a new digital PCR platform (droplet digital PCR or ddPCR) to qPCR using bisulfite converted DNA from 157 blood specimens obtained from ambulatory care controls and patients with primary glioma. We compared both ddPCR and qPCR with conventional flow cytometry (FACS) evaluation of CD3 positive T cells. Repeated measures on the same blood sample revealed ddPCR to be less variable than qPCR. Both qPCR and ddPCR correlated significantly with FACS evaluation of peripheral blood CD3 counts and CD3/total leukocyte values. However, statistical measures of agreement showed that linear concordance was stronger for ddPCR than for qPCR and the absolute values were closer to FACS for ddPCR. Both qPCR and ddPCR could distinguish clinically significant differences in T cell proportions and performed similarly to FACS. Given the higher precision, greater accuracy, and technical simplicity of ddPCR, this approach appears to be a superior DNA methylation based method than conventional qPCR for the assessment of T cells. PMID- 25437052 TI - HLA-DRB1 and HLA-DQB1 methylation changes promote the occurrence and progression of Kazakh ESCC. AB - Human leukocyte antigen II (HLA-II) plays an important role in host immune responses to cancer cells. Changes in gene methylation may result in aberrant expression of HLA-II, serving a key role in the pathogenesis of Kazakh esophageal squamous cell carcinoma (ESCC). We analyzed the expression level of HLA-II (HLA DP, -DQ, and -DR) by immunohistochemistry, as well as the methylation status of HLA-DRB1 and HLA-DQB1 by MassARRAY spectrometry in Xinjiang Kazakh ESCC. Expression of HLA-II in ESCC was significantly higher than that in cancer adjacent normal (ACN) samples (P < 0.05). Decreased HLA-II expression was closely associated with later clinical stages of ESCC (P < 0.05). Hypomethylation of HLA DRB1 and hypermethylation of HLA-DQB1 was significantly correlated with occurrence of Kazakh ESCC (P < 0.01), and mainly manifested as hypomethylation of CpG9, CpG10-11, and CpG16 in HLA-DRB1 and hypermethylation of CpG6-7 and CpG16-17 in HLA-DQB1 (P < 0.01). Moreover, hypomethylation of HLA-DQB1 CpG6-7 correlated with poor differentiation in ESCCs, whereas hypermethylation of HLA-DRB1 CpG16 and hypomethylation of HLA-DQB1 CpG16-17 were significantly associated with later stages of ESCC (P < 0.05). A significant inverse association between HLA-DRB1 CpG9 methylation and HLA-II expression was found in ESCC (P < 0.05). These findings suggest aberrant HLA-DRB1 and HLA-DQB1 methylation contributes to the aberrant expression of HLA-II. These molecular changes may influence the immune response to specific tumor epitopes, promoting the occurrence and progression of Kazakh ESCC. PMID- 25437053 TI - Global histone deacetylase enzymatic activity is an independent prognostic marker associated with a shorter overall survival in chronic lymphocytic leukemia patients. AB - Histone deacetylases (HDAC) play a crucial role in transcriptional regulation and are often deregulated in many cancers. However, global HDAC enzymatic activity has never been investigated in Chronic Lymphocytic Leukemia (CLL). We measured HDAC activity in protein extracts from CD19+ B-cells purified from 114 CLL patients with a median follow-up of 91 months (range: 11-376). HDAC activity was equivalent in CLL and normal B-cells but higher in patients who died during the study than in living patients (152.1 vs. 65.04 pmol; P = 0.0060). Furthermore, HDAC activity correlated with treatment-free survival (TFS; P = 0.0156) and overall survival (OS; P < 0.0001): patients with low HDAC activity (n = 75) had a median TFS and OS of 101 and > 376 months, respectively, whereas patients with high HDAC activity (n = 39) had a median TFS and OS of 47 and 137 months, respectively. Multivariate analyses indicated that HDAC activity is an independent predictor of OS (hazard ratio = 7.68; P = 0.0017). Finally, HDAC activity increased after B-cell receptor stimulation using IgM, suggesting a role for microenvironment stimuli (n = 10; P = 0.0371). In conclusion, high HDAC activity in CLL B-cells is associated with shorter TFS and OS and is an independent marker of OS, refining the use of other prognostic factors. This work provides a biological base for the use of HDAC inhibitors in CLL treatment. PMID- 25437054 TI - Using RNA sequencing for identifying gene imprinting and random monoallelic expression in human placenta. AB - Given the possible critical importance of placental gene imprinting and random monoallelic expression on fetal and infant health, most of those genes must be identified, in order to understand the risks that the baby might meet during pregnancy and after birth. Therefore, the aim of the current study was to introduce a workflow and tools for analyzing imprinted and random monoallelic gene expression in human placenta, by applying whole-transcriptome (WT) RNA sequencing of placental tissue and genotyping of coding DNA variants in family trios. Ten family trios, each with a healthy spontaneous single-term pregnancy, were recruited. Total RNA was extracted for WT analysis, providing the full sequence information for the placental transcriptome. Parental and child blood DNA genotypes were analyzed by exome SNP genotyping microarrays, mapping the inheritance and estimating the abundance of parental expressed alleles. Imprinted genes showed consistent expression from either parental allele, as demonstrated by the SNP content of sequenced transcripts, while monoallelically expressed genes had random activity of parental alleles. We revealed 4 novel possible imprinted genes (LGALS8, LGALS14, PAPPA2 and SPTLC3) and confirmed the imprinting of 4 genes (AIM1, PEG10, RHOBTB3 and ZFAT-AS1) in human placenta. The major finding was the identification of 4 genes (ABP1, BCLAF1, IFI30 and ZFAT) with random allelic bias, expressing one of the parental alleles preferentially. The main functions of the imprinted and monoallelically expressed genes included: i) mediating cellular apoptosis and tissue development; ii) regulating inflammation and immune system; iii) facilitating metabolic processes; and iv) regulating cell cycle. PMID- 25437055 TI - Genome-wide DNA methylation variability in adolescent monozygotic twins followed since birth. AB - DNA methylation patterns are characterized by highly conserved developmental programs, but allow for divergent gene expression resulting from stochastic epigenetic drift or divergent environments. Genome-wide methylation studies in monozygotic (MZ) twins are providing insight into the extent of epigenetic variation that occurs, irrespective of genotype. However, little is known about the variability of DNA methylation patterns in adolescence, a period involving significant and rapid physical, emotional, social, and neurodevelopmental change. Here, we assessed genome-wide DNA methylation using the 450 K Illumina BeadChip in a sample of 37 MZ twin pairs followed longitudinally since birth to investigate: 1) the extent of variation in DNA methylation in identical genetic backgrounds in adolescence and; 2) whether these variations are randomly distributed or enriched in particular functional pathways. We also assessed stability of DNA methylation over 3-6 months to distinguish stable trait-like and variable state-like genes. A pathway analysis found high within-pair variability in genes associated with development, cellular mechanisms, tissue and cell morphology, and various disorders. Test-retest analyses performed in a sub-sample of 8 twin pairs demonstrated enrichment in gene pathways involved in organismal development, cellular growth and proliferation, cell signaling, and particular disorders. The variability found in functional gene pathways may plausibly underlie phenotypic differences in this adolescent MZ twin sample. Furthermore, we assessed stability of methylation over 3-6 months and found that some genes were stable while others were unstable, suggesting that the methylome remains dynamic in adolescence and that dynamic sites tend to be organized in certain gene pathways. PMID- 25437056 TI - Altered promoter nucleosome positioning is an early event in gene silencing. AB - Gene silencing in cancer frequently involves hypermethylation and dense nucleosome occupancy across promoter regions. How a promoter transitions to this silent state is unclear. Using colorectal adenomas, we investigated nucleosome positioning, DNA methylation, and gene expression in the early stages of gene silencing. Genome-wide gene expression correlated with highly positioned nucleosomes upstream and downstream of a nucleosome-depleted transcription start site (TSS). Hypermethylated promoters displayed increased nucleosome occupancy, specifically at the TSS. We investigated 2 genes, CDH1 and CDKN2B, which were silenced in adenomas but lacked promoter hypermethylation. Instead, silencing correlated with loss of nucleosomes from the -2 position upstream of the TSS relative to normal mucosa. In contrast, permanent CDH1 silencing in carcinoma cells was characterized by promoter hypermethylation and dense nucleosome occupancy. Our findings suggest that silenced genes transition through an intermediary stage involving altered promoter nucleosome positioning, before permanent silencing by hypermethylation and dense nucleosome occupancy. PMID- 25437057 TI - MLH1 constitutional and somatic methylation in patients with MLH1 negative tumors fulfilling the revised Bethesda criteria. AB - Lynch syndrome (LS) is a tumor predisposing condition caused by constitutional defects in genes coding for components of the mismatch repair (MMR) apparatus. While hypermethylation of the promoter of the MMR gene MLH1 occurs in about 15% of colorectal cancer samples, it has also been observed as a constitutional alteration, in the absence of DNA sequence mutations, in a small number of LS patients. In order to obtain further insights on the phenotypic characteristics of MLH1 epimutation carriers, we investigated the somatic and constitutional MLH1 methylation status of 14 unrelated subjects with a suspicion of LS who were negative for MMR gene constitutional mutations and whose tumors did not express the MLH1 protein. A novel case of constitutional MLH1 epimutation was identified. This patient was affected with multiple primary tumors, including breast cancer, diagnosed starting from the age of 55 y. Investigation of her offspring by allele specific expression revealed that the epimutation was not stable across generations. We also found MLH1 hypermethylation in cancer samples from 4 additional patients who did not have evidence of constitutional defects. These patients had some characteristics of LS, namely early age at onset and/or positive family history, raising the possibility of genetic influences in the establishment of somatic MLH1 methylation. PMID- 25437058 TI - Gay/queer dynamics and the question of sexual history and identity. AB - This article examines how the essentialist/constructionist and gay/queer divides have been structured by a division between closed and open notions, and it then argues that these gay and queer notions also interrelate. It argues that unhistoricist queer theory has recently drawn attention to this closed/open interrelationship by inadvertently raising (a) doubts about the irreducible openness of queer; (b) questions about its fundamentalism; and (c) reservations about its ability to handle the re-emerging issues of consonances between sexual concepts across history and the importance, usages, and allure of sexual identities. I argue that these concerns are well grounded, and that queer theory may thus have reached its expiration date. PMID- 25437059 TI - Unpasteurised commercial boza as a source of microbial diversity. AB - Boza is a cereal-based fermented beverage widely consumed in many countries of the Balkans. The aim of this study was to investigate the microbiota of three Bulgarian boza samples through a combination of culture-dependent and independent methods with the long-term objective of formulating a multi-strain starter culture specifically destined for the manufacture of new cereal-based drinks. The isolation campaign for lactic acid bacteria (LAB) allowed the identification of Lactobacillus parabuchneri, Lactobacillus fermentum, Lactobacillus coryniformis, Lactobacillus buchneri, Pediococcus parvulus and members of the Lactobacillus casei group. Concerning yeasts, the following isolates were identified: Pichia fermentans, Pichia norvegensis, Pichia guilliermondii (synonym Meyerozyma guilliermondii) and Torulaspora spp. A high intra-species diversity was revealed by Randomly Amplified Polymorphic DNA (RAPD) analysis. In parallel, microbial DNA was directly extracted from the three boza samples, and portions of the rrn operons were analysed through Polymerase Chain Reaction-Denaturing Gradient Gel Electrophoresis (PCR-DGGE). The molecular fingerprinting partially confirmed the results of culturing. Among LAB, the species Weissella confusa, Weissella oryzae, Leuconostoc citreum, Lactococcus lactis, Pediococcus parvulus and Pediococcus ethanolidurans were detected together with members of the Lb. casei group. Among the yeasts, the species P. fermentans, M. guilliermondii, Galactomyces geotrichum and Geotrichum fragrans were found. The overall results confirmed boza as having a rich and heterogeneous biodiversity both in terms of species and genetically diverse strains, thus encouraging its exploitation for the isolation and future technological characterisation of cultures to be selected for the manufacture of innovative cereal-based drinks. PMID- 25437060 TI - Relationship between ecophysiological factors, growth and ochratoxin A contamination of dry-cured sausage based matrices. AB - Dry-cured sausages are colonised by moulds during the ripening process. The temperature and the salt content (which affects water activity, aw) predispose the surface to colonisation by Penicillium species, including Penicillium nordicum and Penicillium verrucosum which can lead to contamination of the sausages with ochratoxin A (OTA). The objective of this work was to obtain scientific data on the impact that interaction between ionic water stress (aw; 0.97, 0.94, 0.90, 0.87 and 0.84) and temperature (30, 25, 20, 15 and 10 degrees C) may have on lag phases prior to growth, growth and OTA production by some P. verrucosum and P. nordicum strains isolated from dry-cured meat products on a dry cured sausage-based medium over a period of 12days. Although P. nordicum had shorter lag phases than P. verrucosum, the latter grew faster than P. nordicum in most conditions tested. For both species, there was no growth and OTA production at 0.84 aw at all the temperatures tested. The fungi were more tolerant at moderate ionic aw conditions (0.94 and 0.90) and 20 and 25 degrees C. In contrast, the patterns of production of OTA were very different from those for growth. Different OTA production profiles between the two OTA-producing species were found. While P. nordicum began producing OTA in most of the conditions tested by day 6, P. verrucosum only produced the toxin in these conditions when the temperature and aw were >10 degrees C and >0.90, respectively. However, the P. verrucosum strain produced much higher concentrations of OTA than the P. nordicum strain in all conditions. We developed contour maps of the optimum and marginal aw*temperature conditions for growth/OTA production on dry-cured sausage based medium for the first time. This suggests that these interacting conditions during the early phases of production must be effectively controlled as these favour growth of the toxigenic Penicillia. Knowledge on the ecophysiology of these two important Penicillium species on these matrices could help to make appropriate technological modifications during the sausage ripening process. Thus, our findings may help in informed decision-making in relation to temperature and salt additions at the beginning of processing/curing. Such changes may favour colonisation of starter cultures over OTA producing Penicillia and minimise OTA contamination risks in dry-cured sausages. This may be then effectively incorporated into the hygienic production system in the framework of HACCP. PMID- 25437061 TI - Binary release of ascorbic acid and lecithin from core-shell nanofibers on blood contacting surface for reducing long-term hemolysis of erythrocyte. AB - There is an urgent need to develop blood-contacting biomaterials with long-term anti-hemolytic capability. To obtain such biomaterials, we coaxially electrospin [ascorbic acid (AA) and lecithin]/poly (ethylene oxide) (PEO) core-shell nanofibers onto the surface of styrene-b-(ethylene-co-butylene)-b-styrene elastomer (SEBS) that has been grafted with poly (ethylene glycol) (PEG) chains. Our strategy is based on that the grafted layers of PEG render the surface hydrophilic to reduce the mechanical injure to red blood cells (RBCs) while the AA and lecithin released from nanofibers on blood-contacting surface can actively interact with RBCs to decrease the oxidative damage to RBCs. We demonstrate that (AA and lecithin)/PEO core-shell structured nanofibers have been fabricated on the PEG grafted surface. The binary release of AA and lecithin in the distilled water is in a controlled manner and lasts for almost 5 days; during RBCs preservation, AA acts as an antioxidant and lecithin as a lipid supplier to the membrane of erythrocytes, resulting in low mechanical fragility and hemolysis of RBCs, as well as high deformability of stored RBCs. Our work thus makes a new approach to fabricate blood-contacting biomaterials with the capability of long term anti-hemolysis. PMID- 25437062 TI - Bacterial interactions and transport in geological formation of alumino-silica clays. AB - Bacterial transport in the subsurface is controlled by their interactions with the surrounding environment, which are determined by the surface properties of the geological formation and bacterial surfaces. In this research, surface thermodynamic properties of Escherichia coli and the geological formation of alumino-silica clays were characterized based on contact angle measurements, which were utilized to quantify the distance-dependent interactions between E. coli and the geological formation according to the traditional and extended Derjaguin, Landau, Verwey and Overbeek (DLVO) theory. E. coli attachment to alumino-silica clays was evaluated in laboratory columns under saturated and steady-state flow conditions. E. coli deposition coefficient and desorption coefficient were simulated using convection-dispersion transport models against E. coli breakthrough curves, which were then linked to interactions between E. coli and the geological formation. It was discovered that E. coli deposition was controlled by the long-ranged electrostatic interaction and E. coli desorption was attributed to the short-ranged Lifshitz-van der Waals and Lewis acid-base interactions. E. coli transport in three layers of different alumino-silica clays was further examined and the breakthrough curve was simulated using E. coli deposition coefficient and desorption coefficient obtained from their individual column experiments. The well-fitted simulation confirmed that E. coli transport observations were interaction-dependent phenomena between E. coli and the geological formation. PMID- 25437063 TI - Controllable promotion of chondrocyte adhesion and growth on PVA hydrogels by controlled release of TGF-beta1 from porous PLGA microspheres. AB - Poly(vinyl alcohol) (PVA) hydrogels have been candidate materials for cartilage tissue engineering. However, the cell non-adhesive nature of PVA hydrogels has been a limit. In this paper, the cell adhesion and growth on PVA hydrogels were promoted by compositing with transform growth factor-beta1 (TGF-beta1) loaded porous poly(D,L-lactide-co-glycolide) (PLGA) microspheres. The porous microspheres were fabricated by a modified double emulsion method with bovine serum albumin (BSA) as porogen. The average pore size of microspheres was manipulated by changing the BSA/PLGA ratio. Such controllable porous structures effectively influenced the encapsulation efficiency (Eencaps) and release profile of TGF-beta1. By compositing PVA hydrogels with such TGF-beta1-loaded PLGA microspheres, chondrocyte adhesion and proliferation were significantly promoted in a controllable manner, as confirmed by fluorescent imaging and quantitative CCK-8 assay. That is, the chondrocyte proliferation was favored by using PLGA microspheres with high Eencaps of TGF-beta1 or by increasing the PLGA microsphere content in the hydrogels. These results demonstrated a facile method to improve the cell adhesion and growth on the intrinsically cell non-adhesive PVA hydrogels, which may find applications in cartilage substitution. PMID- 25437064 TI - Design and in vitro evaluation of biocompatible dexamethasone-loaded nanoparticle dispersions, obtained from nano-emulsions, for inhalatory therapy. AB - Polymeric nanoparticle dispersions containing dexamethasone (DXM) have been prepared from O/W nano-emulsions of the water/polysorbate 80/[4 wt% poly(lactide co-glycolide) acid+0.18 wt% DXM in ethyl acetate] system by a low-energy method at 25 degrees C. Nano-emulsions were formed at O/S ratios between 45/55 and 72/25 and water contents above 70 wt% by the phase inversion composition (PIC) method. The mean hydrodynamic diameter of nano-emulsions with a constant water content of 90 wt% and O/S ratios from 50/50 to 70/30 was below 350 nm as assessed by dynamic light scattering. The nanoparticles obtained from these nano-emulsions (by solvent evaporation) showed mean diameters of around 130 nm, as determined by transmission electron microscopy image analysis. Therapeutic concentrations of DXM were encapsulated in the nano-emulsions prior to nanoparticle preparation. DXM entrapment efficiency of the nanoparticle dispersion (above 74 wt%) decreased at increasing O/S ratios of the precursor nano-emulsion while DXM loading, which was around 10 mg/100 mL, showed the reverse tendency. DXM release from nanoparticle dispersions was about an order of magnitude slower than from an aqueous solution. In vitro studies performed in a lung carcinoma cell line and in vitro haemolysis studies performed in red blood cells revealed a dose-dependent toxicity and haemolytic response, respectively. The as-prepared nanoparticle dispersions were non-toxic up to a concentration of 40 MUg/mL and non-haemolytic up to a concentration of 1 mg/mL. After purification, nanoparticle dispersions were non-toxic up to a concentration of 90 MUg/mL. These results allow concluding that these polymeric nanoparticle dispersions are good candidates for inhalatory therapy. PMID- 25437065 TI - Paclitaxel/epigallocatechin gallate coloaded liposome: a synergistic delivery to control the invasiveness of MDA-MB-231 breast cancer cells. AB - Matrix metalloproteinases (MMPs) have been investigated as a potential target for treating invasive breast cancers. The chemotherapy for breast cancer is often prescribed as a combination of drugs. The present study investigates a novel strategy of combining a MMP inhibitor, Epigallocatechin gallate (EGCG), along with an anticancer drug, Paclitaxel (PTX), in the form of a liposomal co-delivery system. The developed PTX/EGCG co-loaded liposomes showed an entrapment of 77.11+/-2.30% and 59.11+/-3.51% for PTX and EGCG, respectively. The in vitro efficacy of the liposomes was assessed by their ability to promote apoptosis and curtail cell invasion. On all parameters, namely cytotoxicity and caspase-3 activity that are indicators of apoptosis, and MMP-2 and - 9 inhibition and invasion assays that are indicators of cell invasion, the PTX/EGCG co-loaded liposomes showed better results than each of the individual drug loaded liposomes. These findings demonstrate the synergistic outcome of PTX/EGCG combination and indicate the suitability of PTX/EGCG co-loaded liposomes for the treatment of invasive breast cancer. PMID- 25437066 TI - Molybdenum nanoparticles-induced cytotoxicity, oxidative stress, G2/M arrest, and DNA damage in mouse skin fibroblast cells (L929). AB - The present investigation was aimed to study the cytotoxicity, oxidative stress, and genotoxicity induced by molybdenum nanoparticles (Mo-NPs) in mouse skin fibroblast cells (L929). Cells were exposed to different concentrations (1-100 MUg/ml) of Mo-NPs (size 40 nm) for 24 and 48 h. After the exposure, different cytotoxicity assays (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide, MTT; neutral red uptake, NRU; and cellular morphology) and oxidative stress markers (lipid peroxidation, LPO; glutathione, GSH; and catalase) were studied. Further, Mo-NPs-induced intracellular reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), cell cycle arrest, and DNA damage were also studied. L929 cells treated with Mo-NPs showed a concentration- and time-dependent decrease in cell viability and a loss of the normal cell morphology. The percentage cell viability was recorded as 25%, 42%, and 58% by MTT assay and 24%, 46%, and 56% by NRU assay at 25, 50, and 100 MUg/ml of Mo-NPs, respectively after 48 h exposure. Furthermore, the cells showed a significant induction of oxidative stress. This was confirmed by the increase in LPO and ROS generation, as well as the decrease in the GSH and catalase levels. The decrease in MMP also confirms the impaired mitochondrial membrane. The cell cycle analysis and comet assay data revealed that Mo-NPs induced G2/M arrest and DNA damage in a concentration-dependent manner. Our results demonstrated, for the first time, Mo NPs induced cytotoxicity, oxidative stress and genotoxicity in L929 cells. Thus, data suggest the potential hazardous nature of Mo-NPs. PMID- 25437067 TI - RGD peptide-modified multifunctional dendrimer platform for drug encapsulation and targeted inhibition of cancer cells. AB - Development of multifunctional nanoscale drug-delivery systems for targeted cancer therapy still remains a great challenge. Here, we report the synthesis of cyclic arginine-glycine-aspartic acid (RGD) peptide-conjugated generation 5 (G5) poly(amidoamine) dendrimers for anticancer drug encapsulation and targeted therapy of cancer cells overexpressing alphavbeta3 integrins. In this study, amine-terminated G5 dendrimers were used as a platform to be sequentially modified with fluorescein isothiocyanate (FI) via a thiourea linkage and RGD peptide via a polyethylene glycol (PEG) spacer, followed by acetylation of the remaining dendrimer terminal amines. The developed multifunctional dendrimer platform (G5.NHAc-FI-PEG-RGD) was then used to encapsulate an anticancer drug doxorubicin (DOX). We show that approximately six DOX molecules are able to be encapsulated within each dendrimer platform. The formed complexes are water soluble, stable, and able to release DOX in a sustained manner. One- and two dimensional NMR techniques were applied to investigate the interaction between dendrimers and DOX, and the impact of the environmental pH on the release rate of DOX from the dendrimer/DOX complexes was also explored. Furthermore, cell biological studies demonstrate that the encapsulation of DOX within the G5.NHAc FI-PEG-RGD dendrimers does not compromise the anticancer activity of DOX and that the therapeutic efficacy of the dendrimer/DOX complexes is solely related to the encapsulated DOX drug. Importantly, thanks to the role played by RGD-mediated targeting, the developed dendrimer/drug complexes are able to specifically target alphavbeta3 integrin-overexpressing cancer cells and display specific therapeutic efficacy to the target cells. The developed RGD peptide-targeted multifunctional dendrimers may thus be used as a versatile platform for targeted therapy of different types of alphavbeta3 integrin-overexpressing cancer cells. PMID- 25437068 TI - An exploratory study on risk factors for chronic non-communicable diseases among adolescents in Malaysia: overview of the Malaysian Health and Adolescents Longitudinal Research Team study (The MyHeART study). AB - BACKGROUND: The National Health & Morbidity Survey (NHMS) IV (2011) observed that the prevalence of obese children aged less than 18 years in Malaysia is 6.1% compared to 5.4% overweight and obese in NHMS III (2006). As such, this observation is of public health importance as obesity is a forewarning risk factor for chronic diseases such as type-2 diabetes, cardiovascular diseases (CVD) and certain types of cancers. This MyHeART (Malaysian Health and Adolescents longitudinal Research Team) study aims to examine risk factors of non communicable diseases (NCD) among adolescents. METHODS/DESIGN: The MyHeART study is longitudinal cohort study of 1361 schoolchildren (13-years old) attending 15 public secondary schools from the central (Kuala Lumpur and Selangor) and northern (Perak) regions of Peninsular Malaysia. The study used a stratified sampling design to select the study participants. Data collected at baseline included socio-economic, lifestyle (e.g. smoking, physical activity assessment, fitness assessment, seven-day diet history), and environmental information, anthropometric measurements, blood pressure, handgrip strength and bone mineral density. Blood samples for fasting blood glucose and lipid profiles, full blood count, renal profile, as well as bone profile and serum vitamin D were taken. This study cohort will be followed up again when participants turn 15, 17 and lastly, after a period of ten years (around the age of 27). RESULTS: Nine percent of the adolescents from this study were obese. More male participants smoked compared to female participants (15.4% vs. 4.7%). Adolescent males had higher fasting blood glucose but the female participants had lower high density lipoprotein (HDL-cholesterol) and higher low density lipoprotein (LDL cholesterol). In addition, adolescents from the rural area had higher fasting blood glucose, diastolic blood pressure, total cholesterol and LDL-cholesterol. DISCUSSION: Our results demonstrated that adolescents from the rural area are at higher risk of NCDs compared to their urban counterpart. Tailor made public health interventions are highly recommended for adolescents as this may minimise the dreadful NCD burden in adulthood and health disparity between the rural and urban in the near future. PMID- 25437069 TI - Production of in-vitro refolded and highly antigenic SAG1 for development of a sensitive and specific Toxoplasma IgG ELISA. AB - Recombinant antigens are increasingly applied to replace native antigens in serological tests. Surface antigen 1 (SAG1) is a highly immunogenic antigen and probably represents the most explored and used antigen of Toxoplasma gondii for development of serological test kits. The presence of six disulfide bridges in its structure makes SAG1 a highly conformational protein. In fact, antigenicity of SAG1 is greatly dependent on proper disulfide bonding and folding. In-vitro refolding of SAG1 inclusion bodies, produced in Escherichia coli, was reported to result in soluble and antigenic protein. We produced SAG1 in E. coli and highly purified it by a single denaturing immobilized metal affinity chromatography. Refolding of denatured SAG1 was performed by (a) dialysis in the presence of reduced/oxidized glutathione, (b) drop-wise dilution and (c) drop-wise dilution in the presence of CuSo4. Refolding in the presence of oxido-shuffling reagent was much more efficient in producing presumably correctly-folded and highly antigenic SAG1 as demonstrated by non-reducing SDS-gel electrophoresis, ELISA, Western blotting and reversed-phase HPLC. An IgG ELISA developed using SAG1 refolded in the presence of oxido-shuffling reagent displayed high sensitivity and specificity for detection of Toxoplasma IgG antibodies in pregnant women. PMID- 25437070 TI - Bilateral distal tibial transitional ankle fractures. AB - A 13-year-old boy presented to the emergency department with bilateral ankle pain and swelling following a 5-foot fall from a swing set. PMID- 25437071 TI - Microfracture: dead or the future? PMID- 25437072 TI - Dorsal multiple plating without routine transarticular screws for fixation of Lisfranc injury. AB - Following a Lisfranc joint injury, stable fixation of the tarsometatarsal joints is crucial to avoid deformity and posttraumatic osteoarthritis, but the ideal method of fixation remains controversial. Kirschner wire (K-wire) fixation of all involved joints with cast immobilization resulted in loss of position, and was replaced by open reduction with improved fixation using transarticular screws. However, it seems intuitive that transarticular screws will result in further damage to already traumatized joints, and this has led to plate-spanning techniques. The objective of this study was to describe the method of dorsal multiple plating without the routine use of transarticular screws, and to report on the ability of plate fixation to maintain alignment comparable to that of transarticular screw fixation in 15 patients. PMID- 25437074 TI - Use of carbon-fiber-reinforced composite implants in orthopedic surgery. AB - Carbon-fiber-reinforced polyetheretherketone implants offer several benefits over traditional metal implants. Their radiolucent property permits improved, artifact free radiographic imaging. Their lower modulus of elasticity better matches that of bone. Their fatigue strength is greater than most metal implants. This article reviews the use of these implants in orthopedic surgery, including treatment of conditions involving the spine, trauma, tumor, and infection. PMID- 25437073 TI - Intraoperative ultrasound assistance for percutaneous repair of the acute Achilles tendon rupture. AB - Various methods have been used to treat the acute Achilles tendon rupture. Traditional open repair is associated with a higher rate of complications. Percutaneous methods avoid most of the disadvantages of open surgical treatment, but the degree of tendon regeneration cannot be ensured. The authors prospectively followed 40 patients with acute Achilles tendon rupture who underwent percutaneous repair with intraoperative ultrasound assistance an average of 13 months after the injury. No surgery-related complications, such as wounds or deep infections, sural nerve injury, or re-rupture, were detected at follow-up. This technique avoids injury to the sural nerve, minimizes wound complications, and provides a strong repair. PMID- 25437075 TI - Current treatment concepts for "terrible triad" injuries of the elbow. AB - Elbow fracture-dislocations destabilize the elbow, preventing functional rehabilitation. If left untreated, they commonly result in functional compromise and poor outcomes. The "terrible triad" injury is classically described as a combination of a coronoid process and radial head fractures, as well as a posterolateral elbow dislocation. Surgical treatment to restore stable elbow range of motion has evolved in the past few decades based on increased understanding of elbow biomechanics and the anatomy of these injuries. This article highlights current concepts in the treatment of these complicated injuries. PMID- 25437076 TI - No decreased infection rate when using antibiotic-impregnated cement in primary total joint arthroplasty. AB - There has been much debate and controversy about the routine use of antibiotic impregnated bone cement in primary total joint arthroplasty. The purpose of this study was to undertake a meta-analysis to determine whether the use of antibiotic impregnated bone cement would reduce the incidence of infection after primary total joint arthroplasty. Of 313 citations identified for screening, 6 trials reporting 26,791 patients were eligible for data extraction and meta-analysis. The authors found no statistically significant difference between antibiotic impregnated bone cement and plain bone cement in terms of the incidence of infection. The results indicated that the use of antibiotic-impregnated bone cement in primary total joint arthroplasty did not lead to a decrease in the rate of infection. PMID- 25437077 TI - BMP-7 versus BMP-2 for the treatment of long bone nonunion. AB - The authors compared the results of treating nonunion with either bone morphogenetic protein (BMP)-7 or BMP-2. Between 2001 and 2009, 214 limb segments were treated for nonunion with either BMP-7 or BMP-2 at the authors' institution. Sixty-three subjects received 76 units of BMP-7. Radiographic healing occurred in 70% of limb segments at an average of 30 weeks after surgery, and 75% of limb segments were weight bearing at an average of 23 weeks after surgery. In 15.8%, persistent nonunion necessitated additional surgery. Average follow-up was 32 months. One hundred twelve subjects received 138 units of BMP-2. Radiographic healing occurred in 93% of limb segments at an average of 19 weeks after surgery, and 88% were weight bearing at an average of 15 weeks after surgery. In 6.25%, persistent nonunion necessitated additional surgery. Average follow-up was 17 months. Several significant differences were observed. Patients in both BMP-7 and BMP-2 groups were able to fully weight bear at an average of 23 and 15 weeks, respectively (P<.001). Further, both BMP-7 and BMP-2 groups healed at an average of 30 and 19 weeks, respectively (P<.001). Additionally, healing occurred in more limb segments in the BMP-2 group (93%) than in the BMP-7 group (70%) (P<.001). No difference in the complication rate was seen between groups. Patients who received BMP-2 for the treatment of nonunion had a higher rate of radiographic healing, achieved radiographic healing more quickly, and were able to bear weight sooner than those who underwent treatment with BMP-7. PMID- 25437078 TI - Revision hip arthroplasty in patients with a previous total hip replacement for osteonecrosis of the femoral head. AB - Patients with osteonecrosis of the femoral head are typically relatively young and active and often require high rates of revision after primary total hip arthroplasty. However, outcomes of revision hip arthroplasty in this patient population have rarely been reported in the literature. The authors conducted a retrospective review of 72 patients (75 hips) who underwent revision hip arthroplasty with a primary diagnosis of osteonecrosis of the femoral head. Mean age at index revision was 53.3 years (range, 34-76). Components of acetabular revision included a cementless porous-coated cup in 58 hips and an acetabular cage in 3 hips. Components of femoral revision included a fully grit-blasted tapered stem in 30 hips and a proximally porous-coated modular stem in 9 hips. Mean duration of follow-up was 7 years (range, 3-17). Mean Harris Hip Score improved from 49 points preoperatively to 90 points postoperatively. At final follow-up, 11 hips (14.7%) required reoperation because of aseptic loosening (6 hips), infection (2 hips), recurrent dislocation (1 hip), periprosthetic fracture (1 hip), and ceramic fracture (1 hip). Kaplan-Meier survivor-ship with an endpoint of re-revision for any reason was 81% and for mechanical failure was 87.5% for the cup and 100% for the stem at 10 years. Unlike the previous report, the authors' study showed a lower failure rate of the femoral stem after revision hip arthroplasty using modern cementless femoral components in patients with osteonecrosis of the femoral head. Aseptic cup loosening or osteolysis is the most common mechanism of failure at medium-term follow-up. PMID- 25437079 TI - The diagnostic value of pedobarography. AB - Pedobarography can quantify static and dynamic foot pressure. Despite an increase in the clinical use of pedobarography, the results and the clinical diagnosis do not always correlate, leading to confusion and misdiagnosis. The authors evaluated the potential of pedobarography to diagnose several diseases associated with abnormal pressure across the plantar surface. The study included 72 patients (96 cases) between January 2009 and August 2012 with symptoms of excessive plantar pressure. The average age was 50.9 years (range, 18-92). Patients had the lesion for an average of 17 months (range, 8-29). Pedobarographic measurements were used to evaluate the compatibility between the highest pressure on pedobarography and the clinical peak pressure with plantar ulcers or calluses. Maximal peak pressure was evaluated by static and dynamic measurements using numeric and graphic measurements in pedobarography. The diagnostic validity of pedobarography was analyzed by comparing clinical peak pressure and pedobarographic measurements. The diagnostic validity of pedobarography was 17.7% to 51% for static measurement and 13.5% to 49% for dynamic measurement. The diagnostic validity of pedobarography was low for intractable plantar keratosis and metatarsal head callus associated with metatarsophalangeal dislocation in rheumatoid arthritis. However, it was 57% to 100% for Charcot arthropathy with midfoot ulcers. When used to compare numeric pressure and graphic peak pressure for each part of the foot, pedobarography showed low diagnostic correlation. Based on the study results, the diagnostic validity of pedobarography is low. PMID- 25437080 TI - Medical management of fragility fractures of the distal radius. AB - Fragility fractures of the distal radius represent an opportunity to diagnose and treat osteoporosis before further fractures occur. The goal of this study was to determine the prevalence of prescriptions for calcium/vitamin D supplementation and the prevalence of dual-energy x-ray absorptiometry (DEXA) scans in patients who sustained fragility fractures of the distal radius. A further goal was to determine the prevalence of patients who received prescriptions for the treatment of osteoporosis after DEXA scans. The authors performed a retrospective review of all patients 50 years and older who sustained a fragility fracture of the distal radius and were treated by the orthopedic surgery service at the authors' institution from 2004 to 2010. After a fragility fracture of the distal radius, fewer than 25% of previously unidentified at-risk patients received a prescription for vitamin supplementation and underwent a DEXA scan. Women were 7 times more likely than men to receive calcium/vitamin D supplementation, 14 times more likely to undergo a DEXA scan for the evaluation of osteoporosis, and 25 times more likely to receive a prescription for bisphosphonates. Patients who underwent a DEXA scan were 9 times more likely to receive pharmacologic treatment than those who did not undergo this scan. More than half of patients did not receive a prescription for calcium/vitamin D supplementation and did not undergo DEXA scanning as recommended by current National Osteoporosis Foundation guidelines. Most patients who received prescriptions or underwent DEXA scans did so before rather than after fracture, indicating poor compliance with National Osteoporosis Foundation guidelines. PMID- 25437081 TI - Acromial stress fractures: correlation with acromioclavicular osteoarthritis and acromiohumeral distance. AB - Fractures around the acromion are a known complication of reverse total shoulder arthroplasty. The literature provides limited data on the risk factors associated with this complication as well as the ultimate outcomes after nonoperative treatment. The goal of this study was to report clinical outcomes in patients with acromial fractures after nonoperatively treated reverse total shoulder arthroplasty. The authors performed a retrospective review of 125 patients undergoing reverse total shoulder arthroplasty that included several acromial stress fractures in the postoperative period. They prospectively compared radiographic data, including acromiohumeral distance, the presence of acromioclavicular joint arthritis, clinical measures of motion, visual analog scale (VAS) pain score, American Shoulder and Elbow Surgeons (ASES) score, and Single Assessment Numeric Evaluation (SANE) score, in 2 groups based on the presence or absence of fracture in the postoperative period. Fourteen patients (11.2%) had an acromial fracture after reverse total shoulder arthroplasty at an average of 5.1 months postoperatively. Patients who had fractures had worse postoperative forward elevation before fracture (116.6 vs 143.5; P=.02) and greater pain relief after reverse shoulder replacement, before fracture (P=.04). No significant difference was found between groups when the degree of arm lengthening was compared (27.6 vs 26.2 mm), and no difference was found in the prevalence of degenerative acromioclavicular joint changes identified preoperatively (66.4% vs 77.3%). After conservative management, most patients who had an acromial fracture returned to a functional level that was comparable to that achieved before fracture. PMID- 25437082 TI - Accuracy of the lesser trochanter for guiding lag screw insertion in hip fracture management. AB - The goal of this study was to evaluate the accuracy of the lesser trochanter for entry of lag screw placement in the fixation of hip fractures. Radiographs of the pelvis with both hips in 50 Chinese patients were analyzed to determine the accuracy of using the lesser trochanter as a reference landmark for inserting lag screws. The femoral neck was divided into 4 parts, and the second distal part was classified as the safe zone. Cobb angles of 125 degrees and 130 degrees were used as representative lag screw insertion angles, referencing the lateral cortex of the lesser trochanter for measurement, and insertion tracks were drawn on the neck of the femur. The accuracy of lag screw placement in the defined safe zone was evaluated. Accuracy of placement in the safe zone for entry points at the superior tip, apex, and inferior tip of the lesser trochanter were 78%, 39%, and 0%, respectively, for the 125 degrees Cobb angle. Rates for the superior tip, apex, and inferior tip of the lesser trochanter were 31%, 74%, and 6%, respectively, for the 130 degrees Cobb angle. The entry point at the level of the inferior tip of the lesser trochanter had incidence rates of 95% and 71% for cutout for 125 degrees and 130 degrees screws, respectively. The authors found that the superior tip of the lesser trochanter was a good reference point for 125 degrees lag screw insertion and that the apex of the lesser trochanter was a good reference point for 130 degrees lag screw insertion. Entry at the level of the inferior tip of the lesser trochanter has a very high rate of cutout and should be avoided. PMID- 25437083 TI - Effectiveness of Providence nighttime bracing in patients with adolescent idiopathic scoliosis. AB - Interest has increased in adolescent idiopathic scoliosis braces that are worn only part time. One such brace, the Providence brace, is being used with increasing frequency despite limited literature evaluating its ability to alter the natural course of disease. The authors retrospectively identified 34 patients meeting modified Scoliosis Research Society (SRS) inclusion criteria who were treated with the Providence brace. In accordance with SRS criteria, patients were followed for progression more than 5 degrees , progression to more than 45 degrees , and recommendation for or performance of surgical fusion. Seventeen (50%) patients progressed more than 5 degrees , and 9 (26%) progressed to more than 45 degrees and had fusion surgery recommended or performed. Noncompliance was associated with progression to more than 45 degrees (P=.045) and having fusion surgery recommended or performed (P=.045). Males had a higher rate of progression more than 5 degrees than did females (100% vs 41%; P=.015). This is only the second study of the Providence brace to be guided by SRS criteria. The somewhat higher rates of progression more than 5 degrees reported in these 2 studies compared with those reported in earlier studies likely result from this distinction. This study suggests a rate of progression that is similar to or lower than rates reported in natural history studies, possibly supporting the efficacy of the Providence brace. Additional studies using SRS criteria, including high-quality randomized, controlled trials, will be important to further understanding the relative effectiveness of this and other bracing protocols. PMID- 25437084 TI - Damage-control orthopedics versus early total care in the treatment of borderline high-energy pelvic fractures. AB - The purpose of this study was to compare the effectiveness of damage-control orthopedics (DCO) vs early total care (ETC) in the treatment of borderline high energy pelvic fractures. Seventy-two patients with borderline high-energy pelvic fractures were retrospectively reviewed; 39 received DCO and 33 received ETC. Demographic data and initial injury severities were comparable between groups, except for Abbreviated Injury Scale (AIS) head scores and Glasgow Coma Scale (GCS) scores. Regarding postoperative complications, the incidence rates of acute lung injury and acute respiratory distress syndrome and the mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score were significantly lower in the DCO group compared with the ETC group. Similar results were also observed in subgroups stratified by age (younger than 40 years and 40 years and older). Regarding patients with Tile B fractures, there was no significant difference between groups in incidence rates of overall postoperative complications. However, in patients with Tile C fractures, especially in those 40 years and older, the DCO group had a lower incidence rate of ALI and had lower APACHE II scores than did the ETC group. This study's findings indicate that DCO is the most suitable therapeutic option for patients with Tile C fractures, especially for those 40 years and older, whereas ETC is preferred for patients with Tile B fractures, provided that it is possible to avoid a second operation as well as any delays in patient mobilization. PMID- 25437085 TI - Factors influencing functional outcomes in united intertrochanteric hip fractures: a negative effect of lag screw sliding. AB - The purpose of this study was to investigate the factors influencing functional outcomes in elderly patients with united intertrochanteric fractures treated with hip nails and to ascertain whether decreased femoral offset due to lag screw sliding has a negative effect on functional outcomes in these patients. This retrospective study included 65 patients older than 65 years with united intertrochanteric fractures treated with hip nails. Functional outcomes were assessed using the Short Form-36 (SF-36) and a visual analog scale (VAS) 6 months postoperatively. Mean patient age was 77.8 years (range, 65-90 years); mean follow-up was 20.7 months (range, 12-38 months). More lag screw sliding occurred as bone mineral density (BMD) decreased. It was also greater in unstable fractures and acceptable reduction status. Less accurate reduction and greater lag screw sliding showed significant negative effects on most subscales of the SF 36, especially Physical Functioning and Role Physical. A significant positive correlation was observed between the extent of lag screw sliding and VAS. Lag screw sliding affected by fracture type, reduction quality, and BMD has a negative effect on functional outcomes in elderly patients with united intertrochanteric fractures. Therefore, the preservation of anatomical femoral offset as much as possible is needed to obtain better functional outcome through the minimization of lag screw sliding by more accurate reduction, which is a controllable factor, especially in osteoporotic unstable intertrochanteric fractures. PMID- 25437086 TI - Human dermal allograft for massive rotator cuff tears. AB - Previously published studies reported variable results using various suture techniques and reconstruction options for massive rotator cuff tears. Therefore, the current authors retrospectively studied 21 consecutive patients/shoulders with massive rotator cuff tears treated from January 2005 to October 2011 with a human dermal allograft through a mini-open approach. Mean patient age was 58 years (range, 33-72 years). Mean follow-up was 29 months (range, 18-52 months). Ten patients underwent revision repair for a failed rotator cuff repair. The authors measured the tendon gap (mean, 1.7 cm) and acromiohumeral interval (mean, 6.5 mm). They evaluated pain, shoulder range of motion (ROM) and function, patient satisfaction with the operation and outcome, and complications. At last follow-up, all patients experienced significant pain relief (P=.001) and improved ROM (P=.001) and American Shoulder and Elbow Surgeons (ASES) score (P=.001). Eighteen patients reported that they were satisfied or very satisfied and 3 reported that they were not satisfied with the operation and outcome. Comparison of outcomes between patients who underwent primary repair and those who underwent revision repair and between patients who had muscle atrophy and fatty infiltration grades 0 to II and those who had grades III to IV showed no statistically significant differences. A statistically significant correlation was observed between the size of the tendon gap and postoperative pain, ROM (except external rotation), and ASES score (P<.050). No significant correlation was observed between postoperative pain, ROM, and ASES score and the acromiohumeral interval (P>.050). Complications related to the dermal human allograft were not observed. PMID- 25437087 TI - Analysis of risk factors for femoral head necrosis after internal fixation in femoral neck fractures. AB - Femoral head necrosis is a rare but devastating complication following femoral neck fracture. The reported incidence of avascular necrosis after femoral neck fracture fixation varies widely, and there is no consensus regarding its risk factors. The aim of this study was to analyze the risk factors for femoral head necrosis after internal fixation in femoral neck fracture. This retrospective study included 166 patients with femoral neck fractures treated with surgical reduction and internal fixation at the authors' institution from January 2004 to December 2008. Eight patients died for reasons unrelated to the surgery, and 12 patients were lost to follow-up. The remaining 146 patients (146 fractures) were followed until union or until conversion to total hip arthroplasty. The patients included 61 males and 85 females with an average age of 47.5 years (range, 18-68 years). The authors analyzed the following factors: age, sex, Garden classification, reduction quality, surgical methods, injury-to-surgery interval, preoperative traction, weight-bearing time, and implant removal. All patients were followed for a mean of 52 months (range, 6-90 months). The incidence of femoral head necrosis was 14.4% (21/146). Garden classification (P=.012), reduction quality (P=.008), implant removal (P=.020), and preoperative traction (P=.003) were significantly associated with femoral head necrosis. Patient age (P=.990), sex (P=.287), injury-to-surgery interval (P=.360), weight-bearing time (P=.868), and surgical methods (P=.987) were not significantly associated with femoral head necrosis. In multivariate logistic regression analysis, implant removal was not a significant risk factor for femoral head necrosis development (P=.498). Garden classification, reduction quality, and preoperative traction had a significant effect on femoral head necrosis development. PMID- 25437088 TI - Intraprosthetic dislocation of a contemporary dual-mobility design used during conversion THA. AB - Although dual-mobility sockets have been in clinical use for decades in other parts of the world, they recently gained popularity in the United States as an option for primary and revision total hip arthroplasty (THA). Improvements in dual-mobility socket technology include articulation with a metal insert impacted into a metal shell and a femoral head made of highly cross-linked polyethylene. The results and complications associated with the use of dual-mobility sockets employing these technologic advancements are not known. Specifically, intraprosthetic dislocation is a well-known complication of these implants and has been reported extensively in the literature. To the authors' knowledge, its occurrence in a modern dual-mobility socket has not been reported. The authors report a case of early intraprosthetic dislocation of a contemporary dual mobility design used to convert a patient to THA after failed fixation of intertrochanteric hip fracture. At retrieval, there was evidence that the outer bearing may have ceased moving, causing localized focal impingement of the implant neck on the retentive ring. The authors theorized that external hip impingement (pelvic against trochanter) and previous surgery that led to the formation of scar tissue could have caused the outer bearing surface to cease its motion. This ultimately led to impingement of the femoral component neck on the retentive ring, which led to the intraprosthetic dislocation. Dual-mobility cups provide an attractive option to decrease wear and improve stability. Further research is needed to establish the ideal construct design and materials. PMID- 25437089 TI - Foreign body reaction after PLC reconstruction caused by a broken PLLA screw. AB - Foreign body reactions may occur in patients who receive bioabsorbable implants during orthopedic surgery for fractures and ligament repair. The authors describe a 34-year-old man who presented with a palpable tender mass on the lateral aspect of the left knee of 1 month's duration. He underwent posterior cruciate ligament and posterolateral corner reconstruction 3 years earlier. Physical examination showed a 1*1-cm soft, nontender mass without localized warmth on the lateral epicondyle of the distal femur. Magnetic resonance imaging showed a broken screw fragment surrounded by a cyst-like mass. Under general anesthesia, the surgeon excised the screw fragment and the fibrotic mass, enclosing it in the subcutaneous tissue at the lateral epicondyle, the site at which a poly-L-lactic acid bioabsorbable screw had been inserted to fix the graft for posterolateral corner reconstruction. Histologic evaluation showed a foreign body reaction to the degraded screw particles. To the authors' knowledge, this report is the first description of a patient presenting with a delayed foreign body reaction to a broken poly-L-lactic acid bioabsorbable screw at the lateral femoral epicondyle after posterolateral corner reconstruction. Because delayed foreign body reactions can occur at any site of poly-L-lactic acid bioabsorbable screw insertion, care should be taken to avoid screw protrusion during ligament reconstruction because it can lead to screw breakage and delayed foreign body reaction. PMID- 25437090 TI - Upper-extremity thrombosis in a patient after biceps tenodesis. AB - Deep venous thrombosis (DVT) of the upper extremity is uncommon compared with DVT of the lower extremity. Exertional DVT has been described in some athletes, especially in the dominant arm of baseball players. It is important for health care professionals to recognize the signs and symptoms of upper-extremity DVT, which can occur after exertion or after surgery of the upper extremity. Superficial venous thrombosis is also very uncommon in the upper extremity. This article describes a case of superficial venous thrombosis that mimicked DVT in the surgical (right) arm of a recreational baseball player after suprapectoral biceps tenodesis for a painful superior labrum anterior-posterior lesion. Although the superficial venous system of the upper arm has frequent connections to the deeper basilar system, it is uncommon for superficial venous thrombosis to occur concurrently with DVT. It is important for clinicians to understand the distinction between superficial venous thrombosis and DVT in the upper extremity because the physical findings, treatment, and prognosis for these 2 entities differ in the following ways: (1) superficial venous thrombosis may be accompanied by a cord, but DVT is associated with more generalized swelling; (2) superficial venous thrombosis requires symptomatic treatment only, whereas DVT requires anticoagulation; and (3) superficial venous thrombosis typically resolves with few sequelae, whereas upper-extremity DVT increases the risk of future DVT. PMID- 25437091 TI - Acute severe hip pain associated with labral calcific deposition disease. AB - Calcific tendinitis is a term used to describe radiographic evidence of calcific deposition within a tendon. This condition, also known as calcium deposition disease, has been described in the gluteus maximus, the peroneus longus tendon, the popliteus tendon, the longus colli muscle in the neck, and the tendon of the rectus femoris. However, most of the literature on calcific tendinitis relates to crystal deposition within the rotator cuff of the shoulder. The peri-articular pain related to calcium deposition may be indolent and chronic, and patients can have varying degrees of functional deficit. Patients also may present with an acute inflammatory event, with severe incapacitation and restricted passive range of motion and a clinical picture that is concerning for septic arthritis. Severe pain associated with calcific tendonitis usually occurs during the resorptive phase, where there is vascular infiltration of the calcium deposits and histologic evidence of phagocytosis. The authors report a case of calcium deposition disease found within the hip labrum with a clinical presentation of acute, atraumatic, debilitating pain in a patient with underlying femoroacetabular impingement. This clinical picture is similar to that described during the resorptive phase seen in calcific tendonitis of the shoulder. The authors attribute this presentation to acute rupture of the calcium deposit into the intra-articular joint space of the hip. To the authors' knowledge, there are no other reports of this clinical presentation in the literature. PMID- 25437092 TI - Alkaptonuric ochronosis. AB - Alkaptonuria, with its sequel, ochronosis, is a rare disease, with an incidence of 1:125,000 to 1:1 million worldwide. Reported cases of ochronotic arthropathy and other orthopedic manifestations are mostly limited to a single family tree, and few cases have been reported. This study highlights 9 previously unreported patients with sporadic presentation and varied orthopedic manifestations of alkaptonuria. Patient age ranged from 34 to 50 years. One patient who had severe arthropathy of the right hip joint along with subcutaneous nodules over both knees and Achilles tendons underwent total hip replacement. Another patient had intramedullary calcification of the femur. An additional patient had associated caries of the spine at L3, L4, and L5, with resolution of symptoms after antitubercular chemotherapy. Another patient had associated features of hyperthyroidism, which was an incidental finding. A further patient had nonunion fracture of the neck of the femur and underwent total hip replacement. The remaining 4 patients had typical features of low backache and arthritis of the large joints. The parents were nonconsanguineous, and only 2 patients had affected siblings. The remaining 7 patients had sporadic nonfamilial presentation. Diagnosis was established by typical clinical and radiologic findings and biochemical analysis. At 2 years of follow-up, both patients who underwent total hip replacement were normal, with no radiologic signs of loosening or lysis. Clinicians need a high index of suspicion and awareness to make the diagnosis of ochronosis. The current study is unique because of presentation with subcutaneous nodules in 1 patient and associated caries of the spine in another patient. PMID- 25437093 TI - Association of cerebrospinal fluid levels of lateral olfactory tract usher substance (LOTUS) with disease activity in multiple sclerosis. AB - IMPORTANCE: Although multiple sclerosis (MS) is generally considered an autoimmune demyelinating disorder of the central nervous system, axonal degeneration through Nogo receptor-1 signaling was recently recognized as an important pathological feature. Our previous identification of lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor-1 antagonist, prompted us to analyze the relationship between LOTUS levels of cerebrospinal fluid and the clinical course of MS to evaluate whether LOTUS could be a useful biomarker for MS. OBJECTIVE: To examine variations in LOTUS concentrations in the cerebrospinal fluid of patients with MS in accordance with their clinical course. DESIGN, SETTING, AND PARTICIPANTS: Cerebrospinal fluid samples were obtained retrospectively from normal controls (NCs; n = 27) and patients with MS (n = 40), amyotrophic lateral sclerosis (n = 22), and multiple system atrophy (n = 10) between January 1, 2008, and January 1, 2014. Patients with MS were divided into relapsing-remitting MS (RRMS; n = 30) and secondary progressive MS (n = 10). Patients with RRMS were further divided into relapse and remission groups. MAIN OUTCOMES AND MEASURES: The LOTUS concentration in cerebropsinal fluid was quantitatively detected by immunoblotting using a specific LOTUS antibody and the concentrations compared in accordance with the patients' clinical course, such as remission and relapse groups in RRMS and secondary progressive MS. RESULTS: The mean (SD) cerebrospinal fluid LOTUS concentration in the relapse group of RRMS (9.3 [3.6] ug/dL) was lower than that of NCs (19.2 [4.7] ug/dL; P < .001) whereas the level in the remission group of RRMS (19.6 [5.8] ug/dL) was similar to that of NCs. The LOTUS concentration in SPMS (6.7 [1.4] ug/dL; P < .001) was lower than that of NCs and the remission group of RRMS. The LOTUS levels in other neurodegenerative diseases, such as amyotrophic lateral sclerosis and multiple system atrophy, were normal. CONCLUSIONS AND RELEVANCE: Variations in LOTUS concentrations were correlated with disease activity in MS. Therefore, LOTUS concentration may be useful as a possible biomarker for MS. Low LOTUS concentrations may be possibly involved in Nogo receptor-1 signaling, which may induce axonal degeneration in the relapse phase of RRMS and secondary progressive MS. PMID- 25437094 TI - Solvent-induced frequency shifts of 5-hydroxymethylfurfural deduced via infrared spectroscopy and ab initio calculations. AB - Solvent-induced frequency shifts (SIFS) of the carbonyl stretching vibration nu(C?O) of 5-hydroxymethylfurfural were measured in protic, polar aprotic, and nonpolar solvents. The Gutmann acceptor number (AN) was found to correlate with the measured frequency shifts. The SIFS in six solvents were investigated using ab initio electronic structure calculations, treating the solvent implicitly and with an explicit solvent ligand interacting with the carbonyl. The conductor polarizable continuum model (CPCM) of solvation predicted that nu(C?O) shifted according with the dielectric constant as (epsilon - 1)/(2epsilon + 1), in agreement with the analytical predictions of the Kirkwood-Bauer-Magat (KBM) theory for a dipole in a dielectric continuum, but in disagreement with the experimental trend. The experimental SIFS were best predicted using gas-phase complexes of HMF and explicit solvent-ligand. Natural bond orbital (NBO) analysis and Bader's atoms in molecules theory were used to investigate the electronic structure of these complexes. Strong SIFS were found to arise from stronger H bonding interactions, as observed in delocalization of carbonyl lone-pair electrons by H-bonding solvent sigma*(X-H) orbitals, and an increase in charge density and a decrease in local potential energy at the H-bond (3, -1) critical point. Consequently, by predicting the experimental SIFS and examining the electronic structure, we find the first theoretical evidence for treating Gutmann's solvent AN as a measure of solvent Lewis acidity. PMID- 25437095 TI - Long-timescale motions in glycerol-monopalmitate lipid bilayers investigated using molecular dynamics simulation. AB - The occurrence of long-timescale motions in glycerol-1-monopalmitate (GMP) lipid bilayers is investigated based on previously reported 600 ns molecular dynamics simulations of a 2*8*8 GMP bilayer patch in the temperature range 302-338 K, performed at three different hydration levels, or in the presence of the cosolutes methanol or trehalose at three different concentrations. The types of long-timescale motions considered are: (i) the possible phase transitions; (ii) the precession of the relative collective tilt-angle of the two leaflets in the gel phase; (iii) the trans-gauche isomerization of the dihedral angles within the lipid aliphatic tails; and (iv) the flipping of single lipids across the two leaflets. The results provide a picture of GMP bilayers involving a rich spectrum of events occurring on a wide range of timescales, from the 100-ps range isomerization of single dihedral angles, via the 100-ns range of tilt precession motions, to the multi-MUs range of phase transitions and lipid-flipping events. PMID- 25437096 TI - Effect of methanol on the phase-transition properties of glycerol-monopalmitate lipid bilayers investigated using molecular dynamics simulations: in quest of the biphasic effect. AB - The effect of methanol on the phase and phase-transition properties of a 2*8*8 glycerol-1-monopalmitate bilayer patch is investigated using a series of 239 molecular dynamics simulations on the 180 ns timescale, considering methanol concentrations cM and temperatures T in the ranges 0-12.3M and 302-338 K, respectively. The results in the form of hysteresis-corrected transition temperatures Tm are compatible with the expected features of the biphasic effect, with a reversal concentration crev of about 5.2 M. Below this concentration, the main transition is between the liquid crystal (LC) and gel (GL) phases, and Tm decreases upon increasing cM. Above this concentration, the interdigitated (ID) phase is the stable ordered phase instead, and Tm slightly increases upon increasing T up to about 10 M. The analysis of the structural and dynamical properties also reveals very different sensitivities and responses of the three phases to changes in cM. In particular, the properties of the GL phase are insensitive to cM, whereas those of the LC and ID phases are altered via an increase of the area per lipid. For the LC phase, increasing cM promotes disorder and fluidity. For the ID phase, in contrast, increasing cM up to about 10 M slightly increases the ordering and rigidity. Two side issues are also addressed, concerning: (i) the occurrence tilt-precession motions in the GL and ID phases; (ii) the influence of the pressure coupling scheme employed in the simulations, semi- or fully-anisotropic, on the simulation results. PMID- 25437097 TI - DFT studies on armchair (5, 5) SWCNT functionalization. Modification of selected structural and spectroscopic parameters upon two-atom molecule attachment. AB - Density functional theory (DFT) studies on adsorption of several gaseous homo- and hetero-diatomic molecules (AB) including H2, O2, N2, NO and CO on external surface of H-capped pristine armchair (5, 5) single-walled carbon nanotube (SWCNT) were conducted. Structures of C70H10 and the corresponding C70H10-AB adducts were fully optimized at the B3LYP/6-311G* level of theory. Calculated HOMO/LUMO energy gaps (Eg), (13)C NMR chemical shifts and IR/Raman parameters were analyzed and critically compared with available experimental data. Significant changes of carbon NMR atom chemical shifts (up to -100 ppm) and shielding anisotropies (up to -180 ppm) at sites of addition were observed. Functionalized SWCNTs produced IR and Raman spectra different from the pristine nanotube model. The selective changes in vibrational spectra will help in assigning the topology of functionalization at the nanotube wall. PMID- 25437099 TI - Residue profiles of brodifacoum in coastal marine species following an island rodent eradication. AB - The second-generation anticoagulant rodenticide brodifacoum is an effective tool for the eradication of invasive rodents from islands and fenced sanctuaries, for biodiversity restoration. However, broadcast application of brodifacoum bait on islands may expose non-target wildlife in coastal marine environments to brodifacoum, with subsequent secondary exposure risk for humans if such marine wildlife is harvested for consumption. We report a case study of monitoring selected marine species following aerial application of brodifacoum bait in August 2011 to eradicate Norway rats (Rattus norvegicus) from Ulva Island, New Zealand. Residual concentrations of brodifacoum were detected in 3 of 10 species of coastal fish or shellfish sampled 43-176d after bait application commenced. Residual brodifacoum concentrations were found in liver, but not muscle tissue, of 2 of 24 samples of blue cod (0.026 and 0.092 ug/g; Parapercis colias) captured live then euthanized for tissue sampling. Residual brodifacoum concentrations were also found in whole-body samples of 4 of 24 mussels (range=0.001-0.022 ug/g, n=4; Mytilus edulis) and 4 of 24 limpets (range=0.001-0.016 ug/g, n=4; Cellana ornata). Measured residue concentrations in all three species were assessed as unlikely to have eventually caused mortality of the sampled individuals. We also conducted a literature review and determined that in eleven previous accounts of residue examination of coastal marine species following aerial applications of brodifacoum bait, including our results from Ulva Island, the overall rate of residue detection was 5.6% for marine invertebrates (11 of 196 samples tested) and 3.1% for fish (2 of 65 samples tested). Furthermore, our results from Ulva Island are the first known detection of brodifacoum residue in fish liver following an aerial application of brodifacoum bait. Although our findings confirm the potential for coastal marine wildlife to be exposed to brodifacoum following island rodent eradications using aerial bait application, the risk of mortality to exposed individual fish or shellfish appears very low. There is also a very low risk of adverse effects on humans that consume fish or shellfish containing residual concentrations in the ranges reported here. Furthermore, any brodifacoum residues that occur in marine wildlife decline to below detectable concentrations over a period of weeks. Thus potential human exposure to brodifacoum through consumption of marine wildlife containing residual brodifacoum could be minimized by defining 'no take' periods for harvest following bait application and regular monitoring to confirm the absence of detectable residues in relevant marine wildlife. PMID- 25437098 TI - Conformational diversity of bacterial FabH: implications for molecular recognition specificity. AB - The molecular basis of variable substrate and inhibitor specificity of the highly conserved bacterial fatty acid synthase enzyme, FabH, across different bacterial species remains poorly understood. In the current work, we explored the conformational diversity of FabH enzymes to understand the determinants of diverse interaction specificity across Gram-positive and Gram-negative bacteria. Atomistic molecular dynamics simulations reveal that FabH from E. coli and E. faecalis exhibit distinct native state conformational ensembles and dynamic behaviors. Despite strikingly similar substrate binding pockets, hot spot assessment using computational solvent mapping identified quite different favorable binding interactions between the two homologs. Our data suggest that FabH utilizes protein dynamics and seemingly minor sequence and structural differences to modulate its molecular recognition and substrate specificity across bacterial species. These insights will potentially facilitate the rational design and development of antibacterial inhibitors against FabH enzymes. PMID- 25437100 TI - Introducing cholera vaccination in Asia, Africa and Haiti: a meeting report. AB - Orally-administered cholera vaccine (OCV) has been increasingly examined as an additional tool to intervene against endemic and epidemic cholera. In 2013, short and long-term field experience with OCV under nine distinctive field settings was reported from India, Bangladesh, Vietnam, Guinea, Haiti, and Thailand. Lead investigators from each of these projects presented their findings at a symposium chaired by Drs. David A. Sack and Robert H. Hall at the Vaccines for Enteric Diseases (VED) Conference in Bangkok on November 7, 2013. The objective of the symposium was to describe the unique features of each setting and project, share field experience of implementing cholera vaccination, discuss results, and identify constraints to the wider use of OCV. The VED provided a forum where >200 attendees engaged with this exciting and potentially decisive new development in the cholera field. PMID- 25437102 TI - Consensus conference on a composite endpoint for clinical trials on immunosuppressive drugs in lung transplantation. AB - BACKGROUND: In lung transplantation, diverse clinical events may impact patient outcome. In clinical trials comparing intervention strategies, single primary endpoints require large populations, or long study durations, whereas composite endpoints (CEPs) do not take into account the respective impact of their components on patient survival. The objective of this study was to propose consensus recommendations on endpoints for clinical trials on immunosuppressants in lung transplantation. METHODS: The consensus process was managed through the Internet using the Delphi method. Forty experts were invited by the pilot group with the help of the International Society for Heart and Lung Transplantation and The Transplantation Society. In the first round, a questionnaire was made available to the experts to complete, and the responses were analyzed. In each next round, a new questionnaire was developed from the previous responses and sent to the panel members. RESULTS: Consensus between 17 experts was achieved after five rounds. Two score-type CEPs were defined for immunosuppressive drug efficacy (7 items) and for toxicity (15 items). Death related to graft loss or immunosuppressive drug toxicity was attributed a maximum weight of 100. The weights of the items included in the efficacy and toxicity CEPs ranged between 10 and 80 and between 25 and 70, respectively. The CEP scores are calculated by adding the weights of all the items composing them, without exceeding 90 as long as the patient is alive. CONCLUSION: This consensus conference proposed two score type CEPs including relevant endpoints. After validation, they should allow clinical trials with higher statistical power, improving the evaluation of the interventions tested. PMID- 25437103 TI - Facile synthesis of [(NHC)MX(cod)] and [(NHC)MCl(CO)2] (M = Rh, Ir; X = Cl, I) complexes. AB - The reactions of [MCl(cod)]2 (M = Rh, Ir) with different NHC.HX (X = Cl, I), K2CO3 in technical grade acetone under air provide simple access to various [(NHC)MX(cod)] complexes; a facile one-pot synthesis of [(NHC)MCl(CO)2] (M = Rh, Ir) is also reported. PMID- 25437101 TI - Poly I:C adjuvanted inactivated swine influenza vaccine induces heterologous protective immunity in pigs. AB - Swine influenza is widely prevalent in swine herds in North America and Europe causing enormous economic losses and a public health threat. Pigs can be infected by both avian and mammalian influenza viruses and are sources of generation of reassortant influenza viruses capable of causing pandemics in humans. Current commercial vaccines provide satisfactory immunity against homologous viruses; however, protection against heterologous viruses is not adequate. In this study, we evaluated the protective efficacy of an intranasal Poly I:C adjuvanted UV inactivated bivalent swine influenza vaccine consisting of Swine/OH/24366/07 H1N1 and Swine/CO/99 H3N2, referred as PAV, in maternal antibody positive pigs against an antigenic variant and a heterologous swine influenza virus challenge. Groups of three-week-old commercial-grade pigs were immunized intranasally with PAV or a commercial vaccine (CV) twice at 2 weeks intervals. Three weeks after the second immunization, pigs were challenged with the antigenic variant Swine/MN/08 H1N1 (MN08) and the heterologous Swine/NC/10 H1N2 (NC10) influenza virus. Antibodies in serum and respiratory tract, lung lesions, virus shedding in nasal secretions and virus load in lungs were assessed. Intranasal administration of PAV induced challenge viruses specific-hemagglutination inhibition- and IgG antibodies in the serum and IgA and IgG antibodies in the respiratory tract. Importantly, intranasal administration of PAV provided protection against the antigenic variant MN08 and the heterologous NC10 swine influenza viruses as evidenced by significant reductions in lung virus load, gross lung lesions and significantly reduced shedding of challenge viruses in nasal secretions. These results indicate that Poly I:C or its homologues may be effective as vaccine adjuvants capable of generating cross-protective immunity against antigenic variants/heterologous swine influenza viruses in pigs. PMID- 25437105 TI - Post-acute care: who belongs where? PMID- 25437104 TI - Expression and immunoaffinity purification of recombinant soluble human GPR56 protein for the analysis of GPR56 receptor shedding by ELISA. AB - GPR56 is a multi-functional adhesion-class G protein-coupled receptor involved in biological systems as diverse as brain development, male gonad development, myoblast fusion, hematopoietic stem cell maintenance, tumor growth and metastasis, and immune-regulation. Ectodomain shedding of human GPR56 receptor has been demonstrated previously, however the quantitative detection of GPR56 receptor shedding has not been investigated fully due to the lack of appropriate assays. Herein, an efficient system of expression and immune-affinity purification of the recombinant soluble extracellular domain of human GPR56 (sGPR56) protein from a stably transduced human melanoma cell line was established. The identity and functionality of the recombinant human sGPR56 protein were verified by Western blotting and mass spectrometry, and ligand binding assays, respectively. Combined with the use of two recently generated anti-GPR56 monoclonal antibodies, a sensitive sandwich ELISA assay was successfully developed for the quantitative detection of human sGPR56 molecule. We found that GPR56 receptor shedding occurred constitutively and was further increased in activated human melanoma cells expressing endogenous GPR56. In conclusion, we report herein an efficient system for the production and purification of human sGPR56 protein for the establishment of a quantitative ELISA analysis of GPR56 receptor shedding. PMID- 25437107 TI - Development and Psychometric Evaluation of a New Measure for Children's Participation in Hand-Use Life Situations. AB - OBJECTIVE: To describe the development of the Children's Assessment of Participation with Hands, a parent-report questionnaire that assesses children's participation in life situations requiring hand use specifically, and to investigate its construct validity (using Rasch analysis and known-group comparison) and reliability (test-retest reliability and internal consistency). DESIGN: Cross-sectional, validation, and test-retest studies. SETTING: Schools. PARTICIPANTS: Parents/caregivers (N=202) reported on their children aged 2 to 12 years with (n=97) and without disabilities (n=105). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The Children's Assessment of Participation with Hands was developed based on a content review of existing children's participation measures and literature, expert review, and pilot testing. The Children's Assessment of Participation with Hands included 37 items measuring participation diversity, frequency, independence, and desire for change in specific hand-use life situations across 4 domains of self-care, recreation, education, and domestic life and community. RESULTS: Evidence for construct validity of the Children's Assessment of Participation with Hands domains was established through Rasch analysis (after removing 2 misfitting items from the recreational domain and 1 item from the domestic life and community domain). Differences in summary scores of each domain between children with and without disabilities were also significant (P<.01). Test-retest reliability of the Children's Assessment of Participation with Hands was moderate to high (intraclass correlation coefficients, .69-.96), except for the desire for change dimension scale of the recreational domain (.40). Internal consistency was varied across the dimensions/domains. CONCLUSIONS: Results provide preliminary evidence for the construct validity and reliability of the Children's Assessment of Participation with Hands that could be used in clinical and research settings to gain a specific understanding of the impact of children's hand-use difficulties on their participation in life situations requiring hand use. PMID- 25437106 TI - Repetitive transcranial magnetic stimulation in chronic pain: a review of the literature. AB - OBJECTIVE: To review the literature on the analgesic effects of repetitive transcranial magnetic stimulation (rTMS) in chronic pain according to different pain syndromes and stimulation parameters. DATA SOURCES: Publications on rTMS and chronic pain were searched in PubMed and Google Scholar using the following key words: chronic pain, analgesia, transcranial magnetic stimulation, neuropathic pain, fibromyalgia, and complex regional pain syndrome. STUDY SELECTION: This review only included double-blind, controlled studies with >10 participants in each arm that were published from 1996 to 2014 and written in English. Studies with relevant information for the understanding of the effects of rTMS were also cited. DATA EXTRACTION: The following data were retained: type of pain syndrome, type of study, coil type, target, stimulation intensity, frequency, number of pulses, orientation of induced current, number of session, and a brief summary of intervention outcomes. DATA SYNTHESIS: A total of 33 randomized trials were found. Many studies reported significant pain relief by rTMS, especially high frequency stimulation over the primary motor cortex performed in consecutive treatment sessions. Pain relief was frequently >30% compared with control treatment. Neuropathic pain, fibromyalgia, and complex regional pain syndrome were the pain syndromes more frequently studied. However, among all published studies, only a few performed repetitive sessions of rTMS. CONCLUSIONS: rTMS has potential utility in the management of chronic pain; however, studies using maintenance sessions of rTMS and assessing the effects of rTMS on the different aspects of chronic pain are needed to provide a more solid basis for its clinical application for pain relief. PMID- 25437108 TI - Edge contacts of graphene formed by using a controlled plasma treatment. AB - Despite the fact that the outstanding properties of graphene are well known, the electrical performance of the material is limited by the contact resistance at the metal-graphene interface. In this study, we demonstrate the formation of "edge-contacted" graphene through the use of a controlled plasma processing technique that generates a bond between the graphene edge and the contact metal. This technique controls the edge structure of the bond and significantly reduces the contact resistance. This simple approach requires no additional post processing and has been proven to be very effective. In addition, controlled pre plasma processing was applied in order to produce CVD-graphene field effect transistors with an enhanced adhesion and improved carrier mobility. The contact resistance attained by using pre-plasma processing was 270 Omega MUm, which is a decrease of 77%. PMID- 25437109 TI - Tetraphenylborate versus tetraimidazolylborate as counterions for cationic iridium(III) complexes: enhanced electrochemical stabilities and electroluminescence. AB - Tetraimidazolylborate is first used as the counterion of two novel ionic iridium complexes, instead of tetraphenylborate. Both the electrochemical stabilities and electroluminescence are sharply improved. Organic light-emitting diodes have been successfully fabricated with a high current efficiency of 9.48 cd A(-1) and a maximum brightness of 5163 cd m(-2). PMID- 25437110 TI - Multi-modal detection of colon malignancy by NIR-tagged recognition polymers and ultrasound contrast agents. AB - To increase colonoscopy capability to discriminate benign from malignant polyps, we suggest combining two imaging approaches based on targeted polymeric platforms. Water-soluble cationized polyacrylamide (CPAA) was tagged with the near infrared (NIR) dye IR-783-S-Ph-COOH to form Flu-CPAA. The recognition peptide VRPMPLQ (reported to bind specifically to CRC tissues) was then conjugated with the Flu-CPAA to form Flu-CPAA-Pep which was then incorporated into echogenic microbubbles (MBs) made of polylactic acid (PLA) that are highly responsive to ultrasound. The ultimate design includes intravenous administration combined with local ultrasound and intra-colon inspection at the NIR range. In this proof of principle study PLA MBs were prepared by the double emulsion technique and loaded with several types of Flu-CPAA-Pep polymers. After insonation the submicron PLA fragments (SPF)-containing Flu-CPAA-Pep were examined in vitro for their ability to attach to colon cancer cells and in vivo (DMH induced rat model) for their ability to attach to colon malignant tissues and compared to the specific attachment of the free Flu-CPAA-Pep. The generation of SPF-containing Flu-CPAA-Pep resulted in a tissue attachment similar to that of the free, unloaded Flu-CPAA-Pep. The addition of VRPMPLQ to the polymeric backbone of the Flu-CPAA reduced cytotoxicity and improved the specific binding. PMID- 25437111 TI - Cargoing P-gp inhibitors via nanoparticle sensitizes tumor cells against doxorubicin. AB - Inhibitors against multidrug resistance (MDR) efflux transporters have failed in most clinical settings due to unfavorable pharmacokinetic interactions with co administered anti-cancer drug and their inherent toxicities. Nanoparticles (NPs) have shown potential to overcome drug efflux by delivering and localizing therapeutic molecules within tumor mass. In this work, we investigated effect of nanocarrier surface charge and formulation parameters for a hydrophilic and lipophilic MDR inhibitor on their ability to reverse drug resistance. Active inhibition of efflux pumps was achieved by encapsulating first and third generation P-gp inhibitors- verapamil and elacridar respectively in non-ionic, anionic and cationic surfactant-based NPs. The ability of NPs to reverse P glycoprotein (P-gp)-mediated MDR efflux was evaluated in sensitive (A2780) and resistant (A2780Adr) ovarian cancer cell lines by various in vitro accumulation and cytotoxicity assays. Uptake mechanism for NP appears to be caveolae-dependent with 20%-higher internalization in A2780Adr than A2780 cell lines which can be co related to the biophysical membrane composition. Cationic- CTAB NPs showed highest reversal efficacy followed by PVA and SDS-NP (P+S NP) and PVA-NPs. As compared to doxorubicin treated drug resistant cells lines, blank-, verapamil- and elacridar-CTAB-NPs showed 2.6-, 20- and 193-fold lower IC50 values. This work highlights the importance of inhibitor-loaded charged particles to overcome cancer drug resistance. PMID- 25437112 TI - Quantitative analysis of drug losses administered via nasogastric tube--In vitro study. AB - PURPOSE: Drug administration through nasogastric tube (NGT) is a standard practice but the real amount of the delivered drug is unknown. Therefore, we designed a study to determine the losses of various dosage forms administered by different methods through NGT. METHODS: In vitro model was used. Five different administration methods (A-E) and six dosage forms (simple compressed tablets - T/S; film coated tablets - T/FC; enteric coated tablets - T/EC; capsules with powder filling - C/P; capsules containing extended release pellets - C/ER; capsules containing gastro-resistant pellets - C/GR) were investigated. Measurement was repeated six times for each drug-method combination. The overall losses were determined by gravimetry. In method A partial losses associated with each step of drug administration were also determined. RESULTS: Significant drug losses were measured (4-38%). Only methods A (crushing-beaker-syringe-water-NGT) and B (crushing-water-syringe-NGT) were suitable for administration of all tested dosage forms. Method B proved the most effective for all kinds of tablets and C/GR (p<0.05) and tended to be more effective also for C/ER (p=0.052) compared to method A. C/P showed minimal losses for both tested methods (B and E). Flushing of the drug through NGT causes major losses during drug administration compared to crushing and transfer (p<0.05). All methods for intact pellets (C-E) were found inappropriate for clinical practice due to NGT clogging. CONCLUSIONS: Choosing a suitable administration method can significantly affect the amount of drugs delivered through NGT. PMID- 25437113 TI - Improved oral absorption of dutasteride via Soluplus(r)-based supersaturable self emulsifying drug delivery system (S-SEDDS). AB - A novel supersaturable self-emulsifying drug delivery system (S-SEDDS) was formulated to improve the oral absorption of dutasteride (DTS), a 5alpha reductase inhibitor that is poorly water-soluble. A supersaturable system was prepared by employing Soluplus((r)) (polyvinyl caprolactam-polyvinyl acetate polyethylene glycol graft copolymer) as a precipitation inhibitor with a conventional SEDDS vehicle consisted of CapryolTM 90, Cremophor((r)) EL and Transcutol((r)) HP (DTS:SEDDS vehicle:Soluplus((r))=1.0:67.6:10.0 w/v/w). In an in vitro dissolution test in a non-sink condition, the drug dissolution rate from SEDDS was rapidly increased to 72% for an initial period of 5min, but underwent rapid drug precipitation within 2h, decreasing the amount of drug dissolved to one-seventh of its original amount. On the other hand, S-SEDDS resulted in a slower crystallization of DTS by virtue of a precipitation inhibitor, maintaining a 3 times greater dissolution rate after 2h compared to SEDDS. In an in vivo pharmacokinetic study in rats, the S-SEDDS formulation exhibited 3.9-fold greater area-under-curve value than that of the drug suspension and 1.3-fold greater than that of SEDDS. The maximum plasma concentration of S-SEDDS was 5.6- and 2.0-fold higher compared to drug suspension and SEDDS, respectively. The results of this study suggest that the novel supersaturable system may be a promising tool for improving the physicochemical property and oral absorption of the 5alpha reductase inhibitor. PMID- 25437114 TI - Modelling the response surface to predict the hydrodynamic diameters of theranostic magnetic siRNA nanovectors. AB - Short interfering RNAs (siRNAs) appear to be a promising tool to treat various human diseases, such as cancer via the RNA interference (RNAi) mechanism. Since the systemic administration of siRNAs is limited by their capacity to attain the site of action, novel delivery systems are needed. Previously, we reported the formulation of magnetic siRNA nanovectors (MSN) using electrostatic assembly of the following components: (1) functionalized superparamagnetic iron oxide nanoparticles (SPIONs) able to act as agents for magnetic resonance imaging (MRI) and/or thermal therapy, (2) siRNAs as active molecules and (3) chitosan to protect siRNAs and to enhance their transfection efficacy. In this work, experimental design was used to further improve the formulation protocol and to optimize the component quantities. The aim was to obtain response surface plots that will help to optimize and predict the component quantities of the MSNs regarding their hydrodynamic diameter (DH). The influent parameters of the formulation process were determined using a Plackett-Burman design. The results show that the order of incorporation of the components is the most influent parameter on the DH of MSNs. A Box-Behnken design was used to optimize the component quantities. The model equations provided the parameters to obtain MSNs with DH smaller than 100 nm to allow their systemic administration. PMID- 25437115 TI - Scientific considerations concerning the EMA change in the definition of "dose" of the BCS-based biowaiver guideline and implications for bioequivalence. AB - This work discusses the scientific aspects of the definition of dose as the 'highest single oral IR dose' recommended for administration in the SmPC (summary of product characteristics) in the current European Medicines Agency (EMA) 2010 Guideline, for the purpose of biopharmaceutics classification system (BCS)-based biowaiver decision making. Analysis of theoretical and experimental data dealing with drug dissolution and biopharmaceutic drug classification reveals that the drug dose is an important parameter for both drug dissolution and biopharmaceutic classification. The relevant implications for the dose considerations in bioequivalence studies are also discussed briefly. It is suggested that the concept of "the highest single dose oral IR dose recommended for administration in the SmPC" of the EMA 2010 Guideline be abolished. It is advisable, each dose strength be considered separately i.e., whether or not it meets the solubility dissolution regulatory criteria. PMID- 25437116 TI - Absolute Configuration and Conformation of Two Frater-Seebach Alkylation Reaction Products by Film VCD and ECD Spectroscopic Analyses. AB - Two chiroptical spectroscopic techniques, namely, electronic and vibrational circular dichroism (ECD and VCD), as well as NMR spectroscopy have been utilized to determine the absolute configurations and geometries of two Frater-Seebach alkylation reaction products with long hydrocarbon chains. The experimental studies have been complemented with density functional theory calculations. Strong characteristic bisignate VCD signatures in the carbonyl stretching region have been observed for both compounds in film state. Truncated models, i.e., without the long CH2 chains, have been utilized to examine different hydrogen bonding topologies between two monomeric moieties and to simulate the corresponding IR and VCD spectra of the dimers. In addition, the exciton coupling model has also been applied to the -C?O groups of the two monomeric moieties, which can be coupled through intermolecular hydrogen-bonding. On the basis of these simplified approaches, the absolute configurations of the compounds have been unambiguously assigned using VCD and ECD spectroscopy. Spectral simulations in the IR and UV-vis regions have also been carried out with the full dimers to validate the fitness of the truncated model. The study shows that the combination of the film VCD and ECD techniques is a relatively straightforward method to determine the absolution configurations of such synthetic compounds. PMID- 25437117 TI - Interfacial effects of the CuO/GO composite to mediate the side reactions of N,N dimethylformamide fragments. AB - The interface between nanocatalysts and graphene oxide (GO) has been found to play a crucial role in enhancing the catalytic activity and improving the selectivity of amination reactions in N,N-dimethylformamide (DMF). The composite catalysts of CuO/GO used for the catalytic coupling of aryl halides with amines in DMF can completely inhibit the side reaction between the aryl halides and fragments of DMF. With identical amounts of Cu-catalysts, the conversion of iodobenzene and the selectivity for the target product reached 100% when CuO/GO composite catalysts were employed, while these results were 70.3 and 42.8%, respectively, when CuO catalysts were used alone. Experimental evidence confirms that the interfacial effect of CuO/GO is the origination of the improved performance of composite catalysts, which has been found to efficiently transfer fragments of DMF to GO and avoid unexpected side reactions during the catalytic process. PMID- 25437118 TI - The effect of chronic stress on anti-angiogenesis of sunitinib in colorectal cancer models. AB - Epidemiological and experimental evidence has shown that psychological stress can propel cancer progression. However, its role in anti-angiogenic therapy is not well understood. We previously found that exogenous norepinephrine attenuated the effect of sunitinib, a multi-targeted anti-angiogenic agent, in a mouse melanoma model. Here, we further evaluated the effects of chronic stress on sunitinib therapy in colorectal cancer models. We found that chronic restraint stress markedly weakened the efficacy of sunitinib, primarily through promoting the expression of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) to stimulate tumor angiogenesis in vivo. This effect could be sufficiently mimicked by exogenous norepinephrine and blocked by the beta-antagonist propranolol. In vitro, norepinephrine up-regulated expression of VEGF and IL-8 in sunitinib-treated cancer cells mainly through the beta-adrenoceptor-cAMP-PKA signaling pathway. Norepinephrine also abrogated sunitinib-induced inhibition of cancer cell migration, but had no effect on direct anti-proliferative activity of sunitinib on cancer cells. These findings suggest that psychological stress might attenuate anti-angiogenic therapy primarily through activating beta-adrenergic signaling to promote tumor angiogenesis. It is also suggested that beta-blockers might improve anti-angiogenic outcome under psychological stress. PMID- 25437119 TI - Maternal salivary cortisol levels during pregnancy are positively associated with overweight children. AB - INTRODUCTION: Animal and human studies suggest that programing of the hypothalamic-pituitary-adrenal (HPA) axis may be involved in the development of obesity, but human studies of biological indicators of HPA axis activity are lacking. We studied the association between levels of the stress hormone cortisol during pregnancy and overweight offspring during childhood into adolescence. METHODS: Salivary samples from 655 Danish pregnant women with singleton pregnancies (1989-1991) were collected once in the morning and once in the evening in their second and third trimester. We followed the offspring from two to 16 years of age with at least one measurement of height and weight, and classified their body mass index into overweight and normal weight. The adjusted relative difference in median salivary cortisol (with 95% confidence interval (CI)) during pregnancy (the four samples), in second and third trimester (morning and evening samples) between overweight and normal weight offspring was estimated. Furthermore, the adjusted median ratio between morning and evening maternal salivary cortisol level was estimated for normal weight and overweight children. All the analyses were stratified into the equal age groups: 2-6, 7-11, and 12-16 years. RESULTS: We found non-significant higher maternal cortisol levels during pregnancy in offspring that were overweight at the age of 2-6, 7-11 and 12-16 years than in normal weight peers; adjusted relative difference in median salivary cortisol 11% (95% CI: -2; 25), 6% (95% CI: -7; 20), and 9% (95% CI: -4; 24), respectively. A statistically significantly higher level of maternal cortisol was found in the second trimester in 2-6-year-old and 12-16-year-old overweight offspring; relative difference 19% (95% CI: 3; 37), and 20% (95% CI: 3; 41), respectively. The median ratio between morning and evening maternal salivary cortisol level was similar for overweight and normal weight children; e.g. at age 2-6 years in third trimester 4.31 (95% CI: 4.05; 4.60)nmol/l and 4.28 (95% CI: 3.60; 5.09)nmol/l, respectively (P=0.93). CONCLUSION: Our findings suggest a relatively consistent association between pregnancy cortisol levels and overweight offspring, especially in the second trimester. PMID- 25437121 TI - Correction: High throughput first-principles calculations of bixbyite oxides for TCO applications. AB - Correction for 'High throughput first-principles calculations of bixbyite oxides for TCO applications' by Nasrin Sarmadian et al., Phys. Chem. Chem. Phys., 2014, 16, 17724-17733. PMID- 25437120 TI - Environmental enrichment models a naturalistic form of maternal separation and shapes the anxiety response patterns of offspring. AB - Environmental enrichment (EE) mimics positive life experiences by providing enhanced social and physical stimulation. Placement into EE following weaning, or in later life, confers beneficial outcomes on both emotional and cognitive processes. However, anxiety-like behavior is also reported, particularly in rats exposed to enhanced housing during early development. Notably, the quality of maternal behavior affects stress regulation and emotional stability in offspring, yet the impact of environmental context on maternal care has not been thoroughly evaluated, or are the influences of EE on their offspring understood. To investigate the role of EE on these factors we analyzed the details of mother neonate interactions, and juvenile offspring performance on several anxiety measures. Additionally, we evaluated neurochemical differences (i.e. serotonin, corticosterone, GABA, glutamate) in prefrontal cortex and hippocampus as a function of EE, Communal Nesting (CN) and Standard Care (SC). Although EE dams spent significantly less time on the nest and had lower nursing frequencies compared to SC dams, there were no differences in maternal licking/grooming. In offspring, EE increased GLUR1 level and GABA concentrations in the prefrontal cortex of both juvenile male and female rats. A similar pattern for glutamate was only observed in males. Although EE offspring spent less time on the open arms of the elevated plus maze and had faster escape latencies in a light-dark test, there were no other indications of anxiety-like behavior on these measures or when engaged in social interaction with a conspecific. In the wild, rats live in complicated and variable environments. Consequently dams must leave their nest to defend and forage, limiting their duration of direct contact. EE exposure in early development may mimic this naturalistic maternal separation, shaping parental behavior and offspring resiliency to stressors. PMID- 25437122 TI - Approach to the diagnosis of unusual carpal ankylosis from ancient Egypt. AB - OBJECTIVES: Carpal fusion is not an uncommon finding in archaeological bones. The majority of cases are due to inflammatory or infectious diseases and those are usually associated with other major alterations in the skeleton. METHODS: Two distinct individual cases, both adult females recovered from the Necropolis of Sharuna in the Middle Egypt from the Ptolemaic Period (IV to I BC) are presented in this study. Specimen 4323/1 shows a fusion of the scaphoid, lunate and triquetral bones in the right wrist. Specimen 4323/2 is a very rare fusion of a dysplastic lunate bone with the radius in the left wrist. In the proximal end of that left wrist, two possible remains of the flattened scaphoid and triquetral bones are also present. RESULTS: A differential diagnosis of both abnormalities as well as broad research into similar paleopathological cases were carried out: the most probable diagnosis for the specimen 4323/1 is an uncommon carpal coalition of three bones from the same row; the diagnosis of the specimen 4323/2 is more dubious with both rheumatoid arthritis and septic arthritis being strong candidates. CONCLUSIONS: In archaeological remains, carpal fusion should be thoroughly studied in order to ensure an accurate differential diagnosis. PMID- 25437123 TI - Kinetics profiling of gramicidin S synthetase A, a member of nonribosomal peptide synthetases. AB - Nonribosomal peptide synthetases (NRPS) incorporate assorted amino acid substrates into complex natural products. The substrate is activated via the formation of a reactive aminoacyl adenylate and is subsequently attached to the protein template via a thioester bond. The reactive nature of such intermediates, however, leads to side reactions that also break down the high-energy anhydride bond. The off-pathway kinetics or their relative weights compared to that of the on-pathway counterpart remains generally elusive. Here, we introduce multiplatform kinetics profiling to quantify the relative weights of on- and off pathway reactions. Using the well-defined stoichiometry of thioester formation, we integrate a mass spectrometry (MS) kinetics assay, a high-performance liquid chromatography (HPLC) assay, and an ATP-pyrophosphate (PPi) exchange assay to map out a highly efficient on-pathway kinetics profile of the substrate activation and intermediate uploading (>98% relative weight) for wide-type gramicidin S synthetase A (GrsA) and a 87% rate profile for a cysteine-free GrsA mutant. Our kinetics profiling approach complements the existing enzyme-coupled byproduct release assays, unraveling new mechanistic insights of substrate activation/channeling in NRPS enzymes. PMID- 25437124 TI - Design, synthesis, and herbicidal activity of novel substituted 3-(pyridin-2 yl)benzenesulfonamide derivatives. AB - A series of novel substituted 3-(pyridin-2-yl)benzenesulfonamide derivatives were designed and synthesized using 2-phenylpridines as the lead compound by intermediate derivatization methods in an attempt to obtain novel compound candidates for weed control. The herbicidal activity assay in glasshouse tests showed several compounds (II6, II7, II8, II9, II10, II11, III2, III3, III4, and III5) could efficiently control velvet leaf, youth-and-old age, barnyard grass, and foxtail at the 37.5 g/ha active substance. Especially, the activities of II6, II7, III2, and III4 were proved roughly equivalent to the saflufenacil and better than 95% sulcotrione at the same concentration. The result of the herbicidal activity assay in field tests demonstrated that II7 at 60 g/ha active substance could give the same effect as bentazon at 1440 g/ha active substance to control dayflower and nightshade, meanwhile II7 showed better activity than oxyfluorfen to control arrowhead and security to rice. The present work indicates that II7 may be a novel compound candidate for potential herbicide. PMID- 25437125 TI - Fluorescence reports intact quantum dot uptake into roots and translocation to leaves of Arabidopsis thaliana and subsequent ingestion by insect herbivores. AB - We explored the impact of quantum dot (QD) coat characteristics on NP stability, uptake, and translocation in Arabidopsis thaliana, and subsequent transfer to primary consumers, Trichoplusia ni (T. ni). Arabidopsis was exposed to CdSe/CdZnS QDs with three different coatings: Poly(acrylic acid-ethylene glycol) (PAA-EG), polyethylenimine (PEI) and poly(maleic anhydride-alt-1-octadecene)-poly(ethylene glycol) (PMAO-PEG), which are anionic, cationic, and relatively neutral, respectively. PAA-EG-coated QDs were relatively stable and taken up from a hydroponic medium through both Arabidopsis leaf petioles and roots, without apparent aggregation, and showed generally uniform distribution in leaves. In contrast, PEI- and PMAO-PEG-coated QDs displayed destabilization in the hydroponic medium, and generated particulate fluorescence plant tissues, suggesting aggregation. PAA-EG QDs moved faster than PEI QDs through leaf petioles; however, 8-fold more cadmium accumulated in PEI QD-treated leaves than in those exposed to PAA-EG QDs, possibly due to PEI QD dissolution and direct metal uptake. T. ni caterpillars that fed on Arabidopsis exposed to QDs had reduced performance, and QD fluorescence was detected in both T. ni bodies and frass, demonstrating trophic transfer of intact QDs from plants to insects. Overall, this paper demonstrates that QD coat properties influence plant nanoparticle uptake and translocation and can impact transfer to herbivores. PMID- 25437126 TI - Journey of a strut: from filter to missile. PMID- 25437127 TI - Malignant cause of abdominal pain in leukemia: spontaneous splenic rupture. PMID- 25437128 TI - Pitfalls in dosing vancomycin. AB - BACKGROUND: Vancomycin is a frequently used antibiotic for the treatment of methicillin-resistant gram-positive bacteria. Newer guidelines suggest dosing vancomycin to achieve a trough concentration between 15 and 20 mg/L. Achieving this higher concentration requires greater doses of the antibiotic. Even when using a nomogram, these higher doses often result in excessively elevated trough levels and increase the risk for vancomycin-associated acute kidney injury. We undertook this quality improvement project to better understand the reasons contributing to a toxic vancomycin trough level. METHODS: Over a 9-month period, we examined all vancomycin trough concentrations greater than 25 mg/L to determine their cause. RESULTS: Fifty-four elevated levels were identified in 38 patients. In 47 instances, adequate data were available for analysis. We could classify the etiology of the excessive levels into 4 groups: (1) incorrect timing of the blood collection, (2) improper dosing, (3) changing renal function and (4) abnormal pharmacokinetics/pharmacodynamics. CONCLUSIONS: Educational programs could correct the first 3 problems. However, only more frequent therapeutic drug monitoring or use of another, less toxic, antibiotic would remedy the last one. PMID- 25437129 TI - Peptostreptococcus endocarditis presenting as lumbar discitis in an immunocompromised patient. PMID- 25437130 TI - Actors conform, observers react: the effects of behavioral synchrony on conformity. AB - Engaging in synchronous behavior can induce a more general disposition to copy others, which increases the tendency to conform to others' preferences in an unrelated choice situation. In contrast, observing others perform synchronous behavior can induce psychological reactance and decrease conformity to others' preferences. Five experiments confirmed these different effects and circumscribed the conditions in which they occurred. Actors typically focus their attention on the goal to which their synchronous behavior is directed, inducing a copying others mindset that generalizes to later situations. In contrast, observers focus on the actors' behavior independently of the goal to which it pertains. Consequently, they become sensitive to the restrictions on freedom that synchronous behavior requires and experience reactance. However, changing the relative attention that actors and observers pay to these factors can reverse the effects of the actors' synchronous behavior on conformity. PMID- 25437131 TI - Embodied motivation: using a goal systems framework to understand the preference for social and physical warmth. AB - Embodiment research has primarily focused on metaphor-assimilative effects (e.g., perceiving someone to be socially warmer when holding a warm object). Research shows these effects can occur by activating metaphor-associated knowledge constructs. This account is not sufficient, however, for explaining complementary effects--for example, the tendency to prefer social warmth when experiencing physical coldness (Experiment 1). We suggest that socially warm events are considered a means for achieving the goal of reducing physical coldness. Guided by this basic hypothesis and the principles of a goal systems framework, we examine whether the basic relationship between goals and means explains complementary embodiment effects. We find that socially warm activities are preferred over control activities when people are primed with the goal of reducing physical coldness, but not when primed with the concept of coldness (Experiment 2). We also find that activating an alternative goal decreases the attractiveness of socially warm activities when people are feeling cold (Experiment 3). Finally, we examine the effect of social coldness on preferences for physical warmth, showing that the attractiveness of physically warm items among socially excluded people is decreased by activating an alternative goal (Experiment 4). These results suggest that complementary embodiment effects follow the principles of goal activation. PMID- 25437132 TI - Too close for comfort: Stimulus valence moderates the influence of motivational orientation on distance perception. AB - The relationship between approach and avoidance motivational orientations and valenced stimuli has previously been discussed in relation to physical distance. However, it has remained unclear whether approach and avoidance can actually change how people perceive the physical distance to valenced stimuli. Drawing on research on motivational orientation and valence as well as the motivated perception account, we predicted that valenced stimuli incompatible with motivational orientation would be perceived as closer than compatible stimuli because they motivate the goal of resolving the inconsistency arising from discrepant affective information. This prediction was supported in a series of 4 experiments. Findings were consistent across different manipulations of motivational orientation, including motor movements (Experiments 1 and 2) and cognitive procedures (Experiments 3 and 4), and across different types of stimuli, including abstract words (Experiments 1, 2, and 4) and photos of concrete objects (Experiment 3). Experiment 4 further investigated the mechanism behind the influence of incompatibility versus compatibility between motivational orientation and valence on distance perception. The findings showed that, relative to compatibility, incompatibility resulted in participants solving more anagrams, presumably because the goal-related motivational state gave rise to a general state of activation. Furthermore, perceptual estimates were correlated with the activity of the Behavioral Inhibition System (BIS) and the activity of the Behavioral Activation System (BAS) relative to the BIS, further suggesting that goal-related motivation may be associated with perception. Overall, the present research adds to a growing body of evidence suggesting that visual perception is shaped by motivational considerations. PMID- 25437134 TI - Discount and disengage: How chronic negative expressivity undermines partner responsiveness to negative disclosures. AB - Partner responsiveness-the degree to which partners respond with caring, understanding, and validation to one another's disclosures (Reis, Clark, & Holmes, 2004; Reis & Shaver, 1988)--has been heralded as a "core, defining construct" in relationship science (Reis, 2007, p. 28). Yet little is known about the determinants of responsiveness in ongoing relationships. The present research elucidates one such set of processes, focusing in particular on responsiveness to negative disclosures. We predicted that the degree to which a partner behaves responsively to negative disclosures depends on the partner's perception of the discloser's typical expressive tendencies. Results of 5 studies employing both correlational and experimental methods supported the hypothesis that partners are less responsive to negative disclosures made by disclosers whom they perceive to have high negativity baselines-that is, to express negativity frequently--than to identical (Studies 1-4) or equally negative (Study 5) disclosures made by disclosers with lower negativity baselines. We also examined 2 routes through which negativity baselines might affect partner responsiveness: by shaping listener appraisals of the discloser's need for support and by making disengagement from those interactions seem justifiable to listeners. These findings fill an important gap in the responsiveness literature and highlight the utility of considering person-context factors in emotion interpretation and responsiveness processes. PMID- 25437135 TI - Divide and conquer: when and why leaders undermine the cohesive fabric of their group. AB - Cohesion, cooperation, and the formation of positive bonds among group members are key processes that facilitate effective group functioning. Consequently, group leaders usually work to enhance the positive social bonds among group members to facilitate cooperation and group cohesion. The present research suggests, however, that leaders sometimes are motivated to generate divisions- not cooperation--among their subordinates. Although such divisions may undermine group functioning, they can also serve as a means of protecting the leader's own power. Four experiments supported the hypothesis that, when they perceive their power to be threatened, leaders create divisions among their subordinates in order to protect their power and reduce threats posed by potential alliances among those subordinates. Leaders restricted the amount of communication among subordinates (Experiment 1), physically sequestered subordinates (Experiment 2), and prevented subordinates from bonding with one another interpersonally (Experiments 3 and 4). Those behaviors were observed only among dominance motivated leaders (not prestige-motivated leaders), and were directed only toward highly skilled (and thus highly threatening) subordinates. Consistent with the hypothesis that leaders' behavior was driven by a desire to protect their power, the tendency to prevent in-group bonding was eliminated when leaders were assured that their power could not be lost (Experiment 4). These results shed light on factors that may undermine positive social processes within groups. PMID- 25437137 TI - Effects of data sparsity and spatiotemporal variability on hazard maps of workplace noise. AB - Personal sampling, considered a state-of-the-art technique to assess worker exposures to occupational hazards, is often conducted for the duration of a work shift so that time-weighted average (TWA) exposures may be evaluated relative to published occupational exposure limits (OELs). Such cross-shift measurements, however, provide little information on the spatial variability of exposures, except after a very large number of samples. Hazard maps, contour plots (or similar depiction) of hazard intensity throughout the workplace, have gained popularity as a way to locate sources and to visualize spatial variability of physical and chemical hazards within a facility. However, these maps are often generated from short duration measures and have little ability to assess temporal variability. To assess the potential bias that results from the use of short duration measurements to represent the TWA in a hazard map, noise intensity measurements were collected at high spatial and temporal resolution in two facilities. Static monitors were distributed throughout the facility and used to capture the temporal variability at these locations. Roving monitors (typical of the hazard mapping process) captured spatial variability over multiple traverses through the facility. The differences in hazards maps generated with different sampling techniques were evaluated. Hazard maps produced from sparse, roving monitor data were in good agreement with the TWA hazard maps at the facility with low temporal variability. Estimated values were within 5 dB of the TWA over approximately 90% of the facility. However, at the facility with higher temporal variability, large differences between hazard maps were observed for different traverses through the facility. On the second day of sampling, estimates were at least 5 dB different than the TWA for more than half of the locations within the facility. The temporal variability of noise was found to have a greater influence on map accuracy than the spatial sampling resolution. PMID- 25437138 TI - The polymorphisms of the chromatin fiber. AB - In eukaryotes, the genome is packed into chromosomes, each consisting of large polymeric fibers made of DNA bound with proteins (mainly histones) and RNA molecules. The nature and precise 3D organization of this fiber has been a matter of intense speculations and debates. In the emerging picture, the local chromatin state plays a critical role in all fundamental DNA transactions, such as transcriptional control, DNA replication or repair. However, the molecular and structural mechanisms involved remain elusive. The purpose of this review is to give an overview of the tremendous efforts that have been made for almost 40 years to build physiologically relevant models of chromatin structure. The motivation behind building such models was to shift our representation and understanding of DNA transactions from a too simplistic 'naked DNA' view to a more realistic 'coated DNA' view, as a step towards a better framework in which to interpret mechanistically the control of genetic expression and other DNA metabolic processes. The field has evolved from a speculative point of view towards in vitro biochemistry and in silico modeling, but is still longing for experimental in vivo validations of the proposed structures or even proof of concept experiments demonstrating a clear role of a given structure in a metabolic transaction. The mere existence of a chromatin fiber as a relevant biological entity in vivo has been put into serious questioning. Current research is suggesting a possible reconciliation between theoretical studies and experiments, pointing towards a view where the polymorphic and dynamic nature of the chromatin fiber is essential to support its function in genome metabolism. PMID- 25437139 TI - Autopsy observations in lethal short-rib polydactyly syndromes. AB - The short rib-polydactyly syndromes are a heterogeneous group of lethal autosomal recessive disorders (SRP I-IV), which result from cellular ciliary dysfunction during embryogenesis. Diagnosis is conventionally based on radiographic imaging. Since 1976, postmortem investigations of 5 affected fetuses or stillbirths have been undertaken and the visceral abnormalities have been documented. These anomalies are discussed in the context of prenatal differential diagnosis and prognostication following imaging in pregnancy and at autopsy following miscarriage or stillbirth. PMID- 25437140 TI - Transcutaneous vagus nerve stimulation modulates tinnitus-related beta- and gamma band activity. AB - OBJECTIVES: The ability of a treatment method to interfere with tinnitus-related neural activity patterns, such as cortical gamma rhythms, has been suggested to indicate its potential in relieving tinnitus. Therapeutic modulation of gamma band oscillations with vagus nerve stimulation has been recently reported in epileptic patients. The aim of this study was to investigate the effects of transcutaneous vagus nerve stimulation (tVNS) on neural oscillatory patterns. DESIGN: We calculated the power spectral density and synchrony of magnetoencephalography recordings during auditory stimulation in seven tinnitus patients and eight normal-hearing control subjects. Comparisons between subject groups were performed to reveal electrophysiological markers of tinnitus. tVNS specific effects within each group were studied by comparing recording blocks with and without tVNS. We also investigated the correlation of each measure with individual ratings of tinnitus distress, as measured by the tinnitus handicap inventory questionnaire. RESULTS: Tinnitus patients differed from controls in the baseline condition (no tVNS applied), measured by both cortical oscillatory power and synchronization, particularly at beta and gamma frequencies. Importantly, we found tVNS-induced changes in synchrony, correlating strongly with tinnitus handicap inventory scores, at whole-head beta-band (r = -0.857, p = 0.007), whole head gamma-band (r = -0.952, p = 0.0003), and frontal gamma-band (r = -0.952, p = 0.0003). CONCLUSIONS: We conclude that tVNS was successful in modulating tinnitus related beta- and gamma-band activity and thus could have potential as a treatment method for tinnitus. PMID- 25437141 TI - Auditory brainstem implant: electrophysiologic responses and subject perception. AB - OBJECTIVES: The primary aim of this study was to compare the perceptual sensation produced by bipolar electrical stimulation of auditory brainstem implant (ABI) electrodes with the morphology of electrically evoked responses elicited by the same bipolar stimulus in the same unanesthetized, postsurgical state. Secondary aims were to (1) examine the relationships between sensations elicited by the bipolar stimulation used for evoked potential recording and the sensations elicited by the monopolar pulse-train stimulation used by the implant processor, and (2) examine the relationships between evoked potential morphology (elicited by bipolar stimulation) to the sensations elicited by monopolar stimulation. DESIGN: Electrically evoked early-latency and middle-latency responses to bipolar, biphasic low-rate pulses were recorded postoperatively in four adults with ABIs. Before recording, the perceptual sensations elicited by these bipolar stimuli were obtained and categorized as (1) auditory sensations only, (2) mixed sensations (both auditory and nonauditory), (3) side effect (nonauditory sensations), or (4) no sensation. In addition, the sensations elicited by monopolar higher-rate pulse-train stimuli similar to that used in processor programming were measured for all electrodes in the ABI array and classified using the same categories. Comparisons were made between evoked response morphology, bipolar stimulation sensation, and monopolar stimulation sensation. RESULTS: Sensations were classified for 33 bipolar pairs as follows: 21 pairs were auditory, 6 were mixed, 5 were side effect, and 1 was no sensation. When these sensations were compared with the electrically evoked response morphology for these signals, P3 of the electrically evoked auditory brainstem response (eABR) and the presence of a middle-latency positive wave, usually between 15 and 25 msec (electrical early middle-latency response [eMLR]), were only present when the perceptual sensation had an auditory component (either auditory or mixed pairs). The presence of other waves in the early-latency response such as N1 or P2 or a positive wave after 4 msec did not distinguish between only auditory or only nonauditory sensations. For monopolar stimulation, 42 were classified as auditory, 16 were mixed, and 26 were classified as side effect or no sensation. When bipolar sensations were compared with monopolar sensations for the 21 bipolar pairs categorized as auditory, 7 pairs had monopolar sensations of auditory for both electrodes, 9 pairs had only one electrode with a monopolar sensation of auditory, with the remainder having neither electrode as auditory. Of 6 bipolar pairs categorized as mixed, 3 had monopolar auditory sensations for one of the electrodes. When monopolar stimulation was compared with evoked potential morphology elicited by bipolar stimulation, P3 and the eMLR were more likely to be present when one or both of the electrodes in the bipolar pair elicited an auditory or mixed sensation with monopolar stimulation and were less likely to occur when neither of the electrodes had an auditory monopolar sensation. Again, other eABR waves did not distinguish between auditory and nonauditory sensations. CONCLUSIONS: ABI electrodes that are associated with auditory sensations elicited by bipolar stimulation are more likely to elicit evoked responses with a P3 wave or a middle-latency wave. P3 of the eABR and M15 25 of the eMLR are less likely to be present if neither electrode of the bipolar pair evoked an auditory sensation with monopolar stimulation. PMID- 25437142 TI - Five Times Sit-To-Stand test completion times among older women: Influence of seat height and arm position. AB - OBJECTIVE: To investigate the interaction of seat height and arm position with completion times for the Five Times Sit-To-Stand test (FTSTS) in older women. DESIGN: Cross-sectional study. SETTING: University-based rehabilitation centre. SUBJECTS: Thirty-three women (mean age 61.8 years, standard deviation 5.3) participated in this cross-sectional study. METHODS: Time taken to complete the FTSTS with different seat heights (85%, 100% and 115% of knee height) and arm positions (arms across chest, or hands on thighs) was measured with a stopwatch. RESULTS: FTSTS completion times differed significantly between seat heights of 85% and 115% knee height and between seat heights of 100% and 115% knee height for both arm positions. There was no significant difference between FTSTS completion times for the 2 arm positions at any seat height. CONCLUSION: A lower seat height resulted in longer FTSTS completion times in women over 55 years of age, whereas arm position did not significantly affect FTSTS completion times. PMID- 25437143 TI - Cellular changes in the hamster testicular interstitium with ageing and after exposure to short photoperiod. AB - The aim of this study was to evaluate the cellular changes that occur in the hamster testicular interstitium in two very different physiological situations involving testicular involution: ageing and exposure to a short photoperiod. The animals were divided into an 'age group' with three subgroups - young, adult and old animals - and a 'regressed group' with animals subjected to a short photoperiod. The testicular interstitium was characterised by light and electron microscopy. Interstitial cells were studied histochemically with regard to their proliferation, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP in situ nick end labelling (TUNEL+) and testosterone synthetic activity. We identified two types of Leydig cell: Type A cells showed a normal morphology, while Type B cells appeared necrotic. With ageing, pericyte proliferation decreased but there was no variation in the index of TUNEL-positive Leydig cells. In the regressed group, pericyte proliferation was greater and TUNEL-positive cells were not observed in the interstitium. The testicular interstitium suffered few ultrastructural changes during ageing and necrotic Leydig cells were observed. In contrast, an ultrastructural involution of Leydig cells with no necrosis was observed in the regressed group. In conclusion, the testicular interstitium of Mesocricetus auratus showed different cellular changes in the two groups (age and regressed), probably due to the irreversible nature of ageing and the reversible character of changes induced by short photoperiod. PMID- 25437144 TI - Selection of fragments for kinase inhibitor design: decoration is key. AB - In fragment-based screening, the choice of the best suited fragment hit among the detected hits is crucial for success. In our study, a kinase lead compound was fragmented, the hinge-binding motif extracted as a core fragment, and a minilibrary of five similar compounds with fragment-like properties was selected from our proprietary compound database. The structures of five fragments in complex with transforming growth factor beta receptor type 1 kinase domain were determined by X-ray crystallography. Three different binding modes of the fragments are observed that depend on the position and the type of the substitution at the core fragment. The influence of different substituents on the preferred fragment pose was analyzed by various computational approaches. We postulate that the replacement of water molecules leads to the different binding modes. PMID- 25437145 TI - Highly uniform and stable n-type carbon nanotube transistors by using positively charged silicon nitride thin films. AB - Air-stable n-doping of carbon nanotubes is presented by utilizing SiN(x) thin films deposited by plasma-enhanced chemical vapor deposition. The fixed positive charges in SiN(x), arising from (+)Si = N3 dangling bonds induce strong field effect doping of underlying nanotubes. Specifically, an electron doping density of ~ 10(20) cm(-3) is estimated from capacitance voltage measurements of the fixed charge within the SiN(x). This high doping concentration results in thinning of the Schottky barrier widths at the nanotube/metal contacts, thus allowing for efficient injection of electrons by tunnelling. As a proof-of concept, n-type thin-film transistors using random networks of semiconductor enriched nanotubes are presented with an electron mobility of ~ 10 cm(2)/V s, which is comparable to the hole mobility of as-made p-type devices. The devices are highly stable without any noticeable change in the electrical properties upon exposure to ambient air for 30 days. Furthermore, the devices exhibit high uniformity over large areas, which is an important requirement for use in practical applications. The work presents a robust approach for physicochemical doping of carbon nanotubes by relying on field-effect rather than a charge transfer mechanism. PMID- 25437147 TI - Covalency in resonance-assisted halogen bonds demonstrated with cooperativity in N-halo-guanine quartets. AB - Halogen bonds are shown to possess the same characteristics as hydrogen bonds: charge transfer, resonance assistance and cooperativity. This follows from the computational analyses of the structure and bonding in N-halo-base pairs and quartets. The objective was to achieve an understanding of the nature of resonance-assisted halogen bonds (RAXB): how they resemble or differ from the better understood resonance-assisted hydrogen bonds (RAHB) in DNA. We present an accurate physical model of the RAXB based on the molecular orbital theory, which is derived from the corresponding energy decomposition analyses and study of the charge distribution. We show that the RAXB arise from classical electrostatic interaction and also receive strengthening from donor-acceptor interactions within the sigma-electron system. Similar to RAHB, there is also a small stabilization by pi-electron delocalization. This resemblance leads to prove cooperativity in N-halo-guanine quartets, which originates from the charge separation that occurs with donor-acceptor orbital interactions in the sigma electron system. PMID- 25437146 TI - Optimizing the electronic properties of photoactive anticancer oxypyridine bridged dirhodium(II,II) complexes. AB - A series of partial paddlewheel dirhodium compounds of general formula cis [Rh2(xhp)2(CH3CN)n][BF4]2 (n = 5 or 6) were synthesized {xhp = 6-R-2-oxypyridine ligands, R = -CH3 (mhp), -F (fhp), -Cl (chp)}. X-ray crystallographic studies indicate the aforementioned compounds contain two cis-oriented bridging xhp ligands, with the remaining sites being coordinated by CH3CN ligands. The lability of the equatorial (eq) CH3CN groups in these complexes in solution is in the order -CH3 > -Cl > -F, in accord with the more electron rich bridging ligands exerting a stronger trans effect. In the case of cis-[Rh2(chp)2(CH3CN)6][BF4]2 (5), light irradiation enhances the production of the aqua adducts in which eq CH3CN is replaced by H2O molecules, whereas the formation of the aqua species for cis-[Rh2(fhp)2(CH3CN)6][BF4]2 (7) is only slightly increased by irradiation. The potential of both compounds to act as photochemotherapy agents was evaluated. A 16.4-fold increase in cytotoxicity against the HeLa cell line was observed for 5 upon 30 min irradiation (lambda > 400 nm), in contrast to the nontoxic compound 7, which is in accord with the results from the photochemistry. Furthermore, the cell death mechanism induced by 5 was determined to be apoptosis. These results clearly demonstrate the importance of tuning the ligand field around the dimetal center to maximize the photoreactivity and achieve the best photodynamic action. PMID- 25437148 TI - The palladium-catalyzed intermolecular C-H chalcogenation of arenes. AB - Palladium catalyzes the intermolecular chalcogenation of carbazole, 2 phenylpyridine, benzo[h]quinolone, and indole derivatives with disulfides and diselenides via selective C-H bond cleavage, providing a convenient route to thio and selenoethers. PMID- 25437149 TI - Tea Flavanols Block Advanced Glycation of Lens Crystallins Induced by Dehydroascorbic Acid. AB - Growing evidence has shown that ascorbic acid (ASA) can contribute to protein glycation and the formation of advanced glycation end products (AGEs), especially in the lens. The mechanism by which ascorbic acid can cause protein glycation probably originates from its oxidized form, dehydroascorbic acid (DASA), which is a reactive dicarbonyl species. In the present study, we demonstrated for the first time that four tea flavanols, (-)-epigallocatechin 3-O-gallate (EGCG), (-) epigallocatechin (EGC), (-)-epicatechin 3-O-gallate (ECG), and (-)-epicatechin (EC), could significantly trap DASA and consequently form 6C- or 8C-ascorbyl conjugates. Among these four flavanols, EGCG exerted the strongest trapping efficacy by capturing approximate 80% of DASA within 60 min. We successfully purified and identified seven 6C- or 8C-ascorbyl conjugates of flavanols from the chemical reaction between tea flavanols and DASA under slightly basic conditions. Of which, five ascorbyl conjugates, EGCGDASA-2, EGCDASA-2, ECGDASA-1, ECGDASA-2 and ECDASA-1, were recognized as novel compounds. The NMR data showed that positions 6 and 8 of the ring A of flavanols were the major active sites for trapping DASA. We further demonstrated that tea flavanols could effectively inhibit the formation of DASA-induced AGEs via trapping DASA in the bovine lens crystallin-DASA assay. In this assay, 8C-ascorbyl conjugates of flavanols were detected as the major adducts using LC-MS. This study suggests that daily consumption of beverages containing tea flavanols may prevent protein glycation in the lens induced by ascorbic acid and its oxidized products. PMID- 25437151 TI - Perceptual and instrumental assessments of orofacial muscle tone in dysarthric and normal speakers. AB - Clinical assessment of orofacial muscle tone is of interest for differential diagnosis of the dysarthrias, but standardized procedures and normative data are lacking. In this study, perceptual ratings of tone were compared with instrumental measures of tissue stiffness for facial, lingual, and masticatory muscles in 70 individuals with dysarthria. Perceptual and instrumental tone data were discordant and failed to discriminate between five dysarthria types. These results raised concerns about the validity of Myoton-3 stiffness measures in the orofacial muscles. Therefore, a second study evaluated contracted and relaxed orofacial muscles in 10 neurotypical adults. Results for the cheek, masseter, and lateral tongue surface followed predictions, with significantly higher tissue stiffness during contraction. In contradiction, stiffness measures from the superior surface of the tongue were lower during contraction. Superior-to inferior tongue thickness was notably increased during contraction. A third study revealed that tissue thickness up to ~10 mm significantly affected Myoton-3 measures. Altered tissue thickness due to neuromuscular conditions like spasticity and atrophy may have undermined the detection of group differences in the original sample of dysarthric speakers. These experiments underscore the challenges of assessing orofacial muscle tone and identify considerations for quantification of tone-related differences across dysarthria groups in future studies. PMID- 25437152 TI - Examining the role of abstainer prototype favorability as a mediator of the abstainer-norms-drinking-behavior relationship. AB - Past research has indicated that peer influence is associated with risky health behaviors, such as alcohol and other substance use (e.g., Maxwell, 2002; Santor, Messervey, & Kusumakar, 2000). Specifically, research has indicated that believing that more of one's peers use alcohol predicts more favorable prototypes (risk images) of the typical alcohol user (Litt & Stock, 2011; Teunissen et al., 2014). However, it is unclear if this same relationship would hold when considering abstainer (i.e., people who do not use alcohol) cognitions. The primary goal of the present study was to determine whether normative perceptions of peer abstinence from alcohol predict alcohol consumption and whether this relationship is mediated by abstainer prototypes. Results from 2,095 college students (42% male) indicated that the relation between abstainer norms and drinking behavior was mediated by abstainer prototypes such that believing that more peers abstained from alcohol use predicted more favorable prototypes of the typical alcohol abstainer, which in turn predicted lower alcohol use. Results from this study provide important first steps to delineating the relationship between abstainer cognitions and alcohol use. (PsycINFO Database Record PMID- 25437150 TI - Personality change following internet-based cognitive behavior therapy for severe health anxiety. AB - Personality traits have traditionally been viewed as stable, but recent studies suggest that they could be affected through psychological treatment. Internet based cognitive behavior therapy (ICBT) for severe health anxiety (DSM-IV hypochondriasis) has been shown to be effective in reducing health anxiety, but its effect on measures of personality traits has not been investigated. The main aim of this study was to investigate the impact of ICBT on personality traits in the three broad dimensions--neuroticism, extraversion and aggression. We hypothesized that participants in ICBT would reduce their level of neuroticism compared to controls that did not receive the active treatment. No specific predictions were made regarding extraversion and aggression. Data from a randomized controlled trial were used in which participants were allocated to 12 weeks of ICBT (n = 40) or to a basic attention control condition (n = 41). Personality traits were assessed with the Swedish Universities Scales of Personality and the primary outcome of health anxiety was the Health Anxiety Inventory. There was a significant interaction effect of group and time on neuroticism-related scales, indicating larger pre- to post-treatment reductions in the Internet-based CBT group compared to the control condition. Analyses at 6 month follow-up showed that changes were stable. Traits relating to extraversion and aggression were largely unchanged. This study is the first to demonstrate that a brief ICBT intervention for severe health anxiety causes long-term changes in measures of personality traits related to neuroticism. The treatment thus has a broader impact than just reducing health anxiety. TRIAL REGISTRATION: Clinicaltrials.gov (ID NCT00828152). PMID- 25437154 TI - Alcohol consumption in relation to residence status and ethnicity in college students. AB - The present study examined the roles of gender, ethnicity, and residence status in an ethnically diverse sample of undergraduate students who completed the Core Alcohol and Drug Survey. Gender, ethnicity, and residential status were associated with likelihood of binge drinking among students who reported consuming alcohol (non-Hispanic). White students were more likely to report using alcohol than Black students and Asian students. Ethnicity moderated the effects of both residence status and gender on alcohol consumption. Living with one's parents was associated with a lower likelihood of reported alcohol use among Hispanic students, but not among (non-Hispanic) White students. Hispanic women were more likely to report using alcohol than were Hispanic men, but no gender difference in likelihood of alcohol consumption was found among (non-Hispanic) White students. PMID- 25437153 TI - Pilot trial of an expressive writing intervention with HIV-positive methamphetamine-using men who have sex with men. AB - Among men who have sex with men (MSM), the co-occurrence of trauma and stimulant use has negative implications for HIV/AIDS prevention. HIV-positive, methamphetamine-using MSM were recruited to pilot test a 7-session, multicomponent resilient affective processing (RAP) intervention that included expressive writing exercises targeting HIV-related traumatic stress. An open phase pilot with 10 participants provided support for feasibility of intervention delivery such that 99% of the RAP sessions were completed in a 1-month period. Subsequently, 23 additional participants were enrolled in a pilot randomized controlled trial of the RAP intervention (n = 12) versus an attention-control condition that included writing exercises about neutral topics (n = 11). Acceptability was evidenced by participants randomized to RAP expressing significantly more negative emotions in their writing and reporting greater likelihood of recommending expressive writing exercises to a friend living with HIV. Over the 3-month follow-up period, attention-control participants reported significant decreases in HIV-related traumatic stress while RAP intervention participants reported no significant changes. Compared to attention-control participants, those in the RAP intervention reported significant reductions in the frequency of methamphetamine use immediately following the 1-month RAP intervention period. Thematic analyses of RAP expressive writing exercises revealed that multiple negative life events characterized by social stigma or loss contribute to the complex nature of HIV-related traumatic stress. Findings support the feasibility and acceptability of an exposure-based intervention targeting HIV-related traumatic stress. However, more intensive intervention approaches that simultaneously target trauma and stimulant use will likely be needed to optimize HIV/AIDS prevention efforts with this population. (PsycINFO Database Record PMID- 25437156 TI - Editorial. PMID- 25437157 TI - Food control in Switzerland: an overview. AB - Switzerland is a confederation consisting of 26 states, the so-called 'cantons'. In the field of food control, the Swiss federal state is in charge of issuing the regulations (Food law and associated texts), whereas enforcement is assigned to the cantons. The offices in charge of food control are the cantonal laboratories headed by a 'Cantonal chemist'. These offices pursue three main goals: to protect consumer health, to protect the consumer against frauds and to ensure food handling under good hygiene conditions. To that purpose, the Cantonal chemist heads both a laboratory and a staff of inspectors, who are responsible for the control of food products (including meat and drinking water), the control of hygiene and production at factories, stores, restaurants, etc. as well as the control of common goods and household items such as toys, clothing, make-up, dishes, cookware, jewelry and so on. All laboratories and inspection bodies are accredited according to ISO norms EN 17'020 and EN 17'025. The offices headed by the cantonal chemists analyze annually about 110'000 samples on sale or from factories, whereas the inspection bodies perform roughly 45'000 inspections (without primary producers and occasional importers). PMID- 25437155 TI - Transpapillary Gallbladder Stents Can Stabilize or Improve Decompensated Cirrhosis in Patients Awaiting Liver Transplantation. AB - GOALS: To describe the short-term and long-term outcomes in 34 consecutive decompensated cirrhotic patients with symptomatic gallbladder disease undergoing transpapillary gallbladder stent (TGS) placement. BACKGROUND: Endoscopic TGS placement is a minimally invasive means of treating symptomatic gallbladder disease in poor surgical candidates. STUDY: Between June 2005 and June 2011, 34 patients with cirrhosis and symptomatic gallbladder disease underwent attempted TGS placement. RESULTS: Median patient age was 52 years, 56% were hospitalized, and 48% were listed for liver transplantation. The median model for end-stage liver disease (MELD) score was 15 (range, 6 to 40) and 88% were Child-Turcotte Pugh class B/C. A double pigtailed stent was successfully placed in 94% of the patients. At 1-month follow-up, clinical improvement was noted in 82% of the treated subjects and the MELD scores in 14 of 22 (64%) evaluable subjects improved or stabilized. Actuarial transplant-free survival was 53% in the liver transplant candidates with a mean follow-up of 352 days, whereas survival was 44% in the 18 nontransplant candidates with a mean follow-up of 1.5 years. Periprocedural complications included pancreatitis in 5 patients, cholangitis in 3, and 1 patient with cystic duct perforation. In addition, 2 subjects had symptomatic bleeding from traumatic duodenal ulcerations 2 years after TGS placement that necessitated stent removal. CONCLUSIONS: Endoscopic TGS placement was technically feasible in 94% of decompensated cirrhotics and was associated with a relatively low rate of periprocedural (26%) and long-term complications (6%). Stabilization or improvement in clinical status and MELD scores was seen in the majority of treated patients. PMID- 25437158 TI - A personal review on 40 years at the kantonales labor zurich: success - failure - conclusions. AB - My career at the Kantonales Labor Zurich (KLZH) started with the introduction of capillary gas chromatography (GC) and took me through an ideal curriculum: first the elaboration of a solid technical background, then a broad range of applications covering all stages from the development of smart and solid methods, understanding the background of a matter and searching for solutions and risk assessment, lobbying to get solutions implemented, sometimes even writing legislation. Selected milestones are described with how the subject came up, what we did and a critical review of the success we had. This gave ample opportunity to think about consumer protection, efficiency in control and performance of authorities. It was a highly motivating job, but sometimes also frustrating because of the weak position of the authorities in defending public interests against big industry. Authorities should be respected, which primarily means competence, strict implementation of relevant rules and insistence if necessary. Often this has little to do with the number or samples analyzed - on the contrary: high sample throughput often prevents us going into depth. In all, what the food safety authorities are capable of implementing is far from that promised to the consumers by legislation. PMID- 25437159 TI - Prenyl Ethers: Novel Fungal Volatiles Formed by Penicillium digitatum. AB - Prenyl ethyl ether (PEE) was previously described as the cause for a solvent-like off-note in ground hazelnuts, but its origin remained unclear. Investigations were carried out by analytical groups of Coop and Givaudan over four years to elucidate this phenomenon. From mouldy citrus fruits a strain of Penicillium digitatum was isolated and found to form PEE. Formation on citrus and other fruits was prominent and contributed to the particular smell of decayed fruits. Several strains of P. digitatum formed PEE, while other fungal species did not. In contrast to citrus fruit, prenyl methyl ether (PME) was formed as dominant prenyl ether on hazelnuts while only small amounts of PEE were found. PME has not been previously described as volatile metabolite of fungi or as a food-taint. Spiking experiments with deuterated ethanol showed that the ethyl group is likely incorporated into PEE via the aldehyde form. On hazelnuts strongly decayed by P. digitatum yet another prenyl ether was tentatively identified: Prenyl isopropyl ether. Prenyl ethers present a novel group of volatile metabolites of P. digitatum. They are likely typical for this species and have not been described before. Prenyl ethers seem to play a significant role in the smell of food decayed by P. digitatum and should be considered in cases of off-notes and taints. PMID- 25437160 TI - Use of Isotope Ratio Mass Spectrometry (IRMS) Determination ((18)O/(16)O) to Assess the Local Origin of Fish and Asparagus in Western Switzerland. AB - Here we present the use of isotope ratio mass spectrometry (IRMS) for the detection of mislabelling of food produced in Switzerland. The system is based on the analysis of the oxygen isotope distribution in water (delta(18)O). Depending on the location on the earth, lake or groundwater has a specific isotopic distribution, which can serve as a fingerprint in order to verify whether a product has grown by means of the corresponding water. This report presents specifically the IRMS technique and the results obtained in the origin detection of fish grown in selected Swiss lakes as well as asparagus grown in Valais ground. Strengths and limitations of the method are presented for both cited products; on one hand, the technique is relatively universal for any product which contains significant water but on the other hand, it necessitates a rather heavy workload to build up a database of water delta(18)O values of products of different origins. This analytical tool is part of the concept of combating fraud currently in use in Switzerland. PMID- 25437161 TI - Development and Validation of a P-35S, T-nos, T-35S and P-FMV Tetraplex Real-time PCR Screening Method to Detect Regulatory Genes of Genetically Modified Organisms in Food. AB - In routine analysis screening methods based on real-time PCR (polymerase chain reaction) are most commonly used for the detection of genetically modified (GM) plant material in food and feed. Screening tests are based on sequences frequently used for GM development, allowing the detection of a large number of GMOs (genetically modified organisms). Here, we describe the development and validation of a tetraplex real-time PCR screening assay comprising detection systems for the regulatory genes Cauliflower Mosaic Virus 35S promoter, Agrobacterium tumefaciens nos terminator, Cauliflower Mosaic Virus 35S terminator and Figwort Mosaic Virus 34S promoter. Three of the four primer and probe combinations have already been published elsewhere, whereas primers and probe for the 35S terminator have been developed in-house. Adjustment of primer and probe concentrations revealed a high PCR sensitivity with insignificant physical cross talk between the four detection channels. The sensitivity of each PCR-system is sufficient to detect a GMO concentration as low as 0.05% of the containing respective element. The specificity of the described tetraplex is high when tested on DNA from GM maize, soy, rapeseed and tomato. We also demonstrate the robustness of the system by inter-laboratory tests. In conclusion, this method provides a sensitive and reliable screening procedure for the detection of the most frequently used regulatory elements present in GM crops either authorised or unauthorised for food. PMID- 25437162 TI - Unexpected occurrence of caffeine in sleep-inducing herbal teas. AB - Caffeine acts as a weak psychostimulant and is known to cause trouble with sleeping. Therefore, the presence of caffeine in sleep-aid herbal teas was somewhat surprising, and confirmatory investigations were conducted to exclude any possible misidentification. The botanicals of the sedative mixtures were analysed individually by ultra performance liquid chromatography (UPLC) coupled with a time-of-flight high-resolution mass spectrometer (TOF-HRMS), and caffeine was detected in linden (Tilia spp.) extracts. The presence of caffeine was unambiguously confirmed by means of its characteristic mass spectrum acquired during direct analyses of powdered linden by thermal desorption coupled to a GC*GC-TOF-MS. Caffeine content was determined in 11 linden-based samples, with a validated UPLC-MS/MS method using two mass transitions. Concentrations were between traces and 110 mg kg(-1) in the herbal material while those in the corresponding prepared sleep-inducing hot beverages ranged from traces to 226 MUg per cup. PMID- 25437163 TI - The TTC Approach in Practice and its Impact on Risk Assessment and Risk Management in Food Safety. A Regulatory Toxicologist's Perspective. AB - There are many substances in food and drinking water from different contamination sources for which only insufficient or no toxicity data exist. In order to prioritize and preliminarily assess the human health risks, the threshold of toxicological concern (TTC) approach was developed between 1996 and 2004. This concept has since been applied increasingly by regulatory food safety authorities. In parallel, the safety of this approach has been discussed by stakeholders, primarily on a conceptual basis. However, real examples showing the practical benefits of this approach have not been discussed. In this paper, the technical feasibility, applicability, safety, and further benefits of the TTC approach are illustrated and discussed based on four real cases: 1) halogenated contaminants of unknown origin in the drinking water (polychlorinated butadienes), 2) an unwanted by-product from epoxy resin coatings in canned fish (Cyclo-di-BADGE), 3) two cyclic compounds occurring in polyamide food packaging materials and kitchen utensils, and 4) mycotoxins (from Alternaria). These examples from different fields of application clearly demonstrate that the results of the TTC approach are an extremely useful starting point for adequate decisions and actions (if necessary) by risk assessment and risk management in food safety. PMID- 25437164 TI - Development and in-house Validation of a Rapid LC-MS/MS Method for the Semi quantification of Eleven Mycotoxins in Maize Samples. AB - The aim of this study is a current trend in chemical food safety control to increase monitoring of the co-occurrence of mycotoxins. Unsanitary conditions during harvesting, drying, packing and storage in production and processing of cereals can effect mycotoxin contamination. A method was developed for the simultaneous determination of 11 mycotoxins: deoxynivalenol, aflatoxins B1, B2, G1 and G2, ochratoxin A, fumonisins B1 and B2, zearalenone, and toxins T-2 and HT 2, allowing confirmation of their presence in maize samples as well as their identification and semi-quantification. The mycotoxins are extracted with a mixture of methanol/water, diluted with water and 0.1% formic acid and then analyzed by LC-HESI-MS/MS in a single 12 min run in positive mode. Multiple reaction monitoring mode (MRM) is applied by using two abundant fragments for each mycotoxin. Matrix effects are compensated using external matrix-matched calibration curves. Recoveries, calculated by spiking blank maize samples, ranging from 95.2% to 113.4%, were in accordance with the performance criteria required by the European Commission and intraday reproducibility ranged from 4.2% to 13.2%. Proficiency test materials and reference materials were analyzed to assess the accuracy of the method with satisfying results for the 11 mycotoxins. The method was used for monitoring of maize samples on sale in Switzerland. PMID- 25437165 TI - Results of an International Interlaboratory Trial to Determine Twelve Allergens Using Real-time PCR- and ELISA-based Assays. AB - To elucidate the capability of laboratories to determine allergen contents, an international interlaboratory trial was conducted using meat products spiked with 12 allergens. The measurement uncertainty was calculated independent of the applied method simulating realistic situations when comparing analysis certificates from different laboratories. The measurement uncertainty was revealed to be in the best cases +/-100%, in the worst cases quantification exhibited a measurement uncertainty of higher than 200% making quantitative analysis impossible. The measurement uncertainty seemed to depend on the analyte and assays used. PMID- 25437166 TI - Microsatellite Analysis of Perch (Perca fluviatilis) and its Genetic Authentication of Geographical Localization. AB - European perch (Perca fluviatilis) is an economically important freshwater species in Europe. In Switzerland, where the demand largely exceeds the production coming from Swiss lakes, nearly 90% of the requirements come from importation with the majority of perch originating from Estonia and Russia. The price of perch fillet varies considerably depending on the origin. Therefore traceability in the fish food sector plays an increasingly important role for consumer protection. Currently the traceability of perch can be assessed through chemical isotopic analysis. The 180/160 isotopic abundance ratio is used as geographical traceability marker, but several aspects affect the accuracy of the method, i.e. the distinct geographical area ratio differs only very slightly with overlapping standard deviation, the need for a large amount of fish material requires the mix of many fillets, the impossibility of analyzing processed matrix, the comparison of the ratio with the ratio of a sample of the presumed originating water makes the analyses more complicated. New application of DNA markers for the traceability of food products plays an increasingly important role for consumer protection. Microsatellites, which are short tandemly repetitive DNA sequences, are genetic markers of choice for traceability because of their abundance and high polymorphism. Moreover, fluorescent labelling and capillary electrophoresis separation increase efficiency and precision of genotyping microsatellites. The method can also be efficiently applied in processed food products where other methods have limited applications. In this study, we tested the efficiency of three polymorphic microsatellites and their combinations for their ability to correctly assign or exclude 195 reference perch to their origin population. Using the maximum likelihood and Bayesian methods computed by the software GeneClass2, the three loci microsatellite were optimized and allowed the correct assignation of all but two Swiss perch (60/62) into Swiss population. The markers also exclude 132/133 imported fish from the Swiss population with a match probability of more than 95%. The number of markers required for correct assignation differs from species to species, and depends on many factors such as genetic diversity and population structure. For perch populations, the results showed that only three polymorphic microsatellite markers are required to perform a reliable attribution or exclusion of a perch to the Swiss population with more than 98% correct assignations. PMID- 25437167 TI - Targeted Screening and Quantification of dl-PCBs and Dioxins in Various Foodstuffs by Programmed-temperature Vaporizer Large-volume Injection Coupled to GC-MS. AB - In 2009, high concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (dl-PCBs) were found in soils located near the municipal garbage incinerator of Geneva. The matter of food contamination in this area was raised. Based on exposure criteria, a strategy of analysis of animal fats has been established with farmers in the Geneva area. Most methods of analysis of dl-PCBs, dioxins and furans, are based on gas chromatography coupled to high-resolution mass spectrometry (GC-HRMS) and considered as the reference methodology. An innovative approach was developed by programmed-temperature vaporizer large-volume injection (PTV-LV) and gas chromatography coupled with triple quadrupole mass spectrometry (GC-MS/MS) analysis. This analytical method was validated and was found suitable for screening and quantification of target compounds in animal fats (beef, pork, sheep, etc. ). PTV-LV coupled to GC-MS/MS appeared to be a good alternative compared to the GC-HRMS strategy, offering a good compromise between sensitivity, versatility of instrumentation, and economical aspects. A survey of 121 samples was conducted. PMID- 25437168 TI - Wood - An Innovative Component of High-tech Products? 6th Wadenswil Day of Chemistry 2014. AB - Wood is a multifunctional renewable material that could replace oil-based and other non-renewable resources in many applications. In the Swiss National Science Foundation project NFP 66, entitled 'Wood as a resource', researchers are attempting to find ways to use wood more efficiently in the future. The 6th Wadenswil Day of Chemistry, which was organised by the Institute of Chemistry and Biological Chemistry at Zurich University of Applied Sciences in Wadenswil, gave an overview of the innovative activities currently being undertaken in this field. PMID- 25437169 TI - A Ray of Light Piercing through the Clouds The 49th EUCHEMS Conference on Stereochemistry Burgenstock Conference 2014. PMID- 25437170 TI - Optimization of chemical reactor feed by simulations based on a kinetic approach. AB - Chemical incidents are typically caused by loss of control, resulting in runaway reactions or process deviations in different stages of the production. In the case of fed-batch reactors, the problem generally encountered is the accumulation of heat. This is directly related to the temperature of the process, the reaction kinetics and adiabatic temperature rise, which is the maximum temperature attainable in the event of cooling failure. The main possibility to control the heat accumulation is the use of a well-controlled adapted feed. The feed rate can be adjusted by using reaction and reactor dynamic models coupled to Model Predictive Control. Thereby, it is possible to predict the best feed profile respecting the safety constraints. PMID- 25437172 TI - Parasite reveals mitochondrial inheritance machinery. PMID- 25437173 TI - The laboratory in reichenau castle designated as "chemical landmark" on 12 september 2014. PMID- 25437175 TI - Development of a prediction rule for estimating postoperative pulmonary complications. AB - Patient- and procedure-related factors associated with postoperative pulmonary complications (PPCs) have changed over the last decade. Therefore, we sought to identify independent risk factors of PPCs and to develop a clinically applicable scoring system. We retrospectively analyzed clinical data from 2,059 patients who received preoperative evaluations from respiratory physicians between June 2011 and October 2012. A new scoring system for estimating PPCs was developed using beta coefficients of the final multiple regression models. Of the 2,059 patients studied, 140 (6.8%) had PPCs. A multiple logistic regression model revealed seven independent risk factors (with scores in parentheses): age >=70 years (2 points), current smoker (1 point), the presence of airflow limitation (1 point), American Society of Anesthesiologists class >=2 (1 point), serum albumin <4 g/dL (1 point), emergency surgery (2 points), and non-laparoscopic abdominal/cardiac/aortic aneurysm repair surgery (4 points). The area under the curve was 0.79 (95% CI, 0.75-0.83) with the newly developed model. The new risk stratification including laparoscopic surgery has a good discriminative ability for estimating PPCs in our study cohort. Further research is needed to validate this new prediction rule. PMID- 25437177 TI - Determination of monomethylmercury and dimethylmercury in the Arctic marine boundary layer. AB - Our understanding of the biogeochemical cycling of monomethylmercury (MMHg) in the Arctic is incomplete because atmospheric sources and sinks of MMHg are still unclear. We sampled air in the Canadian Arctic marine boundary layer to quantify, for the first time, atmospheric concentrations of methylated Hg species (both MMHg and dimethylmercury (DMHg)), and, estimate the importance of atmospheric deposition as a source of MMHg to Arctic land- and sea-scapes. Overall atmospheric MMHg and DMHg concentrations (mean +/- SD) were 2.9 +/- 3.6 and 3.8 +/- 3.1 (n = 37) pg m(-3), respectively. Concentrations of methylated Hg species in the marine boundary layer varied significantly among our sites, with a predominance of MMHg over Hudson Bay (HB), and DMHg over Canadian Arctic Archipelago (CAA) waters. We concluded that DMHg is of marine origin and that primary production rate and sea-ice cover are major drivers of its concentration in the Canadian Arctic marine boundary layer. Summer wet deposition rates of atmospheric MMHg, likely to be the product of DMHg degradation in the atmosphere, were estimated at 188 +/- 117.5 ng m(-2) and 37 +/- 21.7 ng m(-2) for HB and CAA, respectively, sustaining MMHg concentrations available for biomagnification in the pelagic food web. PMID- 25437176 TI - Different regions of the newcastle disease virus fusion protein modulate pathogenicity. AB - Newcastle disease virus (NDV), also designated as Avian paramyxovirus type 1 (APMV-1), is the causative agent of a notifiable disease of poultry but it exhibits different pathogenicity dependent on the virus strain. The molecular basis for this variability is not fully understood. The efficiency of activation of the fusion protein (F) is determined by presence or absence of a polybasic amino acid sequence at an internal proteolytic cleavage site which is a major determinant of NDV virulence. However, other determinants of pathogenicity must exist since APMV-1 of high (velogenic), intermediate (mesogenic) and low (lentogenic) virulence specify a polybasic F cleavage site. We aimed at elucidation of additional virulence determinants by constructing a recombinant virus that consists of a lentogenic NDV Clone 30 backbone and the F protein gene from a mesogenic pigeon paramyxovirus-1 (PPMV-1) isolate with an intracerebral pathogenicity index (ICPI) of 1.1 specifying the polybasic sequence R-R-K-K-R*F motif at the cleavage site. The resulting virus was characterized by an ICPI of 0.6, indicating a lentogenic pathotype. In contrast, alteration of the cleavage site G-R-Q-G-R*L of the lentogenic Clone 30 to R-R-K-K-R*F resulted in a recombinant virus with an ICPI of 1.36 which was higher than that of parental PPMV-1. Substitution of different regions of the F protein of Clone 30 by those of PPMV-1, while maintaining the polybasic amino acid sequence at the F cleavage site, resulted in recombinant viruses with ICPIs ranging from 0.59 to 1.36 suggesting that virulence is modulated by regions of the F protein other than the polybasic cleavage site. PMID- 25437178 TI - Proton-coupled electron transfer in tyrosine and a beta-hairpin maquette: reaction dynamics on the picosecond time scale. AB - In proteins, proton-coupled electron transfer (PCET) can involve the transient oxidation and reduction of the aromatic amino acid tyrosine. Due to the short life time of tyrosyl radical intermediates, transient absorption spectroscopy provides an important tool in deciphering electron-transfer mechanisms. In this report, the photoionization of solution tyrosine and tyrosinate was investigated using transient, picosecond absorption spectroscopy. The results were compared to data acquired from a tyrosine-containing beta-hairpin peptide. This maquette, peptide A, is an 18-mer that exhibits pi-pi interaction between tyrosine (Y5) and histidine (H14). Y5 and H14 carry out an orthogonal PCET reaction when Y5 is oxidized in the mid-pH range. Photolysis of all samples (280 nm, instrument response: 360 fs) generated a solvated electron signal within 3 ps. A signal from the S1 state and a 410 nm signal from the neutral tyrosyl radical were also formed in 3 ps. Fits to S1 and tyrosyl radical decay profiles revealed biphasic kinetics with time constants of 10-50 and 400-1300 ps. The PCET reaction at pH 9 was associated with a significant decrease in the rate of tyrosyl radical and S1 decay compared to electron transfer (ET) alone (pH 11). This pH dependence was observed both in solution and peptide samples. The pH 9 reaction may occur with a sequential electron-transfer, proton-transfer (ETPT) mechanism. Alternatively, the pH 9 reaction may occur by coupled proton and electron transfer (CPET). CPET would be associated with a reorganization energy larger than that of the pH 11 reaction. Significantly, the decay kinetics of S1 and the tyrosyl radical were accelerated in peptide A compared to solution samples at both pH values. These data suggest either an increase in electronic coupling or a specific, sequence dependent interaction, which facilitates ET and PCET in the beta hairpin. PMID- 25437179 TI - Umbilical cord mesenchymal stromal cells affected by gestational diabetes mellitus display premature aging and mitochondrial dysfunction. AB - Human umbilical cord mesenchymal stromal cells (hUC-MSCs) of Wharton's jelly origin undergo adipogenic, osteogenic, and chondrogenic differentiation in vitro. Recent studies have consistently shown their therapeutic potential in various human disease models. However, the biological effects of major pregnancy complications on the cellular properties of hUC-MSCs remain to be studied. In this study, we compared the basic properties of hUC-MSCs obtained from gestational diabetes mellitus (GDM) patients (GDM-UC-MSCs) and normal pregnant women (N-UC-MSCs). Assessments of cumulative cell growth, MSC marker expression, cellular senescence, and mitochondrial function-related gene expression were performed using a cell count assay, senescence-associated beta-galactosidase staining, quantitative real-time reverse transcription-polymerase chain reaction, immunoblotting, and cell-based mitochondrial functional assay system. When compared with N-UC-MSCs, GDM-UC-MSCs showed decreased cell growth and earlier cellular senescence with accumulation of p16 and p53, even though they expressed similar levels of CD105, CD90, and CD73 MSC marker proteins. GDM-UC-MSCs also displayed significantly lower osteogenic and adipogenic differentiation potentials than N-UC-MSCs. Furthermore, GDM-UC-MSCs exhibited a low mitochondrial activity and significantly reduced expression of the mitochondrial function regulatory genes ND2, ND9, COX1, PGC-1alpha, and TFAM. Here, we report intriguing and novel evidence that maternal metabolic derangement during gestation affects the biological properties of fetal cells, which may be a component of fetal programming. Our findings also underscore the importance of the critical assessment of the biological impact of maternal-fetal conditions in biological studies and clinical applications of hUC-MSCs. PMID- 25437180 TI - Oral nutritional support can shorten the duration of parenteral hydration in end of-life cancer patients: a randomized controlled trial. AB - Tube feeding or hydration is often considered for end-of-life cancer patients despite the negative effects on quality of life. The efficacy of oral nutritional support in this setting is unknown. We conducted a randomized trial to compare the efficacies of an amino acid jelly, Inner Power(r) (IP), and a liquid enteral product, Ensure Liquid(r) (EL), in terminally ill cancer patients. We randomly assigned patients to 3 arms: EL, IP, and EL+IP. The primary endpoint was drip infusion in vein (DIV)-free survival, which was defined as the duration from nutritional support initiation to administration of parenteral hydration. Twenty seven patients were enrolled in the study, of whom 21 were included in the intention-to-treat analysis. The median age of the subjects was 69 yr. There were significant differences between the arms with regard to the median DIV-free survival (0.5, 6.0, and 4.5 days in the EL, IP, and EL + IP arms, respectively; P = 0.05). The median overall survival was 7, 9, and 8 days in the EL, IP, and EL + IP arms, respectively. IP may shorten the duration of parenteral hydration in terminally ill cancer patients and does not affect their survival. PMID- 25437183 TI - Annual reports on Department of Veterans Affairs healthcare utilization among Iraq and Afghanistan War Veterans with traumatic brain injury and comorbidities to inform policy, research, and practice. PMID- 25437181 TI - The effect of different water immersion temperatures on post-exercise parasympathetic reactivation. AB - PURPOSE: We evaluated the effect of different water immersion (WI) temperatures on post-exercise cardiac parasympathetic reactivation. METHODS: Eight young, physically active men participated in four experimental conditions composed of resting (REST), exercise session (resistance and endurance exercises), post exercise recovery strategies, including 15 min of WI at 15 degrees C (CWI), 28 degrees C (TWI), 38 degrees C (HWI) or control (CTRL, seated at room temperature), followed by passive resting. The following indices were assessed before and during WI, 30 min post-WI and 4 hours post-exercise: mean R-R (mR-R), the natural logarithm (ln) of the square root of the mean of the sum of the squares of differences between adjacent normal R-R (ln rMSSD) and the ln of instantaneous beat-to-beat variability (ln SD1). RESULTS: The results showed that during WI mRR was reduced for CTRL, TWI and HWI versus REST, and ln rMSSD and ln SD1 were reduced for TWI and HWI versus REST. During post-WI, mRR, ln rMSSD and ln SD1 were reduced for HWI versus REST, and mRR values for CWI were higher versus CTRL. Four hours post exercise, mRR was reduced for HWI versus REST, although no difference was observed among conditions. CONCLUSIONS: We conclude that CWI accelerates, while HWI blunts post-exercise parasympathetic reactivation, but these recovery strategies are short-lasting and not evident 4 hours after the exercise session. PMID- 25437182 TI - Proteomic profile and in silico analysis in metastatic melanoma with and without BRAF mutation. AB - INTRODUCTION: Selective inhibitors of BRAF, vemurafenib and dabrafenib are the standard of care for metastatic melanoma patients with BRAF V600, while chemotherapy continued to be widely used in BRAF wild type patients. MATERIALS AND METHODS: In order to discover novel candidate biomarkers predictive to treatment, serum of 39 metastatic melanoma vemurafenib (n = 19) or chemotherapy (n = 20) treated patients at baseline, at disease control and at progression, were analyzed using SELDI-TOF technology. In silico analysis was used to identify more significant peaks. RESULTS: In patients with different BRAF status, we found 5 peptides significantly deregulated, with the down-regulation of the m/z 9176 peak strongly associated with BRAF mutation. At baseline as predictive biomarkers we identified 2 peptides - m/z 6411, 4075 - as significantly up-regulated in responders to chemotherapy and 4 peaks - m/z 5900, 12544, 49124 and 11724 - significantly up-regulated in longer vs shorter responders to vemurafenib. After response, 3 peptides (m/z 4658, 18639, and 9307) resulted significantly down regulated while 3 peptides m/z 9292, 7765 and 9176 appeared up-regulated respectively in chemotherapy and vemurafenib responder patients. In vemurafenib treated patients, 16 peaks appeared deregulated at progression compared to baseline time. In silico analysis identified proteins involved in invasiveness (SLAIN1) and resistance (ABCC12) as well as in the pathway of detoxification (NQO1) and apoptosis (RBM10, TOX3, MTEFD1, TSPO2). Proteins associated with the modulation of neuronal plasticity (RIN1) and regulatory activity factors of gene transcription (KLF17, ZBTB44) were also highlighted. CONCLUSION: Our exploratory study highlighted some factors that deserve to be further investigated in order to provide a framework for improving melanoma treatment management through the development of biomarkers which could act as the strongest surrogates of the key biological events in stage IV melanoma. PMID- 25437184 TI - Escherichia coli adaptation to the gut environment: a constant fight for survival. PMID- 25437185 TI - Conference report from the International Congress on Infectious Diseases 2014: Part One. 16th International Congress on Infectious Diseases, Cape Town, South Africa 2-5 April 2014. AB - The 16th International Congress on Infectious Diseases (ICID) was held in Cape Town this year, marking the return of the conference to Africa for the first time in 22 years. While infectious diseases such as malaria, tuberculosis and HIV--all still prevalent in the African healthcare landscape--dominated the program, the conference featured several important sessions on fungal infection and a significant number of posters devoted to this critical medical area. Within the context of the rise of antimicrobial resistance, now identified by the WHO as one of the three greatest threats to human health, came the message that resistance is not limited to antimicrobials, but that antifungal resistance is also a significant and emerging threat worldwide. PMID- 25437186 TI - Potential role of tavaborole for the treatment of onychomycosis. AB - Systemic antifungal treatments are believed to be more effective than topicals for the treatment of onychomycosis; however, they are associated with more risks of adverse events. Tavaborole is the first member of a new class of antifungals that has been developed as a new topical nail solution for the treatment of toenail onychomycosis caused by dermatophytes. During Phase I-III clinical trials, tavaborole 5.0% nail solution showed a favorable safety and efficacy profile. Tavaborole 5.0% received US FDA market approval on 8 July 2014. PMID- 25437187 TI - A prospective study on bacterial and atypical etiology of acute exacerbation in chronic obstructive pulmonary disease. AB - AIM: The bacterial and atypical etiology of acute exacerbations of chronic obstructive pulmonary disease was investigated and the diagnostic techniques used were compared among 92 hospitalized patients. MATERIALS & METHODS: Sputum specimens were investigated using culture and PCR, serological status evaluation was performed and the inflammatory profile was associated with the microbiological results. RESULTS & CONCLUSION: The majority of the patients (65.2%) had very severe airway obstruction. The most common bacteria were Haemophilus influenzae and Pseudomonas aeruginosa (23.9 and 14.1%, respectively). Acinetobacter baumannii- and P. aeruginosa-positive cultures were associated with prolonged hospitalization and severe airway obstruction (p = 0.03 and 0.031, respectively). Chlamydia pneumoniae or Mycoplasma pneumoniae infection was diagnosed in four and two patients, respectively. Discrepant results were detected between PCR and serology, especially regarding C. pneumoniae. PMID- 25437188 TI - Regulation of biofilm formation in Salmonella enterica serovar Typhimurium. AB - In animals, plants and the environment, Salmonella enterica serovar Typhimurium forms the red dry and rough (rdar) biofilm characterized by extracellular matrix components curli and cellulose. With complex expression control by at least ten transcription factors, the bistably expressed orphan response regulator CsgD directs rdar morphotype development. CsgD expression is an integral part of the Hfq regulon and the complex cyclic diguanosine monophosphate signaling network partially controlled by the global RNA-binding protein CsrA. Cell wall turnover and the periplasmic redox status regulate csgD expression on a post transcriptional level by unknown mechanisms. Furthermore, phosphorylation of CsgD is a potential inactivation and degradation signal in biofilm dissolution. Including complex incoherent feed-forward loops, regulation of biofilm formation versus motility and virulence is of recognized complexity. PMID- 25437190 TI - A simple, rapid and sensitive FRET assay for botulinum neurotoxin serotype B detection. AB - Botulinum neurotoxins (BoNTs), the most potent naturally-occurring neurotoxins known to humans, comprise seven distinct serotypes (BoNT/A-G), each of which exhibits unique substrate specificity. Many methods have been developed for BoNT detection, in particular for BoNT/A, with various complexity and sensitivity, while substrate based FRET assay is considered as the most widely used approach due to its simplicity and sensitivity. In this study, we designed a vesicle associated membrane protein 2 (VAMP2) based FRET assay based on the understanding of the VAMP2 and light chain/B (LC/B) interactions in our previous studies. The current design constituted the shortest peptide, VAMP2 (63-85), with FRET dyes (EDAN and Dabcyl) labelled at position 76 and 85, respectively, which showed minimal effect on VAMP2 substrate catalysis by LC/B and therefore enhanced the sensitivity of the assay. The FRET peptide, designated as FVP-B, was specific to LC/B, with a detection sensitivity as low as ~20 pM in 2 h. Importantly, FVP-B showed the potential to be scaled up and used in high throughput screening of LC/B inhibitor. The currently developed FRET assay is one of the most economic and rapid FRET assays for LC/B detection. PMID- 25437191 TI - Recovery from anemia in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation--prevalence, predictors and clinical outcome. AB - INTRODUCTION: Preoperative anemia is common in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI) and has been linked to a poorer outcome--including a higher 1-year mortality. The aim of this study was to investigate the impact of successful TAVI on baseline anemia. METHODS: A total of 253 patients who survived at least 1 year following TAVI were included in this study. The prevalence, predictors and clinical outcome of hemoglobin (Hb)-recovery were assessed. RESULTS: The prevalence of baseline anemia was 49% (n = 124)--recovery from anemia occurred in 40% of the anemic patients (n = 49) at 1 year after TAVI with an increase in mean Hb-level of 1.35 g/dL from baseline. This increase was not related to an improvement in renal function. At multivariate analysis, a high peak gradient (OR 4.82, P = 0.003) was shown to be an independent predictor for Hb-recovery, while blood transfusion (OR 0.31, P = 0.038) and chronic kidney disease (CKD, OR 0.33, P = 0.043) were identified as negative predictors at, respectively, one and two years after TAVI. When compared to patients without baseline anemia, those anemic patients with Hb recovery had a similar functional improvement (OR 0.98, P = 0.975), whereas those without Hb-recovery had a significantly lower likelihood of functional improvement with ?2 NYHA classes (OR 0.49, P = 0.034) and a higher likelihood of re-hospitalization within the first year after TAVI (OR 1.91, P = 0.024). CONCLUSION: Recovery from anemia occurs in 40% of anemic patients at 1 year after TAVI--mainly in those with a high gradient and without CKD. Blood transfusion was found to have a transient adverse effect on this Hb-recovery. Finally, anemic patients without Hb-recovery experience less functional improvement and have a higher re-hospitalization rate within the first year after TAVI. PMID- 25437192 TI - Bimanual and unimanual convergent goal-directed movement times. AB - Three experiments are reported, investigating the effects of using 1 or 2 hands when making convergent low index of difficulty (ID) and visually controlled movements (2 hands meeting together). The experiments involved movements in four different cases-a probe held in the right hand and moved to a target held in the stationary left hand, vice versa of this arrangement, both hands moving with the probe in the right hand and target in the left hand, and vice-versa of this arrangement. Experiments were the standard Fitts' paradigm, moving a pin into a hole and a low-ID task. In Fitts' task, 2-hand movements were faster than 1 hand only at higher IDs; this was also the case in the pin-to-hole transfer task and the movement times were lower when the pin was held in the preferred hand. Movements made with low ID showed a small effect of 1- or 2-handed movements, with the effective amplitude of the movement being reduced by about 20% when 2 hands were used. PMID- 25437189 TI - An intimate link: two-component signal transduction systems and metal transport systems in bacteria. AB - Bacteria have evolved various strategies to contend with high concentrations of environmental heavy metal ions for rapid, adaptive responses to maintain cell viability. Evidence gathered in the past two decades suggests that bacterial two component signal transduction systems (TCSTSs) are intimately involved in monitoring cation accumulation, and can regulate the expression of related metabolic and virulence genes to elicit adaptive responses to changes in the concentration of these ions. Using examples garnered from recent studies, we summarize the cross-regulatory relationships between metal ions and TCSTSs. We present evidence of how bacterial TCSTSs modulate metal ion homeostasis and also how metal ions, in turn, function to control the activities of these signaling systems linked with bacterial survival and virulence. PMID- 25437194 TI - Head Impact Exposure and Neurologic Function of Youth Football Players. AB - Football players are subjected to repetitive impacts that may lead to brain injury and neurologic dysfunction. Knowledge about head impact exposure (HIE) and consequent neurologic function among youth football players is limited. PURPOSE: This study aimed to measure and characterize HIE of youth football players throughout one season and explore associations between HIE and changes in selected clinical measures of neurologic function. METHODS: Twenty-two youth football players (11-13 yr) wore helmets outfitted with a head impact telemetry (HIT) system to quantify head impact frequency, magnitude, duration, and location. Impact data were collected for each practice (27) and game (9) in a single season. Selected clinical measures of balance, oculomotor performance, reaction time, and self-reported symptoms were assessed before and after the season. RESULTS: The median individual head impacts per practice, per game, and throughout the entire season were 9, 12, and 252, respectively. Approximately 50% of all head impacts (6183) had a linear acceleration between 10g and 20g, but nearly 2% were greater than 80g. Overall, the head impact frequency distributions in this study population were similar in magnitude and location as in high school and collegiate football, but total impact frequency was lower. Individual changes in neurologic function were not associated with cumulative HIE. CONCLUSION: This study provides a novel examination of HIE and associations with short-term neurologic function in youth football and notably contributes to the limited HIE data currently available for this population. Whereas youth football players can experience remarkably similar head impact forces as high school players, cumulative subconcussive HIE throughout one youth football season may not be detrimental to short-term clinical measures of neurologic function. PMID- 25437196 TI - Total lesion glycolysis as an IgG4-related disease activity marker. AB - OBJECTIVES: 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) was reported to be useful for monitoring immunoglobulin G4-related disease (IgG4-RD); however, a quantitative FDG-PET/CT analysis such as total lesion glycolysis (TLG) has not yet been conducted. This study aimed to investigate whether TLG would correlate with serum markers in IgG4-RD, and the utility of TLG for disease monitoring. METHODS: This retrospective study included 17 patients (12 men; median age, 62 years) who were followed up at Kyoto University Hospital and underwent FDG-PET/CT from April 2009 to November 2013. TLG was calculated for the involved lesions. Correlations between serum markers [IgG4, soluble IL-2 receptor (sIL-2R), lactate dehydrogenase (LDH), and C-reactive protein (CRP)] and TLG concomitant with FDG PET/CT scans were investigated. Serial changes in TLG were assessed in patients who underwent follow-up FDG-PET/CT (n = 6). RESULTS: The calculated median (IQL) TLG value was 154.8 (63.7-324.4). A significant correlation was found between the sIL-2R level and TLG (P = 0.001, rs = 0.763). In contrast, no correlations were found between the IgG4, LDH, or CRP levels and TLG. Increased or decreased TLG corresponded with clinical disease improvement or worsening. CONCLUSIONS: TLG correlated significantly with the serum sIL-2R level and may be useful for disease monitoring in IgG4-RD. PMID- 25437195 TI - Characterization of the Drosophila group ortholog to the amino-terminus of the alpha-thalassemia and mental retardation X-Linked (ATRX) vertebrate protein. AB - The human ATRX gene encodes hATRX, a chromatin-remodeling protein harboring an helicase/ATPase and ADD domains. The ADD domain has two zinc fingers that bind to histone tails and mediate hATRX binding to chromatin. dAtrx, the putative ATRX homolog in Drosophila melanogaster, has a conserved helicase/ATPase domain but lacks the ADD domain. A bioinformatic search of the Drosophila genome using the human ADD sequence allowed us to identify the CG8290 annotated gene, which encodes three ADD harboring- isoforms generated by alternative splicing. This Drosophila ADD domain is highly similar in structure and in the amino acids which mediate the histone tail contacts to the ADD domain of hATRX as shown by 3D modeling. Very recently the CG8290 annotated gene has been named dadd1. We show through pull-down and CoIP assays that the products of the dadd1 gene interact physically with dAtrxL and HP1a and all of them mainly co-localize in the chromocenter, although euchromatic localization can also be observed through the chromosome arms. We confirm through ChIP analyses that these proteins are present in vivo in the same heterochromatic regions. The three isoforms are expressed throughout development. Flies carrying transheterozygous combinations of the dadd1 and atrx alleles are semi-viable and have different phenotypes including the appearance of melanotic masses. Interestingly, the dAdd1-b and c isoforms have extra domains, such as MADF, which suggest newly acquired functions of these proteins. These results strongly support that, in Drosophila, the atrx gene diverged and that the dadd1-encoded proteins participate with dAtrx in some cellular functions such as heterochromatin maintenance. PMID- 25437197 TI - Short-term add-on tocilizumab and intravenous cyclophosphamide exhibited a remission-inducing effect in a patient with systemic lupus erythematosus with refractory multiorgan involvements including massive pericarditis and glomerulonephritis. AB - We report on a 41-year-old woman with refractory systemic lupus erythematosus with massive pericarditis, macrophage activation syndrome, and glomerulonephritis despite high-dose glucocorticoids and tacrolimus. Tocilizumab dramatically improved pericarditis, and glomerulonephritis was controlled after adding cyclophosphamide. We had to halt tocilizumab and cyclophosphamide due to possible pneumocystis infection after five and three infusions of tocilizumab and intravenous cyclophosphamide, respectively. Nevertheless, no lupus flare had been observed on glucocorticoid monotherapy and enabled further rapid tapering prednisolone. PMID- 25437198 TI - G-quadruplex structures and CpG methylation cause drop-out of the maternal allele in polymerase chain reaction amplification of the imprinted MEST gene promoter. AB - We observed apparent non-Mendelian behaviour of alleles when genotyping a region in a CpG island at the 5' end of the maternally imprinted human MEST isoform. This region contains three single nucleotide polymorphisms (SNPs) in total linkage disequilibrium, such that only two haplotypes occur in the human population. Only one haplotype was detectable in each subject, never both, despite the use of multiple primers and several genotyping methods. We observed that this region contains motifs capable of forming several G-quadruplex structures. Circular dichroism spectroscopy and native polyacrylamide gel electrophoresis confirmed that at least three G-quadruplexes form in vitro in the presence of potassium ions, and one of these structures has a Tm of greater than 99 degrees C in polymerase chain reaction (PCR) buffer. We demonstrate that it is the methylated maternal allele that is always lost during PCR amplification, and that formation of G-quadruplexes and presence of methylated cytosines both contributed to this phenomenon. This observed parent-of-origin specific allelic drop-out has important implications for analysis of imprinted genes in research and diagnostic settings. PMID- 25437199 TI - Piericidin A aggravates Tau pathology in P301S transgenic mice. AB - OBJECTIVE: The P301S mutation in exon 10 of the tau gene causes a hereditary tauopathy. While mitochondrial complex I inhibition has been linked to sporadic tauopathies. Piericidin A is a prototypical member of the group of the piericidins, a class of biologically active natural complex I inhibitors, isolated from streptomyces spp. with global distribution in marine and agricultural habitats. The aim of this study was to determine whether there is a pathogenic interaction of the environmental toxin piericidin A and the P301S mutation. METHODS: Transgenic mice expressing human tau with the P301S-mutation (P301S+/+) and wild-type mice at 12 weeks of age were treated subcutaneously with vehicle (N = 10 P301S+/+, N = 7 wild-type) or piericidin A (N = 9 P301S+/+, N = 9 wild-type mice) at a dose of 0.5 mg/kg/d for a period of 28 days via osmotic minipumps. Tau pathology was measured by stereological counts of cells immunoreative with antibodies against phosphorylated tau (AD2, AT8, AT180, and AT100) and corresponding Western blot analysis. RESULTS: Piericidin A significantly increased the number of phospho-tau immunoreactive cells in the cerebral cortex in P301S+/+ mice, but only to a variable and mild extent in wild type mice. Furthermore, piericidin A led to increased levels of pathologically phosphorylated tau only in P301S+/+ mice. While we observed no apparent cell loss in the frontal cortex, the synaptic density was reduced by piericidin A treatment in P301S+/+ mice. DISCUSSION: This study shows that exposure to piericidin A aggravates the course of genetically determined tau pathology, providing experimental support for the concept of gene-environment interaction in the etiology of tauopathies. PMID- 25437200 TI - The Functional Role of Prion Protein (PrPC) on Autophagy. AB - Cellular prion protein (PrPC) plays an important role in the cellular defense against oxidative stress. However, the exact protective mechanism of PrPC is unclear. Autophagy is essential for survival, differentiation, development, and homeostasis in several organisms. Although the role that autophagy plays in neurodegenerative disease has yet to be established, it is clear that autophagy induced cell death is observed in neurodegenerative disorders that exhibit protein aggregations. Moreover, autophagy can promote cell survival and cell death under various conditions. In this review, we describe the involvement of autophagy in prion disease and the effects of PrPC. PMID- 25437202 TI - Prions in variably protease-sensitive prionopathy: an update. AB - Human prion diseases, including sporadic, familial, and acquired forms such as Creutzfeldt-Jakob disease (CJD), are caused by prions in which an abnormal prion protein (PrPSc) derived from its normal cellular isoform (PrPC) is the only known component. The recently-identified variably protease-sensitive prionopathy (VPSPr) is characterized not only by an atypical clinical phenotype and neuropathology but also by the deposition in the brain of a peculiar PrPSc. Like other forms of human prion disease, the pathogenesis of VPSPr also currently remains unclear. However, the findings of the peculiar features of prions from VPSPr and of the possible association of VPSPr with a known genetic prion disease linked with a valine to isoleucine mutation at residue 180 of PrP reported recently, may be of great importance in enhancing our understanding of not only this atypical human prion disease in particular, but also other prion diseases in general. In this review, we highlight the physicochemical and biological properties of prions from VPSPr and discuss the pathogenesis of VPSPr including the origin and formation of the peculiar prions. PMID- 25437201 TI - Biochemical characterization of prion strains in bank voles. AB - Prions exist as different strains exhibiting distinct disease phenotypes. Currently, the identification of prion strains is still based on biological strain typing in rodents. However, it has been shown that prion strains may be associated with distinct PrPSc biochemical types. Taking advantage of the availability of several prion strains adapted to a novel rodent model, the bank vole, we investigated if any prion strain was actually associated with distinctive PrPSc biochemical characteristics and if it was possible to univocally identify strains through PrPSc biochemical phenotypes. We selected six different vole-adapted strains (three human-derived and three animal-derived) and analyzed PrPSc from individual voles by epitope mapping of protease resistant core of PrPSc (PrPres) and by conformational stability and solubility assay. Overall, we discriminated five out of six prion strains, while two different scrapie strains showed identical PrPSc types. Our results suggest that the biochemical strain typing approach here proposed was highly discriminative, although by itself it did not allow us to identify all prion strains analyzed. PMID- 25437204 TI - Curcumin reduces amyloid fibrillation of prion protein and decreases reactive oxidative stress. AB - Misfolding and aggregation into amyloids of the prion protein (PrP) is responsible for the development of fatal transmissible neurodegenerative diseases. Various studies on curcumin demonstrate promise for the prevention of Alzheimer's disease and inhibition of PrPres accumulation. To evaluate the effect of curcumin on amyloid fibrillation of prion protein, we first investigated the effect of curcumin on mouse prion protein (mPrP) in a cell-free system. Curcumin reduced the prion fibril formation significantly. Furthermore, we monitored the change in apoptosis and reactive oxygen species (ROS) level upon curcumin treatment in mouse neuroblastoma cells (N2a). Curcumin effectively rescues the cells from apoptosis and decreases the ROS level caused by subsequent co incubation with prion amyloid fibrils. The assays in cell-free mPrP and in N2a cells of this work verified the promising effect of curcumin on the prevention of transmissible neurodegenerative diseases. PMID- 25437203 TI - Kuru: a journey back in time from papua new Guinea to the neanderthals' extinction. AB - Kuru, the first human transmissible spongiform encephalopathy was transmitted to chimpanzees by D. Carleton Gajdusek (1923-2008). In this review, I briefly summarize the history of this seminal discovery along its epidemiology, clinical picture, neuropathology and molecular genetics. The discovery of kuru opened new windows into the realms of human medicine and was instrumental in the later transmission of Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker disease as well as the relevance that bovine spongiform encephalopathy had for transmission to humans. The transmission of kuru was one of the greatest contributions to biomedical sciences of the 20th century. PMID- 25437205 TI - Evaluation of the zoonotic potential of transmissible mink encephalopathy. AB - Successful transmission of Transmissible Mink Encephalopathy (TME) to cattle supports the bovine hypothesis for the still controversial origin of TME outbreaks. Human and primate susceptibility to classical Bovine Spongiform Encephalopathy (c-BSE) and the transmissibility of L-type BSE to macaques indicate a low cattle-to-primate species barrier. We therefore evaluated the zoonotic potential of cattle-adapted TME. In less than two years, this strain induced in cynomolgus macaques a neurological disease similar to L-BSE but distinct from c-BSE. TME derived from another donor species (raccoon) induced a similar disease with even shorter incubation periods. L-BSE and cattle-adapted TME were also transmissible to transgenic mice expressing human prion protein (PrP). Secondary transmissions to transgenic mice expressing bovine PrP maintained the features of the three tested bovine strains (cattle TME, c-BSE and L-BSE) regardless of intermediate host. Thus, TME is the third animal prion strain transmissible to both macaques and humanized transgenic mice, suggesting zoonotic potentials that should be considered in the risk analysis of animal prion diseases for human health. Moreover, the similarities between TME and L-BSE are highly suggestive of a link between these strains, and therefore the possible presence of L-BSE for many decades prior to its identification in USA and Europe. PMID- 25437206 TI - Involvement of endogenous retroviruses in prion diseases. AB - For millions of years, vertebrates have been continuously exposed to infection by retroviruses. Ancient retroviral infection of germline cells resulted in the formation and accumulation of inherited retrovirus sequences in host genomes. These inherited retroviruses are referred to as endogenous retroviruses (ERVs), and recent estimates have revealed that a significant portion of animal genomes is made up of ERVs. Although various host factors have suppressed ERV activation, both positive and negative functions have been reported for some ERVs in normal and abnormal physiological conditions, such as in disease states. Similar to other complex diseases, ERV activation has been observed in prion diseases, and this review will discuss the potential involvement of ERVs in prion diseases. PMID- 25437207 TI - An emerging tick-borne disease of humans is caused by a subset of strains with conserved genome structure. AB - The prevalence of tick-borne diseases is increasing worldwide. One such emerging disease is human anaplasmosis. The causative organism, Anaplasma phagocytophilum, is known to infect multiple animal species and cause human fatalities in the U.S., Europe and Asia. Although long known to infect ruminants, it is unclear why there are increasing numbers of human infections. We analyzed the genome sequences of strains infecting humans, animals and ticks from diverse geographic locations. Despite extensive variability amongst these strains, those infecting humans had conserved genome structure including the pfam01617 superfamily that encodes the major, neutralization-sensitive, surface antigen. These data provide potential targets to identify human-infective strains and have significance for understanding the selective pressures that lead to emergence of disease in new species. PMID- 25437208 TI - Culture-independence for surveillance and epidemiology. AB - Culture-independent methods in microbiology (quantitative PCR (qPCR), sequencing, microarrays, direct from sample matrix assisted laser desorption/ionization time of flight mass spectroscopy (MALDI-TOF MS), etc.) are disruptive technology. Rather than providing the same results as culture-based methods more quickly, more cheaply or with improved accuracy, they reveal an unexpected diversity of microbes and illuminate dark corners of undiagnosed disease. At times, they overturn existing definitions of presumably well-understood infections, generating new requirements for clinical diagnosis, surveillance and epidemiology. However, current diagnostic microbiology, infection control and epidemiology rest principally on culture methods elegantly optimized by clinical laboratorians. The clinical significance is interwoven; the new methods are out of context, difficult to interpret and impossible to act upon. Culture independent diagnostics and surveillance methods will not be deployed unless the reported results can be used to select specific therapeutics or infection control measures. To cut the knots surrounding the adoption of culture-independent methods in medical microbiology, culture-dependent methods should be supported by consistent culture-independent methods providing the microbial context. This will temper existing biases and motivate appropriate scrutiny of the older methods and results. PMID- 25437211 TI - Not prism prescription, but prism adaptation rehabilitates spatial neglect; a reply to Bansal, Han and Ciuffreda. PMID- 25437210 TI - Chemical characteristics of water-soluble ions in particulate matter in three metropolitan areas in the North China Plain. AB - PM2.5 and PM10 samples were collected simultaneously in each season in Beijing, Tianjin and Shijiazhuang to identify the characteristics of water-soluble ion compositions in the North China Plain. The water-soluble ions displayed significant seasonal variation. The dominant ions were NO3(-), SO4(2-), NH4(+) and Cl(-), accounting for more than 90% and 86% to the mass of total water soluble ions in PM2.5 and PM10, respectively. The anion/cation ratio indicated that the ion acidity of each city varied both between sites and seasonally. Over 50% of the ion species were enriched in small particles <=1 um in diameter. The [NO3(-)]/[SO4(2-)] ratio indicated that vehicles accounted for the majority of the particulate pollution in Beijing. Shijiazhuang, a city highly reliant on coal combustion, had a higher SO4(2-) concentration. PMID- 25437209 TI - A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease. AB - Therapies that target leukocyte trafficking pathways can reduce disease activity and improve clinical outcomes in multiple sclerosis (MS). Experimental autoimmune encephalomyelitis (EAE) is a widely studied animal model that shares many clinical and histological features with MS. Chemokine-like receptor-1 (CMKLR1) is a chemoattractant receptor that is expressed by key effector cells in EAE and MS, including macrophages, subsets of dendritic cells, natural killer cells and microglia. We previously showed that CMKLR1-deficient (CMKLR1 KO) mice develop less severe clinical and histological EAE than wild-type mice. In this study, we sought to identify CMKLR1 inhibitors that would pharmaceutically recapitulate the CMKLR1 KO phenotype in EAE. We identified 2-(alpha-naphthoyl) ethyltrimethylammonium iodide (alpha-NETA) as a CMKLR1 small molecule antagonist that inhibits chemerin-stimulated beta-arrestin2 association with CMKLR1, as well as chemerin-triggered CMKLR1+ cell migration. alpha-NETA significantly delayed the onset of EAE induced in C57BL/6 mice by both active immunization with myelin oligodendrocyte glycoprotein peptide 35-55 and by adoptive transfer of encephalitogenic T cells. In addition, alpha-NETA treatment significantly reduced mononuclear cell infiltrates within the CNS. This study provides additional proof of-concept data that targeting CMKLR1:chemerin interactions may be beneficial in preventing or treating MS. PMID- 25437212 TI - Does ownership matter? An overview of systematic reviews of the performance of private for-profit, private not-for-profit and public healthcare providers. AB - INTRODUCTION: Ownership of healthcare providers has been considered as one factor that might influence their health and healthcare related performance. The aim of this article was to provide an overview of what is known about the effects on economic, administrative and health related outcomes of different types of ownership of healthcare providers--namely public, private non-for-profit (PNFP) and private for-profit (PFP)--based on the findings of systematic reviews (SR). METHODS AND FINDINGS: An overview of systematic reviews was performed. Different databases were searched in order to select SRs according to an explicit comprehensive criterion. Included SRs were assessed to determine their methodological quality. Of the 5918 references reviewed, fifteen SR were included, but six of them were rated as having major limitations, so they weren't incorporated in the analyses. According to the nine analyzed SR, ownership does seem to have an effect on health and healthcare related outcomes. In the comparison of PFP and PNFP providers, significant differences in terms of mortality of patients and payments to facilities have been found, both being higher in PFP facilities. In terms of quality and economic indicators such as efficiency, there are no concluding results. When comparing PNFP and public providers, as well as for PFP and public providers, no clear differences were found. CONCLUSION: PFP providers seem to have worst results than their PNFP counterparts, but there are still important evidence gaps in the literature that needs to be covered, including the comparison between public and both PFP and PNFP providers. More research is needed in low and middle income countries to understand the impact on and development of healthcare delivery systems. PMID- 25437214 TI - Widening online opportunity. PMID- 25437213 TI - The cultivation of Bt corn producing Cry1Ac toxins does not adversely affect non target arthropods. AB - Transgenic corn producing Cry1Ac toxins from Bacillus thuringiensis (Bt) provides effective control of Asian corn borer, Ostrinia furnacalis (Guenee), and thus reduces insecticide applications. However, whether Bt corn exerts undesirable effects on non-target arthropods (NTAs) is still controversial. We conducted a 2 yr study in Shangzhuang Agricultural Experiment Station to assess the potential impact of Bt corn on field population density, biodiversity, community composition and structure of NTAs. On each sampling date, the total abundance, Shannon's diversity index, Pielou's evenness index and Simpson's diversity index were not significantly affected by Bt corn as compared to non-Bt corn. The "sampling dates" had a significant effect on these indices, but no clear tendencies related to "Bt corn" or "sampling dates X corn variety" interaction were recorded. Principal response curve analysis of variance indicated that Bt corn did not alter the distribution of NTAs communities. Bray-Curtis dissimilarity and distance analysis showed that Cry1Ac toxin exposure did not increase community dissimilarities between Bt and non-Bt corn plots and that the evolution of non-target arthropod community was similar on the two corn varieties. The cultivation of Bt corn failed to show any detrimental evidence on the density of non-target herbivores, predators and parasitoids. The composition of herbivores, predators and parasitoids was identical in Bt and non-Bt corn plots. Taken together, results from the present work support that Bt corn producing Cry1Ac toxins does not adversely affect NTAs. PMID- 25437215 TI - Toward a sustainable intensive care training program. PMID- 25437216 TI - Central venous pressure is a stopping rule, not a target of fluid resuscitation. PMID- 25437217 TI - The CALORIES trial: statistical analysis plan. AB - BACKGROUND: The CALORIES trial is a pragmatic, open, multicentre, randomised controlled trial (RCT) of the clinical effectiveness and cost-effectiveness of early nutritional support via the parenteral route compared with early nutritional support via the enteral route in unplanned admissions to adult general critical care units (CCUs) in the United Kingdom. The trial derives from the need for a large, pragmatic RCT to determine the optimal route of delivery for early nutritional support in the critically ill. OBJECTIVE: To describe the proposed statistical analyses for the evaluation of the clinical effectiveness in the CALORIES trial. METHODS: With the primary and secondary outcomes defined precisely and the approach to safety monitoring and data collection summarised, the planned statistical analyses, including prespecified subgroups and secondary analyses, were developed and are described. RESULTS: The primary outcome is all cause mortality at 30 days. The primary analysis will be reported as a relative risk and absolute risk reduction and tested with the Fisher exact test. Prespecified subgroup analyses will be based on age, degree of malnutrition, acute severity of illness, mechanical ventilation at admission to the CCU, presence of cancer and time from CCU admission to commencement of early nutritional support. Secondary analyses include adjustment for baseline covariates. CONCLUSION: In keeping with best trial practice, we have developed, described and published a statistical analysis plan for the CALORIES trial and are placing it in the public domain before inspecting data from the trial. PMID- 25437218 TI - A randomised controlled trial of standard transfusion versus fresher red blood cell use in intensive care (TRANSFUSE): protocol and statistical analysis plan. AB - OBJECTIVE: To determine if using freshest available rather than standard-issue red blood cells (RBCs) can reduce mortality in critically ill intensive care unit patients. Our study is the largest ongoing randomised controlled trial (RCT) of RBC age in critically ill patients and will help determine if the use of the freshest available RBCs should become standard policy for the critically ill. DESIGN, SETTING AND PARTICIPANTS: A double-blind, multicentre, Phase III RCT of 5000 adult ICU patients in Australia, New Zealand, Europe and the Middle East. INTERVENTIONS: Transfusion of the freshest available RBCs in place of standard care RBCs until hospital discharge. MAIN OUTCOME MEASURES: The primary outcome measure is 90-day all-cause mortality. Secondary outcome measures are time to death, 28-day and 180-day mortality, persistent organ dysfunction combined with death, days alive and free of mechanical ventilation and renal replacement therapy, bloodstream infection in the ICU, length of stay in the ICU and in hospital, proportion of patients with febrile non-haemolytic transfusion reactions, and quality of life at Day 180. RESULTS: A detailed statistical analysis plan with predefined subgroups and secondary analyses has been finalised before results being available, to ensure an unbiased final analysis. CONCLUSIONS: The pragmatic protocol design has been chosen to facilitate translation of the trial results into practice. The TRANSFUSE trial will have important clinical and policy implications, regardless of the outcome. PMID- 25437219 TI - Informed consent in the intensive care unit: the experiences and expectations of patients and their families. AB - OBJECTIVE: To describe the awareness of intensive care unit patients and their next of kin (NoK) about invasive procedures and their expectations of informed consent for procedures in the ICU. DESIGN AND SETTING: A written survey of patients and their NoK in a tertiary, university-affiliated ICU, using multiplechoice questions, Likert scales and comments to generate semiquantitative and qualitative data. PARTICIPANTS: Fifty-one ICU patients and 69 NoK completed the survey. Inclusion criteria were unplanned ICU admission, ICU length-of-stay > 24 hours, English speaking and competent to consent to participate. MAIN OUTCOME MEASURES: Proportion of procedures respondents were aware had occurred during ICU admission; satisfaction with information received; preferred method of receiving information and giving consent; and expectations of when procedural consent is required. RESULTS: Patients and NoK were unaware of many procedures performed during their admission. Respondents correctly identified 49% (95% CI, 45%-53%) of procedures performed during the patient's ICU admission. Despite this, most patients (80%; 95% CI, 69%-91%) and NoK (94%; 95% CI, 89%-100%) were satisfied with information provided about procedures. Over half of respondents (55%; 95% CI, 46%-64%) only expected consent for procedures that were "risky or not routine". About one-quarter (27%; 95% CI, 23%-31%) expected to give consent before every procedure and 15% (95% CI, 11%-18%) expected no procedural consent process. Patients and NoK strongly preferred a verbal rather than written consent process. CONCLUSIONS: Our results suggest there is a limited degree of support for routine procedural consent from ICU patients and their NoK. PMID- 25437220 TI - The association of plasma gamma-aminobutyric acid concentration with postoperative delirium in critically ill patients. AB - OBJECTIVE: Delirium is a common complication in postoperative, critically ill patients. The mechanism of postoperative delirium is not well understood but many studies have shown significant associations between benzodiazepine use, alcohol withdrawal and cirrhosis, and an increased risk of delirium. We aimed to investigate a possible link with alterations of gamma-aminobutyric acid (GABA) activity. DESIGN, SETTING AND PARTICIPANTS: A prospective observational investigation of 40 patients > 20 years old who had undergone elective surgery with general anaesthesia and were expected to need postoperative intensive care for more than 48 hours. We assessed postoperative delirium using the confusion assessment method in the intensive care unit at 1 hour after the operation and on postoperative Day (POD) 1 and POD 2. We collected blood samples for measurement of plasma GABA concentrations before the operation and on POD 1 and 2. MAIN OUTCOME MEASURES: Postoperative delirium and perioperative plasma GABA concentrations in patients with and without delirium. RESULTS: Postoperative delirium occurred in 13 of the patients. Patients with delirium had significantly higher Acute Physiology and Chronic Health Evaluation II scores than patients without delirium. The mean plasma GABA concentration on POD 2 was significantly lower in patients with delirium than in those without delirium. After adjustment of relevant variables, plasma GABA concentration on POD 2 was independently associated with postoperative delirium. CONCLUSIONS: Plasma GABA level on POD 2 has a significant independent association with postoperative delirium. PMID- 25437221 TI - A protocol for the 0.9% saline versus Plasma-Lyte 148 for intensive care fluid therapy (SPLIT) study. AB - BACKGROUND: 0.9% saline is the most commonly used intravenous (IV) fluid in the world. However, recent data raise the possibility that, compared with buffered crystalloid fluids such as Plasma-Lyte 148, the administration of 0.9% saline to intensive care unit patients might increase their risk of acute kidney injury (AKI). OBJECTIVE: To describe the protocol for the 0.9% Saline v Plasma-Lyte 148 for ICU Fluid Therapy (SPLIT) study. METHODS: This is a multicentre, cluster randomised, double crossover feasibility study to be conducted in four New Zealand tertiary ICUs over a 28-week period and will enroll about 2300 participants. All ICU patients who need crystalloid IV fluid therapy (except those with established renal failure needing dialysis and those admitted to the ICU for palliative care) will be enrolled. Participating ICUs will be randomly assigned to 0.9% saline or Plasma-Lyte 148 as the routine crystalloid IV fluid, in a blinded fashion, in four alternating 7-week blocks. MAIN OUTCOME MEASURES: The primary outcome will be the proportion of patients who develop AKI in the ICU. Secondary outcomes will include the difference between the most recent serum creatinine level measured before study enrollment and the peak serum creatinine level in the ICU; use of renal replacement therapy; and ICU and in hospital mortality. All analyses will be conducted on an intention-to-treat basis. RESULTS AND CONCLUSION: The SPLIT study started on 1 April 2014 and will provide preliminary data on the comparative effectiveness of using 0.9% saline v Plasma- Lyte 148 as the routine IV fluid therapy in ICU patients. PMID- 25437222 TI - Computed tomography pulmonary angiogram as a result of medical emergency team calls: a 5-year retrospective audit. AB - OBJECTIVE: To determine the proportion of computed tomography pulmonary angiograms (CTPAs), performed after medical emergency team (MET) calls, that are positive for pulmonary embolism (PE), and whether there are useful clinical predictors of positive CTPA results. DESIGN: All patients from a tertiary referral hospital in Melbourne who had an MET response and an associated CTPA within 6 hours, from 2009 to 2013, were included. We reviewed medical records to assess indications for CTPA, including MET clinical triggers, time of day of the MET (implying the seniority of decision making), chest x-ray results and Wells scores as a clinical decision rule for PE. RESULTS: There were 4578 MET responses (in 3136 patients) over the 5-year study period, from which 70 CTPAs were ordered (2.2% of all patients). A PE was identified in 12 patients (17.1%). The median age of CTPA patients was 70 years (interquartile range, 60-76 years) and most were surgical patients (80%). The major MET triggers for CTPA were hypoxia (42.9%) and hypotension (28.6%). An abnormal chest x-ray was associated with a low likelihood of PE. The Wells scores and MET indications of hypoxia, hypotension and tachycardia were not accurate in predicting the presence or extent of PE. CONCLUSION: Clinical decision rules and MET indications were not significantly associated with the presence of PE on CTPA. However, an abnormal chest x-ray has a high negative predictive value and therefore may be helpful in preventing unnecessary CTPAs. PMID- 25437224 TI - College of Intensive Care Medicine: changes to intensive care medicine training. AB - The College of Intensive Care Medicine provides the standards for training and certification of intensive care medicine specialists in Australia and New Zealand. After reviewing and revising its training program, the College recently launched a new training curriculum for all trainees registering from 2014, aimed at maintaining quality. In this article, we aim to outline the context, changes and future directions for intensive care medicine training in Australia and New Zealand. PMID- 25437223 TI - The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia. AB - BACKGROUND: Allogeneic red blood cell (RBC) transfusion is associated with significant increases in mortality and major morbidity in patients admitted to the intensive care unit, and the blood supplies it requires are an increasingly scarce and costly resource. Despite high levels of compliance with recommended transfusion thresholds in the ICU, RBC transfusion remains common. Novel interventions to reduce the incidence of RBC transfusion are required. OBJECTIVE: To describe the study protocol for a randomised controlled trial, the Intravenous Iron or Placebo for Anaemia in Intensive Care (IRONMAN) trial, comparing intravenous (IV) iron with placebo in patients who are admitted to an ICU and are anaemic. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: A Phase IIb multicentre, randomised, placebo-controlled trial. Patients admitted to the ICU with a haemoglobin (Hb) level < 100 g/L and predicted to require critical care beyond the next calendar day will be randomly assigned in a 1 : 1 ratio to receive IV ferric carboxymaltose (500 mg) or placebo. MAIN OUTCOME MEASURES: The primary end point will be the mean number of RBC units transfused from study enrolment to discharge from hospital. Secondary end points will include change in Hb level and incidence of nosocomial infection. RESULTS AND CONCLUSIONS: The IRONMAN trial is designed to determine whether IV iron administered to patients admitted to an ICU and who are anaemic is associated with a reduction in RBC transfusion, compared with placebo in addition to standard care. The results of this trial may determine whether a Phase III trial of IV iron in ICUs is feasible. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12612001249842). PMID- 25437225 TI - Online availability of research equipment and consumables. PMID- 25437226 TI - Metabolic syndrome among 13 year old adolescents: prevalence and risk factors. AB - BACKGROUND: Obesity and metabolic syndrome is prevalent among Malaysian adolescents and has been associated with certain behavioural factors such as duration of sleep, screen time and physical activity. The aim of the study is to report the prevalence of overweight/obesity, metabolic syndrome and its risk factors among adolescents. METHODS: A multi-staged cluster sampling method was used to select participants from urban and rural schools in Selangor, Perak and Wilayah Persekutuan Kuala Lumpur. Participants underwent anthropometric measurement and physical examination including blood pressure measurement. Blood samples were taken for fasting glucose and lipids and participants answered a self-administered questionnaire. Overweight and obesity was defined using the extrapolated adult body mass index (BMI) cut-offs of >25 kg/m2 and >30 kg/m2, according to the International Obesity Task Force (IOTF) criteria. Metabolic syndrome was defined based on International Diabetes Federation (IDF) 2007 criteria. RESULTS: Data were collected from 1361 participants. After excluding incomplete data and missing values for the variables, we analysed a sample of 1014 participants. Prevalence of overweight and obesity in this population was 25.4% (N = 258). The prevalence of metabolic syndrome was 2.6% in the population and 10% among the overweight and obese adolescents. Participants who slept between 7 and 9 hours a day has a lower risk of developing metabolic syndrome OR 0.38(0.15-0.94). CONCLUSION: Our results provide the prevalence of metabolic syndrome in Malaysian adolescents. Adequate sleep between 7 and 9 hours per day reduces the risk of developing metabolic syndrome. PMID- 25437227 TI - Modeling coupled nanoparticle aggregation and transport in porous media: a Lagrangian approach. AB - Changes in nanoparticle size and shape due to particle-particle interactions (i.e., aggregation or agglomeration) may significantly alter particle mobility and retention in porous media. To date, however, few modeling studies have considered the coupling of transport and particle aggregation processes. The majority of particle transport models employ an Eulerian modeling framework and are, consequently, limited in the types of collisions and aggregate sizes that can be considered. In this work, a more general Lagrangian modeling framework is developed and implemented to explore coupled nanoparticle aggregation and transport processes. The model was verified through comparison of model simulations to published results of an experimental and Eulerian modeling study (Raychoudhury et al., 2012) of carboxymethyl cellulose (CMC)-modified nano-sized zero-valent iron particle (nZVI) transport and retention in water-saturated sand columns. A model sensitivity analysis reveals the influence of influent particle concentration (ca. 70 to 700 mg/L), primary particle size (10-100 nm) and pore water velocity (ca. 1-6 m/day) on particle-particle, and, consequently, particle collector interactions. Model simulations demonstrate that, when environmental conditions promote particle-particle interactions, neglecting aggregation effects can lead to under- or over-estimation of nanoparticle mobility. Results also suggest that the extent to which higher order particle-particle collisions influence aggregation kinetics will increase with the fraction of primary particles. This work demonstrates the potential importance of time-dependent aggregation processes on nanoparticle mobility and provides a numerical model capable of capturing/describing these interactions in water-saturated porous media. PMID- 25437228 TI - Enhancing aerobic biodegradation of 1,2-dibromoethane in groundwater using ethane or propane and inorganic nutrients. AB - 1,2-Dibromoethane (ethylene dibromide; EDB) is a probable human carcinogen that was previously used as both a soil fumigant and a scavenger in leaded gasoline. EDB has been observed to persist in soils and groundwater, particularly under oxic conditions. The objective of this study was to evaluate options to enhance the aerobic degradation of EDB in groundwater, with a particular focus on possible in situ remediation strategies. Propane gas and ethane gas were observed to significantly stimulate the biodegradation of EDB in microcosms constructed with aquifer solids and groundwater from the FS-12 EDB plume at Joint Base Cape Cod (Cape Cod, MA), but only after inorganic nutrients were added. Ethene gas was also effective, but rates were appreciably slower than for ethane and propane. EDB was reduced to <0.02 MUg/L, the Massachusetts state Maximum Contaminant Level (MCL), in microcosms that received ethane gas and inorganic nutrients. An enrichment culture (BE-3R) that grew on ethane or propane gas but not EDB was obtained from the site materials. The degradation of EDB by this culture was inhibited by acetylene gas, suggesting that degradation is catalyzed by a monooxygenase enzyme. The BE-3R culture was also observed to biodegrade 1,2 dichloroethane (DCA), a compound commonly used in conjunction with EDB as a lead scavenger in gasoline. The data suggest that addition of ethane or propane gas with inorganic nutrients may be a viable option to enhance degradation of EDB in groundwater aquifers to below current state or federal MCL values. PMID- 25437231 TI - Identification of human drug targets using machine-learning algorithms. AB - Identification of potential drug targets is a crucial task in the drug-discovery pipeline. Successful identification of candidate drug targets in entire genomes is very useful, and computational prediction methods can speed up this process. In the current work we have developed a sequence-based prediction method for the successful identification and discrimination of human drug target proteins, from human non-drug target proteins. The training features include sequence-based features, such as amino acid composition, amino acid property group composition, and dipeptide composition for generating predictive models. The classification of human drug target proteins presents a classic example of class imbalance. We have addressed this issue by using SMOTE (Synthetic Minority Over-sampling Technique) as a preprocessing step, for balancing the training data with a ratio of 1:1 between drug targets (minority samples) and non-drug targets (majority samples). Using ensemble classification learning method-Rotation Forest and ReliefF feature selection technique for selecting the optimal subset of salient features, the best model with selected features can achieve 87.1% sensitivity, 83.6% specificity, and 85.3% accuracy, with 0.71 Matthews correlation coefficient (mcc) on a tenfold stratified cross-validation test. The subset of identified optimal features may help in assessing the compositional patterns in human drug targets. For further validation, using a rigorous leave-one-out cross-validation test, the model achieved 88.1% sensitivity, 83.0% specificity, 85.5% accuracy, and 0.712 mcc. The proposed method was tested on a second dataset, for which the current pipeline gave promising results. We suggest that the present approach can be applied successfully as a complementary tool to existing methods for novel drug target prediction. PMID- 25437230 TI - Roseomics: a blank slate. AB - Recent technological advances have led to an explosion in the system-wide profiling of biological processes in the study of herpesvirus biology, herein referred to as '-omics'. In many cases these approaches have revealed novel virus induced changes to host cell biology that can be targeted with new antiviral therapeutics. Despite these successes, -omics approaches are not widely applied in the study of roseoloviruses. Here we describe examples of how -omics studies have shaped our understanding of herpesvirus biology, and discuss how these approaches might be used to identify host and viral factors that mediate roseolovirus pathogenesis. PMID- 25437229 TI - Roseolovirus molecular biology: recent advances. AB - Human herpesviruses 6A, 6B, and 7 (HHV-6A, HHV-6B, and HHV-7) are classified within the roseolovirus genus of the betaherpesvirus subfamily. Most humans likely harbor at least two of these large DNA viruses, and 1% of humans harbor germline chromosomally integrated (ci) HHV-6A or HHV-6B genomes. Differences at the genetic level manifest as distinct biologic properties during infection and disease. We provide a brief synopsis of roseolovirus replication and highlight the unique properties of their lifecycle and what is known about the viral gene products that mediate these functions. In the nearly 30 years since their discovery, we have only begun to unlock the molecular strategies these highly evolved pathogens employ to establish and maintain chronic infections in humans. PMID- 25437233 TI - An online agricultural genetics course. AB - In this age of rapidly developing online learning, the advent of a series of talks and supplementary material devoted to genetics in agriculture from Henry Stewart Talks ( http://hstalks.com/main/browse_talks.php?r=776&c=252 ) is welcome indeed. The series is designed for researchers and graduate students in the fields of genetics, plant science, animal science, agricultural science, food science, human nutrition and environmental science, advanced undergraduate students, policy makers and managers in public and private sectors, and continuing professional education/development. PMID- 25437232 TI - Simulation of the microscopic process during initiation of stent thrombosis. AB - OBJECTIVE: Coronary stenting is one of the most commonly used approaches to open coronary arteries blocked due to atherosclerosis. However, stent struts can induce stent thrombosis due to altered hemodynamics and endothelial dysfunction, and the microscopic process is poorly understood. The objective of this study was to determine the microscale processes during the initiation of stent thrombosis. METHODS: We utilized a discrete element computational model to simulate the transport, collision, adhesion, and activation of thousands of individual platelets and red blood cells in thrombus formation around struts and dysfunctional endothelium. RESULTS: As strut height increased, the area of endothelium activated by low shear stress increased, which increased the number of platelets in mural thrombi. These thrombi were generally outside regions of recirculation for shorter struts. For the tallest strut, wall shear stress was sufficiently low to activate the entire endothelium. With the entire endothelium activated by injury or denudation, the number of platelets in mural thrombi was largest for the shortest strut. The type of platelet activation (by high shear stress or contact with activated endothelium) did not greatly affect results. CONCLUSIONS: During the initiation of stent thrombosis, platelets do not necessarily enter recirculation regions or deposit on endothelium near struts, as suggested by previous computational fluid dynamics simulations. Rather, platelets are more likely to deposit on activated endothelium outside recirculation regions and deposit directly on struts. Our study elucidated the effects of different mechanical factors on the roles of platelets and endothelium in stent thrombosis. PMID- 25437234 TI - The GMO case in France: politics, lawlessness and postmodernism. AB - The GMO debacle in France is analyzed in the light of the balance of forces around this controversy, the changes in position of governments and the opponents' strategic use of intimidation. These factors have caused insurmountable difficulties for scientific experimentations and assessment of the technology, as well as for farmers attempting to grow GM maize in this country. The change from a "modern" to a "postmodern" framing of official public debates and scientific institutions has not appeased confrontations concerning GMOs. PMID- 25437235 TI - Risk, regulation and biotechnology: the case of GM crops. AB - The global regulation of products of biotechnology is increasingly divided. Regulatory decisions for genetically modified (GM) crops in North America are predictable and efficient, with numerous countries in Latin and South America, Australia and Asia following this lead. While it might have been possible to argue that Europe's regulations were at one time based on real concerns about minimizing risks and ensuring health and safety, it is increasingly apparent that the entire European Union (EU) regulatory system for GM crops and foods is now driven by political agendas. Countries within the EU are at odds with each other as some have commercial production of GM crops, while others refuse to even develop regulations that could provide for the commercial release of GM crops. This divide in regulatory decision-making is affecting international grain trade, creating challenges for feeding an increasing global population. PMID- 25437236 TI - At the end of the day everything boils down to politics: the evolving of German policy toward GMO crops and the existing stagnation. AB - Today it is "en vogue" to oppose the use of GMO plants not only in the environmental- and consumer-protection movement, the Green and the Social Democratic Party in Germany, but also in the conservative parties of the political spectrum. This article describes how such an atmosphere was able to develop over the last twenty years. An atmosphere in which almost everyone in favor of GMO plants within these parties is now quiet-because the political price of supporting the technology would be simply too high. PMID- 25437237 TI - Development and application of modern agricultural biotechnology in Botswana: the potentials, opportunities and challenges. AB - In Botswana, approximately 40% of the population live in rural areas and derive most of their livelihood from agriculture by keeping livestock and practising arable farming. Due to the nature of their farming practises livestock and crops are exposed to diseases and environmental stresses. These challenges offer opportunities for application of biotechnology to develop adaptable materials to the country's environment. On the other hand, the perceived risk of genetically modified organisms (GMOs) has dimmed the promise of the technology for its application in agriculture. This calls for a holistic approach to the application of biotechnology to address issues of biosafety of GMOs. We have therefore assessed the potentials, challenges and opportunities to apply biotechnology with specific emphasis on agriculture, taking cognisance of requirement for its research, development and application in research and teaching institutions. In order to achieve this, resource availability, infrastructure, human and laboratory requirements were analyzed. The analysis revealed that the country has the capacity to carry out research in biotechnology in the development and production of genetically modified crops for food and fodder crops. These will include gene discovery, genetic transformation and development of systems to comply with the world regulatory framework on biosafety. In view of the challenges facing the country in agriculture, first generation biotech crops could be released for production. Novel GM products for development may include disease diagnosis kits, animal disease vaccines, and nutrient use efficiency, drought, and pest and disease resistant food and fodder crops. PMID- 25437238 TI - The state of genetically modified crop regulation in Canada. AB - Genetically modified (GM) crops were first commercialized in Canada in 1995 and the 2014 crop represents the 20th year of successful production. Prior to the first commercialization of GM crops, Canada reviewed its existing science-based regulatory framework and adapted the existing framework to allow for risk assessments on the new technology to be undertaken in a timely and efficient manner. The result has been the rapid and widespread adoption of GM varieties of canola, corn and soybeans. The first decade of GM crop production precipitated 2 landmark legal cases relating to patent infringement and economic liability, while the second decade witnessed increased political efforts to have GM crops labeled in Canada as well as significant challenges from the low level comingling of GM crops with non-GM commodities. This article reviews the 20 y of GM crop production in Canada from a social science perspective that includes intellectual property, consumer acceptance and low level presence. PMID- 25437239 TI - On risk and regulation: Bt crops in India. AB - Genetic engineering in agriculture raises contentious politics unknown in other applications of molecular technology. Controversy originated and persists for inter-related reasons; these are not primarily, as frequently assumed, differences over scientific findings, but rather about the relationship of science to 'risk.' First, there are inevitably differences in how to interpret 'risk' in situations in which there are no established findings of specific hazard; 'Knightian uncertainty' defines this condition. Science claims no method of resolution in such cases of uncertainty. Second, science has no claim about risk preferences in a normative sense. In genetic engineering, Knightian uncertainty is pervasive; declaring uncertainty to constitute 'risk' enables a precautionary politics in which no conceivable evidence from science can confirm absence of risk. This is the logic of the precautionary state. The logic of the developmental state is quite different: uncertainty is treated as an inevitable component of change, and therefore a logic of acceptable uncertainty, parallel to acceptable risk of the sort deployed in cost-benefit analysis in other spheres of behavior, dominates policy. India's official position on agricultural biotechnology has been promotional, as expected from a developmental state, but regulation of Bt crops has rested in a section of the state operating more on precautionary than developmental logic. As a result, notwithstanding the developmental success of Bt cotton, Bt brinjal [eggplant, aubergine] encountered a moratorium on deployment despite approval by the regulatory scientific body designated to assess biosafety. PMID- 25437240 TI - The politics of Golden Rice. AB - Genetic knowledge applicable to crop improvement has erupted over the past 60 years, and the techniques of introducing genes from one organism to another have enabled new varieties of crops not achievable by previously available methodologies of crop breeding. Research and particularly development of these GMO-crops to a point where they are useful for growers and consumers in most countries is subject to complex national and international rules arising out of the UN's Cartagena Protocol on Biosafety to the Convention on Biological Diversity, with 167 country signatories. (The USA and Canada are not signatories.) The Protocol was developed based on concerns initially expressed in the 1970's that such technology presented unusual risks to man and the environment. Those ideas have comprehensively and authoritatively been proven to be wrong. The Protocol has nevertheless spawned significant regulatory obstacles to the development of GMO-crop technology at great cost to global society and in conflict with many other UN objectives. The suspicion induced by the Protocol is also widely used, overtly or covertly, for political purposes. These points are illustrated by reference to the not-for-profit Golden Rice project. PMID- 25437241 TI - A dubious success: the NGO campaign against GMOs. AB - Genetically engineered agricultural crops are widely grown for animal feed (yellow corn, soybean meal) and for industrial purposes (such as cotton for fabric, or yellow corn for ethanol), but almost nobody grows GMO food staple crops. The only GMO food staple crop planted anywhere is white maize, and only in one country--the Republic of South Africa. It has been two decades now since GMO crops were first planted commercially, yet it is still not legal anywhere to plant GMO wheat or GMO rice. When it comes to GMO food crops, anti-GMO campaigners have thus won a remarkable yet dubious victory. They have not prevented rich countries from using GMO animal feed or GMO cotton, yet farmers and consumers in poor countries need increased productivity for food crops, not animal feed or industrial crops. Today's de facto global ban on GMO food crops therefore looks suspiciously like an outcome designed by the rich and for the rich, with little regard for the interests of the poor. PMID- 25437242 TI - Ascendancy of agricultural biotechnology in the Australian political mainstream coexists with technology criticism by a vocal-minority. AB - Australia is a federation of States. This political structure necessitates collaborative arrangements between Australian governments to harmonize national regulation of gene technology and food standards. Extensive political negotiation among institutions of federal government has managed regulation of GM crops and food. Well-developed human resources in Australian government provided numerous policy documents facilitating a transparent political process. Workable legislation has been devised in the face of criticisms of gene technology though the political process. Conflicts between potential disruptions to food commodity trade by precautionary proposals for environmental protection were one cause of political tensions, and differences in policy priorities at regional political levels versus national and international forums for negotiation were another. Australian policy outcomes on GM crops reflect (a) strong economic self-interest in innovative and productive farming, (b) reliance on global agricultural market reforms through the Cairns trade group and the WTO, and (c) the importance of Codex Alimentarius and WTO instruments SPS and TBT. Precautionary frameworks for GM food safety assurance that are inconsistent with WTO obligations were avoided in legislation. Since 2008 the 2 major parties, Australian Labor Party (ALP) and the Liberals appear to have reached a workable consensus at the Federal policy level about an important role for agricultural biotechnology in Australia's economic future. PMID- 25437243 TI - Adaptive significance of gall formation for a gall-inducing aphids on Japanese elm trees. AB - Insect galls are abnormal plant tissues induced by external stimuli from parasitizing insects. It has been suggested that the stimuli include phytohormones such as auxin and cytokinins produced by the insects. In our study on the role of hormones in gall induction by the aphid Tetraneura nigriabdominalis, it was found that feedback regulation related to auxin and cytokinin activity is absent in gall tissues, even though the aphids contain higher concentrations of those phytohormones than do plant tissues. Moreover, jasmonic acid signaling appears to be compromised in gall tissue, and consequently, the production of volatile organic compounds, which are a typical defense response of host plants to herbivory, is diminished. These findings suggest that these traits of the gall tissue benefit aphids, because the gall tissue is highly sensitive to auxin and cytokinin, which induce and maintain it. The induced defenses against aphid feeding are also compromised. The abnormal responsiveness to phytohormones is regarded as a new type of extended phenotype of gall-inducing insects. PMID- 25437244 TI - The relationship between radiant heat, air temperature and thermal comfort at rest and exercise. AB - The aims of the present work were to investigate the relationships between radiant heat load, air velocity and body temperatures with or without coincidental exercise to determine the physiological mechanisms that drive thermal comfort and thermoregulatory behaviour. Seven male volunteers wearing swimming trunks in 18 degrees C, 22 degrees C or 26 degrees C air were exposed to increasing air velocities up to 3 m s(-1) and self-adjusted the intensity of the direct radiant heat received on the front of the body to just maintain overall thermal comfort, at rest or when cycling (60 W, 60 rpm). During the 30 min of the experiments, skin and rectal temperatures were continuously recorded. We hypothesized that mean body temperature should be maintained stable and the intensity of the radiant heat and the mean skin temperatures would be lower when cycling. In all conditions, mean body temperature was lower when facing winds of 3 m s(-1) than during the first 5 min, without wind. When facing winds, in all but the 26 degrees C air, the radiant heat was statistically higher at rest than when exercising. In 26 degrees C air mean skin temperature was lower at rest than when exercising. No other significant difference was observed. In all air temperatures, high correlation coefficients were observed between the air velocity and the radiant heat load. Other factors that we did not measure may have contributed to the constant overall thermal comfort status despite dropping mean skin and body temperatures. It is suggested that the allowance to behaviourally adjust the thermal environment increases the tolerance of cold discomfort. PMID- 25437245 TI - Pimozide, a novel fatty acid binding protein 4 inhibitor, promotes adipogenesis of 3T3-L1 cells by activating PPARgamma. AB - Pimozide is a conventional antipsychotic of the diphenylbutylpiperidine class that has been clinically used for over 30 years. The obvious side effect of this drug is weight gain. However, the mechanism of pimozide-induced weight gain is still unknown. In the present study, we identified pimozide as a novel fatty acid binding protein 4 (FABP4) inhibitor using molecular docking simulation as well as biochemical characterizations. BMS309403, a well-known FABP4 inhibitor, elevated the basal protein levels of PPARgamma, therefore stimulating adipogenesis in adipocytes. The present study showed that the inhibitory effect of pimozide on FABP4 promoted adipocyte differentiation with the potency proportional to their propensities for weight gain. These effects in adipogenesis by pimozide may help to explain the weight gain that is frequently observed in patients treated with pimozide. PMID- 25437246 TI - Molecular structure and internal rotation of CF3 group of methyl trifluoroacetate: gas electron diffraction, microwave spectroscopy, and quantum chemical calculation studies. AB - The molecular structure of methyl trifluoroacetate (CF3COOCH3) has been determined by gas electron diffraction (GED), microwave spectroscopy (MW), and quantum chemical calculations (QC). QC study provides the optimized geometries and force constants of the molecule. They were used to estimate the structural model for GED study and to calculate the vibrational corrections for GED and MW data. In addition, potential energy curves for the internal rotations of CF3 and CH3 groups have been calculated for anti (dihedral angle of alpha(CCOC) is 180 degrees ) and syn (alpha(CCOC) = 0 degrees ) conformers of methyl trifluoroacetate. Both the GED and MW data revealed the existence of the anti conformer. Molecular constants determined by MW are A0 = 3613.4(3) MHz, B0 = 1521.146(8) MHz, C0 = 1332.264(9) MHz, DeltaJ = 0.09(2) kHz, and DeltaJK = 0.23(6) kHz. The GED data were well-reproduced by the analysis in which a large amplitude motion of the CF3 group was taken into account. The barrier of the internal rotation of the CF3 group was determined to be V3 = 2.3(4) kJ mol(-1), where V3 is the potential coefficient of the assumed potential function, V(phi) = (V3/2)(1 - cos 3phi), and phi is a rotational angle for the CF3 group. The values of geometrical parameters (re structure) of the anti conformer of CF3COOCH3 are r((O?)C-O) = 1.326(6) A, r(O-CH3) = 1.421(4) A, r(C-H(in-plane)) = 1.083(14) A, r(C-H(out-of-plane)) = 1.087(14) A, r(C?O) = 1.190(7) A, r(C-C) = 1.533(4) A, r(C F(in-plane)) = 1.319(4) A, r(C-F(out-of-plane)) = 1.320(6) A, ?COC = 116.3(5) degrees , ?OCH(in-plane) = 105.2 degrees (fixed), ?OCH(out-of-plane) = 110.0 degrees (fixed), ?O?CC = 123.7 degrees (fixed), ?O-CC = 111.2(5) degrees , ?OCO = 125.2(5) degrees , ?CCF = 110.1(3) degrees , and OCCF (out-of-plane dihedral angles) = +/- 121.5(1) degrees . Numbers in parentheses are three times the standard deviations of the data fit. PMID- 25437247 TI - Planning the future of neurology: crisis or opportunity. PMID- 25437250 TI - A 2,2'-bipyridine coordination complex of [ICl2]+. AB - The formation of a new class of I(III) compound is reported; an N,N' chelated iodine cation ([bpy-ICl2](+); bpy = 2,2'-bipyridine). The complex is obtained as an [ICl4](-) salt and is formed via simple reaction of bpy with ICl3. The compound is relatively unstable, but may be stored as a solid and is shown to be competent in the oxidative chlorination of Au(I)-NHC complexes. PMID- 25437249 TI - High-dose chemotherapy for high-risk retinoblastoma: clinical course and outcome of 14 cases in the National Cancer Center, Japan. AB - The prognosis of high-risk retinoblastoma (RB) with extraocular disease, relapse, or invasion of the cut end of the optic nerve is extremely poor. Following the discontinuation of thiotepa production in Japan, BU- and melphalan (Mel)-based regimens have been used, followed by the standard treatment for neuroblastoma. This study retrospectively analyzed 14 high-risk RB patients who underwent high dose chemotherapy (HDC) and hematopoietic SCT; 8 received a BU/Mel conditioning regimen and 6 received other regimens. The disease status at HDC was relapse in 8 patients and extraocular involvement in 5. All patients received peripheral blood stem cell infusion >1.5 * 10(6)/kg. Engraftment occurred within a median of 11 days (BU/Mel: 10-13, others: 9-13). Primary toxicities included mucositis (?grade 3) in 9 patients (4 with BU/Mel, 5 with others). Veno-occlusive disease (VOD) occurred in two 1-year-old patients in the BU/Mel group. There were no treatment related deaths. Of 4 (2 with BU/Mel, 2 with others) patients with central nervous system (CNS) relapse after HDC, 3 died. In conclusion, the BU/Mel regimen may be feasible for high-risk RB under careful monitoring for VOD, particularly in younger patients. CNS relapse associated with a lethal prognosis occurred after all regimens; therefore, further evaluation of HDC efficacy for high-risk RB is required. PMID- 25437248 TI - Comparison of non-myeloablative conditioning regimens for lymphoproliferative disorders. AB - Hematopoietic cell transplantation (HCT) with non-myeloablative (NMA) conditioning for lymphoproliferative diseases (LD) includes fludarabine with and without low-dose TBI. Transplant outcomes were compared among patients aged ?40 years with LD who received a HCT with TBI (N=382) or no-TBI (N=515) NMA from 2001 to 2011. The groups were comparable except for donor, graft, prophylaxis for GVHD, disease status and year of HCT. Cumulative incidences of grades II-IV GVHD at 100 days were 29% and 20% (P=0.001) and of chronic GVHD at 1 year were 54% and 44% (P=0.004) for TBI and no-TBI, respectively. Multivariate analysis of progression/relapse, treatment failure and mortality showed no outcome differences by conditioning. Full donor chimerism at day 100 was observed in 82% vs 64% in the TBI and no-TBI groups, respectively (P=0.006). Subsets of the four most common conditioning/GVHD prophylaxis combinations demonstrated higher rates of grades II-IV acute (P<0.001) and chronic GVHD (P<0.001) among recipients of TBI-mycophenolate mofetil (MMF) compared with other combinations. TBI-based NMA conditioning induces faster full donor chimerism, but overall survival outcomes are comparable to no-TBI regimens. Combinations of TBI and MMF are associated with higher rates of GVHD without impact on survival outcomes in patients with LD. PMID- 25437251 TI - Total Synthesis and Structure Determination of JBIR-108-A 2-Hydroxy-2-(1 hydroxyethyl)-2,3-dihydro-3(2H)-furanone Isolated from Streptomyces gramineus IR087Pi-4. AB - The planar and stereostructures of JBIR-108 isolated from Streptomyces gramineus IR087Pi-4 were determined partly by spectral analysis, and these structural assignments were confirmed and completed by the total synthesis of both 1 epimers. The key stereocenters in JBIR-108 were constructed via a Corey-Bakshi Shibata (CBS) reduction (C-1), vinylogous Mukaiyama aldol reaction (C-7), and Brown crotylation (C-14 and C-15). Although it was difficult to determine the stereochemistries at the C-1 and C-7 positions in the natural product using the modified Mosher's method, the synthesis of two possible C-1 diastereomers enabled the identification of the configurations at the hitherto unknown stereocenters. PMID- 25437252 TI - Website ratings of physicians and their quality of care. PMID- 25437253 TI - Polythiolactone-based redox-responsive layers for the reversible release of functional molecules. AB - The development of thin macromolecular layers with incorporated disulfide bonds that can be disrupted and formed again under redox stimulation is of general interest for drug release applications, because such layers can provide rapid and reversible responses to specific biological systems and signals. However, the preparation of such layers from polythiols remains difficult, because of the fast oxidation of thiol groups in ambient conditions. Here we propose water-soluble thiolactone-containing copolymers as stable precursors containing protected thiol groups, allowing us to produce on demand polythiol layers on gold substrates in the presence of amine derivatives. Electrochemical, water contact angle, X-ray photoelectron spectroscopy, and X-ray reflectometry measurements evidence the formation of uniform copolymer layers containing both anchored and free thiol groups. The number of free thiols increases with the content of thiolactone units in the copolymers. In a second step, a thiolated dye, used as a model drug, was successfully grafted on the free thiol groups through disulfide bonds using mild oxidizing conditions, as proved by fluorescence and quartz crystal microbalance measurements. Finally, the reversible release/regrafting of the dye under redox stimulation is demonstrated. PMID- 25437255 TI - Nitrite-triggered surface plasmon-assisted catalytic conversion of p aminothiophenol to p,p'-dimercaptoazobenzene on gold nanoparticle: surface enhanced Raman scattering investigation and potential for nitrite detection. AB - The stunning large enhancement factor (~10(8)) of the surface-enhanced Raman scattering (SERS) effect leads people to wonder about the underlying enhancement mechanisms of the effect. But, a strong evidence of the existence of one commonly accepted mechanism (chemical enhancement), the origin of the symbolic "b2" bands (ca. 1140,1390, 1432 cm(-1)) of p-aminothiophenol (PATP), was recently found to be a false explanation, which were actually arisen from the product of a surface plasmon-assisted coupling reaction of PATP, p,p'-dimercaptoazobenzene (DMAB). However, the debate is far from over, especially because the mechanism of the above reaction has not been fully understood yet. In this paper, we for the first time report a new surface plasmon-assisted catalytic conversion of PATP to DMAB that NO2(-) ions can trigger the formation of DMAB on gold nanoparticles (GNPs) suspension under light illumination. The mechanism of the conversion is also discussed. All relevant data suggest the nitrite-triggered conversion of PATP to DMAB on GNPs is a surface plasmon-assisted oxidation reaction, involving transfer of multiple electrons from PATP to NO2(-) (electron acceptors) and protons, leading to the formation of DMAB. The proposed mechanisms may also help to understand the unclear surface plasmon-assisted catalytic coupling of PATP on the SERS substrates. Furthermore, inspired by the high selectivity of the above nitrite-triggered catalysis reaction, a simple and fast nitrite screening method was also developed, exhibiting good sensitivity. Considering other advantages of the assay, such as rapidness, simplicity of the detection procedures, and requirement of no sample pretreatment, it is a promising method for on-site fast screening or point-of-care application. PMID- 25437254 TI - Multimodal hazard rate for relapse in breast cancer: quality of data and calibration of computer simulation. AB - Much has occurred since our 2010 report in Cancers. In the past few years we published several extensive reviews of our research so a brief review is all that will be provided here. We proposed in the earlier reports that most relapses in breast cancer occur within 5 years of surgery and seem to be associated with some unspecified manner of surgery-induced metastatic initiation. These events can be identified in relapse data and are correlated with clinical data. In the last few years an unexpected mechanism has become apparent. Retrospective analysis of relapse events by a Brussels anesthesiology group reported that a perioperative NSAID analgesic seems to reduce early relapses five-fold. We then proposed that primary surgery produces a transient period of systemic inflammation. This has now been identified by inflammatory markers in serum post mastectomy. That could explain the early relapses. It is possible that an inexpensive and non-toxic NSAID can reduce breast cancer relapses significantly. We want to take this opportunity to discuss database quality issues and our relapse hazard data in some detail. We also present a demonstration that the computer simulation can be calibrated with Adjuvant-on-line, an often used clinical tool for prognosis in breast cancer. PMID- 25437257 TI - Quantum spintronics: Single spins in silicon carbide. PMID- 25437256 TI - Coherent control of single spins in silicon carbide at room temperature. AB - Spins in solids are cornerstone elements of quantum spintronics. Leading contenders such as defects in diamond or individual phosphorus dopants in silicon have shown spectacular progress, but either lack established nanotechnology or an efficient spin/photon interface. Silicon carbide (SiC) combines the strength of both systems: it has a large bandgap with deep defects and benefits from mature fabrication techniques. Here, we report the characterization of photoluminescence and optical spin polarization from single silicon vacancies in SiC, and demonstrate that single spins can be addressed at room temperature. We show coherent control of a single defect spin and find long spin coherence times under ambient conditions. Our study provides evidence that SiC is a promising system for atomic-scale spintronics and quantum technology. PMID- 25437258 TI - Origin of voltage decay in high-capacity layered oxide electrodes. AB - Although Li-rich layered oxides (Li1+xNiyCozMn1-x-y-zO2 > 250 mAh g(-1)) are attractive electrode materials providing energy densities more than 15% higher than today's commercial Li-ion cells, they suffer from voltage decay on cycling. To elucidate the origin of this phenomenon, we employ chemical substitution in structurally related Li2RuO3 compounds. Li-rich layered Li2Ru1-yTiyO3 phases with capacities of ~240 mAh g(-1) exhibit the characteristic voltage decay on cycling. A combination of transmission electron microscopy and X-ray photoelectron spectroscopy studies reveals that the migration of cations between metal layers and Li layers is an intrinsic feature of the charge-discharge process that increases the trapping of metal ions in interstitial tetrahedral sites. A correlation between these trapped ions and the voltage decay is established by expanding the study to both Li2Ru1-ySnyO3 and Li2RuO3; the slowest decay occurs for the cations with the largest ionic radii. This effect is robust, and the finding provides insights into new chemistry to be explored for developing high capacity layered electrodes that evade voltage decay. PMID- 25437259 TI - Isolated electron spins in silicon carbide with millisecond coherence times. AB - The elimination of defects from SiC has facilitated its move to the forefront of the optoelectronics and power-electronics industries. Nonetheless, because certain SiC defects have electronic states with sharp optical and spin transitions, they are increasingly recognized as a platform for quantum information and nanoscale sensing. Here, we show that individual electron spins in high-purity monocrystalline 4H-SiC can be isolated and coherently controlled. Bound to neutral divacancy defects, these states exhibit exceptionally long ensemble Hahn-echo spin coherence times, exceeding 1 ms. Coherent control of single spins in a material amenable to advanced growth and microfabrication techniques is an exciting route towards wafer-scale quantum technologies. PMID- 25437260 TI - Entropic shrinkage of an oxide glass. AB - Entropic elasticity, a property typical of rubbers and well known in organic polymers with appropriate network structures, is not known to occur in oxide glasses. Here, we report the occurrence of entropic elasticity in phosphate-glass fibres with highly anisotropic structures, drawn by mechanical elongation from supercooled liquids. We observed a large lengthwise shrinkage of ~35% for phosphate glasses with an enhanced one-dimensional structure, as well as a distinct endotherm on reheating them up to temperatures between that of the glass transition temperature and the softening temperature. Our results strongly suggest the possibility of designing oxide glasses with a rubbery nature at high temperatures. PMID- 25437261 TI - A novel open-framework copper borophosphate containing 1-D borophosphate anion with 10-MR windows and 12-MR channels. AB - A novel open-framework copper borophosphate, Na5KCu3[B9P6O33(OH)3].H2O (), has been synthesised by a boric acid flux method. Its structure can be viewed as a 3 D open framework constructed by the connection of Cu(II)O6 octahedra and 1-D (4,4)-connected borophosphate anionic structures composed of trigonal-planar BO2(OH) groups, tetrahedral BO4 and PO4 groups. The compound not only features a novel borophosphate anionic partial structure containing 1-D 12-MR channels, but also exhibits ferromagnetic interactions and high catalytic activity for the oxidative degradation of chitosan. PMID- 25437262 TI - Iron oxide nanoparticle layer templated by polydopamine spheres: a novel scaffold toward hollow-mesoporous magnetic nanoreactors. AB - Superparamagnetic iron oxide nanoparticle layers with high packing density and controlled thickness were in situ deposited on metal-affinity organic templates (polydopamine spheres), via one-pot thermal decomposition. The as synthesized hybrid structure served as a facile nano-scaffold toward hollow-mesoporous magnetic carriers, through surfactant-assisted silica encapsulation and its subsequent calcination. Confined but accessible gold nanoparticles were successfully incorporated into these carriers to form a recyclable catalyst, showing quick magnetic response and a large surface area (642.5 m(2) g(-1)). Current nano-reactors exhibit excellent catalytic performance and high stability in reduction of 4-nitrophenol, together with convenient magnetic separability and good reusability. The integration of compact iron oxide nanoparticle layers with programmable polydopamine templates paves the way to fabricate magnetic-response hollow structures, with high permeability and multi-functionality. PMID- 25437263 TI - Prepartying, drinking games, and extreme drinking among college students: a daily level investigation. AB - INTRODUCTION: Daily data collected over 14 consecutive days were used to examine whether extreme drinking was more likely on days college students reported prepartying (i.e., drinking before going out) or playing drinking games in a multi-ethnic sample of college seniors (analysis subsample: N=399; 57% women; M age=21.48years, SD=.40). METHODS: Multilevel modeling with drinking occasions at Level 1 (1265 drinking days) nested within persons at Level 2 (399 drinkers) was used to predict four extreme drinking behavior outcomes at the daily level: consuming at least 8/10 (women/men) drinks, reaching an estimated blood alcohol concentration (eBAC) of .16% or greater, drinking enough to stumble, and drinking enough to pass out. RESULTS: Prepartying only (29% of drinking days) was more common than playing drinking games only (10%) or engaging in both behaviors on the same day (13%). Odds of extreme drinking were greater among students who frequently engaged in prepartying (ORs: 1.86-2.58) and drinking games (ORs: 1.95 4.16), except prepartying frequency did not predict drinking enough to pass out. On days students prepartied (ORs: 1.58-2.02) and on days they played drinking games (ORs: 1.68-1.78), odds of extreme drinking were elevated, except drinking games did not predict eBAC of .16% or greater. CONCLUSIONS: Extreme drinking is attributable to both person-level characteristics (e.g., preparty frequency) and specific drinking behaviors on a given day. Prepartying and drinking games confer elevated risk of extreme drinking and are important targets in alcohol interventions for college seniors. PMID- 25437264 TI - Substance-use coping and self-rated health among US middle-aged and older adults. AB - The prevalence of alcohol, drug, and tobacco use among US middle-aged and older adults is increasing. A subset of this population uses substances to cope with stress, but the characteristics of these individuals, and the association between substance-use coping and health outcomes remain unclear. We identified correlates of substance-use coping and measured its association with self-rated health in a community-based sample of adults aged 54-99 in the Health and Retirement Study (HRS). In the 2008 HRS, 1351 participants reported their frequency of prescription/other drug-, alcohol-, and cigarette-use coping with stress and reported self-rated health (excellent/very good, good, or fair/poor); 1201 of these participants also reported self-rated health in 2010. One in six participants frequently used substances to cope. The oldest participants were least likely to engage in frequent alcohol-use coping. Those with elevated depressive symptoms were more likely to frequently engage in cigarette- and prescription/other drug-use coping. In multivariable-adjusted analyses, participants who frequently used cigarettes (compared to participants who infrequently used cigarettes) to cope had 2.7 times (95% CI=1.1-6.7) the odds of poor (vs. excellent) self-rated health. Relative to participants who infrequently used prescription/other drugs to cope, participants who frequently used prescription/other drugs to cope had 2.4 times (95% CI=1.1-5.1) the odds of reporting poor self-rated health. The association between prescription/other drug use coping in 2008 and self-rated health in 2010 was statistically significant (relative OR=3.5, 95% CI=1.7-7.2). Participants engaging in substance-use coping likely have particular demographic and clinical characteristics. Interventions to reduce substance-use coping may prevent adverse health outcomes. PMID- 25437265 TI - Alcohol evaluations and acceptability: examining descriptive and injunctive norms among heavy drinkers. AB - OBJECTIVES: This study assessed descriptive and injunctive norms, evaluations of alcohol consequences, and acceptability of drinking. METHODS: Participants were 248 heavy-drinking undergraduates (81.05% female; Mage=23.45). RESULTS: Stronger perceptions of descriptive and injunctive norms for drinking and more positive evaluations of alcohol consequences were positively associated with drinking and the number of drinks considered acceptable. Descriptive and injunctive norms interacted, indicating that injunctive norms were linked with number of acceptable drinks among those with higher descriptive norms. Descriptive norms and evaluations of consequences interacted, indicating that descriptive norms were positively linked with number of acceptable drinks among those with negative evaluations of consequences; however, among those with positive evaluations of consequences, descriptive norms were negatively associated with number of acceptable drinks. Injunctive norms and evaluations of consequences interacted, indicating that injunctive norms were positively associated with number of acceptable drinks, particularly among those with positive evaluations of consequences. A three-way interaction emerged between injunctive and descriptive norms and evaluations of consequences, suggesting that injunctive norms and the number of acceptable drinks were positively associated more strongly among those with negative versus positive evaluations of consequences. Those with higher acceptable drinks also had positive evaluations of consequences and were high in injunctive norms. CONCLUSIONS: Findings supported hypotheses that norms and evaluations of alcohol consequences would interact with respect to drinking and acceptance of drinking. These examinations have practical utility and may inform development and implementation of interventions and programs targeting alcohol misuse among heavy drinking undergraduates. PMID- 25437266 TI - Sexual assault related distress and drinking: the influence of daily reports of social support and coping control. AB - Introduction. A history of sexual assault (SA) is often associated with increased distress and heavy drinking. One's ability to cope with the distress and seek social support has been associated with drinking more generally. However, SA related distress, drinking, and the extent to which a woman engages in adaptive coping or seeks social support is known to vary day-to-day. The goal of the present investigation was to examine the moderating influence of perceived coping control and social support on the event-level association between SA-related distress and drinking. Methods. This study included 133 college women with a history of SA who reported recent heavy drinking. Participants provided daily reports of their SA-related distress, perceived coping control, perceived social support, and alcohol consumption every day for 30days. Results. Results of generalized estimating equation models suggest that coping control moderated the association between distress and drinking such that those with less perceived coping control drank more as their SA-related distress increased from their average. Although social support did not moderate between distress and drinking, decreases in perceived social support were associated with more drinking on that day. Conclusions. The results suggest that daily deviations in SA-related distress may influence alcohol consumption more than average levels of distress, especially among women with low coping control. Interventions for women with SA histories should help them build coping skills as well as adequate social support in order to reduce drinking. PMID- 25437268 TI - Patterns of combustible tobacco use in U.S. young adults and potential response to graphic cigarette health warning labels. AB - In the evolving landscape of tobacco use, it remains unclear how tobacco control efforts should be designed and promoted for maximum impact. The current study links the identification of latent classes of young adult combustible tobacco users with anticipated responses to graphic health warning labels (HWLs). Data were collected in January 2012 using an online address-based panel as part of the Legacy Young Adult Cohort Study, and analyses were conducted in 2013. Latent class analyses identified five groups of tobacco users in a national sample of 4,236 young adults aged 18-34years: (1) little cigar/cigarillo/bidi (LCC) and hookah users (4%); (2) nonusers, open to smoking (3%); (3) daily smokers who self identify as "smokers" (11%); (4) nondaily, light smokers who self-identify as "social or occasional smokers" (9%); and (5) nonusers closed to smoking (73%). Of the nonusers closed to smoking, 23% may be better characterized as at risk for tobacco initiation. Results indicate differences in the potential effectiveness of HWLs across classes. Compared to the daily "smokers," LCC and hookah users (RRR=2.35) and nonusers closed to smoking (RRR=2.33) were more than twice as likely to report that new graphic HWLs would make them think about not smoking. This study supports the potential of graphic HWLs to prevent young nonusers from using tobacco products. It suggests that the extension of prominent HWLs to other tobacco products, including LCCs and hookah tobacco, may also serve a prevention function. PMID- 25437267 TI - Parents' and students' perceptions of college alcohol risk: the role of parental risk perception in intentions to communicate about alcohol. AB - INTRODUCTION: The current study aims to examine discrepancies in parents' and college students' perceptions of alcohol risk and the role of perceived risk in predicting parents' intentions to discuss alcohol with their child. METHODS: In total, 246 college student-parent dyads (56.1% female students, 77.2% mothers) were recruited from a mid-size university. Participants completed measures of absolute likelihood, comparative likelihood, and severity of alcohol consequences. RESULTS: In comparison to students, parents perceived the risks of alcohol poisoning (p<.001), academic impairment (p<.05), and problems with others (p<.05) to be more likely. In addition, parents rated the majority of alcohol consequences (e.g., passing out, regrettable sexual situation, throwing up) as more severe than students (all ps<.001). However, parents tended to be more optimistic than their child about the comparative likelihood of alcohol consequences. After controlling for demographics and past alcohol communication, greater absolute likelihood (beta=.20, p=.016) and less confidence in knowledge of student behavior (beta=.20, p=.013) predicted greater intentions to discuss alcohol. CONCLUSIONS: Providing parents of college students with information about college drinking norms and the likelihood of alcohol consequences may help prompt alcohol-related communication. PMID- 25437269 TI - Stability and change in multi-method measures of impulsivity across residential addictions treatment. AB - INTRODUCTION: Although the relations between constructs related to impulsivity and substance use disorders (SUDs) are well established, recent research suggests that changes in impulsivity may be an important mechanism in the recovery process. However, this evidence is primarily based on studies that have examined the relation between changes in impulsivity and substance involvement across the span of several years using self-report measures; thus, it is unclear if these changes are linked across shorter time intervals or extend to behavioral methods of assessment. METHODS: Using prospective data from 43 participants (mean age=35.06; 60% female) enrolled in residential substance abuse treatment, the extent to which seven facets of impulsivity (i.e., questionnaire-assessed delay discounting, lack of perseverance, lack of planning, negative urgency, positive urgency, sensation seeking, and behaviorally-assessed inhibitory control) changed across approximately 4 weeks of treatment was examined. RESULTS: Dependent group t-tests suggested significant reductions in negative urgency and lack of planning, and significant improvements in inhibitory control. CONCLUSIONS: Findings indicate that specific impulsivity facets show change across relatively short time frames and suggest nonspecific effects of residential treatment on levels of impulsivity. These results inform the functional relation between facets of impulsivity and substance involvement and have implications for assessment and treatment approaches for SUDs. PMID- 25437270 TI - Social support and quality of life in patients with rheumatoid arthritis in Greece. AB - OBJECTIVES: Previous research suggests that social support has beneficial effects for rheumatoid arthritis (RA) patients. Yet, recent studies suggest that sociocultural differences have implications for whether or not the individuals use social support to cope with stressful events. Given the stressful nature of a chronic disabling disease, the purpose of the present study was to investigate the association of structural and functional facets of social support with quality of life (QoL) in Greek RA patients. METHODS: In a cross-sectional study, 127 Greek RA patients completed the Rheumatoid Arthritis Quality of Life questionnaire (RAQoL), the Patient Activity Scale-II (PAS-II), the Quality of Social Support Scale (QSSS), the Social Network Index (measuring social network size and number of social roles) and a visual analogue scale measuring reciprocity. RESULTS: Patients' age, social network size and reciprocity had no significant correlation with QoL. Family income, education level and male gender were positively correlated with QoL. Number of social roles was positively correlated with QoL, but not significantly when disease activity and demographic factors were controlled. Quality of social support was positively correlated with QoL, and the correlation remained statistically significant after controlling for disease activity, demographic variables and number of social roles. CONCLUSIONS: In Greek RA patients, quality of social support predicts quality of life above and beyond disease activity, demographic factors and social integration. Structural aspects of social support were not significant predictors of QoL, in line with previous research on cultural differences in how people utilise their social networks. PMID- 25437271 TI - DEAD-box RNA helicase DDX3X inhibits DENV replication via regulating type one interferon pathway. AB - Dengue virus (DENV) is a mosquito-borne virus that threatens approximately 2.5 billion people worldwide. Vaccines against DENV are currently unavailable. DEAD box RNA helicases (DDXs) have been reported to participate in viral replication and host innate immune response. In the present study, we analyzed the role of 40 DDX proteins during DENV replication. Among these proteins, DDX3X showed antiviral effect against DENV infection. Viral replication significantly increased in DDX3X-silenced cells compared with the controls. The interferon (IFN)-beta transcription level decreased during the early stage of DENV infection in DDX3X-silenced cells compared with that in the controls. DDX3X could stimulate IFN-beta transcription through the IRF3 and the NFkappaB branches in DENV infected cells. Our data imply that DDX3X, a member of DEAD-box RNA helicase, is necessary for IFN production and could inhibit DENV replication. PMID- 25437272 TI - Interplay of the H-bond donor-acceptor role of the distal residues in hydroxyl ligand stabilization of Thermobifida fusca truncated hemoglobin. AB - The unique architecture of the active site of Thermobifida fusca truncated hemoglobin (Tf-trHb) and other globins belonging to the same family has stimulated extensive studies aimed at understanding the interplay between iron bound ligands and distal amino acids. The behavior of the heme-bound hydroxyl, in particular, has generated much interest in view of the relationships between the spin-state equilibrium of the ferric iron atom and hydrogen-bonding capabilities (as either acceptor or donor) of the OH(-) group itself. The present investigation offers a detailed molecular dynamics and spectroscopic picture of the hydroxyl complexes of the WT protein and a combinatorial set of mutants, in which the distal polar residues, TrpG8, TyrCD1, and TyrB10, have been singly, doubly, or triply replaced by a Phe residue. Each mutant is characterized by a complex interplay of interactions in which the hydroxyl ligand may act both as a H-bond donor or acceptor. The resonance Raman stretching frequencies of the Fe-OH moiety, together with electron paramagnetic resonance spectra and MD simulations on each mutant, have enabled the identification of specific contributions to the unique ligand-inclusive H-bond network typical of this globin family. PMID- 25437273 TI - Metabolism of Kaempferia parviflora polymethoxyflavones by human intestinal bacterium Bautia sp. MRG-PMF1. AB - Poylmethoxyflavones (PMFs) are major bioactive flavonoids, which exhibit various biological activities, such as anticancer effects. The biotransformation of PMFs and characterization of a PMF-metabolizing human intestinal bacterium were studied herein for the first time. Hydrolysis of aryl methyl ether functional groups by human fecal samples was observed from the bioconversion of various PMFs. Activity-guided screening for PMF-metabolizing intestinal bacteria under anaerobic conditions resulted in the isolation of a strict anaerobic bacterium, which was identified as Blautia sp. MRG-PMF1. The isolated MRG-PMF1 was able to metabolize various PMFs to the corresponding demethylated flavones. The microbial conversion of bioactive 5,7-dimethoxyflavone (5,7-DMF) and 5,7,4' trimethoxyflavone (5,7,4'-TMF) was studied in detail. 5,7-DMF and 5,7,4'-TMF were completely metabolized to 5,7-dihydroxyflavone (chrysin) and 5,7,4' trihydroxyflavone (apigenin), respectively. From a kinetics study, the methoxy group on the flavone C-7 position was found to be preferentially hydrolyzed. 5 Methoxychrysin, the intermediate of 5,7-DMF metabolism by Blautia sp. MRG-PMF1, was isolated and characterized by nuclear magnetic resonance spectroscopy. Apigenin was produced from the sequential demethylation of 5,7,4'-TMF, via 5,4' dimethoxy-7-hydroxyflavone and 7,4'-dihydroxy-5-methoxyflavone (thevetiaflavone). Not only demethylation activity but also deglycosylation activity was exhibited by Blautia sp. MRG-PMF1, and various flavonoids, including isoflavones, flavones, and flavanones, were found to be metabolized to the corresponding aglycones. The unprecedented PMF demethylation activity of Blautia sp. MRG-PMF1 will expand our understanding of flavonoid metabolism in the human intestine and lead to novel bioactive compounds. PMID- 25437274 TI - Resolved P-metalated nucleoside phosphoramidites. AB - The synthesis of resolved P-metalated nucleoside phosphoramidites is described. These rare compounds were initially prepared with gold as the metal center; however, the gold can be removed using basic phosphines or solid-supported triphenylphosphine. Treatment of the free nucleoside phosphoramidite with a platinum source generated a unique platinated dinucleoside species with a diastereomeric ratio of >99:1. PMID- 25437275 TI - Cryofibrinogenemia associated with cryoglobulinemia--a severe case with amputation of four extremities. PMID- 25437276 TI - Clothing adjustments for concealed soft body armor during moderate physical exertion. AB - Previous research has studied the impact of Level II concealed soft body armor (SBA) on the augmentation of heat storage in a hot environment simulating a typical summer day in the southeastern United States (wet bulb globe temperature [WBGT] = 30 degrees C) and noted a significant difference between macro- and micro-WBGTs. The purpose of this study was to characterize the microclimate (micro-WBGT) under a concealed Level II SBA during 60 min of moderately intense work at two separate macro-WBGTs (26 degrees C and 30 degrees C), and to establish WBGT corrections to allow prediction of heat strain in an individual wearing a concealed Level II SBA. A single trial was performed with nine volunteers (27 +/- 4 years) outfitted with a simulated standard law enforcement uniform and a traditional concealed Level II SBA, in a moderately warm environment (WBGT = 26 degrees C). Each participant performed cycles of 12 min of walking (1.25 L . min(-1)) and 3 min of arm curls (14.3 kg, 0.6 L . min(-1)) with a 5 min rest after every other cycle, for a total of 60 minutes. This trial was compared to an identical previously completed 60-min work bout at 30 degrees C. A two-way repeated measures ANOVA with Post hoc Bonferroni and paired samples t test analysis was conducted. A greater difference between macro- micro-WBGTs existed at 26 degrees C compared to the 30 degrees C macro-WBGT. Under these conditions, a moderate work in Level II SBA requires a WBGT correction of 8.9 degrees C and 6.2 degrees C at macro-WBGTs of 26 degrees C and 30 degrees C, respectively. A modified simple linear regression prediction model was established for mean Micro-WBGT for each macro-WBGTs after the plateau point at the 30 min mark. The derivation regressions at 26 degrees C (R(2) = 0.99), and 30 degrees C (R(2) = 0.99) indicate that micro-WBGT could be predicted for each 15 minutes time at both macro-WBGTs tested for individuals doing moderate intensity (300 Kcals . hr(-1)) work wearing concealed Level II SBA. PMID- 25437278 TI - Preclinical inflammatory rheumatic diseases: an overview and relevant nomenclature. AB - Chronic inflammatory and autoimmune conditions result from an interplay between genetic and environmental factors culminating in the phenotypes of established disease. The transition from health to established disease is relatively well understood in rheumatoid arthritis (RA), which provides an exemplar for other diseases. This article addresses terminologies to describe the phases of disease leading to RA, disease initiation and the point from which disease duration should be timed, the future research agenda suggested by this approach to the definition of phases of disease, and the importance of capturing the patient perspective in research into the earliest phases of disease. PMID- 25437277 TI - Domain dissection of AvrRxo1 for suppressor, avirulence and cytotoxicity functions. AB - AvrRxo1, a type III effector from Xanthomonas oryzae pv. oryzicola (Xoc) which causes bacterial leaf streak (BLS) in rice, can be recognised by non-host resistance protein Rxo1. It triggers a hypersensitive response (HR) in maize. Little is known regarding the virulence function of AvrRxo1. In this study, we determined that AvrRxo1 is able to suppress the HR caused by the non-host resistance recognition of Xanthomonas oryzae pv. oryzae (Xoo) by Nicotiana benthamiana. It is toxic, inducing cell death from transient expression in N. benthamiana, as well as in yeast. Among the four AvrRxo1 alleles from different Xoc strains, we concluded that the toxicity is abolished by a single amino acid substitution at residue 344 in two AvrRxo1 alleles. A series of truncations from the carboxyl terminus (C-terminus) indicate that the complete C-terminus of AvrRxo1 plays an essential role as a suppressor or cytotoxic protein. The C terminus was also required for the avirulence function, but the last two residues were not necessary. The first 52 amino acids of N-terminus are unessential for toxicity. Point mutagenesis experiments indicate that the ATP/GTP binding site motif A is required for all three functions of AvrRxo1, and NLS is required for both the avirulence and the suppression of non-host resistance. The putative thiol protease site is only required for the cytotoxicity function. These results determine that AvrRxo1 plays a role in the complex interaction with host proteins after delivery into plant cells. PMID- 25437279 TI - Gout: a review of nonmodifiable and modifiable risk factors. AB - Gout is a common inflammatory arthritis triggered by the crystallization of uric acid within the joints. Gout affects millions worldwide and has an increasing prevalence. Recent research has been carried out to better qualify and quantify the risk factors predisposing individuals to gout. These can largely be broken into nonmodifiable risk factors, such as gender, age, race, and genetics, and modifiable risk factors, such as diet and lifestyle. Increasing knowledge of factors predisposing certain individuals to gout could potentially lead to improved preventive practices. This review summarizes the nonmodifiable and modifiable risk factors associated with development of gout. PMID- 25437280 TI - Insights from populations at risk for the future development of classified rheumatoid arthritis. AB - Rheumatoid arthritis (RA) develops through a series of stages. In the seropositive subset of classified RA patients, a preclinical stage is present for years before the onset of clinically apparent disease. Relevant preclinical biomarkers include autoantibodies, alterations of lymphoid populations, elevated cytokines/chemokines, genetic/genomic factors, imaging studies, clinical findings, dietary and environmental biomarkers, cardiovascular disease risk assessment, microbiome analyses, and metabolomic changes. Identifying the population of asymptomatic subjects at sufficiently high risk for disease to be informative and representative of "preclinical patients" is a challenge. This article reviews the results of analyses that have been undertaken in these "at risk" subjects. PMID- 25437281 TI - Preclinical systemic lupus erythematosus. AB - Preclinical lupus encompasses a spectrum from enhanced SLE risk without clinical symptoms to individuals with autoantibodies and some SLE clinical features without meeting ACR classification. Studies have identified antibody and serological biomarkers years before disease onset. Incomplete lupus and undifferentiated connective tissue disease may occur during preclinical disease periods, but only 10-20% of these individuals transition to SLE and many have a mild disease course. Further studies are warranted to characterize biomarkers of early disease, identify individuals in need of close monitoring or preventive interventions, and elucidate mechanisms of disease pathogenesis without confounding factors of immunosuppressive medications or organ damage. PMID- 25437284 TI - Detecting the earliest signs of rheumatoid arthritis: symptoms and examination. AB - Signs and symptoms often occur well in advance of a formal diagnosis of rheumatoid arthritis (RA). However, these do not necessarily represent symptoms that are included in classification criteria. Their intensity, frequency, and persistence over time seem to be important in the spectrum from preclinical autoimmunity to classifiable RA. Prospective study of signs and symptoms in individuals at risk for RA will help to determine their onset and relationship with epitope spreading, cytokine evolution, sensitive imaging, and their usefulness in discriminating between individuals patients who will develop incident inflammatory arthritis versus normal controls. PMID- 25437285 TI - Recognition of preclinical and early disease in axial spondyloarthritis. AB - In recent years the early identification of axial spondyloarthritis has become a high priority area of research. Evidence that therapy may slow radiographic progression of disease has heightened the importance of recognition of early disease. However, the concept of early axial spondyloarthritis and natural history of early disease are not fully understood. Future strategies to detect early and preclinical disease may incorporate clinical information, radiographic, serologic, and genetic testing. The risks and benefits of screening and early identification of disease need careful consideration. PMID- 25437282 TI - Genetics, environment, and gene-environment interactions in the development of systemic rheumatic diseases. AB - Rheumatic diseases offer distinct challenges to researchers because of heterogeneity in disease phenotypes, low disease incidence, and geographic variation in genetic and environmental factors. Emerging research areas, including epigenetics, metabolomics, and the microbiome, may provide additional links between genetic and environmental risk factors in the pathogenesis of rheumatic disease. This article reviews the methods used to establish genetic and environmental risk factors and studies gene-environment interactions in rheumatic diseases, and provides specific examples of successes and challenges in identifying gene-environment interactions in rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis. Emerging research strategies and future challenges are discussed. PMID- 25437287 TI - Mucosal immune responses to microbiota in the development of autoimmune disease. AB - The etiology of most systemic autoimmune diseases remains unknown. There is often a preclinical period of systemic autoimmunity prior to the onset of clinically classifiable disease; established and emerging data suggest that dysregulated immune interactions with commensal microbiota may play a role in the initial generation of autoimmunity in this preclinical period. This article reviews potential mechanisms by which alterations of healthy microbiota may induce autoimmunity as well as mucosal microbial associations with autoimmune diseases. If mucosal microbiota lead to the development of autoimmunity, these mucosal sites, microorganisms, and immunologic mechanisms can be targeted to prevent the onset of systemic autoimmune disease. PMID- 25437286 TI - Identifying and treating preclinical and early osteoarthritis. AB - Studies suggest that many persons with painful osteoarthritis already have extensive structural disease including malalignment, which may preclude successful stabilization or reversal of disease; this provides a strong rationale for developing strategies to prevent disease or to identify and treat it early. This article reviews a variety of approaches likely to capture those at high risk of or with early disease. However, given the absence of effective treatments, it is unclear whether structural disease could be successfully slowed or prevented in those with early symptoms or at high risk of disease. PMID- 25437283 TI - Is preclinical autoimmunity benign?: The case of cardiovascular disease. AB - Although there are many examples of autoantibodies in disease-free individuals, they can be a preclinical phenomenon heralding future autoimmune rheumatic disease. They may be a marker for autoreactive B-cell activation and other inflammatory autoimmune processes. The increased prevalence of cardiovascular disease (CVD) in autoimmune rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus, and the increased risk of CVD in patients with rheumatic disease with autoantibodies, suggest that CVD may have autoimmune features. Autoantibodies might be risk markers for subclinical and clinical CVD development not only in patients with rheumatic diseases but in the general population as well. PMID- 25437288 TI - Challenges in imaging in preclinical rheumatoid arthritis. AB - There exists a preclinical phase to the disease progression of rheumatoid arthritis, in which there is evidence of autoimmunity but no overt clinical arthritis. Identifying patients in this phase would allow for early treatment, to potentially halt manifestation of the disease. Imaging, because it is noninvasive, provides an appealing alternative to gold-standard synovial biopsies for identification of these preclinical patients. Ultrasonography, magnetic resonance imaging, and positron emission tomography all have their advantages and disadvantages as imaging modalities in this regard. Further research into alternative imaging modalities with larger cohorts is required to determine the most effective technique. PMID- 25437289 TI - Identification of self-antigen-specific T cells reflecting loss of tolerance in autoimmune disease underpins preventative immunotherapeutic strategies in rheumatoid arthritis. AB - Despite treatment advances, rheumatoid arthritis (RA) is still associated with significant disability, decreased work capacity, and reduced life expectancy. Effective immunotherapies to restore immune tolerance promise greater specificity, lower toxicity, and a longer-term solution to controlling and preventing RA. Design of effective therapies requires a fundamental understanding of the critical immunopathogenetic pathways in RA. This article reviews advances in the understanding of self-antigen-specific T cells in autoimmune diseases including RA and type 1 diabetes, which bring exciting insights to the mechanisms underpinning loss of tolerance and how tolerance could be restored for disease prevention in the preclinical or recent-onset period. PMID- 25437290 TI - Prediction of future rheumatoid arthritis. AB - Rheumatoid arthritis (RA) results from an interaction between genetic susceptibility and environmental factors. Several of these factors are known, such as family history of RA, high birth weight, smoking, silica exposure, alcohol nonuse, obesity, diabetes mellitus, rheumatoid factor, anti-citrullinated protein antibody, and genetic variants such as the shared epitope and protein tyrosine phosphatase nonreceptor type 22. The impact of these factors can be modeled in the 2 main groups at risk of RA: family members of patients with RA and seropositive persons with or without arthralgia. Current models have the potential to select individuals for preventive strategies. PMID- 25437292 TI - Developing evidence-based screening recommendations, with consideration for rheumatology. AB - Screening for presymptomatic disease provides the potential for early intervention and improved outcomes. However, although this practice has potential benefits, it also has potential harms that must be considered. The U.S. Preventive Services Task Force (USPSTF) is a nonfederal panel of experts convened by the Agency for Health Research and Policy to systematically review the evidence for preventive services, including disease screening, and to create evidence-based recommendations for primary care practice in the United States. As rheumatologists contemplate the potential of screening for preclinical disease, understanding the process used by the USPSTF can help guide research efforts supporting such screening. PMID- 25437291 TI - Prevention of rheumatic diseases: strategies, caveats, and future directions. AB - Rheumatic diseases affect a significant portion of the population and lead to increased health care costs, disability, and premature mortality; effective preventive measures for these diseases could lead to substantial improvements in public health. Natural history studies show that for most rheumatic diseases there is a period of preclinical disease development during which abnormal biomarkers or other processes can be detected. These changes are useful to understand mechanisms of disease pathogenesis; in addition, they may be applied to estimate a personal risk of future disease while individuals are still relatively asymptomatic and ultimately be used to identify individuals who may be targeted for preventive interventions. PMID- 25437294 TI - Rheumatic Disease Clinics of North America. Preclinical rheumatic disease. Foreword. PMID- 25437295 TI - Preclinical rheumatic disease. PMID- 25437293 TI - Lessons from type 1 diabetes for understanding natural history and prevention of autoimmune disease. AB - Type 1 diabetes (T1D) is a chronic autoimmune disorder resulting from immune mediated destruction of insulin-producing beta cells within the pancreatic islets. Prediction of T1D is now possible, as having 2 or more islet autoantibodies confers a 100% risk of diabetes development. With the ability to predict disease development, clinical trials to prevent diabetes onset have been completed and are currently under way. This review focuses on the natural history, prediction, and prevention trials in T1D. We review the lessons learned from these attempts at preventing a chronic autoimmune disease and apply the paradigm from T1D prevention to other autoimmune disorders. PMID- 25437296 TI - Pointing towards visuospatial patterns in short-term memory: differential effects on familiarity- and recollection-based judgments. AB - Previous studies have indicated that pointing toward to-be-remembered visuospatial patterns enhances short-term memory (STM) when the presentation of pointing and no-pointing trials is mixed (Chum et al., 2007; Dodd & Shumborski, 2009; Rossi-Arnaud et al., 2012). By contrast, when presentation is blocked, pointing has inhibitory effects on memory (Dodd & Shumborski, 2009; Rossi-Arnaud et al., 2012). In the present study, we demonstrated that pointing has different effects on short-term recollection- and familiarity-based judgments, depending on the length of the visuospatial patterns (5- vs. 7-item arrays) and the interval between the encoding and test phases (2 vs. 5 s). More specifically, pointing decreased the accuracy of recollection-based judgments for 5-item arrays, but not for 7-item arrays (this negative effect did not interact with interval length). In contrast, pointing facilitated familiarity-based judgments when the interval between the study and test phases was 5 s, but not when it was 2 s (this positive effect did not interact with pattern length). We proposed that the negative effects might be accounted for by the simultaneous recruitment of attention resources in the planning and execution of pointing movements. As a consequence, executive resources are diverted from the primary memory task, resulting in a less efficient use of attention-demanding retrieval strategies, like chunking. By contrast, the positive effects on familiarity judgments might reflect the unitization of the to-be-remembered items into a single shape. PMID- 25437297 TI - Phonological effects in forward and backward serial recall: qualitative and quantitative differences. AB - Forward serial recall is affected by a diverse range of phonological factors that are readily replicated and relatively well understood. In contrast with backward recall, these phonological effects are not consistently replicable in that some studies show that the effects are present and some show the effects are absent or severely attenuated. Moreover at the theoretical level there is no consensus about how participants perform backward recall. The current research was aimed at understanding the differences between forward and backward recall by using meta analytic techniques on 16 previously published experiments that examined the effects of benchmark phonological factors on both forward and backward recall. In each of the studies, recall was decomposed into 2 components, the first 2 items output and the remaining later responses. A consistent pattern emerged in the data. Each effect was present in both the early and late output positions in forward recall. The effects were present in the late output positions in backward recall, but the effects were weaker than in forward recall. The phonological variables had little impact on early output in backward recall (with the exceptions of articulatory suppression). The presence of qualitative differences between forward and backward recall and quantitative differences between studies have implications for the theoretical understanding of direction of recall in immediate memory tasks. PMID- 25437298 TI - Intracytoplasmic sperm injection (ICSI) in extreme cases of male infertility. AB - INTRODUCTION: Severely compromised spermatogenesis typical of men with virtual azoospermia or non-obstructive azoospermia requires an extreme search for spermatozoa. Our goal was to evaluate the usefulness of a meticulous search carried out in ejaculated or surgically retrieved specimens in achieving pre- and post-implantation embryo development. PATIENTS AND METHODS: In a retrospective cohort study carried out in an academic institution, intracytoplasmic sperm injection (ICSI) outcomes were reviewed as a function of length of microscopic sperm search in ejaculated and surgically retrieved specimens. Couples whose male partner presented with either virtual or non-obstructive azoospermia were treated by ICSI and categorized according to the time spent in identifying and retrieving enough spermatozoa to inject all the oocyte cohort. Semen parameter, fertilization, pregnancies, deliveries, and child welfare in relation to increasing search time were analyzed and compared. RESULT(S): The maternal and paternal ages were comparable in both ejaculated and testicular sperm extraction (TESE) groups along with the oocytes retrieved. The fertilization rates for both ejaculated and TESE progressively decreased with increasing time (P<0.0001). Clinical pregnancies in the ejaculated cohort remained satifactory. In the TESE cohort, there was a decrease in pregnancy rate with increasing time, from 44% to 23%. In a limited number of cases, offspring health was evaluated in both semen sources and appeared reassuring. CONCLUSION(S): An extensive and at time exhaustive sperm quest yields kinetically and morphologically impaired spermatozoa without apparent impact on embryo developmental competence. Retrieval of spermatozoa from the seminiferous tubules provided more consistent fertilization and pregnancy outcomes than those retrieved from the ejaculate. A trend indicated that pregnancy rate decreased as search time increased in the TESE group. The utilization of the scarce and unselected spermatozoa did not obviously impair embryo development or cause post-implantation errors. PMID- 25437300 TI - Effect of leaving group on the structures of alkylsilane SAMs. AB - Multiple transmission and reflection (MTR) infrared spectroscopy has been used to study the kinetics of the formation of self-assembled monolayers (SAM) of octadecylsilanes with different leaving groups, viz. trichloro, trimethoxy, and triethoxy. It was observed that the chlorosilanes form much denser and crystalline-like SAMs and ethoxysilanes form thin SAMs, while methoxysilanes form extremely thin SAMs. The high sensitivity of the MTR IR technique allows the molecular conformations of the alkyl chains and appearance/disappearance of the silanol groups to be scrutinized in detail. This enables the formulation of models for the structures of the SAMs that are in many ways different than the classical picture of silanes on oxide surfaces. We observe that the structure of SAMs depends on the rate of hydrolysis of the leaving groups and thus their chemical nature. SAMs of chlorosilanes resemble a structure of snow moguls or densely packed umbrellas. SAMs of ethoxysilanes, on the other hand, look like stacks of fallen trees, while the molecules of the ultrathin methoxysilane SAMs are lying nearly parallel to the surface, resembling creepers. PMID- 25437299 TI - Toxoplasma gondii oral infection induces intestinal inflammation and retinochoroiditis in mice genetically selected for immune oral tolerance resistance. AB - Toxoplasmosis is a worldwide disease with most of the infections originating through the oral route and generates various pathological manifestations, ranging from meningoencephalitis to retinochoroiditis and inflammatory bowel disease. Animal models for these pathologies are scarce and have limitations. We evaluated the outcome of Toxoplasma gondii oral infection with 50 or 100 cysts of the ME-49 strain in two lines of mice with extreme phenotypes of susceptibility (TS) or resistance (TR) to immune oral tolerance. Therefore, the aim of this study was to evaluate the behaviour of TS and TR mice, orally infected by T. gondii, and determine its value as a model for inflammatory diseases study. Mortality during the acute stage of the infection for TR was 50% for both dosages, while 10 and 40% of the TS died after infection with these respective dosages. In the chronic stage, the remaining TS succumbed while TR survived for 90 days. The TS displayed higher parasite load with lower intestinal inflammation and cellular proliferation, notwithstanding myocarditis, pneumonitis and meningoencephalitis. TR presented massive necrosis of villi and crypt, comparable to inflammatory bowel disease, with infiltration of lymphoid cells in the lamina propria of the intestines. Also, TR mice infected with 100 cysts presented intense cellular infiltrate within the photoreceptor layer of the eyes, changes in disposition and morphology of the retina cell layers and retinochoroiditis. During the infection, high levels of IL-6 were detected in the serum of TS mice and TR mice presented high amounts of IFN-gamma and TNF-alpha. Both mice lineages developed different disease outcomes, but it is emphasized that TR and TS mice presented acute and chronic stages of the infection, demonstrating that the two lineages offer an attractive model for studying toxoplasmosis. PMID- 25437301 TI - A 24-Week, Open-Label Extension Study to Investigate the Long-term Safety, Tolerability, and Efficacy of 13.3 mg/24 h Rivastigmine Patch in Patients With Severe Alzheimer Disease. AB - The long-term safety, tolerability, and efficacy of high-dose 13.3 mg/24 h rivastigmine patch in severe Alzheimer disease was evaluated in a 24-week, open label extension to the double-blind ACTION study. Safety and tolerability, and efficacy on the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV), Severe Impairment Battery (SIB), and ADCS-Clinical Global Impression of Change (ADCS-CGIC) were assessed. Overall, 197 patients continued on 13.3 mg/24 h patch; 199 uptitrated from 4.6 mg/24 h to 13.3 mg/24 h patch. The incidence of adverse events (AEs), serious AEs and discontinuations due to AEs was similar in patients who continued on, and patients who uptitrated to, 13.3 mg/24 h patch (AEs: 57.9% and 59.8%; serious AEs: 16.2% and 16.1%; discontinuations: 11.2% and 12.1%, respectively). Larger mean changes from double-blind baseline were observed in patients uptitrated on the ADCS-ADL-SIV (-4.6; SD=8.7) and SIB (-7.0; SD=16.6), than those who continued on 13.3 mg/24 h patch (-3.9; SD=8.0 and -4.7; SD=16.8, respectively). ADCS-CGIC scores were comparable. There were no clinically relevant between-group differences in safety and tolerability. Greater decline was observed in patients with delayed uptitration to high-dose 13.3 mg/24 h patch than patients who continued on high-dose patch. PMID- 25437303 TI - Organic-inorganic halide perovskite/crystalline silicon four-terminal tandem solar cells. AB - Tandem solar cells constructed from a crystalline silicon (c-Si) bottom cell and a low-cost top cell offer a promising way to ensure long-term price reductions of photovoltaic modules. We present a four-terminal tandem solar cell consisting of a methyl ammonium lead triiodide (CH3NH3PbI3) top cell and a c-Si heterojunction bottom cell. The CH3NH3PbI3 top cell exhibits broad-band transparency owing to its design free of metallic components and yields a transmittance of >55% in the near-infrared spectral region. This allows the generation of a short-circuit current density of 13.7 mA cm(-2) in the bottom cell. The four-terminal tandem solar cell yields an efficiency of 13.4% (top cell: 6.2%, bottom cell: 7.2%), which is a gain of 1.8%abs with respect to the reference single-junction CH3NH3PbI3 solar cell with metal back contact. We employ the four-terminal tandem solar cell for a detailed investigation of the optical losses and to derive guidelines for further efficiency improvements. Based on a power loss analysis, we estimate that tandem efficiencies of ~28% are attainable using an optically optimized system based on current technology, whereas a fully optimized, ultimate device with matched current could yield up to 31.6%. PMID- 25437304 TI - Sterol fatty acid esters from the mushroom Hericium erinaceum and their PPAR transactivational effects. AB - Six new (erinarols A-F, 1-6) and five known (7-11) ergostane-type sterol fatty acid esters were isolated from the methanol extract of the dried fruiting bodies of Hericium erinaceum. Their chemical structures were elucidated using chemical and physical methods as well as through comparison of NMR and mass spectral data with those reported previously. This is the first comprehensive investigation on ergostane-type sterol fatty acid esters from H. erinaceum. The isolated compounds were evaluated for their PPAR transactivational effects using a luciferase reporter system. Compounds 1 and 2 significantly activated the transcriptional activity of PPARs in a dose-dependent manner, with EC50 values of 8.2 and 6.4 MUM, respectively. Moreover, compounds 1 and 2 also activated PPARalpha and PPARgamma transcriptional activity, with stimulation from 1.3- to 3.9-fold at 20 MUM concentrations. PMID- 25437302 TI - Alzheimer Disease Biomarkers as Outcome Measures for Clinical Trials in MCI. AB - BACKGROUND: The aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI). METHODS: Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer's Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid Abeta1-42 concentration-ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy-HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms. RESULTS: Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency. CONCLUSION: These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials. PMID- 25437305 TI - Validity and reliability of rectus femoris ultrasound measurements: Comparison of curved-array and linear-array transducers. AB - Muscle-mass loss augers increased morbidity and mortality in critically ill patients. Muscle-mass loss can be assessed by wide linear-array ultrasound transducers connected to cumbersome, expensive console units. Whether cheaper, hand-carried units equipped with curved-array transducers can be used as alternatives is unknown. Accordingly, our primary aim was to investigate in 15 nondisabled subjects the validity of measurements of rectus femoris cross sectional area by using a curved-array transducer against a linear-array transducer-the reference-standard technique. In these subjects, we also determined the reliability of measurements obtained by a novice operator versus measurements obtained by an experienced operator. Lastly, the relationship between quadriceps strength and rectus area recorded by two experienced operators with a curved-array transducer was assessed in 17 patients with chronic obstructive pulmonary disease (COPD). In nondisabled subjects, the rectus cross sectional area measured with the curved-array transducer by the novice and experienced operators was valid (intraclass correlation coefficient [ICC]: 0.98, typical percentage error [%TE]: 3.7%) and reliable (ICC: 0.79, %TE: 9.7%). In the subjects with COPD, both reliability (ICC: 0.99) and repeatability (%TE: 7.6% and 9.8%) were high. Rectus area was related to quadriceps strength in COPD for both experienced operators (coefficient of determination: 0.67 and 0.70). In conclusion, measurements of rectus femoris cross-sectional area recorded with a curved-array transducer connected to a hand-carried unit are valid, reliable, and reproducible, leading us to contend that this technique is suitable for cross sectional and longitudinal studies. PMID- 25437308 TI - Factors shaping the delivery of acute inpatient stroke therapy: a narrative synthesis. AB - OBJECTIVE: To investigate factors shaping the delivery of acute inpatient stroke therapy (i.e. occupational therapy, physiotherapy, and speech and language therapy). DATA SOURCES: A systematic search using electronic databases: AMED, CINAHL, Medline, Web of Knowledge and EMBASE. STUDY SELECTION: Qualitative studies (n = 31) investigating delivery of inpatient stroke therapy, published since 1998, were included. DATA EXTRACTION: Narrative synthesis was used as the review method. Textual descriptions, tabulation and thematic ana-lysis were used to categorize findings and explore relationships between studies. DATA SYNTHESIS: DATA SYNTHESIS generated the following themes: the need for a therapeutic environment; power and decision-making; intensity, motivation and appropriateness for active therapy; therapy behind the scenes; the role of teamwork in creating a therapeutic environment. Delivery of therapy was influenced by conceptual, individual and professional factors. CONCLUSION: Conceptual, individual and professional factors impact on the delivery of rehabilitation. Further research is needed to examine how therapists negotiate the sometimes conflicting factors shaping delivery of therapy. PMID- 25437306 TI - EGFR signaling promotes self-renewal through the establishment of cell polarity in Drosophila follicle stem cells. AB - Epithelial stem cells divide asymmetrically, such that one daughter replenishes the stem cell pool and the other differentiates. We found that, in the epithelial follicle stem cell (FSC) lineage of the Drosophila ovary, epidermal growth factor receptor (EGFR) signaling functions specifically in the FSCs to promote the unique partially polarized state of the FSC, establish apical-basal polarity throughout the lineage, and promote FSC maintenance in the niche. In addition, we identified a novel connection between EGFR signaling and the cell-polarity regulator liver kinase B1 (LKB1), which indicates that EGFR signals through both the Ras-Raf-MEK-Erk pathway and through the LKB1-AMPK pathway to suppress apical identity. The development of apical-basal polarity is the earliest visible difference between FSCs and their daughters, and our findings demonstrate that the EGFR-mediated regulation of apical-basal polarity is essential for the segregation of stem cell and daughter cell fates. PMID- 25437307 TI - LINKIN, a new transmembrane protein necessary for cell adhesion. AB - In epithelial collective migration, leader and follower cells migrate while maintaining cell-cell adhesion and tissue polarity. We have identified a conserved protein and interactors required for maintaining cell adhesion during a simple collective migration in the developing C. elegans male gonad. LINKIN is a previously uncharacterized, transmembrane protein conserved throughout Metazoa. We identified seven atypical FG-GAP domains in the extracellular domain, which potentially folds into a beta-propeller structure resembling the alpha-integrin ligand-binding domain. C. elegans LNKN-1 localizes to the plasma membrane of all gonadal cells, with apical and lateral bias. We identified the LINKIN interactors RUVBL1, RUVBL2, and alpha-tubulin by using SILAC mass spectrometry on human HEK 293T cells and testing candidates for lnkn-1-like function in C. elegans male gonad. We propose that LINKIN promotes adhesion between neighboring cells through its extracellular domain and regulates microtubule dynamics through RUVBL proteins at its intracellular domain. PMID- 25437309 TI - A 14-year old girl with reversible hypoglycemic episodes: the role of ASVS. AB - We present the case of a 14-year-old female who experienced several episodes of reversible altered mental status triggered by hypoglycemia. Following endocrine investigation, she was diagnosed with insulinoma. Insulinoma, a rare, differentiated, and functioning neuroendocrine tumor of the pancreas overproduces insulin, thus leading to hypoglycemic episodes. Conventional imaging failed to detect the lesion; therefore, arterial calcium stimulation with venous sampling (ASVS) was used for preoperative localization. The patient recovered without complications after surgical enucleation of the tumor. The ASVS is a useful method for localizing insulinomas when conventional imaging techniques fail, and can help reduce morbidities associated with surgical excision. PMID- 25437310 TI - Experimental and Computational Studies of the Diastereoselective Alkylations of 3 Substituted gamma-Sultams. AB - We report that chiral 3-substituted gamma-sultam alpha-carbanions undergo diastereoselective alkylation reactions with alkyl halides to predominantly produce trans-3,5-disubstituted gamma-sultam products. Quantum mechanical calculations provided a stereoelectronic rationale for the observed diastereoselectivity. PMID- 25437312 TI - Epidemiology at 25 years. PMID- 25437313 TI - Chapter two: wrapping up. PMID- 25437314 TI - If you want to know the end, look at the beginning. PMID- 25437316 TI - Commentary: from estimation to translation: interpreting mediation analysis results in perinatal epidemiology. PMID- 25437315 TI - Controlled direct effects of preeclampsia on neonatal health after accounting for mediation by preterm birth. AB - BACKGROUND: Preeclampsia is characterized by alterations in angiogenic factors that may increase neonatal morbidity independent of preterm birth. METHODS: We estimated the controlled direct effect of preeclampsia on neonatal outcomes independent of preterm birth among 200,103 normotensive and 10,507 preeclamptic singleton pregnancies in the Consortium on Safe Labor (2002-2008). Marginal structural models with stabilized inverse probability weights accounted for potential confounders in the pathway from preeclampsia to preterm birth to neonatal outcomes, including mediator-outcome confounders related to preeclampsia status, such as cesarean delivery. Controlled direct effects of preeclampsia on perinatal mortality, small for gestational age (SGA), neonatal intensive care unit (NICU) admission, respiratory distress syndrome, transient tachypnea of the newborn, anemia, apnea, asphyxia, peri- or intraventricular hemorrhage, and cardiomyopathy were estimated for the hypothesized intervention of term delivery for all infants. RESULTS: When delivery was set at >=37 weeks, preeclampsia increased the odds of perinatal mortality (odds ratio = 2.2 [95% confidence interval = 1.1-4.5], SGA = (1.9 [1.8-2.1]), NICU admission (1.9 [1.7-2.1]), respiratory distress syndrome (2.8 [2.0-3.7], transient tachypnea of the newborn (1.6 [1.3-1.9]), apnea (2.2 [1.6-3.1]), asphyxia (2.7 [1.5-4.9]), and peri- or intraventricular hemorrhage (3.2 [1.4-7.7]). No direct effect of preeclampsia at term was observed for anemia or cardiomyopathy. Our results appear robust in the presence of moderate confounding, and restriction to severe preeclampsia yielded similar findings. CONCLUSION: Preeclampsia was directly associated with adverse neonatal outcomes beyond morbidity mediated by preterm birth. Although severe neonatal outcomes were less common at later gestational ages, marginal structural models suggested elevated neonatal risk due to preeclampsia even if it was possible to deliver all infants at term. PMID- 25437318 TI - Commentary: time-to-pregnancy in the Real World. PMID- 25437319 TI - Noncollapsibility and censoring: what's the bias in estimating effects on survival? PMID- 25437320 TI - War epidemiology: an urgent plea. PMID- 25437317 TI - Prenatal exposure to traffic pollution: associations with reduced fetal growth and rapid infant weight gain. AB - BACKGROUND: Prenatal air pollution exposure inhibits fetal growth, but implications for postnatal growth are unknown. METHODS: We assessed weights and lengths of US infants in the Project Viva cohort at birth and 6 months. We estimated 3rd-trimester residential air pollution exposures using spatiotemporal models. We estimated neighborhood traffic density and roadway proximity at birth address using geographic information systems. We performed linear and logistic regression adjusted for sociodemographic variables, fetal growth, and gestational age at birth. RESULTS: Mean birth weight-for-gestational age z-score (fetal growth) was 0.17 (standard deviation [SD] = 0.97; n = 2,114), 0- to 6-month weight-for-length gain was 0.23 z-units (SD = 1.11; n = 689), and 17% had weight for-length >=95th percentile at 6 months of age. Infants exposed to the highest (vs. lowest) quartile of neighborhood traffic density had lower fetal growth ( 0.13 units [95% confidence interval (CI) = -0.25 to -0.01]), more rapid 0- to 6 month weight-for-length gain (0.25 units [95% CI = 0.01 to 0.49]), and higher odds of weight-for-length >=95th percentile at 6 months (1.84 [95% CI = 1.11 to 3.05]). Neighborhood traffic density was additionally associated with an infant being in both the lowest quartile of fetal growth and the highest quartile of 0- to 6-month weight-for-length gain (Q4 vs. Q1, odds ratio = 3.01 [95% CI = 1.08 to 8.44]). Roadway proximity and 3rd-trimester black carbon exposure were similarly associated with growth outcomes. For 3rd-trimester particulate matter (PM2.5), effect estimates were in the same direction, but smaller and imprecise. CONCLUSIONS: Infants exposed to higher traffic-related pollution in early life may exhibit more rapid postnatal weight gain in addition to reduced fetal growth. PMID- 25437321 TI - Turning temperature measures outside-in. PMID- 25437322 TI - Acute disseminated encephalomyelitis following influenza vaccine. PMID- 25437323 TI - Multi-level model synthesis of median survival time in meta-analysis. PMID- 25437324 TI - Ratio of observed and expected joint effects. PMID- 25437325 TI - Prevalence of Alzheimer disease in US states. PMID- 25437326 TI - Limitations of indicators of HIV case finding. PMID- 25437327 TI - Causal mediation analysis in the presence of a mismeasured outcome. PMID- 25437328 TI - Chronic diseases and societal development, based on the death-risk index. PMID- 25437329 TI - Engineering nanostructures by binding single molecules to single-walled carbon nanotubes. AB - Organic and hybrid organic-inorganic systems are promising candidates for low cost photovoltaics. Recently, perovskite-based systems have been attracting a large amount of research attention, where the highest performing devices employ a small molecule (2,2',7,7'-tetrakis(N,N-di-p-methoxyphenyl-amine)-9,9' spirobifluorene) (Spiro-OMeTAD) hole transporter. Here, we demonstrate the production of single-walled carbon nanotube (SWNT)/single molecule nanostructures using a simple solution processing technique for effective and strong binding of Spiro-OMeTAD to individual polymer-wrapped SWNTs. These small molecules bind very strongly, which causes both large mechanical strain of the nanotubes and also improves the separation of individual SWNTs, thus improving the nanotube photoluminescence quantum efficiency by 1 order of magnitude compared to simple polymer-nanotube nanohybrids. Using absorption and photoluminescence measurements, we show that there is a dramatic variation in the electronic properties of the polymer-NT nanocomposites due to the band alignment formed with Spiro-OMeTAD. These self-assembled nanocomposites offer the potential for integration into high performance optoelectronic such as photovoltaic cells and light emission devices. PMID- 25437330 TI - Baseline EEG pattern on continuous ICU EEG monitoring and incidence of seizures. AB - PURPOSE: To identify the probability of detecting nonconvulsive seizures based on the initial pattern seen in the first 30 minutes of continuous EEG (cEEG) monitoring. METHODS: Continuous EEG monitoring reports from 243 adult patients were reviewed, assessing the baseline cEEG monitoring pattern and the presence of seizures during the entire monitoring period. The baseline EEG patterns were classified into nine categories: seizures, lateralized periodic discharges, generalized periodic discharges, focal epileptiform discharges, burst suppression, asymmetric background, generalized slowing, generalized periodic discharges with triphasic morphology, and normal. RESULTS: Overall, 51 patients (21%) had nonconvulsive seizures at any time during cEEG monitoring. Notably, 112 patients had generalized slowing as the initial EEG pattern, and none of these patients were noted to have seizures. Seizure rates among the types of baseline EEG findings were as follows: lateralized periodic discharges (56%, n = 9), burst suppression (50%, n = 10), generalized periodic discharges (50%, n = 2), normal (33%, n = 3), focal epileptiform discharges (31%, n = 35), and asymmetric background (11%, n = 46). CONCLUSIONS: Patients with only generalized slowing seen on the baseline EEG recording are unlikely to develop seizures on subsequent cEEG monitoring. Depending on the clinical circumstance, the standard duration of cEEG recording (24-48 hours) may be unnecessary in patients with generalized slowing as their only cEEG abnormality. PMID- 25437331 TI - Dynamics of deeply supercooled interfacial water. AB - In this review we discuss the relaxation dynamics of glassy and deeply supercooled water in different types of systems. We compare the dynamics of such interfacial water in ordinary aqueous solutions, hard confinements and biological soft materials. In all these types of systems the dielectric relaxation time of the main water process exhibits a dynamic crossover from a high-temperature non Arrhenius temperature dependence to a low-temperature Arrhenius behavior. Moreover, at large enough water content the low-temperature process is universal and exhibits the same temperature behavior in all types of systems. However, the physical nature of the dynamic crossover is somewhat different for the different types of systems. In ordinary aqueous solutions it is not even a proper dynamic crossover, since the water relaxation decouples from the cooperative alpha relaxation of the solution slightly above the glass transition in the same way as all secondary (beta) relaxations of glass-forming materials. In hard confinements, the physical origin of the dynamic crossover is not fully clear, but it seems to occur when the cooperative main relaxation of water at high temperatures reaches a temperature where the volume required for its cooperative motion exceeds the size of the geometrically-confined water cluster. Due to this confinement effect the alpha-like main relaxation of the confined water seems to transform to a more local beta-relaxation with decreasing temperature. Since this low-temperature beta-relaxation is universal for all systems at high water content it is possible that it can be considered as an intrinsic beta-relaxation of supercooled water, including supercooled bulk water. This possibility, together with other findings for deeply supercooled interfacial water, suggests that the most accepted relaxation scenarios for supercooled bulk water have to be altered. PMID- 25437332 TI - A 3'UTR-associated RNA, FLJ11812 maintains stemness of human embryonic stem cells by targeting miR-4459. AB - The 3' untranslated region (UTR)-associated RNAs (uaRNAs) have important roles in various biological processes, especially in development. However, since they overlap with protein-coding mRNAs, uaRNAs are difficult to study by RNA interference techniques. We recently identified a chemical molecule, 3-benzyl-5 ((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO), that could efficiently induce human embryonic stem cells (hESCs) differentiation, and meanwhile selectively and efficiently downregulate the uaRNA FLJ11812. By acting as a competing endogenous RNA, downregulated FLJ11812 by 3BDO further increased miR 4459 level in hESCs. miR-4459 could decrease the expression of its targets, CDC20B and ATG13, and thus altered stemness via cell cycle and autophagy. Our results revealed that FLJ11812 played a key role in maintenance of stemness of hESCs for the first time. The findings provide new clues and a powerful tool for investigating the action mechanism of FLJ11812 in early development. PMID- 25437333 TI - Effects of EGFR Inhibitor on Helicobacter pylori Induced Gastric Epithelial Pathology in Vivo. AB - Helicobacter pylori transactivates the Epidermal Growth Factor Receptor (EGFR) and predisposes to gastric cancer development in humans and animal models. To examine the importance of EGFR signalling to gastric pathology, this study investigated whether treatment of Mongolian gerbils with a selective EGFR tyrosine kinase inhibitor, EKB-569, altered gastric pathology in chronic H. pylori infection. Gerbils were infected with H. pylori and six weeks later received either EKB-569-supplemented, or control diet, for 32 weeks prior to sacrifice. EKB-569-treated H. pylori-infected gerbils had no difference in H. pylori colonisation or inflammation scores compared to infected animals on control diet, but showed significantly less corpus atrophy, mucous metaplasia and submucosal glandular herniations along with markedly reduced antral and corpus epithelial proliferation to apoptosis ratios. EKB-569-treated infected gerbils had significantly decreased abundance of Cox-2, Adam17 and Egfr gastric transcripts relative to infected animals on control diet. EGFR inhibition by EKB 569 therefore reduced the severity of pre-neoplastic gastric pathology in chronically H. pylori-infected gerbils. EKB-569 increased gastric epithelial apoptosis in H. pylori-infected gerbils which counteracted some of the consequences of increased gastric epithelial cell proliferation. Similar chemopreventative strategies may be useful in humans who are at high risk of developing H.pylori-induced gastric adenocarcinoma. PMID- 25437334 TI - Comprehensive analysis of prokaryotes in environmental water using DNA microarray analysis and whole genome amplification. AB - The microflora in environmental water consists of a high density and diversity of bacterial species that form the foundation of the water ecosystem. Because the majority of these species cannot be cultured in vitro, a different approach is needed to identify prokaryotes in environmental water. A novel DNA microarray was developed as a simplified detection protocol. Multiple DNA probes were designed against each of the 97,927 sequences in the DNA Data Bank of Japan and mounted on a glass chip in duplicate. Evaluation of the microarray was performed using the DNA extracted from one liter of environmental water samples collected from seven sites in Japan. The extracted DNA was uniformly amplified using whole genome amplification (WGA), labeled with Cy3-conjugated 16S rRNA specific primers and hybridized to the microarray. The microarray successfully identified soil bacteria and environment-specific bacteria clusters. The DNA microarray described herein can be a useful tool in evaluating the diversity of prokaryotes and assessing environmental changes such as global warming. PMID- 25437336 TI - Whole-proteome analysis of twelve species of alphaproteobacteria links four pathogens. AB - Thousands of whole-genome and whole-proteome sequences have been made available through advances in sequencing technology, and sequences of millions more organisms will become available in the coming years. This wealth of genetic information will provide numerous opportunities to enhance our understanding of these organisms including a greater understanding of relationships among species. Researchers have used 16S rRNA and other gene sequences to study the evolutionary origins of bacteria, but these strategies do not provide insight into the sharing of genes among bacteria via horizontal transfer. In this work we use an open source software program called pClust to cluster proteins from the complete proteomes of twelve species of Alphaproteobacteria and generate a dendrogram from the resulting orthologous protein clusters. We compare the results with dendrograms constructed using the 16S rRNA gene and multiple sequence alignment of seven housekeeping genes. Analysis of the whole proteomes of these pathogens grouped Rickettsia typhi with three other animal pathogens whereas conventional sequence analysis failed to group these pathogens together. We conclude that whole-proteome analysis can give insight into relationships among species beyond their phylogeny, perhaps reflecting the effects of horizontal gene transfer and potentially providing insight into the functions of shared genes by means of shared phenotypes. PMID- 25437338 TI - Adsorption of MS2 on oxide nanoparticles affects chlorine disinfection and solar inactivation. AB - Adsorption on colloidal particles is one of the environmental processes affecting fate, transport, viability or reproducibility of viruses. This work studied colloidal interactions (adsorption kinetics and isotherms) between different oxide nanoparticles (NPs) (i.e., TiO2, NiO, ZnO, SiO2, and Al2O3) and bacteriophage, MS2. The results shows that that all oxide NPs exhibited strong adsorption capacity for MS2, except SiO2 NPs, which is supported by the extended Derjaguin and Landau, Verwey and Overbeek (EDLVO) theory. Moreover, the implication of such colloidal interactions on water disinfection is manifested by the observations that the presence of TiO2 and ZnO NPs could enhance MS2 inactivation under solar irradiation, whereas NiO and SiO2 decreased MS2 inactivation. By contrast, all of these oxide NPs were found to mitigate chlorine disinfection against MS2 to different extent, and the shielding effect was probably caused by reduced free chlorine and free MS2 in the solution due to sorption onto NPs. Clearly, there is a pressing need to further understand colloidal interactions between engineered NPs and viruses in water to better improve the current water treatment processes and to develop novel nanomaterials for water disinfection. PMID- 25437335 TI - The gastrointestinal microbiome and musculoskeletal diseases: a beneficial role for probiotics and prebiotics. AB - Natural medicines are an attractive option for patients diagnosed with common and debilitating musculoskeletal diseases such as Osteoarthritis (OA) or Rheumatoid Arthritis (RA). The high rate of self-medication with natural products is due to (1) lack of an available cure and (2) serious adverse events associated with chronic use of pharmaceutical medications in particular non-steroidal anti inflammatory drugs (NSAIDs) and high dose paracetamol. Pharmaceuticals to treat pain may disrupt gastrointestinal (GIT) barrier integrity inducing GIT inflammation and a state of and hyper-permeability. Probiotics and prebiotics may comprise plausible therapeutic options that can restore GIT barrier functionality and down regulate pro-inflammatory mediators by modulating the activity of, for example, Clostridia species known to induce pro-inflammatory mediators. The effect may comprise the rescue of gut barrier physiological function. A postulated requirement has been the abrogation of free radical formation by numerous natural antioxidant molecules in order to improve musculoskeletal health outcomes, this notion in our view, is in error. The production of reactive oxygen species (ROS) in different anatomical environments including the GIT by the epithelial lining and the commensal microbe cohort is a regulated process, leading to the formation of hydrogen peroxide which is now well recognized as an essential second messenger required for normal cellular homeostasis and physiological function. The GIT commensal profile that tolerates the host does so by regulating pro-inflammatory and anti-inflammatory GIT mucosal actions through the activity of ROS signaling thereby controlling the activity of pathogenic bacterial species. PMID- 25437339 TI - Anatoxin-a producing Tychonema (Cyanobacteria) in European waterbodies. AB - In order to identify the cyanobacterial species responsible of anatoxin-a (ATX) production in Lake Garda (Northern Italy), an intensive isolation and culturing of filamentous cyanobacteria were established since 2014 from environmental samples. In this work, we report a detailed account of the strategy adopted, which led to the discovery of a new unexpected producer of ATX, Tychonema bourrellyi. So far, this species is the first documented example of cultured Oscillatoriales able to produce ATX isolated from pelagic freshwater ecosystems. The isolated filaments were identified adopting a polyphasic approach, which included microscopic species identification, genetic characterisation and phylogenetic analyses based on 16S rRNA genes. The taxonomic identification was further confirmed by the high (>99%) rbcLX sequence similarities of the T. bourrellyi strains of Lake Garda with those deposited in DNA sequence databases. More than half of the isolates were shown to produce a significant amount of ATX, with cell quota ranging between 0.1 and 2.6 MUg mm(-3), and 0.01 and 0.35 pg cell(-1). The toxic isolates were tested positive for anaC of the anatoxin-a synthetase (ana) gene cluster. These findings were confirmed with the discovery of one ATX producing T. bourrellyi strain isolated in Norway. This strain and a further non-ATX producing Norwegian Tychonema bornetii strain tested positive for the presence of the anaF gene of the ana gene cluster. Conversely, none of the Italian and Norwegian Tychonema strains were positive for microcystins (MCs), which was also confirmed by the absence of mcyE PCR products in all the samples analysed. This work suggests that the only reliable strategy to identify cyanotoxins producers should be based on the isolation of strains and their identification with a polyphasic approach associated to a concurrent metabolomic profiling. PMID- 25437337 TI - The metabolic and ecological interactions of oxalate-degrading bacteria in the Mammalian gut. AB - Oxalate-degrading bacteria comprise a functional group of microorganisms, commonly found in the gastrointestinal tract of mammals. Oxalate is a plant secondary compound (PSC) widely produced by all major taxa of plants and as a terminal metabolite by the mammalian liver. As a toxin, oxalate can have a significant impact on the health of mammals, including humans. Mammals do not have the enzymes required to metabolize oxalate and rely on their gut microbiota for this function. Thus, significant metabolic interactions between the mammalian host and a complex gut microbiota maintain the balance of oxalate in the body. Over a dozen species of gut bacteria are now known to degrade oxalate. This review focuses on the host-microbe and microbe-microbe interactions that regulate the degradation of oxalate by the gut microbiota. We discuss the pathways of oxalate throughout the body and the mammalian gut as a series of differentiated ecosystems that facilitate oxalate degradation. We also explore the mechanisms and functions of microbial oxalate degradation along with the implications for the ecological and evolutionary interactions within the microbiota and for mammalian hosts. Throughout, we consider questions that remain, as well as recent technological advances that can be employed to answer them. PMID- 25437340 TI - Degradation of methanethiol in anaerobic sewers and its correlation with methanogenic activities. AB - Methanethiol (MT) is considered one of the predominant odorants in sewer systems. Therefore, understanding MT transformation in sewers is essential to sewer odor assessment and abatement. In this study, we investigated the degradation of MT in laboratory anaerobic sewers. Experiments were carried out in seven anaerobic sewer reactors with biofilms at different stages of development. MT degradation was found to be strongly dependent on the methanogenic activity of sewer biofilms. The MT degradation rate accelerated with the increase of methanogenic activity of sewer biofilms, resulting in MT accumulation (i.e. net production) in sewer reactors with relatively low methanogenic activities, and MT removal in reactors with higher methanogenic activities. A Monod-type kinetic expression was developed to describe MT degradation kinetics in anaerobic sewers, in which the maximum degradation rate was modeled as a function of the maximum methane production rate through a power function. It was also found that MT concentration had a linear relationship with acetate concentration, which may be used for preliminary assessment of MT presence in anaerobic sewers. PMID- 25437341 TI - Stable isotope probing of acetate fed anaerobic batch incubations shows a partial resistance of acetoclastic methanogenesis catalyzed by Methanosarcina to sudden increase of ammonia level. AB - Ammonia inhibition represents a major operational issue for anaerobic digestion. In order to refine our understanding of the terminal catabolic steps in thermophilic anaerobic digestion under ammonia stress, we studied batch thermophilic acetate fed experiments at low (0.26 g L(-1)) and high (7.00 g L( 1)) Total Ammonia Nitrogen concentrations (TAN). Although methane production started immediately for all incubations and resulted in methane yields close to stoichiometric expectations, a 62-72% decrease of methanogenic rate was observed throughout the incubation at 7.00 g L(-1) of TAN compared to 0.26 g L(-1). Stable Isotope Probing analysis of active microbial communities in (13)C-acetate fed experiments coupled to automated ribosomal intergenic spacer analysis and 16S rDNA pyrotag sequencing confirmed that microbial communities were similar for both TAN conditions. At both TAN levels, the (13)C-labeled bacterial community was mainly affiliated to Clostridia-relatives, with OPB54 bacteria being the most abundant sequence in the heavy DNA 16S rDNA pyrotag library. Sequences closely related to Methanosarcina thermophila were also abundantly retrieved in the heavy DNA fractions, showing that this methanogen was still actively assimilating labeled carbon from acetate at free ammonia nitrogen concentrations up to 916 mg L(-1). Stable isotopic signature analysis of biogas, measured in unlabeled acetate fed experiments that were conducted in parallel, confirmed that acetoclastic methanogenic pathway was dominant at both ammonia concentrations. Our work demonstrates that, besides the syntrophic acetate oxidation pathway, acetoclastic methanogenesis catalyzed by Methanosarcina can also play a major role in methane production at high ammonia levels. PMID- 25437342 TI - Evidence of polycyclic aromatic hydrocarbon biodegradation in a contaminated aquifer by combined application of in situ and laboratory microcosms using (13)C labelled target compounds. AB - The number of approaches to evaluate the biodegradation of polycyclic aromatic hydrocarbons (PAHs) within contaminated aquifers is limited. Here, we demonstrate the applicability of a novel method based on the combination of in situ and laboratory microcosms using (13)C-labelled PAHs as tracer compounds. The biodegradation of four PAHs (naphthalene, fluorene, phenanthrene, and acenaphthene) was investigated in an oxic aquifer at the site of a former gas plant. In situ biodegradation of naphthalene and fluorene was demonstrated using in situ microcosms (BACTRAP((r))s). BACTRAP((r))s amended with either [(13)C6] naphthalene or [(13)C5/(13)C6]-fluorene (50:50) were incubated for a period of over two months in two groundwater wells located at the contaminant source and plume fringe, respectively. Amino acids extracted from BACTRAP((r))-grown cells showed significant (13)C-enrichments with (13)C-fractions of up to 30.4% for naphthalene and 3.8% for fluorene, thus providing evidence for the in situ biodegradation and assimilation of those PAHs at the field site. To quantify the mineralisation of PAHs, laboratory microcosms were set up with BACTRAP((r))-grown cells and groundwater. Naphthalene, fluorene, phenanthrene, or acenaphthene were added as (13)C-labelled substrates. (13)C-enrichment of the produced CO2 revealed mineralisation of between 5.9% and 19.7% for fluorene, between 11.1% and 35.1% for acenaphthene, between 14.2% and 33.1% for phenanthrene, and up to 37.0% for naphthalene over a period of 62 days. Observed PAH mineralisation rates ranged between 17 MUg L(-1) d(-1) and 1639 MUg L(-1) d(-1). The novel approach combining in situ and laboratory microcosms allowed a comprehensive evaluation of PAH biodegradation at the investigated field site, revealing the method's potential for the assessment of PAH degradation within contaminated aquifers. PMID- 25437344 TI - Chondroepitrochlearis Muscle--A Phylogenetic Remnant with Clinical Importance. AB - We report on an infant, presenting with a cord-like accessory muscle crossing the anterior axillary fold. The accessory structure appeared as an axillary web and caused tethering of the humerus together with an abnormal shape of the shoulder. The chondroepitrochlearis muscle is thought to be of phylogenetic origin. In our patient the tendinous sling was resected at the age of 7 month with normalization of function and cosmetics. PMID- 25437345 TI - A method to quantitatively apportion pollutants at high spatial and temporal resolution: the Stochastic Lagrangian Apportionment Method (SLAM). AB - We introduce a method to quantify upwind contributions to concentrations of atmospheric pollutants. The Stochastic Lagrangian Apportionment Method (SLAM) carries out the following: (1) account for chemical transformations and depositional losses; (2) incorporate the effects of turbulent dispersion; (3) simulate the locations of the sources with high spatial and temporal resolution; and (4) minimize the impact from numerical diffusion. SLAM accomplishes these four features by using a time-reversed Lagrangian particle dispersion model and then simulating chemical changes forward in time, while tagging and keeping track of different sources. As an example of SLAM's application, we show its use in apportioning sources contributing to ammonia (NH3) and ammonium particulates (p NH4(+)) at a site in southern Ontario, Canada. Agricultural emissions are seen to dominate contributions to NH3 and p-NH4(+) at the site. The source region of NH3 was significantly smaller than that of p-NH4(+), which covered numerous states of the American Midwest. The source apportionment results from SLAM were compared against those from zeroing-out individual sources ("brute force method"; BFM). The comparisons show SLAM to produce almost identical results as BFM for NH3, but higher concentrations of p-NH4(+), likely due to indirect effects that affect BFM. Finally, uncertainties in the SLAM approach and ways to address such shortcomings by combining SLAM with inverse methods are discussed. PMID- 25437346 TI - The exclusion problem in seasonally forced epidemiological systems. AB - The pathogen exclusion problem is the problem of finding control measures that will exclude a pathogen from an ecological system or, if the system is already disease-free, maintain it in that state. To solve this problem we work within a holistic control theory framework which is consistent with conventional theory for simple systems (where there is no external forcing and constant controls) and seamlessly generalises to complex systems that are subject to multiple component seasonal forcing and targeted variable controls. We develop, customise and integrate a range of numerical and algebraic procedures that provide a coherent methodology powerful enough to solve the exclusion problem in the general case. An important aspect of our solution procedure is its two-stage structure which reveals the epidemiological consequences of the controls used for exclusion. This information augments technical and economic considerations in the design of an acceptable exclusion strategy. Our methodology is used in two examples to show how time-varying controls can exploit the interference and reinforcement created by the external and internal lag structure and encourage the system to 'take over' some of the exclusion effort. On-off control switching, resonant amplification, optimality and controllability are important issues that emerge in the discussion. PMID- 25437343 TI - NNK-induced DNA methyltransferase 1 in lung tumorigenesis in A/J mice and inhibitory effects of (-)-epigallocatechin-3-gallate. AB - DNA methyltransferase 1 (DNMT1), a key enzyme mediating DNA methylation, is known to be elevated in various cancers, including the mouse lung tumors induced by the tobacco-specific carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). However, it is not known whether DNMT1 expression is induced right after NNK treatment and how DNMT1 expression varies throughout lung tumorigenesis. In the present study, we found that administration of NNK to A/J mice caused elevation of DNMT1 in bronchial epithelial cells at Days 1, 3, and 14 after NNK treatment. DNMT1 elevation at Day 1 was accompanied by an increase in phospho-histone H2AX (gamma-H2AX) and phospho-AKT (p-AKT). At Weeks 5 to 20, NNK-induced DNMT1 in lung tissues was in lower levels than the early stages, but was highly elevated in lung tumors at Week 20. In addition, the early induction of p-AKT and gamma-H2AX as well as cleaved caspase-3 in NNK-treated lung tissues was not detected at Weeks 5 to 20 but was elevated in lung tumors. In concordance with DNMT1 elevation, promoter hypermethylation of tumor suppressor genes Cdh13, Prdm2, and Runx3 was observed in lung tissues at Day 3 and in lung tumors. Treatment by EGCG attenuated DNMT1, p-AKT, and gamma-H2AX inductions at Days 1 and 3 and inhibited lung tumorigenesis. PMID- 25437347 TI - Some important points for the selection and exclusion of patients with non alcoholic fatty liver disease. PMID- 25437348 TI - An R2R3-MYB gene, LeAN2, positively regulated the thermo-tolerance in transgenic tomato. AB - LeAN2 is an anthocyanin-associated R2R3-MYB transcription factor, but little is known about its function in imparting thermo-tolerance to higher plants. To examine the function of LeAN2 in the regulation of heat stress in tomato, LeAN2 was isolated and transgenic tomato plants were obtained. Overexpression of LeAN2 under the control of the CaMV35S promoter in tomato induced the up-regulation of several structural genes in the anthocyanin biosynthetic pathway as well as anthocyanin accumulation in transgenic tomato plants. Transgenic tomato plants showed enhanced tolerance to heat stress by maintaining higher fresh weight (FW), net photosynthetic rate (Pn) and maximal photochemical efficiency of photosystem II (PSII) (Fv/Fm) compared with wild-type (WT) plants. Furthermore, transgenic plants showed higher non-enzymatic antioxidant activity, lower levels of reactive oxygen species (ROS), and higher contents of D1 protein than that in WT plants under heat stress. These results indicate that LeAN2 had an important function in heat stress resistance. PMID- 25437349 TI - The number of circulating endothelial progenitor cells in healthy individuals- effect of some anthropometric and environmental factors (a pilot study). AB - PURPOSE: The aim of the study was the evaluation of the number of circulating endothelial progenitor cells (CEPCs) in healthy people and the assessment of the variability of quantitative of CEPCs after 6 weeks. MATERIAL AND METHODS: The study involved 48 healthy individuals; the group consisted of 24 men and 24 women; the mean age of 34. The criterion for the patients' eligibility for the study was the absence of diabetes, thrombosis and cardiovascular diseases such as atherosclerosis, hypertension, and heart failure. Neither did the respondents take any medication that could clearly affect the value of the results. In the whole blood samples the number of circulating endothelial progenitor cells was determined using flow cytometry. During the analysis the fluorescence of 100,000 cells was measured. CEPCs were identified with immunophenotype CD45-, CD31+, CD34+, CD133+. RESULTS: In the study, the median of the number of circulating endothelial progenitor cells in the whole group was 0.41/MUL. There was also recorded an increased number of CEPCs after 6 weeks, as compared to the baseline; the difference was significant. There were no differences in the number of CEPCs between the women and the men. There was found no effect on the number of CEPCs factors such as: smoking, physical activity and alcohol consumption. CONCLUSIONS: The study showed that in healthy individuals the gender had no essential effect on the number of endothelial progenitor cells. Based on the demographic and lifestyle data acquired, it is difficult to explain the increase number of CEPCs after 6 weeks. PMID- 25437350 TI - Upregulation of the sFas/sFasL system in psoriatic patients. AB - PURPOSE: Psoriasis is a chronic, recurrent, inflammatory disease. Recent investigations indicate its autoimmune pathogenesis. Apoptosis plays an important role in the development of many autoimmune diseases. The aim of this study was to evaluate the influence of topical treatment of psoriasis on soluble Fas (sFas) and soluble Fas-ligand (sFasL). MATERIAL/METHODS: Serum concentrations of sFas and sFasL were measured using ELISA in 40 psoriatic patients before and after topical treatment with dithranol and compared to the values obtained from 16 healthy subjects. Data were analyzed with respect to severity of psoriasis, duration of the disease and coexisting obesity, diabetes and hypertension. RESULTS: We found that serum levels of sFas before (11.9+/-2.4ng/mL) and after treatment (12.2+/-2.5ng/mL) were significantly higher in patients with psoriasis as compared to the control group (6.4+/-1.8ng/mL). Concentrations of sFasL did not differ significantly from healthy subjects, but increased after treatment. The sFas/sFasL ratio was significantly higher in psoriasis (128+/-47) than in the control group and, even though it tended to decrease after treatment, it still remained higher than in the control group (65+/-22). Additionally we observed a positive correlation of sFas/sFasL ratio with the age of patients and duration of the disease. Psoriatic patients suffering from hypertension and overweight had significantly higher sFas/sFasL ratio than other psoriatic patients. CONCLUSIONS: Our data indicate upregulation of the sFas/sFasL system in psoriatic patients. We demonstrate association of sFas/sFasL with commorbidities - components of metabolic syndrome. PMID- 25437351 TI - Factors associated with return to work of breast cancer survivors: a systematic review. AB - BACKGROUND: The breast cancer survival rate is the highest among all types of cancers, and survivors returning to work after completing treatment is extremely important in regards to economy and rehabilitation. The aim of this systematic review study is to identify the prevalence of breast cancer survivors who return to work (RTW) and the factors associated to RTW. METHODS: A computer based literature search was carried out. "PubMed, Cochrane Library, Embase, Web of Science, and Science Direct" databases were searched systematically. Our search strategy identified a total of 12,116 papers of which 26 studies met the inclusion criteria and quality assessment. These were original papers published between January 2003 and January 2013. RESULTS: The trends in RTW differ among countries for the breast cancer survivors. The time to RTW after successful cancer treatment also varies among the countries and by ethnicity. The prevalence of the RTW varies from 43% to 93% within one year of diagnosis. The prevalence of the RTW for the Netherland is the lowest in the world (43%). The United States survivors showed the highest RTW (93%) within 12 months of the diagnosis. Numerous barriers and facilitators were identified as factors that affect RTW. For instance, socio-demographic factors such as education and ethnicity; treatment oriented factors such as chemotherapy; work related factors such as heavy physical work; disease related factors such as poor health condition and fatigue; and psychological factors such as depression and emotional distress, act as barriers of RTW. In contrast, social, family, employer support, and financial independency emerge as key facilitators in enabling breast cancer survivors to return and continue work. CONCLUSION: Minimising these identified barriers and strengthening these facilitators could further improve the work condition and increase the percentage of RTW among the breast cancer survivors. PMID- 25437352 TI - Decreased adipogenesis and adipose tissue in mice with inactivated protein phosphatase 5. AB - Glucocorticoids play an important role in the treatment of inflammation and immune disorders, despite side effects, which include metabolic derangements such as central adiposity. These studies examine the role of protein phosphatase 5 (Ppp5) in glucocorticoid receptor (GR) complexes which mediate response to glucocorticoids. Mice homozygous for inactivated Ppp5 (Ppp5D274A/D274A) exhibit decreased adipose tissue surrounding the gonads and kidneys compared with wild type mice. Adipocyte size is smaller, more preadipocytes/stromal cell are present in their gonadal fat tissue and differentiation of preadipocytes to adipocytes is retarded. Glucocorticoid levels are raised and the GR is hyperphosphorylated in adipose tissue of Ppp5D274A/D274A mice at Ser212 and Ser220 (orthologous to human Ser203 and Ser211) in the absence of glucocorticoids. Preadipocyte cultures from Ppp5D274A/D274A mice show decreased down regulation of Delta-like protein 1/preadipocyte factor-1, hyperphosphorylation of extra-cellular signal regulated kinase 2 (ERK2) and increased concentration of (sex determining region Y)-box 9 (SOX9), changes in a pathway essential for preadipocyte differentiation, which leads to decreased concentrations of the transcription factors CEBPbeta and CEBPalpha necessary for the later stages of adipogenesis. The data indicate that Ppp5 plays a crucial role in modifying GR-mediated initiation of adipose tissue differentiation, suggesting that inhibition of Ppp5 may potentially be beneficial to prevent obesity during glucocorticoid treatment. PMID- 25437353 TI - Analysis of neurotransmitter tissue content of Drosophila melanogaster in different life stages. AB - Drosophila melanogaster is a widely used model organism for studying neurological diseases with similar neurotransmission to mammals. While both larva and adult Drosophila have central nervous systems, not much is known about how neurotransmitter tissue content changes through development. In this study, we quantified tyramine, serotonin, octopamine, and dopamine in larval, pupal, and adult fly brains using capillary electrophoresis coupled to fast-scan cyclic voltammetry. Tyramine and octopamine content varied between life stages, with almost no octopamine being present in the pupa, while tyramine levels in the pupa were very high. Adult females had significantly higher dopamine content than males, but no other neurotransmitters were dependent on sex in the adult. Understanding the tissue content of different life stages will be beneficial for future work comparing the effects of diseases on tissue content throughout development. PMID- 25437354 TI - Influence of intrathecal baclofen on the level of consciousness and mental functions after extremely severe traumatic brain injury: brief report. AB - BACKGROUND: Whenever oral treatment or botulinum toxin injections fail to control severe spasticity, a trial with intrathecal baclofen is recommended no earlier than 1 year after brain injury. When irreversible contractures are to be avoided, such a trial might be done earlier. Some have briefly reported cognitive modifications with this treatment. METHODS: During the trial period, intrathecal baclofen is continuously infused by a portable external pump through an intrathecal catheter. The daily dose is adjusted according to the clinical response. If the expected response is obtained by reduction of spasticity, a programmable pump is then implanted. Throughout the procedure, close neuropsychological follow-up is pursued. RESULTS: Two persons with extremely severe brain injury and spasticity received a programmable pump less than 10 months after trauma. Unexpectedly, one emerged from the minimally conscious state and the other from post-traumatic amnesia. CONCLUSIONS: Intrathecal baclofen should be considered within the first year after brain injury whenever spasticity does not respond to medication. ITB lessens the degree of spasticity which in turn facilitates care and, thus, has the potential to limit contractures. After severe brain injury, this treatment might trigger recovery from altered states of consciousness, improve cognition and facilitate rehabilitation. PMID- 25437355 TI - Imidazoline derivative templated synthesis of broccoli-like Bi2S3 and its electrocatalysis towards the direct electrochemistry of hemoglobin. AB - A broccoli-like bismuth sulfide (bBi2S3) was synthesized via a solvothermal method using a self-made imidazoline derivative of 2-undecyl-1-dithioureido-ethyl imidazoline as the soft template. The morphology and chemical constitution of the product were characterized by scanning electron microscope (SEM), transmission electron microscope (TEM) and X-ray diffraction (XRD). Electrochemical characterization experiments show that the bBi2S3 has the higher specific surface area and standard heterogeneous electron transfer rate constant than the rod-like Bi2S3 (rBi2S3). Hemoglobin (Hb) was then chosen as a protein model to investigate the electrocatalytic property of the synthesized bBi2S3. The results show that Hb entrapped in the composite film of chitosan and bBi2S3 displays an excellent direct electrochemistry, and retains its biocatalytic activity toward the electro reduction of hydrogen peroxide. The current response in the amperometry shows a linear response to H2O2 concentrations in the range from 0.4 to 4.8uM with high sensitivity (444uAmM(-1)) and low detection limit (0.096uM). The Michaelis-Menten constant (KM(app)) of the fabricated bioelectrode for H2O2 was determined as low as 1uM. These results demonstrate that the synthesized bBi2S3 offers a new path for the immobilization of redox-active protein and the construction of the third generation biosensors. PMID- 25437356 TI - A "turn-on" fluorescent receptor for detecting tyrosine phosphopeptide using the surface imprinting procedure and the epitope approach. AB - A new strategy for the manufacture of a turn-on fluorescent molecularly imprinted polymer (CdTe/SiO2/MIP) receptor for detecting tyrosine phosphopeptide (pTyr peptide) was proposed. The receptor was prepared by the surface imprinting procedure and the epitope approach with silica-capped CdTe quantum dots (QDs) as core substrate and fluorescent signal, phenylphosphonic acid (PPA) as the dummy template, 1-[3-(trimethoxysilyl) propyl] urea as the functional monomer, and octyltrimethoxysilane as the cross-linker. The synthetic CdTe/SiO2/MIP was able to selectively capture the template PPA and corresponding target pTyr peptide with fluorescence enhancement via the special interaction between them and the recognition cavities. The receptor exhibited the linear fluorescence enhancement to pTyr peptide in the range of 0.5-35MUM, and the detection limit was 0.37MUM. The precision for five replicate detections of pTyr peptide at 20MUM was 2.60% (relative standard deviation). Combining the fluorescence property of the CdTe QDs with the merits of the surface imprinting technique and the epitope approach, the receptor not only owned high recognition site accessibility and good binding affinities for target pTyr peptide, but also improved the fluorescence selectivity of the CdTe QDs, as well revealed the feasibility of fabrication of a turn-on fluorescence probe using the surface imprinting procedure and the epitope approach. PMID- 25437357 TI - Enhanced electrogenerated chemiluminescence of tris(2,2'-bipyridyl)ruthenium(II) system by l-cysteine-capped CdTe quantum dots and its application for the determination of nitrofuran antibiotics. AB - This paper reports a new approach to enhance the electrogenerated chemiluminescence (ECL) of the tris(2,2'-bipyridyl)ruthenium(II) (Ru(bpy)3(2+)) system using resonance energy transfer with l-cysteine-capped cadmium telluride quantum dots (CdTe-QDs) in aqueous solution. The oxidative peak signal of Ru(bpy)3(2+) occurred at a voltage of 1.10V when the potential was cycled between 0.4 and 1.6V using cyclic voltammetry with a carbon screen-printed electrode (SPE) in a 0.11M phosphate buffer at pH 7.50. The l-cysteine-capped CdTe-QDs were synthesized and added into the solution of Ru(bpy)3(2+) to magnify the ECL signal. The ECL emission signal was investigated and the extreme enhancement of the ECL intensity was achieved due to the energy transfer by the l-cysteine capped CdTe-QDs. It was found that the induced ECL from the Ru(bpy)3(2+) CdTe-QDs system was inhibited by the presence of selected nitrofurans. This quenching effect of nitrofuran antibiotics on the anodic ECL of Ru(bpy)3(2+) CdTe-QDs was found to be selective and concentration dependent and was observed to have a linear relationship over the concentration range 10-100*10(-6)M. The detection limits were found to be 0.40, 0.73 and 0.60uM for furaltadone (FTD), furazolidone (FZD) and nitrofurantoin (NFT). In addition, the proposed ECL method was successfully applied to detect the total residuals of selected nitrofuran residues in animal feed samples with satisfactory results. PMID- 25437358 TI - RNA aptamer based electrochemical biosensor for sensitive and selective detection of cAMP. AB - Cyclic adenosine monophosphate (cAMP) is an important small biological molecule associated with the healthy state of living organism. In order to realize highly sensitive and specific detection of cAMP, here an RNA aptamer and electrochemical impedance spectroscopy (EIS) based biosensor enhanced by gold nanoparticles electrodeposited on the surface of gold electrode is designed. The designed aptasensor has a wide effective measuring range from 50pM to 250pM with a detection limit of 50pM in PBS buffer, and an effective measuring range from 50nM to 1MUM with a detection limit of 50nM in serum. The designed biosensor is also able to detect cAMP with high sensitivity, specificity, and stability. Since the biosensor can be easily fabricated with low cost and repeatedly used for at least two times, it owns great potential in wide application fields such as clinical test and food inspection, etc. PMID- 25437359 TI - Impedimetric method for measuring ultra-low E. coli concentrations in human urine. AB - In this study, we developed an interdigitated gold microelectrode-based impedance sensor to detect Escherichia coli (E. coli) in human urine samples for urinary tract infection (UTI) diagnosis. E. coli growth in human urine samples was successfully monitored during a 12-h culture, and the results showed that the maximum relative changes could be measured at 10Hz. An equivalent electrical circuit model was used for evaluating the variations in impedance characteristics of bacterial growth. The equivalent circuit analysis indicated that the change in impedance values at low frequencies was caused by double layer capacitance due to bacterial attachment and formation of biofilm on electrode surface in urine. A linear relationship between the impedance change and initial E. coli concentration was obtained with the coefficient of determination R(2)>0.90 at various growth times of 1, 3, 5, 7, 9 and 12h in urine. Thus our sensor is capable of detecting a wide range of E. coli concentration, 7*10(0) to 7*10(8) cells/ml, in urine samples with high sensitivity. PMID- 25437360 TI - BSA-stabilized Pt nanozyme for peroxidase mimetics and its application on colorimetric detection of mercury(II) ions. AB - Bovine serum albumin (BSA) is chosen as the nucleation templates to synthesize Pt based peroxidase nanomimetics with the average diameter of 2.0nm. The efficient Pt nanozymes consist of 57% Pt(0) and 43% Pt(2+), which possess highly peroxidase like activity with the Km values of 0.119mM and 41.8mM toward 3,3',5,5' tetramethylbenzidine (TMB) and hydrogen peroxide (H2O2), respectively. Interestingly, Hg(2+) is able to down-regulate the enzymatic activity of Pt nanoparticles, mainly through the interactions between Hg(2+) and Pt(0). It is the first report to explore a colorimetric Hg(2+) sensing system on the basis of peroxidase mimicking activities of Pt nanoparticles. One of our most intriguing results is that BSA-stabilized Pt nanozymes demonstrate the ability to sense Hg(2+) ions in aqueous solution without significant interference from other metal ions. The Hg(2+) detection limit of 7.2nM is achieved with a linear response range of 0-120nM, and the developed sensing system is potentially applicable for quantitative determination of Hg(2+) in drinking water. PMID- 25437361 TI - Highly selective "Off-On" fluorescent probe for histidine and its imaging in living cells. AB - A naphthalimide-based fluorescent probe CP has been synthesized with simple steps. It can selectively and sensitively recognize copper ions (Cu(2+)) in HEPES buffer (50mM, pH 7.2). The fluorescence intensity of CP is linearly proportional to the concentration of Cu(2+) ranging from 0-8.3MUM (correlation coefficient R(2)=0.9808). The resulted complex CP@Cu can serve as a turn-on fluorescent probe for the detection of histidine and histidine rich proteins in broad pH application range. Upon the addition of histidine, the fluorescence intensity of CP@Cu exhibits a linear correlation with the concentration of histidine ranging from 0-200MUM (correlation coefficient R(2)=0.9912). Moreover, CP@Cu has potential for imaging histidine in vitro experiments and has promise in real sample applications with great validity. PMID- 25437362 TI - Electrochemical biosensor for DNA demethylase detection based on demethylation triggered endonuclease BstUI and Exonuclease III digestion. AB - Herein, an electrochemical biosensor was fabricated for DNA demethylase detection based on DNA demethylation triggered endonuclease BstUI and Exonuclease III digestion. After the double-strand DNA was demethylated, it can be further digested by BstUI and formed a blunt end at the electrode surface. Then, the remained fragment of DNA-DNA duplex was further cleaved by exonuclease III and led to increased electrochemical signal. Based on this detection strategy, the biosensor showed high sensitivity with low detection limit of 0.15ng/mL. Moreover, the developed method also presented high selectivity and acceptable reproducibility. This work provides a novel detection platform for DNA demethylase detection. PMID- 25437363 TI - OLED-based DNA biochip for Campylobacter spp. detection in poultry meat samples. AB - Integrated biochips are the ideal solution for producing portable diagnostic systems that uncouple diagnosis from centralized laboratories. These portable devices exploit a multi-disciplinary approach, are cost effective and have several advantages including broader accessibility, high sensitivity, quick test results and ease of use. The application of such a device in food safety is considered in this paper. Fluorescence detection of a specific biological probe excited by an optical source is one of the most commonly used methods for quantitative analysis on biochips. In this study, we designed and characterized a miniaturized, highly-sensitive DNA biochip based on a deep-blue organic light emitting diode. The molecular design of the diode was optimized to excite a fluorophore-conjugated DNA probe and tested using real meat samples to obtain a high sensitivity and specificity against one of the most common poultry meat contaminants: Campylobacter spp. Real samples were analyzed also by classical plate methods and molecular methods to validate the results obtained by the new DNA-biochip. The high sensitivity obtained by the OLED based biochip (0.37ng/MUl) and the short time required for the results (about 24h) indicate the usefulness of the system. PMID- 25437364 TI - Label-free and ultrasensitive colorimetric detection of DNA based on target triggered quadratic amplification strategy. AB - Highly sensitive detection of DNA plays a crucial role in biomedical research and clinical diagnosis. Herein, we developed a simple, label-free, isothermal, and ultrasensitive colorimetric method for amplified detection of DNA on the basis of a new quadratic amplification strategy. With the presence of three ingeniously designed hairpin structures and Exonuclease III (Exo III), the target DNA can trigger two independent cycles of reactions: hairpin assembly reaction and Exo III cleavage reaction, which are designed to initiate target DNA recycling amplification and reporter DNA amplification, respectively. Therefore, the proposed method exhibits a high sensitivity toward target DNA with a detection limit of as low as 81 fM, and it can discriminate mismatched DNA from completely matched target DNA. Furthermore, this method could be used as a universal tool for the detection of various DNA sequences and might be further extended for the detection of aptamer-binding molecules. PMID- 25437365 TI - An ultrasensitive and universal photoelectrochemical immunoassay based on enzyme mimetics enhanced signal amplification. AB - An ultrasensitive photoelectrochemical (PEC) immunoassay based on signal amplification by enzyme mimetics was fabricated for the detection of mouse IgG (as a model protein). The PEC immunosensor was constructed by a layer-by-layer assembly of poly (diallyldimethylammonium chloride) (PDDA), CdS quantum dots (QDs), primary antibody (Ab1, polyclonal goat antimouse IgG), and the antigen (Ag, mouse IgG) on an indium-tin oxide (ITO) electrode. Then, the secondary antibody (Ab2, polyclonal goat antimouse IgG) combined to a bio-bar-coded Pt nanoparticle(NP)-G-quadruplex/hemin probe was used for signal amplification. The bio-bar-coded Pt NP-G-quadruplex/hemin probe could catalyze the oxidation of hydroquinone (HQ) using H2O2 as an oxidant, demonstrating its intrinsic enzyme like activity. High sensitivity for the target Ag was achieved by using the bio bar-coded probe as signal amplifier due to its high catalytic activity, a competitive nonproductive absorption of hemin and the steric hindrance caused by the polymeric oxidation products of HQ. For most important, the oxidation product of HQ acted as an efficient electron acceptor of the illuminated CdS QDs. The target Ag could be detected from 0.01pg/mL to 1.0ng/mL with a low detection limit of 6.0fg/mL. The as-obtained immunosensor exhibited high sensitivity, good stability and acceptable reproducibility. This method might be attractive for clinical and biomedical applications. PMID- 25437366 TI - Real-time and label-free analyte detection in a flow-through mode using immobilized fluorescent aptamer/quantum dots molecular switches. AB - Inspired by the goal to create a biosensor with designer specificity for real time detection of unlabeled analytes in a flow-through mode, we designed a miniature flow cell with interchangeable quartz window carrying immobilized aptamer/quantum dot molecular switches as a part of a portable fluorescent setup. The inner surface of the 1.5mm ID, 12ul flow cell quartz window has been modified with the aptamer sensing complexes containing highly-fluorescent quantum dots. The aptamer complexes were designed as molecular switches to undergo conformational change and release fluorescent label upon interaction with the flow of the analyte, causing fluorescence decrease. The specificity of the sensor was designed to address the light chain of Botulinum Neurotoxin A and Ricin Toxin A chain, which could be specifically and repeatedly detected in the flow of 60ul/min with sensitivity comparable to other real-time detection methods. The specifics of quantum dots use as fluorescent labels for continuous monitoring under constant UV illumination were outlined. The possibility for multispecific sensing was explored by testing of bi-specific sensor. This work shows the possibility of surface-bound aptamer sensing for flow-through analyte detection and provides a useful tool to perform surface fluorescent studies in real-time. The flexibility of the described design allows for sensor specificity change through altering the specificity of the aptamer. Future work should address response quantification. The described sensing approach can be adapted to a number of environmental or clinical targets. PMID- 25437367 TI - Novel biosensing methodologies for improving the detection of single nucleotide polymorphism. AB - The growing volume of sequence data confirm more and more candidate single nucleotide polymorphisms (SNPs), which are believed to reveal the genetic basis of individual susceptibility to disease and the diverse responses to treatment. There is therefore an urgent demand for developing the sensitive, rapid, easy-to use, and cost-effective method to identify SNPs. During the last two decades, biosensing techniques have been developed by integrating the unique specificity of biological reactions and the high sensitivity of physical sensors, which provided significant advantages for the detection of SNPs. In this feature article, we focused attention on the strategies of SNP genotyping based on biosensors, including nucleic acid analogs, surface ligation reaction, single base extension, mismatch binding protein, molecular beacon, rolling circle amplification, and strand-displacement amplification. In addition, the perspectives on their advantages, current limitations, and future trends were also discussed. The biosensing technique would provide a promising alternative for the detection of SNPs, and pave the way for the diagnosis of genetic diseases and the design of appropriate treatments. PMID- 25437368 TI - Electrospun graphene decorated MnCo2O4 composite nanofibers for glucose biosensing. AB - Graphene decorated MnCo2O4 composite nanofibers (GMCFs) were synthesized by electrospinning and subsequent calcination in an Ar atmosphere. The structural and morphological characterizations of GMCFs were performed using X-ray diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy, energy dispersive spectroscopy, scanning electron microscopy and transmission electron microscopy. The synthesized GMCFs combine the catalytic activity of spinel-type MnCo2O4 with the remarkable conductivity of graphene. In addition, electrospinning can process MnCo2O4 materials into nanosized architectures with large surface area to prevent magnetic nanoparticles from aggregating. The obtained GMCFs were applied as a novel platform for glucose biosensing. Electrochemical studies show that the developed biosensor exhibits excellent electrocatalytic activity towards glucose oxidation over a wide linear range of 0.005-800uM with a low detection limit of 0.001uM. PMID- 25437369 TI - Detection of T4 polynucleotide kinase activity based on cationic conjugated polymer-mediated fluorescence resonance energy transfer. AB - A simple but robust strategy for sensitive detection of T4 polynucleotide kinase (T4 PNK) activity is developed by means of a DNA phosphorylation-accelerated lambda exonuclease cleavage reaction coupled with cationic conjugated polymer (CCP)-mediated fluorescence resonance energy transfer (FRET). Firstly, a label free hairpin DNA with a 5'-hydroxyl end is designed as the substrate of T4 PNK. SYBR Green I (SGI), a double-stranded DNA (dsDNA)-specific fluorescent dye, can fluoresce only when intercalated to the stem region of the hairpin DNA. When mixed with CCP, the SGI-binding hairpin DNA will be brought in close proximity with the CCP due to strong electrostatic interaction, leading to efficient FRET from CCP to SGI. However, in the presence of T4 PNK, the hairpin DNA would be phosphorylated at its 5'-terminus and thus can be immediately recognized as the initial cleavage site of lambda exonuclease. The phosphorylation-actuated lambda exonuclease reaction will cleave the stem of the hairpin to yield a single stranded DNA, which is unable to combine with SGI and as a result, the FRET signal would decrease gradually in correlation to the T4 PNK activity. Therefore, by recording the change of FRET ratio, T4 PNK activity can be facilely determined in a mix-and-read manner. Due to the light harvesting and fluorescence amplification properties of CCP, high sensitivity is achieved for this homogeneous assay. This new strategy provides a simple detection procedure, easy readout and cost-effective manner for T4 PNK analysis, which shows great potential in the study of polynucleotide kinase-related biological processes. PMID- 25437370 TI - Sensitive detection of tumor cells by a new cytosensor with 3D-MWCNTs array based on vicinal-dithiol-containing proteins (VDPs). AB - Vicinal-dithiol-containing Proteins (VDPs) are overexpressed in cancer cells and become a potential biomarker for aggressive tumors, the synthesized 2-p aminophenyl-1, 3, 2-dithiarsenolane (VTA2) is proved to be a highly selective ligand for vicinal dithiols of VDPs in cells. In this report, we developed a new cytosensor based on three-dimensional (3D)-like VTA2-conjugated multiwalled carbon nanotubes (VTA2@MWCNTs) array modified indium tin oxide (ITO) electrode for sensitive and selective detection of VDPs-overexpression tumor cells. The layer-by-layer assembling and cellular detection performances of the 3D VTA2@MWCNTs-based cytosensor were investigated by atomic force microscopy (AFM) and electrochemical methods including cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and differential pulse voltammetry (DPV). Attributed to signal amplification and targeting recognition of the 3D-structured MWCNTs@VTA2, the fabricated cytosensor showed high specificity and sensitivity to the detection of VDPs-overexpression HL-60 cells ranging from 2.7*10(2) to 2.7*10(7)cellsmL(-1) with a low detection limit of ca. 90cellsmL(-1). Furthermore, the captured cancer cells on the cytosensor also could be directly visualized by optical microscopy technology. This proposed 3D-MWCNTs array-based cytosensing strategy provides a simple, sensitive approach for non-invasive cell detection, presenting potential applications in cancer diagnosis. PMID- 25437371 TI - Electrochemical detection of protein based on hybridization chain reaction assisted formation of copper nanoparticles. AB - In this paper, we report an electrochemical method for highly sensitive and specific detection of protein based on hybridization chain reaction (HCR) assisted formation of copper nanoparticles by using small molecule such as folate linked DNA as probe. In the presence of target protein, taking folate receptor (FR) as the model protein in this study, its binding with folate can protect the probe DNA from exonuclease I-catalyzed degradation, thus the probe DNA can be immobilized onto the electrode surface through the hybridization with capture DNA, triggering HCR on the electrode surface. Subsequently, copper nanoparticles can be formed on the electrode surface by using long duplex DNA oligomers from HCR as templates. Furthermore, copper ions released from acid-dissolution of copper nanoparticles can catalyze the oxidation of omicron-phenylenediamine by dissolved oxygen, leading to significant electrochemical responses. As a result, our method can sensitively detect FR in the linear range from 0.01ng/mL to 100ng/mL with a detection limit of 3pg/mL. It can also specifically distinguish the target protein in both buffer and complex serum samples. Since many other proteins can be assayed by changing the corresponding small molecule, this method may be promising for the development of the technique for protein detections. PMID- 25437372 TI - Electrochemical impediometric detection of anti-HIV drug taking gold nanorods as a sensing interface. AB - In present work, gold nanorods were used for amplification of electrochemical sensing of anti-HIV replication drug i.e. deferiprone. Gold nanorods (nano Au) deposited onto pencil graphite electrode (PGE) has been utilized for covalent immobilization of horse radish peroxidase (HRP), via glutaraldehyde (Glu), for deferiprone detection using impedimetric technique. Gold nanorods (nano Au) prepared were characterized by TEM and XRD. The resulting nano Au sensor exhibited a good response to deferiprone with a wide linear range (0.005-1000uM) and a low detection limit 0.005uM. The biosensor also showed a short response time (within 15s). In addition, the biosensor exhibited high reproducibility, good storage stability and anti-interference ability. The applicability of the nano Au sensor is to determine deferiprone level in spiked urine and serum samples. PMID- 25437373 TI - SPRi determination of inter-peptide interaction by using 3D supramolecular co assembly polyrotaxane film. AB - Accurate measurement of inter-peptide interactions is beneficial for in-depth understanding disease-related protein folding and peptide aggregation, and further for designing and selecting potential peptide drugs to the target antigen. Herein, we demonstrate a 3D polyrotaxane (PRX) surface for detecting peptides interactions by surface plasmon resonance imaging (SPRi). This surface is supramolecular self-assembly monolayer (SAM) structure fabricated by threading alpha-cyclodextrans (alpha-CD) through a linear polyethylene glycol (PEG) chain fixed on gold chip surface to form pseudopolyrotaxane, and further capping the pseudopolyrotaxane with bulky terminated group to form PRX film. The hydroxyl groups of alpha-CD can provide more active sites to increase molecules immobilization density, and PEG chain has unique protein non-fouling feature. We chose Alzheimer's disease marker beta-amyloid 40 (Abeta40) as model peptide, and detected the interaction between it and its inhibitors KLVFFK6 by SPRi. As a striking result, the specific adsorption of KLVFFK6 solution at the concentration of 352MUM on Abeta40-PRX was 700RU, whereas PEG SAM surface gave no significant binding. Interaction between other lower molecular weight peptides was detected via PRX surface, and the relatively weak interactions (KD=1.73*10(-4)M) between LPFFD (Mw=0.6kDa) and amylin20-29 (Mw=1.0kDa) are successfully detected. PMID- 25437374 TI - Upper visual field distractors preferentially bias attention to the left. AB - Pseudoneglect is influenced by vertical visual field stimulation, such that attentional biases are stronger for upper space distractors. Leftward biases result from right hemisphere visuospatial processing, and may be accentuated by additional right hemisphere activation during upper space distraction. Three experiments examined potential explanations for this finding. Experiment 1 controlled for perceptual grouping and leftward biases remained stronger in upper space. Experiment 2 used peripheral distractors to eliminate two further potential explanations: centre-of-mass and framing effects. Eye tracking was included to compare overt and covert attention. Findings supported the occurrence of a stronger leftward attentional bias during upper space distraction. Distractors were rarely fixated, suggesting covert attentional mechanisms are preferentially drawn toward upper space distractors. Experiment 3 employed a cueing paradigm that purposefully directed attention away from centre to determine whether pseudoneglect was influenced by overt attentional orienting. Results indicated that when attention was overtly directed away from centre, the strength of pseudoneglect did not differ based on visual field. It is concluded that covert attention toward upper space distractors recruits additional right hemisphere activation, leading existing leftward biases to be accentuated. PMID- 25437376 TI - Of magnitudes and metaphors: explaining cognitive interactions between space, time, and number. AB - Space, time, and number are fundamental to how we act within and reason about the world. These three experiential domains are systematically intertwined in behavior, language, and the brain. Two main theories have attempted to account for cross-domain interactions. A Theory of Magnitude (ATOM) posits a domain general magnitude system. Conceptual Metaphor Theory (CMT) maintains that cross domain interactions are manifestations of asymmetric mappings that use representations of space to structure the domains of number and time. These theories are often viewed as competing accounts. We propose instead that ATOM and CMT are complementary, each illuminating different aspects of cross-domain interactions. We argue that simple representations of magnitude cannot, on their own, account for the rich, complex interactions between space, time and number described by CMT. On the other hand, ATOM is better at accounting for low-level and language-independent associations that arise early in ontogeny. We conclude by discussing how magnitudes and metaphors are both needed to understand our neural and cognitive web of space, time and number. PMID- 25437375 TI - Abnormal relationship between GABA, neurophysiology and impulsive behavior in neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder characterized by a broad spectrum of cognitive deficits. In particular, executive dysfunction is recognized as a core deficit of NF1, including impairments in executive attention and inhibitory control. Yet, the neural mechanisms behind these important deficits are still unknown. Here, we studied inhibitory control in a visual go/no go task in children and adolescents with NF1 and age- and gender-matched controls (n = 16 per group). We applied a multimodal approach using high-density electroencephalography (EEG), to study the evoked brain responses, and magnetic resonance spectroscopy (MRS) to measure the levels of GABA and glutamate + glutamine in the medial frontal cortex, a brain region that plays a pivotal role in inhibitory control, and also in a control region, the occipital cortex. Finally, we run correlation analyses to identify the relationship between inhibitory control, levels of neurotransmitters, and EEG markers of neural function. Individuals with NF1 showed impaired impulse control and reduced EEG correlates of early visual processing (parieto-occipital P1) and inhibitory control (frontal P3). MRS data revealed a reduction in medial frontal GABA+/tCr (total Creatine) levels in the NF1 group, in parallel with the already reported reduced occipital GABA levels. In contrast, glutamate + glutamine/tCr levels were normal, suggesting the existence of abnormal inhibition/excitation balance in this disorder. Notably, medial frontal but not occipital GABA levels correlated with general intellectual abilities (IQ) in NF1, and inhibitory control in both groups. Surprisingly, the relationship between inhibitory control and medial frontal GABA was reversed in NF1: higher GABA was associated with a faster response style whereas in controls it was related to a cautious strategy. Abnormal GABAergic physiology appears, thus, as an important factor underlying impaired cognition in NF1, in a level and region dependent manner. PMID- 25437378 TI - Islet cell research brings hope for a diabetes cure: meeting report from the 6(th) annual islet society meeting in Stellenbosch, South Africa. AB - The International Diabetes Federation predicts that, over the next twenty years, the largest increase in the prevalence of diabetes will be in the Africa region. Recognizing an unmet need for more focus on Africa and engagement with African scholars, the Islet Society held its 6th annual meeting July 20-21, 2014 in Stellenbosch, South Africa. Here, we present a report that covers the presentations and discussion points from that meeting. Work was presented on a variety of topics and included presentations by a significant proportion of Africa diabetes researchers. Overall, it was an excellent conference, with many new international collaborations initiated. We hope that other groups will also respond to the need for more conferences in Africa and focused on Africa. PMID- 25437377 TI - Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice. AB - Glucose-stimulated insulin secretion (GSIS) is a highly regulated process involving complex interaction of multiple factors. Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) is a susceptibility gene for type 2 diabetes (T2D) and the risk alleles of the KCNQ1 gene appear to be associated with impaired insulin secretion. The role of KCNQ1 channel in insulin secretion has been explored by previous work in clonal pancreatic beta-cells but has yet to be investigated in the context of primary islets as well as intact animals. Genetic studies suggest that altered incretin glucagon-like peptide-1 (GLP-1) secretion might be a potential link between KCNQ1 variants and impaired insulin secretion, but this hypothesis has not been verified so far. In the current study, we examined KCNQ1 expression in pancreas and intestine from normal mice and then investigated the effects of chromanol 293B, a KCNQ1 channel inhibitor, on insulin secretion in vitro and in vivo. By double-immunofluorescence staining, KCNQ1 was detected in insulin-positive beta-cells and GLP-1-positive L-cells. Administration of chromanol 293B enhanced GSIS in cultured islets and intact animals. Along with the potentiated insulin secretion during oral glucose tolerance tests (OGTT), plasma GLP-1 level after gastric glucose load was increased in 293B treated mice. These data not only provided new evidence for the participation of KCNQ1 in GSIS at the level of pancreatic islet and intact animal but also indicated the potential linking role of GLP-1 between KCNQ1 and insulin secretion. PMID- 25437379 TI - Different digestion enzymes used for human pancreatic islet isolation: a mixed treatment comparison (MTC) meta-analysis. AB - Collagenases are critical reagents determining yield and quality of isolated human pancreatic islets and may affect islet transplantation outcome. Some islet transplantation centers have compared 2 or more collagenase blends; however, the results regarding differences in quantity and quality of islets are conflicting. Thus, for the first time, a mixed treatment comparison (MTC) meta-analysis was carried out to compile data about the effect of different collagenases used for human pancreas digestion on islet yield, purity, viability and stimulation index (SI). Pubmed, Embase and Cochrane libraries were searched. Of 755 articles retrieved, a total of 15 articles fulfilled the eligibility criteria and were included in the MTC meta-analysis. Our results revealed that Vitacyte and Liberase MTF were associated with a small increase in islet yield (islet equivalent number/g pancreas) when compared with Sevac enzyme [standardized mean difference (95% credible interval - CrI) = -2.19 (-4.25 to -0.21) and -2.28 ( 4.49 to -0.23), respectively]. However, all other enzyme comparisons did not show any significant difference regarding islet yield. Purity and viability percentages were not significantly different among any of the analyzed digestion enzymes. Interestingly, Vitacyte and Serva NB1 were associated with increased SI when compared with Liberase MTF enzyme [unstandardized weighted mean difference (95% CrI) = -1.69 (-2.87 to -0.51) and -1.07 (-1.79 to -0.39), respectively]. In conclusion, our MTC meta-analysis suggests that the digestion enzymes currently being used for islet isolation works with similar efficiency regarding islet yield, purity and viability; however, Vitacyte and Serva NB1 enzymes seem to be associated with an improved SI as compared with Liberase MTF. PMID- 25437381 TI - In Situ Infrared Spectroscopy of Oligoaniline Intermediates Created under Alkaline Conditions. AB - The progress of the oxidation of aniline with ammonium peroxydisulfate in an alkaline aqueous medium has been monitored in situ by attenuated total reflection (ATR) Fourier transform infrared spectroscopy. The growth of the microspheres and of the film at the ATR crystal surface, as well as the changes proceeding in the surrounding aqueous medium, are reflected in the spectra. The evolution of the spectra and the changes in the molecular structure occurring during aniline oxidation in alkaline medium are discussed with the help of differential spectra. Several processes connected with the various stages of aniline oxidation were distinguished. The progress of hydrolysis of the aniline in water and further an oxidation of aminophenol to benzoquinone imines in the presence of peroxydisulfate in alkaline medium have been detected in the spectra in real time. The precipitated solid oxidation product was analyzed by mass spectrometry. It is composed of oligomers, mainly trimers to octamers, of various molecular structures incorporating in addition to aniline constitutional units also p benzoquinone or p-benzoquinoneimine moieties. PMID- 25437382 TI - Building clinicians-researchers partnerships: lessons from diverse natural settings and practice-oriented initiatives. AB - In this concluding paper, we identify the type of studies conducted by 11 teams of contributors to a special issue on building clinicians-researchers partnerships. Those studies were conducted across a variety of clinical settings. We also integrate the lessons that have emerged from their collaborative initiatives in terms of obstacles faced, strategies adopted to address these challenges, benefits gained, and general recommendations offered to facilitate studies conducted with or by clinicians. The paper ends with the authors' thoughts about the future success of practice-oriented research in general. PMID- 25437380 TI - Pancreatic and duodenal homeobox-1 nuclear localization is regulated by glucose in dispersed rat islets but not in insulin-secreting cell lines. AB - The transcription factor Pancreatic and Duodenal Homeobox-1 (PDX-1) plays a major role in the development and function of pancreatic beta-cells and its mutation results in diabetes. In adult beta-cells, glucose stimulates transcription of the insulin gene in part by regulating PDX-1 expression, stability and activity. Glucose is also thought to modulate PDX-1 nuclear translocation but in vitro studies examining nucleo-cytoplasmic shuttling of endogenous or ectopically expressed PDX-1 in insulin-secreting cell lines have led to conflicting results. Here we show that endogenous PDX-1 undergoes translocation from the cytoplasm to the nucleus in response to glucose in dispersed rat islets but not in insulin secreting MIN6, HIT-T15, or INS832/13 cells. Interestingly, however, we found that a PDX-1-GFP fusion protein can shuttle from the cytoplasm to the nucleus in response to glucose stimulation in HIT-T15 cells. Our results suggest that the regulation of endogenous PDX-1 sub-cellular localization by glucose is observed in primary islets and that care should be taken when interpreting data from insulin-secreting cell lines. PMID- 25437383 TI - Celebrating 40 years of NP trials and triumphs. PMID- 25437384 TI - HPV, cervical cancer risks, and barriers to care for lesbian women. AB - The purpose of this article is to identify Pap testing rates among lesbians and identify reasons for lack of recognition of cervical cancer risks in lesbians. Articles that reported cervical cancer screening rates among lesbians were searched. Between 48% and 81% of lesbians reported recent Pap smears. The lesbian community requires better education, and healthcare providers should promote regular Pap smears for all women. PMID- 25437386 TI - Three decades of structure- and property-based molecular design. AB - Roche has pioneered structure- and property-based molecular design to drug discovery. While this is an ongoing development, the past three decades feature key events that have revolutionized the way drug discovery is conducted in Big Pharma industry. It has been a great privilege to have been involved in this transformation process, to have been able to collaborate with, direct, guide, or simply encourage outstanding experts in various disciplines to build and further develop what has become a major pillar of modern small-molecule drug discovery. This article is an account of major events that took place since the early decision of Roche to implement computer-assisted molecular modeling 32 years ago and is devoted to the key players involved. It highlights the internal build-up of structural biology, with protein X-ray structure determination at its core, and the early setup of bioinformatics. It describes the strategic shift to large compound libraries and high-throughput screening with the development of novel compound storage and ultra-high-throughput screening facilities, as well as the strategic return to focused screening of small motif-based compound libraries. These developments were accompanied by the rise of miniaturized parallel compound property analytics which resulted in a major paradigm shift in medicinal chemistry from linear to multi-dimensional lead optimization. The rapid growth of huge collections of property data stimulated the development of various novel data mining concepts with 'matched molecular pair' analysis and novel variants thereof playing crucial roles. As compound properties got more prominent in molecular design, exploration of specific structural motifs for property modulation became a research activity complementary to target-oriented medicinal chemistry. The exploration of oxetane is given as an example. For the sake of brevity, this account cannot detail all further developments that have taken place in each individual area of structure- and property-based drug discovery and it can only hint at important developments in other disciplines that have equally contributed to major paradigm shifts in Roche's small-molecule drug discovery efforts. PMID- 25437387 TI - SOM230: a new therapeutic modality for Cushing's disease. AB - A rational drug design approach involving transposition of functional groups from SRIF into a reduced size cyclohexapeptide template has led to the discovery of SOM230, a novel, stable cyclohexapeptide somatostatin mimic which exhibits unique high affinity binding to human somatostatin receptors (sst1-5). This unique receptor subtype binding profile, in particular the exceptional high affinity binding to sst5, led to SOM230 being approved by EMEA and FDA in 2012 as the first effective pituitary directed therapeutic modality for Cushing's disease. PMID- 25437388 TI - New trends in (heterogeneous) catalysis for the fine chemicals industry. AB - New catalytic methods and modern trends for the synthesis of fine chemicals, especially vitamins, carotenoids, flavoring and fragrance compounds are presented. In particular the application of heterogeneous catalysis in the formation and production on industrial scale of these classes of organic compounds will be highlighted and its use in the replacement of former stoichiometric processes. PMID- 25437389 TI - Adventures in drug-like chemistry space: from oxetanes to spiroazetidines and beyond! AB - Recently we have documented research efforts aimed at new classes of oxetanes as well as spiroheteroalicyclic ring systems (which we have termed 'Compact Modules') designed to expand the palette of tailored module scaffolds available to medicinal chemists, which constitute an important role for synthetic chemistry in the drug discovery process. An essential component for this process is to provide access to specific molecular topologies with functional group diversity, essential for generating leads that discriminate among biological targets, therefore promoting selectivity and enhancing the safety profile of the final clinical candidates. PMID- 25437390 TI - Combining NHC bis-phenolate ligands with oxophilic metal centers: a powerful approach for the development of robust and highly effective organometallic catalysts. AB - The present paper describes an overview of a novel family of tridentate NHC pincer ligand in which two phenoxide moieties are directly connected to the nitrogen atoms of a central N-heterocyclic carbene. It was envisioned that such a structure might be suitable for coordination to a variety of metal centers across the periodic table, including oxophilic metals. Various metal complexes bearing such ligand are indeed readily accessible in high yields via straightforward routes. Interestingly, a robust zirconium-NHC complex was found to polymerize rac lactide in a highly controlled, living and stereoselective manner to afford heterotactic PLA. PMID- 25437391 TI - Molecular switches as platforms for information processing. AB - This article shows how to teach molecules the basics of logic and how to integrate complicated logic operations with relatively simple molecules. A special focus is put on the realization of multi-level fluorescent switches with chemical inputs as well as on the demonstration of various memory-based operations with all-optical photochromic switches. PMID- 25437392 TI - Quantifying intra- and intermolecular phenomena: challenging yet exciting territory for quantum chemistry. AB - van der Waals interactions occur in all molecules and intermolecular complexes but are poorly described by the most widely used electronic structure framework. This paper addresses the efforts pursued in our laboratory to improve the performance of standard density functional approximations and deliver modern strategies to analyze and fine-tune the underlying physics of intra- and intermolecular interactions. PMID- 25437393 TI - Taming hypervalent bonds and strained rings for catalysis and synthesis. AB - Improving the synthesis of complex organic molecules is essential for progress in many fields such as medicine, agrochemicals or materials. Since 2007, our laboratory has been focusing on the development of non-classical bond disconnections based on the use of small, energy-loaded organic molecules: hypervalent iodine reagents and strained rings. In this overview article, we report our progress since 2011 in these areas. The use of cyclic hypervalent iodine reagents has been extended to the C2-selective alkynylation of indoles, the domino cyclization alkynylation of allenes, the alkynylation of thiols and the azidation of carbonyl compounds. Amino-substituted aminocyclopropanes and aminocyclobutanes were used in [3+2] and [4+2] annulations to access nitrogen rich building blocks, including nucleoside analogues. The first example of dynamic kinetic [3+2] annulation of aminocyclopropanes with both enol ethers and aldehydes was also reported. PMID- 25437394 TI - The von Auwers reaction - history and synthetic applications. AB - Dienones obtained from the facile dearomatization of phenols, can be further transformed to semi-benzenes prone to rearomatize in clean, but sometimes unexpected, fashion. Over a hundred years ago, K. von Auwers found that adding Grignards on dienones would lead spontaneously to subsequent dehydration and a novel aromatizing rearrangement. This reaction was ignored for 50 years before Melvin Newman re-investigated these findings, studied the mechanism, and developed variations on the same theme. Since then, despite the tremendous potential of the reactions, those studies were only rarely mentioned, before finally falling into oblivion. This review aims to provide the reader with a detailed history and comprehensive bibliography of the von Auwers rearrangement, some of its synthetic applications, and new unpublished material in the hope to open new perspectives on this forgotten reaction. PMID- 25437395 TI - Surface chemistry at Swiss Universities of Applied Sciences. AB - In the Swiss Universities of Applied Sciences, a number of research groups are involved in surface science, with different methodological approaches and a broad range of sophisticated characterization techniques. A snapshot of the current research going on in different groups from the University of Applied Sciences and Arts Western Switzerland (HES-SO), the Zurich University of Applied Sciences (ZHAW) and the University of Applied Sciences and Arts Northwestern Switzerland (FHNW) is given. PMID- 25437396 TI - Life sciences at FHNW Muttenz an innovative network of strong partners. AB - The School of Life Sciences at the University of Applied Sciences and Arts Northwestern Switzerland FHNW in Muttenz excels in molecular technology, bioanalytics and in vitro diagnostics - three very active areas of current biotech research. Cooperation with industry partners enables knowledge to be transferred to the education process and gives companies access to qualified individuals and markets. PMID- 25437399 TI - Translational science: a catalyst for real world applications? AB - Science is the systemic search for new knowledge and innovative ideas. Scientific knowledge is empirically based and successful replication of the results is a crucial component of it. Translational science connects this knowledge with real world applications in order to address societal challenges and problems, under the condition that the science-policy interface is taken into account. The aim of this communication is to examine if translational science can be applied to research settings other than health care. PMID- 25437400 TI - An overview of corporate social responsibility in chemical research. PMID- 25437402 TI - Correction: Silk fibroin-keratin based 3D scaffolds as a dermal substitute for skin tissue engineering. AB - Correction for 'Silk fibroin-keratin based 3D scaffolds as a dermal substitute for skin tissue engineering' by Nandana Bhardwaj et al., Integr. Biol., 2015, DOI: 10.1039/c4ib00208c. PMID- 25437403 TI - Identifying key residues for protein allostery through rigid residue scan. AB - Allostery is a ubiquitous process for protein regulatory activity in which a binding event can change a protein's function carried out at a distal site. Despite intensive theoretical and experimental investigation of protein allostery in the past five decades, effective methods have yet to be developed that can systematically identify key residues involved in allosteric mechanisms. In this study, we propose the rigid residue scan as a systematic approach to identify important allosteric residues. The third PDZ domain (PDZ3) in the postsynaptic density 95 protein (PSD-95) is used as a model system, and each amino acid residue is treated as a single rigid body during independent molecular dynamics simulations. Various indices based on cross-correlation matrices are used, which allow for two groups of residues with different functions to be identified. The first group is proposed as "switches" that are needed to "turn on" the binding effect of protein allostery. The second group is proposed as "wire residues" that are needed to propagate energy or information from the binding site to distal locations within the same protein. Among the nine residues suggested as important for PDZ3 intramolecular communication in this study, eight have been reported as critical for allostery in PDZ3. Therefore, the rigid residue scan approach is demonstrated to be an effective method for systemically identifying key residues in protein intramolecular communication and allosteric mechanisms. PMID- 25437404 TI - Neighborhood socioeconomic disadvantage and 30-day rehospitalization: a retrospective cohort study. AB - BACKGROUND: Measures of socioeconomic disadvantage may enable improved targeting of programs to prevent rehospitalizations, but obtaining such information directly from patients can be difficult. Measures of U.S. neighborhood socioeconomic disadvantage are more readily available but are rarely used clinically. OBJECTIVE: To evaluate the association between neighborhood socioeconomic disadvantage at the census block group level, as measured by the Singh validated area deprivation index (ADI), and 30-day rehospitalization. DESIGN: Retrospective cohort study. SETTING: United States. PATIENTS: Random 5% national sample of Medicare patients discharged with congestive heart failure, pneumonia, or myocardial infarction between 2004 and 2009 (n = 255,744). MEASUREMENTS: Medicare data were linked to 2000 census data to construct an ADI for each patient's census block group, which were then sorted into percentiles by increasing ADI. Relationships between neighborhood ADI grouping and 30-day rehospitalization were evaluated using multivariate logistic regression models, controlling for patient sociodemographic characteristics, comorbid conditions and severity, and index hospital characteristics. RESULTS: The 30-day rehospitalization rate did not vary significantly across the least disadvantaged 85% of neighborhoods, which had an average rehospitalization rate of 21%. However, within the most disadvantaged 15% of neighborhoods, rehospitalization rates increased from 22% to 27% with worsening ADI. This relationship persisted after full adjustment, with the most disadvantaged neighborhoods having a rehospitalization risk (adjusted risk ratio, 1.09 [95% CI, 1.05 to 1.12]) similar to that of chronic pulmonary disease (adjusted risk ratio, 1.06 [CI, 1.04 to 1.08]) and greater than that of uncomplicated diabetes (adjusted risk ratio, 0.95 [CI, 0.94 to 0.97]). LIMITATION: No direct markers of care quality or access. CONCLUSION: Residence within a disadvantaged U.S. neighborhood is a rehospitalization predictor of magnitude similar to chronic pulmonary disease. Measures of neighborhood disadvantage, such as the ADI, could potentially be used to inform policy and care after hospital discharge. PRIMARY FUNDING SOURCE: National Institute on Aging and University of Wisconsin School of Medicine and Public Health's Institute for Clinical and Translational Research and Health Innovation Program. PMID- 25437405 TI - Effect of clinical and social risk factors on hospital profiling for stroke readmission: a cohort study. AB - BACKGROUND: The Centers for Medicare & Medicaid Services (CMS) and Veterans Health Administration (VA) will report 30-day stroke readmission rates as a measure of hospital quality. A national debate on whether social risk factors should be included in models developed for hospital profiling is ongoing. OBJECTIVE: To compare a CMS-based model of 30-day readmission with a more comprehensive model that includes measures of social risk (such as homelessness) or clinical factors (such as stroke severity and functional status). DESIGN: Data from a retrospective cohort study were used to develop a CMS-based 30-day readmission model that included age and comorbid conditions based on codes from the International Classification of Diseases, Ninth Revision, Clinical Modification (model 1). This model was then compared with one that included administrative social risk factors (model 2). Finally, the CMS model (model 1) was compared with a model that included social risk and clinical factors from chart review (model 3). These 3 models were used to rank hospitals by 30-day risk standardized readmission rates and examine facility rankings among the models. SETTING: Hospitals in the VA. PARTICIPANTS: Patients hospitalized with stroke in 2007. MEASUREMENTS: 30-day readmission rates. RESULTS: The 30-day readmission rate was 12.8%. The c-statistics for the 3 models were 0.636, 0.646, and 0.661, respectively. All hospitals were classified as performing "as expected" using all 3 models (that is, performance did not differ from the VA national average); therefore, the addition of detailed clinical information or social risk factors did not alter assessment of facility performance. LIMITATION: A predominantly male veteran cohort limits the generalizability of these findings. CONCLUSION: In the VA, more comprehensive models that included social risk and clinical factors did not affect hospital comparisons based on 30-day readmission rates. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs. PMID- 25437406 TI - Diabetes in midlife and cognitive change over 20 years: a cohort study. AB - BACKGROUND: Type 2 diabetes is associated with dementia risk, but evidence is limited for possible associations of diabetes and prediabetes with cognitive decline. OBJECTIVE: To determine whether diabetes in midlife is associated with 20-year cognitive decline and to characterize long-term cognitive decline across clinical categories of hemoglobin A1c (HbA1c) levels. DESIGN: Prospective cohort study. SETTING: The community-based ARIC (Atherosclerosis Risk in Communities) study. PARTICIPANTS: 13,351 black and white adults aged 48 to 67 years at baseline (1990 to 1992). MEASUREMENTS: Diabetes was defined by self-reported physician diagnosis or medication use or HbA1c level of 6.5% or greater. Undiagnosed diabetes, prediabetes, and glucose control in persons with diagnosed diabetes were defined by clinical categories of HbA1c level. Delayed word recall, digit symbol substitution, and word fluency tests were used to assess cognitive performance and were summarized with a global Z score. RESULTS: Diabetes in midlife was associated with a 19% greater cognitive decline over 20 years (adjusted global Z-score difference, -0.15 [;95% CI, -0.22 to -0.08];) compared with no diabetes. Cognitive decline was significantly greater among persons with prediabetes (HbA1c level of 5.7% to 6.4%) than among those with an HbA1c level less than 5.7%. Participants with poorly controlled diabetes (HbA1c level >= 7.0%) had greater decline than those whose diabetes was controlled (adjusted global Z-score difference, -0.16; P = 0.071). Longer-duration diabetes was also associated with greater late-life cognitive decline (P for trend < 0.001). Rates of decline did not differ significantly between white and black persons (P for interaction = 0.44). LIMITATION: Single HbA1c measurement at baseline, 1 test per cognitive domain, and potential geographic confounding of race comparisons. CONCLUSION: Diabetes prevention and glucose control in midlife may protect against late-life cognitive decline. PRIMARY FUNDING SOURCE: National Institutes of Health. PMID- 25437408 TI - Usage and effect of health information exchange: a systematic review. AB - BACKGROUND: Health information exchange (HIE) is increasing in the United States, and it is incentivized by government policies. PURPOSE: To systematically review and evaluate evidence of the use and effect of HIE on clinical care. DATA SOURCES: Selected databases from 1 January 2003 to 31 May 2014. STUDY SELECTION: English-language hypothesis-testing or quantitative studies of several types of data exchange among unaffiliated organizations for use in clinical care that addressed health outcomes, efficiency, utilization, costs, satisfaction, HIE usage, sustainability, and attitudes or barriers. DATA EXTRACTION: Data extraction was done in duplicate. DATA SYNTHESIS: Low-quality evidence from 12 hypothesis-testing studies supports an effect of HIE use on reduced use or costs in the emergency department. Direct evidence that HIEs were used by providers was reported in 21 studies involving 13 distinct HIE organizations, 6 of which were located in New York, and generally showed usage in less than 10% of patient encounters. Findings from 17 studies of sustainability suggest that approximately one quarter of existing HIE organizations consider themselves financially stable. Findings from 38 studies about attitudes and barriers showed that providers, patients, and other stakeholders consider HIE to be valuable, but barriers include technical and workflow issues, costs, and privacy concerns. LIMITATION: Publication bias, possible selective reporting of outcomes, and a dearth of reporting on context and implementation processes. CONCLUSION: Health information exchange use probably reduces emergency department usage and costs in some cases. Effects on other outcomes are unknown. All stakeholders claim to value HIE, but many barriers to acceptance and sustainability exist. A small portion of operational HIEs have been evaluated, and more research is needed to identify and understand success factors. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs. (PROSPERO registration number: CRD42014007469). PMID- 25437407 TI - Geographic variation in cancer-related imaging: Veterans Affairs health care system versus Medicare. AB - BACKGROUND: Geographic variations in use of medical services have been interpreted as indirect evidence of wasteful care. Less overuse of services, however, may not be reliably associated with less geographic variation. OBJECTIVE: To compare average use and geographic variation in use of cancer related imaging between fee-for-service Medicare and the Department of Veterans Affairs (VA) health care system. DESIGN: Observational analysis of cancer-related imaging from 2003 to 2005 using Medicare and VA utilization data linked to cancer registry data. Multilevel models, adjusted for sociodemographic and tumor characteristics, were used to estimate mean differences in annual imaging use between cohorts of Medicare and VA patients within geographic areas and variation in use across areas for each cohort. SETTING: 40 hospital referral regions. PATIENTS: Older men with lung, colorectal, or prostate cancer, including 34,475 traditional Medicare beneficiaries (Medicare cohort) and 6835 VA patients (VA cohort). MEASUREMENTS: Per-patient count of imaging studies for which lung, colorectal, or prostate cancer was the primary diagnosis (each study weighted by a standardized price), and a direct measure of overuse-advanced imaging for prostate cancer at low risk for metastasis. RESULTS: Adjusted annual use of cancer-related imaging was lower in the VA cohort than in the Medicare cohort (price-weighted count, $197 vs. $379 per patient; P < 0.001), as was annual use of advanced imaging for prostate cancer at low risk for metastasis ($41 vs. $117 per patient; P < 0.001). Geographic variation in cancer-related imaging use was similar in magnitude in the VA and Medicare cohorts. LIMITATION: Observational study design. CONCLUSION: Use of cancer-related imaging was lower in the VA health care system than in fee-for-service Medicare, but lower use was not associated with less geographic variation. Geographic variation in service use may not be a reliable indicator of the extent of overuse. PRIMARY FUNDING SOURCE: Doris Duke Charitable Foundation and Department of Veterans Affairs Office of Policy and Planning. PMID- 25437409 TI - Models in the development of clinical practice guidelines. AB - Clinical practice guidelines should be based on the best scientific evidence derived from systematic reviews of primary research. However, these studies often do not provide evidence needed by guideline development groups to evaluate the tradeoffs between benefits and harms. In this article, the authors identify 4 areas where models can bridge the gaps between published evidence and the information needed for guideline development applying new or updated information on disease risk, diagnostic test properties, and treatment efficacy; exploring a more complete array of alternative intervention strategies; assessing benefits and harms over a lifetime horizon; and projecting outcomes for the conditions for which the guideline is intended. The use of modeling as an approach to bridge these gaps (provided that the models are high-quality and adequately validated) is considered. Colorectal and breast cancer screening are used as examples to show the utility of models for these purposes. The authors propose that a modeling study is most useful when strong primary evidence is available to inform the model but critical gaps remain between the evidence and the questions that the guideline group must address. In these cases, model results have a place alongside the findings of systematic reviews to inform health care practice and policy. PMID- 25437412 TI - Exploring variation in care: alternative conceptual models. PMID- 25437411 TI - Considering the role of socioeconomic status in hospital outcomes measures. PMID- 25437413 TI - This little girl dies today, in front of the Americans. PMID- 25437414 TI - Burden of changes in generic pill appearance. PMID- 25437415 TI - Burden of changes in generic pill appearance. PMID- 25437416 TI - Burden of changes in generic pill appearance. PMID- 25437417 TI - Instrumental variable analyses for observational comparative effectiveness research: the paired availability design. PMID- 25437418 TI - Instrumental variable analyses for observational comparative effectiveness research: the paired availability design. PMID- 25437419 TI - Responding to measles in the postelimination era. PMID- 25437420 TI - Responding to measles in the postelimination era. PMID- 25437421 TI - The challenge of deadopting low-value care. PMID- 25437422 TI - The challenge of deadopting low-value care. PMID- 25437424 TI - Summaries for patients: diabetes in midlife and cognitive change over 20 years. PMID- 25437425 TI - In the clinic: hypertension. AB - This issue provides a clinical overview of Hypertension focusing on prevention, diagnosis, treatment, practice improvement, and patient information. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including ACP Smart Medicine and MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of science writers and physician writers. Editorial consultants from ACP Smart Medicine and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult http://smartmedicine.acponline.org, http://mksap.acponline.org, and other resources referenced in each issue of In the Clinic. PMID- 25437426 TI - Premature skin aging features rescued by inhibition of NADPH oxidase activity in XPC-deficient mice. AB - Xeroderma pigmentosum type C (XP-C) is characterized mostly by a predisposition to skin cancers and accelerated photoaging, but little is known about premature skin aging in this disease. By comparing young and old mice, we found that the level of progerin and p16(INK4a) expression, beta-galactosidase activity, and reactive oxygen species, which increase with age, were higher in young Xpc(-/-) mice than in young Xpc(+/+) ones. The expression level of mitochondrial complexes and mitochondrial functions in the skin of young Xpc(-/-) was as low as in control aged Xpc(+/+)animals. Furthermore, the metabolic profile in young Xpc(-/ ) mice resembled that found in aged Xpc(+/+) mice. Furthermore, premature skin aging features in young Xpc(-/-) mice were mostly rescued by inhibition of nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) activity by using a NOX1 peptide inhibitor, suggesting that the continuous oxidative stress due to overactivation of NOX1 has a causative role in the underlying pathophysiology. PMID- 25437429 TI - Symmetrical imidazolium chloride based on (-)-menthol: synthesis, characterization, and theoretical model of the reaction. AB - New symmetrical imidazolium chloride from a natural chiral pool of (1R,2S,5R)-(-) menthol can be efficiently prepared by two different methods. The first method involves a specific type of Menschutkin reaction using novel 1-(1R,2S,5R)-(-) menthoxymethylimidazole as amine, chloromethyl (1R,2S,5R)-(-)-menthyl ether as quaternization agent, and hexane as solvent. In the second method, imidazole, chloromethyl (1R,2S,5R)-(-)-menthyl ether, and DMF are used. To understand this specific type of the reaction, quantum chemical calculations at the DFT level have been used. The preparation and characterization of 1,3-bis[(1R,2S,5R)-(-) menthoxymethyl]imidazolium chloride are reported. PMID- 25437427 TI - Partial maintenance and long-term expansion of murine skin epithelial stem cells by Wnt-3a in vitro. AB - CD49f(+)CD34(+) cells, a skin epithelial stem cell (EpSC)-rich population, were prepared from adult mouse skin and cultured in the presence of Wnt-3a without feeder cells. CD34 expression was retained in about 10% of the cells, which had proliferated about 1,000-fold by day 10, although completely lost by day 14. CD49f(+)CD34(+) cells sorted on day 10 retained canonical Wnt-responsiveness, proliferated markedly in the presence of Wnt-3a, maintained undifferentiated epithelial cell marker expression, and promoted hair follicle development in vivo. Those were subjected to a second 10-day culture with Wnt-3a and sorted, and then the same procedures were repeated a total of 15 times. CD49f(+)CD34(+) cells obtained from each of those cultures retained the same EpSC characteristics as the original cells. CD34(+) and CD34(-) cells were found to produce Wnt-3a and Wnt/beta-catenin inhibitors, respectively. CD34(+) cells resided as small cellular clusters surrounded by a large amount of CD34(-) cells. Furthermore, we found that exogenous Wnt-3a delayed the conversion of CD34(+) cells to CD34(-) cells and induced CD34(-) cells to suppress the production of Wnt/beta-catenin inhibitors, likely leading to generation of a microenvironment favorable for maintaining EpSCs. Our results suggest the possibility of partial long-term maintenance of EpSCs in vitro by Wnt-3a. PMID- 25437428 TI - Genetic diversity of Candidatus Liberibacter asiaticus based on two hypervariable effector genes in Thailand. AB - Huanglongbing (HLB), also known as citrus greening, is one of the most destructive diseases of citrus worldwide. HLB is associated with three species of 'Candidatus Liberibacter' with 'Ca. L. asiaticus' (Las) being the most widely distributed around the world, and the only species detected in Thailand. To understand the genetic diversity of Las bacteria in Thailand, we evaluated two closely-related effector genes, lasAI and lasAII, found within the Las prophages from 239 infected citrus and 55 infected psyllid samples collected from different provinces in Thailand. The results indicated that most of the Las-infected samples collected from Thailand contained at least one prophage sequence with 48.29% containing prophage 1 (FP1), 63.26% containing prophage 2 (FP2), and 19.38% containing both prophages. Interestingly, FP2 was found to be the predominant population in Las-infected citrus samples while Las-infected psyllids contained primarily FP1. The multiple banding patterns that resulted from amplification of lasAI imply extensive variation exists within the full and partial repeat sequence while the single band from lasAII indicates a low amount of variation within the repeat sequence. Phylogenetic analysis of Las-infected samples from 22 provinces in Thailand suggested that the bacterial pathogen may have been introduced to Thailand from China and the Philippines. This is the first report evaluating the genetic variation of a large population of Ca. L. asiaticus infected samples in Thailand using the two effector genes from Las prophage regions. PMID- 25437430 TI - Oxygen vacancy induced bismuth oxyiodide with remarkably increased visible-light absorption and superior photocatalytic performance. AB - With the increasingly serious environmental problems, photocatalysis has recently attracted a great deal of attention, with particular focus on water and air purification and disinfection. Herein, we show an electroreduction strategy to improve significantly the solar absorption and donor density of BiOI nanosheet photocatalyst by introducing oxygen vacancies. These oxygen-deficient BiOI nanosheets exhibit an unexpected red shift of about 100 nm in light absorption band and 1 order of magnitude improvement in donor density compared to the untreated BiOI nanosheets and show 10 times higher photocatalytic activity than the untreated BiOI nanosheets for methyl orange (MO) degradation under visible light irradiation. Moreover, the as-prepared oxygen-deficient BiOI nanosheets also have excellent cycling stability and superior photocatalytic performance toward other dye pollutants. PMID- 25437433 TI - Electrochemical determination of low levels of uranyl by a vibrating gold microelectrode. AB - In this work we report the sensitive electroanalytical detection of uranium(VI) in aqueous solutions. Uranium commonly exists in aqueous solutions in the form of its oxo ion, uranyl (U(VI)O2(2+)). The detection of uranyl has been accomplished by us through its deposition upon reduction by two electrons to the insoluble UO2 using a bare disk gold macroelectrode and anodic stripping voltammetry (ASV). This gave an unsatisfactory detection limit of ca. 1 * 10(-5) M uranyl. Moreover, the evolution of hydrogen bubbles blocked the electrode surface as a result of water reduction at negative deposition potential (-0.7 V vs Ag/AgCl). The application of a 25 MUm diameter Au microwire electrode on which UO2 precipitated at negative potential (-1.2 V) improved substantially the detection limit. Further improvement was accomplished by vibrating the microwire working electrode, which increased the amounts of UO2 deposition due to decreasing the diffusion layer. The effect of the vibrating amplitude and frequency on the electroanalytical response was studied and optimized. Eventually, a detection limit of ca. 1 * 10(-9) M uranyl was achieved using a 5 min deposition time, -1.2 V deposition potential, and vibrating the electrode at frequency of 250 Hz and amplitude of 6 V. PMID- 25437431 TI - Regulation of PKM2 and Nrf2-ARE pathway during benzoquinone induced oxidative stress in yolk sac hematopoietic stem cells. AB - Benzene is an occupational toxicant and an environmental pollutant that is able to induce the production of reactive oxygen species (ROS), causing oxidative stress and damages of the macromolecules in target cells, such as the hematopoietic stem cells. We had previously found that embryonic yolk sac hematopoietic stem cells (YS-HSCs) are more sensitive to benzene toxicity than the adult bone marrow hematopoietic stem cells, and that nuclear factor-erythroid 2-related factor 2 (Nrf2) is the major regulator of cytoprotective responses to oxidative stress. In the present report, we investigated the effect of PKM2 and Nrf2-ARE pathway on the cellular antioxidant response to oxidative stress induced by benzene metabolite benzoquinone (BQ) in YS-HSC isolated from embryonic yolk sac and enriched by magnetic-activated cell sorting (MACS). Treatment of the YS HSC with various concentrations of BQ for 6 hours induces ROS generation in a dose-dependent manner. Additional tests showed that BQ is also capable of inducing expression of NADPH oxidase1 (NOX1), and several other antioxidant enzymes or drug-metabolizing enzymes, including heme oxygenase 1 (HMOX1), superoxide dismutase (SOD), catalase and NAD(P)H dehydrogenase quinone 1 (NQO1). Concomitantly, only the expression of PKM2 protein was decreased by the treatment of BQ but not the PKM2 mRNA, which suggested that BQ may induce PKM2 degradation. Pretreatment of the cells with antioxidant N-acetylcysteine (NAC) decreased ROS generation and prevented BQ-induced PKM2 degradation, suggesting involvement of ROS in the PKM2 protein degradation in cellular response to BQ. These findings suggest that BQ is a potent inducer of ROS generation and the subsequent antioxidant responses of the YS-HSC. The accumulated ROS may attenuate the expression of PKM2, a key regulator of the pyruvate metabolism and glycolysis. PMID- 25437434 TI - Geographic accessibility to clinical trials for advanced cancer in the United States. PMID- 25437435 TI - cellPACK: a virtual mesoscope to model and visualize structural systems biology. AB - cellPACK assembles computational models of the biological mesoscale, an intermediate scale (10-100 nm) between molecular and cellular biology scales. cellPACK's modular architecture unites existing and novel packing algorithms to generate, visualize and analyze comprehensive three-dimensional models of complex biological environments that integrate data from multiple experimental systems biology and structural biology sources. cellPACK is available as open-source code, with tools for validation of models and with 'recipes' and models for five biological systems: blood plasma, cytoplasm, synaptic vesicles, HIV and a mycoplasma cell. We have applied cellPACK to model distributions of HIV envelope protein to test several hypotheses for consistency with experimental observations. Biologists, educators and outreach specialists can interact with cellPACK models, develop new recipes and perform packing experiments through scripting and graphical user interfaces at http://cellPACK.org/. PMID- 25437436 TI - Fine-scale chromatin interaction maps reveal the cis-regulatory landscape of human lincRNA genes. AB - High-throughput methods based on chromosome conformation capture have greatly advanced our understanding of the three-dimensional (3D) organization of genomes but are limited in resolution by their reliance on restriction enzymes. Here we describe a method called DNase Hi-C for comprehensively mapping global chromatin contacts. DNase Hi-C uses DNase I for chromatin fragmentation, leading to greatly improved efficiency and resolution over that of Hi-C. Coupling this method with DNA-capture technology provides a high-throughput approach for targeted mapping of fine-scale chromatin architecture. We applied targeted DNase Hi-C to characterize the 3D organization of 998 large intergenic noncoding RNA (lincRNA) promoters in two human cell lines. Our results revealed that expression of lincRNAs is tightly controlled by complex mechanisms involving both super enhancers and the Polycomb repressive complex. Our results provide the first glimpse of the cell type-specific 3D organization of lincRNA genes. PMID- 25437437 TI - MYC is an early response regulator of human adipogenesis in adipose stem cells. AB - Adipose stem cell (ASC) differentiation is necessary for the proper maintenance and function of adipose tissue. The procurement and characterization of multipotent ASCs has enabled investigation into the molecular determinants driving human adipogenesis. Here, the transcription factor MYC was identified as a significant regulator of ASC differentiation. Expression of MYC transcript and protein was found to accumulate during the initial course of differentiation. Loss-of-function analysis using siRNA mediated knockdown of MYC demonstrated inhibition of hormonally stimulated adipogenesis. MYC exhibited an early and sustained expression pattern that preceded down regulation of key suppressor genes, as well as induction of transcriptional and functional effectors. Glucocorticoid stimulation was identified as a necessary component for MYC induction and was found to impact adipogenesis in a concentration-dependent manner. Global gene expression analysis of MYC knockdown in ASC enriched for functional pathways related to cell adhesion, cytoskeletal remodeling, and transcriptional components of adipogenesis. These results identify a functional role for MYC in promotion of multipotent ASC to the adipogenic lineage. PMID- 25437438 TI - The Rapalogue, CCI-779, improves salivary gland function following radiation. AB - The standard of care for head and neck cancer typically includes surgical resection of the tumor followed by targeted head and neck radiation. However depending on tumor location and stage, some cases may not require surgical resection while others may be treated with chemoradiation. Unfortunately, these radiation treatments cause chronic negative side effects for patients. These side effects are associated with damage to surrounding normal salivary gland tissue and include xerostomia, changes in taste and malnutrition. The underlying mechanisms of chronic radiation-induced salivary gland dysfunction are unknown, however, in rodent models persistently elevated proliferation is correlated with reduced stimulated salivary flow. The rapalogue, CCI-779, has been used in other cell systems to induce autophagy and reduce proliferation, therefore the aim of this study was to determine if CCI-779 could be utilized to ameliorate chronic radiation-induced salivary gland dysfunction. Four to six week old Atg5f/f; Aqp5 Cre, Atg5+/+; Aqp5-Cre and FVB mice were treated with targeted head and neck radiation. FVB mice were treated with CCI-779, chloroquine, or DMSO post radiation. Stimulated salivary flow rates were determined and parotid and submandibular salivary gland tissues were collected for analyses. Mice with a defect in autophagy, via a conditional knockout of Atg5 in the salivary glands, display increased compensatory proliferation in the acinar cell compartment and hypertrophy at 24-72 hours following radiation. FVB mice treated with post therapy CCI-779 have significant improvements in salivary gland physiology as determined by stimulated salivary flow rates, proliferation indices and amylase production and secretion. Consequently, post-radiation use of CCI-779 allows for improvement of salivary gland function and reestablishment of glandular homeostasis. As CCI-779 is already FDA approved for other uses, it could have a secondary use to alleviate the chronic side effects in head and neck cancer patients who have completed anti-tumor therapy. PMID- 25437440 TI - Stepping up ELISpot: Multi-Level Analysis in FluoroSpot Assays. AB - ELISpot is one of the most commonly used immune monitoring assays, which allows the functional assessment of the immune system at the single cell level. With its outstanding sensitivity and ease of performance, the assay has recently advanced from the mere single function cell analysis to multifunctional analysis by implementing detection reagents that are labeled with fluorophores (FluoroSpot), allowing the detection of secretion patterns of two or more analytes in a single well. However, the automated evaluation of such assays presents various challenges for image analysis. Here we dissect the technical and methodological requirements for a reliable analysis of FluoroSpot assays, introduce important quality control measures and provide advice for proper interpretation of results obtained by automated imaging systems. PMID- 25437439 TI - Natural and Synthetic Modulators of the TRPM7 Channel. AB - Transient receptor potential cation channel subfamily M member 7 (TRPM7) is a bi functional protein comprising a TRP ion channel segment linked to an alpha-type protein kinase domain. Genetic inactivation of TRPM7 revealed its central role in magnesium metabolism, cell motility, proliferation and differentiation. TRPM7 is associated with anoxic neuronal death, cardiac fibrosis and tumor progression highlighting TRPM7 as a new drug target. Recently, several laboratories have independently identified pharmacological compounds inhibiting or activating the TRPM7 channel. The recently found TRPM7 modulators were used as new experimental tools to unravel cellular functions of the TRPM7 channel. Here, we provide a concise overview of this emerging field. PMID- 25437441 TI - Triple Cytokine FluoroSpot Analysis of Human Antigen-Specific IFN-gamma, IL-17A and IL-22 Responses. AB - The involvement of T-helper (Th)1, Th17 and Th22 cell subsets, in immunity, as well as in pathological inflammatory reactions, makes it important to determine their relative proportion. A triple FluoroSpot detecting the hallmark cytokines of Th1 (IFN-gamma), Th17 (IL-17A) and Th22 (IL-22) was developed and evaluated using human peripheral blood mononuclear cells from healthy donors incubated with tetanus toxoid, Candida albicans extract, mycobacterial purified protein derivative or medium only. Antigen stimulation yielded mainly cells secreting IFN gamma, IL-17A or IL-22 alone but lower proportions of double-secreting cells were also found; triple-secreting cells were rare. The response to C. albicans contrasted in that higher proportions of IL-17A single secreting as well as co secreting cells, in particular IL-17A/IL-22, were found. The FluoroSpot analysis correlated well with single cytokine ELISpot assays ran in parallel and the methods displayed a comparable sensitivity. The results demonstrate the functionality of the FluoroSpot assay for simultaneous analysis of distinct Th1, Th17, Th22 as well as intermediate cell populations. The method provides a mean for a simple and rapid analysis of the involvement of these cells in immunity and disease. PMID- 25437443 TI - Post-annealing reinforced hollow carbon nitride nanospheres for hydrogen photosynthesis. AB - Hollow-structured g-C3N4 polymers with a high thermal stability up to 550 degrees C and an enhanced photocatalytic activity have been developed by post annealing treatment, which effectively modifies the textural, crystal, and electronic properties of the g-C3N4 semiconductors without extra chemical assistance. This is a unique example of thermally and chemically stable conjugated polymers with hollow nanostructures and optoelectronic properties, promising the development of functional hollow g-C3N4 nanocomposites by chemical modifications like doping, surface grafting, and coupling with other inorganic/polymeric semiconductors with the aid of thermal treatment at high temperatures. PMID- 25437442 TI - Comparison of a novel computerized analysis program and visual interpretation of cardiotocography. AB - OBJECTIVE: To compare a novel computerized analysis program with visual cardiotocography (CTG) interpretation results. METHODS: Sixty-two intrapartum CTG tracings with 20- to 30-minute sections were independently interpreted using a novel computerized analysis program, as well as the visual interpretations of eight obstetricians, to evaluate the baseline fetal heart rate (FHR), baseline FHR variability, number of accelerations, number/type of decelerations, uterine contraction (UC) frequency, and the National Institute of Child Health and Human Development (NICHD) 3-Tier FHR classification system. RESULTS: There was no significant difference in interobserver variation after adding the components of computerized analysis to results from the obstetricians' visual interpretations, with excellent agreement for the baseline FHR (ICC 0.91), the number of accelerations (ICC 0.85), UC frequency (ICC 0.97), and NICHD category I (kappa statistic 0.91); good agreement for baseline variability (kappa statistic 0.68), the numbers of early decelerations (ICC 0.78) and late decelerations (ICC 0.67), category II (kappa statistic 0.78), and overall categories (kappa statistic 0.80); and moderate agreement for the number of variable decelerations (ICC 0.60), and category III (kappa statistic 0.50). CONCLUSIONS: This computerized analysis program is not inferior to visual interpretation, may improve interobserver variations, and could play a vital role in prenatal telemedicine. PMID- 25437444 TI - MSTN, mTOR and FoxO4 are involved in the enhancement of breast muscle growth by methionine in broilers with lower hatching weight. AB - Broilers with lower hatching weight (HW) present poorer performance than those with high HW, but there is limited research on the growth regulation of broilers with lower HW. The objective of this study was to investigate the effect of dietary methionine (Met) levels on the growth performance and breast muscle yield of broilers with different HW and underlying mechanisms. A total of 192 one-day old Arbor Acres broiler chicks with different HW (heavy: 48.3+/-0.1 g, and light: 41.7+/-0.1 g) were allocated to a 2*2 factorial arrangement with 6 replicates of 8 chicks per replicate cage. Control starter (1-21 d) and finisher (22-42 d) diets were formulated to contain 0.50% and 0.43% Met, respectively. Corresponding values for a high Met treatment were 0.60% and 0.53%. Light chicks had lower body weight gain (BWG) and breast muscle yield than heavy chicks when the broilers were fed the control diets. High Met diets improved BWG, gain to feed ratio and breast muscle yield in light but not heavy chicks. Decreased DNA content and increased RNA/DNA and protein/DNA ratios in breast muscle were induced by high Met diets only in light chicks. MSTN mRNA level was decreased by high Met diets only in light chicks, and this decrease was accompanied by a significant increase in MSTN gene exon 1 methylation. In addition, high Met diets increased mTOR phosphorylation, but decreased FoxO4 phosphorylation in breast muscle of light chicks. In conclusion, the BWG and breast muscle yield of light chicks were improved by increasing dietary Met levels probably through alterations of MSTN transcription and phosphorylation of mTOR and FoxO4. PMID- 25437445 TI - Generation of recombination activating gene-1-deficient neonatal piglets: a model of T and B cell deficient severe combined immune deficiency. AB - Although severe combined immune deficiency (SCID) is a very important research model for mice and SCID mice are widely used, there are only few reports describing the SCID pig models. Therefore, additional research in this area is needed. In this study, we describe the generation of Recombination activating gene-1 (Rag-1)-deficient neonatal piglets in Duroc breed using somatic cell nuclear transfer (SCNT) with gene targeting and analysis using fluorescence activated cell sorting (FACS) and histology. We constructed porcine Rag-1 gene targeting vectors for the Exon 2 region and obtained heterozygous/homozygous Rag 1 knockout cell colonies using SCNT. We generated two Rag-1-deficient neonatal piglets and compared them with wild-type neonatal piglets. FACS analysis showed that Rag-1 disruption causes a lack of Immunoglobulin M-positive B cells and CD3 positive T cells in peripheral blood mononuclear cells. Consistent with FACS analysis, histological analysis revealed structural defects and an absence of mature lymphocytes in the spleen, mesenteric lymph node (MLNs), and thymus in Rag 1-deficient piglets. These results confirm that Rag-1 is necessary for the generation of lymphocytes in pigs, and Rag-1-deficient piglets exhibit a T and B cell deficient SCID (T-B-SCID) phenotype similar to that of rodents and humans. The T-B-SCID pigs with Rag-1 deficiency generated in this study could be a suitably versatile model for laboratory, translational, and biomedical research, including the development of a humanized model and assessment of pluripotent stem cells. PMID- 25437446 TI - Characterization of an acidic chitinase from seeds of black soybean (Glycine max (L) Merr Tainan No. 3). AB - Using 4-methylumbelliferyl-beta-D-N,N',N"-triacetylchitotrioside (4-MU-GlcNAc3) as a substrate, an acidic chitinase was purified from seeds of black soybean (Glycine max Tainan no. 3) by ammonium sulfate fractionation and three successive steps of column chromatography. The purified chitinase was a monomeric enzyme with molecular mass of 20.1 kDa and isoelectric point of 4.34. The enzyme catalyzed the hydrolysis of synthetic substrates p-nitrophenyl N-acetyl chitooligosaccharides with chain length from 3 to 5 (GlcNAcn, n = 3-5), and pNp GlcNAc4 was the most degradable substrate. Using pNp-GlcNAc4 as a substrate, the optimal pH for the enzyme reaction was 4.0; kinetic parameters Km and kcat were 245 uM and 10.31 min-1, respectively. This enzyme also showed activity toward CM chitin-RBV, a polymer form of chitin, and N-acetyl chitooligosaccharides, an oligomer form of chitin. The smallest oligomer substrate was an N acetylglucosamine tetramer. These results suggested that this enzyme was an endo splitting chitinase with short substrate cleavage activity and useful for biotechnological applications, in particular for the production of N-acetyl chitooligosaccharides. PMID- 25437448 TI - The resistance of a North American bat species (Eptesicus fuscus) to White-nose Syndrome (WNS). AB - White-nose Syndrome (WNS) is the primary cause of over-winter mortality for little brown (Myotis lucifugus), northern (Myotis septentrionalis), and tricolored (Perimyotis subflavus) bats, and is due to cutaneous infection with the fungus Pseudogymnoascus (Geomyces) destructans (Pd). Cutaneous infection with P. destructans disrupts torpor patterns, which is thought to lead to a premature depletion of body fat reserve. Field studies were conducted at 3 WNS-affected hibernation sites to determine if big brown bats (Eptesicus fuscus) are resistant to Pd. Radio telemetry studies were conducted during 2 winters to determine the torpor patterns of 23 free-ranging E. fuscus hibernating at a site where Pd occurs. The body fat contents of free-ranging E. fuscus and M. lucifugus during hibernation at 2 different WNS-affected sites were also determined. The numbers of bats hibernating at the same site was determined during both: a) 4-7 years prior to the arrival of Pd, and, b) 2-3 years after it first appeared at this site. The torpor bouts of big brown bats hibernating at a WNS-affected site were not significantly different in length from those previously reported for this species. The mean body fat content of E. fuscus in February was nearly twice that of M. lucifugus hibernating at the same WNS-affected sites during this month. The number of M. lucifugus hibernating at one site decreased by 99.6% after P. destructans first appeared, whereas the number of E. fuscus hibernating there actually increased by 43% during the same period. None of the E. fuscus collected during this study had any visible fungal growth or lesions on their skin, whereas virtually all the M. lucifugus collected had visible fungal growth on their wings, muzzle, and ears. These findings indicate that big brown bats are resistant to WNS. PMID- 25437447 TI - Apical localization of inositol 1,4,5-trisphosphate receptors is independent of extended synaptotagmins in hepatocytes. AB - Extended synaptotagmins (E-Syts) are a recently identified family of proteins that tether the endoplasmic reticulum (ER) to the plasma membrane (PM) in part by conferring regulation of cytosolic calcium (Ca2+) at these contact sites (Cell, 2013). However, the mechanism by which E-Syts link this tethering to Ca2+ signaling is unknown. Ca2+ waves in polarized epithelia are initiated by inositol 1,4,5-trisphosphate receptors (InsP3Rs), and these waves begin in the apical region because InsP3Rs are targeted to the ER adjacent to the apical membrane. In this study we investigated whether E-Syts are responsible for this targeting. Primary rat hepatocytes were used as a model system, because a single InsP3R isoform (InsP3R-II) is tethered to the peri-apical ER in these cells. Additionally, it has been established in hepatocytes that the apical localization of InsP3Rs is responsible for Ca2+ waves and secretion and is disrupted in disease states in which secretion is impaired. We found that rat hepatocytes express two of the three identified E-Syts (E-Syt1 and E-Syt2). Individual or simultaneous siRNA knockdown of these proteins did not alter InsP3R-II expression levels, apical localization or average InsP3R-II cluster size. Moreover, apical secretion of the organic anion 5-chloromethylfluorescein diacetate (CMFDA) was not changed in cells lacking E-Syts but was reduced in cells in which cytosolic Ca2+ was buffered. These data provide evidence that E-Syts do not participate in the targeting of InsP3Rs to the apical region. Identifying tethers that bring InsP3Rs to the apical region remains an important question, since mis-targeting of InsP3Rs leads to impaired secretory activity. PMID- 25437449 TI - Adsorption of uranyl on hydroxylated alpha-SiO2(001): a first-principle study. AB - The adsorption of [UO2(H2O)5](2+) on a hydroxylated alpha-SiO2(001) surface was studied by periodic density functional theory (DFT) and ab initio molecular dynamics (AIMD) simulation. The effects of pH, CO2, aqua solution and anionic ligands (OH(-), NO3(-) and Cl(-)) on the adsorption geometry and stability were investigated. The results show that the adsorption of uranyl on a hydroxylated alpha-SiO2(001) surface leads to the formation of inner-sphere complexes, in which the bidentate complex at the double deprotonated site is most favored. The binding strengths of bidentate and monodentate complexes at the same site are similar, and they become weaker as the number of protons increases at the adsorption site, indicating an enhancement of the adsorption strength at higher pH values within a certain range. Strong chemical interaction plays an important role in all inner-sphere complexes. The hydrogen bonds are formed between uranyl and the hydroxylated surface in all inner- and outer-sphere complexes. The presence of CO2 weakens the adsorption of uranyl on the surface by forming uranyl carbonate (CO3(2-), HCO3(-)) complexes. The effect of the anion ligands depends on their charged state and their concentration in solutions. The explicit treatment of water environment in the models has a slight effect on the adsorption configuration. These results are consistent with the experimental observations. PMID- 25437450 TI - Non-infectious aortitis: a report of 32 cases from a single tertiary centre in a 4-year period and literature review. AB - OBJECTIVES: Non-infectious aortitis often presents with non-specific symptoms leading to inappropriate diagnostic delay. We intend to describe the clinical spectrum and outcome of patients with aortitis diagnosed at a single centre. METHODS: We reviewed the clinical charts of patients diagnosed with non infectious aortitis between January 2010 and December 2013 at the Rheumatology Division from a 1.000-bed tertiary teaching hospital from Northern Spain. The diagnosis of aortitis was usually based on FDG-PET-CT scan, and also occasionally on CT or MRI angiography or helical CT-scan. RESULTS: During the period of assessment 32 patients (22 women and 10 men; mean age 68 years [range, 45-87]) were diagnosed with aortitis. The median interval from the onset of symptoms to the diagnosis was 21 months. FDG-PET CT scan was the most common tool used for the diagnosis of aortitis. The underlying conditions were the following: giant cell arteritis (n=13 cases); isolated polymyalgia rheumatica (PMR) (n=11); Sjogren's syndrome (n=2), Takayasu arteritis (n= 1); sarcoidosis (n=1), ulcerative colitis (n=1), psoriatic arthritis (n=1), and large-vessel vasculitis that also involved the aorta (n=2). The most common clinical manifestations at diagnosis were: PMR features, often with atypical clinical presentation (n=23 patients, 72%); diffuse lower limb pain (n=16 patients, 50%); constitutional symptoms (n=12 patients, 37%), inflammatory low back pain (n=9 patients, 28%) and fever (n=7 patients, 22%). Acute phase reactants were increased in most cases (median erythrocyte sedimentation rate 46 mm/1st hour, and a median serum C reactive protein 1.5 mg/dL). CONCLUSIONS: Aortitis is not an uncommon condition. The diagnosis is often delayed. Atypical PMR features, unexplained low back or limb pain, constitutional symptoms along with increased acute phase reactants should be considered 'red flags' to suspect the presence of aortitis. PMID- 25437452 TI - Effect of early postmortem enhancement of calcium lactate/phosphate on quality attributes of beef round muscles under different packaging systems. AB - The objective was to determine the influence of calcium lactate/phosphate enhancement on quality of beef round cuts in high-oxygen modified atmosphere (HiOx-MAP; 80% O2/20% CO2). Mm. semimembranosus (SM), semitendinosus (ST), and adductor (AD) were divided and assigned to water-injected control (CON), 3mM phosphate (STP), or 200mM calcium lactate/3mM phosphate (CAL/STP) treatments at 24h postmortem. Steaks (n=10) were vacuum packaged (VAC) and stored for 9days, then displayed for 7days in VAC or HiOx-MAP. Lipid oxidation, pH, surface color, star probe, and sensory characteristics were evaluated. HiOx-MAP resulted in greater lipid oxidation, more discoloration, and decreased sensory quality of steaks (P<0.05) compared to VAC. However, CAL/STP enhancement significantly reduced lipid oxidation of all steaks, decreased ST and SM star probe values, and improved tenderness of HiOx-MAP packaged AD and SM (P<0.05). Results suggest that CAL/STP enhancement has beneficial effects on lipid stability and sensory attributes of beef round cuts under HiOx-MAP. PMID- 25437451 TI - Effect of feeding diets containing barley, wheat and corn distillers dried grains with solubles on carcass traits and meat quality in growing rabbits. AB - The effect of dietary inclusion of distillers dried grains with solubles (DDGS) on carcass and meat quality of longissimus muscle was studied in 100 growing rabbits from 28 to 59days old. Diets with no DDGS (C), barley (Db20), wheat (Dw20) and corn (Dc20) DDGS at 20% and corn (Dc40) DDGS at 40% were formulated. No effects on most of the carcass traits, texture and water holding capacity were found. Barley and corn DDGS led to a higher dissectible fat percentage. Meat redness was higher with Dw20 and pH was higher with Dw20 and Db20 than with Dc20. Protein and saturated fatty acids concentration declined as corn DDGS level increased. Dc40 led to the lowest saturated/unsaturated fatty acid ratio, atherogenic index and thrombogenic index. In conclusion, dietary inclusion of these DDGS at 20% did not affect most of the carcass and meat quality traits in rabbits. PMID- 25437453 TI - Ripening of salami: assessment of colour and aspect evolution using image analysis and multivariate image analysis. AB - During ripening of salami, colour changes occur due to oxidation phenomena involving myoglobin. Moreover, shrinkage due to dehydration results in aspect modifications, mainly ascribable to fat aggregation. The aim of this work was the application of image analysis (IA) and multivariate image analysis (MIA) techniques to the study of colour and aspect changes occurring in salami during ripening. IA results showed that red, green, blue, and intensity parameters decreased due to the development of a global darker colour, while Heterogeneity increased due to fat aggregation. By applying MIA, different salami slice areas corresponding to fat and three different degrees of oxidised meat were identified and quantified. It was thus possible to study the trend of these different areas as a function of ripening, making objective an evaluation usually performed by subjective visual inspection. PMID- 25437454 TI - Do differences in chemical composition of stem and cap of Amanita muscaria fruiting bodies correlate with topsoil type? AB - Fly agaric (Amanita muscaria) was investigated using a 1H NMR-based metabolomics approach. The caps and stems were studied separately, revealing different metabolic compositions. Additionally, multivariate data analyses of the fungal basidiomata and the type of soil were performed. Compared to the stems, A. muscaria caps exhibited higher concentrations of isoleucine, leucine, valine, alanine, aspartate, asparagine, threonine, lipids (mainly free fatty acids), choline, glycerophosphocholine (GPC), acetate, adenosine, uridine, 4 aminobutyrate, 6-hydroxynicotinate, quinolinate, UDP-carbohydrate and glycerol. Conversely, they exhibited lower concentrations of formate, fumarate, trehalose, alpha- and beta-glucose. Six metabolites, malate, succinate, gluconate, N acetylated compounds (NAC), tyrosine and phenylalanine, were detected in whole A. muscaria fruiting bodies but did not show significant differences in their levels between caps and stems (P value>0.05 and/or OPLS-DA loading correlation coefficient <0.4). This methodology allowed for the differentiation between the fruiting bodies of A. muscaria from mineral and mineral-organic topsoil. Moreover, the metabolomic approach and multivariate tools enabled to ascribe the basidiomata of fly agaric to the type of topsoil. Obtained results revealed that stems metabolome is more dependent on the topsoil type than caps. The correlation between metabolites and topsoil contents together with its properties exhibited mutual dependences. PMID- 25437455 TI - Plasma and liver metabolic profiles in mice subjected to subchronic and mild social defeat stress. AB - To improve the quality of life of animals, understanding of stress-induced changes is necessary. Previously, we established a subchronic and mild social defeat stress (sCSDS) model in mice, which showed significantly higher body weight gain, food intake, and water intake compared to control mice. In this study, we elucidated metabolic profiles of plasma, liver, and urine in sCSDS mice by using metabolome and biochemical analyses. There was no significant difference between defeated and control mice in the plasma metabolites. In the liver of sCSDS mice, levels of taurocyamine (GES), phosphorylcholine, D-alanyl-D-alanine (D-ala-D-ala), and 1-methylnicotinamide (MNA) were elevated compared to controls. Taurine plays a role in osmotic regulation, and GES is a potential inhibitor of the taurine transporter. The polydipsia and increased body water content in sCSDS mice may disrupt body fluid balance following GES elevation. Furthermore, sCSDS increased heart and spleen weight significantly. Because MNA and D-ala-D-ala have anti-inflammatory and hepatoprotective effects, they may reduce inflammation in the liver of sCSDS mice. Finally, suppressed excretion of urine sodium was observed in sCSDS mice. Therefore, sCSDS induces various changes in metabolite concentrations, especially related to osmoregulation and inflammation, that may be used as biomarkers for stress-induced changes in animals. PMID- 25437456 TI - Cytokines induce protein kinase A-mediated signalling by a redox-dependent mechanism in rat renal mesangial cells. AB - Glomerular mesangial cells are smooth muscle cell-like pericytes and are regarded as key players in kidney diseases. In an inflammatory setting, these cells produce high amounts of inflammatory cytokines, chemokines and redox mediators such as reactive oxygen species or nitric oxide (NO). The temporal production of ROS, NO and other redox mediators markedly contributes to the final outcome of inflammatory diseases. Recently, we reported that platelet-derived growth factor forced mesangial cells to activate the regulatory subunit of protein kinase A (PKA RI) by a redox-dependent mechanism but independent from changes in cyclic AMP. This prompted us to further analyze the dimerization of PKA RI and activation of PKA-driven signalling in an inflammatory context. Stimulation of rat mesangial cells with interleukin-1beta and tumour necrosis factor-alpha [2 nM] induced the formation of PKA RI heterodimers in a time-dependent manner. PKA RI dimerization was accompanied with the formation of ROS, NO and peroxynitrite as well as a depletion of reduced glutathione. Furthermore, dimerization of PKA RI was paralleled by enhanced activity of PKA as shown by the phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at serine 157 that was independent of the formation of cyclic AMP. Remarkably, exogenously administered peroxynitrite potently induced dimerization of PKA RI, whereas pharmacologic inhibition of inducible NO synthase (iNOS) and scavenging of peroxynitrite reduced PKA RI dimerization and VASP phosphorylation to control levels thus clearly indicating a causal role for endogenously formed peroxynitrite on PKA signalling. Consequently, the treatment of inflammatory diseases with anti oxidants or NOS inhibitors may alter PKA activity. PMID- 25437457 TI - [GLP-1 receptor agonists: an effective wide-spectrum therapeutic approach in the treatment of type 2 diabetes mellitus]. PMID- 25437458 TI - [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus]. AB - The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes. PMID- 25437459 TI - [Modulation of the incretin effect in the treatment of diabetes]. AB - Modulation of the incretin effect has opened up a new strategy in the treatment of diabetes mellitus type 2 (DM2). To date, this physiological mechanism has been boosted in two ways: firstly, by pharmacological inhibition of the enzyme that physiologically degrades glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP4); secondly, through the development of GLP-1 agonists (GLP-1a) that are resistant to the action of DPP-4. Several clinical trials have shown the clinical superiority of GLPa, which seems to be linked to higher circulating levels of GLP-1. On the other hand, this higher efficacy also seems to be associated with the higher rate of adverse effects associated with aGLP-1 therapy compared with DPP-4 inhibition. These and other differentiating characteristics of the two drug families will determine the choice of drug therapy in the personalized treatment of hyperglycemia in patients with DM2. PMID- 25437460 TI - [Characteristics and types of GLP-1 receptor agonists. An opportunity for individualized therapy]. AB - Glucagon-like peptide 1 (GLP-1) is secreted from enteroendocrine L-cells in response to oral nutrient intake and elicits glucose-stimulated insulin secretion while suppressing glucagon secretion. Moreover slows gastric emptying -reducing postprandial glycemic excursions-, reduces body weight, systolic blood pressure and has beneficial effects in the cardiovascular and central nervous systems. Since the 1990s, the efficacy of GLP-1 in reducing blood glucose levels in type 2 diabetes (DM2) was well known. However, GLP-1 should be administered by chronic subcutaneous infusion because of the rapid cleavage by the enzyme dipeptidyl peptidase 4 (DPP-4). Hence, DPP-4 inhibitors -which increase pseudo physiologically endogenous GLP-1 levels- were developed. In addition, several GLP 1 receptor agonists have been designed to avoid DPP-4-breakdown and/or rapid renal elimination and, therefore, induce a pharmacologic effect in the GLP-1 receptor: short-acting, long-acting, and prolonged-acting GLP-1 analogs. Each class has different structural, pharmacodynamic and clinical properties and could be administered in different therapeutical regimens giving us the opportunity to individualize the therapy of DM2. PMID- 25437461 TI - [Effects of GLP-1 receptor agonists on carbohydrate metabolism control]. AB - Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. PMID- 25437462 TI - [Twice-daily and weekly exenatide: clinical profile of two pioneer formulations in incretin therapy]. AB - GLP-1 receptors agonists have been a substantial change in treatment of type 2 diabetes mellitus, and its weekly administration has broken pre-established schemes. Daily exenatide is administered every 12 hours (BID) subcutaneously, while weekly exenatide is administered once a week. Both molecules share a common mechanism of action but have differential effects on basal and postprandial glucose. We review the major clinical trials with both exenatide BID and weekly exenatide. It can be concluded that exenatide BID shows a hypoglycemic effect similar to other treatments for type 2 DM but adding significant weight loss with low incidence of hypoglycemia. Weekly exenatide decreases HbA1c similar to liraglutide but larger than exenatide BID, both glargine and biphasic insulin, sitagliptin, and pioglitazone, maintaining weight loss and adding to gastrointestinal intolerance the induration at the injection site as a side effect. PMID- 25437463 TI - [Extrapancreatic effects of GLP-1 receptor agonists: an open window towards new treatment goals in type 2 diabetes]. AB - The wide ubiquity of GLP-1 receptors in the body has stimulated the search for different extrapancreatic actions of GLP-1 and its receptor agonists. Thus, severe cardioprotective effects directed on myocardial ischaemia and dysfunction as well as diverse antiaterogenic actions have been reported. Also, native and GLP-1 receptor agonists have demonstrated significant beneficial effects on liver steatosis and fibrosis and on neuronal protection in experimental models of Alzheimer, and Parkinson's disease as well as on cerebral ischaemia. Recent evidences suggest that these drugs may also be useful for prevention and treatment of diabetic retinopathy, nephropathy and peripheral neuropathy. Good results have also been reported in psoriasis. Despite we still need confirmation that these promising effects can be applied to clinical practice, they offer new interesting perspectives for treatment of type 2 diabetes associated complications and give to GLP-1 receptor agonists an even more integral position in diabetes therapy. PMID- 25437464 TI - [Safety and tolerability of GLP-1 receptor agonists]. AB - Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer. PMID- 25437465 TI - [Unmet needs in the treatment of type 2 diabetes]. AB - Type 2 diabetes represents one of the most important health problems, provided due to its high prevalence and significant morbi-mortality. At present time, we know that an intensive control of all cardiovascular risk factors from the beginning prevents the appearance and progression of micro and macrovascular complications. Nevertheless, only few patients achieve the degree of metabolic control recommended by diabetes therapeutic guidelines. This is due to different reasons such as lack of patients compliance and therapeutic inertia by doctors. Also, the available therapeutic approaches are limited. We still do not have the ideal antidiabetic drug, which should be able to be used in all phases of the disease, have sustained durability, be well tolerated not inducing hypoglycaemia, and promote weight loss, cardiovascular protection and reducing morbi-mortality at a low cost. The launching of new drugs with attractive mechanisms of action and few side effects may help to achieve these goals, though we still should wait for the results of studies demonstrating their effect on cardiovascular endpoints. PMID- 25437466 TI - Bioaccessibility of antimony and arsenic in highly polluted soils of the mine area and health risk assessment associated with oral ingestion exposure. AB - In this study, the bioaccessibility and the human health risks of Sb and As in soils from Xikuangshan (XKS) Sb mine, Hunan, China were investigated using two commonly used in vitro extraction methods, Simplified Bioaccessibility Extraction Test (SBET) and Physiologically Based Extraction Test (PBET). Soils in the XKS Sb mine area were mainly co-contaminated by Sb (74.2-16,389; mean: 3061mgkg(-1)) and As (7.40-596; mean: 216mgkg(-1)). The bioaccessibility values of Sb and As in most cases were less than 30%, and the average bioaccessibility values of Sb and As were 5.89+/-6.44% and 2.13+/-2.55% for the SBET extraction; 7.83+/-9.82% and 6.62+/-6.37% for the PBET (Gastric) extraction; and 3.03+/-3.53% and 2.40+/-2.01% for the PBET (Intestinal) extraction, respectively. The bioaccessible Sb and As were significantly positively correlated with the total concentrations, but negatively correlated with the Fe, Al, Mn and organic matter (OM) contents in soils. Risk assessment results based on total concentrations might overestimate the risk existing in the studied area. After considering the bioaccessibility, the Hazard Quotient (HQ) values of Sb for most of the sampling sites and of As for all of the sampling sites became lower than 1. The Carcinogenic Risk (CR) values of As were also significantly reduced, 8.77E-06 and 1.74E-05 on average for the SBET and PBET methods, respectively. Considering the bioaccessibility can provide more applicable guidelines for risk assessments and more rational suggestions in the management of the soils contaminated with Sb and As. PMID- 25437467 TI - Sleep on it: sleep might just be the most important part of daily health--and the biggest new target for biomedical engineering. PMID- 25437468 TI - How's my sleep?: Personal sleep trackers are gaining in popularity, but their accuracy is still open to debate. AB - When it comes to health and fitness, there's an app for just about everything. Want to track how many steps you've taken today? There's an app for that. Want to track the calories you've consumed? There's an app for that, too. And, if you want to know if you got a good night's sleep last night, well, now there's also an app for that. PMID- 25437469 TI - Out of touch : from audio recordings to phone apps to mattress sensors, noncontact systems offer a less cumbersome way to monitor sleep. AB - The impact of poor and disrupted sleep on an individual is significant, affecting the quality of life physiologically, psychologically, and financially. It is estimated that a large population of people who suffer from sleep disorders is unaware of the condition and remains undiagnosed [1], creating a need (and desire) to self-monitor. However, sleep screening is generally cumbersome and complex, requiring multiple wearable sensors (and associated wires) and experts to interpret the large volumes of data. PMID- 25437470 TI - Wireless sleep measurement: sensing sleep and breathing patterns using radio frequency sensors. AB - Despite the fact that we spend nearly one third of our lives asleep, surprisingly little was known about sleep until the 20th century. Now, sleep medicine is firmly established as a significant branch of medical practice, taking its roots strongly from the work of Nathaniel Kleitman and colleagues at the University of Chicago in the 1950s. They were the first to show the existence of rapid eye movement (REM) sleep?commonly associated with ?dreaming?and began the process of opening our eyes to the complex physiological processes that occur during sleep. PMID- 25437471 TI - Polysomnography: understanding this technology's past might guide future developments. AB - Hans Berger published the first human electroencephalograph (EEG) recording in 1924 [1]. He used a device called the string galvanometer to record brain waves on a light-sensitive plate. The fluctuating potential difference from the scalp oscillated at eight to 13 cycles per second (alpha rhythm) when an individual closed his or her eyes and remained relaxed but awake. Berger noted that when a person fell asleep, the alpha rhythm disappeared. Amazingly, to this day, the alpha rhythm disappearance remains the primary marker for defining sleep onset. Years later, Carl Ludwig invented a kymograph (the ?wave writer?) that used a stylus to record electroencephalographic oscillation on a rotating drum. Later, an alternative approach evolved so that the brain wave recordings were inked onto a roll or fan-folded continuous paper strip moving at a constant speed. Mechanical engineers gradually improved the drive mechanisms for moving paper by using rotating sprockets, pinch rollers, and pressure plates. Gear mechanisms were also incorporated to permit speed changes. PMID- 25437472 TI - Engineering sleep disorders: from classical CPAP devices toward new intelligent adaptive ventilatory therapy. AB - Among the most common sleep disorders are those related to disruptions in airflow (apnea) or reductions in the breath amplitude (hypopnea) with or without obstruction of the upper airway (UA). One of the most important sleep disorders is obstructive sleep apnea (OSA). This sleep-?disordered breathing, quantified by the apnea??hypopnea index (AHI), can produce a significant reduction of oxygen saturation and an abnormal elevation of carbon dioxide levels in the blood. Apnea and hypopnea episodes are associated with arousals and sleep fragmentation during the night and compensatory response of the autonomic nervous system. PMID- 25437473 TI - Pediatric sleep-related breathing disorders: advances in imaging and computational modeling. AB - We understand now that sleep of sufficient length and quality is required for good health. This is particularly true for infants and children, who have the added physiologic task of growth and development, as compared to their adult counterparts. Sleep-related breathing disorders (SRBDs) are common in childhood and if unrecognized and not treated can result in significant morbidity. For example, children with obstructive sleep apnea (OSA) can exhibit behavioral, mood, and learning difficulties. If left untreated, alterations in the function of the autonomic nervous system and a chronic inflammatory state result, contributing to the risk of heart disease, stroke, glucose intolerance, and hypertension in adulthood. PMID- 25437474 TI - Data-driven phenotyping : graphical models for model-based phenotyping of sleep apnea. AB - Sleep apnea is a multifactorial disease with a complex underlying physiology, which includes the chemoreflex feedback loop controlling ventilation. The instability of this feedback loop is one of the key factors contributing to a number of sleep disorders, including Cheyne?Stokes respiration and obstructive sleep apnea (OSA). A major limitation of the conventional characterization of this feedback loop is the need for labor-intensive and technically challenging experiments. In recent years, a number of techniques that bring together concepts from signal processing, control theory, and machine learning have proven effective for estimating the overall loop gain of the respiratory control system (see Figure 1) and its major components, chemoreflex gain and plant gain, from noninvasive time-series measurements of ventilation and blood gases. The purpose of this article is to review the existing model-based techniques for phenotyping of sleep apnea, and some of the emerging methodologies, under a unified modeling framework known as graphical models. The hope is that the graphical model perspective provides insight into the future development of techniques for model based phenotyping. Ultimately, such approaches have major clinical relevance since strategies to manipulate physiological parameters may improve sleep apnea severity. For example, oxygen therapy or drugs such as acetazolamide may be used to reduce chemoreflex gain, which may improve sleep apnea in selected patients. PMID- 25437475 TI - Strange musical rhythms. AB - Music, along with its attached rhythm, has been with man for centuries, developing and evolving along with him. Its influence on human behavior and mood can reach levels whose limits are still unknown, especially in everything related to perception, where the whole nervous system is involved. Thus, physiology and psychology become strongly connected areas, while technology, through, for example, the production of music by electronic means, appears as a new unexpected ingredient that traditional composers and musicians of older times could not imagine. Obviously, bioengineering and its multiple branches are not absent either [1]?[4]. The literature is enormous with several specialized journals. When one looks back in time at the evolution of this complex area, the appearance of some kind of sudden jump (as a step function), which took place within a relatively recent short interval, is evident: music is now much more than what it used to be, and rhythm has made a step forward as if resurrecting and renewing the ancient Indian or African drums. PMID- 25437476 TI - Reporting acuity outcomes and refractive accuracy after LASIK. PMID- 25437477 TI - Rate of change of curvature of the corneal stromal surface drives epithelial compensatory changes and remodeling. PMID- 25437478 TI - Comparison of astigmatic correction after femtosecond lenticule extraction and wavefront-guided LASIK for myopic astigmatism. AB - PURPOSE: To compare postoperative astigmatic correction between femtosecond lenticule extraction (FLEx) and wavefront-guided LASIK in eyes with myopic astigmatism. METHODS: Fifty-eight eyes of 41 patients undergoing FLEx and 49 eyes of 29 patients undergoing wavefront-guided LASIK to correct myopic astigmatism were examined. Visual acuity, cylindrical refraction, predictability of the astigmatic correction, and astigmatic vector components were compared between groups 6 months after surgery. RESULTS: There was no statistically significant difference in manifest cylindrical refraction (P = .08) or percentage of eyes within +/- 0.50 diopter (D) of its refraction (P = .11) between the surgical procedures. The index of success in FLEx was statistically significantly better than that of wavefront-guided LASIK (P = .02), although there was no significant difference between the groups in other indices (eg, surgically induced astigmatism, target-induced astigmatism, astigmatic correction index, angle of error, difference vector, and flattening index). Subgroup analysis showed that FLEx had a better index of success (P = .02) and difference vector (P = .04) than wavefront-guided LASIK in the low cylinder subgroup; the angle of error in FLEx was significantly smaller than that of wavefront-guided LASIK in the moderate cylinder subgroup (P = .03). CONCLUSIONS: Both FLEx and wavefront-guided LASIK worked well for the correction of myopic astigmatism by the 6-month follow-up visit. Although FLEx had a better index of success than wavefront-guided LASIK when using vector analysis, it appears equivalent to wavefront-guided LASIK in terms of visual acuity and the correction of astigmatism. PMID- 25437479 TI - Outcomes of small incision lenticule extraction (SMILE) in low myopia. AB - PURPOSE: To report the visual and refractive outcomes of small incision lenticule extraction for low myopia using the VisuMax femtosecond laser (Carl Zeiss Meditec, Jena, Germany). METHODS: A retrospective analysis of 120 consecutive small incision lenticule extraction procedures was performed for low myopia. Inclusion criteria were preoperative spherical equivalent refraction up to -3.50 diopters (D), cylinder up to 1.50 D, and corrected distance visual acuity of 20/20 or better. Outcomes analysis was performed for all eyes with 1-year follow up according to the Standard Graphs for Reporting Refractive Surgery, and also including mesopic contrast sensitivity. RESULTS: One-year data were available for 110 eyes (92%). Preoperatively, mean spherical equivalent refraction was -2.61 +/ 0.54 D (range: -1.03 to -3.50 D) and mean cylinder was 0.55 +/- 0.38 D (range: 0.00 to 1.50 D). Postoperatively, mean spherical equivalent refraction was -0.05 +/- 0.36 D (range: -0.94 to +1.25 D) and mean cylinder was +/- 0.50 D in 84% and +/- 1.00 D in 99% of eyes. Uncorrected distance visual acuity was 20/20 or better in 96% of eyes and 20/25 or better in 100% of eyes. One line of corrected distance visual acuity was lost in 9%, but no eyes lost two or more lines. There was an initial overcorrection in mean spherical equivalent refraction on day 1 (+0.37 D) as expected, which regressed to +0.10 D at 1 month and -0.05 D at 3 months, after which stability was reached (mean spherical equivalent refraction was -0.05 D at 1 year). Contrast sensitivity at 1 year was slightly increased at 3, 6, 12, and 18 cycles per degree (P < .05). CONCLUSIONS: Small incision lenticule extraction for low myopia was found to be safe and effective with outcomes similar to those previously reported for LASIK. PMID- 25437480 TI - Software-based evaluation of toric IOL orientation in a multicenter clinical study. AB - PURPOSE: To evaluate the rotational stability of a new one-piece hydrophobic acrylic toric intraocular lens (IOL) using a custom-developed software for analysis of slit-lamp photographs. METHODS: In a prospective, multicenter study, 174 eyes were implanted with the TECNIS Toric IOL (Abbott Medical Optics, Inc., Santa Ana, CA). A custom-developed software was used to analyze high-resolution slit-lamp photographs of 156 eyes taken at day 1 (baseline) and 1, 3, and 6 months postoperatively. The software uses iris and sclera landmarks to align the baseline image and later images for comparison. Validation of software was performed through repeated analyses of protractor images rotated from 0.1 degrees to 10.0 degrees and randomly selected photographs of 20 eyes. RESULTS: Software validation showed precision (repeatability plus reproducibility variation) of 0.02 degrees using protractor images and 2.22 degrees using slit-lamp photographs. Good quality slit-lamp images and clear landmarks were necessary for precise measurements. At 6 months, 94.2% of eyes had 5 degrees or less change in IOL orientation versus baseline; only 2 eyes (1.4%) had axis shift greater than 30 degrees . Most eyes were within 5 degrees or less of rotation between 1 and 3 months (92.9%) and 3 and 6 months (94.1%). Mean absolute axis change (+/- standard deviation) from 1 day to 6 months was 2.70 degrees +/- 5.51 degrees . CONCLUSIONS: The new custom software was precise and quick in analyzing slit-lamp photographs to determine postoperative toric IOL rotation. PMID- 25437481 TI - A comparison of LASIK flap thickness and morphology between the Intralase 60- and 150-kHz femtosecond lasers. AB - PURPOSE: To prospectively compare the achieved thickness and consistency of LASIK flaps created with a 60- and 150-kHz femtosecond laser. METHODS: One hundred twenty eyes of 60 patients with myopia were treated with LASIK. One eye had flap created by the Intralase FS 60-kHz femtosecond laser (Abbott Medical Optics, Abbott Park, IL) and the fellow eye was treated with the IntraLase iFS 150-kHz femtosecond laser (Abbott Medical Optics). Eyes were randomized according to ocular dominance. Flap morphology and measurements were taken with anterior segment optical coherence tomography (AS-OCT) at the 1-month postoperative visit. RESULTS: AS-OCT showed similar regular planar morphologies in both groups. The mean thickness of the flaps in the FS 60 group was significantly higher than that of the iFS 150 group (105.4 +/- 3.9 MUm vs 103.9 +/- 4.8 MUm, P = .009). The mean deviation from targeted flap thickness was not significantly different between the two groups. CONCLUSIONS: The Intralase iFS 150-kHz femtosecond laser creates flaps of similar thickness and uniformity to the Intralase FS 60-kHz femtosecond laser. PMID- 25437482 TI - Corneal hysteresis, corneal resistance factor, and intraocular pressure measurements in eyes implanted with a small aperture corneal inlay. AB - PURPOSE: To compare the postoperative corneal hysteresis (CH) and corneal resistance factor (CRF) of eyes implanted with a small aperture corneal inlay versus fellow eyes. METHODS: Medical records of patients who underwent small aperture corneal inlay (KAMRA; AcuFocus, Inc., Irvine, CA) implantation were retrospectively reviewed. There were two groups: the implanted and non-implanted. Main outcome measures were CH, CRF, Goldmann-correlated intraocular pressure (IOPg), corneal-compensated IOP (IOPcc), and Goldmann applanation tonometry measurements performed preoperatively and at postoperative week 1 and months 1, 3, and 6. RESULTS: The study included 68 eyes of 34 patients. CH was higher in the implanted group when compared with the non-implanted group at postoperative week 1 (12.2 +/- 3.1 vs 10.9 +/- 1.7 mm Hg; P = .007) and month 1 (12.3 +/- 2.5 vs 10.9 +/- 1.8 mm Hg; P = .001). CRF was higher in the implanted group when compared with the non-implanted group at postoperative week 1 (11.9 +/- 2.9 vs 10.7 +/- 1.6 mm Hg; P = .003) and month 1 (12.5 +/- 2.5 vs 10.4 +/- 1.8 mm Hg; P < .001). IOPcc was higher in the implanted group when compared with the non implanted group at only the first postoperative month (17.1 +/- 3.5 vs 14.3 +/- 2.9 mm Hg; P < .001). There were no statistically significant differences in Goldmann applanation tonometry or IOPg measurements between the two groups (P > .05). At the 3-month postoperative visit, all parameters had returned to baseline and there was no change at the 6-month visit. CONCLUSIONS: Implantation of the KAMRA corneal inlay does not induce a permanent change in CH or CRF. A transient increase in both was seen in the early postoperative period. PMID- 25437483 TI - Evaluation of corneal changes after conventional versus accelerated corneal cross linking: a randomized controlled trial. AB - PURPOSE: To evaluate the outcome of accelerated and conventional corneal cross linking (CXL) procedures regarding their effect on morphological and optical properties of the cornea. METHODS: One hundred fifty-three eyes of 153 patients were evaluated before and during a 15-month follow-up period after CXL (76 eyes in the conventional group and 77 eyes in the accelerated group). Measured variables include corrected distance visual acuity (CDVA), uncorrected distance visual acuity (UDVA), refraction, maximum keratometry, endothelial cell density, anterior and posterior stromal keratocyte density, and subbasal nerve density. All variables were compared between the two study groups. RESULTS: Cylindrical and spherical components of refraction improved significantly during 15 months of follow-up. No difference was observed between the two study groups. UDVA and CDVA improved in the same manner, with no intergroup differences. Endothelial cell density did not change significantly during the follow-up period in either group. K-max increased slightly in the first month of the follow-up, but started to decrease at postoperative visits without any significant difference in the two groups. Anterior stromal keratocyte density and subbasal nerve density decreased significantly in both groups 1 month postoperatively. Both variables had a more significant decrease in the conventional group at all visits before the 1-year visit. At the final 15-month visit, there were no significant differences in any value between the two groups. CONCLUSIONS: Accelerated and conventional CXL seem to have a comparable and acceptable effect on keratoconus in the short-term follow-up period. PMID- 25437484 TI - Accelerated corneal cross-linking in pediatric patients with keratoconus: 24 month outcomes. AB - PURPOSE: To compare the efficiency and safety of accelerated corneal cross linking in pediatric patients with progressive keratoconus. METHODS: In this retrospective interventional case series, 44 eyes of 38 pediatric patients with progressive keratoconus were enrolled. All consecutive patients underwent accelerated corneal cross-linking with settings of 30 mW/cm(2) for 4 minutes, corresponding to a total dose of 7.2 J. The efficacy and safety of the procedure were assessed over a 24-month follow-up period. RESULTS: Mean +/- standard deviation age of 10 girls and 28 boys was 15.3 +/- 2.1 years (range: 9 to 18 years). Uncorrected distance visual acuity improved significantly from 0.52 +/- 0.36 to 0.39 +/- 0.26 logMAR (P = .002), and corrected distance visual acuity improved significantly from 0.38 +/- 0.24 to 0.30 +/- 0.20 logMAR (P < .001). Mean spherical and cylindrical refraction were not significantly altered (P > .001 for both). At the last follow-up visit, the flat keratometry value decreased from baseline from 46.4 +/- 3.0 to 46.0 +/- 2.9 diopters and the steep keratometry value decreased from 50.6 +/- 4.2 to 50.1 +/- 4.0 diopters (P < .001 for both). The total higher-order aberrations, coma, and astigmatism II values were also significantly decreased at 24 months after treatment (P < .05 for all). No serious complications were recorded during the follow-up. CONCLUSIONS: The findings revealed that accelerated corneal cross-linking halted the keratoconus progression without relevant side effects in pediatric patients over a 24-month follow-up period. Visual acuity, keratometric values, and corneal aberrations also improved. PMID- 25437485 TI - Antibacterial efficacy of accelerated photoactivated chromophore for keratitis corneal collagen cross-linking (PACK-CXL). AB - PURPOSE: To investigate whether optimized photoactivated chromophore for keratitis-corneal collagen cross-linking (PACK-CXL) treatment settings allow accelerating treatment while maintaining antibacterial efficacy. METHODS: Staphylococcus aureus and Pseudomonas aeruginosa strains were irradiated with ultraviolet-A light of equal fluence but different intensity settings (18 mW/cm2 for 5 minutes and 36 mW/cm2 for 2.5 minutes). The killing rate was determined by comparing the number of colony-forming units between cross-linked specimens and non-irradiated controls. The potential additional effect of 0.001% benzalkonium chloride was also investigated. RESULTS: The killing rates for Staphylococcus aureus were 92.5% +/- 5.5% (5 minutes at 18 mW/cm2) and 94.4% +/- 2.9% (2.5 minutes at 36 mW/cm2). For Pseudomonas aeruginosa, the killing rates were 93.2% +/- 8.3% (5 minutes at 18 mW/cm2) and 92.9% +/- 5.0% (2.5 minutes at 36 mW/cm2). The presence of benzalkonium chloride in the riboflavin solution did not increase the killing rate significantly. CONCLUSIONS: The antibacterial efficacy of PACK CXL follows the Bunsen-Roscoe law of reciprocity and can be maintained even when the irradiation intensity is considerably increased. These optimized settings may allow a shortened treatment time in the future for PACK-CXL and thus help facilitate the transition from the operating room to the slit lamp for treatment. PMID- 25437486 TI - Accelerated photoactivated chromophore for keratitis-corneal collagen cross linking as a first-line and sole treatment in early fungal keratitis. AB - PURPOSE: To report the use of accelerated photoactivated chromophore for keratitis-corneal collagen cross-linking (PACK-CXL) as a first-line treatment in a patient with an atypical fungal keratitis. METHODS: Case report and literature review. RESULTS: A patient who presented with a painful peripheral corneal infiltrate underwent PACK-CXL with a local limited abrasion and accelerated ultraviolet-A irradiation at 365 MUm and 9 mW/cm2 for 10 minutes. Cultures grew Aureobasidium pullulans. The corneal epithelium closed completely within 3 days and the infiltrate was completely eradicated without administration of antibiotics. CONCLUSIONS: Accelerated PACK-CXL was successfully used as a first line and sole treatment in a case of early fungal keratitis caused by Aureobasidium pullulans. Further characterization of the antifungal effect of PACK-CXL is needed in prospective studies. PMID- 25437487 TI - Interface blood as a new indication for flap lift after LASIK using the WaveLight FS200 femtosecond laser. AB - PURPOSE: To report a new indication for flap lift of interface blood using the WaveLight FS200 femtosecond laser (Alcon Laboratories, Inc., Fort Worth, TX). METHODS: The unique evacuation canal of the FS200 femtosecond laser allows blood from injured limbal vasculature to accumulate. In rare instances, blood extends from the canal into the flap interface, requiring a flap lift. All flap lifts were performed using the microscope in the laser suite on the FS200 femtosecond laser to remove postoperative flap interface blood in 3 eyes of 3 patients. RESULTS: All interface blood was removed and no patients experienced re-bleeding. Postoperatively, patients achieved an uncorrected visual acuity of 20/20. CONCLUSIONS: When intracanal blood is noted, planned incomplete dissection of the flap to the canal edge may prevent the progression of blood in the interface. PMID- 25437488 TI - Development and validation of the compliant and principled sportspersonship scale. AB - PURPOSE: A new measure of sportspersonship, which differentiates between compliance and principled approaches, was developed and initially validated in 3 studies. METHOD: Study 1 developed items, assessed content validity, and proposed a model. Study 2 tested the factorial validity of the model on an independent sample. Study 3 further tested the factorial validity on another independent sample as well as the construct validity. RESULTS: In Study 1, a 71-item questionnaire was developed. Exploratory factor analysis reduced the questionnaire to a 6-factor, 33-item scale explaining 47.70% of the variance. Study 2 tested this revised questionnaire in a series of confirmatory factor analyses, presenting a 24-item and 5-factor model with acceptable fit, chi(2)(242) = 455.9, comparative fit index = .93, Tucker-Lewis Index = .92, standardized root mean square residual = .05, root mean square error of approximation = .04. Study 3 provided some evidence to support the construct validity of the 24-item scale using theoretically associated measures. CONCLUSIONS: This series of studies provided some initial validity evidences of the Compliant and Principled Sportspersonship Scale. PMID- 25437489 TI - Expression, purification, and characterization of almond (Prunus dulcis) allergen Pru du 4. AB - Biochemical characterizations of food allergens are required for understanding the allergenicity of food allergens. Such studies require a relatively large amount of highly purified allergens. The level of Pru du 4 in almond is low, and its expression in a soluble form in Escherichia coli required an expression tag. An MBP tag was used to enhance its expression and solubility. Sumo was used for the first time as a peptidase recognition site. The expression tag was removed with a sumo protease, and the resulting wild-type Pru du 4 was purified chromatographically. The stability of the allergen was investigated with chemical denaturation. The Gibbs free energy of Pru du 4 folding-unfolding transition was determined to be 5.4 +/- 0.7 kcal/mol. PMID- 25437490 TI - Three Rate-Constant Kinetic Model for Permanganate Reactions Autocatalyzed by Colloidal Manganese Dioxide: The Oxidation of L-Phenylalanine. AB - The reduction of permanganate ion to MnO(2)-Mn(2)O(3) soluble colloidal mixed oxide by l-phenylalanine in aqueous phosphate-buffered neutral solutions has been followed by a spectrophotometric method, monitoring the decay of permanganate ion at 525 nm and the formation of the colloidal oxide at 420 nm. The reaction is autocatalyzed by the manganese product, and three rate constants have been required to fit the experimental absorbance-time kinetic data. The reaction shows base catalysis, and the values of the activation parameters at different pHs have been determined. A mechanism including both the nonautocatalytic and the autocatalytic reaction pathways, and in agreement with the available experimental data, has been proposed. Some key features of this mechanism are the following: (i) of the two predominant forms of the amino acid, the anionic form exhibits a stronger reducing power than the zwitterionic form; (ii) the nonautocatalytic reaction pathway starts with the transfer of the hydrogen atom in the alpha position of the amino acid to permanganate ion; and (iii) the autocatalytic reaction pathway involves the reduction of Mn(IV) to Mn(II) by the amino acid and the posterior reoxidation of Mn(II) to Mn(IV) by permanganate ion. PMID- 25437491 TI - Hierarchical control over effortful behavior by rodent medial frontal cortex: A computational model. AB - The anterior cingulate cortex (ACC) has been the focus of intense research interest in recent years. Although separate theories relate ACC function variously to conflict monitoring, reward processing, action selection, decision making, and more, damage to the ACC mostly spares performance on tasks that exercise these functions, indicating that they are not in fact unique to the ACC. Further, most theories do not address the most salient consequence of ACC damage: impoverished action generation in the presence of normal motor ability. In this study we develop a computational model of the rodent medial prefrontal cortex that accounts for the behavioral sequelae of ACC damage, unifies many of the cognitive functions attributed to it, and provides a solution to an outstanding question in cognitive control research-how the control system determines and motivates what tasks to perform. The theory derives from recent developments in the formal study of hierarchical control and learning that highlight computational efficiencies afforded when collections of actions are represented based on their conjoint goals. According to this position, the ACC utilizes reward information to select tasks that are then accomplished through top-down control over action selection by the striatum. Computational simulations capture animal lesion data that implicate the medial prefrontal cortex in regulating physical and cognitive effort. Overall, this theory provides a unifying theoretical framework for understanding the ACC in terms of the pivotal role it plays in the hierarchical organization of effortful behavior. PMID- 25437492 TI - Combinatory actions during object play in psittaciformes (Diopsittaca nobilis, Pionites melanocephala, Cacatua goffini) and corvids (Corvus corax, C. monedula, C. moneduloides). AB - The playful (i.e., not overtly functional) combination of objects is considered a potential ontogenetic and phylogenetic precursor of technical problem solving abilities, as it may lead to affordance learning and honing of mechanical skills. We compared such activities in 6 avian species: 3 psittaciforms (black-headed caiques, red-shouldered macaws, and Goffin cockatoos) and 3 corvids (New Caledonian crows, ravens, and jackdaws). Differences in the type and frequency of object combinations were consistent with species' ecology. Object caching was found predominately in common ravens, which frequently cache food. The most intrinsically structured object combinations were found in New Caledonian crows and Goffin cockatoos, which both stand out for their problem solving abilities in physical tasks. Object insertions prevailed in New Caledonian crows that naturally extract food using tools. Our results support the idea that playful manipulations of inedible objects are linked to physical cognition and problem solving abilities. PMID- 25437493 TI - A dimeric chlorite dismutase exhibits O2-generating activity and acts as a chlorite antioxidant in Klebsiella pneumoniae MGH 78578. AB - Chlorite dismutases (Clds) convert chlorite to O2 and Cl(-), stabilizing heme in the presence of strong oxidants and forming the O?O bond with high efficiency. The enzyme from the pathogen Klebsiella pneumoniae (KpCld) represents a subfamily of Clds that share most of their active site structure with efficient O2 producing Clds, even though they have a truncated monomeric structure, exist as a dimer rather than a pentamer, and come from Gram-negative bacteria without a known need to degrade chlorite. We hypothesized that KpCld, like others in its subfamily, should be able to make O2 and may serve an in vivo antioxidant function. Here, it is demonstrated that it degrades chlorite with limited turnovers relative to the respiratory Clds, in part because of the loss of hypochlorous acid from the active site and destruction of the heme. The observation of hypochlorous acid, the expected leaving group accompanying transfer of an oxygen atom to the ferric heme, is consistent with the more open, solvent-exposed heme environment predicted by spectroscopic measurements and inferred from the crystal structures of related proteins. KpCld is more susceptible to oxidative degradation under turnover conditions than the well characterized Clds associated with perchlorate respiration. However, wild-type K. pneumoniae has a significant growth advantage in the presence of chlorate relative to a Deltacld knockout strain, specifically under nitrate-respiring conditions. This suggests that a physiological function of KpCld may be detoxification of endogenously produced chlorite. PMID- 25437494 TI - Interface matters: the stiffness route to stability of a thermophilic tetrameric malate dehydrogenase. AB - In this work we investigate by computational means the behavior of two orthologous bacterial proteins, a mesophilic and a thermophilic tetrameric malate dehydrogenase (MalDH), at different temperatures. Namely, we quantify how protein mechanical rigidity at different length- and time-scales correlates to protein thermophilicity as commonly believed. In particular by using a clustering analysis strategy to explore the conformational space of the folded proteins, we show that at ambient conditions and at the molecular length-scale the thermophilic variant is indeed more rigid that the mesophilic one. This rigidification is the result of more efficient inter-domain interactions, the strength of which is further quantified via ad hoc free energy calculations. When considered isolated, the thermophilic domain is indeed more flexible than the respective mesophilic one. Upon oligomerization, the induced stiffening of the thermophilic protein propagates from the interface to the active site where the loop, controlling the access to the catalytic pocket, anchors down via an extended network of ion-pairs. On the contrary in the mesophilic tetramer the loop is highly mobile. Simulations at high temperature, could not re-activate the mobility of the loop in the thermophile. This finding opens questions on the similarities of the binding processes for these two homologues at their optimal working temperature and suggests for the thermophilic variant a possible cooperative role of cofactor/substrate. PMID- 25437495 TI - Incidence of intraoperative hypersensitivity reactions: a registry analysis: a registry analysis. AB - BACKGROUND: Previously reported incidences for intraoperative hypersensitivity reactions vary more than 15-fold. The goal was to determine the incidence of intraoperative hypersensitivity events at a U.S. surgical center. METHODS: With institutional review board (Cleveland, Ohio) approval and waiver of written/informed consent, the anesthesia records of adult patients undergoing noncardiac surgery from 2005 to 2011 at the Cleveland Clinic were queried using a novel electronic search protocol developed to identify potential hypersensitivity reactions: cardiovascular collapse defined as systolic arterial blood pressure less than 50 mmHg; administration of epinephrine; administration of diphenhydramine; physician comments in the anesthesia record suggestive of hypersensitivity reactions; laboratory tests for histamine, tryptase, or immunoglobulin-E within 24 h of surgery; and International Classification of Diseases, Ninth Revision, codes suggestive of hypersensitivity reactions. Each electronically identified candidate chart was evaluated by an adjudication committee. Hypersensitivity reactions were graded on a 5-point severity scale. From these data, the authors determined the proportion of operations having adjudicated hypersensitivity reactions, and calculated the 95% exact binomial CI. RESULTS: Among 178,746 records, 4,008 charts were identified by the search strategies. After adjudication, 264 hypersensitivity cases were identified. The overall incidence of hypersensitivity reactions was 1:677 surgeries, corresponding to 15 (95% CI, 13 to 17) cases per 10,000 operations. The incidence of severe hypersensitivity reactions (grades 3 to 5) was 1:4,583, corresponding to 2 (95% CI, 2 to 3) cases per 10,000 operations. CONCLUSIONS: The incidence of severe hypersensitivity reactions was similar to previous reports. However, the overall incidence of hypersensitivity reactions was much greater than reported elsewhere, possibly because of a comprehensive search strategy. PMID- 25437496 TI - Up-regulation of programmed cell death 1 ligand 1 on neutrophils may be involved in sepsis-induced immunosuppression: an animal study and a prospective case control study. AB - BACKGROUND: Recent studies have shown that neutrophils may display an antigen presenting function and inhibit lymphocyte proliferation by expressing programmed cell death 1 ligand 1 (PD-L1). The current study was performed to investigate the effect of neutrophils and their pathophysiological significance during sepsis. METHODS: Neutrophil PD-L1 expression was determined in both septic mice (n = 6) and patients (n = 41). Neutrophils from septic mice were subtyped into PD-L1 and PD-L1 populations to determine their phenotypes and functions. Septic neutrophils were cocultured with lymphocytes to observe the effect of septic neutrophils on lymphocyte apoptosis. RESULTS: The PD-L1 level on neutrophils from septic mice was significantly up-regulated (21.41 +/- 4.76%). This level increased with the progression of sepsis and the migration of neutrophils from the bone marrow to the blood and peritoneal cavity. The percentages of CD11a, CD62L, and C-C chemokine receptor type 2 were lower, whereas the percentages of CD16 and CD64 were higher on PD-L1 neutrophils than on PD-L1 neutrophils. The migratory capacity of PD-L1 neutrophils was compromised. Septic neutrophils induced lymphocyte apoptosis via a contact mechanism, and this process could be reversed by anti-PD-L1 antibody. PD-L1 was also up-regulated on neutrophils from patients with severe sepsis (14.6% [3.75%, 42.1%]). The levels were negatively correlated with the monocyte human leukocyte antigen-DR level and positively correlated with the severity of septic patients. Neutrophil PD-L1 was a predictor for the prognosis of severe sepsis, with an area of 0.74 under the receiver operating curve. CONCLUSIONS: PD-L1 is up-regulated on neutrophils during sepsis, which may be related to sepsis-induced immunosuppression. PMID- 25437497 TI - Fiber-needle swept-source optical coherence tomography system for the identification of the epidural space in piglets. AB - BACKGROUND: Epidural needle insertion is traditionally a blind technique whose success depends on the experience of the operator. The authors describe a novel method using a fiber-needle-based swept-source optical coherence tomography (SSOCT) to identify epidural space. METHODS: An optical fiber probe was placed into a hollow 18-gauge Tuohy needle. It was then inserted by an experienced anesthesiologist to continuously construct a series of two-dimensional SSOCT images by mechanically rotating the optical probe. To quantify this observation, both the average SSOCT signal intensities and their diagnostic potentials were assessed. The insertions were performed three times into both the lumbar and thoracic regions of five pigs using a paramedian approach. RESULTS: A side looking SSOCT is constructed to create a visual image of the underlying structures. The image criteria for the identification of the epidural space from the outside region were generated by the analysis of a training set (n = 100) of ex vivo data. The SSOCT image criteria for in vivo epidural space identification are high sensitivity (0.867 to 0.965) and high specificity (0.838 to 0.935). The mean value of the average signal intensities exhibits statistically significant differences (P < 0.01) and a high discriminatory capacity (area under curve = 0.88) between the epidural space and the outside tissues. CONCLUSIONS: This is the first study to introduce a SSOCT fiber probe embedded in a standard epidural needle. The authors anticipate that this technique will reduce the occurrence of failed epidural blocks and other complications such as dural punctures. PMID- 25437498 TI - Review of the performance of quantitative sensory testing methods to detect hyperalgesia in chronic pain patients on long-term opioids. AB - BACKGROUND: Opioid-induced hyperalgesia is a clinical syndrome whereby patients on long-term opioids become more sensitive to pain while taking opioids. Opioid induced hyperalgesia is characterized by increased pain intensity over time, spreading of pain to other locations, and increased pain sensation to external stimuli. To characterize opioid-induced hyperalgesia, laboratory methods to measure hyperalgesia have been developed. To determine the performance of these methods, the authors conducted a systematic review of clinical studies that incorporate measures of hyperalgesia in chronic pain patients on long-term opioids. METHODS: PubMed and Cochrane databases were searched (terms: opioid induced hyperalgesia, study or trial, and long-term or chronic). Studies published in English were selected if they were conducted in chronic pain patients on long-term opioids and incorporated measures of hyperalgesia; acute/single-dose studies and/or conducted in healthy volunteers were excluded. RESULTS: Fourteen articles made the final selection (11 were selected from the search and 3 others were found from additional sources); there was one randomized controlled trial, one prospective controlled study, three prospective uncontrolled studies, and nine cross-sectional observation studies. Hyperalgesia measurement paradigms used included cold pain, heat pain, pressure pain, electrical pain, ischemic pain, and injection pain. Although none of the stimuli were capable of detecting patients' hyperalgesia, heat pain sensitivity showed some promising results. CONCLUSIONS: None of the measures reviewed herein met the criteria of a definitive standard for the measurement of hyperalgesia. Additional studies that use improved study design should be conducted. PMID- 25437499 TI - Bleeding and the new anticoagulants: strategies and concerns. PMID- 25437501 TI - Mercury isotope signatures in contaminated sediments as a tracer for local industrial pollution sources. AB - Mass-dependent fractionation (MDF) and mass-independent fractionation (MIF) may cause characteristic isotope signatures of different mercury (Hg) sources and help understand transformation processes at contaminated sites. Here, we present Hg isotope data of sediments collected near industrial pollution sources in Sweden contaminated with elemental liquid Hg (mainly chlor-alkali industry) or phenyl-Hg (paper industry). The sediments exhibited a wide range of total Hg concentrations from 0.86 to 99 MUg g(-1), consisting dominantly of organically bound Hg and smaller amounts of sulfide-bound Hg. The three phenyl-Hg sites showed very similar Hg isotope signatures (MDF delta(202)Hg: -0.20/00 to 0.50/00; MIF Delta(199)Hg: -0.050/00 to -0.100/00). In contrast, the four sites contaminated with elemental Hg displayed much greater variations (delta(202)Hg: 2.10/00 to 0.60/00; Delta(199)Hg: -0.190/00 to 0.030/00) but with distinct ranges for the different sites. Sequential extractions revealed that sulfide-bound Hg was in some samples up to 10/00 heavier in delta(202)Hg than organically-bound Hg. The selectivity of the sequential extraction was tested on standard materials prepared with enriched Hg isotopes, which also allowed assessing isotope exchange between different Hg pools. Our results demonstrate that different industrial pollution sources can be distinguished on the basis of Hg isotope signatures, which may additionally record fractionation processes between different Hg pools in the sediments. PMID- 25437503 TI - Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of pyrrolopiperidinone acetic acids as CRTh2 antagonists. AB - Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow dissociation kinetics from the receptor. Structure-kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs. PMID- 25437504 TI - Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists I. AB - A knowledge-based design strategy led to the discovery of several new series of potent and orally bioavailable CRTh2 antagonists where a bicyclic heteroaromatic ring serves as the central core. Structure-kinetic relationships (SKR) opened up the possibility of long receptor residence times. PMID- 25437502 TI - Prevalence of rotavirus genotypes in children younger than 5 years of age before the introduction of a universal rotavirus vaccination program: report of rotavirus surveillance in Turkey. AB - BACKGROUND: Group A rotaviruses are the most common causative agent of acute gastroenteritis among children less than 5 years of age throughout the world. This sentinel surveillance study was aimed to obtain baseline data on the rotavirus G and P genotypes across Turkey before the introduction of a universal rotavirus vaccination program. METHODS: Rotavirus antigen-positive samples were collected from 2102 children less than 5 years of age who attended hospitals participating in the Turkish Rotavirus Surveillance Network. Rotavirus antigen was detected in the laboratories of participating hospitals by commercial serological tests such as latex agglutination, immunochromatographic test or enzyme immunoassay. Rotavirus G and P genotypes were determined by reverse transcription polymerase chain reaction (RT-PCR) using consensus primers detecting the VP7 and VP4 genes, followed by semi-nested type-specific multiplex PCR. RESULTS: RT-PCR found rotavirus RNA in 1644 (78.2%) of the samples tested. The highest rate of rotavirus positivity (38.7%) was observed among children in the 13 to 24 month age group, followed by children in the age group of 25 to 36 months (28.3%). A total of eight different G types, six different P types, and 42 different G-P combinations were obtained. Four common G types (G1, G2, G3, and G9) and two common P types (P[8] and P[4]) accounted for 95.1% and 98.8% of the strains, respectively. G9P[8] was the most common G/P combination found in 40.5% of the strains followed by G1P[8] (21.6%), G2P[8] (9.3%), G2P[4] (6.5%), G3P[8] (3.5%), and finally, G4P[8] (3.4%). These six common genotypes included 83.7% of the strains tested in this study. The rate of uncommon genotypes was 14%. CONCLUSION: The majority of the strains analyzed belonged to the G1-G4 and G9 genotypes, suggesting high coverage of current rotavirus vaccines. This study also demonstrates a dramatic increase in G9 genotype across the country. PMID- 25437505 TI - Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists II: lead optimization. AB - Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles. PMID- 25437506 TI - Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists III: the role of a hydrogen-bond acceptor in long receptor residence times. AB - The correct positioning and orientation of an hydrogen bond acceptor (HBA) in the tail portion of the biaryl series of CRTh2 antagonists is a requirement for long receptor residence time. The HBA in combination with a small steric substituent in the core section (R(core) ? H) gives access to compounds with dissociation half-lives of ? 24h. PMID- 25437508 TI - Dynamics of the ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethylsulphonyl)imide studied by nuclear magnetic resonance dispersion and diffusion. AB - The dynamics of the imidazolium based room temperature ionic liquid Bmim Tf2N was investigated by means of nuclear magnetic resonance relaxation dispersion (NMRD) and nuclear magnetic resonance pulsed field gradient (NMR-PFG) diffusion experiments on the bulk liquid in a wide range of temperatures. Relaxation and diffusion properties were determined for anions and cations individually, giving evidence of heterogeneities in the dynamics of the ionic liquid. The relevant NMR relaxation mechanisms are the inter- and intramolecular dipolar interactions between the molecular ions reflecting the molecular translational and rotational diffusion. Rotational and translational correlation times could be obtained and showed different dependences on temperature. The experimental diffusion values follow the Vogel-Fulcher-Tammann (VFT) relation above a transition temperature Tc~ 1.26 Tg, below which a deviation was observed. Differential scanning calorimetry experiments show a transition at the same temperature. PMID- 25437507 TI - Carbon-hydrogen bond activation, C-N bond coupling, and cycloaddition reactivity of a three-coordinate nickel complex featuring a terminal imido ligand. AB - The three-coordinate imidos (dtbpe)Ni?NR (dtbpe = (t)Bu2PCH2CH2P(t)Bu2, R = 2,6 (i)Pr2C6H3, 2,4,6-Me3C6H2 (Mes), and 1-adamantyl (Ad)), which contain a legitimate Ni-N double bond as well as basic imido nitrogen based on theoretical analysis, readily deprotonate HC=CPh to form the amide acetylide species (dtbpe)Ni{NH(Ar)}(C=CPh). In the case of R = 2,6-(i)Pr2C6H3, reductive carbonylation results in formation of the (dtbpe)Ni(CO)2 along with the N-C coupled product keteneimine PhCH?C?N(2,6- (i)Pr2C6H3). Given the ability of the Ni?N bond to have biradical character as suggested by theoretical analysis, H atom abstraction can also occur in (dtbpe)Ni?N{2,6-(i)Pr2C6H3} when this species is treated with HSn((n)Bu)3. Likewise, the microscopic reverse reaction- conversion of the Ni(I) anilide (dtbpe)Ni{NH(2,6-(i)Pr2C6H3)} to the imido (dtbpe)Ni?N{2,6-(i)Pr2C6H3}--is promoted when using the radical Mes*O(*) (Mes* = 2,4,6-(t)Bu3C6H2). Reactivity studies involving the imido complexes, in particular (dtbpe)Ni?N{2,6-(i)Pr2C6H3}, are also reported with small, unsaturated molecules such as diphenylketene, benzylisocyanate, benzaldehyde, and carbon dioxide, including the formation of C-N and N-N bonds by coupling reactions. In addition to NMR spectroscopic data and combustion analysis, we also report structural studies for all the cycloaddition reactions involving the imido (dtbpe)Ni?N{2,6-(i)Pr2C6H3}. PMID- 25437509 TI - Is there a role for rehabilitation streaming following total knee arthroplasty? Preliminary insights from a randomized controlled trial. AB - OBJECTIVE: To determine whether total knee arthroplasty recipients demonstrating comparatively poor mobility at entry to rehabilitation and who received supervised therapy, had better rehabilitation outcomes than those who received less supervision. DESIGN: Retrospective analysis of randomized trial data. PATIENTS: Total knee arthroplasty participants randomized to supervised (n = 159) or home-based therapy (n = 74). METHODS: Participants were dichotomized based on mean target 6-min walk test (6MWT) pre-therapy (second post-surgical week). Absolute and change in 6MWT and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Function subscales amongst low performers in the supervised (n = 89) and unsupervised (n = 36) groups were compared, as were high performers in the supervised (n = 70) and unsupervised (n = 38) groups. RESULTS: Low performers in the unsupervised compared with the supervised group demonstrated significantly poorer 6MWT scores (absolute delta = 8.5%, p = 0.003; change delta = 8.1%, p = 0.007) when therapy ceased (10 weeks post-surgery). No differences in 6MWT were observed between the high performing subgroups or in the recovery of WOMAC subscales between any subgroups. CONCLUSION: Individuals manifesting comparatively poor mobility at the commencement of physiotherapy may recover their mobility, but not perceived function, more quickly if streamed to supervised therapy. PMID- 25437510 TI - Synthesis of ultrahighly electron-deficient pyrrolo[3,4-d]pyridazine-5,7-dione by inverse electron demand Diels-Alder reaction and its application as electrochromic materials. AB - A new electron acceptor 6-alkylpyrrolo[3,4-d]pyridazine-5,7-dione (PPD) with a very low LUMO level has been synthesized via a challenging inverse electron demand Diels-Alder reaction between thiophene and furan-decorated tetrazine substrates and an electron-deficient 1-alkyl-1H-pyrrole-2,5-dione unit. The PPD monomer has been incorporated into a series of donor-acceptor-type conjugated polymers as electrochromic materials with good optical contrast, fast switching speed, and high coloration efficiency. PMID- 25437511 TI - Ebolavirus hemorrhagic fever and the obstetric patient. PMID- 25437512 TI - The role of additional pulses in electropermeabilization protocols. AB - Electropermeabilization (EP) based protocols such as those applied in medicine, food processing or environmental management, are well established and widely used. The applied voltage, as well as tissue electric conductivity, are of utmost importance for assessing final electropermeabilized area and thus EP effectiveness. Experimental results from literature report that, under certain EP protocols, consecutive pulses increase tissue electric conductivity and even the permeabilization amount. Here we introduce a theoretical model that takes into account this effect in the application of an EP-based protocol, and its validation with experimental measurements. The theoretical model describes the electric field distribution by a nonlinear Laplace equation with a variable conductivity coefficient depending on the electric field, the temperature and the quantity of pulses, and the Penne's Bioheat equation for temperature variations. In the experiments, a vegetable tissue model (potato slice) is used for measuring electric currents and tissue electropermeabilized area in different EP protocols. Experimental measurements show that, during sequential pulses and keeping constant the applied voltage, the electric current density and the blackened (electropermeabilized) area increase. This behavior can only be attributed to a rise in the electric conductivity due to a higher number of pulses. Accordingly, we present a theoretical modeling of an EP protocol that predicts correctly the increment in the electric current density observed experimentally during the addition of pulses. The model also demonstrates that the electric current increase is due to a rise in the electric conductivity, in turn induced by temperature and pulse number, with no significant changes in the electric field distribution. The EP model introduced, based on a novel formulation of the electric conductivity, leads to a more realistic description of the EP phenomenon, hopefully providing more accurate predictions of treatment outcomes. PMID- 25437513 TI - Fully printed flexible fingerprint-like three-axis tactile and slip force and temperature sensors for artificial skin. AB - A three-axis tactile force sensor that determines the touch and slip/friction force may advance artificial skin and robotic applications by fully imitating human skin. The ability to detect slip/friction and tactile forces simultaneously allows unknown objects to be held in robotic applications. However, the functionalities of flexible devices have been limited to a tactile force in one direction due to difficulties fabricating devices on flexible substrates. Here we demonstrate a fully printed fingerprint-like three-axis tactile force and temperature sensor for artificial skin applications. To achieve economic macroscale devices, these sensors are fabricated and integrated using only printing methods. Strain engineering enables the strain distribution to be detected upon applying a slip/friction force. By reading the strain difference at four integrated force sensors for a pixel, both the tactile and slip/friction forces can be analyzed simultaneously. As a proof of concept, the high sensitivity and selectivity for both force and temperature are demonstrated using a 3*3 array artificial skin that senses tactile, slip/friction, and temperature. Multifunctional sensing components for a flexible device are important advances for both practical applications and basic research in flexible electronics. PMID- 25437514 TI - Long-term follow-up of the genital organs and eye lenses in three cases of acute radiation sickness from a 60Co radiation accident in China. AB - A follow-up study aimed primarily at investigating late radiation effects on the genital organs and eye lenses was performed between 1999 and 2010 on three individuals who suffered from acute radiation sickness in China. The examination included a medical history, a physical examination, ultrasonography, laboratory analysis, and an ophthalmologic examination. In Case 1, amenorrhea occurred after exposure to a Co source. The uterus and ovaries were significantly narrowed in the second year following exposure. The estradiol level decreased significantly during the first 3 y; progesterone was lowest in the second year; and levels of follicle-stimulating hormone and luteinizing hormone increased, especially in the first year. The lenses in both eyes appeared opaque 6 mo after the exposure, resulting in a gradual deterioration in visual acuity. In Case 2 (8 y old), the levels of testosterone and estradiol were normal. In Case 3, the levels of testosterone and estradiol were also normal, but the sperm count was 0 from 6 mo to 1 y, and the proportion of abnormal sperm was increased from 3-5 y after the accident. The lenses in Case 3 also began to turn opaque in the ninth year after the accident. In Case 1, the ovarian function was reduced, leading to amenorrhea and early menopause. In Case 3, the sperm count was reduced and the number of abnormal sperm was increased due to testicular damage by radiation. Radiation induced cataracts occurred in both Case 1 and Case 3. PMID- 25437515 TI - A new method to calculate the threshold temperature of a perfect blackbody to protect cornea and lens in the range of 780-3,000 nm. AB - Exposure to IR-A and IR-B radiation, in the wavelength region of 780 nm to 3,000 nm, may lead to the development of cataractogenesis. Estimation of the exposure levels is the first step in controlling adverse health effects. In the present study, the irradiance of a hot blackbody emitter is replaced by its temperature in the exposure limit values for cornea and lens in the range of 780-3,000 nm. This paper explains the development and implementation of a computer code to predict a temperature, defined as Threshold Temperature, which satisfies the exposure limits already proposed by the ICNIRP. To this end, first an infinite series was created for the calculation of spectral radiance by integration with Planck's law. For calculation of irradiance, the initial terms of this infinite series were selected, and integration was performed in the wavelength region of 780 nm to 3,000 nm. Finally, using a computer code, an unknown source temperature that can emit the same irradiance was found. Exposure duration, source area, and observer distance from the hot source were entered as input data in this proposed code. Consequently, it is possible only by measurement of a Planckian emitter temperature and taking into account the distance from source and exposure time for an observer to decide whether the exposure to IR radiation in the range of 780 to 3,000 nm is permissible or not. It seems that the substitution of irradiance by the source temperature is an easier and more convenient way for hygienists to evaluate IR exposures. PMID- 25437516 TI - Tools for placing the radiological health hazard in perspective following a severe emergency at a light water reactor (LWR) or its spent fuel pool. AB - Experience from past nuclear and radiological emergencies shows that placing the radiological health hazard in perspective and having a definition of "safe" are required in order to prevent members of the public, those responsible for protecting the public (i.e., decision makers), and others from taking inappropriate and damaging actions that are not justified based on the radiological health hazard. The principle concerns of the public during a severe nuclear power plant or spent fuel pool emergency are "Am I safe?" and "What should I do to be safe?" However, these questions have not been answered to the satisfaction of the public, despite various protective actions being implemented to ensure their safety. Instead, calculated doses or various measured quantities (e.g., ambient dose rate or radionuclide concentrations) are used to describe the situation to the public without placing them into perspective in terms of the possible radiological health hazard, or if they have, it has been done incorrectly. This has contributed to members of the public taking actions that do more harm than good in the belief that they are protecting themselves. Based on established international guidance, this paper provides a definition of "safe" for the radiological health hazard for use in nuclear or radiological emergencies and a system for putting the radiological health hazard in perspective for quantities most commonly measured after a release resulting from a severe emergency at a light water reactor or its spent fuel pool. PMID- 25437517 TI - Annual and weekly cycles of radioactivity concentration observed in Fukushima City. AB - Weekly cycles in the radioactivity concentration of radiocesium measured in Fukushima City, Japan, are found embedded in an annual cycle of the same. The radioactivity concentration and fallout of radiocesium measured in Fukushima City during the period from June 2011 until July 2013 are analyzed to evaluate mainly their time dependences. Although on average the two quantities decrease at paces much faster than those of local dose rates, both of them show annual cycles, peaking during winter and spring and bottoming otherwise. These annual cycles, which are somewhat out of phase compared to those in Europe, are formed due to weathering. However, the local radioactivity concentration shows weekly cycles also, increasing on weekdays and decreasing at weekends. The causes of these weekly cycles are presumably vehicular traffic and precipitation. Therefore, both human and natural activities are playing important roles at different timescales on atmospheric migration of radiocesium deposited in Fukushima City. PMID- 25437518 TI - Absence of internal radiation contamination by radioactive cesium among children affected by the Fukushima Daiichi nuclear power plant disaster. AB - Chronic internal radiation contamination accounts for a substantial fraction of long-term cumulative radiation exposure among residents in radiation-contaminated areas. However, little information is available on ongoing chronic internal radiation contamination among residents near the crippled Fukushima Daiichi nuclear power plant. Using a whole body counter, internal radiation contamination levels among elementary and middle school students who commute to 22 schools located within Minamisoma city were assessed between May and July 2013 (26 to 28 mo after the disaster). Of 3,299 elementary and middle school students in the city, 3,255 individuals (98%) were screened through school health check-ups. Not a single student was detected with internal radiation contamination due to radioactive cesium. The study found no risk of chronic internal radiation exposure among residents near the crippled nuclear power plant. Current food inspection by local governments, volunteers, and farmers has been functioning well within Fukushima prefecture. However, food management by screening suspected contamination along with whole body counter screening are key public health interventions and should be continued to avoid further internal radiation exposure in radiation-contaminated areas. PMID- 25437519 TI - Calculating patient-specific organ doses from adult body CT scans by Monte Carlo analysis using male-individual voxel phantoms. AB - Computed tomography (CT) dose calculators such as the WAZA-ARI are useful for estimating the radiation dose from CT examination. This study determined correction coefficients for estimating organ doses to patients of any size attended to in daily clinical practice. To this end, the authors constructed voxel phantoms based on the CT images of patients of different size and simulated radiation transport in CT examinations to obtain organ doses using Monte Carlo simulation. The results show that the linear relationship between effective diameter and organ dose can predict patient-specific organ doses. The effective diameter-based prediction can provide accuracy within an error of +/-10%, whereas an error of >20% was observed only in the liver and bladder. These results may contribute to practical irradiation dose calculation from a CT examination depending on individual patient size within a certain degree of accuracy. PMID- 25437520 TI - One size does not fit all: the merit of absorbed doses to the blood in 131I therapy for differentiated thyroid carcinoma. AB - The amount of 131I necessary for successful ablation in patients with differentiated thyroid cancer (DTC) is still subject to debate. This study investigates the relationship of the absorbed dose of radiation to the blood while administering 131I activity with several other parameters in DTC patients. This prospective study included 90 DTC patients who were classified into three groups according to their level of dosage: 3.7 GBq (38.9%), 5.55 GBq (55.6%), and 7.4 GBq (5.5%). Blood dosimetry of treated patients was performed using external whole-body counting with a Geiger Muller dosimeter located 2 m away from the patients. Dose rate was measured at 2, 4, 5, 24, and 48 h after the administration of radioiodine. Based on the results of whole-body dose rate measurements, 48 h after administration of 3.7, 5.55, and 7.4 GBq of radioiodine, absorbed doses to patients' blood were estimated at 0.49 +/- 0.12, 0.71 +/- 0.21, and 0.76 +/- 0.11 Gy, respectively. Increasing radioiodine dosage from 3.7 GBq to 5.55 GBq significantly increased blood dose, while there was no significant difference in blood dose between radioiodine dosages of 5.55 GBq and 7.4 GBq. The absorbed dose to the blood was significantly correlated to the patients' gender and the presence of lymph node metastases, but it was not significantly correlated to the type of pathology and regional or distant metastases. Ablation activities exceeding 5.55 GBq produce no further increase in the accumulated activity per volume of blood. The literature regarding this issue is scarce, and further studies are required to verify these preliminary results. PMID- 25437521 TI - Distribution of 222Rn concentration in an inhabited area adjacent to the Aja granitic heights of Hail Province, Saudi Arabia. AB - Radon-222 has been measured in groundwater, dwellings, and atmosphere of an inhabited area adjacent to the granitic Aja heights of Hail province, Saudi Arabia. The measurements were carried out in the field using a RAD7 instrument. Twenty-eight water samples, collected from drilled wells scattered in the region, were analyzed. Radon-222 concentration ranged from 2.5-95 kBq m(-3) with an average value of about 30.3 kBq m(-3). The higher values were found in wells drawing water from granitic aquifers. Indoor 222Rn was measured in 20 dwellings of rural areas in Hail city and other towns. Concentrations ranged from 12-125.6 Bq m(-3), with an average value of 54.6 Bq m(-3). Outdoor air 222Rn was measured at 16 sites, with values ranging from 6.2-13.3 Bq m(-3), with an average value of 10.5 Bq m(-3). The estimated average effective dose due to inhalation of 222Rn released from water was 0.08 mSv y(-1). The estimated average annual effective dose due to indoor 222Rn was 1.35 mSv, which lies below the effective dose range (3-10 mSv) given as the recommended action level. Based on the average dose rate values, the excess lifetime cancer risk values were estimated as 69.8 * 10(-4) due to indoor radon and 13.4 * 10(-4) due to outdoor radon. PMID- 25437522 TI - In vivo measurement of 241Am in the lungs confounded by activity deposited in other organs. AB - Radioactive material deposited in multiple organs of the body is likely to confound a result of an in vivo measurement performed over the lungs, the most frequently monitored organ for occupational exposure. The significance of this interference was evaluated by measuring anthropometric torso phantoms containing lungs, liver, skeleton, and axillary lymph nodes, each with a precisely known quantity of 241Am uniformly distributed in the organs. Arrays of multiple high resolution germanium detectors were positioned over organs within the torso phantom containing 241Am or over proximal organs without activity to determine the degree of measurement confounding due to photons emitted from other source organs. A set of four mathematical response functions describes the measured count rate with detectors positioned over each of the relevant organs and 241Am contained in the measured organ or one of the other organs selected as a confounder. Simultaneous solution of these equations by matrix algebra, where the diagonal terms of the matrix are calibration factors for a direct measurement of activity in an organ and the off-diagonal terms reflect the contribution (i.e., interference or cross-talk) produced by 241Am in a confounding organ, yields the activity deposited in each of the relevant organs. The matrix solution described in this paper represents a method for adjusting a result of 241Am measured directly in one organ for interferences that may arise from 241Am deposited elsewhere and represents a technically valid procedure to aid in evaluating internal dose based upon in vivo measurements for those radioactive materials known to deposit in multiple organs. PMID- 25437523 TI - Radiation exposure of aviation crewmembers and cancer. AB - Crewmembers are exposed to galactic cosmic radiation on every flight and occasionally to solar protons on polar flights. Data are presented showing that the proton occasions are seven times more frequent than generally believed. Crewmembers are also exposed to neutrons and gamma rays from the sun and to gamma rays from terrestrial thunderstorms. Solar neutrons and gamma rays (1) expose the daylight side of Earth, (2) are most intense at lower latitudes, (3) may be as or more frequent than solar protons, and (4) have relativistic energies. The U.S. agency responsible for crewmember safety only considers the galactic component with respect to its recommended 20 mSv y(-1) limit, but it has an estimate for a thunderstorm dose of 30 mSv. In view of overlooked sources, possible over-limit doses, and lack of dosimetry, dose reconstructions are needed. However, using the agency dose estimates and the compensation procedure for U.S. nuclear weapon workers, the probability of crewmember cancers can be at least as likely as not. Ways to improve the quality of dose estimates are suggested, and a worker's compensation program specific to aviation crewmembers is recommended. PMID- 25437527 TI - Two-week virtual reality training for dementia: Single case feasibility study. AB - Persons with dementia (PWD) are known to have difficulty with participation and focus during physical activity. Virtual reality (VR) offers a unique medium for motor learning but has only been used previously for cognitive assessment for PWD. Our study had two objectives: (1) investigate the feasibility and safety of an exercise-based VR training program in PWD, and (2) investigate its effects on balance and mobility. The intervention consisted of daily (5 d/wk, 1 h each) VR training sessions for 2 wk for a single research participant. Clinical balance and mobility measures were assessed 1 wk prior to, during, 1 wk following, and 1 mo after the intervention. Postintervention interviews provided qualitative feedback from the participant and his caregivers. Results indicate that VR training is feasible, safe, and enjoyable for PWD. However, balance and mobility measures were unaffected. VR training is well tolerated in a single research participant with dementia and is an engaging medium for participation in exercise. PMID- 25437528 TI - Filling and wetting transitions on sinusoidal substrates: a mean-field study of the Landau-Ginzburg model. AB - We study the interfacial phenomenology of a fluid in contact with a one dimensional array of infinitely long grooves of sinusoidal section, characterized by the periodicity length L and amplitude A. The system is modelled by the Landau Ginzburg-Wilson functional, with fluid-substrate couplings which control the wettability of the substrate. We investigate the filling and wetting phenomena within the mean-field approximation, and compare with the predictions of the macroscopic and interfacial Hamiltonian theories. For large values of L and under bulk coexistence conditions, we observe first-order filling transitions between dry (D) and partially filled (F) interfacial states, and wetting transitions between partially filled F and completely wet (W) interfacial states of the same order as for the flat substrate. Depending on the order of the wetting transition, the transition temperature is either shifted towards lower temperatures for first-order wetting or it coincides with the wetting temperature on the flat substrate for continuous wetting. On the other hand, if the groove height is of order of the correlation length, only wetting transitions between D and W states are observed under bulk coexistence conditions. For this case, the transition temperature shift obeys approximately Wenzel's phenomenological law if the substrate favors first-order wetting, but it remains unshifted for continuous wetting. The borderline between the small and large L regimes correspond to a D - F - W triple point if wetting is first-order, and a D - F critical point for continuous wetting. Beyond bulk coexistence conditions, filling and first-order wetting transitions continue into off-coexistence filling and prewetting lines, which end up at critical points. Our findings show that the macroscopic theory only describes accurately the filling transition close to bulk coexistence and large L, while microscopic structure of the fluid is essential to understand wetting and filling away from bulk coexistence. PMID- 25437529 TI - Palladium-Catalyzed Cascade Reaction of 2-Amino-N'-arylbenzohydrazides with Triethyl Orthobenzoates To Construct Indazolo[3,2-b]quinazolinones. AB - A palladium-catalyzed sequential cyclization/C-H activation cascade reaction of 2 amino-N'-arylbenzohydrazides with triethyl orthobenzoates has been developed, providing indazolo[3,2-b]quinazolinones in good to high yields. Two key intermediates of the reaction, 2-phenyl-3-(phenylamino)quinazolinone and C-H insertion palladacycle, were isolated, and their structures were unambiguously confirmed by X-ray crystallography. This method represents an unprecedented example of a halogen-free protocol to access indazolo[3,2-b]quinazolinones. Moreover, this chemistry also provides a useful tool for the discovery of fluorescent materials. PMID- 25437530 TI - Quinoxalines as potent selective CRFRs ligands for monitoring and brain diagnostic. AB - The paper highlighted quinoxalines as potent ligands to corticotropin-releasing factor receptor types 1 and 2. The content includes design and structure-activity relationship of 50 model substances to CRFR1, CRFR2alpha and CRF2beta, respectively. It is important to bear in mind, that our concept has based on challenging research task, designing for selective CRFRs ligands. Because,: (i) These macromolecules can bond more than one ligand, thus causing for a distinct physiological response; (ii) CRFRs also participate readily in protein-protein interactions; (iii) CRFRs have two step activation mechanism and; (iv) CRFR1 has low selectivity. In spite of, numerous research efforts, which have been devoted to the isolation of series peptidic and non-peptidic CRFRs agonists, the poor penetration across blood-brain barrier restricts, their wide application in the clinical practice. Furthermore, the biological role of CRFR2 is not yet fully understood. For that reason, the studies of the structure-activity relationship have significant impact in the field. The great advantages of quinoxalines as prospective ligands are based on their: (a) One-step synthetic road, using mild experimental conditions and, allowing to involve various functional groups in the molecular scaffold as well as good-to-excellent yields, employing Fischer and Hinsberg methods; (b) High selectivity to CRFRs sub-types and; (c) Tunable fluorescence emission within the frame of a large scale of the electromagnetic spectrum ? 500-700 nm. PMID- 25437531 TI - Efficacy of QuadroPulse rTMS for improving motor function after spinal cord injury: Three case studies. AB - CONTEXT/OBJECTIVE: To examine the effects of repetitive QuadroPulse transcranial magnetic stimulation (rTMS(QP)) on hand/leg function after spinal cord injury (SCI). DESIGN: Interventional proof-of-concept study. SETTING: University laboratory. PARTICIPANTS: Three adult subjects with cervical SCI. Interventions Repeated trains of magnetic stimuli were applied to the motor cortical hand/leg area. Several exploratory single-day rTMS(QP) protocols were examined. Ultimately we settled on a protocol using three 5-day trials of (1) rTMS(QP) only; (2) exercise only (targeting hand or leg function); and (3) rTMS(QP) combined with exercise. OUTCOME MEASURES: Hand motor function was assessed by Purdue Pegboard and Complete Minnesota Dexterity tests. Walking function was based on treadmill walking and the Timed Up and Go test. Electromyographic recordings were used for neurophysiological testing of cortical (by single- and double-pulse TMS) and spinal (via tendon taps and electrical nerve stimulation) excitability. RESULTS: Single-day rTMS(QP) application had no clear effect in the 2 subjects whose hand function was targeted, but improved walking speed in the person targeted for walking, accompanied by increased cortical excitability and reduced spinal excitability. All 3 subjects showed functional improvement following the 5-day rTMS(QP) intervention, an effect being even more pronounced after the five-day combined rTMS(QP) + exercise sessions. There were no rTMS(QP)-associated adverse effects. CONCLUSION: Our findings suggest a functional benefit of motor cortical rTMS(QP) after SCI. The effect of rTMS(QP) appears to be augmented when stimulation is accompanied by targeted exercises, warranting expansion of this pilot study to a larger subject population. PMID- 25437532 TI - Activation of the NLRP3 inflammasome in association with calcium oxalate crystal induced reactive oxygen species in kidneys. AB - PURPOSE: We investigated the association of hyperoxaluria and calcium oxalate crystal induced production of reactive oxygen species with activation of the NLRP3 inflammasome. MATERIALS AND METHODS: Eight-week-old male rats were given hydroxy-L-proline to induce hyperoxaluria. A group of rats on the hydroxy-L proline diet also received apocynin, an antioxidant and nonspecific inhibitor of NADPH oxidase. At 28 days the rats were sacrificed and the kidneys were extracted. Microarray analysis was done with the BeadArrayTM Reader. Gene ontology and gene pathway analyses were done with the DAVID (Database for Annotation, Visualization of Integrated Discovery) enrichment analysis tool. Quantitative real-time polymerase chain reaction and immunohistochemical staining were performed to confirm microarray results. RESULTS: Analysis of 22,226 genes revealed that 20 and 24 pathways were highly significant in the cortex and medulla, respectively. In the cortex extracellular matrix-receptor interaction, complement and coagulation cascades, focal adhesion and hypertrophic cardiomyopathy were the most significant pathways. In the medulla complement and coagulation cascades, extracellular matrix-receptor interaction and dilated cardiomyopathy were the major pathways. Genes encoding for PYCARD (ASC), TXNIP, NLRP3, caspase-1, and IL-1beta and 18 were significantly up-regulated in hydroxy L-proline fed rats but in the group that received apocynin these genes were down regulated in the cortex and medulla. Results were verified by quantitative real time polymerase chain reaction with SYBR(r) Green assay and immunohistochemical staining. CONCLUSIONS: Results indicate a role for reactive oxygen species in activation of the NLRP3 inflammasome via TXNIP. This led to a robust inflammatory response in the kidneys of rats with hyperoxaluria and calcium oxalate nephrolithiasis. PMID- 25437533 TI - Time to onset of clinically meaningful improvement with tadalafil 5 mg once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: analysis of data pooled from 4 pivotal, double-blind, placebo controlled studies. AB - PURPOSE: Tadalafil once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia consistently shows statistically significant I-PSS improvements. However, physicians and patients wish to know whether tadalafil provides rapid, clinically meaningful improvement in lower urinary tract symptoms. In this post hoc analysis we integrated results from 4 placebo controlled studies to determine the duration of tadalafil once daily required to achieve clinically meaningful improvement. MATERIALS AND METHODS: We performed post hoc analysis of data integrated from 4 double-blind studies of tadalafil 5 mg and placebo once daily in 742 and 735 men, respectively, 45 years old or older with total I-PSS 13 or greater. Two clinically meaningful improvement categories were assessed, including 1) 3-point or greater baseline to end point total I-PSS improvement and 2) 25% or greater baseline to end point total I-PSS improvement. I-PSS was assessed at weeks 4, 8 and 12 in all studies, week 1 in 2 and week 2 in 1. Results in men treated with tadalafil who showed clinically meaningful improvement (responders) were further examined to determine the earliest time to clinically meaningful improvement. RESULTS: Of 742 tadalafil treated patients 513 (69.1%) and 444 (59.8%) demonstrated category 1 and 2 clinically meaningful improvement, respectively, at the study end point. Of 234 category 1 responders with week 1 assessments 140 (59.8%) achieved clinically meaningful improvement by week 1 and 407 of the total of 513 category 1 responders (79.3%) showed it by week 4. Of the 205 category 2 responders with week 1 assessments 103 (50.2%) achieved clinically meaningful improvement by week 1 while 322 of the 444 category 2 responders (72.5%) did so by week 4. CONCLUSIONS: Tadalafil 5 mg once daily led to clinically meaningful improvement in approximately two-thirds of men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. More than half of this group of tadalafil treated responders achieved clinically meaningful improvement after 1 week of therapy and more than 70% did so within 4 weeks. PMID- 25437534 TI - Antiviral RNA silencing in mammals: no news is not good news. PMID- 25437535 TI - Response to Voinnet et al. PMID- 25437537 TI - Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells. AB - Diabetic cardiomyopathy is a complication of type 2 diabetes, with known contributions of lifestyle and genetics. We develop environmentally and genetically driven in vitro models of the condition using human-induced pluripotent-stem-cell-derived cardiomyocytes. First, we mimic diabetic clinical chemistry to induce a phenotypic surrogate of diabetic cardiomyopathy, observing structural and functional disarray. Next, we consider genetic effects by deriving cardiomyocytes from two diabetic patients with variable disease progression. The cardiomyopathic phenotype is recapitulated in the patient-specific cells basally, with a severity dependent on their original clinical status. These models are incorporated into successive levels of a screening platform, identifying drugs that preserve cardiomyocyte phenotype in vitro during diabetic stress. In this work, we present a patient-specific induced pluripotent stem cell (iPSC) model of a complex metabolic condition, showing the power of this technique for discovery and testing of therapeutic strategies for a disease with ever-increasing clinical significance. PMID- 25437538 TI - The evolutionarily conserved Pol II flap loop contributes to proper transcription termination on short yeast genes. AB - Current models of transcription termination factor recruitment to the RNA polymerase II (Pol II) transcription complex rely exclusively on the direct interaction between the termination factor and phosphorylated isoforms of the Pol II C-terminal domain (CTD). Here, we report that the Pol II flap loop is needed for physical interaction of Pol II with the Pcf11/Clp1 subcomplex of cleavage factor IA (CF IA), which functions in both 3? end processing and Pol II termination, and for proper termination of short RNAs in vitro and in vivo. Deletion of the flap loop reduces the in vivo interaction of Pol II with CF IA but increases the association of Nrd1 during stages of the transcription cycle when the CTD is predominantly Ser5 phosphorylated. We propose a model in which the flap loop coordinates a binding equilibrium between the competing termination factors Pcf11 and Nrd1 to Pol II during termination of short RNA synthesis. PMID- 25437536 TI - Tissue-specific posttranslational modification allows functional targeting of thyrotropin. AB - Thyroid-stimulating hormone (TSH; thyrotropin) is a glycoprotein secreted from the pituitary gland. Pars distalis-derived TSH (PD-TSH) stimulates the thyroid gland to produce thyroid hormones (THs), whereas pars tuberalis-derived TSH (PT TSH) acts on the hypothalamus to regulate seasonal physiology and behavior. However, it had not been clear how these two TSHs avoid functional crosstalk. Here, we show that this regulation is mediated by tissue-specific glycosylation. Although PT-TSH is released into the circulation, it does not stimulate the thyroid gland. PD-TSH is known to have sulfated biantennary N-glycans, and sulfated TSH is rapidly metabolized in the liver. In contrast, PT-TSH has sialylated multibranched N-glycans; in the circulation, it forms the macro-TSH complex with immunoglobulin or albumin, resulting in the loss of its bioactivity. Glycosylation is fundamental to a wide range of biological processes. This report demonstrates its involvement in preventing functional crosstalk of signaling molecules in the body. PMID- 25437539 TI - Targeting the DNA repair pathway in Ewing sarcoma. AB - Ewing sarcoma (EWS) is a tumor of the bone and soft tissue that primarily affects adolescents and young adults. With current therapies, 70% of patients with localized disease survive, but patients with metastatic or recurrent disease have a poor outcome. We found that EWS cell lines are defective in DNA break repair and are sensitive to PARP inhibitors (PARPis). PARPi-induced cytotoxicity in EWS cells was 10- to 1,000-fold higher after administration of the DNA-damaging agents irinotecan or temozolomide. We developed an orthotopic EWS mouse model and performed pharmacokinetic and pharmacodynamic studies using three different PARPis that are in clinical development for pediatric cancer. Irinotecan administered on a low-dose, protracted schedule previously optimized for pediatric patients was an effective DNA-damaging agent when combined with PARPis; it was also better tolerated than combinations with temozolomide. Combining PARPis with irinotecan and temozolomide gave complete and durable responses in more than 80% of the mice. PMID- 25437540 TI - DNA copy-number control through inhibition of replication fork progression. AB - Proper control of DNA replication is essential to ensure faithful transmission of genetic material and prevent chromosomal aberrations that can drive cancer progression and developmental disorders. DNA replication is regulated primarily at the level of initiation and is under strict cell-cycle regulation. Importantly, DNA replication is highly influenced by developmental cues. In Drosophila, specific regions of the genome are repressed for DNA replication during differentiation by the SNF2 domain-containing protein SUUR through an unknown mechanism. We demonstrate that SUUR is recruited to active replication forks and mediates the repression of DNA replication by directly inhibiting replication fork progression instead of functioning as a replication fork barrier. Mass spectrometry identification of SUUR-associated proteins identified the replicative helicase member CDC45 as a SUUR-associated protein, supporting a role for SUUR directly at replication forks. Our results reveal that control of eukaryotic DNA copy number can occur through the inhibition of replication fork progression. PMID- 25437541 TI - Ire1 has distinct catalytic mechanisms for XBP1/HAC1 splicing and RIDD. AB - An evolutionarily conserved unfolded protein response (UPR) component, IRE1, cleaves XBP1/HAC1 introns in order to generate spliced mRNAs that are translated into potent transcription factors. IRE1 also cleaves endoplasmic-reticulum associated RNAs leading to their decay, an activity termed regulated IRE1 dependent decay (RIDD); however, the mechanism by which IRE1 differentiates intron cleavage from RIDD is not well understood. Using in vitro experiments, we found that IRE1 has two different modes of action: XBP1/HAC1 is cleaved by IRE1 subunits acting cooperatively within IRE1 oligomers, whereas a single subunit of IRE1 performs RIDD without cooperativity. Furthermore, these distinct activities can be separated by complementation of catalytically inactive IRE1 RNase and mutations at oligomerization interfaces. Using an IRE1 RNase inhibitor, STF 083010, selective inhibition of XBP1 splicing indicates that XBP1 promotes cell survival, whereas RIDD leads to cell death, revealing modulation of IRE1 activities as a drug-development strategy. PMID- 25437542 TI - Specification of differentiated adult progenitors via inhibition of endocycle entry in the Drosophila trachea. AB - A population of Drosophila adult tracheal progenitor cells arises from differentiated cells of the larval main trachea that retain the ability to reenter the cell cycle and give rise to the multiple adult tracheal cell types. These progenitors are unique to the second tracheal metamere as homologous cells from other segments, express fizzy-related (fzr), the Drosophila homolog of CDH1 protein of the APC complex, and enter endocycle and do not contribute to adult trachea. Here, we examine the mechanisms for their quiescence and show that they reenter the cell cycle by expression of string/cdc25 through ecdysone. Furthermore, we show that preventing endocycle entry is both necessary and sufficient for these tracheal cells to exhibit markers of adult progenitors, thus modifying their genetic program. Finally, we show that Hox-mediated regulation of fzr expression is responsible for progenitor identity and thus specifies a group of differentiated cells with facultative stem cell features. PMID- 25437543 TI - Pattern formation of an epithelial tubule by mechanical instability during epididymal development. AB - A single epithelial tubule undergoes morphogenesis to form a functional shape during the development of internal organs; however, the mechanical processes that are directed by the molecular signals regulating tubular morphogenesis are poorly understood. Here, axial tubular buckling triggered by cell proliferation is shown to drive the morphogenesis of murine epididymal tubules through mechanical interactions between the developing epithelial tubule and its surrounding tissues. Through immunofluorescence labeling and mathematical modeling, epididymal tubule shape formation is found to depend on two factors: cell proliferation area in the tubule and mechanical resistance from the tissues surrounding the tubule. Moreover, experimental perturbations of these two factors alter the shape of the epididymal tubule as predicted by the mathematical model, suggesting that the shape of the epididymal tubule spontaneously emerges through mechanical coupling between developing tissues instead of by growing according to a predetermined fate. PMID- 25437544 TI - The microtubule minus-end-binding protein patronin/PTRN-1 is required for axon regeneration in C. elegans. AB - Precise regulation of microtubule (MT) dynamics is increasingly recognized as a critical determinant of axon regeneration. In contrast to developing neurons, mature axons exhibit noncentrosomal microtubule nucleation. The factors regulating noncentrosomal MT architecture in axon regeneration remain poorly understood. We report that PTRN-1, the C. elegans member of the Patronin/Nezha/calmodulin- and spectrin-associated protein (CAMSAP) family of microtubule minus-end-binding proteins, is critical for efficient axon regeneration in vivo. ptrn-1-null mutants display generally normal developmental axon outgrowth but significantly impaired regenerative regrowth after laser axotomy. Unexpectedly, mature axons in ptrn-1 mutants display elevated numbers of dynamic axonal MTs before and after injury, suggesting that PTRN-1 inhibits MT dynamics. The CKK domain of PTRN-1 is necessary and sufficient for its functions in axon regeneration and MT dynamics and appears to stabilize MTs independent of minus-end localization. Whereas in developing neurons, PTRN-1 inhibits activity of the DLK-1 mitogen-activated protein kinase (MAPK) cascade, we find that, in regeneration, PTRN-1 and DLK-1 function together to promote axonal regrowth. PMID- 25437545 TI - Heterochromatin-mediated gene silencing facilitates the diversification of olfactory neurons. AB - An astounding property of the nervous system is its cellular diversity. This diversity, which was initially realized by morphological and electrophysiological differences, is ultimately produced by variations in gene-expression programs. In most cases, these variations are determined by external cues. However, a growing number of neuronal types have been identified in which inductive signals cannot explain the few but decisive transcriptional differences that cause cell diversification. Here, we show that heterochromatic silencing, which we find is governed by histone methyltransferases G9a (KMT1C) and GLP (KMT1D), is essential for stochastic and singular olfactory receptor (OR) expression. Deletion of G9a and GLP dramatically reduces the complexity of the OR transcriptome, resulting in transcriptional domination by a few ORs and loss of singularity in OR expression. Thus, our data suggest that, in addition to its previously known functions, heterochromatin creates an epigenetic platform that affords stochastic, mutually exclusive gene choices and promotes cellular diversity. PMID- 25437546 TI - Medial entorhinal cortex lesions only partially disrupt hippocampal place cells and hippocampus-dependent place memory. AB - The entorhinal cortex provides the primary cortical projections to the hippocampus, a brain structure critical for memory. However, it remains unclear how the precise firing patterns of medial entorhinal cortex (MEC) cells influence hippocampal physiology and hippocampus-dependent behavior. We found that complete bilateral lesions of the MEC resulted in a lower proportion of active hippocampal cells. The remaining active cells had place fields, but with decreased spatial precision and decreased long-term spatial stability. In addition, MEC rats were as impaired in the water maze as hippocampus rats, while rats with combined MEC and hippocampal lesions had an even greater deficit. However, MEC rats were not impaired on other hippocampus-dependent tasks, including those in which an object location or context was remembered. Thus, the MEC is not necessary for all types of spatial coding or for all types of hippocampus-dependent memory, but it is necessary for the normal acquisition of place memory. PMID- 25437547 TI - Secretory vesicle priming by CAPS is independent of its SNARE-binding MUN domain. AB - Priming of secretory vesicles is a prerequisite for their Ca(2+)-dependent fusion with the plasma membrane. The key vesicle priming proteins, Munc13s and CAPSs, are thought to mediate vesicle priming by regulating the conformation of the t SNARE syntaxin, thereby facilitating SNARE complex assembly. Munc13s execute their priming function through their MUN domain. Given that the MUN domain of Ca(2+)-dependent activator protein for secretion (CAPS) also binds syntaxin, it was assumed that CAPSs prime vesicles through the same mechanism as Munc13s. We studied naturally occurring splice variants of CAPS2 in CAPS1/CAPS2-deficient cells and found that CAPS2 primes vesicles independently of its MUN domain. Instead, the pleckstrin homology domain of CAPS2 seemingly is essential for its priming function. Our findings indicate a priming mode for secretory vesicles. This process apparently requires membrane phospholipids, does not involve the binding or direct conformational regulation of syntaxin by MUN domains of CAPSs, and is therefore not redundant with Munc13 action. PMID- 25437548 TI - Granzyme A produces bioactive IL-1beta through a nonapoptotic inflammasome independent pathway. AB - Bacterial components are recognized by the immune system through activation of the inflammasome, eventually causing processing of the proinflammatory cytokine interleukin-1? (IL-1?), a pleiotropic cytokine and one of the most important mediators of inflammation, through the protease caspase-1. Synthesis of the precursor protein and processing into its bioactive form are tightly regulated, given that disturbed control of IL-1? release can cause severe autoinflammatory diseases or contribute to cancer development. We show that the bacterial Pasteurella multocida toxin (PMT) triggers Il1b gene transcription in macrophages independently of Toll-like receptor signaling through RhoA/Rho-kinase-mediated NF ?? activation. Furthermore, PMT mediates signal transducer and activator of transcription (STAT) protein-controlled granzyme A (a serine protease) expression in macrophages. The exocytosed granzyme A enters target cells and mediates IL-1? maturation independently of caspase-1 and without inducing cytotoxicity. These findings show that macrophages can induce an IL-1?-initiated immune response independently of inflammasome activity. PMID- 25437549 TI - Tumor suppressor p53 alters host cell metabolism to limit Chlamydia trachomatis infection. AB - Obligate intracellular bacteria depend entirely on nutrients from the host cell for their reproduction. Here, we show that obligate intracellular Chlamydia downregulate the central tumor suppressor p53 in human cells. This reduction of p53 levels is mediated by the PI3K-Akt signaling pathway, activation of HDM2, and subsequent proteasomal degradation of p53. The stabilization of p53 in human cells severely impaired chlamydial development and caused the loss of infectious particle formation. DNA-damage-induced p53 interfered with chlamydial development through downregulation of the pentose phosphate pathway (PPP). Increased expression of the PPP key enzyme glucose-6-phosphate dehydrogenase rescued the inhibition of chlamydial growth induced by DNA damage or stabilized p53. Thus, downregulation of p53 is a key event in the chlamydial life cycle that reprograms the host cell to create a metabolic environment supportive of chlamydial growth. PMID- 25437550 TI - Defining midbrain dopaminergic neuron diversity by single-cell gene expression profiling. AB - Effective approaches to neuropsychiatric disorders require detailed understanding of the cellular composition and circuitry of the complex mammalian brain. Here, we present a paradigm for deconstructing the diversity of neurons defined by a specific neurotransmitter using a microfluidic dynamic array to simultaneously evaluate the expression of 96 genes in single neurons. With this approach, we successfully identified multiple molecularly distinct dopamine neuron subtypes and localized them in the adult mouse brain. To validate the anatomical and functional correlates of molecular diversity, we provide evidence that one Vip+ subtype, located in the periaqueductal region, has a discrete projection field within the extended amygdala. Another Aldh1a1+ subtype, located in the substantia nigra, is especially vulnerable in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) model of Parkinson's disease. Overall, this rapid, cost effective approach enables the identification and classification of multiple dopamine neuron subtypes, with distinct molecular, anatomical, and functional properties. PMID- 25437551 TI - Granules harboring translationally active mRNAs provide a platform for P-body formation following stress. AB - The localization of mRNA to defined cytoplasmic sites in eukaryotic cells not only allows localized protein production but also determines the fate of mRNAs. For instance, translationally repressed mRNAs localize to P-bodies and stress granules where their decay and storage, respectively, are directed. Here, we find that several mRNAs are localized to granules in unstressed, actively growing cells. These granules play a key role in the stress-dependent formation of P bodies. Specific glycolytic mRNAs are colocalized in multiple granules per cell, which aggregate during P-body formation. Such aggregation is still observed under conditions or in mutants where P-bodies do not form. In unstressed cells, the mRNA granules appear associated with active translation; this might enable a coregulation of protein expression from the same pathways or complexes. Parallels can be drawn between this coregulation and the advantage of operons in prokaryotic systems. PMID- 25437552 TI - A direct regulatory interaction between chaperonin TRiC and stress-responsive transcription factor HSF1. AB - Heat shock transcription factor 1 (HSF1) is an evolutionarily conserved transcription factor that protects cells from protein-misfolding-induced stress and apoptosis. The mechanisms by which cytosolic protein misfolding leads to HSF1 activation have not been elucidated. Here, we demonstrate that HSF1 is directly regulated by TRiC/CCT, a central ATP-dependent chaperonin complex that folds cytosolic proteins. A small-molecule activator of HSF1, HSF1A, protects cells from stress-induced apoptosis, binds TRiC subunits in vivo and in vitro, and inhibits TRiC activity without perturbation of ATP hydrolysis. Genetic inactivation or depletion of the TRiC complex results in human HSF1 activation, and HSF1A inhibits the direct interaction between purified TRiC and HSF1 in vitro. These results demonstrate a direct regulatory interaction between the cytosolic chaperone machine and a critical transcription factor that protects cells from proteotoxicity, providing a mechanistic basis for signaling perturbations in protein folding to a stress-protective transcription factor. PMID- 25437553 TI - Host cell factor-1 recruitment to E2F-bound and cell-cycle-control genes is mediated by THAP11 and ZNF143. AB - Host cell factor-1 (HCF-1) is a metazoan transcriptional coregulator essential for cell-cycle progression and cell proliferation. Current models suggest a mechanism whereby HCF-1 functions as a direct coregulator of E2F proteins, facilitating the expression of genes necessary for cell proliferation. In this report, we show that HCF-1 recruitment to numerous E2F-bound promoters is mediated by the concerted action of zinc finger transcription factors THAP11 and ZNF143, rather than E2F proteins directly. THAP11, ZNF143, and HCF-1 form a mutually dependent complex on chromatin, which is independent of E2F occupancy. Disruption of the THAP11/ZNF143/HCF-1 complex results in altered expression of cell-cycle control genes and leads to reduced cell proliferation, cell-cycle progression, and cell viability. These data establish a model in which a THAP11/ZNF143/HCF-1 complex is a critical component of the transcriptional regulatory network governing cell proliferation. PMID- 25437554 TI - Structural insights into how Yrb2p accelerates the assembly of the Xpo1p nuclear export complex. AB - Proteins and ribonucleoproteins containing a nuclear export signal (NES) assemble with the exportin Xpo1p (yeast CRM1) and Gsp1p-GTP (yeast Ran-GTP) in the nucleus and exit through the nuclear pore complex. In the cytoplasm, Yrb1p (yeast RanBP1) displaces NES from Xpo1p. Efficient export of NES-cargoes requires Yrb2p (yeast RanBP3), a primarily nuclear protein containing nucleoporin-like phenylalanine glycine (FG) repeats and a low-affinity Gsp1p-binding domain (RanBD). Here, we show that Yrb2p strikingly accelerates the association of Gsp1p-GTP and NES to Xpo1p. We have solved the crystal structure of the Xpo1p-Yrb2p-Gsp1p-GTP complex, a key assembly intermediate that can bind cargo rapidly. Although the NES-binding cleft of Xpo1p is closed in this intermediate, our data suggest that preloading of Gsp1p-GTP onto Xpo1p by Yrb2p, conformational flexibility of Xpo1p, and the low affinity of RanBD enable active displacement of Yrb2p RanBD by NES to occur effectively. The structure also reveals the major binding sites for FG repeats on Xpo1p. PMID- 25437555 TI - Changes in nucleosome occupancy associated with metabolic alterations in aged mammalian liver. AB - Aging is accompanied by physiological impairments, which, in insulin-responsive tissues, including the liver, predispose individuals to metabolic disease. However, the molecular mechanisms underlying these changes remain largely unknown. Here, we analyze genome-wide profiles of RNA and chromatin organization in the liver of young (3 months) and old (21 months) mice. Transcriptional changes suggest that derepression of the nuclear receptors PPARalpha, PPARgamma, and LXRalpha in aged mouse liver leads to activation of targets regulating lipid synthesis and storage, whereas age-dependent changes in nucleosome occupancy are associated with binding sites for both known regulators (forkhead factors and nuclear receptors) and candidates associated with nuclear lamina (Hdac3 and Srf) implicated to govern metabolic function of aging liver. Winged-helix transcription factor Foxa2 and nuclear receptor corepressor Hdac3 exhibit a reciprocal binding pattern at PPARalpha targets contributing to gene expression changes that lead to steatosis in aged liver. PMID- 25437556 TI - Independent stem cell lineages regulate adipose organogenesis and adipose homeostasis. AB - Adipose tissues have striking plasticity, highlighted by childhood and adult obesity. Using adipose lineage analyses, smooth muscle actin (SMA)-mural cell fate mapping, and conditional PPARgamma deletion to block adipocyte differentiation, we find two phases of adipocyte generation that emanate from two independent adipose progenitor compartments: developmental and adult. These two compartments are sequentially required for organ formation and maintenance. Although both developmental and adult progenitors are specified during the developmental period and express PPARgamma, they have distinct microanatomical, functional, morphogenetic, and molecular profiles. Furthermore, the two compartments derive from different lineages; whereas adult adipose progenitors fate-map from an SMA+ mural lineage, developmental progenitors do not. Remarkably, the adult progenitor compartment appears to be specified earlier than the developmental cells and then enters the already developmentally formed adipose depots. Thus, two distinct cell compartments control adipose organ development and organ homeostasis, which may provide a discrete therapeutic target for childhood and adult obesity. PMID- 25437557 TI - Sorting nexin 27 regulates Abeta production through modulating gamma-secretase activity. AB - Patients with Down syndrome (DS) invariably develop Alzheimer's disease (AD) pathology in their 40s. We have recently found that overexpression of a chromosome 21-encoded microRNA-155 results in decreased levels of the membrane trafficking component, SNX27, diminishing glutamate receptor recycling and thereby impairing synaptic functions in DS. Here, we report a function of SNX27 in regulating beta-amyloid (Abeta) generation by modulating gamma-secretase activity. Downregulation of SNX27 using RNAi increased Abeta production, whereas overexpression of full-length SNX27, but not SNX27DeltaPDZ, reversed the RNAi mediated Abeta elevation. Moreover, genetic deletion of Snx27 promoted Abeta production and neuronal loss, whereas overexpression of SNX27 using an adeno associated viral (AAV) vector reduced hippocampal Abeta levels in a transgenic AD mouse model. SNX27 associates with the gamma-secretase complex subunit presenilin 1; this interaction dissociates the gamma-secretase complex, thus decreasing its proteolytic activity. Our study establishes a molecular mechanism for Abeta dependent pathogenesis in both DS and AD. PMID- 25437559 TI - The Telomeric Protein TRF2 Regulates Angiogenesis by Binding and Activating the PDGFRbeta Promoter. AB - Telomeric repeat binding factor 2 (TRF2), which plays a central role in telomere capping, is frequently increased in human tumors. We reveal here that TRF2 is expressed in the vasculature of most human cancer types, where it colocalizes with the Wilms' tumor suppressor WT1. We further show that TRF2 is a transcriptional target of WT1 and is required for proliferation, migration, and tube formation of endothelial cells. These angiogenic effects of TRF2 are uncoupled from its function in telomere capping. Instead, TRF2 binds and transactivates the promoter of the angiogenic tyrosine kinase platelet-derived growth factor receptor beta (PDGFRbeta). These findings reveal an unexpected role of TRF2 in neoangiogenesis and delineate a distinct function of TRF2 as a transcriptional regulator. PMID- 25437558 TI - Expression quantitative trait loci and receptor pharmacology implicate Arg1 and the GABA-A receptor as therapeutic targets in neuroblastoma. AB - The development of targeted therapeutics for neuroblastoma, the third most common tumor in children, has been limited by a poor understanding of growth signaling mechanisms unique to the peripheral nerve precursors from which tumors arise. In this study, we combined genetics with gene-expression analysis in the peripheral sympathetic nervous system to implicate arginase 1 and GABA signaling in tumor formation in vivo. In human neuroblastoma cells, either blockade of ARG1 or benzodiazepine-mediated activation of GABA-A receptors induced apoptosis and inhibited mitogenic signaling through AKT and MAPK. These results suggest that ARG1 and GABA influence both neural development and neuroblastoma and that benzodiazepines in clinical use may have potential applications for neuroblastoma therapy. PMID- 25437560 TI - Deletion of human tarbp2 reveals cellular microRNA targets and cell-cycle function of TRBP. AB - TRBP functions as both a Dicer cofactor and a PKR inhibitor. However, the role of TRBP in microRNA (miRNA) biogenesis is controversial and its regulation of PKR in mitosis remains unexplored. Here, we generate TRBP knockout cells and find altered Dicer-processing sites in a subset of miRNAs but no effect on Dicer stability, miRNA abundance, or Argonaute loading. By generating PACT, another Dicer interactor, and TRBP/PACT double knockout (KO) cells, we further show that TRBP and PACT do not functionally compensate for one another and that only TRBP contributes to Dicer processing. We also report that TRBP is hyperphosphorylated by JNK in M phase when PKR is activated by cellular double-stranded RNAs (dsRNAs). Hyperphosphorylation potentiates the inhibitory activity of TRBP on PKR, suppressing PKR in M-G1 transition. By generating human TRBP KO cells, our study clarifies the role of TRBP and unveils negative feedback regulation of PKR through TRBP phosphorylation. PMID- 25437563 TI - Dual regulation of Fbw7 function and oncogenic transformation by Usp28. AB - Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates the turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-dependent substrate ubiquitination is antagonized by the Usp28 deubiquitinase. Here, we show that Usp28 preferentially antagonizes autocatalytic ubiquitination and stabilizes Fbw7, resulting in dose-dependent effects in Usp28 knockout mice. Monoallelic deletion of Usp28 maintains stable Fbw7 but drives Fbw7 substrate degradation. In contrast, complete knockout triggers Fbw7 degradation and leads to the accumulation of Fbw7 substrates in several tissues and embryonic fibroblasts. On the other hand, overexpression of Usp28 stabilizes both Fbw7 and its substrates. Consequently, both complete loss and ectopic expression of Usp28 promote Ras-driven oncogenic transformation. We propose that dual regulation of Fbw7 activity by Usp28 is a safeguard mechanism for maintaining physiological levels of proto-oncogenic Fbw7 substrates, which is equivalently disrupted by loss or overexpression of Usp28. PMID- 25437561 TI - CD161 defines a transcriptional and functional phenotype across distinct human T cell lineages. AB - The C-type lectin CD161 is expressed by a large proportion of human T lymphocytes of all lineages, including a population known as mucosal-associated invariant T (MAIT) cells. To understand whether different T cell subsets expressing CD161 have similar properties, we examined these populations in parallel using mass cytometry and mRNA microarray approaches. The analysis identified a conserved CD161++/MAIT cell transcriptional signature enriched in CD161+CD8+ T cells, which can be extended to CD161+ CD4+ and CD161+TCRgammadelta+ T cells. Furthermore, this led to the identification of a shared innate-like, TCR-independent response to interleukin (IL)-12 plus IL-18 by different CD161-expressing T cell populations. This response was independent of regulation by CD161, which acted as a costimulatory molecule in the context of T cell receptor stimulation. Expression of CD161 hence identifies a transcriptional and functional phenotype, shared across human T lymphocytes and independent of both T cell receptor (TCR) expression and cell lineage. PMID- 25437562 TI - Structure and cancer immunotherapy of the B7 family member B7x. AB - B7x (B7-H4 or B7S1) is a member of the B7 family that can inhibit T cell function. B7x protein is absent in most normal human tissues and immune cells, but it is overexpressed in human cancers and often correlates with negative clinical outcome. The expression pattern and function of B7x suggest that it may be a potent immunosuppressive pathway in human cancers. Here, we determined the crystal structure of the human B7x immunoglobulin variable (IgV) domain at 1.59 A resolution and mapped the epitopes recognized by monoclonal antibodies. We developed an in vivo system to screen therapeutic monoclonal antibodies against B7x and found that the clone 1H3 significantly inhibited growth of B7x-expressing tumors in vivo via multiple mechanisms. Furthermore, the surviving mice given 1H3 treatment were resistant to tumor rechallenge. Our data suggest that targeting B7x on tumors is a promising cancer immunotherapy and humanized 1H3 may be efficacious for immunotherapy of human cancers. PMID- 25437564 TI - The directional response of chemotactic cells depends on a balance between cytoskeletal architecture and the external gradient. AB - Polarized migrating cells display signal transduction events, such as activation of phosphatidylinositol 3-kinase (PI3K) and Scar/Wave, and respond more readily to chemotactic stimuli at the leading edge. We sought to determine the basis of this polarized sensitivity. Inhibiting actin polymerization leads to uniform sensitivity. However, when human neutrophils were "stalled" by simultaneously blocking actin and myosin dynamics, they maintained the gradient of responsiveness to chemoattractant and also displayed noise-driven PIP3 flashes on the basal membrane, localized toward the front. Thus, polarized sensitivity does not require migration or cytoskeletal dynamics. The threshold for response is correlated with the static F-actin distribution, but not cell shape or volume changes, membrane fluidity, or the preexisting distribution of PI3K. The kinetics of responses to temporal and spatial stimuli were consistent with the local excitation global inhibition model, but the overall direction of the response was biased by the internal axis of polarity. PMID- 25437565 TI - Sequential feedback induction stabilizes the phosphate starvation response in budding yeast. AB - Depletion of essential nutrients triggers regulatory programs that prolong cell growth and survival. Starvation-induced processes increase nutrient transport, mobilize nutrient storage, and recycle nutrients between cellular components. This leads to an effective increase in intracellular nutrients, which may act as a negative feedback that downregulates the starvation program. To examine how cells overcome this potential instability, we followed the transcription response of budding yeast transferred to medium lacking phosphate. Genes were induced in two temporal waves. The first wave was stably maintained and persisted even upon phosphate replenishment, indicating a positive feedback loop. This commitment was abolished after 2 hr with the induction of the second expression wave, coinciding with the reduction in cell growth rate. We show that the overall temporal stability of the expression response depends on the sequential pattern of gene induction. Our results emphasize the key role of gene expression dynamics in optimizing cellular adaptation. PMID- 25437566 TI - A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease. AB - Chaperones are central to the proteostasis network (PN) and safeguard the proteome from misfolding, aggregation, and proteotoxicity. We categorized the human chaperome of 332 genes into network communities using function, localization, interactome, and expression data sets. During human brain aging, expression of 32% of the chaperome, corresponding to ATP-dependent chaperone machines, is repressed, whereas 19.5%, corresponding to ATP-independent chaperones and co-chaperones, are induced. These repression and induction clusters are enhanced in the brains of those with Alzheimer's, Huntington's, or Parkinson's disease. Functional properties of the chaperome were assessed by perturbation in C. elegans and human cell models expressing Abeta, polyglutamine, and Huntingtin. Of 219 C. elegans orthologs, knockdown of 16 enhanced both Abeta and polyQ-associated toxicity. These correspond to 28 human orthologs, of which 52% and 41% are repressed, respectively, in brain aging and disease and 37.5% affected Huntingtin aggregation in human cells. These results identify a critical chaperome subnetwork that functions in aging and disease. PMID- 25437568 TI - Quantitative ChIP-Seq normalization reveals global modulation of the epigenome. AB - Epigenomic profiling by chromatin immunoprecipitation coupled with massively parallel DNA sequencing (ChIP-seq) is a prevailing methodology used to investigate chromatin-based regulation in biological systems such as human disease, but the lack of an empirical methodology to enable normalization among experiments has limited the precision and usefulness of this technique. Here, we describe a method called ChIP with reference exogenous genome (ChIP-Rx) that allows one to perform genome-wide quantitative comparisons of histone modification status across cell populations using defined quantities of a reference epigenome. ChIP-Rx enables the discovery and quantification of dynamic epigenomic profiles across mammalian cells that would otherwise remain hidden using traditional normalization methods. We demonstrate the utility of this method for measuring epigenomic changes following chemical perturbations and show how reference normalization of ChIP-seq experiments enables the discovery of disease-relevant changes in histone modification occupancy. PMID- 25437569 TI - Causes of Uveitis in a Tertiary Center in Chile: A Cross-sectional Retrospective Review. AB - PURPOSE: To describe the pattern of uveitis in a tertiary center in Santiago, Chile. METHODS: We reviewed all of the case records with a presumptive diagnosis of uveitis from patients referred to the Uveitis Department of Hospital del Salvador between 2002 and 2012. Initial assessment was standardized. We tested for association among causes, gender, and age groups. RESULTS: Anterior uveitis was the leading anatomical location of the inflammation (40.4%). A specific etiology was demonstrated in 59% of cases (28.7% infectious). Vogt-Koyanagi Harada syndrome (VKH) was the most frequent cause of uveitis (17.2%). We found association between idiopathic intermediate uveitis, toxocariasis, juvenile idiopathic arthritis, VKH, toxoplasmosis, diabetes mellitus (DM)-associated uveitis, tuberculosis, and idiopathic anterior uveitis and age groups. VKH, DM associated uveitis, and syphilis-associated uveitis were associated with gender. CONCLUSIONS: Our sample shows a distribution of causes of uveitis similar to those in developed countries. The prevalence of VKH is higher than expected. PMID- 25437567 TI - Enhanced specificity and efficiency of the CRISPR/Cas9 system with optimized sgRNA parameters in Drosophila. AB - The CRISPR/Cas9 system has recently emerged as a powerful tool for functional genomic studies in Drosophila melanogaster. However, single-guide RNA (sgRNA) parameters affecting the specificity and efficiency of the system in flies are still not clear. Here, we found that off-target effects did not occur in regions of genomic DNA with three or more nucleotide mismatches to sgRNAs. Importantly, we document for a strong positive correlation between mutagenesis efficiency and sgRNA GC content of the six protospacer-adjacent motif-proximal nucleotides (PAMPNs). Furthermore, by injecting well-designed sgRNA plasmids at the optimal concentration we determined, we could efficiently generate mutations in four genes in one step. Finally, we generated null alleles of HP1a using optimized parameters through homology-directed repair and achieved an overall mutagenesis rate significantly higher than previously reported. Our work demonstrates a comprehensive optimization of sgRNA and promises to vastly simplify CRISPR/Cas9 experiments in Drosophila. PMID- 25437571 TI - Perforation of the sigmoid colon and massive ischemia of the small intestine caused by amyloidosis associated with multiple myeloma: a case report. AB - Amyloidosis is a metabolic disease that results in organ dysfunction because of the deposition of amyloid proteins in body tissues and organs. Amyloid accumulation in the gastrointestinal tract can lead to severe complications with poor outcomes. We report a case showing simultaneous perforation of the sigmoid colon and massive segmental intestinal ischemia caused by amyloidosis associated with multiple myeloma. A 75-year-old woman presented to the emergency department in our hospital with a chief complaint of abdominal pain. Results of several examinations indicated sigmoid colon perforation and acute generalized peritonitis. She underwent an emergency exploratory laparotomy. Operative finding was a perforation of the sigmoid colon and many segmental discoloration sites appeared intraoperatively in the small intestine. A loop colostomy was performed by employing a double-barrel ileostomy with a massive resection of the segmentally discolored small bowel. Pathological findings suggested that the causative factor was amyloidosis with multiple myeloma. The patient was successfully treated with adequate surgery and with melphalan and prednisone after the operation. Meticulous and appropriate treatment for severe complications involving amyloidosis associated with multiple myeloma can prevent a fatal outcome. PMID- 25437572 TI - Outcomes of surgical treatment of primary signet ring cell carcinoma of the colon and rectum: 22 cases reviewed with literature. AB - Colorectal primary signet ring cell carcinoma (PSRCCR) is a rare entity with a dismal prognosis, mainly because of delayed diagnosis. The objective of this study was to investigate the clinicopathologic features and prognostic factors for PSRCCR. This is a retrospective study including the data of 22 patients with PSRCCR who underwent surgery. Patients were categorized by age, sex, tumor site, and stage. Fifteen patients were male. Median age was 40 years. Sites for metastases were lymph nodes (86.4%), peritoneum (40.9%), and liver (9.1%). Most of the patients (91%) had stage III or IV tumors. The rates of curative and palliative resections performed were equal. Mean overall survival and mean progression-free survival times were found to be 33.3 +/- 7.1 months (95% confidence interval, 19.4-47.2 months) and 11.8 +/- 3.5 months (95% confidence interval, 4.9-18.7 months), respectively. It was concluded that site of the tumor, presence of bowel obstruction, peritoneum and lung metastases, adjacent organ infiltration, TNM stage, and efficiency of surgery have significant effects on survival. All in all, these aggressive tumors are generally diagnosed at advanced stages. Depending on the situation, survival is shorter. A high degree of vigilance is required for these patients to avoid the negative impact of late diagnosis on survival. PMID- 25437573 TI - Role of the enteric nervous system in the elongated sigmoid colon of patients with sigmoid volvulus. AB - To clarify the physiologic function of the enteric nervous system (ENS) in the elongated sigmoid colon (ESC) of patients with sigmoid volvulus (SV), we examined the enteric nerve responses in lesional and normal longitudinal muscle strips (LMS) derived from patients with ESC and patients who underwent colon resection for colonic cancers. Thirty preparations of LMS were taken from the lesional sigmoid colons of 10 ESC patients with SV (8 men and 2 women, aged 53 to 80 years, mean 66.2 years). Forty preparations of LMS were taken from the normal sigmoid colons (NSC) of 20 patients with colonic cancer (12 men and 8 women, aged 55 to 76 years, mean 62.3 years). A mechanographic technique was used to evaluate in vitro muscle responses to electrical field stimulation (EFS) before and after treatment with various autonomic nerve blockers. Response to EFS before blockade of the adrenergic and cholinergic nerves was as follows: NSC and ESC significantly demonstrated relaxation reaction rather than contraction reaction (P = 0.0253, P < 0.0001, respectively). ESC showed relaxation reaction more than NSC (P = 0.1138). Response to EFS after blockade of the adrenergic and cholinergic nerves was as follows: NSC and ESC significantly demonstrated relaxation reaction via nonadrenergic noncholinergic (NANC) inhibitory nerves rather than contraction reaction via NANC excitatory nerves (P < 0.0001, P < 0.0001, respectively). ESC with SV significantly showed relaxation reaction more than NSC (P = 0.0092). An increased response of relaxation mediated NANC inhibitory nerves may play a role in impaired motility in the ESC of patients with SV. PMID- 25437574 TI - Sphincter-saving resection of rectal hemangioma based on Doppler transrectal ultrasonography findings: report of a case. AB - A 52-year-old woman was diagnosed with rectal hemangioma that had resulted in chronic bleeding. Klippel-Trenaunay syndrome was diagnosed by clinical examination. She was referred 30 years later because of progressive anemia. Colonoscopy revealed multiple bluish, polypoid nodules with severe vascular congestion and varicosis that had circumferentially spread along the wall from the dentate line to the rectosigmoid lesion. Selective abdominal angiography indicated that the hemangioma fed from the sigmoid artery and superior rectal artery. Doppler transrectal ultrasonography showed heterogeneous lesions with hypoechoic areas mostly in the submucosal layer, partly forming the mosaic pattern of the color flow signal in the intersphincteric layer on the oral side from the dentate line to 1 cm. Anterior resection and coloanal anastomosis with covering ileostomy was performed. Using a transanal approach, mucosectomy and intersphincteric resection were performed based on the Doppler transrectal ultrasonography results. There were no intraoperative complications, and her anemia resolved postoperatively. PMID- 25437575 TI - Puborectal sling interposition combined with seton drainage for pouch-vaginal fistula after rectal cancer surgery with colonic J pouch-anal reconstruction: report of a case. AB - The management of postoperative rectovaginal fistula (RVF) after rectal cancer surgery is difficult and requires reconstruction of the anastomotic site and fistula. Though various surgical procedures have been reported for the repair of RVFs, the results of surgical repair are often unsatisfactory, and failure of the initial repair leads to difficulty in the later operations. Furthermore, it has been reported that cases associated with local infection result in low success rates. We report a case of an 80-year-old woman with a recurrent colonic J pouch vaginal fistula after anoabdominal rectal resection with partial internal sphincteric resection, who achieved a good outcome following a repair using a puborectal sling interposition combined with seton drainage. It may be a useful option for RVF management in repair of such pouch-vaginal fistula after coloanal anastomosis with intersphincteric resection. PMID- 25437576 TI - Characteristics of patients with spontaneous splenic rupture. AB - In the present study, we aim to share our clinical experience in patients with spontaneous splenic rupture. Splenic rupture without trauma is known as spontaneous splenic rupture. The major problems in the management of spontaneous splenic rupture are missed or delayed diagnosis due to the lack of trauma in most cases. The records of all patients, who were admitted to Cerrahpasa Medical Faculty, Istanbul University, were retrospectively reviewed from January 2000 to March 2013. Twelve patients were admitted to the emergency department and they were diagnosed with spontaneous splenic rupture. The mean age was 47.6 years. All patients had complaints of abdominal pain. The mean hematocrit value was 22%. Radiologic assessment revealed hemoperitoneum and/or subcapsular hematoma in 8 patients while splenic abscess was diagnosed in 2 patients. Eleven patients underwent splenectomy whereas one was managed conservatively. The most common cause of spontaneous splenic rupture was determined to be use of anticoagulants. Etiology was considered to be idiopathic in 1 patient. Two patients died in the postoperative period. Although rare, spontaneous splenic rupture must be suspected in emergency patients who have used especially anticoagulants and antiaggregants and who have had no recent history of trauma. One of the important causes of mortality is missed or delayed diagnosis. PMID- 25437577 TI - The current status of emergency operations at a high-volume cancer center. AB - This study aimed to assess the pathogenic causes, clinical conditions, surgical procedures, in-hospital mortality, and operative death associated with emergency operations at a high-volume cancer center. Although many reports have described the contents, operative procedures, and prognosis of elective surgeries in high volume cancer centers, emergency operations have not been studied in sufficient detail. We retrospectively enrolled 28 consecutive patients who underwent emergency surgery. Cases involving operative complications were excluded. The following surgical procedures were performed during emergency operations: closure in 3 cases (10.7%), diversion in 22 cases (78.6%), ileus treatment in 2 cases (7.1%), and hemostasis in 1 case (3.6%). Closure alone was performed only once for peritonitis. Diversion was performed in 17 cases (77.3%) of peritonitis, 4 cases (18.2%) of stenosis of the gastrointestinal tract, and 1 case (4.5%) of bleeding. There was a significant overall difference (P = 0.001). The frequency of emergency operations was very low at a high-volume cancer center. However, the recent shift in treatment approaches toward nonoperative techniques may enhance the status of emergency surgical procedures. The results presented in this study will help prepare for emergency situations and resolve them as quickly and efficiently as possible. PMID- 25437578 TI - Are fibrinogen and complete blood count parameters predictive in incarcerated abdominal hernia repair? AB - Therapeutic delays in cases of external incarcerated hernias typically result in increasing morbidity, mortality, and health expenditures. We investigated the diagnostic role of blood fibrinogen level, white blood count (WBC), mean platelet volume (MPV), and platelet distribution width (PDW) in patients with incarcerated hernia. Two groups, each containing 100 patients, were studied. Group A underwent elective, and group B underwent incarcerated and urgent external hernia repair. We observed high fibrinogen and WBC levels but low MPV and PDW values for patients in group B. Contrary to our expectations, we found lower MPV and PDW values in the complicated group than in the elective group. The morbidity rate and cost burden were higher in group B, and the results were statistically significant. Early operation should be recommended for patients with incarcerated external hernias if their fibrinogen and WBC levels are high. PMID- 25437579 TI - Intraperitoneal microdialysis as a monitoring method in the intensive care unit. AB - Studies on surgical patients provide some evidence of prompt detection of enteric ischemia with microdialysis. The purpose of the study was to measure intraperitoneal microdialysis values (glucose, glycerol, pyruvate, and lactate) in patients hospitalized in an intensive care unit (ICU) with an underlying abdominal surgical condition and to correlate these values with patients' outcomes. Twenty-one patients, 10 female, were enrolled in the study. The intraperitoneal metabolite values were measured for 3 consecutive days, starting from the first day of ICU hospitalization. Descriptive and inferential statistics were performed. The t-test, repeated measures analysis, Holm's test, and a logistic regression model were applied. Level of statistical significance was set at P = 0.05. Mean age of participants was 68.10 +/- 8.02 years old. Survivors exhibited statistically significantly higher glucose values on day 3 (6.61 +/- 2.01 against 3.67 +/- 1.62; P = 0.002). Mean lactate/ pyruvate (L/P) values were above 20 (35.35 +/- 27.11). All non-survivors had a mean three day L/P values greater than 25.94. Low L/P values were related to increased survival possibilities. High microdialysis glucose concentration, high L/P ratio and low glucose concentration were the major findings during the first three ICU hospitalization days in non-survivors. Intraperitoneal microdialysis may serve as a useful tool in understanding enteric ischemia pathophysiology. PMID- 25437580 TI - Trauma Admission CT as a Road Map for IVC Filters. AB - The objective of this study was to determine if admission abdominal/pelvic CT on trauma patients can be used as a novel method to evaluate the inferior vena cava (IVC) anatomy and facilitate potential IVC filter placement. Consecutive trauma admission CT's were reviewed. The potential landing zone for filters was determined by the IVC mid portion between the renal and iliac veins. The IVC landmarks were described anatomically using the thoracic and lumbar vertebral bodies as reference points. The IVC diameter and anatomic anomalies which would affect filter placement were also evaluated from the CT. The records of 610 Trauma patients were reviewed. There were 518 (84.9%) that had an admission CT, forming the basis of the study. The CT for 500 of 518 (96.5%) was of sufficient quality to accurately evaluate the IVC. The third lumbar location of the IVC was a safe landing zone in 476 of 500 (95.2%). Anatomic anomalies were present in 47 of 500 (9.4%). We had the following three conclusions. The admission CT in over 96% of trauma patients can be used to determine the IVC filter landing zone. The third lumbar region of the IVC was a safe landing zone in over 95%. Anatomical anomalies affecting IVC filter placement were revealed in 9.4%. PMID- 25437581 TI - One, two, or three ports in laparoscopic cholecystectomy? AB - Single-port laparoscopic cholecystectomy (LC) has been compared with 3- or 4-port LC. To our knowledge, there are no studies comparing the 3-, 2-, and 1-port techniques. Patients were randomized into 3 groups: LC 1-port using SILS, LC 2 port using a laparoscope with a working channel, and LC 3-port using the standard ports. Pain was evaluated at recovery, 4 hours, 24 hours, day 5, and day 8, using an analog visual scale. Homogenous groups in their demographic characteristics; all confirmed gallbladder lithiasis. At recovery, there was less pain in group 1 (P = 0.002); at 4 hours pain was similar in all groups (P = 0.899); at 24 hours there was less pain in groups 2 and 3 (P = 0.031); and at days 5 and 8 there was marginal (P = 0.053) and significant (P = 0.003) relevance. In terms of pain perception, LC performed through 1 port does not offer advantages when compared with 2 or 3 ports. More clinical trials are needed to confirm these data. PMID- 25437583 TI - Intrahepatic biliary dilatation caused by a small simple hepatic cyst: report of a case. AB - Biliary obstruction caused by small simple cysts is very rare. We present a case of biliary dilatation caused by a simple cyst with a 4-cm diameter. The patient was a 75-year-old woman referred to our hospital for evaluation of a cystic tumor associated with peripheral biliary duct dilatation in the left segment of the liver. Computed tomography and magnetic resonance imaging showed that the cyst probably communicated with the intrahepatic bile duct. Malignant tumors, including intrahepatic papillary neoplasms of the bile duct, could not be ruled out; therefore, we performed surgery with the patient's consent. Histopathologic examination of the resected liver showed that the cystic lesion was a simple cyst. The finding that even small simple cysts can obstruct the biliary tract is important for the management of cystic lesions of the liver. PMID- 25437582 TI - Cytotoxic activity of anticancer drugs on hepatocellular carcinoma cells in hypoxic-hyponutritional culture. AB - To investigate which anticancer drugs and combination of dual drugs could further promote the inhibition of cell growth in vitro against HCC cell line (HepG2) in the hypoxic and hyponutritional culture medium (HHCM) mimicked the different scenarios of transcatheter arterial chemoembolization (TACE). The cells of hepatocellular carcinoma (HCC) treated by TACE suffered various hypoxia and hyponutrition. The cells were treated for 2 hours, 4 hours, 6 hours, and 24 hours, respectively, using 10 drugs including epirubicin (EPI), cisplatin (DDP), mitomycin-C (MMC), oxaliplatin (OXA), hydroxycamptothecin (HCPT), 5-fluorouracil (5-FU), gemcitabine (GEM), docetaxel (DTX), thiotepa (TSPA), and pemetrexed disodium (PEM) in 4 concentrations of HHCM (5%, 10%, 25%, and 50%, respectively) mimicking the scenario of TACE and were assessed using 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cells treated with combinations of dual drugs for 24 hours were also tested. The sensitive drugs with inhibition rates more than 30% were EPI, MMC, HCPT, OXA, and PEM in 4 types of HHCMs. The sensitivity of the cells to treatment with drugs for 24 hours was significantly higher than the sensitivity of the cells to treatment with drugs for 2 hours in 5%, 10%, and 25% HHCM. The sensitivity of the combination of dual drugs was no more than the sensitivity of the single drug with higher sensitivity in 4 concentrations of HHCM. EPI, MMC, HCPT, OXA, and PEM exhibited cytotoxic activity against HepG2 cells in various hypoxia and hyponutrition states. Prolonging the time of exposure could increase the sensitivity of drug, and the combination of dual drugs cannot enhance the cytotoxic effect. PMID- 25437584 TI - The effects of dexketoprofen on endogenous leptin and lipid peroxidation during liver ischemia reperfusion injury. AB - Hepatic ischemia reperfusion (IR) injury has complex mechanisms. We investigated the effect of dexketoprofen on endogenous leptin and malondialdehyde (MDA) levels. Wistar albino rats were divided into 4 equal groups and were subjected to 1-hour ischemia and different subsequent reperfusion intervals. Dexketoprofen was administered in a dose of 25 mg/kg 15 minutes before ischemia induction and 1 hour reperfusion to the Dexketoprofen one-hour reperfusion group, n = 6 (DIR1) group and 6-hour reperfusion to the Dexketoprofen six-hour reperfusion group, n = 6 (DIR6) group. In the control groups, 0.9% physiologic serum (SF) was administered 15 minutes before ischemia induction and 1-hour reperfusion to the one-hour reperfusion group, n = 6 (IR1) group and 6-hour reperfusion to the six hour reperfusion group, n = 6 (IR6) group. Although serum leptin (P = 0.044) and hepatic tissue MDA levels (P = 0.004) were significantly higher in the IR6 group than in the IR1 group, there were no significant differences in dexketoprofen pretreatment between the DIR1 and DIR6 groups. There were no differences in serum MDA levels among the 4 groups, and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were significantly higher in the IR1 (P = 0.026 and P = 0.018, respectively) and IR6 (P = 0.000 and P = 0.002, respectively) groups than in the DIR1 and DIR6 groups. Dexketoprofen pretreatment can protect the liver from IR injury by decreasing inflammation and lipid peroxidation. Our study shows that dexketoprofen has no effects on endogenous leptin during IR injury. PMID- 25437585 TI - Open surgery for hepatic hydatid disease. AB - Hydatid disease is a zoonosis caused by the larvae of Echinococcus granulosus . Humans are an intermediate host and are usually infected by direct contact with dogs or indirectly by contaminated foods. Hydatid disease mainly involves the liver and lungs. The disease can be asymptomatic. Imaging techniques such as ultrasonography and computed tomography are used for diagnosis. The growth of hydatid cysts can lead to complications. Communication between bile duct and cysts is a common complication. The goal of treatment for hydatid disease is to eliminate the parasite with minimum morbidity and mortality. There are 3 treatment options: surgery, chemotherapy, and interventional procedures. Medical treatment has low cure and high recurrence rates. Percutaneous treatment can be performed in select cases. There are many surgical approaches for managing hydatid cysts, although there is no best surgical technique, and conservative and radical procedures are used. Conservative procedures are usually preferred in endemic areas and are easy to perform but are associated with high morbidity and recurrence rates. In these procedures, the parasite is sterilized using a scolicidal agent, and the cyst is evacuated. Radical procedures include hepatic resections and pericystectomy, which have high intraoperative risk and low recurrence rates. Radical procedures should be performed in hepatobiliary centers. The most common postoperative complications are biliary fistulas and cavity-related complications. Endoscopic retrograde cholangiopancreatography can be used to diagnose and treat biliary system complications. Endoscopic sphincterotomy, biliary stenting, and nasobiliary tube drainage are effective for treating postoperative biliary fistulas. PMID- 25437586 TI - Clinical impact of intraoperative navigation using a Doppler ultrasonographic guided vessel tracking technique for pancreaticoduodenectomy. AB - During pancreaticoduodenectomy (PD), early ligation of critical vessels such as the inferior pancreaticoduodenal artery (IPDA) has been reported to reduce blood loss. Color Doppler flow imaging has become the useful diagnostic methods for the delineation of the anatomy. In this study, we assessed the utility of the intraoperative Doppler ultrasonography (Dop-US) guided vessel detection and tracking technique (Dop-Navi) for identifying critical arteries in order to reduce operative bleeding. Ninety patients who received PD for periampullary or pancreatic disease were enrolled. After 14 patients were excluded because of combined resection of portal vein or other organs, the remaining were assigned to 1 of 2 groups: patients for whom Dop-Navi was used (n = 37) and those for whom Dop-Navi was not used (n = 39; controls). We compared the ability of Dop-Navi to identify critical vessels to that of preoperative multi-detector computed tomography (MD-CT), using MD-CT data, as well as compared the perioperative status and postoperative outcome between the 2 patient groups. Intraoperative Dop US was significantly superior to MD-CT in terms of identifying number of vessels and the ability to discriminate the IPDA from the superior mesenteric artery (SMA) based on blood flow velocity. The Dop-Navi patients had shorter operation times (531 min versus 577 min; no significance) and smaller bleeding volumes (1120 mL versus 1590 mL; P < 0.01) than the control patients without increasing postoperative complications. Intraoperative Dop-Navi method allows surgeons to clearly identify the IPDA during PD and to avoid injuries to major arteries. PMID- 25437587 TI - Current and future challenges in the surgical treatment of hepatocellular carcinoma: a review. AB - Challenges in the treatment of hepatocellular carcinoma Hepatocellular carcinoma (HCC) represents one of the most frequent types of cancer worldwide. Surgery, although only a part of the armamentarium against HCC, represents the cornerstone in the management of this aggressive disease. This article will review the current and future challenges in the surgical management of HCC, with a special emphasis on the following areas: (1) the evolution of staging of the disease and the importance of the biological nature and behavior of HCC, (2) the effort to increase resectability, (3) technical innovations and the role of image-guided surgery, and, finally, (4) the role of liver transplantation in the continuum of care for these patients. Although by no means an exhaustive list, the issues mentioned above represent some of the most promising prospects for significant progress in the management of HCC. PMID- 25437588 TI - Effect of 4% chlorhexidine gluconate predisinfection skin scrub prior to hepatectomy: a double-blinded, randomized control study. AB - This trial was designed to compare the efficacy of 4% chlorhexidine gluconate (CHG) with normal saline (NS) as a predisinfection skin-scrub solution prior to standard presurgical skin preparation. Data was collected at a single transplantation center where patients electing resection of hepatic tumors were recruited between October 2011 and September 2012. In total, 100 patients were consecutively enrolled for random assignment to either 4% CHG or NS as a predisinfection skin-scrub solution prior to surgery. Our aim was to assess the comparative antiseptic efficacy of CHG in this setting, focusing on cutaneous microbial colonization (at baseline, preoperatively, and postoperatively) and postsurgical site infections as primary outcome measures. Positivity rates of baseline, preoperative, and postoperative cultures were similar for both groups, showing significant declines (relative to baseline) after skin preparation and no significant postsurgical rebound. Rates of surgical site infection were also similar in both groups (CHG, 6.0%; NS, 4.1%; P = 1.0). For patients with hepatic tumors undergoing hepatectomy, the effect of 4% CHG as a predisinfection scrub solution was similar to that of NS in terms of skin decontamination and surgical site infections. PMID- 25437589 TI - Conversion Therapy Using mFOLFOX6 With Panitumumab for Unresectable Liver Metastases From Multiple Colorectal Cancers With Familial Adenomatous Polyposis. AB - A 39-year-old man received a diagnosis of unresectable multiple liver metastases from multiple colorectal cancers with familial adenomatous polyposis. After construction of an ileostomy, modified FOLFOX6 (mFOLFOX6) with panitumumab was administrated because rectal cancer and sigmoid colon cancer are KRAS wild type. The 13 courses of chemotherapy resulted in a marked reduction in the size of liver metastases and sigmoid colon cancer. Consequently, curative resection with total colectomy, ileal pouch anal anastomosis, and liver metastasis resection with radiofrequency ablation was performed. Progression of KRAS wild-type rectal cancer after chemotherapy suggested that each clone from rectal and sigmoid colon cancer might have a different sensitivity to epidermal growth factor receptor antibody. Immunohistochemical analysis revealed loss of PTEN expression in rectal cancer compared with liver metastases from sigmoid colon cancer, showing that the difference of mFOLFOX6 with panitumumab might be related to activation of the PI3K-AKT pathway. PMID- 25437590 TI - Effect of RET c.2307T>G Polymorphism on the Outcomes of Posterior Sagittal Neurectomy for Hirschsprung Disease Procedure in Indonesian Population. AB - We investigated the effect of RET c.2307T>G polymorphism on the outcomes of posterior sagittal neurectomy for Hirschsprung disease (PSNHD) procedure in Indonesia. Hirschsprung disease (HSCR) is a neurocristopathy characterized by absence of enteric ganglia along variable lengths of the intestine in neonates. The RET c.2307T>G polymorphism has been shown to be associated with HSCR. Many surgical techniques with some advantage and disadvantage were established for HSCR. We have conducted PSNHD in short-segment HSCR patients.Thirty-one nonsyndromic HSCR patients underwent PSNHD. The polymorphism was determined using PCR-RFLP in genomic DNA. The rate of enterocolitis and constipation outcomes following PSNHD were 6 (19%) and 4 (13%) patients, respectively. The RET c.2307T>G polymorphism did not influence either enterocolitis or constipation outcome following PSNHD at P value of 0.07 (OR = 0.28; 95% CI = 0.08-1.05) and 0.67 (OR = 0.58; 95% CI = 0.12-2.76), respectively. Our study suggested that RET c.2307T>G polymorphism may not affect outcomes of PSNHD procedure in Indonesia. Furthermore, a multicenter study with a larger sample size is necessary to clarify this result. PMID- 25437591 TI - Implantation of nerve stump inside a vein and a muscle: comparing neuroma formation in rat. AB - Among many techniques independently reported to manage neuroma formation, manipulation of the nerve stump inside muscle and vein is the most advantageous technique. This study aimed to enrich the basic data of macroscopic appearance and histo-pathology regarding which technique generates less neuroma: nerve stump implantation inside vein or inside muscle. An experimental study with posttest only control-group design was conducted in 24 rats that were randomly arranged into 3 groups. One centimeter of the lateral branch of the right ischiadic nerve was cut. Group A served as the control group, where the proximal nerve stumps were left as they were after the excision; whereas the stumps of groups B and C were implanted inside muscles and veins, respectively. The samples were assessed with histologic examination after 4 weeks to measure the morphometric changes in the nerve endings. The data were statistically analyzed with t test. All rats healed uneventfully. No thrombosis was found within group C, and the stumps were free of neuroma formation. The muscle group formed smaller neuroma than the control group. Statistical analysis showed significant differences between the groups (P < 0.05). The outcome of nerve stump implantation inside the lumen of a vein is superior to the implantation inside a muscle in preventing neuroma formation. PMID- 25437592 TI - Production of intraperitoneal interleukin-6 following open or laparoscopic assisted distal gastrectomy. AB - The interleukin (IL)-6 concentration in plasma or serum has been considered to represent the degree of stress resulting from surgery. However, IL-6 in peritoneal fluid has rarely been considered. The aim of this study was to assess the concentration and amount of IL-6 in peritoneal fluid as indicators of surgical stress. To obtain basic data on peritoneal release of IL-6 during gastric cancer surgery, we measured IL-6 in peritoneal drainage samples, stored for up to 72 hours postoperatively, from patients who had undergone conventional open (ODG group, n = 20) and laparoscopic-assisted (LADG group, n = 19) distal gastrectomy. Within 24 hours, 61 and 77% of the IL-6 was released into the peritoneal cavity in the LADG and ODG groups, respectively. In both groups, the concentration and amount of peritoneal fluid IL-6 were significantly correlated with each other (LADG group: Spearman's rank correlation test [rS] = 0.48, P = 0.04; ODG group: rS = 0.58, P = 0.01). The concentration and amount of IL-6 in peritoneal fluid was 2.8- and 3.6-fold higher in the ODG than in the LADG group, respectively (P < 0.01). With regard to the relationship between the serum C reactive protein (CRP) peak and the concentration or amount of peritoneal fluid IL-6 released within 24 hours, only the concentration of peritoneal fluid IL-6 in the LADG group was significantly correlated (rS = 0.60, P = 0.01) with the serum CRP peak. Our findings suggest that the amount and concentration of IL-6 released into the peritoneal cavity for up to 24 hours after surgery can each be a reliable parameter for assessment of surgical stress. PMID- 25437593 TI - Bouveret's Syndrome: An Overlooked Diagnosis. A Case Report and Review of Literature. AB - Bouveret's syndrome is a rare cause of gastric outlet obstruction. Its diagnosis is often delayed or overlooked. It is characterized by the passage of a large gall bladder stone through a bilio-duodenal fistula, which becomes lodged in the duodenum causing duodenal obstruction. We report the case of a 70-year-old male with a history suggestive of gall bladder disease over a 1-year period. The diagnosis was confirmed by ultrasound, which showed a single large gall bladder stone and the patient was planned for elective laparoscopic cholecystectomy. One week prior to the elective surgery he presented with upper gastrointestinal bleeding for which he was admitted, diagnosed by a gastroenterologist as bleeding duodenal ulcer and treated by local epinephrine injection and blood transfusion. One week later he presented with a picture of acute gastric outlet obstruction, which proved by endoscopy to be due to a large stone impacted in the duodenum. Endoscopic management failed and the stone was managed by open surgery. The patient made a good postoperative recovery and for the last year he has remained free of symptoms. PMID- 25437594 TI - Predicting the amount of intraperitoneal fluid accumulation by computed tomography and its clinical use in patients with perforated peptic ulcer. AB - The correlation between the amount of peritoneal fluid and clinical parameters in patients with perforated peptic ulcer (PPU) has not been investigated. The authors' objective was to derive a reliable formula for determining the amount of peritoneal fluid in patients with PPU before surgery, and to evaluate the correlation between the estimated amount of peritoneal fluid and clinical parameters. We investigated 62 consecutive patients who underwent emergency surgery for PPU, and in whom prediction of the amount of accumulated intraperitoneal fluid was possible by computed tomography (CT) using the methods described by Oriuchi et al. We examined the relationship between the predicted amount of accumulated intraperitoneal fluid and that measured during surgery, and the relationship between the amount of fluid predicted preoperatively or measured during surgery and several clinical parameters. There was a significant positive correlation between the amount of fluid predicted by CT scan and that measured during surgery. When patients with gastric ulcer and duodenal ulcer were analyzed collectively, the predicted amount of intraperitoneal fluid and the amount measured during surgery were each associated with the period from onset until CT scan, perforation size, the Mannheim peritoneal index, and the severity of postoperative complications according to the Clavien-Dindo classification. Our present results suggest that the method of Oriuchi et al is useful for predicting the amount of accumulated intraperitoneal fluid in patients with PPU, and that this would be potentially helpful for treatment decision-making and estimating the severity of postoperative complications. PMID- 25437595 TI - Prognostic role of gastrectomy in patients with gastric cancer with positive peritoneal cytology. AB - This retrospective study identified the optimal treatment strategy for patients with gastric cancer with positive peritoneal cytology. We analyzed clinicopathologic and survival data for 54 patients who had undergone gastrectomy and/or chemotherapy for treatment of gastric cancer with positive peritoneal cytology with (n = 40) or without (n = 14) metastatic disease. The median overall survival did not differ significantly between patients with gastric cancer with positive peritoneal cytology with and without metastatic disease (19 versus 13 months, respectively). Among 14 clinicopathologic variables, the lack of gastrectomy was the only significant independent unfavorable factor for survival (odds ratio, 1.64; 95% confidence interval, 1.04-2.57; P = 0.03). The median overall survival significantly differed among patients who had undergone gastrectomy plus chemotherapy, chemotherapy alone, and gastrectomy alone (25, 10, and 17 months, respectively; P < 0.01). Gastrectomy may be optimal for patients with (gastric cancer with positive peritoneal cytology), considering its favorable prognostic effect with respect to perioperative chemotherapy. PMID- 25437596 TI - Exploratory Analysis to Find Unfavorable Subset of Stage II Gastric Cancer for Which Surgery Alone Is the Standard Treatment; Another Target for Adjuvant Chemotherapy. AB - The aim of the present study was to explore the unfavorable subset of patients with Stage II gastric cancer for whom surgery alone is the standard treatment (T1N2M0, T1N3M0, and T3N0M0). Recurrence-free survival rates were examined in 52 patients with stage T1N2-3M0 and stage T3N0M0 gastric cancer between January 2000 and March 2010. Univariate and multivariate analyses were performed to identify risk factors using a Cox proportional hazards model. The recurrence-free survival (RFS) rates of the patients with stages T1N2, T1N3, and T3N0 cancer were 80.0, 76.4, and 100% at 5 years, respectively. The only significant prognostic factor for the survival rates of the patients with stage pT1N2-3 cancer measured by univariate and multivariate analyses was pathological tumor diameter. The 5-year RFS rates of the patients with stage pT1N2-3 cancer were 60.0%, when the tumor diameters measured <30 mm, and 88.9% when the tumor diameters measured >30 mm (P = 0.0248). These data may suggest that pathological tumor diameter is associated with poor survival in patients with small T1N2-3 tumors. Because our study was a retrospective single-center study with a small sample size, a prospective multicenter study is necessary to confirm whether small tumors are risk factor for the RFS in T1N2-3 disease. PMID- 25437597 TI - Recurrent, spontaneous esophageal ruptures associated with antiphospholipid antibody syndrome: report of a case. AB - A 52-year-old man was admitted to our hospital with a spontaneous esophageal rupture (Boerhaave syndrome) and was successfully treated. Eight years after the first incident, he was readmitted with a recurrent rupture. Recurrence of Boerhaave syndrome is extremely rare, with only 7 cases reported in the English literature. During treatment, the patient was also diagnosed with antiphospholipid syndrome (APS). Although APS is known to cause a variety of symptoms due to vascular thrombosis, recurrence of Boerhaave syndrome, coincident with APS, has never been reported. The pathogenesis of Boerhaave syndrome has not been clearly determined. This report serves to increase awareness of the risk of APS, which results in an increased risk of spontaneous rupture of the esophagus. PMID- 25437598 TI - The outcome of laparoscopic surgery with and without short gastric vessel division for achalasia. AB - Short gastric vessel division (SGVD) has been performed as a part of fundoplication for achalasia. However, whether or not SGVD is necessary is still unknown. Forty-six patients with achalasia who underwent a laparoscopic surgery with or without SGVD were analyzed. A questionnaire was administered to assess the postoperative improvement. Regarding improvement of dysphagia and postoperative reflux, there were no significant differences between SGVD (+) group and SGVD (-) group (P = 0.588 and P = 0.686, respectively). Nineteen patients (95%) in the SGVD (+) group and 24 (92%) in the SGVD (-) group answered that the surgery was satisfactory (P = 0.756). In the SGVD (+) group, the pre- and postsurgical body weight increase was +7.3%. In the SGVD (-) group, it was 8.2%. There was no significant difference of body weight increase between the 2 groups (P = 0.354). SGVD is not always required in laparoscopic surgery for achalasia. PMID- 25437599 TI - Risk factors for renal allograft compartment syndrome. AB - Renal allograft compartment syndrome (RACS) is graft dysfunction secondary to intracompartment hypertension. The purpose of this study was to identify risk factors for RACS. We reviewed 7 cases of established RACS and all intra-abdominal placements of the kidney in order to include potential RACS. We also studied early graft losses in order to rule out a missed RACS. We compared the allograft length and width, recipient height, weight, body mass index, aberrant vessels, site of incision, and side of kidney with the remainder of the cohort as potential predictors of RACS. Among 538 transplants, 40 met the criteria for actual RACS or potential RACS. We uncovered 7 cases of RACS. Only kidney length and width were statistically significant (P = 0.041 and 0.004, respectively). The width was associated with a higher odds ratio than was length (2.315 versus 1.61). Increased allograft length and width should be considered as a potential risk for RACS. PMID- 25437600 TI - Supracostal Approach for PCNL: Is 10th and 11th Intercostal Space Safe According to Clavien Classification System? AB - The purpose of this study was to evaluate the success and morbidity of percutaneous nephrolithotomy (PCNL) performed through the 11th and 10th intercostal space. Between March 2005 and February 2012, 612 patients underwent PCNL, 243 of whom had a supracostal access. The interspace between the 11th and 12th rib was used in 204 cases (group 1) and between the 10th and 11th interspaces in 39 cases (group 2). PCNL was performed using standard supracostal technique in all patients. The operative time, success rate, hospital stay, and complications according to the modified Clavien classification were compared between group 1 and group 2. The stone-free rate was 86.8% in group 1 and 84.6% in group 2 after one session of PCNL. Auxiliary procedures consisting of ureterorenoscopy (URS) and shock wave lithotripsy (SWL) were required in 5 and 7 patients, respectively, in group 1; and in 1 patient each in group 2 . After the auxiliary procedures, stone-free rates increased to 92.6% in group 1 and 89.7% in group 2. A total of 74 (30.4%) complications were documented in the 2 groups according to modified Clavien classification. Grade-I complications were recorded in 20 (8.2%), grade-II in 38 (15.6%), grade-IIIa in 13 (5.3%), and grade-IIIb in 2 (0.8%) patients; grade-IVa was recorded in 1 (0.4%) patient. There were no grade-IVb or grade-V complications. Overall complication rate was 30.9% in group 1 and 28.2% in group 2. Supracostal PCNL in selected cases is effective and safe with acceptable complications. The modified Clavien system provides a standardized grading system for complications of PCNL. PMID- 25437601 TI - Uncommon Complex Anomaly of Inferior Vena Cava and Left Iliac Vein Demonstrated by Multidetector-Row CT Angiography. AB - Retroperitoneal venous anomalies have clinical importance in retroperitoneal and pelvic surgery. Multidetector-row computed tomography (CT) angiography is an important imaging method to be preferred in evaluating vascular structures in this locality. We describe a complex retroperitoneal venous anomaly with a multidetector-row CT angiography. PMID- 25437602 TI - Oxidative Stress and Lipid Peroxidation in the Ischemic Small Intestine: Pathological and Biochemical Evaluation in a Rat model of Superior Mesenteric Ischemia. AB - The purpose of our study was to evaluate the role of oxidative stress and lipid peroxidation in acute mesenteric ischemia. Thirty male Wistar albino rats weighing 240-260 g were randomized into control (no operation), sham (operation without ischemia), and ischemia groups. To induce ischemia, the superior mesenteric artery was sutured. Total antioxidant and oxidant capacity and lipid peroxidase activity were measured in blood samples collected at 0 min, 60 min, and 240 min, and the pathology of ileum segments resected at 240 min was evaluated. Total oxidant status did not differ among the groups. Total antioxidant status increased significantly with time in the ischemia group compared to the control and sham groups (P < 0.001). Although basal arylesterase activity was lower in the ischemia group than controls (P < 0.05), post-ischemia values were similar among the groups. Similarly, basal and stimulated paraoxonase activity in blood samples did not differ among the groups. In conclusion, oxidative stress and lipid peroxidation have no significant role in the pathophysiology of acute mesenteric ischemia. PMID- 25437603 TI - A new anterolateral approach for type C fractures of the distal femur. AB - To provide an anatomic basis for treating type C distal femoral fractures by a new anterolateral approach. Twenty surgical procedures were performed in 10 adult cadaveric specimens using a new anterolateral approach followed by dissection of all lower limbs. The main anterolateral muscles and ligaments were observed. Vessels and nerves related to the new anterolateral approach were also evaluated. Full exposure of the distal femur was achieved. The iliotibial band was protected, and damage to the quadriceps femoris was reduced. The distance between the common peroneal nerve and the new incision line at the level of the lateral epicondyle of the femur was (chi +/- s) 8.19 +/- 0.79 cm (range, 7.48-9.57 cm). This new anterolateral approach to the distal femur is safe. Although it induces slight soft tissue damage, its exposure is excellent. Knee rehabilitation can be performed in the early postoperative period. PMID- 25437604 TI - Healthcare workers' hand microbiome may mediate carriage of hospital pathogens. AB - One function of skin microbiota is to resist colonization and infection by external microorganisms. We sought to detect whether the structure of the hand microbiota of 34 healthcare workers (HCW) in a surgical intensive care unit mediates or modifies the relationship between demographic and behavioral factors and potential pathogen carriage on hands after accounting for pathogen exposure. We used a taxonomic screen (16S rRNA) to characterize the bacterial community, and qPCR to detect presence of Staphylococcus aureus, Enterococcus spp., methicillin-resistant Staphylococcus aureus (MRSA), and Candida albicans on their dominant hands. Hands were sampled weekly over a 3-week period. Age, hand hygiene, and work shift were significantly associated with potential pathogen carriage and the associations were pathogen dependent. Additionally, the overall hand microbiota structure was associated with the carriage of potential pathogens. Hand microbiota community structure may act as a biomarker of pathogen carriage, and modifying that structure may potentially limit pathogen carriage among HCW. PMID- 25437605 TI - Metabolism of cholesterol and bile acids by the gut microbiota. AB - The human gastro-intestinal tract hosts a complex and diverse microbial community, whose collective genetic coding capacity vastly exceeds that of the human genome. As a consequence, the gut microbiota produces metabolites from a large range of molecules that host's enzymes are not able to convert. Among these molecules, two main classes of steroids, cholesterol and bile acids, denote two different examples of bacterial metabolism in the gut. Therefore, cholesterol is mainly converted into coprostanol, a non absorbable sterol which is excreted in the feces. Moreover, this conversion occurs in a part of the human population only. Conversely, the primary bile acids (cholic and chenodeoxycholic acids) are converted to over twenty different secondary bile acid metabolites by the gut microbiota. The main bile salt conversions, which appear in the gut of the whole human population, include deconjugation, oxidation and epimerization of hydroxyl groups at C3, C7 and C12, 7-dehydroxylation, esterification and desulfatation. If the metabolisms of cholesterol and bile acids by the gut microbiota are known for decades, their consequences on human health and disease are poorly understood and only start to be considered. PMID- 25437606 TI - Comparative Genomics Identifies a Potential Marker of Human-Virulent Anaplasma phagocytophilum. AB - We have previously described a comparative genome analysis of nine strains of Anaplasma phagocytophilum that showed similarity between strains infecting humans and U.S. dogs and a more distant relationship with horse and ruminant strains. This suggested that it may be possible to distinguish human-infective strains using simple DNA sequence-based diagnostic tests. This would be of epidemiologic significance in identifying and tracking the presence of virulent strains in tick vector populations. Further analysis identified a gene that was present in several strains, including U.S. Ap-variant 1 (ruminant), MRK (horse), and European sheep, but was deleted in strains infecting U.S. humans and dogs, suggesting that it could be a useful marker of human virulence. A simple PCR test was developed to identify the presence/absence of this gene. The PCR test discriminated A. phagocytophilum strains from clinically affected humans and U.S. dogs from the strains more distantly related in genome sequence. This warrants further testing of globally diverse A. phagocytophilum strains to examine world wide conservation of this gene. PMID- 25437607 TI - Identifying pathogenicity islands in bacterial pathogenomics using computational approaches. AB - High-throughput sequencing technologies have made it possible to study bacteria through analyzing their genome sequences. For instance, comparative genome sequence analyses can reveal the phenomenon such as gene loss, gene gain, or gene exchange in a genome. By analyzing pathogenic bacterial genomes, we can discover that pathogenic genomic regions in many pathogenic bacteria are horizontally transferred from other bacteria, and these regions are also known as pathogenicity islands (PAIs). PAIs have some detectable properties, such as having different genomic signatures than the rest of the host genomes, and containing mobility genes so that they can be integrated into the host genome. In this review, we will discuss various pathogenicity island-associated features and current computational approaches for the identification of PAIs. Existing pathogenicity island databases and related computational resources will also be discussed, so that researchers may find it to be useful for the studies of bacterial evolution and pathogenicity mechanisms. PMID- 25437608 TI - The Natural Antimicrobial Enzyme Lysozyme is Up-Regulated in Gastrointestinal Inflammatory Conditions. AB - The cells that line the mucosa of the human gastrointestinal tract (GI, that is, oral cavity, oesophagus, stomach, small intestine, large intestine, and rectum) are constantly challenged by adverse micro-environmental factors, such as different pH, enzymes, and bacterial flora. With exception of the oral cavity, these microenvironments also contain remnant cocktails of secreted enzymes and bacteria from upper organs along the tract. The density of the GI bacteria varies, from 103/mL near the gastric outlet, to 1010/mL at the ileocecal valve, to 1011 to 1012/mL in the colon. The total microbial population (ca. 1014) exceeds the total number of cells in the tract. It is, therefore, remarkable that despite the prima facie inauspicious mixture of harmful secretions and bacteria, the normal GI mucosa retains a healthy state of cell renewal. To counteract the hostile microenvironment, the GI epithelia react by speeding cell exfoliation (the GI mucosa has a turnover time of two to three days), by increasing peristalsis, by eliminating bacteria through secretion of plasma cell immunoglobulins and by increasing production of natural antibacterial compounds, such as defensin-5 and lysozyme. Only recently, lysozyme was found up-regulated in Barrett's oesophagitis, chronic gastritis, gluten-induced atrophic duodenitis (coeliac disease), collagenous colitis, lymphocytic colitis, and Crohn's colitis. This up-regulation is a response directed to the special types of bacteria recently detected in these diseases. The aim of lysozyme up-regulation is to protect individual mucosal segments to chronic inflammation. The molecular mechanisms connected to the crosstalk between the intraluminal bacterial flora and the production of lysozyme released by the GI mucosae, are discussed. Bacterial resistance continues to exhaust our supply of commercial antibiotics. The potential use of lysozyme to treat infectious diseases is receiving much attention. PMID- 25437609 TI - Live genomics for pathogen monitoring in public health. AB - Whole genome analysis based on next generation sequencing (NGS) now represents an affordable framework in public health systems. Robust analytical pipelines of genomic data provides in short laps of time (hours) information about taxonomy, comparative genomics (pan-genome) and single polymorphisms profiles. Pathogenic organisms of interest can be tracked at the genomic level, allowing monitoring at one-time several variables including: epidemiology, pathogenicity, resistance to antibiotics, virulence, persistence factors, mobile elements and adaptation features. Such information can be obtained not only at large spectra, but also at the "local" level, such as in the event of a recurrent or emergency outbreak. This paper reviews the state of the art in infection diagnostics in the context of modern NGS methodologies. We describe how actuation protocols in a public health environment will benefit from a "streaming approach" (pipeline). Such pipeline would NGS data quality assessment, data mining for comparative analysis, searching differential genetic features, such as virulence, resistance persistence factors and mutation profiles (SNPs and InDels) and formatted "comprehensible" results. Such analytical protocols will enable a quick response to the needs of locally circumscribed outbreaks, providing information on the causes of resistance and genetic tracking elements for rapid detection, and monitoring actuations for present and future occurrences. PMID- 25437610 TI - Evaluation of automated ribosomal intergenic spacer analysis for bacterial fingerprinting of rumen microbiome compared to pyrosequencing technology. AB - The mammalian gut houses a complex microbial community which is believed to play a significant role in host physiology. In recent years, several microbial community analysis methods have been implemented to study the whole gut microbial environment, in contrast to classical microbiological methods focusing on bacteria which can be cultivated. One of these is automated ribosomal intergenic spacer analysis (ARISA), an inexpensive and popular way of analyzing bacterial diversity and community fingerprinting in ecological samples. ARISA uses the natural variability in length of the DNA fragment found between the 16S and 23S genes in different bacterial lineages to infer diversity. This method is now being supplanted by affordable next-generation sequencing technologies that can also simultaneously annotate operational taxonomic units for taxonomic identification. We compared ARISA and pyrosequencing of samples from the rumen microbiome of cows, previously sampled at different stages of development and varying in microbial complexity using several ecological parameters. We revealed close agreement between ARISA and pyrosequencing outputs, especially in their ability to discriminate samples from different ecological niches. In contrast, the ARISA method seemed to underestimate sample richness. The good performance of the relatively inexpensive ARISA makes it relevant for straightforward use in bacterial fingerprinting analysis as well as for quick cross-validation of pyrosequencing data. PMID- 25437612 TI - Prions and prion-like pathogens in neurodegenerative disorders. AB - Prions are unique elements in biology, being able to transmit biological information from one organism to another in the absence of nucleic acids. They have been identified as self-replicating proteinaceous agents responsible for the onset of rare and fatal neurodegenerative disorders-known as transmissible spongiform encephalopathies, or prion diseases-which affect humans and other animal species. More recently, it has been proposed that other proteins associated with common neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, can self-replicate like prions, thus sustaining the spread of neurotoxic entities throughout the nervous system. Here, we review findings that have contributed to expand the prion concept, and discuss if the involved toxic species can be considered bona fide prions, including the capacity to infect other organisms, or whether these pathogenic aggregates share with prions only the capability to self-replicate. PMID- 25437613 TI - Genomic and global approaches to unravelling how hypermutable sequences influence bacterial pathogenesis. AB - Rapid adaptation to fluctuations in the host milieu contributes to the host persistence and virulence of bacterial pathogens. Adaptation is frequently mediated by hypermutable sequences in bacterial pathogens. Early bacterial genomic studies identified the multiplicity and virulence-associated functions of these hypermutable sequences. Thus, simple sequence repeat tracts (SSRs) and site specific recombination were found to control capsular type, lipopolysaccharide structure, pilin diversity and the expression of outer membrane proteins. We review how the population diversity inherent in the SSR-mediated mechanism of localised hypermutation is being unlocked by the investigation of whole genome sequences of disease isolates, analysis of clinical samples and use of model systems. A contrast is presented between the problematical nature of analysing simple sequence repeats in next generation sequencing data and in simpler, pragmatic PCR-based approaches. Specific examples are presented of the potential relevance of this localized hypermutation to meningococcal pathogenesis. This leads us to speculate on the future prospects for unravelling how hypermutable mechanisms may contribute to the transmission, spread and persistence of bacterial pathogens. PMID- 25437611 TI - Genomics-Based Exploration of Virulence Determinants and Host-Specific Adaptations of Pseudomonas syringae Strains Isolated from Grasses. AB - The Pseudomonas syringae species complex has recently been named the number one plant pathogen, due to its economic and environmental impacts, as well as for its role in scientific research. The bacterium has been repeatedly reported to cause outbreaks on bean, cucumber, stone fruit, kiwi and olive tree, as well as on other crop and non-crop plants. It also serves as a model organism for research on the Type III secretion system (T3SS) and plant-pathogen interactions. While most of the current work on this pathogen is either carried out on one of three model strains found on dicot plants with completely sequenced genomes or on isolates obtained from recent outbreaks, not much is known about strains isolated from grasses (Poaceae). Here, we use comparative genomics in order to identify putative virulence-associated genes and other Poaceae-specific adaptations in several newly available genome sequences of strains isolated from grass species. All strains possess only a small number of known Type III effectors, therefore pointing to the importance of non-Type III secreted virulence factors. The implications of this finding are discussed. PMID- 25437615 TI - Genome Sequencing of Xanthomonas vasicola Pathovar vasculorum Reveals Variation in Plasmids and Genes Encoding Lipopolysaccharide Synthesis, Type-IV Pilus and Type-III Secretion Effectors. AB - Xanthomonas vasicola pathovar vasculorum (Xvv) is the bacterial agent causing gumming disease in sugarcane. Here, we compare complete genome sequences for five isolates of Xvv originating from sugarcane and one from maize. This identified two distinct types of lipopolysaccharide synthesis gene clusters among Xvv isolates: one is similar to that of Xanthomonas axonopodis pathovar citri (Xac) and is probably the ancestral type, while the other is similar to those of the sugarcane-inhabiting species, Xanthomonas sacchari. Four of six Xvv isolates harboured sequences similar to the Xac plasmid, pXAC47, and showed a distinct Type-IV pilus (T4P) sequence type, whereas the T4P locus of the other two isolates resembled that of the closely related banana pathogen, Xanthomonas campestris pathovar musacearum (Xcm). The Xvv isolate from maize has lost a gene encoding a homologue of the virulence effector, xopAF, which was present in all five of the sugarcane isolates, while xopL contained a premature stop codon in four out of six isolates. These findings shed new light on evolutionary events since the divergence of Xvv and Xcm, as well as further elucidating the relationships between the two closely related pathogens. PMID- 25437614 TI - Heat Shock Proteins: Intestinal Gatekeepers that Are Influenced by Dietary Components and the Gut Microbiota. AB - Trillions of microorganisms that inhabit the intestinal tract form a diverse and intricate ecosystem with a deeply embedded symbiotic relationship with their hosts. As more detailed information on gut microbiota complexity and functional diversity accumulates, we are learning more about how diet-microbiota interactions can influence the immune system within and outside the gut and host health in general. Heat shock proteins are a set of highly conserved proteins that are present in all types of cells, from microbes to mammals. These proteins carry out crucial intracellular housekeeping functions and unexpected extracellular immuno-regulatory features in order to maintain the mucosal barrier integrity and gut homeostasis. It is becoming evident that the enteric microbiota is one of the major determinants of heat shock protein production in intestinal epithelial cells. This review will focus on the interactions between diet, gut microbiota and their role for regulating heat shock protein production and, furthermore, how these interactions influence the immune system and the integrity of the mucosal barrier. PMID- 25437616 TI - Synthesis, antiproliferative and antibacterial evaluation of C-ring modified colchicine analogues. AB - A series of 10 amine derivatives of colchicine have been obtained with high yields by modification at C(10)-OCH3 position of C-ring and characterized by spectroscopic methods. In vitro cytotoxicity has been evaluated against four human tumour cell lines (HL-60, HL-60/vinc, LoVo, LoVo/DX), as well as antibacterial activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE). From among the compounds tested the most active is colchicine derivative 2h with bis(2 methoxyethyl)amine substituent which is active in nanomolar to submicromolar concentrations and is several times more cytotoxic than cisplatin and doxorubicin. This compound is also effective against the methicillin-resistant Staphylococci strains. PMID- 25437617 TI - Hydroxylated 2,4-diphenyl indenopyridine derivatives as a selective non intercalative topoisomerase IIalpha catalytic inhibitor. AB - For the development of novel anticancer agents, we designed and synthesized hydroxylated 2,4-diphenyl indenopyridines, and evaluated their topoisomerase inhibitory activity as well as their antiproliferative activities against several human cancer cell lines. The structure-activity relationship study showed that indenopyridines with hydroxyl group at meta or para positions of 2- or 4-phenyl ring displayed selective and significant topoisomerase IIalpha (topo IIalpha) inhibitory activity and potent antiproliferative activity. Positive correlation between topo IIalpha inhibition and antiproliferative activity was observed for compounds 15, 16, 18-20, 22, 23, 25 and 26. The mode of action of compound 16 was further evaluated to be a non-intercalative topo IIalpha catalytic inhibitor. PMID- 25437618 TI - Design, synthesis and evaluation of marinopyrrole derivatives as selective inhibitors of Mcl-1 binding to pro-apoptotic Bim and dual Mcl-1/Bcl-xL inhibitors. AB - Inhibition of anti-apoptotic Mcl-1 is a promising anticancer strategy to overcome the survival and chemoresistance of a broad spectrum of human cancers. We previously reported on the identification of a natural product marinopyrrole A (1) that induces apoptosis in Mcl-1-dependent cells through Mcl-1 degradation. Here, we report the design and synthesis of novel marinopyrrole-based analogs and their evaluation as selective inhibitors of Mcl-1 as well as dual Mcl-1/Bcl-xL inhibitors. The most selective Mcl-1 antagonists were 34, 36 and 37 with 16-, 13- and 9-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding, respectively. Among the most potent dual inhibitors is 42 which inhibited Mcl 1/Bim and Bcl-xL/Bim binding 15-fold (IC50 = 600 nM) and 33-fold (500 nM) more potently than (+/-)-marinopyrrole A (1), respectively. Fluorescence quenching, NMR analysis and molecular docking indicated binding of marinopyrroles to the BH3 binding site of Mcl-1. Several marinopyrroles potently decreased Mcl-1 cellular levels and induced caspase 3 activation in human breast cancer cells. Our studies provide novel "lead" marinopyrroles for further optimization as selective Mcl-1 inhibitors and dual Mcl-1 and Bcl-xL inhibitors. PMID- 25437620 TI - Design and synthesis of sulfonamide derivatives of pyrrolidine and piperidine as anti-diabetic agents. AB - Type 2 diabetes (T2D) is a lifestyle disease affecting millions of people worldwide. Various therapies are available for the management of T2D and dipeptidyl peptidase-IV (DPP-IV) inhibition has emerged as a promising therapy for the treatment of type 2 diabetes (T2D). Here we report design, synthesis and in vitro efficacy of sulfonamide derivatives of pyrrolidine and piperidine as anti-diabetic agents. Amongst all the compounds synthesized in this series, 9a, is the most potent (IC50 = 41.17 nM). PMID- 25437621 TI - Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD. AB - A new strategy for treating Pseudomonas aeruginosa infections could be disrupting the Pseudomonas Quinolone Signal (PQS) quorum sensing (QS) system. The goal is to impair communication among the cells and, hence, reduce the expression of virulence factors and the formation of biofilms. PqsD is an essential enzyme for the synthesis of PQS and shares some features with chalcone synthase (CHS2), an enzyme expressed in Medicago sativa. Both proteins are quite similar concerning the size of the active site, the catalytic residues and the electrostatic surface potential at the entrance of the substrate tunnel. Hence, we evaluated selected substrates of the vegetable enzyme as potential inhibitors of the bacterial protein. This similarity-guided approach led to the identification of a new class of PqsD inhibitors having a catechol structure as an essential feature for activity, a saturated linker with two or more carbons and an ester moiety bearing bulky substituents. The developed compounds showed PqsD inhibition with IC50 values in the single-digit micromolar range. The binding mode of these compounds was investigated by Surface Plasmon Resonance (SPR) experiments revealing that their interaction with the protein is not influenced by the presence of the anthranilic acid bound to active site cysteine. Importantly, some compounds reduced the signal molecule production in cellulo. PMID- 25437619 TI - Design and synthesis of protein kinase C epsilon selective diacylglycerol lactones (DAG-lactones). AB - DAG-lactones afford a synthetically accessible, high affinity platform for probing structure activity relationships at the C1 regulatory domain of protein kinase C (PKC). Given the central role of PKC isoforms in cellular signaling, along with their differential biological activities, a critical objective is the design of isoform selective ligands. Here, we report the synthesis of a series of DAG-lactones varying in their side chains, with a particular focus on linoleic acid derivatives. We evaluated their selectivity for PKC epsilon versus PKC alpha both under standard lipid conditions (100% phosphatidylserine, PS) as well as in the presence of a nuclear membrane mimetic lipid mixture (NML). We find that selectivity for PKC epsilon versus PKC alpha tended to be enhanced in the presence of the nuclear membrane mimetic lipid mixture and, for our lead compound, report a selectivity of 32-fold. PMID- 25437622 TI - Synthesis and biological activity of 2,4-di-p-phenolyl-6-2-furanyl-pyridine as a potent topoisomerase II poison. AB - Dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives were simply achieved using Claisen-Schmidt condensation reaction and modified Krohnke pyridine synthetic method. Total forty-five compounds were designed and synthesized which contain hydroxyl groups at ortho, meta or para position of 2- and 4-phenyl rings attached to the central pyridine. They were evaluated for topoisomerase I and II inhibitory activity, and cytotoxicity against several human cancer cell lines for the development of novel antitumor agents. Most of the prepared compounds exhibited significant antiproliferative activity on human cancer cell lines, HCT15 and K562, as well as potent topo II inhibitory activity comparable to or stronger than etoposide. The structure-activity relationship demonstrated that compounds with hydroxyl group at meta or para position of 2-phenyl ring in combination with hydroxyl at ortho, meta or para position of 4-phenyl ring displayed the most potent topoisomerase II inhibitory activity and cytotoxicity. Positive correlation between topoisomerase II inhibition and cytotoxicity was obtained for several compounds (30, 35, 36, 40-45, 49, 54, 56). Compound 56 showed the most potent topoisomerase II inhibitory activity at low concentration and functioned as a topoisomerase poison like the mode of action of etoposide. PMID- 25437624 TI - [Vascular lesions of vocal folds--part 1: horizontal vascular lesions]. AB - BACKGROUND: In recent decades, the endoscopic methods and technologies for laryngeal examination have improved so much that not only epithelial changes, but also vascular changes are recognizable at earlier stages. When comparing newer and older literature, the associated increasingly differentiated descriptions of such visible vascular changes of the vocal folds lead to terminological blurring and shifts of meaning. This complicates the technical-scientific discourse. The aim of the present work is a theoretical and conceptual clarification of early vascular changes of vocal folds. RESULTS: Horizontal changes of benigne vascular diseases, e. g. vessel ectasia, meander, increasing number and branching of vessels, change of direction may develop in to manifest vascular lesions, like varicosis, polyps and in case of ruptures to haemorrhages of vocal folds. These beginning and reversible vascular changes, when early detected and discussed basing on etiological knowledge, may lead to more differentiated prognostic statements and adequate therapeutic decisions, e. g. phonosurgery, functional voice therapy, voice hygiene and voice rest. Vertical vascular changes, like vessel loops, occur primarily in laryngeal papilloma, pre-cancerous and cancerous changes of the vocal folds. Already in small cancerous lesions of the vocal folds the vascular architecture is completely destroyed. PMID- 25437626 TI - [Medical treatment of infants in terms of medico-legal aspects]. PMID- 25437625 TI - [Vaccination against HPV-associated neoplasias]. PMID- 25437627 TI - [Differential diagnosis of nasal obstruction]. AB - Nasal obstruction can have a variety of different causes. The following text describes important diseases of the nose and paranasal sinuses, which are associated with the symptom of nasal obstruction and discusses specifics of diagnosis and therapy. PMID- 25437628 TI - [Regarding "Quiz for specialty certification, Laryngo-Rhino-Otol 2014; 93, page 638". ]. PMID- 25437629 TI - [Regarding "Quiz for specialty certification, Laryngo-Rhino-Otol 2014; 93, page 638"]. PMID- 25437630 TI - [Preoperative checklist]. PMID- 25437631 TI - Predictors of sexual risk behaviour among adolescents from welfare institutions in Malaysia: a cross sectional study. AB - BACKGROUND: In welfare institutions, it is essential to address the health related needs of adolescent populations who often engage in sexual activities. This study examines the association between individual and interpersonal factors concerning sexual risk behaviour (SRB) among adolescents in welfare institutions in Malaysia. METHODS: Data were derived from a cross-sectional study of 1082 adolescents in 22 welfare institutions located across Peninsular Malaysia in 2009. Using supervised self-administered questionnaires, adolescents were asked to assess their self-esteem and to complete questions on pubertal onset, substance use, family structure, family connectedness, parental monitoring, and peer pressure. SRB was measured through scoring of five items: sexual initiation, age of sexual debut, number of sexual partners, condom use, and sex with high risk partners. Multivariate logistic regression analysis was used to examine the various predictors of sexual risk behaviour. RESULTS: The study showed that 55.1% (95%CI = 52.0-58.2) of the total sample was observed to practice sexual risk behaviours. Smoking was the strongest predictor of SRB among male adolescents (OR = 10.3, 95%CI = 1.25-83.9). Among females, high family connectedness (OR = 3.13, 95%CI = 1.64-5.95) seemed to predict the behaviour. CONCLUSION: There were clear gender differences in predicting SRB. Thus, a gender-specific sexual and reproductive health intervention for institutionalised adolescents is recommended. PMID- 25437632 TI - Enhancing depression screening to identify college students at risk for persistent depressive symptoms. AB - BACKGROUND: Depressive symptoms in college students are prevalent and are associated with considerable academic impairment. Many universities have implemented depressive symptom screening programs and the number of students identified as in need of services following screening greatly exceeds available mental health resources. The present study sought to refine depressive symptom screening programs by identifying predictors of a persistent course of depressive symptoms and developing cut-scores for accurately identifying students who will experience a persistent symptom course. METHOD: Students (n=262) who reported elevated depressive symptoms both an initial screening and baseline assessment (n=150) were invited to participate in telephone-based follow-up assessments 4, 8, and 12 months post-baseline. RESULTS: Two depressive symptom courses were identified: a persistently elevated depressive symptoms course and a decreasing depressive symptoms course. Baseline social disconnection and negative feedback seeking both significantly predicted membership in the persistently elevated depressive symptoms course. Cut-scores that robustly discriminated between the two symptom courses were identified. LIMITATIONS: The present sample was predominantly female and Hispanic; the four-month spacing of assessments may have resulted in a failure to identify individuals who experience brief, yet impairing, recurrent depressive episodes. CONCLUSION: These findings can inform approaches to identifying college students most in need of mental health services for depressive symptoms based on the presence of social disconnection and/or negative feedback-seeking. Screening cut-points on social disconnection and negative feedback-seeking measures can reduce the number of cases identified as needing mental health services while retaining the majority of cases who will experience a persistent depressive symptom course. PMID- 25437633 TI - Algorithm for removing scalp signals from functional near-infrared spectroscopy signals in real time using multidistance optodes. AB - A real-time algorithm for removing scalp-blood signals from functional near infrared spectroscopy signals is proposed. Scalp and deep signals have different dependencies on the source-detector distance. These signals were separated using this characteristic. The algorithm was validated through an experiment using a dynamic phantom in which shallow and deep absorptions were independently changed. The algorithm for measurement of oxygenated and deoxygenated hemoglobins using two wavelengths was explicitly obtained. This algorithm is potentially useful for real-time systems, e.g., brain-computer interfaces and neuro-feedback systems. PMID- 25437634 TI - Medical science and the Cruelty to Animals Act 1876: A re-examination of anti vivisectionism in provincial Britain. AB - The Cruelty to Animals Act 1876 was an important but ambiguous piece of legislation. For researchers it stymied British science, yet ensured that vivisection could continue under certain restrictions. For anti-vivisection protestors it was positive proof of the influence of their campaigns, yet overly deferent to Britain's scientific elite. In previous accounts of the Act and the rise of anti-vivisectionism, scientific medicine central to these debates has been treated as monolithic rather than a heterogeneous mix of approaches; and this has gone hand-in-hand with the marginalizing of provincial practices, as scholarship has focused largely on the 'Golden Triangle' of London, Oxford and Cambridge. We look instead at provincial research: brain studies from Wakefield and anthrax investigations in Bradford. The former case elucidates a key role for specific medical science in informing the anti-vivisection movement, whilst the latter demonstrates how the Act affected the particular practices of provincial medical scientists. It will be seen, therefore, how provincial medical practices were both influential upon, and profoundly affected by, the growth of anti vivisectionism and the passing of the Act. This paper emphasises how regional and varied medico-scientific practices were central to the story of the creation and impact of the Cruelty to Animals Act. PMID- 25437635 TI - Guest editors' note: special issue on recent developments in statistical approaches for chemistry and manufacturing control (CMC) and quality-by design(QbD). PMID- 25437636 TI - Production of novel biopolymers in plants: recent technological advances and future prospects. AB - The production of novel biopolymers in plants has the potential to provide renewable sources of industrial materials through agriculture. In this review we will highlight recent progress with plant-based production of polyhydroxyalkanoates (PHAs), silk, elastin, collagen, and cyanophycin with an emphasis on the synthesis of poly[(R)-3-hydroxybutyrate] (PHB), a renewable biodegradable PHA polymer with potential commercial applications in plastics, chemicals, and feed markets. Improved production of PHB has required manipulation of promoters driving expression of transgenes, reduction in activity of endogenous enzymes in competing metabolic pathways, insertion of genes to increase carbon flow to polymer, and basic plant biochemistry to understand metabolic limitations. These experiments have increased our understanding of carbon availability and partitioning in different plant organelles, cell types, and organs, information that is useful for the production of other novel molecules in plants. PMID- 25437637 TI - Editing plant genomes with CRISPR/Cas9. AB - CRISPR/Cas9 is a rapidly developing genome editing technology that has been successfully applied in many organisms, including model and crop plants. Cas9, an RNA-guided DNA endonuclease, can be targeted to specific genomic sequences by engineering a separately encoded guide RNA with which it forms a complex. As only a short RNA sequence must be synthesized to confer recognition of a new target, CRISPR/Cas9 is a relatively cheap and easy to implement technology that has proven to be extremely versatile. Remarkably, in some plant species, homozygous knockout mutants can be produced in a single generation. Together with other sequence-specific nucleases, CRISPR/Cas9 is a game-changing technology that is poised to revolutionise basic research and plant breeding. PMID- 25437638 TI - Updates in inducible transgene expression using viral vectors: from transient to stable expression. AB - The prospect of economically producing useful biologics in plants has greatly increased with the advent of viral vectors. The ability of viral vectors to amplify transgene expression has seen them develop into robust transient platforms for the high-level, rapid production of recombinant proteins. To adapt these systems to stably transformed plants, new ways of deconstructing the virus machinery and linking its expression and replication to chemically controlled promoters have been developed. The more advanced of these stable, inducible hyper expression vectors provide both activated and amplified heterologous transgene expression. Such systems could be deployed in broad acre crops and provide a pathway to fully exploit the advantages of plants as a platform for the manufacture of a wide spectrum of products. PMID- 25437639 TI - Response to Facchin et al.: use of yoked prisms in patients with acquired brain injury: a retrospective analysis. PMID- 25437640 TI - Effect of mycophenolate mofetil on active hepatitis C virus in a woman with lupus nephritis after two years of follow-up. PMID- 25437641 TI - Gcn1 contacts the small ribosomal protein Rps10, which is required for full activation of the protein kinase Gcn2. AB - In eukaryotes, amino acid deprivation leads to the accumulation of uncharged tRNAs that are detected by Gcn2 (general control non-derepressible 2), which in turn phosphorylates eIF2alpha (alpha-subunit of eukaryotic translation initiation factor 2), an essential process for overcoming starvation. In Saccharomyces cerevisiae, sensing amino acid shortages requires that Gcn2 binds directly to its effector protein Gcn1 and both must associate with the ribosome. Our hypothesis is that uncharged tRNAs occur in the ribosomal A-site and that Gcn1 is directly involved in transfer of this starvation signal to Gcn2. In the present paper, we provide evidence that Gcn1 directly contacts the small ribosomal protein S10 (Rps10). Gcn1 residues 1060-1777 showed a yeast two-hybrid (Y2H) interaction with Rps10A. In vitro, Rps10A or Rps10B co-precipitated Gcn1[1060-1777] in an RNA independent manner. rps10ADelta or rps10BDelta strains showed reduced eIF2alpha phosphorylation under replete conditions and shortly after onset of starvation, suggesting that Gcn1-mediated Gcn2 activation was impaired. Overexpression of GST tagged Rps10 reduced growth under amino acid starvation and this was exacerbated by the Gcn1-M7A mutation known to impair Gcn1-ribosome interaction and Gcn2 activity. Under amino acid starvation, eEF3 (eukaryotic translation elongation factor 3) overexpression, known to weaken Gcn1 function on the ribosome, exacerbated the growth defect of rps10ADelta or rps10BDelta strains. Taken together, these data support the idea that Gcn1 contacts ribosome-bound Rps10 to efficiently mediate Gcn2 activation. PMID- 25437642 TI - Rise of post-acute care facilities as a discharge destination of US hospitalizations. PMID- 25437643 TI - Radiometals: towards a new success story in nuclear imaging? AB - Several limitations of (18)F and other non-metallic isotopes have been emphasized by the development of macromolecular biotargeting agents for cancer, including peptides, antibodies, fragments and oligonucleotides, which typically have biological half-lives that are much longer than the radioactive half-life of (18)F. Based on the (18)F-FDG success story, we can wonder whether all critical criteria are or can be fulfilled for the radiometallated bioconjugates to start out from the crowd and which metals have the best chance of success. In this paper we give a brief overview of radiometal isotopes having the potential for PET imaging in terms of physical properties, production capacity and associated chemistry. PMID- 25437647 TI - Superhydrophobic and oleophilic open-cell foams from fibrillar blends of polypropylene and polytetrafluoroethylene. AB - Effective removal of oils from water is of global significance for environmental protection. In this study, we investigate the hydrophobicity and oleophilicity of open-cell polymer foams prepared in a continuous and scalable extrusion process. The material used to prepare the open-cell foams is a fibrillar blend of polypropylene (PP) and polytetrafluoroethylene (PTFE). Scanning electron microscopy (SEM) images of the morphology of the PP/PTFE fibrillar blend reveal that the PTFE has a fibrillar morphology in the PP matrix. SEM micrograph of the extruded foam shows the formation of an interconnected open-cell structure. Using nitrogen pycnometry, the open-cell content is estimated to be 97.7%. A typical bulk density of the open-cell foam is measured to be about 0.07 g cm(-3) corresponding to a void fraction of 92%. Thus, a large three-dimensional space is made available for oil storage. A drop of water on the cross-section of the extruded open-cell foam forms a contact angle of 160 degrees suggesting that the open-cell foam exhibits superhydrophobicity. The open-cell foam can selectively absorb various petroleum products, such as octane, gasoline, diesel, kerosene, light crude oil, and heavy crude oil from water and the uptake capacities range from about 5 to 24 g g(-1). The uptake kinetics can be enhanced by exposing the open-cell foam to high intensity ultrasound which increases the surface porosity of the thin, impervious, foam "skin" layer. The reusability of the foam can be improved by using a matrix polymer which demonstrates superior elastic properties and prevents the foams from undergoing a large permanent deformation upon compression to "squeeze out" the oil. For example, when the PP homopolymer matrix is replaced with a PP random copolymer, the permanent deformation for 10 compressive cycles is reduced from about 30% to 10%. To the best of our knowledge, these PP-based open-cell foams outperform PP-based absorbents conventionally used for oil-spill cleanup applications such as nonwoven PP fibers or melt-blown PP pads. PMID- 25437644 TI - Exogenous C-type natriuretic peptide infusion ameliorates unilateral ureteral obstruction-induced tubulointerstitial fibrosis in rats. AB - Although many experimental therapeutic roles for C-type natriuretic peptide (CNP) have been documented in the field of cardiovascular and pulmonary-vascular disease, the therapeutic uses of CNP to nephropathies are not as well documented. In this study, we established a rat model of unilateral ureteral obstruction (UUO) to observe the beneficial effects of CNP on tubulointerstitial fibrosis (TIF). In UUO rats, CNP administration induced a significant increase in plasma CNP levels, and caused a significant decrease in blood urea nitrogen and creatinine levels. In addition, CNP infusion also alleviated the pathological lesions and collagen IV accumulation in the obstructed kidneys through downregulation of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression. In conclusion, exogenous CNP infusion can ameliorate UUO-induced TIF in rats. However, the use of CNP as a therapeutic agent requires further evaluation before being considered for human TIF. PMID- 25437646 TI - Changes in the cardiac metabolome caused by perhexiline treatment in a mouse model of hypertrophic cardiomyopathy. AB - Energy depletion has been highlighted as an important contributor to the pathology of hypertrophic cardiomyopathy (HCM), a common inherited cardiac disease. Pharmacological reversal of energy depletion appears an attractive approach and the use of perhexiline has been proposed as it is thought to shift myocardial metabolism from fatty acid to glucose utilisation, increasing ATP production and myocardial efficiency. We used the Mybpc3-targeted knock-in mouse model of HCM to investigate changes in the cardiac metabolome following perhexiline treatment. Echocardiography indicated that perhexiline induced partial improvement of some, but not all hypertrophic parameters after six weeks. Non-targeted metabolomics, applying ultra-high performance liquid chromatography mass spectrometry, described a phenotypic modification of the cardiac metabolome with 272 unique metabolites showing a statistically significant change (p < 0.05). Changes in fatty acids and acyl carnitines indicate altered fatty acid transport into mitochondria, implying reduction in fatty acid beta-oxidation. Increased glucose utilisation is indirectly implied through changes in the glycolytic, glycerol, pentose phosphate, tricarboxylic acid and pantothenate pathways. Depleted reduced glutathione and increased production of NADPH suggest reduction in oxidative stress. These data delineate the metabolic changes occurring during improvement of the HCM phenotype and indicate the requirements for further targeted interventions. PMID- 25437645 TI - Hemoglobin-associated oxidative stress in the pericardial compartment of postoperative cardiac surgery patients. AB - Atherosclerosis and valvular heart disease often require treatment with corrective surgery to prevent future myocardial infarction, ischemic heart disease, and heart failure. Mechanisms underlying the development of the associated complications of surgery are multifactorial and have been linked to inflammation and oxidative stress, classically as measured in the blood or plasma of patients. Postoperative pericardial fluid (PO-PCF) has not been investigated in depth with respect to the potential to induce oxidative stress. This is important because cardiac surgery disrupts the integrity of the pericardial membrane surrounding the heart and causes significant alterations in the composition of the pericardial fluid (PCF). This includes contamination with hemolyzed blood and high concentrations of oxidized hemoglobin, which suggests that cardiac surgery results in oxidative stress within the pericardial space. Accordingly, we tested the hypothesis that PO-PCF is highly pro-oxidant and that the potential interaction between inflammatory cell-derived hydrogen peroxide with hemoglobin is associated with oxidative stress. Blood and PCF were collected from 31 patients at the time of surgery and postoperatively from 4 to 48 h after coronary artery bypass grafting, valve replacement, or valve repair (mitral or aortic). PO-PCF contained high concentrations of neutrophils and monocytes, which are capable of generating elevated amounts of superoxide and hydrogen peroxide through the oxidative burst. In addition, PO-PCF primed naive neutrophils resulting in an enhanced oxidative burst upon stimulation. The PO-PCF also contained increased concentrations of cell-free oxidized hemoglobin that was associated with elevated levels of F2alpha isoprostanes and prostaglandins, consistent with both oxidative stress and activation of cyclooxygenase. Lastly, protein analysis of the PO-PCF revealed evidence of protein thiol oxidation and protein carbonylation. We conclude that PO-PCF is highly pro-oxidant and speculate that it may contribute to the risk of postoperative complications. PMID- 25437648 TI - Right ventricular myxoma in a patient with tetralogy of Fallot. AB - INTRODUCTION: Cardiac myxoma is the most common primary cardiac tumour in adulthood and may present in the context of Carney's complex. PRESENTATION OF CASE: A 32-year-old male with a history of repaired tetralogy of Fallot in childhood was admitted with severe pulmonary valve regurgitation and a mobile mass in the right ventricle. The patient underwent pulmonary valve replacement and mass excision. Pathology examination showed myxoma. DISCUSSION: In the majority of cases myxomas originate in the atria, nevertheless they can also be found in a ventricular cavity. Myxoma is a prevalent feature of Carney's complex, an inherited, autosomal disease, characterised by multiple tumours in several organs. Tetralogy of Fallot has also been described in association with Carney's complex. CONCLUSION: Coexistence of tetralogy of Fallot with a cardiac ventricular myxoma in a patient not affected from Carney's complex or other familial syndrome. PMID- 25437649 TI - Floating thumb with double dislocation of carpometacarpal and metacarpo phalangeal joints. AB - INTRODUCTION: Double dislocations of carpometacarpal and metacarpo-phanlageal joints are rare. We report an unusual case of simultaneous dislocation of both CMC and MCP joints in the thumb. PRESENTATION OF CASE: A 31 year old male was admitted following a road traffic accident. He was complaining of pain and deformity of right thumb. The X-ray examination revealed simultaneous dislocation of both CMC and MCP joints. He underwent closed manipulative reduction and percutaneous K wire fixation. The wires were removed after six weeks. After a course of physiotherapy he regained full range of pain free movements. DISCUSSION: The incidence of simultaneous dislocation of both CMC and MCP joints in thumb are associated with high energy injuries. The options of treatment are conservative with cast immobilisation and serial X-rays or operative including closed manipulative reduction and K wire fixation or open reduction and internal fixation. CONCLUSION: The option of treating this rare injury with closed manipulative reduction and percutaneous K wiring gives excellent and predictable results. PMID- 25437650 TI - Metastasis from renal cell carcinoma to thyroid presenting as rapidly growing neck mass. AB - INTRODUCTION: Renal cell carcinoma (RCC) is commonly known as the "internist's tumor" because of its unpredictable behavior. Metastasis to the thyroid gland is rarely found in clinical practice. PRESENTATION OF CASE: We report a rare case of non-thyroid malignancies NTM from renal cell carcinoma 1.5 years after radical nephrectomy in a 58-year-old man with a rapidly growing neck mass. DISCUSSION: Malignant melanoma, breast carcinoma, lung, and skin cancer are the most common sources of non-thyroid malignancies (NTM). Although metastases of NTMs to the thyroid gland are uncommon in clinical practice, it should be considered in patients with a history of prior malignancy and a new thyroid mass. CONCLUSION: Isolated thyroid metastasis should be considered in patients with a previous history of cancer and newly developing thyroid mass. PMID- 25437651 TI - Endobronchial lipomatous hamartoma diagnosed on computed tomography scan in young new mother-A case report. AB - INTRODUCTION: Hamartoma is the most common benign lesion of the lung, but endobronchial localisation is rare. Typically occurs between the fifth and seventh decade of life and in literature has never been described in association with pregnancy. PRESENTATION OF CASE: We report the case of a young woman in whom the tumor seems to have an increase of size after two pregnancies in the course of his life. DISCUSSION: The pulmonary hamartoma is the most common benign lesion of the lung, but endobronchial localisation is rare. Early diagnosis and resection of benign endobronchial tumors may avert significant morbidity and prevent distal lung damage. CONCLUSION: Following histological examination reassessment of the clinical history of our patient led us to hypothesize, on the basis of pathophysiological, a rise in the size of the endobronchial lesion given by hormonal stimulation pregnancy-related. PMID- 25437652 TI - Bilocal recurrence of a neuroendocrine carcinoma of the small intestine: A case report. AB - INTRODUCTION: Neuroendocrine tumors of the small intestine represent about half of all small intestine neoplasms. Recurrence after surgery with curative intention is frequently observed but recurrence rate has not yet been described or analyzed sufficiently. PRESENTATION OF CASE: In this case bilocal recurrence 4 years after curative surgery of an ileocoecal neuroendocrine carcinoma was observed in a 64 year old female. Diagnosis and follow-up was carried out as proposed in current ENETS guidelines using somatostatin receptor scintigraphy for primary diagnosis and Ga-DOTATOC-PET/CT in follow-up. DISCUSSION: We can confirm that PET/CT for somatostatin receptor imaging shows good sensitivity in detecting neuroendocrine neoplasms and should be preferred for diagnostic, if available. For individual adaptation of follow-up procedures, as far as time intervals and preferred imaging methods are concerned, research on recurrence rate and long term outcome after curative surgery should be extended. CONCLUSION: Livelong follow-up after surgical resection of neuroendocrine tumors is necessary and Ga DOTA/TOC-PET/CT should be the method of choice, if available. PMID- 25437653 TI - Swelling of the right thigh for over 30 years-The rare finding of a De Garengeot hernia. AB - INTRODUCTION: Femoral hernias may - in some rare cases - contain the appendix, a phenomenon called de Garengeot hernia. It is usually an incidental finding in hernia repair. We found our case to be of interest because of the long standing femoral swelling before peracute appendicitis led to its removal. PRESENTATION OF CASE: We present the case of a 71-year-old woman with a swelling of the right medial thigh for over more than 30 years. When the swelling suddenly grew in size and became tender, she was referred to our emergency department. Sonographically as well as clinically a femoral hernia was diagnosed. Intraoperatively, the appendix was found and open appendectomy as well as a hernioplasty was performed. DISCUSSION: Open appendectomy is an elegant and safe procedure to repair a long standing de Garengeot hernia. Most case reports call for extensive diagnostics such as CT scan etc. We found a sonography of the femoral region to be conclusive. CONCLUSION: Apart from the inherent risk of sudden incarceration in hernias, De Garengeot hernias can also develop peracute appendicitis years after their formation. This differential diagnosis needs to be taken into consideration in patients presenting with the clinical signs of a femoral hernia. PMID- 25437655 TI - Laparoscopic antral resection with Billroth I reconstruction for a gastric glomus tumor. AB - INTRODUCTION: Gastric glomus tumors are fairly uncommon and mostly benign, with an estimated incidence of 1% of all GI soft tissue tumors. The most common GI site of involvement is the stomach, and in particular the antrum. Some cases have been discovered incidentally, but most are symptomatic presenting with GI bleeding, perforation or abdominal pain. Glomus tumors are submucosal tumors and hence mistaken with the more frequent gastrointestinal stromal tumors. PRESENTATION OF CASE: A 33-year-old woman presented with intermittent dull upper abdominal pain for two days. Abdominal computed tomography (CT) was performed showing a hyperdense mass in the antrum. Endoscopy and endoscopic ultrasound revealed a submucosal antral mass along the greater curvature, suspicious for a gastrointestinal (GI) stromal tumor (GIST), a laparoscopic antrectomy with Billroth I reconstruction was done. Pathological examination revealed that the mass was a gastric glomus tumor. DISCUSSION: The presented case report met all the usual standard criteria commonly used to identify glomus tumors, the uniqueness of the case lies in the occurrence of the glomus tumor in the stomach, first suspected as GIST, then confirmed as a gastric glomus tumor. The vast majority of glomus tumors of the GI tract have been described in the gastric antrum. They occur in adults of all ages with a significant female predominance (78%). CONCLUSION: This case may aid in improving the recognition and diagnosis of this rare entity and in differentiating it from more common GISTs and gastric carcinoids. A built up knowledge between physicians is extremely necessary to avoid common confusion in taking the right medical approach. PMID- 25437654 TI - A case of low-grade fibromyxoid sarcoma with unusual central necrosis in a 77 year-old man confirmed by FUS-CREB3L2 gene fusion. AB - INTRODUCTION: Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft tissue tumor typically affecting young to middle-aged adults. Despite its otherwise benign histologic appearance and indolent nature, it can display fully malignant behavior, and recurrence and metastasis can occur even decades after diagnosis. PRESENTATION OF CASE: Herein, we report a case of LGFMS in the buttock of a 77 year-old man. Magnetic resonance imaging uncovered a well-demarcated tumor measuring 27*20mm with a slightly high intensity on T1-weighted images (WIs) and heterogeneously high intensity on T2-WIs. Histologically, the tumor was composed of bland spindle-shaped cells in a whorled growth pattern with alternating fibrous and myxoid stroma. The tumor stroma was variably hyalinized with arcades of curvilinear capillaries and arterioles with associated perivascular fibrosis. Unusual histology, such as central necrosis and cystic formation, was also noted. Reverse transcription polymerase chain reaction from a formalin-fixed, paraffin embedded biopsy specimen revealed a FUS-CREB3L2 gene fusion (exon6/int/exon5), leading to the diagnosis of LGFMS. DISCUSSION: To the best of our knowledge, this is the second oldest patient to be diagnosed with LGFMS. CONCLUSION: At the time of this report, the patient was alive with no evidence of the disease 4 months after diagnosis without any adjuvant therapy. PMID- 25437656 TI - Endoscopic excision of a lateral ventricular epidermoid-A case report of a novel technique. AB - INTRODUCTION: Epidermoids of the lateral ventricle are relatively rare tumours. As these tumours are soft and relatively avascular, they appear to be ideally suited for endoscopic surgical excision. At present the instruments available are specifically designed for endoscopic intra ventricular surgeries, limitations being inability to rapidly debulk the tumour and achieve adequate haemostasis. We present a case of lateral ventricular epidermoid that was excised endoscopically using a system originally designed for endoscopic disc surgery. PRESENTATION OF CASE: We describe a female patient who presented with recurrent headache and occasional episodes of vomiting since 6 years. Preoperative diagnosis of lateral intra ventricular epidermoid was made with the help of an Magnetic resonance imaging (MRI) of the brain. Intraoperatively, an incision was made over the right Kocher's point and a 2.5cm dural opening was made following a small craniotomy and the Destaudeau endoscope was introduced. A 30 degrees scope and gentle manipulation were used to view the ventricular cavity and ensure near total excision of the tumour. Here we record this novel technique. DISCUSSION: Lateral intra-ventricular tumours are usually approached through a trans-cortical or intra hemispheric approach, under microscope. The use of endoscopes have been largely restricted because of non-availability and relative difficulty in controlling troublesome bleeding, incase of vascular tumours. CONCLUSION: A multi portal endoscope that allows use of routine pituitary instruments would enable the surgeon to achieve haemostasis effectively and, in our opinion, should be a viable alternative to microscope for excision of intra ventricular tumours. PMID- 25437657 TI - Bilateral elastofibroma dorsi: A case report. AB - INTRODUCTION: Elastofibroma dorsi(EFD) is slow-growing, benign, soft tissue tumor of unclear pathogenesis, typically located at the subscapular region of elderly people. It may be unilateral or bilateral. As it exhibits benign behavior, it should be surgically removed only in symptomatic patients. Magnetic resonance imaging (MRI) is a useful tool for assessment of EFD and can potentially help avoid the need for unnecessary biopsy and surgery. PRESENTATION OF CASE: A 62 year-old woman presented with 2 years complaint of back pain, particularly aggravated with shoulder movements and swelling with bilateral elastofibroma dorsi. Both masses were totally excised with bilateral posterolateral subscapular incision. Symptoms were completely controlled and significant discomfort from the surgical procedure was completely resolved with in a few weeks interval from the operation. DISCUSSION: The pathogenesis of the EFD still remains unclear. Elastofibroma dorsi has an unspecific clinical presentation and can be confused with other tumors of the periscapular region Imaging studies are useful for diagnosis. CONCLUSION: Elastofibroma dorsi is benign soft tissue tumor mostly observed in the subscapular regions of elderly female patients. The surgery is indicated in symptomatic cases and must be confined to simple excision of the lesion. PMID- 25437658 TI - Ameloblastic fibro-odontoma. AB - INTRODUCTION: Ameloblastic fibro-odontoma (AFO) is a quite rare, mixed odontogenic tumour generally seen in the early stages of life. Frequent signs of this tumour are asymptomatic swelling, delayed tooth eruption and mixed radiological appearance within well-defined borders. Management of the lesion includes enucleation of the tumour and long-term follow-up. PRESENTATION OF CASE: A 10-year-old girl was referred to our oral and maxillofacial surgery clinic with an incidental radiological finding of radiopaque mass in the posterior region of maxilla. OPG showed unerupted tooth bud of upper right second molar and was being prevented from eruption by the odontome. Under general anaesthesia, the lesion was enucleated and the permanent right upper second molar tooth bud removed. DISCUSSION: Mixed odontogenic tumours are a group of rare and interesting lesions which can mislead the clinician to variety of differential diagnosis. Adequate clinical and radiological investigations, proper surgical excison, accurate histopathological diagnosis, and long term follow up will ensure the right treatment plan for the patient. CONCLUSION: The possibility of a mixed rare tumour should be kept in mind by the clinician where they deal with the swellings of posterior maxilla in children. Histological assessment revealed a final diagnosis of ameloblastic fibro-odontoma. PMID- 25437659 TI - Post-operative bilateral adrenal haemorrhage: A case report. AB - INTRODUCTION: Bilateral adrenal haemorrhage is a rare, but serious, illness carrying an estimated 15% mortality.(1,2) The majority of cases occur in patients with acute, stressful illness, however the exact mechanism underlying adrenal haemorrhage remains unclear. This medical emergency carries significant diagnostic difficulty(4) with non-specific clinical symptoms and variations in electrolyte abnormalities. Timely treatment is important as it prevents both the acute and long-term sequelae of adrenal failure. PRESENTATION OF CASE: This report describes a medical emergency in a surgical patient following emergency surgery for intra-abdominal sepsis. The patient reported non-specific symptoms of confusion, mild pyrexia and vague abdominal pain during the post-operative phase, with subtle electrolyte abnormalities and a low serum cortisol suggestive of adrenal crisis. Timely medical treatment, with intravenous hydrocortisone and intensive monitoring, and appropriate medical follow-up with addition of long term fludrocortisone resulted in a satisfactory outcome. DISCUSSION: This report describes a potentially life-threatening complication of intra-abdominal sepsis with adrenal crisis secondary to bilateral adrenal haemorrhage. In particular, this case highlights the diagnostic difficulty in such surgical patients due to vague symptoms and, in this case, the presence of a presentation variant with acute hyponatraemia and normal potassium. CONCLUSION: This case highlights the importance of awareness of both the symptoms and signs and variation in electrolyte profile when assessing surgical patients post-operatively. In addition, this case highlights the benefit of early recognition and initiation of treatment and the importance of follow-up as long-term medical management is often required to prevent further relapse. PMID- 25437660 TI - Paraduodenal herniation: An internal herniation in a virgin abdomen. AB - INTRODUCTION: A paraduodenal hernia is an uncommon hernia that results from an abnormal rotation of the midgut. Commonly, these hernias are congenital in nature, and are reported to cause 1.5-5.8% of intestinal obstructions. These hernias occur when a part of the jejunum herniates through the posterior portion of the ligament of Treitz. Diagnosing these hernias preoperatively has been shown to be difficult, despite the studies that are available. Early diagnosis is imperative to the patient in order to avoid strangulation of the bowel, which is associated with a high mortality. PRESENTATION OF CASE: In this case, we present a case of a left-sided paraduodenal hernia in a virgin abdomen in a 38-year-old African American male with a herniation of a loop of jejunum through a defect of the posterior portion of the ligament of Treitz. The patient also had a volvulized segment of the proximal jejunum, and part of this bowel was found to be ischemic. DISCUSSION: Acute intestinal obstruction caused by a left paraduodenal hernia is a rare cause of intestinal obstruction. A literary search of PubMed between 1980 and 2012 indicated only 44 cases of intestinal obstruction secondary to a left paraduodenal hernia. CONCLUSION: The patient underwent exploratory laparotomy, and the herniated bowel was found to be ischemic. The hernia was reduced, and the ischemic bowel resected. The defect was closed, and the patient had a non-complicated recovery. PMID- 25437661 TI - Post-splenectomy intrapancreatic accessory spleen mimicking endocrine tumor of the pancreas. AB - INTRODUCTION: Intrapancreatic accessory spleen is an uncommon congenital abnormality of the spleen with no indication for surgical intervention. Among the few cases reported, IPAS coexisted with a normal spleen. We here report the first case of IPAS arising a couple years after splenectomy with the appearance of an endocrine tumor of the pancreas. PRESENTATION OF CASE: A 62-year-old female presented with a one-week history of left upper quadrant discomfort. She had splenectomy for the treatment of hypersplenism caused by cirrhotic portal hypertension two years before this admission. Her physical examination was unremarkable and laboratory data was within the normal range. Both the ultrasonography and magnetic resonance image revealed a small oval-shaped mass in the tail of her pancreas with the diameter 2cm or less. A distal pancreatectomy was performed for the suspection of malignant neuroendocrine tumor of the pancreas. An intrapancreatic accessory spleen was confirmed by the pathologic examination. DISCUSSION: Intrapancreatic accessory spleen is one kind of congenital ectopic spleen without indication for operative intervention. We present the case to support that intrapancreatic accessory spleen may enlarge through a compensatory mechanism, and raise the awareness of this intrapacreatic entity to avoid unnecessary surgical operation. CONCLUSION: IPAS should be highly considered as a differential diagnosis while the lesion is no more than 2.5cm in diameter and/or other accessory spleens show around the splenic hilum. PMID- 25437662 TI - Right sided transmesentric hernia: A rare cause of acute abdomen in adults. AB - INTRODUCTION: Transmesenteric mesocolic hernias are a rare cause of acute abdomen in adults with few reported cases in published literature. PRESENTATION OF CASE: We report a rare case of a 30-year-old male with right-sided transmesenteric hernia of ileum due to a congenital mesocolic defect resulting in acute abdomen, presenting as acute abdomen. The hernia was reduced, small bowel inspected for gangrene and mesenteric hernia repaired, following which the patient made a good recovery and was discharged 5 days later. DISCUSSION: The insidious onset of transmesenteric herniae and lack of specific radiological or laboratory investigations reaffirms the importance of surgeons maintaining a high index of suspicion for this surgical emergency. CONCLUSION: Transmesentric hernia though rare can present as a case of acute abdomen in an emergency. The diagnosis is purely by a CT scan and close monitoring of the patient's general condition in cases of non-specific abdominal pain is essential to identify the rare deteriorating patient for early surgical intervention and optimal outcome. PMID- 25437663 TI - Clinical and surgical management of unilateral prepubertal gynecomastia. AB - INTRODUCTION: Gynecomastia is the benign proliferation of the glandular tissue in the male breast. This condition is thought to be caused by the imbalance between estrogen action relative to androgen action at the breast tissue level. Bilateral gynecomastia is frequently found in the neonatal period, early in puberty, and with increasing age. Prepubertal unilateral gynecomastia in the absence of endocrine abnormalities is extremely rare, with only a few cases in literature. PRESENTATION OF CASE: We present an otherwise healthy boy of 12 years old with unilateral breast masses. No abnormalities were found on ultrasonography and on all endocrine parameters. Treatment consisted in a new "modified" Webster technique. DISCUSSION: The results confirmed validity of this technique in terms of esthetic and functional results, and patient satisfaction. Atypical presentations of gynecomastia are often not recognized. The main pathophysiology of gynecomastia is alteration in the balance between the stimulatory effect of estrogen and the inhibitory effects of androgens on the development of the breast. If there is no causal treatment, surgical resection is the therapy of first choice. CONCLUSION: The exact mechanism of unilateral gynecomastia formation in our case is unclear. The evaluation of unilateral gynecomastia can therefore be complex. In conclusion, the surgical treatment of unilateral gynecomastia requires an individual approach, based on an appropriate diagnostic algorithm. PMID- 25437664 TI - Malignant fibrous histiocytoma presenting with complete opacification of the hemithorax: A case report. AB - BACKGROUND: Malignant fibrous histiocytoma, a subtype of primary lung sarcoma is a very rare disease. It usually presents as a lung nodules and the final diagnosis is made by immunohistochemical studies. METHODS: A 45-year-old patient presented with progressive dyspnea, dry cough and right shoulder pain. Chest X ray revealed complete opacification of the right hemithorax. Chest computed tomography confirmed the presence of a heterogeneous lesion occupying the whole right hemithorax causing a mass effect on the trachea. Ultrasound guided biopsy was done and final pathology was suggestive of malignant fibrous histiocytoma. CONCLUSION: Progressive dyspnea in young otherwise healthy patients should be investigated early on. In our case the presence of right shoulder pain indicates advance disease illustrated by the singular imaging findings. PMID- 25437665 TI - Duodenal perforation by an inferior vena cava filter in a polyarteritis nodosa sufferer. AB - INTRODUCTION: Inferior vena cava (IVC) filters are currently used in the management of pulmonary embolism (PE) and lower limb venous thromboembolism (VTE). Despite their widespread use, associated complications including duodenal perforation have been reported. PRESENTATION OF CASE: We describe a unique case of duodenal perforation 2 years post IVC filter insertion in a patient with polyarteritis nodosa (steroid dependent) and thrombocytopenia secondary to chronic cyclophosphamide use. DISCUSSION: IVC filters are commonly employed in the management of VTE. Associated complications have been reported including filter migration, fracture and adjacent organ perforation. There is growing consensus that temporary IVC filters should be retrieved as soon as possible with dedicated IVC filter registries to ensure patients are not lost to follow-up post insertion. CONCLUSION: Duodenal perforation is a rare complication of IVC filter insertion. This case however illustrates the potentially catastrophic consequences of a relatively common endovascular procedure. Caution should be taken when considering the insertion of IVC filters in patients with longstanding vasculopathies who are on immunosuppressants. PMID- 25437666 TI - Laparoscopic repair of complicated umbilical hernia with Strattice LaparoscopicTM reconstructive tissue matrix. AB - INTRODUCTION: Complex hernias continue to present a challenge. Surgical techniques for repair are carefully considered to reduce risk for complications. Laparoscopic repairs improve postoperative infection rates, and placement of biologic mesh decreases mesh infection rates. However, laparoscopic repairs using biologic mesh is generally challenging due to difficulty with maneuverability. PRESENTATION OF CASE: We present a case of a complex ventral hernia that was laparoscopically repaired using a new FDA cleared laparoscopic biologic graft. The patient had multiple comorbidities, including obesity, hepatitis C, endocarditis secondary to IV drug use, tobacco smoking, bilateral inguinal hernia, and recurrent umbilical hernia. The recurrent hernia was larger, irreducible, and discolored compared to original defect. The patient underwent laparoscopic repair with primary closure and reinforcement with StratticeTM Tissue Matrix Laparoscopic (LifeCell Corporation, Branchburg, NJ). At nine months postoperative, the patient had no evidence of recurrence, infection, or chronic pain, demonstrating early success from the surgical management. DISCUSSION: Presence of multiple comorbidities and incarcerated recurrent hernia increase risk for complications during and/or after hernia repair. Considering these factors, laparoscopic repair with Strattice Laparoscopic and defect closure was a reasonable technique for repair. CONCLUSION: Laparoscopic suture repair reinforced with biologic dermal tissue matrix was successfully performed during a complex hernia repair. PMID- 25437667 TI - Endoscopic removal of intravesical polypropylene suture with plasmakinetic resection after abdominal hysterectomy. AB - INTRODUCTION: Intravesical foreign substances such as mesh or suture are among the rare reasons of recurrent urinary tract infections. Anti-incontinence and prolapsus procedures are associated with mesh/suture extrusion into the bladder, however, this complication is uncommon with abdominal hysterectomy. PRESENTATION OF CASE: A 61-year-old female, obese patient admitted to our clinic with recurrent urinary tract infections and voiding symptoms which were worsened after abdominal hysterectomy. Radiological evaluation revealed an intravesical foreign material within the bladder. The cytoscopy was performed and a polypropylene suture which was inserted from dome, passed through the base and exited from the dome of bladder during abdominal hysterectomy. Transurethral plasmakinetic resection of superficial layer of urothelium between suture entrance and exit sites was performed and suture was removed from the bladder. DISCUSSION: Urogynecological procedures are associated with the increased risk of urethral or ureteral injury, intravesical mesh or suture erosion and fistulae formation. Many different techniques including open, laparoscopic and transvaginal approaches were described for the removal of intravesical mesh/suture extrusion in the literature. Transurethral approach with its minimally invasive and safe nature was used to remove suture in this patient. This technique with the use of plasmakinetic energy has the advantage of decreased risk of bleeding and urothelial injury when compared to monopolar cautery. It also avoids the need for open or extensive surgery which may have a high rate of complications. CONCLUSION: Transurethral resection is the treatment of choice for the removal of intravesical foreign substances. Use of plasmakinetic energy will decrease the risk of complications and avoid the need for open interventions. PMID- 25437668 TI - Aerosol steroids for the treatment of peristomal mucocutaneous breakdown due to severe eczema. AB - INTRODUCTION: We describe a novel treatment of mucocutaneous peristomal junction breakdown in a patient with severe eczema using aerosol steroids, where conventional methods failed to achieve healing. PRESENTATION OF CASE: Observation and photographic evidence showing resolution of severe peristomal eczema in a patient, in whom systemic steroids were contraindicated, using a topical aerosol steroid. We found complete resolution of peristomal eczema and symptoms within four weeks. DISCUSSION: Topical aerosol steroids are better tolerated than alcohol based steroid preparations, achieve improved stoma appliance adherence in comparison to oil based steroid preparations and reduce systemic side effects in comparison to systemic oral steroids. CONCLUSION: Aerosol steroids appear to be a safe and effective way to treat refractory peristomal eczema and may be of use in other peristomal inflammatory conditions including contact dermatitis. PMID- 25437669 TI - High grade angiosarcoma fifteen years after breast conservation therapy with radiation therapy: A case report. AB - INTRODUCTION: Angiosarcoma is a rare tumor of the breast. Secondary angiosarcoma of the breast refers specifically to a tumor that arises after a latency period following radiation. With breast conservation therapy gaining significant popularity to that of mastectomy, more cases of secondary angiosarcoma continue to arise in the irradiated fields of these patients. PRESENTATION OF CASE: The authors describe the case of an 80 year old female who presented fifteen years after her surgery and radiation treatment with two bleeding skin lesions in her breast. These lesions were found to be high grade angiosarcoma upon excision. Due to high cardiac co-morbidity she was treated with re-excision and surveillance. DISCUSSION: This case is an example of a rare sequela to a common procedure. Breast conservation therapy with lumpectomy and radiation has become a popular technique in treating localized breast cancer. Radiation like all therapy has its known adverse effects. Further work is needed with the small amount of published cases of angiosarcoma after breast irradiation so that we may find optimal treatment plans for these patients. Like any rare entity, difficulty lies in accruing enough cases to compare prognosis and results. CONCLUSION: Secondary breast angiosarcoma diagnosis requires frequent follow ups and a high index of suspicion. With mastectomy giving the best chance of treatment in these cases, early detection is crucial in this rare sequela. PMID- 25437670 TI - Case report: The operation for the lumbar disk herniation just after cesarean delivery in the third trimester of pregnancy. AB - INTRODUCTION: Low back pain is common during pregnancy. However, the incidence of symptomatic lumbar disc herniation during pregnancy is very rare. We report a case of lumbar disc herniation underwent discectomy just after cesarean delivery in the third trimester of pregnancy. PRESENTATION OF CASE: A 33-year-old woman presented at 32 weeks gestation. She had a low back pain and the left-sided leg pain below the knee. At 34 weeks gestation, she had severe weakness of the left extension halluces longus, left ankle dorsiflexion. MRI showed a large disc herniation at L4/5 expanded to the spinal canal more. The cesarean delivery was performed in the supine position. The patient was then turned to a prone position, and a left L4/5 discectomy was performed. But the day after surgery, she had a severe low back pain and the right leg pain below the knee. MRI showed a disc herniation at L4/5 on the right side of the spinal canal. At 6 days after the first surgery, a right L4/5 discectomy was performed. In the immediate postoperative period, the patient experienced complete relief of the right leg pain. DISCUSSION: It is necessary to cooperate with a pediatrician, an obstetrician, and an anethesiologists. For obtaining the best outcome on mother and child, it is important to discuss in advance to be able to respond quickly for changeable situation. CONCLUSION: It is necessary to conduct the operation under pregnancy in consideration of the great influence on mother and child. PMID- 25437671 TI - Penetrated sigmoid colon by air gun pellet could be life threatening: A case report. AB - INTRODUCTION: Air and paintball guns have been in existence for over 400 year. Although serious injury or death can result from the use of such guns, previous literature has not mentioned the issue of the penetration of the sigmoid colon by an air gun pellet. PRESENTATION OF CASE: We report a rare case of a 44-year-old Caucasian woman referred to abdominal surgery after an accidental small wound had occurred in the lower left abdominal quadrant that was caused by an air gun pellet. The blood and biochemical analyses were normal but the CT scan revealed the presence of a foreign body - an air gun pellet in the left iliac region of the abdomen. Clinically, during the initial 24h significant changes were not noticed. After 42h, however, pain and local tenderness in the lower left abdominal quadrant was expressed. A laparotomy revealed a retained pellet in the wall of the sigmoid colon and a small leak with colonic content with consecutive local peritonitis also occurred. The foreign body was removed and the opening edges in the colon were excised and closed with the primary suture. DISCUSSION: The hollow organs of the digestive tract, albeit very rarely penetrated by an air gun pellet, do not typically show all signs of an acute abdomen in the early posttraumatic phase. Such injuries can lead to a pronounced infection, which may cause septic shock if not appropriately treated. CONCLUSION: For correct diagnosis, a careful approach and several daily clinical observations are required. PMID- 25437672 TI - Successful management of severe refractory acquired immune bleeding disorder: Prior to insisting surgery. AB - INTRODUCTION: Acquired bleeding disorders are rare and may be missed before surgery. Additionally, they may be refractory to conventional treatments. PRESENTATION OF CASE: A 50-year-old patient experienced prolonged post-operative bleeding when his bleeding disorder was missed prior to his undergoing inguinal herniorrhaphy. Post-operative investigations revealed severe acquired von Willebrand syndrome associated with a monoclonal gammopathy of undetermined significance. A few months later, he required umbilical herniorrhaphy, but he did not respond to attempts to raise his von Willebrand factor antigen and activity levels using conventional therapies, including desmopressin, cryoprecipitate, intravenous immunoglobulin, and Von Willebrand factor concentrate. A triple therapy combination of dexamethasone, intravenous immunoglobulin, and mycophenolate mofetil was administered, with a successful and sustained response, lasting about 2 months. The surgery was performed safely, without any complications. DISCUSSION: Conventional acquired von Willebrand syndrome treatment is usually aimed at replacing von Willebrand factor or stimulating its secretion from storage in endothelial cells. In the present case, the alternative treatment was directed against both the humoral and cell-mediated immune mechanisms. CONCLUSION: This case of acquired bleeding disorder showed that more attention must be given to a patient's coagulation profile, even if only very minor laboratory coagulation derangements are detected prior to surgery, to avoid missing such rare disorders. The described triple therapy demonstrated good effects and may be considered for inclusion in a controlled randomized study to determine its usefulness for other surgeries delayed due to severe acquired bleeding disorders. To the best of our knowledge, this triple combination treatment has not been previously used for the treatment of severe acquired bleeding disorders that are refractory to conventional therapies. PMID- 25437673 TI - Perforated diverticulitis of the sigmoid colon causing a subcutaneous emphysema. AB - INTRODUCTION: Although diverticular disease of the colon is frequent, perforated diverticulitis causing subcutaneous emphysema is a uncommon entity. We wish to present this extremely rare case of perforated colonic diverticulum in the subcutaneous tissue, which is the first one that we have encountered in our practice, along with the accompanying diagnostic and therapeutic issues and a review of the literature. PRESENTATION OF CASE: We report the case of an 83-year old man who admitted to the emergency room due to an abdominal subcutaneous emphysema. Physical examination revealed a severe subcutaneous emphysema especially in the left iliac fossa and abdominal pain. An urgent contrast enhanced abdominal CT scan showed multiple diverticula in the sigmoid colon and multiple air bubbles in the subcutaneous tissue. The exploratory laparotomy identified a perforation of diverticular in subcutaneous tissue. Forty centimeters of colon were resected. The subcutaneous emphysema resolved without specific treatment. The postoperative period was uncomplicated. DISCUSSION: Subcutaneous emphysema of anterior abdomen wall is an obvious physical sign but its etiology is complex to determine and may be potentially lethal. The pathophysiological mechanism involved is the emergence of a pressure gradient between the peritoneum and surrounding structures, causing rupture of the anterior abdominal wall, allowing gas from a perforation to diffuse along tissue planes. CONCLUSION: This physical sign may be of especial value in elderly patient groups amongst whom perforation may be less clinically obvious. General surgeons should bear in mind this rare complication of colonic diverticulosis. PMID- 25437674 TI - Local excision of rectal schwannoma using transanal endoscopic microsurgery: A case report. AB - INTRODUCTION: Schwannoma is a neoplasm originating from the neural crest cells (schwann cells) that form nerve sheaths. These tumors are thought to be benign with little risk of malignant transformation. They rarely affect the gastrointestinal tract, and primary rectal involvement is extremely rare. Until 2013, only 11 cases of anorectal schwannoma have been reported. Optimal surgical treatment of rectal schwannoma has not been established. PRESENTATION OF CASE: We herein describe a 70-year-old woman with a submucosal tumor arising from the posterior wall of the rectum with features mimicking a gastrointestinal stromal tumor. After discussing the operative procedures and obtaining written informed consent, we attempted local excision of the tumor using a transanal endoscopic microsurgery (TEM). The tumor was proved to be S-100 positive schwannoma on immuhistochemical studies. Her postoperative course was uneventful, and there is no evidence of tumor recurrence as of 6 months after surgical excision. DISCUSSION: An extremely rare rectal schwannoma was successfully treated using a TEM without compromising anorectal function. CONCLUSION: TEM is a feasible approach for local excision of rectal tumors with low risk of malignancy. PMID- 25437675 TI - Primary renal artery choriocarcinoma causing secondary renovascular hypertension. AB - INTRODUCTION: Choriocarcinoma is a rare primary germ cell tumour of the ovary composed of cyto- and syncytotrophoblast cells. Most of the choriocarcinomas are normally arising in the gestational trophoblast, gonads and, less frequently, mediastinum, pineal gland and retroperitoneum. PRESENTATION OF CASE: We report a case of primary choriocarcinoma of renal artery causing secondary renovascular hypertension in a 28 years old woman of reproductive age, presenting with abdominal pain, minimal vaginal bleeding and a delayed menstrual period. DISCUSSION: Non-gestational choriocarcinomas, are histologically related to the pregnancy related gestational choriocarcinomas. These two subtypes may have to be differentiated according the clinical and radiological findings and DNA analysis may be used for this purpose as well. In many studies, authors have stated that nongestational choriocarcinoma diagnosis could be implemented in situations where the presence of a pregnancy could not be considered like the prepubertal period. CONCLUSION: Choriocarcinoma should as well be considered among the possibilities in the differential diagnosis of the causes for secondary hypertension, especially within a picture of pregnancy of unknown location, albeit being one of the rarest. PMID- 25437676 TI - Microspheres embolization of juvenile nasopharyngeal angiofibroma in an adult. AB - INTRODUCTION: Juvenile nasopharyngeal angiofibroma (JNA) is a benign though locally aggressive, highly vascular tumor primarily affecting adolescent males which has traditionally posed a significant intraoperative challenge during its resection due to the high risk of uncontrollable hemorrhage. Pre-operative angiographic embolization of the major feeding vessels to the tumor has become a valuable, even necessary, tool in the surgical treatment of these lesions. PRESENTATION OF CASE: Our patient was a 32-year-old man with a chief complaint of recurrent left-sided epistaxis for one year, brisk and continuous for ten days prior to presentation, subsequently found to have a 4cm vascular skull base tumor causing mild expansion of the pterygopalatine fossa. The patient underwent pre operative embolization utilizing 300-500micrometer microspheres injected into the ipsilateral maxillary artery. The following day, the patient underwent definite Stereotactical surgical resection of his JNA tumor. Estimated blood loss during the operation was 50mL, and the patient was discharged the same day. DISCUSSION: Juvenile nasopharyngeal angiofibromas pose a significant bleeding risk for the surgeon due to their highly vascular nature. Pre-operative embolization of juvenile nasopharyngeal angiofibromas can reduce intraoperative blood loss while lessening the risk of massive hemorrhage, shortening operation times, increasing intra-operative visibility, and allowing for easier resection of lesions. CONCLUSION: Pre-operative embolization of JNA is a safe, effective method to prevent against the risk of massive, sometimes fatal, hemorrhage that occurs with these highly vascular tumors. PMID- 25437677 TI - Laparoscopic Nissen Rossetti fundoplication in situs inversus totalis-A blessing in disguise. AB - INTRODUCTION: Laparoscopic Nissen fundoplication and Nissen Rossetti fundoplication represent two different surgical approaches for treating hiatus hernia. We report a Laparoscopic Nissen Rossetti fundoplication (LNRF) for gastro esophageal reflux disease (GERD) in a patient with situs inversus totalis (SIT). PRESENTATION OF CASE: A 38-year-old man with SIT was diagnosed with sliding hiatus hernia. We performed Laparoscopic Nissen Rossetti procedure for this patient. The patient was discharged on first postoperative day after he tolerated oral liquids. DISCUSSION: SIT is a rare anomaly presenting in 1-2 per 10,000 individuals. As this rare anomaly (SIT) led preoperative anticipation of respiratory and blood loss complications the above procedure was chosen. Less operating time, less calculated blood loss and improvement of symptoms with no associated gas bloating syndrome was noted especially with SIT. CONCLUSION: We recommend relook into the Laparoscopic Nissen Rossetti fundoplication as an effective procedure in GERD especially with rare anomalies like SIT. PMID- 25437679 TI - Inflammatory myofibroblastic tumor of the small-bowel mesentery: A case report of nonspecific clinical presentation and a review of the literature. AB - INTRODUCTION: Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm of various anatomical sites, which is histopathologically characterized by spindle shaped cells with myofibroblastic proliferation and inflammatory infiltration. PRESENTATION OF CASE: In this case report, a 37-year-old man presented with nonspecific systemic symptoms, including abdominal pain and weakness, which was diagnosed by multislice computed tomography and ultrasonography. An 8cm*5cm*5cm nodular gray-white firm noninfiltrative mass, which was well localized in the mesentery tissues of small bowel, was observed and the patient underwent surgical resection. DISCUSSION: A review of the literature on IMT of the small-bowel mesentery yielded a small number of previously described cases. This tumor most frequently involves the lungs and arises most commonly in extrapulmonary locations such as the mesentery and omentum. The etiopathogenesis and the clinical course of the disease are unclear. The histological and clinical differential diagnosis of IMT also includes reactive processes and mesenchymal tumors of the gastrointestinal tract. Follow-up after surgical removal documented local recurrence and metastasis. CONCLUSION: The preferred primary treatment is complete surgical excision, and patients require close clinicoradiological follow up. In general, cases treated with complete surgical resection have a good prognosis. PMID- 25437678 TI - Multi-staged flap reconstruction for complex radiation thoracic ulcer. AB - INTRODUCTION: Chest wall reconstruction due to previous radiation therapy can be challenging and complex, requiring a multidisciplinary approach. PRESENTATION OF CASE: The authors present the case of a 84-year-old woman with a right chest wall radionecrosis ulcer, that was submitted to an ablative surgery resulting in a full-thickness defect of 224cm(2), firstly reconstructed with a pedicled omental flap. Due to partial flap necrosis, other debridements and chest wall multi staged flap reconstruction were performed. DISCUSSION: This case highlights that the reconstructive choice should be individualized and dependent on patient and local factors. The authors advise that surgical team should work closely and be well versed in chest wall reconstruction with a variety of pedicled flaps, when a complication occurs. CONCLUSION: A multi-staged flap reconstruction could be a salvage procedure for the coverage of complex, great and complicated chest wall defects due to previous radiation therapy. PMID- 25437680 TI - A 'critical view' on a classical pitfall in laparoscopic cholecystectomy! AB - INTRODUCTION: Laparoscopic cholecystectomy is the most common laparoscopic surgery performed by general surgeons. Although being a routine procedure, classical pitfalls shall be regarded, as misperception of intraoperative anatomy is one of the leading causes of bile duct injuries. The "critical view of safety" in laparoscopic cholecystectomy serves the unequivocal identification of the cystic duct before transection. The aim of this manuscript is to discuss classical pitfalls and bile duct injury avoiding strategies in laparoscopic cholecystectomy, by presenting an interesting case report. PRESENTATION OF CASE: A 71-year-old patient, who previously suffered from a biliary pancreatitis underwent laparoscopic cholecystectomy after ERCP with stone extraction. The intraoperative situs showed a shrunken gallbladder. After placement of four trocars, the gall bladder was grasped in the usual way at the fundus and pulled in the right upper abdomen. Following the dissection of the triangle of Calot, a "critical view of safety" was established. As dissection continued, it however soon became clear that instead of the cystic duct, the common bile duct had been dissected. In order to create an overview, the gallbladder was thereafter mobilized fundus first and further preparation resumed carefully to expose the cystic duct and the common bile duct. Consecutively the operation could be completed in the usual way. DISCUSSION: Despite permanent increase in learning curves and new approaches in laparoscopic techniques, bile duct injuries still remain twice as frequent as in the conventional open approach. In the case presented, transection of the common bile duct was prevented through critical examination of the present anatomy. The "critical view of safety" certainly offers not a full protection to avoid biliary lesions, but may lead to a significant risk minimization when consistently implemented. CONCLUSION: A sufficient mobilization of the gallbladder from its bed is essential in performing a critical view in laparoscopic cholecystectomy. PMID- 25437681 TI - Morgagni hernia treated by reduced port surgery. AB - INTRODUCTION: The laparoscopic repair of a rare diaphragmatic Morgagni hernia using the reduced port approach is described. PRESENTATION OF CASE: An 85-year old female presented with a 2 days history of upper abdominal discomfort and loss of appetite. We diagnosed her condition as a Morgagni hernia by morphological studies and performed laparoscopic mesh placement with a multi-channel port and 12-mm port. This elderly patient had a rapid postoperative recovery. A 2-year follow-up CT showed no recurrence of the hernia. DISCUSSION: Recent trends in laparoscopic procedures have been toward minimizing the number of incisions to reduce invasiveness. This case indicated that the reduced port approach can be considered a suitable and safe procedure for treatment of Morgagni hernia. CONCLUSION: The reduced port approach is a good indication for Morgagni hernia. PMID- 25437682 TI - Hypoglycemia with a large retroperitoneal mass - Case report. AB - INTRODUCTION: Retroperitoneal sarcomas have rarely been reported to secrete insulin-growth factor II (IGF-II) and produce an enigmatic hypoglycemia. IGF-II secreting sarcomas represent an extremely rare subset of soft tissue tumors, and reports are limited to a handful of cases. PRESENTATION OF CASE: The authors present the case of hypoglycemia due to an IGF-II-secreting retroperitoneal sarcoma that was successfully treated by complete surgical resection. This report describes the diagnosis and management of this rare syndrome with 1-year follow up and a review of the literature. DISCUSSION: Steroid and growth hormone therapies also have efficacy to treat this hypoglycemia in some patients. However, outcomes appear better if combined with surgical resection. CONCLUSIONS: The findings of this case report and review of the literature support a primary role for complete tumor resection to address tumor-induced hypoglycemia. PMID- 25437683 TI - Delayed duodenal stump blow-out following total gastrectomy for cancer: Heightened awareness for the continued presence of the surgical past in the present is the key to a successful duodenal stump disruption management. A case report. AB - INTRODUCTION: Duodenal stump disruption remains one of the most dreadful postgastrectomy complications, posing an overwhelming therapeutic challenge. PRESENTATION OF CASE: The present report describes the extremely rare occurrence of a delayed duodenal stump disruption following total gastrectomy with Roux-en-Y esophagojejunostomy for cancer, because of mechanical obstruction of the distal jejunum resulting in increased backpressure on afferent limp and duodenal stump. Surgical management included repair of distal jejunum obstruction, mobilization and re-stapling of the duodenum at the level of its intact second part and retrograde decompressing tube duodenostomy through the proximal jejunum. DISCUSSION: Several strategies have been proposed for the successful management post-gastrectomy duodenal stump disruption however; its treatment planning is absolutely determined by the presence or not of generalized peritonitis and hemodynamic instability with hostile abdomen. In such scenario, urgent reoperation is mandatory and the damage control principle should govern the operative treatment. CONCLUSION: Considering that scientific data about duodenal stump disruption have virtually disappeared from the current medical literature, this report by contradicting the anachronism of this complication aims to serve as a useful reminder for gastrointestinal surgeons to be familiar with the surgical techniques that provide the ability to properly manage this dreadful postoperative complication. PMID- 25437684 TI - Schloffer's tumor: Case report and review of the literature. AB - INTRODUCTION: The so-called Schloffer tumor (ST) is a rare inflammatory pseudotumor. It usually appears several years after abdominal surgery or trauma. PRESENTATION OF CASE: A 32-year-old man was referred to our hospital complaining of a painful mass in the left hypochondrium, postprandial distension and a weight loss of about 14kg. He had had a left inguinal hernioplasty without mesh the previous year. Ultrasonography of the abdomen showed a 2cm*2cm hypoechoic lesion in contact with the abdominal wall. Computerized tomography of the abdomen showed a heterogeneous mass in the great omentum. Laparoscopic exploration revealed an omental mass firmly attached to the abdominal wall. A great deal of purulent fluid spread during the procedure. Due to the difficult exploration, the procedure converted to hand assisted laparoscopy. We find an omental tumor involving the stomach and the transverse colon. Inside the mass there were purulent material and non-absorbable sutures. A drain was left inside the cavity of the abscess. Histological examination showed chronic inflammation. DISCUSSION: ST characteristically presents a central chronic abscess containing non absorbable sutures. It has been described after appendectomy, hernioplasty, hysterectomy, gastrectomy or colonic resections. Although benign, its progressive growth and infiltrating behavior resemble malignant tumors. CONCLUSION: We suggest that a mini-invasive approach should always be performed. The interesting thing about this case is the appearance of the tumor in a place far away from the previous surgical site. A simple drainage and removal of suture material solves the problem of these patients. PMID- 25437685 TI - Abdominal wall hernia and aortic injury secondary to blunt trauma: Case report and review of the literature. AB - INTRODUCTION: Traumatic abdominal wall hernia (TAWH) and traumatic abdominal aortic injury (TAAI) are two uncommon complications secondary to blunt trauma. In both TAWH and TAAI, reported cases are often associated with poly-trauma. TAWH may be initially missed if more pressing issues are identified during the patient's primary survey. TAAI may be an incidental finding on imaging or, if severe, a cause of an acute abdomen and hemodynamic abnormality. PRESENTATION OF CASE: A 54-year-old white male suffered a TAWH and TAAI (pseudoaneurysm) due to severe blunt trauma. TAWH was apparent on physical exam and the TAAI was suspected on computed tomography (CT). The patient's TAWH was managed with a series of abdominal explorations and the TAAI was repaired with endovascular stenting. DISCUSSION: TAWH and TAAI are commonly due to severe blunt trauma from motor vehicle collisions. Diagnosis is made through physical exam, imaging studies, or surgical exploration. A variety of surgical techniques achieve technical success. CONCLUSION: The patient with blunt trauma to the abdomen is at risk for TAWH and TAAI, which are often associated with other injuries. Investigations should include thorough clinical exam through secondary survey and radiologic imaging in the hemodynamically normal patient. PMID- 25437686 TI - Streptococcus pluranimalium: A novel human pathogen? AB - INTRODUCTION: We present the first case of a subdural empyema caused by Streptococcus pluranimalium, in a healthy adolescent male as a possible complication of subclinical frontal sinusitis. Clinical features, diagnostic approach and management of subdural empyema are discussed. PRESENTATION OF CASE: A 17-year-old male with a 2 day history of headache and nausea was referred to our Emergency Department (ED) as a case of possible meningitis. He was afebrile, lethargic and drowsy with significant neck stiffness on examination. Computerized tomography (CT) revealed a large frontotemporoparietal subdural fluid collection with significant midline shift. Subsequent contrast-enhanced CT established the presence of intracranial empyema; the patient underwent immediate burr-hole evacuation of the pus and received 7 weeks of intravenous antibiotics, recovering with no residual neurological deficit. DISCUSSION: The diagnosis of subdural empyema as a complication of asymptomatic sinusitis in an immunocompetent patient with no history of fever or upper respiratory symptoms was unanticipated. Furthermore, the organism Streptococcus pluranimalium that was cultured from the pus has only been documented twice previously in medical literature to cause infection in humans, as it is primarily a pathogen responsible for infection in bovine and avian species. CONCLUSION: Subdural empyema represents a neurosurgical emergency and if left untreated is invariably fatal. Rapid diagnosis, surgical intervention and intensive antibiotic therapy improve both morbidity and mortality. PMID- 25437687 TI - Cryptogenic stroke following abdominal free flap breast reconstruction surgery. AB - INTRODUCTION: Abdominal free flap breast reconstruction is regarded as the gold standard method of post-mastectomy breast reconstruction by many. It is a major surgery which can be associated with varied systemic complications. To date, there have been no reports of cerebrovascular complications in the literature which examine the possible relation between thromboembolism and patent foramen ovale (PFO) in patients undergoing microvascular breast reconstruction. PRESENTATION OF CASE: A 54-year old female with a pre-existing PFO developed a stroke following bilateral mastectomies and immediate free flap breast reconstruction on postoperative day 5. This was attributed to an air embolus caused by central venous pressure line removal. After uneventful intra and early postoperative periods, the patient had collapsed suddenly on day 5 and become unresponsive immediately following the removal of a central venous line. Brain magnetic resonance imaging confirmed a cerebrovascular accident. This resolved within 48h following therapeutic heparinisation. A clinical diagnosis of paradoxical embolism was made and she was subsequently referred to the cardiologists for angiographic closure of the PFO. DISCUSSION: The case study herein reported gives an account that PFO can have considerable health implications in the early postoperative period and conceivably intraoperatively in patients undergoing major reconstructive surgeries. CONCLUSION: Surgeons and cardiologists should be aware of this cerebrovascular complication secondary to PFO following major reconstructive surgery such as microvascular breast reconstruction. It also serves to challenge microvascular surgeons to reconsider routine use of central venous pressure lines in free flap patients who might otherwise have good peripheral vessels for postoperative fluid and antibiotic administration. PMID- 25437688 TI - Emergency thyroidectomy: Due to acute respiratory failure. AB - INTRODUCTION: Giant cervical and mediastinal goiter may lead to acute respiratory failure caused by laryngotracheal compression and airway obstruction. Here, we present a case admitted to the emergency service with a giant goiter along with respiratory failure and poor general health status, which required urgent surgical intervention. PRESENTATION OF CASE: A 71-year-old female admitted to the emergency room with shortness of breath and poor general health status resulting from a giant cervical swelling progressively increased during the last 7 years and constituted severe respiratory failure which has become severe in the last one month. A giant nodular goiter of the left thyroid lobe extending retrosternally, causing tracheal compression, limiting the neck movements was detected with clinical examination and bedside ultrasound. Emergency thyroidectomy was planned. Fiberoptic-assisted awake nasal intubation was performed in the operating room. Emergency total thyroidectomy was performed for the life-threatening respiratory failure. Postoperative period was uneventful. She was transferred from intensive care unit to the ward on postoperative day 3 and was discharged from the hospital on the postoperative 7th day. Benign multinodular hyperplasia was reported on the histopathological report. Patient was included in routine follow-up. DISCUSSION: In the present case tracheal destruction due to compression of the giant goiter was found in agreement with previous reports. Emergency thyroidectomy was performed after awake intubation since it is a common surgical option for the treatment of giant goiter causing severe airway obstruction. CONCLUSION: Respiratory failure due to giant nodular goiter is a life-threatening situation and should be treated immediately by performing awake endotracheal intubation following emergency total thyroidectomy. PMID- 25437689 TI - Intussusception caused by dried apricot: A case report. AB - INTRODUCTION: An unusual cause of intussusception due to small bowel obstruction secondary to dried apricot consumption was encountered. Phytobezoar small bowel obstruction is a rare, but interesting pathology that accounts for 2-4% of small bowel obstructions (18). Even rarer, is an intussusception caused by dried fruit ingestion. We present the case of a 56-year-old female that presented with an intussusception after she ingested a large amount of dried apricots. PRESENTATION OF CASE: The patient is a 56-year-old female with a small bowel obstruction secondary to intussusception in the distal ileum. She was taken to the operating room for a celiotomy where an intussusception of the distal small bowel was found. An enterotomy was performed which revealed dried apricots as the lead point. The intussusception was successfully reduced and the apricots removed. DISCUSSION: Small bowel obstruction due to intussusception can be caused secondary to malignancy, Meckel's Diverticulum, benign neoplasm, and strictures. A less common cause for small bowel obstruction due to intussusception in adults is secondary to mechanical obstruction by bezoars. Risk factors for bezoar formation include previous gastric surgery, diabetes, and mastication problems. CONCLUSION: Bezoars are an extremely rare cause of intussusception in adults. A high level of suspicion needs to exist in the presence of a history of eating dried fruit, history of gastric surgery, diabetes mellitus, and problems with mastication. Various treatment modalities exist to treat obstructions secondary to bezoars, including open reduction and removal of bezoar via enterotomy. PMID- 25437690 TI - Ischemic hepatitis after percutaneous nephrolitotomy: A case report. AB - INTRODUCTION: Ischemic hepatitis (IH) is the necrosis of the centrilobular hepatocytes of liver and is secondary to liver hypoperfusion in most of the cases. The diagnosis is usually based on biochemical findings due to the absence of symptoms and signs. Although the disease course is often mild, and sometimes is even not diagnosed, the outcome is poor if the etiology of hypotension and liver anoxia is not promptly corrected. PRESENTATION OF CASE: A 64-year-old patient who underwent percutaneous nephrolithotomy (PNL) for right renal pelvic stone developed acute IH at first postoperative day as a result of hemorrhage related severe hypotension. After restoring hemodynamic parameters, she completely recovered 2 weeks after the operation. DISCUSSION: IH is a frequent cause of marked serum aminotransferase elevation and most commonly occurs as a result of arterial hypoxemia and insufficient hepatic perfusion. Although no specific treatment of IH exists, stabilizing the hemodynamic parameters of the patient resolves the problem in most of the cases. CONCLUSION: This case is presented to demonstrate that ischemic hepatitis should be kept in mind if severe hemorrhage occurs during PNL. PMID- 25437691 TI - Synthesis, Characterization, Physical Properties, and OLED Application of Single BN-Fused Perylene Diimide. AB - It is very challenging to introduce azaborine into an electron-deficient arene system because of unfavorable intramolecular electrophilic borylation reaction. In this report, we adopted a straightforward methodology to construct a large BN embedded pi-system based on perylene diimide (PDI), which is the first BN annulation example with highly electron-withdrawing polycyclic aromatic hydrocarbons. The physical properties of the as-prepared N,N-dicyclohexyl-1-aza 12-bora-benzoperylene diimide (PDI-1BN) have been fully studied, and its sensing behavior to fluoride ion as well as its OLED performance was also investigated. PMID- 25437692 TI - [Effects of ketamine and midazolam on emergence agitation after sevoflurane anaesthesia in children receiving caudal block: a randomized trial]. AB - BACKGROUND AND OBJECTIVES: Emergence agitation is a common postanaesthetic problem in children after sevoflurane anaesthesia. We aimed to compare the effects of ketamine and midazolam administered intravenously, before the end of surgery, for prevention of emergence agitation in children who received caudal block for pain relief under sevoflurane anaesthesia. METHODS: 62 American Society of Anesthesiologists patient classification status I children, aged 2-7 years, scheduled for inguinal hernia repair, circumcision or orchidopexy were enrolled to the study. Anaesthesia was induced with sevoflurane 8% in a mixture of 50% oxygen and nitrous oxide. After achieving adequate depth of anaesthesia, a laryngeal mask was placed and then caudal block was performed with 0.75mLkg(-1), 0.25% bupivacaine. At the end of the surgery, ketamine 0.25mgkg(-1), midazolam 0.03mgkg(-1) and saline were given to ketamine, midazolam and control groups, respectively. Agitation was assessed using Paediatric Anaesthesia Emergence Delirium scale and postoperative pain was evaluated with modified Children's Hospital of Eastern Ontario Pain Scale. RESULTS AND CONCLUSIONS: Modified Children's Hospital of Eastern Ontario Pain Scale scores were found higher in control group than in ketamine and midazolam groups. Paediatric Anaesthesia Emergence Delirium scores were similar between groups. Modified Children's Hospital of Eastern Ontario Pain Scale and Paediatric Anaesthesia Emergence Delirium scores showed a significant decrease by time in all groups during follow up in postanaesthesia care unit. The present study resulted in satisfactory Paediatric Anaesthesia Emergence Delirium scores which are below 10 in all groups. As a conclusion, neither ketamine nor midazolam added to caudal block under sevoflurane anaesthesia did show further effect on emergence agitation. In addition, pain relief still seems to be the major factor in preventing emergence agitation after sevoflurane anaesthesia. PMID- 25437693 TI - [Effects of dexmedetomidine in conjunction with remote ischemic preconditioning on renal ischemia-reperfusion injury in rats]. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the effects of remote ischemic preconditioning by brief ischemia of unilateral hind limb when combined with dexmedetomidine on renal ischemia-reperfusion injury by histopathology and active caspase-3 immunoreactivity in rats. METHODS: 28 Wistar albino male rats were divided into 4 groups. Group I (Sham, n=7): Laparotomy and renal pedicle dissection were performed at 65th minute of anesthesia and the rats were observed under anesthesia for 130min. Group II (ischemia-reperfusion, n=7): At 65th minute of anesthesia bilateral renal pedicles were clamped. After 60min ischemia 24h of reperfusion was performed. Group III (ischemia reperfusion+dexmedetomidine, n=7): At the fifth minute of reperfusion (100MUg/kg intra-peritoneal) dexmedetomidine was administered with ischemia-reperfusion group. Reperfusion lasted 24h. Group IV (ischemia-reperfusion+remote ischemic preconditioning+dexmedetomidine, n=7): After laparotomy, three cycles of ischemic preconditioning (10min ischemia and 10min reperfusion) were applied to the left hind limb and after 5min with group III. RESULTS: Histopathological injury scores and active caspase-3 immunoreactivity were significantly lower in the Sham group compared to the other groups. Histopathological injury scores in groups III and IV were significantly lower than group II (p=0.03 and p=0.05). Active caspase-3 immunoreactivity was significantly lower in the group IV than group II (p=0.01) and there was no significant difference between group II and group III (p=0.06). CONCLUSIONS: Pharmacologic conditioning with dexmedetomidine and remote ischemic preconditioning when combined with dexmedetomidine significantly decreases renal ischemia-reperfusion injury histomorphologically. Combined use of two methods prevents apoptosis via active caspase-3. PMID- 25437694 TI - [Comparison of different tests to determine difficult intubation in pediatric patients]. AB - BACKGROUND: The difficulties with airway management is the main reason for pediatric anesthesia-related morbidity and mortality. OBJECTIVE: To assess the value of modified Mallampati test, Upper-Lip-Bite test, thyromental distance and the ratio of height to thyromental distance to predict difficult intubation in pediatric patients. DESIGN: Prospective analysis. MEASUREMENTS AND RESULTS: Data were collected from 5 to 11 years old 250 pediatric patients requiring tracheal intubation. The Cormack and Lehane classification was used to evaluate difficult laryngoscopy. Sensitivity, specificity, positive predictive value and AUC values for each test were measured. RESULTS: The sensitivity and specificity of modified Mallampati test were 76.92% and 95.54%, while those for ULBT were 69.23% and 97.32%. The optimal cutoff point for the ratio of height to thyromental distance and thyromental distance for predicting difficult laryngoscopy was 23.5 (sensitivity, 57.69%; specificity, 86.61%) and 5.5cm (sensitivity, 61.54%; specificity, 99.11%). The modified Mallampati was the most sensitive of the tests. The ratio of height to thyromental distance was the least sensitive test. CONCLUSION: These results suggested that the modified Mallampati and Upper-Lip Bite tests may be useful in pediatric patients for predicting difficult intubation. PMID- 25437695 TI - [Subarachnoid clonidine and trauma response in cardiac surgery with cardiopulmonary bypass]. AB - BACKGROUND AND OBJECTIVES: The intense trauma response triggered by cardiopulmonary bypass can lead to increased morbidity and mortality. The present study evaluated whether clonidine, a drug of the class of alpha-2 agonists, administered by spinal route, without association with local anesthetics or opioids, reduces this response in cardiac surgery with cardiopulmonary bypass. METHOD: A total of 27 patients between 18 and 75 years old, divided by non blinded fashion into a control group (15) and a clonidine group (12), were studied. All patients underwent identical technique of general anesthesia. Then, only the clonidine group received 1MUgkg(-1) clonidine by spinal route. Levels of blood glucose, lactate and cortisol were measured at three consecutive times: T1, at the time of installation of invasive arterial pressure; T2, 10min after the first dose for cardioplegia; and T3, at the time of skin suture; and troponin I values at T1 and T3. The variation of results between T2-T1, T3-T2, and T3-T1 was also evaluated. RESULTS: There was a statistically significant difference only with respect to the variation in blood glucose in the clonidine group: T3-T2, p=0.027 and T3-T1, p=0.047. CONCLUSIONS: Spinal clonidine at a dose of 1MUgkg(-1) did not decrease blood measurements of troponin, cortisol, or lactate. Blood glucose suffered a more moderate variation during the procedure in the clonidine group. This fact, already reported in the literature, requires further investigation to be clarified. PMID- 25437696 TI - [Sugammadex versus neostigmine in pediatric patients: a prospective randomized study]. AB - BACKGROUND AND OBJECTIVES: Acetylcholinesterase inhibitors may cause postoperative residual curarization when they are used for reversal of neuromuscular blockade. Sugammadex reverses neuromuscular blockade by chemical encapsulation and is not associated with the side effects that may occur with the use of anticholinesterase agents. Because of increased outpatient surgical procedures postoperative residual curarization and rapid postoperative recovery have a greater importance in the pediatric patient population. The aim of this study was to compare the efficacy of sugammadex and neostigmine on reversing neuromuscular blockade in pediatric patients undergoing outpatient surgical procedures. METHODS: 80 patients, aged 2-12 years, scheduled for outpatient surgery were enrolled in this randomized prospective study. Neuromuscular blockade was achieved with 0.6mgkg(-1) rocuronium and monitorized with train-of four. Group RN (n=40) received 0.03mgkg(-1) neostigmine, Group RS (n=40) received 2mgkg(-1) sugammadex for reversal of rocuronium. Extubation time (time from the reversal of neuromuscular blockade to extubation), train-of-four ratio during this time, time to reach train-of-four>0.9, and probable complications were recorded. RESULTS: There was no significant difference between the patients' characteristics. Extubation time and time to reach train-of-four>0.9 were significantly higher in Group RN (p=0.001, p=0.002). Train-of-four at the time of neostigmine/sugammadex injection in Group RN were significantly higher than in the RS group (p=0.020). Extubation train-of-four ratio was significantly lower in Group RN (p=0.002). CONCLUSION: Sugammadex provides safer extubation with a shorter recovery time than neostigmine in pediatric patients undergoing outpatient surgical procedures. PMID- 25437697 TI - [Comparison of the effects of magnesium sulphate and dexmedetomidine on surgical vision quality in endoscopic sinus surgery: randomized clinical study]. AB - BACKGROUND AND OBJECTIVES: Even a small amount of bleeding during endoscopic sinus surgery can corrupt the endoscopic field and complicate the procedure. Various techniques, including induced hypotension, can minimize bleeding during endoscopic sinus surgery. The aim of this study was to compare the surgical vision quality, haemodynamic parameters, postoperative pain, and other effects of magnesium, a hypotensive agent, with that of dexmedetomidine, which was initially developed for short-term sedation in the intensive care unit but also is an alpha 2 agonist sedative. METHOD: 60 patients between the ages of 18 and 45 years were divided into either the magnesium group (Group M) or the dexmedetomidine group (Group D). In Group M, magnesium sulphate was given at a pre-induction loading dose of 50mgkg(-1) over 10min and maintained at 15mgkg(-1)h(-1); in Group D, dexmedetomidine was given at 1mcgkg(-1) 10min before induction and maintained at 0.6mcgkg(-1)h(-1). Intraoperatively, the haemodynamic and respiratory parameters and 6-point intraoperative surgical field evaluation scale were recorded. During the postoperative period, an 11-point numerical pain scale, the Ramsay sedation scale, the nausea/vomiting scale, the adverse effects profile, and itching parameters were noted. RESULTS: Group D showed a significant decrease in intraoperative surgical field evaluation scale scale score and heart rate. The average operation time was 50min, and Group M had a higher number of prolonged surgeries. No significant difference was found in the other parameters. CONCLUSIONS: Due to its reduction of bleeding and heart rate in endoscopic sinus surgery and its positive impacts on the duration of surgery, we consider dexmedetomidine to be a good alternative to magnesium. PMID- 25437698 TI - [The incidence of emergence delirium and risk factors following sevoflurane use in pediatric patients for day case surgery, Kingston, Jamaica]. AB - BACKGROUND AND OBJECTIVES: Emergence delirium is a distressing complication of the use of sevoflurane for general anesthesia. This study sought to determine the incidence of emergence delirium and risk factors in patients at a specialist pediatric hospital in Kingston, Jamaica. METHODS: This was a cross-sectional, observational study including pediatric patients aged 3-10 years, ASA I and II, undergoing general anesthesia with sevoflurane for elective day-case procedures. Data collected included patients' level of anxiety pre-operatively using the modified Yale Preoperative Anxiety Scale, surgery performed, anesthetic duration and analgesics administered. Postoperatively, patients were assessed for emergence delirium, defined as agitation with non-purposeful movement, restlessness or thrashing; inconsolability and unresponsiveness to nursing and/or parental presence. The need for pharmacological treatment and post-operative complications related to emergence delirium episodes were also noted. RESULTS: 145 children were included, with emergence delirium occurring in 28 (19.3%). Emergence delirium episodes had a mean duration of 6.9+/-7.8min, required pharmacologic intervention in 19 (67.8%) children and were associated with a prolonged recovery time (49.4+/-11.9 versus 29.7+/-10.8min for non-agitated children; p<0.001). Factors positively associated with emergence delirium included younger age (p=0.01, OR 3.3, 95% CI 1.2-8.6) and moderate and severe anxiety prior to induction (p<0.001, OR 5.6, 95% CI 2.3-13.0). Complications of emergence delirium included intravenous line removal (n=1), and surgical site bleeding (n=3). CONCLUSION: Children of younger age with greater preoperative anxiety are at increased risk of developing emergence delirium following general anesthesia with sevoflurane. The overall incidence of emergence delirium was 19%. PMID- 25437699 TI - [Bedside prediction of right subclavian venous catheter insertion length]. AB - BACKGROUND AND OBJECTIVE: The present study aimed to evaluate whether right subclavian vein (SCV) catheter insertion depth can be predicted reliably by the distances from the SCV insertion site to the ipsilateral clavicular notch directly (denoted as I-IC), via the top of the SCV arch, or via the clavicle (denoted as I-T-IC and I-C-IC, respectively). METHOD: In total, 70 SCV catheterizations were studied. The I-IC, I-T-IC, and I-C-IC distances in each case were measured after ultrasound-guided SCV catheter insertion. The actual length of the catheter between the insertion site and the ipsilateral clavicular notch, denoted as L, was calculated by using chest X-ray. RESULTS: L differed from the I-T-IC, I-C-IC, and I-IC distances by 0.14+/-0.53, 2.19+/-1.17, and 0.45+/-0.68cm, respectively. The mean I-T-IC distance was the most similar to the mean L (intraclass correlation coefficient=0.89). The mean I-IC was significantly shorter than L, while the mean I-C-IC was significantly longer. Linear regression analysis provided the following formula: Predicted SCV catheter insertion length (cm)=-0.037+0.036*Height (cm)+0.903*I-T-IC (cm) (adjusted r(2)=0.64). CONCLUSION: The I-T-IC distance may be a reliable bedside predictor of the optimal insertion length for a right SCV cannulation. PMID- 25437700 TI - [The effect of different doses of esmolol on hemodynamic, bispectral index and movement response during orotracheal intubation: prospective, randomized, double blind study]. AB - OBJECTIVE: A prospective, randomized and double-blind study was planned to identify the optimum dose of esmolol infusion to suppress the increase in bispectral index values and the movement and hemodynamic responses to tracheal intubation. MATERIALS AND METHODS: 120 patients were randomly allocated to one of three groups in a double-blind fashion. 2.5mgkg(-1) propofol was administered for anesthesia induction. After loss of consciousness, and before administration of 0.6mgkg(-1) rocuronium, a tourniquet was applied to one arm and inflated to 50mmHg greater than systolic pressure. The patients were divided into 3 groups; 1mgkg(-1)h(-1) esmolol was given as the loading dose and in Group Es50 50MUgkg( 1)min(-1), in Group Es150 150MUgkg(-1)min(-1), and in Group Es250 250MUgkg( 1)min(-1) esmolol infusion was started. Five minutes after the esmolol has been begun, the trachea was intubated; gross movement within the first minute after orotracheal intubation was recorded. RESULTS: Incidence of movement response and the DeltaBIS max values were comparable in Group Es250 and Group Es150, but these values were significantly higher in Group Es50 than in the other two groups. In all three groups in the 1st minute after tracheal intubation heart rate and mean arterial pressure were significantly higher compared to values from before intubation (p<0.05). In the study period there was no significant difference between the groups in terms of heart rate and mean arterial pressure. CONCLUSION: In clinical practise we believe that after 1mgkg(-1) loading dose, 150MUgkg( 1)min(-1) iv esmolol dose is sufficient to suppress responses to tracheal intubation without increasing side effects. PMID- 25437701 TI - [Correlation between oro and hypopharynx shape and position with endotracheal intubation difficulty]. AB - BACKGROUND AND OBJECTIVE: Prediction of intubation difficulty can save patients from major preoperative morbidity or mortality. The purpose of this paper is to assess the correlation between oro-hypo pharynx position, neck size, and length with endotracheal intubation difficulty. The study also explored the diagnostic value of Friedman Staging System in prediction cases with difficult intubation. METHOD: The consecutive 500 ASA (I, II) adult patients undergoing elective surgery were evaluated for oro and hypopharynx shape and position by modified Mallampati, Cormack and Lehane score as well as Friedman obstructive sleep apnea classification systems. Neck circumference and length were also measured. All cases were intubated by a single anesthesiologist who was uninformed of the above evaluation and graded intubation difficulty in visual analog score. Correlation between these findings and difficulty of intubation was assessed. Sensitivity, Specificity, Positive and Negative Predictive Values were also reported. RESULTS: Cormack-Lehane grade had the strongest correlation with difficulty of intubation followed by Friedman palate position. Friedman palate position was the most sensitive and had higher positive and negative predictive values than modified Mallampati classification. Cormack-Lehane grade was found to be the most specific with the highest negative predictive value among the four studied classifications. CONCLUSION: Friedman palate position is a more useful, valuable and sensitive test compared to the modified Mallampati screening test for pre anesthetic prediction of difficult intubation where its involvement in Multivariate model may raise the accuracy and diagnostic value of preoperative assessment of difficult airway. PMID- 25437702 TI - [Comparison of early and late percutaneous tracheotomies in adult intensive care unit]. AB - BACKGROUND AND OBJECTIVES: Percutaneous tracheotomy has become a good alternative for patients thought to have prolonged intubation in intensive care units. The most important benefits of tracheotomy are early discharge of the patient from the intensive care unit and shortening of the time spent in the hospital. Prolonged endotracheal intubation has complications such as laryngeal damage, vocal cord paralysis, glottic and subglottic stenosis, infection and tracheal damage. The objective of our study was to evaluate potential advantages of early percutaneous tracheotomy over late percutaneous tracheotomy in intensive care unit. METHODS: Percutaneous tracheotomies applied to 158 patients in adult intensive care unit have been analyzed retrospectively. Patients were divided into two groups as early and late tracheotomy according to their endotracheal intubation time before percutaneous tracheotomy. Tracheotomies at the 0-7th days of endotracheal intubation were grouped as early and after the 7th day of endotracheal intubation as late tracheotomies. Patients having infection at the site of tracheotomy, patients with difficult or potential difficult intubation, those under 18 years old, patients with positive end-expiratory pressure above 10cmH2O and those with bleeding diathesis or platelet count under 50,000dL(-1) were not included in the study. Durations of mechanical ventilation and intensive care stay were noted. RESULTS: There was no statistical difference among the demographic data of the patients. Mechanical ventilation time and time spent in intensive care unit in the group with early tracheotomy was shorter and the difference was statistically significant (p<0.05). CONCLUSION: Early tracheotomy shortens mechanical ventilation duration and intensive care unit stay. For that reason we suggest early tracheotomy in patients thought to have prolonged intubation. PMID- 25437703 TI - [A unique case of pulmonary artery catheter bleeding from the oximetry connection port]. AB - Pulmonary artery catheter is an invasive monitor usually placed in high-risk cardiac surgical patients to optimize the cardiac functions. We present this case of blood oozing from the oximetry connection port of the pulmonary artery catheter that resulted in the inability to monitor continuous cardiac output requiring replacement of the catheter. The cause of this abnormal bleeding was later confirmed to be due to a manufacturing defect. PMID- 25437704 TI - [Post-operative cycloplegia following ophthalmic surgery: it is NOT anesthesia]. PMID- 25437705 TI - [Continuous bilateral transversus abdominis plane block after abdominal surgery]. PMID- 25437706 TI - [Opening snap off ampoules - a safer and uncomplicated method]. PMID- 25437707 TI - [Importance of maternal body temperature recording after injection of meperidine during spinal anesthesia in patients undergoing cesarean section: an offering for conducting clinical studies]. PMID- 25437708 TI - A de novo designed 2[4Fe-4S] ferredoxin mimic mediates electron transfer. AB - [Fe-S] clusters, nature's modular electron transfer units, are often arranged in chains that support long-range electron transfer. Despite considerable interest, the design of biomimetic artificial systems emulating multicluster-binding proteins, with the final goal of integrating them in man-made oxidoreductases, remains elusive. Here, we report a novel bis-[4Fe-4S] cluster binding protein, DSD-Fdm, in which the two clusters are positioned within a distance of 12 A, compatible with the electronic coupling necessary for efficient electron transfer. The design exploits the structural repeat of coiled coils as well as the symmetry of the starting scaffold, a homodimeric helical protein (DSD). In total, eight hydrophobic residues in the core of DSD were replaced by eight cysteine residues that serve as ligands to the [4Fe-4S] clusters. Incorporation of two [4Fe-4S] clusters proceeds with high yield. The two [4Fe-4S] clusters are located in the hydrophobic core of the helical bundle as characterized by various biophysical techniques. The secondary structure of the apo and holo proteins is conserved; further, the incorporation of clusters results in stabilization of the protein with respect to chemical denaturation. Most importantly, this de novo designed protein can mimic the function of natural ferredoxins: we show here that reduced DSD-Fdm transfers electrons to cytochrome c, thus generating the reduced cyt c stoichiometrically. PMID- 25437710 TI - Approach for discrimination and quantification of electroactive species: kinetics difference revealed by higher harmonics of Fourier transformed sinusoidal voltammetry. AB - Discrimination and quantification of electroactive species are traditionally realized by a potential difference which is mainly determined by thermodynamics. However, the resolution of this approach is limited to tens of millivolts. In this paper, we described an application of Fourier transformed sinusoidal voltammetry (FT-SV) that provides a new approach for discrimination and quantitative evaluation of electroactive species, especially thermodynamic similar ones. Numerical simulation indicates that electron transfer kinetics difference between electroactive species can be revealed by the phase angle of higher order harmonics of FT-SV, and the difference can be amplified order by order. Thus, even a very subtle kinetics difference can be amplified to be distinguishable at a certain order of harmonics. This method was verified with structurally similar ferrocene derivatives which were chosen as the model systems. Although these molecules have very close redox potential (<10 mV), discrimination and selective detection were achieved by as high as the thirteenth harmonics. The results demonstrated the feasibility and reliability of the method. It was also implied that the combination of the traditional thermodynamic method and this kinetics method can form a two-dimension resolved detection method, and it has the potential to extend the resolution of voltammetric techniques to a new level. PMID- 25437709 TI - Toxicity of cobalt oxide nanoparticles to normal cells; an in vitro and in vivo study. AB - The aim of this study was to find out the intracellular signaling transduction pathways involved in cobalt oxide nanoparticles (CoO NPs) mediated oxidative stress in vitro and in vivo system. Cobalt oxide nanoparticles released excess Co++ ions which could activated the NADPH oxidase and helps in generating the reactive oxygen species (ROS). Our results showed that CoO NPs elicited a significant (p<0.05) amount of ROS in lymphocytes. In vitro pretreatment with N acetylene cystine had a protective role on lymphocytes death induced by CoO NPs. In vitro and in vivo results showed the elevated level of TNF-alpha after CoO NPs treatment. This TNF-alpha phosphorylated the p38 mitogen-activated protein kinase followed by activation of caspase 8 and caspase 3 which could induce cell death. This study showed that CoO NPs induced oxidative stress and activated the signaling pathway of TNF-alpha-caspase-8-p38-caspase-3 to primary immune cells. This study suggested that bare CoO NPs are a toxic for primary human immune cells that deals directly with human health. Surface modification or surface functionalization may open the gateway for further use of CoO NPs in different industrial use or in biomedical sciences. PMID- 25437711 TI - Temporal and gestational age trends: what is the effect of obstetric intervention? PMID- 25437712 TI - Can molecular diagnostics usher in a new era for screening, diagnosis, and treatment of ovarian cancer? PMID- 25437713 TI - Association of obstetric intervention with temporal patterns of childbirth. AB - OBJECTIVE: To examine the gestational age at and day and time of delivery in current U.S. obstetric practice. METHODS: We examined electronic records from 72 hospitals in 16 states during a 4-month period during 2013. Day of week of delivery, time of day of delivery, and route of delivery were examined in various subpopulations delivering both with and without obstetric intervention. RESULTS: Records of 21,381 women were examined. The distribution curve for gestational age at delivery peaked at 39 weeks both for the entire group and for the subgroup entering labor spontaneously and delivering vaginally without augmentation. Statistical modeling suggests that medical intervention accounts for only a fraction of the shift in distribution peak from 40 to 39 weeks of gestation. Three temporal peaks of total and primary cesarean delivery were seen on weekdays, corresponding to immediate preclinic, lunch time, and immediate postclinic timeframes. These peaks were not seen on weekend days. The risk of nonelective primary cesarean delivery during a weekday was approximately one third higher than on a weekend (relative rate 1.36, confidence interval 1.24 1.49). CONCLUSION: The recently described shift in peak distribution of U.S. gestational age at delivery from 40 to 39 weeks of gestation may reflect an underlying physiologic change in the U.S. population and is not exclusively related to obstetric intervention. During the work week, factors other than medical necessity appear to have a marked association with both timing of delivery and rate of cesarean delivery and may affect up to one third of primary cesarean deliveries. PMID- 25437714 TI - Detection of somatic TP53 mutations in tampons of patients with high-grade serous ovarian cancer. AB - OBJECTIVE: To investigate whether tumor cells could be detected in the vagina of women with serous ovarian cancer through TP53 analysis of DNA samples collected by placement of a vaginal tampon. METHODS: Women undergoing surgery for a pelvic mass were identified in the gynecologic oncology clinic. They placed a vaginal tampon before surgery, which was removed in the operating room. Cells were isolated and DNA was extracted from both the cells trapped within the tampon and the primary tumor. In patients with serous carcinoma, the DNA was interrogated for the presence of TP53 mutations using a method capable of detecting rare mutant alleles in a mixture of mutant and wild-type DNA. RESULTS: Thirty-three patients were enrolled. Eight patients with advanced serous ovarian cancer were included for analysis. Three had a prior tubal ligation. TP53 mutations were identified in all eight tumor samples. Analysis of the DNA from the tampons revealed mutations in three of the five patients with intact tubes (sensitivity 60%) and in none of the three patients with tubal ligation. In all three participants with mutation detected in the tampon specimen, the tumor and the vaginal DNA harbored the exact same TP53 mutation. The fraction of DNA derived from exfoliated tumor cells ranged from 0.01% to 0.07%. CONCLUSION: In this pilot study, DNA derived from tumor was detected in the vaginas of 60% of patients with ovarian cancer with intact fallopian tubes. With further development, this approach may hold promise for the early detection of this deadly disease. PMID- 25437715 TI - Comparative effectiveness of robotically assisted compared with laparoscopic adnexal surgery for benign gynecologic disease. AB - OBJECTIVE: To perform a population-based analysis to compare the complications and cost of laparoscopic and robotically assisted adnexal surgery. METHODS: A nationwide database was used to analyze the use and outcomes of robotically assisted adnexal surgery from 2009 to 2012. Multivariable mixed effects regression models were developed to examine predictors of use of robotic surgery. After propensity score matching, complications and cost were compared between robotically assisted and laparoscopic surgery. RESULTS: Eighty-seven thousand five hundred fourteen women were identified. From 2009 to 2012, performance of robotic-assisted oophorectomy increased from 3.5% (95% confidence interval [CI] 3.2-3.8%) to 15.0% (95% CI 14.4-15.6%), whereas robotically assisted cystectomy rose from 2.4% (95% CI 2.0-2.7%) to 12.9% (95% CI 12.2-13.5%). The overall complication rate was 7.1% (95% CI 4.0-10.2%) for robotically assisted compared with 6.0% (95% CI 2.9-9.1%) for laparoscopic oophorectomy (odds ratio [OR] 1.20, 95% CI 1.00-1.45; P=.052). Robotic-assisted oophorectomy was associated with a higher rate of intraoperative complications (3.4% compared with 2.1%, OR 1.60, 95% CI 1.21-2.13). The overall complication rate was 3.7% (95% CI -0.8 to 8.2%) after robotically assisted compared with 2.7% (95% CI -1.8 to 7.2%) for laparoscopic cystectomy (OR 1.38, 95% CI 0.95-1.99). The intraoperative complication rate was higher for robotically assisted cystectomy (2.0% compared with 0.9%, OR 2.40, 95% CI 1.31-4.38). Compared with laparoscopy, robotically assisted oophorectomy was associated with $2,504 (95% CI $2,356-2,652) increased total costs and robotically assisted cystectomy $3,310 (95% CI $3,082-3,581) higher costs. CONCLUSION: Use of robotically assisted adnexal surgery increased rapidly. Compared with laparoscopic surgery, robotically assisted adnexal surgery is associated with substantially greater costs and a small, but statistically significant, increase in intraoperative complications. PMID- 25437716 TI - Transcervical intralesional vasopressin injection compared with placebo in hysteroscopic myomectomy: a randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy of transcervical intralesional vasopressin injection to submucous myoma in hysteroscopic myomectomy from 2011 to 2014. METHODS: This was a prospective, randomized, double-blind study in a single center. Forty premenopausal women with symptomatic submucous myoma requiring hysteroscopic myomectomy were randomized to transcervical intralesional vasopressin injection or placebo in a 4:4 ratio. The primary outcome was operative time. Secondary outcomes including fluid volumes, blood loss, and visual clarity were compared between the two groups. RESULTS: The median duration for myomectomy was 19.9 minutes (range 3.1-54.2 minutes) in the vasopressin group compared with 29.0 minutes (range 8.0-60.9 minutes) in the placebo group, a nonsignificant difference (P=.14). There were significant reductions in the median volume of fluid used (4,200 mL [range 1,300-21,000 mL] compared with 9,800 mL (range 1,500-23,000 mL; P=.004) and fluid intravasation (0 mL [range 0-3,100] compared with 300 mL [range -150-3,150 mL; P=.029) in the vasopressin group. The median intraoperative blood loss was reduced (5 mL [range 1-50 mL] compared with 20 mL [range 1-150 mL; P=.002). The operative surgeon rated that 95% of the vasopressin group had "minimal" bleeding compared with 36.8% in the placebo group. The surgical field (visual analog scale [VAS] 9 [range 2-10] compared with 6 [range 2-10; P<.001]; 0=worst visual clarity, 10=best visual clarity) and the effluent fluid (VAS 1 [range 0-7] compared with 4 [range 0-8; P<.001]; 0=clear, 10=unclear) were statistically significantly clearer in the vasopressin group. CONCLUSION: Transcervical intralesional vasopressin injection in hysteroscopic myomectomy did not reduce operative time but did reduce volume of inflow fluid, fluid intravasation, intraoperative blood loss, and improving visual clarity. CLINICAL TRIAL REGISTRATION: Centre for Clinical Research and Biostatistics, http://www.cct.cuhk.edu.hk/Registry/publictriallist.aspx, CUHK_CCT00291. PMID- 25437717 TI - Postablation risk factors for pain and subsequent hysterectomy. AB - OBJECTIVE: To assess patient characteristics associated with pain and hysterectomy after endometrial ablation. METHODS: A retrospective cohort study was performed using data from two large academic medical centers. Three hundred patients who underwent endometrial ablation between January 2006 and May 2013 were identified for study. Data collected included baseline characteristics at the time of ablation, relevant medical history, and ablation technique. Univariate tests of association and logistic regression were used to evaluate risk factors for postablation pain or hysterectomy. RESULTS: Of the 300 women who had endometrial ablation performed during the study period, 270 had follow-up data for analysis. Twenty-three percent developed new or worsening pain after ablation and 19% underwent a hysterectomy. A history of dysmenorrhea gave a 74% higher risk of developing pain (adjusted odds ratio [OR] 1.74, 95% confidence interval [CI] 1.06-2.87) and tubal sterilization conferred more than double the risk (adjusted OR 2.06, 95% CI 1.14-3.70). Women of white race were 45% less likely to develop pain (adjusted OR 0.55, 95% CI 0.34-0.89). For hysterectomy, a history of cesarean delivery more than doubled the risk (adjusted OR 2.33, 95% CI 1.05-5.16), whereas uterine abnormalities on imaging, including leiomyoma, adenomyosis, thickened endometrial strip, and polyps, quadrupled the risk (adjusted OR 3.96, 95% CI 1.25-12.56). A procedure performed in the operating room decreased the risk of hysterectomy by 76% (adjusted OR 0.24, 95% CI 0.07 0.77). Hysterectomies for the indication of pain occurred more than 3 years sooner than for other indications (P<.001). CONCLUSION: Patient characteristics should be considered when counseling patients about the possible outcomes of endometrial ablation. A significant portion of ablations are complicated by postablation pain. PMID- 25437718 TI - Association between body mass index and the timing of pregnancy recognition and entry into prenatal care. AB - OBJECTIVE: To assess whether prepregnancy body mass index (BMI) is independently associated with the timing of pregnancy recognition and initiation of prenatal care. METHODS: Data from 2009 to 2010 were obtained from the Centers for Disease Control and Prevention's Pregnancy Risk Assessment Monitoring System. The 30 participating states contacted sampled mothers 2-4 months after delivery and had them complete the standardized Pregnancy Risk Assessment Monitoring System questionnaire. Prepregnancy BMI was calculated from the participants' self reported prepregnancy weight and height. Timing of pregnancy recognition and initiation of prenatal care were also self-reported on the questionnaire. RESULTS: Among the 72,913 participants, 69,872 (96%) met the eligibility criteria for analysis. After adjustment for maternal race, ethnicity, smoking status in the 3 months before pregnancy, pregnancy intentions, insurance status, maternal age, marital status, maternal education, and parity, there was no association between prepregnancy BMI status and the week of pregnancy recognition. Obese women initiated prenatal care 0.20 weeks earlier on average compared with normal weight women, although the difference was not clinically important (mean difference -0.20, 95% confidence interval [CI] -0.38 to -0.03). When examining the odds of receiving late or no prenatal care, there was no association with prepregnancy BMI. Uninsured women, however, reported initiating prenatal care almost 3 weeks later on average than privately insured women (mean difference 2.83, 95% CI 2.27-3.38) and had a more than fourfold increased odds of receiving late or no prenatal care (odds ratio 4.04, 95% CI 3.13-5.23). CONCLUSION: Prepregnancy BMI was not meaningfully associated with a delay in pregnancy recognition or with increased odds of receiving late or no prenatal care. PMID- 25437719 TI - Second-trimester cordocentesis and the risk of small for gestational age and preterm birth. AB - OBJECTIVE: To estimate the association of cordocentesis with small for gestational age, preterm birth, and low birth weight. METHODS: A cohort study from a tertiary care center. Pregnant women without medical or obstetric complications and without ultrasonographically evident fetal anomalies scheduled for cordocentesis between 16 and 22 weeks of gestation (predominantly to detect severe fetal hemoglobinopathies) were prospectively enrolled and matched to a similarly healthy control group on a one-to-one basis by maternal age, parity, gestational age. and ethnicity. In the cordocentesis group, pregnancies found to be complicated by a fetal hemoglobinopathy or a karyotypic abnormality were excluded. Both groups were followed until delivery. The primary outcomes included the rates of small-for-gestational-age preterm birth and low birth weight and fetal loss. RESULTS: In total, 7,228 women underwent cordocentesis, of whom 5,506 qualified as cases. Of these, 5,039 were matched to women in the control group and had complete outcome data available for the pair. The rates and relative risks (RRs) of small for gestational age (6.9% compared with 4.6%; RR 1.5, 95% confidence interval [CI] 1.3-1.8), preterm birth (12.7 compared with 7.4%; RR 1.7, 95% CI 1.5-1.9), and fetal loss (1.9% compared with 1.0%; RR 1.9, 95% CI 1.4 2.7) were significantly higher among fetuses in the cordocentesis group. However, there were no significant differences in other obstetric complications between the study and control groups. CONCLUSION: Rates of small for gestational age, preterm birth, low-birth weight, and fetal loss are increased among pregnancies with cordocentesis in the second trimester. PMID- 25437720 TI - Predicting fetal acidemia using umbilical venous cord gas parameters. AB - OBJECTIVE: To assess the utility of umbilical cord venous blood gas measures for prediction of umbilical artery pH and base deficit acidemia. METHODS: A retrospective cohort study was conducted of all singletons with valid paired arterial and venous cord gas samples delivered at our institution from January 2006 to March 2012. Fetal acidemia was defined primarily as cord arterial blood gas pH less than 7.0. We also evaluated prediction of acidemia, defined as an arterial base deficit 12 mmol/L or greater. Logistic regression was performed to estimate probabilities of fetal arterial pH and base deficit acidemia given venous blood gas pH or base deficit. Receiver operating characteristic curves were derived to determine predictive ability. Venous blood gas pH and base deficit cutoffs associated with 1% or less, 5%, 10%, and 50% probability of fetal acidemia were identified. RESULTS: Of 23,506 births, 11,455 (49%) met criteria for inclusion. The frequency of arterial blood gas pH less than 7.0 was 127 (1.1%); arterial blood gas base deficit 12 mmol/L or greater was 245 (2.1%). Venous blood gas pH (area under the curve [AUC] 0.949, 95% confidence interval [CI] 0.920-0.979; P<.001) and base deficit (AUC 0.969, 95% CI 0.954-0.983; P<.001) were predictors of acidemia based on arterial blood gas pH and base deficit, respectively. Venous blood gas pH cutoffs associated with 1% or less, 5%, or 10% probabilities of arterial blood gas pH less than 7.0 were 7.23, 7.17, and 7.14, respectively. Venous blood gas base deficit values associated with similar probabilities for base deficit 12 mmol/L or greater were 6.3 or less, 8.2 or less, and 9.0 mmol/L or less. For prediction of arterial blood gas pH, adjusting venous blood gas pH for base deficit increased the AUC (0.961, 95% CI 0.938-0.984). Prediction of arterial blood gas base deficit by venous blood gas base deficit was unchanged by adjustment for pH (AUC 0.969, 95% CI 0.955-0.984). CONCLUSION: We demonstrate that venous blood gas parameters are powerful predictors of arterial blood gas pH and base deficit and can be used to predict the likelihood of fetal acidemia when the cord arterial blood gas is not available. PMID- 25437721 TI - Laboratory abnormalities in pregnancy-associated hypertension: frequency and association with pregnancy outcomes. AB - OBJECTIVE: To estimate the frequency of abnormal laboratory test results in pregnancy-associated hypertension and the relationship with pregnancy outcomes. METHODS: This was a secondary analysis of a multicenter trial of vitamin C and E for prevention of pregnancy-associated hypertension in low-risk nulliparous women. Laboratory abnormalities included: platelets less than 100,000/mm, aspartate aminotransferase 100 units/L or greater, creatinine 1.5 mg/dL or greater, lactate dehydrogenase 600 units/L or greater, total bilirubin 1.2 mg/dL or greater, or evidence of hemolysis on peripheral smear. Mild pregnancy associated hypertension was defined as blood pressure 140-159/90-109 mm Hg. Severe pregnancy-associated hypertension was defined as persistent blood pressure 160/110 mm Hg or greater, acute antihypertensive treatment, or any blood pressure elevation associated with clinical signs of end-organ dysfunction (one or more of headache, epigastric pain, blurred vision, pulmonary edema, eclampsia, or oliguria). Pregnancy outcomes were compared across four groups: I, mild hypertension alone; II, mild hypertension+abnormal laboratory values; III, severe pregnancy-associated hypertension alone; and IV, severe pregnancy-associated hypertension+abnormal laboratory values. RESULTS: Of 9,969 women, 2,752 (27.9%) developed pregnancy-associated hypertension and of these, laboratory abnormalities occurred in 7.3%. Laboratory abnormalities increased with severity of hypertension: mild hypertension alone (4.9%), severe hypertension alone (8.9%), and mild or severe hypertension with clinical signs of end-organ dysfunction (12.2%) (P for trend<.001). Compared with women with mild hypertension alone, the adjusted odds for the perinatal composite (2-fold to 4.8 fold in Category III-IV), preterm birth (2.1-fold to 7.8-fold in Category II-IV), and other adverse perinatal outcomes increase with disease severity, particularly with laboratory abnormalities and severe clinical signs. CONCLUSION: The frequency of abnormal laboratory values in women with pregnancy-associated hypertension increases with disease severity. Adverse perinatal outcomes increase in the presence of abnormal laboratory values, particularly in those with clinical signs, likely atttributable in part to the decision to deliver early. PMID- 25437723 TI - Coronary heart disease mortality and hormone therapy before and after the Women's Health Initiative. AB - OBJECTIVE: To assess whether coronary heart disease mortality in Finnish hormone therapy (HT) users differed before and after 2002 when the Women's Health Initiative study was published. METHODS: The risks of coronary heart disease death in HT users in relation to the age-matched background population were compared between the pre- (1995-2001) and post- (2002-2009) Women's Health Initiative eras. We used a nationwide register on HT (ie, estradiol with or without progestin) reimbursement and linked them to causes of death in 290,272 women aged 40 years or older. RESULTS: Exposure to HT for 1 year or less was accompanied by a 29% reduction (0.71; 0.63-0.80; three per 10,000 fewer deaths) and an exposure of 1-8 years with a 43% reduction (0.57; 0.48-0.66; three per 10,000 fewer deaths) in the risk of coronary heart disease death in the pre Women's Health Initiative era. In the post-Women's Health Initiative era, HT use of 1 year or less was associated with an 18% reduction (0.82; 0.76-1.00; one per 10,000 fewer deaths) and an exposure of 1-8 years with a 54% reduction (0.46; 0.32-0.64; two per 10,000 fewer deaths) in coronary heart disease mortality. Discontinuation of HT was associated with an increased risk of cardiac death of 42% (1.42; 1.17-1.71; seven per 10,000 extra deaths) in the pre-Women's Health Initiative era and 31% (1.31; 0.92-1.82; two per 10,000 extra deaths) in the post Women's Health Initiative era during the first posttreatment year. This risk increase vanished in further follow-up during both eras. CONCLUSION: Changes in HT use after the Women's Health Initiative failed to affect coronary heart disease mortality of HT users in this nationwide study. PMID- 25437722 TI - Identification of iPhone and iPad applications for obstetrics and gynecology providers. AB - OBJECTIVE: To systematically identify the number of applications ("apps") compatible with the iPhone and the iPad that are potentially useful to obstetrician-gynecologists (ob-gyns). METHODS: Obstetrics and gynecology MeSH terms were searched in the Apple iTunes Store. A master list of unique apps was created and the apps were divided into categories and subcategories. RESULTS: A total of 1,816 unique apps using 55 different obstetrics and gynecology MeSH terms were found. Of these unique apps, 242 apps (13.3%) were considered potentially useful to ob-gyns. The MeSH terms that yielded the highest number of potentially useful apps were "gynecology" (23%), "breast cancer" (17%), "obstetrics" (14%), and "pregnancy" (12%). CONCLUSION: Less than 15% of apps found were considered potentially useful to ob-gyns. Thus, the obstetrics and gynecology community is in need of an organized effort to identify, review, and determine the accuracy of apps that can potentially improve the performance of health care providers and lead to better patient outcomes. We propose the formation of a committee to guide in this important task. PMID- 25437724 TI - Biological and behavioral risks for incident Chlamydia trachomatis infection in a prospective cohort. AB - OBJECTIVE: To identify biological and behavioral risks for incident Chlamydia trachomatis among a prospective cohort of young women followed frequently. METHODS: Our cohort of 629 women from two outpatient sites was seen every 4 months (October 2000 through April 2012) for behavioral interviews and infection testing. C trachomatis was tested annually and any time patients reported symptoms or possible exposure using commercial nucleic acid amplification tests. Analyses excluded baseline prevalent C trachomatis infections. Risk factors for incident C trachomatis were assessed using Cox proportional hazards models. Significant risks (P<.10) from bivariate models were entered in a multivariate model adjusted for four covariates chosen a priori (age, race or ethnicity, condom use, study site). Backward stepwise elimination produced a final parsimonious model retaining significant variables (P<.05) and the four adjustment variables. RESULTS: The 629 women attended 9,594 total visits. Median follow-up time was 6.9 years (interquartile range 3.2-9.8), during which 97 (15%) women had incident C trachomatis. In the final multivariate model, incident C trachomatis was independently associated with human papillomavirus at the preceding visit (P<.01), smoking (P=.02), and weekly use of substances besides alcohol and marijuana (P<.01) since the prior visit. Among 207 women with available colpophotographs (1,742 visits), cervical ectopy was not a significant risk factor (P range=.16-.39 for ectopy as continuous and ordinal variables). CONCLUSION: Novel risks for C trachomatis include preceding human papillomavirus, smoking, and substance use, which may reflect both biological and behavioral mechanisms of risk such as immune modulation, higher-risk sexual networks, or both. Improved understanding of the biological bases for C trachomatis risk would inform our strategies for C trachomatis control. PMID- 25437725 TI - Antenatal education to increase exclusive breastfeeding: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of a professional one-to-one antenatal breastfeeding support and education intervention on the exclusivity and duration of breastfeeding. METHODS: A total of 469 primiparous women who attended the antenatal clinics of two geographically distributed public hospitals in Hong Kong were randomized to receive either standard antenatal care or a one-to-one antenatal breastfeeding support and education session. The primary outcome was the prevalence of exclusive breastfeeding at 6 weeks postpartum. Secondary outcomes were the prevalence of exclusive breastfeeding at 3 and 6 months postpartum as well as the overall duration of any and exclusive breastfeeding across the first 6 months postpartum. RESULTS: The exclusive breastfeeding rate in the intervention group was 37.8% at 6 weeks postpartum compared with 36.4% in the standard care group (P=.77; 95% confidence interval [CI] -0.08 to 0.11). There were no significant differences between the two treatment groups in exclusive breastfeeding rates at 3 and 6 months or in the overall duration of any (hazard ratio [HR] 1.11, 95% CI 0.88-1.40] or exclusive breastfeeding (HR 0.96, 95% CI 0.79-1.17). The study had a least 80% power to detect a 50% increase in the rate of exclusive breastfeeding at 6 weeks postpartum. CONCLUSION: In a setting with a high breastfeeding initiation rate, one-to-one antenatal breastfeeding support and education did not increase the exclusivity or duration of breastfeeding. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01648114. PMID- 25437727 TI - Chromosome abnormalities detected by current prenatal screening and noninvasive prenatal testing. AB - OBJECTIVE: To estimate how many additional chromosomal abnormalities can be detected by diagnostic testing compared with noninvasive prenatal testing in a high-risk prenatal population. METHODS: All karyotype results of invasive prenatal testing in singleton pregnancies performed in response to a positive prenatal screen through the California Prenatal Screening Program from April 2009 through December 2012 were examined. Abnormal karyotypes were categorized as to whether the abnormality is detectable by current noninvasive prenatal testing methods. RESULTS: Of 1,324,607 women who had traditional screening during the study period, 68,990 (5.2%) were screen-positive. Of screen-positive women, 26,059 (37.8%) underwent invasive diagnostic testing and 2,993 had an abnormal result (11.5%). Of these, 2,488 (83.1%) were predicted to be detectable with current noninvasive prenatal testing methods, and 506 (16.9%) were considered not currently detectable. Trisomy 21 accounted for 53.2% of the abnormal results (n=1,592). Common aneuploidies, detectable by noninvasive prenatal testing, comprised a higher percentage of abnormal results in older women (P<.01). CONCLUSION: For pregnant women with a positive aneuploidy screen who pursued diagnostic testing, 16.9% of chromosome abnormalities are not currently detectable by noninvasive prenatal testing. Undetectable aneuploidies range from relatively mild to those associated with significant disability. This is important information to be considered by patients, health care providers, and screening programs in evaluating the use of traditional screening and invasive prenatal diagnosis compared with noninvasive prenatal testing. PMID- 25437726 TI - Epidemiologic factors and urogenital infections associated with preterm birth in a midwestern U.S. population. AB - OBJECTIVE: To correlate epidemiologic factors with urogenital infections associated with preterm birth. METHODS: Pregnant women were sequentially included from four Wisconsin cohorts: large urban, midsize urban, small city, and rural city. Demographic, clinical, and current pregnancy data were collected. Cervical and urine specimens were analyzed by microscopy, culture, and polymerase chain reaction for potential pathogens. RESULTS: Six hundred seventy-six women were evaluated. Fifty-four (8.0%) had preterm birth: 12.1% (19/157) large urban, 8.8% (15/170) midsize urban, 9.4% (16/171) small city, and 2.3% (4/178) rural city. Associated host factors and infections varied significantly among sites. Urogenital infection rates, especially Mycoplasma hominis and Ureaplasma parvum, were highest at the large urban site. Large urban site, minority ethnicity, multiple infections, and certain historical factors were associated with preterm birth by univariable analysis. By multivariable analysis, preterm birth was associated with prior preterm birth (adjusted odds ratio [aOR] 2.76, 95% confidence interval [CI] 1.27-6.02) and urinary tract infection (aOR 2.62, 95% CI 1.32-519), and negatively associated with provider-assessed good health (aOR 0.42, 95% CI 0.23-0.76) and group B streptococcal infection treatment (surrogate for health care use) (aOR 0.38, 95% CI 0.15-.99). Risk and protective factors were similar for women with birth at less than 35 weeks, and additionally associated with M hominis (aOR 3.6, 95% CI 1.4-9.7). CONCLUSION: These measured differences among sites are consistent with observations that link epidemiologic factors, both environmental and genetic, with minimally pathogenic vaginal bacteria, inducing preterm birth, especially at less than 35 weeks of gestation. PMID- 25437728 TI - Genetic screening and testing in an episode-based payment model: preserving patient autonomy. AB - The State of Ohio is implementing an episode-based payment model for perinatal care. All costs of care will be tabulated for each live birth and assigned to the delivering provider, creating a three-tiered model for reimbursement for care. Providers will be reimbursed as usual for care that is average in cost and quality, while instituting rewards or penalties for those outside the expected range in either domain. There are few exclusions, and all methods of genetic screening and diagnostic testing are included in the episode cost calculation as proposed. Prenatal ultrasonography, genetic screening, and diagnostic testing are critical components of the delivery of high-quality, evidence-based prenatal care. These tests provide pregnant women with key information about the pregnancy, which, in turn, allows them to work closely with their health care provider to determine optimal prenatal care. The concepts of informed consent and decision-making, cornerstones of the ethical practice of medicine, are founded on the principles of autonomy and respect for persons. These principles recognize that patients' rights to make choices and take actions are based on their personal beliefs and values. Given the personal nature of such decisions, it is critical that patients have unbarred access to prenatal genetic tests if they elect to use them as part of their prenatal care. The proposed restructuring of reimbursement creates a clear conflict between patient autonomy and physician financial incentives. PMID- 25437729 TI - Neonatal survival after prolonged preterm premature rupture of membranes before 24 weeks of gestation. AB - OBJECTIVE: To evaluate neonatal survival after prolonged preterm premature rupture of membranes (PROM) in the era of antenatal corticosteroids, surfactant, and inhaled nitric oxide. METHODS: A single-center retrospective cohort study of neonates born from 2002-2011 after prolonged (1 week or more) preterm (less than 24 weeks of gestation) rupture of membranes was performed. The primary outcome was survival to discharge. Neonates whose membranes ruptured less than 24 hours before delivery (n=116) were matched (2:1) on gestational age at birth, sex, and antenatal corticosteroid exposure with neonates whose membranes ruptured 1 week or more before delivery (n=58). Analysis used conditional logistic regression for categorical data and Wilcoxon signed rank test for continuous data. RESULTS: The prolonged preterm PROM exposed and unexposed cohorts had survival rates of 90% and 95%, respectively, although underpowered to assess the statistical significance (P=.313). Exposed neonates were more likely have pulmonary hypoplasia (26/58 exposed, 1/114 unexposed, P<.001), pulmonary hypertension (21/56 exposed, 10/112 unexposed, P<.001), and pulmonary air leak (21/58 exposed, 14/114 unexposed, P<.001). Gestational age at rupture (20.4 weeks exposed, 22.3 weeks unexposed, P=.189), length of rupture (3.7 weeks exposed, 6.4 weeks unexposed, P=.717), and lowest maximal vertical pocket before 24 weeks of gestation (0 cm exposed, 1.4 cm unexposed, P=.114) did not discriminate between survivors and nonsurvivors after exposure to prolonged preterm PROM. CONCLUSION: With antenatal steroid exposure and aggressive pulmonary management, survival to discharge after prolonged preterm PROM was 90%. Pulmonary morbidities were common. Of note, the data were limited to women who remained pregnant 1 week or longer after rupture of membranes. PMID- 25437730 TI - Preterm premature rupture of membranes and the rate of neonatal sepsis after two courses of antenatal corticosteroids. AB - OBJECTIVE: To evaluate whether a second antenatal corticosteroid course is associated with an increased risk of neonatal sepsis after preterm premature rupture of membranes (PROM). METHODS: This secondary analysis is a cohort study with data from the Maternal-Fetal Medicine Units study on magnesium for neuroprotection. Women with singleton gestations and preterm PROM were eligible. The primary exposure was one compared with two antenatal corticosteroid courses. The primary outcome, neonatal sepsis, was compared between exposed groups. Patient characteristics were analyzed by chi2 for categorical variables and Student t test or Wilcoxon rank-sum for continuous variables where appropriate. Predictors of neonatal sepsis were analyzed by multivariable logistic regression. RESULTS: One thousand six hundred forty-one patients were eligible. Neonatal sepsis was similar among neonates born to mothers who received one or two antenatal corticosteroid courses (16.2% compared with 17.2%, P=.756, respectively). Adjusting for confounders, the factors associated with neonatal sepsis were length of time from membrane rupture to delivery (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.02-2.26), respiratory distress syndrome (OR 2.11, 95% CI 1.45-3.07), gestational age at delivery in days (OR 0.98, 95% CI 0.95-0.99) and birth weight per 100 g (OR 0.85, 95% CI 0.77-0.94). CONCLUSION: A second maternal antenatal corticosteroid course was not associated with an increased rate neonatal sepsis. PMID- 25437731 TI - Diagnosis and surgical treatment of stress urinary incontinence. AB - Stress urinary incontinence (SUI) is a major problem affecting more than 20% of the nation's female population, with increasing prevalence as our population continues to age. Incontinence places a great burden on individuals, and the economic effect is large. Stress urinary incontinence occurs when there is involuntary leakage of urine during coughing, laughing, sneezing, or physical activity. It can be diagnosed during physical examination and by using low-cost office diagnostics. Although nonsurgical treatments provide some benefit, surgical interventions have demonstrated superiority with respect to subjective and objective cure and better long-term improvement. Corrective surgeries for SUI can be grouped into four categories: 1) slings (midurethral slings and slings placed at the ureterovesical junction), 2) retropubic urethropexy, 3) urethral bulking agents, and 4) artificial sphincters. The success and failure of each approach needs to be assessed in the context of individual patients and their circumstances. Slings and retropubic urethropexy are considered first-line surgical options. Since the advent of minimally invasive retropubic midurethral slings such as the tension-free vaginal tape, transobturator tension-free vaginal tape, and single-incision sling, retropubic urethropexy have fallen out of favor. Warnings about mesh use may contribute to a resurgence of retropubic urethropexy procedures such as the Burch procedure. A Burch procedure should still be considered for patients who have an aversion to mesh or if they are undergoing concurrent abdominal approach surgery. Urethral bulking agents are usually reserved for patients with a fixed, nonmobile urethra who cannot tolerate an operative experience or have failed previous antiincontinence procedures. Artificial sphincters should be considered an operation of last resort. PMID- 25437732 TI - What is new in endometrial hyperplasia treatment or prevention? Best articles from the past year. AB - This month we focus on current research in endometrial hyperplasia. Dr. Modesitt discusses five recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 25437733 TI - The life of a junior fellow in the 21st century. PMID- 25437734 TI - Female tubal sterilization: the time has come to routinely consider removal. PMID- 25437735 TI - In reply. PMID- 25437738 TI - Retraction. ACOG Committee Opinion No. 416: The uninsured (Obstet Gynecol 2008;112:731-4). PMID- 25437739 TI - Retraction. ACOG Committee Opinion No. 424: Abortion access and training (Obstet Gynecol 2009;113:247-50). PMID- 25437740 TI - ACOG Practice Bulletin No. 147: Lynch syndrome. PMID- 25437741 TI - ACOG Committee opinion no. 612: Abortion training and education. AB - Access to safe abortion hinges upon the availability of trained abortion providers. The American College of Obstetricians and Gynecologists supports education for students in health care fields as well as clinical training for residents and advanced practice clinicians in abortion care in order to increase the availability of trained abortion providers. The American College of Obstetricians and Gynecologists supports the expansion of abortion education and an increase in the number and types of trained abortion providers in order to ensure women's access to safe abortions. Integrated medical education and universal opt-out training policies help to lessen the stigma of abortion provision and improve access by increasing the number of abortion providers. This Committee Opinion reviews the current status of abortion education, describes initiatives to ensure the availability of appropriate and up-to-date abortion training, and recommends efforts for integrating and improving abortion education in medical schools, residency programs, and advanced practice clinician training programs. PMID- 25437742 TI - ACOG Committee Opinion No. 613: Increasing access to abortion. AB - Safe, legal abortion is a necessary component of women's health care. The American College of Obstetricians and Gynecologists supports the availability of high-quality reproductive health services for all women and is committed to improving access to abortion. Access to abortion is threatened by state and federal government restrictions, limitations on public funding for abortion services and training, stigma, violence against abortion providers, and a dearth of abortion providers. Legislative restrictions fundamentally interfere with the patient-provider relationship and decrease access to abortion for all women, and particularly for low-income women and those living long distances from health care providers. The American College of Obstetricians and Gynecologists calls for advocacy to oppose and overturn restrictions, improve access, and mainstream abortion as an integral component of women's health care. PMID- 25437743 TI - Development of an event-specific hydrolysis probe quantitative real-time polymerase chain reaction assay for Embrapa 5.1 genetically modified common bean (Phaseolus vulgaris). AB - A genetically modified (GM) common bean event, namely Embrapa 5.1, resistant to the bean golden mosaic virus (BGMV), was approved for commercialization in Brazil. Brazilian regulation for genetically modified organism (GMO) labeling requires that any food containing more than 1% GMO be labeled. The event-specific polymerase chain reaction (PCR) method has been the primary trend for GMO identification and quantitation because of its high specificity based on the flanking sequence. This work reports the development of an event-specific assay, named FGM, for Embrapa 5.1 detection and quantitation by use of SYBR Green or hydrolysis probe. The FGM assay specificity was tested for Embrapa 2.3 event (a noncommercial GM common bean also resistant to BGMV), 46 non-GM common bean varieties, and other crop species including maize, GM maize, soybean, and GM soybean. The FGM assay showed high specificity to detect the Embrapa 5.1 event. Standard curves for the FGM assay presented a mean efficiency of 95% and a limit of detection (LOD) of 100 genome copies in the presence of background DNA. The primers and probe developed are suitable for the detection and quantitation of Embrapa 5.1. PMID- 25437746 TI - Ultrafast electronic readout of diamond nitrogen-vacancy centres coupled to graphene. AB - Non-radiative transfer processes are often regarded as loss channels for an optical emitter because they are inherently difficult to access experimentally. Recently, it has been shown that emitters, such as fluorophores and nitrogen vacancy centres in diamond, can exhibit a strong non-radiative energy transfer to graphene. So far, the energy of the transferred electronic excitations has been considered to be lost within the electron bath of the graphene. Here we demonstrate that the transferred excitations can be read out by detecting corresponding currents with a picosecond time resolution. We detect electronically the spin of nitrogen-vacancy centres in diamond and control the non-radiative transfer to graphene by electron spin resonance. Our results open the avenue for incorporating nitrogen-vacancy centres into ultrafast electronic circuits and for harvesting non-radiative transfer processes electronically. PMID- 25437744 TI - K-targeted metabolomic analysis extends chemical subtraction to DESIGNER extracts: selective depletion of extracts of hops (Humulus lupulus). AB - This study introduces a flexible and compound targeted approach to Deplete and Enrich Select Ingredients to Generate Normalized Extract Resources, generating DESIGNER extracts, by means of chemical subtraction or augmentation of metabolites. Targeting metabolites based on their liquid-liquid partition coefficients (K values), K targeting uses countercurrent separation methodology to remove single or multiple compounds from a chemically complex mixture, according to the following equation: DESIGNER extract = total extract +/- target compound(s). Expanding the scope of the recently reported depletion of extracts by immunoaffinity or solid phase liquid chromatography, the present approach allows a more flexible, single- or multi-targeted removal of constituents from complex extracts such as botanicals. Chemical subtraction enables both chemical and biological characterization, including detection of synergism/antagonism by both the subtracted targets and the remaining metabolite mixture, as well as definition of the residual complexity of all fractions. The feasibility of the DESIGNER concept is shown by K-targeted subtraction of four bioactive prenylated phenols, isoxanthohumol (1), 8-prenylnaringenin (2), 6-prenylnaringenin (3), and xanthohumol (4), from a standardized hops (Humulus lupulus L.) extract using specific solvent systems. Conversely, adding K-targeted isolates allows enrichment of the original extract and hence provides an augmented DESIGNER material. Multiple countercurrent separation steps were used to purify each of the four compounds, and four DESIGNER extracts with varying depletions were prepared. The DESIGNER approach innovates the characterization of chemically complex extracts through integration of enabling technologies such as countercurrent separation, K-by-bioactivity, the residual complexity concepts, as well as quantitative analysis by (1)H NMR, LC-MS, and HiFSA-based NMR fingerprinting. PMID- 25437745 TI - A silicon-based photocathode for water reduction with an epitaxial SrTiO3 protection layer and a nanostructured catalyst. AB - The rapidly increasing global demand for energy combined with the environmental impact of fossil fuels has spurred the search for alternative sources of clean energy. One promising approach is to convert solar energy into hydrogen fuel using photoelectrochemical cells. However, the semiconducting photoelectrodes used in these cells typically have low efficiencies and/or stabilities. Here we show that a silicon-based photocathode with a capping epitaxial oxide layer can provide efficient and stable hydrogen production from water. In particular, a thin epitaxial layer of strontium titanate (SrTiO3) was grown directly on Si(001) by molecular beam epitaxy. Photogenerated electrons can be transported easily through this layer because of the conduction-band alignment and lattice match between single-crystalline SrTiO3 and silicon. The approach was used to create a metal-insulator-semiconductor photocathode that, under a broad-spectrum illumination at 100 mW cm(-2), exhibits a maximum photocurrent density of 35 mA cm(-2) and an open circuit potential of 450 mV; there was no observable decrease in performance after 35 hours of operation in 0.5 M H2SO4. The performance of the photocathode was also found to be highly dependent on the size and spacing of the structured metal catalyst. Therefore, mesh-like Ti/Pt nanostructured catalysts were created using a nanosphere lithography lift-off process and an applied-bias photon-to-current efficiency of 4.9% was achieved. PMID- 25437747 TI - Partitioning of on-demand electron pairs. AB - The on-demand generation and separation of entangled photon pairs are key components of quantum information processing in quantum optics. In an electronic analogue, the decomposition of electron pairs represents an essential building block for using the quantum state of ballistic electrons in electron quantum optics. The scattering of electrons has been used to probe the particle statistics of stochastic sources in Hanbury Brown and Twiss experiments and the recent advent of on-demand sources further offers the possibility to achieve indistinguishability between multiple sources in Hong-Ou-Mandel experiments. Cooper pairs impinging stochastically at a mesoscopic beamsplitter have been successfully partitioned, as verified by measuring the coincidence of arrival. Here, we demonstrate the splitting of electron pairs generated on demand. Coincidence correlation measurements allow the reconstruction of the full counting statistics, revealing regimes of statistically independent, distinguishable or correlated partitioning, and have been envisioned as a source of information on the quantum state of the electron pair. The high pair-splitting fidelity opens a path to future on-demand generation of spin-entangled electron pairs from a suitably prepared two-electron quantum-dot ground state. PMID- 25437748 TI - Cardiorespiratory and biomechanical responses to simulated recreational horseback riding in healthy children. AB - PURPOSE: The purpose of this study was to determine the reliability of cardiorespiratory and pelvic kinematic responses to simulated horseback riding (SHBR) and to characterize responses to SHBR relative to walking in apparently healthy children. METHOD: Fifteen healthy children (M(age) = 9.5 +/- 2.6 years) completed SHBR on a commercially available simulator at low intensity (0.27 Hz) and high intensity (0.65 Hz) during 3 sessions on different occasions. Heart rate (HR), blood pressure, and respiratory gases were measured at rest and during steady-state exercise at both intensities. Pelvic displacement was measured during steady-state exercise. Rate of energy expenditure, mean arterial pressure, and rate pressure product (RPP) were calculated. Participants also walked on a treadmill for 26.8 m/min to 80.5 m/min in 13.4-m/min increments at 0% grade during 1 session to compare cardiorespiratory responses with those of SHBR. RESULTS: Physiological variables across all 3 SHBR sessions were similar at both intensities (p>.05 for all). Intraclass correlation coefficients (ICCs) and coefficients of variation indicate good to modest reliability of cardiorespiratory measures during SHBR (ICCs = .542-.996 for oxygen consumption, energy expenditure, and RPP). Cardiorespiratory variables, except for HR, were 2% to 19% greater, and pelvic displacement was up to 37% greater with high-intensity riding. Treadmill walking at all speeds elicited greater physiological responses compared with SHBR (p < .05). CONCLUSION: Cardiorespiratory responses and pelvic kinematics are reproducible with SHBR in young children, and these responses were lower than those elicited by slow treadmill walking. PMID- 25437749 TI - Temperature controlled fluorescence on Au@Ag@PNIPAM-PTEBS microgels: effect of the metal core size on the MEF extension. AB - In this work, we present a novel method to produce thermoresponsive, monodisperse microgels which display temperature-dependent photoluminescence. The system is based on bimetallic cores of Au@Ag encapsulated within thermoresponsive poly(N isopropylacrylamide) microgels and coated with a photoluminescent polymer (poly[2 (3-thienyl)ethoxy-4-butylsulfonate] (PTEBS) using the Layer-by-Layer technique. The electromagnetic radiation used to excite the PTEBS induces a local electromagnetic field on the surface of the bimetallic cores that enhances the excitation and emission rates of the PTEBS, yielding a metal enhanced fluorescence (MEF). This effect was studied as a function of the bimetallic core size and the separation distance between the PTEBS and the bimetallic cores. Our results permit evaluation of the effect that the metallic core size of colloidal particles exerts on the MEF for the first time, and prove the relevance of the metallic cores to extend the effect far away from the metallic surface. PMID- 25437750 TI - Long Non-Coding RNA NEAT1 Associates with SRp40 to Temporally Regulate PPARgamma2 Splicing during Adipogenesis in 3T3-L1 Cells. AB - Long non-coding (lnc) RNAs serve a multitude of functions in cells. NEAT1 RNA is a highly abundant 4 kb lncRNA in nuclei, and coincides with paraspeckles, nuclear domains that control sequestration of paraspeckle proteins. We examined NEAT1 RNA levels and its function in 3T3-L1 cells during differentiation to adipocytes. Levels of NEAT1 transcript, measured by RT-PCR, fluctuated in a temporal manner over the course of differentiation that suggested its role in alternative splicing of PPARgamma mRNA, the major transcription factor driving adipogenesis. When cells were induced to differentiate by a media cocktail of insulin, dexamethasone, and isobutylmethyxanthine (IBMX) on Day 0, NEAT1 levels dropped on Day 4, when the PPARgamma2 variant was spliced and when terminal differentiation occurs The appearance of PPARgamma2 coordinates with the PPARgamma1 variant to drive differentiation of adipocytes. SiRNA used to deplete NEAT1 resulted in the inability of cells to phosphorylate the serine/arginine-rich splicing protein, SRp40. SiRNA treatment for SRp40 resulted in dysregulation of PPARgamma1 and, primarily, PPARgamma2 mRNA levels. SRp40 associated with NEAT1, as shown by RNA IP on days 0 and 8, but decreased on day 4, and concentrations increased over that of IgG control. Overexpression of SRp40 increased PPARgamma2, but not gamma1. Although lncRNA MALAT1 has been investigated in SR protein function, NEAT1 has not been shown to bind SR proteins for phosphorylation such that alternative splicing results. The ability of cells to increase phosphorylated SR proteins for PPARgamma2 splicing suggests that fluxes in NEAT1 levels during adipogenesis regulate alternative splicing events. PMID- 25437752 TI - Activation and enhancement of room-temperature ferromagnetism in Cu-doped anatase TiO2 films by bound magnetic polaron and oxygen defects. AB - Cu-doped anatase TiO2 films grown by magnetron sputtering at room temperature showed the unexpected observation of room-temperature ferromagnetism, which was enhanced or destroyed corresponding to low or high impurity concentration via vacuum annealing. On the basis of the analysis of composition and structure, the most important factor for activating ferromagnetism can be identified as the creation of grain boundary defects. In addition, oxygen defects can be the dominating factor for increasing the saturation moment of the 0.19 at. % Cu-doped TiO2 film from 0.564 to 26.41 emu/cm(3). These results help elucidate the origin of ferromagnetism and emphasize the role of oxygen defects for the application of ferromagnetic films. PMID- 25437751 TI - Pharmaceutical relevant cytokine receptors: lessons from the first drafts of the human proteome. AB - Although a plethora of human proteins are ubiquitously expressed, several proteins with high pharmaceutical relevance show a tissue- or cell-type specific expression pattern. Science across all disciplines, ranging from developmental biology to personalized medicine, would benefit from detailed knowledge about this so-called human proteome. Two recent publications in Nature use large-scale proteomics to create first drafts of the human proteome, which are freely accessible online. In this Letter, we analyze the proteomic data with regard to the expression of three different cytokine receptors, the Tumor Necrosis Factor (TNF)alpha Receptor I (TNFRSF1A) and II (TNFRSF1B) and the Interleukin-6 Receptor (IL-6R). Therapeutic inhibition of these proteins is highly effective in a high number of inflammatory diseases, and TNFalpha blocking agents alone were sold for almost $30 billion in 2013. We find that the known expression pattern of the three receptors is not reflected in the current drafts of the human proteome, as the proteomics data fail to detect protein expression in several cell types and tissues which are known to express these cytokine receptors. Thus, our results suggest that the current drafts of the human proteome are far from complete, and that the data have to be used with caution especially in terms of personalized medicine. PMID- 25437753 TI - Solvation of a Cellulose Microfibril in Imidazolium Acetate Ionic Liquids: Effect of a Cosolvent. AB - The solvation and the onset of dissolution of a cellulose I(beta) microcrystal in ionic liquid media are studied by molecular simulation. Ionic liquids can dissolve large amounts of cellulose, which can later be regenerated from solution, but their high viscosity is an inconvenience. Hydrogen bonding between the anion of the ionic liquid and cellulose is the main aspect determining dissolution. Here we try to elucidate the role of a molecular cosolvent, dimethyl sulfoxide (DMSO), which is an aprotic polar compound, in the system composed of cellulose and the ionic liquid 1-butyl-3-methylimidazolium acetate. We calculated quantities related to specific interactions (mainly hydrogen bonds), conformations, and the structure of local solvation environments, both for a solvated oligomer chain of cellulose and for a model microfibril composed of 36 chains in the I(beta) crystal structure. We compare two solvent systems: the pure ionic liquid and a mixed solvent with an equimolar composition in ionic liquid and DMSO. All entities are represented by detailed all-atom, fully flexible force fields. The main conclusions are that DMSO behaves as an "innocent" cosolvent, lowering the viscosity and accelerating mass transport in the system, but without interacting specifically with cellulose or disrupting the interactions between cellulose with the anions of the ionic liquid. An understanding of solvation in mixed solvents composed of ionic liquids and molecular compounds can enable the design of high-performance media for the use of biomass materials. PMID- 25437755 TI - Preschool center care quality effects on academic achievement: an instrumental variables analysis. AB - Much of child care research has focused on the effects of the quality of care in early childhood settings on children's school readiness skills. Although researchers increased the statistical rigor of their approaches over the past 15 years, researchers' ability to draw causal inferences has been limited because the studies are based on nonexperimental designs. The purpose of the present study was to demonstrate how an instrumental variables approach can be used to estimate causal impacts of preschool center care quality on children's academic achievement when applied to a study in which preschool curricula were randomly assigned across multiple sites. We used data from the Preschool Curriculum Evaluation Research Initiative (PCER; n = 2,700), in which classrooms or preschools were randomly assigned to that grantee's treatment curriculum or "business as usual" conditions in 18 research sites. Using this method, we demonstrate how developmental researchers can exploit the random-assignment designs of multisite studies to investigate characteristics of programs, such as preschool center care quality, that cannot be randomly assigned and their impacts on children's development. We found that the quality of preschool care received by children has significant, albeit modest, effects on children's academic school readiness, with effect sizes of .03 to .14 standard deviation increases in academic achievement associated with a 1 standard deviation increase in quality. Applications and potential policy implications of this method are discussed. PMID- 25437754 TI - Quantitative identification of metastable magnesium carbonate minerals by solid state 13C NMR spectroscopy. AB - In the conversion of CO2 to mineral carbonates for the permanent geosequestration of CO2, there are multiple magnesium carbonate phases that are potential reaction products. Solid-state (13)C NMR is demonstrated as an effective tool for distinguishing magnesium carbonate phases and quantitatively characterizing magnesium carbonate mixtures. Several of these mineral phases include magnesite, hydromagnesite, dypingite, and nesquehonite, which differ in composition by the number of waters of hydration or the number of crystallographic hydroxyl groups. These carbonates often form in mixtures with nearly overlapping (13)C NMR resonances which makes their identification and analysis difficult. In this study, these phases have been investigated with solid-state (13)C NMR spectroscopy, including both static and magic-angle spinning (MAS) experiments. Static spectra yield chemical shift anisotropy (CSA) lineshapes that are indicative of the site-symmetry variations of the carbon environments. MAS spectra yield isotropic chemical shifts for each crystallographically inequivalent carbon and spin-lattice relaxation times, T1, yield characteristic information that assist in species discrimination. These detailed parameters, and the combination of static and MAS analyses, can aid investigations of mixed carbonates by (13)C NMR. PMID- 25437756 TI - Distributional cues and the onset bias in early word segmentation. AB - In previous infant studies on statistics-based word segmentation, the unit of statistical computation was always aligned with the syllabic edge, which had a consonant onset. The current study addressed whether the learning system imposes a constraint that favors word forms beginning with a consonant onset over those beginning with an onsetless sub-syllable, by examining infants' segmentation of vowel-initial non-words in French liaison. French-learning 20- and 24-month-old infants (N = 64) were familiarized with sentences containing variable liaison consonants preceding the same vowel-initial non-word (e.g., /n/onche, /z/onche, /r/onche, /t/onche), such that the distributional cues supported the sub-syllabic target (e.g., onche). After familiarization, we tested sub-syllabic statistical segmentation by presenting the vowel-initial target (e.g., onche) versus another non-familiarized vowel-initial word (e.g., eque). Another group of infants was tested with a consonant-initial mis-segmentation of the target (e.g., zonche) versus another non-familiarized consonant-initial word (e.g., zeque). Results showed that 20-month-olds failed to segment the vowel-initial targets, but they mis-segmented the targets as consonant-initial, indicating that the onset bias dominated over sub-syllabic statistics for word segmentation at this age. Twenty four-month-olds showed ambiguous interpretations (i.e., both vowel-initial segmentation and consonant-initial mis-segmentation), suggesting that the use of statistics to segment sub-syllabic words was emerging while the onset bias continued to have an impact. PMID- 25437757 TI - Modeling pubertal timing and tempo and examining links to behavior problems. AB - Research on the role of puberty in adolescent psychological development requires attention to the meaning and measurement of pubertal development. Particular questions concern the utility of self-report, the need for complex models to describe pubertal development, the psychological significance of pubertal timing vs. tempo, and sex differences in the nature and psychological significance of pubertal development. We used longitudinal self-report data to model linear and logistic trajectories of pubertal development, and used timing and tempo estimates from these models, and from traditional approaches (age at menarche and time from onset of breast development to menarche), to predict psychological outcomes of internalizing and externalizing behavior problems, and early sexual activity. Participants (738 girls, 781 boys) reported annually from ages 9 through 15 on their pubertal development, and they and their parents reported on their behavior in mid-to-late adolescence and early adulthood. Self-reports of pubertal development provided meaningful data for both boys and girls, producing good trajectories, and estimates of individuals' pubertal timing and tempo. A logistic model best fit the group data. Pubertal timing was estimated to be earlier in the logistic compared to linear model, but linear, logistic, and traditional estimates of pubertal timing correlated highly with each other and similarly with psychological outcomes. Pubertal tempo was not consistently estimated, and associations of tempo with timing and with behavior were model dependent. Advances in modeling facilitate the study of some questions about pubertal development, but assumptions of the models affect their utility in psychological studies. PMID- 25437759 TI - Health impact assessment of traffic-related air pollution at the urban project scale: influence of variability and uncertainty. AB - This paper develops and then demonstrates a new approach for quantifying health impacts of traffic-related particulate matter air pollution at the urban project scale that includes variability and uncertainty in the analysis. We focus on primary particulate matter having a diameter less than 2.5 MUm (PM2.5). The new approach accounts for variability in vehicle emissions due to temperature, road grade, and traffic behavior variability; seasonal variability in concentration response coefficients; demographic variability at a fine spatial scale; uncertainty in air quality model accuracy; and uncertainty in concentration response coefficients. We demonstrate the approach for a case study roadway corridor with a population of 16,000, where a new extension of the University of North Carolina (UNC) at Chapel Hill campus is slated for construction. The results indicate that at this case study site, health impact estimates increased by factors of 4-9, depending on the health impact considered, compared to using a conventional health impact assessment approach that overlooks these variability and uncertainty sources. In addition, we demonstrate how the method can be used to assess health disparities. For example, in the case study corridor, our method demonstrates the existence of statistically significant racial disparities in exposure to traffic-related PM2.5 under present-day traffic conditions: the correlation between percent black and annual attributable deaths in each census block is 0.37 (t(114)=4.2, p<0.0001). Overall, our results show that the proposed new campus will cause only a small incremental increase in health risks (annual risk 6*10(-10); lifetime risk 4*10(-8)), compared to if the campus is not built. Nonetheless, the approach we illustrate could be useful for improving the quality of information to support decision-making for other urban development projects. PMID- 25437758 TI - Lateral diffusion of proteins on supported lipid bilayers: additive friction of synaptotagmin 7 C2A-C2B tandem domains. AB - The synaptotagmin (Syt) family of proteins contains tandem C2 domains, C2A and C2B, which bind membranes in the presence of Ca(2+) to trigger vesicle fusion during exocytosis. Despite recent progress, the role and extent of interdomain interactions between C2A and C2B in membrane binding remain unclear. To test whether the two domains interact on a planar lipid bilayer (i.e., experience thermodynamic interdomain contacts), diffusion of fluorescent-tagged C2A, C2B, and C2AB domains from human Syt7 was measured using total internal reflection fluorescence microscopy with single-particle tracking. The C2AB tandem exhibits a lateral diffusion constant approximately half the value of the isolated single domains and does not change when additional residues are engineered into the C2A C2B linker. This is the expected result if C2A and C2B are separated when membrane-bound; theory predicts that C2AB diffusion would be faster if the two domains were close enough together to have interdomain contact. Stopped-flow measurements of membrane dissociation kinetics further support an absence of interdomain interactions, as dissociation kinetics of the C2AB tandem remain unchanged when rigid or flexible linker extensions are included. Together, the results suggest that the two C2 domains of Syt7 bind independently to planar membranes, in contrast to reported interdomain cooperativity in Syt1. PMID- 25437760 TI - Diurnal emissivity dynamics in bare versus biocrusted sand dunes. AB - Land surface emissivity (LSE) in the thermal infrared depends mainly on the ground cover and on changes in soil moisture. The LSE is a critical variable that affects the prediction accuracy of geophysical models requiring land surface temperature as an input, highlighting the need for an accurate derivation of LSE. The primary aim of this study was to test the hypothesis that diurnal changes in emissivity, as detected from space, are larger for areas mostly covered by biocrusts (composed mainly of cyanobacteria) than for bare sand areas. The LSE dynamics were monitored from geostationary orbit by the Spinning Enhanced Visible and Infrared Imager (SEVIRI) over a sand dune field in a coastal desert region extending across both sides of the Israel-Egypt political borderline. Different land-use practices by the two countries have resulted in exposed, active sand dunes on the Egyptian side (Sinai), and dunes stabilized by biocrusts on the Israeli side (Negev). Since biocrusts adsorb more moisture from the atmosphere than bare sand does, and LSE is affected by the soil moisture, diurnal fluctuations in LSE were larger for the crusted dunes in the 8.7 MUm channel. This phenomenon is attributed to water vapor adsorption by the sand/biocrust particles. The results indicate that LSE is sensitive to minor changes in soil water content caused by water vapor adsorption and can, therefore, serve as a tool for quantifying this effect, which has a large spatial impact. As biocrusts cover vast regions in deserts worldwide, this discovery has repercussions for LSE estimations in deserts around the globe, and these LSE variations can potentially have considerable effects on geophysical models from local to regional scales. PMID- 25437761 TI - Spatial, temporal, and source variations of hydrocarbons in marine sediments from Baffin Bay, Eastern Canadian Arctic. AB - With declining sea ice conditions in Arctic regions owing to changing climate, the large prospective reservoirs of oil and gas in Baffin Bay and Davis Strait are increasingly accessible, and the interest in offshore exploration and shipping through these regions has increased. Both of these activities are associated with the risk of hydrocarbon releases into the marine ecosystem. However, hydrocarbons are also present naturally in marine environments, in some cases deriving from oil seeps. We have analyzed hydrocarbon concentrations in eleven sediment cores collected from northern Baffin Bay during 2008 and 2009 Amundsen expeditions and have examined the hydrocarbon compositions in both pre- and post-industrial periods (i.e., before and after 1900) to assess the sources of hydrocarbons, and their temporal and spatial variabilities. Concentrations of SigmaPAHs ranged from 341 to 2693 ng g(-1) dw, with concentrations in cores from sites within the North Water (NOW) Polynya generally higher. Individual PAH concentrations did not exceed concentrations of concern for marine aquatic life, with one exception found in a core collected within the NOW (one of the seven sediment core samples). Hydrocarbon biomarkers, including alkane profiles, OEP (odd-to-even preference), and TAR (terrigenous/aquatic ratios) values indicated that organic carbon at all sites is derived from both terrigenous higher plants and marine algae, the former being of greater significance at coastal sites, and the latter at the deepest sites at the southern boundary of the NOW. Biomarker ratios and chemical profiles indicate that petrogenic sources dominate over combustion sources, and thus long-range atmospheric transport is less significant than inputs from weathering. Present-day and historic pre-1900 hydrocarbon concentrations exhibited less than an order of magnitude difference for most compounds at all sites. The dataset presented here provides a baseline record of hydrocarbon concentrations in Baffin Bay sediments in advance of offshore exploration and increased shipping activities. PMID- 25437762 TI - The delivery of organic contaminants to the Arctic food web: why sea ice matters. AB - For decades sea ice has been perceived as a physical barrier for the loading of contaminants to the Arctic Ocean. We show that sea ice, in fact, facilitates the delivery of organic contaminants to the Arctic marine food web through processes that: 1) are independent of contaminant physical-chemical properties (e.g. 2-3 fold increase in exposure to brine-associated biota), and 2) depend on physical chemical properties and, therefore, differentiate between contaminants (e.g. atmospheric loading of contaminants to melt ponds over the summer, and their subsequent leakage to the ocean). We estimate the concentrations of legacy organochlorine pesticides (OCPs) and current-use pesticides (CUPs) in melt pond water in the Beaufort Sea, Canadian High Arctic, in 2008, at near-gas exchange equilibrium based on Henry's law constants (HLCs), air concentrations and exchange dynamics. CUPs currently present the highest risk of increased exposures through melt pond loading and drainage due to the high ratio of melt pond water to seawater concentration (Melt pond Enrichment Factor, MEF), which ranges from 2 for dacthal to 10 for endosulfan I. Melt pond contaminant enrichment can be perceived as a hypothetical 'pump' delivering contaminants from the atmosphere to the ocean under ice-covered conditions, with 2-10% of CUPs annually entering the Beaufort Sea via this input route compared to the standing stock in the Polar Mixed Layer of the ocean. The abovementioned processes are strongly favored in first-year ice compared to multi-year ice and, therefore, the dynamic balance between contaminant inventories and contaminant deposition to the surface ocean is being widely affected by the large-scale icescape transition taking place in the Arctic. PMID- 25437763 TI - Impact of urbanization and land-use/land-cover change on diurnal temperature range: a case study of tropical urban airshed of India using remote sensing data. AB - Diurnal temperature range (DTR) is an important climate change index. Its knowledge is important to a range of issues and themes in earth sciences central to urban climatology and human-environment interactions. The present study investigates the effect of urbanization on the land surface temperature (LST) based DTR. This study presents spatial and temporal variations of satellite based estimates of annually averaged DTR over megacity Delhi, the capital of India, which are shown for a period of 11 years during 2001-2011 and analyzes this with regard to its land-use/land-cover (LU/LC) changes and population growth. Delhi which witnessed massive urbanization in terms of population growth (decadal growth rate of Delhi during 2001-2011 was 20.96%) and major transformations in the LU/LC (built-up area crossed more than 53%) are experiencing severity in its micro and macroclimate. There was a consistent increase in the areas experiencing DTR below 11 degrees C which typically resembled the 'urban class' viz. from 26.4% in the year 2001 to 65.3% in the year 2011 and subsequently the DTR of entire Delhi which was 12.48 degrees C in the year 2001 gradually reduced to 10.34 degrees C in the year 2011, exhibiting a significant decreasing trend. Rapidly urbanizing areas like Rohini, Dwarka, Vasant Kunj, Kaushambi, Khanjhawala Village, IIT, Safdarjung Airport, etc. registered a significant decreasing trend in the DTR. In the background of the converging DTR, which was primarily due to the increase in the minimum temperatures, a grim situation in terms of potentially net increase in the heat-related mortality rate especially for the young children below 15years of age is envisaged for Delhi. Considering the earlier findings that the level of risk of death remained the highest and longest for Delhi, in comparison to megacities like Sao Paulo and London, the study calls for strong and urgent heat island mitigation measures. PMID- 25437764 TI - Isotopic and hydrogeochemical characterization of high-altitude karst aquifers in complex geological settings. The Ordesa and Monte Perdido National Park (Northern Spain) case study. AB - The Ordesa and Monte Perdido National Park, located in the Southern Pyrenees, constitutes the highest karst system in Western Europe. No previous studies regarding its geochemical and isotopic groundwater characterization are available in this area. This work presents the results of field and sampling campaigns carried out between July 2007 and September 2013. The groundwater presents high calcium bicarbonate contents due to the occurrence of upper Cretaceous and lower Paleocene-Eocene carbonate materials in the studied area. Other relevant processes include dissolution of anhydrite and/or gypsum and incongruent dissolution of Mg-limestone and dolomite. The water stable isotopes (delta(18)O, delta(2)H) show that the oceanic fronts from the Atlantic Ocean are responsible for the high levels of precipitation. In autumn, winter, and spring, a deuterium excess is found in the recharge water, which could be related to local atmospheric transport of low-altitude snow sublimation vapour and its later condensation on the snow surface at higher altitude, where recharge is mostly produced. The recharge zones are mainly between 2500m and 3200ma.s.l. The tritium content of the water suggests short groundwater transit times. The isotopic composition of dissolved sulphate points to the existence of regional fluxes mixed with local discharge in some of the springs. This work highlights the major role played by the altitude difference between the recharge and discharge zones in controlling the chemistry and the vertical variability of the isotopic composition in high-altitude karst aquifers. PMID- 25437765 TI - Biogeochemical plant-soil interaction: variable element composition in leaves of four plant species collected along a south-north transect at the southern tip of Norway. AB - Leaves from four different plant species (birch, willow, juniper, and heather) together with samples of the soil O and C horizons were collected at 44-46 sites along a south-to-north transect extending inland for 200 km from the southern tip of Norway. The transect covers one of the steepest vegetation gradients on Earth, crossing six vegetation zones. Juniper and heather are evergreen, and preferably exclude potentially toxic elements to avoid their accumulation in assimilating tissues, birch and willow shed their leaves in autumn together with the load of potentially toxic elements, and thus can tolerate the uptake of such elements. The plant leaves show the highest concentrations for B, Ca, K, Mg, Mn, P, Rb and S. In the soil O-horizon Ag, Au, As, Bi, Cu, Ge, Hg, In, Pb, Sb, Se, Sn, Te and W are enriched with respect to the C-horizon, whilst Mn and Rb are depleted. Cadmium, Sr and Zn are enriched in willow and Cs, Na and Tl in heather. In terms of concentration gradients from the coast inland, two different patterns are detected: 1) short range with an almost exponential decrease of concentrations from the coast, which appears to be typical for seaspray-related element input, and 2) long range with an almost linear decrease of concentrations with distance from the coast. These patterns differ among the four species, even for one and the same element. Inter-element correlation is different from material to material. Along the transect each of the different plants at the same site individually adapts to the available element combination. High linear correlations in the plants occur between the lanthanides (La, Ce, Y), and interestingly, between P and Ti. The plant/soil system appears highly non-linear and self-regulated. PMID- 25437766 TI - The question of pathogen quantification in disinfected graywater. AB - Graywater (GW) reuse for irrigation is recognized as a sustainable solution for water conservation. One of the major impediments to GW reuse is the presence of pathogenic microorganisms. This study monitored three similar on-site GW treatment systems bi-monthly over the course of a year to compare the presence of pathogens and indicators in raw, biologically treated, and biologically treated and disinfected [by chlorine and ultraviolet light (UV)] GW. The systems were designed to allow the testing of the same batch (collection) of water as it passed through the treatment chain. The samples were analyzed using standard culture-dependent methods and the data were compared to culture-independent DNA based methods. Results suggested that the presence and abundance of fecal coliforms, Escherichia coli, Salmonella enterica, Enterococcus spp., Staphylococcus aureus and Pseudomonas aeruginosa differ among the various GW streams (e.g. raw, biologically treated, and disinfected). The culture-dependent analyses suggested that both chlorine and UV inactivate most of the bacteria tested in the biologically treated GW, albeit at different efficiencies. Conversely, the DNA-based analyses indicated no significant differences in pathogenic bacterial abundance between the biologically treated GW with or without disinfection. To better understand the discrepancies between the results, we repeated the analysis in the laboratory under controlled conditions using Enterococcus faecalis as a model bacterium and obtained similar results. We suggest that disinfection of biologically treated GW with chlorine or UV is effective for treating pathogens, but that the inactivation efficiency cannot be estimated by DNA-based qPCR. PMID- 25437767 TI - Risk-based prioritization methodology for the classification of groundwater pollution sources. AB - Water management is one of the EU environmental priorities and it is one of the most serious challenges that today's major cities are facing. The main European regulation for the protection of water resources is represented by the Water Framework Directive (WFD) and the Groundwater Directive (2006/118/EC) which require the identification, risk-based ranking and management of sources of pollution and the identification of those contamination sources that threaten the achievement of groundwater's good quality status. The aim of this paper is to present a new risk-based prioritization methodology to support the determination of a management strategy for the achievement of the good quality status of groundwater. The proposed methodology encompasses the following steps: 1) hazard analysis, 2) pathway analysis, 3) receptor vulnerability analysis and 4) relative risk estimation. Moreover, by integrating GIS functionalities and Multi Criteria Decision Analysis (MCDA) techniques, it allows to: i) deal with several sources and multiple impacted receptors within the area of concern; ii) identify different receptors' vulnerability levels according to specific groundwater uses; iii) assess the risks posed by all contamination sources in the area; and iv) provide a risk-based ranking of the contamination sources that can threaten the achievement of the groundwater good quality status. The application of the proposed framework to a well-known industrialized area located in the surroundings of Milan (Italy) is illustrated in order to demonstrate the effectiveness of the proposed framework in supporting the identification of intervention priorities. Among the 32 sources analyzed in the case study, three sources received the highest relevance score, due to the medium-high relative risks estimated for Chromium (VI) and Perchloroethylene. The case study application showed that the developed methodology is flexible and easy to adapt to different contexts, thanks to the possibility to introduce specific relevant parameters identified according to expert judgment and data availability. PMID- 25437768 TI - Integrating smart-phone based momentary location tracking with fixed site air quality monitoring for personal exposure assessment. AB - Epidemiological studies investigating relationships between environmental exposures from air pollution and health typically use residential addresses as a single point for exposure, while environmental exposures in transit, at work, school or other locations are largely ignored. Personal exposure monitors measure individuals' exposures over time; however, current personal monitors are intrusive and cannot be operated at a large scale over an extended period of time (e.g., for a continuous three months) and can be very costly. In addition, spatial locations typically cannot be identified when only personal monitors are used. In this paper, we piloted a study that applied momentary location tracking services supplied by smart phones to identify an individual's location in space time for three consecutive months (April 28 to July 28, 2013) using available Wi Fi networks. Individual exposures in space-time to the traffic-related pollutants Nitrogen Oxides (NOX) were estimated by superimposing an annual mean NOX concentration surface modeled using the Land Use Regression (LUR) modeling technique. Individual's exposures were assigned to stationary (including home, work and other stationary locations) and in-transit (including commute and other travel) locations. For the individual, whose home/work addresses were known and the commute route was fixed, it was found that 95.3% of the time, the individual could be accurately identified in space-time. The ambient concentration estimated at the home location was 21.01 ppb. When indoor/outdoor infiltration, indoor sources of air pollution and time spent outdoors were taken into consideration, the individual's cumulative exposures were 28.59 ppb and 96.49 ppb, assuming a respective indoor/outdoor ratio of 1.33 and 5.00. Integrating momentary location tracking services with fixed-site field monitoring, plus indoor-outdoor air exchange calibration, makes exposure assessment of a very large population over an extended time period feasible. PMID- 25437769 TI - Barium ferrite decorated reduced graphene oxide nanocomposite for effective electromagnetic interference shielding. AB - There is an increased interest in the development of high performance microwave shielding materials against electromagnetic pollution in recent years. Barium ferrite decorated reduced graphene oxide (BaFe12O19@RGO) nanocomposite was synthesized by a high energy ball milling technique and its electromagnetic properties were investigated in the frequency range of 12.4-18 GHz (Ku band). The results showed that barium ferrite (BaFe12O19) nanoparticles with an average particle size of 20-30 nm were well distributed and firmly anchored onto the surface of the reduced graphene oxide sheets. The obtained nanocomposite exhibited a saturation magnetization of 18.1 emu g(-1) at room temperature. The presence of BaFe12O19 nanoparticles in the nanocomposite enhances the space charge polarization, natural resonance, multiple scattering and the effective anisotropy energy leading to a high electromagnetic interference shielding effectiveness of 32 dB (~99.9% attenuation) at a critical thickness of 3 mm. The results suggested that the as-prepared BaFe12O19@RGO nanocomposite showed great potential as an effective candidate for a new type of microwave absorbing material. PMID- 25437770 TI - Ir(III)-Catalyzed Aromatic C-H Bond Functionalization via Metal Carbene Migratory Insertion. AB - Ir(III)-catalyzed coupling of aromatic C-H bonds with diazomalonates has been achieved successfully via a metal carbene migratory insertion process. With different types of carbamoyl directing groups, a wide range of arenes, including heteroarenes, can be used as substrates in this Ir(III)-catalyzed C-H functionalization reaction. Mono- and bisfunctionalized products can be obtained selectively simply by changing the number of equivalents of the diazo substrate. Moreover, when diazomalonates bearing one or two tert-butyl groups are used as the substrates, the C-H bond functionalization is followed by decarboxyation, leading to products with a -CH2CO2Me or -CH2CO2H moiety at the position ortho to the directing group. This reaction demonstrates that direct C-H activation and the metal carbene migratory insertion can be merged into one catalytic cycle with an Ir(III) complex as the catalyst. PMID- 25437771 TI - Reduction of residual limb volume in people with transtibial amputation. AB - The early postoperative phase after transtibial amputation is characterized by rapid residual limb volume reduction. Accurate measurement of residual limb volume is important for the timing of fitting a prosthesis. The aim of this study is to analyze the reduction of residual limb volume in people with transtibial amputation and to correlate residual limb volume with residual limb circumference. In a longitudinal cohort study of 21 people who had a transtibial amputation, residual limb volume was measured using a laser scanner and circumference was measured using a tape measure 1 wk postamputation and every 3 wk thereafter until 24 wk postamputation. A linear mixed model analysis was performed with weeks postamputation transformed according to the natural logarithm as predictor. Residual limb volume decreased significantly over time, with a large variation between patients. Residual limb volume does not correlate well with circumference. On average, residual limb volume decreased 200.5 mL (9.7% of the initial volume) per natural logarithm of the weeks postamputation. The decrease in residual limb volume following a transtibial amputation is substantial in the early postamputation phase, followed by a leveling off. It was not possible to determine a specific moment when the residual limb volume had stabilized. PMID- 25437774 TI - Borate fluoride and fluoroborate in alkali-metal borate prepared by an open high temperature solution method. AB - By incorporation of the largest-electronegativity F atoms into borate, two novel halogen-containing borates, Li6RbB2O6F and K3B3O3F6, have been synthesized. Interestingly, Li6RbB2O6F is the first borate fluoride in alkali-metal borate. Meanwhile, K3B3O3F6 appears to be the first confirmed alkali-metal fluoroborate crystal grown by a high-temperature solution in air. PMID- 25437773 TI - Evaluation of in vivo properties of VelosorbTM fast versus VicrylTM rapide in a functional rabbit model of intradermic suture and episiotomy. AB - OBJECTIVE: Fast-absorbing polyglactin 910 is commonly used to suture skin and vaginal incisions. In vitro studies have shown similar tensile strength properties between VelosorbTM Fast and VicrylTM Rapide (Al-Qattan MM. J Hand Surg Br Eur. 2005;30(1):90-91). This randomized study compared VelosorbTM Fast (Covidien) with VicrylTM Rapide (Ethicon) in a rabbit model of intradermic suture and episiotomy. MATERIALS AND METHODS: This randomized prospective study was performed on 20 New Zealand rabbits, in which we realized a mediolateral perineo vaginal incision and two vertical skin incisions of about 8 cm on the abdominal wall. The sutures were randomized between VelosorbTM Fast (Covidien) and VicrylTM Rapide (Ethicon), and each rabbit was treated with the same suture on both vaginal incision and left abdominal incision, while the right abdominal incision was closed with an alternate suture. A macroscopic examination was performed on days 5 and 11. On day 11, animals were sacrificed for histological (Badylak quantitative score) and electron microscopic examinations. Differences were considered significant at p < .05. RESULTS: All of the rabbits survived and were included in the final results. Fifty-one sutures were visible by histologic analysis (27 in the VelosorbTM Fast group and 24 in the VicrylTM Rapide group). The power of the study was >=80%. There was no significant difference between the two groups based on the total histologic Badylak score analysis or the Badylak sub-score analysis. CONCLUSIONS: VelosorbTM Fast seems to be as efficient as VicrylTM Rapide for use in perineal and skin closure. PMID- 25437775 TI - Editorial. PMID- 25437776 TI - Quantitative atomistic simulations of reactive and non-reactive processes. AB - The interpretation of physico-chemical observables in terms of atomic motions is one of the primary objectives of atomistic simulations. Trajectories from a molecular simulation contain much valuable information about the relationship between motion of the atoms and physical observables related to them, provided that the interactions used to generate the trajectories are of sufficiently high quality. On the other hand, many experimental observables are averages over a large number of physical realizations of the system. Thus, a statistically large number of trajectories needs to be generated and analyzed in order to provide a meaningful basis for comparison with and interpretation of experiments. The preferred computational approach which allows such extensive averaging while retaining the quantitative aspects of the intermolecular interactions are accurate force field-based molecular dynamics simulations. This contribution provides an overview of our group's current technological improvements in force field technology and its application to fundamental physico-chemical questions. PMID- 25437772 TI - Epirubicin-adsorbed nanodiamonds kill chemoresistant hepatic cancer stem cells. AB - Chemoresistance is a primary cause of treatment failure in cancer and a common property of tumor-initiating cancer stem cells. Overcoming mechanisms of chemoresistance, particularly in cancer stem cells, can markedly enhance cancer therapy and prevent recurrence and metastasis. This study demonstrates that the delivery of Epirubicin by nanodiamonds is a highly effective nanomedicine-based approach to overcoming chemoresistance in hepatic cancer stem cells. The potent physical adsorption of Epirubicin to nanodiamonds creates a rapidly synthesized and stable nanodiamond-drug complex that promotes endocytic uptake and enhanced tumor cell retention. These attributes mediate the effective killing of both cancer stem cells and noncancer stem cells in vitro and in vivo. Enhanced treatment of both tumor cell populations results in an improved impairment of secondary tumor formation in vivo compared with treatment by unmodified chemotherapeutics. On the basis of these results, nanodiamond-mediated drug delivery may serve as a powerful method for overcoming chemoresistance in cancer stem cells and markedly improving overall treatment against hepatic cancers. PMID- 25437777 TI - Chemical Reactions on Metal-supported Hexagonal Boron Nitride Investigated with Density Functional Theory. AB - Nanotechnology, in order to become ultimately efficient, requires achieving the construction of elemental structures at the atomistic precision. One way toward this goal is using templated surfaces as support for directed synthesis. The nanomesh, a single-atom thick layer of hexagonal boron nitride on Rh(111) [Corso et al., Science 2004, 303, 217], has appeared as one candidate that provides a periodically corrugated structure on the nanometre scale. We present density functional theory studies where we investigate various properties of the nanomesh, ranging from intrinsic defects to covalent functionalisation with hydroxyl radicals. Further we study selective dehalogenation of an organic molecule (I6-CHP) on the nanomesh. This molecule adsorbs at particular sites of the template and has been activated for C-C coupling in recent experiments via dissociation of its halogen ligands. In all cases we find explicit templating effects, either in full agreement with experimental studies or predicting novel phenomena. The studies are evidence for the predictive power of modern electronic structure simulations and the insight that can be gained when used together with experiments on complex chemical structures. PMID- 25437778 TI - Quantum mechanical treatment of variable molecular composition: from 'alchemical' changes of state functions to rational compound design. AB - 'Alchemical' interpolation paths, i.e. coupling systems along fictitious paths without realistic correspondence, are frequently used within materials and molecular modeling simulation protocols for the estimation of changes in state functions such as free energies. We discuss alchemical changes in the context of quantum chemistry, and present illustrative numerical results for the changes of HOMO eigenvalue of the He atom due to alchemical teleportation - the simultaneous annihilation and creation of nuclear charges at different locations. To demonstrate the predictive power of alchemical first order derivatives (Hellmann Feynman) the covalent bond potential of hydrogen fluoride and hydrogen chloride is investigated, as well as the hydrogen bond in the water-water and water hydrogen fluoride dimer, respectively. Based on converged electron densities for one configuration, the versatility of alchemical derivatives is exemplified for the screening of entire binding potentials with reasonable accuracy. Finally, we discuss new constraints for the identification of non-linear coupling potentials for which the energy's Hellmann-Feynman derivative will yield accurate predictions. PMID- 25437779 TI - Non-uniform Continuum Model for Solvated Species Based on Frozen-Density Embedding Theory: The Study Case of Solvatochromism of Coumarin 153. AB - Recent application of the Frozen-Density Embedding Theory based continuum model of the solvent, which is used for calculating solvatochromic shifts in the UV/Vis range, are reviewed. In this model, the solvent is represented as a non-uniform continuum taking into account both the statistical nature of the solvent and specific solute-solvent interactions. It offers, therefore, a computationally attractive alternative to methods in which the solvent is described at atomistic level. The evaluation of the solvatochromic shift involves only two calculations of excitation energy instead of at least hundreds needed to account for inhomogeneous broadening. The present review provides a detailed graphical analysis of the key quantities of this model: the average charge density of the solvent () and the corresponding Frozen-Density Embedding Theory derived embedding potential for coumarin 153. PMID- 25437781 TI - Crossing the Boundaries within Computational Chemistry: From Molecular Dynamics to Cheminformatics and back. AB - The research in the group for computational chemistry at the ETH Zurich focuses on the development of methods and software for classical molecular dynamics simulations and cheminformatics, and their application to biological and chemical questions. Here, important advances and challenges in these subfields of computational chemistry are reviewed and potential opportunities for cross fertilization are outlined. PMID- 25437780 TI - Mechanisms of Ligand-Protein Interaction in Sec-14-like Transporters Investigated by Computer Simulations. AB - We review our recent work on protein-ligand interactions in vitamin transporters of the Sec-14-like protein. Our studies focused on the cellular-retinaldehyde binding protein (CRALBP) and the alpha-tocopherol transfer protein (alpha-TTP). CRALBP is responsible for mobilisation and photo-protection of short-chain cis retinoids in the dim-light visual cycle or rod photoreceptors. alpha-TTP is a key protein responsible for selection and retention of RRR-alpha-tocopherol, the most active isoform of vitamin E in superior animals. Our simulation studies evidence how subtle chemical variations in the substrate can lead to significant distortion in the structure of the complex, and how these changes can either lead to new protein function, or be used to model engineered protein variants with tailored properties. Finally, we show how integration of computational and experimental results can contribute in synergy to the understanding of fundamental processes at the biomolecular scale. PMID- 25437782 TI - "Why and How it Works": The Development of Hypervalent Iodine Reagents as an Illustration for the Collaboration of Chemical Synthesis with Modeling and Simulation. AB - Much of the focus of quantum chemical modeling and simulation is on understanding chemical phenomena and in assisting experiment to further improve and develop the respective chemistry. Given the computational tools available today, rather than assisting the development of new chemicals, modeling and simulation are in the process of making the step towards guiding experiment towards novel targets. In this article we show how an intense collaboration between chemical synthesis and computation leads to a better understanding of hypervalent iodine reagents and how modeling and simulation may direct the search of novel reagents. PMID- 25437783 TI - Predicting the Genes Regulated by MicroRNAs via Binding Sites in the 3' Untranslated and Coding Regions. AB - MicroRNAs form one of the groups of small noncoding RNA molecules that have completely changed our understanding of gene regulatory networks. Because microRNAs have been discovered only relatively recently, most of their functions remain unknown, providing a challenge to both experiment and theory. I review several computational approaches pursued in our group to answer this challenge. In particular, I show that a few rather simple ideas can go a long way in predicting accurately genes regulated by microRNAs via binding sites both in the coding and 3' untranslated regions (3'UTRs). Finally, I mention briefly several applications, including two collaborations with experimental groups, which have shed new light on the latency and reactivation of herpesviruses, and on the maturation of red blood cells. PMID- 25437784 TI - Non-empirical Prediction of the Photophysical and Magnetic Properties of Systems with Open d- and f-Shells Based on Combined Ligand Field and Density Functional Theory (LFDFT). AB - Despite the important growth of ab initio and computational techniques, ligand field theory in molecular science or crystal field theory in condensed matter offers the most intuitive way to calculate multiplet energy levels arising from systems with open shells d and/or f electrons. Over the past decade we have developed a ligand field treatment of inorganic molecular modelling taking advantage of the dominant localization of the frontier orbitals within the metal sphere. This feature, which is observed in any inorganic coordination compound, especially if treated by Density Functional Theory calculation, allows the determination of the electronic structure and properties with a surprising good accuracy. In ligand field theory, the theoretical concepts consider only a single atom center; and treat its interaction with the chemical environment essentially as a perturbation. Therefore success in the simple ligand field theory is no longer questionable, while the more accurate molecular orbital theory does in general over-estimate the metal-ligand covalence, thus yields wave functions that are too delocalized. Although LF theory has always been popular as a semi empirical method when dealing with molecules of high symmetry e.g. cubic symmetry where the number of parameters needed is reasonably small (3 or 5), this is no more the case for molecules without symmetry and involving both an open d- and f shell (# parameters ~90). However, the combination of LF theory and Density Functional (DF) theory that we introduced twenty years ago can easily deal with complex molecules of any symmetry with two and more open shells. The accuracy of these predictions from 1(st) principles achieves quite a high accuracy (<5%) in terms of states energies. Hence, this approach is well suited to predict the magnetic and photo-physical properties arbitrary molecules and materials prior to their synthesis, which is the ultimate goal of each computational chemist. We will illustrate the performance of LFDFT for the design of phosphors that produces light similar to our sun and predict the magnetic anisotropy energy of single ion magnets. PMID- 25437785 TI - Lessons from nature: computational design of biomimetic compounds and processes. AB - Through millions of years of evolution, Nature has accomplished the development of highly efficient and sustainable processes and the idea to understand and copy natural strategies is therefore very appealing. However, in spite of intense experimental and computational research, it has turned out to be a difficult task to design efficient biomimetic systems. Here we discuss a novel strategy for the computational design of biomimetic compounds and processes that consists of i) target selection; ii) atomistic and electronic characterization of the wild type system and the biomimetic compounds; iii) identification of key descriptors through feature selection iv) choice of biomimetic template and v) efficient search of chemical and sequence space for optimization of the biomimetic system. As a proof-of-principles study, this general approach is illustrated for the computational design of a 'green' catalyst mimicking the action of the zinc metalloenzyme Human Carbonic Anhydrase (HCA). HCA is a natural model for CO2 fixation since the enzyme is able to convert CO2 into bicarbonate. Very recently, a weakly active HCA mimic based on a trihelical peptide bundle was synthetized. We have used quantum mechanical/molecular mechanical (QM/MM) Car-Parrinello simulations to study the mechanisms of action of HCA and its peptidic mimic and employed the obtained information to guide the design of improved biomimetic analogues. Applying a genetic algorithm based optimization procedure, we were able to re-engineer and optimize the biomimetic system towards its natural counter part. In a second example, we discuss a similar strategy for the design of biomimetic sensitizers for use in dye-sensitized solar cells. PMID- 25437786 TI - Coping with polypharmacology by computational medicinal chemistry. AB - Predicting the macromolecular targets of drug-like molecules has become everyday practice in medicinal chemistry. We present an overview of our recent research activities in the area of polypharmacology-guided drug design. A focus is put on the self-organizing map (SOM) as a tool for compound clustering and visualization. We show how the SOM can be efficiently used for target-panel prediction, drug re-purposing, and the design of focused compound libraries. We also present the concept of virtual organic synthesis in combination with quantitative estimates of ligand-receptor binding, which we used for de novo designing target-selective ligands. We expect these and related approaches to enable the future discovery of personalized medicines. PMID- 25437789 TI - Non-aqueous Capillary Electrophoresis for the Analysis of Pharmaceutical Acidic Compounds Using Negative ESI-MS. PMID- 25437787 TI - Chemicals inducing seed germination and early seedling development. AB - Seed germination and early seedling development are essential events in the plant life cycle that are controlled largely by the interplay and cross-talk between several plant hormones. Recently, major progress has been achieved in the elucidation at the molecular level of the signalling of these phytohormones. In this review, we summarise the data for the most promising classes of compounds, which could find potential agronomic applications for promoting seed germination and early seedling development even under abiotic stress conditions. Structural modifications of plant hormones are required to improve their biological performance and their specificity to allow commercial application. PMID- 25437790 TI - Mechanically triggered responses of metallosupramolecular polymers. PMID- 25437792 TI - Bothered by abstractness or engaged by cohesion? Experts' explanations enhance novices' deep-learning. AB - Experts' explanations have been shown to better enhance novices' transfer as compared with advanced students' explanations. Based on research on expertise and text comprehension, we investigated whether the abstractness or the cohesion of experts' and intermediates' explanations accounted for novices' learning. In Study 1, we showed that the superior cohesion of experts' explanations accounted for most of novices' transfer, whereas the degree of abstractness did not impact novices' transfer performance. In Study 2, we investigated novices' processing while learning with experts' and intermediates' explanations. We found that novices studying experts' explanations actively self-regulated their processing of the explanations, as they showed mainly deep-processing activities, whereas novices learning with intermediates' explanations were mainly engaged in shallow processing activities by paraphrasing the explanations. Thus, we concluded that subject-matter expertise is a crucial prerequisite for instructors. Despite the abstract character of experts' explanations, their subject-matter expertise enables them to generate highly cohesive explanations that serve as a valuable scaffold for students' construction of flexible knowledge by engaging them in deep-level processing. PMID- 25437793 TI - Effects of cues on target search behavior. AB - Cues in visual scanning task can improve decision accuracy, and they may also affect task performance strategies. We tested the effects of cues on the performance of binary classifications, on the screen scanning procedure participants employed, and on the reported effort in a simulated quality control task. Participants had to decide whether each item in a 5 * 5 matrix of items was intact or faulty. In half the experimental blocks decisions could only be based on the visual properties of the items. In the other half, participants also saw imperfect binary cues and could use them to classify the items as faulty or intact. We used eye tracking to study scan patterns and fixation durations on items. Decision performance improved with cues, and cues affected the scanning of items, with participants mainly scanning cued items and tending to scan them longer. Participants stated that cues reduced their effort when cues were highly valid. We conclude that strategic choices to focus on suspected areas determined the screen scanning procedure, the amount of effort invested in single decisions, and the accuracy of the decisions. We therefore suggest using likelihood ratio cues to help optimize the scanning procedure. PMID- 25437794 TI - The influence of different graphical displays on nonexpert decision making under uncertainty. AB - Understanding how people interpret and use visually presented uncertainty data is an important yet seldom studied aspect of data visualization applications. Current approaches in visualization often display uncertainty as an additional data attribute without a well-defined context. Our goal was to test whether different graphical displays (glyphs) would influence a decision about which of 2 weather forecasts was a more accurate predictor of an uncertain temperature forecast value. We used a statistical inference task based on fictional univariate normal distributions, each characterized by a mean and standard deviation. Participants viewed 1 of 5 different glyph types representing 2 weather forecast distributions. Three of these used variations in spatial encoding to communicate the distributions and the other 2 used nonspatial encoding (brightness or color). Four distribution pairs were created with different relative standard deviations (uncertainty of the forecasts). We found that there was a difference in how decisions were made with spatial versus nonspatial glyphs, but no difference among the spatial glyphs themselves. Furthermore, the effect of different glyph types changed as a function of the variability of the distributions. The results are discussed in the context of how visualizations might improve decision making under uncertainty. PMID- 25437795 TI - Striking the right chord: moving music increases psychological transportation and behavioral intentions. AB - Three experiments among university students (N = 372) investigated the persuasive power of moving (i.e., intensely emotional and "chills"-evoking) music in audio visual advertising. Although advertisers typically aim to increase elaborate processing of the message, these studies illustrate that the persuasive effect of moving music is based on increased narrative transportation ("getting lost" in the ad's story), which reduces critical processing. In Experiment 1, moving music increased transportation and some behavioral intentions (e.g., to donate money). Experiment 2 experimentally increased the salience of manipulative intent of the advertiser, and showed that moving music reduces inferences of manipulative intent, leading in turn to increased behavioral intentions. Experiment 3 tested boundary effects, and showed that moving music fails to increase behavioral intentions when the salience of manipulative intent is either extremely high (which precludes transportation) or extremely low (which precludes reduction of inferences of manipulative intent). Moving music did not increase memory performance, beliefs, and explicit attitudes, suggesting that the influence is affect-based rather cognition-based. Together, these studies illustrate that moving music reduces inferences of manipulation and increases behavioral intentions by transporting viewers into the story of the ad. PMID- 25437796 TI - Soy sauce classification by geographic region and fermentation based on artificial neural network and genetic algorithm. AB - This work demonstrated the possibility of using artificial neural networks to classify soy sauce from China. The aroma profiles of different soy sauce samples were differentiated using headspace solid-phase microextraction. The soy sauce samples were analyzed by gas chromatography-mass spectrometry, and 22 and 15 volatile aroma compounds were selected for sensitivity analysis to classify the samples by fermentation and geographic region, respectively. The 15 selected samples can be classified by fermentation and geographic region with a prediction success rate of 100%. Furans and phenols represented the variables with the greatest contribution in classifying soy sauce samples by fermentation and geographic region, respectively. PMID- 25437797 TI - Silver(I)-catalyzed ring-contractive rearrangement: a new entry to 5-alkylidene-2 cyclopentenones. AB - A novel silver(I)-catalyzed ring-contractive rearrangement of 5-substituted 6 diazo-2-cyclohexenones has been developed, providing a new and efficient access to 5-alkylidene-2-cyclopentenones. The AgOTf-catalyzed reaction proceeds through metal-carbenoid formation followed by endocyclic allyl [1,2] migration with excellent stereoselectivity and broad substrate scope. PMID- 25437798 TI - Integrons in the intestinal microbiota as reservoirs for transmission of antibiotic resistance genes. AB - The human intestinal microbiota plays a major beneficial role in immune development and resistance to pathogens. The use of antibiotics, however, can cause the spread of antibiotic resistance genes within the resident intestinal microbiota. Important vectors for this are integrons. This review therefore focuses on the integrons in non-pathogenic bacteria as a potential source for the development and persistence of multidrug resistance. Integrons are a group of genetic elements which are assembly platforms that can capture specific gene cassettes and express them. Integrons in pathogenic bacteria have been extensively investigated, while integrons in the intestinal microbiota have not yet gained much attention. Knowledge of the integrons residing in the microbiota, however, can potentially aid in controlling the spread of antibiotic resistance genes to pathogens. PMID- 25437799 TI - Morphine attenuates apically-directed cytokine secretion from intestinal epithelial cells in response to enteric pathogens. AB - Epithelial cells represent the first line of host immune defense at mucosal surfaces. Although opioids appear to increase host susceptibility to infection, no studies have examined opioid effects on epithelial immune functions. We tested the hypothesis that morphine alters vectorial cytokine secretion from intestinal epithelial cell (IPEC-J2) monolayers in response to enteropathogens. Both entero adherent Escherichia coli O157:H7 and entero-invasive Salmonella enterica serovar Typhimurium increased apically-directed IL-6 secretion and bi-directional IL-8 secretion from epithelial monolayers, but only IL-6 secretion evoked by E. coli was reduced by morphine acting through a naloxone-sensitive mechanism. Moreover, the respective type 4 and 5 Toll-like receptor agonists, lipopolysaccharide and flagellin, increased IL-8 secretion from monolayers, which was also attenuated by morphine pretreatment. These results suggest that morphine decreases cytokine secretion and potentially phagocyte migration and activation directed towards the mucosal surface; actions that could increase host susceptibility to some enteric infections. PMID- 25437800 TI - High-Throughput Sequencing, a VersatileWeapon to Support Genome-Based Diagnosis in Infectious Diseases: Applications to Clinical Bacteriology. AB - The recent progresses of high-throughput sequencing (HTS) technologies enable easy and cost-reduced access to whole genome sequencing (WGS) or re-sequencing. HTS associated with adapted, automatic and fast bioinformatics solutions for sequencing applications promises an accurate and timely identification and characterization of pathogenic agents. Many studies have demonstrated that data obtained from HTS analysis have allowed genome-based diagnosis, which has been consistent with phenotypic observations. These proofs of concept are probably the first steps toward the future of clinical microbiology. From concept to routine use, many parameters need to be considered to promote HTS as a powerful tool to help physicians and clinicians in microbiological investigations. This review highlights the milestones to be completed toward this purpose. PMID- 25437803 TI - Application of DNA Aptamers and Quantum Dots to Lateral Flow Test Strips for Detection of Foodborne Pathogens with Improved Sensitivity versus Colloidal Gold. AB - Preliminary studies aimed at improving the sensitivity of foodborne pathogen detection via lateral flow (LF) test strips by use of high affinity DNA aptamers for capture and reporter functions when coupled to red-emitting quantum dots (Qdot 655) are reported. A variety of DNA aptamers developed against Escherichia coli, Listeria monocytogenes, and Salmonella enterica were paired in capture and reporter combinations to determine which yielded the strongest detection of their cognate bacteria using a colloidal gold screening system. Several promising sandwich combinations were identified for each of the three bacterial LF strip systems. The best E. coli aptamer-LF system was further studied and yielded a visible limit of detection (LOD) of ~3,000 E. coli 8739 and ~6,000 E. coli O157:H7 in buffer. These LODs were reduced to ~300-600 bacterial cells per test respectively by switching to a Qdot 655 aptamer-LF system. Novel aspects of these assays such as the use of high levels of detergents to avoid quantum dot agglutination and enhance migration in analytical membranes, identification of optimal analytical membrane types, UV-immobilization of capture aptamers, and novel dual biotin/digoxigenin-end labeled aptamer streptavidin-colloidal gold or Qdot 655 conjugates plus anti-digoxigenin antibody control lines are also discussed. In general, this work provides proof-of-principle for highly sensitive aptamer-Qdot LF strip assays for rapid foodborne pathogen detection. PMID- 25437802 TI - Pseudomonas aeruginosa Genome Evolution in Patients and under the Hospital Environment. AB - Pseudomonas aeruginosa is a Gram-negative environmental species and an opportunistic microorganism, establishing itself in vulnerable patients, such as those with cystic fibrosis (CF) or those hospitalized in intensive care units (ICU). It has become a major cause of nosocomial infections worldwide and a serious threat to Public Health because of overuse and misuse of antibiotics that have selected highly resistant strains against which very few therapeutic options exist. Herein is illustrated the intraclonal evolution of the genome of sequential isolates collected in a single CF patient from the early phase of pulmonary colonization to the fatal outcome. We also examined at the whole genome scale a pair of genotypically-related strains made of a drug susceptible, environmental isolate recovered from an ICU sink and of its multidrug resistant counterpart found to infect an ICU patient. Multiple genetic changes accumulated in the CF isolates over the disease time course including SNPs, deletion events and reduction of whole genome size. The strain isolated from the ICU patient displayed an increase in the genome size of 4.8% with major genetic rearrangements as compared to the initial environmental strain. The annotated genomes are given in free access in an interactive web application WallGene designed to facilitate large-scale comparative analysis and thus allowing investigators to explore homologies and syntenies between P. aeruginosa strains, here PAO1 and the five clinical strains described. PMID- 25437801 TI - Leptospiral pathogenomics. AB - Leptospirosis, caused by pathogenic spirochetes belonging to the genus Leptospira, is a zoonosis with important impacts on human and animal health worldwide. Research on the mechanisms of Leptospira pathogenesis has been hindered due to slow growth of infectious strains, poor transformability, and a paucity of genetic tools. As a result of second generation sequencing technologies, there has been an acceleration of leptospiral genome sequencing efforts in the past decade, which has enabled a concomitant increase in functional genomics analyses of Leptospira pathogenesis. A pathogenomics approach, by coupling of pan-genomic analysis of multiple isolates with sequencing of experimentally attenuated highly pathogenic Leptospira, has resulted in the functional inference of virulence factors. The global Leptospira Genome Project supported by the U.S. National Institute of Allergy and Infectious Diseases to which key scientific contributions have been made from the international leptospirosis research community has provided a new roadmap for comprehensive studies of Leptospira and leptospirosis well into the future. This review describes functional genomics approaches to apply the data generated by the Leptospira Genome Project towards deepening our knowledge of virulence factors of Leptospira using the emerging discipline of pathogenomics. PMID- 25437804 TI - Characterization of Antimicrobial Resistance Dissemination across Plasmid Communities Classified by Network Analysis. AB - The global clustering of gene families through network analysis has been demonstrated in whole genome, plasmid, and microbiome analyses. In this study, we carried out a plasmidome network analysis of all available complete bacterial plasmids to determine plasmid associations. A blastp clustering search at 100% aa identity cut-off and sharing at least one gene between plasmids, followed by a multilevel community network analysis revealed that a surprisingly large number of the plasmids were connected by one largest connected component (LCC), with dozens of community sub-groupings. The LCC consisted mainly of Bacilli and Gammaproteobacteria plasmids. Intriguingly, horizontal gene transfer (HGT) was noted between different phyla (i.e., Staphylococcus and Pasteurellaceae), suggesting that Pasteurellaceae can acquire antimicrobial resistance (AMR) genes from closely contacting Staphylococcus spp., which produce the external supplement of V-factor (NAD). Such community network analysis facilitate displaying possible recent HGTs like a class 1 integron, str and tet resistance markers between communities. Furthermore, the distribution of the Inc replicon type and AMR genes, such as the extended-spectrum beta-lactamase (ESBL) CTX-M or the carbapenemases KPC NDM-1, implies that such genes generally circulate within limited communities belonging to typical bacterial genera. Thus, plasmidome network analysis provides a remarkable discriminatory power for plasmid-related HGT and evolution. PMID- 25437805 TI - Mouse models of hepatitis B virus infection comprising host-virus immunologic interactions. AB - Hepatitis B virus (HBV) infection is one of the most prevalent infectious diseases associated with various human liver diseases, including acute, fulminant and chronic hepatitis; liver cirrhosis; and hepatocellular carcinoma. Despite the availability of an HBV vaccine and the development of antiviral therapies, there are still more than 350 million chronically infected people worldwide, approximately 5% of the world population. To understand the virus biology and pathogenesis in HBV-infected patients, several animal models have been developed to mimic hepatic HBV infection and the immune response against HBV, but the narrow host range of HBV infection and lack of a full immune response spectrum in animal models remain significant limitations. Accumulating evidence obtained from studies using a variety of mouse models that recapitulate hepatic HBV infection provides several clues for understanding host-virus immunologic interactions during HBV infection, whereas the determinants of the immune response required for HBV clearance are poorly defined. Therefore, adequate mouse models are urgently needed to elucidate the mechanism of HBV elimination and identify novel targets for antiviral therapies. PMID- 25437806 TI - Secretory IgA is Concentrated in the Outer Layer of Colonic Mucus along with Gut Bacteria. AB - Antibodies of the secretory IgA (SIgA) class comprise the first line of antigen specific immune defense, preventing access of commensal and pathogenic microorganisms and their secreted products into the body proper. In addition to preventing infection, SIgA shapes the composition of the gut microbiome. SIgA is transported across intestinal epithelial cells into gut secretions by the polymeric immunoglobulin receptor (pIgR). The epithelial surface is protected by a thick network of mucus, which is composed of a dense, sterile inner layer and a loose outer layer that is colonized by commensal bacteria. Immunofluorescence microscopy of mouse and human colon tissues demonstrated that the SIgA co localizes with gut bacteria in the outer mucus layer. Using mice genetically deficient for pIgR and/or mucin-2 (Muc2, the major glycoprotein of intestinal mucus), we found that Muc2 but not SIgA was necessary for excluding gut bacteria from the inner mucus layer in the colon. Our findings support a model whereby SIgA is anchored in the outer layer of colonic mucus through combined interactions with mucin proteins and gut bacteria, thus providing immune protection against pathogens while maintaining a mutually beneficial relationship with commensals. PMID- 25437807 TI - Antibiofilm Effect of Octenidine Hydrochloride on Staphylococcus aureus, MRSA and VRSA. AB - Millions of indwelling devices are implanted in patients every year, and staphylococci (S. aureus, MRSA and vancomycin-resistant S. aureus (VRSA)) are responsible for a majority of infections associated with these devices, thereby leading to treatment failures. Once established, staphylococcal biofilms become resistant to antimicrobial treatment and host response, thereby serving as the etiological agent for recurrent infections. This study investigated the efficacy of octenidine hydrochloride (OH) for inhibiting biofilm synthesis and inactivating fully-formed staphylococcal biofilm on different matrices in the presence and absence of serum protein. Polystyrene plates and stainless steel coupons inoculated with S. aureus, MRSA or VRSA were treated with OH (zero, 0.5, one, 2 mM) at 37 degrees C for the prevention of biofilm formation. Additionally, the antibiofilm effect of OH (zero, 2.5, five, 10 mM) on fully formed staphylococcal biofilms on polystyrene plates, stainless steel coupons and urinary catheters was investigated. OH was effective in rapidly inactivating planktonic and biofilm cells of S. aureus, MRSA and VRSA on polystyrene plates, stainless steel coupons and urinary catheters in the presence and absence of serum proteins. The use of two and 10 mM OH completely inactivated S. aureus planktonic cells and biofilm (>6.0 log reduction) on all matrices tested immediately upon exposure. Further, confocal imaging revealed the presence of dead cells and loss in biofilm architecture in the OH-treated samples when compared to intact live biofilm in the control. Results suggest that OH could be applied as an effective antimicrobial to control biofilms of S. aureus, MRSA and VRSA on appropriate hospital surfaces and indwelling devices. PMID- 25437808 TI - WGS Analysis and Interpretation in Clinical and Public Health Microbiology Laboratories: What Are the Requirements and How Do Existing Tools Compare? AB - Recent advances in DNA sequencing technologies have the potential to transform the field of clinical and public health microbiology, and in the last few years numerous case studies have demonstrated successful applications in this context. Among other considerations, a lack of user-friendly data analysis and interpretation tools has been frequently cited as a major barrier to routine use of these techniques. Here we consider the requirements of microbiology laboratories for the analysis, clinical interpretation and management of bacterial whole-genome sequence (WGS) data. Then we discuss relevant, existing WGS analysis tools. We highlight many essential and useful features that are represented among existing tools, but find that no single tool fulfils all of the necessary requirements. We conclude that to fully realise the potential of WGS analyses for clinical and public health microbiology laboratories of all scales, we will need to develop tools specifically with the needs of these laboratories in mind. PMID- 25437809 TI - Pyrosequencing reveals the predominance of pseudomonadaceae in gut microbiome of a gall midge. AB - Gut microbes are known to play various roles in insects such as digestion of inaccessible nutrients, synthesis of deficient amino acids, and interaction with ecological environments, including host plants. Here, we analyzed the gut microbiome in Hessian fly, a serious pest of wheat. A total of 3,654 high quality sequences of the V3 hypervariable region of the 16S rRNA gene were obtained through 454-pyrosequencing. From these sequences, 311 operational taxonomic units (OTUs) were obtained at the >97% similarity cutoff. In the gut of 1st instar, otu01, a member of Pseudomonas, was predominant, representing 90.2% of total sequences. otu13, an unidentified genus in the Pseudomonadaceae family, represented 1.9% of total sequences. The remaining OTUs were each less than 1%. In the gut of the 2nd instar, otu01 and otu13 decreased to 85.5% and 1.5%, respectively. otu04, a member of Buttiauxella, represented 9.7% of total sequences. The remaining OTUs were each less than 1%. In the gut of the 3rd instar, otu01 and otu13 further decreased to 29.0% and 0%, respectively. otu06, otu08, and otu16, also three members of the Pseudomonadaceae family were 13.2%, 8.6%, and 2.3%, respectively. In addition, otu04 and otu14, two members of the Enterobacteriaceae family, were 4.7% and 2.5%; otu18 and otu20, two members of the Xanthomonadaceae family, were 1.3% and 1.2%, respectively; otu12, a member of Achromobacter, was 4.2%; otu19, a member of Undibacterium, was 1.4%; and otu9, otu10, and otu15, members of various families, were 6.1%, 6.3%, and 1.9%, respectively. The investigation into dynamics of Pseudomonas, the most abundant genera, revealed that its population level was at peak in freshly hatched or 1 day larvae as well as in later developmental stages, thus suggesting a prominent role for this bacterium in Hessian fly development and in its interaction with host plants. This study is the first comprehensive survey on bacteria associated with the gut of a gall midge, and provides a foundation for future studies to elucidate the roles of gut microbes in Hessian fly virulence and biology. PMID- 25437811 TI - Quantification of delineation errors of the gross tumor volume on magnetic resonance imaging in uterine cervical cancer using pathology data and deformation correction. AB - BACKGROUND: To safely optimize target volumes using magnetic resonance imaging (MRI) for uterine cervical cancer radiation therapy, MRI findings need to be validated. The aim of this study was to correlate pre-operatively acquired MRI and surgical specimen imaging for uterine cervical cancer patients using deformable image registration and quantify gross tumor volume (GTV) delineation discrepancies. MATERIAL AND METHODS: For 16 retrospectively selected early-stage uterine cervical cancer patients, the cervix-uterus structure, uterine cavity and the GTV were delineated on 2D pathology photos after macroscopic intersection and corresponding pre-operatively acquired T2-weighted 2D sagittal MR images. Segmentations of pathology photos and MR images were simultaneously registered using a three-step multi-image registration strategy. The registration outcome was evaluated by the Dice similarity coefficient (DSC) and the surface distance error (SDE). In addition, GTV expansions within the cervix-uterus structure needed to obtain 95% GTV coverage were determined. RESULTS: After three-step multi-image registration, the median DSC and median SDE were 0.98 and 0.4 mm (cervix-uterus) and 0.90 and 0.4 mm (uterine cavity), respectively. The average SDE around the GTV was 0.7 mm (range, 0.1 mm - 2.6 mm). An underestimation of MRI based GTV delineations was found when no margin was applied, indicated by a mean GTV coverage of 61%. To obtain 95% GTV coverage for 90% of the patients, a minimum 12.0 mm margin around MRI-based GTVs was needed. CONCLUSION: The presented three-step multi-image registration strategy was suitable and accurate to correlate MRI and pathology data for uterine cervical cancer patients. To cover the pathology-based GTV, a margin of at least 12.0 mm around GTV delineations on T2-weighted MRI is needed. PMID- 25437813 TI - A New Method of Airway Management in Patients Undergoing Gasserian Ganglion Thermal Coagulation: Preliminary Results. AB - BACKGROUND: Airway management in patients undergoing neurosurgical interventions for trigeminal neuralgia can often prove difficult. This is because the patient's assistance is required during this neurosurgical intervention, and moreover, the site of puncture lies within the working area of the anesthesiologists. An obvious alternative for airway management is the use of a nasopharyngeally placed tube. The purpose of the present study was to objectify the gas exchange in patients during this new ventilation technique. METHODS: In 5 patients, a tube with a 5 mm internal diameter was placed nasopharyngeally after induction of general anesthesia and ventilation was then manually assisted. The intraoperative partial pressure values of CO(2) (pvCO(2)) and O(2) (pvO(2)) in the venous blood were then compared with their respective patient's preoperative baseline pvCO(2) and pvO(2) levels. Blood pressure, heart rate, and SpO(2) were continuously and noninvasively monitored. During the entire surgical intervention, patients were ventilated with a fraction of inspired oxygen (FiO(2)) of 1.0 and a fresh gas flow of 18 L per minute. RESULTS: All patients exhibited sufficient oxygenation during the entire procedure under manual ventilation. There were no excessive deviations in pvCO(2) from baseline levels. Furthermore, no incidents of hemodynamic instability occurred. Mean duration of the neurosurgical procedure was 54 minutes. Impairment of intraoperative verbal communication was not observed with the nasopharyngeal tube in situ. CONCLUSIONS: This preliminary study suggests that manually assisted ventilation with pure oxygen using a nasopharyngeally placed tube seems to be a sufficient airway management technique during thermal coagulation of the Gasserian ganglion. PMID- 25437814 TI - Histologic features predicting postoperative Crohn's disease recurrence. AB - Recurrence of Crohn's disease (CD) after ileal or colonic resection is common. Many studies have tried to identify predictors of postoperative recurrence (POR) in CD. A wide range of histologic features have been identified, but for most of them, the literature provided conflicting data. In last years, several studies have suggested that histologic findings including inflammatory changes within the enteric nervous system of the resection margin may be associated with CD recurrence. Herein, after briefly summarizing pathophysiology of POR, we review all histological features that have been studied so far: granulomas, histologic appearance at the margin of resection, plexitis, lymphatic vessel density in proximal margin of resection, and morphological analysis of Paneth cells. Granulomas and chronic inflammation at the margin of resection do not seem to predict POR in CD. Active disease at the margin of resection, plexitis, lymphatic vessels density, morphological analysis of Paneth cells may predict POR. Most of these histological features await replication in independent studies. Available evidence indicates that histological findings may be taken into account when developing strategies aimed at preventing postoperative CD recurrence. PMID- 25437810 TI - Antimicrobial Activity of Selected Phytochemicals against Escherichia coli and Staphylococcus aureus and Their Biofilms. AB - Bacteria can be resistant to multiple antibiotics and we are fast approaching a time when antibiotics will not work on some bacterial infections. New antimicrobial compounds are urgently necessary. Plants are considered the greatest source to obtain new antimicrobials. This study aimed to assess the antimicrobial activity of four phytochemicals-7-hydroxycoumarin (7-HC), indole-3 carbinol (I3C), salicylic acid (SA) and saponin (SP)-against Escherichia coli and Staphylococcus aureus, either as planktonic cells or as biofilms. These bacteria are commonly found in hospital-acquired infections. Some aspects on the phytochemicals mode of action, including surface charge, hydrophobicity, motility and quorum-sensing inhibition (QSI) were investigated. In addition, the phytochemicals were combined with three antibiotics in order to assess any synergistic effect. 7-HC and I3C were the most effective phytochemicals against E. coli and S. aureus. Both phytochemicals affected the motility and quorum sensing (QS) activity, which means that they can play an important role in the interference of cell-cell interactions and in biofilm formation and control. However, total biofilm removal was not achieved with any of the selected phytochemicals. Dual combinations between tetracycline (TET), erythromycin (ERY) and ciprofloxacin (CIP) and I3C produced synergistic effects against S. aureus resistant strains. The overall results demonstrates the potential of phytochemicals to control the growth of E. coli and S. aureus in both planktonic and biofilm states. In addition, the phytochemicals demonstrated the potential to act synergistically with antibiotics, contributing to the recycling of old antibiotics that were once considered ineffective due to resistance problems. PMID- 25437815 TI - Involvement of heat shock protein a4/apg-2 in refractory inflammatory bowel disease. AB - BACKGROUND: Expression of heat shock protein A4 (HSPA4, also called Apg-2), a member of the HSP110 family, is induced by several forms of stress. The physiological and pathological functions of HSPA4 in the intestine remain to be elucidated. METHODS: We assessed HSPA4 expression and function by generating HSPA4-deficient mice and using 214 human intestinal mucosa samples from patients with inflammatory bowel disease (IBD). RESULTS: In the colonic mucosa of patients with IBD, a significant correlation was observed between the expression of HSPA4 and antiapoptotic protein Bcl-2, a T-cell-derived cytokine IL-17 or stem cell markers, such as Sox2. In refractory ulcerative colitis, a condition associated with increased cancer risk, expression of HSPA4 and Bcl-2 was increased in inflammatory cells of colonic mucosae. HSPA4 was overexpressed both in cancer cells and immune cells of human colorectal cancers. Patients with high expression of HSPA4 or Bmi1 showed significantly lower response rates upon subsequent steroid therapy as compared with patients with low expression of each gene. HSPA4 deficient mice exhibit more apoptosis and less expression of IL-17/IL-23 in inflammatory cells and less number of Sox2 cells after administration of dextran sodium sulfate than control mice. Transduction of HspaA4 bone marrow into wild type mice reduced the immune response. CONCLUSIONS: Upregulation of Bcl-2 and IL 17 by HSPA4 would control apoptosis of inflammatory cells and immune response in the gut, which might develop treatment resistance in IBD. HSPA4 and Bmi1 would be a useful biomarker for refractory clinical course and a promising approach for a therapeutic strategy in patients with IBD. PMID- 25437817 TI - Autoimmune features are associated with chronic antibiotic-refractory pouchitis. AB - BACKGROUND: Chronic antibiotic-refractory pouchitis (CARP) occurs more frequently in patients with ileal pouch-anal anastomosis (IPAA) with concomitant autoimmune disorders. The aim of this study was to assess the overlap between dysregulated immune features in patients with IPAA and their association with CARP. METHODS: We identified 150 symptomatic patients with IPAA who met inclusion criteria, including measurement of select autoimmune serology. Demographic and clinical variables were compared between patients with and without CARP. RESULTS: Autoimmune thyroid disease was more frequent among patients with CARP. The frequency of primary sclerosing cholangitis (16.7% versus 5.3%; P = 0.04) and serum positivity for microsomal antibody (25% versus 6.1%, P = 0.003) were significantly greater in patients with CARP compared with non-CARP patients, respectively. Increased tissue infiltration by IgG4-expressing plasma cells was detected in 17 of 31 patients (54.8%) in the CARP group as compared with 10/67 (14.9%) in the non-CARP group (P = 0.0001). Forty-seven percent of patients in the CARP group versus 22.8% in the non-CARP group had at least 2 immune features (P = 0.019). Among patients with IgG4 histology, 87% of patients in the CARP group versus 60% in the non-CARP group had at least 1 immune marker (P = 0.004). On multivariate analysis, microsomal antibody expression (odds ratio, 6.8; 95% confidence interval, 1.3-42.6; P = 0.02) and increased IgG4-expressing plasma cells tissue infiltration (odds ratio, 9.6; 95% confidence interval, 3.2-32.6, P = 0.0001) were risk factors for CARP. CONCLUSIONS: There is marked overlap of certain immune markers in patients with pouch dysfunction, especially those with CARP. Microsomal antibody expression and elevated IgG4-positive plasma cell infiltration were independent risk factors for CARP. PMID- 25437816 TI - Costs and resource utilization for diagnosis and treatment during the initial year in a European inflammatory bowel disease inception cohort: an ECCO-EpiCom Study. AB - BACKGROUND: No direct comparison of health care cost in patients with inflammatory bowel disease across the European continent exists. The aim of this study was to assess the costs of investigations and treatment for diagnostics and during the first year after diagnosis in Europe. METHODS: The EpiCom cohort is a prospective population-based inception cohort of unselected inflammatory bowel disease patients from 31 Western and Eastern European centers. Patients were followed every third month from diagnosis, and clinical data regarding treatment and investigations were collected. Costs were calculated in euros (?) using the Danish Health Costs Register. RESULTS: One thousand three hundred sixty-seven patients were followed, 710 with ulcerative colitis, 509 with Crohn's disease, and 148 with inflammatory bowel disease unclassified. Total expenditure for the cohort was ?5,408,174 (investigations: ?2,042,990 [38%], surgery: ?1,427,648 [26%], biologicals: ?781,089 [14%], and standard treatment: ?1,156,520 [22%)]). Mean crude expenditure per patient in Western Europe (Eastern Europe) with Crohn's disease: investigations ?1803 (?2160) (P = 0.44), surgery ?11,489 (?13,973) (P = 0.14), standard treatment ?1027 (?824) (P = 0.51), and biologicals ?7376 (?8307) (P = 0.31). Mean crude expenditure per patient in Western Europe (Eastern Europe) with ulcerative colitis: investigations ?1189 ( ?1518) (P < 0.01), surgery ?18,414 ( ?12,395) (P = 0.18), standard treatment ?896 ( ?798) (P < 0.05), and biologicals ?5681 ( ?72) (P = 0.51). CONCLUSIONS: In this population based unselected cohort, costs during the first year of disease were mainly incurred by investigative procedures and surgeries. However, biologicals accounted for >15% of costs. Long-term follow-up of the cohort is needed to assess the cost-effectiveness of biological agents. PMID- 25437818 TI - Telemedicine in inflammatory bowel disease: opportunities and approaches. AB - This review article summarizes the evidence about telemedicine applications (e.g., telemonitoring, teleconsulting, and tele-education) in the management of patients with inflammatory bowel disease (IBD), and we aim to give an overview of the acceptance and impact of these interventions on health outcomes. Based on the literature search on "inflammatory bowel disease," "Crohn's disease" and "ulcerative colitis" in combination with "e-health," "telemedicine," and "telemanagement," we selected 58 titles and abstracts published up to June 2014 and searched in PubMed, EMBASE, MEDLINE, Cochrane Database, Web of Science and Conference Proceedings. Titles and abstracts were screened for a set of inclusion criteria: e-health intervention, IBD as the main disease, and a primary study performed. Finally, 16 were included for full reading, data extraction, and critical appraisal of the evaluation. Most studies use telemonitoring (home telemanagement system or web portal) and telecare (real-time telephone and image) as telemedicine applications and assessed the feasibility and acceptance of these systems, adherence to treatment, quality of life, and patient knowledge, particularly in patients with ulcerative colitis. Furthermore, some of these studies evaluated the patients' empowerment, health care costs, and safety of telemonitoring in IBD. In conclusion, the health outcomes of telemedicine applications in IBD suggest that these could be implemented in clinical practice because they are safe and feasible applications that are well accepted by the patient and improve adherence, quality of life, and disease knowledge. Further studies with large sample sizes and complex diseases are needed to confirm these results. PMID- 25437820 TI - Male issues of the ileal pouch. AB - : Restorative proctocolectomy with ileal pouch-anal anastomosis is the standard surgical treatment modality for patients with ulcerative colitis who require colectomy. There are special issues related to male gender. We performed systemic literature review on the topic, incorporating the experience in our specialized Center for Ileal Pouch Disorders, and provide recommendations for the identification and management for the gender-specific issues in male patients with ileal pouches. Chronic pouchitis, particularly ischemic pouchitis, anastomotic leak, and presacral sinus are more common in male patients than their female counterparts. Sexual dysfunction can occur after pouch surgery, particularly in those with pouch failure. Diagnosis and management of benign and malignant prostate diseases can be challenging due to the altered pelvic anatomy from the surgery. Digital rectal examination for prostate cancer screening is not reliable. Transpouch biopsy of prostate may lead to pouch fistula or abscess. Pelvic radiation therapy may have an adverse impact on the pouch function. In conclusion, sexual dysfunction and enlarged prostate can occur in patients with the ileal pouch. The measurement of serum prostate-specific antigen is a preferred method for the screening of prostate cancer. If biopsy of the prostate is needed, the perineal route is recommended. The risk for pouch dysfunction and the benefit for oncologic survival of pelvic radiation for prostate cancer should be carefully balanced. PMID- 25437819 TI - T-cell receptor sequencing reveals the clonal diversity and overlap of colonic effector and FOXP3+ T cells in ulcerative colitis. AB - BACKGROUND: FOXP3 regulatory T cell prevent inflammation but are paradoxically increased in ulcerative colitis (UC). Local T-cell activation has been hypothesized to account for increased FOXP3 expression in colon lamina propria (LP) T cells. METHODS: To see if human FOXP3 LP T cells are an activated fraction of otherwise FOXP3 effector T cells and explore their clonal diversity in health and disease, we deep sequenced clonally unique T-cell receptor hypervariable regions of FOXP3 and FOXP3CD4 T-cell subpopulations from inflamed versus noninflamed colon LP or mesenteric lymph nodes of patients with or without UC. RESULTS: The clonal diversity of each LP T-cell population was not different between patients with versus without UC. Repertoire overlap was only seen between a minority of FOXP3 and FOXP3 cells, including recently activated CD38 cells and Th17-like CD161 effector T cells, but this repertoire overlap was not different between patients with versus without UC and was no larger than the overlap between Helios and Helios FOXP3 cells. CONCLUSIONS: Thus, at steady state, only a minority of FOXP3, and particularly Helios, T cells share a T-cell receptor sequence with FOXP3 effector populations in the colon LP, even in UC, revealing distinct clonal origins for LP regulatory T cell and effector T cells in humans. PMID- 25437821 TI - Treatment with egg antigens of Schistosoma mansoni ameliorates experimental colitis in mice through a colonic T-cell-dependent mechanism. AB - BACKGROUND: Helminth-derived molecules are being identified as a new therapeutic approach for immune-mediated diseases. We investigated the anti-inflammatory effect and the immunological mechanisms of Schistosoma mansoni soluble egg antigens (SmSEA) in a mouse model of chronic colitis. METHODS: Colitis was induced in immunocompromised severe combined immunodeficiency mice by the adoptive transfer of CD4CD25CD62L T cells. Two weeks post-transfer, SmSEA treatments were started (study 1: 1 * 20 MUg SmSEA per week 5 times; study 2: 2 * 20 MUg SmSEA per week 3 times). From the start of the treatment (week 2), the clinical outcome and colonic inflammation were assessed at different time points by a clinical disease score and colonoscopy, respectively. At the end of the studies, the colons were harvested for macroscopic examination, and colonic lamina propria mononuclear cells were isolated for flow cytometric T-cell characterization. RESULTS: In both studies, administration of SmSEA in colitis mice improved all the inflammatory parameters studied. However in study 1, this beneficial effect on inflammation diminished with time, and the T-cell characterization of the lamina propria mononuclear cells, performed at week 6, revealed no immunological effects of the SmSEA treatment. In study 2, mice were killed earlier (week 4) and at that time point, we found a significant downregulation of the number of interleukin-17A-producing T cells and a significant upregulation of the number of interleukin-4-producing T cells in the colon of the SmSEA-treated colitis mice. CONCLUSIONS: Our results demonstrated that the administration of SmSEA reduces the severity of colitis in the adoptive transfer mouse model characterized by an increased Th2 response and a suppressed Th17 response in the colon. PMID- 25437822 TI - Role of transient receptor potential channels in intestinal inflammation and visceral pain: novel targets in inflammatory bowel diseases. AB - Transient receptor potential (TRP) channels are a large group of ion channels that are prevalent in mammalian tissues. They are widely distributed in the central and peripheral nervous systems, and in nonneuronal cells, where they are implicated in sensing temperature, noxious substances, and pain. TRPs play an important role in immune response and nociception and, therefore, may be involved in the pathogenesis of inflammatory bowel diseases, whose major symptoms include chronic inflammatory state and abdominal pain. In this review, we summarize what is known on TRP channels in inflammatory bowel disease and visceral pain; we focus in particular on TRPV1, TRPV4, TRPA1, and TRPM. We also analyze scientific reports that evidence potential use of TRP regulators in future inflammatory bowel disease treatment. PMID- 25437823 TI - Colorectal cancer in colitis: a relic of the past? AB - The incidence of dysplasia and colorectal cancer in patients with long-standing colitis seems to be decreasing and controversy surrounds our detection and management strategies. Dysplasia is rarer, flatter, and smaller than in previous decades. Current surveillance guidelines, onerous in terms of colonoscopic workload and an emphasis on random biopsies, have yet to be shown to prevent colon cancers and colon cancer death in these patients. The evidence base for adjunct techniques such as chromoendoscopy is strong but adoption has been slow. We need to better risk-stratify patients with colitis and direct diminishing medical resources accordingly. Modulating dysplasia and cancer risk will involve optimizing medical therapies and focusing our colonoscopic efforts on those who will most likely benefit. PMID- 25437824 TI - Assessment of passive knee stiffness and viscosity in individuals with spinal cord injury using pendulum test. AB - OBJECTIVE: Stiffness and viscosity represent passive resistances to joint motion related with the structural properties of the joint tissue and of the musculotendinous complex. Both parameters can be affected in patients with spinal cord injury (SCI). The purpose of this study was to measure passive knee stiffness and viscosity in patients with SCI with paraplegia and healthy subjects using Wartenberg pendulum test. DESIGN: Non-experimental, cross-sectional, case control design. SETTING: An outpatient physical therapy clinic, University of social welfare and Rehabilitation Science, Iran. PATIENTS: A sample of convenience sample of 30 subjects participated in the study. Subjects were categorized into two groups: individuals with paraplegic SCI (n = 15, age: 34.60 +/- 9.18 years) and 15 able-bodied individuals as control group (n = 15, age: 30.66 +/- 11.13 years). INTERVENTIONS: Not applicable. MAIN MEASURES: Passive pendulum test of Wartenberg was used to measure passive viscous-elastic parameters of the knee (stiffness, viscosity) in all subjects. RESULTS: Statistical analysis (independent t-test) revealed significant difference in the joint stiffness between healthy subjects and those with paraplegic SCI (P = 0.01). However, no significant difference was found in the viscosity between two groups (P = 0.17). Except for first peak flexion angle, all other displacement kinematic parameters exhibited no statistically significant difference between normal subjects and subjects with SCI. CONCLUSIONS: Patients with SCI have significantly greater joint stiffness compared to able-bodied subjects. PMID- 25437825 TI - Oxytocin microinjected into the central amygdaloid nuclei exerts anti-aggressive effects in male rats. AB - We recently demonstrated that acute and chronic intracerebroventricular enhancement of brain OXT levels induces potent anti-aggressive and pro-social explorative effects during social challenges. However, the exact anatomical location in the brain where OXT exerts its action is still elusive. In the present study, we targeted two critical brain areas, i.e. the central amygdala (CeA) and the dorsal raphe (DR), both containing high levels of OXT receptors (OXTRs) and constituting important nodes of the neural circuitry related to aggression. Behavioral effects of local micro-infusion of OXT and OXTR antagonist, L368.899, (alone and combined) were evaluated in resident male rats during confrontations with an unfamiliar male intruder. Our results show that OXT microinjected into the CeA markedly reduced resident's offensive behavior and facilitated social exploration, without affecting other non-aggressive behaviors. The receptor specificity of the behavioral effects was verified when a micro infusion of a selective OXTR antagonist nullified the changes. Pharmacological blockade of CeA OXTRs per se was without clear behavioral effects suggesting that endogenous OXT within the CeA does not play a major inhibitory role on offensiveness. Anatomical specificity was also supported by the absence of relevant behavioral effects when OXT was microinjected into more medial sub regions of the amygdala. Likewise, within the DR neither OXT nor OXTR exerted significant effects on offensive aggression, while microinjection of the 5-HT1A autoreceptor agonist in this region significantly suppressed aggression. In conclusion, our results point at the CeA as an important brain site of action for the anti-aggressive and pro-social explorative effects induced by exogenous enhancement of brain OXT levels. PMID- 25437826 TI - Acid modulation of tetrodotoxin-resistant Na+ channels in rat nociceptive neurons. AB - Under pathological conditions including inflammation, ischemia and incision, extracellular pH falls down as low as 5.4. Although some mediators play pivotal roles in the development and maintenance of inflammatory hyperalgesia by affecting the functional properties of tetrodotoxin-resistant (TTX-R) Na(+) channels, the roles of tissue acidosis in nociceptive transmission mediated by TTX-R Na(+) channels are largely unknown. In the present study, we have investigated the effect of acidic pH on TTX-R Na(+) currents (I(Na)) in small sized sensory neurons isolated from rat trigeminal ganglia using a whole-cell patch clamp technique. Acidic pH decreased the peak amplitude of TTX-R I(Na) in a pH-dependent manner, but weak acid (>=pH 6.0) had a minor inhibitory effect on the TTX-R I(Na). Acidic pH also significantly shifted both the activation and steady-state fast inactivation relationships toward depolarized potentials. In addition, acidic pH had little effect on the use-dependent inhibition, and significantly retarded the development of inactivation and accelerated the recovery from inactivation of TTX-R Na(+) channels. The results suggest that weak acid (>=pH 6.0) makes TTX-R Na(+) channels to be suitable for the repetitive activation at depolarized membrane potentials. Given that both tissue acidosis and inflammatory mediators in inflamed or injured tissues act synergistically to promote nociceptive transmission by affecting the functional properties of TTX-R Na(+) channels, these channels would be, at least in part, a good target to treat inflammatory pain. PMID- 25437827 TI - Implantable cardioverter defibrillator specific rehabilitation improves health cost outcomes: Findings from the COPE-ICD randomized controlled trial. AB - OBJECTIVE: The Copenhagen Outpatient ProgrammE - implantable cardioverter defibrillator (COPE-ICD) trial included patients with implantable cardioverter defibrillators in a randomized controlled trial of rehabilitation. After 6-12 months significant differences were found in favour of the rehabilitation group for exercise capacity, general and mental health. The aim of this paper is to explore the long-term health effects and cost implications associated with the rehabilitation programme; more specifically, (i) to compare implantable cardioverter defibrillator therapy history and mortality between rehabilitation and usual care groups; (ii) to examine the difference between rehabilitation and usual care groups in terms of time to first admission; and (iii) to determine attributable direct costs. METHODS: Patients with first-time implantable cardioverter defibrillator implantation (n = 196) were randomized (1:1) to comprehensive cardiac rehabilitation or usual care. Outcomes were measured by implantable cardioverter defibrillator therapy history from patient records and national register follow-up on mortality, hospital admissions and costs. RESULTS: No significant differences were found after 3 years for implantable cardioverter defibrillator therapy or mortality between rehabilitation and usual care. Time to first admission did not differ. The cost of rehabilitation was 335 USD/276 Euro per patient enrolled in rehabilitation. The total attributable cost of rehabilitation after 3 years was -6,789 USD/-5,593 Euro in favour of rehabilitation. CONCLUSION: No long-term health outcome benefits were found for the rehabilitation programme. However, the rehabilitation programme resulted in a reduction in total attributable direct costs. PMID- 25437828 TI - Toward transparency of financial disclosure. PMID- 25437829 TI - The use of perioperative antithrombotics in posterior segment ocular surgery. PMID- 25437830 TI - Reframing the US Preventive Services Task Force recommendations on screening for glaucoma. PMID- 25437831 TI - Reply: To PMID 24794092. PMID- 25437832 TI - Predicting the need for surgical intervention in pediatric orbital cellulitis. PMID- 25437833 TI - Reduction in mean deviation values in automated perimetry in eyes with multifocal compared to monofocal intraocular lens implants. PMID- 25437834 TI - Reply: To PMID 24784872. PMID- 25437835 TI - Urban legacies and soil management affect the concentration and speciation of trace metals in Los Angeles community garden soils. AB - Heavy metals in urban soils can compromise human health, especially in urban gardens, where gardeners may ingest contaminated dust or crops. To identify patterns of urban garden metal contamination, we measured concentrations and bioavailability of Pb, As, and Cd in soils associated with twelve community gardens in Los Angeles County, CA. This included sequential extractions to partition metals among exchangeable, reducible, organic, or residual fractions. Proximity to road increased all metal concentrations, suggesting vehicle emissions sources. Reducible Pb increased with neighborhood age, suggesting leaded paint as a likely pollutant source. Exchangeable Cd and As both increased with road proximity. Only cultivated soils showed an increase in exchangeable As with road proximity, potentially due to reducing humic acid interactions while Cd bioavailability was mitigated by organic matter. Understanding the geochemical phases and metal bioavailability allows incorporation of contamination patterns into urban planning. PMID- 25437836 TI - [Surgical Risk Profile and Audiological Outcome in the Elderly after Cochlea implantation]. AB - BACKGROUND: The number of elderly patients with indication for cochlear implantation is increasing. Our aim was to investigate whether seniors with cochlea implants differ from younger patients with regard to hearing improvement, surgical complications and rehabilitation. PATIENTS AND METHODS: Patients older than 60 years (ys) having received a cochlea implant in 2007-2012 were included (Group I 60-70 ys; Group II <70 ys). Preoperative risk factors according to ASA Criteria and postoperative complications were analyzed. Improvements in quality of live were evaluated by questionnaire. Audiological outcome was tested by Freiburger speech test and OLSA sentence test with background noise. Patients with comparable conditions for cochlea implantation between 40 and 59 years of age served as control group (Group K). RESULTS: Patient cohort consisted of 94 patients, 29 of which being older than 70 years. Severe complications were inexistent postoperatively. Gr. II achieved a speech perception for numbers of 95% (65 dB) and 50% (65 dB) for monosyllables. The speech perception in Gr. II was not significantly different from Gr. I or K. According to the quality of life test all groups experienced an improvement in their social life. CONCLUSION: Old age itself is no contraindication to cochlea implantation. It has little influence on the postoperative speech perception even though the learning curve of the elderly rises slower. However, careful assessment with regard to surgical risk factors and expected outcome is necessary. PMID- 25437837 TI - [Change of Taste during and after IM- /IG-Radiotherapy for Head and Neck Cancer Patients]. AB - OBJECTIVE: Taste dysfunction is a common side effect during irradiation of head and neck. Our aim was to determine the time-dependent course and a possible dependency of this side effect to the radiation-dose during irradiation with helical tomotherapy. PATIENTS AND METHODS: 31 patients with malignant tumours in the region of head and neck received an IG-/IM-radiotherapy (helical tomotherapy).The median total dose was 63 Gy (range 30-66 Gy). For all patients the subjective taste dysfunction was documented and correlated to the median (D50) tongue dose. RESULTS: A subjective taste dysfunction was registered by the patients themselves after 9 BT (days of radiotherapy) (median). This correlates to a mean dose (D50) of 15.3 Gy (back third of tongue (back ZD)), 11.3 Gy (middle ZD), 8.2 Gy (front ZD). A subjective ageusia occurred after 15 BT (median) (28.9 Gy (back ZD), 22.2 Gy (middle ZD), 17.7 Gy (front ZD)). A starting recovery was registered by 77% of the patients in the first 6-8 weeks after the end of radiotherapy. CONCLUSION: The time-dependent course of taste dysfunction during radiotherapy and the following recovery is predictable. A dependency of taste dysfunction to radiation-dose exists. Based on the collected data a targeted dose reduction to the tongue with a view to minimize the taste dysfunction is thinkable and aim of further studies. PMID- 25437838 TI - [Botulinum Toxin in Functional Hypersalivation--All about Dosage?]. AB - BACKGROUND: The use of botulinum toxin injection in the salivary gland, is taking an increasing significance in the treatment of functional hypersalivation today. With due regard to the off -label use and the prospect of success, dosage levels are not yet standardized. MATERIAL AND METHODS: In a retrospective study, 54 patients resp. 117 treatments were analysed over a period of 5 years according to their dosage levels of botulinum toxin, outcome and side effects. RESULTS: In 90% of the cases, a reduction of saliva after botulinum toxin injections was reported, although a significant number of patients wished for an even greater effect. Compared to the first botulinum toxin injection, we therefore used a higher dosage plan in the following treatment in order to achieve better clinical results. Besides not enough saliva reduction, the main side effects were swallowing problems and thick or sticky saliva in patients with a tracheal cannula. With the exception of insufficient saliva reduction, the other described side effects were irrespective to the dosage level. CONCLUSIONS: Botulinum toxin injection as a treatment of hypersalivation is an effective method with only minor side effects, even in increased dosage levels. Nevertheless, certain modifications according to each individual treatment are required. Possible side effects such as swallowing problems or non-responding situations should always be part of informed consent, especially as the latter is even possible for higher dosage levels. PMID- 25437840 TI - Crystal growth and properties of NLO optical crystal - Butylated Hydroxy Toluene (BHT). AB - Crystallographic, experimental and theoretical density functional theory (DFT) of Butylated Hydroxy Toluene (BHT) are investigated. The grown crystals were identified by single crystal X-ray analysis. The first order hyperpolarizability (beta0) and related properties (beta, alpha0 and Deltaalpha) of BHT is calculated using B3LYP/6-31G(d,p) method on the finite-field approach. The stability of molecule has been analyzed by using NBO/NLMO analysis. The molecular electrostatic potential (MESP) mapping is very useful in the investigation of the molecular structure with its physiochemical property relationship. The calculated HOMO and LUMO energies show that charge transfer occurs within these molecules. Mulliken population analysis on atomic charge is also calculated. Because of vibrational analysis, the thermodynamic properties of the title compound at different temperatures have been calculated. Finally, the UV-Vis spectra and electronic absorption properties are explained and illustrated from the frontier molecular orbitals. The grown crystals were characterized by measuring their thermal properties by Differential Thermal Analysis (DTA) and Thermo Gravimetric Analysis (TGA) measurements. PMID- 25437839 TI - Sphingolipid metabolism regulates development and lifespan in Caenorhabditis elegans. AB - Sphingolipids are a highly conserved lipid component of cell membranes involved in the formation of lipid raft domains that house many of the receptors and cell to-cell signaling factors involved in regulating cell division, maturation, and terminal differentiation. By measuring and manipulating sphingolipid metabolism using pharmacological and genetic tools in Caenorhabditis elegans, we provide evidence that the synthesis and remodeling of specific ceramides (e.g., dC18:1 C24:1), gangliosides (e.g., GM1-C24:1), and sphingomyelins (e.g., dC18:1-C18:1) influence development rate and lifespan. We found that the levels of fatty acid chain desaturation and elongation in many sphingolipid species increased during development and aging, with no such changes in developmentally-arrested dauer larvae or normal adults after food withdrawal (an anti-aging intervention). Pharmacological inhibitors and small interfering RNAs directed against serine palmitoyl transferase and glucosylceramide synthase acted to slow development rate, extend the reproductive period, and increase lifespan. In contrast, worms fed an egg yolk diet rich in sphingolipids exhibited accelerated development and reduced lifespan. Our findings demonstrate that sphingolipid accumulation and remodeling are critical events that determine development rate and lifespan in the nematode model, with both development rate and aging being accelerated by the synthesis of sphingomyelin, and its metabolism to ceramides and gangliosides. PMID- 25437841 TI - Application of normalized spectra in resolving a challenging Orphenadrine and Paracetamol binary mixture. AB - Normalized spectra have a great power in resolving spectral overlap of challenging Orphenadrine (ORP) and Paracetamol (PAR) binary mixture, four smart techniques utilizing the normalized spectra were used in this work, namely, amplitude modulation (AM), simultaneous area ratio subtraction (SARS), simultaneous derivative spectrophotometry (S(1)DD) and ratio H-point standard addition method (RHPSAM). In AM, peak amplitude at 221.6nm of the division spectra was measured for both ORP and PAR determination, while in SARS, concentration of ORP was determined using the area under the curve from 215nm to 222nm of the regenerated ORP zero order absorption spectra, in S(1)DD, concentration of ORP was determined using the peak amplitude at 224nm of the first derivative ratio spectra. PAR concentration was determined directly at 288nm in the division spectra obtained during the manipulation steps in the previous three methods. The last RHPSAM is a dual wavelength method in which two calibrations were plotted at 216nm and 226nm. RH point is the intersection of the two calibration lines, where ORP and PAR concentrations were directly determined from coordinates of RH point. The proposed methods were applied successfully for the determination of ORP and PAR in their dosage form. PMID- 25437842 TI - Photocatalytic detoxification of Acid Red 18 by modified ZnO catalyst under sunlight irradiation. AB - In this work, hybrid structured Bi-Au-ZnO composite was prepared by precipitation decomposition method. This method is mild, economical and efficient. Bi-Au-ZnO was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), transmission electron microscopy (TEM), energy dispersive spectrum (EDS), diffuse reflectance spectra (DRS), photoluminescence spectra (PL) and BET surface area measurements. Photocatalytic activity of Bi-Au-ZnO was evaluated by irradiating the Acid Red 18 (AR 18) dye solution under sun light. Heterostructured Bi-Au-ZnO photocatalyst showed higher photocatalytic activity than those of individual Bi ZnO, Au-ZnO, bare ZnO, and TiO2-P25 at pH 11. The effects of operational parameters such as the amount of catalyst dosage, dye concentration, initial pH on photo mineralization of AR 18 dye have been analyzed. The mineralization of AR 18 has been confirmed by chemical oxygen demand (COD) measurements. A possible mechanism is proposed for the degradation of AR 18 under sun light. Finally, Bi Au-ZnO heterojunction photocatalyst was more stable and could be easily recycled several times opening a new avenue for potential industrial applications. PMID- 25437843 TI - Silicon-containing bis-azomethines: synthesis, structural characterization, evaluation of the photophysical properties and biological activity. AB - A new diamine, (dimethylsilanediyl)bis(methylene)bis(4-aminobenzoate) (1), containing dimethylsilane spacer, was prepared by the condensation of p aminobenzoic acid with bis(chloromethyl)dimethylsilane. This was subsequently reacted with salicylaldehyde, 3-hydroxy-salicylaldehyde, and 3-methoxy salicyladehyde, when corresponding Schiff bases (E) (dimethylsilanediyl)bis(methylene)bis(4-((E)-(2-hydroxybenzilidene)amino)benzoate (2), (E)-(dimethylsilanediyl)bis(methylene)bis(4-((E)-(2 hydroxybenzilidene)amino)benzoate (3), and (E)-(dimethylsilanediyl)bis(methylene) bis(4-((E)-(2-hydroxy-3-methoxybenzilidene)amino)benzoate (4), respectively were formed. All the obtained compounds were structurally characterized by spectral (FT-IR, (1)HNMR, (13)CNMR) analyses and single crystal X-ray diffraction. Photophysical studies revealed that the new prepared Schiff bases are good UV light absorbing and fluorescent materials. Thus, they exhibit strong UV/Vis absorption at 250-400nm and violet or orange emission, in sensitive dependence on the polarity of the solvents and the nature of the substituent (H, OH and OCH3) at the aromatic ring. The antimicrobial activity of these compounds was first studied in vitro by the disk diffusion assay against two species of bacteria and three fungi. The minimum inhibitory concentration was then determined with the reference of standard compounds. The results displayed that Schiff bases 3 and 4 having hydroxy- and methoxy-substituents on the aromatic ring were better inhibitors of both types of species (bacteria and fungi) than standard compounds, Caspofungin and Kanamycin. PMID- 25437845 TI - Synthesis, spectroscopic characterization and pH dependent photometric and electrochemical fate of Schiff bases. AB - A new Schiff base, 1-((4-bromophenylimino) methyl) naphthalen-2-ol (BPIMN) was successfully synthesized and characterized by (1)H NMR, (13)C NMR, FTIR and UV Vis spectroscopy. The results were compared with a structurally related Schiff base, 1-((4-chlorophenylimino) methyl) naphthalen-2-ol (CPIMN). The photometric and electrochemical fate of BPIMN and CPIMN was investigated in a wide pH range. The experimental findings were supported by quantum mechanical approach. The redox mechanistic pathways were proposed on the basis of results obtained electrochemical techniques. Moreover, pH dependent UV-Vis spectroscopy of BPIMN and CPIMN was carried out and the appearance of isosbestic points indicated the existence of these compounds in different tautomeric forms. PMID- 25437844 TI - Structure investigation of three hydrazones Schiff's bases by spectroscopic, thermal and molecular orbital calculations and their biological activities. AB - Three Schiff's bases AI (2(1-hydrazonoethyl)phenol), AII (2, 4-dibromo 6 (hydrazonomethyl)phenol) and AIII (2(hydrazonomethyl)phenol) were prepared as new hydrazone compounds via condensation reactions with molar ratio (1:1) of reactants. Firstly by reaction of 2-hydroxy acetophenone solution and hydrazine hydrate; it gives AI. Secondly condensation between 3,5-dibromo-salicylaldehyde and hydrazine hydrate gives AII. Thirdly condensation between salicylaldehyde and hydrazine hydrate gives AIII. The structures of AI-AIII were characterized by elemental analysis (EA), mass (MS), FT-IR and (1)H NMR spectra, and thermal analyses (TG, DTG, and DTA). The activation thermodynamic parameters, such as, DeltaE(*), DeltaH(*), DeltaS(*) and DeltaG(*) were calculated from the TG curves using Coats-Redfern method. It is important to investigate their molecular structures to know the active groups and weak bond responsible for their biological activities. Consequently in the present work, the obtained thermal (TA) and mass (MS) practical results are confirmed by semi-empirical MO calculations (MOCS) using PM3 procedure. Their biological activities have been tested in vitro against Escherichia coli, Proteus vulgaris, Bacillissubtilies and Staphylococcus aurous bacteria in order to assess their anti-microbial potential. PMID- 25437846 TI - Cryptoporus volvatus extract inhibits influenza virus replication in vitro and in vivo. AB - Influenza virus is the cause of significant morbidity and mortality, posing a serious health threat worldwide. Here, we evaluated the antiviral activities of Cryptoporus volvatus extract on influenza virus infection. Our results demonstrated that the Cryptoporus volvatus extract inhibited different influenza virus strain replication in MDCK cells. Time course analysis indicated that the extract exerted its inhibition at earlier and late stages in the replication cycle of influenza virus. Subsequently, we confirmed that the extract suppressed virus internalization into and released from cells. Moreover, the extract significantly reduced H1N1/09 influenza virus load in lungs and dramatically decreased lung lesions in mice. And most importantly, the extract protected mice from lethal challenge with H1N1/09 influenza virus. Our results suggest that the Cryptoporus volvatus extract could be a potential candidate for the development of a new anti-influenza virus therapy. PMID- 25437847 TI - Hypoglycemic events analysis via recurrent time-to-event (HEART) models. AB - Diabetes affects an estimated 25.8 million people in the United States and is one of the leading causes of death. A major safety concern in treating diabetes is the occurrence of hypoglycemic events. Despite this concern, the current methods of analyzing hypoglycemic events, including the Wilcoxon rank sum test and negative binomial regression, are not satisfactory. The aim of this article is to propose a new model to analyze hypoglycemic events with the goal of making this model a standard method in industry. Our method is based on a gamma frailty recurrent event model. To make this method broadly accessible to practitioners, this article provides many details of how this method works and discusses practical issues with supporting theoretical proofs. In particular, we make efforts to translate conditions and theorems from abstract counting process and martingale theories to intuitive and clinical meaningful explanations. For example, we provide a simple proof and illustration of the coarsening at random condition so that the practitioner can easily verify this condition. Connections and differences with traditional methods are discussed, and we demonstrate that under certain scenarios the widely used Wilcoxon rank sum test and negative binomial regression cannot control type 1 error rates while our proposed method is robust in all these situations. The usefulness of our method is demonstrated through a diabetes dataset which provides new clinical insights on the hypoglycemic data. PMID- 25437849 TI - Inter-wall bridging induced peeling of multi-walled carbon nanotubes during tensile failure in aluminum matrix composites. AB - In situ scanning electron microscopy (SEM) observation of a tensile test was performed to investigate the fracturing behavior of multi-walled carbon nanotubes (MWCNTs) in powder metallurgy Al matrix composites. A multiple peeling phenomenon during MWCNT fracturing was clearly observed. Its formation mechanism and resultant effect on the composite strength were examined. Through transition electron microscopy characterizations, it was observed that defective structures like inter-wall bridges cross-linked adjacent walls of MWCNTs. This structure was helpful to improve the inter-wall bonding conditions, leading to the effective load transfer between walls and resultant peeling behaviors of MWCNTs. These results might provide new understandings of the fracturing mechanisms of carbon nanotube reinforcements for designing high-performance nanocomposites. PMID- 25437850 TI - Ultrastructural aspects of naturally occurring wound in the tunic of two ascidians: Ciona intestinalis and Styela plicata (Tunicata). AB - Efficient wound healing is essential for all animals from insects to mammals. Ciona intestinalis and Styela plicata are solitary ascidians belonging to urochordates, a subphylum that occupies a key phylogenetic position as it includes the closest relative to vertebrates. Urochordate first physical barrier against invaders is the tunic, an extracellular matrix that is constantly exposed to all kinds of insults. Thus, when damage occurs, an innate immune response is triggered to eliminate impaired tissue and potentially pathogenic microbes, and restore tissue functionality. Ultrastructural aspects of the tunic in the wound healing process of two ascidians are described. In the injured areas, we evidenced thinning of the tunic and areas of low fibre density, dense intratunic bacterial and protozoan population, and inflammatory aspects such as the increase in tunic cells, their aggregates, and phagocytosis. This is the first report on tunic physical wounding occurring in the natural habitat. PMID- 25437848 TI - The circadian regulation of sleep: impact of a functional ADA-polymorphism and its association to working memory improvements. AB - Sleep is regulated in a time-of-day dependent manner and profits working memory. However, the impact of the circadian timing system as well as contributions of specific sleep properties to this beneficial effect remains largely unexplored. Moreover, it is unclear to which extent inter-individual differences in sleep wake regulation depend on circadian phase and modulate the association between sleep and working memory. Here, sleep electroencephalography (EEG) was recorded during a 40-h multiple nap protocol, and working memory performance was assessed by the n-back task 10 times before and after each scheduled nap sleep episode. Twenty-four participants were genotyped regarding a functional polymorphism in adenosine deaminase (rs73598374, 12 G/A-, 12 G/G-allele carriers), previously associated with differences in sleep-wake regulation. Our results indicate that genotype-driven differences in sleep depend on circadian phase: heterozygous participants were awake longer and slept less at the end of the biological day, while they exhibited longer non rapid eye movement (NREM) sleep and slow wave sleep concomitant with reduced power between 8-16 Hz at the end of the biological night. Slow wave sleep and NREM sleep delta EEG activity covaried positively with overall working memory performance, independent of circadian phase and genotype. Moreover, REM sleep duration benefitted working memory particularly when occurring in the early morning hours and specifically in heterozygous individuals. Even though based on a small sample size and thus requiring replication, our results suggest genotype-dependent differences in circadian sleep regulation. They further indicate that REM sleep, being under strong circadian control, boosts working memory performance according to genotype in a time-of-day dependent manner. Finally, our data provide first evidence that slow wave sleep and NREM sleep delta activity, majorly regulated by sleep homeostatic mechanisms, is linked to working memory independent of the timing of the sleep episode within the 24-h cycle. PMID- 25437851 TI - Hyperspectral dark-field microscopy of gold nanodisks. AB - The light scattering properties of hexagonal and triangular gold nanodisks were investigated by means of Cytoviva hyperspectral dark-field microscopy, exploring the huge enhancement of the scattered waves associated with the surface plasmon resonance (SPR) effect. Thanks to the high resolution capability of the dark field microscope, the SPR effect turned it possible to probe the individual nanoparticles directly from their hyperspectral images, extrapolating the classical optical resolution limit, and providing their corresponding extinction spectra. Blue spectral shifts involving the in-plane dipolar modes were observed for the hexagonal gold nanodisks in relation to the triangular ones, allowing their spectroscopic differentiation in the dark-field images. PMID- 25437852 TI - Strain analysis of misfit dislocations in alpha-Fe2O 3/alpha-Al2O 3 heterostructure interface by geometric phase analysis. AB - The alpha-Fe2O3/alpha-Al2O3 heterostructure interfaces have been studied using transmission electron microscopy (TEM). The interface exhibited coherent regions separated by equally spaced misfit dislocations. The misfit dislocations were demonstrated to be edge dislocations with dislocation spacing of ~4 nm. The strain fields around the misfit dislocation core were mapped using a combination of geometric phase analysis and high-resolution transmission electron microscopy images. The strain measurement results were compared with the Peierls-Nabarro dislocation model and the Foreman dislocation model. These comparisons show that the Foreman model (a=2) is the most appropriate theoretical model to describe the strain fields of the dislocation core. PMID- 25437853 TI - Ultrastructural studies on the midgut of biting midge Forcipomyia nigra (Winnertz) (Diptera: Ceratopogonidae). AB - Biting midges belonging to the genus Forcipomyia are known to be hematophagous, predatory or saprophagous. Different stages of Forcipomyia nigra midges were investigated to provide a description of midgut ultrastructure. Larvae feeding on decaying organic matter possess simple, straight alimentary tracts whose middle regions are the longest. TEM studies of the larval midgut epithelium reveal that digestive cells show different ultrastructure depending on their age. The older cells with electron-dense cytoplasm degenerate while the younger ones with electron-lucent cytoplasm remain active in digestion. In saprophagous females, the ultrastructure of midgut epithelium changes according to the age of flies. Oogenesis induces degeneration of digestive cells and utilization of reserve material accumulated by them. The midgut epithelia of male midges consist of digestive and regenerative cells that show no evidence of cell degeneration as observed in females. Our results demonstrate differences between midgut digestive cells of males and females. PMID- 25437855 TI - The citation wake of publications detects nobel laureates' papers. AB - For several decades, a leading paradigm of how to quantitatively assess scientific research has been the analysis of the aggregated citation information in a set of scientific publications. Although the representation of this information as a citation network has already been coined in the 1960s, it needed the systematic indexing of scientific literature to allow for impact metrics that actually made use of this network as a whole, improving on the then prevailing metrics that were almost exclusively based on the number of direct citations. However, besides focusing on the assignment of credit, the paper citation network can also be studied in terms of the proliferation of scientific ideas. Here we introduce a simple measure based on the shortest-paths in the paper's in component or, simply speaking, on the shape and size of the wake of a paper within the citation network. Applied to a citation network containing Physical Review publications from more than a century, our approach is able to detect seminal articles which have introduced concepts of obvious importance to the further development of physics. We observe a large fraction of papers co-authored by Nobel Prize laureates in physics among the top-ranked publications. PMID- 25437857 TI - Stroke increases neural stem cells and angiogenesis in the neurogenic niche of the adult mouse. AB - The unique cellular and vascular architecture of the adult ventricular subventricular zone (V/SVZ) neurogenic niche plays an important role in regulating neural stem cell function. However, the in vivo identification of neural stem cells and their relationship to blood vessels within this niche in response to stroke remain largely unknown. Using whole-mount preparation of the lateral ventricle wall, we examined the architecture of neural stem cells and blood vessels in the V/SVZ of adult mouse over the course of 3 months after onset of focal cerebral ischemia. Stroke substantially increased the number of glial fibrillary acidic protein (GFAP) positive neural stem cells that are in contact with the cerebrospinal fluid (CSF) via their apical processes at the center of pinwheel structures formed by ependymal cells residing in the lateral ventricle. Long basal processes of these cells extended to blood vessels beneath the ependymal layer. Moreover, stroke increased V/SVZ endothelial cell proliferation from 2% in non-ischemic mice to 12 and 15% at 7 and 14 days after stroke, respectively. Vascular volume in the V/SVZ was augmented from 3% of the total volume prior to stroke to 6% at 90 days after stroke. Stroke-increased angiogenesis was closely associated with neuroblasts that expanded to nearly encompass the entire lateral ventricular wall in the V/SVZ. These data indicate that stroke induces long-term alterations of the neural stem cell and vascular architecture of the adult V/SVZ neurogenic niche. These post-stroke structural changes may provide insight into neural stem cell mediation of stroke-induced neurogenesis through the interaction of neural stem cells with proteins in the CSF and their sub-ependymal neurovascular interaction. PMID- 25437858 TI - Insecticidal suppression of Asian citrus psyllid Diaphorina citri (Hemiptera: Liviidae) vector of huanglongbing pathogens. AB - Diaphorina citri vectors pathogens that cause 'huanglongbing' or citrus greening disease which poses a serious threat to citrus production worldwide. Vector suppression is critical to reduce disease spread. Efficacy is a main concern when choosing an insecticide. Insecticidal treatments of 49 products or 44 active ingredients (a.i) labeled or experimental were field tested between 2005-2013 as foliar sprays (250 treatments, 39 a.i) or soil applications (47 treatments, 9 a.i) to control D. citri in citrus. A combined effect of nymphal and adult suppression in response to sprays of 23 insecticides representing 9 modes of action (MoA) groups and 3 unknown MoA provided more than 90% reduction of adult D. citri over 24-68 days. Observable effects on nymphs were generally of shorter duration due to rapid maturation of flush. However, reduction of 76-100% nymphs or adults over 99-296 days was seen on young trees receiving drenches of the neonicotinoids imidacloprid, thiamethoxam or clothianidin (MoA 4A) and a novel anthranilic diamide, cyantraniliprole (MoA 28). Effective products identified for foliar sprays to control D. citri provide sufficient MoA groups for rotation to delay evolution of insecticide resistance by D. citri and other pests. However, cyantraniliprole is now the only available alternative for rotation with neonicotinoids in soil application to young trees. Sprays of up to eight of the most effective insecticides could be rotated over a year without repetition of any MoA and little or no recourse to neonicotinoids or cyantraniliprole, so important for protection of young trees. Other considerations effecting decisions of what and when to spray include prevalence of huanglongbing, pest pressure, pre harvest intervals, overall budget, equipment availability, and conservation of beneficial arthropods. Examples of spray programs utilizing broad-spectrum and relatively selective insecticides are provided to improve vector management and may vary depending on individual or regional assessment of all factors. PMID- 25437856 TI - Statistical modeling of the abundance of vectors of West African Rift Valley fever in Barkedji, Senegal. AB - Rift Valley fever is an emerging mosquito-borne disease that represents a threat to human and animal health. The exophilic and exophagic behavior of the two main vector in West Africa (Aedes vexans and Culex poicilipes), adverse events post vaccination, and lack of treatment, render ineffective the disease control. Therefore it is essential to develop an information system that facilitates decision-making and the implementation of adaptation strategies. In East Africa, RVF outbreaks are linked with abnormally high rainfall, and can be predicted up to 5 months in advance by modeling approaches using climatic and environmental parameters. However, the application of these models in West Africa remains unsatisfactory due to a lack of data for animal and human cases and differences in the dynamics of the disease emergence and the vector species involved in transmission. Models have been proposed for West Africa but they were restricted to rainfall impact analysis without a spatial dimension. In this study, we developed a mixed Bayesian statistical model to evaluate the effects of climatic and ecological determinants on the spatiotemporal dynamics of the two main vectors. Adult mosquito abundance data were generated from July to December every fortnight in 2005-2006 at 79 sites, including temporary ponds, bare soils, shrubby savannah, wooded savannah, steppes, and villages in the Barkedji area. The results demonstrate the importance of environmental factors and weather conditions for predicting mosquito abundance. The rainfall and minimum temperature were positively correlated with the abundance of Cx. poicilipes, whereas the maximum temperature had negative effects. The rainfall was negatively correlated with the abundance of Ae. vexans. After combining land cover classes, weather conditions, and vector abundance, our model was used to predict the areas and periods with the highest risks of vector pressure. This information could support decision-making to improve RVF surveillance activities and to implement better intervention strategies. PMID- 25437861 TI - Contributions of pocket depth and electrostatic interactions to affinity and selectivity of receptors for methylated lysine in water. AB - Dynamic combinatorial chemistry was used to generate a set of receptors for peptides containing methylated lysine (KMen, n = 0-3) and study the contribution of electrostatic effects and pocket depth to binding affinity and selectivity. We found that changing the location of a carboxylate resulted in an increase in preference for KMe2, presumably based on ability to form a salt bridge with KMe2. The number of charged groups on either the receptor or peptide guest systematically varied the binding affinities to all guests by approximately 1-1.5 kcal mol(-1), with little influence on selectivity. Lastly, formation of a deeper pocket led to both increased affinity and selectivity for KMe3 over the lower methylation states. From these studies, we identified that the tightest binder was a receptor with greater net charge, with a Kd of 0.2 MUM, and the receptor with the highest selectivity was the one with the deepest pocket, providing 14 fold selectivity between KMe3 and KMe2 and a Kd for KMe3 of 0.3 MUM. This work provides key insights into approaches to improve binding affinity and selectivity in water, while also demonstrating the versatility of dynamic combinatorial chemistry for rapidly exploring the impact of subtle changes in receptor functionality on molecular recognition in water. PMID- 25437860 TI - Burden and correlates of geriatric depression in the Uyghur elderly population, observation from Xinjiang, China. AB - BACKGROUND: With the gradual aging of the population, geriatric depression has become a major public health issue in China owing to its overall upward trend and associated negative socio-economic impact. Dearth of information regarding the burden and correlates of geriatric depression among Uyghur minority population in Xinjiang Autonomous Region, called for a comprehensive survey involving representative sample for designing efficient targeted intervention to control this disabling disease. METHODS: A cross-sectional study was conducted among 1329 consenting Uyghur elderly in 2011 in six randomly selected communities/villages in Xinjiang. Information about socio-demographics, behavior, negative life events, satisfaction regarding income/quality of life and other chronic diseases were collected while assessment of geriatric depression was done using Geriatric Mental State Schedule (GMS). RESULTS: Among these participants, majority were currently married, had attended elementary school or less, had an average annual family income of less than 3000 Yuan/person, had strong religious beliefs while 10.61% (2.77% in urban and 23.60% in rural area) had geriatric depression (5.91% among male and 14.58% among females). 61.83% were suffering from other chronic diseases, 96.16% could take care of themselves and 39.28% had experienced negative events during last two years. Religious belief (AOR = 3.92, 95% CI 1.18 13.03), satisfaction regarding quality of life (AOR = 0.53, 95% CI 0.37-0.84) and income (AOR = 0.75, 95% CI 0.35-1.60), suffering from more chronic diseases (AOR = 1.70, 95% CI 1.42-2.04), experiencing three or more negative events (AOR = 1.72, 95% CI 0.92-3.22) and lack of ability to take self-care (AOR = 2.20, 95% CI 1.09-4.48) were all associated with having geriatric depression with or without adjustment for gender, education and occupation. CONCLUSION: High prevalence of geriatric depression among Uyghur elderly in Xinjiang seemed to call for urgent interventions, specifically targeting rural residents, who experienced more negative life-events, were suffering from chronic diseases and were dissatisfied with their income and quality of life. PMID- 25437859 TI - Comparison of temporal transcriptomic profiles from immature lungs of two rat strains reveals a viral response signature associated with chronic lung dysfunction. AB - Early life respiratory viral infections and atopic characteristics are significant risk factors for the development of childhood asthma. It is hypothesized that repeated respiratory viral infections might induce structural remodeling by interfering with the normal process of lung maturation; however, the specific molecular processes that underlie these pathological changes are not understood. To investigate the molecular basis for these changes, we used an established Sendai virus infection model in weanling rats to compare the post infection transcriptomes of an atopic asthma susceptible strain, Brown Norway, and a non-atopic asthma resistant strain, Fischer 344. Specific to this weanling infection model and not described in adult infection models, Sendai virus in the susceptible, but not the resistant strain, results in morphological abnormalities in distal airways that persist into adulthood. Gene expression data from infected and control lungs across five time points indicated that specific features of the immune response following viral infection were heightened and prolonged in lungs from Brown Norway rats compared with Fischer 344 rats. These features included an increase in macrophage cell number and related gene expression, which then transitioned to an increase in mast cell number and related gene expression. In contrast, infected Fischer F344 lungs exhibited more efficient restoration of the airway epithelial morphology, with transient appearance of basal cell pods near distal airways. Together, these findings indicate that the pronounced macrophage and mast cell responses and abnormal re-epithelialization precede the structural defects that developed and persisted in Brown Norway, but not Fischer 344 lungs. PMID- 25437862 TI - Epidemiological study of primary systemic vasculitides among adults in southern Spain and review of the main epidemiological studies. AB - OBJECTIVES: To study the incidence and prevalence of primary systemic vasculitides (PSV) in the Costa del Sol region (southern Spain) and to compare the major epidemiological studies in PSV with the results obtained in our area. METHODS: Retrospective study including permanent residents >=14 years (or older) diagnosed with PSV at the Hospital Costa del Sol (Marbella, Spain) between 1994 and 2010. Epidemiological data were collected and the annual incidence rate during the study period and the prevalence in 2010 were calculated per million population, except for GCA, which was estimated per 100,000 population >50 years. RESULTS: Seventy-four adult patients were diagnosed with PSV, representing an annual incidence of 15.8 (95%CI 12.2-19.4) patients/million population. These diagnoses included 29 (39.1%) giant cell arteritis (GCA), 5 (6.7%) Takayasu's arteritis (TKA), 3 (4%) poly-arteritis nodosa (PAN), 29 (39.1%) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) [10 (13.5%) granulomatosis with polyangiitis (GPA) (Wegener), 16 (21.6%) microscopic polyangiitis (MPA) and 3 (4%) eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss)], 7 (9.4%) IgA vasculitis (Henoch-Schonlein) (IgAV) and one (1.3%) cryobulinaemic vasculitis (CV). The annual incidence and 2010 prevalence for each of the PSV, respectively, were: GCA: 2.2/12.2; TKA: 1.1/10.5; PAN: 0.6/2.6; AAV: 6.2/44.8 (GPA: 2.1/15.8; MPA: 3.4/23.8; EGPA: 0.6/5.3); IgAV: 1.5/7.9; and CV: 0.2/0. CONCLUSIONS: The first epidemiological study of PSV in southern Spain corroborates their infrequency, with GCA and AAV as the PSV most often diagnosed. In southern Spain, the incidence and prevalence of PSV are lower than in northern Spain and in countries in the Northern Hemisphere. PMID- 25437863 TI - The Eps1p protein disulfide isomerase conserves classic thioredoxin superfamily amino acid motifs but not their functional geometries. AB - The widespread thioredoxin superfamily enzymes typically share the following features: a characteristic alpha-beta fold, the presence of a Cys-X-X-Cys (or Cys X-X-Ser) redox-active motif, and a proline in the cis configuration abutting the redox-active site in the tertiary structure. The Cys-X-X-Cys motif is at the solvent-exposed amino terminus of an alpha-helix, allowing the first cysteine to engage in nucleophilic attack on substrates, or substrates to attack the Cys-X-X Cys disulfide, depending on whether the enzyme functions to reduce, isomerize, or oxidize its targets. We report here the X-ray crystal structure of an enzyme that breaks many of our assumptions regarding the sequence-structure relationship of thioredoxin superfamily proteins. The yeast Protein Disulfide Isomerase family member Eps1p has Cys-X-X-Cys motifs and proline residues at the appropriate primary structural positions in its first two predicted thioredoxin-fold domains. However, crystal structures show that the Cys-X-X-Cys of the second domain is buried and that the adjacent proline is in the trans, rather than the cis isomer. In these configurations, neither the "active-site" disulfide nor the backbone carbonyl preceding the proline is available to interact with substrate. The Eps1p structures thus expand the documented diversity of the PDI oxidoreductase family and demonstrate that conserved sequence motifs in common folds do not guarantee structural or functional conservation. PMID- 25437864 TI - Identification of tumor endothelial cells with high aldehyde dehydrogenase activity and a highly angiogenic phenotype. AB - Tumor blood vessels play an important role in tumor progression and metastasis. It has been reported that tumor endothelial cells (TECs) exhibit highly angiogenic phenotypes compared with those of normal endothelial cells (NECs). TECs show higher proliferative and migratory abilities than those NECs, together with upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Furthermore, compared with NECs, stem cell markers such as Sca-1, CD90, and multidrug resistance 1 are upregulated in TECs, suggesting that stem like cells exist in tumor blood vessels. In this study, to reveal the biological role of stem-like TECs, we analyzed expression of the stem cell marker aldehyde dehydrogenase (ALDH) in TECs and characterized ALDHhigh TECs. TECs and NECs were isolated from melanoma-xenografted nude mice and normal dermis, respectively. ALDH mRNA expression and activity were higher in TECs than those in NECs. Next, ALDHhigh/low TECs were isolated by fluorescence-activated cell sorting to compare their characteristics. Compared with ALDHlow TECs, ALDHhigh TECs formed more tubes on Matrigel-coated plates and sustained the tubular networks longer. Furthermore, VEGFR2 expression was higher in ALDHhigh TECs than that in ALDHlow TECs. In addition, ALDH was expressed in the tumor blood vessels of in vivo mouse models of melanoma and oral carcinoma, but not in normal blood vessels. These findings indicate that ALDHhigh TECs exhibit an angiogenic phenotype. Stem-like TECs may have an essential role in tumor angiogenesis. PMID- 25437866 TI - Impact of transmammary-delivered meloxicam on biomarkers of pain and distress in piglets after castration and tail docking. AB - To investigate a novel route for providing analgesia to processed piglets via transmammary drug delivery, meloxicam was administered orally to sows after farrowing. The objectives of the study were to demonstrate meloxicam transfer from sows to piglets via milk and to describe the analgesic effects in piglets after processing through assessment of pain biomarkers and infrared thermography (IRT). Ten sows received either meloxicam (30 mg/kg) (n = 5) or whey protein (placebo) (n = 5) in their daily feedings, starting four days after farrowing and continuing for three consecutive days. During this period, blood and milk samples were collected at 12-hour intervals. On Day 5 after farrowing, three boars and three gilts from each litter were castrated or sham castrated, tail docked, and administered an iron injection. Piglet blood samples were collected immediately before processing and at predetermined times over an 84-hour period. IRT images were captured at each piglet blood collection point. Plasma was tested to confirm meloxicam concentrations using a validated high-performance liquid chromatography mass spectrometry method. Meloxicam was detected in all piglets nursing on medicated sows at each time point, and the mean (+/- standard error of the mean) meloxicam concentration at castration was 568.9+/-105.8 ng/mL. Furthermore, ex vivo prostaglandin E2 (PGE2) synthesis inhibition was greater in piglets from treated sows compared to controls (p = 0.0059). There was a time-by-treatment interaction for plasma cortisol (p = 0.0009), with meloxicam-treated piglets demonstrating lower cortisol concentrations than control piglets for 10 hours after castration. No differences in mean plasma substance P concentrations between treatment groups were observed (p = 0.67). Lower cranial skin temperatures on IRT were observed in placebo compared to meloxicam-treated piglets (p = 0.015). This study demonstrates the successful transfer of meloxicam from sows to piglets through milk and corresponding analgesia after processing, as evidenced by a decrease in cortisol and PGE2 levels and maintenance of cranial skin temperature. PMID- 25437865 TI - Leukotriene production is increased in abdominal obesity. AB - Obesity is a major risk factor for insulin resistance and type-2 diabetes. A chronic low grade inflammatory state has been described during obesity and associated with insulin resistance pathogenesis. Results from animal studies are in favor of a role of the leukotriene (LT) pathway in obesity induced-insulin resistance. However, there is a paucity of data regarding this association in human obesity. Therefore, the aim of this study was to investigate whether LT production was associated with insulin resistance and other metabolic parameters in a cohort of obese subjects. Forty-six (70% females) obese subjects (BMI?30 kg/m2) without known diabetes and without inflammatory disease (CRP<10 mg/l) were included. Median age was 44 years (16-80) with a median BMI of 36.8 kg/m2 (30 51). Insulin resistance was evaluated by HOMA-IR index and glucose tolerance test. Urinary LTE4 (U-LTE4) concentration was measured by enzyme immune assay. Screening for obstructive sleep apnea was performed. There was a positive association of U-LTE4 with waist to hip ratio, systolic blood pressure and HOMA IR in univariate analysis. Further, waist to hip ratio remained the only parameter significantly correlated with U-LTE4, in adjusted multivariate analysis. Taken together, these results confirm the previously established notion of chronic low grade inflammation in obesity and further suggests a role for the LT pathway in obesity-associated development of insulin resistance in humans. PMID- 25437867 TI - Hyperuricemia and risk of incident hypertension: a systematic review and meta analysis of observational studies. AB - BACKGROUND: Observational studies of the relationship between hyperuricemia and the incidence of hypertension are controversial. We conducted a systematic review and meta-analysis to assess the association and consistency between uric acid levels and the risk of hypertension development. METHODS: We searched MEDLINE, EMBASE, CBM (Chinese Biomedicine Database) through September 2013 and reference lists of retrieved studies to identify cohort studies and nested case-control studies with uric acid levels as exposure and incident hypertension as outcome variables. Two reviewers independently extracted data and assessed study quality using Newcastle-Ottawa Scale. Extracted information included study design, population, definition of hyperuricemia and hypertension, number of incident hypertension, effect sizes, and adjusted confounders. Pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs) for the association between hyperuricemia and risk of hypertension were calculated using a random-effects model. RESULTS: We included 25 studies with 97,824 participants assessing the association between uric acid and incident hypertension in our meta-analysis. The quality of included studies is moderate to high. Random-effects meta-analysis showed that hyperuricemia was associated with a higher risk of incident hypertension, regardless of whether the effect size was adjusted or not, whether the data were categorical or continuous as 1 SD/1 mg/dl increase in uric acid level (unadjusted: RR = 1.73, 95% CI 1.46~2.06 for categorical data, RR = 1.22, 95% CI 1.03~1.45 for a 1 SD increase; adjusted: RR = 1.48, 95% CI 1.33~1.65 for categorical data, RR = 1.15, 95% CI 1.06~1.26 for a 1 mg/dl increase), and the risk is consistent in subgroup analyses and have a dose-response relationship. CONCLUSIONS: Hyperuricemia may modestly increase the risk of hypertension incidence, consistent with a dose-response relationship. PMID- 25437869 TI - MicroRNA-34c expression in donor cells influences the early development of somatic cell nuclear transfer bovine embryos. AB - The essence of the reprogramming activity of somatic cell nuclear transfer (SCNT) embryos is to produce normal fertilized embryos. However, reprogramming of somatic cells is not as efficient as the reprogramming of sperm. In this report, we describe the effect of an inducible, specific miR-34 microRNA expression in donor cells that enables a similar level of sperm:transgene expression on the early development of SCNT embryos. Our results showed that donor cells with doxycycline (dox)-induced miR-34c expression for the preparation of SCNT embryos resulted in altered developmental rates, histone modification (H3K9ac and H3K4me3), and extent of apoptosis. The cleavage rate and blastocyst formation of the induced nuclear transfer (NT) group were significantly increased. The immunofluorescence signal of H3K9ac in embryos in the induced NT group significantly increased in two-cell- and eight-cell-stage embryos; that of H3K4me3 increased significantly in eight-cell-stage embryos. Although significant differences in staining signals of apoptosis were not detected between groups, lower apoptosis levels were observed in the induced NT group. In conclusion, miR 34c expression induced by dox treatment enhances the developmental potential of SCNT embryos, modifies the epigenetic status, and changes blastocyst quality. PMID- 25437870 TI - Development and gene expression of porcine cloned embryos derived from bone marrow stem cells with overexpressing Oct4 and Sox2. AB - The present study compared the potential of porcine bone marrow mesenchymal stem cells (pBMSCs) at different passages as nuclear transfer (NT) donors and the developmental efficiency of NT embryos from donor cells transfected with/without Oct4 and Sox2. Early-passage pBMSCs showed higher proliferation and expression of Oct4 and Sox2 and differentiation potential into mesenchymal lineages than middle and late-passage pBMSCs. Cleavage rate did not differ among pBMSCs at different passages, but NT embryos with early-passage pBMSCs and middle-passage pBMSCs transfected with Oct4 (Oct4-pBMSCs) had significantly (p<0.05) higher blastocyst development than those with middle-passage pBMSCs. The incidence of apoptotic bodies in NT blastocysts from late-passage pBMSCs and Sox2-transfected middle passage pBMSCs (Sox2-pBMSCs) was significantly (p<0.05) higher than others. The transcriptional levels of Oct4, Sox2, Nanog, Cdx2, Dnmt3a, and Igf2r genes were significantly (p<0.05) higher in Oct4- and Sox2-pBMSCs NT embryos. Middle-passage pBMSCs NT embryos revealed lower transcriptional levels of Bcl2 than others, except Sox2-pBMSCs NT embryos. The transcriptional level of Bax increased gradually in NT embryos derived from pBMSCs following extended passages and was significantly (p<0.05) higher in Sox2-pBMSCs NT embryos. Our results demonstrated that early-passage pBMSCs are more potent in expressing transcription factors and displayed higher differentiation ability, and middle-passage pBMSCs transfected with Oct4 improved the developmental efficiency of NT embryos, suggesting that high Oct4 expression cells are more efficient as NT donors. PMID- 25437871 TI - Electrophysiological profiles of induced neurons converted directly from adult human fibroblasts indicate incomplete neuronal conversion. AB - The direct conversion of human fibroblasts to neuronal cells, termed human induced neuronal (hiN) cells, has great potential for future clinical advances. However, previous studies have not provided an in-depth analysis of electrophysiological properties of adult fibroblast-derived hiN cultures. We have examined the electrophysiological profile of hiN cells by measuring passive and active membrane properties, as well as spontaneous and evoked neurotransmission. We found that hiN cells exhibited passive membrane properties equivalent to perinatal rodent neurons. In addition, 30% of hiN cells were incapable of action potential (AP) generation and did not exhibit rectifying membrane currents, and none of the cells displayed firing patterns of typical glutamatergic pyramidal neurons. Finally, hiN cells exhibited neither spontaneous nor evoked neurotransmission. Our results suggest that current methods used to produce hiN cells provide preparations in which cells do not achieve the cellular properties of fully mature neurons, rendering these cells inadequate to investigate pathophysiological mechanisms. PMID- 25437872 TI - beta-Cell differentiation of human pancreatic duct-derived cells after in vitro expansion. AB - beta-Cell replacement therapy is a promising field of research that is currently evaluating new sources of cells for clinical use. Pancreatic epithelial cells are potent candidates for beta-cell engineering, but their large-scale expansion has not been evidenced yet. Here we describe the efficient expansion and beta-cell differentiation of purified human pancreatic duct cells (DCs). When cultured in endothelial growth-promoting media, purified CA19-9(+) cells proliferated extensively and achieved up to 22 population doublings over nine passages. While proliferating, human pancreatic duct-derived cells (HDDCs) downregulated most DC markers, but they retained low CK19 and SOX9 gene expression. HDDCs acquired mesenchymal features but differed from fibroblasts or pancreatic stromal cells. Coexpression of duct and mesenchymal markers suggested that HDDCs were derived from DCs via a partial epithelial-to-mesenchymal transition (EMT). This was supported by the blockade of HDDC appearance in CA19-9(+) cell cultures after incubation with the EMT inhibitor A83-01. After a differentiation protocol mimicking pancreatic development, HDDC populations contained about 2% of immature insulin-producing cells and showed glucose-unresponsive insulin secretion. Downregulation of the mesenchymal phenotype improved beta-cell gene expression profile of differentiated HDDCs without affecting insulin protein expression and secretion. We show that pancreatic ducts represent a new source for engineering large amounts of beta-like-cells with potential for treating diabetes. PMID- 25437873 TI - The Connectome Visualization Utility: software for visualization of human brain networks. AB - In analysis of the human connectome, the connectivity of the human brain is collected from multiple imaging modalities and analyzed using graph theoretical techniques. The dimensionality of human connectivity data is high, and making sense of the complex networks in connectomics requires sophisticated visualization and analysis software. The current availability of software packages to analyze the human connectome is limited. The Connectome Visualization Utility (CVU) is a new software package designed for the visualization and network analysis of human brain networks. CVU complements existing software packages by offering expanded interactive analysis and advanced visualization features, including the automated visualization of networks in three different complementary styles and features the special visualization of scalar graph theoretical properties and modular structure. By decoupling the process of network creation from network visualization and analysis, we ensure that CVU can visualize networks from any imaging modality. CVU offers a graphical user interface, interactive scripting, and represents data uses transparent neuroimaging and matrix-based file types rather than opaque application-specific file formats. PMID- 25437874 TI - Intronic locus determines SHROOM3 expression and potentiates renal allograft fibrosis. AB - Fibrosis underlies the loss of renal function in patients with chronic kidney disease (CKD) and in kidney transplant recipients with chronic allograft nephropathy (CAN). Here, we studied the effect of an intronic SNP in SHROOM3, which has previously been linked to CKD, on the development of CAN in a prospective cohort of renal allograft recipients. The presence of the rs17319721 allele at the SHROOM3 locus in the donor correlated with increased SHROOM3 expression in the allograft. In vitro, we determined that the sequence containing the risk allele at rs17319721 is a transcription factor 7-like 2-dependent (TCF7L2-dependent) enhancer element that functions to increase SHROOM3 transcription. In renal tubular cells, TGF-beta1 administration upregulated SHROOM3 expression in a beta-catenin/TCF7L2-mediated manner, while SHROOM3 in turn facilitated canonical TGF-beta1 signaling and increased alpha1 collagen (COL1A1) expression. Inducible and tubular cell-specific knockdown of Shroom3 markedly abrogated interstitial fibrosis in mice with unilateral ureteric obstruction. Moreover, SHROOM3 expression in allografts at 3 months after transplant and the presence of the SHROOM3 risk allele in the donor correlated with increased allograft fibrosis and with reduced estimated glomerular filtration rate at 12 months after transplant. Our findings suggest that rs17319721 functions as a cis-acting expression quantitative trait locus of SHROOM3 that facilitates TGF-beta1 signaling and contributes to allograft injury. PMID- 25437875 TI - Hepatic TRAP80 selectively regulates lipogenic activity of liver X receptor. AB - Inflammation in response to excess low-density lipoproteins in the blood is an important driver of atherosclerosis development. Due to its ability to enhance ATP-binding cassette A1-dependent (ABCA1-dependent) reverse cholesterol transport (RCT), liver X receptor (LXR) is an attractive target for the treatment of atherosclerosis. However, LXR also upregulates the expression of sterol regulatory element-binding protein 1c (SREBP-1c), leading to increased hepatic triglyceride synthesis, an independent risk factor for atherosclerosis. Here, we developed a strategy to separate the favorable and unfavorable effects of LXR by exploiting the specificity of the coactivator thyroid hormone receptor-associated protein 80 (TRAP80). Using human hepatic cell lines, we determined that TRAP80 selectively promotes the transcription of SREBP-1c but not ABCA1. Adenovirus mediated expression of shTRAP80 inhibited LXR-dependent SREBP-1c expression and RNA polymerase II recruitment to the LXR responsive element (LXRE) of SREBP-1c, but not to the LXRE of ABCA1. In murine models, liver-specific knockdown of TRAP80 ameliorated liver steatosis and hypertriglyceridemia induced by LXR activation and maintained RCT stimulation by the LXR ligand. Together, these data indicate that TRAP80 is a selective regulator of hepatic lipogenesis and is required for LXR-dependent SREBP-1c activation. Moreover, targeting the interaction between TRAP80 and LXR should facilitate the development of potential LXR agonists that effectively prevent atherosclerosis. PMID- 25437876 TI - Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. AB - Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4+ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4+ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4+ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases. PMID- 25437877 TI - Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery causes profound weight loss and improves insulin sensitivity (S(I)) in obese patients. Regular exercise can also improve S(I) in obese individuals; however, it is unknown whether exercise and RYGB surgery-induced weight loss would additively improve S(I) and other cardiometabolic factors. METHODS: We conducted a single-blind, prospective, randomized trial with 128 men and women who recently underwent RYGB surgery (within 1-3 months). Participants were randomized to either a 6-month semi supervised moderate exercise protocol (EX, n = 66) or a health education control (CON; n = 62) intervention. Main outcomes measured included S(I) and glucose effectiveness (S(G)), which were determined from an intravenous glucose tolerance test and minimal modeling. Secondary outcomes measured were cardiorespiratory fitness (VO2 peak) and body composition. Data were analyzed using an intention-to treat (ITT) and per-protocol (PP) approach to assess the efficacy of the exercise intervention (>120 min of exercise/week). RESULTS: 119 (93%) participants completed the interventions, 95% for CON and 91% for EX. There was a significant decrease in body weight and fat mass for both groups (P < 0.001 for time effect). S(I) improved in both groups following the intervention (ITT: CON vs. EX; +1.64 vs. +2.24 min-1/MUU/ml, P = 0.18 for Delta, P < 0.001 for time effect). A PP analysis revealed that exercise produced an additive S(I) improvement (PP: CON vs. EX; +1.57 vs. +2.69 min-1/MUU/ml, P = 0.019) above that of surgery. Exercise also improved S(G) (ITT: CON vs. EX; +0.0023 vs. +0.0063 min-1, P = 0.009) compared with the CON group. Exercise improved cardiorespiratory fitness (VO2 peak) compared with the CON group. CONCLUSION: Moderate exercise following RYGB surgery provides additional improvements in S(I), S(G), and cardiorespiratory fitness compared with a sedentary lifestyle during similar weight loss. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00692367. FUNDING: This study was funded by the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK078192) and an NIH/National Center for Research Resources/Clinical and Translational Science Award (UL1 RR024153). PMID- 25437878 TI - Rare codons capacitate Kras-driven de novo tumorigenesis. AB - The KRAS gene is commonly mutated in human cancers, rendering the encoded small GTPase constitutively active and oncogenic. This gene has the unusual feature of being enriched for rare codons, which limit protein expression. Here, to determine the effect of the rare codon bias of the KRAS gene on de novo tumorigenesis, we introduced synonymous mutations that converted rare codons into common codons in exon 3 of the Kras gene in mice. Compared with control animals, mice with at least 1 copy of this Kras(ex3op) allele had fewer tumors following carcinogen exposure, and this allele was mutated less often, with weaker oncogenic mutations in these tumors. This reduction in tumorigenesis was attributable to higher expression of the Kras(ex3op) allele, which induced growth arrest when oncogenic and exhibited tumor-suppressive activity when not mutated. Together, our data indicate that the inherent rare codon bias of KRAS plays an integral role in tumorigenesis. PMID- 25437880 TI - Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. AB - Premature ovarian failure (POF) is a genetically and phenotypically heterogeneous disorder that includes individuals with manifestations ranging from primary amenorrhea to loss of menstrual function prior to age 40. POF presents as hypergonadotropic hypogonadism and can be part of a syndrome or occur in isolation. Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and hypergonadotropic hypogonadism. The sisters were born to parents who are first cousins. SNP analysis and whole-exome sequencing revealed the presence of a pathogenic variant of the minichromosome maintenance 8 gene (MCM8, c.446C>G; p.P149R) located within a region of homozygosity that was present in the affected daughters but not in their unaffected sisters. Because MCM8 participates in homologous recombination and dsDNA break repair, we tested fibroblasts from the affected sisters for hypersensitivity to chromosomal breaks. Compared with fibroblasts from unaffected daughters, chromosomal break repair was deficient in fibroblasts from the affected individuals, likely due to inhibited recruitment of MCM8 p.P149R to sites of DNA damage. Our study identifies an autosomal recessive disorder caused by an MCM8 mutation that manifests with endocrine dysfunction and genomic instability. PMID- 25437879 TI - Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis. AB - Long-term potentiation (LTP) of synaptic strength between hippocampal neurons is associated with learning and memory, and LTP dysfunction is thought to underlie memory loss. LTP can be temporally and mechanistically classified into decaying (early-phase) LTP and nondecaying (late-phase) LTP. While the nondecaying nature of LTP is thought to depend on protein synthesis and contribute to memory maintenance, little is known about the mechanisms and roles of decaying LTP. Here, we demonstrated that inhibiting endocytosis of postsynaptic alpha-amino-3 hydroxy-5-methyl-isoxazole-4-propionic acid receptors (AMPARs) prevents LTP decay, thereby converting it into nondecaying LTP. Conversely, restoration of AMPAR endocytosis by inhibiting protein kinase Mzeta (PKMzeta) converted nondecaying LTP into decaying LTP. Similarly, inhibition of AMPAR endocytosis prolonged memory retention in normal animals and reduced memory loss in a murine model of Alzheimer's disease. These results strongly suggest that an active process that involves AMPAR endocytosis mediates the decay of LTP and that inhibition of this process can prolong the longevity of LTP as well as memory under both physiological and pathological conditions. PMID- 25437883 TI - Solid-phase synthesis of quinolinone library. AB - Quinolinones have various biological activities, including antibacterial, anticancer, and antiviral properties. The 3-substituted amide quinolin-2(1H)-ones not only show antibacterial activity, but also act as immunomodulators, 5-HT4 receptor agonists, cannabinoid receptor inverse agonists, and AchE and, BuchE inhibitors. To investigate the potent biological activity of 3-substituted amide quinolin-2(1H)-ones, a large number of 3,5-amide substituted-2-oxoquinolinones were prepared by parallel solid-phase synthesis. The compound 5-amino-1-(4 methoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid was loaded onto 4 formyl-3,5-dimethoxyphenoxy (PL-FDMP) resin by reductive amination with high efficiency. Various building blocks were attached to the 3 and 5 positions to yield 3,5-disubstituted-2-oxoquinolinones with high purity and good yield. The ability some of these compound to inhibit the release of IL-1beta, a cytokine involved in the immune response was measured, and they showed about 50% inhibition at 10 MUM. PMID- 25437884 TI - PET/PDT theranostics: synthesis and biological evaluation of a peptide-targeted gallium porphyrin. AB - The development of novel theranostic agents is an important step in the pathway towards personalised medicine, with the combination of diagnostic and therapeutic modalities into a single treatment agent naturally lending itself to the optimisation and personalisation of treatment. In pursuit of the goal of a molecular theranostic suitable for use as a PET radiotracer and a photosensitiser for PDT, a novel radiolabelled peptide-porphyrin conjugate targeting the alpha6beta1-integrin has been developed. (69/71)Ga and (68)Ga labelling of an azide-functionalised porphyrin has been carried out in excellent yields, with subsequent bioconjugation to an alkyne-functionalised peptide demonstrated. alpha6beta1-integrin expression of two cell lines has been evaluated by flow cytometry, and therapeutic potential of the conjugate demonstrated. Evaluation of the phototoxicity of the porphyrin-peptide theranostic conjugate in comparison to an untargeted control porphyrin in vitro, demonstrated significantly enhanced activity for a cell line with higher alpha6beta1-integrin expression when compared with a cell line exhibiting lower alpha6beta1-integrin expression. PMID- 25437881 TI - Statin therapy and risk of fracture: results from the JUPITER randomized clinical trial. AB - IMPORTANCE: Osteoporosis and cardiovascular disease may share common biological pathways, with inflammation playing a role in the development of both. Although observational studies have suggested that statin use is associated with a lower risk of fractures, randomized trial data addressing this issue are scant. OBJECTIVE: To determine whether statin therapy reduces the risk of fracture and, in a secondary analysis, whether baseline levels of the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) are associated with the risk of fracture. DESIGN, SETTING, AND PARTICIPANTS: The JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial was an international, randomized, double-blind, placebo-controlled study enrolling 17,802 men older than 50 years and women older than 60 years with hs CRP level of at least 2 mg/L. Participants were screened from 2003 to 2006 and observed prospectively for up to 5 years (median follow-up, 1.9 years). INTERVENTION: Rosuvastatin calcium, 20 mg daily, or placebo. MAIN OUTCOMES AND MEASURES: Incident fracture was a prespecified secondary end point of JUPITER. Fractures were confirmed by radiographs, computed tomography, bone scan, or other methods. Cox proportional hazards models were used to calculate hazard ratios (HRs) and associated 95% confidence intervals for the risk of fracture according to randomized treatment assignment, as well as increasing tertiles of hs-CRP, controlling for potential confounders. RESULTS: During the study, 431 incident fractures were reported and confirmed. Among participants allocated to rosuvastatin, 221 fractures were confirmed, compared with 210 among those allocated to placebo, such that the incidence of fracture in the rosuvastatin and placebo groups was 1.20 and 1.14 per 100 person-years, respectively (adjusted HR, 1.06 [95% CI, 0.88-1.28]; P = .53). Overall, increasing baseline hs-CRP level was not associated with an increased risk of fractures (adjusted HR for each unit increase in hs-CRP tertile, 1.06 [95% CI, 0.94-1.20]; P for trend, .34). CONCLUSIONS AND RELEVANCE: Among men and women with elevated hs-CRP level enrolled in a large trial of rosuvastatin therapy for cardiovascular disease, statin therapy did not reduce the risk of fracture. Higher baseline hs-CRP level was not associated with an increased risk of incident fracture. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00239681. PMID- 25437882 TI - A comparison of non-integrating reprogramming methods. AB - Human induced pluripotent stem cells (hiPSCs) are useful in disease modeling and drug discovery, and they promise to provide a new generation of cell-based therapeutics. To date there has been no systematic evaluation of the most widely used techniques for generating integration-free hiPSCs. Here we compare Sendai viral (SeV), episomal (Epi) and mRNA transfection mRNA methods using a number of criteria. All methods generated high-quality hiPSCs, but significant differences existed in aneuploidy rates, reprogramming efficiency, reliability and workload. We discuss the advantages and shortcomings of each approach, and present and review the results of a survey of a large number of human reprogramming laboratories on their independent experiences and preferences. Our analysis provides a valuable resource to inform the use of specific reprogramming methods for different laboratories and different applications, including clinical translation. PMID- 25437885 TI - Is it safe to implant bioresorbable scaffolds in ostial side-branch lesions? Impact of 'neo-carina' formation on main-branch flow pattern. Longitudinal clinical observations. AB - Formation of a 'neo-carina' has been reported after bioresorbable vascular scaffolds (BVS) implantation over side-branches. However, as this 'neo-carina' could protrude into the main-branch, its hemodynamic impact remains unknown. We present two cases of BVS implantation for ostial side-branch lesions, and investigate the flow patterns at follow-up and their potential impact. Computational fluid dynamics analysis was performed, using a 3D mesh created by fusion of 3-dimensional angiogram with optical coherence tomography images. In our first case, mild disturbances were seen when 'neo-carina' did not protrude perpendicularly into the main branch. In the second case, extensive flow re distribution was observed due to a more pronounced protrusion of the 'neo carina'. Importantly, these areas of hemodynamic disturbance were observed together with lumen narrowing in a non-stenotic vessel segment. Our case observations highlight the importance of investigating the hemodynamic consequences of BVS implantation in bifurcation lesions and illustrate a novel method to do so in vivo. PMID- 25437886 TI - Endothelial progenitor cells induce transplant arteriosclerosis via VEGFR-1/2 activity. AB - BACKGROUND: Acute rejection (AR) after organ transplantation results in transplant arteriosclerosis (TA). Endothelial progenitor cells (EPCs) are involved in tissue repair and blood vessel formation but are suspected to be a cause of TA. METHODS: In this study, we introduced a syngeneic and allogeneic abdominal aortic transplant model with C57BL/6 and BALB/c mice. Syngeneic and allogeneic grafts were histopathologically analyzed after transplantation. Bone marrow-derived EPCs were injected into transplant model animals to observe their distribution and temporal concentration changes. Changes of vascular endothelial growth factor receptor 1 (VEGFR-1), phosphorylated VEGFR-1 (pVEGFR-1), VEGFR-2, pVEGFR-2, protein kinase B (Akt), pAkt, extracellular signal-regulated kinase 1 (Erk1), pErk1 levels in EPCs upon VEGF165 and the VEGFR inhibitor Vandetanib exposure were analyzed in vitro with western blotting. RESULTS: In the allogeneic transplant group, two weeks after transplantation, formations of new intima layers could be observed, and its proliferation gradually increased to four and six weeks post-transplantation (p < 0.05), accompanied by significant arterial stenoses. Exogenous EPCs mainly localized to the damaged sites of the transplant arteries. In vivo, Vandetanib caused a significant dose dependent decrease of transplant hyperplasia (p < 0.05) and inhibited VEGF related proliferation, migration and adhesion of EPCs. CONCLUSION: Vandetanib treatment can reduce arteriosclerosis induced by abdominal aorta transplantation by blocking VEGFRs in EPCs. PMID- 25437887 TI - Inflammation in childhood type 1 diabetes; influence of glycemic control. AB - OBJECTIVE: Patients with type 1 diabetes have increased mortality from cardiovascular disease, and inflammation is important in the development of atherosclerosis. Our aim was to evaluate the extent of inflammation and the influence of glycemic control in the early phases of atherosclerosis in childhood type 1 diabetes. MATERIALS AND METHODS: A population based cohort representative of all children with type 1 diabetes in Norway was studied. Diabetes patients (n = 314) were compared to healthy controls (n = 120), aged 8-18 years. Circulating levels of VCAM-1, ICAM-1, E-selectin, P-selectin, TNFalpha, IL-6, CRP, MCP-1, IL 18, MMP-9 and TIMP-1 were measured by immunoassays. RESULTS: The diabetes patients had a mean age of 13.7 (SD = 2.8) years, disease duration of 5.5 (SD = 3.4) years and HbA1c of 8.4 (SD = 1.2) % (68 mmol/mol, SD = 13.1). The levels of most of the measured markers were significantly increased in the diabetes group compared to controls. In the diabetes group, all except MCP-1 and MMP-9 were significantly correlated to HbA1c, albeit the relation to VCAM-1 was inverse. There were no significant correlations in the control group. The measured markers were only to a limited degree associated with traditional risk factors. CRP showed the most pronounced difference between diabetes patients and controls and the strongest correlation with HbA1c. The use of oral contraceptives profoundly increased CRP levels, independent of the presence of diabetes. CONCLUSIONS: Our results indicate that inflammation may play an important role in the accelerated atherosclerosis in early type 1 diabetes, and that this process seems primarily driven by hyperglycemia. PMID- 25437888 TI - A high quality diet is associated with reduced systemic inflammation in middle aged individuals. AB - OBJECTIVE: To examine if overall diet quality is associated with cellular and soluble biomarkers of systemic inflammation in middle-aged individuals. METHODS: A group of 667 individuals, aged 63-68 years, selected from the cardiovascular arm of the Malmo Diet and Cancer cohort, participated in this study. Baseline examinations consisted of an extensive socio-demographic questionnaire, anthropometric measurements, blood sampling and detailed dietary data. Mononuclear leukocytes frozen at baseline were thawed and analysed with flow cytometry to quantify monocyte subsets based on CD14 and CD16 expression. Plasma cytokines were measured using multiplexed immune assays. A diet quality index consisting of six components (saturated fatty acids, polyunsaturated fatty acids, fish and shellfish, dietary fibre, fruit and vegetables, and sucrose) was constructed to measure adherence to the Swedish Nutrition Recommendations/Dietary Guidelines. General linear models were used to investigate associations between index scores and several biomarkers of inflammation. RESULTS: A higher percentage of women reported adherence to the nutritional recommendations and had better overall diet quality than men. Participants with higher diet quality were more likely to have a healthier lifestyle. The levels of high-sensitive CRP, S100A8/A9, TNF-alpha, white blood cells, neutrophils, lymphocytes and CD14(+)CD16(++) were lower in participants with higher index scores. The associations remained significant after adjustment for potential confounders. CONCLUSION: In this cross-sectional study, we found that a high diet quality is associated with lower systemic inflammation. As the incidence of cardiovascular disease and cancer is directly correlated with the levels of inflammation, our findings might indicate a protective role of high-quality diet. PMID- 25437889 TI - Circulating retinol binding protein 4 is associated with coronary lesion severity of patients with coronary artery disease. AB - OBJECTIVES: This study was to examine the association between plasma retinol binding protein 4 (RBP4) levels and the complexity of angiographic coronary lesion in patients with coronary artery disease (CAD). METHODS AND RESULTS: A cross-sectional and prospective study was carried out in Guangzhou Chinese population. 672 persons were evaluated by medical history, clinical examination, coronary angiography, and fasting plasma samples, and were followed prospectively for 3 years. We measured the plasma RBP4 levels in 447 women (201 with stable CAD and 246 with acute coronary syndrome [ACS]). Coronary lesions were classified as having a simple or complex appearance based on the visual estimation of the coronary angiograms. Median plasma RBP4 levels were significantly higher in stable CAD patients with complex coronary lesions (n = 84) than in those with simple lesions (n = 117) (38.78[range 32.65-46.91] vs. 30.78 [range 24.48-36.08] MUg/ml, P < 0.001). Multiple logistic regression analysis demonstrated that higher RBP4 levels were independently associated with a 23% higher risk for complex lesions (odds ratio 1.228, 95% confidence interval [CI] 1.061 to 1.358; P = 0.031). Among the ACS patients, who had higher RBP4 levels than the stable CAD patients, those with multiple complex lesions had significantly higher median RBP4 levels than those with a single complex lesion (46.47 MUg/ml [range 37.68 53.29] vs. 38.15 MUg/ml [range 32.26-44.56], P < 0.001). Total plasma RBP4 levels were predictors of cardiac death (hazard ratio [HR]: 1.102; 95% CI: 1.086 to 1.191; P = 0.012) after adjustment for traditional risk factors for CAD. CONCLUSION: Plasma RBP4 levels are significantly associated with coronary lesion complexity in women with stable CAD and ACS and predict incident cardiovascular events. PMID- 25437890 TI - Progression of cardiovascular risk factors in black Africans: 3 year follow up of the SABPA cohort study. AB - Recent work identified a high prevalence of modifiable risk factors for cardiovascular disease (CVD) among urban black South Africans. The aim was to track the progression of CVD risk factors in a multi-ethnic sample of South Africans. Participants were 173 black (aged 47.5 +/- 7.8 yrs) and 186 white teachers (aged 49.6 +/- 9.9 yrs) that were examined at baseline and 3 years follow-up. Blacks demonstrated a substantially higher prevalence of composite CVD burden (defined as history of physician diagnosed heart disease, use of anti hypertensives, anti-diabetic, or statin medications at either time point) compared to whites (49.1 vs. 32.0%, p = 0.012) respectively. After controlling for baseline, the black participants demonstrated greater increases in 24 h systolic and diastolic blood pressure, total cholesterol, fasting glucose, fibrinogen, D-dimer, and waist circumference in comparison with whites. In summary, an adverse progression of CVD risk factors was observed in the whole sample, although to a larger degree in black participants. Aggressive treatment strategies for controlling risk factors in black Africans are needed to reduce the increasing burden of CVD in South Africa. PMID- 25437892 TI - Prevalence and clinical correlates of familial hypercholesterolemia founder mutations in the general population. AB - OBJECTIVE: This study aimed to investigate the exact prevalence of familial hypercholesterolemia (FH) in the general population, taking advantage of the fact that five low-density lipoprotein receptor (LDLR) founder mutations account for 78% of FH cases in Finland. METHODS: Five LDLR founder mutations, FH-North Karelia, FH-Helsinki, FH-Pogosta, FH-Turku, and FH-Pori, were genotyped and serum lipid levels were measured in a large collection of Finnish population cohorts (n = 28,465), including the National FINRISK Study and the Health 2000 Study. Follow up data were obtained from national healthcare registries. RESULTS: The combined prevalence of three of the five FH founder mutations (FH-North Karelia, FH Helsinki, and FH-Pogosta) was 0.12% (95% CI 0.07-0.16%), while FH-Turku and FH Pori were not identified in the present sample cohort. Our data suggest that the estimated total prevalence of FH in Finland is at least 0.17%. Approximately half of the 35 FH mutation carriers used lipid-lowering medication at the time of the baseline investigation. LDL cholesterol levels were on average 2 mmol/L higher in mutation carriers than in non-carriers (p < 0.001) but did not differ between FH mutation carriers with and without lipid-lowering medication. During the follow up for 13 years, one mutation carrier encountered a probable sudden cardiac death, two mutation carriers suffered from a stroke, and one from a myocardial infarction. CONCLUSIONS: In Finland, at least 1 in 600 individuals is estimated to have FH. A marked undertreatment of FH was observed in LDLR mutation carriers. PMID- 25437891 TI - Structural, mechanical and myogenic properties of small mesenteric arteries from ApoE KO mice: characterization and effects of virgin olive oil diets. AB - OBJECTIVE: We analyzed the structural, mechanical, myogenic and functional properties of resistance arteries of ApoE KO compared to wild type (WT) mice. We also determined the influence of saturated fat in comparison to virgin olive oil enriched diets in vascular wall abnormalities. METHODS: Male ApoE KO (ApoE) and WT mice (8-weeks-old) were assigned to the groups: standard chow diet (SD), high fat diet (HFD), virgin olive oil (VOO) and high polyphenol-VOO-enriched diet (Oleaster((r))) (OT) (15% w/w). After 20 weeks, structural, mechanical and myogenic properties of isolated small mesenteric arteries (SMA) were analyzed by pressure myography. For functional studies, vasodilatation to acetylcholine was assessed. Arterial superoxide anion production was measured by ethidium fluorescence. RESULTS: Hypertrophic remodeling and distensibility in ApoE KO SMA was lower compared to WT mice, suggesting an alteration in the autoregulation mechanisms aimed to compensate disease progression. However, ApoE deficiency resulted in a lower impairment in myogenic tone in response to intraluminal pressure, in addition to an improved endothelium-dependent hyperpolarizing vasodilatation. Also, we evidenced the beneficial effects of VOO in contrast to a saturated fat-enriched diet on SMA wall disorders. Only the endothelial function improvement induced by olive oil was dependent on polyphenols content. CONCLUSION: Resistance arteries structure, mechanic, myogenic and functional responses from ApoE KO mice significantly differ from WT mice, evidencing the influence of the type of diet on these disorders. These results are particularly useful to determine the contribution of resistance arteries during the atherosclerotic process and to provide novel insights into the Mediterranean dietary pattern to reduce the burden of atherosclerotic disease. PMID- 25437893 TI - Novel coronary heart disease risk factors at 60-64 years and life course socioeconomic position: the 1946 British birth cohort. AB - Social disadvantage across the life course is associated with a greater risk of coronary heart disease (CHD) and with established CHD risk factors, but less is known about whether novel CHD risk factors show the same patterns. The Medical Research Council National Survey of Health and Development was used to investigate associations between occupational socioeconomic position during childhood, early adulthood and middle age and markers of inflammation (C-reactive protein, interleukin-6), endothelial function (E-selectin, tissue-plasminogen activator), adipocyte function (leptin, adiponectin) and pancreatic beta cell function (proinsulin) measured at 60-64 years. Life course models representing sensitive periods, accumulation of risk and social mobility were compared with a saturated model to ascertain the nature of the relationship between social class across the life course and each of these novel CHD risk factors. For interleukin 6 and leptin, low childhood socioeconomic position alone was associated with high risk factor levels at 60-64 years, while for C-reactive protein and proinsulin, cumulative effects of low socioeconomic position in both childhood and early adulthood were associated with higher (adverse) risk factor levels at 60-64 years. No associations were observed between socioeconomic position at any life period with either endothelial marker or adiponectin. Associations for C-reactive protein, interleukin-6, leptin and proinsulin were reduced considerably by adjustment for body mass index and, to a lesser extent, cigarette smoking. In conclusion, socioeconomic position in early life is an important determinant of several novel CHD risk factors. Body mass index may be an important mediator of these relationships. PMID- 25437895 TI - Relationships of elevated levels of serum hepatic enzymes and alcohol intake with arterial stiffness in men. AB - OBJECTIVE: The present study aimed to evaluate the relationships between elevated serum levels of hepatic enzymes and arterial stiffness and to investigate whether alcohol intake had a modifying effect on these relationships in Japanese men. METHODS: A total of 647 eligible men aged 35-69 years who underwent measurement of brachial-ankle pulse wave velocity (baPWV) as an index of arterial stiffness were evaluated. Information on their lifestyle characteristics were obtained from a structured self-administered questionnaire. Serum biochemical factors, including alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), were determined. The serum ALT and GGT levels were divided into tertiles, and their associations with baPWV values were evaluated using general linear models adjusted for potential confounding factors. The interaction effects between serum hepatic enzymes and alcohol intake on baPWV were further evaluated. RESULTS: Elevated serum ALT and GGT levels were proportionally associated with increased baPWV after adjusting for the multivariable covariates (P values for trend, 0.004 and 0.003, respectively). Further analyses revealed that the proportional associations between serum levels of hepatic enzymes and baPWV were striking in the subjects without alcohol intake but not in those with alcohol intake. The interaction effect between serum GGT level and alcohol intake on baPWV was significant (P for interaction, 0.042). CONCLUSION: These results demonstrate that elevated serum ALT and GGT levels are associated with increased arterial stiffness, independent of the classical atherosclerotic risk factors in Japanese men, and that the association of elevated serum GGT level with arterial stiffness differs according to alcohol intake. PMID- 25437894 TI - Vitamin D status modifies the association between statin use and musculoskeletal pain: a population based study. AB - BACKGROUND: Past studies examining the effect of vitamin D on statin myalgia have been variable; however, these studies were done in limited samples not representative of the general population. We aimed to evaluate whether vitamin D status modifies the association between statin use and musculoskeletal pain in a sample representative of the general population. METHODS: We conducted a cross sectional study using the National Health and Nutrition Examination Survey 2001 2004. Musculoskeletal symptoms and statin use were self-reported. Vitamin D status was assessed using serum 25 hydroxyvitamin D (25[OH]D), categorized as <15 ng/mL or >=15 ng/mL. To evaluate if vitamin D status modifies the association between statin use and prevalent musculoskeletal pain, we performed multivariable adjusted logistic regression models stratified by 25(OH)D status. RESULTS: Among 5907 participants >=40 years old, mean serum 25(OH)D was 23.6 ng/mL (95% CI, 22.9 24.3). In stratified multivariable-adjusted logistic regression models, individuals with 25(OH)D <15 ng/mL, using a statin had a significantly higher odds of musculoskeletal pain compared to those not using a statin (adjusted odds ratio [aOR], 1.90; 95% CI, 1.18-3.05). Among those with 25(OH)D >=15 ng/mL, we found no significant association between statin use and musculoskeletal pain (aOR, 0.91; 95% CI, 0.71-1.16). CONCLUSION: Among adults >= 40 years old with 25(OH)D <15 ng/mL, statin users had nearly 2 times greater odds of reporting musculoskeletal pain compared to non-statin users. Our findings support the hypothesis that vitamin D deficiency modifies the risk of musculoskeletal symptoms experienced with statin use. PMID- 25437896 TI - Ecto-F1-ATPase/P2Y pathways in metabolic and vascular functions of high density lipoproteins. AB - The atheroprotective property of High Density Lipoprotein (HDL) is supported by many epidemiological studies and cellular and in vivo approaches on animal models. While the anti-atherogenic effects of HDL are thought to derive primarily from its role in reverse cholesterol transport, together with anti-inflammatory, anti-oxidant, anti-thrombotic and cytoprotective properties, the mechanisms that support these effects are still not completely understood. However, many advances in identifying the cellular partners involved in HDL functions have been made over the last two decades. This review highlights the diverse roles of the HDL receptor ecto-F1-ATPase coupled to purinergic P2Y receptors in the modulation of important metabolic and vascular functions of HDL. On hepatocytes, the ecto-F1 ATPase is coupled to P2Y13 receptor and contributes to HDL holoparticle endocytosis. On endothelial cells, ecto-F1-ATPase/P2Ys pathway is involved in HDL mediated endothelial protection and HDL transcytosis. The clinical relevance of this F1-ATPase/P2Ys axis in humans has recently been supported by the identification of serum F1-ATPase inhibitor (IF1) as an independent determinant of HDL-Cholesterol (HDL-C) and coronary heart disease risk. Therapeutic strategies targeting F1-ATPase/P2Y pathways for the treatment of atherosclerosis are currently being explored. PMID- 25437898 TI - Catalytic Oxidative Cyclization of 2'-Arylbenzaldehyde Oxime Ethers under Photoinduced Electron Transfer Conditions. AB - A series of 2'-arylbenzaldehyde oxime ethers were synthesized and shown to generate the corresponding phenanthridines upon irradiation in the presence of 9,10-dicyanoanthracene in acetonitrile. Mechanistic studies suggest that the oxidative cyclization reaction sequence is initiated by an electron transfer step followed by nucleophilic attack of the aryl ring onto the nitrogen of the oxime ether. A concave downward Hammett plot is presumably the result of a change in charge distribution in the radical cation species with strongly electron-donating substituents that yields a less electrophilic nitrogen atom and a decreased amount of cyclized product. The reaction is selective (no nitrile byproduct is formed unlike other photochemical reactions involving aldoxime ethers) as well as regiospecific when using 2'-aryl groups with meta-substituents, making this reaction a useful alternative for preparing substituted phenanthridines. PMID- 25437897 TI - Identification of key binding site residues of MCT1 for AR-C155858 reveals the molecular basis of its isoform selectivity. AB - The proton-linked monocarboxylate transporters (MCTs) are required for lactic acid transport into and out of all mammalian cells. Thus, they play an essential role in tumour cells that are usually highly glycolytic and are promising targets for anti-cancer drugs. AR-C155858 is a potent MCT1 inhibitor (Ki ~2 nM) that also inhibits MCT2 when associated with basigin but not MCT4. Previous work [Ovens, M.J. et al. (2010) Biochem. J. 425, 523-530] revealed that AR-C155858 binding to MCT1 occurs from the intracellular side and involves transmembrane helices (TMs) 7-10. In the present paper, we generate a molecular model of MCT4 based on our previous models of MCT1 and identify residues in the intracellular substrate binding cavity that differ significantly between MCT4 and MCT1/MCT2 and so might account for differences in inhibitor binding. We tested their involvement using site-directed mutagenesis (SDM) of MCT1 to change residues individually or in combination with their MCT4 equivalent and determined inhibitor sensitivity following expression in Xenopus oocytes. Phe360 and Ser364 were identified as important for AR-C155858 binding with the F360Y/S364G mutant exhibiting >100-fold reduction in inhibitor sensitivity. To refine the binding site further, we used molecular dynamics (MD) simulations and additional SDM. This approach implicated six more residues whose involvement was confirmed by both transport studies and [3H]-AR-C155858 binding to oocyte membranes. Taken together, our data imply that Asn147, Arg306 and Ser364 are important for directing AR-C155858 to its final binding site which involves interaction of the inhibitor with Lys38, Asp302 and Phe360 (residues that also play key roles in the translocation cycle) and also Leu274 and Ser278. PMID- 25437899 TI - Predicting the subcellular localization of mycobacterial proteins by incorporating the optimal tripeptides into the general form of pseudo amino acid composition. AB - Mycobacterium tuberculosis is a bacterium that causes tuberculosis, one of the most prevalent infectious diseases. Predicting the subcellular localization of mycobacterial proteins in this bacterium may provide vital clues for the prediction of protein function as well as for drug discovery and design. Therefore, a computational method that can predict the subcellular localization of mycobacterial proteins with high precision is highly desirable. We propose a computational method to predict the subcellular localization of mycobacterial proteins. An objective and strict benchmark dataset was constructed after collecting 272 non-redundant proteins from the universal protein resource (the UniProt database). Subsequently, a novel feature selection strategy based on binomial distribution was used to optimize the feature vector. Finally, a subset containing 219 chosen tripeptide features was imported into a support vector machine-based method to estimate the performance of the dataset in accurately and sensitively identifying these proteins. We found that the proposed method gave a maximum overall accuracy of 89.71% with an average accuracy of 81.12% in the jackknife cross-validation. The results indicate that our prediction method gave an efficient and powerful performance when compared with other published methods. We made the proposed method available on a purpose built Web server called MycoSub that is freely accessible at . We anticipate that MycoSub will become a useful tool for studying the functions of mycobacterial proteins and for designing and developing anti-mycobacterium drugs. PMID- 25437900 TI - Remote ester group leads to efficient kinetic resolution of racemic aliphatic alcohols via asymmetric hydrogenation. AB - A highly efficient method for kinetic resolution of racemic aliphatic alcohols without conversion of the hydroxyl group has been realized; the method involves hydrogenation mediated by a remote ester group and is catalyzed by a chiral iridium complex. This powerful, environmentally friendly method provides chiral delta-alkyl-delta-hydroxy esters and delta-alkyl-1,5-diols in good yields with high enantioselectivities even at extremely low catalyst loading (0.001 mol %). PMID- 25437901 TI - A 2014 update on the management of patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic, relapsing autoimmune connective tissue disease, primarily affecting the skin, joints, kidneys, heart, lungs, nervous system, blood elements, and serosal membranes. SLE is characterized by cytokine dysregulation, polyclonal B-cell activation, autoantibody production, and increased immune complex formation due to aberrations involving hyperactive B cells, T cells, and cells of the monocytic lineage. The symptoms of SLE are often diverse and nonspecific, and timely identification of SLE and associated comorbidities in patients is critical as aggressive monitoring and therapy may be warranted, especially in patients with poor prognoses. Based on the up-to-date understanding of the pathophysiology of SLE, the first targeted biological agent belimumab has been approved by the US Food and Drug Administration (FDA) in more than 50 years, and many targeted agents are being evaluated in late-stage clinical trials. There is a clear need to discuss how and when to incorporate new and emerging biological agents in managing patients with SLE. Additionally, the potential for increased risk of infections is a factor that heavily influences the rheumatologist's decision to use biological agents in managing patients with SLE. Hence, in this roundtable educational activity, expert faculty will review and discuss the strategies for timely diagnosis of SLE and associated comorbidities. They will also discuss the current understanding of the pathophysiology of SLE and how new and emerging biological agents help address the underlying pathophysiological aberrations in patients with SLE. The faculty will also review strategies to minimize the risk of infections and other toxicities in patients with SLE. PMID- 25437902 TI - Transient isotachophoresis focusing of DNA and DNA-protein complexes is essentially enhanced by spontaneously dissolved aerial carbon dioxide in electrolytes. AB - The formation of a highly adapted high-E zone is critical to isotachophoresis separation and focusing. Recently, we discovered that the high-E zone is present only in a small portion of electrophoresis channel in the presence of EOF (Liu, S. Q. et al. J. Am. Chem. Soc. 2013, 135, 4644-4647). Accordingly, a much narrower high-E zone is presumably present in t-ITP. If so, it is hard to achieve efficient t-ITP focusing. Indeed, by online coupling t-ITP with CE-LIF immunoassay, the immunocomplexes of carcinogenic BPDE-dG adducts are not efficiently focused using a freshly prepared background electrolyte. Intriguingly, we observed that 20-day stored background electrolyte displays a 10 fold better focusing efficiency. We hypothesize that the unexpected phenomenon is associated with the dissolution of aerial carbon dioxide, which is mainly converted to ionic HCO3(-) in the weak alkaline background electrolyte. Consequently, HCO3(-) of high electrophoretic mobility will be continuously injected into the capillary along with the background electrolyte and act as an alternative leading ion to improve the focusing. By addition of dry ice (without causing significant pH decrease, DeltapH < 0.4) to freshly prepared background electrolytes, we immediately observed the enhanced focusing of immunocomplexes of the DNA adducts. NH4HCO3 and Na2CO3, included in the background electrolyte, also improve the focusing efficiency and reproducibility. All these consistently support our hypothesis. To understand the underlying mechanism, an advanced CE SMFI was exploited to monitor in real time the motion of single DNA molecules and the E change throughout t-ITP. We uncovered that t-ITP can induce a local high-E zone, but the presence of HCO3(-) in the background electrolyte could greatly increase the E value in the high-E zone, which allows more DNA molecules to rapidly move backward and to be efficiently stacked at LE/TE boundary. This study provides new insight into nonuniform electric field-induced electrophoresis focusing. PMID- 25437903 TI - Normal cranial postmortem CT findings in children. AB - INTRODUCTION: Postmortem imaging (both CT and MRI) has become a widely used tool the last few years, both for adults and children. If it would be known which findings are normal postmortem changes, interpretation of abnormal findings becomes less ambiguous. Our aim was to describe postmortem intracranial radiological findings on postmortem CT (PMCT) in children, which did not have a relationship with the cause of death, and to determine whether these findings have a relationship with the postmortem interval or with medical interventions. MATERIALS AND METHODS: We selected all consecutive pediatric autopsies that were performed at the Netherlands Forensic Institute in the period 1-1-2008 to 31-12 2011, whereby the subject underwent total body PMCT. We collected data on age at death, gender, cause of death determined by forensic autopsy and time between death and PMCT. Normal findings that were scored were: gray-white differentiation of the brain, collapse of the ventricles, air in the orbit, fluid accumulation in the frontal and maxillary sinuses, and air in vessels of head and neck. RESULTS: One-hundred-fifty-nine forensic pediatric autopsies were performed in the 4 year study period at the NFI; 77 underwent a total body PMCT, of which 68 were included in the analyses. Fluid accumulation in the sinuses was present 30-40% of the cases in which the sinuses were developed. In 22% of all children intravascular intracranial air, either arterial or venous, was detected. We did not find a relationship between the duration of the postmortem interval and the appearance of any of the findings. Intravenous infusion is not significantly associated with the presence of intravascular air, except for air in the left and right common carotid artery (B=2.9, P=0.05). CONCLUSIONS: By demonstrating the intracranial abnormalities that appear postmortem, we have tried to provide more insight in the range of findings that can be seen with pediatric PMCT. As these findings resemble antemortem pathology, it is important that the radiologist who interprets PMCT has knowledge of these normal postmortem findings. PMID- 25437904 TI - Morphological details in bloodstain particles. AB - During the commission of crimes blood can be transferred to the clothing of the offender or on other crime related objects. Bloodstain particles are sub millimetre sized flakes that are lost from dried bloodstains. The nature of these red particles is easily confirmed using spectroscopic methods. In casework, bloodstain particles showing highly detailed morphological features were observed. These provided a rationale for a series of experiments described in this work. It was found that the "largest" particles are shed from blood deposited on polyester and polyamide woven fabrics. No particles are lost from the stains made on absorbent fabrics and from those made on knitted fabrics. The morphological features observed in bloodstain particles can provide important information on the substrates from which they were lost. PMID- 25437905 TI - A systematic review of public health-aligned recommendations for preparing physical education teacher candidates. AB - PURPOSE: Since Sallis and McKenzie's seminal article in 1991 outlining physical education's role in public health, increased attention has been given to promoting youth physical activity in schools. The present study systematically reviewed the literature from 1991 to 2013 to identify recommendations for the preparation of physical education teacher candidates (PETCs) from a public health perspective. METHOD: Eight online databases (e.g., Educational Resources Information Center, Google Scholar) served as data sources for the study. Multiple combinations of key terms (e.g., physical education teacher education [PETE], public health, health-oriented) were used to identify relevant literature meeting search criteria. A content analysis was used to identify 47 distinct recommendations from 25 included articles and to synthesize these recommendations into major areas of focus. RESULTS: Three major areas of focus were identified: (a) candidate profile (e.g., PETCs should be physically active and fit role models), (b) candidate knowledge (e.g., PETCs should know about behavior change theories), and (c) candidate skills (e.g., PETCs should be able to advocate for school-based physical activity). CONCLUSION: This review can serve as a blueprint for PETE programs seeking to align professional preparation with public health goals. PMID- 25437906 TI - Eye shape using partial coherence interferometry, autorefraction, and SD-OCT. AB - PURPOSE: Peripheral refraction and retinal shape may influence refractive development. Peripheral refraction has been shown to have a high degree of variability and can take considerable time to perform. Spectral domain optical coherence tomography (SD-OCT) and peripheral axial length measures may be more reliable, assuming that the retinal position is more important than the peripheral optics of the lens/cornea. METHODS: Seventy-nine subjects' right eyes were imaged for this study (age range, 22 to 34 years; refractive error, -10 to +5.00). Thirty-degree SD-OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany) images were collected in a radial pattern along with peripheral refraction with an autorefractor (Shin-Nippon Autorefractor) and peripheral axial length measurements with partial coherence interferometry (IOLMaster, Zeiss). Statistics were performed using repeated-measures analysis of variance in SPSS (IBM, Armonk, NY), Bland-Altman analyses, and regression. All measures were converted to diopters to allow direct comparison. RESULTS: Spectral domain OCT showed a retinal shape with an increased curvature for myopes compared with emmetropes/hyperopes. This retinal shape change became significant around 5 degrees. The SD-OCT analysis for retinal shape provides a resolution of 0.026 diopters, which is about 10 times more accurate than using autorefraction (AR) or clinical refractive techniques. Bland-Altman analyses suggest that retinal shape measured by SD-OCT and the partial coherence interferometry method were more consistent with one another than either was with AR. CONCLUSIONS: With more accurate measures of retinal shape using SD-OCT, consistent differences between emmetropes/hyperopes and myopes were found nearer to the fovea than previously reported. Retinal shape may be influenced by central refractive error, and not merely peripheral optics. Partial coherence interferometry and SD-OCT appear to be more accurate than AR, which may be influenced by other factors such as fixation and accommodation. Autorefraction does measure the optics directly, which may be a strength of that method. PMID- 25437907 TI - Head position and intraocular pressure in the lateral decubitus position. AB - PURPOSE: To investigate the effects of different head positions in the lateral decubitus posture on intraocular pressure (IOP). METHODS: Seventeen healthy Korean subjects were included in this prospective observational study. Intraocular pressure measurements were taken with the subjects in the sitting position and the recumbent positions including supine, right lateral decubitus, and left lateral decubitus positions. In right and left lateral decubitus positions, IOP measurements were taken with three different head positions (30 degrees higher, 30 degrees lower, and parallel to the center of the thoracic vertebra) in a randomized sequence. Intraocular pressure was measured using the ICare Pro tonometer in both eyes 5 minutes after assuming each posture. The eye on the lower side in the lateral decubitus position was termed as the dependent eye. We assessed differences in the IOP of the dependent and nondependent eyes in the lateral decubitus positions with different head positions. RESULTS: Regardless of the head position, the dependent eyes showed higher IOP than the nondependent eyes in the lateral decubitus positions except in the left lateral decubitus with high head position (p < 0.001 for all positions except left lateral decubitus, p = 0.083). Low head position significantly increased the IOP of dependent eyes, compared with the neutral or high head positions in lateral decubitus posture. CONCLUSIONS: Low head position elevates the IOP of the dependent eyes compared with neutral head position in the lateral decubitus posture. Proper adjustment of the height of a pillow may help mitigate IOP elevations resulting from lying on the side with a low pillow or with no pillow. PMID- 25437908 TI - Letter to the editor: Reliability of muscle blood flow measurements in orbicularis oculi. PMID- 25437909 TI - Authors' response. PMID- 25437910 TI - Variability of ethics education in laboratory medicine training programs: results of an international survey. AB - BACKGROUND: Ethical considerations are increasingly important in medicine. We aimed to determine the mode and extent of teaching of ethics in training programs in clinical chemistry and laboratory medicine. METHODS: We developed an on-line survey of teaching in areas of ethics relevant to laboratory medicine. Reponses were invited from directors of training programs who were recruited via email to leaders of national organizations. RESULTS: The survey was completed by 80 directors from 24 countries who directed 113 programs. The largest numbers of respondents directed postdoctoral training of scientists (42%) or physicians (33%), post-masters degree programs (33%), and PhD programs (29%). Most programs (82%) were 2years or longer in duration. Formal training was offered in research ethics by 39%, medical ethics by 31%, professional ethics by 24% and business ethics by 9%. The number of reported hours of formal training varied widely, e.g., from 0 to >15h/year for research ethics and from 0 to >15h for medical ethics. Ethics training was required and/or tested in 75% of programs that offered training. A majority (54%) of respondents reported plans to add or enhance training in ethics; many indicated a desire for online resources related to ethics, especially resources with self-assessment tools. CONCLUSION: Formal teaching of ethics is absent from many training programs in clinical chemistry and laboratory medicine, with heterogeneity in the extent and methods of ethics training among the programs that provide the training. A perceived need exists for online training tools, especially tools with self-assessment components. PMID- 25437911 TI - Postural change during venous blood collection is a major source of bias in clinical chemistry testing. AB - BACKGROUND: To investigate the influence of different phlebotomy postures on clinical chemistry testing. MATERIALS AND METHODS: Nineteen volunteers were recruited from the laboratory staff. A first set of samples was drawn after 25 min of resting in supine position, a second after 20 min in sitting position, and a third after 20 min in upright position. Clinical chemistry testing was performed on Roche Cobas C501. RESULTS: The plasma volume change (PVC) was -3.4% from supine to sitting, -14.1% from supine to standing and -9.7% from sitting to standing. Compared to quality specifications for bias, hemoglobin, hematocrit, albumin and total proteins exhibited meaningful increases from supine to sitting, whereas meaningful increases were observed for hemoglobin, hematocrit, albumin, alkaline phosphatase (ALP), amylase, aspartate aminotransferase (AST), total bilirubin, calcium, total and high-density lipoprotein (HDL) cholesterol, gamma glutamyl transferase (GGT), glucose, lactate dehydrogenase (LDH), magnesium, total protein and triglycerides from sitting to standing. The parameters with meaningful bias from sitting to upright were hemoglobin, hematocrit, albumin, ALP, total bilirubin, calcium, total and HDL cholesterol, glucose, LDH and total protein. CONCLUSIONS: These results provide further support to the need of standardizing patient's posture during phlebotomy. PMID- 25437913 TI - Crystal structure of a BRAF kinase domain monomer explains basis for allosteric regulation. AB - Reported RAF kinase domain structures adopt a side-to-side dimer configuration reflective of an 'on' state that underpins an allosteric mechanism of regulation. Atomic details of the monomer 'off' state have been elusive. Reinspection of the BRAF kinase domain structures revealed that sulfonamide inhibitors induce features of an off state, primarily a laterally displaced helix alphaC stabilized by the activation segment helix 1 (AS-H1). These features correlated with the ability of sulfonamides to disrupt human BRAF homodimers in cells, in vitro and in crystals yielding a structure of BRAF in a monomer state. The crystal structure revealed exaggerated, nonproductive positions of helix alphaC and AS H1, the latter of which is the target of potent BRAF oncogenic mutations. Together, this work provides formal proof of an allosteric link between the RAF dimer interface, the activation segment and the catalytic infrastructure. PMID- 25437912 TI - Structure of myosin-1c tail bound to calmodulin provides insights into calcium mediated conformational coupling. AB - Class I myosins can sense cellular mechanical forces and function as tension sensitive anchors or transporters. How mechanical load is transduced from the membrane-binding tail to the force-generating head in myosin-1 is unknown. Here we determined the crystal structure of the entire tail of mouse myosin-1c in complex with apocalmodulin, showing that myosin-1c adopts a stable monomer conformation suited for force transduction. The lever-arm helix and the C terminal extended PH domain of the motor are coupled by a stable post-IQ domain bound to calmodulin in a highly unusual mode. Ca(2+) binding to calmodulin induces major conformational changes in both IQ motifs and the post-IQ domain and increases flexibility of the myosin-1c tail. Our study provides a structural blueprint for the neck and tail domains of myosin-1 and expands the target binding modes of the master Ca(2+)-signal regulator calmodulin. PMID- 25437914 TI - Jatrophanes from Euphorbia squamosa as potent inhibitors of Candida albicans multidrug transporters. AB - A series of structurally related jatrophane diterpenoids (1-6), including the new euphosquamosins A-C (4-6), was purified from the Iranian spurge Euphorbia squamosa and evaluated for its capacity to inhibit drug efflux by multidrug transporters of Candida albicans. Three of these compounds showed an interesting profile of activity. In particular, deacetylserrulatin B (2) and euphosquamosin C (6) strongly inhibited the drug-efflux activity of the primary ABC-transporter CaCdr1p, an effect that translated, in a yeast strain overexpressing this transporter, into an increased sensitivity to fluconazole. These compounds were transported by CaCdr1p, as shown by the observation of an 11-14-fold cross resistance of yeast growth, and could also inhibit the secondary MFS-transporter CaMdr1p. In contrast, euphosquamosin A (4) was selective for CaCdr1p, possibly as a result of a different binding mode. Taken together, these observations suggest jatrophane diterpenes to be a new class of potent inhibitors of multidrug transporters critical for drug resistance in pathogenic yeasts. PMID- 25437918 TI - High-performance lithium-ion battery and symmetric supercapacitors based on FeCo2O4 nanoflakes electrodes. AB - A successive preparation of FeCo2O4 nanoflakes arrays on nickel foam substrates is achieved by a simple hydrothermal synthesis method. After 170 cycles, a high capacity of 905 mAh g(-1) at 200 mA g(-1) current density and very good rate capabilities are obtained for lithium-ion battery because of the 2D porous structures of the nanoflakes arrays. The distinctive structural features provide the battery with excellent electrochemical performance. The symmetric supercapacitor on nonaqueous electrolyte demonstrates high specific capacitance of 433 F g(-1) at 0.1 A g(-1) and 16.7 F g(-1) at high scan rate of 5 V s(-1) and excellent cyclic performance of 2500 cycles of charge-discharge cycling at 2 A g( 1) current density, revealing excellent long-term cyclability of the electrode even under rapid charge-discharge conditions. PMID- 25437917 TI - Krempfielins Q and R, two new eunicellin-based diterpenoids from the soft coral Cladiella krempfi. AB - Two new eunicellin-based diterpenoids, krempfielins Q and R (1 and 2), and one known compound cladieunicellin K (3) have been isolated from a Formosan soft coral Cladiella krempfi. The structures of these two new metabolites were elucidated by extensive spectroscopic analysis. Anti-inflammatory activity of new metabolites to inhibit the superoxide anion generation and elastase release in N formyl-methionyl-leucyl phenylalanine/cytochalasin B (FMLP/CB)-induced human neutrophil cells and cytotoxicity of both new compounds toward five cancer cell lines were reported. PMID- 25437915 TI - Screening nylon-3 polymers, a new class of cationic amphiphiles, for siRNA delivery. AB - Amphiphilic nucleic acid carriers have attracted strong interest. Three groups of nylon-3 copolymers (poly-beta-peptides) possessing different cationic/hydrophobic content were evaluated as siRNA delivery agents in this study. Their ability to condense siRNA was determined in SYBR Gold assays. Their cytotoxicity was tested by MTT assays, their efficiency of delivering Alexa Fluor-488-labeled siRNA intracellularly in the presence and absence of uptake inhibitors was assessed by flow cytometry, and their transfection efficacies were studied by luciferase knockdown in a cell line stably expressing luciferase (H1299/Luc). Endosomal release was determined by confocal laser scanning microscopy and colocalization with lysotracker. All polymers efficiently condensed siRNA at nitrogen-to phosphate (N/P) ratios of 5 or lower, as reflected in hydrodynamic diameters smaller than that at N/P 1. Although several formulations had negative zeta potentials at N/P 1, G2C and G2D polyplexes yielded >80% uptake in H1299/Luc cells, as determined by flow cytometry. Luciferase knockdown (20-65%) was observed after transfection with polyplexes made of the high molecular weight polymers that were the most hydrophobic. The ability of nylon-3 polymers to deliver siRNA intracellularly even at negative zeta potential implies that they mediate transport across cell membranes based on their amphiphilicity. The cellular uptake route was determined to strongly depend on the presence of cholesterol in the cell membrane. These polymers are, therefore, very promising for siRNA delivery at reduced surface charge and toxicity. Our study identified nylon-3 formulations at low N/P ratios for effective gene knockdown, indicating that nylon-3 polymers are a new, promising type of gene delivery agent. PMID- 25437916 TI - Pluripotent state induction in mouse embryonic fibroblast using mRNAs of reprogramming factors. AB - Reprogramming of somatic cells has great potential to provide therapeutic treatments for a number of diseases as well as provide insight into mechanisms underlying early embryonic development. Improvement of induced Pluripotent Stem Cells (iPSCs) generation through mRNA-based methods is currently an area of intense research. This approach provides a number of advantages over previously used methods such as DNA integration and insertional mutagenesis. Using transfection of specifically synthesized mRNAs of various pluripotency factors, we generated iPSCs from mouse embryonic fibroblast (MEF) cells. The genetic, epigenetic and functional properties of the iPSCs were evaluated at different times during the reprogramming process. We successfully introduced synthesized mRNAs, which localized correctly inside the cells and exhibited efficient and stable translation into proteins. Our work demonstrated a robust up-regulation and a gradual promoter de-methylation of the pluripotency markers, including non transfected factors such as Nanog, SSEA-1 (stage-specific embryonic antigen 1) and Rex-1 (ZFP-42, zinc finger protein 42). Using embryonic stem cells (ESCs) conditions to culture the iPS cells resulted in formation of ES-like colonies after approximately 12 days with only five daily repeated transfections. The colonies were positive for alkaline phosphatase and pluripotency-specific markers associated with ESCs. This study revealed the ability of pluripotency induction and generation of mouse mRNA induced pluripotent stem cells (mRNA iPSCs) using transfection of specifically synthesized mRNAs of various pluripotency factors into mouse embryonic fibroblast (MEF) cells. These generated iPSCs exhibited molecular and functional properties similar to ESCs, which indicate that this method is an efficient and viable alternative to ESCs and can be used for further biological, developmental and therapeutic investigations. PMID- 25437919 TI - Glycomic analysis of membrane glycoproteins with bisecting glycosylation from ovarian cancer tissues reveals novel structures and functions. AB - Biomarkers capable of detecting and targeting epithelial ovarian cancer cells for diagnostics and therapeutics would be extremely valuable. Ovarian cancer is the deadliest reproductive malignancy among women in the U.S., killing over 14 000 women each year. Both the lack of presenting symptoms and high mortality rates illustrate the need for earlier diagnosis and improved treatment of this disease. The glycosyltransferase enzyme GnT-III encoded by the Mgat3 gene is responsible for the addition of GlcNAc (N-acetylglucosamine) to form bisecting N-linked glycan structures. GnT-III mRNA expression is amplified in ovarian cancer tissues compared with normal ovarian tissue. We use a lectin capture strategy coupled to nano-ESI-RPLC-MS/MS to isolate and identify the membrane glycoproteins and unique glycan structures associated with GnT-III amplification in human ovarian cancer tissues. Our data illustrate that the majority of membrane glycoproteins with bisecting glycosylation are common to both serous and endometrioid histological subtypes of ovarian cancer, and several have been reported to participate in signaling pathways such as Notch, Wnt, and TGFbeta. PMID- 25437920 TI - Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts. AB - Taurine is a beta-amino acid found in very high concentration in the heart. Depletion of these intracellular stores results in the development of cardiomyopathy, thought to be mediated by abnormal sarcoplasmic reticular (SR) Ca(2+) transport. There is also evidence that taurine directly alters the Ca(2+) sensitivity of myofibrillar proteins. Major regulators of SR Ca(2+) ATPase (SERCA2a) are the phosphorylation status of a regulatory protein, phospholamban, and SERCA2a expression, which are diminished in the failing heart. The failing heart also exhibits reductions in myofibrillar Ca(2+) sensitivity, a property regulated by the phosphorylation of the muscle protein, troponin I. Therefore, we tested the hypothesis that taurine deficiency leads to alterations in SR Ca(2+) ATPase activity related to reduced phospholamban phosphorylation and expression of SERCA2a. We found that a sequence of events, which included elevated protein phosphatase 1 activity, reduced autophosphorylation of CaMKII, and reduced phospholamban phosphorylation, supports the reduction in SR Ca(2+) ATPase activity. However, the reduction in SR Ca(2+) ATPase activity was not caused by reduced SERCA2a expression. Taurine transporter knockout (TauTKO) hearts also exhibited a rightward shift in the Ca(2+) dependence of the myofibrillar Ca(2+) ATPase, a property that is associated with an elevation in phosphorylated troponin I. The findings support the observation that taurine deficient hearts develop systolic and diastolic defects related to reduced SR Ca(2+) ATPase activity, a change mediated in part by reduced phospholamban phosphorylation. PMID- 25437921 TI - TASK-1 current is inhibited by phosphorylation during human and canine chronic atrial fibrillation. AB - Atrial fibrillation (AF) is a common arrhythmia with significant morbidities and only partially adequate therapeutic options. AF is associated with atrial remodeling processes, including changes in the expression and function of ion channels and signaling pathways. TWIK protein-related acid-sensitive K+ channel (TASK)-1, a two-pore domain K+ channel, has been shown to contribute to action potential repolarization as well as to the maintenance of resting membrane potential in isolated myocytes, and TASK-1 inhibition has been associated with the induction of perioperative AF. However, the role of TASK-1 in chronic AF is unknown. The present study investigated the function, expression, and phosphorylation of TASK-1 in chronic AF in atrial tissue from chronically paced canines and in human subjects. TASK-1 current was present in atrial myocytes isolated from human and canine hearts in normal sinus rhythm but was absent in myocytes from humans with AF and in canines after the induction of AF by chronic tachypacing. The addition of phosphatase to the patch pipette rescued TASK-1 current from myocytes isolated from AF hearts, indicating that the change in current is phosphorylation dependent. Western blot analysis showed that total TASK-1 protein levels either did not change or increased slightly in AF, despite the absence of current. In studies of perioperative AF, we have shown that phosphorylation of TASK-1 at Thr383 inhibits the channel. However, phosphorylation at this site was unchanged in atrial tissue from humans with AF or in canines with chronic pacing-induced AF. We conclude that phosphorylation dependent inhibition of TASK-1 is associated with AF, but the phosphorylation site responsible for this inhibition remains to be identified. PMID- 25437923 TI - Thermodynamic investigations of [(phen)2Ru(tatpp)Ru(phen)2](4+) interactions with B-DNA. AB - While the antitumor activity of P(4+) is relatively well understood, the binding mechanism and thermodynamics for formation of (P(4+).DNA) complexes remain in question. The thermodynamic parameters (Ka, DeltaG, DeltaH, and -TDeltaS) for formation of DNA complexes of the ruthenium dimer, [(phen)2Ru(tatpp)Ru(phen)2](4+) (abbreviated as P(4+)), where phen is 1,10 phenanthroline and tatpp is 9,11,20,22-tetraazatetrapyrido[3,2-a:2',3'-c:3",2" 1:2''',3'''-n]-pentacene, were determined using isothermal titration calorimetry. Calorimetric and spectroscopic titration experiments were performed in which P(4+) was added to three duplex DNAs of different lengths. We determined that P(4+) binds to duplex DNA at 298 K with modest affinity (Ka ~ 3.8 * 10(5) M(-1), DeltaG ~ -7.6 kcal/mol), that the enthalpy change is unfavorable (DeltaH ~ +2.1 kcal/mol), and that complex formation is driven by a large favorable change in entropy (-TDeltaS ~ -9.7 kcal/mol). These thermodynamic values were found to be approximately independent of the length of the DNA, and the stoichiometry of the (P(4+).DNA) complexes was determined to be 1 P(4+)/2 DNA bp, at least for the two shorter DNAs. On the basis of the thermodynamic parameters, and the binding stoichiometry (verified in ESI-MS experiments), we conclude that P(4+) is intercalating between two adjacent DNA base pairs and that the neighbor sites on either side of the bound ligand are excluded from binding additional P(4+). PMID- 25437925 TI - Viewpoint: closing the exposure gap. PMID- 25437922 TI - Mending a broken heart: the role of mitophagy in cardioprotection. AB - The heart is highly energy dependent with most of its energy provided by mitochondrial oxidative phosphorylation. Mitochondria also play a role in many other essential cellular processes including metabolite synthesis and calcium storage. Therefore, maintaining a functional population of mitochondria is critical for cardiac function. Efficient degradation and replacement of dysfunctional mitochondria ensures cell survival, particularly in terminally differentiated cells such as cardiac myocytes. Mitochondria are eliminated via mitochondrial autophagy or mitophagy. In the heart, mitophagy is an essential housekeeping process and required for cardiac homeostasis. Reduced autophagy and accumulation of impaired mitochondria have been linked to progression of heart failure and aging. In this review, we discuss the pathways that regulate mitophagy in cells and highlight the cardioprotective role of mitophagy in response to stress and aging. We also discuss the therapeutic potential of targeting mitophagy and directions for future investigation. PMID- 25437924 TI - Understanding the role of manganese dioxide in the oxidation of phenolic compounds by aqueous permanganate. AB - Recent studies have shown that manganese dioxide (MnO2) can significantly accelerate the oxidation kinetics of phenolic compounds such as triclosan and chlorophenols by potassium permanganate (Mn(VII)) in slightly acidic solutions. However, the role of MnO2 (i.e., as an oxidant vs catalyst) is still unclear. In this work, it was demonstrated that Mn(VII) oxidized triclosan (i.e., trichloro-2 phenoxyphenol) and its analogue 2-phenoxyphenol, mainly generating ether bond cleavage products (i.e., 2,4-dichlorophenol and phenol, respectively), while MnO2 reacted with them producing appreciable dimers as well as hydroxylated and quinone-like products. Using these two phenoxyphenols as mechanistic probes, it was interestingly found that MnO2 formed in situ or prepared ex situ greatly accelerated the kinetics but negligibly affected the pathways of their oxidation by Mn(VII) at acidic pH 5. The yields (R) of indicative products 2,4 dichlorophenol and phenol from their respective probes (i.e., molar ratios of product formed to probe lost) under various experimental conditions were quantified. Comparable R values were obtained during the treatment by Mn(VII) in the absence vs presence of MnO2. Meanwhile, it was confirmed that MnO2 could accelerate the kinetics of Mn(VII) oxidation of refractory nitrophenols (i.e., 2 nitrophenol and 4-nitrophenol), which otherwise showed negligible reactivity toward Mn(VII) and MnO2 individually, and the effect of MnO2 was strongly dependent upon its concentration as well as solution pH. These results clearly rule out the role of MnO2 as a mild co-oxidant and suggest a potential catalytic effect on Mn(VII) oxidation of phenolic compounds regardless of their susceptibility to oxidation by MnO2. PMID- 25437926 TI - Propofol (Diprivan(r)) and Intralipid(r) exacerbate insulin resistance in type-2 diabetic hearts by impairing GLUT4 trafficking. AB - BACKGROUND: The IV anesthetic, propofol, when administered as fat emulsion-based formulation (Diprivan) promotes insulin resistance, but the direct effects of propofol and its solvent, Intralipid, on cardiac insulin resistance are unknown. METHODS: Hearts of healthy and type-2 diabetic rats (generated by fructose feeding) were aerobically perfused for 60 minutes with 10 MUM propofol in the formulation of Diprivan or an equivalent concentration of its solvent Intralipid (25 MUM) +/- insulin (100 mU*L). Glucose uptake, glycolysis, and glycogen metabolism were measured using [H]glucose. Activation of Akt, GSK3beta, AMPK, ERK1/2, p38MAPK, S6K1, JNK, protein kinase Ctheta (PKCtheta), and protein kinase CCbetaII (PKCbetaII) was determined using immunoblotting. GLUT4 trafficking and phosphorylations of insulin receptor substrate-1 (IRS-1) at Ser307(h312), Ser1100(h1101), and Tyr608(hTyr612) were measured. Mass spectrometry was used to determine acylcarnitines, phospholipids, and sphingolipids. RESULTS: Diprivan and Intralipid reduced insulin-induced glucose uptake and redirected glucose to glycogen stores in diabetic hearts. Reduced glucose uptake was accompanied by lower GLUT4 trafficking to the sarcolemma. Diprivan and Intralipid inactivated GSK3beta but activated AMPK and ERK1/2 in diabetic hearts. Only Diprivan increased phosphorylation of Akt(Ser473/Thr308) and translocated PKCtheta and PKCbetaII to the sarcolemma in healthy hearts, whereas it activated S6K1 and p38MAPK and translocated PKCbetaII in diabetic hearts. Furthermore, only Diprivan phosphorylated IRS-1 at Ser1100(h1101) in healthy and diabetic hearts. JNK expression, phosphorylation of Ser307(h312) of IRS-1, and PKCtheta expression and translocation were increased, whereas GLUT4 expression was reduced in insulin treated diabetic hearts. Phosphatidylglycerol, phosphatidylethanolamine, and C18 sphingolipids accumulated in Diprivan-perfused and Intralipid-perfused diabetic hearts. CONCLUSIONS: Propofol and Intralipid promote insulin resistance predominantly in type-2 diabetic hearts. PMID- 25437928 TI - Treatment characteristics and outcome of depression among depressed adolescent outpatients with and without comorbid Axis II disorders. AB - In the literature, disagreement exists on the impact of Axis II comorbidity on the treatment outcome of depression. The aim of the present study was to examine in a naturalistic treatment setting the 1-year outcome and treatment characteristics of depressed adolescent outpatients with and without comorbid Axis II disorders. The 151 participants were interviewed for Axis I and II diagnoses at baseline and follow-up. Those diagnosed with a personality disorder were significantly more impaired at follow-up than those without. The given treatment did not differ between the two groups in length, intensity, or hospitalization, but the group with Axis II comorbidity received more psychotropic medication. The treatment outcome of depression was poorer for the group with Axis II disorders compared to those without. In conclusion, a personality disorder diagnosis is a sign of more severe overall symptoms. Special attention should be paid to Axis II traits when planning and conducting the treatment of adolescent depression. PMID- 25437927 TI - Alginate electrodeposition onto three-dimensional porous Co-Ni films as drug delivery platforms. AB - Three-dimensional porous Co-Ni films/alginate hybrid materials have been successfully prepared by electrodeposition to be used as a steerable magnetic device for drug delivery. Firstly, 3D porous Co-Ni films were prepared as substrates for the subsequent electrodeposition of the alginate biopolymer. Cyclic voltammetry, galvanostatic and potentiostatic studies were performed to establish the best conditions to obtain porous Co-Ni films. The electrochemical experiments were carried out in an electrolyte containing the metal salts and ammonium chloride at low pHs. In a second stage, the electrochemical deposition of alginate as a biocompatible polymer drug delivery carrier was performed. The characteristics of the alginate matrix were investigated in terms of electrochemical properties, morphology and drug release. The hybrid material obtained showed soft-magnetic behavior and drug release indicating its suitability to be used as a steerable magnetic drug delivery device. PMID- 25437929 TI - Overt versus covert conduct disorder symptoms and the prospective prediction of antisocial personality disorder. AB - Studies have shown strong continuity between conduct disorder (CD) in adolescence and antisocial personality disorder (APD) in adulthood. Researchers have been trying to explain why some adolescents with CD persist into adult APD and others do not. A few studies reported that overt and covert CD symptoms have a differential predictive power for APD, with mixed results. The present study aimed to evaluate the prospective association of overt and covert CD symptoms with APD in a sample of male adolescents with CD (N = 128, mean age = 15.6, SD = 1.6). Participants were recruited at intake in Quebec Youth Centers and reassessed 3 years later (n = 73). CD and ADHD symptoms were assessed at intake with the DISC-R while APD was assessed 3 years later with the SCID-II. Logistic regression results showed that, contrary to previous prospective studies (Lahey, Loeber, Burke, & Applegate, 2005; Washburn et al., 2007), overt (OR = 2.12, 95% CI [1.29, 3.50]) but not covert (OR = 1.04, 95% CI [0.69, 1.56]) symptoms predicted later APD, controlling for ADHD symptoms and socioeconomic status. It is hypothesized that the divergence with previous studies may be explained by the higher mean number and wider range of overt CD symptoms in our sample. PMID- 25437930 TI - CYP2D6 polymorphism and mental and personality disorders in suicide attempters. AB - Prior studies on the association between the CYP2D6 polymorphism and suicide did not explore whether mental and personality disorders mediate this association. The main objective of the present study was to test an association between CYP2D6 polymorphism and mental and personality disorders among suicide attempters. The MINI and the DSM-IV version of the International Personality Disorder Examination Screening Questionnaire were used to diagnose mental and personality disorders, respectively, in 342 suicide attempters. Suicide attempters were divided into four groups according to their number of CYP2D6 active genes (zero, one, and two or more). Differences in mental and personality disorders across the four groups were measured using linear-by-linear association, chi square-test, and 95% confidence intervals. Suicide attempters carrying two or more active CYP2D6 genes were more likely to be diagnosed with at least one personality disorder than those with one or zero CYP2D6 active genes. PMID- 25437933 TI - Tetragold(I) complexes: solution isomerization and tunable solid-state luminescence. AB - In this study, a new family of tetranuclear gold(I) triphosphine derivatives bearing alkynyl and thiolate groups have been efficiently synthesized by treating the polymeric acetylides (AuC2R)n or a thiolate (AuSPh)n sequentially with the (a) phosphine ligand and (b) cationic complex [Au3(P^P^P)2](3+) (P^P^P = PPh2CH2PPhCH2PPh2). The clusters [Au4(P^P^P)2(C2R)2](2+) [R = Ph (1), biphenyl (2), terphenyl (3), C6H4OMe (4), C6H4NMe2 (5), C6H11O (6), and C6H4CF3 (7)] and [Au4(P^P^P)2(SPh)2](2+) (8) were characterized by X-ray crystallography in the solid state. NMR spectroscopic investigations in solution revealed that the majority of alkynyl clusters 1-7 exist as two isomeric species in slow chemical equilibria. All complexes 1-8 exhibit moderate-to-strong photoemission in the solid state with quantum yields from 0.07 to 0.51. The luminescence behavior was rationalized using quantum chemical density functional theory methods. The high emission efficiency of these tetragold(I) compounds and their good stability in film allowed for the fabrication of an organic electroluminescent device (OLED). Employing complex 5 (Phi = 0.51), an OLED was fabricated under a solution process to give a good external quantum efficiency of 3.1%, corresponding to a current efficiency of 6.1 cd/A and a power efficiency of 5.3 lm/W, with Commission Internationale de I'Eclairage coordinates of (0.52, 0.46). PMID- 25437932 TI - Forward stair descent with hybrid neuroprosthesis after paralysis: Single case study demonstrating feasibility. AB - The ability to negotiate stairs is important for community access and independent mobility but requires more effort and strength than level walking. For this reason, previous attempts to utilize functional neuromuscular stimulation (FNS) to restore stair navigation after spinal cord injury (SCI) have had limited success and are not readily generalizable. Stair descent is particularly challenging because it requires energy absorption via eccentric muscle contractions, a task not easily accomplished with FNS. This article presents the design and initial testing of a hybrid neuroprosthesis with a variable impedance knee mechanism (VIKM-HNP) for stair descent. Using a 16-channel percutaneous FNS system, a muscle activation pattern was synthesized to descend stairs with the VIKM-HNP in a step-by-step fashion. A finite state control system was implemented to deactivate knee extensor stimulation and utilize the VIKM-HNP to absorb energy and regulate descent speed. Feasibility testing was performed on one individual with complete thoracic-level SCI. Stair descent was achieved with maximum upper limb forces of less than 45% body weight compared with previously reported value of 70% with FNS only. The experiments also provided insight into design requirements for future hybrid systems for stair navigation, the implications of which are discussed. PMID- 25437934 TI - How to manage acute herpes zoster affecting trigeminal nerves. PMID- 25437935 TI - Delayed replantation of an avulsed permanent incisor. PMID- 25437936 TI - How to manage spontaneous gingival hemorrhage. PMID- 25437937 TI - Immediate replantation of an avulsed permanent incisor. PMID- 25437938 TI - Are we ready for hiv screening in dental clinics? PMID- 25437939 TI - How to manage “closed lock” disc displacement without reduction with limited opening. PMID- 25437940 TI - Light curing guidelines for practitioners: a consensus statement from the 2014 symposium on light curing in dentistry, Dalhousie University, Halifax, Canada. PMID- 25437941 TI - How to manage tuberosity fracture during extraction. PMID- 25437942 TI - How to manage a patient with a traumatically displaced primary incisor. PMID- 25437943 TI - Improving the oral health of young children of newcomer families: a forum for community members, researchers, and policy-makers. PMID- 25437944 TI - Trends in pediatric dental surgery for severe early childhood caries in Manitoba, Canada. AB - INTRODUCTION: Caries is the most common chronic disease of childhood, and severe forms may necessitate rehabilitative dental surgery. In this study, administrative data related to pediatric dental surgery performed under general anesthesia to treat severe early childhood caries in Manitoba, Canada, were reviewed to determine trends in pediatric dental surgery, as well as geographic, regional and socio-economic variations in surgical rates. METHODS: The total number of dental surgery cases performed under general anesthesia was obtained from provincial administrative databases for fiscal years from 1997-98 to 2006 07. Codes from the International Classification of Diseases and Related Health Problems (9th or 10th revision, as appropriate) were used to identify children who underwent extractions under general anesthesia for a slightly earlier fiscal year period (1996-97 to 2005-06). Each 10-year period was divided into two 5-year periods for comparisons over time. Analyses included descriptive and bivariate statistics, with the data being disaggregated by regional health authority (RHA) or by community area (for Winnipeg). Comparisons for which p <= 0.05 were defined as statistically significant. RESULTS: A total of 18,544 children had dental surgery under general anesthesia between 1997-98 and 2006-07 (mean age +/- standard deviation 3.28 +/- 1.02 years). Many of the children requiring surgery resided in one northern RHA (26.8%) or the Winnipeg RHA (23.8%). More than half of the RHAs (7/11) displayed significant increases in the rate of surgery, with northern RHAs having the highest rates. Within Winnipeg, 3 of the 12 community areas had significant increases in the rate of surgery. Two inner-city neighborhoods accounted for nearly 50% of surgical cases. The rate of extractions under general anesthesia increased significantly in 6 of the 11 RHAs, with northern RHAs having the highest rates. Four Winnipeg communities experienced significant increases in the extraction rate over time. CONCLUSION: Pediatric dental surgery under general anesthesia for treatment of severe early childhood caries is common in Manitoba, and the demand increased in several communities over the study period. These results are being shared with decision-makers and communities to identify regions where oral health promotion is needed. PMID- 25437945 TI - Unexpected soft tissue changes in response to root coverage using an acellular dermal matrix allograft: 12-year follow up. AB - A woman undergoing orthodontic treatment presented with recession and reduced keratinized gingiva on teeth 31 and 41. The patient declined creation of a donor site for conventional autogenous connective soft tissue grafting and opted for an acellular dermal matrix soft tissue substitute for root coverage. Orthodontic treatment followed, and the patient returned for orthognatic surgery after 12 years. Long-term follow up revealed that root coverage remained stable over time and creeping attachment on both teeth was observed. Unexpectedly, an increase in the width of keratinized gingiva was observed. No adverse effects of orthodontic treatment carried out after grafting were observed. PMID- 25437946 TI - End-to-End Invaginated Pancreaticojejunostomy with Three Overlapping U-Sutures--A Safe and Simple Method of Pancreaticoenteric Anastomosis. AB - BACKGROUND: Postoperative pancreatic fistula associated with mortality and morbidity remains an intractable problem after pancreaticoduodenectomy. To date it still carries a notable incidence of roughly 10% to 30% in large series in spite of numerous pharmacological and technical methods that have been proposed to achieve a leakproof pancreatic remnant. METHODS: In order to perform a safe anastomosis to pancreatic remnant with less sophisticated sutures and shorter operative duration, a fast and simple technique of end-to-end invaginated pancreaticojejunostomy with three overlapping U-sutures was devised in our institution. RESULTS: Between April 2011 and July 2013, end-to-end invaginated pancreaticojejunostomy with three overlapping U-sutures technique was used in 23 consecutive cases that underwent pancreaticoduodenectomy in our institute. The median operative time for pancreaticojejunostomy was 12 min. The incidence of pancreatic fistula was 8.7% (n = 2) and both cases were grade A fistula with no clinical impact or delayed hospital discharge. Neither relaparotomy nor postoperative mortality was observed. CONCLUSIONS: The technique of using three overlapping U-sutures in an end-to-end invaginated pancreaticojejunostomy represents a simple management of pancreaticoenteric anastomosis with reliability and applicability, and provides an alternative choice for pancreaticojejunostomy to senior pancreatic surgeons as well as those without experience. PMID- 25437947 TI - SEM analysis of particle size during conventional treatment of CMP process wastewater. AB - Engineered nanomaterials (ENMs) are currently employed by many industries and have different physical and chemical properties from their bulk counterparts that may confer different toxicity. Nanoparticles used or generated in semiconductor manufacturing have the potential to enter the municipal waste stream via wastewater and their ultimate fate in the ecosystem is currently unknown. This study investigates the fate of ENMs used in chemical mechanical planarization (CMP), a polishing process repeatedly utilized in semiconductor manufacturing. Wastewater sampling was conducted throughout the wastewater treatment (WWT) process at the fabrication plant's on-site wastewater treatment facility. The goal of this study was to assess whether the WWT processes resulted in size dependent filtration of particles in the nanoscale regime by analyzing samples using scanning electron microscopy (SEM). Statistical analysis demonstrated no significant differences in particle size between sampling points, indicating low or no selectivity of WWT methods for nanoparticles based on size. All nanoparticles appeared to be of similar morphology (near-spherical), with a high variability in particle size. EDX verified nanoparticles composition of silicon- and/or aluminum-oxide. Nanoparticle sizing data compared between sampling points, including the final sampling point before discharge from the facility, suggested that nanoparticles could be released to the municipal waste stream from industrial sources. PMID- 25437948 TI - Concentrations of phthalate metabolites in breast milk in Korea: estimating exposure to phthalates and potential risks among breast-fed infants. AB - Phthalates have been associated with endocrine disruption and developmental effects in many experimental and epidemiological studies. Developing infants are among the most susceptible populations to endocrine disruption. However, limited information is available on phthalate exposure and its associated risks among breast-fed newborn infants. In the present study, breast milk samples were collected from 62 lactating mothers at 1 month post-partum from four cities of Korea in 2012 and were evaluated for six phthalate metabolites (mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono(2-ethyl-hexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5 oxohexyl) phthalate (MEOHP) and monoethyl phthalate (MEP)). MEP was detected in all breast milk samples, with a median concentration of 0.37 MUg/L, and MiBP, MnBP and MEHP were detected in 79-89% of samples, with median concentrations of 1.10, 1.70, and 2.08 MUg/L, respectively. However, MEHHP and MEOHP, the oxidized forms of di-ethyl-hexyl phthalate (DEHP), were detected in only one sample. For exposure assessment, the levels of phthalate diesters were estimated based on the parent:metabolite ratios in the breast milk that are reported elsewhere. For risk assessment, the endocrine-related toxicity of the monoester was assumed to be the same as that of its diester form. Median daily intake estimates of phthalates, including both monoester and diester forms, through breast milk consumption ranged between 0.91 and 6.52 MUg/kg body weight (bw) for DEHP and between 0.38 and 1.43 MUg/kg bw for di-n-butyl phthalate (DnBP). Based on the estimated daily intake, up to 8% of infants exceeded the reference dose of anti-androgenicity (RfD AA) for DEHP, and 6% of infants exceeded the tolerable daily intake (TDI) for DnBP. Breast milk MiBP and MnBP concentrations showed significant positive associations with maternal consumption of whipped cream or purified water. Considering vulnerability of young infants, efforts to mitigate phthalate exposure among lactating women are warranted. PMID- 25437949 TI - Implications of polluted soil biostimulation and bioaugmentation with spent mushroom substrate (Agaricus bisporus) on the microbial community and polycyclic aromatic hydrocarbons biodegradation. AB - Different applications of spent Agaricus bisporus substrate (SAS), a widespread agro-industrial waste, were investigated with respect to the remediation of a historically polluted soil with Polycyclic Aromatic Hydrocarbons (PAH). In one treatment, the waste was sterilized (SSAS) prior to its application in order to assess its ability to biostimulate, as an organic amendment, the resident soil microbiota and ensuing contaminant degradation. For the other treatments, two bioaugmentation approaches were investigated; the first involved the use of the waste itself and thus implied the application of A. bisporus and the inherent microbiota of the waste. In the second treatment, SAS was sterilized and inoculated again with the fungus to assess its ability to act as a fungal carrier. All these treatments were compared with natural attenuation in terms of their impact on soil heterotrophic and PAH-degrading bacteria, fungal growth, biodiversity of soil microbiota and ability to affect PAH bioavailability and ensuing degradation and detoxification. Results clearly showed that historically PAH contaminated soil was not amenable to natural attenuation. Conversely, the addition of sterilized spent A. bisporus substrate to the soil stimulated resident soil bacteria with ensuing high removals of 3-ring PAH. Both augmentation treatments were more effective in removing highly condensed PAH, some of which known to possess a significant carcinogenic activity. Regardless of the mode of application, the present results strongly support the adequacy of SAS for environmental remediation purposes and open the way to an attractive recycling option of this waste. PMID- 25437950 TI - Health risk to residents and stimulation to inherent bacteria of various heavy metals in soil. AB - The toxicities and effects of various metals and metalloids would be misunderstood by health risks based on their concentrations, when their effects on bacterial and ecological functions in soil are disregarded. This study investigated the concentrations and health risks of heavy metals, soil properties, and bacterial 16S rRNA gene in soil around the largest fresh water lake in North China. The health risks posed by Mn and As were higher than those of other heavy metals and metalloids. Mn, As, and C were significantly correlated with the bacterial species richness indices. According to canonical correspondence analysis, species richness was mainly affected by Mn, Pb, As, and organic matter, while species evenness was mainly affected by Mn, pH, N, C, Cd, and Pb. Covariable analysis confirmed that most effects of metals on bacterial diversity were attributed to the combined effects of metals and soil properties rather than single metals. Most bacteria detected in (almost) all soil were identified as Gammaproteobacteria. Specific bacteria belonging to Proteobacteria (Gamma, Alpha, Epsilon, and Beta), Firmicutes, Actinobacteria, Cyanobacterium, Nitrospirae, and Fusobacterium were only identified in soil with high concentrations of Mn, Pb, and As, indicating their remediation potency. Bacterial abilities and mechanisms in pollutant resistance and element cycling in the region were also discussed. PMID- 25437951 TI - Assessment on the occupational exposure of urban public bus drivers to bioaccessible trace metals through resuspended fraction of settled bus dust. AB - Limited information is available on the bioaccessible fraction of trace metals in the resuspended fraction of settled bus dust in order to estimate bus drivers' occupational exposure. In this study, 45 resuspended fraction of settled dust samples were collected from gasoline and compressed natural gas (CNG) powered buses and analyzed for trace metals and their fraction concentrations using a three-step sequential extraction procedure. Experimental results showed that zinc (Zn) had the greatest bioaccessible fraction, recorded as an average of 608.53 mg/kg, followed in order of decreasing concentration by 129.80 mg/kg lead (Pb), 56.77 mg/kg copper (Cu), 34.03 mg/kg chromium (Cr), 22.05 mg/kg nickel (Ni), 13.17 mg/kg arsenic (As) and 2.77 mg/kg cadmium (Cd). Among the three settled bus dust exposure pathways, ingestion was the main route. Total exposure hazard index (HIt) for non-carcinogenic effect trace metals was lower than the safety level of 1. The incremental lifetime cancer risk (ILCR) for drivers was estimated for trace metal exposure. Pb and Ni presented relatively high potential risks in the non-carcinogenic and potentially carcinogenic health assessment for all drivers. ILCR was in the range of 1.84E-05 to 7.37E-05 and 1.74E-05 to 6.95E-05 for gasoline and CNG buses, respectively. PMID- 25437952 TI - Long-term monitoring data to describe the fate of polycyclic aromatic hydrocarbons in Deepwater Horizon oil submerged off Alabama's beaches. AB - The 2010 Deepwater Horizon (DWH) catastrophe had considerable impact on the ~ 50 km long sandy beach system located along the Alabama shoreline. We present a four year dataset to characterize the temporal evolution of various polycyclic aromatic hydrocarbons (PAHs) and their alkylated homologs trapped in the residual oil buried along the shoreline. Field samples analyzed include the first arrival oil collected from Perdido Bay, Alabama in June 2010, and multiple oil spill samples collected until August 2014. Our field data show that, as of August 2014, DWH oil is still trapped along Alabama's beaches as submerged oil, predominately in the form of surface residual oil balls (SRBs). Chemical characterization data show that various PAHs present in the spilled oil (MC252 crude) weathered by about 45% to 100% when the oil was floating over the open ocean system in the Gulf of Mexico. Light PAHs, such as naphthalenes, were fully depleted, whereas heavy PAHs, such as chrysenes, were only partially depleted by about 45%. However, the rate of PAH weathering appears to have decreased significantly once the oil was buried within the partially-closed SRB environment. Concentration levels of several heavy PAHs have almost remained constant over the past 4 years. Our data also show that evaporation was most likely the primary weathering mechanism for PAH removal when the oil was floating over the ocean, although photo-degradation and other physico-chemical processes could have contributed to some additional weathering. Chemical data presented in this study indicate that submerged oil containing various heavy PAHs (for example, parent and alkylated chrysenes) is likely to remain in the beach system for several years. It is also likely that the organisms living in these beach environments would have an increased risk of exposure to heavy PAHs trapped in the non-recoverable form of buried DWH oil spill residues. PMID- 25437953 TI - Control of PM2.5 in Guangzhou during the 16th Asian Games period: implication for hazy weather prevention. AB - To evaluate the effectiveness of the integrated control measures for reducing PM2.5 (aerosol particles with an aerodynamic diameter of less than 2.5 MUm) and hazy weather, day- and night-time PM2.5 samples were collected at an urban site in Guangzhou during the 16th Asian Games period in November 2010. PM2.5 samples were subject to chemical analysis for major water-soluble ions, organic carbon (OC), element carbon (EC), and biomass burning tracers-anhydrosugar levoglucosan (LG). In addition, aerosol scattering coefficient (bsp) at dry condition and aerosol absorption coefficient (bap) and visibility at ambient condition were measured. The seven major control measures were effective for reducing PM2.5 mass concentration and improving visibility during the Asian Games period. All monitored air pollutants except PM2.5 satisfied the National Ambient Air Quality Standards (NAAQS). However, daily PM2.5 concentrations still exceeded the NAAQS on 47% of the days and hazy weather also occurred on 80% of the days during this period. One factor causing the high frequency of hazy weather occurrence was the increased relative humidity during the Asian Games period. To avoid hazy weather occurrence, new PM2.5 standard was recommended based on visibility calculations using three available aerosol hygroscopic curves previously obtained for this city. The recommended PM2.5 standard was 63 MUgm(-3) under dry condition and lower than 42 MUg m(-3) under humid condition (RH >= 70%). These recommended value s were much stricter than the NAAQS value of 75 MUg m(-3). To reach the new standard, more rigorous control measures for coal industries should be established in the Pearl River Delta (PRD) region. PMID- 25437954 TI - Implications of a consumer-based perspective for the estimation of GHG emissions. The illustrative case of Luxembourg. AB - The Kyoto protocol has established an accounting system for national greenhouse gas (GHG) emissions according to a geographic criterion (producer perspective), such as that proposed by the IPCC guidelines for national GHG inventories. However, the representativeness of this approach is still being debated, because the role of final consumers (consumer perspective) is not considered in the emission allocation system. This paper explores the usefulness of a hybrid analysis, including input-output (IO) and process inventory data, as a complementary tool for estimating and allocating national GHG emissions according to both consumer- and producer-based perspectives. We assess the historical GHG impact profile (from 1995 to 2009) of Luxembourg, which is taken as a case study. The country's net consumption over time is estimated to generate about 28,700 Gg CO2e/year on average. Compared to the conventional IPCC inventory, the IO-based framework typically shows much higher emission estimations. This relevant discrepancy is mainly due to the different points of view obtained from the hybrid model, in particular with regard to the contribution of imported goods and services. Detailing the GHG inventory by economic activity and considering a wider system boundary make the hybrid IO method advantageous as compared to the IPCC approach, but its effective implementation is still limited by the relatively complex modeling system, as well as the lack of coordination and scarce availability of datasets at the national level. PMID- 25437955 TI - Bioavailability of cobalt and iron from citric-acid-adsorbed CoFe2O4 nanoparticles in the terrestrial isopod Porcellio scaber. AB - The aim of this study was to determine whether citric acid adsorbed onto cobalt ferrite (CoFe2O4) nanoparticles (NPs) influences the bioavailability of their constituents Co and Fe. Dissolution of Co and Fe was assessed by two measures: (i) in aqueous suspension using chemical analysis, prior to application onto the food of test organisms; and (ii) in vivo, measuring the bioavailability in the model terrestrial invertebrate (Porcellio scaber, Isopoda, Crustacea). The isopods were exposed to citric-acid-adsorbed CoFe2O4 NPs for 2 weeks, and tissue accumulation of Co and Fe was assessed. This was compared to pristine CoFe2O4 NPs, and CoCl2 and Fe(III) salts as positive controls. The combined data shows that citric acid enhances free metal ion concentration from CoFe2O4 NPs in aqueous suspension, although in vivo, very similar amounts of assimilated Co were found in isopods exposed to both types of NPs. Therefore, evaluation of the dissolution in suspension by chemical means is not a good predictor of metal assimilation of this model organism; body assimilation of Co and Fe is rather governed by the physiological capacity of P. scaber for the uptake of these metals. Moreover, we propose that citric acid, due to its chelating properties, may hinder the uptake of Co that dissolves from citric-acid-adsorbed CoFe2O4 NPs, if citric acid is present in sufficient quantity. PMID- 25437956 TI - Dermatologic applications of direct-to-consumer genomic analysis. PMID- 25437957 TI - The utility of QuantiFERON-TB Gold assay in patients with leprosy: a possible measure of anergy. PMID- 25437958 TI - The Patient Protection and Affordable Care Act's rationing of health care: implications for dermatology. PMID- 25437959 TI - Comments on: DRESS syndrome. PMID- 25437960 TI - Tumor stage mycosis fungoides in nonblood-related family members. PMID- 25437961 TI - Response to: "Tumor stage mycosis fungoides in nonblood-related family members". PMID- 25437962 TI - Comment on "Cutaneous nonmycotic T- and natural killer/T-cell lymphomas: diagnostic challenges and dilemmas". PMID- 25437963 TI - The role of vitamin D in melanoma prevention: evidence and hyperbole. PMID- 25437964 TI - Current dystrophic epidermolysis bullosa research does not match research needs perceived by patients and clinicians. PMID- 25437965 TI - Evaluation of sunscreens distributed by 2 major US retailers for meeting recommendations by the American Academy of Dermatology. PMID- 25437966 TI - Absent in Melanoma 2 is predominantly present in primary melanoma and primary squamous cell carcinoma, but largely absent in metastases of both tumors. PMID- 25437967 TI - Efficacy of oral retinoids in treatment-resistant lichen planopilaris. PMID- 25437968 TI - Treatment of bullous pemphigoid with adjuvant immunoadsorption: a case series. PMID- 25437969 TI - Dendritic cells are prominent in granuloma annulare. PMID- 25437970 TI - Mites and burrows are frequently found in nodular scabies by dermoscopy and histopathology. PMID- 25437971 TI - Quality-of-life impairment in patients with livedoid vasculopathy. PMID- 25437972 TI - Patient-reported outcomes of electrodessication and curettage for treatment of nonmelanoma skin cancer. PMID- 25437973 TI - Modifiable lifestyle factors in psoriasis: screening and counseling practices among dermatologists and dermatology residents in academic institutions. PMID- 25437974 TI - JAAD grand rounds quiz. A case of oral melanosis. PMID- 25437975 TI - JAAD grand rounds quiz. Dusky bullae on the abdomen. PMID- 25437976 TI - JAAD grand rounds quiz. Bullae and nodules on the legs of a 57-year-old woman. PMID- 25437977 TI - Polycystic ovary syndrome: a review for dermatologists: Part I. Diagnosis and manifestations. AB - Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women who are of reproductive age. The pathogenesis involves several associated hormonal pathways that culminate in metabolic, reproductive, and cardiovascular effects. The hallmark features of hyperandrogenism and hyperinsulinemia have systemic long term implications. Dermatologists frequently evaluate and manage the cutaneous manifestations of PCOS (ie, acanthosis nigricans, hirsutism, acne, and alopecia), and therefore play a key role in its diagnosis and management. In part I of this continuing medical education article, we review the definition, etiology, pathogenesis, and clinical features of PCOS. PMID- 25437978 TI - Polycystic ovary syndrome: a review for dermatologists: Part II. Treatment. AB - Dermatologists are in a key position to treat the manifestations of polycystic ovary syndrome (PCOS). The management of PCOS should be tailored to each woman's specific goals, reproductive interests, and particular constellation of symptoms. Therefore, a multidisciplinary approach is recommended. In part II of this continuing medical education article, we present the available safety and efficacy data regarding treatments for women with acne, hirsutism, and androgenetic alopecia. Therapies discussed include lifestyle modification, topical therapies, combined oral contraceptives, antiandrogen agents, and insulin sensitizing drugs. Treatment recommendations are made based on the current available evidence. PMID- 25437983 TI - Dermoscopic misdiagnosis of melanoma in a patient with targetoid hemosiderotic hemangioma. PMID- 25437984 TI - Atypical pigmented lesion of the nipple. PMID- 25437985 TI - Dermoscopy of a clonal (inverted type A) nevus in a child. PMID- 25437987 TI - Dermoscopic findings of poikiloderma in dyskeratosis congenita. PMID- 25437986 TI - Differential diagnosis of a pink nodule with a blue globule. PMID- 25437988 TI - Exodus of Sarcoptes scabiei var. hominis from the threatening blade of Homo sapiens. PMID- 25437989 TI - Mildly heated forceps: a useful instrument for easy and complete removal of ticks on the skin. PMID- 25437990 TI - The figure 8: a new hair biopsy technique. PMID- 25437991 TI - PERFECT-ing technique prior to facial reconstructive surgery: a convenient, inexpensive aid to dermatologic surgical teaching. PMID- 25437992 TI - Vemurafenib-associated gingival hyperplasia in patient with metastatic melanoma. PMID- 25437993 TI - Plaque-like syringoma with involvement of deep reticular dermis. PMID- 25437994 TI - Urticaria pigmentosa complicated with esophageal eosinophilia. PMID- 25437995 TI - Absence of HLA-DR1 positivity in 2 familial cases of frontal fibrosing alopecia. PMID- 25437996 TI - Hidradenitis suppurativa after renal transplantation: complete remission after switching from oral cyclosporine to oral tacrolimus. PMID- 25437997 TI - Ipilimumab-associated Sweet syndrome in a melanoma patient. PMID- 25437998 TI - Disseminated cutaneous leishmaniasis in a patient with Sezary syndrome. PMID- 25437999 TI - Toxic epidermal necrolysis in the absence of circulating T cells: a possible role for resident memory T cells. PMID- 25438000 TI - Varicella zoster virus-associated generalized pustular psoriasis in a baby with heterozygous IL36RN mutation. PMID- 25438001 TI - Skin manifestations associated with chronic recurrent multifocal osteomyelitis in a 9-year-old girl. PMID- 25438002 TI - Are arteriovenous malformations a causative factor for hypertrophic and nodular port-wine stains? PMID- 25438003 TI - Sirolimus-associated regression of benign lymphangioendothelioma. PMID- 25438004 TI - The role of infliximab in the treatment of superficial granulomatous pyoderma of the head and neck. PMID- 25438005 TI - Collagenase ointment and topical timolol gel for treating idiopathic pyoderma gangrenosum. PMID- 25438006 TI - Iminopyridine oxazoline iron catalyst for asymmetric hydroboration of 1,1 disubtituted aryl alkenes. AB - The highly regio- and enantioselective iron-catalyzed anti-Markovnikov hydroboration of 1,1-disubstituted aryl alkenes is reported by using a novel chiral iminopyridine oxazoline (IPO) ligand, in which the iminopyridine group is proposed to stabilize the iron and chiral oxazoline group to control enantioselectivity. This distinct class of reactive IPO ligands will likely be of high value for a large variety of asymmetric transformations using first-row transition metals. PMID- 25438007 TI - Comparison of the Accuracy of Different Transfer Impression Techniques for Osseointegrated Implants. AB - The aim of this study was to evaluate 3 transfer techniques used to obtain working casts of implant-supported prostheses through the marginal misfit and strain induced to metallic framework. Thirty working casts were obtained from a metallic master cast, each one containing 2 implant analogs simulating a clinical situation of 3-unit implant-supported fixed prostheses according to the following transfer impression techniques: group A, squared transfers splinted with dental floss and acrylic resin, sectioned, and re-splinted; group B, squared transfers splinted with dental floss and bis-acrylic resin; and group N, squared transfers not splinted. A metallic framework was made for marginal misfit and strain measurements from the metallic master cast. The misfit between the metallic framework and working casts was evaluated with an optical microscope following the single-screw test protocol. In the same conditions, the strain was evaluated using strain gauges placed on the metallic framework. The data were submitted to one-way analysis of variance followed by the Tukey test (alpha = 5%). For both marginal misfit and strain, there were statistically significant differences between groups A and N (P < .01) and groups B and N (P < .01), with greater values for group N. According to the Pearson test, there was a positive correlation between the misfit and strain variables (r = 0.5642). The results of this study showed that the impression techniques with splinted transfers promoted better accuracy than the nonsplinted technique, regardless of the splinting material used. PMID- 25438008 TI - Molecular identification of isolated fungi from unopened containers of greek yogurt by DNA sequencing of internal transcribed spacer region. AB - In our previous study, we described the development of an internal transcribed spacer (ITS)1 sequencing method, and used this protocol in species-identification of isolated fungi collected from the manufacturing areas of a compounding company known to have caused the multistate fungal meningitis outbreak in the United States. In this follow-up study, we have analyzed the unopened vials of Greek yogurt from the recalled batch to determine the possible cause of microbial contamination in the product. A total of 15 unopened vials of Greek yogurt belonging to the recalled batch were examined for the detection of fungi in these samples known to cause foodborne illness following conventional microbiological protocols. Fungi were isolated from all of the 15 Greek yogurt samples analyzed. The isolated fungi were genetically typed by DNA sequencing of PCR-amplified ITS1 region of rRNA gene. Analysis of data confirmed all of the isolated fungal isolates from the Greek yogurt to be Rhizomucor variabilis. The generated ITS1 sequences matched 100% with the published sequences available in GenBank. In addition, these yogurt samples were also tested for the presence of five types of bacteria (Salmonella, Listeria, Staphylococcus, Bacillus and Escherichia coli) causing foodborne disease in humans, and found negative for all of them. PMID- 25438010 TI - Fitness of Outbreak and Environmental Strains of Escherichia coli O157:H7 in Aerosolizable Soil and Association of Clonal Variation in Stress Gene Regulation. AB - Airborne dust from feedlots is a potential mechanism of contamination of nearby vegetable crops with Escherichia coli O157:H7 (EcO157). We compared the fitness of clinical and environmental strains of EcO157 in <45 um soil from a spinach farm. Differences in survival were observed among the 35 strains with D-values (days for 90% decreases) ranging from 1-12 days. Strains that survived longer, generally, were from environmental sources and lacked expression of curli, a protein associated with attachment and virulence. Furthermore, the proportion of curli-positive (C+) variants of EcO157 strains decreased with repeated soil exposure and the strains that were curli-negative (C-) remained C- post-soil exposure. Soil exposure altered expression of stress-response genes linked to fitness of EcO157, but significant clonal variation in expression was measured. Mutations were detected in the stress-related sigma factor, rpoS, with a greater percentage occurring in parental strains of clinical origin prior to soil exposure. We speculate that these mutations in rpoS may confer a differential expression of genes, associated with mechanisms of survival and/or virulence, and thus may influence the fitness of EcO157. PMID- 25438009 TI - Perturbation of the human microbiome as a contributor to inflammatory bowel disease. AB - The human microbiome consist of the composite genome of native flora that have evolved with humanity over millennia and which contains 150-fold more genes than the human genome. A "healthy" microbiome plays an important role in the maintenance of health and prevention of illness, inclusive of autoimmune disease such as inflammatory bowel disease (IBD). IBD is a prevalent spectrum of disorders, most notably defined by Crohn's disease (CD) and ulcerative colitis (UC), which are associated with considerable suffering, morbidity, and cost. This review presents an outline of the loss of a normal microbiome as an etiology of immune dysregulation and IBD pathogenesis initiation. We, furthermore, summarize the knowledge on the role of a healthy microbiome in terms of its diversity and important functional elements and, lastly, conclude with some of the therapeutic interventions and modalities that are now being explored as potential applications of microbiome-host interactions. PMID- 25438011 TI - Host pathogen relations: exploring animal models for fungal pathogens. AB - Pathogenic fungi cause superficial infections but pose a significant public health risk when infections spread to deeper tissues, such as the lung. Within the last three decades, fungi have been identified as the leading cause of nosocomial infections making them the focus of research. This review outlines the model systems such as the mouse, zebrafish larvae, flies, and nematodes, as well as ex vivo and in vitro systems available to study common fungal pathogens. PMID- 25438012 TI - Exploring the Therapeutic Potentials of iNKT Cells for Anti-HBV Treatment. AB - CD1d-restricted invariant NKT (iNKT) cells are a group of innate-like regulatory T cells that recognize lipid antigens. Both mouse modeling experiments and human clinical studies have suggested a key role for iNKT cells in anti-HBV immunity and these potent T cells can be explored as a novel therapeutic target for anti HBV treatment. We aim to humanize mice in the CD1d/iNKT cell lipid presentation system and provide new research tools for identifying novel anti-HBV agents. PMID- 25438013 TI - Mycobacterium avium Subspecies paratuberculosis: Human Exposure through Environmental and Domestic Aerosols. AB - Mycobacterium avium subspecies paratuberculosis (Map) causes Johne's disease in animals and is significantly associated with Crohn's disease (CD) in humans. Our previous studies have shown Map to be present in U.K. rivers due to land deposition from chronic livestock infection and runoff driven by rainfall. The epidemiology of CD in Cardiff showed a significant association with the River Taff, in which Map can be detected on a regular basis. We have previously hypothesized that aerosols from the river might influence the epidemiology of CD. In this preliminary study, we detected Map by quantitative PCR in one of five aerosol samples collected above the River Taff. In addition, we examined domestic showers from different regions in the U.K. and detected Map in three out of 30 independent samples. In detecting Map in river aerosols and those from domestic showers, this is the first study to provide evidence that aerosols are an exposure route for Map to humans and may play a role in the epidemiology of CD. PMID- 25438015 TI - Small Animal Models for Human Metapneumovirus: Cotton Rat is More Permissive than Hamster and Mouse. AB - Human metapneumovirus (hMPV) is the second most prevalent causative agent of pediatric respiratory infections worldwide. Currently, there are no vaccines or antiviral drugs against this virus. One of the major hurdles in hMPV research is the difficulty to identify a robust small animal model to accurately evaluate the efficacy and safety of vaccines and therapeutics. In this study, we compared the replication and pathogenesis of hMPV in BALB/c mice, Syrian golden hamsters, and cotton rats. It was found that BALB/c mice are not permissive for hMPV infection despite the use of a high dose (6.5 log10 PFU) of virus for intranasal inoculation. In hamsters, hMPV replicated efficiently in nasal turbinates but demonstrated only limited replication in lungs. In cotton rats, hMPV replicated efficiently in both nasal turbinate and lung when intranasally administered with three different doses (4, 5, and 6 log10 PFU) of hMPV. Lungs of cotton rats infected by hMPV developed interstitial pneumonia with mononuclear cells infiltrates and increased lumen exudation. By immunohistochemistry, viral antigens were detected at the luminal surfaces of the bronchial epithelial cells in lungs. Vaccination of cotton rats with hMPV completely protected upper and lower respiratory tract from wildtype challenge. The immunization also elicited elevated serum neutralizing antibody. Collectively, these results demonstrated that cotton rat is a robust small animal model for hMPV infection. PMID- 25438016 TI - Development and validation of a rapid turbidimetric assay to determine the potency of cefuroxime sodium in powder for dissolution for injection. AB - The cefuroxime sodium is a second generation cephalosporin indicated for infections caused by Gram-positive and Gram-negative microorganisms. Although this drug is highly studied and researched regarding the antimicrobial activity, pharmacokinetics and pharmacodynamics, there are few studies regarding the development of analytical methodology for this cephalosporin. Thus, research involving analytical methods is essential and highly relevant to optimize its analysis in the pharmaceutical industry and guarantee the quality of the product already sold. This study describes the development and validation of a microbiological assay applying the turbidimetric method for the determination of cefuroxime, using Micrococcus luteus ATCC 9341 as micro-organism test and 3x3 parallel line assay design, with nine tubes for each assay, as recommended by the Brazilian Pharmacopoeia. The developed and validated method showed excellent results of linearity, seletivity, precision and robustness, in the concentration range from 30.0 to 120.0 mg/mL, with 100.21% accuracy and content 99.97% to cefuroxime sodium in injectable pharmaceutical form. PMID- 25438017 TI - Wild mushroom extracts as inhibitors of bacterial biofilm formation. AB - Microorganisms can colonize a wide variety of medical devices, putting patients in risk for local and systemic infectious complications, including local-site infections, catheter-related bloodstream infections, and endocarditis. These microorganisms are able to grow adhered to almost every surface, forming architecturally complex communities termed biofilms. The use of natural products has been extremely successful in the discovery of new medicine, and mushrooms could be a source of natural antimicrobials. The present study reports the capacity of wild mushroom extracts to inhibit in vitro biofilm formation by multi resistant bacteria. Four Gram-negative bacteria biofilm producers (Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, and Acinetobacter baumannii) isolated from urine were used to verify the activity of Russula delica, Fistulina hepatica, Mycena rosea, Leucopaxilus giganteus, and Lepista nuda extracts. The results obtained showed that all tested mushroom extracts presented some extent of inhibition of biofilm production. Pseudomonas aeruginosa was the microorganism with the highest capacity of biofilm production, being also the most susceptible to the extracts inhibition capacity (equal or higher than 50%). Among the five tested extracts against E. coli, Leucopaxillus giganteus (47.8%) and Mycenas rosea (44.8%) presented the highest inhibition of biofilm formation. The extracts exhibiting the highest inhibitory effect upon P. mirabilis biofilm formation were Sarcodon imbricatus (45.4%) and Russula delica (53.1%). Acinetobacter baumannii was the microorganism with the lowest susceptibility to mushroom extracts inhibitory effect on biofilm production (highest inhibition-almost 29%, by Russula delica extract). This is a pioneer study since, as far as we know, there are no reports on the inhibition of biofilm production by the studied mushroom extracts and in particular against multi-resistant clinical isolates; nevertheless, other studies are required to elucidate the mechanism of action. PMID- 25438014 TI - Biomolecular Mechanisms of Pseudomonas aeruginosa and Escherichia coli Biofilm Formation. AB - Pseudomonas aeruginosa and Escherichia coli are the most prevalent Gram-negative biofilm forming medical device associated pathogens, particularly with respect to catheter associated urinary tract infections. In a similar manner to Gram positive bacteria, Gram-negative biofilm formation is fundamentally determined by a series of steps outlined more fully in this review, namely adhesion, cellular aggregation, and the production of an extracellular polymeric matrix. More specifically this review will explore the biosynthesis and role of pili and flagella in Gram-negative adhesion and accumulation on surfaces in Pseudomonas aeruginosa and Escherichia coli. The process of biofilm maturation is compared and contrasted in both species, namely the production of the exopolysaccharides via the polysaccharide synthesis locus (Psl), pellicle Formation (Pel) and alginic acid synthesis in Pseudomonas aeruginosa, and UDP-4-amino-4-deoxy-l arabinose and colonic acid synthesis in Escherichia coli. An emphasis is placed on the importance of the LuxR homologue sdiA; the luxS/autoinducer-II; an autoinducer-III/epinephrine/norepinephrine and indole mediated Quorum sensing systems in enabling Gram-negative bacteria to adapt to their environments. The majority of Gram-negative biofilms consist of polysaccharides of a simple sugar structure (either homo- or heteropolysaccharides) that provide an optimum environment for the survival and maturation of bacteria, allowing them to display increased resistance to antibiotics and predation. PMID- 25438020 TI - Exploring Dangerous Connections between Klebsiella pneumoniae Biofilms and Healthcare-Associated Infections. AB - Healthcare-associated infections (HAI) are a huge public health concern, particularly when the etiological agents are multidrug resistant. The ability of bacteria to develop biofilm is a helpful skill, both to persist within hospital units and to increase antibiotic resistance. Although the links between antibiotic resistance, biofilms assembly and HAI are consensual, little is known about biofilms. Here, electron microscopy was adopted as a tool to investigate biofilm structures associated with increased antibiotic resistance. The K. pneumoniae strains investigated are able to assemble biofilms, albeit with different kinetics. The biofilm structure and the relative area fractions of bacteria and extracellular matrix depend on the particular strain, as well as the minimal inhibitory concentration (MIC) for the antibiotics. Increased values were found for bacteria organized in biofilms when compared to the respective planktonic forms, except for isolates Kp45 and Kp2948, the MIC values for which remained unchanged for fosfomycin. Altogether, these results showed that the emergence of antimicrobial resistance among bacteria responsible for HAI is a multifactorial phenomenon dependent on antibiotics and on bacteria/biofilm features. PMID- 25438018 TI - Pseudomonas aeruginosa Diversification during Infection Development in Cystic Fibrosis Lungs-A Review. AB - Pseudomonas aeruginosa is the most prevalent pathogen of cystic fibrosis (CF) lung disease. Its long persistence in CF airways is associated with sophisticated mechanisms of adaptation, including biofilm formation, resistance to antibiotics, hypermutability and customized pathogenicity in which virulence factors are expressed according the infection stage. CF adaptation is triggered by high selective pressure of inflamed CF lungs and by antibiotic treatments. Bacteria undergo genetic, phenotypic, and physiological variations that are fastened by the repeating interplay of mutation and selection. During CF infection development, P. aeruginosa gradually shifts from an acute virulent pathogen of early infection to a host-adapted pathogen of chronic infection. This paper reviews the most common changes undergone by P. aeruginosa at each stage of infection development in CF lungs. The comprehensive understanding of the adaptation process of P. aeruginosa may help to design more effective antimicrobial treatments and to identify new targets for future drugs to prevent the progression of infection to chronic stages. PMID- 25438019 TI - Iron and Acinetobacter baumannii Biofilm Formation. AB - Acinetobacter baumannii is an emerging nosocomial pathogen, responsible for infection outbreaks worldwide. The pathogenicity of this bacterium is mainly due to its multidrug-resistance and ability to form biofilm on abiotic surfaces, which facilitate long-term persistence in the hospital setting. Given the crucial role of iron in A. baumannii nutrition and pathogenicity, iron metabolism has been considered as a possible target for chelation-based antibacterial chemotherapy. In this study, we investigated the effect of iron restriction on A. baumannii growth and biofilm formation using different iron chelators and culture conditions. We report substantial inter-strain variability and growth medium dependence for biofilm formation by A. baumannii isolates from veterinary and clinical sources. Neither planktonic nor biofilm growth of A. baumannii was affected by exogenous chelators. Biofilm formation was either stimulated by iron or not responsive to iron in the majority of isolates tested, indicating that iron starvation is not sensed as an overall biofilm-inducing stimulus by A. baumannii. The impressive iron withholding capacity of this bacterium should be taken into account for future development of chelation-based antimicrobial and anti-biofilm therapies. PMID- 25438021 TI - Genetic Characterization of Fungi Isolated from the Environmental Swabs collected from a Compounding Center Known to Cause Multistate Meningitis Outbreak in United States Using ITS Sequencing. AB - A multistate fungal meningitis outbreak started in September of 2012 which spread in 20 states of the United States. The outbreak has been fatal so far, and has affected 751 individuals with 64 deaths among those who received contaminated spinal injections manufactured by a Compounding Center located in Massachusetts. In a preliminary study, Food and Drug Administration (FDA) investigated the outbreak in collaboration with Centers for Disease Control and Prevention (CDC), state and local health departments, and identified four fungal and several bacterial contaminations in the recalled unopened injection vials. This follow-up study was carried out to assess DNA sequencing of the ITS1 region of rRNA gene for rapid identification of fungal pathogens during public health outbreak investigations. A total of 26 environmental swabs were collected from several locations at the manufacturing premises of the Compounding Center known to have caused the outbreak. The swab samples were initially examined by conventional microbiologic protocols and a wide range of fungal species were recovered. Species-identification of these microorganisms was accomplished by nucleotide sequencing of ITS1 region of rRNA gene. Analysis of data confirmed 14 additional fungal species in the swabs analyzed. PMID- 25438023 TI - Role of daptomycin in the induction and persistence of the viable but non culturable state of Staphylococcus aureus biofilms. AB - We have recently demonstrated that antibiotic pressure can induce the viable but non-culturable (VBNC) state in Staphylococcus aureus biofilms. Since dormant bacterial cells can undermine anti-infective therapy, a greater understanding of the role of antibiotics of last resort, including daptomycin, is crucial. Methicillin-resistant S. aureus 10850 biofilms were maintained on non-nutrient (NN) agar in the presence or absence of the MIC of daptomycin until loss of culturability. Viable cells were monitored by epifluorescence microscopy and flow cytometry for 150 days. All biofilms reached non-culturability at 40 days and showed a similar amount of viable cells; however, in biofilms exposed to daptomycin, their number remained unchanged throughout the experiment, whereas in those maintained on NN agar alone, no viable cells were detected after 150 days. Gene expression assays showed that after achievement of non-culturability, 16S rDNA and mecA were expressed by all biofilms, whereas glt expression was found only in daptomycin-exposed biofilms. Our findings suggest that low daptomycin concentrations, such as those that are likely to obtain within biofilms, can influence the viability and gene expression of non-culturable S. aureus cells. Resuscitation experiments are needed to establish the VBNC state of daptomycin exposed biofilms. PMID- 25438022 TI - Antibiotic Resistance Related to Biofilm Formation in Klebsiella pneumoniae. AB - The Gram-negative opportunistic pathogen, Klebsiella pneumoniae, is responsible for causing a spectrum of community-acquired and nosocomial infections and typically infects patients with indwelling medical devices, especially urinary catheters, on which this microorganism is able to grow as a biofilm. The increasingly frequent acquisition of antibiotic resistance by K. pneumoniae strains has given rise to a global spread of this multidrug-resistant pathogen, mostly at the hospital level. This scenario is exacerbated when it is noted that intrinsic resistance to antimicrobial agents dramatically increases when K. pneumoniae strains grow as a biofilm. This review will summarize the findings about the antibiotic resistance related to biofilm formation in K. pneumoniae. PMID- 25438025 TI - Esophageal eosinophilia in pediatric patients with celiac disease: is it a causal or an incidental association? AB - OBJECTIVES: Celiac disease (CD) and eosinophilic esophagitis (EoE) are 2 distinct disease entities affecting the gastrointestinal tract of pediatric patients. Recently it has been suggested that EoE is more prevalent in patients with celiac disease than in the general population. We studied the association between these 2 disease entities in our pediatric patients. METHODS: We reviewed our hospital files for suspected or confirmed cases of CD. Only cases with both duodenal and esophageal biopsies in pediatric patients were included. A total of 120 patients who met these criteria were included as the disease group. We also selected 100 patients with no clinical suspicion of CD and included them as a control group. Slides were reviewed using established criteria for diagnosis of both conditions. Duodenal biopsies were categorized as positive, negative, and suspicious for CD, whereas esophageal biopsies were classified as either positive or negative for esophageal eosinophilia (EE). Serologic and clinical data were additionally collected. RESULTS: Sixty-two (62) cases were considered positive for CD in the disease group; among those 4 (6.5%) showed EE. In the control group, 91 cases were negative for CD, histologically, and 7 of those had EE (7.7%). Although 6 patients in the control group were histologically suspicious for CD, none of them had evidence of EE. CONCLUSIONS: Our findings show that, in our patient population, patients with CD are not more likely to have EE than patients undergoing upper endoscopy for other reasons. Therefore, we suggest that the association between CD and EE is likely incidental and not causal. PMID- 25438026 TI - Feasibility Study of Phragmites karka and Christella dentata Grown in West Bengal as Arsenic Accumulator. AB - A survey was undertaken, in arsenic (As) contaminated area of the Nadia district, West Bengal, India, to find native As accumulator plants. As was determined both in soil and plant parts. The results showed that the mean translocation factor of Pteris vittata L, Phragmites karka (Cav.) Trin. Ex. Steud and Christella dentata Forssk were higher than 1. It thus appeared that these plants can be efficient accumulators of As. Phytoremediation ability of C. dentata and P. karka was evaluated and compared with known As-hyperaccumulators -P. vittata and Adiantum capillus veneris L. Plants were grown in the As spiked soil (25, 50, 75 and 100 mg kg(-1)). As accumulation was found to be highest in P. vittata, 117.18 mg kg( 1) in leaf at 100 mg kg(-1) As treatment, followed by A. capillus veneris, P. karka and C. dentata being 74, 83.87 and 40.36 mg kg(-1), respectively. Lipid peroxidation increased after As exposure in all plants. However, the antioxidant enzyme activity and molecules concentration also increased which helped the plants to overcome As-induced oxidative stress. The study indicates that P. karka and C. dentata could be considered as As-accumulators and find application for As phytoextraction in field conditions. PMID- 25438027 TI - Predictors of placebo response in bipolar depression. AB - The aim of this work is to investigate placebo response rates in placebo controlled randomized clinical trials (RCTs) of pharmacological therapy in bipolar depression (BPD) and to identify predictors of placebo response and clinical trial outcome in BPD. Medline/PubMed publication databases were searched for RCTs of oral drugs used as monotherapy for the treatment of BPD, published between January 1980 and September 2013. Data extracted from 12 manuscripts and one poster, representing a total of 17 clinical trials, were pooled. Pooled response rates for drug and placebo were 55.1 and 39.2%, corresponding to a risk ratio for responding to active treatment versus placebo of 1.29 (P<0.001). The probability of receiving placebo and trial duration correlated with the response rate to placebo. A meta-regression showed that trial duration and baseline severity correlated with the risk ratio of responding to drug versus placebo. There was a trend toward statistical significance for a greater probability of receiving placebo to predict greater drug-placebo 'separation'. In conclusion, several modifiable factors, specifically the probability of receiving placebo, baseline illness severity, and trial duration, correlate with placebo response rates and/or clinical trial outcome in RCTs of pharmacotherapy for BPD, and should be taken into account when designing studies for BPD. PMID- 25438028 TI - Successful treatment of hydroxyzine and dexclorfeniramine maleate in combination with electroconvulsive therapy in a neuroleptic malignant catatonia: a case report. AB - Malign neuroleptic syndrome is a potentially life-threatening condition that is normally treated with electroconvulsive therapy (ECT). In this case report, we discuss a severely agitated and catatonic bipolar I patient who developed a neuroleptic malignant syndrome and did not improve with benzodiazepines and ECT. On the basis of anecdotal reports of the positive effects of antihistamines in psychosis and ECT, we treated our case with a combination of two antihistamines, hydroxyzine and dexclorfeniramine maleate, and ECT, which improved the clinical picture to the point of clinical remission. PMID- 25438029 TI - Predicting students' intention to use stimulants for academic performance enhancement. AB - BACKGROUND: The non-medical use of stimulants for academic performance enhancement is becoming a more common practice among college and university students. OBJECTIVE: The objective of this study is to gain a better understanding of students' intention to use stimulant medication for the purpose of enhancing their academic performance. Based on an extended model of Ajzen's theory of planned behavior, we examined the predictive value of attitude, subjective norm, perceived behavioral control, psychological distress, procrastination, substance use, and alcohol use on students' intention to use stimulants to improve their academic performance. METHODS: The sample consisted of 3,589 Flemish university and college students (mean age: 21.59, SD: 4.09), who participated anonymously in an online survey conducted in March and April 2013. Structural equation modeling was used to investigate the relationships among the study variables. RESULTS: Our results indicate that subjective norm is the strongest predictor of students' intention to use stimulant medication, followed by attitude and perceived behavioral control. To a lesser extent, procrastinating tendencies, psychological distress, and substance abuse contribute to students' intention. Conclusions/ Importance: Based on these findings, we provide several recommendations on how to curtail students' intention to use stimulant medication for the purpose of improving their academic performance. In addition, we urge researchers to identify other psychological variables that might be related to students' intention. PMID- 25438030 TI - Expanding pedestrian injury risk to the body region level: how to model passive safety systems in pedestrian injury risk functions. AB - OBJECTIVE: Assessment of the effectiveness of advanced driver assistance systems (ADAS) plays a crucial role in accident research. A common way to evaluate the effectiveness of new systems is to determine the potentials for injury severity reduction. Because injury risk functions describe the probability of an injury of a given severity conditional on a technical accident severity (closing speed, delta V, barrier equivalent speed, etc.), they are predestined for such evaluations. METHODS: Recent work has stated an approach on how to model the pedestrian injury risk in pedestrian-to-passenger car accidents as a family of functions. This approach gave explicit and easily interpretable formulae for the injury risk conditional on the closing speed of the car. These results are extended to injury risk functions for pedestrian body regions. Starting with a double-checked German In-depth Accident Study (GIDAS) pedestrian-to-car accident data set (N = 444) and a functional-anatomical definition of the body regions, investigations on the influence of specific body regions on the overall injury severity will be presented. As the measure of injury severity, the ISSx, a rescaled version of the well-known Injury Severity Score (ISS), was used. Though traditional ISS is computed by summation of the squares of the 3 most severe injured body regions, ISSx is computed by the summation of the exponentials of the Abbreviated Injury Scale (AIS) severities of the 3 most severely injured body regions. The exponentials used are scaled to fit the ISS range of values between 0 and 75. RESULTS: Three body regions (head/face/neck, thorax, hip/legs) clearly dominated abdominal and upper extremity injuries; that is, the latter 2 body regions had no influence at all on the overall injury risk over the range of technical accident severities. Thus, the ISSx is well described by use of the injury codes from the same body regions for any pedestrian injury severity. As a mathematical consequence, the ISSx becomes explicitly decomposable into the 3 body regions and so are the risk functions as body region-specific risk functions. The risk functions for each body region are stated explicitly for different injury severity levels and compared to the real-world accident data. CONCLUSIONS: The body region-specific risk functions can then be used to model the effect of improved passive safety systems. These modified body region specific injury risk functions are aggregated to a new pedestrian injury risk function. Passive safety systems can therefore be modeled in injury risk functions for the first time. A short example on how the results can be used for assessing the effectiveness of new driver assistance systems concludes the article. PMID- 25438024 TI - Early development of the gut microbiota and immune health. AB - In recent years, the increase in human microbiome research brought about by the rapidly evolving "omic" technologies has established that the balance among the microbial groups present in the human gut, and their multipronged interactions with the host, are crucial for health. On the other hand, epidemiological and experimental support has also grown for the 'early programming hypothesis', according to which factors that act in utero and early in life program the risks for adverse health outcomes later on. The microbiota of the gut develops during infancy, in close interaction with immune development, and with extensive variability across individuals. It follows that the specific process of gut colonization and the microbe-host interactions established in an individual during this period have the potential to represent main determinants of life-long propensity to immune disease. Although much remains to be learnt on the progression of events by which the gut microbiota becomes established and initiates its intimate relationships with the host, and on the long-term repercussions of this process, recent works have advanced significatively in this direction. PMID- 25438031 TI - Increased cortical thickness and altered functional connectivity of the right superior temporal gyrus in left-handers. AB - Altered structure in the temporal cortex has been implicated in the variable language laterality of left-handers (LH). The neuroanatomy of language lateralization and the corresponding synchronous functional connectivity (FC) in handedness cohorts are not, however, fully understood. We used structural and resting-state functional magnetic resonance imaging (fMRI) data to investigate the effect of altered cortical thickness on FC in LH and right-handers (RH). Whole-brain cortical thickness was calculated and compared between the LH and RH. We observed increased cortical thickness in the right superior temporal gyrus (STG) in the LH. A further FC analysis was conducted between the right STG and the remaining voxels in the brain. Compared with RH, the LH showed significantly higher FC in the left STG, right occipital cortex, and lower FC in the left inferior frontal gyrus and supramarginal gyrus. Our findings suggest that LH have atypical connectivity in the language network, with an enhanced role of the STG, findings which provide novel insights into the structural and functional substrates underlying the atypical language development of left-handed individuals. PMID- 25438032 TI - Parsing cognitive and emotional empathy deficits for negative and positive stimuli in frontotemporal dementia. AB - OBJECTIVES: Behavioural variant frontotemporal dementia (bvFTD) is a debilitating neurodegenerative disorder characterized by frontal and temporal lobe atrophy primarily affecting social cognition and emotion, including loss of empathy. Many consider empathy to be a multidimensional construct, including cognitive empathy (the ability to adopt and understand another's perspective) and emotional empathy (the capacity to share another's emotional experience). Cognitive and emotional empathy deficits have been associated with bvFTD; however, little is known regarding the performance of patients with bvFTD on behavioural measures of emotional empathy, and whether empathic responses differ for negative versus positive stimuli. METHODS: 24 patients with bvFTD and 24 healthy controls completed the Multifaceted Empathy Test (MET; Dziobek et al., 2008), a performance-based task that taps both cognitive and emotional facets of empathy, and allows for the discrimination of responses to negative versus positive realistic images. MET scores were also compared with caregiver ratings of patient behaviour on the Interpersonal Reactivity Index, which assesses patients' everyday demonstrations of perspective taking and empathic concern. RESULTS: Patients with bvFTD were less accurate than controls at inferring mental states for negative and positive stimuli. They also demonstrated lower levels of shared emotional experience, more positive emotional reactions, and diminished arousal to negative social stimuli relative to controls. Patients showed reduced emotional reactions to negative non-social stimuli as well. Lastly, the MET and IRI measures of emotional empathy were found to be significantly correlated within the bvFTD group. CONCLUSIONS: The results suggest that patients with bvFTD show a global deficit in cognitive empathy, and deficient emotional empathy for negative, but not positive, experiences. Further, a generalized emotional processing impairment for negative stimuli was observed, which could contribute to the emotional empathy deficit. This work highlights potential treatment targets and a means to assess the impact of novel therapies on socioemotional impairment in bvFTD. PMID- 25438033 TI - Response to the short communication: Effect of interval training on cognitive functioning and cerebral oxygenation in obese patients: a pilot study. PMID- 25438034 TI - Is Anterior Cruciate Reconstruction Superior to Conservative Treatment? AB - Not all patients who have a rupture of the anterior cruciate ligament (ACL) elect to have surgical reconstruction. The aim of this study was to assess the short-to medium-term results of patients who chose conservative management in comparison to patients who had reconstructive surgery within the same time period. Sixty three patients with an ACL injury were retrospectively studied. Forty patients were managed, according to patient choice, with ACL reconstruction and 23 conservatively. Four validated questionnaires were used to assess general and knee-specific function in a cohort with a median age of 32 years and a median follow-up period of 38 months. Patients were matched on demographic variables except for gender. There were no statistically significant differences in the outcome measures, and the majority of patients would proceed with the same treatment in the event the control leg became injured. Patients who elect to have conservative management of an ACL rupture can achieve similar function and satisfaction to those who elect to have reconstruction. Until a large randomized controlled trial is conducted, patients need to be made aware of the merits of both management strategies and the lack of evidence of superiority of one over the other. PMID- 25438035 TI - An empirical model of human aspiration in low-velocity air using CFD investigations. AB - Computational fluid dynamics (CFD) modeling was performed to investigate the aspiration efficiency of the human head in low velocities to examine whether the current inhaled particulate mass (IPM) sampling criterion matches the aspiration efficiency of an inhaling human in airflows common to worker exposures. Data from both mouth and nose inhalation, averaged to assess omnidirectional aspiration efficiencies, were compiled and used to generate a unifying model to relate particle size to aspiration efficiency of the human head. Multiple linear regression was used to generate an empirical model to estimate human aspiration efficiency and included particle size as well as breathing and freestream velocities as dependent variables. A new set of simulated mouth and nose breathing aspiration efficiencies was generated and used to test the fit of empirical models. Further, empirical relationships between test conditions and CFD estimates of aspiration were compared to experimental data from mannequin studies, including both calm-air and ultra-low velocity experiments. While a linear relationship between particle size and aspiration is reported in calm air studies, the CFD simulations identified a more reasonable fit using the square of particle aerodynamic diameter, which better addressed the shape of the efficiency curve's decline toward zero for large particles. The ultimate goal of this work was to develop an empirical model that incorporates real-world variations in critical factors associated with particle aspiration to inform low-velocity modifications to the inhalable particle sampling criterion. PMID- 25438036 TI - Developing piperine towards TRPV1 and GABAA receptor ligands--synthesis of piperine analogs via Heck-coupling of conjugated dienes. AB - Piperine, the pungent alkaloid of black pepper, and several of its derivatives are modulators of gamma-amino butyric acid type A (GABAA) receptors. Concomitantly, this natural product has also been reported to activate transient receptor potential vanilloid type 1 (TRPV1) receptors. We have developed a Heck cross-coupling reaction of conjugated dienamides enabling the rapid assembly of piperine derivatives containing a modified aromatic core. Upon assessment of a focussed compound library, key aromatic substituents were identified selectively affecting either the GABAA or the TRPV1 receptor. PMID- 25438037 TI - Reply to: mast cells in fibromyalgia. PMID- 25438038 TI - Alginate microencapsulated hepatocytes optimised for transplantation in acute liver failure. AB - BACKGROUND AND AIM: Intraperitoneal transplantation of alginate-microencapsulated human hepatocytes is an attractive option for the management of acute liver failure (ALF) providing short-term support to allow native liver regeneration. The main aim of this study was to establish an optimised protocol for production of alginate-encapsulated human hepatocytes and evaluate their suitability for clinical use. METHODS: Human hepatocyte microbeads (HMBs) were prepared using sterile GMP grade materials. We determined physical stability, cell viability, and hepatocyte metabolic function of HMBs using different polymerisation times and cell densities. The immune activation of peripheral blood mononuclear cells (PBMCs) after co-culture with HMBs was studied. Rats with ALF induced by galactosamine were transplanted intraperitoneally with rat hepatocyte microbeads (RMBs) produced using a similar optimised protocol. Survival rate and biochemical profiles were determined. Retrieved microbeads were evaluated for morphology and functionality. RESULTS: The optimised HMBs were of uniform size (583.5+/-3.3 um) and mechanically stable using 15 min polymerisation time compared to 10 min and 20 min (p<0.001). 3D confocal microscopy images demonstrated that hepatocytes with similar cell viability were evenly distributed within HMBs. Cell density of 3.5*10(6) cells/ml provided the highest viability. HMBs incubated in human ascitic fluid showed better cell viability and function than controls. There was no significant activation of PBMCs co-cultured with empty or hepatocyte microbeads, compared to PBMCs alone. Intraperitoneal transplantation of RMBs was safe and significantly improved the severity of liver damage compared to control groups (empty microbeads and medium alone; p<0.01). Retrieved RMBs were intact and free of immune cell adherence and contained viable hepatocytes with preserved function. CONCLUSION: An optimised protocol to produce GMP grade alginate encapsulated human hepatocytes has been established. Transplantation of microbeads provided effective metabolic function in ALF. These high quality HMBs should be suitable for use in clinical transplantation. PMID- 25438039 TI - Treatment adherence and health outcomes in MSM with HIV/AIDS: patients enrolled in "one-stop" and standard care clinics in Wuhan China. AB - BACKGROUND: Conducted in Wuhan China, this study examined follow-up and health markers in HIV patients receiving care in two treatment settings. Participants, all men who have sex with men, were followed for 18-24 months. METHOD: Patients in a "one-stop" service (ACC; N = 89) vs those in standard care clinics (CDC; N = 243) were compared on HIV treatment and retention in care outcomes. RESULTS: Among patients with CD4 cell count ?350 cells/uL, the proportion receiving cART did not differ across clinic groups. The ACC was favored across five other indicators: proportion receiving tests for CD4 cell count at the six-month interval (98.2% vs. 79.4%, 95% CI 13.3-24.3, p = 0.000), proportion with HIV suppression for patients receiving cART for 6 months (86.5% vs. 57.1%, 95% CI 14.1-44.7, p = 0.000), proportion with CD4 cell recovery for patients receiving cART for 12 months (55.8% vs. 22.2%, 95% CI 18.5-48.6, p = 0.000), median time from HIV confirmation to first test for CD4 cell count (7 days, 95% CI 4-8 vs. 10 days, 95% CI 9-12, log-rank p = 0.000) and median time from first CD4 cell count ?350 cells/uL to cART initiation (26 days, 95% CI 16-37 vs. 41.5 days, 95% CI 35 46, log-rank p = 0.031). Clinic groups did not differ on any biomedical indicator at baseline, and no baseline biomedical or demographic variables remained significant in the multivariate analysis. Nonetheless, post-hoc analyses suggest the possibility of self-selection bias. CONCLUSIONS: Study findings lend preliminary support to a one-stop patient-centered care model that may be useful across various HIV care settings. PMID- 25438040 TI - Hyaluronic acid enhances the mechanical properties of tissue-engineered cartilage constructs. AB - There is a need for materials that are well suited for cartilage tissue engineering. Hydrogels have emerged as promising biomaterials for cartilage repair, since, like cartilage, they have high water content, and they allow cells to be encapsulated within the material in a genuinely three-dimensional microenvironment. In this study, we investigated the mechanical properties of tissue-engineered cartilage constructs using in vitro culture models incorporating human chondrocytes from osteoarthritis patients. We evaluated hydrogels formed from mixtures of photocrosslinkable gelatin-methacrylamide (Gel MA) and varying concentrations (0-2%) of hyaluronic acid methacrylate (HA-MA). Initially, only small differences in the stiffness of each hydrogel existed. After 4 weeks of culture, and to a greater extent 8 weeks of culture, HA-MA had striking and concentration dependent impact on the changes in mechanical properties. For example, the initial compressive moduli of cell-laden constructs with 0 and 1% HA-MA were 29 and 41 kPa, respectively. After 8 weeks of culture, the moduli of these constructs had increased to 66 and 147 kPa respectively, representing a net improvement of 69 kPa for gels with 1% HA-MA. Similarly the equilibrium modulus, dynamic modulus, failure strength and failure strain were all improved in constructs containing HA-MA. Differences in mechanical properties did not correlate with glycosaminoglycan content, which did not vary greatly between groups, yet there were clear differences in aggrecan intensity and distribution as assessed using immunostaining. Based on the functional development with time in culture using human chondrocytes, mixtures of Gel-MA and HA-MA are promising candidates for cartilage tissue-engineering applications. PMID- 25438041 TI - An updated meta-analysis of the efficacy and safety of acupuncture treatment for cerebral infarction. AB - BACKGROUND: Ischemic stroke is the second most common cause of death and the primary cause of disability throughout the world. Acupuncture is frequently advocated as an adjunct treatment during stroke rehabilitation. The aim of this study was to update the clinical efficacy and safety of acupuncture for cerebral infarction. METHODS: Randomized controlled trials (RCT) on acupuncture treating cerebral infarction were searched from the following databases: PubMed, EMBASE, Cochrane Library, CNKI, CMB and VIP from inception to October 2013. The data of RCTs meeting the inclusive criteria were extracted according to Cochrane methods. The meta-analyses were conducted using Rev Man 5.0 software. RESULTS: A total of 25 trials involving 2224 patients were included. The results of this meta analysis showed that the groups receiving acupuncture (observation group) were superior to the comparison groups (control group), with significant differences in the Clinical Efficacy Rates [OR = 4.04, 95%CI (2.93, 5.57), P<0.001], Fugl Meyer Assessment [MD = 11.22, 95%CI (7.62, 14.82), P<0.001], Barthel Index Score [MD = 12.84, 95%CI (9.85, 15.82), P<0.001], and Neurological Deficit Score [MD = 2.71, 95% CI (-3.84, -1.94), P<0.001]. Three trials reported minor adverse events. CONCLUSION: Current evidence provisionally demonstrates that acupuncture treatment is superior to either non-acupuncture or conventional therapy for cerebral infarction. Despite this conclusion, given the often low quality of the available trials, further large scale RCTs of better quality are still needed. PMID- 25438042 TI - Etanercept and uveitis: friends or foes? PMID- 25438043 TI - Functional neuroanatomy of executive function after neonatal brain injury in adults who were born very preterm. AB - Individuals who were born very preterm (VPT; <33 gestational weeks) are at risk of experiencing deficits in tasks involving executive function in childhood and beyond. In addition, the type and severity of neonatal brain injury associated with very preterm birth may exert differential effects on executive functioning by altering its neuroanatomical substrates. Here we addressed this question by investigating with functional magnetic resonance imaging (fMRI) the haemodynamic response during executive-type processing using a phonological verbal fluency and a working memory task in VPT-born young adults who had experienced differing degrees of neonatal brain injury. 12 VPT individuals with a history of periventricular haemorrhage and ventricular dilatation (PVH+VD), 17 VPT individuals with a history of uncomplicated periventricular haemorrhage (UPVH), 13 VPT individuals with no history of neonatal brain injury and 17 controls received an MRI scan whilst completing a verbal fluency task with two cognitive loads ('easy' and 'hard' letters). Two groups of VPT individuals (PVH+VD; n = 10, UPVH; n = 8) performed an n-back task with three cognitive loads (1-, 2-, 3 back). Results demonstrated that VPT individuals displayed hyperactivation in frontal, temporal, and parietal cortices and in caudate nucleus, insula and thalamus compared to controls, as demands of the verbal fluency task increased, regardless of type of neonatal brain injury. On the other hand, during the n-back task and as working memory load increased, the PVH+VD group showed less engagement of the frontal cortex than the UPVH group. In conclusion, this study suggests that the functional neuroanatomy of different executive-type processes is altered following VPT birth and that neural activation associated with specific aspects of executive function (i.e., working memory) may be particularly sensitive to the extent of neonatal brain injury. PMID- 25438044 TI - Universal internucleotide statistics in full genomes: a footprint of the DNA structure and packaging? AB - Uncovering the fundamental laws that govern the complex DNA structural organization remains challenging and is largely based upon reconstructions from the primary nucleotide sequences. Here we investigate the distributions of the internucleotide intervals and their persistence properties in complete genomes of various organisms from Archaea and Bacteria to H. Sapiens aiming to reveal the manifestation of the universal DNA architecture. We find that in all considered organisms the internucleotide interval distributions exhibit the same [Formula: see text]-exponential form. While in prokaryotes a single [Formula: see text] exponential function makes the best fit, in eukaryotes the PDF contains additionally a second [Formula: see text]-exponential, which in the human genome makes a perfect approximation over nearly 10 decades. We suggest that this functional form is a footprint of the heterogeneous DNA structure, where the first [Formula: see text]-exponential reflects the universal helical pitch that appears both in pro- and eukaryotic DNA, while the second [Formula: see text] exponential is a specific marker of the large-scale eukaryotic DNA organization. PMID- 25438045 TI - Shining light on benthic macroalgae: mechanisms of complementarity in layered macroalgal assemblages. AB - Phototrophs underpin most ecosystem processes, but to do this they need sufficient light. This critical resource, however, is compromised along many marine shores by increased loads of sediments and nutrients from degraded inland habitats. Increased attenuation of total irradiance within coastal water columns due to turbidity is known to reduce species' depth limits and affect the taxonomic structure and architecture of algal-dominated assemblages, but virtually no attention has been paid to the potential for changes in spectral quality of light energy to impact production dynamics. Pioneering studies over 70 years ago showed how different pigmentation of red, green and brown algae affected absorption spectra, action spectra, and photosynthetic efficiency across the PAR (photosynthetically active radiation) spectrum. Little of this, however, has found its way into ecological syntheses of the impacts of optically active contaminants on coastal macroalgal communities. Here we test the ability of macroalgal assemblages composed of multiple functional groups (including representatives from the chlorophyta, rhodophyta and phaeophyta) to use the total light resource, including different light wavelengths and examine the effects of suspended sediments on the penetration and spectral quality of light in coastal waters. We show that assemblages composed of multiple functional groups are better able to use light throughout the PAR spectrum. Macroalgal assemblages with four sub-canopy species were between 50-75% more productive than assemblages with only one or two sub-canopy species. Furthermore, attenuation of the PAR spectrum showed both a loss of quanta and a shift in spectral distribution with depth across coastal waters of different clarity, with consequences to productivity dynamics of diverse layered assemblages. The processes of light complementarity may help provide a mechanistic understanding of how altered turbidity affects macroalgal assemblages in coastal waters, which are increasingly threatened by diminishing light quantity and altered spectral distributions through sedimentation and eutrophication. PMID- 25438046 TI - Ability to maintain internal arousal and motivation modulates brain responses to emotions. AB - Persistence (PS) is defined as the ability to generate and maintain arousal and motivation internally in the absence of immediate external reward. Low PS individuals tend to become discouraged when expectations are not rapidly fulfilled. The goal of this study was to investigate whether individual differences in PS influence the recruitment of brain regions involved in emotional processing and regulation. In a functional MRI study, 35 subjects judged the emotional intensity of displayed pictures. When processing negative pictures, low PS (vs. high PS) subjects showed higher amygdala and right orbito frontal cortex (OFC) activity but lower left OFC activity. This dissociation in OFC activity suggests greater prefrontal cortical asymmetry for approach/avoidance motivation, suggesting an avoidance response to aversive stimuli in low PS. For positive or neutral stimuli, low PS subjects showed lower activity in the amygdala, striatum, and hippocampus. These results suggest that low PS may involve an imbalance in processing distinct emotional inputs, with greater reactivity to aversive information in regions involved in avoidance behaviour (amygdala, OFC) and dampened response to positive and neutral stimuli across circuits subserving motivated behaviour (striatum, hippocampus, amygdala). Low PS affective style was associated with depression vulnerability. These findings in non-depressed subjects point to a neural mechanism whereby some individuals are more likely to show systematic negative emotional biases, as frequently observed in depression. The assessment of these individual differences, including those that may cause vulnerability to depressive disorders, would therefore constitute a promising approach to risk assessment for depression. PMID- 25438047 TI - Effective therapeutic approach for head and neck cancer by an engineered minibody targeting the EGFR receptor. AB - Cetuximab, a chimeric monoclonal antibody developed for targeting the Epidermal Growth Factor Receptor (EGFR), has been intensively used to treat cancer patients with metastatic colorectal cancer and head and neck cancer. Intact immunoglobulin G (IgG) antibody like cetuximab, however, has some limitations such as high production cost and low penetration rate from vasculature into solid tumor mass due to its large size. In attempt to overcome these limitations, we engineered cetuximab to create single chain variable fragments (scFv-CH3; Minibody) that were expressed in bacterial system. Among three engineered minibodies, we found that MI061 minibody, which is composed of the variable heavy (VH) and light (VL) region joined by an 18-residue peptide linker, displays higher solubility and better extraction properties from bacterial lysate. In addition, we validated that purified MI061 significantly interferes ligand binding to EGFR and blocks EGFR's phosphorylation. By using a protein microarray composed of 16,368 unique human proteins covering around 2,400 plasma membrane associated proteins such as receptors and channels, we also demonstrated that MI061 only recognizes the EGFR but not other proteins as compared with cetuximab. These results indicated that engineered MI061 retains both binding specificity and affinity of cetuximab for EGFR. Although it had relatively short half-life in serum, it was shown to be highly significant anti-tumor effect by inhibiting ERK pathway in A431 xenograft model. Taken together, our present study provides compelling evidence that engineered minibody is more effective and promising agent for in vivo targeting of solid tumors. PMID- 25438049 TI - Why i'm opting out of mammography. PMID- 25438048 TI - The repeat region of the circumsporozoite protein is critical for sporozoite formation and maturation in Plasmodium. AB - The circumsporozoite protein (CSP) is the major surface protein of the sporozoite stage of malaria parasites and has multiple functions as the parasite develops and then migrates from the mosquito midgut to the mammalian liver. The overall structure of CSP is conserved among Plasmodium species, consisting of a species specific central tandem repeat region flanked by two conserved domains: the NH2 terminus and the thrombospondin repeat (TSR) at the COOH-terminus. Although the central repeat region is an immunodominant B-cell epitope and the basis of the only candidate malaria vaccine in Phase III clinical trials, little is known about its functional role(s). We used the rodent malaria model Plasmodium berghei to investigate the role of the CSP tandem repeat region during sporozoite development. Here we describe two mutant parasite lines, one lacking the tandem repeat region (DeltaRep) and the other lacking the NH2-terminus as well as the repeat region (DeltaNDeltaRep). We show that in both mutant lines oocyst formation is unaffected but sporozoite development is defective. PMID- 25438050 TI - Hatching time and alevin growth prior to the onset of exogenous feeding in farmed, wild and hybrid Norwegian Atlantic salmon. AB - The onset of exogenous feeding, when juveniles emerge from the gravel, is a critical event for salmonids where early emergence and large size provide a competitive advantage in the wild. Studying 131 farmed, hybrid and wild Norwegian Atlantic salmon families, originating from four wild populations and two commercial strains, we investigated whether approximately 10 generations of selection for faster growth has also resulted in increased somatic growth prior to the onset of exogenous feeding. In addition, we tested whether relaxed selection in farms has allowed for alterations in hatching time between farmed and wild salmon. Across three cohorts, wild salmon families hatched earlier than farmed salmon families, while hybrid families displayed intermediate hatching times. While the observed differences were small, i.e., 1-15 degree-days (0-3 days, as water temperatures were c. 5-6 degrees C), these data suggest additive genetic variation for hatching time. Alevin length prior to exogenous feeding was positively related to egg size. After removal of egg size effects, no systematic differences in alevin length were observed between the wild and farmed salmon families. While these results indicate additive genetic variation for egg development timing, and wild salmon families consistently hatched earlier than farmed salmon families, these differences were so small they are unlikely to significantly influence early life history competition of farmed and wild salmon in the natural environment. This is especially the case given that the timing of spawning among females can vary by several weeks in some rivers. The general lack of difference in size between farmed and wild alevins, strongly suggest that the documented differences in somatic growth rate between wild and farmed Norwegian Atlantic salmon under hatchery conditions are first detectable after the onset of exogenous feeding. PMID- 25438051 TI - Neonicotinoid-contaminated puddles of water represent a risk of intoxication for honey bees. AB - In recent years, populations of honey bees and other pollinators have been reported to be in decline worldwide. A number of stressors have been identified as potential contributing factors, including the extensive prophylactic use of neonicotinoid insecticides, which are highly toxic to bees, in agriculture. While multiple routes of exposure to these systemic insecticides have been documented for honey bees, contamination from puddle water has not been investigated. In this study, we used a multi-residue method based on LC-MS/MS to analyze samples of puddle water taken in the field during the planting of treated corn and one month later. If honey bees were to collect and drink water from these puddles, our results showed that they would be exposed to various agricultural pesticides. All water samples collected from corn fields were contaminated with at least one neonicotinoid compound, although most contained more than one systemic insecticide. Concentrations of neonicotinoids were higher in early spring, indicating that emission and drifting of contaminated dust during sowing raises contamination levels of puddles. Although the overall average acute risk of drinking water from puddles was relatively low, concentrations of neonicotinoids ranged from 0.01 to 63 ug/L and were sufficient to potentially elicit a wide array of sublethal effects in individuals and colony alike. Our results also suggest that risk assessment of honey bee water resources underestimates the foragers' exposure and consequently miscalculates the risk. In fact, our data shows that honey bees and native pollinators are facing unprecedented cumulative exposure to these insecticides from combined residues in pollen, nectar and water. These findings not only document the impact of this route of exposure for honey bees, they also have implications for the cultivation of a wide variety of crops for which the extensive use of neonicotinoids is currently promoted. PMID- 25438057 TI - Is biomedical research a good investment? AB - As the US addresses its budget dilemma, the easiest items to cut are those with the longest-term payoff. Research stands out among this group. Biomedical research has already been markedly reduced, and further reductions appear to be in store. As a frequent witness in Congressional hearings on such matters, here I discuss the challenge of assessing the value of investments in biomedical research. PMID- 25438056 TI - Adamantyl analogues of paracetamol as potent analgesic drugs via inhibition of TRPA1. AB - Paracetamol also known as acetaminophen, is a widely used analgesic and antipyretic agent. We report the synthesis and biological evaluation of adamantyl analogues of paracetamol with important analgesic properties. The mechanism of nociception of compound 6a/b, an analog of paracetamol, is not exerted through direct interaction with cannabinoid receptors, nor by inhibiting COX. It behaves as an interesting selective TRPA1 channel antagonist, which may be responsible for its analgesic properties, whereas it has no effect on the TRPM8 nor TRPV1 channels. The possibility of replacing a phenyl ring by an adamantyl ring opens new avenues in other fields of medicinal chemistry. PMID- 25438058 TI - A conversation with David Nathan. PMID- 25438055 TI - AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation. AB - Inhibition of a main regulator of cell metabolism, the protein kinase mTOR, induces autophagy and inhibits cell proliferation. However, the molecular pathways involved in the cross-talk between these two mTOR-dependent cell processes are largely unknown. Here we show that the scaffold protein AMBRA1, a member of the autophagy signalling network and a downstream target of mTOR, regulates cell proliferation by facilitating the dephosphorylation and degradation of the proto-oncogene c-Myc. We found that AMBRA1 favours the interaction between c-Myc and its phosphatase PP2A and that, when mTOR is inhibited, it enhances PP2A activity on this specific target, thereby reducing the cell division rate. As expected, such a de-regulation of c-Myc correlates with increased tumorigenesis in AMBRA1-defective systems, thus supporting a role for AMBRA1 as a haploinsufficient tumour suppressor gene. PMID- 25438054 TI - Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase. AB - The Hippo signalling pathway plays important roles in animal development, physiology and tumorigenesis. Understanding how the activity of this pathway is regulated by the cellular microenvironment remains a major challenge. Here we elucidate a molecular mechanism by which hypoxia deactivates Hippo signalling. We demonstrate that the E3 ubiquitin ligase SIAH2 stimulates YAP by destabilizing LATS2, a critical component of the Hippo pathway, in response to hypoxia. Loss of SIAH2 suppresses tumorigenesis in a LATS2-dependent manner in a xenograft mouse model. We further show that YAP complexes with HIF1alpha and is essential for HIF1alpha stability and function in tumours in vivo. LATS2 is downregulated in human breast tumours and negatively correlates with SIAH2 expression levels, indicating that the SIAH2-LATS2 pathway may have a role in human cancer. Our data uncover oxygen availability as a microenvironment signal for the Hippo pathway and have implications for understanding the regulation of Hippo signalling in tumorigenesis. PMID- 25438060 TI - Retraction: Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients. PMID- 25438064 TI - Enhanced field emission and photocatalytic performance of MoS2 titania nanoheterojunctions via two synthetic approaches. AB - Two types of molybdenum disulfide (MoS2) titania nanoheterojunctions with different morphologies were synthesized via two different approaches. They were facile and additive-free hydrothermal processes, which resulted in a high material productivity and controllable morphologies. Both the synthesis and their growth mechanisms are discussed in this paper. The field emission properties of MoS2 titania nanoheterojunctions were investigated in this research. The experimental data indicated that the MoS2@TiO2 heterojunctions had an excellent field emission performance with a turn-on field of 2.2 V MUm(-1) and threshold field of 3.6 V MUm(-1) on Si substrate because of the large quantities of sharp edges. Furthermore, because the p-n heterojunctions were formed, the photocatalytic activities of both composites were evaluated by monitoring the photodegradation of methylene blue. The results showed that the TiO2@MoS2 heterojunctions had better photocatalytic properties with 90% degradation within 100 minutes. The morphological differences generated from different synthetic approaches made a huge impact on the composites' properties. PMID- 25438063 TI - The constitutive activation of Egr-1/C/EBPa mediates the development of type 2 diabetes mellitus by enhancing hepatic gluconeogenesis. AB - The sequential secretion of insulin and glucagon delicately maintains glucose homeostasis by inhibiting or enhancing hepatic gluconeogenesis during postprandial or fasting states, respectively. Increased glucagon/insulin ratio is believed to be a major cause of the hyperglycemia seen in type 2 diabetes. Herein, we reveal that the early growth response gene-1 (Egr-1) can be transiently activated by glucagon in hepatocytes, which mediates glucagon regulated gluconeogenesis by increasing the expression of gluconeogenesis genes. Blockage of Egr-1 function in the liver of mice led to lower fasting blood glucose, better pyruvate tolerance, and higher hepatic glycogen content. The mechanism analysis demonstrated that Egr-1 can directly bind to the promoter of C/EBPa and regulate the expression of gluconeogenesis genes in the later phase of glucagon stimulation. The transient increase of Egr-1 by glucagon kept the glucose homeostasis after fasting for longer periods of time, whereas constitutive Egr-1 elevation found in the liver of db/db mice and high serum glucagon level overactivated the C/EBPa/gluconeogenesis pathway and resulted in hyperglycemia. Blockage of Egr-1 activation in prediabetic db/db mice was able to delay the progression of diabetes. Our results suggest that dysregulation of Egr 1/C/EBPa on glucagon stimulation may provide an alternative mechanistic explanation for type 2 diabetes. PMID- 25438065 TI - Excited-state proton transfer in confined medium. 4-methyl-7-hydroxyflavylium and beta-naphthol incorporated in cucurbit[7]uril. AB - Excited-state proton transfer (ESPT) was studied by fluorescent emission using a mathematical model recast from the Weller theory. The titration curves can be fitted with three parameters: pK(a) (acidity constant of the ground sate), pK(ap)* (apparent acidity constant of the excited state), and eta(A*), the efficiency of excited base formation from the excited acid. beta-Naphthol and 4 metyhl-7-hydroxyflavylium were studied in aqueous solution and upon incorporation in cucurbit[7]uril. For all the compounds studied the interaction with the host leads to 1:1 adducts and the ground-state pK(a) increases upon incorporation. Whereas the ESPT of 4-methyl-7-hydroxyflavylium practically does not change in the presence of the host, in the case of beta-naphthol it is prevented and the fluorescence emission titration curves are coincident with those taken by absorption. The position of the guest inside the host was investigated by NMR experiments and seems to determine the efficiency of the ESPT. The ESPT decreases for the guest, exhibiting a great protection of the phenol to the bulk water interaction. PMID- 25438062 TI - Junctional adhesion molecule A promotes epithelial tight junction assembly to augment lung barrier function. AB - Epithelial barrier function is maintained by tight junction proteins that control paracellular fluid flux. Among these proteins is junctional adhesion molecule A (JAM-A), an Ig fold transmembrane protein. To assess JAM-A function in the lung, we depleted JAM-A in primary alveolar epithelial cells using shRNA. In cultured cells, loss of JAM-A caused an approximately 30% decrease in transepithelial resistance, decreased expression of the tight junction scaffold protein zonula occludens 1, and disrupted junctional localization of the structural transmembrane protein claudin-18. Consistent with findings in other organs, loss of JAM-A decreased beta1 integrin expression and impaired filamentous actin formation. Using a model of mild systemic endoxotemia induced by i.p. injection of lipopolysaccharide, we report that JAM-A(-/-) mice showed increased susceptibility to pulmonary edema. On injury, the enhanced susceptibility of JAM A(-/-) mice to edema correlated with increased, transient disruption of claudin 18, zonula occludens 1, and zonula occludens 2 localization to lung tight junctions in situ along with a delay in up-regulation of claudin-4. In contrast, wild-type mice showed no change in lung tight junction morphologic features in response to mild systemic endotoxemia. These findings support a key role of JAM-A in promoting tight junction homeostasis and lung barrier function by coordinating interactions among claudins, the tight junction scaffold, and the cytoskeleton. PMID- 25438067 TI - Structure and photochemistry of a saccharyl thiotetrazole. AB - The molecular structure and photochemistry of 5-thiosaccharyl-1-methyltetrazole (TSMT) were studied by means of matrix-isolation FTIR spectroscopy, X-ray crystallography, and theoretical calculations. The calculations predicted two conformers of TSMT that differ in energy by more than 15 kJ mol(-1). The infrared spectrum of TSMT isolated in solid argon was fully assigned on the basis of the spectrum calculated (O3LYP/6-311++G(3df,3pd)) for the most stable conformer. In the crystal, TSMT molecules were found to assume the same conformation as for the isolated molecule, with each molecule forming four hydrogen bonds with three neighboring molecules, leading to a network of TSMT oligomers. Upon UV (lambda = 265 nm) irradiation of the matrix-isolated TSMT, two photodegradation pathways were observed, both arising from cleavage of the tetrazolyl ring. Pathway a involves cleavage of the N1-N2 and N3-N4 bonds with extrusion of N2, leading to photostable diazirine and thiocarbodiimide derivatives. The photostability of the photoproduced diazirine under the conditions used precluded its rearrangement to the nitrile imine, as reported for 5-phenyltetrazole by Begue et al. ( J. Am. Chem. Soc. 2012 , 134 , 5339 ). Pathway b involves cleavage of the C5-N1 and N4 N3 bonds, leading to a thiocyanate and methyl azide, the latter undergoing subsequent fragmentation to give CNH. PMID- 25438068 TI - New LaMAsH(x) (M = Co, Ni, or Cu) arsenides with covalent M-H chains. AB - A new series of tetragonal LaPtSi-type mixed-anion arsenides, LaMAsH(x) (M = Co, Ni, or Cu), has been synthesized using high-temperature and high-pressure techniques. The crystal structure of these intermetallic compounds determined via powder neutron diffraction is composed of a 3D framework of three connected planes with the La ions filling the cavities in the structure. Each late transition-metal ion M, all of which have relatively large electronegativities, behaves like a main group element and forms a planar coordination configuration with three As ions. The trigonal-bipyramidal coordination adopted by the H in the cavity, HM2La3, is compressed along the C3 axis, and unusual M-H chains run along the x and y directions, reinforcing the covalent framework. These chains, which are unique in solids, are stabilized by covalent interactions between the M 4s and H 1s orbitals. PMID- 25438066 TI - Prevalence of pregnancy experiences and contraceptive knowledge among single adults in a low socio-economic suburban community in Kuala Lumpur, Malaysia. AB - BACKGROUND: This study aimed to investigate the prevalence of pregnancy experience and its association with contraceptive knowledge among single adults in a low socio-economic suburban community in Kuala Lumpur, Malaysia. METHODS: A cross-sectional survey was conducted in 2012 among the Kerinchi suburban community. Of the total 3,716 individuals surveyed, young single adults between 18 and 35 years old were questioned with regard to their experience with unplanned pregnancy before marriage. Contraceptive knowledge was assessed by a series of questions on identification of method types and the affectivity of condoms for the prevention of sexually transmitted diseases. RESULTS: A total of 226 female and 257 male participants completed the survey. In total, eight female (3.5%) participants reported experience with an unplanned pregnancy before marriage, and five male (1.9 %) participants had the experience of impregnating their partners. The participants had a mean total score of 3.15 (SD = 1.55) for contraceptive knowledge out of a possible maximum score of five. Female participants who had experienced an unplanned pregnancy had a significantly lower contraceptive knowledge score (2.10 +/- 1.48) than who had never experienced pregnancy (3.30 +/- 1.35), p<0.05. Likewise, male participants who had experienced impregnating their partners had a significantly lower contraceptive knowledge score (1.60 +/- 1.50) than those who did not have such experience (3.02 +/- 1.59), p<0.05. CONCLUSION: The results showed evidence of premarital unplanned pregnancy among this suburban community. The low level of contraceptive knowledge found in this study indicates the need for educational strategies designed to improve contraceptive knowledge. PMID- 25438069 TI - Photo-responsive pseudorotaxanes and assemblies. AB - Chemists have achieved a predictable control over various non-covalent interactions and have used these weak interactions in their favour for developing a plethora of intricate functional structures. In this tutorial review we have summarized reports on such supramolecular structures that describe the rational approach in designing host and/or guest components, tagged with an appropriate fluorophore, for achieving the modified optical responses on formation of an assembly. This has relevance for designing new photo-responsive smart or adaptive stimuli responsive functional materials, self-healable materials, with interesting photo-physical property. These are also important in the area of supramolecular chemistry and biophysical chemistry in predicting the relative conformation in solution. PMID- 25438070 TI - Efficacy of stone density on noncontrast computed tomography in predicting the outcome of extracorporeal shock wave lithotripsy for patients with pancreatic stones. AB - OBJECTIVES: Patients with chronic pancreatitis are managed by extracorporeal shock wave lithotripsy (ESWL) for pancreatic stones. Stone density on noncontrast computed tomography (NCCT) is used to predict stone composition and fragility, but no report investigating the pancreatic stone density has been documented. We aimed to assess the usefulness of pancreatic stone density on NCCT in predicting the ESWL outcome. METHODS: We evaluated 128 consecutive patients with pancreatic stones who underwent ESWL. Pancreatic stone density on NCCT was measured in Hounsfield units. Patients with complete stone removal were compared with those with incomplete stone removal. Patient characteristics; imaging findings, including stone density; and interventions were evaluated as potential predictors. The optimal cutoff value of variables to differentiate complete removal from incomplete removal was determined by receiver operating characteristic analysis. RESULTS: Complete stone removal was achieved in 66 patients (51.6%). When the density threshold was set at 820.5 Hounsfield units, complete stone removal was achieved in 52 patients (78.8%) with lower-density stones. In multivariate analysis, single stone (P = 0.007) and lower-density stone (P < 0.001) revealed significant association with complete stone removal. CONCLUSIONS: The measurement of pancreatic stone density before therapy can help predict therapeutic outcomes. PMID- 25438071 TI - Incidence of post-ERCP pancreatitis from direct pancreatic juice collection in hereditary pancreatitis and familial pancreatic cancer before and after the introduction of prophylactic pancreatic stents and rectal diclofenac. AB - OBJECTIVES: Individuals from hereditary pancreatitis (HP) and familial pancreatic cancer (FPC) kindreds are at increased risk of developing pancreatic cancer. Premalignant molecular changes may be detected in pancreatic juice collected by endoscopic retrograde cholangiopancreatography (ERCP). The objective was to determine the risk of post-ERCP pancreatitis (PEP). METHODS: A prospective study (1999-2013) was undertaken of 80 ERCPs (24 in HP and 56 in FPC) from 60 individuals and the impact of PEP prophylaxis using a self-expelling pancreatic stent and 50 mg diclofenac per rectum from 2008. RESULTS: There was no PEP in the HP cohort and 13 (23.2%) PEP from 56 procedures in the FPC cohort (P = 0.0077). Up to 2008 PEP had occurred in 7 (43.8%) of 16 procedures in FPC individuals versus none of 18 procedures in HP individuals (P = 0.0021). After the introduction of prophylaxis, the incidence of PEP fell to 6 (15.0%) of 40 procedures in FPC individuals (P = 0.0347).The odds ratio (95% confidence interval) was 0.23 (0.06-0.84) in favor of prophylaxis (0.035). CONCLUSIONS: Individuals with HP are at minimal risk for PEP. Although the risk of PEP in individuals with FPC can be reduced by using prophylactic self-expelling stents and diclofenac, it remains too high for routine screening. PMID- 25438072 TI - A multicenter study on etiology of acute pancreatitis in Beijing during 5 years. AB - OBJECTIVES: The aim of this study was to determine the etiology tendency of acute pancreatitis (AP) in the Beijing region and the relationship with influencing factors. METHODS: This retrospective multicenter study enrolled 8 representative general hospitals from January 1, 2006 to December 31, 2010. The etiology tendency was analyzed, and the relationship was defined with sex, aging, severity, mortality, recrudesce rate, length of stay, and hospitalization cost. RESULTS: The study enrolled 2461 patients. The total number was increasing year by year. Causes included biliary (1372, 55.75%), alcoholism (246, 10%), hypertriglyceridemia (255, 10.36%), and the others (588, 23.89%). Biliary AP was the most frequent primary cause. Hypertriglyceridemic AP increased at a faster rate than alcoholic AP. There was higher proportion of alcoholic and hypertriglyceridemic AP in men than in women. There is an increase of AP patients with ages 40 to 49 years and older than 70 years. Alcoholic and hypertriglyceridemic AP were higher in patients younger than the age of 50 years, and biliary pancreatitis was higher in patients older than 70 years. Severe AP was classified among 736 patients (29.9%). Etiology distribution was different between severe AP and mild AP (P < 0.001). Mortality in the hospital was 1.54%, and there was no difference in each group. Recrudesce of hypertriglyceridemic AP was higher (P < 0.01). CONCLUSIONS: Acute pancreatitis patients increased year by year in Beijing. Gallstones were the predominant etiological factor. There were different etiology proportion of AP according age, sex, and severity. PMID- 25438073 TI - Proteomic profiling of antigens in circulating immune complexes associated with each of seven autoimmune diseases. AB - OBJECTIVE: Immune complexes (ICs) trigger humoral immune responses. Therefore, the identification of constituent antigens within ICs would have very different clinical significance than identification of free antigens. DESIGN AND METHODS: Here, we applied immune complexome analysis of serum to the study of seven major autoimmune diseases-anti-neutrophil cytoplasmic antibody-associated vasculitis, Takayasu's arteritis, mixed connective tissue disease, dermatomyositis, Sjogren's syndrome, systemic scleroderma, and systemic lupus erythematosus-and healthy donors to comprehensively identify antigens incorporated into circulating ICs and to find disease-specific antigens. RESULTS: We identified 468 distinct IC associated antigens using this method. Importantly, 62 of those antigens were disease-specific antigens, and there were at least three disease-specific antigens for each of the seven autoimmune diseases. Of the disease-specific antigens identified, coiled-coil domain-containing protein 158 and spectrin were identified as potential autoantigens important to SSc and SS pathogenesis, respectively; notable titin and spectrin autoantibodies are reportedly found in SSc and SS patients, respectively. CONCLUSION: Immune complexome analysis may be generally applicable to the study of the relationship between ICs and autoimmune diseases in animals and humans. PMID- 25438074 TI - HDL particle number measured on the Vantera(r), the first clinical NMR analyzer. AB - OBJECTIVES: Nuclear magnetic resonance (NMR) spectroscopy has been successfully applied to the measurement of high-density lipoprotein (HDL) particles, providing particle concentrations for total HDL particle number (HDL-P), HDL subclasses (small, medium, large) and weighted, average HDL size for many years. Key clinical studies have demonstrated that NMR-measured HDL-P was more strongly associated with measures of coronary artery disease and a better predictor of incident cardiovascular disease (CVD) events than HDL-cholesterol (HDL-C). Recently, an NMR-based clinical analyzer, the Vantera((r)), was developed to allow lipoprotein measurements to be performed in the routine, clinical laboratory setting. The aim of this study was to evaluate and report the performance characteristics for HDL-P quantified on the Vantera((r)) Clinical Analyzer. DESIGN AND METHODS: Assay performance was evaluated according to Clinical and Laboratory Standards Institute (CLSI) guidelines. In order to ensure that quantification of HDL-P on the Vantera((r)) Clinical Analyzer was similar to the well-characterized HDL-P assay on the NMR profiler, a method comparison was performed. RESULTS: The within-run and within-lab imprecision ranged from 2.0% to 3.9%. Linearity was established within the range of 10.0 to 65.0 MUmol/L. The reference intervals were different between men (22.0 to 46.0 MUmol/L) and women (26.7 to 52.9 MUmol/L). HDL-P concentrations between two NMR platforms, Vantera((r)) Clinical Analyzer and NMR Profiler, demonstrated excellent correlation (R(2) = 0.98). CONCLUSIONS: The performance characteristics, as well as the primary tube sampling procedure for specimen analysis on the Vantera((r)) Clinical Analyzer, suggest that the HDL-P assay is suitable for routine clinical applications. PMID- 25438076 TI - Welcome to the next step for Oncogenesis. PMID- 25438075 TI - Usefulness of S100A12 as a prognostic biomarker for adverse events in patients with heart failure. AB - OBJECTIVES: S100A12 has been proposed as a novel pivotal factor in inflammation produced by granulocytes. The purpose of this study was to investigate the relationship between S100A12 and chronic heart failure (CHF). DESIGN AND METHODS: One hundred and seventy-seven patients with CHF and 66 subjects without CHF were included in this study. Plasma levels of S100A12 and high-sensitivity C-reactive protein (hs-CRP) were measured in all participants. After a follow-up period of 18months for CHF patients, major cardiovascular events (MCE), including cardiac death and rehospitalization for heart failure, were recorded. RESULTS: Plasma levels of S100A12 were significantly higher in CHF patients than in control subjects (P<0.001) and positively correlated with hs-CRP (r=0.316, P<0.001). S100A12 levels were also higher in MCE patients than in MCE-free patients. The occurrence of MCE increased with advancing plasma S100A12 levels by stratification according to quartiles (Q4 vs Q1, P=0.015). Cox proportional hazards regression analysis revealed that S100A12 was an independent risk factor for MCE in CHF patients (P=0.009). CONCLUSIONS: S100A12 is a potential biomarker of CHF that may provide important information regarding the prediction of MCE in patients with CHF. PMID- 25438077 TI - Effects of lazaroid U-74389G on intestinal ischemia and reperfusion injury in porcine experimental model. AB - BACKGROUND: The readmission of molecular oxygen into an ischemic tissue promotes the oxidation of resuscitated tissue with certain pathophysiologic mechanisms. MATERIALS AND METHODS: Twenty four pigs (male or female) were randomized in this study. The animals were allocated to four groups with an equal number (n = 6) in each group: (1) control group-ischemia for 30 min and reperfusion for 60 min. (2) control group-ischemia for 30 min and reperfusion for 120 min. (3) ischemia for 30 min and immediate iv injection of lazaroid U-74389G and reperfusion for 60 min. (4) ischemia for 30 min and immediate iv injection of lazaroid U-74389G and reperfusion for 120 min. RESULTS: We investigated further the role of an antioxidant molecule such as U-74389G and we concluded that there is statistically significant relation in MDA (malondialdeyde), TNF -alpha (tumor necrosis factor-alpha) measurement in tissue, while the histological score in the groups that the lazaroid was administered was improved. CONCLUSIONS: In many emergency clinical situations, such as reperfusion of the intestine, the role of U-74389G can be protective. PMID- 25438078 TI - Facile synthesis of bis(indolyl)methanes catalyzed by alpha-chymotrypsin. AB - A mild and efficient method catalyzed by alpha-chymotrypsin was developed for the synthesis of bis(indolyl)methanes through a cascade process between indole and aromatic aldehydes. In the ethanol aqueous solution, a green medium, a wide range of aromatic aldehydes could react with indole to afford the desired products with moderate to good yields (from 68% to 95%) using a little alpha-chymotrypsin as catalyst. PMID- 25438079 TI - Mechanisms underlying vasorelaxation induced in rat aorta by galetin 3,6-dimethyl ether, a flavonoid from Piptadenia stipulacea (Benth.) Ducke. AB - In this study, we investigated the relaxant action of galetin 3,6-dimethyl ether (FGAL) on rat aorta. The flavonoid relaxed both PMA- and phenylephrine (Phe) induced contractions (pD2 = 5.36 +/- 0.11 and 4.17 +/- 0.10, respectively), suggesting the involvement of PKC and Phe pathways or alpha1 adrenergic receptor blockade. FGAL inhibited and rightward shifted Phe-induced cumulative contraction response curves, indicating a noncompetitive antagonism of alpha1 adrenergic receptors. The flavonoid was more potent in relaxing 30 mM KCl- than 80 mM KCl induced contractions (pD2 = 5.50 +/- 0.22 and 4.37 +/- 0.12). The vasorelaxant potency of FGAL on Phe-induced contraction was reduced in the presence of 10 mM TEA+. Furthermore, in the presence of apamin, glibenclamide, BaCl2 or 4-AP, FGAL induced relaxation was attenuated, indicating the participation of small conductance calcium-activated K+ channels (SKCa), ATP-sensitive K+ channels (KATP), inward rectifier K+ channels (Kir) and voltage-dependent K+ channels (KV), respectively. FGAL inhibited and rightward shifted CaCl2-induced cumulative contraction-response curves in both depolarizing medium (high K+) and in the presence of verapamil and phenylephrine, suggesting inhibition of Ca2+ influx through voltage-gated calcium channels (CaV) and receptor operated channels (ROCs), respectively. Likewise, FGAL inhibited Phe-induced contractions in Ca2+ free medium, indicating inhibition of Ca2+ release from the sarcoplasmic reticulum (SR). FGAL potentiated the relaxant effect of aminophylline and sildenafil but not milrinone, suggesting the involvement of phosphodiesterase V (PDE V). Thus, the FGAL vasorelaxant mechanism involves noncompetitive antagonism of alpha1 adrenergic receptors, the non-selective opening of K+ channels, inhibition of Ca2+ influx through CaV or ROCs and the inhibition of intracellular Ca2+ release. Additionally, there is the involvement of cyclic nucleotide pathway, particularly through PDE V inhibition. PMID- 25438080 TI - Cloning and characterisation of the gene encoding 3-hydroxy-3-methylglutaryl-CoA synthase in Tripterygium wilfordii. AB - Tripterygium wilfordii is a traditional Chinese medical plant used to treat rheumatoid arthritis and cancer. The main bioactive compounds of the plant are diterpenoids and triterpenoids. 3-Hydroxy-3-methylglutaryl-CoA synthase (HMGS) catalyses the reaction of acetoacetyl-CoA to 3-hydroxy-3-methylglutaryl-CoA, which is the first committed enzyme in the mevalonate (MVA) pathway. The sequence information of HMGS in Tripterygium wilfordii is a basic resource necessary for studying the terpenoids in the plant. In this paper, full-length cDNA encoding HMGS was isolated from Tripterygium wilfordii (abbreviated TwHMGS, GenBank accession number: KM978213). The full length of TwHMGS is 1814 bp, and the gene encodes a protein with 465 amino acids. Sequence comparison revealed that TwHMGS exhibits high similarity to HMGSs of other plants. The tissue expression patterns revealed that the expression level of TwHMGS is highest in the stems and lowest in the roots. Induced expression of TwHMGS can be induced by MeJA, and the expression level is highest 4 h after induction. The functional complement assays in the YML126C knockout yeast demonstrated that TwHMGS participates in yeast terpenoid biosynthesis. PMID- 25438081 TI - Unstable simple volatiles and gas chromatography-tandem mass spectrometry analysis of essential oil from the roots bark of Oplopanax horridus extracted by supercritical fluid extraction. AB - Volatile oil from the root bark of Oplopanax horridus is regarded to be responsible for the clinical uses of the title plant as a respiratory stimulant and expectorant. Therefore, a supercritical fluid extraction method was first employed to extract the volatile oil from the roots bark of O. horridus, which was subsequently analyzed by GC/MS. Forty-eight volatile compounds were identified by GC/MS analysis, including (S,E)-nerolidol (52.5%), tau-cadinol (21.6%) and S-falcarinol (3.6%). Accordingly, the volatile oil (100 g) was subjected to chromatographic separation and purification. As a result, the three compounds, (E)-nerolidol (2 g), tau-cadinol (62 mg) and S-falcarinol (21 mg), were isolated and purified from the volatile oil, the structures of which were unambiguously elucidated by detailed spectroscopic analysis including 1D- and 2D NMR techniques. PMID- 25438082 TI - Synthesis and biological evaluation of novel 10-substituted-7-ethyl-10 hydroxycamptothecin (SN-38) prodrugs. AB - In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2), novel prodrugs of SN-38 (3) were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. The synthesized compounds completely generated SN-38 in pH 7.4 buffer or in human plasma, while remaining stable under acidic conditions. All prodrug compounds demonstrated much greater in vitro antitumor activities against HeLa cells and SGC-7901 cells than irinotecan. The most active compounds, 5h, 7c, 7d, and 7f, exhibited IC50 values that were 1000 times lower against HeLa cells and 30 times lower against SGC-7901 cells than those of irinotecan, and the inhibitory activities of these prodrugs against acetylcholinesterase (AchE) were significantly reduced, with IC50 values more than 6.8 times greater than that of irinotecan. In addition, compound 5e exhibited the same level of tumor growth inhibitory activity as irinotecan (CPT-11) in a human colon xenograft model in vivo. PMID- 25438083 TI - Photocatalysis for renewable energy production using PhotoFuelCells. AB - The present work is a short review of our recent studies on PhotoFuelCells, that is, photoelectrochemical cells which consume a fuel to produce electricity or hydrogen, and presents some unpublished data concerning both electricity and hydrogen production. PhotoFuelCells have been constructed using nanoparticulate titania photoanodes and various cathode electrodes bearing a few different types of electrocatalyst. In the case where the cell functioned with an aerated cathode, the cathode electrode was made of carbon cloth carrying a carbon paste made of carbon black and dispersed Pt nanoparticles. When the cell was operated in the absence of oxygen, the electrocatalyst was deposited on an FTO slide using a special commercial carbon paste, which was again enriched with Pt nanoparticles. Mixing of Pt with carbon paste decreased the quantity of Pt necessary to act as electrocatalyst. PhotoFuelCells can produce electricity without bias and with relatively high open-circuit voltage when they function in the presence of fuel and with an aerated cathode. In that case, titania can be sensitized in the visible region by CdS quantum dots. In the present work, CdS was deposited by the SILAR method. Other metal chalcogenides are not functional as sensitizers because the combined photoanode in their presence does not have enough oxidative power to oxidize the fuel. Concerning hydrogen production, it was found that it is difficult to produce hydrogen in an alkaline environment even under bias, however, this is still possible if losses are minimized. One way to limit losses is to short-circuit anode and cathode electrode and put them close together. This is achieved in the "photoelectrocatalytic leaf", which was presently demonstrated capable of producing hydrogen even in a strongly alkaline environment. PMID- 25438084 TI - Post-polymerization modification of poly(L-glutamic acid) with D-(+)-glucosamine. AB - Carboxyl functional groups of poly(L-glutamic acid) (PGlu) were modified with a D (+)-glucosamine (GlcN) by amidation using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4 methylmorpholinium chloride (DMTMM) as a coupling reagent. The coupling reaction was performed in aqueous medium without protection of hydroxyl functional groups of D-(+)-glucosamine. Poly(L-glutamic acid) and GlcN functionalized polyglutamates (P(Glu-GlcN)) were thoroughly characterized by 1D and 2D NMR spectroscopy and SEC-MALS to gain detailed information on their structure, composition and molar mass characteristics. The results reveal successful functionalization with GlcN through the amide bond and also to a minor extent through ester bond formation in position 1 of GlcN. In addition, a ratio between the alpha- and beta-form of glucosamine substituent coupled to polyglutamate repeating units as well as the content of residual dimethoxy triazinyl active ester moiety in the samples were evaluated. PMID- 25438085 TI - Efficacious gene silencing in serum and significant apoptotic activity induction by survivin downregulation mediated by new cationic gemini tocopheryl lipids. AB - Nonviral gene delivery offers cationic liposomes as promising instruments for the delivery of double-stranded RNA (ds RNA) molecules for successful sequence specific gene silencing (RNA interference). The efficient delivery of siRNA (small interfering RNA) to cells while avoiding unexpected side effects is an important prerequisite for the exploitation of the power of this excellent tool. We present here six new tocopherol based cationic gemini lipids, which induce substantial gene knockdown without any obvious cytotoxicity. All the efficient coliposomal formulations derived from each of these geminis and a helper lipid, dioleoylphosphatidylethanolamine (DOPE), were well characterized using physical methods such as atomic force microscopy (AFM) and dynamic light scattering (DLS). Zeta potential measurements were conducted to estimate the surface charge of these formulations. Flow cytometric analysis showed that the optimized coliposomal formulations could transfect anti-GFP siRNA efficiently in three different GFP expressing cell lines, viz., HEK 293T, HeLa, and Caco-2, significantly better than a potent commercial standard Lipofectamine 2000 (L2K) both in the absence and in the presence of serum (FBS). Notably, the knockdown activity of coliposomes of gemini lipids was not affected even in the presence of serum (10% and 50% FBS) while it dropped down for L2K significantly. Observations under a fluorescence microscope, RT-PCR, and Western blot analysis substantiated the flow cytometry results. The efficient cellular entry of labeled siRNA in GFP expressing cells as evidenced from confocal microscopy put forward these gemini lipids among the potent lipidic carriers for siRNA. The efficient transfection capabilities were also profiled in a more relevant fashion while performing siRNA transfections against survivin (an anti-apoptotic protein) which induced substantial apoptosis. Furthermore, the survivin downregulation improved the therapeutic efficacy levels of an anticancer drug, doxorubicin, significantly. In short, the new tocopherol based gemini lipids appear to be highly promising for achieving siRNA mediated gene knockdown in various cell lines. PMID- 25438086 TI - Pseudosolid, shear-thinning gel formation in binary dispersions of metal oxide nanoparticles at low volume fractions. AB - Hydroxyl groups on the surface of metal oxide nanoparticles (nps) can be protonated or deprotonated depending on solution pH, changing both the magnitude and sign of the nps' surface charge. Binary mixtures of fumed metal oxide nps, dispersed in water at a solution pH where one species is positively charged and the other is negatively charged, form pseudosolid gels at volume fractions as low as 1.5 vol %. This work maps out regions of gel formation for binary mixtures of silica and alumina nps, silica and titania nps, and alumina and titania nps. The microscopic structure of these gels is investigated using transmission electron microscopy (TEM), small-angle x-ray scattering (SAXS), acoustic spectroscopy, and light microscopy. PMID- 25438087 TI - Optoelectrochemical biorecognition by optically transparent highly conductive graphene-modified fluorine-doped tin oxide substrates. AB - Both optical and electrochemical graphene-based sensors have gone through rapid development, reaching high sensitivity at low cost and with fast response time. However, the complex validating biochemical operations, needed for their consistent use, currently limits their effective application. We propose an integration strategy for optoelectrochemical detection that overcomes previous limitations of these sensors used separately. We develop an optoelectrochemical sensor for aptamer-mediated protein detection based on few-layer graphene immobilization on selectively modified fluorine-doped tin oxide (FTO) substrates. Our results show that the electrochemical properties of graphene-modified FTO samples are suitable for complex biological detection due to the stability and inertness of the engineered electrodic interface. In addition, few-layer immobilization of graphene sheets through electrostatic linkage with an electrochemically grafted FTO surface allows obtaining an optically accessible and highly conductive platform. As a proof of concept, we used insulin as the target molecule to reveal in solution. Because of its transparency and low sampling volume (a few microliters), our sensing unit can be easily integrated in lab-on-a-chip cell culture systems for effectively monitoring subnanomolar concentrations of proteins relevant for biomedical applications. PMID- 25438089 TI - Improving the accuracy of vehicle emissions profiles for urban transportation greenhouse gas and air pollution inventories. AB - Metropolitan greenhouse gas and air emissions inventories can better account for the variability in vehicle movement, fleet composition, and infrastructure that exists within and between regions, to develop more accurate information for environmental goals. With emerging access to high quality data, new methods are needed for informing transportation emissions assessment practitioners of the relevant vehicle and infrastructure characteristics that should be prioritized in modeling to improve the accuracy of inventories. The sensitivity of light and heavy-duty vehicle greenhouse gas (GHG) and conventional air pollutant (CAP) emissions to speed, weight, age, and roadway gradient are examined with second-by second velocity profiles on freeway and arterial roads under free-flow and congestion scenarios. By creating upper and lower bounds for each factor, the potential variability which could exist in transportation emissions assessments is estimated. When comparing the effects of changes in these characteristics across U.S. cities against average characteristics of the U.S. fleet and infrastructure, significant variability in emissions is found to exist. GHGs from light-duty vehicles could vary by -2%-11% and CAP by -47%-228% when compared to the baseline. For heavy-duty vehicles, the variability is -21%-55% and -32%-174%, respectively. The results show that cities should more aggressively pursue the integration of emerging big data into regional transportation emissions modeling, and the integration of these data is likely to impact GHG and CAP inventories and how aggressively policies should be implemented to meet reductions. A web-tool is developed to aide cities in improving emissions uncertainty. PMID- 25438088 TI - Application of three-photon excitation FCS to the study of protein oligomerization. AB - Three-photon excitation fluorescence correlation spectroscopy was used to detect oligomerization equilibria of rat liver phosphofructokinase. The fluorescence intensity produced by the three-photon excitation of tryptophan was collected using the DIVER microscope. In this home-built upright microscope, a large area photomultiplier, placed directly below the sample, is used as the detector. The lack of optical elements in the microscope detection path results in a significantly improved detection efficiency in the UV region down to about 300 nm, which encompasses the fluorescence emission from tryptophan. The three-photon excitation autocorrelation decays obtained for phosphofructokinase in the presence of F6P showed the presence of large oligomers. Substitution of F6P with ATP in the buffer medium results in dissociation of the large oligomers, which is reported by the decreased autocorrelation amplitude. The three-photon excitation process was verified from the slope of the log-log plot of intensity against laser power. PMID- 25438090 TI - Parenting stress and children's problem behavior in China: the mediating role of parental psychological aggression. AB - This study examined the mediating effect of parents' psychological aggression in the relationship between parenting stress and children's internalizing (anxiety/depression, withdrawal) and externalizing (aggression, delinquency) problem behaviors 1 year later. Using a sample of 311 intact 2-parent Chinese families with preschoolers, findings revealed that maternal parenting stress had direct effects on children's internalizing and externalizing problem behavior and indirect effects through maternal psychological aggression. However, neither direct nor indirect effects of fathers' parenting stress on children's internalizing and externalizing problem behavior were found. The findings highlight the importance of simultaneously studying the effects of both mothers' and fathers' parenting on their children within a family systems framework. PMID- 25438091 TI - Nanoengineered diamond waveguide as a robust bright platform for nanomagnetometry using shallow nitrogen vacancy centers. AB - Photonic structures in diamond are key to most of its application in quantum technology. Here, we demonstrate tapered nanowaveguides structured directly onto the diamond substrate hosting shallow-implanted nitrogen vacancy (NV) centers. By optimization based on simulations and precise experimental control of the geometry of these pillar-shaped nanowaveguides, we achieve a net photon flux up to ~ 1.7 * 10(6) s(-1). This presents the brightest monolithic bulk diamond structure based on single NV centers so far. We observe no impact on excited state lifetime and electronic spin dephasing time (T2) due to the nanofabrication process. Possessing such high brightness with low background in addition to preserved spin quality, this geometry can improve the current nanomagnetometry sensitivity ~ 5 times. In addition, it facilitates a wide range of diamond defects-based magnetometry applications. As a demonstration, we measure the temperature dependency of T1 relaxation time of a single shallow NV center electronic spin. We observe the two-phonon Raman process to be negligible in comparison to the dominant two-phonon Orbach process. PMID- 25438093 TI - Predicting the voltage dependence of interfacial electrochemical processes at lithium-intercalated graphite edge planes. AB - The applied potential governs lithium-intercalation and electrode passivation reactions in lithium ion batteries, but are challenging to calibrate in condensed phase DFT calculations. In this work, the "anode potential" of charge-neutral lithium-intercalated graphite (LiC6) with oxidized edge planes is computed as a function of Li-content (nLi) at edge planes, using ab initio molecular dynamics (AIMD), a previously introduced Li(+) transfer free energy method, and the experimental Li(+)/Li(s) value as reference. The voltage assignments are corroborated using explicit electron transfer from fluoroethylene carbonate radical anion markers. PF6(-) is shown to decompose electrochemically (i.e., not just thermally) at low potentials imposed by our voltage calibration technique. We demonstrate that excess electrons reside in localized states-in-the-gap in the organic carbonate liquid region, which is not semiconductor-like (band-state like) as widely assumed in the literature. PMID- 25438094 TI - False recognition of instruction-set lures. AB - False remembering has been examined using a variety of procedures, including the Deese-Roediger-McDermott procedure, the false fame procedure and the two-list recognition procedure. We present six experiments in a different empirical framework examining false recognition of words included in the experimental instructions (instruction-set lures). The data show that participants' false alarm rate to instruction-set lures was twice their false alarm rate to standard lures. That result was statistically robust even when (1) the relative strength of targets to instruction-set lures was increased, (2) participants were warned about the instruction-set lures, (3) the instruction-set lures were camouflaged in the study instructions and (4) the instruction-set lures were presented verbally at study but visually at test. False recognition of instruction-set lures was only mitigated when participants were distracted between encountering the instruction-set lures and studying the training list. The results confirm the ease with which recognition succumbs to familiarity and demonstrate the robustness of false recognition. PMID- 25438092 TI - Simultaneous activation of the alpha1A-, alpha1B- and alpha1D-adrenoceptor subtypes in the nucleus accumbens reduces accumbal dopamine efflux in freely moving rats. AB - Intra-accumbal infusion of the alpha1-adrenergic agonist methoxamine, which has comparable affinity for alpha1A-, alpha1B- and alpha1D-adrenoceptor subtypes, fails to alter noradrenaline efflux but reduces dopamine efflux in the nucleus accumbens of rats. In-vivo microdialysis experiments were carried out to analyse the putative contribution of alpha1A-, alpha1B- and alpha1D-adrenoceptor subtypes to the methoxamine-induced decrease in accumbal dopamine efflux in freely moving rats. The drugs used were dissolved in the infusion medium and administered locally through a dialysis membrane. Intra-accumbal infusions of the alpha1A adrenoceptor antagonist 5-methylurapidil (6 pmol), the alpha1B-adrenoceptor antagonist cyclazosin (0.6 and 6 pmol) and the alpha1D-adrenoceptor antagonist BMY 7378 (0.6 pmol) did not alter accumbal efflux of noradrenaline or dopamine: pretreatment with each of these alpha1-adrenoceptor subtype-selective antagonists counteracted the methoxamine (24 pmol)-induced decrease in accumbal dopamine efflux. Doses indicated are the total amount of drug administered over a 60-min infusion period. These results clearly suggest that the alpha1A-, alpha1B- and alpha1D-adrenoceptor subtypes in the nucleus accumbens mediate the alpha1 adrenergic agonist methoxamine-induced decrease in accumbal dopamine efflux. The present study also provides in-vivo neurochemical evidence indicating that concomitant, but not separate, activation of the alpha1A-, alpha1B- and alpha1D adrenoceptors in the nucleus accumbens is required for alpha1-adrenergic inhibition of accumbal dopaminergic activity. PMID- 25438095 TI - Vision-based approach for long-term mobility monitoring: Single case study following total hip replacement. AB - This article presents a single case study on the feasibility of using a low-cost and portable vision-based system (a Microsoft Kinect sensor) to monitor changes in movement patterns before and after a total hip replacement surgery. The primary subject was a male older adult with total hip replacement who performed two different functional tasks: walking and sit-to-stand. The tasks were recorded with a Kinect multiple times, starting from 1 d before the surgery until 9 wk after the surgery. An automated algorithm has been developed to extract the important spatiotemporal characteristics from the video recorded functional tasks (walking and sit-to-stand). Statistical analysis was then performed by Tryon C statistic to study changes in spatiotemporal characteristics between different stages before and after the surgery. The statistical analysis indicated significant difference and slight improvement between all measures from the presurgery to each postsurgery date. The study confirmed that the Kinect sensor and an automated algorithm have the potential to be integrated into a patient's home to monitor changes in mobility during the recovery period. PMID- 25438096 TI - In patients with rheumatoid arthritis, Dickkopf-1 serum levels are correlated with parathyroid hormone, bone erosions and bone mineral density. AB - OBJECTIVES: The objective of this study is to compare the serum levels of Dickkopf-1 (DKK1), a natural inhibitor of Wnt signalling, with parathyroid hormone (PTH) and bone involvement in patients with rheumatoid arthritis (RA). METHODS: This cross-sectional study includes 154 postmenopausal women with RA and 125 healthy controls. DKK1, 25OH vitamin D (25OHD), bone turnover markers, and PTH serum levels were measured by ELISA; lumbar spine and hip bone mineral density (BMD) and the erosion score were obtained. RESULTS: The RA patients and healthy controls were not significantly different in terms of age, body mass index, and 25OHD serum levels. The mean level of DKK1 and PTH were significantly higher in patients with RA than in healthy controls (172+/-68 [SD] vs. 96+/-55 pmoL/L, and 30+/-15 vs 22+/-11, respectively; p<0.0001). DKK1 serum levels were positively correlated with age (p<0.05) only in the healthy controls, while they were correlated with PTH serum levels only in the RA patients (p<0.0001). Among the RA patients, DKK1 levels adjusted for age, PTH and disease duration were significantly higher in patients with bone erosions (176 vs. 167 pmoL/L, respectively; p<0.05). DKK1 levels adjusted for age and PTH were negatively correlated with total hip BMD (p<0.05). In the RA patients not on treatment with bisphosphonates, DKK1 serum levels positively correlated with C-terminal telopeptides of type I collagene serum levels (p<0.05). CONCLUSIONS: In patients with RA, serum levels of DKK1 are significantly increased, correlate with PTH and are associated with increased risk of bone erosions and osteoporosis. However, this finding deserves confirmation in a larger and more selected population. PMID- 25438097 TI - Piezoelectric surgery -a novel technique for laminectomy. AB - OBJECTIVE: Piezoelectric surgery is a novel technology that allows for the osteotomy of mineralized tissue with less risk of damaging underlying soft tissue structures. This selective cutting increases the safety of osteotomies performed in close vicinity to delicate structures such as dura mater, blood vessels, and neural tissue. This study aimed to develop and describe the technique of piezoelectric surgery for dorsal laminectomy and to assess its clinical safety in normal sheep. METHODS: A piezoelectric, dorsal laminectomy technique was developed using ovine cadavers. Following technique development, six live sheep underwent a piezoelectric (n = 6) two-level dorsal laminectomy at L2-L3 and L4-L5 (PiezoL2-3,4-5), and another 30 live sheep underwent a three-level laminectomy at L1, L3, and L5 (PiezoL1,3,5) for a total of 102 laminectomy sites. Surgery time and postoperative complications were recorded. RESULTS: Dorsal laminectomy was safely and accurately performed in 35/36 study sheep using a Piezoelectric surgical instrument. No dural tears were noted in any animal. Non-ambulatory paraparesis in one study sheep (PiezoL1,3,5) led to euthanasia at 48 hr and only mild epidural hematoma was noted on necropsy. No other major postoperative complications were observed in any of the animals. Subjectively, PiezoL was easy to perform and with a rapid learning curve. Mean surgery time was 105 min (range: 75-165 min; median: 97.5) for PiezoL2-3,4-5 and 93 minutes (range 55-100 min; median: 67.5) for PiezoL1,3,5. CONCLUSIONS: Based on our study, PiezoL is considered a safe and viable technique for performing ovine dorsal laminectomy in the preclinical research setting. PMID- 25438098 TI - Mild rhodium(III)-catalyzed C-H allylation with 4-vinyl-1,3-dioxolan-2-ones: direct and stereoselective synthesis of (E)-allylic alcohols. AB - A rhodium(III)-catalyzed C-H direct allylation reaction with 4-vinyl-1,3-dioxolan 2-ones has been developed. The reaction provides a facile and stereoselective access to substituted-(E)-allylic alcohols under mild and redox-neutral reaction conditions. Olefinic C-H activation is applicable, giving multifunctionalized skipped dienes in good yields. Minimal double-bond migration was observed. PMID- 25438099 TI - Does Implant Design Affect Implant Primary Stability? A Resonance Frequency Analysis-Based Randomized Split-Mouth Clinical Trial. AB - The purpose of this study was to assess implant stability in relation to implant design (conical vs. semiconical and wide-pitch vs narrow-pitch) using resonance frequency analysis. Twenty patients with bilateral edentulous maxillary premolar region were selected. In one hemiarch, conical implants with wide pitch (group 1) were installed; in the other hemiarch, semiconical implants with narrow pitch were installed (group 2). The implant allocation was randomized. The implant stability quotient (ISQ) was measured by resonance frequency analysis immediately following implant placement to assess primary stability (time 1) and at 90 days after placement (time 2). In group 1, the mean and standard deviation ISQ for time 1 was 65.8 +/- 6.22 (95% confidence interval [CI], 55 to 80), and for time 2, it was 68.0 +/- 5.52 (95% CI, 57 to 77). In group 2, the mean and standard deviation ISQ was 63.6 +/- 5.95 (95% CI, 52 to 78) for time 1 and 67.0 +/- 5.71 (95% CI, 58 to 78) for time 2. The statistical analysis demonstrated significant difference in the ISQ values between groups at time 1 (P = .007) and no statistical difference at time 2 (P = .54). The greater primary stability of conical implants with wide pitch compared with semiconical implants with narrow pitch might suggest a preference for the former in case of the adoption of immediate or early loading protocols. PMID- 25438101 TI - Morphology and gene expression profile of the submandibular gland of androgen receptor-deficient mice. AB - OBJECTIVES: In the submandibular gland (SMG) of mice, the granular convoluted tubule (GCT) develops preferentially in males dependent on androgens. To clarify the molecular mechanism of androgen action in SMG, we examined the SMG of mice deficient for the androgen receptor (ARKO). DESIGN: The morphological features and gene expression in the SMG of control and ARKO mice with or without hormone treatments were analysed by immunohistochemistry, DNA microarray, and RT-PCR. RESULTS: The development of GCT and expression of GCT-specific products such as NGF were even lower in ARKO male SMG than in control female SMG. The administration of androgens to ARKO males had no effect on SMG, whereas the administration of thyroid hormone (T4) caused the extensive conversion of striated duct cells to GCT cells with the increase of NGF mRNA. Gene expression profiles in control and ARKO male SMG were analysed by DNA microarrays, and genes with higher or lower expression in ARKO male SMG were determined. They were then classified into groups according to their responsiveness to the administration of dihydotestosterone (DHT) or T4 to ARKO males. RT-PCR revealed that, while no gene was responsive to DHT, expression of many genes was up- or down-regulated by T4. CONCLUSIONS: These results confirmed that GCT cell differentiation induced by androgens is dependent on the classical androgen receptor (AR), whereas that by T4 is independent of AR. Differential reactivity of genes to androgens and thyroid hormone in ARKO mice may shed light on the mechanism of androgen action in the SMG. PMID- 25438100 TI - Fluoride alters connexin expression in rat incisor pulp. AB - OBJECTIVE: Connexins (Cxs) are important to control growth and cell differentiation of dental tissues. The aim of the present study was to assess the impact of chronic exposure to sodium fluoride (NaF) on Cxs expression and alkaline phosphatase (ALP) activity in dental pulp, and on morphometric parameters of adult rat mandible and incisors. DESIGN: Three groups of male Wistar rats (22 days-old) were given water containing: (a) 0.3 mg/L (Control), (b) 10 mg/L and (c) 50 mg/L of NaF for eight weeks. Incisor pulp homogenates were prepared for determination of Cx32, Cx43 and Cx45 gene expression, using semi quantitative RT-PCR, and of ALP activity. Morphometric parameters of mandible and incisors were determined on radiographs. RESULTS: Cx43 gene expression increased with exposure to NaF in a dose-dependent manner. Cx32 mRNA levels were higher than controls in the 10mg/L NaF group only; Cx45 mRNA levels were lower in groups given 10 and 50mg/L of NaF than in controls. ALP activity was higher in both high NaF dose groups compared to the control group (p<0.05). Lower incisor diameter was lower in the 50 mg/L NaF than in the control group (p<0.01). None of the mandibular growth parameters were affected by NaF treatment. CONCLUSION: Our results showed that fluorotic alterations in rat incisor were associated with increased Cx43 expression and ALP activity, as well as with changes in the expression pattern of different Cxs in pulp tissue. The observed changes may have a stimulating effect on dentin mineralization. PMID- 25438102 TI - Oestrogen regulates bone resorption and cytokine production in the maxillae of female mice. AB - Oestrogen plays major role in bone metabolism/remodelling. Despite of well established effect of oestrogen deficiency on long bones, it remains unclear whether alveolar bone is affected. We aimed to determine the effect of oestrogen deficiency in the alveolar bone microarchitecture. C57BL6/J and Balb/c mice were ovariectomized and implanted with oil-(OVX) or 17beta-estradiol (E2)-containing (OVX+E2) capsules. Ovary-intact mice were used as controls. The dose of E2 replacement was selected based on trophic effects on the uterus and femur bone loss. As determined by maxillary alveolar bone MicroCT analysis, both C57BL6/J and Balb/c OVX mice displayed decreased trabecular thickness, bone density and bone volume, and increased trabecular separation at 15 and 30 days after ovariectomy. These effects were associated with a reduction of trabecular bone percentage and cortical thickness in the femur. A significant loss of alveolar bone crest was also associated with ovariectomy in both mice strains. The E2 replacement fully prevented ovariectomy-induced alterations in the alveolar and femoral bones. Moreover, TNF-alpha (tumour necrosis factor-alpha) levels and RANKL/OPG (receptor activator of NF-kappaB ligand/osteoprotegerin) ratio were increased in the maxilla after OVX, and these responses were also reversed by E2. In conclusion, oestrogen deficiency causes maxillary alveolar bone loss, which is similar to the effects found in the femur. The release of inflammatory molecules like TNF-alpha, RANKL and OPG is the potential mechanism to the decrease of bone quality and alveolar bone crest. PMID- 25438103 TI - Effect of unintentional partial Achilles tenotomy on Ponseti clubfoot management outcomes. AB - The congenital talipes equinovarus (clubfoot) is one of the most common congenital conditions requiring orthopedic intervention. This study was carried out to evaluate the effect of unintentional partial Achilles tendon cut during percutaneous tenotomy on the success rate of Ponseti management. Percentage of Achilles tendon cut following percutaneous tenotomy was measured by ultrasound in 16 clubfeet (11 patients). After a mean of 21 months of follow-up, the final results (Dimeglio score) were compared between two groups of patients: those with complete tendon cut and those with partial cut. Complications and parameters such as feeling of pop during tenotomy and ankle dorsiflexion during tenotomy were also compared. There was no significant correlation between the percentage of Achilles tendon cut and increase in ankle joint dorsiflexion, age at diagnosis, or pop sensation. There was no statistically significant difference between the two groups in their ankle joint dorsiflexion, feeling of pop, and final follow-up Dimeglio score. No complications were encountered following tenotomy. One patient needed tibialis anterior transfer at his last follow-up visit. Partial cut of Achilles tendon following tenotomy does not necessarily compromise the final results of Ponseti management. Achieving more than 10 degrees -20 degrees ankle dorsiflexion even with a partial tendon cut can ensure good final results. PMID- 25438104 TI - Conservative treatment of severe clubfoot using a novel functional dynamic splint. AB - Forty-six severe clubfeet in 29 patients were treated by serial castings, followed by a newly developed dynamic splint. The mean period of splint usage was 59.9 months and the mean period of follow-up was 81.5 months. Of the patients, 76.1% were satisfied, 87.0% had no functional deficit, and 84.8% had no pain. Radiographical evaluation showed good correction. The mean dorsiflexion angle was -0.8 degrees at the end of cast treatment and 13.6 degrees at the time of the final follow-up. This study clearly showed the effectiveness of a functional dynamic splint for the correction of equinus in cases of severe clubfoot. PMID- 25438105 TI - Clinical outcome of posteromedial versus posteromedial-lateral release for clubfoot. AB - Although the Ponseti serial casting method is the gold standard for the management of clubfoot, surgical correction remains the best option for resistant cases. Therefore, we compared posteromedial and posteromedial-lateral surgical approaches for the correction of resistant clubfoot. Between 2007 and 2013, 68 patients with idiopathic nonsyndromic resistant clubfoot, who were admitted to our referral institute, were enrolled in our study. The patients were divided into two groups. The patients in group 1 (33 cases of clubfoot) underwent posteromedial release with a single incision and those in group 2 (35 cases of clubfoot) underwent posteromedial-lateral release by two separate incisions. The severity of deformity was classified according to the Dimeglio classification. After the operations, all patients were followed up and surgical results as well as acute and chronic complications were evaluated. The patients were followed up for a mean of 43 months, and at the last follow-up visit, the Dimeglio scores in groups 1 and 2 were 4.8+/-3.8 and 3.3+/-2.6, respectively (P=0.04). Outcomes improved in both groups significantly. Although group 2 had more severe deformity, compared with group 1 at the baseline, the final outcome was better in this group. Heel varus and equinus was corrected more appropriately in group 2. Complications such as navicular dorsal subluxation and valgus overcorrection were less common in group 2. In cases of resistant clubfoot, it appears that a posteromedial-lateral approach with two separate incisions not only provides a better correction but is also associated with a lower complication rate in comparison with the single-incision posteromedial approach. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25438106 TI - Osteochondrosis of the accessory ossification centre of the medial malleolus. AB - We report a case of a painful accessory ossification centre of the medial malleolus in an 11-year-old girl who was not involved in sports activities. The patient was treated conservatively, with complete clinical and radiographic healing of the medial malleolus 6 months after the first presentation. We ruled out the uncommon pathological conditions causing chronic pain in the medial malleolus during skeletal growth, such as traction apophysitis of the medial malleolus, osteochondrosis, osteochondritis or avascular necrosis of the distal tibial epiphysis. We speculate that this painful condition may be classified as an osteochondrosis of the accessory ossification centre of the medial malleolus. PMID- 25438107 TI - Epiphysiolysis of the femoral neck due to closed reduction of an adolescent hip dislocation with a 4-year follow-up: a case report and review of the literature. AB - This case study discusses a 13-year-old girl diagnosed with a displaced Salter Harris II fracture of the proximal femoral epiphysis post reduction of a dislocated hip. Radiographs before reduction revealed a small fracture of the inferomedial femoral head. This, however, did not induce concern before reduction. The patient underwent reparative surgery of the epiphysis only to develop a collapsed femoral head, which was remedied through total hip arthroplasty. A decrease in blood flow, the delicacy in reduction, and unknown predispositions might have been contributing factors toward the unique development in this case. PMID- 25438108 TI - Chronic slipping of bilateral distal humeral epiphyses in a gymnastist. AB - In children, fracture-separation of the epiphyseal plate near the elbow joint is a common occurrence. However, separation of the distal humeral epiphysis is very rare, and in most cases, it is caused by high-impact trauma. In all reported cases, there has been a clear mechanism of injury. We report a case of an 11-year old male patient who sustained separation of the distal humeral epiphyses bilaterally after 2 years of gymnastics, without a clear mechanism of injury. This patient had been using the vault since he was 9 years old, although children of that age do not normally perform on the vault. When gymnasts place their hands on the vault with their elbows flexed and subsequently extend their elbows to push off, the biomechanical load is placed equally on the right and left arms. Consequently, this type of repeated stress induces injury to the epiphyseal cartilages bilaterally, resulting in chronic progression of separation of the distal humeral epiphyses. PMID- 25438109 TI - Mediastinal parathyroid adenoma with osteitis fibrosis cystica: robot-assisted thoracic surgical resection. AB - Mediastinal parathyroid adenomas can be resected by sternotomy or video-assisted thoracoscopic surgery. Robot-assisted thoracic surgical approaches have recently been described. We report robot-assisted thoracic surgical resection of a mediastinal parathyroid in a morbidly obese patient. Additional comorbidities included multiple pathological fractures related to hypercalcemia. Intraoperative parathyroid hormone levels confirmed successful removal of the adenoma. Hungry bone syndrome developed after surgery but eventually resolved. Robot-assisted thoracic surgery avoided the need for sternotomy and associated concerns related to poor bone healing. Robot-assisted thoracic surgery has potential advantages over video-assisted thoracoscopic surgery in patients with obesity because of easier instrument articulation within the thoracic cavity rather than at the chest wall. PMID- 25438110 TI - Is there a role for robotic totally endoscopic coronary artery bypass in patients with a colostomy? AB - Preoperative colostomy presents a significant risk of sternal wound complications, mediastinitis, and ostomy injury in patients requiring coronary artery bypass grafting. Less invasive procedures in coronary surgery have a potential to reduce the risk of sternal wound healing problems. Robotic totally endoscopic coronary artery bypass grafting in patients with a colostomy has not been reported. We describe a case of completely endoscopic coronary surgery using the da Vinci Si system in a patient with a transverse colostomy. Single left internal mammary artery grafting to the left anterior coronary artery was performed successfully on the beating heart. We regard this technique as the least invasive method of surgical coronary revascularization with a potential to reduce the risk of surgical site infection and mediastinitis in patients with a colostomy. PMID- 25438111 TI - Minimally invasive coronary artery bypass grafting is associated with improved clinical outcomes. AB - OBJECTIVE: Minimally invasive coronary artery bypass grafting (MICS CABG) via left minithoracotomy is an alternative to off-pump coronary artery bypass (OPCAB) via sternotomy. Our objective was to evaluate the clinical outcomes after MICS CABG versus OPCAB. METHODS: The medical records of patients who underwent MICS CABG from December 2009 to December 2011 and OPCAB from January 2005 to April 2011 were reviewed. Patients who underwent OPCAB were matched 2:1 to patients who underwent MICS CABG by age, sex, preoperative ejection fraction, creatinine concentration, as well as history of diabetes and myocardial infarction. RESULTS: A total of 130 MICS CABG patients were matched with 260 OPCAB patients. Mean bypasses in the MICS CABG and OPCAB groups were 2.1 and 3.2, respectively (P = 0.001). Extubation in the operating room (OR) occurred in 70.0% and 12.7% of patients in the MICS CABG and OPCAB groups, respectively (P = 0.001). Mean postoperative length of stay was 4 days for the MICS CABG patients versus 5 days for the OPCAB patients (P = 0.002) and 3.8 days versus 4.6 days for the MICS CABG patients extubated in the OR compared with those who remained intubated (P = 0.007). There were no 30-day mortalities in the MICS CABG group and 1 in the OPCAB group (P = 0.999). Thirty-day readmissions were similar, with 5.4% and 7.4% in the MICS CABG and OPCAB groups, respectively (P = 0.527). CONCLUSIONS: Minimally invasive coronary artery bypass grafting is safe, and early clinical outcomes are comparable, if not superior in some respects, to OPCAB. Extubation in the OR is feasible, well tolerated, and associated with earlier discharge. Shorter hospital stays may decrease resource use and promote earlier return to activities; however, further research is needed. PMID- 25438112 TI - Robotic application of a novel dual-energy device for left atrial ablation: intraoperative and early postoperative results. AB - OBJECTIVE: Recent trials show that in patients with atrial fibrillation (AF), pulmonary vein isolation performed with bipolar surgical ablation clamps using small bilateral thoracotomies is more effective than pulmonary vein isolation using standard catheter ablation. This improved efficacy comes with higher invasiveness including difficulty in execution and potentially more acute complications. Monopolar "loop" devices overcome these drawbacks but at the potential cost of decreased efficacy. Technology that has bipolar effectiveness but with improved access and safety profiles, capable of being deployed endoscopically on a beating heart, would be desirable. We evaluated an ablation system that may have all of these characteristics. METHODS: Between May 2012 and May 2013, 30 patients were treated surgically for AF using a right-sided endoscopic approach with robotic assistance. In each patient, a "box" ablation lesion set was created around all pulmonary veins with a new linear suction applied dual-mode (monopolar and bipolar) radiofrequency (RF) ablation device that was looped around the pulmonary veins. Temperature-controlled RF was applied for 60 seconds, with a set temperature of 70 degrees C, first in the bipolar mode and then in a separate RF ablation for 60 seconds at 70 degrees C in the monopolar mode. Acute effectiveness of the procedure was assessed using conduction block testing and by attempting to induce sustained AF with rapid atrial pacing. The left atrial appendage (LAA) was occluded in all patients with multiple ENDOLOOP snares using a left video-assisted thoracoscopic surgery approach under transesophageal echocardiography guidance, after which the tip of the LAA was incised to empty the LAA of blood. All patients were seen clinically at 30, 90, and 180 days with routine electrocardiography monitoring: at 6 months, 24-hour Holter monitoring was performed. RESULTS: Acute conduction block was achieved in 93% the of patients, and sustained AF could not be induced by rapid atrial pacing after the surgical ablation procedure in 90% of the patients. At 3- and 6-month follow-up, 88% and 81% of the patients, respectively, were in sinus rhythm. Of 16 the patients seen at 12-month follow-up, 14 (88%) were in sinus rhythm with 44% still on antiarrhythmic medications. CONCLUSIONS: The newly introduced bipolar/monopolar RF ablation device can be easily positioned using a right endoscopic approach. Robotic assistance enables effective fat removal for accurate and easy placement of the device around the pulmonary veins. With the use of this approach, the device is safe and effective in electrically isolating the pulmonary veins. PMID- 25438113 TI - Technique of aortic root reconstruction using a new model of Dacron graft with prefabricated coronary branches. AB - Aortic root reconstruction is a demanding surgical procedure still associated with a significant morbidity. Arguably, the most demanding aspect of the operation is reestablishing continuity between the prosthetic graft replacing the aortic root and the coronary arteries. With the objective of simplifying the possible challenges of coronary reimplantation, we designed a new model of aortic root graft with prefabricated coronary branches. We used this technique in 8 patients (6 males, 2 females; mean age, 54 years). There were 6 modified Bentall procedures and 2 valve-sparing root replacements with the "reimplantation" technique. There was no mortality or morbidity related to the use of this new prosthetic graft. Our purpose was to report in detail the technique of aortic root reconstruction using this new graft with prefabricated coronary branches. The use of this graft may simplify the procedure and offer a valuable tool for aortic root reconstruction in cases where the reimplantation of the coronary buttons may represent a technical challenge. PMID- 25438114 TI - Scenario analysis for biodiversity conservation: a social-ecological system approach in the Australian Alps. AB - Current policy interventions are having limited success in addressing the ongoing decline in global biodiversity. In part, this is attributable to insufficient attention being paid to the social and governance processes that drive decisions and can undermine their implementation. Scenario planning that draws on social ecological systems (SES) analysis provides a useful means to systematically explore and anticipate future uncertainties regarding the interaction between humans and biodiversity outcomes. However, the effective application of SES models has been limited by the insufficient attention given to governance influences. Understanding the influence governance attributes have on the future trajectory of SES is likely to assist choice of effective interventions, as well as needs and opportunities for governance reform. In a case study in the Australian Alps, we explore the potential of joint SES and scenario analyses to identify how governance influences landscape-scale biodiversity outcomes. Novel aspects of our application of these methods were the specification of the focal system's governance attributes according to requirements for adaptive capacity, and constraining scenarios according to the current governance settings while varying key social and biophysical drivers. This approach allowed us to identify how current governance arrangements influence landscape-scale biodiversity outcomes, and establishes a baseline from which the potential benefits of governance reform can be assessed. PMID- 25438115 TI - Rapid and effective decontamination of chlorophenol-contaminated soil by sorption into commercial polymers: concept demonstration and process modeling. AB - Solid phase extraction performed with commercial polymer beads to treat soil contaminated by chlorophenols (4-chlorophenol, 2,4-dichlorophenol and pentachlorophenol) as single compounds and in a mixture has been investigated in this study. Soil-water-polymer partition tests were conducted to determine the relative affinities of single compounds in soil-water and polymer-water pairs. Subsequent soil extraction tests were performed with Hytrel 8206, the polymer showing the highest affinity for the tested chlorophenols. Factors that were examined were polymer type, moisture content, and contamination level. Increased moisture content (up to 100%) improved the extraction efficiency for all three compounds. Extraction tests at this upper level of moisture content showed removal efficiencies >=70% for all the compounds and their ternary mixture, for 24 h of contact time, which is in contrast to the weeks and months, normally required for conventional ex situ remediation processes. A dynamic model characterizing the rate and extent of decontamination was also formulated, calibrated and validated with the experimental data. The proposed model, based on the simplified approach of "lumped parameters" for the mass transfer coefficients, provided very good predictions of the experimental data for the absorptive removal of contaminants from soil at different individual solute levels. Parameters evaluated from calibration by fitting of single compound data, have been successfully applied to predict mixture data, with differences between experimental and predicted data in all cases being <=3%. PMID- 25438116 TI - Exploring the response of net primary productivity variations to urban expansion and climate change: a scenario analysis for Guangdong Province in China. AB - Urban land development alters landscapes and carbon cycle, especially net primary productivity (NPP). Despite projections that NPP is often reduced by urbanization, little is known about NPP changes under future urban expansion and climate change conditions. In this paper, terrestrial NPP was calculated by using Biome-BGC model. However, this model does not explicitly address urban lands. Hence, we proposed a method of NPP-fraction to detect future urban NPP, assuming that the ratio of real NPP to potential NPP for urban cells remains constant for decades. Furthermore, NPP dynamics were explored by integrating the Biome-BGC and the cellular automata (CA), a widely used method for modeling urban growth. Consequently, urban expansion, climate change and their associated effects on the NPP were analyzed for the period of 2010-2039 using Guangdong Province in China as a case study. In addition, four scenarios were designed to reflect future conditions, namely baseline, climate change, urban expansion and comprehensive scenarios. Our analyses indicate that vegetation NPP in urban cells may increase (17.63 gC m(-2) year(-1)-23.35 gC m(-2) year(-1)) in the climate change scenario. However, future urban expansion may cause some NPP losses of 241.61 gC m(-2) year(-1), decupling the NPP increase of the climate change factor. Taking into account both climate change and urban expansion, vegetation NPP in urban area may decrease, minimally at a rate of 228.54 gC m(-2) year(-1) to 231.74 gC m(-2) year(-1). Nevertheless, they may account for an overall NPP increase of 0.78 TgC year(-1) to 1.28 TgC year(-1) in the whole province. All these show that the provincial NPP increase from climate change may offset the NPP decrease from urban expansion. Despite these results, it is of great significance to regulate reasonable expansion of urban lands to maintain carbon balance. PMID- 25438117 TI - Mechanism of cadmium biosorption from aqueous solutions using calcined oyster shells. AB - The physicochemical properties of oyster shell-derived adsorbents prepared by calcination at different temperatures were characterized by elemental analysis, specific surface area, particle size distribution, X-ray diffraction, and scanning electron microscopy. The pH value in natural oyster shell increased from 9 to 12.7 following calcination above 750 degrees C. All of the oyster shell derived adsorbents exhibited a BET surface area that ranged from 1.8 to 64.6 m(2)/g. Clearly, the proportion of particles within the ranges 25-50 MUm and 50 100 MUm increased after calcination, regardless of calcination temperature. The adsorption equilibrium and kinetics of cadmium (Cd) were investigated, and the mechanisms of sorption discussed. Experimental equilibrium data were fitted to a Langmuir adsorption isotherm model. Most Cd adsorption occurred during the initial hours of contact time, and a pseudo-second-order kinetic model best fitted the adsorption process. Cd sorption profiles indicated an initial, low Cd sorption region (25.25-32.36 mg/g) that was associated with calcination temperatures of up to 650 degrees C for 2 h, and a second region that contributed to high Cd sorption from 750 degrees C, with the maximum sorption capacity reaching a value of 1666.67 mg/g at 900 degrees C. The high Cd-removal capacity of oyster shell-derived adsorbents above 750 degrees C is attributed to their enhanced specific surface area, their material porosity, the bulk precipitation of Cd hydroxide and otavite on shell fragments, the formation of ettringite as a secondary precipitate, and ion exchange via Ca ions. This study highlights the effectiveness of calcined oyster shells in Cd removal from highly contaminated water and wastewater. PMID- 25438118 TI - Optimizing chemical conditioning for odour removal of undigested sewage sludge in drying processes. AB - Emission of odours during the thermal drying in sludge handling processes is one of the main sources of odour problems in wastewater treatment plants. The objective of this work was to assess the use of the response surface methodology as a technique to optimize the chemical conditioning process of undigested sewage sludges, in order to improve the dewaterability, and to reduce the odour emissions during the thermal drying of the sludge. Synergistic effects between inorganic conditioners (iron chloride and calcium oxide) were observed in terms of sulphur emissions and odour reduction. The developed quadratic models indicated that optimizing the conditioners dosage is possible to increase a 70% the dewaterability, reducing a 50% and 54% the emission of odour and volatile sulphur compounds respectively. The optimization of the conditioning process was validated experimentally. PMID- 25438119 TI - Evaluation of the developmental toxicity of lead in the Danio rerio body. AB - Lead has been utilized throughout history and is widely distributed and mobilized globally. Although lead in the environment has been somewhat mitigated, the nature of lead and its extensive uses in the past prohibit it from being completely absent from our environment and exposure to lead is still a public health concern. Most studies regarding lead toxicity have focused on the brain. However, little is found in the literature on the effects of lead in other tissues. Here, we utilize the zebrafish model system to investigate effects of lead exposure during early developmental time windows at 24, 48 and 72 h post fertilization in the body. We analyze whole body, notochord and somatic muscle changes, vascular changes of the body, as well as motor neuron alterations. We find lead exposure induces a curved body phenotype with concomitant changes in somite length, decreased notochord staining and abnormal muscle staining using live and in situ approaches. Furthermore, altered vasculature within the somatic regions, loss and/or alternations of motor neuron extension both dorsally and ventrally from the spinal cord, loss of Rohon-Beard sensory neurons, and increased areas of apoptosis were found. We conclude that lead is developmentally toxic to other areas of the developing embryo, not just the brain. PMID- 25438120 TI - Sulfidation of silver nanoparticle reduces its toxicity in zebrafish. AB - Chemical transformations of metal nanoparticles can be an important way to mitigate nanoparticle toxicity. Sulfidation of silver nanoparticle (AgNPs) is a natural process shown to occur in environment. Very few studies, employing microbes and embryonic stages of zebrafish, have shown reduction in AgNPs toxicity as a direct result of sulfidation. However the feasibility of reducing nanoparticle toxicity by sulfidation of AgNPs has never been studied in adult vertebrates. In this study, we have used adult zebrafish as a model to study the efficacy of sulfidation of AgNPs in reducing nanoparticle toxicity by employing a battery of biomarkers in liver and brain. While AgNPs enhanced liver oxidative stress, altered detoxification enzymes and affected brain acetylcholinesterase activity, sulfidation of AgNPs resulted in significant alleviation of changes in these parameters. Histopathological analyses of liver and sulphydryl levels also support the significance of sulfidated AgNPs in controlling the toxicity of AgNPs. Our study provides the first biochemical data on the importance of sulfidation of AgNPs in reducing biological toxicity in adult vertebrates. PMID- 25438121 TI - Toxicogenomic analysis in the combined effect of tributyltin and benzo[a]pyrene on the development of zebrafish embryos. AB - There is a growing recognition that the toxic effects of chemical mixtures are been an important issue in toxicological sciences. Tributyltin (TBT) and benzo[a]pyrene (BaP) are widespread pollutants that occur simultaneously in the aquatic environments. This study was designed to examine comprehensively the combined effects of TBT and BaP on zebrafish (Danio rerio) embryos using toxicogenomic approach combined with biochemical detection and morphological analysis, and tried to gain insight into the mechanisms underlying the combined effects of TBT and BaP. The results of toxicogenomic data indicated that: (1) TBT cotreatment rescued the embryos from decreased hatching ratio caused by BaP alone, while the alteration of gene expression (in this article the phrase gene expression is used as a synonym to gene transcription, although in is acknowledged that gene expression can also be regulated by, e.g., translation and mRNA or protein stability) relative to zebrafish hatching in the BaP groups was resumed by the cotreatment with TBT; (2) BaP cotreatment decreased TBT-mediated dorsal curvature, and alleviated the perturbation of Notch pathway caused by TBT alone; (3) cotreatment with TBT decreased BaP-mediated bradycardia, which might be due to that TBT cotreatment alleviated the perturbation in expression of genes related to cardiac muscle cell development and calcium handling caused by BaP alone; 4) TBT cotreatment brought an antagonistic effect on the BaP-mediated oxidative stress and DNA damage. These results suggested that toxicogenomic approach was available for analyzing combined toxicity with high sensitivity and accuracy, which might improve our understanding and predictability for the combined effects of chemicals. PMID- 25438122 TI - Environmentally relevant concentrations of citalopram partially inhibit feeding in the three-spine stickleback (Gasterosteus aculeatus). AB - Selective Serotonin Re-uptake Inhibitors (SSRI) are mood-altering, psychotropic drugs commonly used in the treatment of depression and other psychological illnesses. Many of them are poorly degraded in sewage treatment plants and enter the environment unaltered. In laboratory studies, they have been demonstrated to affect a wide range of behaviours in aquatic organisms. In this study we investigated the effect of a three-week exposure to 0.15 and 1.5 MUg/l of the SSRI citalopram dissolved in the ambient water on the feeding behaviour in three spine stickleback (Gasterosteus aculeatus). Feeding, measured as the number of attacks performed on a piece of frozen bloodworms during a 10-min period, was reduced by 30-40% in fish exposed to both 0.15 and 1.5 MUg/l citalopram. The effects of the environmentally relevant concentration 0.15 MUg/l on feeding, an important fitness characteristic, suggests that the ecological significance of environmental SSRI exposure may be pronounced. PMID- 25438123 TI - Prolonged SDA and reduced digestive efficiency under elevated CO2 may explain reduced growth in Atlantic cod (Gadus morhua). AB - Land-based aquaculture systems expose fish to elevated dissolved CO2 levels, a factor that is correlated with reduced growth, feed conversion efficiency and body condition index. The physiological basis underlying the pathological effects of environmental hypercapnia is poorly understood, in particular for marine fish species. We investigated whether changes in energy expenditure and the specific dynamic action (SDA) of digestion and assimilation could account for the lower growth of adult Atlantic cod (Gadus morhua) under environmental hypercapnia. Fish acclimated to a partial pressure of 800 MUatm CO2 (0.6 mmHg, 1.5 mg/L) and 9200 MUatm CO2 (7 mmHg, 18.7 mg/L) exhibited no difference in maintenance metabolic rates, which concurs with previous research for this species and other fish species. At 9200 MUatm CO2 Atlantic cod had a significantly diminished (14%) maximum aerobic capacity. While hypercapnia did not affect the amount of oxygen required for the SDA process, it did prolong the SDA duration by 23%. The longer SDA process time may offer an explanation for the observation of lower feed intake, growth and condition factor in long-term hypercapnia studies. Comparison of aerobic scope and cardiac performance during digestion suggested that reduced oxygen delivery capacity under hypercapnia could be one mechanism by which CO2 prolongs SDA, although our results could not definitively demonstrate this effect. PMID- 25438124 TI - Gd(OTf)3-catalyzed synthesis of geranyl esters for the intramolecular radical cyclization of their epoxides mediated by titanocene(III). AB - A selective and mild method for the esterification of a variety of carboxylic acids with geraniol is developed. We demonstrated that the use of triphenylphosphine, I2, 2-methylimidazole or imidazole and a catalytic amount of Gd(OTf)3 resulted to be more active than the previous protocols, providing a 16 membered library of geranyl esters in higher yields and in shorter reaction times. The use of essential oil of palmarosa (Cymbopogon martinii), enriched with geraniol, as a raw material for the synthesis of the target compounds complemented and proved how sustainable and eco-friendly this protocol is. Finally, the selective 6,7-epoxidation of the obtained geranyl esters led us to study their regio-controlled radical cyclization mediated by titanocene(III) for the synthesis of novel (8-hydroxy-9,9-dimethyl-5-methylene cyclohexyl)methyl esters in moderate yields and with excellent stereoselectivities. PMID- 25438125 TI - Respiratory and Limb Muscle Dysfunction in COPD. AB - In the next decade, Chronic Obstructive Pulmonary Disease (COPD) will be a major leading cause of death worldwide. Impaired muscle function and mass are common systemic manifestations in COPD patients and negatively influence survival. Respiratory and limb muscles are usually affected in these patients, thus contributing to poor exercise tolerance and reduced quality of life (QoL). Muscles from the lower limbs are more severely affected than those of the upper limbs and the respiratory muscles. Several epidemiological features of COPD muscle dysfunction are being reviewed. Moreover, the most relevant etiologic factors and biological mechanisms contributing to impaired muscle function and mass loss in respiratory and limb muscles of COPD patients are also being discussed. Currently available therapeutic strategies such as different modalities of exercise training, neuromuscular electrical and magnetic stimulation, respiratory muscle training, pharmacological interventions, nutritional support, and lung volume reduction surgery are also being reviewed, all applied to COPD patients. We claim that body composition and quadriceps muscle strength should be routinely explored in COPD patients in clinical settings, even at early stages of their disease. Despite the progress achieved over the last decade in the description of this relevant systemic manifestation in COPD, much remains to be investigated. Further elucidation of the molecular mechanisms involved in muscle dysfunction, muscle mass loss and poor anabolism will help design novel therapeutic targets. Exercise and muscle training, alone or in combination with nutritional support, is undoubtedly the best treatment option to improve muscle mass and function and QoL in COPD patients. PMID- 25438126 TI - Urinary arsenic speciation profile in ethnic group of the Atacama desert (Chile) exposed to variable arsenic levels in drinking water. AB - Ethnic groups from the Atacama Desert (known as Atacamenos) have been exposed to natural arsenic pollution for over 5000 years. This work presents an integral study that characterizes arsenic species in water used for human consumption. It also describes the metabolism and arsenic elimination through urine in a chronically exposed population in northern Chile. In this region, water contained total arsenic concentrations up to 1250 MUg L(-1), which was almost exclusively As(V). It is also important that this water was ingested directly from natural water sources without any treatment. The ingested arsenic was extensively methylated. In urine 93% of the arsenic was found as methylated arsenic species, such as monomethylarsonic acid [MMA(V)] and dimethylarsinic acid [DMA(V)]. The original ingested inorganic species [As(V)], represent less than 1% of the total urinary arsenic. Methylation activity among individuals can be assessed by measuring primary [inorganic As/methylated As] and secondary methylation [MMA/DMA] indexes. Both methylation indexes were 0.06, indicating a high biological converting capability of As(V) into MMA and then MMA into DMA, compared with the control population and other arsenic exposed populations previously reported. PMID- 25438127 TI - Accumulation of metals in cancerous and healthy tissues of patients with lung cancer in Southern Poland. AB - The aim of this study was to investigate whether the concentrations of metals differ among patients with and without lung cancer with different smoking status and living in industrialized environments. We also evaluated the relationships between metals and blood parameters including hematocrit level (Hct), hemoglobin concentration (Hb), red (RBC) and white (WBC) blood cells numbers. Concentrations of metals were measured with AAS (copper - Cu, iron - Fe, magnesium - Mg, zinc - Zn) and CV-AAS (mercury - Hg). Neither smoking status nor industrialization could be considered as a significant factor for metals accumulation in blood, lungs and tumor tissues, with the exception of mercury which differed in the aspect of industrialization. According to the type of the disease, Fe, Hg and Mg concentrations differed significantly in lungs. Correlations between metals and blood parameters were observed. Additionally, concentrations of Mg, Cu and Zn were correlated between lungs and tumor tissue of patients with cancer as well as they all were related to each other in lungs, tumor and blood tissues. PMID- 25438128 TI - Identification of Enterococcus faecium and Enterococcus faecalis as vanC-type Vancomycin-Resistant Enterococci (VRE) from sewage and river water in the provincial city of Miyazaki, Japan. AB - As a first step for assessing the risk to human health posed by vancomycin resistant enterococci (VRE) in the aquatic environment, we screened sewage and urban river water samples from Miyazaki, Japan for VRE. Because vancomycin resistant organisms are not as prevalent in sewage and river water as vancomycin susceptible organisms, the samples were screened by minimum inhibitory concentration test using the vancomycin-supplemented membrane-Enterococcus indoxyl-beta-d-glucoside (mEI) agar. The isolates, presumed to be enterococci, were identified using 16S rRNA sequencing analysis. The percentages of VRE isolates screened using 4 MUg mL(-1) vancomycin-supplemented mEI agar from sewage and urban river water samples were 12% and 24%, respectively. The vancomycin resistant genes vanC1 and vanC2/3 were detected in the isolates from both samples by PCR analysis. All enterococci isolates containing vanC1, which is a specific gene for vanC-type of VRE, were identified as Enterococcus casseliflavus/gallinarum. Further, 92% enterococci isolates containing vanC2/3 were identified as E. casseliflavus/gallinarum, the remaining isolates containing vanC2/3 were E. faecium (4%) and E. faecalis (4%). Thereafter, the distribution of E. faecium and E. faecalis, which are the major types of enterococci in humans containing vanC2/3, was observed in the water samples collected. PMID- 25438129 TI - Antibiotic resistance in wastewater: occurrence and fate of Enterobacteriaceae producers of class A and class C beta-lactamases. AB - Antibiotics have been intensively used over the last decades in human and animal therapy and livestock, resulting in serious environmental and public health problems, namely due to the antibiotic residues concentration in wastewaters and to the development of antibiotic-resistant bacteria. This study aimed to access the contribution of some anthropological activities, namely urban household, hospital and a wastewater treatment plant, to the spread of antibiotic resistances in the treated wastewater released into the Mondego River, Coimbra, Portugal. Six sampling sites were selected in the wastewater network and in the river. The ampicillin-resistant Enterobacteriaceae of the water samples were enumerated, isolated and phenotypically characterized in relation to their resistance profile to 13 antibiotics. Some isolates were identified into species level and investigated for the presence of class A and class C -lactamases. Results revealed high frequency of resistance to the -lactam group, cefoxitin (53.5%), amoxicillin/clavulanic acid combination (43.5%), cefotaxime (22.7%), aztreonam (21.3) cefpirome (19.2%), ceftazidime (16.2%) and to the non--lactam group, trimethoprim/sulfamethoxazol (21.1%), tetracycline (18.2%), followed by ciprofloxacin (14.1%). The hospital effluent showed the higher rates of resistance to all antibiotic, except two (chloramphenicol and gentamicin). Similarly, higher resistance rates were detected in the wastewater treatment plant (WWTP) effluent compared with the untreated affluent. Regarding the multidrug resistance, the highest incidence was recorded in the hospital sewage and the lowest in the urban waste. The majority of the isolates altogether are potentially extended-spectrum -lactamases positive (ESBL(+)) (51.9%), followed by AmpC(+) (44.4%) and ESBL(+)/AmpC(+) (35.2%). The most prevalent genes among the potential ESBL producers were blaOXA (33.3%), blaTEM (24.1%) and blaCTX-M (5.6%) and among the AmpC producers were blaEBC (38.9%), blaFOX (1.9%) and blaCIT (1.9%). In conclusion, the hospital and the WWTP activities revealed to have the highest contribution to the spread of multidrug resistant bacteria in the study area. Such data is important for future management of the environmental and public health risk of these contaminants. This is the first embracing study in the water network of Coimbra region on the dissemination of antibiotic resistance determinants. Moreover, it is also the first report with the simultaneous detection of multiresistant bacteria producers of AmpC and ESBLs -lactamases in aquatic systems in Portugal. PMID- 25438130 TI - Evaluation of water matrix effects, experimental parameters, and the degradation pathway during the TiO2 photocatalytical treatment of the antibiotic dicloxacillin. AB - The photocalytic degradation of dicloxacillin (DXC) using TiO2 was studied in synthetic and natural waters. The degradation route and the effect of different experimental variables such as pH, applied power, and the initial concentrations of DXC and the catalyst were investigated. The best performances were achieved at a natural pH 5.8 and using 2.0 g L(-1) of TiO2 with 150 W of applied power. The photodegradation process followed Langmuir-Hinshelwood kinetics. The water matrix effect was evaluated in terms of degradation efficiency in the presence of organic compounds (oxalic acid, glucose), Fe(2+) ion and natural water. An increase in degradation was observed when ferrous ion was part of the solution, but the process was inhibited with all evaluated organic compounds. Similarly, inhibition was observed when natural water was used instead of distilled water. The extent of degradation of the process was evaluated following the evolution of chemical oxygen demand (COD), antimicrobial activity (AA), total organic carbon (TOC) and biochemical oxygen demand (BOD5). Total removal of DXC was achieved after 120 min of treatment and 95% mineralization was observed after 480 min of treatment. Additionally, the total removal of antimicrobial activity and a high level of biodegradability were observed after the photocalytical system had been operating for 240 min. PMID- 25438131 TI - A bench-scale assessment for phosphorus release control of sediment by an oxygen releasing compound (ORC). AB - The effects of oxygen-releasing compound (ORC) on the control of phosphorus (P) release as well as the spatial and temporal distribution of P fractions in sediment were studied through a bench-scale test. An ORC with an extended oxygen releasing capacity was prepared. The results of the oxygen-releasing test showed that the ORC provided a prolonged period of oxygen release with a highly effective oxygen content of 60.6% when compared with powdery CaO2. In the bench scale test, an ORC dose of 180 g.m(-2) provided a higher inhibition efficiency for P release within 50 days. With the application of the ORC, the dissolved oxygen (DO) concentration and redox potential (ORP) of the overlying water were notably improved, and the dissolved total phosphorus (DTP) was maintained below 0.689 mg.L(-1) compared to 2.906 mg.L(-1) without the ORC treatment. According to the P fractions distribution, the summation of all detectable P fractions in each sediment layer exhibited an enhanced accumulation tendency with the application of ORC. Higher phosphorus retention efficiencies were observed in the second and third layers of sediment from days 10 to 20 with the ORC. Phosphorus was trapped mainly in the form of iron bound P (Fe-P) and organically bound P (O-P) in sediment with the ORC, whereas the effects of the ORC on exchangeable P (EX-P), apatite-associated P (A-P) and detrital P (De-P) in the sediment sample were not significant. The microbial activities of the sediment samples demonstrated that both the dehydrogenase activity (DHA) and alkaline phosphatase activity (APA) in the upper sediment layer increased with the ORC treatment, which indicated that the mineralization of P was accelerated and the microbial biomass was increased. As the accumulation of P suppressed the release of P, the sediment exhibited an increased P retention efficiency with the application of the ORC. PMID- 25438132 TI - Nitrogen and phosphorus distribution in a constructed wetland fed with treated swine slurry from an anaerobic lagoon. AB - Nitrogen and phosphorus distribution in a constructed wetland fed with treated swine slurry from an anaerobic lagoon were studied. The methodology considered a daily meteorological monitoring site. During 2011 to 2012, water, soil and plants (Schoenoplectus californicus (C.A. Meyer) Sojak, Typha angustifolia (L.)) were seasonally sampled (spring and fall) into the constructed wetland. During study period, results showed that rainfall was the main factor of maintenance hydraulic conditions, while evapotranspiration was driver of variations in water storage level. Nitrogen and phosphorus removal from the water phase were up to 54% and 37%, respectively. Onto soil were adsorbed over 70% nitrogen and 65% phosphorus. Phosphorus was less mobile than nitrogen, since it was bound to oxides Fe-Mn. Inorganic nitrogen species were affected by level water and seasonal vegetable maturation. During spring, N-NH4(+) was the predominant soil species, while in the fall, N-NO3(-) was dominant near the belowground part of Sc and NH4(+) near to the belowground zone of Ta. In addition, nutrients uptake was less than 30% with 64% aboveground-spring and 85% belowground-fall for both plants. Findings showed nitrification process evidences when water levels are below 0.1 m. PMID- 25438134 TI - Enhanced sludge reduction in septic tanks by increasing temperature. AB - Septic tanks in most developing countries are constructed without drainage trenches or leaching fields to treat toilet wastewater and /or grey water. Due to the short hydraulic retention time, effluents of these septic tanks are still highly polluted, and there is usually high accumulation of septic tank sludge or septage containing high levels of organics and pathogens that requires frequent desludging and subsequent treatment. This study aimed to reduce sludge accumulation in septic tanks by increasing temperatures of the septic tank content. An experimental study employing two laboratory-scale septic tanks fed with diluted septage and operating at temperatures of 40 and 30 degrees C was conducted. At steady-state conditions, there were more methanogenic activities occurring in the sludge layer of the septic tank operating at the temperature of 40 degrees C, resulting in less total volatile solids (TVS) or sludge accumulation and more methane (CH4) production than in the unit operating at 30 degrees C. Molecular analysis found more abundance and diversity of methanogenic microorganisms in the septic tank sludge operating at 40 degrees C than at 30 degrees C. The reduced TVS accumulation in the 40 degrees C septic tank would lengthen the period of septage removal, resulting in a cost-saving in desluging and septage treatment. Cost-benefit analysis of increasing temperatures in septic tanks was discussed. PMID- 25438133 TI - Prediction of class membership of biodiesels using chemometrics. AB - Recently, serious scientific and technological attention is paid to creation of alternative energy sources, including biofuels. The assessment of the quality of the biofuels produced and of the raw materials needed for the production technology is an important scientific challenge. One of the major sources for biodiesel production is plant oils material (sunflower, rapeseed, palm, soya etc.). Since plants are complex system from the biota it is not easy to find specific chemical components responsible for their ability to serve as biodiesels. The characterization and classification of plant sources as biofuel material could be reliably estimated only by the use of multivariate statistical approaches (chemometrics). The chemometric expertise makes it possible not only to classify different biofuel sources into similarity classes but also to predict the membership of unknown by origin chemically analyzed samples to already existing classes. The present study deals with the prediction of the class membership of several unknown by origin samples, which are included in a large data set with FAME profiles of biodiesel plant sources. Using a data set from chromatographic analysis of fatty acid methyl esters profiles (FAME) of different plant biodiesel sources and applying the chemometric technique know as partial least squares-discriminant analysis (PLS - DA) a pattern recognition procedure is developed to: I. Model classes of similarity of biodiesel plant sources using their FAME profiles not taking into account the samples with unknown origin; II. Classify correctly the samples with unknown origin to the previously defined classes of biodiesel sources (palm oil, soybean oil, peanut oil, rapeseed oil, sunflower oil and maize oil). The prediction is successfully achieved for all samples with previously unknown origin. This pattern recognition approach is applied for the first time in the field of biodiesel classification and modeling tasks. PMID- 25438135 TI - Occurrence, distribution, and ecological risk assessment of potentially toxic elements in surface sediments of Lake Awassa and Lake Ziway, Ethiopia. AB - Microwave-assisted acid digestion and modified aqua regia (HNO3:HCl:HF:H3BO3) leaching techniques were used for the determination of 15 potentially toxic elements (V, Cr, Fe, Mn, Co, Ni, Cu, Zn, As, Se, Ag, Cd, Sn, Hg and Pb) in sediment samples from Lake Awassa and Lake Ziway, Ethiopia. The digests were subsequently analyzed by inductively coupled plasma-mass spectrometry (ICP-MS) and inductively coupled plasma-optical emission spectrometry (ICP-OES). Mercury was directly determined in the solid samples using an elemental mercury analyzer. The precision and accuracy of the digestion procedures were verified using certified reference materials. The experimental results were in good agreement with the certified values (P < 0.05) and the recoveries were quantitative (>90%). The average relative standard deviations were below 10%. There is significant correlation between the two lakes at the 0.01 level (2-tailed). Using the sediment quality guidelines, both lakes are heavily polluted with Zn and some of the sites are heavily polluted with Cu, Ni and Pb. Based on effect range low (ERL) - effect range medium (ERM), in both lakes for Ag were greater than the ERM, indicating that the areas could be toxic to aquatic organisms, while for Cr, Cu, As and Hg the values were less than ERL. PMID- 25438136 TI - Spatial and temporal variation of heavy metal risk and source in sediments of Dongting Lake wetland, mid-south China. AB - Surface sediments of Dongting Lake wetland were collected from ten sites to investigate variation trend, risk and sources of heavy metal distribution in dry seasons of 2011~2013. The three-year mean concentrations (mg/kg) of Cr, Cu, Pb, Cd, Hg and As were 91.33, 36.27, 54.82, 4.39, 0.19 and 25.67, respectively, which were all higher than the corresponding background values. Sediment quality guidelines (SQGs) and Geo-accumulation index (Igeo) were used for the assessment of pollution level of heavy metals. The pollution risk of Cd, Hg and As were great and that of Cr needed urgent attention because of its obvious increase. Pollution load index (PLI) and geographic information system (GIS) methods were conducted to assess spatial and temporal variation of heavy metal contamination. Results confirmed an increased contamination contribution inflow from Xiang River. Multivariate statistical analyses were applied to identify contribution sources of heavy metal, which showed anthropogenic origin mainly from mining, smelting, chemical industry and agricultural activity. PMID- 25438137 TI - Unintended influence: when our words mean more than we think. PMID- 25438138 TI - Zn deficiency in Brassica napus induces Mo and Mn accumulation associated with chloroplast proteins variation without Zn remobilization. AB - The importance of zinc (Zn) has been of little concern in human nutrition despite a strong decrease of this element in crops since the rise of high yielding varieties. For better food quality, Zn biofortification can be used, but will be optimal only if mechanisms governing Zn management are better known. Using Zn deficiency, we are able to demonstrate that Zn is not remobilized in Brassica napus (B. napus). Thus, remobilization processes should not be targeted by biofortification strategies. This study also complemented previous work by investigating leaf responses to Zn deficiency, especially from proteomic and ionomic points of view, showing for example, an increase in Manganese (Mn) content and of the Mn-dependent protein, Oxygen Evolving Enhancer. PMID- 25438139 TI - Effect of nitrogen and phosphorus deficiency on transcriptional regulation of genes encoding key enzymes of starch metabolism in duckweed (Landoltia punctata). AB - The production of starch by plants influences their use as biofuels. Nitrogen (N) and phosphorus (P) regulate starch gene expression during plant growth and development, yet the role of key enzymes such as ADP-glucose pyrophosphorylase (E.C. 2.7.7.27 AGPase) in starch metabolism during N- and P-deficiency remains unknown. We investigated the effect of N- and P-deficiency on the expression of large (LeAPL1, LeAPL2, and LeAPL3) and small (LeAPS) subunits of AGPase in duckweed (Landoltia punctata) and their correlation with starch content. We first isolated the full-length cDNA encoding LeAPL1 (GenBank Accession No. KJ603244) and LeAPS (GenBank Accession No. KJ603243); they contained open reading frames of 1554 bp (57.7-kDa polypeptide of 517 amino acids) and 1578 bp (57.0 kDa polypeptide of 525 amino acids), respectively. Real-time PCR analysis revealed that LeAPL1 and LeAPL3 were highly expressed during early stages of N-deficiency, while LeAPL2 was only expressed during late stage. However, in response to P deficiency, LeAPL1 and LeAPL2 were upregulated during early stages and LeAPL3 was primarily expressed in the late stage. Interestingly, LeAPS was highly expressed following N-deficiency during both stages, but was only upregulated in the early stage after P-deficiency. The activities of AGPase and soluble starch synthesis enzyme (SSS EC 2.4.1.21) were positively correlated with changes in starch content. Furthermore, LeAPL3 and LeSSS (SSS gene) were positively correlated with changes in starch content during N-deficiency, while LeAPS and LeSSS were correlated with starch content in response to P-deficiency. These results elevate current knowledge of the molecular mechanisms underlying starch synthesis. PMID- 25438140 TI - Enhanced accumulation of carotenoids in sweetpotato plants overexpressing IbOr Ins gene in purple-fleshed sweetpotato cultivar. AB - Sweetpotato [Ipomoea batatas (L.) Lam] is an important root crop that produces low molecular weight antioxidants such as carotenoids and anthocyanin. The sweetpotato orange (IbOr) protein is involved in the accumulation of carotenoids. To increase the levels of carotenoids in the storage roots of sweetpotato, we generated transgenic sweetpotato plants overexpressing IbOr-Ins under the control of the cauliflower mosaic virus (CaMV) 35S promoter in an anthocyanin-rich purple fleshed cultivar (referred to as IbOr plants). IbOr plants exhibited increased carotenoid levels (up to 7-fold) in their storage roots compared to wild type (WT) plants, as revealed by HPLC analysis. The carotenoid contents of IbOr plants were positively correlated with IbOr transcript levels. The levels of zeaxanthin were ~ 12 times elevated in IbOr plants, whereas beta-carotene increased ~ 1.75 times higher than those of WT. Quantitative RT-PCR analysis revealed that most carotenoid biosynthetic pathway genes were up-regulated in the IbOr plants, including PDS, ZDS, LCY-beta, CHY-beta, ZEP and Pftf, whereas LCY-E was down regulated. Interestingly, CCD1, CCD4 and NCED, which are related to the degradation of carotenoids, were also up-regulated in the IbOr plants. Anthocyanin contents and transcription levels of associated biosynthetic genes seemed to be altered in the IbOr plants. The yields of storage roots and aerial parts of IbOr plants and WT plants were not significantly different under field cultivation. Taken together, these results indicate that overexpression of IbOr Ins can increase the carotenoid contents of sweetpotato storage roots. PMID- 25438141 TI - BdBRD1, a brassinosteroid C-6 oxidase homolog in Brachypodium distachyon L., is required for multiple organ development. AB - Brassinosteroids (BRs), known as a kind of phytohormones, play essential roles in plant growth and development. Although the studies on the BR biosynthesis and signaling are extensive in Arabidopsis, little is known in temperate cereals. In this study, bdbrd1-1, a T-DNA insertion mutant from Brachypodium distachyon, was isolated and characterized in details. The bdbrd1-1 mutant showed lots of cellular and morphogenetic defects, including shortened cell shapes, severe dwarfing, twisted leaves and sterile spikes. Sequencing the flanking fragment of the T-DNA and complementation by genomic DNA in the mutant, confirmed that the developmental defects are caused by the T-DNA insertion in BdBRD1, a possible brassinosteroid C-6 oxidase gene. Application of 24-epicastasterone could partly rescue the bdbrd1-1 dwarfing phenotype. Expression analysis of BdBRD1 suggested that bdbrd1-1 is probably a null mutant and its wild type transcript is expressed in various tissues and highest in the leaf sheaths. Meanwhile, measurements on leaf numbers of the main stems or days to the emergence of the inflorescences suggested that bdbrd1-1 is late-flowering. The late-flowering phenotype could be converted by vernalization treatment, although there lacks a typical FLC gene in B. distachyon. The current data provide an insight into the relationship between BRs biosynthesis and individual development in B. distachyon, an emerging model plant for the temperate cereals. PMID- 25438142 TI - Current status of the production of high temperature tolerant transgenic crops for cultivation in warmer climates. AB - Climate change is resulting in heightened incidences of plant heat stress episodes. Production of transgenic crops with enhanced heat stress tolerance is a highly desired agronomic trait for the sustainability of food production in 21st century. We review the current status of our understanding of the high temperature stress response of plants. We specifically deliberate on the progress made in altering levels of heat shock proteins (Hsp100, Hsp70/Hsp40 and sHsps), heat shock factors and specific metabolic proteins in improving plant tolerance to heat stress by transgenic approach. PMID- 25438144 TI - Identification of the expressed protein and the impact of change in ascorbate peroxidase activity related to endodormancy breaking in Pyrus pyrifolia. AB - Endodormancy is an important feature of perennial deciduous fruit trees that survive in the extreme climates brought about by seasonal variation. To acquire a comprehensive knowledge of the biochemical processes occurring just before endodormancy breaking, the buds collected in the pre-breaking period (PP) phase were used as samples to identify the proteins related to the breaking of endodormancy in the Japanese pear (Pyrus pyrifolia Nakai). Using nano-ESI-LC MS/MS analysis, 96 proteins were overlapped by analyses of three times and identified as expressed proteins at the PP stage. Among these proteins, dehydrin, several classes of heat shock proteins (HSP), auxin-binding protein, and auxin induced protein were identified in the floral bud in the PP stage. The majority of these proteins were involved primarily in the oxidation-reduction process. We focused on catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX) as enzymes regulating the levels of hydrogen peroxide (H2O2) in the bud. From measurements taken during the deepest period (DP), PP, mid-breaking period (MP), and late-breaking period (LP) of endodormancy, CAT activity decreased gradually, while APX activity also decreased from DP to MP, but then increased rapidly during LP. Protein data for PP and the rapid increase in APX activity observed in LP provided knowledge of the biochemical processes that regulate the consecutive transition from endodormancy breaking to ecodormancy induction in the Japanese pear. PMID- 25438143 TI - Understanding abiotic stress tolerance mechanisms in soybean: a comparative evaluation of soybean response to drought and flooding stress. AB - Many sources of drought and flooding tolerance have been identified in soybean, however underlying molecular and physiological mechanisms are poorly understood. Therefore, it is important to illuminate different plant responses to these abiotic stresses and understand the mechanisms that confer tolerance. Towards this goal we used four contrasting soybean (Glycine max) genotypes (PI 567690- drought tolerant, Pana--drought susceptible, PI 408105A--flooding tolerant, S99 2281--flooding susceptible) grown under greenhouse conditions and compared genotypic responses to drought and flooding at the physiological, biochemical, and cellular level. We also quantified these variations and tried to infer their role in drought and flooding tolerance in soybean. Our results revealed that different mechanisms contribute to reduction in net photosynthesis under drought and flooding stress. Under drought stress, ABA and stomatal conductance are responsible for reduced photosynthetic rate; while under flooding stress, accumulation of starch granules played a major role. Drought tolerant genotypes PI 567690 and PI 408105A had higher plastoglobule numbers than the susceptible Pana and S99-2281. Drought stress increased the number and size of plastoglobules in most of the genotypes pointing to a possible role in stress tolerance. Interestingly, there were seven fibrillin proteins localized within the plastoglobules that were up-regulated in the drought and flooding tolerant genotypes PI 567690 and PI 408105A, respectively, but down-regulated in the drought susceptible genotype Pana. These results suggest a potential role of Fibrillin proteins, FBN1a, 1b and 7a in soybean response to drought and flooding stress. PMID- 25438145 TI - Post-thaw non-cultured and post-thaw cultured equine cord blood mesenchymal stromal cells equally suppress lymphocyte proliferation in vitro. AB - Multipotent mesenchymal stromal cells (MSC) are receiving increased attention for their non-progenitor immunomodulatory potential. Cryopreservation is commonly used for long-term storage of MSC. Post-thaw MSC proliferation is associated with a lag-phase in vitro. How this lag-phase affect MSC immunomodulatory properties is unknown. We hypothesized that in vitro there is no difference in lymphocyte suppression potential between quick-thawed cryopreserved equine cord blood (CB) MSC immediately included in mixed lymphocyte reaction (MLR) and same MSC allowed post-thaw culture time prior to inclusion in MLR. Cryopreserved CB-MSC from five unrelated foals were compared using two-way MLR. For each of the five unrelated MSC cultures, paired MLR assays of MSC allowed five days of post-thaw culture and MSC included in MLR assay immediately post-thawing were evaluated. We report no difference in the suppression of lymphocyte proliferation by CB-MSC that had undergone post-thaw culture and MSC not cultured post-thaw (p<0.0001). Also, there was no inter-donor variability between the lymphocyte suppressive properties of MSC harvested from the five different donors (p = 0.13). These findings suggest that cryopreserved CB-MSC may have clinical utility immediately upon thawing. One implication hereof is the possibility of using cryopreserved CB MSC at third party locations without the need for cell culture equipment or competencies. PMID- 25438146 TI - Augmented reality for the assessment of children's spatial memory in real settings. AB - Short-term memory can be defined as the capacity for holding a small amount of information in mind in an active state for a short period of time. Although some instruments have been developed to study spatial short-term memory in real environments, there are no instruments that are specifically designed to assess visuospatial short-term memory in an attractive way to children. In this paper, we present the ARSM (Augmented Reality Spatial Memory) task, the first Augmented Reality task that involves a user's movement to assess spatial short-term memory in healthy children. The experimental procedure of the ARSM task was designed to assess the children's skill to retain visuospatial information. They were individually asked to remember the real place where augmented reality objects were located. The children (N = 76) were divided into two groups: preschool (5-6 year olds) and primary school (7-8 year olds). We found a significant improvement in ARSM task performance in the older group. The correlations between scores for the ARSM task and traditional procedures were significant. These traditional procedures were the Dot Matrix subtest for the assessment of visuospatial short term memory of the computerized AWMA-2 battery and a parent's questionnaire about a child's everyday spatial memory. Hence, we suggest that the ARSM task has high verisimilitude with spatial short-term memory skills in real life. In addition, we evaluated the ARSM task's usability and perceived satisfaction. The study revealed that the younger children were more satisfied with the ARSM task. This novel instrument could be useful in detecting visuospatial short-term difficulties that affect specific developmental navigational disorders and/or school academic achievement. PMID- 25438147 TI - Nutritional iron deficiency anemia: magnitude and its predictors among school age children, southwest Ethiopia: a community based cross-sectional study. AB - BACKGROUND: Iron deficiency anemia (IDA) is a global public health problem among school age children, which retards psychomotor development and impairs cognitive performance. There is limited data on prevalence and risk factors for IDA. OBJECTIVE: The aim of this study was to determine the prevalence, severity, and predictors of nutritional IDA in school age children in Southwest Ethiopia. METHODOLOGY: A community based cross-sectional study was conducted in Jimma Town, Southwest Ethiopia from April to July 2013. A total of 616 school children aged 6 to 12 years were included in the study using multistage sampling technique. A structured questionnaire was used to collect sociodemographic data. Five milliliter venous blood was collected from each child for hematological examinations. Anemia was defined as a hemoglobin level lower than 11.5 g/dl and 12 g/dl for age group of 5-11 years and 12-15 years, respectively. Iron deficiency anemia was defined when serum iron and ferritin levels are below 10 umol/l and 15 ug/dl, respectively. Moreover, fresh stool specimen was collected for diagnosis of intestinal parasitic infection. Stained thick and thin blood films were examined for detection of Plasmodium infection and study of red blood cell morphology. Dietary patterns of the study subjects were assessed using food frequency questionnaire and anthropometric measurements were done. Data were analyzed using SPSS V-20.0 for windows. RESULT: Overall, prevalence of anemia was 43.7%, and that of IDA was 37.4%. Not-consuming protein source foods [AOR = 2.30, 95%CI(1.04,5.14)], not-consuming dairy products [AOR = 1.83, 95%CI(1.14,5.14)], not-consuming discretionary calories [AOR = 2.77, 95%CI(1.42,5.40)], low family income [AOR = 6.14, 95%CI(2.90,12.9)] and intestinal parasitic infections [AOR = 1.45, 95%CI(1.23, 5. 27)] were predictors of IDA. CONCLUSION: Iron deficiency anemia is a moderate public health problem in the study site. Dietary deficiencies and intestinal parasitic infections were predictors of IDA. Therefore, emphasis should be given to the strategies for the prevention of risk factors for IDA. PMID- 25438148 TI - Automated stitching of microtubule centerlines across serial electron tomograms. AB - Tracing microtubule centerlines in serial section electron tomography requires microtubules to be stitched across sections, that is lines from different sections need to be aligned, endpoints need to be matched at section boundaries to establish a correspondence between neighboring sections, and corresponding lines need to be connected across multiple sections. We present computational methods for these tasks: 1) An initial alignment is computed using a distance compatibility graph. 2) A fine alignment is then computed with a probabilistic variant of the iterative closest points algorithm, which we extended to handle the orientation of lines by introducing a periodic random variable to the probabilistic formulation. 3) Endpoint correspondence is established by formulating a matching problem in terms of a Markov random field and computing the best matching with belief propagation. Belief propagation is not generally guaranteed to converge to a minimum. We show how convergence can be achieved, nonetheless, with minimal manual input. In addition to stitching microtubule centerlines, the correspondence is also applied to transform and merge the electron tomograms. We applied the proposed methods to samples from the mitotic spindle in C. elegans, the meiotic spindle in X. laevis, and sub-pellicular microtubule arrays in T. brucei. The methods were able to stitch microtubules across section boundaries in good agreement with experts' opinions for the spindle samples. Results, however, were not satisfactory for the microtubule arrays. For certain experiments, such as an analysis of the spindle, the proposed methods can replace manual expert tracing and thus enable the analysis of microtubules over long distances with reasonable manual effort. PMID- 25438150 TI - Estimating cost of road traffic injuries in Iran using willingness to pay (WTP) method. AB - We aimed to use the willingness to pay (WTP) method to calculate the cost of traffic injuries in Iran in 2013. We conducted a cross-sectional questionnaire based study of 846 randomly selected road users. WTP data was collected for four scenarios for vehicle occupants, pedestrians, vehicle drivers, and motorcyclists. Final analysis was carried out using Weibull and maximum likelihood method. Mean WTP was 2,612,050 Iranian rials (IRR). Statistical value of life was estimated according to 20,408 fatalities 402,314,106,073,648 IRR (US$13,410,470,202 based on purchasing power parity at (February 27th, 2014). Injury cost was US$25,637,870,872 (based on 318,802 injured people in 2013, multiple daily traffic volume of 311, and multiple daily payment of 31,030 IRR for 250 working days). The total estimated cost of injury and death cases was 39,048,341,074$. Gross national income of Iran was, US$604,300,000,000 in 2013 and the costs of traffic injuries constituted 6.46% of gross national income. WTP was significantly associated with age, gender, monthly income, daily payment, more payment for time reduction, trip mileage, drivers and occupants from road users. The costs of traffic injuries in Iran in 2013 accounted for 6.64% of gross national income, much higher than the global average. Policymaking and resource allocation to reduce traffic-related death and injury rates have the potential to deliver a huge economic benefit. PMID- 25438149 TI - A virulence factor encoded by a polydnavirus confers tolerance to transgenic tobacco plants against lepidopteran larvae, by impairing nutrient absorption. AB - The biological control of insect pests is based on the use of natural enemies. However, the growing information on the molecular mechanisms underpinning the interactions between insects and their natural antagonists can be exploited to develop "bio-inspired" pest control strategies, mimicking suppression mechanisms shaped by long co-evolutionary processes. Here we focus on a virulence factor encoded by the polydnavirus associated with the braconid wasp Toxoneuron nigriceps (TnBV), an endophagous parasitoid of noctuid moth larvae. This virulence factor (TnBVANK1) is a member of the viral ankyrin (ANK) protein family, and appears to be involved both in immunosuppression and endocrine alterations of the host. Transgenic tobacco plants expressing TnBVANK1 showed insecticide activity and caused developmental delay in Spodoptera littoralis larvae feeding on them. This effect was more evident in a transgenic line showing a higher number of transcripts of the viral gene. However, this effect was not associated with evidence of translocation into the haemocoel of the entire protein, where the receptors of TnBVANK1 are putatively located. Indeed, immunolocalization experiments evidenced the accumulation of this viral protein in the midgut, where it formed a thick layer coating the brush border of epithelial cells. In vitro transport experiments demonstrated that the presence of recombinant TnBVANK1 exerted a dose-dependent negative impact on amino acid transport. These results open new perspectives for insect control and stimulate additional research efforts to pursue the development of novel bioinsecticides, encoded by parasitoid-derived genes. However, future work will have to carefully evaluate any effect that these molecules may have on beneficial insects and on non-target organisms. PMID- 25438152 TI - Two-stage categorization in brand extension evaluation: electrophysiological time course evidence. AB - A brand name can be considered a mental category. Similarity-based categorization theory has been used to explain how consumers judge a new product as a member of a known brand, a process called brand extension evaluation. This study was an event-related potential study conducted in two experiments. The study found a two stage categorization process reflected by the P2 and N400 components in brand extension evaluation. In experiment 1, a prime-probe paradigm was presented in a pair consisting of a brand name and a product name in three conditions, i.e., in category extension, similar-category extension, and out-of-category extension. Although the task was unrelated to brand extension evaluation, P2 distinguished out-of-category extensions from similar-category and in-category ones, and N400 distinguished similar-category extensions from in-category ones. In experiment 2, a prime-probe paradigm with a related task was used, in which product names included subcategory and major-category product names. The N400 elicited by subcategory products was more significantly negative than that elicited by major category products, with no salient difference in P2. We speculated that P2 could reflect the early low-level and similarity-based processing in the first stage, whereas N400 could reflect the late analytic and category-based processing in the second stage. PMID- 25438151 TI - No evidence of harms of probiotic Lactobacillus rhamnosus GG ATCC 53103 in healthy elderly-a phase I open label study to assess safety, tolerability and cytokine responses. AB - BACKGROUND: Although Lactobacillus rhamnosus GG ATCC 53103 (LGG) has been consumed by 2 to 5 million people daily since the mid 1990s, there are few clinical trials describing potential harms of LGG, particularly in the elderly. OBJECTIVES: The primary objective of this open label clinical trial is to assess the safety and tolerability of 1*1010 colony forming units (CFU) of LGG administered orally twice daily to elderly volunteers for 28 days. The secondary objectives were to evaluate the effects of LGG on the gastrointestinal microbiome, host immune response and plasma cytokines. METHODS: Fifteen elderly volunteers, aged 66-80 years received LGG capsules containing 1*1010 CFU, twice daily for 28 days and were followed through day 56. Volunteers completed a daily diary, a telephone call on study days 3, 7 and 14 and study visits in the Clinical Research Center at baseline, day 28 and day 56 to determine whether adverse events had occurred. Assessments included prompted and open-ended questions. RESULTS: There were no serious adverse events. The 15 volunteers had a total of 47 events (range 1-7 per volunteer), 39 (83%) of which were rated as mild and 40% of which were considered related to consuming LGG. Thirty-one (70%) of the events were expected, prompted symptoms while 16 were unexpected events. The most common adverse events were gastrointestinal (bloating, gas, and nausea), 27 rated as mild and 3 rated as moderate. In the exploratory analysis, the pro inflammatory cytokine interleukin 8 decreased during LGG consumption, returning towards baseline one month after discontinuing LGG (p = 0.038) while there was no difference in other pro- or anti-inflammatory plasma cytokines. CONCLUSIONS: Lactobacillus rhamnosus GG ATCC 53103 is safe and well tolerated in healthy adults aged 65 years and older. TRIAL REGISTRATION: ClinicalTrials.gov NCT 01274598. PMID- 25438153 TI - Nationwide experience of treatment with protease inhibitors in chronic hepatitis C patients in Denmark: identification of viral resistance mutations. AB - BACKGROUND AND AIMS: The first standard of care in treatment of chronic HCV genotype 1 infection involving directly acting antivirals was protease inhibitors telaprevir or boceprevir combined with pegylated-interferon and ribavirin (triple therapy). Phase III studies include highly selected patients. Thus, treatment response and development of viral resistance during triple therapy in a routine clinical setting needs to be determined. The aims of this study were to investigate treatment outcome and identify sequence variations after triple therapy in patients with chronic HCV genotype 1 infection in a routine clinical setting. METHODS: 80 patients, who initiated and completed triple therapy in Denmark between May 2011 and November 2012, were included. Demographic data and treatment response were obtained from the Danish Database for Hepatitis B and C. Direct sequencing and clonal analysis of the RT-PCR amplified NS3 protease were performed in patients without cure following triple therapy. RESULTS: 38 (47%) of the patients achieved cure, 15 (19%) discontinued treatment due to adverse events and remained infected, and 27 (34%) experienced relapse or treatment failure of whom 15 of 21 analyzed patients had well-described protease inhibitor resistance variants detected. Most frequently detected protease variants were V36M and/or R155K, and V36M, in patients with genotype 1a and 1b infection, respectively. CONCLUSIONS: The cure rate after triple therapy in a routine clinical setting was 47%, which is substantially lower than in clinical trials. Resistance variants towards protease inhibitors were seen in 71% of patients failing therapy indicating that resistance could have an important role in treatment response. PMID- 25438155 TI - Magnetic resonance imaging of osteophytic, chondral, and subchondral structures in a surgically-induced osteoarthritis rabbit model. AB - OBJECTIVE: This study aimed to assess changes in osteophytic, chondral, and subchondral structures in a surgically-induced osteoarthritis (OA) rabbit model in order to correlate MRI findings with the macroscopic progress of OA and to define the timepoint for disease status in this OA model. METHODS: The OA model was constructed by surgery in thirty rabbits with ten normal rabbits serving as controls (baseline). High-resolution three-dimensional MRI using a 1.5-T coil was performed at baseline, two, four, and eight weeks post-surgery. MRIs of cartilage lesions, subchondral bone lesions, and osteophyte formations were independently assessed by two blinded radiologists. Ten rabbits were sacrificed at baseline, two, four, and eight weeks post-surgery, and macroscopic evaluation was independently performed by two blinded orthopedic surgeons. RESULTS: The signal intensities and morphologies of chondral and subchondral structures by MRI accurately reflected the degree of OA. Cartilage defects progressed from a grade of 0.05-0.15 to 1.15-1.30 to 1.90-1.97 to 3.00-3.35 at each successive time point, respectively (p<0.05). Subchondral bone lesions progressed from a grade of 0.00 to 0.78-0.90 to 1.27-1.58 to 1.95-2.23 at each successive time point, respectively (p = 0.000). Osteophytes progressed from a size (mm) of 0.00 to 0.87 1.06 to 1.24-1.87 to 2.21-3.21 at each successive time point, respectively (p = 0.000). CONCLUSIONS: Serial observations revealed that MRI can accurately detect the progression of cartilage lesions and subchondral bone edema over an eight week period but may not be accurate in detecting osteophyte sizes. Week four post surgery was considered the timepoint between OA-negative and OA-positive status in this OA model. The combination of this OA model with MRI evaluation should provide a promising tool for the pre-clinical evaluation of new disease-modifying osteoarthritis drugs. PMID- 25438154 TI - Altered active zones, vesicle pools, nerve terminal conductivity, and morphology during experimental MuSK myasthenia gravis. AB - Recent studies demonstrate reduced motor-nerve function during autoimmune muscle specific tyrosine kinase (MuSK) myasthenia gravis (MG). To further understand the basis of motor-nerve dysfunction during MuSK-MG, we immunized female C57/B6 mice with purified rat MuSK ectodomain. Nerve-muscle preparations were dissected and neuromuscular junctions (NMJs) studied electrophysiologically, morphologically, and biochemically. While all mice produced antibodies to MuSK, only 40% developed respiratory muscle weakness. In vitro study of respiratory nerve-muscle preparations isolated from these affected mice revealed that 78% of NMJs produced endplate currents (EPCs) with significantly reduced quantal content, although potentiation and depression at 50 Hz remained qualitatively normal. EPC and mEPC amplitude variability indicated significantly reduced number of vesicle-release sites (active zones) and reduced probability of vesicle release. The readily releasable vesicle pool size and the frequency of large amplitude mEPCs also declined. The remaining NMJs had intermittent (4%) or complete (18%) failure of neurotransmitter release in response to 50 Hz nerve stimulation, presumably due to blocked action potential entry into the nerve terminal, which may arise from nerve terminal swelling and thinning. Since MuSK-MG-affected muscles do not express the AChR gamma subunit, the observed prolongation of EPC decay time was not due to inactivity-induced expression of embryonic acetylcholine receptor, but rather to reduced catalytic activity of acetylcholinesterase. Muscle protein levels of MuSK did not change. These findings provide novel insight into the pathophysiology of autoimmune MuSK-MG. PMID- 25438156 TI - Correlation of STAT1 with apoptosis and cell-cycle markers in esophageal squamous cell carcinoma. AB - We recently found evidence that STAT1 in esophageal squamous carcinoma (ESCC) cells exerts tumor suppressor function, and it regulates five key regulators of apoptosis or cell-cycle progression, including Bcl-2, Bcl-xL, survivin, cyclin D1 and p21. In this study, we confirmed these findings in four ESCC cell lines. Using immunohistochemistry, we also assessed the expression of these proteins in 62 primary tumors. The expression of these markers was heterogeneous, ranging 39 to 69% of the cohort. Significant correlation was found between STAT1 and three proteins (p21, Bcl-xL and survivin), whereas only a trend was identified for cyclin D1 and Bcl-2. We then correlated the expression of these proteins with several clinicopathologic parameters including lymph node metastasis, depth of invasion, clinical stage and overall survival. Significant correlations were found between Bcl-2 and deep invasion (p = 0.033), survivin and lymph node metastasis (p = 0.006), as well as cyclin D1 and clinical stage (p = 0.014). Patients with p21-positive tumors had a significantly longer survival compared to those with p21-negative tumors (p = 0.031). To conclude, our findings support the concept that STAT1 exerts its tumor suppressor effects in ESCC via modulating the expression of key regulators of apoptosis and cell-cycle progression. PMID- 25438157 TI - Surgical stress induced depressive and anxiety like behavior are improved by dapsone via modulating NADPH oxidase level. AB - Surgical stress induced depression and anxiety like behavior are common complications among aged individuals suffering from surgery. Recent studies proposed that accumulation of oxidative stress is involved in the etiology of stress induced depression and anxiety. Dapsone possesses antioxidant properties, however, whether dapsone is effective in modulating surgical stress induced brain oxidative damage remains uncertain. The present study aimed to investigate the effect of dapsone on surgical stress induced depressive and anxiety like behavior, and brain oxidative stress in a well-established surgical stress model. Depressive and anxiety like behavior accompanied by elevated brain oxidative stress were observed in aged mice underwent abdominal surgery. Pretreatment with 5 mg/kg dapsone significantly improved the behavioral disorder and ameliorated brain oxidative stress in this model. Further investigation, revealed that surgical stress increased brain NADPH oxidase level, while pretreatment with dapsone abrogated the elevation of NADPH oxidase triggered by surgical stress. These findings suggest that dapsone is effective in improving surgical stress induced brain oxidative damage via down-regulating NADPH oxidase level in aged mice. PMID- 25438161 TI - Amorphous Co3O4 modified CdS nanorods with enhanced visible-light photocatalytic H2-production activity. AB - In this work, amorphous Co3O4 modified CdS nanorods were synthesized by a two step solvothermal/hydrothermal method, and characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), high-resolution transmission electron microscopy, UV-visible spectroscopy, nitrogen absorption and X-ray photoelectron spectroscopy. The photocatalytic performance of the as-synthesized Co3O4-CdS nanorods was evaluated through H2 generation from an aqueous solution containing sulfide and sulfite under visible light (lambda >= 420 nm). The results showed that the photocatalytic activity of CdS nanorods for H2 evolution could be significantly enhanced by loading the amorphous Co3O4. The optimal Co3O4 loading was found to be approximately 3.0 mol%. The as-prepared CdS nanorods with 3 mol% Co3O4 exhibited the highest photocatalytic activity for H2 evolution under visible light irradiation, 236 MUmol g(-1) h(-1), which is 33-fold higher than that of the pristine CdS nanorods. Furthermore, the co-loading of 1 wt% Pt can lead to another three times enhancement in the photocatalytic H2-production activity. The mechanism for the enhanced H2-production performance of Co3O4-CdS nanorods was discussed. The excellent performance of Co3O4-CdS nanorods is mainly ascribed to the loading of amorphous Co3O4 onto the surface of CdS nanorods, which could promote the separation of electron-hole pairs and enhance the stability of CdS nanorods due to the formation of p-n heterojunctions between the Co3O4 and CdS nanorods, thus leading to an enhanced activity for H2 generation. This work demonstrated that the loading of amorphous Co3O4 is a facile strategy to enhance the photocatalytic activity of CdS nanorods, which may provide some potential opportunities for designing other composite photocatalysts for water splitting. PMID- 25438158 TI - Early processing of auditory lexical predictions revealed by ERPs. AB - Auditory lexical processing starts within 200 ms after onset of the critical stimulus. Here, we used electroencephalography (EEG) to investigate whether (1) the so-called N200 effect can be triggered by single-item lexical context, and (2) such effects are robust against temporal violations of the signal. We presented items in which lexical status (i.e., is the stimulus a word or a pseudoword?) was determined at third syllable onset. The critical syllable could be naturally timed or delayed (by ~440 or ~800 ms). Across all conditions, we observed an effect of lexicality that started ~200 ms after third syllable onset (i.e., an N200 effect in naturally timed items and a similar effect superimposed on the P2 for the delayed items). The results indicate that early lexical processes are robust against violations of temporal coherence. PMID- 25438163 TI - A novel method of blood pressure measurement in patients with continuous-flow left ventricular assist devices. PMID- 25438162 TI - Is the burden of oral diseases higher in urban disadvantaged community compared to the national prevalence? AB - BACKGROUND: The urban low income has often been assumed to have the greatest dental treatment needs compared to the general population. However, no studies have been carried out to verify these assumptions. This study was conducted to assess whether there was any difference between the treatment needs of an urban poor population as compared to the general population in order to design an intervention programme for this community. METHODS: A random sampling of living quarters (households) in the selected areas was done. 586 adults over 19 years old living in these households were clinically examined using World Health Organization (WHO) Oral Health Survey criteria 4th edition (1997). RESULTS: The overall prevalence of dental caries, periodontal disease, denture wearers and temporomandibular joint problems were 70.5%, 97.1%, 16.7% and 26%, respectively. The majority (80.5%) needed some form of dental treatment. The highest treatment needs were found in the oldest age group while the lowest were in the youngest group (19-29 years) (p = 0.000). The most prevalent periodontal problem was calculus; regardless of gender, ethnicity and age. Significantly more females (20.5%) wore prosthesis than males (11.1%) (p = 0.003). Prosthetic status and need significantly increased with age (p = 0.000). About one in four adults had Temporo-Mandibular Joint (TMJ) problems. Overall, it was surprising to note that the oral disease burden related to caries, prosthetic status and treatment need were lower in this population as compared to the national average (NOHSA, 2010). However, their periodontal disease status and treatment needs were higher compared to the national average indicating a poor oral hygiene standard. CONCLUSIONS: The evidence does not show that the overall oral disease burden and treatment needs in this urban disadvantaged adult population as higher than the national average, except for periodontal disease. The older age groups and elderly were identified as the most in need for oral health intervention and promotion. An integrated health intervention programme through a multisectoral common risk factor approach in collaboration with the Faculties of Medicine, Dentistry and other agencies is needed for the identified target group. PMID- 25438164 TI - Endovascular repair of a HeartMate II left ventricular assist device. PMID- 25438165 TI - Minimally invasive continuous-flow left ventricular assist device implantation: Avoiding a median sternotomy. PMID- 25438166 TI - Early power elevations and adverse events with the HeartMate II left ventricular assist device: An unsettled issue. PMID- 25438167 TI - Receptor-mediated membrane adhesion of lipid-polymer hybrid (LPH) nanoparticles studied by dissipative particle dynamics simulations. AB - Lipid-polymer hybrid (LPH) nanoparticles represent a novel class of targeted drug delivery platforms that combine the advantages of liposomes and biodegradable polymeric nanoparticles. However, the molecular details of the interaction between LPHs and their target cell membranes remain poorly understood. We have investigated the receptor-mediated membrane adhesion process of a ligand-tethered LPH nanoparticle using extensive dissipative particle dynamics (DPD) simulations. We found that the spontaneous adhesion process follows a first-order kinetics characterized by two distinct stages: a rapid nanoparticle-membrane engagement, followed by a slow growth in the number of ligand-receptor pairs coupled with structural re-organization of both the nanoparticle and the membrane. The number of ligand-receptor pairs increases with the dynamic segregation of ligands and receptors toward the adhesion zone causing an out-of-plane deformation of the membrane. Moreover, the fluidity of the lipid shell allows for strong nanoparticle-membrane interactions to occur even when the ligand density is low. The LPH-membrane avidity is enhanced by the increased stability of each receptor ligand pair due to the geometric confinement and the cooperative effect arising from multiple binding events. Thus, our results reveal the unique advantages of LPH nanoparticles as active cell-targeting nanocarriers and provide some general principles governing nanoparticle-cell interactions that may aid future design of LPHs with improved affinity and specificity for a given target of interest. PMID- 25438168 TI - Evidence for a catalytic six-membered cyclic transition state in aminolysis of 4 nitrophenyl 3,5-dinitrobenzoate in acetonitrile: comparative bronsted-type plot, entropy of activation, and deuterium kinetic isotope effects. AB - A kinetic study for reactions of 4-nitrophenyl 3,5-dinitrobenzoate (1a) with a series of cyclic secondary amines in acetonitrile is reported. Plots of the pseudo-first-order rate constant (kobsd) vs [amine] curve upward, while those of kobsd /[amine] vs [amine] exhibit excellent linear correlations with positive intercepts, indicating that the reaction proceeds through both uncatalyzed and catalyzed routes. Bronsted-type plots for uncatalyzed and catalyzed reactions are linear with betanuc = 1.03 and 0.69, respectively. The DeltaH(?) and DeltaS(?) values measured for the catalytic reaction with morpholine are -0.80 kcal/mol and -61.7 cal/(mol K), respectively. The negative DeltaH(?) with a large negative DeltaS(?) suggests that the reaction proceeds through a highly ordered transition state (i.e., a six-membered cyclic transition state, which includes a second amine molecule that accepts a proton from the aminium moiety of the zwitterionic tetrahedral intermediate and simultaneously donates a proton to the aryloxyl oxygen of the nucleofuge with concomitant C-OAr bond scission). This proposal is consistent with the smaller betanuc value for the catalyzed reaction as compared to the uncatalyzed reaction. An inverse deuterium kinetic isotope effect (DKIE) value of 0.93 and a contrasting normal primary DKIE value of 3.23 for the uncatalyzed and catalyzed routes, respectively, also support the proposed cyclic transition state. PMID- 25438170 TI - Ontogenetic and interspecific metabolic scaling in insects. AB - Design constraints imposed by increasing size cause metabolic rate in animals to increase more slowly than mass. This ubiquitous biological phenomenon is referred to as metabolic scaling. However, mechanistic explanations for interspecific metabolic scaling do not apply to ontogenetic size changes within a species, implying different mechanisms for scaling phenomena. Here, we show that the dynamic energy budget theory approach of compartmentalizing biomass into reserve and structural components provides a unified framework for understanding ontogenetic and interspecific metabolic scaling. We formulate the theory for insects and show that it can account for ontogenetic metabolic scaling during the embryonic and larval phases, as well as the U-shaped respiration curve during pupation. After correcting for the predicted ontogenetic scaling effects, which we show to follow universal curves, the scaling of respiration between species is approximated by a three-quarters power law, supporting past empirical studies on insect metabolic scaling and our theoretical predictions. The ability to explain ontogenetic and interspecific metabolic scaling effects under one consistent framework suggests that the partitioning of biomass into reserve and structure is a necessary foundation to a general metabolic theory. PMID- 25438169 TI - A multi-center, cross-sectional study on the burden of infectious keratitis in China. AB - OBJECTIVE: To understand the prevalence and demographic characteristics of infectious keratitis and infectious corneal blindness. METHODS: A multi-center, population-based cross-sectional study was conducted from January 1 to August 31, 2010. A total of 191,242 individuals of all age groups from 10 geographically representative provinces were sampled using stratified, multi-stage, random and systematic sampling procedures. A majority, 168,673 (88.2%), of those sampled participated in the study. The examination protocol included a structured interview, visual acuity testing, an external eye examination, and an anterior segment examination using a slit lamp. The causes and sequelae of corneal disease were identified using uniform customized protocols. Blindness in one eye caused by infectious keratitis was defined as infectious corneal blindness. RESULTS: The prevalence of past and active infectious keratitis was 0.192% (95% confidence interval [CI], 0.171-0.213%), and the prevalence of viral, bacterial, and fungal keratitis was 0.11%, 0.075%, and 0.007%, respectively. There were 138 cases of infectious corneal blindness in at least one eye in the study population (prevalence of 0.082% [95%CI, 0.068%-0.095%]). Statistical analysis suggested that ocular trauma, alcoholic consumption, low socioeconomic levels, advanced age, and poor education were risk factors for infectious corneal blindness. CONCLUSIONS: Infectious keratitis is the leading cause of corneal blindness in China. Eye care strategies should focus on the prevention and rehabilitation of infectious corneal blindness. PMID- 25438171 TI - Strong natural selection on juveniles maintains a narrow adult hybrid zone in a broadcast spawner. AB - Natural selection can maintain and help form species across different habitats, even when dispersal is high. Selection against inferior migrants (immigrant inviability) acts when locally adapted populations suffer high mortality on dispersal to unsuitable habitats. Habitat-specific populations undergoing divergent selection via immigrant inviability should thus show (1) a change in the ratio of adapted to nonadapted individuals among age/size classes and (2) a cline (defined by the environmental gradient) as selection counterbalances migration. Here we examine the frequencies of two depth-segregated lineages in juveniles and adults of a Caribbean octocoral, Eunicea flexuosa. Distributions of the two lineages in both shallow and deep environments were more distinct when inferred from adults than juveniles. Despite broad larval dispersal, we also found an extremely narrow hybrid zone (<100 m), with coincident clines for molecular and morphological characters of the host coral and its algal symbiont. Effective dispersal estimates derived from the hybrid zone are remarkably small (<20 m) for a broadcast spawner. The large selection coefficient against mismatched genotypes derived from cohort data is consistent with that from field transplant experiments. Narrow hybrid zones and limited effective dispersal may be a common outcome of long periods of postsettlement, prereproductive selection across steep ecological gradients. Strong diversifying selection provides a mechanism to explain the prevalence of depth-segregated sibling species in the sea. PMID- 25438172 TI - Evolutionary consequences of nonselective harvesting in density-dependent populations. AB - There is now considerable empirical evidence that evolutionary changes in many phenotypic characters, such as body mass, age at maturation, and timing of breeding, often occur in populations subject to intense harvesting over longer periods. Here, we analyze the evolutionary component of the selection due to nonselective harvesting, which will operate even under selective harvesting and may generate a large evolutionary response. If phenotype affects susceptibility to density dependence-for example, through resource limitation-then nonselective harvesting can induce evolutionary change through its effect on population density. We provide a model for evolution of a quantitative character in such a fluctuating density-dependent population, using the diffusion approximation to describe jointly the temporal changes in mean phenotype and log population size. We show how nonselective harvesting in particular generates r-selection governed by genetic variation in the strength of density regulation and the magnitude of population fluctuations. We show that r-selection caused by nonselective harvesting is proportional to the mean fraction of the population harvested. We then compare the short-term as well as the long-term evolutionary impact of nonselective harvesting for different harvesting strategies by using the mean harvest fraction for different strategies. This comparison is performed for three different harvesting strategies: constant, proportional, and threshold harvesting. The more ecologically sustainable strategies also produce smaller evolutionary changes. PMID- 25438173 TI - Size-dependent selective mechanisms on males and females and the evolution of sexual size dimorphism in frogs. AB - Sexual size dimorphism (SSD) varies in animals from male biased to female biased. The evolution of SSD is potentially influenced by a number of factors, such as territoriality, fecundity, and temporal breeding patterns (explosive vs. prolonged). In general, frogs show female-biased SSD with broad variance among species. Using comparative methods, we examine how different selective forces affect male and female sizes, and we test hypotheses about size-dependent mechanisms shaping SSD in frogs. Male size was weakly associated with SSD in all size classes, and we found no significant association among SSD, male size, temporal breeding pattern, and male territoriality. In contrast, female size best explained SSD variation across all size classes but especially for small-bodied species. We found a stronger evolutionary association between female body size and fecundity, and this fecundity advantage was highest in explosively breeding species. Our data indicate that the fecundity advantage associated with female body size may not be linear, such that intermediate and large females benefit less with body size increases. Therefore, size-dependent selection in females associated with fecundity and breeding patterns is an important mechanism driving SSD evolution in frogs. Our study underscores the fact that lineage-specific ecology and behavior should be incorporated in comparative analyses of animal SSD. PMID- 25438174 TI - Carotenoid-dependent signals and the evolution of plasma carotenoid levels in birds. AB - Sexual selection has resulted in a wide array of ornaments used in mate choice, and such indicator traits signal quality honestly when they bear costs, precluding cheating. Carotenoid-dependent coloration has attracted considerable attention in this context, because investing carotenoids in coloration has to be traded off against its physiological functions; carotenoids are antioxidants and increase immunocompetence. This trade-off is hypothesized to underlie the honesty of carotenoid-dependent coloration, signaling the "handicap" of allocating carotenoids away from somatic maintenance toward sexual display. Utilizing recent advances in modeling adaptive evolution, we used a comparative approach to investigate the evolution of plasma carotenoid levels using a species-level phylogeny of 178 bird species. We find that the evolutionary optimum for carotenoid levels is higher in lineages that evolved carotenoid-dependent coloration, with strong attraction toward this optimum. Hence, carotenoids do not appear to be limiting, given that higher carotenoid levels readily evolve in response to the evolution of carotenoid-dependent coloration. These findings challenge the assumption that carotenoids are a scarce resource and thus also challenge the hypothesis that physiological resource value of carotenoids underlies honesty of carotenoid-dependent traits. Therefore, the comparative evidence suggests that other factors, such as the acquisition and incorporation of carotenoids, are involved in maintaining signal honesty. PMID- 25438175 TI - The paradox of enrichment in metaecosystems. AB - The paradox of enrichment has been studied almost exclusively within communities or metacommunities, without explicit nutrient dynamics. Yet local recycling of materials from enriched ecosystems may affect the stability of connected ecosystems. Here we study the effect of nutrient, detritus, producer, and consumer spatial flows-combined with changes in regional enrichment-on the stability of a metaecosystem model. We considered both spatially homogeneous and heterogeneous enrichment. We found that nutrient and detritus spatial flows are destabilizing, whereas producer or consumer spatial flows are either neutral or stabilizing. We noticed that detritus spatial flows have only a weak impact on stability. Our study reveals that heterogeneity no longer stabilizes well connected systems when accounting for explicit representation of nutrient dynamics. We also found that intermediate consumer diffusion could lead to multiple equilibria in strongly enriched metaecosystems. Stability can emerge from a top-down control allowing the storage of materials into inorganic form, a mechanism never documented before. In conclusion, local enrichment can be stabilized if spatial flows are strong enough to efficiently redistribute the local excess of enrichment to unfertile ecosystems. However, high regional enrichment can be dampened only by intermediate consumer diffusion rates. PMID- 25438176 TI - Long antibody persistence and transgenerational transfer of immunity in a long lived vertebrate. AB - Although little studied in natural populations, the persistence of immunoglobulins may dramatically affect the dynamics of immunity and the ecology and evolution of host-pathogen interactions involving vertebrate hosts. By means of a multiple-year vaccination design against Newcastle disease virus, we experimentally addressed whether levels of specific antibodies can persist over several years in females of a long-lived procellariiform seabird-Cory's shearwater-and whether maternal antibodies against that antigen could persist over a long period in offspring several years after the mother was exposed. We found that a single vaccination led to high levels of antibodies for several years and that the females transmitted antibodies to their offspring that persisted for several weeks after hatching even 5 years after a single vaccination. The temporal persistence of maternally transferred antibodies in nestlings was highly dependent on the level at hatching. A second vaccination boosted efficiently the level of antibodies in females and thus their transfer to offspring. Overall, these results stress the need to consider the temporal dynamics of immune responses if we are to understand the evolutionary ecology of host-parasite interactions and trade-offs between immunity and other life-history characteristics, in particular in long-lived species. They also have strong implications for conservation when vaccination may be used in natural populations facing disease threats. PMID- 25438177 TI - Bees at war: interspecific battles and nest usurpation in stingless bees. AB - We provide the first evidence for interspecific warfare in bees, a spectacular natural phenomenon that involves a series of aerial battles and leads to thousands of fatalities from both attacking and defending colonies. Molecular analysis of fights at a hive of the Australian stingless bee Tetragonula carbonaria revealed that the attack was launched by a related species, Tetragonula hockingsi, which has only recently extended its habitat into southeastern Queensland. Following a succession of attacks by the same T. hockingsi colony over a 4-month period, the defending T. carbonaria colony was defeated and the hive usurped, with the invading colony installing a new queen. We complemented our direct observations with a 5-year study of more than 260 Tetragonula hives and found interspecific hive changes, which were likely to be usurpation events, occurring in 46 hives over this period. We discuss how fighting swarms and hive usurpation fit with theoretical predictions on the evolution of fatal fighting and highlight the many unexplained features of these battles that warrant further study. PMID- 25438178 TI - Mountain pine beetle seasonal timing and constraints to bivoltinism. AB - Mountain pine beetle tree colonization typically occurs in July and August, with completion of a generation one (univoltinism) or two (semivoltinism) years later. In a 2012 publication, Mitton and Ferrenberg suggested that climate change resulted in an unprecedented generation between June and September (a summer generation), with a concomitant shift to two generations in one year (bivoltinism). Although summer generations are not uncommon in this species, completion of a second generation across winter, between September and June, would be required for bivoltinism, a phenomenon not previously observed. Mitton and Ferrenberg showed that a summer generation can occur, but they failed to adequately track cohorts and provided no compelling evidence for bivoltinism. We demonstrate that a winter generation-and hence bivoltinism-would have been physiologically impossible at the high-elevation site used in Mitton and Ferrenberg due to lower thermal developmental thresholds. The mountain pine beetle is indeed being influenced by climate change. To address the challenges of future population outbreaks of this significant tree mortality agent, however, it is imperative to consider evolved, thermally dependent traits that serve to maintain seasonality. PMID- 25438179 TI - Field studies demonstrate bivoltinism in the mountain pine beetle. PMID- 25438180 TI - Present-day genetic correlations and testing the aerobic capacity model. AB - A recent article by Nespolo and Roff suggests that present-day genetic correlations between resting and maximal metabolic rate do not provide support for the aerobic capacity model for the evolution of endothermy. That conclusion is potentially misleading. The aerobic capacity model makes exacting predictions about genetic architecture. While the presence of a genetic correlation does not support the model per se, the absence of a correlation definitively falsifies the model. Testing for present-day correlations remains a useful endeavor, at least until the model is convincingly falsified or until many attempts to falsify the model fail. PMID- 25438181 TI - Model falsification, quantitative genetics, and the evolution of endothermy: are we choosing the right tool? PMID- 25438184 TI - Hormonal, behavioral, and life-history traits exhibit correlated shifts in relation to population establishment in a novel environment. AB - Climate change, habitat alteration, range expansions, and biological invasions are all predicted to require rapid shifts in multiple traits including behavior and life history, both for initial population establishment and subsequent adaptation. Hormonal mechanisms likely play a key role in facilitating or constraining plastic and genetic responses for suites of traits, but few studies have evaluated their role in shaping contemporary adaptation or diversification. We examined multiple phenotypic adjustments and associated hormonal changes following a recent (early 1980s) colonization event, in which a temperate breeding songbird, the dark-eyed junco (Junco hyemalis), became established in the Mediterranean climate of San Diego, California. The milder climate has led to an extended breeding season and year-round residency, and we document shifts in multiple sexually selected behaviors and plumage traits. Testosterone titers in San Diego were elevated for longer but with a lower peak value compared to a nearby native-range population, and correlations between testosterone and related traits were similar within and among populations. A common garden study indicated that changes in testosterone likely represent plastic responses to the less seasonal environment of the city, providing the context against which subsequent genetic changes in morphology likely occurred. We argue that correlated shifts in multiple traits, organized by underlying physiology, may be a generally important element of many successful adjustments to changing environments. PMID- 25438185 TI - Ant larvae as players in social conflict: relatedness and individual identity mediate cannibalism intensity. AB - Conflict arises among social organisms when individuals differ in their inclusive fitness interests. Ant societies are excellent models for understanding how genetic relatedness mediates conflict intensity. However, although conflicts within colonies typically arise over offspring production, the role of larvae as actors in social conflict has received little attention. We develop and empirically test kin-selection theory of larval egg cannibalism in ant societies. Specifically, we investigate how selection for cannibalism is mediated by nestmate relatedness and larval sex in a mathematical model and then test the model's predictions by measuring cannibalism levels in eight ant species with varying nestmate relatedness. In line with our theoretical predictions, cannibalism levels in larvae were significantly influenced by relatedness and sex. Increased relatedness was associated with reduced levels of cannibalism, indicating that larval behavior is mediated by inclusive-fitness considerations. Levels of cannibalism were significantly higher in male larvae, and our model suggests that this is due to sex differences in the benefits of cannibalism. By examining the selfish interests of larvae and the constraints they face in a social environment, our study presents a novel perspective on conflict in ants and on the evolution of selfish elements in social systems in general. PMID- 25438186 TI - Observation, natural history, and an early post-Darwinian view of plant-animal interactions. PMID- 25438188 TI - Oat fiber as a carrier for curcuminoids. AB - The curcuminoid-carrying potential of oat fiber was examined as a potential route to overcome the low aqueous solubility of curcuminoids. Aqueous dispersions of oat fiber were mixed with curcuminoids solubilized in ethanol to obtain curcuminoids-oat fiber (1% w/w) dispersions in aqueous ethanol (2% v/v). Centrifugation of the curcuminoids-oat fiber dispersions resulted in a supernatant (95.3% w/w: 0.11% w/w protein, 0.17% w/w beta-glucan) and precipitate (4.74% w/w: 0.18% w/w protein, 0.11% w/w beta-glucan) with the curcuminoids being almost equally partitioned into both fractions. Curcuminoids solubility in the supernatant was markedly greater than that in aqueous ethanol and water. The curcuminoids were in the amorphous state in the precipitated fraction and were more stable to degradation than the curcuminoids in the supernatant. These studies show the potential of oat fiber as a carrier for curcuminoids into functional foods. PMID- 25438187 TI - Cryptophane-folate biosensor for (129)xe NMR. AB - Folate-conjugated cryptophane was developed for targeting cryptophane to membrane bound folate receptors that are overexpressed in many human cancers. The cryptophane biosensor was synthesized in 20 nonlinear steps, which included functionalization with folate recognition moiety, solubilizing peptide, and Cy3 fluorophore. Hyperpolarized (129)Xe NMR studies confirmed xenon binding to the folate-conjugated cryptophane. Cellular internalization of biosensor was monitored by confocal laser scanning microscopy and quantified by flow cytometry. Competitive blocking studies confirmed cryptophane endocytosis through a folate receptor-mediated pathway. Flow cytometry revealed 10-fold higher cellular internalization in KB cancer cells overexpressing folate receptors compared to HT 1080 cells with normal folate receptor expression. The biosensor was determined to be nontoxic in HT-1080 and KB cells by MTT assay at low micromolar concentrations typically used for hyperpolarized (129)Xe NMR experiments. PMID- 25438189 TI - Fluorescence and room temperature activity of Y2O3:(Eu3+,Au3+)/palygorskite nanocomposite. AB - The fluorescence and room temperature activity of a palygorskite supported Y2O3:(Eu(3+),Au(3+)) nanocomposite were investigated to design a fluorescence indicated catalyst. The effects of Au(3+) doping on the structure and surface properties of the host material were systematically characterized. The fluorescence intensity of Y2O3:Eu(3+) was affected by Au(3+) doping, which was related to the crystallinity of Y2O3. Excess Au(3+) ions were segregated to the host surface and reduced to metallic Au. The local symmetry of Eu(3+) was reduced by Au(3+) doping, which benefited the energy transfer between Eu(3+) and Au(3+). Energy absorbed by Eu(3+) was transferred from Au(3+) to metallic Au, where electrons were produced. These electrons were absorbed by O2 to change into O2( ), which acted as the oxidant for ortho-dichlorobenzene (o-DCB). The variation of fluorescence intensity during the catalytic reaction was observed. The room temperature catalytic activity of the nanocomposite under UV irradiation was revealed. The as-synthesized nanocomposite might have potential applications in environmental fields. PMID- 25438191 TI - Interaction of G-quadruplexes in the full-length 3' human telomeric overhang. AB - The 3' human telomeric overhang provides ample opportunities for the formation and interaction of G-quadruplexes, which have shown impacts on many biological functions including telomerase activities in the telomere region. However, in the few investigations on DNA constructs that approach to the full length of the human telomeric overhang, the presence of higher-order quadruplex-quadruplex interactions is still a subject of debate. Herein, we employed dynamic splint ligation (DSL) to prepare a DNA construct, 5'-(TTAGGG)24 or 24G, which has the length comparable to the full stretch of 3' human telomeric overhang. Using mechanical unfolding assays in laser tweezers, we observed a minor population (~5%) of higher-order interactions between G-quadruplexes, while the majority of the quadruplexes follow the bead-on-a-string model. Analyses on the noninteracting G-quadruplexes in the 24G construct showed features similar to those of the stand-alone G-quadruplexes in the 5'-(TTAGGG)4 (4G) construct. As each 24G construct contains as many as six G-quadruplexes, this method offers increased throughput for the time-consuming mechanical unfolding experiments of non-B DNA structures. PMID- 25438190 TI - Novel therapeutic approaches to autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by the progressive growth of renal cysts that, over time, destroy the architecture of the renal parenchyma and typically lead to kidney failure by the sixth decade of life. ADPKD is common and represents a leading cause of renal failure worldwide. Currently, there are no Food and Drug Administration-approved treatments for the disease, and the existing standard of care is primarily supportive in nature. However, significant advances in the understanding of the molecular biology of the disease have inspired investigation into potential new therapies. Several drugs designed to slow or arrest the progression of ADPKD have shown promise in preclinical models and clinical trials, including vasopressin receptor antagonists and somatostatin analogs. This article examines the literature underlying the rationale for molecular therapies for ADPKD and reviews the existing clinical evidence for their indication for human patients with the disease. PMID- 25438192 TI - Size- and composition-dependent toxicity of synthetic and soil-derived Fe oxide colloids for the nematode Caenorhabditis elegans. AB - Colloidal iron oxides (FeOx) are increasingly released to the environment due to their use in environmental remediation and biomedical applications, potentially harming living organisms. Size and composition could affect the bioavailability and toxicity of such colloids. Therefore, we investigated the toxicity of selected FeOx with variable aggregate size and variably composed FeOx-associated organic matter (OM) toward the nematode Caenorhabditis elegans. Ferrihydrite colloids containing citrate were taken up by C. elegans with the food and accumulated inside their body. The toxicity of ferrihydrite, goethite, and akaganeite was dependent on aggregate size and specific surface area, with EC50 values for reproduction ranging from 4 to 29 mg Fe L(-1). Experiments with mutant strains lacking mitochondrial superoxide dismutase (sod-2) showed oxidative stress for two FeOx and Fe(3+)-ions, however, revealed that it was not the predominant mechanism of toxicity. The OM composition determined the toxicity of mixed OM-FeOx phases on C. elegans. FeOx associated with humic acids or citrate were less toxic than OM-free FeOx. In contrast, soil-derived ferrihydrite, containing proteins and polysaccharides from mobile OM, was even more toxic than OM-free Fh of similar aggregate size. Consequently, the careful choice of the type of FeOx and the type of associated OM may help in reducing the ecological risks if actively applied to the subsurface. PMID- 25438193 TI - Compression-induced crystallization of amorphous indomethacin in tablets: characterization of spatial heterogeneity by two-dimensional X-ray diffractometry. AB - Tablets of amorphous indomethacin were compressed at 10, 25, 50, or 100 MPa using either an unlubricated or a lubricated die and stored individually at 35 degrees C in sealed Mylar pouches. At selected time points, tablets were analyzed by two dimensional X-ray diffractometry (2D-XRD), which enabled us to profile the extent of drug crystallization in tablets, in both the radial and axial directions. To evaluate the role of lubricant, magnesium stearate was used as "internal" and/or "external" lubricant. Indomethacin crystallization propensity increased as a function of compression pressure, with 100 MPa pressure causing crystallization immediately after compression (detected using synchrotron radiation). However, the drug crystallization was not uniform throughout the tablets. In unlubricated systems, pronounced crystallization at the radial surface could be attributed to die wall friction. The tablet core remained substantially amorphous, irrespective of the compression pressure. Lubrication of the die wall with magnesium stearate, as external lubricant, dramatically decreased drug crystallization at the radial surface. The spatial heterogeneity in drug crystallization, as a function of formulation composition and compression pressure, was systematically investigated. When formulating amorphous systems as tablets, the potential for compression induced crystallization warrants careful consideration. Very low levels of crystallization on the tablet surface, while profoundly affecting product performance (decrease in dissolution rate), may not be readily detected by conventional analytical techniques. Early detection of crystallization could be pivotal in the successful design of a dosage form where, in order to obtain the desired bioavailability, the drug may be in a high energy state. Specialized X-ray diffractometric techniques (2D; use of high intensity synchrotron radiation) enabled detection of very low levels of drug crystallization and revealed the heterogeneity in crystallization within the tablet. PMID- 25438194 TI - Formation of a "Hollow" Interior in the Fourth-Generation Dendrimer with Attached Oligomeric Terminal Segments. AB - By using the Scheutjens-Fleer self-consistent field approach, the structure of the fourth-generation dendrimer with attached terminal chemically different oligomeric segments is studied theoretically. It is demonstrated that an incompatibility of terminal segments with inner dendrimer units leads to formation of a "hollow" core with reduced polymer density in the dendrimer center. This effect is enhanced with a deterioration in the solvent quality for terminal segments. This observation is in accordance with experimental results and molecular dynamics simulation data for an analogous system. It is established that the main factor determining the hollow core formation is the segregation between inner and terminal units because the main driving force for the effect is the localization of the terminal segments at the dendrimer periphery. The influence of structural parameters of dendrimer such as the number of generations and length of the terminal chain on this effect is also studied. PMID- 25438195 TI - Large-area, low-voltage, antiambipolar heterojunctions from solution-processed semiconductors. AB - The emergence of semiconducting materials with inert or dangling bond-free surfaces has created opportunities to form van der Waals heterostructures without the constraints of traditional epitaxial growth. For example, layered two dimensional (2D) semiconductors have been incorporated into heterostructure devices with gate-tunable electronic and optical functionalities. However, 2D materials present processing challenges that have prevented these heterostructures from being produced with sufficient scalability and/or homogeneity to enable their incorporation into large-area integrated circuits. Here, we extend the concept of van der Waals heterojunctions to semiconducting p type single-walled carbon nanotube (s-SWCNT) and n-type amorphous indium gallium zinc oxide (a-IGZO) thin films that can be solution-processed or sputtered with high spatial uniformity at the wafer scale. The resulting large-area, low-voltage p-n heterojunctions exhibit antiambipolar transfer characteristics with high on/off ratios that are well-suited for electronic, optoelectronic, and telecommunication technologies. PMID- 25438196 TI - Effect of glycounits on the antimicrobial properties and toxicity behavior of polymers based on quaternized DMAEMA. AB - Polymers with quaternary ammonium groups such as quaternized poly(2 (dimethylamino)ethyl methacrylate) (PDMAEMAQ) have been used as antimicrobial agents because of their demonstrated good antimicrobial activities against a huge number and types of microbes, although their cytotoxicity is also well-known. In this work block copolymers based on PDMAEMAQ were synthesized containing hydrophobic segments of poly(butyl methacrylate) to improve the antimicrobial activity and glycomonomer units with the aim of decreasing the cytotoxicity of the polymers. Hydrophobic butyl methacrylate (BMA) blocks were chain extended by statistical and block copolymers of DMAEMA and 2-{[(d-glucosamin-2-N yl)carbonylethyl methacrylate (HEMAGl) glycomonomer of different compositions. In order to find the balance between antimicrobial activity and cytotoxicity, the selectivity index of each polymer was obtained from minimum inhibitory concentrations (MIC) and white and red blood cells toxicity measurements. PMID- 25438197 TI - Treatment of moderate rheumatoid arthritis with different strategies in a health resource-limited setting: a cost-effectiveness analysis in the era of biosimilars. AB - OBJECTIVES: This paper aims to explore the cost-effectiveness of reduced doses or discontinuation of etanercept biosimilar (Yisaipu) in patients with moderately active rheumatoid arthritis (RA). METHODS: A discrete event simulation model was developed to project lifetime medical costs and quality-adjusted life-years (QALYs) in moderately active RA. Strategies starting with Yisaipu 50 mg/week for nine months following Yisaipu 50 mg/week, 25 mg/week or MTX maintenance were compared. Resource consumptions related to RA were estimated from the perspective of the Chinese health care system. An endpoint of the American College of Rheumatology (ACR) response was used to estimate the utility scores. Uncertainty in model parameters was analysed by sensitivity analyses. RESULTS: When using ACR as an endpoint for determining successful treatment, strategies starting with Yisaipu 50 mg/week for nine months following Yisaipu 50 mg/week or 25 mg/week maintenance showed the greatest number of QALYs gained (nearly 11.9 and 11.3 with or without rituximab after the failure of Yisaipu, respectively). If decision makers use a threshold of 3*the per capita GDP of China or Shanghai City in 2012, then the strategies most likely to be cost-effective are initial treatment with Yisaipu 50 mg/week for nine months following MTX maintenance and Yisaipu 25 mg/week maintenance, respectively. Results were sensitive to the cost of Yisaipu. CONCLUSIONS: The analysis indicates that, in China, replacing branded etanercept with Yisaipu is likely to be a cost-effective strategy in patients with moderately active RA. PMID- 25438198 TI - Iron-mediated carboarylation/cyclization of propargylanilines with acetals: a concise route to indeno[2,1-c]quinolines. AB - FeCl3- and FeBr3-mediated tandem carboarylation/cyclization of propargylanilines with diethyl benzaldehyde acetals furnished the tetracyclic core of indeno[2,1 c]quinolines. 5-Tosyl-6,7-dihydro-5H-indeno[2,1-c]quinoline and 7H-indeno[2,1 c]quinoline derivatives were obtained in good to excellent yields, respectively, by tuning the FeX3 loadings and/or reaction temperatures. PMID- 25438199 TI - Low basal expression of A2A adenosine receptors and increase in adenosine plasma concentration are associated with positive exercise stress testing. PMID- 25438200 TI - The Notch ligand Delta-like 1 is elevated and associated with mortality in patients with symptomatic aortic stenosis. PMID- 25438201 TI - Three-vessel coronary artery disease evaluation by multimodality imaging with near-infrared spectroscopy (NIRS) plus intravascular ultrasound (IVUS) and optical coherence tomography (OCT). PMID- 25438202 TI - A retinal snap shot may indicate individual risk for cardiovascular disease - the MIPH Eye&Health Study. AB - BACKGROUND: Examination of retinal vasculature can be used to non-invasively quantify changes within the microvasculature of the human body and might be a predictor of cardiovascular disease. This study evaluates associations of the structure of the retinal vasculature with established risk factors for cardiovascular disease. METHODS: A cross-sectional study was performed in a working age population. Several systemic cardiovascular parameters were analyzed and PROCAM- and SCORE-risk estimates were calculated. A quantitative ophthalmological examination including digital fundus imaging has taken place. Central retinal arterial/venous equivalents (CRAE/CRVE) and arterio-venous ratio (AVR) were analyzed using validated software. Associations of retinal vessel parameters and systemic cardiovascular and ocular parameters were calculated by multivariate analysis using SPSS software. A p-value of <0.05 with Bonferroni correction was accepted as significant. RESULTS: 338 probands were included. A smaller CRAE was independently associated with increased mean arterial blood pressure, higher age and higher body-mass index. Regarding CRVE age was inversely associated. Other cardiovascular risk parameters were not associated to the examined retinal vessel equivalents. AVR showed a significant association to mean arterial blood pressure and body-mass-index. PROCAM- and SCORE-risk estimates were negatively associated with CRAE and AVR, but not associated to CRVE. CONCLUSIONS: Arterial retinal vessel analysis and AV-ratio showed associations to established cardiovascular parameters in the study population. PROCAM- and SCORE risk estimates as indicators of cardiovascular risk were associated with the CRAE and the AV-ratio. This suggests that a single snap shot of the retinal vessels may indicate the individual relative risk for cardiovascular events. PMID- 25438203 TI - Myocardial infarction associated with patent foramen ovale and paradoxical embolism: a case series. PMID- 25438204 TI - MSCs modified with HO-1 gene transplantation: a novel therapeutic approach for attenuating myocardial ischemia and reperfusion injury. PMID- 25438205 TI - Myocardial infarction from isolated coronary artery vasculitis in a young patient: a rare case. PMID- 25438206 TI - Increased urine output by ipragliflozin in a non-diabetic patient with a diuretic resistant heart failure. PMID- 25438207 TI - Q wave myocardial infarction of anteroseptal zone: a new classification. PMID- 25438208 TI - Determinants of the direct cost of heart failure hospitalization in a public tertiary hospital. AB - BACKGROUND: Heart failure (HF) is the first reason for hospital admission in the elderly and represents a major financial burden, the greatest part of which results from hospitalization costs. We sought to analyze current HF hospitalization-related expenditure and identify predictors of cost in a public tertiary hospital in Europe. METHOD: We performed a retrospective chart review of 197 consecutive patients, aged 56+/-16years, 80% male, with left ventricular ejection fraction (LVEF) of 30+/-10%, hospitalized for HF in a major university hospital in Athens, Greece. The survey involved the number of hospitalization days, laboratory investigations and medical therapies. Patients who were hospitalized in CCU/ICU or underwent interventional procedures or device implantations were excluded from analysis. Costs were estimated based on the Greek healthcare system perspective in 2013. RESULTS: Patients were hospitalized for a median of 7 days with a total direct cost of ?3198+/-3260/patient. The largest part of the expenses (79%) was attributed to hospitalization (ward), while laboratory investigations and medical treatment accounted for 17% and 4%, respectively. In multivariate analysis, pre-admission New York Heart Association NYHA class (p=0.001), serum creatinine (p=0.003) and NT-proBNP (p=0.004) were significant independent predictors of hospitalization cost. CONCLUSION: Direct cost of HF hospitalization is high particularly in patients with more severe symptoms, profound neurohormonal activation and renal dysfunction. Strategies to lower hospitalization rates are warranted in the current setting of financial constraints faced by many European countries. PMID- 25438209 TI - Don't blindly trust in BNP concentration: a case of constrictive pericarditis. PMID- 25438210 TI - Incomplete stent apposition and very late stent thrombosis after everolimus eluting stent implantation and dual antiplatelet therapy interruption. A case of OCT guided therapy. PMID- 25438211 TI - Effects of patients anxiety and depression scores on coronary flow in patients with normal coronary arteries. PMID- 25438212 TI - Comparison between saddle versus non-saddle pulmonary embolism: insights from nationwide inpatient sample. PMID- 25438213 TI - Dynamic left ventricular outflow tract obstruction causing myocardial ischemia. PMID- 25438214 TI - Red blood cell distribution width and left atrial thrombus or spontaneous echo contrast in patients with non-valvular atrial fibrillation. PMID- 25438215 TI - Exercise intolerance and ventilatory inefficiency improve early after balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension. PMID- 25438216 TI - A simple pre-procedural risk score for contrast-induced nephropathy among patients with chronic total occlusion undergoing percutaneous coronary intervention. PMID- 25438217 TI - Successful management of two pregnant patients with idiopathic pulmonary arterial hypertension. PMID- 25438218 TI - Does oral calcium intake or body habitus relate to the degree of valvular calcification and adverse events in patients with severe aortic stenosis? PMID- 25438219 TI - Impassable brachiocephalic tortuosity in right transradial access: overcoming the curves with the pigtail catheter. PMID- 25438220 TI - High-intensity statin monotherapy versus moderate-intensity statin plus ezetimibe therapy: effects on vascular biomarkers. PMID- 25438222 TI - Resistant hypertension: four years of follow-up of an unusual course after renal denervation in a patient with end stage renal disease. PMID- 25438221 TI - Long-term outcome of multiform premature ventricular complexes in structurally normal heart. AB - BACKGROUND: Multiform premature ventricular complexes (PVCs) are common electrocardiographic abnormalities in patients with structurally normal hearts. However, the prognostic value of these complexes remains unclear. This study aimed to clarify the role of PVC polymorphism in predicting adverse outcomes. METHODS AND RESULT: We examined the database for 24-hour electrocardiography monitoring between January 1, 2002 and December 31, 2004. We analyzed 3351 individuals with apparently normal hearts. Kaplan-Meier curves and multivariate Cox proportional hazards models were employed to estimate the effect of multiform PVC and uniform PVC on the number of incident adverse events. Average follow-up time was 10+/-1years. Patients with multiform PVC were older and had a higher prevalence of comorbidities. In multivariate analysis, patients with multiform PVC had an increased incidence of mortality (hazard ratio [HR]: 1.642, 95% confidence interval [CI]: 1.327-2.031), hospitalization (HR: 1.196, 95% CI: 1.059 1.350), cardiovascular hospitalization (HR: 1.289, 95% CI: 1.030-1.613), new onset heart failure (HF; HR: 1.456, 95% CI: 1.062-1.997), transient ischemic accident (HR: 1.411, 95% CI 1.063-1.873), and new-onset atrial fibrillation (AF; HR: 1.546, 95% CI: 1.058-2.258) compared to the group without PVC. Patients with multiform PVC had a higher rate of mortality (HR: 1.231, 95% CI: 1.033-1.468) and all cause-hospitalization (HR: 1.147, 95% CI: 1.025-1.283) compared with patients with uniform PVC. CONCLUSION: The presence of multiform PVC was associated with a higher incidence of mortality, hospitalization, transient ischemic attack, new onset AF, and new-onset HF independent of other clinical risk factors. PMID- 25438223 TI - Persistent peripheral arteritis long after Kawasaki disease - another documentation of ongoing vascular inflammation. PMID- 25438224 TI - Phrenic nerve lesion: a potential complication of the nMARQ ablation technique. PMID- 25438225 TI - A case of apical ballooning years before Takotsubo cardiomyopathy was first mentioned in 1991 in association with arrhythmogenic cardiomyopathy. PMID- 25438226 TI - Assessment of DNA damage associated with standard or contrast diagnostic echocardiography. PMID- 25438227 TI - Severe rhabdomyolysis after MIHA-bodytec(r) electrostimulation with previous mild hyper-CK-emia and noncompaction. PMID- 25438228 TI - Impact of depression on incident stroke: a meta-analysis. PMID- 25438229 TI - Prognostic value of late gadolinium enhancement in cardiomyopathy: causative risk factor or surrogate marker? PMID- 25438231 TI - Myocardial infarction with normal coronary arteries in double heterozygous sickle cell disease. PMID- 25438230 TI - Challenges in secondary prevention of cardiovascular diseases: a review of the current practice. AB - With the changing demography of populations and increasing prevalence of co morbidity, frail patients and more complex cardiac conditions, the modern medicine is facing novel challenges leading to rapid innovation where evidence and experiences are lacking. This scenario is also evident in cardiovascular disease prevention, which continuously needs to accommodate its ever changing strategies, settings, and goals. The present paper summarises actual challenges of secondary prevention, and discusses how this intervention should not only be effective but also efficient. By this way the paper tries to bridge the gaps between research and real-world findings and thereby may find ways to improve standard care. PMID- 25438232 TI - Resting heart rate and risk of adverse cardiovascular outcomes in asymptomatic aortic stenosis: the SEAS study. AB - BACKGROUND: An elevated resting heart rate (RHR) may be an early sign of cardiac failure, but its prognostic value during watchful waiting in asymptomatic aortic stenosis (AS) is largely unknown. METHODS: RHR was determined by annual ECGs in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study of asymptomatic mild-to-moderate AS patients. Primary endpoint in this substudy was major cardiovascular events (MCEs) and secondary outcomes its individual components. Multivariable Cox-models using serially-measured RHR were used to examine the prognostic impact of RHR per se. RESULTS: 1563 patients were followed for a mean of 4.3years (6751 patient-years of follow-up), 553 (35%) MCEs occurred, 10% (n=151) died, including 75 cardiovascular deaths. In multivariable analysis, baseline RHR was independently associated with MCEs (HR 1.1 per 10min(-1) faster, 95% CI: 1.0-1.3) and cardiovascular mortality (HR 1.3 per 10min(-1) faster, 95% CI: 1.0-1.7, both p<=0.03). Updating RHR with annual in-study reexaminations, time-varying RHR was highly associated with excess MCEs (HR 1.1 per 10min(-1) faster, 95% CI: 1.1-1.3) and cardiovascular mortality (HR 1.4 per 10min(-1) faster, 95% CI: 1.2-1.7, both p<=0.006). The association of RHR with MCEs and cardiovascular mortality was not dependent on atrial fibrillation status (both p>=0.06 for interaction). CONCLUSIONS: RHR is independently associated with MCEs and cardiovascular death in asymptomatic AS (Clinicaltrials.gov; unique identifier NCT00092677). PMID- 25438233 TI - Mid-regional proadrenomedullin levels predict recurrence of atrial fibrillation after catheter ablation. AB - BACKGROUND: We evaluated the prognostic value of mid-regional proadrenomedullin (MR-proADM) in atrial fibrillation (AF) patients undergoing radiofrequency ablation. METHODS: Plasma concentrations of MR-proADM were measured at baseline and after 12months in 87 AF patients in whom radiofrequency ablation was performed. The association between MR-proADM and AF recurrence was tested by univariable and multivariable Cox models. RESULTS: In all 87 patients radiofrequency ablation was successfully performed. Of the total population 54% had paroxysmal AF. The mean left ventricular ejection fraction was 54% (minimum 25%). After 12months of follow-up, 71% of the patients were free of AF recurrence. At baseline, mean MR-proADM in the total population was 0.72nmol/l+/ 0.22. Patients with AF recurrence had significantly higher baseline MR-proADM (0.89nmol/l+/-0.29) as compared with patients without AF recurrence (0.65nmol/l+/ 0.14; p<0.001). After 12months, mean MR-proADM plasma concentration remained higher in patients with AF recurrence (0.81nmol/l+/-0.22 as compared with patients free of AF 0.54nmol/l+/-0.20; p<0.001). Receiver operating characteristic (ROC) curve analysis for MR-proADM yields a specificity of 98% and a sensitivity of 64% with an optimal cut-off value of 0.82nmol/l to predict recurrence of AF after catheter ablation. In the logistic regression analysis only MR-proADM remained independently predictive for AF recurrence. CONCLUSION: This is the first study revealing the association between MR-proADM elevation before ablation and poor outcomes after ablation of AF. Larger studies are needed to validate these results. PMID- 25438234 TI - Ellagic acid prevents monocrotaline-induced pulmonary artery hypertension via inhibiting NLRP3 inflammasome activation in rats. AB - BACKGROUND: Pulmonary artery hypertension (PAH) is characterized by vascular remodeling, high pulmonary blood pressure, and right ventricular hypertrophy. Oxidative stress, inflammation and pulmonary artery remodeling are important components in PAH. Ellagic acid (EA) is a phenolic compound with anti-oxidative, anti-inflammatory, and anti-proliferative properties. This study aimed to investigate whether EA could prevent the development of monocrotaline (MCT) induced PAH in rats. METHODS: Male Sprague-Dawley rats received EA (30 and 50mg/kg/day) or vehicle one day after a single-dose of monocrotaline (MCT, 60mg/kg). Hemodynamic changes, right ventricular hypertrophy, and lung morphological features were assessed 4weeks later. Activation of the NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome pathway in the lungs was assessed using Western blot analysis. RESULTS: MCT induced PAH, oxidative stress, and NLRP3 inflammasome activation in vehicle-treated rats. EA reduced the right ventricle systolic pressure, the right ventricular hypertrophy and the wall thickness/external diameter ratio of the pulmonary arteries compared with vehicle. EA also inhibited the MCT-induced elevation of oxidative stress, NLRP3, and caspase-1, IL-beta in the lungs and the elevated levels of brain natriuretic peptide (BNP) and inflammatory cytokines in serum. CONCLUSIONS: Ellagic acid ameliorates monocrotaline-induced pulmonary artery hypertension via exerting its anti-oxidative property inhibiting NLRP3 inflammasome signal pathway in rats. PMID- 25438235 TI - Incremental value of cardiac magnetic resonance imaging in the diagnostic work-up of patients with apparently idiopathic ventricular arrhythmias of left ventricular origin. PMID- 25438236 TI - Transvenous pacemaker lead extraction by femoral approach. PMID- 25438237 TI - Pericardial effusions in systemic lupus erythematosus - who is most likely to develop tamponade? PMID- 25438238 TI - Lack of "weekend effect" on mortality for pulmonary embolism admissions in 2011: data from nationwide inpatient sample. PMID- 25438239 TI - Flow-mediated dilation: is it just a research tool or a useful biomarker for cardiovascular prognosis. PMID- 25438240 TI - Prognostic impact of global left ventricular hemodynamic afterload in severe aortic stenosis with preserved ejection fraction. AB - INTRODUCTION: Global left ventricular (LV) afterload as assessed by valvulo arterial impedance (Zva), may be an independent predictor of mortality in patients with severe aortic stenosis (AS) and preserved LV ejection fraction (LVEF). However, its quantification using echocardiography may be subject to error measurement. We aimed to determine the prevalence and impact on long-term survival of high Zva, purposely measured by cardiac catheterization. METHODS AND RESULTS: 676 patients with preserved LVEF and severe AS without other valvular heart diseases underwent cardiac catheterization. Zva was derived from catheterization and calculated as follows: mean aortic gradient+systolic blood pressure/indexed LV stroke volume. Zva was considered high when >5mmHg/mL/m(2) based on previous studies. Overall, high Zva was found in 42% of all AS patients. Four-year survival and 8-year survival were significantly reduced in patients with high Zva (74+/-3% and 57+/-4%) as compared to those with low Zva (85+/-2% and 74+/-3%; p=0.002). After adjustment for all other risk factors, Zva was independently associated with reduced long-term survival (hazard ratio [HR]=1.47 95% CI: 1.04-2.09; p=0.029). Of interest, high Zva remained associated with reduced survival as compared to low Zva, in patients with normal LV stroke volume, but was no longer significant in low flow patients (p=0.98). CONCLUSION: High Zva, estimated invasively in our study, is frequent in patients with severe AS, and appears as a robust and independent predictor of survival. Zva should be used as an additional parameter for risk stratification of severe AS, more particularly in patients with normal flow. PMID- 25438241 TI - Rapid determination of lamivudine in human plasma by high-performance liquid chromatography. AB - A simple and rapid high-performance liquid chromatographic method with spectrophotometric detection was developed for the determination of lamivudine in human plasma. Sample preparation was accomplished through protein precipitation with acetonitrile followed by aqueous phase separation using dichloromethane. Lamivudine and the internal standard acyclovir were well separated from endogenous plasma peaks on a Chromolith RP-18e column under isocratic elution with 50 mM sodium dihydrogen phosphate-triethylamine (996:4, v/v), pH 3.2 at 20 degrees C. Total run time at a flow-rate of 1.5 ml/min was less than 5 min. Detection was made at 278 nm. The method was specific and sensitive, with a lower quantification limit of 40 ng/ml and a detection limit of 10 ng/ml. The absolute recovery was 97.7%, while the within- and between-day coefficient of variation and percent error values of the assay method were all less than 7%. The linearity was assessed in the range of 40-2560 in plasma, with a correlation coefficient of greater than 0.999. The method was successfully applied to a bioequivalence study in healthy volunteers. PMID- 25438242 TI - Quantitation of the immunological adjuvants, monophosphoryl lipid A and Quil A in poly (lactic-co-glycolic acid) nanoparticles using high performance liquid chromatography with evaporative light scattering detection. AB - Monophosphoryl lipid A (MPL) and Quil A are two immunological adjuvants commonly used in vaccines. At present no simple, validated methods for the quantification of Quil A and MPL have been previously reported therefore the aim of the current study was to develop a simple, fast and validated method to quantify MPL and Quil A using high performance liquid chromatography evaporative light scattering detection (HPLC-ELSD). The HPLC-ELSD technique was carried out using a ZORBAX Eclipse XDB-C8 column (2.1*50 mm; particle size, 3.5 MUm) in an isocratic elution mode at 25 degrees C. MPL was eluted at a retention time of 1.8 min with methanol-water as the mobile phase and a detector temperature of 75 degrees C. Quil A was resolved as three peaks with retention times of 4.1, 5.5 and 6.4 min with a detector temperature of 30 degrees C and with water-acetonitrile and 0.01% formic acid as the mobile phase. The nebulizer pressure and gain were set at 3.5 bar and 10, respectively. Calibration curves plotted for both the adjuvants had an R(2)>0.997. Accuracy, intra- and inter-day precision were within the accepted limits. The limit of detection for MPL and Quil A were calculated as 1.343 and 2.06 MUg/mL, respectively. The limit of quantification was 2.445 for MPL and 8.97 MUg/mL for Quil A. This analytical method was used to quantify the entrapment and in vitro release of MPL and Quil A in a poly lactic-co-glycolic acid (PLGA) nanoparticle vaccine. PMID- 25438243 TI - Separation and purification of amygdalin from thinned bayberry kernels by macroporous adsorption resins. AB - To utilize the low-value thinned bayberry (Myrica rubra Sieb. et Zucc) kernels (TBKs) waste, an efficient method using macroporous adsorption resins (MARs) for separation and purification of amygdalin from TBKs crude extracts was developed. An aqueous crude sample was prepared from a methanol TBK extract, followed by resin separation. A series of MARs were initially screened for adsorption/desorption of amygdalin in the extract, and D101 was selected for characterization and method development. The static adsorption data of amygdalin on D101 was best fitted to the pseudo-second-order kinetics model. The solute affinity toward D101 at 30 degrees C was described and the equilibrium experimental data were well-fitted to Langmuir and Freundlich isotherms. Through one cycle of dynamic adsorption/desorption, the purity of amygdalin in the extract, determined by HPLC, increased about 17-fold from 4.8% to 82.0%, with 77.9% recovery. The results suggested that D101 resin effectively separate amygdalin from TBKs. PMID- 25438244 TI - Amino acid N-acetylation: metabolic elimination of symmetric dimethylarginine as symmetric N(alpha)-acetyldimethylarginine, determined in human plasma and urine by LC-MS/MS. AB - Symmetric dimethylarginine (SDMA) is considered as a parameter for renal insufficiency superior to the established creatinine. Its applicability for this purpose may be hampered by the fact that SDMA is not exclusively eliminated via the renal route but is also metabolized. In this work, we present a method for the quantification of the metabolite symmetric Nalpha-acetyldimethylarginine (Ac SDMA) by LC-MS/MS in human plasma and urine. D6-Ac-SDMA was used as internal standard. After simple protein precipitation and in-line clean up, the analytes were separated on a porous graphitic carbon column. Calibration functions were linear in the ranges of 0.2-80 nM for plasma and 10-4000 nM for urine. The quantification was matrix independent and the precisions and accuracies were better than 8% at all concentration levels. Concentration found in human plasma and urine was 3.51 nM and 558 nM, respectively, with marked inter-individual differences. PMID- 25438245 TI - Screening approach by ultra-high performance liquid chromatography-tandem mass spectrometry for the blood quantification of thirty-four toxic principles of plant origin. Application to forensic toxicology. AB - Plant poisonings have left their mark on history and still cause many deaths, whether intentional or accidental. The means to show toxicological evidence of such poisonings should be implemented with great care. This article presents a technique for measuring thirty-nine toxic principles of plant origin in the blood, covering a large amount of toxins from local or exotic plants: alpha lobeline, alpha-solanine, aconitine, ajmaline, atropine, brucine, cephalomannine, colchicine, convallatoxin, cymarine, cytisine, digitoxin, digoxin, emetine, gelsemine, ibogaine, jervine, kavain, lanatoside C, lupanine, mitragynine, neriifolin, oleandrin, ouabain, paclitaxel, physostigmine, pilocarpine, podophyllotoxin, proscillaridin A, reserpine, retrorsine, ricinine, scopolamine, senecionine, sparteine, strophanthidin, strychnine, veratridine and yohimbine. Analysis was carried out using an original ultra-high performance liquid chromatography separation coupled with tandem mass spectrometry detection. Extraction was a standard solid phase extraction performed on Oasis((r)) HLB cartridge. Thirty-four of the thirty-nine compounds were put through a validation procedure. The assay was linear in the calibration curve range from 0.5 or 5 MUg/L to 1000 MUg/L according to the compounds. The method is sensitive (LOD from 0.1 to 1.6 MUg/L). The within-day precision of the assay was less than 22.5% at the LLOQ, and the between-day precision was less than 21.5% for 10 MUg/L for all the compounds included. The assay accuracy was in the range of 87.4 to 119.8% for the LLOQ. The extraction recovery and matrix effect ranged from 30 to 106% and from -30 to 14%, respectively. It has proven useful and effective in several difficult forensic cases. PMID- 25438246 TI - Selective adsorption of antiphospholipid and anti-dsDNA autoantibodies on histidine based pseudobioaffinity adsorbent from sera of patients with systemic lupus erythematosus (SLE). AB - Systemic lupus erythematosus (SLE) is an autoimmune diseases characterized by the presence of antiphospholipid and anti-dsDNA autoantibodies in the sera of patients. These autoantibodies and their subclasses have received increasing attention by medical community due to their association with recurrent venous thrombosis, fetal loss and thrombocytopenia. In particular, attention has been paid to IgG subclasses in SLE. The biological and functional properties together with the subclass distribution might therefore influence the course of SLE. The separation and elimination of these autoantibodies from sera of patients can be effective in clinical therapy. In the present study, histidine based pseudobioaffinity adsorbents have been used for the selective adsorption and separation of anti-double stranded DNA (anti-dsDNA), anticardiolipin (aCL) and anti-beta2-glycoprotein-I (anti-beta2-GPI) antibodies from sera of patients with SLE. For this purpose histidine acting as a pseudobiospecific ligand has been coupled to bisoxirane activated sepharose CL-6B for the adsorption and separation of these autoantibodies. The removal of autoantibodies was carried out under gentle adsorption and elution chromatographic conditions at pH values 7.0 and 8.0. Autoantibodies isotypes and subclasses distribution in the separated fractions were studied by enzyme-linked immune-sorbent assay. The obtained results showed that the separated anticardiolipin and anti-beta2-glycoprotein-I autoantibodies belong to IgG1, IgG2 and IgG3subclasses, while those of anti-dsDNA belong to IgM isotype and were shown to have a DNA hydrolyzing activity that hydrolyzes plasmid DNA. The results also indicate a total IgM and IgG recovery superior to 90% of the fraction loaded at pH 7.4 and pH 8.0 respectively. PMID- 25438248 TI - VCAM-1 directed target-sensitive liposomes carrying CCR2 antagonists bind to activated endothelium and reduce adhesion and transmigration of monocytes. AB - Chemokines are critically involved in the development of chronic inflammatory associated diseases such as atherosclerosis. We hypothesized that targeted delivery of compounds to the surface of activated endothelial cells (EC) interferes with chemokine/receptor interaction and thereby efficiently blocks inflammation. We developed PEGylated target-sensitive liposomes (TSL) encapsulating a CCR2 antagonist (Teijin compound 1) coupled with a specific peptide recognized by endothelial VCAM-1 (Vp-TSL-Tj). TSL were characterized for size (by dynamic light scattering), the amount of peptide coupled at the liposomal surface and Teijin release (by HPLC). We report that Vp-TSL-Tj binds specifically to activated EC in vitro and in situ, release the entrapped Teijin and prevent the transmigration of monocytes through activated EC. This is the first evidence that nanocarriers which transport and release chemokine inhibitors at specific pathological sites can reduce chemokine-dependent inflammatory processes. PMID- 25438247 TI - Creatinine, arsenic metabolism, and renal function in an arsenic-exposed population in Bangladesh. AB - Kidney disease is emerging as an arsenic (As)-linked disease outcome, however further evidence of this association is warranted. Our first objective for this paper was to examine the potential renal toxicity of As exposure in Bangladesh. Our second objective relates to examining whether the previously reported positive association between urinary creatinine (uCrn) and As methylation may be explained by renal function. We had hypothesized that these associations relate to supply and demand for s-adenosylmethionine, the methyl donor for both creatine synthesis and As methylation. Alternatively, renal function could influence both As and creatinine excretion, or the As metabolites may influence renal function, which in turn influences uCrn. We conducted a cross-sectional study (N = 478) of adults, composed of a sample recruited in 2001 and a sample recruited in 2003. We assessed renal function using plasma cystatin C, and calculated the estimated glomerular filtration rate (eGFR). Consistent with renal toxicity of As, log-uAs had a marginal inverse association with eGFR in the 2003 sample (b = -5.6, p = 0.07), however this association was not significant in the 2001 sample (b = -1.9, p = 0.24). Adjustment for eGFR did not alter the associations between uCrn and the %uAs metabolites, indicating that GFR does not explain these associations. Increased eGFR was associated with increased odds of having %uInAs >12.2% (2001: OR = 1.01, 95%CI (1.00,1.03); 2003: OR = 1.04, 95%CI (1.01,1.07)). In the 2003 sample only, there was a negative association between eGFR and %uDMA (b = -0.08, p = 0.02). These results may indicate differential effects of renal function on excretion of InAs and DMA. Alternatively, a certain methylation pattern, involving decreased %InAs and increased %DMA, may reduce renal function. Given that these studies were cross-sectional, we cannot distinguish between these two possibilities. Discrepancies between the samples may be due to the higher As exposure, poorer nutrition, and lower As methylation capacity in the 2003 sample. PMID- 25438249 TI - B-cell epitopes in NTS-DBL1alpha of PfEMP1 recognized by human antibodies in Rosetting Plasmodium falciparum. AB - Plasmodium falciparum is the most lethal of the human malaria parasites. The virulence is associated with the capacity of the infected red blood cell (iRBC) to sequester inside the deep microvasculature where it may cause obstruction of the blood-flow when binding is excessive. Rosetting, the adherence of the iRBC to uninfected erythrocytes, has been found associated with severe malaria and found to be mediated by the NTS-DBL1alpha-domain of Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1). Here we show that the reactivity of plasma of Cameroonian children with the surface of the FCR3S1.2-iRBC correlated with the capacity to disrupt rosettes and with the antibody reactivity with a recombinant PfEMP1 (NTS-DBL1alpha of IT4var60) expressed by parasite FCR3S1.2. The plasma reactivity in a microarray, consisting of 96 overlapping 15-mer long peptides covering the NTS-DBL1alpha domain from IT4var60 sequence, was compared with their capacity to disrupt rosettes and we identified five peptides where the reactivity were correlated. Three of the peptides were localized in subdomain-1 and 2. The other two peptide-sequences were localized in the NTS-domain and in subdomain-3. Further, principal component analysis and orthogonal partial least square analysis generated a model that supported these findings. In conclusion, human antibody reactivity with short linear-peptides of NTS-DBL1alpha of PfEMP1 suggests subdomains 1 and 2 to hold anti-rosetting epitopes recognized by anti rosetting antibodies. The data suggest rosetting to be mediated by the variable areas of PfEMP1 but also to involve structurally relatively conserved areas of the molecule that may induce biologically active antibodies. PMID- 25438250 TI - Garlic revisited: antimicrobial activity of allicin-containing garlic extracts against Burkholderia cepacia complex. AB - The antimicrobial activities of garlic and other plant alliums are primarily based on allicin, a thiosulphinate present in crushed garlic bulbs. We set out to determine if pure allicin and aqueous garlic extracts (AGE) exhibit antimicrobial properties against the Burkholderia cepacia complex (Bcc), the major bacterial phytopathogen for alliums and an intrinsically multiresistant and life threatening human pathogen. We prepared an AGE from commercial garlic bulbs and used HPLC to quantify the amount of allicin therein using an aqueous allicin standard (AAS). Initially we determined the minimum inhibitory concentrations (MICs) of the AGE against 38 Bcc isolates; these MICs ranged from 0.5 to 3% (v/v). The antimicrobial activity of pure allicin (AAS) was confirmed by MIC and minimum bactericidal concentration (MBC) assays against a smaller panel of five Bcc isolates; these included three representative strains of the most clinically important species, B. cenocepacia. Time kill assays, in the presence of ten times MIC, showed that the bactericidal activity of AGE and AAS against B. cenocepacia C6433 correlated with the concentration of allicin. We also used protein mass spectrometry analysis to begin to investigate the possible molecular mechanisms of allicin with a recombinant form of a thiol-dependent peroxiredoxin (BCP, Prx) from B. cenocepacia. This revealed that AAS and AGE modifies an essential BCP catalytic cysteine residue and suggests a role for allicin as a general electrophilic reagent that targets protein thiols. To our knowledge, we report the first evidence that allicin and allicin-containing garlic extracts possess inhibitory and bactericidal activities against the Bcc. Present therapeutic options against these life-threatening pathogens are limited; thus, allicin containing compounds merit investigation as adjuncts to existing antibiotics. PMID- 25438251 TI - Nonequilibrium population dynamics of phenotype conversion of cancer cells. AB - Tumorigenesis is a dynamic biological process that involves distinct cancer cell subpopulations proliferating at different rates and interconverting between them. In this paper we proposed a mathematical framework of population dynamics that considers both distinctive growth rates and intercellular transitions between cancer cell populations. Our mathematical framework showed that both growth and transition influence the ratio of cancer cell subpopulations but the latter is more significant. We derived the condition that different cancer cell types can maintain distinctive subpopulations and we also explain why there always exists a stable fixed ratio after cell sorting based on putative surface markers. The cell fraction ratio can be shifted by changing either the growth rates of the subpopulations (Darwinism selection) or by environment-instructed transitions (Lamarckism induction). This insight can help us to understand the dynamics of the heterogeneity of cancer cells and lead us to new strategies to overcome cancer drug resistance. PMID- 25438252 TI - Editorial. Molecular and Cellular Cognition Society (MCCS) meetings. PMID- 25438253 TI - Prognostication in comatose survivors of cardiac arrest: an advisory statement from the European Resuscitation Council and the European Society of Intensive Care Medicine. AB - OBJECTIVES: To review and update the evidence on predictors of poor outcome (death, persistent vegetative state or severe neurological disability) in adult comatose survivors of cardiac arrest, either treated or not treated with controlled temperature, to identify knowledge gaps and to suggest a reliable prognostication strategy. METHODS: GRADE-based systematic review followed by expert consensus achieved using Web-based Delphi methodology, conference calls and face-to-face meetings. Predictors based on clinical examination, electrophysiology, biomarkers and imaging were included. RESULTS AND CONCLUSIONS: Evidence from a total of 73 studies was reviewed. The quality of evidence was low or very low for almost all studies. In patients who are comatose with absent or extensor motor response at >=72 h from arrest, either treated or not treated with controlled temperature, bilateral absence of either pupillary and corneal reflexes or N20 wave of short-latency somatosensory evoked potentials were identified as the most robust predictors. Early status myoclonus, elevated values of neuron specific enolase at 48 72 h from arrest, unreactive malignant EEG patterns after rewarming, and presence of diffuse signs of postanoxic injury on either computed tomography or magnetic resonance imaging were identified as useful but less robust predictors. Prolonged observation and repeated assessments should be considered when results of initial assessment are inconclusive. Although no specific combination of predictors is sufficiently supported by available evidence, a multimodal prognostication approach is recommended in all patients. PMID- 25438254 TI - Cardiac Arrest and Cardiopulmonary Resuscitation Outcome Reports: Update of the Utstein Resuscitation Registry Templates for Out-of-Hospital Cardiac Arrest: A Statement for Healthcare Professionals From a Task Force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian and New Zealand Council on Resuscitation, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Southern Africa, Resuscitation Council of Asia); and the American Heart Association Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. AB - Utstein-style guidelines contribute to improved public health internationally by providing a structured framework with which to compare emergency medical services systems. Advances in resuscitation science, new insights into important predictors of outcome from out-of-hospital cardiac arrest, and lessons learned from methodological research prompted this review and update of the 2004 Utstein guidelines. Representatives of the International Liaison Committee on Resuscitation developed an updated Utstein reporting framework iteratively by meeting face to face, by teleconference, and by Web survey during 2012 through 2014. Herein are recommendations for reporting out-of-hospital cardiac arrest. Data elements were grouped by system factors, dispatch/recognition, patient variables, resuscitation/postresuscitation processes, and outcomes. Elements were classified as core or supplemental using a modified Delphi process primarily based on respondents' assessment of the evidence-based importance of capturing those elements, tempered by the challenges to collect them. New or modified elements reflected consensus on the need to account for emergency medical services system factors, increasing availability of automated external defibrillators, data collection processes, epidemiology trends, increasing use of dispatcher-assisted cardiopulmonary resuscitation, emerging field treatments, postresuscitation care, prognostication tools, and trends in organ recovery. A standard reporting template is recommended to promote standardized reporting. This template facilitates reporting of the bystander-witnessed, shockable rhythm as a measure of emergency medical services system efficacy and all emergency medical services system-treated arrests as a measure of system effectiveness. Several additional important subgroups are identified that enable an estimate of the specific contribution of rhythm and bystander actions that are key determinants of outcome. PMID- 25438255 TI - Subchronic lithium treatment increases the anxiolytic-like effect of mirtazapine on the expression of contextual conditioned fear. AB - Lithium not only has a mood-stabilizing effect but also the augmentation effect of an antidepressant, the mechanism of which remains unclear. Although lithium may augment the effect of mirtazapine, this augmentation has not been confirmed. Using a contextual fear conditioning test in rats, an animal model of anxiety or fear, we examined the effect of subchronic lithium carbonate (in diet) in combination with systemic mirtazapine on the expression of contextual conditioned fear. Mirtazapine (10mg/kg) reduced freezing one day after fear conditioning dose dependently, whereas the anxiolytic-like effect of mirtazapine (10mg/kg) diminished seven days after fear conditioning. When the interval between fear conditioning and testing was seven days, only the combination of subchronic 0.2% Li2CO3 but not 0.05% Li2CO3 with acute mirtazapine (10mg/kg) reduced freezing significantly. These results indicate that subchronic 0.2% Li2CO3 treatment enhanced the anxiolytic-like effect of systemic mirtazapine. This augmentation therapy might be useful for the treatment of anxiety disorders. PMID- 25438256 TI - Efficacy of Thai herbal essential oils as green repellent against mosquito vectors. AB - Repellency activity of Thai essential oils derived from ylang ylang (Cananga odorata (Lamk.) Hook.f. & Thomson: Annonaceae) and lemongrass (Cymbopogon citratus (DC.) Stapf: Poaceae) were tested against two mosquito vectors, Aedes aegypti (L.) and Culex quinquefasciatus (Say). There were compared with two chemical repellents (DEET 20% w/w; Sketolene Shield((r)) and IR3535, ethyl butylacetylaminopropionate 12.5% w/w; Johnson's Baby Clear Lotion Anti Mosquito((r))). Each herbal repellent was applied in three diluents; coconut oil, soybean oil and olive oil at 0.33 MUl/cm(2) on the forearm of volunteers. All herbal repellent exhibited higher repellent activity than IR3535 12.5% w/w, but lower repellent activity than DEET 20% w/w. The C. odorata oil in coconut oil exhibited excellent activity with 98.9% protection from bites of A. aegypti for 88.7+/-10.4 min. In addition, C. citratus in olive oil showed excellent activity with 98.8% protection from bites of C. quinquefasciatus for 170.0+/-9.0 min. While, DEET 20% w/w gave protection for 155.0+/-7.1-182.0+/-12.2 min and 98.5% protection from bites of two mosquito species. However, all herbal repellent provided lower repellency activity (97.4-98.9% protection for 10.5-88.7 min) against A. aegypti than C. quinquefasciatus (98.3-99.2% protection for 60-170 min). Our data exhibited that C. odorata oil and C. citratus oil are suitable to be used as green repellents for mosquito control, which are safe for humans, domestic animals and environmental friendly. PMID- 25438257 TI - The Anopheles arabiensis genetic sexing strain ANO IPCL1 and its application potential for the sterile insect technique in integrated vector management programmes. AB - The Anopheles arabiensis genetic sexing strain ANO IPCL1 was developed based on a dieldrin resistant mutation. The strain has been shown to be practical and reliable in terms of female elimination by dieldrin treatments at larval stages, but has provided some difficulties when treatments were applied at the egg stage. The high natural sterility of this strain has advantages and disadvantages in both mass rearing and the sterilization process. In addition, its recombination rate, although relatively low, poses a threat of strain deterioration if left unchecked in a mass-rearing setting. The males of the ANO IPCL1 have been shown to be equally competitive as lab-reared males of the wild-type Dongola strain, but competitiveness decreased by half when irradiated with 75 Gy-a dose conferring >98% sterility. More controversial issues surround the use of dieldrin a highly persistent organochlorine that is known to bioaccumulate in the food chain. The prospective use of large volumes of dieldrin in a mass-rearing facility and the retention of its residues by the male mosquitoes makes the use of the strain in the context of the sterile insect technique against this vector highly questionable, and therefore its implementation at a large scale cannot be recommended. PMID- 25438258 TI - Occurrence of anti-Toxoplasma gondii antibodies and parasite DNA in raw milk of sheep and goats of local breeds reared in Northeastern Brazil. AB - The aim of the present study was to detect Toxoplasma gondii DNA in raw milk samples of goats and sheep of local breeds from the semi-arid region of the states of Pernambuco and Paraiba, Northeastern Brazil. Serum and milk samples were collected from 243 animals (186 goats and 57 sheep). The Indirect fluorescent antibody test (IFAT) was used to search for anti-T. gondii IgG antibodies with a cutoff of 64. Subsequently, the raw milk samples were subjected to DNA extraction and PCR to detect DNA of T. gondii. The IFAT results showed a 6.58% (16/243) positivity when all the samples were considered and a positivity of 15.78% (9/57) and 3.76% (7/186) for goats and sheep samples, respectively. The PCR assay detected T. gondii DNA in 2.06% (5/243) of all the samples tested. All the PCR positive samples were from goats. This result shows the importance of adopting measures of flock's sanitary management and avoiding the consumption of raw milk may constitute a potential risk to the health of milk consumers in this region. PMID- 25438259 TI - Sequence polymorphisms of Plasmodium vivax tryptophan and alanine rich antigen (PvTARAg55). AB - Since PvTARAg55 protein (PvTARAg55) of Plasmodium vivax (P. vivax) is expressed during the parasite's sporozoite stage, it was strongly suggested, as a potential candidate for the development of a vaccine against malaria. PvTARAg55 polymorphisms were examined among isolates from various locations in Asian countries mainly; thus the current study could set the valuable baseline data for the development of a vaccine and clinical trials. A total of 59 samples were collected from Asian countries and one isolate from Africa. PvTARAg55 gene from 59 isolates was amplified, sequenced, and analyzed. PvTARAg55 contained a highly conserved tryptophan-rich domain (TRD) and a variable alanine-rich domain (ARD). In comparison to the Sal-1 strain, 10 allelic types of PvTARAg55 were found among 59 isolates. The main observed variations were the insertions and deletions of repeated sequences in the Ala-rich domain. Four types of GGVAAAP repeats were found at codon 324. Interestingly, GGVAAAP was found to be majority of Sal-1 type in the world. Two repeats (x2) were found in isolates from Korea, China, and India. Type of total deletion of GGVAAAP and three repeat (x3) were found from Indonesia isolates. Furthermore, "second insertion repeats"-with one or two repeats-were found with AFGAPSGFAPRP amino acid sequences at codon 338. Two repeats (x2) of AFGAPSGFAPRP were found in Indonesia, and PNG isolates. Finally, a "third repeat" was present with TTVNPEA amino acid sequences at codon 429 (the Indonesian isolates had three TTVNPEA sequences at that position). Isolates from ROK revealed "conserved sequences" in tryptophan-rich domain of PvTARAg55 with single amino acid substitutions (M180I). Hence, the extensive antigenic diversity of PvTARAg55 should be taken in account during the vaccine development. PMID- 25438260 TI - Direct and indirect effect of predators on Anopheles gambiae sensu stricto. AB - The increased insecticides resistance by vectors and the ecological harm imposed by insecticides to beneficial organisms drawback mosquitoes chemical control efforts. Biological control would reduce insecticides tolerance and yet biodiversity friend. The predatory and non-predatory effects of Gambusia affinis and Carassius auratus on gravid Anopheles gambiae sensu strict and larvae survivorship were assessed. In determining predation rate, a single starved predator was exposed to third instar larvae of An. gambiae s.s. in different densities 20, 60 and 100. Six replicates in each of the densities for both predators, G. affinis and C. auratus, were set up. The larvae densities were monitored in every 12 and 24 h. In assessing indirect effects: An. gambiae s.s. first instar larvae of three densities 20, 60 and 100 were reared in water from a predator habitat and water from non-predator habitat. Larvae were monitored until they emerged to adults where larval survivorship and sex ratio (Female to total emerged mosquitoes) of the emerged adult from both water habitats were determined. Oviposition preference: twenty gravid females of An. gambiae s.s. were provided with three oviposition choices, one containing water from predator habitat without a predator, the second with water from a predator with a predator and the third with water from non-predatory habitat. The number of eggs laid on each container was counted daily. There were 20 replicates for each predator, G. affinis and C. auratus. Survivorship of An. gambiae s.s. larvae reared in water from non-predator habitat was higher than those reared in water from the predator habitats. Many males emerged in water from non-predatory water habitats while more females emerged from predator's habitats water. More eggs laid in tap water than in water from predator habitat and water from predator habitat with live predator. In 24 h, a starved C. auratus and G. affinis were able to consume 100% of the 3rd instar larvae. The findings from this study suggest that G. affinis and C. auratus may be useful in regulating mosquito populations in favour of beneficial insects. However, a small scale trial shall be needed in complex food chain system to ascertain the observed predation and kairomones effects. PMID- 25438261 TI - Safeguarding human subjects--the role of scientific journals. PMID- 25438262 TI - Inferior alveolar nerve function after sagittal split osteotomy. PMID- 25438263 TI - In reply. PMID- 25438264 TI - Plagiarism identified in JOMS article. PMID- 25438265 TI - Response to July 2014 Perspectives article. PMID- 25438267 TI - Crisis or chronic complaint? PMID- 25438268 TI - Response to Letter to the editor. PMID- 25438269 TI - In search of the highest quality: levels of evidence in oral and maxillofacial surgery. PMID- 25438270 TI - Three-dimensional reconstructions from computed tomographic scans on smartphones and tablets: a simple tutorial for the ward and operating room using public domain software. AB - Handling 3-dimensional reconstructions of computed tomographic scans on portable devices is problematic because of the size of the Digital Imaging and Communications in Medicine (DICOM) stacks. The authors provide a user-friendly method allowing the production, transfer, and sharing of good-quality 3 dimensional reconstructions on smartphones and tablets. PMID- 25438271 TI - Are oral-maxillofacial surgery patients given proper postoperative instructions for disposal of blood-soaked gauze packs? AB - PURPOSE: Although there are Occupational Safety and Health Administration guidelines for the proper disposal of hazardous waste in the dental office, there are no guidelines for patients regarding the disposal of the gauze packs that are usually placed after tooth extraction or other dental surgery. Thus there is the possibility of cross contamination by patients with undiagnosed blood-transmitted viral diseases. The purpose of this study was to determine what, if any, instructions are given by oral and maxillofacial surgeons (OMSs) and if such instructions are adequate. MATERIALS AND METHODS: A 5-question survey was sent electronically to 375 randomly selected OMSs, and there was a 17% response. They were asked whether they provided written and verbal postoperative instructions, whether these included instructions about gauze pack disposal, and whether they gave special instructions to patients with known viral diseases such as hepatitis or human immunodeficiency virus infection. RESULTS: All respondents indicated that they provided both written and verbal postoperative instructions. However, only 1 respondent's instructions indicated how to dispose of the gauze pack, and only 1 gave special instructions to patients with known viral infections. CONCLUSIONS: There is a need for OMSs to provide specific instructions to all patients about the proper disposal of blood-soaked sponges to avoid potential cross contamination. PMID- 25438272 TI - Are muscle relaxants needed for nasal intubation in propofol and remifentanil anesthesia? AB - PURPOSE: The authors hypothesized that a muscle relaxant would have no meaningful difference in intubation conditions during nasal intubation under remifentanil and propofol anesthesia. MATERIALS AND METHODS: This parallel-group, double blinded, randomized controlled trial included 44 patients who received saline (S group; n = 22) or rocuronium (R group; n = 22). In addition to remifentanil 0.5 MUg/kg per minute and propofol 5 mg/kg per hour, propofol 0.5 mg/kg was administered until loss of consciousness. Nasal intubation was performed 10 minutes after administration of R or S 0.6 mg/kg. Significant differences in intubation conditions and salivary amylase levels before and after intubation were tested (P < .05). RESULTS: Vocal cord status (P = .003) and response to intubation or cuff filling (P = .008) were significantly different, but intubation conditions were not. Salivary amylase level was significantly lower with R administration (P = .022). No patient complained of postoperative throat pain and hoarseness. CONCLUSION: Muscle relaxants during nasal intubation performed after bolus administration of propofol 0.9 mg/kg in addition to 10 minutes of remifentanil 0.5 MUg/kg per minute plus propofol 5 mg/kg per hour are unnecessary. PMID- 25438273 TI - Effects of injury or removal of the articular disc on maxillomandibular growth in young rats. AB - PURPOSE: This study analyzed the effects of injury and removal of the articular disc on maxillomandibular growth in young rats. MATERIALS AND METHODS: Thirty 1 month-old male Wistar rats were divided into 3 groups: injury, removal, and sham operated. Unilateral injury of the articular disc, removal of the articular disc, or only surgical access was performed. The animals were sacrificed at 3 months of age. Specimens were submitted to radiographic incidences and cephalometric mensurations were performed using a computer system. Data were subjected to statistical analyses among groups and between sides in each group. RESULTS: There were degenerative changes of the condylar process in the injury and removal groups. Significant differences between sides were observed for length of the premaxilla, height of the mandibular body, and length of the mandible. Concomitant group comparisons showed significant differences in the height of the mandibular body (P = .003) and the length of the mandible (P = .001). There were important decreases to the height of the mandibular body and mandibular length in the injury group, whereas there was an important decrease only for the length of the mandible in the removal group. Specific measurements of mandibular ramus structures exhibited differences between the injury and sham-operated groups and between the removal and sham-operated groups. CONCLUSION: Experimental injury and removal of the articular disc during the growth period in rats had deleterious effects on ramus structures and induced asymmetry of the mandible, with worse outcomes resulting from injury to the articular disc. PMID- 25438274 TI - Does a change in bone mineral density occur in the mandible of Gottingen minipigs after irradiation in correlation with radiation dose and implant surgery? AB - PURPOSE: To date, studies have not agreed on the effects of irradiation on bone mineral density. The aim of our study was to investigate the changes in mandibular bone mineral density after irradiation at various doses with and without surgery. MATERIALS AND METHODS: We implemented a descriptive animal experiment. The sample included 16 female Gottingen Minipigs, randomly assigned to 4 groups and irradiated with equivalent doses of 0, 25, 50, and 70 Gy to the mandibular region. At 3 months after irradiation, the mandibular left premolars and molars were removed, and dental implants were placed. Computed tomography scans were taken before and 6 months after irradiation. The measured bone density was related to a bone phantom to calculate the bone mineral density quotient (BMDQ). The outcome variable was the BMDQ. Other study variables were the radiation dose and surgery. Descriptive and univariate analyses were computed, and significance was set at P <= .05. RESULTS: In the left hemimandible, compared with the control group, a significant decrease in BMDQ was observed: 0.01 at 0 Gy, -0.01 at 25 Gy, -0.06 at 50 Gy, and -0.11 at 70 Gy (P = .023). The right hemimandible compared with the control group also showed a significant decrease in BMDQ: -0.02 at 0 Gy, -0.08 at 25 Gy, -0.09 at 50 Gy, and -0.11 at 70 Gy (P = .007). CONCLUSIONS: The present study used a large animal model to simulate the tissue reactions induced by various radiation doses in the mandible. We found a significant decrease in the BMDQ after irradiation, but no significant correlation could be found between the irradiation dose and a decrease in the BMDQ. PMID- 25438275 TI - Interventional sialoendoscopy for treatment of obstructive sialadenitis. AB - PURPOSE: This follow-up study documents the overall success rate of interventional sialoendoscopy; it is a novel, less invasive treatment for obstructive sialadenitis. PATIENTS AND METHODS: This was a retrospective follow up study of 189 patients who underwent a sialoendoscopic procedure at Massachusetts General Hospital from 2004 through 2013. Included were patients who underwent sialoendoscopic treatment for symptoms and clinical findings consistent with obstructive sialadenitis. Four different interventional sialoendoscopic techniques were used: dilation of stricture and irrigation, stone retrieval by basket, stone fragmentation with lithotripsy or laser, and stone removal by endoscopic-assisted "cutdown" operation using the "modified McGurk" technique. The outcome assessed was whether the patient was asymptomatic at 6 months postoperatively. RESULTS: Interventional endoscopic navigation was accomplished in 164 of 189 patients (87%). In 17 cases, the duct orifice was inaccessible owing to scarring, so the duct could not be navigated. Symptomatic relief was achieved in 148 of 164 patients (90%). Dilatation and lavage for sialadenitis without a stone was accomplished in 52 of 189 patients (28%). Sialoliths were retrieved or fragmented in 137 of 164 cases (84%). CONCLUSION: The results of this study show a high success rate in the treatment of obstructive sialadenitis using interventional sialoendoscopy. PMID- 25438276 TI - What are the potential implications of identifying intracranial internal carotid artery atherosclerotic lesions on cone-beam computed tomography? A systematic review and illustrative case studies. AB - PURPOSE: A systematic literature review was performed to examine the clinical implications of intracranial internal carotid artery calcific atherosclerotic lesions (IICACALs) detected at cone-beam computed tomographic (CBCT) examinations. MATERIALS AND METHODS: The PubMed database was queried in 2 separate searches using the linked search terms non-contrast enhanced cone beam computed tomography and calcified intracranial vascular lesions and non-contrast enhanced computed tomography and calcified intracranial vascular lesions. Reviewed were all English-language articles using CBCT or CT imaging that enrolled neurologically asymptomatic and symptomatic patients. Excluded were studies describing patients with hemorrhagic stroke. Illustrative cases describing incidentally detected IICACALs on CBCT scans are provided. RESULTS: Three articles described identification of IICACALs on CBCT scans of almost 1,500 dental patients. Two of these fully addressed the subject, with 1 noting that IICACALs were benign and another urging patient referral for further workup. Five non-contrast-enhanced CT studies were evaluated in detail; all confirmed IICACALs as a substantive risk marker of advanced stenotic disease in the cerebral circulation, central brain atrophy, concomitant advanced atherosclerotic disease in the cardiovascular circulation, and an indicator of future ischemic events. Five CBCT examinations showing IICACALs in the cavernous and ophthalmic segments are presented. CONCLUSION: Few studies have denoted the importance of identifying IICACALs on CBCT scans. However, all non-contrast-enhanced CT studies emphasized the clinical significance of these lesions in relation to cerebral and cardiovascular disease. Therefore, IICACALs seen on CBCT and CT scans present the same risk and should prompt referral for further evaluation. PMID- 25438277 TI - The marginal mandibular nerve in relation to the inferior border of the mandible. AB - PURPOSE: Injury to the marginal mandibular nerve (MMN) can occur in numerous surgeries involving incisions near the inferior border of the mandible. Injury to this nerve can cause considerable cosmetic and functional deformities. A thorough knowledge and understanding of the anatomic pathway of the MMN is important to avoid permanent nerve damage. The purpose of this study was to determine the position of the marginal mandibular nerve in relation to several key mandibular anatomic landmarks and to identify variations of the nerve as it approaches the inferior border of the mandible. MATERIALS AND METHODS: Human cadavers were dissected superficially from the parotid gland to the mental protuberance to expose the MMN. At complete exposure of the nerve, 5 anatomic landmarks on the inferior border of the mandible were identified and labeled. The distance between the MMN and these landmarks was recorded, and the average measurements were used to approximate the most common pathway of the MMN. RESULTS: It was found that the MMN runs, on average, 0.75 mm below the gonion, 0.08 mm superior to the posterior border of the antegonial notch, 0.06 mm superior to the arc of the antegonial notch, 1.29 mm superior to the anterior border of the antegonial notch, 3.6 mm superior to the point at which the facial artery reaches the inferior border of the mandible, and 10.9 mm superior to the vertical line that extends from the commissure of lip to the inferior border of the mandible. CONCLUSION: These data suggest 3 general pathways of the MMN in relation to the inferior border of the mandible. PMID- 25438278 TI - Anatomic analysis of the conchal bowl cartilage. AB - PURPOSE: The conchal bowl is a portion of auricular cartilage commonly used as an autologous graft for various maxillofacial procedures. Few studies have attempted to describe the anatomy of this region in detail, particularly in relation to the curvature of the conchal bowl. The present study has provided detailed information about the anatomy of the auricular cartilage in the conchal bowl region that could assist in the surgical design of graft harvesting. MATERIALS AND METHODS: A total of 35 pairs of cadaver ears without gross deformity (15 male, 20 female; aged 39 to 99 years) were dissected to completely expose the cartilage skeleton. Each cartilage was stabilized, and the conchal bowl was mapped. The starting reference point was defined as the intersection of the lateral border of the antihelix and the superiormost aspect of the inferior crux. A prefabricated grid was then used to imprint a 4 * 5 matrix of pinpoint ink spots on the surface of each cartilage, with 6-mm increments between each spot. The grid's y and x axes were then aligned with the landmarks above. Next, a MicroScribe 3-dimensional digitizer (ghost3d.com) was used to capture the 3 dimensional coordinates for each point on the ear's surface and the coordinates were transferred into an Excel spreadsheet. After digitization, a Boley gauge was used to measure the thickness of the cartilage at each premarked spot. The gathered data points and measurements were examined to describe our parameters of interest (ie, depth, thickness, and curvature). RESULTS: The average maximum conchal bowl depth was 10.5 +/- 3.0 mm in the female ears and 10.7 +/- 2.5 mm in the male ears. In general, the conchal bowl depth at each point did not differ significantly between the males and females. The mean cartilage thickness ranged from 0.77 to 1.79 mm (mean 1.15 +/- 0.26) in the females and 0.95 to 1.45 mm (mean 1.25 +/- 0.23) in the males. Both genders showed an increase in the conchal bowl depth from inferiorly to superiorly and from posteriorly to anteriorly. The cartilage thickness also increased from posteriorly to anteriorly; however, the exact shape is complex. CONCLUSIONS: A detailed understanding of the facial anatomy is important in the practice of facial surgery. The results we have presented will provide surgeons with information on the overall dimensions, thickness, and curvature of the conchal bowl that could allow more advantageous donor site selection. PMID- 25438279 TI - Positron emission tomography-computed tomography: a superior and one-stop shop modality for treated head and neck carcinoma compared with conventional tomography. AB - PURPOSE: The fusion imaging modality of positron-emission tomography-computed tomography (PET-CT) has emerged as an important modality in the management of recurrent head and neck tumors. The aims of this study were to assess the role of PET-CT in the detection of recurrence in treated head and neck squamous cell carcinoma (HNSCC) and compare neck PET-CT and contrast-enhanced computed tomography (CECT) in the detection of locoregional recurrence with histopathologic correlation. MATERIALS AND METHODS: The study design was prospective and the study consisted of patients with treated HNSCC referred to the Department of Radiology at Rajiv Gandhi Cancer Institute and Research Center for follow-up or for clinical suspicion of recurrence. PET-CT and CECT neck images were obtained to detect recurrence based on clinical suspicion or as routine follow-up. Comparison of CECT and PET-CT results was performed using receiver operating characteristics (ROC) curves for the detection of locoregional recurrence with histopathologic correlation. RESULTS: Fifty-eight patients with treated HNSCC underwent neck PET-CT and CECT to detect recurrence based on clinical suspicion or as routine follow-up. The sensitivity and specificity of PET-CT for the detection of locoregional recurrence were 100% and 97.37%, which were considerably higher than 85% and 71.05% when using CECT. The ROC curve and its analysis showed that regional PET-CT is superior to neck CECT in the detection of locoregional recurrence (P = .02). When considering recurrence at the metastatic site, the sensitivity and specificity of PET-CT were 100% and 97.06%. PET-CT also detected second primary tumors in 2 patients. CONCLUSION: PET CT not only is superior to conventional CECT in the detection of recurrence at locoregional and lymph node sites, but also plays a role in the restaging of recurrent tumors and the detection of distant metastases and second primary tumors. PET-CT, if included in routine post-treatment HNSCC follow-up or in a protocol for suspected recurrence, may have a major impact on the management of patients after treatment of HNSCC. PMID- 25438280 TI - Custom facial reconstruction for osteosarcoma of the jaw. AB - Osteosarcoma accounts for most primary bone cancers in children and young adults. High-grade lesions are typically managed with a combination of chemotherapy and wide-margin surgical excision. Although this malignancy typically affects the metaphyseal region of long bones, it also can be seen in the axial skeleton. Of axial locations, tumors in the head and neck can be particularly troubling to treat. Segmental bone loss after resection of malignant mandibular tumors continues to present important challenges to the reconstructive surgeon. Recent advancements in 3-dimensional modeling have facilitated custom templates for patient-specific reconstructions. This report describes the case of a young woman with osteosarcoma of the mandible undergoing customized template composite facial reconstruction using a vascularized osteoseptocutaneous fibula flap. PMID- 25438281 TI - Supercritical carbon dioxide anchored Fe3O4 nanoparticles on graphene foam and lithium battery performance. AB - Magnetite (Fe3O4) is an attractive electrode material due to its high theoretical capacity, eco-friendliness, and natural abundance. However, its commercial application in lithium-ion batteries is still hindered by its poor cycling stability and low rate capacity resulting from large volume expansion and low conductivity. We present a new approach which makes use of supercritical carbon dioxide to efficiently anchor Fe3O4 nanoparticles (NPs) on graphene foam (GF), which was obtained by chemical vapor deposition in a single step. Without the use of any surfactants, we obtain moderately spaced Fe3O4 NPs arrays on the surface of GF. The particle size of the Fe3O4 NPs exhibits a narrow distribution (11 +/- 4 nm in diameter). As a result, the composites deliver a high capacity of about 1200 mAh g(-1) up to 500 cycles at 1 C (924 mAh g(-1)) and about 300 mAh g(-1) at 20 C, which reaches a record high using Fe3O4 as anode material for lithium-ion batteries. PMID- 25438282 TI - Transjugular liver biopsy. AB - Liver biopsy is still the gold standard for evaluation of acute and chronic liver diseases, despite achievements regarding noninvasive diagnosis and staging in liver diseases. Transjugular liver biopsy (TJLB) has proved a good option when ascites and/or significant coagulopathy precludes a percutaneous approach. Because diagnostic hemodynamic procedures can be performed during the same session, it is useful in many clinical settings, regardless of the absence of percuteaneous contraindications. TJLB is a safe technique able to provide good quality specimens with a low rate of complications. This article presents an overview of TJLB that discusses the technique, applicability, indications, contraindications, complications, and diagnostic accuracy. PMID- 25438283 TI - Measurement of portal pressure. AB - Portal pressure is estimated through measuring the hepatic venous pressure gradient (HVPG). The main clinical applications of HVPG measurements include diagnosis, classification, and monitoring of portal hypertension, risk stratification, identification of candidates for liver resection, and monitoring efficacy of beta-adrenergic blockers. Clinically significant portal hypertension is defined as an HVPG of 10 mm Hg or greater. Patients who experience a reduction in the HVPG of 20% or greater or to lower than 12 mm Hg in response to beta blocker therapy have a markedly decreased risk of bleeding (or rebleeding), ascites, and spontaneous bacterial peritonitis, resulting in improved survival rates. PMID- 25438284 TI - Endoscopic band ligation and esophageal stents for acute variceal bleeding. AB - Patients with portal hypertension and esophageal varices are at risk of bleeding due to a progressive increase in portal pressure that may rupture the variceal wall. Appropriate treatment with initial general measures, such as resuscitation, a restrictive transfusion policy, antibiotic prophylaxis, pharmacologic therapy with vasoconstrictors, and endoscopic therapy with endoscopic band ligation are mandatory. However, 10% to 15% of patients fail initial endoscopic therapy and thus rescue therapies are needed. This article reviews the current endoscopic strategies with band ligation and esophageal stents for patients with acute variceal bleeding. PMID- 25438285 TI - Endoscopic treatment of gastric varices. AB - Gastric varices (GV) are present in one in 5 patients with portal hypertension and variceal bleeding. GV bleeds tend to be more severe with higher mortality. High index of suspicion, early detection and proper locational diagnosis are important. An algorithmic approach to the management of GV bleeding prevents rebleeds and improves survival. Vasoactive drugs should be started with in 30 minutes (door to needle time) and early endotherapy be done. Cyanoacrylate injection in experienced hands achieves hemostasis in >90% patients. A repeat session is sometimes needed for complete obturation of GV. Transjugular intrahepatic portosystemic shunt and balloon retrograde transvenous obliteration are effective rescue options. Secondary prophylaxis of GV bleeding is done with beta-blocker and endotherapy. PMID- 25438286 TI - Endovascular management of gastric varices. AB - Bleeding from gastric varices is a major complication of portal hypertension. Although less common than bleeding associated with esophageal varices, gastric variceal bleeding has a higher mortality. From an endovascular perspective,transjugular intrahepatic portosystemic shunts (TIPS) to decompress the portal circulation and/or balloon-occluded retrograde transvenous obliteration (BRTO) are utilized to address bleeding gastric varices. Until recently, there was a clear medical cultural divide between the strategy of decompressing the portal circulation (TIPS creation, for example) and transvenous obliteration for the management of gastric varices. However, the practice of BRTO is gaining acceptance in the United States and its practice is spreading rapidly. Recently, the American College of Radiology has identified BRTO to be a viable alternative to TIPS in particular anatomical and clinical scenarios. However, the anatomical and clinical applications of BRTO were not defined beyond the conservative approach of resorting to BRTO in non-TIPS candidates. The article discusses the outcomes of BRTO and TIPS for the management of gastric varices individually or in combination. Definitions, endovascular technical concepts and contemporary vascular classifications of gastric variceal systems are described in order to help grasp the complexity of the hemodynamic pathology and hopefully help define the pathology better for future reporting and lay the ground for more defined stratification of patients not only based on comorbidity and hepatic reserve but on anatomy and hemodynamic classifications. PMID- 25438288 TI - Transarterial chemoembolization and yittrium-90 for liver cancer and other lesions. AB - Transarterial chemoembolization (TACE) is the recommended treatment of intermediate stage hepatocellular carcinoma (HCC). Radioembolization with yttrium 90 has overcome the shortcomings of external beam radiation in the treatment of liver cancer. TACE and radioembolization have led to encouraging response, survival, and quality of life outcomes, with reduced toxicity profiles. This result has led to the use of these therapies in patients with hepatic metastases, most commonly from colorectal cancer. This article reviews the current state of the practice of TACE and radioembolization and presents recent scientific data that support their role in the treatment of HCC and hepatic metastatic disease. PMID- 25438289 TI - Endoscopic retrograde cholangiopancreatography for cholangiocarcinoma. AB - Cholangiocarcinoma is an increasingly common malignancy. Patients usually present with biliary obstruction. The role of endoscopic retrograde cholangiopancreatography (ERCP) is almost exclusively for drainage of the biliary tree, although diagnostic ERCP is still performed at the time of drainage to obtain a tissue diagnosis using brush cytology and intraductal biopsies. Peroral cholangioscopy may facilitate tissue diagnosis by allowing for directed biopsies. Biliary drainage is achieved by endoscopic stent placement. Careful preprocedural planning is necessary to select the ideal areas for drainage and to minimize contrast injection and subsequent cholangitis in hilar lesions. PMID- 25438290 TI - Endoscopic retrograde cholangiopancreatography for primary sclerosing cholangitis. AB - Although there are no randomized, controlled trials evaluating the efficacy of endoscopic retrograde cholangiography (ERC) in primary sclerosing cholangitis (PSC) patients, substantial indirect evidence supports the effectiveness of ERC in symptomatic PSC patients with a dominant stricture. Currently, cumulative evidence supports the role of ERC with endoscopic dilation with or without additional short-term stent placement for symptomatic PSC patients with a dominant stricture. Differentiating benign dominant strictures from cholangiocarcinoma (CCA) remains difficult; however, newer endoscopic techniques and advanced cytologic techniques are likely to improve sensitivity for the diagnosis of CCA over that achieved by traditional cytology brushing alone. PMID- 25438291 TI - Endoscopic retrograde cholangiography for biliary anastomotic strictures after liver transplantation. AB - Biliary complications after liver transplantation (LT) are an important cause of morbidity and mortality. In most cases, an anastomosis of the bile duct is performed as a duct-to-duct reconstruction, which makes endoscopic therapy with endoscopic retrograde cholangiography (ERC) feasible. Biliary anastomotic strictures (AS) are the most common cause of biliary complications. The early detection of an AS, which can sometimes be challenging given that its clinical presentation is often subtle, is of key importance to obtain high treatment success. In this review, we focus on the management of AS after LT with a special emphasis on ERC. PMID- 25438287 TI - Transjugular intrahepatic portosystemic shunt. AB - Transjugular intrahepatic portosystemic shunt (TIPS) is an established procedure for the complications of portal hypertension. The largest body of evidence for its use has been supported for recurrent or refractory variceal bleeding and refractory ascites. Its use has also been advocated for acute variceal bleed, hepatic hydrothorax, and hepatorenal syndrome. With the replacement of bare metal stents with polytetrafluoroethylene-covered stents, shunt patency has improved dramatically, thus, improving outcomes. Therefore, reassessment of its utility, management of its complications, and understanding of various TIPS techniques is important. PMID- 25438292 TI - Cholangioscopy in liver disease. AB - Since its introduction, cholangioscopy has been used diagnostically and therapeutically. The working channel size has increased, permitting direct visualization for tissue sampling and to guide application of lithotripsy for difficult stones. Cholangioscopy utilizes endoscope and catheter-based systems. The application of slim gastroscopes for direct cholangioscopy provides better image resolution than conventional systems. Cholangioscopy has proven effective in the management of large biliary stones and for the diagnosis and exclusion of biliary tumors. Commercially available cholangioscopes are fiberoptic; those with digital video technology remain in a prototype development phase. This review covers available cholangioscope technologies, indications, technique, efficacy, and complications. PMID- 25438293 TI - Molecular adsorbent recirculating system and bioartificial devices for liver failure. AB - Acute liver failure and acute-on-chronic liver failure remain clinical problems with unacceptable morbidity and mortality. The development of extracorporeal liver support systems that replace the detoxification, synthetic, and regulatory functions of the native liver represent a long-sought potential solution, but all the devices currently available are still far from ideal. In general, artificial (cell-free) and bioartificial liver support devices have shown their ability to decrease some circulating toxins, to ameliorate hepatic encephalopathy and other intermediate variables, and to be relatively safe. Their effects on the survival of patients with ALF or ACLF, however, have not been conclusively shown. PMID- 25438294 TI - Intensive care unit management of patients with liver failure. AB - Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) usually mandate management within an intensive care unit (ICU). Even though the conditions bear some similarities, precipitating causes, and systemic complications management practices differ. Although early identification of ALF and ACLF, improvements in ICU management, and the widespread availability of liver transplantation have improved mortality, optimal management practices have not been defined. This article summarizes current ICU management practices and identifies areas of management that require further study. PMID- 25438295 TI - Interventional procedures in hepatobiliary diseases. PMID- 25438296 TI - Regioselective patterning of multiple SAMs and applications in surface-guided smart microfluidics. AB - A top-down nanofabrication technology is developed to integrate multiple SAMs (self-assembled monolayers) into regioselective patterns. With ultraviolet light exposure through regioselectively hollowed hard mask, an existing SAM at designated microregions can be removed and a dissimilar kind of SAM can be regrown there. By repeating the photolithography-like process cycle, diverse kinds of SAM building blocks can be laid out as a desired pattern in one microfluidic channel. In order to ensure high quality of the surface modifications, the SAMs are vapor-phase deposited before the channel is closed by a bonding process. For the first time the technique makes it possible to integrate three or more kinds of SAMs in one microchannel. The technique is very useful for multiplex surface functionalization of microfluidic chips where different segments of a microfluidic channel need to be individually modified with different SAMs or into arrayed pattern for surface-guided fluidic properties like hydrophobicity/philicity and/or oleophobicity/philicity, etc. The technique has been well validated by experimental demonstration of various surface-directed flow-guiding functions. By modifying a microchannel surface into an arrayed pattern of multi-SAM "two-tone" stripe array, surface-guiding-induced 3D swirling flow is generated in a microfluidic channel that experimentally exhibits quick oil/water mixing and high-efficiency oil-to-water chemical extraction. PMID- 25438297 TI - Hybrid molecular brushes with chitosan backbone: facile synthesis and surface grafting. AB - We developed a facile route toward amphiphilic hybrid molecular brushes (HMB) with chitosan backbone and concurrently grafted chains of poly(acrylamide) and polystyrene. The grafting occurs through amino groups of chitosan; no extra modification of chitosan is required. The kinetic and molecular weight characteristics of the primary molecular brush CHI-graft-PAAm are studied. The second step is grafting of PS by emulsion polymerization. The resulting HMB CHI graft-PAAm-graft-PS form very stable emulsions. We attached the HMB on solid substrates using chitosan backbone by the "grafting to" approach. Thin films of the immobilized HMB of 3-11 nm thickness completely cover the surface. Being amphiphilic by nature, the immobilized HMB reveal the ability to adapt to the medium, which results in shifting of the hydrophobic/hydrophilic balance over a wide range. PMID- 25438298 TI - Evaluation of contrast enhancement by carbon nanotubes for microwave-induced thermoacoustic tomography. AB - Microwave-induced thermoacoustic tomography (MITAT) is a hybrid method which constructs images with ultrasound spatial resolution while exploiting dielectric contrast at microwave frequency. It has great potential in biomedical imaging especially in early breast cancer detection. The detection of early stage breast tumor in MITAT is challenged by the moderate endogenous dielectric contrast between malignant and healthy glandular tissues. In order to overcome this limitation, the performance of using carbon nanotubes (CNTs) as an imaging contrast enhancement agent is evaluated. First, the influences in dielectric and acoustic properties caused by CNTs are measured. Second, based on the measurements and the published data, numerical breast phantom is created and then used to explore the contrast enhancing effect of CNTs for MITAT, by an integrated simulation approach in both electromagnetic and acoustic field. With an experimental MITAT system, the thermoacoustic responses of tissue mimicking materials with different CNTs concentrations are also quantitatively investigated. Finally, the effectiveness of the contrast agent is also validated experimentally by using a MITAT system. The results show that the using of the dielectric contrast agent can effectively enhance the contrast of the MITAT image. PMID- 25438299 TI - Multilabel region classification and semantic linking for colon segmentation in CT colonography. AB - Accurate and automatic colon segmentation from CT images is a crucial step of many clinical applications in CT colonography, including computer-aided detection (CAD) of colon polyps, 3-D virtual flythrough of the colon, and prone/supine registration. However, the existence of adjacent air-filled organs such as the lung, stomach, and small intestine, and the collapse of the colon due to poor insufflation, render accurate segmentation of the colon a difficult problem. Extra-colonic components can be categorized into two types based on their 3-D connection to the colon: detached and attached extracolonic components (DEC and AEC, respectively). In this paper, we propose graph inference methods to remove extracolonic components to achieve a high quality segmentation. We first decompose each 3-D air-filled object into a set of 3-D regions. A classifier trained with region-level features can be used to identify the colon regions from noncolon regions. After removing obvious DEC, we remove the remaining DEC by modeling the global anatomic structure with an a priori topological constraint and solving a graph inference problem using semantic information provided by a multiclass classifier. Finally, we remove AEC by modeling regions within each 3-D object with a hierarchical conditional random field, solved by graph cut. Experimental results demonstrate that our method outperforms a purely discriminative learning method in detecting true colon regions, while decreasing extra-colonic components in challenging clinical data that includes collapsed cases. PMID- 25438300 TI - Automatic optic disc detection in OCT slices via low-rank reconstruction. AB - Optic disc measurements provide useful diagnostic information as they have correlations with certain eye diseases. In this paper, we provide an automatic method for detecting the optic disc in a single OCT slice. Our method is developed from the observation that the retinal pigment epithelium (RPE) which bounds the optic disc has a low-rank appearance structure that differs from areas within the disc. To detect the disc, our method acquires from the OCT image an RPE appearance model that is specific to the individual and imaging conditions, by learning a low-rank dictionary from image areas known to be part of the RPE according to priors on ocular anatomy. The edge of the RPE, where the optic disc is located, is then found by traversing the retinal layer containing the RPE, reconstructing local appearance with the low-rank model, and detecting the point at which appearance starts to deviate (i.e., increased reconstruction error). To aid in this detection, we also introduce a geometrical constraint called the distance bias that accounts for the smooth shape of the RPE. Experiments demonstrate that our method outperforms other OCT techniques in localizing the optic disc and estimating disc width. Moreover, we also show the potential usage of our method on optic disc area detection in 3-D OCT volumes. PMID- 25438301 TI - Assess sleep stage by modern signal processing techniques. AB - In this paper, two modern adaptive signal processing techniques, empirical intrinsic geometry and synchrosqueezing transform, are applied to quantify different dynamical features of the respiratory and electroencephalographic signals. We show that the proposed features are theoretically rigorously supported, as well as capture the sleep information hidden inside the signals. The features are used as input to multiclass support vector machines with the radial basis function to automatically classify sleep stages. The effectiveness of the classification based on the proposed features is shown to be comparable to human expert classification-the proposed classification of awake, REM, N1, N2, and N3 sleeping stages based on the respiratory signal (resp. respiratory and EEG signals) has the overall accuracy 81.7% (resp. 89.3%) in the relatively normal subject group. In addition, by examining the combination of the respiratory signal with the electroencephalographic signal, we conclude that the respiratory signal consists of ample sleep information, which supplements to the information stored in the electroencephalographic signal. PMID- 25438302 TI - Edge-preserving PET image reconstruction using trust optimization transfer. AB - Iterative image reconstruction for positron emission tomography can improve image quality by using spatial regularization. The most commonly used quadratic penalty often oversmoothes sharp edges and fine features in reconstructed images, while nonquadratic penalties can preserve edges and achieve higher contrast recovery. Existing optimization algorithms such as the expectation maximization (EM) and preconditioned conjugate gradient (PCG) algorithms work well for the quadratic penalty, but are less efficient for high-curvature or nonsmooth edge-preserving regularizations. This paper proposes a new algorithm to accelerate edge preserving image reconstruction by using two strategies: trust surrogate and optimization transfer descent. Trust surrogate approximates the original penalty by a smoother function at each iteration, but guarantees the algorithm to descend monotonically; Optimization transfer descent accelerates a conventional optimization transfer algorithm by using conjugate gradient and line search. Results of computer simulations and real 3-D data show that the proposed algorithm converges much faster than the conventional EM and PCG for smooth edge preserving regularization and can also be more efficient than the current state of-art algorithms for the nonsmooth l1 regularization. PMID- 25438303 TI - An extended algebraic reconstruction technique (E-ART) for dual spectral CT. AB - Compared with standard computed tomography (CT), dual spectral CT (DSCT) has many advantages for object separation, contrast enhancement, artifact reduction, and material composition assessment. But it is generally difficult to reconstruct images from polychromatic projections acquired by DSCT, because of the nonlinear relation between the polychromatic projections and the images to be reconstructed. This paper first models the DSCT reconstruction problem as a nonlinear system problem; and then extend the classic ART method to solve the nonlinear system. One feature of the proposed method is its flexibility. It fits for any scanning configurations commonly used and does not require consistent rays for different X-ray spectra. Another feature of the proposed method is its high degree of parallelism, which means that the method is suitable for acceleration on GPUs (graphic processing units) or other parallel systems. The method is validated with numerical experiments from simulated noise free and noisy data. High quality images are reconstructed with the proposed method from the polychromatic projections of DSCT. The reconstructed images are still satisfactory even if there are certain errors in the estimated X-ray spectra. PMID- 25438304 TI - A Hybrid LDA+gCCA Model for fMRI Data Classification and Visualization. AB - Linear predictive models are applied to functional MRI (fMRI) data to estimate boundaries that predict experimental task states for scans. These boundaries are visualized as statistical parametric maps (SPMs) and range from low to high spatial reproducibility across subjects (e.g., Strother , 2004; LaConte , 2003). Such inter-subject pattern reproducibility is an essential characteristic of interpretable SPMs that generalize across subjects. Therefore, we introduce a flexible hybrid model that optimizes reproducibility by simultaneously enhancing the prediction power and reproducibility. This hybrid model is formed by a weighted summation of the optimization functions of a linear discriminate analysis (LDA) model and a generalized canonical correlation (gCCA) model (Afshin Pour , 2012). LDA preserves the model's ability to discriminate the fMRI scans of multiple brain states while gCCA finds a linear combination for each subject's scans such that the estimated boundary map is reproducible. The hybrid model is implemented in a split-half resampling framework (Strother , 2010) which provides reproducibility (r) and prediction (p) quality metrics. Then the model was compared with LDA, and Gaussian Naive Bayes (GNB). For simulated fMRI data, the hybrid model outperforms the other two techniques in terms of receiver operating characteristic (ROC) curves, particularly for detecting less predictable but spatially reproducible networks. These techniques were applied to real fMRI data to estimate the maps for two task contrasts. Our results indicate that compared to LDA and GNB, the hybrid model can provide maps with large increases in reproducibility for small reductions in prediction, which are jointly closer to the ideal performance point of (p=1, r=1). PMID- 25438305 TI - Graph-Based Airway Tree Reconstruction From Chest CT Scans: Evaluation of Different Features on Five Cohorts. AB - We present a graph-based framework for airway tree reconstruction from computerized tomography (CT) scans and evaluate the performance of different feature categories and their combinations on five lung cohorts. The approach consists of two main processing steps. First, potential airway branch and connection candidates are identified and represented by a graph structure with weighted nodes and edges, respectively. Second, an optimization algorithm is utilized for generating an airway detection result by selecting a subset of airway branches and connections based on graph weights derived from image features. The performance of the algorithm with different feature categories and their combinations was assessed on a set of 50 lung CT scans from five different cohorts, including normal and diseased lungs. Results show trade-offs between feature categories/combinations in terms of correctly (true positive) and incorrectly (false positive) identified airways. Also, the performance of features in dependence of lung cohort was analyzed. Across all cohorts, a good trade-off with high true positive rate (TPR) and low false positive rate (FPR) was achieved by a combination of gray-value, local shape, and structural features. This combination enabled extracting 91.80% of reference airways (TPR) in combination with a low FPR of 1.00%. In addition, this variant was evaluated on the public EXACT'09 test set, and a comparison with other airway detection approaches is provided. One of the main advantages of the presented method is that it is robust against local disturbances/artifacts or other ambiguities that are frequently occurring in lung CT scans. PMID- 25438307 TI - Experimental Comparison of Continuous-Wave and Frequency-Domain Fluorescence Tomography in a Commercial Multi-Modal Scanner. AB - The performance evaluation of a variety of small animal tomography measurement approaches and algorithms for recovery of fluorescent absorption cross section has not been conducted. Herein, we employed an intensified CCD system installed in a commercial small animal CT (Computed Tomography) scanner to compare image reconstructions from time-independent, continuous wave (CW) measurements and from time-dependent, frequency domain (FD) measurements in a series of physical phantoms specifically designed for evaluation. Comparisons were performed as a function of (1) number of projections, (2) the level of preprocessing filters used to improve the signal-to-noise ratio (SNR), (3) endogenous heterogeneity of optical properties, as well as in the cases of (4) two fluorescent targets and (5) a mouse-shaped phantom. Assessment of quantitative recovery of fluorescence absorption cross section was performed using a fully parallel, regularization free, linear reconstruction algorithm with diffusion approximation (DA) and high order simplified spherical harmonics ( SPN) approximation to the radiative transport equation (RTE). The results show that while FD measurements may result in superior image reconstructions over CW measurements, data acquisition times are significantly longer, necessitating further development of multiple detector/source configurations, improved data read-out rates, and detector technology. FD measurements with SP3 reconstructions enabled better quantitative recovery of fluorescent target strength, but required increased computational expense. Despite the developed parallel reconstruction framework being able to achieve more than 60 times speed increase over sequential implementation, further development in faster parallel acceleration strategies for near-real time and real-time image recovery and more precise forward solution is necessary. PMID- 25438306 TI - Magnetic particle imaging with tailored iron oxide nanoparticle tracers. AB - Magnetic particle imaging (MPI) shows promise for medical imaging, particularly in angiography of patients with chronic kidney disease. As the first biomedical imaging technique that truly depends on nanoscale materials properties, MPI requires highly optimized magnetic nanoparticle tracers to generate quality images. Until now, researchers have relied on tracers optimized for MRI T2(*) weighted imaging that are sub-optimal for MPI. Here, we describe new tracers tailored to MPI's unique physics, synthesized using an organic-phase process and functionalized to ensure biocompatibility and adequate in vivo circulation time. Tailored tracers showed up to 3 * greater signal-to-noise ratio and better spatial resolution than existing commercial tracers in MPI images of phantoms. PMID- 25438308 TI - Three-Dimensional Nonrigid MR-TRUS Registration Using Dual Optimization. AB - In this study, we proposed an efficient nonrigid magnetic resonance (MR) to transrectal ultrasound (TRUS) deformable registration method in order to improve the accuracy of targeting suspicious regions during a three dimensional (3-D) TRUS guided prostate biopsy. The proposed deformable registration approach employs the multi-channel modality independent neighborhood descriptor (MIND) as the local similarity feature across the two modalities of MR and TRUS, and a novel and efficient duality-based convex optimization-based algorithmic scheme was introduced to extract the deformations and align the two MIND descriptors. The registration accuracy was evaluated using 20 patient images by calculating the TRE using manually identified corresponding intrinsic fiducials in the whole gland and peripheral zone. Additional performance metrics [Dice similarity coefficient (DSC), mean absolute surface distance (MAD), and maximum absolute surface distance (MAXD)] were also calculated by comparing the MR and TRUS manually segmented prostate surfaces in the registered images. Experimental results showed that the proposed method yielded an overall median TRE of 1.76 mm. The results obtained in terms of DSC showed an average of 80.8+/-7.8% for the apex of the prostate, 92.0+/-3.4% for the mid-gland, 81.7+/-6.4% for the base and 85.7+/-4.7% for the whole gland. The surface distance calculations showed an overall average of 1.84+/-0.52 mm for MAD and 6.90+/-2.07 mm for MAXD. PMID- 25438309 TI - Learning structured models for segmentation of 2-D and 3-D imagery. AB - Efficient and accurate segmentation of cellular structures in microscopic data is an essential task in medical imaging. Many state-of-the-art approaches to image segmentation use structured models whose parameters must be carefully chosen for optimal performance. A popular choice is to learn them using a large-margin framework and more specifically structured support vector machines (SSVM). Although SSVMs are appealing, they suffer from certain limitations. First, they are restricted in practice to linear kernels because the more powerful nonlinear kernels cause the learning to become prohibitively expensive. Second, they require iteratively finding the most violated constraints, which is often intractable for the loopy graphical models used in image segmentation. This requires approximation that can lead to reduced quality of learning. In this paper, we propose three novel techniques to overcome these limitations. We first introduce a method to "kernelize" the features so that a linear SSVM framework can leverage the power of nonlinear kernels without incurring much additional computational cost. Moreover, we employ a working set of constraints to increase the reliability of approximate subgradient methods and introduce a new way to select a suitable step size at each iteration. We demonstrate the strength of our approach on both 2-D and 3-D electron microscopic (EM) image data and show consistent performance improvement over state-of-the-art approaches. PMID- 25438310 TI - Panorama view with spatiotemporal occlusion compensation for 3D video coding. AB - The future of novel 3D display technologies largely depends on the design of efficient techniques for 3D video representation and coding. Recently, multiple view plus depth video formats have attracted many research efforts since they enable intermediate view estimation and permit to efficiently represent and compress 3D video sequences. In this paper, we present spatiotemporal occlusion compensation with panorama view (STOP), a novel 3D video coding technique based on the creation of a panorama view and occlusion coding in terms of spatiotemporal offsets. The panorama picture represents the most of the visual information acquired from multiple views using a single virtual view, characterized by a larger field of view. Encoding the panorama video with state of-the-art HECV and representing occlusions with simple spatiotemporal ancillary information STOP achieves high-compression ratio and good visual quality with competitive results with respect to competing techniques. Moreover, STOP enables free viewpoint 3D TV applications whilst allowing legacy display to get a bidimensional service using a standard video codec and simple cropping operations. PMID- 25438311 TI - Adjoint active surfaces for localization and imaging. AB - This paper addresses the problem of localizing and segmenting regions embedded within a surrounding medium by characterizing their boundaries, as opposed to imaging the entirety of the volume. Active surfaces are used to directly reconstruct the shape of the region of interest. We describe the procedure for finding the optimal surface, which is computed iteratively via gradient descent that exploits the sensitivity of an error minimization functional to changes of the active surface. In doing so, we introduce the adjoint model to compute the sensitivity, and in this respect, the method shares common ground with several other disciplines, such as optimal control. Finally, we illustrate the proposed active surface technique in the framework of wave propagation governed by the scalar Helmholtz equation. Potential applications include electromagnetics, acoustics, geophysics, nondestructive testing, and medical imaging. PMID- 25438312 TI - Discriminative shared Gaussian processes for multiview and view-invariant facial expression recognition. AB - Images of facial expressions are often captured from various views as a result of either head movements or variable camera position. Existing methods for multiview and/or view-invariant facial expression recognition typically perform classification of the observed expression using either classifiers learned separately for each view or a single classifier learned for all views. However, these approaches ignore the fact that different views of a facial expression are just different manifestations of the same facial expression. By accounting for this redundancy, we can design more effective classifiers for the target task. To this end, we propose a discriminative shared Gaussian process latent variable model (DS-GPLVM) for multiview and view-invariant classification of facial expressions from multiple views. In this model, we first learn a discriminative manifold shared by multiple views of a facial expression. Subsequently, we perform facial expression classification in the expression manifold. Finally, classification of an observed facial expression is carried out either in the view invariant manner (using only a single view of the expression) or in the multiview manner (using multiple views of the expression). The proposed model can also be used to perform fusion of different facial features in a principled manner. We validate the proposed DS-GPLVM on both posed and spontaneously displayed facial expressions from three publicly available datasets (MultiPIE, labeled face parts in the wild, and static facial expressions in the wild). We show that this model outperforms the state-of-the-art methods for multiview and view-invariant facial expression classification, and several state-of-the-art methods for multiview learning and feature fusion. PMID- 25438313 TI - Viewing-distance aware super-resolution for high-definition display. AB - In this paper, we propose a novel algorithm for high-definition displays to enlarge low-resolution images while maintaining perceptual constancy (i.e., the same field-of-view, perceptual blur radius, and the retinal image size in viewer's eyes). We model the relationship between a viewer and a display by considering two main aspects of visual perception, i.e., scaling factor and perceptual blur radius. As long as we enlarge an image while adjust its image blur levels on the display, we can maintain viewer's perceptual constancy. We show that the scaling factor should be set in proportion to the viewing distance and the blur levels on the display should be adjusted according to the focal length of a viewer. Toward this, we first refer to edge directions to interpolate a low-resolution image with the increasing of viewing distance and the scaling factor. After images are interpolated, we utilize a local contrast to estimate the spatially varying image blur levels of the interpolated image. We then further adjust the image blur levels using a parametric deblurring method, which combines L1 as well as L2 reconstruction errors, and Tikhonov with total variation regularization terms. By taking these factors into account, high resolution images adaptive to viewing distance on a display can be generated. Experimental results on both natural image metric and user subjective studies across image scales demonstrate that the proposed super-resolution algorithm for high-definition displays performs favorably against the state-of-the-art methods. PMID- 25438314 TI - Semantic sparse recoding of visual content for image applications. AB - This paper presents a new semantic sparse recoding method to generate more descriptive and robust representation of visual content for image applications. Although the visual bag-of-words (BOW) representation has been reported to achieve promising results in different image applications, its visual codebook is completely learnt from low-level visual features using quantization techniques and thus the so-called semantic gap remains unbridgeable. To handle such challenging issue, we utilize the annotations (predicted by algorithms or shared by users) of all the images to improve the original visual BOW representation. This is further formulated as a sparse coding problem so that the noise issue induced by the inaccurate quantization of visual features can also be handled to some extent. By developing an efficient sparse coding algorithm, we successfully generate a new visual BOW representation for image applications. Since such sparse coding has actually incorporated the high-level semantic information into the original visual codebook, we thus consider it as semantic sparse recoding of the visual content. Finally, we apply our semantic sparse recoding method to automatic image annotation and social image classification. The experimental results on several benchmark datasets show the promising performance of our semantic sparse recoding method in these two image applications. PMID- 25438315 TI - A probabilistic approach for color correction in image mosaicking applications. AB - Image mosaicking applications require both geometrical and photometrical registrations between the images that compose the mosaic. This paper proposes a probabilistic color correction algorithm for correcting the photometrical disparities. First, the image to be color corrected is segmented into several regions using mean shift. Then, connected regions are extracted using a region fusion algorithm. Local joint image histograms of each region are modeled as collections of truncated Gaussians using a maximum likelihood estimation procedure. Then, local color palette mapping functions are computed using these sets of Gaussians. The color correction is performed by applying those functions to all the regions of the image. An extensive comparison with ten other state of the art color correction algorithms is presented, using two different image pair data sets. Results show that the proposed approach obtains the best average scores in both data sets and evaluation metrics and is also the most robust to failures. PMID- 25438316 TI - Edge-based intramode selection for depth-map coding in 3D-HEVC. AB - The 3D video extension of High Efficiency Video Coding (3D-HEVC) is the state-of the-art video coding standard for the compression of the multiview video plus depth format. In the 3D-HEVC design, new depth-modeling modes (DMMs) are utilized together with the existing intraprediction modes for depth intracoding. The DMMs can provide more accurate prediction signals and thereby achieve better compression efficiency. However, testing the DMMs in the intramode decision process causes a drastic increase in the computational complexity. In this paper, we propose a fast mode decision algorithm for depth intracoding. The proposed algorithm first performs a simple edge classification in the Hadamard transform domain. Then, based on the edge classification results, the proposed algorithm selectively omits unnecessary DMMs in the mode decision process. Experimental results demonstrate that the proposed algorithm speeds up the mode decision process by up to 37.65% with negligible loss of coding efficiency. PMID- 25438317 TI - A doubly degenerate diffusion model based on the gray level indicator for multiplicative noise removal. AB - Multiplicative noise removal is a challenging task in image processing. Inspired by the impressive performance of nonlinear diffusion models in additive noise removal, we address this problem in the view of nonlinear diffusion equation theories rather than the traditional variation methods. We develop a nonlinear diffusion filter denoising framework, which considers not only the information of the gradient of the image, but also the information of gray levels of the image. Furthermore, under this framework, we propose a doubly degenerate diffusion model for multiplicative noise removal, which is analyzed with respect to some of its properties and behavior in denoising process. In numerical aspects, we present an efficient scheme which uses a stabilization by fast explicit diffusion for the implementation of the multiplicative noise removal model. Finally, the experimental results illustrate effectiveness and efficiency of the proposed model. PMID- 25438318 TI - A computational model of the short-cut rule for 2D shape decomposition. AB - We propose a new 2D shape decomposition method based on the short-cut rule. The short-cut rule originates from cognition research, and states that the human visual system prefers to partition an object into parts using the shortest possible cuts. We propose and implement a computational model for the short-cut rule and apply it to the problem of shape decomposition. The model we proposed generates a set of cut hypotheses passing through the points on the silhouette, which represent the negative minima of curvature. We then show that most part-cut hypotheses can be eliminated by analysis of local properties of each. Finally, the remaining hypotheses are evaluated in ascending length order, which guarantees that of any pair of conflicting cuts only the shortest will be accepted. We demonstrate that, compared with state-of-the-art shape decomposition methods, the proposed approach achieves decomposition results, which better correspond to human intuition as revealed in psychological experiments. PMID- 25438319 TI - Total variation regularization via continuation to recover compressed hyperspectral images. AB - In this paper, we investigate a low-complexity scheme for decoding compressed hyperspectral image data. We have exploited the simplicity of the subgradient method by modifying a total variation-based regularization problem to include a residual constraint, employing convex optimality conditions to provide equivalency between the original and reformed problem statements. A scheme that utilizes spectral smoothness by calculating informed starting points to improve the rate of convergence is introduced. We conduct numerical experiments, using both synthetic and real hyperspectral data, to demonstrate the effectiveness of the reconstruction algorithm and the validity of our method for exploiting spectral smoothness. Evidence from these experiments suggests that the proposed methods have the potential to improve the quality and run times of the future compressed hyperspectral image reconstructions. PMID- 25438321 TI - Gold Nanoprobe-Based Detection of Human Telomerase Reverse Transcriptase (hTERT) Gene Expression. AB - Human Telomerase Reverse Transcriptase (hTERT) gene is expressed in all types of cancers, and it is considered as unique biomarker for early detection, monitoring and prognosis of different cancers. Routinely, the main techniques for detection of hTERT gene expression are based on enzymatic amplifications which need specified equipments, expert personnel and high cost and time. With regarding to the clinical importance of analysis of hTERT gene expression, we have developed a rapid, simple and low cost method which detects hTERT RNA target in 5 MUl reaction scale using gold nanoprobes. The method is based on the inhibition of nanoparticle aggregation in the presence of MgCl 2 and it can be used as a basic technique for development of clinical scale gold nanoprobe nanobiodiagnostics for detection of hTERT gene expression with a limit of detection at fmol/MUl concentrations. PMID- 25438320 TI - Moving Away From Error-Related Potentials to Achieve Spelling Correction in P300 Spellers. AB - P300 spellers can provide a means of communication for individuals with severe neuromuscular limitations. However, its use as an effective communication tool is reliant on high P300 classification accuracies ( > 70%) to account for error revisions. Error-related potentials (ErrP), which are changes in EEG potentials when a person is aware of or perceives erroneous behavior or feedback, have been proposed as inputs to drive corrective mechanisms that veto erroneous actions by BCI systems. The goal of this study is to demonstrate that training an additional ErrP classifier for a P300 speller is not necessary, as we hypothesize that error information is encoded in the P300 classifier responses used for character selection. We perform offline simulations of P300 spelling to compare ErrP and non-ErrP based corrective algorithms. A simple dictionary correction based on string matching and word frequency significantly improved accuracy (35-185%), in contrast to an ErrP-based method that flagged, deleted and replaced erroneous characters (-47-0%) . Providing additional information about the likelihood of characters to a dictionary-based correction further improves accuracy. Our Bayesian dictionary-based correction algorithm that utilizes P300 classifier confidences performed comparably (44-416%) to an oracle ErrP dictionary-based method that assumed perfect ErrP classification (43-433%). PMID- 25438322 TI - Prediction of Tubulin Resonant Frequencies Using the Resonant Recognition Model (RRM). AB - Tubulin proteins were analyzed using the Resonant Recognition Model to predict possible electromagnetic resonances in tubulin and microtubules. We propose that these electromagnetic resonances are caused by charge transfer through the protein molecule. The frequencies of these electromagnetic resonances depend on charge velocity. Using different velocities of charge transfer, we predicted resonant frequencies in different frequency ranges from KHz to THz. These resonant frequencies could be relevant for taxol binding as well as a possible role of microtubules as a macromolecular computer. PMID- 25438323 TI - Grow-cut based automatic cDNA microarray image segmentation. AB - Complementary DNA (cDNA) microarray is a well-established tool for simultaneously studying the expression level of thousands of genes. Segmentation of microarray images is one of the main stages in a microarray experiment. However, it remains an arduous and challenging task due to the poor quality of images. Images suffer from noise, artifacts, and uneven background, while spots depicted on images can be poorly contrasted and deformed. In this paper, an original approach for the segmentation of cDNA microarray images is proposed. First, a preprocessing stage is applied in order to reduce the noise levels of the microarray image. Then, the grow-cut algorithm is applied separately to each spot location, employing an automated seed selection procedure, in order to locate the pixels belonging to spots. Application on datasets containing synthetic and real microarray images shows that the proposed algorithm performs better than other previously proposed methods. Moreover, in order to exploit the independence of the segmentation task for each separate spot location, both a multithreaded CPU and a graphics processing unit (GPU) implementation were evaluated. PMID- 25438324 TI - A Power-Efficient Multichannel Neural Stimulator Using High-Frequency Pulsed Excitation From an Unfiltered Dynamic Supply. AB - This paper presents a neural stimulator system that employs a fundamentally different way of stimulating neural tissue compared to classical constant current stimulation. A stimulation pulse is composed of a sequence of current pulses injected at a frequency of 1 MHz for which the duty cycle is used to control the stimulation intensity. The system features 8 independent channels that connect to any of the 16 electrodes at the output. A sophisticated control system allows for individual control of each channel's stimulation and timing parameters. This flexibility makes the system suitable for complex electrode configurations and current steering applications. Simultaneous multichannel stimulation is implemented using a high frequency alternating technique, which reduces the amount of electrode switches by a factor 8. The system has the advantage of requiring a single inductor as its only external component. Furthermore it offers a high power efficiency, which is nearly independent on both the voltage over the load as well as on the number of simultaneously operated channels. Measurements confirm this: in multichannel mode the power efficiency can be increased for specific cases to 40% compared to 20% that is achieved by state-of-the-art classical constant current stimulators with adaptive power supply. PMID- 25438325 TI - The Effect of Haptic Guidance on Learning a Hybrid Rhythmic-Discrete Motor Task. AB - Bouncing a ball with a racket is a hybrid rhythmic-discrete motor task, combining continuous rhythmic racket movements with discrete impact events. Rhythmicity is exceptionally important in motor learning, because it underlies fundamental movements such as walking. Studies suggested that rhythmic and discrete movements are governed by different control mechanisms at different levels of the Central Nervous System. The aim of this study is to evaluate the effect of fixed/fading haptic guidance on learning to bounce a ball to a desired apex in virtual reality with varying gravity. Changing gravity changes dominance of rhythmic versus discrete control: The higher the value of gravity, the more rhythmic the task; lower values reduce the bouncing frequency and increase dwell times, eventually leading to a repetitive discrete task that requires initiation and termination, resembling target-oriented reaching. Although motor learning in the ball-bouncing task with varying gravity has been studied, the effect of haptic guidance on learning such a hybrid rhythmic-discrete motor task has not been addressed. We performed an experiment with thirty healthy subjects and found that the most effective training condition depended on the degree of rhythmicity: Haptic guidance seems to hamper learning of continuous rhythmic tasks, but it seems to promote learning for repetitive tasks that resemble discrete movements. PMID- 25438326 TI - Reinforcement learning design-based adaptive tracking control with less learning parameters for nonlinear discrete-time MIMO systems. AB - Based on the neural network (NN) approximator, an online reinforcement learning algorithm is proposed for a class of affine multiple input and multiple output (MIMO) nonlinear discrete-time systems with unknown functions and disturbances. In the design procedure, two networks are provided where one is an action network to generate an optimal control signal and the other is a critic network to approximate the cost function. An optimal control signal and adaptation laws can be generated based on two NNs. In the previous approaches, the weights of critic and action networks are updated based on the gradient descent rule and the estimations of optimal weight vectors are directly adjusted in the design. Consequently, compared with the existing results, the main contributions of this paper are: 1) only two parameters are needed to be adjusted, and thus the number of the adaptation laws is smaller than the previous results and 2) the updating parameters do not depend on the number of the subsystems for MIMO systems and the tuning rules are replaced by adjusting the norms on optimal weight vectors in both action and critic networks. It is proven that the tracking errors, the adaptation laws, and the control inputs are uniformly bounded using Lyapunov analysis method. The simulation examples are employed to illustrate the effectiveness of the proposed algorithm. PMID- 25438327 TI - Dynamic Infinite Mixed-Membership Stochastic Blockmodel. AB - Directional and pairwise measurements are often used to model interactions in a social network setting. The mixed-membership stochastic blockmodel (MMSB) was a seminal work in this area, and its ability has been extended. However, models such as MMSB face particular challenges in modeling dynamic networks, for example, with the unknown number of communities. Accordingly, this paper proposes a dynamic infinite mixed-membership stochastic blockmodel, a generalized framework that extends the existing work to potentially infinite communities inside a network in dynamic settings (i.e., networks are observed over time). Additional model parameters are introduced to reflect the degree of persistence among one's memberships at consecutive time stamps. Under this framework, two specific models, namely mixture time variant and mixture time invariant models, are proposed to depict two different time correlation structures. Two effective posterior sampling strategies and their results are presented, respectively, using synthetic and real-world data. PMID- 25438329 TI - myPace: an integrative health platform for supporting weight loss and maintenance behaviors. AB - Obesity is a major health concern caused by unhealthy eating behaviors. Digital weight loss interventions have adopted mobile technology primarily in order to support self-monitoring. However, many available apps are not designed as a part of dietetic practice; therefore, a distinct gap in the research exists relating to technology that supports the patient-practitioner relationship. This paper presents myPace, which is a complete weight loss and management system that is deployed via a smartphone and a PC. It connects dietitians and patients between face-to-face consultations and extends the relationship through patients' regular progress updates and dietitians' tailored and timely advice, for sustained behavior change. The prototype was developed from research into behavior change for weight loss, which furthermore was underpinned by theory and tenets of human support models, such as the supportive accountability framework. We report on an early-phase system design goals via a formative research process, which aimed to implement theoretical principles and match practical dietetic practice. To that end, only the clinical end user's perspective was sought through a coaching think aloud protocol on the first iteration of the prototype and interviews with dietitians. Findings show that the system has many positive design features, but which require further development in order for the system to be fully acceptable within dietetic practice and motivate patient engagement. PMID- 25438328 TI - Automated Localization of Multiple Pelvic Bone Structures on MRI. AB - In this paper, we present a fully automated localization method for multiple pelvic bone structures on magnetic resonance images (MRI). Pelvic bone structures are at present identified manually on MRI to locate reference points for measurement and evaluation of pelvic organ prolapse (POP). Given that this is a time-consuming and subjective procedure, there is a need to localize pelvic bone structures automatically. However, bone structures are not easily differentiable from soft tissue on MRI as their pixel intensities tend to be very similar. In this paper, we present a model that combines support vector machines and nonlinear regression capturing global and local information to automatically identify the bounding boxes of bone structures on MRI. The model identifies the location of the pelvic bone structures by establishing the association between their relative locations and using local information such as texture features. Results show that the proposed method is able to locate the bone structures of interest accurately (dice similarity index >0.75) in 87-91% of the images. This research aims to enable accurate, consistent, and fully automated localization of bone structures on MRI to facilitate and improve the diagnosis of health conditions such as female POP. PMID- 25438330 TI - Laryngeal Tumor Detection and Classification in Endoscopic Video. AB - The development of the narrow-band imaging (NBI) has been increasing the interest of medical specialists in the study of laryngeal microvascular network to establish diagnosis without biopsy and pathological examination. A possible solution to this challenging problem is presented in this paper, which proposes an automatic method based on anisotropic filtering and matched filter to extract the lesion area and segment blood vessels. Lesion classification is then performed based on a statistical analysis of the blood vessels' characteristics, such as thickness, tortuosity, and density. Here, the presented algorithm is applied to 50 NBI endoscopic images of laryngeal diseases and the segmentation and classification accuracies are investigated. The experimental results show the proposed algorithm provides reliable results, reaching an overall classification accuracy rating of 84.3%. This is a highly motivating preliminary result that proves the feasibility of the new method and supports the investment in further research and development to translate this study into clinical practice. Furthermore, to our best knowledge, this is the first time image processing is used to automatically classify laryngeal tumors in endoscopic videos based on tumor vascularization characteristics. Therefore, the introduced system represents an innovation in biomedical and health informatics. PMID- 25438331 TI - Component-Level Tuning of Kinematic Features From Composite Therapist Impressions of Movement Quality. AB - In this paper, we propose a general framework for tuning component-level kinematic features using therapists' overall impressions of movement quality, in the context of a home-based adaptive mixed reality rehabilitation (HAMRR) system. We propose a linear combination of nonlinear kinematic features to model wrist movement, and propose an approach to learn feature thresholds and weights using high-level labels of overall movement quality provided by a therapist. The kinematic features are chosen such that they correlate with the quality of wrist movements to clinical assessment scores. Further, the proposed features are designed to be reliably extracted from an inexpensive and portable motion capture system using a single reflective marker on the wrist. Using a dataset collected from ten stroke survivors, we demonstrate that the framework can be reliably used for movement quality assessment in HAMRR systems. The system is currently being deployed for large-scale evaluations, and will represent an increasingly important application area of motion capture and activity analysis. PMID- 25438332 TI - Content-Based Image Retrieval by Metric Learning From Radiology Reports: Application to Interstitial Lung Diseases. AB - Content-based image retrieval (CBIR) is a search technology that could aid medical diagnosis by retrieving and presenting earlier reported cases that are related to the one being diagnosed. To retrieve relevant cases, CBIR systems depend on supervised learning to map low-level image contents to high-level diagnostic concepts. However, the annotation by medical doctors for training and evaluation purposes is a difficult and time-consuming task, which restricts the supervised learning phase to specific CBIR problems of well-defined clinical applications. This paper proposes a new technique that automatically learns the similarity between the several exams from textual distances extracted from radiology reports, thereby successfully reducing the number of annotations needed. Our method first infers the relation between patients by using information retrieval techniques to determine the textual distances between patient radiology reports. These distances are subsequently used to supervise a metric learning algorithm, that transforms the image space accordingly to textual distances. CBIR systems with different image descriptions and different levels of medical annotations were evaluated, with and without supervision from textual distances, using a database of computer tomography scans of patients with interstitial lung diseases. The proposed method consistently improves CBIR mean average precision, with improvements that can reach 38%, and more marked gains for small annotation sets. Given the overall availability of radiology reports in picture archiving and communication systems, the proposed approach can be broadly applied to CBIR systems in different medical problems, and may facilitate the introduction of CBIR in clinical practice. PMID- 25438333 TI - Evolving Transport Networks With Cellular Automata Models Inspired by Slime Mould. AB - Man-made transport networks and their design are closely related to the shortest path problem and considered amongst the most debated problems of computational intelligence. Apart from using conventional or bio-inspired computer algorithms, many researchers tried to solve this kind of problem using biological computing substrates, gas-discharge solvers, prototypes of a mobile droplet, and hot ice computers. In this aspect, another example of biological computer is the plasmodium of acellular slime mould Physarum polycephalum (P. polycephalum), which is a large single cell visible by an unaided eye and has been proven as a reliable living substrate for implementing biological computing devices for computational geometry, graph-theoretical problems, and optimization and imitation of transport networks. Although P. polycephalum is easy to experiment with, computing devices built with the living slime mould are extremely slow; it takes slime mould days to execute a computation. Consequently, mapping key computing mechanisms of the slime mould onto silicon would allow us to produce efficient bio-inspired computing devices to tackle with hard to solve computational intelligence problems like the aforementioned. Toward this direction, a cellular automaton (CA)-based, Physarum-inspired, network designing model is proposed. This novel CA-based model is inspired by the propagating strategy, the formation of tubular networks, and the computing abilities of the plasmodium of P. polycephalum. The results delivered by the CA model demonstrate a good match with several previously published results of experimental laboratory studies on imitation of man-made transport networks with P. polycephalum. Consequently, the proposed CA model can be used as a virtual, easy-to-access, and biomimicking laboratory emulator that will economize large time periods needed for biological experiments while producing networks almost identical to the tubular networks of the real-slime mould. PMID- 25438334 TI - When Reputation Enforces Evolutionary Cooperation in Unreliable MANETs. AB - In self-organized mobile ad hoc networks (MANETs), network functions rely on cooperation of self-interested nodes, where a challenge is to enforce their mutual cooperation. In this paper, we study cooperative packet forwarding in a one-hop unreliable channel which results from loss of packets and noisy observation of transmissions. We propose an indirect reciprocity framework based on evolutionary game theory, and enforce cooperation of packet forwarding strategies in both structured and unstructured MANETs. Furthermore, we analyze the evolutionary dynamics of cooperative strategies and derive the threshold of benefit-to-cost ratio to guarantee the convergence of cooperation. The numerical simulations verify that the proposed evolutionary game theoretic solution enforces cooperation when the benefit-to-cost ratio of the altruistic exceeds the critical condition. In addition, the network throughput performance of our proposed strategy in structured MANETs is measured, which is in close agreement with that of the full cooperative strategy. PMID- 25438335 TI - Composite Adaptive Fuzzy Output Feedback Control Design for Uncertain Nonlinear Strict-Feedback Systems With Input Saturation. AB - In this paper, a composite adaptive fuzzy output-feedback control approach is proposed for a class of single-input and single-output strict-feedback nonlinear systems with unmeasured states and input saturation. Fuzzy logic systems are utilized to approximate the unknown nonlinear functions, and a fuzzy state observer is designed to estimate the unmeasured states. By utilizing the designed fuzzy state observer, a serial-parallel estimation model is established. Based on adaptive backstepping dynamic surface control technique and utilizing the prediction error between the system states observer model and the serial-parallel estimation model, a new fuzzy controller with the composite parameters adaptive laws are developed. It is proved that all the signals of the closed-loop system are bounded and the system output can follow the given bounded reference signal. A numerical example and simulation comparisons with previous control methods are provided to show the effectiveness of the proposed approach. PMID- 25438340 TI - Arising from the ashes? Environmental health in Detroit. PMID- 25438342 TI - On challenges to the prosthodontics stewardship of the edentulous patient. PMID- 25438343 TI - Exempting mental health peer support services from copayments. Direct final rule. AB - The Department of Veterans Affairs (VA) is taking final action to amend its regulation that sets forth the VA services that are not subject to copayment requirements for inpatient hospital care or outpatient medical care. Specifically, the regulation is amended to exempt mental health peer support services from having any required copayment. This removes a barrier that may have previously discouraged veterans from choosing to use mental health peer support services as a viable care option. VA believes that mental health peer support services are a valuable resource for veterans with mental health conditions and wants to ensure that veterans take full advantage of all resources available to them. PMID- 25438341 TI - Chronic blockade of endothelin A and B receptors using macitentan in experimental renovascular disease. AB - BACKGROUND: Emerging research has identified the endothelin (ET)-1 pathway as a potential target for novel renoprotective therapies. We recently showed that selective ET-A receptor antagonism in chronic renovascular disease (RVD) improves renal function and reduces renal injury. Although ET-A and -B have opposing roles, in some clinical situations they may induce similar effects. Thus, we hypothesized that simultaneous blockade of the ET-A and -B receptors would protect the kidney during RVD. METHODS: Unilateral RVD was induced in pigs. After 6 weeks, single-kidney function was quantified in vivo using multi-detector computer tomography. Pigs were subsequently divided into untreated (RVD, n = 7) or daily-treated with the dual ET-A/B receptor antagonist macitentan (RVD + macitentan, n = 6) for 4 weeks. At 10 weeks, in vivo studies were repeated, then pigs were euthanized and ex vivo studies performed in the stenotic kidney to quantify inflammation, fibrosis, microvascular density and remodeling. RESULTS: Four weeks of macitentan therapy modestly improved renal blood flow (29%, P = 0.06 versus pre-treatment) and showed protective effects on the renal parenchyma by attenuating inflammation and glomerulosclerosis, reducing apoptosis and tubular casts and improving albuminuria and cortical microvessel density. No overt adverse effects were observed. CONCLUSION: Possibly by inducing a pro survival renal microenvironment, macitentan increased renal microvascular density, promoted cell survival and decreased injury, which in turn improved stenotic kidney hemodynamics in our model. Our results further support the safety of using macitentan in patients with concomitant chronic renal disease and supported the feasibility of a new strategy that may preserve the stenotic kidney in RVD. PMID- 25438344 TI - Food labeling; nutrition labeling of standard menu items in restaurants and similar retail food establishments. Final rule. AB - To implement the nutrition labeling provisions of the Patient Protection and Affordable Care Act of 2010 (Affordable Care Act or ACA), the Food and Drug Administration (FDA or we) is requiring disclosure of certain nutrition information for standard menu items in certain restaurants and retail food establishments. The ACA, in part, amended the Federal Food, Drug, and Cosmetic Act (the FD&C Act), among other things, to require restaurants and similar retail food establishments that are part of a chain with 20 or more locations doing business under the same name and offering for sale substantially the same menu items to provide calorie and other nutrition information for standard menu items, including food on display and self-service food. Under provisions of the ACA, restaurants and similar retail food establishments not otherwise covered by the law may elect to become subject to these Federal requirements by registering every other year with FDA. Providing accurate, clear, and consistent nutrition information, including the calorie content of foods, in restaurants and similar retail food establishments will make such nutrition information available to consumers in a direct and accessible manner to enable consumers to make informed and healthful dietary choices. PMID- 25438345 TI - Food labeling; calorie labeling of articles of food in vending machines. Final rule. AB - To implement the vending machine food labeling provisions of the Patient Protection and Affordable Care Act of 2010 (ACA), the Food and Drug Administration (FDA or we) is establishing requirements for providing calorie declarations for food sold from certain vending machines. This final rule will ensure that calorie information is available for certain food sold from a vending machine that does not permit a prospective purchaser to examine the Nutrition Facts Panel before purchasing the article, or does not otherwise provide visible nutrition information at the point of purchase. The declaration of accurate and clear calorie information for food sold from vending machines will make calorie information available to consumers in a direct and accessible manner to enable consumers to make informed and healthful dietary choices. This final rule applies to certain food from vending machines operated by a person engaged in the business of owning or operating 20 or more vending machines. Vending machine operators not subject to the rules may elect to be subject to the Federal requirements by registering with FDA. PMID- 25438346 TI - R A C Chate responds. PMID- 25438347 TI - Reply from author. PMID- 25438348 TI - Movement disorders. PMID- 25438349 TI - In the age of ACOs, the systems of measuring health-care quality remain in their infancy. PMID- 25438350 TI - Planning the path to retirement. PMID- 25438351 TI - Near-death experience. Evidence for their reality. PMID- 25438352 TI - Getting comfortable with death. When the beginning the end are close. PMID- 25438353 TI - Getting comfortable with death. Our answer to Belgium: palliative care for children is preferable to euthanasia. PMID- 25438354 TI - The role of Eugenics in research misconduct. PMID- 25438355 TI - Eureka moment. PMID- 25438356 TI - MSMA applauds elimination of sales of tobacco in pharmacies. PMID- 25438357 TI - The changing nature of Academic Health Sciences Libraries. PMID- 25438358 TI - In memoriam - Bernard Becker (1920-2013). PMID- 25438359 TI - Measuring academic productivity and changing definitions of scientific impact. AB - This manuscript provides a brief overview of the history of communication of scientific research and reporting of scientific research impact outcomes. Current day practices are outlined along with examples of how organizations and libraries are providing tools to evaluate and document the impact of scientific research to provide a meaningful narrative suitable for a variety of purposes and audiences. PMID- 25438360 TI - Libraries and open access support: new roles in the digital publishing era. PMID- 25438361 TI - Libraries and genomics: providing support to health care providers and consumers. PMID- 25438362 TI - Evidence-based medicine: medical librarians providing evidence at the point of care. AB - Evidence-based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. .. by best available external clinical evidence we mean clinically relevant research.' Health care reform authorized by the Affordable Care Act is based on the belief that evidence-based practice (EBP) generates cost savings due to the delivery of more effective care.2 Medical librarians, skilled in identifying appropriate resources and working with multiple complex interfaces, can support clinicians' efforts to practice evidence based medicine by providing time and expertise in articulating the clinical question and identifying the best evidence. PMID- 25438363 TI - Evidence-based medicine and systematic review services at Becker Medical Library. PMID- 25438364 TI - The William Beaumont papers: a life in letters. AB - The Becker Medical Library holds the correspondence, notebooks and casebooks of William Beaumont, the physician known for his landmark publication on human digestion. Beaumont came to St. Louis, Missouri in 1835. He took part in the creation of the first medical professional society and the first medical school west of the Mississippi. His collection sheds light not only on his research and career, but also on the medical profession in the burgeoning American West. PMID- 25438365 TI - More than just medicine: hidden depths in the Becker Library's rare book collections. PMID- 25438366 TI - Epigenetics: modifying the genetic blueprint. AB - The sequence of the human genome represents our genetic blueprint. While it is now possible to draw direct connections between specific DNA sequences and specific physical features and to predict disease risk, the effects of certain genes can be masked by a process called "epigenetics." Here, I summarize our current understanding of epigenetics and it affects gene expression, with impacts on health and aging. PMID- 25438367 TI - Fertility preservation in patients receiving chemotherapy or radiotherapy. AB - The preservation and restoration of fertility are key aspects for enhancing quality of life in cancer survivors. Cytotoxic agents and radiation can produce gonadal dysfunction in both men and women. Survival rates for cancers that occur before or during reproductive age have improved dramatically. Current fertility preservation options are available but limited in males and females. Referral to a reproductive endocrinologist around the time of diagnosis is important to optimize treatment options. PMID- 25438368 TI - Controversies surrounding screening mammography. AB - Screening for breast cancer with mammography has been shown in multiple randomized control trials to decrease breast cancer mortality. Despite this, there are ongoing controversies regarding the benefits and risks of mammographic screening. Different professional groups have published conflicting guidelines regarding when to start screening, how often to screen, and when to stop screening which have added to the confusion. In this article we describe the evidence supporting and challenging the efficacy of mammography and review our real world approach to breast cancer screening. PMID- 25438369 TI - Hypothyroid cardiomyopathy complicated by a left ventricular laminar thrombus. AB - Clinical hypothyroidism is the most common hormone deficiency in the United States and is found in 0.3% of the U.S. population. It is associated with characteristic symptoms that can be readily identified by a careful history and physical examination. Hypothyroidism affects many bodily systems; in particular the cardiovascular system is impacted via multiple mechanisms.3 Occasionally hypothyroidism leads to transient left ventricular systolic dysfunction, termed hypothyroid cardiomyopathy. A rare sequela of this condition is a left ventricular thrombus, which has been described in two case reports thus far. Here we report a third case of reversible hypothyroid cardiomyopathy complicated by a left ventricular laminar thrombus. PMID- 25438370 TI - Clues from hands/Part 2. Personal details about patients revealed by hand examination. AB - This is the second part of a two-part article on personal details revealed by hand examination. Examining hands to determine daily activities was the focus of Part 1 in the July/August 2014 Missouri Medicine. Personal traits and preferences, including pets, nutrition and psychology are presented here. These articles serve as a guide for visual clues on the hands to discern a patient's daily activities and personal preference, thereby providing social information that may help establish rapport between patient and physician and may have medical significance. PMID- 25438371 TI - [Virtue has a price...]. PMID- 25438372 TI - [Antiplatelet agents in secondary prevention of stroke]. AB - Stroke is responsible for high morbidity and mortality. Antiplatelet agents are the cornerstone for secondary prevention of stroke and prescription of aspirin, clopidogrel or aspirin and dipyridamole are recommended based on strong evidence. Whether combining two antiplatelet agents would be more effective is still debated. Studies conducted in the early phase of stroke (from 24 hours to 3 months) show the superiority of dual antiplatelet the- rapy compared to aspirin alone. In contrast, long-term dual antiplatelet therapy is associated with an increased risk of intracranial hemorrhage and therefore deleterious. This article reviews current evidence and outlines future perspectives. PMID- 25438373 TI - [Age-adjusted D-dimers and pulmonary embolism]. AB - Plasma D-dimer measurement is the first diagnostic test performed in patients with a non-high or an unlikely clinical probability of pulmonary embolism (PE) but its clinical usefulness is limited in elderly patients due to a low specificity in this subgroup. PE can be excluded based on D-dimers and clinical probability only in about 5% of patients over 80 years when using the conventional cut-off. Age-adjusted D-dimer cut-off (adjusted cut-off value = age x 10 in patients over 50) increases the specificity of the test without significantly reducing its sensitivity. Using the age-adjusted D-dimer cut-off markedly reduces the need for further diagnostic studies such as computed tomography pulmonary angiography (CTPA). The age-adjusted cut-off has been widely validated in retrospective cohorts, and more recently in a prospective management study. PMID- 25438374 TI - [Atrial fibrillation and obstructive sleep apnea: a fortuitous association?]. AB - Atrial fibrillation (AF) is a frequent arrhythmia and is associated with important morbidity and mortality. It is particularly frequent in patients with obstructive sleep apnea (OSA), occurring in 3 to 5% of these patients. Numerous studies show an association of these two pathologies, independently of classical cardiovascular risk factors and otherconfounders. A pathophysiological link between repeated apnea and cardiac modifications, inflammation and autonomic nervous system disequilibrium has also been demonstrated. The severity of OSA influences development of AF, and appears to make management more complicated. Success of catheter ablation of AF appears to be inferior in patients with OSA. Whilst more robust studies are required to better define the role of OSA in AF, the existing literature establishes a link between these two entities. PMID- 25438375 TI - [Enterococcal infections: from simple to most complex]. AB - Enterococci are microorganisms with a remar- kable ability to adapt to their environment. Two species have a significant clinical implication, Enterococcus faecalis and Enterococcus faecium. The risk factors for colonization and infection must be recognized, including prior treatment with antibiotics such as cephalosporins or quinolones. Because of their native resistance to several classes of antibiotics and the increase of acquired resistance to penicillins, the initial empiric treatment of a severe infection in a patient at risk of enterococcal infection often includes a glycopeptide. A restriction in the empirical use of cephalosporins or quinolones and a targeted antibiotic therapy following receipt of the antibiogram are essential to prevent the emergence of enterococcal strains and especially vancomycin-resistant enterococci. PMID- 25438376 TI - [Subcutaneous antibiotic administration in elderly patients]. AB - Although off-label, subcutaneous (SC) antibiotic administration is not infrequent, particularly among geriatric and palliative-care patients for whom other routes of administration are difficult to establish. Subcutaneous ceftriaxone is the most frequently prescribed antibiotic and it has been approved by some local committees given its favorable pharmacological parameters and relatively low subcutaneous toxicity. Yet pharmacologic and clinical data are lacking. No study has demonstrated non-inferiority of the subcutaneous route in comparison to other parenteral routes of administration. Randomized controlled trials are needed to assess the efficacy and tolerability of subcutaneous antibiotic administration given its frequent use in an aging population. PMID- 25438377 TI - [The risk of bisphosphonate-related osteonecrosis of the jaw]. AB - Bisphosphonates are widely used in the treatment of osteonecrosis and oncology related bone complications. Their use is highly beneficial for the patient, but may be associated with adverse effects. Osteonecrosis of the jaw is an often cited complication of this treatment, but is in practice rarely seen. Its prevalence is low in cases of osteoporosis but a little higher in the oncological setting. Although its pathophysiology is not completely eluci-dated, certain risk factors have been identified such as tooth extraction which often precedes the affection. Management requires a multidisciplinary approach and a conservative treatment is usually preferred. Dealing with this rare condition requires identification of at risk patients so as to apply preventative measures. PMID- 25438378 TI - [Fritz Zorn Syndrome and psycho-neuro-immunology abuse ]. PMID- 25438379 TI - [AIDS: how could HIV-1 spread in silence for over half a century?]. PMID- 25438380 TI - [Mademoiselle K]. PMID- 25438381 TI - [Clinical diagnostic techniques do not suffice for lower urinary tract obstruction]. PMID- 25438382 TI - [Surrogate gestation, the new form of slavery, is also a french passion]. PMID- 25438383 TI - [Alcohol consumption effect on gout risk]. PMID- 25438384 TI - [Two women anesthesiologists, two tragic stories]. PMID- 25438385 TI - [SanteSuisse asks regional government for help with ambulatory care costs]. PMID- 25438386 TI - [Alain Berset wants to permit regional governments to guide physicians to set themselves up]. PMID- 25438387 TI - [Medicine and Society]. PMID- 25438388 TI - Outcome of antiretroviral treatment in patients with AIDS monoinfection and those co-infected with hepatitis B and C viruses and tuberculosis in Ukraine. AB - Antiretroviral therapy reduces AIDS morbidity and mortality as well as decreases HIV transmission by reducing the viral load (VL). We aimed to determine the rate of immunological and virological failure that reflects antiretroviral treatment (ART) effectiveness among the patients of the Kyiv City AIDS Centre and may lead to ART switch in the future. In 59% of patients the prescribed ATR regimen was regarded as successful, in 37% as unsuccessful and 4% of patients were excluded for lacking sufficient follow-up time. Among the cases of unsuccessful ART, the largest part of patients was experiencing secondary immunological failure, on the second place was primary immunological failure. The temporal distribution of primary and secondary failures was also defined. It was shown that the number of patients with treatment failure increases steadily Drug resistance testing is able to reduce the number of unsuccessful ART regimens, but such testing is not a part of the routine testing in Ukraine. PMID- 25438389 TI - Monitoring of congenital anomalies in Latvia. AB - OBJECTIVE: This study provides a description and analysis of characteristics of the monitoring system for congenital anomalies at birth and prevalence trends in Latvia using retrospective analysis of congenital anomalies at birth with cross sectional data on prevalence (national data from Latvia, 2000-2010). METHODS: There are three main monitoring systems on congenital anomalies among newborns and infants: the Medical Birth Register with data on live births with one or more congenital anomalies at birth, the Register on Congenital Anomalies with genetically approved cases for live births and the National Causes of Death Register with data on stillbirths. Methodological problems were analysed by calculating different prevalence rates. The main outcome measures are as follows: prevalence rate, live birth prevalence rate, major congenital anomalies live birth prevalence rate, and stillbirth rate. RESULTS: The live birth period prevalence was 319.7/10,000 live births, and the majoir congenital anomalies live birth prevalence was 211.4/10,000. The period total prevalence rate of births was.323.7/10,000 live births and stillbirths. The stillbirth rate due to congenital anomalies was 6.1/10,000 live and stillbirths. The live birth prevalence with congenital anomalies decreased slightly from the year 2000 tothe year 2010. CONCLUSIONS: The present system of congenital anomaly registration requires improvements for better completeness. Latvia should use the experience.of Nordic countries and introduce a mother's and children's identification number to the Medical Birth Register. It would be helpful to link the information from hospitals and perinatal centres together to validate the congenital anomaly diagnoses of newborns after their discharge from the maternity unit. The monitoring system should also include information on pregnancies with congenital anomalies which do not end in birth, especially terminations of pregnancy. PMID- 25438390 TI - Maternal smoking during pregnancy and birth outcomes in a sample of Romanian women. AB - Smoking during pregnancy is causally associated with reduced birth weight and is strongly related to preterm birth. Smoking cessation in early pregnancy seems to reduce these risks, although the research evidence is limited. In a sample of Romanian women, differences in birth outcomes were assessed between non-smokers and women who continued to smoke during pregnancy and non-smokers and women who stopped smok- ing when they found out about the pregnancy. Pregnant women were recruited in two urban clinics (N= 474). A baseline questionnaire collected information on their smoking status, depressive symptoms, stress, demographics, and other characteristics at recruitment. The women reported the newborn weight and birth term by phone in the first weeks following birth. Descriptive statistics and multivariate regressions were used to ana- lyze the relationship between smoking status during pregnancy and birth outcomes. Over 61% (N = 290) women were non-smokers, 15% (N= 72) smoked during pregnancy, and 24% (N= 112) quit smoking when they found out about the pregnancy. Compared to non-smokers, continuous smokers delivered babies 165 grams lighter (95% CI -313, -17). Women who stopped smoking when they ascertained the pregnancy had higher odds of delivering a newborn who was small for gestational age compared to non-smokers (OR= 2.16, 95% CI 1.05, 4.43). Elevated maternal stress was associated with reduced birth weight (-113 grams, 95% CI -213, -11), and higher odds of a preterm birth (OR=2.8, 95% CI 1.17, 6.76). In a predominantly urban sample of Romanian women, continuous maternal smoking during pregnancy was a risk factor for restricted foetal growth. Smoking cessation when the pregnancy was ascertained did not seem to reduce this risk. Smoking prevention efforts should therefore begin before pregnancy and should integrate psychological components, addressing maternal stress in particular. PMID- 25438391 TI - WHO targets elimination of TB in over 30 countries. PMID- 25438392 TI - Combined effect of selected mineral fibres and tobacco smoke on respiratory tract in rats. AB - The rats were inhaling amosite and wollastonite fibres at two concentrations (30 and 60 mg/m3) one hour every second day and cigarette smoke of 3 cigarettes per day (with the exception of Saturdays and Sundays). They were sacrificed after 6 month of exposure. Bronchoalveolar lavage (BAL) was performed and selected inflammatory and cytotoxic parameters were examined. Amosite: inflammatory parameters were the most changed after 60 mg/m3 in both groups with or without smoking; the cytotoxic parameters were strongly influenced by smoking. Wollastonite (asbestos substitute) inhalation confirmed lower inflammatory and cytotoxic effects on all examined animal groups in comparison with amosite. PMID- 25438393 TI - Factors affecting the success of influenza laboratory diagnosis. AB - Influenza is one of the most common human infectious diseases, and has profound health and economic consequences. The laboratory diag- nosis of influenza virus infections plays an important role in the global surveillance of influenza. Therefore, there is a growing demand for highly sensitive and rapid methods for detecting influenza. The performance of particular diagnostic methods is affected by various factors. In this study, we assess the effects of patients' age and time to diagnosis on the probability of detecting influenza using four diagnostic methods (virus isolation, rapid test, RT-PCR and real-time RT-PCR). We examined 3,546 samples from central and eastern Slovakia during the influenza seasons from 2005-2006 to 2010-2011. In general, the probability of influenza detection significantly decreased with the time from onset of illness to sample collection (T1) as well as with patients' age (AGE). On the contrary, time from sample collection to delivery (T2) did not play a role in the prob- ability of influenza detection. As judged by odds ratios, the virus isolation method was most sensitive to T1, followed by the rapid test and RT-PCR methods. For the effect of AGE, the rapid test and virus isolation methods were more sensitive than PCR based methods. The effects of T1 and AGE were independent of each other. Laboratories which participate in inifluenza surveillance should use several methods to enable rapid and accurate influenza A and B virus detection. PMID- 25438394 TI - Fighting obesity campaign in Turkey: evaluation of media campaign efficacy. AB - AIM: This study aims to determine the frequency of behaviour change and related factors generated in the population through the "Fighting Obesity Campaign" of the Turkish Ministry of Health. METHODS: Twelve statistical regions from NUTS-1 and 18 provinces were selected for the study sample. At least one province from each region was randomly selected, and stratawere defined as urban or rural. Of the sample selected, 2,038 respondents completed a face-to-face survey. Logistic regression analysis was used to analyse the data. Changing behaviour as result of the campaign was defined as the dependent variable. Behaviour change was defined as an individual taking at least one action to increase physical activity, calculate her/his Body Mass Index (BMI) or minimise meal portions. RESULTS: Of the sample selected, 84% of participants lived in urban areas. Of total sample selected, 49.8% were men and 50.2% were women. According to BMI categorisation, 41.4% of participants were underweight or normal weight, 34.3% were overweight and 24.3% were obese. Of the total participants, 85.2% learned about the "Fighting-Obesity Campaign" through television, 28.1% through radio, 11.0% from newspapers, 6.0% from billboards, and 19.2% from other sources. This study revealed that 28.5% of the participants adopted desired behavioural changes after exposure to the campaign. Logistic regression results demonstrated that behaviour change is greater among women, individuals living in urban settings, group of persons approving public spots, obese individuals, and among the 20-39 age group. CONCLUSION: Media campaigns may cause behavioural changes by increasing motivation to prevent obesity within the target population. Con- tinuing these campaigns can lead to success at the national level. PMID- 25438395 TI - Secondary prevention of acute coronary syndrome. Socio-economic and lifestyle determinants: a literature review. AB - Although cardiovascular disease mortality rates seem to decline, especially among middle-aged people in developed countries, the prevalence of acute coronary syndrome (ACS) increases, representing the most common cause of morbidity in both developed and developing countries and generating large economic burden. It is estimated that one fifth of the ACS patients die suddenly and half of them belong to a fast growing popula- tion age-group, i.e., those between 70 and .80 years. A substantial number of these deaths has been attributed to various lifestyles, modifiable factors; therefore, it can be prevented. However, factors such as dietary habits and behaviours, physical activity, life stress and smoking habits, although thoroughly discussed, are not well understood and appreciated in the spectrum of secondary ACS prevention. The latter deserves further attention under the prism of socio-economic status that has changed dramatically in the last years in some populations. The aim of this review was to discuss the role of lifestyle factors on secondary ACS prevention under the prism of individual's socio-economic status. Based on the retrieved information it was revealed that there is vast evidence that secondary prevention of cardiovascular events cannot be accomplished simply through medical treatment, but it requires a multifaceted approach incorporating lifestyle modifications, too. Therefore, public health policy endeavours should be directed towards multifocal strategies, i.e., to motivate and support cardiac patients to consistently follow treatment regimens and to establish more effective and efficient community lifestyle interventions. PMID- 25438396 TI - Medical doctors in Hungary: 30 years after graduation. Data on lifestyle, morbidity, demography and differences between specialties. AB - There are few studies from East and Central European countries on health-status, lifestyle and social circumstances of medical professionals. We evaluated data of a cohort of physicians who had graduated 30 years ago in Hungary and compared the data of their professional carrier, life style, health outcomes, and medical specialties. Questionnaires compiled by an expert group and filled in by 208 physicians (83 men and 125 women) were analysed. Men mostly work as surgeons, women were mostly employed as primary care specialists. Women changed their specialty and/or place of work more often than men. Male primary care physicians had more children than women and others specialists. At graduation, most of them had a normal BMI. Since then, a significant increase in weight and BMI was observed in both genders and across all specialty groups. The largest increase in body weight and BMI (mean 5.27) was recorded among female primary care physicians. Recorded physical activity was low in general, with male primary care specialists being most active and female primary care physicians the least. Female doctors in surgical specialties had longer resting time. Male physicians rarely participated in regular health screenings. The incidence of hypertension was higher than the Hungarian national average for that age. About 5% of primary care physicians identified themselves as regular smokers. Abstinence and regular daily alcohol consumption were reported in equal ratio. Burn-out symptoms were rarely experienced. This generation had started its medical profession before the significant progressive changes in the medicine occurred in the last decades. While physicians do not always follow their own professional advices, their lifestyle proved a little bit healthier than that of the population at large, especially for women and their health outcomes, except hypertension, were also better. In general, they were not satisfied with the financial and working conditions of the recent Hungarian healthcare system. PMID- 25438397 TI - Prevalence of unintentional injuries and related risk factors among university students in Canakkale city, western Turkey. AB - OBJECTIVE: We examined the prevalence of unintentional injuries and associated risk factors among university students in Canakkale city, Turkey. METHODS: A cross-sectional study was conducted in 2007-2008. Atotal of 4,762 students completed the questionnaire. Risk factors associated with the rate of accidents were assessed by chi-square analysis and effects of these factors on unintentional injuries were described by logistic regression analysis. RESULTS: The rate of unintentional injuries among university students was 14.9% during the previous 12 months. The most reported injuries occurred on the road (43.8%), at home (33.2%) and outside the home (26.9%) such as workplaces, schools or sports venues. The prevalence of unintentional injuries was significantly higher in males than females (18.1% vs. 12.0% p <0.05). Results of the logistic regression analysis indicated that male gender (OR 1.51), studying in college and vocational school (OR 1.34), perception of very bad (OR 0.49) or good economic status (OR 0.49), drinking alcohol (OR 1.52), using illicit substances (OR 1.70), having a diagnosed illness (OR 1.36), or having risk of developing depres- sion (OR 1.54) had significant effects on the risk of unintentional injuries (p <0.05). CONCLUSIONS: This study indicated that male gender, studying in college and vocational schools, illicit substance use, poor economic conditions, having a diagnosed illness and risk of developing depression can be risk factors for unintentional injuries among university students. Public health training programmes giving priorityto high-risk groups such as university and high school students may be a valuable tool in reducing unintentional injuries among young people. PMID- 25438398 TI - Member states commit to reduce preventable deaths from heart disease and stroke, cancer, diabetes and lung disease. PMID- 25438399 TI - Epidemiological data and cancer risk assessment: cessation LAG and lingering effect concepts. AB - Cessation lag and lingering effect are two important aspects of risk assessment, and have potential applications to dose-response analysis in risk assessment. In addition to providing insight into biological mode of action, the concept of cessation lag is useful for economic benefit analy- sis. Concept of effect lingering can be used to analyze epidemiological data by uncovering the hidden biological implications related to disease endpoints, thereby advancing current efforts to characterize and reduce risk assessment uncertainties. Multicentre study design is proposed as a way to increase study size and to mitigate criticism of meta-analysis of independent studies. Individual studies from a multicentre study can be either pooled using original data, or combined by meta analysis of summarized results. A multicentre study of large cohort or case control study also offers an exciting opportunity to study the contribution of epigenetic events that may be associated with life-style and environmental risk factors for human health. Methods for optimizing exposure assessment and reducing exposure misclassification represent important but difficult components in epidemiological studies. Biomarkers present a potentially useful approach for improving exposure estimates. PMID- 25438400 TI - Empirical evidence of the efficiency and efficacy of fat taxes and thin subsidies. AB - This study summarizes the empirical literature on fat taxes and thin subsidies to assess their efficiency and efficacy as instruments of public policy to control obesity. Three specific types of taxes are studied in the literature: food group taxes; nutrient taxes; and nutrient index taxes. Anumber of studies use food expenditure data to assess the impact of various taxes on obesity and therefore only indirectly measure the impacts of taxes and subsidies on obesity. These studies generally conclude that food group taxes, nutrient taxes and nutrient index taxes have a small impact on the purchases of food and the nutrients purchased. Other studies use the body mass index as the explanatory variable and thus measure the impacts of taxes on body mass index directly. Nutrient taxes are found to be more effective than food group taxes, although even for nutrient taxes, the effects are small. In general, thin subsidies seem to offer more effective control of obesity than obesity taxes. However, due to the small effects of both fat taxes and thin subsidies, they are not recommended as instruments of food and nutrition policy. PMID- 25438401 TI - World heart day 2014: salt reduction saves lives. PMID- 25438402 TI - Ebola hemorrhagic fever: case fatality rate 90%? PMID- 25438403 TI - [Proud of being different]. PMID- 25438404 TI - [The vulnerable health of transgender persons]. PMID- 25438405 TI - ["Transgender persons experience voyeuristic curiosity"]. PMID- 25438406 TI - [Feeling the pulse of our readers]. PMID- 25438407 TI - [Inquiring and initiating a dialog]. PMID- 25438408 TI - [Competently educated into nursing practice]. PMID- 25438409 TI - ["The personnel which could still immigrate would not be sufficient"]. PMID- 25438410 TI - [Intensive care journal improves quality of life]. PMID- 25438411 TI - [The show begins]. PMID- 25438412 TI - [My gender, my body, my choice]. PMID- 25438413 TI - [A professional attitude conveying benevolence]. PMID- 25438414 TI - [I want an accepting society]. PMID- 25438415 TI - [Discovering the inner dialog]. PMID- 25438416 TI - [Ask questions and encourage dialog]. PMID- 25438417 TI - [Whole individuals to the last day]. PMID- 25438418 TI - [Ultra high frequencies under scrutiny]. PMID- 25438419 TI - [The transgender topic]. PMID- 25438421 TI - [The nurses of Lanaudiere have realized their dream]. PMID- 25438420 TI - [Recipient of the Distinguished Merit Award for 2014, Francine de Montigny]. PMID- 25438423 TI - [Containing the Ebola virus. An unprecedented urgency]. PMID- 25438422 TI - [Hyperbaric medicine. The first certified nurses in Quebec]. PMID- 25438424 TI - [Bell Palsy]. PMID- 25438426 TI - [Nursing care of sex workers]. PMID- 25438425 TI - [Drug addiction, mental disorders and sexually transmitted diseases]. PMID- 25438427 TI - [A cooperative program for nursing students]. PMID- 25438428 TI - [Depression, anxiety and suffering at the end of life. Forgotten realities]. PMID- 25438429 TI - [Clinical informatics and nursing. A missed meeting?]. PMID- 25438430 TI - [Soldier distress. Nurses work with solders suffering from work-related stress]. PMID- 25438431 TI - [Skin tears. Risk evaluation and treatment]. PMID- 25438432 TI - [Alzheimer's disease and the grieving caregiver. Alzheimer's from the point of view of the caregiver]. PMID- 25438433 TI - [Lyme disease]. PMID- 25438434 TI - [Prostate cancer. Advantages of active surveillance]. PMID- 25438435 TI - [The insulin pump is more effective in children with type I diabetes]. PMID- 25438436 TI - [Use of labor induction reduces the risk of cesarean section]. PMID- 25438437 TI - [Leaving against medical advice is risky!]. PMID- 25438438 TI - [Urgent cardiac care. Men received faster care]. PMID- 25438439 TI - [Sleeping medication and elderly women. Better information for better utilization]. PMID- 25438440 TI - [Generic oxycodone. A threat to the US]. PMID- 25438441 TI - Autoinflammation and autoimmunity: pathogenic, clinical, diagnostic and therapeutic aspects. PMID- 25438442 TI - Long-term efficacy of adalimumab in hyperimmunoglobulin D and periodic fever syndrome. PMID- 25438443 TI - The body against self: autoinflammation and autoimmunity. PMID- 25438444 TI - Enhanced myelination in autoimmunity and in normal development induced by glatiramer acetate. PMID- 25438445 TI - Pregnancy in antiphospholipid syndrome: can we improve patient management? PMID- 25438446 TI - Anti-saccharomyces cerevisiae autoantibodies and autoimmune diseases: the sweet and sour of baking yeast. PMID- 25438447 TI - Obesity: an additional piece in the mosaic of autoimmunity. PMID- 25438448 TI - Hereditary angioedema and autoimmunity. PMID- 25438449 TI - Old obstacles but new hopes: trying to understand the fibromyalgia construct. PMID- 25438450 TI - Treating inflammatory bowel disease: from helminths to ova. PMID- 25438451 TI - New potential biomarkers for disease activity and fibrosis in systemic sclerosis. PMID- 25438452 TI - The many faces of B regulatory cells. PMID- 25438453 TI - Mortality due to sepsis in patients with systemic lupus erythematosus and rheumatoid arthritis. PMID- 25438454 TI - Narcolepsy--genes, infections and vaccines: the clues for a new autoimmune disease. PMID- 25438455 TI - Arresting beta-cell destruction in type 1 diabetes mellitus: mobilizing homuncultar autoimmunity to treat autoimmune disease. PMID- 25438456 TI - Harmonization of autoimmune diagnostics with antinuclear antibody testing algorithm: approach of appropriateness and clinical relevance. PMID- 25438457 TI - New biological treatments for psoriatic arthritis. PMID- 25438458 TI - Subcutaneous immunoglobulin G in idiopathic inflammatory myopathies: therapeutic implications. PMID- 25438459 TI - Modulation of adaptive immune response following intravenous immunoglobulin therapy in common variable immunodeficiency. PMID- 25438460 TI - Belimumab for the treatment of refractory systemic lupus erythematosus: real-life experience in the first year of use in 18 Italian patients. PMID- 25438461 TI - The autoimmune side of rheumatic fever. PMID- 25438462 TI - Serpins as players in autoimmune diseases. PMID- 25438463 TI - Vaccination in autoimmune animal models. PMID- 25438464 TI - Cryopyrin-associated periodic syndrome. AB - CAPS is a rare autoinflammatory disease associated with mutations in the NLRP3 gene that result in overactivation of the inflammasome, increased secretion of IL 1beta and IL-18, and systemic inflammation. Genetic testing has allowed for grouping of the three, previously distinct clinical syndromes of FCAS, MWS and NOMID, into a single syndrome termed CAPS. The clinical features include urticarial rash and fever, CNS and musculoskeletal involvement, ocular disorders and progressive deafness. Onset, severity and complications (mainly retardation, seizures, destructive arthropathy and amyloidosis) depend on the specific mutation. Diagnosis is determined by genetic tests but is often delayed due to lack of awareness. In Israel, the relative abundance of other autoinflammatory disorders (FMF, Behcet's disease) may result in misdiagnosis. Treatment is based on IL-1 antagonism, which usually results in prompt clinical response and may prevent amyloidosis. PMID- 25438465 TI - The hyperferritinemic syndromes and CD163: a marker of macrophage activation. PMID- 25438466 TI - The hyperferritinemic syndrome. PMID- 25438467 TI - A phase IB clinical trial with Dekavil (F8-IL10), an immunoregulatory 'armed antibody' for the treatment of rheumatoid arthritis, used in combination wiIh methotrexate. PMID- 25438468 TI - War and peace at the feto-placental front line: recurrent spontaneous abortion. PMID- 25438469 TI - Freedom from fear. PMID- 25438470 TI - The use of diaries to promote recovery after critical illness. AB - Admission to intensive care exposes patients and family members to extreme physical and psychological stress. This stress may cause anxiety, depression and post-traumatic stress disorder (PTSD), which impairs their recovery. Nurses are actively seeking solutions and tools to assist patients and family members to recover after admission to intensive care. PMID- 25438471 TI - Midwives Australia and private practice midwives. PMID- 25438472 TI - Reporting obligations regarding performance issues and workplace matters. PMID- 25438473 TI - Mixed gender accommodation. . PMID- 25438474 TI - [Editorial]. PMID- 25438475 TI - [The Bulletin of the Society of Medical Sciences of the Grand-Duche de Luxembourg: 150 years of existence and other historical facts]. PMID- 25438476 TI - [Historic Development of Clinical Biology Laboratories in Luxembourg]. AB - After a short overview on the development of diagnostic tools in clinical biology at an international level from Antiquity towards today, a history of the clinical biology including public and private institutions in Luxembourg will be outlined. PMID- 25438477 TI - [150 years of dentistry (a non-exhaustive history of the art of dentistry)]. PMID- 25438478 TI - [Training and examination of Luxembourg's veterinarians from 1797 to 1969, a special case]. AB - CONTENT: The training and examination of Luxembourg's veterinarians are dictated during the first forty years of the 19th Century by the French and after by the Dutch. The legislation about the examinations of the Luxembourg's State is in effect from 1841 to 1969. In 1969, the legislation of granting degrees is replaced by the confirmation of foreign titles and degrees of higher education. PMID- 25438479 TI - [Geriatrics from the 19th to the 21st century. 150 years of geriatric medicine: from increasing life expectancy to improving quality of life for the very old]. AB - With the world further aging, geriatric medicine clearly became a necessity: in the 21th century many more people reach older ages by means of continued medical success in expanding lifespan. 150 years ago life expectancy was between 30 to 40 years, but today close to 800 million people are 60 yeas old or more. During the last century aging has been associated with decline and decay, but gradually more people lived ably and healthily in older ages. The expansion in life expectancy has become a synchronism of quality of life: the average 65 year old today is much healthier, physically and mentally fitter, than the average 50 year old 150 years ago, when Alois Alzheimer war born, a period when most nowadays existing geriatric institutions were envisioned and progressively realized over time. Today we strongly believe that a healthy life and, equally, the quality of life of the very old people can be extended with presently existing medical knowledge, based on research, environmental and behavioural changes, by postponing the onset and progression of fatal and disabling diseases and disorders. But very soon ethical considerations concerning all kinds of medical and technological solutions available to maintain or even improve the mental and physical functioning of dependant elderly people will engage our society when deciding how and at what moment in time to make the best decisions and allocate resources. Geriatric medicine will be further challenged by competing and demanding medical and economic needs, when marshalling resources to meet the growing demands of our society for improving care for the very old and often demented adult. PMID- 25438480 TI - [How to cure cancer 1864-2014: 150th anniversary of the Bulletin of the Society of the Medical Sciences]. PMID- 25438481 TI - Treatment of painful diabetic neuropathy. PMID- 25438482 TI - A Clinical Trial of Nitrosense patch for the treatment of patients with painful diabetic neuropathy. AB - AIMS: Impaired nitric oxide synthesis has been implicated as one of the underlying causes of diabetic painful neuropathy (DPN). Hence, effects of a cutaneous, nitric oxide releasing patch (NitroSense Derma Protect) were evaluated in subjects with DPN. METHODS: Fifty diabetics were randomised to active/placebo arms after a 2 wk wash-out period. Patients received 24 mg patches (each patch releases around 9 nmol/cm2/min of nitric oxide) for 3 hrs, every other day during a 3 wks period, or indistinguishable placebo patches. The extent of pain was recorded at start, at each visit and following completion of the study. Changes in pain from baseline were measured using the 11 point lickert scale (PLS), visual analogue scale (VAS), short form mcgill, pain questionnaire (SF-MPQ), present pain intensity (PPI) scale. RESULTS: Subjects treated with patch experienced a statistically significant reduction in pain from baseline when compared to placebo (PLS scale; p = 0.05). Defining responders as subjects with a > 50% reduction in PLS score from baseline, the number needed to treat (NNT) was calculated as 3.0. A significant post-treatment decrease (p = 0.009) in vibration perception threshold (VPT) for left foot after active treatment was observed. CONCLUSIONS: Present results highlight utility of NitroSense Derma Protect as controllable nitric oxide source for patients with DPN. PMID- 25438483 TI - Pattern of antibiotics usage in a community hospital of Malwa region of Punjab, India. AB - To assess the pattern of antibiotic utilisation and outcome of patients with bacteraemia in the hospital. All positive blood cultures (BC) over a 12-month period from January 2011 to December 2011 were retrospectively reviewed. Positive BC were recorded in 54 patients. 51.9% of the patients received antibiotics before or soon after obtaining the BC, and ceftriaxone was the most frequently prescribed antibiotic (42.9%), either alone or in combination with other antibiotics. The bacteraemia was due to gram-negative rods in 84.9% and gram positive cocci in 15.1% of cases. Most common gram-negative bacilli were E. coli, Klebsiella pneumoniae and Salmonella species while most common gram-positive cocci was Staphylococcus aureus. Antibiotics regimen was changed in 37% cases after BC results became available. Most frequent change was addition of meropenem in case of gram-negative bacilli (29.6%) and vancomycin in gram-positive cocci (12.5%).Ten (18.5%) patients developed serious sepsis or septic shock; 3 (30.0%) improved and 7(70.0%) had fatal outcome. Antibiotic selection needs tobe tailor made for each patient. However, most bacteraemia necessitating hospital admission are due to gram-negative bacilli and it should be considered in antibiotic selection prior to BC. PMID- 25438484 TI - Diagnosis of hyperinsulinaemia in a normoglycaemic healthy Indian Population- developing ethnic reference ranges. AB - CONTEXT: Reference limits for diagnosing hyperinsulinaemia are currently derived from non-Indian cohorts and have not been validated in Indians even though it is acknowledged that different patterns of insulin secretion are seen across ethnicities. AIMS: To develop ethnicity specific reference limits for insulin levels in a normoglycaemic healthy Indian cohort in order to derive a clinical cut off for hyperinsulinaemia as an effective screening tool for predicting future risk of metabolic and cardiovascular disease. SETTINGS AND DESIGN: Prospective analysis of plasma insulin levels in healthy normoglycaemic volunteers availing diagnostic facilities at a central reference laboratory in Mumbai. METHODS AND MATERIAL: 122 normoglycaemic males between 19-73 years and 126 females between 19-55 years of age were selected based on a screening questionnaire as per the Clinical Laboratory and Standards Institute (CLSI) guidance document for deriving reference ranges. Fasting insulin levels were analysed using a Chemiluminescent Microparticle Immunoassay platform and derived results were analysed to determine reference limits for insulin. STATISTICAL ANALYSIS USED: A non-parametric method of statistical analysis was used to determine the 2.5 and 97.5% limits with 90% confidence intervals. RESULTS: Reference range for insulin in a normoglycemic Indian cohort was derived as 2.7 17 uIU/ml which established 17 uIU/ml as the clinical cut off for diagnosing hyperinsulinemia in healthy Indians. CONCLUSIONS: Reference limits for insulin in normoglycemic Indians needs to be revised to 2.7-17 uIU/ ml. Clinical cut off for hyperinsulinemia needs to be lowered to 17 uIU/ml from currently used cut offs which range from 25-31 ulU/ml. KEY MESSAGES: Reference limits currently used for diagnosing hyperinsulinemia in healthy normoglycemic adults need to be revised and made specific for different ethnicities. In Indians the upper limit of the normal reference range for insulin levels needs to be brought down to 17 uIU/ml from the existing 25-31 u IU/ml. This modified cut off would help clinicians identify apparently healthy individuals who may need to be screened for a future risk of metabolic and cardiovascular disorders. PMID- 25438485 TI - Neurological manifestations of B(12) deficiency with emphasis on its aetiology. AB - BACKGROUND: It is believed that Pernicious anaemia (PA) is more common in the West. We postulate however that in India PA is probably an important aetiological factor as a cause of Vitamin B12 deficiency in patients having neurological disease. OBJECTIVE: To investigate the aetiological factors resulting in Vitamin B12 (Vit B12) deficiency in patients with subacute combined degeneration (SACD) and other neurological manifestations. METHODS: We undertook a prospective study of 50 patients, all clinically suspected to have Vit B12 deficiency; they were investigated clinically, haematologically, biochemically and radiologically. RESULTS: There was a dominance of males (41 of 50) with the majority in the age group of more than 40 years of age. There was no correlation between the socio economic and dietary status on the one hand and the clinical manifestation on the other. Anti intrinsic factor antibodies (AIFAB) were positive in 19 of 50 patients (38%) and anti parietal cell antibodies (APCAB) were positive in 28 of 50 (56%) patients. CONCLUSION: We conclude that Pernicious anaemia is an important cause of various neurological manifestations including SACD in the Vitamin B12 deficient population in the age group of more than 40 years, irrespective of the socio-economic and dietary status in the Indian subcontinent. It is supported by the presence of AIFAB or APCAB in this group. PMID- 25438486 TI - Comparison of spot urine protein creatinine ratio with 24 hour urine protein for estimation of proteinuria. AB - The objective of our study was to evaluate and standardise the method of spot (random) urine protein creatinine ratio (UP/C) for estimation of proteinuria. The study contained 241 study participants in a tertiary care hospital inclusive of 208 cases and 33 normal volunteers. The 24 hour urine protein estimation was done on 24 hour urine samples and UP/C ratio was calculated on random urine samples. UP/C ratio and 24 hour urine protein estimation had strong correlation with r = 0.9 and p < 0.05 on Pearson's correlation analysis. Receiver operating characteristic analysis showed random UP/C ratio of 0.1171 reliably predicted 24 hour urine total protein equivalent of > 150 mg/24 hrs with sensitivity 100%, specificity 98.1%, positive likelihood ratio 53.5, and negative likelihood ratio 0. UP/C ratio of 3.2 reliably predicted nephrotic range proteinuria at 24 hour urine protein equivalent of > 3.5 g/24 hrs with sensitivity 80%, specificity 100%, positive likelihood ratio 154.4, and negative likelihood ratio 0.2. We conclude that spot/random UP/C ratio is a reliable, simple test to be introduced and adopted in routine practice for monitoring of macro proteinuria. PMID- 25438487 TI - Mycotic popliteal artery aneurysm. AB - The name mycotic aneurysm was coined by Osler to describe aneurysms associated with bacterial endocarditis with an appearance of fresh fungal vegetations; however majority of them are caused by bacteria. Mycotic aneurysm (MA) is a rare complication of infective endocarditis (IE), seen in 3-15% of IE patients. PMID- 25438488 TI - Erythema ab igne. PMID- 25438489 TI - Snake bite with strange skin lesions. PMID- 25438490 TI - Simple testing for obstructive sleep apnoea. PMID- 25438491 TI - Osborn waves. PMID- 25438492 TI - Slow junctional rhythm, QTc prolongation and transient torsades de-pointes following combined use of Ivabradine, Diltiazem and Ranolazine. AB - A case of unstable angina developed slow junctional rhythm with QTc prolongation and transient Torsades de pointes following simultaneous use of Ivabradine, Diltiazem and Ranolazine. Effect of Diltiazem on hepatic isoenzyme CYP 3A could be responsible. Such a combination should be avoided. PMID- 25438493 TI - Takotsubo cardiomyopathy. AB - Acute and rapidly reversible left ventricular dysfunction may be triggered by various emotional and physical insults. The most common precipitant being the death of a close family member but the other reported precipitants include court appearance, fear of a procedure, arguments and surprise parties and reunions. This entity is now well known as stress cardiomyopathy or Takotsubo cardiomyopathy. We report a case of rapidly reversible left ventricular dysfunction following attempted suicide by hanging. PMID- 25438494 TI - Inferior vena caval thrombosis: a rare complication of acute pancreatitis. AB - Inferior vena cava [IVC] thrombosis is a rare complication of acute pancreatitis. Here we report a case of IVC thrombosis with associated portal vein thrombosis complicating recurrent acute pancreatitis related to alcohol in a 31 year old male patient. We discuss the pathogenesis, clinical features and management of IVC thrombosis complicating acute and chronic pancreatitis in brief. The case is being reported for its rarity and early diagnosis as well as prompt treatment are essential for prevention of complications like pulmonary embolism. PMID- 25438495 TI - Sudden bilateral reversible vision loss: a rare presentation of acute intermittent porphyria. AB - Acute intermittent porphyria is a rare disorder, characterised clinically by variable patterns of neurological and metabolic disturbances. We report a rare presentation with sudden onset painless bilateral reversible vision loss of cerebral origin along with a brief review of the underlying pathophysiology. PMID- 25438496 TI - Transient A-V dissociation and severe hypotension due to consumption of Ayurvedic medicine--Vatsanabha (aconitum ferox). AB - A 24 year old married, well educated, female patient presented with complaints of giddiness and blackouts. On evaluation, patient had hypotension and bradycardia. ECG findings were suggestive of complete A-V dissociation. On detailed history patient revealed consumption. of Ayurvedic medicine Vatsanabha for arthritis. This study impresses upon the need for complete history talking and generating awareness regarding the correct and observed use of any drug including alternative medicines. PMID- 25438497 TI - A case of cavernous sinus thrombosis with meningitis caused by community acquired methicillin resistant Staphylococcus aureus. AB - Septic cavernous sinus thrombosis is a rare clinical condition. Although Staphylococcus aureus is the most common pathogen causing septic cavernous sinus thrombosis [CST], it is an uncommon cause of meningitis. We report the first case of CST with meningitis in Hyderabad, Andhra Pradesh, caused by community acquired epidemic strain of Methicillin resistant staphylococcus aureus [MRSA], in a previously healthy individual with no risk factors. The patient recovered completely following treatment with Vancomycin. We consecutively reviewed all cases of community acquired staphylococcus aureus [CA-MRSA] with central nervous system involvement available in literature. PMID- 25438498 TI - Predominant RV endomyocardial fibrosis masking rheumatic mitral stenosis. AB - We report a 30 year female with rheumatic mitral stenosis, presenting with progressive right heart failure without overt leftheart symptoms. Rapid progression to severe right heart failure with moderate pericardial effusion prompted the diagnosis of associated restrictive cardiomyopathy. A MRI scan of the heart revealed diffuse subendocardial scarring of LV and RV explaining patient's rapid downhill course. PMID- 25438499 TI - A case of ADEM following Chikungunya fever. AB - Chikungunya most often is a self-limiting febrile illness with polyarthritis and the virus is not known to be neurotropic. We are reporting a case of chikugunya fever presenting as acute demyelinating encephalomyelitis(ADEM) which is very rare. PMID- 25438500 TI - P S Hench. PMID- 25438501 TI - Michael Servetus--discoverer of pulmonary circulation and a heretic. PMID- 25438502 TI - Endocrine changes in HIV patients. PMID- 25438503 TI - Abdominal pain in diabetes--DKA is not the only cause. PMID- 25438504 TI - Pulse pressure and diastolic dysfunction in young normotensive. PMID- 25438505 TI - Defining a new pathway for family planning in Africa after 2014. PMID- 25438506 TI - Does access to antiretroviral drugs lead to an increase in high-risk sexual behaviour? PMID- 25438507 TI - Abortion care in Ghana: a critical review of the literature. AB - The Government of Ghana has taken important steps to mitigate the impact of unsafe abortion. However, the expected decline in maternal deaths is yet to be realized. This literature review aims to present findings from empirical research directly related to abortion provision in Ghana and identify gaps for future research. A total of four (4) databases were searched with the keywords "Ghana and abortion" and hand review of reference lists was conducted. All abstracts were reviewed. The final include sample was 39 articles. Abortion-related complications represent a large component of admissions to gynecological wards in hospitals in Ghana as well as a large contributor to maternal mortality. Almost half of the included studies were hospital-based, mainly chart reviews. This review has identified gaps in the literature including: interviewing women who have sought unsafe abortions and with healthcare providers who may act as gatekeepers to women wishing to access safe abortion services. PMID- 25438508 TI - A comparative analysis of fertility differentials in Ghana and Nigeria. AB - Nigeria and Ghana are the most densely populated countries in the West African sub-region with fertility levels above world average. Our study compared the two countries' fertility levels and their determinants as well as the differentials in the effect of these factors across the two countries. We carried out a retrospective analysis of data from the Nigeria and Ghana Demographic Health Surveys, 2008. The sample of 33,385 and 4,916 women aged 15-49 years obtained in Nigeria and Ghana respectively was stratified into low, medium and high fertility using reported children ever born. Data was summarized using appropriate descriptive statistics. Factors influencing fertility were identified using ordinal logistic regression at 5% significance level. While unemployment significantly lowers fertility in Nigeria, it wasn't significant in Ghana. In both countries, education, age at first marriage, marital status, urban-rural residence, wealth index and use of oral contraception were the main factors influencing high fertility levels. PMID- 25438509 TI - Determinants of preference of source of injectable contraceptives among rural women in Uganda: a case study of Depo-Provera. AB - Understanding preference of source of contraceptive commodities is essential in enhancing the delivery of family planning services. This paper identifies the determinants of preferred source of Depo-Provera among rural women in Uganda. The analysis is based on data sourced from a Save the Children and Family Health International study involving 642 women who were introduced to the contraceptive three years prior to the evaluation. Data were analyzed at univariate, bivariate and multivariate levels. Private sources were the most preferred of Depo-Provera as compared to public sources. Preference for private sources was more likely among older women (p < 0.05), those who had never experienced stock-outs of Depo Provera (p < 0.01), and those who had obtained their last injectable from private sources (p < 0.01). These findings support the strategy of community-based distribution of contraceptives in enhancing access and utilization of family planning services in Uganda. PMID- 25438510 TI - Defining motivational intensity of need for family planning in Africa. AB - Non-users of contraception differ greatly in their likely motivation to adopt a method or resume use. This study presents a new approach to defining high and low motivation groups by stated intention to use, past use, and unmet need, to determine how these groups differ in characteristics and in region of residence. Data come from 23 DHS surveys in sub-Saharan countries, with representation from the eastern/southern region and western/central region. The low motivation non users, with less past use and less intention to use in the future, are more rural, less educated, and closer to poverty. Motivational intensity is lower in the western/central region, which contains far fewer intenders than the eastern/southern region and where many more report no past use and no unmet need. When used to guide planning, unmet need should be augmented with motivation, since the two classifications do not entirely overlap. Between 10 and 17% of current non-users of family planning are likely highly motivated to use, but are not captured in the unmet need classification. Program implications for these non using groups are discussed. PMID- 25438511 TI - Fertility desires and intentions among HIV-positive women during the post-natal period in Uganda. AB - This study describes the fertility intentions and discusses the potential reproductive health needs of post-natal HIV-infected Ugandan women. HIV-infected mothers attending post-natal services in Kampala, Uganda participated in this cross-sectional study using structured interviewer administered questionnaires. Descriptive statistics and logistic regression models were used to identify predictors of desire for more children. Among 403 participants, 35% desired more children. Of these, 25% wanted another child within 2 years and 75% within 3 years or more. In multivariable analyses, believing that one's partners wanted more children (OR = 2.44; 95% CI = 1.30, 4.59) was associated with the desire for future children while having more living children was negatively associated with the desire for future children (OR = 0.08; 95% CI = 0.02, 0.39). A minority of women desired future pregnancies, and most wanted to delay pregnancy for 3 years. These women are in need of family planning (FP) methods to meet stated desires to delay or end future pregnancies. Perceived partner desire for children also impacts on women's fertility intentions, highlighting the importance of engaging men during the post-natal period.67-77) PMID- 25438512 TI - Obstetric danger signs and factors affecting health seeking behaviour among the Kassena-Nankani of Northern Ghana: a qualitative study. AB - Improving community members' knowledge of obstetric danger signs is one strategy for increasing the use of skilled care during pregnancy and the puerperium. This study explored knowledge of obstetric danger signs among a range of community members, examined the sources of their information, and the perceived factors that affect health seeking behaviour in rural northern Ghana. We conducted 72 in depth interviews and 18 focus groups with community members. All interactions were audio taped, transcribed verbatim and analysed using NVivo 9.0. Community members demonstrated knowledge of a wide range of obstetric danger signs, including excessive bleeding, stomach aches, waist pains, vomiting and fever. Pregnant women learn about danger signs from a range of providers, and regular contact with formal providers typically coincided with increased knowledge of danger signs. Traditional remedies for problems in obstetrics are plentiful and cultural beliefs often restrict the use of allopathic medicine. Increasing knowledge of obstetric danger signs is necessary but not sufficient to overcome cultural preferences for traditional treatments for pregnancy danger signs. PMID- 25438513 TI - Effects of improved access to transportation on emergency obstetric care outcomes in Uganda. AB - Reduction in maternal mortality has not been appreciable in most low-income countries. Improved access to transport for mothers is one way to improve maternal health. This study evaluated a free-of-charge 24-hour ambulance and communication services intervention in Oyam district using 'Caesarean section rate' (CSR) and compared with the neighbouring non-intervention district. Ecological data were collected retrospectively from maternity/theatre registers in October 2010 for 3 years pre and 3 years intervention period. The average CSR in the intervention district increased from 0.57% before the intervention to 1.21% (p = 0.022) during the intervention, while there was no change in the neighbouring district (0.51% to 0.58%, p = 0.512). Hospital deliveries increased by over 50% per year with a slight reduction in the average hospital stillbirths per 1000 hospital births in the intervention district (46.6 to 37.5, p = 0.253). Reliable communication and transport services increased access to and utilization of maternal health services, particularly caesarean delivery services. PMID- 25438514 TI - Rural origin and exposure drives Ghanaian midwives reported future practice. AB - A primary cause of Ghana's higher than global average maternal mortality rate is limited access to maternal care in rural areas. To date, few studies have examined how rural background/training of midwives impacts their future willingness to work in remote areas. The purpose of this paper is to describe the relationship between Ghanaian student midwife place of origin and rural training on their willingness to choose a future rural practice location. A cross sectional computer-based survey was completed by 238 final year Ghanaian midwifery students from two public midwifery training schools located in urban Ghana between October and December 2009. The relationship between rural exposure and willingness to work in rural Ghana was analyzed using independent t-test, chi square, and bivariate logistic regression. Participants who experienced a rural rotation (OR: 1.51, 95% CI: 0.71, 3.22) and those born in a rural area (OR: 2.24, 95% CI: 0.74, 6.75) resulted in greater odds ratio to choose rural practice following graduation. This study indicates an association between midwifery students' place of origin and training and their willingness to practice in a rural area after graduation. PMID- 25438515 TI - Maternal health practices, beliefs and traditions in southeast Madagascar. AB - Contextualising maternal health in countries with high maternal mortality is vital for designing and implementing effective health interventions. A research project was therefore conducted to explore practices, beliefs and traditions around pregnancy, delivery and postpartum in southeast Madagascar. Interviews and focus groups were conducted with 256 pregnant women, mothers of young children, community members and stakeholders; transcripts were analysed to identify and explore predetermined and emerging themes. A questionnaire was also conducted with 373 women of reproductive age from randomly selected households. Data was analysed using STATA. Results confirmed high local rates of maternal mortality and morbidity and revealed a range of traditional health care practices and beliefs impacting on women's health seeking behaviours. The following socio cultural barriers to health were identified: 1) lack of knowledge, 2) risky practices, 3) delays seeking biomedical care, and 4) family and community expectations. Recommendations include educational outreach and behaviour change communications targeted for women, their partners and family, increased engagement with traditional midwives and healers, and capacity building of formal health service providers. PMID- 25438516 TI - Current evidence supporting obstetric fistula prevention strategies in sub Saharan Africa: a systematic review of the literature. AB - Obstetric fistula has been eliminated in developed countries, but remains highly prevalent in sub-Saharan Africa. The End fistula campaign is the first concerted effort to eradicate the disease. The objective of this review is to retrieve and link available evidence to obstetric fistula prevention strategies in sub-Saharan Africa, since the campaign began. We searched databases for original research on obstetric fistula prevention. Fifteen articles meeting inclusion criteria were assessed for quality, and data extraction was performed. Grey literature provided context. Evidences from the articles were linked to prevention strategies retrieved from grey literature. The strategies were classified using an innovative target-focused method. Gaps in the literature show the need for fistula prevention research to aim at systematically measuring incidence and prevalence of the disease, identify the most effective and cost-effective strategies for fistula prevention and utilise innovative tools to measure impact of strategies in order to ensure eradication of fistula. PMID- 25438517 TI - Understanding maternal deaths from the family's perspective: verbal autopsies in rural Tanzania. AB - Maternal mortality rates in rural Tanzania are high. In preparation for the introduction of an intervention to reduce maternal deaths by distribution of misoprostol and erythromycin to women living in rural Rorya District, Mara Region, Tanzania, we conducted a limited verbal autopsy by surveying family members of women who died in childbirth in the previous five years. The purpose of this survey was to understand the circumstances surrounding these deaths. Thirty six family members were interviewed. The majority of the deaths occurred on the roadside as the women made their way to a health facility (23/36). Most of the women were delivered by a TBA (16/36) or family member (13/36). The majority of the family members attributed the death of their loved one to bleeding or retained placenta (32/36). Maternal deaths are common in this rural district of Tanzania because of long distances from the health facilities, difficulty finding transportation, costs of transport and hospital, and women's beliefs about being able to deliver at home and fear of medication. There is a need for increased education of women and their families about the benefits of childbirth in a healthcare facility attended by skilled providers. There is also a role for the community distribution of misoprostol to be used as an alternative uterotonic medication if a facility birth is not possible, as the rates of maternal death from hemorrhage are unacceptably high. PMID- 25438518 TI - Risk factors for transactional sex among young females in post-conflict Liberia. AB - This study aimed to examine the risk factors for engaging in transactional sex among young females in Montserrado County, Liberia. Data from an HIV behavioral survey conducted among young people aged 14 - 25 years were used. The analytical sample included 493 sexually-experienced females. Bivariate and multivariate analyses were conducted. We found that 72% of our sample had ever engaged in transactional sex. Engagement in transactional sex was associated with education (OR: 0.5); reporting no earned income (OR: 1.9); longer duration of sexual activity (OR: 3.5); early sexual debut (OR: 2.5); history of sexual violence (OR: 2.1) and multiple sexual partnerships (OR: 4.0). Respondents' age, residence, and drug/alcohol use were not associated with engagement in transactional sex. HIV interventions should incorporate educational strategies to reduce the prevalence of transactional sex among young people. These strategies should include economic opportunities to offset financial need as well as efforts to eradicate sexual violence. PMID- 25438519 TI - Attitudes of gatekeepers towards adolescent sexual and reproductive health in Ghana. AB - Adults constitute gatekeepers on adolescent sexual and reproductive health (ASRH). This qualitative paper discusses the views of adults on ASRH problems and challenges based on 60 in-depth interviews conducted among adults in Ghana in 2005. Adults were purposively selected based on their roles as parents, teachers, health care providers and community leaders. The major ASRH problems mentioned were teenage pregnancy and HIV/AIDS. The results indicated a number of challenges confronting ASRH promotion including resistance from parents, attitudes of adolescents, communication gap between adults and adolescents and attitudes of health care providers. Among health workers three broad categories were identified: those who were helpful, judgmental and dictators. Some adults supported services for young people while others did not. Some served as mediators and assisted to 'solve' ASRH problems, which occurred in their communities. It is argued that exploring the views of adults about their fears and concerns will contribute to the development of strategies and programmes which will help to improve ASRH. PMID- 25438520 TI - Human papilloma virus vaccine: determinants of acceptability by mothers for adolescents in Nigeria. AB - Vaccination of adolescent females against Human Papilloma Virus (HPV), the causative agent for cervical cancer has recently become available. As minors, parental acceptance of the vaccines for adolescent daughters requires exploration. This was a cross-sectional survey of 201 mothers attending the gynaecology clinic in a University Teaching Hospital in Nigeria on acceptability of the HPV vaccines and its determinants. Although 70% accepted vaccination of their daughters, 30% were unwilling and the commonest reason for unwillingness was that it may encourage sexual promiscuity (62.3%). Mothers with poor knowledge of STI were significantly more unwilling to accept HPV vaccines compared to those with average or good knowledge (p = 0.002). Furthermore, perception of susceptibility to HPV infection by daughters was significantly associated with acceptance of the vaccines (p = 0.0001). Increased advocacy and public enlightenment on cervical cancer control and the role of HPV vaccines in its prevention is still necessary especially in developing countries. PMID- 25438521 TI - Unconsummated marriage in sub-Saharan Africa: case reports. AB - Unconsummated marriage is a condition where newly married couples are unable to achieve penile-vaginal intercourse for variable periods despite desire and several attempts to do so. Its exact cause(s) is/are unknown, but performance anxiety resulting from or leading to other conditions is reportedly the major etiological factor. It is thought to be more prevalent in traditional and conservative religious communities where premarital sexual exposure is strictly prohibited. Most publications on unconsummated marriage have originated from North America, European and Middle Eastern countries. There have not been any such reports from sub-Saharan Africa, which is home to diverse cultures and traditions regarding premarital sex and marriage. This paper presents a sample of four cases with unconsummated marriage managed by the author in his private clinic based in the city of Nairobi Kenya, over the past five years. Possible etiological factors and management approaches are discussed, with a review of relevant literature. PMID- 25438522 TI - [Effects of vitamin E and magnesium on glucolipid metabolism in obese rats ]. AB - OBJECTIVE: To investigate the effects of vitamin E (VE ) and magnesium entantion on glucolipid metabolism in obese rats. METHODS: Seventy-four rats were randomly divided into five groups (normal control group positive E group, Mg group, VE plus Mg group). The doses of V(E) and Mg were 0.23 g/kg feed and 0.31 g/kg feed respectively. They were slaughtered after feed for 67 weeks. Calculate the lipid ratio. Examined the level of serum lipid, plasma glucose, serum insulin, insulin sensitivity index, and the activity of hexokinase and pyruvate kinase. The results of each group were analyzed by One-Way ANOVA and analysis of variance of factorial design. RESULTS: The rat model with nutritional obesity was successfully established that the weight of positive control group was about 20% higher than normal control group. The lipid ratio and plasma triglyceride of VE plus Mg group were 13. 29% and 0. 6 mmol/L respectively, which were significantly lower than that of positive control group (17.24% and 1. 18 mmol/L) (P < 0.05), and the plasma triglyceride of VE plus Mg group was significantly lower than that of VE group (1. 07mmol/ L) (P <0.05). The activity of hexokinase of V~E group and VE plus Mg group were 63. 67 U/L and 64. 61 U/L respectively, significantly higher than that of positive control group (42.79 U/L) and Mg group (44.02 U/L) (P <0.05). CONCLUSION: Supplementation of VE combined with Mg can effectively improve the fat content and triglyceride of obese rats, better than VE alone. Supplementation of VE and Mg is beneficial to obese rats to improve the activity of hexokinase, and adding VE is better than Mg alone. PMID- 25438523 TI - [Setting up the oxidative cell mode with hippocampal cell of primary culture induced by H2O2]. AB - OBJECTIVE: To establish the oxidative cell model with hydrogen peroxide. METHODS: Primary cultured hippocampal neurons were divided into six groups. Each group involved 6 wells of cells in 96 well plate. 100 micro; experimental cells in logarithmic phase after adjusted concentration of 1 X 10(5)/ml were vaccinated in the 96 well plate and cultured in saturated humidity at 37 degree C and under 5% CO2 and 95% air. 5 days later 100 micro; different concentrations of hydrogen peroxide were added. The final concentrations of hydrogen peroxide of groups were successively 0, 50, 100, 150, 200 and 250 micromol/L. After 12, 24, and 48h of treatment respectively, we make sure what is the best time and what is the most approptiate concentration of H2O2 to induce celluar injuries by observing cell morphology through inverted microscope and scanning electron microscope, detecting the cell survival rate with MTT assay, evaluating the cell damage rate with CCK-8 assay, assessing the cell mortality with LDH activity detection kit, examining the cell apoptosis with AnnexinV/PI formation method. RESULT: H2O2 concentration-dependently and time-dependently promoted damage of primary cultured hippocampal neurons. Cells viabilties in concentrations of 50, 100, 150, 200 and 250 micromol/L decreased obviously comparing with normal control group (0 micromol/L hydrogen peroxide). At the concentration of 150 micromol/L hydrogen peroxide and treated with 24h, cell viability was (70.18 +/- 4.66)%, cell damage rate was (28.30 +/- 6.72)%, LDH activity was (208+/-12.24)U/L; early apoptosis rate was (11.53+/-)2.53)% and late apoptosis or necrosis rate was (13.75+/ *2.22)%. CONCLUSION: under the present conditions, treating with 150 micromol/L hydrogen peroxide for 24h can successfully establish the oxidative cell model. PMID- 25438524 TI - [Interaction of polymorphisms of Leptin receptor gene Gln223Arg, MnSOD9Ala/Val genes and smoking in nonalcoholic fatty liver disease]. AB - OBJECTIVE: To investigate the interaction of polymorphisms of leptin receptor (LR) gene Gln223Arg, manganese superoxide dismutase9Ala/Val (MnSOD9Ala/Val) genes and smoking in nonalcoholic fatty liver disease. METHODS: The genetic polymorphisms of LEPR gene Gln223 Arg and MnSOD9Ala/Val were analyzed bypolymorphism-polymerase chain reaction (PCR) technique in peripheral blood leukocytes of 600 NAFLD cases and 600 healthy persons. RESULTS: The frequencies of LR gene Gln223Arg (G/G) and MnSOD9Ala/Val (V/V) were 48. 67% and 50.17% in NAFLD cases and 21. 17% and 21. 50% in healthy controls respectively. Statistical tests showed significant difference in the frequencies between the two groups (P <0.01). The risk of NAFLD with Gln223Arg (G/G) was significantly higher than those of controls (OR = 3. 5309, 95% CI =21. 8165 -5.0724). The individuals who carried with MnSOD9Ala/Val (V/V) had a high risk of NAFLD (OR = 3. 6756, 95% CI = 1. 9137 - 5.5496). Combined analysis of the polymorphisms showed that percentage of Gln223Arg (G/G)/ MnSOD9Ala/Val (V/V) in NAFLD and control groups was40.33% % and 7.50% Respectively (P <0.01). The people who carried with Gln223 Arg (G/G)/ MnSOD9Ala/ Val (V/V) had a high risk of NAFLD (OR = 8. 4014,95% CI= 4. 2926 - 12. 4238). The smoking rate of the case group was significantly higher than which in the control group (OR = 3. 6754, 95% CI = 1. 4193 - 4. 9581, P <0. 01 ), and statistic analysis suggested an interaction between smoking and Gln223Arg ( G/G)/ MnSOD9Ala/Val (V/V) which increase risk of NAFLD ( OR = 9. 8665; OR = 8. 5476). CONCLUSION: Gln223Arg (G/G), MnSOD9Ala/Val (V/V) and smoking are the risk factors in NAFLD, and the significant interactions between geneticpolymorphisms of Gln223Arg,MnSOD9Ala/Val and smoking added the risk of NAFLD. PMID- 25438525 TI - [Effects of different exercise intensity on PPARgamma and relative index in adolescent obesity rats]. AB - OBJECTIVE: Discuss the effects of low, medium, high intensity exercise induced by PPAR gamma and related indexes of diet in obsess SD rats. METHODS: Male SD rats are selected to establish experimental obesity model of SD rats, selecting 32 rats of model successfully and randomly divided into control group, low intensity group, moderate intensity group and high strength group. Each exercise group is trained by treadmill training for 8 weeks. After 8 weeks, their blood and adipose tissue are collected and the body fat and blood lipid are measured. The qRT-PCR method is used to measure the expression of PPAR gamma mRNA in adipose tissue, and immunohistochemical staining method are used to measure the protein expression of PPAR gamma, and ELIASA is used to determine the plasma concentrations of PPARgamma. RESULTS: After the exercise, the exponent of rats' weight and body fat have reduced (P <0. 01), and the exponent groups of lee' s index are indiscrimination(P > 0. 05) , TC expressed as moderate intensity and high intensity decreased compared with the control group (P <0. 05). TG levels in low, medium and high intensity group are lower than those in the control group (P. < 0.01), LDL levels in medium and high intensity groups are higher than the control group (P < 0.05).The concentrations of PPAR plasma in low, medium and high intensity group are higher than in the control group (P <0.05). PPARy mRNA expression in adipose tissue of low, medium and high intensity group are enhanced than the control group. Immunohistochemical results of PPARy is in consistent with the expression of PPARgamma CONCLUSION: Method of different intensity of exercise for 8 weeks have play a significant effect on weight loss and body fat is significantly lower. Besides, it can also improve blood lipid effectively and significantly increases the expression of PPARy in plasma and adipose tissue. PMID- 25438526 TI - [Investigation of urinary cadmium reference of general population in two rural high background areas of soil cadmium and non-cadmium-polluted in China]. AB - OBJECTIVE: To study the reference of urinary. cadmium of the general population in rural high background areas of soil cadmium and non-cadmium contaminated in China. METHODS: In rural high background areas of soil cadmium and non-cadmium contaminated, randomly selected non-occupational-cadmium exposed population 1134 people (male 519, female 615) with each gender and age groups, questionnaire surveyed and collected random urine. Urinary cadmium and urinary creatinine (Cr) concentration were tested, excluding urinary Cr <0.3 g/L and >3 g/L. Analyze the impact factors of urinary cadmium and calculated 95% quantile (P,95 ) of urinary cadmium after correction by urinary Cr. RESULTS: Female median urinary cadmium was significantly higher than men, male smokers median urinary cadmium was significantly higher than male non-smokers (P <0. 05) , but differ slightly in P95. Both men and women, the median and P95 of urinary cadmium were low when 15 30 year-old, and higher when <15 or >30 year-old. According to gender, and 15 30, <15 and >30 years old, analysis the upper limit of cadmium in urine. The 95% upper limit of urinary cadmium of <15 and >30 year-old female (12.24 microg/gCr) was significantly higher than other populations ( <9.0 microg/gCr). Addition, the 95% upper limit of uriniary cadmium of the survey population exceeded the upper limit (5 microg/gCr) of the occupational cadmium poisoning diagnostic criteria in China (GBZ 17-2002). CONCLUSION: In the two rural high background areas of soil cadmium and non-cadmium polluted , urinary cadmium reference of non-cadmium occupational-exposed male is <9.0 microg/gCr, and female <13.0 microg/gCr. PMID- 25438527 TI - [Analysis of dyslipidemia among patients with diabetes mellitus in Jilin Province communities]. AB - OBJECTIVE: To investigate the pattern of dyslipidemia in patients with diabetes mellitus in Jilin province communities, and to provide a theoretical basis for the management of dyslipidemia among patients with diabetes. METHOD: Based on the prevalence and risk factors of chronic diseases survey among adults in Jilin Province 2012 used multistage stratified random sampling design, a total of 1825 community residents aged 18 -79 years-old with diabetes mellitus in 9 districts of Jilin Province undergo the survey with questionnaire(age, gender, history of chronic disease in the past one year), blood index detection (blood glucose, total cholesterol high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides), and anthropometric (height and weight). RESULT: Among 1825 patients with diabetes, 883 males (48.4%), 942 females (51. 6%); the mean age was (55.73 + 10. 27) years old. The mean values of TG,TC,LDL-C and HDL-C were 2. 17,5.17,3.10 and 1.20 mmol/L,the mean values of TC,LDL-C and HDL-C of female were higher than male(P <0. 001). The prevalence of dyslipidenmia. was 66.9% (69.0% in, male and 65.0% in female). The prevalence of dyslipidemia in male was decreased with increasing age(P <0. 001) , the prevalence of dyslipidemia in female was increased with age (P <0. 001). In age groups of 18- , 35 - and 45 - years, the prevalence of dyslipidemia in male was higher than female (P <0. 05,P <0. 001 ,P <0. 001)', however, it was lower than female in 55 and 65 - 79 years old grouips (P < 0.: 05). The prevalence of dyslipidemia of overweight '(71. 8%) and obesity (75. 8%) was higher than normal subjects. Among patients with diabetes, 19. 2% had high total cholesterol, 47. 8% had high triglyceride, 14. 5% had high levels of low-density lipoprotein cholesterol, 29. 2% had low high-density lipoprotein cholesterol. The proportion of diabetic patients two serum lipid values outside of clinical target were 27. 1% , the most prevalent dyslipidemia pattern among diabetic patients was a combination of TG above goal with HDL-C below target, which was observed in 17. 4 % of the patients. The second most common pattern of dyslipidemia was isolated TG increase, which was observed in 15, 9% of the patients. CONCLUSION: The mean values of TG,TC, LDL-C and HDL-C among community residents with diabetes mellitus in Jilin province were higher than the general population. The prevalence of dyslipidemia in male aged 18 -54 years, female aged 55 years and above and overweight or obesity was high; the most prevalent dyslipidemia pattern among diabetic patients was a combination of TG above goal with HDL_C below target. PMID- 25438528 TI - [Effects of high-fat diet on FABP2 mRNA expression in small intestinal tissue of young rats]. AB - OBJECTIVE: To measured FABP2 mRNA expression of small intestinal rats in response to high-fat diet; and to explore the correlation between expression and child obesity in rats. METHODS: The young obese rat models high-fat diet-induced method. Then the expression levels of FABP2 mRNA jejunum and ileum tissues of young rats were detected and analyzed using real time fluorescence quantitative PCR method. The serum biochemical assessed with an automatic biochemical Analyzer. RESULTS: In both rnd obesity group, the expression levels of FABP2 mRNA were highest in ermediate in the jejunum, and lowest in the duodenum both the control obesity group, there' were significant differences among them ( P <0. 05). Compated with control group, the expression levels of FABP2 mRNA in obesity group were significantly decreased (P <0.05); and the levels of blood glucose and serum TG in the obesity group were significantly higher (P < 0.05 ). CONCLUSION: FABP2 mRNA expression was different in diverse segments of intestinal tissue. Feeding high-fat diets allowed rats to reduce the expression levels of FABP2 mRNA in small intestinal tissue, meanwhile, the rats gained weight and elevate serum TG levels. It suggests that FABP2 involves in lipid metabolism, and is associated with the development of childhood obesity. PMID- 25438529 TI - [Effects of daily consumption of milk powder on menstrual cycles and urine sex hormone concentrations of young women]. AB - OBJECTIVE: To observe the effects of daily consumption of milk powder on Healthy young women, including the effect on menstrual cycles, ovulation time and sex hormone concentrations in morning urine. METHOD: Thirty-two young women were recruited as subjects and randomly assigned into two groups for a milk powder consumption experiment which lasted three menstrual cycles. The first menstrual cycle is control cycle, the second menstrual cycle is milk-taking cycle. The subjects take milk diluted by 33g or 55g milk powder each day, from the 4th to the 24th day of the second menstrual cycle. The third menstrual cycles is control cycle after milk-taking. During the whole three menstrual cycle, record the length of each menstrual cycle, determine ovulation time by using basal body temperature and oviposit test paper, collect their morning urine samples at specified times (the 4th, 7th, 10th, 13rd, 16th, 19th and 24th day of first and the third menstrual cycle; the 4th, 5th, 6th, 7th, 9th, 12nd, 15th, 18th, 21st and 24th day of the second menstrual cycle), determine the concentrations of estradiol, pregnanediol and creatinine in morning urine samples; draw the curve of the concentration changing over time and calculate the area under the curve to the 24th day. RESULT: In the high-dose group, the mean of the menstrual cycle length are (29.60 +/-3.180) d, (28.87 +/- 3.021) d, (29.60 +/- 2.995) d, the mean of the ovulation time are (15.47 +/- 2.200) d. There was no significant difference in menstrual cycle length and ovulation time among cycles and between groups (P>0.05). Calculate the difference between the first and the second menstrual cycle, and the difference between the two groups. In the high-dose group, the area under the curve of estradiol concentrations adjusted by creatinine are (7160.28 +/-2305.52), (6700.26 +/-2066.67); (6676.24 +/-2573.89); the area under the curve of pregnanediol concentrations corrected by creatinine are (51.93 +/-18.80), (44.55 +/-14.62) and (46.49 +/-22.44). In the low-dose group, the area under the curve of estradiol concentrations adjusted by creatinine are (6838.21 +/-2573.89), (6611.33 +/-1648.21) and (5949.24 +/ 1437.54)/ The area under the curve of pregnanediol concentrations adjusted by creatinine are (49.25 +/-15.68), (48.79 +/-15.61) and (43.45 +/-12.77). There's no significant difference of the area under the curve among three menstrual cycles and between two groups (P>0.05). CONCLUSION: 21 days' continuous daily consumption of milk powder does not have a significant impact on menstrual cycle, or on the estradiol/pregnanediol concentrations in morning urine. PMID- 25438530 TI - [Relationship of sub-health status to social support and coping styles of left behind middle school students in a reservoir area of Chongqing]. AB - OBJECTIVE: To explore the relationship between sub-health status and social support and coping styles of left-behind middle school students in a reservoir area of Chongqing. METHOD: 2247 students were chosen from three middle school by multistage cluster random sampling in a reservoir of Chongqing, 1528 were left behind students,719 were non-left students, surveyed with questionnaire by Multidimensional Sub-health Questionnaire of Adolescents (MSQA), Social Support Rating Scale (SSRS) and Trait Coping Style Questionnaire (TCSQ). RESULTS: Psychosomatic, physical and psychological sub-health state detection rate of left behind middle school students (10. 73%, 8. 24%, 12. 43%) were higher than non left students (9. 46%, 7. 37% and 10. 29%), but the difference was not statistically significant. Social subjective support, utilization of support and active coping style were protective factors for the sub-health status, grade and negative coping style were risk factors for the sub-health state. Grades, social support and coping style have significantly main effect on sub-health (P<0. 05), social support and negative coping have significantly interaction (P <0. 05). CONCLUSION: Sub-health problem is not prominent, negative coping has an important impact on the sub-health. PMID- 25438531 TI - [Effect of poor dietary behaviors on the overweight and obesity of school-aged children]. AB - OBJECTIVE: To explore the rate of overweight and obesity, and the association between unhealthy dietary behaviors and overweight and obesity among Chinese school-aged children from 9 areas. METHODS: By multiple stage stratified cluster sampling, 814 children aged 7 - 12 years old were chosen, provided with questionnaire and anthropometric measurements. According to the definition from Working Group on Obesity in China, children,were divided into different group, univariate logistic regression and multivariate logistic regression were used to analyze the associations between unhealthy dietary behaviors and overweight and obesity. RESULTS: The rates of overweight and obesity of school-aged children were 22. 88% and 9. 90%, respectively. The rates were higher in urban areas, and second-tier cities were similar with first-tier city. Influence factor analysis revealed skipping breakfast behavior was the influence factor (OR =1. 65, P<0.05, OR= 2. 22, P <0. 01), picky eating behavior was negative correlation (OR =0.43, P<0.01 ; OR = 0. 32, P <0. 01) , and eating fact food and drinking carbonated beverage were picked out by the multivariate logistic regression model. CONCLUSION: School-aged children's overweight and obesity has been an increasingly serious health problem, which were correlated with genetic factor, environmental factor, and dietary behaviors and so on, poor dietary behavior might be influence factor for overweight and obesity, so it is necessary to provide earlier intervention strategies for parents to promote children's good dietary habits. PMID- 25438532 TI - [Prevalence and characterization of cefotaxime and ciprofloxacin co-resistant Escherichia coli isolates in retail chicken carcasses]. AB - OBJECTIVE: To investigate the prevalence and characteristics of cefotaxime in co resistant Escherichia coli isolates in retail chicken samples and provide or the risk assessment and evaluation of new control measures of multi-drug i isolates in retail chicken products. METHODS: Whole chicken carcasses re collected from Shanxi (n = 91), Guangdong (n = 63) and Inner 53) from April to December in 2011, cefotaxime and ciprofloxacin co- li isolates were recovered and subjected to phylogenetic group typing and usceptibility testing. All isolates were further characterized by screening for genes, quinolone resistance determinants by PCR and followed by DNA sis. RESULTS: Cefotaxime and ciprofloxacin co-resistant E. coli isolates in 35.7% (73/207) of retail chicken carcasses. E. coli isolates of oup A were dominant (61.6%, 45/73) and all the isolates showed tant profiles. The dominant resistant profiles were AMP-CAZ-CTX-CIP- (n =34) and AMP-CAZ-CTX-CIP-CHL GEN-SXT-TET (n = 24). Point and ciprofloxac mutations in quinolone resistance determination, regions of topoisomerases were identified in all the isolates and most of the isolates accumulated three (n = 56) or four (n = 12) point mutations. Plasmid mediated quinolone resistant determinants were identified in 50 isolates, including oqxAB (n = 48) , aac(6')-Ib-cr (n = 5) , qnrS1 (n = 5) and qnrS2 (n = 3). Six subtypes of blaCTX-M were identified in 72 E. coli isolates and blaCTX-M 55 (n = 62) was dominant. CONCLUSION: Retail chicken could serve as an important reservoir of cefotaxime and ciprofloxacin co-resistant E. coli isolates. PMID- 25438533 TI - [Application of artificial neural networks in forecasting the number of circulatory system diseases death toll]. AB - OBJECTIVE: Set up the model of forecasting the number of circulatorys death toll based on back-propagation (BP) artificial neural networks discuss the relationship between the circulatory system diseases death toll meteorological factors and ambient air pollution. METHODS: The data of tem deaths, meteorological factors, and ambient air pollution within the m 2004 to 2009 in Nanjing were collected. On the basis of analyzing the ficient between CSDDT meteorological factors and ambient air pollution, leutral network model of CSDDT was built for 2004 - 2008 based on factors and ambient air pollution within the same time, and the data of 2009 est the predictive power of the model. RESULTS: There was a closely system diseases relationship between meteorological factors, ambient air pollution and the circulatory system diseases death toll. The ANN model structure was 17 -16 -1, 17 input notes, 16 hidden notes and 1 output note. The training precision was 0. 005 and the final error was 0. 004 999 42 after 487 training steps. The results of forecast show that predict accuracy over 78. 62%. CONCLUSIONS: This method is easy to be finished with smaller error, and higher ability on circulatory system death toll on independent prediction, which can provide a new method for forecasting medical-meteorological forecast and have the value of further research. PMID- 25438534 TI - [Study on the relationship between obesity and lipid metabolism in children and adolescent in yinchuan]. AB - OBJECTIVE: Discuss the relationship between obesity and hyperlipidemia in children and adolescent. METHODS: According to the BMI classification criteria of overweight and obesity screening in Chinese school-age child and adolescent, and the gender and nationality, age ( <=1 year-old), we performed the 1:1:1 match of the obesity, overweight and normal, there were 321 subjects in each group. Using "national unified measurement and method of youth physical fitness research", we did physical measurements on the subjects, and collected fasting venous blood to do biochemical detections, including blood glucose (FPG), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C ) , low density lipoprotein cholesterol (LDL-C). RESULTS: The differences of weight, waist circumference, hip circumference, SBP, DBP, TG, TC, LDL-C were statistically significant among the three groups (all P <0. 01 or 0. 05), the obese group was significantly higher than the normal group. With the increase of BMI, the abnormal rate of TG and TC were all upward trend, the obese group was significantly higher than the normal group, the differences were statistically significant( all P <0. 01 or 0. 05). After controlling factors of gender, nationality and age, TG was positively correlated with BMI, waist circumference, hip circumference and waist-high ratio (WHtR) (all P <0.01 or 0.05), HDL-C was negatively correlated with and BMI, waist circumference, hip circumference and WHtR (all P <0. 01 or 0. 05). After adjusting gender, nationality and age, with the increase of BMI, the risk for hyperlipidemia increased significantly, the risk of the obese group for hyperlipidemia was 1. 593 times than the normal group (95% CI 1. 144 -2. 220), it was statistically significance (P <0. 01). The level of TC, LDL-C and HDL-C in Muslim children and adolescents were higher than in Han., the level of TG were lower than in Han, but the differences were not statistically significant( All P > 0. 05) ). The abnormal rates of TC, LDL-C in Muslim children and adolescents were higher than in Han, the differences were statistically significant. CONCLUSIONS: The blood lipids levels of obese children and adolescents were obviously higher than that of normal one, especially TG and TC; obesity significantly increased the risk for hyperlipidemia in children and adolescents; the abnormal rates of TC, LDL-C in Muslim children and adolescents were significantly higher than in Han; Whether it is associated with ethnic genetic, remains to be further research. PMID- 25438535 TI - [Investigation on rates of awareness, treatment and control of diabetes mellitus and the influence factors in rural areas of Jilin province]. AB - OBJECTIVE: Assess the rates of awareness, treatment and control of diabetes mellitus and the influence factors in rural areas of Jilin province. METHODS: Multistage stratified random cluster sampling design was used to select participants that carried out with questionnaire interview and physical examination. The analysis was based on a representative sample of 923 diabetes mellitus. Multiple logistic regressions were used to examine socio-demographic factors associated with the levels of awareness, treatment and control of diabetes. RESULTS: Diabetes awareness, treatment, control and control among treated were 68. 9% ,57. 7% ,23. 9% and 41. 5% , respectively in rural area of Jilin province. Multivariable logistic regression analysis showed that the main effect factors on the rates of awareness were gender, family history of diabetes, smoke, drink and exercise. The rates of treatment were associated with age, occupation, family history of diabetes, drink and exercise, and the rates of control were associated gender. CONCLUSIONS: The rates of awareness, treatment and control of diabetes mellitus were expected to be improved in rural areas of Jilin province. The effective preventive strategies which concentrate on the influence factors should be taken to control their blood glucose level. PMID- 25438536 TI - [Determination of prometryne residue in shellfish by gas chromatography]. AB - OBJECTIVE: To develop a method of gas chromatography (GC) for determining residues of promtryne in shellfish. METHODS: The sample was extracted with ethyl acetate, and cleaned-up with Envi-Carb SPE cartridge, alumina-N SPE cartridge, and determined by GC-FPD with DB - 1701 capillary chromatographic column (30 m x0.53 .mm x 0.5um). RESULTS: Good linear was obtained in the concentration range of 0.10-0.96ug/ml with a correlation coefficient of 0. 999. The limit of detection (LOD) was 0.0037 mg/kg and limit of quantity (LOQ) was 0.010 mg/kg. The average recoveries was 83. 7% - 102. 0% and relative standard deviations (RSD) was 0. 54% - 8.14% CONCLUSION: The method is simple, fast and credible, so it can be applied to determination of prometryne in shellfish. PMID- 25438537 TI - [Effects-of combined calories restriction and polyunsaturated fatty acids on colitis in rats]. AB - OBJECTIVE: To explore the effect of n-6 and n-3 polyunsaturated fatty acids combined with calorie restriction( CR) in DSS induced ulcerative colitis rats. METHODS: Forty female rats were randomly divided into five groups, control group, model group, CR group, 5:1 PUFA ad libitum group, 5: 1 PUFA CR group. CR groups provided with a limited daily food allotment of 60% of that eaten by the ad libitum animals for 14 weeks. Ulcerative colitis model in rats were given 5. 0% dextran sulfate sodium in their drinking water for 7 days. RESULTS: 5:1 PUFA CR group significantly decreased body weight, disease activity index, macroscopic and histological score compared to model group. In addition, administration of 5: 1 PUFA CR effectively inhibited MPO activity. The levels of TNF-alpha and IL-6 in the serum with colitis were decreased by 5: 1 PUFA CR (P <0. 05). CONCLUSION: These results suggest that combination of calories restriction and n-6/n-3 =5:1 PUFA may be more beneficial in attenuating the progression of DSS induced ulcerative colitis. PMID- 25438538 TI - [Comparative evaluation of stx-PCR, Vero cell assay and Verotoxin enzyme imminoassay for detection of Shiga toxin-producing Escherichia coli]. AB - OBJECTIVE: To evaluate the suitability of stx-PCR, Vero cell assay and commercial enzyme immunoassay for detection of Shiga toxin Escherichia coli and to compare sensitivity and specificity of three different methods for detection of Shiga toxin-producing Escherichia coli. METHODS: Using stx-PCR, Vero cell assay and commercial enzyme immunoassay to detect 35 Escherichia coli reference strains and 45 strains isolated from food. RESULTS: The three methods all had good specificity. 31 strains gave positive reaction in the Vero cell assay and in the stx-PCR. The consistency between the Vero cell assay and stx-PCR was 100%. Only 38 strains can be detected by commercial enzyme immunoassay. CONCLUSION: stx-PCR method can serve as a routine rapid detection method in the laboratory. Vero cell assay is recommended to be the gold standard to determine whether the bacteria had the functionally active toxin. Commercial kit was suitable for preliminary rapid detection during clinical testing and outbreaks of food-borne disease. PMID- 25438539 TI - [Effects. of N-acetylcysteine on fluoride-induced endoplasmic reticulum stress in sertoli cells]. AB - OBJECTIVE: Investigated the effects of N-acetylcysteine (NAC) on endoplasmic reticulum stress of sertoli cells induced by sodium fluoride (NaF). METHODS: Rat sertoli cells were exposed to various concentration of (0, 6, 12, 24 ug/ml) sodium fluoride with or without 2 mmol/L NAC for 24 hours. The cell viability was evaluated using trypan blue exclusion test. Intracellular reactive oxygen species (ROS) was measured using the fluorescent probe DCFH-DA. Western blot was used to test the expression of GRP78, PERK and CHOP. RESULTS: It was found that treatment with NAC (2 mmol/L) restored the reduced cell viability and excessive oxidative stress (P < 0.01). Moreover, fluoride exposure upregulated the expression of GRP7 8, PERK and CHOP protein (P <0. 01 ). NAC was also found to suppress the levels of GRP78, PERK and CHOP expression in NaF-treated cells (p<0.01). CONCLUSION: Endoplasmic reticulum stress signaling pathways were activated by ROS, and NAC attenuate endoplasmic reticulum stress through inhibiting the levels of ROS in NaF-treated sertoli cells. PMID- 25438540 TI - [Determination of hexabromocyclododecanes diastereoisomers in human breast milk by HPLC-MS/MS]. AB - OBJECTIVE: A method for the determination of ac, 3 and gamma hexabromocyclododecanes (HBCDs) in human breast milk was developed by HPLC-MS/MS. METHODS: 3 -5 g human breast milk powder was spiked with '3C-HBCDs and then been extracted using Soxhlet extraction. The extract was dried and dissolved in 6ml of cyclohexane/ethyl acetate (1:1 ), then purified by gel permeation chromatography (GPC). The effluent was concentrated with rotary evaporation and then re dissolved in hexane. 2ml of sulphuric acid was added to remove the fat for further clean-up. After drying under nitrogen, the supernatant was dissolved in 100 ul of methanol and finally determined by HPLC-MS/MS. RESULTS: The linear range for the three diastereoisomers of HBCDs was in 1 - 50 ug/L, with correlation coefficients ranging from 0. 9997 to 0.998. The detection limits of the three diastereoisomers ranged from 0. 12 to 0. 22 ug/L. The recoveries for three spiking levels ranged from 82. 80% to 110. 60% . The intra-day and inter day relative standard deviations (RSD) were all less than 9. 4%. CONCLUSION: The developed method was simple, convenient and sensitive. It was suitable for the determination of or, P3 and y-HBCDs in breast milk and other matrix in the future. PMID- 25438541 TI - [Study of quercetin on pulmonary fibrosis by silica particles]. AB - OBJECTIVE: To observe the intervention effect of quercetin to silica dust cause pulmonary fibrosis. METHODS: Forty-eight healthy male adult SPF SD rats were selected and they were randomly divided into six groups (control group, 7 d,14 d,21 d and 28d dust group, preventive group). Rats in the control group were administrated 1 ml saline via trachea injection. Rats in dust group and preventive group were give silica solution for 1ml at dose of 50 mg/ml, and the prevention group with quercetin of 50 mg/kg every day lavage treatment intervention. In building on days 7,14,21,28 later, the lung tissue were removaled to HE staining for determining the degree of alveolitis and pulmonary fibrosis. The content of hydroxyproline (HYP) and the activities of catalase (CAT) and glutathione peroxidase (GSH-Px) were detected by using the kits. RESULTS: Alveolar septal edema, inflammatory cell infiltration and fibrosis were not found in control group. In the preventive group, lots of inflammatory cells infiltration were observed on days 7. Inflammatory cells were reduced, the number of the fibroblasts and matrix in alveolar septum were obviously increased, and alveolar structure was damaged on day 14. Pulmonary fibrosis was increased, severe fibrosis was found on day 28. Silicon dust after infected lung tissue expression of HYP content increased, the activity of CAT and GSH-Px decrease gradually. After joining quercetin the expression of HYP content gradually reduce, CAT and GSH-Px activity increased, the difference was statistically significant (P<0.05). CONCLUSION: Quercetin of silica dust caused by pulmonary fibrosis have certain prevention. PMID- 25438542 TI - [Determination of 35 kinds of plasticizers in drinking water by gas chromatography-mass spectrometry]. AB - OBJECTIVE: A method for simultaneous determination of 35 plasticizers in drinking water by gas chromatography-mass spectrometry (GC/MS)was developed. METHOD: The samples were extracted with ethyl acetateand, and separated by DB-5MS column. The identification and quantification were performed by GC/MS in selected ion monitoring (SIM) mode. RESULTS: The calibration curves of plasticizers showed linearity in linear range of 0. 05 - 2. 0 mg/L, and the correlation coefficients (r2 ) higher than 0.995. The limits of detection of the method were 0. 0001 -0. 001 mg/L (S/N =3), and the limit quantification were 0. 0004 - 0. 004 mg/L (S/N = 10). The average recoveries of 35 plasticizers in drinking water ranged from 65% to 118% with the relative standard deviations (RSDs, n =6) of 1.7% - 11. 5%. CONCLUSION: The method is suitable for determination of 35 plasticizers simultaneously in drinking water with easy operation, high accuracy and precision. PMID- 25438543 TI - [Analysis of the internal atmosphere of tableware disinfection cabinet]. AB - OBJECTIVE: To analyze the internal atmosphere of tableware disinfection cabinet, determine the composition and sources of odor gas. METHODS: Analyze the internal atmosphere of tableware disinfection cabinet by solid phase microextraction (SPME) with gas chromatography-mass spectrometry (GC-MS), and study the relationship between organic gas and auxiliary materials by simulating sterilization conditions. RESULTS: The organic gas had been detected in tableware disinfection cabinet both before and after use of it. The paint film and the sealing strip produced 56 and 76 kinds of organic gaseous substances after one cycle of sterilizer work respectively. Both UV irradiation and heating processes made the sealing strip produce 56 kinds of organic gaseous substances. CONCLUSION: UV irradiation and heating will induce auxiliary mainly came from the auxiliary material. PMID- 25438544 TI - [Evaluation on the capability of testing carbon tetrachloride, benzene, methylbenzene, dimethylbenzene, p' p-DDT of the provincial centers for disease control and prevention]. AB - OBJECTIVE: To evaluate the Centers of Disease Control and Prevention's (CDC) provincial divisions' capabilities of detectingconcentrations of organic parameters such as carbon tetrachloride, benzene, methylbenzene, dimethylbenzene and pesticide parameter of p' p-DDT in drinking water, by adopting a quality control assessment methodology of interlaboratory comparison. METHODS: All laboratories had been divided into 2 groups, each of which contained aboutl6 laboratories. Organic concentrations and pesticide concentrations were assigned to 2 sample groups. Testing capabilities of the laboratories were evaluated through the use of robust statistical methods. RESULTS: Thirty CDC provincial divisions, including municipalities under the central government and in autonomous regions, participated in this interlaboratory comparison. Twenty laboratories obtained positive results in all parameters, accounting for 66.7%. Eight laboratories' results were suspicious, accounting for 26.7%. Finally, 2 laboratories produced outliers, accounting for 6.7%. CONCLUSIONS: The majority of provincial CDC participants in this interlaboratory comparison are capable of testing the concentrations of organic parameterssuch as carbon tetrachloride, benzene, and methylbenzene, dimethyl benzene, and pesticide concentrations of p' p-DDT in drinking water. PMID- 25438545 TI - [Evaluation on the capability of testing total dissolved solids of the provincial centers for disease control and prevention]. AB - OBJECTIVE: To evaluate the Centers of Disease Control and Prevention's (CDC) provincial divisions' capabilities of detecting concentrations of organoleptic and physical parameter of total dissolved solids by adopging a quality control assessment methodology of interlaboratory comparison. METHODS: All laboratories had been divided into 2 groups of which contained 16 laboratories. Total dissolvedsolids' concentrations were assigned to 2 sample groups. Testing capabilities of the laboratories were evaluated through the use of robust statistical methods. RESULTS: Thirty-two CDC provincial divisions, including municipalities under the central government and in autonomous regions, participated in this interlaboratory comparison. Thirty laboratories obtained positive results, accounting for 93. 8%. Two laboratories' results were suspicious, accounting for 6. 2%. Finally, no laboratories produced outliers. CONCLUSIONS: The majority of provincial CDC participants in this interlaboratory comparison are capable of testing the concentrations of total dissolvedsolidsin drinking water. PMID- 25438546 TI - [Multiple epimutations in imprinted genes in the human genome and congenital disorders]. AB - The current knowledge on multiple epimutations in imprinted genes and their impact on the disturbances of human prenatal development and the emergence of hereditary diseases are reviewed and analyzed. Genetic mechanisms regulating the epigenetic state of imprinted loci in the human genome are discussed. PMID- 25438547 TI - [Induction of Hsp104 synthesis in Saccharomyces cerevisiae is inhibited by the petite mutation in the stationary growth phase]. AB - The elevation of Hsp104 (heat shock protein) content under heat shock plays a key role in yeast (Saccharomyces cerevisiae) cells. Hsp104 synthesis is increased under heat stress in the stationary growth phase. As shown, the loss of mitochondrial DNA (petite mutation) inhibited the induction of the Hsp104 synthesis under heat stress (39 degrees C) during the transition to the stationary growth phase. Also, the petite mutation suppressed the activity of antioxidant enzymes in the same phase, which led to lower thermotolerance. At the same time, the mutation inhibited production of the reactive oxygen species and prevented cell death under heat shock in the logarithmic growth phase. The results of this study suggest that disruption of the mitochondrial functional state suppresses the expression level of yeast nuclear genes upon transitioning to the stationary growth phase. PMID- 25438548 TI - [The effect of wheat-rye substitution on chromosome elimination: an analysis of univalents' behavior in wheat meiosis with dimonosomy and tetramonosomy]. AB - The effect of wheat-rye chromosome 1Rv/1A, 2R/2D and 6R/6A substitutions characterized by differences in the expression of the equational division of sister centromeres in anaphase I on segregation and the elimination of wheat and rye univalents was investigated. To determine the individual effect of each of the studied chromosomal pairs, a comparative analysis of the univalent behavior in the meiosis of double monosomics 1Rv-1A, 2R-2D, 6R-6A and tetramonosomics 1Rv 2R-1A-2D, 1Rv-6R-1A-6A, 2R-6R-2D-6A was conducted. 2R/2D substitution was experimentally demonstrated to suppress an equational univalents division, while 6R/6A substitution resulted in high frequency chromosomes' elimination, especially in the meiosis of 2R-6R-2D-6A tetramonosomics. Other meiotic mechanisms, together with the sister chromatids separation at anaphase I, may affect the elimination of the final products of univalent segregation. It was demonstrated that the number and pattern of univalent chromosomal behavior affected hybrid plant fertility. PMID- 25438549 TI - [Mitochondrial DNA variation in Olga Bay larch (Larix olgensis A. Henry) from Primorsky Krai of Russia]. AB - Two mitochondrial DNA fragments, nad4(3c-4r) and nad5(1-2r), were sequenced in 58 larch accessions from the range of Larix olgensis A. Henry. Combinations of the nad4 polymorphic sites formed four haplotypes, two of which (H3 and H4) were unique and two (H1, H2) were common. Haplotype H1 was found only in pure L. olgensis from the vicinity of Olga Bay and in a number of accessions from the southern part of the range. Haplotype H2 was detected in the other samples from the range of Olga Bay larch, as well as in hybrid forms. Similarly to the nad4(3c 4r) fragment, the mtDNA fragment UBC460 was able to differentiate larch populations from the range of L. olgensis examined. PMID- 25438550 TI - [Genes for wheat resistance to yellow rust and the role of epiphytoties in the emergence of new races]. AB - The paper presents the results of a multi-year assessment of wheat resistance to yellow rust on an artificial infectious background in the field. The dynamics of the disease in the differentiator-varieties with identified resistance genes is studied. The formation of new races of the pathogen after its epiphytoties is revealed. The loss of resistance of certain genotypes that had "effective genes" and were resistant to the disease at the beginning of the experiment is registered. The age resistance of plants, which is of great importance in breeding of resistant varieties of wheat, is analyzed. PMID- 25438551 TI - Evaluation of bamboo genetic diversity using morphological and SRAP analyses. AB - Bamboo is an important member of the giant grass subfamily Bambusoideae of Poaceae. In this study, 13 bamboo accessions belonging to 5 different genera were subjected to morphological evaluation and sequence-related amplified polymorphism (SRAP) analysis. Unweighted pair-group method of arithmetic averages (UPGMA) cluster analysis was used to construct a dendrogram and to estimate the genetic distances among accessions. On the basis of morphological characteristics, the 13 accessions were distinctly classified into 2 major clusters; 3 varieties, PPYX, PGNK, and PLYY were grouped as cluster A, and 10 accessions were categorized under cluster B. Similarity coefficients ranging from 0.23 to 0.96 indicated abundant genetic variation among bamboo varieties. Approximately 38 SRAP primer combinations generated 186 bands, with 150 bands (80.65%) showing polymorphisms among the 13 accessions. Based on SRAP analysis, 13 bamboo accessions were grouped into 3 major clusters. Five species comprised Cluster I (PASL, PLYY, PTSC, SCNK, and BMAK), which belongs to genus Phyllostachys. Cluster II consisted of 5 varieties, PASL, PLYY, PTSC, SCNK, and BMAK; Cluster III included 3 varieties, PGNK, PLSY, and BMRS. Comparison of the results generated by morphological and SRAP analyses showed that the classification based on SRAP markers was more concordant to the taxonomic results of Gamble than that performed using morphological characters, thus suggesting that SRAP analysis is more efficient in evaluating genetic diversity in bamboos compared to morphological analysis. The SRAP technique serves as an alternative method in assessing genetic diversity within bamboo collections. PMID- 25438552 TI - [Haplotype diversity in the mtDNA cyt b gene in round goby (Neogobius melanostomus (Pallas)) from the Northwestern part of the Black Sea Basin]. AB - To study the genetic causes of successful biological invasion, haplotype diversity in the mtDNA cyt b locus was examined in populations of the round goby (Neogobius malanostomus (Pallas): (Gobidae, Piscs) from the Black Sea basin, which is considered tobe the main source of irruption. It was demonstrated that the haplotype diversity of this species was much higher than was assessed earlier. At the population level, a statistically significant association of haplotype diversity with the individual variation of plastic characters was established. PMID- 25438553 TI - [Position of the genus Azygopterus (Stichaeidae, Perciformes) in the system of the suborder Zoarcoidei as inferred from sequence variation of mitochondrial and nuclear genes]. AB - Analysis of sequence variation in the mitochondrial and nuclear genes in Azygopterus corallinus showed that this species was genetically close to the group uniting the representatives of the families Zoarcidae, Neozoarcidae, and Anarhichadidae. The considerable genetic differences between A. corallinus and the members of the family Stichaedae, to which it was assigned earlier, are consistent with the divergence estimates between the other families of the suborder Zoarcoidei (Zaproridae, Ptilichthyidae, Pholidae, Cryptacanthodidae, Bathymasteridae). PMID- 25438554 TI - [Genetic subdivision of the Buryat population]. AB - The results of an estimation of the level of subdivision in the Buryat ethnos (obtained oh the basis of data published by a number of research teams) are given. Altogether, information about 34 loci, including 25 diallelic loci and 9 STR loci, was analyzed. The results of the analysis, both for the diallelic polymorphic variants in genes predisposed to multifactorial diseases and for neutral STR markers, indicate the subdivision of the genetic structure of the different territorial groups of Buryats. The peculiarities of the ethnogenesis and heterogeneity of the settlement of Buryat tribes on the territory of residence are considered as one possible (but not the sole) explanation of the genetic heterogeneity of different territorial groups of Buryats. It is indicated that it is important to take into account information about the territorial, ethnic, and tribal affiliation of individuals (included in the studied groups) when planning studies aiming to establish a genetic component of the determination of pathological states in humans. PMID- 25438555 TI - [Arginine-vasopressin receptor gene (AVPR1A, AVPR1B) polymorphisms and their relation to personality traits]. AB - The present study aimed to assess the main effects ofAVPRIA (rs11174811, RSI) and AVPRIB (rs28632197, rs33911258) gene polymorphisms, as well as haplotypic, GxE and GxG effects on personality trait variation in 1018 healthy individuals, considering gender and ethnicity confounding. Haplotype analysis revealed an association ofAVPRIA C*S- and C*L-haplotype (rs11174811 and RS1, respectively) and increased (PFDR= 0.016) or decreased (PFDR = 0.031) Extraversion (EPI) in Bashkirs, respectively. The association of AVPR1B G*A-haplotype (rs28632197 and rs33911258, respectively) and decreased Self-transcendence (TCI-125) (P(FDR) = 0.040) was demonstrated in the total sample and in Udmurts. GxE analysis revealed that the birth season modulated the involvement of the AVPR1A (rs11174811) gene marker in the variation of Persistence (TCI-125) in the total sample (P(FDR) = 0.012). The modulating effect of several environmental factors (ethnicity and birth season) on the association of AVPR1A and AVPR1B gene polymorphisms and personality traits was established. PMID- 25438556 TI - Genetic analyses of Xianbei populations about 1,500-1,800 years old. AB - To understand the profile of genetic structure of Xianbei and trace its impacts on the formation and development of the minorities from northern China, we analyzed the sequences of the hypervariable segment I (HVS-I, 16.035-16.398) in mtDNA control region of 17 Tuoba Xianbei remains from Shangdu Dongdajing cemetery (Inner Mongolia). Its haplotype diversity and nucleotide diversity were 0.971 +/- 0.032 and 0.0184 +/- 0.010, respectively, and the haplogroup status presented 29.5% C, 23.5% D4, 17.6% D5, 17.6% A, 5.9% B and 5.9% G. When the data from Qilang Mountain Tuoba remains and other relevant populations were considered, we found that Dongdajing Tuoba Xianbei presented the closest genetic affinity to Qilang Mountain Tuoba Xianbei. Tuoba Xianbei and Murong Xianbei showed a significant differentiation in the maternal lineages. Tuoba Xianbei may contribute to the gene pool of some northern minorities, and it may mix with Xiongnu in northern China. PMID- 25438557 TI - [InR gene expression and octopamine metabolism in Drosophila melanogaster females]. AB - The influence of suppression of the expression of the Drosophila insulin-like receptor gene (InR) in corpus allatum (the gland-synthesizing juvenile hormone) on octopamine and juvenile hormone metabolism and on the development of the stress-reaction in Drosophila melanogaster females was studied. It was demonstrated that the suppression of InR gene expression in corpus allatum induces in D. melanogaster females an increase in the activity of the enzyme that limits the rate of octopamine synthesis (tyrosine decarboxylase), as well as in the level of juvenile hormone degradation and the intensity of the response of octopamine and juvenile hormone metabolism systems to heat stress. It was mentioned that a decrease in InR gene expression in corpus allatum does not influence the activity of OA-dependent N-acetyltransferase (the enzyme that degrades octopamine). It was established that the influence of suppression of the InR gene expression in corpus allatum on octopamine metabolism is mediated by juvenile hormone, since the processing of flies by exogenous juvenile hormone restores the activity oftyrosine decarboxylase in flies with decreased InR expression in corpus allatum up to the normal level. PMID- 25438558 TI - [Bacillus subtilis ypaA gene regulation mechanism involves FMN-binding sensor RNA]. AB - We studied the regulation of the Bacillus subtilis ypaA gene-encoding riboflavin transporter protein involving FMN-dependent sensor RNA. Using translational fusions of the wild-type ypaA gene with the lacZ-reporter gene in the leader region we showed that in vivo ypaA gene expression decreased more than 10-fold in the presence of endogenous FMN. Introduction of two nucleotide substitutions providing stabilization of the sequester hairpins results in almost complete repression of reporter gene expression. Using toeprint assay in vitro it has been shown that FMN presence inhibits the formation of the 30S initiation complexint the ypaA gene leader mRNA. Our results support the model of ypaA gene regulation whereby FMN binding with the ypaA gene leader sequence results in translation suppression through the sequestering of the SD-sequence. PMID- 25438559 TI - [Molecular, neurochemical and neurophysiological mechanisms of plasticity: realization of behavior, learning, consolidation, storage and retrieval of memory]. AB - Described the real pyramidal and extrapyramidal neural networks of the mammalian brain, realizing asbehavior, motor control and involved in learning and memory. The algorithm of postsynaptic excitatory glutamatergic synapses plasticity analyzed, which leads to the modification and storage for a long time, the efficiency of synaptic transmission --ong-term potentiation, long-term depression. Analyzed the mechanisms of plasticity allosteric GABAA(-)redcptors. Described the molecular and cellular mechanisms of the trafficking of GABAA( )receptors and its role in the dynamic modulation of neuronal inhibition. Analyzed molecular and cellular plasticity algorithm of allosteric GABAA( )receptors. Discussed hypoth-sis update neural networks that is realized on a molecular level with the internalization and recycling mechanism specific GABAA( )receptor cluster. It is assumed that the process of transfer from the memory stage storage to the stage of working memory. Deactualization of neural network, which is implemented at the molecular level by the mechanism of internalization specific cluster of GABAA(-)receptor, is a pro-ess of transferring from stage of working or random access memory in the storage stage. PMID- 25438560 TI - [Serotonine and sex steroids in the system of neuroendocrine regulation of amygdala functions]. AB - This review contains modern information about the representation of serotoninergic system in the Amygdala with detailed characteristics of the localization of serotonine fibers and serotonine receptors in nuclear and paleocortical structures. These data indicate the joint participation of serotonine and sex steroids in the regulation of the neuroedocrine function of Amygdala, which have a modulating effect on the secretion and release gonadotropine centers and sexual behavior centers in the hypothalamic area of the brain. The survey also gives information about changes in the exchange of serotonine in the Amygdala's structures in the process of alimentary, maternal, aggressive-defensive and emotional behavior. Systematizes the data on the role of serotonin and sex steroids in the mechanisms involved in the stress response of Amygdala, and its participation in the formation of mood, emotions and the genesis of depression. Presented data on changes in morphometric characteristics of brain structures caused by polymorphic variants of genes of serotoninergic systems and data on the asymmetry of its content. PMID- 25438561 TI - [Music therapy and "brain music": state of the art, problems and perspectives]. AB - Recent literature on the problem of interaction between music and the brain is reviewed and summarized. Mechanisms and effects of two most popular music therapy applications are picked out, including music listening and music making. Special attention is paid to relatively new line of investigations that is called "music of the brain" and deals with transformation of bioelectric processes of human organism into music. Unresolved questions of music therapy are identified and some promising lines of future investigations are delineated. PMID- 25438562 TI - [Functional role of monounsatuilated fatty acids in the human]. AB - This review discusses the metabolism of key monounsaturated fatty acids in human (Omega7-palmitoleic acid, Omega9-oleic acid). These acids are obtained from dietary sources and can also be synthetized endogenously. Palmitoleic and oleic acids belong to different Omega-families of fatty acids and their structural differences may cause variations in their susceptibility to enzyme and free oxygen species attacks. These characteristics may also determine the physiological role of abovementioned acids. This article is dedicated to analysis of peculiar features of human monounsaturated fatty acids metabolism in comparison with other fatty acids in normal and pathological conditions. PMID- 25438563 TI - [Molecular basis of circadian rhythms and principles of circadian disruption]. AB - Current knowledge of core molecular mechanisms of circadian system is reviewed with intent look at consequences of pleiotropic effects of phase and amplitude disturbances in rhythmic expression of genome-transcriptome-proteome elements in development of desynchronized phenotypic functions. Multiple adverse implications of compromised circadian synchronization for health and longevity are discussed. Concept of extracircadian dissemination of output physiological functions as a general feature of phenotypic circadian disorder is PRESENTED. PMID- 25438564 TI - [Nitric oxide in vascular endothelium: control of production and mechanisms of action]. AB - The review analyzes the literature on the regulatory role of NO in blood vessels. Particular attention is paid to the modern ideas about the regulation of expression and activity of endothelial NO-synthase, including those involoving microRNAs--a new class of small regulatory molecules. The physiological mechanisms activating NO-synthase in endothelial cells and key targets of NO pathway in vascular smoth muscle cells are reviewed as well. PMID- 25438565 TI - [On the application of Bergmann's rule to ectothermic organisms: the state of the art]. AB - Bergmann's rule (BR) is a classical eco-geographic rule that relates body size of homoiothermal animals with environmental temperature (or latitude). Contemporary data indicate that latitudinal clines in body size, predicted by BR, also exist in ectothermic organisms and in some groups appear to be fairly common. Despite plenty of data from literature, it is still impossible to estimate the frequency of Bergmann's clines occurrence in ectotherms as thoroughly as it is done for homoiotherms. Within large taxa of ectotherms (Arthropoda, Mollusca, Pisces), Bergmann's clines occur alongside with anti-Bergmann's and U-shaped ones. Since classic explanation of BR, which is based on thermoregulation principles, is not applicable to most ectotherms, quite a few hypotheses have been proposed that appeal to other foundations in search of such an explanation. One part of them suggests a direct modifying influence of temperature, though most authors look for adaptive sense in increase of ectotherms size at high latitudes and/or low temperatures. It appears that a single universal explanation of all the cases of Bergmann's variability in ectotherms can not be formulated. Observed clines, as it seems, arise as a result of synergetic interactions between several factors that are covaried with latitude (or altitude above sea level). It is not always possible to estimate the exact contribution of each one of them. PMID- 25438566 TI - [Oxidative stress, rRNA genes, and antioxidant enzymes in pathogenesis of schizophrenia and autism: modeling and clinical advices]. AB - Ribosomal genes (RG), or genes for rRNA, are represented by multiple tandem repeats in eukaryotic genomes, and just a part of them is transcriptionally active. The quantity of active copies is a stable genome feature which determines the cell's capability for rapid synthesis of proteins, necessary to cope with stress conditions. Low number of active RG copies leads to reduced stress resistance and elevated risk of multifactorial disorders (MFD). Oxidative stress (OS) in the brain cells is believed to be involved in the pathogenesis of infantile autism (IA) and schizophrenia, i.e., MFDs with a manifested genetic predisposition. With autism, OS markers are found almost in every research, whilst with schizophrenia, the OS data are contradictory. Earlier, in a sample of patients with schizophrenia, we have found significantly higher quantity of active RG copies than at the average in healthy population. Here we have estimated the number of active RG copies in a sample of patients with IA (n = 51) and revealed significantly lower mean value than in healthy population. A novel mathematical model of the dynamic pattern of OS has been proposed. The model is realized as an ordinary differential equation system, supposing induction of antioxidant protection enzymes being mediated by reactive oxygen species (ROS), with the subsequent decrease of ROS content in a cell. The rate of synthesis of antioxidant protection enzymes is limited by the ribosome synthesis rate which depends on the number of active RG copies. Analysis of the model showed that the system always approaches a single stable equilibrium point along a damped oscillation trajectory, which in some degree resembles the dynamics of 'predator prey' interaction in Lotka-Volterra model. The stationary ROS level inversely depends on the number of active RG copies. Our study explains the inconsistency of clinical data of OS in schizophrenia and suggests a novel criterion for discriminative cytogenetic diagnostics of schizophrenia and IA, as well as allows to assume that antioxidant therapy should be effective only for children with low number of active RG copies. PMID- 25438567 TI - [Magnetic fields and fish behavior]. AB - In the review, contemporary data on the influence of natural and artificial magnetic fields on fish behavior are considered. In this regard, elasmobranchs and teleosts appear to be studied most exhaustively. Elasmobranchs and some teleosts are able to perceive magnetic fields via electroreceptors. A number of teleosts can sense magnetic fields via sensory cells containing crystals of biogenic magnetite. Laboratory experiments and field observations indicate the influence of magnetic fields on fish locomotor activity and spatial distribution. The geomagnetic field can be used by fish for navigation. Besides, artificial magnetic fields and natural fluctuations of the geomagnetic field can affect fish embryos leading to alterations in their development. It is suggested that, afterwards, these alterations can have an effect on fish behavior. PMID- 25438568 TI - [Resting metabolic rate, stress, testosterone, and induced immune response in "spring" and "fall" males of Campbell dwarf hamsters. Rearing under the long day conditions]. AB - We have studied morphological and physiological traits of even-young males of Campbell dwarf hamsters (Phodopus campbelli Thomas, 1905) born at the end of summer ("fall males") and at the end of winter ("spring males") in a vivarium with constant 14-hour day length (14D:10N). After removal from parental cages at the age of one month, males were kept in isolation under the same light conditions. The results obained signify the statistical difference between "fall" and "spring" males in resting metabolic rate, morphological traits associated with sexual activity, some endocrine and immunologic characteristics. Spring males had higher resting metabolic rate, higher body mass in the middle of experiment, bigger testes, seminal vesicles, higher concentration of testosterone in blood and more intensive T-cell immune response to the intracutaneous injection of phytohemagglutinin. They did not differ significantly in basal level of blood cortisole and antibodies production in response to sheep red blood cells (SRBC) antigen challenge, but possessed lower adrenocortical response to the social stressor and adrenocorticotropic hormone. GLM analysis showed that cortisol level in blood after 10 min encounter of males in the open arena, and resting metabolic rate were the only factors significantly influenced humoral immune response to SRBC. When intensity of T-cell immune response was considered as dependent variable, season turned out to be the only factor in the final model that caused a significant effect. PMID- 25438569 TI - [The infradian rhythm in changes of thyroxine level and related periodicity of feather replacement during the molting in passerine birds]. AB - In the course of 15 days, the thyroxine and corticosterone level was measured daily in blood serum of molting starlings, Sturnus vulgaris, by use of enzyme immunodetection method. Revealed are three-day rhythm in changes of thyroxine level and four-day one in changes of corticosterone level, both rhythms being synchronized in different birds. A beginning of growth of new oar feathers coincides with maximum thyroxine concentration in blood serum and also demonstrates a three-day period. In free-living passerine birds (Passer montamus, Parus major, Chloris chloris) a three-day rhythm is found in the dynamics of feather replacement. This rhythm is manifested synchronously in the studied species that differ in timing of post-nuptial molting. Established is the synchronous manifestation of three-day rhythm in changes of thyroxine level and feather replacement during molting in different passerine species and different birds of the same species. PMID- 25438570 TI - [Epiphytic communities of arboreal formations in Southern Vietnam: an analysis of species composition and synusias structure in dependence on the extent of anthropogenic impact]. AB - Species composition of epiphytic communities within different formations of Phu Quoc Island (Southern Vietnam) is studied. The dependence of species composition and structural complexity of epiphytic communities on formation quality is demonstrated. Representatives of different families differ notably in their sensitivity to disturbances. Most vulnerable are Orchidaceae which represent the dominant group in epiphytic community of rain forest and which drop out almost completely under anthropogenic impacts. In less disturbed forests, epiphyte species diversity increases mainly at the expense of "lower" synusias and directly depends on the formation layering. Diminishing of layering numbers leads to dropping out of species belonging to "lower" synusias. Among epiphytes, the indicators of disturbed communities can be detected, namely species of ruderal strategy (explerents). In primal rain forest, they are absent or barely noticeable. An index is proposed for estimation of epiphytic communitiy complexity. PMID- 25438572 TI - [To the centenary of academician M.S. Giliarov]. PMID- 25438573 TI - [The contribution of M.S. Giliarov to the theory of evolution]. AB - A review is presented of academician M.S. Ghilarov's principal works dealing with general problems of the evolutionary biology. His main attention in the analysis of phylogenetic relationships in invertebrates and regularities of the evolution of main organ systems has been paid to the significance of ecological factors and functional properties of morphological structures. Taking this approach as the basis, M.S. Ghilarov considered ways of animals' adaptation to the terrestrial mode of life through soil as the transit environment. He has developed new approaches to the interpretation of aromorphic and idioadaptive changes in animals' organization and to the origin of the insect metamorphosis. Patterns, being common for all groups of animals, were revealed with regard to the processes of phylogeny and mechanisms of their control by the principle of positive feedbacks. PMID- 25438574 TI - [Earlier steps of the soil ecosystem evolution]. AB - Fossil soils are known since early Praecambrian, long before the occurrence of higher terrestrial plants on the Earth. Primeval biocoenoses on the land and in continental water bodies were floating and bottom prokaryotic mats and films which produced the majority of biomass and with regard to specific productivity were not inferior to any other photosynthetics. Before the occurrence of higher plants, erosion was very strong, resulting in flat relief, absence of permanent streams, domination of wandering rivers and surface runoff; all water bodies were muddy. When floods occurred, which was quite so often, clay particles of muddy water streams isolated bottom-mats from the light and then their considerable part perished. The result was not soil as a uniform bioinert body but rather a "puff pie" consisted of layers of unoxidized charred organic matter and clay prolayers. The burial of unoxidized organic matter contributed to enrichment of the atmosphere with oxygen. Worms and arthropods, which came out to the land and continental water bodies during Cambrian period, mixed up the organic matter with mineral components strengthening the process of soil forming considerably. Soils of the modern type appeared after higher plants expanded in Devonian and displaced bottom-mats in shallow waters. The soil fauna that existed at this time was not so different from the modern one with regard to its evolutionary level. PMID- 25438575 TI - [Importance of competition for pollination in formation of the entomophylous plants complex structure]. AB - Many species of entomophylous plants have a wide range of pollinators, and the same insects visit flowers of many plants. The competition for pollination leads to decreasing in seed production of competing species. However, there exists a variety of adaptations that allow plants to reduce the intensity of competition. A comparative analysis of pollinators spectra has allowed to designate groups (subcomplexes) of plants with regard to dominance of various groups of pollinators: myiophylous (flies from the superfamily Muscomorha dominate), syphidophylous (flies from the family Syrphidae dominate), psychophylous (butterflies dominate), cantharophylous (beetles dominate), nonspecialized and specialized melittophylous (Apidae, mainly bumblebees, dominate). The belonging of plants to a specific subcomplex is defined mainly by the structure of flowers and inflorescences. Modes of mechanical and attractive isolation are discussed that lead to restriction of pollinators composition. Competition abatement between species with similar spectra of pollinators and belonging to the same subcomplex is achieved mainly by spatial (ecological) and temporal (different timing of flowering) isolation. PMID- 25438576 TI - [Trophic chains in soil]. AB - Trophic links of soil animals are extensively diverse but also flexible. Moreover, feeding activity of large soil saprotrophs often cascades into a range of ecosystem-level consequences via the ecological engineering. Better knowledge on the main sources of energy utilized by soil animals is needed for understanding functional structure of soil animal communities and their participation in the global carbon cycling. Using published and original data, we consider the relative importance of dead organic matter and saprotrophic microorganisms as a basal energy source in the detritus-based food chains, the feeding of endogeic macrofauna on the stabilized soil organic matter, and the role of recent photosynthate in the energy budget of soil communities. Soil food webs are spatially and functionally compartmentalized, though the separation of food chains into bacteria- and fungi-based channels seems to be an over simplification. The regulation of the litter decomposition rates via top-down trophic interactions across more than one trophic level is only partly supported by experimental data, but mobile litter-dwelling predators play a crucial role in integrating local food webs within and across neighboring ecosystems. PMID- 25438577 TI - [Zoological diagnostics of soils: imperatives, purposes, and place within soil zoology and pedology]. AB - Zoological diagnostics of soils was conceived by M.S. Ghilarov as a part of soil zoology and intended to be closely related to pedology. He considered zoo-agents as an ecological factor, one among many others, of soil formation. Contemporary soil diagnostics pursues mostly utilitarian goals and is based on conservative properties of the stable part of soil substrate. However, it is admitted that these properties are generated by specific combinations of biological, chemical, and physical phenomena that are called "elementary soil processes" (ESP) and occur nowhere but in soils. Certain ESPs are associated with distinctive combinations of biota, including invertebrates. Pedobionts act as producers of detritus and contribute to humus formation, which is necessary for any ESP starting, thus being its active party. That is why animals, being the most complex and active part of the ESP system, may be treated not only as its indicators but also as its navigators. Monitoring and studying of ESPs in soil is complicated because of inevitable disturbance of soil profile natural composition. Zoo-agents, at the same time, can be registered without habitats changing. Taking into account ecological potency of soil invertebrates that participate in an ESP, spectra of their eco-groups, life forms, and results of their activity, it is possible to diagnose a soil state at different stages of certain ESPs development, with their different combinations, and in different regions or parts of natural environmental gradients. PMID- 25438578 TI - [Transverse folding and the evolution of hind wings in beetles (Insecta, Coleoptera)]. AB - Strong intensification of the protective function of the fore wing in Coleoptera has made their flight apparatus a posteromotoric one and invited an apparatus responsible for folding the hindwings beneath the elytra to develop. Folding apparatus could hardly develop without higher deformability of veins or their parts, which diminished strength properties of the wing support. The effect was stressed by folds that intersected veins. Organization of the folds into a system confined this negative influence to a few wing regions and some veinal sections. This having happened, wing support and folding pattern evolved interrelated, the former into being more flexible, with no or minimum loss of rigidity, and the latter towards being less harmful for the supporting elements, especially axial ones. Monofunctionality, together with very simple structure and little specialization of constituent parts, made the folding pattern very labile during evolution. The folding pattern evolved more rapidly than wing venation, thus defining transformations of the latter. Evolutionary conservatism of wing venation stemmed from that many veins were strongly specialized in performing two conflicting functions. An adaptive compromise was necessary for the conflict to be solved, which determined the wing to orthogenetic development. The main evolutionary trends for wing venation and folding pattern were those towards simplification and a higher complexity, respectively. The beetle wing has passed through two main evolutionary stages. Among them, the first resulted in the development of the "Archostemata" wing type, the second started from the "cantharoid" structural plan. The main evolutionary factors were the infancies of wing posteromotorism at the first stage while the wing strongly influenced by size evolution, with the main trend towards miniaturization, at the second. The archostematan and "cantharoid" morphofunctional wing types differ fundamentally. In the wing of the former kind, folding and flight apparatus, because of considerably overlapping supporting systems, constitute a lasting coadaptive ensemble, with only minor deviations from the ground-plan occurring through evolution. The uprise of the "cantharoid" wing type was an upgrade of morpho functional organization. The region of maximum transverse deformations having been extruded from the remigium basal part, chief supporting axes of the wing increased their rigid properties. The supporting systems of the two wing apparatus became more autonomous, having been separated. This expanded the adaptive zone for the wing strongly, which a great variety of derived wing types have emerged from. PMID- 25438579 TI - [Role of glycogen synthase kinase-3 in mechanisms of learning and memory]. AB - In the current paper a review of the role of GSK-3b in mechanisms of learning and memory is presented. A regulation of GSK-3 by phosphorylation of serine and tyrosine sites and through Wnt signaling pathway by disruption of axin-beta catenin complex is described. The data on participation of GSK-3b in regulation of NMDA-dependent long-term depression and potentiation, and the possible mechanisms of enzyme's influence through NMDA receptors and AMPA endocytosis are shown. A role of GSK-3b in development of Alzheimer's disease through inhibition of Wnt signaling parthway by beta-amyloid resulting in a strengthening of GSK-3b activity with further hyperphosphorylation of tay and formation of the neurofibrillary complexes are also considered. Behaviour of animals with knockout and overexpression of GSK-3b gene and effects of GSK-3 inhibitors in different behavioural models are also described. PMID- 25438580 TI - [The central pattern generators]. AB - The central pattern generator (CPG) is defined as a set of neurons involved in joint production of patterned motor output. The roundtable discussion on the CPG was a part of the 5th All-Russian Conference on Animal Behavior (Moscow, Nov. 21, 2012). The discussion centred on three core themes: 1) the mechanisms of the organization and reconfiguration of pattern generating neuronal ensembles, 2) extrapolations that extend the CPG concept beyond the motor systems, and 3) evolutionary and developmental aspects of CPG. PMID- 25438581 TI - [Interdisciplinary approach to analysis of brain mechanisms of learning difficulties: application to the ADHD children study]. AB - The study presents the interdisciplinary approach to the analysis of the brain mechanisms of learning difficulties in primary schoolchildren. The neuropsychological assessment and the resting-state EEG estimation were applied to analyze the neurophysiological factors of cognitive deficits in children with ADHD symptoms aged 7-8 and 9-10. EEG recordings of children with ADHD symptoms more frequently, as compared to children with typical development, contained EEG patterns of the fronto-thalamic system non-optimal functioning, reflected in frontal theta waves (FTW), right hemisphere local electrical activity (EA) deviations and EEG patterns associated with the general activation deficit arising from the brainstem reticular formation (DA). We specified cognitive impairments associated with different types of resting-state EEG deviations in ADHD children. Children with FTW of both age groups demonstrated pronounced difficulties in programming, regulation and control (executive functions) and verbal performance. Children with right hemisphere local EA abnormalities had executive functions deficit combined with difficulties in nonverbal performance. Children with EEG signs of DA of both age groups had a decreased cognitive processing speed and efficiency. Younger children with DA demonstrated difficulties in nonverbal task performance. Thus, the interdisciplinary study provided the evidence for at least three neurophysiological factors which can specifically impede the cognitive performance in ADHD children. PMID- 25438582 TI - [Age differences in memorizing of sequence of movements of leading and subdominant hand]. AB - Age-specific features of motor short-term memory were studied. Two groups of right-handed volunteers (18-25 and 35-60 years old) reproduced the memorized sequence of six movements by the right hand or by the left one. The mean values of erroneous movements are shown to be significantly higher in elder group, demonstrating the age-dependent reduction of motor short-term memory capacity. More detailed analysis of reproduction of separate elements of the sequence demonstrates that the age-dependent increasing of error value is significant for the leading right hand, but not for the subdominant left one. The data obtained are consistent with the evidences about age-dependent reduction of hemispheric asymmetry and about more pronounced reduction of the accuracy of the movements of the leading hand. According to the hypothesis about hemispheric specialization in coding of movement information (right hemisphere specialization on absolute positional coding, the left one--on relative vector coding, i.e. coding of the movements) the data suppose the age-dependent reduction of the left-hemisphere system of relative coding. The reduction of memory capacity apparently can be explained by the reduction of role of the left hemisphere in functioning of the short-term motor memory owing to age-dependent reduction of hemispheric asymmetry. PMID- 25438583 TI - [Event-related brain activity changes to consonant and dissonant chords in musicans and non-musicans]. AB - The present study assessed brain activity changes related to perception of consonant and dissonant chords by musicians and non-musicians. Perception of dissonant chords in non-musicians was accompanied by increase of lower theta activity over right anterior regions, while consonant chords induced greater theta activity over left anterior regions; this pattern of asymmetrical activation was not observed in musicians. ERP analysis revealed that musicians had greater amplitude of early components (P100, N200) than non-musicians irrespective of chord type. The obtained results reflect more efficient musical harmony processing and, possibly, less emotional perception of chords in musicians. PMID- 25438584 TI - [Correlation between brain stem aminergic neuronal activity and EEG patterns in a wakeful cat]. AB - There was carried out a correlation analysis for the frequency of the background impulse activity of the brain stem monoaminergic neurons and the spectral power of electroencephalogram frequency components in a wakeful cat. The frequency of the background impulse activity in the studied neurons was found to be reliably (p < 0.05) correlated with all basic electroencephalogram rhythms. Among the statistically significant correlations, there were most often observed the positive ones between the background impulse activity of the ventral tegmentum dopaminergic neurons and the locus coeruleus noradrenergic neurons, on the one hand, and the power spectral density of alpha-rhythm, on the other hand (40.3% and 48.0% respectively). Besides, 47.7% of the raphe nuclei serotoninergic neurons under study showed positive correlation between their impulse activity and the spectral power density of beta-rhythm. The results obtained let us assume the possibility of taking specific EEG patterns as markers of activity for the basic cerebral monoaminergic systems. PMID- 25438585 TI - [Active coping style as a risk factor of depressive-like disorders after cronic mild stress]. AB - Effect of chronic mild uncontrollable stress on behaviour was studied on rats with opposite behavioural coping styles--active and passive. In a population of outbred animals, specimens with opposite coping style of behaviour were selected based on their reactions in the active avoidance (AA) test. Both groups were subjected to chronic mild stress during 30 days and tested for depressive behaviour (forced swim test, 32% glucose solution consumption test), anxiety (elevated plus maze) and learning (AA test). The behavioural test showed that depressive behaviour after chronic mild stress is more common in animals with active behaviour strategy. PMID- 25438586 TI - [Application of high-speed video recording for investigation of food-procuring movements in rats]. AB - Application of high-speed video recording of food-procuring movements in rats (obtaining food from a narrow horizontal tube) is described. The method was used to verify details of the performance of the movements and their temporal characteristics. This method expands the view both the single phases of food procuring movement, and the nature of their execution. The possibilities of application this method for investigation of acquisition of lateralized motor skill in rats are discussed. PMID- 25438587 TI - [Cytotoxic effects of etoposide at different stages of differentiation of embryoid bodies formed by mouse embryonic stem cells]. AB - The initial stages of in vitro differentiation of embryonic stem cells are considered as unique three-dimensional models of early development of mammals for basic, pharmacological, and toxicological studies. It has been previously shown (Gordeeva, 2012) that the assessment of embryotoxicity in the model of undifferentiated embryonic stem cells can be insufficiently accurate in predicting toxic effects on mammalian embryos. In view of this, we performed a comparative study of the damaging effects of the cytostatic etoposide in undifferentiated embryonic stem cells and embryoid bodiesof different stages of differentiation that have similar three-dimensional structures with early embryos. The analysis of growth, cell death, and dynamics of differentiation of embryonic stem cells and embryoid bodies exposed to etoposide showed that the cytostatic and cytotoxic effects of etoposide are stage-specific. The damaging effects of etoposide were maximum in the undifferentiated embryonic stem cells and decreased with growth and differentiation of embryoid bodies. We assume that the increase in the cell volume of embryoid bodies and the development of the hypertrophic we suggest that the increase of embryoid body volume and overgrowth of extraembryonic endoderm layer lead to a decrease in the diffusion, transport, and metabolism of chemical and bioactive substances and prevent the damaging effects. PMID- 25438588 TI - [Early morphogenesis of ciliated cells in human oral cavity]. AB - Ciliated cells were found in the epithelium of the oral cavity of human embryos and fetuses starting from the seventh week of prenatal development. At the early stages of prenatal development (until the 13th week), cells with cilia cover most of the dorsal surface of the tongue and the soft palate, whereas they are found only near the gland ducts in the circumvallate and foliate lingual papillae after 17 weeks of development. The ultrastructure of the axoneme of cilia corresponds to the structure of motile cilia and is represented by nine microtubule doublets that surround the central pair of microtubule singlets. An immunohistochemical study performed on weeks 10-12 of development identified nerve endings associated with the ciliated cells. Until the 14th week of development, the cytoplasm of ciliated cells is immunopositive for NSE. The spatial distribution of ciliated cells in the tongue epithelium until the 13th week of development is not related to the morphogenesis of lingual papillae, and their role in the human oral cavity during the first trimester of pregnancy is unclear and requires further study. PMID- 25438589 TI - [Interaction of adrenergic and purinergic receptors in the regulation of rat myocardial contractility in postnatal ontogeny]. AB - beta-Adrenergic receptor agonist isoproterenol and purinergic receptor agonist 2 methylthio-ATP have a positive effect on the myocardial contractile force and show different efficiencies depending on the age of animals. The maximum inotropic effect of agonists on the ventricular myocardial contractility was observed in 21-day-old rat pups. The study of a combined effect of isoproterenol and 2-methylthio-ATP showed that an increase in the sympathetic regulatory effects on the heart of 21-day-old animals, against the background of a high functional activity of beta-adrenergic receptors and P2X receptors of the heart, a combined administration of the agonists led to a mutually complementing effect of an increase in the myocardial contractility. PMID- 25438590 TI - [Obtainment of chimeric blastocysts of mice by methods of laser nanosurgery]. AB - The procedure of obtainment of chimeric blastocysts of mice by laser nanosurgery methods without using any other techniques is described. To perform the experiments, a special laser micromanipulator was invented. The murine embryonic stem cells (ESC), which were transformed with pEF-GFP vector, encoding the green fluorescent protein, were used in the experiments. ESC were introduced into the perivitelline space of murine embryos at the stage of 8 cells using the laser micromanipulator. The operated embryos were cultured in vitro until the stage of emergence from zona pellucida. The fluorescence and its precise localization were registered using a confocal microscope. It was shown for the first time that the inclusions of ESC introduced with the lased micromanipulator were found not only in the inner cell mass (ICM) but also in the trophectoderm of the chimeric blastocyst. The technology of nanosurgical operations at early stage preimplanted mammalian embryos using laser techniques opens great opportunities not only for solution of fundamental tasks of experimental embryology of mammals but also for obtainment of chimeric and transgenic animals with predetermined genotype. PMID- 25438591 TI - [Study of the effect of the gene ERECTA2 on the development of Arabidopsis thaliana shoot]. AB - The role of the gene ER2 in plant development has been studied by the analysis of the erecta2 (er2) mutant of Arabidopsis thaliana (L.) Heynh. It was shown that the mutation er2 provides pleiotropic effect on the development of all aboveground organs. It induces shortening and thickening of the stem, leaves and all flower organs, though it does not change the sensitivity to gibberellin. Changes in the morphology of the shoot organs are due to the changes in cell polarity. The cells get wider and shorter compared to the wild type. It was found that the gene ER2 is located in the lower arm of the chromosome 1. It complementarily interacts with the gene ER that plays an important role in the control of intercellular interactions. PMID- 25438592 TI - [Odontologic anomaly in the American mink Neovison vison (Carnivora, Mustelidae) and possible reasons for its appearance]. AB - The paper describes the phenomenon of substitution of the reduced M2 with a tooth of a complex structure in the American mink Neovison vison Schreber. The anomaly is observed on three skulls out of the 574 examined (0.52%) and is characterized by a clear localization, identical structure, and symmetrical manifestation. Atypical molars have two roots, equally well-developed paraconid, eokonid, hypoconid, and a less pronounced metaconid. Some possible hypotheses for the anomaly that are considered include disruption in the development of the dental germ, mutation, and phenotypic expression of genes that are characteristic of plesiomorphic species of mustelids. The substantiated viewpoint is that the cause of this phenomenon may be the "awakening of dormant genes" as a result of destabilizing selection and hybrid dysgenesis in the area of contact of farm and feral American minks. PMID- 25438593 TI - [Abnormal development of gonads of dwarf females and low survival of their offspring as the cause of rarity of resident populations of Atlantic salmon (Salmo salar L.)]. AB - Fecundity and mass of eggs, as well as survival of offspring, of hatchery-reared small (less than 406 g) females of Atlantic salmon are determined. The absolute fecundity and mass of egg of artificially reared fish are sufficiently less than that of anadromous spawners. Small females are characterized by delayed spawning; histological analysis has demonstrated significant asynchrony in oocyte development of some specimens. Survival of offspring of dwarf females at the early stages of development is lower than of anadromous females. Our results agree completely with the published data. It is suggested that dwarf females are not able to withstand intraspecific and interspecific competition because of low reproductive ability. This explains rarity of natural populations of dwarf (landlocked) forms of Atlantic salmon. PMID- 25438594 TI - [Impairment of regeneration in aging: appropriateness or stochastics?]. AB - There is a viewpoint that suppression of the proliferative capacity of cells and impairment of the regeneration of tissues and organs in aging are a consequence of specially arisen during evolution mechanisms that reduce the risk of malignant transformation and, thus, protect against cancer. At the same time, senescent cells of the body begin to accumulate a variety of macromolecular defects, which, conversely, increase the likelihood of their transformation into cancer cells. Thus, according to the point, the restriction of cell proliferation is a double edged sword, which, on the one hand, reduces the likelihood of developing cancer at an early age, but on the other hand--limits life span due to the accumulation of "damaged" cells in old age. However, it remains unclear why normal human cells in vitro, with none of the mentioned "anticancer" barriers functioning at the organismal level only, NEVER undergo spontaneous malignant transformation. In addition, it is also unclear how the freshwater hydra which, under certain conditions, has really no postmitotic and senescent cells, escapes both aging and cancer and, at such conditions (excluding the need for sexual reproduction), can live almost indefinitely, having a great regenerative potential (new organism can arise even from a 1/100 of the old one). I believe that the restriction of cell proliferation in an aging multicellular organism is not a consequence of implementing a special program. Apparently, there is no special program of aging. It is only a "byproduct" of the program of development, implementation of which in higher organisms suggests the need for the emergence of cell populations with very low or even zero proliferative activity, which determines the limited capacity of relevant organs and tissues to regenerate. At the same time, it is the presence of highly differentiated cell populations, barely able or completely unable to reproduce (neurons, cardiomyocytes, hepatocytes), that ensures the normal functioning of the higher animals and humans. Even the regeneration of these organs with the help of stem cells could lead to a breach of the necessary interactions in complex systems. Reductionism in experimental-gerontological research ("everything is determined by deleterious changes in single cells") that has become widespread in recent decades, stimulated the emergence of a number of model systems for studying mechanisms of aging in isolated cells (Hayflick phenomenon, the model of "stationary phase aging", the cell-kinetic model for testing geroprotectors and geropromoters, etc.). However, at present it seems that the data obtained in such models cannot be automatically applied to the situation in the whole organism. Apparently, the impairment of regulatory processes, realized at the neurohumoral level, still plays the main role in the mechanisms of aging of multicellular organisms, not just the accumulation of macromolecular defects in individual cells. It is possible that it is the deterioration of such regulation that may be the cause of the observed abnormal INCREASE of the intensity of proliferation of some cell populations in old age, resulting in senile acromegaly and age-related rise of numerous benign tumors. It seems that the quality of the cells themselves does not worsen with age as much as reliability of the organism CONTROL over cells, organs and tissues, which leads to an increase in the probability of death. PMID- 25438595 TI - Substitution bias and evolutionary rate of mitochondrial protein-encoding genes in four species of Cecidomyiidae. AB - Five mitochondrial protein-encoding genes (COX1, COX2, CytB, ND4 and ND5) from the wheat midge, Sitodiplosis mosellana (Diptera: Cecidomyiidae), were sequenced and compared with those of 3 other Cecidoidae species, Mayetiola destructor, Rhopalomyia pomum and Asphondylia rosetta. These genes shared similar AT content (74.0-80.1%) and base substitution bias in favour of transversions (68.87-79.72%) over transitions (20.28-37.04%). Substitution saturation analyses indicated fast saturation of transitional substitutions in COX2, CytB, ND4 and ND5, especially at the 3rd codon positions. Analysis of interspecific divergence among the 4 species showed that the sequence divergence rates (evolutionary rates) were in the order of ND4 = CytB > COX2 = ND5 > COX1. Intraspecific genetic polymorphism analysis within the field populations of S. mosellana indicated that ND4 had the highest genetic polymorphism and COX1 the lowest. Genetic variation patterns suggested that COX1 could be used as a molecular marker for phylogenetic analysis across a relatively wide taxonomic range in Cecidomyiidae, while COX2 and ND5 may be useful for estimating relationships at a subgenus level or among closely related species. With its high genetic polymorphism, ND4 was the molecular market most suitable for population genetics studies. These findings will be valuable for our further understanding and studies in evolutionary biology and population genetics for S. mosellana and other Cecidomyiidae insects. PMID- 25438596 TI - [Antimutagenesis of multiphytoadaptogene in yeast saccharomyces]. AB - Multiphytoadaptogene (MPA) consists of plant extracts components including adaptogenes. Genotoxicity analysis revealed the antimutagenic activity of MPA. MPA decreased the direct mutations frequency in ADE4-ADE8 loci induced by UV radiation and nitrous acid by 3.7 and 33 times, respectively. The lethal effect of UV radiation was inhibited when the preparation was used. MPA had no effect on replicative mutagenesis. At the same time it depressed mutagenesis caused by repair errors. The data obtained suggest the antimutagenic activity of multiphytoadaptogene is associated with postreplicative repair activation. PMID- 25438597 TI - [SOS repair of 8-methoxypsoralene monoadducts in DNA of lambda bacteriophage and plasmids is mediated by MucA'2B, but not UmuD'2c (PolV) polymerase]. AB - The light-induced action of 8-methoxypsoralen (8-MOP) on lambda phage and plasmids yields monoadducts and interstrand crosslinks. The survival and clear plaque mutation frequency in the phage photosensitized with 8-MOP and irradiated with UV at wavelength > 320 nm are increased whenthe wild-type host (Escherichia coli uvr+) is subjected to UV irradiation (wavelength = 254 nm) prior to phage inoculation. These phenomena are known as "W reactivation" and "W mutagenesis." It is shown that 8-MOP monoadducts in lambda DNA in- duce clear mutations in the phage inoculated to UV-irradiated excision repair mutants of E. coli only when the error-prone repair is performed by MucA B, but not PolV (UmuD'2C) polymerase. The efficiency of the SOS repair (W reactivation) of 8-MOP monoadducts in plasmid and lambda phage DNA also only increases with the presence of pKM101 plasmid muc+ in E. coli uvr-. PMID- 25438598 TI - [A comparative genetic and cytogenetic mapping of wheat chromosome 5B using introgression lines]. AB - The genetic map of chromosome 5B has been constructed by using microsatellite (SSR) analysis of 381 plants from the F2 population produced by cross of the Chinese Spring (CS) and Renan cultivars. Initially, 180 SSR markers for the common wheat 5B chromosome have been used for analysis of these cultivars. The 32 markers able to detect polymorphism between these cultivars have been located on the genetic map of chromosome 5B. Cytogenetic mapping has involved a set of CS 5B chromosome deletion lines. Totally, 51 SSR markers have been located in ten regions (deletion bins) of this chromosome by SSR analysis of these deletion lines. Five genes--TaCBFIIIc-B10, Vrn--B1, Chi--B1, Skr, and Ph1--have been integrated into the cytogenetic map of chromosome 5B using the markers either specific of or tightly linked to the genes in question. Com- parison of the genetic and cytogenetic maps suggests that recombination is suppressed in the pericentromeric region of chromosome 5B, especially in the short arm segment. The 18 markers localized to deletion bins 5BL16-0.79-1.00 and 5BL8-0.66-0.79 have been used to analyze common wheat introgression lines L842, L5366-180, L73/00i, and L21-4, carrying fragments of alien genomes in the terminal region of 5B long arm. L5366-180 and L842 lines carry a fragment of the Triticum timopheevii 5GL chromosome, while L73/00i ? L21-4 lines, a fragment of the Aegilopsspeltoides 5SL chromosome. As has been shown, the translocated fragments in these four lines are of different lengths, allowing bin 5BL18-0.66-0.79 to be divided into three shorter regions. The utility of wheat introgression lines carrying alien translocations for increasing the resolution of cytogenetic mapping is discussed. PMID- 25438600 TI - [Mitochondrial cytochrome b gene variation in brown bear (Ursus arctos Linnaeus, 1758) from southern part of Russian Far East]. AB - The genetic variability of brown bear Ursus arctos from the southern part of the Russian Far East was first ex- amined based on the variations in the mitochondrial DNA cytochrome b sequence. The presence of two phylogenetic groups of haplotypes described previously for other parts of the species range was demonstrated. Part of the samples belonged to the haplotype group distributed across the whole range, while another part belonged to the rare group previously only reported for Japan and Alaska. These findings partially clarify the pattern of brown-bear colonization on the territory of the Russian Far East and Japan. PMID- 25438599 TI - [Comparative analysis of genetic variability of White Sea Cod (Gadus morhua marisalbi) at allozyme and microsatellite markers]. AB - Variability of cod spawning and feeding schools from Kandalaksha Bay of the White Sea, was examined at six allozyme and eight microsatellite loci. The degree of genetic differentiation at allozyme loci constituted 0 = 0.36% [95% bootstrap interval 0.0458; 0.6743]. The differentiation estimates obtained using microsatellite markers were higher, 0 = 1.33% [0.057; 3.11]. It was demonstrated that the level of genetic diversity in the White Seacod was lower than that established for the Atlantic cod from Barents Sea using the same set of al- lozyme and microsatellite markers. The genetic data obtained support the opinion that the White Sea cod is a reproductively independent group formed as a result of the Holocene dispersal of Atlantic cod. PMID- 25438601 TI - [Reproduction characteristics and Crow's index in different groups of Yevpatoria population]. AB - According to the obstetric history of Yevpatoria residents of postreproductive age, the parameters of the dif- ferential fertility as components of the natural selection (index Crow) in Slavic (Russian and Ukrainian) and non-Slavic individuals have been calculated. It is shown that, in the studied population, in one generation, the index of total selection decreased from 0.3 to 0.32 by reducing the value Im. For Slavic females, the average number of pregnancies is 5.26, while the number of offspring is 1.75, and the index of total selection equals 0.31. For non-Slavic women, these ratings were 4.84, 2.09, and 0.46. In non-Slavic women, natural reproductive losses occur more frequently than in Slavic women, which may be associated with inbreeding, the level of which is usually higher in members of the Muslim faith. The average number of adverse pregnancy outcomes in the non-Slavic families is 0.759, while for Slavic families, it is 0.503. Reproductive problems were observed in 36.4% of Slavic families and 44.8% of non-Slavic families. The index of total selection in non Slavs (0.46) is 1.5 times higher than in Slavs (0.31). The difference is due to the selection component, coupled with differential fertility (0.36 and 0.23, respectively). Interethnic differences in the rate of natural increase can change the ethnic and denominational composition of the city, leading to an increase in the Muslim component. PMID- 25438602 TI - [Frequency and causes of prevalence of p.Arg894* mutation in CLCN1 gene responsible for development of Thomsen's and Becker's myotonias in Russian population]. AB - Thomsen's (TM) and Becker's (BM) Myotonias are nondystrophic myotonias. At present, 150 mutations in the CLCN1 gene, which results in the development of TM and BM, have been described. c.2680C > T (p.Arg894*) is the most common mutation. In the Northern Scandinavian countries, the population frequency of this mutation is 0.87%, while in the Russian Federation, it is equal to 1.2% (this study). Based on the results of a molecular-genetic analysis of CLCN1 gene in patients with nondystrophic myotonias, the calculated frequency of TM and BM in Russia is 1:8165 and 1:710, respectively. We have conducted haplotype analysis using microsatellite markers and intragene SNP, which has shown that the prevalence of p.Arg894* mutation in Russia results from the founder effect, and the time of its scattering is 3680 +/- 1240 years. PMID- 25438603 TI - [Gene-pool structure of Tuvinians inferred from Y-chromosome marker data]. AB - The gene-pool structure of Tuvinians was examined in terms of the composition and frequency of Y-chromosome haplogroups in five geographically distanct populations. In the Tuvinian gene pool, a total of 22 haplogroups were identified with six of these, which were the most frequent (C3c, C3*, N1b, N1c1, Q1a3, and R1a1a). It was demonstrated that eastern regions of Tuva were most different from the other regions in haplotype frequencies. The evaluation of genetic diversity based on the frequencies of biallelic haplogroups and YSTR haplotypes revealed very high diversity values for all samples. In general, the genetic diversity values identified in Tuvinians were the highest for the indigenous ethnic groups of Siberia. The evaluation of the genetic differentiation of the samples examined using the analysis of molecular variance (AMOVA) showed that the gene pool of Tuvinians was relatively poorly differentiated with respect to haplogroup frequencies. Phylogenetic analysis within haplogroup N1b revealed strong founder effect, i.e., reduced diversity and starlike phylogeny of the median network of haplotypes, which formed a separate subcluster exclusive to Tuvinians. It was demonstrated that, in Tuvinians, haplogroup N1c1 was the most heterogeneous in haplotype profile and consisted of three different haplotype clusters, demonstrating considerable differences of western population from the rest of the Tuva populations. Phylogenetic analysis of haplogroups revealed common components for Tuvinians, Khakasses, Altaians, and Mongols. PMID- 25438604 TI - [MED12 gene mutations in women with uterine myoma]. AB - Uterine leiomyoma (UL) is a benign and most common tumor that affects 20-45% of women of fertile age. In this study, we analyzed the MED12 second exon nucleotide sequence from 15 DNA samples extracted from LM of 15 subjects with uterine leiomyoma and 15 DNA samples extracted from peripheral blood leukocytes of the same female subjects. It was shown that somatic mutations in the MED12 gene occur in 73% of cases with deletions of varying sizes and missense mutations being most common at codon 44. Mutations in the MED12 gene could play an indirect role in leiomyoma progression by modifying the activity of other genes that encode proteins involved in growth and tumor progression. PMID- 25438605 TI - [Brain-derived neurotrophic factor gene (BDNF) polymorphism among Moscow citizens]. AB - Recent studies showed that brain-derived neurotrophic factor (BDNF) can participate in pathogenesis of various CNS disorders, being connected with proliferation, differentiation, and survival of neurons. In present study, analysis of occurrence rate was performed for three single nucleotide polymorphisms (SNPs) located in BDNF gene (rs6267 (A/G) allele A-0.265; rs2049046 (A/T) allele A-0.407; rs11030107 (A/G) allele A-0.872) in randomized selection of Moscow citizens. Linkage disequilibrium of rs6165 and rs2049046 loci was shown. Differences in allele frequencies in studied selection and populations of other re- gions were discovered. PMID- 25438606 TI - [Sex determination in ten crane species by DNA marker EE0.6]. AB - Using a unique DNA sequence of W-chromosome EE0.6, we carried out molecular sex determination in 383 individuals often species of cranes (Grusgrus L., G. leucogeranus Pallas, G. japonensis Muller, G. vipio Pallas, G. Canadensis L., G. antigone L., G. monacha Temminck, Anthropoides virgo L., Balearica regulorum Bennett, and B. pavonia L.) kept in zoos and other centers of captive propagation. In 211 birds, sex was determined or verified for the first time. The efficiency of using the sex marker EE0.6 for chicks and immature and adult cranes of different species, as well as for interspecific hybrids was shown. PMID- 25438607 TI - [Molecular genetic polymorphism of androgen receptor gene (AR) in African populations of Hadza and Datoga]. AB - The molecular genetic analysis of the polymorphic variants of the CAG repeat containing locus of the andro- gen receptor (AR) gene was performed in the populations of Hadza and Datoga. Allele frequency distribution patterns were established. Alleles containing 20-25 repeats were the most abundant in both populations were the. The populations studied were compared with Asians (Han), white Americans, and Africans (Ariaal). Sta- tistically significant difference between populations of Hadza and Datoga in the distribution of the AR allelic variants was demonstrated. PMID- 25438609 TI - Effect of fall-related concerns on physical, mental, and social function in community-dwelling older adults: a prospective cohort study. AB - OBJECTIVES: To determine the effect of fall-related concerns on physical, mental, and social function. DESIGN: Community-based prospective cohort study (secondary analysis using control group data from a randomized controlled trial). SETTING: Two municipalities in the south of the Netherlands. PARTICIPANTS: Community dwelling older adults (N = 260). MEASUREMENTS: Two groups were created using Modified Falls Efficacy Scale scores (high and low levels of fall-related concerns). Five outcome measures representing physical, mental, and social function were included: activities of daily living (ADLs), symptoms of depression, feelings of anxiety, social participation, and social support interactions. Outcomes were measured at baseline and at 2, 8, and 14 months. Data were analyzed using analysis of covariance and mixed-effect regression models for longitudinal data, adjusting for age, sex, living status (alone or with another person), educational level, cognitive status, self-perceived health, and falls history at baseline. RESULTS: At baseline, significantly more limitations in ADLs and social participation were found for older persons with high levels of fall related concerns than for those with low levels of concern. These differences persisted over 14 months of follow-up and were consistent over time. No significant differences were found for symptoms of depression, feelings of anxiety, or social support interactions, except for feelings of anxiety at 14 months. CONCLUSION: Older persons with higher levels of fall-related concerns reported up to 14 months poorer ADL and social participation for up to 14 months than those with lower levels of fall-related concerns. From a clinical point of view, the clear relationship between fall-related concerns and ADL dysfunction and social participation may help to target groups who are at risk of developing adverse consequences of concerns about falls. PMID- 25438612 TI - Decrease in lactobacilli in the intestinal microbiota of celiac children with a gluten-free diet, and selection of potentially probiotic strains. AB - The intestinal microbiota would be implicated in pathology associated with celiac disease caused by an abnormal immune system reaction against gluten present in cereal grains. The objectives of this work were to detect through basic methods the changes in the composition of the most common genera of bacteria from the intestinal microbiota of symptom-free celiac disease children with a gluten-free diet compared with healthy children from Tucuman and to select lactobacilli (Lb) strains with probiotic potential from the feces of healthy children. Results demonstrated that the feces of celiac children with a gluten-free diet showed significantly lower counts of Lb (P < 0.05) compared with healthy children, while enterobacteria tended to increase in celiac children. On the basis of these results, isolation of some Lb from the feces of healthy children was carried out. Thus, 5 Lb strains were selected because of their high resistance percentages to gastrointestinal tract conditions. In addition, their autoaggregation and hydrophobicity properties were evaluated: Lactobacillus rhamnosus (LC4) showed the highest percentage of autoaggregation while Lactobacillus paracasei (LC9) showed high hydrophobicity. Based on these results, LC4 and LC9 were selected, and their use as potential probiotic strains to improve signs and symptoms associated with celiac disease is discussed. This is the first study performed in Argentina concerning the relationship between intestinal microbiota and celiac disease in celiac children with a gluten-free diet. In addition, the development of a probiotic food addressed towards celiac patients and designed with Lb isolated from the feces of healthy children from our province represents a promising alternative to improve the quality of life of celiac patients. PMID- 25438610 TI - Reduction of subclinical Salmonella infection in fattening pigs after dietary supplementation with a beta-galactomannan oligosaccharide. AB - AIMS: To assess the efficacy of a beta-galactomannan oligosaccharide (beta-GMOS) for the control of Salmonella infection in fattening pigs. METHODS AND RESULTS: Three different doses (0.5, 3 and 2 kg beta-GMOS per ton of feed) were used during the entire period of growing in three similar and independent field trials carried out in a small fattening unit (~ 100 pigs). Treatment was randomly assigned to half of the pens. Individual serum samples (20-25 per group) were collected at different times during the fattening period and a similar number of faecal samples during the fattening period and at slaughter. In addition, mesenteric lymph nodes were collected at slaughter. Herdcheck((r)) Swine Salmonella ELISA was used for serological analyses, the ISO 6579:2002/Amd 1 : 2007 for bacteriology and the PFGE for molecular characterization of Salmonella strains. The addition of >= 2 kg t(-1) of beta-GMOS to the pig diet during the entire fattening period was associated with a reduction in Salmonella prevalence, shedding and seroconversion. CONCLUSIONS: Feed supplementation with beta-GMOS may be a useful complementary tool for the control of salmonellosis in fattening pigs. SIGNIFICANCE AND IMPACT OF THE STUDY: beta-GMOS may be a complementary way of reducing Salmonella shedding and infection in fattening pigs. PMID- 25438608 TI - The peroxisome proliferator-activated receptors in cardiovascular diseases: experimental benefits and clinical challenges. AB - The peroxisome proliferator-activated receptors, PPARalpha, PPARbeta/delta and PPARgamma, are ligand-activated transcriptional factors belonging to the nuclear receptors superfamily and they are known to play important roles in glucose and lipid metabolism. Experimental studies in animal models of metabolic diseases have also revealed that activation of PPARs protects against the vascular complications of diabetes, hypertension, atherosclerosis, myocardial infarction and stroke, through exerting their anti-inflammatory, anti-atherogenic and antioxidant effects. In clinical trials and post-market surveillance, agonists of PPARs have been shown to effectively prevent cardiovascular events. However, adverse effects, particularly for PPARgamma agonists, are also observed with the use of investigational PPAR agonists and even some approved drugs. Further exploration of underlying mechanisms is needed to develop novel ways of PPAR activation without causing serious side effects. This article reviews the cardiovascular effects of PPARs, with emphasis on the therapeutic potential of PPAR agonists in combating metabolic vascular diseases. PMID- 25438613 TI - Adding strength to endurance training does not enhance aerobic capacity in cyclists. AB - The molecular signaling of mitochondrial biogenesis is enhanced when resistance exercise is added to a bout of endurance exercise. The purpose of the present study was to examine if this mode of concurrent training translates into increased mitochondrial content and improved endurance performance. Moderately trained cyclists performed 8 weeks (two sessions per week) of endurance training only (E, n = 10; 60-min cycling) or endurance training followed by strength training (ES, n = 9; 60-min cycling + leg press). Muscle biopsies were obtained before and after the training period and analyzed for enzyme activities and protein content. Only the ES group increased in leg strength (+19%, P < 0.01), sprint peak power (+5%, P < 0.05), and short-term endurance (+9%, P < 0.01). In contrast, only the E group increased in muscle citrate synthase activity (+11%, P = 0.06), lactate threshold intensity (+3%, P < 0.05), and long-term endurance performance (+4%, P < 0.05). Content of mitochondrial proteins and cycling economy was not affected by training. Contrary to our hypothesis, the results demonstrate that concurrent training does not enhance muscle aerobic capacity and endurance performance in cyclists. PMID- 25438614 TI - Behavioral insights on big data: using social media for predicting biomedical outcomes. AB - Social media 'big data' can provide valuable insights about people's behaviors, such as their likelihood of engaging in risk behaviors or contracting a disease. Although in its infancy, advancing this research provides the promise of predicting health-related behaviors to promptly prepare for and respond to public health emergencies and epidemics. PMID- 25438615 TI - HIV: a vicTIM. AB - TIM proteins are known to promote viral entry into host cells. Unexpectedly, a recent study has shown that TIM proteins also inhibit HIV-1 release from the host cell by directly binding to phosphatidylserine exposed on the virus surface, providing details on a new role of TIM proteins in HIV replication. PMID- 25438616 TI - A novel reverse genetics system for human norovirus. AB - Human noroviruses cause significant morbidity, mortality, and economic losses worldwide. The inability to grow human noroviruses in cell culture has hampered our collective understanding of virus-host interactions and development of therapeutics. A newly described single-plasmid reverse genetics system for noroviruses has the potential to facilitate basic and applied research. PMID- 25438617 TI - The distribution of genetic variance across phenotypic space and the response to selection. AB - The role of adaptation in biological invasions will depend on the availability of genetic variation for traits under selection in the new environment. Although genetic variation is present for most traits in most populations, selection is expected to act on combinations of traits, not individual traits in isolation. The distribution of genetic variance across trait combinations can be characterized by the empirical spectral distribution of the genetic variance covariance (G) matrix. Empirical spectral distributions of G from a range of trait types and taxa all exhibit a characteristic shape; some trait combinations have large levels of genetic variance, while others have very little genetic variance. In this study, we review what is known about the empirical spectral distribution of G and show how it predicts the response to selection across phenotypic space. In particular, trait combinations that form a nearly null genetic subspace with little genetic variance respond only inconsistently to selection. We go on to set out a framework for understanding how the empirical spectral distribution of G may differ from the random expectations that have been developed under random matrix theory (RMT). Using a data set containing a large number of gene expression traits, we illustrate how hypotheses concerning the distribution of multivariate genetic variance can be tested using RMT methods. We suggest that the relative alignment between novel selection pressures during invasion and the nearly null genetic subspace is likely to be an important component of the success or failure of invasion, and for the likelihood of rapid adaptation in small populations in general. PMID- 25438619 TI - White matter hyperintensities of presumed vascular origin: a population-based study in rural Ecuador (The Atahualpa Project). AB - BACKGROUND: Cerebral small vessel disease is probably one of the most common pathogenetic mechanisms underlying stroke in Latin America. However, the importance of silent markers of small vessel disease, including white matter hyperintensities of presumed vascular origin, has not been assessed so far. AIM: The study aims to evaluate prevalence and correlates of white matter hyperintensities in community-dwelling elders living in Atahualpa (rural Ecuador). METHODS: Atahualpa residents aged >= 60 years were identified during a door-to-door survey and invited to undergo brain magnetic resonance imaging for identification and grading white matter hyperintensities and other markers of small vessel disease. Using multivariate logistic regression models, we evaluated whether white matter hyperintensities is associated with demographics, cardiovascular health status, stroke, cerebral microbleeds, and cortical atrophy, after adjusting for the other variables. RESULTS: Out of 258 enrolled persons (mean age, 70 +/- 8 years; 59% women), 172 (67%) had white matter hyperintensities, which were moderate to severe in 63. Analyses showed significant associations of white matter hyperintensities presence and severity with age and cardiovascular health status, as well as with overt and silent strokes, and a trend for association with cerebral microbleeds and cortical atrophy. CONCLUSIONS: Prevalence and correlates of white matter hyperintensities in elders living in rural Ecuador is almost comparable with that reported from industrialized nations, reinforcing the concept that the burden of small vessel disease is on the rise in underserved Latin American populations. PMID- 25438618 TI - Active vision in passive locomotion: real-world free viewing in infants and adults. AB - Visual exploration in infants and adults has been studied using two very different paradigms: free viewing of flat screen displays in desk-mounted eye tracking studies and real-world visual guidance of action in head-mounted eye tracking studies. To test whether classic findings from screen-based studies generalize to real-world visual exploration and to compare natural visual exploration in infants and adults, we tested observers in a new paradigm that combines critical aspects of both previous techniques: free viewing during real world visual exploration. Mothers and their 9-month-old infants wore head-mounted eye trackers while mothers carried their infants in a forward-facing infant carrier through a series of indoor hallways. Demands for visual guidance of action were minimal in mothers and absent for infants, so both engaged in free viewing while moving through the environment. Similar to screen-based studies, during free viewing in the real world low-level saliency was related to gaze direction. In contrast to screen-based studies, only infants - not adults - were biased to look at people, participants of both ages did not show a classic center bias, and mothers and infants did not display high levels of inter-observer consistency. Results indicate that several aspects of visual exploration of a flat screen display do not generalize to visual exploration in the real world. PMID- 25438620 TI - Handover of patient information from the crisis assessment and treatment team to the inpatient psychiatric unit. AB - Handover, or the communication of patient information between clinicians, is a fundamental component of health care. Psychiatric settings are dynamic environments relying on timely and accurate communication to plan care and manage risk. Crisis assessment and treatment teams are the primary interface between community and mental health services in many Australian and international health services, facilitating access to assessment, treatment, and admission to hospital. No previous research has investigated the handover between crisis assessment and treatment teams and inpatient psychiatric units, despite the importance of handover to care planning. The aim of the present study was to identify the nature and types of information transferred during these handovers, and to explore how these guides initial care planning. An observational, exploratory study design was used. A 20-item handover observation tool was used to observe 19 occasions of handover. A prospective audit was undertaken on clinical documentation arising from the admission. Clinical information, including psychiatric history and mental state, were handed over consistently; however, information about consumer preferences was reported less consistently. The present study identified a lack of attention to consumer preferences at handover, despite the current focus on recovery-oriented models for mental health care, and the centrality of respecting consumer preferences within the recovery paradigm. PMID- 25438621 TI - Positive versus negative mental health in emerging adulthood: a national cross sectional survey. AB - BACKGROUND: The dual continuum model suggests that positive mental health not only implies the absence of mental illness, but also constitutes an entity of its own. Measures that encompass both positive and negative mental health in young adults are rare. Thus, we assessed whether dimensions corresponding to positive and negative mental health could be identified in a sample of young individuals. Additionally, we explored how such dimensions were associated with potential health-related factors. METHODS: We obtained data from the Swedish National Public Health Survey 2004-2009 (23,394 women, 18,274 men, aged 16-29 years). We used exploratory factor analysis (EFA) to identify relevant factors revealed by the 12-item General Health Questionnaire (GHQ-12) and confirmatory factor analysis (CFA) to verify the factor structure. We tested the significance of the difference between effects of potential health-related factors on positive mental health (PMH) and negative mental health (NMH). RESULTS: The EFA for the GHQ-12 revealed a two factor model with negative items that had high positive loadings on one factor and lower negative loadings on the other factor. The positive items had loading trends that were opposite those of the negative items. The fit of this model was supported by the CFA, which yielded a significantly better match than a unidimensional model. When we investigated the associations between GHQ scores and potential predictors of health, we found that most potential predictors had significant and opposing effects on both PMH and NMH; with the strongest effects from suicidal ideation and perceived humiliation. CONCLUSIONS: Our results could be seen to indicate that positive and negative mental health are distinct and complementary constructs. Still, the results of our factor analysis may specifically reflect the wording of the items. We conclude that the GHQ-12 is an appropriate tool for its original purpose, to detect "psychiatric morbidity". More refined measures, including predictors of health, are needed to assess PMH and validate the bidimensionality hypothesis. PMID- 25438622 TI - Intestinal transplant registry report: global activity and trends. AB - The Registry has gathered information on intestine transplantation (IT) since 1985. During this time, individual centers have reported progress but small case volumes potentially limit the generalizability of this information. The present study was undertaken to examine recent global IT activity. Activity was assessed with descriptive statistics, Kaplan-Meier survival curves and a multiple variable analysis. Eighty-two programs reported 2887 transplants in 2699 patients. Regional practices and outcomes are now similar worldwide. Current actuarial patient survival rates are 76%, 56% and 43% at 1, 5 and 10 years, respectively. Rates of graft loss beyond 1 year have not improved. Grafts that included a colon segment had better function. Waiting at home for IT, the use of induction immune suppression therapy, inclusion of a liver component and maintenance therapy with rapamycin were associated with better graft survival. Outcomes of IT have modestly improved over the past decade. Case volumes have recently declined. Identifying the root reasons for late graft loss is difficult due to the low case volumes at most centers. The high participation rate in the Registry provides unique opportunities to study these issues. PMID- 25438641 TI - Immune escape phenomenon in molluscum contagiosum and the induction of apoptosis. AB - Molluscum contagiosum (MC) may persist for many weeks, evading host immunity. We studied the mechanism of immune escape phenomenon in MC, and the possible inducer of apoptosis. Using tissue samples of MC, we examined the numbers of epidermal Langerhans cells (LC), the expression levels of macrophage inflammatory protein 3alpha (MIP-3alpha) and thymic stromal lymphopoietin (TSLP), and the apoptotic signals. After molluscum contagiosum virus (MCV) genotyping, we studied the expression of MCV-encoded MC148 mRNA and MC159 mRNA which correspond to viral antagonist for CCR8 and viral Fas-linked interleukin (IL)-1beta converting enzyme (FLICE)-like inhibitor protein (vFLIP), respectively. The nutlin-3-induced apoptosis in MC was observed ex vivo. The numbers of CD1a(+) or Langerin(+) epidermal LC and the expression levels of MIP-3alpha were markedly decreased in MC. The expression of TSLP was enhanced in the lesional epidermis of atopic dermatitis and human papillomavirus-induced warts, whereas the expression was observed locally in MC. All 14 MC samples examined harbored MCV type 1. The MC148 mRNA was detected in all 14 samples and the MC159 mRNA was detected in 13 samples. Apoptotic cells were absent or at a background level in the living layers of MC, but their numbers were increased in the molluscum bodies by overnight incubation with 5 MUmol/L nutlin-3 in culture medium. In conclusion, molluscum bodies are protected from host immune responses and apoptotic signals by being surrounded by LC-depleted epidermal walls and viral immunosuppressive molecules, but could be eradicated by reagents inducing p53-dependent apoptosis. PMID- 25438642 TI - Novel EDA hemizygous frame-shift mutation c. 731delG (p.R244Qfs*36) underlies hypohidrotic ectodermal dysplasia in a Japanese family. PMID- 25438643 TI - Development of terminal hairs following the treatment of pigmented nevus with vellus hairs by Q-switched alexandrite laser. PMID- 25438644 TI - Stage IV malignant melanoma successfully treated with OK-432 and percutaneous ethanol injection therapy after mass reduction surgery. PMID- 25438645 TI - Identification and comparative analysis of microRNAs in barnyardgrass (Echinochloa crus-galli) in response to rice allelopathy. AB - Rice allelopathy is a hot topic in the field of allelopathy, and behaviour of donor allelopathic rice has been well documented. However, few study addresses response of receiver barnyardgrass (BYG). We found that expression of miRNAs relevant to plant hormone signal transduction, nucleotide excision repair and the peroxisome proliferator-activated receptor and p53 signalling pathways was enhanced in BYG co-cultured with the allelopathic rice cultivar PI312777, the expression levels of these miRNAs in BYG plants were positively correlated with allelopathic potential of the co-cultured rice varieties. Treatment of BYG plants with rice-produced phenolic acids also increased miRNA expression in BYG, while treatment with rice-produced terpenoids had no obvious effect on miRNA expression. In the hydroponic system, the largest number of Myxococcus sp. was found in the growth medium containing rice with the highest allelopathic potential. The addition of phenolic acids in the hydroponic medium also increased the number of Myxococcus sp. More interestingly, inoculation with Myxococcus xanthus significantly increased miRNA expression in the treated BYG. Jointed treatments of ferulic acid and M. xanthus led to strongest growth inhibition of BYG. The results suggest that there exist involvement of Myxococcus sp. and mediation of miRNA expression in rice allelopathy against BYG. PMID- 25438647 TI - Clinical remission of psoriatic arthritis in patients receiving continuous biological therapies for 1 year: the experience of an outpatient dermatological clinic for psoriasis. AB - BACKGROUND: The data in the literature concerning the frequency of remission of inflammatory arthritis in patients with psoriatic arthritis (PsA) are limited and conflicting. AIM: To evaluate the frequency of clinical remission in inflammatory arthritis in a cohort of patients with PsA receiving continuous treatment (1 year) with tumour necrosis factor-alpha inhibitors or ustekinumab, as well as the clinical covariates affecting remission. METHODS: We retrospectively evaluated 74 patients with PsA attending our psoriasis outpatient dermatology clinic. Remission of PsA was defined as documented absence of clinical signs related to arthritis (no tender or swollen joints), enthesitis or dactylitis. Patients were examined every 3 months for 1 year. RESULTS: At 1 year > 40% of patients had clinical remission of inflammatory arthritis. Predictors of remission were absence of fibromyalgia (FM) at baseline and having < 11 tender joints. CONCLUSIONS: Clinical remission of inflammatory arthritis can be obtained in a significant proportion of patients by continuous treatment with biological drugs. A large number of tender joints and the presence of FM can make remission less likely. PMID- 25438649 TI - [Stimuli-sensitive polymer systems]. AB - The polymers can be found in different forms in solution (particles, capsules, pseudo-micelles, hydrogels...) or on surface with important prospects in many field applications. These polymer systems are particularly very good candidates to entrap, transport and deliver an active substance in biomedical applications however with many limitations on control of release of a given target. The stimuli-sensitive polymers, also called smart or environmentally sensitive polymers, present physical or chemical changes under the action of small variations of an external stimulus. This signal acts as a stimulus which causes the change of conformation and/or solvation of the macromolecular chains by modifying their various interactions. The stimuli are classified into two broad categories: physical or external stimuli: temperature, mechanical stress, light, magnetic and electric fields; chemical and biochemical or internal stimuli: pH, ionic strength, chemical molecule (glucose, redox) or biochemical (enzymes, antigens...). The use of stimuli-sensitive pathway is widely used in the literature to enhance or trigger the release of an active compound. In this paper, we present the different stimuli addressing the theoretical aspects, polymers corresponding to these stimuli. Some examples illustrate these systems for the controlled release of active compounds. PMID- 25438650 TI - [Advanced glycation end products: A risk factor for human health]. AB - Advanced glycation end products (AGE) result from a chemical reaction between the carbonyl group of reducing sugar and the nucleophilic NH2 of a free amino acid or a protein; lysine and arginine being the main reactive amino acids on proteins. Following this first step, a molecular rearrangement occurs, rearrangement of Amadori resulting to the formation of Maillard products. Glycation can cause the clouding of the lens by inducing reactions crosslinking proteins. Specialized receptors (RAGE, Galectin 3...) bind AGE. The binding to the receptor causes the formation of free radicals, which have a deleterious effect because they are powerful oxidizing agents, but also play the role of intracellular messenger, altering the cell functions. This is especially true at the level of endothelial cells: the attachment of AGE to RAGE receptor causes an increase in vascular permeability. AGE binding to endothelium RAGE and to monocytes-macrophages, led to the production of cytokines, growth factors, to the expression of adhesion molecules, and the production of procoagulant activity. Diabetic retinopathy is related to excessive secretion of vascular growth factor (vascular endothelial growth factor [VEGF]). AGE-RAGE receptor binding causes the synthesis and secretion of VEGF. Increased permeability, facilitation of leukocyte migration, the production of reactive oxygen species, cytokines and VEGF suggest that the AGE could be an element of a cascade of reactions responsible for the diabetic angiopathy and vascular damages observed during aging and chronic renal failure. Balanced diet or some drugs can limit the deleterious effect of AGE. PMID- 25438646 TI - It's time to phase in RHD genotyping for patients with a serologic weak D phenotype. College of American Pathologists Transfusion Medicine Resource Committee Work Group. PMID- 25438651 TI - [Serious adverse events after microbial sealant application in paediatric patients]. AB - BACKGROUND: Integuseal((r)) is a cyanoacrylate-based medical device (IIa class), used in surgery after skin preparation to reduce bacterial contamination. It is not officially contraindicated for children. OBJECTIVES: To describe a case series of skin lesions in pediatric patients after using Integuseal((r)) in cardiac surgery. METHODS: Case series. RESULTS: Between September 2012 and February 2013, 153 pediatric patients were treated by Integuseal((r)) to prepare for a cardiac surgery in our center: 5 patients (2%) had serious cutaneous reactions. The average age of patients having had lesions is 16months (the youngest patient being 1month old and the oldest being 5years and 8months old). ISSUES: The risk factor in the development of skin lesion seems to be particularly related to the patient's age and sternal location. Other medical literature reports instances of cyanoacrylate intolerance in a variety of other situations. CONCLUSION: Using Integuseal((r)) on children does not appear to be safe. PMID- 25438652 TI - Optimising concentrations of antimicrobial agents in pharmaceutical preparations: Case of an oral solution of glycerol and an ophthalmic solution containing cysteamine. AB - INTRODUCTION: In the context of current distrust of antimicrobial preservatives, the quantities of these substances in two pharmaceutical formulas were studied: an ophthalmic solution of cysteamine preserved benzalkonium chloride at 1mg/5mL and Glycerotone((r)) preserved with sorbic acid at 0.1g/100g. The purpose of this work was to verify that a reduction of the quantities of preservative continues to fulfil the requirements for antimicrobial preservation. MATERIAL AND METHODS: The Test of efficacy of antimicrobial preservation, section 5.1.3 of the 8th edition of the European Pharmacopoeia, was carried out on each formulation prepared with decreasing quantities of preservative. RESULTS: The results show that formulations whose preservative concentration was reduced by a factor of four remained compliant with standards. It is to be noted that in formulas without preservative, fungal growth was observed in both the solution of Glycerotone((r)) and the ophthalmic solution containing cysteamine. DISCUSSION: Although there is no question that an antimicrobial preservative is necessary, the quantity of preservative can be reduced without deteriorating the quality of the pharmaceutical product but the minimal effective concentration remains to be determined. CONCLUSION: The formulations of many pharmaceutical products should therefore be examined in order to limit the quantities of preservative while continuing to guarantee patient's safety. PMID- 25438653 TI - Capped guanidino-alpha-cyclodextrin first synthesis based on intramolecular Staudinger-Aza-Wittig (SAW) reaction. AB - An intramolecularly promoted SAW reaction between a phosphinimide and an isocyanate intermediate led to an original bridged trisubstituted ((A,C),E)-alpha cyclodextrin. The latter was in a second step converted into a new capped (ACE) (guanidino)-alpha-cyclodextrin. PMID- 25438654 TI - [Characteristics of systematic reviews about the impact of pharmacists]. AB - INTRODUCTION: The pharmacists' role is varied and numerous articles evaluate the outcomes of pharmaceutical interventions. The main objectives of this study were to establish the characteristics of systematic reviews about pharmacists' interventions that were published in the last five years. METHODS: A literature search was performed on Pubmed for French and English articles published between 01-01-2008 and 31-05-2013. Systematic reviews that presented the role, the interventions and the impact of pharmacists were selected by two research assistants. RESULTS: A total of 46 systematic reviews was identified, amongst which one third (n=15/46, 33 %) were meta-analyses. A quarter of systematic reviews did not evaluate the quality of included articles (n=13/46, 28 %). Twelve themes were identified. A median [min-max] of 16 [2-298] articles was included per systematic review. The most frequent pharmaceutical activities were patient counseling (n=41 systematic reviews), patient chart review (n=29), pharmacotherapy evaluation (n=27) and recommendations (n=26). The least frequent activities were teaching others than patients (n=12) and medical rounds participation (n=7). DISCUSSION: Many elements can influence the completion of pharmacy practice research projects; however, there exists no link between the presence of systematic reviews and the importance of pharmacists in a given healthcare program. CONCLUSION: This study presents the characteristics of 46 systematic reviews about pharmacists interventions published since 2008. PMID- 25438656 TI - Dermatopathology in sub-Saharan Africa: a systematic 5-year analysis of all histopathological diagnoses from the Regional Dermatology Training Centre (RDTC) in Moshi, Tanzania. AB - BACKGROUND: Proper diagnosis of skin diseases relies on dermatopathology, the most important diagnostic technique in dermatology. Unfortunately, there are few dermatopathology institutions in sub-Saharan Africa, where little is known about the spectrum of histopathological features observed. OBJECTIVES: To investigate the spectrum of dermatopathological diagnoses made in a sub-Saharan African reference centre of a large, mainly rural area. PATIENTS/METHODS: To retrospectively evaluate all dermatopathological diagnoses made over a period of 5 years at the Regional Dermatology Training Centre (RDTC) in Moshi, Tanzania. RESULTS: There were a total of 1554 skin biopsy specimens. In 45% of cases, there were inflammatory diseases, most frequently lichenoid conditions. Cutaneous neoplasms represented 30.4% of all diagnoses, with Kaposi's sarcoma (KS) and, less frequently, squamous cell carcinoma (SCC) being the two most common neoplastic conditions. The latter also reflected the intensive management of persons with albinism in the RDTC. The distribution of histological diagnoses seemed to correlate with the overall clinical spectrum of cutaneous diseases managed in the RDTC. CONCLUSIONS: In this African study inflammatory conditions are the main burden of skin diseases leading to a diagnostic biopsy. Our findings provide further evidence that KS, primarily related to the high prevalence of HIV infection is an epidemiological problem. Both SCC and basal cell carcinoma represent another relatively common malignant cutaneous neoplasms, reflecting the presence of specific populations at risk. The challenging spectrum of histological diagnoses observed in this specific African setting with basic working conditions shows that development of laboratory services of good standards and specific training in dermatopathology are urgently needed. PMID- 25438655 TI - [Medication adverse events: Impact of pharmaceutical consultations during the hospitalization of patients]. AB - The medication iatrogenic events are responsible for nearly one iatrogenic event in five. The main purpose of this prospective multicenter study is to determine the effect of pharmaceutical consultations on the occurrence of medication adverse events during hospitalization (MAE). The other objectives are to study the impact of age, of the number of medications and pharmaceutical consultations on the risk of MAE. The pharmaceutical consultation is associated to a complete reassessment done by both a physician and a pharmacist for the home medication, the hospital treatment (3days after admission), the treatment during chemotherapy, and/or, the treatment when the patient goes back home. All MAE are subject to an advice for the patient, additional clinical-biological monitoring and/or prescription changes. Among the 318 patients, 217 (68%) had 1 or more clinically important MAE (89% drug-drug interaction, 8% dosing error, 2% indication error, 1% risk behavior). The patients have had 1121 pharmaceutical consultations (3.2+/-1.4/patient). Thus, the pharmaceutical consultations divided by 2.34 the risk of MAE (unadjusted incidence ratio, P<=0.05). Each consultation decreased by 24% the risk of MAE. Moreover, adding one medication increases from 14 to 30% as a risk of MAE on the population. Pharmaceutical consultations during the hospital stay could reduce significantly the number of medication adverse effects. PMID- 25438657 TI - Effect of Peg-interferon alpha-2a combined with Adefovir in HBV postpartum women with normal levels of ALT and high levels of HBV DNA. AB - BACKGROUND & AIMS: Currently, routine antiviral treatment is not recommended for immune-tolerant subjects with chronic HBV infection. In this study, we assessed the treatment efficacy of combining Peg IFN alpha-2a with Adefovir (CPIA) in chronic HBV infected pregnant women with normal levels of ALT and high levels of HBV after delivery. METHODS: Chronic hepatitis B pregnant women with normal levels of ALT and high levels of HBV DNA were treated with Telbivudine during the third trimester of their pregnancy. After childbirth, based on serological and virological parameters, the patients were either switched to CPIA treatment for 96 weeks or stopped Telbivudine treatment and followed for 48 weeks. RESULTS: A total of 68 patients were enrolled in this study. Thirty (30/68) of them were switched to CPIA treatment after childbirth, 93.3% (28/30) of them achieved virological response, 56.7% (17/30) achieved HBeAg seroclearance and 26.7% (8/30) cleared HBsAg. The HBV DNA and HBeAg levels before CPIA treatment were negatively associated with HBeAg seroclearance. HBsAg and HBeAg levels in week 12 and week 24 after CPIA treatment were negatively associated with HBsAg seroclearance. Thirty-eight (38/68) patients did not receive antiviral treatment after childbirth, and none of them had HBeAg or HBsAg clearance. CONCLUSION: High rates of viral response and clearance were achieved in chronic hepatitis B pregnant woman with normal levels of ALT and high levels of HBV DNA treated by CPIA after childbirth. (231 words). PMID- 25438658 TI - PRL1 modulates root stem cell niche activity and meristem size through WOX5 and PLTs in Arabidopsis. AB - The stem cell niche in the root meristem maintains pluripotent stem cells to ensure a constant supply of cells for root growth. Despite extensive progress, the molecular mechanisms through which root stem cell fates and stem cell niche activity are determined remain largely unknown. In Arabidopsis thaliana, the Pleiotropic Regulatory Locus 1 (PRL1) encodes a WD40-repeat protein subunit of the spliceosome-activating Nineteen Complex (NTC) that plays a role in multiple stress, hormone and developmental signaling pathways. Here, we show that PRL1 is involved in the control of root meristem size and root stem cell niche activity. PRL1 is strongly expressed in the root meristem and its loss of function mutation results in disorganization of the quiescent center (QC), premature stem cell differentiation, aberrant cell division, and reduced root meristem size. Our genetic studies indicate that PRL1 is required for confined expression of the homeodomain transcription factor WOX5 in the QC and acts upstream of the transcription factor PLETHORA (PLT) in modulating stem cell niche activity and root meristem size. These findings define a role for PRL1 as an important determinant of PLT signaling that modulates maintenance of the stem cell niche and root meristem size. PMID- 25438659 TI - The preanalytic phase in veterinary clinical pathology. AB - This article presents the general causes of preanalytic variability with a few examples showing specialists and practitioners that special and improved care should be given to this too often neglected phase. The preanalytic phase of clinical pathology includes all the steps from specimen collection to analysis. It is the phase where most laboratory errors occur in human, and probably also in veterinary clinical pathology. Numerous causes may affect the validity of the results, including technical factors, such as the choice of anticoagulant, the blood vessel sampled, and the duration and conditions of specimen handling. While the latter factors can be defined, influence of biologic and physiologic factors such as feeding and fasting, stress, and biologic and endocrine rhythms can often not be controlled. Nevertheless, as many factors as possible should at least be documented. The importance of the preanalytic phase is often not given the necessary attention, although the validity of the results and consequent clinical decision making and medical management of animal patients would likely be improved if the quality of specimens submitted to the laboratory was optimized. PMID- 25438660 TI - Diabetes mellitus and comorbid depression in Zambia. AB - AIMS: To replicate, in Zambia, a recent global study by the WHO, which reported that the odds of depression were not increased in African people with diabetes, and to explore the sociodemographic and clinical factors associated with depression. METHODS: A total of 773 control subjects and 157 Zambian patients with diabetes completed the Major Depression Inventory and a list of demographic indicators. RESULTS: Compared with control subjects (mean +/- sd Major Depression Inventory score 15.10 +/- 9.19), depressive symptoms were significantly more common in patients with diabetes (mean +/- sd Major Depression Inventory score 19.12 +/- 8.95; P < 0.001). ancova showed that having diabetes [F(1,698) = 16.50, P < 0.001], being female [F(1,698) = 7.35, P < 0.01] and having low socio economic status (F(1,698) = 13.35, P < 0.001) were positive predictors of depression. CONCLUSIONS: Contrary to the WHO study, we found that depression was a common comorbid health problem among Zambian people with diabetes. Clinicians should consider patients' health status, sex and socio-economic status as potential factors predicting depression. PMID- 25438661 TI - Publication of null results. PMID- 25438662 TI - Should guideline panels declare nonfinancial conflicts of interest? PMID- 25438663 TI - Agency for Healthcare Research and Quality Evidence-based Practice Center methods for systematically reviewing complex multicomponent health care interventions. AB - OBJECTIVES: The purpose of this Agency for Healthcare Research and Quality Evidence-based Practice Center methods white paper was to outline approaches to conducting systematic reviews of complex multicomponent health care interventions. STUDY DESIGN AND SETTING: We performed a literature scan and conducted semistructured interviews with international experts who conduct research or systematic reviews of complex multicomponent interventions (CMCIs) or organizational leaders who implement CMCIs in health care. RESULTS: Challenges identified include lack of consistent terminology for such interventions (eg, complex, multicomponent, multidimensional, multifactorial); a wide range of approaches used to frame the review, from grouping interventions by common features to using more theoretical approaches; decisions regarding whether and how to quantitatively analyze the interventions, from holistic to individual component analytic approaches; and incomplete and inconsistent reporting of elements critical to understanding the success and impact of multicomponent interventions, such as methods used for implementation the context in which interventions are implemented. CONCLUSION: We provide a framework for the spectrum of conceptual and analytic approaches to synthesizing studies of multicomponent interventions and an initial list of critical reporting elements for such studies. This information is intended to help systematic reviewers understand the options and tradeoffs available for such reviews. PMID- 25438664 TI - BMP15, fertility and the ovary. PMID- 25438665 TI - Low serum levels of vitamin D are associated with post-stroke depression. AB - BACKGROUND AND PURPOSE: Low serum levels of vitamin D have been associated with depression in non-stroke subjects. Our aim was to examine the possible association between serum vitamin D levels and the development of post-stroke depression (PSD). METHODS: In total, 189 patients with acute ischaemic stroke were consecutively recruited. Serum levels of 25-hydroxyvitamin D [25(OH)D] were measured by competitive protein-binding assay within 24 h after admission. The 17 item Hamilton Depression Scale was used for screening for the existence of depressive symptoms at 1 month after stroke. Patients with a Hamilton Depression Scale score of >=7 were given the Structured Clinical Interview of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, for diagnosis of PSD. Meanwhile, 100 healthy control subjects were also recruited and underwent measurement of 25(OH)D. RESULTS: Fifty-five patients (29.1%) were diagnosed as having PSD at 1 month. Serum vitamin D levels within 24 h after admission were significantly lower in both non-PSD patients and PSD patients than in normal controls. PSD patients had significantly lower vitamin D than non-PSD patients. Serum vitamin D levels (<=37.1 and >=64.1 nmol/l) were independently associated with the development of PSD (odds ratio 8.824, 95% confidence interval 2.011 38.720, P = 0.004, and odds ratio 0.127, 95% confidence interval 0.022-0.718, P = 0.020, respectively). CONCLUSIONS: Serum vitamin D levels within 24 h after admission are found to be associated with PSD and may predict its development at 1 month post-stroke. PMID- 25438666 TI - Monoaminergic drugs for motor recovery after ischemic stroke. AB - Today, administering rTPA thrombolytic therapy within the first hours of a stroke is the only validated drug therapy for improving the spontaneous--and most of the time incomplete--recovery of neurological functions post-stroke. However in the past decade, thanks in part to the considerable advances of neuroimaging techniques, we have learned that spontaneous recovery of neurological functions was associated with a wide intracerebral reorganization of the damaged human brain. The question of whether lesioned-brain plasticity can be modulated by external factors like pharmacological agents is now addressed in the hope of improving recovery and reducing the chronic impairments of stroke patients. In this paper, we review the preclinical and clinical evidence for a direct action of SSRIs in promoting recovery in ischemic stroke patients. PMID- 25438667 TI - A virus that can take the heat. AB - Foot-and-mouth disease virus shows remarkable thermal lability, a property that is a particular problem for vaccine preparations. In this issue of Structure, Rincon and colleagues show that electrostatic repulsion within the capsid is responsible for this lability, and they present rationally designed mutants with increased thermostability. PMID- 25438668 TI - Chemokine-receptor interactions: solving the puzzle, piece by piece. AB - In an important addition to the chemokine field, Millard and colleagues, in this issue of Structure, report the first structure of a CC chemokine in complex with a sulfated peptide derived from its receptor. PMID- 25438669 TI - Native-like photosystem II superstructure at 2.44 A resolution through detergent extraction from the protein crystal. AB - Photosystem II (PSII) catalyzes a key step in photosynthesis, the oxidation of water to oxygen. Excellent structural models exist for the dimeric PSII core complex of cyanobacteria, but higher order physiological assemblies readily dissociate when solubilized from the native thylakoid membrane with detergent. Here, we describe the crystallization of PSII from Thermosynechococcus elongatus with a postcrystallization treatment involving extraction of the detergent C12E8. This resulted in a transition from Type II to Type I-like membrane protein crystals and improved diffraction to 2.44 A resolution. The obtained PSII packing in precise rows, interconnected by specific pairs of galactolipids and a loop in the PsbO subunit specific to cyanobacteria, is superimposable with previous electron microscopy images of the thylakoid membrane. The study provides a detailed model of such a superstructure and its organization of light-harvesting pigments with possible implications for the understanding of their efficient use of solar energy. PMID- 25438670 TI - Structural and functional framework for the autoinhibition of Nedd4-family ubiquitin ligases. AB - Nedd4-family ubiquitin ligases are key regulators of cell surface receptor signaling. Their dysregulation is associated with several human diseases, including cancer. Under normal conditions, the activity of various Nedd4 E3s is controlled through an autoinhibitory interaction of the N-terminal C2 domain with the C-terminal catalytic HECT domain. Here, we report the structural and functional framework for this intramolecular interaction. Our nuclear magnetic resonance (NMR) data and biochemical analyses on Smurf2 and Nedd4 show that the C2 domain has the potential to regulate E3 activity by maintaining the HECT domain in a low-activity state where its ability for transthiolation and noncovalent Ub binding are impaired. PMID- 25438671 TI - Determining the oligomeric structure of proteorhodopsin by Gd3+ -based pulsed dipolar spectroscopy of multiple distances. AB - The structural organization of the functionally relevant, hexameric oligomer of green-absorbing proteorhodopsin (G-PR) was obtained from double electron-electron resonance (DEER) spectroscopy utilizing conventional nitroxide spin labels and recently developed Gd3+ -based spin labels. G-PR with nitroxide or Gd3+ labels was prepared using cysteine mutations at residues Trp58 and Thr177. By combining reliable measurements of multiple interprotein distances in the G-PR hexamer with computer modeling, we obtained a structural model that agrees with the recent crystal structure of the homologous blue-absorbing PR (B-PR) hexamer. These DEER results provide specific distance information in a membrane-mimetic environment and across loop regions that are unresolved in the crystal structure. In addition, the X-band DEER measurements using nitroxide spin labels suffered from multispin effects that, at times, compromised the detection of next-nearest neighbor distances. Performing measurements at high magnetic fields with Gd3+ spin labels increased the sensitivity considerably and alleviated the difficulties caused by multispin interactions. PMID- 25438672 TI - Extracellular vesicles: a platform for the structure determination of membrane proteins by Cryo-EM. AB - Membrane protein-enriched extracellular vesicles (MPEEVs) provide a platform for studying intact membrane proteins natively anchored with the correct topology in genuine biological membranes. This approach circumvents the need to conduct tedious detergent screens for solubilization, purification, and reconstitution required in classical membrane protein studies. We have applied this method to three integral type I membrane proteins, namely the Caenorhabditis elegans cell cell fusion proteins AFF-1 and EFF-1 and the glycoprotein B (gB) from Herpes simplex virus type 1 (HSV1). Electron cryotomography followed by subvolume averaging allowed the 3D reconstruction of EFF-1 and HSV1 gB in the membrane as well as an analysis of the spatial distribution and interprotein interactions on the membrane. MPEEVs have many applications beyond structural/functional investigations, such as facilitating the raising of antibodies, for protein protein interaction assays or for diagnostics use, as biomarkers, and possibly therapeutics. PMID- 25438673 TI - Management of Turner syndrome in adult life and beyond. AB - OBJECTIVE: To describe in practical terms the clinical management in adult life of patients with Turner syndrome. MATERIAL & METHODS: Systematic review of the literature and practical issues. An evaluation of clinical trials, meta-analysis, case reports and reviews assessing the management of different conditions related to Turner syndrome was done using the following data sources: Medline, PubMed (from 1966 to July 2014) and the Cochrane Controlled Clinical Trials Register, Embase (up to July 2014). RESULTS: Extracted information is summarized here on karyotype, screening of malformations, malformations debuting in adult life, final height, treatments with growth hormone, cardiovascular risk, endocrino metabolic and liver abnormalities, sensorineural disorders and osteoporosis and its treatment. CONCLUSIONS: This review provides recommendations for the management of adult patients with Turner syndrome and insight into the associated medical complaints. A link between karyotypes and clinical features suggests a novel hypothesis to explain the different phenotypes and clinical abnormalities of these patients. PMID- 25438677 TI - In Rasmussen encephalitis, hemichannels associated with microglial activation are linked to cortical pyramidal neuron coupling: a possible mechanism for cellular hyperexcitability. AB - AIMS: Rasmussen encephalitis (RE) is a rare but devastating condition, mainly in children, characterized by sustained brain inflammation, atrophy of one cerebral hemisphere, epilepsy, and progressive cognitive deterioration. The etiology of RE induced seizures associated with the inflammatory process remains unknown. METHODS: Cortical tissue samples from children undergoing surgical resections for the treatment of RE (n = 16) and non-RE (n = 12) were compared using electrophysiological, morphological, and immunohistochemical techniques to examine neuronal properties and the relationship with microglial activation using the specific microglia/macrophage calcium-binding protein, IBA1 in conjunction with connexins and pannexin expression. RESULTS: Compared with non-RE cases, pyramidal neurons from RE cases displayed increased cell capacitance and reduced input resistance. However, neuronal somatic areas were not increased in size. Instead, intracellular injection of biocytin led to increased dye coupling between neurons from RE cases. By Western blot, expression of IBA1 and pannexin was increased while connexin 32 was decreased in RE cases compared with non-RE cases. IBA1 immunostaining overlapped with pannexin and connexin 36 in RE cases. CONCLUSIONS: In RE, these results support the notion that a possible mechanism for cellular hyperexcitability may be related to increased intercellular coupling from pannexin linked to increased microglial activation. Such findings suggest that a possible antiseizure treatment for RE may involve the use of gap junction blockers. PMID- 25438679 TI - Is preimplantation genetic diagnosis the ideal embryo selection method in aneuploidy screening? AB - To select cytogenetically normal embryos, preimplantation genetic diagnosis (PGD) aneuploidy screening (AS) is used in numerous centers around the world. Chromosomal abnormalities lead to developmental problems, implantation failure, and early abortion of embryos. The usefulness of PGD in identifying single-gene diseases, human leukocyte antigen typing, X-linked diseases, and specific genetic diseases is well-known. In this review, preimplantation embryo genetics, PGD research studies, and the European Society of Human Reproduction and Embryology PGD Consortium studies and reports are examined. In addition, criteria for embryo selection, technical aspects of PGD-AS, and potential noninvasive embryo selection methods are described. Indications for PGD and possible causes of discordant PGD results between the centers are discussed. The limitations of fluorescence in situ hybridization, and the advantages of the array comparative genomic hybridization are included in this review. Although PGD-AS for patients of advanced maternal age has been shown to improve in vitro fertilization outcomes in some studies, to our knowledge, there is not sufficient evidence to use advanced maternal age as the sole indication for PGD-AS. PGD-AS might be harmful and may not increase the success rates of in vitro fertilization. At the same time PGD, is not recommended for recurrent implantation failure and unexplained recurrent pregnancy loss. PMID- 25438678 TI - Long-acting olanzapine versus long-acting risperidone for schizophrenia in Spain a cost-effectiveness comparison. AB - BACKGROUND: In schizophrenia, medication adherence is critical to achieve better patient outcomes and to avoid relapses, which are responsible for a significant proportion of total healthcare costs for this chronic illness. The aim of this study was to assess the cost-effectiveness of olanzapine long-acting injection (OLAI) compared with risperidone long-acting injection (RLAI) in patients with schizophrenia in Spain. METHODS: A discrete event simulation (DES) model was developed from a Spanish healthcare system perspective to estimate clinical and economic outcomes for patients with schizophrenia over a five-year period. Patients who had earlier responded to oral medication and have a history of relapse due to adherence problems were considered. Identical model populations were treated with either OLAI or RLAI. In the absence of a head-to-head clinical trial, discontinuation and relapse rates were obtained from open-label studies. The model accounted for age, gender, risks of relapse and discontinuation, relapse management, hospitalization, treatment switching and adverse events. Direct medical costs for the year 2011 and outcomes including relapse avoided, life years (LYs), and quality-adjusted life years (QALYs) were discounted at a rate of 3%. RESULTS: When comparing RLAI and OLAI, the model predicts that OLAI would decrease 5-year costs by ?2,940 (Standard Deviation between replications 300.83), and result in a QALY and LY gains of 0.07 (SD 0.019) and 0.04 (SD 0.025), respectively. Patients on OLAI had fewer relapses compared to RLAI (1.392 [SD 0.035] vs. 1.815 [SD 0.035]) and fewer discontinuations (1.222 [SD 0.031] vs. 1.710 [SD 0.039]). Sensitivity analysis indicated that the study was robust and conclusions were largely unaffected by changes in a wide range of parameters. CONCLUSIONS: The present evaluation results in OLAI being dominant over RLAI, meaning that OLAI represents a more effective and less costly alternative compared to RLAI in the treatment of patients with schizophrenia in the Spanish setting. PMID- 25438680 TI - Influence of intravenous anesthetics on neuromonitoring of the recurrent laryngeal nerve during thyroid surgery. AB - Limited reports are available in the literature on the impact of intravenous administration of anesthetics on laryngeal electromyographic (EMG) activity. The purpose of this study was to determine the influence of the two commonly used intravenous anesthetics (propofol and thiamylal) on EMG amplitude evoked from the recurrent laryngeal nerve (RLN) during thyroid surgery. A total of 40 patients were randomized to receive a bolus of propofol (0.5 mg/kg; n = 20) or thiamylal (1.5 mg/kg; n = 20) to increase anesthetic depth when the surgeon found patient movement intraoperatively. Evoked potentials were obtained before and every 1 minute after the administration of each agent for up to 5 minutes by stimulating the RLN. The magnitude of evoked potentials at each time point and hemodynamic response were compared within groups. The mean amplitude of evoked potentials did not change significantly after administration of either propofol or thiamylal (p > 0.05 within groups). Mean arterial pressure measured from 1 minute to 5 minutes was significantly lower in the propofol group than in the thiamylal group (p < 0.05). Heart rate measured within 5 minutes did not differ significantly within groups. Low dose of propofol (0.5 mg/kg) or thiamylal (1.5 mg/kg) did not affect EMG readings during neuromonitoring of the RLN in thyroid surgery. Our results show that thiamylal provides better hemodynamic stability than propofol, and is therefore a preferable agent to increase anesthesia depth and prevent further patient movement during intraoperative neuromonitoring. PMID- 25438681 TI - Local and systemic recurrence patterns of urothelial cancer after radical cystectomy. AB - The aim of this study was to evaluate the local recurrence and distant metastasis rates for urothelial carcinoma of the bladder after radical cystectomy and to identify the predictive factors for local recurrence and distant metastasis. The study population was 347 consecutive patients treated with radical cystectomy for urothelial carcinoma of the bladder at our institution. Local recurrence, distant metastasis, and both local and distant recurrence rates were 49 (14.1%) months, 96 (27.7%) months, and 17 (4.9%) months, respectively. The mean follow-up times to recurrence were 14.37 +/- 13.25 months (range, 2-60 months) and 14.43 +/- 15.72 months (range, 2-109 months) for local recurrence and distant metastasis, respectively (p = 0.808). The mean post-recurrence disease-specific survival (PRDSS) times for local, distant, and both local and distant recurrences were 17.82 +/- 3.18 months, 4.16 +/- 0.39 months, and 11.41 +/- 2.73 months, respectively (p < 0.001). The predictive factors for local recurrence and distant metastasis were stage and nodal involvement (p < 0.001). Sex, grade, lymphovascular invasion (LVI), carcinoma in situ (CIS), and lymph node density (LND; 10% cut-off value) were not predictors for recurrence in the results of the multivariate analysis. The current study demonstrated that stage and pathological nodal involvement were independent predictors of local recurrence and distant metastasis. The results of this study suggest that the early diagnosis and intervention of invasive bladder cancer cases may decrease the number of high stage and lymph node positive cases that have a high risk of local and distant recurrences. The adjuvant treatment options in the presence of risk factors for recurrence may improve survival outcomes. PMID- 25438682 TI - Effect of positive surgical margins on biochemical failure, biochemical recurrence-free survival, and overall survival after radical prostatectomy: median long-term results. AB - The aim of this study was to investigate the median long-term effects of positive surgical margin (PSM) and other prognostic factors on biochemical recurrence-free survival, overall survival, and biochemical failure in patients who underwent radical prostatectomy. Our study included 121 patients with pT2-3N0 disease treated between March 2006 and August 2012. The patients were divided into two groups: those with PSM and those with negative surgical margin (NSM). We analyzed the age, clinical and pathological stages, preoperative and postoperative Gleason scores, duration of the follow-up, adjuvant chemo-/radiotherapy, biochemical failure, biochemical recurrence-free survival, and overall survival in these patients. PSM was found in 25 (20%) patients, whereas 96 patients had NSM. The median follow-up time was 46.6 months (range 12-72 months) for the PSM group and 48.3 months (range 7-149 months) for the NSM group. The biochemical failure rate was 24% in the PSM group and 8.3% in the NSM group (p = 0.029). The biochemical recurrence-free survival was found as 76% in the PSM group and 91.7% in the NSM group. The difference between the groups was not statistically significant (p = 0.06). The overall survival was 100% in both groups. The surgical margins of the radical prostatectomy material is an important pathological indicator for biochemical failure at mid long-term follow-up. We did not find any effect of PSM on overall survival or biochemical recurrence-free survival. PMID- 25438683 TI - Diabetes mellitus is associated with gastroesophageal variceal bleeding in cirrhotic patients. AB - Diabetes mellitus (DM) has been reported to increase the risk of complications of liver cirrhosis of any etiology and subsequent survival. However, the impact of DM on the development of gastroesophageal variceal bleeding (GEVB) remains unclear. We aimed to elucidate whether DM is an independent risk factor for GEVB among cirrhotic patients. A total of 146 consecutive patients with liver cirrhosis (Child-Pugh Class A, n = 75; Class B, n = 40; and Class C, n = 31) were prospectively enrolled. Data on clinical and biochemical characteristics and history of ascites, GEVB, hepatic encephalopathy, and spontaneous bacterial peritonitis were retrospectively reviewed. Of these 146 patients, 37 (25%) had DM. Patients with DM had significantly higher ratio of Child-Pugh Class B/C (p = 0.043), renal insufficiency (p = 0.002), and history of GEVB (p = 0.006) compared with non-DM patients. GEVB was associated with Child-Pugh Class B/C (p = 0.001), ascites (p = 0.002), hepatic encephalopathy (p = 0.023), and low platelet counts (p < 0.001). Based on stepwise multiple logistic regression analysis, Child-Pugh class B/C [odds ratio (OR) = 4.90, p = 0.003] and DM (OR = 2.99, p = 0.022) were identified as independent predictors of GEVB. In the subgroup analysis, DM significantly correlated with GEVB in patients with Child-Pugh Class A (p = 0.042), but not in patients with Child-Pugh Class B/C (p = 0.128). DM is independently associated with GEVB in cirrhotic patients, especially in those with Child-Pugh Class A. PMID- 25438684 TI - Benefits of exercise training and the correlation between aerobic capacity and functional outcomes and quality of life in elderly patients with coronary artery disease. AB - Cardiopulmonary exercise training is beneficial to people with coronary artery disease (CAD). Nevertheless, the correlation between aerobic capacity, and functional mobility and quality of life in elderly CAD patients is less addressed. The purpose of the current study is to investigate the beneficial effects of exercise training in elderly people with CAD, integrating exercise stress testing, functional mobility, handgrip strength, and health-related quality of life. Elderly people with CAD were enrolled from the outpatient clinic of a cardiac rehabilitation unit in a medical center. Participants were assigned to the exercise training group (N = 21) or the usual care group (N = 15). A total of 36 sessions of exercise training, completed in 12 weeks, was prescribed. Echocardiography, exercise stress testing, the 6-minute walking test, Timed Up and Go test, and handgrip strength testing were performed, and the Short-Form 36 questionnaire (SF-36) was administered at baseline and at 12-week follow-up. Peak oxygen consumption improved significantly after training. The heart rate recovery improved from 13.90/minute to 16.62/minute after exercise training. Functional mobility and handgrip strength also improved after training. Significant improvements were found in SF-36 physical function, social function, role limitation due to emotional problems, and mental health domains. A significant correlation between dynamic cardiopulmonary exercise testing parameters, the 6 minute walking test, Timed Up and Go test, handgrip strength, and SF-36 physical function and general health domains was also detected. Twelve-week, 36-session exercise training, including moderate-intensity cardiopulmonary exercise training, strengthening exercise, and balance training, is beneficial to elderly patients with CAD, and cardiopulmonary exercise testing parameters correlate well with balance and quality of life. PMID- 25438685 TI - Macular asymmetry analysis in sighting ocular dominance. AB - Sighting ocular dominance is the preference of one eye over the other in terms of sighting. In this study, our aim was to examine differences in interocular and intraocular macular thickness, interocular fovea-optic disc angle, and foveal blood vessel asymmetries associated with sighting ocular dominance. Ninety eyes of 45 healthy young adults were included in this prospective, cross-sectional, and comparative study. Sighting ocular dominance was determined by a hole-in-the card test. Macular thickness measurements were taken and posterior pole asymmetry analysis conducted with spectral domain optical coherence tomography. The optic disc-fovea angle and visible foveal blood vessel counts were calculated by using the posterior pole retinal images of optical coherence tomography. The mean age of the participants was 27.3 (standard deviation [SD] 6.6) years. There were 20 males and 25 females. The mean total macular area thickness, and mean macular thickness of the superior and inferior hemispheres of the dominant and nondominant eyes were similar (p > 0.05). Macular asymmetry analysis revealed no statistically significant interocular difference (p > 0.05). In the dominant eyes, the mean optic disc-fovea angle was 5.24 degrees (SD 1.77), whereas it was 5.49 degrees (SD 2.58) in the nondominant eyes (p = 0.51). The number of visible blood vessels passing through the fovea was similar in the dominant and nondominant eyes (p > 0.05). These results suggested that interocular and intraocular macular thickness differences, interocular fovea-optic disc angle differences, and number of visible foveal blood vessels are not associated with sighting ocular dominance. PMID- 25438686 TI - Paratesticular malignant mesothelioma in a patient exposed to asbestos for more than 50 years. PMID- 25438687 TI - A report of therapeutic hypothermia for postcardiac arrest care due to thyroid storm. PMID- 25438688 TI - Clinical features of patients with endometriosis on the cesarean scar. PMID- 25438689 TI - The CC-genotype of the cyclooxygenase-2 gene associates with decreased risk of nasopharyngeal carcinoma in a Tunisian population. AB - BACKGROUND: The cyclooxygenase-2 (cox-2) pathway is now recognized to be important in human cancer development and progression. The gene for cox-2 carries a common single nucleotide polymorphism, T8473C, located within a potential functional region in the 3'-UTR of cox-2 gene was identified. We have investigated the frequencies of cox-2 genotypes in Tunisian population to determine whether that polymorphism was associated with the risk of nasopharyngeal carcinoma (NPC) in Tunisian population. MATERIAL AND METHODS: One hundred and eighty-nine NPC patients were compared to 237 healthy controls. RESULTS: The cox-2 T8473C polymorphism was significantly associated with NPC (P=0.031). The CC-genotype and C allele were more frequent in control compared to patients group [CC: OR=0.37; P=0.013; 95% CI: 0.17-0.81; C: OR=0.72; P=0.032; 95% CI: 0.53-0.97]. Multivariate logistic regression analyses revealed that the CC genotype was associated with a significantly decreased risk of NPC (P=0.013). Tumor sizes, histologic grade, presence of primary lymph node metastases, age or sex were not associated with cox-2 genotypes. CONCLUSION: We conclude that the CC genotype and C allele of cox-2 T8473C gene polymorphism are associated with decreased risk of nasopharyngeal carcinoma in a Tunisian population. PMID- 25438690 TI - Laparoendoscopic single-site retroperitoneal lymph node dissection in non seminomatous germ cell malignancy. AB - INTRODUCTION: Umbilical laparoendoscopic single-site (LESS) surgery represents an excellent alternative to laparoscopic or robotic multiport surgery. LESS surgery offers faster recovery, less postoperative pain and optimal cosmetic results. LESS is possible in virtually any urologic surgery. PATIENT AND METHOD: We present a 38-year-old male with BMI 31.2 and with history of stage I nonseminomatous mixed germ cell tumor showing interaortocaval lymph node recurrence without elevation of tumor markers. Patient was undergone to right laparoendoscopic single-site retroperitoneal lymph node dissection (LDRP-LESS) by umbilical approach using a single-site multichannel KeyPort (Richard Wolf GmbH, Knittlingen, Germany). RESULTS: After the placement of the device and triangulation of the clips, we proceeded to operate on posterior parietal peritoneum. The descending colon was mobilized to access the retroperitoneum. Complete retroperitoneal lymph node dissection on the right side from iliac vessels to renal vessels, including the paracaval and interaortocaval space, was performed. The specimen was inserted into a laparoscopic bag and was removed together with multichannel system. Abdominal drainage was not employed. Surgical time was 85 min and estimated bleeding 50 cc. The patient was very satisfied with the cosmetic results and was discharged the following day without needing analgesia. The pathology report revealed metastatic seminoma in 5 of 11 lymph nodes receiving systemic chemotherapy (VP16-CDDPs) for 4 cycles with good tolerance. A year later, the patient was disease-free and had no complications. CONCLUSIONS: Umbilical primary LDRP-LESS, with excellent oncologic and cosmetic results, is feasible in selected cases. This approach could be considered the least invasive surgical option economically advantageous due to the reusable nature of the instruments used. PMID- 25438691 TI - Ultrafine structure of calcium oxalate monohydrate renal calculi. PMID- 25438692 TI - Editorial to special issue: monocytes in homeostasis and disease. PMID- 25438693 TI - Safe and efficient pH sensitive tumor targeting modified liposomes with minimal cytotoxicity. AB - Incorporating the pH-sensitivity of octylamine grafted poly aspartic acid (PASP) with the biocompatibility of liposomes, a novel pH sensitive drug delivery system, octylamine-graft-PASP (PASP-g-C8) modified liposomes (OPLPs), was obtained. Since hydrophobic chains have been grafted into PASP backbones, the octylamine chain could act as the "anchor" to implant onto liposomes. The structure of PASP-g-C8, involving long-chain and hydrophobic anchors can significantly enhance the stability of the drug carrier. The shortcoming of single PASP chain modified liposomes (PLPs), that cannot sustain a slow and controlled release especially in a physiological pH solution (resembling normal tissues of pH 7.4) is thus overcome. Drug release experiments were carried out and the result showed that OPLPs sustained a slow and steady release in comparison with PLPs in the physiological pH 7.4 environment. However, OPLPs can provide a fast release in subacid environment (pH 5.0 of resembled tumor tissues). The results of diameter analysis and zeta potential demonstrated that OPLPs presented a larger diameter and higher electronegativity. Furthermore, in the "chain-anchor" structure of PASP-g-C8, the degree of substitution (DS) of the "anchor" is a remarkable factor to alter the pH-sensitivity of OPLPs. The in vitro tumor inhibition and cell toxicity studies revealed that tumor cells treated with OPLPs survived only 35.0% after 48 h whereas normal cells survived 100% in the same condition. The pH sensitive OPLPs are promising tumor targeting drug delivery with high tumor inhibition and insignificant cytotoxicity. PMID- 25438694 TI - Dieulafoy's disease of the bronchus: report of a case and review of the literature. AB - BACKGROUND: Dieulafoy's disease is a vascular anomaly characterized by the presence of a tortuous dysplastic artery in the submucosa. Although frequently occurring in the gastrointestinal tract, multiple cases of Dieulafoy's disease in the bronchus have been reported in the literature. METHODS AND RESULTS: We report a case of a 15-year-old boy suffering recurrent massive hemoptysis. Bilobectomy stopped bleeding after unsuccessful treatment with embolization of bronchial artery. CONCLUSION: It is concluded a congenital origin of this disease. Angiography and endobronchial ultrasonography can be used to diagnose Dieulafoy's disease of bronchus whereas bronchoscopy biopsy should be avoided. Surgery is needed when embolization fails. PMID- 25438695 TI - Balancing the welfare: the use of non-human primates in research. AB - Until now, there have been no ideal alternatives to replace non-human primates (NHPs) in biomedical research, yet the debate on whether it is appropriate to sacrifice NHPs for research never stops. With recent advances in genomics and the appearance of new technologies, the time is right to return to the problem of finding solutions to balance the welfare of both humans and NHPs. PMID- 25438696 TI - Single-cell sequencing technologies: current and future. AB - Intensively developed in the last few years, single-cell sequencing technologies now present numerous advantages over traditional sequencing methods for solving the problems of biological heterogeneity and low quantities of available biological materials. The application of single-cell sequencing technologies has profoundly changed our understanding of a series of biological phenomena, including gene transcription, embryo development, and carcinogenesis. However, before single-cell sequencing technologies can be used extensively, researchers face the serious challenge of overcoming inherent issues of high amplification bias, low accuracy and reproducibility. Here, we simply summarize the techniques used for single-cell isolation, and review the current technologies used in single-cell genomic, transcriptomic, and epigenomic sequencing. We discuss the merits, defects, and scope of application of single-cell sequencing technologies and then speculate on the direction of future developments. PMID- 25438699 TI - A new-nipponbare rice germplasm with high seed-setting rate. PMID- 25438697 TI - TRAP1 shows clinical significance and promotes cellular migration and invasion through STAT3/MMP2 pathway in human esophageal squamous cell cancer. AB - Tumor necrosis factor receptor-associated protein 1 (TRAP1), an important member of mitochondrial heat shock protein 90 family, is involved in multiple biological processes in several types of tumors. However, its pathological role in esophageal squamous cell cancer (ESCC) remains unknown. Herein, we demonstrated the clinical value of TRAP1, and its role in apoptosis and motility in ESCC. The clinical potential of TRAP1 was investigated through immunohistochemical analysis in 328 ESCC samples, which revealed that strong TRAP1 expression was associated with increased risk of lymph node metastasis, while high TRAP1 expression correlated with poor prognosis. Expression of TRAP1 was found to be an independent prognostic factor for patients with ESCC. Additionally, the upregulation of TRAP1 antagonized cisplatin-induced apoptosis while its downregulation sensitized cells to cisplatin-induced apoptosis. As revealed by the transwell assay, TRAP1 overexpression promoted cellular migration and invasion as compared to the control groups. In contrast, silencing of endogenous TRAP1 expression attenuated the ability of migration and invasion. Finally, the molecular mechanism investigated in the present study demonstrated that TRAP1 mediated migration and invasion occurred through STAT3/MMP2 signaling pathway. In conclusion, TRAP1 may be considered as a molecular predictive marker for prognosis and a novel molecular candidate for therapeutic target in ESCC. PMID- 25438698 TI - STRIPE2 encodes a putative dCMP deaminase that plays an important role in chloroplast development in rice. AB - Mutants with abnormal leaf coloration are good genetic materials for understanding the mechanism of chloroplast development and chlorophyll biosynthesis. In this study, a rice mutant st2 (stripe2) with stripe leaves was identified from the gamma-ray irradiated mutant pool. The st2 mutant exhibited decreased accumulation of chlorophyll and aberrant chloroplasts. Genetic analysis indicated that the st2 mutant was controlled by a single recessive locus. The ST2 gene was finely confined to a 27-kb region on chromosome 1 by the map-based cloning strategy and a 5-bp deletion in Os01g0765000 was identified by sequence analysis. The deletion happened in the joint of exon 3 and intron 3 and led to new spliced products of mRNA. Genetic complementation confirmed that Os01g0765000 is the ST2 gene. We found that the ST2 gene was expressed ubiquitously. Subcellular localization assay showed that the ST2 protein was located in mitochondria. ST2 belongs to the cytidine deaminase-like family and possibly functions as the dCMP deaminase, which catalyzes the formation of dUMP from dCMP by deamination. Additionally, exogenous application of dUMP could partially rescue the st2 phenotype. Therefore, our study identified a putative dCMP deaminase as a novel regulator in chloroplast development for the first time. PMID- 25438700 TI - Identification and profiling of known and novel fiber microRNAs during the secondary wall thickening stage in cotton (Gossypium hirsutum) via high throughput sequencing. PMID- 25438701 TI - Identification of QTLs for branch number in oilseed rape (Brassica napus L.). PMID- 25438702 TI - Cellular serpents and dreaming spires: new frontiers in arginine and pyrimidine biology. PMID- 25438703 TI - Mechano-chemical effects in weakly charged porous media. AB - The paper is concerned with mechano-chemical effects, namely, osmosis and pressure-driven separation of ions that can be observed when a charged porous medium is placed between two electrolyte solutions. The study is focused on porous systems with low equilibrium interfacial potentials (about 30 mV or lower). At such low potentials, osmosis and pressure-driven separation of ions noticeably manifest themselves provided that the ions in the electrolyte solutions have different diffusion coefficients. The analysis is conducted by combining the irreversible thermodynamic approach and the linearized (in terms of the normalized equilibrium interfacial potential) version of the Standard Electrokinetic Model. Osmosis and the pressure-driven separation of ions are considered for an arbitrary mixed electrolyte solution and various porous space geometries. It is shown that the effects under consideration are proportional to a geometrical factor which, for all the considered geometries of porous space, can be expressed as a function of porosity and the Lambda- parameter of porous medium normalized by the Debye length. For all the studied geometries, this function turns out to be weakly dependent on both the porosity and the geometry type. The latter allows for a rough evaluation of the geometrical factor from experimental data on electric conductivity and hydraulic permeability without previous knowledge of the porous space geometry. The obtained results are used to illustrate how the composition of electrolyte solution affects the mechano chemical effects. For various examples of electrolyte solution compositions, the obtained results are capable of describing positive, negative and anomalous osmosis, positive and negative rejection of binary electrolytes, and pressure driven separation of binary electrolyte mixtures. PMID- 25438704 TI - Aluminum chloride impacts dentate gyrus structure in male adult albino Wistar rats. AB - To get better insights into the aluminum neurotoxicity, rats were treated with AlCl3 for increasing doses and periods. Body and brain weights, plasma and brain AlCl3 levels were assayed. Light microscopy observation of brain was performed. AlCl3 exposure showed a significant decrease (p < 0.05) on body and brain weight with the highest dose at 18 months. Statistical analysis confirms no significant interaction during 6 months (rho = 0.357; p > 0.05) while, significant correlation was observed during 12 (rho = 0.836; p < 0.001) and 18 months (rho = 0.769; p < 0.001) between body and brain weight. Plasma and brain AlCl3 concentration increased significantly (p < 0.05) with dose and period dependent manner. Statistical analysis confirms significant interaction between brain concentrations of AlCl3 and administrated doses during 6 (rho = 0.969; p < 0.001), 12 (rho = 0.971; p < 0.001) and 18 months (rho = 0.965; p < 0.001). Similar relation was established between plasma AlCl3 concentration and administrated doses during 6 (rho = 0.970; p < 0.001), 12 (rho = 0.971; p < 0.001) and 18 months (rho = 0.964; p < 0.001). Significant relation was confirmed between plasma and brain AlCl3 concentration during 6 (rho = 0.926; p < 0.001), 12 (rho = 0.983; p < 0.001) and 18 months (rho = 0.906; p < 0.001). Morphological alterations mainly targeted the subgranular layer with modulation of the dentate gyrus appearance. This study highlights the toxic effect of AlCl3 on the brain which may affects learning and memory and seems to be different according to dose and duration of exposure. PMID- 25438705 TI - Is the menstrual cycle truly a vital sign? PMID- 25438706 TI - Menstruation in adolescents: what do we know? And what do we do with the information? AB - The menstrual cycle has been recognized as a vital sign that gives information about the overall health of an adolescent or young adult female. Significant deviations from monthly cycles can signal disease or dysfunction. This review highlights the evidence based parameters for normal puberty, menarche, cyclicity, and amount of bleeding. The review addresses sources of information available online, noting inaccuracies that appear in web sites, even and especially those targeting adolescents. The review includes a call to action to provide accurate information about the menstrual cycle as a VITAL SIGN. PMID- 25438707 TI - Non-obstructive mullerian anomalies. AB - BACKGROUND: The nonobstructive group of anatomic variants involving the reproductive tract includes vaginal agenesis as well as the congenital anomalies of the vagina and uterus, occurring without pain during the pubertal years. OBJECTIVE: The objective is to discuss the non-obstructive morphologic variations in anatomy of the uterus and vagina. DESIGN: Systematic review using the GRADE system. RESULTS: These congenital anomalies are not associated with abnormalities of the external genitalia and therefore may be missed on routine physical examination. When these anomalies do cause symptoms they may be as minor as difficulty with menstrual hygiene or more significant such as primary amenorrhea, dyspareunia, recurrent pregnancy loss, and reproductive complications. CONCLUSIONS: Women with non-obstructive reproductive tract anomalies present at various ages due to the asymptomatic nature or late symptom onset of certain conditions. An MRI is the gold standard in evaluation of such conditions to aid in confirming the mullerian variant. Each condition requires careful counseling because obstetric and gynecologic risks and consequences may differ. Treatment is individualized in cases of uterovaginal agenesis with both nonsurgical and surgical options available for neovagina creation. In cases of uterine or vaginal septae, the treatment timing may vary depending on patient history. Finally, in cases of non-obstructive communicating uterine horns, the risk of ectopic pregnancy is high in the remnant horn. Should a pregnancy occur in this small underdeveloped horn, therefore, excision is recommended. PMID- 25438708 TI - Obstructive reproductive tract anomalies. AB - BACKGROUND: Approximately 7% of girls will have an anatomic abnormality in their reproductive tract, diagnosed before or after puberty. OBJECTIVE: It is important for providers to be aware of the obstructive reproductive tract conditions, the way in which various conditions present, and the way in which such conditions should be managed. DESIGN: Systematic review of the literature using the GRADE evidence system. RESULTS: There is limited data in most areas of obstructive reproductive tract anomalies; however, some retrospective and prospective series with small numbers are still useful to guide clinical practice. CONCLUSIONS: Recommendations are based on limited or inconsistent scientific evidence. Recommendations are based primarily on consensus and expert opinion. PMID- 25438709 TI - Pyrazoloquinazolines: Synthetic strategies and bioactivities. AB - Numerous N-heterocycles are indisputably evidenced to exhibit myriad biological activities. In the recent past, attempts made to condense the various heterocycles have resulted in derivatives possessing better bioactivities. Among many such condensed heterocycles, pyrazoloquinazolines have managed to hold the attention of many researchers, owing to the broad spectrum of activities they portray. This review is the first of its kind to congregate the various pyrazoloquinazolines reported until now and categorizes these structurally isomeric classes into eleven different groups based on the fusion pattern of the ring such as [1,5-c], [5,1-b], [4,3-h], etc. Furthermore, this review is a concerted effort to highlight design, synthetic strategies as well as biological activities of each class of this condensed heterocycle. Structure-activity relationship studies and in silico approaches wherever reported have also been discussed. In addition, manuscript also offers scope for design, synthesis and generation of libraries of unreported classes of pyrazoloquinazolines for the biological evaluation. PMID- 25438710 TI - Automatic dynamic range adjustment for ultrasound B-mode imaging. AB - In medical ultrasound imaging, dynamic range (DR) is defined as the difference between the maximum and minimum values of the displayed signal to display and it is one of the most essential parameters that determine its image quality. Typically, DR is given with a fixed value and adjusted manually by operators, which leads to low clinical productivity and high user dependency. Furthermore, in 3D ultrasound imaging, DR values are unable to be adjusted during 3D data acquisition. A histogram matching method, which equalizes the histogram of an input image based on that from a reference image, can be applied to determine the DR value. However, it could be lead to an over contrasted image. In this paper, a new Automatic Dynamic Range Adjustment (ADRA) method is presented that adaptively adjusts the DR value by manipulating input images similar to a reference image. The proposed ADRA method uses the distance ratio between the log average and each extreme value of a reference image. To evaluate the performance of the ADRA method, the similarity between the reference and input images was measured by computing a correlation coefficient (CC). In in vivo experiments, the CC values were increased by applying the ADRA method from 0.6872 to 0.9870 and from 0.9274 to 0.9939 for kidney and liver data, respectively, compared to the fixed DR case. In addition, the proposed ADRA method showed to outperform the histogram matching method with in vivo liver and kidney data. When using 3D abdominal data with 70 frames, while the CC value from the ADRA method is slightly increased (i.e., 0.6%), the proposed method showed improved image quality in the c-plane compared to its fixed counterpart, which suffered from a shadow artifact. These results indicate that the proposed method can enhance image quality in 2D and 3D ultrasound B-mode imaging by improving the similarity between the reference and input images while eliminating unnecessary manual interaction by the user. PMID- 25438711 TI - Mother to child transmission of HIV: what works and how much is enough? AB - In 2012, 3.3 million children were living with HIV (Human Immunodeficiency virus), of whom 260,000 were new infections. Prevention of mother to child transmission is vital in reducing HIV-related child mortality and morbidity. With intervention the risk of transmission can be as low as 1% and without it, as high as 45%. The WHO (World Health Organisation) recommends a programmatic approach to the prevention of perinatal HIV transmission and has withdrawn option A and introduced option B+. This recommends that all HIV positive pregnant and breastfeeding women receive lifelong triple ARV (antiretroviral) from the point of diagnosis. The infant would then receive 4-6 weeks of ART (antiretroviral therapy) (NVP, nevirapine or AZT, Zidovudine) regardless of the feeding method. Where resources are not limited an individualised approach can be adopted. Worldwide, health care needs to be accessible and HIV testing performed in pregnancy and followed up in a robust but socially sensitive way so that treatment can be initiated appropriately. In either setting the risk of transmission is never zero and countries need to decide for themselves what is the most practical and sustainable approach for their setting, so that the maximum impact on maternal and child mortality and morbidity can be achieved. PMID- 25438712 TI - Feasibility of tailored follow-up for patients with early breast cancer. AB - As the number of breast cancer survivors increases, this study prospectively examined whether tailored follow-up with differentiated number of visits per risk group, based on a prognostic index for local recurrence, is feasible and acceptable for patients and professionals. Between March 2007 and March 2010, 180 breast cancer patients (pT1-2N0-2cM0) were included. Primary endpoint was feasibility of tailored follow-up, based on the number of follow-up visits, patient satisfaction, anxiety and attitude towards follow-up. Secondary endpoints were reasons for visits, incidence, time to detection of local recurrences and the use of alternative care. In the second and third year of follow-up, the results show a 22% reduction in visits per patient in the low-risk group compared to the intermediate-risk group; 2.8 versus 3.6 visits. The majority of interval visits in both groups was initiated by the professional. No significant differences were found in attitude towards follow-up, patient satisfaction, anxiety and depression, alternative health care use or local recurrences between the risk groups. In conclusion, implementation of a tailored follow-up programme with decreased number of visits for low-risk patients is feasible and acceptable to patients. Appointing one coordinating professional, possibly a nurse practitioner, could further reduce the number of follow-up visits. PMID- 25438713 TI - Emotional intelligence--essential for trauma nursing. AB - Patients and their relatives are increasingly considered partners in health and social care decision-making. Numerous political drivers in the UK reflect a commitment to this partnership and to improving the experience of patients and relatives in emergency care environments. As a Lecturer/Practitioner in Emergency Care I recently experienced the London Trauma System as a relative. My dual perspective, as nurse and relative, allowed me to identify a gap in the quality of care akin to emotional intelligence. This paper aims to raise awareness of emotional intelligence (EI), highlight its importance in trauma care and contribute to the development of this concept in trauma nursing and education across the globe. PMID- 25438714 TI - Adherence to the 2010 Dietary Guidelines for Americans and the relationship to adiposity in young women. AB - OBJECTIVE: To determine the relationship between adherence to the 2010 Dietary Guidelines for Americans and adiposity in young women with and without statistical adjustment for physical activity (PA). METHODS: Participants included 324 young women (aged 17-25 years). The researchers measured dietary intake using the Dietary History Questionnaire and determined diet quality using the 2010 Healthy Eating Index (HEI-2010). BOD POD (Cosmed, Rome, Italy, 2006) and accelerometry were used to assess body fat and PA, respectively. RESULTS: Women in the top quartile of HEI-2010 had significantly lower percent body fat than women in the lowest 3 quartiles (F = 3.36; P = .03). Controlling for objectively measured PA weakened this relationship by 20%. These young women (top quartile of HEI-2010) also had 0.37 odds (95% confidence interval, 0.16-0.85) of having body fat > 32%. CONCLUSIONS AND IMPLICATIONS: Young women whose diets most closely meet the 2010 Dietary Guidelines for Americans have lower adiposity. PMID- 25438715 TI - Missed opportunities: a qualitative exploration of the experiences of smoking cessation interventions among socially disadvantaged pregnant women. AB - BACKGROUND AND AIM: Pregnant women who smoke are rarely consulted in the design and evaluation of the interventions that target them. In Australia, women will typically be counselled for smoking cessation as a part of routine antenatal care. However this approach achieves only modest rates of cessation. This study aimed to privilege the perspectives of women from low socioeconomic backgrounds who are most likely to smoke during pregnancy and who are less likely to quit spontaneously. METHODS: Guided by feminist principles, in-depth interviews were undertaken with a purposive sample of six pregnant women, who resided in lower socioeconomic status areas in South Australia. Their experiences and views of being part of a smoking cessation intervention in metropolitan Adelaide were explored. Transcriptions were thematically analysed using an inductive approach and an open coding framework. FINDINGS: An over-arching theme of 'missed opportunities' and four inter-related sub-themes encapsulated the predominantly negative experiences of the intervention for the women. The women's interest in quitting was hindered by a didactic communication style employed by maternity care professionals. The participants' information and support needs were reported as being superficially managed by maternity care professionals or Quitline workers who provided care in routine ways. CONCLUSIONS: These findings indicate that smoking cessation interventions and associated Quitline support needs to become more personalised and sensitive to the needs of women who face barriers posed by complex socio-economic disadvantage. These findings have important policy and practice implications for Australian public maternity care settings where smoking cessation interventions are embedded. PMID- 25438716 TI - Features of endothelial dysfunction in umbilical cord vessels of women with gestational diabetes. AB - BACKGROUND AND AIMS: Gestational diabetes (GDM) is associated with increased oxidative stress and overexpression of inflammatory cytokines, both of which might lead to endothelial dysfunction and vascular disease. As such, GDM could be viewed as a sort of 'short lived' metabolic syndrome. As umbilical cord vessels represent a suitable model for the study of vascular alterations brought about by GDM, the aim of the present work was to characterize the phenotype of human umbilical vein endothelial cells (HUVECs) chronically exposed to hyperglycaemia and to a pro-inflammatory environment during pregnancy so as to identify molecular modifications of cellular homoeostasis eventually impacting on endothelial dysfunction. METHODS AND RESULT: Tissue specimens and HUVECs were obtained from umbilical cords of GDMand control women. As compared to controls, GD-HUVEC exhibited enhanced monocyte adhesion and vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule-1(ICAM-1) expression and exposure on plasma membrane after tumour necrosis factor-alpha(TNF-alpha) stimulation (Western blot, flow cytometer). As compared to control cells, GD-HUVEC in basal conditions exhibited enhanced monocyte adhesion, nitric oxide synthase (NOS) expression and activity (eNOS Real-Time polymerase chain reaction, Western Blot for eNOS total protein and monomers/dimers ratio, conversion of [3H]-L-arginine in [3H]-L-citrulline), increased O(-)(2)egeneration together with increased NT levels (immunofluorescence) and reduced NO bioavailability(guanosine 3',5' monophosphate (cGMP) production, EIA). Furthermore, immunohistochemistry revealed increased eNOS and NT immunoreactivity in GD umbilical cords. CONCLUSION: Endothelial cells exposed in vivo even transiently to hyperglycaemia, oxidative stress and inflammation exhibit durable pro-atherogenic modifications. PMID- 25438717 TI - Valence-band mixing effects in the upper-excited-state magneto-optical responses of colloidal Mn2+-doped CdSe quantum dots. AB - We present an experimental study of the magneto-optical activity of multiple excited excitonic states of manganese-doped CdSe quantum dots chemically prepared by the diffusion doping method. Giant excitonic Zeeman splittings of each of these excited states can be extracted for a series of quantum dot sizes and are found to depend on the radial quantum number of the hole envelope function involved in each transition. As seven out of eight transitions involve the same electron energy state, 1Se, the dominant hole character of each excitonic transition can be identified, making use of the fact that the g-factor of the pure heavy-hole component has a different sign compared to pure light hole or split-off components. Because the magnetic exchange interactions are sensitive to hole state mixing, the giant Zeeman splittings reported here provide clear experimental evidence of quantum-size-induced mixing among valence-band states in nanocrystals. PMID- 25438718 TI - Topological features of rugged fitness landscapes in sequence space. AB - The factors that determine the tempo and mode of protein evolution continue to be a central question in molecular evolution. Traditionally, studies of protein evolution focused on the rates of amino acid substitutions. More recently, with the availability of sequence data and advanced experimental techniques, the focus of attention has shifted toward the study of evolutionary trajectories and the overall layout of protein fitness landscapes. In this review we describe the effect of epistasis on the topology of evolutionary pathways that are likely to be found in fitness landscapes and develop a simple theory to connect the number of maladapted genotypes to the topology of fitness landscapes with epistatic interactions. Finally, we review recent studies that have probed the extent of epistatic interactions and have begun to chart the fitness landscapes in protein sequence space. PMID- 25438719 TI - Thinking too positive? Revisiting current methods of population genetic selection inference. AB - In the age of next-generation sequencing, the availability of increasing amounts and improved quality of data at decreasing cost ought to allow for a better understanding of how natural selection is shaping the genome than ever before. However, alternative forces, such as demography and background selection (BGS), obscure the footprints of positive selection that we would like to identify. In this review, we illustrate recent developments in this area, and outline a roadmap for improved selection inference. We argue (i) that the development and obligatory use of advanced simulation tools is necessary for improved identification of selected loci, (ii) that genomic information from multiple time points will enhance the power of inference, and (iii) that results from experimental evolution should be utilized to better inform population genomic studies. PMID- 25438720 TI - Pharmacokinetic bridging approach for developing biologics-delivery devices: a case study with a golimumab autoinjector. AB - PURPOSE: This Phase 1 pharmacokinetic (PK) comparability study in healthy subjects was performed to compare the PK properties and tolerability of single dose golimumab 100 mg delivered subcutaneously by an autoinjector device or by a standard needle and syringe that had been used for the subcutaneous (SC) delivery of golimumab in pivotal Phase 3 studies. METHODS: Healthy male subjects were randomly assigned to receive a single injection of SC golimumab 100 mg using either the autoinjector or a standard needle and syringe. The PK parameters of golimumab were calculated using noncompartmental analysis. An ANOVA model was applied to compare the 2 injection methods with regard to golimumab C(max) and the AUC from 0 and 49 days after administration (AUC(0-49d)). FINDINGS: In the prespecified evaluable PK population (n = 141), the mean (SD) values for C(max) were 6.6 (3.3) and 6.0 (3.0) ug/mL, and AUC(0-49d) values were 97.4 (43.2) and 88.9 (36.8) ug.d/mL in the autoinjector and needle/syringe groups, respectively. The 90% CI of the geometric mean ratios of the AUC(0-49d) values between the 2 delivery methods was 95.17% to 120.55%; the 90% CI of the geometric mean ratio of C(max) was 96.14% to 127.42%. In a post hoc intent-to-treat analysis using data from all 156 subjects, the 90% CIs of both C(max) and AUC(0-49d) fell within the prespecified range for bioequivalence (80% to 125%). The prevalences of adverse events were similar between the 2 groups. IMPLICATIONS: The totality of the study findings suggests that the PK properties and tolerability of SC administration of golimumab by the 2 delivery methods were comparable. The study results successfully bridged the container-closure change from a liquid-in-vial product to either a prefilled syringe or an autoinjector with the same liquid formulation. PMID- 25438721 TI - Evaluation of the potential for pharmacokinetic drug-drug interaction between armodafinil and carbamazepine in healthy adults. AB - PURPOSE: Polypharmacy is common in psychiatry practice and can lead to an increased risk of drug interactions. Armodafinil, a wakefulness-promoting agent, has been studied as adjunctive therapy for the treatment of major depressive episodes associated with bipolar I disorder. Armodafinil and the mood stabilizer carbamazepine are both inducers of and substrates for cytochrome P450 (CYP3A4). This study was designed to evaluate the bidirectional carbamazepine-armodafinil pharmacokinetic drug-drug interaction. METHODS: This was an open-label, single center study conducted in healthy adult men. Subjects assigned to group 1 received a dose of carbamazepine (200 mg) alone and a dose after pretreatment with daily dosing of armodafinil (titrated to 250 mg/d). Subjects assigned to group 2 received a dose of armodafinil (250 mg) alone and a dose after pretreatment with carbamazepine BID (titrated to 400 mg/d). Pharmacokinetic parameters for carbamazepine, armodafinil, and their major circulating metabolites were determined when dosed alone and after pretreatment with the other drug. The safety and tolerability of armodafinil and carbamazepine were also assessed throughout the study. FINDINGS: Eighty-one subjects enrolled in the study (group 1 = 40; group 2 = 41), of whom 79 (group 1 = 40; group 2 = 39) were evaluable for pharmacokinetic analysis and 80 (group 1 = 40; group 2 = 40) were evaluable for safety analysis. In group 1, pretreatment with armodafinil reduced systemic exposure to carbamazepine by 12% for Cmax and 25% for AUC (based on comparison of geometric means). Similarly, in group 2, pretreatment with carbamazepine reduced systemic exposure to armodafinil by 11% for Cmax and 37% for AUC. Systemic exposure to the metabolites of these agents that are formed via CYP3A4 were increased after pretreatment in each group. There were no new or unexpected adverse events. IMPLICATIONS: Systemic exposure to both carbamazepine and armodafinil was reduced after pretreatment with the other drug; systemic exposure to the metabolites of each drug, which are formed via CYP3A4, was increased. These changes were consistent with the induction of CYP3A4. Both drugs were generally safe and well tolerated alone and in combination under the conditions studied. Dose adjustment may be required when initiating or discontinuing armodafinil and carbamazepine cotherapy. PMID- 25438722 TI - Comparison of the cost-effectiveness of new oral anticoagulants for the prevention of stroke and systemic embolism in atrial fibrillation in a UK setting. AB - PURPOSE: Three new oral anticoagulants (NOACs) have recently become available in the United Kingdom as an alternative to warfarin in the prevention of stroke and systemic embolism in atrial fibrillation. This study examines the relative cost effectiveness of dabigatran (BID dosing of 150 mg or 110 mg based on patient age), rivaroxaban, and apixaban from a UK payer perspective. METHODS: A previously published model that follows up patients through treatment of atrial fibrillation during a lifetime was adapted to allow comparison of the 3 NOACs and warfarin. Acute thromboembolic and bleeding events, as well as long-term consequences of stroke, intracranial hemorrhage, and acute myocardial infarction, were tracked. Relative efficacy was calculated from a formal indirect treatment comparison using data from the 3 key trials (Randomized Evaluation of Long-Term Anticoagulation Therapy, Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation, and Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) of the NOACs. Data from the rivaroxaban trial were adjusted for the difference in international normalized ratio control among warfarin patients versus the other 2 trials. Model outputs included total costs, event rates, and quality-adjusted life-years. FINDINGS: Among the patients taking NOACs, those taking dabigatran had the highest total QALYs (7.68 QALYs), followed by apixaban (7.63 QALYs) and rivaroxaban (7.47 QALYs). Patients taking dabigatran had the lowest total lifetime costs (L23,342), followed by apixaban (L24,014) and rivaroxaban (L25,220). The differences between dabigatran and apixaban were modest but consistent in sensitivity analyses, with the directionality only changing at the limits of the CIs for the relative risks of ischemic stroke or intracranial hemorrhage or when assuming that both treatment discontinuation and post-event disability rates differ by drug. IMPLICATIONS: Dabigatran was found to be economically dominant over rivaroxaban and apixaban in the UK setting. These economic findings are based on relative clinical efficacy from an indirect treatment comparison and would benefit from any data of direct comparisons of the NOACs in the future. PMID- 25438723 TI - Dapoxetine for premature ejaculation: an updated meta-analysis of randomized controlled trials. AB - PURPOSE: Dapoxetine is the first oral agent approved for the treatment of premature ejaculation (PE). However, some countries have not approved its use. The goal of this meta-analysis was to provide more information about the efficacy and safety of dapoxetine in patients with PE. METHODS: We performed a meta analysis of randomized controlled trials (RCTs) comparing dapoxetine with a placebo in patients with PE. Relevant eligible RCTs were identified through comprehensive searches of the Cochrane Central Register of Controlled Trials, EMBASE, and PubMed. Efficacy (intravaginal ejaculatory latency time (IELT), patient global impression of change, perceived control over ejaculation, and satisfaction with sexual intercourse) and safety (treatment-emergent adverse events and discontinuation rates) were studied by using Review Manager version 5.1.0. FINDINGS: Six RCTs involving 5934 patients met the inclusion criteria. The main outcome (IELT) in the dapoxetine group was improved significantly compared with IELT in the placebo group (mean difference, 1.59 [95% CI, 1.30 to 1.88]; P < 0.00001). The 60-mg dose of dapoxetine was more beneficial than the 30-mg dose for IELT (mean difference, -0.47 [95 % CI, -0.73 to -0.20]; P = 0.0005). Although the occurrence of treatment-emergent adverse events in the dapoxetine group was nearly twice that in the placebo group (50.5% vs 27.9%), reports of severe adverse events were rare. IMPLICATIONS: Data from the meta-analysis revealed that treatment with dapoxetine was significantly efficacious in patients with PE. Although adverse events such as nausea, dizziness, diarrhea, insomnia, and headache were common, dapoxetine's overall safety profile was acceptable. PMID- 25438724 TI - Pharmacodynamics, pharmacokinetics, safety, and tolerability of encenicline, a selective alpha7 nicotinic receptor partial agonist, in single ascending-dose and bioavailability studies. AB - PURPOSE: Encenicline (EVP-6124) is a selective alpha7 nicotinic acetylcholine receptor partial agonist being developed for cognitive impairment in Alzheimer's disease and schizophrenia. We report on 2 single-dose studies to assess the relative bioavailability, pharmacokinetic profile, tolerability, and cognitive effects of encenicline in healthy volunteers. METHODS: A single ascending-dose study assessed the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of encenicline in healthy male volunteers. Subjects received a single 1 , 3.5-, 7-, 20-, 60-, or 180-mg oral solution dose of encenicline or placebo. A second single-dose, randomized, open-label, 3-period, crossover study in healthy male and female subjects compared the relative bioavailability of a 1-mg oral capsule versus a 1-mg oral solution dose of encenicline and evaluated the effects of food and sex on encenicline pharmacokinetic profile. FINDINGS: In the first study, encenicline was well tolerated and dose-proportional increases in C(max) (mean range 0.59-100 ng/mL) and AUC0-infinity (mean range 45.6-8890 ng.h/mL) were observed over a 1- to 180-mg dose range. Procognitive effects on the Digit Symbol Substitution Test were maximal at the 20-mg dose. In the second study, encenicline 1-mg oral capsules and oral solution were bioequivalent and there was no observed food effect on encenicline pharmacokinetic profile with the 90% confidence intervals of the treatment ratios for both comparisons (ie, capsule to solution and fed to fasted) for Cmax and AUC being within 80% to 125%. A 30% to 40% higher encenicline exposure in female subjects than respective values in male subjects was consistent with a 33% higher weight of the male subjects. No clinically relevant safety profile or tolerability effects of encenicline were observed. IMPLICATIONS: Encenicline was well tolerated at single doses up to 180 mg, and doses as low as 1 mg had dose- and time-dependent pharmacodynamic effects on the central nervous system. Oral capsule and solution were bioequivalent and were not affected by food. Although a sex effect on pharmacokinetic profile was observed, it was attributable to weight differences. Clinical Trial Registration at EudraCT: 2006-005623-42 and EudracT: 2008-000029-20. PMID- 25438725 TI - Reviewing a clinical decision aid for the selection of anticoagulation treatment in patients with nonvalvular atrial fibrillation: applications in a US managed care health plan database. AB - PURPOSE: The Clinical Decision Aid was created to assist in selecting anticoagulant therapies for patients with nonvalvular atrial fibrillation. The aid incorporates a patient's absolute risk for stroke and bleeding, relative stroke risk reduction, and increase in relative bleeding risk to identify the agent with the lowest net risk. We describe theoretical implications of utilizing the aid at a US managed care population level. METHODS: This retrospective study used claims data from a large US managed care database including enrollees in commercial and Medicare Advantage plans. The distribution of patients across each possible combination of scores on the HAS-BLED scale (evidence of hypertension, abnormal renal or liver function, stroke, bleeding, labile INR, age >65 years, and drugs or alcohol abuse or dependence) and the CHA2DS2-VASc scale (CHADS2 [congestive heart failure, hypertension, age >=75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism] with additional nonmajor stroke risk factors, including age 65-74 years, female sex, and vascular disease) was generated. We assessed the correlation between the HAS-BLED and CHA2DS2-VASc scores and derived the optimal treatment options based on various bleeding ratios. FINDINGS: Data from 48,260 patients were included in the analysis. The MAPD subset had a higher mean HAS-BLED score (2.17 vs 1.39; P < 0.001) and a higher mean CHA2DS2-VASc score (3.35 vs 2.05; P < 0.001) than did the commercial subset. Pearson coefficients suggested a moderate to strong positive correlation between the HAS-BLED and CHA2DS2-VASc scores among the commercial (0.730; P < 0.001) and MAPD (0.568; P < 0.001) enrollees. Based on a 2:1 bleeding-to-stroke risk ratio, 70.50% of patients would be recommended treatment with apixaban; 25.86%, no treatment; 3.62%, acetylsalicylic acid; and 0.01%, dabigatran 150 mg, if the Clinical Decision Aid were to be used for anticoagulant treatment selection. IMPLICATIONS: Evidence-based clinical decision-making tools utilizing risk assessment for recommending a treatment may be valuable for not only health care providers but also health care payers in optimizing care at the population level. PMID- 25438726 TI - Internationally trained pharmacists' perception of their communication proficiency and their views on the impact on patient safety. AB - BACKGROUND: According to Great Britain (GB)'s pharmacy regulator's standards of conduct, ethics and performance, pharmacists have a responsibility to ensure that they have sufficient linguistic skills to communicate and perform their job safely. Yet, very little is known about internationally trained pharmacists' (ITPs) linguistic proficiency. OBJECTIVES: The purpose of this study was to investigate ITPs' perceptions of their communication proficiency and the resultant impact on patient safety. METHODS: Eight focus groups were conducted between May and July 2010, with 31 European Economic Area (EEA) and 11 non-EEA pharmacists who, at the time of the study, practiced in community pharmacy (n = 29) or hospital (n = 13), in London, Manchester, Liverpool and Glasgow. The framework method was used to analyze qualitative data, and the Model of Communicative Proficiency (MCP) served as a framework to handle and explain the data obtained. RESULTS: ITPs experienced communication difficulties through new dialects, use of idioms and colloquial language in their workplace. The differences between the "BBC English" they learned formally and the "Street English" used in GB also led to difficulties. Culture was also recognized as an important aspect of communication. ITPs in this study were adamant that communication difficulty did not compromise patient safety. CONCLUSIONS: Communicative deficiency of ITPs arose primarily from two sources: linguistic competence and socio-cultural competence. These deficiencies could have negative implications for patient safety. The findings of this study should be taken into account when designing adaptation programs for ITPs. PMID- 25438727 TI - Pharmacists' thought processes in making a differential diagnosis using a gastro intestinal case vignette. AB - BACKGROUND: Community pharmacists facilitate patient self-care and, in effect, provide a triage service to primary care medical services. Their ability to perform this role has been questioned, yet research has not explored how pharmacists make these decisions. Better understanding of the processes that shape pharmacists' clinical decisions will allow strategies to be developed to improve "diagnostic" performance. OBJECTIVE: This study aimed to explore community pharmacists thought processes when making a differential diagnosis during referral and triage. METHODS: Using a case vignette, community pharmacists were asked to establish the cause of a simulated patient's signs and symptoms. After each question asked by the pharmacist they were asked to 'think aloud' their thoughts. Pharmacists from the West Midlands, England were recruited through convenience and snowball sampling. The simulated consultations were recorded and transcribed verbatim. Questions asked were coded into pre-determined categories that captured the context of why the question was being asked, which was gained from the 'think aloud' process. RESULTS: Ten pharmacists were interviewed. Seven used an acronym approach to information gathering, and those who used it exclusively did not reach the expected outcome. Three pharmacists exhibited questioning that aligned to medical clinical decision-making and asked more questions that informed the diagnosis than those pharmacists relying on using an acronym; all three arrived at the expected outcome. All pharmacists asked 'safety net' type question/s early on in the consultation. This study was exploratory and the findings must be viewed with caution until larger studies are conducted. CONCLUSIONS: Pharmacists rarely exhibited clinical decision-making and relied heavily on protocol-led questioning strategies. PMID- 25438728 TI - A feasibility study of community pharmacists performing depression screening services. AB - BACKGROUND: Depression is one of the largest causes of disease burden globally but can routinely go undetected in primary care. Screening for depression is an effective way to increase early recognition, and there is an opportunity to utilize pharmacists' skills and accessibility to do this. OBJECTIVES: The overall aim of this study was to determine the feasibility of Australian community pharmacists performing screening and risk assessment services for depression. The specific objectives were to: (1) develop a depression screening training program to aid pharmacists in the screening and risk assessment of depression in community pharmacy, (2) assess the feasibility of pharmacists using a screening tool for depression, (3) assess pharmacists' perspectives on the ease of use of different screening tools in the community pharmacy setting and (4) investigate the barriers and facilitators to pharmacists performing screening and risk assessment services for depression in community pharmacy. METHODS: Twenty pharmacists from 12 community pharmacies were recruited. A training program on depression was developed and delivered to the pharmacists, followed by an eight week data collection period during which pharmacists conducted patient screenings for depression. Semi-structured interviews were conducted at the end of the data collection period to gather pharmacists' reflections on the intervention and to explore the barriers and facilitators to depression screening and risk assessment. RESULTS: Forty-one screening and risk assessments were conducted from 75 consumers who were approached. The majority of consumers screened were female, less than 40 years old and previously known to the pharmacy. More than 70% of consumers were referred on to a GP or psychologist for assessment. Barriers to implementation of the service included time, stigma and a lack of awareness of the pharmacists' role. Facilitators to the service included the accessibility of the pharmacist, having a private consultation area in the pharmacy, awareness campaigns and mental health resources on display. CONCLUSIONS: Pharmacists are capable of performing screening and risk assessment services for depression and making referrals to appropriate health care professionals when required. Pharmacy based depression screening programs have the potential to increase the early detection of depression which may lead to early intervention, and potentially contribute to easing the enormous disease burden associated with depression. PMID- 25438729 TI - Measurement of serum immunoglobulin G in dairy cattle using Fourier-transform infrared spectroscopy: a reagent free approach. AB - Simple, rapid and cost-effective methods are sought for measuring immunoglobulin G (IgG) concentrations in bovine serum, which can be applied for diagnosis of failure of transfer of passive immunity (FTPI). The aim of the present study was to investigate the potential use of Fourier-transform infrared (FTIR) spectroscopy, with partial least squares (PLS) regression, to measure IgG concentrations in bovine serum. Serum samples collected from calves and adult cows were tested in parallel by radial immunodiffusion (RID) assay and FTIR spectroscopy. The sample IgG concentrations obtained by the RID method were linked to pre-processed spectra and divided into two sets: a combined set and a test set. The combined set was used for building a calibration model, while the test set was used to assess the predictive ability of the calibration model, resulting in a root mean squared error of prediction (RMSEP) of 307.5 mg/dL. The concordance correlations between the IgG measured by RID and predicted by FTIR spectroscopy were 0.96 and 0.93 for the combined and test data sets, respectively. Analysis of the data using the Bland-Altman method did not show any evidence of systematic bias between FTIR spectroscopy and RID methods for measurement of IgG. The clinical applicability of FTIR spectroscopy for diagnosis of FTPI was evaluated using the entire data set and showed a sensitivity of 0.91 and specificity of 0.96, using RID as the reference standard. The FTIR spectroscopy method, described in the present study, demonstrates potential as a rapid and reagent-free tool for quantification of IgG in bovine serum, as an aid to diagnosis of FTPI in calves. PMID- 25438730 TI - Re-examining EIPH in racing: stopping the Lasix? PMID- 25438731 TI - The phenotype and activation status of T and NK cells in porcine colostrum suggest these are central/effector memory cells. AB - In pigs, the epitheliochorial placenta does not allow transfer of maternally derived antibodies or immune cells to the fetus. Thus, piglets are dependent on intake of colostrum for acquisition of passive immunity during the neonatal period. As well as immunoglobulin G (IgG), cellular components of colostrum, mainly lymphocytes, can enter the systemic circulation and secondary lymphoid organs of the neonate. In order to understand the function and immunological role of these cells, a flow cytometric study was undertaken to characterise the cellular profile and phenotype of T cells and NK cells present in porcine colostrum. The results indicated that the greatest numbers of lymphocytes were found on the first day of lactation. The predominant cell types in colostrum were CD8(+) single positive T cells (53.6%), followed by CD4(+)CD8(+) double positive T cells (21.1%), CD2(+)CD8(+) gammadelta T cells (15.0%) and NK cells (13.5%). CD4(+) single positive T cells (4.4%) and other gammadelta T cell subpopulations (1.8% CD2(-)CD8(-) and 0.4% CD2(+)CD8(-)) were present in colostrum at low levels. Although the profile of the T cell subpopulations during the first 3 days of lactation remained constant, the absolute numbers of T and NK cells decreased significantly in the first few hours of lactation. Expression of CCR7, CD11b, CD25, CD45RA and MHC class II was used to assess the activation status of T and NK cells in colostrum. T cell subpopulations expressed markers consistent with an effector memory phenotype, indicating that these were antigen-experienced cells. The phenotype of colostral T and NK cells suggests a role in mucosal immunity and potentially in transfer of passive immunity from sow to piglet. PMID- 25438733 TI - Upper airway imaging in pediatric obstructive sleep apnea syndrome. AB - Obstructive sleep apnea syndrome in children is a manifestation of sleep disordered breathing and associated with a number of complications. Structural narrowing of the upper airway in combination with inadequate compensation for a decrease in neuromuscular tone is an important factor in the pathogenesis. Adenotonsillar hypertrophy is the most important predisposing factor. However, many other causes of craniofacial defects may coexist. Additionally, the pathogenesis of narrowing is more complex in certain subgroups such as children with obesity, craniofacial malformations, Down syndrome or neuromuscular disorders. The diagnosis of obstructive sleep apnea is based on an overnight polysomnography. This investigation is expensive, time consuming and not widely available. In view of the major role of structural narrowing, upper airway imaging could be a useful tool for investigating obstructive sleep apnea and in establishing the site(s) of obstruction. Several radiological techniques (lateral neck radiography, cephalometry, computerized tomography, magnetic resonance imaging and post-processing of these images using computational fluid dynamics) have been used to investigate the role of structural alterations in the pathogenesis. We reviewed the literature to examine if upper airway imaging could replace polysomnography in making the diagnosis and if imaging could predict the effect of treatment with a focus on adenotonsillectomy. There is a limited number of high quality studies of imaging predicting the effect of treatment. To avoid unnecessary risks and ineffective surgeries, it seems crucial to couple the exact individual anatomical risk factor with the most appropriate treatment. We conclude that imaging could be a non-invasive tool that could assist in selection of treatment. PMID- 25438732 TI - Serological investigation of transplacental infection with Neospora hughesi and Sarcocystis neurona in broodmares. AB - The aim of the present study was to investigate the likelihood of transplacental transmission of Neospora hughesi and Sarcocystis neurona in foals, born from seropositive mares. Three broodmares with persistent N. hughesi infection gave birth to eight healthy foals over a period of 7 years. These foals were seropositive to N. hughesi prior to colostrum ingestion, with titers ranging between 640 and 20,480, measured by indirect fluorescence antibody test (IFAT). Of 174 foals born at another farm to mares with a high seroprevalence to S. neurona, only one (with a pre-colostrum antibody titer of 80) tested seropositive. Transplacental transmission of N. hughesi seems to occur from latently infected mares to their foals, while this route of transmission does not seem to occur commonly for S. neurona. PMID- 25438734 TI - Management of pseudophakic cystoid macular edema. AB - Pseudophakic cystoid macular edema (PCME) is a common complication following cataract surgery. Acute PCME may resolve spontaneously, but some patients will develop chronic macular edema that affects vision and is difficult to treat. This disease was described more than 50 years ago, and there are multiple options for clinical management. We discuss mechanisms, clinical efficacy, and adverse effects of these treatment modalities. Topical non-steroidal anti-inflammatory agents and corticosteroids are widely used and, when combined, may have a synergistic effect. Intravitreal corticosteroids and anti-vascular endothelial growth factor (anti-VEGF) agents have shown promise when topical medications either fail or have had limited effects. Randomized clinical studies evaluating anti-VEGF agents are needed to fully evaluate benefits and risks. When PCME is either refractory to medical therapy or is associated with significant vitreous involvement, pars plana vitrectomy has been shown to improve outcomes, though it is associated with additional risks. PMID- 25438736 TI - Beliefs about the 'shape' and continuity of healthy sleep as a function of age. AB - OBJECTIVE: Treating insomnia includes challenging unrealistic beliefs that may contribute to anxieties and wakefulness. This study explored beliefs about the shape and continuity of healthy adult sleep at different adult ages. METHODS: Younger (n=113, M=21.4 (2.4)) and older adults (n=110, M=72.3 (7.7)) depicted their concept of the normal sleep of both a healthy 18 and 65 year olds. Plots were drawn to show sleep depth and awakenings across the night. RESULTS: Seventy percent conceptualized healthy sleep as an unbroken U shape and 18 year olds were depicted with deeper sleep than 65 year olds. About 95% of younger adults and three quarters of older adults showed both healthy 18 and 65 year olds sleep without awakenings. CONCLUSION: Unrealistic sleep beliefs are widespread, with healthy sleep usually being mistakenly conceptualized as unbroken, even in older adults. Education that awakenings are part of normal sleep may have preventative health implications and reduce sleep anxieties. PMID- 25438737 TI - Negative regulation of RelA phosphorylation: emerging players and their roles in cancer. AB - NF-kappaB signaling contributes to human disease processes, notably inflammatory diseases and cancer. Many advances have been made in understanding mechanisms responsible for abnormal NF-kappaB activation with RelA post-translational modification, particularly phosphorylation, proven to be critical for RelA function. While the majority of studies have focused on identifying kinases responsible for NF-kappaB phosphorylation and pathway activation, recently progress has also been made in understanding the negative regulators important for restraining RelA activity. Here we summarize negative regulators of RelA phosphorylation, their targeting sites in RelA and biological functions through negative regulation of RelA activation. Finally, we emphasize the tumor suppressor-like roles that these negative regulators can assume in human cancers. PMID- 25438738 TI - Timing of platelet activation of stored plateletpheresis. PMID- 25438739 TI - Immediate provisionalization with a CAD/CAM interim abutment and crown: a guided soft tissue healing technique. AB - A technique is described in which a single interim abutment and crown were fabricated in advance and placed the day of dental implant surgery. The contours of the interim crown were identical to the contours of a tentatively designed definitive prosthesis and allowed the tissue to heal and obtain contours that accommodated the contours of the definitive prosthesis. After osseointegration was established, a definitive impression was made with a custom computer-assisted design and computer-assisted manufacturing impression coping. The definitive prosthesis then was fabricated. PMID- 25438740 TI - Assessment of functional improvement with implant-supported prosthetic rehabilitation after mandibular reconstruction with a microvascular free fibula flap: A study of 25 patients. AB - STATEMENT OF PROBLEM: Mandibular reconstruction with a microvascular free fibula flap is widely used after oncologic resection because it allows functional and esthetic restoration of the mandibular arch and implant-retained prostheses. PURPOSE: The purpose of this study was to highlight the results that can be expected from an implant-supported prosthesis on a free fibula flap. MATERIAL AND METHODS: Patients treated with a microvascular free fibula flap and rehabilitated prosthetically were included. The number of osteotomies, number of implants, type of prosthesis, follow-up after placement of the prosthesis, preimplant surgery, and periimplant complications were reported. Subjective criteria, including patient satisfaction and improvement of masticatory function, were collected by means of a questionnaire that covered the type of diet, restrictions when eating, intelligibility of speech, and communication levels. RESULTS: Twenty-six patients were included: 11 patients had implant-supported dentures, and 15 had fixed prostheses. Prosthetic follow-up was over 5 years for 15 patients and less than 1 year for 2 patients. Hyperplasia was a periimplant complication for 7 patients. Overall, satisfaction was good for 24 patients (score greater than 5/10; mean score, 7.3/10). Esthetics were improved for 20 patients. Speech was improved for 6 patients, and diet improved for 9 patients. CONCLUSIONS: Implant-retained dentures seem preferable for patients, with notable esthetic alteration, although a screw-retained fixed resin-bonded prosthesis remains a good alternative. Improved mastication is more notable with patients who are completely edentulous and with large reconstructions but nevertheless remains disappointing. Whether dental restoration is necessary in treatments with short lateral flaps is worth questioning. PMID- 25438741 TI - Evaluation of defects in surface detail for monophase, 2-phase, and 3-phase impression techniques: an in vitro study. AB - STATEMENT OF THE PROBLEM: Polyvinyl siloxane materials of various consistencies have been tested to reduce defects commonly associated with different definitive impression techniques. PURPOSE: The purpose of this in vitro study was to compare the number of visible defects within the surface of a new 3-phase, 2-step impression injection technique with the number found in the monophase and in the conventional 2-phase, 1-step and 2-phase, 2-step impression techniques. MATERIAL AND METHODS: Two complete crown abutment preparations were impressed 10 times for each of these 4 techniques, which gave 20 abutment impressions for each group. The 3-phase, 2-step impression--injection technique included extra-light--body impression material added for the impression and injected after reinsertion. After the removal of all of these impressions, an examiner counted the number of open voids and bubble-like enclosed voids visible to the naked eye at a working distance of approximately 150 mm. Only the defects in the area of the prepared abutments were included in the assessment. RESULTS: The frequency of defects ranged from 100% of the impressions in the monophase group to 5% with the new 3 phase, 2-step impression injection technique. No statistical differences were seen between the two 2-phase (1-step and 2-step) impression techniques, although there were numerically fewer impressions with defects with 2 steps (45%) than with 1 step (55%). The 3-phase, 2-step impression injection technique had the greatest accuracy, with fewer specimens with defects (5%) than with either of the 2-phase techniques, although these differences did not reach statistical significance. CONCLUSIONS: The 3-phase, 2-step impression injection technique provides improved defect-free reproduction of detail, showing fewer defects than other impression techniques. PMID- 25438742 TI - In vitro shear bond strength of two self-adhesive resin cements to zirconia. AB - STATEMENT OF PROBLEM: Although the use of anatomic-contour zirconia restorations has expanded in the recent past, disagreement still exists as to reliable cementation techniques and materials. PURPOSE: The purpose of this in vitro study was to compare the immediate and artificially aged shear bond strength of 2 commercially available self-adhesive resin cements to zirconia: one with silica coating and silanation as a zirconia surface treatment and the other contained a phosphate monomer, which eliminated the need for a separate primer. MATERIAL AND METHODS: Sixty composite resin rods (2.5 mm in diameter and 3 mm in length) were fabricated from a nano-optimized composite resin by using a polypropylene mold, then light polymerized with a light-emitting diode. zirconia plates (10*10*4mm) were sectioned from an yttrium-stabilized zirconia puck, sintered, and then mounted in autopolymerizing acrylic resin custom tray material. Composite resin rods were cemented to the zirconia plates with 2 different cements. The surface treatment of zirconia followed the manufacturers' instructions for each cement. The specimens were tested for shear bond strength at 3 aging conditions: immediate, after 24 hours of moist storage, and after 30 days of moist storage with 10000 thermocycles. Specimens were loaded to failure in a universal testing machine, and the data were analyzed with 2-way ANOVA (alpha=.05). Weibull parameters (modulus and characteristic strength) also were calculated for each group. RESULTS: Two-way ANOVA revealed that only the aging condition significantly affected the bond strength to zirconia. The cement and the interaction of the cement and aging did not significantly affect the shear bond strength to zirconia. The highest bond strength for both cements was achieved at 24 hours, whereas the lowest bond strength values were recorded in the immediate groups. CONCLUSIONS: No significant differences in bond strength to zirconia were observed between a cement with a silane priming step and an methacryloxydecyl dihydrogen phosphate-containing cement without a separate primer. Aging had a significant effect on the shear bond strength of the 2 self-adhesive resin cements to zirconia. PMID- 25438743 TI - [Socioeconomic inequalities and age and gender differences in cardiovascular risk factors]. AB - OBJECTIVE: To describe the cardiovascular risk factors in a working population in the Balearic Islands and to examine whether differences by social class vary according to age and gender. METHODS: A cross-sectional study was carried out in a sample of active workers aged 20-65 years in the Balearic Islands. The participants were included in the study during their annual work health assessment in 2011. The following variables were collected: occupation, social class, age, gender, height, weight, smoking, blood pressure, lipid profile, and glucose levels. Cardiovascular risk was calculated using two different equations (Framingham and REGICOR). RESULTS: Differences by social class were observed for most cardiovascular risk factors. The pattern of these differences differed depending on age group and gender. Differences in obesity by social class increased with age in women but decreased in men. More differences in hypertension by social class were found among women than among men, with differences increasing with age in both genders. Significant differences by social class were found among women in lipid profile, and these differences increased with age, mainly for low levels of high-density lipoprotein cholesterol. CONCLUSIONS: Inequalities in cardiovascular risk factors by social class were higher among women than among men. Some cardiovascular risk factors such as smoking and obesity showed significant inequalities from a very early age. PMID- 25438744 TI - The functional anatomy and connectivity of thought insertion and alien control of movement. AB - Alien control phenomena are symptoms reported by patients with schizophrenia whereby feelings of control and ownership of thoughts and movements are lost. Comparable alien control experiences occur in culturally influenced dissociative states. We used fMRI and suggestions for automatic writing in highly hypnotically suggestible individuals to investigate the neural underpinnings of alien control. Targeted suggestions selectively reduced subjective ratings of control and ownership for both thought and movement. Thought insertion (TI) was associated with reduced activation of networks supporting language, movement, and self related processing. In contrast, alien control of writing movement was associated with increased activity of a left-lateralised cerebellar-parietal network and decreased activity in brain regions involved in voluntary movement, including sensory-motor hand areas and the thalamus. Both experiences involved a reduction in activity of left supplementary motor area (SMA) and were associated with altered functional connectivity (FC) between SMA and brain regions involved in language processing and movement implementation. Collectively these results indicate the SMA plays a central role in alien control phenomena as a high level executive system involved in the sense that we control and own our thoughts and movements. PMID- 25438745 TI - How do speakers coordinate? Evidence for prediction in a joint word-replacement task. AB - We investigated whether speakers represent their partners' task in a joint naming paradigm. Two participants took turns in naming pictures; occasionally the (initial) picture was replaced by a different picture (target), signaling that they had to stop naming the initial picture. When the same participant had to name the target picture, he or she completed the name of the initial picture more often than when neither participant had to name the target picture. Crucially, when the other participant had to name the target picture, the first participant also completed the name of the initial picture more often than when neither participant named the target picture. However, the tendency to complete the initial name was weaker when the other participant had to name the target than when the same participant went on to name the target. We argue that speakers predict that their partner is about to respond using some, but not all, of the mechanisms they use when they prepare to speak. PMID- 25438746 TI - What does human intracerebral recording tell us about emotions? PMID- 25438747 TI - Neural overlap between resting state and self-relevant activity in human subcallosal cingulate cortex--single unit recording in an intracranial study. AB - High activity of the default mode network (DMN) has been proposed to be central in processing self-relevant events. Thus far, this hypothesis of DMN function has not been tested directly using neurophysiological techniques. To test for the link between frontal midline DMN activity and self-relevant processing we measured neuronal activity (single-neurons' firing rates) in human subcallosal cingulate cortex (SCC) in the course of Deep Brain Stimulation surgery. We find that firing rates in SCC did not change during the presentation of specifically self-relevant stimuli when compared to the preceding pre-stimulus resting state level. In contrast, we observed significant changes in firing rates during other names in SCC. Such rest-self overlap seems to be specific for SCC since increase in firing rates in response to self-relevant stimuli were observed in another region, the subthalamic nucleus, in a group of Parkinson patients receiving deep brain stimulation surgery. These results suggest specific relationship between resting state and self-related activity, rest-self overlap, in specifically SCC as core region of the default-mode network. PMID- 25438748 TI - Coparenting profiles in the context of Mexican-origin teen pregnancy: links to mother-daughter relationship quality and adjustment. AB - The current study explored the multifaceted nature of the mother-adolescent coparental relationship with data from 167 Mexican-origin adolescent mothers and their own mothers at 10 months post childbirth. Profiles of mother-adolescent coparenting were created with latent profile analysis using adolescents' reports of three dimensions of coparenting (communication, involvement, and conflict). Four profiles were identified: (a) Harmonious Coparents (equal involvement, high communication, low conflict); (b) Harmonious-Adolescent Primary (adolescent is more involved than mother, high communication, low conflict); (c) Conflictual Coparents (equal involvement, high communication, high conflict); and (d) Conflictual-Adolescent Primary (adolescent is more involved than mother, moderate communication, high conflict). Families characterized by high mother-daughter conflict and psychological control prior to childbirth were more likely to belong in the Conflictual Coparents profile. In addition, adolescents' and mothers' depressive symptoms and parenting efficacy after childbirth were linked to profile membership, such that the Harmonious-Adolescent Primary profile reported the most positive adjustment patterns, whereas profiles with high coparental conflict (i.e., Conflictual Coparenting and Conflictual-Adolescent Primary profiles) showed the least positive adjustment patterns. Discussion considers the applied implications of identifying precursors to healthy and problematic mother daughter coparenting for families of adolescent mothers in the early years of parenting. PMID- 25438749 TI - Using zirconia-based prosthesis in a complete-mouth reconstruction treatment for worn dentition with the altered vertical dimension of occlusion. AB - This clinical report describes the complete mouth reconstruction of a patient with a worn dentition. Computer-aided design and computer-aided manufacturing processed porcelain fused-to-zirconia prostheses were used to achieve good esthetics, function, and biomechanics. PMID- 25438750 TI - Economic costs of protistan and metazoan parasites to global mariculture. AB - Parasites have a major impact on global finfish and shellfish aquaculture, having significant effects on farm production, sustainability and economic viability. Parasite infections and impacts can, according to pathogen and context, be considered to be either unpredictable/sporadic or predictable/regular. Although both types of infection may result in the loss of stock and incur costs associated with the control and management of infection, predictable infections can also lead to costs associated with prophylaxis and related activities. The estimation of the economic cost of a parasite event is frequently complicated by the complex interplay of numerous factors associated with a specific incident, which may range from direct production losses to downstream socio-economic impacts on livelihoods and satellite industries associated with the primary producer. In this study, we examine the world's major marine and brackish water aquaculture production industries and provide estimates of the potential economic costs attributable to a range of key parasite pathogens using 498 specific events for the purposes of illustration and estimation of costs. This study provides a baseline resource for risk assessment and the development of more robust biosecurity practices, which can in turn help mitigate against and/or minimise the potential impacts of parasite-mediated disease in aquaculture. PMID- 25438751 TI - In silico classification and prediction of VIP derivatives as VPAC1/ VPAC2 receptor agonists/antagonists. AB - Vasoactive intestinal polypeptide (VIP) is an intrinsic 28-amino acid peptide, involved in a wide range of physiologic effects, and therefore considered as a promising drug candidate for the treatment of several diseases. But the clinical application of VIP has been limited for the easy in vivo digestion. Various researches aiming to prolong the VIP half-life, by modifying the VIP structure, have been reported. The first thing to be considered after structural modification is to know it is a VPAC agonist or antagonist. To analyze the structure-activity relationships of VIP derivatives and build classifiers to distinguish newly designed VIPs, here in this work, we collected 46 samples and two classifiers were established respectively for VPAC1 and VPAC2 receptors. The built classifiers are robust and predictive with high sensitivity, specificity and concordance for the prediction set. By analyzing the meanings of the used variables, we found that the electrostatic properties of VIP derivatives are vital in their interactions with VPAC receptors. Finally, these two classifiers were used to predict the bioactivities of novel VIPs, without experimental activities, which were suggested for experimental research groups to test their bioactivities and the possible practical applications in future. PMID- 25438754 TI - In vitro antitumor activity evaluation of some 1,2,4-triazine derivatives bearing piperazine amide moiety against breast cancer cells. AB - A series of 1,2,4-triazine derivatives bearing piperazine amide moiety has been synthesized and investigated for their potential anticancer activities. 1-[4-(5,6 Bis(4-subtituted phenyl)-1,2,4-triazin-3-yl)piperazin-1-yl]-2-[4-(3-substituted phenyl)piperazin-1-yl]ethanone derivative (1-32) compounds were synthesized by a four step synthetic procedure. The activity studies were evaluated using XTT method, BrdU method and flow cytometric analysis on MCF-7 breast cancer cells and NIH/3T3 (mouse embryonic fibroblast cells) healthy cells. Compounds 5 with 3 chlorophenyl and compound 7 with 4-chlorophenyl substitutions were found to be promising antiproliferative agents comparing with an effective anticancer drug, cisplatin. PMID- 25438755 TI - Novel strategy to boost oral anticoagulant activity of blood coagulation enzyme inhibitors based on biotransformation into hydrophilic conjugates. AB - The blood coagulation cascade represents an attractive target for antithrombotic drug development, and recent studies have attempted to identify oral anticoagulants with inhibitory activity for enzymes in this cascade, with particular attention focused on thrombin and factor Xa (fXa) as typical targets. We previously described the discovery of the orally active fXa inhibitor darexaban (1) and reported a unique profile that compound 1 rapidly transformed into glucuronide YM-222714 (2) after oral administration. Here, we propose a novel strategy towards the discovery of an orally active anticoagulant that is based on the bioconversion of a non-amidine inhibitor into the corresponding conjugate to boost ex vivo anticoagulant activity via an increase in hydrophilicity. Computational molecular modeling was utilized to select a template scaffold and design a substitution point to install a potential functional group for conjugation. This strategy led to the identification of the phenol-derived fXa inhibitor ASP8102 (14), which demonstrated highly potent anticoagulant activity after biotransformation into the corresponding glucuronide (16) via oral dosing. PMID- 25438756 TI - A site-selective, irreversible inhibitor of the DNA replication auxiliary factor proliferating cell nuclear antigen (PCNA). AB - Proliferating cell nuclear antigen (PCNA) assumes an indispensable role in supporting cellular DNA replication and repair by organizing numerous protein components of these pathways via a common PCNA-interacting sequence motif called a PIP-box. Given the multifunctional nature of PCNA, the selective inhibition of PIP-box-mediated interactions may represent a new strategy for the chemosensitization of cancer cells to existing DNA-directed therapies; however, promiscuous blockage of these interactions may also be universally deleterious. To address these possibilities, we utilized a chemical strategy to irreversibly block PIP-box-mediated interactions. Initially, we identified and validated PCNA methionine 40 (M40) and histidine 44 (H44) as essential residues for PCNA/PIP-box interactions in general and, more specifically, for efficient PCNA loading onto chromatin within cells. Next, we created a novel small molecule incorporating an electrophilic di-chloro platinum moiety that preferentially alkylated M40 and H44 residues. The compound, designated T2Pt, covalently cross-linked wild-type but not M40A/H44A PCNA, irreversibly inhibited PCNA/PIP-box interactions, and mildly alkylated plasmid DNA in vitro. In cells, T2Pt persistently induced cell cycle arrest, activated ATR-Chk1 signaling and modestly induced DNA strand breaks, features typical of cellular replication stress. Despite sustained activation of the replication stress response by the compound and its modestly genotoxic nature, T2Pt demonstrated little activity in clonogenic survival assays as a single agent, yet sensitized cells to cisplatin. The discovery of T2Pt represents an original effort directed at the development of irreversible PCNA inhibitors and sets the stage for the discovery of analogues more selective for PCNA over other cellular nucleophiles. PMID- 25438757 TI - Identification of novel thiadiazoloacrylamide analogues as inhibitors of dengue-2 virus NS2B/NS3 protease. AB - Dengue virus is endemic throughout tropical and subtropical regions, and cause severe epidemic diseases. The NS2B/NS3 protease is a promising drug target for dengue virus. Herein, we report the discovery and modification of a novel class of thiadiazoloacrylamide derivatives with potent inhibitory activity against the NS2B/NS3 protease. Thiadiazolopyrimidinone 1 was firstly determined as a new chemical structure against NS2B/NS3 from a commercial compound library. Then, we sought to identify similar compounds with the thiadiazoloacrylamide core that would exhibit better activity. A series of analogues were synthesized and fourteen of them were identified with strong inhibitory activities, in which the nitrile group in the linker part was discovered as an essential group for the inhibitory activity. The best of these (8b) demonstrated an IC50 at 2.24MUM based on in vitro DENV2 NS2B-NS3pro assays. PMID- 25438758 TI - Ferrier sulfamidoglycosylation of glycals catalyzed by nitrosonium tetrafluoroborate: towards new carbonic anhydrase glycoinhibitors. AB - Ferrier sulfamidoglycosylation of glycals catalyzed by nitrosonium tetrafluoroborate allowed the preparation of hydroxysulfamide glycosides in good yields with a good alpha stereoselectivity. A variety of mono-saccharide derivatives was synthesized using this new methodology leading to selective and powerful glycoinhibitors of the tumor associated carbonic anhydrases (CA, EC 4.2.1.1) isoforms CA IX and CA XII. PMID- 25438759 TI - Synthesis and evaluation of bivalent ligands for binding to the human melanocortin-4 receptor. AB - Membrane proteins, especially G-protein coupled receptors (GPCRs), are interesting and important theragnostic targets since many of them serve in intracellular signaling critical for all aspects of health and disease. The potential utility of designed bivalent ligands as targeting agents for cancer diagnosis and/or therapy can be evaluated by determining their binding to the corresponding receptors. As proof of concept, GPCR cell surface proteins are shown to be targeted specifically using multivalent ligands. We designed, synthesized, and tested a series of bivalent ligands targeting the over-expressed human melanocortin 4 receptor (hMC4R) in human embryonic kidney (HEK) 293 cells. Based on our data suggesting an optimal linker length of 25+/-10A inferred from the bivalent melanocyte stimulating hormone (MSH) agonist, the truncated heptapeptide, referred to as MSH(7): Ac-Ser-Nle-Glu-His-D-Phe-Arg-Trp-NH2 was used to construct a set of bivalent ligands incorporating a hMC4R antagonist, SHU9119: Ac-Nle-c[Asp-His-2'-D-Nal-Arg-Trp-Lys]-NH2 and another set of bivalent ligands containing the SHU9119 antagonist pharmacophore on both side of the optimized linkers. These two binding motifs within the bivalent constructs were conjoined by semi-rigid (Pro-Gly)3 units with or without the flexible poly(ethylene glycol) (PEGO) moieties. Lanthanide-based competitive binding assays showed bivalent ligands binds to the hMC4R with up to 240-fold higher affinity than the corresponding linked monovalent ligands. PMID- 25438760 TI - Synthesis, insecticidal activities and SAR of novel phthalamides targeting calcium channel. AB - In order to find novel and environmental friendly insecticides targeting the ryanodine receptor, three series of novel phthalamides containing heptafluoroisopropyl group, low fluorine atoms group and non-fluorine group were designed and synthesized. 35 novel structures of three series were obtained. Insecticidal activities of title compounds against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella) indicated that most of title compounds showed moderate to high activities at the tested concentration. The structure-activity relationship (SAR) was discussed in detail. During synthesizing title compounds B8, C7, D1, D9 and D12, their corresponding positional isomers (B8', C7', D1', D9' and D12') were afforded, and their structures were confirmed by 2D NMR. The calcium-imaging technique was also applied to investigate the effects of compounds B2, B10, C4 and C5 on the intracellular calcium ion concentration ([Ca(2+)]i), which indicated that they released stored calcium ions from endoplasmic reticulum, which denoted that some compounds are potential modulators of the insect ryanodine receptor (RyR). PMID- 25438761 TI - Imino [4+4] cycloaddition products as exclusive and biologically relevant acrolein-amine conjugates are intermediates of 3-formyl-3,4-dehydropiperidine (FDP), an acrolein biomarker. AB - We demonstrated synthetically that the eight-membered heterocycles 2,6,9 triazabicyclo[3.3.1]nonanes and 1,5-diazacyclooctanes are the initial and exclusive products of the reaction, through an imino [4+4] cycloaddition, of biologically relevant amines with acrolein. The stabilities of the aminoacetals within the eight-membered heterocycles determined whether the product was subsequently transformed gradually into the 3-formyl-3,4-dehydropiperidine (FDP), which is widely used as an oxidative stress marker. The reactivity profiles discovered in this study suggested that some of the imino [4+4] cycloaddition products are reactive intermediates of FDP and contribute to the mechanisms underlying the oxidative stress response to acrolein. PMID- 25438762 TI - A bicyclic peptide scaffold promotes phosphotyrosine mimicry and cellular uptake. AB - While peptides are promising as probes and therapeutics, targeting intracellular proteins will require greater understanding of highly structured, cell internalized scaffolds. We recently reported BC1, an 11-residue bicyclic peptide that inhibits the Src homology 2 (SH2) domain of growth factor receptor-bound protein 2 (Grb2). In this work, we describe the unique structural and cell uptake properties of BC1 and similar cyclic and bicyclic scaffolds. These constrained scaffolds are taken up by mammalian cells despite their net neutral or negative charges, while unconstrained analogs are not. The mechanism of uptake is shown to be energy-dependent and endocytic, but distinct from that of Tat. The solution structure of BC1 was investigated by NMR and MD simulations, which revealed discrete water-binding sites on BC1 that reduce exposure of backbone amides to bulk water. This represents an original and potentially general strategy for promoting cell uptake. PMID- 25438763 TI - Improving the MDR reversal activity of 6,17-epoxylathyrane diterpenes. AB - Aiming to optimize macrocyclic lathyrane-type diterpenes as effective Pgp modulators, the phytochemical study of the methanolic extract of Euphorbia boetica aerial parts was carried out. Two new macrocyclic 6,17-epoxylathyrane type diterpenes, named epoxyboetiranes A (1) and B (2), along with three known analogues (3-5) were isolated. Epoxyboetirane A (1), a triacetate isolated in large amounts, was hydrolyzed to give epoxylathyrol (6). In order to study the effect of the substitution pattern of the macrocyclic scaffold on MDR reversal, 6 was acylated with aroyl, phenylacetyl, cinnamoyl and alkanoyl chlorides/anhydrides, yielding eight new esters, epoxyboetiranes C-J (7-14). The ability of compounds 1-14 as P-glycoprotein (Pgp, ABCB1) modulators was evaluated through combination of transport and chemosensitivity assays, using L5178Y mouse T lymphoma cell line transfected with the human MDR1 gene. In the transport assay, excepting 1, 3 and 6, the compounds, at non-cytotoxic concentrations, displayed strong MDR reversing activity in a dose-dependent mode, exhibiting all the new acyl derivatives (7-14) a many fold increase in the activity when compared with 1. Apart from 11 and 12, all compounds exhibited remarkable synergistic effects in combination with doxorubicin. An ATPase assay, using membrane vesicles from mammalian cells overexpressing Pgp, was also performed with two representatives of the modulators (4 and 5). The results suggest that both compounds compete with substrates for the Pgp drug-binding sites. PMID- 25438764 TI - Self-adjuvanting vaccine against group A streptococcus: application of fibrillized peptide and immunostimulatory lipid as adjuvant. AB - Peptides are of great interest to be used as vaccine antigens due to their safety, ease of manufacturing and specificity in generating immune response. There have been massive discoveries of peptide antigens over the past decade. However, peptides alone are poorly immunogenic, which demand co-administration with strong adjuvant to enhance their immunogenicity. Recently, fibril-forming peptides such as Q11 and lipoamino acid-based carrier have been identified to induce substantial immune responses when covalently linked to peptide epitope. In this study, we have incorporated either Q11 or lipoamino acids to a peptide epitope (J14) derived from M protein of group A streptococcus to develop self adjuvanting vaccines. J14, Q11 and lipoamino acids were also conjugated together in a single vaccine construct in an attempt to evaluate the synergy effect of combining multiple adjuvants. Physicochemical characterization demonstrated that the vaccine constructs folded differently and self-assembled into nanoparticles. Significantly, only vaccine constructs containing double copies of lipoamino acids (regardless in conjugation with Q11 or not) were capable to induce significant dendritic cells uptake and subsequent J14-specific antibody responses in non-sizes dependent manners. Q11 had minimal impact in enhancing the immunogenicity of J14 even when it was used in combination with lipoamino acids. These findings highlight the impact of lipoamino acids moiety as a promising immunostimulant carrier and its number of attachment to peptide epitope was found to have a profound effect on the vaccine immunogenicity. PMID- 25438765 TI - Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening. AB - Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer's disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening workflow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[3,2-c]quinolin-4(5H)-one inhibitor (10) with ligand efficiency (LE) of 0.3 was identified as the lead molecule. Further SAR optimization led to the discovery of several low micromolar inhibitors with good selectivity. The research represents a new class of potent ATP non competitive CDK5/p25 inhibitors with good CDK2/E selectivity. PMID- 25438766 TI - Inhibition of myeloperoxidase: evaluation of 2H-indazoles and 1H-indazolones. AB - Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The two-step, one-pot Davis-Beirut reaction was used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H2O2 consumption assays. Docking studies as well as toxicophore and Lipinski analyses were performed. Fourteen compounds were found to be potent inhibitors with IC50 values <1MUM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO/H2O2/HOCl/HOBr system. PMID- 25438767 TI - Synthesis and analysis of potential alpha1,3-fucosyltransferase inhibitors. AB - Fucosyltransferases catalyze the transfer of l-fucose from an activated GDP-beta l-fucose to various acceptor molecules such as N-acetyllactosamine. Frequently fucosylation is the final step within the glycosylation machinery, and the resulting glycans are involved in various cellular processes such as cell-cell recognition, adhesion and inflammation or tumor metastasis. The selective blocking of these interactions would thus be a potential promising therapeutic strategy. The syntheses and analyses of various potential alpha1,3 fucosyltransferase inhibitors derived from GDP-beta-l-fucose containing a triazole linker unit is summarized and the observed inhibitory effect was compared with that of small molecules such as GDP or fucose. To examine their specificity and selectivity, all inhibitors were tested with human alpha1,3 fucosyltransferase IX and Helicobacter pylori alpha1,3-fucosyltransferase, which is to date the only alpha1,3-fucosyltransferase with a known high resolution structure. Specific inhibitors which inhibit either H. pylori alpha1,3 fucosyltransferase or human fucosyltransferase IX with Ki values in the micromolar range were identified. In that regard, acetylated GDP-galactose derivative Ac-3 turned out to inhibit H. pylori alpha1,3-fucosyltransferase but not human fucosyltransferase IX, whereas GDP-6-amino-beta-l-fucose 17 showed an appreciably better inhibitory effect on fucosyltransferase IX activity than on that of H. pylori fucosyltransferase. PMID- 25438768 TI - Discovery andw biological evaluation of novel 6,7-disubstituted-4-(2 fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety as c-Met kinase inhibitors. AB - A series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and five typical cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG). Most compounds showed moderate to excellent antiproliferative activity. In this study, a promising compound 34, with a c-Met IC50 value of 1.04nM, was identified as a multitargeted receptor tyrosine kinase inhibitor. The SAR analyses indicated that compounds with halogen group, especially fluoro group, at 4-position on the phenyl ring (moiety B) have potent antitumor activity, and methylation on the 5-atom linker played an important role in the c-Met enzymatic activity. PMID- 25438769 TI - Design and synthesis of novel spin-labeled camptothecin derivatives as potent cytotoxic agents. AB - In our continuing search for natural product-based spin-labeled antitumor drugs, 20 novel spin-labeled camptothecin derivatives were synthesized via a Cu catalyzed one pot reaction and evaluated for cytotoxicity against four human tumor cell lines (A-549, MDA-MB-231, KB, and KBvin). Eighteen of the target compounds (9a, 9b, 9d-9k, 9m-9t) exhibited significant in vitro antiproliferative activity against these four tested tumor cell lines. Compounds 9e and 9j (IC50 0.057 and 0.072MUM, respectively) displayed the greatest cytotoxicity against the multidrug-resistant (MDR) KBvin cell line and merit further development into preclinical and clinical drug candidates for treating cancer including MDR phenotype. PMID- 25438771 TI - Reliabilities of leg and vertical stiffness during treadmill running. AB - The aim of this study was to determine the intra-participant variabilities (i.e. intra-day and inter-day reliabilities) in leg and vertical stiffness, as well as related kinematic parameters, during treadmill running using the sine-wave method. Twenty-two healthy men ran on a treadmill at 4.44 m/s, and the flight and contact times were measured with a high-speed video camera. Three 30-s running bouts with 2-min inter-bout rests were performed to examine the intra-day reliability, and single 30-s running bouts on three separate days with 24- to 48 h inter-bout intervals were performed to examine the inter-day reliability. The reliability statistics included repeated-measure analyses of variance, average inter-trial correlations, intra-class correlation coefficients (ICCs), Cronbach's alpha reliability coefficient, and the coefficient of variation. Both leg and vertical stiffness produced high ICCs within 0.972 and 0.982, respectively, and between 0.922 and 0.873 days, respectively. High values were also observed for all of the reliability coefficients. Similar results were found regarding contact time, flight time, step length, and step rate. It was concluded that the measurements of leg and vertical stiffness, as well as related kinematic parameters, obtained using the sine-wave method during treadmill running at 4.44 m/s, were highly reliable, both within and across days. PMID- 25438770 TI - 2- and 3-substituted imidazo[1,2-a]pyrazines as inhibitors of bacterial type IV secretion. AB - A novel series of 8-amino imidazo[1,2-a]pyrazine derivatives has been developed as inhibitors of the VirB11 ATPase HP0525, a key component of the bacterial type IV secretion system. A flexible synthetic route to both 2- and 3-aryl substituted regioisomers has been developed. The resulting series of imidazo[1,2-a]pyrazines has been used to probe the structure-activity relationships of these inhibitors, which show potential as antibacterial agents. PMID- 25438772 TI - Effect of preoperative eating patterns and preoperative weight loss on the short- and mid-term weight loss results of sleeve gastrectomy. AB - INTRODUCTION: Weight loss depends directly on the adhesion to the postoperative diet in patients undergoing a sleeve gastrectomy. The aim of this study is to evaluate the effect of different preoperative feeding patterns and the adhesion to a preoperative diet on short and mid- term postoperative weight loss. MATERIAL AND METHODS: A prospective study of all morbidly obese patients undergoing a laparoscopic sleeve gastrectomy as a bariatric procedure between 2008 and 2012 was performed. Preoperative feeding patterns and weight loss, preoperatively and postoperatively at 12 and 24 months, were evaluated. RESULTS: A total of 50 patients were included, with a mean preoperative BMI of 51,2+7,9 kg/m(2). All the patients presented a feeding pattern of big eaters, 44% of snackers, 40% of sweet eaters and 48% reported regular ingestion of "light" soft drinks. Mean preoperative excess weight loss (EWL) was 13,4% (range 10-31,4%). At 12 months mean EWL was 83,7% and at 24 months 82,4%. Pre and postoperative EWL showed a direct correlation at 12 and 24 months. Mean EWL was significantly lower in snackers, sweet eaters and those drinking "light" soft drinks regularly. CONCLUSION: Preoperative weight loss correlates directly with postoperative weight loss at 1 and 2 years. Snackers, sweet eaters and "light" soft drink consumers, associated with a big eater pattern, achieve a significantly lower postoperative weight loss. PMID- 25438773 TI - Emergency endoscopy for gastrointestinal bleeding after bariatric surgery. Therapeutic algorithm. AB - OBJECTIVE: Gastrointestinal bleeding (GB) is a potential complication after bariatric surgery and its frequency is around 2-4% according to the literature. The aim of this study is to present our experience with GB after bariatric surgery, its presentation and possible treatment options by means of an algorithm. PATIENTS AND METHOD: From January 2004 to December 2012, we performed 300 consecutive laparoscopic bariatric surgeries. A total of 280 patients underwent a laparoscopic Roux en Y gastric bypass with creation of a gastrojejunal anastomosis using a circular stapler type CEAA No 21 in 265 patients and with a linear stapler in 15 patients. Demographics, clinical presentation, diagnostic evaluation and treatment were reviewed. A total of 20 patients underwent a sleeve gastrectomy. RESULTS: Twenty-seven cases (9%) developed GB. Diagnosis and therapeutic endoscopy was required in 13 patients. The onset of bleeding occurred between the 1(st)-6(th) postop days in 10 patients, and the origin was at the gastrojejunostomy staple-lines, and 3 patients had bleeding from an anastomotic ulcer 15-20 days after surgery. All other patients were managed non-operatively. CONCLUSION: Conservative management of gastrointestinal bleeding is effective in most cases, but endoscopy with therapeutic intent should be considered in patients with severe or recurrent bleeding. Multidisciplinary postoperative follow- up is very important for early detention and treatment of this complication. PMID- 25438775 TI - Giant-cell anaplastic lymphoma in an open thoracostomy cavity. PMID- 25438774 TI - Oncological results according to type of resection for rectal cancer. AB - OBJECTIVE: This multicentre observational study aimed to compare outcomes of anterior resection (AR) and abdominal perineal resection (APR) in patients treated for rectal cancer. METHODS: Between March 2006 and March 2009 a cohort of 1,598 patients diagnosed with low and mid rectal cancer were operated on in the first 38 hospitals included in the Spanish Rectal Cancer Project. In 1,343 patients the procedure was considered curative. Clinical and outcome results were analysed in relation to the type of surgery performed. All patients were included in the analysis of clinical results. The analysis of outcomes was performed only on patients treated by a curative procedure. RESULTS: Of the 1,598 patients, 1,139 (71.3%) underwent an AR and 459 (28.7%) an APR. In 1,343 patients the procedure was performed with curative intent; from these 973 (72.4%) had an AR and 370 (27.6%) an APR. There were no differences between AR and APR in mortality (29 vs. 18 patients; P=.141). After a median follow up of 60.0 [49.0-60.0] months there were no differences in local recurrence (HR 1.68 [0.87-3.23]; P=.12), metastases (HR 1.31 [0.98-1.76]; P=.064). However, overall survival was worse after APR (HR 1.37 [1.00-1.86]; P=.048). CONCLUSION: This study did not identify abdominoperineal excision as a determinant of local recurrence or metastases. However, patients treated by this operation have a decreased overall survival. PMID- 25438776 TI - Cosmetic sequelae after oncoplastic surgery of the breast. Classification and factors for prevention. AB - Oncoplastic surgery is an essential tool in the surgical approach to women with breast cancer. These techniques are not absolute guarantee for a good cosmetic result and therefore some patients will have cosmetic sequelae secondary to poor surgical planning, the effects of adjuvant treatments or the need for resection greater than originally planned. The high frequency of these cosmetic sequelae in oncology practice makes it necessary to classify them for optimal surgical planning. The aim of this paper is to present a classification of cosmetic sequelae after oncoplastic procedures to identify those factors that are crucial to its prevention. This classification contains 4 groups: breast contour deformities, asymmetries, alterations in nipple-areola complex (NAC) and defects in the three dimensional structure of the breast. A significant group of these sequelae (asymmetries and deformities) are associated with breast irradiation and need an accurate information process with patients to set realistic expectations about cosmetic results. Finally, there is another group of sequelae (NAC disorders and three-dimensional structure) that are related to poor planning and deficiencies in surgical approach, therfore specific training is essential for learning these surgical techniques. PMID- 25438779 TI - Integrative glycobiology and future perspectives. PMID- 25438780 TI - Disease resistance: molecular mechanisms and biotechnological applications. Preface. PMID- 25438781 TI - Precision breeding of grapevine (Vitis vinifera L.) for improved traits. AB - This review provides an overview of recent technological advancements that enable precision breeding to genetically improve elite cultivars of grapevine (Vitis vinifera L.). Precision breeding, previously termed "cisgenic" or "intragenic" genetic improvement, necessitates a better understanding and use of genomic resources now becoming accessible. Although it is now a relatively simple task to identify genetic elements and genes from numerous "omics" databases, the control of major agronomic and enological traits often involves the currently unknown participation of many genes and regulatory machineries. In addition, genetic evolution has left numerous vestigial genes and sequences without tangible functions. Thus, it is critical to functionally test each of these genetic entities to determine their real-world functionality or contribution to trait attributes. Toward this goal, several diverse techniques now are in place, including cell culture systems to allow efficient plant regeneration, advanced gene insertion techniques, and, very recently, resources for genomic analyses. Currently, these techniques are being used for high-throughput expression analysis of a wide range of grapevine-derived promoters and disease-related genes. It is envisioned that future research efforts will be extended to the study of promoters and genes functioning to enhance other important traits, such as fruit quality and vigor. PMID- 25438782 TI - Engineered plant virus resistance. AB - Virus diseases are among the key limiting factors that cause significant yield loss and continuously threaten crop production. Resistant cultivars coupled with pesticide application are commonly used to circumvent these threats. One of the limitations of the reliance on resistant cultivars is the inevitable breakdown of resistance due to the multitude of variable virus populations. Similarly, chemical applications to control virus transmitting insect vectors are costly to the farmers, cause adverse health and environmental consequences, and often result in the emergence of resistant vector strains. Thus, exploiting strategies that provide durable and broad-spectrum resistance over diverse environments are of paramount importance. The development of plant gene transfer systems has allowed for the introgression of alien genes into plant genomes for novel disease control strategies, thus providing a mechanism for broadening the genetic resources available to plant breeders. Genetic engineering offers various options for introducing transgenic virus resistance into crop plants to provide a wide range of resistance to viral pathogens. This review examines the current strategies of developing virus resistant transgenic plants. PMID- 25438783 TI - Virus resistance in orchids. AB - Orchid plants, Phalaenopsis and Dendrobium in particular, are commercially valuable ornamental plants sold worldwide. Unfortunately, orchid plants are highly susceptible to viral infection by Cymbidium mosaic virus (CymMV) and Odotoglossum ringspot virus (ORSV), posing a major threat and serious economic loss to the orchid industry worldwide. A major challenge is to generate an effective method to overcome plant viral infection. With the development of optimized orchid transformation biotechnological techniques and the establishment of concepts of pathogen-derived resistance (PDR), the generation of plants resistant to viral infection has been achieved. The PDR concept involves introducing genes that is(are) derived from the virus into the host plant to induce RNA- or protein-mediated resistance. We here review the fundamental mechanism of the PDR concept, and illustrate its application in protecting against viral infection of orchid plants. PMID- 25438784 TI - High-throughput sequencing as an effective approach in profiling small RNAs derived from a hairpin RNA expression vector in woody plants. AB - Hairpin RNA (hpRNA)-mediated gene silencing has proved to be an efficient approach to develop virus-resistant transgenic plants. To characterize small RNA molecules (sRNAs) derived from an hpRNA expression vector in transgenic cherry rootstock plants, we conducted small RNA sequencing of (1) a transgenic rootstock containing an inverted repeat of the partial coat protein of Prunus necrotic ring spot virus (PNRSV-hpRNA); (2) a nontransgenic rootstock; and (3) a PNRSV-infected sweet cherry plant. Analysis of the PNRSV sRNA pools indicated that 24-nt (nucleotide) small interfering RNAs (siRNAs) were the most prevalent sRNAs in the transgenic rootstock whereas the most abundant sRNAs in the PNRSV-infected nontransgenic rootstock were 21-nt siRNAs. In addition, the 24-nt siRNAs of the PNRSV-hpRNA were more abundant on the sense strand than those on the antisense strand in the transgenic rootstock. In contrast, preference in generating PNRSV sRNAs, ranging from 19-nt to 30-nt for sense and antisense strands, was not distinct in the PNRSV-infected nontransgenic sweet cherry. Taken together, this is the first report on profiling hpRNA-derived sRNAs in woody plants using high throughput sequencing technology, which is an efficient way to verify the presence/absence, the abundance, and the sequence features of certain sRNAs. PMID- 25438785 TI - Molecular biology of viroid-host interactions and disease control strategies. AB - Viroids are single-stranded, covalently closed, circular, highly structured noncoding RNAs that cause disease in several economically important crop plants. They replicate autonomously and move systemically in host plants with the aid of the host machinery. In addition to symptomatic infections, viroids also cause latent infections where there is no visual evidence of infection in the host; however, transfer to a susceptible host can result in devastating disease. While there are non-hosts for viroids, no naturally occurring durable resistance has been observed in most host species. Current effective control methods for viroid diseases include detection and eradication, and cultural controls. In addition, heat or cold therapy combined with meristem tip culture has been shown to be effective for elimination of viroids for some viroid-host combinations. An understanding of viroid-host interactions, host susceptibility, and non-host resistance could provide guidance for the design of viroid-resistant plants. Efforts to engineer viroid resistance into host species have been underway for several years, and include the use of antisense RNA, antisense RNA plus ribozymes, a dsRNase, and siRNAs, among others. The results of those efforts and the challenges associated with creating viroid resistant plants are summarized in this review. PMID- 25438786 TI - Molecular and genetic aspects of controlling the soilborne necrotrophic pathogens Rhizoctonia and Pythium. AB - The soilborne necrotrophic pathogens Rhizoctonia and Pythium infect a wide range of crops in the US and worldwide. These pathogens pose challenges to growers because the diseases they cause are not adequately controlled by fungicides, rotation or, for many hosts, natural genetic resistance. Although a combination of management practices are likely to be required for control of Rhizoctonia and Pythium, genetic resistance remains a key missing component. This review discusses the recent deployment of introduced genes and genome-based information for control of Rhizoctonia, with emphasis on three pathosystems: Rhizoctonia solani AG8 and wheat, R. solani AG1-IA and rice, and R. solani AG3 or AG4 and potato. Molecular mechanisms underlying disease suppression will be addressed, if appropriate. Although less is known about genes and factors suppressive to Pythium, pathogen genomics and biological control studies are providing useful leads to effectors and antifungal factors. Prospects for resistance to Rhizoctonia and Pythium spp. will continue to improve with growing knowledge of pathogenicity strategies, host defense gene action relative to the pathogen infection process, and the role of environmental factors on pathogen-host interactions. PMID- 25438787 TI - Trichoderma genes in plants for stress tolerance- status and prospects. AB - Many filamentous fungi from the genus Trichoderma are well known for their anti microbial properties. Certain genes from Trichoderma spp. have been identified and transferred to plants for improving biotic and abiotic stress tolerance, as well for applications in bioremediation. Several Trichoderma genomes have been sequenced and many are in the pipeline, facilitating high throughput gene analysis and increasing the availability of candidate transgenes. This, coupled with improved plant transformation systems, is expected to usher in a new era in plant biotechnology where several genes from these antagonistic fungi can be transferred into plants to achieve enhanced stress tolerance, bioremediation activity, herbicide tolerance, and reduction of phytotoxins. In this review, we illustrate the major achievements made by transforming plants with Trichoderma genes as well as their possible mode of action. Moreover, examples of efficient application of genetically modified plants as biofactories to produce active Trichoderma enzymes are indicated. PMID- 25438788 TI - Cerato-platanins: elicitors and effectors. AB - Cerato-platanins are an interesting group of small, secreted, cysteine-rich proteins that have been implicated in virulence of certain plant pathogenic fungi. The relatively recent discovery of these proteins in plant beneficial fungi like Trichoderma spp., and their positive role in induction of defense in plants against invading pathogens has raised the question as to whether these proteins are effectors or elicitor molecules. Here we present a comprehensive review on the occurrence of these conserved proteins across the fungal kingdom, their structure-function relationships, and their physiological roles in plant pathogenic and symbiotic fungi. We also discuss the usefulness of these proteins in evolving strategies for crop protection through a transgenic approach or direct application as elicitors. PMID- 25438789 TI - Transgenic American chestnuts show enhanced blight resistance and transmit the trait to T1 progeny. AB - American chestnut (Castanea dentata) is a classic example of a native keystone species that was nearly eradicated by an introduced fungal pathogen. This report describes progress made toward producing a fully American chestnut tree with enhanced resistance to the blight fungus (Cryphonectria parasitica). The transgenic American chestnut 'Darling4,' produced through an Agrobacterium co transformation procedure to express a wheat oxalate oxidase gene driven by the VspB vascular promoter, shows enhanced blight resistance at a level intermediate between susceptible American chestnut and resistant Chinese chestnut (Castanea mollissima). Enhanced resistance was identified first with a leaf-inoculation assay using young chestnuts grown indoors, and confirmed with traditional stem inoculations on 3- and 4-year-old field-grown trees. Pollen from 'Darling4' and other events was used to produce transgenic T1 seedlings, which also expressed the enhanced resistance trait in leaf assays. Outcrossed transgenic seedlings have several advantages over tissue-cultured plantlets, including increased genetic diversity and faster initial growth. This represents a major step toward the restoration of the majestic American chestnut. PMID- 25438790 TI - Expression of chloroperoxidase from Pseudomonas pyrrocinia in tobacco plastids for fungal resistance. AB - The chloroperoxidase (cpo) gene from Pseudomonas pyrrocinia was transformed into the plastid genome (plastome) of Nicotiana tabacum var. Petit Havana and transplastomic lines were compared with a nuclear transformant for the same gene. Southern analysis confirmed integration in the plastome and western blotting confirmed the presence of the chloroperoxidase protein (CPO) in higher abundance in transplastomic plants than in cpo nuclear transformants. Northern analysis of primary plastome transformants for cpo showed 15-fold higher transcript abundance than in the nuclear transformant, yet this extent of enhancement was not observed in western blot, enzyme or bioassay, indicating a bottleneck at the post transcriptional level. Representative plants from the two transplastomic lines showed resistance to fungal pathogens in vitro (Aspergillus flavus, Fusarium verticillioides, and Verticillium dahliae) and in planta (Alternaria alternata). PMID- 25438791 TI - Disease resistance breeding in rose: current status and potential of biotechnological tools. AB - The cultivated rose is a multispecies complex for which a high level of disease protection is needed due to the low tolerance of blemishes in ornamental plants. The most important fungal diseases are black spot, powdery mildew, botrytis and downy mildew. Rose rosette, a lethal viral pathogen, is emerging as a devastating disease in North America. Currently rose breeders use a recurrent phenotypic selection approach and perform selection for disease resistance for most pathogen issues in a 2-3 year field trial. Marker assisted selection could accelerate this breeding process. Thus far markers have been identified for resistance to black spot (Rdrs) and powdery mildew and with the ability of genotyping by sequencing to generate 1000s of markers our ability to identify markers useful in plant improvement should increase exponentially. Transgenic rose lines with various fungal resistance genes inserted have shown limited success and RNAi technology has potential to provide virus resistance. Roses, as do other plants, have sequences homologous to characterized R-genes in their genomes, some which have been related to specific disease resistance. With improving next generation sequencing technology, our ability to do genomic and transcriptomic studies of the resistance related genes in both the rose and the pathogens to reveal novel gene targets to develop resistant roses will accelerate. Finally, the development of designer nucleases opens up a potentially non-GMO approach to directly modify a rose's DNA to create a disease resistant rose. Although there is much potential, at present rose breeders are not using marker assisted breeding primarily because a good suite of marker/trait associations (MTA) that would ensure a path to stable disease resistance is not available. As our genomic analytical tools improve, so will our ability to identify useful genes and linked markers. Once these MTAs are available, it will be the cost savings, both in time and money, that will convince the breeders to use the technology. PMID- 25438793 TI - Salicylic acid signaling in disease resistance. AB - Salicylic acid (SA) is a key plant hormone that mediates host responses against microbial pathogens. Identification and characterization of SA interacting/binding proteins is a topic which has always excited scientists studying microbial defense response in plants. It is likely that discovery of a true receptor for SA may greatly advance understanding of this important signaling pathway. SABP2 with its high affinity for SA was previously considered to be a SA receptor. Despite a great deal work we may still not have true a receptor for SA. It is also entirely possible that there may be more than one receptor for SA. This scenario is more likely given the diverse role of SA in various physiological processes in plants including, modulation of opening and closing of stomatal aperture, flowering, seedling germination, thermotolerance, photosynthesis, and drought tolerance. Recent identification of NPR3, NPR4 and NPR1 as potential SA receptors and alpha-ketoglutarate dehydrogenase (KGDHE2), several glutathione S transferases (GSTF) such as SA binding proteins have generated more interest in this field. Some of these SA binding proteins may have direct/indirect role in plant processes other than pathogen defense signaling. Development and use of new techniques with higher specificity to identify SA interacting proteins have shown great promise and have resulted in the identification of several new SA interactors. This review focuses on SA interaction/binding proteins identified so far and their likely role in mediating plant defenses. PMID- 25438794 TI - Multitasking antimicrobial peptides in plant development and host defense against biotic/abiotic stress. AB - Crop losses due to pathogens are a major threat to global food security. Plants employ a multilayer defense against a pathogen including the use of physical barriers (cell wall), induction of hypersensitive defense response (HR), resistance (R) proteins, and synthesis of antimicrobial peptides (AMPs). Unlike a complex R gene-mediated immunity, AMPs directly target diverse microbial pathogens. Many a times, R-mediated immunity breaks down and plant defense is compromised. Although R-gene dependent pathogen resistance has been well studied, comparatively little is known about the interactions of AMPs with host defense and physiology. AMPs are ubiquitous, low molecular weight peptides that display broad spectrum resistance against bacteria, fungi and viruses. In plants, AMPs are mainly classified into cyclotides, defensins, thionins, lipid transfer proteins, snakins, and hevein-like vicilin-like and knottins. Genetic distance lineages suggest their conservation with minimal effect of speciation events during evolution. AMPs provide durable resistance in plants through a combination of membrane lysis and cellular toxicity of the pathogen. Plant hormones - gibberellins, ethylene, jasmonates, and salicylic acid, are among the physiological regulators that regulate the expression of AMPs. Transgenically produced AMP-plants have become a means showing that AMPs are able to mitigate host defense responses while providing durable resistance against pathogens. PMID- 25438792 TI - Microbial signature-triggered plant defense responses and early signaling mechanisms. AB - It has long been observed that microbial elicitors can trigger various cellular responses in plants. Microbial elicitors have recently been referred to as pathogen or microbe-associated molecular patterns (PAMPs or MAMPs) and remarkable progress has been made on research of their corresponding receptors, signaling mechanisms and critical involvement in disease resistance. Plants also generate endogenous signals due to the damage or wounds caused by microbes. These signals were originally called endogenous elicitors and subsequently renamed damage associated molecular patterns (DAMPs) that serve as warning signals for infections. The cellular responses induced by PAMPs and DAMPs include medium alkalinization, ion fluxes across the membrane, reactive oxygen species (ROS) and ethylene production. They collectively contribute to plant pattern-triggered immunity (PTI) and play an important role in plant basal defense against a broad spectrum of microbial infections. In this review, we provide an update on multiple PTI responses and early signaling mechanisms and discuss its potential applications to improve crop disease resistance. PMID- 25438795 TI - Genetic transformation of Ornithogalum via particle bombardment and generation of Pectobacterium carotovorum-resistant plants. AB - Bacterial soft rot caused by Pectobacterium carotovorum subsp. carotovorum (Pcc) is one of the most devastating diseases of Ornithogalum species. No effective control measures are currently available to use against this pathogen; thus, introduction of resistant genes via genetic transformation into this crop is a promising approach. Tachyplesin I, an antimicrobial peptide, has been shown to effectively control numerous pathogenic bacteria, including Pcc. In this study, liquid-grown cell clusters of Ornithogalum dubium and Ornithogalum thyrsoides were bombarded with a pCAMBIA2301 vector containing a celI leader sequence fused to a gene encoding tachyplesin I, a neomycin phosphotransferase (nptII) gene that served as a selectable marker and a beta-glucuronidase (GUS) gene that served as a reporter. Selection was carried out in the dark in liquid medium containing 80mg/L kanamycin. Regeneration was executed in the light after 6-14 months depending on the cultivar. Hundreds of transgenic plantlets were produced and their identity was confirmed through GUS activity assays. PCR and RT-PCR were used to confirm the presence of the target, reporter and selection genes in the divergent lines of plantlets. The resistance of the O. dubium plants to Pcc was evaluated in vitro, following infection with a highly virulent isolate from calla lily. Although control plantlets were completely macerated within a week, 87 putative transgenic subclones displayed varying levels of disease resistance. During three growing seasons in the greenhouse, the transgenic O. dubium lines grew poorly, whereas the transgenic O. thyrsoides plants grew similarly to non transgenic plants. PMID- 25438797 TI - Increased risk of vascular complications in Takayasu's arteritis patients with positive lupus anticoagulant. AB - OBJECTIVES: Previous studies have shown antiphospholipid antibodies (aPL) to be prevalent in primary systemic vasculitides; however, the possible clinical impact of aPL positivity in such patients has not been explored in depth. The aims of this study were to determine the prevalence of aPL in patients with Takayasu's arteritis (TA) and to ascertain whether aPL positivity was predictive of a worse clinical outcome in TA. METHOD: Clinical data were collected retrospectively on 22 TA patients over an 11-year period. Data collected included the presence of lupus anticoagulant (LA) and immunoglobulin (Ig)G and IgM anticardiolipin antibody (aCL) titres. Adverse clinical outcomes included cerebrovascular accident (CVA), transient ischaemic attack (TIA), loss of vision, vascular lesions (carotid, femoral, renal, coronary, or other vessels) requiring stenting, angioplasty, or other surgical intervention, aortic valve replacement, end-stage renal failure or death. RESULTS: Persistently positive aPL or a concurrent diagnosis of antiphospholipid syndrome (APS) was found in 45% (n = 10) of TA patients while 55% (n = 12) had TA alone. LA was present in a significant proportion of TA patients with aPL (p = 0.002). Vascular complications occurred in 70% (n = 7) of TA patients with aPL and in 25% (n = 3) of TA patients without aPL (p = 0.035). LA was associated with a higher prevalence of vascular complications. CONCLUSIONS: Persistently positive aPL are present in a significant proportion of TA patients. This study shows that vascular complications and need for intervention are more prevalent in TA patients with aPL, particularly those with LA. Prospective studies are needed to determine the long term prognosis in such patients. PMID- 25438798 TI - In Memoriam, Arlette Darfeuille-Michaud, PhD. PMID- 25438799 TI - Improved molecular detection of Ehrlichia and Anaplasma species applied to Amblyomma ticks collected from cattle and sheep in Ethiopia. AB - Detection of Ehrlichia and Anaplasma species in animals and tick vectors is crucial for an understanding of the epidemiology of diseases caused by these pathogens. In this study, a pair of primers designated EBR2 and EBR3 was designed from the Anaplasma 16S rDNA sequence and was used along with a previously described primer EHR 16SD for the simultaneous detection of Ehrlichia and Anaplasma species by nested PCR. The primers were used to amplify 925bp of DNA from known species of Ehrlichia and Anaplasma. Restriction with MboII and MspI enzymes allowed Ehrlichia and Anaplasma speciation. Restriction with MboII differentiated between An. marginale, Anaplasma (formerly Ehrlichia) sp. Omatjenne, and An. centrale with An. marginale and Anaplasma (formerly Ehrlichia) sp. Omatjenne yielding 2 distinct fragments each while An. centrale produced 3 distinct bands. Ehrlichia ruminantium and An. phagocytophylum remained undigested. Subsequent restriction with MspI differentiated E. ruminantium from An. phagocytophylum with 2 and 4 fragments, respectively. When used on tick samples from the field, 63 ticks (16.4%) out of 384 collected from cattle and sheep were positive for one or more species of Ehrlichia and Anaplasma. The positivity ranged from 6.3% at Andasa to 36.7% at Habernosa. Higher overall infection rates were found in Amblyomma lepidum than in Amblyomma variegatum ticks (p=0.009). Amblyomma lepidum from Habernosa were more often infected with all detected species of Anaplasma and Ehrlichia than Am. variegatum. At Bako, however, Anaplasma (formerly Ehrlichia) sp. Omatjenne was detected only in Am. variegatum. A significantly higher proportion of ticks collected from cattle (20.6%) was found positive than in those collected from sheep (3.3%) (p=0.003). Simultaneous detection of Ehrlichia and Anaplasma species and correct identification of mixed infections was possible. Since the ticks were collected from animals, the occurrence of the major species of Ehrlichia and Anaplasma in ruminants in the area is confirmed. PMID- 25438800 TI - From protein total synthesis to peptide transamidation and metathesis: playing with the reversibility of N,S-acyl or N,Se-acyl migration reactions. AB - Amide forming reactions are central to the field of peptide and protein synthesis and are considered to be poorly reversible reactions owing to the high stability of peptide bonds. One amide-forming reaction is native chemical ligation (NCL) which is driven by a sulfur to nitrogen acyl migration process from a transient thioester intermediate. However, recent studies have revealed the reversibility of the S,N-acyl shift reaction or of the related Se,N-acyl shift process using mild aqueous conditions. Such chemical processes have great potential for the chemoselective formation of peptide bonds to cysteine or selenocysteine, and open novel avenues in the field of peptide transamidation and metathesis reactions. PMID- 25438801 TI - Abiotic synthesis of RNA in water: a common goal of prebiotic chemistry and bottom-up synthetic biology. AB - For more than half a century chemists have searched for a plausible prebiotic synthesis of RNA. The initial advances of the 1960s and 1970s were followed by decades of measured progress and a growing pessimism about overcoming remaining challenges. Fortunately, the past few years have provided a number of important advances, including new abiotic routes for the synthesis of nucleobases, nucleosides, and nucleotides. Recent discoveries also provide additional support for the hypothesis that RNA is the product of evolution, being preceded by ancestral genetic polymers, or pre-RNAs, that are synthesized more easily than RNA. In some cases, parallel searches for plausible prebiotic routes to RNA and pre-RNAs have provided more than one experimentally verified synthesis of RNA substructures and possible predecessors. Just as the synthesis of a contemporary biological molecule cannot be understood without knowledge of cellular metabolism, it is likely that an integrated approach that takes into account both plausible prebiotic reactions and plausible prebiotic environments will ultimately provide the most satisfactory and unifying chemical scenarios for the origin of nucleic acids. In this context, recent advances towards the abiotic synthesis of RNA and candidates for pre-RNAs are beginning to suggest that some molecules (e.g., urea) were multi-faceted contributors to the origin of nucleic acids, and the origin of life. PMID- 25438802 TI - Purified cell-free systems as standard parts for synthetic biology. AB - A cell free protein synthesis approach is extensively used for biochemical and synthetic biology researches. Unlike lysate based cell free systems, the PURE system is reconstituted with individually purified factors essential for transcriptional and translational processes. Hence, the components in the PURE system can be definitely manipulated as per the desired situation. Because of this high controllability, the PURE system has been applied to a wide range of research scene, such as biochemical analysis in reconstructed system, in vitro protein engineering, reconstitution of an artificial cell. We believe that this purified cell-free protein synthesis system become a basal technology to advance synthetic biology. PMID- 25438803 TI - Editorial overview: synthetic biology. PMID- 25438804 TI - Editorial overview: synthetic biomolecules. PMID- 25438805 TI - [Optic neuritis in juvenile idiopathic arthritis patient]. AB - Optic neuritis (ON) was rarely reported in juvenile idiopathic arthritis (JIA) patients, particularly in those under anti-tumor necrosis factor alpha blockage. However, to our knowledge, the prevalence of ON in JIA population has not been studied. Therefore, 5,793 patients were followed up at our University Hospital and 630 (11%) had JIA. One patient (0.15%) had ON and was reported herein. A 6 year-old male was diagnosed with extended oligoarticular JIA, and received naproxen and methotrexate subsequently replaced by leflunomide. At 11 years old, he was diagnosed with aseptic meningitis, followed by a partial motor seizure with secondary generalization. Brain magnetic resonance imaging (MRI) and electroencephalogram showed diffuse disorganization of the brain electric activity and leflunomide was suspended. Seven days later, the patient presented acute ocular pain, loss of acuity for color, blurred vision, photophobia, redness and short progressive visual loss in the right eye. A fundoscopic exam detected unilateral papilledema without retinal exudates. Orbital MRI suggested right ON. The anti-aquaporin 4 (anti-AQP4) antibody was negative. Pulse therapy with methylprednisolone was administered for five days, and subsequently with prednisone, he had clinical and laboratory improvement. In conclusion, a low prevalence of ON was observed in our JIA population. The absence of anti-AQP4 antibody and the normal brain MRI do not exclude the possibility of demyelinating disease associated with chronic arthritis. Therefore, rigorous follow up is required. PMID- 25438806 TI - Quantitative structure-activity relationship analysis of the pharmacology of para substituted methcathinone analogues. AB - BACKGROUND AND PURPOSE: Methcathinone (MCAT) is a potent monoamine releaser and parent compound to emerging drugs of abuse including mephedrone (4-CH3 MCAT), the para-methyl analogue of MCAT. This study examined quantitative structure-activity relationships (QSAR) for MCAT and six para-substituted MCAT analogues on (a) in vitro potency to promote monoamine release via dopamine and serotonin transporters (DAT and SERT, respectively), and (b) in vivo modulation of intracranial self-stimulation (ICSS), a behavioural procedure used to evaluate abuse potential. Neurochemical and behavioural effects were correlated with steric (Es ), electronic (sigmap ) and lipophilic (pip ) parameters of the para substituents. EXPERIMENTAL APPROACH: For neurochemical studies, drug effects on monoamine release through DAT and SERT were evaluated in rat brain synaptosomes. For behavioural studies, drug effects were tested in male Sprague-Dawley rats implanted with electrodes targeting the medial forebrain bundle and trained to lever-press for electrical brain stimulation. KEY RESULTS: MCAT and all six para substituted analogues increased monoamine release via DAT and SERT and dose- and time-dependently modulated ICSS. In vitro selectivity for DAT versus SERT correlated with in vivo efficacy to produce abuse-related ICSS facilitation. In addition, the Es values of the para substituents correlated with both selectivity for DAT versus SERT and magnitude of ICSS facilitation. CONCLUSIONS AND IMPLICATIONS: Selectivity for DAT versus SERT in vitro is a key determinant of abuse-related ICSS facilitation by these MCAT analogues, and steric aspects of the para substituent of the MCAT scaffold (indicated by Es ) are key determinants of this selectivity. PMID- 25438809 TI - Isolated CNS Hodgkin's lymphoma: implications for tissue diagnosis. AB - CNS involvement in the setting of lymphoid neoplasia is a clinical situation that requires specific diagnosis due to the disparate treatment regimens recommended for neoplasms of specific lymphoid cell types. Cerebrospinal fluid (CSF) sampling may provide sufficient information to determine the presence of abnormal lymphoid cells but may not be able to further specify the malignant cellular population. In cases where abnormal clinical or radiographic features are present, accurate tissue diagnosis is essential. In this report, we define a rare case of primary CNS intramedullary Hodgkin's lymphoma without leptomeningeal dissemination diagnosed via resectional biopsy of a conus medullaris lesion. The patient received post-resection radiation therapy and subsequently demonstrated radiographic and clinical improvement. Lymphoid neoplasia within the CNS comprises a diverse group with varying response and survival rates. Treatment hinges upon accurate diagnosis as chemotherapy varies widely among Hodgkin's and non-Hodgkin's lymphoma. While CSF sampling may yield a positive result with sufficiency to diagnose an abnormal lymphoid cell population, tissue is necessary for further defining cellular pathology. In this report, we define a rare case of primary CNS intramedullary Hodgkin's lymphoma without leptomeningeal dissemination via resectional biopsy of a conus medullaris lesion. In cases where abnormal enhancement is found in eloquent CNS regions and lymphoid neoplasia is suspected, management often entails either stereotactic biopsy or CSF sampling. While CSF analysis may differentiate malignancy at a low rate, tissue diagnosis via paraffin block immunohistochemistry is necessary to further classify malignancy as primary or peripheral, Hodgkin's or non-Hodgkin's lymphoma, or other such as metastatic leptomeningeal dissemination and glioma. Within the subtypes of lymphoid neoplasms, treatment regimens vastly differ and thus accurate tissue diagnosis is paramount. We therefore present a rare case of primary CNS intramedullary Hodgkin's lymphoma without leptomeningeal disease in the setting of immunocompromise diagnosed via open resectional biopsy of the conus medullaris. PMID- 25438807 TI - Changes in bone mineral density may predict the risk of fracture differently in older adults according to fall history. AB - OBJECTIVES: To determine whether the association between change in bone mass density (BMD) over 4 years and risk of hip and nonvertebral fracture differs according to an individual's history of falls. DESIGN: Population-based cohort study. SETTING: Framingham, Massachusetts. PARTICIPANTS: Individuals with two measures of BMD at the femoral neck (mean age 78.8; 310 male, 492 female). MEASUREMENTS: Cox proportional hazards models were used to estimate hazard ratios (HRs) for the association between percentage change in BMD (per sex-specific standard deviation) and risk of incident hip and nonvertebral fracture. Models were stratified based on history of falls (>=1 falls in the past year) and recurrent falls (>=2 falls) ascertained at the time of the second BMD test. Interactions were tested by including the term "fall history * change in BMD" in the models. RESULTS: Mean change in BMD was -0.6%/year; 27.8% of participants reported falls, and 10.8% reported recurrent falls. Seventy-six incident hip and 175 incident nonvertebral fractures occurred over a median follow-up of 9.0 years. There was no difference in the association between change in BMD and hip fracture according to history of falls (P for interaction = .57). The HR associated with change in BMD and nonvertebral fracture was 1.31 (95% confidence interval (CI) = 1.10-1.56) in participants without a history of falls and 0.95 (95% CI 0.70-1.28) in those with a fall (interaction P = .07). Results for recurrent fallers were similar. CONCLUSION: The effect of BMD loss on risk of nonvertebral fracture may be greater in persons without a history of falls. It is possible that change in BMD contributes less to fracture risk when a strong risk factor for fracture, such as falls, is present. PMID- 25438811 TI - Whole-brain radiotherapy in patients with brain metastases from melanoma. AB - AIMS: To describe results of melanoma brain metastases (BM) treated with whole brain radiation (WBRT). METHODS: Retrospective review of patients with melanoma BM treated with WBRT divided into two groups based on the timing of WBRT (at BM diagnosis or recurrence). RESULTS: We identified 61 patients with melanoma BM who received WBRT. For the group treated at diagnosis (n = 39): median overall survival was 3 months; best radiographic response included one partial response, ten stable disease, 18 progressive disease, and ten no follow-up imaging. For the group treated at recurrence (n = 22): median overall survival was 3 months; best radiographic response was three partial response, four stable disease, eight progressive disease, and seven no follow-up imaging. CONCLUSION: WBRT activity was limited; however, its role in symptom palliation is unclear. PMID- 25438810 TI - Diagnosis of pseudoprogression using MRI perfusion in patients with glioblastoma multiforme may predict improved survival. AB - AIMS: This retrospective study determined the survival of glioblastoma patients with or without pseudoprogression. METHODS: A total of 68 patients were included. Overall survival was compared between patients showing pseudoprogression (in most cases diagnosed using perfusion MRI with ferumoxytol) and in patients without pseudoprogession. MGMT methylation status was also analyzed in the pseudoprogression cases. RESULTS: Median survival in 24 (35.3%) patients with pseudoprogression was 34.7 months (95% CI: 20.3-54.1), and 13.4 months (95% CI: 11.1-19.5) in 44 (64.7%) patients without pseudoprogression (p < 0.0001). The longest survival was a median of 54.1 months in patients with combination of pseudoprogression and (MGMT) promoter methylation. CONCLUSION: Pseudoprogression is associated with better outcome, especially if concurring with MGMT promoter methylation. Patients never diagnosed with pseudoprogression had poor survival. This study emphasizes the importance of differentiating tumor progression and pseudoprogression using perfusion MRI. PMID- 25438812 TI - Benefits of dynamic susceptibility-weighted contrast-enhanced perfusion MRI for glioma diagnosis and therapy. AB - Glioma are the most common supra-tentorial brain tumor in the USA with an estimated annual incidence of 17,000 new cases per year. Dynamic susceptibility weighted contrast-enhanced (DSC) perfusion MRI noninvasively characterizes tumor biology allowing for the diagnosis and therapeutic monitoring of glioma. This MRI technique utilizes the rapid changes in signal intensity caused by a rapid intravascular bolus of paramagnetic contrast agent to calculate physiologic perfusion metrics. DSC perfusion MRI has increasingly become an integrated part of glioma imaging. The specific aim of this article is to review the benefits of DSC perfusion MRI in the therapy of glioma. PMID- 25438813 TI - Management of diffuse intrinsic pontine glioma in children: current and future strategies for improving prognosis. AB - Diffuse intrinsic pontine glioma (DIPG) is one of the deadliest pediatric central nervous system cancers in spite of treatment with radiation therapy, the current standard of care. The outcome of affected children remains dismal despite multiple clinical trials that investigated radiation therapy combined with chemotherapy. Recently, multiple genome-wide studies unveiled the distinct molecular characteristics of DIPGs and preclinical models of DIPG were developed to mimic the human disease. Both of these accomplishments have generated tremendous progress in the research of new therapies for children with DIPG. Here we review some of these promising new strategies. PMID- 25438815 TI - Effects of dietary star anise (Illicium verum Hook f) supplementation during gestation and lactation on the performance of lactating multiparous sows and nursing piglets. AB - Thirty-two sows were allocated to four treatments to evaluate the effect of dietary star anise (SA) supplementation during gestation and lactation on the lactational performance of sows. At 85 days of gestation, sows were randomly allotted to one of two diets supplemented with 0.5% SA or basal diet. After farrowing, sows were further allotted to one of two lactation diets supplemented with 0.5% SA or basal diet. On a weekly basis, body weight (BW) of sows and piglets was measured. Blood and milk samples were obtained from the sows and piglets. Number of days from weaning to estrus, milk yield and feed intake were also recorded. Weight gain of piglets from sows fed the SA-supplemented diet during lactation was greater between days 7 and 14, days 14 and 21 and the overall experimental period compared with control groups. Supplementation of SA during lactation improved weaning weight of piglets, milk yield and average daily feed intake (ADFI) of sows. The SA diet increased concentrations of insulin-like growth factor-1 (IGF-1) in ordinary milk and prolactin (PRL) in serum of sows. In conclusion, this study has indicated the beneficial effects of dietary SA addition in improving the lactation performance of sows. PMID- 25438814 TI - Molecular characteristics of pediatric high-grade gliomas. AB - High-grade gliomas (HGGs) are extremely lethal tumors. Survival has not changed significantly in the past decades. The only known prognostic factors in pediatric HGGs (pHGGs) are extent of resection and histologic grade. Treatment has historically been based on adult trials because of the rarity of pHGGs and the lack of genomic tools to explore their unique molecular characteristics. The recent advances in molecular biological data helped divide these tumors into distinct subgroups. In this review, the authors focus on major molecular targets of alterations in pHGGs: histone H3.3, telomeres, PDGFRA, IDH, BRAF (V600E), ACVR1 and NTRK and briefly highlight the difference with the adult counterpart. PMID- 25438821 TI - Dapagliflozin in type 2 diabetes: effectiveness across the spectrum of disease and over time. AB - BACKGROUND: Despite many available therapies, patients with type 2 diabetes mellitus (T2DM) frequently do not achieve/maintain glycaemic control. Furthermore, side effects such as hypoglycaemia and weight gain may limit therapy choices. Dapagliflozin, a selective sodium-glucose cotransporter-2 inhibitor, reduces hyperglycaemia by increasing glucosuria independently of insulin, representing a novel approach in T2DM. Dapagliflozin efficacy, safety and tolerability were evaluated across a wide range of clinical trials. METHODS: Dapagliflozin 10-mg efficacy data from (i) two short-term, active-comparator studies (vs. metformin-XR over 24 weeks and vs. glipizide over 52 weeks), (ii) pooled 24-week analyses of five placebo-controlled trials (as monotherapy or add on therapy), and (iii) long-term studies over 2 years; dapagliflozin 5- and 10-mg pooled safety data from 12 placebo-controlled trials; and cardiovascular safety and malignancy data from 19 dapagliflozin studies were evaluated. RESULTS: In treatment-naive patients (baseline HbA1c 9%), dapagliflozin reduced HbA1c ( 1.45%) similarly to metformin-XR (-1.44%). In metformin-treated patients (baseline HbA1c 7.7%), dapagliflozin achieved a clinically significant reduction (-0.52%) similar to glipizide (-0.52%). In pooled 24-week analyses, dapagliflozin vs. placebo differences in HbA1c, weight and systolic blood pressure (SBP) were 0.60%, -1.61 kg and -3.6 mmHg, respectively. At 2 years, dapagliflozin vs. placebo differences in HbA1c and weight were -0.44 to -0.80% and -2.41 to -3.19 kg, respectively, and vs. glipizide, differences in HbA1c, weight, and SBP were 0.18%, -5.06 kg, and -3.89 mmHg, respectively. Major hypoglycaemia with dapagliflozin was rare (< 0.1%). Urinary tract and genital infections were more common with dapagliflozin, but responded to standard care and rarely led to study discontinuation. Events of renal failure/impairment and malignancies were rare and balanced across treatment groups. Pooled analyses did not indicate that dapagliflozin increased cardiovascular event risk. CONCLUSIONS: Dapagliflozin improved glycaemic control, decreased body weight, and lowered blood pressure across the spectrum of T2DM disease, with maintenance of these benefits over time. PMID- 25438822 TI - Differential expression of immune-related cytokine genes in response to J group avian leukosis virus infection in vivo. AB - Infection with J group avian leukosis virus (ALV-J) can result in immunosuppression and subsequently increased susceptibility to secondary infection. The innate immune system is the first line defense system in prevention of further bacterial and viral infections. Cytokines play key roles in the innate immune system. In this study, we used RT-qPCR technology to test the cytokine mRNA expression levels in various immune tissues, including the spleen, bursa of fabricius and cecal tonsil, in the days following ALV-J infection. The results indicated that in the infected group, the expression levels of interleukin-6 (IL-6), IL-18, interferon-alpha (IFN-alpha) and IFN-gamma significantly increased in the spleen and reached peak levels that were thousandfolds higher than baselines at 9-12 days post-infection (d.p.i.). The levels in the bursa of fabricius slightly increased, and the levels in the cecal tonsil were not significantly altered. Moreover, the pattern of the expression of these three cytokines in the spleens of the infected group was similar to the pattern of viremia of this group. These results suggest that the spleen plays an important role in the interaction between ALV-J infection and the innate immune system. This study contributes to the understanding of innate immune responses to ALV-J infection and also elucidates the mechanisms of the pathogenicity of ALV-J in chickens. PMID- 25438823 TI - The NLstart2run study: Incidence and risk factors of running-related injuries in novice runners. AB - Running is a popular form of physical activity, despite of the high incidence of running-related injuries (RRIs). Because of methodological issues, the etiology of RRIs remains unclear. Therefore, the purposes of the study were to assess the incidence of RRIs and to identify risk factors for RRIs in a large group of novice runners. In total, 1696 runners of a 6-week supervised "Start to Run" program were included in the NLstart2run study. All participants were aged between 18 and 65, completed a baseline questionnaire that covered potential risk factors, and completed at least one running diary. RRIs were registered during the program with a weekly running log. An RRI was defined as a musculo-skeletal complaint of the lower extremity or back attributed to running and hampering running ability for three consecutive training sessions. During the running program, 10.9% of the runners sustained an RRI. The multivariable Cox regression analysis showed that a higher age, higher BMI, previous musculo-skeletal complaints not attributed to sports and no previous running experience were related to RRI. These findings indicate that many novice runners participating in a short-term running program suffer from RRIs. Therefore, the identified risk factors should be considered for screening and prevention purposes. PMID- 25438824 TI - The putative functional ecology and distribution of archaeal communities in sponges, sediment and seawater in a coral reef environment. AB - Archaea play crucial roles in a number of key ecological processes including nitrification and methanogenesis. Although several studies have been conducted on these organisms, the roles and dynamics of coral reef archaeal communities are still poorly understood, particularly in host and nonhost biotopes and in high (HMA) and low microbial abundance (LMA) sponges. Here, archaeal communities detected in six distinct biotopes, namely, sediment, seawater and four different sponge species Stylissa carteri, Stylissa massa, Xestospongia testudinaria and Hyrtios erectus from the Spermonde Archipelago, SW Sulawesi, Indonesia were investigated using 454-pyrosequencing of 16S rRNA genes (OTU cut-off 97%). Archaeal communities from sediment and sponges were dominated by Crenarchaeota, while the seawater community was dominated by Euryarchaeota. The biotope explained almost 75% of the variation in archaeal composition, with clear separation between microbial assemblages from sediment, X. testudinaria and H. erectus (HMA). In contrast, samples from seawater and both Stylissa species (LMA) showed considerable overlap in the ordination and, furthermore, shared most abundant OTUs with the exception of a single dominant OTU specifically enriched in both Stylissa species. Predicted functional gene content in archaeal assemblages also revealed significant differences among biotopes. Different ammonia assimilation strategies were exhibited by the archaeal communities: X. testudinaria, H. erectus and sediment archaeal communities were enriched for glutamate dehydrogenase with mixed specificity (NAD(P)(+) ) pathways, while archaeal planktonic communities were enriched for specific glutamate dehydrogenase (NADP(+) ) and glutamate synthase pathways. Archaeal communities in Stylissa had intermediate levels of enrichment. Our results indicate that archaeal communities in different biotopes have distinct ecophysiological roles. PMID- 25438825 TI - The late positive potential predicts emotion regulation strategy use in school aged children concurrently and two years later. AB - The ability to use cognitive emotion regulation strategies such as reappraisal may be a core component of emotional competence across development, but due to methodological challenges in measuring such strategies, they are rarely studied in young children. One neurophysiological measure, the late positive potential (LPP), has been examined in response to reappraisal as a potential neurosignature for emotion regulatory capacity in adults. The association between the LPP and emotion regulatory capacity in children is unknown. The present study examined whether the LPP during reappraisal could predict greater observed adaptive emotion regulation strategy use in school-aged children over a two-year period. Thirty-two 5- to 7-year-olds participated in two identical lab visits spaced two years apart. EEG was continuously recorded during a computerized reappraisal task in which children viewed unpleasant images paired with either reappraisal or negative stories. Next they completed a disappointing and a frustrating task during which emotion regulation strategies were observed. As predicted, children who showed reappraisal-induced reductions in the LPP at the first assessment used significantly more adaptive ER strategies concurrently and two years later. These findings provide observation-based evidence that the LPP may be a viable neurosignature for emotion regulatory capacity in children. PMID- 25438826 TI - Measures of precision for dissimilarity-based multivariate analysis of ecological communities. AB - Ecological studies require key decisions regarding the appropriate size and number of sampling units. No methods currently exist to measure precision for multivariate assemblage data when dissimilarity-based analyses are intended to follow. Here, we propose a pseudo multivariate dissimilarity-based standard error (MultSE) as a useful quantity for assessing sample-size adequacy in studies of ecological communities. Based on sums of squared dissimilarities, MultSE measures variability in the position of the centroid in the space of a chosen dissimilarity measure under repeated sampling for a given sample size. We describe a novel double resampling method to quantify uncertainty in MultSE values with increasing sample size. For more complex designs, values of MultSE can be calculated from the pseudo residual mean square of a permanova model, with the double resampling done within appropriate cells in the design. R code functions for implementing these techniques, along with ecological examples, are provided. PMID- 25438830 TI - Intrafollicular treatment with prostaglandins PGE2 and PGF2alpha inhibits the formation of luteinised unruptured follicles and restores normal ovulation in mares treated with flunixin-meglumine. AB - REASONS FOR PERFORMING STUDY: Haemorrhagic anovulatory follicle is the most common pathological anovulatory condition in the mare, but its cause remains unknown. An experimental model to induce luteinised unruptured follicles (LUF) with flunixin-meglumine (FM) has been developed. Luteinised unruptured follicles share similar morphological and hormonal characteristics with haemorrhagic anovulatory follicles. OBJECTIVES: To test the effect of intrafollicular administration of prostaglandins PGE2 and PGF2alpha during the periovulatory period on ovulation and pregnancy in FM-treated mares. STUDY DESIGN: In vivo experiment in a crossover design. METHODS: Five mares were followed during 2 oestrous cycles each. All mares were given FM at 1.7 mg/kg bwt i.v. every 12 h from Hour 0 (Hour 0 = human chorionic gonadotrophin treatment) to Hour 36. In treatment cycles (n = 5), at Hour 32 the preovulatory follicle was punctured and 0.5 ml of a solution containing 500 MUg of PGE2 and 125 MUg of PGF2alpha was deposited within the follicle. In control cycles, water for injection was administered into the follicle at the same time. In 3 control and 3 treatment cycles, mares were also inseminated at Hour 24. Diagnosis of ovulation/LUF formation and pregnancy was performed by ultrasound examination between Hours 36 and 72 and 14 days after ovulation/LUF formation, respectively. RESULTS: During the treatment cycles, all mares ovulated normally (100% ovulation rate) 36-48 h after human chorionic gonadotrophin, while in 4 of 5 control cycles the mares developed an LUF (80%, P<0.05). All 3 inseminated mares became pregnant in the treatment cycles, but not in the control cycles. CONCLUSIONS: Intrafollicular treatment with PGE2 and PGF2alpha overcame the anovulatory effect of FM. This sheds new insights into the knowledge on the possible therapeutic options for ovulatory failure in the mare. PMID- 25438831 TI - The stability and nuclear localization of the transcription factor RAP2.12 are dynamically regulated by oxygen concentration. AB - Plants often experience low oxygen conditions as the consequence of reduced oxygen availability in their environment or due to a high activity of respiratory metabolism. Recently, an oxygen sensing pathway was described in Arabidopsis thaliana which involves the migration of an ERF transcription factor (RAP2.12) from the plasma membrane to the nucleus upon hypoxia. Moreover, RAP2.12 protein level is controlled through an oxygen-dependent branch of the N-end rule pathway for proteasomal degradation. Inside the nucleus, RAP2.12 induces the expression of genes involved in the adaptation to reduced oxygen availability. In the present study, we describe the oxygen concentration and time-resolved characterization of RAP2.12 activity. A reduction of the oxygen availability to half the concentration in normal air is sufficient to trigger RAP2.12 relocalization into the nucleus, while nuclear accumulation correlates with the first induction of the molecular response to hypoxia. Nuclear presence of RAP2.12 may not only depend on relocalization of existing protein, but involves de novo synthesis of the transcription factor as well. After re-oxygenation of the tissue, degradation of RAP2.12 in the nucleus was observed within 3 h, concomitant with reduction in hypoxia responsive gene transcripts to normoxic levels. PMID- 25438832 TI - Riboflavin and ultraviolet light for pathogen reduction of murine cytomegalovirus in blood products. AB - BACKGROUND: Two studies were performed to test the effectiveness of riboflavin and ultraviolet (UV) light treatment (Mirasol PRT, Terumo BCT) against murine cytomegalovirus (MCMV). The first study utilized immune-compromised mice to measure the reduction of cell-free MCMV. A second study used a murine model to evaluate the ability of Mirasol PRT to prevent transfusion-transmitted (TT)-MCMV infection. STUDY DESIGN AND METHODS: Human plasma was inoculated with MCMV and then treated with Mirasol PRT. The viral titer was measured using an infectious dose 50% assay in nude mice. Mice were euthanized on Day 10 posttransfusion, and their spleens were tested for the presence of MCMV DNA using polymerase chain reaction (PCR). Mirasol PRT was also evaluated to determine its effectiveness in preventing TT-MCMV in platelets (PLTs) stored in PLT additive solution. PLTs were inoculated with either cell-associated MCMV or cell-free MCMV and then treated with Mirasol PRT. Mice were transfused with treated or untreated product and were euthanized 14 days posttransfusion. Blood and spleens were assayed for MCMV DNA by real-time-PCR. RESULTS: Using nude mice to titer MCMV, a modest 2.1-log reduction was observed in plasma products after Mirasol PRT treatment. TT-MCMV was not observed in the mouse transfusion model when either cell-free or cell associated MCMV was treated with Mirasol PRT; MCMV transmission was uniformly observed in mice transfused with untreated PLTs. CONCLUSIONS: These results suggest that using riboflavin and UV light treatment may be able to reduce the occurrence of transmission of human CMV from infectious PLTs and plasma units. PMID- 25438833 TI - Metastatic melanoma of the transverse colon heralded by vitiligo-like depigmentation: two rare conditions occurring in the same patient. PMID- 25438834 TI - The constellation of dietary factors in adolescent acne: a semantic connectivity map approach. AB - BACKGROUND: Different lifestyle and dietetic factors have been linked with the onset and severity of acne. OBJECTIVE: To assess the complex interconnection between dietetic variables and acne. METHODS: This was a reanalysis of data from a case-control study by using a semantic connectivity map approach. 563 subjects, aged 10-24 years, involved in a case-control study of acne between March 2009 and February 2010, were considered in this study. The analysis evaluated the link between a moderate to severe acne and anthropometric variables, family history and dietetic factors. Analyses were conducted by relying on an artificial adaptive system, the Auto Semantic Connectivity Map (AutoCM). RESULTS: The AutoCM map showed that moderate-severe acne was closely associated with family history of acne in first degree relatives, obesity (BMI >= 30), and high consumption of milk, in particular skim milk, cheese/yogurt, sweets/cakes, chocolate, and a low consumption of fish, and limited intake of fruits/vegetables. CONCLUSION: Our analyses confirm the link between several dietetic items and acne. When providing care, dermatologists should also be aware of the complex interconnection between dietetic factors and acne. PMID- 25438836 TI - Statistics of boundaries in ultrasonic B-scan images. AB - The existence of edges and boundaries in regions of interest (ROIs) in B-scan images alters the statistics of the backscattered echo from the ROI. Boundaries are the result of at least two different types of scattering scenarios in tissue, and the Nakagami model, which is being used extensively in ultrasound, is unlikely to fit the statistics of the backscattered echo under these conditions. Furthermore, there are very few other statistical models exist that describe the statistics of the backscattered echo from regions containing boundaries. In this work, the gamma mixture density and the recently proposed McKay density are explored as two viable models to fill this void. Justifications of these models are presented along with methods for estimating their parameters. Random number simulations and studies on tissue-mimicking phantoms indicate that the McKay and gamma mixture densities are the best for the modeling of the backscattered echo intensity when boundaries are present in the regions of interest. PMID- 25438835 TI - Is vulnerability to cardiometabolic disease in Indians mediated by abdominal adiposity or higher body adiposity. AB - BACKGROUND: Indians may be particularly vulnerable to cardiometabolic disease, potentially due to higher body fat for a given BMI, or a tendency towards depositing abdominal adiposity. The aim of the study is to assess whether different measures of the distribution of adiposity (abdominal versus whole body) or amount of adiposity (DXA versus traditional anthropometric) are better at predicting prevalent cardiometabolic risk markers in an Indian population. METHODS: Participants were recruited from the Indian Migration Study (IMS) and the Andhra Pradesh Children and Parent Study (APCAPS). Participants attended a clinic in Hyderabad, India, January 2009-December 2010. Adiposity was measured by conventional anthropometry (including weight, height, waist) and DXA scanning (whole body and abdominal). Blood samples were taken and assessed for fasting plasma glucose, insulin, cholesterol, and triglycerides and blood pressure was measured. Lifestyle data were collected by questionnaire. RESULTS: We invited 4 617 participants to the clinic (1 995 IMS; 2 622 APCAPS) and examined 918 from IMS (46%) and 1 451 from APCAPS (55%). There were strong and consistent relationships between adiposity and cardiometabolic risk factors. Cardiometabolic risk factors did not appear to be more strongly associated with DXA measures as opposed to BMI, or skinfold measures of body fat. There was some evidence that WHR was more closely related to diabetes than total body adiposity, but this was not apparent for the other measures of abdominal adiposity (DXA measures, waist circumference) or other cardiometablic risk factors. CONCLUSIONS: No strong evidence supports that DXA measures or abdominal measures of adiposity are better at predicting the prevalence of cardiometabolic risk factors in comparison to BMI. PMID- 25438837 TI - Ultrasound quantification of acetabular rounding in hip dysplasia: reliability and correlation to treatment decisions in a retrospective study. AB - Currently, acetabular rounding is only subjectively assessed on ultrasound for developmental dysplasia of the hip. We tested whether acetabular rounding can be quantified reliably and can distinguish between hips requiring and not requiring treatment. Consecutive infants (n = 90) suspected of having dysplasia of the hip, seen at a pediatric orthopedic clinic, were separated into four diagnostic categories (normal, borderline but resolved, treated by brace, treated surgically). Acetabular rounding was assessed by semi-quantitative grade (0 = nil, 1 = mild, 2 = moderate, 3 = severe) by three observers and by direct measurement of acetabular radius of curvature (AROC) by two observers. Inter observer reliability of rounding grade was poor (kappa = 0.30-0.37). AROC had an inter-observer intra-class correlation coefficient of 0.84 and coefficient of variation of 29%-34%. Mean AROC was significantly higher for hips requiring treatment than for those not requiring treatment (3.3 mm vs. 1.6 mm, p = 0.007). AROC reliably quantifies an observation currently being made subjectively by radiologists and surgeons, and may be useful as a supplementary ultrasound index of dysplasia of the hip in future prospective studies. PMID- 25438838 TI - Neurophysiologic correlates of sonication treatment in patients with essential tremor. AB - Transcranial magnetic resonance imaging-guided high-intensity focused ultrasound (MRgHIFU) is gaining attention as a potent substitute for surgical intervention in the treatment of neurologic disorders. To discern the neurophysiologic correlates of its therapeutic effects, we applied MRgHIFU to an intractable neurologic disorder, essential tremor, while measuring magnetoencephalogram mu rhythms from the motor cortex. Focused ultrasound sonication destroyed tissues by focusing a high-energy beam on the ventralis intermedius nucleus of the thalamus. The post-treatment effectiveness was also evaluated using the clinical rating scale for tremors. Thalamic MRgHIFU had substantial therapeutic effects on patients, based on MRgHIFU-mediated improvements in movement control and significant changes in brain mu rhythms. Ultrasonic thalamotomy may reduce hyper excitable activity in the motor cortex, resulting in normalized behavioral activity after sonication treatment. Thus, non-invasive and spatially accurate MRgHIFU technology can serve as a potent therapeutic tool with broad clinical applications. PMID- 25438839 TI - Acoustic output measured by thermal and mechanical indices during fetal echocardiography at the time of the first trimester scan. AB - We measured acoustic output, expressed as the thermal index (TI) and mechanical index (MI), during fetal echocardiography at the time of the first trimester scan. TI and MI were retrieved from the saved displays during gray-mode, high definition color flow Doppler and pulsed-wave Doppler (tricuspid flow) ultrasound examinations of the fetal heart and from the ductus venosus assessment. A total of 399 fetal cardiac examinations were evaluated. There was a significant increase in TI values from B-mode studies (0.07 +/- 0.04 [mean +/- SD]) to color flow mapping (0.2 +/- 0.0) and pulsed-wave Doppler studies (0.36 +/- 0.05). The TI from ductus venosus assessment (0.1 +/- 0.01) was significantly lower than those from Doppler examinations of the heart. MI values from B-mode scans (0.65 +/- 0.12) and color flow mapping (0.71 +/- 0.11) were comparable, although different, and both values were higher than those from pulsed-wave Doppler tricuspid evaluation (0.39 +/- 0.03). There were no differences in MI values from power Doppler assessment between the tricuspid flow and ductus venosus. Safety indices were remarkably stable and were largely constant, especially for color Doppler (TI), tricuspid flow (MI) and ductus venosus assessment (TI, MI). We acquired satisfactory Doppler images and/or signals at acoustic levels that were lower than the actual recommendations and never reached a TI of 0.5. PMID- 25438840 TI - Diagnostic power of longitudinal strain at rest for the detection of obstructive coronary artery disease in patients with type 2 diabetes mellitus. AB - Global longitudinal strain (GLS) measured by 2-D speckle-tracking echocardiography (2-D STE) at rest has been recognized as a sensitive parameter in the detection of significant coronary artery disease (CAD). However, the diagnostic power of 2-D STE in the detection of significant CAD in patients with diabetes mellitus is unknown. Two-dimensional STE features were studied in total of 143 consecutive patients who underwent echocardiography and coronary angiography. Left ventricular global and segmental peak systolic longitudinal strains (PSLSs) were quantified by speckle-tracking imaging. In the presence of obstructive CAD (defined as stenosis >=75%), global PSLS was significantly lower in patients with diabetes mellitus than in patients without (16.65 +/- 2.29% vs. 17.32 +/- 2.27%, p < 0.05). Receiver operating characteristic analysis revealed that global PSLS could effectively detect obstructive CAD in patients without diabetes mellitus (cutoff value: -18.35%, sensitivity: 78.8%, specificity: 77.5%). However, global PSLS could detect obstructive CAD in diabetic patients at a lower cutoff value with inadequate sensitivity and specificity (cutoff value: 17.15%; sensitivity: 61.1%, specificity: 52.9%). In addition, the results for segmental PSLS were similar to those for global PSLS. In conclusion, global and segmental PSLSs at rest were significantly lower in patients with both obstructive CAD and diabetes mellitus than in patients with obstructive CAD only; thus, PSLSs at rest might not be a useful parameter in the detection of obstructive CAD in patients with diabetes mellitus. PMID- 25438841 TI - Ultrasound and microbubble-induced local delivery of MicroRNA-based therapeutics. AB - MicroRNAs are involved in many pathologic processes and are a promising target for therapeutic intervention. However, successful, localized delivery of microRNA based therapeutics is lacking. In this study, cationic ultrasound-responsive microbubbles (MBs) were used to deliver microRNA blockers and mimics in vitro and in vivo. Cationic MBs successfully delivered microRNA blockers to human endothelial cells on ultrasound (US) exposure in vitro. This in vitro US protocol did not successfully deliver microRNA mimics to skeletal muscle of mice, whereas an US protocol that is routinely used for contrast imaging did. Additionally, we used cationic MBs and US to locally deliver antimiR and antagomiR molecules with US causing inertial cavitation. Delivery of antimiR to the extracellular compartments of the muscle was only slightly increased, whereas delivery of antagomiR to the capillaries, myocytes and extracellular space was significantly increased. AntagomiR seems to be a more suitable microRNA blocker than antimiR for use in combination with MBs and US for local delivery. PMID- 25438842 TI - High-intensity focused ultrasound attenuates neural responses of sciatic nerves isolated from normal or neuropathic rats. AB - Patients with diabetic neuropathy often have neuropathic pain. The purpose of our work was to investigate the effects of high-intensity focused ultrasound (HIFU) on the conduction block of normal and neuropathic nerves for soothing pain. Adult male Sprague-Dawley rats were used, and diabetes was induced by streptozotocin injection. Diabetic neuropathy was evaluated with animal behavior tests. Sciatic nerves of both control and neuropathic rats were dissected from the starting point of the sciatic nerve to the point where the sural nerve ends near the ankle. The nerves were stored in Ringer's solution. The in vitro nerve was placed on a self-developed experimental platform for HIFU exposure. Stimulation and recording of the compound action potentials (CAPs) and sensory action potentials (SAPs) were performed. Control and neuropathic nerves exposed or not exposed to HIFU were submitted to histologic analysis. For the control and neuropathic nerves, suppression of CAPs and SAPs started 2 min post-HIFU treatment. Maximum suppression of SAPs was 34.4 +/- 3.2% for the control rats and 11.6 +/- 2.0% and 9.8 +/- 3.0% for rats 4 wk post-injection and 8 wk post-injection, respectively. Time to full recovery was 25, 70 and 80 min, respectively. Histologic analysis revealed that the nerves in which CAPs and SAPs did not fully recover were damaged thermally or mechanically by HIFU. It is feasible to reversibly block nerves with appropriate HIFU treatment. Diabetic nerves were less suppressed by HIFU and were more vulnerable to permanent damage. PMID- 25438843 TI - Echo-tracking technology assessment of carotid artery stiffness in patients with coronary slow flow. AB - Coronary slow flow (CSF) in coronary angiography (CAG) is a well-recognized clinical entity. Previous studies have suggested that microvascular abnormalities and endothelial dysfunction are responsible for CSF. Accordingly, we hypothesized that the CSF phenomenon is a form of atherosclerosis including both small vessels and epicardial coronary arteries. The echo-tracking (ET) technique is a non invasive detection method for early prediction of arterial atherosclerosis. Therefore, we investigated carotid elasticity with the ET technique in patients with CSF. Fifty patients with CSF and 50 patients with normal coronary artery blood flow, as determined by CAG, with a similar distribution of risk factors were recruited. The stiffness parameter (beta), pressure-strain elastic modulus (Ep), arterial compliance (AC), augmentation index (AIx) and local pulse-wave velocity (PWV) were determined at the level of the bilateral common carotid artery (CCA) with using the ET technique. Levels of serum high-sensitivity C reactive protein (hs-HSCRP) were determined for the two groups. beta, Ep and PWV were significantly higher in the CSF group than in the control group (beta: 11.4 +/- 3.76 vs. 9.22 +/- 3.28, p < 0.01; Ep: 153.44 +/- 47.85 vs. 126.40 +/- 43.32, p < 0.01; PWV: 7.26 +/- 1.10 vs. 6.55 +/- 1.02, p < 0.01), but AC was lower in the CSF group than in the control group (0.62 +/- 0.20 vs. 0.74 +/- 0.24, p < 0.01). The elasticity parameters of the bilateral common carotid artery did not significantly differ. The level of hs-HSCRP was correlated positively with beta (r = 0.306, p = 0.015), Ep (r = 0.358, p = 0.005) and PWV (r = 0.306, p = 0.015), but negatively with AC (r = -0.236, p = 0.049). In conclusion, the ET technique is a simple practical method for evaluating carotid artery elasticity, and there is a significant correlation between carotid artery stiffness and level of hs HSCRP in patients with CSF. PMID- 25438844 TI - Microbubble injection enhances inhibition of low-intensity pulsed ultrasound on debris-induced periprosthetic osteolysis in rabbit model. AB - We determined whether the addition of microbubbles enhances the effect of low intensity pulsed ultrasound (LIPUS) on bone-implant integration in an early-stage osteolysis model. The bone canals were injected with titanium particles before implantation to establish the periprosthetic osteolysis model. Before ultrasonic therapy, the microbubble-enhanced LIPUS group (GTi-Us-Mb) received an intra articular injection of microbubbles. Biomechanical testing revealed that GTi-Us Mb had significantly greater fixation strength than the LIPUS group (GTi-Us). Distal periprosthetic bone mineral density was also higher in GTi-Us than in the Ti group (GTi), but no significant increase was detected after administration of microbubbles. Histomorphometric analyses revealed that bone formation around the implant in GTi-Us was enhanced by the addition of microbubbles in GTi-Us-Mb. Taken together, our data indicate that microbubble injection enhances the inhibitory effect of LIPUS on debris-induced osteolysis and further strengthens the mechanical fixation of implants in an early-stage osteolysis model in vivo. PMID- 25438845 TI - A novel ultrasound methodology for estimating spine mineral density. AB - We investigated the possible clinical feasibility and accuracy of an innovative ultrasound (US) method for diagnosis of osteoporosis of the spine. A total of 342 female patients (aged 51-60 y) underwent spinal dual X-ray absorptiometry and abdominal echographic scanning of the lumbar spine. Recruited patients were subdivided into a reference database used for US spectral model construction and a study population for repeatability and accuracy evaluation. US images and radiofrequency signals were analyzed via a new fully automatic algorithm that performed a series of spectral and statistical analyses, providing a novel diagnostic parameter called the osteoporosis score (O.S.). If dual X-ray absorptiometry is assumed to be the gold standard reference, the accuracy of O.S. based diagnoses was 91.1%, with k = 0.859 (p < 0.0001). Significant correlations were also found between O.S.-estimated bone mineral densities and corresponding dual X-ray absorptiometry values, with r(2) values up to 0.73 and a root mean square error of 6.3%-9.3%. The results obtained suggest that the proposed method has the potential for future routine application in US-based diagnosis of osteoporosis. PMID- 25438846 TI - Shaken and stirred: mechanisms of ultrasound-enhanced thrombolysis. AB - The use of ultrasound and microbubbles as an effective adjuvant to thrombolytics has been reported in vitro, ex vivo and in vivo. However, the specific mechanisms underlying ultrasound-enhanced thrombolysis have yet to be elucidated. We present visual observations illustrating two mechanisms of ultrasound-enhanced thrombolysis: acoustic cavitation and radiation force. An in vitro flow model was developed to observe human whole blood clots exposed to human fresh-frozen plasma, recombinant tissue-type plasminogen activator (0, 0.32, 1.58 or 3.15 MUg/mL) and the ultrasound contrast agent Definity (2 MUL/mL). Intermittent, continuous-wave ultrasound (120 kHz, 0.44 MPa peak-to-peak pressure) was used to insonify the perfusate. Ultraharmonic emissions indicative of stable cavitation were monitored with a passive cavitation detector. The clot was observed with an inverted microscope, and images were recorded with a charge-coupled device camera. The images were post-processed to determine the time-dependent clot diameter and root-mean-square velocity of the clot position. Clot lysis occurred preferentially surrounding large, resonant-sized bubbles undergoing stable oscillations. Ultraharmonic emissions from stable cavitation were found to correlate with the lytic rate. Clots were observed to translate synchronously with the initiation and cessation of the ultrasound exposure. The root-mean square velocity of the clot correlated with the lytic rate. These data provide visual documentation of stable cavitation activity and radiation force during sub megahertz sonothrombolysis. The observations of this study suggest that the process of clot lysis is complex, and both stable cavitation and radiation force are mechanistically responsible for this beneficial bio-effect in this in vitro model. PMID- 25438847 TI - Diagnostic performance of axial-strain sonoelastography in confirming clinically diagnosed Achilles tendinopathy: comparison with B-mode ultrasound and color Doppler imaging. AB - This primary aim of this study was to evaluate the diagnostic performance of axial-strain sonoelastography (ASE), B-mode ultrasound (US) and color Doppler US in confirming clinically symptomatic Achilles tendinopathy. The secondary aim was to establish the relationship between the strain ratio during sonoelastography and Victorian Institute of Sport Assessment-Achilles (VISA-A) scores. The VISA-A questionnaire is a validated clinical rating scale that evaluates the symptoms and dysfunction of the Achilles tendon. One hundred twenty Achilles tendons of 120 consecutively registered patients with clinical symptoms of Achilles tendinopathy and another 120 gender- and age-matched, asymptomatic Achilles tendons of 120 healthy volunteers were assessed with B-mode US, ASE and color Doppler US. Symptomatic patients had significantly higher strain ratio scores and softer Achilles tendon properties compared with controls (p < 0.001). The strain ratio was moderately correlated with VISA-A scores (r = -0.62, p < 0.001). The diagnostic accuracy of B-mode US, ASE and color Doppler US in confirming clinically symptomatic Achilles tendinopathy was 94.7%, 97.8% and 82.5% respectively. There was excellent correlation between the clinical reference standard and the grade of tendon quality on ASE (kappa = 0.91, p < 0.05), compared with B-mode US (kappa = 0.74, p < 0.05) and color Doppler imaging (kappa = 0.49, p < 0.05). ASE is an accurate clinical tool in the evaluation of Achilles tendinopathy, with results comparable to those of B-mode US and excellent correlation with clinical findings. The strain ratio may offer promise as a supplementary tool for the objective evaluation of Achilles tendon properties. PMID- 25438848 TI - Effects of phonophoresis and gold nanoparticles in experimental model of muscle overuse: role of oxidative stress. AB - The aim of the study described here was to investigate the effects of pulsed ultrasound and gold nanoparticles (AuNPs) on behavioral, inflammatory and oxidative stress parameters in an experimental model of overuse. Wistar rats performed 21 d of exercise on a treadmill at different intensities and were exposed to ultrasound in the presence or absence of AuNPs. The overuse model promoted behavioral changes and increased creatine kinase, superoxide dismutase and glutathione peroxidase activity, as well as the levels of superoxide, nitrotyrosine, nitric oxide, thiobarbituric acid reactive substance, carbonyl, tumor necrosis factor alpha and interleukin-6. These values were significantly decreased by AuNPs and by AuNPs plus ultrasound. Catalase activity remained unchanged and the glutathione level increased significantly after exposure to AuNPs plus ultrasound. These results suggest a susceptibility to anxiety as well as elevated levels of oxidative stress. However, therapeutic interventions with AuNPs plus ultrasound reduced the production of oxidants and oxidative damage and improved the anti-oxidant defense system. PMID- 25438850 TI - 2-D left ventricular flow estimation by combining speckle tracking with Navier Stokes-based regularization: an in silico, in vitro and in vivo study. AB - Despite the availability of multiple ultrasound approaches to left ventricular (LV) flow characterization in two dimensions, this technique remains in its childhood and further developments seem warranted. This article describes a new methodology for tracking the 2-D LV flow field based on ultrasound data. Hereto, a standard speckle tracking algorithm was modified by using a dynamic kernel embedding Navier-Stokes-based regularization in an iterative manner. The performance of the proposed approach was first quantified in synthetic ultrasound data based on a computational fluid dynamics model of LV flow. Next, an experimental flow phantom setup mimicking the normal human heart was used for experimental validation by employing simultaneous optical particle image velocimetry as a standard reference technique. Finally, the applicability of the approach was tested in a clinical setting. On the basis of the simulated data, pointwise evaluation of the estimated velocity vectors correlated well (mean r = 0.84) with the computational fluid dynamics measurement. During the filling period of the left ventricle, the properties of the main vortex obtained from the proposed method were also measured, and their correlations with the reference measurement were also calculated (radius, r = 0.96; circulation, r = 0.85; weighted center, r = 0.81). In vitro results at 60 bpm during one cardiac cycle confirmed that the algorithm properly measures typical characteristics of the vortex (radius, r = 0.60; circulation, r = 0.81; weighted center, r = 0.92). Preliminary qualitative results on clinical data revealed physiologic flow fields. PMID- 25438849 TI - Loss of echogenicity and onset of cavitation from echogenic liposomes: pulse repetition frequency independence. AB - Echogenic liposomes (ELIP) are being developed for the early detection and treatment of atherosclerotic lesions. An 80% loss of echogenicity of ELIP has been found to be concomitant with the onset of stable and inertial cavitation. The ultrasound pressure amplitude at which this occurs is weakly dependent on pulse duration. It has been reported that the rapid fragmentation threshold of ELIP (based on changes in echogenicity) is dependent on the insonation pulse repetition frequency (PRF). The study described here evaluates the relationship between loss of echogenicity and cavitation emissions from ELIP insonified by duplex Doppler pulses at four PRFs (1.25, 2.5, 5 and 8.33 kHz). Loss of echogenicity was evaluated on B-mode images of ELIP. Cavitation emissions from ELIP were recorded passively on a focused single-element transducer and a linear array. Emissions recorded by the linear array were beamformed, and the spatial widths of stable and inertial cavitation emissions were compared with the calibrated azimuthal beamwidth of the Doppler pulse exceeding the stable and inertial cavitation thresholds. The inertial cavitation thresholds had a very weak dependence on PRF, and stable cavitation thresholds were independent of PRF. The spatial widths of the cavitation emissions recorded by the passive cavitation imaging system agreed with the calibrated Doppler beamwidths. The results also indicate that 64%-79% loss of echogenicity can be used to classify the presence or absence of cavitation emissions with greater than 80% accuracy. PMID- 25438851 TI - Diagnosis of thyroid nodules using virtual touch tissue quantification value and anteroposterior/transverse diameter ratio. AB - This paper proposes an effective approach to differential diagnosis of thyroid nodules using a hierarchical classification model based on the Virtual Touch tissue quantification (VTQ) value and anteroposterior/transverse diameter (A/T) ratio. One hundred twenty nodules (92 benign, 28 malignant) were analyzed using this approach by combining the quantitative elastic characteristic with the conventional sonographic feature. First, nodules were classified as benign (VTQ values <2.27 m/s), malignant (VTQ values >2.73 m/s) and indeterminate (2.27 m/s <= VTQ values <=2.73 m/s) using two cutoff points selected on the basis of receiver operating characteristic analysis. Second, the indeterminate nodules were separated into malignant and benign nodules using an A/T ratio >=1. The advantage of this approach was that it could alleviate the limitation of an overlap in VTQ values between benign and malignant nodules. According to the pathologic results, the accuracy of this approach was 95%. The proposed approach may potentially improve diagnostic accuracy. PMID- 25438852 TI - Evaluation of the development of the fetal anal sphincter with tomography ultrasonography imaging. AB - The aim of the study described here was to examine the potential of tomography ultrasonography imaging (TUI) in evaluation of the fetal anal sphincter. In this prospective cross-sectional study of the fetal anal sphincter with TUI, 326 singleton pregnancies (mean age = 28 y, range: 22-38 y) were scanned at 19-40 wk of gestation. The fetal anal region and ischium were revealed in 320 of 326 patients (98.2%). The normal fetal anal sphincter diameter and ischial space reached maximums of 15 and 39 mm, respectively. The normal fetal anal sphincter diameter and the ischial space were plotted as a function of gestational age (GA) on a linear curve, and the regression equations for normal fetal anal sphincter diameter and ischial space as a function of GA in weeks were obtained. A scatterplot was also created that revealed a significant positive relationship between normal fetal anal sphincter diameter and ischial space. On the basis of these criteria, imperforate anus was diagnosed in one fetus. Ultrasonographic assessment of the fetal anal sphincter and the ischium with TUI is feasible. The reference values reported in this article may be useful in prenatal diagnosis of fetal anal sphincter abnormalities. PMID- 25438853 TI - Progressive attenuation of the longitudinal kinetics in the common carotid artery: preliminary in vivo assessment. AB - Longitudinal kinetics (LOKI) of the arterial wall consists of the shearing motion of the intima-media complex over the adventitia layer in the direction parallel to the blood flow during the cardiac cycle. The aim of this study was to investigate the local variability of LOKI amplitude along the length of the vessel. By use of a previously validated motion-estimation framework, 35 in vivo longitudinal B-mode ultrasound cine loops of healthy common carotid arteries were analyzed. Results indicated that LOKI amplitude is progressively attenuated along the length of the artery, as it is larger in regions located on the proximal side of the image (i.e., toward the heart) and smaller in regions located on the distal side of the image (i.e., toward the head), with an average attenuation coefficient of -2.5 +/- 2.0%/mm. Reported for the first time in this study, this phenomenon is likely to be of great importance in improving understanding of atherosclerosis mechanisms, and has the potential to be a novel index of arterial stiffness. PMID- 25438854 TI - Therapeutic ultrasound suppresses neuropathic pain and upregulation of substance P and neurokinin-1 receptor in rats after peripheral nerve injury. AB - We studied the mechanisms and impact of therapeutic ultrasound (TU) for pain caused by nerve injury. TU began on post-operative day 5 (POD5) and then continued daily for the next 22 d. Sensitivity to thermal and mechanical stimuli and levels of neurokinin-1 receptor, substance P, tumor necrosis factor-alpha and interleukin-6 in the sciatic nerve were examined. On POD7, chronic constriction injury rats undergoing TU at an intensity of 1 W/cm(2), but not 0.25 or 0.5 W/cm(2), had increases in both the mechanical withdrawal threshold and the thermal withdrawal latency compared with the chronic constriction injury group. Moreover, chronic constriction injury rats exhibited upregulation of neurokinin-1 receptor, substance P, tumor necrosis factor-alpha and interleukin-6 in the sciatic nerve on PODs 14 and 28, whereas TU inhibited their increased expression. We suggest that the efficacy of TU is dependent on its ability to limit the upregulation of neurokinin-1 receptor, substance P, tumor necrosis factor-alpha and interleukin-6 around the injured sciatic nerve. PMID- 25438855 TI - Factors that influence kidney shear wave speed assessed by acoustic radiation force impulse elastography in patients without kidney pathology. AB - Our aim was to assess kidney shear wave speed by means of acoustic radiation force impulse (ARFI) elastography in patients without kidney pathology ("normal" patients) and to identify the factors that influence it. We analyzed 91 "normal" patients in whom kidney shear wave speed was assessed by means of ARFI elastography. Five valid ARFI elastographic measurements were obtained in all "normal" patients in both kidneys. In univariate analysis, age (r = -0.370, p = 0.003), gender (female vs. male, r = -0.305, p = 0.003) and measurement depth (r = -0.285, p = 0.01) were significantly correlated with kidney shear wave speed values assessed by ARFI elastography, whereas body mass index, kidney length and renal parenchyma thickness were not correlated. In multivariate analysis, only age (p = 0.006) and gender (p = 0.03) were significantly correlated with kidney shear wave speed values. In conclusion, kidney shear wave speed values assessed by ARFI elastography in "normal" patients are influenced mainly by age and gender and less by measurement depth. PMID- 25438856 TI - In vitro enamel thickness measurements with ultrasound. AB - In the work described here, agreement between ultrasound and histologic measurements of enamel thickness in vitro was investigated. Fifteen extracted human premolars were sectioned coronally to produce 30 sections. The enamel thickness of each specimen was measured with a 15-MHz hand-held ultrasound probe and verified with histology. The speed of sound in enamel was established. Bland Altman analysis, intra-class correlation coefficient and Wilcoxon sign rank test were used to assess agreement. The mean speed of sound in enamel was 6191 +/- 199 m s(-1). Bland-Altman limits of agreement were -0.16 to 0.18 mm when the speed of sound for each specimen was used, and -0.17 to 0.21 mm when the mean speed of sound was used. Intra-class correlation coefficient agreement was 0.97, and the Wilcoxon sign rank test yielded a p-value of 0.55. Using the speed of sound for each specimen results in more accurate measurement of enamel thickness. Ultrasound measurements were in good agreement with histology, which highlights its potential for monitoring the progressive loss of enamel thickness in erosive tooth surface loss. PMID- 25438857 TI - Pennation angle does not influence the age-related differences in echo intensity of the medial gastrocnemius. AB - The reflection of an ultrasound (US) wave is strongest when the propagation direction of the wave is perpendicular to muscle fascicles. Thus, it is possible that muscle echo intensity (EI), a gray-scale US measure of muscle quality, may be influenced by the angulation of muscle fascicles. Therefore, the purpose of this study was to determine if age-related differences in muscle EI values are influenced by differences in pennation angle (PA). Medial gastrocnemius EI and PA were examined using panoramic US imaging in 24 young (19.8 +/- 1.7 y) and 21 older (69.3 +/- 3.3 y) men. The young men had lower EI values (young = 74.1 +/- 6.3 a.u., older = 89.1 +/- 8.8 a.u.) and a greater PA (young = 20.0 +/- 2.9 degrees ; older = 17.2 +/- 2.5 degrees ) compared with the older men (p < 0.01). In addition, there was a negative relationship (r = -0.473, p < 0.01) between PA and EI with both groups combined, but no significant relationship when the young (r = -0.334, p = 0.111) and older (r = -0.147, p = 0.525) men were examined separately. An analysis of covariance revealed that muscle EI values remained different (p < 0.01) between age groups after adjustment for differences in PA. Thus, after statistically adjusting the mean EI values for the differences in PA, there were still significant age-related differences in EI. These findings may provide further support that the age-related changes in muscle EI values reflect changes in tissue composition (i.e., increase in intramuscular fat and/or connective tissue) commonly reported in older adults. PMID- 25438858 TI - Usefulness of real-time elastography strain ratio in the assessment of bile duct ligation-induced liver injury and the hepatoprotective effect of chitosan: an experimental animal study. AB - The purpose of the study described here was to evaluate the usefulness of the elastographic strain ratio in the assessment of liver changes in an experimental animal setting and the hepatoprotective effects of chitosan. Ultrasonography and Strain Ratio calculation were performed before and after bile duct ligation (BDL) in three groups of Wistar albino rats (n = 10 animals per group): (i) rats subjected to bile duct ligation only; (ii) rats subjected to bile duct ligation and administered chitosan for 14 d; (iii) rats subjected to bile duct ligation and administered chitosan for 7 d. The results were compared with the laboratory data and pathologic findings. Strain ratios revealed an increase in liver stiffness after bile duct ligation (p < 0.05), except in the group with chitosan administered for 7 d, and agreed with laboratory and pathology data. In conclusion, strain ratio can be used as an experimental research instrument in the assessment of liver response to injury. To the best of our knowledge, this is the first study reporting on the usefulness of the sonoelastographic liver-to kidney strain ratio in assessing the effects of experimentally induced liver lesions. PMID- 25438859 TI - Ultrasound diagnosis of carotid artery stiffness in patients with ischemic leukoaraiosis. AB - The pathophysiology of ischemic leukoaraiosis (ILA) is unknown. It was recently found that ILA patients have increased aortic stiffness. Carotid stiffness is a more specific parameter and could have value as a non-invasive diagnostic value for ILA. Therefore, using color-coded duplex sonography, we compared local carotid stiffness parameters of 59 patients with ILA with those of 45 well matched controls. The diagnosis of ILA was based on exclusion of other causes of white matter changes seen on magnetic resonance imaging. Pulse wave velocity beta (PWVbeta, m/s), pressure-strain elasticity modulus (Ep, kPa), beta index and augmentation index (Aix, %) values were higher and arterial compliance (AC, mm(2)/kPa) values were lower in the ILA group; however, only Ep and PWVbeta reached statistical significance (p <= 0.05). beta, Ep and PWVbeta exhibited an increasing trend with higher Fazekas score, though only Ep reached significance (p = 0.05). The main conclusion was that Ep and PWVbeta could have a diagnostic role in patients with ILA. PMID- 25438860 TI - Quantitative bone ultrasound at the distal radius in adults with cystic fibrosis. AB - It is of clinical importance to identify bone disease related to cystic fibrosis (CF) early in its course to allow therapeutic interventions that optimize bone health. To test the technical (precision) and clinical (percentage of abnormal results, correlation with clinical parameters) performance of a commercial quantitative ultrasound apparatus for radial measurements, speed of sound (SOS) was measured at the distal third of the left radius with the Omnisense 7000p apparatus (Sunlight Medical, Tel-Aviv, Israel) in a group of young adult CF patients with regular follow-up at the Brussels and Ghent University Hospital. Sixty-three (37 males) CF patients at a median (range) age of 23.5 y (18.1-39.9) were included. SOS, SOS z-score and SOS t-score were respectively 4017 +/- 97 m/s, -0.31 +/- 0.74 and -0.60 +/- 0.78 in males and 4086 +/- 97 m/s, -0.19 +/- 0.75 and -0.51 +/- 0.95 in females. Mean SOS t-score was significantly lower compared with the manufacturer's reference data for males (p < 0.0001) and females (p = 0.01). SOS z- and t-scores correlated with weight z-score and body mass index z-score in females. No significant correlation was found between SOS and forced expiratory volume in 1 s (%). Neither diabetes mellitus nor liver disease was found to influence SOS. Radial quantitative ultrasound has a precision of 0.55%. The SOS is in the low normal range in 14% of CF patients and is influenced by weight in female patients, but not by the severity of the lung disease. PMID- 25438861 TI - Differential diagnosis of gallbladder wall thickening: the usefulness of contrast enhanced ultrasound. AB - he purpose of this study was to evaluate the usefulness of contrast-enhanced ultrasound (CEUS) in the differential diagnosis of gallbladder wall (GBW) thickening and determine the predictors of malignant GBW thickening. One hundred fifty-nine patients with GBW thickening, including 76 men and 83 women, from eight institutions were enrolled. CEUS was performed after injection of a sulfur hexafluoride microbubble-based ultrasound contrast agent. Multiple logistic regression analysis was used to reveal independent predictor sassociated with malignant GBW thickening. The final diagnoses were 48 gallbladder carcinomas and 111 benign gallbladder diseases.Maximal thicknesses of the GBW in malignant and benign GB Wthickening were 17.3 +/- 5.2 (6 - 30) mm and 8.6 +/- 5.1 (4 - 26) mm respectively (p , 0.001). CEUS revealed significant differences in intralesional vessels, enhancement homogeneity, time to hypo-enhancement, inner layer discontinuity, outer layer discontinuity and adjacent liver involvement (all p values , 0.05) between malignant and benign GBW thickening. Patient age . 46.5 y, focal GBW thickening, inner layer discontinuity and outer layer discontinuity were found to be associated with malignancy by multiple logistic regression analysis (all p-values , 0.05). Receiver operating characteristic curve analysis revealed Az values for patient age, focal GBW thickening, inner wall discontinuity and outer wall discontinuity of 0.709 (95%confidence interval [CI]: 0.627-0.790), 0.714 (95% CI: 0.630-0.798), 0.860 (95%CI: 0.791 - 0.928) and 0.858 (95% CI: 0.783 - 0.933), respectively. CEUS is useful in the differential diagnosis between malignant and benign GBW thickening. Focal GBW thickening, inner wall discontinuity and outer wall discontinuity observed on CEUS are diagnostic clues for malignant GBW thickening. PMID- 25438863 TI - Real-time monitoring of high-intensity focused ultrasound thermal therapy using the manifold learning method. AB - High-intensity focused ultrasound (HIFU) induces thermal lesions by increasing the tissue temperature in a tight focal region. The main ultrasound imaging techniques currently used to monitor HIFU treatment are standard pulse-echo B mode ultrasound imaging, ultrasound temperature estimation and elastography-based methods. The present study was carried out on ex vivo animal tissue samples, in which backscattered radiofrequency (RF) signals were acquired in real time at time instances before, during and after HIFU treatment. The manifold learning algorithm, a non-linear dimensionality reduction method, was applied to RF signals whichconstruct B-mode images to detect the HIFU-induced changes among the image frames obtained during HIFU treatment. In this approach, the embedded non linear information in the region of interest of sequential images is represented in a 2-D manifold with the Isomap algorithm, and each image is depicted as a point on the reconstructed manifold. Four distinct regions are chosen in the manifold corresponding to the four phases of HIFU treatment (before HIFU treatment, during HIFU treatment, immediately after HIFU treatment and 10-min after HIFU treatment). It was found that disorganization of the points is achieved by increasing the acoustic power, and if the thermal lesion has been formed, the regions of points related to pre- and post-HIFU significantly differ. Moreover, the manifold embedding was repeated on 2-D moving windows in RF data envelopes related to pre- and post-HIFU exposure data frames. It was concluded that if mean values of the points related to pre- and post-exposure frames in the reconstructed manifold are estimated, and if the Euclidean distance between these two mean values is calculated and the sliding window is moved and this procedure is repeated for the whole image, a new image based on the Euclidean distance can be formed in which the HIFU thermal lesion is detectable. PMID- 25438862 TI - Preliminary in vivo breast vibro-acoustography results with a quasi-2-d array transducer: a step forward. AB - We previously investigated the application of a novel imaging modality, vibro acoustography (VA), using an annular confocal transducer (confocal VA) integrated into a clinical prone stereotactic mammography system, to detect various breast abnormalities. To shorten the scanning time and provide improved coverage of the breast, we have evolved our imaging system by implementing VA on a clinical ultrasound scanner equipped with a ''quasi-2-D'' array transducer. We call this technique ''quasi-2-D vibro-acoustography'' (Q2-DVA). A clinical ultrasound scanner (GE Vivid 7) was modified to perform both ultrasound imaging and VAusing an array transducer consisting of a matrix of 12 rows by 70 columns of ultrasound elements. The newly designed system was used to perform VA on patients with either benign or cancerous lesions. Our results indicate that benign and malignant solid breast lesions were easily detected using our newly modified VA system. It was also possible to detect microcalcifications within the breast. Our results suggest that with further development, Q2-DVA could provide high resolution diagnostic information in the clinical setting and may be used either as a stand-alone or as a complementary tool in support of other clinical imaging modalities. PMID- 25438864 TI - acoustic assessment of a konjac-carrageenan tissue-mimicking material aT 5-60 MHZ. AB - The acoustic properties of a robust tissue-mimicking material based on konjac carrageenan at ultrasound frequencies in the range 5-60 MHz are described. Acoustic properties were characterized using two methods: a broadband reflection substitution technique using a commercially available preclinical ultrasound scanner (Vevo 770, FUJIFILM VisualSonics, Toronto, ON, Canada), and a dedicated high-frequency ultrasound facility developed at the National Physical Laboratory (NPL, Teddington, UK), which employed a broadband through-transmission substitution technique. The mean speed of sound across the measured frequencies was found to be 1551.7 +/- 12.7 and 1547.7 +/- 3.3 m s21, respectively. The attenuation exhibited a non-linear dependence on frequency, f (MHz), in the form of a polynomial function: 0.009787f2 1 0.2671f and 0.01024f2 1 0.3639f, respectively. The characterization of this tissue-mimicking material will provide reference data for designing phantoms for preclinical systems, which may, in certain applications such as flow phantoms, require a physically more robust tissuemimicking material than is currently available. PMID- 25438865 TI - Plastid proteome prediction for diatoms and other algae with secondary plastids of the red lineage. AB - The plastids of ecologically and economically important algae from phyla such as stramenopiles, dinoflagellates and cryptophytes were acquired via a secondary endosymbiosis and are surrounded by three or four membranes. Nuclear-encoded plastid-localized proteins contain N-terminal bipartite targeting peptides with the conserved amino acid sequence motif 'ASAFAP'. Here we identify the plastid proteomes of two diatoms, Thalassiosira pseudonana and Phaeodactylum tricornutum, using a customized prediction tool (ASAFind) that identifies nuclear-encoded plastid proteins in algae with secondary plastids of the red lineage based on the output of SignalP and the identification of conserved 'ASAFAP' motifs and transit peptides. We tested ASAFind against a large reference dataset of diatom proteins with experimentally confirmed subcellular localization and found that the tool accurately identified plastid-localized proteins with both high sensitivity and high specificity. To identify nucleus-encoded plastid proteins of T. pseudonana and P. tricornutum we generated optimized sets of gene models for both whole genomes, to increase the percentage of full-length proteins compared with previous assembly model sets. ASAFind applied to these optimized sets revealed that about 8% of the proteins encoded in their nuclear genomes were predicted to be plastid localized and therefore represent the putative plastid proteomes of these algae. PMID- 25438866 TI - Light alcohol consumption plays a protective role against non-alcoholic fatty liver disease in Japanese men with metabolic syndrome. AB - BACKGROUND & AIMS: Although excess alcohol consumption has been believed to cause liver injury, light alcohol consumption (LAC) has been reported to play a protective role against fatty liver in recent studies. However, the association between non-alcoholic fatty liver disease (NAFLD) and LAC in men with metabolic syndrome (MS) is unclear. The aim of this study was to examine the association between NAFLD and LAC in men with MS. METHODS: Subjects were 1055 men with MS who underwent a regular health check-up and drank less 20 g/day of alcohol. A distinction was made between non-drinkers and light drinkers and the association between NAFLD and LAC in men with MS was elucidated. NAFLD was referred as fatty liver with alanine aminotransferase (ALT) levels ?31 IU/L in this study. RESULTS: Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and the prevalence of NAFLD were significantly lower in light drinkers than in non drinkers. Logistic regression analysis showed body mass index (BMI), waist circumference (WC), uric acid (UA), haemoglobin A1c (HbA1c), visceral fat type MS and LAC (odds ratios: 0.654; 95% confidence intervals: 0.473-0.906; <0.05) were significant predictors of the prevalence of NAFLD. CONCLUSION: The prevalence of NAFLD in light drinkers was significantly lower than in non-drinkers, and supporting previous reports studying the general population, LAC is one of the significant predictors of a decreased prevalence of NAFLD in men with MS. PMID- 25438870 TI - Giant hepatic hemangioma versus conventional hepatic hemangioma: clinical findings, risk factors, and management. AB - BACKGROUND: Giant hepatic hemangiomas (GHHs) are those that are larger than 4 cm in size. AIMS: The aim of this study was to describe GHH clinical findings, their risk factors, diagnostic approach and management, and to compare these data with those of conventional hemangiomas. METHODS: We performed a retrospective analysis of patients diagnosed with hemangiomas, whether by imaging studies or histopathology, at our hospital within the time frame of 1990-2008. The medical records of each patient were reviewed to obtain clinical and surgical data. RESULTS: Of the 57 patients with liver hemangioma, 41 (72%) were women and 32 (56%) had GHH. Liver hemangioma median size was 4.49 cm. In regard to the patients with GHH, 31.2% were asymptomatic and when symptoms presented, pain was the most common. Both symptoms and oral contraceptive exposure were more common in the GHH patients. Nine patients with GHH underwent surgery: 2 open biopsies due to diagnostic uncertainty, one enucleation, and 6 resections. CONCLUSIONS: GHHs are more prevalent in women and when symptomatic, pain is the most frequent complaint. Diagnosis is usually made through imaging studies, but when there is diagnostic doubt, surgical exploration is sometimes needed. Oral contraceptive use is most likely more of a risk factor for GHH than for conventional hemangioma, but this association needs to be studied further. PMID- 25438871 TI - Risk of the development of Type 2 diabetes in relation to overall obesity, abdominal obesity and the clustering of metabolic abnormalities in Japanese individuals: does metabolically healthy overweight really exist? The Niigata Wellness Study. AB - AIMS: We investigated the risk of developing diabetes across various metabolic phenotypes by considering the presence of overall adiposity or abdominal adiposity and the number of metabolic abnormalities and aimed to clarify whether a 'healthy overweight' phenotype, that is, overweight with no metabolic abnormalities, was protective of the development of diabetes. METHODS: We studied 29 564 Japanese individuals without diabetes. The 5-year incidence of diabetes was assessed according to a combination of either overweight (BMI >= 25.0 kg/m(2) ) or abdominal obesity (waist circumference >= 90 cm in men and >= 80 cm in women) and the number of metabolic factors present (hypertension, elevated triglyceride concentration, low HDL cholesterol concentration and impaired fasting glucose). RESULTS: A total of 1188 individuals developed diabetes. Compared with normal weight individuals with none of the four metabolic abnormalities, in overweight individuals with none of the four abnormalities there was an odds ratio (OR) of 2.32 [95% confidence interval (CI) 1.50, 3.59] for diabetes; having any one metabolic abnormality increased the risk of developing diabetes among normal weight individuals [OR 3.23 (2.55, 4.10)] and overweight individuals [OR 5.00 (3.77, 6.63)]. Among overweight individuals, the presence of impaired fasting glucose alone substantially elevated the risk of diabetes by 8.98-fold (5.52, 14.6) in comparison with the absence of the four metabolic factors. CONCLUSIONS: Being 'healthy overweight' was associated with a higher OR of developing future diabetes among Japanese individuals than normal weight individuals with no metabolic abnormalities, and being overweight with one or more abnormalities had a further elevated OR compared with 'healthy overweight' people. PMID- 25438872 TI - Identification of a novel large deletion in a patient with severe factor V deficiency using an in-house F5 MLPA assay. AB - Factor V (FV) deficiency is a rare autosomal recessive bleeding disorder caused by mutations in the F5 gene. FV-deficient patients in whom no mutation or only one mutation is found may harbour large gene rearrangements, which are not detected by conventional mutation screening strategies. The aim of this study was to develop and validate a multiplex ligation-dependent probe amplification (MLPA) assay for the detection of large deletions and duplications in the F5 gene. Twenty-two MLPA probes targeting 19 of the 25 exons and the upstream and downstream regions of the F5 gene were designed and tested in 10 normal controls, a patient with a known heterozygous deletion of F5 exons 1-7 (positive control) and 14 genetically unexplained FV-deficient patients. MLPA results were confirmed by digital PCR on a QuantStudio(TM) 3D Digital PCR System. The F5-specific probes yielded a reproducible peak profile in normal controls, correctly detected the known deletion in the positive control and suggested the presence of a novel deletion of exons 9-10 in a patient with undetectable FV levels and only one identified mutation. Follow-up by chip-based digital PCR, long-range PCR and direct sequencing confirmed that this patient carried a heterozygous F5 deletion of 1823 bp extending from intron 8 to intron 10. Bioinformatics sequence analysis pinpointed repetitive elements that might have originated the deletion. In conclusion, we have developed and validated an MLPA assay for the detection of gross F5 gene rearrangements. This assay may represent a valuable tool for the molecular diagnosis of FV deficiency. PMID- 25438873 TI - Radiology and imaging techniques in severe trauma. PMID- 25438874 TI - [Characteristics of deep sedation in gastrointestinal endoscopic procedures performed by intensivists]. AB - OBJECTIVE: To determine tolerance, pain intensity, percentage of tests completed successfully and complications of deep sedation controlled by intensivists during gastrointestinal endoscopic procedures. DESIGN: A one-year, prospective observational study was carried out. SETTING: Department of Intensive Care intervention in the Endoscopy Unit of Hospital Universitario del Tajo (Spain). PATIENTS: Subjects over 15 years of age subjected to endoscopic procedures under deep sedation. RESULTS: A total of 868 patients were sedated during the study period, with the conduction of 1010 endoscopic procedures. The degree of tolerance was considered adequate ("Very good"/"Good") in 96.9% of the patients (95%CI: 95.7-98.1%), with a median score of 0 on the pain visual analog scale. A total of 988 endoscopic procedures were successfully completed (97.8%; 95%CI: 96.9-98.8%): 675 colonoscopies (97.1%) and 305 endoscopies (99.7%). Complications were recorded in 106 patients (12.2%; 95%CI: 10.0-14.5%). The most frequent being desaturation (6.1%), rhythm disturbances (5.1%) and hypotension (2.4%). CONCLUSION: Gastrointestinal endoscopic procedures under sedation controlled by intensivists are well tolerated and satisfactory for the patient, and are successfully completed in a very large percentage of cases. The procedures are associated with frequent minor complications that are resolved successfully. PMID- 25438875 TI - [Role of propofol in verapamil intoxication]. PMID- 25438876 TI - [Digestive bleeding secondary to hemobilia due to cryptogenic arteriobiliary fistula]. PMID- 25438878 TI - Neurogenic differentiation of dental pulp stem cells to neuron-like cells in dopaminergic and motor neuronal inductive media. AB - BACKGROUND/PURPOSE: Dental pulp stem cells (DPSCs) have been proposed as a promising source of stem cells in nerve regeneration due to their close embryonic origin and ease of harvest. The aim of this study was to evaluate the efficacy of dopaminergic and motor neuronal inductive media on transdifferentiation of human DPSCs (hDPSCs) into neuron-like cells. METHODS: Isolation, cultivation, and identification of hDPSCs were performed with morphological analyses and flow cytometry. The proliferation potential of DPSCs was evaluated with an XTT [(2,3 bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide)] assay. Media for the induction of dopaminergic and spinal motor neuronal differentiation were prepared. The efficacy of neural induction was evaluated by detecting the expression of neuron cell-specific cell markers in DPSCs by immunocytochemistry and quantitative real-time reverse transcription polymerase chain reaction (RT PCR). RESULTS: In the XTT assay, there was a 2.6- or 2-fold decrease in DPSCs cultured in dopaminergic or motor neuronal inductive media, respectively. The proportions of betaIII-tubulin (betaIII-tub), glial fibrillary acidic protein (GFAP), and oligodendrocyte (O1)-positive cells were significantly higher in DPSCs cultured in both neuronal inductive media compared with those cultured in control media. Furthermore, hDPSC-derived dopaminergic and spinal motor neuron cells after induction expressed a higher density of neuron cell markers than those before induction. CONCLUSION: These findings suggest that in response to the neuronal inductive stimuli, a greater proportion of DPSCs stop proliferation and acquire a phenotype resembling mature neurons. Such neural crest-derived adult DPSCs may provide an alternative stem cell source for therapy-based treatments of neuronal disorders and injury. PMID- 25438877 TI - Money for medication: a randomized controlled study on the effectiveness of financial incentives to improve medication adherence in patients with psychotic disorders. AB - BACKGROUND: Non-adherence with antipsychotic medication is a frequently occurring problem, particularly among patients with psychotic disorders. Prior research has generally shown encouraging results for interventions based on 'Contingency Management' (CM), in which desirable behaviour is encouraged by providing rewards contingent upon the behaviour. However, little is known about the application of CM on medication adherence in patients with psychotic disorders. An earlier pilot study by our study group showed promising results in reducing admission days and increasing adherence. The current study is a randomized controlled trial concerning the effectiveness of a CM procedure called 'Money for Medication' (M4M), aimed at improving adherence with antipsychotic depot medication in psychotic disorder patients. METHODS/DESIGN: Outpatients (n =168) with a psychotic disorder will be randomly assigned to either the experimental group (n =84), receiving a financial reward for each accepted antipsychotic medication depot, or the control group (n =84), receiving treatment as usual without financial rewards. Patients are included regardless of their previous adherence. The intervention has a duration of twelve months. During the subsequent six months follow-up, the effects of discontinuing the intervention on depot acceptance will be assessed. The primary goal of this study is to assess the effectiveness of providing financial incentives for improving adherence with antipsychotic depot medication (during and after the intervention). The primary outcome measure is the percentage of accepted depots in comparison to prescription. Secondary, we will consider alternative measures of medication acceptance, i.e. the longest period of uninterrupted depot acceptance and the time expired before depot is taken. Additionally, the effectiveness of the experimental intervention will be assessed in terms of psychosocial functioning, substance use, medication side-effects, quality of life, motivation, cost-utility and patients' and clinicians' attitudes towards M4M. DISCUSSION: This RCT assesses the effectiveness and side-effects of financial incentives in improving adherence with antipsychotic depot medication in patients with psychotic disorders. This study is designed to assess whether M4M is an effective intervention to improve patients' acceptance of their antipsychotic depot medication and to examine how this intervention contributes to patients' functioning and wellbeing. TRIAL REGISTRATION: NTR2350 . PMID- 25438879 TI - Depolarizing GABA and developmental epilepsies. AB - Early in development, GABA, which is the main inhibitory neurotransmitter in adult brain, depolarizes immature neurons and exerts dual--excitatory and shunting/inhibitory--effects in the developing neuronal networks. The present review discusses some general questions, including the properties of excitation at depolarizing GABAergic synapse and shunting inhibition by depolarizing GABA; technical issues in exploration of depolarizing GABA using various techniques and preparations, including the developmental aspects of traumatic injury and what is known (or rather unknown) on the actions of GABA in vivo; complex roles of depolarizing GABA in developmental epilepsies, including a contribution of depolarizing GABA to enhanced excitability in the immature networks, caused by repetitive seizures accumulation of intracellular chloride concentration that increases excitatory GABA power and its synchronizing proconvulsive effects, and correction of chloride homeostasis as a potential strategy to treat neonatal seizures. PMID- 25438880 TI - Pre-synaptic localization of the gamma-secretase-inhibiting protein p24alpha2 in the mammalian brain. AB - Dysregulated metabolism and consequent extracellular accumulation of amyloid-beta (Abeta) peptides in the brain underlie the pathogenesis of Alzheimer's disease. Extracellular Abeta in the brain parenchyma is mainly secreted from the pre synaptic terminals of neuronal cells in a synaptic activity-dependent manner. The p24 family member p24alpha2 reportedly attenuates Abeta generation by inhibiting gamma-secretase processing of amyloid precursor protein; however, the pattern of expression and localization of p24alpha2 in the brain remains unknown. We performed immunohistochemical staining and subcellular fractionation for p24alpha2 in the mouse brain. Immunostaining showed that p24alpha2 is broadly distributed in the gray matter of the central nervous system and is predominantly localized to synapses. Subcellular fractionation revealed prominent localization of p24alpha2 in the pre-synaptic terminals. Immunoisolation of synaptic vesicles (SV) indicated that p24alpha2 is condensed at active zone-docked SV. During development, p24alpha2 expression is highest in the post-natal period and gradually decreases with age. We also confirmed that amyloid precursor protein and gamma-secretase components are localized at active zone-docked SV. Our results suggest a novel functional role for p24alpha2 in the regulation of synaptic transmission and synaptogenesis, and provide evidence for the participation of p24alpha2 in the regulation of Abeta generation and secretion in the brain. The p24 family member p24alpha2 attenuates amyloid-beta (Abeta) generation by inhibiting the gamma-secretase processing. We report that p24alpha2 is condensed at active zone-docked synaptic vesicles in the brain. p24alpha2 expression is highest in the post-natal period and gradually decreases with age. Our results suggest a novel function for p24alpha2 at the synapse, including the regulation of brain Abeta generation. PMID- 25438881 TI - Mandibular surgery: technologic and technical improvements. AB - The ability of surgeons to use advanced techniques can significantly improve both surgical outcome and patient satisfaction. Surgical evolution in mandibular orthognathic surgery is no exception, because advancements have aided both surgical planning and technique. It is important for clinicians to be aware of the historical progression of improvements in this technique and appreciate the technologic advancements as they are happening. Computer-driven surgical planning is becoming increasingly popular, providing surgeons and patients with the ability to adjust to intraoperative and postoperative variations. By using these capabilities, clinicians are now able to give patients the best possible outcomes. PMID- 25438882 TI - Management of cleft lip and palate and cleft orthognathic considerations. AB - Cleft lip and palate are among the most common congenital anomalies in humans. The treatment of this group of patients is best conducted by a multidisciplinary team approach. This article discusses the accepted treatment algorithm and timeline, as well as special considerations for this patient group when performing orthognathic surgery. Patients with cleft lip and palate often present with significantly more technical and challenging procedures, so clinicians should familiarize themselves with these special considerations before attempting to care for these individuals. PMID- 25438883 TI - Synthesis and antimycobacterial evaluation of 5-alkylamino-N-phenylpyrazine-2 carboxamides. AB - Substitution of chlorine in 5-chloro-N-phenylpyrazine-2-carboxamide (1) with simple n-alkylamines yielded a series of 5-alkylamino-N-phenylpyrazine-2 carboxamides (propylamino to octylamino derivatives), which possessed similar or increased activity against Mycobacterium tuberculosis H37Rv compared to parent 5 chloro derivative (1), with MIC ranging from 2.5 to 12.2 MUM. 5-Butylamino to 5 heptylamino derivatives exerted similar activity also against Mycobacterium kansasii. Importantly, the substitution led also to significant decrease of in vitro cytotoxicity in HepG2 cell line. 5-Heptylamino-N-phenylpyrazine-2 carboxamide (1e) exerted MIC=2.5 MUM (M.tbc) and IC50 >250 MUM (HepG2). Further modification of alkylamino chain with terminal methoxy or hydroxy group lead to compounds with decreased or none activity, the decrease was proportional to the decrease of lipophilicity. 5-(2-Phenylethylamino) and 5-(3-phenylpropylamino) derivatives were also of decreased activity. On contrary to alkylamino derivatives derived from 1, alkylamino derivatives derived from 5-chloro-N-2 chlorophenylpyrazine-2-carboxamide (2) possessed substantially decreased or none activity. None of the prepared compounds was active against Mycobacterium avium. PMID- 25438884 TI - A dual inhibitor of matrix metalloproteinases and a disintegrin and metalloproteinases, [18F]FB-ML5, as a molecular probe for non-invasive MMP/ADAM targeted imaging. AB - BACKGROUND: Numerous clinical studies have shown a correlation between increased matrix metalloproteinase (MMP)/a disintegrin and metalloproteinase (ADAM) activity and poor outcome of cancer. Various MMP inhibitors (MMPIs) have been developed for therapeutic purposes in oncology. In addition, molecular imaging of MMP/ADAM levels in vivo would allow the diagnosis of tumors. We selected the dual inhibitor of MMPs and ADAMs, ML5, which is a hydroxamate-based inhibitor with affinities for many MMPs and ADAMs. ML5 was radiolabelled with (18)F and the newly obtained radiolabelled inhibitor was evaluated in vitro and in vivo. MATERIALS AND METHODS: ML5 was radiolabelled by direct acylation with N succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB) for PET (positron emission tomography). The resulting radiotracer [(18)F]FB-ML5 was evaluated in vitro in human bronchial epithelium 16HBE cells and breast cancer MCF-7 cells. The non radioactive probe FB-ML5 and native ML5 were tested in a fluorogenic inhibition assay against MMP-2, -9, -12 and ADAM-17. The in vivo kinetics of [(18)F]FB-ML5 were examined in a HT1080 tumor-bearing mouse model. Specificity of probe binding was examined by co-injection of 0 or 2.5mg/kg ML5. RESULTS: ML5 and FB-ML5 showed high affinity for MMP-2, -9, -12 and ADAM-17; indeed IC50 values were respectively 7.4 +/- 2.0, 19.5 +/- 2.8, 2.0 +/- 0.2 and 5.7 +/- 2.2 nM and 12.5 +/- 3.1, 31.5 +/- 13.7, 138.0 +/- 10.9 and 24.7 +/- 2.8 nM. Radiochemical yield of HPLC-purified [(18)F]FB-ML5 was 13-16% (corrected for decay). Cellular binding of [(18)F]FB-ML5 was reduced by 36.6% and 27.5% in MCF-7 and 16 HBE cells, respectively, after co-incubation with 10 MUM of ML5. In microPET scans, HT1080 tumors exhibited a low and homogeneous uptake of the tracer. Tumors of mice injected with [(18)F]FB-ML5 showed a SUVmean of 0.145 +/- 0.064 (n=6) which decreased to 0.041 +/- 0.027 (n=6) after target blocking (p<0.05). Ex vivo biodistribution showed a rapid excretion through the kidneys and the liver. Metabolite assays indicated that the parent tracer represented 23.2 +/- 7.3% (n=2) of total radioactivity in plasma, at 90 min post injection (p.i.). CONCLUSION: The nanomolar affinity MMP/ADAM inhibitor ML5 was successfully labelled with (18)F. [(18)F]FB-ML5 demonstrated rather low binding in ADAM-17 overexpressing cell lines. [(18)F]FB-ML5 uptake showed significant reduction in the HT1080 tumor in vivo after co-injection of ML5. [(18)F]FB-ML5 may be suitable for the visualization/quantification of diseases overexpressing simultaneously MMPs and ADAMs. PMID- 25438886 TI - Back to basics: importance of nursing interventions in the elderly critical care patient. AB - The global population is aging, and with that comes new challenges. Optimal care must be delivered to minimize the time spent in the acute care setting. Avoiding costly complications and focusing on health promotion rather than disease management will be key. Geriatrics is a complex patient population and basic nursing care is essential to prevent unnecessary complications if our health care system is to survive. Our profession is ill prepared to optimally care for this patient population. PMID- 25438885 TI - Contributions of motoneuron hyperexcitability to clinical spasticity in hemispheric stroke survivors. AB - OBJECTIVE: Muscle spasticity is one of the major impairments that limits recovery in hemispheric stroke survivors. One potential contributing mechanism is hyperexcitability of motoneurons. Previously, the response latency of the surface electromyogram (EMG) record evoked by joint rotation has been used to characterize motoneuron excitability. Given the limitations of this method, the objective of the current study was to reexamine the excitability of motoneurons in chronic stroke survivors by estimating reflex latency using single motor unit discharge. METHODS: We quantified the excitability of spastic motoneurons using the response latency of a single motor unit discharge elicited by a position controlled tap on the biceps brachii tendon. We applied tendon taps of different amplitudes on the biceps tendons of both arms of the stroke survivors. Unitary reflex responses were recorded using intramuscular EMG recordings. RESULTS: Our results showed that the latency of unitary discharge was systematically shorter in the spastic muscle compared with the contralateral muscle, and this effect was consistent across multiple tap amplitudes. CONCLUSIONS: This method allowed us to quantify latencies more accurately, potentially enabling a more rigorous analysis of contributing mechanisms. SIGNIFICANCE: The findings provide evidence supporting a contribution of hyperexcitable motoneurons to muscle spasticity. PMID- 25438887 TI - Application of a Comprehensive Unit-based Safety Program in critical care: the royal exchange. AB - This article discusses the history of the Comprehensive Unit-based Safety Program (CUSP) and how it is used to foster a culture of safety. CUSP involves interdisciplinary teamwork and empowers nurses at all levels to pioneer changes and develop leadership skills. A case study is presented to show how CUSP was used effectively in critical care to create a standardized handover of patients from the operating room to the intensive care unit. PMID- 25438888 TI - Incidence and prevention of delirium in critical care patients. AB - Delirium in the intensive care unit is prevalent and a topic of high interest. Although it has been studied a great deal, screening, prevention, and management remain difficult. There are many causes of delirium and equally as many approaches to prevention and treatment. Two case studies sharing the challenges and successes of education, prevention, and treatment of delirium are presented in the context of complex adaptive systems. PMID- 25438889 TI - Stroke care using a hub and spoke model with telemedicine. AB - Stroke is the fourth leading cause of death in the United States. On average, someone has a stroke every 40 seconds. The gaps for patients diagnosed with a stroke are the availability of physicians who specialize in stroke care and access to evidence-based stroke care. Telemedicine has assisted in bridging this gap to provide effective stroke treatment. The purpose of this article is to describe how the implementation of a hub and spoke model using telemedicine has assisted in increasing patient access to neurology expertise and receiving evidence-based treatment of recombinant tissue plasminogen activator, thereby improving patient outcomes. PMID- 25438890 TI - Application of a robot for critical care rounding in small rural hospitals. AB - The purpose of this article is to present an option for a model of care that allows small rural hospitals to be able to provide specialty physicians for critical care patient needs in lieu of on-site critical care physician coverage. A real-time, 2-way audio and video remote presence robot is used to bring a specialist to the bedside to interact with patients. This article discusses improvements in quality and finance outcomes as well as care team and patient satisfaction associated with this model. Discussion also includes expansion of the care model to the emergency department for acute stroke care. PMID- 25438891 TI - Driving sepsis mortality down: emergency department and critical care partnerships. AB - This article describes the Baylor Health Care System (BHCS) approach to decreasing sepsis-related mortality within a large complex adaptive health care system. BHCS implemented sepsis care improvement initiatives based on the Surviving Sepsis Campaign early goal directed therapy guidelines. By adhering to rigorous process improvement and evidence-based practice principles, BHCS has demonstrated improvements in sepsis care processes and a significant reduction in sepsis mortality. PMID- 25438892 TI - Implications and interventions related to obstructive sleep apnea. AB - Surgical patients with known or unknown obstructive sleep apnea are at increased risk for postoperative complications. By implementing evidence-based practices and a validated screening tool, the postoperative surgical patients at the authors' hospital have a decreased risk of postoperative complications, specifically oversedation. This article discusses the pathophysiology, prevalence, risk factors, care of the postsurgical patient, and use of the validated STOP-Bang questionnaire with obstructive sleep apnea as the focus. PMID- 25438893 TI - Therapeutic hypothermia after cardiac arrest and return of spontaneous circulation: it's complicated. AB - Providing evidence-based care to patients with return of spontaneous circulation after a cardiac arrest is a recent complex innovation. Once resuscitated patients must be assessed for appropriateness for therapeutic hypothermia, be cooled in a timely manner, maintained while hypothermic, rewarmed within a specified time frame, and then assessed for whether hypothermia was successful for the patient through neuroprognostication. Nurses caring for therapeutic hypothermia patients must be knowledgeable and prepared to provide care to the patient and family. This article provides an overview of the complexity of therapeutic hypothermia for patients with return of spontaneous circulation in the form of a case study. PMID- 25438894 TI - Open access in the critical care environment. AB - Open access has become an important topic in critical care over the last 3 years. In the past, critical care had restricted access and set visitation guidelines to protect patients. This article provides a review of the literature related to open access in the critical care environment, including the impact on patients, families, and health care providers. The ultimate goal is to provide care centered on patients and families and to create a healing environment to ensure safe passage of patients through their hospital stays. This outcome could lead to increased patient/family satisfaction. PMID- 25438895 TI - Review of evidence about family presence during resuscitation. AB - Family presence during resuscitation (FPDR) has not been implemented consistently as standard practice across health care settings despite the availability of supporting research and recommendations from professional organizations. Health care providers, patients, families, and the public have divergent attitudes about FPDR. Inconsistencies in if, when, and how FPDR is offered can lead to inequities in care. This article presents relevant research on attitudes about FPDR and interventions to help change practice. The authors also share their experience with a project to implement FPDR in a medical intensive care unit. PMID- 25438896 TI - Palliative care in the intensive care unit. AB - Most patients who receive terminal care in the intensive care setting die after withdrawing or limiting of life-sustaining measures provided in the intensive care setting. The integration of palliative care into the intensive care unit (ICU) provides care, comfort, and planning for patients, families, and the medical staff to help decrease the emotional, spiritual, and psychological stress of a patient's death. Quality measures for palliative care in the ICU are discussed along with case studies to demonstrate how this integration is beneficial for a patient and family. Integrating palliative care into the ICU is also examined in regards to the complex adaptive system. PMID- 25438897 TI - Driving hospital-acquired pressure ulcers to zero. AB - The prevention of hospital-acquired pressure ulcers remains a top priority for health care facilities worldwide. This article discusses a process improvement in an intensive care unit where the unit-acquired pressure ulcer rate was dropped from 30% to 0% by front-line staff nurses. The key areas addressed by the staff were education, creating a process for turning patients during bedside report, and the creation of a documentation tool for accurate skin/wound assessment. Involving front-line staff in the prevention methodology creates a process that is quickly adopted by staff, peer-to-peer accountability in accurate skin/wound assessment, and positive outcomes. PMID- 25438898 TI - Fall prevention in high-risk patients. AB - In the oncology population, disease process and treatment factors place patients at risk for falls. Fall bundles provide a framework for developing comprehensive fall programs in oncology. Small sample size of interventional studies and focus on ambulatory and geriatric populations limit the applicability of results. Additional research is needed. PMID- 25438899 TI - Overview of extracorporeal membrane oxygenation in cardiogenic shock. AB - In recent years, the use of extracorporeal membrane oxygenators (ECMO) has proliferated in cardiovascular intensive care units (ICUs) partially due to advances in technology with the development of smaller, more portable machines, and the increasing numbers of patients with end-stage heart failure and cardiogenic shock. The use of ECMO has been found to improve survival rates in this deadly situation. Due to higher volumes of patients requiring ECMO, additional qualified resources for providing ECMO services may be necessary. The purpose of this article was to review cardiogenic shock etiologies, the role of ECMO, and to discuss the transition process of implementing a nurse-run ECMO program. PMID- 25438900 TI - Transitional care models: preventing readmissions for high-risk patient populations. AB - Transition from hospital to home is a vulnerable period for older adults with multiple chronic conditions. A pilot of the Transitional Care Model at a community hospital reduced readmission rates for patients with heart failure by 48%. This article shares the experience of a large metropolitan health care system in expanding transitional care across facilities to decrease readmission rates. PMID- 25438901 TI - The application of the acute care nurse practitioner role in a cardiovascular patient population. AB - This article presents an overview of the role of an acute care nurse practitioner (ACNP) in an acute care setting caring for patients with cardiovascular issues. Discussion includes the evolution of the ACNP role, the consensus model for advanced practice registered nurse regulation, and a case study highlighting the role of the ACNP while caring for a hemodynamically unstable patient. The case study articulates the ACNP's role as liaison between the patient, family members, collaborating physicians, and nurses. PMID- 25438902 TI - Quality. PMID- 25438904 TI - Impact of chronic total occlusion revascularization in patients with acute myocardial infarction treated by primary percutaneous coronary intervention. AB - Coronary chronic total occlusion (CTO) carries a poor outcome in patients with acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention (PCI). We sought to investigate the prognostic impact of a staged successful CTO-PCI in patients with AMI treated with primary PCI. Outcome analysis included consecutive patients treated by successful primary PCI with coexisting non-infarct-related artery CTO who survived after 1 week from AMI. A comparison between patients with successful CTO-PCI and patients with failed or nonattempted CTO-PCI was performed. The primary end points of the study were 1 year and 3-year cardiac survival. Of 1,911 patients who underwent successful primary PCI for AMI from 2003 to 2012, 169 (10%) had non-infarct-related artery CTO of a major branch. A staged CTO-PCI attempt was performed in 74 patients (44%) and was successful in 58 (success rate 78%). All patients with successful CTO-PCI received drug-eluting stents. In the successful CTO-PCI group, a complete coronary revascularization was achieved in 88% of the patients. The 1-year cardiac mortality rate was 1.7% in the successful CTO-PCI group and 12% in nonattempted or failed CTO-PCI group (p = 0.025). Successful CTO-PCI was an independent predictor of 3-year cardiac survival (hazard ratio 0.20, 95% confidence interval 0.05 to 0.92, p = 0.038). In conclusion, successful CTO-PCI in survivors after primary PCI is associated with improved long-term cardiac survival. PMID- 25438903 TI - Impact of acute and chronic hyperglycemia on in-hospital outcomes of patients with acute myocardial infarction. AB - This study was undertaken to assess the impact of acute hyperglycemia (acute-HG) and chronic hyperglycemia (chronic-HG) on short-term outcomes in patients with acute myocardial infarction (AMI). This study consisted of 696 patients with AMI. Acute-HG was defined as admission plasma glucose >=200 mg/dl and chronic-HG as hemoglobin A1c >=6.5%. Acute-HG was associated with higher peak serum creatine kinase (4,094 +/- 4,594 vs 2,526 +/- 2,227 IU/L, p <0.001) and in-hospital mortality (9.8% vs 1.6%, p <0.001). On the contrary, there was no significant difference in peak creatine kinase (2,803 +/- 2,661 vs 2,940 +/- 3,181 IU/L, p = 0.59) and mortality (3.3 vs 3.7%, p = 0.79) between patients with chronic-HG and those without. Multivariate analysis showed that admission plasma glucose was an independent predictor of in-hospital mortality (odds ratio 1.15, 95% confidence interval 1.05 to 1.27, p <0.001), but hemoglobin A1c was not. When only patients with acute-HG were analyzed, chronic-HG was associated with a significantly smaller infarct size (3,221 +/- 3,001 vs 5,904 +/- 6,473 IU/L, p <0.001) and lower in-hospital mortality (5.5 vs 18.9%, p = 0.01). In conclusion, these results suggested that acute-HG, but not chronic-HG, was associated with adverse short-term outcomes after AMI. Paradoxically, in patients with acute-HG, chronic HG might abate the adverse effects of acute-HG. PMID- 25438905 TI - Impact of non-chest pain complaint as a presenting symptom on door-to-balloon time and clinical outcomes in patients with acute ST-elevation myocardial infarction. AB - Many patients with ST-elevation myocardial infarctions (STEMIs) have non-chest pain complaints and are given low priority during triage. This prospective, multicenter, observational, registry-based study investigated the impact of non chest pain complaints on door-to-balloon (DTB) time and clinical outcomes. Patients with STEMI who had undergone primary percutaneous coronary intervention were compared with respect to the presence of chest pain or non-chest pain complaints as presenting symptoms. To eliminate biased estimates, a propensity score model was built, and 2 cohorts of 1:1 matched patients were obtained. Propensity matching identified 2 cohorts of 976 patients each. After comparing patients with chest pain and those with non-chest pain complaints, significant delays in the median DTB time were noted (74 vs 84 minutes, respectively; p <0.001). Non-chest pain complaints were independent predictors of DTB time in the multivariate linear regression models. In-hospital mortality (adjusted hazard ratio [HR] 1.402, 95% confidence interval [CI] 0.727 to 2.705, p = 0.313), all cause mortality (adjusted HR 1.175, 95% CI 0.453 to 3.853, p = 0.642), and major adverse cardiac events at follow-up (adjusted HR 0.139, 95% CI 0.876 to 1.48, p = 0.331) did not differ between the 2 groups of patients. In conclusion, short- and long-term clinical outcomes in patients with STEMI with non-chest pain complaints do not differ from those of patients with chest pain as the presenting symptom, despite having delayed diagnosis and reperfusion. PMID- 25438906 TI - Impact of health care system delay in patients with ST-elevation myocardial infarction on return to labor market and work retirement. AB - System delay (delay from emergency medical service call to reperfusion with primary percutaneous coronary intervention [PPCI]) is acknowledged as a performance measure in ST-elevation myocardial infarction (STEMI), as shorter system delay is associated with lower mortality. It is unknown whether system delay also impacts ability to stay in the labor market. Therefore, the aim of the study was to evaluate whether system delay is associated with duration of absence from work or time to retirement from work among patients with STEMI treated with PPCI. We conducted a population-based cohort study including patients <=67 years of age who were admitted with STEMI from January 1, 1999, to December 1, 2011 and treated with PPCI. Data were derived from Danish population-based registries. Only patients who were full- or part-time employed before their STEMI admission were included. Association between system delay and time to return to the labor market was analyzed using a competing-risk regression analysis. Association between system delay and time to retirement from work was analyzed using a Cox regression model. A total of 4,061 patients were included. Ninety-three percent returned to the labor market during 4 years of follow-up, and 41% retired during 8 years of follow-up. After adjustment, system delay >120 minutes was associated with reduced resumption of work (subhazard ratio 0.86, 95% confidence interval 0.81 to 0.92) and earlier retirement from work (hazard ratio 1.21, 95% confidence interval 1.08 to 1.36). In conclusion, system delay was associated with reduced work resumption and earlier retirement. This highlights the value of system delay as a performance measure in treating patients with STEMI. PMID- 25438907 TI - Current trend of acute myocardial infarction in Korea (from the Korea Acute Myocardial Infarction Registry from 2006 to 2013). AB - Although the incidence of acute myocardial infarction (AMI) in Korea has been rapidly changed because of westernization of diet, lifestyle, and aging of the population, the recent trend of the myocardial infarction have not been reported by classification. We investigated recent trends in the incidence and mortality associated with the 2 major types of AMI. We reviewed 39,978 patients registered in the Korea Acute Myocardial Infarction Registry for either ST-segment elevation acute myocardial infarction (STEMI) or non-ST-segment elevation acute myocardial infarction (NSTEMI) from 2006 to 2013. When the rate for AMI were investigated according to each year, the incidence rates of STEMI decreased markedly from 60.5% in 2006 to 48.1% in 2013 (p <0.001). In contrast, a gradual increase in the incidence rates of NSTEMI was observed from 39.5% in 2006 to 51.9% in 2013 (p <0.001). As risk factors, hypertension, diabetes mellitus, and dyslipidemia were much more common in patients with NSTEMI than STEMI. Among medical treatments, the use of beta blockers, angiotensin receptor blocker, and statin were increased from 2006 to 2013 in patients with STEMI and NSTEMI. Patients with STEMI and NSTEMI were more inclined to be increasingly treated by invasive treatments with percutaneous coronary intervention. In conclusion, this study demonstrated that the trend of myocardial infarction has been changed rapidly in the aspect of risk factors, ratio of STEMI versus NSTEMI, and therapeutic strategies during the recent 8 years in Korea. PMID- 25438908 TI - Effect of anemia on frequency of short- and long-term clinical events in acute coronary syndromes (from the Acute Catheterization and Urgent Intervention Triage Strategy Trial). AB - There are limited data on the impact of anemia on clinical outcomes in unstable angina and non-ST-segment elevation myocardial infarction treated with an early invasive strategy. We sought to determine the short- and long-term clinical events among patients with and without anemia enrolled in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. Anemia was defined as baseline hemoglobin of <13 g/dl for men and <12 g/dl for women. The primary end points were composite ischemia (death, myocardial infarction, or unplanned revascularization for ischemia) and major bleeding assessed in hospital, at 1 month, and at 1 year. Among the 13,819 patients in the ACUITY trial, information regarding anemia was available in 13,032 (94.3%), 2,199 of whom (16.9%) had anemia. Patients with anemia compared with those without anemia had significantly increased adverse event rates in-hospital (composite ischemia 6.6% vs 4.8%, p = 0.0004; major bleeding 7.3% vs 3.3%, p <0.0001), at 1 month (composite ischemia 10% vs 7.2%, p <0.0001, major bleeding 8.8% vs 3.9%, p <0.0001), and 1 year (composite ischemia 21.7% vs 15.3%, p <0.0001). Anemia was an independent predictor of death at 1 year (hazard ratio 1.77, 95% confidence interval [CI] 1.29 to 2.44, p = 0.0005). Composite ischemia was significantly more common among patients who developed in-hospital non-coronary artery bypass surgery major bleeding compared with those who did not (anemic patients 1-year relative risk 2.19, 95% CI 1.67 to 2.88, p <0.0001; nonanemic patients relative risk 2.16, 95% CI 1.76 to 2.65, p <0.0001). In conclusion, in the ACUITY trial, baseline anemia was strongly associated with adverse early and late clinical events, especially in those who developed major bleeding. PMID- 25438909 TI - Predictors of outcomes of contrast-induced acute kidney injury after percutaneous coronary intervention in patients with chronic kidney disease. AB - Contrast-induced acute kidney injury (CI-AKI) is a serious complication that is difficult to predict in patients with chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI). The aim of this study was to investigate predictors and clinical outcomes of CI-AKI in patients with CKD after PCI. A total of 297 patients with CKD who underwent PCI from September 2006 to December 2011 were enrolled. CI-AKI was defined as serum creatinine level either >=25% or >=0.5 mg/dl from baseline within 72 hours after PCI. The primary outcome was all-cause death. The median follow-up duration was 26 months (interquartile range 12 to 40), and CI-AKI occurred in 55 patients (19%). In multivariate logistic regression analyses, the development of CI-AKI was associated with female gender, left ventricular systolic dysfunction, acute myocardial infarction, PCI for left main disease, serum hemoglobin level, and a contrast volume to creatinine clearance ratio >6.0. The development of CI-AKI was significantly associated with increased in-hospital mortality (18.2% vs 3.7%, p = 0.001). Cox proportional-hazard analysis showed that the incidence of all-cause death was significantly higher in patients who developed CI-AKI than in those without CI-AKI (41.8% vs 16.1%, adjusted hazard ratio 3.0, 95% confidence interval 1.6 to 5.6, p <0.001). In conclusion, female gender, left ventricular systolic dysfunction, acute myocardial infarction, PCI for left main disease, serum hemoglobin level, and contrast volume to creatinine clearance ratio >6.0 are independent predictors of CI-AKI. The development of CI-AKI is significantly associated with increased in-hospital and long-term adverse clinical outcomes in patients with CKD undergoing PCI. PMID- 25438910 TI - Impact of hepatitis C seropositivity on the risk of coronary heart disease events. AB - Chronic infections have been shown to enhance atherogenicity. However, the association between chronic hepatitis C (HCV) and coronary heart disease (CHD) remains controversial. We examined the risk for CHD events in patients with HCV with an emphasis on the risk of CHD events with active infection. We conducted a retrospective cohort study using the enterprise data warehouse at the University of Arkansas for Medical Sciences. HCV positive and negative patients were identified based on serology, and incident CHD events were studied. Patient characteristics at entry were compared either by the analysis of variance or F test (continuous variables) or by a chi-square test (categorical variables). The joint effect of risk factors for incident CHD was evaluated using logistic regression. A total of 8,251 HCV antibody positive, 1,434 HCV RNA positive, and 14,799 HCV negative patients were identified. Patients with HCV antibody and RNA positivity had a higher incidence of hypertension, diabetes mellitus, obesity, and chronic lung disease, but lower serum cholesterol levels compared with patients who were HCV negative (p <0.001). HCV seropositive patients had a higher incidence of CHD events compared with controls (4.9% vs 3.2%, p <0.001). In the HCV cohort, patients with detectable HCV RNA had a significantly higher incidence of CHD events compared with patients who were only HCV antibody positive with no detectable RNA (5.9% vs 4.7%, p = 0.04). In multivariate logistic regression analyses, both HCV antibody positivity (odds ratio 1.32, 95% confidence interval 1.09 to 1.60, p <0.001) and HCV RNA positivity (odds ratio 1.59, 95% confidence interval 1.13 to 2.26, p <0.001) were independent risk factors for incident CHD events. In conclusion, there is an increased incidence of CHD events in patients with HCV seropositivity and the incidence is much higher in patients with detectable HCV RNA compared with patients with remote infection who are only antibody positive. Lipid profile does not appear to be a good cardiovascular risk stratification tool in patients with HVC. PMID- 25438911 TI - Cardiorespiratory responses to table tennis in low-fit coronary patients and implications for exercise training. AB - Racquet sports may evoke excessive aerobic and/or cardiac demands for many coronary patients with impaired cardiorespiratory fitness. We evaluated the cardiorespiratory and hemodynamic responses to table tennis in clinically stable patients with coronary disease. Low-risk cardiac men (n = 10, mean +/- SD, age = 67.6 +/- 8.8 years) satisfying inclusion criteria (functional capacity <=8 metabolic equivalents [METs] without evidence of impaired left ventricular function, significant dysrhythmias, signs and/or symptoms of myocardial ischemia, or orthopedic limitations), completed the study. Patients were monitored for heart rate (HR), blood pressure, rating of perceived exertion (6 to 20 scale), and electrocardiographic responses during a 10-minute bout of recreational table tennis. Metabolic data were directly obtained using breath-by-breath measurements of oxygen consumption. Treadmill testing in our subjects revealed an average estimated exercise capacity of 6.8 +/- 1.4 METs. Aerobic requirements of table tennis averaged 3.2 +/- 0.5 METs; however, there was considerable variation in the oxygen consumption response to play (2.0 to 5.0 METs). Peak HR and systolic blood pressure responses during table tennis were 98.0 +/- 8.5 beats/min and 140.4 +/- 16.2 mm Hg, respectively. The average HR during table tennis represented 83% of the highest HR attained during treadmill testing. Rating of perceived exertion during table tennis averaged 10.6 +/- 1.7, signifying "fairly light" exertion. In conclusion, table tennis represents a relatively safe and potentially beneficial leisure-time activity for cardiac patients with impaired levels of cardiorespiratory fitness. The average aerobic requirement of table tennis approximated prescribed exercise training workloads for most of our patients. PMID- 25438912 TI - Outcomes of patients with anemia and acute decompensated heart failure with preserved versus reduced ejection fraction (from the ARIC study community surveillance). AB - Anemia is associated with poor prognosis in patients hospitalized with acute decompensated heart failure (ADHF). Whether the impact of anemia differs by heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF) is uncertain. We examined hospital surveillance data captured by the Atherosclerosis Risk in Communities Study from January 1, 2005, to December 31, 2010. Diagnoses of ADHF were validated by standardized physician review of the medical record. Anemia was classified using the World Health Organization criteria (<12 g/dl for women and <13 g/dl for men), and HF type was determined by the ejection fraction (<40% for HFrEF and >=40% for HFpEF). Hospital length of stay and 1-year mortality outcomes were analyzed by multivariable regression, weighted to account for the sampling design, and adjusted for demographics and clinical covariates. Over 6 years, 15,461 (weighted) hospitalized events for ADHF (59% HFrEF) occurred in the catchment of the Atherosclerosis Risk in Communities, based on 3,309 sampled events. Anemia was associated with a mortality hazard ratio of 2.1 (95% confidence interval [CI] 1.6 to 2.7) in patients classified with HFpEF and 1.4 (95% CI 1.1 to 1.7) in those with HFrEF; p for interaction = 0.05. The mean increase in length of hospital stay associated with anemia was 3.5 days (95% CI 3.4 to 3.6) for patients with HFpEF, compared with 1.8 days (95% CI 1.7 to 1.9) for those with HFrEF; p for interaction <0.0001. In conclusion, the incremental risks of death and lengthened hospital stay associated with anemia are more pronounced in ADHF patients classified with HFpEF than HFrEF. PMID- 25438913 TI - Comparison of age (<75 Years versus >=75 Years) to risk of ventricular tachyarrhythmias and implantable cardioverter defibrillator shocks (from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). AB - There are limited data regarding the effect of age on the risk of ventricular tachyarrhythmias (VTAs). The present study was designed to compare the risk for VTAs in young and older patients with left bundle branch block (LBBB) and mildly symptomatic heart failure who receive device therapy. The risk of the first ventricular tachycardia (VT) or ventricular fibrillation (VF) event and the risk of first appropriate implantable cardioverter defibrillator (ICD) shock was compared between young (<75 years, n = 1,037) and older (>=75 years, n = 227) patients with LBBB enrolled in Multicenter Automatic Implantation Trial with Cardiac Resynchronization Therapy. The cumulative incidence of a first VTA through 2 years of follow-up was significantly lower in older patients than in younger patients. Multivariate analysis showed that older patients experienced a significantly lower risk of VT/VF (hazard ratio 0.38, 95% confidence interval 0.22 to 0.64, p <0.001) and a significantly lower risk of appropriate ICD shocks (hazard ratio 0.37, 95% confidence interval 0.17 to 0.82, p = 0.014) compared with younger patients. Each increasing decade of life was associated with a 19% (p = 0.002) and 22% (p = 0.018) reduction in the risk of VT/VF and appropriate ICD shocks, respectively. The lower risk of VT/VF and appropriate ICD shocks in older patients was evident in patients implanted with an ICD only and in those implanted with a cardiac resynchronization therapy with defibrillator. In conclusion, in patients with LBBB and mild symptoms of heart failure, aging is associated with a significant decrease in the incidence of VT/VF and ICD shocks. PMID- 25438914 TI - Atrial fibrillation, stroke, and mortality rates after transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation (TAVI) is considered a suitable treatment for patients with severe symptomatic aortic stenosis and high operative risk. Our aim was to evaluate the effect of preprocedural and new-onset atrial fibrillation (NOAF) on mortality and stroke in patients who underwent TAVI. We performed a single-center study of 380 consecutive patients enrolled to a TAVI registry. NOAF was defined as postprocedural atrial fibrillation (AF) occurring within 30 days after the procedure. Patients were followed up for a mean of 528 +/- 364 days. During follow-up, 19 (5%) new episodes of stroke occurred, of whom 6 and 18 cases occurred within 30 days and 1 year, respectively. Overall mortality during the follow-up was 68 (20%), of those 12 and 58 patients died within 30 days and 1 year, respectively. NOAF occurred in 31 (8.2%) patients and was not associated with higher stroke or mortality rates at 30 days or 1 year of follow-up. Notably, compared with patients without previous AF, patients with previous AF at baseline had increased rates of stroke and mortality at 1-year follow-up (2.1% vs 9.6%, p = 0.01, and 8.2% vs 34.9%, p <0.01; respectively). In multivariate analysis, AF at baseline but not NOAF was a significant predictor of mortality throughout the follow-up period (HR 2.2, 95% confidence interval 1.3 to 3.8, p = 0.003, and HR 1.5, 95% confidence interval 0.5 to 4.1, p = 0.390, respectively). In conclusion, previous AF at baseline but not NOAF significantly increases stroke and mortality rates after TAVI. The inclusion of AF into future TAVI risk stratification scores should be strongly considered. PMID- 25438915 TI - Usefulness and validation of the survival posT TAVI score for survival after transcatheter aortic valve implantation for aortic stenosis. AB - Surgical risk scores fail to accurately predict mortality after transcatheter aortic valve implantation (TAVI). The aim of this study was to develop and validate a dedicated risk score for accurate estimation of mortality risk in these patients. All consecutive patients who underwent TAVI at 6 international institutions were enrolled. Predictors for 1-year all-cause mortality were identified by means of Cox multivariate analysis and incorporated in a prediction score. Accuracy of the score was derived and externally validated for 30-day and 1-year mortality. The net classification improvement compared with the Society of Thoracic Surgeons (STS) score was appraised. A total of 1,064 patients constituted the derivation cohort and 180 patients constituted the external validation cohort. A total of 165 patients (15%) died at 1-year follow-up. Previous stroke (odds ratio [OR] 1.80, 1.4 to 3), inverse of renal clearance (OR 8, 6 to 14), and systolic pulmonary arterial pressure >=50 mm Hg (OR 2.10, 1.5 to 3) were independently related to 1-year mortality. Area under the curve (AUC) of the survival post TAVI (STT) for 1-year mortality was 0.68 (0.62 to 0.71). At 30 days, 65 patients (7%) had died and the AUC for the STT at this time point was 0.66 (0.64 to 0.75). In the external validation cohorts, the AUC of the STT were 0.66 (0.56 to 0.7) for 30-day and 0.67 (0.62 to 0.71) for 1-year mortality. Net reclassification improvement for STT compared with STS was 31% (p <0.001) for 30 day mortality and 14% (p <0.001) for 1-year mortality. In conclusion, the STT score represents an easy and accurate tool to assess the risk of short-term and mid-term mortality in patients undergoing TAVI. PMID- 25438916 TI - Impact of flow and left ventricular strain on outcome of patients with preserved left ventricular ejection fraction and low gradient severe aortic stenosis undergoing aortic valve replacement. AB - The prognostic implications of flow, assessed by stroke volume index (SVi), and left ventricular (LV) global longitudinal strain on survival of patients with low gradient severe aortic stenosis (AS) and preserved LV ejection fraction are debated. The aim of this study was to evaluate the impact of flow and LV global longitudinal strain on survival in these patients treated with aortic valve replacement (AVR). Patients with low-gradient severe AS with preserved LV ejection fraction treated with AVR (n = 134, mean age 76 +/- 10 years, 50% men) were included in the present study. Aortic valve hemodynamics and LV function were assessed with 2-dimensional, Doppler and speckle-tracking echocardiography before AVR. Patients were dichotomized on the basis of low (SVi <=35 ml/m(2)) or normal (SVi >35 ml/m(2)) flow and impaired (>-15%) or more preserved (<=-15%) global longitudinal strain. The end point was all-cause mortality. During a median follow-up period of 1.8 years (interquartile range 0.5 to 3) after AVR, 26 patients (19.4%) died. Survival was better for patients with SVi >35 ml/m(2) or global longitudinal strain <=-15% compared with those with SVi <=35 ml/m(2) or global longitudinal strain >-15% (log-rank p = 0.01). Atrial fibrillation (hazard ratio 5.40, 95% confidence interval 1.81 to 16.07, p = 0.002) and chronic kidney disease (hazard ratio 3.67, 95% confidence interval 1.49 to 9.06, p = 0.005) were the clinical variables independently associated with all-cause mortality. The addition of global longitudinal strain (chi-square = 19.87, p = 0.029, C statistic = 0.74) or SVi (chi-square = 29.62, p <0.001, C-statistic = 0.80) to a baseline model including atrial fibrillation and chronic kidney disease (chi square = 14.52, C-statistic = 0.68) improved risk stratification of these patients. In conclusion, flow and LV global longitudinal strain are independently associated with survival after AVR in patients with low-gradient severe AS with preserved LV ejection fraction. PMID- 25438917 TI - A meta-analysis of mortality and major adverse cardiovascular and cerebrovascular events in patients undergoing transfemoral versus transapical transcatheter aortic valve implantation using edwards valve for severe aortic stenosis. AB - The purpose of this meta-analysis was to compare 1 year mortality and major adverse cardiovascular and cerebrovascular events between transfemoral (TF) transcatheter aortic valve implantation (TAVI) and transapical (TA) TAVI performed using Edwards valves. PubMed, Embase, and the Cochrane Center Register of Controlled Trials were searched for studies published from January 2000 through March 2014. Seventeen studies met the inclusion criteria and were included in the analysis. This meta-analysis included total of 2,978 patients with severe aortic stenosis not eligible for traditional surgical procedures who underwent TF TAVI (n = 1,465) or TA TAVI (n = 1,513). End points were in hospital, 30-day, and 1-year all-cause mortality, stroke, myocardial infarction, major bleeding, and major vascular complications. Odds ratios (ORs) with 95% confidence interval (CIs) were computed, and p values <0.05 were considered to indicate statistical significance. The studies were homogenous for all outcomes except 1-year mortality. There was no significant difference between the TF and TA TAVI groups for 1-year mortality (OR 0.64, 95% CI 0.34 to 1.2, p = 0.16), incidence of stroke (OR 1.14, 95% CI 0.76 to 1.71, p = 0.52), incidence of myocardial infarction (OR 0.62, 95% CI 0.23 to 1.7, p = 0.35), and incidence of bleeding events (OR 0.76, 95% CI 0.51 to 1.14, p = 0.19). Thirty-day all-cause mortality was significantly less with TF TAVI compared with TA TAVI (OR 0.59, 95% CI 0.45 to 0.76, p <0.0001). Major vascular events were significantly higher in the TF TAVI group compared with the TA TAVI group (OR 4.33, 95% CI 3.14 to 5.97, p <0.00001). In conclusion, the results of this meta-analysis of 2,978 patients revealed that TA TAVI had similar 1-year major adverse cardiovascular and cerebrovascular events, fewer major vascular complications, but higher 30-day mortality compared with TF TAVI. In patients with contraindications to TF TAVI, TA TAVI is a reasonable option, although further randomized trials are warranted for evaluating long-term clinical outcomes between TF and TA TAVI. PMID- 25438918 TI - A novel NKX2.5 loss-of-function mutation associated with congenital bicuspid aortic valve. AB - Bicuspid aortic valve (BAV) is the most common form of congenital cardiovascular defect in humans and is associated with substantial morbidity and mortality. Emerging evidence demonstrates that genetic risk factors play an important role in the pathogenesis of BAV. However, BAV is a genetically heterogenous disorder, and the genetic defects underpinning BAV in most patients remain to be identified. In the present study, the coding exons and flanking introns of the NKX2.5 gene, which encodes a homeodomain-containing transcription factor essential for the normal development of the aortic valve, were sequenced in 142 unrelated patients with BAV. The available relatives of the mutation carrier and 200 unrelated healthy subjects used as controls were also genotyped for NKX2.5. The functional characteristics of the mutation were delineated by using a dual luciferase reporter assay system. As a result, a novel heterozygous NKX2.5 mutation, p.K192X, was identified in a family with BAV transmitted in an autosomal dominant pattern. The nonsense mutation was absent in 400 control chromosomes. Functional analyses revealed that the mutant NKX2.5 had no transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation abolished the synergistic transcriptional activation between NKX2.5 and GATA5, another transcription factor crucial for the aortic valvular morphogenesis. In conclusion, this study is the first to link an NKX2.5 loss-of function mutation to enhanced susceptibility to human BAV, providing novel insight into the molecular mechanism of BAV and suggesting potential implications for genetic counseling and clinical care of families presenting with BAV. PMID- 25438919 TI - Relation of right ventricular mass and volume to functional health status in repaired tetralogy of Fallot. AB - After repair of tetralogy of Fallot, right ventricular (RV) mass and mass:volume ratio may reflect RV remodeling and adverse outcomes. This study aimed to evaluate the relation of RV mass to functional health status and subsequent adverse RV remodeling and to determine whether RV mass measurement in systole could improve reproducibility. In 53 patients with tetralogy of Fallot (median 29 years old) who previously underwent cardiovascular magnetic resonance and completed the Short Form 36, version 2 (Optum, Eden Prairie, MN), short-axis images were analyzed for RV end-diastolic volume and diastolic and systolic mass, indexed to body surface area. The most recent subsequent cardiovascular magnetic resonance study (before pulmonary valve or conduit replacement) was evaluated for change in RV end-diastolic volume and ejection fraction. Diastolic indexed mass >=37.3 g/m(2) (odds ratio 7.6, p = 0.02) predicted decreased general health scores. In patients with normal RV ejection fraction, indexed mass correlated with Physical Component Summary and general health scores. RV diastolic mass:volume ratio >0.2 had a strong association with subsequent increase in RV end-diastolic volume (odds ratio 26.1, p = 0.002). Systolic RV mass measurement had excellent correlation with diastolic measurement (r = 0.97, p <0.0001), but did not improve intraobserver or interobserver variability. In conclusion, RV mass relates to functional health status and adverse RV remodeling and can be measured with good reproducibility. RV mass should be routinely evaluated in this population and is best measured in diastole; further study is necessary to evaluate longitudinal changes in functional health status and RV parameters. PMID- 25438920 TI - Effect of early enrollment on outcomes in cardiac rehabilitation. AB - Outpatient cardiac rehabilitation (CR) is most beneficial when delivered 1 to 3 weeks after the index cardiac event. The effects of delayed enrollment on subsequent outcomes are unclear. A total of 1,241 patients were enrolled in CR after recent (<1 year) treatment of cardiac events or postcardiac surgery. Risk factors and metabolic equivalent levels (METs) during aerobic exercise were calculated before and after CR. The mean CR delay time was 34 days (maximum of 327). Delay time >30 days was associated with older age, female gender, nonwhite race, being unemployed, and increased length of hospital stay before CR after index cardiac event (p <0.05 vs 0 to 15 and 16 to 30 days for all comparisons). Patients with delay time >30 days had significant improvements in all CR metrics, but peak METs and weight improvements were lesser in magnitude compared with patients with CR delay times 0 to 15 and 16 to 30 days. After multivariate adjustment, delay time >30 days remained an independent predictor of decreased MET improvement compared with delay time 0 to 15 days (beta = -0.59, p <0.001). In conclusion, time to enrollment in CR varies substantially and is independently linked to demographics and length of index hospital stay. Delayed enrollment in CR is directly related to patient outcomes. Although all patients showed improvements in key metrics regardless of delay time, CR was of greatest benefit, particularly for weight and exercise capacity, when initiated within 15 days of the index event. PMID- 25438921 TI - Impact of transesophageal echocardiography on management in patients with suspected cardioembolic stroke. AB - Transesophageal echocardiography (TEE) is frequently performed in patients with acute ischemic cerebrovascular events to exclude a cardioembolic source. We aimed to determine the clinical impact of TEE on management. This is a retrospective single-center study of 1,458 consecutive patients hospitalized with acute ischemic stroke or transient ischemic attack who underwent TEE for evaluation of a suspected cardioembolic cause. Significant TEE findings were determined for each patient as recorded on the TEE report. The medical record was reviewed for baseline, clinical, and demographic variables and to determine whether significant management changes occurred as a result of the TEE findings. Potential significant changes in management included initiation of anticoagulation, placement of a patent foramen ovale (PFO) closure device, initiation of antibiotic therapy for endocarditis, surgical PFO closure, other cardiac surgery, and coil embolization of a pulmonary arteriovenous malformation. A significant change in management occurred in 243 patients (16.7%); 173 (71%) underwent treatment for PFO with a percutaneous PFO closure device (n = 100), initiation of chronic systemic anticoagulation (n = 68), or surgical PFO closure (n = 5). Additional findings leading to a change in management included endocarditis (n = 20), aortic arch atheroma (n = 14), intracardiac thrombus (n = 13), pulmonary arteriovenous malformation (n = 2), aortic valve fibroelastoma (n = 2), other valve masses (n = 4), and miscellaneous causes (n = 15). In conclusion, in patients with suspected cardioembolic stroke, TEE findings led to a change in management in 16.7% of patients. Of these, most (71%) were directed at prevention of subsequent paradoxical emboli in patients with PFO. PMID- 25438923 TI - Sudden cardiac death and cardiovascular pathology: from anatomic theater to double helix. AB - The experience as a cardiovascular pathologist on sudden cardiac death (SCD) in the young and the impact that the findings had on in vivo diagnosis, treatment, and prevention are herein reported. The story dates back in the late 70s, when a series of juvenile sudden deaths occurred in the Veneto Region, North East of Italy. A successful application for a prospective study on young people dying suddenly (<35 years old, sudden infant death syndrome excluded) was submitted to the regional health authorities, thus implementing a network of collaboration with anatomic and forensic pathologists, to collect all such events and to gather epidemiological data. The project is still in progress, and since then we studied >650 hundreds consecutive juvenile SCD cases, allowing to identify the culprit diseases with abnormalities in the various cardiac structures (aorta, coronary arteries, myocardium, valves, and conduction system). The long standing Veneto Region experience clearly shows that autopsy still plays a pivotal role in the study and prevention of SCD and should be carried out regularly in the young. With time, the investigation of SCD necessarily moved from the classic postmortem study to molecular autopsy. In conclusion, SCD prevention in the young has to be faced by an interdisciplinary team, including pathologists, cardiologists, sport physicians, and geneticists, with a translational approach; the clinicopathologic correlation method still being the polar-star. In other words, the game in the fight against SCD is still played in the anatomical theater, the place where "death enjoys to save lives." PMID- 25438922 TI - Relations between depressive symptoms, anxiety, and T Wave abnormalities in subjects without clinically-apparent cardiovascular disease (from the Multi Ethnic Study of Atherosclerosis [MESA]). AB - The aim of this study was to test the hypothesis that depression and anxiety are associated with electrocardiographic (ECG) repolarization abnormalities in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort free of symptomatic cardiovascular disease. Depressive symptoms were assessed by using the Center for Epidemiologic Studies Depression Scale and trait anxiety symptoms by using the Spielberger State-Trait Anxiety Inventory; both were categorized according to uppermost quartile. T-wave inversions in ECG leads other than V1 to V3 were obtained from electrocardiograms obtained at rest during the baseline examination. Participants with major intraventricular conduction abnormalities and those taking antiarrhythmics, antidepressants, and/or antipsychotics were excluded. Logistic regression models were estimated with multivariable adjustment for traditional cardiovascular disease risk factors. Among 5,906 participants, elevated depressive symptoms were associated with increased odds of T-wave inversion after multivariable adjustment (odds ratio 2.02, 95% confidence interval 1.33 to 3.06, p = 0.001), whereas greater trait anxiety was associated with reduced odds of T-wave inversion (odds ratio 0.47, 95% confidence interval 0.29 to 0.77, p = 0.003). The divergent associations of depressive symptoms and trait anxiety with ECG T-wave inversions were similar in men and women, and these associations were present across the racial and ethnic subgroups (non-Hispanic white, African-American, Hispanic, and Chinese). In conclusion, symptoms of depression and anxiety were independently yet oppositely associated with ECG T wave inversions. Negative emotions may have a differential impact on cardiovascular mortality through unique relations with cardiac repolarization. PMID- 25438924 TI - Aggressive and nonaggressive translocation t(6;11) renal cell carcinoma: comparative study of 6 cases and review of the literature. AB - t(6;11) renal cell carcinoma (RCC) has been recognized as a rare and mostly nonaggressive tumor (NAT). The criteria for distinguishing aggressive tumors (AT) from NATs are not well established. A total of 6 cases were selected for the study. Five cases of t(6;11) RCCs behaved nonaggressively, and 1 was carcinoma with aggressive behavior. The tumors were analyzed morphologically using immunohistochemistry and by molecular-genetic methods. The specimen of aggressive t(6;11) RCC was from a 77-year-old woman who died of the disease 2.5 months after diagnosis. The specimens of nonaggressive t(6;11) RCCs were from 3 women and 2 men whose ages range between 15 and 54 years. Follow-up was available in all cases (2.5 months-8 years). The tumor size ranged from 3 to 14 cm in nonaggressive t(6;11) RCC. In the aggressive carcinoma, the tumor size was 12 cm. All tumors (6/6) were well circumscribed. Aggressive t(6;11) RCC was widely necrotic. Six (100%) of 6 all tumors displayed a solid/alveolar architecture with occasional tubules and pseudorosettes. Pseudopapillary formations lined by bizarre polymorphic cells were found focally in the aggressive t(6;11) RCC case. Mitoses, though rare, were found as well. All cases (AT and NAT) were positive for HMB-45, Melan-A, Cathepsin K, and cytokeratins. CD117 positivity was seen in 4 of 5 NATs, as well as in the primary and metastatic lesions of the AT. mTOR was positive in 2 of 5 NATs and vimentin in 4 of 5 NATs. Vimentin was negative in the primary lesion of the AT, as well as in the metastasis found in the adrenal gland. Translocation t(6;11)(Alpha-TFEB) or TFEB break was detected in 4 of 5 NATs and in the AT case. Aggressive tumor showed amplification of TFEB locus. Losses of part of chromosome 1 and chromosome 22 were found in 1 of 5 NATs and in the AT. CONCLUSIONS: (1) Aggressive t(6;11) RCCs generally occur in the older population in comparison with their indolent counterparts. (2) In regard to the histologic findings in ATs, 3 of 5 so far published cases were morphologically not typical for t(6;11) RCC. Of the 3 cases, 2 cases lacked a small cell component and 1 closely mimicked clear cell-type RCC. (3) Necroses were only present in aggressive t(6;11) RCC. (4) Amplification of TFEB locus was also found only in the aggressive t(6;11) RCC. PMID- 25438925 TI - Solid pseudopapilllary neoplasm of the pancreas. A clinicopathologic study of 25 cases from Pakistan and review of Literature. AB - Our aim was to describe the clinicopathologic features of cases of solid pseudopapillary neoplasm (SPN) of the pancreas diagnosed in our section. We retrieved hematoxylin and eosin and immunohistochemistry slides of SPN of pancreas diagnosed between 2002 and 2014 and reviewed slides. A total of 25 cases were included in the study. All were females. Age ranged from 12 to 45 years with mean age of 24 years. Tail of pancreas was the commonest location (40%). Tumor size ranged from 2.5 to 20 cm (mean tumor size, 9.5 cm). Distal pancreatectomy and pancreaticoduodenectomy were the commonest types of surgical resections performed. Most cases were confined to the pancreas. However, 2 cases extended beyond the pancreas, and an additional case metastasized to the omentum and liver. Pseudopapillary architecture and hyaline globules were the commonest histologic features, seen in 100% and 84% of cases, respectively. Vimentin, cluster of differentiation 10, cluster of differentiation 56, and neuron-specific enolase were the most useful immunohistochemical stains. Of those cases, in which follow-up was available, almost all (except 1) patients were alive and well even several years after resection. In conclusion, SPN is a rare tumor in our practice. As in international studies, our study also showed predilection for young females and excellent prognosis after surgical resection. PMID- 25438926 TI - Hepatoid differentiation in renal cell carcinoma: a rare histologic pattern with clinical significance. AB - Hepatoid adenocarcinoma is a rare extrahepatic aggressive tumor defined by morphologic and immunohistochemical evidences of hepatoid differentiation. In this study, clinicopathologic features of 3 cases of hepatoid renal cell carcinoma (RCC) were analyzed. Case I was a 53-year-old man with stage III, with 1,460 ng/ml of serum alpha-fetoprotein (AFP) and a 12 cm-sized stage III RCC, which was a combined clear cell and papillary RCC type 2 with sarcomatoid dedifferentiation. Case II was a 62-year-old woman with stage IV, 6.5-cm clear cell RCC and 40,800 ng/mL of serum AFP. Case III was a 51-year-old woman with stage I, 1.6-cm Xp11 translocation RCC and 313.3 ng/mL of serum AFP. Cases I and II died of the disease at 26 and 21 months after radical nephrectomy, respectively. Case III was alive without the disease for 20 months at the last follow-up. Microscopically, three cases show hepatoid carcinoma areas with eosinophilic to clear cells, arranged in trabeculae, separated by thin sinusoidal vessels, in addition to diagnostic features of corresponding RCC subtypes. The tumor cells in these hepatoid carcinoma areas as well as at least focally in RCC areas were immunopositive for AFP in all three cases, but were immunonegative for other hepatic markers (Hep Par1, polyclonal CEA, and glypican 3). This report suggests that the hepatoid features with AFP production are aberrant differentiation that can be developed in various RCC subtypes. Recognizing hepatoid RCC will help explain abnormal elevation of serum AFP levelS, which can be used as a serum surveillance marker. PMID- 25438927 TI - Synovial sarcoma: defining features and diagnostic evolution. AB - Synovial sarcoma (SS) is a malignant mesenchymal neoplasm with variable epithelial differentiation, with a propensity to occur in young adults and which can arise at almost any site. It is generally viewed and treated as a high-grade sarcoma. As one of the first sarcomas to be defined by the presence of a specific chromosomal translocation leading to the production of the SS18-SSX fusion oncogene, it is perhaps the archetypal "translocation-associated sarcoma," and its translocation remains unique to this tumor type. Synovial sarcoma has a variety of morphologic patterns, but its chief forms are the classic biphasic pattern, of glandular or solid epithelial structures with monomorphic spindle cells and the monophasic pattern, of fascicles of spindle cells with only immunohistochemical or ultrastructural evidence of epithelial differentiation. However, there is significant morphologic heterogeneity and overlap with a variety of other neoplasms, which can cause diagnostic challenge, particularly as the immunoprofile is varied, SS18-SSX is not detected in 100% of SSs, and they may occur at unusual sites. Correct diagnosis is clinically important, due to the relative chemosensitivity of SS in relation to other sarcomas, for prognostication and because of the potential for treatment with specific targeted therapies in the near future. We review SS, with emphasis on the diagnostic spectrum, recent immunohistochemical and genetic findings, and the differential diagnosis. PMID- 25438928 TI - Two-dimensional cardiothoracic ratio for evaluation of cardiac size in German shepherd dogs. AB - OBJECTIVES: To evaluate cardiac size in normal German shepherd dogs (GSD) using the two-dimensional cardiothoracic ratio (CTR) and to use this measure for diagnosing GSD with altered cardiac size. ANIMALS: One hundred clinically normal GSD as well as 46 GSD with altered cardiac size (microcardia or cardiomegaly). METHODS: The CTR was computed as the percentage area of the cardiac silhouette relative to the area of the dog's thorax. Measurements were performed using a digital software program on lateral and ventro-dorsal radiographs at the points of peak inspiration and expiration. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic accuracy of the CTR for diagnosing cardiomegaly or microcardia. RESULTS: The mean (+/-SD) CTR on lateral radiographs of normal dogs was 27.60% +/- 1.10% and 30.13% +/- 1.42% at the points of peak inspiration and expiration, respectively. For ventro-dorsal radiographs, mean CTR was 30.45% +/- 1.39% at peak inspiration and 33.34% +/- 1.46% at peak expiration. The cutoff value of the CTR for diagnosing microcardia on lateral radiographs was 22.98% (inspiration) and 25.06% (expiration), compared to 25.03% (inspiration) and 23.97% (expiration) on ventro-dorsal radiographs. Cutoff values for diagnosing cardiomegaly were 30.28% (inspiration) and 33.44% (expiration) on lateral radiographs and 36.80% (inspiration) and 37.99% (expiration) on ventro dorsal radiographs. CONCLUSIONS: CTR may provide a clinically useful tool for evaluating cardiac size in dogs. PMID- 25438929 TI - The genetics of diabetic pregnancy. AB - Advancements in molecular technology coupled with a greater awareness of the human genome and epigenome have broadened our understanding of the genetic contributions to the diabetic pregnancy. There are multiple genes and pathways that can result in a hyperglycemic environment for the fetus. Exposure to this environment in utero has an impact on the risk of adult-onset chronic diseases. How identification of an individual's genetic variants will impact clinical care and outcomes will continue to evolve as our understanding grows. PMID- 25438930 TI - Impact of maternal nutrition on pregnancy outcome--does it matter what pregnant women eat? AB - Pregnancy presents a unique epoque in life with considerable potential to influence not only maternal health but also the health of the next generation. Nutritional interventions in pregnancy can influence maternal, foetal and infant health. This chapter describes the findings of a large randomised controlled trial on the impact of a low glycaemic index diet on maternal and foetal health and discusses areas of future research in this important area. PMID- 25438931 TI - Health and disease in children born after assistive reproductive therapies (ART. AB - In vitro fertilisation (IVF) and other assisted reproductive therapies (ART) offer hope to subfertile couples worldwide. At least 5 million ART children have been born to date. Their health is an issue that is increasingly relevant: first, to those children and young adults themselves; second, to couples considering fertility treatment; and third, to the general population as ART has progressed from experimental treatment to routine practice. Many concerns about the potential risks to these children have been voiced with varying degrees of supportive evidence. This article summarises some key long-term data. Current evidence suggests that ART does increase risk of: higher order pregnancy (with its inherent pre- and perinatal risks); prematurity and low birth weight; congenital malformations in particular of the male urogenital system; imprinting disorders. Reassuringly, evidence points away from an increased overall cancer risk or differences in neurodevelopmental outcomes. Many unknowns remain, including future fertility and cardiovascular risks and risk of cerebral palsy. PMID- 25438932 TI - [Pleural effusion: diagnosis and management]. AB - Pleural effusion management is a common clinical situation associated with numerous pulmonary, pleural or extra-pulmonary diseases. A systematic approach is needed to enable a rapid diagnosis and an appropriate treatment. Pleural fluid analysis is the first step to perform which allows a presumptive diagnosis in most cases. Otherwise, further analysis of the pleural fluid or thoracic imaging or pleural biopsy may be necessary. This review aims at highlighting the important elements of the work-up required by a pleural effusion. PMID- 25438933 TI - Pulmonary nodule tracking using chest computed tomography in a histoplasmosis endemic area. AB - OBJECTIVE: In areas with endemic histoplasmosis, incidental pulmonary nodules are common. Rate of malignancy and applicability of current tracking guidelines in these regions remain unclear. METHODS: A total of 148 cases of incidental pulmonary nodules tracked with chest computed tomography were reviewed for radiologic characteristics, diagnosis, number, and size. RESULTS: Of the nodules, 87.8% were benign and 12.2% malignant; 30% of nodules >20mm were malignant. Number of nodules (P=.14) and granulomatous disease (P=.71) were not related to malignant diagnosis. CONCLUSION: Malignancy was lower than expected in nodules >20mm. Appropriate tracking guidelines for incidentally discovered nodules in histoplasmosis endemic regions must be determined. PMID- 25438934 TI - Massively parallel sequencing of complete mitochondrial genomes from hair shaft samples. AB - Though shed hairs are one of the most commonly encountered evidence types, they are among the most limited in terms of DNA quantity and quality. As a result, DNA testing has historically focused on the recovery of just about 600 base pairs of the mitochondrial DNA control region. Here, we describe our success in recovering complete mitochondrial genome (mtGenome) data (~16,569bp) from single shed hairs. By employing massively parallel sequencing (MPS), we demonstrate that particular hair samples yield DNA sufficient in quantity and quality to produce 2-3kb mtGenome amplicons and that entire mtGenome data can be recovered from hair extracts even without PCR enrichment. Most importantly, we describe a small amplicon multiplex assay comprised of sixty-two primer sets that can be routinely applied to the compromised hair samples typically encountered in forensic casework. In all samples tested here, the MPS data recovered using any one of the three methods were consistent with the control Sanger sequence data developed from high quality known specimens. Given the recently demonstrated value of complete mtGenome data in terms of discrimination power among randomly sampled individuals, the possibility of recovering mtGenome data from the most compromised and limited evidentiary material is likely to vastly increase the utility of mtDNA testing for hair evidence. PMID- 25438935 TI - The swimming behavior of Artemia (Anostraca): new experimental and observational data. AB - Artemia (Anostraca) is among the most primitive and ancient groups of crustaceans. Artemia spp. play a dominant role in the ecosystems of hypersaline waters, and often they are the only animals in these extreme biotopes. Most ethological studies on Artemia have been conducted on nauplii and metanauplii. We made ethological observations on Artemia under laboratory conditions and in the natural waters of Crimea, where we studied growth and ontogenetic changes of swimming behavior. Growth occurred during the first 50 days up to a size of 9.5 10.5mm, after which time the size did not increase (some females lived up to 6.5 months). A strong positive relation was found between maximal speed and individual length, which varied between 0.4 and 10.5mm; it may be approximated by the power equation: Vmax=1.205.K(0.820), where Vmax is the maximal speed of Artemia (in mms(-1)) of the length K (in mm). There is no similar relation between average speed and length of Artemia. The average speed of adults was 40 60% lower in environments with microalgae compared to media without food. The duration of the "riding position" for mating pairs of Artemia urmiana in our experiments varied from 10 to 27 days. In lakes we observed different Artemia aggregations varying in size and form. We conclude that the swimming behavior of Artemia is quite complex and diverse, and develops during ontogeny. PMID- 25438936 TI - Improving reliability of live/dead cell counting through automated image mosaicing. AB - Cell counting is one of the basic needs of most biological experiments. Numerous methods and systems have been studied to improve the reliability of counting. However, at present, manual cell counting performed with a hemocytometer still represents the gold standard, despite several problems limiting reproducibility and repeatability of the counts and, at the end, jeopardizing their reliability in general. We present our own approach based on image processing techniques to improve counting reliability. It works in two stages: first building a high resolution image of the hemocytometer's grid, then counting the live and dead cells by tagging the image with flags of different colours. In particular, we introduce GridMos (http://sourceforge.net/p/gridmos), a fully-automated mosaicing method to obtain a mosaic representing the whole hemocytometer's grid. In addition to offering more significant statistics, the mosaic "freezes" the culture status, thus permitting analysis by more than one operator. Finally, the mosaic achieved can thus be tagged by using an image editor, thus markedly improving counting reliability. The experiments performed confirm the improvements brought about by the proposed counting approach in terms of both reproducibility and repeatability, also suggesting the use of a mosaic of an entire hemocytometer's grid, then labelled trough an image editor, as the best likely candidate for the new gold standard method in cell counting. PMID- 25438937 TI - A randomised controlled trial of high dose vitamin D in recent-onset type 2 diabetes. AB - AIMS: Vitamin D insufficiency has been associated with impaired pancreatic beta cell function. We aimed to determine if high dose oral vitamin D3 (D) improves beta-cell function and glycaemia in type 2 diabetes. METHODS: Fifty adults with type 2 diabetes diagnosed less than 12 months, with normal baseline serum 25-OH D (25D), were randomised to 6000 IU D (n=26) or placebo (n=24) daily for 6 months. Beta-cell function was measured by glucagon-stimulated serum C-peptide (delta C peptide [DCP], nmol/l). Secondary outcome measures were fasting plasma glucose (FPG), post-prandial blood glucose (PPG), HbA1c and insulin resistance (HOMA-IR). RESULTS: In the D group, median serum 25D (nmol/l) increased from 59 to 150 (3 months) and 128 (6 months) and median serum 1,25D (pmol/l) from 135 to 200 and 190. After 3 months, change in DCP from baseline in D (+0.04) and placebo (-0.08) was not different (P=0.112). However, change in FPG (mmol/l) was significantly lower in D (-0.40) compared to placebo (+0.1) (P=0.007), as was the change in PPG in D (-0.30) compared to placebo (+0.8) (P=0.005). Change in HbA1c (%) between D (-0.20) and placebo (-0.10) was not different (P=0.459). At 6 months, changes from baseline in DCP, FPG, PPG and HbA1c were not different between groups. CONCLUSION: Oral D3 supplementation in type 2 diabetes was associated with transient improvement in glycaemia, but without a measurable change in beta-cell function this effect is unlikely to be biologically significant. High dose D3 therefore appears to offer little or no therapeutic benefit in type 2 diabetes. PMID- 25438938 TI - Clinical significance of serum ferritin level as an independent predictor of insulin resistance in Korean men. AB - AIMS: Elevated serum ferritin level has been reported to be associated with type 2 diabetes mellitus and metabolic syndrome, which have significant relation with insulin resistance (IR). However, clinical association between serum ferritin level and IR remained unclear. Accordingly, this study was designed to evaluate the longitudinal effects of baseline serum ferritin level on the development of IR. METHODS: An IR-free 22,057 healthy Korean men (HOMA-IR<2.7), who had participated in a medical health check-up program in 2005, were followed up until 2010. During follow up, the development rate of IR, defined in case of HOMA IR>=2.7, was monitored according to the quartile groups of serum ferritin levels. Cox proportional hazards models were used to measure the hazard ratios (HRs) of baseline serum ferritin levels on IR. RESULTS: During 77,471.1 person-years of follow-up, 4494 incident cases of insulin resistance developed between 2006 and 2010 (overall development rate: 20.4%). The development rate of IR increased in proportion to the baseline serum ferritin levels (quartile 1: 16.7%, quartile 2: 18.5%, quartile 3: 19.9%, quartile 4: 25.5%, P<0.001). After adjusting for multiple covariates, the HRs (95% CI) for IR, comparing the second to the fourth quartile of serum ferritin levels with the first quartile, were 1.11 (0.99-1.24), 1.19 (1.07-1.33) and 1.51 (1.35-1.68), respectively (P for trend <0.001). CONCLUSIONS: Elevated serum ferritin level was independently associated with the future development of IR in Korean men. PMID- 25438939 TI - Clinician views and knowledge regarding healthcare provision in the postpartum period for women with recent gestational diabetes: a systematic review of qualitative/survey studies. AB - AIM: To examine clinician views and knowledge regarding postpartum healthcare provision for women who have experienced gestational diabetes (GDM). METHODS: Systematic review that searched PubMed, Web of Science, EMBASE and CINAHL. Qualitative studies and surveys, with clinicians as participants, which reported pre-specified outcomes, including barriers and facilitators to postpartum care for GDM, were included. Two authors independently assessed quality and undertook thematic synthesis. RESULTS: Eleven surveys and two interview studies were included (4435 clinicians). Key themes included adequacy of knowledge of risk of type 2 diabetes mellitus (T2DM), gaps between knowledge and practice relating to postpartum screening, and differing perceptions of the value of postpartum screening. Clinicians perceived that women faced obstacles to accessing healthcare, and a need for improved GDM education. Studies reported shortfalls in systems to ensure postpartum screening occurs, and a need to improve communication and collaboration relating to care of women who have experienced GDM. The surveys were often limited in their depth and ability to identify remedial strategies. CONCLUSIONS: Barriers to provision of care for women who have had GDM, such as lack of communication of the diagnosis, need to be addressed, and further interview studies exploring clinician views on screening for T2DM are required. PMID- 25438940 TI - Somatic cells initiate primordial follicle activation and govern the development of dormant oocytes in mice. AB - BACKGROUND: The majority of oocytes in the mammalian ovary are dormant oocytes that are enclosed in primordial follicles by several somatic cells, which we refer to as primordial follicle granulosa cells (pfGCs). Very little is known, however, about how the pfGCs control the activation of primordial follicles and the developmental fates of dormant oocytes. RESULTS: By targeting molecules in pfGCs with several mutant mouse models, we demonstrate that the somatic pfGCs initiate the activation of primordial follicles and govern the quiescence or awakening of dormant oocytes. Inhibition of mTORC1 signaling in pfGCs prevents the differentiation of pfGCs into granulosa cells, and this arrests the dormant oocytes in their quiescent states, leading to oocyte death. Overactivation of mTORC1 signaling in pfGCs accelerates the differentiation of pfGCs into granulosa cells and causes premature activation of all dormant oocytes and primordial follicles. We further show that pfGCs trigger the awakening of dormant oocytes through KIT ligand (KITL), and we present an essential communication network between the somatic cells and germ cells that is based on signaling between the mTORC1-KITL cascade in pfGCs and KIT-PI3K signaling in oocytes. CONCLUSIONS: Our findings provide a relatively complete picture of how mammalian primordial follicles are activated. The microenvironment surrounding primordial follicles can activate mTORC1-KITL signaling in pfGCs, and these cells trigger the awakening of dormant oocytes and complete the process of follicular activation. Such communication between the microenvironment, somatic cells, and germ cells is essential to maintaining the proper reproductive lifespan in mammals. PMID- 25438942 TI - GCP-WD mediates gamma-TuRC recruitment and the geometry of microtubule nucleation in interphase arrays of Arabidopsis. AB - Many differentiated animal cells, and all higher plant cells, build interphase microtubule arrays of specific architectures without benefit of a central organizer, such as a centrosome, to control the location and geometry of microtubule nucleation. These acentrosomal arrays support essential cell functions such as morphogenesis, but the mechanisms by which the new microtubules are positioned and oriented are poorly understood. In higher plants, nucleation of microtubules arises from distributed gamma-tubulin ring complexes (gamma TuRCs) at the cell cortex that are associated primarily with existing microtubules and from which new microtubules are nucleated in a geometrically bimodal fashion, either in parallel to the mother microtubule or as a branching event at a mean angle of approximately 40 degrees to the mother microtubule. By imaging the dynamics of individual nucleation events in Arabidopsis, we found that a conserved peripheral protein of the gamma-TuRC, GCP-WD/NEDD1, associated with motile gamma-TuRCs and localized to nucleation events. Knockdown of this essential protein resulted in reduction of gamma-TuRC recruitment to cortical microtubules and total nucleation frequency, showing that GCP-WD controls gamma TuRC positioning and function in these interphase arrays. Further, we discovered an unexpected role for GCP-WD in determining the geometry of microtubule dependent microtubule nucleation, where it acts to increase the likelihood of branching over parallel nucleation. Cells with normally complex patterns of cortical array organization constructed simpler arrays with cell-wide ordering, suggesting that control of nucleation frequency, positioning, and geometry by GCP WD allows plant cells to build alternative cortical array architectures. PMID- 25438941 TI - Sex, age, and hunger regulate behavioral prioritization through dynamic modulation of chemoreceptor expression. AB - BACKGROUND: Adaptive behavioral prioritization requires flexible outputs from fixed neural circuits. In C. elegans, the prioritization of feeding versus mate searching depends on biological sex (males will abandon food to search for mates, whereas hermaphrodites will not) as well as developmental stage and feeding status. Previously, we found that males are less attracted than hermaphrodites to the food-associated odorant diacetyl, suggesting that sensory modulation may contribute to behavioral prioritization. RESULTS: We show that somatic sex acts cell autonomously to reconfigure the olfactory circuit by regulating a key chemoreceptor, odr-10, in the AWA neurons. Moreover, we find that odr-10 has a significant role in food detection, the regulation of which contributes to sex differences in behavioral prioritization. Overexpression of odr-10 increases male food attraction and decreases off-food exploration; conversely, loss of odr-10 impairs food taxis in both sexes. In larvae, both sexes prioritize feeding over exploration; correspondingly, the sexes have equal odr-10 expression and food attraction. Food deprivation, which transiently favors feeding over exploration in adult males, increases male food attraction by activating odr-10 expression. Furthermore, the weak expression of odr-10 in well-fed adult males has important adaptive value, allowing males to efficiently locate mates in a patchy food environment. CONCLUSIONS: We find that modulated expression of a single chemoreceptor plays a key role in naturally occurring variation in the prioritization of feeding and exploration. The convergence of three independent regulatory inputs--somatic sex, age, and feeding status--on chemoreceptor expression highlights sensory function as a key source of plasticity in neural circuits. PMID- 25438943 TI - A unique plant ESCRT component, FREE1, regulates multivesicular body protein sorting and plant growth. AB - Tight control of membrane protein homeostasis by selective degradation is crucial for proper cell signaling and multicellular organismal development. Membrane proteins destined for degradation, such as misfolded proteins or activated receptors, are usually ubiquitinated and sorted into the intraluminal vesicles (ILVs) of prevacuolar compartments/multivesicular bodies (PVCs/MVBs), which then fuse with vacuoles/lysosomes to deliver their contents to the lumen for degradation by luminal proteases. The formation of ILVs and the sorting of ubiquitinated membrane cargoes into them are facilitated by the endosomal sorting complex required for transport (ESCRT) machinery. Plants possess most evolutionarily conserved members of the ESCRT machinery but apparently lack orthologs of ESCRT-0 subunits and the ESCRT-I component Mvb12. Here, we identified a unique plant ESCRT component called FYVE domain protein required for endosomal sorting 1 (FREE1). FREE1 binds to phosphatidylinositol-3-phosphate (PI3P) and ubiquitin and specifically interacts with Vps23 via PTAP-like tetrapeptide motifs to be incorporated into the ESCRT-I complex. Arabidopsis free1 mutant is seedling lethal and defective in the formation of ILVs in MVBs. Consequently, endocytosed plasma membrane (PM) proteins destined for degradation, such as the auxin efflux carrier PIN2, cannot reach the lumen of the vacuole and mislocalize to the tonoplast. Collectively, our findings provide the first functional characterization of a plant FYVE domain protein, which is essential for plant growth via its role as a unique evolutionary ESCRT component for MVB biogenesis and vacuolar sorting of membrane proteins. PMID- 25438944 TI - Observation of reward delivery to a conspecific modulates dopamine release in ventral striatum. AB - Dopamine (DA) neurons increase and decrease firing for rewards that are better and worse than expected, respectively. These correlates have been observed at the level of single-unit firing and in measurements of phasic DA release in ventral striatum (VS). Here, we ask whether DA release is modulated by delivery of reward, not to oneself, but to a conspecific. It is unknown what, if anything, DA release encodes during social situations in which one animal witnesses another animal receive reward. It might be predicted that DA release will increase, suggesting that watching a conspecific receive reward is a favorable outcome. Conversely, DA release may be entirely dependent on personal experience, or perhaps observation of receipt of reward might be experienced as a negative outcome because another individual, rather than oneself, receives the reward. Our data show that animals display a mixture of affective states during observation of conspecific reward, first exhibiting increases in appetitive calls (50 kHz), then exhibiting increases in aversive calls (22 kHz). Like ultrasonic vocalizations (USVs), DA signals were modulated by delivery of reward to the conspecific. We show stronger DA release during observation of the conspecific receiving reward relative to observation of reward delivered to an empty box, but only on the first trial. During the following trials, this relationship reversed: DA release was reduced during observation of the conspecific receiving reward. These findings suggest that positive and negative states associated with conspecific reward delivery modulate DA signals related to learning in social situations. PMID- 25438945 TI - Four days of visual contrast deprivation reveals limits of neuronal adaptation. AB - Sensory systems continuously adjust their function to match changes in the environment. Such adaptation produces large perceptual effects, and its pervasiveness makes it a key part of understanding cortical function generally. In visual contrast adaptation, for example, brief exposure to vertical stripes can dramatically alter the apparent orientation and intensity of similarly oriented patterns (e.g., [4-7]). However, many environmental changes are long lasting. How does the visual system adjust to such challenges? Most past work on contrast adaptation has adapted subjects for just a few minutes. Only a few studies have examined durations greater than 1 hr, and none have exceeded 1 day. Here, we measured perceptual effects of adaptation in humans who viewed a world lacking vertical information for 4 days continuously. As expected, adaptation increased in magnitude during the first day, but it then showed a drop in strength. The decrease in adaptation is surprising because the adapting environment remained constant, and in short-term work, adaptation always strengthens or at least is maintained under such conditions. It indicates that the classical effects of contrast adaptation, which arise largely in primary visual cortex, are not maintained after approximately 1 day. Results from day 2 through day 4 further showed that slower adaptive processes can overcome this limit. Because adaptation is generally beneficial overall, its limits argue that the brain is sensitive to costs that arise when the neural code changes. These costs may determine when and how cortex can alter its function. PMID- 25438946 TI - Collapse of amphibian communities due to an introduced Ranavirus. AB - The emergence of infectious diseases with a broad host range can have a dramatic impact on entire communities and has become one of the main threats to biodiversity. Here, we report the simultaneous exploitation of entire communities of potential hosts with associated severe declines following invasion by a novel viral pathogen. We found two phylogenetically related, highly virulent viruses (genus Ranavirus, family Iridoviridae) causing mass mortality in multiple, diverse amphibian hosts in northern Spain, as well as a third, relatively avirulent virus. We document host declines in multiple species at multiple sites in the region. Our work reveals a group of pathogens that seem to have preexisting capacity to infect and evade immunity in multiple diverse and novel hosts, and that are exerting massive impacts on host communities. This report provides an exceptional record of host population trends being tracked in real time following emergence of a wildlife disease and a striking example of a novel, generalist pathogen repeatedly crossing the species barrier with catastrophic consequences at the level of host communities. PMID- 25438947 TI - Zooplankton may serve as transmission vectors for viruses infecting algal blooms in the ocean. AB - Marine viruses are recognized as a major driving force regulating phytoplankton community composition and nutrient cycling in the oceans. Yet, little is known about mechanisms that influence viral dispersal in aquatic systems, other than physical processes, and that lead to the rapid demise of large-scale algal blooms in the oceans. Here, we show that copepods, abundant migrating crustaceans that graze on phytoplankton, as well as other zooplankton can accumulate and mediate the transmission of viruses infecting Emiliania huxleyi, a bloom-forming coccolithophore that plays an important role in the carbon cycle. We detected by PCR that >80% of copepods collected during a North Atlantic E. huxleyi bloom carried E. huxleyi virus (EhV) DNA. We demonstrated by isolating a new infectious EhV strain from a copepod microbiome that these viruses are infectious. We further showed that EhVs can accumulate in high titers within zooplankton guts during feeding or can be adsorbed to their surface. Subsequently, EhV can be dispersed by detachment or via viral-dense fecal pellets over a period of 1 day postfeeding on EhV-infected algal cells, readily infecting new host populations. Intriguingly, the passage through zooplankton guts prolonged EhV's half-life of infectivity by 35%, relative to free virions in seawater, potentially enhancing viral transmission. We propose that zooplankton, swimming through topographically adjacent phytoplankton micropatches and migrating daily over large areas across physically separated water masses, can serve as viral vectors, boosting host virus contact rates and potentially accelerating the demise of large-scale phytoplankton blooms. PMID- 25438948 TI - A group of segmental premotor interneurons regulates the speed of axial locomotion in Drosophila larvae. AB - BACKGROUND: Animals control the speed of motion to meet behavioral demands. Yet, the underlying neuronal mechanisms remain poorly understood. Here we show that a class of segmentally arrayed local interneurons (period-positive median segmental interneurons, or PMSIs) regulates the speed of peristaltic locomotion in Drosophila larvae. RESULTS: PMSIs formed glutamatergic synapses on motor neurons and, when optogenetically activated, inhibited motor activity, indicating that they are inhibitory premotor interneurons. Calcium imaging showed that PMSIs are rhythmically active during peristalsis with a short time delay in relation to motor neurons. Optogenetic silencing of these neurons elongated the duration of motor bursting and greatly reduced the speed of larval locomotion. CONCLUSIONS: Our results suggest that PMSIs control the speed of axial locomotion by limiting, via inhibition, the duration of motor outputs in each segment. Similar mechanisms are found in the regulation of mammalian limb locomotion, suggesting that common strategies may be used to control the speed of animal movements in a diversity of species. PMID- 25438949 TI - Self-reported sleep disturbance is associated with Alzheimer's disease risk in men. AB - OBJECTIVE: To study the association between self-reported sleep disturbances and dementia risk. METHODS: Self-reported sleep disturbances and established risk factors for dementia were measured in men at ages 50 (n = 1574) and 70 (n = 1029) years. Dementia incidence was determined by reviewing their patient history between ages 50 and 90 years. In addition, plasma levels of beta-amyloid (Abeta) peptides 1-40 and 1-42 were measured at ages 70, 77, and 82 years. RESULTS: Cox regression demonstrated that men with self-reported sleep disturbances had a higher risk of developing dementia (+33%) and Alzheimer's disease (AD, +51%) than men without self-reported sleep disturbances (both P < .05). Binary logistic regression showed the increased risk for both dementia (+114%) and AD (+192%) were highest when sleep disturbance was reported at age 70 years (both P < .001). No group differences were found in Abeta levels. CONCLUSION: Improving sleep quality may help reduce the neurodegenerative risk in older men. PMID- 25438950 TI - Apoptotic effects and glucose-6-phosphate dehydrogenase responses in liver and gill tissues of rainbow trout treated with chlorpyrifos. AB - We investigated apoptotic effects and changes in glucose-6-phosphate dehydrogenase (G6PD) enzyme activity in liver and gill tissues of fish exposed to chlorpyrifos. Three different chlorpyrifos doses (2.25, 4.5 and 6.75 MUg/L) were administrated to rainbow trout at different time intervals (24, 48, 72 and 96 h). Acute exposure to chlorpyrifos showed time dependent decrease in G6PD enzyme activity at all concentrations (p < 0.05). Immunohistochemical results showed that chlorpyrifos caused mucous cell loss in gill tissue and apoptosis via caspase-3 activation in fish. The present study suggested that chlorpyrifos inhibits G6PD enzyme and causes mucous cell loss in gill and apoptosis in gill and liver tissues. PMID- 25438951 TI - Anisometropia in children with neurofibromatosis type 1 and unilateral optic glioma. PMID- 25438952 TI - Rapamycin protects against apoptotic neuronal death and improves neurologic function after traumatic brain injury in mice via modulation of the mTOR-p53-Bax axis. AB - BACKGROUND: Rapamycin has proven to be a neuroprotective agent in traumatic brain injury (TBI). However, there is a lack of data regarding the effect of rapamycin on apoptotic neuronal death after TBI. Thus, the present study was designed to detect the modulatory role of rapamycin on apoptosis and explore the potential involvement of the mammalian target of rapamycin (mTOR)-p53-Bax axis after TBI. MATERIAL AND METHODS: Neurologic severity score tests were performed to measure behavioral outcomes. The effect of rapamycin treatment on neuronal death was analyzed using immunofluorescence analysis of NeuN. Terminal deoxynucleotidyl transferase-mediated dUTP nick 3'-end labeling was performed to detect apoptotic cells. The expression of Bax and phosphorylated protein of p53 was detected using Western blotting analyses and immunofluorescence staining. Phosphorylated protein of the mTOR in the ipsilateral cortex was detected using Western blotting analyses. RESULTS: Rapamycin administration after TBI was associated with an increased number of neurons, decreased apoptosis index, and improved neurobehavioral function, which was potentially mediated by inactivation of the mTOR-p53-Bax axis. CONCLUSIONS: Rapamycin can protect neurons from apoptotic neuronal death after TBI. This study presents a new insight into the antiapoptosis mechanisms, which are responsible for the neuroprotection of rapamycin, with the potential involvement of the mTOR-p53-Bax axis. PMID- 25438953 TI - Penetrating cardiac injuries and the evolving management algorithm in the current era. AB - BACKGROUND: Penetrating cardiac injuries carry a significant mortality, especially if operative intervention is delayed because of diagnostic difficulties. METHODS AND MATERIALS: We reviewed our experience of 134 consecutive cases over a 6 year period. For the initial 5 years, the diagnosis was based on clinical grounds only. During the final year of study, focused ultrasound focused abdominal sonar for trauma (FAST) and subxiphoid pericardial window were introduced. RESULTS: Ninety-six per cent (128/134) were males and the overall mean age was 27 y. Eighty-four per cent (112/134) sustained isolated cardiac injury and the remaining sixteen per cent (22/134) had concurrent injuries elsewhere. A total of 10 FAST's were performed and the sensitivity was 20%. Fifteen subxiphoid pericardial window were performed (8 had diagnostic uncertainty, 2 with double jeopardy, and 5 with delayed tamponade) and had a sensitivity of 100%. The survival rate for the 109 patients from the pre-adjunct period was 83% and 88% for the 25 patients in the post-adjunct period, which was not statistically significant (P value = 0.765). There was no significant difference in the complication rate, mean intensive care unit stay, or mean total hospital stay. CONCLUSIONS: Penetrating cardiac injuries are highly lethal. A high index of suspicion, coupled with early operative intervention remains the key in securing the survival of these patients. PMID- 25438954 TI - Oxidative stress in multi-port and single-port cholecystectomy. AB - BACKGROUND: This study was designed to analyze and compare plasma levels of 8 isoprostane (8-epiPGF2alpha), a biomarker of lipid peroxidation, and uric acid (UA), a marker of the antioxidant status, in standard laparoscopic (LC) and laparoendoscopic single-site cholecystectomy (LSSC). MATERIALS AND METHODS: Forty patients with noncomplicated cholelithiasis were randomized to undergo either LSSC (n = 20) or LC (n = 20). The patients had body mass index <30, American Society of Anesthesiologists score I or II, and no previous upper gastrointestinal surgery. Blood samples were taken preoperatively and 6 h and 24 h postoperatively. Levels of 8-epiPGF2alpha were determined using enzyme-linked immunosorbent assay, whereas levels of UA were calculated using automated analyzer. RESULTS: No significant differences were observed in operative data among the groups. Levels of 8-epiPGF2alpha were significantly higher in LSSC compared with LC at 6 h (P = 0.003) and 24 h (P < 0.001). 8-epiPGF2alpha levels showed significant changes over time in LC (LSSC: P = 0.720, LC: P < 0.001). UA levels were significantly higher in LC compared with LSSC, 24 h postoperatively (P = 0.021). No significant changes over time in the UA levels in both groups (LSSC: P = 0.056, LC: P = 0.205). CONCLUSIONS: LSSC is associated with increased oxidative stress compared with LC. Further studies are needed to confirm these results. PMID- 25438955 TI - Role of Kupffer cells in ischemic injury in alcoholic fatty liver. AB - BACKGROUND: This study was designed to evaluate the role of Kupffer cells (KCs) in hepatic drug metabolizing dysfunction after hepatic ischemia-reperfusion (IR) in alcoholic fatty liver. MATERIALS AND METHODS: Rats were fed the Lieber-DeCarli diet for 5 wk to develop alcoholic fatty liver, then were subjected to 90 min of hepatic ischemia and 5 h of reperfusion. For ablation of KCs, rats were pretreated with gadolinium chloride (GdCl3) 48 and 24 h before the IR procedure. RESULTS: After the IR procedure, ethanol diet (ED)-fed rats had higher serum aminotransferase activity compared with the control diet-fed rats. These changes were attenuated by GdCl3. The ED-fed rats exhibited increased hepatic microsomal total cytochrome P450 (CYP) content and nicotinamide adenine dinucleotide phosphate-CYP reductase and CYP1A1, 1A2, 2B1, and 2E1 isozyme activity. After hepatic IR, these increases were reduced to lower levels than observed in the sham group, except CYP2E1 activity. Increases in CYP2E1 activity and its expression were augmented after hepatic IR in ED-fed animals, but were attenuated by GdCl3. Finally, toll-like receptor 4 and myeloid differentiation primary response gene 88 protein expression, nuclear translocation of nuclear factor kappaB and activator protein 1, and levels of proinflammatory mediators were further increased in ED-fed animals compared with control diet-fed animals after IR. These increases were attenuated by GdCl3. CONCLUSIONS: We suggest that KCs contribute to hepatic drug metabolizing dysfunction during hepatic IR in alcoholic fatty liver via the toll-like receptors 4-mediated inflammatory response. PMID- 25438956 TI - Neutrophil extracellular traps in patients with sepsis. AB - BACKGROUND: Release of neutrophil extracellular traps (NETs) has been identified as an important aspect of innate immunity. We examined whether sepsis had any influence on ex vivo generation of NETs by neutrophils. MATERIALS AND METHODS: We isolated neutrophils from consecutive patients with sepsis (n = 17) and without sepsis (n = 18) admitted to the intensive care unit. Neutrophils were activated by incubation with phorbol-12-myristate-13-acetate (PMA) to induce release of NETs, and NET formation was assessed by measuring the extracellular DNA level. Immunolabeling and fluorescence imaging were also performed. Extracellular killing of bacteria by NETs was studied by co-culture of Escherichia coli and neutrophils in the presence of a phagocytosis inhibitor. To assess in vivo NET formation, plasma levels of cell-free DNA and histones were measured. RESULTS: After stimulation with PMA, neutrophils isolated from septic patients released 4.08 +/- 1.02% of their total DNA, whereas neutrophils from nonseptic patients released 29.06 +/- 2.94% (P = <0.0001). Immunofluorescent staining of released DNA, elastase, and myeloperoxidase also revealed similar results. Neutrophils from nonseptic patients showed effective extracellular killing of E coli through NETs, whereas neutrophils from septic patients did not (P < 0.001). Plasma levels of cell-free DNA and histones were higher in septic patients than nonseptic patients (P < 0.001). CONCLUSIONS: The ex vivo generation of NETs is downregulated in neutrophils isolated from patients with sepsis. However, it is unclear whether in vivo NET formation is also impaired during sepsis, so further investigation is necessary. PMID- 25438957 TI - Determinants of 30-d readmission after colectomy. AB - BACKGROUND: Readmission after colectomy has become an important metric for measuring quality of care. Our aim was to investigate the impact of patient and hospital characteristics on 30-d readmission rates among patients undergoing colectomies in Pennsylvania. METHODS: Data were obtained from the Pennsylvania Health Care Cost Containment Council, which included all patients undergoing colectomy during 2011 (n = 10,155). Characteristics of non-readmitted and readmitted patients were compared with univariate tests. The primary outcome was 30-d readmission, which was modeled using multivariable logistic regression. RESULTS: Of the 10,155 patients who underwent colectomy, 1492 (14.7%) were readmitted within 30 d of discharge. Readmission was influenced by the underlying diagnosis (P < 0.001). Additionally, readmission was more likely with a Charlson comorbidity index >= 2 (odds ratio [OR] = 1.57, P < 0.001), emergent admission (OR = 1.26, P = 0.001), an in-hospital complication (OR = 1.46, P < 0.001), lowest quartile for surgeon volume (OR = 1.24, P = 0.01), and construction of an ileostomy (OR = 2.31, P < 0.001). Factors associated with decreased likelihood of readmission included laparoscopic surgery (OR = 0.73, P < 0.001). No association with hospital volume was found. CONCLUSIONS: A 30-d readmission after colectomy is influenced by numerous patient- and surgeon-related factors. Reducing in hospital complications, and improving patient education after ileostomy construction, provide substantial targets for intervention. Our data also suggest that there may be a critical range of colectomies performed annually by surgeons, greater than which no additional benefit is conferred in reducing readmissions, but below which there is an increased risk of readmission. Further research is needed to determine the influence of laparoscopic surgery in reducing readmission in equally matched patient populations. PMID- 25438958 TI - Control devices and steering strategies in pathway surgery. AB - For pathway surgery, that is, minimally invasive procedures carried out transluminally or through instrument-created pathways, handheld maneuverable instruments are being developed. As the accompanying control interfaces of such instruments have not been optimized for intuitive manipulation, we investigated the effect of control mode (1DoF or 2DoF), and control device (joystick or handgrip) on human performance in a navigation task. The experiments were conducted using the Endo-PaC (Endoscopic-Path Controller), a simulator that emulates the shaft and handle of a maneuverable instrument, combined with custom developed software animating pathway surgical scenarios. Participants were asked to guide a virtual instrument without collisions toward a target located at the end of a virtual curved tunnel. The performance was assessed in terms of task completion time, path length traveled by the virtual instrument, motion smoothness, collision metrics, subjective workload, and personal preference. The results indicate that 2DoF control leads to faster task completion and fewer collisions with the tunnel wall combined with a strong subjective preference compared with 1DoF control. Handgrip control appeared to be more intuitive to master than joystick control. However, the participants experienced greater physical demand and had longer path lengths with handgrip than joystick control. PMID- 25438959 TI - Loss of N-cadherin is associated with loss of E-cadherin expression and poor outcomes of liver resection in hepatocellular carcinoma. AB - BACKGROUND: Our previous study suggested that N-cadherin was downregulated in hepatocellular carcinoma (HCC). Our aim in this study was to investigate the correlation between N- and E-cadherin expression in HCC and its clinical significance. METHODS: Eighty-six patients with HCC undergoing liver resection were retrospectively studied. N- and E-cadherin expression in HCC and adjacent liver tissue were investigated using immunohistochemistry and immunofluorescence. The correlation between the expression status of both cadherins and surgical outcomes was analyzed. RESULTS: In 23 patients negative for E-cadherin expression, 19 of them (82.6%) were also negative for N-cadherin expression. In 30 patients with heterogeneous expression of E-cadherin, 20 of them (66.7%) also had heterogeneous expression of N-cadherin. In 33 patients with uniformly positive expression of E-cadherin, 19 of them (57.6%) also had uniformly positive expression of N-cadherin. Therefore, there was a positive correlation between expression patterns of N- and E-cadherins. Concurrent loss of both N- and E cadherin expressions was significantly associated with absence of the tumor capsule, vascular invasion, and poor differentiation. The 1- and 3-y disease-free survival rates were 27% and 9%, respectively, and the 1- and 3-y overall survival rates were 64.3% and 14.3%, respectively, in patients with concurrent loss of both cadherins, which were significantly worse than those with concurrent uniformly positive expression or heterogeneous expression of both cadherins. CONCLUSIONS: Loss of N-cadherin was positively correlated with loss of E-cadherin in HCC. Concurrent loss of both N- and E-cadherin expressions was associated with poor surgical outcomes of HCC patients undergoing liver resection. PMID- 25438960 TI - Effects of ischemic preconditioning protocols on skeletal muscle ischemia reperfusion injury. AB - BACKGROUND: Ischemic preconditioning (IPC) is described as brief ischemia reperfusion (I/R) cycles to induce tolerance to subsequent in response to longer I/R insults. Various IPC protocols can be performed in four combinations as follows: at early or late phases and on local or distant organs. Although many experimental studies have been performed on IPC, no consensus has been established on which IPC protocol is most effective. The aims of the present study were as follows: (1) to compare the variables of preconditioning in different combinations (in early versus late phases; local versus remote organ implementations) and (2) to determine the most therapeutic IPC protocol(s). MATERIALS AND METHODS: A subtotal hind limb amputation model with clamping an intact femoral pedicle was used for I/R injury. IPC was induced using hind limb tourniquet with 3 * 10 min I/R cycles before longer I/R insult. Forty-nine rats were divided into seven groups (n = 7), sham, IsO (ischemia only), I/R, early ischemic preconditioning (e-IPC), late ischemic preconditioning (l-IPC), early remote ischemic preconditioning (e-RIPC), and l-RIPC (late-remote) groups, respectively. In the sham group, pedicle occlusion was not performed. Six hours ischemia was challenged in the IsO group. Three hours ischemia followed by 3 h reperfusion was performed in the I/R group. The e-IPC group was immediately preconditioned, whereas the l-IPC group was preconditioned 24 h before I/R injury on the same hind limb. In the e-RIPC and l-RIPC groups, the same protocols were performed on the contralateral hind limb. At the end of the experiments, skeletal muscle tissue samples were obtained for biochemical analysis (Malondialdehyde [MDA], catalase, myeloperoxidase [MPO], and nitric oxide end products [NOx]), light microscopy, and caspase-3 immunohistochemistry for determination of apoptosis. RESULTS: Tissue biochemical markers were improved in nearly all the IPC groups compared with IsO and I/R groups (P < 0.05). Similarly, the histologic damage scores were decreased in all the IPC groups (P < 0.05). The lowest damage score was in the e-RIPC group followed by the l-RIPC, e-IPC, and l-IPC groups, respectively. The apoptosis scores were significantly high in the I/R group compared with the e-RIPC and l-RIPC groups (P < 0.05). Although apoptosis scores of the e-IPC and l-IPC groups were lower than the I/R group, this finding was not statistically significant (P > 0.05). CONCLUSIONS: All IPC protocols were effective in reducing I/R injury. Among these protocols, e-RIPC achieved most protection. PMID- 25438962 TI - Robotic-assisted laparoscopic transplant-to-native ureteroureterostomy in a pediatric patient. AB - OBJECTIVE: Management of late-occurring or long (>3 cm) post-transplant ureteral strictures usually requires open surgery, which includes ureteroureterostomy (UU) as an option. Recently, robotic-assisted laparoscopic UU for ectopic ureters in a duplicated system has been described. We report a case of a robotic-assisted laparoscopic transplant-to-native side-to-side UU in a 14-year-old girl with a stricture of nearly two-thirds of her transplant ureter 5 years after a cadaveric renal transplant. RESULTS: Robotic-assisted laparoscopic native-to-transplant UU was performed with resultant durable improvement in the patient's hydronephrosis and kidney function. CONCLUSION: Based on our case and review of the literature, robotic-assisted laparoscopic UU should be part of the armamentarium for long or late-occurring transplant ureteral strictures. PMID- 25438961 TI - Adjuvant neurotrophic factors in peripheral nerve repair with chondroitin sulfate proteoglycan-reduced acellular nerve allografts. AB - BACKGROUND: Acellular nerve allografts are now standard tools in peripheral nerve repair because of decreased donor site morbidity and operative time savings. Preparation of nerve allografts involves several steps of decellularization and modification of extracellular matrix to remove chondroitin sulfate proteoglycans (CSPGs), which have been shown to inhibit neurite outgrowth through a poorly understood mechanism involving RhoA and extracellular matrix-integrin interactions. Chondroitinase ABC (ChABC) is an enzyme that degrades CSPG molecules and has been shown to promote neurite outgrowth after injury of the central and peripheral nervous systems. Variable results after ChABC treatment make it difficult to predict the effects of this drug in human nerve allografts, especially in the presence of native extracellular signaling molecules. Several studies have shown cross-talk between neurotrophic factor and CSPG signaling pathways, but their interaction remains poorly understood. In this study, we examined the adjuvant effects of nerve growth factor (NGF) and glial cell line derived neurotrophic factor (GDNF) on neurite outgrowth postinjury in CSPG reduced substrates and acellular nerve allografts. MATERIALS AND METHODS: E12 chicken DRG explants were cultured in medium containing ChABC, ChABC + NGF, ChABC + GDNF, or control media. Explants were imaged at 3 d and neurite outgrowths measured. The rat sciatic nerve injury model involved a 1-cm sciatic nerve gap that was microsurgically repaired with ChABC-pretreated acellular nerve allografts. Before implantation, nerve allografts were incubated in NGF, GDNF, or sterile water. Nerve histology was evaluated at 5 d and 8 wk postinjury. RESULTS: The addition of GDNF in vitro produced significant increase in sensory neurite length at 3 d compared with ChABC alone (P < 0.01), whereas NGF was not significantly different from control. In vivo adjuvant NGF produced increases in total myelinated axon count (P < 0.005) and motor axon count (P < 0.01), whereas significantly reducing IB4+ nociceptor axon count (P < 0.01). There were no significant differences produced by in vivo adjuvant GDNF. CONCLUSIONS: This study provides initial evidence that CSPG-reduced nerve grafts may disinhibit the prosurvival effects of NGF in vivo, promoting motor axon outgrowth and reducing regeneration of specific nociceptive neurons. Our results support further investigation of adjuvant NGF therapy in CSPG-reduced acellular nerve grafts. PMID- 25438963 TI - Disagreement between self-reported and clinician-ascertained suicidal ideation and its correlation with depression and anxiety severity in patients with major depressive disorder or bipolar disorder. AB - OBJECTIVES: To study the disagreement between self-reported suicidal ideation (SR SI) and clinician-ascertained suicidal ideation (CA-SI) and its correlation with depression and anxiety severity in patients with major depressive disorder (MDD) or bipolar disorder (BPD). METHODS: Routine clinical outpatients were diagnosed with the MINI-STEP-BD version. SR-SI was extracted from the 16 Item Quick Inventory of Depression Symptomatology Self-Report (QIDS-SR-16) item 12. CA-SI was extracted from a modified Suicide Assessment module of the MINI. Depression and anxiety severity were measured with the QIDS-SR-16 and Zung Self-Rating Anxiety Scale. Chi-square, Fisher exact, and bivariate linear logistic regression were used for analyses. RESULTS: Of 103 patients with MDD, 5.8% endorsed any CA SI and 22.4% endorsed any SR-SI. Of the 147 patients with BPD, 18.4% endorsed any CA-SI and 35.9% endorsed any SR-SI. The agreement between any SR-SI and any CA-SI was 83.5% for MDD and 83.1% for BPD, with weighted Kappa of 0.30 and 0.43, respectively. QIDS-SR-16 score, female gender, and >=4 year college education were associated with increased risk for disagreement, 15.44 +/- 4.52 versus 18.39 +/- 3.49 points (p = 0.0026), 67% versus 46% (p = 0.0783), and 61% versus 29% (p = 0.0096). The disagreement was positively correlated to depression severity in both MDD and BPD with a correlation coefficient R(2) = 0.40 and 0.79, respectively, but was only positively correlated to anxiety severity in BPD with a R(2) = 0.46. CONCLUSION: Self-reported questionnaire was more likely to reveal higher frequency and severity of SI than clinician-ascertained, suggesting that a combination of self-reported and clinical-ascertained suicidal risk assessment with measuring depression and anxiety severity may be necessary for suicide prevention. PMID- 25438965 TI - A randomized intervention of reminder letter for human papillomavirus vaccine series completion. AB - PURPOSE: Completion rate for the three-dose series of the human papillomavirus (HPV) vaccine has generally been low. This study evaluated the effectiveness of a reminder letter intervention on HPV vaccine three-dose series completion. METHODS: Female members of Kaiser Permanente Southern California Health Plan who received at least one dose, but not more than two doses, of the HPV vaccine by February 13, 2013, and who were between ages 9 and 26 years at the time of first HPV vaccination were included. Eighty percent of these females were randomized to receive the reminder letter, and 20% were randomized to receive standard of care (control). The reminder letters were mailed quarterly to those who had not completed the series. The proportion of series completion at the end of the 12 month evaluation period was compared using chi-square test. RESULTS: A total of 9,760 females were included in the intervention group and 2,445 in the control group. HPV vaccine series completion was 56.4% in the intervention group and 46.6% in the control groups (p < .001). The effect of the intervention appeared to be stronger in girls aged 9-17 years compared with young women aged 18-26 years at the first dose and in blacks compared with whites. CONCLUSIONS: Reminder letters scheduled quarterly were effective to enhance HPV vaccine series completion among those who initiated the vaccine. However, a large gap in series completion remained despite the intervention. Future studies should address other barriers to series completion, including those at the providers and the health care system level. PMID- 25438964 TI - The effectiveness of a web-based resource in improving postconcussion management in high schools. AB - PURPOSE: Because many sports concussions happen during school-sponsored sports events, most state concussion laws specifically hold schools accountable for coach training and effective concussion management practices. Brain 101: The Concussion Playbook is a Web-based intervention that includes training in sports concussion for each member of the school community, presents guidelines on creating a concussion management team, and includes strategies for supporting students in the classroom. METHODS: The group randomized controlled trial examined the efficacy of Brain 101 in managing sports concussion. Participating high schools (N = 25) were randomly assigned to the Brain 101 intervention or control. Fall athletes and their parents completed online training, and Brain 101 school administrators were directed to create concussion management policy and procedures. RESULTS: Student athletes and parents at Brain 101 schools significantly outperformed those at control schools on sports concussion knowledge, knowledge application, and behavioral intention to implement effective concussion management practices. Students who had concussions in Brain 101 schools received more varied academic accommodations than students in control schools. CONCLUSIONS: Brain 101 can help schools create a comprehensive schoolwide concussion management program. It requires minimal expenditures and offers engaging and effective education for teachers, coaches, parents, and students. PMID- 25438966 TI - Short-term evaluation of a skill-development sexual education program for Spanish adolescents compared with a well-established program. AB - PURPOSE: The Centers for Disease Control and Prevention highlights the importance of evaluating interventions rigorously and recommends evaluating new interventions against interventions with established efficacy. Competencias para adolescentes con una sexualidad saludable (COMPAS) is a school-based HIV prevention program that has been shown to be effective in reducing sexual risk behaviors among adolescents in Spain. This study evaluates the efficacy of COMPAS program compared with a Spanish-culture adapted version of !Cuidate! (Take Care of Yourself), an evidence-based HIV prevention curriculum designed for Latino adolescents in the US. METHODS: This cluster randomized controlled trial involved 1,563 adolescents attending 18 public high schools located in 5 provinces of Spain. The schools invited to participate were enrolled and randomly assigned to the three experimental conditions: COMPAS, !Cuidate!, and control group (CG; no intervention). RESULTS: Generalized estimating equation analyses revealed that both interventions improved attitudes toward people living with human immunodeficiency syndrome (HIV)/AIDS and the HIV test and increased HIV/sexually transmitted infection knowledge and intention to engage in safer sex behaviors compared with the CG. Although only COMPAS increased participants' sexual risk perception and attitude toward condom use compared with the CG, the two interventions did not significantly differ on any outcome. CONCLUSIONS: When compared with an established program, COMPAS was at least as effective at increasing the intention to engage in safer sex behaviors as the evidence-based intervention. PMID- 25438967 TI - Women's perspectives on age restrictions for over-the-counter access to oral contraceptives. AB - PURPOSE: There is a growing movement for an over-the-counter (OTC) oral contraceptive (OC) in the United States. This study aimed to explore women's views regarding an age restriction for an OTC OC. METHODS: From November to December 2011, we administered a nationally representative survey of U.S. women aged 18-44 years who were at risk of unintended pregnancy to explore their opinions of an age restriction for an OTC OC. A total of 2,046 women completed the survey. Weighted proportions were calculated, and logistic regression was used to identify covariates associated with supporting an age restriction. Chi square tests of potential advantages and disadvantages of OTC access to OCs by support for an age restriction were also performed. RESULTS: Overall, 26% of respondents supported an age restriction for an OTC OC; 28% were against an age restriction, and 46% were unsure. In multivariable analysis controlling for overall support for OTC access to OCs and for other covariates, women were more likely to support an age restriction for an OTC OC if they had less than a high school degree (odds ratio [OR], 2.5), a high school degree (OR, 1.6), or some college (OR, 1.6) compared with a college degree; if they were married compared with never married (OR, 2.1); and if they lived in the Midwest (OR, 2.1) or South (OR, 2.1) compared with the West. CONCLUSIONS: A minority of women support an age restriction. Women's concerns about a potential OTC OC should be addressed through education and ongoing research. PMID- 25438969 TI - The role of social support and social context on the incidence of attempted suicide among adolescents living in extremely impoverished communities. AB - PURPOSE: Evaluate the impact of social support and social context on suicide attempt in disadvantaged adolescents, and calculate that longitudinal risk of suicide attempt. METHODS: Seven thousand two hundred ninety-nine adolescents were used to evaluate the effect of social support and context on suicide attempt, and to estimate the overall risk of suicide attempt. RESULTS: Increased peer support reduced the risk of suicide attempt, and increased perceived inevitability of violence led to an increase in risk among 9-year-old children. As children age, the effect of overall peer support remains consistent, while there is a reduction in the effect of inevitability of violence. Approximately 36% of extremely impoverished adolescents attempt suicide by the age of 19. CONCLUSIONS: The current study provides insight into the nature of suicide attempt within a grossly understudied population. Social support and social context have an important impact on suicidal behavior in extremely disadvantaged adolescents. PMID- 25438968 TI - Prospective association between overvaluation of weight and binge eating among overweight adolescent girls. AB - PURPOSE: We investigated whether overvaluation of weight, defined as having a high degree of concern with weight such that it unduly influences self evaluation, was prospectively associated with binge eating onset among overweight adolescent girls and whether overvaluation of weight signaled greater impairment among those with weekly binge eating. METHODS: We used generalized estimating equations to assess the prospective association between weight overvaluation at Time 1 and the onset of weekly binge eating at Time 2 among 767 overweight adolescent girls (ages 12-18 years) participating in the Growing Up Today Study. In a cross-sectional analysis of overweight girls with weekly binge eating at Time 2, we examined whether overvaluation of weight was associated with greater impairment assessed by examining their rates of more severe depressive symptoms and low subjective social status. RESULTS: At Time 1, 24.5% of overweight/obese girls overvalued weight. Overweight girls who overvalued weight were more likely to have started binge eating weekly 2 years later (odds ratio, 2.9; 95% confidence interval [CI], 1.2-7.3). Among overweight girls who reported weekly binge eating at Time 2, those who overvalued weight were at greater risk of having more severe depressive symptoms (odds ratio, 10.4; 95% CI, 1.3-85.6). Also among girls with weekly binge eating at Time 2, we saw a significant association between continuous measures of overvaluation and subjective social status (beta, .71; 95% CI, .08-1.34) but not in analyses using binary measures. CONCLUSIONS: We found that overvaluation was associated with the development of weekly binge eating in overweight girls and with greater impairment among those with weekly binge eating. PMID- 25438970 TI - [The Clubhouse model for people with severe mental illnesses: Literature review and French experiment]. AB - AIM: The aim of this article is 1) to present the Clubhouse (CH) Model and the first French CH, and 2) study the empirical background on the efficiency of the CH concerning employment, quality of life and hospitalization for people with mental illness. HISTORICAL, THEORETICAL AND INSTITUTIONAL BACKGROUND: The first Clubhouse was created sixty years ago in the U.S. The Clubhouse model of psychosocial rehabilitation is a program that offers to people with mental illness support and opportunities to find a job and return to a normal social life. The Clubhouse model has been built over the years thanks to the experiences of members and staff. It is based on "36 standards" (rules which each Clubhouse follows in order to attain its goals). Supported by associations and families of people with mental illness, health professionals, and the international federation of Clubhouses (Clubhouse International), the first Clubhouse in France has opened in November 2011. This non-medicalized association and its co management by both members and staff are innovative in France. The aims of the Clubhouse are founded on the concept of empowerment and "peer-help", and on the fight against isolation and stigmatization. Clubhouses offer day-programs which allow people with mental illness to have a sense of community and a useful purpose within the association. Indeed, the salaried management team is voluntarily understaffed so that the participation of members is necessary and so that they can benefit from the opportunities for useful activity within the Clubhouse, developing a real opportunity of empowerment. METHOD: In order to study the efficiency of CH, we conducted a systematic review of publications on CH, first in the database of Club House International (500 publications) and second, in the scientific data base (Psycinfo, Psycarticles, Academic Search Premier, Medline et Science Direct) (205 publications included in the 500). We identified 64 scientific studies. We have selected 28 of them that focused on the variable: employment, quality of life and hospitalisation. RESULTS: Clubhouses have shown their effectiveness regarding employment, quality of life and hospitalization. Indeed, several studies compare Clubhouses with other programs of psychosocial rehabilitation. The results have demonstrated that Clubhouses' members: find more salaried work, find jobs of higher quality, have a better quality of life and face fewer hospitalizations, than people in other psychosocial rehabilitation programs. DISCUSSION: We discuss the interest of the CH in France using the experiment of the CH in Paris. This experiment in providing an innovative place of support, mutual aid, and autonomy is currently successful in France. Over 18 months, a team of 65 members and 3 staff members has come together. This enthusiasm is probably due to the fact that the Clubhouse in Paris is a place which helps people with mental illness establish a daily rhythm, social usefulness and affective links, all essential for recovery, in a context different from the usual medically supervised care in other settings: people are treated as individuals rather than as "sick persons" or "patients". This article discusses the benefits of this new model of psychosocial rehabilitation in France, by presenting the originality and complimentarity of this concept, in comparison with other health structures. PMID- 25438971 TI - Effects of thyroid hormones on the heart. AB - Thyroid hormones have a significant impact on heart function, mediated by genomic and non-genomic effects. Consequently, thyroid hormone deficiencies, as well as excesses, are expected to result in profound changes in cardiac function regulation and cardiovascular hemodynamics. Thyroid hormones upregulate the expression of the sarcoplasmic reticulum calcium-activated ATPase and downregulate the expression of phospholamban. Overall, hyperthyroidism is characterized by an increase in resting heart rate, blood volume, stroke volume, myocardial contractility, and ejection fraction. The development of "high-output heart failure" in hyperthyroidism may be due to "tachycardia-mediated cardiomyopathy". On the other hand, in a hypothyroid state, thyroid hormone deficiency results in lower heart rate and weakening of myocardial contraction and relaxation, with prolonged systolic and early diastolic times. Cardiac preload is decreased due to impaired diastolic function. Cardiac afterload is increased, and chronotropic and inotropic functions are reduced. Subclinical thyroid dysfunction is relatively common in patients over 65 years of age. In general, subclinical hypothyroidism increases the risk of coronary heart disease (CHD) mortality and CHD events, but not of total mortality. The risk of CHD mortality and atrial fibrillation (but not other outcomes) in subclinical hyperthyroidism is higher among patients with very low levels of thyrotropin. Finally, medications such as amiodarone may induce hypothyroidism (mediated by the Wolff-Chaikoff), as well as hyperthyroidism (mediated by the Jod-Basedow effect). In both instances, the underlying cause is the high concentration of iodine in this medication. PMID- 25438972 TI - Personalized Drug Therapy in Cystic Fibrosis: From Fiction to Reality. AB - Personalized drug therapy for cystic fibrosis (CF) is a long-term dream for CF patients, caregivers, physicians and researchers. After years of study, the fiction of personalized treatment has turned to hope. Basic information about CFTR mutations classes and new treatments is needed if we are to deal properly with the new CF era. The problems involved in this issue, however, should be evaluated with greater care and attention. VX-770 is a new drug available to treat CF patients with some class III CFTR mutations and other drugs are being studied regarding other classes. The scientific literature has constantly given information about each therapy, both in vitro and in vivo. The hope is increasing. Nevertheless the "scientific world" still lacks information about patients' reality and daily health related practical needs. Clinical trials have showed good evaluation of some drugs so far, but clinical response is a wide spectrum yet to be analyzed: CFTR mutations spectrum, costs related to the treatment with new drugs (for VX-770 therapy), variability of CF clinical expression, limitations to test in vitro drugs, absence of good clinical markers to evaluate drug response, absence of long-term studies and with patients below six years old, multidrug treatment used to improve the expression response, and finally, the most important problem, who will benefit from the new drugs therapy, are issues that constitute a barrier that should be overcome. Personalized drug therapy may not be a fiction anymore, but it is not yet a reality for all CF patients. PMID- 25438973 TI - Targeting drugs to APJ receptor: the prospect of treatment of hypertension and other cardiovascular diseases. AB - The APJ is a class A, rhodopsin-like G protein-coupled receptor (GPCR) with high sequence similarity to the angiotensin receptor AT1. APJ has been shown to be widely expressed in humans tissues, including the central nervous system, cardiovascular system, adipocytes and others. APJ plays an important role in the occurrence and development of cardiovascular and metabolic diseases including atherosclerosis (AS), coronary heart disease (CAD), heart failure(HF), pulmonary arterial hypertension (PAH), myocardial hypertrophy and atrial fibrillation, especially hypertension. Previous researchers found that apelin/APJ could induce vasodilation and then reduce blood pressure. Despite APJ is closely associated with many diseases, there are no drugs that can activate or inhibit APJ directly. In the current review, we have summarized recently reported peptides, small molecule agonists and antagonists targeting APJ. Given the role of apelin/APJ in hypertension and other cardiovascular diseases, we believe that the peptides and compounds based on APJ will be developed for treatment of these diseases. PMID- 25438974 TI - The effects of extracellular ATP and its receptor antagonists on pig oocytes during in vitro maturation. AB - We measured the ATP concentrations in the porcine follicular fluid derived from three sizes of follicles (small: 6 mm in diameter). Then, the effects of pre treatment (100 MUM each for 30 min before maturation) with antagonists for extracellular ATP receptor P2X or P2Y on the nuclear maturation rate of cumulus cell-enclosed (COs) or -denuded oocytes (DOs) up to the preovulatory stage in the presence or absence of 20 nM ATP (a similar concentration to that of medium-sized follicle fluid) were investigated. The antagonists used were pyridoxalphosphate-6 azophenyl-2',4'-disulfonic acid (PPADS) or reactive blue 2 (RB2), for extracellular ATP receptor P2X and P2Y, respectively. In addition, the embryonic development rates of COs pre-treated with RB2 were also evaluated. It was found that when the follicular sizes increased, the ATP concentrations significantly decreased (P < 0.05). No differences were observed in the nuclear maturation rates among all COs, regardless of pre-treatment with (+) or without (-) PPADS and in the presence (+) or absence (-) of ATP during maturation. In contrast, the nuclear maturation rate of the COs, but not DOs, in the ATP(-) RB2(+) group was significantly lower (P < 0.05) than that of the ATP(-) RB2(-) and ATP(+)RB2(-) groups. The pronuclear formation and blastocyst formation rates by parthenogenetic activation in the ATP(-) RB2(+) and ATP(+) RB2(+) groups were significantly lower (P < 0.05) than those in the ATP(-) RB2(-) group. In conclusion, it is suggested that the nuclear maturation of porcine oocytes may be influenced by the ATP receptor P2Y present in the cumulus cells. PMID- 25438976 TI - Can we simulate an action that we temporarily cannot perform? AB - AIMS OF THE STUDY: The scope of individuals' motor repertoire and expertise influences the way they perceive the actions of others. When observing skilled actions, experts recruit the cortical network subserving action perception (action observation network, AON) to a greater extent than non-experts. However, it remains unknown whether and how a temporary motor injury affects activation within the AON. MATERIALS AND METHODS: To investigate this issue, brain hemodynamic activity was recorded twice in thirteen national female gymnasts suffering from a lower extremity injury at the onset of the experiment. The gymnasts were scanned one month after the injury and were shown gymnastics routines they were able and temporarily unable to perform. Six months later, after complete recovery, they were scanned again and shown the same routines they were now able to practice. RESULTS: Results showed: first, that the level of activity within the inferior parietal lobule and MT/V5/EBA (extrastriate body area), areas constitutive of the AON, was independent of the gymnasts' physical condition. Second, when gymnasts were hurt (vs. when recovered), higher activity in the cerebellum was detected. CONCLUSION: The equal contribution of MT/V5/EBA and inferior parietal lobule during the observation of movements the gymnasts were able or unable to practice suggests respectively that physical provisional incapacity does not interfere with the perceptual processing of body shape and motion information, and that motor expertise may prevent the decay of sensorimotor representations. Higher activations in the cerebellum may suggest that this structure plays a role in dissociating perceived physically feasible movements from those that are provisionally unfeasible. PMID- 25438977 TI - Neurocognitive processing of emotion facial expressions in individuals with self reported depressive symptoms: the role of personality and anxiety. AB - AIMS OF THE STUDY: Neurocognition may constitute one of the numerous factors that mediate the reciprocal influences between personality and depression. The present study explored the influence of personality and anxiety traits on the neurocognitive processing of emotional faces and specifically focused on personal characteristics related to negative (harm avoidance - HA) and positive affectivity (self-directedness - SD) and to anxiety. MATERIAL AND METHODS: Twenty participants with self-reported depressive symptoms and 18 control participants were selected based on their BDI-II scores. Personality (TCI-R), anxiety and attention were measured and event-related potentials (ERPs) were recorded during an implicit emotional face perception task (fear, sadness, happiness, neutrality). RESULTS: The participants who self-reported depressive symptoms had higher HA, lower SD and higher anxiety compared to controls. Controls showed enhanced P300 and LPP amplitudes for fear. Individuals with self-reported depression showed reduced ERPs amplitudes for happiness. HA did not account for the difference between the groups but high HA and high anxiety were positively correlated with enhanced P300 amplitude for fear in participants with depressive symptoms. In contrast, SD accounted for the difference between the groups but was not correlated to the ERP components' amplitudes recorded for facial expressions. Other personality dimensions (reward dependence, cooperativeness) influenced the ERPs recorded for facial emotions. CONCLUSION: Personality dimensions influence the neurocognitive processing of emotional faces in individuals with self reported depressive symptoms, which may constitute a cognitive vulnerability to depression. PMID- 25438978 TI - Visual processing during recovery from vegetative state to consciousness: comparing behavioral indices to brain responses. AB - BACKGROUND: Auditory stimulation is often used to evoke responses in unresponsive patients who have suffered severe brain injury. In order to investigate visual responses, we examined visual evoked potentials (VEPs) and behavioral responses to visual stimuli in vegetative patients during recovery to consciousness. METHODS: Behavioral responses to visual stimuli (visual localization, comprehension of written commands, and object manipulation) and flash VEPs were repeatedly examined in eleven vegetative patients every two weeks for an average period of 2.6months, and patients' VEPs were compared to a healthy control group. Long-term outcome of the patients was assessed 2-3years later. RESULTS: Visual response scores increased during recovery to consciousness for all scales: visual localization, comprehension of written commands, and object manipulation. VEP amplitudes were smaller, and latencies were longer in the patient group relative to the controls. VEPs characteristics at first measurement were related to long term outcome up to three years after injury. CONCLUSIONS: Our findings show the improvement of visual responding with recovery from the vegetative state to consciousness. Elementary visual processing is present, yet according to VEP responses, poorer in vegetative and minimally conscious state than in healthy controls, and remains poorer when patients recovered to consciousness. However, initial VEPs are related to long-term outcome. PMID- 25438980 TI - PureEEG: automatic EEG artifact removal for epilepsy monitoring. AB - AIM OF THE STUDY: A novel method for removal of artifacts from long-term EEGs was developed and evaluated. The method targets most types of artifacts and works without user interaction. MATERIALS AND METHODS: The method is based on a neurophysiological model and utilizes an iterative Bayesian estimation scheme. The performance was evaluated by two independent reviewers. From 48 consecutive epilepsy patients, 102 twenty-second seizure onset EEGs were used to evaluate artifacts before and after artifact removal and regarding the erroneous attenuation of true EEG patterns. RESULTS: The two reviewers found "major improvements" in 59% and 49% of the EEG epochs respectively, and "minor improvements" in 38% and 47% of the epochs, respectively. The answer "similar or worse" was chosen only in 0% and 4%, respectively. Neither of the reviewers found "major attenuations", i.e., a significant attenuation of significant EEG patterns. Most EEG epochs were found to be either "mostly preserved" or "all preserved". A "minor attenuation" was found only in 0% and 17%, respectively. CONCLUSIONS: The proposed artifact removal algorithm effectively removes artifacts from EEGs and improves the readability of EEGs impaired by artifacts. Only in rare cases did the algorithm slightly attenuate EEG patterns, but the clear visibility of significant patterns was preserved in all cases of this study. Current artifact removal methods work either semi-automatically or with insufficient reliability for clinical use, whereas the "PureEEG" method works fully automatically and leaves true EEG patterns unchanged with a high reliability. PMID- 25438981 TI - Exploring moderating effects of John Henryism Active Coping on the relationship between education and cardiovascular measures in Korean Americans. AB - OBJECTIVE: John Henryism Active Coping (JHAC) is defined as a strong behavioral predisposition to cope with stressors in an effortful and determined manner. The well-known inverse relationship between socioeconomic status (SES) and blood pressure (BP) has been hypothesized to be stronger for individuals who have high JHAC than those with low JHAC, suggesting that JHAC may place people with low SES at higher cardiovascular risk. Previous studies testing this hypothesis have presented mixed findings; therefore, this study was conducted to test the JHAC hypothesis by examining the main and interaction effects of SES and JHAC on cardiovascular risk (measured by BP and arterial stiffness [AS]). METHODS: The sample was 102 Korean Americans (aged 21-60years). Measures included age, sex, body mass index, smoking, SES (measured by income and education), JHAC (measured by the 12-item JHAC Scale), BP, and AS. RESULTS: In terms of the SES measures, only education was significantly related to systolic BP (p=0.003), diastolic BP (p=0.001), and AS (p<0.000). The interaction effects of education and JHAC on systolic BP and AS were also significant (p=0.019 and p=0.018, respectively), indicating that the inverse relationships of education to systolic BP and AS were more prominent in subjects with lower JHAC scores. CONCLUSION: Contrary to the JHAC hypothesis, JHAC may be associated with low cardiovascular risk in people with low education in certain groups. Studies are recommended to examine potential beneficial effects of JHAC on cardiovascular health in a larger sample and to identify their mechanisms. PMID- 25438979 TI - Kinematic and kinetic analysis of the inter- and intra-applicator assessment of the Babinski reflex. AB - AIMS OF THE STUDY: The first aim was to quantify variability in the mechanical technique used by neurologists to elicit the Babinski reflex. The second aim of the study was to assess if the mechanical technique is an important determinant of the subsequent reflex response. MATERIALS AND METHODS: In this study, twelve neurologists elicited the Babinski reflex five times on the same foot of the same participant using a special reflex hammer which recorded the force and duration of the stroke. Hallux movement, tibialis anterior maximum EMG amplitude and pain felt by the participant for each stroke were recorded. RESULTS: A large inter- and intra-applicator variability was shown amongst the neurologists. The change in hallux angle was significantly correlated with the duration of the stroke (R(2)=0.18, P<0.01), maximum (R(2)=0.14, P=0.01) and average (R(2)=0.17, P<0.01) force used to elicit the reflex. No correlations were shown between the hammer forces and duration and the maximum amplitude of the tibialis anterior. Significant correlations were shown between the pain score and the maximum (R(2)=0.15, P<0.01) and average (R(2)=0.17, P=0.001) force used to elicit the Babinski reflex. CONCLUSION: These results indicate that there was substantial variation when performing the Babinski reflex test within and between neurologists which could lead to differences in the resultant reflex and therefore may affect subsequent diagnoses. PMID- 25438982 TI - Towards a better understanding of MS pain: a systematic review of potentially modifiable psychosocial factors. AB - OBJECTIVE: Pain is a common symptom of Multiple Sclerosis (MS). Biomedical treatments achieve only modest reductions in pain severity suggesting that this approach may be too narrow. The aim of this systematic review was to assess evidence for associations between modifiable psychosocial factors and MS pain severity and pain interference and use this evidence to develop a preliminary biopsychosocial model of MS pain. METHODS: Empirical studies of pain in MS utilising standardised pain severity and pain interference measures were included. Online databases (Cochrane, PsychInfo, EMBASE, CINAHL, Medline, Web of Science and World Cat) and reference sections of included articles were searched, and corresponding authors contacted to identify unpublished studies. Information about design, sample size, MS type, time since diagnosis, psychosocial and pain measures and key findings were extracted. Thirty-one studies were assessed for quality and a narrative synthesis was conducted. RESULTS: Similar to primary chronic pain, most studies reported small to medium associations between several psychosocial factors and pain severity and interference. Pain catastrophizing showed consistently strong associations with pain interference. Preliminary findings revealed a strong correlation between pain acceptance and pain interference. However, fear-avoidance appeared less important in MS, and other forms of behavioural avoidance were not explored. CONCLUSIONS: A preliminary model of MS pain outlining specific psychosocial factors is presented with a conceptual formulation from both traditional, and contextual, cognitive behavioural perspectives. Pain catastrophizing, acceptance, and endurance, as opposed to fear avoidance, responses are highlighted as potentially important treatment targets in MS, and directions for future research are outlined. PMID- 25438985 TI - Patients with rheumatoid arthritis have better functional and working ability but poorer general health and higher comorbidity rates today than in the late 1990s. AB - OBJECTIVES: Better treatment strategies and therapeutic options have changed the treatment of rheumatoid arthritis (RA) during the past decade. Our objective was to examine clinical and patient-reported outcomes in patients with RA treated in 1998-99 and 2011-12. METHOD: The cross-sectional observational study included 303 consecutive outpatients (n = 103 in 1998-99 and n = 200 in 2011-12) from the same outpatient clinic. Patient questionnaires included patients' sociodemographics, the Health Assessment Questionnaire (HAQ) for functional ability, the Nottingham Health Profile (NHP) for health-related quality of life (HRQoL), self-reported general health (GH), and operations performed due to RA. A clinical examination was conducted for all patients. Comorbidities according to the Charlson Comorbidity Index (CCI), anti-rheumatic drugs and medications were recorded and the HAQ and NHP dimensions calculated. The results from these two patient cohorts were compared. RESULTS: The cohorts were comparable with regard to age, sex, and RA duration while the patients in the 2011-12 cohort were less often seropositive for rheumatoid factor (RF), had a better socioeconomic situation, better functional and working ability, and a decreased rate of RA surgery. The patients in 2011-12 had higher comorbidities and poorer GH while the HRQoL dimensions did not differ between the cohorts except for better mobility in 2011-12. Methotrexate (MTX) and combinations of conventional anti-rheumatic drugs were more frequently used in 2011-12. Biologicals were used only in 2011-12. CONCLUSIONS: According to our results, more active anti-rheumatic therapy coincides with better RA-related outcomes. However, the result was the opposite with regard to overall health and comorbidities. Is this a new challenge in the treatment RA? PMID- 25438986 TI - Diagnosis of bladder tumours in patients with macroscopic haematuria: a prospective comparison of split-bolus computed tomography urography, magnetic resonance urography and flexible cystoscopy. AB - OBJECTIVE: The aim of this study was to compare split-bolus computed tomography urography (CTU), magnetic resonance urography (MRU) and flexible cystoscopy in patients with macroscopic haematuria regarding the diagnosis of bladder tumours. MATERIALS AND METHODS: In this prospective study, 150 patients underwent CTU, MRU and flexible cystoscopy. Two uroradiologists individually reviewed the images without any clinical information, using a questionnaire. Patient records and pathology reports were also reviewed. RESULTS: At flexible cystoscopy, MRU and CTU, 32, 19 and 15 bladder lesions were identified, respectively. Histopathology showed that 13 of the 29 biopsied lesions were transitional cell carcinomas. Compared with the histopathology, the sensitivity and specificity for detection of tumours by CTU and MRU were 61.5% and 94.9%, and 79.9% and 93.4%, respectively. False-positive detection of bladder tumours, compared with histopathology, was reported in seven CTUs and nine MRUs, whereas the number of false-negative findings was five for CTUs and three for MRUs. CONCLUSIONS: Split bolus CTU or MRU cannot replace cystoscopy in cases of macroscopic haematuria. MRU has a higher sensitivity than split-bolus CTU, and is a potential alternative to flexible cystoscopy. Patients with a low risk of bladder cancer may forgo flexible cystoscopy if a bladder tumour is identified by either CTU or MRU, and proceed straight to transuretheral resection of the bladder. PMID- 25438987 TI - Penile cancer in Scandinavia: Current practice and future perspectives. PMID- 25438988 TI - Length of life gained with surgical treatment of prostate cancer: A population based analysis. AB - OBJECTIVE: The aim of this study was to analyse relative survival, excess mortality and gain in life expectancy in men who underwent radical prostatectomy (RP) for localized prostate cancer (PCa) between 1995 and 2011 in Denmark. MATERIAL AND METHODS: The study population comprised the complete cohort of 6489 men who underwent RP between 1995 and 2011. Risk of mortality was calculated using a competing risk model. Relative survival, excess mortality rate (EMR) and gain in life expectancy in men undergoing RP were calculated using a matched cohort Danish population based on date of birth and date of surgery. RESULTS: During follow-up 328 patients died, 109 (33.2%) of PCa and 219 (66.8%) of other causes. The cumulative incidence of PCa mortality was 5.8% [95% confidence interval (CI) 4.4, 7.2] after 10 years. Relative survival was significantly above 1.0 for RP patients, except for high-risk patients. EMR was -9.34 (95% CI -10.56, -8.13) after 10 years, i.e. nine men would die in excess of the general population. Overall, the gain in life expectancy in men undergoing RP compared with the general population was 0.41 years. CONCLUSION: This population-based study demonstrated that the gain in life expectancy with RP compared with the general population in Denmark is minimal. PMID- 25438989 TI - Prevalence of lower urinary tract symptoms and level of quality of life in men and women with chronic pelvic pain. AB - OBJECTIVES: The aim of this study was to evaluate the prevalence of lower urinary tract symptoms and quality of life in patients with chronic pelvic pain syndrome (CPPS). MATERIALS AND METHODS: The McGill Pain Questionnaire, Dutch Leiden/Leuven Version (MPQ-DLV), Pain Disability Index (PDI), National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), Interstitial Cystitis Symptom Index (ICSI) and Pelvic Pain and Urinary/Frequency Symptom Scale (PUF) were used, based on their specific properties, to assess the symptoms and impact on the quality of life. Total scores and domains were compared for gender. RESULTS: The studied group (N = 35; 18 male, 17 female) showed a good distribution in gender for age [Mann-Whitney U test (MW-U) p = 0.4] and body mass index (MW-U p = 0.2). The MPQ DLV showed significantly higher scores for pain in women for Pain Rating Index - Affective (MW-U p = 0.030) and Total (MW-U p = 0.031), and Visual Analogue Scale for Pain - Most (MW-U p = 0.005). Women were less sexually active (PUF-SA) (chi squared test p = 0.021) and had a significantly higher disability (PDI-T) (MW-U p = 0.005) and MPQ - Quality of Life (MW-U p = 0.003). The urinary symptoms showed similar results for gender (chi-squared test p > 0.05). CONCLUSIONS: A wide variety of symptoms and a negative impact on quality of life were shown. No differences in lower urinary tract symptoms were found between genders. Women were less sexually active than men. Chronic pelvic pain had a significantly higher negative impact on the level of quality of life in women than in men. PMID- 25438990 TI - The role of nurse support within an Internet-delivered weight management intervention: A qualitative study. AB - This qualitative study explored patients' experiences of nurse support for an Internet-delivered weight management intervention. Eighteen patients who had received either basic or regular nurse support (three or seven contacts, respectively) for the Internet intervention were interviewed. The data were analysed using thematic analysis. The findings suggest that more regular support for Internet interventions may have the potential to inhibit the development of autonomous motivation for weight loss, which might lead to problems in sustaining losses after support ends. Further research is now needed to confirm whether motivation is influenced by frequency of nurse support in Internet interventions in order to inform the development of optimal support which promotes sustained weight loss. PMID- 25438991 TI - Time-course study of different innate immune mediators produced by UV-irradiated skin: comparative effects of short and daily versus a single harmful UV exposure. AB - The modulatory effects of solar UV radiation on the immune system have been widely studied. As the skin is the main target of UV radiation, our purpose was to compare the impact on skin innate immunity of two contrasting ways to be exposed to sunlight. Hairless mice were UV irradiated with a single high UV dose simulating a harmful exposure, or with repetitive low UV doses simulating short occasional daily exposures. Skin samples were taken at different times after UV irradiation to evaluate skin histology, inflammatory cell recruitment, epidermal T-cell population and the mitochondrial function of epidermal cells. The transcriptional profiles of pro-inflammatory cytokines, chemokines, antimicrobial peptides and Toll-like receptors were evaluated by RT-PCR and ELISA in tissue homogenates. Finally, a lymphangiography was performed to assess modification in the lymphatic vessel system. A single high UV dose produces a deep inflammatory state characterized by the production of pro-inflammatory cytokines and chemokines that, in turn, induces the recruitment of neutrophils and macrophages into the irradiated area. On the other hand, repetitive low UV doses drive the skin to a photo-induced alert state in which there is no sign of inflammation, but the epithelium undergoes changes in thickness, the lymphatic circulation increases, and the transcription of antimicrobial peptides is induced. PMID- 25438992 TI - Suppression of TRPM7 inhibits proliferation, migration, and invasion of malignant human glioma cells. AB - BACKGROUND: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a dismal prognosis. Despite intensive study on tumor biology, the underlying mechanisms of the unlimited proliferation and progressive local invasion are still poorly understood, and no effective treatment has been developed for GBM patients. AIMS: We determine the role of TRPM7 channels in the growth, migration, and infiltration of malignant glioma cells. METHODS: Using a combination of RT-PCR, Western blot, and patch-clamp techniques, we demonstrated the expression of functional TRPM7 channels of A172 cells, a human glioma cell line, as well as in human glioma tissues. Furthermore, we evaluated the role of TRPM7 in growth, migration, and infiltration of A172 cells with MTT and transwell migration and invasion assays. RESULTS: We showed the expression of functional TRPM7 channels in both A172 cells and human glioma tissues. Suppression of TRPM7 expression with TRPM7-siRNA dramatically reduced the proliferation, migration, and invasion of A172 cells. Pharmacological inhibition of TRPM7 channel with 2 aminoethoxydiphenyl borate (2-APB) showed a similar effect as TRPM7-siRNA. CONCLUSION: We demonstrate that human glioma cells express functional TRPM7 channel and that activation of this channel plays an important role in the proliferation, migration, and invasion of malignant glioma cells. TRPM7 channel may represent a novel and promising target for therapeutic intervention of malignant glioma. PMID- 25438993 TI - Ultra-endurance exercise induces stress and inflammation and affects circulating hematopoietic progenitor cell function. AB - Although amateur sports have become increasingly competitive within recent decades, there are as yet few studies on the possible health risks for athletes. This study aims to determine the impact of ultra-endurance exercise-induced stress on the number and function of circulating hematopoietic progenitor cells (CPCs) and hematological, inflammatory, clinical, metabolic, and stress parameters in moderately trained amateur athletes. Following ultra-endurance exercise, there were significant increases in leukocytes, platelets, interleukin 6, fibrinogen, tissue enzymes, blood lactate, serum cortisol, and matrix metalloproteinase-9. Ultra-endurance exercise did not influence the number of CPCs but resulted in a highly significant decline of CPC functionality after the competition. Furthermore, Epstein-Barr virus was seen to be reactivated in one of seven athletes. The link between exercise-induced stress and decline of CPC functionality is supported by a negative correlation between cortisol and CPC function. We conclude that ultra-endurance exercise induces metabolic stress and an inflammatory response that affects not only mature hematopoietic cells but also the function of the immature hematopoietic stem and progenitor cell fraction, which make up the immune system and provide for regeneration. PMID- 25438994 TI - Investigation of sunlight-induced deterioration of aroma of pummelo (Citrus maxima) essential oil. AB - Deterioration of aromas of pummelo essential oil (EO) induced by sunlight was compared to those induced by heat and oxygen exposure using the techniques of sensory evaluation and GC-MS analysis. The sunlight-exposed EO was found to possess an oily off-flavor odor, which was significantly different from its counterparts induced by oxygen and heat. The strong oily note of the sunlight exposed EO was attributed to the existence of linalool oxides and limonene oxides, as well as the lack of neral and geranial, for which UV sunlight was revealed to be the critical contributor causing the chemical reactions for the aroma changes. The results demonstrated that UV sunlight could significantly affect the aroma of the pummelo EO, providing valuable information that will benefit the production and storage of EO-based aromatic products. PMID- 25438995 TI - Immuno-oncology comes of age-introduction. PMID- 25438996 TI - Current perspectives on immunotherapy. AB - After many years of disappointments, the successful development and commercialization of the first immune checkpoint inhibitor, and regulatory approval of a dendritic cell (DC)-based cancer vaccine has led to renewed interest and enthusiasm for cancer immunotherapy. Approval of ipilimumab, an antibody targeting cytotoxic T-lymphocyte-associated antigen 4 for advanced melanoma, and sipuleucel-T, an autologous DC-based vaccine for advanced prostate cancer have brought immunotherapy to the forefront of cancer therapeutics and made the goal of long-term tumor control for patients with advanced metastatic disease seem achievable. Additionally, encouraging data from early clinical trials of other immune checkpoint inhibitors targeting programmed cell death 1 and programmed cell death ligand 1 and numerous therapeutic vaccines in development have further expanded interest in the potential of cancer immunotherapy. These recent developments represent the fruits of years of preclinical and clinical research to better understand the complex mechanisms of immune regulation and the ways in which tumors exploit those mechanisms to evade and avoid the antitumor immune response. PMID- 25438997 TI - Mechanism of action of immunotherapy. AB - The immune system plays a vital role in regulating the growth of tumors. Some types of inflammatory responses can promote tumor growth, while a tumor-specific adaptive immune response can potentially control tumor growth. Malignancies have the ability to evade the immune system, and proliferate and metastasize. The goal of immunotherapy is to marshal the specificity and long-term memory of the adaptive immune response to achieve durable tumor regression and possible cure, although, to date, this has been achieved in only a small subset of patients. A variety of approaches to immunotherapy have been investigated. These include administration of exogenous cytokines or therapeutic vaccines to increase the frequency of tumor-specific T cells, adoptive transfer of tumor-specific immune effector cells, and, more recently, the application of a variety of immune checkpoint inhibitors and agonists of co-stimulatory receptors to overcome tumor induced immune-suppressive mechanisms. Some approaches have been more successful than others for reasons that are now becoming apparent, and these observations have led to an exciting resurgence in clinical research to develop more effective immunotherapeutic strategies. PMID- 25438998 TI - Future approaches in immunotherapy. AB - Advances in our understanding of the complex mechanisms of immune regulation and the interactions between tumor cells and the immune system have provided a solid foundation for advancing cancer immunotherapy and have inspired novel therapeutic strategies. Optimizing the effectiveness of immunotherapy will require targeting the antitumor immune response at multiple levels, and this may be achieved through synergistic combinations. Examples include combining two cancer vaccines to achieve a "prime and boost" effect, combining two immune checkpoint inhibitors, combining immunotherapy with targeted agents, or combining immunotherapy with low-dose chemotherapy or radiation. Immune checkpoint inhibitors, such as ipilimumab and nivolumab, will likely play an important role in the future of immunotherapy. The ability to block key pathways by which tumor cells seek to evade or suppress the immune response is critical to realizing the potential of cancer immunotherapy. Other exciting advances include recombinant oncolytic viruses and adoptive transfer of chimeric antigen receptor T cells. However, many challenges remain if durable tumor eradication with minimal toxicity is to be achieved in a broader population of cancer patients. PMID- 25438999 TI - Comment on: Is glycosylated hemoglobin A1 c associated with increased risk for severe early postoperative complications in nondiabetics after laparoscopic gastric bypass? PMID- 25439001 TI - Bariatric surgery in the very young.... a stitch in time or a rush to judgment? PMID- 25439000 TI - Co-morbidity resolution in morbidly obese children and adolescents undergoing sleeve gastrectomy. AB - BACKGROUND: Bariatric surgery is becoming important for the reversal of co morbidities in children and adolescents. We previously reported the safety and efficacy of laparoscopic sleeve gastrectomy (LSG) in the pediatric population. However, evidence pertaining to the effect of LSG on co-morbidities in this age group is scarce. The objective of this study was to assess the remission and improvement of co-morbidities (dyslipidemia, hypertension, diabetes, and obstructive sleep apnea) after LSG in children and adolescents. METHODS: Anthropometric changes, complications, remission, and improvement in co morbidities were assessed over 3 years. OSA was diagnosed using the Pediatric Sleep Questionnaire (PSQ) and polysomnography and its resolution was assessed according to PSQ score alone. Diabetes, prediabetes, hypertension, prehypertension, and dyslipidemia were assessed using standard pediatric-specific definitions. RESULTS: The review yielded 226 patients; 74 patients were prepubertal (5-12 yr of age, mean: 9.8+/-2.3), 115 adolescents (13-17 yr of age, mean: 15.4+/-1.7), and 37 were young adults (18-21 yr of age, mean: 19.2+/-.8). Overall mean age was 14.4+/-4.0 years (range: 4.94-20.99), and 50.4% were females. Mean body mass index (BMI) and BMI z score were 48.2+/-10.1 kg/m(2) and 2.99+/-.35, respectively. Mean BMI z score at 1, 2, and 3 years postoperative was 2.01+/-.87, 2.00+/-1.07, and 1.66+/-.65, respectively. Mean preoperative height was 158.0+/-15.1 cm, and at 1, 2, and 3 years postoperative, it was 160.3+/-13.4, 161.4+/-14.1, and 163.2+/-11.1, respectively. All patients at different age groups experienced normal growth velocity. Within 2 years of follow-up, 90.3% of co-morbidities were in remission or improved, 64.9% of which were within the first 3 months postoperatively. No further improvement or remission was observed beyond 2 years, and there was no recurrence up to 3 years in patients who were seen in follow-up. The lost to follow-up in each of the 3 years was 4.2%, 7.6%, and 15.3%, respectively. CONCLUSION: LSG performed on children and adolescents results in remission or improvement of>90% of co-morbidities within 2 years after bariatric surgery with few complications, no mortality, and normal growth. PMID- 25439002 TI - Comment on: "experience of excess skin after gastric bypass or duodenal switch in patients with super obesity". PMID- 25439005 TI - A neglected giant metastatic melanoma. PMID- 25439003 TI - Bariatric surgery-induced weight loss changes immune markers in the endometrium of morbidly obese women. AB - BACKGROUND: Obesity has been linked to abnormal estrogen regulation, endometrial hyperplasia, and endometrial cancer (EC). Our group has shown that hormone receptor expression profiles in the endometria of morbidly obese women change with weight loss, in some cases concordantly with resolving hyperplasia; however other potential drivers of neoplasia, including altered immunologic tolerance exist. The objective of this study was to evaluate the effect of bariatric surgery induced weight loss on the expression patterns of nonhormone receptor biomarkers associated with cancer and immunity. METHODS: Endometrial biopsies were obtained from 59 asymptomatic, morbidly obese women at the time of bariatric surgery and again 1 year postsurgery. Tissue microarrays were created and immunohistochemical stains for CD3, CD20, and PTEN were performed on all samples and evaluated by 2 blinded pathologists independently. Approximately 50% of participants had sufficient tissue for analysis at both visits. McNemar/Bowker tests of symmetry were performed to compare proportions between categories for matched pairs (pre- and post-treatment). RESULTS: Endometrial hyperplasia was identified in 4 women despite negative clinical histories and resolution of hyperplasia after weight loss occurred in 3 women. While overall no significant differences were observed between matched pre and postsurgery levels of CD20 and CD3 positive cells, a tendency toward decreased expression levels from baseline status was observed for CD20. No differences were observed for PTEN. CONCLUSION: Our data demonstrate that the prevalence of endometrial pathology appears to be partially mitigated by weight loss. Weight loss is associated with alterations in the hormone receptor profiles, but these data suggest that changes in the immune response, as measure be expression of CD20+, may be relevant targets for EC prevention research. PMID- 25439007 TI - Life-stage differences in spatial genetic structure in an irruptive forest insect: implications for dispersal and spatial synchrony. AB - Dispersal determines the flux of individuals, energy and information and is therefore a key determinant of ecological and evolutionary dynamics. Yet, it remains difficult to quantify its importance relative to other factors. This is particularly true in cyclic populations in which demography, drift and dispersal contribute to spatio-temporal variability in genetic structure. Improved understanding of how dispersal influences spatial genetic structure is needed to disentangle the multiple processes that give rise to spatial synchrony in irruptive species. In this study, we examined spatial genetic structure in an economically important irruptive forest insect, the spruce budworm (Choristoneura fumiferana) to better characterize how dispersal, demography and ecological context interact to influence spatial synchrony in a localized outbreak. We characterized spatial variation in microsatellite allele frequencies using 231 individuals and seven geographic locations. We show that (i) gene flow among populations is likely very high (Fst ~ 0); (ii) despite an overall low level of genetic structure, important differences exist between adult (moth) and juvenile (larvae) life stages; and (iii) the localized outbreak is the likely source of moths captured elsewhere in our study area. This study demonstrates the potential of using molecular methods to distinguish residents from migrants and for understanding how dispersal contributes to spatial synchronization. In irruptive populations, the strength of genetic structure depends on the timing of data collection (e.g. trough vs. peak), location and dispersal. Taking into account this ecological context allows us to make more general characterizations of how dispersal can affect spatial synchrony in irruptive populations. PMID- 25439006 TI - Effectiveness of computerized clinical decision support systems for asthma and chronic obstructive pulmonary disease in primary care: a systematic review. AB - BACKGROUND: The use of computerized clinical decision support systems may improve the diagnosis and ongoing management of chronic diseases, which requires recurrent visits to multiple health professionals, disease and medication monitoring and modification of patient behavior. The aim of this review was to systematically review randomized controlled trials evaluating the effectiveness of computerized clinical decision systems (CCDSS) in the care of people with asthma and COPD. METHODS: Randomized controlled trials published between 2003 and 2013 were searched using multiple electronic databases Medline, EMBASE, CINAHL, IPA, Informit, PsychINFO, Compendex, and Cochrane Clinical Controlled Trials Register databases. To be included, RCTs had to evaluate the role of the CCDSSs for asthma and/or COPD in primary care. RESULTS: Nineteen studies representing 16 RCTs met our inclusion criteria. The majority of the trials were conducted in patients with asthma. Study quality was generally high. Meta-analysis was not conducted because of methodological and clinical heterogeneity. The use of CCDSS improved asthma and COPD care in 14 of the 19 studies reviewed (74%). Nine of the nineteen studies showed statistically significant (p < 0.05) improvement in the primary outcomes measured. The majority of the studies evaluated health care process measures as their primary outcomes (10/19). CONCLUSION: Evidence supports the effectiveness of CCDSS in the care of people with asthma. However there is very little information of its use in COPD care. Although there is considerable improvement in the health care process measures and clinical outcomes through the use of CCDSSs, its effects on user workload and efficiency, safety, costs of care, provider and patient satisfaction remain understudied. PMID- 25439008 TI - Cone beam breast CT with multiplanar and three dimensional visualization in differentiating breast masses compared with mammography. AB - OBJECTIVE: This pilot study was to evaluate cone beam breast computed tomography (CBBCT) with multiplanar and three dimensional (3D) visualization in differentiating breast masses in comparison with two-view mammograms. METHODS: Sixty-five consecutive female patients (67 breasts) were scanned by CBBCT after conventional two-view mammography (Hologic, Motarget, compression factor 0.8). For CBBCT imaging, three hundred (1024 * 768 * 16b) two-dimensional (2D) projection images were acquired by rotating the x-ray tube and a flat panel detector (FPD) 360 degree around one breast. Three-dimensional CBBCT images were reconstructed from the 2D projections. Visage CS 3.0 and Amira 5.2.2 were used to visualize reconstructed CBBCT images. RESULTS: Eighty-five breast masses in this study were evaluated and categorized under the breast imaging reporting and data system (BI-RADS) according to plain CBBCT images and two-view mammograms, respectively, prior to biopsy. BI-RADS category of each breast was compared with biopsy histopathology. The results showed that CBBCT with multiplanar and 3D visualization would be helpful to identify the margin and characteristics of breast masses. The category variance ratios for CBBCT under the BI-RADS were 23.5% for malignant tumors (MTs) and 27.3% for benign lesions in comparison with pathology, which were evidently closer to the histopathology results than those of two-view mammograms, p value <0.01. With the receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) of CBBCT was 0.911, larger than that (AUC 0.827) of two-view mammograms, p value <0.01. CONCLUSION: CBBCT will be a distinctive noninvasive technology in differentiating and categorizing breast masses under BI-RADS. CBBCT may be considerably more effective to identify breast masses, especially some small, uncertain or multifocal masses than conventional two-view mammography. PMID- 25439009 TI - Prevalence of asymptomatic coronary disease in fibrosing idiopathic interstitial pneumonias. AB - BACKGROUND: Because of growing body of interest on the association between fibrosing idiopathic interstitial pneumonias (f-IIP) and ischaemic heart disease, we initiated this prospective study to evaluate the prevalence of asymptomatic coronary artery disease (CAD) in patients with f-IIP. METHODS: Forty-two patients with f-IIP underwent noninvasive screening for CAD that included (a) a chest CT examination enabling calculation of the coronary artery calcium (CAC) score, then depiction of coronary artery stenosis; and (b) stress myocardial perfusion scintigraphy (MPS). Patients with significant coronary abnormalities, defined by a CAC score >400 or coronary artery stenosis >50% at CT and/or perfusion defect >5% at MPS, were referred to the cardiologist. Coronary angiography was indicated in presence of a perfusion defect >10% at MPS or significant left main or proximal left anterior descending stenosis whatever MPS findings. RESULTS: Combining CT and MPS, significant abnormalities were detected in 32/42 patients (76%). The cardiologist: (a) did not consider further investigation in 21 patients (CT abnormalities but no ischaemia at MPS: 12/21; false-positive findings at MPS: 3/21; poor respiratory condition: 6/21); (b) proceeded to coronary angiography in 11 patients which confirmed significant stenoses in 5 patients (5/42; 12%). In the worst-case-scenario (i.e., inclusion of 6 patients with significant coronary artery abnormalities who were not investigated due to poor respiratory condition), the prevalence of CAD reached 26% (11/42). CONCLUSION: In the studied population of patients with f-IIP, asymptomatic CAD ranged between 12% and 26%. PMID- 25439010 TI - A novel mechanism for cytoprotection against hypoxic injury: delta-opioid receptor-mediated increase in Nrf2 translocation. AB - BACKGROUND AND PURPOSE: Hypoxia/reoxygenation induces synthesis of reactive oxygen species (ROS) which can attack macromolecules and cause brain injury. The transcription factor, nuclear factor (erythroid-derived 2)-like 2, (Nrf2), ia potent activator of genes with an antioxidant responsive element and Nrf2 can counteract oxidative injury by increasing expression of several antioxidative genes in response to ROS stress. Here, we show that activation of the delta opioid receptor (DOR) increasedNrf2 protein expression and translocation, thereby leading to cytoprotection. EXPERIMENTAL APPROACH: We used HEK293t cells exposed to 0.5% O2 for 16 h and then reoxygenated for 4 h as a model of hypoxia reperfusion (H/R) injury. Real time PCR, Western blotting, siRNA and immunohistochemical techniques were used to follow Nrf2 expression and activity. Cell viability and damage (as LDH leakage) were also measured. KEY RESULTS: H/R injury triggered Nrf2 translocation into the nucleus and up-regulated expression of several downstream genes, relevant to antioxidation, such as NAD(P)H: quinone oxidoreductase (NQO1). Incubation with the DOR agonist UFP-512 enhanced Nrf2 protein expression and translocation and up-regulated its downstream genes in normoxia and further increased Nrf2 expression and translocation after H/R, protecting the cells against loss of viability and damage. The effect of UFP-512 on Nrf2 nuclear translocation was blocked by the DOR antagonist, naltrindole. Also, DOR-mediated cytoprotection was strongly inhibited after transfection of HEK293t cells with Nrf2 siRNA. CONCLUSIONS AND IMPLICATIONS: The DOR agonist UFP 512 was cytoprotective against H/R injury and this effect was partly dependent on DOR-mediated increase in Nrf2 function. PMID- 25439011 TI - Cesium radioactivity in peripheral blood is linearly correlated to that in skeletal muscle: analyses of cattle within the evacuation zone of the Fukushima Daiichi Nuclear Power Plant. AB - The accident at the Fukushima Daiichi Nuclear Power Plant (FNPP) released a large amount of radioactive substances into the environment. Furthermore, beef contaminated with radioactive cesium above the 500 Bq/kg safety standard was circulated in the food chain in 2011. Japanese consumers remain concerned about the safety of radioactively contaminated food. In our previous study, we detected a linear correlation between radioactive cesium ((137) Cs) activity in blood and muscle around 500 to 2500 Bq/kg in cattle. However, it was unclear whether the correlation was maintained at a lower radioactivity close to the current safety standard of 100 Bq/kg. In this study, we evaluated 17 cattle in the FNPP evacuation zone that had a (137) Cs blood level less than 10 Bq/kg. The results showed a linear correlation between blood (137) Cs and muscle (137) Cs (Y = 28.0X, R(2) = 0.590) at low radioactivity concentration, indicating that cesium radioactivity in the muscle can be estimated from blood radioactivity. This technique would be useful in detecting high-risk cattle before they enter the market, and will contribute to food safety. PMID- 25439012 TI - Influence of the duration of the second stage of labor on the likelihood of obstetric anal sphincter injury. AB - BACKGROUND: Duration of the second stage of labor has been suggested as an independent risk factor for clinically detectable obstetric anal sphincter injury in low-risk nulliparous women. METHODS: A retrospective 5-year cohort study was conducted in a UK obstetrics center which included a high-risk delivery unit and a low-risk birthing center. The study included 4,831 nulliparous women with vertex-presenting, single, live-born infants at term, stratified according to spontaneous or instrumental delivery. Binary logistic regression models were used to examine the association between duration of second stage and sphincter injury. RESULTS: Three-hundred twenty-five of 4,831 women (6.7%) sustained sphincter injuries. In spontaneously delivering women, no association between duration of the second stage and the likelihood of sphincter injury was recorded. Factors associated with increased likelihood of sphincter injury included older maternal age, higher birthweight, and Southeast Asian ethnicity. In contrast, for women undergoing instrumental delivery, a longer second stage was associated with an increased sphincter injury risk of 6 percent per 15 minutes in the second stage of labor before delivery. CONCLUSIONS: For spontaneous vaginal deliveries, duration of the second stage of labor was not an independent risk factor for obstetric anal sphincter injury. The association between prolonged second stage and sphincter injury for instrumental deliveries is likely explained by the risk posed by the use of the instruments themselves or by delay in initiating instrumental assistance. Attempts to modify the duration of the second stage for prevention of sphincter injuries are unlikely to be beneficial and may be detrimental. PMID- 25439013 TI - Evaluation and treatment of developmental hip dysplasia in the newborn and infant. AB - Developmental dysplasia of the hip (DDH) encompasses a spectrum of physical and imaging findings. The child's hip will not develop normally if it remains unstable and anatomically abnormal by walking age. Therefore, careful physical examination of all infants to diagnosis and treat significant DDH is critical to provide the best possible functional outcome. Regardless of the practice setting, all health professionals who care for newborns and infants should be trained to evaluate the infant hip for instability and to provide appropriate and early conservative treatment or referral. PMID- 25439014 TI - Transient synovitis, septic hip, and Legg-Calve-Perthes disease: an approach to the correct diagnosis. AB - Transient synovitis, septic hip, and Legg-Calve-Perthes disease are common conditions in children. Distinguishing between these disorders can be a diagnostic challenge. Similar presentations, in an age group difficult to examine, coupled with literature that is confusing creates difficulty. It is important to make the correct diagnosis of septic hip in a timely fashion to avoid serious and potentially crippling consequences. As there is no single test for discriminating between these conditions, knowledge of the nuances of clinical presentation, physical examination, laboratory investigations, and imaging is essential. Judicious use of clinical algorithms can complement clinical acumen. PMID- 25439015 TI - Slipped capital femoral epiphysis: how to evaluate with a review and update of treatment. AB - Slipped capital femoral epiphysis (SCFE) involves displacement of the proximal femoral metaphysis relative to a fixed epiphysis, usually during a period of rapid growth and unique physeal susceptibility. Patients have characteristic clinical, histologic, and radiologic features. Several clinical signs and medical diagnoses should prompt radiologic and laboratory workup. Limp or hip or knee pain in a patient 10 to 16 years old should include SCFE in the differential. If confirmed, appropriate treatment involves proximal femoral physeal stabilization and/or realignment. The optimal surgical treatment of severe SCFE and its late sequela remain an evolving and controversial subject. PMID- 25439017 TI - Assessment and treatment of knee pain in the child and adolescent athlete. AB - Knee pain in children and adolescents is one of the most prevalent complaints in a pediatric practice, accounting for at least a third of musculoskeletal complaints. Accurate diagnosis requires an understanding of knee anatomy and patterns of knee injuries and skill in physical examination. This review covers the most common causes of knee pain in children and adolescents, including overuse issues, such as Osgood-Schlatter and osteochondritis dissecans, as well as traumatic injuries, including tibial spine fractures and anterior cruciate ligament injuries. PMID- 25439016 TI - Assessment and treatment of hip pain in the adolescent athlete. AB - Hip pain in the adolescent athlete is a common source of functional impairment and can limit athletic performance. In the past, many intra- and extra-articular hip abnormalities went unrecognized and were left untreated because of insufficient diagnostic imaging and limited surgical options. However, over the past 20 years, there has been a tremendous expansion research, and the understanding of the etiology of hip pain among such athletes has grown. Improvements in imaging modalities and technical innovations have led to greater diagnostic insights and creative new treatment strategies. This article explores the etiology and treatment of hip pain in the adolescent athlete. PMID- 25439018 TI - Lower extremity rotational and angular issues in children. AB - Familial concern regarding perceived rotational and angular deformities is a common part of any primary care practice. It is essential for the medical practitioner to understand the wide normal range in children and the natural history of lower extremity development over time. Most lower extremity rotational and angular issues in young children resolve spontaneously over time, and require little or no intervention. In the current atmosphere of medical cost containment, coupled with the shortage of pediatric orthopedic surgeons, many of these patients should be managed by the primary care provider and do not require referral for more specialized care. PMID- 25439019 TI - Foot pain in the child and adolescent. AB - There are multiple causes of pediatric foot and ankle pain. Although conservative measures are appropriate for initial management, patients with refractory pain should be given consideration for further intervention. This review highlights some of the most common causes of foot and ankle pain in the child, with specific attention to demographics, etiologies, diagnostic workup, and treatment options. PMID- 25439020 TI - Evaluation and treatment of childhood musculoskeletal injury in the office. AB - Evaluation and treatment of acute musculoskeletal injuries can be rewarding for primary care providers. They are common presenting complaints, and with appropriate management, many patients make a full recovery in a short period of time. This article reviews basic principles of evaluation of acutely injured children, treatment strategies, and common injuries, and gives an overview of similar but more dangerous conditions that require referral. PMID- 25439021 TI - Update on evaluation and treatment of scoliosis. AB - Scoliosis is a spinal deformity that can be seen in children of all ages. It is most commonly seen as an adolescent idiopathic condition. Progressive scoliosis between 25 degrees and 45 degrees before skeletal and physiologic maturity can be treated with a brace, whereas progressive scoliosis greater than 50 degrees should be treated surgically. For children younger than 10 years, it is important to not only prevent scoliosis from worsening but to also maintain the growth of the spine and chest wall through the use of growth-friendly surgical techniques. Spinal fusion and instrumentation surgery is generally reserved for adolescent patients. PMID- 25439022 TI - Update on the evaluation and treatment of osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that presents with a wide clinical phenotype spectrum: from perinatal lethality and severe deformities to very mild forms without fractures. Most cases of OI are due to autosomal dominant mutations of the type I collagen genes. A multidisciplinary approach with rehabilitation, orthopedic surgery, and consideration of medical therapy with bisphosphonates underpins current management. Greater understanding of the pathogenesis of OI may lead to novel, therapeutic approaches to help improve clinical symptoms of children with OI in the future. PMID- 25439023 TI - Pediatric orthopedics. Foreword. PMID- 25439024 TI - Pediatric orthopedics for the primary care provider. Preface. PMID- 25439025 TI - Community-acquired pneumonia: why aren't national antibiotic guidelines followed? AB - AIMS: Adherence to guidelines for the management of community-acquired pneumonia (CAP) has been shown to improve patients' clinical outcomes. This study aimed to assess adherence to the Australian Therapeutic Guidelines (TG14) for the empirical management of CAP, and explore the potential barriers affecting adherence to these guidelines. METHODS: Medical records were reviewed for all patients who were diagnosed with CAP within 24 h of presentation at the Royal Hobart Hospital, the main teaching hospital in Tasmania, Australia, between July 2010 and March 2011. A survey of emergency department and medical team prescribers was also undertaken to identify potential barriers to adhere with the guidelines. chi(2) and Fisher's exact tests were used to test the significance between categorical data. To compare categorical and scale data, the Mann-Whitney U-test was used. RESULTS: A total of 193 patient records were assessed. The overall adherence to TG14 for the empirical antibiotic management of CAP was 16.1% (3.1%, 20.7% and 25.4% for patients with mild, moderate and severe CAP, respectively). Ceftriaxone was prescribed to 34.4%, 26.8% and 57.4% of patients with mild, moderate and severe CAP, respectively. The response rate to the barrier survey was 43.1%; of those who responded, 46.4% thought the influence of senior doctors on junior doctors could be a factor affecting adherence to the guidelines. Other barriers noted were a lack of guideline awareness (39.3%), the requirement to calculate the severity of CAP (35.7%), and the existence of other guidelines that conflict with TG14 (28.6%). CONCLUSIONS: Adherence to CAP treatment guidelines was poor, especially in patients with mild disease. Prescribing was mainly influenced by senior doctors. Efforts to improve compliance with CAP treatment guidelines should consider the potential barriers that hinder adherence. PMID- 25439026 TI - Meal timing influences daily caloric intake in healthy adults. AB - The role that meal pattern plays in weight regulation is a popular topic of scientific and common debate. The goal of this study was to evaluate the relationship between meal timing with caloric intake and body mass index (BMI). We hypothesized that late meal timing and eating closer to sleep onset time would be associated with greater energy intake and higher BMI. Participants included 59 individuals recruited from the community. Rest/activity patterns were assessed using 7 days of wrist actigraphy, and caloric intake was evaluated using 7 days of diet logs. Results demonstrated that the timing of meals was associated with overall energy intake but not with BMI. In multivariate analyses controlling for age, sex, sleep duration, and timing, eating more frequently, later timing of the last meal, and a shorter duration between last meal and sleep onset predicted higher total caloric intake. In a mediational model, eating frequency explained the relationship between eating closer to sleep onset and total caloric intake. Results suggest that later relative timing of meals, particularly eating close to sleep, could lead to weight gain due to a greater number of eating occasions and higher total daily caloric intake. These findings have important implications for the development of novel, time-based interventions for weight management. PMID- 25439027 TI - Sulforaphane increases the survival rate in rats with fulminant hepatic failure induced by D-galactosamine and lipopolysaccharide. AB - Fulminant hepatic failure (FHF) is a life-threatening clinical syndrome, with liver transplantation being the only effective therapy. Sulforaphane (SFN) is a natural compound that is extracted from cruciferous vegetables and possesses potent anti-inflammatory, antioxidant, and anticancer activities. This study was designed to test the hypothesis that SFN (3 mg/kg) may protect against FHF induced in rats by administering a combination of D-galactosamine (GalN; 300 mg/kg) and lipopolysaccharide (LPS; 30 MUg/kg). The rats were given a single intraperitoneal injection of SFN, 1 hour before the FHF induction. Sulforaphane reduced the mortality and alleviated the pathological liver injury. In addition, SFN significantly reduced the increase in serum aminotransferase activities and lipid peroxidation. The glutathione content decreased in the GalN/LPS group, and this decrease was attenuated by SFN. Increases in serum tumor necrosis factor alpha, interleukin-6, and interleukin-10, which were observed in GalN/LPS-treated rats, were significantly reduced after using SFN. The GalN/LPS treatment increased the expression of superoxide dismutase-1, glutathione peroxidase 2, catalase, and heme oxygenase-1 genes. Sulforaphane inhibited the induction of reactive oxygen species scavenging proteins. Moreover, SFN inhibited GalN/LPS induced caspase-3 activation and suppressed FAS and FASL expression. These findings suggest that SFN alleviates GalN/LPS-induced liver injury, possibly by exerting antioxidant, anti-inflammatory, and antiapoptotic effects and modulating certain antioxidant defense enzymes. PMID- 25439030 TI - President's message. PMID- 25439029 TI - Increasing leucine concentration stimulates mechanistic target of rapamycin signaling and cell growth in C2C12 skeletal muscle cells. AB - Leucine is a key amino acid for initiating translation in muscle cells, but the dose-dependent effects of leucine on intracellular signaling are poorly characterized. This study examined the effect that increasing doses of leucine would have on changes in mechanistic target of rapamycin (mTOR)-mediated signaling, rates of protein synthesis, and cell size in C2C12 cells. We hypothesized that a leucine "threshold" exists, which represents the minimum stimulus required to initiate mTOR signaling in muscle cells. Acute exposure to 1.5, 3.2, 5.0, and 16.1 mM leucine increased phosphorylation of mTOR(Ser2448) (~1.4-fold; P < .04), 4E-BP1 (Thr37/46) (~1.9-fold; P < .001), and rpS6(Ser235/6) (~2.3-fold; P < .001). However, only p70S6k(Thr389) exhibited a dose-dependent response to leucine with all treatments higher than control (~4-fold; P < .001) and at least 5 mM higher than the 1.5-mM concentration (1.2-fold; P < .02). Rates of protein synthesis were not altered by any treatment. Seven days of exposure to 0.5, 1.5, 5.0, and 16.5 mM leucine resulted in an increase in cell size in at least 5 mM treatments (~1.6-fold, P < .001 vs control). Our findings indicate that even at low leucine concentrations, phosphorylation of proteins regulating translation initiation signaling is enhanced. The phosphorylation of p70S6k(Thr389) follows a leucine dose-response relationship, although this was not reflected by the acute protein synthetic response. Nevertheless, under the conditions of the present study, it appears that leucine concentrations of at least 5 mM are necessary to enhance cell growth. PMID- 25439031 TI - International Journal for Parasitology. PMID- 25439028 TI - Dietary broccoli mildly improves neuroinflammation in aged mice but does not reduce lipopolysaccharide-induced sickness behavior. AB - Aging is associated with oxidative stress and heightened inflammatory response to infection. Dietary interventions to reduce these changes are therefore desirable. Broccoli contains glucoraphanin, which is converted to sulforaphane (SFN) by plant myrosinase during cooking preparation or digestion. Sulforaphane increases antioxidant enzymes including NAD(P)H quinone oxidoreductase and heme oxygenase I and inhibits inflammatory cytokines. We hypothesized that dietary broccoli would support an antioxidant response in brain and periphery of aged mice and inhibit lipopolysaccharide (LPS)-induced inflammation and sickness. Young adult and aged mice were fed control or 10% broccoli diet for 28 days before an intraperitoneal LPS injection. Social interactions were assessed 2, 4, 8, and 24 hours after LPS, and mRNA was quantified in liver and brain at 24 hours. Dietary broccoli did not ameliorate LPS-induced decrease in social interactions in young or aged mice. Interleukin-1beta (IL-1beta) expression was unaffected by broccoli consumption but was induced by LPS in brain and liver of adult and aged mice. In addition, IL 1beta was elevated in brain of aged mice without LPS. Broccoli consumption decreased age-elevated cytochrome b-245 beta, an oxidative stress marker, and reduced glial activation markers in aged mice. Collectively, these data suggest that 10% broccoli diet provides a modest reduction in age-related oxidative stress and glial reactivity, but is insufficient to inhibit LPS-induced inflammation. Thus, it is likely that SFN would need to be provided in supplement form to control the inflammatory response to LPS. PMID- 25439032 TI - Color and Gloss of Nano-Filled Resin-Modified Glass Ionomers and Resin Composites. AB - OBJECTIVE: The study aims to compare in vitro stain resistance, color stability, gloss, and gloss retention of a nano-filled resin-modified glass ionomers (RMGIs) to a traditional RMGI and resin-based composites (RBCs). MATERIALS AND METHODS: Specimens (N = 20) were fabricated from a nano-filled RBC (Filtek Supreme Plus, 3M ESPE, St. Paul, MN, USA), a nanohybrid RBC (Clearfil Majesty Esthetic, Kuraray; Tokyo, Japan), a nano-filled RMGI (Ketac Nano, 3M ESPE), and traditional RMGI (Fuji II LC, GC America, Chicago, IL, USA). L*a*b* values were recorded with a spectrophotometer, and gloss was measured with a glossmeter. For each material, 10 specimens were stored in distilled water in darkness for 1 week and 10 specimens were placed in a staining solution for 1 week. After storage, specimens were cleaned and L*a*b* and gloss measurements were remeasured. RESULTS: Data were analyzed by analysis of variance (ANOVA) and Tukey analyses. Regarding color change, materials ranked: Ketac = Fuji > Filtek > Clearfil in water, and Ketac > Fuji > Filtek > Clearfil in staining solution. Prior to storage, the initial gloss of the materials ranked: Filtek >= Clearfil >= Ketac > Fuji. After storage, the materials ranked: Filtek = Clearfil > Ketac > Fuji in water, and Filtek > Clearfil > Ketac > Fuji in staining solution. Gloss retention was similar for all materials in water and gloss retention ranked: Filtek = Clearfil > Ketac = Fuji in staining solution. CONCLUSIONS: The nano-RMGI showed less stain resistance but higher gloss than the traditional RMGI. Both RMGIs had more color change, less stain resistance, lower gloss and less gloss retention than the RBCs. CLINICAL SIGNIFICANCE: The clinician should be aware that the use of a nano-RMGI may improve the gloss of an RMGI restoration; however, color change will likely occur, particularly if the patient consumes a staining diet. PMID- 25439033 TI - Depression, anxiety, antidepressant use, and cardiovascular disease among Hispanic men and women of different national backgrounds: results from the Hispanic Community Health Study/Study of Latinos. AB - PURPOSE: To describe prevalence and relationships to cardiovascular morbidity of depression, anxiety, and medication use among Hispanic/Latinos of different ethnic backgrounds. METHODS: Cross-sectional analysis of 15,864 men and women aged 18 to 74 years in the population-based Hispanic Community Health Study/Study of Latinos. Depressive and anxiety symptoms were assessed with shortened Center for Epidemiological Studies Depression Scale and Spielberger Trait Anxiety Scale. RESULTS: Prevalence of high depressive symptoms ranged from low of 22.3% (95% confidence interval [CI], 20.4-24.3) to high of 38.0% (95% CI, 35.2-41.0) among those of Mexican or Puerto Rican background, respectively. Adjusted odds ratios for depression rose monotonically with number of cardiovascular disease (CVD) risk factor from 1.46 (95% CI, 1.18-1.75) for those with one risk factors to 4.36 (95% CI, 2.47-7.70) for those with five risk factors. Antidepressant medication was used by 5% with striking differences between those with and without history of CVD (15.4% and 4.6%, respectively) and between insured (8.2%) and uninsured (1.8%). CONCLUSIONS: Among US Hispanics/Latinos, high depression and anxiety symptoms varied nearly twofold by Hispanic background and sex, history of CVD, and increasing number of CVD risk factors. Antidepressant medication use was lower than in the general population, suggesting under treatment especially among those who had no health insurance. PMID- 25439034 TI - Adverse Events Due to Chiropractic and Other Manual Therapies for Infants and Children: A Review of the Literature. AB - OBJECTIVE: The purpose of this study was to review the literature for cases of adverse events in infants and children treated by chiropractors or other manual therapists, identifying treatment type and if a preexisting pathology was present. METHOD: English language, peer-reviewed journals and non-peer-reviewed case reports discussing adverse events (ranging from minor to serious) were systematically searched from inception of the relevant searchable bibliographic databases through March 2014. Articles not referring to infants or children were excluded. RESULTS: Thirty-one articles met the selection criteria. A total of 12 articles reporting 15 serious adverse events were found. Three deaths occurred under the care of various providers (1 physical therapist, 1 unknown practitioner, and 1 craniosacral therapist) and 12 serious injuries were reported (7 chiropractors/doctors of chiropractic, 1 medical practitioner, 1 osteopath, 2 physical therapists, and 1 unknown practitioner). High-velocity, extension, and rotational spinal manipulation was reported in most cases, with 1 case involving forcibly applied craniosacral dural tension and another involving use of an adjusting instrument. Underlying preexisting pathology was identified in a majority of the cases. CONCLUSION: Published cases of serious adverse events in infants and children receiving chiropractic, osteopathic, physiotherapy, or manual medical therapy are rare. The 3 deaths that have been reported were associated with various manual therapists; however, no deaths associated with chiropractic care were found in the literature to date. Because underlying preexisting pathology was associated in a majority of reported cases, performing a thorough history and examination to exclude anatomical or neurologic anomalies before applying any manual therapy may further reduce adverse events across all manual therapy professions. PMID- 25439036 TI - Knowing what we are talking about: the CORE-Hom database on clinical research in homeopathy is an important advance. PMID- 25439035 TI - Relationship between chiropractic teaching institutions and practice characteristics among Canadian doctors of chiropractic: a random sample survey. AB - OBJECTIVE: The objectives of this study were to determine if faction membership among Canadian doctors of chiropractic (DCs) is associated with differences in educational program characteristics among English-speaking Canadian and United States chiropractic colleges and to determine if those differences are expressed in terms of surveyed attitudes and behaviors regarding treatment efficacy, radiographic imaging, vaccinations, and interprofessional referrals. This study also aims to identify if educational programs may be a potential source of multiple professional identities. METHODS: A randomly selected sample of Canadian DCs, stratified across the English-speaking provinces, was surveyed by mail. Survey items included school of graduation, self-categorization by chiropractic subgroup, perceptions of condition-specific treatment efficacy, use of plain film radiographic imaging, vaccination attitudes/behaviors, and patient referral patterns. Self-categorization by chiropractic subgroup included: the unorthodox faction (associates the chiropractic subluxation as an encumbrance to the expression of health) and the orthodox perspective (associates with musculoskeletal joint dysfunction, public health, and lifestyle concerns). For data analysis, chiropractic schools were divided into 2 groups according to location: English-speaking Canada and the US. The US was further clustered into liberal ("interested in mixing elements of modern and alternative therapies into the practice of chiropractic") and conservative categories ("chiropractors who believe in continuing the traditions of chiropractic"). RESULTS: Of 740 deliverable questionnaires, 503 were returned for a response rate of 68%. chi(2) Testing revealed significant differences in self-categorized faction membership associated with the clustering of colleges based on ideological viewpoints (chi(2) = 27.06; P = .000). Descriptive results revealed a relationship between school of origin and perceived treatment efficacy, use of radiographic imaging, and vaccination attitudes. No significant differences were found relative to interprofessional referral patterns. CONCLUSION: Chiropractic program attended is a significant predictor of orthodox vs unorthodox faction membership and professional practice characteristics for Canadian DCs. This suggests that the current chiropractic education system may contribute to multiple professional identities. PMID- 25439037 TI - CORE-Hom: a powerful and exhaustive database of clinical trials in homeopathy. AB - The CORE-Hom database was created to answer the need for a reliable and publicly available source of information in the field of clinical research in homeopathy. As of May 2014 it held 1048 entries of clinical trials, observational studies and surveys in the field of homeopathy, including second publications and re analyses. 352 of the trials referenced in the database were published in peer reviewed journals, 198 of which were randomised controlled trials. The most often used remedies were Arnica montana (n = 103) and Traumeel((r)) (n = 40). The most studied medical conditions were respiratory tract infections (n = 126) and traumatic injuries (n = 110). The aim of this article is to introduce the database to the public, describing and explaining the interface, features and content of the CORE-Hom database. PMID- 25439038 TI - Efficacy of homeopathic intervention in subclinical hypothyroidism with or without autoimmune thyroiditis in children: an exploratory randomized control study. AB - INTRODUCTION: The decision to treat subclinical hypothyroidism (SCH) with or without autoimmune thyroiditis (AIT) in children, presents a clinical dilemma. This study was undertaken to evaluate the efficacy of individualized homeopathy in these cases. METHODS: The study is an exploratory, randomized, placebo controlled, single blind trial. Out of 5059 school children (06-18 years) screened for thyroid disorders, 537 children had SCH/AIT and 194 consented to participate. Based on primary outcome measures (TSH and/or antiTPOab) three major groups were formed: Group A - SCH + AIT (n = 38; high TSH with antiTPOab+), Group B - AIT (n = 47; normal TSH with antiTPOab+) and Group C - SCH (n = 109; only high TSH) and were further randomized to two subgroups-verum and control. Individualized homeopathy or identical placebo was given to respective subgroup. 162 patients completed 18 months of study. RESULTS: Baseline characteristics were similar in all the subgroups. The post treatment serum TSH (Group A and C) returned to normal limits in 85.94% of verum and 64.29% of controls (p < 0.006), while serum AntiTPOab titers (Group A and B) returned within normal limits in 70.27%of verum and 27.02%controls (p < 0.05). Eight children (10.5%) progressed to overt hypothyroidism (OH) from control group. CONCLUSION: A statistically significant decline in serum TSH values and antiTPOab titers indicates that the homeopathic intervention has not only the potential to treat SCH with or without antiTPOab but may also prevent progression to OH. PMID- 25439039 TI - Open-label uncontrolled pilot study to evaluate complementary therapy with Ruta graveolens 9c in patients with advanced cancer. AB - BACKGROUND: Patients with advanced metastatic disease are often treated aggressively with multiple lines of chemotherapy, even in the last month of life. The benefit of such an approach remains uncertain. The objective of the study was to investigate whether Ruta graveolens 9c homeopathic medicine can improve quality of life (QoL) and tumour progression in patients with advanced cancer. MATERIAL AND METHODS: This was a single-centre, open-label, uncontrolled, pilot study. Patients (>18-years, life-expectancy >=3 months, performance status <=2) with locally-advanced solid tumours or metastases, previously treated with all available standard anti-cancer treatments were recruited. Oral treatment consisted of two 1-mL ampoules of Ruta graveolens (9c dilution) given daily for a minimum of 8 weeks, or until tumour and/or clinical progression. Primary outcome was QoL measured using the EORTC QLQ-C30 questionnaire. Secondary outcome measures were anxiety/depression measured using the Hospital Anxiety and Depression Scale (HADS), WHO performance status (PS), tumour progression assessed using RECIST criteria and tumour markers, survival and tolerance. RESULTS: Thirty one patients were included (mean age: 64.3 years). Mean duration of treatment was 3.3 months (median: 2.1). QoL global health status improved significantly between baseline and week 8 (P < 0.001) and week 16 (P = 0.035), but was at the limit of significance (P = 0.057) at the end of the study. There was no significant change in anxiety/depression or PS during treatment. Ruta graveolens 9c had no obvious effect on tumour progression. Median survival was 6.7 months [95%CI: 4.8-14.9]. Ruta graveolens 9c was well-tolerated. CONCLUSION: Some patients treated with Ruta graveolens 9c had a transitory improvement in QoL, but the effectiveness of this treatment remains to be confirmed in further studies. PMID- 25439040 TI - Management of the early symptoms of influenza-like illnesses and ear, nose and throat (ENT) disorders by pharmacists. AB - BACKGROUND: Pharmacists play a key role in primary healthcare, but the characteristics of patients who consult a pharmacist directly rather than going to their general practitioner (GP) are unknown. Our aim was to describe the socio demographic and clinical characteristics of patients who seek direct therapeutic advice from a pharmacist for influenza-like illness (ILI) or ear, nose and throat (ENT) disorders, the types of medicines dispensed and patient satisfaction with the advice received. METHODS: This prospective, observational study was carried out on a random sample of French pharmacies between November 2010 and March 2011. Patients (>=12-years) with early symptoms of ILI or ENT disorders (<36 h duration) who received treatment were included. Socio-demographic data, symptom severity and disease impact on daily activities and sleep were recorded at inclusion. Symptom evolution and patient satisfaction were assessed after 3 days of treatment. RESULTS: 573 patients (mean age: 42.5 +/- 16.2 years; 61.9% female) were recruited by 133 pharmacies. Two-thirds of patients (63.2%) visited the pharmacy early (<24 h) after symptom onset. The most common symptoms were runny nose (56.4%), sore throat (54.6%) and cough (49.0%). Patients were given 2.6 +/- 1.2 medications; 98.4% of patients received allopathic (usually paracetamol, 33.5%) and 25.3% homeopathic (Oscillococcinum, 56.6%) treatment, usually combined with allopathy. Compliance was good and 77.2% of patients continued treatment for 3 days. Most symptoms improved significantly after 3 days and quality of life was enhanced. 85.9% of patients were satisfied with the advice received. CONCLUSIONS: Seeking a pharmacist's advice for the management of ILI and ENT disorders has several public health benefits. The clinical improvement and high patient satisfaction observed validate the role of the pharmacist as a health professional of first resort. PMID- 25439041 TI - Homeopathy and health related Quality of Life: a patient satisfaction survey in six European countries and Brazil. AB - BACKGROUND: Many patients throughout the world consult homeopathic medical doctors. Using a similar methodology as in a first survey published in 2002 a second survey was done including 919 adults receiving homeopathic treatment in six European countries and Brazil aimed to look at who are they, their reasons for consultations and expectations and satisfaction with homeopathy prescribed by a homeopathic doctor after a follow-up time of six months. METHOD: An initial questionnaire included demographic information and questions for assessing health related Quality of Life (QoL). A follow-up questionnaire collected data on changes in QoL. RESULTS: 77% patients had initially used conventional treatments and 23% other non-conventional treatments. Satisfaction of patients with the medical homeopathic consultation is high. The difference between the final QoL scores after six months and the baseline are positive. Reported differences between baseline and final index range from 3.87 to 10.41 depending on diagnosis. Taking 7% as a reference value for 'minimal clinically significant difference', this is reached for 3 of 8 conditions. Changes in complaint limitations visual scales are positive. Conclusions on clinical impact must be cautious. 6% of the patients experienced side-effects which they attributed to homeopathic treatment. 7.8% of the patients reported significant aggravation at the beginning of the homeopathic treatment and 26.2% slight aggravation of symptoms. CONCLUSIONS: The satisfaction of patients using a medical homeopathic approach is linked to the perceived competence of the doctor homeopath, the perceived improvement of the main complaints limitations and the time dedicated to them by the doctor. PMID- 25439042 TI - Pediatric homeopathy: a prospective observational survey based on parent proxy reports of their children's health-related Quality of Life in six European countries and Brazil. AB - BACKGROUND: Many European citizens regularly consult homeopathic doctors. Especially for children there is very little data available about the reasons they visit a homeopathic doctor. What are the expectations of the parents consulting a Homeopath MD with their child, who are they and last but not least are they satisfied with their initiative? This study including 773 children from six European countries and Brazil is aimed to look at parent-proxy satisfaction with homeopathic treatment prescribed for their children by a homeopathic doctor after a follow-up of two months. The questionnaire was developed from the methodology used in a survey of adults published in 2002. METHOD: An initial questionnaire included demographic information and questions for assessing health related Quality of Life (QoL). A follow-up questionnaire collected data on changes in QoL. RESULTS: The demographic characteristics of respondents showed more male children (53.1%) but more female parent-proxies (93.4%). 73.7% of respondents had previously tried conventional treatments; 26.3% non-conventional approaches. Satisfaction with the medical homeopathic consultation was high. Reported differences between baseline and final QoL ondexes are positive for all four studied conditions. It range from 3.206 to 10.188. Considering 7% as a reference value for "minimal clinical difference", this is reached for 2 on 4 conditions (8.473 and 10.188). Changes in complaint limitations visual scales are positive, even if uncertain for skin complaints and influenced parents satisfaction. Conclusions on clinical impact must be cautious. 4.2% of patients experienced side-effects which they attribute to homeopathic treatment. 10.1% of patients reported significant aggravation at the beginning of homeopathic treatment, 19% slight aggravation of symptoms. CONCLUSIONS: The satisfaction of parents using a medical homeopathic approach for their children is linked to the perceived competence of the doctor homeopath, the perceived improvement of the main complaint limitations and the completeness of the received information. PMID- 25439043 TI - Modulation of inflammation response to murine cutaneous Leishmaniasis by homeopathic medicines: Antimonium crudum 30cH. AB - BACKGROUND: Leishmaniasis is a zoonotic disease caused by protozoan parasites of the mononuclear phagocytic system. The modulation activity of these cells can interfere in the host/parasite relationship and influences the prognosis. METHODS: We evaluated the effects of the homeopathic preparation Antimonium crudum 30cH on experimental infection induced by Leishmania (L.) amazonensis. Male Balb/c mice were inoculated with 2 * 10(6)Leishmania (L.) amazonensis promastigotes into the footpad and, after 48 h (acute phase) or 60 days (chronic phase), cell population of lymphocytes and phagocytes present in the peritoneal washing fluid and spleen were analyzed by flow cytometry and histopathology, with histometry of the subcutaneous primary lesion, local lymph node and spleen. Immunohistochemistry was performed to quantify CD3 (T lymphocyte), CD45RA (B lymphocyte) and CD11b (phagocytes) positive cells. RESULTS: In treated mice, during the acute phase, there was significant increase of the macroscopic lesion, associated to inflammatory edema, as well increase in the number of free amastigotes and B lymphocytes inside the lesion. Increase of B lymphocytes (predominantly B-2 cells) was also seen in the local lymph node, spleen and peritoneum. In the chronic phase, the inflammatory process in the infection focus was reduced, with reduced phagocyte migration and peritoneal increase of B-1a cells (precursors of B-2 immunoglobulin producers cells) and T CD8+ cells. CONCLUSION: The treatment of mice with Antimonium crudum 30cH induced a predominantly B cell pattern of immune response in Leishmania (L.) amazonensis experimental infection, alongside the increase of free amastigote forms number in the infection site. The clinical significance of this study is discussed, further studies are suggested. PMID- 25439044 TI - Modulation of inflammation response to murine cutaneous Leishmaniosis by homeopathic medicines: thymulin 5cH. AB - BACKGROUND: In previous studies, we observed that thymulin 5cH could modulate BCG (Bacillus Calmette-Guerin) induced chronic inflammation by increasing peritoneal B1 stem cells differentiation into phagocytes and improving phagocytosis efficiency. METHODS: We used the same protocol to study the effects of thymulin 5cH in the experimental murine Leishmaniasis, in order to elucidate some aspects of the parasite-host relation under this homeopathic treatment. Male Balb/c mice were orally treated with thymulin 5cH or vehicle during 60 days, after the subcutaneous inoculation of 2 * 10(6) units of Leishmania (L.) amazonensis into the footpad. Washied inflammatory cell suspension from peritoneal cavity, spleen, local lymph node and infected subcutaneous tissue were harvested after 2 and 60 days from infection to quantify the inflammation cells by flow cytometry and histometry methods. RESULTS: After a transitory increase of peritoneal T reg cells, treated mice presented, chronically, increase in the peritoneal and spleen B1 cells percentage (p = 0.0001) in relation to other cell types; more organized and exuberant inflammation response in the infection site, and decrease in the number of parasites per field inside the primary lesion (p = 0.05). No difference was seen in local lymph node histology. CONCLUSIONS: Thymulin 5cH is able to improve B1 cell activation and Leishmania (L) amazonensis phagocytosis efficiency in mice, similarly to that observed previously in BCG experimental infection. PMID- 25439046 TI - European qualification in general surgery: Quo vadis? PMID- 25439045 TI - The role of serotonin and its receptors in activation of immune responses and inflammation. AB - Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter and hormone that contributes to the regulation of various physiological functions by its actions in the central nervous system (CNS) and in the respective organ systems. Peripheral 5-HT is predominantly produced by enterochromaffin (EC) cells of the gastrointestinal (GI) tract. These gut-resident cells produce much more 5-HT than all neuronal and other sources combined, establishing EC cells as the main source of this biogenic amine in the human body. Peripheral 5-HT is also a potent immune modulator and affects various immune cells through its receptors and via the recently identified process of serotonylation. Alterations in 5-HT signalling have been described in inflammatory conditions of the gut, such as inflammatory bowel disease. The association between 5-HT and inflammation, however, is not limited to the gut, as changes in 5-HT levels have also been reported in patients with allergic airway inflammation and rheumatoid arthritis. Based on searches for terms such as '5-HT', 'EC cell', 'immune cells' and 'inflammation' in pubmed.gov as well as by utilizing pertinent reviews, the current review aims to provide an update on the role of 5-HT in biological functions with a particular focus on immune activation and inflammation. PMID- 25439047 TI - Comparison of plasma exchange procedures using three apheresis systems. AB - BACKGROUND: A new protocol for the Amicus separator (Fresenius Kabi) enables the device to perform plasma exchange (PE). The aim of the study was to compare retrospectively the plasma removal efficiency (PRE) of the Amicus, the Optia (TerumoBCT), and the Spectra (TerumoBCT) when performing PEs. STUDY DESIGN AND METHODS: We retrospectively reviewed patients who received at least one PE with the Amicus and at least one PE with the Optia, the Spectra, or both. We collected data regarding PRE, volume of anticoagulant and calcium-magnesium (Ca-Mg) solution infused, and changes in laboratory data from patients' blood sampled immediately before starting and immediately after finishing each PE procedure: complete blood count, coagulation, acid-base equilibrium, and biochemistry variables. We also collected severe adverse events (AEs). RESULTS: We performed 18, 44, and 14 PEs with the Amicus, Optia, and Spectra, respectively. We observed significant differences among the Amicus, Optia, and Spectra regarding PRE (79.8 +/- 8.2, 82.9 +/- 5.8, and 70.4 +/- 8.2%; p < 0.001), volume of anticoagulant infused (542 +/- 196, 687 +/- 120, and 647 +/- 111 mL; p = 0.002), volume of Ca Mg solution infused (81 +/- 28, 56 +/- 16, and 63 +/- 15 mL; p < 0.001), absolute change of ionic Ca (-0.04 +/- 0.13, -0.05 +/- 0.12, and -0.19 +/- 0.16 mmol/L; p = 0.002), and absolute change of Na (1.18 +/- 1.97, 1.02 +/- 1.93, and 3.71 +/- 1.98 mEq/L; p < 0.001). We observed no significant differences in other analytic variables and we observed no severe AEs. CONCLUSION: The Amicus device could effectively perform PE procedures. In terms of PRE, the Amicus and Optia were similar, but both devices were superior to the Spectra. The Amicus used a lower volume of anticoagulant when compared with the Optia. PMID- 25439048 TI - The impact of diabetes-related complications on healthcare costs: new results from the UKPDS (UKPDS 84). AB - AIMS: To estimate the immediate and long-term inpatient and non-inpatient costs for Type 2 diabetes-related complications. METHODS: The costs of all consultations, visits, admissions and procedures associated with diabetes-related complications during UK Prospective Diabetes Study post-trial monitoring in the period 1997-2007 were estimated using hospitalization records for 2791 patients in England and resource use questionnaires that were administered to 3589 patients across the UK. RESULTS: The estimated (95% CI) inpatient care costs (in 2012 pounds sterling) in the event year for the example of a 60-year-old man were: non-fatal ischaemic heart disease L9767 (L7038-L12 696); amputation L9546 (L6416-L13 463); non-fatal stroke L6805 (L3856-L10 278); non-fatal myocardial infarction L6379 (L4290-L8339); fatal stroke L3954 (L2012-L6428); fatal ischaemic heart disease L3766 (L746-L5512); heart failure L3191 (L1678-4903); fatal myocardial infarction L1521 (L647-L2670); and blindness in one eye L1355 (L415 L2655). In subsequent years, estimated (95% CI) costs ranged from L1792 (L1060 L2943) for amputations to L453 (L315-L691) for blindness in one eye. Costs of non inpatient healthcare in the event year were: amputation L2699 (L1409-L4126); blindness in one eye L1790 (L878-L3056); non-fatal stroke L1019 (L770-L1499); nonfatal myocardial infarction L1963 (L794-L1157); heart failure L979 (L708 L1344); non-fatal ischaemic heart disease L864 (L718-L1014); and cataract extraction L700 (L619-L780). In each subsequent year, non-inpatient costs ranged from L1611 (L1193-L2116) for amputations to L654 (L572-L799) for ischaemic heart disease. CONCLUSIONS: Diabetic complications are associated with substantial immediate and long-term healthcare costs. Our comprehensive new estimates of these costs, derived from detailed recent UK Prospective Diabetes Study post trial data, should aid researchers and health policy analyses. PMID- 25439050 TI - [Chronic diarrhea syndrome secondary to celiac disease in an octogenarian]. PMID- 25439049 TI - [Unrecognized diagnosis of delirium among elderly patients presenting to the emergency department]. PMID- 25439051 TI - [Silicotuberculosis, a cause of fever of unknown origin in the elderly. A case report]. PMID- 25439052 TI - [Mediastinal lipoma in an elderly patient]. PMID- 25439053 TI - Pokemon proto-oncogene in oral cancer: potential role in the early phase of tumorigenesis. AB - OBJECTIVES: Oral squamous cell carcinoma (OSCC) represents about 90% of all oral neoplasms with a poor clinical prognosis. To improve survival of OSCC patients, it is fundamental to understand the basic molecular mechanisms characterizing oral carcinogenesis. Dysregulation of oncogenes and tumor suppressor genes seems to play a central role in tumorigenesis, including malignant transformation of the oral cavity. MATERIALS AND METHODS: We analyzed the expression levels of the pro-oncogenic transcription factor Pokemon through real-time PCR, Western blot and immunohistochemistry in tumor, and normal oral tissue samples obtained from 22 patients with OSCC. The relationship between tumor characteristics and the level of Pokemon intratumor expression was also analyzed. RESULTS: Pokemon was significantly downregulated in OSCC. In particular, both mRNA and protein levels (tumor vs normal tissue) inversely correlated with histological grading, suggesting its potential role as a prognostic factor for OSCC. Moreover, a significant inverse correlation was found between Pokemon protein expression levels (OSCC vs normal oral mucosa) and tumor size, supporting the hypothesis that Pokemon could play an important role in the early phase of tumor expansion. CONCLUSION: This work shows that reduced expression of Pokemon is a peculiar feature of OSCC. Additional studies may establish the effective role of Pokemon in oral tumorigenesis. PMID- 25439054 TI - A generalized matching law analysis of cocaine vs. food choice in rhesus monkeys: effects of candidate 'agonist-based' medications on sensitivity to reinforcement. AB - BACKGROUND: We have previously demonstrated reductions in cocaine choice produced by either continuous 14-day phendimetrazine and d-amphetamine treatment or removing cocaine availability under a cocaine vs. food choice procedure in rhesus monkeys. The aim of the present investigation was to apply the concatenated generalized matching law (GML) to cocaine vs. food choice dose-effect functions incorporating sensitivity to both the relative magnitude and price of each reinforcer. Our goal was to determine potential behavioral mechanisms underlying pharmacological treatment efficacy to decrease cocaine choice. METHODS: A multi model comparison approach was used to characterize dose- and time-course effects of both pharmacological and environmental manipulations on sensitivity to reinforcement. RESULTS: GML models provided an excellent fit of the cocaine choice dose-effect functions in individual monkeys. Reductions in cocaine choice by both pharmacological and environmental manipulations were principally produced by systematic decreases in sensitivity to reinforcer price and non-systematic changes in sensitivity to reinforcer magnitude. CONCLUSIONS: The modeling approach used provides a theoretical link between the experimental analysis of choice and pharmacological treatments being evaluated as candidate 'agonist based' medications for cocaine addiction. The analysis suggests that monoamine releaser treatment efficacy to decrease cocaine choice was mediated by selectively increasing the relative price of cocaine. Overall, the net behavioral effect of these pharmacological treatments was to increase substitutability of food pellets, a nondrug reinforcer, for cocaine. PMID- 25439058 TI - Seed dormancy cycling in Arabidopsis: chromatin remodelling and regulation of DOG1 in response to seasonal environmental signals. AB - The involvement of chromatin remodelling in dormancy cycling in the soil seed bank (SSB) is poorly understood. Natural variation between the winter and summer annual Arabidopsis ecotypes Cvi and Bur was exploited to investigate the expression of genes involved in chromatin remodelling via histone 2B (H2B) ubiquitination/de-ubiquitination and histone acetylation/deacetylation, the repressive histone methyl transferases CURLY LEAF (CLF) and SWINGER (SWN), and the gene silencing repressor ROS1 (REPRESSOR OF SILENCING1) and promoter of silencing KYP/SUVH4 (KRYPTONITE), during dormancy cycling in the SSB. ROS1 expression was positively correlated with dormancy while the reverse was observed for CLF and KYP/SUVH4. We propose ROS1 dependent repression of silencing and a sequential requirement of CLF and KYP/SUVH4 dependent gene repression and silencing for the maintenance and suppression of dormancy during dormancy cycling. Seasonal expression of H2B modifying genes was correlated negatively with temperature and positively with DOG1 expression, as were histone acetyltransferase genes, with histone deacetylases positively correlated with temperature. Changes in the histone marks H3K4me3 and H3K27me3 were seen on DOG1 (DELAY OF GERMINATION1) in Cvi during dormancy cycling. H3K4me3 activating marks remained stable along DOG1. During relief of dormancy, H3K27me3 repressive marks slowly accumulated and accelerated on exposure to light completing dormancy loss. We propose that these marks on DOG1 serve as a thermal sensing mechanism during dormancy cycling in preparation for light repression of dormancy. Overall, chromatin remodelling plays a vital role in temporal sensing through regulation of gene expression. PMID- 25439059 TI - [Type 2 neurofibromatosis: intergenerational differences in genetic and clinical expression]. AB - INTRODUCTION: Neurofibromatosis type 2 (NF2) is a rare dominantly inherited disease. Its clinical presentation can be completely different in children and adults and early diagnosis is often difficult. The NF2 gene molecular analysis can help for diagnosis, but its result can be negative in case of NF2 mosaicism. OBSERVATIONS: We report the case of a 43-year-old man who had developed a severe phenotype with bilateral vestibular schwannomas at 19 years of age. His son presented a retinal hamartoma with loss of vision in his right eye at 2 months of age. At 9 years of age, asymptomatic schwannomas of the cranial nerves were discovered: cranial nerves X (left), XI (left), and VIII (bilateral). Partial constitutional NF2 deletion (from exons 2-7) was detected in his son. The deletion was not detectable in the DNA blood of his father and we strongly suspect a mosaic form of NF2. CONCLUSION: Ophthalmological manifestations can be the initial sign of NF2 in childhood. These features must be actively sought during the first year of life in individuals at risk of NF2. NF2 mosaicism is often described as a mild form of NF2 with a very low risk of transmission to the carrier's children. We show that NF2 mosaicism can sometimes develop severe NF2 symptoms and we confirm that the transmission risk to the offspring depends on the proportion of zygotes carrying the mutation. NF2 remains a life-limiting and life-spoiling condition. Early diagnosis is necessary to prevent complications and the follow-up of NF2 patients must be organized throughout life in specialty centers. PMID- 25439061 TI - From hypertransaminasemia to mucopolysaccharidosis IIIA. AB - ?: Mucopolysaccharidosis type III (MPS III; Sanfilippo syndrome) is a metabolic disorder characterized by the deficiency of a lysosomal enzyme catalyzing the catabolic pathway of heparan sulphate. MPS III presents with progressive mental deterioration, speech delay and behavioural problems with subtle somatic features, which can often lead to misdiagnosis with idiopathic developmental/speech delay, attention deficit/hyperactivity disorder or autism. We report a case of a 5-year-old boy with developmental delay and behaviour problems admitted to the Department of Paediatrics due to chronic hypertransaminasemia. The patient developed normally until the age of 2 years when he was referred to a paediatric neurologist for suspected motor and speech delay. Liver function tests were unexpectedly found elevated at the age of 3.5 years. Physical examination revealed obesity, mildly coarse facial features and stocky hands. He showed mental retardation and mild motor delay. The clinical picture strongly suggested mucopolysaccharidosis. The diagnosis of MPS IIIA was confirmed by decreased activity of heparan N-sulfatase in leucocytes. CONCLUSION: We strongly recommend screening for MPS III in children with severe behavioural abnormalities with hyperactivity, psychomotor or speech deterioration and failure to achieve early developmental milestones particularly with facial dysmorphism. PMID- 25439062 TI - The global challenge of a healthy stomach. PMID- 25439055 TI - A familial risk enriched cohort as a platform for testing early interventions to prevent severe mental illness. AB - BACKGROUND: Severe mental illness (SMI), including schizophrenia, bipolar disorder and severe depression, is responsible for a substantial proportion of disability in the population. This article describes the aims and design of a research study that takes a novel approach to targeted prevention of SMI. It is based on the rationale that early developmental antecedents to SMI are likely to be more malleable than fully developed mood or psychotic disorders and that low risk interventions targeting antecedents may reduce the risk of SMI. METHODS/DESIGN: Families Overcoming Risks and Building Opportunities for Well being (FORBOW) is an accelerated cohort study that includes a large proportion of offspring of parents with SMI and embeds intervention trials in a cohort multiple randomized controlled trial (cmRCT) design. Antecedents are conditions of the individual that are distressing but not severely impairing, predict SMI with moderate-to-large effect sizes and precede the onset of SMI by at least several years. FORBOW focuses on the following antecedents: affective lability, anxiety, psychotic-like experiences, basic symptoms, sleep problems, somatic symptoms, cannabis use and cognitive delay. Enrolment of offspring over a broad age range (0 to 21 years) will allow researchers to draw conclusions on a longer developmental period from a study of shorter duration. Annual assessments cover a full range of psychopathology, cognitive abilities, eligibility criteria for interventions and outcomes. Pre-emptive early interventions (PEI) will include skill training for parents of younger children and courses in emotional well being skills based on cognitive behavioural therapy for older children and youth. A sample enriched for familial risk of SMI will enhance statistical power for testing the efficacy of PEI. DISCUSSION: FORBOW offers a platform for efficient and unbiased testing of interventions selected according to best available evidence. Since few differences exist between familial and 'sporadic' SMI, the same interventions are likely to be effective in the general population. Comparison of short-term efficacy of PEI on antecedents and the long term efficacy for preventing the onset of SMI will provide an experimental test of the etiological role of antecedents in the development of SMI. PMID- 25439063 TI - Gastric acid secretion: changes during a century. AB - The advances in knowledge of gastric physiology within the past century have been the most exciting and important in this area of interest for many decades. The aim of this presentation consists of a comprehensive review of the extensive recent literature on this topic in order to highlight milestones in the field of gastric physiology, in particular in gastric acid secretion, gastric pathophysiology, acid-related diseases and use of acid regulatory drugs. Moreover, in the 21st century there have been many epidemiologic changes as well as a decrease of Helicobacter pylori infection and gastric cancer together with an increase of gastroesophageal reflux disease and the related increase of pomp proton inhibitor wide use. PMID- 25439064 TI - The stomach-brain axis. AB - The stomach has distinct functions in relation to the ingestion and handling of solids and liquids. These functions include storage of the food before it is gradually emptied into the duodenum, mechanical crushing of larger food particles to increase the surface area, secretion of an acidic enzyme rich gastric juice and mixing the ingested food with the gastric juice. In addition, the stomach 'senses' the composition of the gastric content and this information is passed via the vagal nerve to the lateral hypothalamus and the limbic system, most likely as palatability signals that influence eating behaviour. Other sensory qualities related to the stimulation of gastric tension receptors are satiety and fullness. Receptors that respond to macronutrient content or gastric wall tension influence appetite and meal related hormone responses. The ingestion of food - in contrast to an infusion of nutrients into the stomach - has distinct effects on the activation of specific brain regions. Brain areas such as thalamus, amygdala, putamen and praecuneus are activated by the ingestion of food. Gastric nutrient infusion evokes greater activation in the hippocampus and anterior cingulate. The brain integrates these interrelated neural and hormonal signals arising from the stomach as well as visual, olfactory and anticipatory stimuli that ultimately influence eating and other behavioural patterns. Furthermore, there is now good evidence from experimental studies that gastric afferents influence mood, and animal studies point towards the possibility that gastric dysfunction may be a risk factor for mood disorders such as anxiety and depression. The stomach is also not only colonised by Helicobacter pylori but a large array of bacteria. While there is sufficient evidence to suggest that H. pylori may alter caloric intake and mood, the role of other gastric microbiome for the brain function is unknown. To address this appropriate targeted gastric microbiome studies would be required instead of widely utilised opportunistic stool microbiome studies. In summary, it is now well established that there are important links between the brain and the stomach that have significant effects on gastric function. However, the stomach also influences the brain. Disturbances in the crosstalk between the stomach and the brain may manifest as functional GI disorders while disturbances in the stomach-brain communication may also result in an altered regulation of satiety and as a consequence may affect eating behaviour and mood. These observations may enable the identification of novel therapies targeted at the gastroduodenum that positively alter brain function and treat or prevent conditions such as obesity or functional gastrointestinal disorders. PMID- 25439065 TI - Pharmacological and alimentary alteration of the gastric barrier. AB - The gastric barrier contains several lines of defence which protect the epithelium from harmful microbes and toxins. Pre-mucosal defence mechanisms include secreted acid (HCl 0.1 mmol/L) and pepsin, which are capable of denaturing tissue. A tightly adherent mucous layer provides the next line of defence, and physically separates any potentially hazardous substance in the lumen from the mucosal surface. Apical secretion of HCO3(-) maintains a non acidic microenvironment at the mucosal surface. Membrane-bound phospholipids repel soluble toxins, and sulphydryls scavenge reactive oxygen species. However, when noxious agents overwhelm these mechanisms, the epithelium is damaged. Herein, we discuss the pathological and physiological basis for several disease states which are associated with a breakdown in one or more components of the gastric barrier, including: Helicobacter pylori-associated gastritis, atrophic gastritis, stress-related mucosal disease, age-related gastropathy and portal hypertensive gastropathy. The effect of non-steroidal anti-inflammatory drugs and proton pump inhibitors on the gastric mucosa, is explored. Finally, we outline the alterations in mucosal defence caused by alcohol, caffeine, minerals and vitamins. PMID- 25439066 TI - The gastrointestinal microbiome - functional interference between stomach and intestine. AB - The gastrointestinal (GI) tract is a complex and dynamic network with interplay between various gut mucosal cells and their defence molecules, the immune system, food particles, and the resident microbiota. This ecosystem acts as a functional unit organized as a semipermeable multi-layer system that allows the absorption of nutrients and macromolecules required for human metabolic processes and, on the other hand, protects the individual from potentially invasive microorganisms. Commensal microbiota and the host are a unique entity in a continuum along the GI tract, every change in one of these players is able to modify the whole homeostasis. In the stomach, Helicobacter pylori is a gram-negative pathogen that is widespread all over the world, infecting more than 50% of the world's population. In this scenario, H. pylori infection is associated with changes in the gastric microenvironment, which in turn affects the gastric microbiota composition, but also might trigger large intestinal microbiota changes. It is able to influence all the vital pathways of human system and also to influence microbiota composition along the GI tract. This can cause a change in the normal functions exerted by intestinal commensal microorganisms leading to a new gastrointestinal physiological balance. This review focuses and speculates on the possible interactions between gastric microorganisms and intestinal microbiota and on the consequences of this interplay in modulating gut health. PMID- 25439067 TI - Clinical relevance of Helicobacter pylori vacA and cagA genotypes in gastric carcinoma. AB - Helicobacter pylori infection is the major etiological factor of gastric carcinoma. This disease is the result of a long, multistep, and multifactorial process, which occurs only in a small proportion of patients infected with H. pylori. Gastric carcinoma development is influenced by host genetic susceptibility factors, environmental factors, and H. pylori virulence. H. pylori is genetically highly variable, and variability that affects H. pylori virulence factors may be useful to identify strains with different degrees of pathogenicity. This review will focus on VacA and CagA that have polymorphic regions that impact their functional properties. The characterization of H. pylori vacA and cagA-associated could be useful for identifying patients at highest risk of disease, who could be offered H. pylori eradication therapy and who could be included in programs of more intensive surveillance in an attempt to reduce gastric carcinoma incidence. PMID- 25439068 TI - Helicobacter pylori: the balance between a role as colonizer and pathogen. AB - The isolation of Helicobacter pylori from the human stomach produced significant changes in how gastroenterologists, immunologists, epidemiologists, pathologists and microbiologists have approached gastro-duodenal diseases in the last half of the XX century. However, research of this organism has progressed greatly in the first decade of this century, evidence suggest that H. pylori is associated with disease only in humans older than 40 years, while, the lack of H. pylori colonization is associated with the emergence of new diseases, particularly in younger individuals. These differing effects of H. pylori colonization have created two contrasting concepts: the 'bad' and the 'good' Helicobacter. Following from renewed interest in the normal human microbiome, we need to reconsider our definitions and perhaps recognize that H. pylori might be a normal member of the human gastric microbiome in ancient humans that gradually, as results of the improvement in our environment, is disappearing. PMID- 25439069 TI - Chronic gastritis - an update. AB - Helicobacter pylori is the main aetiologic factor for chronic gastritis worldwide. The degree of inflammation and the evolution of this form of chronic gastritis can vary largely depending on bacterial virulence factors, host susceptibility factors and environmental conditions. Autoimmune gastritis is another cause of chronic inflammation in the stomach, which can occur in all age groups. This disease presents typically with vitamin B12 deficiency and pernicious anaemia. The presence of anti-parietal cell antibodies is highly specific for the diagnosis. The role of H. pylori as a trigger for autoimmune gastritis remains uncertain. Other rare conditions for chronic gastritis are chronic inflammatory conditions such as Crohn's disease or on the background of lymphocytic or collagenous gastroenteropathies. PMID- 25439070 TI - Individual risk stratification of gastric cancer: evolving concepts and their impact on clinical practice. AB - Gastric cancer (GC) is the third leading cause of cancer-related death worldwide and it mostly develops in long-standing inflammatory conditions, and Helicobacter pylori-gastritis, in particular. Despite the increasing understanding of both the phenotypic alterations and the molecular mechanisms occurring during GC multi step carcinogenesis, no reliable biomarker is available to be reliably implemented into GC secondary prevention strategies. Multidisciplinary diagnostic approaches integrating endoscopy, serology, histology and molecular profiling currently appears as the most appropriate approach for patients' stratification into different GC risk classes. PMID- 25439071 TI - Hereditary diffuse gastric cancer - pathophysiology and clinical management. AB - Hereditary Diffuse Gastric Cancer is an autosomal dominant inherited gastric cancer syndrome caused by germline alterations in CDH1 (E-cadherin) and CTNNA1 (alpha-E-catenin) genes. Germline CDH1 alterations encompass small frameshifts, splice-site, nonsense, and missense mutations, as well as large rearrangements. Most CDH1 truncating mutations are pathogenic, and several missense CDH1 mutations have a deleterious effect on E-cadherin function. CDH1 testing should be performed in probands. Screening of at-risk individuals is indicated from the age of consent following counselling with a multidisciplinary team. In mutation positive individuals prophylactic gastrectomy is recommended. Endoscopic surveillance is an option for those refusing/postponing gastrectomy, those with mutations of undetermined significance, and in CDH1-negative families. Ongoing research focus on the search of genetic causes other than CDH1 or CTNNA1 germline defects; assessment of the pathogenicity and penetrance of CDH1 missense mutations and identification of somatic mechanisms behind the progression from early (indolent) lesions to invasive (lethal) carcinomas. PMID- 25439072 TI - Gastric MALT lymphoma - update on diagnosis and treatment. AB - Gastrointestinal lymphoma represent a heterogenous group with differences in pathogenesis, treatment and prognosis. Gastric MALT lymphoma is the most common entity. Helicobacter pylori has been identified as its decisive pathogenetic factor. Once a definitive diagnosis has been established a staging procedure is obligatory for defining the stage of disease. H. pylori eradication is the treatment of choice in all MALT lymphoma patients being infected by the bacterium. In some 70-80% of patients with stages I/II complete regression of the lymphoma will develop after successful eradication of H. pylori. Another 20% of patients will reveal minimal histological residuals after eradication. They can be successfully managed by a watch-and-wait strategy if initial endoscopic abnormalities disappear. At present, it is unclear if this strategy can be also offered to patients with persisting minimal endoscopic abnormalities. Why eradication therapy is effective in some patients with negative H. pylori status is highly speculative at present. Non-responders to H. pylori therapy are transferrred to radiotherapy in stages I/II or to immuno-chemotherapy in stages III/IV. PMID- 25439073 TI - Advanced endoscopic imaging for gastric cancer assessment: new insights with new optics? AB - The most immediate strategy for improving survival of gastric cancer patients is secondary prevention through diagnosis of early gastric cancer either through screening or follow-up of individuals at high risk. Endoscopy examination is therefore of paramount importance and two general steps are to be known in assessing gastric mucosa - detection and characterization. Over the past decade, the advent of advanced endoscopic imaging technology led to diverse descriptions of these modalities reporting them to be useful in this setting. In this review, we aim at summarizing the current evidence on the use of advance imaging in individuals at high-risk (i.e., advance stages of gastric atrophy/intestinal metaplasia) and in those harbouring neoplastic lesions, and address its potential usefulness providing the readers a framework to use in daily practice. Further research is also suggested. PMID- 25439075 TI - The fight against gastric cancer - the IARC Working Group report. AB - Gastric cancer is the third cause of cancer death worldwide, and Helicobacter pylori infection causes almost 90% of non-cardia cancers, the predominant type. H. pylori infection is treatable, and in clinical trials there is evidence of a 30-40% reduction in incidence of gastric cancer among treated subjects. However, with a few exceptions, there are no public health programmes for gastric cancer prevention. In December 2013, the International Agency for Research on Cancer (IARC), organized a Working Group of international experts to discuss and make recommendations for gastric cancer control. The Working Group considered that the enormous burden of disease, which is not expected to decline in the coming decades, requires decisive public health action to include gastric cancer in cancer control programmes. Interventions should be tailored to the local conditions and consider population-based screening and eradication of H. pylori, in the context of evaluation of feasibility, efficacy and adverse consequences. PMID- 25439076 TI - Sleep duration and cardiometabolic risk factors among individuals with type 2 diabetes. AB - OBJECTIVE: To examine the association between sleep duration and cardiometabolic risk factors among individuals with recently diagnosed type 2 diabetes (n = 391). METHODS: Sleep duration was derived using a combination of questionnaire and objective heart rate and movement sensing in the UK ADDITION-Plus study (2002 2007). Adjusted means were estimated for individual cardiometabolic risk factors and clustered cardiometabolic risk (CCMR) by five categories of sleep duration. RESULTS: We observed a J-shaped association between sleep duration and CCMR - individuals sleeping 7 to <8 h had a significantly better CCMR profile than those sleeping >=9 h. Independent of physical activity and sedentary time, individuals sleeping 7 to <8 h had lower triacylglycerol (0.62 mmol/l (0.29, 1.06)) and higher high-density lipoprotein (HDL)-cholesterol levels (0.23 mmol/l (0.16, 0.30)) compared with those sleeping >=9 h, and a lower waist circumference (7.87 cm (6.06, 9.68)) and body mass index (BMI) (3.47 kg/m(2) (2.69, 4.25)) than those sleeping <6 h. Although sleeping 7 to <8 h was associated with lower levels of systolic and diastolic blood pressure, HbA1c, total cholesterol, and low-density lipoprotein (LDL)-cholesterol, these associations were not statistically significant. CONCLUSIONS: Sleep duration has a J-shaped association with CCMR in individuals with diabetes, independent of potential confounding. Health promotion interventions might highlight the importance of adequate sleep in this high-risk population. PMID- 25439074 TI - Implementation of gastric cancer screening - the global experience. AB - Gastric cancer (GC) is still an important global healthcare problem, and in absolute figures it is going to remain at the present level in foreseeable future. In general, survival of patients with GC is poor mainly due to advanced stage diagnosis. Early-stage GC can be cured by endoscopic resection or less invasive surgical treatment. Unfortunately, there is no appropriate screening strategy available for global application. This article provides a description of established national and regional GC screening programs and the screening modalities used. This review also summarizes current approaches to develop cancer screening biomarkers. Although candidates with initial promising results have been suggested, moving discovery into clinical practice is still a major challenge. Well-designed biomarker studies, with systematic validation steps, are needed to decrease the burden of this fatal disease. PMID- 25439078 TI - New websites: Nutrition and Dietetics PRO and the public. PMID- 25439079 TI - Do you know What's Cooking? Check out the USDA Mixing Bowl. PMID- 25439077 TI - Association of inflammation and oxidative stress with obstructive sleep apnea in ischemic stroke patients. AB - OBJECTIVE: The role of obstructive sleep apnea (OSA) in the mortality and further cardiovascular risk in subjects with ischemic stroke remains a contentious issue. Oxidative stress and inflammatory reaction due to OSA have seldom been studied in stable ischemic stroke patients. PATIENTS/METHODS: This cross-sectional, prospective study involved 92 consecutive ischemic stroke patients who were admitted to the Rehabilitation ward. All subjects received polysomnography and laboratory tests for oxidative stress and inflammatory biomarkers, including: C reactive protein (CRP), interleukin 6 (IL-6), total antioxidant capacity (TAC), and urinary 8-hydroxy-2-deoxyguanosine. Differences in study variables between patients with or without severe OSA were compared, and multivariate linear regression analyses were used to assess the relationship between OSA severity and target biomarkers. RESULTS: Participants in the severe OSA group were significantly older (p = 0.002), had a significantly higher risk of hypertension (p = 0.021) and a lower level of CRP (p = 0.006). Among the subjects with ischemic stroke and severe OSA, the levels of CRP, IL-6, and TAC were positively correlated with the desaturation index (DI) and the TAC levels were negatively correlated with mean arterial oxygen saturation (SaO2). Regression analysis results indicated that the TAC levels remained significantly and negatively correlated with mean SaO2 levels. Moreover, the CRP levels remained significantly correlated with the apnea-hypopnea index and DI after controlling for covariates. CONCLUSIONS: The present study demonstrated that a preferentially adaptive antioxidative response to hypoxia emerges, and the role of OSA with respect to inflammatory reaction is attenuated, in ischemic stroke patients with OSA. PMID- 25439080 TI - 2013 American Heart Association/American College of Cardiology Guideline on Lifestyle Management to Reduce Cardiovascular Risk: practice opportunities for registered dietitian nutritionists. PMID- 25439081 TI - 2013 American Heart Association/American College of Cardiology/the Obesity Society Guideline for the Management of Overweight and Obesity in Adults: implications and new opportunities for registered dietitian nutritionists. PMID- 25439082 TI - Position of the Academy of Nutrition and Dietetics: food and water safety. AB - It is the position of the Academy of Nutrition and Dietetics that all people should have access to a safe food and water supply. The Academy of Nutrition and Dietetics supports science-based food and water regulations and recommendations that are applied consistently across all foods and water regulated by all agencies and incorporate traceability and recall to limit food- and waterborne outbreaks. Registered dietitian nutritionists and dietetic technicians, registered, are encouraged to participate in policy decisions, program development, and implementation of a food safety culture. Food safety affects all segments of the population in a global society, and, although the United States food and water system has many protections in place, food safety continues to be a public health concern. The Centers for Disease Control and Prevention estimates that one in six Americans are sickened, 128,000 are hospitalized, and 3,000 die annually from foodborne disease. Using the Centers for Disease Control and Prevention estimates for foodborne illness, it is estimated that the basic cost of-illness averages $1,068/episode with a total annual cost of $51 billion. The food safety system is challenged by changing demographics, consumer preferences for convenience and variety, and issues of concern in the commercial food chain and in regulatory systems. The 2011-enacted Food Safety Modernization Act is an extensive expansion of federal food regulatory authority that mandates a risk based food safety system approach and focuses on comprehensive science-based preventive measures across the total food safety system. Registered dietitian nutritionists and dietetic technicians, registered, have unique roles in promoting and establishing food safety cultures in foodservice settings, clinical practices, community settings, and in public venues because their training integrates food; science; and health, both preventive and therapeutic. PMID- 25439083 TI - Is there a diet for histamine intolerance? PMID- 25439084 TI - Exercise and severe major depression: effect on symptom severity and quality of life at discharge in an inpatient cohort. AB - BACKGROUND: Exercise is a potential treatment for depression. However, few studies have evaluated the role of adjunct exercise in the treatment of severely major depressed inpatients. The goal of this study was to evaluate the effects of add-on exercise on the usual treatment of severely depressed inpatients. METHODS: Fifty participants were randomized to an exercise (exercise + usual treatment) or a control (usual treatment) group. Twenty-five patients were randomly allocated to each group. The participants in the exercise group performed three sessions per week throughout the hospitalization period, with a goal dose of 16.5 kcal/kg/week plus the usual pharmacological treatment. Depressive symptoms and the Quality of Life (QoL) of the participants were assessed at the baseline, the second week, and discharge. RESULTS: A significant group * time interaction was found for depressive symptoms and the physical and psychological domains of QoL. Differences between groups occurred at the second week and discharge with respect to depressive symptoms and the physical and psychological domains of QoL. There was no difference in the remission rate at discharge (48% and 32% for the exercise and control group, respectively). An NNT of 6.25 was found. No significant baseline characteristics predict remission at discharge. CONCLUSION: Add-on exercise is an efficacious treatment for severely depressed inpatients, improving their depressive symptoms and QoL. Initial acceptance of exercise remains a challenge. PMID- 25439086 TI - The Effect of early physiotherapy on the recovery of mandibular function after orthognathic surgery for Class III correction: part I--jaw-motion analysis. AB - The aim of this prospective study was to compare the mandibular range of motion in Class III patients with and without early physiotherapy after orthognathic surgery (OGS). This study consisted of 63 Class III patients who underwent 2-jaw OGS. The experimental group comprised 31 patients who received early systematic physical rehabilitation. The control group consisted of 32 patients who did not have physical rehabilitation. Twelve variables of 3-dimensional (3D) jaw-motion analysis (JMA) were recorded before surgery (T1) and 6 weeks (T2) and 6 months (T3) after surgery. A 2-sample t test was conducted to compare the JMA results between the two groups at different time points. At T2, the JMA data were measured to be 77.5%-145.7% of presurgical values in the experimental group, and 60.3%-90.6% in the control group. At T3, the measurements were 112.2%-179.2% of presurgical values in the experimental group, and 77.6%-157.2% in the control group. The patients in the experimental group exhibited more favorable recovery than did those in the control group, from T1 to T2 and T1 to T3. However, after termination of physiotherapy, no significant difference in the extent of recovery was observed between groups up to 6 months after OGS. PMID- 25439087 TI - On oral and cranio-maxillofacial surgery in Byzantium, addenda. PMID- 25439085 TI - Will the right Robin patient rise, please? Definitions and criteria during management of Robin sequence patients in the Netherlands and Belgium. AB - BACKGROUND: Robin Sequence (RS) is characterized by micrognathia and upper airway obstruction (UAO), with or without cleft palate, causing respiratory and feeding problems. Management options are: positioning; nasopharyngeal airway (NPA); tongue-lip adhesion (TLA); mandibular distraction (MDO); and tracheostomy. Controversy exists in literature regarding RS definition and management. Here we describe definitions, management strategies and criteria in opting for management strategies, used by Dutch and Belgian cleft teams. METHODS: A specifically designed questionnaire was sent to members of all 16 Dutch and Belgian cleft teams. RESULTS: 14 cleft teams returned 35 questionnaires. All used micrognathia as definition criterion, 93.4% cleft palate, 51.5%glossoptosis and 45.7% UAO. Six different RS definitions were used; even within a single team >1 definition was used. All teams used different management strategies: all used positioning, 10 NPA, 6 TLA, 7 MDO, 8 tracheostomy, 5 refer patients with invasive treatment indication. Criteria in opting management modalities were: O2-saturation (89.3%), clinical presentation (86.2%), growth and feeding problems (69.0%), polysomnography (62.1%), and differed within teams. CONCLUSION: The Dutch and Belgian cleft teams use variable RS definitions, different management modalities and criteria in choosing management strategies. A single, strict definition and evidence-based management guidelines should be formulated for optimal patient care. PMID- 25439088 TI - Development plates for stable internal fixation: Study of mechanical resistance in simulated fractures of the mandibular condyle. AB - OBJECTIVE: To develop Y-shaped plates with different thicknesses to be used in simulated fractures of the mandibular condyle. Ten plates were developed in Y shape, containing eight holes, and 30 synthetic polyurethane mandible replicas were developed for the study. MATERIAL AND METHODS: The load test was performed on an Instron Model 4411 universal testing machine, applying load in the mediolateral and anterior-posterior positions on the head of the condyle. Two-way ANOVA with Tukey testing with a 5% significance level was used. RESULTS: It was observed that when the load was applied in the medial-lateral plate of greater thickness (1.5 mm), it gave the highest strength, while in the anteroposterior direction, the plate with the highest resistance was of the lesser thickness (0.6 mm). A plate with a thickness of 1.5 mm was the one with the highest average value for all displacements. In the anteroposterior direction, the highest values of resistance were seen in the displacement of 15 mm. CONCLUSION: After comparing the values of the biomechanical testing found in the scientific literature, it is suggested that the use of Y plates are suitable for use in subcondylar fractures within the limitations of the study. PMID- 25439089 TI - The effect of early physiotherapy on the recovery of mandibular function after orthognathic surgery for class III correction. Part II: electromyographic activity of masticatory muscles. AB - The study was conducted to evaluate the effect of early physical rehabilitation by comparing the differences of surface electromyographic (sEMG) activity in the masseter and anterior temporalis muscles after surgical correction of skeletal class III malocclusion. The prospective study included 63 patients; the experimental groups contained 31 patients who received early systematic physical rehabilitation; the control group (32 patients) did not receive physiotherapy. The amplitude of sEMG in the masticatory muscles reached 72.6-121.3% and 37.5 64.6% of pre-surgical values in the experimental and control groups respectively at 6 weeks after orthognathic surgery (OGS). At 6 months after OGS, the sEMG reached 135.1-233.4% and 89.6-122.5% of pre-surgical values in the experimental and control groups respectively. Most variables in the sEMG examination indicated that recovery of the masticatory muscles in the experimental group was better than the control group as estimated in the early phase (T1 to T2) and the total phase (T1 to T3); there were no significant differences between the mean recovery percentages in the later phase (T2 to T3). Early physical rehabilitative therapy is helpful for early recovery of muscle activity in masticatory muscles after OGS. After termination of physical therapy, no significant difference in recovery was indicated in patients with or without early physiotherapy. PMID- 25439090 TI - A positively charged lysine residue at VP2 131 position allows for the enhanced adaptability of foot-and-mouth disease virus serotype A in BHK-21 cells. AB - Field outbreak strains of foot-and-mouth disease virus (FMDV) infect host cells through certain Arg-Gly-Asp (RGD) dependent integrin family of cellular receptors. In contrast, FMDV adapted in non-host cell cultures are reported to acquire the ability to infect cells via heparin sulphate (HS) or other unidentified cell surface molecules. It has been reported that during the serial passage of FMDV serotype A in BHK-21 cell culture, VP2 E131K (E2131K) substitution was fixed within the heparin sulphate binding site. The fixation of positively charged residue at position VP2 131 of serotype A is considered to associate with the ability to utilise alternative receptor. In this study, an infectious full-length cDNA clone for Indian FMDV vaccine strain A IND 40/2000 was constructed. Through site-directed mutagenesis on the cDNA clone, recombinant virus containing positive charged amino acid residue at position VP2 131 was rescued. The recombinant mutated virus was shown to have specific and strong affinity for HS and demonstrated an enhanced infectivity in BHK-21 cell line. The introduction of lysine residue at VP2 131 position that allows cell culture adaptation of FMDV serotype A could be exploited for the generation of vaccine seed stocks with improved growth properties in BHK-21 cell line. PMID- 25439091 TI - Production and characterization of single-chain antibody (scFv) against 3ABC non structural protein in Escherichia coli for sero-diagnosis of Foot and Mouth Disease virus. AB - Differentiation of Foot-and-Mouth Disease infected from vaccinated animals is essential for effective implementation of vaccination based control programme. Detection of antibodies against 3ABC non-structural protein of FMD virus by immunodiagnostic assays provides reliable indication of FMD infection. Sero monitoring of FMD in the large country like India is a big task where thousands of serum samples are annually screened. Currently, monoclonal or polyclonal antibodies are widely used in these immunodiagnostic assays. Considering the large population of livestock in the country, an economical and replenishable alternative of these antibodies was required. In this study, specific short chain variable fragment (scFv) antibody against 3B region of 3ABC poly-protein was developed. High level of scFv expression in Escherichia coli system was obtained by careful optimization in four different strains. Two formats of enzyme immunoassays (sandwich and competitive ELISAs) were optimized using scFv with objective to differentiate FMD infected among the vaccinated population. The assays were statistically validated by testing 2150 serum samples. Diagnostic sensitivity/specificity of sandwich and competitive ELISAs were determined by ROC method as 92.2%/95.5% and 89.5%/93.5%, respectively. This study demonstrated that scFv is a suitable alternate for immunodiagnosis of FMD on large scale. PMID- 25439092 TI - Chicken anemia virus and avian gyrovirus 2 as contaminants in poultry vaccines. AB - This study focuses on the detection of chicken anemia virus (CAV) and avian gyrovirus 2 (AGV2) genomes in commercially available poultry vaccines. A duplex quantitative real-time PCR (dqPCR), capable of identifying genomes of both viruses in a single assay, was employed to determine the viral loads of these agents in commercially available vaccines. Thirty five vaccines from eight manufacturers (32 prepared with live and 3 with inactivated microorganisms) were examined. Genomes of CAV were detected as contaminants in 6/32 live vaccines and in 1/3 inactivated vaccines. The CAV genome loads ranged from 6.4 to 173.4 per 50 ng of vaccine DNA (equivalent to 0.07 to 0.69 genome copies per dose of vaccine). Likewise, AGV2 genomes were detected in 9/32 live vaccines, with viral loads ranging from 93 to 156,187 per 50 ng of vaccine DNA (equivalent to 0.28-9176 genome copies per dose of vaccine). These findings provide evidence for the possibility of contamination of poultry vaccines with CAV and AGV2 and they also emphasize the need of searching for these agents in vaccines in order to ensure the absence of such potential contaminants. PMID- 25439093 TI - Practical management of cumulative anthropogenic impacts with working marine examples. AB - Human pressure on the environment is expanding and intensifying, especially in coastal and offshore areas. Major contributors to this are the current push for offshore renewable energy sources, which are thought of as environmentally friendly sources of power, as well as the continued demand for petroleum. Human disturbances, including the noise almost ubiquitously associated with human activity, are likely to increase the incidence, magnitude, and duration of adverse effects on marine life, including stress responses. Stress responses have the potential to induce fitness consequences for individuals, which add to more obvious directed takes (e.g., hunting or fishing) to increase the overall population-level impact. To meet the requirements of marine spatial planning and ecosystem-based management, many efforts are ongoing to quantify the cumulative impacts of all human actions on marine species or populations. Meanwhile, regulators face the challenge of managing these accumulating and interacting impacts with limited scientific guidance. We believe there is scientific support for capping the level of impact for (at a minimum) populations in decline or with unknown statuses. This cap on impact can be facilitated through implementation of regular application cycles for project authorization or improved programmatic and aggregated impact assessments that simultaneously consider multiple projects. Cross-company collaborations and a better incorporation of uncertainty into decision making could also help limit, if not reduce, cumulative impacts of multiple human activities. These simple management steps may also form the basis of a rudimentary form of marine spatial planning and could be used in support of future ecosystem-based management efforts. PMID- 25439095 TI - The lasting effects of process-specific versus stimulus-specific learning during infancy. AB - The capacity to tell the difference between two faces within an infrequently experienced face group (e.g. other species, other race) declines from 6 to 9 months of age unless infants learn to match these faces with individual-level names. Similarly, the use of individual-level labels can also facilitate differentiation of a group of non-face objects (strollers). This early learning leads to increased neural specialization for previously unfamiliar face or object groups. The current investigation aimed to determine whether early conceptual learning between 6 and 9 months leads to sustained behavioral advantages and neural changes in these same children at 4-6 years of age. Results suggest that relative to a control group of children with no previous training and to children with infant category-level naming experience, children with early individual level training exhibited faster response times to human faces. Further, individual-level training with a face group - but not an object group - led to more adult-like neural responses for human faces. These results suggest that early individual-level learning results in long-lasting process-specific effects, which benefit categories that continue to be perceived and recognized at the individual level (e.g. human faces). PMID- 25439094 TI - Mild cognitive dysfunction does not affect diabetes mellitus control in minority elderly adults. AB - OBJECTIVES: To determine whether older adults with type 2 diabetes mellitus and cognitive dysfunction have poorer metabolic control of glycosylated hemoglobin, systolic blood pressure, and low-density lipoprotein cholesterol than those without cognitive dysfunction. DESIGN: Prospective cohort study. SETTING: A minority cohort in New York City previously recruited for a trial of telemedicine. PARTICIPANTS: Persons aged 73.0 +/- 3.0 (N = 613; 69.5% female; 82.5% Hispanic, 15.5% non-Hispanic black). MEASUREMENTS: Participants were classified with executive or memory dysfunction based on standardized score cutoffs (<16th percentile) for the Color Trails Test and Selective Reminding Test. Linear mixed models were used to compare repeated measures of the metabolic measures and evaluate the rates of change in individuals with and without dysfunction. RESULTS: Of the 613 participants, 331 (54%) had executive dysfunction, 202 (33%) had memory dysfunction, and 96 (16%) had both. Over a median of 2 years, participants with executive or memory dysfunction did not exhibit significantly poorer metabolic control than those without executive function or memory type cognitive dysfunction. CONCLUSION: Cognitive dysfunction in the mild range did not seem to affect diabetes mellitus control parameters in this multiethnic cohort of older adults with diabetes mellitus, although it cannot be excluded that cognitive impairment was overcome through assistance from formal or informal caregivers. It is possible that more-severe cognitive dysfunction could affect control. PMID- 25439096 TI - Quantitative positron emission tomography of mGluR5 in rat brain with [(18) F]PSS232 at minimal invasiveness and reduced model complexity. AB - Imaging the density of metabotropic glutamate receptor 5 (mGluR5) in brain by positron emission tomography (PET) is of interest in relation to several brain disorders. We have recently introduced [(18) F]PSS232, an F-18-labeled analog of the mGluR5-targeting [(11) C]ABP688. Quantitative PET requires kinetic modeling with an input function (IF) or an appropriate reference tissue model. We aimed at minimizing invasiveness of IF recording in rat and employing this protocol for mGluR5 quantitative PET with [(18) F]PSS232. We further aimed at defining models of low complexity for quantitative PET with [(18) F]PSS232. The IF was recorded in an arterio-venous shunt applied by minimally invasive cannulation. PET data were analyzed with a modified two-tissue compartment model including a single variable for radiometabolite correction in brain. We further evaluated a simple reference tissue model. Receptor-dependent accumulation was similar to [(11) C]ABP688 at lower unspecific accumulation of unchanged [(18) F]PSS232, in agreement with its higher plasma protein binding and lower lipophilicity. The minimally invasive protocol revealed similar results as the invasive shunt method and parameters calculated with the modified two-tissue compartment model were similar to those calculated with the standard model. The simple area under the curve ratios agreed with the Logan reference method. [(18) F]PSS232 is a promising radioligand for mGluR5 quantification. Methods were evaluated to quantify mGluR5 in rat brain by PET with [(18) F]PSS232. We present a minimally invasive protocol for input function recording. A two-tissue compartment model correcting for radiometabolites at reduced complexity is compared with the standard model. Finally, we demonstrate and explain why for [(18) F]PSS232 the area-under-the-curve ratio is a valid alternative to the Logan reference tissue analysis. PMID- 25439097 TI - A novel test for recessive contributions to complex diseases implicates Bardet Biedl syndrome gene BBS10 in idiopathic type 2 diabetes and obesity. AB - Rare-variant association studies in common, complex diseases are customarily conducted under an additive risk model in both single-variant and burden testing. Here, we describe a method to improve detection of rare recessive variants in complex diseases termed RAFT (recessive-allele-frequency-based test). We found that RAFT outperforms existing approaches when the variant influences disease risk in a recessive manner on simulated data. We then applied our method to 1,791 Finnish individuals with type 2 diabetes (T2D) and 2,657 matched control subjects. In BBS10, we discovered a rare variant (c.1189A>G [p.Ile397Val]; rs202042386) that confers risk of T2D in a recessive state (p = 1.38 * 10(-6)) and would be missed by conventional methods. Testing of this variant in an established in vivo zebrafish model confirmed the variant to be pathogenic. Taken together, these data suggest that RAFT can effectively reveal rare recessive contributions to complex diseases overlooked by conventional association tests. PMID- 25439098 TI - Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome. AB - 5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three genes. We describe 11 individuals with clinical features of 5q31.3 microdeletion syndrome and de novo mutations in PURA, encoding transcriptional activator protein Pur-alpha, within the critical region. These data implicate causative PURA mutations responsible for the severe neurological phenotypes observed in this syndrome. PMID- 25439100 TI - Prediction of prognosis to lamivudine in patients with spontaneous reactivation of hepatitis B virus-related acute-on-chronic liver failure: using virologic response at week 4. AB - BACKGROUND/AIMS: Current results had demonstrated lamivudine (LAM) contributed to improve liver function and short-term prognosis in patients with hepatitis B virus-related acute-on-chronic liver failure (ACLF), but data concerning the outcome of long-term prognosis are limited. Our objective was to explore the prediction value of early viral response for prognosis and LAM resistance in ACLF patients with lamivudine treatment within 96weeks. METHODS: One hundred and forty consecutive subjects were recruited, 76 patients were treated with LAM and supportive treatment (LAM group) and 64 patients only received supportive treatment (non-NAs group). All the patients were followed up until death or 96weeks. The primary end point was overall survival rate at 96weeks, as well as the relationship between the virologic response at weeks 4 or 12 and prognosis and resistance at 96weeks. RESULTS: At 96weeks, the cumulative survival was higher in the LAM group than that in the non-NA group (43/76 (56.58%) vs 9/64 (14.06%), respectively, p=0.000). The survival rate of patients achieved complete viral response (CVR) at week 4 was higher than that of those with partial virologic response (PVR) during the 96-week follow-up (27/29 [93.10%] vs 16/45 [35.56%], p=0.000). In CVR patients, there was a significant improvement in model for end-stage liver failure (MELD) scores compared to PVR. Logistic recurrence indicated that both 4-week CVR and MELD scores were an independent predictor of the 96-week survival. Twelve patients developed LAM resistance (22.22%); all of them came from the PVR at 4weeks. CONCLUSION: LAM can significantly improve the long-term survival rate, and 4weeks CVR can predict the long-term clinical outcome and LAM-resistant in patients with HBV-related ACLF. PMID- 25439101 TI - Long-term follow-up after anticoagulant treatment withdrawal in patients with deep venous thrombosis and inferior vena cava agenesis. PMID- 25439102 TI - Stress and aging. PMID- 25439107 TI - [QuiPO: who inject EPO?]. AB - INTRODUCTION: Erythropoiesis Stimulating Agents (ESA) are largely prescribed before dialysis stage to chronic kidney disease patients. In accordance to current international guidelines, lots have been made by pharmacological companies in order to improve self management of ESAs: subcutaneaous administration, pencil devices, mutidose cartridges, low injection volume, very fine needles, once a month injections but none is currently known on the percentage of patients who actually do self administration of ESAs. PATIENTS AND METHODS: We conducted a simple prospective questionnaire study in different nephrology departments in France, on pre-dialysis patients. Questionnaires have been fulfilled by randomly selected French nephrologists during visits with outpatients treated by ESA. Costs have been evaluated by ESA and nurse visit direct costs in euros and compared by a Wilcoxon test. RESULTS: Within 6 months, 143 questionnaires of outpatients have been completed. The characteristics of the population are as followed: 53% men, mean age 66.4+/-16.9 y/o, 38.6% of diabetics, mean estimated Glomerular Filtration Rate (eGFR by MDRD formula) 22.8+/-11.6 mL/min/1.73 m(2). ESAs are prescribed as follow: Aranesp((r)) (50.3%), Mircera((r)) (36.3%), NeoRecormon((r)) (10.5%), Eprex((r)) (2.1%) and Retacrit((r)) (0.7%). ESA self administration concerns only 24.8% of the patients their while most of the patients (70.2%) ask a nurse for injection without any differences between ESAs (P=0.24), sex (P=0.81) or presence of diabetes (P=0.78). ESA self administration is more frequent for working patients (56.8% versus 34.7%; P=0.0002). Moreover, for 86.7% of the patients, nurse comes at home and in 60% of the cases only for this injection. Finally, 42% of the patients feel improvement as soon as a couple of hours after injection whatever ESA used (0-45 days). In addition, mean haemoglobin level is 11.4+/-1.3g/dL, mean ferritinemia is 229+/-211UI/mL. Non surprisingly, nurse injection regimen is more expensive than self injection (P=0.0016). DISCUSSION: This simple questionnaire shows that despite efforts made to improve ESA self administration, a minority of patients are in fact proceeding to ESA self administration. Asking for a nurse, does not help patient to be independent, and increases health cost. Efforts have to be made in order to help patients for ESA self administration. PMID- 25439109 TI - Total hip modularity: truth and consequences. PMID- 25439108 TI - [Fanconi syndrome in a 22-year-old African patient]. AB - Acquired Fanconi syndrome can occur in patients with monoclonal gammopathy or after exposure to heavy metals or drug agents such as ifosfamide, and some antiretroviral therapies. Fanconi syndrome is characterized by a dysfunctional of the proximal tubular responsible in its complete form for polyuria, hypokalemia, glycosuria, hypophosphatemia and low molecular weight proteinuria. We report the case of a 22-year-old patient hospitalized with an acute renal failure secondary to a tubulo-interstitial nephritis associated with a complete Fanconi syndrome in a context of a poor general condition and fever. We described and analyzed the process leading to the diagnosis. PMID- 25439110 TI - A missed diagnosis: acute encephalopathy with biphasic seizures and late reduced diffusion. AB - Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a very rare encephalopathy subtype which is characterized by biphasic seizures and disturbance of consciousness in the acute stage followed in the subacute stage by restricted diffusion in the subcortical white matter and finally resulting in cerebral atrophy on magnetic resonance imaging. Although exact pathogenesis of AESD is uncertain, the etiology of AESD has been attributed to viral and bacterial infection. Here we report a case of AESD in a 15-year-old mentally and motor retarded patient, diagnosed based on clinicoradiological correlation. PMID- 25439111 TI - Positioning clinical nurse specialists and nurse practitioners as change champions to implement a pain protocol in long-term care. AB - Pain management for older adults in long-term care (LTC) has been recognized as a problem internationally. The purpose of this study was to explore the role of a clinical nurse specialist (CNS) and nurse practitioner (NP) as change champions during the implementation of an evidence-based pain protocol in LTC. In this exploratory, multiple-case design study, we collected data from two LTC homes in Ontario, Canada. Three data sources were used: participant observation of an NP and a CNS for 18 hours each over a 3-week period; CNS and NP diaries recording strategies, barriers, and facilitators to the implementation process; and interviews with members of the interdisciplinary team to explore perceptions about the NP and CNS role in implementing the pain protocol. Data were analyzed using thematic content analysis. The NP and CNS used a variety of effective strategies to promote pain management changes in practice including educational outreach with team members, reminders to nursing staff to highlight the pain protocol and educate about practice changes, chart audits and feedback to the nursing staff, interdisciplinary working group meetings, ad hoc meetings with nursing staff, and resident assessment using advanced skills. The CNS and NP are ideal champions to implement pain management protocols and likely other quality improvement initiatives. PMID- 25439112 TI - Role of self-care in sickle cell disease. AB - Self-care is an important aspect of managing a chronic disease. In sickle cell disease (SCD), home self-care contributes to individual pain management and thus pain crisis prevention. A better understanding of self-care can help health care providers equip patients with the resources and skills necessary to participate in their disease management. The aim of this study was to examine factors that influence self-care among young adults with SCD. A descriptive, cross-sectional study was conducted using secondary data analysis. Participants were recruited from two SCD clinics in the southeastern United States. The sample consisted of 103 young adults, ages 18 to 30 years, with SCD. Bivariate correlations and regression analyses were used to evaluate the relationships among SCD self efficacy, social support, sociodemographics, self-care, and hospital visits for pain crises. Study participants were primarily women (61.2%), unemployed or disabled (68%), lived with family (73.8%), and had an annual average of three hospital visits for pain crises. Participants, on average, had 12 years of education, an annual household income of $35,724, and were 24 years old. Social support (p = .001), SCD self-efficacy (p = .002), and years of education (p = .043) were significantly related to self-care. Of the hypothesized variables, only income was significantly associated with hospital visits for pain crises (r = -0.219, p = .05). Individuals with SCD may benefit from self-care interventions that enhance social support, SCD self-efficacy, and access to education. To inform intervention development, further investigation is needed regarding daily self-care behaviors used by young adults with SCD. PMID- 25439113 TI - The pain experience of inpatients in a teaching hospital: revisiting a strategic priority. AB - For hospital executives and clinicians to improve pain management, organizations must examine the current pain experience of in-patients beyond simply measuring patient satisfaction. The aim of this study was to quantify the prevalence of pain among adult in-patients and the degree of interference pain had on daily activities. A descriptive, cross-sectional study was undertaken in a 530 bed tertiary care, teaching hospital in central Canada. A convenience sample (N = 88) of adult medical-surgical patients completed the Short Form-Brief Pain Inventory survey. Pain prevalence was 70.4%. The mean pain severity score was 3.76 (standard deviation, SD = 2.88) and mean pain interference score on daily activities was 4.56 (SD = 3.93). The most frequently identified site of pain was the lower extremities (n = 15, 28%). Women had higher mean scores on pain "right now" compared to men (p < 0.05). The sample majority (n = 81) indicated hospital staff asked about the presence of pain. Seventy-nine percent (n = 57) reported hospital staff "always" did everything they could to help manage pain. Eighty four percent (n = 61) selected "always" or "usually" to describe their ability to be involved in deciding pain treatments. The mean pain relief score from treatments was 61% (SD = 34.79). Significant positive correlations were found between pain intensity ratings and pain interference on all daily activities (p < 0.001). Pain prevalence remains high with a significant relationship between pain and activities of daily living. The study provides baseline data to direct future initiatives at improving pain management. PMID- 25439099 TI - Gout, allopurinol intake and clinical outcomes in the hospitalized multimorbid elderly. AB - BACKGROUND: Increased serum uric acid has been considered a cardiovascular risk factor but no study has assessed its relation with hospital mortality or length of stay. On the basis of data obtained from a prospective registry, the prevalence of gout/hyperuricemia and its association with these and other clinical parameters was evaluated in an Italian cohort of elderly patients acutely admitted to internal medicine or geriatric wards. METHODS: While the prevalence of gout was calculated by counting patients with this diagnosis hyperuricemia was inferred in patients taking allopurinol at hospital admission or discharge, on the assumption that this drug was only prescribed owing to the finding of high serum levels of uric acid. A series of clinical and demographic variables were evaluated for their association with gout/hyperuricemia. RESULTS: Of 1380 patients, 139 (10%) had a diagnosis of gout or were prescribed allopurinol. They had more co-morbidities (7.0 vs 5.6; P<0.0001) and consumed more drugs (6.8 vs 5.0; P<0.0001). The CIRS (co-morbidity index) was worse in these patients (OR 1.28 95% CI 1.15-1.41). Multivariable regression analysis showed that only renal and heart failures were independently associated with gout/allopurinol intake. Moreover, this combined event was associated with an increased risk of adverse events during hospitalization (OR 1.66, 95% CI 1.16 2.36), but not with the risk of re-hospitalization, length of hospital stay or death. CONCLUSIONS: Gout/allopurinol intake has a high prevalence in elderly patients acutely admitted to hospital and are associated with renal and cardiovascular diseases, an increased rate of adverse events and a high degree of drug consumption. In contrast, this finding did not affect the length of hospitalization nor hospital mortality. PMID- 25439114 TI - Can presence of a dog reduce pain and distress in children during venipuncture? AB - The aim of this study was to investigate the effectiveness of animal-assisted intervention as distraction for reducing children's pain and distress before, during, and after standard blood collection procedure. Fifty children (ages 4-11 years) undergoing venipuncture were randomly assigned to the experimental group (EG; n = 25) or to the control group (CG; n = 25). The blood collection procedure was carried on the children in the EG arm in the presence of a dog, whereas no dog was present when venipuncture was conducted on children in CG. In both cases, parents accompanied the child in the procedure room. Distress experienced by the child was measured with the Amended Observation Scale of Behavioral Distress, while perceived pain was measured with a visual analog scale or the Wong Baker Scale (Faces Scale); levels of cortisol in blood also were analyzed. Parental anxiety during the procedure was measured with State Trait Anxiety Inventory. Children assigned to the EG group reacted with less distress than children in the CG arm. Furthermore, cortisol levels were lower in the EG group compared with the CG group. There were no significant differences in pain ratings and in the level of parental anxiety. It appears that the presence of dogs during blood draw procedures reduces distress in children. PMID- 25439115 TI - Generating and selecting pain indicators for brain-injured critical care patients. AB - Current pain assessment tools for nonverbal critical care patients may not be appropriate for those with brain injury, as these patients demonstrate specific responses to pain. The aim of this study was to generate and select items that could be used to assess pain in brain-injured patients. A sequential mixed-method design was chosen with three consecutive steps: 1. Generate items with a literature review, the results of a pilot study, and interviews with 18 clinicians using the nominal group technique. 2. Evaluate content validity with 10 clinicians and four scientists, using a web-based questionnaire. 3. Describe and reduce items with the observation of 116 brain-injured patients in the intensive care unit during common painful procedures. This study took place between May 2010 and October 2011 in two tertiary hospitals in Western Switzerland. Forty-seven items were generated and reduced to 33 during the content validity process. The behaviors most frequently observed during turning were closing the eyes (58.6%), eye movements (57.8%), ventilator asynchrony (55.2%), and frowning/brow lowering (50%). Five items were observed in less than 5% of the patients during nociceptive procedure. Constant motor activity was observed more frequently at rest than during nociceptive stimulation. All physiologic items showed little variability and their reliability was low. Based on these results, the number of items was reduced to 23. This study identified items that could be specific to brain-injured patients and found that the variability of physiologic items was poorly assessed by clinicians. PMID- 25439116 TI - Guided Imagery for Adolescent Post-spinal Fusion Pain Management: A Pilot Study. AB - Orthopedic surgery for adolescent idiopathic scoliosis entails anxiety and severe postoperative pain. The aim of this pilot study was to investigate an intervention for adolescent post-spinal fusion pain management in patients from a tertiary care hospital in Montreal, Canada. Participants were adolescents and young adults ages 11 to 20 years undergoing spinal fusion. Participants were randomized to standard care or standard care with adjunct intervention. The intervention consisted of a DVD with information and guided imagery/relaxation exercises to practice at least three times a week at home. A nurse screened the DVD with the patient preoperatively and at discharge (T1) and telephoned 2 weeks post-discharge (T2) to reinforce the technique. Both groups completed questionnaires at T1, T2, and T3 (1-month postoperative follow-up). Outcome measures included pain intensity, anxiety, coping mechanisms, and daily activities. From March 2010 to June 2011, we enrolled 40 of 45 eligible participants (n = 20 per group), average age 15 +/- 2.1 years, 7 participants were male. Compared with the control group, the experimental group experienced significantly less overall pain at all time points, with moderate to large effect sizes at T2, T3 (p <= .007). Worst pain in 24 hours was moderately decreased at T2 (p = .01). State-trait anxiety remained high. On a 10-point scale, a median 2.5-point benefit was seen in eating and sleeping (Mann-Whitney test, p = .002), and 2 points in walking (Mann-Whitney test, p = .003). Coping strategies showed no significant differences. Addition of a guided imagery and relaxation exercise DVD for home use was more effective than standard care alone for postoperative pain. Our nonpharmacologic adjunct looks promising. Larger sample size and longer (6-9 months) follow-up will permit refinement. PMID- 25439118 TI - Impact of epidural analgesia on quality of life and pain in advanced cancer patients. AB - Patients with advanced cancer often experience chronic postoperative pain and poor quality of life. The objective of this study was to determine if epidural self-controlled analgesia reduced the incidence of chronic pain and improved the quality of life when compared with intravenous self-controlled analgesia. A total of 50 patients diagnosed with advanced cancer who received analgesia treatment were randomly divided into two groups, epidural self-controlled analgesia group (EA group, n = 26) and intravenous self-controlled analgesia group (IA group, n = 24). Visual analog scale (VAS) and Karnofsky score were used to assess the pain and the quality of life, respectively. A multifunction monitor was used to continuously record the physical signs of patients after treatment. The physical signs, such as heart failure, respiration, pulse, blood pressure, and oxygen saturation, in the two groups were better after analgesia treatment. Meanwhile, the respiration and oxygen saturation in the EA group were significantly improved compared with that of the IA group (p < .05). The VAS in the EA group was significantly lower than that in the IA group (p < .05), and the Karnofsky score in the EA group was significantly higher than that in the IA group (p < .05). Moreover, patients treated with EA felt more satisfied and experienced fewer complications than those with IA (p < .05). The epidural self-controlled analgesia may greatly improve the quality of life and relieve the pain in patients with advanced cancer. PMID- 25439117 TI - Quality pain management practices in a university hospital. AB - Despite available guidelines and efforts to improve pain management, pain remains prevalent in hospitals. The aim of this study was to explore whether pain management practices in a university hospital were in line with guidelines on acute, geriatric, and cancer pain. This was a descriptive, correlational, and point-prevalence study conducted at a university hospital with 282 adults, who were hospitalized for 24 hours and were alert and able to participate. Patient self-report data were collected with the American Pain Society questionnaire and pain management data were collected from medical records. Adequacy of treatment was measured with the Pain Management Index, calculated for prescribed and administered treatments. The mean age of participants was 68.9 years (SD = 17; range 18-100); 49% were women; and 72% were on medical services. Pain assessment was documented for 57% of patients, of those, 27% had pain severity documented with a standardized scale. Most patients (85%) were prescribed analgesics and multimodal therapy was prescribed for 60%. Prescribed treatment was adequate for 78% of patients, whereas 64% were administered adequate treatment. The odds of receiving adequate treatment were higher (odds ratio, 3.44; 95% confidence interval, 1.38-8.60) when pain severity was documented. Nonpharmacologic methods were used by 34% of patients. Although the majority of patients had an analgesic prescription, many did not receive adequate treatment. The use of pain severity scales was associated with the provision of more adequate pain treatment. To provide quality pain management, pain assessment needs to be improved and available treatments used to meet patient needs. PMID- 25439120 TI - Auricular point acupressure as an adjunct analgesic treatment for cancer patients: a feasibility study. AB - This study aimed (1) to examine the feasibility of an auricular point acupressure (APA) research protocol in terms of recruitment and for the assessment and management of pain and (2) to examine the potential APA analgesic effects for cancer patients. This study was a repeated-measures one-group design. Participants were recruited from the cancer center follow-up clinic affiliated with a large university hospital in the northeastern United States. Participants included 50 patients aged 55-87 years with a diagnosis of cancer. Participants received 7 days of APA treatment for their pain. After appropriate acupoints were identified, vaccaria seeds were carefully taped onto each selected auricular point on each ear. The study recruitment and retention rates were 92% and 91%, respectively. Importantly, the study found preliminary evidence for the analgesic effects of APA for cancer pain management. For example, by the end of the 7-day study, APA reduced pain intensity more than 55% for "worst pain" and about 57% for "average pain" and "pain intensity." Moreover, the use of pain medication was reduced during the APA treatment (e.g., 78% of patients [n = 39] took less pain medication than before the treatment). APA appears to be highly acceptable to patients with cancer-related pain. However, without a placebo control, we cannot draw conclusive evidence for the analgesic effect of APA for cancer patients. A sham group must be added to future studies to differentiate the true effects of APA from the possible psychological effects of the APA treatment. PMID- 25439119 TI - Perceived injustice predicts stress and pain in adults with sickle cell disease. AB - Research evidence shows that perceived injustice is a context-based unfair treatment that has negative influence on health outcomes. We examined the contribution of patients' perceived injustice regarding interactions with health care providers to stress and pain in adults with sickle cell disease (SCD). This study was a cross-sectional correlational pilot study. Included in the study were adults with SCD who received their care from a university-affiliated comprehensive sickle cell clinic. Participants were 52 adults whose mean age was 34 +/- 11 years (minimum [min] 20 years, maximum [max] 70 years). Most of the patients were African American (n = 48, 92%) and female (n = 41, 79%). Forty eight patients (92%) reported having a high school diploma or higher. Participants completed the perceived injustice questionnaire, perceived stress questionnaire, and the PAINReportIt, which includes questions to measure pain and demographics. We analyzed the data using the linear regression analyses. Perceived injustice from doctors was a significant predictor of perceived stress (p < .001) and pain (p = .002). Perceived injustice from nurses also was a significant predictor of perceived stress (p < .001) and pain (p = .02). The procedural, distributive, and informational domains of perceived injustice attributed to both doctors and nurses consistently predicted patients' perceived stress, but only the procedural and distributive domains of perceived injustice consistently predicted patients' pain. Findings suggest that perceived injustice was negatively associated with stress and pain in adults with SCD and warrant further investigation in a larger sample. PMID- 25439122 TI - Knowledge and attitudes regarding pediatric pain in Mongolian nurses. AB - The World Health Organization and the International Association for Study of Pain cite the significance of pediatric pain as a significant global health issue. Developing countries may have increased needs compared with developed countries because of limited resources and lack of training. In Mongolia a paucity of data exist regarding nursing knowledge of pediatric pain management. The purpose of this project was to assess the current knowledge of pediatric pain and to assess the effectiveness of educational intervention on improving knowledge and attitudes of pediatric nurses working at a major children's hospital in Mongolia. Knowledge and attitudes of Mongolian nurses were evaluated before and after a 2 hour educational intervention. The translated Modified Mongolian Pediatric Nurses' Knowledge and Attitudes Survey Regarding Pain-Shriner's Revision survey was used as a pre- and postintervention assessment instrument with local nurses at a pediatric hospital in Ulaanbaatar, Mongolia. One hundred sixty-seven nurses attended the conference, with 155 nurses completing the pre- and postsurveys. The mean score on the presurvey was 12.7 out of 35 (26.4% correct), whereas the mean score on the postsurvey score was 16.7 out of 35 (47.8% correct). A paired t test showed a significant statistical difference between scores (p < .0001). Pediatric nurses in Mongolia demonstrate insufficient knowledge of pediatric pain management. The educational intervention was effective in improving pediatric pain knowledge and attitudes in Mongolian nurses. It is recommended to establish similar educational endeavors with nurses around the world to improve pain knowledge and attitudes. PMID- 25439121 TI - Application of Nonpharmacologic Methods to Relieve Pain During Labor: The Point of View of Primiparous Women. AB - The aim of this study was to assess the application of nonpharmacologic methods to relieve pain during birthing from the point of view of primiparous women. To achieve this goal, a cross-sectional study was developed with 188 primiparous women interviewed using a standardized form on the day they were discharged from the hospital. Results indicated that the most-used nonpharmacologic method was emotional support provided by the woman's companion (97.3%), followed by warm showers (91.5%); however, the highest degree of satisfaction derived from focused attention. In the assessment of the general degree of satisfaction with the methods studied, primiparous women experienced a high level of general satisfaction (88.3%). Significant associations between this result and changes in position (p = .0340, odds ratio [OR] 3.29, confidence interval [CI] 95% 1.13 9.52) and focused attention (p = .0326, OR 2.61, CI 95% 1.06-6.43) were observed. There was a significant association between the general score for satisfaction and the emotional support of an obstetrics nurse (p = .0096, OR 3.78, CI 95% 1.49 9.55), of the obstetrician (p = .0031, OR 3.74, CI 95% 1.5-9.33), and of the nurse's aide (p = .0303, OR 4.56, CI 95% 1.03-20.24). We concluded that in the obstetric center where the study was conducted, nearly all the nonpharmacologic methods available are being adopted by the members of the healthcare team, with the participation of a companion. However, those that generate the highest degree of satisfaction are not those most used. PMID- 25439124 TI - Knowledge of and Attitudes Regarding Postoperative Pain among the Pediatric Cardiac Nursing Staff: An Indian Experience. AB - Pain following cardiac intervention in children is a common, but complex phenomenon. Identifying and reporting pain is the responsibility of the nursing staff, who are the primary caregivers and spend the most time with the patients. Inadequately managed pain in children may lead to multiple short- and long-term adverse effects. The aim of this cross-sectional study was to assess the knowledge and attitudes regarding postoperative pain in children among the nursing staff at B.M. Patel Cardiac Center, Karamsad, Anand, Gujarat, India. The study included 42 of the 45 nurses employed in the cardiac center. The nurses participating in the study were responsible for the care of the pediatric patients. A modified Knowledge and Attitudes Survey Regarding Pain and a sociodemographic questionnaire were administered after obtaining written informed consent. The study was approved by the institutional Human Research Ethics Committee. Mean (SD) experience in years of the nursing staff was 2.32 (1.69) years (range 1 month to 5 years). Of the nurses, 67% were posted in the cardiac surgical intensive care unit (ICU). The mean (SD) score for true/false questions was 11.48 (2.95; range 7,19). The average correct response rate of the true/false questions was 45.9%. Knowledge about pain was only affected by the ward in which the nurse was posted. In first (asymptomatic) and second (symptomatic) case scenarios, 78.6% and 59.5% underestimated pain, respectively. Knowledge and attitudes regarding pain and its management is poor among nurses. Targeted training sessions and repeated reinforcement sessions are essential for holistic patient care. PMID- 25439123 TI - Impact of a Script-based Communication Intervention on Patient Satisfaction with Pain Management. AB - Pain is a common complaint among hospitalized patients no matter the diagnosis. Pain has a negative effect on many aspects of a patient's life, including quality of life, sleep, and activities of daily living as well as increased health care expenses. The aim of this study was to evaluate the effectiveness of an intervention (script-based communication, use of white boards, and hourly rounding) related to pain management on patient satisfaction with nurses' management of pain. A prospective, quasi-experimental pretest-posttest design was used. Data were collected from two units that provided care for patients with a variety of medical-surgical diagnoses in a hospital located in an academic health sciences center in the southern United States. When nurses used clear and consistent communication with patients in pain, a positive effect was seen in patient satisfaction with pain management over time. This intervention was simple and effective. It could be replicated in a variety of health care organizations. PMID- 25439125 TI - A Systematic Review of the Prevalence and Measurement of Chronic Pain in Asian Adults. AB - There are limited epidemiologic studies on chronic pain in Asian populations. The aim of this review was to gather all epidemiologic studies of chronic pain in Asian countries and systematically describe the measurement and prevalence of chronic pain in Asian adults. A systematic review was performed using PubMed, MEDLINE, EMBASE, Psych INFO, Cochrane Database for Systematic Review, and CINAHL. Additional studies were identified manually by searching bibliographies. We identified 19 relevant articles for this review. Most articles used the definition of chronic pain set by the International Association for the Study of Pain. The majority of the articles used simple single-question methods to measure chronic pain. The prevalence of chronic pain among Asian adults ranges from 7.1% (Malaysia) to 61% (Cambodia and Northern Iraq), whereas among the Asian geriatric population, the prevalence is even higher and ranges from 42% to 90.8%. This review showed that there is great variation in the reported prevalence of chronic pain in Asian adults and the prevalence of chronic pain is high among the Asian geriatric population. To measure the distribution of chronic pain in adults, a uniform measurement strategy should be adopted. PMID- 25439126 TI - Evaluation of pain in healthy newborns and in newborns with developmental problems (Down syndrome). AB - Newborns are often subjected to invasive and painful medical procedures. This happens even more frequently when they require hospitalization. The aim of this paper was to evaluate pain in healthy newborns and in newborns with Down syndrome (DS). We performed a prospective cohort study in the neonatal service of the San Cecilio University Hospital in Granada (Spain) from January 2008 to September 2013. The universe of our study comprised a study group of 20 newborns with DS and a control group of 20 newborns without DS. All of the infants were hospitalized, and thus had to undergo painful medical procedures. The variables studied were basal recovery time (as reflected in crying and the normalization of biological constants), number of punctures, oxygen saturation, heartbeat, blood pressure, response to skin-to-skin contact, and gestational age. The evaluation was performed during blood extraction, vein canalization, and heel puncture. The significant differences in the basal recovery time between the two groups of newborns indicated that those with DS were slower to express pain, and when they did, their response was not as clearly defined as that of babies without DS. The oxygen saturation in babies with DS after the puncture was found to be significantly lower than that of the control group (p < .001). The results of this study revealed that babies with DS were not as quick to perceive pain after a puncture. However, when pain was finally perceived, it persisted for a longer time. This situation should be taken into account in the design of pharmacologic and nonpharmacologic therapies. PMID- 25439127 TI - Overcoming barriers to effective pain management: the use of professionally directed small group discussions. AB - Inadequate assessment and management of pain among critical care patients can lead to ineffective care delivery and an increased length of stay. Nurses' lack of knowledge regarding appropriate assessment and treatment, as well as negative biases toward specific patient populations, can lead to poor pain control. Our aim was to evaluate the effectiveness of professionally directed small group discussions on critical care nurses' knowledge and biases related to pain management. A quasi-experiment was conducted at a 383-bed Magnet((r)) redesignated hospital in the southeastern United States. Critical care nurses (N = 32) participated in the study. A modified Brockopp and Warden Pain Knowledge Questionnaire was administered before and after the small group sessions. These sessions were 45 minutes in length, consisted of two to six nurses per group, and focused on effective pain management strategies. Results indicated that mean knowledge scores differed significantly and in a positive direction after intervention [preintervention mean = 18.28, standard deviation = 2.33; postintervention mean = 22.16, standard deviation = 1.70; t(31) = -8.87, p < .001]. Post-bias scores (amount of time and energy nurses would spend attending to patients' pain) were significantly higher for 6 of 15 patient populations. The strongest bias against treating patients' pain was toward unconscious and mechanically ventilated individuals. After the implementation of professionally directed small group discussions with critical care nurses, knowledge levels related to pain management increased and biases toward specific patient populations decreased. PMID- 25439128 TI - The seasonal variation of emission of greenhouse gases from a full-scale sewage treatment plant. AB - The seasonal variety of greenhouse gas (GHGs) emissions and the main emission source in a sewage treatment plant were investigated. The emission coefficient to treated wastewater was 291gCO2m(-3). The main source of GHGs was CO2 from the consumption of electricity, nitrous oxide from the sludge incineration process, and methane from the water treatment process. They accounted for 43.4%, 41.7% and 8.3% of the total amount of GHGs emissions, respectively. The amount of methane was plotted as a function of water temperature ranging between 13.3 and 27.3 degrees C. An aeration tank was the main source of methane emission from all the units. Almost all the methane was emitted from the aeration tank, which accounted for 86.4% of the total gaseous methane emission. However, 18.4% of the methane was produced in sewage lines, 15.4% in the primary sedimentation tank, and 60.0% in the aeration tank. PMID- 25439129 TI - Nitrogen doped carbon nanoparticles enhanced extracellular electron transfer for high-performance microbial fuel cells anode. AB - Nitrogen doped carbon nanoparticles (NDCN) were applied to modify the carbon cloth anodes of microbial fuel cells (MFCs) inoculated with Shewanella oneidensis MR-1, one of the most well-studied exoelectrogens. Experimental results demonstrated that the use of NDCN increased anodic absorption of flavins (i.e., the soluble electron mediator secreted by S. oneidensis MR-1), facilitating shuttle-mediated extracellular electron transfer. In addition, we also found that NDCN enabled enhanced contact-based direct electron transfer via outer-membrane c type cytochromes. Taken together, the performance of MFCs with the NDCN-modified anode was enormously enhanced, delivering a maximum power density 3.5 times' higher than that of the MFCs without the modification of carbon cloth anodes. PMID- 25439130 TI - Pathways and factors for food safety and food security at PFOS contaminated sites within a problem based learning approach. AB - Perfluorooctanesulfonic acid (PFOS) and related substances have been listed in Annex B of the Stockholm Convention. The implementation requires inventories of use, stockpiles, and environmental contamination including contaminated sites and measures for (risk) reduction and phase out. In most countries monitoring capacity is not available and therefore other approaches for assessment of contaminated sites are needed. Available informations about PFOS contamination in hot spot areas and its bio-accumulation in the food webs have been merged to build up a worst-case scenario We model PFOS transfer from 1 to 100ngL(-1) range in water to extensive and free-range food producing animals, also via the spread of contaminated sludges on agriculture soils. The modeling indicates that forages represented 78% of the exposure in ruminants, while soil accounted for >80% in outdoor poultry/eggs and pigs. From the carry-over rates derived from literature, in pork liver, egg, and feral fish computed concentration falls at 101, 28 and 2.7ngg(-1), respectively, under the 1ngL(-1) PFOS scenario. Assuming a major consumption of food produced from a contaminated area, advisories on egg and fish, supported by good agriculture/farming practices could abate 75% of the human food intake. Such advisories would allow people to become resilient in a PFOS contaminated area through an empowerment of the food choices, bringing the alimentary exposure toward the current Tolerable Daily Intake (TDI) of 150ngkg( 1)bodyweightd(-1) proposed by the European Food Safety Authority (EFSA). PMID- 25439131 TI - Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I. Challenges and research needs in ecotoxicology. AB - To elucidate the effects of chemicals on populations of different species in the environment, efficient testing and modeling approaches are needed that consider multiple stressors and allow reliable extrapolation of responses across species. An adverse outcome pathway (AOP) is a concept that provides a framework for organizing knowledge about the progression of toxicity events across scales of biological organization that lead to adverse outcomes relevant for risk assessment. In this paper, we focus on exploring how the AOP concept can be used to guide research aimed at improving both our understanding of chronic toxicity, including delayed toxicity as well as epigenetic and transgenerational effects of chemicals, and our ability to predict adverse outcomes. A better understanding of the influence of subtle toxicity on individual and population fitness would support a broader integration of sublethal endpoints into risk assessment frameworks. Detailed mechanistic knowledge would facilitate the development of alternative testing methods as well as help prioritize higher tier toxicity testing. We argue that targeted development of AOPs supports both of these aspects by promoting the elucidation of molecular mechanisms and their contribution to relevant toxicity outcomes across biological scales. We further discuss information requirements and challenges in application of AOPs for chemical- and site-specific risk assessment and for extrapolation across species. We provide recommendations for potential extension of the AOP framework to incorporate information on exposure, toxicokinetics and situation-specific ecological contexts, and discuss common interfaces that can be employed to couple AOPs with computational modeling approaches and with evolutionary life history theory. The extended AOP framework can serve as a venue for integration of knowledge derived from various sources, including empirical data as well as molecular, quantitative and evolutionary-based models describing species responses to toxicants. This will allow a more efficient application of AOP knowledge for quantitative chemical- and site-specific risk assessment as well as for extrapolation across species in the future. PMID- 25439132 TI - Local application of Aqua Titan improves symptoms of temporomandibular joint muscle disorder: a preliminary study. AB - Aqua Titan (AT), comprising microscopic titanium particles dispersed in water, has been reported to have beneficial effects on muscle tissue. This study investigated the effects of local application of AT on symptoms in patients with muscle disorders of the temporomandibular joint (TMJ) compared to patients with joint disorders of the TMJ. Sixteen patients with unilateral masseter muscle pain during motion (muscle disorder group) and six patients with unilateral TMJ pain during motion (joint disorder group) applied an AT-permeated patch over the painful area every night for 2 weeks. Symptoms were evaluated clinically at the initial visit and 1 and 2 weeks later. Clinical symptoms in the joint disorder group showed no tendency towards improvement after 2 weeks. In contrast, mouth opening range with/without pain, visual analogue scale (VAS) scores for pain during mouth opening and eating, and activities of daily living (ADL) scores in the muscle disorder group were improved significantly after 2 weeks. Multiple comparison tests in the muscle disorder group showed significant improvements in the VAS for eating and ADL score after 1 week. These results suggest that the AT patch has a potential supplementary role in the treatment of patients with muscle disorders of the TMJ. PMID- 25439133 TI - Evolution of spatially structured host-parasite interactions. AB - Spatial structure has dramatic effects on the demography and the evolution of species. A large variety of theoretical models have attempted to understand how local dispersal may shape the coevolution of interacting species such as host parasite interactions. The lack of a unifying framework is a serious impediment for anyone willing to understand current theory. Here, we review previous theoretical studies in the light of a single epidemiological model that allows us to explore the effects of both host and parasite migration rates on the evolution and coevolution of various life-history traits. We discuss the impact of local dispersal on parasite virulence, various host defence strategies and local adaptation. Our analysis shows that evolutionary and coevolutionary outcomes crucially depend on the details of the host-parasite life cycle and on which life history trait is involved in the interaction. We also discuss experimental studies that support the effects of spatial structure on the evolution of host parasite interactions. This review highlights major similarities between some theoretical results, but it also reveals an important gap between evolutionary and coevolutionary models. We discuss possible ways to bridge this gap within a more unified framework that would reconcile spatial epidemiology, evolution and coevolution. PMID- 25439134 TI - The influence of undergraduate education on professional practice transition: a comparative descriptive study. AB - BACKGROUND: Graduates from Problem/Context Based Learning (CBL) undergraduate nursing programs often express concern that they may not be as well prepared for transition to graduate nursing practice as their colleagues from more traditional lecture-based programs. AIMS: To determine if there is a difference in how graduates from CBL and non-CBL programs describe their transition to graduate practice within the first 2 years of graduation. METHODS: This was a comparative descriptive study that involved the use of a web-based survey. A convenience sample of 163 graduate nurses with 1 to 2 years of experience consented to be part of the study. They completed a researcher-designed questionnaire, which consisted of 26 items based on entry to practice competencies identified by the provincial professional nursing organization. RESULTS: There was no significant difference in the transition experience of graduates from CBL and traditional education programs within their first 2 years following graduation. These results confirm the findings of authors who compared transition among CBL and non-CBL graduates who had graduated anywhere from six months to several years following graduation. CONCLUSIONS: It is clear that CBL programs do prepare graduates to successfully transition into graduate nurse practice. Graduates from both CBL and non-CBL programs indicated a need for more formal agency sponsored orientation and transition assistance programs at the beginning of their initial employment. PMID- 25439135 TI - Dietary phytate, zinc and hidden zinc deficiency. AB - Epidemiological data suggest at least one in five humans are at risk of zinc deficiency. This is in large part because the phytate in cereals and legumes has not been removed during food preparation. Phytate, a potent indigestible ligand for zinc prevents it's absorption. Without knowledge of the frequency of consumption of foods rich in phytate, and foods rich in bioavailable zinc, the recognition of zinc deficiency early in the illness may be difficult. Plasma zinc is insensitive to early zinc deficiency. Serum ferritin concentration<=20MUg/L is a potential indirect biomarker. Early effects of zinc deficiency are chemical, functional and may be "hidden". The clinical problem is illustrated by 2 studies that involved US Mexican-American children, and US premenopausal women. The children were consuming home diets that included traditional foods high in phytate. The premenopausal women were not eating red meat on a regular basis, and their consumption of phytate was mainly from bran breakfast cereals. In both studies the presence of zinc deficiency was proven by functional responses to controlled zinc treatment. In the children lean-mass, reasoning, and immunity were significantly affected. In the women memory, reasoning, and eye-hand coordination were significantly affected. A screening self-administered food frequency questionnaire for office might help caregiver's identify patients at risk of zinc deficiency. PMID- 25439136 TI - The effect of adding zinc to vitamin A on IGF-1, bone age and linear growth in stunted children. AB - A randomized, double-blind, placebo controlled trial of a single dose of 200,000 I.U. of vitamin A with daily zinc supplementation was conducted with children in Mojo village, Surabaya City. Children aged 48 to 60 months were randomized to receive a single dose of 200,000 I.U. of vitamin A plus zinc sulfate (n=12) or a single dose of 200,000 I.U. of vitamin A (n=12) plus placebo six days a week for six months. Children were evaluated weekly for nutrient intake and for IGF-1, C reactive protein levels, gamma globulin levels, serum zinc, serum retinol, bone age and the index height for age at six months. At the end of the study, there was a significant increase in the serum retinol level (p<0.03), serum zinc level (p<0.03), IGF-1 hormone (p<0.04) and Z-score height for age (p<0.001), bone age (p<0.01), and gamma globulin level (p<0.04) and a significant decrease in the amount of infection/inflammation measured by CRP level (p<0.001). There was also a significant correlation between CRP level and height for age (p<0.01), and between gamma level and height for age (p<0.01). These results suggest that combined vitamin A and zinc supplementation reduces the risk of infection and increases linear growth among children, and thus may play a key role in controlling infection and stunted growth for children under five years old. PMID- 25439137 TI - Darwin's experimentalism. PMID- 25439138 TI - 'The art itself is nature': Darwin, domestic varieties and the scientific revolution. AB - Common to both the scientific and Darwinian revolutions were discussions challenging the distinction between art and nature. Was art a part of nature? Could art be used as a model for nature? This intellectual congruence, however, is more than just nominal. Charles Darwin and Asa Gray, for example, were well aware of the 17th century debates which preceded them through the works of such revered English writers as William Shakespeare and Thomas Browne. Furthermore, they used their understandings of these debates to inform and express their own thinking about the relation between artificial and natural selection. PMID- 25439139 TI - Parents' experiences of family functioning, health and social support provided by nurses--a pilot study in paediatric intensive care. AB - OBJECTIVES: The objective of this study was to describe parents' experiences of family functioning, health and social support provided by nursing personnel, while their child was in intensive care, and to determine how social support was associated with family functioning and family health. DESIGN: Cross-sectional study. SETTING: The data were collected by a self-administered questionnaire from 31 parents of critically ill children from 2010 to 2011. The data were analysed statistically. MAIN OUTCOME MEASURES: The parents considered their family functioning, health and social support provided by the nursing personnel to be good. RESULTS: The sub-area of family functioning that rated the lowest was strengths of family, whereas the lowest rated sub-area of family health was ill being. Child's previous hospital treatments were associated with family health. Parents, whose child had already been in hospital care, reported more well-being and less ill-being than parents with children hospitalised for the first time. Parents' education was associated with family functioning, family health and social support given by the nurses. Weak positive correlation was also found between social support given by nurses and family health experienced by parents. CONCLUSION: There is a need to discuss how nursing care can further support parental resources. PMID- 25439140 TI - Use of high frequency ultrasound to detect changes in skin integrity: An image evaluation validation procedure. AB - OBJECTIVES: High frequency ultrasound (HFUS) scanning may be used for prevention, detection and monitoring of pressure ulcers in patients at risk and is amenable for portable, bedside use by a variety of clinicians. Limited data are available about the criteria to determine an ideal image or measures of tissue changes representative of tissue injury. We developed and evaluated criteria for overall image quality and measures of tissue integrity. METHODS: In 40 mechanically ventilated adults in 3 ICUs, 241 HFUS sacral images were evaluated for agreement using criteria for overall image quality and tissue changes (dermal, hypodermal layer thickness and layer density). RESULTS: HFUS sacral images (N=241) were evaluated in three analyses and showed poor agreement in all three analyses using the specific criteria for global quality, however when criteria were collapsed agreement was good to substantial. Evaluator agreement for layer thickness and layer density was also good. CONCLUSIONS: A global rating is adequate for identifying good images. Agreement for measurements of layer thickness and density were also good and may be useful to identify early changes in tissue integrity leading to tissue injury. Additional data are needed concerning the association of changes in layer thickness and layer density to eventual tissue injury. PMID- 25439141 TI - Evaluation of postgraduate critical care nursing students' attitudes to, and engagement with, Team-Based Learning: a descriptive study. AB - OBJECTIVE: The aim of this study was to evaluate postgraduate critical care nursing students' attitudes to, and engagement with, Team-Based Learning (TBL). RESEARCH METHODOLOGY/DESIGN: A descriptive pre and post interventional design was used. Study data were collected by surveys and observation. SETTING: University postgraduate critical care nursing programme. MAIN OUTCOME MEASURES: Students' attitudes to learning within teams (Team Experience Questionnaire) and student engagement (observed and self-reports). RESULTS: Twenty-eight of 32 students agreed to participate (87% response rate). There were significant changes in students' attitudes to learning within teams including increases in overall satisfaction with team experience, team impact on quality of learning, team impact on clinical reasoning ability and professional development. There was no significant increase in satisfaction with peer evaluation. Observation and survey results showed higher student engagement in TBL classes compared with standard lecturing. CONCLUSION: Postgraduate critical care nursing students responded positively to the introduction of TBL and showed increased engagement with learning. In turn, these factors enhanced nurses' professional skills in teamwork, communication, problem solving and higher order critical thinking. Developing professional skills and advancing knowledge should be core to all critical care nursing education programmes to improve the quality and safety of patient care. PMID- 25439142 TI - End-of-life care in critical care: where nursing can make the difference? A call for papers. PMID- 25439143 TI - Histologic features of alopecias: part II: scarring alopecias. AB - The diagnosis of disorders of the hair and scalp can generally be made on clinical grounds, but clinical signs are not always diagnostic and in some cases more invasive techniques, such as a biopsy, may be necessary. This 2-part article is a detailed review of the histologic features of the main types of alopecia based on the traditional classification of these disorders into 2 major groups: scarring and nonscarring alopecias. Scarring alopecias are disorders in which the hair follicle is replaced by fibrous scar tissue, a process that leads to permanent hair loss. In nonscarring alopecias, the follicles are preserved and hair growth can resume when the cause of the problem is eliminated. In the second part of this review, we describe the histologic features of the main forms of scarring alopecia. Since a close clinical-pathological correlation is essential for making a correct histopathologic diagnosis of alopecia, we also include a brief description of the clinical features of the principal forms of this disorder. PMID- 25439144 TI - A tumor in images: anetodermic pilomatrixoma. PMID- 25439145 TI - Geometric alopecia after embolization of a ruptured aneurysm. PMID- 25439146 TI - Diagnostic and therapeutic techniques in lentigo maligna: an update. PMID- 25439147 TI - Multiple cutaneous and uterine leiomyomatosis or reed syndrome: a retrospective study of 13 cases. AB - INTRODUCTION: Multiple cutaneous and uterine leiomyomatosis (MCUL), or Reed syndrome, is characterized by the presence of cutaneous leiomyomas arising from the arrector pili muscles and, in women, by uterine leiomyomas. In some cases, MCUL is associated with renal cell carcinoma. This syndrome is an autosomal dominant disorder caused by a heterozygous germline mutation of the gene that encodes fumarate hydratase, a Krebs cycle enzyme that acts as a tumor suppressor. OBJECTIVE: To review the cases of MCUL diagnosed at 2 university hospitals over a 5-year period (2008-2013). MATERIAL AND METHODS: This was a retrospective study of 13 cases of MCUL that investigated demographic, clinical, and histologic characteristics, as well as possible associations with other diseases and treatments received. RESULTS: We identified 13 patients (10 women and 3 men) who had been diagnosed with MCUL. The mean age at diagnosis was 53 years. All the patients had multiple cutaneous leiomyomas; in 12 (92%) the distribution was clustered and 9 (69%) also had disseminated solitary lesions. In 1 patient (7.7%), the pattern of distribution was linear. Uterine fibroids requiring hysterectomy were present in 90% of the women. Nine patients were screened for renal lesions; no cases of renal cell carcinoma were detected but benign renal lesions were found in 4 patients. CONCLUSION: The clinical and histologic characteristics of the 13 cases of MCUL reviewed were similar to those reported in the literature. The most common cutaneous manifestation was a type 2 segmental pattern. It is important for dermatologists to identify cutaneous leiomyomas and be aware of the possible association with MCUL. PMID- 25439148 TI - Kinship care. PMID- 25439149 TI - The National Children's Study 2014: commentary on a recent National Research Council/Institute of Medicine Report. PMID- 25439150 TI - Educational scholarship in academic pediatrics: reflecting on our past and looking forward to our future. PMID- 25439151 TI - The research home: partnering with families. PMID- 25439152 TI - Yes, there are developmental emergencies. PMID- 25439153 TI - New program requirements present challenges and inspire innovations in med-peds programs. PMID- 25439155 TI - Mental health beliefs and barriers to accessing mental health services in youth aging out of foster care. AB - OBJECTIVE: To examine the perspectives of youth on factors that influence mental health service use after aging out of foster care. METHODS: Focus groups were conducted with youth with a history of mental health needs and previous service use who had aged out of foster care. Questions were informed by the Health Belief Model and addressed 4 domains: youth perceptions of the "threat of mental health problems," treatment benefits versus barriers to accessing mental health services, self-efficacy, and "cues to action." Data were analyzed using a modified grounded-theory approach. RESULTS: Youth (N = 28) reported ongoing mental health problems affecting their functioning; however, they articulated variable levels of reliance on formal mental health treatment versus their own ability to resolve these problems without treatment. Past mental health service experiences influenced whether youth viewed treatment options as beneficial. Youth identified limited self-efficacy and insufficient psychosocial supports "cueing action" during their transition out of foster care. Barriers to accessing mental health services included difficulties obtaining health insurance, finding a mental health provider, scheduling appointments, and transportation. CONCLUSIONS: Youths' perceptions of their mental health needs, self-efficacy, psychosocial supports during transition, and access barriers influence mental health service use after aging out of foster care. Results suggest that strategies are needed to 1) help youth and clinicians negotiate shared understanding of mental health treatment needs and options, 2) incorporate mental health into transition planning, and 3) address insurance and other systemic barriers to accessing mental health services after aging out of foster care. PMID- 25439154 TI - Health status and type of out-of-home placement: informal kinship care in an investigated sample. AB - OBJECTIVE: To assess the sociodemographic, health, and mental health of children in different types of out-of-home placements after investigation by child welfare agencies; to determine whether there are systematic differences in the children and their caregivers by type of out-of-home placements; and to provide the first description of these characteristics in a nationally representative sample for children in informal kinship care after child welfare involvement. METHODS: Using data from the National Survey of Child and Adolescent Well-being (NSCAW II), we compared children (0-17.5 years) in formal nonkinship foster care, formal kinship foster care, and informal kinship care shortly after a child welfare investigation. All analyses were weighted to reflect the sampling design. RESULTS: Children in informal kinship care are at comparable risk of having chronic health conditions and poorer health but are less likely to receive school based services. All children in kinship care (formal and informal) are less likely to be reported to have mental health problems and are more likely to live with older caregivers whose educational level is low and whose health is reportedly poorer. CONCLUSIONS: Although children in kinship care have health problems similar to children in nonkinship foster care, they are likely to live in families with fewer economic and educational resources. This mismatch between need and access has implications for the long-term well-being of the children who are living in informal kinship arrangements without system-level support of formal foster care. PMID- 25439157 TI - Risk score for predicting adolescent mental health problems among children using parental report only: the TRAILS study. AB - OBJECTIVE: To construct a risk score for adolescent mental health problems among children, using parental data only and without potentially stigmatizing mental health items. METHODS: We prospectively derived a prediction model for mental health problems at age 16 using data from parent report on 1676 children aged 11 from the general population. Mental health problems were considered present in the top 15% scores on the combined Achenbach ratings. The model was validated in a separate cohort (n = 336) children. A risk score was constructed for practical application. RESULTS: In the derivation cohort, 248 (14.8%) had mental health problems at follow-up. Predictors in the final model were gender, maternal educational level, family history of psychopathology, math achievement at school, frequently moving house, severe disease or death in the family, parental divorce, and child frustration level. The model was well calibrated, showed good discriminatory power (area under the curve 0.75; 95% confidence interval 0.72 0.78), and validated well. The risk score stratified children in classes of risk ranging from 6.6% to 52.2%. CONCLUSIONS: A risk score based on parent-reported data only and without mental health items accurately estimated the 5-year risk of adolescent mental health problems among children from the general population. Children with high risk may benefit from further monitoring or intervention. The risk score may be particularly suitable when parents want to circumvent an explicit discussion on possible mental health problems of their child. PMID- 25439158 TI - The greater good: how supervising physicians make entrustment decisions in the pediatric emergency department. AB - BACKGROUND: Graduate medical education is transitioning to the use of entrustable professional activities to contextualize educational competencies. Factors influencing entrustment decisions have been reported in adult medicine. Knowing how such decisions are made in pediatrics is critical to this transition. PURPOSE: To understand how supervisors determine the level of procedural supervision to provide a resident, taking into consideration simulation performance; to understand factors that affect supervisors' transparency to parents about residents' procedural experience. METHODS: We conducted 18 one-on one interviews with supervisors in a tertiary care pediatric emergency department, iteratively revising interview questions as patterns in the data were elucidated. Two researchers independently coded transcripts and then met with the investigative team to refine codes and create themes. RESULTS: Five factors influenced supervisors' entrustment decisions: 1) resident characteristics that include self-reported confidence, seniority, and prior interactions with the resident; 2) supervisor style; 3) nature of the procedure/characteristics of the patient; 4) environmental factors; and 5) parental preferences. Supervisors thought that task-based simulators provided practice opportunities but that simulated performance did not provide evidence for entrustment. Supervisors reported selectively omitting details about a resident's experience level to families to optimize experiential learning for residents they entrusted to perform a procedure. CONCLUSIONS: In pediatrics, supervisors consider various factors when making decisions regarding resident procedural readiness, including parental preferences. An educational system using entrustable professional activities may facilitate holistic assessment and foster expertise-informed decisions about residents' progression toward entrustment; such a system may also lessen supervisors' need to omit information to parents about residents' procedural readiness. PMID- 25439156 TI - Cumulative social risk exposure, infant birth weight, and cognitive delay in infancy. AB - OBJECTIVE: To determine the effect of exposure to multiple social risks on cognitive delay at 9 months of age; and whether obstetric factors mediate the relationship between cumulative social risk and cognitive delay. METHODS: Data were from 8950 mother-child dyads participating in the first wave of the Early Childhood Longitudinal Study, Birth Cohort. Cognitive delay was defined as falling in the lowest 10% of mental scale scores from the Bayley Short Form Research Edition. Five social risk factors were combined and categorized into a social risk index. Staged multivariable logistic regressions were used to investigate whether obstetric factors mediated the impact of social risk on the odds of cognitive delay. RESULTS: Infants with cognitive delay were more likely to live with social risks than infants without cognitive delay. The percentage of infants with cognitive delay increased with the number of social risks. In adjusted analyses, exposure to multiple social risk factors was associated with higher odds of cognitive delay at 9 months of age (adjusted odds ratio 2.11; 95% confidence interval 1.18-3.78 for 4 or more risks vs no risks). Accounting for birth weight attenuated this relationship (P < .001). CONCLUSIONS: This population-based study investigated the independent and cumulative effects of social risk factors on cognitive delay in infancy. Findings revealed a significant cumulative relationship between exposure to social risk and cognitive delay, which was partly mediated by birth weight. Programs that address the social context of US infants are needed to improve their developmental trajectories. PMID- 25439159 TI - Pediatric residency program handover: before and after the ACGME requirement. AB - OBJECTIVE: To determine what changes occurred in pediatric residency programs with regards to handover education and assessment before and after the Accreditation Council for Graduate Medical Education (ACGME) requirement mandating monitoring safe handover practices in July 2011. METHODS: We sent surveys at 2 time periods to all pediatric program directors in the United States, as identified from a list provided by the Association of Pediatric Program Directors. Respondents were asked about their program demographics, whether they had handover curricula, how trainees were taught to perform handovers, and perceived barriers to effective handover. RESULTS: Response rates were 58% in both survey years. After the ACGME requirement, only 1 of 3 of programs reported a handover curriculum with goals, objectives, and assessment tools. There was a statistically significant increase in the percentage of those responding that resident handover education primarily occurred by role modeling (66% vs 82%; P < .05). Other learners (visiting residents, medical students) also continued to learn handover skills by role modeling (55% vs 56%; P = NS). Lack of feedback and interruptions were recognized as barriers to successful handover by program directors in both survey years. CONCLUSIONS: There is a continued need for handover curricula with didactic and practical components as well as assessment pieces within pediatric residency programs. Barriers to effective handover such as lack of feedback and interruptions continue to be major problems. There is a lack of faculty ownership and interest in learner handover that may affect long-term successes. Because role modeling continues to be the main way in which trainees learn handover, specific attention should be given to teach role-modeling techniques. PMID- 25439160 TI - Oral health opinions and practices of pediatricians: updated results from a national survey. AB - BACKGROUND: Professional guidelines and state Medicaid policies encourage pediatricians to provide oral health screening, anticipatory guidance, and fluoride varnish application to young patients. Because oral health activities are becoming more common in medical offices, the objective of this study was to assess pediatricians' attitudes and practices related to oral health and examine changes since 2008. METHODS: As part of the 2012 Periodic Survey of Fellows, a random sample of 1638 members of the American Academy of Pediatrics was surveyed on their participation in oral health promotion activities. Univariate statistics were used to examine pediatricians' attitudes, practices, and barriers related to screening, risk assessment, counseling, and topical fluoride application among patients from birth to 3 years of age. Bivariate statistics were used to examine changes since 2008. RESULTS: Analyses were limited to 402 pediatricians who provided preventive care (51% of all respondents). Most respondents supported providing oral health activities in medical offices, but fewer reported engaging in these activities with most patients. Significantly more respondents agreed they should apply fluoride varnish (2008, 19%; 2012, 41%), but only 7% report doing so with >75% of patients. Although significantly more respondents reported receiving oral health training, limited time, lack of training and billing remain barriers to delivering these services. CONCLUSIONS: Pediatricians continue to have widespread support for, but less direct involvement with oral health activities in clinical practice. Existing methods of training should be examined to identify methods effective at increasing pediatricians' participation in oral health activities. PMID- 25439161 TI - Predictors of unmet dental need in children with autism spectrum disorder: results from a national sample. AB - OBJECTIVE: Unmet dental need in children with autism spectrum disorder (ASD) is common. We tested hypotheses that lacking a medical home or having characteristics of more severe ASD is positively associated with having unmet dental need among children with ASD. METHODS: Using data from the 2009 to 2010 National Survey of Children with Special Health Care Needs, we analyzed 2772 children 5 to 17 years old with ASD. We theorized that unmet dental need would be positively associated with not having a medical home and having characteristics of more severe ASD (eg, parent reported severe ASD, an intellectual disability, communication, or behavior difficulties). Prevalence of unmet dental need was estimated, and unadjusted and adjusted odds ratios, 95% confidence intervals, and P values were computed using survey methods for logistic regression. RESULTS: Nationally, 15.1% of children with ASD had unmet dental need. Among children with ASD, those without a medical home were more apt to have unmet dental need than those with a medical home (adjusted odds ratio, 4.46; 95% confidence interval, 2.59-7.69). Children with ASD with intellectual disability or greater communication or behavioral difficulties had greater odds of unmet dental need than those with ASD without these characteristics. Parent-reported ASD severity was not associated with unmet dental need. CONCLUSIONS: Children with ASD without a medical home and with characteristics suggestive of increased ASD-related difficulties were more apt to have unmet dental need. Pediatricians might use these findings to aid in identifying children with ASD who might not receive all needed dental care. PMID- 25439162 TI - Population-level obesity surveillance: monitoring childhood body mass index z score in a safety-net system. AB - OBJECTIVE: To determine the utility of repeated patient-level body mass index (BMI) measurements among higher-risk patients seen at safety-net clinics as a community-level monitoring tool for overweight and obesity population trends. METHODS: Data from a network of urban, federally qualified community health centers with computerized tracking of BMI at sequential outpatient visits were analyzed. We performed a longitudinal observational study over 8 years (2005 2012) with children stratified by weight status groups on the basis of BMI. Changes in BMI z-scores were used to estimate population trends among children 2 to 11 years old, with at least 2 visits (at least 1 year apart), for whom weight and height were measured. RESULTS: Among children (n = 33,542), the rate of overweight was 16% and rate of obesity was 18% at their last visit. Children were followed for an average of 3.24 +/- 1.76 years to measure trends and change in weight status from earlier to later childhood. Children who were obese at first visit had increased odds (adjusted odds ratio 27.8, 95% confidence interval 25.6 30.2) of being obese by last visit. Mean change in BMI z-score per person-year of observation was 0.10 +/- 0.38, with a differing rate of change based on weight status category at last visit (not overweight = 0.06 +/- 0.39; overweight = 0.17 +/- 0.34; obese = 0.19 +/- 0.36). Change in BMI z-score per person-year decreased for 40% of obese children; however, their weight status group remained unchanged. CONCLUSIONS: Childhood obesity prevalence was high, with substantial progression to overweight and obesity from first to last visit. Clinically derived BMI z score per person-year measures can effectively show population trends not observed using standard weight status categories. PMID- 25439164 TI - Review of in vivo studies of dimethyl sulfoxide cryopreserved platelets. AB - A literature review was conducted to assess the efficacy and safety of dimethyl sulfoxide (DMSO) cryopreserved platelets for potential military use. In vivo DMSO cryopreserved platelet studies published between 1972 and June of 2013 were reviewed. Assessed were the methods of cryopreservation, posttransfusion platelet responses, prevention or control of bleeding, and adverse events. Using the Department of Defense's preferred 6% DMSO cryopreservation method with centrifugation to remove the DMSO plasma before freezing at -65 degrees C and no postthaw wash, mean radiolabeled platelet recoveries in 32 normal subjects were 33% +/- 10% (52% +/- 12% of the same subject's fresh platelet recoveries), and survivals were 7.5 +/- 1.2 days (89% +/- 15% of fresh platelet survivals). Using a variety of methods to freeze autologous platelets from 178 normal subjects, mean radiolabeled platelet recoveries were consistently 39% +/- 9%, and survivals, 7.4 +/- 1.4 days. More than 3000 cryopreserved platelet transfusions were given to 1334 patients. There were 19 hematology/oncology patient studies, and, in 9, mean 1-hour corrected count increments were 11 100 +/- 3600 (range, 5700-15 800) after cryopreserved autologous platelet transfusions. In 5 studies, bleeding times improved after transfusion; in 3, there was either no improvement or a variable response. In 4 studies, there was immediate cessation of bleeding after transfusion; in 3 studies, patients being supported only with cryopreserved platelets had no bleeding. In 1 cardiopulmonary bypass study, cryopreserved platelets resulted in significantly less bleeding vs standard platelets. In 3 trauma studies, cryopreserved platelets were hemostatically effective. No significant adverse events were reported in any study. In summary, cryopreserved platelets have platelet recoveries that are about half of fresh platelets, but survivals are only minimally reduced. The platelets appear hemostatically effective and have no significant adverse events. PMID- 25439163 TI - Exploring innovative approaches and patient-centered outcomes from positive outliers in childhood obesity. AB - OBJECTIVE: New approaches for obesity prevention and management can be gleaned from positive outliers-that is, individuals who have succeeded in changing health behaviors and reducing their body mass index (BMI) in the context of adverse built and social environments. We explored perspectives and strategies of parents of positive outlier children living in high-risk neighborhoods. METHODS: We collected up to 5 years of height/weight data from the electronic health records of 22,443 Massachusetts children, ages 6 to 12 years, seen for well-child care. We identified children with any history of BMI in the 95th percentile or higher (n = 4007) and generated a BMI z-score slope for each child using a linear mixed effects model. We recruited parents for focus groups from the subsample of children with negative slopes who also lived in zip codes where >15% of children were obese. We analyzed focus group transcripts using an immersion/crystallization approach. RESULTS: We reached thematic saturation after 5 focus groups with 41 parents. Commonly cited outcomes that mattered most to parents and motivated change were child inactivity, above-average clothing sizes, exercise intolerance, and negative peer interactions; few reported BMI as a motivator. Convergent strategies among positive outlier families were family level changes, parent modeling, consistency, household rules/limits, and creativity in overcoming resistance. Parents voiced preferences for obesity interventions that include tailored education and support that extend outside clinical settings and are delivered by both health care professionals and successful peers. CONCLUSIONS: Successful strategies learned from positive outlier families can be generalized and tested to accelerate progress in reducing childhood obesity. PMID- 25439165 TI - 3-week whole body vibration does not improve gait function in mildly affected multiple sclerosis patients--a randomized controlled trial. AB - OBJECTIVE: To investigate the effects of whole body vibration (WBV) training on gait function in persons with mild multiple sclerosis (MS). DESIGN: A randomized controlled trial. SUBJECTS: 18 patients with MS were assigned randomly to WBV (intervention group) or to placebo WBV. METHODS: Both groups performed a 3-week training period under static conditions on a vibration platform. In the placebo group, the vibration platform was covered and therefore vibrations could not operate. Gait function (gait velocity, stride length, double support phase, single-step variability left and right) was assessed at baseline, after 3-weeks of WBV intervention or sham WBV, 4-weeks after baseline, and 5-weeks after baseline using a mobile plantar food pressure system and the "Timed Up and Go" test under four different gait conditions (comfortable overground gait, comfortable gait on treadmill, -20% comfortable gait velocity on treadmill and +20% comfortable gait velocity on treadmill). RESULTS: None of the outcome measures of gait function showed statistically significant alterations following 3-weeks of intervention/placebo WBV. CONCLUSION: The applied protocol of WBV does not show a meaningful improvement of gait function in mildly affected MS patients. PMID- 25439166 TI - Sarcoid neuropathy: correlation of nerve ultrasound, electrophysiological and clinical findings. AB - INTRODUCTION: We present the nerve ultrasound findings in sarcoid neuropathy and examine their correlation with electrophysiology and functional disability. MATERIALS AND METHODS: 40 healthy controls and 13 patients with sarcoid neuropathy underwent clinical, sonographic and electrophysiological evaluation, a mean of 2.1 years (SD +/- 0.7) after disease onset. RESULTS: Nerve ultrasound revealed significantly higher cross sectional area (CSA) values of the ulnar (elbow, p<0.001), fibular (fibular head, p<0.001), sural (between the lateral and the medial head of the gastrocnemius muscle, p<0.001) and tibial nerves (ankle and popliteal fossa, p<0.001), when compared to controls. The electroneurography documented significantly lower values of the 1) compound muscle action potentials (cMAPs) in the median, fibular and tibial nerves (p<0.001), and 2) sensory nerve action potential (sNAP) in the median, ulnar and sural nerves (p<0.001). A significant correlation between sonographic and electrophysiological findings in the group with sarcoid neuropathy was found only between cMAP and CSA of the ulnar nerve at the elbow (r=0.894, p<0.001). Neither nerve sonography nor electrophysiology correlated with functional disability. DISCUSSION: Sarcoid neuropathy seems to show predominantly CSA enlargement in peripheral nerves of the lower extremities, without any significant correlation to electrophysiological findings. The electroneurography documented signs of sensorimotor axonal loss in various peripheral nerves. Neither nerve sonography nor electrophysiology correlated with functional disability. PMID- 25439167 TI - The Virtual Peg Insertion Test as an assessment of upper limb coordination in ARSACS patients: a pilot study. AB - OBJECTIVE: This paper introduces a novel assessment tool to provide clinicians with quantitative and more objective measures of upper limb coordination in patients suffering from Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS). The Virtual Peg Insertion Test (VPIT) involves manipulating an instrumented handle in order to move nine pegs into nine holes displayed in a virtual environment. The main outcome measures were the number of zero-crossings of the hand acceleration vector, as a measure of movement coordination and the total time required to complete the insertion of the nine pegs, as a measure of overall upper limb performance. RESULTS: 8?9 patients with ARSACS were able to complete five repetitions with the VPIT. Patients were found to be significantly less coordinated and slower than age-matched healthy subjects (p<0.01). Performance of ARSACS patients was positively correlated with the Nine-Hole Peg Test (r=0.85, p<0.01) and with age (r=0.93, p<0.01), indicative of the degenerative nature of the disease. CONCLUSION(S): This study presents preliminary results on the use of a robotics and virtual reality assessment tool with ARSACS patients. Results highlight its potential to assess impaired coordination and monitor its progression over time. PMID- 25439168 TI - Production of (211)At by a vertical beam irradiation method. AB - We produced (211)At by irradiating the semi-sealed encapsulated Bi target with an external vertical beam. At 28.5MeV, the yield of (211)At was 22MBq/MUAh (600MUCi/MUAh). (211)At was recovered by dry distillation, and 80% of the produced (211)At was successfully obtained in dry Na(211)At form within 2h from the end of bombardment (EOB). The radionuclidic purity of (211)At was >99% at 5h from EOB. PMID- 25439169 TI - Treatment options for symptomatic carotid stenosis: timing and approach. AB - Stroke is a major cause of morbidity and mortality and up to 15-20% of ischemic strokes can be attributed to atherosclerotic internal carotid artery disease. The treatment of carotid artery disease has been the subject of a wealth of literature in the past twenty years since the publication of the landmark randomized controlled trials, the North American Symptomatic Carotid Endarterectomy Trial and the European Carotid Surgery Trial, in the early 1990s. Although these landmark trials have helped establish the current guidelines for treatment of patients with symptomatic carotid artery disease, there have since been major advancements in the medical treatment of cardiovascular disease and there still remains a great deal of controversy regarding the timing and technical approach to carotid revascularization. In particular, there has been a wealth of literature to determine whether carotid endarterectomy or carotid stenting should be used for revascularization and when this revascularization should occur following onset of symptoms. This update offers an overview of the standards for diagnosis and medical treatment of patients with symptomatic carotid artery disease, the indications for surgical revascularization and a review of the most pertinent literature as it pertains to the more controversial issues of technical approach and timing of surgical revascularization following onset of symptoms in patients with carotid artery disease. PMID- 25439170 TI - Why is the management of asymptomatic carotid disease so controversial? AB - BACKGROUND: Despite level I evidence supporting a role for carotid endarterectomy (CEA) in the management of patients with asymptomatic carotid disease, there is surprisingly little international consensus regarding the optimal way to manage these patients. METHODS: Review of current strategies for managing asymptomatic carotid disease MAIN FINDINGS: Those favouring a pro-interventional approach argue that: (i) until new randomised trials demonstrate that best medical therapy (BMT) is better than CEA or carotid artery stenting (CAS) in preventing stroke, guidelines of practice should remain unchanged; (ii) strokes secondary to carotid thromboembolism harboured a potentially treatable asymptomatic lesion prior to the event. Because 80% of strokes are not preceded by a TIA/minor stroke, CEA/CAS is the only way of preventing these strokes; (iii) screening for carotid disease could identify patients with significant asymptomatic stenoses who could undergo prophylactic CEA/CAS in order to prevent avoidable stroke; (iv) international guidelines already advise that only 'highly-selected' patients should undergo CEA/CAS; (v) the 30-day risks of death/stroke after CEA/CAS are diminishing and this will increase long-term stroke prevention and (vi) the alleged decline in annualized stroke rates in medically treated patients is based upon flawed data. CONCLUSIONS: The inescapable conclusion is that only a relatively small proportion of asymptomatic patients benefit from prophylactic CEA/CAS. The key question, therefore, remains; is society prepared to invest sufficient resources in identifying these 'high risk for stroke' patients so that they can benefit from aggressive BMT and CEA or CAS, leaving the majority of lower risk patients to be treated medically? PMID- 25439171 TI - Care and cure. An integrated approach to psychosomatic medicine: a report from the second annual conference the EAPM, Sibiu, 2014. PMID- 25439172 TI - Cardiovascular news 2013/2014. AB - During 2013 and the first months of 2014, numerous studies have been published in the cardiovascular field. New guidelines have appeared for managing arterial hypertension and reducing cardiovascular risk by lowering cholesterol levels. New data have emerged on the considerable lipid-lowering efficacy of monoclonal antibodies against PCSK-9, in contrast, however, to the clinical trials directed towards raising HDL-cholesterol with nicotinic acid, which have not shown a reduction in the rate of cardiovascular complications. In the field of hypertension, neither stent placement in patients with renovascular hypertension nor sympathetic denervation in patients with resistant hypertension has been shown to be effective in reducing blood pressure. In terms of antithrombotic treatment, the pharmacogenetic tests do not seem useful for maintaining patients anticoagulated with warfarin within the therapeutic range for longer periods. Moreover, there is increasing evidence that, for patients with coronary artery disease and atrial fibrillation, antiplatelet therapy adds no benefit to anticoagulation therapy and is associated with a greater risk of bleeding. Lastly, a Mediterranean diet could prevent the onset of diabetes, while bariatric surgery could be a reasonable option for improving the disease in patients with obesity. Many of these studies have immediate practice applications in daily clinical practice. PMID- 25439173 TI - Editors' farewell. PMID- 25439174 TI - Reorganization of medical specialization. Beyond the law of management of health professions. AB - More than 30 years after the creation of postgraduate medical training program in Spain supported by the MIR system, a thorough review of it becomes essential. This was the goal of the LOPS law enacted in 2003. The development of the LOPS is being slow and difficult to enforce, because master lines have to be achieved in order to develop the training of specialists in accordance with internationals standards and, simultaneously, with the reform that is taking place in the undergraduate education. The start up of the medical core will be the cornerstone of this project. The principles of the LOPS provide an opportunity for the training of competent physician in basic general medical practice followed by a progressive specialization supported on a solid foundation. And these principles have to prevail over corporate interests. PMID- 25439175 TI - Myocardial infarction in a patient with normal coronary angiography. PMID- 25439176 TI - Strategies for improving education on night-float rotations: a review. AB - INTRODUCTION: Night float rotations (NF) have been developed as a means of achieving duty hour compliance among residency programs. These were initially pioneered in the late 1980s as a response to fatigue among residents. The NF experience had its genesis in work hour reform and providing hospital service moreso than education. However, as NF has become ubiquitous, it is not clear that we have adequately revisited the educational component of this experience. We systematically reviewed the literature on educational aspects of a night float experience. METHODS: PubMed searches were conducted for the terms "night float" and "night, curriculum, residency." This yielded 320 articles. Concerning educational aspects of the NF reduced the total to 134 articles. Editorials and those concerning procedural volumes or handoffs were also excluded. Most articles used surveys as methodology, so formal statistical analysis was not possible. RESULTS: In total, 42 independent articles were found that directly related to the educational value of NF rotations, spanning all of the medical disciplines. Each study was searched for interventions or strategies that may affect the educational value of the NF experience. These may be grouped broadly into 3 discrete categories: (1) attention to the sleep-wake cycle, (2) addition of personal to augment the experience and (3) incorporation of formal educational elements to night rotations. A summary of these strategies is presented in Table 3. CONCLUSIONS: NF is a practical solution to the challenge of work hour restrictions in residency, and is likely to persist in the future. Some educational issues arise due to the altered physiology of a reversed sleep-wake cycle, which may be best resolved through structural limitations of the night rotations. Other deficiencies are based on lack of interactions, for which there are strategies to improving the NF educational experience. PMID- 25439177 TI - Assessment of competence in surgical skills using functional magnetic resonance imaging: a feasibility study. AB - BACKGROUND: Patient safety is fundamental to modern medical practice; safe surgery saves lives. Ensuring surgical competence is becoming more difficult at a time when surgeons are being trained in fewer hours. Accurate objective assessment of technical skills ability is lacking in standardization. Functional magnetic resonance imaging (fMRI) has a long history in neuroscience, psychiatry, and cognitive studies. Many studies have explored levels of perceived expertise in sports and musical ability. Little has been published on actual rather than perceived motor skills. This study sought to assess the feasibility of utilizing a novel assessment method by measuring blood oxygen level-dependent signal changes (BOLD) in specific brain regions via fMRI during a surgical skills task. METHODS: Images were acquired using fMRI in a pilot study of 9 subjects (3 experts, 3 intermediates, and 3 novices) when performing and imagining performing a basic surgical procedure: hand tying of surgical knots. Level of expertise was based on years of experience and clinical grade. The quality and quantity of knots were assessed objectively by 2 experts who were independent of the study and blinded to the ability of the candidate. The effect of subject head motion caused by the task itself was assessed. The efficacy of fMRI data analyses in removing artifacts caused by this noise source in the data was explored. RESULTS: Shifts of less than 1 voxel (3 * 3 * 3.55 mm(3)) were recorded in all participants and were successfully corrected in all cases in the fMRI preprocessing step. Decreased BOLD activity was observed in experts compared to novices when "knot tying" was compared with the control "finger tap." Increased BOLD activity was observed in experts compared with novices when "imagining a task" in the primary visual cortex, an area important in perceptual learning. Experts and intermediates performed consistently with 100% square knots. Novices had an average of 2 slip knots. Regarding knot quantity, the number of knots ranged from 14 to 26 in novices, 38 to 47 in intermediates, and 54 to 58 in experts. A Kruskal-Wallis rank sum test revealed that the difference between the 3 groups was statistically significant in the quantity of square knots tied (p = 0.147). Specific regions of interest identified concurred with findings of previous studies and included the left supramarginal, left rolandic operculum, and left postcentral regions. CONCLUSION: We found that fMRI is a feasible method of exploring actual and perceived motor skill abilities. Head motion during performance of a motor skill does not preclude the attainment of meaningful data. Larger numbers are needed to further investigate these early findings. PMID- 25439178 TI - Design and validation of a novel assessment tool for laparoscopic suturing of the vaginal cuff during hysterectomy. AB - OBJECTIVE: The aim of this study was to design and validate a new assessment tool for laparoscopic vaginal cuff suturing in a box trainer. DESIGN: A primary grading tool was constructed including a novel checklist component and a previously validated global rating scale. A four-step validation process was then undertaken. Face validity was determined by a survey of a panel of experts in the field of minimally invasive gynecologic surgery. Content validity was assessed via analysis of consistency and variability of the experts' ratings, and items were removed or rephrased according to the experts' comments. PARTICIPANTS: Overall, five novices and five expert laparoscopic surgeons were videotaped performing suture closure of a latex vaginal cuff model in a box trainer. The videotapes were reviewed by two raters. Discriminate validity, along with interrater and intrarater reliabilities, was assessed by analysis of the video ratings. SETTING: The Simulation, Training, Research, and Technology Utilization System center at Brigham and Women's Hospital, a tertiary medical center in Boston, MA. RESULTS: The final assessment tool is presented. CONCLUSION: We have validated an assessment tool for vaginal cuff suturing in a box trainer. PMID- 25439179 TI - A new virtual-reality training module for laparoscopic surgical skills and equipment handling: can multitasking be trained? A randomized controlled trial. AB - OBJECTIVE: During laparoscopic surgery distractions often occur and multitasking between surgery and other tasks, such as technical equipment handling, is a necessary competence. In psychological research, reduction of adverse effects of distraction is demonstrated when specifically multitasking is trained. The aim of this study was to examine whether multitasking and more specifically task switching can be trained in a virtual-reality (VR) laparoscopic skills simulator. DESIGN: After randomization, the control group trained separately with an insufflator simulation module and a laparoscopic skills exercise module on a VR simulator. In the intervention group, insufflator module and VR skills exercises were combined to develop a new integrated training in which multitasking was a required competence. At random moments, problems with the insufflator appeared and forced the trainee to multitask. During several repetitions of a different multitask VR skills exercise as posttest, performance parameters (laparoscopy time, insufflator time, and errors) were measured and compared between both the groups as well with a pretest exercise to establish the learning effect. A face validity questionnaire was filled afterward. SETTING: University Medical Centre Utrecht, The Netherlands. PARTICIPANTS: Medical and PhD students (n = 42) from University Medical Centre Utrecht, without previous experience in laparoscopic simulation, were randomly assigned to either intervention (n = 21) or control group (n = 21). RESULTS: All participants performed better in the posttest exercises without distraction of the insufflator compared with the exercises in which multitasking was necessary to solve the insufflator problems. After training, the intervention group was significantly quicker in solving the insufflator problems (mean = 1.60Log(s) vs 1.70Log(s), p = 0.02). No significant differences between both the groups were seen in laparoscopy time and errors. CONCLUSION: Multitasking has negative effects on the laparoscopic performance. This study suggests an additional learning effect of training multitasking in VR laparoscopy simulation, because the trainees are able to handle a secondary task (solving insufflator problems) quicker. These results may aid the development of laparoscopy VR training programs in approximating real-life laparoscopic surgery. PMID- 25439180 TI - Publish or perish, and pay--the new paradigm of open-access journals. AB - OBJECTIVES: The new open-access journal business model is changing the publication landscape and residents and junior faculty should be aware of these changes. DESIGN: A national survey of surgery program directors and residents was performed. RESULTS: Open-access journals have been growing over the past decade, and many traditional printed journals are also sponsoring open-access options (the hybrid model) for accepted articles. Authors need to be aware of the new publishing paradigm and potential costs involved in publishing their work. PMID- 25439181 TI - Training of hysteroscopic skills in residency program: the Dutch experience. AB - STUDY OBJECTIVE: To evaluate whether hysteroscopy training in the Dutch gynecological residency program is judged as sufficient in daily practice, by assessment of the opinion on hysteroscopy training and current performance of hysteroscopic procedures. In addition, the extent of progress in comparison with that of the residency program of a decade ago is reviewed. DESIGN: Survey (Canadian Task Force Classification III). PARTICIPANTS: Postgraduate years 5 and 6 residents in obstetrics and gynecology and gynecologists who finished residency within 2008 to 2013 in the Netherlands. INTERVENTION: Subjects received an online survey regarding performance and training of hysteroscopy, self-perceived competence, and hysteroscopic skills acquirement. RESULTS: Response rate was 65% of the residents and 73% of the gynecologists. Most residents felt adequately prepared for basic hysteroscopic procedures (86.7%), but significantly less share this opinion for advanced procedures (64.5%) (p < 0.01). In comparison with their peers in 2003, the current residents demonstrated a 10% higher appreciation of the training curriculum. However, their self-perceived competence did not increase, except for diagnostic hysteroscopy. Regarding daily practice, not only do more gynecologists perform advanced procedures nowadays but also their competence level received higher scores in comparison with gynecologists in 2003. Lack of simulation training was indicated to be the most important factor during residency that could be enhanced for optimal acquirement of hysteroscopic skills. CONCLUSION: Implementation of hysteroscopic procedures taught during residency training in the Netherlands has improved since 2003 and is judged as sufficient for basic procedures. The skills of surgical educators have progressed toward a level in which gynecologists feel competent to teach and supervise advanced hysteroscopic procedures. Even though the residency preparation for hysteroscopy is more highly appreciated than a decade ago, this study indicated that simulation training might serve as an additional method to improve hysteroscopic skills acquisition. Future research is needed to determine the value of simulation training in hysteroscopy. PMID- 25439182 TI - What factors are associated with frequent unhealthy snack-food consumption among Australian secondary-school students? AB - OBJECTIVE: To examine demographic and behavioural correlates of unhealthy snack food consumption among Australian secondary-school students and the association between their perceptions of availability, convenience and intake with consumption. DESIGN: Cross-sectional survey of students' eating, physical activity and sedentary behaviours using validated instruments administered via an online questionnaire. SETTING: Australian secondary schools across all states/territories. SUBJECTS: Secondary-school students aged 12-17 years participating in the 2009-10 National Secondary Students' Diet and Activity (NaSSDA) survey (n 12 188). RESULTS: Approximately one in five students (21 %) reported consuming unhealthy snack foods >=14 times/week ('frequent snackers'). After adjusting for all covariates, older students and those with a BMI of >=25 kg/m2 were less likely to be frequent snackers, while students who reported high fast-food and high sugar-sweetened beverage consumption and those who watched television for >2 h/d were more likely to snack frequently. Furthermore, after adjusting for all covariates and demographic factors, students who agreed that snack foods are usually available at home, convenient to buy and that they eat too many snack foods were more likely to be snacking frequently. Conversely, students who agreed that fruit is a convenient snack were less likely to be frequent snackers. CONCLUSIONS: Frequent unhealthy snack-food consumption appears to cluster with other poor health behaviours. Perceptions of availability and convenience are factors most readily amenable to change, and findings suggest interventions should focus on decreasing the availability of unhealthy snack foods in the home and promoting healthier options such as fruit as convenient snacks. PMID- 25439185 TI - Maxillofacial fibro-osseous lesions. AB - During the last decade much has changed in our understanding of fibro-osseous lesions (FOLs) of the jaws with regards to their imaging, their nomenclature and classification, and their potential impact on the overall health of the patient. The changes in nomenclature, classification, and the FOLs' potential association with important syndromes are discussed with the assistance of a flowchart. The lesions, fibrous dysplasia (FD), ossifying fibroma (OF), and osseous dysplasia (OD), though with similar histopathology, have very different clinical and radiological presentations, behaviour, and treatment outcomes. FD of the jaw, which though becoming inactive, does not involute and therefore requires life long review to monitor for occasional reactivation. OF is completely removed surgically as it has a propensity to recur. No treatment is generally required for an OD unless it is infected or displays expansion. Lesions outside the jaws associated with FOLs of the jaws are identified. Radiology remains central to the diagnosis of FOLs of the jaw, because the pathologist is still not able to distinguish between them. The advent of cone-beam computed tomography (CBCT) with its better radiation dose reduction, accessibility, and spatial resolution has transformed imaging of FOLs. Their presentations on CBCT and the clinical indications for its use are discussed. PMID- 25439186 TI - Clinical impact of FDG PET-CT on the management of patients with locally advanced cervical carcinoma. AB - AIM: To evaluate the impact of staging FDG PET-CT on the initial management of patients with locally advanced cervical carcinoma (LACC) and any prognostic variables predicting survival. MATERIALS AND METHODS: Retrospective analysis of consecutive patients undergoing FDG PET-CT for staging of LACC in a single tertiary referral centre, between April 2008 and August 2011. Comparison was made between MRI and PET-CT findings and any subsequent impact on treatment intent or radiotherapy planning was evaluated. RESULTS: Sixty-three patients underwent FDG PET-CT for initial staging of LACC. Major impact on management was found in 20 patients (32%), a minor impact in five (8%), and no impact in 38 (60%). In those patients where PET-CT had a major impact, 12 had more extensive local nodal involvement, five had occult metastatic disease, two had synchronous tumours, and one patient had equivocal lymph nodes on MRI characterized as negative. PET positive nodal status at diagnosis was found to be a statistically significant predictor of relapse-free survival (p < 0.05). CONCLUSION: Staging FDG PET-CT has a major impact on the initial management of approximately one-third of patients with LACC by altering treatment intent and/or radiotherapy planning. PET-defined nodal status is a poor prognostic indicator. PMID- 25439187 TI - Assessment of thromboprophylaxis in medical patients hospitalized in Andalusia. A multicenter study. AB - BACKGROUND AND OBJECTIVES: Hospitalized patients are a population at risk for venous thromboembolism (VTE). The PRETEMED-2007 clinical practice guidelines help identify high-risk medical patients who are suited to thromboprophylaxis. These guidelines therefore provide a standard for prophylaxis in such patients. We evaluated the risk of VTE and the adjustment of thromboprophylaxis to the standards of the PRETEMED-2007 guidelines in patients hospitalized in internal medicine departments. PATIENTS AND METHODS: An observational, cross-sectional multicenter study was performed in 2010 in 16 hospitals in Andalusia and included 20 consecutive patients per center. The study variables were age, sex, risk factors for VTE and hemorrhage, the risk-adjusted PRETEMED of VTE, adjustment of thromboembolic prophylaxis at admission and at discharge and hospital mortality. RESULTS: The study included 293 patients (57.8% men) with a mean age of 69 (+/ 15) years. The most common triggers for VTE were acute severe infection (27.3%) and neoplasia (16.4%). Some 43.4% of the patients presented a risk of hemorrhage. The risk of VTE at admission and discharge was high in 47.8% and 31% and moderate in 8.2% and 10.6%, respectively. A total of 91.7% and 17.3% of the patients underwent prophylaxis with low-molecular-weight heparin on admission and at discharge, respectively. The prescription was appropriate for 59.9% of the patients at admission (overutilization 38.4%, underutilization 1.7%) and for 74.7% at discharge (overutilization 5.4%, underutilization 19.9%). The adjustment was greater in patients older than 60 years and with greater hemorrhagic risk. CONCLUSIONS: For 60% of the patients admitted to the departments of internal medicine in Andalusia, the thromboprophylaxis was appropriate. The inadequacy of thromboprophylaxis (40%) is mostly due to overutilization. These results suggest significant space for improvement. PMID- 25439188 TI - Behcet disease and refractory pyoderma gangrenosum with response to infliximab. PMID- 25439189 TI - Biliary ileus. PMID- 25439191 TI - Determining attainment of nursing standards: the use of behavioural cues to enhance clarity and transparency in student clinical assessment. PMID- 25439190 TI - Parthenolide inhibits pro-inflammatory cytokine production and exhibits protective effects on progression of collagen-induced arthritis in a rat model. AB - OBJECTIVES: Progressive destruction of synovial joint cartilage and bone occurs in pathological conditions such as rheumatoid arthritis (RA) because of the overproduction of pro-inflammatory cytokines and activation of nuclear factor kappa B (NF-kappaB). Through the screening of NF-kappaB inhibitors by a luciferase reporter gene assay, we identified parthenolide (PAR) as the most potent NF-kappaB inhibitor, among several PAR analogue compounds. This study was undertaken to determine whether PAR inhibits pro-inflammatory cytokine production, cartilage degradation, and inflammatory arthritis. METHOD: The mRNA levels of pro-inflammatory cytokines were examined by real-time polymerase chain reaction (PCR). Proteoglycan content and release were determined by measuring glycosaminoglycan (GAG) levels using the dimethylmethylene blue (DMMB) dye binding assay. The potential role of PAR in treatment of arthritis was studied using a collagen-induced arthritis (CIA) model. RESULTS: We established that PAR, as a prototype compound, suppressed lipopolysaccharide (LPS)- and tumour necrosis factor (TNF)-alpha-induced increases in matrix metalloproteinase (MMP)-1, MMP-3, inducible nitric oxide synthase (iNOS), and interleukin (IL)-1beta mRNA in chondrocytes. In addition, PAR prevented proteoglycan degradation triggered by pro-inflammatory cytokines. PAR treatment at the onset of CIA symptoms significantly reduced synovitis, inflammation, and pannus formation scores. Reduced synovial inflammation after PAR treatment was also reflected in significantly less bone erosion and cartilage damage. CONCLUSIONS: These data indicate a protective effect of PAR on the catabolic insults of pro-inflammatory cytokines on chondrocyte metabolism and GAG release in vitro and in CIA. PAR had anti-inflammatory and structure-modifying effects on experimental arthritis, suggesting that PAR may be useful as a potential alternative or adjunct therapy for inflammatory arthritis. PMID- 25439192 TI - Antiretroviral therapy adherence in a sample of men with low socioeconomic status: The role of task-specific treatment self-efficacy. AB - Disparities continue to persist in HIV care and treatment outcomes among racial/ethnic minorities, men who have sex with men (MSM), and individuals with low socioeconomic status. Much research has identified treatment self-efficacy as a key factor in antiretroviral therapy adherence and subsequent treatment outcomes. Few studies, however, have elaborated on these links and their potential in reducing HIV treatment disparities by examining the role of task specific types of treatment self-efficacy. In this study, we examined the effect of four types of task-specific treatment self-efficacy on antiretroviral adherence among patients in a predominantly racial/ethnic minority sample of HIV seropositive MSM with low socioeconomic status. We grouped participants by duration of treatment to determine whether certain types of self-efficacy were more salient based on treatment experience. We found that participants with optimal adherence tended to have higher levels of task-specific self-efficacy related to medication management and mood management than participants with suboptimal adherence. After a Bonferroni correction for multiple comparisons, only task-specific self-efficacy for medication management showed significant effects on adherence. Findings suggest that using focused, task-specific measures of treatment self-efficacy could strengthen our ability to aid patients at risk for adherence difficulties and tailor interventions to more effectively meet their needs. PMID- 25439193 TI - Adverse responses to products or treatments. PMID- 25439194 TI - Self-ligation and faster treatment time--a myth? PMID- 25439195 TI - Authors' response. PMID- 25439196 TI - Forces and moments generated by removable thermoplastic aligners. PMID- 25439197 TI - Authors' response. PMID- 25439198 TI - Analysis of data in removable thermoplastic aligner study. PMID- 25439199 TI - Authors' response. PMID- 25439200 TI - It is all about definitions. PMID- 25439201 TI - Waiting for the litmus test? PMID- 25439202 TI - Ethics in orthodontics. PMID- 25439203 TI - Above and beyond. PMID- 25439205 TI - Effects of pilot holes on longitudinal miniscrew stability and bony adaptation. AB - INTRODUCTION: The purposes of this study were to longitudinally evaluate the effects of pilot holes on miniscrew implant (MSI) stability and to determine whether the effects can be attributed to the quality or the quantity of bone surrounding the MSI. METHODS: Using a randomized split-mouth design in 6 skeletally mature female foxhound-mix dogs, 17 MSIs (1.6 mm outer diameter) placed with pilot holes (1.1 mm) were compared with 17 identical MSIs placed without pilot holes. Implant stability quotient measurements of MSI stability were taken weekly for 7 weeks. Using microcomputed tomography with an isotropic resolution of 6 MUm, bone volume fractions were measured for 3 layers of bone (6 24, 24-42, and 42-60 MUm) surrounding the MSIs. RESULTS: At placement, the MSIs with pilot holes showed significantly (P <0.05) higher implant stability quotient values than did the MSIs placed without pilot holes (48.3 vs 47.5). Over time, the implant stability quotient values decreased significantly more for the MSIs placed with pilot holes than for those placed without pilot holes. After 7 weeks, the most coronal aspect of the 6- to 24-MUm layer of cortical bone and the most coronal aspects of all 3 layers of trabecular bone showed significantly larger bone volume fractions for the MSIs placed without pilot holes than for those placed with pilot holes. CONCLUSIONS: MSIs placed with pilot holes show greater primary stability, but greater decreases in stability over time, due primarily to having less trabecular bone surrounding them. PMID- 25439206 TI - Effectiveness of Er:YAG laser-aided fiberotomy and low-level laser therapy in alleviating relapse of rotated incisors. AB - INTRODUCTION: In this study, we compared the effectiveness of laser-aided circumferential supracrestal fiberotomy (CSF) and low-level laser therapy (LLLT) with conventional CSF in reducing relapse of corrected rotations. METHODS: The study included 24 patients who were at the finishing stage of orthodontic treatment and had at least 1 maxillary incisor with 30 degrees to 70 degrees of rotation before starting therapy. The subjects were divided into 4 groups by treatment: conventional CSF, Er:YAG laser-aided CSF, LLLT, and control. After alginate impressions were taken, the archwire was sectioned from the experimental incisors, and they were allowed to relapse. The second impression was taken 1 month later, and the degree and percentage of relapse were calculated in photographs taken from the dental models. Gingival recession, pocket depth, and pain were also measured in the CSF groups. RESULTS: The mean percentages of relapse were 9.7% in the conventional CSF, 12.7% in the Er:YAG laser-aided CSF, 11.7% in the LLLT, and 27.8% in the control groups. Relapse was significantly greater in the control than the experimental groups (P <0.05), which were not statistically different from each other. The changes in sulcus depth and gingival recession were small and not significantly different among the CSF groups (P >0.05), but pain intensity was greater in subjects who underwent conventional CSF (P = 0.003). CONCLUSIONS: Er:YAG laser-aided CSF proved to be an effective alternative to conventional CSF in reducing rotational relapse. LLLT with excessively high energy density was also as effective as the CSF procedures in alleviating relapse, at least in the short term. PMID- 25439207 TI - Facial soft-tissue thickness in patients affected by bilateral cleft lip and palate: a retrospective cone-beam computed tomography study. AB - INTRODUCTION: The purposes of this study were to evaluate the facial soft-tissue thicknesses and craniofacial morphologies of patients affected by bilateral cleft lip and palate (BCLP) and to compare the findings with a well-matched control group without any clefts using cone-beam computed tomography. METHODS: The study sample consisted of 40 retrospectively and randomly selected patients divided into 2 groups: a BCLP group (20 patients; mean age, 13.78 +/- 3.20 years) and an age- and sex-matched control group without clefts (20 patients; mean age, 13.94 +/- 2.52 years). Craniofacial and facial soft-tissue thickness measurements were made with cone-beam computed tomography. The Student t test and multiple linear regression analyses were performed for the statistical evaluations. RESULTS: The BCLP group had an increased SN-MP angle (P = 0.003), a decreased Co-A (P = 0.000), and retruded maxillary (P = 0.000) and mandibular (P = 0.026) incisors. In addition, patients affected by BCLP had statistically significantly decreased thickness measurements for the variables subnasale (P = 0.005) and labrale superior (P = 0.026) compared with the controls. The most predictive variables were found at U1-SN (r = 0.417, P = 0.004), IMPA (r = 0.368, P = 0.010), and ANB (r = -0.297, P = 0.031) for subnasale and U1-SN (r = 0.284, P = 0.038) for labrale superior. CONCLUSIONS: The BCLP group showed greater vertical growth, greater retrusion of the maxilla and the maxillary and mandibular incisors, and decreased subnasale and labrale superior thicknesses compared with the well matched controls without clefts. These differences should be taken into account when planning orthodontic and orthognathic surgery treatment for those patients. PMID- 25439209 TI - Overview of registered studies in orthodontics: Evaluation of the ClinicalTrials.gov registry. AB - INTRODUCTION: The Food and Drug Administration Modernization Act of 1997 made it mandatory for all phase II through IV trials regulated by this Act to be registered. After this, the National Institutes of Health created ClinicalTrials.gov, which is a registry of publicly and privately supported clinical studies of human participants. The objective of this study was to examine the characteristics of registered studies in orthodontics. METHODS: The ClinicalTrials.gov Web site was used to query all registered orthodontic studies. The search term used was "orthodontics." No limitations were placed for the time period. All registered studies regardless of their recruitment status, study results, and study type were selected for analysis. RESULTS: A total of 64 orthodontic studies were registered as of January 1, 2014. Of these, 52 were interventional, and 12 were observational. Close to 60% of the interventional studies and 66.7% of the observational studies had sample sizes of 50 or fewer subjects. About 21.2% of the interventional studies and 16.7% of the observational studies had sample sizes greater than 100. Only 1 study was funded by the National Institutes of Health, and the rest were funded by "other" or "industry" sources. Close to 87.7% of the interventional studies were randomized. Interventional model assignments included factorial assignment (3.9%), parallel assignments (74.5%), crossover assignment (7.8%), and single-group assignment (13.7%). Most studies were treatment oriented (80.4%). The types of masking used by the interventional studies included open label (28.9%), single blind (44.2%), and double blind (26.9%). Outcome assessors were blinded in only 6 studies. CONCLUSIONS: Orthodontic studies registered in ClinicalTrials.gov are dominated by small single-center studies. There are wide variations with regard to treatment allocation approaches and randomization methods in the studies. These results also indicate the need for multicenter clinical studies in orthodontics. PMID- 25439208 TI - Perceptions of dental professionals and laypeople to altered maxillary incisor crowding. AB - INTRODUCTION: The aim of this study was to determine how sensitive dental specialists and laypeople are to maxillary incisor crowding when viewed from the front. METHODS: Computer technology was used to create a series of photographs of the incisors of a smiling woman viewed from the front. The photographs showed varying degrees of maxillary incisor crowding classified according to Little's irregularity index (LII). The incisors illustrated in the photos were ranked on a scale from perfect alignment to severely crowded. The rating was done by 4 groups of people: orthodontists, general dentists, laypeople with experience of orthodontic treatment, and laypeople with no history of orthodontic treatment. RESULTS: The orthodontists and the general dentists noted misalignment of 1 central incisor when the LII reached 1.5 mm, whereas the laypeople with or without experience of orthodontic treatment were sensitive to 2.0 mm of crowding. When the LII reached 2.0 mm for 1 lateral incisor, it triggered the orthodontists to consider providing orthodontic treatment, whereas this degree of irregularity was ignored by the general dentists and laypeople. When both central incisors were misaligned, the orthodontists were sensitive to the fact at 2.0 mm of LII, whereas the general dentists and the laypeople with experience of orthodontic treatment became sensitive at 3.0 mm of LII, and the laypeople with no history of orthodontic treatment were sensitive at 4.0 mm of LII. When both lateral incisors were misaligned, the orthodontists noted the crowding at an LII of 3.0 mm, the general dentists became sensitive at an LII of 4.0 mm, whereas both the laypeople with experience of orthodontic treatment and the laypeople with no history of orthodontic treatment ignored it. When the crowding of all maxillary incisors reached an LII of 4 mm, both the orthodontists and the general dentists were alerted to the fact, but both the laypeople with experience of orthodontic treatment and the laypeople with no history of orthodontic treatment were sensitive only to a total incisor crowding equal to an LII of 6.0 mm. CONCLUSIONS: Orthodontists are more critical than other groups when evaluating the misalignment of the maxillary incisors. It appears that the central incisors play a more important role than do the lateral incisors when dental crowding impacts smile esthetics. For all observer groups, it also appears that people are more sensitive to the misalignment of a single tooth than they are to the same level of crowding distributed over multiple teeth. PMID- 25439210 TI - Outcomes and stability in patients with anterior open bite and long anterior face height treated with temporary anchorage devices and a maxillary intrusion splint. AB - INTRODUCTION: Temporary skeletal anchorage devices now offer the possibility of closing anterior open bites and decreasing anterior face height by intruding maxillary posterior teeth, but data for treatment outcomes are lacking. This article presents outcomes and posttreatment changes for consecutive patients treated with a standardized technique. METHODS: The sample included 33 consecutive patients who had intrusion of maxillary posterior teeth with a maxillary occlusal splint and nickel-titanium coil springs to temporary anchorage devices in the zygomatic buttress area, buccal and apical to the maxillary molars. Of this group, 30 had adequate cephalograms available for the period of treatment, 27 had cephalograms including 1-year posttreatment, and 25 had cephalograms from 2 years or longer. RESULTS: During splint therapy, the mean molar intrusion was 2.3 mm. The mean decrease in anterior face height was 1.6 mm, less than expected because of a 0.6-mm mean eruption of the mandibular molars. During the postintrusion orthodontics, the mean change in maxillary molar position was a 0.2-mm extrusion, and there was a mean 0.5-mm increase in face height. Positive overbite was maintained in all patients, with a slight elongation (<2 mm) of the incisors contributing to this. During the 1 year of posttreatment retention, the mean changes were a further eruption of 0.5 mm of the maxillary molars, whereas the mandibular molars intruded by 0.6 mm, and there was a small decrease in anterior face height. Changes beyond 1 year posttreatment were small and attributable to growth rather than relapse in tooth positions. CONCLUSIONS: Intrusion of the maxillary posterior teeth can give satisfactory correction of moderately severe anterior open bites, but 0.5 to 1.5 mm of reeruption of these teeth is likely to occur. Controlling the vertical position of the mandibular molars so that they do not erupt as the maxillary teeth are intruded is important in obtaining a decrease in face height. PMID- 25439212 TI - Effect of occlusal vertical dimension changes on postsurgical skeletal changes in a surgery-first approach for skeletal Class III deformities. AB - INTRODUCTION: The purposes of this study were to investigate the relationship between occlusal vertical dimension (VD) changes and postsurgical skeletal changes in the surgery-first approach and to derive regression models for the final mandibular setback at B-point. METHODS: This retrospective study included 40 patients (16 men, 24 women; ages, 22.6 +/- 4.0 years) who had undergone a bimaxillary surgery-first approach. Using cephalograms generated from cone-beam computed tomography representing the presurgical, postsurgical, and posttreatment stages, skeletal landmarks in the maxilla and mandible were investigated to derive multivariate linear regression-based prediction models. Additionally, a patient classification based on the VD was established and verified to generate regression models for the classified groups. RESULTS: For the nonincreased VD group, the surgical setback of B-point was its predictor for the final mandibular setback (R(2) at 92%). Meanwhile, the final mandibular setback of the increased VD group was predicted according to the surgical upward movement of pogonion, the postsurgical horizontal position of A-point, and the postsurgical vertical position of the coronoid process (R(2) at 94%). CONCLUSIONS: The results of this study support the clinical observation that the more increased the vertical occlusal dimension after surgery, the less predictable the position of B-point at the posttreatment stage. PMID- 25439211 TI - ACTN3 R577X genotypes associate with Class II and deepbite malocclusions. AB - INTRODUCTION: alpha-Actinins are myofibril anchor proteins that influence the contractile properties of skeletal muscles. ACTN2 is expressed in slow type I and fast type II fibers, whereas ACTN3 is expressed only in fast fibers. ACTN3 homozygosity for the 577X stop codon (ie, changing 577RR to 577XX, the R577X polymorphism) results in the absence of alpha-actinin-3 in about 18% of Europeans, diminishes fast contractile ability, enhances endurance performance, and reduces bone mass or bone mineral density. We have examined ACTN3 expression and genetic variation in the masseter muscle of orthognathic surgery patients to determine the genotype associations with malocclusion. METHODS: Clinical information, masseter muscle biopsies, and saliva samples were obtained from 60 subjects. Genotyping for ACTN3 single nucleotide polymorphisms, real-time polymerase chain reaction quantitation of muscle gene message, and muscle morphometric fiber type properties were compared to determine statistical differences between genotype and phenotype. RESULTS: Muscle mRNA expression level was significantly different for ACTN3 single nucleotide polymorphism genotypes (P <0.01). The frequency of ACTN3 genotypes was significantly different for the sagittal and vertical classifications of malocclusion, with the clearest association being elevated 577XX genotype in skeletal Class II malocclusion (P = 0.003). This genotype also resulted in significantly smaller diameters of fast type II fibers in masseter muscles (P = 0.002). CONCLUSION: ACTN3 577XX is overrepresented in subjects with skeletal Class II malocclusion, suggesting a biologic influence during bone growth. ACTN3 577XX is underrepresented in subjects with deepbite malocclusion, suggesting that muscle differences contribute to variations in vertical facial dimensions. PMID- 25439213 TI - Accelerated orthodontic tooth movement: molecular mechanisms. AB - Accelerating orthodontic tooth movement can significantly reduce treatment duration and risks of side effects. The rate of orthodontic tooth movement is chiefly determined by the remodeling of tissues surrounding the roots; this in turn is under the control of molecular mechanisms regulating cellular behaviors in the alveolar bone and periodontal ligament. This review summarizes the current knowledge on the molecular mechanisms underlying accelerated orthodontic tooth movement, and the clinical and experimental methods that accelerate orthodontic tooth movement with possible molecular mechanisms. The review also shows directions for future studies to develop more clinically applicable methods to accelerate orthodontic tooth movement. PMID- 25439214 TI - Randomized and nonrandomized studies: complementary or competing? AB - Both randomized and nonrandomized studies are integral to orthodontic research and practice because they permit evaluation of relationships between exposures and outcomes, allowing the efficacy, effectiveness, and safety of interventions to be assessed. These designs allow clinical decisions to be informed. Nonrandomized designs include nonrandomized clinical trials, cohort studies, case control studies, cross-sectional studies, case series, and ecological studies. There is debate surrounding the optimal research design; however, both randomized and nonrandomized designs are important to build a broad, informative evidence base. The designs are therefore complementary, with unique advantages and limitations. The applicability of either approach hinges on the clinical question posed, the feasibility of studying it, and ethical considerations. PMID- 25439215 TI - Can cone-beam computed tomography superimposition help orthodontists better understand relapse in surgical patients? AB - This case report describes the interdisciplinary treatment of a 19-year-old Brazilian man with a Class I malocclusion, a hyperdivergent profile, an anterior open bite, and signs of temporomandibular joint internal derangement. The treatment plan included evaluation with a temporomandibular joint specialist and a rheumatologist, orthodontic appliances, and maxillomandibular surgical advancement with counterclockwise rotation. Cone-beam computed tomography images were taken before and after surgery at different times and superimposed at the cranial base to assess the changes after orthognathic surgery and to monitor quantitatively the internal derangement of the temporomandibular joints and surgical relapse. Our protocol can improve the orthodontist's understanding of surgical instability, demonstrate the clinical value of cone-beam computed tomography analysis beyond the multiplanar reconstruction, and guide patient management for the best outcome possible. PMID- 25439216 TI - Severe anterior open bite with mandibular retrusion treated with multiloop edgewise archwires and microimplant anchorage complemented by genioplasty. AB - In this case report, we introduce the combined use of multiloop edgewise archwire and microimplant anchorage to treat an 18-year-old Chinese woman who had a severe anterior open bite and a retrusive chin. Her diagnosis included a skeletal Class II base with severe anterior open bite, backward rotated mandible, and mesially tipped buccal dentition. The treatment plan emphasized vertical control of the posterior dentoalveolar dimension. Microimplant anchors were placed in the mandibular buccal segment to provide rigid anchorage and deliver intruding forces to the posterior teeth; a multiloop edgewise archwire was applied to generate uprighting forces to the maxillary and mandibular posterior teeth. Intrusion and uprighting of the posterior teeth contributed to the counterclockwise rotation of the mandibular plane, which consequently contributed to the facial profile improvement. Orthognathic genioplasty was implemented to further improve the chin prominence. After 1.5 years of retention, ideal intercuspation was evident, and the improved facial contour was stable. PMID- 25439217 TI - Treacher Collins syndrome: a case study. AB - Treacher Collins syndrome is a disorder of craniofacial development with high penetrance and variable expressivity. Its incidence is approximately 1 in 50,000 live births. In this article, we describe the orthodontic treatment of an 11-year old boy with Treacher Collins syndrome. PMID- 25439218 TI - Clinical use of a direct chairside oral scanner: an assessment of accuracy, time, and patient acceptance. AB - INTRODUCTION: Chairside oral scanners allow direct digital acquisition of the intraoral situation and can eliminate the need for conventional impressions. In this study, we aimed to assess accuracy, scan time, and patient acceptance of a chairside oral scanner when used for full-arch scans; these are critical factors for acceptance of this technology in the orthodontic setting. METHODS: Fifteen patients had digital models made from both intraoral scans (Lava COS; 3M ESPE, St Paul, Minn) and alginate impressions. Each procedure was timed, and patient preference was assessed with a survey. In addition, digital models were made from 5 plaster model pairs using the intraoral scanner and an orthodontic model scanner. Model pairs were digitally superimposed, and differences between models were quantified. Accuracy was assessed using the Bland-Altman method. Time differences were tested for statistical significance with the Student t test. RESULTS: Digital models made using the chairside oral scanner and either impressions or the orthodontic model scanner did not differ significantly. The chair time required to take impressions was significantly shorter than the time required for the intraoral scans. When processing time was included, the time requirement did not differ significantly between methods. Although 73.3% of the patients preferred impressions because they were "easier" or "faster," 26.7% preferred the scan because it was "more comfortable." CONCLUSIONS: Despite the high accuracy of chairside oral scanners, alginate impressions are still the preferred model acquisition method with respect to chair time and patient acceptance. As digital technology continues to progress, intraoral scanning may become more accepted for use in orthodontics. PMID- 25439219 TI - Litigation and legislation. Considering consideration. PMID- 25439220 TI - Cohort studies: part 2. PMID- 25439221 TI - Clinical significance of microRNA 138 and cyclin D3 in hepatocellular carcinoma. AB - BACKGROUND: MicroRNA 138 (miR-138) is recently shown to inhibit tumor growth and block cell cycle arrest of hepatocellular carcinoma (HCC) by targeting cyclin D3 (CCND3). The aim of this study was to investigate the clinical significance of miR-138 and CCND3 in human HCC, which remains unclear. METHODS: Quantitative real time polymerase chain reaction analysis was performed to detect the expression levels of miR-138 and CCND3 messenger RNA (mRNA) in 180 self-pairs of HCC and noncancerous liver tissues. RESULTS: Compared with noncancerous liver tissues, the expression levels of miR-138 in HCC tissues were significantly downregulated (P < 0.001), whereas the expression levels of CCND3 mRNA in HCC tissues were significantly upregulated (P < 0.001). There was a negative correlation between miR-138 and CCND3 mRNA expression in HCC tissues (r = -0.56, P = 0.02). Additionally, statistical analysis showed that the combined miR 138 downregulation and CCND3 upregulation (miR-138-low-CCND3-high) was significantly associated with the advanced tumor-node-metastasis stage (P = 0.008) and the presence of portal vein invasion (P = 0.008) and lymph node metastasis (P = 0.01). More importantly, a significant trend was identified between the combined expression of miR-138-low-CCND3-high in HCC and worsening clinical prognosis. Multivariate survival analysis further recognized miR-138-low-CCND3-high expression as an independent prognostic factor for patients with HCC. CONCLUSIONS: Our data suggest that the combined expression of miR-138 and its direct target CCND3 may be correlated with significant characteristics of HCC. MiR-138 downregulation and CCND3 upregulation maybe concurrently associated with prognosis in patients with HCC. PMID- 25439222 TI - Orthotopic pancreatic tumors detected by optoacoustic tomography using Syndecan 1. AB - BACKGROUND: Advances in small animal imaging have improved the detection and monitoring of cancer in vivo; although with orthotopic models, precise localization of tumors remains a challenge. In this study, we evaluated multispectral optoacoustic tomography (MSOT) as an imaging modality to detect pancreatic adenocarcinoma in an orthotopic murine model. METHODS: In vitro binding of Syndecan-1 probe to the human pancreatic cancer cell line S2VP10 was evaluated on flow cytometry. For in vivo testing, S2VP10 cells were orthotopically implanted into the pancreas of severe combined immunodeficiency mice. At 7 d after implantation, the mice were intravenously injected with Syndecan-1 probe, and tumor uptake was evaluated with MSOT at multiple time points. Comparison was made with a free-dye control, indocyanine green (ICG). Probe uptake was verified ex vivo with fluorescent imaging. RESULTS: Syndecan-1 probe demonstrated partial binding to S2VP10 cells in vitro. In vivo, Syndecan-1 probe preferentially accumulated in the pancreas tumor (480 MSOT a.u.) compared with off-target organs, including the liver (67 MSOT a.u.) and kidney (96 MSOT a.u.). Syndecan-1 probe accumulation peaked at 6 h (480 MSOT a.u.), whereas the ICG control dye failed to demonstrate similar retention within the tumor bed (0.0003 MSOT a.u.). At peak accumulation, signal intensity was 480 MSOT a.u., resulting in several times greater signal in the tumor bed than in the kidney or liver. Ex vivo fluorescent imaging comparing tumor signal with that within off target organs confirmed the in vivo results. CONCLUSIONS: MSOT demonstrates successful accumulation of Syndecan-1 probe within pancreatic tumors, and provides high-resolution images, which allow noninvasive, real-time comparison of signal within individual organs. Syndecan-1 probe preferentially accumulates within a pancreatic adenocarcinoma model, with minimal off-target effects. PMID- 25439224 TI - Image-guided prediction of pseudocyst formation in pediatric pancreatic trauma. AB - BACKGROUND: To determine if there is an effective alternative to the current standard of computed tomography (CT) grading of pediatric pancreatic injuries. We hypothesized that the Wong grading scale, which is based on the depth and location of the pancreatic laceration, is more predictive of pseudocyst formation than the American Association for the Surgery of Trauma (AAST) scale after nonoperative management of traumatic pancreatic injury in children. MATERIALS AND METHODS: A retrospective review of children admitted for pancreatic trauma to two level 1 pediatric trauma centers between 2000 and 2012 was conducted. Patients who underwent primary operation were excluded. Initial CT scans were reviewed by two radiologists blinded to clinical outcomes, and injury grades from both scales were assigned. The primary outcome was pseudocyst formation. RESULTS: Fifty-three patients (ages 7 mo-17 y) were included. As per the Wong scale, pseudocysts occurred in 0/20 patients with grade A injuries, 2/17 (12%) with BI/CI injuries, and 9/15 (60%) with BII/CII injuries. Using the AAST scale, pseudocysts developed in 2/27 (7%) patients with grade I/II injuries, 7/20 (35%) patients with III/IV/V injuries, and 1/6 (17%) patients with a scan that was indeterminate between grades II and III. Positive Predictive value, negative predictive value, sensitivity, and specificity for pseudocyst formation were all higher using the Wong scale (AAST/Wong: Positive Predictive value 42%/50%, negative predictive value 91%/94%, sensitivity 80%/82%, and specificity 65%/77%). CONCLUSIONS: The Wong CT grading scale may be superior to the AAST scale for early risk stratification for pseudocyst development after nonoperative management of pediatric pancreatic trauma; however, a larger study is needed for verification of these findings. PMID- 25439223 TI - Structure, process, and outcomes in skilled nursing facilities: understanding what happens to surgical patients when they cannot go home. A systematic review. AB - BACKGROUND: The surgical population is aging, and greater numbers of surgical patients are being discharged to skilled nursing facilities. Post-acute care is a poorly understood but very important aspect of our healthcare system. METHODS: This systematic review examines the current body of literature surrounding the structural, process of care, and outcomes measurements for patients in skilled nursing facilities. English language articles published between 1998 and 2011 that purposed to examine nursing facility structure, process of care, and/or outcomes were included. RESULTS & CONCLUSIONS: Abstracts (2129) were screened and 102 articles were reviewed in full. Twenty-nine articles were included in the qualitative synthesis. The role of the care setting and care delivery in contributing to outcomes has not been well studied, and no strong conclusions can be made. This area of care currently represents a "black box" to practicing surgeons. An understanding of these factors maybe instrumental to determining future directions for research to maximize positive outcomes for these patients. PMID- 25439225 TI - The role of air pollutants in atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease and a growing health concern, especially in children, because of its high prevalence and associated low quality of life. Genetic predisposition, environmental triggers, or interactions between them contribute to the pathophysiology of AD. Therefore, it is very important to identify and control risk factors from the environment in susceptible subjects for successful treatment and prevention. Both indoor and outdoor air pollution, which are of increasing concern with urbanization, are well-known environmental risk factors for asthma, whereas there is relatively little evidence in AD. This review highlights epidemiologic and experimental data on the role of air pollution in patients with AD. Recent evidence suggests that a variety of air pollutants, such as environmental tobacco smoke, volatile organic compounds, formaldehyde, toluene, nitrogen dioxide, and particulate matter, act as risk factors for the development or aggravation of AD. These air pollutants probably induce oxidative stress in the skin, leading to skin barrier dysfunction or immune dysregulation. However, these results are still controversial because of the low number of studies, limitations in study design, inaccurate assessment of exposure and absorption, and many other issues. Further research about the adverse effects of air pollution on AD will help to expand our understanding and to establish a better strategy for the prevention and management of AD. PMID- 25439226 TI - Environmental effects on immune responses in patients with atopy and asthma. AB - Despite attempts and some successes to improve air quality over the decades, current US national trends suggest that exposure to outdoor and indoor air pollution remains a significant risk factor for both the development of asthma and the triggering of asthma symptoms. Emerging science also suggests that environmental exposures during the prenatal period and early childhood years increase the risk of asthma. Multiple mechanisms mediate this risk because a wide range of deleterious air pollutants contribute to the pathogenesis of asthma across a variety of complex asthma phenotypes. In this review we will consider the role of altered innate and adaptive immune responses, gene-environment interactions, epigenetic regulation, and possibly gene-environment-epigene interactions. Gaining a greater understanding of the mechanisms that underlie the effect of exposure to air pollution on asthma, allergies, and other airway diseases can identify targets for therapy. Such interventions will include pollutant source reduction among those most exposed and most vulnerable and novel pharmaceutical strategies to reduce asthma morbidity. PMID- 25439229 TI - Comparison of indoor allergen levels in urban and suburban Detroit. PMID- 25439228 TI - Cost of near-roadway and regional air pollution-attributable childhood asthma in Los Angeles County. AB - BACKGROUND: Emerging evidence suggests that near-roadway air pollution (NRP) exposure causes childhood asthma. The associated costs are not well documented. OBJECTIVE: We estimated the cost of childhood asthma attributable to residential NRP exposure and regional ozone (O3) and nitrogen dioxide (NO2) levels in Los Angeles County. We developed a novel approach to apportion the costs between these exposures under different pollution scenarios. METHODS: We integrated results from a study of willingness to pay to reduce the burden of asthma with results from studies of health care use and charges to estimate the costs of an asthma case and exacerbation. We applied those costs to the number of asthma cases and exacerbations caused by regional pollution in 2007 and to hypothetical scenarios of a 20% reduction in regional pollution in combination with a 20% reduction or increase in the proportion of the total population living within 75 m of a major roadway. RESULTS: Cost of air pollution-related asthma in Los Angeles County in 2007 was $441 million for O3 and $202 million for NO2 in 2010 dollars. Cost of routine care (care in absence of exacerbation) accounted for 18% of the combined NRP and O3 cost and 39% of the combined NRP and NO2 cost; these costs were not recognized in previous analyses. NRP-attributable asthma accounted for 43% (O3) to 51% (NO2) of the total annual cost of exacerbations and routine care associated with pollution. Hypothetical scenarios showed that costs from increased NRP exposure might offset savings from reduced regional pollution. CONCLUSIONS: Our model disaggregates the costs of regional pollution and NRP exposure and illustrates how they might vary under alternative exposure scenarios. The cost of air pollution is a substantial burden on families and an economic loss for society. PMID- 25439231 TI - Optimal duration of allergen immunotherapy. PMID- 25439230 TI - Transmission of allergen-specific IgG and IgE from maternal blood into breast milk visualized with microarray technology. PMID- 25439232 TI - Nurses and the euthanasia debate: reflections from New Zealand. AB - AIM: Through an examination of the present situation relating to legalizing euthanasia and/or physician-assisted death in New Zealand, this paper is intended to encourage nurses worldwide to ponder about their own position on the ever present topic of assisted dying and euthanasia. BACKGROUND: In New Zealand, euthanasia remains illegal, but in 2012, the 'End of Life Choice Bill' was put in the ballot for potential selection for consideration by Parliament, later to be withdrawn. However, it is increasingly likely that New Zealand will follow international trends to offer people a choice about how their lives should end, and that such a Bill will be resubmitted in the near future. Undoubtedly, the passage of such legislation would have an impact on the day-to-day practices of nurses who work with dying people. SOURCES OF EVIDENCE: This article has been prepared following a comprehensive review of appropriate literature both in New Zealand and overseas. DISCUSSION: This article aims to highlight the importance of nursing input into any national debates concerning proposed euthanasia or assisted dying laws. The discussion therefore covers New Zealand's experience of such proposed legislation, that is, the draft Bill itself and the implications for nurses, the history of the assisted dying debate in New Zealand, public and professional opinion, and national and international nursing responses to euthanasia. CONCLUSION: New Zealand nurses will eventually have an opportunity to make their views on proposed euthanasia legislation known, and what such legislation might mean for their practice. Nurses everywhere should seriously consider their own knowledge and viewpoint on this vitally important topic, and be prepared to respond as both individuals and as part of their professional bodies when the time inevitably arrives. The result will be a better informed set of policies, regulations and legislation leading to a more meaningful and dignified experience for dying people and their families. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Nurses need to be fully informed about, and contribute to, proposed euthanasia or assisted dying legislation. They have extensive expertise in care of the dying, and should therefore be ready to influence law, policy and future nursing practices. PMID- 25439233 TI - Stabilizing Dog Populations and Improving Animal and Public Health Through a Participatory Approach in Indigenous Communities. AB - Free-roaming dog populations are a global concern for animal and human health including transmission of infectious disease (e.g. rabies, distemper and parasites), dog bite injuries/mortalities, animal welfare and adverse effects on wildlife. In Saskatchewan (SK), Canada, veterinary care is difficult to access in the remote and sparsely inhabited northern half of the province, where the population is predominately Indigenous. Even where veterinary clinics are readily available, there are important barriers such as cost, lack of transportation, unique cultural perspectives on dog husbandry and perceived need for veterinary care. We report the effects of introducing a community action plan designed to improve animal and human health, increase animal health literacy and benefit community well-being in two Indigenous communities where a dog-related child fatality recently occurred. Initial door-to-door dog demographic surveys indicated that most dogs were sexually intact (92% of 382 dogs), and few had ever been vaccinated (6%) or dewormed (6%). Approximately three animal-related injuries requiring medical care were reported in the communities per 1000 persons per year (95% CL: 1.6-6.6), and approximately 86% of 145 environmentally collected dog faecal samples contained parasites, far above levels reported in other urban or rural settings in SK. Following two subsidized spay/neuter clinics and active rehoming of dogs, parasite levels in dog faeces decreased significantly (P < 0.001), and important changes were observed in the dog demographic profile. This project demonstrates the importance of engaging people using familiar, local resources and taking a community specific approach. As well, it highlights the value of integrated, cross-jurisdictional cooperation, utilizing the resources of university researchers, veterinary personnel, public health, environmental health and community-based advocates to work together to solve complex issues in One Health. On-going surveillance on dog bites, parasite levels and dog demographics are needed to measure the long-term sustainability of benefits to dog, human and wildlife health. PMID- 25439234 TI - Reviving an old HIV-1 gene: the HIV-1 antisense protein. AB - The existence of an HIV-1 protein translated from an antisense transcript was suggested over 25 years ago. However, this Antisense Protein (ASP) gene has still not been completely accepted by the HIV-1 research community. The aim of this review is to discuss recent findings, which suggest that ASP needs to be considered as a viral gene, playing an important role in HIV-1 replication and persistence. In past years, several studies have highlighted the existence of HIV 1 antisense transcripts. More recently, we and others have convincingly demonstrated that this transcript produces a protein with a unique distribution and a rapid turnover, when expressed in mammalian cells. Furthermore, a role in autophagy and HIV-1 replication has been associated with this protein. In light of these recent reports, we believe that ASP needs to be added to the schematic representation of the HIV-1 proviral DNA and requires further investigation, as it could represent a new potential target for anti-retroviral therapies and vaccine strategies. PMID- 25439235 TI - HIV extracellular Tat: myth or reality? AB - The human immunodeficiency virus type 1 (HIV) eradication will require elimination of HIV infected cells. No antiretroviral treatments (ART) or vaccine approaches have been able to reduce significantly the level of HIV infected cells in peripheral blood. This inefficacy is generally explained by the presence of a major reservoir of latent HIV infected cells in the central nervous system (CNS) that would be a sanctuary where Cytotoxic T Lymphocytes (CTL) have no access and would refresh peripheral blood with activated HIV infected cells. In this review, the presence of a major reservoir in the CNS appears to be inconsistent with recent clinical studies measuring HIV DNA. The major reservoirs are gut tissue, rectal tissue and the peripheral blood where HIV infected cells survive in an environment containing CTL. Extracellular Tat might protect HIV infected cells from CTL due to its capacity to cross CTL membranes and trigger apoptosis. Evidences of Tat secretion from HIV infected cells are shown with the detection of Tat antibodies in different clinical studies. Presence of neutralizing Tat antibodies in cohorts of patients who were exposed to HIV but who are now seronegative is described. The conclusion of this review is that a vaccine eliciting neutralizing antibodies against Tat might significantly reduce the level of HIV infected cells, what ART or other vaccine approaches have been unable to achieve now. It could be a first step towards HIV eradication. PMID- 25439236 TI - Cardiac morbidity in an HIV-1 lipodystrophy patient cohort expressing the TNF alpha-238 G/A single nucleotide gene polymorphism. AB - In the current study we investigated the prevalence of the TNF-alpha 238G/A single nucleotide polymorphism (SNP) of the TNF-alpha gene in the development of lipodystrophy among HIV-1 infected individuals who had been receiving antiretroviral therapy (ART) in the immunodeficiency clinics of the National AIDS Research Institute (NARI) at Pune, India. We assessed the association of this SNP with the development of lipoatrophy/dyslipidemia and insulin resistance in these patients and measured carotid intima thickening which is a surrogate marker for chronic cardiac morbidity. Our results show that the incidence of the TNF-alpha 238G/A SNP is ~ two fold higher in patients with lipodystrophy as compared to those without lipodystrophy. Patients with lipodystrophy demonstrated a higher likelihood of the development of metabolic syndrome as evident by increased insulin sensitivity and increased percentage (%) beta cell function. Further, a significant increase in left carotid intima thickness was observed in patients with lipodystrophy. Our study validates the association of the TNF-alpha 238G/A SNP allelic variant with the development of HIV- lipodystrophy via the modulation of TNF-alpha production, which contributes to dyslipidemia, increased lipolysis, increased insulin resistance, altered differentiation of adipocytes and increased carotid intima thickness. The contribution of genetic determinants such as the TNF-alpha 238G/A SNP to lipodystrophy, may provide insight into the mechanisms that underlie this disease condition and may be useful in the future for personalized therapy. Additionally, these findings will be useful in monitoring chronic cardiac morbidities among HIV infected individuals who express this SNP. PMID- 25439237 TI - Evaluation of the Coaches Educators training implementation of the PAPA project: A comparison between Norway and France. AB - This study cross-culturally compares the implementation process of the Empowering CoachingTM training program to grassroots coaches (GCs) by trained Coach Educators (CEs) from the Promoting Adolescent Physical Activity project in Norway and France. This program targets children's health through coach training to create a more positive environment. Using the RE-AIM framework, indicators of implementation processes at staff level were defined for adoption, implementation, and maintenance. CEs (n = 18) were interviewed about their professional use of the training, and video-filmed delivering the intervention trial workshops. GCs (n = 185) responded to a questionnaire after the workshops. Results showed that CEs were keen to participate in this project (16/18; 89%), to stay involved (12/16; 75%), and to diffuse the principles after the research project (12/12; 100%). CE training seemed effective as results indicated that CEs applied the principles of the program during the workshops and covered a high degree of the content (78%). Cross-cultural differences were found as the French Football Federation CE dropped out of the program, as Norwegian CEs delivered the content with higher fidelity and had higher enjoyment and pace scores than French CEs. More indicators are needed to use the RE-AIM framework for cross-cultural comparison. PMID- 25439239 TI - The rhetoric of patient and family centred care: an institutional ethnography into what actually happens. AB - AIMS: This paper uses Dorothy Smith's institutional ethnography to examine technological advances designed to improve nurses' work. The analysis interrogates how nurses' work is coordinated, in disquieting ways, in an apparent commitment to 'patient and family centred care'. BACKGROUND: The discussion is part of a larger programme of research that focuses ethnographic attention on nurses' activating technological managerial improvement strategies. DESIGN: This discussion paper describes suboptimal hospital experiences to show how they were organized. The institutional ethnographic analysis addresses discrepancies that arise between the different organizational standpoints. Overall the discussion focuses on how institutional ethnographers enquire into people's everyday activities to discover and make understandable, in the material world, what actually happens that shapes them. DATA SOURCES: Data include observations and interviews with nurses, nurse managers, patients and families. It also includes screenshots of computer fields and other documents being used by nurses. IMPLICATIONS FOR NURSING: Nursing work is methodically being oriented to interests that undermine nurses' capacity to contribute their knowledgeable activity to intervene in people's health and well-being. CONCLUSION: Nurses' work is overwhelmed with the imperative to discharge patients. This happens with an ideological construction of patient centred care that obscures what is actually happening. PMID- 25439241 TI - Comparative genomics in the Asteraceae reveals little evidence for parallel evolutionary change in invasive taxa. AB - Asteraceae, the largest family of flowering plants, has given rise to many notorious invasive species. Using publicly available transcriptome assemblies from 35 Asteraceae, including six major invasive species, we examined evidence for micro- and macro-evolutionary genomic changes associated with invasion. To detect episodes of positive selection repeated across multiple introductions, we conducted comparisons between native and introduced genotypes from six focal species and identified genes with elevated rates of amino acid change (dN/dS). We then looked for evidence of positive selection at a broader phylogenetic scale across all taxa. As invasive species may experience founder events during colonization and spread, we also looked for evidence of increased genetic load in introduced genotypes. We rarely found evidence for parallel changes in orthologous genes in the intraspecific comparisons, but in some cases we identified changes in members of the same gene family. Using among-species comparisons, we detected positive selection in 0.003-0.69% and 2.4-7.8% of the genes using site and stochastic branch-site models, respectively. These genes had diverse putative functions, including defence response, stress response and herbicide resistance, although there was no clear pattern in the GO terms. There was no indication that introduced genotypes have a higher proportion of deleterious alleles than native genotypes in the six focal species, suggesting multiple introductions and admixture mitigated the impact of drift. Our findings provide little evidence for common genomic responses in invasive taxa of the Asteraceae and hence suggest that multiple evolutionary pathways may lead to adaptation during introduction and spread in these species. PMID- 25439240 TI - Vitamin E attenuates neurotoxicity induced by deltamethrin in rats. AB - BACKGROUND: The safety of Deltamethrin (DM) has been raised as a point of concern. The current investigation was envisaged to explore the responsiveness of oxidative stress parameters, DNA fragmentation and expression levels of TP53, cycloxygenase 2 (COX2) and cytochrome p4502E1 (CYP2E1) as toxicological endpoint in rats treated with DM. as well as attention was provided to the neuroprotective effect of vitamin E (VE). METHODS: Four different groups of rats were used in this study, group I served as control, group II received DM (0.6 mg/kg BW), group III received both DM plus VE and finally group IV received VE only (200 mg/kg BW). The treatment regimen was extending for one month for all groups and the brain tissues were collected for further analysis. RESULTS: The obtained results showed a highly statistically significant increase in lipid peroxidation (LPO) content, nitric oxide concentration, and DNA fragmentation percentage and expression level of CYP2E1, TP53 and COX2 genes, in addition statistical significant reduction in total antioxidant capacity in DM treated group as compared to control were detected. Oral administration of VE attenuated the neurotoxic effects of DM through improvement of oxidative status, DNA fragmentation percentage and suppressing the expression level of CYP2E1, TP53 and COX2 genes. CONCLUSION: From this study we concluded that VE supplementation has beneficial impacts on DM neurotoxicity in rats through its antioxidant and antiapoptotic properties. PMID- 25439242 TI - Nail lichen planus - a possible new indication for oral alitretinoin. PMID- 25439243 TI - The public health workforce: moving forward in the 21st century. PMID- 25439244 TI - Turning the focus to workforce surveillance: a workforce data set we can count on. PMID- 25439245 TI - On the road to a stronger public health workforce: visual tools to address complex challenges. AB - The public health workforce is vital to protecting the health and safety of the public, yet for years, state and local governmental public health agencies have reported substantial workforce losses and other challenges to the workforce that threaten the public's health. These challenges are complex, often involve multiple influencing or related causal factors, and demand comprehensive solutions. However, proposed solutions often focus on selected factors and might be fragmented rather than comprehensive. This paper describes approaches to characterizing the situation more comprehensively and includes two visual tools: (1) a fishbone, or Ishikawa, diagram that depicts multiple factors affecting the public health workforce; and (2) a roadmap that displays key elements-goals and strategies-to strengthen the public health workforce, thus moving from the problems depicted in the fishbone toward solutions. The visual tools aid thinking about ways to strengthen the public health workforce through collective solutions and to help leverage resources and build on each other's work. The strategic roadmap is intended to serve as a dynamic tool for partnership, prioritization, and gap assessment. These tools reflect and support CDC's commitment to working with partners on the highest priorities for strengthening the workforce to improve the public's health. PMID- 25439246 TI - Education in public health: expanding the frontiers. PMID- 25439247 TI - A strategic approach to public health workforce development and capacity building. AB - In February 2010, CDC's National Center for HIV/AIDS, Viral Hepatitis, Sexually Transmitted Disease (STD), and Tuberculosis (TB) Prevention (NCHHSTP) formally institutionalized workforce development and capacity building (WDCB) as one of six overarching goals in its 2010-2015 Strategic Plan. Annually, workforce team members finalize an action plan that lays the foundation for programs to be implemented for NCHHSTP's workforce that year. This paper describes selected WDCB programs implemented by NCHHSTP during the last 4 years in the three strategic goal areas: (1) attracting, recruiting, and retaining a diverse and sustainable workforce; (2) providing staff with development opportunities to ensure the effective and innovative delivery of NCHHSTP programs; and (3) continuously recognizing performance and achievements of staff and creating an atmosphere that promotes a healthy work-life balance. Programs have included but are not limited to an Ambassador Program for new hires, career development training for all staff, leadership and coaching for mid-level managers, and a Laboratory Workforce Development Initiative for laboratory scientists. Additionally, the paper discusses three overarching areas-employee communication, evaluation and continuous review to guide program development, and the implementation of key organizational and leadership structures to ensure accountability and continuity of programs. Since 2010, many lessons have been learned regarding strategic approaches to scaling up organization-wide public health workforce development and capacity building. Perhaps the most important is the value of ensuring the high-level strategic prioritization of this issue, demonstrating to staff and partners the importance of this imperative in achieving NCHHSTP's mission. PMID- 25439248 TI - Public health and community medicine instruction and physician practice location. AB - BACKGROUND: Experts have historically recommended better integration of public health content into medical education. Whether this adoption is associated with physician practice location has not been studied. PURPOSE: To examine the association between medical student perception of their public health and community medicine instruction and practice location in a Health Professional Shortage Area. METHODS: Descriptive analysis and a regression model assessed the significance and strength of the association between medical student perception of their public health and community medicine instruction and practice location using data from the Medical School Graduation Questionnaire 1997-2004, 2013 American Medical Association Physician Masterfile, and 2013 Health Professional Shortage Areas. RESULTS: A higher proportion of medical students with an intent to practice in underserved areas reported inadequate instruction in public health and community medicine than those without such intentions. Students reporting adequate public health and community medicine instruction are slightly more likely to practice in a Health Professional Shortage Area, controlling for their intent to practice in underserved areas. CONCLUSIONS: Findings suggest an association between perceptions of public health and community medicine instruction and practice location. Improved public health and community medicine instruction may support medical students' preparation and ability to integrate public health skills into practices in underserved settings. More research is needed to ascertain factors enabling better incorporation of public health and community medicine in medical education. PMID- 25439249 TI - Beyond content: leadership development through a journal club. AB - CDC designed its Health Systems Integration Program to prepare leaders to function at the interface of public health and health care. Specific Health Systems Integration Program competencies in the areas of communication, analysis and assessment, and health systems were developed to nurture evidence-based decision-making and leadership skills crucial for future public health leaders. The program therefore designed an innovative journal club as part of its competency-based curriculum not only to meet the standard goals for a journal club-critical reading, interpretation, and acquiring content knowledge-but also to foster leadership development. This report describes the Health Systems Integration Program journal club format, its implementation, challenges, and key elements of success. Other programs using a journal club model as a learning format might consider using the Health Systems Integration Program's innovative approach that focuses on leadership development. PMID- 25439250 TI - Enumeration of the governmental public health workforce, 2014. AB - BACKGROUND: Regular assessment of the size and composition of the U.S. public health workforce has been a challenge for decades. Previous enumeration efforts estimated 450,000 public health workers in governmental and voluntary agencies in 2000, and 326,602 governmental public health workers in 2012, although differences in enumeration methodology and the definitions of public health worker between the two make comparisons problematic. PURPOSE: To estimate the size of the governmental public health workforce in 14 occupational classifications recommended for categorizing public health workers. METHODS: Six data sources were used to develop enumeration estimates: five for state and local public health workers and one for the federal public health workforce. Statistical adjustments were made to address missing data, overcounting, and duplicate counting of workers across surveys. Data were collected for 2010-2013; analyses were conducted in 2014. RESULTS: The multiple data sources yielded an estimate of 290,988 (range=231,464-341,053) public health workers in governmental agencies, 50%, 30%, and 20% of whom provide services in local, state, and federal public health settings, respectively. Administrative or clerical personnel (19%) represent the largest group of workers, followed by public health nurses (16%); environmental health workers (8%); public health managers (6%); and laboratory workers (5%). CONCLUSIONS: Using multiple data sources for public health workforce enumeration potentially improves accuracy of estimates but also adds methodologic complexity. Improvement of data sources and development of a standardized study methodology is needed for continuous monitoring of public health workforce size and composition. PMID- 25439251 TI - Public health workforce taxonomy. AB - Thoroughly characterizing and continuously monitoring the public health workforce is necessary for ensuring capacity to deliver public health services. A prerequisite for this is to develop a standardized methodology for classifying public health workers, permitting valid comparisons across agencies and over time, which does not exist for the public health workforce. An expert working group, all of whom are authors on this paper, was convened during 2012-2014 to develop a public health workforce taxonomy. The purpose of the taxonomy is to facilitate the systematic characterization of all public health workers while delineating a set of minimum data elements to be used in workforce surveys. The taxonomy will improve the comparability across surveys, assist with estimating duplicate counting of workers, provide a framework for describing the size and composition of the workforce, and address other challenges to workforce enumeration. The taxonomy consists of 12 axes, with each axis describing a key characteristic of public health workers. Within each axis are multiple categories, and sometimes subcategories, that further define that worker characteristic. The workforce taxonomy axes are occupation, workplace setting, employer, education, licensure, certification, job tasks, program area, public health specialization area, funding source, condition of employment, and demographics. The taxonomy is not intended to serve as a replacement for occupational classifications but rather is a tool for systematically categorizing worker characteristics. The taxonomy will continue to evolve as organizations implement it and recommend ways to improve this tool for more accurate workforce data collection. PMID- 25439252 TI - Understanding the local public health workforce: labels versus substance. AB - BACKGROUND: The workforce is a key component of the nation's public health (PH) infrastructure, but little is known about the skills of local health department (LHD) workers to guide policy and planning. PURPOSE: To profile a sample of LHD workers using classification schemes for PH work (the substance of what is done) and PH job titles (the labeling of what is done) to determine if work content is consistent with job classifications. METHODS: A secondary analysis was conducted on data collected from 2,734 employees from 19 LHDs using a taxonomy of 151 essential tasks performed, knowledge possessed, and resources available. Each employee was classified by job title using a schema developed by PH experts. The inter-rater agreement was calculated within job classes and congruence on tasks, knowledge, and resources for five exemplar classes was examined. RESULTS: The average response rate was 89%. Overall, workers exhibited moderate agreement on tasks and poor agreement on knowledge and resources. Job classes with higher agreement included agency directors and community workers; those with lower agreement were mid-level managers such as program directors. CONCLUSIONS: Findings suggest that local PH workers within a job class perform similar tasks but vary in training and access to resources. Job classes that are specific and focused have higher agreement whereas job classes that perform in many roles show less agreement. The PH worker classification may not match employees' skill sets or how LHDs allocate resources, which may be a contributor to unexplained fluctuation in public health system performance. PMID- 25439253 TI - Changes in public health workforce composition: proportion of part-time workforce and its correlates, 2008-2013. AB - BACKGROUND: State and local public health department infrastructure in the U.S. was impacted by the 2008 economic recession. The nature and impact of these staffing changes have not been well characterized, especially for the part-time public health workforce. PURPOSE: To estimate the number of part-time workers in state and local health departments (LHDs) and examine the correlates of change in the part-time LHD workforce between 2008 and 2013. METHODS: We used workforce data from the 2008 and 2013 National Association of County and City Health Officials (n=1,543) and Association of State and Territorial Health Officials (n=24) profiles. We employed a Monte Carlo simulation to estimate the possible and plausible proportion of the workforce that was part-time, over various assumptions. Next, we employed a multinomial regression assessing correlates of the change in staffing composition among LHDs, including jurisdiction and organizational characteristics, as well measures of community involvement. RESULTS: Nationally representative estimates suggest that the local public health workforce decreased from 191,000 to 168,000 between 2008 and 2013. During that period, the part-time workforce decreased from 25% to 20% of those totals. At the state level, part-time workers accounted for less than 10% of the total workforce among responding states in 2013. Smaller and multi-county jurisdictions employed relatively more part-time workers. CONCLUSIONS: This is the first study to create national estimates regarding the size of the part-time public health workforce and estimate those changes over time. A relatively small proportion of the public health workforce is part-time and may be decreasing. PMID- 25439254 TI - Workforce turnover at local health departments: nature, characteristics, and implications. AB - BACKGROUND: Employee turnover, defined as total separations from employment, is expensive, can result in lost capacity, and can limit local health departments' (LHDs') ability to respond to public health needs. Despite the importance of workforce capacity in public health, little is known about workforce turnover in LHDs. PURPOSE: To examine the extent to which LHDs experience turnover and identify LHD characteristics that are associated with turnover. METHODS: A cross sectional data set of employee turnover and LHD characteristics from the 2013 National Profile of LHDs was analyzed. Descriptive statistics and bivariate analyses were conducted in 2014 on turnover rates. The effect of the following LHD characteristics on turnover rates were examined: population size, governance type, degree of urbanization, top executive experience level, expenditures per capita, and LHD budget cuts. RESULTS: In 2013, LHDs experienced a mean turnover rate of 9.88%; approximately one third of turnover was due to retirements. LHDs with shared state and local governance experienced a higher turnover rate than LHDs with exclusive state or local governance. LHDs that are units of state agencies had a significantly higher retirement rate than those governed by local authorities. Top executive experience level, per capita expenditures, and LHD budget cuts were also related to turnover rates. CONCLUSIONS: LHDs experienced a lower overall turnover rate than state health departments in 2011 and lower than all local and state government agencies in 2012. Strengthening leadership skills of new top executives and ensuring adequate funding may reduce turnover in LHDs. PMID- 25439255 TI - Aligning public health workforce competencies with population health improvement goals. PMID- 25439256 TI - Public health accreditation addresses issues facing the public health workforce. AB - As the Public Health Accreditation Board (PHAB) launched the nation's only accreditation program for state, local, tribal, and territorial health departments in September 2011, attention to the issues facing the public health workforce in these health departments was included. PHAB developed several measures in the accreditation standards and measures related to public health workforce development. The accreditation process calls upon health departments to focus more intentionally on their current workforce, while also supporting the development of future public health workers. Working with a group of public health workforce thought leaders, PHAB developed a long-range plan for the expectation of accredited health departments in workforce development. Beginning with the development of intentional standardization in workforce development and moving into future challenges and issues, PHAB uses its platform of quality improvement to bring emphasis on the current and future public health workforce. This article describes the development of the workforce components of public health department accreditation as well as future plans to ensure that the momentum continues. Using data from the accredited health departments at the time of article submission, PHAB also describes some of the approaches that governmental public health departments that have completed the accreditation process are using to develop their own workforce and support the development of the future public health workforce. Challenges faced by health departments in these areas are also described. PMID- 25439257 TI - Public health practice competency improvement among nurses. AB - BACKGROUND: Recommendations for improving public health workforce competency led to an academic-practice partnership project conducted to improve competency for providing essential public health services among public health nurses. PURPOSE: To measure competency for public health practice at baseline, identify factors associated with higher competency, document change in competency over 4 years, and assess differential effects associated with project participation. METHODS: Perceived competency was assessed using a validated instrument administered through online surveys at baseline (2007) and 4-year follow-up (2011). Analysis was completed in 2014. Overall means and SDs were calculated for each domain in the competency scale. Differences in means by role were tested using multivariate analysis of variance. Factors associated with higher competency were identified using regression analysis. Mean comparisons between baseline and follow-up were tested using paired samples t test and ANCOVA was used to test differential effects of project participation. RESULTS: Baseline competency levels were low in most domains. Managers reported higher competency in all domains compared to staff. Mean scores in all domains were higher on follow-up than baseline. Factors associated with higher competency in some domains included expected frequency of performance, higher degree, and younger age. Participants in project activities had higher mean competency scores than those who did not, with statistically significant differences (p<0.05) observed in four of nine domains. CONCLUSIONS: Participation in workforce development can contribute to improved perceived competency for public health practice among nurses. Continued investment in workforce development aimed at improving competency and additional research on competency assessment is warranted. PMID- 25439258 TI - Public health training in internal medicine residency programs: a national survey. AB - BACKGROUND: The IOM recommends public health training for all physicians. Data characterizing such training of internal medicine (IM) residents are lacking. PURPOSE: To describe the current state of public health education at IM residency programs, characterize programs offering public health education, and quantify interest in expanding training opportunities. METHODS: IM residency program directors from the 380 Accreditation Council for Graduate Medical Education accredited residency programs in the U.S were invited to participate in a cross sectional survey. Responses were received from 127 programs (33%). Data were collected July-December 2012 and analyzed in January 2013. Participants were queried on domestic public health training offered, perceived resident interest in and satisfaction with this training, and interest in expanding training. RESULTS: Eighty-four respondents (66%) provide some form of public health training, but structure and content vary widely. In many programs offering public health training, few residents (<10%) receive it. Although 93 programs (73%) integrate public health into core curricula, only three topics were common to a majority of these programs. Sixty-six respondents (52%) offer clinical training at community-based health centers. Most residency program directors (90%) are very or somewhat interested in expanding their public health training. CONCLUSIONS: This study characterizes the structures and content of public health training across IM residency programs. The wide range highlights the diverse definition of "public health training" used by IM residency program directors and lack of universal public health competencies required for IM physicians. Opportunities exist for collaboration among residency programs and between IM and public health educators to share best practices. PMID- 25439260 TI - The CDC/Council of state and territorial epidemiologists applied epidemiology fellowship program: evaluation of the first 9 years. AB - BACKGROUND: The Council of State and Territorial Epidemiologists (CSTE) implemented the Applied Epidemiology Fellowship (AEF) in 2003 to train public health professionals in applied epidemiology and strengthen applied epidemiology capacity within public health institutions to address the identified challenges. The CSTE recently evaluated the outcomes of the fellowship across the last 9 years. PURPOSE: To review the findings from the outcome evaluation of the first nine classes of AEF alumni with particular attention to how the fellowship affected alumni careers, mentors' careers, host site agency capacity, and competencies of the applied epidemiology workforce. METHODS: The mixed-methods evaluation used surveys and administrative data. Administrative data were gathered over the past 9 years and the surveys were collected in late 2013 and early 2014. Descriptive statistics and qualitative thematic analysis were conducted in early 2014 to examine the data from more than 130 alumni and 150 mentors. RESULTS: More than half the alumni (67%) indicated the fellowship was essential to their long-term career. In addition, 79% of the mentors indicated that participating in the fellowship had a positive impact on their career. Mentors also indicated significant impacts on host site capacity. A majority (88%) of alumni had worked for at least 1 year or more in government public health environments after the fellowship. CONCLUSIONS: Evaluation findings support previous research indicating need for competency-based field-based training programs that include a strong mentoring component. These characteristics in a field-based training program can increase applied epidemiology capacity in various ways. PMID- 25439259 TI - Training racial and ethnic minority students for careers in public health sciences. AB - BACKGROUND: A workforce that resembles the society it serves is likely to be more effective in improving health equity for racial and ethnic minorities in the U.S. Racial and ethnic minorities are underrepresented in the U.S. public health professions. Project Imhotep is operated by Morehouse College with funding and technical assistance from CDC. Imhotep trains racial and ethnic minority students for entry into graduate and professional training programs for careers in the public health sciences. The curriculum focuses on biostatistics, epidemiology, and occupational safety and health with practical training in statistical data analysis, scientific writing, and oral presentation skills. PURPOSE: To describe the Imhotep program and highlight some of its outcomes. METHODS: Data were collected every year by self-administered questionnaire or follow-up telephone and e-mail interviews of students who participated in Imhotep during 1982-2010 and were followed through December 2013. RESULTS: Findings demonstrated that 100% of the 481 trained students earned bachelor's degrees; 73.2% earned graduate degrees (53% earned master's degrees, 11.1% earned medical degrees, and 7.3% earned other doctoral degrees); and 60% entered public health careers. CONCLUSIONS: The Imhotep program has improved the representation of racial and ethnic minorities among public health professionals in the U.S. A diverse workforce involving Imhotep graduates could augment the pool of pubic health professionals who make strategic and tactical decisions around program design and resource allocation that impact health in the most affected communities. PMID- 25439261 TI - Epidemiology in a changing world. PMID- 25439262 TI - Public health informatics and the public health workforce in an era of change. PMID- 25439263 TI - Building a culture of health: challenges for the public health workforce. PMID- 25439264 TI - Leveraging public health nursing to build a culture of health. PMID- 25439265 TI - 3-iodothyroacetic acid, a metabolite of thyroid hormone, induces itch and reduces threshold to noxious and to painful heat stimuli in mice. AB - BACKGROUND AND PURPOSE: Itch is associated with increased sensitization to nociceptive stimuli. We investigated whether 3-iodothyroacetic acid (TA1), by releasing histamine, induces itch and increases sensitization to noxious and painful heat stimuli. EXPERIMENTAL APPROACH: Itch was evaluated after s.c. administration of TA1 (0.4, 1.32 and 4 MUg.kg(-1) ). Mice threshold to noxious (NHT) and to painful heat stimuli were evaluated by the increasing-temperature hot plate (from 45.5 to 49.5 degrees C) or by the hot plate (51.5 degrees C) test, respectively, 15 min after i.p. injection of TA1 (0.4, 1.32 and 4 MUg.kg( 1) ). Itch, NHT and pain threshold evaluation were repeated in mice pretreated with pyrilamine. Itch and NHT were also measured in HDC(+/+) and HDC(-/-) following injection of saline or TA1 (1.32, 4 and 11 MUg.kg(-1) ; s.c. and i.p.). pERK1/2 levels were determined by Western blot in dorsal root ganglia (DRG) isolated from CD1 mice 15 min after they received (i.p.): saline, saline and noxious heat stimulus (46.5 degrees C), TA1 (0.1, 0.4, 1.32, 4 MUg.kg(-1) ) or TA1 1.32 MUg.kg(-1) and noxious heat stimulus. KEY RESULTS: TA1 0.4 and 1.32 MUg.kg(-1) induced itch and reduced NHT; pyrilamine pretreatment prevented both of these effects. TA1 4 MUg.kg(-1) (i.p.) reduced pain threshold without inducing itch or modifying NHT. In HDC(-/-) mice, TA1 failed to induce itch and to reduce NHT. In DRG, pERK1/2 levels were significantly increased by noxious heat stimuli and by TA1 0.1, 0.4 and 1.32 MUg.kg(-1) ; i.p. CONCLUSIONS AND IMPLICATIONS: Increased TA1 levels induce itch and an enhanced sensitivity to noxious heat stimuli suggesting that TA1 might represent a potential cause of itch in thyroid diseases. PMID- 25439266 TI - Insulin-independent actions of glucagon-like peptide-1 in wethers. AB - Insulin-independent actions of glucagon-like peptide-1 (GLP-1) are not yet clear in ruminants. Four Suffolk mature wethers (60.0 +/- 6.7 kg body weight (BW)) were intravenously infused with insulin (0.5 mU/kg BW/min; from 0 to 90 min) and GLP-1 (0.5 MUg/kg BW/min; from 60 to 150 min) with both hormones co-administered from 60 to 90 min, in a repeated-measure design under euglycemic clamp for 150 min, to investigate whether GLP-1 has insulin-independent actions. Jugular blood samples were taken at 15-min intervals for plasma hormones and metabolites analysis. Compared to baseline concentrations (at 0 min), insulin infusion decreased (P < 0.05) plasma concentrations of glucagon, non-esterified fatty acids (NEFA), lactate, nonessential amino acids (NEAA), branched-chain amino acids (BCAA), total amino acids (TAA) and urea nitrogen (UN). Insulin plus GLP-1 infusion induced a greater increase (P < 0.05) in plasma concentrations of insulin and triglyceride (TG), but decreased (P < 0.05) glucagon, total cholesterol (T-Cho), NEAA and UN plasma concentrations. GLP-1 infusion increased (P < 0.05) NEFA, beta hydroxybutyrate and TG, but decreased (P < 0.05) glucagon, T-Cho, NEAA, BCAA and UN plasma concentrations. In conclusion, GLP-1 exerts extrapancreatic roles in ruminants not only insulin-independent but probably, in contrast to non ruminants, antagonistic to insulin effects. PMID- 25439267 TI - Geriatric dentistry content in the curriculum of the dental schools in Chile. AB - OBJECTIVE: The purpose of this study was to identify the status of pre-doctoral geriatric dentistry education among all Chilean dental schools. BACKGROUND: Chile is one of the most rapidly ageing countries in Latin America. Consequently, specific knowledge and training on the needs of elderly populations need to be emphasised in dental schools. The current extent and methods of teaching geriatric dentistry among the dental schools in Chile are unknown. MATERIALS AND METHODS: A web-based questionnaire was developed and sent to all 19 Chilean dental schools to identify which schools had a formal programme on geriatric dentistry and ask about their format, content and type of training of the faculty who taught in the programmes. Data were analysed, and a comparison was made among the schools. RESULTS: Sixteen (84%) of the participant schools reported teaching at least some aspects of geriatric dentistry, using various methodologies, but only 7 (37%) had specific courses. Of those schools reporting a didactic content on geriatric dentistry, 71% included clinical training, either in the school's dental clinics or in an extramural service. Contents mostly included demographics of ageing, theories of ageing and medical conditions. More than half of the faculty (57%) stated that they had formal training in geriatric dentistry, 43% were trained in prosthodontics, public health or other areas. CONCLUSIONS: Although most dental schools taught geriatric dentistry, only some had a specific course. Most schools with formal courses followed the international curriculum guidelines for geriatric dentistry. PMID- 25439268 TI - Shared decision making and the use of a patient decision aid in advanced serious illness: provider and patient perspectives. AB - OBJECTIVE: Patients with advanced serious illness face many complex decisions. Patient decision aids (PtDAs) can help with complex decision making but are underutilized. This study assessed barriers and facilitators to the use of a PtDA designed for serious illness. METHODS: Providers and patients were asked about their experiences in making decisions around serious illness and their opinions towards the PtDA. Seven focus groups were digitally recorded, transcribed and analysed using a general qualitative inductive method. RESULTS: Domain 1 - clinical context within which the PtDA would be utilized including three themes: (1a) role: PtDA might compete with the physician's role; (1b) logistics: it was unclear when and how such a PtDA should be implemented; and (1c) meaning: what it will mean to the patient if the physician recommends viewing of this PtDA. Domain 2 - broader global context: (2a) death-denying culture; and (2b) physician concerns that the PtDA was biased towards palliative care. CONCLUSION: Physicians' concerns were rooted in deeper concerns about palliative care and a death-denying culture. Patients were more open to using the PtDA than physicians, suggesting 'it's never too early'. PRACTICE IMPLICATIONS: PtDAs for serious illness can maximize early opportunities for goals of care conversations and shared decision making. PMID- 25439269 TI - Analytical characterization of the role of phospholipids in platelet adhesion and secretion. AB - The cellular phospholipid membrane plays an important role in cell function and cell-cell communication, but its biocomplexity and dynamic nature presents a challenge for examining cellular uptake of phospholipids and the resultant effects on cell function. Platelets, small anuclear circulating cell bodies that influence a wide variety of physiological functions through their dynamic secretory and adhesion behavior, present an ideal platform for exploring the effects of exogenous phospholipids on membrane phospholipid content and cell function. In this work, a broad range of platelet functions are quantitatively assessed by leveraging a variety of analytical chemistry techniques, including ultraperformance liquid chromatography-tandem electrospray ionization mass spectrometry (UPLC-MS/MS), vasculature-mimicking microfluidic analysis, and single cell carbon-fiber microelectrode amperometry (CFMA). The relative enrichments of phosphatidylserine (PS) and phosphatidylethanolamine (PE) were characterized with UPLC-MS/MS, and the effects of the enrichment of these two phospholipids on both platelet secretory behavior and adhesion were examined. Results show that, in fact, both PS and PE influence platelet adhesion and secretion. PS was enriched dramatically and decreased platelet adhesion as well as secretion from delta-, alpha-, and lysosomal granules. PE enrichment was moderate and increased secretion from platelet lysosomes. These insights illuminate the critical connection between membrane phospholipid character and platelet behavior, and both the methods and results presented herein are likely translatable to other mammalian cell systems. PMID- 25439271 TI - The oral microbiome and oral cancer. AB - The role that bacteria play in the etiology and predisposition to cancer is of increasing interest, particularly since the development of high-throughput genetic-based assays. With this technology, it has become possible to comprehensively examine entire microbiomes as a functional entity. This article focuses on the understanding of bacteria and its association with oral squamous cell carcinoma. PMID- 25439270 TI - The interrelationships of the gut microbiome and inflammation in colorectal carcinogenesis. AB - The cause of colorectal cancer (CRC) is multifactorial, with genetic, molecular, inflammatory, and environmental risk factors. Recently, the gut microbiota has been recognized as a new environmental contributor to CRC in both animal models and human studies. An additional interplay of the gut microbiome with inflammation is also evident in studies that have shown that inflammation alone or the presence of bacteria/bacterial metabolites alone is not enough to promote tumorigenesis. Rather, complex interrelationships with the gut microbiome, inflammation, genetics, and other environmental factors are evident in progression of colorectal tumors. PMID- 25439272 TI - Microbiome, innate immunity, and esophageal adenocarcinoma. AB - With the development of culture-independent technique, a complex microbiome has been established and described in the distal esophagus. The incidence of esophageal adenocarcinoma (EAC) has increased dramatically in the United States. Studies documenting an altered microbiome associated with EAC and its precedents suggest that dysbiosis may be contributing to carcinogenesis, potentially mediated by interactions with toll-like receptors. Investigations attempting to associate viruses with EAC have not been as consistent. Currently available data are cross-sectional and therefore cannot prove causal relationships. Prospectively, microbiome studies open a new avenue to the understanding of the etiology and pathogenesis of reflux disorders and EAC. PMID- 25439273 TI - Microbiome in human immunodeficiency virus infection. AB - Human immunodeficiency virus (HIV) primary infection occurs at mucosa tissues, suggesting an intricate interplay between the microbiome and HIV infection. Recent advanced technologies of high-throughput sequencing and bioinformatics allow researchers to explore nonculturable microbes, including bacteria, virus, and fungi, and their association with diseases. HIV/simian immunodeficiency virus infection is associated with microbiome shifts and immune activation that may affect the outcome of disease progression. In this review, the authors focus on microbiome in HIV infection at various mucosal compartments. Understanding the relationship between microbiome and HIV may offer insights into development of better strategies for HIV prevention and treatment. PMID- 25439274 TI - The changing landscape of the vaginal microbiome. AB - Deep sequence analysis of the vaginal microbiome is revealing an unexpected complexity that was not anticipated as recently as several years ago. The lack of clarity in the definition of a healthy vaginal microbiome, much less an unhealthy vaginal microbiome, underscores the need for more investigation of these phenomena. Some clarity may be gained by the careful analysis of the genomes of the specific bacteria in these women. Ongoing studies will clarify this process and offer relief for women with recurring vaginal maladies and hope for pregnant women to avoid the experience of preterm birth. PMID- 25439275 TI - The genetic predisposition and the interplay of host genetics and gut microbiome in Crohn disease. AB - Extensive genetic studies have identified more than 140 loci predisposing to Crohn disease (CD). Several major CD susceptibility genes have been shown to impair biological function with regard to immune response to recognizing and clearance of bacterial infection. Recent human microbiome studies suggest that the gut microbiome composition is differentiated in carriers of many risk variants of major CD susceptibility genes. This interplay between host genetics and its associated gut microbiome may play an essential role in the pathogenesis of CD. The ongoing microbiome research is aimed to investigate the detailed host genetics-microbiome interacting mechanism. PMID- 25439277 TI - Review of the emerging treatment of Clostridium difficile infection with fecal microbiota transplantation and insights into future challenges. AB - Clostridium difficile infection (CDI) is one of the most common health care associated infections in the United States. Currently, there are no standardized methods to prepare or deliver the fecal microbiota transplantation (FMT). Various methods are used to prepare the FMT, which is usually administered via nasogastric tube, colonoscopy, or by enema. Several clinical trials are underway to assess the true efficacy and safety of FMT for CDI. These trials include CDI studies assessing FMT via colonoscopy and frozen encapsulation, fresh versus frozen-and-thawed FMT by enema, FMT compared with a vancomycin taper, and FMT in the pediatric population. PMID- 25439278 TI - Beyond infectious disease: welcome to the era of population microbiology. PMID- 25439276 TI - The impact of proton pump inhibitors on the human gastrointestinal microbiome. AB - Potent gastric acid suppression using proton pump inhibitors (PPIs) is common in clinical practice but may have important effects on human health that are mediated through changes in the gastrointestinal microbiome. In the esophagus, PPIs change the normal bacterial milieu to decrease distal esophageal exposure to inflammatory gram-negative bacteria. In the stomach, PPIs alter the abundance and location of gastric Helicobacter pylori and other bacteria. In the small bowel, PPIs cause polymicrobial small bowel bacterial overgrowth and have been associated with the diagnosis of celiac disease. In the colon, PPIs associate with incident but not recurrent Clostridium difficile infection. PMID- 25439279 TI - The effect of numeracy level on completeness of home blood pressure monitoring. AB - Home blood pressure monitoring (HBPM) readings predict the increased risks of cardiovascular events and end-organ damage independent of office blood pressure (BP). Numeracy (the ability to handle numbers) may limit the feasibility of patients' performing HBPM. The authors analyzed data from 409 adults recruited from 12 North Carolina primary care clinics who completed a three-item numeracy assessment, the Rapid Estimate of Adult Literacy in Medicine-Short Form health literacy assessment, and HBPM over 2 weeks. Among the 409 participants, 73% were college graduates and 69% had adequate numeracy. Completion of HBPM was greater among those with adequate numeracy (96.2% vs 93.7%; P=.009) and did not correlate with health literacy scores. More participants with adequate numeracy reported completion of >=85% of readings than those with low numeracy (95% vs 88%; P=.018). Adequate numeracy, but not high literacy, is associated with more complete HBPM reporting. Whether higher numeracy is associated with more accurate self-reported readings is an area of future research. PMID- 25439280 TI - Progress in understanding electro-mechanical signalling in the myometrium. AB - In this review, we give a state-of-the-art account of uterine contractility, focussing on excitation-contraction (electro-mechanical) coupling (ECC). This will show how electrophysiological data and intracellular calcium measurements can be related to more modern techniques such as confocal microscopy and molecular biology, to advance our understanding of mechanical output and its modulation in the smooth muscle of the uterus, the myometrium. This new knowledge and understanding, for example concerning the role of the sarcoplasmic reticulum (SR), or stretch-activated K channels, when linked to biochemical and molecular pathways, provides a clearer and better informed basis for the development of new drugs and targets. These are urgently needed to combat dysfunctions in excitation contraction coupling that are clinically challenging, such as preterm labour, slow to progress labours and post-partum haemorrhage. It remains the case that scientific progress still needs to be made in areas such as pacemaking and understanding interactions between the uterine environment and ion channel activity. PMID- 25439281 TI - Concerns and perceptions about necessity in relation to insulin therapy in an ethnically diverse UK population with Type 2 diabetes: a qualitative study focusing mainly on people of South Asian origin. AB - AIM: To explore attitudes towards insulin acceptance an ethnically diverse population of people with Type 2 diabetes. METHODS: We conducted semi-structured interviews using a topic guide based on a literature review and findings from our previous study, which explored the perspectives of healthcare professionals about insulin initiation and management. Analysis of data involved undertaking an abductive reasoning approach in response to emerging themes. RESULTS: Participants discussed not only their concerns about insulin therapy, but also their views and beliefs about the necessity of insulin. Their attitudes to insulin treatment could be mapped into four main typologies. These fitted with an attitudinal scale based on the Necessity-Concerns Framework described in the medication adherence literature, comprising four attitudes: accepting, sceptical, ambivalent and indifferent. Decisions about accepting insulin involved balancing concerns (such as needle size) against the perceived necessity of insulin (generally, inadequacy of oral medication). The South Asian and white participants had similar concerns, but these were sometimes greater in South Asian participants, because of the influence of negative views and experiences of other insulin users. CONCLUSIONS: When discussing insulin with people with Type 2 diabetes, healthcare providers need to ensure that they explore and contribute to patients' understanding and interpretation of the necessity of insulin as well as discussing their concerns. Furthermore, they should be aware of how an individual's social context can influence his/her perceptions about the necessity of insulin as well as their concerns, and that this influence may be greater in some South Asian populations. PMID- 25439282 TI - Full-mouth scaling and root planing combined with azithromycin to treat peri implantitis. AB - BACKGROUND: Full-mouth scaling and root planing combined with azithromycin is clinically and bacteriologically effective for the treatment of chronic periodontitis. This study aimed to investigate the clinical and bacteriological effects of this combination treatment in patients with peri-implantitis. METHODS: Twenty adult patients with both chronic periodontitis and peri-implantitis were randomly divided into two groups (10: test, 10: control). All patients underwent full-mouth scaling and root planing but the test group received azithromycin for 3 days before the procedure. The probing depth, bleeding on probing, and the gingival index were assessed clinically. Bacterial samples were obtained before treatment at 1 week and 1, 3, 6, 9 and 12 months after treatment. Quantitative and qualitative analyses were performed using the polymerase chain reaction Invader method. RESULTS: All clinical parameters showed better improvement in both periodontitis and peri-implantitis in the test group. Periodontal bacteria were more effectively reduced in the test group, but gradually increased around implants 6 months after treatment and natural teeth 9 months after treatment. CONCLUSIONS: Full-mouth scaling and root planing combined with azithromycin was temporarily useful for the treatment of peri-implantitis. Clinical improvements were maintained for about 9 months but periodontal bacteria increased again 6 months after treatment. PMID- 25439283 TI - Bioavailability of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) in biosolids-amended soils to earthworms (Eisenia fetida). AB - The bioavailability of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) in seven biosolids-amended soils without any additionally spiking to earthworms (Eisenia fetida) was studied. The uptake and elimination kinetics of PFOS and PFOA fit a one-compartment first-order kinetic model. PFOS displayed higher uptake and lower elimination rate coefficients, and longer time to reach steady-state (t(ss)) than those of PFOA. The bioaccumulation factors (BAFs) of PFOS and PFOA ranged 1.54-4.12 and 0.52-1.34 g(soil) g(worm)(-1), respectively. The BAFs and tss decreased with increasing concentrations of PFOS and PFOA in soils. Stepwise multiple regression analysis was used to elucidate the bioavailability of PFOS and PFOA. The results showed that the total concentrations of PFOS and PFOA, and organic matter (OM) contents in soils explained 87.2% and 91.3% of the variation in bioavailable PFOS and PFOA, respectively. PFOS and PFOA concentrations exhibited positive influence and OM contents showed the negative influence on the accumulation of PFOS and PFOA in earthworms. Soil pH and clay contents played relatively unimportant role in PFOS and PFOA bioavailability. PMID- 25439284 TI - The human cerebellum: a review of physiologic neuroanatomy. AB - The cerebellum resides in the posterior cranial fossa dorsal to the brainstem and has diverse connections to the cerebrum, brain stem, and spinal cord. It is anatomically and physiologically divided into distinct functional compartments and is composed of highly regular arrays of neuronal units, each sharing the same basic cerebellar microcircuitry. Its circuitry is critically involved in motor control and motor learning, and its role in nonmotor cognitive and affective functions is becoming increasingly recognized. This article describes the cerebellar gross and histologic neuroanatomy in relation to its function, and the relevance of cerebellar circuitry and firing patterns to motor learning. PMID- 25439285 TI - Clinical manifestations of cerebellar disease. AB - Clinical manifestations of cerebellar disease include ataxia and tremor, as well as nystagmus, dysarthria, and cognitive dysfunction. Recognition of the cerebellar pattern of disease can aid in the prompt and correct diagnosis and lead to appropriate treatment and rehabilitation to minimize disability. PMID- 25439286 TI - Acute ataxias: differential diagnosis and treatment approach. AB - In many cases, acute ataxia presents a neurologic emergency that must be assessed and treated effectively in order to save a patient's life and protect the patient from potential permanent complications and disabilities. A thorough knowledge of cerebellar anatomy and physiology and familiarity with common causes of acute ataxia, enable the clinician to develop a rapid and effective diagnostic approach and effective management approach. PMID- 25439287 TI - The cerebellum and sleep. AB - The importance of the cerebellum in sleep disorders, and vice versa, is only beginning to be understood. Advanced neuroimaging modalities have revealed cerebellar changes in both common and rare sleep disorders. Sleep disorders in those with genetic cerebellar disease, such as spinocerebellar ataxia, Friedreich ataxia, Joubert syndrome, and ataxia-telangiectasia, include excessive daytime sleepiness, restless legs syndrome, periodic limb movements of sleep, obstructive apnea, central apnea, and rapid eye movement behavior disorder. Sleep medicine is an important and under-recognized part of the neurologic evaluation in those with cerebellar disease. PMID- 25439289 TI - Neuro-oncological disorders of the cerebellum. AB - This article provides an overview of the intra-axial tumors that affect the cerebellum, which can be categorized by location and age. For each tumor, we review conventional neuroimaging findings and discuss the value of more advanced neuroimaging techniques. Current management strategies are also briefly discussed. Finally, cerebellar paraneoplastic disorders and medication-induced cerebellar disorders are discussed. PMID- 25439288 TI - Toxic-metabolic, nutritional, and medicinal-induced disorders of cerebellum. AB - The human cerebellum is composed of 2 hemispheres and a narrow medial section (vermis). Three pairs of dense fiber bundles (peduncles) connect the cerebellum to the brain. The cerebellum possesses widespread outgoing connections. Insult can result in neurologic deficits, including ataxia, hypotonia, dysarthria, and ocular motility problems. It is particularly susceptible to toxic effects of metabolic and medicinal insults. The cerebellum is potentially sensitive to alcohol, drug exposure, illicit drugs, and environmental poisons (mercury, lead, manganese, and toluene/benzene derivatives). The astute clinician must be aware of the multiple potential factors that can adversely affect cerebellar function. PMID- 25439290 TI - Traumatic injury to the posterior fossa. AB - Traumatic injury to the posterior fossa is a complex pathologic condition because of the great heterogeneity of lesions present. Treatment of primary brain injuries and prevention of secondary brain injuries is the mainstay of management. It is imperative to recognize traumatic lesions of the posterior fossa early because of the occurrence of rapid neurologic decline. The decision regarding whether or not to proceed with surgical intervention depends on the patient's clinical condition, neurologic status, and imaging findings. Nonoperative management should be considered only if the patient is fully conscious and the associated posterior fossa lesions are small with little or no mass effect. PMID- 25439291 TI - Multiple sclerosis and the cerebellum. AB - Multiple sclerosis (MS) is an inflammatory, demyelinating disease that has unpredictable symptomatology and severity. Cerebellar manifestations in MS can be present at any time of the clinical course. Early cerebellar findings are a predictor of disability and disease progression. Most patients have cerebellar manifestations once they enter the progressive stages of the disease. Of the cerebellar findings, tremor is by far the most common. PMID- 25439292 TI - Cerebellar infarction. AB - Cerebellar infarction presents with symptoms of nausea, vomiting, and dizziness and thus mimics benign conditions such as viral gastroenteritis or labyrinthitis, which constitutes a good proportion of patients seen in the emergency department. A physician is often faced with the task of identifying the few cases in which cerebellar stroke is the underlying cause instead. In-depth knowledge of the signs and symptoms of cerebellar infarction is therefore essential. Large infarctions or the ones with hemorrhagic conversion can lead to tissue swelling and complications such as obstructive hydrocephalus and brainstem compression. This article summarizes the current multidisciplinary approach to cerebellar stroke. PMID- 25439293 TI - Cerebellar hemorrhage. AB - The clinical presentation of cerebellar hemorrhage can range from symptoms mimicking ischemic stroke to catastrophic neurologic decline. Symptomatology largely depends on the size of the hemorrhage and the degree of perilesional edema. The posterior fossa is a tight compartment with virtually no additional space to accommodate the mass effect. Thus, the hematoma and its associated swelling can cause obstructive hydrocephalus and brainstem compression, in severe cases contributing to early mortality, but outcome can be good if surgical intervention is appropriately timed. This article summarizes the current multidisciplinary approach to cerebellar hemorrhage, and addresses the controversies regarding its optimal management. PMID- 25439294 TI - Neuro-ophthalmic manifestations of cerebellar disease. AB - The cerebellum is responsible for refining ocular movements, thereby guaranteeing the best possible visual acuity and clarity despite changes in body or head positions or movement of the object of interest. The cerebellum is involved in the control of all eye movements, in their real-time, immediate modulation, and in their long-term adaptive calibration. The flocculus-paraflocculus complex and the caudal vermis (nodulus and uvula) together constitute the vestibulocerebellum. Lesions affecting these different regions give rise to 3 principal clinical cerebellar syndromes. This article discusses the various neuro ophthalmic manifestations of various cerebellar disorders, as well as some therapeutic options for oscillopsia. PMID- 25439295 TI - The role of the cerebellum in cognition: beyond coordination in the central nervous system. AB - Our understanding of the contribution of the cerebellum to neurocognition is still in a nascent stage, essentially because of the historical negligence of the nonmotor role of the cerebellum. But it is also because the cerebellum acts primarily as a rather subtle modulator of neurocognitive processes. If this modulating function is impaired, deficits arise that are quantitatively and qualitatively different from the deficits produced by lesions of the supratentorial structures. This article reviews in further detail the current understanding of cognitive deficits associated with cerebellar impairments and unravels its modulating role in cognitive and behavioral processes. PMID- 25439296 TI - The role of the cerebellum in neurobiology of psychiatric disorders. AB - For a long time, cerebellum was only known for its role in movement coordination and until recently, its role in non-motor brain function was largely ignored. Recent evidences has expanded the concept of coordination, from voluntary movements and orientation of the body to nearly every cerebral function including emotion regulation, social cognition, and time perception. This article aims to review the current evidences supporting the role of the cerebellum in the pathophysiology of psychiatric disorders, including studies using volumetric and/or functional imaging techniques, genetic and molecular studies, and clinical reports. The implication of these findings, their potential use, and future directions are also discussed. PMID- 25439297 TI - Infections of the cerebellum. AB - Although the cerebellum can be affected by any infection that also involves other parts of the brain parenchyma, cerebrospinal fluid, or nerve roots, a limited range of infections targets cerebellar structures preferentially. Thus, a primarily cerebellar syndrome narrows infectious differential diagnostic considerations. The differential diagnosis of rapidly evolving cerebellar signs suggesting infection includes prescription or illicit drug intoxications or adverse reactions, inflammatory pseudotumor, paraneoplastic processes, and acute postinfectious cerebellitis. This article discusses the diagnosis and differential diagnosis of viral, bacterial, fungal, and prion pathogens affecting the cerebellum in patterns predictable by pace of illness and by involved neuroanatomic structures. PMID- 25439298 TI - Cerebellar diseases. Preface. PMID- 25439299 TI - Gene and protein expression of oestrogen-beta and progesterone receptors in facial melasma and adjacent healthy skin in women. AB - OBJECTIVE: Compare gene and protein expression for oestrogen receptor-beta (ER beta) and progesterone receptor (PR) in facial melasma and adjacent healthy skin. METHODS: A cross-sectional study including 42 women with facial melasma, conducted at the Dermatology Service of Botucatu Medical School of Sao Paulo State University, Brazil. Biopsies of the melasma skin were performed, together with healthy surrounding skin. The gene expression (real-time PCR) of the hormone receptors in the tissue was evaluated. Subsequently, skin fragments were immunostained for nuclear ER-beta and PR, evaluated according to their HSCORE (epidermis) and percentage of staining per microscopic field (dermis). RESULTS: Messenger RNA tissue expression for ER-beta and PR showed no difference between melasma-affected skin fragments and the healthy perilesional areas (P > 0.2). Median nuclear epithelial expression for ER-beta and PR was higher in lesioned skin (HSCORE 157 and 58) than in the healthy perilesional skin (HSCORE 97 and 19; P < 0.01), with no difference in dermal immunostaining. Nuclear histological expression for ER-beta was associated to sun-induced melasma and negative familiar background; PR expression was associated to sun-induced melasma and darker phototypes. CONCLUSION: No difference was observed in gene expression for oestrogen-beta and progesterone receptors in melasma-affected skin compared with adjacent healthy skin. However, the higher protein expression of these receptors in melasma-affected epithelia suggests hormonal participation in the pathogenesis of this disease. PMID- 25439300 TI - Level of male involvement and associated factors in family planning services utilization among married men in Debremarkos town, Northwest Ethiopia. AB - BACKGROUND: Men's participation is crucial to the success of family planning programs and women's empowerment and associated with better outcomes in reproductive health such as contraceptive acceptance and continuation, and safer sexual behaviors. Limited choice and access to methods, attitudes of men towards family planning, perceived fear of side-effects, poor quality of available services, cultural or religious oppositions and gender-based barriers are some of the reasons for low utilization of family planning. Hence, this study assessed the level of male involvement in family planning services utilization and its associated factors in Debremarkos town, Northwest Ethiopia. METHODS: A community based cross-sectional study was conducted from October to November, 2013. Multi stage sampling technique was used to select 524 eligible samples. Data were collected by using semi-structured questionnaires. Epi Info and SPSS were used to enter and analyze the data; univariate, bivariate and logistic regression analyses were performed to display the outputs. RESULTS: Only 44 (8.4%) respondents were using or directly participating in the use of family planning services mainly male condoms. The reasons mentioned for the low participation were the desire to have more children, wife or partner refusal, fear of side effects, religious prohibition, lack of awareness about contraceptives and the thinking that it is the only issue for women. Opinion about family planning services, men approval and current use of family planning methods were associated with male involvement in the services utilization. CONCLUSIONS: In this study, the level of male involvement was low. Lack of information, inaccessibility to the services and the desire to have more children were found to be the reasons for low male involvement in family planning services utilization. Governmental and nongovernmental organizations, donors and relevant stakeholders should ensure availability, accessibility and sustained advocacy for use of family planning services. The family planning programs should incorporate the responsibility and role of males in the uptake of family planning services. PMID- 25439301 TI - Congenital corneal anesthesia. AB - PURPOSE: To report the various clinical presentations of congenital corneal anesthesia. METHODS: The medical records of children diagnosed with congenital corneal anesthesia between January 2006 and June 2012 at the L.V. Prasad Eye Institute, Hyderabad, India, were retrospectively reviewed for demographics and clinical characteristics. RESULTS: A total of 40 patients (29 males) were included. Median age at presentation was 12 months (interquartile range, 6-60 months). Bilateral involvement was noted in 28 cases (70%). Generalized pain insensitivity with anhidrosis was documented in 10 cases (25%). The spectrum of corneal lesions included geographic epithelial defects (32 eyes), sterile ulcers (15 eyes), sterile ulcers with hypopyon (11 eyes), secondary bacterial keratitis (2 eyes), superficial/ deep corneal vascularisation (5 eyes). Generalized anesthesia with self-mutilating behavior was recognized in 10 cases. In all cases, sterile corneal ulcers resolved on average 30 days after permanent 2/3 width paramedian tarsorrhapy. One eye progressed to the stage of anterior staphyloma and subsequently underwent auto evisceration. Four eyes that underwent keratoplasty for visual rehabilitation had poor outcomes. CONCLUSIONS: Accurate diagnosis, recognition of risk factors, and thorough neurological assessment is important for lessening long-term sequelae of congenital corneal anesthesia. Judicious use of tear substitutes and expedited tarsorrhaphy is crucial to restoration of useful vision in these children. PMID- 25439302 TI - Effect of intraocular pressure control on central corneal thickness, horizontal corneal diameter, and axial length in primary congenital glaucoma. AB - PURPOSE: To assess the effect of intraocular pressure (IOP) control on central corneal thickness (CCT), horizontal corneal diameter (HCD), and axial length (AL) in primary congenital glaucoma (PCG). METHODS: The medical records of children under 10 years of age surgically treated for PCG from 2003 to 2012 were retrospectively reviewed to identify patients with IOP of <=12 mm Hg with a minimum of 6 months' follow-up. Pre- and post-treatment IOP, CCT, HCD, and AL values were correlated and compared with those of healthy age-matched controls. RESULTS: A total of 131 controls and 20 patients (12 bilateral; 8 unilateral) were included. Mean follow-up was 32.4 months. In 24 eyes IOP was controlled by 1 trabeculotomy, with 6 eyes requiring antiglaucoma medication; in 5 eyes, by 2 trabeculotomies, without medication; and in 3 eyes, by 2 trabeculotomies plus 1 with mitomycin-C and 2 eyes requiring antiglaucomatous medication. The mean IOP was 15.69 +/- 5.31 mm Hg preoperatively and 6.16 +/- 2.42 mm Hg at final follow up. Mean pre- and postoperative CCT values were, respectively, 614.38 +/- 89.41 MUm and 548.56 +/- 63.12 MUm; HCD, 13.45 +/- 1.00 mm and 13.98 +/- 1.01 mm, respectively; AL, 24.57 +/- 2.71 mm and 25.37 +/- 2.66 mm, respectively. All differences were statistically significant (P <= 0.002). In 40% of patients, post treatment CCT values were comparable to those of controls; in 6.2%, HCD measurements; and in 26%, AL measurements. Pre- and post-treatment measurements were positively correlated (P <= 0.009). CONCLUSIONS: Controlling IOP had a positive effect on the CCT, HCD, and AL in patients with congenital glaucoma. PMID- 25439304 TI - Sterile subperiosteal fluid collections accompanying orbital wall infarction in sickle-cell disease. AB - Infarction of the orbital wall is an uncommon manifestation of sickle cell disease (SCD) that may mimic an infectious process. We report a patient with two separate orbital infarctions with different presenting symptoms involving different bones. Radiologic-guided sampling of a periosteal fluid collection in the first episode showed likely sterile inflammatory exudates. This case highlights the range of findings in orbital wall infarction in SCD as well as helpful clinical and imaging entities that may differentiate infarction from infection, allowing early diagnosis and appropriate management. PMID- 25439303 TI - Ophthalmologic correlates of disease severity in children and adolescents with Wolfram syndrome. AB - PURPOSE: To describe an ophthalmic phenotype in children at relatively early stages of Wolfram syndrome. METHODS: Quantitative ophthalmic testing of visual acuity, color vision, automated visual field sensitivity, optic nerve pallor and cupping, and retinal nerve fiber layer (RNFL) thickness assessed by optical coherence tomography (OCT) was performed in 18 subjects 5-25 years of age. Subjects were also examined for presence or absence of afferent pupillary defects, cataracts, nystagmus, and strabismus. RESULTS: Subnormal visual acuity was detected in 89% of subjects, color vision deficits in 94%, visual field defects in 100%, optic disk pallor in 94%, abnormally large optic nerve cup:disk ratio in 33%, thinned RNFL in 100%, afferent pupillary defects in 61%, cataracts in 22%, nystagmus in 39%, and strabismus in 39% of subjects. RNFL thinning (P < 0.001), afferent pupillary defects (P = 0.01), strabismus (P = 0.04), and nystagmus (P = 0.04) were associated with more severe disease using the Wolfram United Rating Scale. CONCLUSIONS: Children and adolescents with Wolfram syndrome have multiple ophthalmic markers that correlate with overall disease severity. RNFL thickness measured by OCT may be the most reliable early marker. PMID- 25439305 TI - Improved visual function with dietary intervention in a child with lipemia retinalis. AB - We present a 4.8-year-old female with grade 3 lipemia retinalis due to lipoprotein lipase deficiency, an abnormal electroretinogram, and bilateral decreased visual acuity. Strict dietary intervention resulted in reversal of lipemia retinalis, normalization of her electroretinogram, and improved visual acuity in both eyes. PMID- 25439306 TI - Congenital oculomotor nerve palsy due to effects of carotid artery agenesis. AB - Isolated carotid artery agenesis is not generally recognized as a cause of congenital oculomotor nerve palsy. We report this rare association in 2 children and examine the underlying mechanism. PMID- 25439307 TI - Isolated oculomotor palsy in a child caused by an internal carotid artery aneurysm. PMID- 25439308 TI - Clinical evolution of bilateral Brown syndrome. PMID- 25439309 TI - TOND1 confers tolerance to nitrogen deficiency in rice. AB - Nitrogen (N), the most important mineral nutrient for plants, is critical to agricultural production systems. N deficiency severely affects rice growth and decreases rice yields. However, excessive use of N fertilizer has caused severe pollution to agricultural and ecological environments. The necessity of breeding of crops that require lower input of N fertilizer has been recognized. Here we identified a major quantitative trait locus on chromosome 12, Tolerance Of Nitrogen Deficiency 1 (TOND1), that confers tolerance to N deficiency in the indica cultivar Teqing. Sequence verification of 75 indica and 75 japonica cultivars from 18 countries and regions demonstrated that only 27.3% of cultivars (41 indica cultivars) contain TOND1, whereas 72.7% of cultivars, including the remaining 34 indica cultivars and all 75 japonica cultivars, do not harbor the TOND1 allele. Over-expression of TOND1 increased the tolerance to N deficiency in the TOND1-deficient rice cultivars. The identification of TOND1 provides a molecular basis for breeding rice varieties with improved grain yield despite decreased input of N fertilizers. PMID- 25439310 TI - Hyperfractionated radiotherapy. PMID- 25439311 TI - Patients' acceptability of different fentanyl products for breakthrough cancer pain. PMID- 25439317 TI - Contrast-enhanced ultrasonography to evaluate changes in renal cortical microcirculation induced by noradrenaline: a pilot study. AB - INTRODUCTION: We used contrast-enhanced ultrasound (CEUS) to estimate the effect of an increase in mean arterial pressure (MAP) induced by noradrenaline infusion on renal microvascular cortical perfusion in critically ill patients. METHODS: Twelve patients requiring a noradrenaline infusion to maintain a MAP more than 60 mmHg within 48 hours of intensive care unit admission were included in the study. Renal CEUS scans with destruction-replenishment sequences and Sonovue(r) (Bracco, Milano Italy) as a contrast agent, were performed at baseline (MAP 60 to 65 mmHg) and after a noradrenaline-induced increase in MAP to 80 to 85 mmHg. RESULTS: There was no adverse effect associated with ultrasound contrast agent administration or increase in noradrenaline infusion rate. Adequate images were obtained in all patients at all study times. To reach the higher MAP target, median noradrenaline infusion rate was increased from 10 to 14 MUg/min. Noradrenaline-induced increases in MAP were not associated with a significant change in overall CEUS derived mean perfusion indices (median perfusion index 3056 (interquartile range: 2438 to 6771) arbitrary units (a.u.) at baseline versus 4101 (3067 to 5981) a.u. after MAP increase, P = 0.38). At individual level, however, we observed important heterogeneity in responses (range -51% to +97% changes from baseline). CONCLUSIONS: A noradrenaline-induced increase in MAP was not associated with an overall increase in renal cortical perfusion as estimated by CEUS. However, at individual level, such response was heterogeneous and unpredictable suggesting great variability in pressure responsiveness within a cohort with a similar clinical phenotype. PMID- 25439318 TI - Persistent breast pain following breast cancer surgery is associated with persistent sensory changes, pain interference, and functional impairments. AB - Interindividual variability exists in persistent breast pain following breast cancer surgery. Recently, we used growth mixture modeling to identify 3 subgroups of women (N = 398) with distinct persistent breast pain trajectories (ie, mild, moderate, severe) over 6 months following surgery. The purposes of this study were to identify demographic and clinical characteristics that differed among the breast pain classes and, using linear mixed effects modeling, to examine how changes over time and in sensitivity in the breast scar area, pain qualities, pain interference, and hand and arm function differed among these classes. Several demographic and clinical characteristics differentiated the breast pain classes. Of note, 60 to 80% of breast scar sites tested were much less sensitive than the unaffected breast. Significant group effects were observed for pain qualities and interference scores, such that, on average, women in the severe pain class reported higher scores than women in the moderate pain class. In addition, women in the moderate pain class reported higher scores than women in the mild pain class. Compared to women in the mild pain class, women in the severe pain class had significantly impaired grip strength, and women in the moderate and severe pain classes had impaired flexion and abduction. PERSPECTIVE: Subgroups of women with persistent postsurgical breast pain differed primarily with respect to the severity rather than the nature or underlying mechanisms of breast pain. Pervasive sensory loss and the association between persistent breast pain and sustained interference with function suggest the need for long-term clinical follow-up. PMID- 25439319 TI - Persistent arm pain is distinct from persistent breast pain following breast cancer surgery. AB - Persistent pain following breast cancer surgery is well documented. However, it is not well characterized in terms of the anatomic site affected (ie, breast, arm). In 2 separate growth mixture modeling analyses, we identified subgroups of women (N = 398) with distinct breast pain and arm pain trajectories. The fact that these latent classes differed by anatomic site, types of tissue affected, and neural innervation patterns suggests the need for separate evaluations of these distinct persistent pain conditions. The purposes of this companion study were to identify demographic and clinical characteristics that differed between the 2 arm pain classes and determine if differences existed over time in sensitivity in the upper inner arm and axillary lymph node dissection sites, pain qualities, pain interference, and hand and arm function, as well as to compare findings with persistent breast pain. Higher occurrence rates for depression and lymphedema were found in the moderate arm pain class. Regardless of pain group membership, sensory loss was observed in the upper inner arm and axillary lymph node dissection site. Arm pain was described similarly to neuropathic pain and interfered with daily functioning. Persistent arm pain was associated with sustained impairments in shoulder mobility. PERSPECTIVE: For persistent breast and arm pain, changes in sensation following breast cancer surgery were notable. Persistent arm pain was associated with sustained interference with daily functioning and upper body mobility impairments. Long-term management of persistent pain following breast cancer surgery is warranted to improve the quality of survivorship for these women. PMID- 25439320 TI - Transcriptional adaptations during long-term persistence of Staphylococcus aureus in the airways of a cystic fibrosis patient. AB - The lungs of Cystic fibrosis (CF) patients are often colonized and/or infected by Staphylococcus aureus for years, mostly by one predominant clone. For long-term survival in this environment, S. aureus needs to adapt during its interactions with host factors, antibiotics, and other pathogens. Here, we study long-term transcriptional as well as genomic adaptations of an isogenic pair of S. aureus isolates from a single patient using RNA sequencing (RNA-Seq) and whole genome sequencing (WGS). Mimicking in vivo conditions, we cultivated the S. aureus isolates using artificial sputum medium before harvesting RNA for subsequent analysis. We confirmed our RNA-Seq data using quantitative real-time (qRT)-PCR and additionally investigated intermediate isolates from the same patient representing in total 13.2 years of persistence in the CF airways. Comparative RNA-Seq analysis of the first and the last ("late") isolate revealed significant differences in the late isolate after 13.2 years of persistence. Of the 2545 genes expressed in both isolates that were cultivated aerobically, 256 genes were up- and 161 were down-regulated with a minimum 2-fold change (2f). Focusing on 25 highly (>=8f) up- (n=9) or down- (n=16) regulated genes, we identified several genes encoding for virulence factors involved in immune evasion, bacterial spread or secretion (e.g. spa, sak, and esxA). Moreover, these genes displayed similar expression trends under aerobic, microaerophilic and anaerobic conditions. Further qRT-PCR-experiments of highly up- or down-regulated genes within intermediate S. aureus isolates resulted in different gene expression patterns over the years. Using sequencing analysis of the differently expressed genes and their upstream regions in the late S. aureus isolate resulted in only few genomic alterations. Comparative transcriptomic analysis revealed adaptive changes affecting mainly genes involved in host-pathogen interaction. Although the underlying mechanisms were not known, our results suggest adaptive processes beyond genomic mutations triggered by local factors rather than by activation of global regulators. PMID- 25439321 TI - Ileal neuroendocrine tumors show elevated activation of mammalian target of rapamycin complex. AB - BACKGROUND: Neuroendocrine tumors (NETs) of the ileum are sporadic tumors derived from submucosal gastrointestinal stem cells. They often show clinical symptoms only after hepatic metastasation when curative therapy is limited or impossible. In this study, we analyzed the expression of the candidate genes mammalian target of rapamycin (mTOR), alpha thalassemia/mental retardation syndrome X-linked (ATRX), and death domain-associated protein (DAXX) to investigate the specific oncogenetics and potential therapeutic options for ileal NETs. METHODS: In a prospective database, all patients who underwent surgical removal of a NET of the ileum between 2001 and 2011 were specified. Expression analysis was performed for mTOR, ATRX, and DAXX by immunohistochemistry of paraffin-embedded tumor samples. To evaluate the results the immunoreactive score was applied. Normal tissue and tumor tissue were analyzed for the comparison of gene expression levels using quantitative-real-time polymerase chain reaction for ATRX and mTOR genes. Results were correlated under pathologic and clinical aspects. RESULTS: A total of 69 patients were admitted to the study. Positive cytosolic expression of the potential oncogene mTOR was immunohistochemically detected in 76.2% of the human probes. A loss of nuclear ATRX expression was detected in 13.0% of the samples. A nonexpression of the DAXX-protein in cell nuclei was not found (0%). Gene transcript levels did not show a significant alteration in ileal NETs in comparison with normal tissue. CONCLUSIONS: mTOR is overexpressed in ileal NETs. Additionally, the loss of ATRX expression was registered, thus underlying a tumorigenic role in a subgroup of these tumors. To enable potential therapeutic application of mTOR inhibitors, further trials with larger study groups are needed. PMID- 25439323 TI - Biologicals, platelet apoptosis and human diseases: An outlook. AB - Platelets, once considered mediators of hemostasis and thrombosis, are now known to be involved in wound healing, inflammation, cardiovascular diseases, diabetes, arthritis, and cancer. Recent reports attest that platelets possess the cellular machinery to undergo apoptosis and that platelet apoptosis can be triggered by myriad stimuli including chemical and physical agonists, and pathophysiological conditions. Augmented rate of platelet apoptosis leads to thrombocytopenia, bleeding disorders and microparticle generation. Despite knowing the significant role of platelets in health and disease, and that any alterations in platelet functions can wreak havoc to the health, the offshoot reactions of therapeutic drugs on platelets and the far-reaching consequences are often neglected. The present review focuses on the impact of platelet apoptosis and the role of platelet-derived microparticles on different pathophysiological conditions. It also touches upon the effects of biologicals on platelets, and discusses the need to overcome the adverse effects of pro-apoptotic drugs through auxiliary therapy. PMID- 25439322 TI - Luminal solutions protect mucosal barrier during extended preservation. AB - BACKGROUND: Mucosal barrier injury during intestinal preservation (IP) and transplantation favors life-threatening infections. Luminal delivery of solutions containing amino acids or polyethylene glycols (PEGs) may improve preservation results and reduce this injury. We tested if solutions containing glutamine and PEG influence the mucosal injury. MATERIALS AND METHODS: Rat intestines were perfused and stored in Viaspan-University of Wisconsin solution. Before IP, a PEG 3350 solution was introduced intraluminally alone (group 1) or supplemented with 40 mmol/L L-glutamine (group 2). Controls underwent vascular flush alone (group 3). Preservation injury was evaluated after 8, 14, and 24 h by histology and goblet cell count. Tight-junction proteins zonula occludens-1, claudin-3, claudin 4, and caveolin-1 were studied by immunofluorescence. Maltase and caspase-3 activity were also analyzed. RESULTS: Group 1 showed mild edema at 8 h and mucosal disruption by 24 h; these features were greatly improved in group 2 where continuous mucosa was found after 24 h of IP. Intestines in group 3 did worse at all time points with subepithelial edema (Park/Chiu grade 3) and marked goblet cell depletion; caspase-3 activity was lowest in group 2. Tight-junction proteins varied continuously during IP; zonula occludens-1 expression and colocalization with claudins decreased significantly in group 3 but not in other groups. Claudin 3 was distinctly localized in the membrane, but stained diffuse, cytoplasmic at later time-points. Claudin-4 changed to a cytoplasmic granular pattern. No caveolin-1 colocalization was observed. CONCLUSIONS: Luminal PEG and glutamine delay epithelial breakdown and preserve several important mucosal features during extended IP. PMID- 25439324 TI - Resolving whether botanic gardens are on the road to conservation or a pathway for plant invasions. AB - A global conservation goal is to understand the pathways through which invasive species are introduced into new regions. Botanic gardens are a pathway for the introduction of invasive non-native plants, but a quantitative assessment of the risks they pose has not been performed. I analyzed data on the living collections of over 3000 botanic gardens worldwide to quantify the temporal trend in the representation of non-native species; the relative composition of threatened, ornamental, or invasive non-native plant species; and the frequency with which botanic gardens implement procedures to address invasive species. While almost all of the world's worst invasive non-native plants occurred in one or more living collections (99%), less than one-quarter of red-listed threatened species were cultivated (23%). Even when cultivated, individual threatened species occurred in few living collections (7.3), while non-native species were on average grown in 6 times as many botanic gardens (44.3). As a result, a botanic garden could, on average, cultivate four times as many invasive non-native species (20) as red-listed threatened species (5). Although the risk posed by a single living collection is small, the probability of invasion increases with the number of botanic gardens within a region. Thus, while both the size of living collections and the proportion of non-native species cultivated have declined during the 20th century, this reduction in risk is offset by the 10-fold increase in the number of botanic gardens established worldwide. Unfortunately, botanic gardens rarely implement regional codes of conduct to prevent plant invasions, few have an invasive species policy, and there is limited monitoring of garden escapes. This lack of preparedness is of particular concern given the rapid increase in living collections worldwide since 1950, particularly in South America and Asia, and highlights past patterns of introduction will be a poor guide to determining future invasion risks. PMID- 25439325 TI - Trends in kidney transplant outcomes in older adults. AB - OBJECTIVES: To estimate mortality and death-censored graft loss according to year of kidney transplant (KT) between 1990 and 2011. DESIGN: Cohort study. SETTING: The Scientific Registry of Transplant Recipients (SRTR). PARTICIPANTS: KT recipients aged 65 and older at the time of transplantation (N = 30,207). MEASUREMENTS: Mortality and death-censored graft loss ascertained through center report and linkage to Social Security Death Master File and to Medicare. RESULTS: Older adults currently account for 18.4% of KT recipients, up from 3.4% in 1990; similar increases were noted for deceased donor (5.4 times percentage increase) and live donor (9.1 times percentage increase) transplants. Current recipients are not only older, but also more likely to be female and African American, have lengthier pretransplant dialysis, have diabetes mellitus or hypertension, and receive marginal kidneys. Mortality for older deceased donor recipients between 2009 and 2011 was 57% lower (hazard ratio (HR) = 0.43, 95% confidence interval (CI) = 0.33-0.56, P < .001) than between 1990 and 1993; mortality for older live donor recipients was 50% lower (HR = 0.50, 95% CI = 0.36-0.68, P < .001). Death censored graft loss for older deceased donor recipients between 2009 and 2011 was 65% lower (HR = 0.35, 95% CI = 0.29-0.42, P < .001) than between 1990 and 1993; death-censored graft loss for older live donor recipients was 59% lower (HR = 0.41, 95% CI = 0.24-0.70, P < .001). CONCLUSION: Despite a major increase in number of older adults transplanted and an expanding window of transplant eligibility, mortality and graft loss have decreased substantially for this recipient population. These trends are important to understand for patient counseling and transplant referral. PMID- 25439326 TI - Concurrent and lasting effects of emotion regulation on amygdala response in adolescence and young adulthood. AB - This study used functional MRI (fMRI) to examine a novel aspect of emotion regulation in adolescent development: whether age predicts differences in both the concurrent and lasting effects of emotion regulation on amygdala response. In the first, active regulation, phase of the testing session, fMRI data were collected while 56 healthy individuals (age range: 10.50-22.92 years) reappraised aversive stimuli so as to diminish negative responses to them. After a short delay, the second, re-presentation, phase involved passively viewing the aversive images from the reappraisal task. During active regulation, older individuals showed greater drops in negative affect and inverse rostrolateral prefrontal amygdala connectivity. During re-presentation, older individuals continued to show lasting reductions in the amygdala response to aversive stimuli they had previously reappraised, an effect mediated by rostrolateral PFC. These data suggest that one source of heightened emotionality in adolescence is a diminished ability to cognitively down-regulate aversive reactions. PMID- 25439329 TI - Critical limb ischemia. AB - Critical limb ischemia (CLI), the most advanced form of peripheral artery disease (PAD), carries grave implications with regard to morbidity and mortality. Within 1 year of CLI diagnosis, 40% to 50% of diabetics will experience an amputation, and 20% to 25% will die. Management is optimally directed at increasing blood flow to the affected extremity to relieve rest pain, heal ischemic ulcerations, avoid limb loss, and prevent cardiovascular events. This management is achieved by guideline-directed medical therapy and risk factor modification, whereas the mainstay of therapy remains revascularization by endovascular or surgical means for patients who are deemed potential candidates. PMID- 25439330 TI - Contemporary treatment of venous thromboembolic disease. AB - Venous thromboembolism (VTE) is a potentially fatal condition and includes deep vein thrombosis and pulmonary embolism. The novel oral anticoagulants, which include the direct thrombin and factor Xa inhibitors, have been shown to be safe and effective for the treatment of VTE. Additional interventions include thrombolysis and the use of inferior vena cava filters. The purpose of this article is to provide a contemporary review of the treatment of VTE. PMID- 25439331 TI - Renal artery stenosis. AB - Atherosclerotic renal artery stenosis (RAS) is the single largest cause of secondary hypertension; it is associated with progressive renal insufficiency and causes cardiovascular complications such as refractory heart failure and flash pulmonary edema. Medical therapy, including risk factor modification, renin angiotensin-aldosterone system antagonists, lipid-lowering agents, and antiplatelet therapy, is advised in all patients. Patients with uncontrolled renovascular hypertension despite optimal medical therapy, ischemic nephropathy, and cardiac destabilization syndromes who have severe RAS are likely to benefit from renal artery revascularization. Screening for RAS can be done with Doppler ultrasonography, CT angiography, and magnetic resonance angiography. PMID- 25439327 TI - Sigma receptor 1 activation attenuates release of inflammatory cytokines MIP1gamma, MIP2, MIP3alpha, and IL12 (p40/p70) by retinal Muller glial cells. AB - The high-affinity sigma receptor 1 (sigmaR1) ligand (+)-pentazocine ((+)-PTZ) affords profound retinal neuroprotection in vitro and in vivo by a yet-unknown mechanism. A common feature of retinal disease is Muller cell reactive gliosis, which includes cytokine release. Here, we investigated whether lipopolysaccharide (LPS) stimulates cytokine release by primary mouse Muller cells and whether (+) PTZ alters release. Using a highly sensitive inflammatory antibody array we observed significant release of macrophage inflammatory proteins (MIP1gamma, MIP2, MIP3alpha) and interleukin-12 (IL12 (p40/p70)) in LPS-treated cells compared to controls, and a significant decrease in secretion upon (+)-PTZ treatment. Muller cells from sigmaR1 knockout mice demonstrated increased MIP1gamma, MIP2, MIP3alpha and IL12 (p40/p70) secretion when exposed to LPS compared to LPS-stimulated WT cells. We investigated whether cytokine secretion was accompanied by cytosolic-to-nuclear NFkappaB translocation and whether endothelial cell adhesion/migration was altered by released cytokines. Cells exposed to LPS demonstrated increased NFkappaB nuclear location, which was reduced significantly in (+)-PTZ-treated cells. Media conditioned by LPS stimulated-Muller cells induced leukocyte-endothelial cell adhesion and endothelial cell migration, which was attenuated by (+)-PTZ treatment. The findings suggest that release of certain inflammatory cytokines by Muller cells can be attenuated by sigmaR1 ligands providing insights into the retinal neuroprotective role of this receptor. PMID- 25439332 TI - Resistant hypertension: medical management and alternative therapies. AB - Resistant hypertension affects 20% to 30% of patients with high blood pressure (BP). It is defined as failure to achieve goal BP despite using at least 3 antihypertensive drugs of different classes, at maximal tolerated doses, one of which must be a diuretic. Persistent suboptimal BP is the most common attributable risk for death worldwide and its prevalence will most likely increase over the next decade. We review the epidemiologic aspects and diagnostic challenges of resistant hypertension, barriers to achieving proper BP control, and causes of secondary hypertension. Lifestyle modification and pharmacologic and device approaches to treatment are discussed. PMID- 25439333 TI - Advances in peripheral arterial disease endovascular revascularization. AB - Significant advances have been made in the endovascular treatment of lower extremity arterial occlusive disease. Since the 2011 update, technologies has developed and allowed for the revascularization of complex vascular lesions. Although this technical success is encouraging, these technologies must provide measurable long-term clinical success at a reasonable cost. Large, randomized, controlled trials need to be designed to focus on clinical outcomes and success rates for treatment. These future studies will serve as the guide by which clinicians can provide the most successful clinical and cost effect care in treating patients with lower-extremity peripheral artery disease. PMID- 25439334 TI - Reperfusion therapy in the acute management of ischemic stroke. AB - Reperfusion, or restoration of blood flow, is an effective means of reducing disability in the setting of acute stroke. Reperfusion therapies, such as intravenous thrombolysis or endovascular and interventional procedures, fit within the existing stroke system of care. There are currently 4 devices cleared by the Food and Drug Administration for recanalization of arterial occlusion in patients with ischemic stroke. Endovascular device technology and advanced imaging technology continue to evolve with newer devices suggesting greater recanalization success. A new paradigm using advanced imaging to select patients in combination with newer devices is being tested and may lead to great improvements in care. PMID- 25439335 TI - Contemporary medical management of peripheral arterial disease: a focus on risk reduction and symptom relief for intermittent claudication. AB - Peripheral arterial disease (PAD) is primarily caused by progressive systemic atherosclerosis manifesting in the lower extremities. This review addresses the epidemiology, clinical presentation and evaluation, and medical management of PAD, with a focus on intermittent claudication. Key advances in the recognition of cardiovascular risk in asymptomatic individuals with mildly abnormal ankle brachial index, newer reflections on exercise therapy, and a review of established and investigational agents for the treatment of symptomatic PAD, such as cilostazol, statins, and angiotensin-converting enzyme inhibitors, are highlighted. PMID- 25439336 TI - Preoperative cardiovascular evaluation in patients undergoing vascular surgery. AB - Vascular surgery is associated with a higher incidence of perioperative cardiovascular morbidity and mortality compared with other noncardiac surgeries. Patients undergoing vascular surgery represent a higher-risk population, usually because of the presence of generalized arterial disease and multiple comorbidities. The overwhelming perioperative cardiac event is myocardial infarction. This article offers a tailored approach to preoperative cardiovascular management for patients undergoing vascular surgery. The use and limitations of well-established guidelines and clinical risk indices for patients undergoing noncardiac surgery are described as it pertains to vascular surgery in particular. Furthermore, the role and benefit of noninvasive stress testing, coronary revascularization, and medical therapy before vascular surgery are discussed. PMID- 25439337 TI - Peripheral drug-eluting technology. AB - This article reviews current knowledge and applications of drug-eluting devices in the treatment of peripheral arterial disease. The authors briefly report on the performance of plain old balloon angioplasty and bare metal stents in femoro popliteal and below-the-knee lesions. This article explains the rationale behind the development of drug-eluting devices and describes the main technical features of currently available drug-eluting stents and drug-coated balloons. Dedicated sections discuss the results of trials investigating the potential benefits of these devices used in femoro-popliteal and infra-popliteal arterial vascular beds. Finally, ongoing studies and potential novel applications of drug-eluting technologies in other vascular beds are mentioned. PMID- 25439338 TI - Vascular disease. Preface. PMID- 25439328 TI - Management of extracranial carotid artery disease. AB - Stroke is the third leading cause of death in developed nations. Up to 88% of strokes are ischemic in nature. Extracranial carotid artery atherosclerotic disease is the third leading cause of ischemic stroke in the general population and the second most common nontraumatic cause among adults younger than 45 years. This article provides comprehensive, evidence-based recommendations for the management of extracranial atherosclerotic disease, including imaging for screening and diagnosis, medical management, and interventional management. PMID- 25439339 TI - Clinically significant fatigue after stroke: a longitudinal cohort study. AB - OBJECTIVE: Fatigue is often distressing for stroke survivors. The time course of clinically significant fatigue in the first year after stroke is uncertain. We aimed to determine the frequency, severity and time course of clinically significant fatigue in the first 12 months after stroke onset. METHODS: We recruited patients with a recent acute stroke. At about one month, six months and 12 months, we performed a structured interview to identify clinically significant fatigue (case definition), and assessed fatigue severity (Fatigue Assessment Scale (FAS)). RESULTS: Of 157 patients who initially consented, 136 attended at least one assessment. At one month, 43/132 (33%) had clinically significant fatigue. Eighty-six attended all three assessments, of whom clinically significant fatigue was present in 24 (28%) at one month, 20 (23%) at six months and 18 (21%) at 12 months; their median (IQR) FAS scores were 23 (18 to 29), 21 (17 to 25) and 22.5 (17 to 28) at one, six and 12 months respectively. Of 101 patients who attended at least the one and six month assessments, fatigue status did not change in 65 (64%), with 9 (9%) fatigued throughout and 56 (55%) non fatigued throughout; 15 (15%) became non-fatigued, 9 (9%) became fatigued, and in 12 (12%) fatigue status fluctuated across three assessments. CONCLUSION: Clinically significant fatigue affected a third of patients one month after stroke. About two thirds of these patients had become non-fatigued by six months, most of whom remained non-fatigued at 12months. Fatigue persists in a third at 12 months. PMID- 25439340 TI - Intranasal oxytocin enhances positive self-attribution in healthy men. AB - OBJECTIVE: A growing body of studies consistently demonstrates that social responsiveness toward others is influenced by the neurohormone oxytocin. However, the potential role of oxytocin for self-perception remains relatively unexplored. Thus, we investigated whether oxytocin administration influences the self attribution of positive and negative adjectives at the early, effortful stage of self-related information processing. METHODS: Sixty healthy male participants received either 24I.U. oxytocin or a placebo in a randomized double-blind study before completing a sorting task, in which they were instructed to co-classify, as fast as possible, positive and negative adjectives into either self or non self categories. RESULTS: Oxytocin-treated participants reported stronger positive attitudes toward themselves compared to placebo. CONCLUSIONS: The present findings demonstrate that oxytocin administration influences the early stage of self-related information processing and suggests that the oxytocinergic system might be involved in psychopathological conditions characterized by a negative representation of self. PMID- 25439341 TI - Saliva pH as a biomarker of exam stress and a predictor of exam performance. AB - BACKGROUND: Salivary pH is regulated by the sympathetic and parasympathetic nervous system; therefore, it may serve as a biomarker of stress. AIMS: To assess the associations between the cognitive and emotional dimensions of exam stress and pH levels, and the predictability of salivary pH in relation to test performance. METHODS: A prospective study. Eighty-three nursing students answered a questionnaire on stress appraisals, experienced stress, test anxiety (including worry and emotionality subscales) and health behaviors, and gave a saliva sample for measuring pH on the morning of their first term exam and three months later. Their performance on the test (grades) was also recorded. RESULTS: Levels of pH in saliva were higher (levels of acidity were lower) in the post exam compared to the exam period, in parallel to lower threat appraisal, experienced stress, and test anxiety levels post exam. Controlling for smoking, physical activity and working hours per week, pH levels at both time points were predicted by appraised threat regarding the exam situation, experienced stress, and the emotionality dimension of test anxiety. pH at Time 1 predicted performance on the exams and mediated the associations of experienced stress and emotionality subscale with test performance. CONCLUSIONS: the present study indicates that pH levels may serve as a reliable, accessible and inexpensive means by which to assess the degree of physiological reactions to exams and other naturalistic stressors. PMID- 25439346 TI - Diffuse large B-cell lymphoma occurring in an ovarian cystic teratoma: expanding the spectrum of large B-cell lymphoma associated with chronic inflammation. AB - Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is a well-recognized entity, originally recorded as pyothorax-associated lymphoma because of the association with artificial pneumothorax. Clinically, it is characterized by a mass arising in a long-standing inflammation and by a poor prognosis. Recently, DLBCL-CI has been described growing along the wall of a preexisting cyst, without forming a mass. Here we describe a case of DLBCL-CI arising in the wall of a mature cystic teratoma of the ovary. On histology, the cystic surface of the cyst was infiltrated by large lymphocytes, immunoreacting with CD20, Multiple Myeloma Oncogene-1/Interferon Regulating Factor-4 (MUM1/IRF4), and PAX5 and positive for Epstein-Barr virus. "Cystic" DLBCL-CIs usually hold an indolent behavior despite heterogeneous therapeutic approaches. Some authors understandably wonder whether patients affected by "cystic" DLBCL CIs are at risk for overtreatment, and, consequently, DLBCL-CIs associated with cystic lesions should be classified as an entity separated from classic pyothorax associated lymphomas. PMID- 25439347 TI - Comments on De Boer JE et al. The global burden and stigma of epilepsy. Epilepsy & behavior 2008;12:540-546. PMID- 25439348 TI - Comments on Harden CL et al. A pilot study of mood in epilepsy patients treated with vagus nerve stimulation. Epilepsy & behavior 2000;1:93-99. PMID- 25439350 TI - Impact of physical exercise therapy on behavioral and psychosocial aspects of epilepsy. PMID- 25439351 TI - The allergic asthma phenotype. AB - Allergic asthma is the most common asthma phenotype. It usually is defined by the presence of sensitization to environmental allergens, although a clinical correlation between exposure and symptoms further supports the diagnosis. The average age of onset of allergic asthma is younger than that of nonallergic asthma. Although the spectrum of allergic asthma may vary from mild to severe, studies have reported that allergic versus nonallergic asthma is less severe. There is an increased prevalence of allergic rhinoconjunctivitis and atopic dermatitis in patients with allergic asthma. Total IgE levels usually are higher in allergic versus nonallergic asthma, but levels substantially overlap between the 2 groups. Increased Th2 cytokines have been demonstrated in secretions and peripheral blood of patients with allergic asthma. Atopy has been reported to be inversely associated with persistent airflow obstruction and airway remodeling. Clusters with a high prevalence of early onset atopic asthma have been frequently reported in statistical phenotyping studies, but the various clusters of patients with atopy were quite heterogeneous in terms of symptom severity, pulmonary function, and tendency for exacerbations. Implications for future research regarding the allergic asthma phenotype are described. PMID- 25439352 TI - Asthma phenotypes: nonallergic (intrinsic) asthma. AB - The definition of nonallergic asthma includes that subset of subjects with asthma and with whom allergic sensitization cannot be demonstrated. These individuals should have negative skin prick test or in vitro specific-IgE test to a panel of seasonal and perennial allergens. Nonallergic asthma occurs in 10% to 33% of individuals with asthma and has a later onset than allergic asthma, with a female predominance. Nonallergic asthma appears to be more severe than allergic asthma in many cases and may be less responsive to standard therapy. Although many of the immunopathologic features of nonallergic asthma are similar to those observed with allergic asthma, some differences have been described, including a higher expression of RANTES in mucosa and bronchoalveolar lavage fluid, as well as a higher GM-CSF receptor alpha expression. Unbiased statistical methods, such as cluster analysis and latent class analysis, indicate that the lack of atopy is not the most important defining factor in assigning an individual to many specific phenotypes but rather is more important in some phenotypes than others, and appears to modulate the clinical expression of the disease. Despite an appreciation of this clinical entity for many years, many of its clinical implications remain unclear. PMID- 25439353 TI - Aspirin or other nonsteroidal inflammatory agent exacerbated asthma. AB - Aspirin-exacerbated respiratory disease (AERD) is an asthma phenotype with a prevalence that ranges from 2% to 25% of the asthma population. The 2% prevalence applies to patients with mild and 25% to severe, persistent asthma. COX-1 inhibiting nonsteroidal anti-inflammatory drugs, including aspirin, aggravate the preexisting upper and lower respiratory disease, sometimes in a life-threatening manner. The upper airway disease is characterized by an eosinophilic, hyperplastic rhinosinusitis with polyps. Eosinophilia, both peripheral and in the airways with Th2 inflammation, characterizes this disease. The role of allergic sensitivity in AERD is unclear, even though more than 30% of affected patients produce specific IgE to environmental allergens. Clinically, the respiratory symptoms are not usually associated with allergen exposure. The mechanism responsible for this phenotype is likely related to leukotriene (LT) metabolism because patients who are affected compared with patients who were aspirin tolerant, produce greater amounts of cysteinyl LTs. The synthesis of cysteinyl LTs is further increased after aspirin challenge and symptom exacerbation. Eosinophilia as well as a variety of other biologic markers, for example, Th2 cytokines, peripheral blood periostin, and LT enzymes and receptors, are associated with AERD both in the blood and in respiratory mucosa. These markers may help identify patients with AERD, but aspirin or other nonsteroidal anti inflammatory drugs challenge is the primary means to confirm the diagnosis. A variety of single nucleotide polymorphisms and genes are associated with AERD, but the studies to date are limited to select populations and have not conclusively demonstrated a uniform genetic pattern in subjects with this disease. Treatment of AERD can be challenging because the nasal symptoms, including polyposis, are often refractory to both surgery and medical treatment, and the asthma can be difficult to control. Aspirin desensitization, followed by daily aspirin administration, can improve both upper and lower respiratory tract symptoms in up to 60% of individuals. PMID- 25439355 TI - Childhood asthma-predictive phenotype. AB - Wheezing is a fairly common symptom in early childhood, but only some of these toddlers will experience continued wheezing symptoms in later childhood. The definition of the asthma-predictive phenotype is in children with frequent, recurrent wheezing in early life who have risk factors associated with the continuation of asthma symptoms in later life. Several asthma-predictive phenotypes were developed retrospectively based on large, longitudinal cohort studies; however, it can be difficult to differentiate these phenotypes clinically as the expression of symptoms, and risk factors can change with time. Genetic, environmental, developmental, and host factors and their interactions may contribute to the development, severity, and persistence of the asthma phenotype over time. Key characteristics that distinguish the childhood asthma predictive phenotype include the following: male sex; a history of wheezing, with lower respiratory tract infections; history of parental asthma; history of atopic dermatitis; eosinophilia; early sensitization to food or aeroallergens; or lower lung function in early life. PMID- 25439354 TI - Infection-related asthma. AB - The role of infection in asthma is varied in that it may exacerbate established asthma or contribute to the initial development of the clinical onset of asthma. Mounting evidence implicates both roles with particular viral pathogens, namely human rhinovirus and respiratory syncytial virus, among the most likely culprits in asthma inception. Once asthma is present, infection, particularly viral infection, is a common precipitant of asthma exacerbations. Bacterial infections and colonization also have been associated with exacerbation and recurrent wheeze, an effect that may be independent or a cofactor with viruses. Atypical bacterial infections such as Mycoplasma pneumoniae and Chlamydia pneumoniae and fungi in the case of allergic bronchopulmonary aspergillosis, also play a potential role in inducing and exacerbating this disease. In addition, certain individuals may have a genetic predisposition toward viral-induced wheezing and the development of asthma. This article will discuss host and environmental factors, common pathogens, clinical characteristic, and genetic influences associated with infection-related asthma. PMID- 25439356 TI - Developing and emerging clinical asthma phenotypes. AB - For more than a century, clinicians have attempted to subdivide asthma into different phenotypes based on triggers that cause asthma attacks, the course of the disease, or the prognosis. The first phenotypes that were described included allergic asthma, intrinsic or nonallergic asthma, infectious asthma, and aspirin exacerbated asthma. These phenotypes are being reviewed elsewhere in this issue of the journal. The present article focuses on developing and emerging clinical asthma phenotypes. First, asthma phenotypes that are associated with environmental exposures (occupational agents, cigarette smoke, air pollution, cold dry air); second, asthma phenotypes that are associated with specific symptoms or clinical characteristics (cough, obesity, adult onset of disease); and third, asthma phenotypes that are based on biomarkers. This latter approach is the most promising because it attempts to identify asthma phenotypes with different underlying mechanisms so that therapies can be better targeted toward disease-specific features and disease outcomes can be improved. PMID- 25439357 TI - Asthma phenotypes: an approach to the diagnosis and treatment of asthma. AB - I teach that "Asthma is the most treatable of all chronic diseases known to mankind." Yet, outcome data from throughout the world (emergency department visits, hospitalizations, and quality of life) indicate that the diagnosis and treatment of asthma are not optimal and need improvement. Why? First, asthma is not thought of as a complex, heterogeneous disease or syndrome that consists of different phenotypes and endotypes. Second, asthma is variable, particularly in its severity, and is influenced by known, unknown, avoidable, and unavoidable environmental factors. Third, treatment usually requires complex inhalational devices that are difficult to understand and use, and with which adherence is suboptimal. Continued education on how to appropriately use medications, particularly inhaled medications, is absolutely essential, and knowledge and access to a backup treatment plan to be initiated by the patient for an asthma flare is necessary. Fourth, assessment of asthma is primarily based on symptoms, and, at times, all symptoms are due to asthma, but many times some or all symptoms are due to unrecognized and untreated comorbid or coexisting conditions. Too often, asthma is viewed as a disease that occurs in isolation, and comorbid and coexisting conditions are not appropriately identified and treated. Allergists/immunologists are well suited to provide the type of comprehensive care required to optimize asthma outcomes for the benefit of individual patients and society. PMID- 25439358 TI - Oral manifestations of allergic, infectious, and immune-mediated disease. AB - Patients often have oral symptoms, and physicians frequently identify lesions during routine oral examination. Being able to associate these concerns and findings with systemic disease is important to providing effective management of these conditions. This review summarizes the etiology, presentation, and treatment of many oral lesions associated with systemic diseases and infections. The primary focus was on lesions associated with allergic, infectious, and immune mediated disease; however, other common concerns are addressed as well as lesions that may be misinterpreted as disease and how to address unknown lesions. PMID- 25439359 TI - Fiscal implications of newborn screening in the diagnosis of severe combined immunodeficiency. AB - In the United States, newborn screening (NBS) is currently recommended for identification of 31 debilitating and potentially fatal conditions. However, individual states determine which of the recommended conditions are screened. The addition of severe combined immunodeficiency (SCID) screening to the recommended NBS panel has been fully instituted by 18 states, with another 11 states piloting programs or planning to begin screening in 2014. Untreated, SCID is uniformly fatal by 2 years of age. Hematopoietic stem cell transplantation usually is curative, but the success rate depends on the age at which the procedure is performed. Short-term implementation costs may be a barrier to adding SCID to states' NBS panels. A retrospective economic analysis was performed to determine the cost-effectiveness of NBS for early (<3.5 months) versus late (>=3.5 months) treatment of children with SCID at 3 centers over 5 years. The mean total charges at these centers for late treatment were 4 times greater than early treatment ($1.43 million vs $365,785, respectively). Mean charges for intensive care treatments were >5 times higher ($350,252 vs $66,379), and operating room anesthesia charges were approximately 4 times higher ($57,105 vs $15,885). The cost-effectiveness of early treatment for SCID provides a strong economic rationale for the addition of SCID screening to NBS programs of other states. PMID- 25439360 TI - Allergic bronchopulmonary aspergillosis. AB - There remains a lack of agreement on diagnostic criteria and approaches to treatment of patients with allergic bronchopulmonary aspergillosis (ABPA). The results of a survey of American Academy of Allergy, Asthma, & Immunology members regarding these 2 issues are presented and compared for concordance with published recommendations. The literature was reviewed for pertinent reports, and an electronic survey was conducted of American Academy of Allergy, Asthma, & Immunology members and fellows regarding diagnostic criteria, numbers of patients evaluated for ABPA, and treatment approaches. From 508 respondents to the survey sent to 5155 US physicians in the American Academy of Allergy, Asthma, & Immunology database of members and fellows, 245 health professionals (48%) had treated at least 1 patient with ABPA in the previous year. For the diagnosis of ABPA, there was a difference in the threshold concentration of total serum IgE because 44.9% used >=417 kU/L, whereas 42.0% used >=1000 kU/L. Analysis of these findings suggests that ABPA might be underdiagnosed. With regard to pharmacotherapy, oral steroids were recommended for 97.1% of patients and oral steroids plus inhaled corticosteroids plus antifungal agent were used with 41.2% of patients. The armamentarium for treatment of ABPA includes oral corticosteroids as the initial treatment with inhaled corticosteroids used for management of persistent asthma. Azoles remain adjunctive. Published experience with omalizumab has been limited. PMID- 25439362 TI - Another predictive score for childhood asthma: the search remains. PMID- 25439361 TI - Optimum predictors of childhood asthma: persistent wheeze or the Asthma Predictive Index? AB - BACKGROUND: The Asthma Predictive Index (API) and persistent wheezing phenotypes are associated with childhood asthma, but previous studies have not assessed their ability to predict objectively confirmed asthma. OBJECTIVE: To determine whether the University of Cincinnati API Index (ucAPI) and/or persistent wheezing at age 3 can accurately predict objectively confirmed asthma at age 7. METHODS: Data from the Cincinnati Childhood Allergy and Air Pollution Study, a high-risk prospective birth cohort, was used. Asthma was defined as parent-reported or physician-diagnosed asthma objectively confirmed by a change in FEV1 of >=12% after bronchodilator or a positive methacholine challenge (PC20 <= 4 mg/mL); or as prior treatment with daily asthma controller medication(s). Multivariate logistic regression was used to investigate the relationship between confirmed asthma at age 7 and a positive ucAPI (adapted and modified from prior published API definitions) and persistent wheezing at age 3. RESULTS: At age 7, 103 of 589 children (17.5%) satisfied the criteria for asthma. Confirmed asthma at age 7 was significantly associated with a positive ucAPI (adjusted odds ratio [aOR] 13.3 [95% CI, 7.0-25.2]; P < .01) and the persistent wheezing phenotype (aOR 9.8 [95% CI, 4.9-19.5]; P < .01) at age 3. Allergic persistent wheezing was associated with a significantly higher risk of asthma (aOR 10.4 [95% CI, 4.1-26.0]; P < .01) than nonallergic persistent wheezing (aOR 5.4 [95% CI, 2.04-14.06]; P < .01). CONCLUSION: Both a positive ucAPI and persistent wheeze at age 3 were associated with objectively confirmed asthma at age 7; however, the highest risk was associated with ucAPI. These results demonstrate the ucAPI as a clinically useful tool for predicting future asthma in school-age children. PMID- 25439364 TI - Prediction of airway inflammation in patients with asymptomatic asthma by using lung sound analysis. AB - BACKGROUND: The intensity and frequency of sounds in a lung sound analysis (LSA) may be related to airway constriction; however, whether any factors of an LSA can predict airway eosinophilic inflammation in patients with asthma is unknown. OBJECTIVE: To determine whether an LSA can predict airway eosinophilic inflammation in patients with asymptomatic asthma. METHODS: The expiratory inspiratory ratios of sound power in the low-frequency range (E-I LF) from 36 patients with asymptomatic asthma were compared with those of 14 healthy controls. The relations of E-I LF with airway eosinophilic inflammation were analyzed. The E-I LF cutoff value for predicting airway eosinophilic inflammation also was analyzed. RESULTS: The mean +/- SD E-I LF was higher in the patients with asthma and with increased sputum eosinophils than in those patients without increased sputum eosinophils (0.45 +/- 0.24 vs 0.20 +/- 0.12; P < .001) or in the healthy controls (0.25 +/- 0.10; P = .003). A multiple regression analysis showed that the sputum eosinophil ratio and exhaled nitric oxide were independently correlated with E-I LF, P = .0003 and P = .032, respectively. For the prediction of increased sputum eosinophils and increased fractional exhaled nitric oxide levels, the E-I LF thresholds of 0.29 and 0.30 showed sensitivities of 0.80 and 0.74 and specificities of 0.83 and 0.77, respectively. CONCLUSIONS: We showed that LSAs can safely predict airway inflammation of patients with asymptomatic asthma. PMID- 25439363 TI - Comparative effectiveness of budesonide-formoterol combination and fluticasone salmeterol combination for asthma management: a United States retrospective database analysis. AB - BACKGROUND: Comparative effectiveness of the budesonide-formoterol fumarate dihydrate combination (BFC) and the fluticasone propionate-salmeterol combination (FSC) therapy on asthma exacerbation has not been assessed in real-world settings in the United States. OBJECTIVE: To compare exacerbation rates and health care utilization for patients with asthma who initiate BFC versus FSC therapy. METHODS: This retrospective cohort comparative effectiveness study queried medical and pharmacy data for patients with asthma from a large managed care data repository that covers major US population centers. The patients were 12 to 64 years old, with >=12 months of pre- and postindex enrollment and >=1 pharmacy claim(s) for BFC or FSC initiated during June 1, 2007, and September 30, 2010; the first prescription fill date was defined as the index date. Patients with other respiratory diseases and/or cancer were excluded. Exacerbation was defined as asthma-related hospitalization, emergency department visit, and/or oral corticosteroid prescription fill. Cohorts were matched by using propensity scores. RESULTS: A total of 3043 patients per cohort were matched and balanced. During the 12 months following the initiation the BFC cohort had lower adjusted exacerbations per person year versus the FSC cohort (0.85 vs 0.93; RR 0.92, 95% CI [0.85-0.99]), lower oral corticosteroid fill rates, and fewer asthma-related emergency department visits but comparable asthma-related hospitalization. CONCLUSIONS: Asthma exacerbation was lower for BFC versus FSC initiators due to lower rates of oral corticosteroid use and asthma-related emergency department visits, which indicate better treatment effectiveness of those patients initiated with BFC compared with FSC. PMID- 25439366 TI - High blood eosinophil count is a risk factor for future asthma exacerbations in adult persistent asthma. AB - BACKGROUND: Exacerbation-associated uncontrolled asthma represents a major public health problem. The relationship of elevated blood eosinophils to this process needs study. OBJECTIVE: To determine whether a high blood eosinophil count is a risk factor for future asthma exacerbations in adult persistent asthma. METHODS: By using electronic pharmacy and health care data from Kaiser Permanente Southern California, 2392 patients, ages 18 to 64 years, were identified who met the Health Effectiveness Data and Information Set 2-year criteria for persistent asthma, did not manifest chronic obstructive pulmonary disease and other major illnesses, and had a blood eosinophil determination in 2010. Exacerbations (primary outcome) were defined as asthma outpatient visits that required systemic corticosteroid dispensing within +/-7 days or asthma emergency department visits or hospitalizations. A period of >=8 days defined a new exacerbation. Multivariate modelling used negative binomial and Poisson regression to examine the association between a blood eosinophil count determined in 2010 and risk of exacerbations, and >=7 short-acting beta2-agonist (SABA) canisters dispensed (secondary outcome) in 2011 by adjusting for demographics, comorbidities, and asthma burden. RESULTS: The rate of asthma exacerbations in 2011 was 0.41 events per person year (95% CI, 0.37-0.45). Eosinophil count >=400/mm(3) in 2010 was a risk factor for asthma exacerbations in 2011 (adjusted rate ratio 1.31 [95% CI, 1.07-1.60]; P = .009) and >=7 SABA dispensed (adjusted risk ratio 1.17 [95% CI, 1.03-1.1.33]; P = .015). CONCLUSION: A high blood eosinophil count is a risk factor for increased future asthma exacerbations and excessive short-acting beta2 agonist use after adjustment of potential confounders in adults with persistent asthma, which suggests a higher disease burden in patients with asthma and with high blood eosinophil counts. PMID- 25439365 TI - A multicenter observational study of US adults with acute asthma: who are the frequent users of the emergency department? AB - BACKGROUND: Despite the substantial burden of asthma-related emergency department (ED) visits, there have been no recent multicenter efforts to characterize this high-risk population. OBJECTIVE: We aimed to characterize patients with asthma according to their frequency of ED visits and to identify factors associated with frequent ED visits. METHODS: A multicenter chart review study of 48 EDs across 23 US states. We identified ED patients ages 18 to 54 years with acute asthma during 2011 and 2012. Primary outcome was frequency of ED visits for acute asthma in the past year, excluding the index ED visit. RESULTS: Of the 1890 enrolled patients, 863 patients (46%) had 1 or more (frequent) ED visits in the past year. Specifically, 28% had 1 to 2 visits, 11% had 3 to 5 visits, and 7% had 6 or more visits. Among frequent ED users, guideline-recommended management was suboptimal. For example, of patients with 6 or more ED visits, 85% lacked evidence of prior evaluation by an asthma specialist, and 43% were not treated with inhaled corticosteroids. In a multivariable model, significant predictors of frequent ED visits were public insurance, no insurance, and markers for chronic asthma severity (all P < .05). Stronger associations were found among those with a higher frequency of asthma-related ED visits (eg, 6 or more ED visits). CONCLUSION: This multicenter study of US adults with acute asthma demonstrated many frequent ED users and suboptimal preventive management in this high-risk population. Future reductions in asthma morbidity and associated health care utilization will require continued efforts to bridge these major gaps in asthma care. PMID- 25439368 TI - The prevalence of severe asthma and low asthma control among Danish adults. AB - BACKGROUND: The prevalence of severe asthma is unknown. However, international expert statements estimate that severe asthma represents 5% to 10 % of the entire asthma population. OBJECTIVE: Based on register data from a nationwide population, we wanted to investigate the prevalence of severe asthma, the extent of asthma control, and contact with specialist care. METHODS: A descriptive cross sectional register study was performed. By using a nationwide prescription database, we identified current patients with asthma (age, 18-44 years) in 2010. Severity was classified as severe versus mild-moderate asthma according to the level of antiasthma treatment. We investigated prescription drug use, hospitalizations, emergency department visits, and outpatient clinic visits according to severity. RESULTS: Among a nationwide population, we identified 61,583 current patients with asthma. Based on the level of antiasthma treatment, 8.1% of identified patients was classified as having severe asthma. Low asthma control (dispensed prescriptions of prednisolone, emergency department visits, hospitalization, or excessive short-acting beta2-agonist use) was more frequent in subjects with severe asthma (36.4% vs 25.2%, P < .0001); 63.8% with severe asthma and low asthma control were not managed by specialist care. Patients with severe asthma with specialist contact more frequently had impaired asthma control compared with subjects not treated by a specialist (44.4% vs 33.1%, P < .0001). CONCLUSION: Based on the level of treatment, 8.1% of a nationwide population of current patients with asthma was classified as having severe asthma. Low asthma control was more frequent among subjects with severe asthma, and only a minority had access to specialist care. There is room for optimizing asthma management, particularly among patients with severe disease. PMID- 25439369 TI - Safety and outcomes of test doses for the evaluation of adverse drug reactions: a 5-year retrospective review. AB - BACKGROUND: Graded challenges are the criterion standard for evaluating adverse drug reactions (ADR). Evidence-based guidelines regarding the optimal number of steps for challenges are lacking. OBJECTIVE: To determine the safety and outcomes of 1- or 2-step test doses among patients with ADRs seen by the allergy/immunology consult service and to compare the outcomes of 1- or 2-step test doses with multistep challenges performed during the same time period. METHODS: We conducted a retrospective chart review of all 1- or 2-step test doses and multistep challenges at a single academic center between 2008 and 2013. Patient demographics, symptoms of initial ADRs, and outcomes of test doses and multistep challenges were reviewed. ADRs were classified by type and were graded by severity. Outcomes of 1- or 2-step test doses were compared with multistep challenges. RESULTS: We identified 456 patients who underwent 497 one- or 2-step test doses (mean age, 51 years; 67.5% female patients). The most common drugs that prompted test doses were beta-lactams (62%). The majority of patients (n = 444 [89%]) did not experience any ADRs during test doses. ADRs that occurred during test doses (n = 53 [11%]) were most commonly non-immune-mediated (45%) or IgE-mediated (32%), with grade 1 or 2 severity (100%). Forty-nine percent of ADRs during test doses did not receive any treatment. The ADR rate during multistep challenges (10/82 [12%]) was similar to test doses. CONCLUSION: One- or 2-step test doses were safe for evaluation of ADRs. Multistep challenges did not confer added safety. Furthermore, 1- or 2-step test doses did not raise concern for induction of tolerance. PMID- 25439370 TI - Mast cell activation syndrome: improved identification by combined determinations of serum tryptase and 24-hour urine 11beta-prostaglandin2alpha. AB - BACKGROUND: Mast cell activation syndrome (MCAS) describes patients with episodes of mast cell mediator release, with negative bone marrow biopsy results, and the failure to meet the criteria for systemic mastocytosis. OBJECTIVE: Identify elevation of mast cell mediators of patients with MCAS. METHODS: We performed a retrospective study of 25 patients with MCAS who were evaluated at Mayo Clinic from 2006 to 2012. Patients were reviewed for MCAS symptoms and mast cell mediators, including serum tryptase and 24-hour urine N-methyl histamine (N-MH) and 11beta-prostaglandin-F2alpha (11beta-PGF2alpha). The study was approved by the institutional review board. RESULTS: Urinary 11beta-PGF2alpha was the most frequently elevated product in MCAS of our 25-patient cohort. Flushing and pruritus had the greatest correlation with elevation of 24-hour urine 11beta PGF2alpha value at baseline. The serum tryptase level was elevated in 10 patients, whereas the N-MH level was elevated with 2 patients. Eight of 9 patients with MCAS and with elevated 24-hour urine 11beta-PGF2alpha who underwent aspirin therapy and follow-up urinary studies had normalization of this mediator (1 patient did not have a follow-up urine study). Six of these 9 patients with MCAS who underwent aspirin therapy had symptomatic improvement. CONCLUSION: We recommend measurement of 24-hour urine 11beta-PGF2alpha and serum tryptase levels of patients with symptoms suggestive of MCAS. Measurement of 24-hour urine 11beta PGF2alpha and serum tryptase levels can help avoid misdiagnosis and overinterpretation of MCAS symptoms in clinical practice. Given that an elevation of 24-hour urine N-MH level was found only in 2 patients, measurement of this mediator may be less helpful in diagnosing MCAS. We recommend aspirin therapy for patients with MCAS and with elevated 24-hour urine 11beta-PGF2alpha levels. PMID- 25439367 TI - Predictors of severe exacerbations, poor asthma control, and beta-agonist overuse for patients with asthma. AB - BACKGROUND: Predictors of asthma exacerbations, poor asthma control, or extreme beta-agonist overuse may be of clinical utility in the management of asthma. OBJECTIVE: To investigate characteristics that predict subsequent adverse outcomes in asthma. METHODS: An independent 24-week, randomized controlled trial of 303 adult patients with asthma who are at risk, which compared the efficacy of SMART (single budesonide-formoterol inhaler as maintenance and reliever therapy) with a fixed-dose regimen with salbutamol as reliever ("Standard"). Inhaled medication use was measured by electronic monitoring. Baseline characteristics that were predictors of subsequent severe asthma exacerbations, poor asthma control (Asthma Control Questionnaire -5 score >=1.5), and "extreme" beta-agonist overuse (>16 budesonide-formoterol actuations/d in SMART and >32 salbutamol actuations/d in Standard) were assessed by multivariate analyses. RESULTS: FEV1 % predicted (rate ratio [RR] 1.14 [95% CI, 1.03-1.27] per 10% lower), more previous exacerbations (RR 1.15 [95% CI, 1.01-1.31]), Standard therapy (RR 1.62 [95% CI, 1.07-2.47]), and female sex (RR 2.18 [95% CI, 1.29-3.67]) were associated with future severe exacerbations. Asthma Control Questionnaire--5 (regression coefficient 0.20 [95% CI, 0.13-0.27] per 0.5 points higher) and age (regression coefficient 0.09 [95% CI, 0.01-0.17] per decade older) were associated with future poorly controlled asthma. Higher reliever use (RR 1.63 [95% CI, 1.36-1.95] per categorical score in Asthma Control Questionnaire question no. 6), Maori ethnicity (RR 2.20 [95% CI, 1.43-3.38]) and FEV1 % predicted (RR 1.16 [95% CI, 1.03-1.31] per 10% lower) were associated with future extreme beta-agonist overuse. CONCLUSION: Future severe asthma exacerbations, poor asthma control, and extreme beta-agonist overuse are predicted by different baseline clinical and demographic characteristics and management approaches in at-risk asthma. PMID- 25439371 TI - Atopy and development of cancer: a population-based prospective study. AB - BACKGROUND: Atopy is the familial or personal propensity to develop IgE antibodies against environmental allergens. Atopy, theoretically, could both prevent and promote the development of cancer. However, evidence from epidemiologic studies has been inconclusive. OBJECTIVE: We investigated the longitudinal association between atopy and the incidence of total and specific types of cancers of 5 Danish population-based studies. METHODS: Atopy was defined as serum specific IgE positivity against inhalant allergens. A total of 14,849 persons were followed up prospectively by linkage to the Danish Cancer Registry. We used Cox regression analysis, and risk was expressed as hazard ratios (HR) (95% CIs) for persons with atopy versus those without atopy. RESULTS: There were 1919 incident cancers (median follow-up, 11.8 years). There were no statistically significant associations between atopy and risk of any cancer (HR 1.00 [95% CI, 0.89-1.12]), any cancer excluding nonmelanoma skin cancer (HR 0.93 [95% CI, 0.82 1.07]), head and neck cancer (HR 1.74 [95% CI, 0.98-3.09]), colorectal cancer (HR 0.92 [95% CI, 0.64-1.32]), cancer of the bronchus and lung (HR 0.78 [95% CI, 0.54 1.13]), breast cancer (HR 1.00 [95% CI, 0.73-1.37]), cancer of the uterus (HR 0.90 [95% CI, 0.43- 1.88]), prostate cancer (HR 0.79 [95% CI, 0.53-1.18]), urinary cancer (HR 1.08 [95% CI, 0.60-1.96]), malignant melanoma (HR 0.95 [95% CI, 0.54-1.66]), and nonmelanoma skin cancer (HR 1.20 [95% CI, 0.98-1.47]). CONCLUSION: Our data did not support the hypothesis that atopy is associated with an altered risk of total cancer development, although effects of atopy on specific types of cancer cannot be excluded. PMID- 25439372 TI - Dissociation between history and challenge in patients with physical urticaria. AB - BACKGROUND: Physical urticaria is a subtype of chronic urticaria induced by a physical stimulus. OBJECTIVE: To evaluate the consistency between a history of physical urticaria and results of challenge testing. METHODS: Seventy-six subjects, ages 3 to 77 years old, were referred with the diagnosis of a physical urticaria and were evaluated by using challenge testing directed toward the presenting diagnosis, yet included other stimuli based on history. The majority of subjects were tested to 3 or more stimuli, thus 294 provocation tests were performed. Fifty-seven subjects were surveyed for the status of their physical urticaria at least 1 year after initial evaluation. RESULTS: Of the 76 subjects with a positive history of a physical urticaria, 38% (n = 29) were challenge negative to the presenting diagnosis. Eight subjects within the challenge negative group reacted positively to additional testing, thus 28% (n = 21) remained negative to all challenge testing, which allowed discontinuation of medications and avoidance behavior. A negative challenge result was less likely with subjects who presented with cold-induced urticaria (25%), delayed pressure urticaria (25%), and dermatographism (29%), yet more common with cholinergic (65%) and solar urticaria (67%). A 1-year follow-up survey of 57 subjects was consistent with initial results. Nineteen of this subgroup were rechallenged for the presenting diagnosis, and the outcome was unchanged in 17 subjects and, in 2 subjects the urticaria had resolved. CONCLUSIONS: The diagnosis by history of a physical urticaria should be verified by testing whenever possible and particularly if the condition is judged as severe and thus requires both significant life-style changes and pharmacologic intervention. PMID- 25439373 TI - An unusual, delayed, localized bullous reaction after subcutaneous allergen immunotherapy. PMID- 25439374 TI - Clinical and immunologic assessment of a cluster method during allergen immunotherapy refill dosing. PMID- 25439375 TI - Factitious angioedema: a mimic of refractory "angioedema". PMID- 25439376 TI - Is skin testing reliable for confirming sensitization to seminal fluid proteins? PMID- 25439377 TI - Acute generalized exanthematous pustulosis due to benznidazole. PMID- 25439378 TI - Successful treatment of eczema coxsackium with wet wrap therapy and low-dose topical corticosteroid. PMID- 25439379 TI - Iodinated contrast media-induced acute generalized exanthematous pustulosis confirmed by delayed skin tests. PMID- 25439380 TI - Percutaneous and intradermal allergy skin test utilization in the United States 2012 Medicare population. PMID- 25439381 TI - A rare presentation of EBV+ mucocutaneous ulcer that led to a diagnosis of hypogammaglobulinemia. PMID- 25439382 TI - Telangiectasia macularis eruptiva perstans or highly vascularized urticaria pigmentosa? PMID- 25439383 TI - Cross-reactivity between carbapenems: two case reports. PMID- 25439384 TI - Idiopathic nonhistaminergic angioedema successfully treated with ecallantide, icatibant, and C1 esterase inhibitor replacement. PMID- 25439385 TI - Unilateral choanal atresia in a child with recurrent infections. PMID- 25439386 TI - A case report of allergy to exenatide. PMID- 25439387 TI - Granulomatous-lymphocytic interstitial lung disease in a patient with common variable immunodeficiency. PMID- 25439388 TI - Drug-induced anaphylaxis in children: nonsteroidal anti-inflammatory drugs and drug provocation test. PMID- 25439389 TI - Reply: To PMID 25017529. PMID- 25439390 TI - The otolaryngologist and deafness. PMID- 25439391 TI - Prefrontal activity measured by functional near infrared spectroscopy during probabilistic inference in subjects with persecutory delusions. AB - Jumping to conclusions (JTC) is a probabilistic reasoning bias and is thought to contribute to delusion formation. Neurobiological correlates of the JTC bias are not known. We aimed to examine the rostral prefrontal cortex (rPFC) activity with functional near infrared spectroscopy during a modified version of the Beads in a Jar Task (BIJT) in subjects with persecutory delusions (N=25). In BIJT participants are presented beads either drawn from one of the two jars with opposite probability ratios (PRs) of colored beads and are required to decide from which jar beads are being drawn. We administered the BIJT with 90/10 and 55/45 PRs. Compared to healthy controls (N=20), patients reached a decision earlier in both conditions. While the medial rPFC regions were more active in the 90/10 condition in controls compared to patients, lateral rPFC activation was higher in the 55/45 condition in patients than controls. Only in the control group, there was a marked decline in the lateral rPFC activation in the 55/45 condition compared to the 90/10 condition. The activity in the lateral rPFC was negatively correlated with the amount of beads drawn in healthy controls but not in subjects with persecutory delusions. Our results suggest that during the BIJT, rPFC does not function as a single unit and rather consists of functional subunits that are organized differently in patients and controls. The failure to deactivate the lateral rPFC may be associated with earlier decisions in subjects with persecutory delusions. PMID- 25439392 TI - Social environmental risk factors for transition to psychosis in an Ultra-High Risk population. AB - OBJECTIVE: Despite social environmental factors such as deprivation, urbanicity, migration and adversity being established risk factors for psychotic disorders, there is a paucity of knowledge on the influence of social environmental risk factors in the UHR population. Firstly, we aimed to investigate the association between social deprivation and risk of transition and secondly, we aimed to investigate the association between migration status and the risk of transition. METHOD: UHR individuals at the Personal Assessment and Crisis Evaluation (PACE) service in Melbourne were included. Social deprivation as assessed according to postal code area of residence was obtained from census data and Cox regression analysis was used to calculate hazard ratios. RESULTS: A total of 219 UHR individuals were included and over the median follow-up time of 4.8years, 32 individuals (14.6%) were known to have transitioned to a psychotic disorder. 8.8% of UHR individuals were first generation migrants and 41.9% were second generation migrants. The level of social deprivation was not associated with the risk of transition (p=0.83). Similarly, first or second generation migrants did not have an increased risk of transition to psychosis (p=0.84). CONCLUSIONS: Despite being established risk factors for psychotic disorders, social deprivation and migrant status have not been found to increase the risk of transition in a UHR population. PMID- 25439393 TI - Neural basis of altered physical and social causality judgements in schizophrenia. AB - Patients with schizophrenia (SZ) often make aberrant cause and effect inferences in non-social and social situations. Likewise, patients may perceive cause-and effect relationships abnormally as a result of an alteration in the physiology of perception. The neural basis for dysfunctions in causality judgements in the context of both physical motion and social motion is unknown. The current study used functional magnetic resonance imaging (fMRI) to investigate a group of patients with SZ and a group of control subjects performing judgements of causality on animated collision sequences (launch-events, Michotte, 1963) and comparable "social" motion stimuli. In both types of animations, similar motion trajectories of the affected object were configured, using parametrical variations of space (angle deviation) and time (delay). At the behavioural level, SZ patients made more physical and less social causal judgements than control subjects, and their judgements were less influenced by motion attributes (angle/time delay). In the patients group, fMRI revealed greater BOLD-responses, during both physical and social causality judgements (group*task interaction), in the left inferior frontal gyrus (L.IFG). Across conditions (main effect), L.IFG interconnectivity with bilateral occipital cortex was reduced in the patient group. This study provides the first insight into the neural correlates of altered causal judgements in SZ. Patients with SZ tended to over-estimate physical and under-estimate social causality. In both physical and social contexts, patients are influenced less by motion parameters (space and time) than control subjects. Imaging findings of L.IFG-disconnectivity and task-related hyper-activation in the patient group could indicate common dysfunctions in the neural activations needed to integrate external cue-information (space/time) with explicit (top-down) cause-effect judgements of object motions in physical and social settings. PMID- 25439395 TI - Selection on outlier loci and their association with adaptive phenotypes in Littorina saxatilis contact zones. AB - A fundamental issue in speciation research is to evaluate phenotypic variation and the genomics driving the evolution of reproductive isolation between sister taxa. Above all, hybrid zones are excellent study systems for researchers to examine the association of genetic differentiation, phenotypic variation and the strength of selection. We investigated two contact zones in the marine gastropod Littorina saxatilis and utilized landmark-based geometric morphometric analysis together with amplified fragment length polymorphism (AFLP) markers to assess phenotypic and genomic divergence between ecotypes under divergent selection. From genetic markers, we calculated the cline width, linkage disequilibrium and the average effective selection on a locus. Additionally, we conducted an association analysis linking the outlier loci and phenotypic variation between ecotypes and show that a proportion of outlier loci are associated with key adaptive phenotypic traits. PMID- 25439394 TI - The efficacy of targeted health agents education to reduce the duration of untreated psychosis in a rural population. AB - The duration of untreated psychosis (DUP) is a key determinant in the severity of symptoms in patients with schizophrenia. DUP is a modifiable factor that if reduced can improve patient outcome and treatment response. We sought to decrease DUP in rural Argentina by instituting annual training of local health agents to better identify signs of mental illness and offer earlier intervention. DUP was estimated using Schedules of Clinical Assessment in Neuropsychiatry (SCAN). Ongoing training was correlated with a reduction in DUP. Reducing DUP through better screening can decrease the psychosocial burden of disease and improve the trajectory of psychosis. PMID- 25439396 TI - Enteral access in adults. AB - Enteral feeding is widely used for hospitalized patients but is also used for ambulatory persons living at home or in home care settings. Aside from decisions that must be made about appropriate nutrient delivery, choices related to which type of enteral access will be used and the procedures for enteral access surveillance are extremely important. In this paper we review the various techniques for establishment of enteral access in adult patients. Prevention and treatment of potential complications are detailed. The use of protocols that are written by a multidisciplinary nutrition team is mandatory. It is also of vital importance to discuss treatment plans with the patient and care givers, to assure appropriate follow-up, and to consider ethical issues related to enteral feeding. PMID- 25439397 TI - Effects of thermoregulatory vasoconstriction on pulse hemoglobin measurements using a co-oximeter in patients undergoing surgery. AB - STUDY OBJECTIVE: To validate intraoperative pulse hemoglobin (SpHb) measurements in anesthetized patients with large forearm temperature - fingertip temperature gradients. DESIGN: prospective and observational study. SETTING: Operating room of a university hospital. PATIENTS: 28 patients undergoing surgery during general anesthesia, requiring arterial blood withdrawal. INTERVENTIONS: Radial arterial blood pressure, forearm and fingertip skin surface temperatures, and SpHb were monitored. MEASUREMENTS: Paired SpHb and arterial hemoglobin (Hb) measurements at different skin-surface temperature gradients. MAIN RESULTS: A total of 175 paired SpHb and arterial Hb measurements were analyzed. The mean SpHb to arterial Hb differences in each group were 0.33 +/- 1.41g/dL in the < 1 degrees C group of the forearm temperature - fingertip temperature gradient, -0.31 +/- 1.24g/dL in the 1 - 2 degrees C group, - 0.59 +/- 1.11g/dL in the 2 - 3 degrees C group, and 0.53 +/- 0.87g/dL in the > 3 degrees C group (P < 0.05). The percentage of nonmeasurable SpHb due to low perfusion state was 0% (0 of 115 paired measurements) in the < 1 degrees C group, 6.7% (2 of 30 pairs) in the 1 - 2 degrees C group, 16.7% (3 of 18 pairs) in the 2 - 3 degrees C group, and 66.7% (8 of 12 pairs) in the > 3 degrees C group. CONCLUSION: SpHb measured at fingertip was significantly affected by the perfusion state, with lower perfusion associated with lower SpHb. Thermoregulatory vasoconstriction affects measurement of SpHb. PMID- 25439398 TI - Incidental discovery of a partial anomalous pulmonary venous connection in the surgical critical care unit. AB - Routine chest roentgenogram to confirm catheter placement in a postsurgical patient showed a left-sided internal jugular central venous catheter that did not appear to cross the midline. Arterial blood gas samples showed greater oxygenation from the central catheter as compared with the peripheral arterial sample. However, a transduced waveform showed a venous tracing and pressure. Computed tomographic scan of the thorax without intravenous contrast showed a partial anomalous pulmonary venous connection with drainage of the left upper lobe pulmonary vein into the innominate vein. PMID- 25439399 TI - Impact of isoproterenol infusion on BIS and metabolic values in pediatric patients undergoing electrophysiology studies. AB - STUDY OBJECTIVE: To study changes in BIS values and metabolic parameters during an infusion of isoproterenol in pediatric patients. DESIGN: Retrospective study approved By Committee For The Protection Of Human Subjects at University Of Texas Medical School at Houston. SETTING: University-affiliated children's hospital. MEASUREMENTS: The records of pediatric patients undergoing general anesthesia for electrophysiology procedures were analyzed. Electronic data collected included Bispectral Index (BIS) values, anesthetics (eg, opioids, expired concentration of inhaled anesthetics, muscle relaxants), hemodynamic values (ie, heart rate, invasive blood pressure), respiratory parameters [ie, tidal volume, respiratory rate, end-tidal CO2 (ETCO2)], and routine arterial blood gases. These parameters were analyzed 10 minutes prior to the start of the isoproterenol infusion (T-pre) and 10 minutes after isoproterenol had reduced the cardiac cycle length by 20% (T infusion). MAIN RESULTS: Of the 29 records that were screened, 22 met the above criteria (mean age 13 +/- 5 yrs). BIS values increased by an average of 8 (33 +/- 8 to 41 +/- 10; P < 0.001) during the isoproterenol infusion. Statistically significant increases in ETCO2 (median 33 - 36 mmHg; P = 0.01), PaCO2 (35 - 38 mmHg; P = 0.002), and lactate (1.1 -1.5 mg/dL; P < 0.001) occurred with infusion of isoproterenol. Patients undergoing controlled mechanical ventilation showed an increase in ETCO2 (mean 34 +/- 6 mmHg to 37 +/- 5 mmHg; P = 0.001) whereas those breathing spontaneously had an increase in minute ventilation (average increase 111 +/- 30 mL/kg). CONCLUSIONS: Isoproterenol increases metabolic, respiratory, and BIS values in pediatric patients during general anesthesia. We recommend the use of BIS, close monitoring of ETCO2, and careful titration of anesthetics during isoproterenol infusion, especially when lighter planes of general anesthesia are requested for pediatric electrophysiologic procedures. PMID- 25439400 TI - Observational study of Mallampati changes after prone spinal surgery. AB - STUDY OBJECTIVE: To evaluate airway changes in patients undergoing surgery in the prone position. DESIGN: Single-arm observational study. PATIENTS: Patients between 18 to 65 years old, scheduled for prone spinal surgery; 74 patients were enrolled and 54 patients were analyzed. INTERVENTION: The initial airway examination was graded according to the Samsoon and Young modification of the Mallampati classification (MMP). Airway photographs were obtained in a standardized manner and were repeated 20 minutes after extubation. The photographs were then randomized. MEASUREMENTS: Subjects' age, gender, race, weight, duration of surgery, amount of crystalloid fluid given, and estimated blood loss were recorded. Three senior anesthesiologists who were blinded to the origin of the photographs analyzed and graded the airways. MAIN RESULTS: All statistical tests showed significance between pre-MMP and post-MMP scores (P<0.001). There was no difference between pre and post interobserver MMP scores. The MMPs of 12 patients (22%) did not change and MMP scores were changed in 42 patients (78%): 30 (71%) patients by one class, 10 (24%) patients by two classes, and two patients (5%) by three classes. There was no correlation between patients whose MMP was changed and length of surgery or crystalloid administered. CONCLUSION: Modified Mallampati scores increased in the majority of patients after spinal surgery in the prone position. PMID- 25439401 TI - Selective blockade of the dorsal scapular nerve for scapula surgery. AB - The dorsal scapular nerve, a proximal branch of the brachial plexus, may be imaged using ultrasound. This nerve supplies the rhomboid and levator scapulae muscles while providing significant sensory innervation to the scapula. An ultrasound-guided nerve block of the dorsal scapular nerve provided analgesia after surgery of the scapula. Selective blockade of this nerve, without blocking the remainder of the brachial plexus, results in specific analgesia of the scapula, sparing sensory and motor function of the ipsilateral arm. PMID- 25439403 TI - Postoperative complications in patients with obstructive sleep apnea: a meta analysis. AB - STUDY OBJECTIVE: To determine whether a diagnosis of obstructive sleep apnea (OSA) imparts an increased risk of postoperative respiratory failure, cardiac events, and intensive care unit (ICU) transfer than patients with no OSA diagnosis. DESIGN: Systematic review and meta-analysis. SETTING: Academic Veterans Affairs Medical Center. MEASUREMENTS: PubMed, EMBASE, CINAHL, and ISI Web of Knowledge databases were searched through April 2013 for studies that examined the relationship between OSA and postoperative respiratory and cardiac complications among adults. Either fixed or random-effects models were used to calculate the pooled risk estimates. Sensitivity analysis was conducted to examine the robustness of pooled outcomes. MAIN RESULTS: Seventeen studies with a total of 7,162 patients were included. Overall, OSA was associated with significant increase in risk of respiratory failure [odds ratio (OR) 2.42; 95% confidence intervals (CI) 1.53 - 3.84; P = 0.0002] and cardiac events postoperatively (OR = 1.63; 95% CI 1.16 - 2.29; P = 0.005). Heterogeneity was low for these outcomes (I(2) = 5% and 0%, respectively). ICU transfer occurred also more frequently in patients with OSA (OR 2.46; 95% CI 1.29 - 4.68; P = 0.006). These results did not materially change in the sensitivity analyses according to various inclusion criteria. CONCLUSIONS: Surgical patients with OSA are at increased risk of postoperative respiratory failure, cardiac events, and ICU transfer. PMID- 25439404 TI - Cardiovascular collapse and hypoxemia in a man with a right-sided mediastinal mass, undiagnosed atrial septal defect, and right-to-left shunt. AB - A 65 year old man presented with fever, pancytopenia, hypoxemia, and cardiovascular collapse requiring intensive care unit admission. Computed tomographic pulmonary angiogram showed a right-sided mediastinal mass adjacent to the right atrium. The patient had a video-assisted thoracoscopic surgical biopsy of the mass, with selective bronchial blockade to maximize oxygenation during lung isolation. Intraoperative transesophageal echocardiography showed an unexpected large atrial secundum defect with a right-to-left shunt and intracardiac mass. This shunt could be reversed with a norepinephrine infusion, resulting in improved oxygenation. Histopathology showed potentially curative diffuse large B cell lymphoma (DLBCL). PMID- 25439402 TI - Dexmedetomidine sedation after cardiac surgery decreases atrial arrhythmias. AB - STUDY OBJECTIVE: To determine whether postoperative cardiac surgery patients who are sedated with dexmedetomidine have fewer atrial arrhythmias, and whether dexmedetomidine is associated with fewer renal and more gastrointestinal (GI) complications. DESIGN: Retrospective study. SETTING: Urban academic hospital. MEASUREMENTS: The records of 765 postoperative cardiac surgery patients who were given dexmedetomidine for postoperative sedation in the intensive care unit (ICU) were studied. Data from the hospital's Cardiac Anesthesiology database between the years 2005 and 2010 were evaluated. Records of patients whose ASA physical status was > 4 or who were < 18 years of age were excluded from the study. Patients who were and were not given dexmedetomidine were compared for postoperative sedation within three days after cardiac surgery using multivariable logistic regression, adjusting for imbalanced covariables. MAIN RESULTS: The records of 17,776 patients, including 765 cardiac patients given dexmedetomidine for postoperative sedation in the ICU, were reviewed. Patients who received postoperative dexmedetomidine had a lower risk of having atrial arrhythmias: (OR 0.74 (95% CI: 0.60, 0.91; P = 0.004). Dexmedetomidine was not associated with 30-day mortality (1.10, 0.40 - 3.02; P = 0.86), or with any of the following 30-day outcomes: surgical infection (0.72, 0.36-1.42; P = 0.34), systemic infection (1.38, 0.93 - 2.05; P = 0.11), GI complications (1.34, 0.74 - 2.42; P = 0.33), or renal complications (1.23, 0.70 - 2.15; P = 0.48). CONCLUSIONS: Dexmedetomidine use after cardiac surgery was associated with a lower incidence of atrial arrhythmias. PMID- 25439405 TI - Retroperitoneal hemorrhage from an unrecognized puncture of the lumbar right segmental artery during lumbar chemical sympathectomy: diagnosis and management. AB - Lumbar chemical sympathectomy has been performed using fluoroscopic guidance for needle positioning. An 84 year old woman with atherosclerosis obliterans was referred to the pain clinic for intractable cold allodynia of her right foot. A thermogram showed decreased temperature of both feet compared with temperatures above both ankles. The patient agreed to undergo lumbar chemical sympathectomy using fluoroscopy after being informed of the associated risks of nerve injury, hemorrhage, infection, transient back pain, and transient hypotension. During the procedure and three hours afterward, no abnormal signs or symptoms were found except an increase in right leg temperature. The patient was ambulatory after the procedure. However, one day after undergoing lumbar chemical sympathectomy, she visited our emergency department for abdominal discomfort and postural dizziness. Her blood pressure was 80/50 mmHg, and flank tenderness was noted. Retroperitoneal hemorrhage from the second right lumbar segmental artery was shown on computed tomography and angiography. Vital signs were stabilized immediately after embolization into the right lumbar segmental artery. PMID- 25439406 TI - Adducted vocal cords relieved by neuromuscular blocking drug: a cause of impaired mechanical ventilation when using a laryngeal mask airway: two photographically documented cases. AB - Two cases of vocal cord closure, which was responsible for acute intraoperative impairment of mechanical ventilation in two patients with entropy-controlled depth of anesthesia, are reported. Administration of low-dose neuromuscular blocking drug was associated with immediate vocal cord relaxation and restoration of efficient mechanical ventilation. PMID- 25439407 TI - The effects of propofol-midazolam-ketamine co-induction on hemodynamic changes and catecholamine response. AB - STUDY OBJECTIVE: To compare the clinical efficacy of co-induction with propofol midazolam-ketamine with etomidate as the sole induction agent. DESIGN: Prospective, double-blinded, randomized controlled trial. SETTING: Operating room of a university hospital. PATIENTS: 60 ASA physical status 1 and 2 patients scheduled for limited elective surgery requiring general anesthesia. INTERVENTIONS: Patients were randomized to two groups to receive etomidate 0.3 mg/kg (single-drug group) or propofol 0.6 mg/kg + ketamine 0.8 mg/kg + midazolam 0.06 mg/kg (three-drug group). MEASUREMENTS: Hemodynamic responses (systolic and diastolic blood pressure, and mean arterial pressure) were examined at baseline and at one, three, and 5 minutes after tracheal intubation. Plasma catecholamine levels were measured at baseline, one, and 5 minutes after tracheal intubation. MAIN RESULTS: Heart rate (HR) changes differed significantly between the two groups at three minutes (P = 0.01) and 5 minutes (P = 0.00) after tracheal intubation. However, the HR increase in the three-drug group was in the acceptable range. Percentage changes of epinephrine level differed between the two groups at 5 minutes after tracheal intubation (P = 0.03). CONCLUSIONS: The higher norepinephrine/epinephrine ratio noted in the single-drug group may be implicated in lower adrenal sympathetic activity. Propofol-midazolam-ketamine co induction may be used instead of etomidate for anesthesia induction in patients with hemodynamic instability. PMID- 25439408 TI - Anesthetic management in a child with Rolland-Desbuquois type dyssegmental dysplasia. AB - A case of a 17-month-old boy with dissegmental dysplasia of the Rolland Desbuquois type, who was scheduled for bilateral inguinal herniotomy, is presented. Preoperative assessment showed limited mouth opening, head extension, and kyphosis. Intubation with a size 4 mm endotracheal tube (ETT) was achieved with fiberoptic bronchoscopy, after which surgery proceeded uneventfully and the ETT was carefully removed. Copious airway secretions required frequent suctioning. On the second postoperative day, respiratory status stabilized, and the patient was discharged home. PMID- 25439409 TI - Catecholamine release induces elevation in plasma lactate levels in patients undergoing adrenalectomy for pheochromocytoma. AB - STUDY OBJECTIVE: To determine the relationship between preoperative catecholamine levels and intraoperative peak plasma lactate levels in patients who underwent adrenalectomy for pheochromocytoma. DESIGN: Retrospective observational study. SETTING: Operating room in one university hospital. MEASUREMENTS: The records of 27 ASA physical status 1 and 2 patients who underwent adrenalectomy for pheochromocytoma were studied. Preoperative catecholamine levels and intraoperative plasma lactate levels were recorded. MAIN RESULTS: Twenty cases had high lactate levels (>2 mmol/L). Preoperative urine epinephrine levels and urine metanephrine levels showed a moderate correlation with intraoperative peak plasma lactate levels (rs = 0.475 and rs = 0.499, respectively; Spearman's rank correlation test). Receiver operating characteristic (ROC) curve analysis for preoperative urine epinephrine levels showed good performance for prediction of high lactate levels [>2 mmol/L, area under the curve (AUC) =0.800], whereas ROC for preoperative urine norepinephrine levels showed no predictive performance for high lactate levels. CONCLUSIONS: Catecholamine release caused by surgical manipulation may be a possible cause of intraoperative transient lactic acidosis, and it should be considered as a differential diagnosis of intraoperative lactic acidosis. Intraoperative peak plasma lactate level was correlated with preoperative epinephrine-releasing activity. PMID- 25439410 TI - Evaluation of anesthetic technique on surgical site infections (SSIs) at a single institution. AB - STUDY OBJECTIVE: To determine whether the previously published relationship between anesthetic technique and rate of surgical site infections (SSIs) was influenced by institution specific effects. DESIGN: Retrospective Review of Quality Assurance and Hospital Epidemiology databases. SETTING: Metropolitan medical center. MEASUREMENTS: The records of 7,751 patients who underwent knee or hip joint replacement from 2004 to 2010 were analyzed. Data regarding anesthetic technique, age, ASA status, gender, postoperative temperature, duration of anesthesia and type of surgery were from the department of anesthesiology quality assurance database and SSI cases were identified from the department of epidemiology database. The impact of anesthetic technique and other variables was assessed using bivariate and multivariate techniques. MAIN RESULTS: There was no association of anesthetic technique on the rate of SSI. Duration of anesthesia and ASA status were associated with effects on the rate of SSI. CONCLUSIONS: The impact of anesthetic technique on SSI following hip and knee replacement surgery may be site specific and using locally gathered quality data may assist in assessing specific institutional impact. PMID- 25439411 TI - The incidence of coagulopathy in pregnant patients with intrahepatic cholestasis: should we delay or avoid neuraxial analgesia? AB - STUDY OBJECTIVE: To estimate the incidence of coagulopathy in patients with intrahepatic cholestasis inhepatic cholestasis of pregnancy (ICP). DESIGN: Retrospective cohort investigation. SETTING: University medical center. MEASUREMENTS: The records of 319 parturients who met study inclusion criteria were reviewed for various laboratory values. The primary outcome was the incidence of abnormal hemostasis, defined as prothrombin time (PT) greater than 14.5 seconds (INR>1.2). The incidence of postpartum hemorrhage was evaluated as a secondary outcome. MAIN RESULTS: The incidence (95% CI) of abnormal PT was 0% (0 to 1.8). Other coagulation tests [partial thromboplastin time (PTT) and platelet count] were also normal, even in study subjects with significant (>5 times) elevation of liver enzymes. The incidence of postpartum hemorrhage after vaginal delivery was 2.4% (4 of 208 pts) and 6.3% (7 of 111 pts) after Cesarean delivery. CONCLUSIONS: Coagulation abnormalities are rare in pregnant patients with ICP, even when a strict criterion is utilized (INR<1.2). The use of neuraxial anesthesia and/or analgesia may not necessarily be delayed in parturients with isolated ICP. PMID- 25439412 TI - Propofol and diabetes insipidus. AB - A case in which the intraoperative administration of propofol was strongly associated with an acute episode of diabetes insipidus is presented. PMID- 25439413 TI - Effects of prophylactic ramosetron and ondansetron on corrected QT interval during general anesthesia. AB - STUDY OBJECTIVE: To evaluate whether ramosetron increases the corrected QT (QTc) interval. DESIGN: Prospective, randomized, controlled study. SETTING: Operating room. PATIENTS: 135 patients undergoing elective laparoscopic cholecystectomy. INTERVENTION: Patients were allocated to three groups to receive ondansetron 4 mg (Group O4), ramosetron 0.3 mg (Group R), or ondansetron 8 mg (Group O8). The study drugs were administered intravenously approximately 15 minutes before the end of surgery. MEASUREMENT: The QT interval for 10 minutes after administration was recorded. The QTc interval was calculated according to the Fridericia (QTcF) formula. The primary outcome was the QTcF interval among the three groups during the 10 minutes after administration of the study drugs. MAIN RESULTS: The QTcF interval was not significantly prolonged after administration of ondansetron 4 mg and ramosetron. It was significantly increased from one minute after administration until 7 minutes after ondansetron 8 mg (Group O8). The QTcF interval was significantly longer in Group O8 at 1, 2, 3, 4, and 5 minutes. CONCLUSIONS: The prophylactic administration 0.3 mg of ramosetron does not increase the QTc interval. Ondansetron 8 mg increases the QTc interval more so than 4 mg of ondansetron. PMID- 25439414 TI - Superior laryngeal nerve block: an anatomical study comparing two techniques. AB - STUDY OBJECTIVE: To determine whether an anterior approach is as successful as the conventional posterior approach to superior laryngeal nerve block. DESIGN: Prospective observational study. SETTING: University anatomy laboratory. PATIENTS: 20 formalin-fixed adult human cadavers. MEASUREMENTS: Simulated superior laryngeal nerve blocks were performed by a single operator using 3 mL of 0.01% analine blue dye with a 23-gauge Quincke tip needle. Two different landmark techniques were used on each undissected cadaver: 1) the conventional posterior approach using the hyoid bone as a palpable landmark, with injection at the posterior third of the thyrohyoid membrane; and 2) the anterior approach, using the anterior thyroid notch of the thyroid cartilage, with injection at the anterior third of the thyrohyoid membrane. The spread of analine dye was observed. An injection was deemed successful if the entire paraglottic space was stained or the superior laryngeal nerve stained as it entered the paraglottic space. MAIN RESULTS: Both techniques were equally successful after 40 injections. CONCLUSION: There was no significant difference in success in staining the superior laryngeal nerve in human cadavers between the conventional posterior approach and an anterior approach. PMID- 25439415 TI - The effect of epidural lidocaine administration on sedation of propofol general anesthesia: a randomized trial. AB - STUDY OBJECTIVE: To examine the influence of epidural and intravenous (IV) lidocaine, and height of the epidural sensory block, on the dose of propofol required for induction of general anesthesia. DESIGN: Randomized controlled study. SETTING: University hospital. PATIENTS: 66 adult, ASA physical status 1 and 2 patients, aged 25 to 65 years, undergoing elective abdominal surgery. INTERVENTIONS: Patients were randomized to 4 groups: the epidural saline control group (Group C; L2-L3 puncture, epidural and IV saline), the IV lidocaine group (Group IV; L2-L3 puncture, saline epidural, IV lidocaine 1 mg/kg), the lumbar epidural lidocaine group (Group EL; L2-L3 puncture, 1.5% lidocaine epidural, IV saline), and the thoracic epidural lidocaine group (Group ET; T9-T10 puncture, 1.5%lidocaine epidural, IV saline). Two minutes after the beginning of the infusion of IV lidocaine or saline, propofol anesthesia was initiated. MEASUREMENTS: Mean arterial blood pressure (MAP), heart rate (HR), and sensory block height were monitored. The induction dose of propofol, its estimated effect site concentration (Ce), and plasma concentration were measured at various time points. Finally, we recorded the time taken for the bispectral index (BIS) to decrease to 60, the plasma concentration of lidocaine at induction, and the occurrence of adverse events. The induction time (when BIS reached 60) also was recorded. MAIN RESULTS: The induction propofol dose, Ce, and plasma concentration of propofol when BIS equaled 60 were significantly lower in Group IV, Group EL, and Group ET than Group C. The above parameters in Group ET (T9 - T10 puncture) were significantly less than in Group EL (L2 - L3 puncture). The induction doses of propofol and plasma concentration of propofol and lidocaine were significantly higher in Group IV than in Groups EL or ET. CONCLUSIONS: Epidural and IV lidocaine reduce the dose of propofol required to induce general anesthesia. Administration of lidocaine via the epidural route reduces anesthetic requirements more so than the IV route. Propofol requirements were further reduced in patients with higher sensory epidural block. PMID- 25439416 TI - Simulation-based education with deliberate practice may improve intraoperative handoff skills: a pilot study. AB - STUDY OBJECTIVE: To examine the results of simulation-based education with deliberate practice on the acquisition of handoff skills by studying resident intraoperative handoff communication performances. DESIGN: Preinvention and postintervention pilot study. SETTING: Simulated operating room of a university affiliated hospital. MEASUREMENTS: Resident handoff performances during 27 encounters simulating elective surgery were studied. Ten residents (CA-1, CA-2, and CA-3) participated in a one-day simulation-based handoff course. Each resident repeated simulated handoffs to deliberately practice with an intraoperative handoff checklist. One year later, 7 of the 10 residents participated in simulated intraoperative handoffs. All handoffs were videotaped and later scored for accuracy by trained raters. A handoff assessment tool was used to characterize the type and frequency of communication failures. The percentage of handoff errors and omissions were compared before simulation and postsimulation-based education with deliberate practice and at one year following the course. MAIN RESULTS: Initially, the overall communication failure rate, defined as the percentage of handoff omissions plus errors, was 29.7%. After deliberate practice with the intraoperative handoff checklist, the communication failure rate decreased to 16.8%, and decreased further to 13.2% one year after the course. CONCLUSIONS: Simulation-based education using deliberate practice may result in improved intraoperative handoff communication and retention of skills at one year. PMID- 25439417 TI - Absence of analgesic effect of intravenous melatonin administration during daytime after laparoscopic cholecystectomy: a randomized trial. AB - STUDY OBJECTIVE: To investigate whether melatonin administered intraoperatively reduced pain following laparoscopic cholecystectomy. DESIGN: Randomized, placebo controlled, double-blinded study. SETTING: Two surgical departments in Copenhagen. PATIENTS: 44 women between 18 and 70 years of age, who were surgical candidates for laparoscopic cholecystectomy. INTERVENTIONS: Patients were anesthetized by a standard protocol and received a standard multimodal postoperative analgesic regimen. Patients undergoing surgery were admitted on the day of surgery and were discharged the day after surgery. Ten mg of intravenous (IV) melatonin or placebo were administered at the time of surgical incision. MEASUREMENTS: Pain was assessed by a set of questionnaires documenting "pain at rest" using a visual analog scale (VAS). The use of rescue medication was recorded. Sleep quality and general well-being were measured on separate VAS scales. Sleepiness was assessed by the Karolinska Sleepiness Scale. MAIN RESULTS: Forty-four patients were included and randomized to the study. Three patients did not complete the study. No differences in VAS pain scores, sleep quality, general well-being, or sleepiness were found between the two groups in the postoperative period. The use of postoperative rescue medication did not differ between the groups. CONCLUSIONS: The use of 10mg of IV melatonin administered during laparoscopic cholecystectomy did not affect postoperative pain or use of analgesic medication. PMID- 25439418 TI - Effect of one anesthetic exposure on long-term behavioral changes in children. AB - STUDY OBJECTIVE: To determine the association between one anesthetic exposure and behavioral outcome at age 10 to 12 years. DESIGN: Retrospective comparative study. SETTING: University-affiliated pediatrics department. MEASUREMENTS: The medical records of children who underwent anesthesia between January 2004 and December 2005 at our institution were reviewed. The records of 292 children were included in the study group and 300 children in the control group. The study group involved children who had one anesthetic exposure before age of 4 years and the control group had children who were not exposed to anesthesia. The primary outcome was behavioral change as assessed by the Eyberg Child Behavior Inventory (ECBI) questionnaire. MAIN RESULTS: The rate of behavioral abnormalities before the age of 11 years was 28.4% in the study group (P<0.001) and 5.7% in the control group. The risk of developing behavioral abnormalities was prominent in children being exposed to surgery versus those exposed during a diagnostic procedure (32.4% vs 4.8%; P<0.0001). Eighty-three point nine percent of the children who were exposed to longer duration anesthesia (more than 3 hrs) had behavioral abnormalities (P<0.0001), while 48.8% of children who received anesthesia at younger ages (0 - 6 mos) had behavioral abnormalities (P<0.0001). Exposure to multiple anesthetic agents versus one anesthetic agent was a significant risk factor for development of behavioral abnormalities (P<0.0001). CONCLUSION: The incidence of behavioral abnormalities increased when anesthesia and surgery were accompanied by younger age, longer duration of surgery, and use of multiple anesthetic agents. PMID- 25439420 TI - Training for perioperative smoking cessation interventions: a national survey of anesthesiology program directors and residents. AB - STUDY OBJECTIVE: To ascertain current knowledge, attitudes, and practices of anesthesiology residents regarding tobacco control, and to determine the characteristics of current residency training offered in tobacco control. DESIGN: Electronically distributed survey instrument of anesthesiology residency program directors and residents. SETTING: University medical center. MEASUREMENTS AND MAIN RESULTS: The program director and resident response rates were 75/131 (57.3%) and 490/1182 (41.4%), respectively. Programs currently provide education regarding the perioperative consequences of smoking and, with the exception of the effect of smoking cessation shortly before surgery, resident knowledge reflected this curricular emphasis. However, the strong majority of programs did not offer education on how to ask about smoking status and advise cessation (79.5%) or help tobacco users quit before surgery (89.0%), though both program directors and residents felt these topics should be covered. A strong majority of residents (87.8%) felt the perioperative period was an effective time to assist in long-term smoking cessation, and desired education on tobacco control. Barriers to helping patients quit preoperatively included lack of time and low confidence in counseling abilities. CONCLUSIONS: A need exists for expanded formal education on perioperative tobacco cessation interventions for anesthesiology residents. PMID- 25439419 TI - Optimal dose of succinylcholine for tracheal intubation in patients during inhalation induction with sevoflurane: a randomized controlled trial. AB - STUDY OBJECTIVE: To determine the dose of succinylcholine during inhalation induction of a patient. DESIGNED: Prospective, double-blind, randomized study. SETTING: Operating room of a university hospital. PATIENTS: 180 adult, ASA physical status 1 and 2 patients with a suspected difficult airway, who were scheduled for surgery. INTERVENTIONS: Nonpremedicated patients were anesthetized with inhalation of 8% sevoflurane, followed by succinylcholine. Group 1 received intravenous (IV) succinylcholine 0.3 mg/kg, Group 2 had IV succinylcholine 0.6 mg/kg, and Group 3 was given IV succinylcholine 1.0 mg/kg. Direct laryngoscopy and tracheal intubation were performed after onset of succinylcholine. MEASUREMENTS: Intubation conditions were scored as excellent, good, or poor. The recovery time of spontaneous respiration, end-tidal carbon dioxide partial pressure (PETCO2), and pulse oxygen saturation (SpO2) were recorded. MAIN RESULTS: Acceptable conditions (excellent and good) for intubation were rated in 80% of Group 1 patients (0.3 mg/kg succhinylcholine), 91.7% of Group 2 patients (0.6 mg/kg), and 93.3% of Group 3 patients (1.0 mg/kg), respectively. Intubation scores were similar in Groups 2 and 3, and were significantly higher than in Group 1 patients (0.3 mg; P < 0.01). Time to recovery of spontaneous respiration in Group 3 was significantly prolonged compared with Groups 1 and 2 (238 +/- 59 sec vs 132 +/- 43 sec, P < 0.001; 238 +/- 59 sec vs 151 +/- 47 sec, P < 0.001, respectively). SpO2 in Group 3 did not differ significantly from Group 1 and 2 values. However, PETCO2 in Group 3 was significantly higher than in Groups 1 or 2. CONCLUSIONS: Succinylcholine at a dose of 0.6 mg/kg IV provided intubation conditions similar to succinylcholine at 1.0 mg/kg IV, and recovery of spontaneous respiration following a 0.6 mg/kg dose of succinylcholine was significantly shorter. PMID- 25439421 TI - High-frequency jet ventilation using the Arndt bronchial blocker for refractory hypoxemia during one-lung ventilation in a myasthenic patient with asthma. AB - A novel method in the management of refractory severe hypoxemia during one-lung ventilation (OLV) in a patient who presented with myasthenia gravis, asthma, a symptomatic mediastinal mass, hiatal hernia, and a moderate pericardial effusion is presented. The patient was scheduled for excision of a large anterior mediastinal mass and creation of a pericardial window through a left thoracotomy. One-lung ventilation was achieved using an Arndt bronchial blocker. High frequency jet ventilation (HFJV) was applied to the surgical nondependent lung through the lumen of the Arndt endobronchial blocker with titration of positive end-expiratory pressure to the dependent lung. Oxygenation improved significantly. The use of HFJV through the Arndt blocker offers an effective method for treatment of refractory hypoxemia during OLV. PMID- 25439422 TI - Anaphylaxis to succinylated gelatin in a patient with a meat allergy: galactose alpha(1, 3)-galactose (alpha-gal) as antigenic determinant. AB - Specific immunoglobulin E (sIgE) antibodies towards the galactose-alpha(1,3) galactose (alpha-gal) moieties may elicit life-threatening and fatal anaphylactic reactions. Patients sensitized to alpha-gal moieties from mammalian meat may also react towards mammalian gelatins and gelatin-containing drugs such as bovine gelatin-based colloid plasma substitute. The case of a 56 year old woman with a meat allergy who suffered anaphylaxis to succinylated gelatin is reported. PMID- 25439423 TI - A patient who received clopidogrel with an indwelling epidural catheter. AB - A patient with a drug-eluting stent placed 18 months earlier received a thoracic epidural for perioperative analgesic control as part of her thoracotomy. Postoperatively, the patient was started on clopidogrel for secondary prevention. After consultation with the Hematology service and a platelet function assay, the patient was transfused two pools of platelets and the epidural catheter was removed on postoperative day 4. The patient then underwent hourly neurologic checks for 24 hours and was discharged several days later without any negative sequelae. If neuraxial techniques and the need for clopidogrel prophylaxis come into direct conflict, vigilance is necessary for warning signs of epidural hematoma and platelet transfusion should be considered to reverse the effects of the drug. PMID- 25439424 TI - Difficult airway management in a patient with combined severe deep neck abscess and acute epiglottitis with abscess. PMID- 25439425 TI - A simple maneuver for negotiating an obstructing floppy or "horseshoe" epiglottis or prominent arytenoids when using a channeled, indirect laryngoscope. PMID- 25439426 TI - Modified prone positioning for dorsal spine surgery in a patient with postural deformity due to spasticity of lower limbs. PMID- 25439427 TI - Glycyrrhizin administration for inhibition of mucus production during one-lung ventilation. PMID- 25439428 TI - Severe hypophosphatemia: a rare cause of postoperative muscle weakness. PMID- 25439430 TI - Genetic variations of IL17F and IL23A show associations with Behcet's disease and Vogt-Koyanagi-Harada syndrome. AB - PURPOSE: To investigate the associations of IL17A, IL17F, IL23A, and IL23R copy number variants (CNVs) with Vogt-Koyanagi-Harada (VKH) syndrome and Behcet's disease (BD) and the possible mechanisms involved. DESIGN: Two-stage case-control and functional studies. PARTICIPANTS: A total of 1159 VKH patients, 1036 BD patients, and 2050 controls were enrolled. METHODS: TaqMan real-time polymerase chain reaction assay was used for genotyping of copy number variant. Cell proliferation was measured by colorimetric assay. MAIN OUTCOME MEASURES: Association of CNVs in IL17A, IL17F, IL23A, and IL23R with BD and VKH syndrome and the functional roles of IL17F CNVs. RESULTS: Increased frequencies of more than 2 copies of IL17F and IL23A were found in BD patients as compared with controls (IL17F: P=4.17*10(-8); odds ratio [OR], 2.2; IL23A: P=2.86*10(-11); OR, 2.8, respectively). A similar result was found for VKH syndrome (IL17F: P=2.84*10(-13); OR, 2.7; IL23A: P=4.46*10(-17); OR, 3.4, respectively). Interestingly, the association of IL17F and IL23A with BD was found only in male patients (IL17F: P=1.06*10(-6); OR, 2.3; IL23A, P=3.81*10(-8); OR, 2.8, respectively), but not in female patients. No association of CNVs in IL17A and IL23R was found for BD and VKH syndrome. IL17F protein levels were correlated positively with gene copy numbers (P=3.43*10(-7)). Individuals with high IL17F copies showed enhanced peripheral blood mononuclear cells (PBMC) proliferation (P=5.67*10(-3)). CONCLUSIONS: High gene copy numbers of IL17F and IL23A were associated with BD and VKH syndrome. Enhanced IL17F protein production and PBMC proliferation were associated with high IL17F copy numbers. PMID- 25439429 TI - Improvement in vision-related function with intravitreal aflibercept: data from phase 3 studies in wet age-related macular degeneration. AB - PURPOSE: To evaluate the effect of intravitreal aflibercept injection on visual function in wet age-related macular degeneration (AMD). DESIGN: Prospective, multicenter, double-masked, active-controlled, parallel-group, randomized phase 3 clinical studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW] 1 and 2 [clinicaltrials.gov identifiers, NCT00509795 and NCT00637377, respectively]). PARTICIPANTS: Patients (n=2419) with active, treatment-naive, exudative AMD. This analysis included patients who received intravitreal aflibercept 2.0 mg every 8 weeks (2q8; n=607) or ranibizumab 0.5 mg every 4 weeks (0.5q4; n=595). INTERVENTION: Patients were randomized 1:1:1:1 to receive intravitreal aflibercept 2q8 (after 3 initial monthly doses), intravitreal aflibercept 2q4, intravitreal aflibercept 0.5q4, or ranibizumab 0.5q4 in the study eye. Patients in the intravitreal aflibercept 2q8 group received a sham injection alternating with active treatment. MAIN OUTCOME MEASURES: The 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) was administered at baseline and at weeks 12, 24, 36, and 52. The NEI VFQ-25 subscale scores were compared between intravitreal aflibercept 2q8 and ranibizumab 0.5q4 treatment arms, the approved dosing for each agent worldwide. Change in composite NEI VFQ-25 score was evaluated based on categorical change in visual acuity (worsened, unchanged, improved). RESULTS: Baseline NEI VFQ-25 scores were similar for both treatments in both studies. Mean change from baseline to 52 weeks was similar for ranibizumab 0.5q4 and intravitreal aflibercept 2q8 across all 12 subscales, with the greatest improvements noted for mental health and general vision (9.0-11.6 points, both treatments, both studies). Improvement of 4 points or more (both treatments, both studies) also was observed for subscales near vision, distance vision, role difficulties, and dependency. Mean change from baseline to 52 weeks in NEI VFQ-25 composite score (pooled data) stratified by clinical response showed meaningful improvement only in patients who gained 5 Early Treatment Diabetic Retinopathy letters or more (7.3 and 7.8 points for intravitreal aflibercept 2q8 and ranibizumab 0.5q4, respectively). CONCLUSIONS: Visual function outcomes were similar across all NEI VFQ-25 subscales over 52 weeks for intravitreal aflibercept 2q8 and ranibizumab 0.5q4, with clinically meaningful improvement recorded in 6 of 12 subscales. PMID- 25439431 TI - Primary transpupillary thermotherapy for choroidal melanoma in 391 cases: importance of risk factors in tumor control. AB - PURPOSE: To report the long-term outcome of primary transpupillary thermotherapy (TTT) for choroidal melanoma. DESIGN: Retrospective review of medical records. PARTICIPANTS: We included 391 patients with choroidal melanoma treated between 1995 and 2012 at the Oncology Service, Wills Eye Hospital, Philadelphia. METHODS: We delivered TTT with an infrared diode laser. MAIN OUTCOME MEASURES: Local tumor recurrence, Snellen visual acuity after TTT, and distant metastasis. RESULTS: Of 391 patients, 311 (80%) were treated from 1995 to 2000 and 80 (20%) from 2001 to 2012. Tumors in the 2001 to 2012 group were ultrasonographically thinner (2.2 vs. 2.7 mm), more distant from the optic disc (3.2 vs. 2.5 mm) and foveola (4.0 vs. 2.0 mm), were less often located in the macular area (14% vs. 40%), and had lower rates of acoustic hollowness on B-scan ultrasonography (63% vs. 84%), subretinal fluid (58% vs. 90%), and orange pigment (50% vs. 70%). Kaplan-Meier estimates for tumor recurrence in the 1995 to 2000 group were 29% at 5 years and 42% at 10 years, whereas estimates for tumor recurrence in the 2001-2012 group were 11% at 5 years and 15% at 10 years. Of 108 recurrent tumors 20 were controlled with additional TTT and 62 required plaque radiation (n=60) or proton beam radiation (n=2), with enucleation necessary in 26 patients. Tumor recurrence correlated with the number of high-risk tumor features: 10-year recurrence was 18% in those with 1 or 2 risk factors, 35% in those with 3 to 5 factors, and 55% in those with 6 or 7 factors. On multivariate analysis, features predictive of tumor recurrence were presence of symptoms (P<0.001), shorter distance between the tumor and the optic disc (P=0.026), subretinal fluid (P=0.035), thickness of residual tumor scar (P<0.001), and elevation of residual tumor scar (P<0.001). The only factor predictive of extraocular tumor extension was intraocular tumor recurrence after TTT treated with additional TTT (P=0.007). Presence of orange pigment before TTT (P=0.019), tumor recurrence (P=0.002), and extraocular tumor extension (P=0.017) were predictive of distant metastasis. CONCLUSION: This study shows a direct correlation between a larger number of high-risk tumor features and higher rates of tumor recurrence after primary TTT of (small) choroidal melanoma. We advise that, when possible, small choroidal melanomas with multiple risk factors be treated with methods other than TTT. PMID- 25439432 TI - Myopia control during orthokeratology lens wear in children using a novel study design. AB - PURPOSE: To investigate the effect of overnight orthokeratology (OK) contact lens wear on axial length growth in East Asian children with progressive myopia. DESIGN: A prospective, randomized, contralateral-eye crossover study conducted over a 1-year period. PARTICIPANTS: We enrolled 26 myopic children (age range, 10.8-17.0 years) of East Asian ethnicity. METHODS: Subjects were fitted with overnight OK in 1 eye, chosen at random, and conventional rigid gas-permeable (GP) lenses for daytime wear in the contralateral eye. Lenses were worn for 6 months. After a 2-week recovery period without lens wear, lens-eye combinations were reversed and lens wear was continued for a further 6 months, followed by another 2-week recovery period without lens wear. Axial eye length was monitored at baseline and every 3 months using an IOLMaster biometer. Corneal topography (Medmont E300) and objective refraction (Shin-Nippon NVision-K 5001 autorefractor) were also measured to confirm that OK lens wear was efficacious in correcting myopia. MAIN OUTCOME MEASUREMENTS: Axial length elongation and myopia progression with OK were compared with conventional daytime rigid contact lens wear. RESULTS: After 6 months of lens wear, axial length had increased by 0.04+/ 0.06 mm (mean+/-standard deviation) in the GP eye (P=0.011) but showed no change (-0.02+/-0.05 mm) in the OK eye (P=0.888). During the second 6-month phase of lens wear, in the OK eye there was no change from baseline in axial length at 12 months (-0.04+/-0.08 mm; P=0.218). However, in the GP eye, the 12-month increase in axial length was significant (0.09+/-0.09 mm; P<0.001). The GP lens-wearing eye showed progressive axial length growth throughout the study. CONCLUSIONS: These results provide evidence that, at least in the initial months of lens wear, overnight OK inhibits axial eye growth and myopia progression compared with conventional GP lenses. Apparent shortening of axial length early in OK lens wear may reflect the contribution of OK-induced central corneal thinning, combined with choroidal thickening or recovery due to a reduction or neutralization of the myopiogenic stimulus to eye growth in these myopic children. PMID- 25439433 TI - Chronic central serous chorioretinopathy is associated with genetic variants implicated in age-related macular degeneration. AB - PURPOSE: In this study, single nucleotide polymorphisms (SNPs) at 19 loci, previously associated with age-related macular degeneration (AMD), were systematically tested for association in patients with chronic central serous chorioretinopathy (cCSC). In addition, we evaluated the effect of detailed phenotyping on these genetic associations. DESIGN: Case-control study. PARTICIPANTS: We included 292 cCSC patients, 1147 AMD patients, and 1311 control individuals. METHODS: We genotyped SNPs at 19 AMD-associated loci and 6 additional SNPs at the complement factor H (CFH) locus. Phenotyping of all patients was based on fundoscopy, spectral-domain optical coherence tomography, fluorescein angiography (FA), and indocyanine green angiography. MAIN OUTCOME MEASURES: We measured the allele frequencies of 25 AMD-associated SNPs and CFH haplotype frequencies in patients with cCSC and the effect of phenotypic subdivision of cCSC on genetic associations. RESULTS: One SNP in ARMS2 (rs10490924) was significant after Bonferroni correction (Punadjusted=0.002; odds ratio [OR]=0.64). The SNPs at 3 other AMD loci (CFH, TNFRSF10A, ADAMTS9) showed a trend toward association with typical cCSC. Further analysis of the CFH locus identified 2 SNPs that significantly conferred increased risk for cCSC and 1 that was protective. The CFH-H3 haplotype was also found to be protective (P=0.01; OR=0.54). Using multimodal imaging, 197 patients were classified as having typical cCSC, 52 patients had unilateral abnormalities on FA that were otherwise typical of cCSC, and 43 patients had a clinical picture that could be compatible with cCSC, but with features that could also indicate other macular diseases. Significant differences of the minor allele frequencies of the tested SNPs were observed between these 3 phenotypic subgroups. CONCLUSIONS: Chronic CSC is associated with genetic variants in ARMS2 and CFH, indicating a genetic and pathophysiologic overlap between cCSC and AMD. Intriguingly, alleles in ARMS2 and CFH that confer risk of AMD may be protective for cCSC, and alleles in CFH that are protective for AMD confer risk for cCSC. Significant differences in allele frequencies were found among the phenotypic subgroups for several SNPs, illustrating the importance of correct clinical classification. PMID- 25439434 TI - Transscleral permeation of subtenon triamcinolone in different vitreoretinal diseases. PMID- 25439435 TI - Treatment of diabetic macular edema with an inhibitor of vascular endothelial protein tyrosine phosphatase that activates Tie2. AB - PURPOSE: AKB-9778 is a small-molecule competitive inhibitor of vascular endothelial-protein tyrosine phosphatase (VE-PTP) that promotes Tie2 activation and reduces vascular leakage and neovascularization in mouse models. The purpose of this study was to test the safety, tolerability, pharmacokinetics, and biological activity of AKB-9778 in patients with diabetic macular edema (DME). DESIGN: Open-label, dose-escalation clinical trial. PARTICIPANTS: Four dose cohorts of 6 patients with DME self-administered subcutaneous injections of 5 mg, 15 mg, 22.5 mg, or 30 mg AKB-9778 twice daily for 4 weeks. METHODS: Patients were seen weekly during a 4-week treatment period for safety assessments, best corrected visual acuity (BCVA) assessment by Early Treatment Diabetic Retinopathy Study protocol, and measurement of central subfield thickness (CST) by spectral domain optical coherence tomography. Additional safety assessments were performed at 6, 8, and 12 weeks. MAIN OUTCOME MEASURES: Safety assessments, change from baseline BCVA, and change from baseline CST. RESULTS: All doses were well tolerated. A modest, transient reduction in blood pressure and adverse events consistent with vasodilatory activity of AKB-9778 emerged at doses of 22.5 mg or more twice daily. At the week 4 primary end point, BCVA improved 5 letters or more from baseline in 13 of the 18 patients receiving 15 mg or more twice daily; 1 patient improved by 10 to 15 letters, and 2 patients improved by more than 15 letters. Among 18 patients receiving 15 mg or more twice daily, CST decreased by more than 100 MUm in 5 patients and by 50 to 100 MUm in 2 patients. There was a significant correlation between reduction in CST and improvement in BCVA. CONCLUSIONS: No safety concerns were identified after systemic administration of AKB-9778 for 4 weeks in patients with DME, and doses of 15 mg or more twice daily reduced macular edema and improved vision in some patients. This is a preliminary demonstration of clinical safety and efficacy of a VE-PTP inhibitor and Tie2 activator. PMID- 25439436 TI - Referral patterns in advanced non-small cell lung cancer: impact on delivery of treatment and survival in a contemporary population based cohort. AB - INTRODUCTION: Chemotherapy improves overall survival (OS) in advanced non-small cell lung cancer (NSCLC), yet low rates of chemotherapy utilization have been observed. We sought to characterize the clinical effectiveness of chemotherapy in the general population by evaluating referral patterns, predictors of chemotherapy receipt and outcomes. METHODS: All referred cases of stage IIIB/IV NSCLC in British Columbia from January 1 to December 31, 2009 were retrospectively reviewed. Patient demographics, tumor characteristics and treatments were extracted. OS was estimated using the Kaplan-Meier method. Cox Proportional Hazards modeling was used to control for confounding variables. Multiple logistic regression was used to assess factors that predicted for chemotherapy treatment. RESULTS: 1373 patients were identified. Median age 70 years, 53% male, 37% ECOG >= 3. HISTOLOGY: 34% non-squamous, 21% squamous and 46% NOS. 748 (54%) patients were assessed by medical oncology and 417 (30%) received chemotherapy. Predictors of chemotherapy treatment were younger age, ECOG 0-2, living in a rural area and not receiving radiotherapy. There was an improvement in OS in patients who received chemotherapy at 13.1 months versus best supportive care 5.4 months (p<0.0001). This remained statistically significant when controlling for ECOG, sex, age, histology (HR 0.68, CI 0.59-0.78). CONCLUSIONS: In this population-based setting, 37% of patients had an ECOG >= 3 at the time of referral, 54% were assessed by a medical oncologist and only 30% received chemotherapy. This is despite the awareness that chemotherapy significantly improves survival. Strategies to optimize appropriate referral such that patients do not miss out on life-prolonging therapy should be evaluated. PMID- 25439437 TI - Comparison of survival and hospitalization rates between Medicare patients with advanced NSCLC treated with bevacizumab-carboplatin-paclitaxel and carboplatin paclitaxel: a retrospective cohort study. AB - OBJECTIVE: The use of bevacizumab in advanced non-squamous non-small cell lung cancer (NSCLC) is controversial among elderly patients. This study aimed to compare overall survival for Medicare patients diagnosed with NSCLC and treated with either first-line bevacizumab-carboplatin-paclitaxel (BCP) or carboplatin paclitaxel (CP). METHODS: Patients >= 65 years old, first diagnosed with non squamous NSCLC stage IIIB/IV between 2006 and 2009, and treated with either first line BCP or CP, were selected from the SEER-Medicare database that links cancer registry and US Medicare claims data. Kaplan-Meier estimates were used to evaluate survival. Multivariable Cox proportional hazards models were used to compare the effect of BCP versus CP on the hazard of death. Age-stratified analyses were conducted for patients aged 65-74 and >= 75 years. RESULTS: Of 1706 patients in the study sample, 592 (34.7%) received BCP and 1114 (65.3%) received CP; 692 (40.6%) were >= 75 years. Adjusted median survival time in the BCP versus CP cohorts was 10.5 versus 8.5 months (p = 0.008). The difference in median survival favoring the BCP cohort was statistically significant for both patients aged >= 75 years (2.8 months, p = 0.019), and patients aged 65-74 years (1.5 months, p = 0.018). The adjusted hazard of death did not differ between the cohorts (HR: 0.96, 95% CI: 0.86-1.06); however, during the first year of follow up, when most deaths (>60%) occurred, the hazard of death was 18% lower for the BCP cohort (HR: 0.82, 95% CI: 0.71-0.94). BCP patients also had 18% fewer hospital admissions than CP patients (adjusted incidence rate ratio (IRR): 0.82, 95% CI: 0.72-0.94) and 23% fewer inpatient days (IRR: 0.77, 95% CI: 0.65-0.91). CONCLUSIONS: In this retrospective analysis of Medicare patients in the SEER database, first-line therapy with BCP was associated with longer survival and fewer hospitalizations than CP. PMID- 25439438 TI - Ultrafiltration of equine digital lamellar tissue. AB - There are no experimentally validated pharmacological means of preventing laminitis; however, locally acting pharmaceutical agents with the potential to prevent laminitis have been identified. Demonstrating therapeutic drug concentrations in lamellar tissue is essential for evaluating the efficacy of these agents. The aim of this study was to develop an experimental technique for repeatedly sampling lamellar interstitial fluid. A technique for placing ultrafiltration probes was developed in vitro using 15 cadaver limbs. Subsequently, lamellar ultrafiltration probes were placed in one forelimb in six living horses. Interstitial fluid was collected continuously from the probes as ultrafiltrate for 4 (n = 4) or 14 days (n = 2). The rate of ultrafiltrate collection was calculated every 12 h. Biochemical analyses were performed on ultrafiltrate collected on night 1 (12-24 h post-implantation) and night 4 (84-96 h post-implantation). Sections surrounding the probe and control tissue from the contralateral limb were harvested, stained with H&E and Masson's trichrome and scored based on the tissue response to the probe. Ultrafiltration probes were placed in the lamellar tissue in all six horses. Ultrafiltrate was collected from these probes at 55 (30-63) MUL/h (median [interquartile range]). Fluid production decreased significantly with time from night 3 onwards (P < 0.05). There was no significant change in the constituents of the ultrafiltrate between nights 1 and 4 (P > 0.05). The technique was well tolerated. This study demonstrates that ultrafiltration can be used to sample equine digital lamellar interstitial fluid, and has potential for measuring lamellar drug levels. PMID- 25439439 TI - Relationship between automated total nucleated cell count and enumeration of cells on direct smears of canine synovial fluid. AB - Canine osteoarthritis is a common disorder seen in veterinary clinical practice and causes considerable morbidity in dogs as they age. Synovial fluid analysis is an important tool for diagnosis and treatment of canine joint disease and obtaining a total nucleated cell count (TNCC) is particularly important. However, the low sample volumes obtained during arthrocentesis are often insufficient for performing an automated TNCC, thereby limiting diagnostic interpretation. The aim of the present study was to investigate whether estimation of TNCC in canine synovial fluid could be achieved by performing manual cell counts on direct smears of fluid. Fifty-eight synovial fluid samples, taken by arthrocentesis from 48 dogs, were included in the study. Direct smears of synovial fluid were prepared, and hyaluronidase added before cell counts were obtained using a commercial laser-based instrument. A protocol was established to count nucleated cells in a specific region of the smear, using a serpentine counting pattern; the mean number of nucleated cells per 400 * field was then calculated. There was a positive correlation between the automated TNCC and mean manual cell count, with more variability at higher TNCC. Regression analysis was performed to estimate TNCC from manual counts. By this method, 78% of the samples were correctly predicted to fall into one of three categories (within the reference interval, mildly to moderately increased, or markedly increased) relative to the automated TNCC. Intra-observer and inter-observer agreement was good to excellent. The results of the study suggest that interpretation of canine synovial fluid samples of low volume can be aided by methodical manual counting of cells on direct smears. PMID- 25439440 TI - Equine sarcoid: In situ demonstration of matrix metalloproteinase expression. AB - Sarcoids are the most prevalent equine skin tumours and remain a therapeutic challenge due to their differing clinical morphology, local aggressive behaviour, and high recurrence following surgical treatment. In vitro, sarcoid derived fibroblasts are invasive and express matrix metalloproteinase (MMP) -1, -2 and 9. It was hypothesised that the MMPs produced by neoplastic cells play a role in both their local invasiveness and interaction with the overlying epidermis (picket fence formation). The objective of this morphological study was to investigate the local behaviour and in situ MMP expression pattern in sarcoids of different clinical types. A total of 43 surgically excised sarcoids were examined by histology, immunohistology for the expression of MMP-1, -2 and -9, and transmission electron microscopy. Regardless of the clinical type, sarcoids showed local invasion of the dermis and damage to the basement membrane in areas of interaction with the epidermis. This was associated with MMP-1 expression in both neoplastic cells and epidermis. The results suggest a link between MMP-1 expression and the local aggressiveness of sarcoids regardless of the clinical type. PMID- 25439441 TI - Dynamics of uterine infections with Escherichia coli, Streptococcus uberis and Trueperella pyogenes in post-partum dairy cows and their association with clinical endometritis. AB - The diversity and dynamics of the uterine microbiota of dairy cows are poorly understood although it is becoming increasingly evident that they play a crucial role in the development of metritis and endometritis. Fourier-transform infrared (FTIR) spectroscopy was used to monitor the bovine microbiota of 40 cows on the day of calving and days 3, 9, 15, and 21 after parturition, and to investigate the associations of selected species with clinical endometritis (CE). Trueperella pyogenes (43.5%), Escherichia coli (21.5%), Bacillus spp. (21.0%) and Streptococcus uberis (18.5%) were the most frequently isolated microbes. Analyses of different sampling time points revealed that the presence of S. uberis on day 3 increased the risk of subsequent T. pyogenes infection on day 9 (odds ratio [OR] = 5.1, 95% confidence interval [CI] = 1.2-22.6). T. pyogenes infection (OR = 36.0, 95% CI = 3.8-343.2) and retained fetal membranes (RFM) (OR = 12.4, 95%CI = 1.4-112.7) were significant risk factors for CE. Cows with S. uberis on day 3 tended to have greater odds of CE than S. uberis-negative cows (OR = 7.1, 95% CI = 0.9-55.6). Chemometric analysis revealed significant differences in the metabolic profile of S. uberis strains isolated from cows with different vaginal discharge scores. This is the first study showing the association of specific S. uberis subtypes with the uterine health status of post-partum dairy cows. The study demonstrates that uterine clearance is a highly dynamic process, during which time bacteria show distinct patterns of progression, and provides information about interactions between bacterial species involved in the occurrence of CE. PMID- 25439442 TI - In vitro susceptibilities of caprine Mycoplasma agalactiae field isolates to six antimicrobial agents using the E test methodology. AB - The minimum inhibitory concentrations (MICs) of enrofloxacin, ciprofloxacin, spectinomycin, tetracycline, spiramycin and erythromycin against 30 caprine Greek isolates of Mycoplasma agalactiae were determined using E test methodology. The E test strips were placed on Eaton's agar medium without antimicrobials and phenol red. MICs were then read by determining where the growth inhibition zone intersected with the MIC scale on the strip. An MIC value of 8 ug/mL was considered as a guide to mycoplasma resistance. All isolates were sensitive to fluoroquinolones (MIC50, 0.19 g/mL; MIC90, 0.38 ug/mL; highest MIC, 0.5 ug/mL), spectinomycin (MIC50, 0.5 ug/mL; MIC90, 1 ug/mL; highest MIC, 1 ug/mL), and spiramycin (MIC50, 1 ug/mL; MIC90, 1.5 ug/mL; highest MIC, 2 ug/mL). Two strains exhibited resistance to tetracycline (MIC 32 ug/mL) but these were not found to carry any of the tet(M), tet(O), and tet(S) resistance genes. Finally all isolates expressed resistance to erythromycin (MIC50, 128 ug/mL; MIC90, >256 ug/mL). PMID- 25439443 TI - Classification of primary hepatic tumours in the cat. AB - Hepatic tumours in dogs have recently been re-classified to follow a revised human classification system that takes account of identified hepatic progenitor cells. This study investigated the presence and relative frequency of morphological types of feline primary hepatic neoplasms and aimed to determine whether a similar new classification scheme could be applied in cats. Feline primary liver tumours (n = 61) were examined histologically and with a series of immunohistochemical markers. Six cases of nodular hyperplasia and 21 tumours of hepatocellular origin were diagnosed. The latter were subdivided into hepatocellular tumours that were well differentiated and had no evidence of metastases (n = 18) and tumours that showed poorly differentiated areas with marked cellular and nuclear pleomorphism and had intrahepatic and, or, distant metastases (n = 3). These malignant feline hepatocellular tumours maintained their hepatocellular characteristics (HepPar-1, MRP2, pCEA positive) and were negative, or only <5% positive, for K19. Twenty-five cholangiocellular tumours were diagnosed and all had intrahepatic and, or, distant metastases. Eight NSE positive small cell carcinomas (carcinoids) were diagnosed and subdivided into small cell carcinomas with HPC characteristics (K19 positive) and neuroendocrine carcinomas (K19 negative). In addition, one squamous cell carcinoma originating from the distal part of the choledochal duct was recognised. Feline primary hepatic neoplasms can be sub-divided into benign and malignant hepatocellular tumours, cholangiocellular carcinomas, small cell carcinomas with HPC characteristics, neuroendocrine carcinomas and squamous cell carcinomas. The marked species difference justifies a specific classification for feline primary hepatic neoplasms. PMID- 25439444 TI - Proactive and reactive neuromuscular control in subjects with chronic ankle instability: evidence from a pilot study on landing. AB - To understand why subjects with chronic ankle instability (CAI) have frequent sprains, one must study the preparation/reactions of these subjects to situations related to ankle inversion in real life. In the present pilot study, we examined whether subjects with CAI altered their neuromuscular control and reflex responses during and after ankle perturbations in landing. EMG signals were collected from the tibialis anterior (TA), peroneus longus (PL), medial gastrocnemius (MG), and gluteus medius (GLM) of both legs in 9 subjects with CAI and 9 subjects with intact ankles (control). A trapdoor was used to produce an ankle inversion of 25 degrees with the left leg (control) or the affected leg (CAI) in 0%, 50% or 100% of the landing trials. As compared to controls, subjects with CAI had increased proactive activity in the contralateral side prior to touchdown during landing trials with 50% (PL) and 100% (PL and MG) chance of inversion (all, p < 0.05). The increase proactive control on the contralateral side could be part of a strategy to smooth the impact of landing on the affected side in subjects with CAI. Following touchdown, the CAI group showed decreased ipsilateral short latency reflex (SLR) responses in all test conditions both in distal (PL and MG) and in proximal muscles (GLM) on the affected side (all, p < 0.05). Finally, subjects with CAI adjusted their reflex gain differently as compared to controls when exposed to a possible inversion. Overall, individuals with CAI displayed different neuromuscular strategies from controls while landing. PMID- 25439445 TI - Resistant hypertension due to unilateral renal artery occlusion as the first presentation of antiphospholipid syndrome. AB - Resistant hypertension in the setting of renal artery occlusion should prompt further investigation for secondary causes in a young patient. We present renal artery occlusion in the setting of antiphospholipid syndrome as the initial presentation successfully treated with percutaneous intervention. This case is followed by review of the literature. PMID- 25439446 TI - Novel characterization method for fibrous materials using non-contact acoustics: material properties revealed by ultrasonic perturbations. AB - Fibrous materials are unique hierarchical complex structures exhibiting a range of mechanical, thermal, optical and electrical properties. The inherent discontinuity at micro and macro levels, heterogeneity and multi-scale porosity differentiates fibrous materials from other engineering materials that are typically continuum in nature. These structural complexities greatly influence the techniques and modalities that can be applied to characterize fibrous materials. Typically, the material response to an applied external force is measured and used as a characteristic number of the specimen. In general, a range of equipment is in use to obtain these numbers to signify the material properties. Nevertheless, obtaining these numbers for materials like fiber ensembles is often time consuming, destructive, and requires multiple modalities. It is hypothesized that the material response to an applied acoustic frequency would provide a robust alternative characterization mode for rapid and non destructive material analysis. This research proposes applying air-coupled ultrasonic acoustics to characterize fibrous materials. Ultrasonic frequency waves transmitted through fibrous assemblies were feature extracted to understand the correlation between the applied frequency and the material properties. Mechanical and thermal characteristics were analyzed using ultrasonic features such as time of flight, signal velocity, power and the rate of attenuation of signal amplitude. Subsequently, these temporal and spectral characteristics were mapped with the standard low-stress mechanical and thermal properties via an empirical artificial intelligence engine. A high correlation of >0.92 (S.D. 0.06) was observed between the ultrasonic features and the standard measurements. The proposed ultrasonic technique can be used toward rapid characterization of dynamic behavior of flexible fibrous assemblies. PMID- 25439447 TI - Prevalence and characteristics of Streptococcus pneumoniae "putative serotype 6E" isolates from Asian countries. AB - The prevalence, antimicrobial susceptibility, and genotypes of Streptococcus pneumoniae "putative serotype 6E" isolates from Asian countries were investigated. A total of 244 S. pneumoniae serogroup 6 isolates obtained from 11 Asian countries were included in this study. Of the 244 serogroup 6 isolates, 101 (41.4%) were typed as "putative serotype 6E," followed by serotypes 6A, 6B, 6C, and 6D (27.0, 20.1, 5.7, and 5.7%, respectively). Multilocus sequence typing revealed that clonal complex (CC) 90, including ST90 and its variants, was the most prevalent clonal group of "putative serotype 6E" isolates (n = 63; 62.4%). CC146 and CC315 were also found frequently in some of the countries. Most of the "putative serotype 6E" isolates showed very high resistance rates against cefuroxime, erythromycin, azithromycin, clarithromycin, clindamycin, and trimethoprim/sulfamethoxazole, probably due to their highly resistant to antimicrobials clone, CC90. Our results indicate that "putative serotype 6E" is prevalent in Asian countries. The clonal dissemination of "putative serotype 6E" isolates was also identified. PMID- 25439448 TI - Impact on in-hospital outcomes with drug-eluting stents versus bare-metal stents (from 665,804 procedures). AB - Contemporary large-scale data, regarding in-hospital outcomes depending on the types of stent used for percutaneous coronary intervention (PCI) is lacking. We queried the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample from 2006 to 2011 using the International Classification of Diseases, Ninth Revision, Clinical Modification procedure code 36.06 (bare-metal coronary artery stent, BMS) or 36.07 (drug-eluting coronary artery stent, DES) for PCI. All analyses were performed using the designated weighting specified to the Nationwide Inpatient Sample database to minimize bias. Primary outcome was in hospital mortality. Wald's chi-square test was used for categorical variables. We built a hierarchical 2 level model adjusted for multiple confounding factors, with hospital identification incorporated as random effects in the model and propensity match analyses were used to adjust confounding variables. A total of 665,804 procedures were analyzed, which were representative of 3,277,884 procedures in the United States. Use of bare-metal stents (BMS) was associated with greater occurrence of in-hospital mortality compared with that of drug eluting stents (DES; 1.4% vs 0.5%, p <0.001). The association stayed significant after adjustment of various possible confounding factors (odds ratio for DES versus BMS 0.59 [0.54 to 0.64, p <0.001]) and also in propensity matched cohorts (1.2% vs 0.7%, p <0.001). The results continued to be similar in the following high-risk subgroups: diabetes (0.57 [0.50 to 0.64, <0.001]), acute myocardial infarction and/or shock (0.53 [0.49 to 0.57, <0.001]), age >80 (0.66 [0.58 to 0.74, <0.001]), and multivessel PCI (0.55 [0.46 to 0.66, <0.001]). In conclusion, DES use was associated with lesser in-hospital mortality compared with BMS. This outcome benefit was seen across subgroups in various subgroups including elderly, diabetics, and acute myocardial infarction as well as multivessel interventions. PMID- 25439449 TI - Safety profile of subjects treated to very low low-density lipoprotein cholesterol levels (<30 mg/dl) with rosuvastatin 20 mg daily (from JUPITER). AB - Recent US guidelines expand the indications for high-intensity statin therapy, yet data on the safety of attaining very low-density lipoprotein cholesterol (LDL C) levels are scarce. Among 16,304 participants in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) with on-treatment LDL-C levels, we identified 767 who did and 7,387 who did not achieve LDL-C <30 mg/dl on rosuvastatin 20 mg daily and 718 participants who did and 7,436 who did not achieve LDL-C reductions of >=70% on rosuvastatin, and 8,150 allocated to placebo. In participants with an LDL-C <30 mg/dl, we observed an increase in the risk of physician-reported type 2 diabetes with an adjusted hazard ratio (95% confidence interval) of 1.56 (1.09 to 2.23, p = 0.01) and physician-reported hematuria (hazard ratio 2.10 [1.39 to 3.19], p <0.001) compared with rosuvastatin-treated participants with LDL-C >=30 mg/dl. There was also an increased risk of certain musculoskeletal, hepatobiliary, and psychiatric disorders. No difference in renal failure, cancer, memory impairment, or hemorrhagic stroke was observed, although there were few events in these categories. In rosuvastatin-treated participants, achieving LDL-C reduction >=70% versus <70% did not appear to be associated with increased risk of hepatobiliary, renal, or urinary disorders. In conclusion, in this post hoc analysis in the JUPITER, achieving LDL-C levels <30 mg/dl with high-intensity statin therapy appeared to be generally well tolerated but associated with certain adverse events, including more physician-reported diabetes, hematuria, hepatobiliary disorders, and insomnia. These data may guide the monitoring of patients on intensive statin therapy and adverse events in trials of therapies that lead to very low LDL-C levels. PMID- 25439450 TI - Relation of resting heart rate to risk for all-cause mortality by gender after considering exercise capacity (the Henry Ford exercise testing project). AB - Whether resting heart rate (RHR) predicts mortality independent of fitness is not well established, particularly among women. We analyzed data from 56,634 subjects (49% women) without known coronary artery disease or atrial fibrillation who underwent a clinically indicated exercise stress test. Baseline RHR was divided into 5 groups with <60 beats/min as reference. The Social Security Death Index was used to ascertain vital status. Cox hazard models were performed to determine the association of RHR with all-cause mortality, major adverse cardiovascular events, myocardial infarction, or revascularization after sequential adjustment for demographics, cardiovascular disease risk factors, medications, and fitness (metabolic equivalents). The mean age was 53 +/- 12 years and mean RHR was 73 +/- 12 beats/min. More than half of the participants were referred for chest pain; 81% completed an adequate stress test and mean metabolic equivalents achieved was 9.2 +/- 3. There were 6,255 deaths over 11.0-year mean follow-up. There was an increased risk of all-cause mortality with increasing RHR (p trend <0.001). Compared with the lowest RHR group, participants with an RHR >=90 beats/min had a significantly increased risk of mortality even after adjustment for fitness (hazard ratio 1.22, 95% confidence interval 1.10 to 1.35). This relationship remained significant for men, but not significant for women after adjustment for fitness (p interaction <0.001). No significant associations were seen for men or women with major adverse cardiovascular events, myocardial infarction, or revascularization after accounting for fitness. In conclusion, after adjustment for fitness, elevated RHR was an independent risk factor for all-cause mortality in men but not women, suggesting gender differences in the utility of RHR for risk stratification. PMID- 25439451 TI - Impact of the use of transradial versus transfemoral approach as secondary access in transcatheter aortic valve implantation procedures. AB - No data exist on the impact of vascular complications related to the secondary access site in transcatheter aortic valve implantation (TAVI). The objectives of this nonrandomized study were to determine the rate of vascular complications related to the secondary access site in TAVI procedures and to evaluate the clinical impact of using the radial versus femoral approach as a secondary access in such procedures. A total of 462 consecutive patients (mean age 79 +/- 9 years, 50% men) who underwent TAVI were included. The femoral approach (FA) was used as the secondary access (for the insertion of a 5F pigtail catheter) in 335 patients and the radial approach (RA) in 127 patients. Thirty-day events were prospectively collected. There were no baseline differences between groups, except for a higher prevalence of women and peripheral disease in the FA group (p <0.05 for both). A total of 74 vascular access site complications occurred in 70 patients (15%), and 23% of them (29% in the FA group) were related to the secondary access. The use of FA as secondary access was associated with a higher rate of vascular complications (5.0% vs 0% in the RA group, p = 0.005, adjusted p = 0.014). All major vascular complications related to the secondary access occurred in the FA group (3% vs 0% in the RA group, p = 0.040, adjusted p = 0.049), and this translated into a higher rate of major and/or life-threatening bleeding events related to the secondary access in the FA group (3% vs 0% in the RA group, p = 0.040, adjusted p = 0.049). In conclusion, about 1/4 of vascular access site complications in TAVI are related to the secondary access. The use of the RA as a secondary access was associated with a major reduction in vascular complications. These results highlight the impact of secondary access vascular complications in TAVI procedures and support the use of the RA as the preferred secondary access. PMID- 25439452 TI - A national clinical quality program for Veterans Affairs catheterization laboratories (from the Veterans Affairs clinical assessment, reporting, and tracking program). AB - A "learning health care system", as outlined in a recent Institute of Medicine report, harnesses real-time clinical data to continuously measure and improve clinical care. However, most current efforts to understand and improve the quality of care rely on retrospective chart abstractions complied long after the provision of clinical care. To align more closely with the goals of a learning health care system, we present the novel design and initial results of the Veterans Affairs (VA) Clinical Assessment, Reporting, and Tracking (CART) program a national clinical quality program for VA cardiac catheterization laboratories that harnesses real-time clinical data to support clinical care and quality monitoring efforts. Integrated within the VA electronic health record, the CART program uses a specialized software platform to collect real-time patient and procedural data for all VA patients undergoing coronary procedures in VA catheterization laboratories. The program began in 2005 and currently contains data on 434,967 catheterization laboratory procedures, including 272,097 coronary angiograms and 86,481 percutaneous coronary interventions, performed by 801 clinicians on 246,967 patients. We present the initial data from the CART program and describe 3 quality-monitoring programs that use its unique characteristics procedural and complications feedback to individual labs, coronary device surveillance, and major adverse event peer review. The VA CART program is a novel approach to electronic health record design that supports clinical care, quality, and safety in VA catheterization laboratories. Its approach holds promise in achieving the goals of a learning health care system. PMID- 25439453 TI - Peter Andrew McCullough, MD, MPH: an interview with the editor. PMID- 25439454 TI - Reproducibility of Vertebral Fracture Assessment Readings From Dual-energy X-ray Absorptiometry in Both a Population-based and Clinical Cohort: Cohen's and Uniform Kappa. AB - Vertebral fracture assessments (VFAs) using dual-energy X-ray absorptiometry increase vertebral fracture detection in clinical practice and are highly reproducible. Measures of reproducibility are dependent on the frequency and distribution of the event. The aim of this study was to compare 2 reproducibility measures, reliability and agreement, in VFA readings in both a population-based and a clinical cohort. We measured agreement and reliability by uniform kappa and Cohen's kappa for vertebral reading and fracture identification: 360 VFAs from a population-based cohort and 85 from a clinical cohort. In the population-based cohort, 12% of vertebrae were unreadable. Vertebral fracture prevalence ranged from 3% to 4%. Inter-reader and intrareader reliability with Cohen's kappa was fair to good (0.35-0.71 and 0.36-0.74, respectively), with good inter-reader and intrareader agreement by uniform kappa (0.74-0.98 and 0.76-0.99, respectively). In the clinical cohort, 15% of vertebrae were unreadable, and vertebral fracture prevalence ranged from 7.6% to 8.1%. Inter-reader reliability was moderate to good (0.43-0.71), and the agreement was good (0.68-0.91). In clinical situations, the levels of reproducibility measured by the 2 kappa statistics are concordant, so that either could be used to measure agreement and reliability. However, if events are rare, as in a population-based cohort, we recommend evaluating reproducibility using the uniform kappa, as Cohen's kappa may be less accurate. PMID- 25439455 TI - DXA performance in a pediatric population: precision of body composition measurements in healthy term-born infants using dual-energy X-ray absorptiometry. AB - Dual-energy X-ray absorptiometry (DXA) has been hailed as a golden standard for measuring body composition in adults but remains to be fully assessed for the infant population. A total of 64 newborn infants were allocated to 1 of 3 groups. All underwent 2 Hologic Discovery A DXA scans. Suboptimal scans were reconstructed, and an investigation into the success of adjustment was carried out. Depending on group, the factors of weight change and repositioning were investigated. Test-retest variation and coefficients of variation for DXA body composition estimates were calculated. Furthermore, the effects of flannel sheets and breast milk were investigated using a pediatric phantom. Reconstruction of suboptimal scans resulted in more accurate body weight estimates. Moderate weight change and repositioning had no significant effect on the variation between scans. No significant body composition changes occurred between scans. The test retest variation varied between 6.3% and 11.8%. Flannel sheets and breast milk affected DXA results significantly. High precision of DXA measurements was obtained in our newborn population. Reconstructing scans is a viable way of correcting minor movement artifacts. Moderate weight changes and repositioning have no significant effect on DXA results, whereas flannel sheets and milk do. PMID- 25439456 TI - Fibroblast Growth Factor-23, Sclerostin, and Bone Microarchitecture in Patients With Osteoporotic Fractures of the Proximal Femur: A Cross-sectional Study. AB - This cross-sectional observational cohort study was designed to simultaneously investigate bone microarchitecture and serum markers of bone metabolism in elderly osteoporotic patients experiencing a trochanteric or femoral neck fracture. Special emphasis was put on renal function, sclerostin and fibroblast growth factor-23 (FGF-23). Eighty-two patients (median age: 84 years; 49 trochanteric fractures) scheduled for emergency surgery due to an osteoporotic fracture participated. Bone specimens for ex vivo microcomputed X-ray tomography were sampled during surgery. Blood samples for laboratory workup were collected before surgery (t0) and 1 day afterward (t1). Fifty-eight patients consented to dual-energy X-ray absorptiometry scanning of the lumbar spine and/or contralateral femoral neck after recovery during the in-patient stay. Samples were grouped according to the site of fracture. Regression coefficients were controlled for age and/or estimated glomerular filtration rate (eGFR), if appropriate. Patients experiencing a femoral neck fracture presented with better preserved renal function (eGFR) and lower C-terminal fragment of fibroblast growth factor-23 (cFGF-23) concentrations compared to those with trochanteric fractures. By contrast, serum sclerostin was similar at both time points and did not differ between groups. Age-adjusted correlation analysis revealed negative associations between eGFR and cFGF-23 determined at t1 (R=-0.34; p<0.05) as well as between eGFR and sclerostin levels at t0 (R=-0.45; p<0.05) in patients with trochanteric and femoral neck fractures, respectively. Our study provides evidence that not only an age-related decline of renal function but also the type of skeletal injury may contribute to the circulating concentrations of cFGF-23. PMID- 25439458 TI - A time for reflection and thanks. PMID- 25439457 TI - Three-dimensional quantitative analysis of the bone density of mandibular condyle in dentulous and edentulous jaws: an in vivo study. AB - Studies have reported that masticatory function and occlusal force are low in edentulous patients, which brings about a change in the density, thickness, and alignment of bony trabeculae. However, studies that have quantitatively measured the differential cortical and medullary bone densities of the mandibular condyle in vivo remain rare. This study determined and compared the cortical and medullary bone density of the mandibular condyle in dentulous and edentulous jaws, using multidetector computed tomography (CT). Forty mandibular condyles with no clinical signs of temporomandibular disorders were investigated in 2 groups with 10 subjects (aged 50-80 yr) in each group (group I: dentulous subjects with maintained occlusion; group II: completely edentulous patients) with multidetector CT. The density of condylar cortical and medullary bone was determined by using bone density analysis algorithms available within the proprietary software. Data were analyzed statistically with the 1-way analysis of variance test (p<0.05). The mean cortical bone density of the right and left condyles of group I was 686.11+/-102.78 Hounsfield unit (HU) and 775.91+/-89.62 HU, respectively and that of group II was 531.33+/-289.73 HU and 648.53+/-294.39 HU, respectively. The mean medullary bone density of the right and left condyles was maximum in group I subjects (429.69+/-102.62 HU and 486.62+/-108.60 HU, respectively) than in group II subjects (214.89+/-104.37 HU and 205.36+/-90.91 HU, respectively) with a statistically significant decrease in the mean scores (p<0.001). Within the limitations of this study, it can be concluded that the cortical and medullary densities of the mandibular condyle are more in dentulous than the edentulous jaws. PMID- 25439459 TI - Treatment of severe hypertriglyceridaemia. PMID- 25439460 TI - Treatment of severe hypertriglyceridaemia--authors' reply. PMID- 25439461 TI - Risks and benefits of childhood physical activity. PMID- 25439463 TI - Leptin: 20 years later. PMID- 25439464 TI - Solomon Tesfaye: preventing complications of diabetic neuropathy. PMID- 25439465 TI - A game of millimeters. PMID- 25439466 TI - STAT3, Cten, and lung cancer: simultaneous excitement and caution. PMID- 25439467 TI - A randomized assessment of an advanced tissue preservation technology in the juvenile sheep model. AB - BACKGROUND: Despite improved anticalcification technology, bioprosthetic heart valves still cannot be used in younger patients because of progressive structural valve degeneration. A novel advanced tissue preservation technology was developed that uses stable functional group capping and preservation by glycerolization. Valves incorporating this novel technology can be stored in a dry condition and do not require rinsing before use. The aim of the study was to assess the effects of this new technology in terms of valve function and durability in a chronic sheep model of orthotopic implantation. METHODS: Forty-five juvenile sheep were randomized and either a Perimount mitral valve (6900P, control group) or the same valve design incorporating the novel tissue preservation technology (test group) was implanted in the mitral position. All valves were 25 mm. A transthoracic echocardiography was performed at 1 week and at 8 months postoperatively. The animals were then killed, an autopsy was performed, and the valves were examined radiographically (soft tissue radiograph), histologically (hematoxylin and eosin and Von Kossa staining), and chemically (calcium content). Exclusion criteria for analysis included surgical or procedural death, bacterial endocarditis or other diseases leading to premature death. RESULTS: Thirty-one animals (14 controls and 17 test animals) remained in perfect condition during the 8-month follow-up period. Echocardiography at 1 week showed normal valve function in both groups. At 8 months, cardiac output increased significantly to the same extent in both groups (vs baseline; P < .01). The mean transvalvular pressure gradient also increased but significantly more in the control group compared with the test group (P = .03). Flow turbulence across the prosthesis was increased in the control valves compared with the test valves. The test valves had significantly less calcium content than the controls (1.9 +/- 0.3 vs 6.8 +/- 1.6 MUg/mg; P = .002). This was confirmed by radiographic analysis and histology. CONCLUSIONS: This study demonstrates that the novel tissue preservation technology, when applied to the Perimount mitral valve, significantly improves hemodynamic and anticalcification properties compared with the standard Perimount, a valve currently considered the standard of care. PMID- 25439470 TI - Surgical treatment for patients with complete atrioventricular block after device closure of perimembranous ventricular septal defects. PMID- 25439469 TI - Spot the mesh: six-month follow-up. PMID- 25439468 TI - Pneumonectomy for lung cancer: contemporary national early morbidity and mortality outcomes. AB - OBJECTIVE: The study objective was to determine contemporary early outcomes associated with pneumonectomy for lung cancer and to identify their predictors using a nationally representative general thoracic surgery database (EPITHOR). METHODS: After discarding inconsistent files, a group of 4498 patients who underwent elective pneumonectomy for primary lung cancer between 2003 and 2013 was selected. Logistic regression analysis was performed on variables for mortality and major adverse events. Then, a propensity score analysis was adjusted for imbalances in baseline characteristics between patients with or without neoadjuvant treatment. RESULTS: Operative mortality was 7.8%. Surgical, cardiovascular, pulmonary, and infectious complications rates were 14.9%, 14.1%, 11.5%, and 2.7%, respectively. None of these complications were predicted by the performance of a neoadjuvant therapy. Operative mortality analysis, adjusted for the propensity scores, identified age greater than 65 years (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.5-2.9; P < .001), underweight body mass index category (OR, 2.2; 95% CI, 1.2-4.0; P = .009), American Society of Anesthesiologists score of 3 or greater (OR, 2.310; 95% CI, 1.615-3.304; P < .001), right laterality of the procedure (OR, 1.8; 95% CI, 1.1-2.4; P = .011), performance of an extended pneumonectomy (OR, 1.5; 95% CI, 1.1-2.1; P = .018), and absence of systematic lymphadenectomy (OR, 2.9; 95% CI, 1.1-7.8; P = .027) as risk predictors. Induction therapy (OR, 0.63; 95% CI, 0.5-0.9; P = .005) and overweight body mass index category (OR, 0.60; 95% CI, 0.4-0.9; P = .033) were protective factors. CONCLUSIONS: Several risk factors for major adverse early outcomes after pneumonectomy for cancer were identified. Overweight patients and those who received induction therapy had paradoxically lower adjusted risks of mortality. PMID- 25439471 TI - Intra-annular mitral valve replacement in neonates and infants. PMID- 25439472 TI - Doubt about effectiveness of lung metastasectomy for sarcoma. PMID- 25439473 TI - Does peritoneal dialysis improve outcomes after heart surgery in infants? PMID- 25439474 TI - Oh where, oh where can that little nodule be? PMID- 25439475 TI - The classic elephant trunk technique for staged thoracic and thoracoabdominal aortic repair: long-term results. AB - OBJECTIVE: The classic elephant trunk (ET) technique has become the standard approach for patients with diffuse aortic disease requiring a staged thoracic and thoracoabdominal aortic repair. The aim of this study was to assess long-term outcomes and predictors for survival after surgical repair of extensive thoracic aortic disease with the ET technique. METHODS: Between 1984 and 2013, 248 consecutive patients were treated in our institution and analyzed retrospectively. Follow-up consisted of outpatient clinic visits including postoperative computed tomography imaging at 3 months and annually thereafter. Second-stage intervention was indicated if the diameter of the descending or thoracoabdominal aorta was greater than or equal to 60 mm, in case of a rapidly growing aneurysm and/or symptoms. RESULTS: Mean age was 65 +/- 10 years; 44% were male. After first-stage ET, in-hospital mortality was 8% and permanent neurologic deficits were observed in 2% of patients. Median follow-up after the first stage was 48 months (range, 1-210 months). One hundred twelve patients (45%) underwent second-stage ET. Overall survival after first-stage ET was 75% and 67% at 5 and 10 years, respectively. Survival in patients with second-stage ET was 87%, compared with 65% in the group who did not undergo second-stage ET at the 5-year follow-up (P < .001) and 67% compared with 36% at the 10-year follow-up (P < .001). Predictor for mortality was the absence of second-stage ET (P = .044). CONCLUSIONS: A 2-stage approach for diffuse aortic disease is a safe method. The acceptable mortality at the first stage justifies the use of the classic ET technique and allows subsequent repair of the distal aorta. Long-term survival is increased when both stages are completed. PMID- 25439476 TI - The pros and cons of intensive insulin therapy. PMID- 25439477 TI - No to infant euthanasia. PMID- 25439479 TI - Understanding and not only observing: the key to success in tissue engineering? PMID- 25439480 TI - Technical skills assessment in thoracic surgery education: we won't get fooled again. PMID- 25439482 TI - Cardiac cannibalism. PMID- 25439481 TI - Blood transfusion balance: too much, not enough, or just right. PMID- 25439483 TI - Neuromonitoring during cardiothoracic surgery: the signal and the noise. PMID- 25439478 TI - Oxidant stress regulatory genetic variation in recipients and donors contributes to risk of primary graft dysfunction after lung transplantation. AB - OBJECTIVE: Oxidant stress pathway activation during ischemia reperfusion injury may contribute to the development of primary graft dysfunction (PGD) after lung transplantation. We hypothesized that oxidant stress gene variation in recipients and donors is associated with PGD. METHODS: Donors and recipients from the Lung Transplant Outcomes Group (LTOG) cohort were genotyped using the Illumina IBC chip filtered for oxidant stress pathway genes. Single nucleotide polymorphisms (SNPs) grouped into SNP sets based on haplotype blocks within 49 oxidant stress genes selected from gene ontology pathways and literature review were tested for PGD association using a sequencing kernel association test. Analyses were adjusted for clinical confounding variables and population stratification. RESULTS: Three hundred ninety-two donors and 1038 recipients met genetic quality control standards. Thirty percent of patients developed grade 3 PGD within 72 hours. Donor NADPH oxidase 3 (NOX3) was associated with PGD (P = .01) with 5 individual significant loci (P values between .006 and .03). In recipients, variation in glutathione peroxidase (GPX1) and NRF-2 (NFE2L2) was significantly associated with PGD (P = .01 for both). The GPX1 association included 3 individual loci (P values between .006 and .049) and the NFE2L2 association included 2 loci (P = .03 and .05). Significant epistatic effects influencing PGD susceptibility were evident between 3 different donor blocks of NOX3 and recipient NFE2L2 (P = .026, P = .017, and P = .031). CONCLUSIONS: Our study has prioritized GPX1, NOX3, and NFE2L2 genes for future research in PGD pathogenesis, and highlights a donor-recipient interaction of NOX3 and NFE2L2 that increases the risk of PGD. PMID- 25439484 TI - Neurocognitive function in children after anterior temporal lobectomy with amygdalohippocampectomy. AB - BACKGROUND: We assessed the postoperative neurocognitive function after temporal lobectomy in children with temporal lobe epilepsy. METHODS: This was a retrospective analysis of the data of 20 patients with Engel's class I or II outcomes after anterior temporal lobectomy with amygdalohippocampectomy between 2005 and 2008. Twenty children underwent resection of either dominant (n = 8) or nondominant (n = 12) temporal lobes, and their median age at surgery was 12.8 +/- 3.2 years. We serially assessed intelligence and memory function as measured by the Korean-Wechsler Scales of Intelligence and Rey-Kim Memory test both before and after surgery. RESULTS: Intelligence quotient (IQ) and memory quotient scores remained stable during a 3.6-year median follow-up in these children after the surgery. There was no decrease of IQ or memory quotient scores in either the dominant or non-dominant hemisphere groups. Later onset of epilepsy, a shorter epilepsy duration, a smaller number of antiepileptic drugs, and postoperative seizure-free outcomes were significant good predictors of the postoperative IQ. CONCLUSION: Temporal lobectomy in children did not provoke a significant decline in intelligence or memory function. Early surgical treatment in children with intractable seizures of temporal lobe origin may result in better neurocognitive outcomes. PMID- 25439485 TI - Assessing motor function in young children with transcranial magnetic stimulation. AB - OBJECTIVE: Accurate noninvasive assessment of motor function using functional MRI (fMRI) and magnetoencephalography (MEG) is a challenge in patients who are very young or who are developmentally delayed. In such cases, passive mapping of the sensorimotor cortex is performed under sedation. We examined the feasibility of using transcranial magnetic stimulation (TMS) as a motor mapping tool in awake children younger than 3 years of age. METHODS: Six children underwent motor mapping with TMS while awake as well as passive sensorimotor mapping under conscious sedation with MEG during tactile stimulation (n = 5) and fMRI during passive hand movements (n = 4). RESULTS: Stimulation of the motor cortex via TMS successfully elicited evoked responses in contralateral hand muscles in 5 patients. The location of primary motor cortex in the precentral gyrus identified by TMS corresponded with the postcentral location of the primary sensory cortex identified by MEG in 2 patients and to the sensorimotor cortex identified by fMRI in 3 children. In this cohort, we demonstrate that TMS can illuminate abnormalities in motor physiology including motor reorganization. We also demonstrate the feasibility of using TMS-derived contralateral silent periods to approximate the location of motor cortex in the absence of an evoked response. When compared to chronological age, performance functioning level appears to be better in predicting successful mapping outcome with TMS. CONCLUSIONS: Our findings indicate that awake TMS is a safe alternative to MEG and fMRI performed under sedation to localize the motor cortex and provides additional insight into the underlying pathophysiology and motor plasticity in toddlers. PMID- 25439486 TI - Structural focal temporal lobe seizures in a child with lipoproteinosis. AB - BACKGROUND: Lipoproteinosis is a rare autosomal recessive disorder caused by a mutation in a gene (ECM1) on chromosome 1q21. Alterations of membrane and vessels in the dermal-epidermal junction represent the pathologic background of the disease. Calcification in the temporal lobes and hippocampi are common and may be associated with epileptic seizures. PATIENT DESCRIPTION: We describe a 7-year-old girl with lipoproteinosis who presented with hoarseness, typical skin lesions, and seizures. RESULTS: Video electroencephalography demonstrated focal temporal lobe seizures. Intelligence quotient was normal, but psychologic tests revealed depressed mood. Neuroimaging revealed bilateral mesial temporal lobe calcifications. CONCLUSIONS: The report reveals that the temporal lobe calcifications and the consequent epileptic seizures can appear even very early. The psychological signs may reflect limbic system dysfunction. PMID- 25439487 TI - A venous malformation presenting as toe walking. PMID- 25439488 TI - Disruption of SOX6 is associated with a rapid-onset dopa-responsive movement disorder, delayed development, and dysmorphic features. AB - BACKGROUND: Sox6 is a transcription factor that is crucial for the differentiation and development of cortical interneurons and dopaminergic neurons of the substantia nigra pars compact. Loss-of-function mutations might thus result in complex paroxysmal diseases such as epilepsy syndromes or movement disorders. PATIENT: We present a 15-year-old boy with delayed speech development and attention deficit hyperactivity disorder who presented with a rapid-onset generalized dopa-responsive dystonia. RESULTS: Neurological examination revealed generalized dystonic and frequent athetoid movements of the arms, trunk, and neck. Gait was severely impaired secondary to frequent dystonic postures. Both a resting tremor and action tremors were observed in both hands. Speech was dysarthric but language comprehension was unimpaired. Testing for saccadic dysfunction revealed hypometric horizontal and vertical saccades. Physical examination was otherwise significant for a pectus carinatum and splenomegaly. Laboratory studies, brain magnetic resonance imaging, and electroencephalography were unremarkable. Treatment with levodopa/carbidopa led to a complete and sustained remission of neurological symptoms. Genetic testing revealed a mono allelic de novo 84-kb deletion on chromosome 11p15.2 encompassing exons 14-16 of the SOX6 gene (chr11: 15944880-16029095, NCBI 37/hg19). CONCLUSIONS: This is the first report of a dopa-responsive movement disorder associated with SOX6 disruption. SOX6 mutations should be considered in the differential diagnosis of unexplained dopa-responsive dystonia syndromes. PMID- 25439489 TI - Paroxysmal tonic upward gaze complicating Angelman syndrome. AB - BACKGROUND: Paroxysmal tonic upward gaze is a childhood oculomotor syndrome characterized by episodes of conjugate upward deviation of the eyes. Its pathogenesis is unknown, and the etiology is heterogeneous. PATIENT DESCRIPTION: We describe a 2-year-old girl with Angelman syndrome who developed paroxysmal tonic upward gaze at 9 months of age. She presented with developmental delay, blond hair, jerky movements, ataxia, and epilepsy. Genetic testing revealed a maternal deletion of 15q11-13, confirming Angelman syndrome. CONCLUSIONS: This is the first report of Angelman syndrome complicated by paroxysmal tonic upward gaze. Both transient paroxysmal tonic upward gaze and Angelman syndrome have been associated with dopaminergic neurons. We speculate that the dopaminergic abnormalities present in Angelman syndrome may cause paroxysmal tonic upward gaze. PMID- 25439490 TI - Neonatal neurology--my personal journey and some lessons learned. PMID- 25439491 TI - A boy with arachnoid cyst, a fall, and temporary and reversible visual impairment. AB - BACKGROUND: Temporal arachnoid cysts have been shown to interfere with the function of nervous structures, both cerebral cortex and cranial nerves. METHODS AND RESULTS: In this case report we describe a boy with a left temporal arachnoid cyst with a sudden onset of visual impairment 4 days after a mild trauma to the head. A perimetry test revealed a complete nasal hemianopia of the left eye, which normalized rapidly after an emergency craniotomy with cyst fenestration 3 hours after the patient experienced the reduced vision. CONCLUSIONS: The observed, reversible effect on vision is most probably caused by pressure exerted by the medial part of the cyst on the left optic nerve. We believe this is the first time such a case has been described. PMID- 25439492 TI - Fever of unknown origin as the initial manifestation of valproate-induced Fanconi syndrome. AB - BACKGROUND: Valproate-induced Fanconi syndrome is a rare adverse effect of valproate. Severely disabled patients who require tube feeding are reported to be susceptible to valproate-induced Fanconi syndrome. Although most patients with valproate-induced Fanconi syndrome are asymptomatic and detected incidentally with findings such as hypophosphatemia, hypouricemia, increased urinary beta2 microglobulin, and generalized hyperaminoaciduria, clinical symptoms such as bone fracture, fever, tachypnea, and edema have been reported. PATIENT DESCRIPTION: This 15-year-old, severely disabled, tube-fed, male patient with cytochrome oxidase deficiency had taken valproate for 3 years when he developed fever for 3 weeks. Hypophosphatemia, hypouricemia, hypokalemia, increased urinary beta2 microglobulin, and generalized hyperaminoaciduria, as well as hypocarnitinemia, were found, indicating that he had Fanconi syndrome. Valproate was the most likely cause of Fanconi syndrome in this patient. After discontinuation of valproate, the fever resolved immediately, and the laboratory findings normalized. CONCLUSION: Valproate-induced Fanconi syndrome should be considered when individuals taking valproate develop fever of unknown origin. PMID- 25439494 TI - Multiple large dilated Virchow-Robin spaces in a 12-year-old with neurofibromatosis type 2. PMID- 25439493 TI - Identical ATP1A3 mutation causes alternating hemiplegia of childhood and rapid onset dystonia parkinsonism phenotypes. AB - BACKGROUND: Alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism are two separate movement disorders with different dominant mutations in the same sodium-potassium transporter ATPase subunit gene, ATP1A3. PATIENT: We present a child with topiramate-responsive alternating hemiplegia of childhood who was tested for an ATP1A3 gene mutation. RESULTS: Gene sequencing revealed an identical ATP1A3 mutation as in three typical adult-onset rapid-onset dystonia parkinsonism cases but never previously described in an alternating hemiplegia of childhood case. CONCLUSION: The discordance of these phenotypes suggests that there are other undiscovered environmental, genetic, or epigenetic factors influencing the development of alternating hemiplegia of childhood or rapid-onset dystonia parkinsonism. PMID- 25439495 TI - Multiple exostoses presenting with high cervical myelopathy in the first decade of life. PMID- 25439496 TI - Withdrawal of medical marijuana. PMID- 25439497 TI - Carpal tunnel syndrome in a child with Down syndrome. PMID- 25439498 TI - Symmetric thalamic lesions in a patient with a myoclonic epilepsy with ragged red fibers-Leigh spectrum phenotype due to the m.A8344G mutation. PMID- 25439499 TI - The social life of laughter. AB - Laughter is often considered to be the product of humour. However, laughter is a social emotion, occurring most often in interactions, where it is associated with bonding, agreement, affection, and emotional regulation. Laughter is underpinned by complex neural systems, allowing it to be used flexibly. In humans and chimpanzees, social (voluntary) laughter is distinctly different from evoked (involuntary) laughter, a distinction which is also seen in brain imaging studies of laughter. PMID- 25439500 TI - Cerium oxide nanoparticles alter the antioxidant capacity but do not impact tuber ionome in Raphanus sativus (L). AB - The effects of nCeO2 on food quality are not well known yet. This research was performed to determine the impact of nCeO2 on radish (Raphanus sativus L.). Plants were cultivated to full maturity in potting soil treated with nCeO2 at concentrations of 0, 62.5, 125, 250, and 500 mg/kg. Germination, growth, photosynthesis, ionome, and antioxidants were evaluated at different growth stages. Results showed that at 500 mg/kg, nCeO2 significantly retarded seed germination but did not reduce the number of germinated seeds. None of the treatments affected gas exchange, photosynthesis, growth, phenols, flavonoids, and nutrients' accumulation in tubers and leaves of adult plants. However, tubers' antioxidant capacity, expressed as FRAP, ABTS(*-) and DPPH, increased by 30%, 32%, and 85%, respectively, in plants treated with 250 mg nCeO2kg(-1) soil. In addition, cerium accumulation in tubers of plants treated with 250 and 500 mg/kg reached 72 and 142 mg/kg d wt, respectively. This suggests that nCeO2 could improve the radical scavenging potency of radish but it might introduce nCeO2 into the food chain with unknown consequences. PMID- 25439502 TI - Assessing intentions to eat low-glycemic index foods by adults with diabetes using a new questionnaire based on the theory of planned behaviour. AB - OBJECTIVE: The Canadian Diabetes Association recommends that people with diabetes choose foods with low-glycemic index (GI). This study developed a questionnaire measuring Theory of Planned Behaviour (TPB) constructs relative to consuming a low-GI diet by people with diabetes so as to achieve a better understanding of which TPB constructs, demographic characteristics and diabetes-related variables best predict intention to consume a low-GI diet. METHOD: A questionnaire to measure intentions to consume a low-GI diet was developed based on TPB constructs and was administered to 369 adults (30 to 75 years) with type 1 or type 2 diabetes. Responses were analyzed using multiple linear regression. RESULTS: More than 90% of participants (mean age, 56.5+/-10.8 years; mean body mass index, 30.5+/-7.2 kg/m(2)) cited reduction and maintenance of healthy blood glucose levels as an advantage of eating low-GI foods. Older age, higher income, female gender, having type 2 diabetes, diabetes treatment (diet only) and understanding of the GI were positively associated with intention to eat a low-GI diet. TPB constructs that significantly predicted intentions to eat a low-GI diet were instrumental attitude (beta = 0.24, p<0.001); subjective norms (beta = 0.13, p=0.007); and perceived behavioural control (beta = 0.55, p<0.001). CONCLUSIONS: This new questionnaire is a valid tool to assess TPB constructs contributing to intentions to eat a low-GI diet by people with diabetes. Future studies that use this questionnaire can shed light on how TPB concepts in clinical practice can help people with diabetes to change their dietary intake. PMID- 25439501 TI - Preventing diabetes in primary care: a feasibility cluster randomized trial. AB - OBJECTIVE: To determine the feasibility of implementing a large-scale primary care-based diabetes prevention trial. METHODS: A feasibility cluster randomized controlled trial was conducted in British Columbia, Canada, amongst adults with prediabetes using the Facilitated Lifestyle Intervention Prescription (FLIP) vs. usual care. FLIP included lifestyle advice, a pedometer, and telephone support from a lifestyle facilitator for 6 months. Indicators of feasibility included recruitment rates of family practices, participants and facilitators, as well as feasibility and retention rates in the FLIP program and study protocols. RESULTS: Six family practices participated; 59 patients were enrolled between October 2012 and March 2013. The trial protocol was acceptable to practices and participants and had a 95% participant retention rate over the 6 months (56/59). Adherence to the intervention was high (97%), with 34 of 35 patients continuing to receive telephone calls from the facilitator for 6 months. The mean cost of the intervention was C$144 per person. Compared with control, intervention participants significantly reduced weight by 3.2 kg (95% CI, 1.7 to 4.6); body mass index by 1.2 (95% CI, 0.7 to 1.7) and waist circumference by 3 cm (95% CI, 0.3 to 5.7). CONCLUSIONS: It is feasible to implement FLIP and to conduct a trial to assess effectiveness. A larger trial with longer follow up to assess progression to diabetes is warranted. PMID- 25439503 TI - Promoting advance directives and ethical wills with the HIV-aging cohort by first assessing clinician knowledge and comfort level. PMID- 25439504 TI - Dual role of leukotriene B4 receptor type 1 in experimental sepsis. AB - BACKGROUND: The controversial results from different studies suggested that leukocyte recruitment mediated by leukotriene B4 (LTB4) and its receptor might improve pathogen clearance, but might also aggravate organ injury during sepsis. The present study was performed to compare the effect of BLT1 ligand LTB4 and its antagonist U-75302 on the development of sepsis. METHODS: Sepsis in mice was induced by cecal ligation and puncture (CLP). The mice were allocated into sham group, CLP group, U-75302 group, and LTB4 group. In the latter three groups, CLP mice were treated by intraperitoneal saline, U-75302, and LTB4, respectively. Their effect on the progression of sepsis were compared by histopathologic tests, level of systemic cytokines, counts of immune cells and bacterial clearance, and survival rate. RESULTS: The histopathologic tests showed that U-75302 attenuated lung injury, whereas LTB4 aggravated liver injury. LTB4 increased the plasma levels of interleukin-6, tumor necrosis factor-alpha, and U-75302 increased the level of plasma interleukin-10. LTB4 increased whereas U-75302 reduced the neutrophil numbers in the peritoneal lavage fluid. LTB4 also increased the number of peritoneal and splenic CD4(+) and CD8(+) T cells. Bacterial clearance in blood and peritoneal lavage fluid was significantly enhanced in the LTB4 group. Both U 75302 and LTB4 did not change the survival rate significantly compared with vehicle, but mortality in the LTB4 group was significantly higher than in the U 75302 group. Dose response analyses were also performed to compare the effect of U-75302 and LTB4 at different doses. Different doses of both agents did not influence the survival rate of CLP mice. CONCLUSIONS: U-75302 attenuates sepsis induced organ injury, whereas LTB4 increases the leukocyte recruitment toward infection site, but LTB4 showed a more lethal effect than U-75302 during polymicrobial sepsis. PMID- 25439506 TI - Decision support tool use in colorectal surgery: what is the role? AB - BACKGROUND: Decision support tools prioritizing transitional care can help decrease medical readmissions but little evidence exists within surgical specialties. MATERIALS AND METHODS: This study evaluated the use of early screen for discharge planning and discharge decision support system screening tools or selective multidisciplinary clinical evaluation for targeting post-acute care interventions among higher risk colorectal surgery patients based on 30-d readmission status. Patients with positive screening tool scores underwent standard discharge planning education and evaluation during index operation hospitalization and were referred for targeted post-acute interventions; patients with negative screening tool scores were further clinically evaluated for selective referral for post-acute interventions. RESULTS: We identified 300 colorectal surgery patients; 30.3% (n = 91) of patients had a positive screening score (early screen for discharge planning and/or discharge decision support system). Positive screening scores did not correlate with hospital readmission (35% of readmitted patients versus 29% of non-readmitted had a positive screen; P = 0.424). After negative screening scores, selective referral based on clinical assessment for postdischarge interventions helped to concentrate resources in patients who were later readmitted. Index hospitalization complications were significantly associated with positive screening tool scores whereas postdischarge complications were most predictive of readmission. CONCLUSIONS: Among colorectal surgery patients, selective clinical referrals appeared to be the best method for targeting post-acute interventions in patients at higher risk for readmission. Future research should focus on improving existing processes of care to reduce postoperative complications and constructing better tools to assess individual patients' needs for targeted interventions in the post-acute setting. PMID- 25439505 TI - Lipopolysaccharide and cytokines inhibit rat cardiomyocyte contractility in vitro. AB - BACKGROUND: Sepsis-induced cardiomyopathy (SIC) is thought to be the result of detrimental effects of inflammatory mediators on the cardiac muscle. Here we studied the effects of prolonged (24 +/- 4 h) exposure of adult rat ventricular myocytes (ARVM) to bacterial lipopolysaccharide (LPS) and inflammatory cytokines tumor necrosis factor (TNF) and interleukins-1 (IL-1) and IL-6. MATERIALS AND METHODS: We measured sarcomere shortening (SS) and cellular calcium (Ca(2+)) transients (DeltaCai, with fura-2 AM) in isolated cardiomyocytes externally paced at 5 Hz at 37 degrees C. RESULTS: SS decreased after incubation with LPS (100 MUg/mL), IL-1 (100 ng/mL), and IL-6 (30 ng/mL), but not with lesser doses of these mediators, or TNF (10-100 ng/mL). A combination of LPS (100 MUg/mL), TNF, IL-1, and IL-6 (each 100 ng/mL; i.e., "Cytomix-100") induced a maximal decrease in SS and DeltaCai. Sarcoplasmic reticulum (SR) Ca(2+) load (CaSR, measured with caffeine) was unchanged by Cytomix-100; however, SR fractional release (DeltaCai/CaSR) was decreased. Underlying these effects, Ca(2+) influx into the cell (via L-type Ca(2+) channels, LTCC) and Ca(2+) extrusion via Na(+)/Ca(2+) exchange were decreased by Cytomix-100. SR Ca(2+) pump (SERCA) (SR Ca(2+) ATPase) was not affected. CONCLUSIONS: Prolonged exposure of ARVM to a mixture of LPS and inflammatory cytokines inhibits cell contractility. The effect is mediated by the inhibition of Ca(2+) influx via LTCC, and partially opposed by the inhibition of Na(+)/Ca(2+) exchange. Because both mechanisms are commonly seen in animal models of SIC, we conclude that prolonged challenge with Cytomix-100 of ARVM may represent an accurate in vitro model for SIC. PMID- 25439507 TI - Predictors of mortality and morbidity for acute care surgery patients. AB - BACKGROUND: As the implementation of exclusive acute care surgery (ACS) services thrives, prognostication for mortality and morbidity will be important to complement clinical management of these diverse and complex patients. Our objective is to investigate prognostic risk factors from patient level characteristics and clinical presentation to predict outcomes including mortality, postoperative complications, intensive care unit (ICU) admission and prolonged duration of hospital stay. METHODS: Retrospective review of all emergency general surgery admissions over a 1-year period at a large teaching hospital was conducted. Factors collected included history of present illness, physical exam and laboratory parameters at presentation. Univariate analysis was performed to examine the relationship between each variable and our outcomes with chi-square for categorical variables and the Wilcoxon rank-sum statistic for continuous variables. Multivariate analysis was performed using backward stepwise logistic regression to evaluate for independent predictors. RESULTS: A total of 527 ACS admissions were identified with 8.1% requiring ICU stay and an overall crude mortality rate of 3.04%. Operative management was required in 258 patients with 22% having postoperative complications. Use of anti-coagulants, systolic blood pressure <90, hypothermia and leukopenia were independent predictors of in hospital mortality. Leukopenia, smoking and tachycardia at presentation were also prognostic for the development of postoperative complications. For ICU admission, use of anti-coagulants, leukopenia, leukocytosis and tachypnea at presentation were all independent predictive factors. A prolonged length of stay was associated with increasing age, higher American Society of Anesthesiologists class, tachycardia and presence of complications on multivariate analysis. CONCLUSIONS: Factors present at initial presentation can be used to predict morbidity and mortality in ACS patients. PMID- 25439508 TI - Cyclic tensile strain on vocal fold fibroblasts inhibits cigarette smoke-induced inflammation: implications for Reinke edema. AB - OBJECTIVES: To investigate whether patients with Reinke edema are more extrovertive than patients with carcinoma and, whether cyclic tensile strain (CTS) attenuates cigarette smoke condensate (CSC)-induced inflammation in human vocal fold fibroblasts (HVFF). STUDY DESIGN: In vitro and ex vivo study. METHODS: Clinical investigation and Eysenck personality questionnaire were performed to evaluate the personality and smoking status in individuals among groups. 3-(4,5) dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay was applied to test the viabilities of cultured HVFF exposed to CSC and/or CTS. The messenger RNA (mRNA) and protein expressions of cluster of differentiation 44 (CD44), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-9 (MMP-9) in tissues from Reinke edema, paracancerous site, normal vocal fold, and in HVFF with different treatments were measured by reverse transcriptase polymerase chain reaction or western blot, respectively. RESULTS: Patients with either Reinke edema or carcinoma were moderate/heavy smokers; the extraversion score, however, was higher in Reinke edema patients than that in carcinoma patients. CD44 mRNA and protein expressions were significantly higher, whereas, COX-2 and MMP-9 expressions were significantly lower in Reinke edema tissues than those in paracancerous tissues. Treatment of HVFF with CSC led to the decrease in cell viability, the reduction in CD44 expression, but, the increase in COX-2 and MMP-9 expressions and, moreover, administration of CTS inhibited such effects of CSC on HVFF. CONCLUSIONS: Our results demonstrate that Reinke edema patients have more extrovert personality characteristics in comparison to carcinoma patients and, importantly, CTS attenuates CSC-induced inflammation in HVFF. Phonatory vibration may be a mechanism for lower expression of proinflammatory mediators in Reinke edema tissues in spite of cigarette smoke exposure. PMID- 25439510 TI - Effect of application of transcutaneous electrical nerve stimulation and laryngeal manual therapy in dysphonic women: clinical trial. AB - OBJECTIVE: To verify the effect of the Transcutaneous Electrical Nerve Stimulation (TENS) and of Laryngeal Manual Therapy (LMT) and to compare the two techniques in relation to vocal/laryngeal symptoms, pain, and vocal quality after these resources were administered in dysphonic women. STUDY DESIGN: Control trial. METHOD: A total of 20 women with bilateral vocal nodules participated. All of the volunteers underwent investigation of vocal/laryngeal symptoms, musculoskeletal pain, and vocal register. The volunteers were subdivided into: 1. TENS Group (10 volunteers)-TENS application; 2. LMT Group (10 volunteers)-LMT application; both groups received 12 sessions of treatment, twice a week, lasting 20 minutes each. After treatment, the initial assessments were repeated. Data were statistically analyzed by Wilcoxon and signal test (P < 0.05). RESULTS: After TENS, there was significant improvement in the "high pitched voice" and "effort to speak" symptoms; there was significantly lower frequency of pain in the posterior neck and shoulder; TENS significantly reduced the intensity of pain in the posterior neck, shoulder, and upper back. The auditory perceptual analysis showed improvement only in the strain parameter after TENS. After LMT, there was improvement of the "sore throat," significantly lower incidence of pain in the anterior neck, and the pain intensity in the posterior neck decreased. CONCLUSION: When compared with the LMT, TENS appeared to be a treatment method intended to be used as a complement to voice therapy, considering the parameters evaluated and controlled. PMID- 25439509 TI - Direct and octave-shifted pitch matching during nonword imitations in men, women, and children. AB - OBJECTIVES: To evaluate whether children, women, and men match the speaker's fundamental frequency (F0) during nonword imitation directly when the target F0 is within the responders' vocal ranges and at octave-shifted levels when the target is outside their vocal ranges, and to evaluate the role of a history of speech sound disorder (SSD) in the adult participants. STUDY DESIGN: Observational. METHODS: Nonword sets spoken by a man and a woman were imitated by 14 men, 21 women, and 19 children. Approximately half of the adults and two thirds of the children had a history of SSD. F0 in the imitations was compared with that in the targets and in the participants' nonimitated control word productions. RESULTS: When the target F0 was within the responders' vocal ranges, the imitations approximated the target F0. Men imitating a woman's voice approximated F0 levels one octave below the target F0. Children imitating a man's voice approximated F0 levels one octave above the target F0. Women imitating a man's voice approximated the target F0 at a ratio of 1.5 known as the perfect fifth in music. A history of SSD did not influence the results. CONCLUSIONS: This study replicates previous findings showing that target F0 was a salient aspect of the stimuli that was imitated along with the targets' segmental and prosodic components without explicit prompting. It is the first to show F0 convergence not only directly but also at relevant target/imitation intervals including the octave interval. PMID- 25439511 TI - How we eat what we eat: identifying meal routines and practices most strongly associated with healthy and unhealthy dietary factors among young adults. AB - OBJECTIVE: (i) To examine associations between young adults' meal routines and practices (e.g. food preparation, meal skipping, eating on the run) and key dietary indicators (fruit/vegetable, fast-food and sugar-sweetened beverage intakes) and (ii) to develop indices of protective and risky meal practices most strongly associated with diet. DESIGN: Cross-sectional survey. SETTING: Minneapolis/St. Paul metropolitan area, Minnesota (USA). SUBJECTS: A diverse sample of community college and public university students (n 1013). RESULTS: Meal routines and practices most strongly associated with healthy dietary patterns were related to home food preparation (i.e. preparing meals at home, preparing meals with vegetables) and meal regularity (i.e. routine consumption of evening meals and breakfast). In contrast, factors most strongly associated with poor dietary patterns included eating on the run, using media while eating and purchasing foods/beverages on campus. A Protective Factors Index, summing selected protective meal routines and practices, was positively associated with fruit/vegetable consumption and negatively associated with fast-food and sugar sweetened beverage consumption (P<0.001). A Risky Factors Index yielded significant, positive associations with fast-food and sugar-sweetened beverage consumption (P<0.001). The probability test for the association between the Risky Factors Index and fruit/vegetable intake was P=0.05. CONCLUSIONS: Meal routines and practices were significantly associated with young adults' dietary patterns, suggesting that ways in which individuals structure mealtimes and contextual characteristics of eating likely influence food choice. Thus, in addition to considering specific food choices, it also may be important to consider the context of mealtimes in developing dietary messaging and guidelines. PMID- 25439523 TI - The impact of cognitive impairment on perceived workforce performance: results from the International Mood Disorders Collaborative Project. AB - BACKGROUND: Cognitive dysfunction and depression severity are key mediators of workplace adjustment in adults with major depressive disorder (MDD). Herein, we sought to determine the extent to which measures of depression severity and cognitive dysfunction were associated with perceived global disability, workplace performance and quality of life. METHOD: A post hoc analysis was conducted using data from 260 participants with a diagnosis of DSM-IV-TR-defined MDD who were enrolled in the International Mood Disorders Collaborative Project (IMDCP) between January 2008 and July 2013. Measures of workplace function, global disability, depression severity, cognitive function, and quality of life were employed. These data were analyzed using a multiple variable linear regression equations. RESULTS: Perceived global disability was significantly predicted by clinical ratings of depression severity (beta=0.54), and perceived inattention (beta=0.24), accounting for 37% of the variance. In addition, perceived inattention (beta=0.58) and clinical ratings of depression severity (beta=0.18), were also significant predictors of perceived workplace productivity/performance, accounting for 38% of the variance. Finally, both clinical ratings of depression severity (beta=-0.54), and perceived inattention (beta=-0.18) were significant inverse predictors of perceived quality of life, accounting for 34% of the variance. CONCLUSION: The overarching finding in the analysis herein is that workplace performance variability is explained by subjective measures of cognitive dysfunction to a greater extent than total depression symptom severity. Conversely, total depression symptom severity accounts for a greater degree of variability in global measures of disability relative to cognitive measures. Treatment strategies for adults with major depressive disorder should address issues of cognitive dysfunction to improve workforce participation and performance. PMID- 25439525 TI - Editorial overview: cell signalling and gene regulation: another step up the beaten path. PMID- 25439524 TI - Insight and neurocognitive functioning in bipolar subjects. AB - BACKGROUND: Insight concerning having a mental illness has been found to influence outcome and effectiveness of treatment. It has been studied mainly in the area of schizophrenia with few studies addressing other disorders. This study evaluates insight in individuals with bipolar disorder using the Scale to Assess Unawareness of Mental Disorder (SUMD), a comprehensive interview for evaluation of awareness of illness and attribution of symptoms. The hypothesis was that in bipolar disorder level of awareness may be associated with numerous factors including neurocognitive function, structural changes in the frontal lobes and hippocampus evaluated by MRI, neurocognitive status, severity of mania and other psychiatric symptoms and comorbid alcoholism. METHOD: In order to evaluate this hypothesis 33 individuals with DSM-IV diagnosed bipolar disorder, some with and some without comorbid alcoholism, were administered the SUMD and a number of other procedures including a quantitative MRI measuring volume of the frontal lobes and hippocampus, a brief battery of neurocognitive tests, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale. The data were analyzed by comparing participants with and without alcoholism on these procedures using t tests and by linear multiple regression, with SUMD ratings of awareness and attribution as the dependent variables and variable sets from the other procedures administered as multivariate independent variables. RESULTS: The median score obtained from the SUMD for current awareness was in a range between full awareness and uncertainty concerning presence of a mental disorder. For attribution, the median score indicated that attribution was usually made to the illness itself. None of the differences between participants with and without comorbid alcoholism were significant for the SUMD awareness and attribution scores, neurocognitive or MRI variables. The multiple regression analyses only showed a significant degree of association between the SUMD awareness score and the Young Mania Rating Scale (r(2)=.632, p<.05). A stepwise analysis indicated that items assessing degree of insight, irritability, and sleep disturbance met criteria for entry into the regression equation. None of the regression analyses for the SUMD attribution item were significant. CONCLUSIONS: Apparently unlike the case for schizophrenia, most of the participants, all of whom had bipolar disorder, were aware of their symptoms and correctly related them to a mental disorder. Hypotheses concerning the relationships between degree of unawareness and possible contributors to its development including comorbid alcoholism, cognitive dysfunction and structural reduction of gray matter in the frontal region and hippocampus, were not associated with degree of unawareness but symptoms of mania were significantly associated. The apparent reason for this result is that the sample obtained a SUMD modal awareness score of 1 or 2, reflecting the area between full awareness and uncertainty about having a mental disorder. None of the participants were rated as having a 5 response reflecting the belief that s/he does not have a mental disorder. PMID- 25439526 TI - Anti-high mobility group box 1 (anti-HMGB1) antibodies are not related to the occurrence of cutaneous lesions in systemic lupus erythematosus. AB - OBJECTIVES: To investigate whether serum anti-high mobility group box 1 (anti HMGB1) antibodies are related to the development of skin lesions in systemic lupus erythematosus (SLE). METHOD: This study involved 21 SLE patients with skin lesions, 18 without skin lesions, and 22 healthy controls. The presence and serum levels of anti-HMGB1-IgG and -IgM were measured by western blot and enzyme-linked immunosorbent assay (ELISA), respectively. HMGB1 expression and serum antibodies deposited in the skin were visualized by immunofluorescence staining. RESULTS: Using western blot analysis, we detected anti-HMGB1-IgG antibodies in 13 out of 21 SLE patients with skin lesions and 11 out of 18 SLE patients without skin lesions (p > 0.05). Serum levels of anti-HMGB1-IgG measured by ELISA were also comparable between the two groups of SLE patients (p > 0.05) but were higher in patients than in healthy controls (p < 0.05). Similar results were found with serum anti-HMGB1-IgM antibodies. HMGB1 accumulated under the stratum corneum in lupus cutaneous lesions without forming immune complexes with IgG or IgM, which were mainly observed along the epidermal-dermal junction. Furthermore, serum anti HMGB1-IgM was higher in the group of patients with arthritis than in those without arthritis. CONCLUSIONS: Based on the findings of the current study, it is unlikely that anti-HMGB1 antibodies play a role in the development of SLE cutaneous lesions. PMID- 25439527 TI - 'Women at risk': the health and social vulnerabilities of the regular female partners of men who inject drugs in Delhi, India. AB - Needle and syringe sharing is common among people who inject drugs and so is unprotected sex, which consequently puts their sex partners at risk of sexually transmitted infections (STIs) including HIV and other blood-borne infections, like hepatitis. We undertook a nested study with the regular female partners of men who inject drugs participating in a longitudinal HIV incidence study in Delhi, India. In-depth interviews were conducted with female partners of 32 men. The interviews aimed to gather focused and contextual knowledge of determinants of safe sex and reproductive health needs of these women. Information obtained through interviews was triangulated and linked to the baseline behavioural data of their partner (index men who injected drugs). The study findings illustrate that women in monogamous relationships have a low perception of STI- and HIV related risk. Additionally, lack of awareness about hepatitis B and C is a cause of concern. Findings also suggest impact of male drug use on the fertility of the female partner. It is critical to empower regular female partners to build their self-risk assessment skills and self-efficacy to negotiate condom use. Future work must explore the role of drug abuse among men who inject drugs in predicting fertility and reproductive morbidity among their female partners. PMID- 25439528 TI - Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: a 40-year odyssey. AB - INTRODUCTION: All tested cancer cell types are methionine dependent in that the cells arrest and eventually die when deprived of methionine, a condition that is generally nontoxic to normal cells. Methionine dependence is the only known general metabolic defect in cancer. Methionine-deprived cancer cells arrest at the S/G2 phase, an unusual position for cell cycle arrest. In order to exploit the cancer-specific metabolic defect of methionine dependence, methioninases were developed. AREAS COVERED: The present Expert Opinion describes the phenomena of methionine dependence and a methioninase cloned from Pseudomonas putida (chemical name: l-methionine alpha-deamino-gamma-mercaptomethane lyase [EC 4.4.1.11]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer as well as in macaque monkeys and a pilot Phase I trial of human cancer patients. Efficacy of rMETase has been demonstrated against various cancer types in mouse models. EXPERT OPINION: The most promising application of rMETase therapy is in sequential combination therapy, whereby the cancer cells within a tumor are trapped in S/G2 by methioninase treatment and then treated with chemotherapeutic agents active against cells in S/G2. PMID- 25439529 TI - Feasibility of near-infrared spectroscopic tomography for intraoperative functional cerebral monitoring: a primate study. AB - OBJECTIVE: The wide-ranging manipulations to the cardiovascular system that frequently occur during cardiac surgery can expose the brain to variations in its blood supply that could prove deleterious. As a first step to developing a resource suitable for monitoring such changes, we detected the hemodynamic events induced in the brain of a primate model, using high-density near-infrared spectroscopy combined with tomographic reconstruction methods and validated the findings using established radiologic and histologic techniques. METHODS: Continuous monitoring of the relative changes in the components of the cerebral hemoglobin signal was performed using high-density near-infrared spectroscopy (270 source-detector channel array) in anesthetized bonnet macaques with the brain exposed to induced ischemia and other acute events. A comparative analysis (exact binomial test) applied to reconstructed 3-dimensional images before and after the events and between cerebral hemispheres, combined with postprocedure magnetic resonance imaging, and postmortem histopathologic examination of the macaques' brains was performed to document and validate the spatial features revealed by the optical findings. RESULTS: Relative changes in the measured and calculated components of the hemoglobin signal, in response to the performed manipulations, revealed substantial concurrence among the reconstructed 3 dimensional images, magnetic resonance imaging of the macaques' brains, and postmortem histopathologic examination findings. Concurrence was seen when the manipulated hemoglobin concentration and associated oxygenation levels were either increased or decreased, and whether they were bilateral or restricted to a specified hemisphere. CONCLUSIONS: Continuous near-infrared spectroscopy tomography has been shown to accurately capture and localize cerebral ischemia, vasodilatation, and hemorrhage in primates in real time. These findings are directly applicable to clinical intraoperative functional cerebral monitoring. PMID- 25439530 TI - Workup for proteinuria. AB - The kidney has anatomic and physiologic features that prevent protein from reaching the urine. In disease processes, this natural mechanism is disrupted, causing protein to leak into the urine. Proteinuria can be used as a marker for disease and disease progression. The general anatomy of the glomerulus along with preliminary workup to evaluate disease based on history, physical and urinalysis results are reviewed in this article. Examples of commonly encountered diseases in the outpatient setting and relevance of proteinuria in chronic kidney disease along with general complications and treatments are also reviewed. PMID- 25439531 TI - Work-up of hematuria. AB - Hematuria is a common clinical manifestation of diseases affecting the urinary system. Sometimes it may not represent any underlying disease and is of no clinical significance, especially when it is transient in young adult patients. However, it may represent underlying intrinsic kidney disease or malignancy in patients, even if transient. Therefore, detection of hematuria in the appropriate clinical setting and further investigation based on the individual clinical scenario helps establish correct diagnosis and guide further management. This article discusses the etiologies and workup of hematuria. PMID- 25439532 TI - Secondary hypertension, issues in diagnosis and treatment. AB - Secondary hypertension (SH) often implies a correctable form of nonessential hypertension. Often certain clinical clues prompt a more extensive evaluation of the causes of the hypertension. Renovascular disease, intrinsic renal disease, primary hyperaldosteronism, and obstructive sleep apnea represent the most common causes of SH. This article defines the disorder and details its epidemiology, prevalence, pathophysiology, physical findings, and treatment strategies. PMID- 25439533 TI - Renin-angiotensin-aldosterone system inhibition: overview of the therapeutic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and direct renin inhibitors. AB - Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at present. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events. PMID- 25439534 TI - Evaluation of acute kidney injury in the hospital setting. AB - Acute kidney injury (AKI) is becoming more prevalent in the hospital setting and is associated with the worst prognostic outcomes, including increased mortality. Many different factors contribute to the development of AKI in hospitalized patients, including medications, older age, sepsis, and comorbid conditions. Correct evaluation and management of AKI requires investigation and understanding of important causative factors for each of the 3 pathophysiologic categories of renal failure. Preventative efforts rely on prompt recognition of AKI while avoiding iatrogenic insults in the hospital setting. PMID- 25439535 TI - Nonsteroidal antiinflammatory drugs, cyclooxygenase-2, and the kidneys. AB - Nonsteroidal antiinflammatory drugs (NSAIDs) are one of the most commonly used classes of medications in the world, which function by inhibiting the cyclooxygenase (COX) enzymes and downregulating the inflammatory pathway. COX enzymes are constitutively expressed in the kidneys and function to maintain a homeostatic environment in terms of maintaining the glomerular filtration rate, blood pressure, sodium, water, and osmotic regulation. When the COX enzymes are inhibited by NSAIDs, a multitude of renal and vascular complications occur. This article aims to enlighten primary care physicians of the complications that arise with NSAIDs from a renal perspective and to present some management strategies. PMID- 25439536 TI - Diagnosis and evaluation of renal cysts. AB - Renal cysts are commonly encountered in clinical practice. Although most cysts found on routine imaging studies are benign, there must be an index of suspicion to exclude a neoplastic process or the presence of a multicystic disorder. This article focuses on the more common adult cystic diseases, including simple and complex renal cysts, autosomal-dominant polycystic kidney disease, and acquired cystic kidney disease. PMID- 25439537 TI - The primary care physician/nephrologist partnership in treating chronic kidney disease. AB - Chronic kidney disease (CKD) continues to be an ever-increasing health problem in the United States and elsewhere. Diabetes mellitus and hypertension remain the primary causes, and much of this is related to increased rates of obesity. Studies have demonstrated that early referral to a nephrologist can be life saving and can also markedly improve quality of life. Besides recommending treatments for CKD, early referral can assist in medication management and in minimizing exposure to potential nephrotoxins. In patients who progress to end stage renal disease, having an established patient-PCP-nephrologist relationship can ease the transition to renal replacement therapy or transplantation. PMID- 25439538 TI - Evaluation and management of the older adult with chronic kidney disease. AB - Chronic kidney disease (CKD) has a high prevalence in the elderly population. Almost half of the population reaches moderate impairment (CKD 3) by 65 years of age. This article describes CKD staging in the geriatric population and several common clinical presentations of renal disease. Diagnosis and treatment regimens of CKD are discussed. Geriatric patients are at an increased risk for renal dysfunction from many causes. Some causes are inherent with aging, such as gross structural and cellular changes, decrease in physiologic function, and lowered vascular compensatory reserve. Exposures, including medications and diagnostic testing, are contributors to acute kidney injury. PMID- 25439539 TI - Obesity-related kidney disease. AB - The prevalence of chronic kidney disease (CKD) is increasing, and the epidemic of obesity is one of the causes. Obesity exacerbates hypertension as a risk factor for CKD, causing vasoconstriction and salt and water retention. Obesity also worsens glucose intolerance and insulin resistance as risk factors for CKD. Obesity targets the kidney by triggering novel pathways of intrarenal inflammation, recruiting professional immunologic cells through metaflammation. Obesity-related glomerulopathy has emerged as a distinct pathologic variant of focal segmental glomerulosclerosis. No definitive treatments have come about for obesity-related glomerulopathy, but among the most promising prospects is aggressive weight loss, including bariatric surgery. PMID- 25439540 TI - Medical management of the kidney transplant recipient: a practical approach for the primary care provider. AB - Kidney transplant recipients (KTRs) commonly present with complex medical issues that are best managed jointly by both their primary care physician and the kidney transplant center. Hypertension, diabetes, dyslipidemias, and obesity are frequently present in the KTR population and the successful management of these comorbidities is essential in achieving excellent posttransplant outcomes. Cardiovascular disease is the leading cause of mortality in KTRs, and interventions that mitigate the risk factors that contribute to these adverse outcomes are an important part of the long-term management of a KTR. PMID- 25439541 TI - "I don't take creatinine". Foreword. PMID- 25439542 TI - Ambulatory nephrology. Preface. PMID- 25439543 TI - Visual syndrome of prematurity. PMID- 25439544 TI - Meat Juice Serology and Improved Food Chain Information as Control Tools for Pork Related Public Health Hazards. AB - The seroprevalence of Salmonella spp., pathogenic Yersinia spp., Toxoplasma gondii and Trichinella spp. was studied in 1353 finishing pigs from 259 farms that were allocated according to farm types: large fattening farms (>= 1000 pig places), small fattening farms (< 1000 pig places) and farrow-to-finish farms. The antibodies were analysed with commercial ELISA kits in meat juice samples that were collected at Finnish slaughterhouses. Salmonella antibodies were rare (3% of pigs, 14% of farms) when the cut-off optical density (OD) value 0.2 was used. Antibodies to pathogenic Yersinia spp. and T. gondii were detected in 57% of pigs and 85% of farms (OD >= 0.3) and in 3% of pigs and 9% of farms (OD >= 0.15), respectively. No antibodies to Trichinella spp. were detected (OD >= 0.3). The European Food Safety Authority (EFSA) considers Salmonella spp., Yersinia enterocolitica, T. gondii and Trichinella spp. as the most relevant biological hazards in the context of meat inspection of pigs. The seroprevalence of these important zoonotic pathogens was low in Finland, except that of Yersinia. The seroprevalence of Toxoplasma was significantly higher in pigs originating from small-scale fattening farms (P < 0.05). Strong positive correlation was observed at the animal level between Salmonella and Yersinia seropositivity and between Salmonella and Toxoplasma seropositivity (P < 0.05). We suggest that these results reflect the level and importance of biosecurity measures applied on the farms. Meat juice serology at slaughter is a useful tool for targeting measures to control these pathogens. The information obtained from analyses should be used as part of the food chain information (FCI). PMID- 25439545 TI - The secreted antigen, HP0175, of Helicobacter pylori links the unfolded protein response (UPR) to autophagy in gastric epithelial cells. AB - Autophagy is an intracellular catabolic process that is required to maintain cellular homeostasis. Pathogen-elicited host cell autophagy may favour containment of infection or may help in bacterial survival. Pathogens have developed the ability to modulate host autophagy. The secreted antigen HP0175, a peptidyl prolyl cis,trans isomerase of Helicobacter pylori, has moonlighting functions with reference to host cells. Here we show that it executes autophagy in gastric epithelial cells. Autophagy is dependent on the unfolded protein response (UPR) that activates the expression of PKR-like ER kinase (PERK). This is accompanied by phosphorylation of eukaryotic initiation factor 2alpha (eIF 2alpha) and transcriptional activation of ATF4 and CHOP. Knockdown of UPR-related genes inhibits the conversion of LC3I to LC3II, a marker of autophagy. The autophagy-inducing ability of H. pylori is compromised when cells are infected with an isogenic hp0175 mutant. Autophagy precedes apoptosis. Silencing of BECLIN1 augments cleavage of caspase 3 as well as apoptosis. Increased apoptosis of gastric epithelial cells is known to be linked to H. pylori-mediated gastric inflammation and carcinogenesis. To the best of our knowledge, this study provides the first demonstration of how HP0175 endowed with moonlighting functions links UPR-dependent autophagy and apoptosis during H. pylori infection. PMID- 25439546 TI - Human rights of the mentally ill in Indonesia. AB - BACKGROUND: The mentally ill are vulnerable to human rights violations, particularly in Indonesia, where shackling is widespread. AIM: The aim of this study was to understand the provision of mental health care in Indonesia, thereby identifying ways to improve care and better support carers. METHODS: Grounded theory methods were used. Study participants included health professionals, non health professionals and individuals living with a mental disorder who were well at the time (n = 49). Data were collected through interviews conducted in 2011 and 2012. RESULTS: The core category of this grounded theory is 'connecting care' a term coined by the authors to describe a model of care that involves health professionals and non-health professionals, such as family members. Four main factors influence care-providers' decision-making: competence, willingness, available resources and compliance with institutional policy. Health professionals are influenced most strongly by institutional policy when deciding whether to accept or shift responsibility to provide care. Non-health professionals base their decisions largely on personal circumstances. Jointly made decisions can be matched or unmatched. Unmatched decisions can result in forced provision of care, increasing risks of human rights violations. LIMITATIONS: Generalization of this grounded theory is difficult as the research was conducted in two provinces of Indonesia. CONCLUSION: Institutional policy was important in the process of connecting care for the mentally ill in Indonesia and needs to be underpinned by legislation to protect human rights. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Strengthening mental health legislation in Indonesia will allow nurses to connect care more effectively. PMID- 25439547 TI - Thyroglossal duct cyst and ectopic thyroid: surgical management. AB - The embryology, presentation, imaging, and treatment of the thyroglossal duct cyst will be reviewed. Anatomic features and surgical technique to prevent complications and recurrence will be discussed. Included in the discussion will be the management of thyroglossal duct cyst malignancy and ectopic thyroid. PMID- 25439548 TI - Head and neck vascular lesions. AB - Vascular lesions of the head and neck are complex and diverse. These include infantile hemangioma, venous malformations, lymphatic malformations, and arteriovenous malformations, among others. Vascular malformations and tumors display different growth patterns and require different approaches to treatment. Therefore, accurate diagnosis is of utmost importance. This article is a guide for the diagnosis and management of vascular lesions of the head and neck. PMID- 25439549 TI - Pediatric thyroid nodules and malignancy. AB - Proper management of pediatric thyroid nodules is crucial to achieving good outcomes. It is important to obtain a thorough history, including prior radiation exposure and family history of thyroid cancer and any symptoms of hypothyroidism or hyperthyroidism. A complete physical examination with special attention to the thyroid gland and any cervical lymphadenopathy is important. Nodules between 5 and 10 mm with risk factors (clinical or sonographic) and all nodules greater than 10 mm should undergo a fine-needle aspiration biopsy. A comprehensive center of pediatric specialists is the best environment for treatment of these patients. PMID- 25439550 TI - Endoscopic endonasal surgery for sinonasal and skull base lesions in the pediatric population. AB - Endoscopic endonasal skull base surgical techniques, initially developed in adult patients, are being utilized with increasing frequency in pediatric patients to treat sinonasal and skull base lesions. This article reviews the current state of endoscopic endonasal approaches to the skull base to both treat disease and reconstruct the skull base in pediatric patients. Sinonasal and skull base embryology and anatomy are reviewed as a foundation for understanding the disease processes and surgical techniques. Selected skull base pathologies and conditions that involve the pediatric skull base are also reviewed. PMID- 25439551 TI - Pediatric teratoma and dermoid cysts. AB - Teratomas and dermoid cysts are germ cell neoplasms. This article focuses on cervical and craniofacial teratomas. Presentation of these neoplasms varies in degree of severity, from cosmetic deformities to airway distress requiring emergent intervention. Nasal lesions (particularly if suspicious for a nasal dermoid) require imaging before biopsy to assess for intracranial extension. Treatment consists of airway management if respiratory distress is present, and early surgical intervention. Postoperative follow-up is required to monitor for recurrence. PMID- 25439552 TI - Pediatric inflammatory adenopathy. AB - The differential diagnosis in pediatric lymphadenopathy includes bacterial, viral, fungal, and idiopathic causes. A systematic approach to patient evaluation is necessary because the differential diagnosis, presentation, and work up must consider infectious, immunologic, neoplastic, and idiopathic disorders. A thorough history and examination are vital to determining the diagnosis and ruling out a malignant process. PMID- 25439553 TI - Disorders and tumors of the salivary glands in children. AB - Salivary gland neoplasms are rare in children. In infants most tumors are benign hemangiomas, with some notable exceptions, such as sialoblastomas. An asymptomatic swelling in the periauricular region is the most common presenting complaint in older children. Approximately 50% of these lesions are malignant, which dictates a thorough diagnostic evaluation by a head and neck surgeon. Surgical excision is the primary treatment modality. Prognosis is primarily determined by histopathologic findings. This review discusses neoplastic lesions of the salivary glands in children, and malignant epithelial tumors in particular. PMID- 25439554 TI - Pediatric lingual and other intraoral lesions. AB - This article explores pediatric lingual and other intraoral lesions. First the embryology and anatomy of the oral anatomy is outlined. Then the article discusses infections and inflammatory diseases, congenital malformations, benign neoplasms, and malignant tumors. PMID- 25439555 TI - Congenital lesions of epithelial origin. AB - Defects of embryologic development give rise to a variety of congenital lesions arising from the epithelium and are among the most common congenital lesions of the head and neck in the pediatric population. This article presents several congenital lesions of epithelial origin, including congenital midline cervical cleft, pilomatrixoma, dermoid, foregut duplication cysts, and preauricular sinuses and pits. In addition, the management of these lesions is reviewed. PMID- 25439556 TI - Imaging of pediatric head and neck masses. AB - Medical imaging is an important tool in the evaluation and classification of pediatric head and neck masses. Such lesions may include congenital, inflammatory, infectious, vascular, or neoplastic processes. Ultrasound is often the first line modality in the workup of a neck mass in a child, followed by MRI or CT depending on the scenario. This information must be interpreted in the context of the patient's clinical history, physical examination, and demographics. The medical imaging workup of a neck mass in a child must be focused to yield the maximum information possible while minimizing the risks of radiation and sedation. PMID- 25439557 TI - Pediatric head and neck masses. Preface. PMID- 25439558 TI - 10-20-30 training increases performance and lowers blood pressure and VEGF in runners. AB - The present study examined the effect of training by the 10-20-30 concept on performance, blood pressure (BP), and skeletal muscle angiogenesis as well as the feasibility of completing high-intensity interval training in local running communities. One hundred sixty recreational runners were divided into either a control group (CON; n = 28), or a 10-20-30 training group (10-20-30; n = 132) replacing two of three weekly training sessions with 10-20-30 training for 8 weeks and performance of a 5-km run (5-K) and BP was measured. VO2max was measured and resting muscle biopsies were taken in a subgroup of runners (n = 18). 10-20-30 improved 5-K time (38 s) and lowered systolic BP (2 +/- 1 mmHg). For hypertensive subjects in 10-20-30 (n = 30), systolic and diastolic BP was lowered by 5 +/- 4 and 3 +/- 2 mmHg, respectively, which was a greater reduction than in the non-hypertensive subjects (n = 102). 10-20-30 increased VO2max but did not influence muscle fiber area, distribution or capillarization, whereas the expression of the pro-angiogenic vascular endothelial growth factor (VEGF) was lowered by 22%. No changes were observed in CON. These results suggest that 10-20 30 training is an effective and easily implemented training intervention improving endurance performance, VO2max and lowering BP in recreational runners, but does not affect muscle morphology and reduces muscle VEGF. PMID- 25439559 TI - Metabolite profile, antioxidant capacity, and inhibition of digestive enzymes in infusions of peppermint (Mentha piperita) grown under drought stress. AB - Peppermint (Mentha piperita) infusions represent an important source of antioxidants, which can be enhanced by inducing abiotic stress in plants. The aim of this study was to evaluate the effect of drought stress on peppermint cultivation as well as the metabolite profile, antioxidant capacity, and inhibition of digestive enzymes of resulting infusions. At 45 days after planting, irrigation was suppressed until 85 (control), 65, 35, 24, and 12% soil moisture (SM) was reached. The results showed that 35, 24, and 12% SM decreased fresh (20%) and dry (5%) weight. The 35 and 24% SM treatments significantly increased total phenolic and flavonoid contents as well as antioxidant capacity. Coumaric acid, quercetin, luteolin, and naringenin were detected only in some drought treatments; however, in these infusions, fewer amino acids and unsaturated fatty acids were identified. The 24 and 12% SM treatments slightly improved inhibition of pancreatic lipase and alpha-amylase activity. Therefore, induction of moderate water stress in peppermint is recommended to enhance its biological properties. PMID- 25439560 TI - Reason, emotion, compassion: can altruism survive professionalisation in the humanitarian sector? AB - The humanitarian sector has grown enormously over the past two decades. Some fear that professionalisation comes at the expense of altruistic volunteering. This may be a valid concern if altruism is the product of organisational culture and individual experiences rather than an innate trait. This paper examines advances in evolutionary biology and neurology that provide evidence in support of both the nature and nurture arguments, echoing earlier insights from social sciences. It then questions to what extent humanitarian principles build on altruistic impulses or instead seek to constrain them, and reviews recruitment profiles of selected humanitarian organisations and applicants' letters accordingly. This initial investigation warrants further research to identify how altruism as a personal trait and an organisational principle has influenced diverse humanitarian actors and traditions. This paper outlines how training curricula and organisational reward systems can build on-rather than stifle-natural altruism to nurture critical, reflexive practitioners. PMID- 25439562 TI - Reconstructing the demographic history of orang-utans using Approximate Bayesian Computation. AB - Investigating how different evolutionary forces have shaped patterns of DNA variation within and among species requires detailed knowledge of their demographic history. Orang-utans, whose distribution is currently restricted to the South-East Asian islands of Borneo (Pongo pygmaeus) and Sumatra (Pongo abelii), have likely experienced a complex demographic history, influenced by recurrent changes in climate and sea levels, volcanic activities and anthropogenic pressures. Using the most extensive sample set of wild orang-utans to date, we employed an Approximate Bayesian Computation (ABC) approach to test the fit of 12 different demographic scenarios to the observed patterns of variation in autosomal, X-chromosomal, mitochondrial and Y-chromosomal markers. In the best-fitting model, Sumatran orang-utans exhibit a deep split of populations north and south of Lake Toba, probably caused by multiple eruptions of the Toba volcano. In addition, we found signals for a strong decline in all Sumatran populations ~24 ka, probably associated with hunting by human colonizers. In contrast, Bornean orang-utans experienced a severe bottleneck ~135 ka, followed by a population expansion and substructuring starting ~82 ka, which we link to an expansion from a glacial refugium. We showed that orang-utans went through drastic changes in population size and connectedness, caused by recurrent contraction and expansion of rainforest habitat during Pleistocene glaciations and probably hunting by early humans. Our findings emphasize the fact that important aspects of the evolutionary past of species with complex demographic histories might remain obscured when applying overly simplified models. PMID- 25439561 TI - The effect and underlying mechanism of Timosaponin B-II on RGC-5 necroptosis induced by hydrogen peroxide. AB - BACKGROUND: Necroptosis is an important mode of cell death, which is due to oxidant stress accumulation. Our previous study indicated that oxidant stresses could be reduced by Timosaponin B-II (TBII), a kind of Chinese herb RhizomaAnemarrhenae monomer extraction. We wonder the possible effect of Timosaponin B-II, whether it can protect cells from necroptosis via reducing the oxidant stress, in RGC-5 following hydrogen peroxide (H2O2) insult. METHODS: RGC 5 cells were grown in DMEM, the model group was exposed in H2O2 with the concentration of 300 MUM, and the experimental group was pre-treated with Timosaponin B-II at different concentrations (1 MUM, 10 MUM, 100 MUM and 1000 MUM) for 24 hrs. MTT assay was carried out to measure the cytotoxicity of H2O2, MDA concentration assay was executed to evaluate the degree of oxidative stress, TNF-alpha ELISA Assay was used to measure the concentration of TNF-alpha, finally, the degree of necrosis were analyzed using flow cytometry. RESULTS: We first constructed the cell injury model of necroptosis in RGC-5 upon H2O2 exposure. Morphological observation and MTT assay were used to evaluate the degree of RGC-5 death. MDA assay were carried out to describe the degree of oxidant stress. Annexin V/PI staining was used to detect necroptotic cells pre treated with or without Timosaponin B-II following H2O2 injury. TNF-alpha ELISA was carried out to detect the TNF-alpha accumulation in RGC-5. Upon using Timosaponin B-II with concentration of 100 MUM, the percentage of cell viability was increased from 50% to 75%, and the necrosis of cells was reduced from 35% to 20% comparing with H2O2 injury group. Oxidant stress and TNF-alpha was reduced upon injury which decreased the ratio of RGC-5 necroptosis. CONCLUSION: Our study found out that Timosaponin B-II might reduce necroptosis via inhibition of ROS and TNF-alpha accumulation in RGC-5 following H2O2 injury. PMID- 25439563 TI - Plasma parameters related to energy and lipid metabolism in periparturient Modenese and Italian Friesian cows. AB - The aim of this work was to compare energy and lipid metabolism during the peripartum period between Modenese (MO) and Italian Friesian (IF) cows. The study was carried out on 33 pluriparous pregnant cows, 19 IF and 14 MO, reared together in the same herd and kept under equal conditions of management and nutrition. Blood was sampled from jugular vein starting 4 week before expected calving date until 4 week post-calving, once weekly. Plasma was analysed for glucose, NEFA, BHBA, triglycerides and cholesterol concentrations. Body condition score (BCS) was assessed weekly after blood sampling. Data from antepartum (a.p.) and post partum (p.p.) periods were separately analysed as repeated measures by a linear mixed models with the effect of breed, time and their interaction as main factors and random cow within breed. The energy status differed between the two breeds during the peripartum period. We observed higher BCS a.p. and p.p. and lower BCS variations p.p. in MO compared to IF group. Modenese cows showed lower glucose and cholesterol concentrations (p < 0.001), but higher NEFA values, NEFA to cholesterol and NEFA to albumin ratios (p < 0.001) during a.p.; on the contrary, IF cows had higher (p < 0.05) cholesterol, NEFA, BHBA levels and NEFA to albumin ratio than MO ones during p.p. The differences observed between the two breeds suggest how MO cows are subjected to lipid mobilization during late gestation; on the contrary, IF cows are predisposed to mobilize their lipid reserves at the beginning of lactation to support high production. The results indicate a diverse ability to cope with metabolic stress and suggest the hypothesis that the differences in concentrations of plasma parameters and their variation amplitude around the calving period might depend on the different genetic merit for milk production between the two breeds. PMID- 25439564 TI - Unravelling the mystery of sepsis. PMID- 25439565 TI - Neonatal ventilation trials need specific funding. PMID- 25439566 TI - Inhaled steroids in COPD: when should they be used? PMID- 25439567 TI - Expression of concern. PMID- 25439568 TI - Dorothy Stopford Price. PMID- 25439570 TI - Respiratory infections in patients undergoing mechanical ventilation. PMID- 25439569 TI - Combination therapy: the future of management for idiopathic pulmonary fibrosis? AB - Findings from recently published placebo-controlled trials in idiopathic pulmonary fibrosis have established that pirfenidone and nintedanib prevent about 50% of the decline in forced vital capacity typically seen in this disease; future trials are therefore unlikely to use placebo as a control group for ethical reasons. Future clinical assessment will probably include add-on trials in which a new drug is combined with an intervention with established efficacy; this development is in turn likely to herald the use of combination regimens in clinical practice. Personalised medicine (the selection of monotherapies on the basis of individualised biomarker signal) is an intrinsically attractive alternative approach, but is unlikely to be useful in routine management of idiopathic pulmonary fibrosis in the medium-term future because of the complex nature of the disease's pathogenesis. In this Personal View, we review the pleiotropic nature of disease pathogenesis in idiopathic pulmonary disease, the use of combination regimens in other selected chronic lung diseases, and the conceptual basis for combination therapies in interstitial lung disorders other than idiopathic pulmonary fibrosis. On the basis of these considerations, and the emergence of data from add-on trials, we believe that the future of management for idiopathic pulmonary fibrosis lies in the development of combination regimens. PMID- 25439571 TI - Why use the home sleep test? PMID- 25439572 TI - Sleep apnoea in the elderly - authors' reply. PMID- 25439573 TI - Sleep apnoea in the elderly. PMID- 25439574 TI - Gene therapy for childhood neurological disease. PMID- 25439575 TI - American Board of Psychiatry and Neurology certification in epilepsy: just what the doctor ordered, another board examination. PMID- 25439576 TI - Gene therapy for muscular dystrophy: moving the field forward. AB - Gene therapy for the muscular dystrophies has evolved as a promising treatment for this progressive group of disorders. Although corticosteroids and/or supportive treatments remain the standard of care for Duchenne muscular dystrophy, loss of ambulation, respiratory failure, and compromised cardiac function is the inevitable outcome. Recent developments in genetically mediated therapies have allowed for personalized treatments that strategically target individual muscular dystrophy subtypes based on disease pathomechanism and phenotype. In this review, we highlight the therapeutic progress with emphasis on evolving preclinical data and our own experience in completed clinical trials and others currently underway. We also discuss the lessons we have learned along the way and the strategies developed to overcome limitations and obstacles in this field. PMID- 25439578 TI - Stimulant use in patients with sturge-weber syndrome: safety and efficacy. AB - BACKGROUND: Sturge-Weber syndrome is characterized by a facial port-wine birthmark, vascular eye abnormalities, and a leptomeningeal angioma. Attention and behavioral issues are common in Sturge-Weber syndrome. However, literature evidence for stimulant treatment is minimal. This study evaluates stimulant medication safety and efficacy in individuals with Sturge-Weber syndrome. METHODS: The research database of the Hunter Nelson Sturge-Weber Center (n = 210 subjects in the database) was reviewed for stimulant use. Twelve patients (mean age 10.5 years, age range 4 to 21 years) on stimulants were seen between 2003 and 2012. A retrospective chart review obtained comorbid diagnoses, stimulant type and dosage, medication side effects, vital signs, and medication efficacy. RESULTS: All 12 patients had brain involvement (unilateral, nine; bilateral, three). Additional comorbidities included epilepsy (twelve), hemiparesis (eight), headaches (eight), and vision deficits (six). Eight patients reported side effects, primarily appetite suppression (four) and headaches (three). There were no statistically significant changes in weight or blood pressure 6 months after medication initiation. Medication efficacy was subjectively reported in 11 patients. Seven patients remained on stimulants at their most recent follow-up visit. CONCLUSIONS: This study preliminarily evaluates stimulant medication use in a small group of Sturge-Weber syndrome patients. Stimulants were tolerated and effective in most subjects. Side effects were mostly minor and medication did not negatively affect growth or vital signs. Stimulant medication may be a safe and effective intervention for Sturge-Weber syndrome children with attention issues/attention deficit hyperactivity disorder. Further studies with larger sample sizes are needed. PMID- 25439579 TI - A novel nonsense mutation in SCN9A in a Moroccan child with congenital insensitivity to pain. AB - BACKGROUND: Congenital insensitivity to pain is a rare autosomal recessive disease. Individuals who are diagnosed with congenital insensitivity to pain usually present severely impaired pain perception, and in some cases, they also manifest a decreased sense of smell (anosmia). This disease is caused by loss of function mutations affecting the SCN9A gene, which encodes the voltage-gated sodium channel Nav1.7. It is noteworthy that nearly every mutation linking this particular channel to congenital insensitivity to pain has been demonstrated to underlie the translation of a truncated protein. METHODS: Complete sequencing of the SCN9A gene in a Moroccan 3-year-old child with congenital insensitivity to pain. RESULT: We identified a homozygous nonsense mutation (c.4795C>T) in exon 27, that results in codon stop in the amino acid (p.R1599X). CONCLUSION: In this report we present a previously unreported homozygous nonsense mutation present in a consanguineous Moroccan congenital insensitivity to pain patient with anosmia. The identification of this mutation extends the spectrum of mutations affecting the Nav1.7 channel, and it confirms earlier studies that established Nav1.7 roles in nociception and the sense of smell. PMID- 25439580 TI - S1P-induced airway smooth muscle hyperresponsiveness and lung inflammation in vivo: molecular and cellular mechanisms. AB - BACKGROUND AND PURPOSE: Sphingosine-1-phosphate (S1P) has been shown to be involved in the asthmatic disease as well in preclinical mouse experimental models of this disease. The aim of this study was to understand the mechanism(s) underlying S1P effects on the lung. EXPERIMENTAL APPROACH: BALB/c, mast cell deficient and Nude mice were injected with S1P (s.c.) on days 0 and 7. Functional, molecular and cellular studies were performed. KEY RESULTS: S1P administration to BALB/c mice increased airway smooth muscle reactivity, mucus production, PGD2 , IgE, IL-4 and IL-13 release. These features were associated to a higher recruitment of mast cells to the lung. Mast cell-deficient Kit (W) ( sh/) (W) (-sh) mice injected with S1P did not display airway smooth muscle hyper reactivity. However, lung inflammation and IgE production were still present. Treatment in vivo with the anti-CD23 antibody B3B4, which blocks IgE production, inhibited both S1P-induced airway smooth muscle reactivity in vitro and lung inflammation. S1P administration to Nude mice did not elicit airway smooth muscle hyper-reactivity and lung inflammation. Naive (untreated) mice subjected to the adoptive transfer of CD4+ T-cells harvested from S1P-treated mice presented all the features elicited by S1P in the lung. CONCLUSIONS AND IMPLICATIONS: S1P triggers a cascade of events that sequentially involves T-cells, IgE and mast cells reproducing several asthma-like features. This model may represent a useful tool for defining the role of S1P in the mechanism of action of currently-used drugs as well as in the development of new therapeutic approaches for asthma-like diseases. PMID- 25439577 TI - Erythropoietin and hypothermia for hypoxic-ischemic encephalopathy. AB - BACKGROUND: Erythropoietin is neuroprotective in animal models of neonatal hypoxic-ischemic encephalopathy. We previously reported a phase I safety and pharmacokinetic study of erythropoietin in neonates. This article presents the neurodevelopmental follow-up of infants who were enrolled in the phase I clinical trial. METHODS: We enrolled 24 newborns with hypoxic-ischemic encephalopathy in a dose-escalation study. Patients received up to six doses of erythropoietin in addition to hypothermia. All infants underwent neonatal brain magnetic resonance imaging (MRI) reviewed by a single neuroradiologist. Moderate-to-severe neurodevelopmental disability was defined as cerebral palsy with Gross Motor Function Classification System levels III-V or cognitive impairment based on Bayley Scales of Infant Development II mental developmental index or Bayley III cognitive composite score. RESULTS: Outcomes were available for 22 of 24 infants, at mean age 22 months (range, 8-34 months). There were no deaths. Eight (36%) had moderate-to-severe brain injury on neonatal MRI. Moderate-to-severe disability occurred in one child (4.5%), in the setting of moderate-to-severe basal ganglia and/or thalamic injury. Seven infants with moderate-to-severe watershed injury exhibited the following outcomes: normal (three), mild language delay (two), mild hemiplegic cerebral palsy (one), and epilepsy (one). All 11 patients with a normal brain MRI had a normal outcome. CONCLUSIONS: This study is the first to describe neurodevelopmental outcomes in infants who received high doses of erythropoietin and hypothermia during the neonatal period. The findings suggest that future studies are warranted to assess the efficacy of this new potential neuroprotective therapy. PMID- 25439581 TI - Sentinel surveillance of invasive candidiasis in Spain: epidemiology and antifungal susceptibility. AB - In order to know the epidemiology and the changes of antifungal resistance in invasive candidiasis (IC) we carried out this prospective study of Candida strains belonging to patients admitted to 26 Spanish hospitals from June 2011 to June 2012 diagnosed with IC. Clinical information and the identity of the Candida species were collected and antifungal susceptibility was tested using broth microdilution in five agents: amphotericin B, fluconazole, voriconazole, caspofungin and anidulafungin. A total of 705 cases-isolates were documented. Most of the patients suffered from candidemia and several underlying diseases and more than half of them were neutropenic or under immunosuppressive therapy, factors associated with higher mortality. Thirty percent of global mortality was documented. C. albicans was the most frequently isolated species, although an increase of non-C. albicans species was observed. Resistance to fluconazole was of 3.4%, lower than in previous years (6.3%). C. parapsilosis presented a higher MIC90 of echinocandins compared to other species. PMID- 25439583 TI - Effects of nitrate addition to a diet on fermentation and microbial populations in the rumen of goats, with special reference to Selenomonas ruminantium having the ability to reduce nitrate and nitrite. AB - This study investigated the effects of dietary nitrate addition on ruminal fermentation characteristics and microbial populations in goats. The involvement of Selenomonas ruminantium in nitrate and nitrite reduction in the rumen was also examined. As the result of nitrate feeding, the total concentration of ruminal volatile fatty acids decreased, whereas the acetate : propionate ratio and the concentrations of ammonia and lactate increased. Populations of methanogens, protozoa and fungi, as estimated by real-time PCR, were greatly decreased as a result of nitrate inclusion in the diet. There was modest or little impact of nitrate on the populations of prevailing species or genus of bacteria in the rumen, whereas Streptococcus bovis and S. ruminantium significantly increased. Both the activities of nitrate reductase (NaR) and nitrite reductase (NiR) per total mass of ruminal bacteria were increased by nitrate feeding. Quantification of the genes encoding NaR and NiR by real-time PCR with primers specific for S. ruminantium showed that these genes were increased by feeding nitrate, suggesting that the growth of nitrate- and nitrite-reducing S. ruminantium is stimulated by nitrate addition. Thus, S. ruminantium is likely to play a major role in nitrate and nitrite reduction in the rumen. PMID- 25439582 TI - Evaluation of repetitive element polymerase chain reaction for surveillance of methicillin-resistant Staphylococcus aureus at a large academic medical center and community hospitals. AB - Repetitive element polymerase chain reaction (rep-PCR) typing has been used for methicillin-resistant Staphylococcus aureus (MRSA) strain characterization. The goal of this study was to determine if a rapid commercial rep-PCR system, DiversiLabTM (DL; bioMerieux, Durham, NC, USA), could be used for MRSA surveillance at a large medical center and community hospitals. A total of 1286 MRSA isolates genotyped by the DL system were distributed into 84 distinct rep PCR patterns: 737/1286 (57%) were clustered into 6 major rep-PCR patterns. A subset of 220 isolates was further typed by pulsed-field gel electrophoresis (PFGE), spa typing, and SCCmec typing. The 220 isolates were distributed into 80 rep-PCR patterns, 94 PFGE pulsotypes, 27 spa, and 3 SCCmec types. The DL rep-PCR system is sufficient for surveillance, but the DL system alone cannot be used to compare data to other institutions until a standardized nomenclature is established and the DL MRSA reference library is expanded. PMID- 25439584 TI - Influence of melaleuca and copaiba oils on Candida albicans adhesion. AB - OBJECTIVE: To evaluate the efficacy of Melaleuca alternifolia and Copaifera officinalis in inhibiting the adhesion of Candida albicans biofilm. BACKGROUND: Over 65% of denture wearers suffer from denture stomatitis, which is one of the most prevalent forms of oral candidiasis. This disease is characterised by the inflammation of the oral mucosa in contact with the contaminated denture. The contaminated denture contributes to the switch of C. albicans from yeast to its pathogenic hyphal form. Candida albicans adheres and colonises the polymethylmethacrylate resin surfaces and thus contributes to the development of denture stomatitis. MATERIALS AND METHODS: The minimal inhibitory concentration (MIC) of M. alternifolia and Co. officinalis was assessed by the agar dilution method. Sixty-six thermopolymerised acrylic resin squares were used and treated with phosphate-buffered saline, sodium hypochlorite 1%, melaleuca 0.75%, melaleuca 0.375%, melaleuca 0.188% and copaiba 10%. For adherence and biofilm formation, the treated squares were placed in six-well tissue culture plates containing 1 * 10(7) cells/ml of ATCC1023 or SC5314 in Roswell Park Memorial Institute (RPMI) medium, and after 12 h, the planktonic cells were counted. RESULTS: Copaiba oil did not inhibit C. albicans growth. However, melaleuca oil showed an MIC value of 0.375% (3.4 mg/ml) for ATCC10231 and 0.093% (0.84 mg/ml) for SC5314. CONCLUSIONS: Our results demonstrated that M. alternifolia oil inhibited the growth of C. albicans. Moreover, both oils promoted significant adhesion reduction in the tested strains. These findings suggest the possibility of using these oils in prophylaxes against candidiasis. PMID- 25439585 TI - Oxidative stress drivers and modulators in obesity and cardiovascular disease: from biomarkers to therapeutic approach. AB - This review article is intended to describe how oxidative stress regulates cardiovascular disease development and progression. Epigenetic mechanisms related to oxidative stress, as well as more reliable biomarkers of oxidative stress, are emerging over the last years as potentially useful tools to design therapeutic approaches aimed at modulating enhanced oxidative stress "in vivo", thereby mitigating the consequent atherosclerotic burden. As a paradigm, we describe the case of obesity, in which the intertwining among oxidative stress, due to caloric overload, chronic low-grade inflammation induced by adipose tissue dysfunction, and platelet activation represents a vicious cycle favoring the progression of atherothrombosis. Oxidative stress is a major player in the pathobiology of cardiovascular disease (CVD). Reactive oxygen species (ROS)- dependent signaling pathways prompt transcriptional and epigenetic dysregulation, inducing chronic low-grade inflammation, platelet activation and endothelial dysfunction. In addition, several oxidative biomarkers have been proposed with the potential to improve current understanding of the mechanisms underlying CVD. These include ROS generating and/or quenching molecules, and ROS-modified compounds, such as F2 isoprostanes. There is also increasing evidence that noncoding micro- RNA (mi RNA) are critically involved in post- transcriptional regulation of cell functions, including ROS generation, inflammation, regulation of cell proliferation, adipocyte differentiation, angiogenesis and apoptosis. These molecules have promising translational potential as both markers of disease and site of targeted interventions. Finally, oxidative stress is a critical target of several cardioprotective drugs and nutraceuticals, including antidiabetic agents, statins, renin-angiotensin system blockers, polyphenols and other antioxidants. Further understanding of ROS-generating mechanisms, their biological role as well as potential therapeutic implications would translate into consistent benefits for effective CV prevention. PMID- 25439587 TI - Multi-modal imaging and cancer therapy using lanthanide oxide nanoparticles: current status and perspectives. AB - Biomedical imaging is an essential tool for diagnosis and therapy of diseases such as cancers. It is likely true that medicine has developed with biomedical imaging methods. Sensitivity and resolution of biomedical imaging methods can be improved with imaging agents. Furthermore, it will be ideal if imaging agents could be also used as therapeutic agents. Therefore, one dose can be used for both diagnosis and therapy of diseases (i.e., theragnosis). This will simplify medical treatment of diseases, and will be also a benefit to patients. Mixed (Ln(1x)Ln(2y)O3, x + y = 2) or unmixed (Ln2O3) lanthanide (Ln) oxide nanoparticles (Ln = Eu, Gd, Dy, Tb, Ho, Er) are potential multi-modal imaging and cancer therapeutic agents. The lanthanides have a variety of magnetic and optical properties, useful for magnetic resonance imaging (MRI) and fluorescent imaging (FI), respectively. They also highly attenuate X-ray beam, useful for X-ray computed tomography (CT). In addition gadolinium-157 ((157)Gd) has the highest thermal neutron capture cross section among stable radionuclides, useful for gadolinium neutron capture therapy (GdNCT). Therefore, mixed or unmixed lanthanide oxide nanoparticles can be used for multi-modal imaging methods (i.e., MRI-FI, MRI-CT, CT-FI, and MRICT- FI) and cancer therapy (i.e., GdNCT). Since mixed or unmixed lanthanide oxide nanoparticles are single-phase and solid-state, they can be easily synthesized, and are compact and robust, which will be beneficial to biomedical applications. In this review physical properties of the lanthanides, synthesis, characterizations, multi-modal imagings, and cancer therapy of mixed and unmixed lanthanide oxide nanoparticles are discussed. PMID- 25439588 TI - Recent advances of p53-MDM2 small molecule inhibitors (2011-present). AB - P53 is an important transcriptional factor that plays a pivotal role in different biological process (cell cycle, apoptosis, DNA repair, angiogenesis and cellular metabolism). While p53 binds to the promoter and increases the gene expression of Mdm2, MDM2 protein directly binds to p53 and inhibits its activity. Therefore, inhibitor of p53 and MDM2 has been considered as a potential cancer therapeutic agent due to the critical inhibitory role of MDM2 on p53. Small-molecule inhibitor of p53-MDM2 has been designed to serve as an effective way to treat cancer. Several compounds have moved into different phase of clinical trials based on major advances in the development of small-molecule inhibitors in recent years. Since there are few reviews covering the structure- activity relationship analysis of recent p53-MDM2 inhibitors reported from 2011 to the present time, in this review, attentions are focused on the development of p53-MDM2 inhibitors published from 2011 to the present time. PMID- 25439589 TI - Endless peptides--circular forms in nature. AB - Nature provides us with an enormous diversity of chemical structures which is an inspiration to chemists and pharmacologists seeking new drug candidates. Circular peptides which have been identified in bacteria, fungi, plants and some mammals but not in humans display exceptional stability and potent bioactivities. They play important roles as defense molecules for their host organisms, providing protection against microorganisms or insects and therefore can be adapted as scaffolds in drug development. Here we try to summarize the most important facts about the origin, biosynthesis and activities of this interesting group of natural products. PMID- 25439590 TI - Determination of the sulfur isotope ratio in carbonyl sulfide using gas chromatography/isotope ratio mass spectrometry on fragment ions 32S+, 33S+, and 34S+. AB - Little is known about the sulfur isotopic composition of carbonyl sulfide (OCS), the most abundant atmospheric sulfur species. We present a promising new analytical method for measuring the stable sulfur isotopic compositions (delta(33)S, delta(34)S, and Delta(33)S) of OCS using nanomole level samples. The direct isotopic analytical technique consists of two parts: a concentration line and online gas chromatography-isotope ratio mass spectrometry (GC-IRMS) using fragmentation ions (32)S(+), (33)S(+), and (34)S(+). The current levels of measurement precision for OCS samples greater than 8 nmol are 0.420/00, 0.620/00, and 0.230/00 for delta(33)S, delta(34)S, and Delta(33)S, respectively. These delta and Delta values show a slight dependence on the amount of injected OCS for volumes smaller than 8 nmol. The isotope values obtained from the GC-IRMS method were calibrated against those measured by a conventional SF6 method. We report the first measurement of the sulfur isotopic composition of OCS in air collected at Kawasaki, Kanagawa, Japan. The delta(34)S value obtained for OCS (4.9 +/- 0.30/00) was lower than the previous estimate of 110/00. When the delta(34)S value for OCS from the atmospheric sample is postulated as the global signal, this finding, coupled with isotopic fractionation for OCS sink reactions in the stratosphere, explains the reported delta(34)S for background stratospheric sulfate. This suggests that OCS is a potentially important source for background (nonepisodic or nonvolcanic) stratospheric sulfate aerosols. PMID- 25439591 TI - Patterns of evolution. PMID- 25439586 TI - Key sites for P2X receptor function and multimerization: overview of mutagenesis studies on a structural basis. AB - P2X receptors constitute a seven-member family (P2X1-7) of extracellular ATP gated cation channels of widespread expression. Because P2X receptors have been implicated in neurological, inflammatory and cardiovascular diseases, they constitute promising drug targets. Since the first P2X cDNA sequences became available in 1994, numerous site-directed mutagenesis studies have been conducted to disclose key sites of P2X receptor function and oligomerization. The publication of the 3-A crystal structures of the zebrafish P2X4 (zfP2X4) receptor in the homotrimeric apo-closed and ATP-bound open states in 2009 and 2012, respectively, has ushered a new era by allowing for the interpretation of the wealth of molecular data in terms of specific three-dimensional models and by paving the way for designing more-decisive experiments. Thanks to these structures, the last five years have provided invaluable insight into our understanding of the structure and function of the P2X receptor class of ligandgated ion channels. In this review, we provide an overview of mutagenesis studies of the pre- and post-crystal structure eras that identified amino acid residues of key importance for ligand binding, channel gating, ion flow, formation of the pore and the channel gate, and desensitization. In addition, the sites that are involved in the trimerization of P2X receptors are reviewed based on mutagenesis studies and interface contacts that were predicted by the zfP2X4 crystal structures. PMID- 25439593 TI - Associations of coefficient of variation of serum GH with previous radiotherapy, hypopituitarism and cardiac disease in patients with treated acromegaly. AB - BACKGROUND: Cardiovascular complications represent the biggest cause of mortality in acromegaly. It is therefore important to optimally stratify acromegalic patients according to disease activity and complication risk. GH is secreted in a pulsatile manner from the pituitary gland, but GH pulsatility is not routinely assessed clinically. The coefficient of variation of serum GH (GHCV) during oral glucose tolerance test (OGTT) quantifies the variation of GH secretion in patients with acromegaly, but has not been reported previously. AIM: To investigate whether GHCV during OGTT is associated with clinical parameters predicted to relate with hypothalamo-pituitary dysfunction during acromegaly, such as radiotherapy treatment, pituitary deficiency and cardiac disease. METHODS: GHCV was calculated during 584 OGTTs and compared with nadir serum GH and IGF-1 in 111 acromegalic patients treated at a single centre. RESULTS: Acromegalic patients treated with radiotherapy had a 37% lower level of GHCV when compared to the nonradiotherapy group (mean GHCV: 0.298 +/- 0.015, no radiotherapy; 0.189 +/- 0.007, radiotherapy; P < 0.001). Neither serum IGF-1 nor nadir GH was significantly altered in the radiotherapy group. Mean GHCV was 50% lower in the acromegalic patients with cardiac failure when compared to acromegalic patients with normal echocardiogram (0.161 +/- 0.034 vs 0.297 +/- 0.055; P < 0.05). Neither serum IGF-1 nor nadir GH was significantly altered during cardiac failure. CONCLUSION: Our preliminary data suggest that GHCV during OGTT may be reduced during acromegaly in patients with previous radiotherapy, pituitary deficiencies and cardiac disease. Larger studies are required to determine whether GHCV could provide help to assess the morbidity status of patients with treated acromegaly. PMID- 25439594 TI - Long-term efficacy of the Baerveldt 250 mm2 compared with the Baerveldt 350 mm2 implant. AB - PURPOSE: To investigate the long-term surgical outcomes of the Baerveldt 250 mm2 versus Baerveldt 350 mm2 glaucoma drainage implants (GDIs) (Abbott Laboratories Inc., Abbott Park, IL) in the treatment of refractory glaucoma. DESIGN: Comparative case study. PARTICIPANTS: A total of 89 consecutive eyes in 86 patients treated at Dean McGee Eye Institute between January 2006 and December 2008. METHODS: We retrospectively reviewed patient data from the following postoperative visits: 1 week, 1 month, 2 months, 3 months, 6 months, and every 3 months thereafter. Postoperative complications were also recorded. The mean follow-up time was 40 months (range, 2-78 months) for the Baerveldt 250 mm2 group and 31 months (range, 3-75 months) for the Baerveldt 350 mm2 group. MAIN OUTCOME MEASURES: The primary outcome measure was surgical success. Secondary outcome measures included visual acuity (VA), intraocular pressure (IOP), and number of medications. RESULTS: There was no difference in surgical success (P=0.98). No significant differences were observed in VA measured using the logarithm of the minimum angle of resolution (logMAR) scale, IOP, and number of medications at the last visit (P=0.09, 0.23, and 0.82, respectively). Complication and failure rates were comparable (P=0.82 and 0.64, respectively). CONCLUSIONS: With a mean follow up of 40 and 31 months, no differences in surgical success, VA, IOP, number of medications at the last visit, and complication/failure rates were noted between the Baerveldt 250 mm2 and 350 mm2 GDIs, respectively. The size of the GDI may not be associated with surgical outcomes. PMID- 25439595 TI - Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy. AB - PURPOSE: To assess the effects of intravitreal ranibizumab on diabetic retinopathy (DR) severity when administered for up to 3 years, evaluate the effect of delayed initiation of ranibizumab therapy on DR severity, and identify baseline patient characteristics associated with the development of proliferative DR (PDR). DESIGN: Exploratory analyses of phase III, randomized, double-masked, sham-controlled multicenter clinical trials. PARTICIPANTS: Adults with diabetic macular edema (DME) (N = 759), baseline best-corrected visual acuity 20/40 to 20/320 Snellen equivalent, and central foveal thickness >=275 MUm. METHODS: Patients were randomized to monthly 0.3 or 0.5 mg ranibizumab or sham injections. Sham participants could switch to 0.5 mg ranibizumab during the third year (sham/0.5 mg crossover). Baseline risk factors were evaluated to explore potential associations with development of PDR. Time to first development of PDR was analyzed by Kaplan-Meier methods to calculate cumulative probabilities by group. MAIN OUTCOME MEASURES: Study eye change on the Early Treatment Diabetic Retinopathy Study severity scale and a composite clinical outcome evaluating progression to PDR based on photographic changes plus clinically important events defining PDR. RESULTS: At month 36, a greater proportion of ranibizumab-treated eyes had >=2- or >=3-step DR improvement compared with sham/0.5 mg crossover. A >=3-step improvement was achieved at 36 months by 3.3%, 15.0%, and 13.2% of sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab-treated eyes, respectively (P < 0.0001). Through 36 months, 39.1% of eyes in the sham/0.5 mg group developed PDR, as measured by composite outcome, compared with 18.3% and 17.1% of eyes treated with 0.3 or 0.5 mg ranibizumab, respectively. The presence of macular capillary nonperfusion at baseline seems to be associated with progression to PDR in ranibizumab-treated eyes but did not meaningfully influence visual acuity improvement in eyes with DME after ranibizumab therapy. CONCLUSIONS: Ranibizumab, as administered to patients with DME for 12 to 36 months in these studies, can both improve DR severity and prevent worsening. Prolonged delays in initiation of ranibizumab therapy may limit this therapeutic effect. Although uncommon, the development of PDR still occurs in a small percentage of eyes undergoing anti vascular endothelial growth factor therapy and may be related to the presence of macular nonperfusion. PMID- 25439596 TI - Clinical outcome of 500 consecutive cases undergoing Descemet's membrane endothelial keratoplasty. AB - PURPOSE: To evaluate the clinical outcome of 500 consecutive cases after Descemet's membrane endothelial keratoplasty (DMEK) and the effect of technique standardization. DESIGN: Prospective, interventional case series at a tertiary referral center. PARTICIPANTS: A total of 500 eyes of 393 patients who underwent DMEK for Fuchs' endothelial corneal dystrophy, bullous keratopathy, or previous corneal transplant failure. METHODS: Best-corrected visual acuity (BCVA), endothelial cell density (ECD), pachymetry, and intraoperative and postoperative complications were evaluated before and 1, 3, and 6 months after DMEK. MAIN OUTCOME MEASURES: Comparison between 2 groups (group I: cases 1-250, outcome of "early surgeries" during transition to technique standardization; group II: cases 251-500, outcome of "late surgeries" after technique standardization). RESULTS: At 6 months, 75% of eyes reached a BCVA of >=20/25 (>=0.8), 41% of eyes achieved >=20/20 (>=1.0), and 13% of eyes achieved >=20/18 (>=1.2) (n=418) when excluding eyes with ocular comorbidities (n=57). When including all available eyes at 6 months (n=475), 66% of eyes reached a BCVA of >=20/25 (>=0.8), and 36% of eyes achieved >=20/20 (>=1.0). Mean ECD decreased by 37% (+/-18%) to 1600 (+/-490) cells/mm2 (n=447) at 6 months (P<0.001). Postoperative pachymetry averaged 525 (+/-46) MUm compared with 667 (+/-92) MUm preoperatively (P<0.001). None of these parameters differed among the 2 groups (P>0.05). (Partial) graft detachment presented in 79 eyes (15.8%), and 26 eyes (5.2%) required a secondary surgery within the first 6 months (re-bubbling in 15, secondary keratoplasty in 11). With technique standardization, the postoperative complication rate decreased from 23.2% to 10% (P<0.001) and the rate of secondary surgeries decreased from 6.8% to 3.6% (P=0.10). CONCLUSIONS: In comparison with earlier endothelial keratoplasty techniques, DMEK may consistently give higher visual outcomes and faster visual rehabilitation. When used for the extended spectrum of endothelial pathologies, DMEK proved feasible with a relatively low risk of complications. Technique standardization may have contributed to a lower graft detachment rate and a relatively low secondary intervention rate. As such, DMEK may become the first choice of treatment in corneal endothelial disease. PMID- 25439597 TI - Vitreous evaluation: a diagnostic challenge. AB - PURPOSE: To categorize vitrectomy cytologic diagnoses and ancillary tests to address appropriate processing of low-volume vitreous samples. DESIGN: Retrospective case series. PARTICIPANTS: Five thousand seven hundred thirty-six vitreous samples. METHODS: Cytologic diagnoses of therapeutic and diagnostic vitrectomy samples and their processing protocols from 3 teaching institutions were reviewed. MAIN OUTCOME MEASURES: Diagnostic results were categorized as negative for malignancy, suspicious for malignancy, and positive for malignancy. All ancillary studies performed were documented, including special stains, immunohistochemistry analysis, cytokine levels, and polymerase chain reaction (PCR) analysis. RESULTS: Of the 5736 vitreous samples analyzed, 4683 (81.64%) were from Tufts Medical Center (TMC), 955 (16.65%) were from Boston Medical Center (BMC), and 98 (1.70%) were from Massachusetts Eye Research and Surgery Institution (MERSI). Cases from TMC and BMC were therapeutic and diagnostic vitrectomies, and MERSI cases were diagnostic vitrectomies. Most vitrectomies showed negative results for malignancy: 99.47% of TMC cases, 99.89% of BMC cases, and 79.6% of MERSI cases. These included vitreous hemorrhage and inflammatory or infectious findings. Ancillary studies performed in this category included Periodic Acid-Schiff staining for fungi, PCR analysis for toxoplasmosis, cytomegalovirus, Epstein-Barr virus (EBV), herpes simplex virus I and II, and vitreous cultures for infections (coagulase-negative Staphylococcus, Candida, Fusarium, and Propionibacterium species). Interleukin (IL) 10-to-IL-6 ratios were performed on 38.7% of cases from MERSI. Fourteen cases from TMC were suspicious for malignancy based on cytologic evaluation. Eleven cases from TMC, 1 case from BMC, and 20 cases from MERSI showed positive results for malignancy and included B-cell lymphoma, retinoblastoma, melanoma, and metastatic adenocarcinoma. The ancillary testing included PCR for heavy chain immunoglobulin gene rearrangements, immunohistochemistry for EBV, in situ hybridization for kappa and lambda light chains, and cytogenetics. CONCLUSIONS: This is the largest data pool of reported cytologic diagnoses of diagnostic and therapeutic vitrectomy samples. Cytologic evaluation of therapeutic vitrectomy samples provides a valuable baseline of nonpathologic findings that assist in differentiation between malignancy, infections, and inflammatory conditions. Allocation of small-volume vitreous samples to select ancillary testing from the plethora of available diagnostic tests requires preoperative communication between surgeons and pathologists to ensure appropriate and timely treatment methods. PMID- 25439598 TI - A statistical analysis of metamorphopsia in 7106 amsler grids. PMID- 25439599 TI - Enophthalmos and choroidal atrophy after intraophthalmic artery chemotherapy for retinoblastoma. PMID- 25439601 TI - Retinal nerve fiber layer thickness measurements: uveitis, a major confounding factor. AB - OBJECTIVE: To evaluate optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) measurements in patients with active and quiescent uveitis with and without glaucoma and compare results to the published age-adjusted normative data. DESIGN: Comparative, retrospective pilot study. PARTICIPANTS: Consecutive patients with uveitis who underwent OCT RNFL measurements between December 2011 and October 2012 were identified: 76 uveitic eyes without glaucoma and 135 uveitic eyes with glaucoma. INTERVENTION: We conducted OCT of the RNFL. MAIN OUTCOME MEASURES: Global and sectoral RNFL thickness measurements. RESULTS: In 19 nonglaucomatous, uveitic eyes with active inflammation, mean global and all sectoral RNFL measurements were greater than the normative 95th percentile. The mean global RNFL OCT measurement was 140.5 microns in such eyes compared with 107.8 microns in the 57 nonglaucomatous, quiescent, uveitic eyes (P=0.008). These measurements were significantly higher than the average of 95.3 microns reported in normal eyes (P<0.001). All mean sectoral measurements except superonasal were significantly higher in active compared with quiescent uveitic eyes (P=0.002 0.05). In glaucomatous eyes with both quiescent and active uveitis, the mean global RNFL measurements on OCT were 92.3 and 95.7 microns, respectively. These measurements were significantly higher than the mean global RNFL thickness (65.3 microns) reported in eyes with the same stage (moderate) of nonuveitic glaucoma. CONCLUSIONS: Uveitis is a major confounding factor in assessing the thickness of the RNFL. A significant thickening of the RNFL was found in patients with active uveitis and a greater RNFL thickness than anticipated in patients with uveitic glaucoma. These data raise concerns about the comparative value of RNFL scans as a method to detect and monitor glaucoma in uveitic eyes. PMID- 25439602 TI - Subperiosteal abscess of the orbit: evolving pathogens and the therapeutic protocol. AB - PURPOSE: Because of widespread antibiotic use, immunization against selective species, and the emergence of hypervirulent organisms, we sought to determine changes over time in the bacteriology of sinusitis-related subperiosteal abscess (SPA) of the orbit and their impact on patient outcomes under a uniform management protocol. DESIGN: Comparative case series. SUBJECTS: Patients<=18 years of age with sinusitis-related SPA treated from 2002 to 2012; comparable cohorts from earlier time frames. METHODS: We analyzed culture results and outcomes in surgical cases, compared overall and age-specific results with those in a 1977 through 1992 patient series, and compared the proportion of patients<9 years old requiring surgery among 1988 through 1998, 1999 through 2008, and current cohorts. MAIN OUTCOME MEASURES: Patients requiring surgery; prevalence of pathogens; criteria prompting surgery; visual and systemic outcomes. RESULTS: Ninety-four patients met inclusion criteria: 53 (56%) recovered with medical therapy alone and 41 (44%) underwent surgical drainage. Compared with the 1977 through 1992 cohort, there was increased representation of Streptococcus anginosus group, S aureus, and group A beta-streptococci. Methicillin-resistant S aureus (MRSA) accounted for 4 of 7 S aureus isolates. Of 94 patients, 74 (79%) were <9 years of age: 53 (72%) recovered without surgery and 21 (28%) underwent drainage. Comparable figures were 67.5% versus 32.5% and 85% versus 15% in 1988 through 1998 and 1999 through 2008 cohorts, respectively. Whereas patients>=9 years old in the 1977 through 1992 cohort had a higher proportion of positive cultures and more varied pathogens than younger patients, in the current series both groups had similar culture yields and aerobic constituencies. Anaerobes were isolated from only patients>=9 years old in both series. In cases positive for MRSA and other aggressive aerobes, initial findings prompted early drainage; outcomes were not compromised by adherence to the treatment protocol. CONCLUSIONS: The proportion of children<9 years requiring surgery for sinusitis related SPA has remained a minority (15%-32.5%), without a clear upward trend over 25 years. Anaerobes continue not to factor in the younger subgroup, but more aggressive aerobic pathogens, including MRSA, have emerged. In such cases, surgical criteria that supersede age are triggered under the current treatment algorithm, and modification is not recommended. PMID- 25439600 TI - Poorer neurodevelopmental outcomes associated with cystoid macular edema identified in preterm infants in the intensive care nursery. AB - PURPOSE: To evaluate the association between cystoid macular edema (CME) observed in very preterm infants and developmental outcomes at 18 to 24 months corrected age. DESIGN: Cohort study. PARTICIPANTS: Infants born at or less than 1500 g or at or less than 30 weeks postmenstrual age who underwent screening for retinopathy of prematurity (ROP) in an intensive care nursery. METHODS: Bedside handheld spectral-domain optical coherence tomography (SD OCT; Envisu, Bioptigen, Inc, Research Triangle Park, NC) imaging was obtained from preterm infants who were being screened for ROP and graded for presence of CME, central foveal thickness (CFT), inner nuclear layer thickness, and foveal-to-parafoveal thickness ratio. At 18 to 24 months corrected age, the children were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition. MAIN OUTCOME MEASURES: Scores on the Bayley cognitive, language, and motor subscales. RESULTS: Among 77 children with SD OCT imaging, 53 were evaluated with the Bayley Scales. Compared with children who did not have CME as infants (n=22), the mean score for children who had CME (n=31) was 7.3 points (95% confidence interval [CI], -15.5 to 0.9; P=0.08) lower on the cognitive subscale, 14.1 points (95% CI, -22.7 to -5.5; P=0.002) lower for the language subscale, and 11.5 points (95% CI, -21.6 to -1.3; P=0.03) lower for the motor subscale. Differences were maintained after adjusting for gestational age and birth weight. Severity of CME, as assessed by foveal-to-parafoveal thickness ratio, within the CME group correlated with poorer cognitive (R2=0.16, P=0.03) and motor (R2=0.15, P=0.03) development. CONCLUSIONS: Cystoid macular edema observed on SD OCT in very preterm infants screened for ROP is associated with poorer language and motor skills at 18 to 24 months corrected age. Evaluation of the retina with SD-OCT may serve as an indicator of neurodevelopmental health for very preterm infants in the intensive care nursery. PMID- 25439603 TI - Impact of digital imaging and communications in medicine workflow on the integration of patient demographics and ophthalmic test data. AB - PURPOSE: To determine the impact of a Digital Imaging and Communications in Medicine (DICOM) workflow on the linkage of demographic information to ophthalmic testing data. DESIGN: Evaluation of technology. PARTICIPANTS: Six hundred ninety nine visual field testing encounters performed by 6 ophthalmic technicians and the transfer error queue of 37 442 ophthalmic test results. METHODS: At 3 months before and 6 and 18 months after implementation of a DICOM workflow, technicians recorded the work required to enter, confirm, or edit patient demographics in each visual field device. We also determined the proportion of imaging tests sent to an error queue for manual reconciliation because of incorrect demographic information before and 3, 6, and 18 months after the DICOM workflow was established. MAIN OUTCOME MEASURES: The proportion of testing encounters for which staff had to enter, edit, or merge patient demographics and the proportion of misfiled images. RESULTS: Staff entered, edited, or merged data for 48% of patients before implementation (n = 237). This decreased to 24% within 6 months and 20% within 18 months of implementing the DICOM archive (n = 230 and n = 232, respectively). Staff could locate a patient in a DICOM work list for 97% of encounters at 3 months and 99% at 18 months. Before implementation, 9.2% of the images required additional intervention to be associated with the correct patient (n = 3581). This decreased by 85% over 6 months to 1.4% (n = 9979; P < 0.01). There was an increase in the percentage of misfiled images between 6 and 18 months from 1.4% to 2.2% (n = 24 549; P < 0.01), representing an overall 76% decrease over 18 months relative to the pre-DICOM period. CONCLUSIONS: Implementation of a DICOM-compatible workflow in an ophthalmology clinic reduced the need to enter or edit patient demographic information into imaging or testing devices by more than 50% and reduced the need to manage misfiled images by 76%. In a clinical environment that demands both efficiency and patient safety, the DICOM workflow is an important update to current practice. PMID- 25439604 TI - Cost of intraocular lens versus contact lens treatment after unilateral congenital cataract surgery in the infant aphakia treatment study at age 5 years. AB - PURPOSE: To analyze differences in the cost of treatment for infants randomized to primary intraocular lens (IOL) implantation versus optical correction with a contact lens (CL) after unilateral cataract surgery in the Infant Aphakia Treatment Study (IATS). DESIGN: Retrospective cost analysis of a prospective, randomized clinical trial based on Georgia Medicaid reimbursement data as well as actual costs of supplies used during the study, adjusted for inflation. PARTICIPANTS: The IATS is a multicenter (n = 12), randomized clinical trial comparing the optical treatment of aphakia with either primary IOL implantation (n = 57) or CL correction (n = 57) in 114 infants with unilateral congenital cataract. INTERVENTION: One hundred fourteen infants underwent unilateral cataract surgery and were either corrected optically by primary IOL implantation at the time of surgery or were corrected with a CL after surgery. MAIN OUTCOME MEASURES: The mean cost of cataract surgery and all additional surgeries, examinations, and supplies used up to 5 years of age. RESULTS: The 5-year treatment cost of an infant with a unilateral congenital cataract corrected optically with an IOL was $27 090 versus $25 331 for a patient treated with a CL after initial cataract surgery. The total cost of supplies was $3204 in the IOL group versus $7728 in the CL group. CONCLUSIONS: Unilateral cataract surgery in infancy coupled with primary IOL implantation is approximately 7% more expensive than aphakia and CL correction. Patient costs are more than double with CL versus IOL treatment. PMID- 25439605 TI - The verification of nucleic acid amplification testing (Gen-Probe Aptima Assay) for chlamydia trachomatis from ocular samples. AB - OBJECTIVE: Chlamydia trachomatis conjunctivitis may present with extended symptoms, and it can have social ramifications as a sexually transmitted disease. For appropriate therapy, C. trachomatis conjunctivitis should be diagnosed definitively. This study presents the verification of nucleic acid amplification testing (NAAT; Gen-Probe Aptima Combo 2 assay) for detection of C. trachomatis ribosomal RNA (rRNA) from direct ocular samples. DESIGN: Retrospective laboratory verification study. SUBJECTS: Patients with infectious conjunctivitis. METHODS: A battery of 25 true-positive specimens (direct ocular specimens from patients with symptoms consistent with C. trachomatis conjunctivitis and with previously demonstrated positive polymerase chain reaction [PCR] results for C. trachomatis DNA by Roche Amplicor) and 25 true-negative specimens (direct ocular specimens with culture-positive results for herpes simplex virus [n = 5], adenovirus [n = 5], Haemophilus influenzae [n = 5], and Streptococcus pneumoniae [n = 5]), and transport medium (n = 5) were tested for C. trachomatis rRNA by NAAT. These true negative specimens have differential etiologic agents of infectious conjunctivitis. The 25 C. trachomatis specimens with PCR-positive results (obtained May 1994-May 2012) and 20 true-negative infectious ocular specimens (obtained December 2008-August 2013) were collected with soft-tipped applicators and placed in transport medium. All excess specimens were stored at -80 degrees C. All samples were centrifuged at 13,000 rpm for 1 hour at 6 degrees C. For each sample, using the Aptima Unisex collection blue swab, a specimen was collected from the conical apex of the storage tube where a pellet was formed. The Aptima Unisex collection swab was placed in a tube of Aptima swab transport medium for testing. All samples were tested in duplicate. MAIN OUTCOME MEASURES: Detection of C. trachomatis rRNA. RESULTS: Of 25 true-positive samples, 24 (96%) were positive by NAAT, whereas 25 of 25 true-negative samples (100%) showed negative results. The sensitivity, specificity, positive predictive value, negative predictive value, and efficiency were determined to be 96%, 100%, 100%, 96%, and 98%, respectively. CONCLUSIONS: The detection of C. trachomatis in ocular specimens by NAAT was verified for laboratory diagnosis. The test will be evaluated prospectively to determine future test performance precisely. PMID- 25439607 TI - Phenotypic variability associated with the D226N allele of IMPDH1. PMID- 25439606 TI - Five-year treatment outcomes in the Ahmed Baerveldt comparison study. AB - PURPOSE: To compare the 5-year outcomes of the Ahmed FP7 Glaucoma Valve (AGV) (New World Medical, Cucamonga, CA) and the Baerveldt 101-350 Glaucoma Implant (BGI) (Abbott Medical Optics, Abbott Park, IL) for the treatment of refractory glaucoma. DESIGN: Multicenter, randomized, controlled clinical trial. PARTICIPANTS: A total of 276 patients, including 143 in the AGV group and 133 in the BGI group. METHODS: Patients aged 18 to 85 years with previous intraocular surgery or refractory glaucoma and intraocular pressure (IOP) of >=18 mmHg in whom glaucoma drainage implant (GDI) surgery was planned were randomized to implantation of an AGV or a BGI. MAIN OUTCOME MEASURES: Surgical failure, IOP, visual acuity (VA), use of glaucoma medications, and complications. RESULTS: At 5 years, IOP (mean +/- standard deviation [SD]) was 14.7+/-4.4 mmHg in the AGV group and 12.7+/-4.5 mmHg in the BGI group (P = 0.015). The number of glaucoma medications in use at 5 years (mean +/- SD) was 2.2+/-1.4 in the AGV group and 1.8+/-1.5 in the BGI group (P = 0.28). The cumulative probability of failure during 5 years of follow-up was 44.7% in the AGV group and 39.4% in the BGI group (P = 0.65). The number of subjects failing because of inadequately controlled IOP or reoperation for glaucoma was 46 in the AGV group (80% of AGV failures) and 25 in the BGI group (53% of BGI failures; P = 0.003). Eleven eyes in the AGV group (20% of AGV failures) experienced persistent hypotony, explantation of implant, or loss of light perception compared with 22 eyes (47% of failures) in the BGI group. Change in logarithm of the minimum angle of resolution VA (mean +/- SD) at 5 years was 0.42+/-0.99 in the AGV group and 0.43+/-0.84 in the BGI group (P = 0.97). CONCLUSIONS: Similar rates of surgical success were observed with both implants at 5 years. The BGI produced greater IOP reduction and a lower rate of glaucoma reoperation than the AGV, but the BGI was associated with twice as many failures because of safety issues. PMID- 25439608 TI - Hypotony maculopathy obtained by retro-mode retinal imaging. PMID- 25439609 TI - Management of posterior uveal melanoma: past, present, and future: the 2014 Charles L. Schepens lecture. AB - PURPOSE: To review the management of ciliary body and choroidal melanoma (posterior uveal melanoma [PUM]) over the last century with an emphasis on changing concepts. DESIGN: Retrospective review. PARTICIPANTS: Review of personal experience over 40 years and pertinent literature on management of PUM. METHODS: Diagnosis and therapy for PUM. MAIN OUTCOME MEASURES: Patient survival. RESULTS: In the early 1900s, most patients presented with a large symptomatic melanoma that necessitated enucleation, and the systemic prognosis was poor. In the 1970s, controversy erupted regarding the role of enucleation for PUM. Some authorities advocated prompt enucleation, and others proposed that enucleation promoted metastasis, known as the "Zimmerman hypothesis." Others recommended observation, withholding treatment until tumor growth was documented. During the 1970s, there was a trend toward eye-saving procedures, including laser photocoagulation, surgical removal of tumor, and techniques of radiotherapy. Despite local treatment success, systemic prognosis remained guarded with approximately 40% mortality overall. However, there was convincing evidence that smaller tumors offered a significantly better prognosis. Currently, there is a movement toward earlier identification and treatment of small melanomas using clinical factors predictive of malignant potential, in keeping with similar philosophy regarding other cancers. Further understanding of melanoma cytogenetics and molecular pathways have helped to recognize patients at risk for metastasis. At-risk patients are offered systemic therapeutic trials to prevent metastasis. We anticipate that the future management of PUM will focus on detection of clinical and imaging clues for earliest diagnosis, prompt local tumor treatment, and systemic targeted therapies for microscopic metastasis or prevention of metastasis. Personalized evaluation of patient-specific melanoma molecular pathway signature could allow for therapeutic intervention at a site specific to the pathway abnormality that leads to the development of melanoma. CONCLUSIONS: Management of PUM has made major strides over the past century from the days of enucleation for massive, fatal tumor to early detection of smallest tumors with a more favorable prognosis. Current and future targeted specific tumor pathway interruption using systemic agents could improve survival. PMID- 25439610 TI - Vertical diplopia and ptosis from removal of the orbital roof in pterional craniotomy. AB - PURPOSE: To describe a newly recognized clinical syndrome consisting of ptosis, diplopia, vertical gaze limitation, and abduction weakness that can occur after orbital roof removal during orbito-zygomatic-pterional craniotomy. DESIGN: Case series. PARTICIPANTS: Eight study patients (7 women), 44 to 80 years of age, with neuro-ophthalmic symptoms after pterional craniotomy. METHODS: Case description of 8 study patients. MAIN OUTCOME MEASURES: Presence of ptosis, diplopia, and gaze limitation. RESULTS: Eight patients had neuro-ophthalmic findings after pterional craniotomy for meningioma removal or aneurysm clipping. The cardinal features were ptosis, limited elevation, and hypotropia. Three patients also had limitation of downgaze and 2 patients had limitation of abduction. Imaging showed loss of the fat layers that normally envelop the superior rectus and levator palpebrae superioris. The muscles appeared attached to the defect in the orbital roof. Ptosis and diplopia developed in 2 patients despite Medpor titanium mesh implants. Deficits in all patients showed spontaneous improvement. In 2 patients, a levator advancement was required to repair ptosis. In 3 patients, an inferior rectus recession using an adjustable suture was performed to treat vertical diplopia. Follow-up a mean of 6.5 years later revealed that all patients had a slight residual upgaze deficit, but alignment was orthotropic in primary gaze. CONCLUSIONS: After pterional craniotomy, ptosis, diplopia, and vertical gaze limitation can result from tethering of the superior rectus-levator palpebrae superioris complex to the surgical defect in the orbital roof. Lateral rectus function sometimes is compromised by muscle attachment to the lateral orbital osteotomy. This syndrome occurs in approximately 1% of patients after removal of the orbital roof and can be treated, if necessary, by prism glasses or surgery. PMID- 25439612 TI - Randomized, controlled trial in groups C and D retinoblastoma. PMID- 25439614 TI - Intravitreal Ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. AB - OBJECTIVE: To report 5-year results from a previously reported trial evaluating intravitreal 0.5 mg ranibizumab with prompt versus deferred (for >=24 weeks) focal/grid laser treatment for diabetic macular edema (DME). DESIGN: Multicenter, randomized clinical trial. PARTICIPANTS: Among participants from the trial with 3 years of follow-up who subsequently consented to a 2-year extension and survived through 5 years, 124 (97%) and 111 (92%) completed the 5-year visit in the prompt and deferred groups, respectively. METHODS: Random assignment to ranibizumab every 4 weeks until no longer improving (with resumption if worsening) and prompt or deferred (>=24 weeks) focal/grid laser treatment. MAIN OUTCOME MEASURES: Best corrected visual acuity at the 5-year visit. RESULTS: The mean change in visual acuity letter score from baseline to the 5-year visit was +7.2 letters in the prompt laser group compared with +9.8 letters in the deferred laser group (mean difference, -2.6 letters; 95% confidence interval, -5.5 to +0.4 letters; P = 0.09). At the 5-year visit in the prompt versus deferred laser groups, there was vision loss of >=10 letters in 9% versus 8%, an improvement of >=10 letters in 46% versus 58%, and an improvement of >=15 letters in 27% versus 38% of participants, respectively. From baseline to 5 years, 56% of participants in the deferred group did not receive laser. The median number of injections was 13 versus 17 in the prompt and deferral groups, including 54% and 45% receiving no injections during year 4 and 62% and 52% receiving no injections during year 5, respectively. CONCLUSIONS: Five-year results suggest focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better than deferring laser treatment for >=24 weeks in eyes with DME involving the central macula with vision impairment. Although more than half of eyes in which laser treatment is deferred may avoid laser for at least 5 years, such eyes may require more injections to achieve these results when following this protocol. Most eyes treated with ranibizumab and either prompt or deferred laser maintain vision gains obtained by the first year through 5 years with little additional treatment after 3 years. PMID- 25439616 TI - Who in the World Is the WHO? PMID- 25439615 TI - Inter-eye differences in patients with pseudoexfoliation syndrome presenting with intraocular lens dislocation. AB - PURPOSE: To analyze differences in glaucoma diagnosis and glaucoma severity between fellow eyes in patients with pseudoexfoliation syndrome (PXF) who present with intraocular lens (IOL) dislocation. DESIGN: Retrospective matched case control study. Eyes presenting with IOL dislocation (case group) were compared with fellow eyes (control group). PARTICIPANTS: Patients from a tertiary referral practice in Mississauga, Ontario, Canada. METHODS: Consecutive patients with PXF and prior bilateral uneventful cataract surgeries with in-the-bag IOLs who presented with IOL dislocation between 2008 and 2013 were identified (n=71). Indicators of glaucoma severity were compared between fellow eyes using McNemar's test and Wilcoxon signed-rank tests. Indicators of glaucoma severity were also compared pre- and post-IOL exchange/repositioning in the eye with IOL dislocation. MAIN OUTCOME MEASURES: Glaucoma diagnosis, corrected distance visual acuity (CDVA), intraocular pressure (IOP), optic nerve cup-to-disc (C/D) ratio, mean deviation (MD) on visual field, retinal nerve fiber layer (RNFL) thickness, and glaucoma medication requirements (GMRs). RESULTS: Seventy-one participants were included. The affected eye was more likely to have glaucoma (P<0.0001) and have more severe glaucoma (P=0.0001). In addition, the affected eye had worse mean CDVA (1.14+/-0.79 logarithm of the minimum angle of resolution [logMAR] vs. 0.35+/-0.46 logMAR, P<0.0005), higher mean IOP (19.2+/-7.2 vs. 14.7+/-3.6, P<0.0005), higher C/D ratio (0.54+/-0.22 vs. 0.51+/-0.20, P=0.006), greater mean number of glaucoma medication classes (1.4+/-1.4 vs. 0.5+/-1.1, P<0.0005), worse MD (-13.83+/-6.89 decibels [dB] vs. -6.59+/-6.63 dB, P<0.0005), and worse mean RNFL thickness (69.2+/-26.3 vs. 82.4+/-13.7, P=0.001). In the affected eye, there were early postoperative improvements in mean CDVA, IOP, and GMRs. CONCLUSIONS: In patients with PXF, the eye presenting with IOL dislocation was more likely than its fellow eye to have a diagnosis of glaucoma and to have glaucoma of greater severity. PMID- 25439617 TI - Survey of radiologist attitudes and perceptions regarding the incorporation of a departmental peer review system. AB - PURPOSE: The aim of this study was to investigate the attitudes and perceptions of staff radiologists regarding the incorporation of a nonanonymous peer review system at an academic hospital. METHODS: A questionnaire gauging knowledge of, attitudes toward, and perceptions regarding peer review was distributed to all staff radiologists at a large academic hospital. The survey was distributed before the implementation of a nonanonymous peer review system. Data were analyzed using descriptive statistics. Responses were cross-tabulated according to subspecialty and number of years in practice. RESULTS: The majority of respondents agreed that peer review is important for improving patient care (31 of 36 [86%]) and professional development (29 of 36 [81%]), but the vast majority (33 of 36 [92%]) believed that peer review should be anonymous. Twenty-six of 36 respondents (72%) believed that peer review will not be safe from malpractice issues, 24 of 36 (67%) agreed that it has the potential to damage interpersonal relationships within the department, and 15 of 36 (42%) believed that it may influence their job security or rankings within the department. Significant differences were identified between radiologists with more and fewer years of practice experience. CONCLUSIONS: The incorporation of a nonanonymous peer review system generates anxiety and uncertainty within a radiology department. The investigation of physicians' attitudes toward and perceptions about peer review is important for understanding the potential impact not only on patient care but also on radiologists' relationships and psychology in the workplace. PMID- 25439613 TI - Identification of torque teno virus in culture-negative endophthalmitis by representational deep DNA sequencing. AB - PURPOSE: To test the hypothesis that uncultured organisms may be present in cases of culture-negative endophthalmitis by use of deep DNA sequencing of vitreous biopsies. DESIGN: Single-center, consecutive, prospective, observational study. PARTICIPANTS: Aqueous or vitreous biopsies from 21 consecutive patients presenting with presumed infectious endophthalmitis and 7 vitreous samples from patients undergoing surgery for noninfectious retinal disorders. METHODS: Traditional bacterial and fungal culture, 16S quantitative polymerase chain reaction (qPCR), and a representational deep-sequencing method (biome representational in silico karyotyping [BRiSK]) were applied in parallel to samples to identify DNA sequences corresponding to potential pathogens. MAIN OUTCOME MEASURES: Presence of potential pathogen DNA in ocular samples. RESULTS: Zero of 7 control eyes undergoing routine vitreous surgery yielded positive results for bacteria or virus by culture or 16S polymerase chain reaction (PCR). A total of 14 of the 21 samples (66.7%) from eyes harboring suspected infectious endophthalmitis were culture-positive, the most common being Staphylococcal and Streptococcal species. There was good agreement among culture, 16S bacterial PCR, and BRiSK methodologies for culture-positive cases (Fleiss' kappa of 0.621). 16S PCR did not yield a recognizable pathogen sequence in any culture-negative sample, whereas BRiSK suggested the presence of Streptococcus in 1 culture negative sample. With the use of BRiSK, 57.1% of culture-positive and 100% of culture-negative samples demonstrated the presence of torque teno virus (TTV) sequences, compared with none in the controls (P=0.0005, Fisher exact test). The presence of TTV viral DNA was confirmed in 7 cases by qPCR. No other known viruses or potential pathogens were identified in these samples. CONCLUSIONS: Culture, 16S qPCR, and BRiSK provide complementary information in presumed infectious endophthalmitis. The majority of culture-negative endophthalmitis samples did not contain significant levels of bacterial DNA. "Culture negativity" does not seem to be due to failure of growth of fastidious bacteria. The small DNA virus TTV was unexpectedly found in all culture-negative samples and some culture-positive samples. This study cannot distinguish whether TTV is a direct intraocular pathogen, an adjuvant for inflammation, a general marker of inflammation, or a commensal virus but provides a testable hypothesis for a pathogenic mechanism in culture-negative endophthalmitis. PMID- 25439618 TI - The impact of social media on readership of a peer-reviewed medical journal. AB - PURPOSE: Social media microblogging has made major inroads in physician education and information exchange. The authors evaluated their early experience with Twitter "tweet chat" sessions as a medium to expand the reach and audience of a peer-reviewed radiology journal. METHODS: The authors analyzed Twitter activity metadata tagged with the #JACR hashtag from the first 6 tweet chat sessions sponsored and promoted by JACR. The assessment included multiple metrics: radiologist versus nonradiologist session participants, individual tweets, tweets with embedded web links, common words, retweets, and impressions. We correlated Twitter metrics with temporally related journal website activity. RESULTS: Each session generated a mean of 444 +/- 172 tweets contributed by a mean of 33 +/- 14 participants (45.4% nonradiologists) and resulted in a mean of 1,163,712 +/- 441,971 impressions. Per session, a mean of 19 +/- 7.6 tweets contained web links, and 138 +/- 35.6 tweets were retweets. Monthly journal website article views increased from 31,220 to 41,017 (+31.4%), journal website visits increased from 9,192 to 11,539 (+25.5%), and unique visitors increased from 7,368 to 8,841 (+20%). Since JACR tweet chats were initiated, mean monthly journal website visits and page views per month directly from twitter.com increased from 24 to 101 (+321%) and from 38 to 159 (+318%), respectively. CONCLUSIONS: Early experience with JACR tweet chats demonstrates that organizing Twitter microblogging activities around topics of general interest to their target readership bears the potential for medical journals to increase their audiences and reach. PMID- 25439611 TI - The effect of donor diabetes history on graft failure and endothelial cell density 10 years after penetrating keratoplasty. AB - OBJECTIVE: To examine the long-term effect of donor diabetes history on graft failure and endothelial cell density (ECD) after penetrating keratoplasty (PK) in the Cornea Donor Study. DESIGN: Multicenter, prospective, double-masked, controlled clinical trial. PARTICIPANTS: One thousand ninety subjects undergoing PK for a moderate risk condition, principally Fuchs' dystrophy or pseudophakic or aphakic corneal edema, were enrolled by 105 surgeons from 80 clinical sites in the United States. METHODS: Corneas from donors 12 to 75 years of age were assigned by 43 eye banks to participants without respect to recipient factors. Donor and recipient diabetes status was determined from existing medical records. Images of the central endothelium were obtained before surgery (baseline) and at intervals for 10 years after surgery and were analyzed by a central image analysis reading center to determine ECD. MAIN OUTCOME MEASURES: Time to graft failure (regraft or cloudy cornea for 3 consecutive months) and ECD. RESULTS: There was no statistically significant association of donor diabetes history with 10-year graft failure, baseline ECD, 10-year ECD, or ECD values longitudinally over time in unadjusted analyses, nor after adjusting for donor age and other significant covariates. The 10-year graft failure rate was 23% in the 199 patients receiving a cornea from a donor with diabetes versus 26% in the 891 patients receiving a cornea from a donor without diabetes (95% confidence interval for the difference, -10% to 6%; unadjusted P=0.60). Baseline ECD (P=0.71), 10-year ECD (P>0.99), and changes in ECD over 10 years (P=0.86) were similar comparing donor groups with and without diabetes. CONCLUSIONS: The study results do not suggest an association between donor diabetes and PK outcome. However, the assessment of donor diabetes was imprecise and based on historical data only. The increasing frequency of diabetes in the aging population in the United States affects the donor pool. Thus, the impact of donor diabetes on long term endothelial health after PK or endothelial keratoplasty, or both, warrants further study with more precise measures of diabetes and its complications. PMID- 25439619 TI - Continued growth in emergency department imaging is bucking the overall trends. AB - PURPOSE: The aim of this study was to examine recent trends in imaging utilization in emergency departments (EDs) in the Medicare population. METHODS: The 2002 to 2012 Medicare Part B databases were used. Imaging studies were categorized by modality. Medicare's place-of-service codes identified those studies performed in ED patients. Specialty codes identified the specialties of the interpreting physicians. Utilization rates per 1,000 Medicare beneficiaries were calculated. Trends were assessed in plain radiography (XR), CT, noncardiac ultrasound, MRI, and nuclear medicine. RESULTS: XR and CT were the most widely used modalities in ED patients. From 2002 to 2012, the XR utilization rate per 1,000 increased from 248.7 to 320.0 (+29%), and CT increased from 57.2 to 147.9 (+159%). Utilization rates of the other modalities were much lower. Ultrasound increased from 9.5 to 21.0 (+121%), while MRI increased from 1.4 to 5.1 (+264%). Growth in these 4 modalities was continuous and did not show the flattening that has characterized the utilization trends in other places of service. Nuclear medicine use was very low and remained essentially flat. During the study period, CT accrued 91 new examinations per 1,000, followed by XR at 71 and ultrasound at 11.5. The vast majority of examinations were interpreted by radiologists. CONCLUSIONS: Despite the cessation of overall utilization growth of the various modalities in recent years, ED utilization rates continued to increase. The greatest increases, in terms of accrued new examinations per 1,000, were seen in CT and XR. This suggests that radiologists and ED physicians need to work together to better manage imaging utilization. PMID- 25439620 TI - International perspectives on radiology practice metrics: Australia, France, Germany, Japan, New Zealand, Spain, the UK and USA. PMID- 25439621 TI - Author's Reply. PMID- 25439622 TI - Primary temporal region squamous cell carcinoma diagnosed by a superficial temporal artery biopsy. AB - BACKGROUND: Superficial temporal artery biopsy is a frequent procedure performed in the diagnosis of giant cell arteritis. METHODS AND RESULTS: An otherwise healthy 69-year-old man presented with 2months complaint of right temporal region pain. Giant cell arteritis was suspected and a temporal artery biopsy was performed. The histopathology revealed perineural invasion of squamous cell carcinoma (SCC). A thorough investigation revealed no other primary site for the SCC and the patient was treated with surgical excision. CONCLUSION: Malignancy is rarely found in superficial temporal artery biopsies and lymphoma is the most common malignancy reported. In this rare case, the patient had right temporal pain explained by perineural invasion of a primary SCC in the right temporal region, which was treated with surgical excision guided by perioperative fresh frozen histology. PMID- 25439623 TI - [18F]-FDG PET-CT prediction of response to induction chemotherapy in head and neck squamous cell carcinoma: preliminary findings. AB - OBJECTIVES: The present study assessed the predictive value of [18F]-FDG PET-CT (positron emission tomography with 18-fluoro-eoxyglucose radiotracer, coupled to computerized tomography) for response to induction chemotherapy in head and neck squamous cell carcinoma (HNSCC). MATERIAL AND METHODS: [18F]-FDG PET-CT was systematically performed before treatment initiation and after the first cycle of chemotherapy. Results were compared with those of endoscopy and pathologic analysis of biopsy and surgical specimens. RESULTS: This preliminary study included 21 previously untreated HNSCC patients. A decrease of more than 30% in SUVmax (maximum standard uptake value) during induction was predictive of tumor response to chemotherapy (P=0.04). PET-CT measurement of hypermetabolic volume based on a predetermined SUV threshold (SUV=2.5), on the other hand, proved non predictive. CONCLUSION: These preliminary findings are promising. A larger sample, however, would be required in order to determine a more precise SUVmax reduction cut-off threshold during induction. Other methods for determining metabolic volume thresholds will be investigated. If functional imaging proves contributive, it could enable early screening of non-responders, avoiding unnecessary intoxication. PMID- 25439624 TI - A retropharyngeal mass. Diagnosis: Antoni A type schwannoma. PMID- 25439625 TI - Possible role of anti-inflammatory drugs in complications of pharyngitis. A retrospective analysis of 163 cases. AB - OBJECTIVES: Complications of pharyngitis (peritonsillar abscess, retropharyngeal abscess, and cervical cellulitis) are rare, but appear to be on the increase over recent years and many of these patients have been treated by anti-inflammatory drugs prior to admission. The purpose of this study was to review the current epidemiological data concerning these complications and investigate a possible correlation with anti-inflammatory drug use. MATERIAL AND METHODS: A single centre retrospective review of epidemiological, clinical and microbiological data was performed on the medical charts of patients hospitalised for peritonsillar abscess, retropharyngeal abscess or cervical cellulitis between 2005 and 2010. RESULTS: Over a six-year period, 163 patients were hospitalised for complications of pharyngitis, with a sex-ratio of 1.82 (104/57). The number of cases of peritonsillar abscess (PTA) increased from 13 to 28 cases per year from 2005 to 2010 and the number of cases of retropharyngeal abscess increased from three to six cases per year over the same period. The number of cases of cellulitis remained stable with an average of 1.82 cases per year. Each year, significantly more patients with an abscess were admitted to our unit with a history of anti inflammatory drug use (13.3 +/- 4.6) than without anti-inflammatory drug use (7.8+/-4.3) (P<0.01). Micro-organisms were identified in 80% of cases, with mixed strains in 73% of cases, Streptococcus in 72% of samples and Streptococcus pyogenes in 19% of cases of PTA. A favourable outcome was observed in all patients in response to medical and surgical treatment. CONCLUSION: In line with the literature, we observed an increasing incidence of complications of pharyngitis. The present series comprised significantly more patients admitted for PTA with a history of anti-inflammatory drug use. A multicentre prospective controlled study in Nantes on a large cohort is currently underway and will probably confirm these preliminary results. PMID- 25439626 TI - Cysts along the intracranial margin of sinonasal tumors. PMID- 25439627 TI - Negative-pressure wound therapy for the treatment of pharyngocutaneous fistula. AB - INTRODUCTION: Pharyngocutaneous fistula is a well-known complication of head and neck cancer surgery.The purpose of this study was to determine the value of negative-pressure wound therapy (NPWT) for the treatment of these fistulas. NPWT is used in many fields of medicine, but its use in otorhinolaryngology has been rarely reported. NPWT is a cost-effective means to accelerate wound healing. PATIENTS AND METHODS: A single-centre retrospective study was conducted on 7 patients with pharyngo-cutaneous fistula following surgery for squamous cell carcinoma between January 2011 and April 2013.These fistulas were treated by negative-pressure wound therapy (NPWT). RESULTS: This series comprised seven male patients with a mean age of 65 years and 9 months. The mean duration of treatment was 23 days (range: 11 to 42 days). Two patients had a history of radiotherapy for pharyngolaryngeal cancer. Negative-pressure wound therapy achieved cure of the fistula in all patients with satisfactory acceptability. Mean follow-up was 10 months (range: 6 months to 2 years). CONCLUSION: Negative-pressure wound therapy represents a valuable treatment option in certain settings for the management of pharyngocutaneous fistula following head and neck cancer surgery. PMID- 25439628 TI - 'Fire at will': the emergence of habitual fire use 350,000 years ago. AB - The use of fire is central to human survival and to the processes of becoming human. The earliest evidence for hominin use of fire dates to more than a million years ago. However, only when fire use became a regular part of human behavioral adaptations could its benefits be fully realized and its evolutionary consequences fully expressed. It remains an open question when the use of fire shifted from occasional and opportunistic to habitual and planned. Understanding the time frame of this 'technological mutation' will help explain aspects of our anatomical evolution and encephalization over the last million years. It will also provide an important perspective on hominin dispersals out of Africa and the colonization of temperate environments, as well as the origins of social developments such as the formation of provisioned base camps. Frequencies of burnt flints from a 16-m-deep sequence of archaeological deposits at Tabun Cave, Israel, together with data from the broader Levantine archaeological record, demonstrate that regular or habitual fire use developed in the region between 350,000-320,000 years ago. While hominins may have used fire occasionally, perhaps opportunistically, for some million years, we argue here that it only became a consistent element in behavioral adaptations during the second part of the Middle Pleistocene. PMID- 25439629 TI - A comparison of catarrhine genetic distances with pelvic and cranial morphology: implications for determining hominin phylogeny. AB - Inferring the evolutionary history of the hominins is necessarily reliant on comparative analyses of fossilized skeletal anatomy. However, the reliability of different primate skeletal regions for recovering phylogenetic relationships is currently poorly understood. Historically, postcranial variation has largely been conceived of as reflecting locomotory and postural adaptation. The shape of the os coxae is central to such discussions given the divergent morphology displayed by the bipedal hominin pelvis relative to other primate taxa. While previous cladistic studies have suggested that postcranial and cranial datasets do not differ in terms of their propensity for homoplasy, methodological issues such as the numbers of characters and their quantification make it difficult to evaluate these findings. Here, we circumvent these problems by constructing morphological distance matrices based on cranial, mandibular and os coxae three-dimensional shape. Statistical comparisons of these morphological distance matrices against a single genetic distance matrix for 11 catarrhine taxa show that cranial and os coxae shape reflect genetic relationships better than the mandible when humans are included, and that the cranium and os coxae do not differ statistically in terms of their genetic correlations. When humans were excluded from the analyses, all three anatomical regions were equally strongly correlated with genetic distance. Moreover, a second analysis focusing solely on os coxae variation of 16 taxa demonstrated that os coxae shape correctly recovers catarrhine taxonomic relationships at the sub-family level, even when humans are included. Taken together, our results suggest that there is no a priori reason to favor cranial shape data over os coxae morphology when inferring the genetic relationships of extant or extinct primate taxa. Morphological similarities between humans and other primates differ depending on the skeletal element, suggesting that combining skeletal elements into a single analysis may provide more accurate reconstructions of genetic relationships. PMID- 25439631 TI - Occlusal splint versus modified nociceptive trigeminal inhibition splint in bruxism therapy: a randomized, controlled trial using surface electromyography. AB - BACKGROUND: An occlusal splint and a modified nociceptive trigeminal inhibition splint (AMPS, anterior deprogrammer, Kois deprogrammer, Lucia jig, etc.) are commonly and quite frequently used in the treatment of masticatory muscle disorders, although their sustainable and long-lasting effect on these muscles' function is still not very well known. Results of scant surface electromyography studies in patients with temporomandibular disorders have been contradictory. The aim of this study was to evaluate both devices in bruxism therapy; EMG activity levels during postural activity and maximum voluntary contraction of the superficial temporal and masseter muscles were compared before and after 30 days of treatment. METHODS: Surface electromyography of the examined muscles was performed in two groups of bruxers (15 patients each). Patients in the first group used occlusal splints, while those in the second used modified nociceptive trigeminal inhibition splints. The trial was randomized, controlled and semi blind. RESULTS: Neither device affected the asymmetry index or postural activity/maximum voluntary contraction ratio after 1 month of treatment. CONCLUSIONS: Neither the occlusal nor the nociceptive trigeminal inhibition splint showed any significant influence on the examined muscles. Different scientific methods should be considered in clinical applications that require either direct influence on the muscles' bioelectrical activity or a quantitative measurement of the treatment quality. PMID- 25439632 TI - [Mortality in patients with infective endocarditis treated in two different centers with on-site cardiac surgery]. PMID- 25439630 TI - Associations of depression with impaired glucose regulation, newly diagnosed diabetes and previously diagnosed diabetes in Chinese adults. AB - AIM: To examine the association between depression and impaired glucose regulation, newly diagnosed diabetes and previously diagnosed diabetes in middle aged and elderly Chinese people, and whether depression was associated with different treatment regimens or durations of diabetes. METHODS: A cross-sectional study was performed among 229,047 adults living in the community aged >= 40 years from 25 centres in China. The self-reported depression rating scale Patient Health Questionnaire 9 (PHQ-9) was used to diagnose probable and sub-threshold depression. Glucose metabolism status was determined according to World Health Organization 1999 diagnostic criteria. RESULTS: The numbers of participants with normal glucose regulation, impaired glucose regulation, newly diagnosed diabetes and previously diagnosed diabetes were 120,458, 59,512, 24,826 and 24,251, respectively. The prevalence of sub-threshold depression in the total sample of participants was 4.8% (4.8%, 4.8%, 4.4% and 5.6% from normal glucose regulation to previously diagnosed diabetes, respectively), and the prevalence of probable depression was 1.1% (1.1%, 1.0%, 0.9% and 1.8% from normal glucose regulation to previously diagnosed diabetes, respectively). Compared with participants with normal glucose regulation, those with previously diagnosed diabetes had increased odds of probable depression [odds ratio (OR) = 1.61, 95% confidence interval (CI) 1.39-1.87] and sub-threshold depression (OR = 1.14, 95% CI 1.06-1.24), after adjustment for multiple confounding factors. Newly diagnosed diabetes or impaired glucose regulation was not associated with depression. Among those with previously diagnosed diabetes, insulin treatment was associated with greater odds of depression compared with no treatment or oral anti-diabetic medicine. CONCLUSION: Previously diagnosed diabetes, but not newly diagnosed diabetes or impaired glucose regulation, was associated with a higher prevalence of depression. Patients receiving insulin were more likely to have depression than those not receiving treatment or being treated with oral anti-diabetic medicine. PMID- 25439633 TI - [A 19 year old Brazilian male with severe iron deficiency anemia]. PMID- 25439634 TI - [Isolation of rapidly growing mycobacteria from samples of skin and soft tissue. An etiology to consider]. PMID- 25439635 TI - Aging: physiology, disease, and abuse. AB - There are physiologic changes associated with aging. There are also medical conditions that occur more commonly with advancing age. These changes and conditions increase an older adult's vulnerability to and injuries from abuse or neglect. An older adult may have more difficulty recovering from an abuse incident. The investigation of abuse or neglect may be more difficult because of aging changes. PMID- 25439636 TI - Understanding the medical markers of elder abuse and neglect: physical examination findings. AB - A specific foundation of knowledge is important for evaluating potential abuse from physical findings in the older adult. The standard physical examination is a foundation for detecting many types of abuse. An understanding of traumatic injuries, including patterns of injury, is important for health care providers, and inclusion of elder abuse in the differential diagnosis of patient care is essential. One must possess the skills needed to piece the history, including functional capabilities, and physical findings together. Armed with this skill set, health care providers will develop the confidence needed to identify and intervene in cases of elder abuse. PMID- 25439637 TI - Medical and laboratory indicators of elder abuse and neglect. AB - Elder abuse and neglect are highly prevalent but woefully underdetected and underreported. The presentation is rarely clear and requires the piecing together of clues that create a mosaic of the full picture. More research needed to better characterize findings that, when identified, can contribute to certainty in cases of suspected abuse. Medical and laboratory data can be helpful in the successful determination of abuse and neglect. PMID- 25439638 TI - Common presentations of elder abuse in health care settings. AB - Health care professionals encounter elder abuse in the community and in medical offices, emergency rooms, hospitals, and long-term care facilities. Keen awareness of risk factors for elder abuse and the variety of presentations in different health settings helps promote detection, treatment, and prevention of elder abuse. PMID- 25439639 TI - Prevention and early identification of elder abuse. AB - Elder abuse is a public health problem growing more pervasive despite being grossly underreported and underdetected. Annually, many vulnerable older adults suffer various forms of abuse threatening their overall health, quality of life, and survival. To better protect our aging population, we must overcome obstacles such as ageism, lack of geriatric health professional training, and low screening practices in clinical settings. Addressing these challenges is not sufficient for eliminating the abuse of older adults, but it is necessary for diminishing the potential for abuse and the associated negative health outcomes. PMID- 25439640 TI - Elder physical abuse. AB - Physical abuse of the elderly is a significant public health concern. The true prevalence of all types is unknown, and under-reporting is known to be significant. The geriatric population is projected to increase dramatically over the next 10 years, and the number of abused individuals is projected to increase also. It is critical that health care providers feel competent in addressing physical elder abuse. This article presents cases illustrating the variety of presenting symptoms that may be attributed to physical elder abuse. PMID- 25439641 TI - Elder neglect. AB - Because neglect is the most common form of elder abuse, identifying patients who are vulnerable to neglect allows clinicians to intervene early and potentially prevent situations that can escalate and lead to harm or even death. Health care workers have a unique opportunity to uncover these unfortunate situations and in many cases may be the only other contact isolated vulnerable patients have with the outside world. Responding appropriately and quickly when neglect is suspected and using a team approach can improve the health and well-being of older victims of neglect. PMID- 25439642 TI - Case series of sexual assault in older persons. AB - In this article, sexual assault of older persons is analyzed in a literature review and case series, and exemplar pseudocases of suspected older person sexual assault are discussed. PMID- 25439643 TI - Medical implications of elder abuse: self-neglect. AB - Self-neglect, the most common form of elder mistreatment seen by Adult Protective Service Agencies across the United States, is an often unrecognized geriatric syndrome characterized by squalor and unsafe living circumstances. It is a result of medical, neurologic, or psychiatric disorders coupled with lack of capacity for self-care and self-protection in the absence of necessary services or medical care, and leads to increased morbidity and mortality. Clinicians should evaluate self-neglecters and plan interventions based on comprehensive geriatric assessment and capacity assessment. State and federal policies are needed to address the pressing needs of this vulnerable population of seniors. PMID- 25439644 TI - Evaluating abuse in the patient with dementia. AB - For patients with dementia, abuse ranges from subtle scams to outright physical violence. As dementia progresses, abuse escalates. The stages of dementia--mild cognitive impairment, mild dementia, moderate dementia, and severe dementia--lend themselves to varied presentations of abuse. Knowing which types of abuse are more prominent at each stage aids the clinician in anticipating risk of abuse and patient and caregiver needs. Interviewing the victim is crucial in uncovering, documenting, and intervening in an abuse situation. A clinician who is skilled in drawing out the facts while remaining supportive of the patient is key in ending the victimization. PMID- 25439645 TI - Mental health/psychiatric issues in elder abuse and neglect. AB - Elder abuse may be defined as a violation of a vulnerable older person's human and civil rights. Psychiatric illness is an important cause of vulnerability to abuse, especially when it is comorbid with other risk factors, such as physical frailty, sensory impairment, social isolation, and physical dependency. Health care providers are likely to encounter elder abuse regularly, and therefore have an important role in its detection and management, and in the treatment of subsequent psychiatric illness. This article reviews the relationships between psychiatric illnesses and elder abuse and neglect, examines the psychiatric consequences, and discusses how these may be treated. PMID- 25439646 TI - The role of capacity assessments in elder abuse investigations and guardianships. AB - Capacity evaluations of older adults assist in determining whether a situation should be considered elder/dependent adult abuse and which type of intervention is warranted. Capacity evaluations must integrate multiple sources of data and focus on functional abilities. Understanding the legal standard underlying the capacity needed for a specific decision is key in making a clinical opinion relevant in legal settings. Capacity evaluations for guardianships help to identify preserved abilities and make recommendations to enhance decisional and functional capacities that promote the dignity and independence of older adults. PMID- 25439647 TI - Care of the victim. AB - The number of elder abuse cases is expected to rise as the number of persons older than age 65 doubles over the next 20 years. Patients affected by elder abuse present in all care settings, including inpatient and outpatient clinical care, emergency rooms, long-term care facilities, and home care. Victims have significant medical consequences, physical and psychological, and often need additional resources, including legal guidance. Health care professionals need additional training to be effective advocates for survivors of elder abuse. Care of the victim must also be recognized as an equally important topic for research and education. PMID- 25439649 TI - Medical implications of elder abuse and neglect. PMID- 25439648 TI - Health professionals' roles and relationships with other agencies. AB - Health professionals play a vital role in addressing elder abuse by identifying and reporting elder abuse and caring for survivors. However, most are unaware of the opportunities to work with allied professionals in elder abuse intervention. This article discusses the various roles of interdisciplinary members and the contribution of health care professionals in these teams. Terminology used in elder abuse teamwork is discussed. PMID- 25439650 TI - Vaccination with a genotype 1 modified live vaccine against porcine reproductive and respiratory syndrome virus significantly reduces viremia, viral shedding and transmission of the virus in a quasi-natural experimental model. AB - The present study assessed the efficacy of vaccination against genotype 1 porcine reproductive and respiratory syndrome virus (PRRSV) in terms of reduction of the transmission. Ninety-eight 3-week-old piglets were divided in two groups: V (n=40) and NV (n=58) that were housed separately. V animals were vaccinated with a commercial genotype 1 PRRSV vaccine while NV were kept as controls. On day 35 post-vaccination, 14 NV pigs were separated and inoculated intranasally with 2 ml of a heterologous genotype 1 PRRSV isolate ("seeder" pigs, SP). The other V and NV animals were distributed in groups of 5 pigs each. Two days later, one SP was introduced into each pen to expose V and NV to PRRSV. Sentinel pigs were allocated in adjacent pens. Follow-up was of 21 days. All NV (30/30) became viremic after contact with SP while only 53% of V pigs were detected so (21/40, p<0.05). Vaccination shortened viremia (12.2+/-4 versus 3.7+/-3.4 days in NV and V pigs, respectively, p<0.01). The 50% survival time for becoming infected (Kaplan-Meier) for V was 21 days (CI95%=14.1-27.9) compared to 7 days (CI95%=5.2 8.7) for NV animals (p<0.01). These differences were reflected in the R value as well: 2.78 (CI95%=2.13-3.43) for NV and 0.53 (CI95%=0.19-0.76) for V pigs (p<0.05). All sentinel pigs (10/10) in pens adjacent to NV+SP pens got infected compared to 1/4 sentinel pigs allocated contiguous to a V+SP pen. These data show that vaccination of piglets significantly decrease parameters related to PRRSV transmission. PMID- 25439652 TI - Origins and evolution of reproductive immunology: a personal perspective. AB - This is a brief personal assessment of the origins and development of the field of reproductive immunology from the 19th century to the present day, with special reference to the founding of the Journal of Reproductive Immunology in 1979. PMID- 25439651 TI - Multiple sampling and discriminatory fingerprinting reveals clonally complex and compartmentalized infections by M. bovis in cattle. AB - The combination of new genotyping tools and a more exhaustive sampling policy in the analysis of infection by Mycobacterium tuberculosis has shown that infection by this pathogen is more complex than initially expected. Mixed infections, coexistence of clonal variants from a parental strain, and compartmentalized infections are all different modalities of this clonal complexity. Until recently, genotyping of Mycobacterium bovis in animal populations was based on spoligotyping and analysis of a single isolate per infection; therefore, clonal complexity is probably underdetected. We used multiple sampling combined with highly discriminatory MIRU-VNTR to study compartmentalized infections by M. bovis in a low-tuberculosis prevalence setting. We spoligotyped the M. bovis isolates from two or more anatomic locations sampled from 55 animals on 39 independent farms. Compartmentalized infections, with two different strains infecting independent lymph nodes in the same animal, were found in six cases (10.9%). MIRU VNTR analysis confirmed that the compartmentalization was strict and that only one strain was present in each infected node. MIRU-VNTR analysis of additional infected animals on one of the farms confirmed that the compartmentalized infection was a consequence of superinfection, since the two strains were independently infecting other animals. This same analysis revealed the emergence of a microevolved clonal variant in one of the lymph nodes of the compartmentalized animal. Clonal complexity must also be taken into consideration in M. bovis infection, even in low-prevalence settings, and analyses must be adapted to detect it and increase the accuracy of molecular epidemiology studies. PMID- 25439653 TI - Reduced striatal dopamine transporter density associated with working memory deficits in opioid-dependent male subjects: a SPECT study. AB - Research on the effects of repeated opioid use on striatal dopamine transporters has yielded inconsistent results, possibly confounded by a history of methamphetamine or methadone exposure in opioid-dependent individuals. Previous studies have shown that striatal dopamine transporter density is positively correlated with the cognitive performance of healthy volunteers. This study aimed to investigate changes in striatal dopamine transporter density and their functional significance in opioid-dependent individuals. Single-photon emission computed tomography with [(99m) Tc]TRODAT-1 as a ligand was used to measure striatal dopamine transporter levels in 20 opioid-dependent individuals and 20 age- and sex-matched healthy controls. Opioid-dependent individuals had no history of methamphetamine or methadone use. The Wisconsin Card Sorting Test (WCST) was performed to assess neurocognitive function. We found that compared with healthy controls, opioid-dependent individuals showed a significant reduction in striatal dopamine transporter density. They also showed poorer performance on the WCST in terms of the trials administered, total errors, perseverative responses, perseverative errors, and non-perseverative errors. Striatal dopamine transporter levels negatively correlated with non-perseverative errors not only in opioid-dependent individuals but also in healthy controls. These findings suggest that in human, repeated opioid exposure reduces striatal dopamine transporter density, which can be associated with non-perseverative errors. Non-perseverative errors may be one of the more sensitive parameters in WCST to identify working memory deficits associated with striatal dopamine transporter reduction. Moreover, we suggest that whether opioid-associated neurotoxicity is reversible depends on the brain region. PMID- 25439654 TI - Improvement of the facial evenness of leave-on skincare products by a modified application method in Chinese women. AB - OBJECTIVE: To understand the habits of Chinese women applying leave-on skincare products (LOSCP) and to improve female facial evenness of anti-ageing cosmetics through modifying facial skincare smear ways. METHODS: A questionnaire on the method of applying LOSCP was distributed to 60 women with habit of using LOSCP. Their facial images before and after applying LOSCP were taken, and their positioning and grey value were used to analyse the effects of different applying methods on the uniformity of facial LOSCP. RESULTS: LOSCP including anti-ageing cosmetics have been widely used among Chinese women for a long time. However, some women do not concern how to properly apply LOSCP. In our survey, the main focal points of the face are forehead, malar region, cheek, mouth corners and chin when they looking into the mirror, and mouth corners and inner canthus are often overlooked when applying cosmetic products. The image analysis found that after applying the LOSCP, the greyscale of the forehead, glabella, malar region, upper lip region and jaw changed significantly whereas that of canthus, mouth corners and lateral cheek region was not significantly different. Applying an improved smear method (11-point method)could significantly increase the grey values of various facial areas. CONCLUSION: The way of Chinese women applying LOSCP may result in facial unevenness of skin products. By improving facial skincare smear method, one can make the products even in all facial areas, thereby ensuring the efficacy of anti-ageing cosmetics. Thus, further improvement and education regarding skincare is required. PMID- 25439656 TI - Pediatric Urology Fall Congress Las Vegas, Nevada September 19-22, 2013. Editorial. PMID- 25439655 TI - Classical swine fever virus induces oxidative stress in swine umbilical vein endothelial cells. AB - BACKGROUND: Classical swine fever virus (CSFV) infection causes significant losses of pigs, which is characterized by hemorrhage, disseminated intravascular coagulation and leucopenia. The swine vascular endothelial cell is a primary target cell for CSFV. The aim of this study was to determine the role of CSFV infection in inducing oxidative stress (OS) in vascular endothelial cells. RESULTS: We demonstrated that CSFV infection induced oxidative stress in swine umbilical vein endothelial cells (SUVECs), characterized by the induction of reactive oxygen species (ROS) production and the elevations of porcine antioxidant proteins thioredoxin (Trx), peroxiredoxin-6 (PRDX-6) and heme oxygenase-1 (HO-1) expression. Furthermore, cyclooxygenase-2 (COX-2), a pro inflammatory protein related to oxidative stress, was up-regulated while anti inflammatory protein peroxisome proliferator-activated receptor-gamma (PPAR gamma), an important mediator in vascular functional regulation, was down regulated in the CSFV infected cells. In addition, antioxidants showed significant inhibitory effects on the CSFV replication, indicating a close relationship between CSFV replication and OS induced in the host cells. CONCLUSIONS: Our results indicated that CSFV infection induced oxidative stress in SUVECs. These findings provide novel information on the mechanism by which CSFV can alter intracellular events associated with the viral infection. PMID- 25439657 TI - Impact of nephrectomy on long-term renal function in non-syndromic children treated for unifocal Wilms tumor. AB - OBJECTIVE: The present study is designed to assess the long-term renal function of children who underwent radical nephrectomy for unifocal Wilms tumor. METHODS: A single institution retrospective cohort study of non-syndromic children treated with radical nephrectomy for unifocal Wilms tumor between 1995 and 2011 was performed to identify risk factors for decreased glomerular filtration rate (GFR). The primary endpoint was decrease in age-adjusted GFR below normal published ranges. The secondary endpoint was progression to chronic renal insufficiency (CRI). RESULTS: A total of 55 patients were identified in the cohort. Eight (15%) patients exhibited decreased age-adjusted GFR during the follow-up period, with 2 (4%) progressing to CRI. Increasing time between surgery and the last known GFR follow-up was associated with decreased GFR, with the normal GFR group having median follow-up of 7.32 years versus 11.47 years (p = 0.019) in the decreased GFR group. CONCLUSIONS: A trend toward decline in GFR was detected with longer follow-up. Longer follow-up may reveal that clinically significant decline in renal function occurs years following nephrectomy among a subset of Wilms tumor survivors, even among those who do not progress to end stage renal disease. PMID- 25439658 TI - Population and health services research. PMID- 25439659 TI - Reactive oxygen species-provoked mitochondria-dependent cell death during ageing of elm (Ulmus pumila L.) seeds. AB - Previous studies have shown that controlled deterioration treatment (CDT) induces programmed cell death in elm (Ulmus pumila L.) seeds, which undergo certain fundamental processes that are comparable to apoptosis in animals. In this study, the essential characteristics of mitochondrial physiology in elm seeds during CDT were identified by cellular ultrastructural analysis, whole-body optical imaging, Western blotting and semi-quantitative RT-PCR. The alteration in mitochondrial morphology was an early event during CDT, as indicated by progressive dynamic mitochondrial changes and rupture of the mitochondrial outer membrane; loss of mitochondrial transmembrane potential (Deltapsi(m)) ensued, and mitochondrial ATP levels decreased. The mitochondrial permeability transition pore inhibitor cyclosporine A effectively suppressed these changes during ageing. The in situ localization of production of reactive oxygen species (ROS), and evaluation of the expression of voltage-dependent anion-selective channel and cyclophilin D indicated that the levels of mitochondrial permeability transition pore components were positively correlated with ROS production, leading to an imbalance of the cellular redox potential and ultimately to programmed cell death. Pre-incubation with ascorbic acid slowed loss of mitochondrial Deltapsi(m), and decreased the effect of CDT on seed viability. However, there were no significant changes in multiple antioxidant elements or chaperones in the mitochondria during early stages of ageing. Our results indicate that CDT induces dynamic changes in mitochondrial physiology via increased ROS production, ultimately resulting in an irreversible loss of seed viability. PMID- 25439660 TI - Alcohol consumption and incidence of type 2 diabetes. Results from the CoLaus study. AB - BACKGROUND AND AIMS: Moderate alcohol consumption has been shown to decrease the risk of type 2 diabetes (T2DM), but whether this association is also valid for impaired fasting glucose (IFG) is less well known. We aimed at assessing the impact of alcohol consumption and of type of alcoholic beverage on the incidence of T2DM and T2DM + IFG. METHODS AND RESULTS: As many as 4765 participants (2613 women, mean age 51.7 +/- 10.5 years) without T2DM at baseline and followed for an average of 5.5 years. The association between alcohol consumption, type of alcoholic beverage and outcomes was assessed after adjustment for a validated T2DM risk score. During follow-up 284 participants developed T2DM and 643 developed IFG. On bivariate analysis, alcohol consumption was positively associated with the risk of developing T2DM or T2DM + IFG. Moderate (14-27 units/week) alcohol consumption tended to be associated with a lower risk of T2DM, but no protective effect was found for T2DM + IFG. Multivariable-adjusted odds ratio (OR) and (95% confidence interval) for T2DM: 0.89 (0.65-1.22), 0.66 (0.42-1.03) and 1.63 (0.93-2.84) for 1-13, 14-27 and 28 + units/week, respectively (p for quadratic trend < 0.005). For T2DM + IFG, the corresponding ORs were 1.09 (0.90-1.32), 1.33 (1.02-1.74) and 1.54 (0.99-2.39), respectively, p for trend = 0.03. No specific effect of alcoholic beverage (wine, beer or spirits) was found for T2DM or for T2DM + IFG. CONCLUSION: Moderate alcohol consumption is associated with a reduced risk of developing T2DM, but not of developing T2DM + IFG. No specific effect of type of alcoholic beverage was found. PMID- 25439661 TI - Effects of HDL-modifiers on cardiovascular outcomes: a meta-analysis of randomized trials. AB - BACKGROUND AND AIM: High density lipoproteins (HDL) have been addressed as a potential strategy for cardiovascular prevention, with great controversies on pharmacological approaches for HDL-elevation. Our aim was to compare HDL-rising treatment with niacin or CETP-inhibitors with optimal medical therapy in cardiovascular outcome. METHODS AND RESULTS: Randomized trials were searched. Primary endpoint was cardiovascular death, secondary were: non fatal myocardial infarction; coronary revascularization; cerebrovascular accidents and safety endpoints. As many as 18 randomized trials, for a total of 69,515 patients, were included. HDL-modifiers did not reduce cardiovascular mortality (2.3%vs3.4%; OR [95%CI] = 0.96 [0.87-1.05], p = 0.37, phet = 0.58), with no benefit from niacin/CETP inhibitors according to patients' risk profile (beta [95%CI] = -0.14 [-0.29 to 0.02], p = 0.09) or the amount of HDL increase (beta [95%CI] = 0.014 [ 0.008 to 0.04], p = 0.21). Niacin but not CETP-I reduced myocardial infarction and coronary revascularization, but higher rate of SAE occurred with HDL modifiers (OR [95%CI] = 1.24 [1.18-1.31], p < 0.00001, phet = 0.02), in particular new onset of diabetes with niacin and worsening of hypertension with CETP-inhibitors. CONCLUSIONS: Niacin and CETP inhibitors do not influence cardiovascular mortality. Significant benefits in MI and coronary revascularization were observed with niacin, despite the higher occurrence of diabetes. PMID- 25439662 TI - Dietary intake of heme iron and risk of cardiovascular disease: a dose-response meta-analysis of prospective cohort studies. AB - BACKGROUND AND AIMS: Iron is thought to play a fundamentally important role in the development of cardiovascular disease (CVD). This meta-analysis was performed to investigate the dose-response association between dietary intake of iron (including heme and non-heme iron) and the risk of CVD. METHODS AND RESULTS: We performed a search of the PubMed and Embase databases for prospective cohort studies of the association between dietary iron intake and CVD risk. Thirteen articles comprising 252,164 participants and 15,040 CVD cases were eligible for inclusion. Heme iron intake was associated significantly with increased risk of cardiovascular disease, and the pooled relative risk (RR) for each 1 mg/day increment was 1.07 (95% confidence interval: 1.01 to 1.14, I2 = 59.7%). We also found evidence of a curvilinear association (P < 0.05 for non-linearity). In contrast, we found no association between CVD risk and dietary non-heme (0.98, 0.96 to 1.01, I2 = 15.8%) or total iron (1.00, 0.94 to 1.06, I2 = 30.4%). Subgroup analyses revealed that the association between heme iron intake and CVD risk was stronger among non-fatal cases (1.19, 1.07-1.33) and American patients (1.31, 1.11-1.56). CONCLUSIONS: Higher dietary intake of heme iron is associated with an increased risk of cardiovascular disease, whereas no association was found between CVD and non-heme iron intake or total iron intake. These findings may have important public health implications with respect to preventing cardiovascular disease. PMID- 25439663 TI - Left ventricular diastolic function and cardiometabolic factors in obese normotensive children. AB - BACKGROUND AND AIM: Left ventricular (LV) hypertrophy and diastolic function have been found to be associated with obesity and hypertension in adults. However, there are scarce data about the association of obesity itself to cardiac alteration in children. The aim of this study was to detect early changes in LV structure and function in obese children and whether they are associated with the biomarkers of metabolic risk and endothelial activation. METHODS AND RESULTS: A total of 130 children aged 7-16 years (88 obese and 42 normal-weight children) were studied. All children had normal resting blood pressure. Two-dimensional ultrasound with M-mode imaging was performed to assess the LV mass index (LVMi), calculated as LV mass/height(2.7), and the peak diastolic of pulmonary venous flow velocity (PVFD). Tissue Doppler imaging was used to analyze ventricular performance through the ratio of the transmitral peak early filling velocity to the early average diastolic peak myocardial velocity (E/E'). The indicators of metabolic control, inflammation, and endothelial cell activation were evaluated. Compared to the controls, the obese subjects had significantly higher LVMi and E/E' and lower PVFD values, the two latest being found especially in severely obese subjects. In the multivariate analysis, the parameters of diastolic function (E/E' and PVFD) were independently associated with obesity, apolipoprotein A1, soluble vascular cell endothelial molecule-1 (sVCAM-1), and retinol-binding protein 4 (RBP4). CONCLUSION: An echocardiographic evaluation of diastolic function is a useful tool to detect early cardiac changes in obese children. Emergent cardiovascular risk markers such as apolipoprotein A1, RBP4, and sVCAM-1 are associated with the parameters of diastolic function. PMID- 25439670 TI - [Consensus document for the detection and management of chronic kidney disease: Coordination opportunity]. PMID- 25439671 TI - Seeing risk and allocating responsibility: talk of culture and its consequences on the work of patient safety. AB - To improve patient safety, hospitals have implemented interventions to change their culture. Although there is great enthusiasm for these interventions at policy and management levels, we know little about how clinicians talk about "culture" as they do the work of quality and safety improvement. This article investigates the way talk of culture arises in situ, showing how it is a trope that can frustrate, obscure, and prevent the collective social action necessary to change practice. The findings are based on a two-year ethnographic case study of a large hospital in the United States that undertook an organization-wide safety improvement initiative. They show that culture is frequently talked about as a behavioral trait of individuals, which makes the identification of social barriers and facilitators difficult. Culture talk can also obscure uncomfortable, yet crucial social phenomena, including history, politics and inequalities in power that may contribute to unsafe care delivery. The consequences of this obscurity are (1) practices that might make care safer are not considered, and (2) responsibility for enacting safe practice is allocated to those with the least authority and capacity to mitigate risk. The article closes by discussing how talk of culture obscures the role of social context and its contribution to risk in patient safety. PMID- 25439669 TI - Tumor-expressed adrenomedullin accelerates breast cancer bone metastasis. AB - INTRODUCTION: Adrenomedullin (AM) is secreted by breast cancer cells and increased by hypoxia. It is a multifunctional peptide that stimulates angiogenesis and proliferation. The peptide is also a potent paracrine stimulator of osteoblasts and bone formation, suggesting a role in skeletal metastases-a major site of treatment-refractory tumor growth in patients with advanced disease. METHODS: The role of adrenomedullin in bone metastases was tested by stable overexpression in MDA-MB-231 breast cancer cells, which cause osteolytic bone metastases in a standard animal model. Cells with fivefold increased expression of AM were characterized in vitro, inoculated into immunodeficient mice and compared for their ability to form bone metastases versus control subclones. Bone destruction was monitored by X-ray, and tumor burden and osteoclast numbers were determined by quantitative histomorphometry. The effects of AM overexpression on tumor growth and angiogenesis in the mammary fat pad were determined. The effects of AM peptide on osteoclast-like multinucleated cell formation were tested in vitro. A small-molecule AM antagonist was tested for its effects on AM-stimulated ex vivo bone cell cultures and co-cultures with tumor cells, where responses of tumor and bone were distinguished by species-specific real-time PCR. RESULTS: Overexpression of AM mRNA did not alter cell proliferation in vitro, expression of tumor-secreted factors or cell cycle progression. AM-overexpressing cells caused osteolytic bone metastases to develop more rapidly, which was accompanied by decreased survival. In the mammary fat pad, tumors grew more rapidly with unchanged blood vessel formation. Tumor growth in the bone was also more rapid, and osteoclasts were increased. AM peptide potently stimulated bone cultures ex vivo; responses that were blocked by small molecule adrenomedullin antagonists in the absence of cellular toxicity. Antagonist treatment dramatically suppressed tumor growth in bone and decreased markers of osteoclast activity. CONCLUSIONS: The results identify AM as a target for therapeutic intervention against bone metastases. Adrenomedullin potentiates osteolytic responses in bone to metastatic breast cancer cells. Small-molecule antagonists can effectively block bone-mediated responses to tumor-secreted adrenomedullin, and such agents warrant development for testing in vivo. PMID- 25439672 TI - Is AMPK the savior of the failing heart? AB - Heart failure (HF) is one of the leading causes of death, affecting more than 20 million people worldwide. A vast array of pathophysiological and molecular events contributes to the development and eventual worsening of HF. Of these, defects in myocardial metabolic processes that normally result in proper ATP production necessary to maintain contractile function appear to be a major contributor to HF pathogenesis. A key player involved in regulating myocardial metabolism is AMP activated protein kinase (AMPK), a major regulatory kinase controlling numerous metabolic pathways. Here, we review the metabolic changes that occur in HF, what role alterations in energy metabolism has in its progression, and the involvement of AMPK in this context. PMID- 25439673 TI - Debate: Should dialysis at home be mandatory for all suitable ESRD patients?: patients should not be forced onto home dialysis. AB - Outcomes are similar between hospital-based hemodialysis and less expensive home based therapies, especially home peritoneal dialysis. Because of this, some have argued that all suitable patients should be forced to these less expensive modalities. However, such an approach would violate the ethical principles of autonomy and maleficence, and would run counter to the movement toward patient centered care. Therefore, from a North American perspective, home dialysis should be actively promoted for suitable patients, but should not be mandatory. Extending these arguments into newer paradigms of home- and community-based dialysis, with paid assistance, will be a challenge as traditional cost effectiveness arguments may not be definitive and effective. Nephrology will need to embrace new methods for evaluation of therapies and to develop and endorse sophisticated principles of advocacy to influence health care policy and funding decision makers to maximize nonhospital-based, patient-centered care and improve outcomes in the future. PMID- 25439674 TI - Self-neglect in an elderly community-dwelling U.S. Chinese population: findings from the Population Study of Chinese Elderly in Chicago study. AB - This study aimed to examine the prevalence of self-neglect and its specific behaviors in an elderly community-dwelling U.S. Chinese population through a population-based cohort study (PINE Study) in the greater Chicago area. Community dwelling population of older Chinese adults were interviewed from 2011 to 2013 (n = 3,159). The personal and home environment of participants was rated based on prevalence of hoarding behavior, personal hygiene, repairs needed on the home, sanitary condition of the home, and adequacy of utilities. Prevalence estimates were presented according to self-reported quality of life (QOL). It was found that the prevalence of self-neglect was 18.2% for mild self-neglect and 10.9% for moderate to severe self-neglect. Unsanitary conditions (17.0%) was the most prevalent, followed by need for home repair (16.3%), hoarding behavior (14.9%), poor personal hygiene (11.3%), and inadequate utilities (4.2%). The prevalence of elder self-neglect of all severities and of all types was higher in older adults with fair or poor QOL than in those with good or very good QOL. Poorer QOL was significantly associated with greater risk of self-neglect of all severities (mild self-neglect: odds ratio (OR) = 1.93, 95% confidence interval (CI) = 1.26 2.96, P < .001; moderate to severe self-neglect: OR = 3.58, 95% CI = 1.79-7.13, P < .001) and specific personal and environmental hazards. The study's authors conclude that elder self-neglect is prevalent, especially in elderly adults with poorer QOL. Future research is needed to examine risk and protective factors associated with elder self-neglect. PMID- 25439675 TI - Radiofrequency ablation-induced upregulation of hypoxia-inducible factor-1alpha can be suppressed with adjuvant bortezomib or liposomal chemotherapy. AB - PURPOSE: To characterize upregulation of hypoxia-inducible factor (HIF)-1alpha after radiofrequency (RF) ablation and the influence of an adjuvant HIF-1alpha inhibitor (bortezomib) and nanodrugs on modulating RF ablation-upregulated hypoxic pathways. MATERIALS AND METHODS: Fisher 344 rats (n = 68) were used. First, RF ablation-induced periablational HIF-1alpha expression was evaluated in normal liver or subcutaneous R3230 tumors (14-16 mm). Next, the effect of varying RF ablation thermal dose (varying tip temperature 50 degrees C-90 degrees C for 2 20 minutes) on HIF-1alpha expression was studied in R3230 tumors. Third, RF ablation was performed in R3230 tumors without or with an adjuvant HIF-1alpha inhibitor, bortezomib (single intraperitoneal dose 0.1 mg/kg). Finally, the combination RF ablation and intravenous liposomal chemotherapeutics with known increases in periablational cellular cytotoxicity (doxorubicin, paclitaxel, and quercetin) was assessed for effect on periablational HIF-1alpha. Outcome measures included immunohistochemistry of HIF-1alpha and heat shock protein 70 (marker of nonlethal thermal injury). RESULTS: RF ablation increased periablational HIF 1alpha in both normal liver and R3230 tumor, peaking at 24-72 hours. Tumor RF ablation had similar HIF-1alpha rim thickness but significantly greater percent cell positivity compared with hepatic RF ablation (P < .001). HIF-1alpha after ablation was the same regardless of thermal dose. Bortezomib suppressed HIF 1alpha (rim thickness, 68.7 um +/- 21.5 vs 210.3 um +/- 85.1 for RF ablation alone; P < .02) and increased ablation size (11.0 mm +/- 1.5 vs 7.7 mm +/- 0.6 for RF ablation alone; P < .002). Finally, all three nanodrugs suppressed RF ablation-induced HIF-1alpha (ie, rim thickness and cell positivity; P < .02 for all comparisons), with liposomal doxorubicin suppressing HIF-1alpha the most (P < .03). CONCLUSIONS: RF ablation upregulates HIF-1alpha in normal liver and tumor in a temperature-independent manner. This progrowth, hypoxia pathway can be successfully suppressed with an adjuvant HIF-1alpha-specific inhibitor, bortezomib, or non-HIF-1alpha-specific liposomal chemotherapy. PMID- 25439676 TI - Quality improvement guidelines for pediatric gastrostomy and gastrojejunostomy tube placement. PMID- 25439677 TI - Gingival crevicular fluid proteomes in health, gingivitis and chronic periodontitis. AB - OBJECTIVE: The aim of this study was to compare the proteome composition of gingival crevicular fluid obtained from healthy periodontium, gingivitis and chronic periodontitis affected sites. BACKGROUND: Owing to its site-specific nature, gingival crevicular fluid is ideal for studying biological processes that occur during periodontal health and disease progression. However, few studies have been conducted into the gingival crevicular fluid proteome due to the small volumes obtained. METHODS: Fifteen males were chosen for each of three different groups, healthy periodontium, gingivitis and chronic periodontitis. They were categorized based on clinical measurements including probing depth, bleeding on probing, plaque index, radiographic bone level, modified gingival index and smoking status. Gingival crevicular fluid was collected from each patient, pooled into healthy, gingivitis and chronic periodontitis groups and their proteome analyzed by gel electrophoresis and liquid chromatography electrospray ionization ion trap tandem mass spectrometry. RESULTS: One hundred and twenty-one proteins in total were identified, and two-thirds of these were identified in all three conditions. Forty-two proteins were considered to have changed in abundance. Of note, cystatin B and cystatin S decreased in abundance from health to gingivitis and further in chronic periodontitis. Complement proteins demonstrated an increase from health to gingivitis followed by a decrease in chronic periodontitis. Immunoglobulins, keratin proteins, fibronectin, lactotransferrin precursor, 14-3-3 protein zeta/delta, neutrophil defensin 3 and alpha-actinin exhibited fluctuations in levels. CONCLUSION: The gingival crevicular fluid proteome in each clinical condition was different and its analysis may assist us in understanding periodontal pathogenesis. PMID- 25439679 TI - Provision for cancer patients a priority in primary care reforms. PMID- 25439678 TI - The effects of early foster care intervention on attention biases in previously institutionalized children in Romania. AB - Children raised in institutions experience psychosocial deprivation that can negatively impact attention skills and emotion regulation, which subsequently may influence behavioral regulation and social relationships. The current study examined visual attention biases in 8-year-old children who were part of the Bucharest Early Intervention Project (BEIP). Relations among attention biases and concurrent social outcomes were also investigated. In early childhood, 136 children abandoned at birth or shortly thereafter into institutional care were randomized to receive a high-quality foster care intervention or care-as-usual within the context of the Bucharest Early Intervention Project (BEIP). At 8 years of age, 50 care-as-usual, 55 foster care, and 52 community controls performed a behavioral dot-probe task, and indices of attention biases to threat and positive stimuli were calculated. Concurrent data on social behavior were collected. Children placed into the foster care intervention had a significant attention bias toward positive stimuli, while children who received care-as-usual had a significant bias toward threat. Children in the foster care intervention had a significantly larger positive bias when compared to the care-as-usual group. A positive bias was related to more social engagement, more prosocial behavior, less externalizing disorders, and less emotionally withdrawn behavior. The magnitude of positive bias was predicted by age of placement into foster care among children with a history of institutionalization. An attention bias towards positive stimuli was associated with reduced risk for behavioral problems amongst children who experienced early psychosocial deprivation. Research assessing attention biases in children experiencing early environmental stress may refine our understanding of the mechanisms underlying risk for later psychiatric and social disorders and inform prevention efforts. PMID- 25439680 TI - How do the AMAROS trial results change practice? PMID- 25439681 TI - Towards a chemotherapy-free approach in indolent lymphoma. PMID- 25439682 TI - Global burden of human papillomavirus-positive head and neck cancers. PMID- 25439683 TI - Length of chemotherapy and use of bevacizumab for breast cancer. PMID- 25439684 TI - Pan-HER inhibition in EGFR wild-type non-small-cell lung cancer. PMID- 25439685 TI - Improving prognosis after surgery for gastric cancer. PMID- 25439686 TI - Effect of docetaxel on safety and efficacy of radium-223. PMID- 25439687 TI - Uncaria tomentosa, the cat's whiskers or claws? PMID- 25439688 TI - Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. AB - BACKGROUND: If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects. METHODS: Patients with T1-2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5 year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov, number NCT00014612. FINDINGS: Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6.1 years (IQR 4.1-8.0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0.43% (95% CI 0.00 0.92) after axillary lymph node dissection versus 1.19% (0.31-2.08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non inferiority test on the hazard ratio was 0.00-5.27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years. INTERPRETATION: Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1-2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity. FUNDING: EORTC Charitable Trust. PMID- 25439690 TI - HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis. AB - BACKGROUND: We aimed to provide updated information about the global estimates of attributable fraction and type distribution of human papillomavirus (HPV) in head and neck squamous cell carcinomas by doing a systematic review and meta-analysis. METHODS: We did a literature search on PubMed to identify studies that used PCR for detection of HPV DNA in head and neck squamous cell carcinomas with information about HPV genotype distribution. We included studies that tested 20 or more biopsies per cancer site and were published between July 15, 1990, and Feb 29, 2012. We collected information about sex, risk factors, HPV detection methods, and biomarkers of potentially HPV-induced carcinogenesis (E6/E7 mRNA and p16(INK4a)). If it was not possible to abstract the required information directly from the paper, we contacted the authors. We did a meta-analysis to produce pooled prevalence estimates including a meta-regression to explore sources of heterogeneity. FINDINGS: 148 studies were included, contributing data for 12 163 cases of head and neck squamous cell carcinoma from 44 countries. HPV DNA was detected in 3837 cases. HPV16 accounted for 82.2% (95% CI 77.7-86.4) of all HPV DNA positive cases. By cancer site, pooled HPV DNA prevalence estimates were 45.8% (95% CI 38.9-52.9) for oropharynx, 22.1% (16.4-28.3) for larynx (including hypopharynx), and 24.2% (18.7-30.2) for oral cavity. The percent positivity of p16(INK4a) positive cases in HPV-positive oropharyngeal cancer cases was 86.7% (95% CI 79.2-92.9) and of E6/E7 mRNA positive cases was 86.9% (73.2-96.8). The estimate of HPV attributable fraction in oropharyngeal cancer defined by expression of positive cases of E6/E7 mRNA was 39.8% and of p16(INK4a) was 39.7%. Of subsites, tonsils (53.9%, 95% CI 46.4-61.3) had the highest HPV DNA prevalence. HPV DNA prevalence varied significantly by anatomical site, geographic region, but not by sex or tobacco or alcohol consumption. INTERPRETATION: The contribution of HPV prevalence in head and neck squamous cell carcinoma and in particular that of HPV16 in the oropharynx shows the potential benefit of prophylactic vaccines. FUNDING: European Commission. PMID- 25439691 TI - Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. AB - BACKGROUND: Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study. METHODS: In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554. FINDINGS: Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 2.6 months (95% CI 1.9-2.8) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0.941, 95% CI 0.802-1.104, one-sided log-rank p=0.229). For patients with wild-type KRAS, median progression-free survival was 2.6 months for dacomitinib (95% CI 1.9-2.9) and erlotinib (95% CI 1.9-3.0; stratified HR 1.022, 95% CI 0.834-1.253, one-sided p=0.587). In patients who received at least one dose of study drug, the most frequent grade 3-4 adverse events were diarrhoea (47 [11%] patients in the dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [<1%]). Serious adverse events were reported in 52 (12%) patients receiving dacomitinib and 40 (9%) patients receiving erlotinib. INTERPRETATION: Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations. FUNDING: Pfizer. PMID- 25439689 TI - Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. AB - BACKGROUND: Standard treatments for indolent non-Hodgkin lymphomas are often toxic, and most patients ultimately relapse. Lenalidomide, an immunomodulatory agent, is effective as monotherapy for relapsed indolent non-Hodgkin lymphoma. We assessed the efficacy and safety of lenalidomide plus rituximab in patients with untreated, advanced stage indolent non-Hodgkin lymphoma. METHODS: In this phase 2 trial, undertaken at one instution, patients with follicular lymphoma and marginal zone lymphoma were given lenalidomide, orally, at 20 mg/day on days 1-21 of each 28-day cycle. For patients with small lymphocytic lymphoma, dosing began at 10 mg/day to avoid tumour flare, with an escalation of 5 mg/month to 20 mg/day. Rituximab was given at 375 mg/m(2) as an intravenous infusion on day 1 of each cycle. Patients responding after six cycles could continue therapy for up to 12 cycles. The primary endpoint was overall response, defined as the proportion of patients who achieved a partial or complete response; patients were assessed for response if they had any post-baseline tumour assessment. This trial is registered with ClinicalTrials.gov, number NCT00695786. FINDINGS: 110 patients with follicular lymphoma (n=50), marginal zone lymphoma (n=30), and small lymphocytic lymphoma (n=30) were enrolled from June 30, 2008, until Aug 12, 2011. 93 of 103 evaluable patients had an overall response (90%, 95% CI 83-95). Complete responses occurred in 65 (63%, 95% CI 53-72) and partial responses in 28 patients (27%, 19-37). Of 46 evaluable patients with follicular lymphoma, 40 (87%) patients had a complete response and five (11%) had a partial response. Of 27 evaluable patients with marginal zone lymphoma, 18 (67%) had a complete response and six (22%) had a partial response. Of 30 evaluable patients with small lymphocytic lymphoma, seven (23%) had a complete response and 17 (57%) had a partial response. The most common grade 3 or 4 adverse events were neutropenia (38 [35%] of 110 patients), muscle pain (ten [9%]), rash (eight [7%]), cough, dyspnoea, or other pulmonary symptoms (five [5%]), fatigue (five [5%]), thrombosis (five [5%]), and thrombocytopenia (four [4%]). INTERPRETATION: Lenalidomide plus rituximab is well tolerated and highly active as initial treatment for indolent non-Hodgkin lymphoma. An international phase 3 study (NCT01476787) to compare this regimen with chemotherapy in patients with untreated follicular lymphoma is in progress. FUNDING: Celgene Corporation and Richard Spencer Lewis Memorial Foundation and Cancer Center Support Grant. PMID- 25439692 TI - Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial. AB - BACKGROUND: Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. METHODS: In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged >=18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. FINDINGS: Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23.4 months (IQR 15.6-29.6) for patients in the dacomitinib group and 24.4 months (11.5-38.9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6.83 months [95% CI 6.08-7.49] for dacomitinib vs 6.31 months [5.32-7.52] for placebo; hazard ratio [HR] 1.00 [95% CI 0.83-1.21]; p=0.506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2.66 months [1.91-3.32] vs 1.38 months [0.99-1.74], respectively; HR 0.66 [95% CI 0.55-0.79]; p<0.0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0.001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0.98, 95% CI 0.67-1.44) and EGFR wild-type tumours (0.93, 0.71-1.21; pinteraction=0.69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2.10, 1.05-4.22) and patients with KRAS wild-type tumours (0.79, 0.61-1.03; pinteraction=0.08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0.0001), dyspnoea (p=0.049), and pain (p=0.041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]). INTERPRETATION: Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. FUNDING: Canadian Cancer Society Research Institute and Pfizer. PMID- 25439694 TI - Efficacy and safety of radium-223 dichloride in patients with castration resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. AB - BACKGROUND: Primary results from the phase 3 ALSYMPCA trial showed that radium 223 dichloride (radium-223), a targeted alpha-emitter, improved overall survival compared with placebo and was well tolerated in patients with castration resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223. METHODS: In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT00699751. FINDINGS: Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio [HR] 0.70, 95% CI 0.56-0.88; p=0.002; no previous docetaxel use, HR 0.69, 0.52-0.92; p=0.01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium 223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3-4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3-4 thrombocytopenia with radium-223 than with placebo (31 [9%] of 347 patients vs five [3%] of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven [3%] of 253 patients vs one [1%] of 130 patients). The incidences of grade 3-4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups. INTERPRETATION: Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. FUNDING: Algeta ASA and Bayer HealthCare Pharmaceuticals. PMID- 25439693 TI - Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. AB - BACKGROUND: The CLASSIC trial was done to compare adjuvant capecitabine plus oxaliplatin versus observation after D2 gastrectomy for patients with stage II or III gastric cancer. The planned interim analysis of CLASSIC (median follow-up 34 months) showed that adjuvant capecitabine plus oxaliplatin significantly improved disease-free survival, the primary endpoint, compared with observation after D2 gastrectomy. We report the 5-year follow-up data from the trial. METHODS: CLASSIC was a phase 3, randomised, open-label study done at 35 cancer centres, medical centres, and hospitals in China, South Korea, and Taiwan. Patients with stage II IIIB gastric cancer who underwent curative D2 gastrectomy were randomly assigned (1:1) after surgery to receive adjuvant chemotherapy with capecitabine and oxaliplatin (eight 3-week cycles of oral capecitabine 1000 mg/m(2) twice daily on days 1-14 plus intravenous oxaliplatin 130 mg/m(2) on day 1) for 6 months or observation alone. Randomisation was stratified by country and disease stage with a permuted block (size four) design. Neither patients nor investigators were masked to treatment assignment. The primary outcome was 3-year disease-free survival in the intention-to-treat population. This analysis presents the final preplanned assessment of outcomes after 5 years. The study is registered with ClinicalTrials.gov, NCT00411229. FINDINGS: We enrolled 1035 patients: 520 were randomly assigned to adjuvant capecitabine and oxaliplatin, and 515 to observation. Median follow-up for this analysis in the intention-to-treat population was 62.4 months (IQR 54-70). 139 (27%) patients had disease-free survival events in the adjuvant capecitabine and oxaliplatin group versus 203 (39%) patients in the observation group (stratified hazard ratio [HR] 0.58, 95% CI 0.47-0.72; p<0.0001). Estimated 5-year disease-free survival was 68% (95% CI 63-73) in the adjuvant capecitabine and oxaliplatin group versus 53% (47-58) in the observation alone group. By the clinical cutoff date, 103 patients (20%) had died in the adjuvant capecitabine and oxaliplatin group versus 141 patients (27%) in the observation group (stratified HR 0.66, 95% CI 0.51-0.85; p=0.0015). Estimated 5-year overall survival was 78% (95% CI 74-82) in the adjuvant capecitabine and oxaliplatin group versus 69% (64-73) in the observation group. Adverse event data were not collected after the primary analysis. INTERPRETATION: Adjuvant treatment with capecitabine plus oxaliplatin after D2 gastrectomy should be considered for patients with operable stage II or III gastric cancer. FUNDING: F Hoffmann La-Roche and Sanofi. PMID- 25439695 TI - NHS privatisation: a step too far. PMID- 25439697 TI - Local treatments for metastases of renal cell carcinoma: a systematic review. AB - Local treatment of metastases such as metastasectomy or radiotherapy remains controversial in the treatment of metastatic renal cell carcinoma. To investigate the benefits and harms of various local treatments, we did a systematic review of all types of comparative studies on local treatment of metastases from renal cell carcinoma in any organ. Interventions included metastasectomy, radiotherapy modalities, and no local treatment. The results suggest that patients treated with complete metastasectomy have better survival and symptom control (including pain relief in bone metastases) than those treated with either incomplete or no metastasectomy. Nevertheless, the available evidence was marred by high risks of bias and confounding across all studies. Although the findings presented here should be interpreted with caution, they and the identified gaps in knowledge should provide guidance for clinicians and researchers, and directions for further research. PMID- 25439696 TI - International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. AB - This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any differences in outcome that might occur as a result of the new disease definition. PMID- 25439698 TI - Effect of HIV infection on the outcome of cancer therapy in children. AB - SUMMARY: Systematic studies comparing the outcomes of cancer treatment between children with and without HIV are scarce. The literature seems to suggest that, even with present therapeutic advances, prognosis is poor with HIV infection. The aim of this Review was to assess scientific publications from 1990 to present, addressing the difficulties associated with treatment of cancer in children with AIDS and the adaptive changes in therapy. Although much progress has been achieved, further research is needed about antiretroviral and cytotoxic drug interactions, the optimum use of supportive therapy including stem cells and bone marrow transplant, the timing of the initiation of highly active antiretroviral therapy, and the optimum use of protease inhibitors. PMID- 25439704 TI - Hearing loss in a pediatric patient following cisplatin chemotherapy and subsequent exposure to excessive noise. AB - Cisplatin is a commonly-used chemotherapeutic agent that is highly-effective against a variety of pediatric cancers. Unfortunately, it may lead to ototoxicity, with serious consequences on the quality of life of survivors. Patients remain at risk of progression of ototoxicity even after completion of treatment. We report the case of a medulloblastoma survivor with previously documented normal hearing, who developed significant hearing loss and tinnitus following exposure to excessive noise at a nightclub three years after completion of treatment. We highlight the importance of long-term audiological follow up and education about the increased risk of hearing loss in this population. PMID- 25439699 TI - The biological and clinical effects of smoking by patients with cancer and strategies to implement evidence-based tobacco cessation support. AB - Tobacco use is an established risk factor for the development of several cancers; however, far less work has been done to understand the effects of continued smoking on cancer treatment outcomes, and structured tobacco cessation efforts are not well incorporated into the standard care for patients with cancer. In this Review we discuss the known biological effects of smoking on cancer cell biology and emphasise the clinical effects of continued smoking in patients with cancer treated with chemotherapy or radiotherapy. Although evidence supports the need for inclusion of dedicated tobacco cessation efforts for patients with cancer, clinicians should consider the methods used to provide evidence-based tobacco cessation support and the available resources to deliver and maintain consistent tobacco cessation support. We also address the variables to consider in the design and implementation of a sustainable tobacco cessation programme. PMID- 25439705 TI - European Oncology Nursing Society (EONS) at 30: much has been achieved, but there is still more to do. PMID- 25439706 TI - Clavicle length, throwing performance and the reconstruction of the Homo erectus shoulder. AB - Powerful, accurate throwing may have been an important mode of early hunting and defense. Previous work has shown that throwing performance is functionally linked to several anatomical shifts in the upper body that occurred during human evolution. The final shift to occur is the inferior reorientation of the shoulder. Fossil scapulae show the earliest evidence of a more inferior glenoid in Homo erectus. However, where the scapula rests on the thorax is uncertain. The relative length of the clavicle, the only skeletal attachment of the scapula to the torso, is quite variable. Depending on which fossils or skeletal measures are used to reconstruct the H. erectus shoulder, either a novel, anteriorly facing shoulder configuration or a modern human-like lateral orientation is possible. These competing hypotheses have led to very different conclusions regarding the throwing ability and hunting behavior of early Homo. Here, we evaluate competing models of H. erectus shoulder morphology and examine how these models relate to throwing performance. To address these questions, we collected skeletal measures from fossil and extant taxa, as well as anthropometric (N = 36) and kinematic (N = 27) data from Daasanach throwers from northwestern Kenya. Our data show that all H. erectus fossil clavicles fall within the normal range of modern human variation. We find that a commonly used metric for normalizing clavicle length, the claviculohumeral ratio, poorly predicts shoulder position on the torso. Furthermore, no significant relationship between clavicle length and any measure of throwing performance was found. These data support reconstructing the H. erectus shoulder as modern human-like, with a laterally facing glenoid, and suggest that the capacity for high speed throwing dates back nearly two million years. PMID- 25439707 TI - Food material properties and early hominin processing techniques. AB - Although early Homo is hypothesized to have used tools more than australopiths to process foods prior to consumption, it is unknown how much the food processing techniques they used altered the material properties of foods, and therefore the masticatory forces they generated, and how well they were able to comminute foods. This study presents experimental data on changes to food material properties caused by mechanical tenderization (pounding with a stone tool) and cooking (dry roasting) of two foods likely to have been important components of the hominin diet: meat and tubers. Mechanical tenderization significantly decreased tuber toughness by 42%, but had no effect on meat toughness. Roasting significantly decreased several material properties of tubers correlated with masticatory effort including toughness (49%), fracture stress (28%) and elastic modulus (45%), but increased the toughness (77%), fracture stress (50%-222%), and elastic modulus of muscle fibers in meat (308%). Despite increasing many material properties of meat associated with higher masticatory forces, roasting also decreased measured energy loss by 28%, which likely makes it easier to chew. These results suggest that the use of food processing techniques by early Homo probably differed for meat and tubers, but together would have reduced masticatory effort, helping to relax selection to maintain large, robust faces and large, thickly enameled teeth. PMID- 25439708 TI - Neandertal growth: what are the costs? AB - Energetic approaches have been increasingly used to address key issues in Neandertal palaeoecology and palaeobiology. Previous research has focused exclusively on the energy requirements of adults and highlights the high energy demands of these individuals compared with modern humans. Less attention has been paid to the energy requirements of sub-adult Neandertals, even though this age group could provide clues for a better understanding of Neandertal life history. Accordingly, herein, we estimate the energy costs of maintenance and growth in Neandertal infants and children from one to six years of age and compare these costs with values for modern humans. Statural growth models for two modern human populations (Beasain and Evenki) and an average Neandertal model population are used to establish weight growth models. In turn, these models of body weight growth are used to estimate key components of energetic variables (basal metabolic rate, total energy expenditure, energy of growth and daily energy requirements). Between three and six years of age, Neandertal children have slightly lower basal and growth energy costs than do modern humans of the same age, due primarily to their smaller body mass and slower growth rates. The reduction in energy allocated to growth is likely the result of metabolic adaptations to other somatic factors and thermal stress. Data from contemporary human infants and children suggest that even mild cold stress increases non shivering thermogenesis, thus elevating metabolic needs by 50% or more. These results suggest that thermal stress likely played a strong role in shaping the delayed developmental patterns and lower energy allocated to growth during early life in Neandertals relative to Homo sapiens. PMID- 25439709 TI - The PACT trial: PAtient Centered Telerehabilitation: effectiveness of software supported and traditional mirror therapy in patients with phantom limb pain following lower limb amputation: protocol of a multicentre randomised controlled trial. AB - INTRODUCTION: Non-pharmacological interventions such as mirror therapy are gaining increased recognition in the treatment of phantom limb pain; however, the evidence in people with phantom limb pain is still weak. In addition, compliance to self-delivered exercises is generally low. The aim of this randomised controlled study is to investigate the effectiveness of mirror therapy supported by telerehabilitation on the intensity, duration and frequency of phantom limb pain and limitations in daily activities compared to traditional mirror therapy and care as usual in people following lower limb amputation. METHOD: A three-arm multi-centre randomised controlled trial will be performed. Participants will be randomly assigned to care as usual, traditional mirror therapy or mirror therapy supported by telerehabilitation. During the first 4 weeks, at least 10 individual sessions will take place in every group. After the first 4 weeks, participants will be encouraged to perform self-delivered exercises over a period of 6 weeks. Outcomes will be assessed at 4 and 10 weeks after baseline and at 6 months follow up. The primary outcome measure is the average intensity of phantom limb pain during the last week. Secondary outcome measures include the different dimensions of phantom limb pain, pain-related limitations in daily activities, global perceived effect, pain-specific self-efficacy, and quality of life. DISCUSSION: Several questions concerning the study design that emerged during the preparation of this trial will be discussed. This will include how these questions were addressed and arguments for the choices that were made. PMID- 25439711 TI - PREvention STudy On preventing or reducing disability from musculoskeletal complaints in music school students (PRESTO): protocol of a randomised controlled trial. AB - INTRODUCTION: Up to 87% of professional musicians develop work-related complaints of the musculoskeletal system during their careers. Music school students are at specific risk for developing musculoskeletal complaints and disabilities. This study aims to evaluate the effectiveness of a biopsychosocial prevention program to prevent or reduce disabilities from playing-related musculoskeletal disorders. Secondary objectives are evaluation of cost-effectiveness and feasibility. METHODS: Healthy, first or second year students (n=150) will be asked to participate in a multicentre, single-blinded, parallel-group randomised controlled trial. Students randomised to the intervention group (n=75) will participate in a biopsychosocial prevention program that addresses playing related health problems and provides postural training according to the Mensendieck or Cesar methods of postural exercise therapy, while incorporating aspects from behavioural change theories. A control group (n=75) will participate in a program that stimulates a healthy physical activity level using a pedometer, which conforms to international recommendations. No long-term effects are expected from this control intervention. Total follow-up duration is two years. The primary outcome measure is disability (Disabilities of Arm, Shoulder and Hand questionnaire). The secondary outcome measures are pain, quality of life and changes in health behaviour. Multilevel mixed-effect logistic or linear regression analyses will be performed to analyse the effects of the program on the aforementioned outcome measurements. Furthermore, cost-effectiveness, cost utility and feasibility will be analysed. DISCUSSION: It is believed that this is the first comprehensive randomised controlled trial on the effect and rationale of a biopsychosocial prevention program for music students. PMID- 25439713 TI - Effect of Schroth exercises on curve characteristics and clinical outcomes in adolescent idiopathic scoliosis: protocol for a multicentre randomised controlled trial. AB - INTRODUCTION: The promising results of Schroth scoliosis-specific exercises for adolescent idiopathic scoliosis found in low-quality studies will be strengthened by confirmation in a randomised controlled trial. RESEARCH QUESTIONS: 1. Are Schroth exercises combined with standard care for 6 months more effective than standard care alone in improving radiographic and clinical outcomes for adolescents with idiopathic scoliosis? 2. Will the outcomes of the control group (who will be offered Schroth therapy delayed by 6 months) improve after 6 months of Schroth therapy? 3. Are the effects maintained 6 months after discontinuing the supervised intervention? DESIGN: This is an assessor-blinded and statistician blinded randomised controlled trial with transfer of the controls to the exercise group after 6 months. PARTICIPANTS AND SETTING: Two hundred and fifty-eight consecutive adolescents with idiopathic scoliosis, aged 10 to 16 years, treated with or without a brace, with curves between 10 and 45 deg Cobb and Risser sign <= 3 will be recruited from three scoliosis clinics. INTERVENTION: Combined with standard care, the Schroth group will receive five individual training sessions, followed by weekly group classes and daily home exercises for 6 months. CONTROL: Controls will only receive standard care consisting of observation or bracing, and will be offered Schroth therapy 6 months later. MEASUREMENTS: Curve severity (Cobb angle) and vertebral rotation will be assessed from radiographs at baseline, 6 and 12 months. Secondary clinical outcomes (back muscle endurance, surface topography measures of posture, and self-reported perceived spinal appearance and quality of life) will be assessed at baseline, and every 3 months until 1-year follow-up. ANALYSIS: Data will be analysed using intention-to-treat linear mixed models. DISCUSSION: The results will demonstrate whether Schroth exercises combined with standard of care can improve outcomes in adolescents with idiopathic scoliosis. This study has potential to influence clinical practice worldwide, where exercises are not routinely prescribed for adolescents with idiopathic scoliosis. PMID- 25439716 TI - A caregiver-mediated home-based intervention improves physical functioning and social participation in people with chronic stroke. PMID- 25439717 TI - Exercise classes supervised by a physiotherapist may be better at restoring function after frozen shoulder than individual physiotherapy. PMID- 25439719 TI - Multimodal physiotherapy may be no better than sham treatment for people with hip osteoarthritis. PMID- 25439722 TI - Cross-tissue and tissue-specific eQTLs: partitioning the heritability of a complex trait. AB - Top signals from genome-wide association studies (GWASs) of type 2 diabetes (T2D) are enriched with expression quantitative trait loci (eQTLs) identified in skeletal muscle and adipose tissue. We therefore hypothesized that such eQTLs might account for a disproportionate share of the heritability estimated from all SNPs interrogated through GWASs. To test this hypothesis, we applied linear mixed models to the Wellcome Trust Case Control Consortium (WTCCC) T2D data set and to data sets representing Mexican Americans from Starr County, TX, and Mexicans from Mexico City. We estimated the proportion of phenotypic variance attributable to the additive effect of all variants interrogated in these GWASs, as well as a much smaller set of variants identified as eQTLs in human adipose tissue, skeletal muscle, and lymphoblastoid cell lines. The narrow-sense heritability explained by all interrogated SNPs in each of these data sets was substantially greater than the heritability accounted for by genome-wide-significant SNPs (~10%); GWAS SNPs explained over 50% of phenotypic variance in the WTCCC, Starr County, and Mexico City data sets. The estimate of heritability attributable to cross-tissue eQTLs was greater in the WTCCC data set and among lean Hispanics, whereas adipose eQTLs significantly explained heritability among Hispanics with a body mass index >= 30. These results support an important role for regulatory variants in the genetic component of T2D susceptibility, particularly for eQTLs that elicit effects across insulin-responsive peripheral tissues. PMID- 25439724 TI - PRIMUS: rapid reconstruction of pedigrees from genome-wide estimates of identity by descent. AB - Understanding and correctly utilizing relatedness among samples is essential for genetic analysis; however, managing sample records and pedigrees can often be error prone and incomplete. Data sets ascertained by random sampling often harbor cryptic relatedness that can be leveraged in genetic analyses for maximizing power. We have developed a method that uses genome-wide estimates of pairwise identity by descent to identify families and quickly reconstruct and score all possible pedigrees that fit the genetic data by using up to third-degree relatives, and we have included it in the software package PRIMUS (Pedigree Reconstruction and Identification of the Maximally Unrelated Set). Here, we validate its performance on simulated, clinical, and HapMap pedigrees. Among these samples, we demonstrate that PRIMUS can verify reported pedigree structures and identify cryptic relationships. Finally, we show that PRIMUS reconstructed pedigrees, all of which were previously unknown, for 203 families from a cohort collected in Starr County, TX (1,890 samples). PMID- 25439725 TI - Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes. AB - The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly. We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO. PMID- 25439726 TI - Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. AB - Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-MU-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels. PMID- 25439727 TI - A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency. AB - Rhizomelic chondrodysplasia punctata (RCDP) is a group of disorders with overlapping clinical features including rhizomelia, chondrodysplasia punctata, coronal clefts, cervical dysplasia, congenital cataracts, profound postnatal growth retardation, severe intellectual disability, and seizures. Mutations in PEX7, GNPAT, and AGPS, all involved in the plasmalogen-biosynthesis pathway, have been described in individuals with RCDP. Here, we report the identification of mutations in another gene in plasmalogen biosynthesis, fatty acyl-CoA reductase 1 (FAR1), in two families affected by severe intellectual disability, early-onset epilepsy, microcephaly, congenital cataracts, growth retardation, and spasticity. Exome analyses revealed a homozygous in-frame indel mutation (c.495_507delinsT [p.Glu165_Pro169delinsAsp]) in two siblings from a consanguineous family and compound-heterozygous mutations (c.[787C>T];[1094A>G], p.[Arg263(*)];[Asp365Gly]) in a third unrelated individual. FAR1 reduces fatty acids to their respective fatty alcohols for the plasmalogen-biosynthesis pathway. To assess the pathogenicity of the identified mutations, we transfected human embryonic kidney 293 cells with plasmids encoding FAR1 with either wild-type or mutated constructs and extracted the lipids from the cells. We screened the lipids with gas chromatography and mass spectrometry and found that all three mutations abolished the reductase activity of FAR1, given that no fatty alcohols could be detected. We also observed reduced plasmalogens in red blood cells in one individual to a range similar to that seen in individuals with RCDP, further supporting abolished FAR1 activity. We thus expand the spectrum of clinical features associated with defects in plasmalogen biosynthesis to include FAR1 deficiency as a cause of syndromic severe intellectual disability with cataracts, epilepsy, and growth retardation but without rhizomelia. PMID- 25439729 TI - Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome. AB - Filippi syndrome is a rare, presumably autosomal-recessive disorder characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi. Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities. We performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two affected children and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfs(*)6), in CKAP2L, encoding the protein cytoskeleton-associated protein 2-like (CKAP2L). The function of this protein was unknown until it was rediscovered in mice as Radmis (radial fiber and mitotic spindle) and shown to play a pivotal role in cell division of neural progenitors. Sanger sequencing of CKAP2L in a further eight unrelated individuals with clinical features consistent with Filippi syndrome revealed biallelic mutations in four subjects. In contrast to wild-type lymphoblastoid cell lines (LCLs), dividing LCLs established from the individuals homozygous for the c.571dupA mutation did not show CKAP2L at the spindle poles. Furthermore, in cells from the affected individuals, we observed an increase in the number of disorganized spindle microtubules owing to multipolar configurations and defects in chromosome segregation. The observed cellular phenotypes are in keeping with data from in vitro and in vivo knockdown studies performed in human cells and mice, respectively. Our findings show that loss-of-function mutations in CKAP2L are a major cause of Filippi syndrome. PMID- 25439730 TI - Evaluation of specific humoral and cellular immune responses against the major capsid L1 protein of cutaneous wart-associated alpha-Papillomaviruses in solid organ transplant recipients. AB - BACKGROUND: Infection with different species of cutaneous human papillomaviruses (cHPV) of genus alpha (calphaHPVs) and associated skin disease are highly prevalent in solid organ transplant recipients (OTR), documenting the importance of the immunological control of HPV infection. OBJECTIVES: To investigate the natural course of calphaHPV-specific cellular and humoral immune responses during systemic long-term immunosuppression. METHODS: Integrating bead-based multiplex serology and flow cytometry we analyzed natural calphaHPV-specific antibodies and T(H) cell responses against the major capsid protein L1 of HPV types 2, 27, 57 (species 4) and 3, 10 and 77 (species 2) in sera and blood of OTR before and after initiation of iatrogenic immunosuppression and in comparison to immunocompetent individuals (IC). RESULTS: Among OTR we observed an overall 42% decrease in humoral L1-specific immune responses during the course of iatrogenic immunosuppression, comparing median values 30 d before and 30 d after initiation of immunosuppressive therapy (p < 0.05). This difference disappeared after long term (>1 year) immunosuppression. The predominant cellular L1-specific immune response was of type T(H)1 (CD4(+)CD40L(+)IL-2(+)IFN-gamma(+)). Consistent with the detected L1-specific antibody titers, L1-specific T(H)1 responses were unchanged in long-term immunosuppressed OTR compared to IC. Notably, calphaHPV-L1 specific IL-2(+)/CD40L(+)CD4(+) or IFN-gamma(+)/CD40L(+) CD4(+) T(H) cell responses against any of the calphaHPV-L1 types were significantly higher in OTR with clinically apparent common warts. CONCLUSION: The systemic humoral immune response against calphaHPV may reflect the individual degree of iatrogenic immunosuppression indicating a higher susceptibility for calphaHPV infection among OTR during the early phase after organ transplantation. Humoral calphaHPV specific immune responses may show a reconstitution to pre-transplantation levels despite continuous potent immunosuppression. PMID- 25439728 TI - Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome. AB - Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum. PMID- 25439732 TI - Hypoxia and hypoxia-inducible factors in myeloid cell-driven host defense and tissue homeostasis. AB - The impact of tissue oxygenation and hypoxia on immune cells has been recognized as a major determinant of host defense and tissue homeostasis. In this review, we will summarize the available data on tissue oxygenation in inflamed and infected tissue and the effect of low tissue oxygenation on myeloid cell function. Furthermore, we will highlight effects of the master regulators of the cellular hypoxic response, hypoxia-inducible transcription factors (HIF), in myeloid cells in antimicrobial defense and tissue homeostasis. PMID- 25439731 TI - Sorption-desorption of carbamazepine by palygorskite-montmorillonite (PM) filter medium. AB - Palygorskite-montmorillonite (PM) was studied as a potential sewage treatment effluent filter material for carbamazepine. Batch sorption experiments were conducted as a function of granule size (0.3-0.6, 1.7-2.0 and 2.8mm) and different sewage effluent conditions (pH, ionic strength and temperature). Results showed PM had a mix of fibrous and plate-like morphologies. Sorption and desorption isotherms were fitted to the Freundlich model. Sorption is granule size-dependent and the medium granule size would be an appropriate size for optimizing both flow and carbamazepine retention. Highest and lowest sorption capacities corresponded to the smallest and the largest granule sizes, respectively. The lowest and the highest equilibrium aqueous (Ce) and sorbed (qe) carbamazepine concentrations were 0.4 mg L(-1) and 4.5 mg L(-1), and 0.6 mg kg( 1) and 411.8 mg kg(-1), respectively. Observed higher relative sorption at elevated concentrations with a Freundlich exponent greater than one, indicated cooperative sorption. The sorption-desorption hysteresis (isotherm non singularity) indicated irreversible sorption. Higher sorption observed at higher rather than at lower ionic strength conditions is likely due to a salting-out effect. Negative free energy and the inverse sorption capacity-temperature relationship indicated the carbamazepine sorption process was favorable or spontaneous. Solution pH had little effect on sorption. PMID- 25439723 TI - Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. AB - Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (hg(2)) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of hg(2) from imputed SNPs (5.1* enrichment; p = 3.7 * 10(-17)) and 38% (SE = 4%) of hg(2) from genotyped SNPs (1.6* enrichment, p = 1.0 * 10(-4)). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of hg(2) despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease. PMID- 25439733 TI - A diagnostic meta-analysis of the Patient Health Questionnaire-9 (PHQ-9) algorithm scoring method as a screen for depression. AB - BACKGROUND: The depression module of the Patient Health Questionnaire-9 (PHQ-9) is a widely used depression screening instrument in nonpsychiatric settings. The PHQ-9 can be scored using different methods, including an algorithm based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and a cut-off based on summed-item scores. The algorithm was the originally proposed scoring method to screen for depression. We summarized the diagnostic test accuracy of the PHQ-9 using the algorithm scoring method across a range of validation studies and compared the diagnostic properties of the PHQ-9 using the algorithm and summed scoring method at the proposed cut-off point of 10. METHODS: We performed a systematic review of diagnostic accuracy studies of the PHQ-9 using the algorithm scoring method to detect major depressive disorder (MDD). We used meta-analytic methods to calculate summary sensitivity, specificity, likelihood ratios and diagnostic odds ratios for diagnosing MDD of the PHQ-9 using algorithm scoring method. In studies that reported both scoring methods (algorithm and summed-item scoring at proposed cut-off point of >=10), we compared the diagnostic properties of the PHQ-9 using these methods. RESULTS: We found 27 validation studies that validated the algorithm scoring method of the PHQ-9 in various settings. There was substantial heterogeneity across studies, which makes the pooled results difficult to interpret. In general, sensitivity was low whereas specificity was good. Thirteen studies reported the diagnostic properties of the PHQ-9 for both scoring methods. Pooled sensitivity for algorithm scoring method was lower while specificities were good for both scoring methods. Heterogeneity was consistently high; therefore, caution should be used when interpreting these results. INTERPRETATION: This review shows that, if the algorithm scoring method is used, the PHQ-9 has a low sensitivity for detecting MDD. This could be due to the rating scale categories of the measure, higher specificity or other factors that warrant further research. The summed-item score method at proposed cut-off point of >=10 has better diagnostic performance for screening purposes or where a high sensitivity is needed. PMID- 25439734 TI - Novel ecosystems: concept or inconvenient reality? A response to Murcia et al. PMID- 25439735 TI - Developing effective tools for conservation behaviorists: reply to Greggor et al. PMID- 25439736 TI - Restriction of replication fork regression activities by a conserved SMC complex. AB - Conserved, multitasking DNA helicases mediate diverse DNA transactions and are relevant for human disease pathogenesis. These helicases and their regulation help maintain genome stability during DNA replication and repair. We show that the structural maintenance of chromosome complex Smc5-Smc6 restrains the replication fork regression activity of Mph1 helicase, but not its D loop disruptive activity. This regulatory mechanism enables flexibility in replication fork repair without interfering with DNA break repair. In vitro studies find that Smc5-Smc6 binds to a Mph1 region required for efficient fork regression, preventing assembly of Mph1 oligomers at the junction of DNA forks. In vivo impairment of this regulatory mechanism compensates for the inactivation of another fork regression helicase and increases reliance on joint DNA structure removal or avoidance. Our findings provide molecular insights into replication fork repair regulation and uncover a role of Smc5-Smc6 in directing Mph1 activity toward a specific biochemical outcome. PMID- 25439738 TI - Charcot-Marie-Tooth: are you testing for proteinuria? AB - Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of inherited disorders affecting motor and sensory nerves of the peripheral nervous system. CMT has been reported to be associated with renal diseases, mostly focal segmental glomerulosclerosis (FSGS). However, it was unknown whether these two clinical manifestations represent one common underlying disorder or separate disease entities. Several reports have shown a high prevalence of mutations (75%) in the inverted formin gene (INF2) in patients with CMT associated glomerulopathy, suggesting that these mutations are a common cause of the dual phenotype. For this reason, we strongly suggest to screen for proteinuria in CMT patients, in order to identify patients with this renal neurologic phenotype in an early stage, and to perform genetic testing for INF2 mutations. PMID- 25439737 TI - Rett-like onset in late-infantile neuronal ceroid lipofuscinosis (CLN7) caused by compound heterozygous mutation in the MFSD8 gene and review of the literature data on clinical onset signs. AB - BACKGROUND: We present clinical and molecular findings of a patient with ceroid lipofuscinosis CLN7, with a compound heterozygous mutation of the MFSD8 gene, with Rett syndrome clinical signs onset and a later development of full picture of vLINCL. CASE PRESENTATION: A 7 years-old female patient with normal development until the age 12 months, developed Rett like clinical picture (psychomotor regression, microcephaly, stereotypic hands movements in the midline, hyperventilation episodes) present at the onset of her condition (age 18 months), features still present at the initial evaluation in our clinic at age 5 years. RESULTS: MECP2 (methyl CpG binding protein 2) gene mutation was negative. At age 6 years she was readmitted for severe ataxia and blindness, seizures, and severe developmental regression leading to NCL (neuronal ceroid lipofuscinosis) suspicion. EEG showed slow background with IRDA (intermittent rhythmic delta activity). A conjunctive biopsy showed abnormal curvilinear and fingerprint lysosomal deposits, and genetic analysis revealed two heterozygous mutations of MFSD8 gene (c.881C > A p.Thr294Lys and c.754 + 2T > A) each inherited from carrier parents and a heterozygous variant (c.470A>C p.Asp157Ala) of CLN5 gene. CONCLUSION: NCL should be suspected and MFSD8 genetic testing should also be considered in patients with Rett like phenotype at onset and negative MECP2 mutation. Such cases should be carefully and frequently re-evaluated in order to avoid delayed diagnosis and offer proper genetic advice to the family. In our knowledge, this might be the first case of CLN7 disease with Rett like onset described in the literature, which developed typical vLINCL clinical phenotype after age 5.5 years. A short review of the literature showing NCL onset modalities is presented. PMID- 25439739 TI - Unusual developmental pattern of brain lateralization in young boys with autism spectrum disorder: Power analysis with child-sized magnetoencephalography. AB - AIMS: Autism spectrum disorder (ASD) is often described as comprising an unusual brain growth pattern and aberrant brain lateralization. Although it is important to study the pathophysiology of the developing ASD cortex, examples of physiological brain lateralization in young children with ASD have yet to be well examined. METHODS: Thirty-eight boys with ASD (aged 3-7 years) and 38 typically developing (TD) boys (aged 3-8 years) concentrated on video programs and their brain activities were measured non-invasively. We employed a customized child sized magnetoencephalography system in which the sensors were located as close to the brain as possible for optimal recording in young children. To produce a credible laterality index of the brain oscillations, we defined two clusters of sensors corresponding to the right and left hemispheres. We focused on the laterality index ([left - right]/[left+right]) of the relative power band in seven frequency bands. RESULTS: The TD group displayed significantly rightward lateralized brain oscillations in the theta-1 frequency bands compared to the ASD group. CONCLUSIONS: This is the first study to demonstrate unusual brain lateralization of brain oscillations measured by magnetoencephalography in young children with ASD. PMID- 25439741 TI - Genetic alterations in renal cell carcinoma with rhabdoid differentiation. AB - Renal cell carcinoma with rhabdoid differentiation (RCC-R) in adult patients is an aggressive variant of renal cancer with no known specific genetic alterations. The aim of this study was to characterize genome-wide genetic aberrations in RCC R via utilization of high-density single-nucleotide polymorphism (SNP) arrays. We identified 20 cases of RCC-R, which displayed both clear cell renal cell carcinoma and rhabdoid histomorphologic components. DNA was extracted from formalin-fixed, paraffin-embedded tissue (from clear cell renal cell carcinoma and RCC-R areas from each case) and subjected to high-density SNP array assay. Genetic aberrations present in 10% of cases were considered significant. In areas with clear cell histomorphology, gains were most commonly observed in chromosomes 5q (66.7%, 10/15), 7 (46.7%, 7/15), and 8q (46.7%, 7/15); and losses were most commonly identified in chromosomes 14 (60%, 9/15), 8p (46.7%, 7/15), and 22 (46.7%, 7/15). In areas with rhabdoid differentiation, gains were most commonly observed in chromosome 7 (58.8%, 10/17); and losses were most commonly identified in chromosomes 9 (70.6%, 12/17), 14 (58.8%, 10/17), 4 (52.9%, 9/17), and 17p (52.9%, 9/17). Rhabdoid cells shared many chromosomal abnormalities and exhibited a greater number of copy number variations in comparison with coexisting clear cells. Loss of 11p was specific for rhabdoid differentiation, with loss found in 29.4% of rhabdoid components compared with 0% of clear cell areas. The greater number of overall genetic alterations in the rhabdoid cells and the shared genetic background between rhabdoid and clear cell areas suggest genetic evolution of the rhabdoid cells that correlates with histomorphologic progression. PMID- 25439742 TI - Improved repeatability of nasal potential difference with a larger surface catheter. AB - OBJECTIVE: To increase the power of nasal potential difference (NPD) as a biomarker of CFTR function, improvement of its repeatability is needed. We evaluated the improvement in repeatability resulting from measuring NPD (1) over a larger surface area and (2) at a fixed location. METHODS: To assess repeatability, NPD was measured on two occasions with a new method using a larger surface catheter at fixed locations on the nasal floor (LSC-floor(5cm) and LSC floor(3cm)) or at the most negative basal potential (LSC-floor(max)); with a sidehole catheter on the nasal floor at 5 cm) from the nasal margin (SHC floor(5cm)) or at the most negative potential (SHC-floor(max)); and with an endhole catheter below the inferior surface of the lower turbinate at the most negative potential (EHC-turb(max)). RESULTS: The within-subject standard deviation (S(w)) for repeated measurements of the total chloride response in the controls was smallest with the LSC-floor at a fixed location (LSC-floor(5cm) 3.1 mV; 95% CI 2.3-4.6 mV) and highest with the SHC-floor (SHC-floor(max) 14.6 mV; 95% CI 10.9-22.2 mV) or the EHC-turbinate (EHC-turb(max) 12.5 mV; 95% CI 10.7 23.0 mV) at the most negative basal potential. Measuring with the LSC-floor at the maximal potential increased the Sw (LSC-floor(max) 8.8 mV, 95% CI 6.0-16.1 mV, p=0.009 vs LSC-floor(5cm)), while measuring with the SHC-floor at a fixed location slightly decreased the Sw (SHC-floor(5cm) 9.8 mV, 95% CI 8.9-20.6 mV, p=0.06 vs SHC-floor(max)). In patients with cystic fibrosis, the S(w) was comparable, between 2.2 mV and 4.3 mV. Sample size calculations for trials using NPD to assess changes in ion transport showed that the number of subjects to be included could be approximately halved measuring with the larger surface catheter at a fixed location vs SHC or EHC at fixed locations. CONCLUSION: Measuring the NPD at a fixed location and over a larger surface resulted in increased repeatability and thereby also power as a biomarker of CFTR modulation. PMID- 25439740 TI - Consistent PLAG1 and HMGA2 abnormalities distinguish carcinoma ex-pleomorphic adenoma from its de novo counterparts. AB - Carcinoma ex-pleomorphic adenoma (CA ex-PA) is a malignant salivary gland tumor that arises in association with pleomorphic adenoma (PA). Both PA and CA ex-PA have a broad spectrum of histology, and distinction from their histologic mimics may be difficult based on morphology alone. PLAG1 and HMGA2 abnormalities are the most common genetic events in both PA and CA ex-PA; however, the use of PLAG1 and HMGA2 as adjunct molecular tests has not been well established. Fluorescence in situ hybridization for PLAG1 and HMGA2 was performed on 22 CA ex-PA (10 myoepithelial carcinomas [MECAs], 10 salivary duct carcinomas [SDCs], 1 carcinoma with squamoglandular features, and 1 mixed MECA-adenocarcinoma not otherwise specified), 20 de novo carcinomas (11 MECAs and 9 SDCs), 16 PAs, and 11 PA histologic mimics. All except 3 CAs ex-PA (86%) were positive for PLAG1 or HMGA2 rearrangements/amplifications. In contrast, 18 (90%) of 20 de novo carcinomas lacked abnormalities in PLAG1 or HMGA2 (P < .01). PLAG1 or HMGA2 rearrangements were identified in 6 (67%) of 9 hypocellular myxoid PAs and in 2 (29%) of 7 cellular PAs. Furthermore, all morphologic mimics of PA were negative for PLAG1 or HMGA2. PLAG1 and HMGA2 rearrangements are the most common genetic events in CA ex-PA regardless of the histologic subtype. Unlike CA ex-PA, de novo carcinomas were negative for PLAG1 and HMGA2. Interestingly, rearrangements of PLAG1/HMGA2 were identified in most hypocellular PAs but only in a small subset of cellular PAs. Fluorescence in situ hybridization for PLAG1 or HMGA2 can be used to distinguish between PA and CA ex-PA and their morphologic mimics. PMID- 25439743 TI - Ventriculo-peritoneal shunt malfunction due to complete migration and subgaleal coiling of the proximal and distal catheters. AB - Ventriculo-peritoneal (VP) shunt malfunction due to proximal and distal catheter migration has been rarely reported in the literature. Shunt migration has been proposed to occur as a result of a combination of various mechanisms, including the windlass effect, retained memory of the shunt tubing, inadequate shunt fixation, and increased intra-abdominal pressures. We describe a rare case of a 6 week-old child who presented in our department with VP shunt malfunction due to complete proximal migration and coiling of the peritoneal and ventricular VP shunt catheters within a subgaleal pocket at the left occipital area. PMID- 25439744 TI - A unilateral open door laminoplasty technique: prospective analysis of the relationship between midline extensor muscle preservation and postoperative neck pain. AB - Since laminoplasty was first introduced, several techniques have been developed to reduce postoperative neck pain and progressive kyphosis following this procedure. We describe the importance of deep muscle preservation to prevent postoperative neck pain following cervical posterior surgery, using the inter muscular plane. We performed cervical laminoplasty on 10 patients from March to July 2012. The mean follow-up duration was 14.6 (range 12-18) months, and the mean age was 58.8 (48-68) years. There were eight men and two women in the study cohort, which consisted of eight cases of cervical spondylotic myelopathy and two cases of ossification of the posterior longitudinal ligament. The Japanese Orthopaedic Association (JOA) score and neck disability index (NDI) score were assessed before and at 6 and 12 months after surgery. The numeric rating scale (NRS) for neck pain was evaluated at 1, 3, 6, and 12 months after surgery. CT scan was performed immediately after the operation, and a radiograph was performed preoperatively and during the follow-up evaluation at 1, 3, 6, and 12 months after surgery. The preoperative JOA and NDI scores improved in all patients. Although there were two patients who complained of moderate postoperative neck pain (NRS 4 and 5), their condition gradually improved. Seven patients had mild or no neck pain (below NRS 3) at the 12 month follow-up. In addition, the cervical alignment was well maintained in all but one patient. Although larger prospective cohorts, longer follow-up periods, and comparative analyses are still needed, the clinical and radiological outcomes observed in the short 12 month period in this small cohort are promising. PMID- 25439745 TI - An investigation of diffusion imaging techniques in the evaluation of spinocerebellar ataxia and multisystem atrophy. AB - Multisystem system atrophy and spinocerebellar ataxia are rare neurodegenerative ataxias that can be difficult to diagnose, with important prognostic and treatment implications. The purpose of this study is to evaluate various methods of diffusion imaging and tractography in their effectiveness at differentiating these diseases from control subjects. Our secondary aim is determining whether diffusion abnormalities correspond with clinical disease severity. Diffusion imaging and tractography were performed on five patients and seven age-matched controls. Fractional anisotropy, generalized fractional anisotropy, and apparent diffusion coefficient values and corticospinal tract volumes were measured within various diffusion and probabilistic tractography models, including standard diffusion tensor and Q-ball tractography. Standard diffusion based fractional anisotropy and apparent diffusion coefficient values were significantly altered in patients versus controls in the middle cerebellar peduncles and central pons. Tractography based fractional anisotropy and generalized fractional anisotropy values were significantly lower in patients versus controls when corticospinal tracts were drawn in a craniocaudal direction (bilaterally using Q-ball imaging, only on the right using diffusion tensor imaging). The right corticospinal tract volume was significantly smaller in patients versus controls when created using Q ball imaging in a caudocranial direction. There was no correlation between diffusion alteration and clinical symptomatology. In conclusion, various diffusion-based techniques can be effective in differentiating ataxic patients from control subjects, although the selection of diffusion algorithm and tract growth technique and direction is non-trivial. PMID- 25439746 TI - Anterior visual pathway cavernous malformations. AB - Anterior visual pathway cavernous malformations (CM) are rare diagnoses with poorly-defined natural history and management. A systematic review of all reports of anterior visual pathway CM was performed to identify all English-language articles with histopathologically-proven anterior visual pathway CM published from 1950 to December 2013. Patient demographics, presenting symptoms, CM location, treatment modality and clinical outcome were recorded and analyzed. The case of a 60-year-old woman from our institution with acute-on-chronic visual disturbance secondary to visual pathway CM is presented. Including the current patient, 70 cases of anterior visual pathway CM have been published to our knowledge. The average patient age is 34.8 +/- standard deviation of 14.2 years, with a female preponderance (n = 37, 52.9%). The majority of patients had an acute (n = 44; 62.9%; 95% confidence interval [CI] 0.51-0.73) onset of symptoms. In at least 55.6% (n = 40) of patients, the cause of visual disturbance was initially misdiagnosed. The majority (91.4%; n = 64) of patients underwent craniotomy, with complete resection and subtotal resection achieved in 53.1% (n = 34; 95%CI 0.41-0.65) and 17.2% (n = 11; 95%CI 0.10-0.28) of all surgical patients, respectively. Comparing surgically managed patients, complete resection improved visual deficits in 59.0% (n = 20; 95%CI 0.42-0.75), while subtotal resection improved visual deficits in 50.0% (n = 5; 95%CI 0.24-0.76; p = 0.62). CM is an important differential diagnosis for suprasellar lesions presenting with visual disturbance. A high index of suspicion is required in its diagnosis. Expeditious operative management is recommended to improve clinical outcomes. PMID- 25439747 TI - Stereotactic radiosurgery of meningiomas following resection: predictors of progression. AB - Residual or recurrent meningiomas after initial surgical resection are commonly treated with stereotactic radiosurgery (SRS), but progression of these tumors following radiosurgery is difficult to predict. We performed a retrospective review of 60 consecutive patients who underwent resection and subsequent Gamma Knife (Elekta AB, Stockholm, Sweden) radiosurgery for residual or recurrent meningiomas at our institution from 2001-2012. Patients were subdivided by Simpson resection grade and World Health Organization (WHO) grade. Cox multivariate regression and Kaplan-Meier analyses were performed to assess risk of tumor progression. There were 45 men (75%) and 15 women (25%) with a median age of 56.8 years (range 26.5-82 years). The median follow-up period was 34.9 months (range 6-108.4 months). Simpson grade 1-3 resection was achieved in 17 patients (28.3%) and grade 4 resection in 43 patients (71.7%). Thirty-four tumors (56.7%) were WHO grade 1, and 22 (36.7%) were WHO grade 2-3. Time from resection to SRS was significantly shorter in patients with Simpson grade 4 resection compared to grade 1-3 resection (p<0.01), but did not differ by WHO grade (p=0.17). Post-SRS complications occurred in five patients (8.3%). Overall, 19 patients (31.7%) experienced progression at a median of 15.3 months (range 1.2 61.4 months). Maximum tumor diameter >2.5 cm at the time of SRS (p=0.02) and increasing WHO grade (p<0.01) were predictive of progression in multivariate analysis. Simpson resection grade did not affect progression-free survival (p=0.90). The mortality rate over the study period was 8.3%. SRS offers effective tumor control for residual or recurrent meningiomas following resection, especially for small benign tumors. PMID- 25439748 TI - Predictors of functional outcome following treatment of posterior fossa arteriovenous malformations. AB - Posterior fossa arteriovenous malformations (AVM) present particular therapeutic challenges. Studies aimed at clarifying risk of hemorrhage focus on obliteration rates, but few have addressed functional outcomes in these patients. In this study, we aim to explore the predictors of good functional outcome for posterior fossa AVM after treatment. A retrospective review of patients diagnosed with posterior fossa AVM at our institution from 1990 to 2013 was performed, and 61 patients met the inclusion criteria. Functional outcomes were assessed using the modified Rankin Scale (mRS), and mRS ? 1 was defined as good outcome. Within our cohort, 39 patients presented with hemorrhage (64.0%). Spetzler-Martin grades were I (n = 9, 14.8%), II (n = 20, 32.8%), III (n = 22, 36.1%), IV (n = 8, 13.1%), and V (n = 2, 3.3%). Patients were treated with surgery (n = 8), radiosurgery (n = 34), embolization (n = 2) or multimodal therapies (n = 8). Nine patients did not undergo treatment. Average follow-up was 41.9 months. Obliteration of AVM was confirmed in 44.3% of patients (n = 27). Forty-three patients (70.5%) achieved good functional outcomes (mRS ? 1). The absence of pre treatment symptoms (p < 0.01) and AVM obliteration (p = 0.04) were predictive of good functional outcomes. In contrast, non-hemorrhagic presentation was not a significant predictor (p = 0.60). Asymptomatic presentation and AVM obliteration are associated with good functional outcomes in patients with posterior fossa AVM. Non-hemorrhagic presentation does not necessarily predict good functional outcome. Therefore treatment should not be considered only for those who present with hemorrhage. Posterior fossa AVM should be considered for definitive treatment in order to prevent future hemorrhages and subsequent poor functional outcomes. PMID- 25439749 TI - A novel treatment strategy for glioblastoma multiforme and glioma associated seizures: increasing glutamate uptake with PPARgamma agonists. AB - The established role of glutamate in the pathogenesis of glioma-associated seizures (GAS) led us to investigate a novel treatment method using an established drug class, peroxisome proliferator activated receptor (PPAR) gamma agonists. Previously, sulfasalazine has been shown to prevent release of glutamate from glioma cells and prevent GAS in rodent models. However, raising protein mediated glutamate transport via excitatory amino acid transporter 2 (EAAT2) has not been investigated previously to our knowledge. PPAR gamma agonists are known to upregulate functional EAAT2 expression in astrocytes and prevent excitotoxicity caused by glutamate excess. These agents are also known to have anti-neoplastic mechanisms. Herein we discuss and review the potential mechanisms of these drugs and highlight a novel potential treatment for GAS. PMID- 25439750 TI - Point of care coagulation testing in neurosurgery. AB - Impaired haemostasis represents a major risk factor for bleeding complications in neurosurgical patients. Coagulopathy commonly occurs after (brain) trauma and major haemorrhage or originates from antithrombotic medication. Point of care (POC) devices for bedside assessment of haemostatic parameters are increasingly used in various medical specialties. Results can be instantly implemented into treatment modalities as results are delivered within a very short period. POC coagulation testing has also shown beneficial effects in the treatment of neurosurgical patients. Identification of hyperfibrinolysis is achieved through viscoelastic testing of haemostasis and bedside coagulometry hastens the management of anticoagulated patients in need of urgent neurosurgical procedures. Results of POC testing of platelet function have been correlated with patient outcomes after traumatic brain injury and furthermore, quantification of antiplatelet medication effects on platelet activity is made possible through the use of these devices. Further studies are needed to characterise the potential of POC testing of platelet function. Antiplatelet medication plays an important role in regard to haemorrhagic and thromboembolic risks. Therefore, POC testing of platelet activity may improve treatment modalities in patients undergoing neurosurgical procedures as well as neurointerventional procedures (such as intracranial stent placement). In this article we summarise the available data of POC testing in neurosurgical patients and discuss the potential of these devices in this field. POC technologies have improved patient care in various medical fields and in our view it is likely that this will also apply to the field of neurosurgery. PMID- 25439751 TI - A method for complete angiographic obliteration of a brain arteriovenous malformation in a single session through a single pedicle. AB - Historically, the endovascular treatment of arteriovenous malformations (AVM) has largely been relegated to an adjunctive role to open surgical and radiosurgical methods. In this article, we describe a novel endovascular approach to the treatment of brain AVM using Onyx (ev3 Endovascular, Plymouth, MN, USA), which may allow for a complete angiographic obliteration in a single treatment session. Twelve patients underwent Onyx embolization of an AVM using a novel "reverse plug and push" technique in which a plug is formed around the treatment catheter prior to injecting Onyx into the AVM. The plug mitigates the risk of backflow and catheter entrapment, thereby allowing the user to inject higher volumes of Onyx at higher injection rates. Patient demographics, AVM characteristics, and treatment details were reviewed. Using the "reverse plug then push" technique, an average of 8.8 mL of Onyx was injected into the AVM in a single session. In every case, the microcatheter was removed easily with minimal traction pressure. Complete angiographic obliteration was achieved in 83% of patients after a single treatment. Morbidity and mortality were 8% each. The "reverse plug then push" technique allows for a more rapid injection of Onyx due to the formation of a well-controlled plug prior to treatment, mitigating the risk of catheter entrapment by Onyx reflux. With further refinement, this technique may present a viable curative option for treatment of select brain AVM. PMID- 25439752 TI - Overexpression of microRNA biogenesis machinery: Drosha, DGCR8 and Dicer in multiple sclerosis patients. AB - We aimed to evaluate the expression of the major components of microRNA biogenesis machinery including Drosha, Dicer and DiGeorge syndrome critical region gene 8 (DGCR8) in multiple sclerosis (MS) patients. The expression levels of these components in relapsing remitting multiple sclerosis (RRMS) patients were significantly up-regulated in comparison to healthy controls. DGCR8 was up regulated 4.9 times in RRMS patients versus healthy controls, and Drosha was up regulated 3.58 times. Additionally, the expression level of Dicer was 2.11 times higher in RRMS patients than the healthy controls. In conclusion, our results suggest that overexpression of Drosha, Dicer and DGCR8 may contribute to the pathogenesis of MS. Further investigation may introduce microRNA biogenesis machinery as MS markers and therapeutic targets. PMID- 25439753 TI - Comparison of the different surgical approaches for lumbar interbody fusion. AB - This review will outline the history of spinal fusion. It will compare the different approaches currently in use for interbody fusion. A comparison of the techniques, including minimally invasive surgery and graft options will be included. Lumbar interbody fusion is a commonly performed surgical procedure for a variety of spinal disorders, especially degenerative disease. Currently this procedure is performed using anterior, lateral, transforaminal and posterior approaches. Minimally invasive techniques have been increasing in popularity in recent years. A posterior approach is frequently used and has good fusion rates and low complication rates but is limited by the thecal and nerve root retraction. The transforaminal interbody fusion avoids some of these complications and is therefore preferable in some situations, especially revision surgery. An anterior approach avoids the spinal cord and cauda equina all together, but has issues with visceral exposure complications. Lateral lumbar interbody fusion has a risk of lumbar plexus injury with dissection through the psoas muscle. Studies show less intraoperative blood loss for minimally invasive techniques, but there is no long-term data. Iliac crest is the gold standard for bone graft, although adjuncts such as bone morphogenetic proteins are being used more frequently, despite their controversial history. More high-level studies are needed to make generalisations regarding the outcomes of one technique compared with another. PMID- 25439754 TI - Risk factors for postoperative cerebrospinal fluid leak and meningitis after expanded endoscopic endonasal surgery. AB - Postoperative cerebrospinal fluid (CSF) leak is a serious complication of transsphenoidal surgery, which can lead to meningitis and often requires reparative surgery. We sought to identify preoperative risk factors for CSF leaks and meningitis. We reviewed 98 consecutive expanded endoscopic endonasal surgeries performed from 2008-2012 and analyzed preoperative comorbidities, intraoperative techniques, and postoperative care. Univariate and multivariate analyses were performed. The most common pathologies addressed included pituitary adenoma, Rathke cyst, chordoma, esthesioneuroblastoma, meningioma, nasopharyngeal carcinoma, and squamous cell carcinoma. There were 11 CSF leaks (11%) and 10 central nervous system (CNS) infections (10%). Univariate and multivariate analysis of preoperative risk factors showed that patients with non-ideal body mass index (BMI) were associated with higher rate of postoperative CSF leak and meningitis (both p<0.01). Also, patients with increasing age were associated with increased CSF leak (p = 0.03) and the length of time a lumbar drain was used postoperatively was associated with infection in a univariate analysis. In addition, three of three endoscopic transsphenoidal surgeries combined with open cranial surgery had a postoperative CSF leak and CNS infection rate which was a considerably higher rate than for transsphenoidal surgeries alone or surgeries staged with open cases (p<0.01 and p=0.04, respectively) In this series of expanded endoscopic transsphenoidal surgeries, preoperative BMI remains the most important preoperative predictor for CSF leak and infection. Other risk factors include age, intraoperative CSF leak, lumbar drain duration, and cranial combined cases. Risks associated with complex surgical resections when combining open and endoscopic approaches could be minimized by staging these procedures. PMID- 25439755 TI - A male Fabry disease patient treated with intravenous thrombolysis for acute ischemic stroke. AB - The use of intravenous thrombolytic therapy for acute ischemic stroke is associated with improved outcomes. Fabry disease is an X-linked glycosphingolipid storage disease with vascular endothelial deposits. Affected males with the classic phenotype develop renal, cardiac, and cerebrovascular disease and die prematurely. However, Fabry disease is rare in young men with first ischemic stroke of undetermined cause. We report a 38-year-old man with acute aphasia and a left M2 segment of the middle cerebral artery thrombus with no recanalization who was finally diagnosed with Fabry disease after left ventricular hypertrophy of undetermined cause had been identified. A gene test revealed a R227X mutation typical of Fabry disease with the classical phenotype. To our knowledge our patient is the first reported male Fabry patient who was given intravenous thrombolytic therapy and the first reported Fabry patient who received intravenous thrombolytic therapy between 3 and 4.5 hours of the symptom onset. Despite favorable prognostic indicators on admission imaging, our patient suffered a significant stroke and had an unfavorable clinical outcome. Fortunately, the episode was not complicated by intracranial hemorrhage. Further studies are needed to evaluate the efficacy and safety of intravenous thrombolytic therapy in treating patients with Fabry disease and acute ischemic stroke. PMID- 25439756 TI - Cortical thinning in type 2 diabetes mellitus and recovering effects of insulin therapy. AB - The purpose of this study was to explore the brain structural changes in type 2 diabetes and the effect of insulin on the brain using a surface-based cortical thickness analysis. High-resolution three-dimensional T1-weighted fast spoiled gradient recalled echo MRI were obtained from 11 patients with type 2 diabetes before and after insulin therapy. The cortical thickness over the entire brain was calculated, and cross-sectional and longitudinal surface-based cortical thickness analyses were also performed. Regional cortical thinning was demonstrated in the middle temporal gyrus, posterior cingulate gyrus, precuneus, right lateral occipital gyrus and entorhinal cortex bilaterally for patients with type 2 diabetes mellitus compared with normal controls. Cortical thickening was seen in the middle temporal gyrus, entorhinal cortex and left inferior temporal gyrus bilaterally after patients underwent 1 year of insulin therapy. These findings suggest that insulin therapy may have recovering effects on the brain cortex in type 2 diabetes mellitus. The precise mechanism should be investigated further. PMID- 25439757 TI - Rapid eye movement sleep behavior disorder after bilateral subthalamic stimulation in Parkinson's disease. AB - The effect of subthalamic nucleus (STN) deep brain stimulation (DBS) on rapid eye movement sleep behavior disorder (RBD) in Parkinson's disease (PD) is not well known. We evaluated the change in the incidence of probable RBD after bilateral STN DBS in PD patients. Ninety patients with PD treated with bilateral STN DBS underwent retrospective assessment of RBD by interview before and after DBS. Forty-seven (52.2%) of the 90 patients had RBD preoperatively. RBD was resolved only in one patient and persisted in 46 patients at 1 year after DBS. RBD developed de novo in 16 patients (de novo RBD group) within 1 year after DBS, resulting in 62 (68.9%) of the 90 patients having RBD 1 year after DBS. Patients with RBD at any time within 1 year after DBS (RBD group, n = 63) were older than the patients without RBD (non-RBD group, n = 27). The sum of the Unified Parkinson Disease Rating Scale (UPDRS) axial score for the "on" state was lower in the RBD group than in the non-RBD group after DBS (p = 0.029). Comparing the de novo RBD group and non-RBD group, the UPDRS Part III and total score and the levodopa equivalent daily doses for the "on" states decreased more in the de novo RBD group than in the non-RBD group (p < 0.05). The incidence of clinical RBD increased after bilateral STN DBS because de novo RBD developed and pre-existing RBD persisted after DBS. PMID- 25439758 TI - Benefit of cerebrospinal fluid spectrophotometry in the assessment of CT scan negative suspected subarachnoid haemorrhage: a diagnostic accuracy study. AB - This study aimed to determine if performing cerebrospinal fluid spectrophotometry in addition to visual inspection detects more ruptured cerebral aneurysms than performing cerebrospinal fluid visual inspection alone in patients with a normal head CT scan but suspected of suffering an aneurysmal subarachnoid haemorrhage (SAH). We performed a single-centre retrospective study of patients presenting to the emergency department of a tertiary hospital who underwent both head CT scan and lumbar puncture to exclude SAH. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of an approach utilising both spectrophotometry and visual inspection (combined approach) was compared to visual inspection alone. A total of 409 patients (mean age 37.8 years, 56.2% female) were recruited and six (1.5%) had a cerebral aneurysm on angiography. The sensitivity of visual inspection was 50% (95% confidence interval [CI]: 12.4-82.6%), specificity was 99% (95% CI: 97.5-99.7%), PPV was 42.9% (95% CI: 10.4-81.3%) and NPV was 99.2% (95% CI: 97.8-99.8%). The combined approach had a sensitivity of 100% (95% CI: 54.1-100%), specificity of 79.7% (95% CI: 75.4-83.5%), PPV of 6.8% (95% CI: 2.6-14.3%) and a NPV of 100% (95% CI: 98.8 100%). The sensitivity of the combined approach was not significantly different to that of visual inspection alone (p=0.25). Visual inspection had a significantly higher specificity than the combined approach (p<0.01). The combined approach detected more cases of aneurysmal SAH than visual inspection alone, however the difference in sensitivity was not statistically significant. Visual xanthochromia should prompt angiography because of a superior specificity and PPV. Due to its reduced sensitivity, caution should be applied when using only visual inspection of the supernatant. PMID- 25439759 TI - A hyaluronic acid-binding contact lens with enhanced water retention. AB - PURPOSE: As a main component of an artificial tear or eyedrop, hyaluronic acid (HA) prolongs water retention, slows tear removal, improves tear film stability, reduces protein adsorption at the ocular surface and permits uninterrupted blinking. Here, we hypothesized that the contact lens modified with an HA-binding peptide (HABpep) could locally bind and concentrate exogenous HA present in eyedrops to the modified contact lens surface, which exhibited superior water retention. METHODS: To bind HA, a contact lens surface was covalently modified by HABpep with and without a poly(ethylene glycol) (PEG) spacer. Bound HA and its retention over time on the modified surfaces were evaluated by fluorescence measurements. A comparative water evaporation study was performed to determine water retention in an HA-bound contact lens. RESULTS: Fluorescence studies showed that the contact lens was successfully modified by HABpep with or without a PEG spacer, and HA bound to the contact lens surface. Furthermore, the bound HA via HABpep significantly reduced water loss from the modified contact lens. CONCLUSION: HABpep strategies that locally bind and concentrate HA to create a thin coating of a therapeutic molecule on surfaces could provide physical and biological benefits to treat ocular surface dysfunction. The surface bound HA via HABpep enhanced water retention in the modified contact lens. PMID- 25439760 TI - Comment on 'Distribution of normal superficial ocular vessels in digital images'. PMID- 25439761 TI - ACC/AHA/AACVPR/AAFP/ANA concepts for clinician-patient shared accountability in performance measures: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures. PMID- 25439762 TI - Racial and ethnic differences in the home food environment explain disparities in dietary practices of middle school children in Texas. AB - OBJECTIVE: To examine racial and ethnic differences among middle school children in the home food environment (HFE) and the extent to which associations of healthy and unhealthy eating with the HFE differ by race and ethnicity. DESIGN: Cross-sectional secondary analyses of baseline data from Coordinated Approach to Child Health Middle School, a school-based intervention targeting obesity and obesogenic behaviors among middle school children in Austin, TX. PARTICIPANTS: A total of 2,502 children (mean age, 13.9 years; 58% Hispanic, 28% white, and 14% black). VARIABLES MEASURED: Availability and accessibility of healthy foods, and parental support of healthy eating, and family meals. Consumption of both healthy and unhealthy foods was examined. ANALYSIS: Differences across racial and ethnic groups in aspects of HFE were estimated using linear regression. Models also examined racial and ethnic differences in consumption of healthy and unhealthy foods. If adjusting for HFE, such differences were accounted for. RESULTS: White children had significantly better HFEs than Hispanic and black children with greater availability and accessibility of healthy foods (P < .001). Adjusting for a healthy HFE reduced disparities in consumption of healthy foods but not in consumption of unhealthy foods. CONCLUSIONS AND IMPLICATIONS: Improved HFE may increase healthy eating among ethnic minorities but is unlikely to reduce unhealthy eating. PMID- 25439763 TI - "Adopt-a-patient" approach in nutrition assessment and counseling curriculum. PMID- 25439764 TI - A school gardening and healthy snack program increased Aboriginal First Nations children's preferences toward vegetables and fruit. AB - OBJECTIVE: The researchers evaluated the impact of a 7-month gardening and 4 month vegetable and fruit snack program on Aboriginal First Nations children's home consumption and preferences toward vegetables and fruit. METHODS: The intervention was based on the Social Cognitive Theory. Children in grades 1-6 planted and tended classroom container gardens and prepared and ate what grew. At baseline and 7 months later, children tasted and rated 17 vegetables and fruit using a Likert scale and indicated whether they ate each food at home. RESULTS: Data were collected from 76 of 116 children (65.5%). Preference scores for vegetables, fruit, and vegetables and fruit combined increased over the 7 months (P < .017). Self-reported home consumption did not change. CONCLUSIONS AND IMPLICATIONS: School interventions have the potential to increase children's preferences for vegetables and fruit. Family participation is likely required, along with increased community availability of produce, to promote home consumption. PMID- 25439765 TI - Deep Convolutional Neural Networks for large-scale speech tasks. AB - Convolutional Neural Networks (CNNs) are an alternative type of neural network that can be used to reduce spectral variations and model spectral correlations which exist in signals. Since speech signals exhibit both of these properties, we hypothesize that CNNs are a more effective model for speech compared to Deep Neural Networks (DNNs). In this paper, we explore applying CNNs to large vocabulary continuous speech recognition (LVCSR) tasks. First, we determine the appropriate architecture to make CNNs effective compared to DNNs for LVCSR tasks. Specifically, we focus on how many convolutional layers are needed, what is an appropriate number of hidden units, what is the best pooling strategy. Second, investigate how to incorporate speaker-adapted features, which cannot directly be modeled by CNNs as they do not obey locality in frequency, into the CNN framework. Third, given the importance of sequence training for speech tasks, we introduce a strategy to use ReLU+dropout during Hessian-free sequence training of CNNs. Experiments on 3 LVCSR tasks indicate that a CNN with the proposed speaker adapted and ReLU+dropout ideas allow for a 12%-14% relative improvement in WER over a strong DNN system, achieving state-of-the art results in these 3 tasks. PMID- 25439766 TI - Flow simulations and validation for the first cohort of patients undergoing the Y graft Fontan procedure. AB - OBJECTIVES: In this study, with the use of computational fluid dynamics, we evaluate the postoperative hemodynamic performance of the first cohort of patients undergoing a handcrafted Y-graft Fontan procedure and validate simulation predictions of hepatic blood flow distribution against in vivo clinical data. METHODS: An 18-12 * 2-mm handcrafted Y-graft modification of the Fontan procedure was performed in 6 patients. Early (at the time of discharge) and 6-month postoperative 3-dimensional magnetic resonance imaging data were collected. Patient-specific models were constructed for flow simulations. RESULTS: Hepatic blood flow distribution varied among patients. Lung perfusion data (n = 3) showed good agreement with simulations. Postoperative asymmetry in hepatic blood flow distribution was reduced 6 months postoperatively. In 1 patient, low wall shear stress was found in the left limb of the Y-graft, corresponding to the location of subsequent thrombosis in the patient. CONCLUSIONS: The credibility and accuracy of simulation-based predictions of postoperative hepatic flow distribution for the Fontan surgery have been validated by in vivo lung perfusion data. The performance of the Y-graft design is highly patient-specific. The anastomosis location is likely the most important factor influencing hepatic blood flow distribution. Although the development of thrombosis is multifactorial, the occurrence in 1 patient suggests that simulations should not solely consider the hepatic blood flow distribution but also aim to avoid low wall shear stress in the limbs. PMID- 25439767 TI - A study of brain protection during total arch replacement comparing antegrade cerebral perfusion versus hypothermic circulatory arrest, with or without retrograde cerebral perfusion: analysis based on the Japan Adult Cardiovascular Surgery Database. AB - OBJECTIVES: Antegrade cerebral perfusion and hypothermic circulatory arrest, with or without retrograde cerebral perfusion, are 2 major types of brain protection that are used during aortic arch surgery. We conducted a comparative study of these methods in patients undergoing total arch replacement to evaluate the clinical outcomes in Japan, based on the Japan Adult Cardiovascular Surgery Database. METHODS: A total of 16,218 patients underwent total arch replacement between 2009 and 2012. Patients with acute aortic dissection or ruptured aneurysm, or who underwent emergency surgery were excluded, leaving 8169 patients for analysis. For the brain protection method, 7038 patients had antegrade cerebral perfusion and 1141 patients had hypothermic circulatory arrest/retrograde cerebral perfusion. A nonmatched comparison was made between the 2 groups, and propensity score analysis was performed among 1141 patients. RESULTS: The matched paired analysis showed that the minimum rectal temperature was lower in the hypothermic circulatory arrest/retrograde cerebral perfusion group (21.2 degrees C +/- 3.7 degrees C vs 24.2 degrees C +/- 3.2 degrees C) and that the duration of cardiopulmonary bypass and cardiac ischemia was longer in the antegrade cerebral perfusion group. There were no significant differences between the antegrade cerebral perfusion and hypothermic circulatory arrest/retrograde cerebral perfusion groups with regard to 30-day mortality (3.2% vs 4.0%), hospital mortality (6.0% vs 7.1%), incidence of stroke (6.7% vs 8.6%), or transient neurologic disorder (4.1% vs 4.4%). There was no difference in a composite outcome of hospital death, bleeding, prolonged ventilation, need for dialysis, stroke, and infection (antegrade cerebral perfusion 28.4% vs hypothermic circulatory arrest 30.1%). However, hypothermic circulatory arrest/retrograde cerebral perfusion resulted in a significantly higher rate of prolonged stay in the intensive care unit (>8 days: 24.2% vs 15.6%). CONCLUSIONS: Hypothermic circulatory arrest/retrograde cerebral perfusion and antegrade cerebral perfusion provide comparable clinical outcomes with regard to mortality and stroke rates, but hypothermic circulatory arrest/retrograde cerebral perfusion resulted in a higher incidence of prolonged intensive care unit stay. Antegrade cerebral perfusion might be preferred as the brain protection method for complicated aortic arch procedures. PMID- 25439768 TI - Intraoperative conversion from video-assisted thoracoscopic surgery lobectomy to open thoracotomy: a study of causes and implications. AB - OBJECTIVE: To study causes and implications of intraoperative conversion to thoracotomy during video-assisted thoracoscopic surgery (VATS) lobectomy. METHODS: We performed an institutional review of patients undergoing lobectomy for known or suspected lung cancer with root cause analysis of every conversion from VATS to open thoracotomy. RESULTS: Between 2004 and 2012, 1227 patients underwent lobectomy. Of these, 517 procedures (42%) were completed via VATS, 87 procedures (7%) were converted to open procedures, and 623 procedures (51%) were performed via planned thoracotomy. Patients undergoing thoracotomy were younger and had a higher incidence of prior lung cancers. Planned thoracotomy and conversion group patients had higher clinical T stage than patients in the VATS group, whereas the planned thoracotomy group had higher pathologic stage than patients in the other groups. Postoperative complications were more frequent in patients in the conversion group (46%) than in the VATS group (23%; P < .001), but similar to the open group (42%; P = .56). Validating a previous classification of causes for conversion, 22 out of 87 conversions (25%) were due to vascular causes, 56 conversions (64%) were for anatomy (eg, adhesions or tumor size), and 8 conversions (9%) were the result of lymph nodes. No specific imaging variables predicted conversion. Within the conversion groups, emergent (20 out of 87; 23%) and planned (67 out of 87; 77%) conversion groups were similar in patient and tumor characteristics and incidence of perioperative morbidity. The conversion rate for VATS lobectomy dropped from 21 out of 74 (28%), to 29 out of 194 (15%), to 37 out of 336 (11%) (P < .001) over 3-year intervals. Over the same periods, the proportion of operations started via VATS increased significantly. CONCLUSIONS: With increasing experience, a higher proportion of lobectomy operations can be completed thoracoscopically. VATS should be strongly considered as the initial approach for the majority of patients undergoing lobectomy. PMID- 25439769 TI - Utility of mediastinoscopy in clinical stage I lung cancers at risk for occult mediastinal nodal metastases. AB - OBJECTIVE: The prevalence of mediastinal lymph node metastases is unknown for patients with clinical N0 lung cancer who are thought to be at high risk for occult nodal metastases. Further, the utility of mediastinoscopy in these patients is unknown. We performed a prospective trial to evaluate the utility of routine cervical mediastinoscopy for patients who may be at high risk of occult nodal metastases. METHODS: From January 1, 2008, July 31, 2013, 90 patients with lung cancer with clinical stage T2N0 or T1N0 with standardized uptake value greater than 10 by positron emission tomography/computed tomography underwent routine cervical mediastinoscopy before lung resection. Biopsy of a minimum of 3 nodal stations at mediastinoscopy and a minimum of 4 nodal stations with lung resection was advised. The prevalence of nodal metastases at mediastinoscopy and lung resection was recorded. RESULTS: Some 64% of patients with lung cancer were male with a mean age of 67.3 years. A total of 81 patients had clinical T2N0 and 9 patients had T1N0 with standardized uptake value greater than 10. Mean tumor size was 4.3 +/- 1.7 cm, and mean standardized uptake value was 13.5 +/- 6.8. One patient (1.1%) had occult metastases detected at mediastinoscopy. A total of 86 patients underwent surgical resection; 4 patients (4.6%) were upstaged to pN2, and 18 patients (21%) were upstaged to pN1. Of 90 patients with clinically staged N0 lung cancer by positron emission tomography/computed tomography, 5.6% (5) were upstaged to pN2 and 20% (18) were upstaged to pN1 (total nodal upstaging = 25.6%). CONCLUSIONS: Mediastinoscopy seems to have limited utility in these patients with T1 and T2 clinically staged N0 by positron emission tomography/computed tomography. Selective use of mediastinoscopy is recommended, along with thorough mediastinal lymph node evaluation in all patients at the time of lung cancer resection. PMID- 25439770 TI - Changing glucose control target and risk of surgical site infection in a Southeast Asian population. AB - OBJECTIVE: Hyperglycemia is associated with surgical site infection and mortality in cardiac surgical patients. There is overriding evidence that glycemic control improves morbidity and mortality. However, the optimal glucose range in these patients remains controversial. Intensive glucose control can lead to mortality among critically ill adults because of episodic, moderate hypoglycemia. Therefore, we examined the effect of different glucose target control on the incidence of surgical site infection in our prospective cohort of diabetic and nondiabetic patients undergoing coronary artery bypass grafting. METHODS: Data from 1442 patients who underwent elective coronary artery bypass grafting at a tertiary heart center in Singapore from 2009 to 2011 were obtained. The first glucose level on arrival in the cardiothoracic intensive care unit was set at 4 to 8 mmol/L in 2009 and 2010 and 4 to 10 mmol/L in 2011. Glucose control was achieved with intravenous insulin infusion with a strict glucose monitoring protocol. Clinical covariates were analyzed, with surgical site infection as the primary outcome. RESULTS: The majority of patients presenting for coronary artery bypass grafting were male, Chinese, and diabetic. Diabetic patients had significantly higher glucose levels on arrival in the cardiothoracic intensive care unit. The change in target glucose control was independently associated with an increase in surgical site infection (odds ratio, 2.280; 95% confidence interval, 1.250-4.162; P = .007). Subgroup analysis revealed that unlike in nondiabetic patients, a less stringent target was independently associated with a significant increase in surgical site infection incidence from 2.2% to 6.9% for the diabetic patients (odds ratio, 3.131; 95% confidence interval, 1.431-6.851; P = .004). CONCLUSIONS: A target blood glucose of less than 8 mmol/L was associated with a lower incidence of surgical site infection in diabetic patients presenting for elective coronary artery bypass grafting in the local Southeast Asian population. PMID- 25439771 TI - One-year results of thoracic endovascular aortic repair for blunt thoracic aortic injury (RESCUE trial). AB - OBJECTIVE: One-year outcomes of the RESCUE trial (endovascular aortic repair using Valiant Captivia for blunt thoracic aortic injury) are reported. METHODS: RESCUE is a prospective, nonrandomized, multicenter trial. Fifty patients with blunt thoracic aortic injury were enrolled between April 2010 and January 2012. One-year outcomes included secondary procedures, device-, procedure-, and/or aorta-related adverse events, and all-cause mortality. RESULTS: Mean patient age was 40.7 +/- 17.4 years; 76% of patients were male. Fifty-two thoracic stent grafts were implanted within a median of 1 day of injury. Seventy percent (35 of 50) of aortic injuries were grade III or higher, including 1 free rupture. The mean Injury Severity Score was 37.6 +/- 14.3. Vascular access, device delivery, and deployment were successful in all patients. The left subclavian artery was completely covered in 40% (20 of 50) and partially covered in 18% of patients (9 of 50). There were no strokes or spinal cord injuries. Median procedure time was 90.5 minutes; median hospital stay was 11 days. All-cause mortality within 1 year was 12%. There were no conversions to open repair. Four patients (8%) had subclavian artery revascularization; 1 preoperatively; 3 others postoperatively on days 8, 36, and 103. There were no device-related adverse events. During follow-up, 1 patient (2%) had aortic-related and 9 patients (18%) had procedure related adverse events. CONCLUSIONS: TEVAR has favorable early midterm outcomes in the treatment of blunt thoracic aortic injury, and remains the treatment modality of choice. Longevity of the stent grafts in this young patient population has yet to be established. PMID- 25439772 TI - Do differences in early hemodynamic performance of current generation biologic aortic valves predict outcomes 1 year following surgery? AB - OBJECTIVE: Small early postoperative hemodynamic differences were noted in a randomized comparison of 3 current-generation bioprosthetic aortic valves. Whether these differences persist and influence clinical outcomes 1 year following implantation is unknown. METHODS: Three hundred adults with severe aortic stenosis undergoing valve replacement were randomized to receive the Epic (St Jude, St Paul, Minn) (n = 99), Magna (Edwards LifeSciences Inc, Irvine, Calif) (n = 100), or Mitroflow (Sorin Biomedica Spa, Saluggio, Italy) (n = 101) bioprostheses. Hemodynamic valve performance was examined by echocardiography at 1 year, and clinical outcomes were assessed in 241 patients (79 Epic, 77 Magna, and 85 Mitroflow; P = .437). RESULTS: Mean age was 75 +/- 8 years and 164 were men (68%). Between dismissal and 1 year there were 9 deaths (3.7%) (Epic: 3.7%, Magna: 5.0%, and Mitroflow: 2.3%; P = .654), 6 episodes of heart failure (2.5%) (Epic: 1.3%, Magna: 1.3%, and Mitroflow: 5.8%; P = .265), 27 instances of atrial fibrillation/flutter (11.2%) (Epic: 8.1%, Magna: 11.0%, and Mitroflow: 7.9%; P = .577) and no strokes/transient ischemic attacks. One-year echocardiography demonstrated small hemodynamic differences between Epic, Magna, and Mitroflow bioprostheses in mean gradient (15.2 +/- 5.5, 12.3 +/- 4.3, and 16.2 +/- 5.7 mm Hg, respectively; P < .001) and indexed aortic valve area (0.93 +/- 0.28, 1.04 +/ 0.28, and 0.96 +/- -0.26 cm(2)/m(2), respectively; P = .015). Several early trends persisted when stratifying data by echocardiographic annulus diameter, universal annulus size, and implant size, particularly with annular size >=23 mm. Overall left ventricular mass index regression between dismissal and 1 year was 16.5 +/- 28.1 g/m(2), and was similar among groups (P = .262). There were no aortic valve reoperations. CONCLUSIONS: Despite midterm persistence of small hemodynamic differences amongst current-generation porcine and pericardial aortic valves, our prospective randomized comparison reveals that clinical outcomes and mass regression are equivalent between devices at 1 year. These encouraging trends must continue to be assessed during longitudinal follow-up. PMID- 25439773 TI - Long-term results of biventricular repair after initial Giessen hybrid approach for hypoplastic left heart variants. AB - OBJECTIVE: This article presents the long-term results of our patients with a diagnosis of hypoplastic left heart syndrome (HLHS), hypoplastic left heart complex (HLHC), and variants who received a biventricular repair following hybrid stage I with ductal stenting and bilateral pulmonary artery banding. METHODS: Between June 1998 and June 2013, a total of 154 patients with hypoplastic left heart structures underwent a hybrid stage I procedure. Forty patients were definitely treated by creating a biventricular circulation. Median age and body weight of patients before hybrid stage I were 8.5 days (2-40) and 3.0 kg (1.6 3.8), respectively. The diagnoses were HLHS with mitral and aortic stenosis (n = 7), HLHC (n = 15), HLHC with interrupted aortic arch (n = 9), critical aortic stenosis with hypoplastic aortic arch (n = 4), imbalanced atrioventricular septal defect with hypoplastic aortic arch (n = 2), double-outlet right ventricle with hypoplastic aortic arch (n = 2), and d-transposition of the great arteries with interrupted aortic arch (n = 1). Median age at the time of biventricular correction was 6.7 months (1.6-13.8). The patients were treated with direct biventricular correction, including repair of intracardiac defects (n = 32), Norwood/Rastelli or Yasui (n = 4), arterial switch (n = 2), Rastelli (n = 1), and Ross-Konno (n = 1) operations with ascending aortic/aortic arch reconstruction. RESULTS: All patients survived hybrid stage I. Median survival after biventricular correction is 7.9 years (0.9-14.9). Overall mortality was 10% (4 patients) at 4 weeks, 5 weeks, 6 weeks, and 4 months after biventricular correction, respectively. One patient had to be switched to univentricular circulation and another patient underwent orthotopic heart transplantation 3 and 4 months after biventricular correction, respectively. CONCLUSIONS: The Giessen hybrid approach is an alternative to the conventional strategy to treat neonates with HLHS, HLHC, and variants. Biventricular repair after hybrid stage I is feasible and can be performed with satisfactory long-term survival. PMID- 25439774 TI - Practice improves performance on a coronary anastomosis simulator, attending surgeon supervision does not. AB - OBJECTIVES: Enthusiasm for simulation early in cardiothoracic surgery training is growing, yet evidence demonstrating its utility is limited. We examined the effect of supervised and unsupervised training on coronary anastomosis performance in a randomized trial among medical students. METHODS: Forty-five medical students were recruited for this single-blinded, randomized controlled trial using a low-fidelity simulator. After viewing an instructional video, all participants attempted an anastomosis. Subsequently, the participants were randomized to 1 of 3 groups: control (n = 15), unsupervised training (n = 15), or supervised training with a cardiothoracic surgeon or fellow (n = 15). Both the supervised and unsupervised groups practiced for 1 hour per week. After 4 weeks, the participants repeated the anastomosis. All pre- and posttraining performances were videotaped and rated independently by 3 cardiothoracic surgeons blinded to the randomization. All raters scored 13 assessment items on a 1 to 5 (low-high) scale along with an overall pass/fail rating. RESULTS: After the training period, all 3 groups showed significant improvements in composite scores (control: +0.52 +/- 0.69 [P = .014], unsupervised: +1.05 +/- 0.48 [P < .001], and supervised: +1.10 +/- 0.84 [P < .001]). Compared with control group, both supervised (P = .005) and unsupervised trainees (P = .005) demonstrated a significant improvement. Between the supervised and unsupervised groups there were no statistically significant differences in composite scores. CONCLUSIONS: Practice on low-fidelity simulators enabled trainees to improve on a broad range of skills; however, the additional effect of attending-level supervision is limited. In an era of increasing staff surgeon responsibilities, unsupervised practice may be sufficient for inexperienced trainees. PMID- 25439775 TI - Pathologic von Willebrand factor degradation with a left ventricular assist device occurs via two distinct mechanisms: mechanical demolition and enzymatic cleavage. AB - OBJECTIVES: Bleeding is an important source of morbidity in patients with a left ventricular assist device. Evidence suggests a major role for von Willebrand factor. However, limited data exist to explain the mechanism(s) of von Willebrand factor degradation during left ventricular assist device support. We investigated whether left ventricular assist device-related shear stress and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13, the von Willebrand factor protease) altered von Willebrand factor metabolism. METHODS: Whole blood was collected from patients (n = 8) with a left ventricular assist device. von Willebrand factor multimers and degradation fragments were characterized with electrophoresis and immunoblotting. To investigate mechanisms, an in vitro model was developed to generate the supraphysiologic shear stress of a continuous-flow left ventricular assist device. Normal human blood (n = 8) was cycled in a laboratory vortexer (~2400 rpm, shear stress ~175 dyne/cm(2), 4 hours) to reproduce the pathologic degradation of von Willebrand factor that occurs during left ventricular assist device support. To investigate the specific mechanistic roles of shear stress and ADAMTS-13 in von Willebrand factor degradation, purified von Willebrand factor protein +/- ADAMTS-13 protease were exposed to supraphysiologic shear stress in the vortexer. von Willebrand factor multimers and 11 von Willebrand factor degradation fragments were characterized with electrophoresis and immunoblotting. RESULTS: Left ventricular assist device support reduced large von Willebrand factor multimers and significantly increased 10/11 von Willebrand factor degradation fragments (P < .05). Normal human blood exposed to supraphysiologic shear stress in the vortexer demonstrated the same profile of von Willebrand factor degradation fragments as in a patient with a left ventricular assist device. Supraphysiologic shear stress alone caused modest mechanical demolition of large von Willebrand factor multimers into smaller multimers but did not greatly generate von Willebrand factor fragments. In the presence of supraphysiologic shear stress, ADAMTS-13 completely eliminated large von Willebrand factor multimers and generated statistically significant amounts of 11/11 von Willebrand factor degradation fragments (P < .05). The profile of von Willebrand factor fragments generated was identical to the profile that was observed in vivo in patients with a left ventricular assist device. CONCLUSIONS: Supraphysiologic shear stress alone causes physical demolition of large von Willebrand factor multimers into smaller von Willebrand factor multimers. In the setting of supraphysiologic shear stress, ADAMTS-13 cleaves large von Willebrand factor multimers into von Willebrand factor degradation fragments. ADAMTS-13 may be a therapeutic target to reduce von Willebrand factor degradation and bleeding complications in patients with a left ventricular assist device. PMID- 25439776 TI - Hospital volume, mitral repair rates, and mortality in mitral valve surgery in the elderly: an analysis of US hospitals treating Medicare fee-for-service patients. AB - BACKGROUND: The volume-outcome relationship has been suggested as a quality metric in mitral valve surgery and would be particularly relevant in the elderly because of their greater burden of comorbidities and higher perioperative risk. METHODS AND RESULTS: The study included 1239 hospitals performing mitral valve surgery on Medicare beneficiaries from 2000 through 2009. Only 9% of hospitals performed more than 40 mitral operations per year, 29% performed 5 or less, and 51% performed 10 or less. Mitral repair rates were low; 22.7% of hospitals performed 1 or less, 65.1% performed 5 or less, and only 5.6% performed more than 20 mitral repairs per year in those aged 65 years or more. Repair rates increased with increasing volume of mitral operations per year: 5 or less, 30.5%; 6 to 10, 32.9%; 11 to 20, 34.9%; 21 to 40, 38.8%; and more than 40, 42.0% (P = .0001). Hospitals with lower volume had significantly higher adjusted operative mortality compared with hospitals performing more than 40 cases per year: 5 or less cases per year, odds ratio (OR) 1.58 (95% confidence interval [CI], 1.40-1.78); 6 to 10 cases per year, OR 1.29 (95% CI, 1.17-1.43); 11 to 20 cases per year, OR 1.17 (95% CI, 1.07-1.28); 21 to 40 cases per year, OR 1.15 (95% CI, 1.05-1.26). Hospitals with lower mitral repair rates had an increased likelihood of operative mortality relative to the top quartile: lowest quartile, OR 1.31 (95% CI, 1.20 1.44); second quartile, OR 1.18 (95% CI, 1.09-1.29); and third quartile, OR 1.14 (95% CI, 1.05-1.24). Long-term mortality beyond 6 months was also higher in low volume hospitals: 5 or less cases year, hazard ratio (HR) 1.11 (95% CI, 1.06 1.18); 6 to 10 cases per year, OR 1.06 (95% CI, 1.02-1.10) compared with hospitals performing more than 40 cases per year. CONCLUSIONS: Most hospitals perform few mitral valve operations on elderly patients. Greater volume of mitral procedures was associated with higher repair rates. Both greater volume of mitral procedures and increasing mitral repair rates were associated with decreased mortality. PMID- 25439777 TI - Long-term results and predictors of survival after surgical resection of patients with lung cancer and interstitial lung diseases. AB - OBJECTIVES: Patients with interstitial lung diseases have a poor prognosis and are at increased risk of developing lung cancer. We evaluated the survival and predictors of survival after surgical resection in lung cancers in patients with interstitial lung diseases. METHODS: We retrospectively analyzed data from 1763 patients with non-small cell lung cancer with a clinical diagnosis of interstitial lung disease who underwent pulmonary resection between 2000 and 2009 at 61 Japanese institutions. RESULTS: Male patients (90.4%) and smokers (93.8%) were in the majority. The overall 5-year survival was 40%. The 5-year survivals were 59%, 42%, 43%, 29%, 25%, 17%, and 16% for patients with stage Ia, Ib, IIa, IIb, IIIa, IIIb, and IV, respectively. Patients with stage IA had a 5-year survival of 33.2%, 61.0%, and 68.4% in the wedge resection, segmentectomy, and lobectomy groups, respectively (log-rank test, P = .0038). The leading cause of death was cancer recurrence (50.2%), followed by respiratory failure (26.8%). Wedge resection reduced mortality due to respiratory failure when compared with that of lobectomy (P = .022). Multivariable analysis revealed that the type of surgical procedure, predicted percent vital capacity, and tumor locations were independent predictors for survival. The 5-year survival was 20% for patients with stage Ia with a predicted percent vital capacity of 80% or less, and 64.3% for patients with a predicted percent vital capacity greater than 80% (log-rank test, P < .0001). CONCLUSIONS: In these patients, there are competing risks of death. Wedge resection reduced death caused by respiratory failure but resulted in poorer long-term prognosis than lobectomy. For patients with poor predictors of survival, such as predicted percent vital capacity of 80% or less, surgical resection should be limited. PMID- 25439778 TI - C-terminal tensin-like protein mediates invasion of human lung cancer cells and is regulated by signal transducer and activator of transcription 3. AB - OBJECTIVES: C-terminal tensin-like (Cten) protein, a component of focal adhesions, contributes to cell motility and invasion in multiple human cancers. Epidermal growth factor can activate signal transducer and activator of transcription 3, and both contribute to invasion through focal adhesion interactions. We hypothesize that Cten may mediate invasion of lung cancer cells provided by epidermal growth factor via signal transducer and activator of transcription 3. METHODS: Four human non-small cell lung cancer cell lines were treated with epidermal growth factor to evaluate activation of the signal transducer and activator of transcription 3 pathway and induction of Cten expression. Chemical inhibition of signal transducer and activator of transcription 3 was used to evaluate the effect on epidermal growth factor induced Cten expression. Protein expression was quantified by Western blot. H125 and A549 cells were transduced with short-hairpin RNA via lentiviral vector to knockdown expression of Cten. An in vitro transwell invasion assay was used to assess the effects of Cten knockdown on cell invasion (n = 3 for all experiments). RESULTS: Stimulation of lung cancer cells with epidermal growth factor activated the signal transducer and activator of transcription 3 pathway and induced expression of Cten in all cell lines. Signal transducer and activator of transcription 3 inhibition significantly reduced epidermal growth factor induced expression of Cten in H125 (P < .0001), H358 (P = .006), and H441 (P = .014) cells in a dose-dependent manner. Knockdown of Cten expression resulted in significant decreases in cellular invasion in both H125 (P = .0036) and A549 (P = .0006) cells. CONCLUSIONS: These are the first findings in lung cancer to demonstrate that Cten expression mediates invasion of human lung cancer cells and is upregulated by epidermal growth factor via signal transducer and activator of transcription 3 pathway. Cten should be considered a potential therapeutic target for lung cancer. PMID- 25439780 TI - Aborted sternotomy due to unexpected porcelain aorta: does transcatheter aortic valve replacement offer an alternative choice? AB - OBJECTIVES: Surgical aortic valve replacement is challenging in patients with severe aortic calcification. Some patients undergo sternotomy and have the operation aborted because of intraoperative discovery of severe calcification. Hypothermic circulatory arrest and transcatheter aortic valve replacement offer clampless treatment options for aortic stenosis. The study objectives are to characterize patients who are referred after sternotomy was aborted for porcelain aorta and to describe the treatment outcomes. METHODS: From 2001 to 2013, 19 patients presented after attempt at surgical aortic valve replacement was aborted because of porcelain aorta. Patients presented with aortic stenosis (n = 16), regurgitation (n = 1), or both (n = 2). Off-pump coronary bypass was performed in 10 patients. At the Cleveland Clinic, patients underwent surgical aortic valve replacement (n = 7) or transcatheter aortic valvve replacement (n = 12). The median interval between aborted aortic valve replacement and definitive treatment was 9.6 months. The mean age was 74 +/- 11 years. The mean transvalvular gradient was 51 +/- 18 mm Hg, and area was 0.6 cm(2). Axillary cannulation was used in all patients undergoing surgical aortic valve replacement, but only 4 required circulatory arrest. The transcatheter aortic valve replacement approach was transfemoral (n = 5), transapical (n = 6), or transaortic (n = 1). RESULTS: The mean postoperative gradient was 13 +/- 4 mm Hg. There was no mortality, stroke, renal failure, or reoperation for bleeding. One patient required a second valve implantation for paravalvular leak. The median hospital length of stay was 8 days. Five late noncardiac deaths occurred at a median follow-up of 16 months. CONCLUSIONS: Both surgical aortic valve replacement and transcatheter aortic valve replacement are safe and effective options after aborted sternotomy in patients with porcelain aorta who are referred to a high-risk valve center. Procedure selection may be tailored to individual patients on the basis of aortic morphology and comorbidities. Patients with aortic stenosis at risk for calcific aortic disease should be screened with cross-sectional imaging preoperatively. PMID- 25439779 TI - Preconditioning of skeletal myoblast-based engineered tissue constructs enables functional coupling to myocardium in vivo. AB - OBJECTIVE: Skeletal myoblasts fuse to form functional syncytial myotubes as an integral part of the skeletal muscle. During this differentiation process, expression of proteins for mechanical and electrical integration is seized, which is a major drawback for the application of skeletal myoblasts in cardiac regenerative cell therapy, because global heart function depends on intercellular communication. METHODS: Mechanically preconditioned engineered tissue constructs containing neonatal mouse skeletal myoblasts were transplanted epicardially. A Y chromosomal specific polymerase chain reaction (PCR) was undertaken up to 10 weeks after transplantation to confirm the presence of grafted cells. Histologic and electrophysiologic analyses were carried out 1 week after transplantation. RESULTS: Cells within the grafted construct expressed connexin 43 at the interface to the host myocardium, indicating electrical coupling, confirmed by sharp electrode recordings. Analyses of the maximum stimulation frequency (5.65 +/- 0.37 Hz), conduction velocity (0.087 +/- 0.011 m/s) and sensitivity for pharmacologic conduction block (0.736 +/- 0.080 mM 1-heptanol) revealed effective electrophysiologic coupling between graft and host cells, although significantly less robust than in native myocardial tissue (maximum stimulation frequency, 11.616 +/- 0.238 Hz, P < .001; conduction velocity, 0.300 +/- 0.057 m/s, P < .01; conduction block, 1.983 +/- 0.077 mM 1-heptanol, P < .001). CONCLUSIONS: Although untreated skeletal myoblasts cannot couple to cardiomyocytes, we confirm that mechanical preconditioning enables transplanted skeletal myoblasts to functionally interact with cardiomyocytes in vivo and, thus, reinvigorate the concept of skeletal myoblast-based cardiac cell therapy. PMID- 25439781 TI - Contemporary outcomes of open thoracoabdominal aortic aneurysm repair in octogenarians. AB - OBJECTIVES: We sought to evaluate our contemporary outcomes with open thoracoabdominal aortic aneurysm (TAAA) repair in octogenarians to determine whether open TAAA repair is a viable option, with acceptable risk, in this elderly cohort. METHODS: We analyzed clinical data from 1267 enrolled patients who underwent open TAAA repair between 2003 and 2013. Eighty-eight patients (7%) were octogenarians (median age, 82 years; range, 80-92 years) and 1179 were 79 years of age or less. RESULTS: Aneurysm rupture was more common in octogenarians (14% vs 4.7%, P = .001), whereas aortic dissections predominated in younger patients (43.9% vs 13%, P < .001). Octogenarians had higher rates of visceral branch endarterectomy/stenting (58% vs 33.5%, P < .001), adverse postoperative outcomes (36% vs 15.3%, P < .001), operative mortality (26% vs 6.9%, P < .001), and prolonged hospital stay (P = .004). Among octogenarians, preoperative aortic dissection was most commonly associated with extent I repair (42% vs <10% for other extents, P < .001). Extent II repairs most frequently necessitated concomitant visceral-branch procedures and carried the highest risk of mortality (62%). Extent I and III repairs carried intermediate operative risk, and extent IV repairs posed the least risk (11%). Multivariate modeling analysis identified extent II TAAA (P = .001; odds ratio, 11.6), presence of concomitant dissection (P = .02; odds ratio, 5.6), and aneurysm rupture (P = .02; odds ratio, 5.7) as independent predictors of operative mortality in octogenarians. CONCLUSIONS: Open extent II TAAA repair carries significant risk for octogenarians; extent I, III, and IV repairs incur more reasonable postoperative risk. Although TAAA repair should not be denied to octogenarians based solely on age, extensive TAAA repair should be performed with caution. PMID- 25439782 TI - Surgical anatomy of the aortic root: implication for valve-sparing reimplantation and aortic valve annuloplasty. AB - BACKGROUND: To enhance the reproducibility of aortic valve-sparing reimplantation and annuloplasty, we analyzed the topographic relationship between the ventriculoaortic junction (VAJ), basal ring (BR), and sinotubular junction (STJ). The root base thickness is also quantified. METHOD: Fifty-eight fresh human aortic valves were analyzed. The root was dissected to the limit where the aortic wall terminates into the cardiac structures (VAJ). Root height was measured externally from the STJ to the VAJ and internally from the STJ to the BR defined as the plane passing through the cusps nadir. The root base thickness was measured at the BR and orthogonal to the internal wall; except at the right coronary sinus, where it was measured between the BR internally and the VAJ externally. Measurements were taken at the middle of the 3 sinuses and commissures. RESULTS: The VAJ is at the same level as the BR from the noncoronary sinus (-0.1 +/- 0.9 mm) to the left coronary sinus (0.5 +/- 1.3 mm); it is above the BR from the left/right commissure (4.6 +/- 1.4 mm) to the right/non commissure (2.5 +/- 1.6 mm). The external root height was highest at the non/left commissure (21.5 +/- 2.6 mm) followed by the right/non commissure (19.2 +/- 2.3 mm) then the left/right commissure (15.7 +/- 2.2 mm) (P < .05). The mean root base thickness was 3.2 mm, ranging from 1 +/- 0 mm at the left/non commissure to 6.2 +/- 1.2 mm at the right coronary sinus (P < .001). CONCLUSIONS: The VAJ is not planar; it is above the level of the BR from the left/right to the right/non commissure. As a consequence, the external height of the non/left commissure is greater than the other 2 commissures. These findings should be taken into consideration when performing aortic valve-sparing reimplantation or external annuloplasty. PMID- 25439783 TI - The 4E-BP1/eIF4E ratio is a determinant for rapamycin response in esophageal cancer cells. AB - OBJECTIVES: Rapamycin inhibits products of molecular pathways in esophageal squamous cell carcinoma and limits tumor cell growth by targeting 4E-BP1- and eIF4E-dependent gene translation. In this study, we investigate the influence of 4E-BP1-to-eIF4E ratio on rapamycin response in esophageal squamous cell carcinoma cells, and the underlying mechanism is discussed. METHODS: The response to rapamycin treatment was examined in 6 esophageal cancer cell lines. Adjustment of the 4E-BP1/eIF4E ratio was carried out by knockdown or overexpression of 4E-BP1 and eIF4E. The relationship between Egr-1 and 4E-BP1 expression in esophageal cancer cells was also studied. RESULTS: The 4E-BP1/eIF4E ratio was adjusted to evaluate the response to rapamycin treatment in TE1 and TE2 esophageal cancer cells. TE2 cells are sensitized to rapamycin treatment after overexpression of 4E BP1 or knockdown of eIF4E; TE1 cells become resistant to rapamycin after knockdown of 4E-BP1 or overexpression of eIF4E. These data suggest that the 4E BP1/eIF4E ratio is a determinant for the response of TE1 and TE2 cells to rapamycin treatment. Egr-1 expression was higher in TE2 cells compared with other esophageal cancer cell lines, and its knockdown increased 4E-BP1 expression in TE2 cells, which became sensitive to rapamycin treatment. CONCLUSIONS: The 4E BP1/eIF4E ratio is a determinant of the response of rapamycin treatment in esophageal cancer cells. Egr-1 can reduce 4E-BP1 gene expression and render esophageal squamous cell carcinoma cells resistant to rapamycin with a relatively low 4E-BP1/eIF4E ratio. Thus, the 4E-BP1/eIF4E ratio may represent a therapeutic index for the prediction of clinical outcome of rapamycin treatment in patients with esophageal squamous cell carcinoma. PMID- 25439784 TI - Reexamining remodeling. AB - OBJECTIVE: Root remodeling was proposed as valve-preserving root replacement to treat patients with aortic regurgitation and root aneurysm. The objective of this retrospective study was to review 18 years of experience with root remodeling and to identify predictors of valve durability. METHODS: Between October 1995 and December 2013, root remodeling was performed in 747 patients. The aortic valve anatomy was tricuspid in 431 patients, bicuspid in 290 patients, and unicuspid in 26 patients. Aortic aneurysm was present in 688 patients, and 59 procedures were performed for acute aortic dissection type A. The severity of aortic regurgitation ranged from grade 0 to IV (grade 0, 1%; grade 1, 8%; grade 2, 26%; grade 3, 62%; grade 4, 3%; median, 3). All patients underwent root remodeling, concomitant operations were performed in 352 patients, and cusp repair was used in 690 procedures. RESULTS: Hospital mortality was 2%. Overall freedom from reoperation was 92% at 10 years and 91% at 15 years. Overall freedom from reoperation was 95% for tricuspid valves at 10 and 15 years, 89% for bicuspid aortic valves at 10 years (P = .006), and 83% for bicuspid aortic valves at 15 years. By multivariate analysis, the strongest risk factors for failure were an aortoventricular junction 28 mm or greater (hazard ratio, 1.43) and the use of a pericardial patch as part of cusp repair (hazard ratio, 6.24). CONCLUSIONS: Root remodeling continues to be a viable option in valve-preserving root replacement. If combined with careful assessment and, if necessary, correction of aortic valve geometry, reproducible restoration of aortic valve function can be achieved with good long term durability. PMID- 25439785 TI - Predictors of early and medium-term outcome of 200 consecutive aortic valve and root repairs. AB - OBJECTIVES: Advantages of aortic valve repair and root reconstruction include maintenance of natural valve hemodynamic parameters and avoidance of prosthetic valve-related complications. However, general acceptance of valve reconstruction may be limited by paucity of long-term follow-up data from only a few centers. This report is intended to supplement existing outcome information for aortic valve repair. METHODS: Between 2003 and 2013, 200 consecutive patients (149 men, 51 women; mean age, 52.1 years) with significant aortic regurgitation and aortic root enlargement underwent aortic valve repair and associated root reconstruction. The same prospective selection criteria and systematic valve repair approaches were followed throughout the study. Root management consisted of either root remodeling or reimplantation with Dacron prostheses. Kaplan-Meier techniques were used to assess major end points of all-cause mortality, reoperation, and repair failure. Univariable log-rank testing was used to identify associations between risk factors and major events. RESULTS: Early mortality was 2% (4 patients), and early repair failure was 3% (6 patients). New York Heart Association functional class was found to be a risk factor for early mortality and morbidity (odds ratio, 3.3; P = .03), whereas crossclamp time and cardiopulmonary time were risk factors for early mortality (odds ratio, 1.04; 95% confidence interval, 1-1.07; P = .01 and odds ratio, 1.02; 95% confidence interval, 1-1.03; P = .02), respectively. Survival at a mean follow-up of 48.6 +/ 34.3 months (median follow-up, 43.6 months; range, 17.8-78 months) was 94%, with a freedom from reoperation of 91%. Univariable risk factors for mortality were preoperative New York Heart Association functional class and requirement for root replacement. Repair failure and reoperation were associated with bicuspid valve anatomy, subcommissural annuloplasty, and complex leaflet repair. Freedom from repair failure was associated with aortic reimplantation. CONCLUSIONS: Data from a prospective cohort of patients undergoing aortic valve repair and root reconstruction reinforce the satisfactory medium-term results obtained with valve reconstruction. Further analysis of these patient outcomes is necessary to draw definitive conclusions on operative techniques. PMID- 25439786 TI - Technical feasibility and intermediate outcomes of using a handcrafted, area preserving, bifurcated Y-graft modification of the Fontan procedure. AB - OBJECTIVES: To demonstrate the technical feasibility and describe intermediate outcomes for the initial patients undergoing handcrafted, area-preserving, Y graft modification of the Fontan procedure. METHODS: A retrospective review of a pilot study was undertaken to describe preoperative, intraoperative, and postoperative results. RESULTS: Six patients underwent successful procedures and remain alive 3 to 4 years later. The median age at operation was 3.3 years, and median weight was 13.2 kg. Five operations were done without cardiopulmonary bypass and no intraoperative pressure gradients were found. Five patients were extubated by postoperative day 1, Fontan pressures were 12 to 14 mm Hg, transpulmonary gradients were 6 to 8 mm Hg, and no renal or hepatic function abnormalities were found. Length of stay was 10 to 64 days. One patient required venovenous extracorporeal membrane oxygenation for previously undiagnosed plastic bronchitis (64-day stay); another required reoperation for an incidentally diagnosed aortic thrombus (44-day stay). One patient had occlusion of a Y-graft limb noted on magnetic resonance imaging follow-up at 3 months. Catheterization showed excellent hemodynamic parameters and no Fontan obstruction. Occlusion was believed to be due to right-sided pulmonary arteriovenous malformations and widely discrepant flow (80%) to the right lung leading to low flow in the left limb. CONCLUSIONS: The area-preserving, bifurcated Y-graft Fontan modification is technically feasible and shows excellent intermediate outcomes. Additional study is required to determine whether the advantages seen in the computational models will be realized in patients over the long-term, and to optimize patient selection for each of the various Fontan options now available. PMID- 25439787 TI - The Ross procedure using autologous support of the pulmonary autograft: techniques and late results. AB - OBJECTIVES: It is hypothesized that by performing radical aortic root manipulation and then autologous support for the pulmonary autograft in the Ross procedure, this will maintain aortic root size and should, in turn, lead to the demonstrated low incidence of late aortic regurgitation and need for reoperation on the aortic root and valve. METHODS: Aortic root size was measured echocardiographically both preoperatively and then at second yearly intervals in 322 consecutive patients who underwent a Ross operation between October 1992 and June 2013 with autologous support of the pulmonary autograft root using the patient's own aorta. This technique, a variant of the inclusion cylinder method, has been developed with the aim of minimizing prosthetic materials in the aortic root. RESULTS: Measures to reduce aortic root size included annulus reduction in 201 patients (62.4%) and reduction in aortic sinus or sinotubular junction in 159 patients (49.4%). Maximal aortic root diameter postoperatively at 5, 10, and 15 years was 34.0, 34.6, and 34.7 mm, respectively. Eleven reoperations were required during the study period for progressive aortic regurgitation (none for aortic root enlargement), with freedom from reoperation being 96% at both 15 years and 18 years. Preoperative pure aortic regurgitation, aortic annulus, and sinotubular junction enlargement were risk factors for reoperation. CONCLUSIONS: This inclusion method of pulmonary autograft implantation leads to minimal increases in aortic root size over time, with no reoperations for aortic root dilatation and a low requirement for aortic valve reoperation. The Ross procedure deserves to remain on the surgical menu for aortic valve replacement. PMID- 25439788 TI - Prevention of ventilator-associated pneumonia in the cardiothoracic intensive care unit: back to basics. PMID- 25439789 TI - Prospectively ECG-triggered high-pitch coronary angiography with third-generation dual-source CT at 70 kVp tube voltage: feasibility, image quality, radiation dose, and effect of iterative reconstruction. AB - BACKGROUND: Low tube voltage reduces radiation exposure in coronary CT angiography (CTA). Using 70 kVp tube potential has so far not been possible because CT systems were unable to provide sufficiently high tube current with low voltage. OBJECTIVE: We evaluated feasibility, image quality (IQ), and radiation dose of coronary CTA using a third-generation dual-source CT system capable of producing 450 mAs tube current at 70 kVp tube voltage. METHODS: Coronary CTA was performed in 26 consecutive patients with suspected coronary artery disease, selected for body weight <100 kg and heart rate <60 beats/min. High-pitch spiral acquisition was used. Filtered back projection (FBP) and iterative reconstruction (IR) algorithms were applied. IQ was assessed using a 4-point rating scale (1 = excellent, 4 = nondiagnostic) and objective parameters. RESULTS: Mean age was 62 +/- 9 years (46% males; mean body mass index, 27.7 +/- 3.8 kg/m(2); mean heart rate, 54 +/- 5 beats/min). Mean dose-length product was 20.6 +/- 1.9 mGy * cm; mean estimated effective radiation dose was 0.3 +/- 0.03 mSv. Diagnostic IQ was found in 365 of 367 (FBP) and 366 of 367 (IR) segments (P nonsignificant). IQ was rated "excellent" in 53% (FBP) and 86% (IR) segments (P = .001) and "nondiagnostic" in 2 (FBP) and 1 segment (IR) (P nonsignificant). Mean IQ score was lesser in FBP vs IR (1.5 +/- 0.4 vs 1.1 +/- 0.2; P < .001). Image noise was lower in IR vs FBP (60 +/- 10 HU vs 74 +/- 8 HU; P < .001). CONCLUSION: In patients <100 kg and with a regular heart rate <60 beats/min, third-generation dual-source CT using high-pitch spiral acquisition and 70 kVp tube voltage is feasible and provides both robust IQ and very low radiation exposure. PMID- 25439790 TI - Our preoccupation with ultra-low dose radiation exposure. Low contrast resolution and cardiovascular CT imaging. PMID- 25439791 TI - Precision phenotyping, panomics, and system-level bioinformatics to delineate complex biologies of atherosclerosis: rationale and design of the "Genetic Loci and the Burden of Atherosclerotic Lesions" study. AB - BACKGROUND: Complex biological networks of atherosclerosis are largely unknown. OBJECTIVE: The main objective of the Genetic Loci and the Burden of Atherosclerotic Lesions study is to assemble comprehensive biological networks of atherosclerosis using advanced cardiovascular imaging for phenotyping, a panomic approach to identify underlying genomic, proteomic, metabolomic, and lipidomic underpinnings, analyzed by systems biology-driven bioinformatics. METHODS: By design, this is a hypothesis-free unbiased discovery study collecting a large number of biologically related factors to examine biological associations between genomic, proteomic, metabolomic, lipidomic, and phenotypic factors of atherosclerosis. The Genetic Loci and the Burden of Atherosclerotic Lesions study (NCT01738828) is a prospective, multicenter, international observational study of atherosclerotic coronary artery disease. Approximately 7500 patients are enrolled and undergo non-contrast-enhanced coronary calcium scanning by CT for the detection and quantification of coronary artery calcium, as well as coronary artery CT angiography for the detection and quantification of plaque, stenosis, and overall coronary artery disease burden. In addition, patients undergo whole genome sequencing, DNA methylation, whole blood-based transcriptome sequencing, unbiased proteomics based on mass spectrometry, as well as metabolomics and lipidomics on a mass spectrometry platform. The study is analyzed in 3 subsequent phases, and each phase consists of a discovery cohort and an independent validation cohort. For the primary analysis, the primary phenotype will be the presence of any atherosclerotic plaque, as detected by cardiac CT. Additional phenotypic analyses will include per patient maximal luminal stenosis defined as 50% and 70% diameter stenosis. Single-omic and multi-omic associations will be examined for each phenotype; putative biomarkers will be assessed for association, calibration, discrimination, and reclassification. PMID- 25439792 TI - Ultra-low dose comprehensive cardiac CT imaging in a patient with acute myocarditis. AB - The ability of contrast-enhanced CT to detect "late enhancement" in a fashion similar to magnetic resonance imaging has been previously reported. We report a case of acute myocarditis with coronary CT angiography as well as "late enhancement" imaging with ultra-low effective radiation dose. PMID- 25439793 TI - The role of endoglin in kidney fibrosis. AB - Tubulointerstitial fibrosis and glomerulosclerosis, are a major feature of end stage chronic kidney disease (CKD), characterised by an excessive accumulation of extracellular matrix (ECM) proteins. Transforming growth factor beta-1 (TGF beta1) is a cytokine with an important role in many steps of renal fibrosis such as myofibroblast activation and proliferation, ECM protein synthesis and inflammatory cell infiltration. Endoglin is a TGF-beta co-receptor that modulates TGF-beta responses in different cell types. In numerous cells types, such as mesangial cells or myoblasts, endoglin regulates negatively TGF-beta-induced ECM protein expression. However, recently it has been demonstrated that 'in vivo' endoglin promotes fibrotic responses. Furthermore, several studies have demonstrated an increase of endoglin expression in experimental models of renal fibrosis in the kidney and other tissues. Nevertheless, the role of endoglin in renal fibrosis development is unclear and a question arises: Does endoglin protect against renal fibrosis or promotes its development? The purpose of this review is to critically analyse the recent knowledge relating to endoglin and renal fibrosis. Knowledge of endoglin role in this pathology is necessary to consider endoglin as a possible therapeutic target against renal fibrosis. PMID- 25439794 TI - Incidental abdominopelvic findings on expanded field-of-view lumbar spinal MRI: frequency, clinical importance, and concordance in interpretation by neuroimaging and body imaging radiologists. AB - AIM: To characterize the frequency of identification, clinical importance, and concordance in interpretation of incidental abdominopelvic findings identified on routine lumbar spinal MRI using supplemental expanded field-of-view (FOV) coronal imaging. MATERIALS AND METHODS: All lumbar spinal MRI reports over a 12-month period were retrospectively reviewed for the presence of incidental abdominopelvic findings identified using expanded FOV coronal imaging. Medical records were used to identify those findings that received follow-up, which were then categorized according to final diagnosis and classified as "indeterminate," "likely clinically unimportant," and "likely clinically important". All cases that received follow-up were blindly and independently re-reviewed by a neuroimaging radiologist and body-imaging radiologist, and reviewer performances were compared to assess for agreement with regard to lesion significance, need for follow-up, and other parameters. RESULTS: In total, 2067 reports were reviewed: 687 (33.2%) featured one or more incidental abdominopelvic findings, and 102 (4.9%) findings received further evaluation. Of these, 11 (10.9%) were classified as "indeterminate," 50 (49%) as "likely clinically unimportant," and 41 (40.1%) were classified as "likely clinically important." Excellent agreement was observed between the reviewing radiologists for all evaluated parameters. CONCLUSION: The addition of an expanded FOV coronal sequence to the standard lumbar spinal MRI protocol was associated with the identification of a large number of incidental abdominopelvic findings, the minority of which represent likely clinically important findings. Most incidental findings were confidently dismissed by a neuroimaging radiologist as likely clinically unimportant without utilization of additional clinical or radiographic resources. PMID- 25439795 TI - Satisfaction with known, open-identity, or unknown sperm donors: reports from lesbian mothers of 17-year-old adolescents. AB - OBJECTIVE: To assess whether lesbian mothers of 17-year-old adolescents conceived through donor insemination are satisfied with their choice of a known, open identity, or unknown sperm donor and whether the mothers' satisfaction is associated with psychological health problems in the index adolescent offspring. DESIGN: Mixed-method study. SETTING: Not applicable. PATIENT(S): One hundred twenty-nine lesbian mothers and 77 index offspring. INTERVENTION(S): Semistructured interviews with the mothers conducted by telephone and the State Trait Personality Inventory (STPI) completed online by the adolescent offspring. MAIN OUTCOME MEASURE(S): Satisfaction with the type of sperm donor selected was assessed through multiple choice questions, and adolescent psychological health problems by the STPI. The reasons for the mothers' (dis)satisfaction were evaluated through a thematic analysis of transcribed interviews. RESULT(S): Overall, 77.5% of mothers were satisfied with the type of donor chosen. There were no significant differences between birth mothers and comothers on (dis)satisfaction. In comparing satisfied with dissatisfied birth mothers by donor type, the only significant differences were that those selecting open identity donors were more satisfied than dissatisfied and that those using unknown donors were more dissatisfied than satisfied; (dis)satisfaction with donor type was unrelated to offspring psychological health problems. Qualitative analyses revealed six themes concerning all mothers' reasons for (dis)satisfaction. CONCLUSION(S): Donor access and custody concerns were the primary themes mentioned by lesbian mothers regarding their (dis)satisfaction with the type of sperm donor they had selected. PMID- 25439798 TI - Keeping clinicians in research: the Clinical Research/Reproductive Scientist Training Program (CREST) strategy, 2006-2012. PMID- 25439796 TI - Biomarkers of exposure to molybdenum and other metals in relation to testosterone among men from the United States National Health and Nutrition Examination Survey 2011-2012. AB - OBJECTIVE: To examine the potential associations between biomarkers of metal exposure and serum testosterone in men of reproductive age in the general US population. DESIGN: Cross-sectional epidemiology study with adjustment for potential confounders. SETTING: Not applicable. PATIENT(S): Men recruited in the United States National Health and Nutrition Examination Survey (NHANES). INTERVENTION(S): Metal concentrations measured in whole blood, urine, and/or serum samples collected from 484 men. MAIN OUTCOME MEASURE(S): Serum T concentration. RESULT(S): Concentrations of the metals were detected in 69%-100% of the samples. In adjusted analyses where metals were modeled as a continuous variable, we found significant inverse associations between urinary molybdenum and serum copper and serum T, whereas there were significant positive associations between blood lead and cadmium and serum T. When metals were categorized into quartiles, analyses for serum copper and blood lead and cadmium produced significant associations in the same direction as the continuous measures. A suggestive inverse association was observed between quartiles of urinary molybdenum and serum T, but the association was statistically significant when molybdenum was categorized into quintiles. Significant positive associations were also observed for quartiles of blood Se and serum Zn and serum T. CONCLUSION(S): These findings add to the limited human evidence that exposure to molybdenum and other metals is associated with altered T in men, which may have important implications for male health. More research is needed to confirm the findings of our study. PMID- 25439797 TI - Fluorescent in situ hybridization of human sperm: diagnostics, indications, and therapeutic implications. AB - Male factor infertility is a relatively common condition, affecting at least 6% of men of reproductive age. Typically, men with unknown genetic abnormalities resort to using assisted reproductive techniques (ART) to achieve their reproductive goals. Infertile men who father biological children using ART could have a higher incidence of aneuploidy, which is a deviation from the normal haploid or diploid chromosomal state. Aneuploidy can be evaluated using fluorescent in situ hybridization (FISH), a cytogenetic assay that gives an estimate of the frequencies of chromosomal abnormalities. The chromosomes that are generally analyzed in FISH (13, 18, 21, X, and Y) are associated with aneuploidies that are compatible with life. The technique is indicated for various reasons but primarily in [1] men who despite normal semen parameters suffer recurrent pregnancy loss, and [2] men with normal semen parameters, who are undergoing in vitro fertilization but still experiencing recurrent implantation failure. As a screening tool, the technique can help in reproductive and genetic counseling of affected couples, or those who have previously experienced failure of ART. A qualitative analysis of FISH study results allows couples to make informed reproductive choices. Given the increasing clinical use of FISH in various infertility diagnoses, and the development of novel adjunct technologies, one can expect much progress in the areas of preimplantation genetic screening, diagnostics, and therapeutics. PMID- 25439799 TI - Pregnancy after allogeneic uterus transplantation in the rat: perinatal outcome and growth trajectory. AB - OBJECTIVE: To investigate whether allogeneic uterine grafts in a rat model, with tacrolimus immunosuppression, can harbor pregnancies that result in offspring with normal postnatal growth. DESIGN: Experimental animal study. SETTING: University hospital. ANIMAL(S): Lewis rats as uterus donors and Piebald-Virol Glaxo rats as recipients. INTERVENTION(S): Animals were allocated to one of the following three groups: allogeneic uterus transplantation with end-to-side anastomosis to the external iliac vessels and immunosuppression with tacrolimus (UT+Tac; n = 10); sham surgery and immunosuppression with tacrolimus (Sham+Tac; n = 10); or sham surgery (Sham; n = 10). The rats were subsequently introduced to male rats with proven fertility and in the event of resulting pregnancy cesarean sections were performed on day 22 of pregnancy. MAIN OUTCOME MEASURE(S): Graft viability, fertility rate, perinatal death, birth weight, postnatal birth trajectory. RESULT(S): Pregnancy rate was higher in the control groups (70% Sham and 80% Sham+Tac) than in the transplanted group (50% UT+Tac), although these differences did not reach the significance threshold. There were no differences between groups regarding number of living pups or neonatal deaths. Pups born from UT+Tac mothers had birth weights similar to external control animals from our breeding colony (BC): UT+Tac males 6.2 +/- 0.2 g, UT+Tac females 5.5 +/- 0.6 g, BC males 5.8 +/- 0.2 g, BC females 5.2 +/- 0.3 g; n.s. Evaluation of uteri and placentas of pregnant animals revealed a somewhat reduced vascular density in both tissues in the UT+Tac group, and that was not seen in the Sham+Tac group. CONCLUSION(S): Allogeneic uterus transplantation and immunosuppression with tacrolimus is compatible with normal pregnancy and perinatal outcome in a rat model. PMID- 25439800 TI - Reactive oxygen species in human semen: validation and qualification of a chemiluminescence assay. AB - OBJECTIVE: To standardize and validate an assay for reactive oxygen species (ROS) in human semen. DESIGN: ROS levels assayed in blanks, negative and positive control samples (30% H2O2), and human semen, with the use of a luminol-based chemiluminescence assay measured in a single tube luminometer. SETTING: Andrology laboratory. PATIENT(S): Semen samples from 19 men attending for routine semen analysis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): ROS levels reported in relative light units (RLU) per second, adjusted for sperm concentration. RESULT(S): The ROS assay equipment performed according to expectations, generating a chemiluminescence signal for positive control samples and semen samples that decayed rapidly and was captured within 10 minutes. Blanks and negative control samples gave negligible readings. There was no significant intra or interassay variation. Interference from extraneous factors was negligible. The assay distinguished changes in ROS over a wide range of concentrations and provided consistent results between reagent batches. Working reagents remained stable for 3 months. Acceptable levels for negative and positive control samples were established to set criteria for the test passing or failing on any given day. The assay was sensitive to ambient temperature >25 degrees C. ROS declined significantly with time after ejaculation. Mechanical agitation doubled ROS production in semen. CONCLUSION(S): These results validate the ROS assay and demonstrate that it is a highly reliable and accurate diagnostic test. PMID- 25439801 TI - Impact of sperm morphology on the likelihood of pregnancy after intrauterine insemination. AB - OBJECTIVE: To determine whether there is a difference in ongoing pregnancy rates (PRs) between patients undergoing IUI with strict sperm morphology <=4% compared with >4% on initial semen analysis. DESIGN: Retrospective chart review with multivariate analysis. SETTING: Academic outpatient reproductive center. PATIENT(S): A total of 408 couples with male and/or female factor infertility and known strict sperm morphology (SSM). INTERVENTION(S): A total of 856 IUIs with partner's sperm (IUI-P). MAIN OUTCOME MEASURE(S): Ongoing PRs based on ultrasound documentation of intrauterine pregnancy with fetal heart tones. RESULT(S): There is no statistically significant difference in per cycle PRs when comparing patients with a strict sperm morphology of <=4% versus >4% who undergo IUI-P (17.3% vs. 16.7%; odds ratio 0.954, 95% confidence interval 0.66-1.37). Multiple potential confounding factors were assessed using multivariate analysis. CONCLUSION(S): Strict sperm morphology <=4% is not associated with lower PRs in couples undergoing IUI-P, and thus should not be the sole reason for advancing to IVF. PMID- 25439802 TI - Clinically recognizable error rate after the transfer of comprehensive chromosomal screened euploid embryos is low. AB - OBJECTIVE: To determine the clinically recognizable error rate with the use of quantitative polymerase chain reaction (qPCR)-based comprehensive chromosomal screening (CCS). DESIGN: Retrospective study. SETTING: Multiple fertility centers. PATIENT(S): All patients receiving euploid designated embryos. INTERVENTION(S): Trophectoderm biopsy for CCS. MAIN OUTCOME MEASURE(S): Evaluation of the pregnancy outcomes following the transfer of qPCR-designated euploid embryos. Calculation of the clinically recognizable error rate. RESULT(S): A total of 3,168 transfers led to 2,354 pregnancies (74.3%). Of 4,794 CCS euploid embryos transferred, 2,976 gestational sacs developed, reflecting a clinical implantation rate of 62.1%. In the cases where a miscarriage occurred and products of conception were available for analysis, ten were ultimately found to be aneuploid. Seven were identified in the products of conception following clinical losses and three in ongoing pregnancies. The clinically recognizable error rate per embryo designated as euploid was 0.21% (95% confidence interval [CI] 0.10-0.37). The clinically recognizable error rate per transfer was 0.32% (95% CI 0.16-0.56). The clinically recognizable error rate per ongoing pregnancy was 0.13% (95% CI 0.03-0.37). Three products of conception from aneuploid losses were available to the molecular laboratory for detailed examination, and all of them demonstrated fetal mosaicism. CONCLUSION(S): The clinically recognizable error rate with qPCR-based CCS is real but quite low. Although evaluated in only a limited number of specimens, mosaicism appears to play a prominent role in misdiagnoses. Mosaic errors present a genuine limit to the effectiveness of aneuploidy screening, because they are not attributable to technical issues in the embryology or analytic laboratories. PMID- 25439803 TI - Assessment of follicular fluid leptin levels and insulin resistance as outcome predictors in women undergoing in vitro fertilization-intracytoplasmic sperm injection. AB - OBJECTIVE: To analyze follicular fluid leptin (FFL) levels, abdominal obesity, and insulin resistance as predictors of in vitro fertilization (IVF) intracytoplasmic sperm injection (ICSI) outcome. DESIGN: Observational study. SETTING: Academic medical center. PATIENT(S): A sample of 130 infertile women aged 26-40 years without polycystic ovary syndrome. INTERVENTION(S): Measurement of FFL levels in controlled ovarian hyperstimulation cycles with an antagonist and agonist protocol for IVF-ICSI. MAIN OUTCOME MEASURE(S): Live birth rate. RESULT(S): Mean FFL values were significantly higher in pregnancies not ending in a live birth, even after adjustment for waist circumference and insulin resistance. A multivariable model obtained with the use of logistic binary regression analysis showed that waist circumference and insulin resistance had no influence over IVF-ICSI outcomes, but a higher number of follicles, lower serum progesterone levels on the day before alpha-hCG administration, and lower FFL concentrations were significantly associated with a higher probability of having a live birth. The multivariate model reached a sensitivity of 87% and a specificity of 71% for predicting the possibility of pregnancy ending in a live birth. CONCLUSION(S): High FFL levels were associated with abdominal obesity, insulin resistance, and a lower live birth rate after IVF-ICSI. Further investigations are warranted to define the precise roles of leptin, obesity, and insulin resistance on IVF-ICSI outcomes. PMID- 25439804 TI - Beyond the American Society for Reproductive Medicine transfer guidelines: how many cleavage-stage embryos are safe to transfer in women >=43 years old? AB - OBJECTIVE: To determine the number of cleavage-stage embryos that can be safely transferred in women >=43 years old. DESIGN: Retrospective cohort. SETTING: Academic medical center. PATIENT(S): All patients >=43 years old undergoing transfer of five or more cleavage-stage embryos during the period from January 2004 through April 2012. INTERVENTION(S): In vitro fertilization. MAIN OUTCOME MEASURE(S): A total of 567 cycles in 464 patients aged 43-45 years, whose IVF cycles were characterized by transfer of five to eight cleavage-stage embryos were identified. Clinical outcomes and risk of multiples were analyzed, stratifying by age and number of embryos transferred. RESULT(S): Live birth rates per transfer were 14.4%, 9.4%, and 1.3% for women aged 43, 44, and 45 years, respectively. In 43-year-old women, 2.9% (2/69) of pregnancies were triplet gestations (one selective reduction and one spontaneous reduction). Twin birth rate was 16.3%, 6.7%, and 0 (of all live births) for ages 43, 44, and 45 years, respectively. There was no higher order multiple births. Women aged 43 and 44 years having five or more embryos transferred experienced higher clinical pregnancy rates (PRs) than those patients receiving a transfer of three or four embryos. Clinical outcomes for patients undergoing transfer with six or more embryos were not better than those undergoing transfer with five embryos. CONCLUSION(S): Transferring five or more day 3 embryos may be a safe option for patients >=43 years of age, as it is associated with an overall low rate of multiple gestations. Having more than five embryos available for transfer on day 5 is associated with improved IVF outcomes. Whether this benefit is from the additional embryo(s) for transfer or the inherently better prognosis of such patients remains to be determined. PMID- 25439805 TI - Blastocysts can be rebiopsied for preimplantation genetic diagnosis and screening. AB - OBJECTIVE: To evaluate the clinical value of re-examining the test-failure blastocysts in preimplantation genetic diagnosis/screening cycles. DESIGN: Retrospective study. SETTING: University-affiliated center. PATIENT(S): Women with test-failure blastocysts cryopreserved in preimplantation genetic diagnosis/screening cycles. INTERVENTION(S): Cryopreserved test-failure blastocysts were warmed and underwent a second round of biopsy, single nucleotide polymorphism microarray analysis, and vitrification, and the normal blastocysts were warmed again for ET. MAIN OUTCOME MEASURE(S): The percentage of test-failure blastocysts for transfer, the implantation rate per transferred blastocyst, and the live birth rate. RESULT(S): A total of 106 test-failure blastocysts from 77 cycles were warmed for re-examination. A total of 73 blastocysts that completely expanded were considered to have survived the warming process and were successfully rebiopsied. After single nucleotide polymorphism array analysis, 70 blastocysts yielded whole genome amplification product, and 31 had normal chromosomes (44.3%). A total of 19 normal blastocysts were warmed for ET, of which 18 survived and were transferred. The clinical pregnancy rate (implantation rate) was 50.0% in 10 single blastocyst transfer cycles, and all the implanted blastocysts resulted in healthy live births. CONCLUSION(S): Test-failure blastocysts that survived from the first warming procedure can tolerate a second round of biopsy, vitrification, and warming, have a high chance of having normal chromosomes, and are worth being re-examined. PMID- 25439806 TI - Ectopic pregnancy rates and racial disparities in the Medicaid population, 2004 2008. AB - OBJECTIVE: To assess 2004-2008 ectopic pregnancy rates among Medicaid recipients in 14 states and 2000-2008 time trends in three states and to identify differences in rate by race/ethnicity. DESIGN: Secondary analysis of Medicaid administrative claims data. SETTING: Not applicable. PATIENT(S): Women ages 15-44 enrolled in Medicaid in Arizona, California, Colorado, Florida, Illinois, Indiana, Iowa, Louisiana, Massachusetts, Michigan, Minnesota, Mississippi, New York, or Texas in 2004-2008 (n = 19,135,106) and in California, Illinois, and New York in 2000-2003. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Number of ectopic pregnancies divided by the number of total pregnancies (spontaneous abortions, induced abortions, ectopic pregnancies, and all births). RESULT(S): The 2004-2008 Medicaid ectopic pregnancy rate for all 14 states combined was 1.40% of all reported pregnancies. Adjusted for age, the rate was 1.47%. Ectopic pregnancy incidence was 2.3 per 1,000 woman-years. In states for which longer term data were available (California, Illinois, and New York), the rate declined significantly in 2000-2008. In all 14 states, black women were more likely to experience an ectopic pregnancy compared with whites (relative risk, 1.46; 95% confidence interval, 1.45-1.47). CONCLUSION(S): Ectopic pregnancy remains an important health risk for women enrolled in Medicaid. Black women are at consistently higher risk than whites. PMID- 25439807 TI - Hepatitis B virus infection and the risk of male infertility: a population-based analysis. AB - OBJECTIVE: To evaluate the risk of male infertility among patients with hepatitis B virus (HBV) infection. DESIGN: A nationwide, population-based cohort study. SETTING: Not applicable. PATIENT(S): Men infected with HBV (n = 5,138) and men without HBV infection (n = 25,690). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Male infertility, as defined by the International Classification of Diseases, Ninth Revision, Clinical Modification. RESULT(S): The incidence of infertility was 1.59 times higher in patients with HBV infection than in those without HBV infection (2.21 vs. 1.39 per 1,000 person-years). The risk of developing infertility remained significant among patients with HBV infection (hazard ratio 1.52, 95% confidence interval 1.20-1.92) after adjusting for covariates in a multivariate Cox proportional hazards model. CONCLUSION(S): The data show an increased incidence and risk of infertility among men with HBV infection compared with men without HBV. PMID- 25439808 TI - Marital stability and repartnering: infertility-related stress trajectories of unsuccessful fertility treatment. AB - OBJECTIVE: To compare the trajectories of infertility-related stress between patients who remain in the same relationship and patients who repartner. DESIGN: Longitudinal cohort study using latent growth modeling. SETTING: Fertility centers. PATIENT(S): Childless men and women evaluated before starting a new cycle of fertility treatment and observed for a 5-year period of unsuccessful treatments. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Marital stability and infertility-related stress. RESULT(S): The majority of patients (86%) remained with their initial partner, but 14% of participants separated and repartnered while pursuing fertility treatments. Marital stability significantly predicted the initial status of infertility stress and infertility stress growth levels. Specifically, patients who repartnered had higher infertility stress levels at all time points compared with those who remained in the same relationship, regardless of the partner they were with at assessment. Furthermore, results showed an increasing stress trajectory over time for those who repartnered, compared with those who remained in a stable relationship. CONCLUSION(S): Men and women in fertility treatment who form a second union have higher initial levels of stress in their original relationship and higher changes in stress levels over the course of treatments. These findings suggest that high infertility-related stress levels before entering fertility treatment can negatively affect the stability of marital relationships and lead to repartnering. PMID- 25439809 TI - Ovarian morphology and function during growth hormone therapy of short girls born small for gestational age. AB - OBJECTIVE: To study the effect of growth hormone (GH) treatment on ovarian and uterine morphology and function in short, prepubertal small-for-gestational-age (SGA) girls. DESIGN: A multinational, randomized controlled trial on safety and efficacy of GH therapy in short, prepubertal children born SGA. SETTING: Not applicable. PATIENT(S): A subgroup of 18 Danish girls born SGA included in North European SGA Study (NESGAS). INTERVENTION(S): One year of GH treatment (67 MUg/kg/day) followed by 2 years of randomized GH treatment (67 MUg/kg/day, 35 MUg/kg/day, or IGF-I titrated). MAIN OUTCOME MEASURE(S): Data on anthropometrics, reproductive hormones, and ultrasonographic examination of the internal genitalia were collected during 36 months of GH treatment. RESULT(S): Uterine and ovarian volume increased significantly during 3 years of treatment (64% and 110%, respectively) but remained low within normal reference ranges. Ovarian follicles became visible in 58% after 1 year compared with 28% before GH therapy. Anti Mullerian hormone increased significantly during the 3 years of GH therapy but remained within the normal range. Precocious puberty was observed in one girl; another girl developed multicystic ovaries. CONCLUSION(S): GH treatment was associated with statistically significant growth of the internal genitalia, but remained within the normal range. As altered pubertal development and ovarian morphology were found in 2 of 18 girls, monitoring of puberty and ovarian function during GH therapy in SGA girls is prudent. Altogether, the findings are reassuring. However, long-term effects of GH treatment on adult reproductive function remain unknown. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2005-001507 19. PMID- 25439810 TI - Chromothripsis: potential origin in gametogenesis and preimplantation cell divisions. A review. AB - OBJECTIVE: To review the discovery of chromothripsis and analyze its impact on human reproduction. DESIGN: Database and literature analysis. SETTING: University hospital. PATIENT(S): Carriers of massive and complex chromosomal rearrangements. INTERVENTION(S): Cytogenetic analysis and molecular testing (fluorescence in situ hybridization, microarray, whole-genome sequencing). MAIN OUTCOME MEASURE(S): Chromothripsis occurrence in human gametes and preimplantation embryos, with regard to the potential causative mechanisms described in literature. RESULT(S): Databases were searched for the literature published up to March 2014. Chromothripsis is characterized by the shattering of one (or a few) chromosome segments followed by a haphazard reassembly of the fragments generated, arising through a single initial catastrophic event. Several mechanisms involving abortive apoptosis, telomere erosion, mitotic errors, micronuclei formation, and p53 inactivation might cause chromothripsis. The remarkable point is that all these plausible mechanisms have been identified in the field of human reproduction as causal factors for reproductive failures and the genesis of chromosomal abnormalities. Specific features of gametogenesis and early embryonic development such as the weakness of cell cycle and mitosis checkpoints and the rapid kinetics of division in germ cells and early cleavage embryos may contribute to the emergence of chromothripsis. CONCLUSION(S): The discovery of this new class of massive chromosomal rearrangement has deeply modified our understanding on the genesis of complex genomic rearrangements. Data presented in this review support the assumption that chromothripsis could operate in human germlines and during early embryonic development. Chromothripsis might arise more frequently than previously thought in both gametogenesis and early human embryogenesis. PMID- 25439811 TI - Preventable health and cost burden of adverse birth outcomes associated with pregestational diabetes in the United States. AB - OBJECTIVE: Preconception care for women with diabetes can reduce the occurrence of adverse birth outcomes. We aimed to estimate the preconception care (PCC) preventable health and cost burden of adverse birth outcomes associated with diagnosed and undiagnosed pregestational diabetes mellitus (PGDM) in the United States. STUDY DESIGN: Among women of reproductive age (15-44 years), we estimated age- and race/ethnicity-specific prevalence of diagnosed and undiagnosed diabetes. We applied age and race/ethnicity-specific pregnancy rates, estimates of the risk reduction from PCC for 3 adverse birth outcomes (preterm birth, major birth defects, and perinatal mortality), and lifetime medical and lost productivity costs for children with those outcomes. Using a probabilistic model, we estimated the reduction in adverse birth outcomes and costs associated with universal PCC compared with no PCC among women with PGDM. We did not assess maternal outcomes and associated costs. RESULTS: We estimated 2.2% of US births are to women with PGDM. Among women with diagnosed diabetes, universal PCC might avert 8397 (90% prediction interval [PI], 5252-11,449) preterm deliveries, 3725 (90% PI, 3259-4126) birth defects, and 1872 (90% PI, 1239-2415) perinatal deaths annually. Associated discounted lifetime costs averted for the affected cohort of children could be as high as $4.3 billion (90% PI, 3.4-5.1 billion) (2012 US dollars). PCC among women with undiagnosed diabetes could yield an additional $1.2 billion (90% PI, 951 million-1.4 billion) in averted cost. CONCLUSION: Results suggest a substantial health and cost burden associated with PGDM that could be prevented by universal PCC, which might offset the cost of providing such care. PMID- 25439812 TI - Society for maternal-fetal medicine (SMFM) special report: the maternal-fetal medicine subspecialists' role within a health care system. AB - A maternal-fetal medicine (MFM) subspecialist has advanced knowledge of the medical, surgical, obstetrical, fetal, and genetic complications of pregnancy and their effects on both the mother and fetus. MFM subspecialists are complementary to obstetric care providers in providing consultations, co-management, or transfer of care for complicated patients before, during, and after pregnancy. The MFM subspecialist provides peer and patient education and performs research concerning the most recent approaches and treatments for obstetrical problems, thus promoting risk-appropriate care for these complicated pregnancies. The relationship between the obstetric care provider and the MFM subspecialist depends on the acuity of the maternal and/or fetal condition and the local resources. To achieve the goal of promoting early access and sustained adequate prenatal care for all pregnant women, we encourage collaboration with obstetricians, family physicians, certified midwives, and others, and we also encourage providing preconception, prenatal, and postpartum care counseling and coordination. Effective communication between all obstetric care team members is imperative. This special report was written with the intent that it would be broad in scope and appeal to a diverse readership, including administrators, allowing it to be applied to various systems of care both horizontally and vertically. We understand that these relationships are often complex and there are more models of care than could be addressed in this document. However, we aimed to promote the development of a highly effective team approach to the care of the high-risk pregnancy that will be useful in the most common models for obstetric care in the United States. The MFM subspecialist functions most effectively within a fully integrated and collaborative health care environment. This document defines the various roles that the MFM subspecialist can fulfill within different heath care systems through consultation, co-management, and transfer of care, as well as education, research, and leadership. PMID- 25439813 TI - Screening approach for gestational diabetes in twin pregnancies. AB - OBJECTIVE: The objective of this study was to evaluate the ideal cutoff for the glucose challenge test (GCT) in twin pregnancies undergoing screening for gestational diabetes mellitus (GDM). STUDY DESIGN: A historical cohort of patients with twin pregnancies were identified from 1 maternal-fetal medicine practice from 2005 through 2013. All patients were administered a 1-hour, 50-g GCT between 24-28 weeks' gestation. All patients with a GCT of >=130 mg/dL underwent a 3-hour, 100-g oral glucose tolerance test. The diagnosis of GDM was made if 2 of the 4 values on the oral glucose tolerance test were abnormal (Carpenter and Coustan). The testing characteristics of the GCT for diagnosis of GDM were evaluated using 3 selected cutoffs: >=130, >=135, and >=140 mg/dL. We excluded all patients diagnosed with GDM <24 weeks. RESULTS: In all, 475 patients with twin pregnancies underwent a GCT between 24-28 weeks. The incidence of GDM was 6.5%. The positive screen rate using the 3 selected cutoffs were: >=130 mg/dL, 34.7%; >=135 mg/dL, 28.6%; and >=140 mg/dL, 23.4%. A GCT cutoff of >=135 mg/dL maintained 100% sensitivity, with a specificity of 76.4%. Using this cutoff, the positive predictive value was 22.8% and the negative predictive value was 100%. Compared to a cutoff of >=130 mg/dL, a cutoff of >=135 mg/dL resulted in 6.1% less patients testing positive while maintaining the same 100% sensitivity. CONCLUSION: In twin pregnancies, the optimal 1-hour, 50-g GCT screening cutoff appears to be >=135 mg/dL. PMID- 25439823 TI - Determination of 2-methoxyestradiol by chemiluminescence based on luminol-KMnO4 CdTe quantum dots system. AB - In this study, water-soluble CdTe quantum-dots (QDs) capped with glutathione (GSH) was synthesized. It was found that CdTe QDs could greatly enhance the chemiluminescence (CL) emission from the luminol-KMnO4 system in alkaline medium, and 4 nm CdTe QDs was used as catalysts to enhance the reaction sensitivity. The CL intensity of CdTe QDs-luminol-KMnO4 was strongly inhibited in the presence of 2-methoxyestradiol (2-ME) and the relative CL intensity was in linear correlation with the concentration of 2-ME. Based on this inhibition, a novel CL method with a lower detection limit and wider linear range was developed for the determination of 2-ME. The detection limit of plasma samples was 3.07*10(-10) g mL(-1) with a relative standard deviation of 0.24% for 8.0*10(-9) g mL(-1) 2-ME. The method was successfully applied for determination of 2-ME in plasma samples. The possible CL reaction mechanism was also discussed briefly. PMID- 25439837 TI - Macrophage migration inhibitory factor as a potential biomarker of endometriosis. AB - OBJECTIVE: To evaluate the expression of MIF, CD74, and COX-2 in normal, ectopic, and eutopic endometrium during the menstrual cycle and to assess MIF level in peripheral blood. DESIGN: The expressions of MIF, CD74, and COX-2 in normal, ectopic, and eutopic endometrium were evaluated with the use of real-time polymerase chain reaction. MIF protein in peripheral blood samples was checked with the use of ELISA. SETTING: Reproductive biomedicine research center. PATIENT(S): Sixteen normal women and 20 women with endometriosis. INTERVENTION(S): Ectopic biopsies were obtained with the use of laparoscopic procedure, and eutopic and control biopsies were obtained with the use of Pipelle. Peripheral blood samples were collected before laparoscopy. MAIN OUTCOME MEASURE(S): The expression of MIF, CD74, and COX-2 in normal, ectopic and eutopic endometrium during the menstrual cycle and the expression level of MIF in peripheral blood samples. RESULT(S): Relative mRNA expression of MIF, CD74, and COX-2 were significantly higher in ectopic endometrium than in eutopic and control endometrium. Also, there were significant differences in expression of these genes in normal, ectopic, and eutopic endometrium during the menstrual cycle. Moreover, women with endometriosis had significantly higher circulating levels of MIF compared with control subjects. CONCLUSION(S): Dynamic expression of MIF, CD74, and COX-2 during the menstrual cycle could play an essential role in reproduction, inflammation, and endometrium reconstruction. A higher expression of these genes in ectopic endometrium can be considered as a molecular biomarker for endometriosis development and pathophysiology. Also, a high level of MIF in blood serum can act as a biomarker in the diagnosis of endometriosis. PMID- 25439838 TI - Timing of postpartum intrauterine device placement: a cost-effectiveness analysis. AB - OBJECTIVE: To determine if immediate postpartum (PP) intrauterine device (IUD) placement prevents pregnancy and is cost-effective compared with routine placement. DESIGN: We developed a decision-analysis model to determine the number of pregnancies prevented and the cost-effectiveness of immediate PP IUD placement defined as within the first 10 minutes of placental expulsion compared with routine placement at the PP visit. Associated costs and probability estimates for adherence to PP follow-up, IUD placement, expulsion, and pregnancy were determined from the literature. SETTING: Hospital and outpatient facility. PATIENT(S): Women desiring PP IUDs. INTERVENTION(S): IUD placement. MAIN OUTCOME MEASURE(S): The main outcome measure was the number of pregnancies prevented per 1,000 women. The secondary outcome was an incremental cost-effectiveness ratio (ICER) defined as the marginal cost per quality-adjusted life-year (QALY) gained. An ICER of <$50,000/QALY gained was considered to be cost-effective. RESULT(S): Immediate PP IUD placement prevented 88 unintended pregnancies per 1,000 women over a 2-year time horizon. Immediate PP IUD placement was the dominant strategy. For every 1,000 women who desired a PP IUD, attempted immediate PP placement resulted in a cost savings of $282,540 and a gain of 10 QALYs. The model is most sensitive to the cost of an undesired pregnancy. When the cost of a live birth is <$6,000, immediate placement is no longer cost-saving but remains cost-effective. Monte Carlo simulation demonstrates that immediate PP IUD placement is cost effective in 99% of simulations. CONCLUSION(S): Immediate PP IUD placement is a dominant strategy that prevents unintended pregnancy. PMID- 25439839 TI - Impact of assisted reproductive technology on the incidence of multiple-gestation infants: a population perspective. AB - OBJECTIVE: To study the value of a population view in assessing assisted reproductive technology (ART) multiple-gestation infants. DESIGN: Descriptive comparison of ART treatment and population statistics in seven developed countries (United States [U.S.], South Korea, United Kingdom, the Netherlands, Australia, Belgium, Denmark) with varying ART utilization and single-embryo transfer (SET) rates. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The contribution of ART multiple gestation infants to the total number of multiple-gestation infants in a population was calculated in relation to utilization of ART and SET rates. RESULT(S): The number of ART treatments leading to embryo transfer varied from 304 per million inhabitants in the U.S. to 1,518 in Denmark. The percentage of ART cycles that utilized SET varied from 8.8% in South Korea to 53.3% in Australia. Reflecting both utilization rates and SET rates, the percentage of multiple-gestation infants in the population attributed to ART ranged from 14.7% in South Korea to 29.0% in Denmark. CONCLUSION(S): In seven countries, the contribution of ART multiple-gestation infants to all multiple-gestation infants varies from 14.7% to 29.0%, a percentage that was influenced by both the SET rate per cycle and ART utilization rates. In the monitoring of safety and efficacy of fertility treatment, registration of the percentage of SET cycles alone might not be sufficient. PMID- 25439840 TI - Intrafollicular cortisol levels inversely correlate with cumulus cell lipid content as a possible energy source during oocyte meiotic resumption in women undergoing ovarian stimulation for in vitro fertilization. AB - OBJECTIVE: To determine whether follicular fluid (FF) cortisol levels affect cumulus cell (CC) lipid content during oocyte meiotic resumption, and whether CCs express genes for glucocorticoid action. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENT(S): Thirty-seven nonobese women underwent ovarian stimulation for in vitro fertilization (IVF). INTERVENTION(S): At oocyte retrieval, FF was aspirated from the first follicle (>16 mm in size) of each ovary and pooled CCs were collected. MAIN OUTCOME MEASURE(S): Follicular fluid cortisol and cortisone analysis was performed with the use of liquid chromatography-tandem mass spectrometry. CCs were stained with lipid fluorescent dye Bodipy FL C16 to determine lipid content with the use of confocal microscopy. Quantitative real-time polymerase chain reaction was used to detect CC gene expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) types 1 and 2, glucocorticoid receptor (NR3C1), lipoprotein lipase (LPL), and hormone-sensitive lipase (HSL). RESULT(S): Adjusting for maternal age, FF cortisol levels negatively correlated with CC lipid content and positively correlated with numbers of total and mature oocytes. CCs expressed genes for 11beta-HSD type 1 as the predominant 11beta-HSD isoform, NR3C1, LPL, and HSL. CONCLUSION(S): FF cortisol levels may regulate CC lipolysis during oocyte meiotic resumption and affect oocyte quality during IVF. PMID- 25439842 TI - Preconceptional thyroid-stimulating hormone levels and outcomes of intrauterine insemination among euthyroid infertile women. AB - OBJECTIVE: To evaluate differences in intrauterine insemination (IUI) outcomes among euthyroid women with preconceptional thyroid-stimulating hormone (TSH) values in the normal (0.4-2.4 mIU/L) and high-normal (2.5-4.9 mIU/L) ranges. DESIGN: Cohort study. SETTING: A single fertility center. PATIENT(S): A total of 1,477 women who underwent 4,064 IUI cycles between the years 2004 and 2012. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth, clinical pregnancy, spontaneous abortion (SAB), and IUI cycle parameters. RESULT(S): Cycles were categorized into 4 groups based on preconceptional TSH values: 0.40-1.36 mIU/L; 1.37-1.86 mIU/L; 1.87-2.49 mIU/L; and 2.50-4.99 mIU/L. No statistically significant differences were found in IUI cycle parameters, clinical pregnancy rates, or live births per initiated cycle among the 4 TSH groups. However, preconceptional TSH was inversely related to SAB and positively related to live birth among women who achieved a clinical pregnancy. In this group of women, cycles with TSH values between 2.5 and 4.9 mIU/L were related to lower odds of SAB (odds ratio: 0.32; 95% confidence interval: 0.16-0.65) and higher odds of live birth (odds ratio: 2.80; 95% confidence interval: 1.43-5.48) compared with cycles among women in the lowest TSH group. CONCLUSION(S): Among euthyroid patients, preconceptional TSH values in the high-normal range (between 2.5 and 4.9 mIU/L) are not associated with adverse IUI outcomes. PMID- 25439841 TI - Maternal undernutrition induces premature reproductive senescence in adult female rat offspring. AB - OBJECTIVE: To determine the effects of maternal undernutrition (MUN) on the reproductive axis of aging offspring. DESIGN: Animal (rat) study. SETTING: Research laboratory. ANIMAL(S): Female Sprague-Dawley rats. INTERVENTION(S): Food restriction during the second half of pregnancy in rats. MAIN OUTCOME MEASURE(S): Circulating gonadotropins, antimullerian hormone (AMH), ovarian morphology, estrous cyclicity, and gene expression studies in the hypothalamus and ovary in 1 day-old (P1) and aging adult offspring. RESULT(S): Offspring of MUN dams had low birth weight (LBW) and by adult age developed obesity. In addition, 80% of adult LBW offspring had disruption of estrous cycle by 8 months of age, with the majority of animals in persistent estrous. Ovarian morphology was consistent with acyclicity, with ovaries exhibiting large cystic structures and reduced corpora lutea. There was an elevation in circulating T, increased ovarian expression of enzymes involved in androgen synthesis, an increase in plasma LH/FSH levels, a reduction in E2 levels, and no changes in AMH in adult LBW offspring compared with in control offspring. Hypothalamic expression of leptin receptor (ObRb), estrogen receptor-alpha (ER-alpha), and GnRH protein was altered in an age dependent manner with increased ObRb and ER-alpha expression in P1 LBW hypothalami and a reversal of this expression pattern in adult LBW hypothalami. CONCLUSION(S): Our data indicate that the maternal nutritional environment programs the reproductive potential of the offspring through alteration of the hypothalamic-pituitary-gonadal axis. The premature reproductive senescence in LBW offspring could be secondary to the development of obesity and hyperleptinemia in these animals in adult life. PMID- 25439843 TI - Genomic and genetic variation in E2F transcription factor-1 in men with nonobstructive azoospermia. AB - OBJECTIVE: To identify gene dosage changes associated with nonobstructive azoospermia (NOA) using array comparative genomic hybridization (aCGH). DESIGN: Prospective study. SETTING: Medical school. PATIENT(S): One hundred ten men with NOA and 78 fertile controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The study has four distinct analytic components: aCGH, a molecular karyotype that detects copy number variations (CNVs); Taqman CNV assays to validate CNVs; mutation identification by Sanger sequencing; and histological analyses of testicular tissues. RESULT(S): A microduplication at 20q11.22 encompassing E2F transcription factor-1 (E2F1) was identified in one of eight men with NOA analyzed using aCGH. CNVs were confirmed and in an additional 102 men with NOA screened using Taqman CNV assays, for a total of 110 NOA men analyzed for CNVs in E2F1. Eight of 110 (7.3%) NOA men had microduplications or microdeletions of E2F1 that were absent in fertile controls. CONCLUSION(S): E2F1 microduplications or microdeletions are present in men with NOA (7.3%). Duplications or deletions of E2F1 occur very rarely in the general population (0.011%), but E2F1 gene dosage changes, previously reported only in cancers, are present in a subset of NOA men. These results recapitulate the infertility phenotype seen in mice lacking or overexpressing E2f1. PMID- 25439844 TI - Prolonging oocyte in vitro culture and handling time does not compensate for a shorter interval from human chorionic gonadotropin administration to oocyte pickup. AB - OBJECTIVE: To assess the impact of oocyte aspiration, denudation, and sperm injection timing in relation to oocyte hCG exposure time on intracytoplasmic sperm injection (ICSI) outcome. DESIGN: Cohort study. SETTING: Tertiary medical center. PATIENT(S): A total of 614 consecutive ICSI cycles were performed in 421 patients aged <38 years with at least three aspirated oocytes and no more than three previous treatments. INTERVENTION(S): Gonadotropin-releasing hormone agonist or GnRH antagonist suppression; oocyte pickup (OPU)-hCG interval more/less than 36 hours; OPU-denudation interval more/less than 2 hours; denudation-ICSI interval more/less than 1 hour. MAIN OUTCOME MEASURE(S): Fertilization, embryo transfer, and pregnancy rates. RESULT(S): Late OPU was associated with more available embryos than early OPU and significantly higher rates of fertilization (66.0% +/- 22.8% vs. 61.8% +/- 24.3%), ET (99.5% vs. 96.2%), and pregnancy (47.2% vs. 35.4%). This advantage was more pronounced in GnRH agonist cycles. The length of incubation before or after denudation had no effect, regardless of OPU timing. On logistic stepwise regression, OPU timing was the only significant independent predictor of pregnancy (odds ratio 1.6, 95% confidence interval 1.17-2.29). CONCLUSION(S): The timing of OPU has a predominant effect on ICSI success, especially in GnRH agonist cycles. Delaying oocyte denudation or sperm injection does not compensate for insufficient postpriming exposure to the follicular environment. PMID- 25439846 TI - Uterus transplantation trial: 1-year outcome. AB - OBJECTIVE: To report the 12-month outcome of seven patients with viable uteri after uterus transplantation (UTx). DESIGN: Prospective observational study. SETTING: University hospital. PATIENT(S): Seven patients with absolute uterine infertility and viable uteri for 12 months after live-donor UTx. INTERVENTION(S): Predetermined immunosuppression was with tacrolimus and mychophenolate mofetil (MMF) during 6 months, whereupon MMF should be withdrawn. Frequent ultrasound examinations were performed to assess uterine appearance and uterine artery blood flow. Cervical biopsies (for histological detection of rejection) were obtained at preset time points, with temporary adjustments of immunosuppression if there were signs of rejection. Menstruations were systematically recorded. MAIN OUTCOME MEASURE(S): Menstruation, uterine artery blood flow, histology of cervical biopsies, and blood levels of tacrolimus. RESULT(S): All patients showed regular menses after 1-2 months. Uterine artery blood flow was unchanged, with a median pulsatility index of 1.9 (range, 0.5-5.4). Blood levels of tacrolimus were approximately 10, 9, and 8 (MUg/L) during months 2, 9, and 12, respectively. Four recipients showed mild inflammation in biopsies after MMF withdrawal and were treated with corticosteroids and azathioprine during the remainder of the 12 months. Subclinical rejection episodes were detected on ectocervical biopsies in five recipients. Histology showed apoptotic bodies and occasional spongiosis in the squamous epithelium. Moderate infiltration of lymphocytes and neutrophils was seen in the epithelial/stromal interface. All rejection episodes were successfully treated for 2 weeks with corticosteroids or dose increments of tacrolimus. CONCLUSION(S): We demonstrate long-term uterine viability after UTx, with continued menstruation and unaltered uterine artery blood flow. Subclinical rejection episodes were effectively reversed by temporary increase of immunosuppression. CLINICAL TRIAL REGISTRATION NUMBER: NCT01844362. PMID- 25439845 TI - Granulocyte colony-stimulating factor prevents loss of spermatogenesis after sterilizing busulfan chemotherapy. AB - OBJECTIVE: To determine whether granulocyte colony-stimulating factor (G-CSF) could prevent loss of spermatogenesis induced by busulfan chemotherapy via protection of undifferentiated spermatogonia, which might serve as an adjuvant approach to preserving male fertility among cancer patients. DESIGN: Laboratory animal study. SETTING: University. ANIMAL(S): Laboratory mice. INTERVENTION(S): Five-week-old mice were treated with a sterilizing busulfan dose and with 7 days of G-CSF or vehicle treatment and evaluated 10 weeks later (experiment 1) or 24 hours after treatment (experiment 2). MAIN OUTCOME MEASURE(S): Experiment 1: testis weights, epididymal sperm counts, testis histology. Experiment 2: PLZF immunofluorescent costaining with apoptotic markers. Molecular analysis of G-CSF receptor expression in undifferentiated spermatogonia. RESULT(S): Ten weeks after treatment, busulfan-treated mice that also received treatment with G-CSF exhibited significantly better recovery of spermatogenesis and epididymal sperm counts than animals receiving busulfan alone. G-CSF led to increased numbers of PLZF+ spermatogonia 24 hours after treatment that was not accompanied by changes in apoptosis. To address the cellular target of G-CSF, mRNA for the G-CSF receptor, Csf3r, was found in adult mouse testes and cultured THY1+ (undifferentiated) spermatogonia, and cell-surface localized CSF3R was observed on 3% of cultured THY1+ spermatogonia. CONCLUSION(S): These results demonstrate that G-CSF protects spermatogenesis from gonadotoxic insult (busulfan) in rodents, and this may occur via direct action on CSF3R+ undifferentiated spermatogonia. G-CSF treatment might be an effective adjuvant therapy to preserve male fertility in cancer patients receiving sterilizing treatments. PMID- 25439847 TI - Copy number variation associated with meiotic arrest in idiopathic male infertility. AB - OBJECTIVE: To assess the association between copy number variations (CNVs) and meiotic arrest and azoospermic men. DESIGN: Genetic association study. SETTING: University. PATIENT(S): Australian men: 19 with histologically confirmed meiotic arrest, 110 men with azoospermia in the absence of histologic data, and 97 fertile men (controls). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The identification of CNV by microarray and/or multiplex ligation-dependent probe amplification (MLPA), and the localization of unique CNV encoded proteins to the human testis. RESULT(S): Microarray identified two CNVs unique to meiosis arrest patients. One containing the MYRIP gene and a second containing LRRC4C and the long noncoding RNA LOC100507205. All three genes are transcribed in the human testis, and MYRIP and LRRC4C localize to meiotic cells. The reverse genetic screen for CNVs in meiosis genes identified in mouse models further identified CNVs including HSPA2 as being associated with azoospermia. CONCLUSION(S): These data raise the possibility that, while relatively rare, CNVs may contribute to human male infertility and that CNV screening should be incorporated into long term plans for genome profiling as a diagnostic tool. PMID- 25439848 TI - Oocyte donation outcome after oncological treatment in cancer survivors. AB - OBJECTIVE: To study reproductive outcome in patients cured of cancer who required oocyte donation (OD) owing to iatrogenic ovarian dysfunction. DESIGN: Multicenter, unmatched, retrospective cohorts study. SETTING: Private, university affiliated group of clinics. PATIENT(S): Women treated and cured of cancer (n = 142) who underwent 333 cycles of OD (exposed group) and women without a previous cancer diagnosis (n = 17,844) who underwent 29,778 cycles of OD (unexposed cohort) between January 2000 and January 2012. INTERVENTION(S): Retrospective chart review. MAIN OUTCOME MEASURE(S): Pregnancy, implantation, miscarriage, and ongoing pregnancy rates. RESULT(S): There were no differences in terms of pregnancy (55.7% vs. 54.7%), implantation (39.8% vs. 38.2%), miscarriage (29.5% vs. 26.9%), or delivery rates (39.3% vs. 39.9%) between the unexposed group and the patients previously diagnosed and cured of cancer, respectively. There was no correlation between OD outcome and cancer type. CONCLUSION(S): Endometrial receptivity in women treated and cured of cancer was comparable to that of general patients without previous malignancies who had received OD, based on the largest series available in the literature. PMID- 25439849 TI - Urinary tract endometriosis in patients with deep infiltrating endometriosis: prevalence, symptoms, management, and proposal for a new clinical classification. AB - OBJECTIVE: To analyze the prevalence of urinary tract endometriosis (UTE) in patients with deep infiltrating endometriosis (DIE) and to define potential criteria for preoperative workup. DESIGN: Retrospective study. SETTING: University hospital. PATIENT(S): Six hundred ninety-seven patients with endometriosis. INTERVENTION(S): Excision of all endometriotic lesions. MAIN OUTCOME MEASURE(S): Correlation of preoperative features and intraoperative findings in patients with UTE. RESULT(S): Out of 213 patients presenting DIE, 52.6% suffered from UTE. In patients with ureteral endometriosis, symptoms were not specific. Among the patients with bladder endometriosis, 68.8% complained of urinary symptoms compared to 7.9% in the group of patients without UTE. In patients with rectovaginal endometriosis, the probability of ureterolysis showed a linear correlation with the size of the nodule. We found that 3 cm in diameter provided a specific cutoff value for the likelihood of ureteric involvement. CONCLUSION(S): The prevalence of UTE has often been underestimated. Preoperative questioning is important in the search for bladder endometriosis. The size of the nodule is one of the few reliable criteria in preoperative assessment that can suggest ureteric involvement. We propose a classification of ureteral endometriosis that will allow the standardization of terminology and help to compare the outcome of different surgical treatment in randomized studies. PMID- 25439850 TI - Sperm morphology and reproductive outcomes: a perplexing relationship. PMID- 25439851 TI - Is ovarian reserve related to blood type? PMID- 25439852 TI - [Treatment-resistant anxiety disorders: A literature review of drug therapy strategies]. AB - Anxiety disorders are widespread psychiatric conditions with significant social and professional disability, poor quality of life, an increased risk of suicide, and frequent attendance of medical services. Serotonin reuptake inhibitors (SRI) and serotonin and norepinephrine reuptake inhibitors (SNRI) have demonstrated a rather robust efficacy for the treatment of most of anxiety disorders. Nevertheless a substantial number of patients are resistant or still suffer from residual symptoms despite this first line treatment. The objective of our paper is to review relevant studies for the pharmacologic management of anxiety disorders resistant to the first line treatment. For this purpose, we conducted a pubmed/medline search for double-blind placebo-controlled trials of treatment resistant anxiety disorders. An adequate trial for a SRI in the treatment of obsessive-compulsive disorder (OCD) should continue for at least 12 weeks. Special considerations of the comorbidities and symptom profile could help in the choice of an appropriate pharmacotherapy. Several trials have highlighted the efficacy of antipsychotics as an add-on to SRI in treatment-resistant OCD such as haloperidol more so when comorbid with a tic disorder, or risperidone that can reduce OCD as well as depressive symptoms. Aripiprazole has been shown efficacious in two placebo-controlled double-blind trials, while the efficacy of quetiapine and olanzapine remains controversial. Other trials showed some efficacy of anticonvulsants (lamotrigine, topiramate), pindolol, memantin and N acetylcystein as an adjunctive treatment to SRI for resistant OCD. Few trials have investigated selective serotonin reuptake inhibitors (SSRI) or SNRI resistant generalized anxiety disorder showing a failure of adjunctive therapy with olanzapine, quetiapine, ziprasidone and risperidone. These studies were underpowered and very limited in number. Adjunctive risperidone for resistant post-traumatic stress disorder (PTSD) showed benefit in some but not all trials. Olanzapine was beneficial for the reduction of the CAPS score in addition to the improvement of sleep disturbances. Furthermore, prazosin was efficacious by reducing PTSD symptoms, sleep disturbances, nightmares, and psychological distress. One double-blind placebo-controlled study was conducted to investigate treatment-resistant social phobia showing no benefit of pindolol add-on paroxetine. Our results demonstrate that the pharmacological management of treatment-resistant anxiety disorders is not sufficiently investigated in double blind placebo-controlled trials, despite a growing evidence in favor of antipsychotics and some other pharmacological agents in resistant OCD and, to a lesser extent, PTSD. Hence, there is a crucial need for larger double-blind placebo-controlled trials for resistant anxiety disorders. Finally, being out of the scope of our review, we omitted studies of non-pharmacologic therapies. PMID- 25439853 TI - [The 5 mental dimensions identified in early maladaptive schemas statistical analysis of Young's schema questionnaire (YSQ-s3)]. AB - INTRODUCTION: Schemas represent a stable vision of oneself. Young's schema questionnaire-s3 (YSQ-s3) presents 90 perceptions of oneself, specifying 18 early maladaptive schemas (EMS). We studied the intensity and inter-relations of these 18 EMS and how they pool together into a specific domain. METHOD: Two hundred and ninety four subjects (294 patients from a French private practice in psychiatry and 12 volunteers) filled in a French version of the YSQ-s3. Item scores range from 1 to 6. Only the scores of 4 "true for me during most of my life" or higher were kept for the statistical analysis. Data analysis was conducted using descriptive statistics, principal component analysis (PCA) and hierarchical clustering analysis (HCA). RESULTS: The EMS mean scores ranged from 3.4 to 12.9 and standard deviations from 5.9 to 9.7. EMS score correlations range from 0.009 to 0.55. The principal component analysis (PCA), that provides linear combinations of each EMS score, yields only one meaningful component. Indeed, the screen plot that provides the eigen values associated with each principal component, suggests keeping only the first component. This component presents a size-effect and represents the "global scores intensity". The hierarchical clustering analysis (HC) fits the 18 EMS in 5 domains (r(2) = 0.4): (1) "avoidance" (with 3 EMS: emotional deprivation, social isolation/alienation, emotional inhibition), (2)"give" (with 1 EMS: self-sacrifice), (3) "take" (with 3 EMS: entitlement/grandiosity, insufficient self-control/self-discipline, approval seeking/recognition-seeking) (4) "awareness" (with 8 EMS: abandonment/instability, mistrust/abuse, defectiveness/shame, dependence/incompetence, vulnerability to harm or illness, enmeshment/undeveloped self, failure, subjugation) (5) "faith" (with 3 EMS: negativity/pessimism, unrelenting standards/hyper-criticalness, punitiveness). When the HC analysis is applied to the population (n = 294), it yields 6 classes of patients. The mean score of the 5 domains, described above, can describe these classes. DISCUSSION: These 5 domains do not completely fit Young's five "primary infantile needs" domains. Only 2/3 of the EMS are correctly attributed to the "primary infantile needs" domains. The 5 domains seem closely related to the 5 dimensions of the NEO PI-R or to the 5 domains of personality disorders (criteria b) described in the DSM-5. In our understanding the dimensions "avoidance, give, take" represent 3 types of relationship to others (on behavioral level). The dimension "awareness" represents the fears and losses (on the emotional level) and "faith" represents beliefs and consciousness (on the cognitive level). The intensity of the 5 domains inside each class of patients could guide the clinical interpretation, specifically for personality disorders. PMID- 25439854 TI - [Consequences of tobacco, cocaine and cannabis consumption during pregnancy on the pregnancy itself, on the newborn and on child development: A review]. AB - BACKGROUND: Substance use has increased worldwide. Based on these data, we may think that substance use has also increased during pregnancy, but epidemiological data are scarce in this population. The potential consequences of tobacco, cocaine or cannabis use during pregnancy are a major public health concern. The combined use of different substances during pregnancy may have serious consequences on the pregnancy and on child development. METHODS: In this paper, we will describe the potential consequences for the newborn, child and adolescent after being exposed to tobacco, cannabis and cocaine in utero. For this purpose, we will review all retrospective and prospective studies (in English and French) referenced in PubMed reporting on the somatic or psychiatric consequences of alcohol, tobacco and drug consumption by pregnant women on newborn and children. Consumption during pregnancy was assessed in these studies using simple questionnaires, biomarkers analysis or both. RESULTS: Generally speaking, these pregnancies are at high risk for both the mother and the foetus: for example, an increased risk of miscarriage or of reduced length of gestation, an increased risk of uterine apoplexy and placenta praevia, more premature births and/or hypotrophy were reported. The occurrence of a newborn's withdrawal syndrome may be misdiagnosed. Many consequences on child development may be observed such as growth disorders, learning or motor disorders, language disorders, cognitive disorders (attention, memory, executive functions), attention deficit disorders with impulsivity or with hyperactivity (ADHD), and memory disorders. The prevalence of depressive or anxiety disorders may also be increased in these children. The risk of addictive disorders or schizophrenia in children exposed in utero to illicit drugs or tobacco is still unknown. The combined use of different substances increases, consequently it is difficult to disentangle the consequences on child development of each of the drugs used during pregnancy owing to potential interactions between these drugs. The consequences on child development will also depend on the dose and on the time of drug use during pregnancy. DISCUSSION: The National Institute of Drug Abuse reported that 75% of the infants exposed in utero to one or more substances will present medical problems during childhood, as compared to only 27% of the non-exposed infants. However, the medical consequences are still a matter of controversies. Methodological biases, such as the use of different rating scales among studies, and the heterogeneity of the populations included are main limitations. Further studies are needed using larger cohorts and longer follow-up periods. PMID- 25439855 TI - [Negative hallucination, self-onsciousness and ageing]. AB - BACKGROUND: Negative hallucinations are characterized by a defect in perception of an object or a person, or a denial of the existence of their perception. Negative hallucinations create blank spaces, due to both an impossible representation and an incapability of investment in reality. They have a close relationship with Cotard's syndrome, delusional theme of organ denial observed in melancholic syndromes in the elderly. METHODS: Phenomenological approach. The phenomenology of negative hallucinations provides quite an amount of information on the origin of the psychotic symptoms when one is rather old. RESULTS: The connections between hallucinations, mood disorders and negative symptoms are often difficult to live with for the nearest and dearest. Negative hallucinations require a strict approach to identify their expression that is crucial because a wide heterogeneity exists within the pathological pictures, as in Cotard's syndrome. Although the negative hallucination has an anti traumatic function in elderly people fighting against mental pain, it still represents a deficiency in symbolization. The prevalence of this symptom is without doubt underestimated, although its presence often underlines thymic suffering that is more striking. These hallucinatory symptoms have an important impact on the patients' daily life, and they appear to be prisoners of a suffering, which cannot be revealed. CONCLUSIONS: We propose in this article to review the clinical symptoms of negative hallucinations in the elderly and the way to manage them. The medicinal approaches are not always effective. A greater place must be given to what is in connection with the body, aiming at a strong impact and thus to offer non pharmacological approaches, such as somatic ones, which can be either invasive (electroconvulsive therapy) or not (transcranial magnetic stimulation). PMID- 25439856 TI - [Pseudodementia, what are we talking about? Part II: From Stertz to Alzheimer: A psychogenic disease after trauma]. AB - OBJECTIVE: The aim of this work is to give a new anchorage for the initial concept of pseudodementia, its basic definitions and actual clinical implications. The original definition and framework of the concept are misidentified and therefore need to be reintroduced and analysed here. This approach, beyond its heuristic and epistemological goal, has a practical aim: to adjust the psychopathological point of view on pseudodementia. METHODOLOGY: In addition to a conventional survey based on search engines (Medline, PsychINFO and google book), we conducted a systematic review of the concomitant papers related to the rise of the concept. RESULTS: Three moments of conceptualization are identified and linked to Wernicke's successors at the university of Breslau. Firstly, Stertz (1910) has described pseudodementia as a psychogenic illness that could occur after any trauma. According to our research, it is probably the first written use of the term pseudodementia in its psychogenic meaning. Secondly, we present Bonhoeffer's approach based on psychogenic reactions (1911). Finally, the views of Alzheimer and his student Schuppius are described: their understanding of pseudodementia is open to psychoanalytic concepts (1914). DISCUSSION: The concept of pseudodementia (Pseudodemenz) takes shape in a particular period of German history: the promulgation of laws settling railway (1871) and industrial accidents (1884) but also the law of compensation of the traumatic neurosis (1889), the nosological specificity of which was debated. German psychiatry of the beginning of the 20th century was strongly imbued with a moralizing sense of national duty. The disqualification of traumatic neurosis has been followed by a unanimous recognition of traumatic hysteria and its psychogenic hypothesis. As a consequence, traumatic events were rarely taken into consideration and the issue was moved into the private sphere (Privatsache) by questioning patients' morbid wishes. Breslau's psychiatrists analyzed the cognitive disorders of pseudodementia with regard to an ideogenic model of the trauma, which emphasized the subjectivity but which was still facing the primacy of the consciousness. It is in this context, and by reducing the question of the pseudodementia to the situations of detention (Gansersche Syndrom) and pension neuroses (Rentenneurosen), that Bonhoeffer promoted the notion of "wishing to be sick" (Wille zur Krankheit). This conception gave a social component to mental disorders but placed in the foreground a suggestive phenomenon, which Raecke included as secondary to the primary symptom of hysterical inhibition. Thus, Schuppius's article under the tutoring of Alois Alzheimer offers a double testimony. On one hand, it shows how neuropsychiatry was, by then, at least partially open to the notion of an unconscious causality. On the other hand, it exposes a hidden aspect of Alois Alzheimer: a brilliant histopathologist capable of interest for psychodynamic mechanisms. CONCLUSION: In his famous study of 1961, Leslie Gordon Kiloh argues that the concept of pseudodementia does not belong to any nosological system, is purely descriptive and does not imply an accurate diagnosis. The present work shows a very different conclusion. Initially, the term was introduced in German psychiatry to describe cases of hysterical psychogenic illness after trauma (psychogene Erkrankungen nach Trauma) in which the mechanism of inhibition was discussed. Topologically, we can even define its emergence in the Breslau's university and psychiatric clinic in which Wernicke, Stertz, Bonhoeffer and Alzheimer himself, promoted it. One should also note that the category of hysteria referred to an array of functional mental disorders, including "hysterical psychosis" (hysterische Psychosen). PMID- 25439857 TI - [Prosocial intervention in children and adolescents with autism spectrum disorder without intellectual disability: benefits of videotaping therapy sessions]. AB - INTRODUCTION: The category of pervasive developmental disorders (PDD) without intellectual disability (including Asperger syndrome and high-functioning autism) has increased steadily among individuals since the 1980s. Although some symptoms may decrease with age, functional disability persists and is largely related to abnormalities in social interaction. Within the framework of PDD without intellectual disability, improving social skills appears to be a primary target for intervention programs. Despite a recent increase in the number of studies on this topic, few validated programs are yet available for clinical settings. BACKGROUND: We have developed an intervention targeting the improvement of social skills from the analysis of video sequences. The goal of this intervention is to promote communication within the group through sharing their interests and emotions, and to enhance the understanding of social situations. In order to assess the efficiency of this intervention, we have conducted a prospective, open, and uncontrolled study. First, it aimed at assessing the immediate effect of our intervention on a single social skill (communication) in an experimental situation (in the group) and in an ecological situations (family and school). Second, this study aimed at assessing the effects of this intervention on the subjects' social adjustment. METHOD: This study included 16 individuals with high functioning autism/Asperger syndrome. Participants were evaluated before and after a 6-month video-based training using measures of socio-communicative and adaptive skills. RESULTS: Results revealed a statistically significant increase in the communication skills not only in the group (15.5%), but also at home (13.7%) and at school (8.7%). The evaluation of socio-adaptive behavior indicates a statistically significant increase in communication (12%), family (7%) and social autonomy (8%), and leisure activities (8%). DISCUSSION: The communication and social adjustment scores obtained upon inclusion were low, despite low autistic intensity scores. However, the improvement at six months was significant for most studied variables. These results are consistent with our clinical findings and seem partly explained by the use of video supports as the mediator of exchanges within the group. However, because of some methodological limitations, the conclusions on the effects of the intervention should be nuanced. CONCLUSIONS: This type of intervention seems to be an interesting therapeutic indication for individuals with high-functioning autism/Asperger syndrome. The first results are encouraging, and all participants enjoyed attending the meetings. These conclusion elements encourage us to continue this intervention and to pursue further research by studying the impact on the individuals' quality of life. PMID- 25439858 TI - [Psychiatric comorbidity related to children with attention deficit hyperactivity disorder at schools in Sfax, Tunisia]. AB - INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a prevalent behavioral disorder particularly noticed among school children. It is often associated with other psychological troubles at the origin of an additional difficulty that has to be overcome. OBJECTIVE: Our research's aim was to study the comorbidity of school-aged children diagnosed with ADHD in Sfax, Tunisia. SUBJECTS AND METHODS: A cross-sectional descriptive study was carried out from 1st April 2008 to 1st October 2008. Five hundred and thirteen pupils aged between 6 and 12, from primary arbitrarily chosen schools from Sfax were subjected to this study. Measurements were carried out in two steps: parents and teachers of each child filled in separately Conners questionnaire, then children with a score in subscales inattention, hyperactivity impulsivity higher than 70 were selected for psychiatric interview that was intended to confirm or to invalidate the ADHD diagnosis and the possible comorbid diagnosis. The diagnoses were made according to DSM-IV-TR. RESULTS: We have noticed that 109 pupils exhibited at least one pathological score on the Conners questionnaire. After interviewing these 109 pupils, the results have shown that 51 among them fulfilled criteria of ADHD. Prevalence of ADHD was found to be 9.94 %. About 72.54 % of children with ADHD had one or more comorbid disorder: learning disabilities (23.52 % of cases), anxiety disorder (31.37 % of cases), oppositional defiant disorder in (15.68 % of cases), mood disorder (3.92 % of cases), enuresis (13.72 % of cases) and slight mental retardation (1.95 % of cases). CONCLUSION: We can say that this study has shown that ADHD school children's psychiatric comorbidity is similar to any other previous study. PMID- 25439859 TI - [Neuroscience in the Courtroom: From responsibility to dangerousness, ethical issues raised by the new French law]. AB - AIM: In the past few years, spectacular progress in neuroscience has led to the emergence of a new interdisciplinary field, the so-called "neurolaw" whose goal is to explore the effects of neuroscientific discoveries on legal proceedings and legal rules and standards. In the United States, a number of neuroscientific researches are designed specifically to explore legally relevant topics and a case-law has already been developed. In Europe, neuroscientific evidence is increasingly being used in criminal courtrooms, as part of psychiatric testimony, nourishing the debate about the legal implications of brain research in psychiatric-legal settings. Though largely debated, up to now the use of neuroscience in legal contexts had not specifically been regulated by any legislation. In 2011, with the new bioethics law, France has become the first country to admit by law the use of brain imaging in judicial expertise. According to the new law, brain imaging techniques can be used only for medical purposes, or scientific research, or in the context of judicial expertise. This study aims to give an overview of the current state of the neurolaw in the US and Europe, and to investigate the ethical issues raised by this new law and its potential impact on the rights and civil liberties of the offenders. METHOD: An overview of the emergence and development of "neurolaw" in the United States and Europe is given. Then, the new French law is examined in the light of the relevant debates in the French parliament. Consequently, we outline the current tendencies in Neurolaw literature to focus on assessments of responsibility, rather than dangerousness. This tendency is analysed notably in relation to the legal context relevant to criminal policies in France, where recent changes in the legislation and practice of forensic psychiatry show that dangerousness assessments have become paramount in the process of judicial decision. Finally, the potential interpretations of neuroscientific data introduced into psychiatric testimonies by judges are explored. RESULTS: The examination of parliamentary debates showed that the new French law allowing neuroimaging techniques in judicial expertise was introduced in the aim to provide a legal framework that would protect the subject against potential misuses of neuroscience. The underlying fear above all, was that this technology be used as a lie detector, or as a means to predict the subject's behaviour. However, the possibility of such misuse remains open. Contrary to the legislator's wish, the defendant is not fully guaranteed against uses of neuroimaging techniques in criminal courts that would go against their interests and rights. In fact, the examination of the recently adopted legislation in France shows that assessments of dangerousness and of risk of recidivism have become central elements of the criminal policy, which makes it possible, if not likely that neuroimaging techniques be used for the evaluation of the dangerousness of the defendant. This could entail risks for the latter, as judges could perceive neuroscientific data as hard evidence, more scientific and reliable than the soft data of traditional psychiatry. If such neuroscientific data are interpreted as signs of potential dangerousness of a subject rather than as signs of criminal responsibility, defendants may become subjected to longer penalties or measures aiming to ensure public safety in the detriment of their freedom. CONCLUSION: In the current context of accentuated societal need for security, the judge and the expert-psychiatrist are increasingly asked to evaluate the dangerousness of a subject, regardless of their responsibility. Influenced by this policy model, the judge might tend to use neuroscientific data introduced by an expert as signs of dangerousness. Such uses, especially when they subjugate an individual's interest to those of society, might entail serious threats to an individual's freedom and civil liberties. PMID- 25439860 TI - Chitosan/fucoidan multilayer nanocapsules as a vehicle for controlled release of bioactive compounds. AB - Hollow multilayer nanocapsules were successfully prepared through layer-by-layer assembly of two bioactive polysaccharides, chitosan and fucoidan. The stepwise adsorption of 10 chitosan/fucoidan layers and the consequent formation of a multilayer film on polystyrene nanoparticles (used as templates) were followed through zeta-potential measurement and the removal of the polystyrene core was confirmed by FTIR analysis. The chitosan/fucoidan nanocapsules morphology and size were evaluated by SEM and TEM, which showed that after the core removal, the nanocapsules maintained their spherical shape and a decrease of size occurred. A cationic bioactive compound, poly-L-lysine (PLL), was chosen to evaluate the loading and release behaviour of the nanocapsules. The chitosan/fucoidan nanocapsules showed a good capacity for the encapsulation and loading of PLL, which shows to be influenced by the initial PLL concentration and the method of encapsulation used. The results of fitting the linear superimposition model to the experimental data of PLL release suggest an anomalous behaviour, with one main polymer relaxation. The PLL release was found to be pH-dependent: at pH 2 relaxation is the governing phenomenon and at pH 7 Fick's diffusion is the main mechanism of PLL release. Chitosan/fucoidan nanocapsules is a promising delivery system for water soluble bioactive compounds, such as PLL, showing a great potential of application in food and pharmaceutical industries. PMID- 25439861 TI - New insights on the thermal analysis of low moisture composite foods. AB - Low moisture baked products were investigated with a view to characterising the effect of both formulation and humidity on their physical stability. At the end of the baking process, the samples were in the amorphous state as a result of starch gelatinization and sugar melting. Their thermal properties were analyzed with differential scanning calorimetry and their glass transitions were studied. The DSC thermograms were thoroughly studied through a Gaussian deconvolution of the first derivative of their heat flow. This approach evidenced a multiple phase behavior with different glass transitions in composite systems. They were associated with either a polymer-rich phase and/or a plasticizer (sugar)-rich phase whose behavior depended on the sample water content. This novel approach of thermal properties suggested new insights: considering the phase behavior of complex systems and thus the properties of their individual phases could contribute to a better understanding of the physical stability of the products. PMID- 25439864 TI - Preparation and properties of a starch-based wood adhesive with high bonding strength and water resistance. AB - A Highly efficient method was developed for preparing starch-based wood adhesives with high performance, using H2O2, a silane coupling agent and an olefin monomer as an oxidant, cross-linking agent and comonomer, respectively. The effects of various parameters on the shear adhesive strength were investigated in the dry state (DS) and wet state (WS). The results indicated that the bonding strength of starch-based wood adhesives could reach 7.88 MPa in dry state and 4.09 MPa in wet state. The oxidation could reduce the content of the hydroxyl transforming into carboxyl and aldehyde groups, and the graft copolymerization enhanced the thermal stability, which improved the bonding strength and water resistance. The starch based adhesive and the fractures in the bonded joints were analyzed via Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and thermogravimetric analysis (TGA). The improved properties were attributed to the modified of microstructure of the graft-copolymerized starch-based adhesive. PMID- 25439863 TI - Extraction and antioxidant activity of polysaccharides from Rana chensinensis skin. AB - The extraction process of polysaccharides from Rana chensinensis skin was optimized by using a Box-Behnken design. The optimum extraction conditions were as follows: extraction time, 4.96h; extraction temperature, 100 degrees C; ratio of water to raw material, 60; and extraction frequency, 1. Under these conditions, the experimental polysaccharide yield was 2.03+/-0.14%, which agreed with the predicted yield. The purified polysaccharide RCSP II was successfully obtained by diethylaminoethanol-Sepharose and Sepharose CL-6B column chromatography. In vitro experiments showed that RCSP II exhibited a strong scavenging activity against superoxide anion and 1,1-diphenyl-2-picrylhydrazyl radicals but a weak scavenging activity against hydroxyl radicals. RCSP II also showed a strong reducing capacity. Thus, this polysaccharide can be used as a natural antioxidant in functional foods or medicines. PMID- 25439862 TI - Development of tannic acid/chitosan/pullulan composite nanofibers from aqueous solution for potential applications as wound dressing. AB - This study presents the successful development of biocompatible tannic acid (TA)/chitosan (CS)/pullulan (PL) composite nanofibers (NFs) with synergistic antibacterial activity against the Gram-negative bacteria Escherichia coli. The NFs were developed utilizing the forcespinning((r)) (FS) technique from CS-CA aqueous solutions to avoid the usage of toxic organic solvents. The ternary nanofibrous membranes were crosslinked to become water stable for potential applications as wound dressing. The morphology, structure, water solubility, water absorption capability and thermal properties of the NFs were characterized. The ternary composite membrane exhibits good water absorption ability with rapid uptake rate. This novel membrane favors fibroblast cell attachment and growth by providing a 3D environment which mimics the extracellular matrix (ECM) in skin and allows cells to move through the fibrous structure resulting in interlayer growth throughout the membrane, thus favoring potential for deep and intricate wound healing. PMID- 25439865 TI - Inhibition of alpha-glucosidase by polysaccharides from the fruit hull of Camellia oleifera Abel. AB - We isolated and purified polysaccharides from the Camellia oleifera Abel. fruit hull and studied its hypoglycemic potential. Our results revealed six polysaccharides (CFPA-1-5 & CFPB) from the aqueous extract from the defatted C. oleifera fruit hull. Purified polysaccharides (purity >90%) were investigated for the inhibition of alpha-glucosidase activity in vitro. Two polysaccharides, CFPB and CFPA-3 were present in high concentration in the fruit hull and showed a dose dependent inhibition of alpha-glucosidase activity, with IC50 concentrations of 11.80 and 10.95 MUg/mL, respectively. This result suggests that polysaccharides (CFP) extracted from the fruit hull of C. oleifera may have potential as functional foods with featuring a hypoglycemic effect. PMID- 25439866 TI - Dissolving pulp from jute stick. AB - Jute stick is woody portion of jute plant, which remain as leftover after extracting bast fibre. Presently, it is being used for fencing in the rural area. In this investigation, biorefinery concept was initiated in producing dissolving pulp from jute stick by pre-hydrolysis kraft process. At 170 degrees C for 1h of pre-hydrolysis, 70% of hemicelluloses was dissolved with negligible loss of alpha cellulose. At this condition, 75% of dissolved sugars in the pre-hydrolysis liquor were in the oligomeric form. The pre-hydrolysed jute stick was subsequently pulped by kraft process with the variation of active alkali. The pulp yield was 36.2% with kappa number 18.5 at the conditions of 16% active alkali for 2h of cooking at 170 degrees C. Final pulp was produced with 92% alpha cellulose and 89% brightness after D0EpD1EpD1 bleaching. The produced dissolving pulp can be used in rayon production. PMID- 25439867 TI - Hydrolysis of cellulose catalyzed by novel acidic ionic liquids. AB - The conversion of cellulosic biomass directly into valuable chemicals becomes a hot subject. Six novel acidic ionic liquids (ILs) based on 2-phenyl-2-imidazoline were synthesized and characterized by UV-VIS, TGA, and NMR. The novel acidic ionic liquids were investigated as catalysts for the hydrolysis of cellulose in 1 butyl-3-methylimidazolium chloride ([Bmim]Cl). The acidic ionic liquids with anions HSO4(-) and Cl(-) showed better catalytic performance for the hydrolysis of cellulose than those with H2PO4(-). The temperature and dosage of water affect significantly the yield of total reducing sugar (TRS). When the hydrolysis of cellulose was catalyzed by 1-propyl sulfonic acid-2-phenyl imidazoline hydrogensulfate (IL-1) and the dosage of water was 0.2g, the TRS yield was up to 85.1% within 60 min at 100 degrees C. These new acidic ionic liquids catalysts are expected to have a wide application in the conversion of cellulose into valuable chemicals. PMID- 25439868 TI - Feasibility study of the naturally occurring dialdehyde carboxymethyl cellulose for biological tissue fixation. AB - The aim of this study was to evaluate the crosslinking effect of dialdehyde carboxymethyl cellulose (DCMC) on decellularized porcine aortas. Before implanted, biological tissues must be chemically modified to avoid rapid enzymatic degradation and serious immune response. To overcome limitations like high cytotoxicity and susceptibility to calcification caused by glutaraldehyde (GA), a traditional crosslinking reagent, dialdehyde carboxymethyl cellulose (DCMC) was employed to fix biological tissues. The crosslinking characteristics and cytotoxicity of aortas fixed by DCMC were all investigated. The results indicated that DCMC-fixation significantly increased the mechanical strength and the capacity of enzymatic hydrolytic resistance of tissues. The histological examination showed that the microcosmic structures of tissues were all preserved well after DCMC fixation. In addition, the data obtained from MTT assay confirmed that the cytotoxicity of DCMC-fixed tissues was significantly lower than glutaraldehyde-fixed counterparts. In a word, the present study demonstrated DCMC might be an effective crosslinking reagent for biological tissue fixation with low cytotoxicity. PMID- 25439869 TI - Effect of hydrothermal pretreatment on solubility and formation of kenaf cellulose membrane and hydrogel. AB - The hydrothermal pretreatment on kenaf core pulp (KCP) was carried out using an autoclave heated in a oil bath at 140 degrees C for 0.5/1/3/5h. The hydrothermal pretreated kenaf (HPK) was dissolved in a LiOH/urea aqueous solution and subsequently used to produce cellulose membrane and hydrogel. The effects of hydrothermal pretreatment time on solubility, viscosity, crystallinity and morphology of the cellulose membrane and hydrogel were investigated. The hydrothermal pretreatment leads to higher cellulose solubility and higher viscosity of the cellulose solution. The formation of cellulose II and crystallinity index of the cellulose membrane and hydrogel were examined by X-ray diffraction (XRD). The pore size of the cellulose membrane and hydrogel displayed an upward trend with respect to the hydrothermal pretreatment period observed under a field emission scanning electron microscope (FESEM). This finding provides an efficient procedure to improve the solubility, viscosity and properties of regenerated cellulose products. PMID- 25439870 TI - Electrospun novel super-absorbent based on polysaccharide-polyvinyl alcohol montmorillonite clay nanocomposites. AB - A novel super-absorbent material was fabricated by electrospinning the natural polysaccharide pullulan (PULL) with polyvinyl alcohol (PVA) and montmorillonite (MMT) clay to form nonwoven webs, which were then heat treated. Transmission electron microscopy (TEM) micrographs, X-ray diffraction (XRD) patterns, and Fourier transform infrared (FTIR) analysis of the novel super-absorbent nanofibers suggest the coexistence of PULL, PVA, and MMT through the exfoliation of MMT layers in the super-absorbent nanofiber composite. The heat-treated PULL/PVA/MMT webs loaded with 5 wt% MMT electrospun nanofibers exhibited a water absorbency of 143.42 g g(-1) in distilled water and a water absorbency of 39.75 g g(-1) in a 0.9 wt% NaCl solution. Under extremely dry conditions, the PULL/PVA/MMT webs exhibited the ability to retain 43% distilled water and 38% saline water after being exposed to the atmosphere for one week. The heat treatment improved the crystallinity of the electrospun PULL/PVA/MMT super absorbent webs and thus made the webs highly stable in aqueous environments. Overall, the addition of MMT resulted in improved thermal stability and mechanical properties and increased the water absorbency of the PULL/PVA/MMT composite. PMID- 25439871 TI - Effects of acidic functional groups on dielectric properties of sodium alginates and carrageenans in water. AB - This study investigated the dielectric properties of sodium alginates and carrageenans in water at frequencies between 100 MHz and 20 GHz in regard to water-hydrocolloid interactions via acidic functional groups. Both sodium alginates and carrageenans showed conduction loss at lower frequencies and dielectric loss at higher frequencies. Reduction and desulfation of sodium alginates and carrageenans, which decreased the numbers of acidic functional groups, decreased their conduction loss. In addition, H(+)-form carrageenans showed the highest ionic conduction. Correlational analysis of dielectric properties and related physical parameters showed that the loss tangent (tandelta) of the hydrocolloid solution was determined by the conductivity of the aqueous solution. Especially at pH below 2, strong H(+) conduction was associated with high tandelta probably due to the Grotthuss mechanism. The molecular dynamics of free water and H(+), viscosity conditions were also suggested to be associated with dielectric property of water-hydrocolloid system. PMID- 25439872 TI - Direct study of fluorescently-labelled barley beta-glucan fate in an in vitro human colon digestion model. AB - beta-Glucans from cereals are beta(1-3)(1-4)-mixed linkage linear homopolysaccharides of D-glucopyranosyl residues, recently recognised as functional components of foods with benefits in maintaining the health of the digestive tract not least through a prebiotic effect. Here we describe the development of methodology to facilitate the study of beta-glucans as prebiotics. Relatively short beta-glucan fragments (DP 6-50) were produced by partial hydrolysis of beta-glucan fibres with Lichenase then functionalised at their reducing end with a tetramethylrhodamine dye. Their enzymatic break down by human colon microbiota in an in vitro fermentation model was examined. Digestion products were isolated by virtue of their fluorescence labels, identified and characterised using capillary electrophoresis and mass spectrometry. Complete digestion of the labelled substrates was indicated, as fluorescently labelled glucose was obtained as the final product. Furthermore, a pathway of enzymatic breakdown was proposed on the basis of a time course experiment; initial fast hydrolysis with an endo-1,3(4)-beta-glucanase was followed by slow degradation with an exo-1,4-beta-glucanase and finally slow action of an exo-1,3-beta glucanase. PMID- 25439873 TI - Combining FT-IR spectroscopy and multivariate analysis for qualitative and quantitative analysis of the cell wall composition changes during apples development. AB - The aim of this work was to quantitatively and qualitatively determine the composition of the cell wall material from apples during development by means of Fourier transform infrared (FT-IR) spectroscopy. The FT-IR region of 1500-800 cm( 1), containing characteristic bands for galacturonic acid, hemicellulose and cellulose, was examined using principal component analysis (PCA), k-means clustering and partial least squares (PLS). The samples were differentiated by development stage and cultivar using PCA and k-means clustering. PLS calibration models for galacturonic acid, hemicellulose and cellulose content from FT-IR spectra were developed and validated with the reference data. PLS models were tested using the root-mean-square errors of cross-validation for contents of galacturonic acid, hemicellulose and cellulose which was 8.30 mg/g, 4.08% and 1.74%, respectively. It was proven that FT-IR spectroscopy combined with chemometric methods has potential for fast and reliable determination of the main constituents of fruit cell walls. PMID- 25439874 TI - Viscosity based quantification of endogenous beta-glucanase activity in flour. AB - High molecular weight (MW) is a key parameter for cereal beta-glucans physiological benefits like decreased serum cholesterol and attenuated post prandial blood glucose. However, the activity of endogenous flour enzymes during bread production results in a decrease of beta-glucan MW. The depolymerization of a standard beta-glucan solution by different flour extracts (wheat, barley and rye) was followed by measuring the viscosity decrease with a Rheometer. The slope of the inverse viscosity (1/eta) against degradation time was used to quantify beta-glucanase activity by comparison with slopes obtained with known concentrations of the beta-glucanase Lichenase. Results correlated well with depolymerization rates estimated by HPSEC. The viscosity based method is rapid (20 min per sample), accurate (<=6% variation), and a powerful screening tool for identifying flour fractions with low beta-glucanase activity, treatments that can inactivate beta-glucanases in flour, or the development of beta-glucanase inhibitors for the use in e.g. bread making. PMID- 25439875 TI - Effect of ripening and heat processing on the physicochemical and rheological properties of pepper pectins. AB - Water-, chelator-, and alkali-soluble pectins were isolated from raw and heat processed Jalapeno peppers (green and red) and their physiochemical and rheological properties were determined. The yield, tristimulus color, degree of methyl esterification, monosaccharide composition, molecular weights distribution, and protein content depended on ripening and heat processing. The viscosity properties of pectins were independent of ripening. The water-soluble pectin was the most abundant pectin. Pectins from grilled peppers showed the lowest L* values. The alkali-soluble pectin showed the highest protein content. The content of xylose, rhamnose, and mannose in pectins was highly altered by tested factors. The degree of methyl esterification of pectins ranged from 26.8 to 91.6%. The peak Mw of the main fraction of tested pectins was sequentially reduced by ripening and heat processing. Pectins from raw peppers showed the best viscosity properties. PMID- 25439876 TI - Anti-HIV activity of fucoidans from three brown seaweed species. AB - Fucoidans are sulfated polysaccharides derived from marine brown algae. In the current work the anti-HIV activity of three fucoidans, extracted from three brown seaweeds Sargassum mcclurei, Sargassum polycystum and Turbinara ornata and collected from Nha Trang bay, Vietnam was investigated. Fucoidans extracted from the three species displayed similar antiviral activities with a mean IC50 ranging from 0.33 to 0.7 MUg/ml while displaying no cell toxicity. Our results showed that the anti-HIV activity of fucoidans is not primarily linked to the sulfate content and the appropriate position of sulfate groups in the fucoidan backbones was also not associated with the antiviral activity. Fucoidans inhibited HIV-1 infection when they were pre-incubated with the virus but not with the cells, and not after infection, blocking the early steps of HIV entry into target cells. These data contribute to a better understanding of the influence of fucoidans structural characteristics on their biological activity. PMID- 25439877 TI - Study of the physical properties of calcium alginate hydrogel beads containing vineyard pruning waste for dye removal. AB - In this work the morphological and surface properties of a biocomposite formulated with vineyard pruning waste entrapped in calcium alginate hydrogel beads were studied. The formulation of the calcium alginate hydrogel beads, containing vineyard pruning waste, was based on the capacity of this green adsorbent to remove dye compounds from wastewater, observing that in the optimum condition (1.25% of cellulosic residue, 2.2% of sodium alginate and 0.475 mol L( 1) CaCl2) the percentage of dyes was reduced up to 74.6%. At lower concentration of CaCl2, high-resolution optical images show that the elongation of the vineyard alginate biocomposite decreased, whereas the compactness increased. Moreover, higher concentrations of cellulosic residue increased the biocomposite roundness in comparison with biocomposite without the cellulosic residue. Interferometric perfilometry analysis (Ra, Rq, Rz and Rt) revealed that high concentrations of CaCl2 increased the roughness of the of the calcium alginate hydrogel beads observing vesicles in the external surface. PMID- 25439878 TI - Synthesis and characterization of pectin derivative with antitumor property against Caco-2 colon cancer cells. AB - New pectin derivative (Pec-MA) was obtained in specific reaction conditions. The presence of maleoyl groups in Pec-MA structure was confirmed by (1)H NMR and FTIR spectroscopy. The substitution degree of Pec-MA (DS=24%) was determined by (1)H NMR. The properties of Pec-MA were investigated through WAXS, TGA/DTG, SEM and zeta potential techniques. The Pec-MA presented amorphous characteristics and higher-thermal stability compared to raw pectin (Pec). In addition, considerable morphological differences between Pec-MA and Pec were observed by SEM. The cytotoxic effect on the Caco-2 cells showed that the Pec-MA significantly inhibited the growth of colon cancer cells whereas the Pec-MA does not show any cytotoxic effect on the VERO healthy cells. This result opens new perspectives for the manufacture of biomaterials based on Pec with anti-tumor properties. PMID- 25439879 TI - Catalytic hydrothermal conversion of carboxymethyl cellulose to value-added chemicals over metal-organic framework MIL-53(Al). AB - Catalytic hydrolysis of biomass over solid catalysts can be one of the most efficient pathways for a future sustainable society dependent on cellulose biomass. In this work metal-organic framework MIL-53(Al) without any functionalization was directly employed as an efficient heterogeneous catalyst for the hydrolysis of carboxymethyl cellulose (CMC) to 5-hydroxymethyl furaldehyde (5-HMF) in aqueous phase. A 5-HMF molar yield of 40.3% and total reducing sugar (TRS) molar yield of 54.2% were obtained with water as single solvent at 473 K for 4 h. The catalyst could be reused three times without losing activity to a greater extent. With the remarkable advantages such as the use of water as single solvent and MIL-53(Al) as a novel heterogeneous green catalyst, the work provides a new platform for the production of value added chemicals and liquid fuels from biomass. PMID- 25439880 TI - Fibrinolytic, anti-inflammatory and anti-microbial properties of alpha-(1-3) glucans produced from Streptococcus mutans (MTCC 497). AB - Streptococcus mutans (MTCC 497) cell associated alpha-(1-3)-glucans were isolated, characterized and evaluated for their bioactivity profile. Acid hydrolysis of alpha-(1-3)-glucans revealed presence of glucose moieties. Water insoluble alpha-(1-3)-glucans (WIG) were sulfated to convert them into water soluble glucans which were characterized by FT-IR spectral studies. The sulfation of WIG was confirmed by the presence of -O-SO3- and C-O-SO3- characteristic peaks at 1240 and 820 cm(-1). MALDI-TOF analysis of sulfated alpha-(1-3)-glucan revealed 1.2 to 9kDa fragmentation. Antibacterial profile studies revealed higher growth inhibitory activity against Gram negative than Gram positive bacterial strains by sulfated alpha-(1-3)-glucans. One-fold higher anti-inflammatory activity with IC50 value of 0.11mg/ml was observed with sulfated alpha-(1-3) glucans over WIG. Time dependent fibrinolytic potential without requirement of tissue plasminogen activators was observed for sulfated alpha-(1-3)-glucans. This is the first report demonstrating the fibrinolytic and anti-inflammatory property for sulfated alpha-(1-3)-glucans. PMID- 25439881 TI - Chitosan-hyaluronic acid polyelectrolyte complex scaffold crosslinked with genipin for immobilization and controlled release of BMP-2. AB - Polyelectrolyte complex (PEC) is formed when polymers with opposite charges are combined in solution. PECs are recently gaining attention as carriers for controlled release of drugs and proteins. Herein, bone morphogenetic protein-2 (BMP-2) was immobilized in a PEC of natural polymers, chitosan and hyaluronic acid. Charge-to-charge stoichiometry of the formed PEC was estimated based on turbidity of combined chitosan and hyaluronic acid solutions. Free amino groups in chitosan were crosslinked with different amounts of genipin. The degree of crosslinking, consequently its effects in vitro in terms of swelling, degradation and cytocompatibility were analyzed. Immobilization of three different amount of BMP-2 in chitosan-hyaluronic acid PEC scaffold resulted sustained release of the growth factor for more than 30 days. Immobilization efficacies varied from 61% to 76% depending on the amount of BMP-2. Finally effects in osteogenic differentiation of the PEC with BMP-2 to MC3T3-E1 cells were determined by reverse transcriptase PCR. PMID- 25439883 TI - Removal of cadmium(II) from aqueous solutions by chemically modified maize straw. AB - A new regenerable adsorbent was successfully prepared by modifying maize straw (MS) with succinic anhydride in xylene. The succinylated-maize straw (S-MS) was characterized by FTIR, solid-state MAS (13)C NMR spectroscopy, SEM-EDX and point of zero charge analysis. NaS-MS was successfully obtained after deprotonating the carboxylic acid groups of S-MS by Na2CO3 solution. Batch experiments were carried out with NaS-MS for the removal of Cd(II). The effects of pH, adsorbent dosage, contact time, initial concentration and temperature were investigated. The experimental data were best described by a pseudo-second-order kinetics and Langmuir adsorption models. Thermodynamic parameters (DeltaG, DeltaH, and DeltaS) were also calculated from data obtained from experiments performed to study the effect of temperatures. NaS-MS could be regenerated at least five times in saturated NaCl solution without any loss. Furthermore, ~97% of adsorbed Cd(II) ions could be recovered as the metal oxide. Finally, the adsorption mechanism of NaS-MS was discussed. PMID- 25439882 TI - Structure and properties of hydroxyapatite/hydroxyethyl cellulose acetate composite films. AB - The main aim of this research work was to develop a new inorganic-organic film. Hydroxyapaptite (HAp) particles that represent the inorganic phase was mixed well with hydroxyethyl cellulose acetate (HECA), which representing the organic phase and then the inorganic-organic films were fabricated by evaporating of the solvent. The structure as well as the properties of the formed films were characterized using different analytical tools such as field emission scanning electron microscopy (FEG-SEM), thermo-gravimetric analysis (TGA), Fourier transform infra-red (FT-IR) spectroscopy. The obtained results revealed that, the HAp nanoparticles was well dispersed and well immobilized throughout the formed films. This can be attributed to the role of the nano- and micropores in the HECA substrate. In addition, a strong interaction occurred between HAp and HECA matrix. The results showed also good thermal stability and miscibility as well. PMID- 25439885 TI - Effect of commercial cellulases and refining on kraft pulp properties: correlations between treatment impacts and enzymatic activity components. AB - The importance of enzymes as biotechnological catalysts for paper industry is now recognized. In this study, five cellulase formulations were used for fibre modification. The number of PFI revolutions decreased by about 50% while achieving the same freeness value (decrease in CSF by 200 mL) with the enzymatic pretreatment. The physical properties of handsheets were modified after enzymatic pretreatment followed by PFI refining. A slight decrease in tear strength was observed with enzymes C1 and C4 at pH 7 while the most decrease in tear was observed after C2, C3, C5 treatments. C1 and C4 which had xylanase activity improved paper properties, while other enzymes had a negative impact. Therefore, the intricate balance between cellulolytic and hemicellulolytic activity is the key to optimizing biorefining and paper properties. It was also observed that C1 impact was pH dependent, which supports the importance of pH in developing an enzymatic strategy for refining energy reduction. PMID- 25439884 TI - Influence of reaction parameters on carboxymethylation of rice starches with varying amylose contents. AB - The influence of reaction parameters on the carboxymethylation of rice starches with different amylose contents was investigated. Rice starches with varying amylose contents showed various degrees of susceptibility to the reaction conditions. The maximum degree of substitution (DS) for all three rice starches was obtained under similar reaction conditions which involved a reaction medium consisting of isopropanol-water at the ratio of 90:10, a molar ratio of NaOH:AGU at 1.5 and a reaction temperature and time of 40 degrees C and 3 h. Under these conditions, the DS for all rice starches was similar; however, when the reaction was performed under conditions using lower NaOH concentration, the effect of starch types on the DS was observed. The results could be explained in terms of the granular/structural features of the different rice starches, their degrees of granular swelling as influenced by the reaction conditions and the accessibility of the etherifying reagents to starch molecules. PMID- 25439886 TI - Structural characterization, sulfation and antitumor activity of a polysaccharide fraction from Cyclina sinensis. AB - In the present study, we investigated the preliminary structure, sulfation and antitumor activity of a polysaccharide fraction from Cyclina sinensis (CSPS-1). Results of structural characterization showed that the backbone chain of CSPS-1 was composed of glucose linked by alpha-(1->4) glycosidic bond, and the branch chain was attached to backbone chain by (1->6) glycosidic bond. CSPS-1 was sulfated by chlorosulfonic acid-pyridine method under different modification conditions according to the orthogonal test L9(3(4)), affording nine sulfated polysaccharides (CSPS-1-S). The optimal sulfation conditions for CSPS-1 were reaction temperature of 65 degrees C, reaction time of 2h and chlorosulfonic acid pyridine ratio of 1:4. Structural analysis revealed that sulfation had occurred at position of C-6 in CSPS-1. In addition, CSPS-1-S exhibited significantly higher inhibitory activity in vitro against human gastric cancer BGC-823 cells. PMID- 25439887 TI - Changes of wood cell walls in response to hygro-mechanical steam treatment. AB - The effects of compression combined with steam treatment (CS-treatment), i.e. a hygro-mechanical steam treatment on Spruce wood were studied on a cell-structure level to understand the chemical and physical changes of the secondary cell wall occurring under such conditions. Specially, imaging FT-IR microscopy, nanoindentation and dynamic vapour absorption were used to track changes in the chemical structure, in micromechanical and hygroscopic properties. It was shown that CS-treatment resulted in different changes in morphological, chemical and physical properties of the cell wall, in comparison with those under pure steam treatment. After CS-treatment, the cellular structure displayed significant deformations, and the biopolymer components, e.g. hemicellulose and lignin, were degraded, resulting in decreased hygroscopicity and increased mechanical properties of the wood compared to both untreated and steam treated wood. Moreover, CS-treatment resulted in a higher degree of degradation especially in earlywood compared to a more uniform behaviour of wood treated only by steam. PMID- 25439888 TI - Effect of cellulose nanocrystals and gelatin in corn starch plasticized films. AB - Cellulose at the nanoparticle scale has been studied as a reinforcement for biodegradable matrices to improve film properties. The goal has been to investigate the properties of starch/gelatin/cellulose nanocrystals (CNC) films. Eleven treatments were considered using RCCD (rotatable central composite design), in addition to four control treatments. For each assay, the following dependent variables were measured: water vapor permeability (WVP), thickness, opacity and mechanical properties. The microstructure and thermal properties of the films were also assessed. Increases in gelatin and CNC concentrations lead to increases in film thickness, strength and elongation at break. The films containing only gelatin in their matrix displayed better results than the starch films, and the addition of CNC had a positive effect on the assessed response variables. The films exhibited homogeneous and cohesive structures, indicating strong interactions between the filler and matrix. Films with low levels of gelatin and CNC presented the maximum degradation temperature. PMID- 25439889 TI - Wood mimetic hydrogel beads for enzyme immobilization. AB - Wood component-based composite hydrogels have potential applications in biomedical fields owing to their low cost, biodegradability, and biocompatibility. The controllable properties of wood mimetic composites containing three major wood components are useful for enzyme immobilization. Here, lipase from Candida rugosa was entrapped in wood mimetic beads containing cellulose, xylan, and lignin by dissolving wood components with lipase in [Emim][Ac], followed by reconstitution. Lipase entrapped in cellulose/xylan/lignin beads in a 5:3:2 ratio showed the highest activity; this ratio is very similar to that in natural wood. The lipase entrapped in various wood mimetic beads showed increased thermal and pH stability. The half-life times of lipase entrapped in cellulose/alkali lignin hydrogel were 31- and 82-times higher than those of free lipase during incubation under denaturing conditions of high temperature and low pH, respectively. Owing to their biocompatibility, biodegradability, and controllable properties, wood mimetic hydrogel beads can be used to immobilize various enzymes for applications in the biomedical, bioelectronic, and biocatalytic fields. PMID- 25439890 TI - Rheological, emulsifying and thermostability properties of two exopolysaccharides produced by Bacillus amyloliquefaciens LPL061. AB - The rheological, emulsification, thermostability and certain physicochemical properties of two purified exopolysaccharides from Bacillus amyloliquefaciens LPL061 were studied. EPS1 showed entangled spider mesh structure that composed of dense rope with homogeneous hexagonal particles under scanning electron microscopy. EPS2 had a porous sponge structure with uniform cylindrical particles. The two exopolysaccharides showed higher intrinsic viscosity and better emulsification activity with sunflower seed oil, rice oil, olive oil and peanut oil compared to guar gum. EPS1 is the most promising one for applications in the industry, as it had high intrinsic viscosity, apparent viscosity and thermostablity in aqueous solution, dense entangled structure and good emulsification activity. PMID- 25439891 TI - Green chitosan-carbon dots nanocomposite hydrogel film with superior properties. AB - In this work we report novel chitosan-carbon dots nanocomposite hydrogel films. A new green source "tea" was used as precursor for carbon dots (CDs). The electrostatic interaction of positive charge on chitosan and negative charge on CDs prepared from tea was used for the successful preparation of a stable and robust chitosan-carbon dots nanocomposite hydrogel film. The hydrogel films were characterized by UV-visible spectroscopy, X-ray diffraction (XRD), Fourier transformed infra-red spectroscopy (FTIR), scanning electron microscope (SEM), fluorescent microscopy, thermogravimetric analysis (TGA) and contact angle analysis. It was observed that chitosan-carbon dots hydrogel films are soft but tough with superior UV-visible blocking, swelling, thermal and mechanical properties in comparison to chitosan hydrogel film. Moreover chitosan-carbon dots films are more water repellent (hydrophobic) as indicated by their high contact angle values. Thus, fabrication of such green soft but tough biocompatible chitosan-carbon dots nanocomposite hydrogel films offers tremendous bio-medical and industrial applications. PMID- 25439892 TI - Effects of corn fiber gum (CFG) on the pasting and thermal behaviors of maize starch. AB - Corn fiber gum (CFG) was a novel arabinoxylan hydrocolloid and recent researches showed its considerable potential in food processing. In this study, the interactions of maize starch and CFG were studied. Maize starch/CFG blend gels were prepared from maize starch suspension mixing with 0.1%, 0.25%, 0.5%, 1.0% (w/w) CFG. The pasting and thermal properties, rheological properties, microstructure, leached amylose and swelling power characteristics were evaluated. Compared with the reference, CFG addition lowered peak viscosity and breakdown of the composite system, but increased final viscosity in RVA measurement. The swelling power and the amount of leached amylose of maize starch gels were reduced as the addition concentration of CFG increased. The thermal characteristics of maize starch/CFG mixtures varied insignificantly as determined in DSC heating process. Rheological parameters, such as storage modulus (G') and loss modulus (G"), of the maize starches were observed to increase when CFG was present, supporting the hypothesis that the interaction between CFG and amylose could happen in the composite system. Confocal laser scanning microscopy (CLSM) confirmed changes in gels microstructure as starch components tended to be inhibited from leaching out of the granules when CFG was added, and the morphology of starch granule was more compact when CFG was added. PMID- 25439893 TI - Modulation in the rheological behaviour of porcine pepsin treated guar galactomannan on admixture with kappa-carrageenan. AB - The non-specific action of pepsin on guar galactomannan (GG) resulted in selective removal of galactose residues, leading to the formation of galactose - depleted guar galactomannan (GDGG) with decrease in Mw and change in G: M ratio of 1:3.4, thus mimicking that of locust bean gum (LBG). Admixture of GDGG with kappa-carrageenan revealed a two fold increase in the magnitude of elasticity (G') compared to kappa-carrageenan alone, suggesting a synergistic interaction similar to LBG with kappa-carrageenan. Blends of GDGG and LBG with kappa carrageenan at a concentration of 40% (w/w, 0.8% total biopolymer) showed a maximum increase in G'. The GDGG/kappa-carrageenan blend also showed a Tm of 47 degrees C, similar to LBG/kappa-carrageenan blend. Thus, debranching of guar galactomannan by the catalytic action of pepsin is beneficial for improved functional properties and diversified applications. PMID- 25439894 TI - Impact of variety type and particle size distribution on starch enzymatic hydrolysis and functional properties of tef flours. AB - Tef grain is becoming very attractive in the Western countries since it is a gluten-free grain with appreciated nutritional advantages. However there is little information of its functional properties and starch digestibility and how they are affected by variety type and particle size distribution. This work evaluates the effect of the grain variety and the mill used on tef flour physico chemical and functional properties, mainly derived from starch behavior. In vitro starch digestibility of the flours by Englyst method was assessed. Two types of mills were used to obtain whole flours of different granulation. Rice and wheat flours were analyzed as references. Protein molecular weight distribution and flour structure by SEM were also analyzed to justify some of the differences found among the cereals studied. Tef cultivar and mill type exhibited important effect on granulation, bulking density and starch damage, affecting the processing performance of the flours and determining the hydration and pasting properties. The color was darker although one of the white varieties had a lightness near the reference flours. Different granulation of tef flour induced different in vitro starch digestibility. The disc attrition mill led to higher starch digestibility rate index and rapidly available glucose, probably as consequence of a higher damaged starch content. The results confirm the adequacy of tef flour as ingredient in the formulation of new cereal based foods and the importance of the variety and the mill on its functional properties. PMID- 25439895 TI - Preparation and properties of cellulose/silver nanocomposite fibers. AB - We prepared cellulose/silver nanocomposite fibers by soaking the cellulose fibers in AgNO3 aqueous solution, which was heated at 80 degrees C for 24h to synthesize Ag nanoparticles in situ. The structure and properties of the composite fibers were characterized by FT-IR, X-ray diffraction (XRD), scanning electron microscopy (SEM), transmitting electron microscopy (TEM), thermo-gravimetric analysis (TGA) and tensile testing. The content and diameter of the Ag nanoparticles (NPs) increased from 0.15% to 2.40% and from 7.2 nm to 12.5 nm, respectively. In our findings, the pores of the cellulose fiber at wet state were used as a microreactor to synthesize Ag nanopariticles. The cellulose/Ag nanocomposite fibers exhibited good mechanical properties and thermal stability. Antibacterial experiment revealed excellent antibacterial activity of the cellulose nanocomposite fibers against Staphylococcus aureus. The cellulose/silver nanocomposite fibers would have great potential in antibacterial textile and wound handling due to easy industrialization. PMID- 25439896 TI - Synthesis, characterization and antimicrobial properties of grafted sugarcane bagasse/silver nanocomposites. AB - Sugarcane bagasse (SCB) was grafted with acrylamide (AAm) and glycidyl methacrylate (GMA) by chemical oxidation method. The effect of monomer/initiator molar ratio, reaction time, reaction temperature and material to liquor ratio on the degree of grafting was investigated. The optimum conditions for grafting were: monomer/initiator molar ratio 1 for AAm and 2 for GMA, reaction time 4h, reaction temperature 80 degrees C and materials to liquor ratio 1:20. Silver nanoparticles (AgNPs) were prepared and characterized by X-ray diffraction (XRD) and transmission electron microscopy (TEM). Ungrafted SCB, SCB-g-AAm and SCB-g GMA were impregnated into silver (Ag) nanoparticles colloidal solution. The ungrafted SCB, grafted SCB and their nanocomposites with Ag nanoparticles were characterized by FT-IR spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy (SEM). The grafted SCB/Ag nanoparticles exhibit better antimicrobial activity against Escherichia coli as the model Gram-negative bacteria, Staphylococcus aureus as the model Gram-positive bacteria and Aspergillus flavus and Candida albicans (yeasts) than ungrafted SCB/AgNPs. PMID- 25439897 TI - Biopolymer starch mediated synthetic route of multi-spheres and donut ZnO structures. AB - A starch-assisted synthetic methodology of multispheres ZnO-starch biocomposites was developed. An additional thermal processing of the ZnO-starch composites induces the formation of ZnO with donut-like morphology. The synthesis of single phase zinc oxide with a spherical morphology is conditioned by the presence of starch, which acts as template, stabilizing/capping agent. The synthesized structures present significant photocatalytic activities; a total phenol mineralization is attained with the donut-like ZnO photocatalyst under visible light irradiation, due to a cumulative effect of the its relatively large specific surface area, high crystallinity and favorable combination of defects for band narrowing, which together permit an enhanced utilization rate of the light. PMID- 25439898 TI - Modification of arabinogalactan propargyl ethers by triazolyl functions. AB - Polysaccharide arabinogalactan (AG) has been modified by triazolyl functions via the copper-catalyzed 1,3-dipolar addition of azides to propargyl ethers. A range of new AG triazolo derivatives bearing benzyl, 4-vinylbenzyl, 1-naphthylmethyl, (1-vinylimidazol-2-yl)methyl, (1-ethylimidazol-2-yl)methyl, (1-vinylbenzimidazol 2-yl)methyl, allyl, carboxymethyl (as Na-salt) substituents is prepared by "one pot" approach from organic azides generated in situ and AG propargyl ethers. The latter (degree of substitution 2.0-2.2) are converted into 1,2,3-triazolo AGs in DMSO/water mixture in the presence of CuSO4.5H2O/sodium ascorbate/Et3N in 82-94% yields and with 60-100% conversion. PMID- 25439899 TI - Rice starch granule amylolysis--differentiating effects of particle size, morphology, thermal properties and crystalline polymorph. AB - The underlying mechanism of amylolysis of rice starch granules was investigated using isolated starch granules from wild-type, as well as SBEIIb mutant and down regulated lines. Fused granule agglomerates isolated from mutant and transgenic lines were hydrolysed at similar rates by amylases, and had similar crystalline patterns and thermal properties as individual granules. Surface pores, a feature previously only reported for A-polymorphic starch granules, were also observed in B- and C-polymorphic rice starch granules. Although the microscopic patterns of hydrolysis among granules with different crystalline polymorphs were qualitatively similar, the extent and the rate of amylolysis were different, suggesting that B-type crystalline polymorphs are intrinsically more resistant to enzymatic hydrolysis than A-type in rice starch granules. It is proposed that the slightly longer branch lengths of amylopectin which leads to the formation of more stable B-type double helical structures compared to their A-type counterparts is the major parameter, with other factors such as granule size, surface pores and interior channels having secondary roles, in determining the rate of enzymatic hydrolysis of rice starch granules. PMID- 25439900 TI - Preparation of silver-coated cotton fabrics using silver carbamate via thermal reduction and their properties. AB - In this study, cotton fabric was successfully coated with silver to have both antibacterial and conductive properties through a facile thermal reduction process at a low temperature using silver 2-ethylhexylcarbamate as the starting material. The cotton fabric modified with 3-mercaptopropyltriethoxysilane was padded with a solution of silver 2-ethylhexylcarbamate in methanol and then reduced for the in situ generation of Ag nanoparticles by only heating at 130 degrees C. The silver-coated cotton fabrics (cotton/Ag) were examined by a scanning electron microscopy (SEM), X-ray diffraction (XRD), energy dispersive X ray (EDX) and X-ray photoelectron spectroscopy (XPS) analyses. The morphology of cotton/Ag nanocomposite fabrics conveyed a uniform and continuous layer of silver metal on the cotton surface. The results indicated that the silver nanoparticles were assembled on cotton fibers with a size range from 20 to 100 nm. The cotton/Ag imparts high conductivity to the textiles with electric resistance as low as 3.92+/-0.18 Omega. The antibacterial effects of the treated cotton fabric against Escherichia coli O157:H7 (ATCC 43889) and Staphylococcus aureus (ATCC 25923) were examined and found to be excellent. PMID- 25439901 TI - Precise tailoring of tyramine-based hyaluronan hydrogel properties using DMTMM conjugation. AB - Injectable tyramine modified hyaluronic acid (HA-Tyr) hydrogels which are bio orthogonally cross-linked with horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) are excellent candidate biomaterials for drug delivery, regenerative medicine and tissue engineering. Ligation of tyramine to HA has been reported using the very well established N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) chemistry. Here we demonstrate the applicability of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) as an alternative coupling agent to synthesize HA-Tyr conjugates. The optimized derivatization process allows accurate control of the degree of substituted Tyr on hyaluronan (DSmol). Hence, viscoelastic properties, in vitro swelling and enzymatic digestion profiles of the crosslinked hydrogels can be precisely tuned via DSmol. Our study demonstrates the advantages of DMTMM conjugation as a powerful tool to synthesize HA-Tyr hydrogels with properties exactly tailored for biomedical applications. PMID- 25439902 TI - Characterization of exopolymeric substances from selected Rhodopseudomonas palustris strains and their ability to adsorb sodium ions. AB - Removal of Na(+) by binding with exopolymeric substances (EPS) from Rhodopseudomonas palustris TN114 and PP803 was investigated. The moderate negative correlation pairs (rp) between remaining Alcian blue and amount of Na(+) adsorbed on EPS from strains TN114 and PP803 were -0.652 and -0.609. Both strains showed positive relationships between the amounts of EPS produced and bacterial growth. EPS from strain PP803 had a higher efficiency in removing Na(+) than the EPS from strain TN114 based on their EC50 values (1.79 and 1.49 mg/mL for TN114 and PP803, respectively). The principal component from EPS of strain PP803 which was responsible for salt removal was purified and it was identified as a polysaccharide (~18 kDa) mainly composed of galacturonic acid. Overall results suggested that EPS is a key factor that our strains used to bind Na(+) allowing their survival in high NaCl concentrations. PMID- 25439903 TI - Facile preparation of surface N-halamine chitin nanofiber to endow antibacterial and antifungal activities. AB - N-halamine chitin nanofiber (NF) film was prepared by the reaction of chitin NF film with sodium hypochlorite solution to endow the film with antibacterial and antifungal activities. The amount of active chlorine content loaded on the chitin NF film depended on the sodium hypochlorite concentration and reaction time. FT IR, UV-vis, XRD, and TG analyses showed that the N-H bond was substituted to the N-Cl bond and that the reaction took place at the chitin NF surface. After chlorination, the characteristic nanochitin morphology was maintained. Although the active chlorine content of the film gradually decreased by disassociation of the N-Cl bond, chlorine was rechargeable into chitin NF by another sodium hypochlorite solution treatment. The chlorinated chitin NF film showed strong efficacies against Gram-negative and -positive bacteria of Escherichia coli and Staphylococcus aureus, respectively. Moreover, the films showed 100% and 80% inhibition of spore germination when faced against Alternaria alternata and Penicillium digitatum fungi, respectively. PMID- 25439904 TI - Electrospinning of agar/PVA aqueous solutions and its relation with rheological properties. AB - In this work, we report the successful fabrication of agar-based nanofibers by electrospinning technique, using water as solvent media. A tubeless spinneret was attached inside the electrospinning chamber, operating at 50 degrees C, to avoid agar gelation. Agar pure solution (1 wt%) showed inadequate spinnability regardless of the used electrospinning conditions. The addition of a co-blending polymer such as PVA (10 wt% starting solution) improved the solutions viscoelasticity and hence, the solutions spinnability. Agar/PVA solutions were prepared with different mass ratios (100/0, 50/50, 40/60, 30/70, 20/80 and 0/100) and electrospun at various sets of electrospinning conditions. Best nanofibers were obtained with 30/70 and 20/80 agar/PVA blends while samples with higher agar contents (50/50 and 40/60 agar/PVA) were harder to process and led to discontinuous fibrous mats. This first set of encouraging results can open a new window of opportunities for agar-based biomaterials in the form of nanofibers. PMID- 25439905 TI - Effect of plasticizers on the barrier and mechanical properties of biomimetic composites of chitosan and clay. AB - Biomimetic composites of polymer and clay are known to possess high mechanical strength and excellent barrier properties. However, the ductility of these composites is always low. One way to overcome this limitation consists on the incorporation of plasticizers which work effectively for the pure polymer. It is shown here that an imidazolium-based ionic liquid is a more effective plasticizer for chitosan, in terms of suppression of the glass transition temperature and mechanical properties, than the more commonly used glycerol. This might result from the ionic interaction between both species that is not present when glycerol is used as the plasticizer. Biomimetic composites of chitosan and clay were also prepared containing these two plasticizers. A similar effect on the mechanical properties was observed as for the pure polymer, that is, even at a very low (~12%) final concentration, the ionic liquid was a better plasticizer than glycerol, being able to double the ductility of the composites. Regarding barrier properties, no difference was observed between the original and the plasticized composites. This study thus shows that the incorporation of plasticizers is an effective method to improve the flexibility of biomimetic composites without deleterious effect on their excellent barrier properties. PMID- 25439906 TI - Studies on the effect of storage time and plasticizers on the structural variations in thermoplastic starch. AB - Starch was combined with plasticizers such as glycerol, sorbitol, glycerol/sorbitol and urea/ethanolamine blends by means of high shear extrusion process to prepare thermoplastic starch (TPS). Effect of storage time and plasticizers on the structural stability of melt processed TPS was investigated. Morphological observation, X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy reveal that melt extrusion process is efficient in transforming granular starch into a plasticized starch for all plasticizer compositions. XRD analysis highlights major changes in the microstructure of plasticized starch, and dependence of crystalline type and degree of crystallinity mainly on the plasticizer composition and storage time. Dynamical mechanical analysis (DMA) yields a decrease of the peak intensity of loss factor with aging time. The effect of ageing on tensile strength also appears to be highly dependent on the plasticizer composition. Thus, through different plasticizer combinations and ageing, starch-based materials with significant differences in tensile properties can be obtained, which may be tuned to meet the requirements of a wide range of applications. PMID- 25439907 TI - Compare study cellulose/Mn3O4 composites using four types of alkalis by sonochemistry method. AB - The purpose of this article was to explore the influences of alkalis types on the cellulose/Mn3O4 composites via a sonochemistry method. In this study, cellulose/Mn3O4 composites were successfully fabricated using four types of alkalis (urea (CO(NH2)2), hexamethylenetetramine ((CH2)6N4, HMT), NaOH, and KOH) by an environmentally-friendly sonochemistry method. The phase, shape, thermal stability, and the formation mechanism of the cellulose composites were researched in detail. Experimental results demonstrated that the types of alkalis played an important role in the phase, shape, dispersion, and thermal stability of cellulose/Mn3O4 composites. By thermal treatment of cellulose/Mn3O4 composites at 600 degrees C for 3h in air, the Mn3O4 crystals were obtained. This novel method reported here maybe has a guiding significance for the synthesis of manganese oxide materials and other metal oxides using cellulose as template. PMID- 25439908 TI - Processing and analysis of chitosan nanocomposites reinforced with chitin whiskers and tannic acid as a crosslinker. AB - Chitosan film reinforced with nano-sized chitin whiskers and crosslinked using tannic acid was synthesized by the casting-vaporation method. The mechanical and physicochemical properties of several film samples (consisting of different ratio of chitin and tannic acid) were compared with neat chitosan. Tensile tests show that the addition of chitin improves the nanocomposite films mechanical properties up to 137% compared to neat chitosan, but this is slightly degraded when tannic acid is introduced. However, tannic acid and chitin whisker content greatly reduced moisture content by 294% and water solubility by 13%. Transmission electron microscopy (TEM) and Fourier-transform-infrared spectroscopy (FTIR) were used to investigate the morphology and molecular interaction of film. X-ray diffraction results indicated that the samples with chitin whiskers had a more rigid structure. The addition of tannic acid changed the structure into an anhydrous crystalline conformation when compared to neat chitosan film. PMID- 25439909 TI - Co-electrospun poly(E-caprolactone)/cellulose nanofibers-fabrication and characterization. AB - We report fabrication of poly (E-caprolactone) (PCL)/cellulose (CEL) nanofiber blends via co-electrospinning for the possible use as biofilters and biosensor strips. Five different ratios of PCL to CEL were fabricated to investigate the wicking behavior. The cellulose acetate (CA) was taken as precursor to make cellulose nanofibers. Double nozzles were employed for jetting constituent polymers toward collector drum independently and resultant nanofibers webs were deacetylated in aqueous alkaline solution to convert CA into CEL as confirmed by FTIR spectra. FTIR further revealed that there is no effect of deacetylation on PCL nanofiber. The morphology of each blend webs under SEM showed uniform and bead-free nanofibers. Wicking behavior for five different ratios of PCL/CEL suggested that increasing CEL ratio in the blend enhanced the wicking front height; however, X-ray diffraction patterns of PCL/CEL showed a slight decrease in crystallinity. PMID- 25439910 TI - Effects of montmorillonite addition on the performance of starch-based wood adhesive. AB - Effects of montmorillonite (MMT) addition on the performance of corn starch-based wood adhesive were investigated. It was found that MMT addition could enhance the shear strength of the starch-based wood adhesive. The shear strength of the adhesive with 5% (w/w, dry starch basis) MMT reached 10.6 MPa in the dry state, which was almost twice that of the same adhesive without MMT. Addition of 5% MMT also produced an approximately 1.2-fold increase in the shear strength in the wet state. Although this addition caused an increase in the viscosity, the resulting adhesive retained both good mobility and viscosity stability during storage. MMT also enhanced the shear-thinning and solid-like behaviors of the adhesive, compared with the adhesive without MMT. Finally, MMT addition improved the thermal stability of the adhesive. In conclusion, addition of MMT to starch-based wood adhesives can improve their overall performance, enhancing their value as alternatives for traditional petrochemical-based wood adhesives. PMID- 25439911 TI - Effects of glycerol on the molecular mobility and hydrogen bond network in starch matrix. AB - The effects of glycerol on molecular mobility and hydrogen bonding network in an amorphous glassy starch matrix were studied using phosphorescence and IR spectroscopy. Amorphous potato starch films containing varying amounts of glycerol (0, 5, 10, 20 and 30 wt.%) were formulated by rapidly dehydrating aqueous potato starch gel (5%, w/v) with a corresponding content of glycerol; X ray diffraction data confirm that the films contained negligible content of crystalline starch. Erythrosin B (Ery B) phosphorescence was used to monitor the molecular mobility of these matrices over the temperature range from 0 to 100 degrees C. Analysis of Ery B emission peak frequency, band width and intensity decay provided information about thermally-activated modes of molecular mobility in the matrix. Dipolar relaxation around the triplet state of Ery B was enhanced by addition of glycerol and the extent of relaxation increased at low and intermediate but decreased at higher temperature. The glycerol content-dependent onset temperature for this transition was 70 degrees C for pure starch and decreased to 40 degrees C for a matrix with 30% glycerol. Measurements of the rate of non-radiative decay from the Ery B triplet state indicated that glycerol plasticized the starch matrix above ~10 wt.% while acting as an antiplastizer to increase the matrix molecular mobility at lower content. These matrix properties were related to glycerol-dependent increases in hydrogen bond strength as measured by IR. PMID- 25439912 TI - Influence of elasticity on the syneresis properties of kappa-carrageenan gels. AB - Kappa-carrageenan hydrogels spontaneously release fluid (syneresis) under certain elasticity conditions, which depend on the temperature, the salt concentration in the gel (KCl) and the polysaccharide concentration. Strong and weak gels exhibit notably weak syneresis properties. The maximum syneresis was found at intermediate elasticity where the gel was neither strong nor weak. The variation in the gel composition indicated that the fluid is released according to the thermal retraction coefficient, which depends on the elasticity. Experiments revealed a dynamic equilibrium of the syneresis process where syneresis fluid was not withdrawn. However, once the fluid was removed from the gel surface, the release of solvent starts again if the elasticity is below the compressive pressure in the gel. Therefore, swelling of the gel is suggested as an explanation for the dynamic equilibrium of the syneresis process. PMID- 25439913 TI - Effect of pullulan on the short-term and long-term retrogradation of rice starch. AB - The effect of pullulan (PUL) on the retrogradation of rice starch (RS) was investigated by means of rapid visco-analyzer (RVA), rotational rheometer, differential scanning calorimetry (DSC), and X-ray diffraction (XRD). RVA results showed that addition of pullulan significantly decreased the breakdown and setback values, which meant that the short-term retrogradation of RS was inhibited. The dynamic time sweep of samples also proved the retarding effect of pullulan on the retrogradation of RS. DSC curves showed clearly that pullulan significantly reduced the retrogradation enthalpy of amylopectin, and the kinetics of retrogradation was analyzed using the Avrami model. XRD results showed that recrystallinity of RS was reduced from 11.565% to 8.841% with the addition of pullulan and this was in line with the DSC results. It could be concluded that the addition of pullulan apparently influenced not only the short term retrogradation of amylose, but also the long-term retrogradation of amylopectin. PMID- 25439914 TI - Rheological and structural characterization of HA/PVA-SbQ composites film-forming solutions and resulting films as affected by UV irradiation time. AB - Hyaluronan (HA)/poly (vinyl alcohol) bearing styrylpyridinium groups (PVA-SbQ) composites film-forming solutions were prepared by a negatively charged HA and an oppositely charged PVA-SbQ. The rheological properties and structural characterization of HA/PVA-SbQ composites in aqueous solution were investigated. Zeta potential measurements and TEM were utilized to explore the formation of HA/PVA-SbQ complex micelles in aqueous solution. UV spectra and DLS experiments confirmed that the micelles are photo-crosslinkable. HA/PVA-SbQ composites films were prepared by a casting method. The microstructure and properties of the film were analyzed by SEM, optical transmittance, DSC, XRD and tensile testing. The crosslinked HA/PVA-SbQ composites films exhibited higher UV light shielding and visible light transparency and better mechanical and water vapor barrier properties as well as thermal stability than the uncrosslinked HA/PVA-SbQ composites films, indicating the formation of three-dimensional network structure. This work provided a good way for increasing the mechanical, thermal, water vapor barrier, and optical properties of HA materials for the packaging material. PMID- 25439915 TI - Column adsorption of perchlorate by amine-crosslinked biopolymer based resin and its biological, chemical regeneration properties. AB - Column adsorption of perchlorate by amine-crosslinked biopolymer based resin was investigated by considering the bed depth, stream flow rate and influent pH. The empty bed contact time (EBCT) increased with the growth of bed depths, meanwhile rising flow rate at constant bed depth (3.4 cm) decreased the breakthrough time. It was observed that perchlorate adsorption capacity was optimum at neutral condition (pH: 6.0, 170.4 mg/g), and decreased at acidic (pH: 3.0, 96.4 mg/g) or alkalic (pH: 12.0, 72.8 mg/g) influents. The predominant strains of the acclimated sludge for resin biological regeneration were the beta-subclass of Proteobacteria. Biological regeneration of the saturated amine-crosslinked biopolymer based resin with mixed bacteria have shown its merit with regeneration and biological perchlorate destruction simultaneously, although its regeneration efficiency was only 61.2-84.1% by contrast to chemical regeneration with efficiency more than 95%. PMID- 25439916 TI - In situ NMR spectroscopy: inulin biomass conversion in ZnCl2 molten salt hydrate medium-SnCl4 addition controls product distribution. AB - The dehydration of inulin biomass to the platform chemicals, 5 hydroxymethylfurfural (5-HMF) and levulinic acid (LA), in ZnCl2 molten salt hydrate medium was investigated. The influence of the Lewis acid catalyst, SnCl4, on the product distribution was examined. An in situ(1)H NMR technique was employed to follow the reaction at the molecular level. The experimental results revealed that only 5-HMF was obtained from degradation of inulin biomass in ZnCl2 molten salt hydrate medium, while the LA was gradually becoming the main product when the reaction temperature was increased in the presence of the Lewis acid catalyst SnCl4. In situ NMR spectroscopy could monitor the reaction and give valuable insight. PMID- 25439917 TI - Development of a 96-well plate iodine binding assay for amylose content determination. AB - Cereal starch amylose/amylopectin (AM/AP) is critical in functional properties for food and industrial applications. Conventional methods of AM/AP are time consuming and labor intensive making it difficult to screen the large sample sets necessary for evaluating breeding samples and investigating environmental impact on starch development. The objective was to adapt and optimize the iodine binding assay in a 96-well plate format for measurement at both lambda 620 nm and lambda 510 nm. The standard curve for amylose content was scaled to a 96-well plate format and demonstrated R(2) values of 0.999 and 0.993 for single and dual wavelengths, respectively. The plate methods were applicable over large ranges of amylose contents: high amylose maize starch at 61.7+/-2.3%, normal wheat starch at 29.0+/-0.74%, and a waxy maize starch at 1.2+/-0.9%. The method exhibited slightly greater amylose content values than the Concanavalin A method for normal type starches; but is consistent with cuvette scale iodine binding assays. PMID- 25439918 TI - Anti-inflammatory effects of orally administered glucosamine oligomer in an experimental model of inflammatory bowel disease. AB - Anti-inflammatory effects of oral administration of the glucosamine oligomers (chito-oligosaccharides: COS) were evaluated in an experimental model of inflammatory bowel disease (IBD). Oral administration of COS improved shortening of colon length and tissue injury (as assessed by histology) in mice. Oral administration of COS inhibited inflammation in the colonic mucosa by suppression of myeloperoxidase activation in inflammatory cells, as well as activation of nuclear factor-kappa B, cyclooxygenase-2, and inducible nitric oxide synthase. Oral administration of COS also reduced serum levels of pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6). Moreover, it prolonged survival time in mice. These data suggest that COS have anti-inflammatory effects in an experimental model of IBD, and could be new functional foods for IBD patients. PMID- 25439919 TI - Preparation and characterization of functionalized cellulose nanocrystals. AB - In this work, a series of functional nanocrystals (F-CNCs) was successfully produced by an efficient preparation method, combining acid hydrolysis and Fischer esterification with various organic acids. Functionalities such as ATRP initiators, double bonds, triple bonds, and thiols could be incorporated on CNCs. Surface modification was confirmed by FT-IR, XPS, and elemental analysis. Physical properties of F-CNCs were assessed by AFM, XRD and TGA. Moreover, ATRP initiator functionalized CNCs were utilized to graft poly(methyl methacrylate) via ATRP, thiol functionalized CNCs were reacted with Ellman's reagent to determine the thiol content and dye disperse red 13 was attached to alkyne functionalized CNCs to estimate the propiolate content. The herein presented method is a highly versatile and straightforward procedure for the preparation of F-CNCs which is believed to be a better alternative for the commonly utilized, extensive, multistep, and time consuming post functionalization methods. PMID- 25439920 TI - Effects of alpha-amylase reaction mechanisms on analysis of resistant-starch contents. AB - This study aimed to understand differences in the resistant starch (RS) contents of native and modified starches obtained using two standard methods of RS content analysis: AOAC Method 991.43 and 2002.02. The largest differences were observed in native potato starch, cross-linked wheat distarch phosphate, and high-amylose corn starch stearic-acid complex (RS5) between using AOAC Method 991.43 with Bacillus licheniformis alpha-amylase (BL) and AOAC Method 2002.02 with porcine pancreatic alpha-amylase (PPA). To determine possible reasons for these differences, we hydrolyzed raw-starch granules with BL and PPA with equal activity at pH 6.9 and 37 degrees C for up to 84 h and observed the starch granules displayed distinct morphological differences after the hydrolysis. Starches hydrolyzed by BL showed erosion on the surface of the granules; those hydrolyzed by PPA showed pitting on granule surfaces. These results suggested that enzyme reaction mechanisms, including the sizes of the binding sites and the reaction patterns of the two enzymes, contributed to the differences in the RS contents obtained using different methods of RS analysis. PMID- 25439921 TI - Structural features and antitumor activity of a novel polysaccharide from alkaline extract of Phellinus linteus mycelia. AB - A novel high molecular weight polysaccharide (PL-N1) was isolated from alkaline extract of the cultured Phellinus linteus mycelia. The weight average molecular weight (Mw) of PL-N1 was estimated at 343,000kDa. PL-N1 comprised arabinose, xylose, glucose, and galactose in the molar ratio of 4.0:6.7:1.3:1.0. The chemical structure of PL-N1 was investigated by FTIR and NMR spectroscopies and methylation analysis. The results showed that the backbone of PL-N1 comprised (1 >4)-linked beta-D-xylopyranosyl residues, (1->2)-linked alpha-D-xylopyranosyl residues, (1->4)-linked alpha-D-glucopyranosyl residues, (1->5)-linked beta-D arabinofuranosyl residues, (1->4)-linked beta-D-xylopyranosyl residues which branched at O-2, and (1->4)-linked beta-D-galactopyranosyl residues which branched at O-6. The branches consisted of (1->)-linked alpha-D-arabinofuranosyl residues. Antitumor activity assay in vitro showed that PL-N1 could inhibit the growth of HepG2 cells to a certain extent in a dose-dependent manner. Thus, PL-N1 may be developed as a potential, natural antitumor agent and functional food. PMID- 25439922 TI - Comparison between the interactions of the cationic surfactant DODAB with xanthan and galactomannan. AB - The interactions of the cationic surfactant DODAB with anionic xanthan (XAN) and nonionic galactomannan (GMC) polysaccharides in solution were investigated using tensiometry, differential scanning microcalorimetry (MU-DSC), zeta potential and dynamic light scattering (DLS) techniques and by the calculated thermodynamic parameters of DeltaG(ves)(0), DeltaG(ads)(0), Gamma(max) and a(min). The surfactant formed large unilamellar vesicles (LUV) that aggregated with both the polymers in solution. Increasing DODAB concentrations resulted in greater and greater DODAB-XAN aggregates, high turbidity and even precipitation, while DODAB GMC aggregates remained equal sized, clear solution and no precipitation observed. Further addition of DODAB to XAN solution was able to resuspend the precipitates. The interactions with both polysaccharides resulted in a more spontaneous adsorption of the DODAB-polymer aggregates at the air/solution interface with lower surfactant population. PMID- 25439923 TI - Tissue engineering scaffolds electrospun from cotton cellulose. AB - Nonwovens of cellulose nanofibers were fabricated by electrospinning of cotton cellulose in its LiCl/DMAc solution. The key factors associated with the electrospinning process, including the intrinsic properties of cellulose solutions, the rotating speed of collector and the applied voltage, were systematically investigated. XRD data indicated the electrospun nanofibers were almost amorphous. When increasing the rotating speed of the collector, preferential alignment of fibers along the drawing direction and improved molecular orientation were revealed by scanning electron microscope and polarized FTIR, respectively. Tensile tests indicated the strength of the nonwovens along the orientation direction could be largely improved when collected at a higher speed. In light of the excellent biocompatibility and biodegradability as well as their unique porous structure, the nonwovens were further assessed as potential tissue engineering scaffolds. Cell culture experiments demonstrated human dental follicle cells could proliferate rapidly not only on the surface but also in the entire scaffold. PMID- 25439924 TI - Mechanisms of depolymerization and activation of a polysialic acid and its tetramer by hydrogen peroxide. AB - Naturally occurring polysialic acid (PSA), appropriately functionalized, has been widely used in different biological products. The present paper describes an original approach which enables to both activate and depolymerize the PSA, by reacting with hydrogen peroxide. In order to understand the mechanisms, we investigate the course of H2O2 reactions with the native PSA and with a simpler model, the tetrasialic acid (4SA). Three recurrent reactions were observed. First, we detected a very fast and irreversible decarbonylation at the reducing end of the polysaccharide. Then, the hydroxyl radicals (generated via the Fenton reaction) were responsible for the depolymerization of glycosidic linkages by substitution reactions. Finally, the oxidation of hydroxyl groups led to the formation of carbonyl groups and the carbohydrate's activation. PMID- 25439925 TI - Highly versatile nanohydrogel platform based on riboflavin-polysaccharide derivatives useful in the development of intrinsically fluorescent and cytocompatible drug carriers. AB - In this work we describe a new nanohydrogel platform, based on polysaccharides modified with the hydrophobic and fluorescent molecule riboflavin tetrabutyrate, which leads to innovative structures useful for drug delivery applications. Hyaluronic acid and pullulan were chosen as representative of anionic and neutral polysaccharides, respectively, and the bromohexyl derivative of riboflavin tetrabutyrate was chemically linked to these polymer chains. Because of such derivatization, polymer chains were able to self-assemble in aqueous environment thus forming nanohydrogels, with mean diameters of about 312 and 210 nm, for hyaluronan and pullulan, respectively. These new nanohydrogels showed low polydispersity index, and negative zeta-potential. Moreover, the nanohydrogels, which can be easily loaded with model drugs, showed long-term stability in water and physiological conditions and excellent cytocompatibility. All these properties allow to consider these intrinsically fluorescent nanohydrogels suitable for the formulation of innovative drug dosage forms. PMID- 25439926 TI - Interplay of thermal and covalent gelation of silanized hydroxypropyl methyl cellulose gels. AB - Silanized hydroxypropyl methyl cellulose (Si-HPMC) is a biocompatible polysaccharide that forms a covalently crosslinked hydrogel at all temperatures due to silanol condensation. Unmodified HPMC forms reversible turbid physical gels when heated above 55 degrees C. The interaction between thermal gelation and covalent crosslinking of Si-HPMC was investigated with rheology, turbidity and microscopy. Thermal gelation of the HPMC backbone was found to reinforce Si-HPMC gels at room temperature. However, simultaneous thermal and covalent crosslinking at higher temperatures led to weaker turbid gels at room temperature. The effect of the pH and the addition of orthophosphate on the elastic modulus and the gelation kinetics was investigated. PMID- 25439927 TI - Formation of self-extinguishing flame retardant biobased coating on cotton fabrics via Layer-by-Layer assembly of chitin derivatives. AB - The self-extinguishing coating, consisting of biobased chitin derivatives, phosphorylated chitin and deacetylated chitin (chitosan), was deposited on cotton fabrics via the Layer-by-Layer (LbL) assembled method. The content of phosphorylated chitin prepared on cotton fabrics surface is dependent on the bilayers' number and concentration of phosphorylated chitin. In the vertical flame test, the cotton fabric with 20 bilayers prepared at the high phosphorylated chitin concentration (2 wt%) could extinguish the flame. Microcombustion calorimetry result showed that all coated cotton fabrics showed lower peak heat-release rate and total heat-release values compared with that of the pure one. Thermogravimetric analysis result indicated that thermal and thermal oxidation stability of all coated cotton fabrics were enhanced in the high temperature range (400-700 degrees C). This work provided the flame retardant multilayer films based on fully biobased chitin derivatives on cotton fabrics to enhance its flame retardancy. PMID- 25439928 TI - Use of gum arabic to improve the fabrication of chitosan-gelatin-based nanofibers for tissue engineering. AB - Current techniques for fabricating chitosan-gelatin-based nanofibers require the use of corrosive and expensive solvents. Our novel method, however, using gum arabic and a mild (20 wt%) aqueous acetic acid solution as solvent can produce a solution with much higher chitosan-gelatin content (16 wt%). Without gum arabic, which greatly decreases the viscosity of the solution, such an outcome was unachievable. The solution was utilized to prepare electrospun chitosan-gelatin polyvinyl alcohol-gum arabic nanofibers with a weight ratio of 8:8:2:0.5 (C8G8P2A0.5 nanofibers), in which polyvinyl alcohol could stabilize the electrospinning process. The stability and tensile strength (2.53 MPa) of C8G8P2A0.5 nanofibers (mats) were enhanced by glutaraldehyde crosslinking. Furthermore, mesenchymal stem cells attached and proliferated well on the mat. The strength-enhanced and cytocompatible C8G8P2A0.5 mats are thereby suitable for tissue engineering applications. More importantly, we have created a less expensive and safer method (one not using hazardous solvents) to fabricate chitosan-gelatin-based nanofibers. PMID- 25439929 TI - Fractionation of oil palm frond hemicelluloses by water or alkaline impregnation and steam explosion. AB - Steam explosion of oil palm frond has been carried out under different temperatures between 180 and 210 degrees C for 4 min (severity of 2.96-3.84) after impregnation of the frond chips with water or KOH solution. The effects of impregnation and steam explosion conditions of oil palm fronds on the water soluble fraction and insoluble fraction were investigated. The maximum yield of hemicelluloses in water soluble fractions recovered was 23.49% and 25.33% for water and KOH impregnation, treated with steam explosion at temperature of 210 degrees C (severity of 3.84) with a fractionation efficiency of 77.30% and 83.32%, respectively. Under this condition, the water insoluble fractions contained celluloses at 60.83% and 64.80% for water and KOH impregnation, respectively. The steam explosion temperature of 210 degrees C for 4 min (logR(o) 3.84) was found to be the best condition in the extraction of hemicelluloses from OPF for both types of impregnation. PMID- 25439930 TI - Mode of action of Bacillus licheniformis pectin methylesterase on highly methylesterified and acetylated pectins. AB - A gene encoding a putative pectinesterase from Bacillus licheniformis DSM13 was cloned and expressed in Escherichia coli. The resulting recombinant enzyme (BliPME) was purified and characterized as a pectin methylesterase. The enzyme showed maximum activity at pH 8.0 and 50 degrees C. BliPME is able to release up to 100% of the methylesters from lime pectin (DM 34-76->DM 0) and up to 73% of all methylesters from SBPs (DM 30-73->DM 14). BliPME efficiently de methylesterifies lemon pectins and SBPs in a blockwise manner and is quite tolerant towards the acetyl groups present within the SBPs. Detailed analysis of the BliPME-modified pectins using HILIC-MSn and the classical calcium reactivity measurement showed that the enzyme generates pectins with low methylesterification (lime and SBP) and high acetyl content (SBP) while creating blocks of nonmethylesterified galacturonic acid residues. The high activity of BliPME towards highly methylesterified and acetylated pectins makes this novel esterase more efficient in removing methylesters from highly esterified beet pectin compared to other PMEs, e.g. Aspergillus niger PME. PMID- 25439931 TI - Cationization of heparin for film applications. AB - Trimethylammonium-2-hydroxypropyl-(TMAHP) spacer was introduced into heparin (H) and the prepared films were characterized by elemental analysis, NMR, SEC-MALS, TG/DTG/DTA, AFM and mechanical tester. When quaternized at the ratio of H/NaOH/alkylating agent/H2O=0.1-1/0-2/0.1-1/50-500 mmol, H was substituted at A6 and A3 positions. The formation of double-substituted structures by substitution of free hydroxyl group of the previously introduced TMAHP substituent is evident. In the absence of NaOH (H/GTMAC/H2O=1:1:500) the most drastic decrease of M(n) to 8.639 kg/mol and M(w)/M(n) at 1.48 was observed in comparison to H (Mn=9532 g/mol with M(w)/M(n)=1.38). The film mechanical properties were better on H (E=4030 MPa; sigma(b)=65 MPa; E(b)=4.6%) than on quaternized specimens (E=2500-3340 MPa; sigma(b)=25-40 MPa; E(b)=1.7-1.8%). The AFM images did not prove relation between mechanical properties and surface shape. PMID- 25439932 TI - Cellulosic/wool pigment prints with remarkable antibacterial functionalities. AB - Several bio-active agents namely choline chloride, triclosan derivative, PEG-600 and 4-hydroxybenzophenone were successfully included into solvent-free pigment formulations, in a single-stage process, followed by screen printing and microwave-fixation to obtain antibacterial functionalized cellulosic/wool pigment prints. Results obtained signify that both the improvement in functionalization and coloration properties are governed by type of antibacterial agent, kind of substrate as well as pigment colorant. The imparted antibacterial activity of the loaded bio-active agents follows the decreasing order: G+ve (Staphylococcus aureus)>G-ve (Escherichia coli), keeping other parameters constant. The imparted functional and coloration properties showed no significant decrease even after 15 washings. Mode of interactions among the nominated substrates, the pigment paste constituents and the bioactive agents were also proposed. PMID- 25439933 TI - Synthesis of nano silver on cellulosic denim fabric producing yellow colored garment with antibacterial properties. AB - In this study, an aged-look denim fabric with antibacterial property was prepared in one single step process. For this purpose, the simultaneous antibacterial finishing and discoloration of denim fabric was carried out through reduction of indigo dye and silver nitrate by glucose in alkaline media using a conventional garment washing machine. The uniform distribution of silver nanoparticles on the fiber surface was confirmed by scanning electron microscope and energy dispersive X-ray spectroscopy. The treated fabrics were also characterized by X-ray diffraction (XRD) and Raman spectroscopy. Due to the color changes during the process, the color coordinates of the treated samples were also measured. Findings suggest the potential of the proposed method in producing old-look denim fabric with desirable yellow appearance and reasonable antibacterial activity against Staphylococcus aureus and Escherichia coli with low toxicity for human. PMID- 25439934 TI - Development of thermoplastic starch blown film by incorporating plasticized chitosan. AB - The objective of the present work was to improve blown film extrusion processability and properties of thermoplastic starch (TPS) film by incorporating plasticized chitosan, with a content of 0.37-1.45%. The effects of chitosan on extrusion processability and melt flow ability of TPS, as well as that on appearance, optical properties, thermal properties, viscoelastic properties and tensile properties of the films were investigated. The possible interactions between chitosan and starch molecules were evaluated by FTIR and XRD techniques. Chitosan and starch molecules could interact via hydrogen bonds, as confirmed from the blue shift of OH bands and the reduction of V-type crystal formation. Although the incorporation of chitosan caused decreased extensibility and melt flow ability, as well as increased yellowness and opacity, the films possessed better extrusion processability, increased tensile strength, rigidity, thermal stability and UV absorption, as well as reduced water absorption and surface stickiness. The obtained TPS/chitosan-based films offer real potential application in the food industry, e.g. as edible films. PMID- 25439935 TI - Development, validation and influence factor analysis of a near-infrared method for the molecular weight determination of xanthan gum. AB - A practical molecular weight determination model of xanthan gum (XG), based on near-infrared (NIR) spectroscopy, was built in this study. Two sample measurement modules, integrating sphere module and fiber-optic probe module, were compared, and the best partial least square (PLS) regression model was based on fiber-optic probe module. The values of coefficient of determination in calibration (R(2)c), coefficient of determination in prediction (R(2)p), residual predictive deviation (RPD) and root mean square error of prediction (RMSEP) were 0.967, 0.975, 6.028 and 0.250*10(6)Da, respectively. The molecular weight range, linearity, accuracy and precision of the established method were also validated. Furthermore, influence factors on this method were discussed in order to establish an appropriate measurement protocol. Results showed that the proposed NIR method may be suitable for practical applications in manufacturing plants and probably be accepted as a good alternative approach for fast determination of molecular weight of XG in production process. PMID- 25439936 TI - Mode of encapsulation of linezolid by beta-cyclodextrin and its role in bovine serum albumin binding. AB - We describe, in this article, the associative interaction between Linezolid and beta-Cyclodextrin, and the influence of beta-Cyclodextrin on Linezolid's binding to Bovine serum albumin. beta-Cyclodextrin forms a 1:1 inclusion complex with Linezolid, with a binding constant value of 3.51*10(2)M(-1). The binding is studied using ultraviolet-visible absorption, fluorescence, nuclear magnetic resonance, and rotating-frame overhauser effect spectroscopic techniques. The amide substituent on the oxazolidinone ring of Linezolid is involved in its binding to beta-Cyclodextrin. The binding of the Linezolid to bovine serum albumin, in the absence and the presence of beta-Cyclodextrin, is studied by analyzing the fluorescence quenching and Forster resonance energy transfer. The Stern-Volmer quenching constant, the binding constant, and energy transfer occurring on the interaction of the Linezolid with BSA are found to be smaller in the presence of beta-Cyclodextrin than in water. PMID- 25439937 TI - NMR investigation of the complexation and chiral discrimination of pyrazole sulfonamide derivatives with cyclodextrins. AB - The complexes formed between six original chiral diaryl-pyrazole sulfonamide derivatives, displaying poor solubility, and various CDs (native alpha-, beta- and gamma-CDs, hydroxypropylated HP-beta-CD, methylated Me-beta-CD or amino NH2 beta-CD) were studied by 1D and 2D (1)H NMR at physiological pH in order to determine their apparent binding constant, stoichiometry and structure of the supramolecular assembly. For some complexes, the spectra obtained for free racemic compound and for racemic compound in presence of CD indicate a splitting of signal(s). Additional experiments with pure enantiomer and enriched enantiomer allow us to attribute this behavior to chiral discrimination. The complexing ability of the native beta-CD towards our compounds appears the most promising since binding values around 7*10(2)M(-1) are obtained. The two-dimensional ROESY ((1)H-(1)H) experiments prove the inclusion of the aliphatic part of the compound in the CD cavity. It is noteworthy that this inclusion occurs via the smaller opening of the cavity. PMID- 25439938 TI - Preparation of starch nanospheres through hydrophobic modification followed by initial water dialysis. AB - Starch nanospheres smaller than 200 nm were produced from hydrophobically modified starch by using initial water dialysis method. The hydrophobic modification of starch was performed by using octenyl succinic anhydride (OSA). The resultant starch nanospheres were characterized by using Fourier transformation infrared (FTIR) spectroscopy, (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy and fluorescence spectroscopy, scanning electron microscopy (SEM) and dynamic light scattering (DLS). Effects of degree of substitution (DS) in OSA-starch, initial water content and OSA-starch concentration on morphology and particle size of starch nanospheres were evaluated. The SEM micrographs showed that starch nanospheres with spherical shape and sharp edge can be produced at DS values ?0.67. The particle size of starch nanospheres decreased significantly (P<0.05) with increase in DS of OSA starch and increase in the initial water content, whereas the particle size increased significantly (P<0.05) with the increase in the concentration of OSA starch. These OSA-starch nanospheres can be preferentially used to microencapsulate hydrophobic drugs. PMID- 25439939 TI - Aminoacids as non-traditional plasticizers of maltodextrins fast-dissolving films. AB - This study explored the effect of aminoacids as non-traditional plasticizers of maltodextrins fast dissolving films. 5% w/w glycine and proline decreased the glass transition temperature (Tg) of maltodextrins from 102.6+/-2.0 degrees C to 73.1+/-1.4 degrees C and 76.1+/-0.7 degrees C, respectively; meanwhile the binary mixture made with lysine had a Tg value of 83.6+/-2.2 degrees C. At the same time, all aminoacids increased the DeltaCp values. The shift of the thermal data were due to profound effect on the hydrogen bonding as evidenced by ATR-FTIR spectra since the OH stretching and scissoring bands decreased of about 15-26 cm( 1). A linear relationship was found (R(2)=0.9334) between HOH scissoring wavenumbers and Tg values. The addition of glycine and proline resulted effective in reducing the elastic modulus (about 50%) and tensile strength (about three times) and, therefore, can be used to increase the film ductility. PMID- 25439940 TI - Flocculation and adsorption properties of biodegradable gum-ghatti-grafted poly(acrylamide-co-methacrylic acid) hydrogels. AB - This study reports the microwave-assisted synthesis of gum-ghatti (Gg)-grafted poly(acrylamide-co-methacrylic acid) (AAm-co-MAA) hydrogels for the development of biodegradable flocculants and adsorbents. The synthesized hydrogels were characterized using TGA, FTIR and SEM. TGA studies revealed that the synthesized hydrogels were thermally more stable than pristine Gg and exhibited maximum swelling capacity of 1959% at 60 degrees C in neutral pH. The optimal Gg-cl-P(AAm co-MAA) hydrogel was successfully employed for the removal of saline water from various petroleum fraction-saline emulsions. The maximum flocculation efficiency was achieved in an acidic clay suspension with a 15 mg polymer dose at 40 degrees C. Moreover, the synthesized hydrogel adsorbed 94% and 75% of Pb(2+) and Cu(2+), respectively, from aqueous solutions. Finally, the Gg-cl-P(AAm-co-MAA) hydrogel could be degraded completely within 50 days. In summary, the Gg-cl-P(AAm-co-MAA) hydrogel was demonstrated to have potential for use as flocculants and heavy metal absorbents for industrial waste water treatment. PMID- 25439941 TI - Evaluation of in situ injectable hydrogels as controlled release device for ANXA1 derived peptide in wound healing. AB - In this paper, for the first time, hydrogels containing Annexin A1 N-terminal derived peptide, Ac2-26, as a novel dressing were successfully developed for dermal wound repair application. High mannuronic (M) content alginate and low molecular weight chitosan have been used as hydrogel carrier. Peptide recovery analyses, FTIR studies and molecular modelling highlighted chemical interactions between peptide and hydrogel polymers. Ac2-26 resulted entrapped into chitosan hydrogel matrix that prevented its release, whereas such interaction in alginate hydrogel slowed down peptide diffusion enabling its sustained release till 72 h. In vivo wound healing studies conducted on mice dorsal wounds indicate that after the 9th day of post wounding Ac2-26/alginate hydrogels could significantly accelerate wound healing, with complete closure of the wound on day 14th. Therefore, these results suggest that the developed of Ac2-26 high M content alginate hydrogel could be a promising wound dressing with potential application in dermal wound healing. PMID- 25439942 TI - Preparation and characterization of BC/PAM-AgNPs nanocomposites for antibacterial applications. AB - In this work, a bacterial cellulose/polyacrylamide (BC/PAM) double network composite was prepared to act as the template for in situ synthesis of silver nanoparticles (AgNPs). Effects of reaction conditions of the BC/PAM composite were investigated on its microstructure, mechanical properties and thermal stabilities. Both the BC/PAM composite and pure BC were utilized to prepare the corresponding silver impregnated nanocomposites, i.e., BC/PAM-AgNPs and BC-AgNPs, by an environmental friendly method, UV irradiation. The influences of the templates were investigated on the AgNPs formation and the antibacterial activities of the nanocomposites by both the zone of inhibition and dynamic shake flask methods. It was shown that the BC/PAM composite displayed a denser microstructure and higher thermal stabilities than pure BC. The BC/PAM-AgNPs nanocomposite exhibited a bigger particle size and lower mass content of AgNPs than the BC-AgNPs one. For the antibacterial test, two nanocomposites exhibited a close antibacterial effect, with a high log reduction above 3 and killing ratio above 99.9%, respectively. PMID- 25439943 TI - Immunomodulatory activity of heparan sulfate mimetics from Escherichia coli K5 capsular polysaccharide in vitro. AB - Escherichia coli K5 capsular polysaccharide (K5PS) has been used as starting material to synthesize heparan sulfate (HS) mimetics with various biological properties. This study determined the immunomodulatory activities of K5PS through the sulfation process. The immunomodulatory effects of sulfated K5 polysaccharide derivatives were evaluated in vitro on murine macrophages and lymphocytes. Results indicated that HS mimetics with high sulfation in the O-position stimulated cell proliferation of macrophages and lymphocytes, significantly enhanced cytokine secretion and upregulated the cytotoxicity of NK cells. This study suggests that high sulfation in O-position of HS is required for the immunomodulatory activities. PMID- 25439944 TI - Liposome-loaded chitosan physical hydrogel: toward a promising delayed-release biosystem. AB - This work deals with the elaboration of an original biosystem in view of its application as drug delayed-release device in biomedical area. This innovative "hybrid" system is composed of phosphatidylcholine liposomes entrapped within a chitosan physical hydrogel (only constituted of polymer and water). To this end, pre-formed liposomes were suspended into chitosan solutions, and the polymer gelation process was subsequently carried out following particular experimental conditions. This liposome incorporation did absolutely not prevent the gel formation as shown by rheological properties of the resulting tridimensional matrix. The presence of liposomes within the hydrogel was confirmed by fluorescence and cryo-scanning electron microscopies. Then, the expected concept of delayed-release of this "hybrid" system was proved using a model water soluble molecule (carboxyfluorescein, CF) encapsulated in liposomes, themselves incorporated into the chitosan hydrogel. The CF release was assayed after repeated and intensive washings of hydrogels, and was found to be higher in the CF-in-hydrogel systems in comparison with the CF-in-liposomes-in-hydrogel ones, demonstrating a CF delayed-release thanks to lipid vesicles. PMID- 25439945 TI - Effect of different alkaline solutions on crystalline structure of cellulose at different temperatures. AB - Effect of alkaline solutions such as 10% NaOH, NaOH/urea and NaOH/ethylene glycol solutions on crystalline structure of different cellulosic fibers (cotton linter and filter paper) was investigated at room temperature and -4 degrees C. The highest dissolution of cotton linter and filter paper was observed in NaOH/ethylene glycol at both temperatures. X-ray patterns of treated cotton linter with different alkaline solutions at low temperature showed only two diffractions at 2theta=12.5 degrees and 21.0 degrees , which belonged to the crystalline structure of cellulose II. CP/MAS (13)C NMR spectra showed the doublet peaks at 89.2 ppm and 88.3 ppm representing C4 resonance for cellulose I at room temperature, Whereas, at low temperature the doublet peaks were observed at 89.2 ppm and 87.8 ppm representing C4 resonance for cellulose II. Degree of polymerization of cellulose plays an important role in cellulose dissolution in different alkaline solutions and temperatures, where, a low temperature gives high dissolutions percentage with change in crystalline structure from cellulose I to cellulose II forms. PMID- 25439946 TI - Characterization of cellulose and other exopolysaccharides produced from Gluconacetobacter strains. AB - This study characterized the cellulosic and non-cellulosic exopolysaccharides (EPS) produced by four Gluconacetobacter strains. The yields of bacterial cellulose and water-soluble polysaccharides were dependent on both carbon source and Gluconacetobacter strain. The carbon substrate also affected the composition of the free EPS. When galactose served as an exclusive carbon source, Gluconacetobacter xylinus (G. xylinus) ATCC 53524 and ATCC 700178 produced a distinct alkaline stable crystalline product, which influenced the crystallization of cellulose. Gluconacetobacter hansenii (G. hansenii) ATCC 23769 and ATCC 53582, however, did not exhibit any significant change in cellulose crystal properties when galactose was used as the carbon source. Microscopic observation further confirmed significant incorporation of EPS into the cellulose composites. The cellulosic network produced from galactose medium showed distinctive morphological and structural features compared to that from glucose medium. PMID- 25439947 TI - Further improvement of flame retardancy of polyaniline-deposited paper composite through using phytic acid as dopant or co-dopant. AB - Polyaniline (PANI)-deposited electrically conductive and flame retardant paper composite was prepared using phytic acid (PA) as dopant or co-dopant. PA as doping acid greatly improved the flame retardancy of PANI-deposited paper composite whilst the conductivity was lower compared with using 5-sulfosalicylic acid (SSA) as doping acid. Lower temperature was favorable to obtain PANI deposited paper composite with both higher conductivity and better flame retardancy. Conductivity of PANI-deposited paper composite increased with increase of doping acid concentration and the suitable PA concentration range was 0.15-0.3 mol/L depending on the requirement of conductivity and flame retardancy. The PANI-deposited paper composite was characterized by SEM, TGA and XPS. The outstanding flame retardancy of PA-doped paper composite was caused by the synergetic effect of PANI coating and H3PO4. Both higher flame retardancy and higher conductivity of PANI-deposited paper composite were obtained by co-doping of SSA with PA. PMID- 25439948 TI - Screening of complex fucoidans from four brown algae species as procoagulant agents. AB - Fucoidans are complex sulfated polysaccharides extracted from brown algae. Depending on the concentration, they have been shown to stimulate and inhibit blood coagulation in vitro. Promotion of coagulation is mediated by blocking tissue factor pathway inhibitor (TFPI). We screened fucoidan extracts from four brown algae species in vitro with respect to their potential to improve coagulation in bleeding disorders. The fucoidans' pro- and anticoagulant activities were assessed by global hemostatic and standard clotting assays. Results showed that fucoidans improved coagulation parameters. Some fucoidans also activated the contact pathway of coagulation, an undesired property reported for sulfated glycosaminoglycans. Chemical evaluation of fucoidans' complex and variable structure included molecular weight (Mw), polydispersity (polyD), structural heterogeneity, and organic and inorganic impurities. Herewith, we describe a screening strategy that facilitates the identification of crude fucoidan extracts with desired biological and structural properties for improvement of compromised coagulation like in hemophilia. PMID- 25439949 TI - Porous chitosan doped with graphene oxide as highly effective adsorbent for methyl orange and amido black 10B. AB - In the current study, porous chitosan aerogels doped with small amount of graphene oxide (CSGO aerogels) with high porosity (97.96-98.78%), extraordinarily high water absorption (5848-8917%) and low density (0.021-0.035 g cm(-3)) were prepared and used as adsorbents for two azo dyes methyl orange (MO) and amido black 10B (AB10B). The adsorption behavior of these CSGO aerogels and some influence factors such as pH value, graphene oxide (GO) loading, concentration of pollutants, as well as adsorption kinetics were studied. Specifically, the adsorption capacity for MO is 686.89 mg g(-1), the highest comparing with other publication results, and it is 573.47 mg g(-1) for AB10B. Since they are biodegradable, non-toxic, efficient, low-cost and easy to prepare, we believe that these porous CSGO aerogels will be a promising candidate for dye removal. PMID- 25439950 TI - Optimization of culture medium compositions for gellan gum production by a halobacterium Sphingomonas paucimobilis. AB - The effect of culture medium compositions on gellan gum production produced by fermentation with a halobacterium Sphingomonas paucimobilis QHZJUJW CGMCC2428 was studied. In this work, a fractional factorial design was applied to investigate the main factors that affected gellan gum production by S. paucimobilis QHZJUJW CGMCC2428. Sucrose was the best carbon source for gellan gum and peptone displayed better inducing effect. Central composite design and response surface methodology were adopted to derive a statistical model for optimizing submerged culture medium composition. These experimental results showed that the optimum culture medium for producing gellan gum was composed of 40.00 (w/v) sucrose, 3.00% peptone (w/v), MgSO4 (w/v), 9.20% KH2PO4 (w/v), 7.50% Na2HPO4 (w/v), 4.30% K2SO4 (w/v), pH 6.8-7.0. The maximal gellan gum was 19.89+/-0.68 g/L, which was agreed closely with the predicated value (20.12 g/L). After incubated for 72 h under the optimized culture medium in 5-L bioreactor, the gellan gum fermentation reached about 19.90+/-0.68 g/L, which was higher than that in the initial cultivation medium. PMID- 25439951 TI - Optimization of enzymolysis-ultrasonic assisted extraction of polysaccharides from Momordica charabtia L. by response surface methodology. AB - An efficient enzymolysis-ultrasonic assisted extraction (EUAE) was developed and optimized for the extraction of polysaccharide from Momordica charabtia L. The single factor experiments and orthogonal experiments were used for the key experimental factors and their test range. Based on the preliminary experimental results, the response surface methodology (RSM) and Box-Behnken design (BBD) were applied for the optimization of EUAE conditions. Using the multiple regression analysis and analysis of variance (ANOVA), the experimental data were fitted to a second-order polynomial equation and were used to generate the mathematical model of optimization experiments. The optimal extraction conditions were as follows: a pH of 4.38, a extraction temperature of 52.02 degrees C and a extraction time of 36.87 min. Under the optimal extraction conditions, the extraction yield of Momordica charabtia L. polysaccharides (MCP) was 29.75+/-0.48%, which was well matched with the predicted value (29.80%) of the BBD model. PMID- 25439952 TI - Physical properties and antibacterial activity of chitosan/acemannan mixed systems. AB - The aim of the present study was to investigate the mechanical and thermal properties of mixed chitosan-acemannan (CS-AC) mixed gels and the antibacterial activity of dilute mixed solutions of both polysaccharides. Physical hydrogels of chitosan comprising varying amounts of non-gelling acemannan were prepared by controlled neutralization of chitosan using ammonia. As the overall acemannan concentration in the mixed hydrogel increased while fixing that of CS, the mechanical strength decreased. These results indicate that AC perturbs the formation of elastic junctions and overall connectivity as it occurs in the isolated CS network. Heterotypic associations between CS and AC leading to the formation of more compact microdomains may be at play in reducing the density of the gel network consolidated by CS, possibly due to shorter gel junctions. Micro DSC studies at pH 12.0 seem consistent with the suggestion that molecular heterotypic associations between CS and AC may be at play in determining the overall physical properties of the mixed gel systems. In dilute solution, CS showed antimicrobial activity against Staphylococcus aureus but not against Escherichia coli; AC did not exert antimicrobial activity against any of the two bacterial species. In blended solutions of both polysaccharides, as the amount of AC increased, the antimicrobial activity of the system against S. aureus ceased. In conclusion, this study demonstrates that it is feasible to incorporate acemannan in chitosan-acemannan gels and that although the mechanical strength decreases due to the presence of AC, the gel network persists even at high amount of AC. This study anticipates that the CS-AC mixed gels may offer promise for the future development of biomaterials such as scaffolds to be used in wound therapy. PMID- 25439953 TI - Synthesis of a microhydrogel composite from cellulose nanowhiskers and starch for drug delivery. AB - This work describes the preparation of a microhydrogel composite from cellulose nanowhiskers (CNW) and starch in an ultrasound assisted-emulsion. CNW, which showed rod-like morphology, was obtained by acid hydrolysis of cane-based cellulose. The introduction of vinyl bonds to both CNW and starch enabled us to create the microhydrogel composite in which CNW played a role as a covalent cross linker. Furthermore, CNW may act as an emulsifying agent for emulsion, improving both sphericity and homogeneity of the microparticles. The drug release was regulated in response to changes in the CNW amounts. The modeling of the release kinetics indicated that the drug release is driven by an anomalous mechanism and that the addition of CNW to starch microparticles led to differences in that mechanism. The release rate became ca. 2.9 times slower when CNW is added. When combined with starch, CNW played a role as a retardant factor for drug release. PMID- 25439954 TI - Controlled release of thiamin in a glassy kappa-carrageenan/glucose syrup matrix. AB - The work dealt with the diffusional mobility of thiamin embedded in a high-solid matrix of kappa-carrageenan with glucose syrup. It utilized thermomechanical analysis in the form of modulated differential scanning calorimetry and small deformation dynamic oscillation in shear, Fourier transform infrared spectroscopy, wide angle X-ray diffraction, scanning electron microscopy and UV vis spectrophotometry. The structural properties of the matrix were assessed in a temperature induced rubber-to-glass transformation. A thiamin-dye binding assay was employed to monitor the diffusion process of the vitamin from the high-solid preparation to ethylene glycol. The relationship between mechanical properties of the carbohydrate matrix and vitamin mobility was assessed via the application of the combined framework of the free volume theory and the predictions of the reaction rate theory. Results argue that the transport of the micronutrient is governed by the structural relaxation of the high-solid matrix. These were further treated with the concept of Fickian diffusion coefficient to provide the rate of the bioactive compound mobility within the present experimental settings. PMID- 25439955 TI - Ultrasound-assisted extraction of pectin from sisal waste. AB - In this study, an efficient ultrasound-assisted extraction (UAE) of pectin from sisal waste was investigated and optimized. Response surface methodology (RSM) based on a three-level four-factor Box-Behnken response surface design (BBD) was employed to optimize the extraction conditions (ultrasonic power, extraction temperature, extraction time and solid-liquid ratio). Analysis of variance showed that the contribution of a quadratic model was significant for the pectin extraction yield. The experimental yield (29.32%) was obtained under the optimal condition (ultrasonic power of 61 W, temperature of 50 degrees C, time of 26 min and SL ratio of 1:28 g/ml) was well agreement with predicted values. Therefore, ultrasound-assisted extraction could be used as an alternative method to extract pectin from sisal waste with the advantages of lower extraction temperatures, shorter extraction time and reduced energy consumption. PMID- 25439956 TI - Iron(II) binding by cereal beta-glucan. AB - Beta-glucan is a dietary fiber, which possesses several health benefits, such as cholesterol lowering, however this fiber is easily degraded in the presence of Fenton reagents. In the present study, the iron binding capacity of oat beta glucan and barley beta-glucan was evaluated by investigating the kinetics of the Fenton reaction at pH 2.7 and 4.7 using stopped flow spectroscopy. The rate constant of the Fenton reaction is not affected by the presence of the beta glucans in a solution pH 2.7, hence none of the beta-glucans bind iron(II) at this pH. However, at pH 4.7, the kinetics of the Fenton reaction vary between acetate buffer (k=2.8*10(2)M(-1)s(-1)), barley beta-glucan (k=2.2*10(2)M(-1)s( 1)) and oat beta-glucan (k=1.2*10(2)M(-1)s(-1)), which demonstrates that barley beta-glucan and oat beta-glucan form complexes with iron(II). Moreover, oat beta glucan shows a stronger affinity for iron(II) than barley beta-glucan, and may thereby reduce the formation of hydroxyl radicals and diminish the rate of viscosity loss of the oat beta-glucan solution, as shown by the ESR and rheological data. The results presented in this study suggest that cereal beta glucans can potentially reduce the bioavailability of iron. PMID- 25439957 TI - Ferulic acid-coupled chitosan: thermal stability and utilization as an antioxidant for biodegradable active packaging film. AB - The aim of the present research was to study the thermal stability of ferulic acid after coupling onto chitosan, and the possibility of using ferulic acid coupled chitosan (FA-CTS) as an antioxidant for biodegradable active packaging film. FA-CTS was incorporated into biodegradable film via a two-step process, i.e. compounding extrusion at temperatures up to 150 degrees C followed by blown film extrusion at temperatures up to 175 degrees C. Although incorporation of FA CTS with a content of 0.02-0.16% (w/w) caused decreased water vapor barrier property and reduced extensibility, the biodegradable films possessed improved oxygen barrier property and antioxidant activity. Radical scavenging activity and reducing power of film containing FA-CTS were higher than those of film containing naked ferulic acid, by about 254% and 94%, respectively. Tensile strength and rigidity of the films were not significantly affected by the addition of FA-CTS with a content of 0.02-0.08% (w/w). The above results suggested that FA-CTS could potentially be used as an antioxidant for active packaging film. PMID- 25439958 TI - Tunable thermal and flame response of phosphonated oligoallylamines layer by layer assemblies on cotton. AB - In the present paper we have demonstrated how the change of the layer by layer deposition parameters can influence the final properties of cotton fabrics in terms of coating morphology, thermal stability and flammability. To this aim, novel synthetized oligoallylamines and phosphonated oligoallylamines have been assembled on the surface of cotton exploiting different molecular weights and pH conditions. Low molecular weights have yielded an incomplete "island growth" coating while high molecular weight resulted in a homogeneous coating which thickness was controlled by the adopted pH. Both low and high molecular weight assemblies induced a reduction of the cellulose decomposition temperatures that was, conversely, delayed by coatings assembled at pH=10. All assemblies were able to improve cotton flammability by suppressing the afterglow phenomenon; the best results in terms of flame spread and final residue have been achieved by high molecular weight assemblies. PMID- 25439959 TI - Nano-web structures constructed with a cellulose acetate/lithium chloride/polyethylene oxide hybrid: modeling, fabrication and characterization. AB - Electrospun nano-web structures (ENWSs) were successfully fabricated from ionized binary solution of cellulose(Mn30)/polyethylene oxide(Mn200) (CA/PEO of 0.5-1.5). Final concentration of polymers was 12% (w/v) in the solution, and lithium chloride was used as ionizing agent. Response surface methodology (RSM) was applied to the optimize fabrication of ENWSs. Results of multiple linear regression analysis revealed that the solution properties and ENWSs morphology were strongly influenced by CA/PEO. An increase in PEO amount increased the viscosity which is a function of molecular weight, and as a result raised the entanglement of polymeric solution but decreased the surface tension that all support nanofibers fabrication. The size of nanofibers decreased with reducing PEO and LiCl concentration. Increasing the content of LiCl promoted the electrical conductivity (EC) value; however, junction zones were formed. The overall optimum region was found to be at combined level of 1.5% CA/PEO and 0.49% (w/v) LiCl. PMID- 25439960 TI - Gelling polysaccharide from Chondrus armatus and its oligosaccharides: the structural peculiarities and anti-inflammatory activity. AB - Structural peculiarities of low molecular weight (LMW) sample obtained by mild acid hydrolysis of kappa-carrageenan from Chondrus armatus was investigated by a rapid mass spectrometric method. The selected conditions allowed avoiding excess destruction of 3,6-AnGal residues that was shown by using tandem (MS/MS) mode. Main oligosaccharide fraction with molecular weight 2.3 kg/mol, obtained by mild acid hydrolysis was chosen for the analysis. It was shown that fragments with even degree of polymerization (DP) were mostly built of (-G4S-DA-)n repeating unit, n=1-5. Some fragments with odd DP were shown to contain -DA2S- insertions, being the fragments of iota-type blocks, which were randomly distributed along the polysaccharide chain as single insertions. The anti-inflammatory activity (on acetic acid-induced colitis in mice) of the initial polymer and its derivatives was studied. The anti-inflammatory effect of the polymer was observed at a dose of 5mg/kg. Polysaccharide decreased the degree of colon damage more than twice and area of damage in 40%. PMID- 25439961 TI - Synthesis and characterization of a novel graft copolymer of partially carboxymethylated guar gum and N-vinylformamide. AB - Graft copolymer of partially carboxymethylated guar gum (CMGOH) and N vinylformamide (NVF) was synthesized by free radical polymerization using 2,2 Azobis [2-(2-imadazolin-2-yl) propane] dihydrochloride (AIPH) as initiator. The effect of various reaction parameters such as concentration of NVF, CMGOH, sulphuric acid and AIPH, as well as reaction time and temperature were investigated, and the grafting conditions were optimized. Percent total conversion, % grafting, grafting efficiency (%) and percent add on under different conditions were evaluated and compared. The reaction mechanism for graft copolymerization discussed. Studies on swelling, metal ion uptake and flocculation properties were carried out in aqueous medium and the results obtained are presented and discussed. Both CMGOH and its corresponding graft copolymer samples were characterized by Fourier transform infrared spectroscopy and thermogravimetric analysis. Looking at the reasonable results obtained, the synthesized graft copolymers CMGOH-g-NVF, may be exploited as potential candidates for some industrial important applications as flocculent superabsorbent, and other similar applications. PMID- 25439962 TI - Basic effects of pulp refining on fiber properties--a review. AB - The requirement for high quality pulps which are widely used in paper industries has increased the demand for pulp refining (beating) process. Pulp refining is a promising approach to improve the pulp quality by changing the fiber characteristics. The diversity of research on the effect of refining on fiber properties which is due to the different pulp sources, pulp consistency and refining equipment has interested us to provide a review on the studies over the last decade. In this article, the influence of pulp refining on structural properties i.e., fibrillations, fine formation, fiber length, fiber curl, crystallinity and distribution of surface chemical compositions is reviewed. The effect of pulp refining on electrokinetic properties of fiber e.g., surface and total charges of pulps is discussed. In addition, an overview of different refining theories, refiners as well as some tests for assessing the pulp refining is presented. PMID- 25439963 TI - To the editor of Carbohydrate polymers. PMID- 25439964 TI - Poly(glycerol sebacate)/poly(butylene succinate-butylene dilinoleate) fibrous scaffolds for cardiac tissue engineering. AB - The present article investigates the use of a novel electrospun fibrous blend of poly(glycerol sebacate) (PGS) and poly(butylene succinate-butylene dilinoleate) (PBS-DLA) as a candidate for cardiac tissue engineering. Random electrospun fibers with various PGS/PBS-DLA compositions (70/30, 60/40, 50/50, and 0/100) were fabricated. To examine the suitability of these fiber blends for heart patches, their morphology, as well as their physical, chemical, and mechanical properties were measured before examining their biocompatibility through cell adhesion. The fabricated fibers were bead-free and exhibited a relatively narrow diameter distribution. The addition of PBS-DLA to PGS resulted in an increase of the average fiber diameter, whereas increasing the amount of PBS-DLA decreased the hydrophilicity and the water uptake of the nanofibrous scaffolds to values that approached those of neat PBS-DLA nanofibers. Moreover, the addition of PBS DLA significantly increased the elastic modulus. Initial toxicity studies with C2C12 myoblast cells up to 72 h confirmed nontoxic behavior of the blends. Immunofluorescence analyses and scanning electron microscopy analyses confirmed that C2C12 cells showed better cell attachment and proliferation on electrospun mats with higher PBS-DLA content. However, immunofluorescence analyses of the 3 day-old rat cardiomyocytes cultured for 2 and 5 days demonstrated better attachment on the 70/30 fibers containing well-aligned sarcomeres and expressing high amounts of connexin 43 in cellular junctions indicating efficient cell-to cell communication. It can be concluded, therefore, that fibrous PGS/PBS-DLA scaffolds exhibit promising characteristics as a biomaterial for cardiac patch applications. PMID- 25439965 TI - Treatment of iatrogenic sialoceles and fistulas in the parotid gland with ultrasound-guided injection of botulinum toxin A. PMID- 25439966 TI - Considering prior plausibility in clinical trials does not mean ignoring scientific evidence. PMID- 25439967 TI - Nanomedicine-based drug targeting for psoriasis: potentials and emerging trends in nanoscale pharmacotherapy. AB - INTRODUCTION: Psoriasis is a T-cell mediated autoimmune inflammatory skin disease recognized by skin surface inflammation, epidermal proliferation, hyperkeratosis, angiogenesis and anomalous keratinization. Currently, various pharmacotherapies are available for it; however, pharmacotherapy based on conventional formulations can provide therapeutic benefits only to a limited extent. Recent advancement in nanotechnology-based nanomedicines has led to the possibility of improving the efficacy and safety of pharmacotherapeutic agents for psoriasis. AREAS COVERED: This review covers the brief pathophysiology of psoriasis, available medications and its associated challenges in treatment. Collective accounts of various drugs acting on different molecular targets of psoriasis and the role of nanomedicines in their effective targeting are discussed. Moreover, newer approaches in psoriatic therapy such as combination drug targeting and physical techniques of topical permeation enhancement along with nanomedicines are also discussed. EXPERT OPINION: Novel nanomedicines (such as liposomes, polymeric nanoparticles, etc.) have shown their potential in improving therapeutic benefits of antipsoriatic drugs by increasing their therapeutic efficacy with minimal toxicity. Nevertheless, while the results on animal models using nanomedicine based drug targeting of psoriasis via different route seem promising, lack of sufficient evidence in a clinical setup is a constraint and more clinical studies on the efficacy and safety of nanomedicines in psoriasis therapy are required. PMID- 25439968 TI - Continuity and change. PMID- 25439969 TI - The evolution of the role of the psychiatric mental health advanced practice registered nurse in the United States. PMID- 25439970 TI - The factor structure of posttraumatic stress disorder symptoms in patients with traumatic spinal cord injuries. AB - The current study investigated the factor structure of posttraumatic stress disorder (PTSD) symptoms in a sample of 256 patients with traumatic spinal cord injuries (SCI) in China. The confirmatory factor analysis results showed that a five-factor model composed of intrusion, avoidance, emotional numbing, dysphoric arousal, and anxious arousal fits the data significantly better than the tripartite DSM-IV model and the two well-supported four-factor models, and the C3 symptom (inability to recall important aspect of the trauma) loaded weakly on its corresponding factor. Implications and limitations for the results are discussed. PMID- 25439971 TI - The roles of social support in helping chinese women with antenatal depressive and anxiety symptoms cope with perceived stress. AB - A community-based sample of 755 pregnant Chinese women were recruited to test the direct and moderating effects of social support in mitigating perceived stress associated with antenatal depressive or anxiety symptoms. The Social Support Rating Scale, the Perceived Stress Scale, the Edinburgh Depressive Postnatal Scale and the Zung Self-Rating Anxiety Scale were used. Social support was found to have direct effects and moderating effects on the women's perceived stress on antenatal depressive and anxiety symptoms in multiple linear regression models. This knowledge of the separate effects of social support on behavioral health is important to psychiatric nurse in planning preventive interventions. PMID- 25439972 TI - Effectiveness of mindfulness-based cognitive therapy for co-morbid depression in drug-dependent males. AB - The present study aimed at examining the effect of Mindfulness-Based Cognitive Therapy (MBCT) in decreasing depression symptoms in dully diagnosed males (drug dependent males with co-morbid depression).An experimental research design with pre- and post-tests and a control group was used. The sample of the study comprised 33 drug-dependent men who also endorsed depression symptoms on the Beck Depression Inventory II (BDI-II). All the selected individuals were assigned randomly to either the intervention group or control group (16 to the intervention and 17 to the control group). The intervention group experienced eight 2-h sessions of training in MBCT. At the end of the training, the subjects were once again evaluated using the BDI-II. Analysis of co-variance was used to analyze the data. The results suggested that MBCT did contribute to a significant decrease in the depression symptoms of the dully diagnosed individuals. It is recommended that the MBCT be used for treating depression in drug-dependent males undergoing detoxification and treatment for their drug dependence. PMID- 25439973 TI - Multidisciplinary parent education for caregivers of children with autism spectrum disorders. AB - This quasi-experimental study aimed to determine the effectiveness of a multidisciplinary parent education program focused on improving health-related quality of life (HRQOL) for caregivers of children with autism spectrum disorders (ASD). This study included 42 participants (22 intervention, 20 wait-list control) who were the main caregivers of children with ASD. Data were collected at baseline and post-intervention. At the end of the multidisciplinary parent education program, significant improvements were observed in the mental HRQOL, family functioning, self-efficacy and positive coping style. The results indicate that a multidisciplinary parent education program, designed for caregivers of children with ASD, may have positive effects on caregivers' mental health-related quality of life, while having little effect on their physical health-related quality of life. PMID- 25439974 TI - Predictors of health-related quality of life in Chinese caregivers of children with autism spectrum disorders: a cross-sectional study. AB - The purpose of this study was to identify the predictors of health-related quality of life (HRQOL) among caregivers of children with autism spectrum disorders (ASD) in China. Two hundred and seventy-three caregivers were surveyed using questionnaires on HRQOL, family functioning, coping style, social support, and caregiver burden. Besides socio-demographic characteristics of children with ASD and their caregivers, results demonstrate that family functioning, coping style, social support, caregiver burden are predictors of HRQOL in caregivers of children with ASD, and these predictors correlated with each other. These results indicate that comprehensive intervention, which focuses on improving caregivers' coping strategies, social support (especially from family members and friends) and family functioning, and on releasing caregiver burden, should be provided to caregivers of children with ASD. PMID- 25439975 TI - Outcomes following treatment of veterans for substance and tobacco addiction. AB - Persons who use tobacco in addition to alcohol and other drugs have increased health risks and mortality rates. The purpose of this study was to evaluate the impact of participation in a tobacco cessation program on tobacco, alcohol, and other drug use in a population seeking treatment for substance use disorders (SUDs). Tobacco, alcohol, and other drug use were assessed by urine drug screens, breathalyzer readings, and self-report. Veterans (N=137) with a tobacco use disorder enrolled in inpatient program for the treatment of SUDs at the Salem Veterans Affairs Medical Center participated in tobacco cessation education as part of their treatment programming. Use of tobacco, drugs and/or alcohol was evaluated upon admission, 2 weeks following admission, at discharge and 1 month following graduation. The 1-month follow-up rate was 70.8%, with 97 veterans completing the follow-up assessment. Of those 97 veterans, 90.7% (n=88) reported abstinence from alcohol and 91.8% (n=89) reported abstinence from other drugs of abuse. Fourteen veterans (14.4%) reported abstinence from tobacco at the 1-month follow-up. The veterans reporting abstinence from tobacco use also reported abstinence from alcohol and other drugs at the 1-month follow-up. PMID- 25439976 TI - The silence of mental health issues within university environments: a quantitative study. AB - A descriptive study was used to examine the attitudes and experiences of staff and students towards mental health problems. Staff completed the "Attitude towards mental illness survey", and students who self-identified having a mental health problem completed the "Stigma scale". Using an online collection process, data from 270 staff and 201 students showed that the "silence" surrounding mental health problems permeates the university environment and impacts on help seeking behaviors, the provision of support and on the recovery and wellbeing of affected individuals. Universities must decrease stigma and foster social inclusion to build self-esteem in people who have mental health problems. PMID- 25439977 TI - Association of metacognitive beliefs, obsessive beliefs and symptom severity with quality of life in obsessive-compulsive patients. AB - The aim of this study was to evaluate the association of obsessive beliefs, obsessive-compulsive disorder severity and metacognitive beliefs to the quality of life in patients with obsessive-compulsive disorder (OCD). Sixty one adults with a principal diagnosis of OCD were recruited for the study. Participants were assessed by trained clinicians using an unstructured clinical interview, the Obsessive Beliefs Questionnaire, the Yale-Brown Obsessive-Compulsive Scale, the Metacognitive Beliefs Questionnaire and the WHO Quality of Life Questionnaire. Data were analyzed using Pearson's of correlation coefficients and multiple regression analyses. Findings indicate that obsessive beliefs, severity total OCD and metacognitive beliefs were associated with total quality of life scores. Regression analysis revealed that while OCD total severity explained 40.1% of the variance in total quality of life, obsessive beliefs (perfectionism/certainty domain) and metacognitions (cognitive self-consciousness and negative beliefs about thoughts in general) explained an additional 13.7%, 7.7% and 5.4% of the variance in QoL. Findings indicate that the metacognitive beliefs associated with OCD symptom severity are different from that associated with quality of life. The implications are that metacognitive therapy aimed at symptom reduction may not necessarily result in improved QoL in OCD patients. PMID- 25439978 TI - Challenges and movement to resolution for persons living with diabetes. PMID- 25439979 TI - Electroconvulsive therapy: thoughts for nursing. PMID- 25439980 TI - Rab33B and its autophagic Atg5/12/16L1 effector assist in hepatitis B virus naked capsid formation and release. AB - Hepatitis B virus morphogenesis is accompanied by the production and release of non-enveloped capsids/nucleocapsids. Capsid particles are formed inside the cell cytosol by multimerization of core protein subunits and ultimately exported in an uncommon coatless state. Here, we investigated potential roles of Rab GTPases in capsid formation and trafficking by using RNA interference and overexpression studies. Naked capsid release does not require functions of the endosome associated Rab5, Rab7 and Rab27 proteins, but depends on functional Rab33B, a GTPase participating in autophagosome formation via interaction with the Atg5 Atg12/Atg16L1 complex. During capsid formation, Rab33B acts in conjunction with its effector, as silencing of Atg5, Atg12 and Atg16L1 also impaired capsid egress. Analysis of capsid maturation steps revealed that Rab33B and Atg5/12/16L1 are required for proper particle assembly and/or stability. In support, the capsid protein was found to interact with Atg5 and colocalize with Atg5/12/16L1, implicating that autophagy pathway functions are involved in capsid biogenesis. However, a complete and functional autophagy pathway is dispensable for capsid release, as judged by knockdown analysis of Atg8/LC3 family members and pharmaceutical ablation of canonical autophagy. Experiments aimed at analysing the capsid release-stimulating activity of the Alix protein provide further evidence for a link between capsid formation and autophagy. PMID- 25439981 TI - Nurses' perceptions of patient safety culture in Jordanian hospitals. AB - BACKGROUND: Patients' safety culture is a key aspect in determining healthcare organizations' ability to address and reduce risks of patients. Nurses play a major role in patients' safety because they are accountable for direct and continuous patient care. There is little known information about patients' safety culture in Jordanian hospitals, particularly from the perspective of healthcare providers. AIM: The study aimed to assess patient safety culture in Jordanian hospitals from nurses' perspective. METHODS: A cross-sectional, descriptive design was utilized. A total number of 658 nurses participated in the current study. Data were collected using an Arabic version of the hospital survey of patients' safety culture. FINDINGS: Teamwork within unit dimensions had a high positive response, and was perceived by nurses to be the only strong suit in Jordanian hospitals. Areas that required improvement, as perceived by nurses, are as follows: communication openness, staffing, handoff and transition, non punitive responses to errors, and teamwork across units. Regression analysis revealed factors, from nurses' perspectives, that influenced patients' safety culture in Jordanian hospital. Factors included age, total years of experience, working in university hospitals, utilizing evidence-based practice and working in hospitals that consider patient safety to be a priority. LIMITATIONS: Participants in this study were limited to nurses. Therefore, there is a need to assess patient safety culture from other healthcare providers' perspectives. Moreover, the use of a self-reported questionnaire introduced the social desirability biases. CONCLUSION: The current study provides insight into how nurses perceive patient safety culture. Results of this study have revealed that there is a need to replace the traditional culture of shame/blame with a non punitive culture. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Study results implied that improving patient safety culture requires a fundamental transformation of nurses' work environment. New policies to improve collaboration between units of hospitals would improve patients' safety. PMID- 25439983 TI - PUFA biosynthesis pathway in marine scallop Chlamys nobilis Reeve. AB - Long-chain polyunsaturated fatty acids (LC-PUFAs) are essential in important physiological processes. However, the endogenous PUFA biosynthesis pathway is poorly understood in marine bivalves. Previously, a fatty acyl desaturase (Fad) with Delta5 activity was functionally characterized and an elongase termed Elovl2/5 was reported to efficiently elongate 18:2n-6 and 18:3n-3 to 20:2n-6 and 20:3n-3 respectively in Chlamys nobilis. In this study, another elongase and another Fad were identified. Functional characterization in recombinant yeast showed that the newly cloned elongase can elongate 20:4n-6 and 20:5n-3 to C22 and C24, while the newly cloned scallop Fad exhibited a Delta8-desaturation activity, and could desaturate exogenously added PUFA 20:3n-3 and 20:2n-6 to 20:4n-3 and 20:3n-6 respectively, providing the first compelling evidence that noble scallop could de novo biosynthesize 20:5n-3 and 20:4n-6 from PUFA precursors though the "Delta8 pathway". No Delta6 or Delta4 activity was detected for this Fad. Searching against our scallop transcriptome database failed to find any other Fad like genes, indicating that noble scallop might have limited ability to biosynthesize 22:6n-3. Interestingly, like previously characterized Elovl2/5, the two newly cloned genes showed less efficient activity toward n-3 PUFA substrates than their homologous n-6 substrates, resulting in a relatively low efficiency to biosynthesize n-3 PUFA, implying an adaption to marine environment. PMID- 25439982 TI - Genomic influences on alcohol problems in a population-based sample of young adults. AB - AIMS: Alcohol problems (AP) contribute substantially to the global disease burden. Twin and family studies suggest that AP are genetically influenced, although few studies have identified variants or genes that are robustly associated with risk. This study identifies genetic and genomic influences on AP during young adulthood, which is often when drinking habits are established. DESIGN: We conducted a genome-wide association study of AP. We further conducted gene-based tests, gene ontology analyses and functional genomic enrichment analyses to assess genomic factors beyond single variants that are relevant to AP. SETTING: The Avon Longitudinal Study of Parents and Children, a large population-based study of a UK birth cohort. PARTICIPANTS: Genetic and phenotypical data were available for 4304 participants. MEASUREMENTS: The AP phenotype was a factor score derived from items from the Alcohol Use Disorders Identification Test, symptoms of DSM-IV alcohol dependence, and three additional problem-related items. FINDINGS: One variant met genome-wide significance criteria. Four out of 22,880 genes subjected to gene-based analyses survived a stringent significance threshold (q < 0.05); none of these have been implicated previously in alcohol-related phenotypes. Several biologically plausible gene ontologies were statistically over-represented among implicated single nucleotide polymorphisms (SNPs). SNPs on the Illumina 550 K SNP chip accounted for ~5% of the phenotypical variance in AP. CONCLUSIONS: Genetic and genomic factors appear to play a role in alcohol problems in young adults. Genes involved in nervous system-related processes, such as signal transduction and neurogenesis, potentially contribute to liability to alcohol problems, as do genes expressed in non-brain tissues. PMID- 25439984 TI - Changes in metabolic phenotypes of Plasmodium falciparum in vitro cultures during gametocyte development. AB - BACKGROUND: Gametocytes are the Plasmodium life stage that is solely responsible for malaria transmission. Despite their important role in perpetuating malaria, gametocyte differentiation and development is poorly understood. METHODS: To shed light on the biochemical changes that occur during asexual and gametocyte development, metabolic characterization of media from in vitro intra-erythrocytic Plasmodium falciparum cultures was performed throughout gametocyte development by applying 1H nuclear magnetic spectroscopy, and using sham erythrocyte cultures as controls. Spectral differences between parasite and sham cultures were assessed via principal component analyses and partial-least squares analyses, and univariate statistical methods. RESULTS: Clear parasite-associated changes in metabolism were observed throughout the culture period, revealing differences between asexual parasites and gametocyte stages. With culture progression and development of gametocytes, parasitic release of the glycolytic end products lactate, pyruvate, alanine, and glycerol, were found to be dramatically reduced whilst acetate release was greatly increased. Also, uptake of lipid moieties CH(2), CH(3), and CH = CH-CH(2)-CH(2) increased throughout gametocyte development, peaking with maturity. CONCLUSIONS: This study uniquely presents an initial characterization of the metabolic exchange between parasite and culture medium during in vitro P. falciparum gametocyte culture. Results suggest that energy metabolism and lipid utilization between the asexual stages and gametocytes is different. This study provides new insights for gametocyte specific nutritional requirements to aid future optimization and standardization of in vitro gametocyte cultivation, and highlights areas of novel gametocyte cell biology that deserve to be studied in greater detail and may yield new targets for transmission-blocking drugs. PMID- 25439985 TI - A steep ramp test is valid for estimating maximal power and oxygen uptake during a standard ramp test in type 2 diabetes. AB - A short maximal steep ramp test (SRT, 25 W/10 s) has been proposed to guide exercise interventions in type 2 diabetes, but requires validation. This study aims to (a) determine the relationship between Wmax and VO2peak reached during SRT and the standard ramp test (RT); (b) obtain test-retest reliability; and (c) document electrocardiogram (ECG) abnormalities during SRT. Type 2 diabetes patients (35 men, 26 women) performed a cycle ergometer-based RT (women 1.2; men 1.8 W/6 s) and SRT on separate days. A random subgroup (n = 42) repeated the SRT. ECG, heart rate, and VO2 were monitored. Wmax during RT: 193 +/- 63 (men) and 106 +/- 33 W (women). Wmax during SRT: 193 +/- 63 (men) and 188 +/- 55 W (women). The relationship between RT and SRT was described by men RT VO2peak (mL/min) = 152 + 7.67 * Wmax SRT1 (r: 0.859); women RT V O 2 p e a k (mL/min) = 603 + 4.75 * Wmax SRT1 (r: 0.771); intraclass correlation coefficients between first (SRT1) and second SRT Wmax (SRT2) were men 0.951 [95% confidence interval (CI) 0.899-0.977] and women 0.908 (95% CI 0.727-0.971). No adverse events were noted during any of the exercise tests. This validation study indicates that the SRT is a low-risk, accurate, and reliable test to estimate maximal aerobic capacity during the RT to design exercise interventions in type 2 diabetes patients. PMID- 25439986 TI - [Precision medicine, decision medicine]. PMID- 25439987 TI - [uPA/PAI-1, Oncotype DXTM, MammaPrint((r)). Prognosis and predictive values for clinical utility in breast cancer management]. AB - CONTEXT AND AIMS: Breast cancer prognosis and predictive biomarkers development would allow sparing some patients from chemotherapy or identifying patients for whom chemotherapy would be indicated. In this context, in 2009, the French National Cancer Institute, a National Health and Science Agency dedicated to cancer, in collaboration with the French society of senology and breast pathology (SFSPM) published a report on the assessment of the prognostic and the predictive clinical validity of tissular biomarkers, uPA/PAI-1, Oncotype DXTM and MammaPrint((r)), in breast cancer management. They concluded that only the uPA/PAI-1 prognosis value reached the highest level of evidence (LOE I according to Hayes 1998 classification). In 2012, it was decided to update this report since new data have emerged and because information disparities among clinicians have been identified. This article aims to present the main conclusions together with the levels of evidence associated with those conclusions. METHODS: The updating process was based on literature published since 2009 appraisal and on multidisciplinary and independent experts' opinion. The levels of evidence (LOE) used are those of the classification defined by Simon in 2009 (updated Hayes 1998 classification): LOE IA and LOE IB: high level of evidence; LOE IIB and LOE IIC: intermediate level of evidence; LOE IIIC and LOE IV-VD: low level of evidence. CONCLUSIONS: Among patients without lymph-node involvement, uPA/PAI-1, invasion process biomarkers, reach the highest level of evidence for 10 years recurrence free survival prognosis (LOE IA according to Simon). The predictive value to anthracyclins chemotherapy remains to be confirmed. Oncotype DXTM and MammaPrint((r)) prognosis and predictive value do not reach the LOE I level. This updating' process confirms the 2009 levels of evidence for all the three biomarkers prognosis value. Besides, concerning Oncotype DXTM and MammaPrint((r)), new data do not allow to conclude neither to their complementary clinical information to other clinicopathological existing biomarkers nor to a favorable cost-efficiency ratio in therapeutic decision making and this because of the methodological weakness and uncertainty that are identified in the selected studies. Practically, beyond the prognosis and predictive biomarkers validity, the clinical utility of a new biomarker for chemotherapy indication depends on its clinical added information with regard to validated biomarkers (HR, HER2 and Ki67) and to clinicopathological parameters. Since they are the sole validated biomarkers of the invasion process, uPA/PAI-1 could complete clinical information of other clinicopathological factors and consequently could confer an added clinical value. However, data concerning the impact of this information on chemotherapy clinical indication are lacking. PMID- 25439988 TI - [2014 update of the GEFPICS' recommendations for HER2 status determination in breast cancers in France]. AB - International guidelines on HER2 determination in breast cancer have just been updated by the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP), on the basis of more than ten-year practice, results of clinical trials and concordance studies. The GEFPICS group, composed of expert pathologists in breast cancer, herein presents these recommendations, adapted to the French routine practice. These guidelines highlight the possible diagnosis difficulties with regards to HER2 status determination, such as intra-tumor heterogeneity, special histological subtypes and biomarker re-evaluation during metastatic relapse. Pre-analytical issues and updated scoring criteria (especially for equivocal cases) are detailed, in order to decrease the occurrence of false negative cases. In the era of personalized medicine, pathologists are more than ever involved in the quality of oncotheranostic biomarker evaluation. PMID- 25439989 TI - [Pre-analytical stage for biomarker assessment in breast cancer: 2014 update of the GEFPICS' guidelines in France]. AB - Biomarker assessment of breast cancer tumor samples is part of the routine workflow of pathology laboratories. International guidelines have recently been updated, with special regards to the pre-analytical steps that are critical for the quality of immunohistochemical and in situ hybridization procedures, whatever the biomarker analyzed. Fixation and specimen handling protocols must be standardized, validated and carefully tracked. Cooperation and training of the personnel involved in the specimen workflow (e.g. radiologists, surgeons, nurses, technicians and pathologists) are of paramount importance. The GEFPICS' update of the recommendations herein details and comments the different steps of the pre analytical process. Application of these guidelines and participation to quality insurance programs are mandatory to ensure the correct evaluation of oncotheranostic biomarkers. PMID- 25439990 TI - [KHSV/EBV associated germinotropic lymphoproliferative disorder: a rare entity, case report and review of the literature]. AB - We report a case of KSHV/EBV associated germinotropic lymphoproliferative disorder (LPG) in a 49-year-old African patient, without immunosuppression. LPG is a rare entity arising in immunocompetent patients in opposition to other lymphoproliferative disorders associated to Kaposi sarcoma-associated herpes virus (KSHV). The disease presents itself as localized lymphadenopathy with an infiltration of germinal centers by plasmablastic cells coinfected by KSHV and EBV (Epstein-Barr Virus). After treatment, the outcome is favorable. Differential diagnosis in our case, due to the presence of clusters of Hodgkin-like cells in the mantle zone, included lymphocyte rich classic Hodgkin lymphoma (LHCRL) and nodular lymphocyte predominant Hodgkin lymphoma (LHNPL). Finally, we highlight the differential diagnostic criteria of KSHV lymphoproliferative diseases. PMID- 25439991 TI - [Eccrine porocarcinoma with Bowenoid changes: a challenging diagnosis of adnexal neoplasm]. AB - Eccrine porocarcinoma is a rare malignant sweat gland tumor, representing less than 0.01% of all cutaneous neoplasms, with eccrin differentiation. Its acrosynringeal origin and physiopathology still remain discussed. The prognosis of this carcinoma is held to be poor with a significant risk of lymph node metastasis and local recurrence. Also, this not specific tumor can be a challenging histological diagnosis, in particular, in Bowenoid variant. We report a case of Bowenoid and keratinizing variant of eccrine porocarcinoma of the left ring finger with pejorative evolution and initial diagnosis of infiltrating squamous cell carcinoma arising in Bowen's disease. The knowledge of these patterns and identification of eccrine differentiation of the tumor are essential for the diagnosis and for adapted therapeutic care. PMID- 25439992 TI - [Mammary analog secretory carcinoma of the parotid gland]. AB - Mammary analog secretory carcinoma (MASC) of the parotid gland is a rare and recently described lesion. We report the case of a 46-year-old man with a tumor of the parotid gland which was carried to the diagnosis of MASC. Diagnostic was confirmed by highlighting the ETV6-NTRK3 gene translocation. However, some morphologic and immunohistochemical features are suggestive of this entity. This carcinoma should be distinguished from its main differential diagnoses: acinic cell carcinoma and low grade cribriform cystadenocarcinoma. PMID- 25439993 TI - [Erythemato-violaceous nodule of the back: case for diagnostic]. PMID- 25439994 TI - [Inflammatory ovary lesion]. PMID- 25439995 TI - [Subcutaneous painful nodule of the leg]. PMID- 25439996 TI - [An exceptional cause of skin tumor]. PMID- 25439997 TI - Neuropeptide Y pathways in anxiety-related disorders. PMID- 25439998 TI - Elucidating the neural mechanisms of cognitive-behavioral therapy: a commentary on treatment changes in neural correlates of subliminal and supraliminal threat in individuals with spider phobia. PMID- 25439999 TI - A lighter shade of trauma. PMID- 25440000 TI - The promise of acceptance as an NGO security management approach. AB - This paper explores three questions related to acceptance as a security management approach. Acceptance draws upon relationships with community members, authorities, belligerents and other stakeholders to provide consent for the presence and activities of a non-governmental organisation (NGO), thereby reducing threats from these actors. Little is documented about how NGOs gain and maintain acceptance, how they assess and monitor the presence and degree of acceptance, or how they determine whether acceptance is effective in a particular context. Based on field research conducted in April 2011 in Kenya, South Sudan and Uganda, we address each of these three issues and argue that acceptance must be actively sought as both a programme and a security management strategy. In the paper we delineate elements common to all three contexts as well as missed opportunities, which identify areas that NGOs can and should address as part of an acceptance approach. PMID- 25440001 TI - Investigation of the leptin levels in the blood serum of Cyprinus carpio (Linnaeus, 1758) and Capoeta trutta (Heckel, 1843). AB - Leptin is a peptide hormone secreted by adipose tissues in the various teleost fish and vertebrates. Leptin has been suggested to have an important role in a range physiological function, including regulation of food intake, reproduction, immune function, energy expenditure, lipid and carbohydrate metabolism. In this study, leptin levels in the blood serum of Cyprinus carpio and Capoeta trutta were determined. Then the results were compared between two species and between sexes of each species. In addition, leptin levels were also compared with the body weight and length of both C. carpio and C. trutta. Leptin level was analysed using available enzyme-linked immunoassay (ELISA) kit (Rat leptin ELISA kit, catalog no: SK00050-08). Leptin levels showed no significant difference (p > 0.05) that in relation to between two species and between sexes of each species. It has been shown that not significantly correlated when examined correlations between the leptin level in blood serum and body weight (r = 0.192, p = 0.380) or length (r = 0.102, p = 0.644) of C. carpio. Similarly, the correlations between leptin level in blood serum and body weight (r = 0.021, p = 0.959) or length (r = 0.123, p = 0.595) of C. trutta were also not significant. PMID- 25440002 TI - Spontaneous splenic rupture after thrombolysis for ischemic stroke. AB - Spontaneous spleen rupture with no recent report of trauma is an extremely rare and life-threatening cause of intraperitoneal hemorrhage.We present the first case of an atraumatic pathological splenic rupture following alteplase thrombolysis for ischemic stroke. PMID- 25440003 TI - Seizure-induced acute coronary syndrome: the value of postictal screening. PMID- 25440004 TI - Airway control in case of a mass toxicological event: superiority of second generation supraglottic airway devices. AB - INTRODUCTION: Early respiratory support and airway (AW) control with endotracheal intubation (ETI) are crucial in mass toxicology events and must be performed while wearing chemical personal protective equipment (C-PPE). AIM: The aim of this study is to evaluate the efficiency of AW control by using second-generation supraglottic AW devices (SADs) as compared with ETI and first-generation SAD while wearing C-PPE. METHODS: This is a randomized crossover trial involving 117 medical practitioners. Four AW management devices were examined: endotracheal tube, the first-generation SAD, laryngeal mask AW unique and 2 second-generation SAD, the laryngeal tube suction disposable, and supreme laryngeal mask AW (SLMA). Primary end point measured were success or failure, number of attempts, and time needed to achieve successful device insertion. Secondary end point was a subjective appraisal of the AW devices by study population. RESULTS: More attempts were required to achieve AW control with endotracheal tube, with and without C-PPE (P<.001). Time to achieve AW control with ETI was, on average, 88% longer than required with other devices and improved with practice. The mean times to achieve an AW were longer when operators were equipped with C-PPE as compared with standard clothing. Subjectively, difficulty levels were significantly higher for ETI than for all other devices (P<.0001). CONCLUSIONS: When compared with ETI, the use of SADs significantly shortened the time for AW control while wearing C-PPE. Second-generation SAD were superior to laryngeal mask AW unique. These finding suggest that SADs may be used in a mass toxicology event as a bridge, until definite AW control is achieved. PMID- 25440005 TI - Digestible and metabolizable energy in corn grains from different origins for growing pigs. AB - An experiment was conducted to determine the digestible energy (DE) and metabolizable energy (ME) concentrations in nine sources of corn grains fed to growing pigs and to compare the energy values among their countries of origin. A total of nine sources of corn grains including five sources of yellow corn from the United States (USY), two sources of yellow corn from South Africa (SAY), and two sources of white corn from South Africa (SAW) were used. Nine barrows with an initial body weight of 37.1 +/- 8.6 kg were allotted to a 9 * 9 Latin square design with nine diets and nine periods. The DE concentration in SAY (3347 kcal/kg) was greater (P < 0.001) than in USY (3269 kcal/kg), but was less (P < 0.001) than in SAW (3436 kcal/kg) on an as-fed basis. Similarly, the ME concentration in SAY (3291 kcal/kg) was greater (P < 0.001) than in USY (3209 kcal/kg), but was less (P < 0.001) than in SAW (3386 kcal/kg). In conclusion, the DE and ME concentrations in nine sources of corn grains are different among their countries of origin. PMID- 25440007 TI - Association between alcohol consumption and periodontal disease among older Nigerians in plateau state: a preliminary study. AB - OBJECTIVE: To report the periodontal status of older adults in Plateau State, Nigeria, and determine its Association with alcohol consumption. BACKGROUND: Periodontal disease is common among Nigerians, and the prevalence increases with age. The role that alcohol consumption plays in the occurrence of the disease among Africans is uncertain. MATERIALS AND METHODS: Sample selection was performed using a multistage cluster sampling technique among older adults in Plateau State, Nigeria. Interviews, using structured questionnaires, were conducted for each of the participants. Clinical examinations were then carried out to determine the occurrence of periodontal disease, assessed by clinical attachment loss and probing depth. RESULTS: The prevalence of periodontal disease was 79%, being severe in 46% of the population. Almost half of the participants (46.7%) examined were still actively consuming alcohol, among which 48% reported a history of intoxication. There was no statistically significant relationship between periodontal disease and the frequency of alcohol consumption, or quantity consumed on each occasion. However, alcohol consumption was highly correlated with periodontal disease among those who reported intoxication from the drink (r = 0.095; p = 0.033). A history of intoxication with alcohol was the only significant predictor of periodontal disease, after adjusting for age and gender. CONCLUSION: Periodontal disease was highly prevalent among older Nigerians in this study. Apart from those who reported intoxication from alcohol, there was no statistically significant relationship between the prevalence of periodontal disease and the frequency of alcohol consumption or the quantity consumed on each occasion. PMID- 25440006 TI - AT-1001: a high-affinity alpha3beta4 nAChR ligand with novel nicotine-suppressive pharmacology. AB - BACKGROUND AND PURPOSE: The alpha3beta4 subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediating nicotine reinforcement processes. AT-1001 has been recently described as a high-affinity and selective alpha3beta4 nAChR antagonist that blocks nicotine self-administration in rats. The aim of this study was to investigate the mechanism of action underlying the nicotine-suppressive effects of AT-1001. EXPERIMENTAL APPROACH: Effects of AT 1001 were determined using in vitro assays and rat models of nicotine addiction, and compared with varenicline. KEY RESULTS: AT-1001 and its analogue AT-1012 were functionally selective as antagonists for alpha3beta4 over alpha4beta2 nAChRs, but not to the same extent as the binding selectivity, and had partial agonist activity at alpha3beta4 nAChRs. In contrast, varenicline was a partial agonist at alpha4beta2, a weak agonist at alpha3beta4 and inhibited alpha4beta2 at a much lower concentration than it inhibited alpha3beta4 nAChRs. AT-1001 and varenicline also had very different in vivo properties. Firstly, AT-1001 did not exhibit reinforcing properties per se while varenicline was self-administered. Secondly, systemic treatment with AT-1001 did not induce reinstatement of nicotine seeking but rather attenuated reinstatement induced by varenicline, as well as nicotine. Finally, unlike varenicline, AT-1001 selectively blocked nicotine self administration without altering alcohol lever pressing as assessed in an operant co-administration paradigm. CONCLUSIONS AND IMPLICATIONS: These findings describe a more complex AT-1001 in vitro profile than previously appreciated and provide further support for the potential of AT-1001 and congeners as clinically useful compounds for smoking cessation, with a mechanism of action distinct from currently available medications. PMID- 25440008 TI - The rtPA increases MMP-9 activity in serum during ischaemic stroke. AB - BACKGROUND AND PURPOSE: To find the relationship between rtPA treatment vs. MMP-9 activity, MMP-3, and TIMP-1 serum levels related to patients' neurological status during acute ischaemic stroke (IS). MATERIAL AND METHODS: 35 IS patients were enrolled. 14 of them underwent thrombolytic therapy with Actylise (rtPA group). The serum samples were obtained at 3 time-points for rtPA group (time-point 0: 1st-4th hour of stroke; time-point 1 - immediately after rtPA administration; time-point 2 - on day 5-7 from stroke onset). Remaining patients had venous blood collection at two time-points: time-point 1 - 5th-10th hour of stroke and time point 2 - on day 5-7 of stroke. MMP-9 was analyzed with gelatin zymography, MMP-3 and TIMP-1 serum levels were analyzed with ELISA method. NIHSS improvement ratio (IR) was calculated as a difference between NIHSS score at the admission and discharge of patient. RESULTS: The active form of MMP-9 (86kDa) was not observed in any analyzed samples. Total MMP-9 activity was significantly elevated at time point 1 in rtPA group in comparison with non-rtPA group. MMP-3 serum level significantly decreased during rtPA administration in comparison with non-rtPA group and it was restored at time-point 2. MMP-3 negatively correlated with IR values (p=0.06). CONCLUSIONS: Thrombolysis applied for IS treatment increases MMP 9 activity in serum, however, rtPA does not facilitate the conversion of pro-MMP 9 into the active form. Our results also suggest the involvement of MMP-3 to the biochemical processes occurring during acute phase of IS. PMID- 25440009 TI - Endoscopic drainage of orbital abscesses aided with intraoperative sonography. AB - BACKGROUND AND PURPOSE: Accurate localization and adequate visualization of the superiorly or inferiorly located subperiosteal orbital abscesses or intraorbital abscess is difficult with transnasal endoscopic approach. Sonography is a well known and effective tool for evaluation of orbital pathologies but no paper documenting intraoperative application of this method in orbital abscess surgery has been published to date. MATERIAL AND METHODS: We present a series of 12 patients in whom orbital abscesses were drained endoscopically with an aid of neuronavigation and intraoperative ultrasonography. The abscesses were localized subperiosteally in the medial (n=6), superior (n=2) or inferior (n=1) part of the orbit whereas in 3 patients the abscess was localized in the intraconal space. RESULTS: According to intraoperative sonographic imaging complete drainage of the abscess was achieved in 11 out of 12 patients and no complications occurred. Intraoperative sonography helped to limit opening of the orbital wall in the medial subperiosteal abscesses, enabled check-up for completeness of drainage of the far extending pouches in the superior and inferior subperiosteal abscesses and enabled visualization of the tip of surgical instrument when reaching deeply located intraorbital abscesses. CONCLUSIONS: Intraoperative ultrasonography facilitates the endoscopic management of orbital abscesses, especially those which are difficult to reach due to subperiosteal location in the superior and inferior parts of the orbit, or abscesses localized intraorbitally. PMID- 25440010 TI - Reproductive life characteristics in females affected with Parkinson's disease and in healthy control subjects - a comparative study on Polish population. AB - BACKGROUND: Sex and blood level of sex hormones play a key role not only in the susceptibility to develop Parkinson's disease (PD) but also influence the natural course of the disease. The aim of this study was to compare reproductive lifespan events in females affected with PD and in "non-parkinsonian" age matched subjects and to evaluate whether the whole life endogenous oestrogen level is associated with variables describing the course of the disease. MATERIALS AND METHODS: Reproductive lifespan, age at menarche, age at menopause, gynaecological interventions and parity were compared in 76 women with idiopathic PD and in the age-adjusted control group of 74 subjects. Affected women underwent neurological and psychological assessment. Data were analysed using Mann-Whitney U Test and Spearman Rank Correlation Test. RESULTS: Women affected with PD had a shorter reproductive lifespan and experienced final menstruation earlier than the control group. Early menopause was reported by 24% of the patients and only by 16% of the control subjects. Parkinsonian women reported more commonly the history of surgical menopause. Duration of reproductive lifespan, age at menopause and the type of menopause influenced both motor and cognitive functioning of patients. CONCLUSIONS: There may be a relationship between the lifetime average endogenous oestrogen level and the susceptibility to develop PD. Longer reproductive lifespan resulting in higher "whole life" female sex steroids concentrations may exert a protective effect on central nervous system, resulting in milder course of the disease. PMID- 25440011 TI - The challenges of hypervolemic therapy in patients after subarachnoid haemorrhage. AB - PURPOSE: The triple-H therapy is widely used for cerebral vasospasm (CV) prevention and treatment in patients after subarachnoid haemorrhage (SAH). However, this practice is based on low level evidence. Aim of this study was to evaluate errors in fluid administration, fluid balance monitoring and bedside charts completeness during a trial of triple-H therapy. MATERIALS AND METHODS: An audit of the SAH patient charts was performed. A total of 508 fluid measurements were performed in 41 patients (6 with delayed cerebral ischaemia; DCI) during 14 days of observation. RESULTS: Underestimating for intravenous drugs was the most frequent error (80.6%; 112), resulting in a false positive fluid balance in 2.4% of estimations. In 38.6% of the negative fluid balance cases, the physicians did not order additional fluids for the next 24h. In spite of that, the fluid intake was significantly increased after DCI diagnosis. The mean and median intake values were 3.5 and 3.8l/24h respectively, although 40% of the fluid balances were negative. The positive to negative fluid balance ratio was decreasing in the course of the 14 day observation. CONCLUSIONS: This study revealed inconsistencies in the fluid orders as well as mistakes in the fluid monitoring, which illustrates the difficulties of fluid therapy and reinforces the need for strong evidence-based guidelines for hypervolemic therapy in SAH. PMID- 25440012 TI - Impairment of neuromuscular transmission in transient global amnesia - does it really exist? AB - BACKGROUND: The main hypotheses regarding mechanisms of transient global amnesia (TGA) are ischemia in hippocampal structures, epileptic genesis, and migraine. In accordance with the hypothesis of a shared, common pathophysiological mechanism in both TGA and migraine, neuromuscular transmission (NMT) abnormalities previously found in migraine were also suspected in TGA. OBJECTIVE: The aim of our study was to analyze NMT in TGA patients to reveal a subclinical impairment of neuromuscular transmission as a possible indicator of underlying channelopathy, which would point to a shared etiology with migraine. MATERIALS AND METHODS: The study group consisted of 15 patients (6 males) with TGA (mean age 69.5+/-7.4yrs). The duration of amnesia ranged from 1 to 6h (mean 4.4h). Single fiber electromyography (SFEMG), the most sensitive tool for NMT assessment, of the voluntarily activated frontal muscle was performed 1-5 days after a TGA incident. RESULTS: Abnormal SFEMG was found in 1 patient (6.6%). In all other patients, SFEMG was in the normal range. CONCLUSION: Our neurophysiological study does not confirm NMT defects in TGA. The role of channelopathy with NMT dysfunction in the pathogenesis of TGA is rather unlikely, whereas subclinical NMT abnormalities were certainly proven in migraine. PMID- 25440014 TI - Risk factors for re-bleeding of aneurysmal subarachnoid hemorrhage: meta-analysis of observational studies. AB - OBJECTIVE: The mortality of re-bleeding following aneurysmal subarachnoid hemorrhage is high, and surviving patients often have poor clinical condition and worse outcome than patients with a single bleed. In this study, we performed an updated systematic review and meta-analysis to determine the most common risk factors for re-bleeding in this patient population, with the goal of providing neurologists, neurosurgeons, neuro-interventionalists with a simple and fast method to evaluate the re-bleeding risk for aneurysmal subarachnoid hemorrhage. METHOD: We conducted a thorough meta-analysis of the risk factors associated with re-bleeding or re-rupture of intracranial aneurysms in cases published between 2000 and 2013. Pooled mean difference was calculated for the continuous variables (age), and pooled odds ratio (OR) was calculated for categorical factors. If heterogeneity was significant (p<0.05), a random effect model was applied; otherwise, a fixed model was used. Testing for pooled effects and statistical significance for each potential risk factor were analyzed using Review Manager software. RESULTS: Our literature search identified 174 articles. Of these, only seven retrospective studies met the inclusion criteria. These seven studies consisted of 2470 patients, 283 of which had aneurysmal re-bleeding, resulting in a weighted average rate of re-bleeding of 11.3% with 95% confidence interval [CI]: 10.1-12.6. In this population, sex (OR 1.46; 95% CI: 1.11-1.92), high systolic blood pressure [SBP] (OR 2.52; 95% CI: 1.40-4.53), aneurysm size (OR 3.00; 95% CI: 2.06-4.37), clinical condition (Hunt & Hess) (OR 4.94; 95% CI: 2.29,10.68), and Fisher grade (OR 2.29; 95% CI: 1.45, 3.61) were statistically significant risk factors for re-bleeding. CONCLUSION: Sex, high SBP, high Fisher grade, aneurysm size larger than 10mm, and poor clinical condition were independent risk factors for aneurysmal re-bleeding. The importance of early aneurysm intervention and careful consideration of patient risk factors should be emphasized to eliminate the risk of re-bleeding and poor outcome. PMID- 25440013 TI - rs2070424 of the SOD1 gene is associated with risk of Alzheimer's disease. AB - OBJECTIVE: Oxidative stress plays an important role in Alzheimer's disease (AD) etiopathogenesis. There were several studies that showed impaired antioxidant defense system (ADS) enzymes expression or activity in AD patients. There are only few studies evaluating the importance of ADS gene single nucleotide polymorphisms (SNPs) as risk factors of AD. We evaluated association between chosen SNPs of the enzymes of the ADS and risk of AD. METHODS: We included 400 AD patients and 402 healthy controls. We studied rs1041740, rs4998557 and rs2070424 of the SOD1 gene, rs2855116, rs5746136 and rs4880 of the SOD2 gene and rs3448, rs1050450 and rs1800668 of the GPx-1 gene (real time PCR). To determine the APOE gene common polymorphism, two single-nucleotide polymorphisms (SNPs; NCBI SNPs rs429358 and rs7412) were genotyped (TaqMan assays, Applied Biosystems [ABI], Foster City, CA, USA). The genotype and gender frequencies were compared between the studied groups by the chi(2) test and mean age by the t-Student test. RESULTS: Among all studied SNPs only rs2070424 of the SOD1 gene was a protective factor for AD in an additive (OR=0.47; 95% CI=0.30-0.74, p=0.001) and recessive (OR=0.47; 95% CI=0.30-0.75, p=0.002) models including age, gender and APOE gene status. CONCLUSIONS: rs2070424 polymorphism of the SOD1 gene is a risk factor for AD in Polish population. Allel G and genotype AG and GG are protective factors for AD. PMID- 25440015 TI - Papillary tumor of the pineal region. Report of two cases and literature review. AB - Papillary tumor of the pineal region (PTPR) was introduced to the WHO classification in 2007. This rare tumor of little known natural history and unpredictable behavior was described in fewer than 100 cases. Its optimal treatment is not established yet. We report another two cases of PTPR in whom tumors were totally removed via supracerebellar infratentorial approach and both were treated with radiotherapy. In a 37-year-old man the operation was delayed 6 years after the first tumor diagnosis and subsequent shunt placement. He has no complaints 10 years after the onset of the disease. A 45-year-old woman has no complaints 24 months after surgery. Our experience and the data from literature indicate that a total tumor removal is the major prognostic factor. PMID- 25440016 TI - Coexistence of cervico-thoracic extradural en-plaque meningioma with multiple intracranial meningiomas. AB - Meningioma is one of the most common tumors in the spinal cord. Extradural and en plaque variety of meningioma occur less frequently. A 47-year-old woman is presented with radiculopathy signs. Magnetic resonance imaging revealed a lesion from C6 through T3 vertebral levels compressing the cord both anteriorly and posteriorly. Subtotally excision was performed and histopathologic signs showed transitional type of meningioma (WHO Grade 1). Post operatively, she had good neurological recovery. Intraoperative findings point out that the en-plaque meningioma was pure extradural. Twelve cases of pure extradural en-plaque meningioma have been reported in the literature. Besides, to the best our knowledge coexistence of "en plaque" spinal epidural meningioma with meningiomas in cranial cavity has not been reported. Complete resection is mandatory to prevent recurrence. Moreover, it is considerably difficult to remove the parts of tumor over anterior of the dura without complication. PMID- 25440017 TI - Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) - a case report and review of literature. AB - CANVAS (cerebellar ataxia with neuropathy and vestibular areflexia syndrome) is a rare neurological syndrome of unknown etiology. The main clinical features include bilateral vestibulopathy, cerebellar ataxia and sensory neuropathy. An abnormal visually enhanced vestibulo-ocular reflex is the hallmark of the disease. We present a case of 58-year-old male patient who has demonstrated gait disturbance, imbalance and paresthesia of feet for 2 years. On examination ataxia of gait, diminished knee and ankle reflexes, absence of plantar reflexes, fasciculations of thigh muscles, gaze-evoked downbeat nystagmus and abnormal visually enhanced vestibulo-ocular reflex were found. Brain magnetic resonance imaging revealed cerebellar atrophy. Vestibular function testing showed severely reduced horizontal nystagmus in response to bithermal caloric stimulation. Nerve conduction study revealed loss of upper and lower limb sensory nerve action potentials. The course of illness was progressive with ataxic gait and unsteadiness as the most disabling symptoms. We report 4-year follow-up of the patient since the beginning of the disease. PMID- 25440018 TI - Pure alexia after damage to the right fusiform gyrus in a right-handed male. AB - Pure alexia refers to a rare acquired reading disorder commonly associated with damage to the posterior part of the left medial occipito-temporal (fusiform) gyrus, which is known as the visual word-form area (VWFA) and thought to be the neural basis for visual processing of letters and words. Right-sided lesions very rarely lead to pure alexia in right-handed individuals. We report a case of a 33 year-old right-handed man with isolated pure alexia resulting from a hemorrhagic lesion to the right fusiform gyrus. A limited recovery of reading skills was observed within six weeks post onset. During this period, the patient spontaneously developed a letter-by-letter reading strategy. Functional magnetic resonance imaging revealed right-hemisphere dominance for language as well as bilateral reading-related activity in the fusiform gyri. Our case indicates that pure alexia may arise as a consequence of damage to the right fusiform gyrus even in right-handed patients (who still may have right hemisphere dominance for language and reading skills), and may lead to a severe reading disorder, as in individuals with left-hemisphere dominance for language. PMID- 25440019 TI - Disappearance of white matter lesions on MRI and clinical recovery after initiating antiretroviral therapy in a case of HIV infection presenting as spastic paraparesis. AB - We present a case of a 30-year-old Polish female who presented with increasing for about 2 years spastic paraparesis and urinary incontinence. She denied any risky sexual behaviors, drug abuse, there was no history of surgery or blood transfusions. MRI of the brain showed diffuse, hyperintensive in T2, poorly defined lesions in the white matter. About 3 months later paraparesis increased and control MRI showed progression of previously described lesions. She was then diagnosed with HIV infection. There was a suspicion of progressive multifocal leucoencephalopathy (PML) or vacuolar myelopathy in the course of HIV infection. Antiretroviral treatment was initiated leading, together with rehabilitation, to a progressive improvement of symptoms. Pathological lesions on brain MRI completely disappeared. In conclusion, HIV test should be done in every patient with neurological signs of unknown cause. PMID- 25440020 TI - High-wire act: the poised genome and cellular memory. AB - Emerging evidence aided by genome-wide analysis of chromatin and transcriptional states has shed light on the mechanisms by which stem cells achieve cellular memory. The epigenetic and transcriptional plasticity governing stem cell behavior is highlighted by the identification of 'poised' genes, which permit cells to maintain readiness to undertake alternate developmental fates. This review focuses on two crucial mechanisms of gene poising: bivalent chromatin marks and RNA polymerase II stalling. We provide the context for these mechanisms by exploring the current consensus on the regulation of chromatin states, especially in quiescent adult stem cells, where poised genes are critical for recapitulating developmental choices, leading to regenerative function. PMID- 25440021 TI - Electrochemical sensor based on electrodeposited graphene-Au modified electrode and nanoAu carrier amplified signal strategy for attomolar mercury detection. AB - An electrochemical sensor was developed for attomolar Hg(2+) detection. Three single-stranded DNA probes were rationally designed for selective and sensitive detection of the target, which combined T-Hg(2+)-T coordination chemistry and the characteristic of convenient modification of electrochemical signal indicator. Graphene and nanoAu were successively electrodeposited on a glass carbon electrode surface to improve the electrode conductivity and functionalize with the 10-mer thymine-rich DNA probe (P1). NanoAu carriers functionalized with 29 mer guanine-rich DNA probe (P3) labeled methyl blue (MB-nanoAu-P 3s) were used to further strengthen signal response. In the presence of Hg(2+), a T-T mismatched dsDNA would occur between P1 and a 22-mer thymine-rich DNA probe (P2) on the electrode surface due to T-Hg(2+)-T coordination chemistry. Followed by adding the MB-nanoAu-P 3s for hybridization with P2, square wave voltammetry was executed. Under optimal conditions, Hg(2+) could be detected in the range from 1.0 aM to 100 nM with a detection limit of 0.001 aM. Selectivity measurements reveal that the sensor is specific for Hg(2+) even with interference by high concentrations of other metal ions. Three different environmental samples were analyzed by the sensor and the results were compared with that from an atomic fluorescence spectrometry. The developed sensor was demonstrated to achieve excellent detectability. It may be applied to development of ultrasensitive detection strategies. PMID- 25440023 TI - Amyloidogenicity of p53: A Hidden Link Between Protein Misfolding and Cancer. AB - Pathogenic aggregation is closely associated with various protein misfolding diseases such as type 2 diabetes mellitusand Alzheimer's disease. Amyloidogenic proteins that have a propensity to assemble into amyloid oligomers and fibrils form the aggregates. The tumor suppressor p53, a transcription factor that regulates the cell cycle and apoptosis, is also amyloidogenic. In tumor models, both wild type and mutant p53 proteins show aggregation kinetics and morphology similar to those of classical amyloidogenic proteins, such as -amyloid peptide and -synuclein. Wild type p53 loses its anticancer activity when it aggregates, while p53 mutants with enhanced amyloidogenicity show accelerated aggregation. So far, amyloidogenic p53 mutations have been implicated in more than ten different types of cancer, suggesting a connection between p53 aggregation and cancer. Therefore, inhibition of both inherent and mutation induced p53 aggregation may stabilize p53 in a functional conformation and provide a novel approach to cancer prevention and treatment. Here, we summarize recent findings on carcinogenic aggregation of wild type p53 and its clinical mutants, structure-dependent amyloidogenesis of p53, and several promising strategies based on inhibition of p53 aggregation are also discussed. PMID- 25440022 TI - Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer? AB - OBJECTIVE: Medullary thyroid carcinoma (MTC) is a rare disease that can be inherited or sporadic; its pathogenesis is related to activating mutations in the RET gene. DESIGN: This study describes our 20-year experience regarding RET genetic screening in MTC. PATIENTS AND METHODS: We performed RET genetic screening in 1556 subjects, 1007 with an apparently sporadic MTC, 95 with a familial form and 454 relatives of RET-positive patients with MTC. RESULTS: A germline RET mutation was found in 68 of 1007 (6.7%) patients with sporadic MTC, while 939 patients with MTC were negative for germline RET mutations. We then identified a total of 137 gene carriers (GC). These subjects initiated a clinical evaluation for the diagnosis of MEN 2. A total of 139 MEN 2 families have been followed: 94 FMTC, 33 MEN 2A and 12 MEN 2B. Thirty-three different germline RET mutations were identified. Codon 804 was the most frequently altered codon particularly in FMTC (32/94, 34%), while codon 634 was the most frequently altered codon in MEN 2A (31/33, 94%); MEN 2B cases were exclusively associated with an M918T mutation at exon 16. CONCLUSIONS: Our 20-year study demonstrated that RET genetic screening is highly specific and sensitive, and it allows the reclassification as hereditary of apparently sporadic cases and the identification of GC who require an adequate follow-up. We confirmed that FMTC is the most prevalent MEN 2 syndrome and that it is strongly correlated with noncysteine RET mutations. According to these findings, a new paradigm of follow up of hereditary MTC cases might be considered in the next future. PMID- 25440024 TI - Are all beta-blockers the same? Nebivolol vasodilator properties and evidence for relevance in treatment of hypertension. PMID- 25440025 TI - Outcomes of abdominal wall reconstruction with acellular dermal matrix are not affected by wound contamination. AB - BACKGROUND: The optimal type of mesh for complex abdominal wall reconstruction has not been elucidated. We hypothesized that AWRs using acellular dermal matrix (ADM) experience low rates of surgical site occurrence (SSO) and surgical site infection, despite increasing degrees of wound contamination. STUDY DESIGN: We retrospectively reviewed prospectively collected data from consecutive abdominal wall reconstructions with ADM over a 9-year period. Outcomes of abdominal wall reconstructions were compared between patients with different CDC wound classifications. Univariate and multivariate logistic regression and Cox proportional hazard regression analyses identified potential associations and predictive/protective factors. RESULTS: The 359 patients had a mean follow-up of 28.3 +/- 19.0 months. Reconstruction of clean wounds (n = 171) required fewer reoperations than that of combined contaminated (n = 188) wounds (2.3% vs 11.2%; p = 0.001) and trended toward experiencing fewer SSOs (19.9% vs 28.7%, p = 0.052). There were no significant differences between clean and combined contaminated cases in 30-day SSI (8.8% vs 8.0%), hernia recurrence (9.9% vs 10.1%), and mesh removal (1.2% vs 1.1%) rates. Independent predictors of SSO included body mass index >=30 kg/m(2) (odds ratio [OR] 3.6; p < 0.001), 1 or more comorbidities (OR 2.5; p = 0.008), and defect width >=15 cm (OR 1.8; p = 0.02). CONCLUSIONS: Complex abdominal wall reconstructions using ADM demonstrated similar rates of complications between the different CDC wound classifications. This is in contradistinction to published outcomes for abdominal wall reconstruction using synthetic mesh that show progressively higher complication rates with increasing degrees of contamination. These data support the use of ADM rather than synthetic mesh for complex abdominal wall reconstruction in the setting of wound contamination. PMID- 25440026 TI - Association of discharge home with home health care and 30-day readmission after pancreatectomy. AB - BACKGROUND: We sought to determine if discharge home with home health care (HHC) is an independent predictor of increased readmission after pancreatectomy. STUDY DESIGN: We examined 30-day readmissions in patients undergoing pancreatectomy using the Healthcare Cost and Utilization Project State Inpatient Database for California from 2009 to 2011. Readmissions were categorized as severe or nonsevere using the Modified Accordion Severity Grading System. Multivariable logistic regression models were used to examine the association of discharge home with HHC and 30-day readmission using discharge home without HHC as the reference group. Propensity score matching was used as an additional analysis to compare the rate of 30-day readmission between patients discharged home with HHC with patients discharged home without HHC. RESULTS: Of 3,573 patients who underwent pancreatectomy, 752 (21.0%) were readmitted within 30 days of discharge. In a multivariable logistic regression model, discharge home with HHC was an independent predictor of increased 30-day readmission (odds ratio = 1.37; 95% CI, 1.11-1.69; p = 0.004). Using propensity score matching, patients who received HHC had a significantly increased rate of 30-day readmission compared with patients discharged home without HHC (24.3% vs 19.8%; p < 0.001). Patients discharged home with HHC had a significantly increased rate of nonsevere readmission compared with those discharged home without HHC, by univariate comparison (19.2% vs 13.9%; p < 0.001), but not severe readmission (6.4% vs 4.7%; p = 0.08). In multivariable logistic regression models, excluding patients discharged to facilities, discharge home with HHC was an independent predictor of increased nonsevere readmissions (odds ratio = 1.41; 95% CI, 1.11-1.79; p = 0.005), but not severe readmissions (odds ratio = 1.31; 95% CI, 0.88-1.93; p = 0.18). CONCLUSIONS: Discharge home with HHC after pancreatectomy is an independent predictor of increased 30-day readmission; specifically, these services are associated with increased nonsevere readmissions, but not severe readmissions. PMID- 25440028 TI - Invited commentary. PMID- 25440027 TI - Airway pressure release ventilation reduces conducting airway micro-strain in lung injury. AB - BACKGROUND: Improper mechanical ventilation can exacerbate acute lung damage, causing a secondary ventilator-induced lung injury (VILI). We hypothesized that VILI can be reduced by modifying specific components of the ventilation waveform (mechanical breath), and we studied the impact of airway pressure release ventilation (APRV) and controlled mandatory ventilation (CMV) on the lung micro anatomy (alveoli and conducting airways). The distribution of gas during inspiration and expiration and the strain generated during mechanical ventilation in the micro-anatomy (micro-strain) were calculated. STUDY DESIGN: Rats were anesthetized, surgically prepared, and randomized into 1 uninjured control group (n = 2) and 4 groups with lung injury: APRV 75% (n = 2), time at expiration (TLow) set to terminate appropriately at 75% of peak expiratory flow rate (PEFR); APRV 10% (n = 2), TLow set to terminate inappropriately at 10% of PEFR; CMV with PEEP 5 cm H2O (PEEP 5; n = 2); or PEEP 16 cm H2O (PEEP 16; n = 2). Lung injury was induced in the experimental groups by Tween lavage and ventilated with their respective settings. Lungs were fixed at peak inspiration and end expiration for standard histology. Conducting airway and alveolar air space areas were quantified and conducting airway micro-strain was calculated. RESULTS: All lung injury groups redistributed inspired gas away from alveoli into the conducting airways. The APRV 75% minimized gas redistribution and micro-strain in the conducting airways and provided the alveolar air space occupancy most similar to control at both inspiration and expiration. CONCLUSIONS: In an injured lung, APRV 75% maintained micro-anatomic gas distribution similar to that of the normal lung. The lung protection demonstrated in previous studies using APRV 75% may be due to a more homogeneous distribution of gas at the micro-anatomic level as well as a reduction in conducting airway micro-strain. PMID- 25440029 TI - Dilemma of stage II colon cancer and decision making for adjuvant chemotherapy. PMID- 25440030 TI - Video of the transdiaphragmatic extrapericardial approach of the inferior vena cava: in reply to Mizuno and colleagues. PMID- 25440031 TI - Transdiaphragmatic extrapericardial approach of the inferior vena cava. PMID- 25440032 TI - Concerns about evaluating the effect of noise and music in the operating room. PMID- 25440033 TI - Individualized decision making in treatment: in reply to Pellino and colleagues. PMID- 25440034 TI - Preventing surgical site events: any role for negative pressure wound therapy? PMID- 25440035 TI - The migrated liver transplantation candidate: waitlist time affects mortality. PMID- 25440036 TI - Liver transplantation: it's all about location, location, location: in reply to Lee and colleagues. PMID- 25440037 TI - No evidence to support ambulation for reducing postoperative venous thromboembolism. PMID- 25440038 TI - Reducing postoperative venous thromboembolism complications: in reply to Lau and colleagues. PMID- 25440039 TI - Bariatric surgery and vitamin deficiencies. PMID- 25440040 TI - Bariatric surgery and nutritional assessment: in reply to Lindquist and Lee. PMID- 25440041 TI - Restorative proctocolectomy in pediatric patients. PMID- 25440043 TI - Modified technique for one-handed double throw surgical tying. PMID- 25440044 TI - Blood PGC-1alpha Concentration Predicts Myocardial Salvage and Ventricular Remodeling After ST-segment Elevation Acute Myocardial Infarction. AB - INTRODUCTION AND OBJECTIVES: Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is a metabolic regulator induced during ischemia that prevents cardiac remodeling in animal models. The activity of PGC-1alpha can be estimated in patients with ST-segment elevation acute myocardial infarction. The aim of the present study was to evaluate the value of blood PGC-1alpha levels in predicting the extent of necrosis and ventricular remodeling after infarction. METHODS: In this prospective study of 31 patients with a first myocardial infarction in an anterior location and successful reperfusion, PGC-1alpha expression in peripheral blood on admission and at 72 hours was correlated with myocardial injury, ventricular volume, and systolic function at 6 months. Edema and myocardial necrosis were estimated using cardiac magnetic resonance imaging during the first week. At 6 months, infarct size and ventricular remodeling, defined as an increase > 10% of the left ventricular end-diastolic volume, was evaluated by follow-up magnetic resonance imaging. Myocardial salvage was defined as the difference between the edema and necrosis areas. RESULTS: Greater myocardial salvage was seen in patients with detectable PGC-1alpha levels at admission (mean [standard deviation (SD)], 18.3% [5.3%] vs 4.5% [3.9%]; P = .04). Induction of PGC-1alpha at 72 hours correlated with greater ventricular remodeling (change in left ventricular end-diastolic volume at 6 months, 29.7% [11.2%] vs 1.2% [5.8%]; P = .04). CONCLUSIONS: Baseline PGC-1alpha expression and an attenuated systemic response after acute myocardial infarction are associated with greater myocardial salvage and predict less ventricular remodeling. PMID- 25440045 TI - Characterization of the nodal slow pathway in patients with nodal reentrant tachycardia: clinical implications for guiding ablation. AB - INTRODUCTION AND OBJECTIVES: Nodal slow pathway ablation is the treatment of choice for nodal reentrant tachycardia. No demographic, anatomic, or electrophysiologic variables have been reported to predict an exact location of the slow pathway in the atrioventricular node or its proximity to the fast pathway. The purpose of this study was to analyze these variables. METHODS: The study prospectively included 54 patients (17 men; mean age, 55 [16] years) who had undergone successful slow pathway ablation. The refractory periods of both pathways and their differential conduction time were measured, and calculations were performed to obtain the distance from the His-bundle region (location of the fast pathway) to the coronary sinus ostium (to estimate the anteroposterior length of the triangle of Koch) and to the slow pathway area. RESULTS: The differential conduction time (139 [98] ms) did not correlate with the His coronary sinus distance (19 [6] mm; P=.6) or the His-slow pathway distance (14 [4] mm; P=.4). When the His-coronary sinus distance was larger, the His-slow pathway distance was also larger (r=0.652; P<.01) and the anatomic correlation between the triangle dimensions and the separation between the two pathways was confirmed. In patients older than 70 years, smaller triangle sizes and a shorter distance between both pathways were observed (P<.001). CONCLUSIONS: A greater anteroposterior dimension of the triangle of Koch is associated with a slow pathway location farther from the fast pathway. In elderly patients the two pathways are closer together (higher risk of atrioventricular block). PMID- 25440046 TI - Assessment of Degree of Anticoagulation Control in Patients With Atrial Fibrillation in Primary Health Care in Galicia, Spain: ANFAGAL Study. AB - INTRODUCTION AND OBJECTIVES: To determine the degree of control of patients on anticoagulants in follow-up in primary care in Galicia and investigate whether time in therapeutic range as estimated using the number of acceptable controls is comparable with the estimation using the Rosendaal method. METHODS: Transversal study that included patients older than 65 years, diagnosed with nonvalvular atrial fibrillation, on anticoagulants for at least 1 year. Control was considered good when the time in therapeutic range was greater than 65%, estimated by the Rosendaal method, or 60% estimated by the number of acceptable controls. RESULTS: We enrolled 511 patients (53.0% women; mean [standard deviation] age, 77.8 [0.6] years). Overall, 41.5% of the patients were in therapeutic range at fewer than 60% of the controls and 42.7% spent less than 65% of follow-up in therapeutic range, as estimated with the Rosendaal method. In the group of patients with poor control, we observed more drugs (6.8 [0.4] vs 5.7 [0.3]; P<.0001), greater presence of kidney disease (24.3% vs 17.0%; P=.05), and higher HAS-BLED scores (3.8 [0.1] vs 2.5 [0.1]; P<.0001). The cutoff of 60% for number of acceptable controls had a sensitivity and specificity of 79.4% and 86.7%, respectively, with an area under the curve of 0.92 (95%CI, 0.87-0.97). CONCLUSIONS: More than 40% of patients on anticoagulants do not reach the minimum time in therapeutic range to benefit from anticoagulation. The factors associated with worse control were kidney disease and high risk of cerebral hemorrhage. The 2 methods of estimation are comparable. PMID- 25440047 TI - Optimal medical treatment: is it the worst option in multivessel coronary disease? PMID- 25440048 TI - The multifaceted metabolic microbiome-marching toward function. PMID- 25440049 TI - Mammalian-microbial cometabolism of L-carnitine in the context of atherosclerosis. AB - gamma-butyrobetaine has long been known as the precursor of endogenous L carnitine synthesis. In this issue, Koeth et al. (2014) demonstrate that it is also a major metabolite of L-carnitine degradation by gut bacteria that precedes the enteric production of trimethylamine and trimethylamine-N-oxide. PMID- 25440050 TI - A bitter aftertaste: unintended effects of artificial sweeteners on the gut microbiome. AB - Intestinal microbial communities regulate a range of host physiological functions, from energy harvest and glucose homeostasis to immune development and regulation. Suez et al. (2014) recently demonstrated that artificial sweeteners alter gut microbial communities, leading to glucose intolerance in both mice and humans. PMID- 25440052 TI - Linking DNA damage, NAD(+)/SIRT1, and aging. AB - Diseases due to DNA damage repair machinery defects can resemble premature aging. In this issue of Cell Metabolism, Scheibye-Knudsen et al. (2014) demonstrate that increasing NAD(+) levels may reverse the inactivation of Sirt1 and mitochondrial defects in Cockayne Syndrome B that stem from nuclear NAD(+) depletion by the DNA repair protein PARP. PMID- 25440051 TI - C16:0-ceramide signals insulin resistance. AB - A substantive literature has accumulated implicating sphingolipids, in particular ceramides, as mediators of insulin resistance in metabolic syndrome. Thanks to recent technical advances in mouse genetics and lipidomics, two independent laboratories identify the same sphingolipid, C16:0-ceramide, as principal mediator of obesity-related insulin resistance (Turpin et al., 2014; Raichur et al., 2014). PMID- 25440053 TI - Inflammation versus host defense in obesity. AB - Obesity is characterized by a state of low-grade, chronic inflammation. Wang et al. (2014) report that immune cells from obese mice have decreased production of IL-22, a cytokine involved in immune responses and inflammation, and reveal therapeutic effects of exogenous IL-22 against obesity-linked metabolic dysfunctions. PMID- 25440054 TI - Specialized metabolites from the microbiome in health and disease. AB - The microbiota, and the genes that comprise its microbiome, play key roles in human health. Host-microbe interactions affect immunity, metabolism, development, and behavior, and dysbiosis of gut bacteria contributes to disease. Despite advances in correlating changes in the microbiota with various conditions, specific mechanisms of host-microbiota signaling remain largely elusive. We discuss the synthesis of microbial metabolites, their absorption, and potential physiological effects on the host. We propose that the effects of specialized metabolites may explain present knowledge gaps in linking the gut microbiota to biological host mechanisms during initial colonization, and in health and disease. PMID- 25440055 TI - Determining microbial products and identifying molecular targets in the human microbiome. AB - Human-associated microbes are the source of many bioactive microbial products (proteins and metabolites) that play key functions both in human host pathways and in microbe-microbe interactions. Culture-independent studies now provide an accelerated means of exploring novel bioactives in the human microbiome; however, intriguingly, a substantial fraction of the microbial metagenome cannot be mapped to annotated genes or isolate genomes and is thus of unknown function. Meta'omic approaches, including metagenomic sequencing, metatranscriptomics, metabolomics, and integration of multiple assay types, represent an opportunity to efficiently explore this large pool of potential therapeutics. In combination with appropriate follow-up validation, high-throughput culture-independent assays can be combined with computational approaches to identify and characterize novel and biologically interesting microbial products. Here we briefly review the state of microbial product identification and characterization and discuss possible next steps to catalog and leverage the large uncharted fraction of the microbial metagenome. PMID- 25440056 TI - Vitamin B12 as a modulator of gut microbial ecology. AB - The microbial mechanisms and key metabolites that shape the composition of the human gut microbiota are largely unknown, impeding efforts to manipulate dysbiotic microbial communities toward stability and health. Vitamins, which by definition are not synthesized in sufficient quantities by the host and can mediate fundamental biological processes in microbes, represent an attractive target for reshaping microbial communities. Here, we discuss how vitamin B12 (cobalamin) impacts diverse host-microbe symbioses. Although cobalamin is synthesized by some human gut microbes, it is a precious resource in the gut and is likely not provisioned to the host in significant quantities. However, this vitamin may make an unrecognized contribution in shaping the structure and function of human gut microbial communities. PMID- 25440057 TI - gamma-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. AB - L-carnitine, a nutrient in red meat, was recently reported to accelerate atherosclerosis via a metaorganismal pathway involving gut microbial trimethylamine (TMA) formation and host hepatic conversion into trimethylamine-N oxide (TMAO). Herein, we show that following L-carnitine ingestion, gamma butyrobetaine (gammaBB) is produced as an intermediary metabolite by gut microbes at a site anatomically proximal to and at a rate ~1,000-fold higher than the formation of TMA. Moreover, we show that gammaBB is the major gut microbial metabolite formed from dietary L-carnitine in mice, is converted into TMA and TMAO in a gut microbiota-dependent manner (like dietary L-carnitine), and accelerates atherosclerosis. Gut microbial composition and functional metabolic studies reveal that distinct taxa are associated with the production of gammaBB or TMA/TMAO from dietary L-carnitine. Moreover, despite their close structural similarity, chronic dietary exposure to L-carnitine or gammaBB promotes development of functionally distinct microbial communities optimized for the metabolism of L-carnitine or gammaBB, respectively. PMID- 25440058 TI - Reducing macrophage proteoglycan sulfation increases atherosclerosis and obesity through enhanced type I interferon signaling. AB - Heparan sulfate proteoglycans (HSPGs) are an important constituent of the macrophage glycocalyx and extracellular microenvironment. To examine their role in atherogenesis, we inactivated the biosynthetic gene N-acetylglucosamine N deacetylase-N-sulfotransferase 1 (Ndst1) in macrophages and crossbred the strain to Ldlr(-/-) mice. When placed on an atherogenic diet, Ldlr(-/ )Ndst1(f/f)LysMCre(+) mice had increased atherosclerotic plaque area and volume compared to Ldlr(-/-) mice. Diminished sulfation of heparan sulfate resulted in enhanced chemokine expression; increased macrophages in plaques; increased expression of ACAT2, a key enzyme in cholesterol ester storage; and increased foam cell conversion. Motif analysis of promoters of upregulated genes suggested increased type I interferon signaling, which was confirmed by elevation of STAT1 phosphorylation induced by IFN-beta. The proinflammatory macrophages derived from Ndst1(f/f)LysMCre(+) mice also sensitized the animals to diet-induced obesity. We propose that macrophage HSPGs control basal activation of macrophages by maintaining type I interferon reception in a quiescent state through sequestration of IFN-beta. PMID- 25440060 TI - Hif-2alpha promotes degradation of mammalian peroxisomes by selective autophagy. AB - Peroxisomes play a central role in lipid metabolism, and their function depends on molecular oxygen. Low oxygen tension or von Hippel-Lindau (Vhl) tumor suppressor loss is known to stabilize hypoxia-inducible factors alpha (Hif-1alpha and Hif-2alpha) to mediate adaptive responses, but it remains unknown if peroxisome homeostasis and metabolism are interconnected with Hif-alpha signaling. By studying liver-specific Vhl, Vhl/Hif1alpha, and Vhl/Hif2alpha knockout mice, we demonstrate a regulatory function of Hif-2alpha signaling on peroxisomes. Hif-2alpha activation augments peroxisome turnover by selective autophagy (pexophagy) and thereby changes lipid composition reminiscent of peroxisomal disorders. The autophagy receptor Nbr1 localizes to peroxisomes and is likewise degraded by Hif-2alpha-mediated pexophagy. Furthermore, we demonstrate that peroxisome abundance is reduced in VHL-deficient human clear cell renal cell carcinomas with high HIF-2alpha levels. These results establish Hif-2alpha as a negative regulator of peroxisome abundance and metabolism and suggest a mechanism by which cells attune peroxisomal function with oxygen availability. PMID- 25440059 TI - A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome. AB - Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in genes encoding the DNA repair proteins CS group A or B (CSA or CSB). Since dietary interventions can alter neurodegenerative processes, Csb(m/m) mice were given a high-fat, caloric restricted, or resveratrol-supplemented diet. High-fat feeding rescued the metabolic, transcriptomic, and behavioral phenotypes of Csb(m/m) mice. Furthermore, premature aging in CS mice, nematodes, and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, beta-hydroxybutyrate levels are increased by the high-fat diet, and beta-hydroxybutyrate, PARP inhibition, or NAD(+) supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB can displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, beta hydroxybutyrate and NAD(+), through the deacetylase SIRT1 and suggests possible interventions for CS. PMID- 25440061 TI - The LXR-Idol axis differentially regulates plasma LDL levels in primates and mice. AB - The LXR-regulated E3 ubiquitin ligase IDOL controls LDLR receptor stability independent of SREBP and PCSK9, but its relevance to plasma lipid levels is unknown. Here we demonstrate that the effects of the LXR-IDOL axis are both tissue and species specific. In mice, LXR agonist induces Idol transcript levels in peripheral tissues but not in liver, and does not change plasma LDL levels. Accordingly, Idol-deficient mice exhibit elevated LDLR protein levels in peripheral tissues, but not in the liver. By contrast, LXR activation in cynomolgus monkeys induces hepatic IDOL expression, reduces LDLR protein levels, and raises plasma LDL levels. Knockdown of IDOL in monkeys with an antisense oligonucleotide blunts the effect of LXR agonist on LDL levels. These results implicate IDOL as a modulator of plasma lipid levels in primates and support further investigation into IDOL inhibition as a potential strategy for LDL lowering in humans. PMID- 25440062 TI - Place and health in diabetes: the neighbourhood environment and risk of depression in adults with type 2 diabetes. AB - BACKGROUND: Depression is a common co-illness in people with diabetes. Evidence suggests that the neighbourhood environment impacts the risk of depression, but few studies have investigated this effect in those with diabetes. We examined the effect of a range of neighbourhood characteristics on depression in people with Type 2 diabetes. METHODS: This cohort study used five waves of data from 1298 participants with Type 2 diabetes from the Diabetes Health Study (2008-2013). We assessed depression using the Patient Health Questionnaire. We measured neighbourhood deprivation using census data; density of services using geospatial data; level of greenness using satellite imagery; and perceived neighbourhood characteristics using survey data. The effect of neighbourhood factors on risk of depression was estimated using survival analysis, adjusting for sociodemographic variables. We tested effect modification by age, sex and socio-economic characteristics using interaction terms. RESULTS: More physical activity facilities, cultural services and a greater level of greenness in the neighbourhood were associated with a lower risk of depression in our sample, even after adjusting for confounders. Material deprivation was associated with increased risk of depression, particularly in participants who were older or retired. CONCLUSIONS: Characteristics of neighbourhoods were associated with the risk of depression in people with Type 2 diabetes and there were vulnerable subgroups within this association. Clinicians are encouraged to consider the neighbourhood environment of their patients when assessing the risk of depression. Future intervention research is need for health policy recommendations. PMID- 25440063 TI - Persistent organic pollutants in a marine bivalve on the Marennes-Oleron Bay and the Gironde Estuary (French Atlantic Coast) - part 1: bioaccumulation. AB - The aim of this study was to determine 1) the relevance of using the Pacific oyster Crassostrea gigas as a sentinel organism, at a juvenile stage, for polycyclic aromatic hydrocarbon (PAH) and persistent organic pollutant (polychlorobiphenyl, PCB, polybromodimethylether, PBDE, and organochlorine pesticide, OCP) contamination, 2) the potential levels of chemical organic contamination in the Marennes-Oleron Bay, and their potential sources and 3) the potential influence of physiological or environmental factors on contaminant body burdens in oysters. To this end, juvenile oysters purchased from an oyster hatchery were transplanted to a reference site, in Bouin, and to different transplantation sites in the Marennes-Oleron Bay, the first oyster production area in France, and in the Gironde Estuary, the biggest estuary in Occidental Europe. Transplantations were done during summer and winter. Whole oyster soft tissues from each site were analysed for PAHs, PCBs, PBDEs and OCPs. Results obtained with a transplantation period of 3months suggest that C. gigas, at the juvenile stage, is a relevant sentinel organism for short-term assessment of contamination for these contaminants. In addition, no significant effects of physiological factors on contaminant body burdens were observed. Principal component analysis revealed two distinct groups of contaminants (PAHs and OPCs, and PCBs and PBDEs) and three groups of sites: 1) the reference site, 2) Les Palles (LP) and Boyard (BOY) in winter and 3) all the other sites. The group of LP and BOY was clearly defined by the levels of PAHs and OCPs, suggesting higher levels of contamination of these chemical compounds on these sites, potentially due to local contamination sources. In addition, no relevant effects of physiological or environmental factors on contaminant body burdens were observed. Results suggest also a predominance of contaminants related to agricultural activities along the Marennes-Oleron Bay, and therefore, further studies on the presence of pesticides in this region should be considered. PMID- 25440064 TI - Pontine and extrapontine myelinolysis secondary to glycemic fluctuation. PMID- 25440065 TI - Clinical management departments for the neurosciences. AB - INTRODUCTION: Neuroscience-related clinical management departments (UGC in Spanish) represent a means of organising hospitals to deliver patient-centred care as well as specific clinical and administrative management models. DEVELOPMENT: The authors review the different UGC models in Spain and their implementation processes as well as any functional problems. We pay special attention to departments treating neurological patients. CONCLUSIONS: Neuroscience-related specialties may offer a good framework for the units that they contain. This may be due to the inherent variability and costs associated with neurological patients, the vital level of coordination that must be present between units providing care, and probably to the dynamic nature of the neurosciences as well. Difficulties associated with implementing and gaining acceptance for the new model have limited such UGCs until now. PMID- 25440066 TI - Asymptomatic colpocephaly and partial agenesis of corpus callosum. PMID- 25440067 TI - Corpora amylacea in the neocortex in patients with temporal lobe epilepsy and focal cortical dysplasia. AB - INTRODUCTION: Corpora amylacea (CoA) are present in about 60% of atrophic hippocampi resected from patients with drug resistant temporal lobe epilepsy (DRTLE). They have also been described in the lateral temporal neocortex, although less frequently. OBJECTIVE: The objective is to measure the presence, distribution and density of CoA in the lateral temporal lobes of patients with DRTLE and focal cortical dysplasia (FCD), also examining how CoA density may be linked to demographic and clinical traits. METHODS: Resected tissue from 35 patients was analysed. CoA density was assessed with a semi-quantitative scale according to the criteria established by Cherian et al. RESULTS: Presence of CoA in the neocortex of 9 patients was associated with hippocampal sclerosis (FCD type iiia, 7 cases), disembryoplastic neuroepithelial tumour (FCD type iiib, 1 case), and cavernous angioma (FCD type iiic, 1 case). The meningeal surface (MS) was involved in all cases, and 8 cases displayed CoA in the cerebral parenchyma (white matter) and around blood vessels. CoA density on the MS showed a negative correlation with age at seizure onset (r = -0.828, P<.05) and a positive correlation with disease duration (r = 0.678, P<.05) but not with postoperative clinical outcome. CONCLUSIONS: Patients with DRTLE and a primary lesion (hippocampal sclerosis, tumour, vascular malformation) associated with mild FCD were shown to have CoA deposits in the neocortex. No association was found between presence of CoA and clinical outcome one year after surgery. PMID- 25440069 TI - Exposures of the humerus for fracture fixation. AB - The care of humeral shaft fractures is undergoing a transition to more aggressive treatment methods with more frequent operative fixation. The upper arm has an extensive network of nerves, arteries, and veins that must be protected during any operative exposure. The ultimate goal of fixation of a humerus fracture is rigid stabilization to allow early range of motion, protection of the neurovascular structures, and preservation of the triceps mechanism posteriorly and the anterior elbow flexor muscles. PMID- 25440068 TI - Exposures of the shoulder and upper humerus. AB - Extensile and adequate exposures of the shoulder and upper humerus are important in trauma surgery. The standard deltopectoral approach can be extended distally to expose the whole humerus if necessary. Often, wide exposures of the upper humerus are necessary to reduce complex fractures and apply the plate on the lateral aspect of the humerus. A thorough knowledge of the anatomy as well as strategies of nerve mobilization is necessary for achieving adequate exposures in this area. This article details the many exposure methods for the shoulder, upper humerus, and their extensile extensions. PMID- 25440070 TI - Exposures of the elbow. AB - This article describes the basic bony, ligamentous, and neurologic anatomy of the structures about the elbow. The surgical exposures of the elbow joint are described, providing details of the various posterior, lateral, and medial approaches to the articular segments. Clinical applications describing the potential benefits of each surgical exposure are provided as examples. PMID- 25440071 TI - Exposure of the forearm and distal radius. AB - Approaches to the forearm use internervous planes to allow adequate bone exposure and prevent muscle denervation. The Henry approach utilizes the plane between muscles supplied by the median and radial nerves. The Thompson approach utilizes the plane between muscles supplied by the radial and posterior interosseous nerves. The distal radius may be approached volarly. The extended flexor carpi radialis approach is useful for intraarticular fractures, subacute fractures, and malunions. The distal radius can be approached dorsally by releasing the third dorsal compartment and continuing the dissection subperiosteally. Choice of approach depends on the injury pattern and the need for exposure. PMID- 25440072 TI - Exposures of the wrist and distal radioulnar joint. AB - This article reviews the superficial, skeletal, and ligamentous anatomy of the wrist. Standard and alternative exposures of the wrist joint and the distal radioulnar joint are discussed, emphasizing the importance of avoiding nerve injury. Standard exposure of the wrist joint is used in the treatment of carpal ligament injuries, fractures, and dislocations. Case presentations illustrate these techniques. PMID- 25440073 TI - Surgical exposures of the hand. AB - Surgical approaches to the hand are commonly executed in the treatment of fractures, ligament injuries, and less commonly in the resection of bony tumors. Careful design and execution of these surgical approaches translates into superior functional and aesthetic outcomes. We have provided a thorough review of commonly used approaches to the hand by evaluating each of these approaches in the context of core principles including safety, versatility, preservation of stability, and aesthetic outcomes. PMID- 25440074 TI - Soft tissue coverage of the upper extremity: an overview. AB - Prehension is a complex function of the hand that gives it mechanical precision combined with a standard sensory pattern. The priority in soft tissue reconstruction for the upper extremity is to restore function. Significant injury to the upper extremity may result after trauma because of various etiologies. The timing and choice of soft tissue coverage for upper extremity defects warrant special consideration to avoid prolonged immobilization, which can result in joint stiffness, tendon adhesions, scar contractures, and ultimately, loss of function. This article reviews the various reconstructive options and considerations involved in providing coverage for upper extremity soft tissue defects. PMID- 25440075 TI - Soft tissue coverage of the arm. AB - The latissimus dorsi muscle is the main flap used for soft tissue coverage of the arm. It can be tailored to size or tissue type (skin and/or muscle), and can provide function for elbow flexion and extension. When required it can cover both the arm and elbow. PMID- 25440076 TI - Soft tissue coverage of the elbow. AB - Our discussion considers pedicled flaps about the elbow and free flaps. Local pedicle flaps are indicated in situations in which anatomic structures or implants are exposed and are absent native tissue or blood supply, or are at risk of infection. PMID- 25440077 TI - Hand flaps. AB - The role of the hand as the primary form of interaction with the surrounding physical environment is often underappreciated, and injuries to it can become especially debilitating. The hand has evolved into a complex, intricate structural conglomeration of bones, joints, tendons, ligaments, and neurovascular structures, with an overlying soft tissue envelope that is varied and adapted to particular functions. Wounds to the hand requiring flap coverage warrant careful planning. Increasing knowledge of anatomy has led to the description of many flaps. This article presents a review of the commonly used flaps in reconstruction of the hand and the various considerations involved. PMID- 25440078 TI - Options for surgical exposure and soft tissue coverage in upper extremity trauma. PMID- 25440079 TI - Differential behavior patterns in cynomolgus monkey Macaca fascicularis in home cage in response to human gaze. AB - BACKGROUND: Non-human primates, when encountering human beings, show wariness and alertness. These behaviors differ when there is direct human gaze vs. when human averts his gaze. METHODS: We observed cynomolgus monkey in their home cage and studied their behaviors in response to human gaze. Four behaviors were analyzed: opening mouth, staring at observer, agitated activity, and approaching observer. RESULTS: Three behaviors appeared to be sensitive to human gaze between when the human observer gazed at the monkey and when the human observer looked away. Individual animals also displayed subpatterns of responses to human gaze. CONCLUSIONS: These results indicate that, even in their home cage, monkeys display a heightened level of awareness when gazed upon by a human observer, suggesting that human gaze may elicit emotional reactions. Further, under the human gaze, distinct behavioral subpatterns were apparent within the monkey cohort in our study, indicative of subgroups within the cohort. PMID- 25440080 TI - Development of a candidate method for forensic microbial genotyping using multiplex pyrosequencing combined with a universal biotinylated primer. AB - Bacterial genotyping can be used for crime scene investigations and contribute to the attribution of biological attacks for microbial forensics. PyroMark ID Pyrosequencer as an accurate detection platform for single nucleotide polymorphisms (SNPs) has been applied to identify and resolve microorganisms involved in closely Escherichia coli O157:H7 (E. coli O157:H7). To explore more applications and improve the efficiency for pyrosequencing in this field, we developed a method integrated multiplex pyrosequencing with a universal primer. Two multiplex pyrosequencing assays with a universal biotinylated primer were designed to analyze five SNPs located in four gene of E. coli O157:H7 strain. The accuracy of the established assays was validated by genotyping reference strain E. coli O157:H7 EDL933 and E. coli K-12. We also demonstrated that two multiplex pyrosequencing assays were specific and sensitive for genotyping closely related E. coli O157 strains. Reproducibility of results and multiplexing capability were evaluated by a comparison of this method with the monoplex pyrosequencing. Furthermore, these two multiplex pyrosequencing assays have been successfully applied to detect 11 E. coli O157 strains isolated from 1504 Chinese livestock samples. This method reduces costs and time consumption in the process of pyrosequencing analysis, and potentially serves as a rapid tool and reliable candidate strategy for the microbial identification and other genotyping application. PMID- 25440082 TI - Risk factors of striae gravidarum. AB - BACKGROUND: Stretch marks are a common skin disorder. Pregnancy-related lesions are defined as striae gravidarum. The root cause of striae formation remains unknown. OBJECTIVE: The aim of this paper was to identify the risk factors associated with striae gravidarum (SG) development. PATIENTS AND METHODS: The study was conducted at Plastic, Reconstructive and Aesthetic Surgery Clinic and Obstetrics Outpatient Department among 299 Caucasian women maximum 6 months after the delivery, regardless of whether they were primiparas or multiparas. RESULTS: Among the women participating in the study, 71.2% (213 of 299) developed striae gravidarum at least in one site. Logistic regression analysis showed that four of the analysed factors were independent predictors of striae gravidarum occurrence: family history of SG, BMI before pregnancy, the lack of chronic diseases and birthweight (P < 0.0001). It has been found that the presence of striae distensae on the breasts increases the risk of SG development (71.4% vs. 28.6%, P = 0.0008), whereas the presence of these lesions on the thighs decreases the risk (23% vs. 77%, P = 0.0076). CONCLUSION: In this study, we presented a model that can help to predict the risk of SG formation, including family history of SG, BMI before pregnancy, birthweight and chronic diseases. Moreover, women with stretch marks on their breasts should know that the risk of SG development is significantly higher, whereas lesions on the thighs do not increase such a risk. PMID- 25440081 TI - Recent updates on incubation of drug craving: a mini-review. AB - Cue-induced drug craving progressively increases after prolonged withdrawal from drug self-administration in laboratory animals, a behavioral phenomenon termed 'incubation of drug craving.' Studies over the years have revealed several important neural mechanisms contributing to incubation of drug craving. In this mini-review, we first discuss three excellent Addiction Biology publications on incubation of drug craving in both human and laboratory animals. We then review several key publications from the past year on behavioral and mechanistic findings related to incubation of drug craving. PMID- 25440083 TI - Mycoplasma ovipneumoniae induces inflammatory response in sheep airway epithelial cells via a MyD88-dependent TLR signaling pathway. AB - Mycoplasma ovipneumoniae (M. ovipneumoniae) is a bacterium that specifically infects sheep and goat and causes ovine infectious pleuropneumonia. In an effort to understand the pathogen-host interaction between the M. ovipneumoniae and airway epithelial cells, we investigated the host inflammatory response using a primary air-liquid interface (ALI) epithelial culture model generated from bronchial epithelial cells of Ningxia Tan sheep (Ovis aries). The ALI culture of sheep bronchial epithelial cells showed a fully differentiated epithelium comprising distinct epithelial types, including the basal, ciliated and goblet cells. Exposure of ALI cultures to M. ovipneumoniae led to increased expression of Toll-like receptors (TLRs), and components of the myeloid differentiation factor 88 (MyD88)-dependent TLR signaling pathway, including the MyD88, TNF receptor-associated factor 6 (TRAF6), IL-1 receptor-associated kinases (IRAKs) and nuclear factor-kappa B (NF-kappaB), as well as subsequent pro-inflammatory cytokines in the epithelial cells. Of interest, infection with M. ovipneumoniae failed to induce the expression of TANK-binding kinase 1 (TBK1), TRAF3 and interferon regulatory factor 3 (IRF3), key components of the MyD88-independent signaling pathway. These results suggest that the MyD88-dependent TLR pathway may play a crucial role in sheep airway epithelial cells in response to M. ovipneumoniae infection, which also indicate that the ALI culture system may be a reliable model for investigating pathogen-host interactions between M. ovipneumoniae and airway epithelial cells. PMID- 25440084 TI - Transcriptional analysis of porcine circovirus-like virus P1. AB - BACKGROUND: Recently identified porcine circovirus-like virus P1 has the smallest DNA viral genome. In this study, we identified the viral genes and their corresponding mRNA transcripts. RESULTS: The RNAs of P1, synthesized in porcine kidney cells, were examined with northern blotting and PCR analyses. Eight virus specific RNAs were detected. Four mRNAs (open reading frames (ORFs) 1, 2, 4, and 5) are encoded by the viral (-) strand and four (ORFs 3, 6, 7, and 8) are encoded by the viral (+) strand. All proteins encoded by the ORFs of the P1 virus are less than 50 amino acids in length, except that encoded by ORF1 (113 amino acids). CONCLUSIONS: We show a very complex viral transcription pattern in P1 infected cells. PMID- 25440085 TI - A direction-selective local-thresholding method, DSLT, in combination with a dye based method for automated three-dimensional segmentation of cells and airspaces in developing leaves. AB - Quantifying the anatomical data acquired from three-dimensional (3D) images has become increasingly important in recent years. Visualization and image segmentation are essential for acquiring accurate and detailed anatomical data from images; however, plant tissues such as leaves are difficult to image by confocal or multi-photon laser scanning microscopy because their airspaces generate optical aberrations. To overcome this problem, we established a staining method based on Nile Red in silicone-oil solution. Our staining method enables color differentiation between lipid bilayer membranes and airspaces, while minimizing any damage to leaf development. By repeated applications of our staining method we performed time-lapse imaging of a leaf over 5 days. To counteract the drastic decline in signal-to-noise ratio at greater tissue depths, we also developed a local thresholding method (direction-selective local thresholding, DSLT) and an automated iterative segmentation algorithm. The segmentation algorithm uses the DSLT to extract the anatomical structures. Using the proposed methods, we accurately segmented 3D images of intact leaves to single-cell resolution, and measured the airspace volumes in intact leaves. PMID- 25440089 TI - E2F4 regulatory program predicts patient survival prognosis in breast cancer. AB - INTRODUCTION: Genetic and molecular signatures have been incorporated into cancer prognosis prediction and treatment decisions with good success over the past decade. Clinically, these signatures are usually used in early-stage cancers to evaluate whether they require adjuvant therapy following surgical resection. A molecular signature that is prognostic across more clinical contexts would be a useful addition to current signatures. METHODS: We defined a signature for the ubiquitous tissue factor, E2F4, based on its shared target genes in multiple tissues. These target genes were identified by chromatin immunoprecipitation sequencing (ChIP-seq) experiments using a probabilistic method. We then computationally calculated the regulatory activity score (RAS) of E2F4 in cancer tissues, and examined how E2F4 RAS correlates with patient survival. RESULTS: Genes in our E2F4 signature were 21-fold more likely to be correlated with breast cancer patient survival time compared to randomly selected genes. Using eight independent breast cancer datasets containing over 1,900 unique samples, we stratified patients into low and high E2F4 RAS groups. E2F4 activity stratification was highly predictive of patient outcome, and our results remained robust even when controlling for many factors including patient age, tumor size, grade, estrogen receptor (ER) status, lymph node (LN) status, whether the patient received adjuvant therapy, and the patient's other prognostic indices such as Adjuvant! and the Nottingham Prognostic Index scores. Furthermore, the fractions of samples with positive E2F4 RAS vary in different intrinsic breast cancer subtypes, consistent with the different survival profiles of these subtypes. CONCLUSIONS: We defined a prognostic signature, the E2F4 regulatory activity score, and showed it to be significantly predictive of patient outcome in breast cancer regardless of treatment status and the states of many other clinicopathological variables. It can be used in conjunction with other breast cancer classification methods such as Oncotype DX to improve clinical outcome prediction. PMID- 25440090 TI - Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. AB - The programmed death 1 (PD-1) receptor and its ligands programmed death ligand 1 (PD-L1) and PD-L2, members of the CD28 and B7 families, play critical roles in T cell coinhibition and exhaustion. Overexpression of PD-L1 and PD-1 on tumor cells and tumor-infiltrating lymphocytes, respectively, correlates with poor disease outcome in some human cancers. Monoclonal antibodies (mAbs) blockading the PD 1/PD-L1 pathway have been developed for cancer immunotherapy via enhancing T cell functions. Clinical trials with mAbs to PD-1 and PD-L1 have shown impressive response rates in patients, particularly for melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), and bladder cancer. Further studies are needed to dissect the mechanisms of variable response rate, to identify biomarkers for clinical response, to develop small-molecule inhibitors, and to combine these treatments with other therapies. PMID- 25440092 TI - Left ventricular noncompaction: a genetic cardiomyopathy looking for diagnostic criteria. PMID- 25440091 TI - The relationship of left ventricular trabeculation to ventricular function and structure over a 9.5-year follow-up: the MESA study. AB - BACKGROUND: Left ventricular (LV) trabeculation is highly variable among individuals and is increased in some diseases (e.g., congenital heart disease or cardiomyopathies), but its significance in population-representative individuals is unknown. OBJECTIVES: The goal of this study was to determine if excessive LV trabeculation in population-representative individuals is associated with preceding changes in cardiac volumes and function. METHODS: For technical reasons, the extent of trabeculation, which is expressed as the ratio of noncompacted to compacted (NC/C) myocardium, was measured on cardiac magnetic resonance (CMR) long-axis cine images in 2,742 participants in the MESA (Multi Ethnic Study of Atherosclerosis) (mean age 68.7 years; 52.3% women; 56.4% with hypertension; 16.8% with diabetes) at examination 5. These were considered in quintiles of trabeculation extent; the NC/C ratio of quintile 5 was 2.46 to 5.41. We determined the relationship between the maximal NC/C ratio and the preceding change (9.5 years between examinations 1 and 5) in end-systolic volume indexed (ESVi) to body surface area. Secondary analyses assessed the associations between the maximal NC/C ratio and preceding changes in end-diastolic volume indexed (EDVi) to body surface area and the ejection fraction (EF). RESULTS: Over 9.5 years, the ESVi decreased by 1.3 ml/m(2), the EDVi decreased by 5.1 ml/m(2), and the EF decreased by 0.6% (p < 0.0001). Even in subjects with excessive trabeculation, there were no clinically relevant differences in LV volumes and systolic function changes among the quintiles of trabeculation extent. CONCLUSIONS: Greater extent of, and even excessive, LV trabeculation measured in end-diastole in asymptomatic population-representative individuals appeared benign and was not associated with deterioration in LV volumes or function during an almost 10-year period. PMID- 25440093 TI - Vector flow mapping in obstructive hypertrophic cardiomyopathy to assess the relationship of early systolic left ventricular flow and the mitral valve. AB - BACKGROUND: The hydrodynamic cause of systolic anterior motion of the mitral valve (SAM) is unresolved. OBJECTIVES: This study hypothesized that echocardiographic vector flow mapping, a new echocardiographic technique, would provide insights into the cause of early SAM in obstructive hypertrophic cardiomyopathy (HCM). METHODS: We analyzed the spatial relationship of left ventricular (LV) flow and the mitral valve leaflets (MVL) on 3-chamber vector flow mapping frames, and performed mitral valve measurements on 2-dimensional frames in patients with obstructive and nonobstructive HCM and in normal patients. RESULTS: We compared 82 patients (22 obstructive HCM, 23 nonobstructive HCM, and 37 normal) by measuring 164 LV pre- and post-SAM velocity vector flow maps, 82 maximum isovolumic vortices, and 328 2-dimensional frames. We observed color flow and velocity vector flow posterior to the MVL impacting them in the early systolic frames of 95% of obstructive HCM, 22% of nonobstructive HCM, and 11% of normal patients (p < 0.001). In both pre- and post-SAM frames, we measured a high angle of attack >60 degrees of local vector flow onto the posterior surface of the leaflets whether the flow was ejection (59%) or the early systolic isovolumic vortex (41%). Ricochet of vector flow, rebounding off the leaflet into the cul-de-sac, was noted in 82% of the obstructed HCM, 9% of nonobstructive HCM, and none (0%) of the control patients (p < 0.001). Flow velocities in the LV outflow tract on the pre-SAM frame 1 and 2 mm from the tip of the anterior leaflet were low: 39 and 43 cm/s, respectively. CONCLUSIONS: Early systolic flow impacts the posterior surfaces of protruding MVL initiating SAM in obstructive HCM. PMID- 25440094 TI - Diastolic leading to systolic anterior motion: new technology reveals physiology. PMID- 25440096 TI - Cor pulmonale parvus: patting the elephant. PMID- 25440095 TI - Cor pulmonale parvus in chronic obstructive pulmonary disease and emphysema: the MESA COPD study. AB - BACKGROUND: The classic cardiovascular complication of chronic obstructive pulmonary disease (COPD) is cor pulmonale or right ventricular (RV) enlargement. Most studies of cor pulmonale were conducted decades ago. OBJECTIVES: This study sought to examine RV changes in contemporary COPD and emphysema using cardiac magnetic resonance (CMR) imaging. METHODS: We performed a case-control study nested predominantly in 2 general population studies of 310 participants with COPD and control subjects 50 to 79 years of age with >=10 pack-years of smoking who were free of clinical cardiovascular disease. RV volumes and mass were assessed using magnetic resonance imaging. COPD and COPD severity were defined according to standard spirometric criteria. The percentage of emphysema was defined as the percentage of lung regions <-950 Hounsfield units on full-lung computed tomography; emphysema subtypes were scored by radiologists. Results were adjusted for age, race/ethnicity, sex, height, weight, smoking status, pack years, systemic hypertension, and sleep apnea. RESULTS: Right ventricular end diastolic volume (RVEDV) was reduced in COPD compared with control subjects (-7.8 ml; 95% confidence interval: -15.0 to -0.5 ml; p = 0.04). Increasing severity of COPD was associated with lower RVEDV (p = 0.004) and lower RV stroke volume (p < 0.001). RV mass and ejection fraction were similar between the groups. A greater percentage of emphysema also was associated with lower RVEDV (p = 0.005) and stroke volume (p < 0.001), as was the presence of centrilobular and paraseptal emphysema. CONCLUSIONS: RV volumes are lower without significant alterations in RV mass and ejection fraction in contemporary COPD, and this reduction is related to the greater percentage of emphysema on computed tomography. PMID- 25440097 TI - Atrial fibrillation promotion with long-term repetitive obstructive sleep apnea in a rat model. AB - BACKGROUND: Obstructive sleep apnea (OSA) importantly contributes to the occurrence of atrial fibrillation (AF) in humans, but the mechanisms are poorly understood. Experimental research has provided insights into AF promotion by acute OSA episodes. However, patients with OSA usually have frequent nocturnal episodes for some time before manifesting AF. OBJECTIVES: The goal of this study was to test the hypothesis that repetitive OSA causes cardiac remodeling that predisposes to AF. METHODS: We mimicked OSA by using a mechanical ventilator and closing the airway at end-expiration with a 3-way stopcock (OSA rats). Matched control groups included rats with the ventilator stopped but airway left open (open airway rats) and continuously ventilated rats (sham rats). OSA rats were exposed to 20 consecutive 2-min cycles of 40 s of apnea/80 s of ventilation per day, 5 days per week for 4 weeks. RESULTS: OSA significantly increased the duration of AF from (median [interquartile range]) 2.6 s [1.9 s to 8.9 s] (shams) and 16 s [1.8 s to 93 s] (open airway) to 49s [34 s to 444 s]. AF inducibility increased to 56% (9 of 16) of OSA rats; this is up from 15% (2 of 13) and 13% (2 of 15) in open airway and sham rats, respectively (p < 0.05). OSA rats exhibited substantial atrial conduction slowing on optical mapping, along with connexin-43 down-regulation on both quantitative immunofluorescence (expression reduced by 58% vs sham rats) and Western blot (reduced by 38%), as well as increased atrial fibrous tissue content (by 71%). OSA also caused left ventricular hypertrophy, dilation, and diastolic dysfunction and enhanced AF inducibility during superimposed acute OSA episodes to 82.4% of rats. CONCLUSIONS: Chronically repeated OSA episodes cause AF-promoting cardiac remodeling, with conduction abnormalities related to connexin dysregulation and fibrosis playing a prominent role. This novel animal model provides mechanistic insights into an important clinical problem and may be useful for further exploration of underlying mechanisms and therapeutic approaches. PMID- 25440098 TI - Obstructive sleep apnea and atrial fibrillation: is the link real? PMID- 25440100 TI - Hypoplastic left heart syndrome: looking back, looking forward. PMID- 25440101 TI - The ACC looks to balance emerging science and clinical practice guideline development. PMID- 25440099 TI - Impact of initial shunt type on cardiac size and function in children with single right ventricle anomalies before the Fontan procedure: the single ventricle reconstruction extension trial. AB - BACKGROUND: In children with single right ventricular (RV) anomalies, changes in RV size and function may be influenced by shunt type chosen at the time of the Norwood procedure. OBJECTIVES: The study sought to identify shunt-related differences in echocardiographic findings at 14 months and <=6 months pre-Fontan in survivors of the Norwood procedure. METHODS: We compared 2-dimensional and Doppler echocardiographic indices of RV size and function, neo-aortic and tricuspid valve annulus dimensions and function, and aortic size and patency at 14.1 +/- 1.2 months and 33.6 +/- 9.6 months in subjects randomized to a Norwood procedure using either the modified Blalock-Taussig shunt (MBTS) or right ventricle to pulmonary artery shunt (RVPAS). RESULTS: Acceptable echocardiograms were available at both time points in 240 subjects (114 MBTS, 126 RVPAS). At 14 months, all indices were similar between shunt groups. From the 14-month to pre Fontan echocardiogram, the MBTS group had stable indexed RV volumes and ejection fraction, while the RVPAS group had increased RV end-systolic volume (p = 0.004) and decreased right ventricular ejection fraction (RVEF) (p = 0.004). From 14 months to pre-Fontan, the treatment groups were similar with respect to decline in indexed neo-aortic valve area, >mild neo-aortic valve regurgitation (<5% at each time), indexed tricuspid valve area, and >=moderate tricuspid valve regurgitation (<20% at each time). CONCLUSIONS: Initial Norwood shunt type influences pre-Fontan RV remodeling during the second and third years of life in survivors with single RV anomalies, with greater RVEF deterioration after RVPAS. Encouragingly, other indices of RV function remain stable before Fontan regardless of shunt type. (Comparison of Two Types of Shunts in Infants with Single Ventricle Defect Undergoing Staged Reconstruction-Pediatric Heart Network; NCT00115934). PMID- 25440102 TI - A journey toward converging 3 passions: research, patient care, and education. PMID- 25440103 TI - The journey to becoming an adult learner: from dependent to self-directed learning. PMID- 25440105 TI - Reply: prognostic role of CMR imaging after myocardial infarction. PMID- 25440104 TI - Prognostic role of CMR imaging after myocardial infarction. PMID- 25440106 TI - Cervical length--time to report the rate of change? PMID- 25440107 TI - Resident participation in laparoscopic hysterectomy: balancing education with safety. PMID- 25440108 TI - Non-vitamin K oral anticoagulants in atrial fibrillation: Where are we now? AB - Atrial fibrillation (AF) confers increased risk of stroke and other thromboembolic events, and oral anticoagulation therefore is the essential part of AF management to reduce the risk of these complications. Until recently, the vitamin K antagonists (VKAs, e.g., warfarin) were the only oral anticoagulants available, acting by decreased synthesis of vitamin K-dependent coagulation factors (II, VI, IX, and X). The VKAs had many limitations: delayed onset and prolonged offset of action, variability of anticoagulant effect among patients, multiple food and drug interactions affecting pharmacological properties of warfarin, narrow therapeutic window, and obligatory regular laboratory control, which all made warfarin "inconvenient" both for patients and clinicians. The limitations of VKAs led to development of a new class of drugs collectively defined as non-VKA oral anticoagulants (NOACs), which included direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban). The NOACs avoid many of the VKA drawbacks. In this review, we will focus on the current evidence justifying the use of NOACs in non-valvular AF. PMID- 25440109 TI - Green dialysis: the environmental challenges ahead. AB - The US Environmental Protection Agency Resource Conservation website begins: "Natural resource and energy conservation is achieved by managing materials more efficiently--reduce, reuse, recycle," yet healthcare agencies have been slow to heed and practice this simple message. In dialysis practice, notable for a recurrent, per capita resource consumption and waste generation profile second to none in healthcare, efforts to: (1) minimize water use and wastage; (2) consider strategies to reduce power consumption and/or use alternative power options; (3) develop optimal waste management and reusable material recycling programs; (4) design smart buildings that work with and for their environment; (5) establish research programs that explore environmental practice; all have been largely ignored by mainstream nephrology. Some countries are doing far better than others. In the United Kingdom and some European jurisdictions, exceptional recent progress has been made to develop, adopt, and coordinate eco-practice within dialysis programs. These programs set an example for others to follow. Elsewhere, progress has been piecemeal, at best. This review explores the current extent of "green" or eco-dialysis practices. While noting where progress has been made, it also suggests potential new research avenues to develop and follow. One thing seems certain: as global efforts to combat climate change and carbon generation accelerate, the environmental impact of dialysis practice will come under increasing regulatory focus. It is far preferable for the sector to take proactive steps, rather than to await the heavy hand of government or administration to force reluctant and costly compliance on the un-prepared. PMID- 25440110 TI - Effect of lemongrass tea consumption on estimated glomerular filtration rate and creatinine clearance rate. AB - OBJECTIVES: The existing research findings regarding the effects of lemongrass (Cymbopogon citratus) tea on renal function indices are conflicting and inconclusive. In the present study, we investigated the effects of infusions prepared from C citratus leaves on creatinine clearance rate (CCr) and estimated glomerular filtration rate (eGFR) in humans. DESIGN AND METHODS: One hundred five subjects (55 men and 50 women) aged 18 to 35 years were randomly assigned to groups set to orally receive infusions prepared from 2, 4, or 8 g of C citratus leaf powder once daily, for 30 days. Serum and urinary levels of urea, creatinine, pH, specific gravity, uric acid, electrolytes, diuretic indices, and eGFR were assessed at days 0, 10, and 30 after the initiation of treatment. Results obtained on days10 and 30 were compared with baseline values. RESULTS: CCr and eGFR decreased significantly at day 30 in both male and female subjects in all the groups and in females treated with infusion prepared from 8 g of C citratus leaf powder for 10 days. At day 10, CCr and eGFR were unchanged in those treated with infusions prepared from 2 or 4 g of the leaf powder, whereas diuretic indices (urine volume, urination frequency, diuretic action, and saliuretic indices) increased above the baseline levels. Serum and urinary creatinine levels significantly increased (P < .05) in both male and female subjects in all the groups. Serum urea significantly increased in the groups treated with infusions prepared from 4 or 8 g of the leaf powder (P < .05) for 30 days. Serum electrolytes remained unchanged, but their urinary levels increased. CONCLUSIONS: We observed dose- and time-dependent adverse effects of C citratus on CCr and eGFR. At a high dose or with prolonged treatment with a low dose, eGFR decrease may be followed by a decline in the other renal function indices. PMID- 25440111 TI - Shared medical appointments to screen for geriatric syndromes: preliminary data from a quality improvement initiative. AB - Older adults are at greater risk of developing conditions that affect health outcomes, quality of life, and costs of care. Screening for geriatric conditions such as memory loss, fall risk, and depression may contribute to the prevention of adverse physical and mental comorbidities, unnecessary hospitalizations, and premature nursing home admissions. Because screening is not consistently performed in primary care settings, a shared medical appointment (SMA) program was developed to fill this gap in care. The goals of the program were to improve early identification of at-risk individuals and ensure appropriate follow-up for memory loss, fall risk, and depression; facilitate discussion about prevention, diagnosis, and treatment of these conditions; implement strategies to reduce risks for these conditions; and increase access to screening and expand preventive health services for older adults. Between August 2011 and May 2013, 136 individuals aged 60 and older participated in the program. Three case studies highlighting the psychosocial and physiological findings of participation in the program are presented. Preliminary data suggest that SMAs are an effective model of regularly screening at-risk older adults that augments primary care practice by facilitating early detection and referral for syndromes that may otherwise be missed or delayed. PMID- 25440112 TI - Regulation of adrenomedullin and nitric oxide production by periodontal bacteria. AB - OBJECTIVES: In periodontitis the host response to bacterial challenge includes activity of the multifunctional molecules adrenomedullin (AM) and nitric oxide (NO). The aim of this study was to investigate the role of periodontal bacteria in regulating the production of these molecules from cultured cells. MATERIAL AND METHODS: Regulation of AM and NO production from oral keratinocytes when challenged with culture supernatants from Aggregatibacter actinomycetemcomitans, Campylobacter rectus, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia, Veillonella atypica, Streptococcus salivarius and Candida albicans was examined. AM and NO were measured in cell culture supernatants using an enzyme-linked immunosorbent assay and the nitrate/nitrite (NO metabolites) Griess assay respectively. Cellular production of AM and inducible NO synthase was also analysed in target cells by immunofluorescence and Western blot analysis. The inter-relationship of AM and NO production were further investigated with macrophages. RESULTS: A. actinomycetemcomitans and C. rectus induced maximal levels of both AM and NO after 6 and 48 h respectively from oral keratinocytes. AM production in macrophages was upregulated in response to the NO donor S-nitrosoglutathione and partially blocked by the inducible NO synthase inhibitor, N(omega) -Nitro-l-arginine methyl ester hydrochloride. Likewise, NO production was increased upon exposure to AM, while the AM receptor antagonist AM 22-52 reduced the release of NO. CONCLUSIONS: Pathogens associated with aggressive periodontitis, A. actinomycetemcomitans and C. rectus, were more effective than those associated with chronic periodontitis, P. gingivalis and Prev. intermedia, and commensals, S. salivarius and V. atypica, as regards the upregulation of AM and NO production from oral keratinocytes. Interaction between these molecules was also demonstrated with macrophages. Understanding the coordinated regulation of AM and NO production in response to periodontal bacteria may identify ways to promote their protective effects and minimize destructive potential. PMID- 25440113 TI - The neural correlates of emotion processing in juvenile offenders. AB - Individuals with severe antisocial behaviour often demonstrate abnormalities or difficulties in emotion processing. Antisocial behaviour typically onsets before adulthood and is reflected in antisocial individuals at the biological level. We therefore conducted a brain-based study of emotion processing in juvenile offenders. Male adolescent offenders and age-matched non-offenders passively viewed emotional images whilst their brain activity was recorded using electroencephalography. The early posterior negativity (EPN) and the late positive potential (LPP) components were used as indices of emotion processing. For both juvenile offenders and non-offenders, the EPN differentiated unpleasant images from other image types, suggesting that early perceptual processing was not impaired in the offender group. In line with normal emotion processing, the LPP was significantly enhanced following unpleasant images for non-offenders. However, for juvenile offenders, the LPP did not differ across image categories, indicative of deficient emotional processing. The findings indicated that this brain-based hypo-reactivity occurred during a late stage of cognitive processing and was not a consequence of atypical early visual attention or perception. This study is the first to show attenuated emotion processing in juvenile offenders at the neural level. Overall, these results have the potential to inform interventions for juvenile offending. PMID- 25440115 TI - Differences between murine and human sepsis. AB - Sepsis can be defined as a systemic inflammatory response syndrome occurring in the presence of an infectious source. Over the past 25 years, numerous guidelines have been established to clarify definitions and improve the overall management of clinical sepsis. In light of these multiple paradigm shifts, this review attempts to summarize the innate immunologic alterations that manifest during sepsis, establish and compare mouse models of sepsis with the clinical course, and discuss the authors' views on additional elements that should be considered in modeling and predicting clinical sepsis from the standpoint of a basic research setting. PMID- 25440114 TI - Stromal expression of miR-21 identifies high-risk group in triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is an aggressive subtype defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Expression of miR-21, an oncomiR, is frequently altered and may be distinctly expressed in the tumor stroma. Because tumor lesions are a complex mixture of cell types, we hypothesized that analysis of miR-21 expression at single-cell resolution could provide more accurate information to assess disease recurrence risk and BC-related death. We implemented a fully automated, tissue slide-based assay to detect miR-21 expression in 988 patients with BC. The miR-21(High) group exhibited shorter recurrence-free survival [hazard ratio (HR), 1.71; P < 0.001] and BC-specific survival (HR, 1.96; P < 0.001) in multivariate regression analyses. When tumor compartment and levels of miR-21 expression were considered, significant associations with poor clinical outcome were detected exclusively in tumor epithelia from estrogen receptor- and/or progesterone receptor-positive human epidermal growth factor receptor 2-negative cases [recurrence-free survival: HR, 3.67 (P = 0.006); BC-specific survival: HR, 5.13 (P = 0.002)] and in tumor stroma from TNBC cases [recurrence-free survival: HR, 2.59 (P = 0.013); BC-specific survival: HR, 3.37 (P = 0.003)]. These findings suggest that the context of altered miR-21 expression provides clinically relevant information. Importantly, miR-21 expression was predominantly up regulated and potentially prognostic in the tumor stroma of TNBC. PMID- 25440117 TI - Advancing technologies for the diagnosis and management of infections. AB - Infections remain a significant problem among surgical patients. Technological advances, especially in the arena of nano-technology, have markedly improved the ability to detect, prevent and treat surgical infections. No longer limited to culture-based methods of pathogen detection or standard antimicrobial therapies, options for management of surgical infections are rapidly expanding. Such advances are critical in this era of rapidly developing resistant and virulent strains of organisms. Further, our understanding of the host pathogen interaction grows exponentially with the development of computer-based modeling, aiding in expediting research endeavors. PMID- 25440116 TI - The opposing forces of the intestinal microbiome and the emerging pathobiome. AB - This article summarizes emerging concepts on the role of the intestinal microbiome in surgical patients. Revolutionary research over the past decade has shown that human beings live in close and constant contact with boundless communities of microbes. Recent innovations in the study of the human microbiome are reviewed. To demonstrate the applicability of these studies to surgical disease, the authors discuss what is known about the role of microbes in the pathogenesis of perioperative complications. Enhanced awareness of the human microbiome will empower clinicians to adopt novel practices in the prevention and treatment of a variety of surgical conditions. PMID- 25440118 TI - Infection control in the intensive care unit. AB - It is critical for health care personnel to recognize and appreciate the detrimental impact of intensive care unit (ICU)-acquired infections. The economic, clinical, and social expenses to patients and hospitals are overwhelming. To limit the incidence of ICU-acquired infections, aggressive infection control measures must be implemented and enforced. Researchers and national committees have developed and continue to develop evidence-based guidelines to control ICU infections. A multifaceted approach, including infection prevention committees, antimicrobial stewardship programs, daily reassessments-intervention bundles, identifying and minimizing risk factors, and continuing staff education programs, is essential. Infection control in the ICU is an evolving area of critical care research. PMID- 25440120 TI - Upcoming rules and benchmarks concerning the monitoring of and the payment for surgical infections. AB - There has been a good deal of dialogue about pay for performance and linking outcomes with reimbursement, especially given the recent national health care legislation. Many such concerns are caused by upcoming changes that have been outlined in the Affordable Care Act. This article discusses these upcoming changes and reviews some of the literature that supports them, specifically those related to surgical infections. Likewise, the lack of support for some of these changes in the academic literature is discussed. Finally, some of the proposed key benchmarks and the methodologies behind the design of those benchmarks are discussed. PMID- 25440121 TI - Bloodstream infections and central line-associated bloodstream infections. AB - It is estimated that more than 575,000 individuals develop bloodstream infections (BSI) annually in North America, accounting for nearly 80,000 deaths. Central line-associated BSI (CLABSI) is a major contributor to the cost of health care. Although primary BSI may be seen by the surgeon, a secondary BSI is more likely to be encountered, especially CLABSI. Prompt identification of the source of infection in patients with secondary BSI is paramount. This practice allows early source control and initiation of appropriate antimicrobial therapy, with subsequent improvement in outcomes. An understanding of evidence-based preventative measures and bundles is important. PMID- 25440122 TI - Surgical site infections. AB - Surgical site infections are a major contributor to morbidity and mortality in postsurgical care. Risk for surgical site infection is multifactorial and includes a host of microbial, patient-related, and procedure-related factors. Prevention of surgical infection relies on optimization of patient factors and use of a variety of evidence-based pharmacologic and nonpharmacologic measures. At the forefront of these measures is antimicrobial prophylaxis, which has been shown to be effective at reducing risk of surgical site infection. As guidelines for prevention of surgical site infection become increasingly complex and nuanced, surgical infection outcomes are increasing tied to quality outcome and performances measures. PMID- 25440123 TI - Prosthetic joint infections. AB - Prosthetic joint infections (PJIs) are often managed by surgical treatment of irrigation and debridement (I&D) in acute infections, and 1-stage or 2-stage exchange arthroplasty in chronic infections. Patients who undergo I&D have had lower success rates compared with patients who undergo exchange arthroplasty, especially if resistant organisms are encountered. In patients who cannot undergo surgical reconstruction, resection arthroplasty, fusion, or amputation may be performed. Patients who are poor surgical candidates may be treated with chronic antibiotic suppression. Despite these treatments, PJIs may not be fully eradicated, and future research should be performed to prevent the development of PJIs. PMID- 25440124 TI - Surgical intervention for thoracic infections. AB - Multidisciplinary management of thoracic infection, including experts in thoracic surgery, pulmonology, infectious disease, and radiology, is ideal for optimal outcomes. Initial assessment of parapneumonic effusion and empyema requires computed tomographic evaluation and consideration for fluid sampling or drainage. Goals for the treatment of parapneumonic effusion and empyema include drainage of the pleural space and complete lung reexpansion. Pulmonary abscess is often successfully treated with antibiotics and observation. Surgical intervention for the treatment of fungal or tuberculous lung disease should be undertaken by experienced surgeons following multidisciplinary assessment. Sternoclavicular joint infection often requires joint resection. PMID- 25440125 TI - Pneumonia: challenges in the definition, diagnosis, and management of disease. AB - Defining health care-associated pneumonia, which includes both hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), is problematic and controversial. Aspiration pneumonia is often included as a subtype of HAP but may be related to community-acquired aspiration events. Scoring systems exist and new surveillance guidelines have been implemented to make early recognition of pneumonia more precise and objective. Management and prevention should follow recommendations, including early empirical therapy, targeted therapy, and limited duration of treatment. Patients with trauma present a challenge to the diagnosis and management of pneumonia, because of increased risk for aspiration and underlying chest and pulmonary injury. PMID- 25440119 TI - Resistant pathogens, fungi, and viruses. AB - Although originally described in Staphylococcus aureus, resistance among bacteria has now become a race to determine which classes of bacteria will become more resistant. Availability of antibacterial agents has allowed the development of entirely new diseases caused by nonbacterial pathogens, related largely to fungi that are inherently resistant to antibacterials. This article presents the growing body of knowledge of the herpes family of viruses, and their occurrence and consequences in patients with concomitant surgical disease or critical illness. The focus is on previously immunocompetent patients, as the impact of herpes viruses in immunosuppressed patients has received thorough coverage elsewhere. PMID- 25440126 TI - Intra-abdominal Infections. AB - Intra-abdominal infections are multifactorial, but all require prompt identification, diagnosis, and treatment. Resuscitation, early antibiotic administration, and source control are crucial. Antibiotic administration should initially be broad spectrum and target the most likely pathogens. When cultures are available, antibiotics should be narrowed and limited in duration. The method of source control depends on the anatomic site, site accessibility, and the patient's clinical condition. Patient-specific factors (advanced age and chronic medical conditions) as well as disease-specific factors (health care-associated infections and inability to obtain source control) combine to affect patient morbidity and mortality. PMID- 25440127 TI - Clostridium difficile infection: prevention, treatment, and surgical management. AB - Clostridium difficile is increasing in both incidence and severity. Although metronidazole and vancomycin remain the gold standard for medical management, and surgical colectomy the gold standard for surgical management, new treatment alternatives, including the creation of a diverting loop ileostomy along with colonic lavage and vancomycin enemas, are being investigated that may lead to changes in the current treatment algorithms. The most exciting development in the treatment options for C difficile infection, however, is likely to be novel immunologic agents, which hold the potential to reduce the incidence, mortality, and costs associated with C difficile. PMID- 25440128 TI - Urinary tract infections in surgical patients. AB - Catheter-associated urinary tract infections (CAUTI) are common in surgical patients. CAUTI are associated with adverse patient outcomes, and negatively affects public safety reporting and reimbursement. Inappropriate catheter use and prolonged catheter duration are major risk factors for CAUTI. CAUTI pathogenesis and treatment are complicated by the presence of biofilms. Prevention strategies include accurate identification and tracking of CAUTIs, and the development of institutional guidelines for the appropriate use, duration, alternatives, and removal of indwelling urinary catheters. PMID- 25440129 TI - Surgical infections. PMID- 25440130 TI - Surgical infections. PMID- 25440131 TI - Is resection of the tendon edge necessary to enhance the healing process? An evaluation of the expression of collagen type I, IL-1beta, IFN-gamma, IL-4, and IL-13 in the distal 1 cm of a torn supraspinatus tendon: part II. AB - BACKGROUND: Type I collagen proin pro-in expression in a damaged supraspinatus tendon is thought to be dependent on the distance from the edge of the tear and the local expression of pro-inflammatory, anti-proliferative, and pro proliferative cytokines. The study evaluates the expression of type I collagen, pro-inflammatory interleukin (IL) 1beta, anti-proliferative interferon-gamma (IFN gamma), and pro-proliferative IL-4 and IL-13 cytokines along a 1-cm section taken from the edge of a torn supraspinatus tendon. Three sections were taken: 3 mm distal to the tear, 3 mm proximal to the tear, and the 4-mm middle section between them. METHODS: Nine patients (average age, 58 years) were included in the study. All fulfilled strict inclusion criteria regarding tear morphology and reconstruction technique. Samples were taken from the ruptured supraspinatus tendon at the time of arthroscopic repair. Quantitative real-time polymerase chain reaction assay was used for analysis. RESULTS: The expression of type I collagen, IL-4, and IL-13 significantly increased and that of IL-1beta and IFN gamma decreased from the distal to the proximal parts of the tendon edge (P < .05). CONCLUSIONS: The expression of type I collagen is dependent on the distance from the edge of the torn supraspinatus tendon, the balance between anti proliferative IFN-gamma and pro-proliferative IL-4 and IL-13, and the expression of pro-inflammatory IL-1beta. Hence, whereas resection of the distal 3 mm of the torn supraspinatus tendon edge eliminates its least valuable part, resection between 4 and 7 mm may enhance the healing process by reaching a reasonable compromise between the mechanical features of the tendon characterized by collagen type I expression and the technical abilities of reconstruction. PMID- 25440132 TI - Nutrition, modernity and the archaeological record: coastal resources and nutrition among Middle Stone Age hunter-gatherers on the Western Cape coast of South Africa. AB - In this paper, we assess the nutritional value of some marine and terrestrial food resources available to Middle Stone Age hunter-gatherers in the Western Cape of South Africa with respect to an important macronutrient (protein) and an essential micronutrient (iron) and introduce a framework for assessing the relative utility of marine and terrestrial resources. Whilst the ability to extract nutrients from the environment has always been a lynchpin in archaeologists' reconstructions of human evolution, a recent paradigm shift has recognized the role of marine resources in encephalization. Nutritional research indicates that marine ecosystems are the best source for long chain polyunsaturated fatty acids essential for proper brain development, and excavations at securely dated archaeological sites in South Africa provide firm evidence for the exploitation of marine resources by Middle Stone Age hunter gatherers from at least Marine Isotope Stage 5 (130 ka), and possibly even earlier. Because marine molluscs are abundant, predictably located and easily harvested, they would have been readily available to all members of the community, in contrast to terrestrial resources. The improving archaeological record gives important clues to resource choice, but many more nutritional observations are needed to determine the extent to which marine resources could have met the nutrient requirements of prehistoric people. Our observations indicate that marine and terrestrial fauna are both excellent sources of protein, and that marine molluscs have higher iron concentrations than we expected for invertebrate fauna. We calculate the number of individual food items from a selection of marine and terrestrial species needed to provide the protein and iron requirements of a hypothetical group of hunter-gatherers, identify contrasts in peoples' requirements for and access to nutrients and resources, and discuss the implications for prehistoric subsistence strategies and human evolution. PMID- 25440133 TI - Calcaneal robusticity in Plio-Pleistocene hominins: implications for locomotor diversity and phylogeny. AB - A key pedal adaptation to bipedality is a relatively large, weight-bearing calcaneus. The earliest evidence for a human-like, robust calcaneus is at 3.2 Ma in Australopithecus afarensis (A.L. 333-8, A.L. 333-55, A.L. 333-37) from Hadar, Ethiopia. Australopithecus sediba at 1.98 Ma from Malapa, South Africa displays a unique combination of primitive australopith features and more derived Homo-like features, but surprisingly is characterized by a gracile, chimpanzee-like calcaneus. The differences in calcaneal morphology suggest that these taxa differed in the frequency of arboreality and in the manner of foot function during terrestrial bipedal locomotion. This study examines calcaneal morphology in extant hominids (i.e., great apes and humans; N = 95) and fossil hominins (N = 5) to better understand the evolutionary development of calcaneal robusticity in early hominins. In particular, this study focuses on two additional fossil hominin calcanei that have not figured prominently in previous discussions of calcaneal robusticity: StW 352 and Omo 33-74-896. A measure of calcaneal robusticity was quantified as the ratio of calcaneal tuber cross-sectional area to calcaneal tuber length, which significantly differs between humans and non humans using a sequential Bonferroni alpha adjustment for multiple comparisons. Additional multivariate analyses using Mosimann shape variables show that StW 352 and Omo 33-74-896 are more similar to Au. sediba in calcaneal tuber morphology than to Au. afarensis, suggesting that the latter taxon is better adapted for terrestrial bipedalism than at least some later species of Australopithecus. This finding implies the possibility of several complex evolutionary scenarios involving either multiple reversals in postcranial morphology in Australopithecus or the independent acquisition of adaptations to terrestrial bipedalism in Au. afarensis and Homo. PMID- 25440134 TI - A revision of hominin fossil teeth from Fontana Ranuccio (Middle Pleistocene, Anagni, Frosinone, Italy). AB - The Fontana Ranuccio hominin teeth (FR, Latium, Italy) are dated to the Middle Pleistocene. In previous studies these teeth were classified as two lower (left and right) second molars, one lower left central incisor and a badly worn incisor crown, the exact position of which could not be determined. In 2012 these remains were acquired by the Anthropological Service of S.B.A.L. (Italian Ministry of Culture) and for this reason re-analysed. In a thorough revision we have reassessed them both morphologically and dimensionally as two lower (left and right) first molars, one lower left lateral incisor and a possible upper left canine. The comparison with penecontemporaneous and diachronic samples shows that the Fontana Ranuccio teeth are morphologically similar to Atapuerca-Sima de los Huesos, Arago XIII and Neanderthal samples. PMID- 25440135 TI - The geology and chronology of the Acheulean deposits in the Mieso area (East Central Ethiopia). AB - This paper presents the Quaternary sequence of the Mieso area of Central-East Ethiopia, located in the piedmont between the SE Ethiopian Escarpment and the Main Ethiopian Rift-Afar Rift transition sector.In this region, a piedmont alluvial plain is terraced at p25 m above the two main fluvial courses, the Mieso and Yabdo Rivers. The piedmont sedimentary sequence is divided into three stratigraphic units separated by unconformities. Mieso Units I and II contain late Acheulean assemblages and a weakly consolidated alluvial sequence, consisting mainly of fine sediments with buried soils and, to a lesser degree, conglomerates. Palaeo-wetland areas were common in the alluvial plain, represented by patches of tufas, stromatolites and clays. At present, the piedmont alluvial surface is preserved mainly on a dark brown soil formed at the top of Unit II. Unit III corresponds to a fluvial deposit overlying Unit II, and is defined by sands, silty clays and gravels, including several Later Stone Age (LSA) occurrences. Three fine-grained tephra levels are interbedded in Unit I (tuffs TBI and TA) and II (tuff CB), and are usually spatially-constrained and reworked. Argon/argon (40Ar/39Ar) dating from tuff TA, an ash deposit preserved in a palustrine environment, yielded an age of 0.212 +/- 0.016 Ma (millions of years ago). This date places thetop of Unit I in the late Middle Pleistocene, with Acheulean sites below and above tuff TA. Regional correlations tentatively place the base of Unit I around the Early-Middle Pleistocene boundary, Unit II inthe late Middle Pleistocene and within the Late Pleistocene, and the LSA occurrences of Unit III in the LatePleistoceneeHolocene. PMID- 25440136 TI - Differences in body composition and physical functions associated with sarcopenia in Chinese elderly: reference values and prevalence. AB - This study investigates the age-related differences in skeletal muscle mass (SM), muscle strength and physical performance in mainland Chinese. Based on available data, the reference values (criteria) for the definition of sarcopenia in elderly Chinese were explored. Body composition measurements were obtained using a bioelectrical impedance analyzer (BIA); muscle strength was determined by handgrip strength (HS); and physical function was evaluated by the subjects' 6-m gait speed (GS). In this study, HS and GS declined significantly after 55 years and very dramatically after 75 years. Appendicular SM index of <7.61kg/m(2) (males) and <6.43kg/m(2) (females); HS of <27kg (males) and <16kg (females); and GS of <0.98m/s (males) and <0.88m/s (females) were considered as low SM, low HS and low GS. Applying these suggested criteria to the study population, there were 9.55% and 6.63% of the subjects with low SM, 20.10% and 18.46% with low GS, and 14.07% and 15.38% with low HS in elderly males and females, respectively. Utilizing Asian Working Group for Sarcopenia (AWGS) criteria in our population results in a very low prevalence of low SM and low GS. If Western criteria for sarcopenia were adopted, the prevalence of low GS and low HS would be 2-4 times higher in the studied population, also exhibiting significant gender differences. These findings indicate that it is necessary to establish an outcomes-based and ethnic-specific set of reference values for the diagnosis of sarcopenia in elderly Chinese. PMID- 25440137 TI - Fatty degeneration of gluteus minimus muscle as a predictor of falls. AB - The cause of falls is multifactorial, however, hip fractures in elderly would be prevented if accidental falls are predictable. We assessed magnetic resonance images of 38 patients with groin pain after taking a fall whose fracture could not be detected by plain X-rays, and 45 patients with no episode of falls. Their ages were over 65 years. Fatty degeneration of muscles, gluteus maximus, gluteus medius, gluteus minimus, obturator externus, adductor longus, rectus femoris and iliopsoas muscles, were evaluated by Goutallier's staging. Odds ratio was calculated by a logistic regression analysis allocating dependent variable for falls and independent variables for Goutallier's stage, age and gender. The fatty degeneration of gluteus maximus muscle was generalized, while that of gluteus minimus muscle was unevenly distributed, especially in anterior area. Gluteus minimus muscle initiated its fatty degeneration earlier than gluteus medius muscle. Odds ratio of falling was 3.2 (95% confidence intervals: 1, 14, 8.94) for Goutallier' stage of the gluteus medius muscle. Fatty degeneration of gluteus medius muscle has a crucial role in providing stability of the pelvis including hip joint. Evaluating fatty streaks in the gluteus minimus muscle could help give early indication to those who have a higher risk of falling. PMID- 25440138 TI - Life threatening chop injuries to the head: optimising injury interpretation using three dimensional computerised tomography (3DCT) reconstruction of pre treatment imaging. AB - Computerised tomography (CT) is being increasingly advocated to support post mortem investigation of death but the value of using CT data already captured during emergency imaging, prior to treatment of life threatening injuries, remains under recognised and inadequately explored. We demonstrate the value of three dimensional computerised tomography (3D CT) reconstructions of such data, in interpreting the injuries sustained by a male who survived after being subjected to an assault with an axe and whose surface injuries had been debrided and sutured, before any photography was undertaken. The 3D CT images captured most of the scalp, face and skull vault trauma prior to the surgical intervention. Taken with other evidence, this indicated that the victim had received at least four separate blows to the face and head with a sharp chopping weapon; evidence which proved to be centrally important in the subsequent criminal court proceedings. This case also illustrated the effectiveness of joint interpretation of 3D CT reconstructed images in medico-legal casework, by experienced consultants in forensic pathology and radiology and the potential value of reviewing emergency pre-treatment CT imaging in any serious head injury allegedly sustained in an assault. This is likely to be particularly valuable when sharp or blunt weapon damage to bone is suspected. PMID- 25440139 TI - Fatal firearm injuries in autopsy cases at central Bangkok, Thailand: a 10-year retrospective study. AB - Even though there have been previously published reports on firearm injuries in various countries, the incidence and pattern of death from firearm injuries in Thailand have not been studied before. In present study, 149 fatal firearm injuries from 2002 to 2011 were reviewed. At total of 7126 autopsies, fatal firearm injuries comprised of 2.09% (n = 149) of total autopsies cases. Among those victims, 136 were male (91.3%), 13 (8.7%) were female. The youngest age of victim was 10 years and the oldest was 79 years. Mean age of the victims was 33.79 years and median age was 30 years. Outdoor incident was the most common scene of crime. Night time incident (18:00 PM-05:59 AM) was higher than day time one. Most of the cases occurred in week ends (n = 52). Homicide (77.2%) was the most frequent manner of death. Head/face and chest were the most common sites of entrance. The autopsy report also study on entrance wound, range and types of projectiles. Blood alcohol concentration was examined in 122 cases and 38 victims showed positive results, 11 cases revealed using of illegal substances in blood and urine analysis. This study also included the association between manner of death and other factors. Age group, time of incidence, place of incidence, number of entrance wound and range showed statistically significant association with manner of death. PMID- 25440140 TI - Exploring time of death from potassium, sodium, chloride, glucose & calcium analysis of postmortem synovial fluid in semi arid climate. AB - Estimation of time of death (TOD) with fair accuracy from postmortem changes still remains an important but difficult task to be performed by every autopsy surgeon under different climatic conditions. The environment plays an important role in the process of decomposition and thereby affecting the levels of electrolytes and other biochemical parameters in the postmortem samples. Since, there is limited information available on the levels of these biochemical parameters from semi arid environment, the present study was aimed to explore time of death by analyzing electrolyte, glucose and calcium levels of postmortem synovial fluid collected from samples under such climatic conditions. The synovial fluid samples from two hundred and ten bodies brought to University College of Medical Sciences and associated Guru Teg Bahadur Hospital Delhi for medico-legal postmortem examination, during the period of November 2010 to April 2012, were analyzed for potassium, sodium, chloride, glucose and calcium. Univariate regression analysis of electrolyte concentrations of synovial fluid showed significant positive relationship between time of death and potassium (r = 0.840, p = 0.000). However, there was negative relationship between time of death and sodium (r = -0.175, p = 0.011) & glucose (r = -0.427, p = 0.000) and no significant relationship was found between time of death and calcium (r = 0.099, p = 0.152) & chloride (r = 0.082, p = 0.24) among the samples analyzed. PMID- 25440141 TI - Usefulness of pericardial and pleural fluids for the postmortem diagnosis of sepsis. AB - The purpose of this study was to evaluate the postmortem distributions of procalcitonin (PCT), C-reactive protein (CRP), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and soluble interleukin-2 receptor (sIL 2R) levels in postmortem serum from femoral blood, pericardial fluid and pleural fluid in a series of sepsis-related fatalities (12 subjects) and control cases (20 subjects) that underwent medico-legal investigations. Our aim was to assess the diagnostic potential of the results obtained from pericardial and pleural fluid analysis in identifying sepsis-related deaths. All sepsis-related cases had a documented, clinical diagnosis that was established in vivo during hospitalization. Pneumonia was the main infectious focus identified during autopsy and histology. Pseudomonas aeruginosa, Klebsiella pnemoniae and Escherichia coli were the most commonly identified bacteria in blood and lung tissue cultures. The preliminary results corroborate the usefulness of PCT, CRP, sTREM-1 and sIL-2R determination in postmortem serum for the identification of sepsis-related deaths. Moreover, the data suggest that, as far as PCT, CRP, sTREM 1 and sIL-2R measurements are concerned, pericardial and pleural fluids can be considered suitable alternatives to postmortem serum should femoral blood prove unavailable at autopsy. PMID- 25440142 TI - Domestic violence against elderly with disability. AB - Abuse against elders with disabilities is a growing problem as the world population ages. Though they require mandatory reporting, these cases are most frequently not detected or not reported by health professionals for a variety of reasons, including the difficulty of making an accurate diagnosis. By performing a retrospective analysis of alleged domestic violence cases against elders with moderate or severe disability, presented to medical forensic examination at the North Branch of the National Institute of Legal Medicine and Forensic Sciences of Portugal, in Porto, between 2005 and 2013 (n = 70), we aimed to improve our knowledge of some demographic and forensic characteristics of these cases as well as improve their detection and prevention. The most frequently reported type of abuse was physical (86%), allegedly perpetrated by male abusers (63%) living with their victims (90%), who were most commonly their children (47%) or partners (49%; when victims are married). The victims were most frequently female (63%) who had motor disabilities (49%) and presented a history of previous episodes of abuse in 74% of cases; however, only 28% were previously reported. The physical consequences were most frequently minor injuries (95%) with permanent consequences (scars) in only 6.8% of the cases. The injuries were multiple in the majority of the cases (64%), and the preferred locations were the head and neck (75%). Elderly females with motor disabilities appear to have a greatest risk of domestic violence, which translates, most frequently, into multiple injuries that are mainly in the head and neck. PMID- 25440143 TI - Suspicious child female deaths in Great Cairo and Giza during 2011-2012. AB - Childhood mortality is a measure of a nation's health. A statistical analysis on suspicious child female deaths was done in two years period from 1st January 2011 to 31st December 2012. It's incidence was (4%) of all autopsied cases. The adolescent group (16-18 yrs) was highly involved 44 cases (27.5%). The majority of cases were known (82%) and they were from Great Cairo (60%) especially poor areas. Incidences were prevalent in March (15%), indoor (58%) and homicide was main manner in (42.5%) of cases. A relative was the main perpetrator in (50%) of homicidal cases. Wounds were observed in (43%) of cases. The head and neck regions were injured (50%) and signs of abuse were detected in (16%) of the studied cases. These results may be a guide for developing prevention policy. PMID- 25440144 TI - Are Australian paramedics adequately trained and prepared for intimate partner violence? A pilot study. AB - Intimate partner violence (IPV) is a common occurrence in Australian society and has far reaching health, social and economic impacts, particularly for females who are the most common victims. It is theorised that paramedics frequently encounter IPV in the field and in some cases are the only agency which deal with IPV victims in the out-of-hospital setting. Thus paramedics have a unique opportunity to increase discovery, treatment and reporting, however there is little formal training in managing IPV for most Australian paramedics. We evaluated the level of basic knowledge as well as self-reported preparedness and frequency of encountering IPV in a selection of 50 Australian paramedics using a cross-sectional descriptive study design with a paper-based questionnaire. Ninety percent of the paramedics reported encountering at least 1 case of suspected IPV in the last year, with the average number of cases being 3.66. Only 22% reported that they felt confident managing IPV cases. Sixty six percent of participants were unaware there is no mandatory reporting of IPV in their region. The vast majority of participants stated that they felt additional education and training would be most helpful to improving their ability to manage IPV cases. Participants had a poor knowledge and poor preparedness for IPV prior to undertaking a targeted education session. There is an urgent need for additional research of the needs and best methods to educate and train paramedics to appropriately respond to IPV cases. PMID- 25440145 TI - Frequency of intracranial injury in cadavers with head trauma with and without scalp injury in Tehran. AB - Traumatic brain injury is a major cause of morbidity, disability and mortality in patients with head injury. The aim of this study was to elucidate the frequency of intracranial injury in cadavers with head trauma with and without scalp injury in Tehran. In this analytical cross-sectional study, we investigated 187 cadavers who died due to head trauma in motor vehicle accident or after falling in Tehran from November 2013 to February 2014. Age, sex, mechanism of trauma, scalp injury, sub-scalp bruising, skull fracture, hemorrhage including subdural hemorrhage (SDH), epidural hemorrhage (EDH), subarachnoid hemorrhage (SAH) and contusion were recorded from examination and autopsy. One hundred and eighty seven cadavers (165 (88.2%) male and 22 (11.8%) female) with head injury with the mean age of 36.14 years (SD = 15) were recruited in this study. Mechanism of trauma was motor vehicle accident in 147 (78.6%) cadavers and falling in 40 (21.4%) cadavers. One hundred and fifty eight (84.5%) had SDH, 44 (23.5%) had EDH, 162 (86.6%) had SAH and 139 (74.3%) had contusion. Hemorrhage was seen in 132 (93%) cadavers who had scalp injury and 36 (80%) cadavers who did not have scalp injury (p = 0.01). Overall, 168 (89.8%) cadavers had hemorrhage and 139 (74.3%) had contusion. There was a significant correlation between intracranial injuries and scalp injury (p < 0.05). There was not a significant correlation between EDH and scalp injury (p = 0.52). Consequently, in patients with head trauma, complete examination should be performed but absence of findings in examination cannot exclude intracranial injury. PMID- 25440146 TI - A child death as a result of physical violence during toilet training. AB - Enuresis and delayed bladder control are a common source of psychosocial concern for both parents and children. Different cultures have different norms with regard to parenting attitudes. The fact that in Turkey, parents consider enuresis or encopresis as a sign of laziness, misbehavior, or disobedience rather than a medical disorder may cause children to be exposed to physical and emotional violence and maltreatment by the family as a corrective strategy. We present a case in this paper which had a fatal outcome due to physical violence against a child as an educational measure and a toilet training method. PMID- 25440147 TI - Distribution & diagnostic efficacy of cardiac markers CK-MB & LDH in pericardial fluid for postmortem diagnosis of ischemic heart disease. AB - The aim of the present study is to evaluate the diagnostic efficacy of biochemical markers creatine kinase-MB (CK-MB) and LDH in pericardial fluid for postmortem diagnosis of ischemic heart disease (IHD). We studied 119 medico-legal autopsies selected during a period of 2 years. Subjects were assigned into diagnostic groups upon final cause of death as follows: (1) sudden cardiac death due to IHD's (n = 52), (2) violent asphyxia (n = 24); (3) polytraumatic deaths (n = 20); (4) natural deaths excluding cardiac causes (n = 23). Pericardial fluid samples were tested for estimating enzyme levels. Histological examination was performed with hematoxylin and eosin (H&E) stain on myocardial tissue samples. We observed highest levels of CK-MB & LDH in deaths due to IHD's. Kruskal-Wallis test revels significant differences in activities of CK-MB (P = 0.0001) and LDH (P = 0.0065) amongst all diagnostic groups. Mann-Whitney test showed highly significant (P < 0.0001) levels of CK-MB in group 1 as compared to other diagnostic groups. However, LDH levels were non-discriminatory (P = 0.0827) between cases of IHD's and cases of other natural deaths. CK-MB levels were statistically non-significant between cases divided as myocardial infarction (MI) and severe coronary artery disease in group 1, hence its role for postmortem detection of MI is somewhat limiting. However, sensitivity and negative predictive values of its cut off level obtained in cases of IHD's are nearly equal to diagnostic efficacy in clinical settings. Hence, it can be useful additional diagnostic tool for autopsy diagnosis of IHD's. Whereas, LDH is not useful for postmortem diagnosis in these cases. PMID- 25440148 TI - A response to: Macroscopically detected female genital injury after consensual and non-consensual vaginal penetration: a prospective comparison study [20 (2013) 884-901]. PMID- 25440149 TI - Response to letter to the editor entitled: Macroscopically detected female genital injury after consensual and non-consensual vaginal penetration: a prospective comparison study [20(2013) 884-901]. PMID- 25440150 TI - Systemic inflammatory response and survival in patients undergoing curative resection of oral squamous cell carcinoma. AB - Prognostic stratification in squamous cell carcinoma (SCC) of the head and neck has traditionally relied on the pathological staging of a tumour, but it is increasingly being recognised that host-related factors have an important role in the assessment of survival and recurrence. We aimed to evaluate the prognostic value of systemic inflammation scores including the modified Glasgow Prognostic Score (mGPS) in patients undergoing potentially curative resection for oral SCC. We retrospectively identified 178 patients who had curative operations for cancer of the oral cavity and soft palate between January 2006 and April 2011. Among the inclusion criteria were preoperative estimates of C-reactive protein and serum albumin. We analysed established pathological prognostic factors and scores for systemic inflammation as predictors of cancer-specific and overall survival. On univariate analysis, the mGPS was a significant predictor of both cancer-specific (p<0.001) and overall survival (p<0.001), and it remained an independent predictor of cancer-specific (HR: 2.12, 95% CI 1.49 to 3.00; p<0.001) and overall survival (HR: 1.69, 95% CI 1.23 to 2.31; p=0.001) on Cox regression analysis. The mGPS of activated systemic inflammation seems to be a powerful adverse prognostic indicator in resectable oral SCC. PMID- 25440154 TI - In vivo activity of daptomycin/colistin combination therapy in a Galleria mellonella model of Acinetobacter baumannii infection. AB - Antimicrobial treatment of multidrug-resistant Acinetobacter baumannii (MDR-AB) infections continues to pose significant challenges. With limited options, clinicians have been pushed towards using unorthodox combinations of licensed antibiotics. Although daptomycin/colistin combination appears to be a promising treatment option based on in vitro data, further preclinical work is needed. In this study, the A. baumannii-Galleria mellonella system was employed to study the in vivo efficacy of this combination in order to determine whether it should be explored further for the treatment of MDR-AB infections. The antimicrobial activity of colistin alone and in combination with daptomycin was assessed versus an A. baumannii type strain (ATCC 19606) and a MDR-AB clinical strain (GN2231) isolated in Anhui, China. Synergy studies were performed using the microtitre plate chequerboard assay and time-kill methodology. The in vivo activity of daptomycin/colistin combination was assessed using a G. mellonella larvae model. The combination of daptomycin and colistin was bactericidal against both strains tested. In chequerboard assays, daptomycin was highly active against A. baumannii when combined with colistin [fractional inhibitory concentration index (FICI) of <0.5]. Treatment of G. mellonella larvae infected with lethal doses of A. baumannii resulted in significantly enhanced survival rates when daptomycin was given with colistin compared with colistin treatment alone (P<0.05). This work suggests that daptomycin/colistin combination is highly active against A. baumannii both in vitro and in a simple invertebrate model of infection. PMID- 25440155 TI - Fibromyalgia has a larger impact on physical health than on psychological health, yet both are markedly affected: the al-Andalus project. AB - OBJECTIVES: To characterize a representative sample of fibromyalgia women based on a set of relevant factors known to be related to this disease. To distinguish specific factors of the disease from other symptoms that might also exist in non fibromyalgia women. To test whether fibromyalgia affects more severely physical or psychological outcomes. METHODS: A total of 459 fibromyalgia women vs. 214 non fibromyalgia (control) women from Southern Spain (Andalusia) took part in this cross-sectional study. Several instruments were used to assess tenderness, impact of fibromyalgia, fatigue, health-related quality of life, mental health, and cognitive performance. RESULTS: Overall, fibromyalgia women showed a worse status in pain, fatigue, health-related quality of life, depression, and anxiety than controls (P < 0.01). In general, the observed associations presented very large effect sizes (Cohen's d from ~1 to ~5.5). No differences between fibromyalgia and controls were observed in cognitive and memory performance, except for delayed recall, but the observed effect size was low (~0.25). The effect size observed for the global physical component (~3.3) was larger than that for the global psychological component (~1.3), all P < 0.001. CONCLUSIONS: Our results reinforce the understanding of fibromyalgia as a polysymptomatic distress condition with pain as its main symptom. Our findings support that fibromyalgia seems to have a greater impact on physical than on psychological outcomes, though both are largely affected. PMID- 25440156 TI - Should your algorithm include plasma rich in growth factors in the light of its clinical efficacy and safety?: By Vaquerizo V. et al. PMID- 25440157 TI - Should your algorithm include plasma rich in growth factors in the light of its clinical efficacy and safety? PMID- 25440159 TI - Is there a doctor on the plane? PMID- 25440158 TI - The durability of abatacept as a first and subsequent biologic and improvement in HAQ from a large multi-site real-world study. AB - OBJECTIVES: Assessment of the effectiveness of newer biologics such as abatacept is essential in real-world practice. METHODS: RA patients administered infusions of abatacept via the Orencia Response Program network with at least one follow-up evaluation were included. The number needed to treat (NNT) to improve HAQ by at least the minimal clinically important difference (MID >= 0.22) and abatacept survival and differences between biologic-naive and TNFi-experienced patients were assessed. RESULTS: Among 2929 patients enrolled, 1771 (60.5%) were eligible for analysis (mean age was 57.6 years, disease duration was 16.5 +/- 11.0 (SD) years, 77.2% were female, and 79.2% had past TNFi), with mean follow-up of 13.8 +/- 12.3 (SD) months. Half had comorbidities including hypertension (17%), diabetes (8.4%), asthma (6.0%), hypothyroidism (5.7%), and hyperlipidemia (4.0%). Mean (SE) durability of treatment was 26.8 (0.53) months, where 66% were receiving abatacept at 12 months and 53% at 24 months. Patient survival was longer where abatacept was the first biologic vs. post-TNFi (P = 0.0001). In the use of abatacept as a first biologic, 70% achieved MID in HAQ vs. 71% if post TNFi (P = 0.65) with NNT to improve one patient with at least MID of HAQ was 1.4. CONCLUSIONS: Abatacept is effective in improving HAQ in RA both pre and post first biologic in real-world patients with comorbidities. For those still on abatacept, HAQ continued to improve over the first 2 years. The durability of abatacept is better as a first biologic, but NNT to improve HAQ patients on treatment is the same post-DMARDs and post-TNFi. For treatment durability and HAQ MID achievement, abatacept use as a first biologic is better. PMID- 25440160 TI - Examination of the heart. PMID- 25440161 TI - Glucose transporter 1 deficiency syndrome and hemiplegic migraines as a dominant presenting clinical feature. AB - Glucose transporter 1 deficiency syndrome (OMIM 606777) is a treatable epileptic encephalopathy caused by mutations in the SLC2A1 gene (OMIM 138140) causing impaired glucose transport into the brain. The classical phenotype is associated with seizures, developmental delay, ataxia and spasticity; however, milder phenotypes are emerging. We describe an 8-year-old boy with glucose transporter 1 deficiency syndrome whose clinical presentation was dominated by hemiplegic migraines that resolved with institution of a modified Atkins diet. PMID- 25440166 TI - Benign skin lesion in a neonate. PMID- 25440168 TI - Reply: Australian evidence-based website: Raising Children Network. PMID- 25440167 TI - Unusual appearance of nails. PMID- 25440169 TI - Reply: Australian evidence-based website: Raising Children Network. PMID- 25440172 TI - A normal renal ultrasound scan excludes major abnormalities on dimercaptosuccinic acid in children with urinary tract infections. PMID- 25440171 TI - Benchmarking the management of children with haemophilia in Australia. PMID- 25440175 TI - Giant eyelid molluscum contagiosum presenting as preseptal cellulitis. PMID- 25440177 TI - Validation of the Barcelona Bio-Heart Failure Risk Calculator in a cohort from Boston. PMID- 25440178 TI - Mitochondrial cardiomyopathies associated with the m.3243A>G mutation in the MT TL1 gene: two sides of the same coin. PMID- 25440179 TI - DIOCLES: Some caveats and new questions. PMID- 25440180 TI - Non-ventricular, Clinical, and Functional Features of the RyR2(R420Q) Mutation Causing Catecholaminergic Polymorphic Ventricular Tachycardia. AB - INTRODUCTION AND OBJECTIVES: Catecholaminergic polymorphic ventricular tachycardia is a malignant disease, due to mutations in proteins controlling Ca(2+) homeostasis. While the phenotype is characterized by polymorphic ventricular arrhythmias under stress, supraventricular arrhythmias may occur and are not fully characterized. METHODS: Twenty-five relatives from a Spanish family with several sudden deaths were evaluated with electrocardiogram, exercise testing, and optional epinephrine challenge. Selective RyR2 sequencing in an affected individual and cascade screening in the rest of the family was offered. The RyR2(R420Q) mutation was generated in HEK-293 cells using site-directed mutagenesis to conduct in vitro functional studies. RESULTS: The exercise testing unmasked catecholaminergic polymorphic ventricular tachycardia in 8 relatives (sensitivity = 89%; positive predictive value = 100%; negative predictive value = 93%), all of them carrying the heterozygous RyR2(R420Q) mutation, which was also present in the proband and a young girl without exercise testing, a 91% penetrance at the end of the follow-up. Remarkably, sinus bradycardia, atrial and junctional arrhythmias, and/or giant post-effort U-waves were identified in patients. Upon permeabilization and in intact cells, the RyR2(R420Q) expressing cells showed a smaller peak of Ca(2+) release than RyR2 wild-type cells. However, at physiologic intracellular Ca(2+) concentration, equivalent to the diastolic cytosolic concentration, the RyR2(R420Q) released more Ca(2+) and oscillated faster than RyR2 wild-type cells. CONCLUSIONS: The missense RyR2(R420Q) mutation was identified in the N-terminus of the RyR2 gene in this highly symptomatic family. Remarkably, this mutation is associated with sinus bradycardia, atrial and junctional arrhythmias, and giant U-waves. Collectively, functional heterologous expression studies suggest that the RyR2(R420Q) behaves as an aberrant channel, as a loss- or gain-of-function mutation depending on cytosolic intracellular Ca(2+) concentration. PMID- 25440181 TI - Obesity and vascular events in type 2 diabetes mellitus. PMID- 25440182 TI - Monitoring liver macrophages using nanobodies targeting Vsig4: concanavalin A induced acute hepatitis as paradigm. AB - Kupffer cells (KCs) are liver resident macrophages which are important for tissue homeostasis and have been implicated in immunogenic, tolerogenic and pathogenic immune reactions depending on the insult. These cells and the biomarkers they express thus represent interesting in vivo sensors for monitoring liver inflammation. In the current study, we explored whether KCs can be monitored non invasively using single-photon-emission computed tomography (SPECT) with (99m)Tc labeled nanobodies (Nbs) targeting selected biomarkers. Nbs targeting V-set and immunoglobulin domain-containing 4 (Vsig4) or macrophage mannose receptor (MMR) accumulated in the liver of untreated mice. The liver targeting of anti-Vsig4 Nbs, but not anti-MMR Nbs, was blunted upon depletion of macrophages, highlighting specificity of anti-Vsig4 Nbs for liver macrophage imaging. Ex vivo flow cytometry and immunohistochemistry analysis confirmed that anti-Vsig4 Nbs specifically targeted KCs but no other cell types in the liver. Upon induction of acute hepatitis using concanavalin A (ConA), down-regulation of the in vivo imaging signal obtained using anti-Vsig4 Nbs reflected reduction in KC numbers and transient modulation of Vsig4 expression on KCs. Overall, these results indicate that Nbs targeting Vsig4 as molecular imaging biomarker enable non invasive monitoring of KCs during hepatic inflammation. PMID- 25440184 TI - [The visual snow phenomenon.] AB - INTRODUCTION: Visual snow is a symptom described by some patients and poorly recognized by ophthalmologists. It consists in the permanent perception of a textured or a snowy vision, sometimes associated with palinopsia, exaggerated perception of the blue field entoptic phenomenon and photophobia. We report a group of patients suffering from visual snow in order to precise its characteristics and discuss its pathophysiology. MATERIALS AND METHODS: Prospective study of patients diagnosed between September 2010 and December 2012 with a visual snow phenomenon. For each patient, a formal ophthalmologic examination, an Amsler grid test, an automated visual field (central 20 degrees ), a color vision test (15 Hue), a full field, a pattern and a multifocal electroretinogram as well as flash and pattern visual evoked potentials (Metrovision(c)) were performed. A brain imaging was not systematically performed. RESULTS: Twelve patients aged 9-48old were included (six men and six women, 85 % of students). Several signs were variably associated with the visual snow phenomenon: palinopsia (50 %), constant blue field entoptic phenomenon (40 %), photophobia (30 %), migraine (30 %); in 20 % of cases, an initial toxic intake was found (20 %). DISCUSSION: This study highlights the reproducibility of typical symptoms described by patients reporting the visual snow phenomenon. This feature strongly supports the organic origin of the phenomenon. The pathophysiology of this phenomenon, however, remains unclear; the hypothesis of a lower threshold for perception of entoptic images cannot entirely account for the reported symptoms. PMID- 25440183 TI - Peak Bone Mass and Patterns of Change in Total Bone Mineral Density and Bone Mineral Contents From Childhood Into Young Adulthood. AB - The literature has not reached a consensus on the age when peak bone mass is achieved. This study examines growth patterns of total bone mineral content (TBMC) and total bone mineral density (TBMD), peak bone mass, effect of concurrent anthropometry measures, and physical activity on growth patterns in a sample of 312 white males and 343 females aged 8-30 yr. We analyzed data from participants enrolled in Fels Longitudinal Study. Descriptive analysis was used to ascertain characteristics of participants and growth patterns of TBMC and TBMD. Mixed effects models were applied to predict ages at attainment of peak TBMC and TBMD and assess the effects of height, weight, body mass index (BMI), and habitual physical activity on the attainment. Significant differences between sexes were observed for measures of TBMC and TBMD, and differences varied with age. For females, predicted median ages at peak TBMC and TBMD attainments are 21.96 yr (interquartile range [IQR]: 21.81-22.21) and 22.31 yr (IQR: 21.95 22.59), respectively. For males, predicted median ages are 23.34 yr (IQR: 24.34 26.19) and 26.86 yr (IQR: 25.14-27.98) respectively. For females, height, weight, and BMI, but not physical activity, had significant influences on attainment of TBMC and TBMD (p<0.01). For males, weight and BMI, but not height and physical activity, exerted significant influence on attainment of TBMC and TBMD (p<0.01), and also modified correlations between age and peak TBMC and TBMD. Our results suggest that (1) for both sexes, trajectories of TBMC and TBMD follow a curvilinear pattern between ages 8 and 30 yr; (2) predicted ages at peak TBMC and TBMD are from early to late 20s for both white males and females, with females reaching their peaks significantly earlier than males; and (3) concurrent height, weight, and BMI, but not habitual physical activity, exert significant effects on trajectories of TBMC and TBMD. PMID- 25440185 TI - [Glaucoma medications, preservatives and the ocular surface.] AB - Several clinical and experimental studies have demonstrated that ocular surface disease is common in glaucoma patients receiving chronic glaucoma drops, and that the preservatives in these drops play a major role in the occurrence of ocular surface disease. These ocular surface changes may induce both symptoms reported by the patients and anterior segment clinical signs, and should be systematically assessed by history and exam in all glaucoma patients. In these patients with ocular surface disease, reducing the amount of preservatives administered to the eye should be strived for, rather than adding additional eye drops to alleviate or mask the side effects of the glaucoma drops. PMID- 25440186 TI - Subjective vs objective predictors of functional knee joint performance in anterior cruciate ligament-reconstructed patients--do we need both? AB - BACKGROUND: Associations between objective and subjective measures of knee function may facilitate rehabilitation in ACL-patients. AIM: The aim of this study is to investigate if a test-battery of functional and/or muscle outcomes are associated with Knee osteoarthritis outcome score (KOOS) subscales (Sport/Rec and QOL) in ACL-reconstructed patients. METHODS: 23 hamstring auto-graft ACL reconstructed men (mean age: 27.2 standard deviation 7.5 years, BMI: 25.4 standard deviation 3.2 time since surgery: 27 standard deviation 7 months) completed KOOS-questionnaire and an objective test-battery: (i) one-leg maximal jump for distance (OLJD), isometric maximal voluntary contraction (MVC) for (ii) knee extensors and (iii) flexors, and (iv) maximal counter movement jump (CMJ). Sagittal kinematic data were recorded during CMJ using a 6-camera Vicon MX system. Multilevel linear regression analysis was used to determine the strength of associations between KOOS parameters (Sport/Rec and QOL) that a priori were defined as dependent variables and 4 models of independent outcomes from the test battery. RESULTS: Moderate associations between OLJD and Sport/Rec (r(2)=0.26, p<0.01) and QOL (r(2)=0.26, p<0.01) were observed (Model 1). Adding knee extensor or flexor MVC to the analysis (Model 2) increased the strength of the associations (up to r(2)=0.53, p<0.01, and r(2)=0.31, p=0.02 for Sport/Rec and QOL, respectively). Adding both knee extensor and knee flexor MVC to the analysis (Model 3) did not improve the regression model and only minor increases were observed when including kinematic data of CMJ (Model 4). CONCLUSION: Moderate-to large proportion (31-53%) of the variation in KOOS was explained by OLJD and MVC which may add to design effective future rehabilitation interventions for ACL patients. PMID- 25440187 TI - Osteochondral grafting for failed knee osteochondritis dissecans repairs. AB - BACKGROUND: Revision of failed surgical treatments of osteochondritis dissecans (OCD) lesions remains a challenge without an obvious solution. The aim of this study was to evaluate seven consecutive patients undergoing osteochondral grafting of a failed OCD repair. METHODS: The mean time from surgery to the latest evaluation was 7.0 years. IKDC, WOMAC, Tegner, and MRI studies were collected both preoperatively and during follow-up. Evaluation of the graft was assessed using the magnetic resonance observation of cartilage repair tissue (MOCART) grading system. RESULTS: Over the course of the study period, five patients required additional surgery with a study median of one additional surgery (range, zero to 3). At most recent follow-up, there was significant improvement from preoperative values in median IKDC (p=0.004), WOMAC (p=0.030), and Tegner (p=0.012). Complete cartilage fill and adjacent tissue integration of the paste graft were observed by MRI evaluation in five of the seven (71.4%) patients. Definitive correlation between clinical outcomes and MRI scores was not observed. CONCLUSIONS: This study shows promising results of osteochondral grafting as a viable option for the revision of failed OCD lesion repairs; however, more patients are needed to fully support its efficacy in these challenging failed revision cases. PMID- 25440188 TI - Baseline concentration of 210Po and 210Pb in Sargassum from the northern Gulf. AB - This baseline study highlights the (210)Po and (210)Pb concentration in two species of the benthic macroalgae Sargassum from northern Gulf, also known as the ROPME Sea Area (RSA). Within the marine environment, (210)Po is initially absorbed from water and concentrated by phytoplankton and macroalgae, and this concentrated (210)Po can then readily be passed along to the higher trophic level of the marine food web. The (210)Po concentration measured in Sargassum boveanum (22.5-25.6 Bq kg(-1)) was higher than that in Sargassum oligocystum (20.2-22.5 Bq kg(-1)), but is not statistically significant (p>0.064), where as the difference between (210)Pb concentrations in Sargassum boveanum (15.3-16.8 Bq kg(-1)) and Sargassum oligocystum (18.4-22.0 Bq kg(-1)) was statistically significant (p>0.019). The measured concentration factor for (210)Po in Sargassum in the northern Gulf varied between 0.55 and 1.2*10(4), values higher to the IAEA recommended value of 1*10(3). The (210)Po enrichment is observed in both the species of Sargassum,(210)Po/(210)Pb ratio was >1 at all the stations for all the samples. PMID- 25440189 TI - A comparative study of marine litter on the seafloor of coastal areas in the Eastern Mediterranean and Black Seas. AB - In the present work, abundance, spatial distribution and qualitative composition, of benthic marine litter, were investigated in five study areas from the Eastern Mediterranean and Black Seas (Saronikos, Patras and Echinades Gulfs; Limassol Gulf; Constanta Bay). Surveys were performed using the monitoring protocol proposed by the Technical Group for Marine Litter. Densities ranged from 24items/km(2) to 1211items/km(2), with the Saronikos Gulf being the most affected area. Plastics were predominant in all study areas ranging from 45.2% to 95%. Metals and Glass/Ceramics reached maximum values of 21.9% and of 22.4%. The size distribution of litter items showed that ?50% fall into medium size categories (10*10cm, 20*20cm) along with an elevated percentage of small-sized (<5*5cm) plastic litter items. The comparative analysis of the data highlighted the dependence of the marine litter problem on many local factors (human sources and oceanographic conditions) and the urgent need for specific actions. PMID- 25440190 TI - Unexpected abundance and long-term relative stability of the brown alga Cystoseira amentacea, hitherto regarded as a threatened species, in the north western Mediterranean Sea. AB - Cystoseira amentacea is a Mediterranean endemic alga thriving on very shallow rocky substrates. It has been considered as a threatened species, having experienced a steady decline and is therefore protected by international conventions. The historical distribution of the species has been assessed along the French Mediterranean coast, on the basis of 467 articles and herbarium vouchers. We have produced an accurate map of its current distribution and abundance along 1832 km of coastline, through in situ surveys. C. amentacea was observed along 1125 km of shoreline, including 33% of almost continuous or continuous belt. In most of its range, there is no evidence of loss, except in 4 areas of Provence, French Riviera and Corsica. A significant relation was found between the absence or low abundance of C. amentacea and the vicinity of ports and large sewage outfalls. The status of conservation of the species should therefore be reassessed. PMID- 25440191 TI - PCB concentrations in plankton size classes, a temporal study in Marseille Bay, Western Mediterranean Sea. AB - PCB levels in plankton were investigated in the Bay of Marseille, Western Mediterranean Sea, between September 2010 and October 2011. Concentrations of PCB congeners (CB 18, CB 52, CB 101, CB 118, CB 138, CB 153, CB 180) were determined in three plankton size-classes (60-200, 200-500 and 500-1000MUm) together with different parameters: chlorophyll content, plankton dry-weight biomass, carbon and nitrogen stable isotope ratios and plankton-community structure. The ?PCB7 concentrations ranged between 14.2 and 88.1ngg(-1)d.w., for all size classes and all sampling periods. The results do not show the biomass dilution effect and indicate moderate but significant biomagnification with plankton trophic position estimated by delta(15)N signatures. Equilibrium with water phase may notably contribute in controlling the PCB levels in the plankton. More generally, presented results imply that PCB accumulation in the plankton is an effect of abiotic and trophic complex interactions in the Bay of Marseille. PMID- 25440192 TI - Responses of calcification of massive and encrusting corals to past, present, and near-future ocean carbon dioxide concentrations. AB - In this study, we report the acidification impact mimicking the pre-industrial, the present, and near-future oceans on calcification of two coral species (Porites australiensis, Isopora palifera) by using precise pCO2 control system which can produce acidified seawater under stable pCO2 values with low variations. In the analyses, we performed Bayesian modeling approaches incorporating the variations of pCO2 and compared the results between our modeling approach and classical statistical one. The results showed highest calcification rates in pre-industrial pCO2 level and gradual decreases of calcification in the near-future ocean acidification level, which suggests that ongoing and near-future ocean acidification would negatively impact coral calcification. In addition, it was expected that the variations of parameters of carbon chemistry may affect the inference of the best model on calcification responses to these parameters between Bayesian modeling approach and classical statistical one even under stable pCO2 values with low variations. PMID- 25440193 TI - Macrodebris and microplastics from beaches in Slovenia. AB - The amount of marine debris in the environment is increasing worldwide, which results in an array of negative effects to biota. This study provides the first account of macrodebris on the beach and microplastics in the sediment (shoreline and infralittoral) in relation to tourism activities in Slovenia. The study assessed the quality and quantity of macrodebris and the quality, size and quantity of microplastics at six beaches, contrasting those under the influences of tourism and those that were not. Beach cleanliness was estimated using the Clean Coast Index. Tourism did not seem to have an effect on macrodebris or microplastic quantity at beaches. Over 64% of macrodebris was plastic, and microplastics were ubiquitous, which calls for classification of plastics as hazardous materials. Standard measures for marine debris assessment are needed, especially in the form of an all-encompassing debris index. Recommendations for future assessments are provided for the Adriatic region. PMID- 25440194 TI - Biodegradation of nitrobenzene in a lysogeny broth medium by a novel halophilic bacterium Bacillus licheniformis. AB - The Bacillus licheniformis strain YX2, a novel nitrobenzene-degrading halophilic bacterium, was isolated from active sludge obtained from a pesticide factory. Strain YX2 can withstand highly acidic and alkaline conditions and high temperatures. Degradation of nitrobenzene (200mgL(-1)) by YX2 exceeded 70% after 72h in lysogeny broth medium (pH 4-9). Under optimal degradation conditions (33 degrees C, pH 7 in LB medium) YX2 degraded 50, 100, 200, and 600mgL(-1) nitrobenzene within 36, 36, 72, and 156h, respectively. Even in the presence of benzene, phenol or aniline, strain YX2 efficiently degraded nitrobenzene. Furthermore, strain YX2 completely degraded 600mgL(-1) nitrobenzene in 7% NaCl (w/w). Thus, our data show that strain YX2 may have promise for removing nitrobenzene from complex wastewaters with high salinity and variable pH. PMID- 25440195 TI - Temporal trends and bioavailability assessment of heavy metals in the sediments of Deception Bay, Queensland, Australia. AB - Thirteen sites in Deception Bay, Queensland, Australia were sampled three times over a period of 7 months and assessed for contamination by a range of heavy metals, primarily As, Cd, Cr, Cu, Pb and Hg. Fraction analysis, enrichment factors and Principal Components Analysis-Absolute Principal Component Scores (PCA-APCS) analysis were conducted in order to identify the potential bioavailability of these elements of concern and their sources. Hg and Te were identified as the elements of highest enrichment in Deception Bay while marine sediments, shipping and antifouling agents were identified as the sources of the Weak Acid Extractable Metals (WE-M), with antifouling agents showing long residence time for mercury contamination. This has significant implications for the future of monitoring and regulation of heavy metal contamination within Deception Bay. PMID- 25440197 TI - Reduced stimulation and pain management: general and manual. PMID- 25440196 TI - Assessing PAHs pollution in Qingdao coastal area (China) by the combination of chemical and biochemical responses in scallops, Chlamys farreri. AB - The PAHs concentrations in seawater and tissues from the scallop Chlamys farreri were detected in three sites in Qingdao, China in 2011. The PAHs concentrations in seawater ranged from 25.32 ng/L to 314.62 ng/L. There were significant differences (p<0.05) between the residual levels among scallop tissues. The highest concentrations of PAHs in seawater and tissues were found in S2. The ethoxyresorufin-O-deethylase (EROD) activity of the digestive gland and the malondialdehyde (MDA) contents of the digestive gland and gill were sensitive to PAHs (p<0.05). This study integrated the PAHs concentrations in seawater, residual levels, the variation of biochemical response and the correlation coefficient analysis, and concluded that Qingdao is a medium PAH-contaminated area on a global scale. The highest PAHs were accumulated in the digestive gland followed by the gill, soft tissue and adductor muscle. The EROD activity of the digestive gland and the MDA contents of the digestive gland and gill could be applied to assess the PAHs pollution status in Qingdao, China. PMID- 25440198 TI - Idiopathic scoliosis: the tethered spine II: post-surgical pain. AB - The treatment of severe chronic pain in young people following surgery for the correction of curvatures of idiopathic scoliosis (IS) is presented through two case histories. Effective treatment involved release of myofascial trigger points (TrPs) known to refer pain into the spine, and treatment of related fascia and joint dysfunction. The TrPs found to be contributing to spinal area pain were located in muscles at some distance from the spine rather than in the paraspinal muscles. Referred pain from these TrPs apparently accounted for pain throughout the base of the neck and thoracolumbar spine. Exploratory surgery was considered for one patient to address pain following rod placement but the second surgery became unnecessary when the pain was controlled with treatment of the myofascial pain and joint dysfunction. The other individual had both scoliosis and hyperkyphosis, had undergone primary scoliosis surgery, and subsequently underwent a second surgery to remove hardware in an attempt to address her persistent pain following the initial surgery (and because of dislodged screws). The second surgery did not, however, reduce her pain. In both cases these individuals, with severe chronic pain following scoliosis corrective surgery, experienced a marked decrease of pain after myofascial treatment. As will be discussed below, despite the fact that a significant minority of individuals who have scoliosis corrective surgery are thought to require a second surgery, and despite the fact that pain is the most common reason leading to such revision surgery, myofascial pain syndrome (MPS) had apparently not previously been considered as a possible factor in their pain. PMID- 25440199 TI - British fascia symposium: review. PMID- 25440200 TI - Whether lidocaine or dry needling should be the favored treatment after meta analysis. PMID- 25440201 TI - The effect of trunk coordination exercise on dynamic postural control using a Core Noodle. AB - OBJECTIVE: To investigate the influence of trunk coordination exercise on dynamic postural control relative to postural sway. METHOD: The effects of trunk coordination exercises were examined using a Core Noodle for the postural sway in healthy students who were assigned to an exercise or control group. The independent variable was the extent of exposure to Core Noodle exercise, and the dependent variable was dynamic postural control. A stabilometer, which measures dynamic postural control, was used to evaluate the effectiveness of the exercises. In addition, center of gravity movements were assessed using a Gravicorder G-620 stabilometer in which the subject was asked to shift their center of gravity between 2 circles on a computer monitor. Pre- and post intervention dynamic postural control was statistically evaluated between the exercise group and control group using the Mann-Whitney test. Finally, we investigated the application of these exercises for a stroke patient. RESULTS AND CONCLUSION: For post-intervention, the envelop area, mean length of the pathways between 2 circles, and the number of circles were significantly higher in the exercise group. Trunk coordination exercise performed Core Noodle may be used to enhance the dynamic postural balance of healthy young adults, and it can also be adapted for stroke patients. PMID- 25440202 TI - Effects of a training program based on the proprioceptive neuromuscular facilitation method on post-stroke motor recovery: a preliminary study. AB - This preliminary study sought to analyze the effects of a training program based on the Proprioceptive Neuromuscular Facilitation (PNF) method on motor recovery of individuals with chronic post-stroke hemiparesis. Eleven individuals with chronic hemiparesis (mean lesion time of 19.64 months) after unilateral and non recurrent stroke underwent training based on PNF method for twelve sessions, being evaluated for motor function - using the Stroke Rehabilitation Assessment of Movement (STREAM) instrument; functionality, by the Functional Independence Measure (FIM); and gait kinematic (using the Qualisys Motion Capture System), at baseline and post-training. Significant changes in FIM (from median 67 to median 68; P = .043) and STREAM scores (from median 47 to median 55; P = .003) were observed. Data showed significant changes in motor function and functionality after training, suggesting that this program can be useful for rehabilitation of chronic stroke survivors. PMID- 25440203 TI - Effects of non-surgical joint distraction in the treatment of severe knee osteoarthritis. AB - PURPOSE: The aim of this study was to evaluate the clinical results of non surgical knee distraction in patients with severe knee osteoarthritis. METHOD: forty female patients with severe knee osteoarthritis were randomly divided in two groups. A standard physiotherapy treatment was applied to both groups and in one group it was accompanied with 20 min knee joint distraction. The patients were treated for 10 sessions. Clinical examination consisted of functional examination, completion of a quality of life questionnaire, pain scale, and assessment of joint mobility and joint edema. RESULT: The standard physiotherapy treatment accompanied by knee distraction resulted in significantly higher improvement in pain (P = 0.004), functional ability (P = 0.02), quality of life (P = 0.002) and knee flexion range of motion (p = 0.02) compared to the standard physiotherapy treatment alone post treatment and after 1 month follow up. CONCLUSION: Adding knee distraction to standard physiotherapy treatment can result in further improvement in pain relief, increased functional ability and better quality of life in patients with severe knee osteoarthritis. PMID- 25440204 TI - Differences and similarities in postural alterations caused by sadness and depression. AB - The present study investigated the existence of a relationship between depression and body posture in 40 women, aged between 20 and 30 years, who had normal body mass indices (or were underweight) and absence of neurological, psychiatric, or musculoskeletal disorders. The aim of the present study was to investigate the existence of a relationship between sadness, depression and the posture represented by the angle of Tales, head inclination, shoulder inclination, and forward head and shoulder protrusion. The degree of depression was rated on analogue scales representing current and usual depression and current and usual sadness and by the Beck Depression Inventory. The results indicated that a relationship exists between: Beck depression and the angle of Tales (p = 0.01), current depression and inclination of the head (p = 0.05) and inclination of the shoulders (p = 0.006), and usual depression and protrusion of the shoulder (p = 0.02). Inclination of the shoulders is associated with current sadness (p = 0.03; r = 0.443) and usual sadness (p = 0.04; r = 0.401). Usual sadness is also associated with protrusion of the shoulder (p = 0.05; r = 0.492). No associations were found with protrusion of the head and the emotional variables assessed. The conclusion was that depression and sadness might possibly change posture. Consequently, postural assessment and treatment may assist in diagnosing and treating depression. PMID- 25440205 TI - Lower thoracic syndrome - a differential screen for back pain following vertical compression injury: a case report. AB - A 36-year-old male experienced left sided back and radiating flank pain, following a fall on his buttock. A detailed medical evaluation ruled out the presence of red flags. Initial examination revealed positive findings of comparable local tenderness over the left T11, T12 and left paraspinal area, and a 2 cm shortening of the left leg. 8 treatment visits for a period of 4 weeks addressed mechanical dysfunction at the T11, T12, lumbar and pelvic region, comprising manual therapy, therapeutic exercise and pain relieving modalities. Reduction of local tenderness, back and radiating flank pain was observed. Additionally, resolution of the persistent apparent shortening of his left leg was observed, following a high velocity thrust (HVT) manipulation of the T11, T12 segments. The vertebral motion segment of T11, T12, the thoracoabdominal nerves, the 12th rib, the quadratus lumborum and the serratus posterior inferior are speculated to be potential symptom mediators. The findings in the case report suggest the lower thoracic region to be included during the evaluation process of back pain, especially when the mechanism of injury is a vertical compression. PMID- 25440206 TI - The Happy Antics programme: Holistic exercise for people with dementia. AB - BACKGROUND: Holistic exercise for people with dementia could have psychological and physical benefits, but there is a lack of research on the experience of this type of exercise. Therefore, the objective of this study was to determine the feasibility and acceptance of holistic exercise among people with dementia. METHOD: A holistic exercise programme for people with dementia was designed and implemented. Semi-structured interviews were undertaken to explore participants' experience of holistic exercise, transcribed verbatim and analyzed. RESULTS: Seven themes were generated from the data. They were enjoyment, relaxation, keeping active, social interaction, pain relief, learning something new and intention to continue, respectively. CONCLUSION: The results of the current small scale study provide evidence for the feasibility and acceptance of holistic exercise for people with dementia. In addition, participants appeared to benefit in terms of psychological and physical wellbeing. PMID- 25440207 TI - Effects of yoga on arm volume among women with breast cancer related lymphedema: A pilot study. AB - Lymphedema affects 3-58% of survivors of breast cancer and can result in upper extremity impairments. Exercise can be beneficial in managing lymphedema. Yoga practice has been minimally studied for its effects on breast cancer related lymphedema (BCRL). The purpose of this study was to determine the effect of yoga on arm volume, quality of life (QOL), self-reported arm function, and hand grip strength in women with BCRL. Six women with BCRL participated in modified Hatha yoga 3*/week for 8 weeks. Compression sleeves were worn during yoga sessions. Arm volume, QOL, self-reported arm function, and hand grip strength were measured at baseline, half-way, and at the conclusion of yoga practice. Arm volume significantly decreased from baseline (2423.3 ml +/- 597.2) to final measures (2370.8 ml +/- 577.2) (p = .02). No significant changes in QOL (p = .12), self reported arm function (p = .34), or hand grip strength (p = .26) were found. Yoga may be beneficial in the management of lymphedema. PMID- 25440208 TI - Inadvertent recovery in communication deficits following the upper limb mirror therapy in stroke: A case report. AB - Broca's aphasia is the most challenging communication deficit in stroke. Left inferior frontal gyrus (IFG), a key region of the mirror-neuron system, gets lesioned in Broca's aphasia. Mirror therapy (MT), a form of action-observation, may trigger the mirror neurons. The aim of this study was to report a case of poststroke subject with Broca's aphasia, who exhibited an inadvertent and significant improvement in speech after MT for the paretic upper limb. The 20 month old stroke patient underwent MT through goal-directed tasks. He received a total absence of spontaneous speech, writing, and naming. After 45 sessions of task-based MT for the upper limb, he showed tremendous recovery in expressive communication. He had fluent and comprehensive communication; however, with a low pitch and minor pronunciation errors. He showed a substantial change (from 18/100 to 79/100) on the Communicative Effective Index, particularly, on items such as expressing emotions, one-to-one conversation, naming, and spontaneous conversation. PMID- 25440209 TI - Upper cervical mobility, posture and myofascial trigger points in subjects with episodic migraine: Case-control study. AB - OBJECTIVES: To evaluate the association between episodic migraines and the prevalence of myofascial trigger points (MTrPs) in the sternocleidomastoid and upper trapezius, forward head posture (FHP), neck range of motion (ROM) and cervical facet joint stiffness. METHODS: 20 physiotherapy students with episodic migraines and 20 age- and sex matched healthy controls were included in this observational case-control study. Demographics and headache status were evaluated through questionnaires. Active neck ROM, presence of MTrPs, and cervical facet joint mobility were assessed by physical examination. FHP was measured using a lateral digital photograph taken in a sitting position. RESULTS: No significant differences were found in neck ROM measurements and FHP between the migraine and control groups. Significant differences were found in the prevalence of cervical facet joints stiffness in Occiput-C1 (chi(2) = 4.444, p = 0.035) and C1-C2 (chi(2) = 10.157, p = 0.001), but not in other segments. Significant differences were found in the prevalence of active and latent MTrPs between the migraine and control subjects in the right trapezius (chi(2) = 11.649, p = 0.003) and right sternocleidomastoid (chi(2) = 8.485, p = 0.014). CONCLUSIONS: Our findings support the hypothesis that the prevalence of MTrPs in neck muscles and hypomobility in the upper cervical facet joints are associated with migraines. PMID- 25440210 TI - Treatment of tension-type headache with articulatory and suboccipital soft tissue therapy: A double-blind, randomized, placebo-controlled clinical trial. AB - This study researches the effectiveness of two manual therapy treatments focused on the suboccipital region for tension-type headache. A randomized double-blind clinical trial was conducted over a period of four weeks with a follow-up at one month. Eighty-four patients with a mean age of 39.7 years (SD 11.4) with tension type headache were assigned to 4 groups which included the following manual therapy treatment: suboccipital soft tissue inhibition; occiput-atlas-axis global manipulation; combination of both techniques; and a control group. The primary assessment consisted of collecting socio-demographic data and headache characteristics in a one-month base period, data such as age, gender, severity of pain, intensity and frequency of headache, among other. Outcome secondary assessment were: impact of headache, disability, ranges of motion of the craniocervical junction, frequency and intensity of headache, and pericranial tenderness. In the month prior to the study, average pain intensity, was rated at 6.49 (SD 1.69), and 66.7% subjects suffered headaches of moderate intensity. After 8 weeks, statistically significant improvements were noted. OAA manipulative treatment and combined therapy treatments proved to be more effective than suboccipital soft tissue inhibition for tension-type headache. The treatment with suboccipital soft tissue inhibition, despite producing less significant results, also has positive effects on different aspects of headache. PMID- 25440211 TI - Towards a Rosetta Stone of manual therapeutic methodology. PMID- 25440212 TI - Natale et. al.'s response to Stecco's fascial nomenclature editorial. AB - Despite their importance in anatomy, physiology, pathology and surgery, the fasciae and the fascial spaces have been poorly described in classic textbooks. This little attention depends on the fact that these fasciae vary in thickness and composition, especially at the cervical level. Indeed, in the main literature they have been described in different forms. Furthermore, the definition itself of the fascia is not consistent in a variety of authors. As a consequence, different criteria have been used to define and classify the fascial systems. In this paper, a brief terminological history and the most common nomenclatures and classifications of the fascia have been summarized. PMID- 25440213 TI - Kumka's response to Stecco's fascial nomenclature editorial. PMID- 25440214 TI - Myers' response to Tozzi's editorial. PMID- 25440215 TI - Influence of instrument assisted soft tissue treatment techniques on myofascial trigger points. AB - OBJECTIVE: The purpose of this study was to examine the influence of instrument assisted soft tissue techniques (IASTT) on myofascial trigger points (MTrP). DESIGN: Randomized, controlled study with the researcher assessing the MTrP sensitivity blinded to the treatment rendered. PARTICIPANTS: Phase 1 = 27; Phase 2 = 22. INTERVENTION: MTrPs were identified in the upper back. In phase 1, two MTrPs (right & left) were identified. One was treated with IASTT, the other was a control. In phase 2, one MTrP was identified in a treatment and a control group. In each phase, the treatment groups received six treatments of IASTT. OUTCOME MEASURES: Sensitivity threshold of the MTrP was assessed with a dolorimeter. RESULTS: There was a significant improvement in both groups over time but there was no difference between the treatment and control groups. CONCLUSIONS: The use of a pressure dolorimeter may have served as a form of ischemic compression treatment. This assessment tool may have been a mitigating factor in the over shadowing any potential influence of the IASTT on the MTrP. Thus, another assessment tool needs to be identified for MTrP assessment. Until that technique is identified, the effect of IASTT on MTrPs in inconclusive. PMID- 25440216 TI - Fascial Manipulation((r)) method applied to pubescent postural hyperkyphosis: A pilot study. AB - BACKGROUND: Treatment of pubescent postural hyperkyphosis commonly includes postural exercises and auto-elongation. Myofascial imbalances can be involved in functional, sagittal plane deviations of spinal curves. This pilot-study assesses the effects of one manual therapy approach that addresses fascial dysfunctions (Fascial Manipulation((r))) in pubescent subjects with postural hyperkyphosis. METHODS: 17 subjects (mean age 11.8 DS 0.8; 9 males, 8 females) were evaluated for familiarity; psychological aspects; sport; pain; anteposition of shoulders, head, and pelvis; distance C7 and L3 from plumb-line; distance fingers to floor on forward bend. Each subject received 2-4 weekly sessions of Fascial Manipulation((r)). Parameters were evaluated before and after manual treatment, with a follow-up at 7 months. RESULTS: A statistically significant difference (p < 0.05) was present in all the parameters analysed before and after treatment and at a 7 month follow-up. CONCLUSIONS: Results suggest that Fascial Manipulation((r)) could represent an approach to integrate into treatment of postural hyperkyphosis in pubescent subjects. PMID- 25440217 TI - The middle crossed syndrome - New insights into core function. PMID- 25440218 TI - Assessing and correcting the middle crossed syndrome. PMID- 25440219 TI - Immediate improvements in activation amplitude levels of the deep abdominal muscle following a sacroiliac joint manipulation during rapid upper limb movement. AB - OBJECTIVE: To assess the immediate effects on the electrical activity of the transversus abdominis/internal oblique (TrA/IO) muscle during rapid voluntary upper limb movements before and after a sacroiliac joint (SIJ) manipulation. METHODS: Twenty healthy subjects who had innominate fixation, assessed by standing flexion test, were recruited. All subjects were submitted to SIJ manipulation and the TrA/IO muscles were evaluated bilaterally, before and after the procedure, through surface electromyography while ten random rapid upper limb flexions or abductions were performed. Normality was accepted, and the paired t test was used to determine data differences (p < 0.05). The correlations were calculated using Pearson correlation coefficient. RESULTS: All subjects presented an increase of SIJ mobility after manipulation (negative standing flexion test). Significant differences in muscle activation were noted to ipsi- and contralateral TrA/IO recruitment, prior to (A1) and after (A2) the manipulation. The A2 data were statistically greater than those in the A1. The Pearson coefficient revealed a strong correlation between the TrA/IO side and the increase in muscle activation amplitude level. Also, the data showed a moderate to strong correlation between this last variable and the moments of evaluation. CONCLUSION: The SIJ manipulation immediately improved the electrical activity of the TrA/IO muscle during rapid voluntary upper limb movements, suggesting improved segment stability and an increment to the afferent stimuli in order to affect the motor response. PMID- 25440220 TI - Lumbopelvic muscle activation patterns in three stances under graded loading conditions: Proposing a tensegrity model for load transfer through the sacroiliac joints. AB - PURPOSE: According to the conventional arch model of the pelvis, stability of the sacroiliac joints may require a predominance of form and force closure mechanisms: the greater the vertical shear force at the sacroiliac joints, the greater the reliance on self-bracing by horizontally or obliquely oriented muscles (such as the internal oblique). But what happens to the arch model when a person stands on one leg? In such cases, the pelvis no longer has imposts, leaving both the arch, and the arch model theory, without support. Do lumbopelvic muscle activation patterns in one-legged stances under load suggest compatibility with a different model? This study compares lumbopelvic muscle activation patterns in two-legged and one-legged stances in response to four levels of graded trunk loading in order to further our understanding the stabilization of the sacroiliac joints. METHODS: Thirty male subjects experienced four levels of trunk loading (0%, 5%, 10% and 15% of body weight) by holding a bucket at one side, at three conditions: 1) two-legged standing with the bucket in the dominant hand, 2) ipsilateral loading: one-legged standing with the bucket in the dominant hand while using the same-side leg, and 3) contralateral loading: one-legged standing using the same leg used in condition 2, but with the bucket in the non dominant hand. During these tasks, EMG signals from eight lumbopelvic muscles were collected. ANOVA with repeated design was performed on normalized EMG's to test the main effect of load and condition, and interaction effects of load by condition. RESULTS: Latissimus dorsi and erector spinae muscles showed an antagonistic pattern of activity toward the direction of load which may suggest these muscles as lateral trunk stabilizers. Internal oblique muscles showed a co activation pattern with increasing task demand, which may function to increase lumbopelvic stability (P < 0.05). No unilateral pattern of the internal obliques was observed during all trials. CONCLUSIONS: Our results suggest that the lumbopelvic region uses a similar strategy for load transfer in both double and single leg support positions which is not compatible with the arch analogy. Our findings are more consistent with a suspensory system (wire-spoke wheel model). If our proposed model holds true, the pelvic ring can only be integrated by adjusting tension in the spokes and by preserving rim integrity or continuity. Thus, we propose that in order to restore tension integrity throughout the pelvic ring, efforts to unlock restrictions, muscular correction of positional faults and lumbopelvic or even respiratory exercises following sacroiliac joint dysfunctions must be taken into consideration. Our hypothetical model may initiate thinking and act as a guide to future work based on a biomechanical approach to the problem of sacroiliac joint dysfunction. PMID- 25440221 TI - The low diagonal (oblique) sit exercise. PMID- 25440222 TI - Pathophysiological basis for compromised health beyond generations: role of maternal high-fat diet and low-grade chronic inflammation. AB - Early exposure to a fat-enriched diet programs the developmental profile and thus is associated with disease susceptibility in subsequent generations. Chronic low grade inflammation, resulting from maternal high-fat diet, is activated in the fetal environment and in many organs of offspring, including placenta, adipose, liver, vascular system and brain. The prevalence of an inflammatory response is highly associated with obesity incidence, cardiovascular diseases, nonalcoholic fatty liver disease and brain damage. Substantial studies using high-fat model have consistently demonstrated the incidence of such inflammatory reactions; however, the potential contribution of active inflammation toward the physiological outcomes and developmental diseases is neither discussed in depth nor systemically integrated. Therefore, we aim to summarize the current findings in regards to how a maternal high-fat diet influences the inflammatory status, and probable pathogenic effects on the offspring. More importantly, since limited research has been conducted to reveal the epigenetic regulation of these inflammatory markers by maternal high-fat diet, we sincerely hope that our review will not only outline the pathophysiological relevance of inflammation but also identify a future direction for mechanistic investigation and clinical application. PMID- 25440223 TI - Clinical use of microRNAs as potential non-invasive biomarkers for detecting non small cell lung cancer: a meta-analysis. AB - Emerging studies have revealed that microRNA (miRNA) in body fluid may serve as a potential biomarker to detect non-small cell lung cancer (NSCLC). However, the diagnostic accuracy of miRNA for NSCLC detection is still under debate because there is inconsistency in previous studies. Hence, we conducted this meta analysis to comprehensively evaluate the diagnostic performance of miRNA. A systematic literature search was performed to retrieve relevant articles in PubMed and other databases, and STATA 12.0 (StataCorp, College Station, TX, USA) was used to calculate the pooled parameters. A total of 28 articles involving 2121 NSCLC patients and 1582 healthy controls were included in this meta analysis. The overall pooled sensitivity and specificity of miRNA were 0.75 and 0.79, respectively. The pooled positive likelihood ratio was 3.6, negative likelihood ratio was 0.32 and diagnostic odds ratio was 12. The area under the curve (AUC) was 0.84. Subgroup and meta-regression analyses established that miRNA assays were more accurate in Caucasian populations (AUC of 0.86, sensitivity of 0.79 and specificity of 0.82, respectively) than in Asian populations (AUC, sensitivity and specificity of 0.83, 0.72 and 0.80, respectively). In addition, the multiple miRNA assays (AUC of 0.89, sensitivity of 0.83 and specificity of 0.82, respectively) showed a higher accuracy than single miRNA assays (AUC, sensitivity and specificity of 0.81, 0.77 and 0.71, respectively) in NSCLC detection. Subgroup analyses based on specimen types suggested that blood-based miRNA (AUC of 0.86, sensitivity of 0.78 and specificity of 0.80, respectively) may have a higher diagnostic accuracy as biomarkers than sputum-based miRNA (AUC of 0.81, sensitivity of 0.69 and specificity of 0.80, respectively). In conclusion, miRNA may serve as a potential biomarker in NSCLS detection, especially the multiple miRNA from blood, with a relatively high diagnostic accuracy. PMID- 25440224 TI - Assessing, monitoring and managing continuous intravenous sedation for critically ill adult patients and implications for emergency nursing practice: A systematic literature review. AB - BACKGROUND: Critically ill mechanically ventilated patients in ED have complex needs; chief among these is adequate sedation in addition to effective pain relief. Emergency nurses are increasingly responsible sedation and analgesia for this complex cohort of patients. The aim of this review was to examine (1) the evidence around assessing, monitoring and managing continuous intravenous sedation for critically ill adult patients, and (2) the implications for emergency nursing practice. STUDY DESIGN: Systematic review. METHOD: The review of literature extended from 1946 to 2013 and examined peer review journal articles, policy and guidelines to provide a more complex understanding of a phenomenon of concern. A total of 98 articles were incorporated and comprehensively examined. RESULTS: Analysis of the literature identified several implications for emergency nursing practice and the management of continuous intravenous sedation: workload, education, monitoring and assessing sedation and policy. CONCLUSION: Limited literature was found that directly addressed Australasian emergency nursing practices' in managing on-going intravenous sedation and analgesia for patients. Balancing patient sedation and analgesia requires highly complex knowledge, skills and expertise; the degree of education and training required is above that obtained during pre-registration nurse training. No state or national models of education or training were identified to support ED nurses' practices in managing sedation. Little research has addressed the safety of continuous sedation use in ED. PMID- 25440225 TI - Disaster nursing in Iran: challenges and opportunities. AB - BACKGROUND AND OBJECTIVE: Disaster nursing was one of the first forms of nursing practice in Iran, and nurses have long served voluntarily in disasters. Despite their key role throughout a disaster management cycle, few studies have examined nurses' unique role in the management of disasters in this region of the world. METHODS: An integrative narrative analysis of international research published in English and Persian studies between years 2000 and 2013 was conducted. RESULTS: Analysis of the 32 articles yielded two major: organisational and managerial challenges, and challenges linked to the educational system. The most significant factors linked to the role of nurses in disasters included the lack of identification of those who educated nurses to serve in critical conditions, defects in university's educational systems and lack of in-service training for nurses with regard to disasters. CONCLUSIONS: The integration of dedicate organisational units to educate human workforces, formalising a relationship between nursing staff and the disaster organisations, creative educational content, and effective economical systems to educate nurses may further enable disaster preparedness and response. PMID- 25440227 TI - In reply to: "Validating an HIV risk score". PMID- 25440226 TI - Congenital peripheral primitive neuroectodermal tumor: a case treated successfully with multimodality treatment. AB - Neonatal tumors comprise less than two percent of childhood malignancies. Most are solid tumors, most common histologies being teratoma and neuroblastoma. We encountered a child who was detected to have a right arm mass on antenatal sonogram, which was diagnosed to be a primitive neuroectodermal tumor involving the triceps on fine needle aspiration cytology performed in the post-natal period. The child was successfully treated with multimodality treatment consisting of surgery, chemotherapy and radiotherapy. We also discuss briefly the problems associated with therapy in neonatal period. A review of all cases reported to have congenital Ewing's sarcoma family of tumors is presented. Novel therapies are needed to improve efficacy and decrease the devastating side effects of treatment in this age group. PMID- 25440228 TI - Bilateral carotid and vertebral artery dissection: a life-threatening cause of postpartum headache. PMID- 25440229 TI - Intraosseous access learning curve; is it really practical? PMID- 25440230 TI - Prevention of emergency physician migratory contamination in a cluster randomized trial to increase tissue plasminogen activator use in stroke (the INSTINCT trial). AB - OBJECTIVES: Cluster randomized trials (CRTs) are increasingly used to evaluate quality improvement interventions aimed at health care providers. In trials testing emergency department (ED) interventions, migration of emergency physicians (EPs) between hospitals is an important concern, as contamination may affect both internal and external validity. We hypothesized that geographically isolating EDs would prevent migratory contamination in a CRT designed to increase ED delivery of tissue plasminogen activator (tPA) in stroke (the INSTINCT trial). METHODS: INSTINCT was a prospective, cluster randomized, controlled trial. Twenty four Michigan community hospitals were randomly selected in matched pairs for study. Contamination was defined at the cluster level, with substantial contamination defined a priori as greater than 10% of EPs affected. Nonadherence, total crossover (contamination+nonadherence), migration distance, and characteristics were determined. RESULTS: Three hundred seven EPs were identified at all sites. Overall, 7 (2.3%) changed study sites. One moved between control sites, leaving 6 (2.0%) total crossovers. Of these, 2 (0.7%) moved from intervention to control (contamination); and 4 (1.3%) moved from control to intervention (nonadherence). Contamination was observed in 2 of 12 control sites, with 17% and 9% contamination of the total site EP workforce at follow-up, respectively. Average migration distance was 42 miles for all EPs moving in the study and 35 miles for EPs moving from intervention to control sites. CONCLUSION: The mobile nature of EPs should be considered in the design of quality improvement CRTs. Increased reporting of contamination in CRTs is encouraged to clarify thresholds and facilitate CRT design. PMID- 25440232 TI - Comparison of 3 different intraosseous access devices for adult during resuscitation. Randomized crossover manikin study. AB - BACKGROUND: The study was designed to investigate the success rate and time of insertion intraosseous access during simulated resuscitation. MATERIAL AND METHODS: This was a randomized crossover study involving 107 paramedics. They were timed from start of insertion attempt to successful insertion and asked to score perceived difficulty of intraosseus access devices. Bone injection gun (BIG) (WaisMed Company, Houston, TX), EZ-IO (Vidacare, Shavano Park, TX) and Jamshidi (Carefusion, San Diego, CA) were used in this study. RESULTS: Success rates for first intraosseus iniecition attempt were higher for the BIG (91.59%) than EX-IO (82.66%) or Jamshidi (47.66%). Mean procedure time was 2.0+/-0.7 vs 3.1+/-0.9 minutes for EZ-IO vs 4.2+/-1.0 minutes for Jamshidi. CONCLUSIONS: The use of BIG is associated with excellent success rates for insertion and appears easier to use than EZ-IO or Jamshidi Intraosseus Needle. Further work to evaluate the use of the intraosseus access device in the emergency medical services is required. PMID- 25440231 TI - Pelvic ultrasonography and length of stay in the ED: an observational study. AB - OBJECTIVES: We compared emergency physician-performed pelvic ultrasonography (EPPU) with radiology department-performed pelvic ultrasonography (RPPU) in emergency department (ED) female patients requiring pelvic ultrasonography and their outcomes in relation to ED length of stay, ED readmission, and alternative diagnosis, within a 14-day follow-up period. METHODS: This was a prospective, observational study of female patients of reproductive age who required either an EPPU or RPPU for their ED evaluation. We hypothesized that patients receiving EPPU would have a length of stay reduction greater than or equal to 60 minutes, as compared with RPPU. Statistical analyses included an independent-samples t test and multivariate regression modeling to control for factors associated with ED LOS. RESULTS: Eighteen resident physicians performed EPPU, with 15 attending physicians supervising. Forty-eight patients received only EPPU, and 84 patients received only RPPU. In univariate analysis, those who received EPPU had an ED LOS 162 minutes less than those who received RPPU (95% confidence interval, 106-209 minutes). In multivariate analysis controlling for gynecologist consultation, disposition, and pregnancy status, patients who received EPPU had an ED LOS reduction of 108 minutes when compared with RPPU (95% confidence interval, 38-166 minutes). Five patients (10%) who had received EPPU and were discharged from the ED returned to the ED within 2 weeks, but none had alternative diagnoses. CONCLUSIONS: Patients with EPPU had statistically and clinically significant reductions in ED LOS, even when controlling for disposition, gynecologist consultation in the ED, and pregnancy status. No patients in the study had an alternative diagnosis within 2 weeks of EPPU. PMID- 25440233 TI - Anisakiasis presenting to the ED: clinical manifestations, time course, hematologic tests, computed tomographic findings, and treatment. AB - BACKGROUND: The prevalence of anisakiasis is rare in the United States and Europe compared with that in Japan, with few reports of its presentation in the emergency department (ED). This study describes the clinical, hematologic, computed tomographic (CT) characteristics, and treatment in gastric and small intestinal anisakiasis patients in the ED. METHODS: We retrospectively reviewed the data of 83 consecutive anisakiasis presentations in our ED between 2003 and 2012. Gastric anisakiasis was endoscopically diagnosed with the Anisakis polypide. Small intestinal anisakiasis was diagnosed based on both hematologic (Anisakis antibody) and CT findings. RESULTS: Of the 83 cases, 39 had gastric anisakiasis and 44 had small intestinal anisakiasis based on our diagnostic criteria. Although all patients had abdominal pain, the gastric anisakiasis group developed symptoms significantly earlier (peaking within 6 hours) than the small intestinal anisakiasis group (peaking within 48 hours), and fewer patients with gastric anisakiasis needed admission therapy (5% vs 57%, P<.01). All patients in the gastric and 40 (91%) in the small intestinal anisakiasis group had a history of raw seafood ingestion. Computed tomographic findings revealed edematous wall thickening in all patients, and ascites and phlegmon of the mesenteric fat were more frequently observed in the small intestinal anisakiasis group. CONCLUSIONS: In the ED, early and accurate diagnosis of anisakiasis is important to treat and explain to the patient, and diagnosis can be facilitated by a history of raw seafood ingestion, evaluation of the time-to-symptom development, and classic CT findings. PMID- 25440234 TI - Reversible common peroneal nerve palsy as a complication of therapeutic hypothermia using surface cooling device. PMID- 25440235 TI - Barriers and enablers to emergency department nurses' management of patients' pain. AB - Pain is the most common reason for presentation to the emergency department (ED). On presentation patients expect rapid pain relief, yet this is often not met. Despite extensive improvements in analgesia medication there are still barriers to nurses' assessment, management, documentation, and reassessment of pain. The aim of this study is to identify barriers, enablers, and current nursing knowledge regarding pain management. Using an anonymous quantitative web-based survey, members of the College of Emergency Nurses New Zealand were invited to complete a questionnaire on pain assessment and management. The questionnaires were analyzed using descriptive statistics. Enablers to ED nurses' improved management of pain were the provision of nurse-initiated analgesic protocols and pain management champions. Common barriers perceived by the respondents were the responsibility of caring for acutely ill patients as well as a patient with pain. Similar barriers to previous research were identified and included lack of time, workload, reluctance of clinicians to prescribe analgesia, and the lack of nursing knowledge regarding opioid administration. Raising awareness that oligoanalgesia exists in the ED is essential. This research suggested that nurses would benefit from ongoing education on the usage of opioids. Nurses' attitude regarding patients' right to expect total pain relief as a consequence of treatment was also an issue. ED nurses, by virtue of their role, are in a unique position to be leaders in pain assessment and pain management. PMID- 25440236 TI - The influence of providing perches and string on activity levels, fearfulness and leg health in commercial broiler chickens. AB - The aim of this study was to assess the effect of providing environmental enrichment in the form of perches and string on the behaviour and welfare of commercial broiler chickens. Houses containing ~23 000 broiler chickens were assigned to one of four treatments in a 2*2 factorial design. Treatments involved two levels of access to perches (P) (present (24/house) '+P' or absent '-P') and two levels of access to string (S) (present (24/house) '+S' or absent '-S'). All houses contained windows, and 30 straw bales were provided from day 10 of the rearing cycle. Treatments were applied in one of four houses on a single farm, and were replicated over four production cycles. Behaviour and leg health were observed in weeks 3 to 5 of the rearing cycle. Production performance and environmental parameters were also measured. There was an interaction between perches and age in the percentage of birds observed lying, with higher percentages of birds observed lying in the +P treatment than in the -P treatment during weeks 4 and 5. There was also a significant interaction between string and age in the percentage of birds observed in locomotion, with higher percentages observed in locomotion in the -S treatment than in the +S treatment during weeks 4 and 5. There was also an interaction between string and age in average gait scores, with lower gait scores in the +S treatment than in the -S treatment during weeks 3 and 5 but not within week 4. Daytime observations showed that perches and strings were used frequently, with one bout of perching occurring approximately every 80 s/perch, and one bout of pecking at string occurring every 78 s/string on average. There was a significant effect of age on use of perches (P<0.001) and string (P<0.001), with perching peaking during week 5 and string pecking peaking during week 3. We conclude that commercial broilers in windowed houses with access to straw bales display an interest in additional enrichment stimuli in the form of perches and string, and therefore that these stimuli have the potential to improve welfare. In addition, provision of string as a pecking device appeared to positively influence walking ability. However, this effect was numerically small, was only shown in certain weeks and was not reflected in the other leg health measure (latency to lie). The results also showed an apparent negative effect of string and perches on the activity levels of birds (recorded away from the immediate vicinity of these enrichments) towards the end of the production cycle. These results emphasise the need for further research into optimum design and layout of enrichment stimuli for modern broilers in windowed houses to ensure that their provision leads to clear welfare benefits. PMID- 25440237 TI - Philosophers are doing something different now: quantitative data. AB - The philosophical study of mind in the twentieth century was dominated by a research program that used a priori methods to address foundational questions. Since that time, however, the philosophical study of mind has undergone a dramatic shift. To provide a more accurate picture of contemporary philosophical work, I compared a sample of highly cited philosophy papers from the past five years with a sample of highly cited philosophy papers from the twentieth century. In the twentieth century sample, the majority of papers used purely a priori methods, while only a minority cited results from empirical studies. In the sample from the past five years, the methodology is radically different. The majority of papers cite results from empirical studies, a sizable proportion report original experimental results, and only a small minority are purely a priori. Overall, the results of the review suggest that the philosophical study of mind has become considerably more integrated into the broader interdisciplinary field of cognitive science. PMID- 25440261 TI - Epileptic focus localization based on resting state interictal MEG recordings is feasible irrespective of the presence or absence of spikes. AB - OBJECTIVE: To investigate whether epileptogenic focus localization is possible based on resting state connectivity analysis of magnetoencephalographic (MEG) data. METHODS: A multivariate autoregressive (MVAR) model was constructed using the sensor space data and was projected to the source space using lead field and inverse matrix. The generalized partial directed coherence was estimated from the MVAR model in the source space. The dipole with the maximum information inflow was hypothesized to be within the epileptogenic focus. RESULTS: Applying the focus localization algorithm (FLA) to the interictal MEG recordings from five patients with neocortical epilepsy, who underwent presurgical evaluation for the identification of epileptogenic focus, we were able to correctly localize the focus, on the basis of maximum interictal information inflow in the presence or absence of interictal epileptic spikes in the data, with three out of five patients undergoing resective surgery and being seizure free since. CONCLUSION: Our preliminary results suggest that accurate localization of the epileptogenic focus may be accomplished using noninvasive spontaneous "resting-state" recordings of relatively brief duration and without the need to capture definite interictal and/or ictal abnormalities. SIGNIFICANCE: Epileptogenic focus localization is possible through connectivity analysis of resting state MEG data irrespective of the presence/absence of spikes. PMID- 25440262 TI - Erythropoietin and glucose homeostasis in women at varying degrees of future diabetic risk. AB - AIMS/BACKGROUND: Recently, there has been considerable interest in the potential anti-diabetic effects of erythropoietin in animal models. It is not known, however, whether endogenous erythropoietin is associated with glucose regulation in humans. METHODS: We evaluated the longitudinal relationship between endogenous erythropoietin at 3-months postpartum and glucose homeostasis at 12-months postpartum in a cohort of 229 women with varying degrees of glucose intolerance in their recent pregnancy, a model of the early natural history of pre diabetes/diabetes. The women reflected the full spectrum of glucose tolerance in pregnancy from normal (n=63) to mildly abnormal (n=65) to gestational impaired glucose tolerance (n=46) to gestational diabetes (n=55), and hence a broad range of future diabetic risk. RESULTS: At 3-months postpartum, there was no difference in serum erythropoietin between these 4 groups (p=0.22). After covariate adjustment, erythropoietin was not associated with beta-cell function, insulin sensitivity, or glycemia at either 3- or 12-months postpartum. On multiple linear regression analyses, however, erythropoietin at 3-months emerged as an independent predictor of both systolic (beta=0.51326, p=0.003) and diastolic blood pressure (beta=0.3321, p=0.01) at 12-months. CONCLUSION: Endogenous erythropoietin is not associated with glucose homeostasis early in the natural history of metabolic disease, but may be relevant to vascular health. PMID- 25440263 TI - Choosing a screening tool to assess disordered eating in adolescents with type 1 diabetes mellitus. PMID- 25440264 TI - Aortopulmonary window and the interrupted aortic arch: midterm results with use of the single-patch technique. AB - BACKGROUND: An aortopulmonary window (APW) associated with an interrupted aortic arch (IAA) can be associated with significant rates of perioperative mortality and recurrent arch obstruction. We assessed the outcomes associated with the use of a single pericardial patch technique for primary repair. METHODS: Between 2002 and 2011, 9 neonates and 2 infants with APW and IAA underwent single-stage repair, under a hypothermic (28 degrees C) continuous cardiopulmonary bypass with antegrade selective cerebral perfusion. A single autologous pericardial patch (glutaraldehyde-fixed) was used both to augment the IAA end-to-side anastomosis and to close the APW by use of the "sandwich" technique. RESULTS: The IAA was type A in 6 patients and type B in 5 patients. The APW morphology was type I in 6 patients, type II in 4 patients, and type III in 1 patient. The median age and weight at operation were 11 days (range, 6 to 180 days) and 2.6 kg (range, 2.2 to 6.5 kg), respectively. The mean cardiopulmonary bypass and aortic cross-clamp times were 108.6 +/- 27.5 minutes and 49.3 +/- 13.4 minutes, respectively. One patient required additional closure of a ventricular septal defect. Delayed sternal closure was performed in 8 patients. The mean follow-up time was 6 +/- 3 years. There were no early and no late deaths. Postoperative morbidity consisted of one postoperative stroke with no late sequelae. There were no reoperations. The last follow-up visits confirmed the absence of recurrent aortic arch obstruction and pulmonary artery branch stenosis in all patients. CONCLUSIONS: Primary anatomic repair of APW associated with IAA can be safely performed. The efficiency of the single-patch technique was confirmed by the restoration of normal functional anatomy of the great arteries and aortic arch during follow-up. PMID- 25440265 TI - Effects of cell-saving devices and filters on transfusion in cardiac surgery: a multicenter randomized study. AB - BACKGROUND: Cell-saving devices (CS) are frequently used in cardiac surgery to reduce transfusion requirements, but convincing evidence from randomized clinical trials is missing. Filtration of salvaged blood in combination with the CS is widely used to improve the quality of retransfused blood, but there are no data to justify this approach. METHODS: To determine the contribution of CS and filters on transfusion requirements, we performed a multicenter factorial randomized clinical trial in two academic and four nonacademic hospitals. Patients undergoing elective coronary, valve, or combined surgical procedures were included. The primary end point was the number of allogeneic blood products transfused in each group during hospital admission. RESULTS: From 738 included patients, 716 patients completed the study (CS+filter, 175; CS, 189; filter, 175; neither CS nor filter, 177). There was no significant effect of CS or filter on the total number of blood products (fraction [95% confidence interval]: CS, 0.96 [0.79, 1.18]; filter, 1.17 [0.96, 1.43]). Use of a CS significantly reduced red blood cell transfusions within 24 hours (0.75 [0.61,0.92]), but not during hospital stay (0.86 [0.71, 1.05]). Use of a CS was significantly associated with increased transfusions of fresh frozen plasma (1.39 [1.04, 1.86]), but not with platelets (1.25 [0.93, 1.68]). Use of a CS significantly reduced the percentage of patients who received any transfusion (odds ratio [95% confidence interval]: 0.67 [0.49, 0.91]), whereas filters did not (0.92 [0.68, 1.25]). CONCLUSIONS: Use of a CS, with or without a filter, does not reduce the total number of allogeneic blood products, but reduces the percentage of patients who need blood products during cardiac surgery. PMID- 25440266 TI - Influences of chronic obstructive pulmonary disease on outcomes of total arch replacement. AB - BACKGROUND: Although an association between chronic obstructive pulmonary disease (COPD) and adverse surgical outcomes has been proposed, the impact of COPD severity on postoperative outcomes remains unclear. Our objective was to analyze the prognostic implication of COPD severity on outcomes after total aortic arch replacement. METHODS: Between October 1999 and December 2012, 269 patients undergoing total arch replacement through median sternotomy, who were elective cases with preoperative spirometry records, were retrospectively reviewed. Patients were divided into four groups: control group, with ratio of forced expiratory volume of air in 1 second (FEV1) to forced vital capacity (FVC) of 70% or greater; mild airflow obstruction, with FEV1/FVC ratio less than 70% and FEV1 80% or greater of predicted; moderate airflow obstruction, FEV1/FVC ratio less than 70% and FEV1 50% to 79% of predicted; severe airflow obstruction, FEV1/FVC ratio less than 70% and FEV1 less than 50% of predicted. Symptoms of functional dyspnea and disability were also assessed. Multivariate logistic and Cox regression methods were used to determine if there was an independent association between COPD and short-term and long-term outcomes, respectively. RESULTS: The in hospital mortality rate was 2.2% (6 of 269). A consistent trend of increasing frequency of postoperative respiratory complications with advanced airflow obstruction was noted. In multivariate analysis, in-hospital mortality (p = 0.022), incidence of respiratory complications (p = 0.021) and overall mortality (p = 0.025) was significantly associated with the symptoms of COPD, respectively. CONCLUSIONS: The severity of COPD as defined by spirometry and symptoms of functional dyspnea may be an important prognostic marker of patients undergoing total arch replacement. PMID- 25440267 TI - Increased time from neoadjuvant chemoradiation to surgery is associated with higher pathologic complete response rates in esophageal cancer. AB - BACKGROUND: The interval between neoadjuvant chemoradiation treatment and surgery has been described as an important predictor of pathologic response to therapy in nonesophageal cancer sites. We retrospectively reviewed our experience with patients who underwent neoadjuvant chemoradiation and esophagectomy to better understand the impact of the timing of surgery on pathologic complete response rates in esophageal cancer. METHODS: Two hundred thirty-one sequentially treated patients from 2000 to 2011 were identified for this study; 88 of these patients completed neoadjuvant chemoradiation followed by esophagectomy at our institution. The interval between completion of chemoradiation and surgery was calculated for each patient. The patients were categorized into quartiles and also into 3-week interval groups. Treatment factors and surgical morbidity data, including the estimated blood loss and length of operative stay, were also assessed. RESULTS: Quartiles for the neoadjuvant chemoradiation to surgery interval were less than 45 days, 46 to 50 days, 51 to 63 days, and 64+ days. Corresponding pathologic complete response rates were 12.5%, 20.0%, 22.7%, and 40.9% (p = 0.03). Results for 3-week intervals were similar (p = 0.02). There was no association between increasing time interval between the ending of neoadjuvant chemoradiation to surgery and length of stay longer than 2 weeks. CONCLUSIONS: A longer interval between completion of neoadjuvant chemoradiation and surgery was associated with higher pathologic complete response rates without an impact on surgical morbidity. PMID- 25440268 TI - An increased incidence of conduit endocarditis in patients receiving bovine jugular vein grafts compared to cryopreserved homograft for right ventricular outflow reconstruction. AB - BACKGROUND: We compared the outcome of patients receiving bovine jugular vein grafts versus cryopreserved homografts for right ventricular outflow tract reconstruction. METHODS: Between 2000 and 2012, 379 conduits (244 bovine jugular vein grafts, 135 homografts) were implanted in 298 patients (median age 50 months) with a median follow-up of 3.4 years. RESULTS: Freedom from reoperation at 1, 5, and 7 years was 96.3%, 79.3%, and 64.2% after bovine jugular vein graft and 94.6%, 75.7%, and 68.6% after homograft insertion (p = 0.086). There were 24 cases of endocarditis, 23 associated with bovine jugular vein grafts (9.4%) and 1 associated with a homograft (0.7%; p < 0.001) at median follow-up of 44 months (range, 15 days to 10 years) after conduit implantation. After endocarditis, 15 of 24 conduits were replaced. Three patients had recurrent endocarditis in the revised conduit. Multivariate logistic regression analysis showed age less than 3 years and endocarditis to be significant risk factors associated with conduit replacement. Age more than 3 years and bovine jugular vein grafts were significant risk factors for graft endocarditis. Patients more than 3 years of age at bovine jugular vein graft implantation had significantly lower freedom from reoperation (p = 0.01). CONCLUSIONS: Compared with homograft conduits, the use of bovine jugular vein grafts for right ventricular outflow tract reconstruction was associated with a significantly higher incidence of bacterial endocarditis and conduit deterioration in older children at our institution. That may influence decision making regarding conduit choice for right ventricular outflow tract reconstruction. Patients and practitioners should be aware of the late risks of bacterial endocarditis after bovine jugular vein graft implantation. PMID- 25440269 TI - Videothoracoscopy versus thoracotomy for the treatment of spontaneous pneumothorax: a propensity score analysis. AB - BACKGROUND: Few randomized controlled trials have been published on outcomes after treatment of spontaneous pneumothorax. The objective of this study was to assess recurrence, pulmonary complications, prolonged air leak, and hospital duration of stay in patients undergoing videothoracoscopic surgery (VATS) or thoracotomy for spontaneous pneumothorax. METHODS: From January 2005 to December 2012, 7,396 patients underwent operations for spontaneous pneumothorax and were entered into the French national database. The propensity score, which is the conditional probability of assignment to a particular treatment given a vector of observed covariates, was used for the analysis. Three statistical analyses were performed: matching, subclassification, and the inverse probability of treatment weighting. The primary end point was recurrence, defined as a pneumothorax requiring a chest tube or new operation. The secondary end point was pulmonary complications, prolonged air leak, and hospital duration of stay. RESULTS: VATS was performed in 6,419 patients and thoracotomy in 997 patients. Pleurodesis was performed by abrasion or pleurectomy in 5,873 patients (79%) and by using a chemical agent in 1,523 patients (21%). The median time to recurrence was 3 months (range, 1 to 76 months). The recurrence rate was higher in the VATS group regardless of the statistical analysis that was used: 2.1 for unmatched samples, 2.5 for matched samples, 2.3 for subclassification, and 1.7 for the inverse probability of treatment weighting. VATS significantly reduced the hospital duration of stay by 1 day but did not significantly reduce pulmonary complications or prolonged air leak. CONCLUSIONS: VATS reduced the hospital duration of stay, but the risk of recurrence was higher. This information should be delivered to patients before pneumothorax operations. PMID- 25440270 TI - Prognostic value of different lymph node staging methods in esophageal squamous cell carcinoma after esophagectomy. AB - BACKGROUND: This study aimed to investigate the prognostic value of number of involved lymph nodes, number of removed lymph nodes, ratio of involved to removed nodes (lymph node ratio), and number of negative lymph nodes in esophageal squamous cell carcinoma (ESCC) patients after esophagectomy. METHODS: A retrospective review of 603 patients receiving esophagectomy for ESCC was made. Cox regression analysis was performed to identify significant prognostic factors. RESULTS: The median follow-up time was 36.7 months, and the 5-year overall survival (OS) was 43.5%. Patients with negative lymph node count >= 14 had better survival (p < 0.001). Univariate Cox analysis showed that the number of involved lymph nodes, number of removed lymph nodes, lymph node ratio, and number of negative lymph nodes influenced OS (p < 0.05 for all). Multivariate Cox analysis indicated that the number of involved lymph nodes and number of negative lymph nodes were independent prognostic factors for OS, and a higher number of negative lymph nodes was associated with lower mortality. The number of removed lymph nodes and lymph node ratio had no significant effect on OS. The number of negative lymph nodes had prognostic value in different lymph node stages and in two-field or three-field lymphadenectomy. CONCLUSIONS: For ESCC patients after esophagectomy, the number of involved lymph nodes and the number of negative lymph nodes had a better prognostic value than did the number of removed lymph nodes and lymph node ratio. PMID- 25440271 TI - Unexpected lymph node disease in resections for pulmonary metastases. AB - BACKGROUND: Pulmonary metastasectomy is widely accepted for different malignant diseases. The role of mediastinal lymph node (LN) dissection in these procedures is discussed controversially. We evaluated our results of LN removal at the time of pulmonary metastasectomy with respect to the frequency of unexpected LN disease. METHODS: This was a retrospective analysis of 313 resections performed in 209 patients. Operations were performed in curative intention. Patients with known thoracic LN involvement and those without lymphadenectomy (n = 43) were excluded. Patients were analyzed according the type of LN dissection. Subgroups of different primary cancers were evaluated separately. RESULTS: Sublobar resections were performed in 256 procedures with lymphadenectomy, and 14 patients underwent lobectomy. Patients underwent radical lymphadenectomy (n = 158) or LN sampling (n = 112). The overall incidence of unexpected tumor in LN was 17% (radical lymphadenectomy, 15.8%; sampling, 18.8%). Unexpected LN involvement was found in 17 patients (35.5%) with breast cancer, in 120 (9.2%) with colorectal cancer, and in 53 (20.8%) with renal cell carcinoma. The 5-year survival was 30.2% if LN were tumor negative and 25% if positive (p = 0.19). LN sampling vs radical removal had no significant effect on 5-year survival (23.6% vs 30.9%; p = 0.29). CONCLUSIONS: Dissection of mediastinal LN in resection of lung metastases will reveal unexpected LN involvement in a relevant proportion of patients, in particular in breast and renal cancer. Routine LN dissection appears necessary and may become important for further therapeutic decisions. On the basis of our data, LN sampling seems to be sufficient. PMID- 25440272 TI - Now or later: evaluating the importance of chemotherapy timing in resectable stage III (N2) lung cancer in the National Cancer Database. AB - BACKGROUND: Preoperative chemotherapy improves the survival of surgically managed stage III non-small cell lung cancer (NSCLC). A proportion of stage III NSCLC patients in the United States have undergone operations primarily and been given chemotherapy postoperatively. It is unclear whether postoperative chemotherapy is as effective as preoperative chemotherapy. Our objective was to determine the survival of resected stage III NSCLC according to the timing of chemotherapy. METHODS: The National Cancer Database (NCDB) was queried for clinical T1-4N2M0 NSCLC (cstage III-cN2) undergoing lobectomy or pneumonectomy between 2003 and 2006. RESULTS: 1,356 patients with surgically managed cstage III-cN2 disease who received preoperative chemotherapy were compared with 649 patients receiving postoperative chemotherapy. In a Cox proportional hazards model with adjustment for demographics, comorbidities, and tumor attributes, the results of postoperative chemotherapy appeared similar to those of preoperative chemotherapy (hazard ratio [HR] = 1.05, 95% confidence interval [CI] 0.93-1.19, p = 0.438). In separate Cox models, the results of postoperative chemotherapy alone were similar to those of preoperative chemotherapy alone (HR = 1.106, 95% CI 0.91-1.344, p = 0.3124). The results of postoperative chemotherapy + radiation were similar to those of preoperative chemotherapy + radiation (HR = 1.125, 95% CI 0.949-1.333, p = -0.175). CONCLUSIONS: Adjusted comparison of preoperative and postoperative chemotherapy results for cstage III-N2 NSCLC in the NCDB failed to identify a superior chemotherapy approach. This suggests that a more rigorous examination of the widely held view that preoperative chemotherapy is superior may be warranted. PMID- 25440273 TI - Effect of timing and route of methylprednisolone administration during pediatric cardiac surgical procedures. AB - BACKGROUND: We compared the antiinflammatory and cardioprotective effects of the two most common regimens of corticosteroid administration in pediatric cardiac surgical procedures: a single dose delivered either at anesthesia induction or by cardiopulmonary bypass (CPB) prime. METHODS: Forty-five children, aged between 1 and 18 months and undergoing ventricular septal or atrioventricular septal defect correction, were randomized in double-blind fashion into three groups. The anesthesia induction group received 30 mg/kg methylprednisolone intravenously after anesthesia induction, and the CPB-prime group received 30 mg/kg methylprednisolone by CPB circuit. The placebo group received saline solution. Plasma concentrations of methylprednisolone, interleukin (IL)-6, IL-8 and IL-10, and troponin were measured at anesthesia induction before the study drug, 30 minutes on CPB, after patients were weaned from CPB, and 6 hours after cessation of CPB. RESULTS: Equally high methylprednisolone concentrations were detected in both methylprednisolone groups, but the measured peak concentration occurred earlier in the induction group. Significantly lower IL-8 concentrations were observed just after patients were weaned from and 6 hours after CPB in the anesthesia induction group compared with the placebo (p = 0.002, p = 0.001) and prime groups (p = 0.003, p = 0.006). Significant reductions of troponin were detected in both methylprednisolone groups compared with placebo (induction, p = 0.001; prime, p = 0.002) 6 hours after patients were weaned from CPB. CONCLUSIONS: Methylprednisolone administration at anesthesia induction was superior in terms of antiinflammatory action. Methylprednisolone administration in CPB-prime only a few minutes before aortic cross-clamping and cardioplegia resulted in mean troponin reductions similar to those of administration at anesthesia induction. Corticosteroids may have direct cardioprotective properties, as reported in experimental studies. PMID- 25440274 TI - Energetic implications of vessel growth and flow changes over time in Fontan patients. AB - BACKGROUND: As patients with a single-ventricle physiology age, long-term complications inherent to this population become more evident. Previous studies have focused on correlating anatomic and hemodynamic performance, but there is little information of how these variables change with time. Vessel growth and flow rate changes were quantified using cardiac magnetic resonance and their effects on hemodynamics were assessed, which could affect the long-term outcome. METHODS: Forty-eight patients with a lateral tunnel or extracardiac conduit Fontan who underwent two cardiac magnetic resonance scans (average interval, 5.1 +/- 2.3 years) were studied. Total cavopulmonary connection anatomic and flow variables were reconstructed and normalized to body surface area(1/2). Total cavopulmonary connection hemodynamic efficiency (indexed power loss) was obtained through computational fluid dynamic modeling. RESULTS: Absolute vessel diameters increased with time, normalized diameters decreased, and vessel mean flow rates remained unchanged. Indexed power loss changed significantly in the cohort, as well as in patients in whom the minimum normalized left pulmonary artery decreased. Age at first scan and connection type (lateral tunnel or extracardiac conduit) were not associated with changes in indexed power loss. CONCLUSIONS: We present the largest serial cardiac magnetic resonance Fontan cohort to date. Although flow rates increased proportionally to body surface area, vessel diameters did not match somatic growth. As a result, energy losses increased significantly with time in the cohort analyzed. PMID- 25440275 TI - Changes in pulmonary function in lung cancer patients after video-assisted thoracic surgery. AB - BACKGROUND: Video-assisted thoracoscopic surgery (VATS) is widely performed in patients with resectable non-small cell lung cancer. However, it is unknown whether VATS sublobar resection has advantages compared with VATS lobectomy in preserving pulmonary function. METHODS: Three hundred patients with non-small cell lung cancer who underwent VATS were enrolled. Pulmonary function tests were performed three times: preoperatively, and at 3 and 12 months postoperatively. Pulmonary function was compared between the VATS lobectomy group (n = 227) and the VATS sublobar resection group (n = 73). RESULTS: The VATS sublobar resection group had greater preserved pulmonary function than the VATS lobectomy group at 3 and 12 months postoperatively (p < 0.001). However, a VATS lobectomy of the right upper or right middle lobe revealed no difference in forced vital capacity ( 1.21% versus -1.45%; p = 0.88) or the diffusion capacity of carbon monoxide ( 3.99% versus -2.45%; p = 0.61) compared with VATS sublobar resection after 12 months. In those who underwent VATS of the right lower lobe, forced expiratory volume in 1 second (-8.60% versus -3.69%; p = 0.12) was not different between the two groups after 12 months. Video-assisted thoracoscopic surgery lobectomy of the left upper or left lower lobe resulted in lower pulmonary function than VATS sublobar resection (p < 0.05). CONCLUSIONS: Patients with non-small cell lung cancer who underwent VATS sublobar resection demonstrated greater pulmonary function than those who underwent VATS lobectomy. However, in right-side VATS lobectomy, some differences dissipated at 1 year. PMID- 25440276 TI - Unilateral postoperative pulmonary edema after minimally invasive cardiac surgical procedures: a case-control study. AB - BACKGROUND: Unilateral postoperative pulmonary edema is an underreported adverse event after a minimally invasive cardiac surgical procedure that combines right minithoracotomy with cardiopulmonary bypass. We sought to characterize its incidence, risk factors, and morbidity. METHODS: We conducted a retrospective case-control study of all cardiac surgical procedures that combined right-sided minithoracotomy with cardiopulmonary bypass at our institution over 8 consecutive years. Unilateral postoperative pulmonary edema was defined on the chest radiograph taken on the first postoperative day as relatively increased opacification of the right versus left hemithorax involving at least 20% of the hemithorax, not better explained by atelectasis. Baseline characteristics, potential risk factors, and outcomes were subject to univariable and multivariable analysis. RESULTS: Radiographs were available for 277 of 278 patients; of those, 68 (25%) met our definition of unilateral postoperative pulmonary edema. Patients with unilateral postoperative pulmonary edema had higher mortality and were more likely to have a lower postoperative PaO2/FIO2 ratio, to require vasoactive medications and mechanical ventilation for longer than 24 hours, and to have longer lengths of stay in the intensive care unit and the hospital. Unilateral postoperative pulmonary edema was independently associated with chronic obstructive pulmonary disease (odds ratio [OR] 4.79; 95% confidence interval [CI] 1.28 to 18.0; p = 0.02); pulmonary hypertension, right ventricular dysfunction, or both (OR 2.92; 95% CI 1.41 to 6.03; p = 0.004); and increasing cardiopulmonary bypass time (OR 1.019; 95% CI 1.011 to 1.027 per additional minute; p <0.001). CONCLUSIONS: Unilateral postoperative pulmonary edema after minimally invasive cardiac surgical procedures is common, carries significant morbidity, and has identifiable risk factors. Further research is needed to enable a better understanding of the pathophysiology and clinical implications of unilateral postoperative pulmonary edema. PMID- 25440277 TI - Long-term outcomes of wedge resection for pulmonary ground-glass opacity nodules. AB - BACKGROUND: We aimed to characterize ground-glass opacity (GGO) nodules and evaluate the prognosis of clinical stage IA lung adenocarcinoma with GGO nodules after wedge resection. METHODS: Patients who underwent wedge resection for early stage lung cancer and proven adenocarcinoma on postoperative pathologic report were enrolled in the study between 2004 and 2010. Radiologic findings of the main tumor were evaluated for ground-glass opacities with chest computed tomography (CT). We divided patients into two groups based on the consolidation-to-tumor ratio (C/T ratio <= 0.25, pure GGO group; C/T ratio > 0.25, mixed GGO group). Overall survival and recurrence-free survival were analyzed for all patients. RESULTS: A total of 97 patients were included in our study. Among these, 71 patients were categorized into the pure GGO group and 26 patients into the mixed GGO group. The 5-year overall survival rate was 98.6% in the pure GGO group and 95.5% in the mixed GGO group (p = 0.663). Five patients (5.1%) experienced recurrences; only 1 patient (1/71, 1.4%) in the pure GGO group and 4 patients (4/26, 15.3%) in the mixed GGO group had recurrence. CONCLUSIONS: GGO-dominant clinical stage IA lung adenocarcinoma (pure GGO group) showed an excellent prognosis. Wedge resection should be carefully considered for patients with mixed GGO nodules (C/T ratio >0.25) because of the high recurrence rate. Radiologic noninvasiveness (C/T ratio <= 0.25) might be a good indicator for candidates for sublobar resection in cases of early stage lung adenocarcinoma. PMID- 25440278 TI - Protective effects of pulsatile flow during cardiopulmonary bypass. AB - BACKGROUND: Children with congenital heart disease are often operated at a very young age. Cardiopulmonary bypass (CPB) has become indispensable for these sometimes very complex operations, but one cannot neglect a possible negative impact of CPB on organ function. Traditionally, CPB was developed with non pulsatile flow but there are clinical observations that pulsatile flow might be superior with improved patient outcomes. Therefore, we attempted to elucidate whether CPB with pulsatile flow preserves organ integrity compared with nonpulsatile flow. METHODS: We studied 27 piglets of 4 weeks age and divided them into 3 experimental groups: control group (no CPB); non-pulsatile and pulsatile CBP with 90-minutes CPB and 120-minutes recovery and reperfusion. Thereafter, histology of kidney, liver, and hippocampus was performed. Moreover, we measured adenosine triphosphate (ATP) content in these organs. RESULTS: Histologic evaluation revealed that laminar flow produced significant cellular edema in the kidney and hippocampus. Additionally, markers for hypoxia, apoptosis, and nitrosative stress were elevated but predominately in the hippocampus and proximal tubules of the kidney. Most of these alterations were reduced to or near control levels with pulsatile CPB. Moreover, ATP content of all 3 organs examined was higher and kidney and liver enzymes were lower in the pulsatile group compared with the non-pulsatile CPB. With regard to histologic changes, the liver seemed to be a less sensitive organ. CONCLUSIONS: In our study during pulsatile CPB, organ damage was significantly attenuated as compared with non-pulsatile CPB. Therefore, in pediatric patients pulsatile CPB may improve clinical outcomes. PMID- 25440279 TI - Methylene blue staining: a new technique for identifying intersegmental planes in anatomic segmentectomy. AB - BACKGROUND: Pulmonary segmentectomy is being increasingly used to resect small lung nodules; however, identifying the intersegmental plane is difficult. We describe a new methylene blue staining technique that we developed to identify the intersegmental planes in anatomic segmentectomy using video-assisted thoracic surgery (VATS) or thoracotomy and to evaluate its feasibility and safety. METHODS: Between October 2013 and December 2013, 14 consecutive patients with lung disease underwent anatomic segmentectomy at our institution (10 VATS, 4 conventional thoracotomy). Methylene blue 0.1% (20 mL) was slowly injected into the bronchus of the target pulmonary segments using an intravenous needle after division of the artery, vein, and bronchus of the target segments, and the boundaries were detected, followed by anatomic segmentectomy. RESULTS: The staining took only 3 min. The target pulmonary segments stained blue, allowing for the clear identification of the intersegmental plane on both the surface and in the lung parenchyma, and all operations were successfully completed. Staining did not affect pathologic examination of the resected specimens. The fluid that drained from the chest tube and the patients' sputum, urine, and feces were not blue. There were no perioperative deaths or major complications. CONCLUSIONS: To our knowledge, this study is the first to report a safe and feasible methylene blue staining method for identifying the lung segment borders that does not require any special equipment. More importantly, this method can clearly detect the intersegmental planes on the pleural surface and within the lung parenchyma, enabling thoracic surgeons to accurately perform anatomic segmentectomy. PMID- 25440280 TI - Society of Thoracic Surgeons score predicts kidney injury in patients not undergoing bypass surgery. AB - BACKGROUND: Acute kidney injury (AKI) is an established indicator of all-cause mortality in a coronary care unit (CCU), and evaluating the risks of renal dysfunction can guide treatment decisions. In this study we used the Society of Thoracic Surgeons (STS) score to predict the incidence of AKI in CCU patients who had not undergone coronary artery bypass surgery (CABG) after a cardiac angiogram. METHODS: The study cohort comprised 126 patients diagnosed with 2 or 3 coronary vessels disease who did not receive CABG during their hospital course. This study was performed in the CCU of a tertiary referral university hospital between September 2012 and August 2013. The STS score was evaluated with adjustment in all patients and the outcomes of the risk of mortality, morbidity, or mortality and renal failure were selected for predicting assessment. Furthermore, the performance of the STS scores was compared with that of other scoring systems. RESULTS: A total of 28.5% (36 of 126) of the patients had AKI of varying severity. For predicting AKI, the STS renal failure score was excellent, with areas under the receiver operating characteristic curve of 0.851 +/- 0.039, p < 0.001. When compared with other scoring systems, the STS renal failure score demonstrated the highest discriminatory power, the most favorable Youden index, and the highest overall correctness of prediction. CONCLUSIONS: The STS score is an effective tool for predicting AKI in patients with coronary artery disease who have not undergone CABG. Frequent monitoring of serum creatinine level or early application of AKI biomarkers are warranted for STS renal failure 5.7% or greater. PMID- 25440281 TI - A risk score to predict acute renal failure in adult patients after lung transplantation. AB - BACKGROUND: Despite the significant morbidity associated with renal failure after lung transplantation (LTx), no predictive models currently exist. Accordingly, the purpose of this study was to develop a preoperative risk score based on recipient-, donor-, and transplant-specific characteristics to predict postoperative acute renal failure in candidates for transplantation. METHODS: The United Network of Organ Sharing (UNOS) database was queried for adult patients (>= 18 years of age) undergoing LTx between 2005 and 2012. The population was randomly divided into derivation (80%) and validation (20%) cohorts. The primary outcome of interest was new-onset renal failure. Variables predictive of acute renal failure (exploratory p value < 0.2) within the derivation cohort were incorporated into a multivariable logistic regression model. Odds ratios were used to assign values to the independent predictors of postoperative renal failure to construct the risk stratification score (RSS). RESULTS: During the study period, 10,963 patients underwent lung transplantation, and the incidence of renal failure was 5.5% (598 patients). Baseline recipient-, donor-, and transplant-related factors were similar between the cohorts. Eighteen covariates were included in the multivariable model, and 10 were assigned values based on their relative odds ratios (ORs). Scores were stratified into 3 groups, with an observed rate of acute renal failure of 3.1%, 5.3%, and 15.6% in the low-, moderate-, and high-risk groups, respectively. The incidence of renal failure was found to be significantly increased in the highest risk group (p < 0.001). Furthermore, the risk model's predicted rates of renal failure highly correlated with actual rates observed in the population (r = 0.86). CONCLUSIONS: We introduce a novel and simple RSS that is highly predictive of renal failure after LTx. PMID- 25440282 TI - Postoperative atrial fibrillation after thoracic aortic surgery. AB - BACKGROUND: Postoperative atrial fibrillation (POAF) increases considerably the chances of morbidity and mortality after cardiac surgery. The objective of this study was to identify the major risk factors responsible for POAF after thoracic aortic surgery in order to define preventive measures. METHODS: We analyzed 12,260 records (between January 1, 2004, and December 31, 2008) obtained from the Japan Adult Cardiovascular Surgery Database. Patients with history of AF were excluded. Data were collected for 12 preoperative and 10 operative risk factors that had been proven or believed to influence POAF. The relationship between the risk factors and outcome was assessed by the Fisher exact test, Student t test, and multiple logistic regression analysis. RESULTS: The patients' mean age (+/- standard deviation) was 67.5 +/- 12.7 years, and 27% of the subjects were women. The incidence of POAF was 17.1%. The following risk factors were associated with increased POAF: age (p < 0.0001), history of smoking (p < = 0.020), hypertension (p = 0.020), congestive heart failure (p < 0.0001), urgent operation (p = 0.023), and concomitant with nonelective coronary artery bypass (p = 0.022). Postoperative mortality and postoperative stroke were significantly increased in patients with POAF (p < 0.0001 in both cases). The odds ratios for the POAF risk factors were as follows: replacement of the ascending aorta, 1.67; aortic arch, 1.62; aortic root, 1.42; concomitant with valve operation, 1.35; age, 1.27; and urgent operation, 1.22. CONCLUSIONS: Several risk factors contribute to the incidence of POAF after thoracic aortic surgery. We found that POAF significantly increased 30-day operative mortality (p < 0.0001). Our findings can be used to develop a risk stratification system for the prediction of POAF. PMID- 25440283 TI - Intraatrial conduit Fontan procedure: indications, operative techniques, and clinical outcomes. AB - BACKGROUND: The intraatrial conduit (IAC) Fontan procedure is one of the Fontan modifications and is usually not considered the first choice. In this large series, we report our experience of the IAC Fontan procedure for the treatment of a functional single ventricle and review its indications, techniques, and clinical outcomes. METHODS: Between 2009 and 2013, 101 patients with a functional single ventricle underwent an IAC Fontan procedure. The median surgical age was 44 months and weight was 15 kg. The cardiac malformations included tricuspid atresia in 10, double-inlet left ventricle in 8, double-inlet right ventricle in 15, double-outlet right ventricle in 18, congenitally corrected transposition of the great arteries in 11, complete atrioventricular septal defect in 8; criss cross in 1, pulmonary atresia with intact ventricular septum in 3, Ebstein anomaly in 3, and others in 3. Heterotaxy syndrome was found in 21 patients. An intraatrial polytetrafluoroethylene conduit was implanted to construct the Fontan pathway. In 75 patients, a 2.7-mm to 4.5-mm fenestration was made to reduce the intraconduit pressure. Eighty-three patients had previously undergone a Glenn operation. Median follow-up was 29 months (range, 2 to 60 months). Doppler echocardiography, electrocardiography, and Holter monitoring were used to evaluate hemodynamic performance and arrhythmias. RESULTS: There were 2 hospital deaths, 1 Fontan takedown, and 3 midterm deaths. Conduit thrombosis developed in 1 patient. Atrial flutter developed in 2 patients, who underwent electrical cardioversion. Junctional bradycardia developed in 2 patients, but they did not require permanent pacemakers. Overall survival was 97.0% at 1 year and 94.1% at 5 years. CONCLUSIONS: The IAC modification provides excellent operative and midterm outcomes in most patients with a functional single ventricle. However, a longer follow-up time is required to demonstrate its real advantages. PMID- 25440284 TI - Comparison of aortic diameter and area after endovascular treatment of aortic dissection. AB - BACKGROUND: Different methods have been used to assess remodeling of the thoracic aorta after endovascular treatment of Stanford type B aortic dissections. Changes in morphology may be described using diameter, area, or volume. The aim of this study was to determine if aortic diameter measurements could be used to approximate aortic area in order to refine reporting standards. METHODS: The study population encompassed 100 patients enrolled in the VIRTUE registry (designed to assess thoracic endografting with the Valiant Stent Graft System [Medtronic, Minneapolis, MN] for the treatment of type B aortic dissections). Diameter and area measurements of the true lumen, false lumen, and whole aorta were made using three-dimensional computed tomographic (3D CT) workstations, at different anatomic locations. Measurements included preoperative, postoperative, and follow-up scans. The Pearson test was used to determine general correlation between diameter and volume at each location. Scatter plots were drawn and linear regression models were used to draw a line of best fit. Comparison of these with nonlinear models was performed. RESULTS: Aortic true and false lumen diameter and area showed good correlation (p < 0.001) in the majority of anatomic locations. This relationship was present preoperatively and during follow-up (p < 0.001). The linear regression models fit well with high R(2) values. At very large aortic sizes nonlinear models were a slightly better fit, but this was not significant. CONCLUSIONS: Aortic diameter measurements correlate with luminal areas in patients with type B aortic dissection. This implies area increases proportionately with diameter over time. Therefore, diameter measurements using multiplanar reconstructions based on a central luminal line appear to be adequate when assessing aortic remodeling after endovascular treatment of aortic dissection. PMID- 25440285 TI - The prognostic importance of the number of dissected lymph nodes after induction chemoradiotherapy for esophageal cancer. AB - BACKGROUND: Analyses of adequacy of lymph node dissection during resection of esophageal cancer are based on patients who have not undergone induction chemoradiotherapy. We sought to determine the minimum number of dissected lymph nodes necessary to ensure adequate staging after induction chemoradiotherapy. METHODS: A prospectively maintained thoracic surgery database was queried to identify consecutive patients undergoing postinduction esophagectomy from 1996 to 2010. Cox proportional hazard and recursive partitioning survival analyses were performed. RESULTS: Complete lymph node data were available for 395 patients. Mean age was 59.5 years, and 64 patients (16%) were female. The median number of dissected lymph nodes was 8 (range, 0 to 63). When pathologic (p)T stage, pN stage, and the number of dissected lymph nodes were used as predictors, only pN stage (odds ratio, 1.3; 95% confidence interval, 1.2 to 1.7) and age (odds ratio, 1.03; 95% confidence interval, 1.01 to 1.04) independently predicted survival. Recursive partitioning was performed on 262 pN0 patients using T stage and the number of dissected lymph nodes as predictors. No pN0 patient with 28 lymph nodes dissected died during follow-up. For patients with fewer than 28 lymph nodes dissected, the next prognostic factor was T stage. For pT1-2 N0 patients, the number of lymph nodes dissected did not affect survival. For pT3-4 N0 patients, a significant survival decrement was noted for patients with fewer than 7 lymph nodes dissected compared with those with more than 7 lymph nodes dissected. CONCLUSIONS: T stage determines prognosis in postinduction pN0 patients with fewer than 28 lymph nodes evaluated. Postinduction pT3N0 patients with fewer than 7 lymph nodes evaluated are understaged. PMID- 25440286 TI - Right ventricular performance after valve repair for chronic degenerative mitral regurgitation. AB - BACKGROUND: Our aim was to assess right ventricular (RV) performance after mitral valve repair by use of RV focused echocardiography and to evaluate the influence of elevated pulmonary artery systolic pressure (PASP) on RV recovery. METHODS: Forty consecutive patients undergoing mitral valve repair were prospectively investigated with RV focused echocardiography, including two-dimensional speckle tracking-derived longitudinal strain and measurement of N-terminal protype-B natriuretic peptide levels performed on the day before operation and 6 months postoperatively. RESULTS: The 30-day mortality was 0%. Overall survival was 97.5% +/- 2.5% at 6-month follow-up, and the prevalence of postoperative RV dysfunction was 61% (n = 22). Conventional longitudinal indices of RV function decreased significantly after operation (n = 36): tricuspid annular plane systolic excursion (mean 24 +/- 5 mm vs mean 15 +/- 3 mm, p < 0.001), systolic peak velocity (mean 14 +/- 3 cm/s vs mean 10 +/- 2 cm/s, p < 0.001), isovolumic acceleration time (mean 2.5 +/- 1.0 cm/s(2) vs mean 2.1 +/- 0.7 cm/s(2), p = 0.022), but the RV free wall, septal, and global strain did not change significantly. Patients with preoperative PASP above 50 mm Hg showed a significant change in postoperative RV global strain compared with those whose PASP was 50 mm Hg or below (mean difference 10% +/- 30% vs -17% +/- 23%, p = 0.033). CONCLUSIONS: RV dysfunction was common at 6-month follow-up. Pulmonary hypertension, although reversible after operation, had a negative effect on RV function. Speckle tracking-derived RV strain may assist in the prioritization of surgical referrals to avoid biventricular impairment. PMID- 25440287 TI - Endoscopic management with over-the-scope clips for intestinal bleeding of Behcet's disease. PMID- 25440288 TI - Efficacy and safety of the band and slough technique for endoscopic therapy of nonampullary duodenal adenomas: a case series. AB - BACKGROUND: Endoscopic resection of nonampullary duodenal adenomas (NADAs) is effective but carries substantial procedural risks. Therapeutic banding for treatment of duodenal mucosal neoplasia has not been studied. We report a novel band and slough (BAS) technique for therapy of NADA without endoscopic resection. OBJECTIVE: Efficacy and safety of BAS. DESIGN: Retrospective review of a prospective database. SETTING: Community hospital. PATIENTS: Patients with sporadic and familial biopsy-proven NADA without invasive cancer undergoing BAS. INTERVENTION: Patients were treated with BAS without endoscopic resection on an outpatient basis. A follow-up telephone call was made by a nurse at 24 hours. Follow-up endoscopy was performed at 8 weeks, with further therapy of residual NADA. In patients with minimal residual NADA not amenable to banding, argon plasma coagulation (APC) "touch-up" was used. Subsequent endoscopic surveillance was performed. MAIN OUTCOME MEASUREMENTS: Complete histologic remission of NADA after successful BAS and postprocedure bleeding, perforation, and pain. RESULTS: Ten patients, average age 65 years, 6 male, with sporadic/familial adenomatous polyposis NADA 8 of 2 (6 tubular adenoma and 4 tubulovillous adenoma) were treated. Mean (largest) NADA was 12.5 mm (20 mm). Five patients achieved complete remission after a single session. Among 5 patients requiring further therapy, 3 were treated with repeat banding with or without APC and 2 with APC alone. The average number of bands per session was 4.4. Patients were followed up to 24 months without NADA recurrence. None of the patients had acute or delayed adverse events of bleeding, perforation, or postprocedure pain. LIMITATIONS: Lack of polyp tissue retrieval. CONCLUSION: BAS appears to be a safe and potentially effective endoscopic treatment for NADA. However, larger studies are needed to corroborate these findings. PMID- 25440290 TI - Direct current stimulation of primary motor cortex and cerebellum and botulinum toxin a injections in a person with cervical dystonia. PMID- 25440289 TI - Cortical network switching: possible role of the lateral septum and cholinergic arousal. AB - BACKGROUND: Cortical networks undergo large-scale switching between states of increased or decreased activity in normal sleep and cognition as well as in pathological conditions such as epilepsy. We previously found that focal hippocampal seizures in rats induce increased neuronal firing and cerebral blood flow in subcortical structures including the lateral septal area, along with frontal cortical slow oscillations resembling slow wave sleep. In addition, stimulation of the lateral septum in the absence of a seizure resulted in cortical deactivation with slow oscillations. HYPOTHESIS: We hypothesized that lateral septal activation might cause neocortical deactivation indirectly, possibly through impaired subcortical arousal. But how does subcortical stimulation cause slow wave activity in frontal cortex? How do arousal neurotransmitter levels (e.g. acetylcholine) change in cortex during the excitation of inhibitory projection nuclei? METHODS AND RESULTS: In the current study, we used simultaneous electrophysiology and enzyme-based amperometry in a rat model, and found a decrease in choline, along with slow wave activity in orbital frontal cortex during lateral septal stimulation in the absence of seizures. In contrast, the choline signal and local field potential in frontal cortex had no significant changes when stimulating the hippocampus, but showed increased choline and decreased slow wave activity with an arousal stimulus produced by toe pinch. CONCLUSIONS: These findings indicate that the activation of subcortical inhibitory structures (such as lateral septum) can depress subcortical cholinergic arousal. This mechanism may play an important role in large-scale transitions of cortical activity in focal seizures, as well as in normal cortical function. PMID- 25440291 TI - Safe management of a bipolar depressed patient with prefrontal repetitive transcranial magnetic stimulation (rTMS) Over 7 years and >2 million stimuli. PMID- 25440292 TI - One swallow does not a summer make. PMID- 25440293 TI - The Danish contribution to the European DEMOCOPHES project: A description of cadmium, cotinine and mercury levels in Danish mother-child pairs and the perspectives of supplementary sampling and measurements. AB - Human biomonitoring (HBM) is an important tool, increasingly used for measuring true levels of the body burdens of environmental chemicals in the general population. In Europe, a harmonized HBM program was needed to open the possibility to compare levels across borders. To explore the prospect of a harmonized European HBM project, DEMOCOPHES (DEMOnstration of a study to COordinate and Perform Human biomonitoring on a European Scale) was completed in 17 European countries. The basic measurements performed in all implemented countries of DEMOCOPHES included cadmium, cotinine and phthalate metabolites in urine and mercury in hair. In the Danish participants, significant correlations between mothers and children for mercury in hair and cotinine in urine were found. Mercury in hair was further significantly associated with intake of fish and area of residence. Cadmium was positively associated with BMI in mothers and an association between cadmium and cotinine was also found. As expected high cotinine levels were found in smoking mothers. For both mercury and cadmium significantly higher concentrations were found in the mothers compared to their children. In Denmark, the DEMOCOPHES project was co-financed by the Danish ministries of health, environment and food safety. The co-financing ministries agreed to finance a number of supplementary measurements of substances of current toxicological, public and regulatory interest. This also included blood sampling from the participants. The collected urine and blood samples were analyzed for a range of other persistent and non-persistent environmental chemicals as well as two biomarkers of effect. The variety of supplementary measurements gives the researchers further information on the exposure status of the participants and creates a basis for valuable knowledge on the pattern of exposure to various chemicals. PMID- 25440296 TI - Practice and play in the development of German top-level professional football players. AB - This study examined the developmental sporting activities of 52 German football first Bundesliga professionals (including 18 senior national team members) and 50 fourth to sixth league amateur players. They reported their volumes of organised football practice/training, including its "microstructure" (proportions of physical conditioning, skill exercises and playing forms), non-organised leisure football play and engagement in other sports through their career, respectively. Analyses revealed that the Bundesliga professionals performed moderate amounts of organised football practice/training throughout their career. They accumulated 4264 (mean value) hours over ~16 years before debuting in 1st Bundesliga; senior National Team debut was preceded by 4532 hours (mean) over ~17 years. Within the "microstructure" of organised practice/training, the proportion of playing forms developed from ~52% (childhood) to ~45% (adolescence) and ~40% (adulthood) and physical conditioning from ~13% to ~14% and ~23%. Outside organised involvement, these players engaged in extensive non-organised leisure football play making ~68%, ~54% and ~9% of all football involvement. Subsuming organised and non organised football, ~86% (childhood), ~73% (adolescence) and ~43% (adulthood) of all activity was game play (exclusive matchplay). National Team differed from amateurs in more non-organised leisure football in childhood, more engagement in other sports in adolescence, later specialisation, and in more organised football only at age 22+ years. Relative to numerous other studies, these players performed less organised practice, particularly less physical conditioning, but greater proportions of playing activities. The findings are discussed relative to the significance of playing forms and variable involvements and are reflected against the deliberate practice and Developmental Model of Sport Participation (DMSP) frameworks. PMID- 25440294 TI - Interpreting biomarker data from the COPHES/DEMOCOPHES twin projects: Using external exposure data to understand biomarker differences among countries. AB - In 2011 and 2012, the COPHES/DEMOCOPHES twin projects performed the first ever harmonized human biomonitoring survey in 17 European countries. In more than 1800 mother-child pairs, individual lifestyle data were collected and cadmium, cotinine and certain phthalate metabolites were measured in urine. Total mercury was determined in hair samples. While the main goal of the COPHES/DEMOCOPHES twin projects was to develop and test harmonized protocols and procedures, the goal of the current paper is to investigate whether the observed differences in biomarker values among the countries implementing DEMOCOPHES can be interpreted using information from external databases on environmental quality and lifestyle. In general, 13 countries having implemented DEMOCOPHES provided high-quality data from external sources that were relevant for interpretation purposes. However, some data were not available for reporting or were not in line with predefined specifications. Therefore, only part of the external information could be included in the statistical analyses. Nonetheless, there was a highly significant correlation between national levels of fish consumption and mercury in hair, the strength of antismoking legislation was significantly related to urinary cotinine levels, and we were able to show indications that also urinary cadmium levels were associated with environmental quality and food quality. These results again show the potential of biomonitoring data to provide added value for (the evaluation of) evidence-informed policy making. PMID- 25440297 TI - Severe perineal trauma is rising, but let us not overreact. PMID- 25440295 TI - Urinary BPA measurements in children and mothers from six European member states: Overall results and determinants of exposure. AB - For the first time in Europe, both European-wide and country-specific levels of urinary Bisphenol A (BPA) were obtained through a harmonized protocol for participant recruitment, sampling and quality controlled biomarker analysis in the frame of the twin projects COPHES and DEMOCOPHES. 674 child-mother pairs were recruited through schools or population registers from six European member states (Belgium, Denmark, Luxembourg, Slovenia, Spain and Sweden). Children (5-12 y) and mothers donated a urine sample. Information on socio-demographic characteristics, life style, dietary habits, and educational level of the parents was provided by mothers. After exclusion of urine samples with creatinine values below 300 mg/L or above 3000 mg/L, 653 children and 639 mothers remained for which BPA was measured. The geometric mean (with 95% confidence intervals) and 90th percentile were calculated for BPA separately in children and in mothers and were named "European reference values". After adjustment for confounders (age and creatinine), average exposure values in each country were compared with the mean of the "European reference values" by means of a weighted analysis of variance. Overall geometric means of all countries (95% CI) adjusted for urinary creatinine, age and gender were 2.04 (1.87-2.24) ug/L and 1.88 (1.71-2.07) ug/L for children (n=653) and mothers (n=639), respectively. Multiple regression analysis was used to identify significant environmental, geographical, personal or life style related determinants. Consumption of canned food and social class (represented by the highest educational level of the family) were the most important predictors for the urinary levels of BPA in mothers and children. The individual BPA levels in children were significantly correlated with the levels in their mothers (r=0.265, p<0.001), which may suggest a possible common environmental/dietary factor that influences the biomarker level in each pair. Exposure of the general European population was well below the current health based guidance values and no participant had BPA values higher than the health based guidance values. PMID- 25440298 TI - Sources, responses and moderators of childbirth fear in Australian women: a qualitative investigation. AB - BACKGROUND: around 20% of women suffer childbirth fear causing them significant distress and often leading to requests for caesarean section. In Sweden, fearful pregnant women are offered counselling; however, in Australia, no dedicated service caters for the specific needs of these women. Indeed scant research has been conducted in Australia and little is known about women's concerns and if these align to those reported in the international literature. AIM: to describe the sources, responses and moderators of childbirth fear in a group of pregnant women assessed as having high levels of childbirth fear. METHOD: comparative analysis was used to identify common concepts and generate themes that represented women's perspectives of childbirth fear. Data consisted of 43 tape recorded telephone conversations with highly fearful pregnant women who were participating in a large randomised controlled trial known as BELIEF (Birth Emotions, Looking to Improve Expectant Fear). FINDINGS: women's fears were conceptualised into three themes: fear stimuli; fear responses; and fear moderators. Lack of confidence to birth, fear of the unknown, internalising other women's negative stories, perineal tearing and labour pain were common concerns for first time mothers. For multiparous women, not having had personal feelings resolved following their previous birth and negative experiences of last birth influenced current expectations for their upcoming birth. Themes common to both groups were: unmet information and support needs, feelings of loss of control and lack of input in to decision-making. Some women however, chose to avoid birth planning in order to cope during pregnancy. CONCLUSION: Australian women had similar childbirth concerns to those reported in the international literature. However unique to this study was finding two opposing discourses; one of preoccupation with negative events and the other; avoidance of planning for labour and birth. Provision of woman centred maternity models that minimise obstetric intervention, offer personalised conversations following birth, and are sensitive to identifying; listening and assisting women to modify their fears in early pregnancy are required to promote positive anticipation and preparation for birth. PMID- 25440299 TI - Is bioavailability altered in generic versus brand anticonvulsants? AB - Therapeutic window of anticonvulsants is not a wide one, with phenytoin being one extreme, which can be classified as a narrow therapeutic index drug, since its ratio between the least toxic and the least effective concentration is less than twofold. In order to obtain marketing authorization, a generic anticonvulsant should demonstrate relative bioequivalence with its brand-name counterpart. However, although bioequivalent, generic anticonvulsants still do not have the same bioavailability as brand-name drugs, which may lead to larger fluctuations of steady-state plasma concentrations, and sometimes to loss of seizure control if a patient is switched from brand-name to generic or from generic to generic anticonvulsant. Generic anticonvulsants are effective, safe and affordable drugs for treatment of epilepsy, and patients could be successfully treated with them from the very beginning. It is switching from brand-name to generic anticonvulsant or from one generic anticonvulsant to another that should be avoided in clinical practice, since subtle differences in bioavailability may disturb optimal degree of seizure control to which the patient was previously successfully titrated. PMID- 25440300 TI - Detection of African Swine Fever Antibodies in Experimental and Field Samples from the Russian Federation: Implications for Control. AB - African swine fever (ASF) re-entered in Europe in 2007 by Georgia rapidly affecting neighbouring countries. Since then, ASF has caused severe problems to the Russian Federation (RF) and spread to Northern and Western regions, including Ukraine (2012 and 2014) and Belarus (2013). At the beginning of 2014, dead wild boars were found in Lithuania and Poland. Several outbreaks have been later notified in the European Union(EU), affecting domestic pigs and wild boar of Latvia, Lithuania and Poland, and also wild boar in Estonia, causing major problems for the EU pig sector. Some studies have been performed with this ASFV isolate, revealing that it belongs to genotype II and causes an acute form of the disease. However, few data are available about the presence of antibodies in field and experimental samples from the affected area. This study analysed samples from experimental infections with ASFV isolated from the RF in 2013 (74 sera and 3 tissue exudates), and field samples from the RF from 2013 to 2014 (266 samples, including 32 and 7 tissue exudates from domestic pigs and wild boar, respectively). All samples were tested by a commercial ELISA and, some of them (79), also by immunochromatographic tests. Positive and doubtful samples were confirmed by immunoblotting test. Positive results were found in experimental and field samples, which confirm the presence of antibodies against ASFV in the RF. Antibodies were detected in animals inoculated with three different ASFV isolates, with some differences found among them. Only a small percentage of field samples was positive for ASF antibodies (3.7%), in agreement with other observations that reported a high virulence for the ASFV isolates in the area. These results confirm the potential presence of survivor animals that should be considered in affected areas to help design effective control and eradication plans against ASF. PMID- 25440302 TI - Autism spectrum disorders: ten tips to support me. PMID- 25440301 TI - Here/in this issue there/abstract thinking: healthy moms, healthy babies (and brains). PMID- 25440303 TI - Music to my brain: could music training be used to improve adolescent brain development? PMID- 25440304 TI - Is seeking a panacea for anorexia nervosa a fool's errand? Long-term outcomes of family-based treatment. PMID- 25440305 TI - Cortical thickness maturation and duration of music training: health-promoting activities shape brain development. AB - OBJECTIVE: To assess the extent to which playing a musical instrument is associated with cortical thickness development among healthy youths. METHOD: Participants were part of the National Institutes of Health (NIH) Magnetic Resonance Imaging (MRI) Study of Normal Brain Development. This study followed a longitudinal design such that participants underwent MRI scanning and behavioral testing on up to 3 separate visits, occurring at 2-year intervals. MRI, IQ, and music training data were available for 232 youths (334 scans), ranging from 6 to 18 years of age. Cortical thickness was regressed against the number of years that each youth had played a musical instrument. Next, thickness was regressed against an "Age * Years of Playing" interaction term. Age, gender, total brain volume, and scanner were controlled for in analyses. Participant ID was entered as a random effect to account for within-person dependence. False discovery rate correction was applied (p <= .05). RESULTS: There was no association between thickness and years playing a musical instrument. The "Age * Years of Playing" interaction was associated with thickness in motor, premotor, and supplementary motor cortices, as well as prefrontal and parietal cortices. Follow-up analysis revealed that music training was associated with an increased rate of thickness maturation. Results were largely unchanged when IQ and handedness were included as covariates. CONCLUSION: Playing a musical instrument was associated with more rapid cortical thickness maturation within areas implicated in motor planning and coordination, visuospatial ability, and emotion and impulse regulation. However, given the quasi-experimental nature of this study, we cannot rule out the influence of confounding variables. PMID- 25440306 TI - Relapse from remission at two- to four-year follow-up in two treatments for adolescent anorexia nervosa. AB - OBJECTIVE: Long-term follow-up studies documenting maintenance of treatment effects are few in adolescent anorexia nervosa (AN). This exploratory study reports relapse from full remission and attainment of remission during a 4-year open follow-up period using a convenience sample of a subgroup of 65% (n = 79) from an original cohort of 121 participants who completed a randomized clinical trial comparing family-based therapy (FBT) and adolescent-focused individual therapy (AFT). METHOD: Follow-up assessments were completed up to 4 years posttreatment (average, 3.26 years). Available participants completed the Eating Disorder Examination as well as self-report measures of self-esteem and depression at 2 to 4 years posttreatment. RESULTS: Two participants (6.1%) relapsed (FBT: n = 1, 4.5%; AFT: n = 1, 9.1%), on average 1.98 years (SD = 0.14 years) after remission was achieved at 1-year follow-up. Ten new participants (22.7%) achieved remission (FBT: n = 1, 5.9%; AFT: n = 9, 33.3%). Mean time to remission for this group was 2.01 years (SD = 0.82 years) from 1-year follow-up. There were no differences based on treatment group assignment in either relapse from full remission or new remission during long-term follow-up. Other psychopathology was stable over time. CONCLUSION: There were few changes in the clinical presentation of participants who were assessed at long-term follow-up. These data suggest that outcomes are generally stable posttreatment regardless of treatment type once remission is achieved. Clinical trial registration information-Effectiveness of Family-Based Versus Individual Psychotherapy in Treating Adolescents With Anorexia Nervosa; http://www.clinicaltrials.gov/; NCT00149786. PMID- 25440307 TI - Child- and family-focused cognitive-behavioral therapy for pediatric bipolar disorder: a randomized clinical trial. AB - OBJECTIVE: Previous studies have found that family-based psychosocial treatments are effective adjuncts to pharmacotherapy among adults and adolescents with bipolar disorder (BD). The objective of this study was to compare the efficacy of adjunctive child- and family-focused cognitive-behavioral therapy (CFF-CBT) to psychotherapy as usual (control) for mood symptom severity and global functioning in children with BD. METHOD: Sixty-nine youth, aged 7 to 13 years (mean = 9.19, SD = 1.61) with DSM-IV-TR bipolar I, II, or not otherwise specified (NOS) disorder were randomly assigned to CFF-CBT or control groups. Both treatments consisted of 12 weekly sessions followed by 6 monthly booster sessions delivered over a total of 9 months. Independent evaluators assessed participants at baseline, week 4, week 8, week 12 (posttreatment), and week 39 (6-month follow up). RESULTS: Participants in CFF-CBT attended more sessions, were less likely to drop out, and reported greater satisfaction with treatment than controls. CFF-CBT demonstrated efficacy compared to the control treatment in reducing parent reported mania at posttreatment and depression symptoms at posttreatment and follow-up. Global functioning did not differ at posttreatment but was higher among CFF-CBT participants at follow-up. CONCLUSION: CFF-CBT may be efficacious in reducing acute mood symptoms and improving long-term psychosocial functioning among children with BD. PMID- 25440308 TI - Second-generation antipsychotic use in children and adolescents: a six-month prospective cohort study in drug-naive patients. AB - OBJECTIVE: To assess weight and metabolic effects of 6 months of treatment with second-generation antipsychotics in naive/quasi-naive youths. METHOD: This study looked at a nonrandomized, naturalistic, multicenter, inception cohort study of 279 patients aged 4 to 17 years (mean = 14.6 +/- 2.9 years). Of those, 248 (88.8%) received a single antipsychotic (risperidone, olanzapine, or quetiapine) and completed 2 visits, and 178 (63.8%) completed the 6-month follow-up. Patients had schizophrenia-spectrum disorders (44.5%), mood-spectrum disorders (23.2%), disruptive behavioral disorders (17.3%), or other disorders (15.1%). Fifteen age- and gender-matched, healthy, nonmedicated individuals served as a comparison group. RESULTS: From baseline to 1 month, 3 months, and 6 months, all anthropometric measures increased significantly with each antipsychotic, that is, 6-month changes with risperidone (n = 157; 7.1 kg and 0.66 body mass index [BMI] z score), olanzapine (n = 44; 11.5 kg and 1.08 BMI z score), and quetiapine (n = 47; 6.3 kg and 0.54 BMI z score), but not in healthy control participants (-0.11 kg and 0.006 BMI z score). Fasting metabolic parameters increased significantly with risperidone (glucose [3.8] mg/dL, insulin [4.9] mU/L, homeostasis model assessment of insulin resistance [HOMA-IR: 1.2], triglycerides [15.6] mg/dL), and olanzapine (glucose [5.0] mg/dL, total cholesterol [21.2] mg/dL, and low-density lipoprotein cholesterol [44.6] mg/dL), but not with quetiapine or in healthy control participants. The percentage of research participants considered to be "at risk of adverse health outcome" increased during the 6 months from 8.9% to 29.2% for risperidone (p < .0001), 6.8% to 38.1% for olanzapine (p < .0001), and 6.3% to 4.0% for quetiapine (p = .91). CONCLUSION: Olanzapine, quetiapine, and risperidone increase body weight but have different cardiometabolic side effect profiles and different temporal side effect patterns. PMID- 25440309 TI - Developmental trajectories of irritability and bidirectional associations with maternal depression. AB - OBJECTIVE: Irritability is a dimensional trait in typical development and a common presenting symptom in many psychiatric disorders, including depression. However, little is known about the developmental trajectory of irritability or how child irritability interacts with maternal depression. The present study identifies classes of irritability trajectories from toddlerhood to middle childhood; characterizes maternal depression and other family, social environment, and child variables within each irritability trajectory class; and, as a more exploratory analysis, examines bidirectional associations between maternal depression and child irritability. METHOD: A total of 4,898 families from the Fragile Families and Child Wellbeing Study reported on irritability symptoms at ages 3, 5, and 9 years, assessed with items from the Child Behavior Checklist. Parental major depressive episode was assessed using the Composite International Diagnostic Interview-Short Form at child ages 1, 3, 5, and 9 years. RESULTS: A latent class growth analysis identified 5 irritability classes: low decreasing; moderate decreasing; high steady; initially very high, then decreasing; and high increasing. Children with more severe irritability trajectories are more likely to have mothers with recurrent depression, and, with the exception of the most severe (high increasing irritability) class, were more likely to have mothers who were exposed to violence. Moreover, paternal depression and alcohol abuse, as well as maternal drug and alcohol abuse, were also risk factors for membership in the more severe irritability classes. A latent auto-regressive cross-lag model showed that child irritability at ages 3 and 5 years is associated with increased mother depression at ages 5 and 9, respectively. Conversely, mother depression at child ages 1 and 3 years is associated with increased child irritability at 3 and 5. CONCLUSION: Irritability development across toddlerhood and middle childhood has 5 main trajectory types, which differ on maternal depression recurrence and exposure to violence. Maternal depression and child irritability influence each other bidirectionally, particularly early in development. Understanding irritability development and its bidirectional relationship with maternal depression and association with violence exposure may help identify intervention targets. PMID- 25440310 TI - Longitudinal patterns of cortisol regulation differ in maltreated and nonmaltreated children. AB - OBJECTIVE: Child maltreatment is associated with dysregulation of stress mediating systems and an increased risk of mental and physical health problems. Specifically, disruptions in hypothalamic-pituitary-adrenal (HPA) axis regulation have been reported in maltreated children. The current study investigates whether increased cortisol variability is responsible for inconsistent patterns in the literature. METHOD: This study modeled cortisol activity over 20 weeks in 187 maltreated and 154 nonmaltreated children (mean = 8.4 years, SD = 1.8 years) in order to capture week-to-week cortisol patterns. Maltreatment was assessed through coding of Department of Human Services records. Children attended an after-school program 1 day per week for 20 weeks, where saliva was collected at the same time each day and subsequently assayed for cortisol. RESULTS: Multiple group growth curves indicated that maltreated and non-maltreated children differ in longitudinal cortisol patterns. Maltreated children showed higher variance in the initial cortisol levels and slope over time compared to nonmaltreated children, indicating greater between-person variability in the maltreated group. Maltreated children with higher cortisol at the first assessment showed cortisol suppression over time, indicating potential HPA blunting after chronic high cortisol levels. The severity, timing, and number of subtypes of maltreatment predicted individuals' cortisol variability, and both maltreatment status and greater cortisol variability predicted more behavior problems. CONCLUSION: Interventions for maltreated children may benefit from pre- and post-intervention HPA assessments to determine a component of treatment efficacy. As maltreatment dimensions predicted differential cortisol regulation, assessment of maltreatment experiences is necessary to understand alterations in behavior and HPA regulation post-intervention. PMID- 25440313 TI - Stark discrepancy in pediatric bipolar diagnoses between the US and UK/Australia. PMID- 25440311 TI - Repetitive behavior in 12-month-olds later classified with autism spectrum disorder. AB - OBJECTIVE: As compared to the utility of early emerging social communicative risk markers for predicting a later diagnosis of autism spectrum disorder (ASD), less is known about the relevance of early patterns of restricted and repetitive behaviors. We examined patterns of stereotyped motor mannerisms and repetitive manipulation of objects in 12-month-olds at high and low risk for developing ASD, all of whom were assessed for ASD at 24 months. METHOD: Observational coding of repetitive object manipulation and stereotyped motor behaviors in digital recordings of the Communication and Symbolic Behavior Scales was conducted using the Repetitive and Stereotyped Movement Scales for 3 groups of 12-month-olds: low risk infants (LR, n = 53); high-familial-risk infants who did not meet diagnostic criteria for ASD at 24 months (HR-negative, n = 75); and high-familial-risk infants who met diagnostic criteria for ASD at 24 months (HR-ASD, n = 30). RESULTS: The HR-ASD group showed significantly more stereotyped motor mannerisms than both the HR-negative group (p = .025) and the LR group (p = .001). The HR ASD and HR-negative groups demonstrated statistically equivalent repetitive object manipulation scores (p = .431), and both groups showed significantly more repetitive object manipulation than the LR group (p < .040). Combining the motor and object stereotypy scores into a Repetitive and Stereotyped Movement Scales (RSMS) composite yielded a disorder-continuum effect such that each group was significantly different from one another (LR < HR-negative < HR-ASD). CONCLUSION: These results suggest that targeted assessment of repetitive behavior during infancy may augment early ASD identification efforts. PMID- 25440314 TI - In reply. PMID- 25440312 TI - Atypical frontal-striatal-thalamic circuit white matter development in pediatric obsessive-compulsive disorder. AB - OBJECTIVE: Atypical development of frontal-striatal-thalamic circuitry (FSTC) has been hypothesized to underlie the early course of obsessive-compulsive disorder (OCD); however, the development of FSTC white matter tracts remains to be studied in young patients. METHOD: To address this gap, we scanned 36 patients with pediatric OCD compared to 27 healthy controls, aged 8 to 19 years, with diffusion tensor imaging (DTI) to measure fractional anisotropy (FA), an index of white matter coherence. Tract-based spatial statistics (TBSS) were used to test differential effects of age on FA, across the whole brain, in those with OCD compared to healthy youth, followed by analyses in a priori regions of interest (anterior corpus callosum, anterior cingulum bundle, and anterior limb of the internal capsule [ALIC]) to further characterize developmental differences between groups. RESULTS: Patients with OCD showed more pronounced age-related increases in FA than controls in regions of interest, as well as several other white matter tracts. In patients, greater FA in anterior cingulum bundle correlated with more severe symptoms after controlling for age. CONCLUSIONS: Our findings support theories of atypical FSTC maturation in pediatric OCD by providing the first evidence for altered trajectories of white matter development in anterior corpus callosum, anterior cingulum bundle, and ALIC in young patients. Steeper age-related increases of FA in these and other select white matter tracts in OCD, compared to those in healthy controls, may derive from an early delay in white matter development and/or prolonged white matter growth; however, confirmation of these possibilities awaits longitudinal work. PMID- 25440316 TI - Subversion of the cytoskeleton by intracellular bacteria: lessons from Listeria, Salmonella and Vibrio. AB - Entry into host cells and intracellular persistence by invasive bacteria are tightly coupled to the ability of the bacterium to disrupt the eukaryotic cytoskeletal machinery. Herein we review the main strategies used by three intracellular pathogens to harness key modulators of the cytoskeleton. Two of these bacteria, namely Listeria monocytogenes and Salmonella enterica serovar Typhimurium, exhibit quite distinct intracellular lifestyles and therefore provide a comprehensive panel for the understanding of the intricate bacteria cytoskeleton interplay during infections. The emerging intracellular pathogen Vibrio parahaemolyticus is depicted as a developing model for the uncovering of novel mechanisms used to hijack the cytoskeleton. PMID- 25440317 TI - Improving student nurses' aged care understandings through a supported placement. AB - AIM: The study aimed to identify the potential for aged care placements to deliver benefits for second year nursing students when conducted within a supportive framework with debriefing and critical reflection opportunities. BACKGROUND: Given the ageing population and complex care needs of aged care facility residents, exacerbated by the high prevalence of dementia, the healthcare workforce's ability to meet older people's care needs is paramount. Yet research shows that nursing students are disengaged from aged care. METHODS: Using a quasi-experimental mixed method design within an action research framework, 40 students were allocated a 3-week supported placement in 2011-2012 at one of the two intervention residential aged care facilities in Tasmania, Australia. Staff formed mentor action research groups in each facility and participated in a pre-placement capacity-building programme. Thirty-nine students were placed across 14 control facilities. Data were collected via meetings with students and pre-post placement questionnaires on placement experiences, attitudes and dementia knowledge. RESULTS: The intervention facility placement programme led to mentors and students being well prepared for the placement and to students experiencing enhanced teaching and learning derived from high levels of mentor support and increased autonomy. Students' knowledge, understanding and attitudes around aged care and dementia improved. DISCUSSION: Mentors working together within an action research framework can provide a supported residential aged care placement for nursing students that improves students' aged care attitudes and understandings. CONCLUSION AND IMPLICATIONS FOR NURSING AND HEALTH POLICY: Provision of quality, supported aged care student placements is vital to prepare a new generation of nurses who will have to deal with the complex chronic healthcare needs associated with an ageing population. PMID- 25440318 TI - Preparation and biological evaluation of (99m)Tc-labelled phenazine dioxides as potential tracers for hypoxia imaging. AB - The aim of this study was to investigate the capability of phenazine dioxides, recognized bioreductive antitumour agents, as carriers for (99m)Tc in order to generate potential theranostic radiopharmaceuticals towards hypoxic solid tumours. Two different phenazine dioxides were used as ligands for the (99m)Tc tricarbonyl core in order to prepare the potential radiopharmaceuticals. The main physicochemical and biological properties were evaluated. Biodistribution of the two radiotracers was studied at different time points after intravenous injection in tumour bearing animals. Both compounds were obtained in high yield and radiochemichal purity. They were stable in labelling milieu, in human plasma and in the presence of histidine. Biodistribution studies in mice were characterized by slow blood clearance and persistent liver uptake, results that correlate with the values of lipophilicities and protein binding. Both the complexes showed good tumour uptake, which remained constant during the studied period. Tumour/muscle ratios proved very favourable, comparable to those of FMISO in the same animal model. On the other hand, tumour/blood ratios were low due to high blood uptake. The use of phenazine dioxides as ligands for the preparation of potential (99m)Tc radiopharmaceuticals towards solid tumours is possible since tumour uptake and retention are promising although high blood and liver uptake are drawbacks worth consideration. PMID- 25440319 TI - Lichen nitidus presenting with nail changes--case report and review of the literature. AB - Lichen nitidus of the nail is rare and can precede the onset of skin lesions. Delayed diagnosis is common. We present an unusual case of lichen nitidus associated nail changes that preceded the onset of skin lesions in a 4-year-old Indian girl. We also conduct a review of six other cases of lichen nitidus with nail involvement from the English-language literature. Clues to the diagnosis of lichen nitidus include violaceous or pigmentary changes of the nail fold and subtle lichenoid papules on the affected digits. Lichen nitidus of the nails appears to be less severe than nail changes of lichen planus and is generally self-limiting. Understanding the natural history of lichen nitidus of the nails will help physicians better counsel patients and their families. PMID- 25440320 TI - Harnessing the Potential of Mesenchymal Stem Cells for IVD Regeneration. AB - Intervertebral disc (IVD) degeneration is one of the leading causes of low back pain, which affects a large proportion of the global population at a huge socioeconomic burden. Current treatments focus primarily on symptomatic pain relief or surgery, but offer relatively poor long-term efficacy as they fail to address the pathogenesis of the underlying IVD degeneration. In order to offer improved clinical outcomes, a number of biological and regenerative therapies are currently being developed which target the disease at a molecular and cellular level and aim to restore IVD function. This review focusses on the considerations for development of cell-based therapies for IVD regeneration. In particular it focusses on the identification of novel progenitor cell populations within the IVD and the application of mesenchymal stem cells (MSCs) in IVD tissue engineering, which are being increasingly studied as they offer huge potential for tissue regeneration. Additionally it highlights how the growing understanding of the molecular phenotype of IVD cells is allowing tailored differentiation strategies to be developed and how MSC source and choice of growth factor influences cell phenotype and appropriate tissue formation. Finally, it reviews the range of functional biomaterials being developed to aid MSC delivery and differentiation, and discusses the potential impact the degenerate IVD microenvironmental niche may have on MSC behaviour following implantation. PMID- 25440321 TI - Incidence and molecular characterization of Glucose-6-Phosphate Dehydrogenase deficiency among neonates for newborn screening in Chaozhou, China. AB - INTRODUCTION: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is highly prevalent in southern China. The aim of this study is to assess the extent of this disease in Chinese neonates and determine its molecular characteristics using a novel molecular screening method. METHODS: A total of 2500 neonates were routinely screened for G6PD deficiency using a modified fluorescent spot test (FST). PCR-high-resolution melting (HRM) analysis was then used for the molecular assay. RESULTS: The overall incidence of G6PD deficiency was 2.68% in our study cohort. Frequency in male population was 3.22% (44 neonates of 1365 male neonates), and in female population was 2.03% (23 neonates of 1135 female neonates). Of the 67 newborns suspected to be G6PD deficient based on FST (44 males, 23 females), 58 of 67 (87%) were detected with gene alterations. Seven kinds of mutations [c.95A>G, c.392G>T, c.493A>G, c.871G>A, c.1360C>T, c.1376G>T, and c.1388G>A] were identified by HRM analysis. CONCLUSION: Routine newborn screening in Chaozhou, China with a relatively high prevalence of G6PD deficiency is justified and meets the World Health Organization recommendation. The usage of molecular diagnosis can favor the detection of heterozygotes which can be a supplement to regular newborn screening and useful for premarital and prenatal diagnosis for G6PD deficiency. PMID- 25440322 TI - Paradoxical consequence of human chorionic gonadotropin misuse. AB - Recombinant human chorionic gonadotropin (hCG) is commonly misused as a weight reducing or performance enhancing agent but is associated with increased risk of thromboembolic events. A 29-year-old female with a history of obesity was admitted to our center with a diagnosis of ischemic stroke. Etiologic workup revealed a large patent foramen ovale and history of recent use of hCG as part of a weight loss regimen. This report highlights the potential complications of hCG therapy, particularly when used for unapproved indications and without medical supervision. PMID- 25440323 TI - The "heart appearance" sign in bilateral pontine infarction. AB - BACKGROUND: Although rarely seen, bilateral anteromedial infarction of the pons demonstrates the characteristic "heart appearance" sign on magnetic resonance imaging (MRI). This sign has hitherto been described in only 2 patients before this article. This typical pattern can be attributed to atherosclerotic or thrombotic involvement of bilateral paramedian and short circumferential pontine arteries supplying the anteromedial pons. METHODS AND RESULTS: A 60-year-old man, a known patient of primary hypertension and diabetes mellitus, presented with a posterior circulation stroke. Urgent computerized tomography and MRI revealed a "heart-shaped" area of acute infarction in the anteromedian mid-pons. A few scattered infarcts were also noted in the posterior and inferior part of the right cerebellar hemisphere. The basilar artery appeared normal with preserved flow void on MRI, and there were no signs of hemorrhage. These findings were consistent with acute nonhemorrhagic infarcts involving bilateral paramedian and short circumferential pontine arteries and the right posterior inferior cerebellar artery. A repeat MRI performed after a week disclosed hemorrhagic transformation and enhancement of the pontine infarction. The basilar artery appeared normal on magnetic resonance angiography. CONCLUSIONS: Recognizing the "heart appearance" sign in a stroke-like episode may be helpful in differentiating bilateral anteromedial pontine infarction from other pathologic processes involving the pons. PMID- 25440324 TI - Exercise training and recreational activities to promote executive functions in chronic stroke: a proof-of-concept study. AB - BACKGROUND: Stroke survivors represent a target population in need of intervention strategies to promote cognitive function and prevent dementia. Both exercise and recreational activities are promising strategies. We assessed the effect of a 6-month exercise and recreation program on executive functions in adults with chronic stroke. METHODS: A 6-month ancillary study within a multicentre randomized trial. Twenty-eight chronic stroke survivors (ie, >= 12 months since an index stroke) were randomized to 1 of 2 experimental groups: intervention (INT; n = 12) or delayed intervention (D-INT; n = 16). Participants of the INT group received a 6-month community-based structured program that included 2 sessions of exercise training and 1 session of recreation and leisure activities per week. Participants of the D-INT group received usual care. The primary outcome measure was the Stroop Test, a cognitive test of selective attention and conflict resolution. Secondary cognitive measures included set shifting and working memory. Mood, functional capacity, and general balance and mobility were additional secondary outcome measures. RESULTS: Compared with the D INT group, the INT group significantly improved selective attention and conflict resolution (P = .02), working memory (P = .04), and functional capacity (P = .02) at the end of the 6-month intervention period. Improved selective attention and conflict resolution was significantly associated with functional capacity at 6 months (r = .39; P = .04). CONCLUSIONS: This is the first randomized study to demonstrate that an exercise and recreation program can significantly benefit executive functions in community-dwelling chronic stroke survivors who are mildly cognitively impaired-a population at high-risk for dementia and functional decline. Thus, clinicians should consider prescribing exercise and recreational activities in the cognitive rehabilitation of chronic stroke survivors. PMID- 25440325 TI - Utility of 3-dimensional ultrasound imaging to evaluate carotid artery stenosis: comparison with magnetic resonance angiography. AB - BACKGROUND: We evaluated the utility of 3-dimensional (3-D) ultrasound imaging for assessment of carotid artery stenosis, as compared with similar assessment via magnetic resonance angiography (MRA). METHODS: Subjects comprised 58 patients with carotid stenosis who underwent both 3-D ultrasound imaging and MRA. We studied whether abnormal findings detected by ultrasound imaging could be diagnosed using MRA. Ultrasound images were generated using Voluson 730 Expert and Voluson E8. RESULTS: The degree of stenosis was mild in 17, moderate in 16, and severe in 25 patients, according to ultrasound imaging. Stenosis could not be recognized using MRA in 4 of 17 patients diagnosed with mild stenosis using ultrasound imaging. Ultrasound imaging showed ulceration in 13 patients and mobile plaque in 6 patients. When assessing these patients, MRA showed ulceration in only 2 of 13 patients and did not detect mobile plaque in any of these 6 patients. Static 3-D B mode images demonstrated distributions of plaque, ulceration, and mobile plaque, and static 3-D flow images showed flow configuration as a total structure. Real-time 3-D B mode images demonstrated plaque and vessel movement. Carotid artery stenting was not selected for patients diagnosed with ulceration or mobile plaque. CONCLUSIONS: Ultrasound imaging was necessary to detect mild stenosis, ulcerated plaque, or mobile plaque in comparison with MRA, and 3-D ultrasound imaging was useful to recognize carotid stenosis and flow pattern as a total structure by static and real-time 3-D demonstration. This information may contribute to surgical planning. PMID- 25440326 TI - Quality assurance monitoring of a citywide transportation protocol improves clinical indicators of intravenous tissue plasminogen activator therapy: a community-based, longitudinal study. AB - BACKGROUND: Stroke-bypass transportation to the stroke center by paramedics is important to maximize the efficiency of intravenous tissue plasminogen activator (iv-tPA) therapy. To improve access to stroke thrombolysis, a citywide protocol was launched on January 2007 in Kawasaki City (population 1.4 million) using the Maria Prehospital Stroke Scale (MPSS), and quality assurance monitoring has been performed every 6 months. The aim was to identify whether the citywide quality assurance monitoring improves the process and outcome of iv-tPA therapy. METHODS: All of the MPSS-based transportation data prospectively recorded by the Kawasaki City Fire Department and the associated clinical data in the 11 hospitals that accept stroke-bypass transfers were merged every 6 months for the quality assurance monitoring. Clinical indicators such as ambulance call-to-door time, onset-to-needle time, door-to-needle time, frequency of thrombolytic use, and outcome of thrombolytic therapy were analyzed. These clinical indicators were also compared between patients transferred on weekdays and on weekends. RESULTS: A total of 2049 patients was registered from April 2009 to March 2013. Their mean age was 70.4 +/- 13.2 (range, 24-98) years, and 64.3% were male. Ambulance call to-door time decreased gradually from 37.5 +/- 12.5 minutes to 33.9 +/- 11.7 minutes over 4 years (P = .000, analysis of variance with the post hoc Dunnett test). Onset-to-needle time and door-to-needle time were similar over the 4 years. Good outcome (modified Rankin Scale score <2) after iv-tPA therapy increased from 24.1% to 35.3% (P = .045, 2010 vs. 2012). No deleterious effect of weekend admission was observed based on these clinical indicators. CONCLUSIONS: A citywide MPSS-based transportation protocol significantly decreased the delay in the ambulance call-to-door time. The implementation of standardized cross institutional quality assurance programs for acute stroke therapy may improve the process and outcome of iv-tPA therapy in the community. PMID- 25440327 TI - Increased pulsatility of the intracranial blood flow spectral waveform on transcranial Doppler does not point to peripheral arterial disease in stroke patients. AB - BACKGROUND: Peripheral arterial disease (PAD) is common in patients with acute cerebral ischemia. Indexes of resistance derived from the systolic and diastolic velocities are routinely used in diagnostic transcranial Doppler (TCD) to detect intracranial arterial disease. We sought to explore whether these indexes can predict the presence of PAD in acute cerebral ischemia. METHODS: We prospectively evaluated consecutive patients with acute cerebral ischemia. On TCD, peak systolic and end-diastolic velocities in both middle cerebral and basilar arteries were manually measured to calculate pulsatility index (PI) and resistance index (RI). Increased resistance was defined as PI equal to 1.2 or more and RI equal to .75 or more. Ankle-brachial index (ABI) measurements were performed and an ABI equal to .9 or more was considered predictive of definite PAD. RESULTS: We included 95 patients (45 male, 50 female) aged 66 +/- 9 years with a median National Institutes Health Stroke Scale score of 3 (interquartile range, 8) points. The ABI was abnormal and consistent with definite PAD in 24 of 95 (25.3%; 95% confidence interval [CI], 16.4-34.2) patients. Increased PI did not differ among patients with and without PAD (20.8% vs. 28.2%, P = .60). Only 1 patient with PAD had increased RI as opposed to 4 patients without PAD (4.2% vs. 5.6%, P = 1.0). Increased PI was not found to be an independent predictor of PAD (odds ratio [OR], .68; 95% CI, .22-2.12; P = .51). Increases in both PI and RI independently predicted arterial hypertension (OR, 1.62; 95% CI, 1.19-2.21; P = .002 and OR, 3.20; 95% CI, 1.51-6.77; P = .002, respectively). CONCLUSIONS: Our findings indicate that PAD cannot be inferred from intracranial flow parameters predictive of arterial disease and risk factors such as hypertension among patients with acute cerebral ischemia. PMID- 25440328 TI - Reduced estimated glomerular filtration rate affects outcomes 3 months after intracerebral hemorrhage: the stroke acute management with urgent risk-factor assessment and improvement-intracerebral hemorrhage study. AB - BACKGROUND: The effect of renal dysfunction on intracerebral hemorrhage (ICH) remains unclear. We investigated associations of renal dysfunction assessed by estimated glomerular filtration rate (eGFR) with clinical courses and outcomes in ICH patients. METHODS: From a prospective, multicenter, observational study, 203 patients who had supratentorial ICH within 3 hours of onset were included. Patients were classified into 3 groups based on eGFR: Group 1 (eGFR < 60 mL/minute/m(2)), Group 2 (60-89), and Group 3 (>= 90). Outcomes included neurologic deterioration within 72 hours, hematoma expansion (> 33% in volume) at 24 hours, and favorable (modified Rankin Scale [mRS] <= 2) or unfavorable (mRS >= 5) outcome at 3 months. RESULTS: Thirty-seven patients (16 women, 74.6 +/- 13.2 years) were assigned to Group 1, 99 (34 women, 65.2 +/- 11.4 years) to Group 2, and 67 (30 women, 61.3 +/- 9.4 years) to Group 3. Significant differences were found in age (P < .001) and initial systolic blood pressure among the groups (208.4 +/- 18.0, 201.9 +/- 15.1, and 198.1 +/- 14.2 mm Hg for Group 1, 2, and 3, respectively; P = .006). Similar rates of neurologic deterioration (14%, 6%, and 6%) and hematoma expansion (16%, 14%, and 18%) were observed among the groups. However, in Group 1, favorable outcome was less frequent (17%, 48%, and 42%; P = .002) and unfavorable outcome was more frequent (24%, 7%, and 6%; P = .013) than in the other groups. After adjustment for confounders, eGFR < 60 mL/minute/m(2) was independently associated with both favorable outcome (odds ratio [OR], .21; 95% CI, .07-.54) and unfavorable outcome (OR, 5.64; 95% CI, 1.80-18.58). CONCLUSIONS: Renal dysfunction (eGFR < 60 mL/minute/m(2)) was associated with poor clinical outcome after ICH. PMID- 25440329 TI - Atorvastatin treatment and carotid plaque morphology in first-ever atherosclerotic transient ischemic attack/stroke: a case-control study. AB - BACKGROUND: A relationship between echolucency of carotid plaques and the consequent risk of ipsilateral ischemic stroke has been observed. An aggressive lipid-lowering therapy may increase the echogenicity of carotid plaque in patients with elevated low-density lipoprotein cholesterol levels. The aim of this study is to prospectively evaluate the long-term effect of high-dose atorvastatin on carotid plaque morphology in patients with first-ever transient ischemic attack or stroke. METHODS: All patients with symptomatic first ischemic atherosclerotic cerebrovascular event occurred within the previous 10 days were enrolled. Carotid Doppler ultrasound of the neck vessels with 7-11 MHz probe for the definition of the atherosclerotic carotid framework was performed. The analysis of the gray-scale median (GSM) of each plate was carried out with image processing software. RESULTS: A total of 240 symptomatic plaques were included and divided into 3 groups: 80 in group A (atorvastatin 80 mg), 80 in group B (atorvastatin 40 mg), and 80 to group C (no atorvastatin). GSM score increases significantly more extensive in group A than in group B (+48.65 vs. +39.46, P < .02) and group C (+48.65 vs. 19.3, P = .0002). An inverse association between reduction of low-density lipoprotein and the increase in the GSM score (r = .456, P = .007) has been observed. Moreover, the reduction of high-sensitive C reactive protein correlates inversely with the increase of the GSM (r = -.398, P = .021). CONCLUSIONS: Dose-dependent effect of atorvastatin on symptomatic carotid plaque morphology may suggest a specific role of this drug in the atherosclerotic stroke prevention. PMID- 25440330 TI - Targeted delivery of extracellular matrix protected against neurologic defects after focal ischemia reperfusion in rats. AB - Ischemic stroke is one of the leading causes of morbidity and mortality worldwide and characterized by defective angiogenesis. The functional sequences (RGDs, GRGDSPASSPISC) derived from fibronectin have been confirmed to augment angiogenesis in vivo and in vitro. However, delivery of peptides into the brain parenchyma has been hampered by the presence of the blood-brain barrier (BBB). We fused RGDs with penetratin (Antp) derived from Drosophila antennapedia homeodomain protein to improve the penetration of peptides through BBB into ischemic hemisphere. We found Antp-RGDs successfully not only penetrate the SH SY5Y cells but also penetrated through BBB into ischemic hemisphere by intraperitoneal injection. In addition, application of Antp-RGDs to the focal cerebral ischemic reperfusion injury in rats resulted in the reduction of cerebral ischemic volume and the improvement of neurologic score according to the 21-point score. We further demonstrated that activation of phosphorylation extracellular-signal related kinase 1/2 (p-ERK 1/2) and upregulation of gene VEGF resulted from post-treatment with Antp-RGDs 2 hours after reperfusion onset might at least partly contribute to the benefic changes after focal cerebral ischemic reperfusion injury in rats. Our data suggested that Antp-RGDs may serve as an attractive therapeutic intervention for treating ischemic stroke. PMID- 25440331 TI - Replacing paper with digital recording. AB - Addressing the needs to achieve the highest standards at multidisciplinary team meetings at the Stroke Unit of Broomfield Hospital, an electronic version is applied instead of the traditional paper model. This is to ensure that patients within the unit are receiving appropriate care and their progress is monitored throughout their entire journey. This also enables the stroke team to retrieve old information anywhere in the hospital, electronically, from previous documentations to compare progress of rehabilitation. The electronic model also helps when assessing readmission or those who attend the stroke clinics to clarify new onset changes from residual weakness. The tool kit estimates Barthel Index score for activities of daily living and Rivermead Mobility Index for physical capacity assessment weekly as the team attending the meetings. The goals from all disciplines, physiotherapists, occupational therapists, speech and language therapists, and nurses are clearly documented along with patient cognition, emotion, and perception. This initiative commenced in late April 2013 and the first clinical outcome assessments performed at the beginning of September 2013, enabling the stroke team to assess rehabilitation activities and achievements. Front-line staff expressed satisfaction with the initiative model, which successfully managed to monitor and analyze the rehabilitation activities within the stroke unit. PMID- 25440332 TI - A prototype worldwide survey of diagnostic and treatment modalities for stroke. AB - Stroke is a global health problem. However, very little is known about stroke care in low- to middle-income countries. Obtaining country-specific information could enable us to develop targeted programs to improve stroke care. We surveyed neurologists from 12 countries (Chile, Georgia, Nigeria, Qatar, India, Lithuania, Kazakhstan, Indonesia, Denmark, Brazil, Belgium, and Bangladesh) using a web based survey tool. Data were analyzed both for individual countries and by income classification (low income, lower middle income, upper middle income, and high income). Six percent (n = 200) of 3123 targeted physicians completed the survey. There was a significant correlation between income classification and access and affordability of head computed tomography scan (rho = .215, P = .002), transthoracic echocardiogram (rho = .181, P = .012), extracranial carotid Doppler ultrasound (rho = .312, P <= .000), cardiac telemetry (rho = .353, P <= .000), and stroke treatments such as intravenous thrombolysis (rho = .276, P <= .001), and carotid endarterectomy (rho = .214, P <= .004); stroke quality measures such as venous thromboembolism prophylaxis during hospital stay (rho = .163, P <= .022), discharge from hospital on antithrombotic therapy (rho = .266, P <= .000), consideration for acute thrombolytic therapy (rho = .358, P <= .000), and antithrombotic therapy prescribed by end of hospital day 2 (rho = .334, P <= .000). However, there was no significant correlation between income classification and the access and affordability of antiplatelet agents, vitamin K antagonists and statins, anticoagulation for atrial fibrillation/flutter, statin medication, stroke education, and assessment for rehabilitation. Our study shows that it is possible to get an overview of stroke treatment measures in different countries by conducting an internet-based survey. The generalizability of the findings may be limited by the low survey response rate. PMID- 25440334 TI - Bilateral asymmetrical asterixis as limb-shaking transient ischemic attack in bilateral carotid stenosis. AB - Asterixis as limb-shaking transient ischemic attack (TIA) is rare and poorly understood. Bilateral asymmetrical asterixis as limb-shaking TIA has not been reported in carotid stenosis. A 69-year-old gentleman presented with a TIA episode (dysarthria, right-arm weakness, and numbness). Bilateral asterixis was observed and was more severe on the right side. No prior infarcts were noted in the thalamus. Liver function was normal. A computerized tomography angiogram revealed 85%stenosis of the right internal carotid artery (ICA) and 65% stenosis of the left ICA. Three days after left ICA endarterectomy, the patient had complete disappearance of bilateral asterixis, with the right side showing initial improvement. The bilateral asterixis observed is proposed to be secondary to hemodynamic impairment and hypoperfusion of certain brain territory with resolution on revascularization. PMID- 25440333 TI - The impact of absent A1 segment on ischemic stroke characteristics and outcomes. AB - BACKGROUND: A1 segment is the proximal portion of anterior cerebral artery. Absence of the A1 segment can compromise anterior cerebral collateral blood flow. Few studies have examined the association of an absent A1 segment and ischemic stroke outcome. We sought to determine the association between A1 absence and affected vessel territory, stroke volume, and outcomes among patients with acute ischemic stroke (AIS). METHODS: A retrospective review of prospectively identified patients with AIS from July 2008 to March 2013 was performed. Patients without intracranial vascular imaging were excluded. We compared patients with absent A1 to patients with bilateral A1 segments in terms of demographics, stroke severity (as measured by National Institute of Health Stroke Scale [NIHSS]), vascular distribution, and in-hospital mortality using the chi-square test and logistic regression. RESULTS: Of the 1146 patients with AIS and intracranial vascular imaging, 5.9% patients (n = 68) had absent A1. Compared with other AIS patients, those with absent A1 were older (65 vs. 63 years old, respectively, P = .016). There was no difference between groups in terms of the vascular distribution or the side of the stroke. The median volume of the infracted tissue was similar across the groups even when it was stratified according to the Treatment of Acute Stroke Trial classification. Patients with an absent A1 had twice higher odds of in-hospital mortality (odds ratio, 2.4; 95% confidence interval, 1.1-5.2; P = .028); however, significance was lost after adjusting to age, NIHSS at baseline, and glucose on admission. Other outcome measures were similar across the groups. CONCLUSIONS: In our sample, patients with an absent A1 segment did not have a specific vascular distribution, larger infarct volume, or worse outcomes. PMID- 25440335 TI - Multiple cerebral myxomatous aneurysms: what is the optimal treatment? AB - BACKGROUND: Multiple cerebral aneurysms resulting from cardiac myxoma is a very rare disease, and the optimal treatment is not yet determined. We present 2 cases of multiple cerebral myxomatous aneurysms and give an overview of the English literature pertaining to this disease. METHODS: We described 2 new cases of multiple cerebral myxomatous aneurysms and performed a search of English literature in PubMed and Google Scholar. Keywords used were as follows (single word or combination): "neoplastic aneurysm," "oncotic aneurysm," "aneurysm," and "myxoma." Only patients with multiple cerebral aneurysms resulting from cardiac myxoma and contained adequate follow-up information pertinent to the analysis were included. RESULTS: One patient underwent craniotomy for resection of an aneurysm. Microscopic examination demonstrated the myxoma in the aneurysmal wall. The other patient was managed conservatively. Thirty-five cases meeting the previously mentioned criteria were found in the literature. This disease was typically diagnosed in young adults (median age = 38 years). Females were more frequently affected (F/M ratio, 2.7:1). A total of 78.4% were managed conservatively. A total of 16.2% underwent craniotomy for aneurysm resection and/or hematoma evacuation. At follow-up, 64.9% were stable, 10.8% revealed disappearance of aneurysms, 10.8% showed enlargement of aneurysms, and the mortality rate was 13.5%. CONCLUSIONS: Patients with multiple cerebral aneurysms should routinely be evaluated for cardiac myxoma and vice versa. Conservative treatment is recommended for most of the patients. Prognosis is good in most patients. PMID- 25440336 TI - Adverse events after unruptured cerebral aneurysm treatment: a single-center experience with clipping/coil embolization combined units. AB - BACKGROUND: Indications of clipping (Clip) or coil embolization (Coil) for unruptured cerebral aneurysms (uAN) was not elaborated because prediction of rupture and risk of treatment are difficult. This study aims to determine the risk-benefit analysis of treating uAN by a comprehensive and retrospective investigation of the adverse events and sequelae in patients treated by our Clip/Coil combined units. METHODS: Clip and Coil were performed in 141 and 80 patients, respectively; Clip for middle cerebral artery AN and Coil for paraclinoid or basilar apex AN. Worsening of modified Rankin scale or mini-mental state examination was defined as major morbidity. Minor morbidity or transient morbidity was defined as other neurologic deficits. Mortality and these morbidities were considered as serious adverse events. Convulsion or events outside the brain were defined as mild adverse events. RESULTS: Total mortality and major morbidity were low. Incidence of serious adverse events was not significantly different between the Clip and Coil (17 patients [12.1%] and 6 patients [7.5%]), but the number of total adverse events was significantly different (32 patients [22.7%] in Clip vs. 8 patients [10.0%] in Coil). Because mild morbidities were significantly more frequent in the Clip (20 patients [14.2%]) compared with the Coil (2 patients [2.5%]). Convulsion occurred in 11 (7.8%) patients in the Clip but none in the Coil. CONCLUSIONS: Our combined unit decreased the occurrence of mortality/major morbidity; however, minor adverse effects were common, especially in the Clip group because of many intrinsic problems of Clip itself. This result suggests further consideration for the treatment modality for uAN. PMID- 25440337 TI - Telephone audit for monitoring stroke unit facilities: a post hoc analysis from PROSIT study. AB - BACKGROUND: Although several valid approaches exist to measure the number and the quality of acute stroke units, only few studies tested their reliability. This study is aimed at establishing whether the telephone administration of the PROject of Stroke unIt ITaly (PROSIT) audit questionnaire is reliable compared with direct face-to-face interview. METHODS: Forty-three medical leaders in charge of in-hospital stroke services were interviewed twice using the same PROSIT questionnaire with 2 different modalities. First, the interviewers approached the medical leaders by telephone. Thereafter, they went to the hospital site and performed a direct face-to-face interview. Six independent couples of trained researchers conducted the audit interviews. The degree of intermodality agreement was measured with kappa statistic. RESULTS: We found a perfect agreement for stroke units identification between the 2 different audit modalities (K = 1.00; standard error [SE], 1.525). The agreement was also very good for stroke dedicated beds (K = 1.00; SE, 1.525) and dedicated personnel (K = 1.00; SE, 1.525), which are the 2 components of stroke unit definition. The agreement was lower for declared in use process of care and availability of diagnostic investigations. CONCLUSIONS: The telephone audit can be used for monitoring stroke unit structures. It is more rapid, less expensive, and can repeatedly be used at appropriate intervals. However, a reliable description of the process of care and diagnostic investigations indicators should be obtained by either local site audit visit or prospective stroke register based on individual patient data. PMID- 25440338 TI - The influence of depressive symptoms on quality of life after stroke: a prospective study. AB - BACKGROUND: Poststroke depressive symptoms have prospectively predicted impairment of health-related quality of life (HRQOL). However, it is not known whether such predictive effect is independent of HRQOL at 1 month after stroke. This study aimed to investigate the impact of depressive symptoms at 1 and 3 months after stroke on the 3-month poststroke HRQOL and to investigate the influence of the HRQOL measured at 1 month after stroke on these relationships. METHODS: We prospectively evaluated 67 patients at 1 and 3 months after a first ever ischemic stroke from 106 eligible patients who have been consecutively admitted to the neurology ward of a teaching hospital. A psychiatrist assessed the presence of depressive symptoms using the 31-item version of the Hamilton Rating Scale for Depression and the HRQOL was assessed with the 36-item Short Form Health Survey from the Medical Outcomes Study. We used linear regression to measure the impact of depressive symptoms, HRQOL at 1 month, and potential confounders on HRQOL at 3 months. RESULTS: We found an association between depressive symptoms at 1 month and HRQOL at 3 months after the stroke; however, this association was not significant when adjusting for the 1 month poststroke HRQOL. Depressive symptoms at 3 months were associated with HRQOL at 3 months after stroke, independently of the poststroke HRQOL at 1 month and potential confounders. CONCLUSIONS: Current depressive symptoms at 3 months are important for HRQOL at 3 months after stroke; however, regarding the prospective prediction, HRQOL at 1 month is the most relevant factor. PMID- 25440339 TI - Predictors of long-term outcome after intravenous or intra-arterial recombinant tissue plasminogen activator treatment in the eastern Hungarian thrombolysis database. AB - BACKGROUND: This prospective single-center study aimed to identify features determining long-term outcome after thrombolysis in a Central European stroke population. METHODS: Between 1 January, 2004, and 31 December, 2010, 415 patients were treated with recombinant tissue plasminogen activator at the Department of Neurology, University of Debrecen. Stroke severity by the National Institute of Health Stroke Scale score (NIHSSS) and imaging findings by the Alberta Stroke Programme Early Computed Tomography score (ASPECTS) were evaluated on admission and 1 day later. The modified Rankin Scale (mRS) at 3 months and case fatality at 1 year were evaluated. Independent predictors of outcome were identified by multivariate testing. RESULTS: Data of 369 patients were analyzed. Median NIHSSS was 12 (interquartile range [IQR], 8-17) on admission and 10 (IQR, 5-16) at 24 hours. Arterial occlusion was found in 55%. Symptomatic intracerebral hemorrhage (SICH) was detected in 3.8%. Outcome was significantly worse, and SICH was more frequent in intra-arterially treated patients. At 3 months, one third of the patients were independent (mRS <= 2), and 23% were dead. At 1 year 2 of 3 patients were alive. Significant independent predictors of disability at 3 months were 24-hour NIHSSS, admission ASPECTS, admission glucose level, and treatment modality. Only the 24-hour NIHSSS was a significant predictor of case fatality at 1 year. CONCLUSIONS: Although short-term outcome was similar, the 3-month and 1 year outcomes were worse than data from previous reports. A more efficient health care program should be implemented after stroke to maintain the favorable effect of thrombolysis in the long term. PMID- 25440340 TI - The radical scavenger edaravone improves neurologic function and perihematomal glucose metabolism after acute intracerebral hemorrhage. AB - Oxidative injury caused by reactive oxygen species plays an important role in the progression of intracerebral hemorrhage (ICH)-induced secondary brain injury. Previous studies have demonstrated that the free radical scavenger edaravone may prevent neuronal injury and brain edema after ICH. However, the influence of edaravone on cerebral metabolism in the early stages after ICH and the underlying mechanism have not been fully investigated. In the present study, we investigated the effect of edaravone on perihematomal glucose metabolism using (18)F fluorordeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). Additionally, the neurologic deficits, brain edemas, and cell death that followed ICH were quantitatively analyzed. After blood infusion, the rats treated with edaravone showed significant improvement in both forelimb placing and corner turn tests compared with those treated with vehicle. Moreover, the brain water content of the edaravone-treated group was significantly decreased compared with that of the vehicle group on day 3 after ICH. PET/CT images of ICH rats exhibited obvious decreases in FDG standardized uptake values in perihematomal region on day 3, and the lesion-to-normal ratio of the edaravone treated ICH rats was significantly increased compared with that of the control rats. Calculation of the brain injury volumes from the PET/CT images revealed that the volumes of the blood-induced injuries were significantly smaller in the edaravone group compared with the vehicle group. Terminal Deoxynucleotidyl Transferase-mediated dUTP Nick End Labeling assays performed 3 days after ICH revealed that the numbers of apoptotic cells in perihematomal region of edaravone treated ICH rats were decreased relative to the vehicle group. Thus, the present study demonstrates that edaravone has scavenging properties that attenuate neurologic behavioral deficits and brain edema in the early period of ICH. Additionally, edaravone may improve cerebral metabolism around the hematoma by attenuating apoptotic cell death after ICH. PMID- 25440341 TI - A manual carotid compression technique to overcome difficult filter protection device retrieval during carotid artery stenting. AB - BACKGROUND: We investigated the incidence of embolic protection device retrieval difficulties at carotid artery stenting (CAS) with a closed-cell stent and demonstrated the usefulness of a manual carotid compression assist technique. METHODS: Between July 2010 and October 2013, we performed 156 CAS procedures using self-expandable closed-cell stents. All procedures were performed with the aid of a filter design embolic protection device. We used FilterWire EZ in 118 procedures and SpiderFX in 38 procedures. The embolic protection device was usually retrieved by the accessory retrieval sheath after CAS. We applied a manual carotid compression technique when it was difficult to navigate the retrieval sheath through the deployed stent. We compared clinical outcomes in patients where simple retrieval was possible with patients where the manual carotid compression assisted technique was used for retrieval. RESULTS: Among the 156 CAS procedures, we encountered 12 (7.7%) where embolic protection device retrieval was hampered at the proximal stent terminus. Our manual carotid compression technique overcame this difficulty without eliciting neurologic events, artery dissection, or stent deformity. CONCLUSIONS: In patients undergoing closed-cell stent placement, embolic protection device retrieval difficulties may be encountered at the proximal stent terminus. Manual carotid compression assisted retrieval is an easy, readily available solution to overcome these difficulties. PMID- 25440342 TI - A novel approach to diagnose reversible cerebral vasoconstriction syndrome: a case series. AB - BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is classically diagnosed based on the presence of severe thunderclap headache, focal neurologic symptoms, and the radiographic findings of reversible diffuse segmental cerebral vasoconstriction. We present a diagnostic test that may assist in the clinical diagnosis and facilitate treatment. METHODS: From October 1, 2010, to August 1, 2013, we identified consecutive patients who presented with a presumptive diagnosis of RCVS and underwent cerebral diagnostic angiography with intra arterial (IA) vasodilator therapy. Medical records including clinical presentation, radiographic, and angiographic images were all reviewed. RESULTS: We identified a total of 7 patients (4 females; age range, 22-56; mean, 45 years) who met our inclusion criteria. Four patients received a combination of milrinone and nicardipine infusion either in the internal carotid arteries or in the left vertebral artery; the remaining patients received IA therapy solely with either nicardipine or milrinone. Five patients had a positive angiographic response, defined as significant improvement or resolution of the blood vessels irregularities. All 5 patients had a definite discharge diagnosis of RCVS. The remaining 2 patients had a negative angiographic response and based on their clinical and radiographic course had a final diagnosis of intracranial atherosclerotic disease. CONCLUSIONS: Our small case series suggest that IA administration of vasodilators is safe and may aid in distinguishing vasodilator responsive syndromes such as RCVS from other causes. Further study is required with long-term clinical outcome to determine the utility of this diagnostic test. PMID- 25440343 TI - Transcranial color flow imaging can evaluate the severity of periventricular hyperintensity. AB - BACKGROUND: The goal of this study was to investigate the relationship between white matter lesions on magnetic resonance imaging and flow parameters in the middle cerebral artery (MCA) measured by transcranial color flow imaging. METHODS: Patients with acute ischemic stroke or transient ischemic attack were included. The relationship between severities of periventricular hyperintensity (PVH) and ultrasonographic parameters in the MCA was investigated. The frequency of PVH was calculated for different categories according to the presence or absence of 2 considerable parameters according to the value of area under the receiver operating characteristic curve. RESULTS: MCA flow was successfully measured in 203 temporal windows among 124 patients. After determining the cutoff value of end-diastolic velocity (EDV) and pulsatility index (PI) for the presence of PVH, 4 different categories were established: Category A, EDV more than 40 cm/second and PI less than .7; Category B, EDV more than 40 cm/second and PI more than .7; Category C, EDV less than 40 cm/second and PI less than .7; and Category D, EDV less than 40 cm/second and PI more than .7. The prevalence of PVH gradually increased along with category (P < .01). CONCLUSIONS: The evaluation of MCA parameters using the combination of PI and EDV may be useful for the prediction of PVH. PMID- 25440344 TI - Biomarker research for moyamoya disease in cerebrospinal fluid using surface enhanced laser desorption/ionization time-of-flight mass spectrometry. AB - Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by steno occlusive change in bilateral internal carotid arteries with unknown etiology. To discover biomarker candidates in cerebrospinal fluid from MMD patients, proteome analysis was performed by the surface-enhanced laser desorption/ionization time of-flight mass spectrometry. Three peptides, 4473Da, 4475Da, and 6253Da, were significantly elevated in MMD group. A positive correlation between 4473Da peptide and postoperative angiogenesis was determined. Twenty MMD patients were enrolled in this pilot study, including 11 pediatric cases less than 18 years of age (mean age, 8.67 years) and 9 adult MMD patients (mean age, 38.1 years). This study also includes 17 control cases with the mean age of 27.9 years old. In conclusion, 4473Da peptide is supposed to be a reliable biomarker of MMD. 4473Da peptide showed higher intensity peaks especially in younger MMD patients, and it was proved to be highly related to postoperative angiogenesis. Further study is needed to show how 4473Da peptide is involved with the etiology and the onset of MMD. PMID- 25440345 TI - Higher fasting glucose next day after intravenous thrombolysis is independently associated with poor outcome in acute ischemic stroke. AB - BACKGROUND: We aimed to test the outcome-predictive power of routine fasting glucose (FG) obtained at second day after onset in intravenous thrombolysis (IVT) acute ischemic stroke (AIS) patients. METHODS: We identified AIS patients presenting to our institution between December 2011 and July 2013 within 4.5 hours of onset, who received admission glucose (AG) before IVT, FG, and glycated hemoglobin (HbA1c) the second day after admission, from our prospectively recorded stroke database. Multivariate logistic regression was used to assess the association of FG and 90-day modified Rankin Scale (mRS). RESULTS: Between December 2011 and July 2013, a total of 166 AIS patients received intravenous plasminogen activator. Of those, 119 patients who have AG before IVT, FG, and HbA1c the second day were included in the study. FG independently predicted 90 day clinical unfavorable outcome (mRS, 3-6 with an odds ratio of 1.576; 95% confidence interval [CI], 1.053-2.358; P = .027). This association was not significant in AG (P = .714), HbA1c (P = .655), and history of diabetes (P = .547). In receiver operating characteristic analysis, increased FG was associated with 90-day mRS (3-6) with an area under curve of .72, (95% CI, .65-.9; P = .001). CONCLUSIONS: FG is a powerful predictor associated with the outcome in IVT treated AIS patients independent of AG and HbA1c. PMID- 25440346 TI - Can trained field community workers identify stroke using a stroke symptom questionnaire as well as neurologists? Adaptation and validation of a community worker administered stroke symptom questionnaire in a peri-urban Pakistani community. AB - BACKGROUND: Stroke is a leading cause of morbidity and mortality worldwide. There is a paucity of data from South Asia where stroke is highly prevalent. Validated tools administrable by community health workers (CHWs) are required to identify stroke in the community in a resource-strapped region such as this. METHODS: The study was conducted in a transitional slum in Karachi, Pakistan. Questionnaire to Verify Stroke-Free Status (QVSFS) was adapted and translated into Urdu. Two CHWs, trained by a neurologist, selected 322 community-dwelling subjects using purposive sampling. Each CHW collected data independently, which was validated by a vascular neurologist who directly examined each participant. To assess the effect of audit and feedback, data from the final 10% of the subjects were collected after a second training session for the CHWs. Sensitivity, specificity, and Cohen kappa were determined for the CHW-administered questionnaire against neurovascular assessment. RESULTS: Mean age of participants was 56.5 years with 71% of participants being women. The sensitivity and specificity of the questionnaire of detecting stroke was 77.1% (confidence interval [CI], 64.1-86.9) and 85.8% (CI, 83.5-87.5), respectively. The chance-corrected agreement using the Cohen kappa statistic was .51 (CI, .38-.60). Kappa ranged from .37 to .58 for each of the 7 stroke symptoms. Hemianesthesia (72.9%) and hemiplegia (64.6%) were the most sensitive symptoms. The performance and agreement improved from moderate to substantial after audit and feedback. CONCLUSIONS: We found a reasonable sensitivity and specificity and moderate agreement between CHW-administered QVSFS and assessment by a vascular neurologist. PMID- 25440347 TI - Adherence to oral anticoagulation in secondary stroke prevention--the first year of direct oral anticoagulants. AB - BACKGROUND: Patients with ischemic stroke caused by atrial fibrillation (AF) have a high risk of recurrence without adequate secondary prevention with oral anticoagulation (OAC). We investigated adherence to OAC in the first year after introduction of direct oral anticoagulants. METHODS: In 284 appropriate patients, the rate of anticoagulation (AC) at discharge, adherence at 90 days and 1 year, changes between substances, and predictors for adherence to AC were analyzed. Functional outcome was assessed using the modified Rankin Scale score. RESULTS: AC was initiated in 70.3% of survivors before discharge. In these patients, only 8.6% and 9.9% discontinued AC after 90 days and 1 year, respectively. In 22.1%, AC was recommended but not started before discharge. Only 53.2% of them received AC at 90 days, increasing to 67.5% at 1 year. A total of 7.6% of patients were deemed unsuitable for AC, none of them subsequently received AC. Overall, 85.4% of patients suitable for AC were treated at 1-year follow-up. No independent predictors for withholding AC were identified. Switching of medication occurred in only a minority of patients within the first year. CONCLUSIONS: AC is feasible in more than 90% patients with acute ischemic stroke and AF. When initiated during the acute hospital stay, AC is discontinued in only a minority of patients. However, if AC is recommended but not started during initial hospitalization the rate of AC treatment at 90 days and 1 year is much lower. Therefore, AC should be initiated within the acute hospital stay whenever possible. PMID- 25440348 TI - Methylenetetrahydrofolate reductase gene A1298C polymorphism in pediatric stroke- case-control and family-based study. AB - Moderate hyperhomocysteinemia is one of the risk factors of pediatric stroke. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme, which regulates homocysteine metabolism, and some polymorphisms of gene encoding this enzyme are associated with a decreased activity of the enzyme. The aim of the study was to assess an association between the A1298C polymorphism and pediatric stroke. We also evaluated a possible synergistic effect of A1298C and C677T polymorphisms of this gene. The study group consisted of 88 children after ischemic stroke, 142 of their parents and 111 controls. The A1298C polymorphism was genotyped using the restriction fragment length polymorphism method. We used 2 study designs: a case-control model and a family-based association test. The Statistica 7.1 and EpiInfo 6 softwares were used in all analyses. We did not observe any statistically significant differences either in the transmission of the A allele in the family-based test or in the frequency of the A allele in the patients group compared with the controls. We also did not notice any significant additive or synergistic effects between the A1298C and C677T polymorphisms. An analysis of the results obtained in this study and a critical review of previously published studies indicate that the A1298C polymorphism of the MTHFR gene is not related to ischemic stroke in children. PMID- 25440349 TI - Is there an association between cerebral microbleeds and leukoaraiosis? AB - PURPOSE: Cerebral microbleeds (CMBs) are small dot-like lesions appearing as hyposignals on gradient echo (GRE) T2* magnetic resonance (MR) sequences, whereas the leukoaraiosis (LA) indicates the presence of patchy areas of hypersignal on fluid-attenuated inversion recovery (FLAIR) MR sequences in the periventricular white matter. The purpose of this work was to evaluate the association between LA and CMBs. MATERIAL AND METHODS: Eighty-five consecutive (men 55; median age 64 years) patients were retrospectively analyzed using a 1.5 T system; CMBs were studied using a T2*-weighted GRE sequence and classified as absent (grade 1), mild (grade 2; total number of microbleeds, 1-2), moderate (grade 3; total number of microbleeds, 3-10), and severe (grade 4; total number of microbleeds, >10). LA was assessed with FLAIR MR sequences and was graded based on the European Task Force on Age-Related White Matter Changes as follows: 1 (no lesions), 2 (focal lesions > 5 mm), 3 (early confluent lesions), and 4 (diffuse involvement of an entire brain region). RESULTS: We considered 170 cerebral hemispheres. The prevalence of CMBs was 24.7% (42 of 170), whereas the prevalence of LA was 27.1% (46 of 170). A statistically significant correlation was observed between LA and CMBs (correlation rho = .495, P value = .001). Multiple logistic regression analysis showed an association between CMBs and cerebrovascular symptoms (P = .0023). CONCLUSION: Results of this study suggest an association between CMBs and LA. Moreover, we found that LA is associated with the presence of cerebrovascular symptoms. PMID- 25440350 TI - Incompleteness of the Circle of Willis correlates poorly with imaging evidence of small vessel disease. A population-based study in rural Ecuador (the Atahualpa project). AB - BACKGROUND: Studies looking for an association between incompleteness of the Circle of Willis (CoW) and small vessel disease (SVD) markers are scarce and conflicting. We aimed to evaluate this association in an unbiased population based study conducted in Atahualpa (rural Ecuador). METHODS: Atahualpa residents 60 years of age or more were identified during a door-to-door survey and invited to undergo magnetic resonance imaging for identification of SVD markers, including white matter hyperintensities (WMHs), strokes, and deep microbleeds. Magnetic resonance imaging (MRA) was used for classifying the CoW according to the presence or absence of one A1 segment of the anterior cerebral artery or one or both P1 segments of posterior cerebral arteries. RESULTS: Of 311 eligible persons, 258 were enrolled. Mean age was 70 +/- 8 years, 59% were women, and 74% had a poor cardiovascular health (CVH) status. Of these, 172 patients (67%) had WMH, 40 patients (16%) had SVD-related strokes, and 23 patients (9%) had deep microbleeds. MRA revealed a complete CoW in 157 persons (61%). Persons with SVD markers were older than those without markers (P < .0001). A poor CVH status was noted in 79% of persons with at least 1 SVD marker and in 65% of those with no markers (P = .02). Logistic regression models showed no association of incompleteness of the CoW with any marker of SVD-alone or in combination-after adjusting for age, sex, and CVH status. CONCLUSIONS: Lack of association between incompleteness of CoW and SVD markers suggest that genetically determined variants in the intracranial vasculature are not responsible for the high prevalence of SVD among native South American populations. PMID- 25440351 TI - Borax partially prevents neurologic disability and oxidative stress in experimental spinal cord ischemia/reperfusion injury. AB - OBJECTIVES: The aim of this study is to investigate the potential effects of borax on ischemia/reperfusion injury of the rat spinal cord. METHODS: Twenty-one Wistar albino rats were divided into 3 groups: sham (no ischemia/reperfusion), ischemia/reperfusion, and borax (ischemia/reperfusion + borax); each group was consist of 7 animals. Infrarenal aortic cross clamp was applied for 30 minutes to generate spinal cord ischemia. Animals were evaluated functionally with the Basso, Beattie, and Bresnahan scoring system and inclined-plane test. The spinal cord tissue samples were harvested to analyze tissue concentrations of nitric oxide, nitric oxide synthase activity, xanthine oxidase activity, total antioxidant capacity, and total oxidant status and to perform histopathological examination. RESULTS: At the 72nd hour after ischemia, the borax group had significantly higher Basso, Beattie, and Bresnahan and inclined-plane scores than those of ischemia/reperfusion group. Histopathological examination of spinal cord tissues in borax group showed that treatment with borax significantly reduced the degree of spinal cord edema, inflammation, and tissue injury disclosed by light microscopy. Xanthine oxidase activity and total oxidant status levels of the ischemia/reperfusion group were significantly higher than those of the sham and borax groups (P < .05), and total antioxidant capacity levels of borax group were significantly higher than those of the ischemia/reperfusion group (P < .05). There was not a significantly difference between the sham and borax groups in terms of total antioxidant capacity levels (P > .05). The nitric oxide levels and nitric oxide synthase activity of all groups were similar (P > .05). CONCLUSIONS: Borax treatment seems to protect the spinal cord against injury in a rat ischemia/reperfusion model and improve neurological outcome. PMID- 25440352 TI - Troponin-I is a predictor of a delayed diagnosis of atrial fibrillation in acute ischemic stroke and transient ischemic attack. AB - BACKGROUND: Prolonged cardiac monitoring detects higher rates of atrial fibrillation (AF) in ischemic stroke and transient ischemic attack (TIA) but is costly and has practical implications. The use of admission troponin-I (TnI) level to identify patients at high risk of delayed AF detection was investigated. METHODS: Consecutive ischemic stroke and TIA cases presenting to our institute over a 13-month period were identified from the Irish Stroke and TIA Register. Electronic databases and case notes were examined. "Delayed" AF was diagnosed after a sinus rhythm admission electrocardiogram and no documented history. Group comparisons were made by AF status. The association between TnI and AF was investigated using a multivariate regression model. RESULTS: A total of 185 cases (130 ischemic stroke) were analyzed. Mean age (standard deviation) was 73.3 (13.9) years, 47% female. Sixty-two cases (33.5%) had AF. The first documented presentation of AF was found in 21 cases, on admission electrocardiogram (n = 11) or inpatient telemetry (delayed, n = 10). TnI was higher in those with delayed AF than in those without AF (W = 194; P = .036). A higher proportion of those with an elevated TnI (30%) than those with a normal TnI (6.1%) had delayed diagnosis of AF (chi(2) = 6.41, P = .011). Having an abnormal TnI was a significant independent predictor of delayed AF detection (odds ratio, 5.8; P = .037). CONCLUSIONS: TnI elevation is associated with a higher likelihood of subsequent AF diagnosis. Identification of these higher risk stroke and TIA cases for more intensive cardiac monitoring may improve stroke secondary prevention practices. PMID- 25440353 TI - Long-term survival of older Australian women with a history of stroke. AB - BACKGROUND: Although many people survive an initial stroke, little is known about long-term impacts of stroke on survival. METHODS: Data from the Australian Longitudinal Study on Women's Health were used to compare 12-year survival rates in older women with prevalent stroke, incident stroke, and no stroke. Cox regression models were fitted to assess the effect of lifestyle and demographic characteristics on the relationship between stroke and all-cause mortality. The "no stroke" group was used as the reference category in all statistical models. RESULTS: At baseline, 4% of the women reported a previous stroke (prevalent stroke). At survey 2 in 1999, a further 3% reported having a stroke between 1996 and 1999 (incident stroke). Stroke was significantly associated with reduced long term survival. Age-adjusted hazards ratios (HRs) were: 1.64 (1.43-1.89) for the "prevalent stroke" group and 2.29 (1.97-2.66) for the "incident stroke" group. Adjusting for comorbidities reduced the HRs, but the risk of death was still significantly higher in the 2 stroke groups. Adjusting for demographic and lifestyle factors did not make any further difference to the relationship between stroke and survival. However, obesity and past smoking were also risk factors for mortality. CONCLUSIONS: This study highlights the long-term impacts of stroke on life expectancy and the importance of comorbidities and other lifestyle factors in affecting poststroke survival. PMID- 25440354 TI - Risk factors of cerebral microbleeds in strictly deep or lobar brain regions differed. AB - BACKGROUND: T2*-weighted gradient echo magnetic resonance imaging is sensitive in detecting cerebral microbleeds (MBs), but there are few reports on the risk factors of MBs in different brain regions. Therefore, we aimed to investigate whether the risk factors associated with the presence of MBs in strictly deep or lobar brain regions were different. METHODS: This study consisted of 696 consecutive acute ischemic stroke patients from 6 hospitals in the Chinese IntraCranial AtheroSclerosis Study. We evaluated the number and location of MBs, severity of lacune and leukoaraiosis (LA), and etiologic subtype of ischemic stroke. Multivariable logistic regression was used to analyze risk factors of MBs in different brain regions. RESULTS: Among 696 acute ischemic stroke patients, 162 patients (23.3%) had MBs. Of them, 62 patients had strictly deep brain MBs, 49 patients had strictly lobar MBs. There was a significant correlation between the number of MBs, the number of lacune, and the severity of LA (P < .0001). In multivariable logistic regression analysis, both strictly deep and strictly lobar brain, MBs were significantly associated with history of cerebral hemorrhage (P = .037 and P = .026, respectively), presence of lacune (P = .004 and P = .032, respectively), and severe LA (P = .002 and P = .008, respectively). However, MBs in strictly deep regions were significantly associated with higher mean arterial pressure (P = .030), and those in strictly lobar brain regions were significantly associated with older age (P = .023). CONCLUSIONS: The risk factors of MBs in strictly deep or lobar regions differ modestly, which may be related to heterogeneous vascular pathologic changes. PMID- 25440355 TI - Knowledge of stroke risk factors among Nigerians at high risk. AB - BACKGROUND: Although the first step toward effective primary prevention of stroke is awareness of its risk factors, there is limited information on knowledge of these risk factors among Nigerians at increased risk. We assessed the knowledge of risk factors for stroke among Nigerians at high risk. METHOD: Using an interviewer-administered questionnaire in a cross-sectional design, high-risk patients (defined as those with a diagnosis of hypertension and/or diabetes) attending the specialist medical outpatient clinics of the University of Ilorin Teaching Hospital were requested to mention all the stroke risk factors they knew. The outcome measure was ability to mention at least 1 well-documented modifiable or potentially modifiable risk factor. Binary logistic regression analysis was used to determine predictors of the outcome measure. RESULTS: The mean age of the respondents was 56.4 +/- 12.6 years. Only 39.8% were able to mention at least 1 well-documented modifiable or potentially modifiable risk factor; hypertension was the most recognized (34.7%). Other risk factors mentioned by the respondents were: diabetes (7.3%), alcohol intake (4.5%), smoking (3.8%), overweight and obesity (1.9%), and heart disease (.6%). Factors found to be significantly associated with ability to correctly mention at least 1 stroke risk factor were younger age (<55 years), more than 12 years of formal education, family history of stroke, urban residence, and previous health education on stroke. CONCLUSIONS: Despite being at high risk, knowledge of stroke risk factors is poor among our respondents. Intensive health education is needed to improve on this poor knowledge. PMID- 25440356 TI - Predictive factors for epilepsy in moyamoya disease. AB - BACKGROUND: Epilepsy cannot always be recognized in patients with moyamoya disease. In this report, the clinical features of patients with epilepsy were evaluated for assessing the predictive factors of epilepsy in moyamoya disease. METHODS: A total of 64 consecutive patients with moyamoya disease were included in this study. During their follow-up periods, 7 patients were diagnosed with epilepsy. Then, the patients with epilepsy were compared with the patients without epilepsy regarding their clinical features. RESULTS: Analysis of patient background characteristics revealed a significantly higher incidence of epilepsy in patients with high modified Rankin Scale (mRS) scores, high cerebrovascular attack scores, onset age of 3 years or less, early seizures, cortical involvement, stroke subtype, and diffuse brain atrophy. A logistic analysis of epilepsy data revealed significant differences between the 2 groups in mRS score, cerebrovascular attack score, onset age 3 years or less, early seizure, cortical involvement, stroke subtype, and diffuse brain atrophy. Of these, significant differences were noted in 3 items (mRS score, early seizure, and diffuse brain atrophy) on multivariate analysis. These 3 items were selected as the basis of our new moyamoya disease epilepsy risk scale (MDERS), which we then evaluated. The cutoff value estimated by the receiver operating characteristic curve was set at 1 (sensitivity, .857; specificity, .825) or 2 (sensitivity, .571; specificity, 1.000). CONCLUSIONS: Epilepsy in moyamoya disease is associated with clinical factors and is not an independent category. For prediction of epilepsy in moyamoya disease, MDERS is a simple and convenient assessment scale. PMID- 25440357 TI - Orolingual angiodema associated with alteplase treatment of acute stroke: a reappraisal. AB - BACKGROUND: Orolingual angioedema has been increasingly recognized as a potentially life-threatening complication associated with alteplase treatment of stroke. Concomitant treatment with an angiotension converting enzyme inhibitor (ACEi) and localization of infarction in the territory of middle cerebral artery seem to be associated with a higher risk of this complication. METHODS: We report the cases of orolingual angioedema among the patients undergoing alteplase treatment in our Stroke Unit. Additionally, we reviewed the literature to evaluate the pathophysiology, clinical characteristics, and treatment options. RESULTS: In our Stroke Unit, among 236 patients given alteplase for acute stroke, 8 patients (3.4%) developed angioedema. The clinical picture varied from localized labial edema to extensive lingual edema with respiratory distress but in all cases it gradually resolved with symptomatic treatment. Seven patients had a hemispheric stroke (4 with lateralized angioedema, contralateral to the ischemic lesion), whereas the other 1 patient had a right superior cerebellar artery stroke (with lateralized angioedema, ipsilateral to the ischemic lesion). The National Institutes of Health Stroke Scale score at admission ranged from 6 to 24 (median 12.5). Five patients were taking an ACEi. Our results are similar to previously published data. In the literature, it appears that orolingual angioedema occurs in .2-5.1% of all stroke patients receiving Alteplase treatment. CONCLUSIONS: Orolingual angioedema is a potential complication of which treating physicians in stroke units need to be aware, even in those cases without history of ACEi treatment and without infarction in the territory of the middle cerebral artery. All patients who receive alteplase treatment should be monitored carefully. PMID- 25440358 TI - Safety and outcomes in stroke mimics after intravenous tissue plasminogen activator administration: a single-center experience. AB - BACKGROUND: Patients with symptoms that impersonate a stroke but are later found to have an alternate diagnosis are termed stroke mimics. Stroke mimics treated with intravenous (IV) tissue plasminogen activator (t-PA) are exposed to hemorrhagic complications without benefit. The objective of this study is to describe the characteristics, safety, and outcomes of stroke mimic patients treated with t-PA within 4.5 hours. METHODS: All patients hospitalized after IV t PA treatment at a tertiary care hospital and primary stroke center from January 2008 through December 2011 were reviewed. Stroke mimics were determined by review of clinical and imaging findings. Stroke mimics are described and compared with acute ischemic stroke patients for demographics, clinical characteristics, and bleeding complications. RESULTS: We identified 38 stroke mimic (12%) and 285 ischemic stroke (88%) t-PA-treated patients. Compared with ischemic stroke patients, mimic patients were younger, more often female, and reported a history of stroke more often. There were no differences in race, baseline stroke scale, or onset to treatment time. There were no intracerebral hemorrhages or deaths in the mimic patients but there were 2 systemic hemorrhages (5.2%). CONCLUSIONS: Treatment of mimic patients with IV t-PA appears to be safe in this cohort. Concern for intracerebral hemorrhage in mimic patients need not dissuade clinicians from administering t-PA when significant concern for ischemic etiology exists. PMID- 25440359 TI - Intra-arterial administration of papaverine during mechanical thrombectomy for acute ischemic stroke. AB - BACKGROUND: The use of stent retrievers for mechanical thrombectomy in acute ischemic stroke may induce significant vasospasm, which at the early phases of reperfusion may be crucial for rethrombosis of the recanalized vessel. We aimed to study whether the use of intra-arterial papaverine in selected cases of vasospasm was associated with improved cerebral perfusion, arterial reocclusion, or increased hemorrhagic complications. METHODS: We retrospectively studied 9 consecutive patients with large artery acute occlusion, treated with stent retriever and intra-arterial papaverine. Onset to administration of intravenous recombinant tissue-plasminogen activator time, baseline National Institute of Health Stroke Scale, time to reperfusion, number of passes of the stent retriever, modified Rankin Scale score at discharge, postprocedural hemorrhage, onset to reperfusion time, papaverine dose, and thrombolysis in cerebral infarction grade were recorded in all patients. RESULTS: After papaverine administration, the caliber of the infused arteries and their flow was increased in all cases. In none of the treated cases a reocclusion occurred after papaverine infusion. In one of the studied patients (11%), a parenchymal bleeding occurred 36 hours postoperatively. CONCLUSIONS: This small study suggests that intra-arterial infusion of papaverine for the treatment of cerebral vasospasm after mechanical thrombectomy in acute ischemic stroke is effective and safe. PMID- 25440361 TI - Incidence, mortality, and risk factors for oral anticoagulant-associated intracranial hemorrhage in patients with atrial fibrillation. AB - Warfarin, a vitamin K epoxide reductase inhibitor, is the oral anticoagulant most commonly used to reduce the risk of stroke in patients with atrial fibrillation (AF). Warfarin has proved to be efficacious for this purpose in multiple clinical trials. However, warfarin use is laborious and associated with an increased risk of intracranial hemorrhage (ICH). Various factors increase the risk of warfarin related ICH, including older age, intensity of anticoagulation, hypertension, and history of cerebrovascular disease. The emergence of newer classes of oral anticoagulants will offer therapeutic alternatives to reduce the risk of stroke in patients with AF. Recently, the United States Food and Drug Administration approved 3 new agents--dabigatran etexilate, a direct thrombin inhibitor, and rivaroxaban and apixaban, factor Xa inhibitors-to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF. We discuss the incidence, mortality, and risk factors predisposing to oral anticoagulant-associated ICH in patients with AF. PMID- 25440360 TI - Phone-based intervention under nurse guidance after stroke: concept for lowering blood pressure after stroke in Sub-Saharan Africa. AB - Over the last 4 decades, rates of stroke occurrence in low- and middle-income countries (LMIC) have roughly doubled, whereas they have substantively decreased in high-income countries. Most of these LMIC are in Sub-Saharan Africa (SSA) where the burden of stroke will probably continue to rise over the next few decades because of an ongoing epidemiologic transition. Moreover, SSA is circumstantially distinct: socioeconomic obstacles, cultural barriers, underdiagnosis, uncoordinated care, and shortage of physicians impede the ability of SSA countries to implement cardiovascular disease prevention among people with diabetes mellitus in a timely and sustainable manner. Reducing the burden of stroke in SSA may necessitate an initial emphasis on high-risk individuals motivated to improve their health, multidisciplinary care coordination initiatives with clinical decision support, evidence-based interventions tailored for cultural relevance, task shifting from physicians to nurses and other health providers, use of novel patient-accessible tools, and a multilevel approach that incorporates individual- and system-level components. This article proposes a theory-based integrated blood pressure (BP) self-management intervention called Phone-based Intervention under Nurse Guidance after Stroke (PINGS) that could be tested among hospitalized stroke patients with poorly controlled hypertension encountered in SSA. PINGS would comprise the implementation of nurse-run BP control clinics and administration of health technology (personalized phone text messaging and home telemonitoring), aimed at boosting patient self-efficacy and intrinsic motivation for sustained adherence to antihypertensive medications. PMID- 25440362 TI - Clinical outcomes after thrombectomy for acute ischemic stroke on weekends versus weekdays. AB - BACKGROUND: The objective of this study was to determine whether clinical outcomes differed in acute ischemic stroke (AIS) patients who underwent thrombectomy on weekends versus weekdays. METHODS: Patients with a primary diagnosis of AIS who underwent thrombectomy were identified from the Nationwide Inpatient Sample from 2005 to 2011 and stratified according to weekend or weekday admission. Logistic regression analysis was performed to identify factors associated with moderate-to-severe disability at hospital discharge in teaching and nonteaching hospitals. RESULTS: Of 12,055 patients with AIS who underwent thrombectomy during the study period, 2862 (23.7%) were admitted on a weekend. In a multivariate logistic regression analysis, factors associated with moderate or severe disability at discharge in nonteaching hospitals were weekend admission (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.0-2.8; P = .04), diagnosis of hypertension (OR, 1.9; 95% CI, 1.0-3.6; P = .05), and Medicare or Medicaid insurance status (OR, 2.1; 95% CI 1.1-4.3; P = .02); factors associated with moderate or severe disability at discharge in teaching hospitals were age >70 years (OR, 1.5; 95% CI, 1.1-2.2; P = .02), pneumonia (OR, 4.7; 95% CI, 2.2-10.2; P < .0001), sepsis (OR, 8.2; 95% CI, 1.2-54.8; P = .03), intracranial hemorrhage (OR, 3.3; 95% CI, 1.8-6.1; P = .0001), and treatment in a Northwest hospital region (OR, 1.7; 95% CI, 1.2-2.4; P = .03). CONCLUSIONS: AIS patients undergoing thrombectomy who were admitted to nonteaching hospitals on weekends were more likely to be discharged with moderate-to-severe disability than those admitted on weekdays. No weekend effect on discharge clinical outcome was seen in teaching hospitals. PMID- 25440363 TI - Alteration in bioenergetic regulators, SirT1 and Parp1 expression precedes oxidative stress in rats subjected to transient cerebral focal ischemia: molecular and histopathologic evidences. AB - The present study was undertaken to identify the time-dependent changes in bioenergetic regulators and oxidative stress markers levels and also to ascertain which occurs early in focal cerebral ischemia. The status of bioenergetic regulators (nicotinamide adenine dinucleotide, Silent information regulator Transporter 1 (SirT1) and Poly adenosine diphosphate--ribose polymerase 1 (Parp1)) and oxidative stress markers' (lipid peroxidation and nitric oxide) levels along with excitatory neurochemical glutamate, neuronal nuclei (NeuN), glial fibrillary acidic protein (GFAP), and caspase 3 at various durations of reperfusion viz 0, 1, 6, 24, 72, and 166 hours was investigated in rats subjected to 2 hours of middle cerebral artery occlusion. Six hours after reperfusion, a significant downregulation in SirT1 and upregulation in Parp1 expressions were observed in striatal region of ischemic-reperfused rats compared with ischemic rats. Peak elevation in glutamate content was recorded at 72 hours, and maximum level of lipid peroxidation and nitric oxide contents were observed at 166 hours. A significant decrease in NeuN and increase in GFAP-positive cells were observed at 24 and 72 hours, respectively, in cortical, striatal, and hippocampal regions. These data reveal that change in bioenergetic regulators occurs earlier than excitotoxicity and oxidative stress in cerebral stroke. From the data, it can also be inferred that appropriate therapeutic intervention, that is, bioenergetic modulators at early period and either glutamatergic and/or antioxidant therapy at delayed period may yield a better therapeutic outcome. PMID- 25440364 TI - Assessment of platelet function in acute ischemic stroke patients previously treated with aspirin. AB - BACKGROUND: Platelet inhibition measured by platelet function tests could be critical to understand the reasons for early recurrence and to guide therapeutic recommendations. We assess the platelet function during the acute phase of ischemic stroke in patients pretreated with aspirin who continue their treatment with aspirin only, are started on clopidogrel only, or add clopidogrel to aspirin. METHODS: Sixty-four patients were taking aspirin before the stroke. Depending on the administered antiplatelet, 3 groups were defined: ASA: patients who continued on aspirin orally or intravenous acetylsalicylate of lysine, n = 30; CLO: patients who discontinued aspirin and were started on clopidogrel, n = 16; and ASA + CLO: patients who were prescribed both aspirin and clopidogrel, n = 10. Collagen-induced thromboxane A2 (TXA2) synthesis, ADP (adenosine diphosphate) induced aggregation, and occlusion time (PF-100) were measured. RESULTS: CLO group only had a marked elevation of TXA2 (17.44 +/- 15.62 ng/mL, P = .000) and a shortening of the platelet function analyzer (PFA)-100 closure time (157.13 +/- 88 seconds, P = .047) compared with the other 2 groups (ASA: TXA2, .62 +/- 1.59 ng/mL; ASA + CLO: TXA2 1.79 +/- 4.59 ng/mL). They achieved a small (13%) but significant reduction of ADP-induced aggregation (87.00 +/- 23.06 mm, P = .008) compared with the ASA group (102.82 +/- 22.38 seconds). CONCLUSIONS: Stopping aspirin intake within the first 72 hours of the acute stroke drastically increases TXA2 synthesis. During the same time window, the freshly prescribed clopidogrel manages to reduce the ADP-induced aggregation only slightly (13%). This study offers analytic proof that the common practice of replacing aspirin with clopidogrel does not leave stroke patients fully protected during the first days after an ischemic stroke. Possible solutions could be to preserve aspirin during a few days or to use loading doses of clopidogrel at hospital admission. PMID- 25440365 TI - Long-term magnetic resonance angiography follow-up for recanalized vessels after mechanical thrombectomy. AB - BACKGROUND: Mechanical thrombectomy is an effective revascularization therapy for acute intracranial large vessel occlusion. We retrospectively evaluated magnetic resonance angiography (MRA) follow-up data to assess the long-term patency of recanalized vessels after mechanical thrombectomy. METHODS: We retrospectively reviewed medical records of consecutive patients who had undergone mechanical thrombectomy for intravenous tissue plasminogen activator-failed/ineligible acute intracranial major vessel occlusion between October 2010 and April 2013 at our institution. MRA follow-up was performed at baseline and at 24 +/- 6 hours and 3 months after mechanical thrombectomy. RESULTS: Forty-nine patients underwent mechanical thrombectomy for acute intracranial major vessel occlusion. Mean age was 69.7 +/- 11.5 years, and baseline median National Institute of Health Stroke Scale score was 15 (range, 8-24). Occlusion was found in the internal carotid artery in 18 patients (36.7%), middle cerebral artery in 26 patients (53%), and vertebral-basilar arteries in 5 patients (10.2%). Successful recanalization, as defined by a thrombolysis in cerebral infarction flow grade of 2b or 3, was achieved in 40 patients (81.6%). MRA follow-up at 24 hours after the treatment revealed that reocclusion of recanalized vessels was observed in 3 of 38 patients (7.9%). Long-term MRA follow-up showed that 2 of 27 patients (8.3%) developed diffuse severe stenosis of treated vessels. Both the patients had undergone treatment for middle cerebral artery occlusion with the Merci retriever and had been administered only anticoagulants, but not any antiplatelets. CONCLUSIONS: Reocclusion or late stenosis of successfully recanalized vessels was observed in 16.2% of patients. Long-term MRA follow-up of recanalized vessels will be useful, in particular, for the patient with middle cerebral artery occlusion who undergoes mechanical thrombectomy. PMID- 25440366 TI - Collateral flow and brain changes on computed tomography angiography predict infarct volume on early diffusion-weighted imaging. AB - BACKGROUND: We investigated whether a computed tomography (CT)-based score could predict a large infarct (>= 80 mL) on early diffusion-weighted magnetic resonance imaging (DWI). METHODS: Acute stroke patients considered for endovascular therapy within 8 hours of the onset of symptoms were included. The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) was determined on noncontrast CT and computed tomography angiography source images (CTA-SI). Limited collateral flow was defined as less than 50% collateral filling on CTA-SI. RESULTS: Fifty-six patients were analyzed. National Institutes of Health Stroke Scale score was 20 (15-24) in the large infarct group and 16 (11-20) in the small infarct group (P = .049). ASPECTS on noncontrast CT and CTA-SI was 5 (3-8) and 3 (2-6) in the large infarct group and 9 (8-10) and 8 (7-9) in the small infarct group (both P < .001), respectively. Limited collateral flow was frequent in the large infarct group than in the small infarct group (92% vs. 11%, P < .001). Multivariate analysis found that CTA-SI ASPECTS less than or equal to 5 (odds ratio [OR], 40.55; 95% confidence interval [CI], 1.10-1493.44; P = .044) and limited collateral flow (OR, 114.64; 95% CI, 1.93-6812.79; P = .023) were associated with a large infarct. Absence of ASPECTS less than or equal to 5 and limited collateral flow on CTA-SI predicted absence of a large infarct with a sensitivity of .89, specificity of 1.00, positive predictive value of 1.00, and negative predictive value of .71. CONCLUSIONS: Assessment of ASPECTS and collateral flow on CTA-SI may be able to exclude a patient with large infarct on early DWI. PMID- 25440367 TI - Does large vessel occlusion affect clinical outcome in stroke with mild neurologic deficits after intravenous thrombolysis? AB - BACKGROUND: Large vessel occlusion (LVO) is associated with poor functional outcome in acute ischemic stroke. Given the uncertainty whether LVO has the same significance in mild and severe stroke, we compared functional outcomes after intravenous thrombolysis, based on severity and LVO. METHODS: Ischemic stroke patients were thrombolyzed in less than 4.5 hours after onset between 2007 and 2013. LVO was defined as occlusion of one of the following arteries: internal carotid, middle cerebral (M1/M2), anterior cerebral (A1), posterior cerebral (P1), basilar, or vertebral (V4) arteries on prethrombolysis computed tomography angiography. Mild stroke was defined as baseline National Institutes of Health Stroke Scale (NIHSS) score 0-6. Favorable outcome was defined as modified Rankin Scale (mRS) score 0-1 at 3 months or equal to the prestroke mRS. RESULTS: There were 175 acute stroke patients, median age 74 years (interquartile range [IQR], 64-83), median baseline NIHSS = 11 (IQR, 5-16), and 63 of 175 patients (36%) with mild stroke. LVO was associated with worse outcome in severe stroke (age-adjusted odds ratio [OR] of favorable outcome, .42; 95% confidence interval [CI], .19-.93; P = .033) and mortality (age-adjusted OR, 3.52; 95% CI, 1.08-11.48; P = .037). Although the difference in favorable outcome between mild stroke patients with and without LVO was not significant (55.6% vs. 74.1%, P = .262; age-adjusted OR of favorable outcome, .42; 95% CI, .1-1.84; P = .251), the similarity of effects across both subgroups cannot be excluded (LVO-by-stroke severity interaction test, P = .906). CONCLUSIONS: LVO is associated with worse functional outcome and mortality in severe stroke after intravenous thrombolysis. Although significant association between LVO and outcome in mild stroke was not found, there were similar effects on outcome and a larger study might well confirm a relationship. PMID- 25440369 TI - Depiction of the vasa vasorum during carotid endarterectomy by intraoperative videoangiography. AB - BACKGROUND: The aim of the study was to investigate the depiction of the carotid artery by fluorescein sodium (FS) videoangiography compared with indocyanine green (ICG) videoangiography, focusing on how the vasa vasorum of the carotid artery is depicted. METHODS: Thirty-five patients (19 FS patients, 16 ICG patients, mean age 69.4 +/- 5.1 years, mean degree of stenosis 78.7% +/- 11.7%) who underwent a carotid endarterectomy (CEA) were enrolled. FS (5-6 mg/kg) or ICG (.2-.3 mg/kg) was injected intravenously as a bolus before the arterectomy during the CEA. The intravascular fluorescence signal was recorded with a digital video camera integrated on a microscope. Magnetic resonance imaging black-blood (BB) T1 weighted imaging (WI) was preoperatively performed using a 1.5-T whole-body imager, and the signal intensity ratio relative to the ipsilateral sternocleidomastoid muscle on BB-T1WI (BB-SIR) was calculated. We also performed an immunohistochemistry study using CD31 and CD68 antibodies for plaque specimens. RESULTS: In the FS videoangiography series, the vasa vasorum of carotid adventitia was depicted first, followed by augmentation of FS of the wall and partially the inner lumen (pattern A) in 6 cases. Augmentation of FS of the wall and inner lumen prior or simultaneous to the depiction of the vasa vasorum of the carotid adventitia (pattern B) were observed in 13 cases. The average BB SIR value of the pattern B cases was significantly higher than that in the pattern A group (P < .05). Most of the plaques with BB-SIR values higher than 1.25 also belonged to the pattern B group (90.9%). Microvessels stained by CD31 and macrophages stained by CD68 were more frequently observed in the high-BB-SIR plaques. In contrast, the ICG videoangiography uniformly showed pattern B in all 16 cases, because of the fluorolucency of the carotid wall revealed by the ICG. CONCLUSIONS: The early depiction of adventitial vasa vasorum in FS videoangiography was inversely associated with the BB-SIR values of the plaques, along with many microvessels and macrophages that have been reported to have a tendency of intraplaque hemorrhage or symptoms. The present results may support the idea of an intimal origin of the neovascularization in vulnerable carotid plaques, and they demonstrated the potential of intraoperative plaque imaging by FS videoangiography. PMID- 25440370 TI - Acute stroke symptoms: do differences exist between sexes? AB - BACKGROUND: Previous studies have reported that women with stroke often present different stroke symptoms than men. The aim of our study was to assess for the relevance of these differences from a large case series. METHODS: Consecutive patients admitted to the Stroke Unit at the University of Perugia, with acute stroke or transient ischemic attack between 1 June, 2005, and May 2012, and recorded in Perugia Stroke Registry were prospectively included. Associations between the recorded symptoms and sex were assessed by preliminary cross tabulations with the Chi-square test or Fisher exact test with Yate correction when appropriate. Multivariable regression analysis was used to identify independent predictors of a single symptom including sex as an independent variable. RESULTS: Overall, 1072 men and 811 women were included in this study. Women had a higher average age at onset (75.40 +/- 12.90 years in women and 70.14 +/- 12.61 years in men) and presented more severe strokes with higher National Institute of Health Stroke Scale scores than men, whereas men were more likely to have a posterior stroke.Regarding symptoms, multivariate analysis revealed correlations between postural instability and male sex and between dysphagia and female sex. CONCLUSIONS: We found no differences in the clinical presentation of stroke between the sexes, except that men were more likely to have postural instability and females were more likely to have dysphagia. These findings suggest that stroke locations and stroke severity were associated with sex. PMID- 25440371 TI - Acute free-floating carotid artery thrombus causing stroke in a young patient: unique etiology and management using endovascular approach. AB - Atherosclerotic disease accounts for 20%-30% of strokes in the general population. In young adults, it is an unexpected event and its causes involve diverse pathologies. Herein, we describe a unique case of acute embolic stroke in a young adult patient due to the presence of a large clot in the right common and internal carotid arteries, as a result of an extrinsic cause. Surgical clot retrieval was considered unsafe at that point in time in view of the active inflammatory changes surrounding the affected vessels. This was eventually treated with a novel endovascular technique, a unique alternative to open surgery, with excellent clinical outcome. To our knowledge, the penumbra system has never been used for thrombus removal in a nonacute setting. PMID- 25440368 TI - A case-control study of the effectiveness of tissue plasminogen activator on 6 month patients--reported outcomes and health care utilization. AB - We examined the benefit of tissue plasminogen activator (tPA), delivered as part of usual stroke management, on patient-reported outcomes and health care utilization. Using a case control design, patients who received tPA as part of usual stroke management were compared with patients who would have received tPA had they arrived to the hospital within the therapeutic time window. Data were collected from surveys 6 months after stroke using standardized patient-reported outcome measures and questions about health care utilization. Demographic and medical data were acquired from hospital records. Patients were matched on stroke severity, age, race, and gender. Matching was done with 1:2 ratio of tPA to controls. Results were compared between groups with 1-tailed tests because of a directionally specific hypothesis in favor of the tPA group. The tPA (n = 78) and control (n = 156) groups were matched across variables, except for stroke severity, which was better in the control group; subsequent analyses controlled for this mismatch. The tPA group reported better physical function, communication, cognitive ability, depressive symptomatology, and quality of life/participation compared with the control group. Fewer people in the tPA group reported skilled nursing facility stays, emergency department visits, and rehospitalizations after their stroke compared with controls. Reports of other postacute services were not different between groups. Although it is known that tPA reduces disability, this is the first study to demonstrate the effectiveness of tPA in improving meaningful, patient-reported outcomes. Thus, use of tPA provides a large benefit to the daily lives of people with ischemic stroke. PMID- 25440372 TI - Antiplasmodial activity of chloroquine analogs against chloroquine-resistant parasites, docking studies and mechanisms of drug action. AB - BACKGROUND: Given the threat of resistance of human malaria parasites, including to artemisinin derivatives, new agents are needed. Chloroquine (CQ) has been the most widely used anti-malarial, and new analogs (CQAns) presenting alkynes and side chain variations with high antiplasmodial activity were evaluated. METHODS: Six diaminealkyne and diaminedialkyne CQAns were evaluated against CQ-resistant (CQ-R) (W2) and CQ-sensitive (CQ-S) (3D7) Plasmodium falciparum parasites in culture. Drug cytotoxicity to a human hepatoma cell line (HepG2) evaluated, allowed to calculate the drug selectivity index (SI), a ratio of drug toxicity to activity in vitro. The CQAns were re-evaluated against CQ-resistant and sensitive P. berghei parasites in mice using the suppressive test. Docking studies with the CQAns and the human (HssLDH) or plasmodial lactate dehydrogenase (PfLDH) enzymes, and, a beta-haematin formation assay were performed using a lipid as a catalyst to promote crystallization in vitro. RESULTS: All tested CQAns were highly active against CQ-R P. falciparum parasites, exhibiting half maximal inhibitory concentration (IC(50)) values below 1 MUMU. CQAn33 and CQAn37 had the highest SIs. Docking studies revealed the best conformation of CQAn33 inside the binding pocket of PfLDH; specificity between the residues involved in H-bonds of the PfLDH with CQAn37. CQAn33 and CQAn37 were also shown to be weak inhibitors of PfLDH. CQAn33 and CQAn37 inhibited beta-haematin formation with either a similar or a 2-fold higher IC(50) value, respectively, compared with CQ. CQAn37 was active in mice with P. berghei, reducing parasitaemia by 100%. CQAn33, -39 and -45 also inhibited CQ-resistant P. berghei parasites in mice, whereas high doses of CQ were inactive. CONCLUSIONS: The presence of an alkyne group and the size of the side chain affected anti-P. falciparum activity in vitro. Docking studies suggested a mechanism of action other than PfLDH inhibition. The beta haematin assay suggested the presence of an additional mechanism of action of CQAn33 and CQAn37. Tests with CQAn34, CQAn37, CQAn39 and CQAn45 confirmed previous results against P. berghei malaria in mice, and CQAn33, 39 and 45 were active against CQ-resistant parasites, but CQAn28 and CQAn34 were not. The result likely reflects structure-activity relationships related to the resistant phenotype. PMID- 25440373 TI - Short-term effects of acupuncture and stretching on myofascial trigger point pain of the neck: a blinded, placebo-controlled RCT. AB - OBJECTIVES: This trial aimed to evaluate the short-term effectiveness of acupuncture plus stretching to reduce pain and improve range of motion in patients afflicted by cervical myofascial pain syndrome. DESIGN: Randomized, blinded, placebo-controlled crossover study. INTERVENTION: Nineteen patients (11 females, eight males, 33 +/- 14 years) with myofascial neck pain in randomized order received the following treatments with one week washout between: acupuncture, acupuncture plus stretching, and placebo laser acupuncture. MAIN OUTCOME MEASURES: Mechanical pain threshold (MPT, measured with a pressure algometer) represented the primary outcome. Secondary outcomes were motion related pain (Visual Analogue Scale, VAS) and cervical range of motion (ROM, recorded by means of an ultrasonic 3D movement analysis system). Outcomes were assessed immediately prior as well as 5, 15 and 30 min post treatment. Friedman tests with post hoc Bonferroni-Holm correction were applied to compare differences between treatments. RESULTS: Both acupuncture as well as acupuncture plus stretching increased MPT by five, respectively, 11 percent post treatment. However, only acupuncture in combination with stretching was superior to placebo (p<0.05). There were no significant differences between interventions at 15 and 30 min post treatment. VAS did not differ between treatments at any measurement. Five minutes after application of acupuncture plus stretching, ROM was significantly increased in the frontal and the transversal plane compared to placebo (p<0.05). CONCLUSIONS: The combination of acupuncture and stretching could represent a suitable treatment option to improve cervical movement behavior and reduce trigger point pain in the short-term. However, additional studies further discriminating the placebo effects are still warranted. PMID- 25440374 TI - Shenzhu Tiaopi granule combined with lifestyle intervention therapy for impaired glucose tolerance: a randomized controlled trial. AB - OBJECTIVE: The purpose of the study was to evaluate the clinical effects of the Shenzhu Tiaopi granule (SZTP) combined with a lifestyle intervention in patients with impaired glucose tolerance (IGT), who also had a spleen deficiency and damp overabundance syndrome (SDDOS). METHODS: After a one-month washout period, a total of 514 patients were randomly assigned to the control (lifestyle intervention) and experimental (SZTP plus lifestyle intervention) groups, with 257 patients in each group. Patients in the control group received the lifestyle intervention (diet and exercise) for 12 months, while the patients in the experimental group were treated with SZTP plus the lifestyle intervention for 12 months. The Traditional Chinese Medicinal (TCM) symptom scores were observed in each group before and after treatment; the conversion rates from IGT to diabetes mellitus (DM) were also measured. RESULTS: Following 12 months of treatment, the conversion rate from IGT to DM in the experimental group was significantly lower than in the control group (8.52% vs. 15.28%, P<0.05). A significantly higher number of patients with IGT reverted to normal blood glucose levels in the experimental group than in the control group (42.15% vs. 32.87%, P<0.05). In addition, after following the treatment for 12 months, the TCM symptoms of patients in the experimental group were markedly alleviated, as compared to the control group (P<0.01). CONCLUSION: The combination of SZTP and lifestyle intervention showed a reduction in the conversion from IGT to DM, and an increase in the conversion from IGT to normal blood glucose levels. PMID- 25440375 TI - Lipid-modifying effects of adjunctive therapy with curcuminoids-piperine combination in patients with metabolic syndrome: results of a randomized controlled trial. AB - BACKGROUND: Dyslipidemia is an established feature of metabolic syndrome (MS) that is associated with an increased risk of atherosclerotic cardiovascular disease. Curcuminoids are natural products with anti-atherosclerotic and lipid modifying effects but their efficacy in patients with MS has not yet been tested. OBJECTIVE: To investigate the effects of bioavailability-enhanced curcuminoids, as adjunctive to standard of care, on serum lipid concentrations in patients with MS. METHODS: Patients diagnosed with MS according to the NCEP-ATPIII criteria who were receiving standard of care were assigned to either curcuminoids (C3 complex((r)); 1000 mg/day; n=50) or placebo (n=50; matched with drug capsules in shape and color) for 8 weeks. In order to improve the oral bioavailability, curcuminoids were co-administered with piperine (bioperine((r))) in a ratio of 100:1. Serum concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, small dense LDL (sdLDL), lipoprotein(a) [Lp(a)], and non-HDL-C were determined at baseline and at the end of 8-week treatment period. RESULTS: Curcuminoids were more effective than placebo in reducing serum LDL-C, non-HDL-C, total cholesterol, triglycerides and Lp(a), and elevating HDL-C concentrations. However, changes in serum sdLDL levels were found to be comparable between the study groups. The effects of curcuminoids on triglycerides, non-HDL-C, total cholesterol and Lp(a) remained significant after adjustment for baseline values of lipids and body mass index. CONCLUSION: Curcuminoids-piperine combination is an efficacious adjunctive therapy in patients with MS and can modify serum lipid concentrations beyond what is achieved with standard of care. PMID- 25440376 TI - Effects of auricular stimulation in the cavum conchae on glucometabolism in patients with type 2 diabetes mellitus. AB - OBJECTIVE: To investigate the effect of auricular stimulation in cavum conchae on the glycemic control for patients with type 2 diabetes mellitus. METHODS: Seventy one cases were treated with auricular electrical stimulator in the cavum choncha for 30 min, once daily for consecutive 3 months. The changes on the fasting plasma glucose (FBG), 2-h postprandial blood glucose after a 75 g oral glucose load (P2BG), glycated hemoglobin (HbA1c), blood urea nitrogen (BUN), serum creatinine (SCr), total cholesterol (TC) and aspartate transaminase (AST) were compared before and after the treatment. RESULTS: The level of the HbA1c was significantly decreased (P<0.05), and there were also statistically significant decreases in BUN, SCr, TC and AST after the treatment (P<0.05). A few patients (n=7) reduced the dose of the hypoglycemic agents in response to repeated hypoglycemia during the treatment. CONCLUSION: The stimulation in the cavum conchae of patients with types 2 diabetes mellitus may help decrease HbA1c, BUN, SCr, TC and AST, and may be an effective treatment for type 2 diabetes mellitus. PMID- 25440377 TI - Effects of Elaeagnus angustifolia L. supplementation on serum levels of inflammatory cytokines and matrix metalloproteinases in females with knee osteoarthritis. AB - OBJECTIVE: In an attempt to investigate new strategies aimed at reducing inflammation in osteoarthritis, the anti-inflammatory effect of Elaeagnus angustifolia L. as a complementary treatment was evaluated in females with knee osteoarthritis. METHOD: In this clinical trial, 90 females with mild to moderate osteoarthritis were assigned to two intervention and one placebo groups. In addition to the conventional therapy, the patients in intervention groups received 15g/day of E. angustifolia L. medulla and whole fruit powders respectively for 8 weeks. The levels of tumor necrosis factor-alpha (TNF-alpha), interleukine-1beta (IL-1beta), interleukine-10 (IL-10), matrix metalloproteinase 1 (MMP-1) and -13 (MMP-13) were measured with human ELISA kits. Paired t-test and ANOVA were used for statistical analysis. RESULTS: The statistically significant decrease was observed in the mean levels of serum TNF-alpha in the medulla (0.004) and whole fruit (0.001) groups after 8 weeks of supplementation. In contrast to the placebo group, there was a significant rise in the mean levels of serum IL-10 in medulla (p-value=0.01) and whole fruit groups (p-value=0.009) at the end of study. The interventions resulted in significant decrease in the mean levels of serum MMP-1 in the medulla (0.001) and whole fruit (0.002) groups. After the interventions, no significant changes were observed in the serum IL 1beta and MMP-13 levels. CONCLUSION: Daily supplementation with E. angustifolia L. in both forms of medulla and whole fruit powders appeared to be effective for decreasing inflammatory cytokines (TNF-alpha and MMP-1) and enhancing anti inflammatory cytokines (IL-10). PMID- 25440378 TI - 'Less like a drug than a drug': the use of St John's wort among people who self identify as having depression and/or anxiety symptoms. AB - OBJECTIVE: St John's wort (SJW) is one of the most commonly used complementary medicines (CM) for the self-treatment of depression which can be accessed with or without health professional advice. While there is evidence to support its effectiveness in depression it has potential for serious side effects and interactions with many pharmaceuticals and herbs. Despite the potential risks, we know little about consumer perspectives on the use of SJW. Our research aimed to understand, from their own perspective, how and why people use SJW for management of self-identified 'depression, stress or worries'. DESIGN: A qualitative design, focusing on understanding the reasons for SJW use. A purposive sampling strategy was used to recruit 41 people who self-identified as having used SJW for 'depression stress or worries' from the community in Melbourne, Australia. In depth face-to-face interviews were conducted. Interviews were taped, transcribed and analysed thematically. RESULTS: Three themes emerged as to why participants used SJW - ease of access of SJW, perceptions of effectiveness and safety of SJW enabling control over its use, and the perceived benefits of using a natural product. Generally, participants did not reserve use of SJW only for mild depressive symptoms. CONCLUSIONS: People use many self-care strategies to manage symptoms of depression, including more severe symptoms. While there is often a preference for more natural approaches like SJW, people experiment and continue to use what they perceive is most effective for them. PMID- 25440379 TI - The clinical absolute and relative scoring system-a quantitative scale measuring myasthenia gravis severity and outcome used in the traditional Chinese medicine. AB - Myasthenia gravis (MG) is a chronic autoimmune disease caused by autoantigen against the nicotine acetylcholine receptor at the neuromuscular junction. With modern treatment facilities, the treatment effect and outcome for MG has been greatly improved with MG and non-MG patients enjoying the same life expectancy. Many classifications of disease distribution and severity have been set up and tested all over the world, mainly in the western world. However, the absolute and relative scoring system for evaluating the severity and treatment effect of MG in China where traditional Chinese medicine (TCM) has been practiced for thousands of years has not been introduced worldwide. The TCM has achieved a great success in the treatment of MG in the country with a huge population. This article serves to introduce this scoring system to the world. PMID- 25440381 TI - The use of conventional and complementary therapies for insomnia among Hong Kong Chinese: a telephone survey. AB - OBJECTIVE: To examine the prevalence and utilization pattern of complementary and alternative medicine (CAM) for insomnia in Hong Kong. METHODS: Respondents were selected from the general population and interviewed by telephone Their sleep was assessed by a Chinese version of the Brief Insomnia Questionnaire (BIQ) and CAM use by a checklist. Prevalence findings were weighted by the BIQ insomnia diagnosis, age, and sex. RESULTS: 402 respondents completed the survey. The population-weighted prevalence of any treatment in the past 12 months was 21.3%, any CAM use at 12.3%, any conventional treatment at 6.5%, and alcohol use at 1.6%; however, 46.6% of the BIQ insomnia cases did not seek treatment. The most commonly used CAM modalities was Chinese herbal medicine (7.9%), followed by acupuncture (1.7%) and Western herbal products (1.7%). Most CAM therapies were used infrequently and without consultation of healthcare professionals. Only BIQ insomnia diagnosis and being female were found predictive of CAM use. CONCLUSIONS: Apart from Chinese herbal medicine and acupuncture, the use of conventional treatments, CAM, and alcohol for trouble sleeping was all less common in Hong Kong. Public education on the consequences of insomnia and various treatment modalities is needed. PMID- 25440380 TI - Potential synergistic effects of Chinese herbal prescription FTZ components detected in blood towards hepatic lipid-modulating targets. AB - OBJECTIVE: Our goal in this study aims to explain the polypharmacological mechanism at the molecular level responsible for the effectiveness of a traditional Chinese medicine (TCM) prescription FTZ to treat hyperlipidemia and related disease. DESIGN: By MDL((r)) ISIS_Base 2.5, we constructed a compound database based on the FTZ constituents, which were detected in the rat serum after oral administration of the TCM through ultra-performance liquid chromatography/quadruple-time-of-flight mass-spectrometry (UPLC/Q-TOF-MS/MS) method. After validation of the virtual docking system, we used molecular screening by LigandFit which is a computational method for the shape-directed rapid docking of ligands to target protein active sites, to investigate the interactions between the components in database and lipid-modulating targets in the liver. RESULTS: In the prescription FTZ ingredients, there were sixteen constituents including jatrorrhizine, etc. showed potential effects towards the hyperlipidemia-related targets: HMG-CoA reductase (HMGR), squalene synthase (SQS), oxidosqualene cyclase (OSC), cholesteryl ester transfer protein (CETP), liver X receptor (LXR), farnesoid X receptor (FXR) and peroxisome proliferator activated receptors (PPARalpha and PPARgamma). Among the eight herbs in prescription FTZ, Rhizoma Coptidis (RC) plays the most important role in whole effect from FTZ on hyperlipidemia related disease. CONCLUSIONS: Our research demonstrated that Chinese medicine formula FTZ has multi-target synergistic effect on hyperlipidemia and suggests the pharmacodynamic material basis could be jatrorrhizine, berberrubine, berberine and salidroside. PMID- 25440382 TI - "I assumed that one was a placebo": exploring the consent process in a sham controlled acupressure trial. AB - OBJECTIVES: In clinical trials where participants are likely to be able to distinguish between true and sham interventions, informing participants that they may receive a sham intervention increases the likelihood of participants 'breaking the blind' and invalidating trial findings. The present study explored participants' perceptions of the consent process in a sham controlled acupressure trial which did not explicitly indicate participants may receive a sham intervention. DESIGN: Nested qualitative study within a randomised sham controlled trial of acupressure wristbands for chemotherapy-related nausea. Convenience sample of 26 patients participated in semi-structured interviews. Interviews were audio-recorded and transcribed verbatim. Transcripts analysed thematically using framework analysis. SETTING: Study conducted within three geographical sites in the UK: Manchester, Liverpool, and Plymouth. RESULTS: All participants indicated that they believed they were fully informed when providing written consent to participate in the trial. Participants' perceived it was acceptable to employ a sham intervention within the trial of acupressure wristbands without informing potential participants that they may receive a sham treatment. Despite the fact that participants were not informed that one of the treatment arms was a sham intervention the majority indicated they assumed one of the treatment arms would be placebo. CONCLUSIONS: Many trials of acupuncture and acupressure do not inform participants they may receive a sham intervention. The current study indicates patients' perceive this approach to the consent process as acceptable. However, the fact participants assume one treatment may be placebo threatens the methodological basis for utilising this approach to the consent process. PMID- 25440383 TI - Components and reporting of yoga interventions for musculoskeletal conditions: a systematic review of randomised controlled trials. AB - OBJECTIVES: To identify the content and reporting details of randomised controlled trials of yoga for musculoskeletal conditions through a systematic review of the literature. DESIGN: Twenty electronic databases were searched to identify randomised controlled trials (RCTs) of yoga interventions for musculoskeletal conditions. Eligibility criteria were full-text, peer reviewed articles, of RCTs with yoga as a primary intervention, on a population aged 18 years and over, with a clinical diagnosis of a musculoskeletal condition. Data relating to study characteristics, yoga styles, yoga practices, home practice, and reporting were extracted and summarised. RESULTS: Seventeen articles met inclusion criteria, representing five musculoskeletal conditions: low back pain, osteoarthritis, rheumatoid arthritis, kyphosis, and fibromyalgia. 15 studies were non-residential, and two were residential. Study duration ranged from 1 to 24 weeks; weekly dosage of yoga ranged from 1 to 56h. Five styles of posture-based Hatha yoga were specified. Intervention content included seven yoga practises: postures, breathing, relaxation, meditation, philosophy, chanting, and cleansing practises. Ten studies either encouraged or requested home practice. Reporting details included class plans, posture lists, and diagrams. Due to insufficient detail regarding delivery of the yoga intervention only eight of the 17 interventions were considered replicable as reported. CONCLUSIONS: Evaluation of study characteristics and yoga components indicated several areas of homogeneity across studies, suggesting an existing degree of standardisation. However, heterogeneity related to intervention content and reporting impeded determination of intervention content and delivery. Standardisation of content, nomenclature, and reporting details is recommended to enhance protocol transparency, replication, and comparison of intervention effectiveness. PMID- 25440385 TI - Effectiveness of horticultural therapy: a systematic review of randomized controlled trials. AB - AIM: To summarize the evidence from randomized controlled trials (RCTs) on the effects of horticultural therapy (HT). METHODS: Studies were eligible if they were RCTs. Studies included one treatment group in which HT was applied. We searched the following databases from 1990 up to August 20, 2013: MEDLINE via PubMed, CINAHL, Web of Science, Ichushi-Web, GHL, WPRIM, and PsyclNFO. We also searched all Cochrane Database and Campbell Systematic Reviews up to September 20, 2013. RESULTS: Four studies met all inclusion criteria. The language of all eligible publications was English and Korean. Target diseases and/or symptoms were dementia, severe mental illness such as schizophrenia, bipolar disorder, and major depression, frail elderly in nursing home, and hemiplegic patients after stroke. These studies showed significant effectiveness in one or more outcomes for mental health and behavior. However, our review especially detected omissions of the following descriptions: method used to generate randomization, concealment, blinding, and intention-to-treat analysis. In addition, the results of this study suggested that the RCTs conducted have been of relatively low quality. CONCLUSION: Although there was insufficient evidence in the studies of HT due to poor methodological and reporting quality and heterogeneity, HT may be an effective treatment for mental and behavioral disorders such as dementia, schizophrenia, depression, and terminal-care for cancer. PMID- 25440386 TI - Therapeutic potential of Panax ginseng and ginsenosides in the treatment of chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major global health burden and will become the third largest cause of death in the world by 2030. It is currently believed that an exaggerated inflammatory response to inhaled irritants, in particular cigarette smoke, cause progressive airflow limitation. This inflammation, where macrophages, neutrophils and lymphocytes are prominent, leads to oxidative stress, emphysema, airways fibrosis and mucus hypersecretion. COPD responds poorly to current anti-inflammatory treatments including corticosteroids, which produce little or no benefit. Panax ginseng has a long history of use in Chinese medicine for respiratory conditions, including asthma and COPD. OBJECTIVES: In this perspective we consider the therapeutic potential of Panax ginseng for the treatment of COPD. RESULTS: Panax ginseng and its compounds, ginsenosides, have reported effects through multiple mechanisms but primarily have anti-inflammatory and anti-oxidative effects. Ginsenosides are functional ligands of glucocorticoid receptors and appear to inhibit kinase phosphorylation including MAPK and ERK1/2, NF-kappaB transcription factor induction/translocation, and DNA binding. They also inhibit pro-inflammatory mediators, TNF-alpha, IL-6, IL-8, ROS, and proteases such as MMP-9. Panax ginseng protects against oxidative stress by increasing anti-oxidative enzymes and reducing the production of oxidants. CONCLUSION: Given that Panax ginseng and ginsenosides appear to inhibit processes related to COPD pathogenesis, they represent an attractive therapeutic target for the treatment of COPD. PMID- 25440387 TI - Safety aspects of Chinese herbal medicine in pregnancy-re-evaluation of experimental data of two animal studies and the clinical experience. AB - INTRODUCTION: Chinese herbal medicine is an increasingly popular worldwide medical therapy which also has an impact in pregnancy. However, the question of its drug safety during pregnancy remains unresolved. Potential problems include teratogenicity, abortion, perinatal toxicity, pre- and postnatal developmental abnormalities, and eventually an increased risk for carcinomas in the offspring. Standard Materia Medica textbooks contain unreliable information when it comes to risks during pregnancy. Wang and co-workers conducted an experimental study (WS) on mice in which they investigated the effects of 17 Chinese medicinals regarding embryotoxicity and fetotoxicity. All these drugs seemed to exhibit multiple significant toxic effects. Another study by Li and co-workers (LS) investigated the reproductive toxicity of Atractylodis macrocephalae Rhizoma in mice, rats and rabbits. They described an increased pre- and postnatal mortality and, at high doses, congenital malformations. In an attempt to identify the risks of the tested medicinals during pregnancy, we analysed these two experimental studies and compared their results with possible safety data for humans from two reviews of clinical studies on threatened miscarriage (AR and CR). METHODS: We re evaluated WS and LS in relation to accordance with internationally accepted rules, equivalence to human dose, biometric accuracy, plausibility, and coherence. Eligible studies of the two reviews on threatened miscarriage were evaluated for specific pregnancy risks concerning the 17 medicinals tested in WS and LS. RESULTS: We found that WS does not conform to international ICH guidelines and includes many inconsistencies, implausibilities and several severe biometrical flaws. It reported a total of 364 significant events out of which 145 false significant results are expected. The data-handling pointed to irregularities. Analysis of LS exhibited also many inconsistencies. The results regarding congenital malformations were statistically insignificant and are based on small case numbers. Insofar as the safety data of the 17 medicinals were documented by eligible studies of the two reviews, there was no indication of an increased abortion rate in humans. Fetal growth retardation was not observed in the human studies. For neonatal health and postnatal development, there were sufficient safety data only for a few medicinals in the human studies. As for teratogenicity, only small case numbers (0 to 109) were available from the human data. CONCLUSION: WS and LS are not reliable data sources for deriving pregnancy risks in humans for the tested Chinese medicinals. In addition, the results appear to contradict the outcomes observed in the treatment of humans. Regarding teratogenicity, for most Chinese medicinals, neither the safety nor the risk during pregnancy can be definitively ascertained. Further studies on the risks of Chinese medicinals during pregnancy are urgently needed. PMID- 25440384 TI - Comparison groups in yoga research: a systematic review and critical evaluation of the literature. AB - OBJECTIVES: Comparison groups are essential for accurate testing and interpretation of yoga intervention trials. However, selecting proper comparison groups is difficult because yoga comprises a very heterogeneous set of practices and its mechanisms of effect have not been conclusively established. METHODS: We conducted a systematic review of the control and comparison groups used in published randomized controlled trials (RCTs) of yoga. RESULTS: We located 128 RCTs that met our inclusion criteria; of these, 65 included only a passive control and 63 included at least one active comparison group. Primary comparison groups were physical exercise (43%), relaxation/meditation (20%), and education (16%). Studies rarely provided a strong rationale for choice of comparison. Considering year of publication, the use of active controls in yoga research appears to be slowly increasing over time. CONCLUSIONS: Given that yoga has been established as a potentially powerful intervention, future research should use active control groups. Further, care is needed to select comparison conditions that help to isolate the specific mechanisms of yoga's effects. PMID- 25440388 TI - Blood--the most important humour? PMID- 25440389 TI - Modern banking, collection, compatibility testing and storage of blood and blood components. AB - The clinical practice of blood transfusion has changed considerably over the last few decades. The potential risk of transfusion transmissible diseases has directed efforts towards the production of safe and high quality blood. All transfusion services now operate in an environment of ever-increasing regulatory controls encompassing all aspects of blood collection, processing and storage. Stringent donor selection, identification of pathogens that can be transmitted through blood, and development of technologies that can enhance the quality of blood, have all led to a substantial reduction in potential risks and complications associated with blood transfusion. In this article, we will discuss the current standards required for the manufacture of blood, starting from blood collection, through processing and on to storage. PMID- 25440390 TI - Evidence and triggers for the transfusion of blood and blood products. AB - Allogeneic red cell transfusion is a commonly used treatment to improve the oxygen carrying capacity of blood during the peri-operative period. Increasing arterial oxygen content by increasing haemoglobin does not necessarily increase tissue oxygen delivery or uptake. Although the evidence-base for red cell transfusion practice is incomplete, randomised studies across a range of clinical settings, including surgery, consistently support the restrictive use of red cells, with no evidence of benefit for maintaining patients at higher haemoglobin thresholds (liberal strategy). A recent meta-analysis of 7593 patients concluded that a restrictive transfusion strategy was associated with a reduced risk of healthcare-associated infections (pneumonia, mediastinitis, wound infection, sepsis) when compared with a liberal transfusion strategy. The degree to which the optimal haemoglobin concentration or transfusion trigger should be modified for patients with additional specific risk factors (e.g. ischaemic heart disease), remains less clear and requires further research. Although most clinical practice guidelines recommend restrictive use of red cells, and many blood transfusion services have seen marked falls in overall usage of red cells, the use of other blood components such as fresh frozen plasma, platelets, and cryoprecipitate has risen. In clinical practice, administration of fresh frozen plasma is usually guided by laboratory tests of coagulation, mainly prothrombin time, international normalised ratio and activated partial thromboplastin time, but the predictive value of these tests to predict bleeding is poor. PMID- 25440391 TI - Pre-operative anaemia. AB - Pre-operative anaemia is a relatively common finding, affecting a third of patients undergoing elective surgery. Traditionally associated with chronic disease, management has historically focused on the use of blood transfusion as a solution for anaemia in the peri-operative period. Data from large series now suggest that anaemia is an independent risk associated with poor outcome in both cardiac and non-cardiac surgery. Furthermore, blood transfusion does not appear to ameliorate this risk, and in fact may increase the risk of postoperative complications and hospital length of stay. Consequently, there is a need to identify, diagnose and manage pre-operative anaemia to reduce surgical risk. Discoveries in the pathways of iron metabolism have found that chronic disease can cause a state of functional iron deficiency leading to anaemia. The key iron regulatory protein hepcidin, activated in response to inflammation, inhibits absorption of iron from the gastrointestinal tract and further reduces bioavailability of iron stores for red cell production. Consequently, although iron stores (predominantly ferritin) may be normal, the transport of iron either from the gastrointestinal tract or iron stores to the bone marrow is inhibited, leading to a state of 'functional' iron deficiency and subsequent anaemia. Since absorption from the gastrointestinal tract is blocked, increasing oral iron intake is ineffective, and studies are now looking at the role of intravenous iron to treat anaemia in the surgical setting. In this article, we review the incidence and impact of anaemia on the pre-operative patient. We explain how anaemia may be caused by functional iron deficiency, and how iron deficiency anaemia may be diagnosed and treated. PMID- 25440392 TI - The pathophysiology and consequences of red blood cell storage. AB - Red cell transfusion therapy is a common treatment modality in contemporary medical practice. Although blood collection and administration is safer and more efficient than ever before, red cells undergo multiple metabolic and structural changes during storage that may compromise their functionality and viability following transfusion. The clinical relevance of these changes is a hotly debated topic that continues to be a matter of intense investigation. In the current review, we begin with an in-depth overview of the pathophysiological mechanisms underlying red cell storage, with a focus on altered metabolism, oxidative stress and red cell membrane damage. We proceed to review the current state of evidence on the clinical relevance and consequences of the red cell storage lesion, while discussing the strengths and limitations of clinical studies. PMID- 25440393 TI - Red cell transfusion and the immune system. AB - Understanding the complex immunological consequences of red cell transfusion is essential if we are to use this valuable resource wisely and safely. The decision to transfuse red cells should be made after serious considerations of the associated risks and benefits. Immunological risks of transfusion include major incompatibility reactions and transfusion-related acute lung injury, while other immunological insults such as transfusion-related immunomodulation are relatively underappreciated. Red cell transfusions should be acknowledged as immunological exposures, with consequences weighed against expected benefits. This article reviews immunological consequences and the emerging evidence that may inform risk benefit considerations in clinical practice. PMID- 25440394 TI - The current place of aprotinin in the management of bleeding. AB - There is a considerable difference between the mechanism of action of the lysine analogues, tranexamic acid and epsilon-aminocaproic acid, and the serine protease inhibitor aprotinin. Aprotinin acts to inactivate free plasmin, but with little effect on bound plasmin, whereas the lysine analogues are designed to prevent excessive plasmin formation by fitting into plasminogen's lysine-binding site to prevent the binding of plasminogen to fibrin. Aprotinin is associated with a reduction in bleeding and transfusion requirements following major surgery, and has a dose-response profile, compared with no dose-response effect in the one study investigating tranexamic acid in cardiac surgical patients. Following its withdrawal in 2007, which is explained in detail in this review, the regulators have now licensed aprotinin for myocardial revascularisation only, which is relatively low-risk for bleeding. PMID- 25440395 TI - The current place of tranexamic acid in the management of bleeding. AB - There has been an explosion of interest in the ability of tranexamic acid to reduce morbidity and mortality in surgical and traumatic bleeding. Tranexamic acid has been shown to reduce mortality due to traumatic bleeding by a third, without apparent safety issues. It is now clearly established that intravenous tranexamic acid reduces blood loss in patients with surgical bleeding and the need for transfusion. It can also be used topically to reduce bleeding. Its use is being explored further in large pragmatic trials in traumatic head injury, postpartum haemorrhage and in upper gastro-intestinal haemorrhage. There are few side effects from the use of tranexamic acid except when administered in high dose where neurological events have been noted, possibly relating to tranexamic acid interfering with cerebral GABA and glycine receptors. However, clinical studies suggest that there is no increased efficacy in using a higher dose, and that a dose of 1 g intravenously in an adult patient has maximal efficacy, which is not increased by higher doses. The CRASH-2 trauma trial clearly showed no increase in thrombotic events after its use in trauma, indeed there was a significant reduction in myocardial infarction. However, trials of tranexamic acid in surgery have failed to adequately study its effects on the risk of postoperative venous and possible reduction in arterial thrombo-embolism, and this needs to be the subject of future research. PMID- 25440396 TI - Practical management of major blood loss. AB - The pathophysiology of bleeding, regardless of cause, is complex and ill understood. For traumatic or sudden unexpected haemorrhage, the use of transfusion packs with red cells, fresh frozen plasma, cryoprecipitate and platelets being given in ratios of between 1:1 and 1:3 seems reasonable. This removes the requirement for 'wait and see tests' and should be part of an overall resuscitation and stabilisation plan that may improve outcome following sudden haemorrhage. The replacement of fresh frozen plasma and cryoprecipitate with low volume, targeted concentrates is attractive. There is increasing evidence for the efficacy and safety of fibrinogen concentrates as a single agent. The combination of fibrinogen and prothrombin complex concentrates could be powerful and has the possibility to the management of bleeding and improve outcome in patients but, as yet, remains unproven. PMID- 25440397 TI - Management of peri-operative anti-thrombotic therapy. AB - The management of antithrombotic therapy in the peri-operative setting is a common problem, balancing haemorrhagic risk with continued treatment and thrombotic risk when discontinued. High-quality evidence is lacking regarding the optimal approach for patients on oral anticoagulants or antiplatelet agents. This review discusses the available evidence for the management of patients on warfarin, non-vitamin K antagonist oral anticoagulant drugs, and antiplatelet therapy in the peri-operative setting. Bridging therapy for patients on warfarin should be considered for those at highest risk of thrombosis, whereas it may not be necessary for those on non-vitamin K antagonist oral anticoagulant drugs given the reduced time off anticoagulation and their more predictable pharmacokinetics. Aspirin can be continued for most procedures. Dual antiplatelet agents for patients with a recently inserted coronary artery stent should be continued if possible but decisions should be individualised and taken after multidisciplinary discussion. PMID- 25440398 TI - Laboratory monitoring of haemostasis. AB - Peri-operative coagulation monitoring should begin with the assessment of individual bleeding risk using a standardised bleeding history before the surgical procedure. Laboratory testing should be performed if this history is abnormal or peri-operative bleeding is anticipated. This process sensitively identifies those at risk of peri-operative bleeding and therefore minimises their peri-operative risk, without costly and time-consuming population testing. There are multiple potential causes of haemostatic derangement within the peri operative period, and an understanding of both normal haemostasis and the coagulation tests available to detect coagulopathy is required to optimise patient management. In bleeding patients, routine coagulation tests should be requested, but one should be aware of the major limitations that exist. Delay whilst waiting for these laboratory results, which, in turn, aggravates coagulopathy, bleeding, blood product requirements, length of surgery and overall morbidity and mortality. PMID- 25440399 TI - Point-of-care monitoring of haemostasis. AB - Recent research in the management of haemorrhage has led to several changes in clinical practice. Evidence is accumulating that point-of-care testing results in fewer transfusions, improved patient outcomes, and reduced hospital costs. However, there is still insufficient high quality evidence to support transfusion guidelines and algorithms based on point-of-care tests alone, and more robust studies are needed. The implementation of point-of-care testing requires institutional support and senior clinical leadership to realise the benefits, with educational programmes, audit, and feedback regarding transfusion practice. A change in philosophy is required, from performing testing only when there is an obvious bleeding problem, towards the concept of routinely monitoring high-risk patients throughout the surgical procedure. This informs clinical practice, establishes normal ranges for that population, identifies patients at risk and allows early identification and treatment of evolving coagulopathy. PMID- 25440400 TI - Haemostatic management of obstetric haemorrhage. AB - The haemostatic management of major obstetric haemorrhage remains challenging, and current published guidance relies heavily on experience from the non-pregnant population and expert opinion. In recent years, an interest in the implications of relative hypofibrinogenaemia, point-of-care monitoring of coagulation abnormalities, and the potential to give goal-directed therapy to correct coagulopathies, have created the possibility of significantly challenging and changing guidance. There is evidence that the haemostatic impairment in the pregnant population is different from trauma-induced bleeding, and the type and rate of onset of coagulopathies differ depending on the underlying cause. This review examines areas such as possible intervention points, describes evidence for over-transfusion of fresh frozen plasma in some situations and challenges conventional thinking on formulaic management. It also examines the rationale for other therapeutic options, including fibrinogen concentrate and tranexamic acid. PMID- 25440402 TI - The pathogenesis of traumatic coagulopathy. AB - Over the last 10 years, the management of major haemorrhage in trauma patients has changed radically. This is mainly due to the recognition that many patients who are bleeding when they come in to the emergency department have an established coagulopathy before the haemodilution effects of fluid resuscitation. This has led to the use of new terminology: acute traumatic coagulopathy, acute coagulopathy of trauma shock or trauma-induced coagulopathy. The recognition of acute traumatic coagulopathy is important, because we now understand that its presence is a prognostic indicator, as it is associated with poor clinical outcome. This has driven a change in clinical management, so that the previous approach of maintaining an adequate circulating volume and oxygen carrying capacity before, as a secondary event, dealing with coagulopathy, has changed to haemostatic resuscitation as early as possible. While there is as yet no universally accepted assay or definition, many experts use prolongation of the prothrombin time to indicate that there is, indeed, a coagulopathy. Hypoxia, acidosis and hypothermia and hormonal, immunological and cytokine production, alongside consumption and blood loss, and the dilutional effects of resuscitation may occur to varying extents depending on the type of tissue damaged, the type and extent of injury, predisposing to, or amplifying, activation of coagulation, platelets, fibrinolysis. These are discussed in detail within the article. PMID- 25440401 TI - Haemostatic management of cardiac surgical haemorrhage. AB - Almost 30,000 cardiopulmonary bypass operations are performed in the UK every year, consuming a considerable portion of the UK blood supply. Each year, in cardiac surgery, 90% of blood products are used by only 10% of patients, and over the past 25 years, much innovation and research has gone into improving peri operative diagnosis and therapy for these patients. Visco-elastic tests performed at the bedside, with modifications to allow direct quantification of fibrinogen levels, are probably the biggest advancement. There is no clear advantage of thromboelastometry over thromboelastography, and the published literature remains scarce. Visco-elastic testing has recently been coupled with the systematic replacement of clotting factors by means of factor concentrates, with objective improvement in terms of blood loss, red blood cell usage and surgical re exploration. The National Institute for Health and Care Excellence has reviewed the available evidence and recommended visco-elastic tests as cost effective in cardiac surgery. Factor concentrates, however, carry significant risks, particularly unnecessary donor exposures, potential selective over-correction of partial deficiencies and the possibility that the postoperative risk of venous thromboembolism is increased; as yet there are no data on risk-benefit analysis. There are a number of promising drugs used in topical haemostasis, but the requirement to apply these before major bleeding is manifest limits their use considerably. Hyperfibrinolysis is less important than in the past due to the wide spread adoption of antifibrinolytic agents and close intra-operative monitoring of heparin effect. PMID- 25440403 TI - Management of traumatic haemorrhage--the European perspective. AB - Trauma-induced coagulopathy represents a life-threatening complication in severely injured patients. To avoid exsanguination, rapid surgical bleeding control coupled with immediate and aggressive haemostatic treatment is mandatory. In most trauma centres, coagulation therapy is established with transfusion of high volumes of fresh frozen plasma. Due to logistic issues, only busy trauma facilities store pre-thawed plasma ready for immediate transfusion. Thus, substantial time delays have been reported between the first unit of red blood cells transfused and the administration of fresh frozen plasma. An alternative for rapid improvement of haemostatic capacity is purified coagulation factor concentrates. They contain a well-defined concentration of coagulation proteins, carry a low risk for transfusion-related lung injury and virus transmission, and are available for immediate use without the need for blood group matching. In some European trauma centres, treatment algorithms have been developed for the administration of coagulation factor concentrates based on visco-elastic test results. PMID- 25440404 TI - Management of traumatic haemorrhage--the US perspective. AB - As compared with European practice, the American approach to resuscitation from traumatic haemorrhage de-emphasises pre-hospital interventions in favour of rapid transport to definitive care; limits initial surgical interventions under the damage control model; uses crystalloid as the initial fluid of choice; and follows an empiric 1:1:1 approach to transfusion with red cells, plasma and platelets in hemodynamically unstable and actively bleeding patients. The use of bedside visco-elastic testing to guide coagulation support is not as widespread as in Europe, while the early administration of tranexamic acid is more selective. PMID- 25440405 TI - Surgery in patients with inherited bleeding disorders. AB - It is estimated that up to 1% of the general population has a congenital bleeding disorder. With this level of disease burden, it is more likely than not that any practising surgeon or anaesthetist will, at one time or another, have occasion to manage one such patient. Congenital haemophilia, both A and B, von Willebrand's disease, and inherited qualitative platelet defects, constitute the bulk of these disorders, with the rest distributed between much rarer conditions. Although looking after such patients will continue to pose a challenge to anaesthetists, recent and continuing advances in haemostatic products, coupled with increasing awareness of haemostatic care, means that surgery in this challenging group of patients is safer now than ever before, and can now be undertaken with a degree of confidence not possible even two decades ago. Central to these recent successes has been the continuing evolution of specialised healthcare services; in particular, Haemophilia Comprehensive Care Centres. Of equal importance, at least in developed countries, has been the ease of access to highly purified, safe and effective haemostatic products. The key to successful surgical management of the patient with a bleeding disorder is a multidisciplinary approach involving not only surgeons, anaesthetists and haematologists, but also laboratory scientists, specialist physiotherapists and haemophilia nurses. With careful planning, most surgical and invasive procedures can be carried out safely in persons with haemophilia and other bleeding disorders. PMID- 25440406 TI - The management of abnormal haemostasis in the ICU. AB - The aetiology and management of haemostatic abnormalities in critical care patients are considered in this narrative review. The mechanisms of normal haemostasis and derangements that occur as a result of sepsis and organ dysfunction are discussed. Finally, the management of haemostatic abnormalities as they relate to critical care practice are considered, including the management of heparin-induced thrombocytopenia. PMID- 25440408 TI - NGO collaboration in community post-disaster reconstruction: field research following the 2008 Wenchuan earthquake in China. AB - The number of communities affected by disasters has been rising. As a result, non governmental organisations (NGOs) that attend community post-disaster reconstruction are often unable to deliver all requirements and have to develop cooperative approaches. However, this collaboration can cause problems because of the complex environments, the fight for limited resources and uncoordinated management, all of which result in poor service delivery to the communities, adding to their woes. From extensive field research and case studies conducted in the post-Wenchuan earthquake-stricken communities, this paper introduces an integrated collaboration framework for community post-disaster reconstruction with the focus on three types of NGOs: international, government organised and civil. The proposed collaboration framework examines the three interrelated components of organisational structure, operational processes and reconstruction goals/implementation areas. Of great significance in better promoting collaborative participation between NGOs are the crucial concepts of participatory reconstruction, double-layer collaborative networks, and circular review and revision. PMID- 25440409 TI - Alcohol-related morbidity and mortality within siblings. AB - AIMS: To estimate the association between educational status and alcohol-related somatic and non-somatic morbidity and mortality among full siblings in comparison with non-related individuals. DESIGN: Cohort study. SETTING: Denmark. PARTICIPANTS: Approximately 1.4 million full siblings born in Denmark between 1950 and 1979 were followed from age 28-58 years or censoring due to alcohol related hospitalization and mortality. MEASUREMENTS: Cox regression analyses were used to estimate associations of educational status with alcohol-related outcomes. Results from cohort analyses based on non-related individuals and inter sibling analyses were compared. FINDINGS: A lower educational status was associated with a higher rate of alcohol-related outcomes, especially among the youngest (aged 28-37 years) and individuals born 1970-79. Compared with the cohort analyses, the associations attenuated slightly in the inter-sibling analysis. For example, in the cohort analysis, females with a basic school education born 1970-79 had an increased rate of alcohol-related non-somatic morbidity and mortality [hazard rate ratio (HR) = 4.05, 95% confidence interval (CI) = 3.27-5.02] compared to those with a vocational education. In the inter sibling analysis, the HR attenuated (HR = 2.66, 95% CI = 1.95-3.63). For alcohol related somatic outcomes the corresponding figures were HR = 3.47 (95% CI = 2.63 4.58) and HR = 3.36 (95% CI = 2.10-5.38), respectively. In general, the associations were stronger among females than males (aged 28-37) in the analyses of alcohol-related non-somatic outcomes. Health conditions earlier in life explained only a minor part of the associations. CONCLUSIONS: The association between educational status and alcohol-related somatic and non-somatic morbidity and mortality is only driven by familial factors to a small degree. PMID- 25440407 TI - Processing of audiovisually congruent and incongruent speech in school-age children with a history of specific language impairment: a behavioral and event related potentials study. AB - Previous studies indicate that at least some aspects of audiovisual speech perception are impaired in children with specific language impairment (SLI). However, whether audiovisual processing difficulties are also present in older children with a history of this disorder is unknown. By combining electrophysiological and behavioral measures, we examined perception of both audiovisually congruent and audiovisually incongruent speech in school-age children with a history of SLI (H-SLI), their typically developing (TD) peers, and adults. In the first experiment, all participants watched videos of a talker articulating syllables 'ba', 'da', and 'ga' under three conditions - audiovisual (AV), auditory only (A), and visual only (V). The amplitude of the N1 (but not of the P2) event-related component elicited in the AV condition was significantly reduced compared to the N1 amplitude measured from the sum of the A and V conditions in all groups of participants. Because N1 attenuation to AV speech is thought to index the degree to which facial movements predict the onset of the auditory signal, our findings suggest that this aspect of audiovisual speech perception is mature by mid-childhood and is normal in the H-SLI children. In the second experiment, participants watched videos of audivisually incongruent syllables created to elicit the so-called McGurk illusion (with an auditory 'pa' dubbed onto a visual articulation of 'ka', and the expectant perception being that of 'ta' if audiovisual integration took place). As a group, H-SLI children were significantly more likely than either TD children or adults to hear the McGurk syllable as 'pa' (in agreement with its auditory component) than as 'ka' (in agreement with its visual component), suggesting that susceptibility to the McGurk illusion is reduced in at least some children with a history of SLI. Taken together, the results of the two experiments argue against global audiovisual integration impairment in children with a history of SLI and suggest that, when present, audiovisual integration difficulties in this population likely stem from a later (non-sensory) stage of processing. PMID- 25440410 TI - The use of a Berlin Heart EXCOR LVAD in a child receiving chemotherapy for Castleman's disease. AB - We present the unique case of a pediatric patient who received chemotherapy for a diagnosis of CD, while mechanically supported with a Berlin EXCOR LVAD secondary to restrictive cardiomyopathy. A four-yr-old previously healthy male with restrictive cardiomyopathy required MCS after cardiac arrest but was diagnosed with multicentric CD, a non-malignant lymphoproliferative disorder fueled by excessive IL-6 production. Treatment with IL-6 blockade (tocilizumab) every two wk and methylprednisolone had no effect on his lymph nodes or cardiac function while on temporary RotaFlow. A Berlin LVAD was placed for treatment with rituximab, COP, vincristine, and methylprednisolone. After three courses of chemotherapy, his inflammatory markers normalized and his lymphadenopathy decreased but cardiac function remained severely depressed. He tolerated chemotherapy on the Berlin but required frequent titrations of his anti coagulation regimen and he did suffer a hemorrhagic stroke. His clinical status improved significantly with rehabilitation, and he tolerated heart transplantation without further complications. MCS is a feasible option as a bridge to recovery or heart transplant eligibility for patients with hemodynamic collapse requiring chemotherapy but it does necessitate close titration of the anti-coagulation regimen to coincide with changes in the inflammatory state. PMID- 25440411 TI - Assessment of voice quality: Current state-of-the-art. AB - Voice quality is not clearly defined but it can be concluded that it is a multidimensional perceived construct. Therefore, there are broadly two approaches to measure voice quality: (1) subjective measurements to score a client's voice that reflects his or her judgment of the voice and (2) objective measurements by applying specific algorithm to quantify certain aspects of a correlate of vocal production. This paper proposes a collection and discusses a number of critical issues of the current state-of-the-art in voice quality assessments of auditory perceptual judgment, objective-acoustic analysis and aerodynamic measurements in clinical practice and research that maybe helpful for clinicians and researchers. PMID- 25440412 TI - Steroid-dependent sensorineural hearing loss in a patient with Charcot-Marie Tooth disease showing auditory neuropathy. AB - Charcot-Marie-Tooth disease (CMT) is the most common form of hereditary sensorimotor neuropathy and sometimes involves disorders of the peripheral auditory system. We present a case of steroid-dependent auditory neuropathy associated with CMT, in which the patient experienced 3 episodes of acute exacerbation of hearing loss and successful rescue of hearing by prednisolone. An 8-year-old boy was referred to the otolaryngology department at the University Hospital. He had been diagnosed with CMT type 1 (demyelinating type) at the Child Neurology Department and was suffering from mild hearing loss due to auditory neuropathy. An audiological diagnosis of auditory neuropathy was confirmed by auditory brainstem response and distortion-product otoacoustic emissions. At 9 years and 0 months old, 9 years and 2 months old, and 10 years and 0 months old, he had experienced acute exacerbations of hearing loss, each of which was successfully rescued by intravenous or oral prednisolone within 2 weeks. Steroid responsive cases of CMT have been reported, but this is the first case report of steroid-responsive sensorineural hearing loss in CMT. The present case may have implications for the mechanisms of action of glucocorticoids in the treatment of sensorineural hearing loss. PMID- 25440413 TI - Non renal effects of aldosterone. PMID- 25440414 TI - Osteobiologics in foot and ankle surgery. AB - Osteobiological agents are a welcome addition to the surgeon's armamentarium. These products should always be thought of as a complement to good surgical principles and construct. As history has shown, nothing outperforms the osteogenic properties of autograft bone. Even if allograft is procured for use, an attempt should be made to combine it with autograft if possible, given the primary indexprocedure in which it will be used. Structural support from corticocancellous autografts is also greater than allografts, which lose mechanical strength during the sterilization and preservation process. Bone fillers without structural support should be used only when there are other means of cortical contact. The ability of the human skeletal system to repair itself is amazing. Osseous healing relieson a complicated series of intrinsic and extrinsic factors. Some of these factors include a stable fixation construct, nutritional status, good surgical technique, and good decision making. Autogenous bone graft remains the gold standard, and the presence of native growth factors and osteogenic cells is mandatory to repair these deformities. When this microenvironment is disruptive, nonunion may result.Understanding the mechanisms of bony healing contributes to the available osteobiologics, which give the foot and ankle surgeon additional tools to enhance the reparative process of bony defects and the ability of the foot to restore itself. PMID- 25440415 TI - Bone graft substitute: allograft and xenograft. AB - Rapid bone graft incorporation for structural rigidity is essential. Early range of motion, exercise, and weight-bearing are keys to rehabilitation. Structural and nonstructural bone grafts add length, height, and volume to alter alignment, function, and appearance. Bone graft types include: corticocancellous autograft, allograft, xenograft, and synthetic graft. Autogenic grafts are harvested from the patient, less likely to be rejected, and more likely to be incorporated; however, harvesting adds a procedure and donor site complication is common. Allografts, xenografts, and synthetic grafts eliminate secondary procedures and donor site complications; however, rejection and slower incorporation can occur. PMID- 25440416 TI - Bone morphogenetic proteins: indications and uses. AB - The BMPs are a group of growth factors that have varied roles in the development and maintenance of many organ systems. Several of the BMPs have osteogenic potential, and exert their effects via complex and highly regulated pathways. At present, only rhBMP-2 and rhBMP-7 are available for clinical use, but only rhBMP 2 is readily available, and from a practical standpoint is considered the only commercially available BMP. Only a few studies exist on BMP use in foot and ankle surgery, but these have shown promising results with low complication rates. BMP is an adjuvant to bone healing,and does not substitute for structural bone needs. In addition, rhBMP-2 outside spinal fusions is considered to be US Food and Drug Administration off-label, and should be used only in patients who are at high risk for bone healing problems. PMID- 25440417 TI - Healing in the new millennium: bone stimulators: an overview of where we've been and where we may be heading. AB - Electromagnetic fields and their uses in bone healing have been fairly well studied, with most results showing improvement in healing of both bone and cartilage. Most supportive data are found in relation to the spine, femur, and tibia, but there is increasing evidence for its use in the foot and ankle for treatment of nonunions and as an adjunctive device in arthrodeses, particularly in high-risk populations. There are varying data and a significant variety of quality in the current research and publications concerning the use of electrical bone stimulation in the treatment of the foot and ankle. Thus, there is a definite need for further investigation and high-quality study designs to determine the most effective treatment modalities and pathologies best used with bone stimulation. Bone stimulation should be viewed as an adjunctive procedure in which the surgeon optimizes the high-risk patient both medically or surgically whenever possible. But when used appropriately, bone stimulation has the potential to influence outcomes and aid in bone healing when complications arise and in high-risk populations. PMID- 25440418 TI - Absorbable biologically based internal fixation. AB - Absorbable devices for use in internal fixation have advanced over the years to become reliable and cost-effective alternatives to metallic hardware. In the past, biodegradable fixation involved a laborious implantation process, and induced osteolysis and inflammatory reactions. Modern iterations exhibit increased strength, smoother resorption, and lower rates of reactivity. A newer generation manufactured from silk has emerged that may address existing limitations and provide a greater range of fixation applications. PMID- 25440419 TI - The future of carbon-based scaffolds in foot and ankle surgery. AB - Carbon may represent an alternative material suitable for future development as a soft-tissue substitute that potentially optimizes the biological and mechanical properties required for a graft product used in surgery. In addition, other modes of characterization such as 3-dimensional computational modeling may offer an insight into material performance in a biological environment. Further investigation is required to characterize and model the relationships between biological, mechanical, and design properties of this material to maximize its potential as a biomechanical scaffold and vehicle for delivering biologics that promote tissue repair and regeneration. PMID- 25440420 TI - Cartilage allograft techniques and materials. AB - Hyaline cartilage is avascular in nature, relying on surrounding synovial fluid for its nutrient supply. Lacking an inflammatory response, hyaline cartilage is unable to be repaired itself after injury. BMS technique allows reparative cartilage to be produced, taking the form of fibrocartilage. Fibrocartilage is weaker than hyaline cartilage. Various cartilage allograft materials are available for reparative techniques. The cartilage allograft materials discussed herein include fresh allograft transplantation, ACEM, and particulated juvenile articular cartilage. PMID- 25440421 TI - Sports medicine and platelet-rich plasma: nonsurgical therapy. AB - A Cochrane Review was performed to assess the effects of platelet-rich therapies for treating musculoskeletal soft tissue injuries. Selection criteria were randomized and quasirandomized controlled trials (RCTs) that compared platelet rich therapy with either placebo, autologous whole blood, dry needling, or no platelet-rich therapy for people with acute or chronic musculoskeletal soft tissue injuries. Primary outcomes were functional status, pain, and adverse effects. The investigators found 19 studies that compared platelet-rich therapy with placebo, autologous whole blood, dry needling, or no platelet-rich therapy. Disorders included rotator cuff tears (arthroscopic repair; 6 trials); shoulder impingement syndrome surgery (1 trial); elbow epicondylitis (3 trials); anterior cruciate ligament (ACL) reconstruction (4 trials), ACL reconstruction (donor graft site application; 2 trials), patellar tendinopathy (1 trial), Achilles tendinopathy (1 trial), and acute Achilles rupture surgical repair (1 trial). They further subdivided the studies based on type of treatment, including tendinopathies in which platelet-rich therapy injections were the main treatment (5 trials), and surgical augmentation procedures in which platelet-rich therapy was applied during surgery (14 trials). The conclusion was that there is currently insufficient evidence to support the use of platelet-rich therapy for treating musculoskeletal soft tissue injuries. Researchers contemplating RCTs should consider the coverage of currently ongoing trials when assessing the need for future RCTs on specific conditions. There is a need for standardization of PRP preparation methods. At this time, the use of PRP in foot and ankle surgery as an orthobiologic does not have an absolute indication. Many of the studies are lower evidence-based from surgical techniques. Several in vitro studies have shown that growth factors promote the regeneration of bone, cartilage, and tendons. More clinical studies are needed to evaluate the use of PRP as an orthobiologic. In the author's opinion, PRP does have a role when conservative treatment has failed and the next treatment option is an invasive surgical procedure PMID- 25440422 TI - Growth factors in wound healing: the present and the future? AB - Numerous clinical studies have confirmed the pivotal role growth factors play in wound healing and their diminished levels in the chronic wound. Despite promising early studies treating chronic wounds with growth factors, results with traditional bolus dosing of a single growth factor have yielded insignificant results. Disappointing results have been theorized to be the result of growth factors inherent short half-life, a hostile microenvironment rich in protease activity, and poor delivery mechanisms failing to deliver effective dosages in an appropriate temporal manner. Advances in tissue engineering and regenerative medicine have provided technologies capable of delivering multiple growth factors in a spatially oriented approach. These technologies include polymer systems, scaffolds, and hydrogels that have demonstrated improved response by target tissues when growth factors are delivered in this biomimetic fashion. With improved delivery systems, treatment of chronic wounds with growth factors has the potential to accelerate healing in a manner not previously realized with traditional delivery approaches. PMID- 25440423 TI - Bioengineered alternative tissues in diabetic wound healing. AB - New advances in medicine and technology continually change how clinicians treat patients with the aim of improving outcomes. As technology continues to improve, the ability to treat patients will improve as well. Great progress has been made in diabetic wound healing with BATs and there will continue to be improvement with new products in the future. However, the current literature is replete with small case series and small cohort studies. With the exception of the pivotal trials conducted more than a decade ago, there is a lack of robust evidence for the use of BATs. More advanced BATs, including the use of MSCs, show promise but have yet to be studied in a rigid manner. It is important to apply fundamental principles of DFU care, including maximizing perfusion, off-loading, and debridement, before using of these more advanced therapies. PMID- 25440424 TI - The use of human amnion/chorion membrane in the clinical setting for lower extremity repair: a review. AB - Unsuccessful healing represents a significant medical dilemma for both patients and clinicians and create a financial burden on the health care system. Despite the efforts of physicians, many injuries fail to heal with standard care alone. For decades human amniotic membrane composed of both amnion and chorion has shown remarkable therapeutic potential, but only recent preservation methods have allowed its widespread use. Variations in configurations and the ability to micronize the material allow clinical uses that were previously not possible. Although there are limited data available regarding most amniotic membrane-based products, there is substantial preclinical and clinical evidence supporting the rationale and effectiveness of dHACM allograft as a treatment modality. The rapidly growing body of evidence suggests that the properties inherent in dHACM promote tissue regeneration and healing, recruiting patients' own stem cells into the wounded area. Randomized controlled trials evaluating dHACM now include more than 200 patients collectively and the results consistently show improved healing. Use of dHACM has been shown to be more clinically effective and cost effective than other frequently used advanced wound care products. This cost effectiveness results from dHACM showing higher healing rates and more rapid healing than other advanced wound care products. Cost-effectiveness is also enhanced through the availability of grafts of multiple sizes, which reduces wastage, and through ease of handling and storage for clinical use. Ongoing and future studies will further define and establish the value of amniotic membrane for chronic tissue repair and regeneration. PMID- 25440425 TI - Recent advances in acellular regenerative tissue scaffolds. AB - The management of chronic wounds is a considerable challenge for foot and ankle surgeons. The well-established tenets of adequate vascular supply, debridement with eradication of infection, and offloading must be employed in the management of all extremity wounds. Regenerative scaffolds are a viable means of reestablishing a favorable wound environment. The matrix facilitates cell migration, chemoattraction, angiogenesis, wound bed granulation, and expedited wound closure. Although studies have demonstrated success with acellular matrices, a multimodal approach should always be employed to improve healing success. Negative pressure wound therapy, compression, offloading, and antibiotics are advocated to improve outcomes. Acellular graft selection requires a multifactorial analysis, taking into consideration the specific patient and wound characteristics as well as the differences between acellular matrices. Patient age, comorbidities, activity level, and ability to comply with protocol as well as wound etiology, duration, depth, surface area, exudate, bacterial burden, location, vascular status, ischemic status, and presentation are all critical components. To effectively choose a matrix, the clinician must have a comprehensive understanding of the products available and the data validating their use. The mechanisms by which the acellular matrix accelerates wound healing and increases the likelihood of wound healing continue to be investigated. However, it is clear that these acellular biologic tissue scaffolds are incorporating into the host tissue, with resultant revascularization and cellular repopulation. Moving forward, additional investigations examining the effectiveness of acellular biologic tissue scaffolds to improve healing in complex, nondiabetic wounds are warranted. PMID- 25440426 TI - Foreword. Current update on orthobiologics in foot and ankle surgery. PMID- 25440427 TI - Preface. Current update on orthobiologics in foot and ankle surgery. PMID- 25440428 TI - Evidence for transfer of radicals between oil-in-water emulsion droplets as detected by the probe (E,E)-3,5-bis(4-phenyl-1,3-butadienyl)-4,4-difluoro-4-bora 3a,4a-diaza-s-indacene, BODIPY(665/676.). AB - (E,E)-3,5-Bis(4-phenyl-1,3-butadienyl)-4,4-difluoro-4-bora-3a,4a-diaza-s indacene, BODIPY(665/676), is a lipophilic radical-sensitive fluorescent probe that can be used to study radical-driven lipid autoxidation. The sensitivity of BODIPY(665/676) was studied in the presence of radical initiators di-tert-butyl peroxide and 2,2'-azobis(2,4-dimethyl)valeronitrile (AMVN). In both cases the fluorescence of BODIPY(665/676) changed more in saturated medium-chain triglyceride oil than in linseed or sunflower oils, where the high degree of unsaturation is expected to give more pronounced radical-derived lipid oxidation. It was suggested that BODIPY(665/676), as the only available oxidizable substance in the saturated oil, was directly attacked by radicals, resulting in high rates of probe oxidation, while in the unsaturated oils, radicals attacked either unsaturated fatty acids or BODIPY(665/676), resulting in lower rates of probe oxidation. Confocal microscopy studies with BODIPY(665/676) as a radical sensitive probe combined with oxygen consumption measurements of mixtures of oil in-water emulsions showed that radicals could be transferred between oil droplets and thereby spread radical-driven oxidation between neighboring droplets. PMID- 25440429 TI - The Coaching Behavior Scale for Sport (CBS-S): A psychometric evaluation of the Swedish version. AB - The present study validated a Swedish version of the 47-item Coaching Behavior Scale for Sport (CBS-S). Sample 1 consisted of 506 team sport athletes [262 men and 244 women; mean age: 22.20, standard deviation (SD) = 3.90] distributed across 41 coaches at the two highest national levels of various sports. Athletes completed the CBS-S and established questionnaires of coaching behaviors (LSS), self-confidence (CSAI-2R), and coach-athlete relationship (CART-Q). An additional sample of 39 basketball players (21 men and 18 women; mean age = 17.40, SD = 2.39) completed the CBS-S twice, approximately 4 weeks apart. Confirmatory factor analysis showed an acceptable model fit for the seven-factor version of the CBS S, although two items of the negative personal rapport subscale displayed insufficient factor loadings. Correlations between the subscales of the CBS-S and established instruments were in accordance with theoretical expectations, supporting the concurrent validity. Cronbach's alpha (> 0.82) for all dimensions provided support for the reliability of the CBS-S, and test-retest correlations indicated moderate stability over time. Cultural differences in the assessment of coaching behaviors and the usability of the CBS-S by coaches for self-reflection and development are discussed. PMID- 25440430 TI - The adverse effect profile of oral azathioprine in pediatric atopic dermatitis, and recommendations for monitoring. AB - BACKGROUND: Azathioprine is efficacious in the treatment of severe childhood atopic dermatitis; however, robust data on adverse effects in this population are lacking. OBJECTIVE: We sought to assess adverse effects of azathioprine treatment in a pediatric atopic dermatitis cohort, and make recommendations for monitoring based on these data. METHODS: Blood test results for all 82 children prescribed oral azathioprine for atopic dermatitis in our department between 2010 and 2012 were collated prospectively, and clinical notes were reviewed retrospectively. RESULTS: Mean age at commencing azathioprine was 8.3 years (SEM 0.4). Mean maximum doses were 2.4 mg/kg (SEM 0.1) and 1.5 mg/kg (SEM 0.1) for normal and reduced serum thiopurine-S-methyltransferase levels, respectively. Adverse effects on blood indices occurred in 34 of 82 patients (41%), with pronounced effects in 18 of 82 (22%) after a median time of 0.4 years. Two patients stopped therapy as a result of abnormal blood indices. Clinical adverse effects occurred in 16 of 82 (20%), two resulting in cessation of therapy. Incidence of adverse effects was unaffected by age, sex, thiopurine-S-methyltransferase level, and drug dose on multivariate regression. LIMITATIONS: Comparison with other studies is limited by varying definitions of adverse effects. CONCLUSION: Oral azathioprine was associated with few pronounced adverse effects for the duration of use and dosage in this cohort. Recommendations for monitoring are made. PMID- 25440431 TI - Incidence and risk factors for skin cancer following lung transplantation. AB - BACKGROUND: Relative to other solid-organ transplantations, limited studies characterize skin cancer among lung-transplant recipients. OBJECTIVE: We sought to assess the cumulative incidence, tumor burden, and risk factors for skin cancer among patients with lung transplantation. METHODS: Medical records of patients at Mayo Clinic who had undergone lung transplantation between 1990 and 2011 were reviewed (N = 166). RESULTS: At 5 and 10 years posttransplantation the cumulative incidence was 31% and 47% for any skin cancer, 28% and 42% for squamous cell carcinoma, 12% and 21% for basal cell carcinoma, and 53% and 86% for death, respectively. Four patients died of metastatic squamous cell carcinoma. The cumulative incidence for a subsequent skin cancer of the same type 4 years after an initial skin cancer was 85% and 43% for squamous and basal cell carcinoma, respectively. Increasing age, male gender, skin cancer history, and more recent year of transplantation were associated with increased risk of skin cancer posttransplantation. Sirolimus was not associated with decreased risk, nor did voriconazole show an increased risk for skin cancer. LIMITATIONS: Retrospective and tertiary single-center design of the study is a limitation. CONCLUSIONS: Skin cancers frequently occur in lung-transplant recipients. The risk of subsequent skin cancer is increased substantially in patients who develop a skin cancer after their transplantation. PMID- 25440432 TI - Expression of helper T cell master regulators in inflammatory dermatoses and primary cutaneous T-cell lymphomas: diagnostic implications. AB - BACKGROUND: Mycosis fungoides (MF) is a neoplasm of skin-homing CD4(+) helper T (TH) lymphocytes with dysregulation of TH1 and TH2 immunity. Diagnosis of MF is challenging, as there is significant morphologic overlap with other dermatologic entities. OBJECTIVE: We investigated diagnostic utility of TH1- and TH2-specific markers, T-bet, and GATA-3, respectively, in MF and its reactive and neoplastic mimics. METHODS: Immunohistochemical staining for CD3/T-bet and CD3/GATA-3 was performed on inflammatory dermatoses (n = 56), MF (n = 37), Sezary syndrome (SS; n = 8), and cutaneous anaplastic large cell lymphoma (C-ALCL; n = 14). RESULTS: Inflammatory dermatoses showed epidermal T cells predominantly expressing GATA-3, except psoriasis, which exhibited a mixed GATA-3/T-bet staining. In contrast, neoplastic T cells in patch stage MF showed markedly increased T-bet positivity with minimal GATA-3 expression. Plaque stage MF had a mixed T-bet/GATA-3 phenotype, whereas tumor stage MF and SS exhibited diffuse GATA-3 expression. C ALCL lacked significant staining for both markers. LIMITATIONS: Sample size was relatively small. CONCLUSIONS: A predominance of T-bet(+) T cells in the epidermis support patch stage MF over dermatitis. A predominance of GATA-3(+) T cells in the dermis support CD30(+) MF with large cell transformation over C ALCL. These stains do not allow distinction between dermatitis and cutaneous infiltrates of SS. PMID- 25440433 TI - Histiocytoid Sweet syndrome is infiltrated predominantly by M2-like macrophages. AB - BACKGROUND: Histiocytoid Sweet syndrome (HSS) is a rare variant of Sweet syndrome (SS). The nature of histiocytoid cells is still uncertain. OBJECTIVE: We sought to offer a comprehensive overview on clinical features of HSS and further information on immunohistochemical phenotype of the infiltrate. METHODS: The clinical, histologic, and immunohistochemical features of 12 of our patients with HSS and all cases retrieved through a PubMed search were analyzed. RESULTS: Lesions consisted of erythematous-violaceous papules and plaques, randomly distributed mostly on the trunk and the limbs. Three patients had myelodysplastic syndrome and 1 had a monoclonal gammopathy. The infiltrate was mainly composed of CD68(+)CD163(+)myeloperoxidase(+)myeloid cell nuclear differentiation antigen(+)CD117(-)CD15(-)CD34(-), a phenotype suggestive of M2-like macrophages. A few mature neutrophils and lymphocytes were also present. Review of all HSS cases showed no sex predominance and no extracutaneous infiltrates; inconstant presence of fever and blood neutrophilia; association with hematologic or solid neoplasms (26%), autoimmune conditions (12%), and infectious diseases (10%); and good response to steroid treatment, with rare relapses or recurrences. LIMITATIONS: The study includes a limited case series. The pathogenesis of the disease remains to be clarified. CONCLUSIONS: HSS lesions are infiltrated mostly by M2-like macrophages. The clinical features present more similarities than differences with SS. PMID- 25440434 TI - Melanoma in patients with chronic lymphocytic leukemia and non-Hodgkin lymphoma. AB - BACKGROUND: The relationship between melanoma and chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL) has been minimally investigated. OBJECTIVE: The objective of this study was to examine the incidence of melanoma in patients with a history of CLL or NHL, and their associated mortality. METHODS: Cohorts of Kaiser Permanente Southern California members with a history of CLL and NHL were identified. Age-adjusted incidence density rates of melanoma among patients with CLL or NHL were compared with rates of melanoma among the general population of Kaiser Permanente Southern California patients. The mortality of patients with melanoma was examined using Cox proportional hazards modeling. RESULTS: The age adjusted incidence rate per 100,000 person-years for melanoma among patients with either CLL or NHL was 107 (95% confidence interval 84.4-129.6) versus 25.9 among the general population (95% confidence interval 84.4-129.6, P < .001). Patients with melanoma and a history of CLL or NHL had 2.46 greater odds of death compared with those without CLL or NHL (95% confidence interval 1.77-3.41). LIMITATIONS: This study was retrospective in nature; the International Classification of Diseases, Ninth Revision codes used may contain diagnostic errors; and only overall survival was used in our analysis. CONCLUSIONS: Patients with a history of CLL or NHL have a higher incidence of melanoma. Patients with CLL or NHL who are subsequently given the diagnosis of melanoma have a higher mortality than patients with melanoma without a preceding diagnosis of CLL. PMID- 25440435 TI - Metastatic melanomas of unknown primary show better prognosis than those of known primary: a systematic review and meta-analysis of observational studies. AB - BACKGROUND: Melanoma of unknown primary (MUP) is a condition of metastatic melanoma without a primary lesion. OBJECTIVE: We sought to identify the prognosis of MUP compared with melanoma of known primary (MKP). METHODS: We searched for observational studies containing at least 10 patients with MUP from MEDLINE and EMBASE from inception to December 22, 2012. The outcomes of interest were overall and disease-free survival; meta-analyses of hazard ratio stratified by stage using a random effects model were performed. In addition, second systematic review identified risk factors influencing the survival of patients with MUP. RESULTS: Eighteen studies including 2084 patients with MUP and 5894 with MKP were included. MUP had a better overall survival compared with MKP in stage III (15 studies; hazard ratio 0.83, 95% confidence interval 0.73-0.96, P = .010) and stage IV (6 studies; hazard ratio 0.85, 95% confidence interval 0.75-0.96, P = .008). Secondly, 22 studies including 3312 patients with MUP were reviewed, and increased stage and old age were the risk factors in patients with MUP. LIMITATIONS: Diverse observational studies were reviewed, and selection and reporting biases are possible. CONCLUSIONS: The current meta-analyses suggest better survival outcomes in patients with MUP than those in patients with MKP with the same corresponding tumor stage. PMID- 25440436 TI - Outcome of patients with de novo versus nevus-associated melanoma. AB - BACKGROUND: Prior reports indicate a wide range of melanomas in histopathologic contiguity with a nevus, and an associated nevus has unclear prognostic implications in melanoma. OBJECTIVE: We sought to investigate the relationship among nevus-associated melanomas, sentinel lymph node status, and overall survival. METHODS: We conducted a retrospective analysis of 850 patients with cutaneous melanoma and sentinel lymph node removed at Massachusetts General Hospital from 1998 through 2008 and meta-analysis of the literature. RESULTS: Nevus-associated melanomas represented 28% (235/850) of cases and were significantly correlated with younger age (P = .03), truncal site (P = .0005), superficial spreading type (P < .0001), and absent ulceration (P = .005). There was no association with sentinel lymph node status (P = .94) and no survival difference between nevus-associated versus de novo melanoma (P = .41). Meta analysis of over 4000 cases revealed a similar percentage of associated nevi (32%). LIMITATIONS: This was a retrospective study. CONCLUSIONS: Approximately 30% of melanomas are associated with a nevus. The presence of a nevus associated with a melanoma has no prognostic implication in sentinel lymph node status or overall survival. PMID- 25440437 TI - A split-face evaluation of a novel pigment-lightening agent compared with no treatment and hydroquinone. AB - BACKGROUND: Lignin peroxidase is a cosmetic skin-lightening alternative that breaks down plant cell walls and melanin. OBJECTIVE: This research examined the topical efficacy of lignin peroxidase in pigment lightening. METHODS: Sixty women aged 18 to 65 years with mild to moderate facial dyspigmentation were enrolled for 12 weeks in 2 cohorts. Cohort 1 applied lignin peroxidase to 1 randomized side of the face and nothing to the opposite side. Cohort 2 applied lignin peroxidase to 1 facial side and generic hydroquinone to the other. Investigator, subject, and dermospectrophotometer measurements were obtained. RESULTS: In cohort 1, improved skin texture (P < .001), roughness (P < .001), and overall appearance (P = .002) was noted at week 2 with lignin peroxidase versus no treatment. By week 12, there was a decrease in spot size with lignin peroxidase versus no treatment (P = .014). This was confirmed by a statistically significant reduction in melanin scores with the dermospectrophotometer on lignin peroxidase treated side at weeks 4, 8, and 12 (P = .003) and a similar reduction in Melasma Area Severity Index score. Cohort 2 demonstrated parity between lignin peroxidase and hydroquinone, but lignin peroxidase was statistically superior in skin texture and roughness. LIMITATIONS: The sample size was limited. CONCLUSIONS: Lignin peroxidase might be an over-the-counter skin-lightening preparation with efficacy parity to hydroquinone. PMID- 25440438 TI - Mortality in women with pregnancy-associated malignant melanoma. AB - BACKGROUND: Malignant melanoma (MM) is one of the most common malignancies in young women. It remains debated whether a MM diagnosed during pregnancy or lactation has a worse prognosis. OBJECTIVE: We sought to examine mortality in women with pregnancy-associated MM (PAMM) (diagnosed during pregnancy and up to 2 years postpartum). METHODS: This was a population-based cohort study based on information retrieved from the Swedish Cancer and Multi-Generation Registers. Hazard ratios with 95% confidence intervals adjusted for age, period, education, parity, and tumor location were estimated. RESULTS: In total, 6857 women and girls aged 15 to 44 years with a diagnosis of cutaneous MM between 1963 and 2009 were identified. Of these, 1019 cases were classified as PAMM. The cause-specific mortality did not differ between PAMM and MM not diagnosed near childbirth (adjusted hazard ratio 1.09, 95% confidence interval 0.83-1.42). LIMITATIONS: Information on stage at diagnosis was available only for a subset of patients CONCLUSION: Overall, the cause-specific mortality in women and girls with PAMM did not differ from that in women and girls with non-PAMM. The current findings do not provide evidence of an adverse prognostic influence of pregnancy or a recent birth. PMID- 25440440 TI - Hidradenitis suppurativa is a systemic disease with substantial comorbidity burden: a chart-verified case-control analysis. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease involving intertriginous skin. Previous epidemiologic studies have been limited by small sample size. OBJECTIVE: We sought to describe the prevalence and comorbidities of HS in a large patient care database. METHODS: In this retrospective case-control study, we chart-validated all patients within a hospital database who received at least 1 billing code for HS between 1980 and 2013. Verified cases were matched with controls based on age, gender, and race. Prevalences of a priori selected comorbidities were compared between HS and control groups. RESULTS: A total of 2292 patients at Massachusetts General Hospital received at least 1 code for HS. A total of 1776 cases had a validated diagnosis of HS, yielding a prevalence of 0.08%. In unadjusted analysis, all comorbidities were diagnosed significantly more in HS compared with control including (in rank order of likelihood): smoking, arthropathies, dyslipidemia, polycystic ovarian syndrome, psychiatric disorders, obesity, drug dependence, hypertension, diabetes, thyroid disease, alcohol dependence, and lymphoma (all P < .01). LIMITATIONS: Control subjects were not validated for absence of HS and comorbidity validation was not performed for either group. CONCLUSIONS: Our results highlights the high comorbidity burden of patients with HS compared with matched control subjects. PMID- 25440439 TI - Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma. AB - BACKGROUND: BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) frequently cause cutaneous adverse events. OBJECTIVE: We sought to investigate the cutaneous safety profile of BRAFi versus BRAFi and MEKi combination regimens. METHODS: We performed a retrospective cohort study, collecting data from 44 patients with melanoma treated either with BRAFi (vemurafenib or dabrafenib) or BRAFi and MEKi combination regimens (vemurafenib + cobimetinib or dabrafenib + trametinib). Patient characteristics, and the occurrence and severity of cutaneous adverse events, are described. RESULTS: The development of cutaneous adverse events was significantly less frequent (P = .012) and occurred after longer treatment time (P = .025) in patients treated with BRAFi and MEKi combination regimen compared with patients treated with BRAFi monotherapy. Among patients who received both BRAFi and the combination of BRAFi and MEKi at different time points during their treatment course, the development of squamous cell carcinoma or keratoacanthoma was significantly less frequent when they received the combination regimen (P = .008). Patients receiving vemurafenib developed more cutaneous adverse events (P = .001) and in particular more photosensitivity (P = .010) than patients who did not. LIMITATIONS: There were a limited number of patients. CONCLUSION: Combination regimen with BRAFi and MEKi shows fewer cutaneous adverse events and longer cutaneous adverse event-free interval compared with BRAFi monotherapy. PMID- 25440441 TI - [Results of a telemedicine program for primary care patients with type 2 diabetes]. AB - OBJECTIVE: To evaluate the impact of a telemedicine program on self-perceived health in patients with type 2 diabetes in primary care, as well as patient acceptance of and satisfaction with this program. METHOD: We conducted an 18 month follow-up through telemedicine in 52 diabetic patients. The study design was non-experimental (before and after). In addition to weekly electronic transmission of fasting glucose levels, we regularly provided advice to patients about healthy habits. RESULTS: No statistically significant differences were observed when mean blood glucose values were compared during follow-up. However, at the end of participation, the mean score in self-perceived health was significantly higher than at the initial assessment (70.5+/-12.8 vs. 62.8+/-15.0, p=0.02). After 18 months of participation in the telemedicine program, 57.7% of patients were satisfied and 38.5% were very satisfied. CONCLUSIONS: Although glycemic control did not improve during the follow-up, electronic transmission of information was found to be feasible and satisfactory for patients. The patients reported a higher level of self-perceived health. PMID- 25440442 TI - Effect of different doses of nandrolone decanoate on lipid peroxidation, DNA fragmentation, sperm abnormality and histopathology of testes of male Wister rats. AB - The present study aims of to investigate the effects of low and high doses of nandrolone decanoate (ND) on histopathology and apoptosis of the spermatogenic cells as well as lipid peroxidation, antioxidant enzyme activities, sperm abnormality and DNA fragmentation. Eighteen animals were divided into three groups each group contain six animals. The rats were divided into three groups as following: Group 1 was administered saline (control). Group 2, received nandrolone decanoate (3 mg/kg/weekly) (low dose) with intramuscular injection. Group 3, received intramuscular injection dose of nandrolone decanoate (10 mg/kg/weekly) (high dose). After 8 weeks, caspase-3 assay was used to determine the apoptotic cells. The sperm parameters, lipid peroxidation, antioxidant enzyme activities and testosterone concentration were also investigated in the experimental groups of both low and high dose compared to the control groups. Treated group with high dose showed degenerated germinal epithelial cells sloughed in the lumina of seminiferous tubules, where almost seminiferous tubules were devoid of spermatids and spermatozoa compared to control and group treated with low dose. Also, a significant increase of lipid peroxidation levels and heat shock proteins was observed in two groups administrated with two different doses of ND while, antioxidant enzyme activities, and testosterone concentration was significantly decreased in two treated group when compared with control. Administration of ND at high and low doses leads to deteriorated sperm parameters, DNA fragmentation and testicular apoptosis. In conclusion, the administration ND at high doses more effective on lipid peroxidation, antioxidant enzyme activities, sperm abnormality, histopathology, apoptotic and DNA changes compared to low dose group and to control group. PMID- 25440447 TI - On national strategies to improve both education and health--an open letter. PMID- 25440443 TI - Liquid chromatography high-resolution mass spectrometry for fatty acid profiling. AB - Quantification of fatty acids has been crucial to elucidate lipid biosynthesis pathways in plants. To date, fatty acid identification and quantification has relied mainly on gas chromatography (GC) coupled to flame ionization detection (FID) or mass spectrometry (MS), which requires the derivatization of samples and the use of chemical standards for annotation. Here we present an alternative method based on a simple procedure for the hydrolysis of lipids, so that fatty acids can be quantified by liquid chromatography mass spectrometry (LC-MS) analysis. Proper peak annotation of the fatty acids in the LC-MS-based methods has been achieved by LC-MS measurements of authentic standard compounds and elemental formula annotation supported by (13)C isotope-labeled Arabidopsis. As a proof of concept, we have compared the analysis by LC-MS and GC-FID of two previously characterized Arabidopsis thaliana knock-out mutants for FAD6 and FAD7 desaturase genes. These results are discussed in light of lipidomic profiles obtained from the same samples. In addition, we performed untargeted LC-MS analysis to determine the fatty acid content of two diatom species. Our results indicate that both LC-MS and GC-FID analyses are comparable, but that because of higher sensitivity and selectivity the LC-MS-based method allows for a broader coverage and determination of novel fatty acids. PMID- 25440448 TI - The relationship between school-level characteristics and implementation fidelity of a coordinated school health childhood obesity prevention intervention. AB - BACKGROUND: Curtailing childhood obesity is a public health imperative. Although multicomponent school-based programs reduce obesity among children, less is known about the implementation fidelity of these interventions. This study examines process evaluation findings for the Healthy, Energetic Ready, Outstanding, Enthusiastic, Schools (HEROES) Initiative, a tri-state school-based childhood obesity prevention intervention based on the coordinated school health (CSH) model. METHODS: Site visits were conducted that included key stakeholder interviews, observation, and document review. Scores were given for 8 domains, and a total implementation score was calculated. Two-way analyses of variance were conducted to examine the relationship of 4 school-level characteristics: elementary vs. middle/high schools, public vs. private schools, district vs. building level implementation, and socioeconomic status on each implementation area. RESULTS: Overall, schools had high fidelity scores, although some domains were implemented more successfully than others. Three school-level characteristics were associated with 1 or more domains, with elementary schools and schools implementing at the building level consistently having higher implementation scores than their counterparts. CONCLUSIONS: Process evaluation findings provide insight into successes and challenges schools implementing the CSH approach may encounter. Although preliminary, these findings on school-level characteristics establish a new area of research related to school-based childhood obesity prevention programs' implementation fidelity. PMID- 25440449 TI - Prevalence of and attitudes about concussion in Irish schools' rugby union players. AB - BACKGROUND: Youth rugby players represent 45.2% (N = 69,472) of the Irish rugby union playing population. The risk and consequences of concussion injury are of particular concern in these young athletes, but limited epidemiological data exists. This study investigated annual and lifetime prevalence of concussion in an Irish schoolboy rugby union cohort. METHODS: An anonymous cross-sectional survey of youth rugby players was conducted. Diagnosed concussion was defined as an incident where diagnosis was confirmed by a health professional or coach. Demographics, prevalence, and attitudes to concussion were collated. Data were analyzed with descriptive statistics, chi-square test, t-tests, Mann-Whitney tests, and logistic regression. RESULTS: Overall, 304 youth (aged 12-18 years) responded. Lifetime prevalence of diagnosed concussion was 19.4%, with annual (2010) prevalence 6.6%. Approximately 25.4% of players with diagnosed concussions returned to play without medical advice. Internal motivation (11.8%) was the predominant factor in feeling pressure to play while concussed. A desire for further concussion education was expressed by 89.5% of participants. CONCLUSIONS: Reform is required to prevent and manage concussion injuries among youth players in the rugby union, including mandatory education specific to concussion and implementation of return-to-play protocols. These findings have relevance for governing bodies, coaches, clinicians, schools, parents, and rugby union players. PMID- 25440450 TI - Effects of daily physical education on physical fitness and weight status in middle school adolescents. AB - BACKGROUND: In 2009, the Pennsylvania Department of Health developed the Active Schools Program (ASP) which required 30 minutes of daily physical education (PE) in middle schools to reduce childhood obesity. This investigation evaluated the ASP effects on physical fitness and weight status in middle school adolescents throughout 1 academic year. METHODS: A quasi-experimental design was used to recruit middle schools into an intervention group (N = 30) or control group (N = 9). RESULTS: Physical fitness outcomes had larger intervention effects than weight status outcomes. These effects were most profound among at-risk students. Multiple linear regression analysis provided a best-guess effect of daily PE on body mass index (BMI) percentile of -1.2, 95% confidence interval (CI) (-1.9, 0.5) for at-risk females and -0.8, 95% CI (-1.5, -0.1) for at-risk males. Much of this benefit is attributable to the differential increase in physical fitness achieved by students with the benefit of having daily PE. CONCLUSIONS: Thirty minutes of daily PE can be considered a scientific approach to ameliorate health outcomes in at-risk middle school adolescents, particularly among females. Improvements on BMI percentile among at-risk youth are presaged by greater improvements in physical fitness. This investigation supports a school-based approach aimed to improve behavioral risk factors as a means to reduce childhood obesity. PMID- 25440451 TI - Youth walking and biking rates vary by environments around 5 Louisiana schools. AB - BACKGROUND: The prevalence of obesity in children is high, and many do not meet physical activity recommendations. The Safe Routes to School (SRTS) program encourages school-aged children to walk and bike to school. We assessed the condition of the walking/biking environment around schools in Louisiana prior to the state's first SRTS program. METHODS: Assessments were made at the neighborhood level with the Pedestrian Environmental Data Scan (PEDS) instrument, and at the school and individual levels using the National SRTS Center's teacher tallies and parent surveys. PEDS scores were developed to rate conduciveness to walking/bicycling of proposed SRTS routes. Sites' scores were compared with the percentage of students who walk/bike to school. Five schools in Louisiana were evaluated. RESULTS: Overall, more students walked (range: 2.4-17.4%) than biked (range: 0.3-4.5%) to school with more students walking home than to school. Predictors of walking/biking to school include distance from school, speed of traffic, school encouragement, and if a student asked permission. Sites with the highest PEDS score had the highest percentage of students who walked/biked to school. CONCLUSIONS: There is a role and a need for the SRTS program. The environment and other factors influence biking and walking to school. PMID- 25440452 TI - School influences on the physical activity of African American, Latino, and White girls. AB - BACKGROUND: The purpose of this research was to examine the impact of school related variables on the physical activity (PA) levels of early adolescent African American, Latino, and White girls. METHODS: Data were collected from 353 African American (N = 123), Latino (N = 118), and White (N = 112) girls. Physical activity levels included a PA latent factor and minutes per day of moderate-to vigorous physical activity (MVPA). School variables included hours of physical education (PE), PE enjoyment, school physical environment, recess activity, and active transport to/from school. Multiple-group structural equation modeling examined relations between school variables and PA across ethnic groups. RESULTS: Hours of PE were positively related to higher PA factor scores. Active transport was related to higher PA factor scores for White girls only, and to greater MVPA for African American girls only. Hours of PE were related to PE enjoyment and the school physical environment for some ethnic groups. Physical education enjoyment was related to more recess activity among African American and Latino girls, and PE enjoyment was associated with more active transport to school for all girls. CONCLUSIONS: Physical education participation and active transport significantly contribute to girls' levels of PA, with differences across ethnic groups. PMID- 25440453 TI - Playing fair: the contribution of high-functioning recess to overall school climate in low-income elementary schools. AB - BACKGROUND: Recess is a part of the elementary school day with strong implications for school climate. Positive school climate has been linked to a host of favorable student outcomes, from attendance to achievement. We examine 6 low-income elementary schools' experiences implementing a recess-based program designed to provide safe, healthy, and inclusive play to study how improving recess functioning can affect school climate. METHODS: Data from teacher, principal, and recess coach interviews; student focus groups; recess observations; and a teacher survey are triangulated to understand the ways that recess changed during implementation. Comparing schools that achieved higher- and lower-functioning recesses, we link recess functioning with school climate. RESULTS: Recess improved in all schools, but 4 of the 6 achieved a higher functioning recess. In these schools, teachers and principals agreed that by the end of the year, recess offered opportunities for student engagement, conflict resolution, pro-social skill development, and emotional and physical safety. Respondents in these four schools linked these changes to improved overall school climate. CONCLUSIONS: Recess is an important part of the school day for contributing to school climate. Creating a positive recess climate helps students to be engaged in meaningful play and return to class ready to learn. PMID- 25440454 TI - A comprehensive review of school-based body mass index screening programs and their implications for school health: do the controversies accurately reflect the research? AB - BACKGROUND: Whereas legislation for body mass index (BMI) surveillance and screening programs has passed in 25 states, the programs are often subject to ethical debates about confidentiality and privacy, school-to-parent communication, and safety and self-esteem issues for students. Despite this debate, no comprehensive analysis has been completed that compares and contrasts how these issues differentially affect schools, parents, and students. METHODS: A keyword search from electronic databases and a review of state legislation related to BMI surveillance and screening were used to identify relevant literature and data focused on surveillance and screening policies, BMI report cards, and parental perceptions of BMI screenings and their child's weight status [corrected]. RESULTS: This article addresses the gap of previous literature by outlining the ethical considerations and implications that BMI screening programs and report cards have for schools, parents, and students, and links these with outcome studies to address whether these controversies are supported by research. CONCLUSIONS: Despite the controversies surrounding these programs, this review shows that they can be valuable for all parties and demonstrates BMI screening programs to be vital to the development of robust school-based obesity prevention programs and promotion of healthy lifestyles in schools. PMID- 25440455 TI - Bone regeneration in experimental animals using calcium phosphate cement combined with platelet growth factors and human growth hormone. AB - Many substances (growth factors and hormones) have osteoinduction properties and when added to some osteoconduction biomaterial they accelerate bone neoformation properties. MATERIALS: The materials included 15 New Zealand rabbits, calcium phosphate cement (Calcibon((r))), human growth hormone (GH), and plasma rich in platelets (PRP). METHODS: Each animal was operated on in both proximal tibias and a critical size bone defect of 6mm of diameter was made. The animals were separated into the following study groups: Control (regeneration only by Calcibon(r)), PRP (regeneration by Calcibon(r) and PRP), GH (regeneration by Calcibon(r) and GH). All the animals were sacrificed at 28 days. An evaluation was made of the appearance of the proximal extreme of rabbit tibiae in all the animals, and to check the filling of the critical size defect. A histological assessment was made of the tissue response, the presence of new bone formation, and the appearance of the biomaterial. Morphometry was performed using the MIP 45 image analyser. ANOVA statistical analysis was performed using the Statgraphics software application. RESULTS: The macroscopic appearance of the critical defect was better in the PRP and the GH group than in the control group. Histologically greater new bone formation was found in the PRP and GH groups. No statistically significant differences were detected in the morphometric study between bone formation observed in the PRP group and the control group. Significant differences in increased bone formation were found in the GH group (p=0.03) compared to the other two groups. CONCLUSION: GH facilitates bone regeneration in critical defects filled with calcium phosphate cement in the time period studied in New Zealand rabbits. PMID- 25440456 TI - [Polyethylene replacement by cementing a new component over the osseointegrated metal-back]. AB - OBJECTIVE: In uncemented revision total hip replacement due to polyethylene wear, the metal cup needs to be maintained when its stability is checked during surgery, only replacing the polyethylene that is cemented if anchoring is not possible. The aim of the present study was to evaluate the medium-term clinical and radiological results of a polyethylene liner cemented into an osseointegrated acetabular shell component. MATERIAL AND METHOD: A retrospective analysis was performed on 15 patients in whom the surgical indication was polyethylene wear, with a mean follow-up of 6.1 years (range 3.5-9.7 years). The Harris Hip Score was used to assess the clinical results before surgery and at the end of follow up. Anteroposterior and axial X-rays of the hip were taken to rule out complications. RESULTS: The mean Harris Hip Score improved, increasing from 64.7 points before the surgery to 80.3 at the end of follow-up. The osteolytic lesions disappeared, or at least the size did not increase, in the follow-up X-rays. One patient (6.7%) suffered 2 dislocation episodes that were treated without the need for surgery. Another patient presented with aseptic loosening of the femoral stem that required a replacement. CONCLUSIONS: Cementing the polyethylene liner, when anchoring is not possible, in an uncemented osseointegrated metal shell is a technique that offers good results in the medium term, and which may minimise the complications that may occur with the replacement of the shell component, without compromising its stability. PMID- 25440457 TI - Effects of dietary energy level on lipid metabolism-related gene expression in subcutaneous adipose tissue of Yellow breed x Simmental cattle. AB - This study was conducted to estimate the effect of dietary energy level on lipid metabolism-related gene expression of subcutaneous adipose tissue in Yellow breed * Simmental cattle. The experiment was conducted for 60 days. The results showed that final weight, average daily gain, average backfat thickness, (testicles + kidney + pelvic) fat percentage and subcutaneous fat percentage in the high and medium energy groups were significantly higher than in the low-energy group but that the feed conversion ratio was significantly lower. The glucose, triglycerides, cholesterol, high-density lipoprotein and low-density lipoprotein in the high-energy group were significantly higher than in the low-energy group. With dietary energy increasing the activities of lipoprotein lipase (LPL), fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) significantly increased, whereas hormone-sensitive lipase (HSL) and carnitine palmitoyltransferase-1 (CPT 1) significantly diminished. Peroxisome proliferator-activated receptor gamma (PPARgamma), LPL, FAS, sterol regulatory element binding protein 1 (SREBP-1), ACC, stearoyl-CoA desaturase (SCD) and adipocyte-fatty acid binding proteins (A FABP) gene expression were significantly increased by dietary energy increasing, and HSL and CPT-1 gene expression were significantly decreased. These results indicated that with dietary energy increasing, the subcutaneous fat accumulation mainly increased due to adipose tissue lipogenic gene expression and decreased lipolytic gene expression. PMID- 25440459 TI - The role of nitric oxide in predicting revisit of patients with exacerbated chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with high mortality and morbidity. OBJECTIVE: The aim of the present study was to determine the role of nitric oxide (NO) and other possible factors in predicting the revisit of patients with COPD exacerbation to the emergency department (ED). METHODS: This is a prospective cohort study on patients with exacerbated COPD in the ED setting. Bedside nasal NO values were measured with a hand-held analyzer device. Revisit to the ED has been defined as any unscheduled visit to an ED or to primary physician's office within 2 weeks of the initial ED visit for worsening COPD symptoms. A follow-up survey via telephone was conducted on all patients at the end of 2 weeks. RESULTS: The data from 64 patients who visited the ED once was compared to 28 revisits. Total of 92 patients were analyzed and variables were compared. The rate of revisits to the ED was 30%. Nasal NO measurement could not predict the revisits of patients with COPD exacerbation to the ED. The mean respiratory rate, exacerbations in previous year, home nebulizer therapy, prescribed antibiotic at discharge, home oxygen therapy, and abnormal chest x-ray studies were associated with increased rate of revisits to ED in univariate analysis. After multivariate analysis, only the mean respiratory rate at presentation and the prescribed antibiotic at discharge were significant determinants. CONCLUSIONS: There was no statistically significant difference measured in NO level at presentation or before discharge between the groups. The mean respiratory rate at presentation and the prescribed antibiotic at discharge may predict the return of a COPD-exacerbated patient within 14 days to ED. PMID- 25440460 TI - Tony McMichael. 3.10.42 - 26.9.14. PMID- 25440458 TI - Shifts in endotracheal tube position due to chest compressions: a simulation comparison by fixation method. AB - BACKGROUND: Endotracheal tube placement during resuscitation is important for definite tracheal protection. Accidental extubation due to endotracheal tube displacement is a rare event that can result in severe complications. OBJECTIVE: This study evaluated how endotracheal tube displacement is affected by tape vs. tube holder fixation using a manikin and auto-chest compression machine simulation. METHODS: The endotracheal tube was placed in either a shallow or a deep position, with the tube cuff at the center of the glottis or 26 cm from the incisors in an advanced lifesaving simulator. Trials were performed five times in each setting with: no fixation; Durapore(r) tape fixation; Multipore(r) tape fixation; and Thomas tube holder(r) fixation. After 10 min of automated chest compressions, endotracheal tube shift was measured. Statistical analysis was performed with one-way repeated analysis of variance or chi(2) test, with p < 0.05 considered significant. RESULTS: In the shallow setting, endotracheal tube extubation occurred in all trials with no fixation, Durapore, and Multipore. In contrast, no extubation occurred in the Tube holder trials (p < 0.05). In the deep setting, no extubation was confirmed in any trial. Relative to no fixation (0.56 +/- 0.11 cm), endotracheal tube shift was significantly less in the Durapore tape, Multipore tape, and Tube holder groups (p < 0.05). Of the three fixation methods, Tube holder (0.04 +/- 0.05 cm) showed significantly less shift (p < 0.05) relative to Durapore (0.28 +/- 0.04 cm) and Multipore (0.32 +/- 0.08 cm). CONCLUSION: Endotracheal tube displacement occurs less with Tube holder fixation than with Durapore tape or Multipore tape during simulation of continuous chest compressions. PMID- 25440461 TI - What did you do at work today? PMID- 25440462 TI - Urgently needed: voices for integrity in public policy making. PMID- 25440463 TI - Rates of overweight and obesity in a sample of Australian young people and their carers in out-of-home residential care. PMID- 25440465 TI - Moving university campuses tobacco-free: collective responsibility and collaboration the key to a healthier Victoria. PMID- 25440464 TI - A different approach to Indigenous drink driving is needed to incorporate cultural factors in outer regional and remote Australia. PMID- 25440466 TI - How has Welfare to Work reform affected the mental health of single parents in Australia? PMID- 25440467 TI - Do childcare services provide foods in line with the 2013 Australian Dietary guidelines? A cross-sectional study. PMID- 25440469 TI - Effect of administration route and dose escalation on plasma and intestinal concentrations of enrofloxacin and ciprofloxacin in broiler chickens. AB - BACKGROUND: The (mis)use of fluoroquinolones in the fowl industry has led to an alarming incidence of fluoroquinolone resistance in pathogenic as well as commensal bacteria. Next to simply reducing antimicrobial consumption, optimizing dosage regimens can be regarded as a suitable strategy to reduce antimicrobial resistance development without jeopardizing therapy efficacy and outcome. A first step in order to limit antimicrobial resistance is to assess the exposure of the intestinal microbiota to enrofloxacin after different treatment strategies. Therefore, a study was conducted in broiler chickens to assess the effect of route of administration (oral versus intramuscular) and dose escalation (10 and 50 mg/kg body weight) on plasma and intestinal concentrations of enrofloxacin and its main metabolite ciprofloxacin after treatment with enrofloxacin once daily for five consecutive days. Four different parts of the intestinal tract were sampled: ileum, cecum, colon and cloaca. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to quantify both analytes in plasma and intestinal content. Sample preparation prior to LC-MS/MS analysis consisted of extraction with ethyl acetate. For intestinal content samples PBS buffer was added before extraction. The supernatant was evaporated to dryness and resuspended in water prior to analysis. RESULTS: The results in plasma and intestinal content demonstrated that biotransformation of enro- to ciprofloxacin in broiler chickens is limited. In general, the intestinal microbiota in cecum and colon is exposed to significant levels of enrofloxacin after conventional treatment (21-130 MUg/g). A clear increase of intestinal concentrations was demonstrated after administration of a five-fold higher dose (31-454 MUg/g). After intramuscular administration, intestinal concentrations were comparable, except for the higher levels in cloaca due to the complete bioavailability and urinary excretion. CONCLUSIONS: The intestinal microbiota is exposed to high levels of the antimicrobial, after oral as well as parenteral therapy. Furthermore, a dose and time dependent correlation was observed. The impact of the detected intestinal levels on resistance selection in the intestinal microbiota has to be further investigated. PMID- 25440470 TI - The relationship between the contralateral collateral supply and myocardial viability on cardiovascular magnetic resonance: can the angiogram predict functional recovery? AB - BACKGROUND: A collateral circulation which supplies a myocardial territory, subtended by a chronic total occlusion (CTO), may be observed at invasive coronary angiography. The prognostic and protective role of such collateralisation is well demonstrated suggesting that a good collateral circulation may be a predictor of myocardial viability, but current evidence is discrepant. The aim of this study is to assess the relationship between collateralisation from the contralateral epicardial vessels and myocardial viability by cardiovascular magnetic resonance (CMR). METHOD: Consecutive patients with CTO having had both CMR and invasive coronary angiography were retrospectively identified. The collateral circulation was graded with the Cohen and Rentrop classification. CMR images were graded per segment for wall motion (1: normal/hyperkinetic, 2: hypokinetic, 3: akinetic, or 4: dyskinetic) and wall motion score index (WMSI) was calculated. The segmental transmurality of late gadolinium enhancement was scored as 1 (0%), 2 (1-25%), 3 (26-50%), 4 (51-75%) and 5 (76-100%). RESULTS: A good collateral circulation was more likely to supply viable myocardium (p=0.01). There was no relationship between collateral circulation supply and wall motion score index (WMSI), however, increasing transmurality of LGE was significantly associated with higher mean WMSI representing increasing dysfunctional myocardium (p<0.001). CONCLUSION: The presence of collateral coronary circulation at angiography predicts the presence of viability on cardiovascular MRI, with a gradation of greater viability associated with improving Rentrop grade. A collateral circulation at angiography should, therefore, prompt more formal assessment of viability and consideration of revascularisation in order for the patient to obtain the associated functional and prognostic improvement. PMID- 25440472 TI - The efficacy and safety of transradial percutaneous coronary intervention vs transfemoral percutaneous coronary intervention for ST-segment elevation myocardial infarction patients: a meta-analysis. PMID- 25440471 TI - Myocardial scar characteristics based on cardiac magnetic resonance imaging is associated with ventricular tachyarrhythmia in patients with ischemic cardiomyopathy. AB - OBJECTIVES: We hypothesized that myocardial scar characterization using cardiac magnetic resonance imaging (CMR) may be associated with the occurrence of ventricular tachyarrhythmia (VT), appropriate implantable cardioverter defibrillator (ICD) therapy and mortality. BACKGROUND: Since a minority of patients with prophylactic ICD implantation receive appropriate ICD therapy, there is a need for more effective risk stratification for primary prevention in patients with ischemic cardiomyopathy. METHODS AND RESULTS: In 99 patients with ischemic cardiomyopathy, CMR was performed prior to ICD implantation. We assessed if CMR indices (cardiac mass, LVEF) and CMR scar characteristics (infarct core mass, peri-infarction mass and the ratio's between left ventricular mass, infarct core mass and peri-infarction mass) were associated with outcome. The primary endpoint was sustained VT and/or appropriate ICD therapy. The secondary endpoint was all-cause mortality. During a median follow-up of 5.4 years (IQR 4.5-6.6 years), 34 patients reached the primary end-point (17 appropriate ICD shocks) and 26 patients died. In multivariable Cox regression analysis, peri-infarction to core-infarction ratio (HR 2.01, 95%CI: 1.17-3.44, p=0.01) was independently and significantly associated with the primary endpoint, whereas NYHA-class and lower LVEF were not. Conversely, age (HR 1.06, 95% CI: 1.01-1.12, p=0.02) and lower LVEF (HR 0.95, 95% CI: 0.91-1.00, p=0.04) were independently associated with all cause mortality, mainly due to heart failure. CONCLUSION: A relatively large peri infarction mass is associated with sustained VT and/or appropriate ICD therapy, whereas age and lower LVEF are associated with mortality. CMR based tissue characterization could aid in the prediction of specific outcome measures and in clinical decision making. PMID- 25440473 TI - An invitation to get to know your editor. PMID- 25440474 TI - Circulating anti-Mullerian hormone levels in relation to nutritional status and selected adipokines levels in polycystic ovary syndrome. AB - OBJECTIVE: The aim of the study was to analyse the relationship between nutritional status, selected adipokines and plasma anti-Mullerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS). STUDY DESIGN PATIENTS AND MEASUREMENTS: A prospective, cross-sectional study, involving 87 PCOS (48 obese) women and 67 non-PCOS women (36 obese). Anthropometric parameters were measured, and body composition was determined by the bioimpedance method. Fasting serum glucose, androgens, FSH, LH, SHBG, insulin, AMH, apelin-36, adiponectin, leptin and omentin-1 were measured. RESULTS: Plasma AMH levels were significantly higher in PCOS compared to the non-PCOS group (7.8 +/- 4.3 ng/ml vs 44 +/- 2.4 ng/ml; P < 0.001). Furthermore, AMH levels were higher in both PCOS and non-PCOS normal weight than in obese subgroups (8.9 +/- 4.4 ng/ml vs 7.0 +/- 4.0 ng/ml; P < 0.05 and 5.1 +/- 2.4 ng/ml vs 3.9 +/- 2.3 ng/ml; P < 0.05). There were negative correlations between AMH levels and anthropometric parameters (body mass, BMI, fat mass and percentage, as well as waist circumference) and plasma omentin-1 concentrations (R = -0.28, P < 0.001; R = -0.30, P < 0.001; R = -0.36, P < 0.001; R = -0.34, P < 0.001; R = -0.23, P < 0.01; and R = -0.20, P < 0.05, respectively) in all study groups. In multiple regression analysis, circulating AMH level variability was explained by omentin-1 levels and anthropometric parameters (excluding waist circumference). CONCLUSIONS: In this observational study, nutritional status appears to be the main factor influencing circulating AMH levels independent of PCOS. The observed AMH association with omentin-1 levels suggests that this adipokine may be a link between hormonal dysfunction of adipose tissue related to obesity and decreased AMH secretion. PMID- 25440475 TI - Pyramids and roundtables: a reflection on leadership. AB - By the nature of their career choice, surgeons are leaders at a variety of levels. The rise to leadership positions in surgery often requires scaling a steep pyramid. Many young surgeons are poorly prepared for what is frequently a competition with their peers. Some of the qualities young surgeons must possess to ascend the leadership pyramid are summarized by the "HOPES" of leadership: Honesty, recognition of Opportunity, having a Plan, knowing your Environment, and Self-assessment. PMID- 25440476 TI - Surgical lessons from the lake. AB - After circumnavigating Lake Michigan during a sabbatical in the summer of 2011, the lessons learned from this experience and the surgical parallels between boating and life as a surgeon will be discussed. Topics will include the use of surgical checklists, teamwork and communication, leadership, and surgical mentorship. PMID- 25440477 TI - A comparison of postoperative effects of bariatric surgery on medical markers of morbidity. AB - BACKGROUND: Bariatric surgery reduces the prevalence of diabetes and improves lipid profiles. Low-density lipoprotein particle (LDL-P) is a more accurate predictor of cardiovascular events than high-density lipoprotein (HDL) and LDL cholesterol. The effects of bariatric procedures on LDL-P have not been previously reported. METHODS: Two hundred thirty patients undergoing bariatric surgery, including gastric bypass, sleeve gastrectomy, and laparoscopic adjustable gastric band placement at a single institution were included. HDL, LDL, hemoglobin A1c, and LDL-P were measured preoperatively and at 3, 6, and 12 months postoperatively. Weight was recorded at baseline and after 1 year. RESULTS: There was a decrease in serum LDL-P levels, averaging 472.58 (P < .0001) over 1 year. HDL levels increased. Hemoglobin A1c and LDL levels declined. On average, patients lost 58% of excess weight. CONCLUSION: LDL-P significantly decreased after bariatric surgery in relation to weight loss. It may be inferred that bariatric surgery decreases the risk of cardiovascular events. PMID- 25440478 TI - Can it wait until morning? A comparison of nighttime versus daytime cholecystectomy for acute cholecystitis. AB - BACKGROUND: The urgency of laparoscopic cholecystectomy for acute cholecystitis is under debate. We hypothesized that nighttime cholecystectomy is associated with decreased length of stay. METHODS: Retrospective review of 1,140 patients at 2 large urban referral centers with acute cholecystitis who underwent daytime (7 am to 7 pm) versus nighttime (7 pm to 7 am) cholecystectomy was conducted. RESULTS: Nighttime cholecystectomy did not affect the overall length of stay (3.7 vs 3.8 days, P = .08) or complication rate (5% vs 7%, P = .5) versus daytime cholecystectomy. Nighttime cholecystectomy was associated with a higher conversion rate to open cholecystectomy (11% vs 6%, P = .008). On multivariable analysis, independent predictors of conversion to open surgery were nighttime cholecystectomy, age, and gangrenous cholecystitis (P = .01). The only predictor of complications was gangrenous cholecystitis (P = .02). CONCLUSIONS: Nighttime cholecystectomy is associated with an increased conversion to open surgery without decrease in length of stay or complications. These findings suggest that laparoscopic cholecystectomy for acute cholecystitis should be delayed until normal working hours. PMID- 25440479 TI - Alvimopan reduces length of stay and costs in patients undergoing segmental colonic resections: results from multicenter national administrative database. AB - BACKGROUND: Alvimopan (Entereg), a peripherally acting mu-opioid receptor antagonist, has been shown to expedite recovery of bowel function after colon resection surgery. Most data are available from industry-sponsored trials. This study aims to evaluate the clinical impact of this drug on perioperative outcomes and costs in patients undergoing segmental colonic resection for diverticular disease. METHODS: A large administrative database maintained by the University Health System Consortium, an alliance of over 200 academic and affiliate hospitals, was queried from 2008 to 2011. International Classification of Diseases, 9th Revision, Clinical Modification codes for segmental colon resection because of diverticular disease were used to identify 2 matched cohorts of adult patients. University Health System Consortium's clinical resource manager was used to access pharmacy data and compare it with patient outcomes. RESULTS: Five thousand two hundred ninety-nine patients met the above criteria. Four hundred thirty-eight patients received alvimopan and 4,861 did not. Regardless of laparoscopic or open approach, alvimopan significantly improved the postoperative length of stay (4.43 +/- 2.02 vs 5.92 +/- 3.79, P < .0001), cost (9,974 +/- 4,077 vs 11,303 +/- 6,968, P < .0001), and intensive care unit admission rate (1.83% vs 7.20%, P < .05), with no significant difference in mortality (.0% vs .19%, P = 1.000), morbidity (5.93% vs 8.39%, P = .08), or 30-day readmission rate (4.40% vs 4.63%, P = .90). CONCLUSIONS: Alvimopan significantly reduced length of stay, days in the intensive care unit, and hospital cost for patients undergoing colonic segmental resections. Unlike some previously reported studies, we also observed a significant reduction in the length of stay in patients undergoing laparoscopic colectomies who received the drug. Alvimopan may reduce total healthcare costs if used as part of a best care practice model for colon resections. PMID- 25440480 TI - Electromagnetic interference caused by common surgical energy-based devices on an implanted cardiac defibrillator. AB - BACKGROUND: Surgical energy-based devices emit energy, which can interfere with other electronic devices (eg, implanted cardiac pacemakers and/or defibrillators). The purpose of this study was to quantify the amount of unintentional energy (electromagnetic interference [EMI]) transferred to an implanted cardiac defibrillator by common surgical energy-based devices. METHODS: A transvenous cardiac defibrillator was implanted in an anesthetized pig. The primary outcome measure was the average maximum EMI occurring on the implanted cardiac device during activations of multiple different surgical energy-based devices. RESULTS: The EMI transferred to the implanted cardiac device is as follows: traditional bipolar 30 W .01 +/- .004 mV, advanced bipolar .004 +/- .003 mV, ultrasonic shears .01 +/- .004 mV, monopolar Bovie 30 W coagulation .50 +/- .20 mV, monopolar Bovie 30 W blend .92 +/- .63 mV, monopolar instrument without dispersive electrode .21 +/- .07 mV, plasma energy 3.48 +/- .78 mV, and argon beam coagulator 2.58 +/- .34 mV. CONCLUSION: Surgeons can minimize EMI on implanted cardiac defibrillators by preferentially utilizing bipolar and ultrasonic devices. PMID- 25440481 TI - Image-guided placement of long-term central venous catheters reduces complications and cost. AB - BACKGROUND: The goals of this study were to evaluate the complication rate for intraoperative placement of a long-term central venous catheter (CVC) using intraoperative ultrasound (US) and fluoroscopy and to examine the feasibility for eliminating routine postprocedure chest X-ray. METHODS: Retrospective data pertaining to operative insertion of long-term CVC were collected and the rate of procedural complications was determined. RESULTS: From January 2008 to August 2013, 351 CVCs were placed via the internal jugular vein using US. Of these, 93% had a single, successful internal jugular vein insertion. The complications included 4 arterial sticks (1.14%). Starting in October 2012, postprocedure chest radiography (CXR) was eliminated in 170 cases, with no complications. A total of $29,750 in charges were deferred by CXR elimination. CONCLUSIONS: This review supports the use of US for CVC placement with fluoroscopy in reducing the rate of procedural complications. Additionally, with fluoroscopic imaging, postprocedural CXR can be eliminated with associated healthcare savings. PMID- 25440482 TI - Can surgical performance benchmarking be generalized across multiple outcomes databases: a comparison of University HealthSystem Consortium and National Surgical Quality Improvement Program. AB - BACKGROUND: Surgeon's performance is tracked using patient outcomes databases. We compared data on patients undergoing laparoscopic cholecystectomy from 2 large databases with significant institutional overlap to see if either patient characteristics or outcomes were similar enough to accurately compare performance. METHODS: Data from 2009 to 2011 were collected from University HealthSystem Consortium (UHC) and National Surgical Quality Improvement Program (NSQIP). UHC and NSQIP collect data from over 200 and 400 medical centers, respectively, with an overlap of 70. Patient demographics, pre-existing medical conditions, operative details, and outcomes were compared. RESULTS: Fifty-six thousand one hundred ninety-seven UHC patients and 56,197 NSQIP patients met criteria. Groups were matched by age, sex, and pre-existing comorbidities. Outcomes for NSQIP and UHC differed, including mortality (.20% NSQIP vs .12% UHC; P < .0001), morbidity (2.0% vs 1.5%; P < .0001), wound infection (.07% vs .33%; P < .0001), pneumonia (.38% vs .75%; P < .0001), urinary tract infections (.62% vs .01%; P < .0001), and length of hospital stay (1.8 +/- 7.5 vs 3.8 +/- 3.7 days; P = .0004), respectively. CONCLUSIONS: Surgical outcomes are significantly different between databases and resulting performance data may be significantly biased. A single unified national database may be required to correct this problem. PMID- 25440483 TI - Outcomes of endovascular management of acute thoracic aortic emergencies in an academic level 1 trauma center. AB - BACKGROUND: Thoracic aortic emergencies account for 10% of thoracic-related admissions in the United States and remain associated with high morbidity and mortality rates. Open repair has declined owing to the emergence of thoracic endovascular aortic repair (TEVAR), but data on emergency TEVAR use for acute aortic pathology remain limited. We therefore reviewed our experience. METHODS: We retrospectively evaluated emergency descending thoracic aortic endovascular interventions performed at a single academic level 1 trauma center between January 2005 and August 2013 including all cases of traumatic aortic injury, ruptured descending thoracic aneurysm, penetrating atherosclerotic ulcer, aortoenteric fistula, and acute complicated type B dissection. Demographics, clinical data, and outcomes were extracted. Stepwise logistic regression was used to identify independent risk factors for death. RESULTS: During the study period, 51 patients underwent TEVAR; 22 cases (43.1%) were performed emergently (11 patients [50.0%] traumatic aortic injury; 4 [18.2%] ruptured descending thoracic aneurysm; 4 [18.2%] complicated type B dissection; 2 [9.1%] penetrating aortic ulcer; and 1 [4.5%] aortoenteric fistula). Overall, 72.7% (n = 16) were male with a mean age of 54.8 +/- 15.9 years. Nineteen patients (86.4%) required only a single TEVAR procedure, whereas 2 (9.1%) required additional endovascular therapy, and 1 (4.5%) open thoracotomy. Four traumatic aortic injury patients required exploratory laparotomy for concomitant intra-abdominal injuries. During a mean hospital length of stay of 18.9 days (range, 1 to 76 days), 3 patients (13.6%) developed major complications. In-hospital mortality was 27.2%, consisting of 6 deaths from traumatic brain injury (1); exsanguination in the operating room before repair could be achieved (2); bowel ischemia (1) and multisystem organ failure (1); and family withdrawal of care (1). A stepwise logistic regression model identified 24-hour packed red blood cell requirements >=4 units, admission mean arterial pressure <60 mm Hg, and 24-hour fresh frozen plasma to packed red blood cell (pRBC) ratio <1:1.5 as independent risk factors for death in this cohort. During a mean follow-up of 369 days (range, 35 to 957 days), no subsequent major complications or deaths occurred. All patients underwent serial computed tomographic angiography surveillance, and no device related problems were identified during intermediate follow-up. CONCLUSIONS: Thoracic aortic emergencies remain challenging. Our experience in a moderate volume center supports the utilization of TEVAR in the acute setting. Twenty-four hour pRBC requirements >=4 units, admission mean arterial pressure <60 mm Hg, and 24 hour fresh frozen plasma to pRBC ratio <1:1.5 were independently associated with death. PMID- 25440484 TI - The Geriatric Trauma Institute: reducing the increasing burden of senior trauma care. AB - BACKGROUND: Owing to parallel advances in health care and an aging population, geriatric injury has become an increasing burden to trauma systems, suggesting that specific clinical pathways may improve the care of this cohort. We created a dedicated Geriatric Trauma Institute, with multidisciplinary support, as a part of our existing trauma program, theorizing that the Geriatric Trauma Institute would promote quality care, reduce the length of stay, and reduce hospital charges. METHODS: We performed a retrospective analysis of the prospective database of our level 1 trauma center. Patients aged 65 years or older were identified over 12 months, representing 5 months prior and also after the implementation of the new program. RESULTS: The mean length of stay was reduced for admissions to a nontrauma vs geriatric trauma service (5.64 vs 4.43 days; P = .03), generating a charge reduction of 21.4% in only the first 5 months after program implementation. CONCLUSIONS: Our preliminary findings, which require longer-term analysis, suggest that a dedicated geriatric trauma multidisciplinary system promotes quality patient care, improves throughput, and results in significant cost savings via reduced length of stay and concomitant hospital charges. PMID- 25440486 TI - Achieving endoscopic competency in a general surgery residency. AB - BACKGROUND: In 2006, the Residency Review Committee for Surgery increased the total number of required endoscopy cases for graduating residents. Our goal was to evaluate general surgery resident competency in endoscopy, focusing on quality measures. METHODS: A 9-year retrospective review was conducted of 29 residents. Total number of endoscopies performed throughout residency was recorded. Procedures performed as fifth-year residents with indirect supervision were evaluated for quality measures. RESULTS: An average of 76 esophagogastroduodenoscopies and 147 colonoscopies were performed through their first 4 years of residency. Chief residents performed an average of 16 esophagogastroduodenoscopies and 22 colonoscopies. Of colonoscopies performed during their fifth year, 191 were performed while the resident had only indirect supervision. During these cases, cecal intubation was achieved in 90.6% of cases, an average of .48 polyps were identified, and average scope withdrawal time was 13.4 +/- 7.1 minutes. CONCLUSIONS: Our data indicate that surgery residents achieve competency in colonoscopy before performing 140 colonoscopies, supporting the concept that surgery residencies can function as an excellent training ground for endoscopy. PMID- 25440485 TI - Is USMLE Step 1 score a valid predictor of success in surgical residency? AB - BACKGROUND: Many programs rely extensively on United States Medical Licensing Examination (USMLE) scores for interviews/selection of surgical residents. However, their predictive ability remains controversial. We examined the association between USMLE scores and success in surgical residency. METHODS: We compared USMLE scores for 123 general surgical residents who trained in the past 20 years and their performance evaluation. Scores were normalized to the mean for the testing year and expressed as a ratio (1 = mean). Performances were evaluated by (1) rotation evaluations; (2) "dropouts;" (3) overall American Board of Surgery pass rate; (4) first-time American Board of Surgery pass rate; and (5) a retrospective comprehensive faculty evaluation. For the latter, 16 surgeons (average faculty tenure 22 years) rated residents on a 1 to 4 score (1 = fair; 4 = excellent). RESULTS: Rotation evaluations by faculty and "drop out" rates were not associated with USMLE score differences (dropouts had average above the mean). One hundred percent of general surgery practitioners achieved board certification regardless of USMLE score but trainees with an average above the mean had a higher first-time pass rate (P = .04). Data from the comprehensive faculty evaluations were conflicting: there was a moderate degree of correlation between board scores and faculty evaluations (r = .287, P = .001). However, a score above the mean was associated with a faculty ranking of 3 to 4 in only 51.7% of trainees. CONCLUSION: Higher USMLE scores were associated with higher faculty evaluations and first-time board pass rates. However, their positive predictive value was only 50% for higher faculty evaluations and a high overall board pass rate can be achieved regardless of USMLE scores. USMLE Step 1 score is a valid tool for selecting residents but caution might be indicated in using it as a single selection factor. PMID- 25440487 TI - Metastasectomy of neuroendocrine tumors in patients with multiple endocrine neoplasia type 1. AB - BACKGROUND: Neuroendocrine (NE) tumors commonly afflict patients with multiple endocrine neoplasia type 1 (MEN1). It is thought that patients with MEN1 have improved survival compared with individuals with analogous lesions. The role of metastasectomy of NE tumors in MEN1 patients is not clearly defined. METHODS: A review of MEN1 patients undergoing surgery for NE tumors from 1994 to 2010 at a single tertiary care center was performed. Tumor function, the extent of metastasis, R0 resection, and survival were analyzed. RESULTS: We identified 30 patients who underwent resection including synchronous and metachronous metastasectomy. Synchronous metastases were identified in 19 patients (63%), whereas 11 (37%) had metachronous disease. R0 resection was achieved in 93% of patients. Estimated 10-year survival is 86.4% (95% confidence interval, 60% to 100%) with no factors predictive of overall survival. The disease-free interval at 1, 5, and 10 years was 89%, 50%, and 19%, respectively, with recurrence occurring at a median of 5.4 years (95% confidence interval, 77.7% to 100%). Synchronous metastasis (P = .0072; hazard ratio [HR], 3.4) and nonfunctioning tumors (P = .014; HR, 3.3) were more likely to recur, whereas age (P = .09; HR, 1.5), gender (P = .49; HR, 1.3), and the site of metastasis (P = .81; HR, 1.1) did not influence recurrence. DISCUSSION: Patients with MEN1 benefit from resection of metastatic NE disease. Despite a high recurrence rate, survival and disease-free interval is favorable vs patients without MEN1. PMID- 25440488 TI - Optimal utilization of a breast care advanced practice clinician. AB - BACKGROUND: Incorporation of "lean" business philosophy within health care has the goal of adding value by reducing cost and improving quality. Applying these principles to the role of Advance Practice Clinicians (APCs) is relevant because they have become essential members of the healthcare team. METHODS: An independent surgical breast care clinic directed by an APC was created with measurements of success to include the following: time to obtain an appointment, financial viability, and patient/APC/MD satisfaction. RESULTS: During the study period, there was a trend toward a decreased median time to obtain an appointment. Monthly APC charges increased from $388 to $30,800. The mean provider satisfaction score by Press Ganey was 96% for the APC and 95.8% for the surgeon. Both clinicians expressed significant satisfaction with clinic development. CONCLUSIONS: Overall, initiation of an APC breast clinic met the proposed goals of success. The use of lean philosophy demonstrates that implementation of change can result in added value in patient care. PMID- 25440489 TI - Eliminating catheter-associated urinary tract infections in the intensive care unit: is it an attainable goal? AB - BACKGROUND: Purpose of this study is to determine strategies to decrease catheter associated urinary tract infection (CAUTI) in intensive care unit (ICU) patients. METHODS: ICU patients with an indwelling urinary catheter (UC) in one tertiary hospital were monitored for CAUTI. Interventions were implemented sequentially with quarterly data collection. Outcome measures were infection ratio (IR = number of infections/catheter days [CD] * 1000) and device utilization rate (DUR = catheter days/patient days). RESULTS: CDs and DUR decreased (fiscal year 2008: CD, 11,414; DUR, .85 vs fiscal year 2013: CD, 8,144; DUR, .70). IR increased with suspension of prepackaged baths (IR, 3.2 to 3.5 to 4.9 to 5.0), twice daily UC care (IR, 4.8 to 6.7), emptying UC bags at 400 mL (IR, 6.7 to 9.2). Two-person UC placement (IR, 5.6 to 4.8), physician notification of CAUTI (IR, 6.1 to 4.8), and reinstitution of prepackaged baths and daily UC care (IR, 4.8 to 3.7) decreased CAUTI rates. CONCLUSIONS: Decreasing CAUTI in the ICU requires diligent monitoring and constant practice re-evaluation. Elimination of CAUTI in the ICU may not be possible. PMID- 25440490 TI - The impact of early flow and brain oxygen crisis on the outcome of patients with severe traumatic brain injury. AB - BACKGROUND: Multimodality monitoring and goal-directed therapy may not prevent blood flow and brain oxygen (Flow/BrOx) crisis. We sought to determine the impact of these events on outcome in patients with severe traumatic brain injury (sTBI). METHODS: Twenty-four patients with sTBI were treated to maintain intracranial pressure (ICP) less than or equal to 20 mm Hg, cerebral perfusion pressure (CPP) greater than or equal to 60 mm Hg, brain oxygen greater than or equal to 20 mm Hg, and near infrared spectroscopy greater than or equal to 60%. Flow/BrOx crisis events were recorded. The 14-day predicted mortality was compared with actual mortality. RESULTS: Nonsurvivors had a significantly higher number of crisis events nonresponsive to treatment (P < .05). Mortality was 87.5% in patients with greater than or equal to 20 events versus 6.3% in patients with less than 20 events. The predicted mortality was 58%, whereas actual mortality was 33.3% (8/24), yielding a 42% reduction in mortality. CONCLUSIONS: A multimodality monitoring and goal-directed therapy may decrease mortality in sTBI. However, Flow/BrOx crisis events still occur and predict a poor outcome. PMID- 25440491 TI - An experimental model of hemothorax autotransfusion: impact on coagulation. AB - BACKGROUND: Traumatic hemothorax (HTX) has been demonstrated to predictably contain low fibrinogen, low hematocrit, and low platelet counts. When analyzed on its own, shed HTX demonstrates coagulopathy. However, when mixed with normal pooled plasma (NPP) at physiologically relevant dilutions, HTX demonstrates accelerated coagulation. We hypothesize that when HTX is mixed with a patient's own plasma, the mixture will demonstrate hypercoagulability. The accelerated coagulation of this mixture would have important implications for the autotransfusion of HTX as a method of resuscitating a trauma patient. METHODS: Adult trauma patients from whom greater than 140 mL of HTX was evacuated within 1 hour of tube thoracostomy were included. HTX was sampled at 1 hour after evacuation, and a portion of the sample was centrifuged and stored as frozen plasma for later analysis. The remainder of the sample was analyzed (coagulation, hematology, electrolytes), and values were compared with concurrent venous values extracted via chart review. A citrate tube containing the patient's venous blood was additionally spun down and frozen for subsequent mixing study analysis. Coagulation was further evaluated by mixing serial dilutions of the previously frozen HTX with NPP. Additionally, the previously frozen HTX was mixed in serial dilutions with the previously frozen sample of patient plasma (PTP). RESULTS: Subjects (10) were enrolled based on inclusion criteria and collection of a discarded venous sample. In HTX samples analyzed alone, no thrombus was formed in any coagulation test (activated partial thromboplastin time [aPTT] > 180). The median aPTT value of PTP alone was 25.5. In 1-hour specimens mixed at a clinically relevant dilution of 1:4, HTX mixed with NPP had a mediana PTT value of 26.0, whereas HTX mixed with PTP had a median aPTT value of 21.7. Thus, the mixture of HTX + PTP demonstrated a statistically significantly lower aPTT than the mixture of HTX + NPP (P = 0.01). Additionally, the mixture of HTX and PTP shows a statistically significantly lower aPTT value than PTP alone (P = 0.03), indicating a hypercoagulable state. CONCLUSIONS: HTX demonstrates coagulopathy when analyzed independently, but is hypercoagulable when mixed with NPP or PTP. Furthermore, mixing studies show a statistically significantly lower aPTT when HTX is mixed with PTP versus HTX mixed with NPP. Thus, autotransfusion of HTX would likely produce a hypercoagulable state in vivo, and should not be used in place of other blood products to resuscitate a trauma patient. The autotransfusion of HTX may, however, be of use in a resource-limited environment where other blood products are not available. PMID- 25440492 TI - Pelvic ring fractures: has mortality improved following the implementation of damage control resuscitation? AB - BACKGROUND: Over the last 10 years, the paradigm of damage control resuscitation (DCR) has been associated with improved patient outcomes. This study investigates the outcomes of both closed and open pelvic ring fractures at a single institution before and after the formal implementation of DCR principles. METHODS: A retrospective chart review was performed in an urban level I trauma center of all patients who sustained open or closed pelvic ring fractures between 2002 and 2012. RESULTS: Two thousand two hundred forty-seven patients presented with pelvic fractures between 2002 and 2012. Overall mortality was 10% (n = 212). Only 8% of all patients with closed fractures required DCR compared with 28% of patients with open fractures. There was no difference in mortality when comparing DCR and pre-DCR cohorts for either open or closed pelvic fractures. CONCLUSIONS: Interestingly, although DCR seems to lead to more efficient initial resuscitations, further improvements in patient mortality were not realized with formal implementation of DCR principles. PMID- 25440493 TI - An overview on 2-arylquinolin-4(1H)-ones and related structures as tubulin polymerisation inhibitors. AB - Agents that interfere with tubulin function have a broad anti-tumour spectrum and they represent one of the most significant classes of anti-cancer agents. In the past few years, several small synthetic molecules that have an azaflavone nucleus as a core structure have been identified as tubulin inhibitors. Among these, several arylquinolinones, arylnaphthyridinones, arylquinazolinones and arylpyrroloquinolinones have shown to exert their anticancer activity through inhibition of tubulin polymerisation via the colchicine binding site. They arrest the cell growth at G2/M phase providing cell death via both mitotic and apoptotic pathway. Recently, some of them proved to be multi-inhibitor simultaneously targeting both PI3K-Akt-mTOR pathway and the microtubule cytoskeleton. Furthermore, some were demonstrated to possess effective anti-angiogenic properties similar to that of natural compounds combretastatine-A4 and vincristine. This article reviews the synthesis, biological activities and SARs of the main classes of azaflavones. Brief mention of the subtype 2- styrylquinazolinones has also been made. PMID- 25440494 TI - Multicomponent reactions in antimitotic drug discovery. AB - As enabling technology, the development and application of multicomponent reactions (MCRs) are now an integral part of the work of any major medical research unit. Targeted MCR approaches focused on specific antimitotic pathways afford new solutions for the medicinal chemistry of the XXI century. In this review, the contribution of these procedures to the discovery of antimitotic drugs that are currently in clinical trials or already in the market is discussed. PMID- 25440495 TI - Forestier-Rotes-Querol's disease. PMID- 25440497 TI - Seated movement indexes emotion and its regulation in posttraumatic stress disorder. AB - This paper reports the results of a study that administered an emotion regulation task to Operation Enduring Freedom/Operation Iraqi Freedom veterans diagnosed with posttraumatic stress disorder (27) and to healthy controls (23). Seated movement and postural responses were transduced with a sensitive accelerometer attached to the underside of a low-mass cantilevered chair. Consistent with prior studies in which subjects stood on force plates, aversive photographs induced attenuation of nondirectional movement in patients and controls. Regarding seated postural responses, controls leaned towards neutral photographs and away from aversive ones, while participants with PTSD did the opposite. Regulation had no impact on seated movement but was associated with a seated postural withdrawal from the computer screen. PMID- 25440498 TI - Palliative care: a frontier that should be explored by radiologists. PMID- 25440496 TI - Biclonal gammopathies: Retrospective study of 47 patients. AB - OBJECTIVES: Biclonal gammopathies are characterized by the clonal proliferation of plasma cells or their B-lymphoid progenitors and are associated with the production of abnormal immunoglobulins (M proteins or paraproteins). There are no known studies that have analyzed this disease in Spain. We studied the underlying diseases, characteristics of paraproteins and the evolution of a series of patients with biclonal gammopathy. MATERIAL AND METHODS: We reviewed clonal gammopathies at the Department of Immunology of Hospital Puerta de Hierro in Madrid, between 1970 and 2011, selecting those patients with biclonal gammopathy in one reading. We collected data on the patient's epidemiology, underlying disease, associated diseases, therapies and paraprotein and immunoglobulin levels. RESULTS: Of the 1626 cases of clonal gammapathies, 47 were biclonal gammopathy (2.89%). The median follow-up was 2 years. The main associated condition was biclonal gammopathies of undetermined significance (BGUS). The most common paraprotein combination was IgG-IgG. Upon conducting a second paraprotein reading, 81% of the patients had lost at least 1 monoclonal component. A third of the patients had not undergone treatment. CONCLUSIONS: Biclonal gammopathy are fundamentally associated with biclonal gammopathies of undetermined significance. No biclonal gammopathies of undetermined significance evolved to a malignant disease. In a high percentage of patients, at least 1 of the 2 clonal components disappeared, sometimes spontaneously. PMID- 25440499 TI - Canadian Heart Rhythm Society and Canadian Association of Radiologists consensus statement on magnetic resonance imaging with cardiac implantable electronic devices. AB - Magnetic resonance imaging (MRI) has historically been considered contraindicated for individuals with cardiac implantable electronic devices (CIEDs) such as pacemakers and implantable defibrillators. Magnetic resonance scanners produce magnetic fields that can interact negatively with the metallic components of CIEDs. However, as CIED technology has advanced, newer MRI conditional devices have been developed that are now in clinical use and these systems have had demonstrated safety in the MRI environment. Despite the supportive data of such CIED systems, physicians remain reluctant to perform MRI scanning of conditional devices. This joint statement by the Canadian Heart Rhythm Society and the Canadian Association of Radiologists describes a collaborative process by which CIED specialists and clinics can work with radiology departments and specialists to safely perform MRI in patients with MRI conditional CIED systems. The steps required for patient and scanning preparation and the roles and responsibilities of the CIED and radiology departments are outlined. We also briefly outline the risks and a process by which patients with nonconditional CIEDs might also receive MRI in highly specialized centres. This document supports MRI in patients with MRI conditional CIEDs and offers recommendations on how this can be implemented safely and effectively. PMID- 25440501 TI - Clinical significance of a presystolic wave on Doppler examination of the left ventricular outflow tract. AB - A presystolic wave (PSW) is commonly seen on Doppler examination of the left ventricular outflow tract (LVOT), but is little studied. We conducted a retrospective study to assess the prevalence of the PSW, correlations with various Doppler parameters, and its clinical significance. Two hundred echocardiograms, 100 with ejection fraction (EF) >55% and 100 with EF <45%, were reviewed. Mitral inflow velocities, septal annular velocities, LVOT, and PSW velocities were measured. Major adverse cardiovascular events (MACE [death, heart failure hospitalization, atrial fibrillation, and stroke]) were compared between those with and without a PSW, in both EF groups. Mean age was 58 +/- 15 years; 56% were men and 69% were African-American. PSW prevalence was similar between normal (68%) and reduced EF groups (62%). However, its velocity was less in the low EF group (37 +/- 10 vs 48 +/- 16 cm/s, p <0.0001). In subjects with normal EF PSW velocity correlated with mitral A velocity (rho = 0.43, p = 0.0003). In subjects with reduced EF the association with A velocity was not significant (rho = 0.22, p = 0.09), but there was a significant association with annular a' velocity (rho = 0.38, p = 0.002). Over a mean follow-up of 1.7 +/- 0.3 years, 57 subjects (28%) experienced MACE. Those without a PSW had more MACE (39% vs 23%, p = 0.02); PSW absence remained predictive of MACE after adjustment for multiple variables, especially in patients with reduced EF. In conclusion, PSW is common in the LVOT. Its presence and magnitude are associated with measures of atrial contraction. Its absence is associated with increased rates of adverse events, especially in patients with low EF. PMID- 25440500 TI - Persistence of evidence-based medication use after discharge from academic versus nonacademic hospitals among patients with non-ST-segment elevation myocardial infarction. AB - There is increasing emphasis on optimizing evidence-based medication (EBM) persistence as a means to improve longitudinal patient outcomes after acute myocardial infarction (MI); yet it is unknown whether differences in medication persistence exist between patients discharged from academic versus nonacademic hospitals. We linked Medicare pharmacy claims data with 3,184 patients with non ST-segment elevation MI >65 years of age who were treated in 2006 at 253 hospitals participating in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology and American Heart Association guidelines registry. Using multivariate regression, we compared persistent filling of beta blockers, angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers, clopidogrel, and statins at 90 days and 1 year postdischarge between patients discharged from academic and nonacademic hospitals. Patients treated at academic hospitals were more frequently nonwhite (19% vs 8%, p <0.001) and had a greater co-morbidity burden (Charlson score >=4 in 36% vs 30%, p = 0.001) than patients treated at nonacademic hospitals. Composite persistence to all EBMs prescribed at discharge was low and not significantly different between academic and nonacademic hospitals at 90 days (46% vs 45%, adjusted incidence rate ratio = 0.99, 95% confidence interval 0.95 to 1.04) and at 1 year (39% vs 39%, adjusted incidence rate ratio = 1.02, 95% confidence interval 0.98 to 1.07). Rates of persistence to EBMs were similar between patients with MI >65 years old treated at academic versus nonacademic hospitals; however, persistence rates are low both early and late postdischarge, highlighting a continued need for quality improvement efforts to optimize post-MI management. PMID- 25440502 TI - Synthesis and evaluation of sulfonylethyl-containing phosphotriesters of 3'-azido 3'-deoxythymidine as anticancer prodrugs. AB - A series of bis(sulfonylethyl) and mono(sulfonylethyl) phenyl phosphotriesters of zidovudine (3'-azido-3'-deoxythymidine, AZT) were synthesized as potential anticancer prodrugs that liberate AZT monophosphate via nonenzymatic beta elimination mechanism. Stability studies demonstrated that all the synthesized prodrugs spontaneously liberate AZT monophosphate with half-lives in the range of 0.07-278.8h under model physiological conditions in 0.1M phosphate buffer at pH 7.4 and 37 degrees C. Analogous to aldophosphamide, the elimination rates were accelerated in the presence of reconstituted human plasma under the same conditions. Among the compounds, 3, 4, 8, and 10 were comparable or superior to AZT against five established human cancerous cell lines in vitro. Moreover, the selected compounds were equally sensitive to both the wild-type osteosarcoma 143 B and the thymidine kinase-deficient 143 B/TK(-) cell lines. The findings are consistent with that these compounds deliver AZT monophosphate intracellularly. PMID- 25440503 TI - Impact of climate change and population growth on a risk assessment for endocrine disruption in fish due to steroid estrogens in England and Wales. AB - In England and Wales, steroid estrogens: estrone, estradiol and ethinylestradiol have previously been identified as the main chemicals causing endocrine disruption in male fish. A national risk assessment is already available for intersex in fish arising from estrogens under current flow conditions. This study presents, to our knowledge, the first set of national catchment-based risk assessments for steroid estrogen under future scenarios. The river flows and temperatures were perturbed using three climate change scenarios (ranging from relatively dry to wet). The effects of demographic changes on estrogen consumption and human population served by sewage treatment works were also included. Compared to the current situation, the results indicated increased future risk:the percentage of high risk category sites, where endocrine disruption is more likely to occur, increased. These increases were mainly caused by changes in human population. This study provides regulators with valuable information to prepare for this potential increased risk. PMID- 25440504 TI - Glycoprotein IIb/IIIa inhibitors increase bleeding: the elephant in the cardiac catheterization laboratory. PMID- 25440505 TI - Bivalirudin versus heparin for percutaneous coronary intervention: an updated meta-analysis of randomized controlled trials. AB - AIMS: Given controversy over anticoagulation regimens for percutaneous coronary intervention (PCI), we performed an updated meta-analysis of randomized controlled trials (RCTs) to compare bivalirudin versus heparin. METHODS AND RESULTS: Medline/Pubmed and Cochrane CENTRAL were searched for all RCTs comparing bivalirudin with provisional glycoprotein IIb/IIIa inhibitor (GPI) use versus heparin with provisional or routine GPI use for PCI. Pooled estimates of 30day outcomes, presented as risk ratios (RR) [95% confidence intervals], were generated with random-effect models. Our analysis included 14 studies with 30,446 patients that were randomized to bivalirudin with provisional GPI use (n=14,869) versus heparin with provisional (n=6451) or routine GPI use (n=9126). There was no significant difference between anticoagulation with bivalirudin compared with heparin for death (RR 0.95 [0.78-1.14]) or myocardial infarction (RR 1.10 [0.97 1.25]). Early stent thrombosis was significantly greater with bivalirudin compared with heparin (RR 1.61 [1.18-2.20], p=0.003), especially in patients undergoing primary PCI (2.15 [1.15-4.03], p=0.02). However, bivalirudin reduced the risk of major bleeding (RR 0.59 [0.51-0.70], p<0.0001) and TIMI major bleeding (RR 0.59 [0.48-0.72], p<0.0001) compared with heparin. Meta-regression analysis demonstrated that bleeding risk with use of heparin significantly increases with increasing GPI use (p=0.02). CONCLUSION: Meta-analysis of 14 RCTs with 30,446 patients demonstrated that bivalirudin is associated with higher risk of stent thrombosis but lower risk of major bleeding compared with heparin. PMID- 25440506 TI - Safety and efficacy of everolimus-eluting stents compared with first-generation drug-eluting stents in patients undergoing primary percutaneous coronary intervention. AB - OBJECTIVE: To assess the safety and efficacy everolimus-eluting stents (EES) compared with first-generation drug-eluting stents (DES) in patients with acute myocardial infarction (MI) undergoing primary percutaneous coronary intervention (PCI). BACKGROUND: EES have been associated with improved clinical outcomes compared to paclitaxel-eluting stents (PES) and with similar outcomes compared to sirolimus-eluting stents (SES). METHODS: A total of 520 patients who presented with ST-elevation myocardial infarction (STEMI) from 2003 to 2013, who underwent primary PCI with DES, were retrospectively analyzed. Of these, 247 received SES, 136 PES, and 137 EES. Patients were followed up to 2 years for major adverse cardiac events (MACE). Univariate and multivariate models detected correlates to outcome. RESULTS: EES implantation, compared with PES and SES, resulted in comparable rates of MACE (8.8% vs. 16.2%, p=0.06 and 8.8% vs. 12.6%, respectively, p=0.26), stent thrombosis, MI, and target lesion revascularization. Patients who received EES had lower rates of all-cause mortality (3.7% vs. 12.6% vs. 9.4%, p=0.03) at 1-year follow up. However, in the univariate and multivariate analyses, stent type was not independently associated with the primary outcome or with all-cause mortality. Diabetes mellitus and number of stents implanted were independently associated with the primary outcome. CONCLUSION: While EES seem to be associated with better outcome when compared to PES, the main correlates of STEMI patients are the presence of diabetes and number of stents implanted, and not the type of stent used for intervention. PMID- 25440507 TI - Adherence to diabetes medication: a systematic review. AB - AIMS: To investigate the extent of and factors associated with adherence to Type 2 diabetes medication. METHODS: The CINAHL, Embase, International Pharmaceutical Abstracts, Medline, PubMed and PsychINFO databases were searched for the period January 2004 to July 2013. Papers were included in the present review if they reported the prevalence of adherence (the percentage of the study population that is classified as adherent) to Type 2 diabetes medication and used validated adherence measures with a defined cut-off point to indicate adherence. Reported factors were classified as potential predictors if the studies that examined that particular variable reported consistent findings. RESULTS: Of the 27 studies included in the present review, the prevalence of adherence ranged from 38.5 to 93.1%. Only six out of 27 studies (22.2%) reported prevalence of adherence of >= 80% among their study population. Depression and medication cost were found to be consistent and potentially modifiable predictors for diabetes medication-taking behaviour. The associations between adherence and other factors were inconsistent among the reviewed studies. CONCLUSIONS: Adherence to diabetes medication remains an ongoing problem. This review has highlighted the urgent need to develop consensus about what constitutes good adherence in diabetes. Further research is needed to clarify modifiable factors, in addition to depression and medication cost, that influence adherence and may provide a focus for targeted interventions to promote adherence, optimize diabetes control and limit the progression of diabetes. PMID- 25440508 TI - Safety of ultrasound contrast agents in patients with intracardiac shunts. PMID- 25440510 TI - Quantification of the position, orientation, and surface area of bone loss in type B2 glenoids. AB - BACKGROUND: The purpose of this computed tomography-based study was to quantify erosions in B2 glenoids. We hypothesized that erosions do not occur symmetrically and that they have a predictable orientation. METHODS: This study evaluated 55 type B2 glenoid cases. Computed tomography data were used to create three dimensional reconstructions, and point coordinates were extracted from each reconstruction for morphologic analysis of the osteoarthritic glenoid and humerus. RESULTS: There was a significant difference between the mean orientation angle (28 degrees +/- 11 degrees ) of the posterior glenoid line of erosion and the superoinferior axis (P < .001), which resulted in the average erosion being directed toward the 8-o'clock position. On average, the erosion started 1.6 +/- 3.4 mm posterior to the glenoid center point. In 35% of B2 cases, the line of erosion was curved. The mean surface area was 763 +/- 296 mm(2) for the neoglenoid and 957 +/- 276 mm(2) for the paleoglenoid, indicating that the neoglenoid occupied 44% +/- 12% of the total glenoid area. In this cohort, the mean radius of the humeral head neoarticulation was 32 +/- 6 mm, the neoglenoid radius was 37 +/- 8 mm, and the paleoglenoid radius was 34 +/- 7 mm. The radius of the humeral head was significantly less than that of the neoglenoid (P < .001) and the paleoglenoid (P = .009). In addition, the radius of the neoglenoid was significantly greater than the radius of the paleoglenoid (P = .012). DISCUSSION: Type B2 glenoids have a predictable wear pattern, which is not axisymmetric to the glenoid superoinferior axis. In addition, the identified anatomic characteristics of B2 erosions will aid surgeons in the operative management of bone loss and may assist manufacturers in the design of augmented components. PMID- 25440509 TI - A YadA-like autotransporter, Hag1 in Veillonella atypica is a multivalent hemagglutinin involved in adherence to oral streptococci, Porphyromonas gingivalis, and human oral buccal cells. AB - Dental biofilm development is a sequential process, and adherence between microbes and the salivary pellicle (adhesion) as well as among different microbes (co-adhesion or coaggregation) plays a critical role in building a biofilm community. The Veillonella species are among the most predominant species in the oral cavity and coaggregate with many initial, early, middle, and late colonizers. Similar to oral fusobacteria, they are also considered bridging species in biofilm development. However, the mechanism of this ability has yet to be reported, due to the previous lack of a genetic transformation system in the entire genus. In this study, we used our recently discovered transformable Veillonella strain, Veillonella atypica OK5, to probe the mechanism of coaggregation between Veillonella species and other oral bacteria. By insertional inactivation of all eight putative hemagglutinin genes, we identified one gene, hag1, which is involved in V. atypica coaggregation with the initial colonizers Streptococcus gordonii, Streptococcus oralis and Streptococcus cristatus, and the periodontal pathogen Porphyromonas gingivalis. The hag1 mutant also abolished adherence to human buccal cells. Inhibition assays using various chemical or physiological treatments suggest different mechanisms being involved in coaggregation with different partners. The entire hag1 gene was sequenced and shown to be the largest known bacterial hemagglutinin gene. PMID- 25440511 TI - Obesity is associated with increased postoperative complications after operative management of proximal humerus fractures. AB - BACKGROUND: Obesity has become a significant public health concern in the United States. The goal of this study was to assess the effect of obesity on postoperative complications after operative management of proximal humerus fractures by use of a national database. METHODS: Patients who underwent operative management of a proximal humerus fracture were identified in a national database by Current Procedural Terminology codes for procedures in patients with International Classification of Diseases, Ninth Revision (ICD-9) codes for proximal humerus fracture, including (1) open reduction and internal fixation, (2) intramedullary nailing, (3) hemiarthroplasty, and (4) total shoulder arthroplasty. These groups were then divided into obese and nonobese cohorts by use of ICD-9 codes for obesity, morbid obesity, or body mass index >30. Each cohort was then assessed for local and systemic complications within 90 days and mortality within 2 years postoperatively. Odds ratios and 95% confidence intervals were calculated. RESULTS: From 2005 to 2011, 20,319 patients who underwent operative management of proximal humerus fractures were identified, including 14,833 (73.0%) open reduction and internal fixation, 1368 (9.2%) intramedullary nail, 3391 (16.7%) hemiarthroplasty, and 727 (3.6%) shoulder arthroplasty. Overall, 3794 patients (18.7%) were coded as obese, morbidly obese, or body mass index >30. In each operative group, obesity was associated with a substantial increase in local and systemic complications. CONCLUSIONS: Obesity and its resultant medical comorbidities are associated with increased rates of postoperative complications after operative management of proximal humerus fractures. Obese patients for whom operative management of proximal humerus fractures is planned should be counseled preoperatively about their increased risk for postoperative complications. PMID- 25440512 TI - Filling Index Score of Remplissage (FISOR): a useful measurement tool to evaluate structural outcome after remplissage. AB - BACKGROUND: The purpose of this study was to evaluate and to grade the extent of filling into the Hill-Sachs lesion quantitatively by use of magnetic resonance arthrography after an arthroscopic remplissage procedure. METHODS: The current study enrolled 23 patients who underwent arthroscopic Bankart repair with a remplissage procedure for a large or engaging Hill-Sachs lesion confirmed by arthroscopic findings. The postoperative filling index was classified into 5 categories by axial and sagittal views of T2-weighted images on magnetic resonance arthrography: complete filling (4 points); partial filling with minor defect (3 points); partial filling with major defect (2 points); minimal filling with significant free fluid level (1 point); and filling failure with dehiscence (0 point). Filling Index Score of Remplissage (FISOR) was also calculated from the total sum of points in the axial and sagittal planes and classified into 5 grades. RESULTS: The FISOR was 8 points in 13 patients, 7 points in 2 patients, 6 points in 3 patients, 5 points in 1 patient, 4 points in 1 patient, 3 points in 1 patient, 2 points in 1 patient, and 0 point in 1 patient. According to the FISOR grades, these results were recorded as excellent in 15 patients (65.2%), good in 4 patients (17.4%), fair in 2 patients (8.7%), poor in 1 patient (4.3%), and no evidence of filling in 1 patient (4.3%). CONCLUSION: The FISOR would be a useful measurement tool for the evaluation of structural outcomes after the remplissage procedure. PMID- 25440513 TI - Postoperative accuracy analysis of three-dimensional corrective osteotomy for cubitus varus deformity with a custom-made surgical guide based on computer simulation. AB - BACKGROUND: For correction of cubitus varus deformity resulting from supracondylar fracture of the humerus, we developed an operative method with use of a custom-made surgical guide, designed on the basis of 3-dimensional (3D) computer simulation with computed tomography data. The purpose of this study was to investigate the postoperative accuracy of this system in clinical cases. METHODS: Subjects included 17 consecutive patients (13 males and 4 females) with cubitus varus deformity after supracondylar fracture. Patients underwent 3D corrective osteotomy with use of a custom-made surgical guide. Postoperative computed tomography scan was performed after bone union diagnosis on plain radiographs, and postoperative 3D bone models were compared with preoperative simulation by surface registration technique. In addition, we evaluated radiographic parameters (humerus-elbow-wrist angle and tilting angle) and range of elbow motion at the most recent follow-up. RESULTS: Mean errors in 3D corrective osteotomy were 0.6 degrees +/- 0.7 degrees in varus-valgus rotation, 0.8 degrees +/- 1.3 degrees in flexion-extension rotation, 2.9 degrees +/- 2.8 degrees in internal-external rotation, 1.7 +/- 1.8 mm in anterior-posterior translation, 1.3 +/- 1.8 mm in lateral-medial translation, and 7.1 +/- 6.3 mm in proximal-distal translation. The mean humerus-elbow-wrist angle on plain radiographs of the affected side was 15 degrees in varus before surgery and improved to 6 degrees in valgus after surgery. The mean tilting angle of the affected side was 31 degrees before surgery and improved to 40 degrees after surgery. CONCLUSION: The 3D correction of cubitus varus deformity was performed accurately within the allowable error limits. PMID- 25440514 TI - The effect of humeral version on teres minor muscle moment arm, length, and impingement in reverse shoulder arthroplasty during activities of daily living. AB - BACKGROUND: External rotation can be compromised after reverse total shoulder arthroplasty (RTSA). A functional teres minor (TM) is relatively common in patients with posterosuperior tears of the rotator cuff, and its function should be enhanced for better postoperative results. The aim of this study was to investigate how the version of humeral fixation can affect the TM rotational moment arm and muscle length as well as impingement after RTSA. METHODS: A 3 dimensional shoulder model was used to describe RTSA. Four humeral fixation versions were tested: +20 degrees , 0 degrees , -20 degrees , and -40 degrees (+, anteverted; -, retroverted). TM rotational moment arm and length as well as impingement-free range of motion were calculated for a set of 3 simple clinical motions: (1) scapula plane abduction (0 degrees -150 degrees ); (2) internal/external rotation with the arm in adduction; and (3) internal/external rotation with the arm in abduction. Six common activities of daily living were also evaluated. RESULTS: An anteverted fixation maximized TM moment arms, but it also resulted in very short muscle length (compared with normal) and increased inferior impingement. In contrast, 40 degrees humeral retroversion resulted in the longest TM muscle length, but it also showed the smallest moment arms and increased anterior impingement in some of the activities of daily living. CONCLUSIONS: Even if TM external rotation moment arm is higher in RTSA than in a normal shoulder, the decreased length could impair its force generation. The 0 degrees and 20 degrees retroversion was the optimum compromise between sufficient TM length and moment arm with minimum impingement. PMID- 25440515 TI - Clinical outcomes after decompression of the nerve to the teres minor in patients with idiopathic isolated teres minor fatty atrophy. AB - BACKGROUND: The purpose of this manuscript is to describe what we believe to be the first series of patients surgically treated for idiopathic isolated teres minor atrophy and to present the results of surgical decompression of the nerve to the teres minor. METHODS: This is a retrospective cohort of 22 patients who underwent decompression of the nerve to the teres minor for isolated teres minor atrophy. Clinical data including duration of symptoms, additional diagnoses, concurrent procedures, preoperative physical examination findings, imaging data, and preoperative visual analog scale (VAS), Simple Shoulder Test (SST), and American Shoulder and Elbow Surgeons (ASES) scores were collected from the medical record. Postoperative patient-based clinical outcome measures including VAS, SST, and ASES scores were obtained during clinical examination or by telephone interview. RESULTS: Average length of follow-up was 26 months. Nine patients had concurrent procedures performed. Preoperatively, 12 of 14 (86%) had external rotation weakness in Hornblower's position. Postoperatively, pain scores decreased an average of 4 points; ASES scores increased 31.7 +/- 20.2 points; SST scores increased 3.1 +/- 2.3 points. No external rotation weakness was noted postoperatively in any tested patient. Two patients developed adhesive capsulitis. No other complications occurred. CONCLUSIONS: Isolated compression of the nerve to the teres minor is a rare and novel clinical entity. In properly selected cases, open release of the fascial sling enveloping the nerve branches to the teres minor can provide relief of symptoms and clinical improvement. PMID- 25440516 TI - Outcome of transfer of the sternal head of the pectoralis major with its bone insertion to the scapula to manage scapular winging. AB - HYPOTHESIS: The purpose of this study was to evaluate the outcome of transfer of the sternal head of the pectoralis major with its bone insertion to the inferior pole of the scapula for symptomatic winging. METHODS: Our study included 51 patients with serratus anterior dysfunction secondary to chronic muscle or long thoracic nerve injury. Indications included pain, scapular winging, and limited active motion after failed conservative management. All patients underwent transfer of the sternal head of the pectoralis major with its bone insertion to the scapular inferior pole. Computed tomography scan was performed at 3 months postoperatively to evaluate bone healing. RESULTS: At an average follow-up of 29 months (range, 12-46 months), 45 patients had complete and 6 patients had partial resolution of the scapular winging. Patients had significant improvements in their shoulder abduction, forward flexion, and pain levels (P < .01). The mean shoulder Constant score improved from 49 preoperatively to 82 postoperatively; the shoulder subjective value improved from 60% to 84%; and the Disabilities of the Arm, Shoulder, and Hand score improved from 58 to 14 (P < .01). Computed tomography scans at an average of 3 months postoperatively demonstrated full healing in 41 patients and partial healing in 10. CONCLUSION: Pectoralis major transfer of the sternal head with its bone insertion to the inferior pole of the scapula is a reliable transfer to stabilize and to restore the function of the scapula in patients with symptomatic winging. This technique allows the ability to directly transfer the tendon to the scapula with bone-to-bone healing, leading to faster healing and a quicker return to unrestricted activities. PMID- 25440517 TI - Reliability of patient self-assessment of shoulder range of motion and strength after shoulder arthroplasty. AB - BACKGROUND: Patient-derived self-assessment potentially minimizes loss of valuable outcomes data, conserves medical resources, and benefits patients by saving valuable time out of work and travel expenses. The purpose of this study was to determine the physician-patient correlation of a patient-derived outcomes questionnaire that assesses range of motion (ROM) and strength after shoulder arthroplasty. METHODS: One hundred twenty consecutive patients completed a home based questionnaire before their 1-year postoperative visit after shoulder arthroplasty. The questionnaire contained demographic information such as age, gender, type of surgery, education level, and income. Diagram-based questions, in which patients were asked to identify the image representing their own active shoulder ROM in various planes, were included. Patients were asked to perform a strength examination using premeasured zip-lock bags filled with water that correspond to predetermined weights up to 2.72 kg. The kappa statistics were used to assess the degree of agreement between the patient's self-assessment and the clinician's measures. RESULTS: The kappa statistics indicated moderate clinician patient agreement (0.5-0.59) on items related to ROM and substantial to almost perfect agreement (0.62-0.92) on items related to strength (forward flexion and abduction). A majority of patients (>88%) correctly estimated their ROM within 1 grade of the clinician's measurement. Patients tended to err toward overestimating their ROM. CONCLUSIONS: This patient-derived questionnaire provides a moderate to high level of agreement with clinician assessment. This assessment questionnaire may be an important tool in facilitating both clinical and research follow-up of patient outcomes after shoulder arthroplasty. PMID- 25440518 TI - The epidemiology of closed reduction for simple elbow dislocations and the incidence of early subsequent open reduction. AB - BACKGROUND: Simple elbow dislocations are often treated with closed reduction (CR); however, the rate of CR failure and factors that may predict failure have been largely underinvestigated. The objectives of this study were (1) to determine the incidence of elbow dislocations treated by CR in a universal health care system and (2) to identify patient characteristics associated with failed CR, defined as the subsequent need for open reduction. METHODS: Patients >=16 years old who underwent elbow CR by a physician between 1994 and 2010 were identified from administrative databases. Concurrent elbow fractures were excluded. The incidence density rate (IDR) of CR per 100,000 eligible person years among the general population was calculated. Failed CR was defined as subsequent open reduction with or without ligament repair or reconstruction within 90 days. Patient and provider characteristics were modeled in a multivariate logistic regression for failure. RESULTS: The cohort consisted of 4878 patients (median age, 41 years) who underwent CR (IDR, 2.65 per 100,000 person-years), and 75 (1.5%) underwent subsequent open reduction with or without ligament repair or reconstruction (median time, 15 days). Young men (<=20 years) had the highest IDR (7.45 per 100,000 person-years), twice that of young women (P = .005). Patient characteristics associated with failed CR included older age (P = .001), admission to the hospital (P < .0001), >1 attempted CR (P = .001), and new orthopedic consultation in the 4 weeks after the CR (P = .02). CONCLUSION: Young men are at highest risk for CR for simple elbow dislocations; however, older patients are more likely to require open intervention, as are those with markers of a difficult reduction signifying potentially greater soft tissue damage. A comprehensive understanding of the epidemiology of simple elbow dislocation will aid management decisions. PMID- 25440519 TI - National utilization of reverse total shoulder arthroplasty in the United States. AB - BACKGROUND: The substantial increase in the utilization of shoulder arthroplasty in the United States during the past decade is partly attributable to the growing acceptance of reverse shoulder arthroplasty (RSA). This study compared the national utilization of and indications for shoulder hemiarthroplasty, total shoulder arthroplasty (TSA), and RSA. METHODS: The Nationwide Inpatient Sample was used to identify shoulder arthroplasty procedures performed in the United States in 2011. Indicating diagnoses, demographics, and hospital characteristics were identified for each shoulder arthroplasty procedure. Multivariable regression identified factors associated with long hospital stays. RESULTS: An estimated 66,485 shoulder arthroplasty procedures were identified (33% RSA, 44% TSA, and 23% hemiarthroplasty). Common diagnoses for RSA were rotator cuff tear and arthritis (80%) and proximal humerus fracture (10%). TSA was performed for osteoarthritis in 93% of cases. Hemiarthroplasty was performed for osteoarthritis (45%) and proximal humerus fracture (38%). One quarter of proximal humerus fractures treated with arthroplasty received RSA compared with 69.8% that underwent hemiarthroplasty. Mortality occurred in 0.08% of patients with atraumatic diagnoses but in 0.53% of patients with proximal humerus fractures (P < .001). Older patients with comorbidities often had longer hospital stays, as did those with government insurance. CONCLUSIONS: RSAs accounted for one third of all shoulder arthroplasty procedures in the United States in 2011. Whereas the majority of RSAs are performed for rotator cuff tear arthropathy, one quarter of proximal humerus fractures are treated with RSA, suggesting the strong uptake of this relatively new procedure in the United States. PMID- 25440520 TI - Rethinking the advantage of zero-HLA mismatches in unrelated living donor kidney transplantation: implications on kidney paired donation. AB - The OPTN/UNOS Kidney Paired Donation (KPD) Pilot Program allocates priority to zero-HLA mismatches. However, in unrelated living donor kidney transplants (LDKT) the same donor source in KPD-no study has shown whether zero-HLA mismatches provide any advantage over >0 HLA mismatches. We hypothesize that zero-HLA mismatches among unrelated LDKT do not benefit graft survival. This retrospective SRTR database study analyzed LDKT recipients from 1987 to 2012. Among unrelated LDKT, subjects with zero-HLA mismatches were compared to a 1:1-5 matched (by donor age +/-1 year and year of transplantation) control cohort with >0 HLA mismatches. The primary endpoint was death-censored graft survival. Among 32,654 unrelated LDKT recipients, 83 had zero-HLA mismatches and were matched to 407 controls with >0 HLA mismatches. Kaplan-Meier analyses for death-censored graft and patient survival showed no difference between study and control cohorts. In multivariate marginal Cox models, zero-HLA mismatches saw no benefit with death censored graft survival (HR = 1.46, 95% CI 0.78-2.73) or patient survival (HR = 1.43, 95% CI 0.68-3.01). Our data suggest that in unrelated LDKT, zero-HLA mismatches may not offer any survival advantage. Therefore, particular study of zero-HLA mismatching is needed to validate its place in the OPTN/UNOS KPD Pilot Program allocation algorithm. PMID- 25440521 TI - Echinococcus canadensis, E. borealis, and E. intermedius. What's in a name? AB - The phylogenetic relationships of the G6, G7, G8, and G10 genotypes of Echinococcus granulosus are well defined, but their taxonomic status is currently unresolved. We apply an evolutionary species concept to infer that the G6 and G7 genotypes represent a single species that is different to both the G8 and G10 genotypes, and that the G8 and G10 genotypes are also on different evolutionary trajectories and, therefore, should be regarded as separate species. The names Echinococcus intermedius, Echinococcus canadensis, and Echinococcus borealis have been previously proposed for these three taxa (G6/7, G10 and G8, respectively) and we argue that it may be appropriate to resurrect these names. The correct delimitation and formal recognition of species of Echinococcus may have important veterinary and public health consequences. PMID- 25440522 TI - Determining research priorities through partnership with patients: an overview. AB - There is an increasing level of emphasis being placed on health care providers and funders to incorporate patient-centered care into research. Involving patients and caregivers in establishing research priorities ensures the relevance of the research produced. Priority setting is a process that can be used to produce a robust set of research questions that researchers can address over the coming years. One of the methods for determining research priorities that involves patients, caregivers and clinicians is the James Lind Alliance priority setting partnership model. This method is focused on being exclusive, transparent, and evidence-based. Using a recent example of patients on or nearing dialysis, we highlight the key steps to assess research priorities in patients, caregivers and clinicians: (i) formation of a steering committee to guide the overall process; (ii) form priority setting partnerships; (iii) identify and gather research uncertainties; (iv) process and collate submitted research uncertainties; and (v) final priority setting workshop to determine the top 10 research priorities. PMID- 25440524 TI - Applying machine learning techniques for ADME-Tox prediction: a review. AB - INTRODUCTION: Pharmacokinetics involves the study of absorption, distribution, metabolism, excretion and toxicity of xenobiotics (ADME-Tox). In this sense, the ADME-Tox profile of a bioactive compound can impact its efficacy and safety. Moreover, efficacy and safety were considered some of the major causes of clinical failures in the development of new chemical entities. In this context, machine learning (ML) techniques have been often used in ADME-Tox studies due to the existence of compounds with known pharmacokinetic properties available for generating predictive models. AREAS COVERED: This review examines the growth in the use of some ML techniques in ADME-Tox studies, in particular supervised and unsupervised techniques. Also, some critical points (e.g., size of the data set and type of output variable) must be considered during the generation of models that relate ADME-Tox properties and biological activity. EXPERT OPINION: ML techniques have been successfully employed in pharmacokinetic studies, helping the complex process of designing new drug candidates from the use of reliable ML models. An application of this procedure would be the prediction of ADME-Tox properties from studies of quantitative structure-activity relationships or the discovery of new compounds from a virtual screening using filters based on results obtained from ML techniques. PMID- 25440525 TI - Does non-erosive rheumatoid arthritis exist? A cross-sectional analysis and a systematic literature review. AB - OBJECTIVE: To evaluate the prevalence and factors associated with non-erosive rheumatoid arthritis (RA). METHODS: First, a cross-sectional analytical study was performed. Non-erosive disease, defined as the absence of any erosion on X-rays after 5 years of RA, was evaluated in 500 patients. Further and additional evaluations including ultrasonography (US) and computed tomography (CT) were performed in those patients meeting the eligibility criteria. The Spearman correlation coefficient, kappa analysis, and Kendall's W test were used to analyze the data. Second, a systematic literature review (SLR) was performed following the PRISMA guidelines. RESULTS: Of a total of 40 patients meeting the eligibility criteria for non-erosive RA, eight patients were confirmed to have non-erosive RA by the three methods. A positive correlation between non-erosive RA and shorter disease duration, antinuclear antibodies positivity, lower rheumatoid factor (RF) and C-reactive protein titers, lower global visual analog scale values, toxic exposures, and lower disease activity-(RAPID3) was found. In addition, an inverse correlation with anticyclic citrullinated peptide antibodies (ACPA) positivity and medication use was observed. From the SLR, it was corroborated that factors associated with this subphenotype were shorter disease duration, younger disease onset, negative ACPA and RF titers, low cytokine levels, and some genetic markers. CONCLUSION: Non-erosive RA is rare, occurring in less than 2% of cases. These findings improve on the understanding of RA patients who present without erosions and are likely to have less severe disease. PMID- 25440526 TI - Reply from authors re: Francesco Montorsi, Giorgio Gandaglia. Sentinel node biopsy for prostate cancer: a useless surgical exercise? Eur urol 2014;66:999 1000: Removing nodes that count rather than counting nodes that don't. PMID- 25440527 TI - Recurrent pustular eruption masquerading as pustular psoriasis in Netherton syndrome. AB - We report a unique presentation of Netherton syndrome with recurrent pustular eruptions leading to an erroneous diagnosis of infantile pustular psoriasis. Light microscopy of eyebrow hair showed trichorrhexis invaginata, consistent with Netherton syndrome. PMID- 25440528 TI - Predisposing factors for musculoskeletal symptoms in intensive care unit nurses. AB - INTRODUCTION: Intensive care unit nurses have more ergonomic risks than nurses working in other units in hospital. BACKGROUND: Although musculoskeletal disorders are common among intensive care nurses, studies on the prevalence of symptoms, as well as associated factors, are scarce. AIM: This is a cross sectional study to investigate the prevalence of musculoskeletal symptoms and associated factors in intensive care nurses. METHODS: The study population comprised 1515 nurses working in the intensive care units of public, private and university hospitals in Turkey. The study sample included 323 nurses selected by stratified random sampling. Data were obtained by a tailored data collection form, a workplace observation form and a Rapid Upper Limb Assessment tool to delineate ergonomic risks. Statistical Package for the Social Sciences 21.0 software was used in the statistical analysis. RESULTS: The highest prevalence for the musculoskeletal symptoms of the nurses was in the legs, lower back and back. Most of the nurses had encountered musculoskeletal pain or discomfort related to the previous month. The risky body movements that were frequently performed by the nurses during a shift were 'turning the patient' and 'bending down'. DISCUSSION: The final Rapid Upper Limb Assessment score for the patient turning movement was found to be higher than for the bending down movement. CONCLUSIONS: Musculoskeletal symptoms, which may occur in any region of the body, are mainly associated with organizational factors, such as type of hospital, type of shift work and frequency of changes in work schedule, rather than with personal factors. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Nursing administrators should determine the ergonomic risks of intensive care unit nurses by using Rapid Upper Limb Assessment tool. Health policy makers should develop occupational health teams, and 'ergonomic risk prevention programs' should be implemented throughout the units. PMID- 25440529 TI - Tuberculin skin test positivity without tuberculosis contact: A major challenge in childhood. AB - AIM: Worldwide, tuberculin skin tests (TSTs) commonly give false positive results for those who had been given the Bacillus-Calmette-Guerin vaccine such as is routinely administered in Turkey. This study aimed to evaluate the patients referred to us who had positive TSTs despite lack of tuberculosis (TB) disease contacts. METHODS: Between September 2011 and September 2012, 183 patients were prospectively evaluated for differential diagnosis of TST positivity despite lack of TB disease contact. They were then followed up by us to determine an accurate diagnosis. RESULTS: Among our patients' most common symptoms indicating a need for TST were chronic cough, productive cough or sputum expectoration, and recurrent or persistent wheezing. Chest x-rays were taken of all patients, and the findings were noted. Interferon gamma release assays were performed on 75% of the patients, of which 96% were negative for TB. The most common final diagnoses were asthma (44%), allergic rhinitis (13%), bronchopneumonia (11%) and reactive lymphadenitis (6.5%). Further evaluations for TB were required of 36 patients, and TB disease was established in 12 of them (6.5%). CONCLUSIONS: In patients who had had no known TB contact, the most common symptom indicating need for TST was chronic cough; the most common diagnoses were asthma and allergic rhinitis. Cavitary lesions, haemoptysis, persistent infiltration, pleural effusion and thoracic lymphadenopathy despite antibiotherapy should alert physicians to the possibility of TB. PMID- 25440530 TI - Histological studies of neuroprotective effects of Curcuma longa Linn. on neuronal loss induced by dexamethasone treatment in the rat hippocampus. AB - Long term exposure to dexamethasone (Dx) is associated with brain damage especially in the hippocampus via the oxidative stress pathway. Previously, an ethanolic extract from Curcuma longa Linn. (CL) containing the curcumin constituent has been reported to produce antioxidant effects. However, its neuroprotective property on brain histology has remained unexplored. This study has examined the effects of a CL extract on the densities of cresyl violet positive neurons and glial fibrillary acidic protein immunoreactive (GFAP-ir) astrocytes in the hippocampus of Dx treated male rats. It showed that 21 days of Dx treatment (0.5mg/kg, i.p. once daily) significantly reduced the densities of cresyl violet positive neurons in the sub-areas CA1, CA3 and the dentate gyrus, but not in the CA2 area. However, CL pretreatment (100mg/kg, p.o.) was found to significantly restore neuronal densities in the CA1 and dentate gyrus. In addition, Dx treatment also significantly decreased the densities of the GFAP-ir astrocytes in the sub-areas CA1, CA3 and the dentate gyrus. However, CL pretreatment (100mg/kg, p.o.) failed to protect the loss of astrocytes in these sub-areas. These findings confirm the neuroprotective effects of the CL extract and indicate that the cause of astrocyte loss might be partially reduced by a non oxidative mechanism. Moreover, the detection of neuronal and glial densities was suitable method to study brain damage and the effects of treatment. PMID- 25440532 TI - Identification and localization of gastrointestinal hormones in the skin of the bullfrog Rana catesbeiana during periods of activity and hibernation. AB - Amphibian skin and its secretions contain a wide variety of biogenic amines and biologically active peptides, some of which are either identical or highly homologous to gastrointestinal hormones (GHs) of higher vertebrates. This study investigated the distribution density and immunoreactive (IR) intensity of 5 hydroxytryptamine (5-HT), gastrin (GAS), somatostatin (SS), pancreatic polypeptide (PP), neuropeptide Y (NPY) and glucagon (GLU) IR cells in the skin of the bullfrog Rana catesbeiana during periods of activity and hibernation. The results indicated that the six types of GHs were all present in the bullfrog skin and were most predominant in the epidermis and mucous glands. In dorsal skin, the density of the GHs-IR cells in mucous glands was higher than that in epidermis except for GAS-IR cells. In ventral skin, the density of 5-HT, PP and NPY-IR cells in mucous glands was also higher than that in the epidermis. During hibernation, the density of the six types of GHs-IR cells and the IR intensity of GAS, SS, NPY and GLU-IR cells in the epidermis of dorsal skin increased significantly. The IR intensity of SS, PP and NPY-IR cells in granular glands of ventral skin also increased significantly during hibernation. These results suggested that multiple types of GHs-IR cells present in the skin of R. catesbeiana, may play important roles in the regulation of the physiological functions of skin. Also, adaptive changes in the density and IR intensity of GHs IR cells occurred during hibernation. PMID- 25440531 TI - Dynamic distribution of ERK, p38 and JNK during the development of pancreatic ductal adenocarcinoma. AB - We recently discovered that oncogenic c-kit is highly expressed concomitantly with the development of pancreatic ductal adenocarcinoma (PDAC). Since oncogenic c-kit may activate major pathways of protein tyrosine phosphorylation, we decided to investigate this issue in the major protein phosphorylation cascades. In normal pancreas labeling with antiphosphorylated ERK1/2 (pERK1/2) antibody was mainly confined to islets of Langerhans in close overlapping with insulin containing cells. Phosphorylated p38 (pp38) showed a similar pattern of distribution, while only weak labeling was evident for pJNK and no labeling of pMEK was observed. As expected, general ERK1/2 (gERK1/2), general p38 (gp38), general JNK (gJNK) as well as general MEK (gMEK) were all evident in islets of Langerhans and in the exocrine tissue. In early development of PDAC, pERK1/2 and pp38 retained their localization in islets of Langerhans. Intensive staining of pERK1/2 was also evident in the cancerous ducts, while the labeling with antibodies to pp38 was more moderate. While pJNK staining in islets of Langerhans was weak, with no labeling in the cancerous ducts, antibodies to gJNK revealed intensive staining suggesting the weak staining of pJNK is not due to the lack of the enzyme. In a more advanced stage of PDAC the carcinomas were clearly stained with pERK1/2 and pp38, while moderate staining with pJNK was also evident. In liver metastases, the cancer cells were heavily labeled with all three phospho MAPKs. It should be noted that the localization of all three kinases was mainly in the cell nuclei. In the more advanced stage of PDAC, heavy labeling was evident using antibodies to gERK1/2, gp38, gJNK and gMEK. However, no labeling to pMEK was evident in parallel sections. Our data suggest that both in normal and cancerous pancreas, most of the MAPK activities are located in islets of Langerhans and cancerous ducts. It is suggested that using inhibitors to protein kinases may attenuate the progression of the disease. PMID- 25440533 TI - Reliability and criterion-related validity with a smartphone used in timed-up-and go test. AB - BACKGROUND: The capacity to diagnosys, quantify and evaluate movement beyond the general confines of a clinical environment under effectiveness conditions may alleviate rampant strain on limited, expensive and highly specialized medical resources. An iPhone 4(r) mounted a three dimensional accelerometer subsystem with highly robust software applications. The present study aimed to evaluate the reliability and concurrent criterion-related validity of the accelerations with an iPhone 4(r) in an Extended Timed Get Up and Go test. Extended Timed Get Up and Go is a clinical test with that the patient get up from the chair and walking ten meters, turn and coming back to the chair. METHODS: A repeated measure, cross sectional, analytical study. Test-retest reliability of the kinematic measurements of the iPhone 4(r) compared with a standard validated laboratory device. We calculated the Coefficient of Multiple Correlation between the two sensors acceleration signal of each subject, in each sub-stage, in each of the three Extended Timed Get Up and Go test trials. To investigate statistical agreement between the two sensors we used the Bland-Altman method. RESULTS: With respect to the analysis of the correlation data in the present work, the Coefficient of Multiple Correlation of the five subjects in their triplicated trials were as follows: in sub-phase Sit to Stand the ranged between r = 0.991 to 0.842; in Gait Go, r = 0.967 to 0.852; in Turn, 0.979 to 0.798; in Gait Come, 0.964 to 0.887; and in Turn to Stand to Sit, 0.992 to 0.877. All the correlations between the sensors were significant (p < 0.001). The Bland-Altman plots obtained showed a solid tendency to stay at close to zero, especially on the y and x-axes, during the five phases of the Extended Timed Get Up and Go test. CONCLUSIONS: The inertial sensor mounted in the iPhone 4(r) is sufficiently reliable and accurate to evaluate and identify the kinematic patterns in an Extended Timed Get and Go test. While analysis and interpretation of 3D kinematics data continue to be dauntingly complex, the iPhone 4(r) makes the task of acquiring the data relatively inexpensive and easy to use. PMID- 25440534 TI - Ian Jacobs: From paramedic to professor, 1958-2014. PMID- 25440535 TI - Cardioversion. PMID- 25440538 TI - Co-payments in medical care. PMID- 25440551 TI - Characterization of the bacterial biodiversity in Pico cheese (an artisanal Azorean food). AB - This work presents the first study on the bacterial communities in Pico cheese, a traditional cheese of the Azores (Portugal), made from raw cow's milk. Pyrosequencing of tagged amplicons of the V3-V4 regions of the 16S rDNA and Operational Taxonomic Unit-based (OTU-based) analysis were applied to obtain an overall idea of the microbiota in Pico cheese and to elucidate possible differences between cheese-makers (A, B and C) and maturation times. Pyrosequencing revealed a high bacterial diversity in Pico cheese. Four phyla (Firmicutes, Proteobacteria, Actinobacteria and Bacteroidetes) and 54 genera were identified. The predominant genus was Lactococcus (77% of the sequences). Sequences belonging to major cheese-borne pathogens were not found. Staphylococcus accounted for 0.5% of the sequences. Significant differences in bacterial community composition were observed between cheese-maker B and the other two units that participated in the study. However, OTU analysis identified a set of taxa (Lactococcus, Streptococcus, Acinetobacter, Enterococcus, Lactobacillus, Staphylococcus, Rothia, Pantoea and unclassified genera belonging to the Enterobacteriaceae family) that would represent the core components of artisanal Pico cheese microbiota. A diverse bacterial community was present at early maturation, with an increase in the number of phylotypes up to 2 weeks, followed by a decrease at the end of ripening. The most remarkable trend in abundance patterns throughout ripening was an increase in the number of sequences belonging to the Lactobacillus genus, with a concomitant decrease in Acinetobacter, and Stenotrophomonas. Microbial rank abundance curves showed that Pico cheese's bacterial communities are characterized by a few dominant taxa and many low-abundance, highly diverse taxa that integrate the so-called "rare biosphere". PMID- 25440552 TI - Influence of mycorrhizal fungi on fate of E. coli O157:H7 and Salmonella in soil and internalization into Romaine lettuce plants. AB - The objectives of this study were to determine the influence of a symbiotic arbuscular mycorrhizal (AM) fungus on persistence of Salmonella and enterohemorrhagic Escherichia coli O157:H7 (EHEC) within soil, and survival within Romaine lettuce. Romaine seedlings were grown with or without AM fungi. Soil surrounding plants was inoculated with ca. 8 log CFU/plant of either Salmonella enterica or E. coli EHEC composites. Samples (soil, root, and shoot) were analyzed on days 1, 8, 15 and 22 for Salmonella and EHEC by direct plating and selective enrichment. Twenty-four hours after inoculation, populations of Salmonella and EHEC, respectively, were 4.20 and 3.24 log CFU/root, 2.52 and 1.17 log CFU/shoot, and 5.46 and 5.17 log CFU/g soil. By selective enrichment, samples tested positive for Salmonella or EHEC at day 22 at rates of 94 and 68% (shoot), 97 and 56% (root), and 100 and 75% (soil), respectively, suggesting that Salmonella has a greater propensity for survival than EHEC. Salmonella populations in soil remained as high as 4.35 log CFU/g by day 22, while EHEC populations dropped to 1.12 log CFU/g in the same amount of time. Ninety-two percent of all Romaine leaves in our study were positive for internalized Salmonella from days 8 to 22 and remained as high as 1.26 log CFU/shoot on day 22 in AM fungi+Romaine plants. There were no differences (P>0.05) between the survival of either pathogen based on the presence or absence of mycorrhizal fungi. Results of this study suggest that AM fungi do not affect the internalization and/or survival of either S. enterica or E. coli O157:H7 in Romaine lettuce seedlings. Our results should provide Romaine lettuce farmers confidence that the presence and/or application of AM fungi to crop soil is not a contributing factor to the internalization and survival of Salmonella or E. coli O157:H7 within Romaine lettuce plants. PMID- 25440553 TI - Fast and discriminative CoSYPS detection system of viable Salmonella spp. and Listeria spp. in carcass swab samples. AB - In this study, the complete CoSYPS Path Food workflow including all steps, namely swab sample enrichment, SYBR(r)Green qPCR detection of Salmonella spp. and Listeria spp., isolation and confirmation of the detected strain, was validated on beef carcass swabs. To perform the validation, the results of the complete workflow were compared, according to the ISO 16140:2003, with the ISO reference methods for detection, isolation and confirmation of Listeria monocytogenes and Salmonella spp. The results showed that the relative level of detection and the limit of detection of the complete workflow and ISO reference methods are in a range from 2 to 16 CFU/swab for both bacteria. The relative specificity, sensitivity and accuracy identified during this validation were all 100% since the results obtained with the complete CoSYPS Path Food workflow and the ISO reference methods were identical (Cohen's kappa index=1.00). In addition the complete CoSYPS Path Food workflow is able to provide detection results (negative or presumptive positive) in half the time needed as for the ISO reference methods. These results demonstrate that the performance of the complete CoSYPS Path Food workflow is not only comparable to the ISO reference methods but also provides a faster response for the verification of beef carcasses before commercial distribution. PMID- 25440554 TI - Characterization of a multidrug resistant C. difficile meat isolate. AB - Clostridium difficile is a pathogen of significant public health concern causing a life-threatening, toxin-mediated enteric disease in humans. The incidence and severity of the disease associated with C. difficile have increased in the US with the emergence of hypervirulent strains and community associated outbreaks. The detection of genotypically similar and identical C. difficile strains implicated from human infections in foods and food animals indicates the potential role of food as a source of community associated C. difficile disease. One hundred samples each of ground beef, pork and chicken obtained from geographically distant grocery stores in Connecticut were tested for C. difficile. Positive isolates were characterized by ribotyping, antibiotic susceptibility, toxin production and whole genome sequencing. Of the 300 meat samples, only two pork samples tested positive for C. difficile indicating a very low prevalence of C. difficile in meat. The isolates were non toxigenic; however, genome characterization revealed the presence of several antibiotic resistance genes and mobile elements that can potentially contribute to generation of multidrug resistant toxigenic C. difficile by horizontal gene transfer. Further studies are warranted to investigate potential food-borne transmission of the meat isolates and development of multi-drug resistance in these strains. PMID- 25440555 TI - Transcriptional response of selected genes of Salmonella enterica serovar Typhimurium biofilm cells during inactivation by superheated steam. AB - Superheated steam (SHS), produced by the addition of heat to saturated steam (SS) at the same pressure, has great advantages over conventional heat sterilization due to its high temperature and accelerated drying rate. We previously demonstrated that treatment with SHS at 200 degrees C for 10 sec inactivated Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes biofilm cells on the surface of stainless steel to below the detection limit. However, bacteria withstanding heat stress become more resistant to other stress conditions, and may be more virulent when consumed by a host. Herein, we studied the transcriptional regulation of genes important for stress resistance and virulence in Salmonella biofilms after SHS treatments. Genes encoding heat shock proteins and general stress resistance proteins showed transcriptional surges after 1 sec of SHS treatment at 200 degrees C, with parallel induction of stress related regulator genes including rpoE, rpoS, and rpoH. Interestingly, Salmonella biofilm cells exposed to SHS showed decreased transcription of flagella and Salmonella pathogenicity island-1 (SPI-1) genes required for motility and invasion of host cells, respectively, whereas increased transcription of SPI-2 genes, important for bacterial survival and replication inside host cells, was detected. When the transcriptional response was compared between cells treated with SHS (200 degrees C) and SS (100 degrees C), SHS caused immediate changes in gene expression by shorter treatments. Understanding the status of Salmonella virulence and stress resistance induced by SHS treatments is important for wider application of SHS in controlling Salmonella biofilm formation during food production. PMID- 25440556 TI - Probabilistic exposure assessment model to estimate aseptic-UHT product failure rate. AB - Aseptic-Ultra-High-Temperature (UHT) products are manufactured to be free of microorganisms capable of growing in the food at normal non-refrigerated conditions at which the food is likely to be held during manufacture, distribution and storage. Two important phases within the process are widely recognised as critical in controlling microbial contamination: the sterilisation steps and the following aseptic steps. Of the microbial hazards, the pathogen spore formers Clostridium botulinum and Bacillus cereus are deemed the most pertinent to be controlled. In addition, due to a relatively high thermal resistance, Geobacillus stearothermophilus spores are considered a concern for spoilage of low acid aseptic-UHT products. A probabilistic exposure assessment model has been developed in order to assess the aseptic-UHT product failure rate associated with these three bacteria. It was a Modular Process Risk Model, based on nine modules. They described: i) the microbial contamination introduced by the raw materials, either from the product (i.e. milk, cocoa and dextrose powders and water) or the packaging (i.e. bottle and sealing component), ii) the sterilisation processes, of either the product or the packaging material, iii) the possible recontamination during subsequent processing of both product and packaging. The Sterility Failure Rate (SFR) was defined as the sum of bottles contaminated for each batch, divided by the total number of bottles produced per process line run (10(6) batches simulated per process line). The SFR associated with the three bacteria was estimated at the last step of the process (i.e. after Module 9) but also after each module, allowing for the identification of modules, and responsible contamination pathways, with higher or lower intermediate SFR. The model contained 42 controlled settings associated with factory environment, process line or product formulation, and more than 55 probabilistic inputs corresponding to inputs with variability conditional to a mean uncertainty. It was developed in @Risk and run through Monte Carlo simulations. Overall, the highest SFR was associated with G. stearothermophilus (380000 bottles contaminated in 10(11) bottles produced) and the lowest to C. botulinum (3 bottles contaminated in 10(11) bottles produced). Unsurprisingly, SFR due to G. stearothermophilus was due to its ability to survive the UHT treatment. More interestingly, it was identified that SFR due to B. cereus (17000 bottles contaminated in 10(11) bottles produced) was due to an airborne recontamination of the aseptic tank (49%) and a post-sterilisation packaging contamination (33%). A deeper analysis (sensitivity and scenario analyses) was done to investigate how the SFR due to B. cereus could be reduced by changing the process settings related to potential air recontamination source. PMID- 25440557 TI - Culture bound syndromes: disease entities or simply concepts of distress? PMID- 25440558 TI - Impact of Mental Health Care Bill on caregivers of mentally ill: Boon or bane. AB - BACKGROUND: To improvise the shortcomings of existing of mental health legislation (The Mental Health Act, 1987) of India, amendments have been made which ultimately conceptualized, to form the Mental Health Care Bill. Mental Health Care Bill has brought a revolutionary change in the existing mental health legislation which is in its final phase of approval. METHOD: Many of the changes brought by the Mental Health Care Bill has been appreciated at different level, at the same time it has received robust criticism for over-legalizing and complicating the delivery of mental health care. RESULT: Caregivers play a pivotal role in the management of psychiatric illness in developing countries like India and they face a lot of challenges for providing support to the mentally ill patients. DISCUSSION: The social, economical, physical as well as the psychological wellbeing of the caregivers are significantly affected while providing care to the mentally ill. The forthcoming Mental Health Care Bill is likely to have a noteworthy impact on the caregivers. It's high time to analyze, its projected impact on the caregivers of patients suffering from mental illness. PMID- 25440559 TI - A review of drug policy in the Golden Crescent: towards the development of more effective solutions. AB - There is a high prevalence of drug trafficking and misuse in Asia. Drugs grown in Afghanistan are trafficked through Iran and Pakistan to the rest of the world. This has led to an increase in the prevalence of drug use disorders in these regions, especially heroin. This has in turn led to an increase in the use of syringes and syringe sharing which has resulted in the exponential spread of blood borne diseases such as HIV/AIDS. A lack of awareness of the detrimental use of heroin, syringe sharing and the concept of HIV has been revealed. The literature reviewed provides evidence for a change in policy with an increase in epidemiological and clinical research in these regions as well as an increase in public awareness. PMID- 25440560 TI - Effect of Sudarshan Kriya on male prisoners with non psychotic psychiatric disorders: a randomized control trial. AB - OBJECTIVES: To investigate whether Sudarshan Kriya and related practices (SK&P) can lead to increased global assessment of functioning (GAF) and increased feeling of wellness in male prisoners with a non psychotic psychiatric disorder. METHODOLOGY: This is a six month parallel randomized controlled study with sample size of 230 male prisoners. Participants meeting inclusion and exclusion criteria were assigned to a study or control group by simple random allocation in which random allocation sequence was generated using a random number table. Each individual study participant was involved in a daily program of SK&P for six weeks. Each individual control participant was instructed to sit in an armchair with his eyes closed and gentle attention to their breath for duration of six weeks. To be included in this study, a participant must be a male prisoner diagnosed to be suffering from a psychiatric disorder (except psychosis and bipolar affective disorder [BPAD]) by ICD-10 (DCR) criteria with age between 18 and 65 years. RESULTS: Majority of subjects were unemployed married individuals, educated until undermatric level and not having occupational skills of more than an unskilled labor level. Practicing SK&P for six weeks led to improvement in mean+/-SD score of study participants in GAF, anxiety (ANX), depressed mood (DEP), positive well being (PWB), general health (GH), self control (SC), vitality (VT) and total positive general well being (PGWB). Change in mean+/-SD score of study participants when compared with control participants was statistically significant in terms of GAF, ANX, DEP, PWB, GH and PGWB. Increase in SC and VT scores was statistically insignificant when compared with control participants. CONCLUSION: Practicing SK&P helps in improving GAF, PWB, GH and total PGWB of an individual. SK&P also causes significant reduction in anxiety and depression levels. Effect of SK&P on SC and VT is insignificant. PMID- 25440561 TI - Distinguishing between autism spectrum disorder and attention deficit hyperactivity disorder by using behavioral checklists, cognitive assessments, and neuropsychological test battery. AB - Children with attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) share many common symptoms, including attention deficit, behavioral problems, and difficulties with social skills. The aim of this study was to distinguish between ASD and ADHD by identifying the characteristic features of both the disorders, by using multidimensional assessments, including screening behavioral checklists, cognitive assessments, and comprehensive neurological battery. After screening for comorbid disorders, we carefully selected age-, sex-, IQ-, and socio-economic status-matched children with typical development (TD). In the Wechsler Intelligence Scale for children, a lower score was observed for the ASD group than for the TD group in Picture concept, which is a subscale of perceptual reasoning. A lower score was shown by the ADHD group than by the TD group in the spatial working memory test in the Cambridge Neuropsychological Test Automated Battery (CANTAB((r))). Although ASD and ADHD have many similar symptoms, they can be differentiated by focusing on the behavioral and cognitive characteristics of executive function. PMID- 25440562 TI - Reduced telomere length in subjects with dementia and diabetes mellitus type 2 is independent of apolipoprotein E4 genotype. AB - Apolipoprotein E4 gene is associated with increased risk of dementia with comorbid diabetes mellitus. Both dementia and diabetes mellitus type 2 are independently associated with telomere shortening. We assessed relative telomere length and apolipoprotein E genotype in subjects with dementia (n=70) and cognitively normal control groups (n=55) with and without comorbid diabetes mellitus type 2. Relative telomere length was highest in the control group (Q2=0.91) followed by dementia (Q2=0.48) and dementia with comorbid diabetes mellitus type 2 (Q2=0.39). Apolipoprotein E4 allele frequency was highest in dementia with comorbid diabetes mellitus type 2 (0.26). Apolipoprotein E4 allele was not significantly associated with telomere attrition in both dementia and cognitively normal group irrespective of comorbid diabetes mellitus type 2 (P>0.05). The findings suggest that relative telomere length is unrelated to apolipoprotein E4 genotype in dementia and cognitive normal subjects with or without comorbid diabetes mellitus type 2. PMID- 25440563 TI - Interactional aspects of care during hospitalization: perspectives of family caregivers of psychiatrically ill in a tertiary care setting in India. AB - There are very few studies on user-perspectives about mental health care services that explore perspectives of family caregivers in India. An exploratory study was undertaken to understand the perceived importance of various aspects of interactions with mental health service providers during hospitalization, from the perspectives of family caregivers. In addition, it also aimed at documenting their actual experience of interactional aspects of care during the hospitalization of their relatives. The study was conducted on fifty family caregivers of patients with varied psychiatric diagnoses hospitalized in a tertiary psychiatric care setting in South India. Measures of Interactional aspects of care were developed to assess perceived importance of six different interactional domains of care and the actual experience of care in these domains. Provision of informational inputs and addressing of concerns raised emerged as the domains of care given highest importance. The item pertaining to 'sharing with the caregiver about different alternatives for treatment' received negative ratings in terms of actual experience by maximum number of participants (18%). Significant differences on perceived importance of four domains of interactional aspects of care (dignity, confidentiality and fairness, addressing concerns raised, informational inputs and prompt attention and consistent care) emerged between caregiver subgroups based on educational level of the caregiver, socio economic status, hospitalization history and broad diagnostic categories. In addition, the care givers of patients with psychoses assigned significantly more positive ratings on actual experience for all the domains of interactional aspects of care. The findings have implications for further research and practice. PMID- 25440564 TI - A regressional analysis of maladaptive rumination, illness perception and negative emotional outcomes in Asian patients suffering from depressive disorder. AB - Although illness perception has been shown to be associated with illness outcomes in various chronic physical diseases, the association of illness perception and rumination are not well elucidated in mental disorders. This study aims to investigate the mediational effects of adaptive and maladaptive rumination in the relationship between illness perception and negative emotions (depression, anxiety and stress) in male and female patients (N=110) suffering from depressive disorders. The results showed that maladaptive rumination mediated the relationship between illness perception and negative emotions in both male and female depressive patients. However, no mediating effects of adaptive rumination were found in the relationship between illness perception and negative emotion. Maladaptive rumination mediated the relationship between perceived identity, chronicity of illness, consequences of illness and emotional representation of illness and negative emotions in males. It also mediated the relationship between perceived identity and emotional representation of illness and negative emotions in females. The results, possible clinical implications and limitations of this study are also discussed. PMID- 25440565 TI - Somatic symptoms, perceived stress and perceived job satisfaction among nurses working in an Indian psychiatric hospital. AB - BACKGROUND: High stress perception by nurses caring for psychiatric patients can lead to somatic symptoms which impact on their job satisfaction perception. OBJECTIVE: To assess and correlate the level of somatic symptoms, perceived stress and perceived job satisfaction among the subjects. DESIGN: The authors used a descriptive correlation design to invite 150 nurses of both genders working for more than one year with psychiatric patients. The Scale for Assessment of Somatic Symptoms (Chaturvedi et al., 1987) and a Visual Analogue Scale (VAS) for stress and job satisfaction perception were used to collect data. RESULTS: The nurses (128) reported mainly pain related (4.87+/-2.97) somatic symptoms. Somatic symptoms positively correlated (r=0.302) with stress perception and negatively correlated (r=-0.231) with perceived job satisfaction, while perceived stress and perceived job satisfaction were negatively correlated (r= 0.460, p=0.000). CONCLUSION: The results indicate a need for stress management interventions. PMID- 25440566 TI - Who seeks treatment for alcohol problems? Demography and alcohol-use characteristics of patients in taboo and non-taboo drinking groups attending professional alcohol services in Nepal. AB - INTRODUCTION: Only few individuals with alcohol problems seek help; those who do have not been described adequately. Here, we summarize the demographic and alcohol-related features of inpatients attending professional alcohol services in Nepal and examine differences between patients with and without social taboos about drinking. METHODS: Fully structured interviews including the Composite International Diagnostic Interview and the Alcohol Use Disorder Identification Test were administered to 177 men and 21 women consecutively admitted to eight alcohol treatment centres in Kathmandu. RESULTS: Altogether, 164 patients (83%) had alcohol dependence and 24 patients (12%) had alcohol abuse. The sample had a mean age of 35.3 years (SD 10.1) with a time lag of 16.8 years (SD 9.8) from start of habitual drinking to first entry into treatment. Most (62%) were married, lived in urban areas (72%), had above-average income (57%), received adequate social support (71%), and belonged to social groups in which drinking is taboo (57%). Individuals in non-taboo group more often lived in urban areas, had lower socioeconomic status, more often reported parental problem drinking and started drinking at a younger age, whereas individuals in the taboo group more often had late onset, risky drinking, and waited longer before seeking treatment (P<0.05). CONCLUSION: Traditionally alcohol non-using castes and people with higher socioeconomic status over-represent professional alcohol services in Kathmandu. This, and high levels of hazardous and harmful alcohol use, indicate changing trends concerning social tolerance towards alcohol in Nepalese society in recent times and a heavy burden associated with alcohol disorders. PMID- 25440567 TI - Validation and effect of demographic variables on perceived quality of life by adolescents. AB - The objectives of the current study were to examine the psychometric properties of the WHOQOL-BREF (English and Hindi language) on Indian adolescents and to explore the role of demographic variables on quality of life. Data from 1327 students, aged 11-21 years was collected with mean age=15.36 years (SD=1.42 years). The results of validation indicated that English and Hindi version of WHOQOL-BREF was a moderate model fit. Overall quality of life and satisfaction with health both predicted the various domains of quality of life, thus demonstrating acceptable predictive validity. Results of multivariate analysis demonstrated that adolescents differed significantly on demographic variables. Adolescents who attended private school possessed significantly better quality of life (overall), physical health, psychological well-being and environmental conditions as compared to adolescents who attended government school. Rural adolescents had significantly higher perceived quality of life (overall), physical health, psychological well-being, social relationships and environmental conditions as compared to urban adolescents. PMID- 25440568 TI - Review of electroconvulsive therapy practice from a tertiary Child and Adolescent Psychiatry Centre. AB - AIMS AND OBJECTIVES: The use of electroconvulsive therapy (ECT) in children and adolescents is a controversial issue. This study was done to examine the pattern and practice as well as the outcome of electroconvulsive therapy administered to children and adolescents admitted to a tertiary care centre. METHODOLOGY: A 10 year retrospective chart review of all children and adolescents (up to 16 years of age) admitted in the Child and Adolescent Psychiatry Centre, National Institute of Mental Health and Neurosciences (NIMHANS) who had received at least 1 session of ECT was done. Information regarding diagnosis, reasons for prescribing electroconvulsive therapy, details regarding the procedure and outcome variables was collected from the records. Clinical Global Impressions (CGI) scale rating of the severity of illness and improvement seen were done by 2 trained psychiatrists independently. RESULTS: 22 children and adolescents received electroconvulsive therapy over 10 years. There were an equal number of boys and girls. All received modified ECT. Most patients who received electroconvulsive therapy were severely ill. Catatonic symptoms 54.5% (12) were the most common reason for prescribing electroconvulsive therapy. It was efficacious in 77.3% (17) of the patients. Electroconvulsive therapy was relatively safe, and most experienced no acute side effects. 68.2% (15) who were on follow up and did not experience any long term side effects due to the electroconvulsive therapy. CONCLUSIONS: Electroconvulsive therapy has a place in the acute management of severe childhood psychiatric disorders. Further long term prospective studies are required. PMID- 25440570 TI - Consensus statements on adherence issues in schizophrenia for Hong Kong. AB - AIM: In view of the clinical importance of the adherence issues in schizophrenia management, a consensus group of experienced local psychiatrists and nurse specialists gathered to outline a number of consensus statements for clinicians to consider enhancing adherence in their patients. PROCESS: Prior to the consensus group meeting, three core members drafted eight statements on the issue of adherence in schizophrenia. Using a modified Delphi method, published literature and published guidelines regarding the management of schizophrenia were reviewed by the full panel during the group meeting. After discussion and reflection from each individual member of the consensus group, the eight statements were reworded and electronically voted on anonymously in two steps: acceptance on quality of evidence and practicability in implementation. RESULTS: After modifications of the original statements, there was very high overall level of agreement and acceptance (reaching international standard) on all the five areas of adherence within the eight statements of the finalised statement. CONCLUSIONS: The present consensus statements are the first in Hong Kong to address systematically adherence issues in schizophrenia management. They include areas on adherence assessment and definition, treatment strategies in enhancing adherence, and treatment considerations at specific phases of schizophrenia. They are tailored to be of practical utility in the local Hong Kong setting. PMID- 25440569 TI - Neuroleptic malignant syndrome following abrupt anti-cholinergic withdrawal: a case report. PMID- 25440571 TI - Inhibition of Left Ventricular Pacing during Cardiac Resynchronization. PMID- 25440573 TI - Ambulatory vs office blood pressure monitoring in renal transplant recipients. AB - Hypertension is common following renal transplantation and has adverse effects on cardiovascular and graft health. Ambulatory blood pressure monitoring (ABPM) is better at overall blood pressure (BP) assessment and is necessary to diagnose nocturnal hypertension, which is also implicated in poor outcomes. The authors performed a retrospective analysis of 98 renal transplant recipients (RTRs) and compared office BP and ambulatory BP recordings. ABPM revealed discordance between office BP and ambulatory BP in 61% of patients, with 3% caused by white coat and 58% caused by masked hypertension (of which 33% were caused by isolated nocturnal hypertension). Overall, mean systolic BP was 3.6 mm Hg (0.5-6.5) and diastolic BP was 7.5 mm Hg (5.7-9.3) higher via ambulatory BP than office BP. This was independent of estimated glomerular filtration rate, proteinuria, transplant time/type, and comorbidities. A total of 42% of patients had their management changed after results from ABPM. ABPM should be routinely offered as part of hypertension management in RTRs. PMID- 25440572 TI - Chronic exercise normalizes changes in Cav 1.2 and KCa 1.1 channels in mesenteric arteries from spontaneously hypertensive rats. AB - BACKGROUND AND PURPOSE: Regular physical activity is an effective non pharmacological therapy for prevention and control of hypertension. However, the underlying mechanisms are not fully understood. Accumulating evidence shows that the elevated vascular tone in hypertension is a consequence of the 'ion channel remodelling' that occurs during sustained high BP. The present study investigated the effects of aerobic exercise on the electrical remodelling of L-type Ca(2+) (Cav 1.2) and large-conductance Ca(2+) -activated K(+) (KCa 1.1) channels in mesenteric arteries (MAs) from spontaneously hypertensive rats (SHRs). EXPERIMENTAL APPROACH: SHRs and normotensive (Wistar-Kyoto) rats were subjected to aerobic training or kept sedentary, and vascular mechanical and functional properties were evaluated. KEY RESULTS: Exercise did not affect the heart weight, but reduced the heart rate and body weight in SHR. In mesenteric arterial myocytes, exercise normalized the increased Cav 1.2 and KCa 1.1 current density in SHRs. Exercise also ameliorated the increased open probability and mean open time of the single KCa 1.1 channel in hypertension. The isometric contraction study revealed that both nifedipine (Cav 1.2 channel blocker) and NS11021 (KCa 1.1 channel activator) induced concentration-dependent vasorelaxation in MAs precontracted with noradrenaline. Exercise normalized the increased sensitivity of tissues to nifedipine and NS11021 in SHR. Furthermore, protein expression of the Cav 1.2 alpha1C -subunit together with the KCa 1.1 alpha- and beta1-subunit was significantly increased in SHRs; and exercise ameliorated these molecular alterations in hypertension. CONCLUSIONS AND IMPLICATIONS: Chronic exercise reduces BP and restores vascular function in MAs from SHR, which might be related to the correction of the Cav 1.2 and KCa 1.1 channel remodelling during hypertension. PMID- 25440574 TI - ["En face" OCT in the diagnosis and follow-up of macular commotion retinae]. PMID- 25440575 TI - A common fallacy of observational medication studies in diabetes. PMID- 25440576 TI - Biomechanical risk factors for knee osteoarthritis when using passive and powered ankle-foot prostheses. AB - BACKGROUND: Gait compensations following transtibial amputation negatively affect sound limb loading and increase the risk of knee osteoarthritis. Push-off assistance provided by new powered prostheses may decrease the demands on the sound limb. However, their effects in a young population in the early stages of prosthetic use are still unknown. The purpose of this study was to compare limb loading between 1. passive and powered ankle-foot prostheses, 2. sound and amputated limbs, and 3. individuals with amputations in the relatively early stages of prosthetic use and controls. METHODS: Ten young, active individuals with unilateral transtibial amputation and 10 controls underwent biomechanical gait analysis at three speeds. The peak external knee flexor and adductor moments, adductor moment's angular impulse, peak vertical ground reaction force and loading rate were calculated. Repeated measures ANOVAs compared between limbs, prostheses, and groups. FINDINGS: The powered prosthesis did not decrease the sound limb's peak adduction moment or its impulse, but did decrease the external flexor moment, peak vertical force and loading rate as speed increased. The powered prosthesis decreased the loading rate from controls. The sound limb did not display a significantly greater risk for knee osteoarthritis than the intact limb or than controls in either device. INTERPRETATION: In the early stages of prosthetic use, young individuals with transtibial amputation display few biomechanical risk factors for knee osteoarthritis development. However, a powered ankle-foot prosthesis still offers some benefits and may be used prophylactically to mitigate potential increases of these variables with continued prosthetic use over time. PMID- 25440577 TI - Flamingo, a seven-pass transmembrane cadherin, cooperates with Netrin/Frazzled in Drosophila midline guidance. AB - During central nervous system development, several guidance cues and receptors, as well as cell adhesion molecules, are required for guiding axons across the midline and along the anterior-posterior axis. In Drosophila, commissural axons sense the midline attractants Netrin A and B (Net) through Frazzled (Fra) receptors. Despite their importance, lack of Net or fra affects only some commissures, suggesting that additional molecules can fulfill this function. Recently, planar cell polarity (PCP) proteins have been implicated in midline axon guidance in both vertebrate and invertebrate systems. Here, we report that the atypical cadherin and PCP molecule Flamingo/Starry night (Fmi/Stan) acts jointly with Net/Fra signaling during midline development. Additional removal of fmi strongly increases the guidance defects in Net/fra mutants. Rescue and domain deletion experiments suggest that Fmi signaling facilitates commissural pathfinding potentially by mediating axonal fasciculation in a partly homophilic manner. Altogether, our results indicate that contact-mediated cell adhesion via Fmi acts in addition to the Net/Fra guidance system during axon pathfinding across the midline, underlining the importance of PCP molecules during vertebrates and invertebrates midline development. PMID- 25440578 TI - Low-frequency versus high-frequency subthalamic nucleus deep brain stimulation on postural control and gait in Parkinson's disease: a quantitative study. AB - BACKGROUND: High frequency stimulation (HFS) of the subthalamic nucleus (STN-DBS) has been shown to have little impact on postural control and gait improvements in Parkinson's disease (PD). There is a lack of consensus and quantitative evidence to suggest that stimulating STN at a lower frequency (LFS) as compared to HFS will be superior in improving symptoms. OBJECTIVE/HYPOTHESIS: To determine if postural control and gait characteristics of persons with PD improve at an LFS (60 Hz) compared to HFS (>100 Hz). We hypothesized that persons with PD would perform better on postural control and gait measures at LFS. METHODS: Nineteen participants with bilateral STN-DBS underwent UPDRS, static and dynamic postural control using gait initiation, and gait evaluations in three stimulation conditions (baseline voltage stable across conditions: OFF, LFS of 60 Hz, and HFS of >100 Hz). Additionally 10/19 participants were also stimulated at 30 Hz and 60 Hz and at higher voltages. A one-way ANOVA was performed to compare the conditions. RESULTS: Total UPDRS-III score, step length and velocity during gait initiation, and gait speed significantly improved during 60 Hz and >100 Hz conditions when compared to the OFF condition (P < 0.05). There were no significant differences between 60 Hz and >100 Hz conditions. Using LFS at higher voltage showed no improvement over >100 Hz condition. CONCLUSIONS: The positive effects of both LFS and HFS on postural control and gait were similar and clinical changes were relatively small. LFS may not help improve postural control, and gait particularly for persons with PD who do not develop gait related disorders after HFS. PMID- 25440579 TI - The role of human brain area hMT+ in the perception of global motion investigated with repetitive transcranial magnetic stimulation (rTMS). AB - BACKGROUND: Psychophysical evidence suggests that the perception of the motion and color of moving stimuli are determined separately in the human brain. Here we aim to determine the role of visual cortical areas hMT+ and V1/V2 in each task by measuring the effect of rTMS of each area using an off-line continuous theta burst stimulation (cTBS) protocol. METHODS: In the motion task, the direction of moving dots was identified using a global motion stimulus that avoids tracking, and in the detection task for the same stimulus, the presence of the dots was detected regardless of motion. Performance was measured using forced-choice methods in 8 subjects, both before and at 4 time-intervals in the 1-hour after brain stimulation. All experiments were done using achromatic and isoluminant, red-green chromatic stimuli. RESULTS: Performance on global motion for both achromatic and chromatic stimuli was significantly impaired following cTBS of visual area hMT+, with a maximum effect occurring 11 min after stimulation. In comparison, there was no effect of cTBS on the motion task for areas V1/V2 or the vertex (control). cTBS did not affect the detection task in either area. CONCLUSIONS: Our experiments validate the use of cTBS as an advantageous off-line rTMS protocol for studying visual areas. The results indicate a causal link between neural activity in area hMT+ and perception of motion of isoluminant chromatic stimuli. We conclude that area hMT+ is part of a common pathway processing the global motion of chromatic and achromatic stimuli, but is not involved in their detection. PMID- 25440580 TI - PyC60-naphthacrown system: a new supramolecular recognition element. AB - Fulleropyrrolidine (PyC60) and a binaphthyl bridged crown ether macrocyclic receptor (1) undergoes spontaneous self-assembly phenomenon in solution to generate a new supramolecular recognition element having binding constant value of ~5.83*10(4)dm(3)mol(-1). Lifetime measurement reveals a static quenching mechanism behind the deactivation of photoexcited state of 1 in presence of PyC60. The results obtained from this work would definitely reinforce bridged cyclic crown ether as one of the most suitable fragments for the molecular recognition of various macrocyclic receptor(s) in near future. PMID- 25440582 TI - Quantum chemical calculations on elucidation of molecular structure and spectroscopic insights on 2-amino-4-methoxy-6-methylpyrimidine and 2-amino-5 bromo-6-methyl-4-pyrimidinol--a comparative study. AB - The FTIR and FT-Raman spectra of 2-amino-4-methoxy-6-methylpyrimidine (AMMP) and 2-amino-5-bromo-6-methyl-4-pyrimidinol (ABMP) have been recorded in the region 4000-450 and 4000-100 cm(-1), respectively. The optimized geometry, frequency and intensity of the vibrational bands of AMMP and ABMP were obtained by the density functional theory (DFT) using 6-311++G(**) basis set. The harmonic vibrational frequencies were calculated and the scaled values have been compared with experimental FTIR and FT-Raman spectra. The observed and the calculated frequencies are found to be in good agreement. The (1)H and (13)C NMR spectra have been recorded. The (1)H and (13)C nuclear magnetic resonance chemical shifts of the molecule were also calculated using the gauge independent atomic orbital (GIAO) method. The theoretical UV-visible spectrum of the compound using TD-DFT method and the electronic properties, such as HOMO and LUMO energies, are performed by time-dependent DFT (TD-DFT) approach. The calculated HOMO and LUMO energies show that charge transfer occurs within molecule. The first order hyperpolarizability (beta0) and its related components of AMMP and ABMP are calculated using DFT/6-311++G(**) method on the finite-field approach. The natural atomic charges of the molecules were also discussed. The change in electron density (ED) in the sigma(*) antibonding orbitals and stabilization energies E(2) have been calculated by natural bond orbital (NBO) analysis to give clear evidence of stabilization originating in the hyper conjugation of hydrogen bonded interactions. PMID- 25440581 TI - Synthesis of novel binary and ternary complexes derived from 1-(2-hydroxy benzoyl)-4-phenylthiosemicarbazide (L(1)) and 2,2'-dipyridyl (L(2)) with Co(II), Cu(II) and Zn(II) salts. AB - The complexes derived the reactions of 1-(2-hydroxybenzoyl)-4 phenylthiosemicarbazide (L(1)) with MX2 (M = Co(II), Cu(II) and Zn(II) ions; X = Cl(-) in case of Co(II) and Cu(II) ions, Cl(-) and Ac(-) in case of Zn(II)) in EtOH, were synthesized and characterized. The results suggested that the complexes have the general formulae, [Cu(L(1)-2H)(EtOH)(H2O)2]?H2O, [Co(L(1) 2H)(EtOH)(H2O)]?2H2O and [Zn(L(1)-2H)(EtOH)]. Also, the ternary complexes, derived from the reactions 2,2'-dipyridyl (L(2)) with the metals salts followed by adding a solution of the L(1) were synthesized and having the general formulae, [Cu2(L(2))(L(1)-2H)(H2O)(OH)2]?1/2H2O, [Co(L(2))(L(1)-2H)]?1.5EtOH?3H2O and [Zn(L(2))(L(1)-2H)]?EtOH. The binary and ternary complexes were characterized by elemental analyses, molar conductivities, spectral (IR, UV-Vis, (1)H-NMR and mass), thermal and magnetic measurements. The existence of OH group in the ternary complexes was confirmed by IR spectra. The amounts of solvent were determined from the results of TGA. The biological activity for the ligand and two complexes were tested against DNA. PMID- 25440583 TI - An SEM, EDS and vibrational spectroscopic study of the silicate mineral meliphanite (Ca,Na)2Be[(Si,Al)2O6(F,OH)]. AB - The mineral meliphanite (Ca,Na)2Be[(Si,Al)2O6(F,OH)] is a crystalline sodium calcium beryllium silicate which has the potential to be used as piezoelectric material and for other ferroelectric applications. The mineral has been characterized by a combination of scanning electron microscopy (SEM) with energy dispersive spectroscopy (EDS) and vibrational spectroscopy. EDS analysis shows a material with high concentrations of Si and Ca and low amounts of Na, Al and F. Beryllium was not detected. Raman bands at 1016 and 1050 cm(-1) are assigned to the SiO and AlOH stretching vibrations of three dimensional siloxane units. The infrared spectrum of meliphanite is very broad in comparison with the Raman spectrum. Raman bands at 472 and 510 cm(-1) are assigned to OSiO bending modes. Raman spectroscopy identifies bands in the OH stretching region. Raman spectroscopy with complimentary infrared spectroscopy enables the characterization of the silicate mineral meliphanite. PMID- 25440584 TI - Nuclear magnetic resonance, vibrational spectroscopic studies, physico-chemical properties and computational calculations on (nitrophenyl) octahydroquinolindiones by DFT method. AB - In the present study, 2'-nitrophenyloctahydroquinolinedione and its 3' nitrophenyl isomer were synthesized and characterized by FT-IR, FT-Raman, (1)H NMR and (13)C NMR spectroscopy. The molecular geometry, vibrational frequencies, (1)H and (13)C NMR chemical shift values of the synthesized compounds in the ground state have been calculated by using the density functional theory (DFT) method with the 6-311++G (d,p) basis set and compared with the experimental data. The complete vibrational assignments of wave numbers were made on the basis of potential energy distribution using GAR2PED programme. Isotropic chemical shifts for (1)H and (13)C NMR were calculated using gauge-invariant atomic orbital (GIAO) method. The experimental vibrational frequencies, (1)H and (13)C NMR chemical shift values were found to be in good agreement with the theoretical values. On the basis of vibrational analysis, molecular electrostatic potential and the standard thermodynamic functions have been investigated. PMID- 25440585 TI - Vibrational spectral investigation, NBO, first hyperpolarizability and UV-Vis spectral analysis of 3,5-dichlorobenzonitrile and m-bromobenzonitrile by ab initio and density functional theory methods. AB - The FT-IR and FT-Raman spectra of 3,5-dichlorobenzonitrile and m bromobenzonitrile have been recorded in the region 4000-400 cm(-1) and 3500-50 cm(-1), respectively. The optimized geometry, wave numbers and intensity of vibrational bonds of title molecules are obtained by ab initio and DFT level of theory with complete relaxation in the potential energy surface using 6-311++G(d, p) basis set. A complete vibrational assignments aided by the theoretical harmonic frequency, analysis have been proposed. The harmonic vibrational frequencies calculated have been compared with experimental FT-IR and FT-Raman spectra. The observed and calculated frequencies are found to be in good agreement. Stability of the molecule arising from hyperconjugative interactions, charge delocalization have been analyzed using natural bond orbital (NBO) analysis. The UV-Vis spectral analysis of the molecules has also been done which confirms the charge transfer of the molecules. Furthermore, the first hyperpolarizability and total dipole moment of the molecules have been calculated. PMID- 25440590 TI - [Nursing professionals and health care assistants' perception of patient safety culture in the operating room]. AB - OBJECTIVES: To assess nursing professionals and health care assistants' perceptions, opinions and behaviours on patient safety culture in the operating room of a public hospital of the Spanish National Health Service. To describe strengths and weaknesses or opportunities for improvement according to the Agency for Healthcare Research and Quality criteria, as well as to determine the number of events reported. METHOD: A descriptive, cross-sectional study was conducted using the Spanish version of the questionnaire Hospital Survey on Patient Safety Culture. The sample consisted of nursing professionals, who agreed to participate voluntarily in this study and met the selection criteria. A descriptive and inferential analysis was performed depending on the nature of the variables and the application conditions of statistical tests. Significance if p < .05. RESULTS: In total, 74 nursing professionals responded (63.2%). No strengths were found in the operating theatre, and improvements are needed concerning staffing (64.0%), and hospital management support for patient safety (52.9%). A total of 52.3% (n = 65) gave patient safety a score from 7 to 8.99 (on a 10 point scale); 79.7% (n = 72) reported no events last year. The total variance explained by the regression model was 0.56 for "Frequency of incident reporting" and 0.26 for "Overall perception of safety". CONCLUSIONS: There was a more positive perception of patient safety culture at unit level. Weaknesses have been identified, and they can be used to design specific intervention activities to improve patient safety culture in other nearby operating theatres. PMID- 25440591 TI - Visceral adiposity and the risk of metabolic syndrome across body mass index: the MESA Study. AB - OBJECTIVES: This study sought to evaluate differential effects of visceral fat (VF) and subcutaneous fat and their effects on metabolic syndrome (MetS) risk across body mass index (BMI) categories. BACKGROUND: The regional distribution of adipose tissue is an emerging risk factor for cardiometabolic disease, although serial changes in fat distribution have not been extensively investigated. VF and its alterations over time may be a better marker for risk than BMI in normal weight and overweight or obese individuals. METHODS: We studied 1,511 individuals in the MESA (Multi-Ethnic Study of Atherosclerosis) with adiposity assessment by computed tomography (CT). A total of 253 participants without MetS at initial scan underwent repeat CT (median interval 3.3 years). We used discrete Cox regression with net reclassification to investigate whether baseline and changes in VF area are associated with MetS. RESULTS: Higher VF was associated with cardiometabolic risk and coronary artery calcification, regardless of BMI. After adjustment, VF was more strongly associated with incident MetS than subcutaneous fat regardless of weight, with a 28% greater MetS hazard per 100 cm(2)/m VF area and significant net reclassification (net reclassification index: 0.44, 95% confidence interval [CI]: 0.29 to 0.60) over clinical risk. In individuals with serial imaging, initial VF (hazard ratio: 1.24 per 100 cm(2)/m, 95% CI: 1.08 to 1.44 per 100 cm(2)/m, p = 0.003) and change in VF (hazard ratio: 1.05 per 5% change, 95% CI: 1.01 to 1.08 per 5% change, p = 0.02) were associated with MetS after adjustment. Changes in subcutaneous fat were not associated with incident MetS after adjustment for clinical risk and VF area. CONCLUSIONS: VF is modestly associated with BMI. However, across BMI, a single measure of and longitudinal change in VF predict MetS, even accounting for weight changes. Visceral adiposity is essential to assessing cardiometabolic risk, regardless of age, race, or BMI, and may serve as a marker and target of therapy in cardiometabolic disease. PMID- 25440592 TI - Clinical outcome of isolated tricuspid regurgitation. AB - OBJECTIVES: The aim of this study was to assess the outcome of isolated tricuspid regurgitation (TR) and the added value of quantitative evaluation of its severity. BACKGROUND: TR is of uncertain clinical outcome due to confounding comorbidities. Isolated TR (without significant comorbidities, structural valve disease, significant pulmonary artery systolic pressure elevation by Doppler, or overt cardiac cause) is of unknown clinical outcome. METHODS: In patients with isolated TR assessed both qualitatively and quantitatively by a proximal isovelocity surface area method, a long-term outcome analysis was conducted. Patients with severe comorbid diseases were excluded. RESULTS: The study involved 353 patients with isolated TR (age 70 years; 33% male; ejection fraction, 63%; all with right ventricular systolic pressure <50 mm Hg). Severe isolated TR was diagnosed in 76 patients (21.5%) qualitatively and 68 patients (19.3%) by quantitative criteria (effective regurgitant orifice [ERO] >=40 mm(2)). The 10 year survival and cardiac event rates were 63 +/- 5% and 29 +/- 5%. Severe isolated TR independently predicted higher mortality (adjusted hazard ratio: 1.78 [95% confidence interval (CI): 1.10 to 2.82], p = 0.02 for qualitative definition and 2.67 [95% CI: 1.66 to 4.23] for an ERO >=40 mm(2), p < 0.0001). The addition of grading by quantitative criteria in nested models eliminated the significance of the qualitative grading and improved the model prediction (p < 0.001 for survival and p = 0.02 for cardiac events). The 10-year survival rate was lower with an ERO >=40 mm(2) versus <40 mm(2) (38 +/- 7% vs. 70 +/- 6%; p < 0.0001), independent of all characteristics, right ventricular size or function, comorbidity, or pulmonary pressure (p < 0.0001 for all), and lower than expected in the general population (p < 0.001). Freedom from cardiac events was lower with an ERO >=40 mm(2) versus <40 mm(2) independently of all characteristics, right ventricular size or function, comorbidity, or pulmonary pressure (p < 0.0001 for all). Cardiac surgery for severe isolated TR was rarely performed (16 +/- 5% 5 years after diagnosis). CONCLUSIONS: Isolated TR can be severe and is associated with excess mortality and morbidity, warranting heightened attention to diagnosis and quantitation. Quantitative assessment of TR, particularly ERO measurement, is a powerful independent predictor of outcome, superior to standard qualitative assessment. PMID- 25440593 TI - 3D fusion of LV venous anatomy on fluoroscopy venograms with epicardial surface on SPECT myocardial perfusion images for guiding CRT LV lead placement. AB - OBJECTIVES: The aim of this study was to develop a 3-dimensional (3D) fusion tool kit to integrate left ventricular (LV) venous anatomy on fluoroscopy venograms with LV epicardial surface on single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) for guiding cardiac resynchronization therapy (CRT) LV lead placement. BACKGROUND: LV lead position is important for CRT response. For LV lead placement into viable regions with late activation, it is important to visualize both LV venous anatomy and myocardium. METHODS: Major LV veins were manually identified on fluoroscopic venograms and automatically reconstructed into a 3D anatomy. 3D LV epicardial surface was extracted from SPECT MPI. SPECT-vein fusion that consisted of geometric alignment, landmark based registration, and vessel-surface overlay was developed to fuse the 3D venous anatomy with the epicardial surface. The accuracy of this tool was evaluated using computed tomography (CT) venograms. LV epicardial surfaces and veins were manually identified on the CT images and registered with the SPECT image by an independent operator. The locations of the fluoroscopic and CT veins on the SPECT epicardial surfaces were compared using absolute distances on SPECT short-axis slice and the 17-segment model. RESULTS: Ten CRT patients were enrolled. The distance between the corresponding fluoroscopic and CT veins on the short-axis epicardial surfaces was 4.6 +/- 3.6 mm (range 0 to 16.9 mm). The presence of the corresponding fluoroscopic and CT veins in the 17-segment model agreed well with a kappa value of 0.87 (95% confidence interval: 0.82 to 0.93). The tool kit was used to guide LV lead placement in a catheter laboratory and showed clinical feasibility and benefit to the patient. CONCLUSIONS: A tool kit has been developed to reconstruct 3D LV venous anatomy from dual-view fluoroscopic venograms and to fuse it with LV epicardial surface on SPECT MPI. It is technically accurate for guiding LV lead placement by the 17-segment model and is feasible for clinical use in the catheterization laboratory. PMID- 25440594 TI - Pleiotropic effects of statin in therapy in heart failure: a review. AB - Clinical trials demonstrated that statin therapy is associated with a significant reduction in cardiovascular morbidity and mortality when used for either primary or secondary prevention of cardiovascular events. Several studies have shown that statins, having an important effect in the prevention of acute coronary syndromes, are also able to prevent heart failure (HF) in patients with coronary artery disease. This review summarizes the experimental and clinical evidence regarding the role of statins in the management of HF. PMID- 25440595 TI - Platelet Inhibition Agents: Current and Future P2Y12 Receptor Antagonists. AB - Percutaneous coronary intervention is widely used to reduce the risk of death or cardiovascular events in patients with acute coronary syndromes. Dual antiplatelet treatment with aspirin and clopidogrel has become routine practice to prevent thrombotic events after coronary surgery. Despite advances of significant reduction of thrombotic complications in this adjunctive therapy, major adverse cardiovascular events still occur, suggesting the need for development of novel antiplatelet agents that act as superior alternatives to current standard regimen. Recently developed antiplatelet agents (prasugrel, ticagrelor, cangrelor and elinogrel) efficiently antagonize P2Y12 receptor, a key platelet activating signaling pathway, and thereby inhibit aggregation induced by mediators such as ADP, collagen, thrombin and TXA2. We provide an evidence-based review on the pharmacological and clinical performance of clopidogrel and novel antiplatelet agents that antagonize P2Y12 receptors. PMID- 25440597 TI - A systematic review on levosimendan in paediatric patients. AB - Levosimendan is a calcium-sensitizing agent that improves cardiac function, hemodynamic performance, and survival in critically ill adult patient. Few data exist on its off-label use in paediatric patients. We therefore performed a systematic review updated in September 2013 of all the published articles describing the use of levosimendan in paediatric patients. We identified 24 studies published in the period 2004-2013 that included a total of 623 patients, the largest one being a case series of 293 patients. Most of the patients underwent cardiac surgery, other settings consisting of chronic heart failure, primary congenital heart diseases and sepsis and cancer-associated cardiac dysfunction. Most studies reported improvement in ventricular function, central venous oxygen saturation, serum lactate levels or cardiac index. The 5 randomized studies published so far have all been performed in cardiac surgery and suggest a beneficial effect on hemodynamic data with no effect on intensive care unit stay, hospital stay or survival. Side effects (e.g. hypotension) were reported. This inodilator merits to be investigated with further randomized trials focusing on clinically relevant outcomes. PMID- 25440596 TI - Is there a Role for Cortisol in the Accumulation of Lipids in the Intima a Crucial Step of Atherogenesis? AB - Accumulation of lipids in the intima is the initial and crucial step in atherogenesis, but, this step is not always synonymous with atherogenesis. The factors that trigger the mechanisms modulating lipid accumulation in the vessel wall and in the subsequent development of atherosclerotic plaque remain unclear. In this review we evaluate whether atherogenesis is modulated by cortisol, the end hormone of the stress-related anti-inflammatory system. The amount of accumulated lipids in the intima depends on the balance between the penetration and efflux of cholesterol from the artery wall. We assess whether cortisol is involved in this balance. Cortisol can increase the penetration of lipids, and, simultaneously, might reduce their efflux from the intima. We also report a critical analysis on whether atherogenesis, which has a local nature, can be modulated by a systemic factor. In addition, we comment on the synergistic action of cortisol with insulin in atherogenesis, and consider relevant recent clinical evidence regarding the role of cortisol in atherosclerosis. Glucocorticoids, by triggering the mechanisms that favor the penetration of lipids in the intima, and modulating factors that control the efflux of cholesterol from the artery wall, may lead to the formation of atherosclerotic plaques. Thus, cortisol may have a role in atherogenesis. This may have important clinical, therapeutic and preventive implications. PMID- 25440598 TI - Effect of non-antihypertensive drugs on endothelial function in hypertensive subjects evaluated by flow-mediated vasodilation. AB - Hypertension (HTN) is a major risk factor for atherosclerosis. Flow-mediated vasodilation (FMD) is an ultrasonic method used to evaluate endothelial function, which is associated with HTN and related complications. We summarized clinical trials focusing on the effects of non-antihypertensive drugs on endothelial function, as evaluated by FMD, in patients with HTN. Hypercholesterolemic patients with HTN who used the cholesterol- lowering drugs HMG-CoA reductase inhibitors (statins) had improved FMD with a reduction in cholesterol levels and no significant change in blood pressure (BP). Non-diabetic patients with HTN who used the insulinsensitizing drug pioglitazone had improved FMD with a reduction in insulin resistance. Obese patients with HTN who used the anti-obesity drug orlistat had improved FMD with a reduction in BP and weight, and the improvement in FMD was correlated with weight reduction. Patients with HTN who used the selective cyclocxygenase-2 inhibitor celecoxib had improved FMD with no significant change in BP. Hypercholesterolemic patients with HTN who used aspirin added to a statin had improved FMD with a reduction in BP. Patients with HTN who used the advanced glycation endproduct crosslink breaker alagebrium had improved FMD with no significant change in BP. Postmenopausal women with HTN who used estrogen-replacement therapy had improved FMD. The possibility of improvement in FMD levels has, therefore, been suggested with several non-antihypertensive drugs. In addition to the direct effects of antihypertensive drugs on endothelial function, use of these non-antihypertensive drugs may give important insights into HTN management. PMID- 25440599 TI - Hoarding and eating pathology: the mediating role of emotion regulation. AB - Hoarding disorder is characterized by persistent difficulty discarding possessions resulting in clutter that precludes one from using living areas for their intended purposes. The limited empirical work available has suggested a strong link between hoarding and various non-psychiatric conditions, including obesity. Despite these associations, no research has examined the link between hoarding and other forms of eating pathology including symptoms associated with binge eating. Moreover, little is known about mechanisms that may account for this relationship. The current study examined the associations between hoarding severity, obesity, and symptoms associated with binge eating in a sample (N=97) of individuals with elevated hoarding symptoms. Results revealed that hoarding severity was associated with increased body mass index (BMI) and symptoms of binge eating. In addition, difficulties regulating emotions mediated the association between hoarding and eating concerns. Considering the lack of information on hoarding behaviors, as well as its classification as a new diagnosis within DSM-5, these findings add considerably to a growing body of literature on hoarding disorder. PMID- 25440600 TI - Impact of ADHD symptoms on clinical and cognitive aspects of problem gambling. AB - BACKGROUND: Problem gambling is common across cultures, and has been conceptualized in terms of impulsivity. While elevated rates of attention deficit hyperactivity disorder (ADHD) have been observed in problem gamblers, the relationship between these two conditions, and other dissociable forms of impulsivity, has received little research attention. METHODS: N=126 non-treatment seeking young adults with problem gambling were recruited from the community, and were grouped according to the presence or absence of probable current ADHD. Clinical and cognitive measures pertaining to impulsivity were collected via detailed psychiatric assessment, questionnaires, and computerized neuropsychological tests. These variables were compared between groups. RESULTS: Probable current ADHD was identified in 21.4% of the sample, and was associated with earlier age at onset of gambling behaviors, higher Barratt impulsivity scores (all three subscales), greater caffeine intake, worse response inhibition (Stop-Signal Test), and impaired decision-making (greater proportion of points gambled, Cambridge Gamble Test). Problem gamblers with and without ADHD did not differ on demographic characteristics or the rate of other psychiatric disorders, depression scores, nicotine and alcohol consumption, and body mass index. No significant group differences were found for general response speed, working memory, or executive planning. CONCLUSIONS: ADHD is common in young adults with dysfunctional gambling behaviors and is associated with elevated questionnaire and cognitive based measures of impulsivity, along with heightened caffeine use. Future work should study the causal nature between these factors and the treatment implications of these findings. PMID- 25440601 TI - NRG Oncology research opportunities within the new National Clinical Trials Network. PMID- 25440602 TI - Therapeutic monoclonal antibodies: introduction. PMID- 25440604 TI - Therapeutic antibodies in breast cancer. AB - The discovery of HER2 and development of trastuzumab pioneered the field of targeted therapy in breast cancer. Hoping to emulate the same clinical success, pharmaceutical companies have developed several antibodies against newly identified membrane-bound targets. Unfortunately, none of these agents has yet matched the thousands of lives saved by trastuzumab. In this article we review the most advanced therapeutic antibodies in breast cancer. While acknowledging their unquestionable benefit, we emphasize the need to better understand their biology and mechanisms of action in order to optimize their use in defined patient populations. PMID- 25440606 TI - Radioimmunoconjugates for the treatment of cancer. AB - Radioimmunotherapy (RIT) has been developed for more than 30 years. Two products targeting the CD20 antigen are approved in the treatment of non-Hodgkin B-cell lymphoma (NHBL): iodine 131-tositumomab and yttrium 90-ibritumomab tiuxetan. RIT can be integrated in clinical practice for the treatment of patients with relapsed or refractory follicular lymphoma (FL) or as consolidation after induction chemotherapy. High-dose treatment, RIT in first-line treatment, fractionated RIT, and use of new humanized monoclonal antibodies (MAbs), in particular targeting CD22, showed promising results in NHBL. In other hemopathies, such as multiple myeloma, efficacy has been demonstrated in preclinical studies. In solid tumors, more resistant to radiation and less accessible to large molecules such as MAbs, clinical efficacy remains limited. However, pretargeting methods have shown clinical efficacy. Finally, new beta emitters such as lutetium 177, with better physical properties will further improve the safety of RIT and alpha emitters, such as bismuth 213 or astatine 211, offer the theoretical possibility to eradicate the last microscopic clusters of tumor cells, in the consolidation setting. Personalized treatments, based on quantitative positron emission tomography (PET), pre-therapeutic imaging, and dosimetry procedures, also could be applied to adapt injected activity to each patient. PMID- 25440603 TI - Specificity delivers: therapeutic role of tumor antigen-specific antibodies in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDA) is among the most deadly cancers with less than 5% of the patients living beyond 5 years post-diagnosis. Lack of early diagnostic biomarkers and resistance to current therapies help explain these disappointing numbers. Thus, more effective and better-targeted therapies are needed quickly. Monoclonal antibodies offer an attractive alternative targeted therapy option for PDA because they are highly specific and potent. However, currently available monoclonal antibody therapies for PDA are still in their infancy with a low success rate and low likelihood of being approved. The challenges faced by these therapies include the following: lack of predictive and response biomarkers, unfavorable safety profiles, expression of targets not restricted to the cancer cells, flawed preclinical model systems, drug resistance, and PDA's complex nature. Additionally, discovery of novel PDA specific antigen targets, present on the cell surface or in the extracellular matrix, is needed. Predictive and response markers also need to be determined for PDA patient subgroups so that the most appropriate effective therapy can be delivered. Serologic approaches, recombinant antibody-producing technologies, and advances in antibody engineering techniques will help to identify these predictive biomarkers and aid in the development of new therapeutic antibodies. A combinatorial approach simultaneously targeting antigens on the PDA cell, stroma, and immunosuppressive cells should be employed. PMID- 25440605 TI - GD2-targeted immunotherapy and radioimmunotherapy. AB - Ganglioside GD2 is a tumor-associated surface antigen found in a broad spectrum of human cancers and stem cells. They include pediatric embryonal tumors (neuroblastoma, retinoblastoma, brain tumors, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma), as well as adult cancers (small cell lung cancer, melanoma, soft tissue sarcomas). Because of its restricted normal tissue distribution, GD2 has been proven safe for antibody targeting. Anti-GD2 antibody is now incorporated into the standard of care for the treatment of high-risk metastatic neuroblastoma. Building on this experience, novel combinations of antibodies, cytokines, cells, and genetically engineered products all directed at GD2 are rapidly moving into the clinic. In this review, past and present immunotherapy trials directed at GD2 will be summarized, highlighting the lessons learned and the future directions. PMID- 25440608 TI - The next generation of antibody drug conjugates. AB - Antibody-drug conjugates (ADCs) represent a promising therapeutic modality for the clinical management of cancer. The recent approvals of brentuximab vedotin and ado-trastuzumab emtansine plus emerging data for many molecules in clinical trials highlight the potential for ADCs to offer new therapeutic options for patients. Currently, more than 30 ADCs are being evaluated in early- or late stage clinical trials. Accordingly, much has been done to refine and transform the early-generation ADCs to the highly effective products that we now have in clinical development. These changes include a better understanding of optimal target selection, advances in antibody engineering, improvements in linker/payload conjugation strategies, and the generation of highly potent ADC payloads. In this review, we detail the current status of ADCs in both preclinical and clinical development, highlight technological advancements in ADC development, and speculate towards the future of this targeted therapeutic platform. PMID- 25440607 TI - Antibody-cytokine fusion proteins for treatment of cancer: engineering cytokines for improved efficacy and safety. AB - The true potential of cytokine therapies in cancer treatment is limited by the inability to deliver optimal concentrations into tumor sites due to dose-limiting systemic toxicities. To maximize the efficacy of cytokine therapy, recombinant antibody-cytokine fusion proteins have been constructed by a number of groups to harness the tumor-targeting ability of monoclonal antibodies. The aim is to guide cytokines specifically to tumor sites where they might stimulate more optimal anti-tumor immune responses while avoiding the systemic toxicities of free cytokine therapy. Antibody-cytokine fusion proteins containing interleukin (IL) 2, IL-12, IL-21, tumor necrosis factor (TNF)alpha, and interferons (IFNs) alpha, beta, and gamma have been constructed and have shown anti-tumor activity in preclinical and early-phase clinical studies. Future priorities for development of this technology include optimization of tumor targeting, bioactivity of the fused cytokine, and choice of appropriate agents for combination therapies. This review is intended to serve as a framework for engineering an ideal antibody cytokine fusion protein, focusing on previously developed constructs and their clinical trial results. PMID- 25440609 TI - Tumor-antigen-binding bispecific antibodies for cancer treatment. AB - Bi- and multispecific antibody derivatives (bsAbs) can be considered as the next generation of targeted biologics for cancer therapy. The general concept of bsAbs is a physical connection of recombinant antibody-derived entities with at least two binding specificities. This generates bsAbs that bind at least two antigens or epitopes, thus altering their binding functionalities and specificities in comparison to "normal" antibodies. Most bsAbs are produced as recombinant proteins, either as large IgG-like proteins that contain Fc regions, or as smaller entities with multiple antigen-binding regions but without Fc. Application of bsAbs in experimental cancer therapy currently includes molecules that bind different cell surface proteins to achieve more complete blockage of proliferative or angiogenesis-associated pathways. This approach of blocking more than one pathway component, or to simultaneously hit complementing pathways, also may limit potential escape mechanisms of cancer cells. BsAbs also are applied in the clinic as vehicles to deliver immune effector cells and/or cytokines to tumors. PMID- 25440610 TI - From monoclonal antibodies to chimeric antigen receptors for the treatment of human malignancies. AB - Monoclonal antibodies (mAbs) and their directly derived cell-based application known as chimeric antigen receptors (CARs) ensue from the need to develop novel therapeutic strategies that retain high anti-tumor activity, but carry reduced toxicity compared to conventional chemo- and radiotherapies. In this concise review article, we will summarize the application of antibodies designed to target antigens expressed by tumor cells, and the transition from these antibodies to the generation of CARs. PMID- 25440611 TI - Postulated mechanisms of resistance of B-cell non-Hodgkin lymphoma to rituximab treatment regimens: strategies to overcome resistance. AB - Antibody-mediated immunotherapy has gained significant momentum since 1997 when the US Food and Drug Administration approved the first monoclonal antibody (mAb) for the treatment of B-cell non-Hodgkin lymphoma (B-NHL), namely, rituximab (chimeric anti-CD20 mAb). Subsequently, more than 20 approved mAbs have been in use clinically for the treatment of various cancers and several non-cancer related diseases. Further, the combination treatment of mAbs with chemotherapy, immunotherapy, proteaosome inhibitors, and other inhibitors has resulted in synergistic anti-tumor activity with significant objective clinical responses. Despite their successful clinical use, the underlying mechanisms of rituximab's in vivo activities remain elusive. Further, it is not clear why a subset of patients is initially unresponsive and many responding patients become refractory and resistant to further treatments; hence, the underlying mechanisms of resistance are not known, Attempts have been made to develop model systems to investigate resistance to mAb therapy with the hope to apply the findings in both the generation of new therapeutics and in their use as new prognostic biomarkers. This review focuses on the development of resistance to rituximab treatments and discusses possible underlying mechanisms of action, postulated mechanisms of resistance in model systems, and suggested means to overcome resistance. Several prior reviews on the subject of rituximab resistance have been published and the present review both complements as well as adds new topics of relevance. PMID- 25440613 TI - Novel tumor antigen-specific monoclonal antibody-based immunotherapy to eradicate both differentiated cancer cells and cancer-initiating cells in solid tumors. AB - A growing body of experimental and clinical evidence strongly suggests that the resistance of cancer-initiating cells (CICs) to conventional therapies represents a major obstacle to the successful treatment of a malignant disease. To overcome this limitation a novel combinatorial tumor antigen (TA)-specific monoclonal antibody (mAb) strategy has been developed. In this strategy TA-specific mAbs are combined with chemotherapeutic agents and/or small molecules that inhibit aberrantly activated signaling pathways in cancer cells and especially in CICs. The in vitro results we have obtained indicate that this strategy is very effective in eradicating both differentiated cancer cells and CICs in several types of malignant disease. If the in vitro results have in vivo relevance, the strategy we have designed may have an impact on the treatment of malignant diseases. PMID- 25440614 TI - A case of vasculitis in a breast cancer patient treated with T-DM1. PMID- 25440612 TI - Tumor antigen-specific monoclonal antibodies and induction of T-cell immunity. AB - For decades the primary available cancer therapies were relatively nonspecific cytotoxic agents which, while effective in some patients, were limited by narrow therapeutic indices, extensive toxicity and development of resistance, likely due to tumor heterogeneity. Although these chemotherapies remain common tools of conventional treatment, the approval of a growing number of tumor antigen (TA) specific monoclonal antibodies (mAbs) by the US Food and Drug Administration has driven a shift in the paradigm of cancer therapy. For a subset of patients with lymphoma, colorectal, head and neck, and breast cancers, the inclusion of rituximab (anti-CD20), cetuximab (anti-human epidermal growth factor 1), and trastuzumab (anti-human epidermal growth factor 2) has resulted in overall improved clinical response rates and survival advantages. The mechanisms that contribute to these effects are limited not only to inhibition of signaling pathways but also include cell-mediated cytotoxicity by innate immune cells and priming of effector cells of adoptive immunity triggered by the TA-specific mAb. However, as the use of these therapeutic mAbs has become more widespread, it has been observed that there is significant variability of response in patients treated with these agents. Thus, the factors that mediate this variability in clinical responses must be elucidated to optimize the use of TA-specific mAbs. PMID- 25440615 TI - Seasonal and interannual variations in feeding station behavior of cattle: effects of sward and meteorological conditions. AB - A feeding station is the area of forage a grazing animal can reach without moving its forefeet. Grazing behavior can be divided into residence within feeding stations (with bites as benefits) and movement between feeding stations (with steps as costs). However, relatively little information has been reported on how grazing animals modify their feeding station behavior seasonally and interannually in response to varying environmental conditions. The feeding station behavior of beef cows (Japanese Black) stocked on a tropical grass pasture (bahiagrass dominant) was monitored for 4 years (2010 to 2013) in order to investigate the association of feeding station behavior with meteorological and sward conditions across the seasons and years. Mean air temperature during stocking often exceeded 30 degrees C during summer months. A severe summer drought in 2013 decreased herbage mass and sward height of the pasture and increased nitrogen concentration of herbage from summer to autumn. A markedly high feeding station number per unit foraging time, low bite numbers per feeding station and a low bite rate were observed in summer 2013 compared with the other seasons and years. Bite number per feeding station was explained by a multiple regression equation, where sward height and dry matter digestibility of herbage had a positive effect, whereas air temperature during stocking had a negative effect (R 2=0.658, P<0.01). Feeding station number per minute was negatively correlated with bite number per feeding station (r=-0.838, P<0.001). It was interpreted that cows modified bite number per feeding station in response to the sward and meteorological conditions, and this largely determined the number of feeding stations the animals visited per minute. The results indicate potential value of bite number per feeding station as an indicator of daily intake in grazing animals, and an opportunity for livestock and pasture managers to control feeding station behavior of animals through managements (e.g. fertilizer application, manipulation of stocking intensity and stocking time within the day). PMID- 25440616 TI - Mitral valve repair: an echocardiographic review: Part 2. AB - Echocardiographic imaging of the mitral valve before and immediately after repair is crucial to the immediate and long-term outcome. Prior to mitral valve repair, echocardiographic imaging helps determine the feasibility and method of repair. After the repair, echocardiographic imaging displays the new baseline anatomy, assesses function, and determines whether or not further management is necessary. Three-dimensional imaging has improved the assessment of the mitral valve and facilitates communication with the surgeon by providing the surgeon with an image that he/she might see upon opening up the atrium. Further advancements in imaging will continue to improve the understanding of the function and dysfunction of the mitral valve both before and after repair. This information will improve treatment options, timing of invasive therapies, and advancements of repair techniques to yield better short- and long-term patient outcomes. The purpose of this review was to connect the echocardiographic evaluation with the surgical procedure. Bridging the pre- and post-CPB imaging with the surgical procedure allows a greater understanding of mitral valve repair. PMID- 25440617 TI - Pro: bronchial blockers should be used routinely for providing one-lung ventilation. PMID- 25440618 TI - Dexmedetomidine does not reduce atrial fibrillation after lung cancer surgery. AB - OBJECTIVE: To evaluate whether the use of intraoperative dexmedetomidine (DEX) during lung cancer surgery may reduce the incidence of postoperative atrial fibrillation (POAF). DESIGN: A retrospective study. SETTING: Academic hospital. PARTICIPANTS: Seven hundred three adult patients with non-small-cell lung cancer. MEASUREMENTS AND MAIN RESULTS: Patients younger than 18 years of age with a history of atrial fibrillation were excluded. Episodes of atrial fibrillation were identified from electronic medical records and consisted of cardiology consultations, electrocardiogram records, and use of anti-arrhythmic medications within the postoperative admission time. The Wilcoxon rank sum test was used to evaluate the difference in a continuous variable between patient groups. Fisher's exact test or the chi-square test was used to evaluate the association between 2 categorical variables. Logistic regression models were used for multivariate analysis. Overall POAF incidence was 136 of 703 (19.35%), with a mean onset of 3.01+/-2.03 days after surgery. Among patients, 204 (29.02%) received DEX intraoperatively. Male gender and age were strong predictors of POAF. POAF incidence was comparable between patients who were (n=93, 21.1%) and were not (n=43, 18.6%) treated with DEX (p=0.46). The mean onset time of arrhythmia was similar in both groups (DEX users: 2.93+/-2.49 days; non-DEX users: 3.05+/-1.79 days; p=0.146). CONCLUSION: These results were similar to those published elsewhere on POAF incidence and risk factors. This study could not confirm the hypothesis that the intraoperative use of DEX is associated with a reduced rate of POAF after thoracic surgery for lung cancer. PMID- 25440619 TI - The use of preoperative B-type natriuretic peptide as a predictor of atrial fibrillation after thoracic surgery: systematic review and meta-analysis. AB - OBJECTIVE: To determine whether elevated preoperative B-type natriuretic peptide (NP) measurements are an independent predictor of atrial fibrillation (AF) in patients having thoracic surgery. DESIGN: Systematic review and meta-analysis. SETTING: In-hospital and 30 days after thoracic surgery. PARTICIPANTS: The 742 patients who participated in the 5 observational studies. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: EMBASE, OVID Health Star, Ovid Medline, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ProQuest Dissertations and Theses A&I databases were searched for all studies of noncardiac thoracic surgery patients in whom a preoperative NP was measured up to 1 month before surgery, and that measured the incidence of postoperative AF. Studies were included regardless of their language, sample size, publication status, or study design. Study quality was evaluated using the Newcastle Ottowa Scale. The combined incidence of postoperative AF was 14.5% (n=108/742), and the NP thresholds used to predict AF varied among studies. An elevated preoperative NP measurement was associated with an OR of 3.13 (95% CI 1.38-7.12; I2=87%) for postoperative AF, with the sensitivity analysis reporting an OR of 9.51 (95% CI 4.66-19.40; I2=0). CONCLUSION: Patients with an elevated preoperative NP measurement are at an increased risk of postoperative AF. There may be value in incorporating NP measurement into existing AF risk prediction models. PMID- 25440620 TI - Impact of anesthetic handover on mortality and morbidity in cardiac surgery: a cohort study. AB - OBJECTIVE: Clinical handover is a critical moment in patient care. The authors tested the hypothesis that handover of anesthesia care is associated with increased mortality and morbidity in patients undergoing cardiac surgery. DESIGN: This was a single-center, retrospective cohort study of prospectively collected data. SETTING: The study was conducted in a quaternary care cardiac surgery center and university research hospital. PARTICIPANTS: All patients undergoing cardiac surgical procedures between April 1, 1999 and October 31, 2009 were included in the study. INTERVENTIONS: Propensity-score matching was used to adjust for differences between patients who received intraoperative handover of anesthesia care and those who did not, and in-hospital mortality and morbidity were compared using multivariate logistic modeling. MEASUREMENTS AND MAIN RESULTS: 14,421 patients met the inclusion criteria for this study; handover occurred in 966 cases (6.7%). After propensity-score matching, 7,137 patients were included for analysis. In-hospital mortality was 5.4% in the handover group and 4.0% in the non-handover group (match-adjusted odds ratio, 1.425; 95% confidence interval, 1.013-2.006; p = 0.0422); the incidence of major morbidity was 18.5% in the handover group and 15.6% in the non-handover group (match adjusted odds ratio, 1.274; 95% confidence interval, 1.037-1.564; p = 0.0212). CONCLUSIONS: Handover of anesthetic care during cardiac surgery is associated with a 43% greater risk of in-hospital mortality and 27% greater risk of major morbidity. Further studies are required to explore this relationship and to systematically evaluate and improve the process of handover. PMID- 25440621 TI - Air in the Moustache Can Choke the Left Ventricle. PMID- 25440622 TI - Evaluation of cerebral oxygenation and perfusion with conversion from an arterial to-systemic shunt circulation to the bidirectional Glenn circulation in patients with univentricular cardiac abnormalities. AB - OBJECTIVE: Superior vena cava pressure after the bidirectional Glenn operation usually is higher than that associated with the preceding shunt-dependent circulation. The aim of the present study was to determine whether the acute elevation in central venous pressure was associated with changes in cerebral oxygenation and perfusion. DESIGN: Single-center prospective, observational cohort study. SETTING: Academic children's hospital. PARTICIPANTS: Infants with single-ventricle lesions and surgically placed systemic-to-pulmonary artery shunts undergoing the bidirectional Glenn operation. INTERVENTIONS: Near-infrared spectroscopy and transcranial Doppler sonography were used to measure regional cerebral oxygen saturation and cerebral blood flow velocity. MEASUREMENTS AND MAIN RESULTS: Mean differences in regional cerebral oxygen saturation and cerebral blood flow velocity before anesthetic induction and shortly before hospital discharge were compared using the F-test in repeated measures analysis of variance. In the 24 infants studied, mean cerebral oxygen saturation increased from 49%+/-2% to 57%+/-2% (p = 0.007), mean cerebral blood flow velocity decreased from 57+/-4 cm/s to 47+/-4 cm/s (p = 0.026), and peak systolic cerebral blood flow velocity decreased from 111+/-6 cm/s to 99+/-6 cm/s (p = 0.046) after the bidirectional Glenn operation. Mean central venous pressure was 8+/-2 mmHg postinduction of anesthesia and 14+/-4 mmHg on the first postoperative day and was not associated with a change in cerebral perfusion pressure (p = 0.35). CONCLUSIONS: The bidirectional Glenn operation in infants with a shunt-dependent circulation is associated with an improvement in cerebral oxygenation, and the lower cerebral blood flow velocity is likely a response of intact cerebral autoregulation. PMID- 25440623 TI - The effect of intraoperative 6% balanced hydroxyethyl starch (130/0.4) during cardiac surgery on transfusion requirements. AB - OBJECTIVES: To compare transfusion requirements in adult cardiac surgery patients when balanced hydroxyethyl starches (HES) (130/0.4) or balanced crystalloids is used for pump prime and intraoperative fluid therapy. DESIGN: Data were obtained retrospectively from medical records and perfusion charts. Matching based on propensity scores was used to adjust for potential confounders. SETTING: A university hospital. PARTICIPANTS: Adult patients undergoing cardiac surgery with the use of cardiopulmonary bypass. INTERVENTIONS: Allocation to one of the study groups according to whether balanced HES or balanced crystalloids was used for pump prime and intraoperative fluid therapy. MEASUREMENTS AND MAIN RESULTS: 240 propensity-matched patients were retained for final analyses. Forty-eight patients (40%) of the colloid group and 28 patients (23.3%) of the crystalloid group received blood products, with an odd ratio (95% CI) of 2.1(1.2-3.8 (P=0.009). After bypass HES patients had lower hemoglobin levels (8.4 [1.3] gr/dL vs 9.6 [2] gr/dL; P<0.001) and a higher cumulative chest drain output after 3 hours (180 [210] mL vs 140 [100] mL, P<0.001]. Heparinase thromboelastogram (TEG(r)) showed longer K times (2.5[1.1] vs 1.6[0.8], P<0.001) and lower maximal amplitudes (55.1[12.5] vs 63.4[9.8], P=0.008). CONCLUSIONS: HES patients required more transfusions, owing to greater hemodilution, HES-induced clotting disturbances, and bleeding. PMID- 25440624 TI - Bilateral lung transplantation in a patient receiving rivaroxaban anticoagulation. PMID- 25440625 TI - Intraoperative transesophageal echocardiography: Monere to Decidere. PMID- 25440626 TI - Intraoperative transesophageal echocardiography for positioning transvenous temporary pacing wire. PMID- 25440627 TI - Preliminary experience with combined inhaled milrinone and prostacyclin in cardiac surgical patients with pulmonary hypertension. AB - OBJECTIVE: To retrospectively evaluate the effects of combined inhaled prostacyclin and milrinone to reduce the severity of pulmonary hypertension when administered prior to cardiopulmonary bypass. DESIGN: Retrospective case control analysis of high-risk patients undergoing cardiac surgery. SETTING: Single cardiac center. PARTICIPANTS: Sixty one adult cardiac surgical patients with pulmonary hypertension, 40 of whom received inhalation therapy. INTERVENTION: Inhaled milrinone and inhaled prostacyclin were administered before cardiopulmonary bypass (CPB). MEASUREMENTS AND MAIN RESULTS: Administration of both inhaled prostacyclin and milrinone was associated with reductions in central venous pressure, and mean pulmonary artery pressure, increases in cardiac index, heart rate, and the mean arterial-to-mean pulmonary artery pressure ratio (p < 0.05), with no significant change in mean arterial pressure. The rate of difficult and complex separation from CPB was 51% in the inhaled group and 70% in the control group (p = 0.1638). Postoperative vasoactive requirement was reduced at 12 hours (35.9 v 73.7% p<0.01) and 24 hours (25.6 v 57.9% p<0.05) postoperatively in the combined inhaled agent group. Hospital length of stay and mortality were similar between the groups. CONCLUSION: Preemptive treatment of pulmonary hypertension with a combination of inhaled prostacyclin and milrinone before CPB was associated with a reduction in the severity of pulmonary hypertension. In addition, a significant reduction in vasoactive support in the intensive care unit during the first 24 hours after cardiac surgery was observed. The impact of this strategy on postoperative survival needs to be determined. PMID- 25440628 TI - CASE 2--2015: extracorporeal membrane oxygenation as a bridge to clinical recovery in life-threatening autoimmune acute respiratory distress syndrome. PMID- 25440629 TI - Regional tolerance to acute normovolemic hemodilution: evidence that the kidney may be at greatest risk. AB - OBJECTIVE: To evaluate the regional tolerance to acute normovolemic hemodilution (ANH). DESIGN: Prospective animal study. SETTING: University research laboratory. PARTICIPANTS: Nine anesthetized (isoflurane) dogs. INTERVENTIONS: Hematocrit reduced in 10% decrements using dextran-for-blood exchange until cardiac insufficiency observed. MEASUREMENTS AND MAIN RESULTS: Cardiac index (CI) was measured using thermodilution and regional blood flow (RBF) in myocardium, brain, spinal cord, kidney, liver, duodenum, pancreas, spleen, skeletal muscle, and skin with radioactive microspheres. Oxygen delivery (DO2) was calculated from the product of respective blood flow and arterial oxygen content. Systemic oxygen extraction (EO2) and oxygen consumption (VO2) were calculated. Increases in CI during ANH were inadequate to prevent decreases in systemic DO2; however, an increased systemic EO2 maintained VO2 during graded ANH to hematocrit<10%. In the myocardium, brain, and spinal cord, increases in RBF were sufficient to maintain DO2 across the entire range of hematocrits, but this was not the case in the other organs studied. Of note, renal DO2 first decreased at a hematocrit of 30% and was only 25% of baseline at a hematocrit of 10%. CONCLUSIONS: During graded ANH, increases in RBF were sufficient to maintain DO2 in only the heart, brain, and spinal cord. The especially marked decrease in DO2 in the kidney, combined with previous physiologic studies demonstrating its inability to augment EO2, suggest that this organ may be the most at risk of hypoxic damage during ANH. PMID- 25440630 TI - Pulmonary dysfunction after lung transplantation: the dilemma of coexisting mitral regurgitation. AB - A case of MR progression after single-lung transplant as a significant contributor to postoperative respiratory failure is reported. Pre-existing MR may progress due to the decompressive effects of lung transplantation on RV dimension and consequent alteration of MV geometry. This case highlights the importance of intraoperative TEE findings, especially pertaining to valvulopathies in the setting of lung transplantation. Postoperative surveillance of significant findings is imperative when any new symptoms are being investigated. PMID- 25440631 TI - Intraoperative transesophageal echocardiography diagnosis of concomitant hypertrophic cardiomyopathy with anomalous insertion of a papillary muscle band to the interventricular septum in a patient for aortic valve replacement. PMID- 25440632 TI - Complications of spinal fluid drainage in thoracic and thoracoabdominal aortic aneurysm surgery in 724 patients treated from 1987 to 2013. AB - OBJECTIVE: To study complications from spinal fluid drainage in open thoracic/thoracoabdominal and thoracic endovascular aortic aneurysm repairs to define risks of spinal fluid drainage. DESIGN: Retrospective, prospectively maintained, institutionally approved database. SETTING: Single institution university center. PARTICIPANTS: 724 patients treated from 1987 to 2013 INTERVENTIONS: The authors drained spinal fluid to a pressure<=6 mmHg during thoracic aortic occlusion/reperfusion in open and <=8 mmHg after stent deployment in endovascular procedures. Low pressure was maintained until leg strength was documented. If bloody fluid appeared, drainage was stopped. Head computed tomography (CT) and, if indicated, spine CT and magnetic resonance imaging (MRI) were performed for bloody spinal fluid or neurologic deficit. MEASUREMENTS AND MAIN RESULTS: Spinal fluid drainage was studied for bloody fluid, CT/MRI identified intracranial and spinal bleeding, neurologic deficit, and death. Seventy-three patients (10.1%) had bloody fluid; 38 (5.2%) had intracranial blood on CT. One patient had spinal epidural hematoma. Higher volume of fluid drained and higher central venous pressure during proximal clamping were associated with intracranial blood. Most patients with intracranial blood were asymptomatic. Six patients had neurologic deficits: of the 6, 3 died (0.4%), 1 (0.1%) had permanent hemiparesis, and 2 recovered. Three of the six deficits were delayed, associated with heparin anticoagulation. CONCLUSIONS: 10% of patients had bloody spinal fluid; half of these had intracranial bleeding, which was almost always asymptomatic. In these patients, immediately stopping drainage and correcting coagulopathy may decrease the risk of serious complications. Neurologic deficit from spinal fluid drainage is uncommon (0.8%), but has high morbidity and mortality. PMID- 25440633 TI - Reducing acute kidney injury through risk factor modification? It's no small task! PMID- 25440634 TI - Preoperative point-of-care platelet function testing in cardiac surgery. AB - OBJECTIVE: To investigate if the use of preoperative platelet function testing (PFT) as part of a transfusion algorithm reduced blood product usage in coronary artery bypass surgery (CABG). DESIGN: Prospective, randomized, controlled trial. SETTING: A cardiothoracic hospital. PARTICIPANTS: 249 patients having CABG surgery. INTERVENTIONS: The patients were allocated randomly to PFT preoperatively with Multiple Electrode Aggregometry (MEA, Group A), TEG PlateletMapping (PM, Group B) or none (control, Group C). Post-bypass bleeding management was determined by a transfusion algorithm. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was blood product transfusion in the first 48 hours post-surgery. There was a significant reduction in all blood product transfusion between Groups A (MEA) and B (PM) and Group C (control) (median number of units transfused, 2 (A)/2 (B)/ 4(C), p=0.02). Those in A and B received fewer units of red cells (median number of units, 0 (A)/1 (B) /2 (C), p=0.006) and fresh frozen plasma than the control Group C (median number of units, 0 (A)/0 (B)/2 (C), p<0.001), without receiving significantly more units of platelets (median number of units, 1 (A)/1 (B)/0 (C), p=0.11). In those who had taken an adenosine disphosphate (ADP)-receptor antagonist within 5 days (n=173), these results were amplified, and additionally, there was a significant cost saving (median cost, A=L1738.53, B=L1736.96, C=L3191.80 p=0.006). CONCLUSION: Preoperative PFT as part of a point-of-care testing-based transfusion algorithm led to a reduction in blood transfusion. There is a potential cost saving in those who have taken an ADP-receptor antagonist within 5 days. PMID- 25440635 TI - Cilostazol attenuates spinal cord ischemia-reperfusion injury in rabbits. AB - OBJECTIVE: The aim of this study was to evaluate the pretreatment effect of cilostazol on spinal cord ischemia-reperfusion injury. DESIGN: Prospective, interventional study. SETTING: Research laboratory, single institution. PARTICIPANTS: Twenty-four New Zealand white rabbits. INTERVENTIONS: Twenty-four rabbits were divided into 3 equal groups: group I (sham), group II (ischemia reperfusion, control group), and group III (cilostazol, administered orally 30 mg/kg/day for 3 days before the surgery). Spinal cord ischemia was induced by clamping the aorta both below the left renal artery and above the iliac bifurcation for 30 minutes. Seventy-two hours postoperatively, the motor function of the lower limbs was evaluated in each animal according to the modified Tarlov score. Spinal cord and blood samples were taken for histopathologic and biochemical analyses at the 72nd hour of reperfusion. MEASUREMENTS AND MAIN RESULTS: All rabbits in the ischemia-reperfusion group (group II) showed severe neurologic deficits. The median (IQR) Tarlov scores postoperatively at 72 hours in groups I, II, and III were 5.0(-), 2.0(1.0), and 4.5(1.0), respectively. Administration of cilostazol resulted in a significant reduction in motor dysfunction when compared with the ischemia-reperfusion group (p<0.001). In the ischemia-reperfusion group, serum and tissue glutathione peroxidase and superoxide dismutase activity were significantly less compared with the sham group (group I) (p<0.05). Serum and tissue glutathione peroxidase and superoxide dismutase levels in the cilostazol-treated group (group III) were higher compared with the ischemia-reperfusion group (p<0.05). In the cilostazol-treated group, serum and tissue malondialdehyde levels were lower compared with the ischemia reperfusion group (p<0.05). Histopathologic analysis found decreased neuronal injury in the cilostazol group when compared with the ischemia-reperfusion group (p< 0.05). CONCLUSIONS: This study showed that pretreatment with cilostazol significantly ameliorated neurologic functional outcome and attenuated neuronal histopathologic injury after transient aortic occlusion in rabbits. PMID- 25440636 TI - Optimal Respiratory Rate for Low-Tidal Volume and Two-Lung Ventilation in Thoracoscopic Bleb Resection. AB - OBJECTIVES: One-lung ventilation is considered to be mandatory in video-assisted thoracoscopic surgery. However, the authors showed in a previous report that two lung ventilation with low tidal volume is feasible in thoracoscopic bleb resection (TBR). In this study, they evaluated optimal respiratory rate during TBR under two-lung ventilation with low-tidal volume anesthesia. DESIGN: A prospective, randomized, single-blinded intervention study. SETTING: An operating room in a teaching hospital. PARTICIPANTS: Forty-eight patients who underwent scheduled TBR under general anesthesia. INTERVENTIONS: TBR was performed under low-tidal-volume (5 mL/kg), two-lung ventilation. Respiratory rate (RR) varied according to the protocol: 15 (group I), 18 (group II), and 22 cycles/min (group III). Using block randomization method, 16 patients were assigned to each of 3 groups. MEASUREMENTS AND MAIN RESULTS: Minute ventilation of group I was lowered significantly compared with the other groups (p<0.001). The results of arterial blood gas analysis were in the physiologic range in all patients. Surgery and anesthetic times and number of endostaples used were not significantly different among the 3 groups. CONCLUSIONS: The RR of 15 cycles/min with low-tidal volume (5 mL/kg) and two-lung ventilation did not produce abnormal physiologic changes including arterial pH, partial arterial oxygen pressure, and partial pressure of carbon dioxide and guaranteed an optimal surgical field. Therefore, these setting are considered acceptable for two-lung ventilation during TBR. PMID- 25440637 TI - Type of anesthesia and postoperative delirium after vascular surgery: reply. PMID- 25440638 TI - Frailty should determine type of anesthesia in reducing postoperative delirium after vascular surgery and not vice versa. PMID- 25440639 TI - Perioperative management of patients with left ventricular assist devices undergoing noncardiac procedures: a survey of current practices. AB - OBJECTIVES: To describe perioperative management of patients with left ventricular assist devices (LVAD) in noncardiac procedures. DESIGN: Survey of (1) respondent demographic characteristics, (2) anesthetic practices for LVAD patients having endoscopies, and (3) low-risk surgeries requiring general anesthesia. SETTING: Internet-based. PARTICIPANTS: Society of Cardiovascular Anesthesiologists membership. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Inpatient endoscopic procedures were done mainly in the endoscopy suite (71.7%) by a solo practitioner or 1:1 staffing ratio 59% of the time. LVAD-specific support personnel were present in more than 80% of all procedures. Both endoscopy and surgical patients used post-anesthesia recovery units and intensive care units for recovery; however, compared with endoscopy patients, surgical patients recovered in the ICU more frequently (45.5% v 29.1%, p<0.001). In addition, 18% of endoscopy patients recovered on site. Regarding patient monitoring, more than 90% of responders used electrocardiogram, pulse oximetry, end-tidal CO2, and blood pressure monitors on LVAD patients. Responders reported using arterial catheters to monitor blood pressure in 49% of endoscopy cases and 71% of surgical patients. The reported use of invasive monitors by individual clinicians was related inversely to institutional LVAD volume (p = 0.04 and p = 0.01 in endoscopy and surgical procedures, respectively). CONCLUSIONS: This survey found heterogeneity in hospital resource utilization for noncardiac LVAD procedures. There was a decrease in the use of invasive monitors with increased institutional LVAD volume in both endoscopy and surgical procedures. PMID- 25440640 TI - Real-time measurement of rectal mucosal microcirculation during cardiopulmonary bypass. AB - OBJECTIVES: Mesenteric ischemia is still a fatal event after cardiac procedures. No adequate intraoperative methods are available to monitor the gastrointestinal mucosal microcirculation in real-time conditions. The aim of the study was to assess a newly designed microprobe using laser Doppler flowmetry and remission spectroscopy. DESIGN: One-group, prospective, nonrandomized, open, pilot diagnostic study. SETTING: Monocenter university hospital. PARTICIPANTS: 50 patients (n = 38 males, 67+/-6 years) scheduled for cardiopulmonary bypass (CPB) were prospectively included. INTERVENTION: During anesthetic induction, the transrectal microprobe (30*15 mm) was positioned between the inferior and middle rectal valve (5-8 cm). Time periods were summarized at T1 = pre-CPB, T2 = CPB, T3 = post-CPB. MEASUREMENTS AND MAIN RESULTS: In 39 of 50 patients, data recruitment with the microprobe was successful. Measurement failures were due to fecal contaminations and probe dislocations. Rectal blood flow and velocity significantly decreased after bypass initiation (T2). Lowest flow rates were recorded after cross-clamp removal and did not recover at the end of bypass (T3). No side effects of the probe were noted. CONCLUSIONS: The new microprobe allows reproducible, safe, intraoperative, real-time evaluation of the rectal mucosal microcirculation. It could be a useful diagnostic tool to prevent mesenteric ischemia by optimizing extracorporeal circulation in future studies. However, first correlation of rectal blood flow and postoperative events (eg, ischemia, lactate) in a large cohort are necessary. PMID- 25440641 TI - A review of 364 perioperative rescue echocardiograms: findings of an anesthesiologist-staffed perioperative echocardiography service. AB - OBJECTIVE: Review the findings and use of rescue echocardiography performed by the Division of Perioperative Echocardiography and its impact on patient management. DESIGN: Retrospective observational study. SETTING: Single institution, tertiary care hospital. PARTICIPANTS: Three hundred sixty-four consecutive rescue echocardiograms in the perioperative setting. INTERVENTIONS: Rescue transesophageal or rescue transthoracic echocardiography. MEASUREMENTS AND MAIN RESULTS: Of a total of 1,675 perioperative echocardiograms performed in a 28 month period, 364 (21.8%) were rescue studies. Of these, 95.9% were transesophageal and 4.1% were transthoracic. Location at time of rescue echocardiography was intraoperative (55.5%), postoperative (44.2%), and preoperative (0.3%). No single diagnosis predominated the intraoperative or postoperative environment, and the frequency of common etiologies did not allow for assumption. There was a change in management for 214 patients (59%) as the result of findings. The methods used in performing rescue echocardiography at the authors' institution are reported. CONCLUSIONS: The heterogeneity of diagnoses and the frequency with which rescue echocardiography changed management further supports the growing body of evidence that the hemodynamically unstable perioperative patient benefits from its use. PMID- 25440642 TI - Extracorporeal membrane oxygenation-assisted esophagectomy. PMID- 25440643 TI - Vasopressin does not raise cardiac enzymes following cardiac surgery: a randomized double-blind clinical trial. AB - OBJECTIVE: The aim of this study was to investigate the relationship between intraoperative vasopressin infusion and postoperative cardiac enzymes. DESIGN: A prospective, double-blind, randomized, controlled study. SETTING: A single tertiary cardiac center. PARTICIPANTS: One hundred consecutive patients undergoing cardiac surgery with or without cardiopulmonary bypass. INTERVENTIONS: The study was approved by the Institutional Review Board, and patients provided informed consent to participate. Patients were randomized by computer into 2 equal groups: Vasopressin or control. The blinded study included vasopressin administered at a dose of 1.8 U/h or 1.8 mL/h of normal saline, along with catecholamines. The drug was administered continually during surgery while patients needed catecholamines. The intervention was discontinued upon admission to the intensive care unit when information regarding the true character of the drug was reported to the doctor in charge of patients in the intensive care unit by one of the investigators. Primary outcomes were CK-MB and troponin T levels measured at 0, 6, and 12 hours postoperatively. MEASUREMENTS AND MAIN RESULTS: Of the 100 patients, 8 were excluded; the remaining 92 were randomized to either the vasopressin (n = 47) or control (n = 45) group. There were no significant differences in demographic data between the groups. Postoperatively at 0, 6, and 12 hours, there were no differences in CK-MB (U/l) (37.5 +/- 57.9 v 32.0 +/- 21.5, 29.4 +/- 41.1 v 24.4 +/- 23.1, and 21.4 +/- 21.3 v. 21.8 +/- 32.4, respectively) and troponin T (752.4 +/- 638.2 v 762.7 +/- 557.1, 753.8 +/- 507.3 v 777.6 +/- 515.0, and 774.6 +/- 572.6 v 698.7 +/- 540.2, respectively) values. CONCLUSIONS: Vasopressin infusion has been used to treat catecholamine unresponsive shock. In this study, intraoperative vasopressin was used safely as a possible first-line drug for treating hypotension; however, it did not increase the levels of cardiac enzymes after cardiac surgery. PMID- 25440644 TI - Perioperative goal-directed therapy. PMID- 25440645 TI - Postoperative Stroke Following Administration of Intraoperative Recombinant Tissue Plasminogen Activator for the Treatment of Intracardiac Thrombus During Liver Transplantation. PMID- 25440646 TI - Remote ischemic preconditioning prevents deterioration of short-term postoperative cognitive function after cardiac surgery using cardiopulmonary bypass: results of a pilot investigation. AB - OBJECTIVE: Remote ischemic preconditioning (RIPC) exerts neuroprotective effects in models of cerebral ischemia-reperfusion injury. The authors tested the hypothesis that RIPC decreases the incidence of postoperative delirium and prevents deterioration of short-term postoperative cognitive function in isoflurane-fentanyl-anesthetized patients undergoing cardiac surgery using cardiopulmonary bypass (CPB). DESIGN: Randomized, blinded, single-center pilot investigation. SETTING: Veterans Affairs Medical Center. PARTICIPANTS: Thirty age and education-matched men>=55 years of age undergoing elective coronary artery or valve surgery using CPB. Fifteen nonsurgical patients also were enrolled. INTERVENTIONS: RIPC was produced after induction of anesthesia using 4 cycles of brief (5 minutes) upper extremity ischemia (tourniquet inflation to 200 mmHg) interspersed with 5-minute periods of reperfusion (tourniquet deflation). MEASUREMENTS AND MAIN RESULTS: The Intensive Care Delirium Screening Checklist was used to assess delirium before and each day after surgery for as many as 5 consecutive days. Recent verbal and nonverbal memory and executive functions were assessed before and 1 week after surgery using a standard neuropsychometric test battery or at 1-week intervals in nonsurgical controls. The Geriatric Depression and the Hachinski Ischemia scales were used to identify the presence of clinical depression and vascular dementia, respectively. No differences in delirium scores were observed between RIPC and control groups (p=0.54). Baseline neurocognitive scores were similar in patients with versus without RIPC in all 3 cognitive domains. Significant declines in performance on 2 nonverbal memory tests (figure reconstruction and delayed figure reproduction; p=0.001 and p=0.003, respectively) and 1 verbal memory test (delayed story recall; p=0.0004) were observed 1 week after surgery in patients who were not treated with RIPC. There were no changes in performance of measures of executive function in this group. In contrast, performance on all cognitive tests was unchanged after compared with before surgery in patients receiving RIPC. At least a 1-standard deviation decline from baseline in cognitive performance was detected in figure reconstruction, delayed figure reproduction, immediate story recall, and delayed story recall in patients who were not exposed to RIPC. The incidence of at least a 1-standard deviation decline in neuropsychometric tests was observed in significantly fewer (1 v 9; p<0.0001) patients with versus without RIPC treatment based on composite Z-scores. Overall cognitive performance after surgery was better in patients treated with versus without RIPC (p=0.002). Clinical depression and vascular dementia were not detected in either group. CONCLUSION: The results of this pilot investigation indicated that RIPC prevented deterioration of short-term postoperative cognitive function but were unable to detect any difference in delirium in isoflurane-fentanyl-anesthetized patients undergoing cardiac surgery using CPB. PMID- 25440647 TI - Transesophageal echocardiographic diagnosis of severe functional tricuspid stenosis during infected implantable cardioverter-defibrillator lead extraction. PMID- 25440648 TI - Case 3-2015: preventing adverse outcomes in the very elderly cardiac surgical patients. PMID- 25440649 TI - Ethical dilemmas of adult ECMO: emerging conceptual challenges. PMID- 25440650 TI - Current use of the pulmonary artery catheter in cardiac surgery: a survey study. AB - OBJECTIVE: Because of its invasive nature, debated effect on patient outcome, and the development of alternative hemodynamic monitoring technologies, the intraoperative use of the pulmonary artery catheter (PAC) has significantly decreased. The authors conducted a survey of the members of the Society of Cardiovascular Anesthesiologists (SCA) to assess current use of the PAC and alternative hemodynamic monitoring technologies in patients undergoing cardiac surgery. DESIGN: A survey study. SETTING: Hospitals in North America, Europe, Asia, Australia, New Zealand, and South America. PARTICIPANTS: SCA members in North America, Europe, Asia, Australia, New Zealand, and South America. INTERVENTIONS: The survey was e-mailed by the SCA to roughly 6,000 of its members. MEASUREMENTS AND MAIN RESULTS: The survey was left open for 30 days. Respondents accessed the survey via a secured web-based database. A total of 854 questionnaires were completed. A total of 705 (82.6%) were from North American members. Four hundred twelve of the respondents (48.1%) worked in a private practice setting, while 350 (40.9%) were from an academic practice. A majority of the respondents (57.9%) were from hospitals that performed more than 400 cardiac surgeries a year, a subset of which (29.6%) did more than 800 cases annually. For cases using cardiopulmonary bypass, 583 (68.2%) of the respondents used a PAC more than 75% of the time, while 30 (3.5%) did not use the PAC at all. Ninety four percent of respondents used transesophageal echocardiography (TEE) as part of the intraoperative monitoring. When not using a PAC, FloTrac/Vigileo was the alternative cardiac monitoring modality in 15.2% of the responses. Similar trends in monitor preferences were seen in off-pump coronary artery bypass grafting and minimally invasive/robotic heart surgery. CONCLUSIONS: The results of this study suggested that a majority of the respondents still prefer to use the PAC for most cardiac surgeries. Subgroup analysis of the data revealed that geographical location, type of practice, and surgeon support played a significant role in the decision to use a PAC. Although most respondents prefer to use TEE as a complimentary tool, TEE also remains the most popular supplemental/alternative hemodynamic monitoring technology. PMID- 25440651 TI - Case 13--2014: Management of pulmonary hemorrhage after pulmonary endarterectomy with venovenous extracorporeal membrane oxygenation without systemic anticoagulation. PMID- 25440652 TI - Percutaneous superior vena cava drainage during minimally invasive mitral valve surgery: a randomized, crossover study. AB - OBJECTIVE: Minimally invasive techniques commonly are applied to mitral valve surgery; however, there has been little research investigating the optimal methods of cardiopulmonary bypass for the right minithoracotomy approach. Controversy exists as to whether a percutaneous superior vena cava drainage cannula (PSVC) is necessary during these operations. The authors, therefore, sought to determine the effect of using a percutaneous superior vena cava catheter on brain near-infrared spectroscopy, blood lactate levels, hemodynamics and surgical parameters. DESIGN: Randomized, blinded, crossover trial. SETTING: Tertiary care university hospital. PARTICIPANTS: Patients undergoing minimally invasive mitral valve surgery via a right minithoracotomy. INTERVENTIONS: Twenty minutes of either clamped or unclamped percutaneous superior vena cava neck catheter drainage, during mitral valve repair. MEASUREMENT AND MAIN RESULTS: For the primary outcome of brain near-infrared spectroscopy, there were no differences between the two groups (percutaneous superior vena cava clamped 55.0%+/-11.6% versus unclamped 56.1%+/-10.2%) (p = 0.283). For the secondary outcomes pH (clamped 7.35+/-0.05 versus unclamped 7.37+/-0.05 p = 0.015), surgical score (clamped 1.96+/-1.14 versus unclamped 1.22+/-0.51 p = 0.002) and CVP (clamped 11.6 mmHg+/-4.8 mmHg versus unclamped 6.1 mmHg+/-6.1 mmHg p<0.001) were significantly different. CONCLUSIONS: The use of a percutaneous superior vena cava drainage improved surgical visualization and lowered CVP, but had no effect on brain near infrared spectroscopy during minimally invasive mitral valve surgery. (ClinicalTrials.gov Identifier: NCT01166841). PMID- 25440653 TI - Teaching concepts of transesophageal echocardiography via Web-based modules. AB - OBJECTIVES: Teaching transesophageal echocardiography (TEE) remains challenging. The authors hypothesized that using online modules with live teaching in an echo training course would be feasible and result in superior knowledge acquisition to live teaching only. DESIGN: In this prospective cohort study, the authors implemented a TEE course with online modules and live teaching and compared it to a live-teaching-only version. SETTING: The online-and-live-teaching version of the course consisted of online modules and live sessions at Beth Israel Deaconess Medical Center (BIDMC), an academic medical center. The live-teaching-only version consisted of live sessions at BIDMC. PARTICIPANTS: Course participants included anesthesia trainees at BIDMC. INTERVENTIONS: Trainees taking the online and-live-teaching version viewed online modules before live review lectures and simulation. Trainees taking the live-teaching-only version viewed live lectures before simulation. MEASUREMENTS AND MAIN RESULTS: Twenty-seven trainees completed the online-and-live-teaching version; six completed the live-teaching-only version. Trainees took a course exam after the first and last live sessions. For the online-and-live-teaching version, average pretest and posttest scores were 62.0%+/-13.7% and 77.5%+/-8.1%, respectively; pretest and posttest passing (>=70%) rates were 29.6% and 85.2%, respectively. Compared to the live-teaching only version, the average pretest score was not significantly different (p=0.17), but the average posttest score was significantly higher (p=0.01). Trainee comfort with, and knowledge of, TEE increased after both versions. Trainees rated the utility of the live lectures and online modules similarly. CONCLUSIONS: A multimodal TEE curriculum increased trainees' knowledge of TEE concepts and had a positive reception from trainees. PMID- 25440654 TI - Improved Performance of the Fourth-Generation FloTrac/Vigileo System for Tracking Cardiac Output Changes. AB - OBJECTIVES: The aims of this study were to compare cardiac output (CO) measured by the new fourth-generation FloTracTM/VigileoTM system (Version 4.00) (COFVS) with that measured by a pulmonary artery catheter (COREF), and to investigate the ability of COFVS to track CO changes induced by increased peripheral resistance. DESIGN: Prospective study. SETTING: University Hospital. PARTICIPANTS: Twenty three patients undergoing cardiac surgery. INTERVENTIONS: Phenylephrine (100 ug) was administered. MEASUREMENTS AND MAIN RESULTS: Hemodynamic variables, including CO(REF) and CO(FVS), were measured before and after phenylephrine administration. Bland-Altman analysis was used to assess the discrepancy between CO(REF) and CO(FVS). Four-quadrant plot and polar-plot analyses were utilized to evaluate the trending ability of CO(FVS) against CO(REF) after phenylephrine boluses. One hundred thirty-six hemodynamic interventions were performed. The bias shown by the Bland-Altman analysis was-0.66 L/min, and the percentage error was 55.4%. The bias was significantly correlated with the systemic vascular resistance index (SVRI) before phenylephrine administration (p<0.001, r(2) = 0.420). The concordance rate determined by four-quadrant plot analysis and the angular concordance rate calculated using polar-plot analysis were 87.0% and 83.0%, respectively. Additionally, this trending ability was not affected by SVRI state. CONCLUSIONS: The trending ability of the new fourth-generation FloTracTM/VigileoTM system after increased vasomotor tone was greatly improved compared with previous versions; however, the discrepancy of the new system in CO measurement was not clinically acceptable, as in previous versions. For clinical application in critically ill patients, this vasomotor tone-dependent disagreement must be decreased. PMID- 25440655 TI - The efficacy and safety of epidural-based analgesia in a case series of patients undergoing lung transplantation. AB - OBJECTIVE: Successful pain management after lung transplantation is critical to ensure adequate respiratory effort and graft expansion. The authors investigated whether thoracic epidural analgesia (TEA) provided adequate pain control after lung transplantation without added morbidity. DESIGN: Retrospective review. SETTING: University teaching hospital. PARTICIPANTS: One hundred twenty-three patients who presented to this institution for lung transplantation from January 2008 to June 2013. INTERVENTIONS: Patient demographics, postoperative pain scores, and epidural-related complications were abstracted from the institutional electronic database. The authors used the previously validated Quality of Recovery (QoR) score and Visual Analog Scale (VAS) as measures of recovery. MEASUREMENTS AND MAIN RESULTS: Of the 123 patients who underwent lung transplantation in this time frame, 119 patients had thoracic epidurals placed for postoperative analgesia. The mean age was 49.4 years (range, 18-73), and 60 (50.4%) were male. The most common indications for transplant were pulmonary fibrosis (33.6%), cystic fibrosis (26.1%), and chronic obstructive pulmonary disease (20.2%). The median length of stay in the intensive care unit and duration of mechanical ventilation were 21 and 1.2 days, respectively. Eight (6.7%) patients experienced postoperative pulmonary compromise (eg, pneumonia, prolonged intubation). No serious complications were associated with TEA placement. On days 1, 3, and 7 after TEA placement, the mean QoR was 7.6, 9.4, and 9.7, and the mean VAS was 2.5, 2.1, and 2.0, respectively. CONCLUSIONS: In this case series, the authors observed excellent analgesia and no serious complications associated with TEA. Therefore, an epidural-centric approach to pain control after lung transplantation should be considered in appropriate patients. PMID- 25440656 TI - Con: a bronchial blocker is not a substitute for a double-lumen endobronchial tube. PMID- 25440657 TI - Acute kidney injury is independently associated with higher mortality after cardiac surgery. AB - OBJECTIVES: To investigate the incidence of acute kidney injury after cardiac surgery and its association with mortality in a patient population receiving ibuprofen and gentamicin perioperatively. DESIGN: Retrospective study with Cox regression analysis to control for possible preoperative, intraoperative and postoperative confounders. SETTING: University hospital-based single-center study. PARTICIPANTS: All patients who underwent coronary artery bypass grafting +/- valve surgery during 2012. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Acute surgery within 24 hours of coronary angiography, previous nephrectomy, preoperative sCr >2.26 mg/dL and selective cerebral perfusion during cardiopulmonary bypass were used as exclusion criteria. Acute kidney injury was defined, using the Acute Kidney Injury Network (AKIN) criteria. Six hundred eight patients were included in the study. Mean age was 68.2 +/- 9.7 years, and 81% were males. Acute kidney injury was seen in 28.1% of the patients. Overall mortality at one year was 7% and 3% in the no-AKI group. At one year, mortality was 15% in patients with AKIN stage 1 and AKIN stage 2 compared to 70% in AKIN stage 3. A hazard ratio of 2.34 (95% CI: 1.21-4.51, p = 0.011) and 5.62 (95% CI: 2.42-13.06), p<0.0001) were found for AKIN stage 1 and 2/3 combined, respectively. CONCLUSIONS: More than 28% of the patients undergoing elective or subacute cardiac surgery developed AKI in this contemporary cohort. Furthermore, acute kidney injury was an independent predictor of increased mortality irrespective of the perioperative risk factors. PMID- 25440658 TI - Atmospheric pressure gas chromatography-time-of-flight-mass spectrometry (APGC ToF-MS) for the determination of regulated and emerging contaminants in aqueous samples after stir bar sorptive extraction (SBSE). AB - This work presents the development, optimization and validation of a multi residue method for the simultaneous determination of 102 contaminants, including fragrances, UV filters, repellents, endocrine disruptors, biocides, polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and several types of pesticides in aqueous matrices. Water samples were processed using stir bar sorptive extraction (SBSE) after the optimization of several parameters: agitation time, ionic strength, presence of organic modifiers, pH, and volume of the derivatizing agent. Target compounds were extracted from the bars by liquid desorption (LD). Separation, identification and quantification of analytes were carried out by gas chromatography (GC) coupled to time-of-flight (ToF-MS) mass spectrometry. A new ionization source, atmospheric pressure gas chromatography (APGC), was tested. The optimized protocol showed acceptable recovery percentages (50-100%) and limits of detection below 1ngL(-1) for most of the compounds. Occurrence of 21 out of 102 analytes was confirmed in several environmental aquatic matrices, including seawater, sewage effluent, river water and groundwater. Non-target compounds such as organophosphorus flame retardants were also identified in real samples by accurate mass measurement of their molecular ions using GC-APGC-ToF-MS. To the best of our knowledge, this is the first time that this technique has been applied for the analysis of contaminants in aquatic systems. By employing lower energy than the more widely used electron impact ionization (EI), AGPC provides significant advantages over EI for those substances very susceptible to high fragmentation (e.g., fragrances, pyrethroids). PMID- 25440659 TI - Re-evaluation of effective carbon number (ECN) approach to predict response factors of 'compounds lacking authentic standards or surrogates' (CLASS) by thermal desorption analysis with GC-MS. AB - In our recent study, we experimentally demonstrated the feasibility of an effective carbon number (ECN) approach for the prediction of the response factor (RF) values of 'compounds lacking authentic standards or surrogates' (CLASS) using a certified 54-mix containing 38 halogenated analytes as a pseudo-unknown. Although our recent analysis performed well in terms of RF predictive power for a 25-component learning set (for both Q-MS and TOF-MS detection), large physically unrealistic negative ECN and carbon number equivalent (CNE) values were noted for TOF-MS detection, e.g., ECN (acetic acid)=-16.96. Hence, to further improve the ECN-based quantitation procedure of CLASS, we re-challenged RF vs. ECN linear regression analysis with additional descriptors (i.e., Cl, Br, CC, and a group ECN offset (Ok)) using the 1-point RF values. With an Ok, all compound classes, e.g., halo-alkanes/-alkenes and aromatics can now be fitted to yield consistently positive set of ECN values for most analytes (e.g., 3 outliers out of 29, Q-MS detection). In this way, we were able to further refine our approach so that the absolute percentage difference (PD)+/-standard deviation (SD) between mass detected vs. mass loaded is reduced from 39.0+/-34.1% (previous work) to 13.1+/ 12.0% (this work) for 29 C1C4 halocarbons (Q-MS detector). PMID- 25440660 TI - Optimization of the operating conditions of solid sampling electrothermal vaporization coupled to inductively coupled plasma optical emission spectrometry for the sensitive direct analysis of powdered rice. AB - Two different approaches were used to improve the capabilities of solid sampling (SS) electrothermal vaporization (ETV) coupled to inductively coupled plasma optical emission spectrometry (ICP-OES) for the direct analysis of powdered rice. Firstly, a cooling step immediately before and after the vaporization step in the ETV temperature program resulted in a much sharper analyte signal peak. Secondly, point-by-point internal standardization with an Ar emission line significantly improved the linearity of calibration curves obtained with an increasing amount of rice flour certified reference material (CRM). Under the optimized conditions, detection limits ranged from 0.01 to 6ngg(-1) in the solid, depending on the element and wavelength selected. The method was validated through the quantitative analysis of corn bran and wheat flour CRMs. Application of the method to the multi-elemental analysis of 4-mg aliquots of real organic long grain rice (white and brown) also gave results for Al, As, Co, Cu, Fe, Mg, Se, Pb and Zn in agreement with those obtained by inductively coupled plasma mass spectrometry following acid digestion of 0.2-g aliquots. As the analysis takes roughly 5min per sample (2.5min for grinding, 0.5-1min for weighing a 4-mg aliquot and 87s for the ETV program), this approach shows great promise for fast screening of food samples. PMID- 25440661 TI - Partial least squares density modeling (PLS-DM) - a new class-modeling strategy applied to the authentication of olives in brine by near-infrared spectroscopy. AB - A new class-modeling method, referred to as partial least squares density modeling (PLS-DM), is presented. The method is based on partial least squares (PLS), using a distance-based sample density measurement as the response variable. Potential function probability density is subsequently calculated on PLS scores and used, jointly with residual Q statistics, to develop efficient class models. The influence of adjustable model parameters on the resulting performances has been critically studied by means of cross-validation and application of the Pareto optimality criterion. The method has been applied to verify the authenticity of olives in brine from cultivar Taggiasca, based on near infrared (NIR) spectra recorded on homogenized solid samples. Two independent test sets were used for model validation. The final optimal model was characterized by high efficiency and equilibrate balance between sensitivity and specificity values, if compared with those obtained by application of well established class-modeling methods, such as soft independent modeling of class analogy (SIMCA) and unequal dispersed classes (UNEQ). PMID- 25440662 TI - Ultrasonic microdialysis coupled with capillary electrophoresis electrochemiluminescence study the interaction between trimetazidine dihydrochloride and human serum albumin. AB - The paper describes a homemade ultrasonic microdialysis device coupled with capillary electrophoresis electrochemiluminescence (CE-ECL) for studying the interaction between human serum albumin (HSA) and trimetazidine dihydrochloride (TMZ). The time required for equilibrium by ultrasonic microdialysis was 45min, which was far less than that by traditional dialysis (240min). It took 80min to achieve the required combination equilibrium by normal incubation and only 20min by ultrasonic. Compared with traditional dialysis, the use of ultrasonic microdialysis simplified experimental procedures, shortened experimental time and saved consumption of sample. A simple, sensitive and selective determination of TMZ was developed using CE-ECL and the parameters that affected ECL intensity were optimized. Under the optimized conditions, the linear range of TMZ was from 0.075 to 80MUmol/L (r(2)=0.9974). The detection limit was 26nmol/L with RSD of 2.8%. The number of binding sites and binding constant were 1.54 and 15.17L/mol, respectively. PMID- 25440663 TI - Comparative study of graphene nanosheet- and multiwall carbon nanotube-based electrochemical sensor for the sensitive detection of cadmium. AB - A novel nanocomposite was obtained through the controlled surface modification of graphene nanosheets (nanographene) with Nafion by ultrasonic oscillation. The composite was used as an ultrasensitive platform for the detection of cadmium ions (Cd(2+)) by differential pulse anodic stripping voltammetry (DPASV) analysis. The performance of the nanographene-based sensor was systematically compared with that of a multiwall carbon nanotube (MWCNT)-modified sensor. The results indicate that the nanographene-based sensor exhibits significant advantages over the MWCNT-based sensor in terms of repeatability, sensitivity and limit of detection (LOD). The nanographene-based sensor displayed superior analytical performance over a linear range of Cd(2+) concentrations from 0.25MUgL(-1) to 5MUgL(-1), with a LOD of 3.5ngL(-1). This sensor was also used to systematically screen for 6 types of chemicals, including sodium salts, magnesium salts and zinc salts. It was observed that the sensor could successfully differentiate cadmium ions from interferents (magnesium salts, zinc salts, etc.). The nanographene-based sensor was also demonstrated to be a promising and reliable tool for the rapid detection of cadmium existing in tap water and for the rapid on-site analysis of critical pollution levels of cadmium. PMID- 25440664 TI - NiCoBP-doped carbon nanotube hybrid: a novel oxidase mimetic system for highly efficient electrochemical immunoassay. AB - NiCoBP-doped multi-walled carbon nanotube (NiCoBP-MWCNT) was first synthesized by using induced electroless-plating method and functionalized with the biomolecules for highly efficient electrochemical immunoassay of prostate-specific antigen (PSA, used as a model analyte). We discovered that the as-synthesized NiCoBP MWCNT had the ability to catalyze the glucose oxidization with a stable and well defined redox peak. The catalytic current increased with the increment of the immobilized NiCoBP-MWCNT on the electrode. Transmission electron microscope (TEM) and energy dispersive X-ray spectrometry (EDX) were employed to characterize the as-prepared NiCoBP-MWCNT. Using the NiCoBP-MWCNT-conjugated anti-PSA antibody as the signal-transduction tag, a new enzyme-free electrochemical immunoassay protocol could be designed for the detection of target PSA on the capture antibody-functionalized immunosensing interface. Experimental results revealed that the designed immunoassay system could exhibit good electrochemical responses toward target PSA, and allowed the detection of PSA at a concentration as low as 0.035ngmL(-1). More importantly, the NiCoBP-MWCNT-based oxidase mimetic system could be further extended for the monitoring of other low-abundance proteins or disease-related biomarkers by tuning the target antibody. PMID- 25440665 TI - Development of pre-concentration procedure for the determination of Hg isotope ratios in seawater samples. AB - Hg concentrations in seawater are usually too low to allow direct (without pre concentration and removal of salt matrix) measurement of its isotope ratios with multicollector-inductively coupled plasma mass spectrometry (MC-ICP-MS). Therefore, a new method for the pre-concentration of Hg from large volumes of seawater was developed. The final method allows for relatively fast (about 2.5Lh( 1)) and quantitative pre-concentration of Hg from seawater samples with an average Hg recovery of 98+/-6%. Using this newly developed method we determined Hg isotope ratios in seawater. Reference seawater samples were compared to samples potentially impacted by anthropogenic activity. The results show negative mass dependent fractionation relative to the NIST 3133 Hg standard with delta(202)Hg values in the range from -0.500/00 to -1.500/00. In addition, positive mass independent fractionation of (200)Hg was observed for samples from reference sites, while impacted sites did not show significant Delta(200)Hg values. Although the influence of the impacted sediments is limited to the seawater and particulate matter in very close proximity to the sediment, this observation may raise the possibility of using Delta(200)Hg to distinguish between samples from impacted and reference sites. PMID- 25440666 TI - On-line double isotope dilution laser ablation inductively coupled plasma mass spectrometry for the quantitative analysis of solid materials. AB - We report on the determination of trace elements in solid samples by the combination of on-line double isotope dilution and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The proposed method requires the sequential analysis of the sample and a certified natural abundance standard by on-line IDMS using the same isotopically-enriched spike solution. In this way, the mass fraction of the analyte in the sample can be directly referred to the certified standard so the previous characterization of the spike solution is not required. To validate the procedure, Sr, Rb and Pb were determined in certified reference materials with different matrices, including silicate glasses (SRM 610, 612 and 614) and powdered samples (PACS-2, SRM 2710a, SRM 1944, SRM 2702 and SRM 2780). The analysis of powdered samples was carried out both by the preparation of pressed pellets and by lithium borate fusion. Experimental results for the analysis of powdered samples were in agreement with the certified values for all materials. Relative standard deviations in the range of 6-21% for pressed pellets and 3-21% for fused solids were obtained from n=3 independent measurements. Minimal sample preparation, data treatment and consumption of the isotopically enriched isotopes are the main advantages of the method over previously reported approaches. PMID- 25440667 TI - Molecular mass spectrometry in metallodrug development: a case of mapping transferrin-mediated transformations for a ruthenium(III) anticancer drug. AB - Electrospray ionization mass spectrometry (ESI-MS) techniques have been used to characterize the speciation of a Ru(III) anticancer drug, indazolium trans [tetrachloridobis(1H-indazole) ruthenate(III)], upon its binding to transferrin and the impact of cellular reducing components on drug-transferrin adducts. Using time-of-flight ESI-MS, the polymorphism of apo- (iron-free) and holo-form (iron saturated) of the protein was confirmed. While the ruthenium moieties bound to each of five isoforms under simulated extracellular conditions are essentially identical in numbers for apo- and holo-transferrin, distinct differences were found in the composition of Ru(III) species attached to either of the protein forms, which are dominated by differently coordinated aquated complexes. On the other hand, at least one of the RuN bonds in metal-organic framework remains intact even after prolonged interaction with the protein. Triple quadrupole tandem ESI-MS measurements demonstrated that the ruthenium species released from drug adducts with holo-transferrin in simulated cancer cytosol are underwent strong ligand exchange (as compared to the protein-bound forms) but most strikingly, they contain the metal center in the reduced Ru(II) state. In vitro probing the extra- and intracellular interactions of promising Ru(III) drug candidate performed by ESI-MS is thought to shed light on the transportation to tumor cells by transferrin and on the activation to more reactive species by the reducing environment of solid tumors. PMID- 25440668 TI - A calixarene-based ion-selective electrode for thallium(I) detection. AB - Three new calixarene Tl(+) ionophores have been utilized in Tl(+) ion-selective electrodes (ISEs) yielding Nernstian response in the concentration range of 10( 2)-10(-6)M TlNO3 with a non-optimized filling solution in a conventional liquid contact ISE configuration. The complex formation constants (logbetaIL) for two of the calixarene derivatives with thallium(I) (i.e. 6.44 and 5.85) were measured using the sandwich membrane technique, with the other ionophore immeasurable due to eventual precipitation of the ionophore during these long-term experiments. Furthermore, the unbiased selectivity coefficients for these ionophores displayed excellent selectivity against Zn(2+), Ca(2+), Ba(2+), Cu(2+), Cd(2+) and Al(3+) with moderate selectivity against Pb(2+), Li(+), Na(+), H(+), K(+), NH4(+) and Cs(+), noting that silver was the only significant interferent with these calixarene-based ionophores. When optimizing the filling solution in a liquid contact ISE, it was possible to achieve a lower limit of detection of approximately 8nM according to the IUPAC definition. Last, the new ionophores were also evaluated in four solid-contact (SC) designs leading to Nernstian response, with the best response noted with a SC electrode utilizing a gold substrate, a poly(3-octylthiophene) (POT) ion-to-electron transducer and a poly(methyl methacrylate)-poly(decyl methacrylate) (PMMA-PDMA) co-polymer membrane. This electrode exhibited a slope of 58.4mVdecade(-1) and a lower detection limit of 30.2nM. Due to the presence of an undesirable water layer and/or leaching of redox mediator from the graphite redox buffered SC, a coated wire electrode on gold and graphite redox buffered SC yielded grossly inferior detection limits against the polypyrrole/PVC SC and POT/PMMA-PDMA SC ISEs that did not display signs of a water layer or leaching of SC ingredients into the membrane. PMID- 25440669 TI - A visual strip sensor for determination of iron. AB - A visual strip has been developed for sensing iron in different aqueous samples like natural water and fruit juices. The sensor has been synthesized by UV radiation induced graft polymerization of acrylamide monomer in microporous poly(propylene) base. For physical immobilization of iron selective reagent, the in situ polymerization of acrylamide has been carried out in the presence of 1,10 phenanthroline. The loaded strip on interaction with Fe(II) in aqueous solution turned into orange red color and the intensity of the color was found to be directly proportional to the amount of Fe(II) in the aqueous sample. The minimal sensor response with naked eye was found for 50ngmL(-1) of Fe in 15min of interaction. However, as low as 20ngmL(-1) Fe could be quantified using a spectrophotometer. The detection limit calculated using the 3s/S criteria, where 's' is the standard deviation of the absorbance of blank reagent loaded strip and 'S' is the slope of the linear calibration plot, was 1.0ngmL(-1). The strip was applied to measure Fe in a variety of samples such as ground water and fruit juices. PMID- 25440670 TI - Synergistic electrocatalytic effect of nanostructured mixed films formed by functionalised gold nanoparticles and bisphthalocyanines. AB - A synergistic electrocatalytic effect was observed in sensors where two electrocatalytic materials (functionalized gold nanoparticles and lutetium bisphthalocyanine) were co-deposited using the Langmuir-Blodgett technique. Films were prepared using a novel method where water soluble functionalised gold nanoparticles [(11-mercaptoundecyl)tetra(ethylene glycol)] (SAuNPs) were inserted in floating films of lutetium bisphthalocyanine (LuPc2) and dimethyldioctadecylammonium bromide (DODAB) as the amphiphilic matrix. The formation of stable and homogeneous mixed films was confirmed by pi-A isotherms, BAM, UV-vis and Raman spectroscopy, as well as by SEM and TEM microscopy. The synergistic effect towards hydroquinone of the electrodes modified with LuPc2:DODAB/SAuNP was characterised by an increase in the intensity of the redox peaks and a reduction of the overpotential. This synergistic electrocatalytic effect arose from the interaction between the SAuNPs and the phthalocyanines that occur in the Langmuir-Blodgett films and from the high surface area provided by the nanostructured films. The sensitivity increased with the amount of LuPc2 and SAuNPs inserted in the films and limits of detection in the range of 10(-7)molL( 1) were attained. PMID- 25440671 TI - Novel computer-aided diagnostic system for colorectal lesions by using endocytoscopy (with videos). AB - BACKGROUND: Endocytoscopy enables in vivo observation of nuclei at 450* magnification during GI endoscopy, thus allowing precise prediction of lesion pathology. However, because it requires training and experience, it may be beneficial only when performed by expert endoscopists. OBJECTIVE: To develop and evaluate a novel computer-aided diagnosis system for endocytoscopic imaging (EC CAD) of colorectal lesions. DESIGN: Pilot study. SETTING: University hospital. PATIENTS: One hundred fifty-two patients with small colorectal polyps (<=10 mm) who had undergone endocytoscopy. INTERVENTION: Test sets of white-light endoscopic images and endocytoscopic images from 176 small colorectal polyps (137 neoplastic and 39 non-neoplastic polyps) were assessed by EC-CAD, 2 expert endoscopists, and 2 trainee endoscopists. MAIN OUTCOME MEASUREMENT: Sensitivity, specificity, and accuracy in predicting neoplastic change by EC-CAD comparing expert and trainee endoscopists. RESULTS: EC-CAD had a sensitivity of 92.0% and an accuracy of 89.2%; these were comparable to those achieved by expert endoscopists (92.7% and 92.3%; P = .868 and .256, respectively) and significantly higher than those achieved by trainee endoscopists (81.8% and 80.4%; P < .001 and .002, respectively). EC-CAD achieved a specificity of 79.5%; this did not differ significantly from that achieved by the experts and trainees. EC-CAD also enabled instant diagnosis, taking only 0.3 seconds for each lesion with perfect reproducibility. LIMITATIONS: No sample size calculation. CONCLUSIONS: EC-CAD provides fully automated instant classification of colorectal polyps with excellent sensitivity, accuracy, and objectivity. Thus, it can be a powerful tool for facilitating decision making during routine colonoscopy. PMID- 25440672 TI - Successful removal of intrahepatic bile duct stone using a novel basket catheter. PMID- 25440673 TI - Submucosal endoscopy as an aid to full-thickness resection: pilot study in the porcine stomach. AB - BACKGROUND: Endoscopic full-thickness resection (EFTR) is commonly performed with laparoscopic assistance. Submucosal endoscopy with full-thickness resection (SEFTR) is a new technique that combines submucosal endoscopy with the mucosal safety valve flap method to enable EFTR. OBJECTIVE: Pilot evaluation of the feasibility and safety of SEFTR in an animal model. DESIGN: In vivo animal study. SETTING: Developmental endoscopy unit/animal research unit. INTERVENTION: Five domestic pigs, under general anesthesia, were used. A 2-cm gastric target area was marked. A circumferential mucosal incision was made. Two parallel submucosal tunnels on opposite sides of the incision were made. The mucosa at the proximal and distal tunnel ends was cut. A suture was passed through the tunnels encircling the target. T bars with sutures were placed full thickness outside the target and brought out of the mouth. Pulling the oral sutures raised the target while the targeted area was cinched serosa to serosa with the encircling suture. Full-thickness excision was then performed without closure. MAIN OUTCOME MEASUREMENTS: Rate of adverse events, procedure times, adverse events, and difficulty scales were recorded prospectively. RESULTS: Circumferential mucosal incisions, submucosal tunnels, and connections were completed in all. In the first case, looping of the target lesion failed. In the remaining 4 cases, looping, cinching, and lifting were completed. Full-thickness resections were completed in 3 of 4 pigs. There were no procedural adverse events and no damage to adjacent organs. LIMITATIONS: Acute animal study. Procedures were performed by an endoscopist skilled in the submucosal endoscopy with the mucosal safety valve flap method. CONCLUSION: This pilot experience suggests that SEFTR is feasible and could be safe. PMID- 25440674 TI - Cholecystoduodenostomy and duodenal stenting for relief of biliary and gastric outlet obstruction. PMID- 25440675 TI - Endoluminal flexible endoscopic suturing for minimally invasive therapies. PMID- 25440676 TI - Precut sphincterotomy: efficacy for ductal access and the risk of adverse events. AB - BACKGROUND: Successful ductal access is achieved in 90% of patients who undergo ERCP. Precut sphincterotomy has been advocated when routine cannulation is not possible. OBJECTIVE: To evaluate the efficacy of precut sphincterotomy for ductal access and the risk of adverse events including post-ERCP pancreatitis (PEP) associated with it. DESIGN: Retrospective analysis of ERCP procedures performed from 2002 to 2011. SETTING: Referral center. PATIENTS: A total of 10,202 consecutive patients who underwent native cannulation ERCP. MAIN OUTCOME MEASUREMENTS: Efficacy for ductal access and risk of adverse events including PEP. RESULTS: A total of 706 patients required precut sphincterotomy, 614 of whom (86.9%) had successful biliary cannulation. PEP was diagnosed in 58 (8.2 %), perforation in 6 (0.8%), and bleeding in 49 (6.9%) patients. On multivariate analysis, unsuccessful precut sphincterotomy (odds ratio [OR] 2.59; 95% confidence interval [CI], 1.53-4.40; P < .001) and female sex (OR 1.95; 95% CI, 1.23-3.07; P = .004) were associated with increased risk of the development of adverse events. Female sex (OR 2.42; 95% CI, 1.29-4.55; P = .006) and sphincter of Oddi dysfunction (OR 2.77; 95% CI, 1.16-6.60; P = .02) were associated with an increased risk of PEP. LIMITATIONS: Retrospective study. CONCLUSIONS: Precut sphincterotomy is effective in achieving ductal access when standard cannulation techniques fail. A successful precut sphincterotomy is not associated with an increased risk of adverse events. PMID- 25440677 TI - Underwater submucosal resection of a carcinoid tumor of the duodenal bulb. PMID- 25440678 TI - Comparative effectiveness of biliary brush cytology and intraductal biopsy for detection of malignant biliary strictures: a systematic review and meta-analysis. AB - BACKGROUND: Evaluation of indeterminate biliary strictures typically involves collection and analysis of tissue or cells. Brush cytology and intraductal biopsies that are routinely performed during ERCP to assess malignant-appearing biliary strictures are limited by relatively low sensitivity. OBJECTIVE: To study the comparative effectiveness of brushings for cytology and intraductal biopsies in the etiology of biliary strictures. DESIGN: Meta-analysis. SETTING: Referral center. PATIENTS: PUBMED and Embase databases were reviewed for studies published to April 2014 where diagnostic correlation of histology was available. INTERVENTION: Database and review of study findings. MAIN OUTCOME MEASUREMENTS: Sensitivity and specificity. RESULTS: The pooled sensitivity and specificity of brushings for the diagnosis of malignant biliary strictures was 45% (95% confidence interval [CI], 40%-50%) and 99% (95% CI, 98%-100%), respectively. The pooled diagnostic odds ratio to detect malignant biliary strictures was 33.43 (95% CI, 14.29-78.24). For intraductal biopsies, the pooled sensitivity and specificity were 48.1% (95% CI, 42.8%-53.4%) and 99.2% (95% CI, 97.6%-99.8%), respectively. The pooled diagnostic odds ratio to detect malignant biliary strictures was 43.18 (95% CI, 19.39-95.83). A combination of both modalities only modestly increased the sensitivity (59.4%; 95% CI, 53.7%-64.8%) with a specificity of 100% (95% CI, 98.8%-100.0%). The Begg-Mazumdar and Egger tests indicated a low potential for publication bias. LIMITATIONS: Inclusion of low quality studies. CONCLUSION: Our study suggests that both brushings and biopsy are comparable and have limited sensitivity for the diagnosis of malignant biliary strictures. A combination of both only modestly increases the sensitivity. PMID- 25440679 TI - Polyglycolic acid sheets and fibrin glue decrease the risk of bleeding after endoscopic submucosal dissection of gastric neoplasms (with video). AB - BACKGROUND: The prevention of bleeding after endoscopic submucosal dissection (ESD) for gastric neoplasms is still an important problem. OBJECTIVE: To investigate the efficacy and safety of a shielding method that uses polyglycolic acid (PGA) sheets and fibrin glue to prevent post-ESD bleeding in high-risk patients. DESIGN: A nonrandomized trial with historical control subjects. SETTING: A single academic hospital in Japan. PATIENTS: From July 2013 to February 2014, 45 ESD-induced ulcers in 41 patients with a high risk of bleeding were enrolled in a study group. Forty-one consecutive ESD-induced ulcers in 37 control subjects with a high risk of bleeding were treated in 2013 before the first enrollment. INTERVENTIONS: We placed PGA sheets on the mucosal defect and fixed with fibrin glue in the study group. MAIN OUTCOME MEASUREMENTS: The post ESD bleeding rate. RESULTS: The post-ESD bleeding occurred at a rate of 6.7% in the study group (3/45 lesions) and 22.0% in the historical control group (9/41 lesions). There was a significant difference in the post-ESD bleeding rate between the 2 groups (P = .041). LIMITATIONS: A nonrandomized trial with historical control subjects; a single-center analysis; small sample size. CONCLUSIONS: The endoscopic tissue shielding method with PGA sheets and fibrin glue appears to be promising for the prevention of post-ESD bleeding. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000011058.). PMID- 25440680 TI - Endoscopy and EUS are key for effective surveillance and management of duodenal adenomas in familial adenomatous polyposis. AB - BACKGROUND: Patients with familial adenomatous polyposis (FAP) are prone to developing duodenal adenoma and cancer. Optimal surveillance and management of these adenomas are not well established. OBJECTIVE: We assessed the outcome of FAP patients undergoing intense multimodal surveillance and subsequent endoscopic resection of advanced lesions. PATIENTS: Eighty consecutive FAP patients enrolled during 2001 to 2011 from the Familial Cancer Clinic of a tertiary hospital as part of routine surveillance. DESIGN: Case series, prospective in years 2006 to 2011 and retrospective in years 2001 to 2006. SETTING AND INTERVENTION: Patients were followed by annual forward-view and/or side-view upper endoscopy. A biopsy sample was obtained from visible lesions and normal papillae. Ampullary adenomas were further assessed by EUS to determine dimensions and resectability. Advanced adenomas (size >= 10 mm, villous type, high-grade dysplasia) underwent endoscopic ampullectomy or polypectomy and continued surveillance. MAIN OUTCOME MEASUREMENTS: Detection of advanced adenomas by endoscopy and EUS, endoscopic maintenance of duodenum free of advanced adenoma and cancer. RESULTS: Patients (38 men and 42 women, mean age 32.68 +/- 13.60) were followed 7.2 years and underwent 5.36 diagnostic studies on average. Thirty-eight patients had ampullary adenomas. Advanced adenoma was diagnosed by endoscopy in 10 patients. Importantly, EUS upstaged 9 additional patients to advanced adenoma and downstaged 1, thus altering the treatment course in 36% of patients performing EUS. Endoscopic ampullectomy was performed in 15 patients. Adenoma recurred in 10. Five remained nonadvanced and 5 in advanced stages: 3 were successfully retreated endoscopically and 2 ultimately required surgery for residual adenoma. Advanced nonampullary adenomas were successfully resected endoscopically in 23 patients. No patient had duodenal cancer during the study period. LIMITATIONS: Limited follow-up period, young age group, uncontrolled study. CONCLUSIONS: In an intense surveillance program for FAP patients, both endoscopy and EUS were key in accurate selection of advanced adenomas for endoscopic resection. During a 10 year period, only 2 patients required elective surgery and no cancer was observed. PMID- 25440681 TI - Pulsating pseudoaneurysm in a walled-off necrosis. PMID- 25440682 TI - EUS-guided choledochojejunostomy with a lumen-apposing metal stent in a post Whipple patient. PMID- 25440684 TI - Endoscopic mucosal resection of an early-stage gastric cancer. PMID- 25440683 TI - Endoscopic needle-knife treatment of mucosal bridges in the multicompartment ileal pouch. PMID- 25440685 TI - EUS-guided choledochoduodenostomy for cholangitis caused by mucin derived from intraductal papillary-mucinous neoplasms penetrating the bile duct. PMID- 25440686 TI - Effect of prior biopsy sampling, tattoo placement, and snare sampling on endoscopic resection of large nonpedunculated colorectal lesions. AB - BACKGROUND: Endoscopic manipulations, including biopsy sampling, tattoo application on the lesion itself, and sampling of the lesion with a polypectomy snare, are frequently performed on large nonpedunculated colorectal lesions >= 20 mm (LNCL) before referral for endoscopic resection. OBJECTIVE: To assess the effect of prior manipulations on the technical difficulty and recurrence rates of subsequent endoscopic treatment. DESIGN: Retrospective study. SETTING: Two referral centers. PATIENTS: Patients with LNCL referred for endoscopic resection. INTERVENTIONS: Endoscopic resection. MAIN OUTCOME MEASUREMENT: En-bloc resection rate, rate of successful complete endoscopic resection without the need for ablation of visible residual, recurrence rate on follow-up, independent predictive factors for en-bloc resection, complete resection without ablation of visible residual, and recurrence. RESULTS: A total of 132 lesions was analyzed: 46 lesions without any prior manipulation, 44 with prior biopsy sampling only, and 42 with prior advanced manipulation including tattoo and/or snare sampling. The en-bloc resection rate was 34.8% for nonmanipulated lesions, 15.9% for lesions with prior biopsy sampling, and 4.8% for lesions with prior advanced manipulation (P = .001). Complete endoscopic resection without the need for ablation of visible residual was performed in 93.5% of nonmanipulated lesions, 68.2% of lesions with prior biopsy sampling, and 50% of lesions with prior advanced manipulation (P < .001). Recurrence rates were 7.7%, 40.7%, and 53.8% in the 3 groups (P = .001). In multivariate analysis, prior biopsy sampling was an independent predictor for inability to perform complete resection without ablation of visible residual (odds ratio .24, P < .05) and for recurrence (odds ratio 11.5, P = .004) compared with nonmanipulated lesions. Prior advanced manipulation was an independent predictor for inability to perform en-bloc resection (odds ratio .024, P = .001), for inability to perform complete resection without ablation of visible residual (odds ratio .081, P < .001), and for recurrence (odds ratio 18.8, P = .001). LIMITATIONS: Retrospective study. CONCLUSIONS: Prior biopsy sampling and advanced manipulation have significant deleterious effects on endoscopic treatment of LNCL. PMID- 25440687 TI - Right-sided adenoma detection with retroflexion versus forward-view colonoscopy. AB - BACKGROUND: Colonoscopy and polypectomy can prevent up to 80% of colon cancer; however, a significant adenoma miss rate still exists, particularly in the right side of the colon. OBJECTIVE: To assess whether retroflexion in the right side of the colon significantly improves the adenoma detection rate (ADR) over forward view assessment. DESIGN: Multicenter prospective cohort study. SETTING: Three tertiary care public and 2 private hospitals. PATIENTS: A total of 1351 consecutive adult patients undergoing elective colonoscopy. INTERVENTION: Withdrawal from the cecum was performed in the forward view initially and identified polyps removed. Once the hepatic flexure was reached, the cecum was reintubated and the right side of the colon was assessed in the retroflexed view to the hepatic flexure. MAIN OUTCOME MEASUREMENTS: ADR in the retroflexed view when compared with forward-view examination of the right side of the colon. RESULTS: Retroflexion was successful in 95.9% of patients, with looping the predominant (69.6%) reason for failure. Forward-view assessment of the right side of the colon identified 642 polyps, of which 531 were adenomas yielding a polyp and ADR of 28.57% and 24.64%, respectively. Retroflexion identified a further 84 polyps of which 75 were adenomas, improving the polyp and ADR to 30.57% and 26.4%, respectively. LIMITATIONS: Observational study. CONCLUSION: Right-sided retroflexion was successful in most of our cohort with a statistically significant but small increase in ADR. Right-sided retroflexion is safe when performed by experienced endoscopists with no adverse events observed in this cohort. ( CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12613000424707.). PMID- 25440688 TI - Macroscopic on-site quality evaluation of biopsy specimens to improve the diagnostic accuracy during EUS-guided FNA using a 19-gauge needle for solid lesions: a single-center prospective pilot study (MOSE study). AB - BACKGROUND: Although rapid on-site cytologic evaluation provides high efficacy of EUS-guided FNA (EUS-FNA), its availability is limited. Alternatively, macroscopic on-site quality evaluation (MOSE) may increase the efficacy of EUS-FNA. OBJECTIVE: To assess the efficacy of MOSE in estimating the adequacy of histologic core specimens obtained by EUS-FNA using a standard 19-gauge needle (19GN) for solid lesions. DESIGN: A prospective pilot study. SETTING: Tertiary care referral center. PATIENTS: One hundred patients with solid lesions (n = 111 lesions). INTERVENTIONS: EUS-FNA using 19GN MAIN OUTCOME MEASUREMENTS: The relation of a macroscopic visible core (MVC) in the FNA specimens on MOSE with histologic core and the diagnostic yields were studied. RESULTS: The feasibility of EUS-FNA using a 19GN was 99%. The final diagnoses were malignancy in 83 lesions and benign in 28. MOSE revealed MVC in 91.1% with the median length of 8 mm. Histologic core was confirmed in 78.9%. The receiver-operating characteristic curve of the length of MVC for the presence of histologic core showed the cut-off MVC length of 4 mm with area under the curve of .893. Comparisons of per-pass diagnostic yields showed significantly superior histologic, cytologic, and overall diagnostic yields in MVC >= 4 mm as compared with <4 mm. The multivariate analysis for false-negative pass identified lesion in the pancreas and MVC < 4 mm as significant risk factors. No adverse events were seen. LIMITATIONS: Single center, limited operators CONCLUSION: MVC of >=4 mm on MOSE can be an indicator of specimen adequacy and can improve diagnostic yield; however, additional FNA may be recommended for pancreatic lesions. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000010417.). PMID- 25440689 TI - Use of bedside transabdominal US in facilitating emergent intensive care unit ERCP without fluoroscopy. PMID- 25440690 TI - Magnified endoscopic findings with a barnacle-like appearance in enterocolitis associated with sepsis. PMID- 25440691 TI - Endoscopic submucosal dissection for colorectal lateral spreading tumors larger than 10 cm: is it feasible? AB - BACKGROUND: Colorectal endoscopic submucosal dissection (ESD) was applied to lesions, such as giant colorectal lateral spreading tumors (LSTs) > 10 cm, by an expert ESD endoscopist despite several limitations, such as a relatively high perforation rate and high technical difficulty. OBJECTIVE: To investigate the feasibility and safety of ESD for giant colorectal LSTs >= 10 cm. DESIGN: Retrospective study. SETTING: Tertiary-care center. PATIENTS: A total of 163 patients underwent colorectal ESD between 2009 and 2014 by a single expert ESD endoscopist at Gangnam Severance Hospital, Seoul, Korea. Among them, 9 patients had giant colorectal LSTs >= 10 cm. INTERVENTIONS: Review of records. MAIN OUTCOME MEASUREMENTS: Clinicopathologic factors and oncologic outcome associated with ESD between giant colorectal LSTs and others. RESULTS: Colorectal LSTs >= 10 cm were classified as giant colorectal LSTs. Nine giant colorectal LST lesions were localized to the following regions: descending colon (n = 1), sigmoid colon (n = 1), and rectum (n = 7). The average maximal diameter of giant colorectal LSTs was 120.8 mm, and the procedure time was 270.0 minutes. Two lesions were of the whole nodular type, and 7 were focal nodular lesions. The en bloc and curative resection rates for ESD for giant colorectal LSTs were 88.9% and 100%, respectively. The adverse event rate was 44.4%. No strictures, local recurrences, or distant metastases occurred over a mean follow-up period of 27.1 months. LIMITATIONS: Retrospective, single-center study. CONCLUSIONS: ESD of giant colorectal LSTs appears to be a feasible and curative treatment, even though it is associated with a higher adverse event rate, higher degree of technical difficulty, and longer procedure time. PMID- 25440692 TI - Cap-assisted argon plasma coagulation. PMID- 25440693 TI - The concordance of endoscopic and histologic findings of 1000 pediatric EGDs. AB - BACKGROUND: Pediatric gastroenterologists frequently perform routine endoscopic biopsies despite normal-appearing mucosa during EGD. Older small studies have supported this practice. OBJECTIVE: To re-evaluate the concordance between endoscopic appearance and histology in the era of high-definition endoscopy. DESIGN: Retrospective cohort study. SETTING: Single tertiary care center. PATIENTS: A total of 1000 pediatric patients undergoing initial EGD. MAIN OUTCOME MEASUREMENTS: Endoscopic and histologic findings. RESULTS: The overall rate of an endoscopic finding was 34.7%, which was 40.4% of a histologic finding. Concordance between the presence of any endoscopic finding and any histologic finding in all locations was 69.9% (Cohen's kappa coefficient=0.32). In the esophagus, the concordance between any endoscopic finding and any histologic finding was 82.6% (kappa=0.45). The stomach was 73.2% concordant (kappa=0.18), and the duodenum was 89.3% concordant (kappa=0.42). The kappa coefficient decreased when comparing specific findings in each location; it was 0.34 in the esophagus, 0.17 in the stomach, and 0.34 in the duodenum. If biopsy specimens had only been obtained when the endoscopist identified abnormal mucosa, 48.5% of the pathologic findings would have been missed. In patients with histology consistent with eosinophilic esophagitis, 30.2% had normal-appearing mucosa. For celiac disease, 43% had normal-appearing mucosa. In the stomach, an abnormal endoscopic appearance was more likely to have normal histology. LIMITATIONS: The single center, retrospective nature and more endoscopists than pathologists. CONCLUSIONS: These data support the routine collection of biopsy specimens in the duodenum, stomach, and esophagus during EGD in pediatric patients. PMID- 25440694 TI - Ultrasound-guided intermediate cervical plexus block for carotid endarterectomy using a new anterior approach: a two-centre prospective observational study. AB - The aim of this prospective, double-centre, observational study performed in 116 patients was to describe a new anterior approach of ultrasound-guided intermediate cervical plexus block for carotid endarterectomy. The median (IQR [range]) volume of ropivacaine 0.5% administered was 30 (25-30 [20-45]) ml. Supplemental local anaesthesia (infiltration and topical) was needed in 66 (57%) patients. Overall, 41 (35%) patients needed additional sedation (18 midazolam; 23 remifentanil). There was no intra-operative complication or systemic toxicity of ropivacaine. One regional anaesthesia procedure was converted to general anaesthesia because of patient agitation. Adverse effects were of short duration and did not affect surgery. Satisfaction scores were high for 92 (79%) patients (63 satisfied; 29 very satisfied) and 104 (90%) surgeons (51 satisfied; 53 very satisfied). This study shows that the ultrasound-guided intermediate cervical plexus block using an anterior approach is feasible and provides similar results to other regional techniques during carotid endarterectomy. PMID- 25440695 TI - How communities' perceptions of disasters influence disaster response: managing landslides on Mount Elgon, Uganda. AB - The aim of this paper is to assess the role of people's perception in disaster management. It is based on a study carried out along the slopes of Mount Elgon in Eastern Uganda. People living in the study area have experienced a number of landslides, but the landslide in 2010 had the most far-reaching effects on community livelihoods and resulted in a major setback to development efforts in the area. Experiences of landslides have enabled the local people to develop a number of interpretations of the causes and effects of the phenomena. The study revealed that community members did not share uniform perceptions. Whereas some members advanced technical or physical explanations for the 2010 disaster, others believed that some form of divine power was behind it. Strengthening social networks and integrating communities' perceptions in intervention mechanisms were identified as possible ways of managing future landslide disasters. PMID- 25440696 TI - Temporomandibular disorders in fibromyalgia syndrome: a short-communication. AB - Fibromyalgia syndrome (FMS) is a chronic painful syndrome and the coexistence of a painful condition caused by Temporomandibular Disorders (TMD) and FMS has been frequently raised for several studies, however, more likely hypothesis is that a set of FMS characteristics may lead to the onset of TMD symptoms and they are not merely coexisting conditions. Therefore, our aim is presenting a review of literature about the relation between fibromyalgia and the signs and symptoms of temporomandibular disorders. For this purpose, a bibliographic search was performed of the period of 1990-2013, in the Medline, Pubmed, Lilacs and Scielo databases, using the keywords fibromyalgia, temporomandibular disorders and facial pain. Here we present a set of findings in the literature showing that fibromyalgia can lead to TMD symptoms. These studies demonstrated greater involvement of the stomatognathic system in FMS and myogenic disorders of masticatory system are the most commonly found in those patients. FMS appears to have a series of characteristics that constitute predisposing and triggering factors for TMD. PMID- 25440697 TI - [Additive effect of zoledronic acid and alfacalcidol in the treatment of disuse osteoporosis in rats]. AB - OBJECTIVES: Disuse by bed rest, limb immobilization or space flight causes rapid bone loss. We conducted the present study to investigate the therapeutic effects of zoledronic acid (ZOL), alone and in combination with alfacalcidol (ALF) in a rat model of disuse osteoporosis. METHODS: In the present study, 3-month-old male Wistar rats had their right hind-limb immobilized (RHLI) for 10 weeks to induce osteopenia, then were divided into four groups: 1- RHLI positive control; 2- RHLI plus ZOL (50 MUg/kg, i.v. single dose); 3- RHLI plus ALF (0.5 MUg/kg, oral gauge daily); 4- RHLI plus ALF (0.5 MUg/kg, oral gauge daily) plus ZOL (50 MUg/kg, i.v. single dose) for another 10 weeks. One group of non-immobilized rats was used as negative control. At the end of the treatment, the femurs were removed and tested for bone porosity, bone mechanical properties, and bone dry and ash weight. RESULTS: Combination therapy with ZOL plus ALF was more effective in decreasing bone porosity than each drug administered as monotherapy in RHLI rats. With respect to improvement in the mechanical strength of the femoral mid-shaft, the combination treatment of ZOL plus ALF was more effective than each drug administered as a monotherapy. Moreover, combination therapy using ZOL plus ALF was more effective in improving dry bone and ash weight, than single-drug therapy using ZOL or ALF in RHLI rats. CONCLUSIONS: These data suggest that combination therapy with ZOL plus ALF represents a potentially useful therapeutic option for the treatment of disuse osteoporosis. PMID- 25440698 TI - [Infliximab is effective in difficult-to-control peripheral ulcerative keratitis. A report of three cases]. AB - Peripheral ulcerative keratitis is caused by an inflammatory and destructive process of the perilimbal peripheral cornea. This inflammation is due to immune complex deposition in this region of the cornea and in adjacent vessels. It can be idiopathic, or a manifestation of systemic disease such as rheumatoid arthritis, vasculitis of small vessels associated with ANCA, relapsing polychondritis, systemic lupus erythematosus and Crohn's disease. Its treatment includes the use of high-dose corticosteroids and, in some cases, the concomitant use of immunosuppressants such as methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide or cyclosporine. The use of immunobiological agents can be a strategy in cases of difficult control. The authors describe the treatment of three patients who, after failure with the use of corticosteroids or immunosuppressants, showed good response after the use of infliximab. PMID- 25440699 TI - [Occupational therapy in rheumatoid arthritis: what rheumatologists need to know?]. AB - Interventions focusing on education and self-management of rheumatoid arthritis (RA) by the patient improves adherence and effectiveness of early treatment. The combination of pharmacologic and rehabilitation treatment aims to maximize the possibilities of intervention, delaying the appearance of new symptoms, reducing disability and minimizing sequelae, decreasing the impact of symptoms on patient's functionality. Occupational therapy is a health profession that aims to improve the performance of daily activities by the patient, providing means for the prevention of functional limitations, adaptation to lifestyle changes and maintenance or improvement of psychosocial health. Due to the systemic nature of RA, multidisciplinary follow-up is necessary for the proper management of the impact of the disease on various aspects of life. As a member of the health team, occupational therapists objective to improve and maintaining functional capacity of the patient, preventing the progression of deformities, assisting the process of understanding and coping with the disease and providing means for carrying out the activities required for the engagement of the individual in meaningful occupations, favoring autonomy and independence in self-care activities, employment, educational, social and leisure. The objective of this review is to familiarize the rheumatologist with the tools used for assessment and intervention in occupational therapy, focusing on the application of these principles to the treatment of patients with RA. PMID- 25440704 TI - [Nailfold capillaroscopy: relevance to the practice of rheumatology]. AB - Nailfold capillaroscopy is a simple, low-cost method, that is extremely important in the evaluation of patients with Raynaud's phenomenon and of patients with systemic sclerosis (SSc) spectrum diseases. Besides its importance for the early diagnosis of SSc, nailfold capillaroscopy is a useful tool to identify scleroderma patients with high risk for development of vascular and visceral complications and death. The inclusion of capillaroscopy in the new classification criteria for SSc of the American College of Rheumatology (ACR) and European League Against Rheumatism (Eular) gives a new impetus to the use and dissemination of the method. In this paper, we present a didactic, non-systematic review on the subject, with emphasis on advances recently described. PMID- 25440700 TI - [Factors associated with osteopenia and osteoporosis in women undergoing bone mineral density test]. AB - The aim of this study was to determine the prevalence of osteopenia and osteoporosis in a female population, that had bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) in a specialized clinic in the south of Brazil. We conducted a cross-sectional study including 1,871 women that performed scans between January and December 2012. We conducted a logistic regression analysis with all independent variables and outcomes (osteopenia, osteoporosis and fracture risk). According to DXA results, 36.5% of women had normal BMD, 49.8% were diagnosed with osteopenia and 13.7% with osteoporosis. Menopause and age over 50 years old were risk factors for osteopenia and osteoporosis while prior hysterectomy and BMI greater than 25 were protective factors. For the outcome of fracture at any site the risk factors were age over 50 years old, osteopenia and osteoporosis (OR = 2.09, 95% CI:1,28-3, 40) and (OR = 2.49, 95% CI:1,65-3, 74), respectively. PMID- 25440705 TI - [Comparison of the Disease Activity Score-28 and Juvenile Arthritis Disease Activity Score in the juvenile idiopathic arthritis]. AB - INTRODUCTION: the assessment of the activity of rheumatoid arthritis and juvenile idiopathic arthritis is made by means of different tools, respectively DAS-28 and JADAS. OBJECTIVE: To compare DAS-28 and JADAS with scores of 71, 27 and 10 joint counts in juvenile idiopathic arthritis. METHOD: A secondary analysis of a phase III placebo-controlled trial, testing safety and efficacy of abatacept was conducted in 8 patients with 178 assessment visits. Joint count scores for active and limited joints, physician's and parents' global assessment by 0-10cm Visual Analog Scale, and erythrocyte sedimentation rate normalized to 0-10 scale, in all visits. The comparison among the activity indices in different observations was made through Anova or adjusted gamma model. The paired observations between DAS 28 and JADAS 71, 27 and 10, respectively, were analyzed by linear regression. RESULTS: There were significant differences among individual measures, except for ESR, in the first four months of biological treatment, when five of the eight patients reached ACR-Pedi 30, with improvement. The indices of DAS-28, JADAS 71, 27 and 10 also showed significant difference during follow-up. Linear regression adjusted model between DAS-28 and JADAS resulted in mathematical formulas for conversion: [DAS-28=0.0709 (JADAS 71)+1.267] (R(2)=0.49); [DAS-28=0.084 (JADAS 27) +1.7404] (R(2)=0.47) and [DAS-28=0.1129 (JADAS-10) +1.5748] (R(2)=0.50). CONCLUSION: The conversion of scores of DAS-28 and JADAS 71, 27 and 10 for this mathematical model would allow equivalent application of both in adolescents with arthritis. PMID- 25440706 TI - Effects of muscle stretching exercises in the treatment of fibromyalgia: a systematic review. AB - OBJECTIVE: This study has the objective to systematize scientific evidences about the use of muscle stretching exercises in the treatment of FM. METHODOLOGY: It was performed from retrospective research without chronological and linguistic limits, at databases of MEDLINE, LILACS, SciELO and PEDro, as well as at PubMed search tool. Data collection was performed by two independent reviewers in October 2012, with the search strategy formulated by crossing descriptors and relevant terms to the topic in English, Portuguese and Spanish languages. Randomized clinical trials, only with patients with a clinical diagnosis of fibromyalgia and muscle stretching exercises as a therapeutic measure at least in one of the intervention groups were included. Included studies were assessed for methodological quality using PEDro scale and their references analyzed to highlight additional sources. The search amounted to an average of 6,794 items. Only five articles were selected, one being excluded because of its low methodological quality. Pain was assessed unanimously. The method and timing of interventions varied widely, there was poor mention of the parameters used in the stretches and absence of specific physical examinations. RESULTS: There was significant improvement in all studies regarding pain, besides as related to quality of life and physical condition. CONCLUSION: It is clear the importance of muscle stretching in the treatment of FM, however, there is a need for further studies to establish the real benefits of the technique, because the majority of published studies shows low methodological quality and there is a lack of standardization regarding the use of this resource. PMID- 25440707 TI - Intensity of anticoagulation in the treatment of thrombosis in the antiphospholipid syndrome: a meta-analysis. AB - INTRODUCTION: Discussion about the intensity of warfarin in patients with antiphospholipid syndrome (APS) remains present in our days. OBJECTIVES: To evaluate which intensity of anticoagulation with warfarin is associated with a greater reduction of thromboembolic events in the treatment of patients with APS, as well as assess the risk of bleeding in the different treatment modalities. METHODOLOGY: A systematic review of the literature was carried out with search from electronic databases: PubMed, LILACS and SciELO, with the use of the key words: treatment, warfarin, antiphospholipid syndrome, antiphospholipid antibody syndrome and their respective translations into Portuguese, in different combinations. In addition, a meta-analysis with the aid of Review Manager 5.2 software by Cochrane was performed. RESULTS: Only two articles met the inclusion criteria for this study. Regarding the main outcome assessed in this study, the two studies showed similar values, indicating higher frequency of thrombotic events in high-intensity groups. The comparative analysis of the randomized clinical trial evaluated showed an increased thrombotic risk for those patients who received intervention with high-intensity warfarin. Another finding of the meta-analysis was the higher incidence of minor bleeding, also in the experimental group, that received warfarin keeping International Normalized Ratio (INR) > 3. CONCLUSION: In individuals with APS and prevalence of venous events, the use of moderate intensity (MI) anticoagulation (INR: 2-3) is the most suitable. However, this evidence cannot yet be extended to patients with arterial events, due to the limited representation of this sample of subjects in the two clinical trials included in this meta-analysis. PMID- 25440708 TI - [Possible changes in energy-minimizer mechanisms of locomotion due to chronic low back pain - a literature review]. AB - One goal of the locomotion is to move the body in the space at the most economical way possible. However, little is known about the mechanical and energetic aspects of locomotion that are affected by low back pain. And in case of occurring some damage, little is known about how the mechanical and energetic characteristics of the locomotion are manifested in functional activities, especially with respect to the energy-minimizer mechanisms during locomotion. This study aimed: a) to describe the main energy-minimizer mechanisms of locomotion; b) to check if there are signs of damage on the mechanical and energetic characteristics of the locomotion due to chronic low back pain (CLBP) which may endanger the energy-minimizer mechanisms. This study is characterized as a narrative literature review. The main theory that explains the minimization of energy expenditure during the locomotion is the inverted pendulum mechanism, by which the energy-minimizer mechanism converts kinetic energy into potential energy of the center of mass and vice-versa during the step. This mechanism is strongly influenced by spatio-temporal gait (locomotion) parameters such as step length and preferred walking speed, which, in turn, may be severely altered in patients with chronic low back pain. However, much remains to be understood about the effects of chronic low back pain on the individual's ability to practice an economic locomotion, because functional impairment may compromise the mechanical and energetic characteristics of this type of gait, making it more costly. Thus, there are indications that such changes may compromise the functional energy minimizer mechanisms. PMID- 25440709 TI - [Nephrotic syndrome as the first manifestation of juvenile systemic scleroderma.] AB - Renal involvement occurs in 1%-12% in juvenile systemic sclerosis (JSSc) patients, mainly with arterial hypertension, proteinuria and scleroderma renal crisis. We report herein a patient who presented nephrotic syndrome (NS) as the first manifestation of JSSc with focal segmental glomerulosclerosis (FSGS). A female patient presented steroid-sensitive NS at the age of 12 years. At 14 years, she had orbital and lower limbs edema, arterial hypertension, sclerodactyly and proximal skin sclerosis. Moderate capillary dilation and mild focal devascularization were observed in nailfold capillaroscopy, compatible with early stage of scleroderma (scleroderma pattern). Percutaneous renal biopsy guided by ultrasound revealed focal segmental glomerulosclerosis and direct immunofluorescence were negative. Therefore, she fullfilled the provisional classification criteria for JSSc. Patient was treated with oral 25-hydroxyvitamin D (800 IU/day), methotrexate (0.5mg/kg/week) and amlodipin (0.15 mg/kg). Prednisone (60 mg/m2/day) was administered for 4 consecutive weeks, followed by alternate-day (40mg/m2) for 2 consecutive months, with tapering for 4 months and then stopping this medication. Currently she is being treated with methotrexate 15 mg/week, without edema and proteinuria. In conclusion, we reported a rare case of NS with FSGS as the first manifestation of scleroderma. Therefore, renal biopsy is mandatory in JSSc patients with sustained proteinuria or NS. PMID- 25440710 TI - Leptin and adiponectin in patients with systemic lupus erythematosus: clinical and laboratory correlations. AB - OBJECTIVE: To evaluate the serum levels of leptin and adiponectin in patients with systemic lupus erythematosus (SLE) and correlate their levels with disease activity, presence of autoantibodies and clinical manifestations. METHODS: 52 women with SLE and 33 healthy women were evaluated. The patients were divided into two groups, the first with active SLE and the second with inactive SLE. Patients with SLEDAI >=3 were considered active. Serum levels of leptin (ng/ml) and adiponectin (MUg/ml) were measured by enzyme immunoassay. RESULTS: There was a significant difference in leptin levels between SLE and controls (20.7 +/- 17.1 vs. 8.0 +/- 5.0 ng/mL, P <0.001), but no significant difference in adiponectin levels (87.5 +/- 69.7 vs. 118.1 +/- 70.6 pg/ml, P = 0.053). No significant difference in levels of leptin and adiponectin was noted between inactive and active SLE groups. There was a significant association between low levels of leptin and positivity for anticardiolipin (aCL) (P = 0.025) and lupus anticoagulant (LA) (p = 0.003) and a significant association between high levels of leptin and the presence of renal disease (p <0.001). However, there was no association between adiponectin levels with autoantibodies and clinical features in SLE patients. CONCLUSION: Patients with SLE had elevated leptin levels, with association with renal involvement. Leptin and adiponectin were not correlated with disease activity. Low levels of leptin have been associated with the presence of LA and aCL. PMID- 25440711 TI - Meanings of the sickening process for patients with systemic lupus erythematosus: a review of the literature. AB - Systemic lupus erythematosus is an autoimmune disease that causes many psychological repercussions that have been studied through qualitative research. These are considered relevant, since they reveal the amplitude experienced by patients. Given this importance, this study aims to map the qualitative production in this theme, derived from studies of experiences of adult patients of both genders and that had used as a tool a semi-structured interview and/or field observations, and had made use of a sampling by a saturation criterion to determine the number of participants in each study. The survey was conducted in Pubmed, Lilacs, Psycinfo e Cochrane databases, searching productions in English and Portuguese idioms published between January 2005 and June 2012. The 19 revised papers that have dealt with patients in the acute phase of the disease showed themes that were categorized into eight topics that contemplated the experienced process at various stages, from the onset of the disease, extending through the knowledge of the diagnosis and the understanding of the manifestations of the disease, drug treatment and general care, evolution and prognosis. The collected papers also point to the difficulty of understanding, of the patients, on what consists the remission phase, revealing also that this is a clinical stage underexplored by psychological studies. PMID- 25440712 TI - Relapsing polychondritis with severe hearing loss. AB - Relapsing polychondritis is an uncommon, immune-mediated condition characterized by episodes of inflammation of cartilaginous structures, especially the ears, nose, joints and respiratory tract. RP also affects proteoglycan-rich structures such as the eyes, heart, blood vessels and inner ear. Around one third of cases are associated with other diseases such as vasculitides, connective tissue diseases or myelodysplastic syndrome. Disorders of the inner ear occur in 40-50% of patients. Profound hearing loss is rare. The aim of this study was to describe the case of a patient with relapsing polychondritis associated with severe bilateral hearing loss and clinical manifestations of systemic vasculitis. This study reinforces the importance of an early diagnosis and immediate treatment in case of severe manifestations of the disease. PMID- 25440713 TI - Exploring the potential of small RNA subunit and ITS sequences for resolving phylogenetic relationships within the phylum Ctenophora. AB - Ctenophores are a phylum of non-bilaterian marine (mostly planktonic) animals, characterised by several unique synapomorphies (e.g., comb rows, apical organ). Relationships between and within the nine recognised ctenophore orders are far from understood, notably due to a paucity of phylogenetically informative anatomical characters. Previous attempts to address ctenophore phylogeny using molecular data (18S rRNA) led to poorly resolved trees but demonstrated the paraphyly of the order Cydippida. Here we compiled an updated 18S rRNA data set, notably including a few newly sequenced species representing previously unsampled families (Lampeidae, Euryhamphaeidae), and we constructed an additional more rapidly evolving ITS1 + 5.8S rRNA + ITS2 alignment. These data sets were analysed separately and in combination under a probabilistic framework, using different methods (maximum likelihood, Bayesian inference) and models (e.g., doublet model to accommodate secondary structure; data partitioning). An important lesson from our exploration of these datasets is that the fast-evolving internal transcribed spacer (ITS) regions are useful markers for reconstructing high-level relationships within ctenophores. Our results confirm the paraphyly of the order Cydippida (and thus a "cydippid-like" ctenophore common ancestor) and suggest that the family Mertensiidae could be the sister group of all other ctenophores. The family Lampeidae (also part of the former "Cydippida") is probably the sister group of the order Platyctenida (benthic ctenophores). The order Beroida might not be monophyletic, due to the position of Beroe abyssicola outside of a clade grouping the other Beroe species and members of the "Cydippida" family Haeckeliidae. Many relationships (e.g. between Pleurobrachiidae, Beroida, Cestida, Lobata, Thalassocalycida) remain unresolved. Future progress in understanding ctenophore phylogeny will come from the use of additional rapidly evolving markers and improvement of taxonomic sampling. PMID- 25440714 TI - Membrane pore formation at protein-lipid interfaces. AB - Pore-forming proteins (PFPs) interact with lipid bilayers to compromise membrane integrity. Many PFPs function by inserting a ring of oligomerized subunits into the bilayer to form a protein-lined hydrophilic channel. However, mounting evidence suggests that PFPs can also generate 'proteolipidic' pores by contributing to the fusion of inner and outer bilayer leaflets to form a toroidal structure. We discuss here toroidal pore formation by peptides including melittin, protegrin, and Alzheimer's Abeta1-41, as well as by PFPs from several evolutionarily unrelated families: the colicin/Bcl-2 grouping including the pro apoptotic protein Bax, actinoporins derived from sea anemones, and the membrane attack complex-perforin/cholesterol dependent cytolysin (MACPF/CDC) set of proteins. We also explore how the structure and biological role of toroidal pores might be investigated further. PMID- 25440715 TI - Ice-binding proteins: a remarkable diversity of structures for stopping and starting ice growth. AB - Antifreeze proteins (AFPs) were discovered in marine fishes that need protection from freezing. These ice-binding proteins (IBPs) are widespread across biological kingdoms, and their functions include freeze tolerance and ice adhesion. Consistent with recent independent evolution, AFPs have remarkably diverse folds that rely heavily on hydrogen- and disulfide-bonding. AFP ice-binding sites are typically flat, extensive, relatively hydrophobic, and are thought to organize water into an ice-like arrangement that merges and freezes with the quasi-liquid layer next to the ice lattice. In this article, the roles, properties, and structure-function interactions of IBPs are reviewed, and their relationship to ice nucleation proteins, which promote freezing at high subzero temperatures, is explored. PMID- 25440716 TI - Ultrasensitivity part II: multisite phosphorylation, stoichiometric inhibitors, and positive feedback. AB - In this series of reviews, we are examining ultrasensitive responses, the switch like input-output relationships that contribute to signal processing in a wide variety of signaling contexts. In the first part of this series, we explored one mechanism for generating ultrasensitivity, zero-order ultrasensitivity, where the saturation of two converting enzymes allows the output to switch from low to high over a tight range of input levels. In this second installment, we focus on three conceptually distinct mechanisms for ultrasensitivity: multisite phosphorylation, stoichiometric inhibitors, and positive feedback. We also examine several related mechanisms and concepts, including cooperativity, reciprocal regulation, coherent feed-forward regulation, and substrate competition, and provide several examples of signaling processes where these mechanisms are known or are suspected to be applicable. PMID- 25440718 TI - Peer victimization predicts psychological symptoms beyond the effects of child maltreatment. AB - Experiences of peer victimization have been repeatedly associated with psychological symptoms and disorders. However, as peer victimization is correlated with child maltreatment occurring within the family, it remains unclear whether the pathological effect of peer victimization is an artifact that can be attributed to previous aversive events. To separate the effects of peer victimization from child maltreatment, we studied both event types as well as psychological symptoms in a mixed clinical sample of ambulant and psychiatric patients (N=168), a self-selected community sample recruited through the internet (N=995), and a student sample (N=272). Hierarchical regression analyses showed that, after controlling for child maltreatment, peer victimization accounted for an incremental proportion of the variance of different symptom dimensions in each sample. These results indicate that peer victimization is an independent predictor of psychopathology. PMID- 25440717 TI - Urea retranslocation from senescing Arabidopsis leaves is promoted by DUR3 mediated urea retrieval from leaf apoplast. AB - In plants, urea derives either from root uptake or protein degradation. Although large quantities of urea are released during senescence, urea is mainly seen as a short-lived nitrogen (N) catabolite serving urease-mediated hydrolysis to ammonium. Here, we investigated the roles of DUR3 and of urea in N remobilization. During natural leaf senescence urea concentrations and DUR3 transcript levels showed a parallel increase with senescence markers like ORE1 in a plant age- and leaf age-dependent manner. Deletion of DUR3 decreased urea accumulation in leaves, whereas the fraction of urea lost to the leaf apoplast was enhanced. Under natural and N deficiency-induced senescence DUR3 promoter activity was highest in the vasculature, but was also found in surrounding bundle sheath and mesophyll cells. An analysis of petiole exudates from wild-type leaves revealed that N from urea accounted for >13% of amino acid N. Urea export from senescent leaves further increased in ureG-2 deletion mutants lacking urease activity. In the dur3 ureG double insertion line the absence of DUR3 reduced urea export from leaf petioles. These results indicate that urea can serve as an early metabolic marker for leaf senescence, and that DUR3-mediated urea retrieval contributes to the retranslocation of N from urea during leaf senescence. PMID- 25440719 TI - Ovarian tumors and tumor-like lesions in the first three decades. AB - The relative frequency of ovarian tumors and tumor-like lesions that occur in young females (defined in this article as up to 30 years of age) differs considerably from that seen in older patients. The spectrum of lesions encountered is reviewed, with emphasis on those disproportionately seen in younger patients, particularly primitive germ cell tumors, certain tumors in the sex cord-stromal family, the distinctive tumor known as small cell carcinoma of hypercalcemic type, and selected tumor-like lesions. Comments are made initially on the relative frequency of the various well-known categories of ovarian neoplasia in the first three decades, compared to females overall, and differences within the first three decades are noted. Some of the more noteworthy of these include the occurrence of follicular cysts in neonates due to in-utero maternal stimulation, and the often large size of these lesions, with sometimes dramatic clinical manifestations; the relative rarity of the commonest germ cell tumor of the ovary, the dermoid cyst, in the very early years of life; the peak incidence of all primitive germ cell tumors in the mid to late teens and early 20s; the peak of small cell carcinoma of hypercalcemic type in the early 20s; the preponderance for the juvenile granulosa cell tumor to occur in the first two decades and for one distinctive form of Sertoli-Leydig cell tumor, the retiform variant, to peak at about 15 years of age; the occasional finding of mucinous cystic tumors, usually benign, in the teenage years, and their greater frequency than other surface epithelial neoplasms; a gradual increase in frequency of all types of surface epithelial neoplasia, but particularly mucinous tumors and serous tumors as patients move through the 20s; and the rarity of metastatic neoplasia in the first three decades in general, but with occasional dramatic examples such as some Krukenberg tumors being seen in these years, as may some of the distinctive tumors of the young such as neuroblastoma. Consideration of the gross and microscopic features, and differential diagnosis, of individual neoplasms follows the introductory remarks and emphasizes the importance of gross pathology. An example of the latter is the marked difference in most cases between a dermoid cyst and an immature teratoma, the former being dominantly cystic and the latter dominantly solid, and the latter on average twice as large as the former. Caution should be exercised in entertaining a diagnosis of immature teratoma if a lesion is grossly a typical dermoid cyst. The treacherous shared gross characteristics and age distribution of the dysgerminoma and small cell carcinoma of hypercalcemic type are noted. The rarity of monodermal teratomas and malignant neoplasms such as squamous cell carcinoma arising in dermoid cysts in the first three decades is noted. The distinctive features of two recently described stromal neoplasms, microcystic stromal tumor and luteinized thecomas of the type associated with sclerosing peritonitis, are emphasized as is the varied differential diagnosis of the juvenile granulosa cell tumor and Sertoli-Leydig cell tumor. Sections on ovarian tumors and tumor-like lesions in pregnant patients and tumor-like lesions overall conclude the article. PMID- 25440720 TI - Testicular and paratesticular tumors and tumor-like lesions in the first 2 decades. AB - The spectrum of testicular tumors and tumor-like lesions that affect young patients (defined for purposes of this article as less than 20 years old) differs significantly from that in an older age group. Although germ cell tumors remain the single largest category, they are a smaller proportion than in adults. Furthermore the pathogenesis and behavior of comparably named germ cell tumors differ depending on whether or not they have developed in prepubertal or postpubertal patients. This is most apparent for the teratomas, which are almost uniformly benign in children but, with some notable exceptions, malignant in the older patients. But even the most common malignant tumor of the testis in children, the yolk sac tumor, despite its identical morphology, lacks the association with other germ cell tumor types, including intratubular germ cell neoplasia, and more aggressive behavior that typify the adult tumors. Among the sex cord-stromal tumors, the juvenile granulosa cell tumor predominates in children, mostly occurs in those under 1-year old, and, for all intents and purposes, is not seen in the postpubertal period. It has a distinctive morphology and, to date, a uniformly benign outcome. There are additional tumors in the sex cord-stromal group that are mostly seen in young patients, including the large cell calcifying Sertoli cell tumor and intratubular large cell hyalinizing Sertoli cell neoplasia. The former is sometimes associated with the Carney syndrome and, to date, all of the latter with the Peutz-Jeghers syndrome. The subtypes of lymphomas and leukemias that involve the testis in children are rare in older patients, and similar remarks pertain to the metastatic tumors, where neuroblastoma (especially) and Wilms' tumor are most common but may be mimicked by primary tumors originating in the paratestis. The pseudoneoplastic lesion, the testicular "tumor" of the adrenogenital syndrome, is usually found in young patients and bears a strong resemblance to the Leydig cell tumor, although there are features that allow its distinction, which is important given its frequently bilateral nature and amenability to medical management through glucocorticoid administration. One of the preferential sites for embryonal rhabdomyosarcoma is the paratestis of young patients, where the spindle cell variant predominates. The melanotic neuroectodermal tumor (retinal anlage tumor) usually occurs in the first year of life, typically involves the epididymis, and uncommonly metastasizes. Occasional cases of the desmoplastic small round cell tumor present in the paratestis of teenagers, and some distinctive tumor-like lesions of the paratestis may also be seen, including meconium periorchitis and splenic-gonadal fusion (occupying both testis and paratestis). These tumors and tumor-like lesions and many others are discussed in this review with the hope it will provide the diagnostic pathologist aid in recognizing the lesions and providing some insight into their clinical significance. PMID- 25440721 TI - Introduction. PMID- 25440722 TI - Quantitative polymerase chain reaction for detection of human herpesvirus-7 infection in umbilical cord blood donors. AB - OBJECTIVE: Umbilical cord blood (UCB) has been a reasonable alternative to granulocyte colony-stimulating factor-mobilized peripheral blood or bone marrow, as a source of hematopoietic stem cells with a lower risk of graft-versus-host disease. In immunocompromised hosts after transplantation, the risk of viral infection in adults, especially with beta-herpesviruses such as human herpesvirus 7 (HHV-7), may be increased. This virus in immunocompromised patients can be reactivated from latency and converted to an active phase. Therefore, light-upon extension real-time polymerase chain reaction (PCR) was developed to assess the prevalence and load of HHV-7 in the plasma and buffy coat of donors. METHODS: About 825 UCB samples under standard protocol from donors were collected. Then, DNA from plasma and buffy coat was extracted and quantitative real-time PCR was performed with light-upon-extension primers. RESULTS: Overall, HHV-7 was detected in 3.64% (30/825) of UCB donors. HHV-7 DNA was detected in 26 (3.2%) buffy coat samples (latent infection), and only 4 (0.48%) of them were positive for HHV-7 DNA in plasma samples (active infection); the mean HHV-7 viral load was 1.31 * 10(1) copies/mL in latent infection, and 1.94 * 10(5) copies/mL in active infection. CONCLUSIONS: We suggest that real-time PCR in plasma and buffy coat could be a useful method to detect active and latent HHV-7 infection in UCB donors and determine its role in subsequent transmission events. PMID- 25440723 TI - The association between depression, weight loss and leptin/ghrelin levels in male patients with head and neck cancer undergoing radiotherapy. AB - OBJECTIVE: This study investigated the relationship between weight loss, depression and anxiety, and appetite hormones, leptin and ghrelin levels in patients with head and neck cancer (HNC), as well as the effect of radiotherapy and antidepressant treatment on weight and these hormones. METHODS: Forty male patients with HNC and twenty physically and mentally healthy male controls were recruited for the study. Psychiatric status was evaluated with clinical interview and psychometric tests. All patients received radiotherapy and antidepressant treatment with mirtazapine that was given to patients with psychiatric disorders. Serum leptin and ghrelin levels were measured pre- and post-treatment in the patients and once in the controls. RESULTS: There was no significant difference between the serum leptin and ghrelin levels of patients and controls. The leptin levels of the patients were decreased by radiotherapy. Eleven patients were diagnosed with major depressive disorder and adjustment disorder and were classed as depressive patients. Depressive patients were affected more by radiotherapy with respect to weight loss. The basal leptin levels of depressive patients were also lower than non-depressive patients and controls. CONCLUSION: It seems that depression aggravated weight loss and, in addition, decreased leptin levels in cancer patients. Detection and treatment of psychiatric disorders may improve prognosis by preventing weight loss as well as by providing psychiatric treatment in cancer patients. PMID- 25440724 TI - Individual risk factors for physician boundary violations: the role of attachment style, childhood trauma and maladaptive beliefs. AB - OBJECTIVE: The assessment and remediation of boundary-challenged health care professionals is enhanced through examination of individual risk factors. We assessed three such factors - attachment style, childhood trauma and maladaptive beliefs - in 100 attendees (mostly physicians) of a continuing medical education (CME) professional boundaries course. We propose a theoretical model that draws a causal arc from childhood maltreatment through insecure attachment and maladaptive beliefs to elevated risk for boundary violations. METHODS: We administered the Experiences in Close Relationships Questionnaire Revised (ECR R), Childhood Trauma Questionnaire (CTQ) and Young Schema Questionnaire (YSQ) to 100 health care professionals attending a CME course on professional boundaries. Experts rated participant autobiographies to determine attachment style and early adversities. Correlations and relationships between self-ratings and expert ratings and among different risk factors were examined. RESULTS: One fifth of participants reported moderate to severe childhood abuse; sixty percent reported moderate to severe emotional neglect. Despite this, average attachment anxiety and attachment avoidance were low, and more than half of participants were rated "secure" by experts. Childhood maltreatment was correlated with attachment anxiety and avoidance and predicted expert-rated insecure attachment and maladaptive beliefs. CONCLUSIONS: Our findings support a potential link between childhood adversity and boundary difficulties, partly mediated by insecure attachment and early maladaptive beliefs. Furthermore, these results suggest that boundary education programs and professional wellness programs may be enhanced with a focus on sequelae of childhood maltreatment, attachment and common maladaptive thinking patterns. PMID- 25440725 TI - Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate the efficacy of coenzyme Q10 (CoQ10) supplementation on statin-induced myopathy. PARTICIPANTS AND METHODS: We searched the MEDLINE, Cochrane Library, Scopus, and EMBASE databases (November 1, 1987, to May 1, 2014) to identify randomized controlled trials investigating the impact of CoQ10 on muscle pain and plasma creatine kinase (CK) activity as 2 measures of statin induced myalgia. Two independent reviewers extracted data on study characteristics, methods, and outcomes. RESULTS: We included 6 studies with 302 patients receiving statin therapy: 5 studies with 226 participants evaluated the effect of CoQ10 supplementation on plasma CK activity, and 5 studies (4 used in the CK analysis and 1 other study) with 253 participants were included to assess the effect of CoQ10 supplementation on muscle pain. Compared with the control group, plasma CK activity was increased after CoQ10 supplementation, but this change was not significant (mean difference, 11.69 U/L [to convert to MUkat/L, multiply by 0.0167]; 95% CI, -14.25 to 37.63 U/L; P=.38). Likewise, CoQ10 supplementation had no significant effect on muscle pain despite a trend toward a decrease (standardized mean difference, -0.53; 95% CI, -1.33 to 0.28; P=.20). No dose-effect association between changes in plasma CK activity (slope, -0.001; 95% CI, -0.004 to 0.001; P=.33) or in the indices of muscle pain (slope, 0.002; 95% CI, -0.005 to 0.010; P=.67) and administered doses of CoQ10 were observed. CONCLUSION: The results of this meta-analysis of available randomized controlled trials do not suggest any significant benefit of CoQ10 supplementation in improving statin-induced myopathy. Larger, well-designed trials are necessary to confirm the findings from this meta-analysis. PMID- 25440726 TI - Non-anti-infective effects of antimicrobials and their clinical applications: a review. AB - Antimicrobial agents are undoubtedly one of the key advances in the history of modern medicine and infectious diseases, improving the clinical outcomes of infection owing to their inhibitory effects on microbial growth. However, many antimicrobial agents also have biological activities stemming from their interactions with host receptors and effects on host inflammatory responses and other human or bacterial cellular biological pathways. These result in clinical uses of antimicrobial drugs that are distinct from their direct bacteriostatic or bactericidal properties. We reviewed the published literature regarding non-anti infective therapeutic properties and proposed clinical applications of selected antimicrobials, specifically, macrolides, tetracyclines, sulfonamides, and ketoconazole. The clinical applications reviewed were varied, and we focused on uses that were clinically relevant (in terms of importance and burden of disease) and where published evidence exists. Such uses include chronic inflammatory pulmonary and skin disorders, chronic periodontitis, gastrointestinal dysmotility, rheumatoid arthritis, and cancer. Most of these potential therapeutic uses are not Food and Drug Administration approved. Clinicians need to weigh the use of antimicrobial agents for their non-anti-infective benefits, considering potential adverse effects and long-term effect on microbial resistance. PMID- 25440727 TI - Sudden cardiac death from the perspective of coronary artery disease. AB - Sudden cardiac death accounts for approximately 50% of all deaths attributed to cardiovascular disease in the United States. It is most commonly associated with coronary artery disease and can be its initial manifestation or may occur in the period after an acute myocardial infarction. Decreasing the rate of sudden cardiac death requires the identification and treatment of at-risk patients through evidence-based pharmacotherapy and interventional strategies aimed at primary and secondary prevention. For this review, we searched PubMed for potentially relevant articles published from January 1, 1970, through March 1, 2014, using the following key search terms: sudden cardiac death, ischemic heart disease, coronary artery disease, myocardial infarction, and cardiac arrest. Searches were enhanced by scanning bibliographies of identified articles, and those deemed relevant were selected for full-text review. This review outlines various mechanisms for sudden cardiac death in the setting of coronary artery disease, describes risk factors for sudden cardiac death, explores the management of cardiac arrest, and outlines optimal practice for the monitoring and treatment of patients after an acute ST-segment elevation myocardial infarction to decrease the risk of sudden death. PMID- 25440728 TI - Phosphorylation regulates fibrillation of an aggregation core peptide in the second repeat of microtubule-binding domain of human tau. AB - Hyperphosphorylation of the microtubule-associated protein tau is believed to play a crucial role in the neurofibrillary tangles formation in Alzheimer's disease brain. In this study, fibril formation of peptides containing the critical sequences for tau aggregation VQIINK and a plausible serine phosphorylation site of tau at its C-terminal was investigated. All the peptides formed fibrils with the typical cross-b structural core. However, stability of the fibrils was highly sensitive to the pH conditions for the phosphorylated VQIINK peptide, suggesting a regulatory role of phosphorylation for the amyloid formation of tau. PMID- 25440729 TI - Synthesis and anticancer activity of quinopimaric and maleopimaric acids' derivatives. AB - A series of quinopimaric and maleopimaric acids' derivatives modified in the E ring, at the carbonyl- and carboxyl-groups were synthesized and their in vitro cytotoxic activity was evaluated at the National Cancer Institute, USA. Methyl esters of dihydroquinopimaric, 1a,4a-dehydroquinopimaric, 2,3-epoxyquinopimaric, 1-ethylenketal-dihydroquinopimaric, 1-ethylenketal-4 hydroxyiminodihydroquinopimaric acids displayed an activity on renal cancer, leukemia, colon cancer and breast cancer cell lines in concentration 10(-5) M. Methyl 1,4-dihydroxyiminodihydroquinopimarate showed both a potent and broad spectrum of cytotoxic activity against NSC lung cancer, colon cancer, breast cancer, renal cancer and leukemia and revealed in vivo antineoplastic activity towards mouse solid transplantable mammary carcinoma Ca755 and colon adenocarcinoma AKATOL. The information about antineoplastic activity of the studied quinopimaric and maleopimaric acids' derivatives will be used for hit to lead optimization in these chemical series. PMID- 25440731 TI - Microwave-assisted synthesis of phenanthroimidazole derivatives as stabilizer of c-myc G-quadruplex DNA. AB - c-myc G-quadruplex DNA, which plays a central role in tumor progression and resistance, has been extensively investigated as potential target of antitumor drugs. In this paper, a series of phenanthroimidazole derives have been synthesized under irradiation of microwave in yields of 51-80%. The antitumor activity of these compounds against various tumor cells has been evaluated, and the results show that these compounds exhibit great inhibition to MDA-MB-231, MCF 7 and Hela cells, especially 5 inhibit the growth of MDA-MB-231 cells with IC50 about 3.6 lM. The further studies show that 5 can bind and stabilize c-myc G4 DNA in p-p stacking mode, which confirmed by the hypochromise in the electronic spectra of 5 with the increasing of c-myc G4 DNA. When dealt with 5, the strength of CD signal attributed to c-myc G4 DNA is decreased and the FRET melting point of c-myc G4 DNA is increased. Moreover, the molecule docking calculation was conducted to show that 5 suitably stack onto the 50 G-quartet surface, and parallels to the surfaces of the G5 and G-quartet consisting of G7, G11, G16, and G20. As a result, the replication of c-myc oligomers is blocked by 5. In a word, this type of phenanthroimidazole derives can act as potential inhibitor against breast cancer cells by binding and stabilizing c-myc G4 DNA through p-p stacking. PMID- 25440730 TI - Synthesis and structure-activity relationships of small molecule inhibitors of the simian virus 40 T antigen oncoprotein, an anti-polyomaviral target. AB - Polyomavirus infections are common and relatively benign in the general human population but can become pathogenic in immunosuppressed patients. Because most treatments for polyomavirusassociated diseases nonspecifically target DNA replication, existing treatments for polyomavirus infection possess undesirable side effects. However, all polyomaviruses express Large Tumor Antigen (T Ag), which is unique to this virus family and may serve as a therapeutic target. Previous screening of pyrimidinone-peptoid hybrid compounds identified MAL2-11B and a MAL2-11B tetrazole derivative as inhibitors of viral replication and T Ag ATPase activity (IC50 of ~20-50 MUM. To improve upon this scaffold and to develop a structure-activity relationship for this new class of antiviral agents, several iterative series of MAL2-11B derivatives were synthesized. The replacement of a flexible methylene chain linker with a benzyl group or, alternatively, the addition of an ortho-methyl substituent on the biphenyl side chain in MAL2-11B yielded an IC50 of 50 MUM, which retained antiviral activity. After combining both structural motifs, a new lead compound was identified that inhibited T Ag ATPase activity with an IC50 of 50 MUM. We suggest that the knowledge gained from the structure-activity relationship and a further refinement cycle of the MAL2 11B scaffold will provide a specific, novel therapeutic treatment option for polyomavirus infections and their associated diseases. PMID- 25440732 TI - Synthesis of triazole Schiff bases: novel inhibitors of nucleotide pyrophosphatase/phosphodiesterase-1. AB - A series of Schiff base triazoles 1-25 was synthesized and evaluated for their nucleotide pyrophosphatase/phosphodiesterase-1 inhibitory activities. Among twenty-five compounds, three compounds 10 (IC50 = 132.20 +/- 2.89 lM), 13 (IC50 = 152.83 +/- 2.39 lM), and 22 (IC50 = 251.0 +/- 6.64 lM) were identified as potent inhibitors with superior activities than the standard EDTA (IC50 = 277.69 +/- 2.52 lM). The newly identified inhibitors may open a new avenue for the development of treatment of phosphodiesterase-I related disorders. These compounds were also evaluated for carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase inhibitory potential and were found to be inactive. The compounds showed non-toxic effect towards PC3 cell lines. PMID- 25440733 TI - Are dysfunctional attitudes and beliefs about sleep unique to primary insomnia? AB - OBJECTIVE: Dysfunctional thinking about sleep is a central aspect in the perpetuation of primary insomnia and a target symptom of cognitive behavioral therapy for insomnia (CBT-I). Insomnia symptoms also occur in other sleep disorders, but it is not known to what extent it is related to dysfunctional thinking about sleep. METHODS: The Dysfunctional Beliefs and Attitudes about Sleep Scale (DBAS) was administered to inpatients at a sleep center. The following groups were included: 34 patients with primary insomnia (PI), 30 patients with sleep apnea syndrome (SAS), 31 patients with restless legs syndrome (RLS), 26 patients with SAS comorbid with RLS (SAS + RLS), and 24 patients with idiopathic hypersomnia or narcolepsy. Eighty-four healthy subjects served as a control group. The DBAS scores were compared across the different sleep disorders and correlated with polysomnographic (PSG) variables, subjective sleep parameters, scores of the Beck Depression Inventory (BDI), and the Regensburg Insomnia Scale (RIS; measuring psychological symptoms of insomnia). RESULTS: Compared to healthy controls, DBAS scores were increased in PI, RLS and RLS + SAS. There was a low correlation between DBAS scores and PSG variables, moderate correlations between DBAS and subjective sleep parameters and BDI scores (r = 0.528), and a high correlation between DBAS and the RIS score (r = 0.603). CONCLUSION: The observation of increased DBAS scores in other sleep disorders besides primary insomnia underscores the usefulness of a broadened diagnostic procedure and suggests that CBT-I modules may be a complementary treatment tool for these disorders. PMID- 25440734 TI - Psychiatric collaborations in the Hispanic world. PMID- 25440737 TI - Contemporary thoughts on lower eyelid/midface aging. AB - Midfacial aging is a multifactorial, 3-D process that involves volume loss, volume descent, and skin alterations. Every anatomic component of the midface is affected. This article discusses the morphologic consequences of midfacial aging and reviews the salient literature relating to the numerous factors that contribute to an aged appearance of the lower eyelid and midface. PMID- 25440735 TI - Pharmacogenetic study of second-generation antipsychotic long-term treatment metabolic side effects (the SLiM Study): rationale, objectives, design and sample description. AB - AIM: Weight gain is an important and common side effect of second generation antipsychotics (SGAs). Furthermore, these drugs can induce other side effects associated with higher cardiovascular morbidity and mortality, such as insulin resistance, diabetes or metabolic syndrome. Preliminary studies show that inter individual genetic differences produce varying degrees of vulnerability to the different SGA-induced side effects. The Second-generation antipsychotic Long-term treatment Metabolic side effects (SLiM) study aims to identify clinical, environmental and genetic factors that explain inter-individual differences in weight gain and metabolic changes in drug-naive patients after six months of treatment with SGAs. MATERIALS AND METHODS: The SLIM study is a multicenter, observational, six-month pharmacogenetic study where a cohort of 307 drug-naive paediatric and adult patients (age range 8.8-90.1 years) and a cohort of 150 age- and sex- matched healthy controls (7.8-73.2 years) were recruited. RESULTS: This paper describes the rationale, objectives and design of the study and provides a description of the sample at baseline. CONCLUSIONS: Results from the SLiM study will provide a better understanding of the clinical, environmental, and genetic factors involved in weight gain and metabolic disturbances associated with SGA treatment. PMID- 25440736 TI - Comments about the differences in the number of suicide deaths in Spain. PMID- 25440738 TI - An algorithmic approach to multimodality midfacial rejuvenation using a new classification system for midfacial aging. AB - Midfacial aging is the result of the complex interplay between the osseous skeleton, facial retaining ligaments, soft tissues envelope, facial fat compartments, and the overlying skin elasticity. As a result of the many anatomic components involved in midfacial aging, the authors proposed a classification system based on distinct anatomic factors to direct surgical treatment. Evidence based data suggest that midface rejuvenation often requires a multimodality approach to obtain desired results, especially in patients with more advanced aging and poor tissue elasticity, or those with hypoplastic midfacial skeletal structure. PMID- 25440740 TI - Transconjunctival lower lid blepharoplasty with and without fat repositioning. AB - The transconjunctival approach to lower lid blepharoplasty provides access for both fat resection and transposition to soften tear trough deformities and correct infraorbital fat herniation. Overall, there is a paradigm shift that has focused more on enhancing lower lid-cheek shape and contour and preserving orbital volume PMID- 25440739 TI - Dark circles: etiology and management options. AB - Given their multifactorial nature and the fact that individual patients may have more than a single underlying cause, cosmetic practitioners should be well versed in a number of potential treatment options encompassing all facets of under-eye dark circles. New therapeutic options are also forthcoming. Longer-lasting HA fillers, wavelength tunable laser devices, and topicals speeding up healing and enhancing results after fractionated laser therapy will all serve to make the future of dark circle treatment unabatedly bright. PMID- 25440741 TI - Transcutaneous lower blepharoplasty with fat transposition. AB - Fat preservation lower lid blepharoplasty is the authors' preferred technique for surgical rejuvenation of the aging lower lid. Key technical refinements are overlaid on a conceptual framework developed over the past 2 decades by several investigators. The use of the orbicularis oculi muscle suspension flap is a useful adjunct to the transcutaneous approach to lower lid blepharoplasty. PMID- 25440742 TI - Complications of lower blepharoplasty and midface lifting. AB - Lower eyelid blepharoplasty and midface lifting share a complex anatomy, which should be mastered before attempting these types of surgeries. In recent years, there have been significant contributions to rejuvenating this area. A thorough understanding of the rejuvenative approaches and their outcomes is imperative. Thus, the problem must be preoperatively evaluated to offer the appropriate technique and minimize complications. PMID- 25440743 TI - Management of postblepharoplasty lower eyelid retraction. AB - Future advances in the treatment of lower eyelid retraction will likely focus on new synthetic graft materials that are inert and stable with minimal potential for reabsorption. Other advances may focus on biomodulating agents that reduce the risk of retraction at the time of cosmetic eyelid surgery or reverse existing exuberant scarring. Nonsurgical options are viable for modest cases, and these conservative measures may continue to improve, but, for severe retraction, surgery still offers the best promise of correction. PMID- 25440744 TI - Aesthetic canthal suspension. AB - Support of the lower eyelid with canthal suspension is a useful tool in the prevention of complications of lower blepharoplasty with particular relevance to eyelids with increased lower lid laxity, relatively prominent globes, and negative vector configuration of the eyelid-cheek junction. Caution is required in surgical management of this highly delicate anatomic area, as relatively small adjustments can result in relatively large changes that can alter the shape and appearance of the lower eyelids. Management options include canthopexy, orbicularis sling, and modified canthoplasty. The most conservative surgical management option is canthopexy, which supports the lower eyelid over either the short or long term. The use of the orbicularis sling technique avoids surgery around the relatively complex lateral canthus, but may not be suitable for cases without a need for a skin incision or a history of dry eye. Canthoplasty is generally reserved for more marked laxity, which is less common in the group of patients seeking aesthetic blepharoplasty. PMID- 25440745 TI - The management of festoons. AB - The management of patients with festoons is a highly challenging undertaking with potential to drastically alter the appearance of those afflicted. Traditional teaching has focused on excision and tightening of the pathologic muscle with subsequent removal of excess skin. Recognition of the interactions between all subunits of the face has resulted in a recent shift in focus, with the new trend being techniques aimed at redraping the soft tissues with the intent of reproducing a more natural rejuvenation of the lower lid-cheek interface. Where direct excision techniques simply remove the deformed tissue, redraping techniques actually elevate the midface soft tissues and tighten the pathologically lax orbicularis muscle, thereby counteracting the downward descent associated with the aging process. The optimal treatment is as yet unclear but seems to be a combination of elevation of soft tissue, tightening of orbicularis muscle, and removal of excess skin and or muscle to properly address all the manifestations of this interesting process. PMID- 25440746 TI - The transeyelid midface lift. AB - The transeyelid approach to midface lift is an elegant approach for mild descent of malar soft tissue. The subciliary approach is the most commonly used and technically less challenging for surgeons experienced in facelift techniques. This technique in midface rejuvenation also has the advantage of ease of combining with other periocular and mid and upper face rejuvenation, such as blepharoplasty and forehead lift. Complication is rare with lid malposition, scaring, and temporary nerve function impairment being the most common. PMID- 25440747 TI - Transtemporal midface lifting to blend the lower eyelid-cheek junction. AB - When examining the results of this technique, improvement is noticed in the infraorbital hollowing, midface tissue ptosis, depth of nasolabial folds, and degree of jowling. The greatest overall improvement is the extent of midface ptosis and infraorbital hollowing at the lower eyelid-cheek junction followed by improvement in the nasolabial region. Improvement in jowling was common but less significant than the improvement of the midface structures. The authors think that this dramatic improvement is owing to multiple factors. With wide and complete release of the central and lateral midfacial structures, the en bloc suspension of the SOOF and malar fat pad is thoroughly accomplished. Unlike other midfacial techniques, the transtemporal midface achieves pull in 2 vectors, directing the repositioning of tissuesboth superiorly and laterally. The superior vector repositions the SOOF and malar fat pad over the bony infraorbital rim and malar/zygomatic complex, whereas the lateral pull effaces the nasolabialfold. This superior vector more accurately reverses the forces of aging displayed on the ptotic midface. Lastly, although this technique is not designed primarily to eliminate jowling at the mandible, it has been noted that elevation of 1.0 to 1.5 cm of skin overlying the mandible is typical. Although the endoscopic forehead midface lift is not without its complications or pitfalls, all of these can be minimized, easily managed, or avoided completely through the intraoperative techniques and postoperative care. Careful and deliberate preoperative counseling of patients regarding the possible bumps in the road to recovery is critical. By using the techniques available to limit and manage complications and setting appropriate patient expectations should these complications occur, the endoscopic forehead midface lift can become an extremely powerful and safe technique in the facial cosmetic surgeon's armamentarium to efface the lid-cheek junction with a high degree of patient satisfaction. PMID- 25440748 TI - Autologous fat grafting for midface rejuvenation. AB - The authors have been performing autologous fat grafting for facial rejuvenation for 15 years and the procedure has evolved significantly during this time. In the beginning, the authors were primarily transferring to nasolabial folds, lips, and cheeks and found that the only patients who were satisfied with the procedure were cheek patients. To this day, the authors maintain that for isolated filling of lips and nasolabial folds, off the- shelf fillers are a better alternative. The authors treat these areas, however, as part of a current philosophy of smaller volumes over larger areas. In the early 2000s, the understanding of the volumetric nature of the aging process began to gain traction and global volumetric treatment became the authors' standard therapy. During that time, the authors developed a technique that led to an algorithmic approach to the surgery that allowed standard reproducible results for all surgeons. With the greater adoption of volumetric rejuvenation, an era of "more volume is better" has been entered, which is producing unnatural results. The authors' theory of facial shadow patterns explains more precisely why volume leads to facial rejuvenation and the understanding necessary to produce subtle more natural results. Currently, the authors are interested in quantitatively documenting results and evolving autologous fat transfer to a more predictable procedure. PMID- 25440749 TI - Midface implants: surgical and nonsurgical alternatives. AB - The midface has suffered vigorous challenges in terms of rejuvenation techniques over the years. A variety of alternatives are available for facial skeletal and soft tissue volume enhancement. No technique is ideal in every patient. After a thorough facial analysis, the surgeon must consider the advantages and disadvantages of implant-based volume enhancement in the context of each individual patient to determine the most appropriate option. Computer modeling provides improved methods to assess volumetric changes to augment and restore the facial volume. It is our belief that the multiple planes of dissection offered by the midface also allow us to redrape the soft tissues 3-dimensionally and continue to offer the consistency and longevity with implant-based midface rejuvenation. PMID- 25440750 TI - Deep plane face lifting for midface rejuvenation. AB - The deep-plane midface lift offers many advantages in midface rejuvenation. Anatomic analysis of aging and embryologic evidence both support surgical facial "degloving" in the sub-SMAS plane and resuspension of the platysma/SMAS unit. This approach offers more complete repositioning of facial soft tissue compared with nonsurgical techniques, delivering accurate, direct treatment of deeper anatomic aspects of facial aging. The well-vascularized deep-plane flap minimizes complications. Outcomes can be maximized because tension exists "invisibly," only at the fascia level. Consistent, natural,and long-lasting aesthetic results are achieved. PMID- 25440751 TI - Preface. Lower eyelid and midface aesthetics and rejuvenation: views from four disciplines. PMID- 25440752 TI - The use of Latin squares and related block designs in implementation research. PMID- 25440753 TI - Principles and application of range of motion and stretching in companion animals. AB - Optimal function after injury, surgery, or in patients with chronic conditions requires adequate motion in joints, muscles, tendon, fascia, and skin. Range of motion and stretching exercises are commonly used in companion animal rehabilitation programs to maintain or improve motion of musculoskeletal tissues. Range of motion exercises and stretching prevent adhesions from forming, help scar tissue remodeling, may improve muscle tone, and prevent future injury from occurring. Stretching is used to avoid loss of motion or to regain lost joint motion. Stretching is done manually, using external coaptation, or using therapeutic exercises. Careful documentation of range of motion is necessary. PMID- 25440754 TI - Rehabilitation and physical therapy for the neurologic veterinary patient. AB - A comprehensive physiotherapy plan for neurology patients manages pain, prevents secondary complications, and supports the health and function of musculoskeletal tissues during recovery. Neurologically impaired patients range in ability from complete immobility (tetraplegia/paraplegia), partial mobility (tetraparesis/paraparesis), mild ataxia, to pain only. Important considerations for the design of a physiotherapy program include access to the patient, level of staff support, and safety of staff, patient, and client during treatments. A thorough overview of the treatment plan and expected outcome should be discussed with the client at the onset of therapy and should be reviewed frequently, particularly as the patient's status changes. PMID- 25440755 TI - Effects of fermented soybean meal on innate immunity-related gene expressions in nursery pigs acutely challenged with lipopolysaccharides. AB - This experiment was to determine if replacing soybean meal with fermented soybean meal (FSBM) would reduce the innate immune response after lipopolysaccharide challenge and the changes of gene expression profiles associated with this response. Forty-eight 21 day-old pigs were housed individually and fed three diets for 15 days: CON (a diet without FSBM or spray-dried plasma protein; SDPP), PP7 (a diet with 7% SDPP), and FS10 (a diet with 10% FSBM). Pigs were fitted with a jugular vein catheters receiving lipopolysaccharide challenge (25 MUg/kg body weight (BW)) on day 15. Blood was collected for 5 h at 30-min intervals to measure cortisol. Expressions of gene transcripts in total RNA from leukocytes were compared using an oligonucleotide microarray at 210 min after lipopolysaccharides injection. Cortisol of FS10 was lower (P < 0.05) than CON after lipopolysaccharides challenge. The expression levels of 17 transcripts, including cytosolic glutathione peroxidase and glutathione S-transferase A4-4 were increased (P < 0.05), whereas 23 genes including adiponectin, neonatal Fc receptor and tumor necrosis factor ligand superfamily member 5 were decreased (P < 0.05) in FS10. This study suggests that FSBM-fed pigs can modulate expression of genes related to inflammatory response and anti-oxidant activity which can be a potential reason for reduced serum cortisol. PMID- 25440756 TI - The determinants of thermal comfort in cool water. AB - Water-based activities may result in the loss of thermal comfort (TC). We hypothesized that in cooling water, the hands and feet would be responsible. Supine immersions were conducted in up to five clothing conditions (exposing various regions), as well as investigations to determine if a "reference" skin temperature (Tsk) distribution in thermoneutral air would help interpret our findings. After 10 min in 34.5 degrees C water, the temperature was decreased to 19.5 degrees C over 20 min; eight resting or exercising volunteers reported when they no longer felt comfortable and which region was responsible. TC, rectal temperature, and Tsk were measured. Rather than the extremities, the lower back and chest caused the loss of overall TC. At this point, mean (SD) chest Tsk was 3.3 (1.7) degrees C lower than the reference temperature (P = 0.005), and 3.8 (1.5) degrees C lower for the back (P = 0.002). Finger Tsk was 3.1 (2.7) degrees C higher than the reference temperature (P = 0.037). In cool and cooling water, hands and feet, already adapted to colder air temperatures, will not cause discomfort. Contrarily, more discomfort may arise from the chest and lower back, as these regions cool by more than normal. Thus, Tsk distribution in thermoneutral air may help understand variations in TC responses across the body. PMID- 25440757 TI - Does residing in urban or rural areas affect the incidence of polypharmacy among older adults in western China? AB - The aim of this study is to explore the differences among older adults who are rural or urban residents with respects to their socioeconomic position, chronic health conditions and medication use. This cross-sectional study included 887 community-dwelling older adults (>=60 years) from western China. Trained interviewers collected data from all of the study subjects through face-to-face interviews. Polypharmacy was defined as the concomitant use of five or more medications. A total of 717 participants were included in the study analyses. Compared with their urban counterparts, the older adults in rural China were more likely to have more chronic health conditions, and a lower education level, annual income and insurance coverage rate. In addition, the rural inhabitants were less likely to use medications (58.7% vs. 75.7%, p<0.001). The intensity of medication use (the mean number of drugs) was 1.7 for rural residents and 2.3 for urban residents (p<0.001). The prevalence of polypharmacy was significantly lower in rural residents than urban residents (11.5% vs. 17.5%, p=0.021). Urban residence (odds ratios (OR) 1.89, 95% confidence intervals (CI) 1.03-3.48), number of chronic conditions (OR 1.95, 95% CI 1.16-3.30), diabetes (OR 4.14, 95% CI 2.33-7.37), and cardiovascular disease (CVD) (OR 2.09, 95% CI 1.25-3.51) were positively associated with polypharmacy, whereas good self-rated health (OR 0.32, 95% CI 0.16-0.65) was negatively associated with polypharmacy. In conclusion, urban residence is independently associated with polypharmacy in Chinese elders regardless of chronic health conditions and socioeconomic status. PMID- 25440758 TI - Moral distress among healthcare professionals: report of an institution-wide survey. AB - PURPOSE: Moral distress is a phenomenon affecting many professionals across healthcare settings. Few studies have used a standard measure of moral distress to assess and compare differences among professions and settings. DESIGN: A descriptive, comparative design was used to study moral distress among all healthcare professionals and all settings at one large healthcare system in January 2011. METHODS: Data were gathered via a web-based survey of demographics, the Moral Distress Scale-Revised (MDS-R), and a shortened version of Olson's Hospital Ethical Climate Scale (HECS-S). FINDINGS: Five hundred ninety-two (592) clinicians completed usable surveys (22%). Moral distress was present in all professional groups. Nurses and other professionals involved in direct patient care had significantly higher moral distress than physicians (p = .001) and other indirect care professionals (p < .001). Moral distress was negatively correlated with ethical workplace climate (r = -0.516; p < .001). Watching patient care suffer due to lack of continuity and poor communication were the highest-ranked sources of moral distress for all professional groups, but the groups varied in other identified sources. Providers working in adult or intensive care unit (ICU) settings had higher levels of moral distress than did clinicians in pediatric or non-ICU settings (p < .001). Providers who left or considered leaving a position had significantly higher moral distress levels than those who never considered leaving (p < .001). Providers who had training in end-of-life care had higher average levels of moral distress than those without this training (p = .005). CONCLUSIONS: Although there may be differences in perspectives and experiences, moral distress is a common experience for clinicians, regardless of profession. CLINICAL RELEVANCE: Moral distress is associated with burnout and intention to leave a position. By understanding its root causes, interventions can be tailored to minimize moral distress with the ultimate goal of enhancing patient care, staff satisfaction, and retention. PMID- 25440759 TI - Electrosurgical management of Hunner ulcers in a referral center's interstitial cystitis population. AB - OBJECTIVE: To characterize electrocautery (EC) as a valid treatment option in interstitial cystitis (IC) patients with Hunner ulcers (HUs). METHODS: From 1997 to 2013, a single urologist's IC population was retrospectively reviewed to identify HU patients as well as their demographics, operative characteristics, and response to a 2-page questionnaire evaluating parameters of their experience with EC. Descriptive statistics, Pearson chi-square test, Student t test, and Pearson coefficient were used. RESULTS: Two hundred fourteen EC procedures were performed in 76 patients (87% women; mean age, 66 +/- 1.67 years). Fifty-one patients (69%) who underwent multiple EC had mean initial bladder capacity of 438.62 +/- 27.90 mL and final bladder capacity of 422.40 +/- 30.10 mL. Mean number of EC procedures was 2.98 +/- 0.25 (range, 1-11). Mean time between sessions was 14.52 +/- 1.34 months (range, 1-121 months). Fifty-two patients (68%) completed our questionnaire, with 13.54 +/- 1.28 years of symptoms and 10.66 +/- 0.96 years since diagnosis. Ranking IC treatments, 37 patients (84%) reported EC most beneficial. On a 0-10 (none to worst possible) scale before and after EC, frequency improved from 9.04 +/- 1.30 to 3.65 +/- 2.75 (P <.001), urgency from 8.40 +/- 2.38 to 3.28 +/- 2.71 (P <.001), and pain from 8.62 +/- 2.36 to 2.68 +/- 2.55 (P <.001). Overall, 89.6% of patients noted some degree of symptom improvement after EC; 56.3% of patients had marked improvement. A total of 98% of patients would undergo EC again. CONCLUSION: EC of HU is an effective and safe procedure with high patient satisfaction that does not diminish bladder capacity. PMID- 25440760 TI - S100A3 suppression inhibits in vitro and in vivo tumor growth and invasion of human castration-resistant prostate cancer cells. AB - OBJECTIVE: To investigate the role of S100A3 and the effect of S100A3 inhibition on human castration-resistant prostate cancer (CRPC) cells by using in vitro and in vivo functional assays. MATERIALS AND METHODS: Using human CRPC cells (PC3 and DU145), S100A3 expression levels were assessed by reverse transcription polymerase chain reaction and Western blot analysis. After S100A3-specific small interfering ribonucleic acid (RNA) treatment, cell viability was determined by Cell Counting Kit-8 assay, and apoptotic cell fractions were evaluated by flow cytometry. The invasive properties of these cells and the expression pattern of matrix metalloproteinases (MMPs) were assessed using transwell migration assays, reverse transcription-polymerase chain reaction, and gelatin zymography. Finally, the in vivo efficacy of S100A3 inhibition on human CRPC cells was investigated using human tumor xenograft models in nude mice. RESULTS: Human CRPC cells showed overexpression of S100A3, and its suppression reduced cell viability owing to apoptotic cell death. Additionally, S100A3 inhibition decreased the invasiveness of human CRPC cells. Moreover, MMP-2 and MMP-9 were downregulated in PC3, whereas only MMP-9 was downregulated in D145 after S100A3 inhibition. In human CRPC xenograft models, we noted a marked reduction in tumor growth in mice injected with S100A3 short hairpin RNA-transfected PC3 and DU145 cells. CONCLUSION: Human CRPC cells showed upregulation of S100A3 expression, and S100A3 inhibition reduced tumor cell viability. S100A3 inhibition reduced invasion capability with downregulation of MMP expression. More importantly, S100A3 inhibition resulted in tumor growth suppression in human CRPC xenograft models, suggesting S100A3 could serve as a novel therapeutic target for the treatment of human CRPC. PMID- 25440761 TI - Vesicourethral fistula after retrograde primary endoscopic realignment in posterior urethral injury. AB - A 22-year-old male patient presented with iatrogenic vesicourethral fistula after immediate retrograde endoscopic realignment of urethra after a posterior urethral injury associated with pelvic fracture. PMID- 25440762 TI - Comparison of outcomes in patients undergoing percutaneous renal cryoablation with sedation vs general anesthesia. AB - OBJECTIVE: To compare the efficacy and safety of local anesthesia with conscious sedation (LACS) with general anesthesia (GA) in patients undergoing percutaneous renal cryoablation (PRC) for renal cortical neoplasms. METHODS: We performed a retrospective review of patients undergoing PRC between 2003 and 2013. Patient demographics, tumor characteristics, and perioperative and postoperative follow up data were recorded and analyzed. We compared 3 principal outcomes across the GA and LACS groups: anesthesia-related outcomes, treatment failure, and complications. RESULTS: A total of 235 patients with available data were included. Of these, 82 underwent PRC under GA and 153 patients under LACS. The 2 groups were similar with regard to age, gender, body mass index, American Society of Anesthesiologists score, tumor features, preoperative serum creatinine level, and hematocrit value. The GA and LACS groups had a similar percentage of patients with biopsy-proven renal cell carcinoma (68.5% and 64.2%, respectively; P = .62). The mean follow-up time for GA and LACS was 37 and 21 months, respectively (P <.0001). The mean procedure time for GA was significantly longer compared with LACS (133 vs 102 minutes; P <.001), and the mean hospital stay was shorter under LACS (1.08 vs 1.95 days; P <.0001). There was no difference in immediate failure (0% and 1.9%; P = .051) or recurrences (11% and 3.9%, respectively; P = .051) between GA and LACS groups. There was no difference in intraoperative and postoperative treatment-related complications between the 2 groups. CONCLUSION: PRC for small renal masses under LACS is effective and safe. PRC with LACS has the advantage of decreased procedure time and a shorter hospital stay. PMID- 25440763 TI - The dual mTORC1 and mTORC2 inhibitor PP242 shows strong antitumor activity in a pheochromocytoma PC12 cell tumor model. AB - OBJECTIVE: To assess the activity of mTOR and downstream effector proteins in the mTOR pathway after treatment with a dual mTOR complex 1 and 2 (mTORC1/2) inhibitor (PP242) compared with that of mTOR complex 1 (mTORC1) inhibitor (rapamycin) using a xenograft tumor model. METHODS: Pheochromocytoma PC12 cell were xenografted into nude mice. Animals were treated with PP242 and rapamycin. Mean tumor volume was compared across groups. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining was used to detect apoptosis. Immunoblot analysis was performed to assess mTORC1/2 activity using p Akt, p-S6, and p-4E-BP1. The expression of the antiapoptotic protein Bcl-2, pro apoptotic protein Bax, and the mediator of angiogenesis vascular endothelial growth factor were also investigated. RESULTS: The mean tumor volume of PP242 was significantly lower than in other groups. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling results showed that PP242 markedly increased cell apoptosis compared with other groups. Immunoblot analysis of tumor lysates treated with PP242 demonstrated inhibition of activated p-Akt. We also observed that only PP242, but not rapamycin, significantly reduced Bcl-2 expression and markedly increased Bax expression. Rapamycin decreased vascular endothelial growth factor expression, but not nearly as striking as seen in the PP242 group. CONCLUSION: Our study showed that PP242 showed strong antitumor activity in a pheochromocytoma PC12 cell tumor model. Based on our study, dual mTORC1/2 kinase inhibitors warrant further investigation as a potential treatment for malignant pheochromocytomas or paragangliomas. PMID- 25440764 TI - Transformation, communication, and engagement. PMID- 25440765 TI - [Endovascular therapy in the treatment of acute ischemic stroke: what the cardiologist should know]. AB - INTRODUCTION: Interventional cardiology procedures are regularly exposed to ischemic neurological complications. IV fibrinolysis is the only approved treatment in ischemic stroke but is very often contraindicated in these situations. Many techniques of interventional neuroradiology (mechanical thrombectomy) have been developed over the past years and are used to treat these patients. OBSERVATION: We report the case of two patients who were admitted in emergency for ischemic stroke with contraindication to IV fibrinolysis (cardioversion for atrial fibrillation under anticoagulation; 24 hours after carotid surgery). These patients were treated by endovascular thrombectomy procedure. DISCUSSION: After validation of IV fibrinolysis within 4.5 hours after stroke onset, techniques of mechanical thrombectomy have gradually been developed, either as a complementary treatment or as an alternative in the case of CI to fibrinolysis. These endovascular thrombectomy devices currently allow recanalization of proximal cerebral occlusions, which correlates with a favorable clinical prognosis. A review of the literature is provided, along with a discussion about the techniques currently being improved, their advantages and disadvantages and the selection of patients that can benefit from endovascular procedures. CONCLUSION: In the case of a sudden occurrence of a neurological deficit during a cardiovascular procedure, a "thrombolysis alert" should be triggered. This will permit the rapid establishment of a clinico-radiological report for selecting stroke patients eligible for a procedure of recanalization by thrombolysis and/or mechanical thrombectomy. PMID- 25440766 TI - [Infections associated with percutaneous arterial closure devices: medico-legal issues]. AB - Percutaneous suture closure devices have reduced the time needed for manual compression and hospital stays, but several meta-analysis emphasized a higher risk of vascular damages compared to manual compression. Two cases of infections on percutaneous suture closure devices were analyzed; which had medico-legal issues. Beyond the medical point of view, the patient's complaints, the way lawyers and medical experts have examined the cases were analyzed and resulted in physicians and hospitals being sentenced. Rather than stigmatizing those devices, we just want to invite cardiologists not to underestimate this serious risk. Before using those devices, physicians should balance the risk-benefit ratio, follow prevention guidelines, and most of all, be aware of any single signs of emerging infection to detect and treat them early, and thus reduce the severity of infections thanks to a targeted antibiotic treatment adapted to the antibiogram and an active role of vascular surgeons. PMID- 25440767 TI - [Neonatal lupus and maternofetal transmission of anti-SSA/Ro and anti-SSB/La antibodies]. AB - Neonatal lupus (NL) is a rare syndrome caused by placental transfer of maternal anti-SSA/Ro (60 and 52kDa) or anti-SSB/La antibodies. The aim of this study was to evaluate the clinical and biological profile of NL at the neonatal unit of Sfax, Tunisia, over a 10-year period. Six mother-NB pairs (two sets of twins and two sisters) had positive ANA by transplacental transmission during the study period. The ANA pattern was speckled and the NBs' sera titer was half that of their mothers'. Anti-SSA, anti-Ro52, and anti-SSB were found in 100%, 33%, and 50% of the mothers' sera, respectively. The transmission of anti-SSA was observed in four pregnancies out of six, anti-Ro52 in two pregnancies out of two, and anti SSB in one pregnancy out of three. The patients' clinical records showed that two NBs had a congenital heart block: one with anti-SSA, whose mother had Sjogren syndrome, and another with anti-SSA, anti-SSB, anti-Ro52, and anti-mitochondrial antibodies (M2 type), whose mother had no diagnosis at the child's birth (cutaneous erythema and positive ANA with the same profile). Cutaneous signs (erythema, petechia) were described in three NBs out of six. The two sets of fraternal twins had cutaneous signs with the same ANA titer and profile (no anti SSA transmission from their mother with lupus and anti-phospholipid syndrome). The two sisters' (two pregnancies 3 years apart) mother had Sjogren syndrome, one of them had heart block with positive anti-SSA, and the other was asymptomatic with anti-SSA and anti-Ro52. The same mother had a history of three pregnancies with two NBs who died of heart block. PMID- 25440768 TI - [Prostaglandins and the immune response at the intestinal submucosal level. A potential site for interference with the repeated use of paracetamol and ibuprofen at a young age?]. AB - Immune deviations have been shown to exponentially increase in young children. As a consequence, research investigating possible environmental reasons for this increase is considered a public health priority. An improved understanding of the immunity of the intestinal submucosal lamina propria has demonstrated the importance of prostaglandins (PGE2s) on its local development with general immune consequences further on. PGE2s appear at this intestinal submucosal level from the metabolism of arachidonic acid mediated by type-2 cyclooxygenases (COX2s) situated in the membranes of many immune cells. The potential risk of repeated inhibition of PGE2 synthesis at a young age has been demonstrated in experiments with animals systemically exposed to a non-steroidal anti-inflammatory drug (NSAID). The repeatedly exposed animal cannot develop tolerance to food antigens and exhibits autoimmune deviations. Acetaminophen (paracetamol) and ibuprofen are analgesic and antipyretic medications given to children either alone or in combination, most often without medical prescription. Recently, it has been demonstrated that paracetamol, like ibuprofen, also carries, besides its central action, a non-selective inhibitory action on peripheral COXs. However, this inhibitory action only relates to physiological concentrations of arachidonic acid and explains the difference in their respective anti-inflammatory effects. Since recently published data have repeatedly reported an increase of immune deviations associated with paracetamol exposure at a young age, it appears important to better understand the possible negative impact of excessive and repetitive inhibitions of the physiological synthesis of prostaglandins by COX2s in childhood during which all immune mechanisms are built up at the intestinal submucosal level. Therefore, a well-designed prospective strategy for pharmacovigilance of these COX inhibitors repeatedly given during childhood is urgently needed. PMID- 25440769 TI - Unusual association of myasthenia gravis and ulcerative colitis in a 14-year-old boy. AB - Ulcerative colitis (UC) is a chronic inflammatory condition. Its incidence is 0.8 per 100,000 children per year and median age at diagnosis is 14.1 years in the pediatric population. Extradigestive manifestations are frequent in inflammatory bowel disease (IBD), but neurologic disorders are rarely associated. We report the case of a 14-year-old boy who was diagnosed with UC and thereafter autoimmune hepatitis with primary sclerosing cholangitis. Two months later, he also developed myasthenia gravis, another autoimmune disease. Physicians should be aware of the possibility of an association between several autoimmune diseases in patients with IBD in order to improve disease outcomes. PMID- 25440770 TI - [Nutrition of pregnant women: consequences for fetal growth and adult diseases]. AB - The developmental origins of human adult disease are thought to be secondary to a perturbation of the embryonic or fetal development, which leads to metabolic disorders such as diabetes or hypertension at adulthood. Maternal undernutrition or overnutrition, repeated glucocorticosteroids administered to the mother, or placental dysfunction are the most frequently considered causal factors. Therefore, it is necessary that the pediatrician is aware of these phenomena, as this knowledge may contribute to the prevention of adult diseases. Little is known yet, however, on the pathophysiological or epigenetic mechanisms that lead to theses observations, and more studies are needed both in humans and animal models. PMID- 25440772 TI - Editorial comment for Huang et al. PMID- 25440771 TI - Association of neighbourhood unemployment rate with incident Type 2 diabetes mellitus in five German regions. AB - AIM: To analyse the association of neighbourhood unemployment with incident self reported physician-diagnosed Type 2 diabetes in a population aged 45-74 years from five German regions. METHODS: Study participants were linked via their addresses at baseline to particular neighbourhoods. Individual-level data from five population-based studies were pooled and combined with contextual data on neighbourhood unemployment. Type 2 diabetes was assessed according to a self reported physician diagnosis of diabetes. We estimated proportional hazard models (Weibull distribution) in order to obtain hazard ratios and 95% CIs of Type 2 diabetes mellitus, taking into account interval-censoring and clustering. RESULTS: We included 7250 participants residing in 228 inner city neighbourhoods in five German regions in our analysis. The incidence rate was 12.6 per 1000 person-years (95% CI 11.4-13.8). The risk of Type 2 diabetes mellitus was higher in men [hazard ratio 1.79 (95% CI 1.47-2.18)] than in women and higher in people with a low education level [hazard ratio 1.55 (95% CI 1.18-2.02)] than in those with a high education level. Independently of individual-level characteristics, we found a higher risk of Type 2 diabetes mellitus in neighbourhoods with high levels of unemployment [quintile 5; hazard ratio 1.72 (95% CI 1.23-2.42)] than in neighbourhoods with low unemployment (quintile 1). CONCLUSIONS: Low education level and high neighbourhood unemployment were independently associated with an elevated risk of Type 2 diabetes mellitus. Studies examining the impact of the residential environment on Type 2 diabetes mellitus will provide knowledge that is essential for the identification of high-risk populations. PMID- 25440773 TI - Automatic validation of computational models using pseudo-3D spatio-temporal model checking. AB - BACKGROUND: Computational models play an increasingly important role in systems biology for generating predictions and in synthetic biology as executable prototypes/designs. For real life (clinical) applications there is a need to scale up and build more complex spatio-temporal multiscale models; these could enable investigating how changes at small scales reflect at large scales and viceversa. Results generated by computational models can be applied to real life applications only if the models have been validated first. Traditional in silico model checking techniques only capture how non-dimensional properties (e.g. concentrations) evolve over time and are suitable for small scale systems (e.g. metabolic pathways). The validation of larger scale systems (e.g. multicellular populations) additionally requires capturing how spatial patterns and their properties change over time, which are not considered by traditional non-spatial approaches. RESULTS: We developed and implemented a methodology for the automatic validation of computational models with respect to both their spatial and temporal properties. Stochastic biological systems are represented by abstract models which assume a linear structure of time and a pseudo-3D representation of space (2D space plus a density measure). Time series data generated by such models is provided as input to parameterised image processing modules which automatically detect and analyse spatial patterns (e.g. cell) and clusters of such patterns (e.g. cellular population). For capturing how spatial and numeric properties change over time the Probabilistic Bounded Linear Spatial Temporal Logic is introduced. Given a collection of time series data and a formal spatio temporal specification the model checker Mudi ( http://mudi.modelchecking.org ) determines probabilistically if the formal specification holds for the computational model or not. Mudi is an approximate probabilistic model checking platform which enables users to choose between frequentist and Bayesian, estimate and statistical hypothesis testing based validation approaches. We illustrate the expressivity and efficiency of our approach based on two biological case studies namely phase variation patterning in bacterial colony growth and the chemotactic aggregation of cells. CONCLUSIONS: The formal methodology implemented in Mudi enables the validation of computational models against spatio-temporal logic properties and is a precursor to the development and validation of more complex multidimensional and multiscale models. PMID- 25440774 TI - Prevalence of physiological heart murmurs in a population of 95 healthy young adult dogs. AB - OBJECTIVES: To determine the prevalence of physiological heart murmurs in healthy young adult dogs. MATERIALS AND METHODS: Healthy dogs aged between 1 and 5 years were enrolled prospectively. All participating dogs underwent physical examination, urinalysis, blood testing and blood pressure measurement. Cardiac auscultations were performed by three independent examiners. Dogs with heart murmurs underwent echocardiography, to exclude cardiovascular abnormalities. RESULTS: Of 109 dogs evaluated, 95 completed the study. Heart murmurs were detected in 22 dogs. Interobserver agreement for murmur detection was moderate to fair (weighted kappa 0 . 29-0 . 56). On the basis of two different sets of echocardiographic criteria, physiological heart murmurs were diagnosed in 6 and 11 dogs, respectively, giving a prevalence of 6-12%. All physiological heart murmurs were systolic and low-grade (I-III/VI). Most were louder towards the left heart base and some radiated up to the thoracic inlet. The epidemiological features of dogs with physiological heart murmurs did not differ significantly from those of dogs without murmurs (P > 0 . 10). CLINICAL SIGNIFICANCE: This study shows that physiological heart murmurs may not be limited to growing dogs or specific breeds, as they were commonly encountered in this population of healthy young adult dogs. PMID- 25440775 TI - Platelet factor 4 limits Th17 differentiation and ischaemia-reperfusion injury after liver transplantation in mice. AB - Liver ischaemia/reperfusion injury (IRI) is a serious pathologic process encountered in a number of clinical syndromes including liver transplantation, liver resection, trauma and haemorrhagic shock. Platelet factor 4 (PF4) was the first discovered CXC chemokine and is found in platelet granules at very high concentration. In this study, we provide strong evidence that PF4 is involved directly in liver innate immune response against IRI by regulating Th17 differentiation. PF4 deficiency aggravates liver IRI, as shown by higher serum alanine aminotransferase (ALT) levels and Suzuki scores. PF4 deficiency promotes Th17 response with higher levels of IL-23, IL-6 and IL-17, which aggravates liver IRI. Furthermore, PF4 deficiency limits suppressor of cytokine signalling 3 (SOCS3) expressions, and PF4 fails to suppress expression of IL-17 in cells transfected with SOCS3 SiRNA. In conclusion, PF4 limits liver IRI through IL-17 inhibition via upregulation of SOCS3. PMID- 25440776 TI - Spatial estimation: a non-Bayesian alternative. AB - A large collection of estimation phenomena (e.g. biases arising when adults or children estimate remembered locations of objects in bounded spaces; Huttenlocher, Newcombe & Sandberg, 1994) are commonly explained in terms of complex Bayesian models. We provide evidence that some of these phenomena may be modeled instead by a simpler non-Bayesian alternative. Undergraduates and 9- to 10-year-olds completed a speeded linear position estimation task. Bias in both groups' estimates could be explained in terms of a simple psychophysical model of proportion estimation. Moreover, some individual data were not compatible with the requirements of the more complex Bayesian model. PMID- 25440777 TI - The impact of small-for-gestational-age on neonatal outcome among very-low-birth weight infants. AB - BACKGROUND: This study aimed to evaluate the impact of small-for-gestational-age (SGA) on mortality and morbidity in very-low-birth-weight (VLBW) infants. METHODS: We conducted a retrospective cohort study on VLBW infants registered at the Premature Baby Foundation of Taiwan between 2007 and 2011. All 21 neonatal departments in Taiwan participated in the data collection, and a total of 4636 VLBW infants were registered during the study period. The SGA group (n = 560) was selected from the database on the basis of birth weight below the 10(th) percentile for gestational age, whereas the appropriate-weight-for-gestational age (AGA) group (n = 1120) included infants randomly selected via incidence density sampling with a 2:1 match for each SGA case. The association of SGA with individual outcome variables including mortality, respiratory distress syndrome, necrotizing enterocolitis, retinopathy of prematurity (ROP), intraventricular hemorrhage, periventricular leukomalacia, and bronchopulmonary dysplasia (BPD) was evaluated after adjustment for potential confounders. RESULTS: The SGA group was associated with increased risks of mortality [odds ratio (OR) 1.89; 95% confidence interval (CI) 1.39-2.58], severe ROP (OR 1.56; 95% CI 1.13-2.14), and BPD (OR 2.08; 95% CI 1.58-2.75) compared to the AGA group. Further subgroup analysis showed that SGA had significant effects on mortality in the VLBW infants with a gestational age of 24-29 weeks, as well as on BPD in those with a gestational age of 27-32 weeks. By contrast, the association of SGA with severe ROP was only significant in the VLBW infants with a gestational age of 27-29 weeks. CONCLUSION: Our data provide evidence that SGA may be associated with increased risks of neonatal mortality, ROP, and BPD in VLBW infants. PMID- 25440778 TI - Disseminated Cunninghamella bertholletiae Infection During Induction Chemotherapy in a Girl with High-Risk Acute Lymphoblastic Leukemia. AB - Invasive fungal infections in children with acute lymphoblastic leukemia have been a major cause of mortality. Recent reports have described increasing incidence of invasive non-Aspergillus mold infections in patients with hematological malignancies. It is always challenging to treat invasive fungal infection and underlying hematological malignancies successfully. Here we report a girl with high-risk acute lymphoblastic leukemia who developed disseminated Cunninghamella bertholletiae infection during induction chemotherapy. This case illustrates the difficulties of diagnosis and treatment of invasive C. bertholletiae infection. It also highlights the necessity for physicians to keep high suspicion and awareness for this infrequent fungal infection. PMID- 25440779 TI - Nationwide Birth Weight and Gestational Age-specific Neonatal Mortality Rate in Taiwan. AB - BACKGROUND: There are limited nationwide data relating to neonatal mortality rate in Taiwan. This study aims to provide updated national birth weight/gestational age-specific neonatal mortality reference rates. METHODS: We abstracted the birth registration database from the Ministry of Interior in Taiwan from 1998 to 2002 and linked the data to the death registration database from the Ministry of Health and Welfare in Taiwan between 1998 and 2003. We included 1,331,785 infants born between 20 weeks and 44 weeks of gestation and weighing within the median +/ 2 interquartile ranges in their age group in this study. We calculated the birth weight/gestational age-specific neonatal mortality rates of different genders by birth weight increments of 250 g and at gestational age intervals of 1 week. A Poisson regression model was used in modeling the mortality data. RESULTS: A total of 4,169 deaths occurred within 28 days of life out of a total of 1,331,785 live births between 20 weeks and 44 weeks of gestation, giving a neonatal mortality rate (0-27 days) of 3.39 per 1000 live births for males and 2.80 per 1000 for females. The infant mortality rate remained higher in the male (5.91 per 1000) than the female (5.10 per 1000) population within the 1(st) year of life. Birth weight/gestational age-specific neonatal mortality rates were plotted with curves representing the 10(th) and 90(th) birth weight percentiles. The risk of an early neonatal death (0-6 days) does not exceed 50% except for female neonates < 500 g and <= 23 weeks, which implies that the limit of viability is now at 23 weeks for females. CONCLUSION: We have provided an easy-to-use birth weight/gestational age-specific neonatal mortality rate chart as a reference document that physicians and parents can use to make decisions based on ethical considerations relating to whether to give palliative care or further invasive management. The normative data are crucial for public health policies on neonatal care in Taiwan. PMID- 25440780 TI - Retroviral nucleocapsid protein and assembly. Foreword. PMID- 25440781 TI - Structural complexity of macroalgae influences epifaunal assemblages associated with native and invasive species. AB - Habitat structure is a primary factor determining the organism distribution. Here, two native and one invasive macroalgal species, apparently different in morphology, were sampled to examine the effects of habitat complexity on the abundance (N), taxon richness (S) and structure of their associated epifaunal assemblages by means of univariate and multivariate techniques. Dry weight and fractal measures were used as proxies of habitat quantity and habitat architecture respectively. Results revealed significant differences in the complexity and in N, S and the structure of epifaunal assemblages among macroalgae and significant correlations between complexity and epifauna. Results suggested that, beside the effect of habitat quantity, the habitat architecture also seems to play a significant role in shaping epifaunal assemblages. Complexity of the studied invasive macroalga significantly differed from that of native species and hosted also different assemblages. Therefore, our findings suggest that invasive macroalgae, if structurally different from native species, induce changes in the associated epifauna. PMID- 25440782 TI - Trophic influences on mercury accumulation in top pelagic predators from offshore New England waters of the northwest Atlantic Ocean. AB - Trophic pathways and size-based bioaccumulation rates of total mercury were evaluated among recreationally caught albacore tuna (Thunnus alalunga), yellowfin tuna (Thunnus albacares), shortfin mako shark (Isurus oxyrinchus), thresher shark (Alopias vulpinus), and dolphinfish (Coryphaena hippurus) from offshore southern New England waters of the northwest Atlantic Ocean between 2008 and 2011. Mercury concentrations were highest in mako (2.65 +/- 1.16 ppm) and thresher sharks (0.87 +/- 0.71 ppm), and significantly lower in teleosts (albacore, 0.45 +/- 0.14 ppm; yellowfin, 0.32 +/- 0.09 ppm; dolphinfish, 0.20 +/- 0.17 ppm). The relationship between body size and mercury concentration was positive and linear for tunas, and positive and exponential for sharks and dolphinfish. Mercury increased exponentially with delta (15)N values, a proxy for trophic position, across all species. Results demonstrate mercury levels are positively related to size, diet and trophic position in sharks, tunas, and dolphinfish, and the majority of fishes exhibited concentrations greater than the US EPA recommended limit. PMID- 25440783 TI - Coexistence of congeneric native and invasive species: the case of the green algae Codium spp. in northwestern Spain. AB - We examined the patterns of distribution and abundance, and reproductive traits (presence of gametophytes and size at time of reproduction) in the invasive Codium fragile ssp. fragile and the native C. tomentosum and C. vermilara on intertidal habitats of NW Spain at two dates. All three species coexist in the locations and habitats studied, although abundances were low. We found a greater proportion of C. fragile ssp. fragile towards the east of the Cantabrian coast and on upper levels on the shore, where conditions are more stressful. The proportion of thalli bearing gametangia in C. fragile ssp. fragile was greater than in the native species in all habitats. The presence of gametangia was size dependent for all species, with the invasive species maturing at a smaller size, which combined with the previous features, might confer competitive advantages to this species over the native species. We also demonstrated that molecular analyses are necessary for the correct identification of C. fragile subspecies. PMID- 25440784 TI - Feeding response in marine copepods as a measure of acute toxicity of four anti sea lice pesticides. AB - Anti-sea lice pesticides used in salmon aquaculture are released directly into the environment where non-target organisms, including zooplankton, may be exposed. The toxicity of four pesticides to field-collected copepods was examined in 1-h exposures with lethality and feeding endpoints determined 5-h post exposure using staining techniques. Copepods were immobilized within 1 h, at aquaculture treatment concentrations of deltamethrin (AlphaMax), cypermethrin (Excis), and hydrogen peroxide (InteroxParamove50). All organisms showed vital staining, indicating immobilized organisms were still alive, thus LC50s were not determined. Feeding on carmine particles was inhibited and EC50s ranged from 0.017 to 0.067 MUg deltamethrin/L, 0.098-0.36 MUg cypermethrin/L, and 2.6-10 mg hydrogen peroxide/L, representing 30- to 117-fold, 13- to 51-fold, and 120- to 460-fold dilutions of the respective aquaculture treatments. No effects were observed in copepods exposed to azamethiphos (Salmosan) at 5-times the aquaculture treatment. Acute exposure to three of the four pesticides affected feeding and mobility of copepods at environmentally-realistic concentrations. PMID- 25440785 TI - Does the marine biotoxin okadaic acid cause DNA fragmentation in the blue mussel and the pacific oyster? AB - Two bivalve species of global economic importance: the blue mussel, Mytilus edulis and the pacific oyster, Crassostrea gigas were exposed in vivo, to the diarrhoetic shellfish toxin okadaic acid (OA), and impacts on DNA fragmentation were measured. Shellfish were exposed using two different regimes, the first was a single (24 h) exposure of 2.5 nM OA (~0.1 MUg/shellfish) and algal feed at the beginning of the trial (T0), after which shellfish were only fed algae. The second was daily exposure of shellfish to two different concentrations of OA mixed with the algal feed over 7 days; 1.2 nM OA (~0.05 MUg OA/shellfish/day) and 50 nM OA (~2 MUg OA/shellfish/day). Haemolymph and hepatopancreas cells were extracted following 1, 3 and 7 days exposure. Cell viability was measured using the trypan blue exclusion assay and remained above 85% for both cell types. DNA fragmentation was examined using the single-cell gel electrophoresis (comet) assay. A significant increase in DNA fragmentation was observed in the two cell types from both species relative to the controls. This increase was greater in the pacific oyster at the higher toxin concentration. However, there was no difference in the proportion of damage measured between the two cell types, and a classic dose response was not observed, increasing toxin concentration did not correspond to increased DNA fragmentation. PMID- 25440786 TI - Study of the bile proteome of Atlantic cod (Gadus morhua): Multi-biological markers of exposure to polycyclic aromatic hydrocarbons. AB - PAH metabolites present in bile are well-known biological markers of exposure in fish, and their investigation is recommended by the ICES (International Council for the Exploration of the Sea) and the OSPAR convention (Convention for the Protection of the Marine Environment of the North-East Atlantic) for monitoring purposes. Development of analytical strategies for fish bile is encouraged by the need for more sensitive and informative markers (e.g., capable of tracking the PAH composition of contamination sources) and strengthened by recent results in both fish genomics and proteomics. Herein, the study of the Atlantic cod bile proteome is presented. Preliminary testing for discovering new sensitive markers in the form of expressed proteins affected by PAH exposure (i.e., PAH-protein adducts) is reported. Protein markers were identified using LC-MS/MS analysis, as single biological indicators. Through multivariate analyses, the overall proteome was revealed to be a sensitive multi-biological marker of exposure to PAHs. PMID- 25440787 TI - Individualizing treatment choices using quantitative methods. PMID- 25440788 TI - Antiplatelet and anticoagulation agents in acute coronary syndromes: what is the current status and what does the future hold? AB - Mortality and morbidity in acute coronary syndromes (ACSs), caused principally by plaque erosion or rupture leading to thrombus formation and myocardial ischemia, have been reduced by a combination of antithrombotic agents (antiplatelet drugs and anticoagulants) and early revascularization. Aspirin is the foundation antiplatelet agent. New P2Y12 receptor inhibitors (prasugrel and ticagrelor) have clear benefits compared with clopidogrel for dual antiplatelet therapy, and cangrelor or vorapaxar, a thrombin receptor inhibitor, may be of value in specific settings. Anticoagulation uses 1 of 4 choices: bivalirudin, unfractionated heparin, enoxaparin, and fondaparinux. Moreover, some patients (such as those who have chronic atrial fibrillation) require triple therapy with aspirin, clopidogrel, plus an anticoagulant, frequently a vitamin K antagonist. New oral anticoagulants have been shown to be at least as effective as vitamin K antagonists in atrial fibrillation and led to fewer bleeding complications. Finally, the combination of aspirin, clopidogrel, and low-dose rivaroxaban has recently been approved by the European Medicines Agency (but not the Food and Drug Administration) for secondary prevention after ACS. Several strategies have been developed to balance the potential benefit of antithrombotic therapy against the risk of bleeding complications, for example, radial access in coronary angiography or restricted use of combination therapy, and others are under investigation, such as discontinuation of aspirin. This overview summarizes the current status of antithrombotic therapy in ACS and describes strategies currently explored to optimize its benefit/risk ratio. PMID- 25440789 TI - How can we optimize the processes of care for acute coronary syndromes to improve outcomes? AB - Acute coronary syndromes (ACS), either ST-elevation myocardial infarction or non ST-elevation ACS, are still one of the most common cardiac emergencies with substantial morbidity and mortality. The availability of evidence-based treatments, such as early and intense platelet inhibition and anticoagulation, and timely reperfusion and revascularization, has substantially improved outcomes in patients with ACS. The implementation of streamlined processes of care for patients with ST-elevation myocardial infarction and non-ST-elevation ACS over the last decade including both appropriate tools, especially cardiac troponin, for rapid diagnosis and risk stratification and for decision support, and the widespread availability of modern antithrombotic and interventional treatments, have reduced morbidity and mortality to unprecedented low levels. These changes in the process of care require a synchronized approach, and research using a team based strategy and effective regional networks has allowed healthcare systems to provide modern treatments for most patients with ACS. There are still areas needing improvement, such as the delivery of care to people in rural areas or with delayed time to treatment. PMID- 25440790 TI - Cardiac and vascular effects of fingolimod: mechanistic basis and clinical implications. AB - Fingolimod, a sphingosine-1-phosphate receptor (S1PR) modulator, was the first oral disease-modifying therapy approved for relapsing forms of multiple sclerosis; it reduces autoreactive lymphocytes' egress from lymphoid tissues by down-regulating S1PRs. Sphingosine-1-phosphate signaling is implicated in a range of physiologic functions, and S1PRs are expressed differentially in various tissues, including the cardiovascular system. Modulation of S1PRs on cardiac cells provides an explanation for the transient effects of fingolimod on heart rate and atrioventricular conduction at initiation of fingolimod therapy, and for the mild but more persistent effects on blood pressure observed in some patients on long-term treatment. This review describes the nontherapeutic actions of fingolimod in the context of sphingosine-1-phosphate signaling in the cardiovascular system, as well as providing a summary of the associated clinical implications useful to physicians considering initiation of fingolimod therapy in patients. A transient reduction in heart rate (mean decrease of 8 beats per minute) and, less commonly, a temporary delay in atrioventricular conduction observed in some patients when initiating fingolimod therapy are both due to activation of S1PR subtype 1 on cardiac myocytes. These effects are a reflection of fingolimod first acting as a full S1PR agonist and thereafter functioning as an S1PR antagonist after down-regulation of S1PR subtype 1 at the cell surface. For most individuals, first-dose effects of fingolimod are asymptomatic, but all patients need to be monitored for at least 6 hours after the first dose, in accordance with the label recommendations. PMID- 25440792 TI - APPOSITION V: STENTYS coronary stent system clinical trial in subjects with ST segment elevation myocardial infarction--rationale and design. AB - BACKGROUND: Primary percutaneous coronary intervention (PCI) has considerably improved clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) when compared with thrombolytic therapy. Prognosis after primary PCI might be further improved by decreasing stent-related complications such as stent thrombosis. The STENTYS self-apposing stent has been shown to be superior compared with balloon-expandable stents with regard to stent apposition. The current prospective randomized trial was designed to evaluate whether the superior stent apposition of the STENTYS stent results in clinical outcomes that are at least noninferior to a conventional balloon-expandable stent. METHODS: The APPOSITION V is a prospective, multicenter, international, single-blinded, randomized controlled trial in STEMI patients. Randomization will be performed in a 2:1 ratio between the self-apposing nitinol bare-metal STENTYS stent and the balloon-expandable bare-metal MULTI-LINK. The primary end point is defined as target vessel failure, which is a composite of cardiac death, target vessel related recurrent myocardial infarction, or clinically driven target vessel revascularization, at 1-year follow-up. Baseline intravascular ultrasound and optical coherence tomography (OCT) substudies will be performed in 212 and 60 subjects, respectively, and a repeat angiography at 12 to 13 months will be performed in 105 subjects, including intravascular ultrasound and OCT (in the 60 OCT patients). This study is registered on ClinicalTrials.gov with number NCT01732341. CONCLUSION: APPOSITION V will be the first randomized trial powered on clinical end points that directly compares the STENTYS self-apposing stent with a conventional balloon-expandable stent in patients presenting with STEMI undergoing primary PCI. PMID- 25440791 TI - The palliative care in heart failure trial: rationale and design. AB - BACKGROUND: The progressive nature of heart failure (HF) coupled with high mortality and poor quality of life mandates greater attention to palliative care as a routine component of advanced HF management. Limited evidence exists from randomized, controlled trials supporting the use of interdisciplinary palliative care in HF. METHODS: PAL-HF is a prospective, controlled, unblinded, single center study of an interdisciplinary palliative care intervention in 200 patients with advanced HF estimated to have a high likelihood of mortality or rehospitalization in the ensuing 6 months. The 6-month PAL-HF intervention focuses on physical and psychosocial symptom relief, attention to spiritual concerns, and advanced care planning. The primary end point is health-related quality of life measured by the Kansas City Cardiomyopathy Questionnaire and the Functional Assessment of Chronic Illness Therapy with Palliative Care Subscale score at 6 months. Secondary end points include changes in anxiety/depression, spiritual well-being, caregiver satisfaction, cost and resource utilization, and a composite of death, HF hospitalization, and quality of life. CONCLUSIONS: PAL HF is a randomized, controlled clinical trial that will help evaluate the efficacy and cost effectiveness of palliative care in advanced HF using a patient centered outcome as well as clinical and economic end points. PMID- 25440793 TI - Rationale and design of a double-blind, multicenter, randomized, placebo controlled clinical trial of early administration of intravenous beta-blockers in patients with ST-elevation myocardial infarction before primary percutaneous coronary intervention: EARLY beta-blocker administration before primary PCI in patients with ST-elevation myocardial infarction trial. AB - BACKGROUND: beta-Blockers have a class 1a recommendation in the treatment of patients with ST-elevation myocardial infarctions (STEMIs), as they are associated with a reduced mortality, recurrent myocardial infarction, life threatening arrhythmias, and with prevention of unfavorable left ventricular remodeling. Whether early administration before primary percutaneous coronary intervention (PCI) of intravenous beta-blockers reduces the infarct size in the current era is unknown. HYPOTHESIS: We postulate that the early administration of beta-blockers will reduce the myocardial infarcted area as assessed by magnetic resonance imaging (MRI) at 30 days. DESIGN: In a multinational, multicenter, double-blind, placebo-controlled, randomized trial, patients with symptoms and signs of STEMI and transferred to a hospital for primary PCI will be randomized in a 1:1 fashion to intravenous metoprolol (5 mg twice daily) administration or placebo. Before admission, study treatment will be started as soon as possible after the diagnosis of STEMI. After admission, primary PCI will be performed as per standard of care. After primary PCI, medical treatment will occur as per current guidelines in all patients, including the use of oral beta-blockers. The primary end point is the myocardial infarct size as assessed by MRI at 30 days. Based on a superiority design and assuming an 18% relative infarct size reduction (from 28% to 23.5%), 408 patients are required to be enrolled, accounting for 20% drop-out (alpha = .05 and power = 80%). SUMMARY: The EARLY-BAMI trial is a multinational, multicenter, double-blind, placebo-controlled, randomized clinical trial that will investigate the impact of intravenous metoprolol administration before primary PCI for STEMI on myocardial infarct size as measured with MRI at 30 days. PMID- 25440794 TI - Rationale and design for PACE: patients with intermittent claudication injected with ALDH bright cells. AB - Peripheral artery disease (PAD) is recognized as a public health issue because of its prevalence, functional limitations, and increased risk of systemic ischemic events. Current treatments for claudication, the primary symptom in patients with PAD, have limitations. Cells identified using cytosolic enzyme aldehyde dehydrogenase (ALDH) may benefit patients with severe PAD but has not been studied in patients with claudication. PACE is a randomized, double-blind, placebo-controlled clinical trial conducted by the Cardiovascular Cell Therapy Research Network to assess the safety and efficacy of autologous bone marrow derived ALDH(br) cells delivered by direct intramuscular injections in 80 patients with symptom-limiting intermittent claudication. Eligible patients will have a significant stenosis or occlusion of infrainguinal arteries and a resting ankle-brachial index less than 0.90 and will be randomized 1:1 to cell or placebo treatment with a 1-year follow-up. The primary end points are the change in peak walking time and leg collateral arterial anatomy, calf muscle blood flow, and tissue perfusion as determined by magnetic resonance imaging at 6 months compared with baseline. The latter 3 measurements are new physiologic lower extremity tissue perfusion and PAD imaging-based end points that may help to quantify the biologic and mechanistic effects of cell therapy. This trial will collect important mechanistic and clinical information on the safety and efficacy of ALDH(br) cells in patients with claudication and provide valuable insight into the utility of advanced magnetic resonance imaging end points. PMID- 25440795 TI - Platelet function monitoring in elderly patients on prasugrel after stenting for an acute coronary syndrome: design of the randomized antarctic study. AB - BACKGROUND: Elderly patients are at high risk for both ischemic and bleeding events. Platelet monitoring offers the opportunity to individualized antiplatelet therapy to optimize the therapeutic risk/benefit ratio. STUDY DESIGN: The ANTARCTIC study is designed to demonstrate the superiority of a strategy of platelet function monitoring with dose and drug adjustment in patients initially on prasugrel 5 mg as compared with a more conventional strategy using prasugrel 5 mg without monitoring and without adjustment (Conventional Treatment Arm) to reduce the primary end point evaluated 1 year after stent percutaneous coronary intervention in elderly patients presenting with an acute coronary syndrome (ACS). ANTARCTIC is a multicenter, prospective, open-label study with 2 parallel arms. A total of 852 elderly patients (>= 75 years) undergoing stent percutaneous coronary intervention for ACS are to be enrolled. The primary end point is the time to first occurrence of cardiovascular death, myocardial infarction, stroke, definite stent thrombosis, urgent revascularization, and bleeding complications (Bleeding Academic Research Consortium definition 2, 3, or 5). Platelet function analyses will be performed 14 days after randomization and repeated 14 days later in patients who require a change in treatment. CONCLUSION: ANTARCTIC is a nationwide, prospective, open-label study testing a strategy of platelet function monitoring with dose and drug adjustment to reduce ischemic and bleeding complications in elderly ACS patients undergoing coronary stenting. PMID- 25440797 TI - Rationale and design of a randomized controlled trial evaluating community health worker-based interventions for the secondary prevention of acute coronary syndromes in India (SPREAD). AB - BACKGROUND: There is a need to evaluate and implement cost-effective strategies to improve adherence to treatments in coronary heart disease. There are no studies from low- to middle income countries (LMICs) evaluating trained community health worker (CHW)-based interventions for the secondary prevention of coronary heart disease. METHODS: We designed a hospital-based, open randomized trial of CHW-based interventions versus standard care. Patients after an acute coronary syndrome (ACS) were randomized to an intervention group (a CHW-based intervention package, comprising education tools to enhance self-care and adherence, and regular follow-up by the CHW) or to standard care for 12 months during which study outcomes were recorded. The CHWs were trained over a period of 6 months. The primary outcome measure was medication adherence. The secondary outcomes were differences in adherence to lifestyle modification, physiological parameters (blood pressure [BP], body weight, body mass index [BMI], heart rate, lipids), and major adverse cardiovascular events. RESULTS: We recruited 806 patients stabilized after an ACS from 14 hospitals in 13 Indian cities. The mean age was 56.4 (+/- 11.32) years, and 17.2% were females. A high prevalence of risk factors such as hypertension (43.4%), diabetes (31.9%), tobacco consumption (35.4%), and inadequate physical activity (70.5%) was documented. A little over half had ST elevation myocardial infarction (53.7%), and 46.3% had non-ST-elevation myocardial infarction or unstable angina. CONCLUSION: The CHW interventions and training for SPREAD have been developed and adapted for local use. The results and experience of this study will be important to counter the burden of cardiovascular diseases in low- to middle income countries. PMID- 25440798 TI - Tradeoff between bleeding and stent thrombosis in different dual antiplatelet therapy regimes: Importance of case fatality rates and effective treatment durations. AB - BACKGROUND: The tradeoff between stent thrombosis (ST) and major bleeding (MB) of 12- versus 6-month dual antiplatelet therapy (DAPT) after coronary stent implantation has not been clearly defined. METHODS: Definite/probable ST and MB (TIMI major and Bleeding Academic Research Consortium (BARC) >= 3) were compared in 2 subsequent trials with similar inclusion criteria but different DAPT duration, that is, BASKET (6 months; n = 557) and BASKET-PROVE (12 months; n = 2,314), between months 0 to 6 (DAPT in both trials), 7 to 12 (DAPT in BASKET PROVE only), and 13 to 24 (aspirin in both trials) using propensity score adjusted, time-stratified Cox proportional hazard models. RESULTS: Overall, event rates were low with fewer ST but similar MB in prolonged DAPT. Analysis of the 3 periods showed a uniform pattern for ST (interaction DAPT/period; P = .145) but an inconsistent pattern for MB (interaction DAPT/period; P < .001 for TIMI major and P = .046 for BARC >= 3), with more MB occurring during months 7 to 12 with prolonged DAPT. Considering observed case fatality rates of 31% with ST and 11% with MB, the extrapolated prevention of 27 ST deaths and the excess of 5 MB deaths resulted in an expected benefit of 22 survivors/10,000 patients treated over 2 years with prolonged DAPT. CONCLUSION: Despite overall low event rates, prolonged DAPT was associated with more MB during months 7 to 12 according to the interaction DAPT/period. Given the higher observed case fatality rates of ST versus MB, 12- versus 6-month DAPT was associated with an extrapolated reduction in mortality. Effective treatment periods and case fatality rates seem important in the analysis of different DAPT durations, specifically with regard to ongoing trials. PMID- 25440796 TI - Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. AB - BACKGROUND: Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS. DESIGN: This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C >= 70 mg/dL, non-high density lipoprotein cholesterol >= 100 mg/dL, or apolipoprotein B >= 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred. SUMMARY: ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS. PMID- 25440799 TI - Transesophageal echocardiography in patients with cryptogenic ischemic stroke: a systematic review. AB - BACKGROUND: The clinical utility of routine transesophageal echocardiography (TEE) for patients with unexplained ischemic stroke is controversial. We performed a systematic review to determine the frequency of detection of new cardiac findings in patients with cryptogenic ischemic stroke (IS) undergoing transesophageal echocardiography (TEE). METHODS: Systematic review and meta analysis of cohort studies of consecutive patients with "cryptogenic" IS undergoing TEE after routine etiologic workup. Patients were categorized into 2 groups: A (< 55 years) and B (>= 55 years). Outcomes included proportion of patients with new TEE-detected cardiac findings and proportion of patients commenced on oral anticoagulation after TEE. RESULTS: Twenty-seven studies were included (n = 5,653). We identified significant heterogeneity among studies and report a range of prevalence rates and I2 statistic as our primary analysis. Prevalence of individual cardiac findings on TEE varied significantly among studies; patent foramen ovale (A: 12.0%-57.8%, I2 = 89.9%; B: 3.9%-43.5%, I2 = 86.7%), atrial septal aneurysm (A: 0-48.9%, I2 = 91.9%; B: 3.5%-25.0%, I2 = 84.5%), left atrial thrombus (A: 0-10.9%, I2 = 61.1%; B: 0-21.2%, I2 = 91.7%), spontaneous echo contrast (A: 0-11.9%, I2 = 57.2%; B: 0-21.3%, I2 = 89.8%), and aortic atheroma (A: 0-9.6%, I2 = 53.8%; B: 2.8%-44.4%, I2 = 89.7%). Definitions of common findings were not provided for many studies. Five studies (n = 591) reported on the proportion of patients who were commenced on anticoagulant therapy after TEE (range 0-30.7%). CONCLUSIONS: Routine TEE in patients with cryptogenic IS identifies cardiac findings in a large proportion. However, there is marked interstudy variation in the definition and prevalence of common findings. Transesophageal echocardiography-detected findings prompted the introduction of anticoagulant therapy in up to one-third of patients. However, these were mostly not for established guideline-based indications based on randomized controlled trial evidence. It is unclear if routine use of TEE in patients with cryptogenic IS is indicated. PMID- 25440800 TI - Association between process quality measures for heart failure and mortality among US veterans. AB - BACKGROUND: The few available studies of the Centers for Medicare and Medicaid Services Hospital Inpatient Quality Reporting (IQR) care process indicators have not linked receipt of recommended care processes in heart failure (HF) with lower mortality. Because the Veterans Health Administration (VHA) also tracks hospital inpatient quality reporting indicators, in addition to VHA-specific inpatient (pneumococcal and influenza vaccination) and outpatient (angiotensin-converting enzyme inhibitor [ACEI] or angiotensin receptor blocker [ARB] use for left ventricular [LV] dysfunction and LV function documentation) care process indicators, we examined the association between receipt of these care processes and 30-day and 1-year mortality. METHODS: Retrospective study of 107,045 patients with HF treated at 128 VHA hospitals between 2001 and 2007 and followed up through 2008. We assessed the relationship between receipt of each HF care process and death at 30 days (inpatients only) and 1 year (all patients), using generalized estimating equations to adjust for clinical characteristics and clustering within hospitals. RESULTS: Overall, inpatient/outpatient use of ACEI/ARB and receipt of pneumococcal or influenza vaccinations were related to lower risks of 30-day and/or 1-year mortality (adjusted odds ratios 0.51-0.77 for vaccinations and 0.60-0.78 for ACEI/ARB use). Conversely, discharge instructions, inpatient/outpatient LV function assessment, or weight instructions before admission were either not related or related to a slightly increase in mortality. Stratified analyses by various mortality risk subgroups did not reveal discernable "dose-response" relationship between mortality risk stratification and the association of care process and mortality. CONCLUSIONS: Receipt of care processes related to recommended medications and vaccinations were associated with lower 30-day and/or 1-year risk-adjusted mortality in patients with HF. Receipt of care processes that assess patient counseling or chart documentation was not related to lower mortality. PMID- 25440801 TI - Outcomes in patients with heart failure with preserved, borderline, and reduced ejection fraction in the Medicare population. AB - BACKGROUND: Studies on outcomes among patients with heart failure (HF) with preserved left ventricular ejection fraction (HFpEF), borderline left ventricular ejection fraction (HFbEF), and reduced left ventricular ejection fraction (HFrEF) remain limited. We sought to characterize mortality and readmission in patients with HF in the contemporary era. METHODS: Get With The Guidelines-HF was linked to Medicare data for longitudinal follow-up. Patients were grouped into HFpEF (left ventricular ejection fraction [EF] >= 50%), HFbEF (40% <= EF < 50%), and HFrEF (EF < 40%). Multivariable models were constructed to examine the relationship between EF and outcomes at 30 days and 1 year and to study trends over time. RESULTS: A total of 40,239 patients from 220 hospitals between 2005 and 2011 were included in the study: 18,897 (47%) had HFpEF, 5,626 (14%) had HFbEF, and 15,716 (39%) had HFrEF. In crude survival analysis, patients with HFrEF had slightly increased mortality compared with HFbEF and HFpEF. After risk adjustment, mortality at 1 year was not significantly different for HFrEF, HFbEF, and HFpEF (HFrEF vs HFpEF, hazard ratio [HR] 1.040 [95% CI 0.998-1.084], and HFbEF vs HFpEF, HR 0.967 [95% CI 0.917-1.020]). Patients with HFpEF had increased risk of all-cause readmission compared with HFrEF. Conversely, risk of cardiovascular and HF readmissions were higher in HFrEF and HFbEF compared with HFpEF. CONCLUSIONS: Among patients hospitalized with HF, patients with HFpEF and HFbEF had slightly lower mortality and higher all-cause readmission risk than patients with HFrEF, although the mortality differences did not persist after risk adjustment. Irrespective of EF, these patients experience substantial mortality and readmission highlighting the need for new therapeutic strategies. PMID- 25440802 TI - Lack of association between chronic exposure to biomass fuel smoke and markers of right ventricular pressure overload at high altitude. AB - BACKGROUND: Chronic exposure to biomass fuel smoke has been implicated in the development of pulmonary hypertension and right ventricular pressure/volume overload through activation of inflammation, increase in vascular resistance, and endothelial dysfunction. We sought to compare N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and echocardiography-derived pulmonary artery systolic pressure (PASP) levels in a high-altitude population-based study in Peru with and without chronic exposure to biomass fuel smoke. METHODS: NT-pro-BNP levels were measured in 519 adults (275 with and 244 without chronic exposure to biomass fuel smoke). Participants answered sociodemographics and clinical history questionnaires, underwent a clinical examination and blood testing for cardiopulmonary biomarkers. PASP was measured in a subgroup of 153 (31%) subjects. RESULTS: The study group consisted of 280 men (54%) and 239 women (46%). Average age was 56 years and average body mass index was 27 kg/m(2). In multivariable analysis, there was no association between chronic exposure to biomass fuel smoke and NT-pro-BNP (P = .31) or PASP (P = .31). In the subgroup in which both NT-pro-BNP levels and PASP were measured, there was strong evidence of an association between these two variables (rho = 0.24, 95% CI 0.09-0.39; P = .003). We found that age, high sensitivity C-reactive protein, being male, and systolic blood pressure were positively associated with NT-pro-BNP levels whereas body mass index, low-density/high-density lipoprotein ratio, and Homeostasis Model of Assessment-Insulin Resistance were negatively associated (all P <= .02). CONCLUSIONS: In this population-based study in a high-altitude setting, neither NT-pro-BNP levels nor echocardiography-derived PASP were associated with chronic exposure to biomass fuel smoke. PMID- 25440804 TI - Mechanisms of sex and age differences in ventricular repolarization in humans. AB - INTRODUCTION: Corrected QT interval (QTc) is shorter in postpubertal men than in women; however, QTc lengthens as men age and testosterone levels decrease. Animal studies have demonstrated that testosterone decreases L-type calcium current and increases slow delayed rectifier potassium current; however, it is not known how these contribute to QTc differences by sex and age in humans. We separately analyzed early versus late repolarization duration and performed simulations of the effect of testosterone on the electrocardiogram (ECG) to examine the mechanism of sex and age differences in QTc in humans. METHODS: Twelve-lead ECGs from 2,235 healthy subjects (41% women) in Thorough QT studies were analyzed to characterize sex- and age-dependent differences in depolarization (QRS), early repolarization (J-T(peak)), and late repolarization (T(peak)-T(end)). In addition, we simulated the effects of testosterone on calcium current, slow delayed rectifier potassium current, and surface ECG intervals. RESULTS: QTc was shorter in men than in women (394 +/- 16 vs 408 +/- 15 milliseconds, P < .001), which was due to shorter early repolarization (213 +/- 16 vs 242 +/- 16 milliseconds, P < .001), as men had longer depolarization (94 +/- 7 vs 89 +/- 7 milliseconds, P < .001) and longer late repolarization (87 +/- 10 vs 78 +/- 9 milliseconds, P < .001). Sex difference in QTc decreased with age and was due to changes in early repolarization. Simulations showed that the early repolarization changes were most influenced by testosterone's effect on calcium current. CONCLUSION: Shorter QTc in men compared to women is explained by shorter early repolarization, and this difference decreases with age. These sex and age differences in repolarization appear to be caused by testosterone effects on calcium current. PMID- 25440803 TI - Real-time use of instantaneous wave-free ratio: results of the ADVISE in practice: an international, multicenter evaluation of instantaneous wave-free ratio in clinical practice. AB - OBJECTIVES: To evaluate the first experience of real-time instantaneous wave-free ratio (iFR) measurement by clinicians. BACKGROUND: The iFR is a new vasodilator free index of coronary stenosis severity, calculated as a trans-lesion pressure ratio during a specific period of baseline diastole, when distal resistance is lowest and stable. Because all previous studies have calculated iFR offline, the feasibility of real-time iFR measurement has never been assessed. METHODS: Three hundred ninety-two stenoses with angiographically intermediate stenoses were included in this multicenter international analysis. Instantaneous wave-free ratio and fractional flow reserve (FFR) were performed in real time on commercially available consoles. The classification agreement of coronary stenoses between iFR and FFR was calculated. RESULTS: Instantaneous wave-free ratio and FFR maintain a close level of diagnostic agreement when both are measured by clinicians in real time (for a clinical 0.80 FFR cutoff: area under the receiver operating characteristic curve [ROC(AUC)] 0.87, classification match 80%, and optimal iFR cutoff 0.90; for a ischemic 0.75 FFR cutoff: iFR ROC(AUC) 0.90, classification match 88%, and optimal iFR cutoff 0.85; if the FFR 0.75-0.80 gray zone is accounted for: ROC(AUC) 0.93, classification match 92%). When iFR and FFR are evaluated together in a hybrid decision-making strategy, 61% of the population is spared from vasodilator while maintaining a 94% overall agreement with FFR lesion classification. CONCLUSION: When measured in real time, iFR maintains the close relationship to FFR reported in offline studies. These findings confirm the feasibility and reliability of real-time iFR calculation by clinicians. PMID- 25440805 TI - Routine invasive management early after fibrinolysis: relationship between baseline risk and treatment effects in a pooled patient-level analysis of 7 randomized controlled trials. AB - BACKGROUND: The efficacy of a routine invasive strategy early after fibrinolysis in relation to baseline risk status is unclear. We sought to characterize the interaction between patient risk and treatment with routine invasive strategy early after fibrinolysis for ST-segment elevation myocardial infarction. METHODS: We pooled 2,974 patients from 7 randomized trials of fibrinolysis-treated patients with ST-segment elevation myocardial infarction comparing a routine early invasive strategy with a standard approach of percutaneous coronary intervention (PCI) guided by recurrent ischemia or need for rescue. Cox proportional hazards regression was used to examine the interaction between baseline patient risk classified by Thrombolysis in Myocardial Infarction risk score (low/intermediate: <= 5 [n = 2,697] vs high: > 5 [n = 277]) and treatment with routine early invasive strategy. RESULTS: Time to PCI after fibrinolysis was longer among patients randomized to standard treatment compared with routine early invasive strategy in the low/intermediate-risk strata (median 11.4 vs 3.5 hours), but was only marginally different between the 2 groups in the high-risk strata (median 4.1 vs 3.5 hours). There was a significant interaction between treatment assignment and risk status for the composite of 30-day death or reinfarction (P = .01). Compared with standard treatment, routine early invasive strategy was associated with lower 30-day death/reinfarction in the low/intermediate-risk stratum (7.5% vs 4.0%, P < .001), but not in the high-risk stratum (14.9% vs 19.6%, P = .45). CONCLUSIONS: Although clearly beneficial among the larger subgroup of patients at low/intermediate risk, the benefit of a routine early invasive strategy was not evident in the smaller subgroup of higher risk patients in the context of an increased requirement for urgent PCI in the comparative standard treatment arm. PMID- 25440806 TI - The association of myocardial infarction process of care measures and in-hospital mortality: a report from the NCDR(r). AB - BACKGROUND: The Center for Medicare and Medicaid Services (CMS) publicly reports "core process of care measures" along with 30-day mortality rates for patients with acute myocardial infarction; the American College of Cardiology/American Heart Association has a similar but expanded set of performance measures. METHODS: We sought to determine whether hospital-level adherence with these process performance measures was associated with risk-adjusted in-hospital mortality among 96,340 ST-segment elevation myocardial infarction (STEMI) and 145,832 non-STEMI (NSTEMI) patients in the National Cardiovascular Data Registry(r) ACTION Registry-Get With the GuidelinesTM admitted from January 2007 to March 2011 from 372 US sites. Hospitals were grouped based on risk-adjusted in hospital mortality: low (20%), middle (60%), and high mortality (20%). RESULTS: The mean (SD) mortality from low to high hospital mortality groups for STEMI was 4.9% (0.9%), 5.8% (0.3%), and 7.0% (0.5%); and that for NSTEMI was 3.3% (0.2%), 4.0% (0.2%), and 4.9% (0.3%). Adherence to individual process measures was high, with composite measure adherences exceeding 88%. Composite adherence for both CMS and American College of Cardiology/American Heart Association performance measures was inversely associated with risk-adjusted hospital mortality. However, the association was low for STEMI hospitals and not significant for NSTEMI hospitals. Variation tended to be higher for CMS measures for higher-mortality hospitals. CONCLUSIONS: Although process performance was associated with hospital mortality, the association was low for STEMI and nonsignificant for NSTEMI hospitals, thus supporting the need to measure complementary metrics of acute myocardial infarction quality of care. PMID- 25440807 TI - Sevoflurane in acute myocardial infarction: a pilot randomized study. AB - BACKGROUND: Experimental evidence suggests that the inhalational anesthetic sevoflurane has a cardioprotective effect. Our objective was to determine if sedation with sevoflurane will reduce infarct size in patients with acute myocardial infarction (MI) who are treated with primary percutaneous coronary intervention (PCI). METHODS: We randomized 50 patients presenting with a first acute ST-elevation MI treated by primary PCI within 6 hours from symptom onset to sedation with sevoflurane inhalation or standard sedation (control). Coronary flow at the end of PCI was assessed by corrected Thrombolysis In Myocardial Infarction frame count. Myocardial reperfusion was assessed by ST-segment resolution 60 minutes post-PCI. Infarct size was assessed by release of creatinine kinase (CK) and troponin T. RESULTS: There was no difference in the primary end point: troponin T or CK release adjusted to the area at risk, between groups. However, among patients with anterior MI, there was a trend toward lower CK (P = .05) and nonsignificant decrease in troponin (P = .11) levels in the sevoflurane group. Corrected Thrombolysis In Myocardial Infarction frame count was 12.3 +/- 1.5 in the sevoflurane group and 15.6 +/- 9.1 in the control group (P = .16). There was more ST resolution in patients treated by sevoflurane 80.7% +/- 25.8% versus 56.6% +/- 35.7% (P = .01). Sevoflurane had no significant adverse effect during administration. CONCLUSIONS: Sevoflurane administration during primary PCI did not reduce infarct size. There was a trend toward a reduction in infarct size among patients with anterior MI. Sevoflurane administration was associated with improvement in ST-segment resolution. PMID- 25440808 TI - Frailty and other geriatric conditions for risk stratification of older patients with acute coronary syndrome. AB - BACKGROUND: Geriatric conditions may predict outcomes beyond age and standard risk factors. Our aim was to investigate a wide spectrum of geriatric conditions in survivors after an acute coronary syndrome. METHODS: A total of 342 patients older than 65 years were included. At hospital discharge, 5 geriatric conditions were evaluated: frailty (Fried and Green scores), physical disability (Barthel index), instrumental disability (Lawton-Brody scale), cognitive impairment (Pfeiffer questionnaire), and comorbidity (Charlson and simple comorbidity indexes). The outcomes were postdischarge mortality and the composite of death/myocardial infarction during a 30-month median follow-up. RESULTS: Seventy four (22%) patients died and 105 (31%) suffered from the composite end point. Through univariable analysis, all individual geriatric indexes were associated with outcomes, mainly mortality. Of all of them, frailty using the Green score had the strongest discriminative accuracy (area under the receiver operating characteristic curve 0.76 for mortality). After full adjustment including clinical and geriatric data, the Green score was the only independent predictive geriatric condition (per point; mortality: hazard ratio 1.25, 95% CI 1.15-1.36, P = .0001; composite end point: hazard ratio 1.16, 95% CI 1.09-1.24, P = .0001). A Green score >= 5 points was the strongest mortality predictor. The addition of the Green score to the clinical model improved discrimination (area under the receiver operating characteristic curve 0.823 vs 0.846) and significantly reclassified mortality risk (net reclassification improvement 26.3, 95% CI 1.4 43.5; integrated discrimination improvement 4.0, 95% CI 0.8-9.0). The incremental predictive information was even greater over the GRACE score. CONCLUSIONS: Frailty captures most of the prognostic information provided by geriatric conditions after acute coronary syndromes. The Green score performed better than the other geriatric indexes. PMID- 25440809 TI - Early high-dose rosuvastatin and cardioprotection in the protective effect of rosuvastatin and antiplatelet therapy on contrast-induced acute kidney injury and myocardial damage in patients with acute coronary syndrome (PRATO-ACS) study. AB - BACKGROUND: There is a strong correlation between adverse clinical events and peak values of myocardial necrosis markers in non-ST-elevation acute coronary syndrome patients. In this clinical setting, high-dose statin treatment exerts acute beneficial effects against renal and myocardial damage. The aim of this report was to evaluate if, on admission, high-dose rosuvastatin can exert cardioprotective effects when administered in addition to high-dose clopidogrel. METHODS: In the PRATO-ACS trial, 504 consecutive statin-naive non-ST-elevation acute coronary syndrome patients scheduled for early invasive strategy and pretreated with high-dose clopidogrel were randomly assigned to rosuvastatin (40 mg on admission followed by 20 mg/d; statin group, n = 252) or no statin treatment (control group, n = 252). Serial myocardial biomarker samples were collected before and after angiography and/or percutaneous coronary intervention. The primary end point was the peak level of cardiac troponin I (cTnI) during the index event. RESULTS: Statin-treated patients presented median cTnI peak values similar to controls (3.9 [0.6-12.8] vs 3.5 [1.2-11.9] ng/mL, respectively; P = .60]; no differences were found between the 2 groups in cTnI and creatine kinase MB values at any time point, in either preangiography and postangiography peak values or their cumulative release. In patients submitted to percutaneous coronary intervention, periprocedural myocardial infarction occurred in 8 (4.7%) of 171 statin-treated and 7 (4.3%) of 162 control patients (P = .87). CONCLUSION: In the PRATO-ACS trial, early high-dose rosuvastatin did not show cardioprotective effects when administered in addition to high-dose clopidogrel. PMID- 25440810 TI - Causes and timing of death during long-term follow-up after transcatheter aortic valve replacement. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) is an effective therapeutic option for patients with severe aortic stenosis at high risk for surgery. Identification of causes of death after TAVR may help improve patient selection and outcome. METHODS: We enrolled 874 consecutive patients who underwent TAVR at 3 centers using all approved bioprostheses and different access routes. Clinical outcomes during follow-up were defined according to the Valve Academic Research Consortium 2 definitions. Causes of deaths were carefully investigated. RESULTS: Mean logistic European System for Cardiac Operative Risk Evaluation was 23.5% +/- 15.3%; Society of Thoracic Surgery score, 9.0% +/- 8.2%. The Corevalve (Medtronic, Minneapolis, MN) was used in 41.3%; the Edwards Sapien (Edwards Lifesciences Inc., Irvine, CA) in 57.3%. Vascular access was transfemoral in 75.7%. In-hospital mortality was 5.0%. Cumulative mortality rates at 1 to 3 years were 12.4%, 23.4%, and 31.5%, respectively. Landmark analysis showed a significantly higher incidence of cardiovascular (CV) death in the first 6 months of follow-up and a significantly higher incidence of non-CV death thereafter. At Cox regression analysis, the independent predictors of in-hospital mortality were acute kidney injury grades 2 to 3 (hazard ratio [HR] 3.41) life threatening bleeding (HR 4.26), major bleeding (HR 4.61), and myocardial infarction (HR 3.89). The independent predictors of postdischarge mortality were chronic obstructive pulmonary disease (HR 1.48), left ventricular ejection fraction at discharge (HR 0.98), and glomerular filtration rate <30 mL/min per 1.73 m(2) (HR 1.64). CONCLUSIONS: Around a third of patients treated with TAVR in daily practice die within the first 3 years of follow-up. Early mortality is predominantly CV, whereas late mortality is mainly non-CV, and it is often due to preexisting comorbidity. PMID- 25440812 TI - Early experience with attain stability, an activefixation LV lead: virtues and pitfalls. AB - BACKGROUND: Appropriate left ventricle (LV) lead placement is integral to successful cardiac resynchronization therapy (CRT). Lead dislodgement and phrenic nerve stimulation (PNS) are major obstacles. A recent trial of an active fixation LV lead (Attain Stability 20066, Medtronic Inc., Tilburg, the Netherlands) has shown promising results. We share our initial experience with this novel active fixation LV lead. METHODS: A Medtronic active fixation lead 20066 was used in eight consecutive patients for CRT. An optimal site was chosen and recommended maneuvers were applied for lead fixation. Push and pull maneuvers were used to test stability. RESULTS: There were two initial dislodgements after which we used a transvalvular insertion (TVI) tool that was used in the hemostatic valve during rotation of the lead so that the torque was easily transmitted to the tip. It also allowed better tactile feedback during push-pull tests. There were no further dislodgements in the subsequent six patients. However, in one patient the lead could not be unscrewed due to the tip getting wedged at a distal smaller vein. Repositioning of the LV lead was done in three patients due to PNS or pacing issues. The median time for LV lead placement was 16.5 minutes (interquartile range 9-25 minutes). CONCLUSION: The Medtronic Attain Stability 20066 active fixation LV lead can potentially be implanted at any pacing site avoiding PNS and providing better stability. The learning curve is short and additional tricks can be learnt to improve success. Use of TVI while the lead is rotated is beneficial. PMID- 25440813 TI - Special issue: abstracts from the international workshop on chemical science and pharmaceutical research, 25-28 september 2014, beijing, china. PMID- 25440811 TI - Hush now baby: mothers' and fathers' strategies for soothing their infants and associated parenting outcomes. AB - OBJECTIVES: The purpose of this study was to examine the types of soothing behaviors used by mothers and fathers of infants, differences in use trajectories over time, and associated parenting outcomes. METHODS: A longitudinal study of 241 families expecting their second child was performed. Data were collected at 1, 4, and 8 postnatal months and included measures of parental soothing techniques, involvement in soothing, distress in response to infant crying, and parenting self-efficacy. RESULTS: The average number of soothing techniques used was 7.7 for mothers and 5.9 for fathers. Soothing frequency decreased over time, and change patterns of soothing differed over time by gender. In couples who shared responsibility for soothing, fathers felt more efficacious in parenting and mothers were less upset by infant crying. DISCUSSION: Clinicians are encouraged to support fathers' engagement in infant soothing, facilitate the development of fathers' parenting confidence, and promote fathers' involvement in children's health and health care. PMID- 25440814 TI - Reclassification rates are higher among African American men than Caucasians on active surveillance. AB - OBJECTIVE: To evaluate the risk of reclassification on serial biopsy for Caucasian and African American (AA) men with very low-risk (VLR) prostate cancer enrolled in a large prospective active surveillance (AS) registry. METHODS: The Johns Hopkins AS registry is a prospective observational study that has enrolled 982 men since 1994. Including only men who met all National Comprehensive Cancer Network VLR criteria (clinical stage <=T1, Gleason score <=6, prostate-specific antigen [PSA] level <10 ng/mL, PSA density <0.15 ng/mL/cm(3), positive cores <3, percent cancer per core <=50), we analyzed a cohort of 654 men (615 Caucasians and 39 AAs). The association of race with reclassification on serial biopsy was assessed with competing-risks regressions. RESULTS: AA men on AS were more likely than Caucasians to experience upgrading on serial biopsy (36% vs 16%; adjusted P <.001). Adjusting for PSA level, prostate size, volume of cancer on biopsy, treatment year, and body mass index, AA race was an independent predictor of biopsy reclassification (subdistribution hazard ratio, 1.8; P = .003). Examining specific modes of reclassification, AA race was independently associated with reclassification by grade (subdistribution hazard ratio, 3.0; P = .002) but not by volume. CONCLUSION: AA men with VLR prostate cancer followed on AS are at significantly higher risk of grade reclassification compared with Caucasians. Therefore, if the goal of AS is to selectively monitor men with low-grade disease, AA men may require alternate selection criteria. PMID- 25440815 TI - The performance of a modified RENAL nephrometry score in predicting renal mass radiofrequency ablation success. AB - OBJECTIVE: To assess the predictive performance of a modified RENAL nephrometry score for renal tumors undergoing radiofrequency ablation (RFA). METHODS: Patients who underwent RFA were identified from 2002 to 2011, and RENAL nephrometry scoring was performed for each. A modified RENAL (m-RENAL) nephrometry score was created to account for the small sizes of tumors ablated for which the size variable, R, was adjusted. A size of 3 cm was calculated as the optimal cutoff for the R component of the m-RENAL nephrometry score, and tumors were given an R score of 1 if <3 cm, 2 if 3-4 cm, or 3 if >4 cm. Other RENAL variables were unchanged. Oncologic outcomes were stratified by complexity tertiles defined as low (4-6), medium (7-9), and high (10-12). Outcomes were reported as initial ablation success (IAS), recurrence-free survival (RFS), and metastatic-free survival (MFS). The Kaplan-Meir method was used to estimate survival based on complexity tertile. RESULTS: Two hundred forty patients were identified who underwent RFA, of which 192 patients were eligible for analysis. Median follow-up was 32.2 months, and median tumor size was 2.4 cm. IAS was achieved in 185 of 192 patients (96.4%). Overall, the estimated 3-year RFS was 95.1% and MFS was 97.3%. There was no statistical difference between complexity tertiles using the standard RENAL nephrometry score; however, the m-RENAL nephrometry score was significantly associated with IAS and RFS (P = .027 and P = .003, respectively). There were too few events (n = 3) to perform statistical analysis for MFS. CONCLUSION: A modification to the size variable increases the performance of the RENAL nephrometry score when used to stratify RFA ablation success. PMID- 25440816 TI - Asymptomatic lower pole small renal stones: shock wave lithotripsy, flexible ureteroscopy, or observation? A prospective randomized trial. AB - OBJECTIVE: To present the outcomes of flexible ureteroscopy (F-URS), shock wave lithotripsy (SWL), and observation in the management of asymptomatic lower calyceal stones. METHODS: A total of 150 patients with asymptomatic lower calyceal stones were randomized into F-URS (group 1), SWL (group 2), and observation (group 3) groups. The main criteria for patient enrollment were having asymptomatic single lower pole stones <1 cm. RESULTS: In F-URS, the mean stone-free rate was 92% (46 of 50). The mean number of sessions for the SWL group was 1.48 +/- 0.65. Stone-free rate was 90% (45 of 50). In the observation group, patients were followed up for a mean of 21.02 +/- 3.65 months. Three stones passed spontaneously without any symptoms. Pain developed in 3 patients during follow-up, and 2 of them passed a stone and responded to analgesics without further treatment. Complication rates for groups 1 and 2 were similar, but group 2 had higher Clavien grades. CONCLUSION: For asymptomatic small-sized lower calyceal stones, SWL and F-URS are established treatment modalities. However, with low auxiliary treatment rates, observation may be an option for the management of nonsymptomatic small-sized lower pole kidney stones. PMID- 25440817 TI - A validated low-cost training model for suprapubic catheter insertion. AB - OBJECTIVE: To describe an anatomically correct simulator for use in suprapubic catheter (SPC) insertion training. METHODS: A scale reproduction of an adult male pelvis with bony landmarks and a subcutaneous fluid-filled reservoir was created using platinum cured silicone rubber. This model was evaluated by 6 expert urologists for content validity with a 16-item 5-point rating scale used to evaluate domains relevant to the simulator-physical attributes, realism of experience, realism of materials, and global rating. The simulator was used by 25 general surgeons from rural practices participating in a 2-day comprehensive specialized surgical skills course. RESULTS: The domains were scored between 1 and 5; 1 being "not at all realistic" and 5 being "highly realistic, no changes needed." The average expert ratings of the domains were 3.9 (physical attributes), 4.3 (realism of experience), and 3.9 (realism of materials). The simulator was rated more valuable as a training tool (4.5) compared with a testing tool (3.8) with an average global rating of 4.1. CONCLUSION: Experts and trainees reported high satisfaction with their experience using this simulator. Preliminary evidence suggests this simulator is a useful tool that can be integrated into training programs to facilitate learning this necessary urologic skill. PMID- 25440818 TI - Extent of extraprostatic extension independently influences biochemical recurrence-free survival: evidence for further pT3 subclassification. AB - OBJECTIVE: To evaluate the impact of the extent of extraprostatic extension (EPE) on biochemical recurrence-free survival (BCRFS) after radical prostatectomy (RP). MATERIALS AND METHODS: We queried our RP database from 2004 to 2013. Extent of EPE on RP was divided into 3 groups: no EPE, focal EPE (F-EPE; a few extraprostatic cancer glands on 1-2 slides), and nonfocal EPE (NF-EPE). Multivariate Cox proportional hazard models determined the influence of EPE on BCRFS. RESULTS: A total of 10,750 men underwent RP during the study period. Of these, 7843 men (73.0%) had no EPE, 1258 (11.7%) men had F-EPE, and 1649 men had (15.3%) NF-EPE. Overall BCRFS was worse in men with NF-EPE than those with F-EPE or no EPE. In a multivariate model, F-EPE and NF-EPE were both independently associated with worse BCRFS compared with no EPE (F-EPE: hazard ratio, 2.41; 95% confidence interval, 1.84-3.10; P <.0001; NF-EPE: hazard ratio, 3.57; 95% confidence interval, 2.89-4.40; P <.0001). When stratified by Gleason score in men without seminal vesicle invasion or lymph node metastases, there was no difference in BCRFS for Gleason score <6, 3 + 4 = 7, 4 + 3 = 7, and 8 for F-EPE vs no EPE; however, patients with Gleason score of 9-10 with F-EPE had worse BCRFS. Patients with NF-EPE had significantly worse BCRFS for Gleason score <6, 7, and 8 and a trend for worse BCRFS for Gleason score 9-10 compared with no EPE. CONCLUSION: Although all men with EPE have higher BCRFS after RP, men with NF-EPE have worse BCRFS than those with F-EPE, supporting the need to substratify pT3a prostate cancer in the American Joint Committee on Cancer staging system. PMID- 25440819 TI - Impact of the 2012 United States Preventive Services Task Force statement on prostate-specific antigen screening: analysis of urologic and primary care practices. AB - OBJECTIVE: To identify the effect of the 2012 United States Preventive Services Task Force (USPSTF) prostate-specific antigen (PSA) recommendation statement on primary care referral patterns and urologists' decision making. METHODS: Men referred to our institution for newly elevated PSA level from June 2011 to June 2013 were identified. Patients with a prior history of prostate cancer or biopsy were excluded. Clinical and management parameters were compared between those presenting in the year before vs the year after the USPSTF statement. Factors predictive of receiving a prostate biopsy were identified using multivariate regression analysis. RESULTS: A total of 201 men were identified in the pre USPSTF period and 212 men, thereafter. The groups were comparable in age, race, prostate cancer family history, PSA values, and digital rectal examination findings. At the initial evaluation, patients presenting after the statement were more likely to undergo PCA3 testing (27% vs 11%; P <.01) and repeat PSA testing (82% vs 72%; P = .02) and less likely to undergo immediate biopsy (16% vs 24%; P = .03). The proportion of patients ultimately receiving a biopsy was equivalent. The groups were similar in the percentage of positive biopsies, Gleason distribution, and D'Amico risk. African American race and family history were predictors for receiving a biopsy in the post-USPSTF group but not in the pre USPSTF group. CONCLUSION: The 2012 USPSTF recommendation statement has not affected the number or clinical characteristics of patients referred to a tertiary center for elevated PSA level. After recommendation, urologists ordered significantly more PCA3 and repeat PSA tests and recommended fewer biopsies at the initial visit. The fraction of patients ultimately receiving a biopsy remained the same. PMID- 25440820 TI - Supine transgluteal vs prone position in extracorporeal shock wave lithotripsy of distal ureteric stones. AB - OBJECTIVE: To evaluate of efficacy of transgluteal (supine) approach for shock wave lithotripsy (SWL) in treatment of distal ureteric stones. PATIENTS AND METHODS: This prospective, randomized, comparative study was conducted on 98 patients. Patients were randomly assigned into 2 groups: group A (n = 49; prone position) and group B (n = 49; supine position, transgluteal). Inclusion criteria included patients with radiopaque lower ureteric stones <=10 mm. Exclusion criteria included radiolucent stones, stones >10 mm, the need for any auxiliary procedure, and any contraindication for SWL. Post-SWL evaluation included plain x ray of kidney, ureter, and bladder at 2 weeks after treatment and then at monthly intervals after treatment for 3 months. Stone-free status was defined as no residual stone fragments visible on plain x-ray. Treatment failure was defined as persistence of stone fragments at 3 months or the need for ureteroscopy. RESULTS: Stone-free rate after 1 treatment session was achieved in 44.9% and 75.5% for prone and supine positions, respectively. Proceeding to ureteroscopy, after failure of the second SWL session to clear the stones, was done in 34.7% and 8.2% for prone and supine positions, respectively. The overall success rate for SWL treatment in prone and supine groups was 65.3% and 91.8%, respectively (P <.001). CONCLUSION: Transgluteal SWL while patient in supine position proved efficacy for treatment of distal ureteric stones. Larger group studies comparing the results of SWL in supine position with those of prone position and also with those of ureteroscopy may enrich our data to reach a consensus for the ideal management of distal ureteric stones. PMID- 25440821 TI - Quantification of asymptomatic kidney stone burden by computed tomography for predicting future symptomatic stone events. AB - OBJECTIVE: To find the optimal characterization of asymptomatic radiographic stone burden on computed tomography (CT) scans. METHODS: A survey was sent to stone formers who underwent a CT scan while asymptomatic during a stone clinic evaluation. Symptomatic stone passage events after CT scan were detected by survey and medical record review. Radiographic stone burden was quantified by number of stones, largest stone diameter, automated total stone volume (TSV), and bilateral stones and then compared as predictors of stone events. RESULTS: There were 550 stone formers; 43% had a stone event for a median of 4.7 years after the CT scan. Stone burden by quartiles was 0-1, 2-3, 4-6, and >=7 for number of stones; 0-2, 3-4, 5-7, and >=8 mm for largest stone diameter; and 0-8, 9-78, 79 280, and >=281 mm(3) for TSV; 48% had bilateral stones. The hazard ratios (HRs) for symptomatic event was 1.30 (P <.001) for the number of stones per quartile, 1.26 (P <.001) for largest stone diameter per quartile, 1.38 (P <.001) for TSV per quartile, and 1.80 (P <.001) for bilateral stones. On multivariate analysis, only TSV was an independent predictor of symptomatic events (HR, 1.35 per quartile; P = .01). This risk of events with TSV was also independent of demographics, urine chemistries, and stone composition. Among the 53 patients with interim events between CT scans, a rapid increase in TSV between CT scans (>570 mm(3) per year) predicted subsequent events (HR, 2.8; P = .05). CONCLUSION: Automated TSV is more predictive of symptomatic events than manual methods for quantifying stone burden on CT scan. PMID- 25440822 TI - Comparative study of the treatment of renal stones with flexible ureterorenoscopy in normal weight, obese, and morbidly obese patients. AB - OBJECTIVE: To compare the efficacy and the safety of flexible ureterorenoscopy (f URS) in the treatment of kidney stones according to the body mass index (BMI), which seems to be less influenced by weight compared with shock wave lithotripsy and percutaneous nephrolithotomy. METHODS: We conducted a retrospective monocentric study in patients with a known BMI who underwent an f-URS for kidney stones between 2006 and 2008. Success rates in the obese patients (OP) group (BMI >=30 kg/m(2)) were compared with success rates in the normal weight patients (NWP) control group (BMI <25 kg/m(2)). Patients with a BMI >=40 kg/m(2) were defined as morbidly obese patients (MOP), a subgroup of the OP group. The success was defined as a stone-free status (no or <=2 mm residual stone) at the time of control, 3 months after the procedure assessed by kidneys-ureters-bladder radiography coupled with ultrasound (only in NWP with radiopaque stones), or computed tomography-scan. RESULTS: A total of 327 procedures were performed, including 97 f-URS in 87 OP (including 14 procedures in 13 MOP) and 230 procedures for 188 NWP. The overall success rate was 67.4% and 68% in the NWP and OP, respectively; P = .91 (71.4% in the MOP subgroup). Success rates decreased with an increasing stone size without any differences between the groups. Regardless of location and stone size (<10, 10-20, >20 mm), there was no statistical difference in the success rate. Postoperative morbidity was similar in both groups and occurred in 2.44% of cases. CONCLUSION: f-URS for kidney stones resulted in similar outcomes in NWP and OP, and even MOP, regardless of stone size and location and with equivalent morbidity. PMID- 25440823 TI - Percutaneous nephrolithotomy in pelvic kidneys: is the ultrasound-guided puncture safe? AB - OBJECTIVE: To demonstrate our experience with the use of ultrasound (USG) for puncture guidance while performing percutaneous nephrolithotomy in ectopic pelvic kidneys. METHODS: From January 1990 to December 2013, we have performed percutaneous nephrolithotomy in 26 patients with USG-guided punctures. The stones were solitary in 15 patients (58%) and multiple in 11 patients (42%). The mean stone size was 22 mm (range, 10-50 mm), including 3 staghorn calculi. All procedures were performed in an oblique-supine position, and the intraoperative complications as the postoperative outcome were reviewed. RESULTS: The mean operative time was 93 minutes, achieving complete stone clearance in 22 (88%) of the patients. One of the patients had urine leakage after removing nephrostomy, needing postoperative double J stenting. One patient had significant intraoperative bleeding requiring staging of the procedure and blood transfusion. No bowel injuries were identified. Mean hospitalization time was 5.6 days. CONCLUSION: USG-guided puncture is a safe and effective approach to the collecting system even in renal anomalies like in pelvic ectopic kidneys when performed in experienced hands. PMID- 25440824 TI - Robotic partial nephrectomy for completely endophytic renal tumors: complications and functional and oncologic outcomes during a 4-year median period of follow-up. AB - OBJECTIVE: To evaluate the renal functional outcome, the oncologic safety, and the occurrence of complications after robotic-assisted laparoscopic partial nephrectomy (RPN) for completely endophytic tumors. MATERIAL AND METHODS: Data of 45 patients with completely endophytic tumors, 116 patients with mesophytic, and 64 patients with exophytic masses who underwent RPN were retrospectively analyzed. Perioperative, oncologic, and functional data were evaluated and analyzed with SPSS, version 18. RESULTS: Demographic characteristics were similar among the groups. The median follow-up of the endophytic, the mesophytic, and the exophytic groups were 48, 43, and 38 months, respectively. Endophytic masses were more likely to be malignant and have a higher overall tumor complexity, estimated by the RENAL score (9 vs 8 vs 5.5; P <.01; P = .02). We did not detect any statistically significant differences among the groups regarding blood loss volume, transfusion rates, length of stay, and intraoperative and postoperative complications (P = .49, .25, .87, .42, and .20, respectively). There was a statistically significant difference in the estimated glomerular filtration rate percentage change on the first postoperative day (P = .02), but this significance was not observed after the first week. The patients in the endophytic group showed a tendency toward increased rates of positive surgical margins compared with the mesophytic and exophytic groups (P = .06). However, there were not any significant differences regarding the recurrence-free survival rates (P = .335) and the overall mortality rates (P = .570) according to the Kaplan-Meier analysis. CONCLUSION: In experienced institutes, RPN for entirely intraparenchymal masses is a feasible procedure in terms of complication rates, functional and oncologic outcomes during an intermediate-term period of follow up. PMID- 25440825 TI - The association between impaired autophagy and the development of congenital ureteropelvic junction obstruction. AB - OBJECTIVE: To investigate the association between impaired autophagy in smooth muscle cells and the development of congenital ureteropelvic junction (UPJ) obstruction (UPJO). MATERIALS AND METHODS: Tissue specimens were obtained from 40 patients with unilateral UPJO and were divided into 3 sections as renal pelvis, site of obstruction, and the ureter distal to obstruction. Control specimens were obtained from the UPJ of 40 age-matched cadavers. Autophagy was evaluated by image analysis techniques for the expression of light chain 3 (LC3) after immunohistochemical staining of LC3 rabbit polyclonal antibody and Western blot analysis; additionally, myocyte apoptosis was determined using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, 4',6-diamidino 2-phenylindole staining, and p53 immunohistochemical staining. To assess the possible role of cell senescence, P21 and P16 immunohistochemistry staining was applied. Cellular proliferation was assessed by image analysis of proliferating cell nuclear antigen-stained specimens. RESULTS: LC3 expression was significantly increased at the renal pelvis (P <.05). Apoptotic indices of smooth muscle cells and Bcl-2 were significantly greater at the site of UPJO (5.15 +/- 0.91) compared with the UPJs of the control group (P <.001). A significant negative correlation was found between TUNEL and LC3 in all sections of the obstructed UPJ complex (P <.05). Proliferating cell nuclear antigen and LC3 were positively correlated in the renal pelvis and UPJ (P <.05); however, no specimen was stained for p16, p21, and p53. CONCLUSION: In conclusion, impaired autophagy is associated with the development of congenital UPJO. Nonetheless, further studies are mandated to establish its etiologic role. PMID- 25440826 TI - Urinary retention in children. AB - OBJECTIVE: To describe the causes and outcome of urinary retention in children and assess its prevalence by gender and age. METHODS: The medical records of all children (aged <18 years) who presented to the emergency room with acute urinary retention from 2000 to 2012 were reviewed. Patients with postoperative urinary retention, a known neurologic disorder, and neonates were excluded. Data were collected on patient demographics and cause, treatment, and outcome of the urinary retention. Findings were evaluated and compared by age and gender. RESULTS: The study group comprised 42 boys (75%) and 14 girls (25%). Median follow-up time was 25 months. Causes of urinary retention were mechanical obstruction in 14 patients (25%), infection or inflammation in 10 (18%), fecal impaction in 7 (13%), neurologic disorders in 6 (11%), gynecologic disorders in 4 (7%), and behavioral processes in 3 patients (5%); 12 patients (21%) were idiopathic. All patients with mechanical obstruction were boys, of whom 5 had a pelvic tumor. Age distribution was bimodal: 29% of the events occurred between ages 3 and 5 years, and 32%, between ages 10 and 13 years. Fifteen children underwent surgery. Three children required continuous catheterization during follow-up. CONCLUSION: Urinary retention in children is characterized by a variable etiology and bimodal age distribution. The high rate of severe underlying disease is noteworthy and should alert physicians to the importance of a prompt, comprehensive, primary evaluation of this patient population in a hospital setting to initiate appropriate treatment and avoid complications. PMID- 25440827 TI - Reactivity of diabetic urinary bladder to the cholinesterase inhibitor neostigmine. AB - OBJECTIVE: To examine the effects of neostigmine, an acetylcholinesterase inhibitor that has been used to treat impaired bladder emptying on diabetic rat urinary bladder smooth muscle. METHODS: Rat urinary detrusor muscle strips were suspended in organ baths containing Krebs' solution for isometric tension recording. Streptozotocin-diabetic (12 weeks) bladder tissue activity compared with control was assessed by using electrical field stimulation (EFS) in the presence and absence of the cholinesterase inhibitor, neostigmine. RESULTS: EFS induced contractions; a major part of it is cholinergic in origin. Neostigmine significantly enhanced EFS-induced contractions in diabetic strips than control at all frequencies. Neostigmine caused concentration-dependent contractions of control and diabetic bladder tissues, which were completely abolished by atropine. Carbachol-induced bladder contraction was significantly reduced in diabetes. CONCLUSION: In diabetes mellitus, cholinesterase modulation (increase) may play a role in the development of inadequate bladder contraction, seen in later stage diabetic bladder dysfunction. PMID- 25440828 TI - The new approach to classification: rethinking cognition and behavior in epilepsy. AB - There has been considerable debate surrounding the benefits and drawbacks of the new approach to classifying the epilepsies released by the ILAE Commission on Classification and Terminology (2005-2009). This new approach has significant implications for the way we conceptualize and assess cognition and behavior in epilepsy; however, as yet, there has been limited discussion of these issues in the field. The purpose of this Targeted Review is to spark this discussion by encouraging researchers and clinicians to think about the changes that the new approach may bring. These may include (i) reframing the way we think about the comorbidities of epilepsy, (ii) more precisely characterizing the cognitive and behavioral phenotypes of electroclinical syndromes, (iii) more carefully mapping the longitudinal trajectory of cognitive and behavioral features relative to the timing of seizures, and (iv) considering the links between cognitive, behavioral, and neurological phenotypes in the new classification scheme. It is hoped that such changes will aid translation of the advances in cognitive and behavioral neuroscience into routine clinical practice by providing purer markers of disease and more targeted treatments. A Special Issue canvassing such issues will be forthcoming that will consider current knowledge of the cognitive and behavioral features of the epilepsies from the view of the new classification scheme. PMID- 25440829 TI - Metabolic and mitochondrial disorders associated with epilepsy in children with autism spectrum disorder. AB - Autism spectrum disorder (ASD) affects a significant number of individuals in the United States, with the prevalence continuing to grow. A significant proportion of individuals with ASD have comorbid medical conditions such as epilepsy. In fact, treatment-resistant epilepsy appears to have a higher prevalence in children with ASD than in children without ASD, suggesting that current antiepileptic treatments may be suboptimal in controlling seizures in many individuals with ASD. Many individuals with ASD also appear to have underlying metabolic conditions. Metabolic conditions such as mitochondrial disease and dysfunction and abnormalities in cerebral folate metabolism may affect a substantial number of children with ASD, while other metabolic conditions that have been associated with ASD such as disorders of creatine, cholesterol, pyridoxine, biotin, carnitine, gamma-aminobutyric acid, purine, pyrimidine, and amino acid metabolism and urea cycle disorders have also been associated with ASD without the prevalence clearly known. Interestingly, all of these metabolic conditions have been associated with epilepsy in children with ASD. The identification and treatment of these disorders could improve the underlying metabolic derangements and potentially improve behavior and seizure frequency and/or severity in these individuals. This paper provides an overview of these metabolic disorders in the context of ASD and discusses their characteristics, diagnostic testing, and treatment with concentration on mitochondrial disorders. To this end, this paper aims to help optimize the diagnosis and treatment of children with ASD and epilepsy. This article is part of a Special Issue entitled "Autism and Epilepsy". PMID- 25440830 TI - Commentary on Szaflarski's "Social determinants of health in epilepsy" in Epilepsy & Behavior. PMID- 25440831 TI - Comments on Jones JE et al. Rates and risk factors for suicide, suicidal ideation, and suicide attempts in chronic epilepsy. Epilepsy & Behavior 2003;4(Suppl. 3):S31-38. PMID- 25440832 TI - Comments on Hughes JR. The Mozart effect. Epilepsy & behavior 2001;2:369-417. PMID- 25440833 TI - Comments on Loddenkemper et al. Lateralizing signs during seizures in focal epilepsy. Epilepsy & behavior 2005;7:1-17. PMID- 25440834 TI - Comments on Maganti R et al. Nonconvulsive status epilepticus. Epilepsy & behavior 2008;12:572-586. PMID- 25440835 TI - Happy anniversary from founding associate editor Dr. Orrin Devinsky. PMID- 25440837 TI - Intellectual glasnost at the interface. PMID- 25440838 TI - My personal history with Epilepsy & behavior. PMID- 25440840 TI - Epilepsy & behavior: making people with epilepsy the focus. PMID- 25440841 TI - Trends and group differences in the association between educational attainment and U.S. adult mortality: implications for understanding education's causal influence. AB - Has the shape of the association between educational attainment and U.S. adult mortality changed in recent decades? If so, is it changing consistently across demographic groups? What can changes in the shape of the association tell us about the possible mechanisms in play for improving health and lowering mortality risk over the adult life course? This paper develops the argument that societal technological change may have had profound effects on the importance of educational attainment - particularly advanced education - in the U.S. adult population for garnering health advantages and that these changes should be reflected in changes in the functional form of the association between educational attainment and mortality. We review the historical evidence on the changing functional form of the association, drawing on studies based in the United States, to assess whether these changes are consistent with our argument about the role of technological change. We also provide an updated analysis of these functional form patterns and trends, contrasting data from the early 21st Century with data from the late 20th Century. This updated evidence suggests that the shape of the association between educational attainment and U.S. adult mortality appears to be reflecting lower and lower adult mortality for very highly educated Americans compared to their low-educated counterparts in the 21st Century. We draw on this review and updated evidence to reflect on the question whether education's association with adult mortality has become increasingly causal in recent decades, why, and the potential research, policy, and global implications of these changes. PMID- 25440842 TI - Curling's ulcer - have these stress ulcers gone extinct? PMID- 25440843 TI - Anti-inflammative effect of glycyrrhizin on rat thermal injury via inhibition of high-mobility group box 1 protein. AB - AIM: Glycyrrhizin (Gly) has been reported as an inhibitor of extracellular HMGB1 (high-mobility group box 1 protein) cytokine's activity, and protects spinal cord, liver, heart and brain against ischemia-reperfusion-induced injury in rats. The purpose of this study was to investigate the protective effect of Gly in rat skin thermal injury model and to elucidate the underlying mechanisms. METHODS: Twenty-four male Sprague-Dawley rats (200-250g) were randomly divided into control group, vehicle-treated and Gly-treated burn groups, each group contained eight animals. In the latter two groups, rats were subjected to 30% TBSA (Total Body Surface Area) full-thickness scald injury. In Gly-treated burn group, glycyrrhizin (60mg/kg) was administered intraperitoneally immediately after and at 24th hour burn; in vehicle-treated burn group, Ringer's solution (4ml/kg, as a vehicle) was administered intraperitoneally immediately after and at 24th hour burn. The animals were sacrificed at 48h after injury. Aortic blood samples were obtained to detect tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) with ELISA (Enzyme-Linked Immuno Sorbent Assay) kits. Lung, liver and kidney tissue samples were collected to determine the expression of HMGB1 mRNA and protein. HMGB1 mRNA level was semiquantitatively measured by Real-Time PCR using beta-actin as an internal standard, and protein expression of HMGBI was determined by Western blot. RESULTS: Severe skin scald injury caused a significant increase in plasma TNF-alpha and IL-1beta versus the control group (P<0.001) in 48h after burns. Intraperitoneal administration of Gly (60mg/kg) significantly reduced the levels of serum TNF-alpha and IL-1beta (P<0.01). Gly treatment reduced these biochemical indices accompanied by lower level of HMGB1 protein (P<0.05) and mRNA expression (P<0.01). CONCLUSION: These results demonstrate that Gly possesses an anti-inflammation effect to protect the remote organs from burn-induced injury. PMID- 25440844 TI - Airborne bacterial dispersal during and after dressing and bed changes on burns patients. AB - BACKGROUND: It is acknowledged that activities such as dressing changes and bed sheet changes are high-risk events; creating surges in levels of airborne bacteria. Burns patients are particularly high dispersers of pathogens; due to their large, often contaminated, wound areas. Prevention of nosocomial cross contamination is therefore one of the major challenges faced by the burns team. In order to assess the contribution of airborne spread of bacteria, air samples were taken repeatedly throughout and following these events, to quantify levels of airborne bacteria. METHODS: Air samples were taken at 3-min intervals before, during and after a dressing and bed change on a burns patient using a sieve impaction method. Following incubation, bacterial colonies were enumerated to calculate bacterial colony forming units per m(3) (cfu/m(3)) at each time point. Statistical analysis was performed, whereby the period before the high-risk event took place acted as a control period. The periods during and after the dressing and bed sheet changes were examined for significant differences in airborne bacterial levels relative to the control period. The study was carried out four times, on three patients with burns between 35% total burn surface area (TBSA) and 51% TBSA. RESULTS: There were significant increases in airborne bacteria levels, regardless of whether the dressing change or bed sheet change took place first. Of particular note, is the finding that significantly high levels (up to 2614cfu/m(3)) of airborne bacteria were shown to persist for up to approximately 1h after these activities ended. DISCUSSION: This is the most accurate picture to date of the rapidly changing levels of airborne bacteria within the room of a burns patient undergoing a dressing change and bed change. The novel demonstration of a significant increase in the airborne bacterial load during these events has implications for infection control on burns units. Furthermore, as these increased levels remained for approximately 1h afterwards, persons entering the room both during and after such events may act as vectors of transmission of infection. It is suggested that appropriate personal protective equipment should be worn by anyone entering the room, and that rooms should be quarantined for a period of time following these events. CONCLUSION: Airborne bacteria significantly increase during dressing and sheet changes on moderate size burns, and remain elevated for up to an hour following their cessation. PMID- 25440845 TI - A population-based study of the epidemiology of acute adult burns in Ecuador from 2005 to 2014. AB - OBJECTIVES: To describe the demographic, risk factor, occupational, and morbidity and mortality characteristics of burns in adults in Ecuador using national data. These data are from the only specialized public hospital in Ecuador that has a 12 bed burn unit. METHODS: The National Institute of Statistics and Census provided data from the burn unit of the Hospital Eugenio Espejo, in Quito. Three different datasets pertaining to burn deaths, burn unit inpatient admissions, and hospital discharge were analyzed. Patients who died or were discharged before entering the burn unit were not included in this analysis. RESULTS: During the 10-year period, 1106 patients were admitted to the burn unit, men represent 69.37% with 768 cases and women represent 30.62% with 337 patients; the number of patients per year was on average 123 cases; the average age was 33-34 years old, with a range between 16 and 96 years old. Heat (thermal) burns represent 65.78% followed by electrical with 30.53%, friction burns with 2.06%, and chemical burns with 1.62%. Domestic methane gas was the most frequent agent causing thermal burns and the most affected occupational groups are construction workers and people who stay at home. The overall mortality is 10.2% and the average length of stay was 23 days. CONCLUSIONS: Thermal burns are more frequent than any other cause of burns. Electrical burns are more frequent in Ecuador than anywhere else according to our research, meaning that control and prevention of workplace safety, urban planning, and home safety are scarce. The most affected groups are those dedicated to labor work. Finally, mortality in hospitalized patient is higher when compared with developed countries. PMID- 25440846 TI - Adipose-derived stem cells cultivated on electrospun l-lactide/glycolide copolymer fleece and gelatin hydrogels under flow conditions - aiming physiological reality in hypodermis tissue engineering. AB - INTRODUCTION: Generation of adipose tissue for burn patients that suffer from an irreversible loss of the hypodermis is still one of the most complex challenges in tissue engineering. Electrospun materials with their micro- and nanostructures are already well established for their use as extracellular matrix substitutes. Gelatin is widely used in tissue engineering to gain thickness and volume. Under conventional static cultivation methods the supply of nutrients and transport of toxic metabolites is controlled by diffusion and therefore highly dependent on size and porosity of the biomaterial. A widely used method in order to overcome these limitations is the medium perfusion of 3D biomaterial-cell-constructs. In this study we combined perfusion bioreactor cultivation techniques with electrospun poly(l-lactide-co-glycolide) (P(LLG)) and gelatin hydrogels together with adipose-derived stem cells (ASCs) for a new approach in soft tissue engineering. METHODS: ASCs were seeded on P(LLG) scaffolds and in gelatin hydrogels and cultivated for 24 hours under static conditions. Thereafter, biomaterials were cultivated under static conditions or in a bioreactor system for three, nine or twelve days with a medium flow of 0.3ml/min. Viability, morphology and differentiation of cells was monitored. RESULTS: ASCs seeded on P(LLG) scaffolds had a physiological morphology and good viability and were able to migrate from one electrospun scaffold to another under flow conditions but not migrate through the mesh. Differentiated ASCs showed lipid droplet formations after 21 days. Cells in hydrogels were viable but showed rounded morphology. Under flow conditions, morphology of cells was more diffuse. DISCUSSION: ASCs could be cultivated on P(LLG) scaffolds and in gelatin hydrogels under flow conditions and showed good cell viability as well as the potential to differentiate. These results should be a next step to a physiological three dimensional construct for soft tissue engineering and regeneration. PMID- 25440847 TI - Burns in patients over 90: a fifteen-year series from a regional burns centre. AB - The elderly constitute an expanding subgroup within society, and may have differences in health needs compared to younger patients. The specific needs and outcomes of elderly patients with burns have been widely studied. However, the definition of elderly often used in previous studies is a cut off of 65 years old. Within this broadly defined group, the very elderly may have distinct health care needs and issues. This study investigated aetiology, management and outcome of burns in those over 90 years treated at a single UK burns service over a period of 15 years between 1998 and 2013, and compares these data to published data describing 'younger' elderly burns patients. Twenty two patients were included, with a 2:1 female:male ration, and a mean 9%TBSA burn. Six of the 22 died during their admission, and those who survived averaged 8 days inpatient stay per %TBSA. The very elderly with burns may fare worse than younger elderly patients. Although burns in the very elderly are relatively infrequent events, they require significant resource. Further work to optimise their outcome is required. PMID- 25440848 TI - 3D photography is an accurate technique for measuring small wound areas. PMID- 25440849 TI - Childhood burns in Sulaimaniyah province, Iraqi Kurdistan: a prospective study of admissions and outpatients. AB - BACKGROUND: While it is globally observed that young children are at a higher risk of burn injuries, little is known about childhood burns in Iraqi Kurdistan. This study was undertaken to describe the epidemiology of burns amongst pre school children in this region. METHODS: A prospective study was undertaken from November 2007 to November 2008 involving all children aged 0-5 years attending the burns centre in Sulaimaniyah province for a new burn injury whether treated as an outpatient or admitted to hospital. RESULTS: 1,122 children attended the burns centre of whom 944 (84%) were interviewed (male 53%, female 47%). Mean age was 1.9 years with children aged 1 year comprising 32% and those aged 2 years comprising 21% of the sample. The incidence of burns was 1044/100,000 person years (1030 in females and 1057 in males). Mechanisms of injury included scalds (80%), contact burns (12%) flames (6%) and other mechanisms (2%). Almost 97% of burns occurred at home including 43% in the kitchen. Winter was the commonest season (36%) followed by autumn (24%). There were 3 peak times of injury during the day corresponding to meal times. The majority of burns were caused by hot water (44%) and tea (20%) and the most common equipment/products responsible were tea utensils (41%). There were 237 admissions with an admission rate of 95 per 100,000 person-years. Scald injuries accounted for most admissions (84%). Median total body surface area affected by the burn or scald (TBSA) was 11% and median hospital stay was 7 days. In-hospital mortality was 8%. Mortality rate was 4% when TBSA was <=25%, and 100% when TBSA was over 50%. CONCLUSION: Burn incidence is high in young children especially those aged 1-2 years. Preventive interventions targeted at families with young children & focusing on home safety measures could be effective in reducing childhood burns. PMID- 25440850 TI - Should pyogenic granulomas following burns be excised? AB - BACKGROUND: Patients with pygenic granuloma following burns (PGB) presents dramatic clinical features which are different from those with classic pyogenic granuloma. This review aims to discuss whether pyogenic granuloma following burns (PGB) need excision or not. METHODS: Using the PubMed, EMBASE, Cochrane Library and web of science databases. All articles which discussed diagnosis and treatment of pyogenic granuloma following burns with histological results were included from 1978 to 2013. Reports from meetings were not included. Only articles published in English were included. RESULTS: Twenty one articles excluded from a total of 32 studies. One study was excluded from the 11 descriptive studies because of typical histological results. The rest, 10 studies were case reports. Only one article was published in French, whose abstract was published in French and English. Patients with PGB presented six distinctive clinical features. First, all the patients had burns initially. The second, PGB acutely erupted between 1 and 4 weeks in patients' burned area, which may be infected by bacteria, fungus and virus. The fourth, PGB can be classified into proliferative and shrivelling stages. The fifth, three hisiological characteristics including hyperkeratosis or acanthosis, numerous newly formed proliferative vascular, edematous stroma with infiltration by plasma cells and lymphocytes. Finally, recurrence, 6 out of 16 patients with PGB involuted spontaneously with no recurrence. Three out of 16 patients were conservatively managed with no recurrence, neither patients (5) who had surgery and 2 patients treated with electro coagulation had recurrence. CONCLUSIONS: PGB lesions are benign based on clinical features and histological examinations. The clinical process of PGB could be divided into proliferative and shrivelling stages. Conservative treatment including wound management and antibiotic could be chosen firstly, especially when large PGBs are on the face or other important area of one's body. When conservative treatment is ineffective, a surgery could be chosen. PMID- 25440851 TI - Reconstruction of transhumeral amputation stumps with ipsilateral pedicled latissimus dorsi myocutaneous flap in high voltage electrical burns. AB - Injury due to high-voltage (>1000V) electricity is one of the most challenging problems in emergency medicine and plastic surgery. Extremity amputation because of electrical injury yields a stump that leaves vital structures, such as bone, muscle, blood vessels, and nerves, exposed; these structures should be covered with appropriate tissue. We designed a retrospective study that included twelve patients with a high-voltage electrical injury followed by trans-humeral amputation who were evaluated between 2004 and 2013. The ages of the patients ranged between 8 and 35 years (mean, 16.9 years). Following amputation, the defects were covered with an ipsilateral pedicled latissimus dorsi (LD) myocutaneous flap for stump protection and functional transfer. We concluded that the use of an ipsilateral LD myocutaneous flap is an adequate surgical operation in upper extremity amputations resulting from high-voltage electrical burn injuries and that this procedure permits stump length maintenance, contributes to arm functioning, avoids extended operation times, and prepares patients for prosthesis usage. PMID- 25440852 TI - Hydrogen-rich saline resuscitation alleviates inflammation induced by severe burn with delayed resuscitation. AB - Severe burns with delayed resuscitation are associated with high morbidity which is attributed to ischemia-reperfusion injury. This study was undertaken to investigate the effect of hydrogen-rich saline known as a significant selective antioxidant on the inflammatory reaction induced by severe burns with delayed resuscitation. By establishing the model of severe burns with delayed resuscitation in rats, we recorded improvement on the mortality, secretion of cytokines and reaction of oxidative stress of rats treated with hydrogen-rich saline. We found that resuscitation by hydrogen-rich saline alleviated inflammation significantly. We further detected the change of the key nuclear factor NF-kappaB contributed to inflammation. The expression of both NF-kappaB and phosphorylated NF-kappaB in rats having severe burns with delayed resuscitation by hydrogen-rich saline was lower than that in rats with delayed resuscitation with Ringers' solution. Our data imply that hydrogen-rich saline significantly improves the inflammatory reaction in rats with severe burns with delayed resuscitation, possibly by inhibiting activation of NF-kappaB. PMID- 25440853 TI - Epidemiology and outcome analysis of scalds in children caused by "guo lian kang": an 11-year review in a burn center in China. AB - OBJECTIVES: The objective of this study was to investigate the epidemiological characteristics of scalds induced by "guo lian kang" (literally "stove connected to bed") in children. METHODS: The demographic, burn features, outcome, and other information of 0-14-year-old children with "guo lian kang"-induced scalds admitted to the burn treatment center of the 322 Hospital of the People's Liberation Army in Datong from 30 September 2001 to 31 December 2011 were analyzed. RESULTS: Among the 1993 children clearly documented with scalds due to hot liquid in vessels, 795 (39.89%) had burns due to "guo lian kang." The proportion of the pediatric burns caused by "guo lian kang" was 55.56% in 2002 and 37.30% in 2011, with a decreasing trend. One-year-old children accounted for the highest proportion of children with burns due to "guo lian kang" (male:female=1.54:1). Scalding mostly occurred from October to May; the most common times were around 8:00 AM, 11:00 AM, and 7:00 PM. Most scalds occurred on the upper limbs, 90.22% of which were dermal burns. The median burn area was 11% of the total body surface area. The burn agent was mainly hot water in pots. Scalding mostly occurred when the children accidentally sat on, or fell or stepped into the pot while playing. Among the children with "guo lian kang" induced scalds, up to 42.26% of the children did not receive any treatment before hospital admission, and 18.86% of the children were admitted to the hospital >=6h after the occurrence of burns. In addition, 74.97% of the children's families can afford the medical expenses, while 5.28% abandoned treatment because of financial difficulties. There were no significant differences between children with scalds caused by "guo lian kang" and scalds caused due to other reasons considering the age and sex. Compared to scalds due to other reasons, children with "guo lian kang"-induced scalds had greater burn area and depth, shock incidence, surgery rate, blood transfusion rate, length of hospital stay, and hospitalization costs. CONCLUSION: Preventive measures against burns should be taken from October to May and mainly during cooking time in order to prevent burns in children less than 3 years of age, especially in 1-year-old boys. The most simple and effective preventive measure is to install a barrier between the pot and bed. The incidence of shock in children may be reduced if parents and primary medical staff undergo training to perform first aid for burns and if there are improvements in the referral system after burns. PMID- 25440854 TI - Scald burns in children aged 14 and younger in Australia and New Zealand-an analysis based on the Burn Registry of Australia and New Zealand (BRANZ). AB - INTRODUCTION: Scalds are a common injury in children and a frequent reason for hospitalisation despite being a preventable injury. METHODS: This retrospective two year study reports data from 730 children aged 14 years or younger who sustained a scald between 2009 and 2010 and were admitted to a burns centre in Australia or New Zealand. Data were extracted from the Burn Registry of Australia and New Zealand (BRANZ), which included data from 13 burns centres in Australia and New Zealand. RESULTS: Scald injury contributed 56% (95% CI 53-59%) of all pediatric burns. There were two high risk groups; male toddlers age one to two, contributing 34% (95% CI 31-38%) of all scalds, and indigenous children who were over 3 times more likely to experience a scald requiring admission to a burns unit than their non-indigenous peers. First aid cooling by non-professionals was initiated in 89% (95% CI 86-91%) of cases but only 20% (95% CI 16-23%) performed it as recommended. CONCLUSION: This study highlights that effective burn first aid reduces hospital stay and reinforces the need to encourage, carers and bystanders to deliver effective first aid and the importance of targeted prevention campaigns that reduce the burden of pediatric scald burns in Australia and New Zealand. PMID- 25440855 TI - Burns and epilepsy--review and case report. AB - Decompensation of epilepsy in burned patients may be caused by several factors. Burn is a classic etiology of systemic inflammatory response syndrome, and evolves into two physiological phases. The first 48h after injury corresponds to the first phase involving severe hypovolemic shock. The second phase corresponds to the hypermetabolic response to burns. Altered pharmacokinetics of anticonvulsant drugs is observed. Albumin and other plasma proteins are reduced, leading to increased free fraction of phenytoin, resulting in greater clearance and a lower total drug concentration. Associated with metabolic changes of burned patient, this fact predisposes to seizures in epileptic burned patients. The authors present the case of an epileptic 36-year-old-woman who developed recurrent seizures after a thermal injury, despite using the same medications and doses of anticonvulsant drugs of last 12 years, with controlled epilepsy. PMID- 25440856 TI - Management of acid burns: experience from Bangladesh. AB - Acid burn injuries in Bangladesh primarily occur as a result of intentional attacks although there are incidences of accidental acid burns in industry, on the street, and at home. A total of 126 patients with acid burns, 95 from attacks and 31 from accidents, were studied from July 2004 to December 2012. A diagnosis of acid burn was made from history, physical examination and in some cases from chemical analysis of the patients' clothing. Alkali burns were excluded from the study. In the burn unit of Dhaka Medical College Hospital, we applied a slightly different protocol for management of acid burns, beginning with plain water irrigation of the wound, which effectively reduced burn depth and the requirement of surgical treatment. Application of hydrocolloid dressing for 48-72 h helped with the assessment of depth and the course of treatment. Early excision and grafting gives good results but resultant acid trickling creates a marble cake like appearance of the wound separated by the vital skin. Excision with a scalpel and direct stitching of the wounds are often a good option. Observation of patients on follow-up revealed that wounds showed a tendency for hypertrophy. Application of pressure garments and other scar treatments were given in all cases unless the burn was highly superficial. PMID- 25440857 TI - A new model for the standardization of experimental burn wounds. AB - BACKGROUND: Burns are common and recurrent events treated by physicians on a daily basis at most emergency rooms around the world. There is a constant need to understand the physiopathology of burns, so as to minimize their devastating results. The objective of the present report is to describe a burn apparatus in association with an innovative method of animal fixation, as to produce burns of varying sizes and depths. METHODS: Rats were subjected to burns of 60 degrees C, 70 degrees C, and 80 degrees C for 10 s and after 3 days half of the rats in each group were killed and the resulting lesions were analyzed using histological techniques. In the other half of the rats the wound was measured weakly until complete re-epithelialization. RESULTS: All burns were easily visible and the histological feature for the 60 degrees C burn was a superficial second-degree burn (28% of the dermis), for 70 degrees C we observed a deep second-degree burn (72% of the dermis), and in the 80 degrees C group, a third degree-burn was present (100% of the dermis). CONCLUSIONS: This is a safe, reliable, easy to construct and use model that has the ability to produce a regular and uniform reproducible burn due to precise temperature control associated with standardized animal positioning. PMID- 25440858 TI - Burn surface area calculation instead of burn size estimation: our opinion. PMID- 25440859 TI - Use of point-of-care ultrasound in Connecticut emergency departments. AB - BACKGROUND: Point-of-care ultrasound (PoC US) is now taught and used in nearly all academic emergency departments (EDs), but prior surveys have shown that adoption in the community ED setting is much lower. OBJECTIVE: Our aim was to characterize the current practice of emergency physician (EP)-performed PoC US in Connecticut. METHODS: We conducted a 20-question online survey of all ED directors in Connecticut to determine how PoC US is utilized. The questions addressed ED demographics, ownership of ultrasound (US) equipment, frequency of PoC US performance in general and by examination type, credentialing patterns, quality assurance methods, and billing patterns. RESULTS: The response rate was 83% (25 of 30). Almost all (96%) respondent EDs owned at least one US machine, and 24% used US regularly for diverse applications according to 2008 American College of Emergency Physicians (ACEP) guidelines. PoC US was most commonly used for Focused Assessment with Sonography in Trauma examinations, procedural guidance, and assessing the aorta for an abdominal aortic aneurysm. Although 64% reported hospital ultrasonography privileges, 40% did not keep any record of PoC US performed in the ED. More than half (56%) required an over-read by radiology, and 36% required an over-read by another EP (e.g., ED Ultrasound Director). Only 8% of EDs billed for PoC US. CONCLUSIONS: Most Connecticut EDs own an US machine and have hospital privileges for PoC US. However, a minority use or bill for PoC US regularly for diffuse applications, and most do not have a quality assurance program as described by ACEP guidelines. PMID- 25440860 TI - Intracranial bleeds after minor and minimal head injury in patients on warfarin. AB - BACKGROUND: There is little evidence to guide physicians on management of patients who sustain head injuries while on warfarin. OBJECTIVES: Our objective was to determine the rate of intracranial bleeding in anticoagulated patients with minor and minimal head injuries and the association with clinical features and international normalized ratio (INR). METHODS: We conducted a historical cohort study of adult patients, taking warfarin, at two tertiary care emergency departments over 2 years with minor (Glasgow Coma Score 13-15, with loss of consciousness, amnesia, or confusion) or minimal (Glasgow Coma Score 15 without loss of consciousness, amnesia, or confusion) head injuries. Patients with penetrating injuries, INR < 1.5, or a new focal neurological deficit were excluded. Our outcome, intracranial bleeding, was determined by the radiologist's final computed tomography (CT) report for imaging performed within 2 weeks. RESULTS: There were 176 patients enrolled, of which 157 (89.2%) had CT and 28 (15.9%) had intracranial bleeding. Comparing patients with and without intracranial bleeding found no significant differences in INR, and loss of consciousness was associated with higher rate of intracranial bleeding. The rate of intracranial bleeding in the minor and minimal head injury groups was 21.9% and 4.8%, respectively. CONCLUSIONS: The rate of intracranial bleeding in patients on warfarin is considerable. Loss of consciousness is associated with high rates of intracranial bleeding. This study supports a low threshold for ordering CT scans for anticoagulated patients with head injuries. PMID- 25440861 TI - Delayed hemothorax caused by thymic bleeding after blunt chest trauma. PMID- 25440862 TI - Corneal hydrops. PMID- 25440863 TI - Freestanding emergency departments and the trauma patient. AB - BACKGROUND: Freestanding emergency departments (FEDs) continue to grow in number and more research is needed on these facilities. OBJECTIVE: We sought to characterize the types of injuries and patients who initially presented to two FEDs and were transferred to the main tertiary care ED for trauma team consult and admission. METHODS: This retrospective cohort descriptive study examined medical records of adult trauma patients who were initially seen at an FED and then transferred to the main ED. All patients who received a trauma consultation were included. Data collection included demographics, initial mode of transport to the ED, injury, mechanism of injury, ED, hospital course and outcome. RESULTS: Mean age was 61.8 +/- 23.8, 96.7% were Caucasian and 52.5% were male. Mode of transport to the FEDs included private vehicle (46.4%) and emergency medical services (53.6%). The main injury mechanisms were fall from standing (51.9%) and fall from an object (16%). A total of 12.7% were from motor vehicle accidents and 6.6% presented from bicycle and all-terrain vehicle accidents. Blunt traumatic injuries accounted for 97.8% (n = 177) patients. Computed tomography scanning was performed on 90.1% of patients. Median ED length of stay was 189 min. Mean hospital length of stay was 3 days and 2.2% (n = 4) of patients died from their injuries. CONCLUSIONS: Understanding the patients and traumatic injuries that present to FEDs will guide training and identify resources needed for patients requiring additional care at a trauma center. PMID- 25440864 TI - Total right ovarian vein thrombosis after cesarean section. PMID- 25440865 TI - Occipital nerve blocks in the treatment of headaches: safety and efficacy. AB - BACKGROUND: Considering current limitations in known treatment options and the significant disability associated with headache disorders, investigation of additional options is needed. Although occipital nerve blocks (ONBs) are currently being utilized frequently in specialty settings, the potential role of ONBs as an alternative to opioids for the management of acute headache episodes in primary and emergency care settings is not yet understood. OBJECTIVE: Our aim was to conduct a systematic literature review of the available evidence regarding the use of ONBs for the management of acute headaches, and then determine its potential for use in the emergency care setting. Techniques, medication selection, adverse reactions, frequency of use, candidates, and measures that can help improve safety were reviewed in order to better evaluate the usefulness of this tool in emergency care. DISCUSSION: Occipital nerve blocks are technically simple procedures that are highly successful in providing dramatic pain relief results. They are also a relatively safe and beneficial alternative to other headache treatment options. Case reports and research have demonstrated that ONBs can be performed safely in outpatient settings. However, due to the paucity of literature on the use of ONBs in emergency care settings, it can only be speculated that the same outcomes can be achieved. CONCLUSIONS: Interest in the use of ONBs in acute care settings is increasing. Current evidence supports that ONBs can be delivered safely in an outpatient setting by providers who have been trained in and have practiced this procedure. Although additional research is needed, current evidence supports that ONBs can be useful in treating acute headaches in an emergency care setting. PMID- 25440866 TI - Cerebral venous sinus thrombophlebitis as a complication of acute otitis media. AB - BACKGROUND: While headache is a common emergency department chief complaint, cerebral venous sinus thrombosis (CVST) is an infrequently encountered cause of headache and is often not included in emergency physicians' differential diagnoses for headache. Our objective is to review the latest data on epidemiology, presenting symptoms, diagnosis, and treatment of CVST. CASE REPORT: A 27-year-old female presented to our emergency department with headache, blurred vision, and vomiting a day after being diagnosed with acute otitis media. Computed tomography scan of the brain without contrast in the emergency department was suggestive of CVST. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although a rare cause of headache, CVST should be considered for a subset of patients presenting to the emergency department with the common complaint of headache. CVST is diagnosed by magnetic resonance venogram or computed tomography venogram of the brain. Anticoagulation with close monitoring in consultation with appropriate experts is a safe first-line therapy for CVST, even in patients with hemorrhage on initial imaging. PMID- 25440867 TI - Timely pain management in the emergency department. AB - BACKGROUND: Delivering timely pain relief remains a challenge for most emergency departments. OBJECTIVE: To evaluate the effectiveness of a policy aimed at delivering analgesics within 30 min to patients presenting to an emergency department with severe pain. METHODS: Subjects were aged >=19 years, had a principal diagnosis of renal colic, hip fracture, or sickle cell disease, reported a pain score >=8 on a scale of 0 to 10 at triage, and continued to report a score in this range until receiving analgesia. The study compared proportions of patients receiving analgesics within the 30-min target, median time to analgesic administration, and median time to relief of severe pain (decline in pain level to score <8) during 6 months before vs. 6 months after implementation of the new pain management policy. RESULTS: Paradoxically, the median total waiting time to analgesic administration increased from 64 min (n = 75) to 80 min (n = 70) after policy implementation (p = 0.01), and the proportion of patients receiving analgesics within 30 min declined from 17% (13/75) to 7% (5/70) (p = 0.08). Median time to relief of severe pain did not differ significantly between periods (130.5 vs. 153 min; p = 0.31). CONCLUSIONS: After implementation of the new pain management policy, the proportion of patients with severe pain receiving analgesics within 30 min actually declined. Although a 30 min target may be unrealistic, it seems reasonable to conclude that something is wrong when patients with notoriously painful conditions must typically wait 1-2 h to obtain relief. Given the millions of individuals who receive care in emergency departments nationwide each year, the suffering caused by delays occurs on a large scale, so creative approaches are clearly needed to overcome the obstacles. PMID- 25440868 TI - Not another boring lecture: engaging learners with active learning techniques. AB - BACKGROUND: Core content in Emergency Medicine Residency Programs is traditionally covered in didactic sessions, despite evidence suggesting that learners do not retain a significant portion of what is taught during lectures. DISCUSSION: We describe techniques that medical educators can use when leading teaching sessions to foster engagement and encourage self-directed learning, based on current literature and evidence about learning. CONCLUSIONS: When these techniques are incorporated, sessions can be effective in delivering core knowledge, contextualizing content, and explaining difficult concepts, leading to increased learning. PMID- 25440869 TI - An evidence-based medicine curriculum implemented in journal club improves resident performance on the Fresno test. AB - BACKGROUND: Journal club is a standard component of residency education. Journal club focuses on review and interpretation of the medical literature with varying degrees of evidence-based medicine (EBM) education. OBJECTIVES: To evaluate learning of EBM principles with an EBM curriculum implemented as a component of journal club. EBM competency was established using the Fresno test, a validated 12-question instrument of short-answer and essay-style questions to assess competency in EBM. METHODS: An EBM curriculum was implemented that consisted of a focus on EBM topics (e.g., study validity, bias, confidence intervals, search strategies) using a structured journal club format using a peer instruction model. The Fresno test was used prior to and after the implementation of the first year of this curriculum to measure effectiveness of the intervention. A hierarchical multivariable model using generalized estimating equations was used to account for repeated measures in the primary outcome of change in total Fresno test score. RESULTS: The total test scores did not increase significantly (105.4 vs. 120.9, p = 0.058) in the before-after analysis. The only subscore showing improvement was interpretation of study validity (32.1 vs. 40.4 points, p = 0.03). Attendance was significantly associated with Fresno test score, with those attending >= 6/11 sessions (55%) scoring 28.2 points higher (p = 0.003), and those attending fewer than six sessions scoring only 1.9 points higher (p = 0.81) than in the preintervention group. CONCLUSION: An EBM curriculum implemented as part of journal club improves performance on the Fresno test among residents who attended at least six journal club sessions. PMID- 25440870 TI - Ainhum leading to fifth-digit amputation. PMID- 25440871 TI - Delivering home hemodialysis: is there still a role for real-time treatment monitoring? AB - Remote real-time treatment monitoring for home hemodialysis (HHD) was driven by concerns over patient safety in the early era of HHD. However, decades of clinical experience supported by objective data suggest that HHD is very safe and that remote monitoring is unlikely to avert serious adverse events. As a result, such remote monitoring is not routinely offered in the current era and is generally considered an unnecessary expense. However, a one-size-fits-all approach to abandon remote monitoring may overlook potential opportunities: to improve the clinical care of patients dialyzing at home; and to give patients the confidence to perform HHD in an unsupervised setting. PMID- 25440876 TI - Reply to: Time to resize the role of everolimus as treatment of hepatocellular carcinoma recurrence after liver transplant. PMID- 25440877 TI - Sequencing the head and neck cancer genome: implications for therapy. AB - Head and neck squamous cell carcinoma (HNSCC) is a disease with significant morbidity and mortality. The advancement of next-generation sequencing technologies now enables the landscape of genetic alterations in HNSCCs to be deciphered. In this review, we describe the mutation spectrum discovered in HNSCCs, especially human papilloma virus-associated and/or tobacco smoke exposure associated HNSCCs. We also describe related research from two independent investigators and from the Cancer Genome Atlas. Emphasis is placed on the therapeutic implications of genes frequently altered in HNSCCs (i.e., TP53, PIK3CA, and NOTCH1) and their corresponding pathways, with a particular focus on recent findings of Notch signaling pathway activation in HNSCC. We also discuss the application of integrated genomic pathway-based analysis for precision cancer therapy in HNSCC. PMID- 25440878 TI - Synthesis, physicochemical and biological evaluation of technetium-99m labeled lapatinib as a novel potential tumor imaging agent of Her-2 positive breast cancer. AB - Tumors that are Her-2-positive tend to grow and spread more quickly than other types of breast cancer. Overexpression of Her-2 can be a predictive biomarker for stratification of patients for therapy with Herceptin (containing humanized IgG1 monoclonal antibody trastuzumab) or Tykerb (containing lapatinib di-p toluenesulfonate) drug. Usually, Her-2 status is determined by immunohistochemical (IHC) as well as fluorescent or chromogenic in situ hybridisation (FISH or CISH) analysis of biopsy material. The objective of the present work was to standardize the conjugation of anti-cancer drug lapatinib (which recognizes selectively the Her-2 extracellular domain) with technetium-99m complex, of type '4+1', to obtain (99m)Tc(NS3)(CN-lapatinib) conjugate for use as in vivo tracer of the Her-2 expression in breast cancer. The conjugate (99m)Tc(NS3)(CN-lapatinib) was formed with high yield, high radiochemical purity and specific activity within the range 25-30 GBq/MUmol. The biological in vitro and in vivo studies of the conjugate showed its high affinity to Her-2 receptor (Kd = 3.5 +/- 0.4 nM, Ki = 2.9 +/- 0.5 nM, Bmax = 2.4 +/- 0.3 nM, approximate number of 2.4 * 10(6) binding sites per cell, IC50 = 41.2 +/- 0.4 nM) and also pointed out to the clearance through the hepatic and renal route in comparable degree. Basing on these results one can conclude that (99m)Tc(NS3)(CN-lapatinib) conjugate could be a promising radiopharmaceutical for in vivo diagnosis of the Her-2 status in breast with impact on treatment planning. PMID- 25440879 TI - Design, synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine derivatives possessing diaryl semicarbazone scaffolds as potent antitumor agents. AB - A series of novel thieno[3,2-d]pyrimidine derivatives possessing diaryl semicarbazone scaffolds were designed, synthesized and evaluated for their anticancer activity. Most compounds displayed good to excellent potency against four tested cancer cell lines as compared with GDC-0941 and sorafenib. In this study, a promising compound 36 (PI3Kalpha IC50 = 0.027 MUM) was identified, which showed the most potent antitumor activities with IC50 values of 0.057 MUM, 0.039 MUM, 0.25 MUM, and 0.23 MUM against H460, HT-29, MKN-45 and MDA-MB-231 cell lines, respectively. In addition, the SAR analyses indicated that compounds with 4-morpholino group at the C-4 position of thieno[3,2-d]pyrimidine moiety exhibited superior activities than compounds bearing chain amino groups. In addition, compounds with mono-methoxy group at the 3-position or dimethyl groups at the 3,5-position on the terminal phenyl ring were more active. The SAR analyses will guide us to further refine the structure of the thieno[3,2 d]pyrimidine derivatives to achieve optimum anticancer activity. PMID- 25440880 TI - Organotin complexes containing carboxylate ligands with maleimide and naphthalimide derived partial structures: TrxR inhibition, cytotoxicity and activity in resistant cancer cells. AB - Di-n-butyltin(IV) carboxylate and tri-n-butyltin(IV) carboxylate derivatives have demonstrated strong cytotoxic effects in different types of tumor cells. Complexes with carboxylate ligands that contain maleimide and naphthalimide derived partial structures were synthesized, characterized and investigated for inhibition of the tumor-relevant enzyme thioredoxin reductase and antiproliferative effects in cancer cells. The complexes were moderate inhibitors of thioredoxin reductase with activities in the micromolar range and triggered strong cytotoxic effects in MCF-7 breast cancer and HT-29 colon carcinoma cells. Interestingly, selected complexes were highly active in vincristine and daunorubicin resistant Nalm-6 cells. PMID- 25440881 TI - 1H-1,2,3-triazole tethered isatin-ferrocene conjugates: Synthesis and in vitro antimalarial evaluation. AB - 1H-1,2,3-triazole tethered isatin-ferrocene conjugates were synthesized and evaluated for their antiplasmodial activities against chloroquine-susceptible (3D7) and chloroquine-resistant (W2) strains of Plasmodium falciparum. The conjugates 5f and 5h with an optimum combination of electron-withdrawing halogen substituent at C-5 position of isatin ring and a propyl chain, introduced as linker, proved to be most potent and non-cytotoxic among the series with IC50 values of 3.76 and 4.58 MUM against 3D7 and W2 strains, respectively. PMID- 25440882 TI - Synthesis and biological evaluation of new oxadiazoline-substituted naphthalenyl acetates as anticancer agents. AB - A series of new oxadiazoline-substituted naphthalenyl acetates 3a-e and oxadiazoline-substituted 4-methoxynaphthalenyl acetates 7b-e were synthesized and tested by the National Cancer Institute (NCI) for their in vitro anticancer activity. The two derivatives bearing acetoxy groups at the 1 and 3 positions of the phenyl ring 3c and 7c were the most active showing significant anticancer activity against all tested cancer cell lines, with GI50 values ranging from 0.175 to 3.91 MUM, and 0.306-11.7 MUM, respectively. The selectivity of compound 3c was greater for non-solid tumor cell lines. Computational prediction of molecular and pharmacokinetic properties revealed that both compounds are safe and compound 7c had a good drug-likeness score. PMID- 25440883 TI - Thiazolidine-2,4-diones as multi-targeted scaffold in medicinal chemistry: Potential anticancer agents. AB - A variety of substituents on the thiazolidine-2,4-dione(TZD) nucleus have provided a wide spectrum of biological activities by the using of different mechanism on various target sites. PPARgamma ligands have recently been demonstrated to affect cell proliferation, differentiation and apoptosis of different cell types. Currently, some of the TZDs are designed for the treatment of human cancers expressing high levels of PPARgamma because it is assumed that activation of PPARgamma mediates their anticancer activity. Another site for TZDs is survival signaling pathways under growth factor loops have been implicated in cancer development, progression, and metastasis. The Raf/MEK/ERK, Wnt and PI3K/Akt signalling cascades are the most commonly up-regulated in human cancers. In the present review, various derivatives of thiazolidine-2,4-diones its SAR and different signaling pathways involved to produce anticancer activity been highlighted. PMID- 25440884 TI - Synthetic derivatives of aromatic abietane diterpenoids and their biological activities. AB - Naturally occurring aromatic abietane diterpenoids (dehydroabietanes) exhibit a wide range of biological activities. A number of synthetic studies aimed at modifying the abietane skeleton in order to obtain new potential chemotherapeutic agents have been reported. In this study, the biological activities of synthetic derivatives of aromatic abietane diterpenoids are reviewed. PMID- 25440885 TI - Gadolinium-based contrast agents targeted to amyloid aggregates for the early diagnosis of Alzheimer's disease by MRI. AB - While important efforts were made in the development of positron emission tomography (PET) tracers for the in vivo molecular diagnosis of Alzheimer's disease, very few investigations to develop magnetic resonance imaging (MRI) probes were performed. Here, a new generation of Gd(III)-based contrast agents (CAs) is proposed to detect the amyloid beta-protein (Abeta) aggregates by MRI, one of the earliest biological hallmarks of the pathology. A building block strategy was used to synthesize a library of 16 CAs to investigate structure activity relationships (SARs) on physicochemical properties and binding affinity for the Abeta aggregates. Three types of blocks were used to modulate the CA structures: (i) the Gd(III) chelates (Gd(III)-DOTA and Gd(III)-PCTA), (ii) the biovectors (2-arylbenzothiazole, 2-arylbenzoxazole and stilbene derivatives) and (iii) the linkers (neutrals, positives and negatives with several lengths). These investigations revealed unexpected SARs and a difficulty of these probes to cross the blood-brain barrier (BBB). General insights for the development of Gd(III) based CAs to detect the Abeta aggregates are described. PMID- 25440886 TI - Synthesis of dihydroresveratrol glycosides and evaluation of their activity against melanogenesis in B16F0 melanoma cells. AB - Dihydroresveratrol glucoside 1 isolated from Camellia oleifera and its xyloside derivative 2 were synthesized for the first time in 5 steps from TBS-protected aldehyde 4. Natural product 1 is a potent melanogenesis inhibitor in B16F0 melanoma cells (approximately 40 fold more potent than kojic acid). In contrast, the synthetic product 2 stimulates melanogenesis, suggesting that a single hydroxymethyl group in the glycoside substituent of dihydroresveratrols is responsible for inhibition or activation of melanogenesis. PMID- 25440887 TI - A randomized comparison of novel biodegradable polymer- and durable polymer coated cobalt-chromium sirolimus-eluting stents. AB - OBJECTIVES: The aim of this study was to investigate the hypothesis that a novel biodegradable polymer-coated, cobalt-chromium (CoCr), sirolimus-eluting stent (BP SES) is noninferior in safety and efficacy outcomes compared with a durable polymer (DP)-SES. BACKGROUND: No randomized trials have the compared safety and efficacy of BP-SES versus DP-SES on similar CoCr platforms, thereby isolating the effect of the polymer type. METHODS: In this prospective, single-blind, randomized trial conducted at 32 Chinese sites, 2,737 patients eligible for coronary stenting were treated with BP- or DP-SES in a 2:1 ratio. The primary endpoint was 12-month target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction, or clinically indicated target lesion revascularization. Secondary endpoints included TLF components, and definite/probable stent thrombosis. RESULTS: At 12 months, the difference in the primary endpoint of TLF between BP-SES (6.3%) and DP-SES (6.1%) groups was 0.25% (95% confidence interval: -1.67% to 2.17%, p for noninferiority = 0.0002), demonstrating noninferiority of BP-SES to DP-SES. Individual TLF components of cardiac death (0.7% vs. 0.6%, p = 0.62), target vessel myocardial infarction (3.6% vs. 4.3%, p = 0.39), and clinically indicated target lesion revascularization (2.6% vs. 2.2%, p = 0.50) were similar, as were low definite/probable stent thrombosis rates (0.4% vs. 0.6%, p = 0.55). CONCLUSIONS: In this large-scale real-world trial, BP-SES was noninferior to DP-SES for 1-year TLF. (Evaluate Safety and Effectiveness of the Tivoli (r) DES and the Firebird (r) DES for Treatment of Coronary Revascularization; NCT01681381). PMID- 25440889 TI - Prognostic value of exercise capacity in patients with coronary artery disease: the FIT (Henry Ford ExercIse Testing) project. AB - OBJECTIVE: To examine the prognostic value of exercise capacity in patients with nonrevascularized and revascularized coronary artery disease (CAD) seen in routine clinical practice. PATIENTS AND METHODS: We analyzed 9852 adults with known CAD (mean +/- SD age, 61+/-12 years; 69% men [n=6836], 31% black race [n=3005]) from The Henry Ford ExercIse Testing (FIT) Project, a retrospective cohort study of patients who underwent physician-referred stress testing at a single health care system between January 1, 1991, and May 31, 2009. Patients were categorized by revascularization status (nonrevascularized, percutaneous coronary intervention [PCI], or coronary artery bypass graft [CABG] surgery) and by metabolic equivalents (METs) achieved on stress testing. Using Cox regression models, hazard ratios for mortality, myocardial infarction (MI), and downstream revascularizations were calculated after adjusting for potential confounders, including cardiac risk factors, pertinent medications, and stress testing indication. RESULTS: There were 3824 all-cause deaths during median follow-up of 11.5 years. In addition, 1880 MIs, and 1930 revascularizations were ascertained. Each 1-MET increment in exercise capacity was associated with a hazard ratio (95% CI) of 0.87 (0.85-0.89), 0.87 (0.85-0.90), and 0.86 (0.84-0.89) for mortality; 0.98 (0.96-1.01), 0.88 (0.84-0.92), and 0.93 (0.90-0.97) for MI; and 0.94 (0.92 0.96), 0.91 (0.88-0.95), and 0.96 (0.92-0.99) for downstream revascularizations in the nonrevascularized, PCI, and CABG groups, respectively. In each MET category, the nonrevascularized group had similar mortality risk as and higher MI and downstream revascularization risk than the PCI and CABG surgery groups (P<.05). CONCLUSION: Exercise capacity was a strong predictor of mortality, MI, and downstream revascularizations in this cohort. Furthermore, patients with similar exercise capacities had an equivalent mortality risk, irrespective of baseline revascularization status. PMID- 25440891 TI - Nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and gastrointestinal injury: contrasting interactions in the stomach and small intestine. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) are among the most frequently prescribed groups of drugs worldwide. The use of NSAIDs is associated with a high number of significant adverse effects. Recently, the safety of PPIs has also been challenged. Capsule endoscopy studies reveal that even low-dose NSAIDs are responsible for gut mucosal injury and numerous clinical adverse effects, for example, bleeding and anemia, that might be difficult to diagnose. The frequent use of PPIs can exacerbate NSAID-induced small intestinal injury by altering intestinal microbiota. Thus, the use of PPI is considered to be an independent risk factor associated with NSAID-associated enteropathy. In this review, we discuss this important clinical problem and review relevant aspects of epidemiology, pathophysiology, and management. We also present the hypothesis that even minor and subclinical injury to the intestinal mucosa can result in significant, though delayed, metabolic consequences, which may seriously affect the health of an individual. PubMed was searched using the following key words (each key word alone and in combination): gut microbiota, microbiome, non-steroidal anti inflammatory drugs, proton pump inhibitors, enteropathy, probiotic, antibiotic, mucosal injury, enteroscopy, and capsule endoscopy. Google engine search was also carried out to identify additional relevant articles. Both original and review articles published in English were reviewed. PMID- 25440890 TI - Resting heart rate in first year survivors of myocardial infarction and long-term mortality: a community study. AB - OBJECTIVE: To evaluate the long-term prognostic effect of resting heart rate (HR) at index myocardial infarction (MI) and during the first year after MI among 1 year survivors. PATIENTS AND METHODS: The community-based cohort consisted of 1571 patients hospitalized with an incident MI from January 1, 1983, through December 31, 2007, in Olmsted County, Minnesota, who were in sinus rhythm at index MI and had HR measurements on electrocardiography at index and during the first year after MI. Outcomes were all-cause and cardiovascular deaths. RESULTS: During a median follow-up of 7.0 years, 627 deaths and 311 cardiovascular deaths occurred. Using patients with HRs of 60/min or less as the referent, this study found that long-term all-cause mortality risk increased progressively with increasing HR at index (hazard ratio, 1.62; 95% CI, 1.25-2.09) and even more with increasing HR during the first year after MI (hazard ratio, 2.16; 95% CI, 1.64 2.84) for patients with HRs greater than 90/min, adjusting for clinical characteristics and beta-blocker use. Similar results were observed for cardiovascular mortality (adjusted hazard ratio, 1.66; 95% CI, 1.14-2.42; and adjusted hazard ratio, 1.93; 95% CI, 1.27-2.94; for HR at index and within 1 year after MI, respectively). CONCLUSION: These data from a large MI community cohort indicate that HR is a strong predictor of long-term all-cause and cardiovascular mortality not only at initial presentation of MI but also during the first year of follow-up. PMID- 25440888 TI - The childhood obesity epidemic as a result of nongenetic evolution: the maternal resources hypothesis. AB - Over the past century, socioenvironmental evolution (eg, reduced pathogenic load, decreased physical activity, and improved nutrition) led to cumulative increments in maternal energy resources (ie, body mass and adiposity) and decrements in energy expenditure and metabolic control. These decrements reduced the competition between maternal and fetal energy demands and increased the availability of energy substrates to the intrauterine milieu. This perturbation of mother-conceptus energy partitioning stimulated fetal pancreatic beta-cell and adipocyte hyperplasia, thereby inducing an enduring competitive dominance of adipocytes over other tissues in the acquisition and sequestering of nutrient energy via intensified insulin secretion and hyperplastic adiposity. At menarche, the competitive dominance of adipocytes was further amplified via hormone-induced adipocyte hyperplasia and weight-induced decrements in physical activity. These metabolic and behavioral effects were propagated progressively when obese, inactive, metabolically compromised women produced progressively larger, more inactive, metabolically compromised children. Consequently, the evolution of human energy metabolism was markedly altered. This phenotypic evolution was exacerbated by increments in the use of cesarean sections, which allowed both the larger fetuses and the metabolically compromised mothers who produced them to survive and reproduce. Thus, natural selection was iatrogenically rendered artificial selection, and the frequency of obese, inactive, metabolically compromised phenotypes increased in the global population. By the late 20th century, a metabolic tipping point was reached at which the postprandial insulin response was so intense, the relative number of adipocytes so large, and inactivity so pervasive that the competitive dominance of adipocytes in the sequestering of nutrient energy was inevitable and obesity was unavoidable. PMID- 25440892 TI - Testing the bi-dimensional effects of attitudes on behavioural intentions and subsequent behaviour. AB - Attitudes are typically treated as unidimensional predictors of both behavioural intentions and subsequent behaviour. On the basis of previous research showing that attitudes comprise two independent, positive and negative dimensions, we hypothesized that attitudes would be bi-dimensional predictors of both behavioural intentions and subsequent behaviour. We focused on health-risk behaviours. We therefore also hypothesized that the positive dimension of attitude (evaluations of positive behavioural outcomes) would better predict both behavioural intentions and subsequent behaviour than would the negative dimension, consistent with the positivity bias/offset principle. In Study 1 (cross sectional design), N = 109 university students completed questionnaire measures of their intentions to binge-drink and the positive and negative dimensions of attitude. Consistent with the hypotheses, both attitude dimensions independently predicted behavioural intentions and the positive dimension was a significantly better predictor than was the negative dimension. The same pattern of findings emerged in Study 2 (cross sectional design; N = 186 university students) when we predicted intentions to binge-drink, smoke and consume a high fat diet. Similarly, in Study 3 (prospective design; N = 1,232 speed limit offenders), both the positive and negative dimensions of attitude predicted subsequent (6-month post-baseline) speeding behaviour on two different road types and the positive dimension was the better predictor. The implications for understanding the motivation of behaviour and the development of behaviour-change interventions are discussed. PMID- 25440893 TI - Risk of dysphagia and speech and language delay in PHACE syndrome. AB - PHACE (posterior fossa, hemangioma, arterial lesions, cardiac, and eye) syndrome consists of infantile hemangiomas of the head and neck along with a spectrum of noncutaneous anomalies. Neurodevelopmental abnormalities have also been noted. Here we describe the association between PHACE syndrome and abnormalities in oropharyngeal development and coordination manifesting as dysphagia or speech and language delay. A retrospective chart review was conducted of 34 patients with PHACE syndrome. Data were collected from prior clinical notes and radiographic studies and the results of a comprehensive questionnaire that those who attended the July 2012 PHACE Syndrome Family Conference completed. Seventeen of 34 patients with PHACE syndrome and signs or symptoms of dysphagia or speech or language problems were included for analysis. Nine had dysphagia, seven had a history of cardiac surgery, four had a posterior fossa malformation, and seven had lip or oropharynx hemangiomas. Speech or language delay was noted in 16; posterior fossa abnormalities and lip or oropharynx hemangiomas were the most commonly seen associated finding in this group. There was considerable overlap between subset populations with dysphagia, speech delay, and language delay. A subset of individuals with PHACE syndrome experience dysphagia, speech delay, or language delay. This risk seems to be greater in certain subsets of patients, including those with posterior fossa malformations or lip or oropharynx hemangiomas and those with a history of cardiac surgery. Although this descriptive study was not comprehensive enough to examine prevalence, the high incidence of dysphagia and speech and language delay seen in our cohort warrants future prospective studies to further investigate the association. PMID- 25440894 TI - Probing in vivo dynamics of mitochondria and cortical actin networks using high speed atomic force/fluorescence microscopy. AB - The dynamics of the cell membrane and submembrane structures are closely linked, facilitating various cellular activities. Although cell surface research and cortical actin studies have shown independent mechanisms for the cell membrane and the actin network, it has been difficult to obtain a comprehensive understanding of the dynamics of these structures in live cells. Here, we used a combined atomic force/optical microscope system to analyze membrane-based cellular events at nanometer-scale resolution in live cells. Imaging the COS-7 cell surface showed detailed structural properties of membrane invagination events corresponding to endocytosis and exocytosis. In addition, the movement of mitochondria and the spatiotemporal dynamics of the cortical F-actin network were directly visualized in vivo. Cortical actin microdomains with sizes ranging from 1.7*10(4) to 1.4*10(5) nm2 were dynamically rearranged by newly appearing actin filaments, which sometimes accompanied membrane invaginations, suggesting that these events are integrated with the dynamic regulation of submembrane organizations maintained by actin turnovers. These results provide novel insights into the structural aspects of the entire cell membrane machinery which can be visualized with high temporal and spatial resolution. PMID- 25440895 TI - Origin, distribution and toxicological potential of polycyclic aromatic hydrocarbons in surface sediments from the Bushehr coast, the Persian Gulf. AB - To evaluate the hazards of polycyclic aromatic hydrocarbons (PAHs) in the Bushehr coastal zones, 12 surface sediments were analyzed. The ?14PAHs concentrations varied from 371 to 611 ng g(-1) dw. The primary sources of the observed PAHs were pyrolytic processes, demonstrating the dominance of petroleum-related combustion inputs. The ERL/ERM and TEL/PEL values showed that there was a moderate level of toxicity risk for some PAHs. The toxicological significance of the pollutants was assessed using the toxic equivalency factor (TEF) to calculate both the toxic equivalent for dioxins (TEQTCDD) and the TEQ carcinogenic risks. Dibenz(a,h)anthracene exhibited the highest proportion in the TEQs, ranging from 49% to 56% (TEQcarc) and from 29% to 39% (TEQTCDD) regarding the overall toxicity in the sampled sediments. This result suggests that the ambient dibenz(a,h)anthracene concentration represents the risk posed by PAHs in the sediments. Moreover, using a specific sediment criterion demonstrated the bioaccumulation potential of benzo(a)pyrene for humans in the sampled sediments. PMID- 25440896 TI - Inactivation of microalgae in ballast water with pulse intense light treatment. AB - The exotic emission of ballast water has threatened the coastal ecological environment and people's health in many countries. This paper firstly introduces pulse intense light to treat ballast water. 99.9 +/- 0.09% inactivation of Heterosigma akashiwo and 99.9 +/- 0.16% inactivation of Pyramimonas sp. are observed under treatment conditions of 350 V pulse peak voltage, 15 Hz pulse frequency, 5 ms pulse width and 1.78 L/min flow rate. The energy consumption of the self-designed pulse intense light treatment system is about 2.90-5.14 times higher than that of the typical commercial UV ballast water treatment system. The results indicate that pulse intense light is an effective technique for ballast water treatment, while it is only a competitive one when drastic decreasing in energy consumption is accomplished. PMID- 25440897 TI - A reassessment of the use of Posidonia oceanica and Mytilus galloprovincialis to biomonitor the coastal pollution of trace elements: New tools and tips. AB - The present study gives a summary using state-of-the-art technology to monitor Posidonia oceanica and Mytilus galloprovincialis as bioindicators of the pollution of the Mediterranean littoral with trace elements (TEs), and discusses their complementarity and specificities in terms of TE bioaccumulation. Furthermore, this study presents two complementary indices, the Trace Element Spatial Variation Index (TESVI) and the Trace Element Pollution Index (TEPI): these indices were shown to be relevant monitoring tools since they led to the ordering of TEs according to the overall spatial variability of their environmental levels (TESVI) and to the relevant comparison of the global TE pollution between monitored sites (TEPI). In addition, this study also discusses some underestimated aspects of P. oceanica and M. galloprovincialis bioaccumulation behaviour, with regard to their life style and ecophysiology. It finally points out the necessity of developing consensual protocols between monitoring surveys in order to publish reliable and comparable results. PMID- 25440902 TI - Editorial: "Injurious RBD and DEB frequency: are they related?". PMID- 25440903 TI - Rethinking voxel-wise lesion-deficit analysis: a new challenge for computational neuropsychology. PMID- 25440904 TI - Sex-specific dose-response analysis of genotoxicity in cyproterone acetate treated F344 rats. AB - Cyproterone acetate (CPA), a synthetic hormonal drug, induces rat liver tumors in a sex-specific manner, with five-fold higher doses needed to induce liver tumors in male rats compared to females. In order to evaluate the potential of the in vivo alkaline Comet assay to predict the sex-specific carcinogenicity of CPA, CPA induced direct DNA damage (DNA strand breaks and alkali-labile sites) were evaluated in the livers of both male and female F344 rats. In addition, secondary oxidative DNA damage was measured concurrently utilizing the human 8-oxoguanine DNA-N-glycosylase (hOGG1) and EndonucleaseIII (EndoIII)-modified in vivo alkaline Comet assays and the reticulocyte micronucleus (MN) frequency was analyzed in peripheral blood. Groups of 5 seven-week-old male and female F344 rats received olive oil or 10, 25, 50 or 100 mg/kg bw CPA in olive oil by gavage at 0, 24, and 45 h and were sacrificed at 48 h. CPA-induced direct DNA damage in rat liver showed the same sex-specific pattern as its hepatotumorigenicity: a five-fold higher dose of CPA was needed to induce a statistically significant increase in direct DNA damage in livers of males compared to females. However, peripheral blood MN frequency was weak in both sexes and CPA-induced oxidative DNA damage was generally greater in male than female rat livers. Taken together, our results demonstrate concordance in the sex-specificity of CPA in the in vivo alkaline Comet assay and cancer bioassay, while the induction of oxidative DNA damage by CPA was not directly correlated with its tumorigenicity. PMID- 25440905 TI - Cyto-genotoxicity assessment of potential radioprotector, 3,3' diselenodipropionic acid (DSePA) in Chinese Hamster Ovary (CHO) cells and human peripheral blood lymphocytes. AB - Our previous study showed that 3,3'-diselenodipropionic acid (DSePA), a simple, stable, and water-soluble organoselenium exhibiting glutathione peroxidase (GPx) like activity offered good radioprotection under in vitro and in vivo conditions. Herein, we investigated the anti-genotoxic effect of DSePA in model cellular systems such as Chinese Hamster Ovary (CHO) cell line and human peripheral lymphocytes after exposure to gamma-radiation. The measurements on the induction of gamma-H2AX foci and micronuclei frequency in the cell nuclei indicated that pretreatment with DSePA significantly prevented the radiation induced DNA damage or genotoxicity and subsequent cytotoxicity without exerting its own toxicity. The maximum protective effect of DSePA was seen at a pre-treatment concentration of 3 MUg/ml. The mechanistic investigations in CHO cells revealed that DSePA pretreatment prevented the radiation induced ROS generation, lipid peroxidation and subsequent apoptosis in these cells. Further, it was seen to augment the mRNA expressions of GPx2 significantly and GPx4 marginally without causing much change in the total GPx activity after radiation exposure. These results suggested the roles of GPx2 and GPx4 in DSePA mediated radioprotection. In conclusion our results confirm the nongenotoxic nature of the DSePA and validate its radioprotective efficacy and mechanisms of action in model cellular systems. PMID- 25440906 TI - Effects of soil pH on the Vicia-micronucleus genotoxicity assay. AB - In the field of contaminated sites and soil management, chemical analyses only bring typological data about pollution. As far as bioavailability and effects on organisms are concerned, we need ecotoxicology tools. In this domain, among many existing tests, we chose to study genotoxicity because it is a short-term endpoint with long-term consequences. The aim of this study is to assess the effects of soil pH on the results of the Vicia faba root tip micronucleus test for the two following reasons: (i) to define the pH range within which the test can be performed without modifying the soil to be tested, within the framework of the ISO standard of the test and (ii) to provides information about the effects of the pH on the genotoxic potential of soils. In this context, we modified the pH of a standard soil with HCl or NaOH and we spiked the matrix with copper (2, 4 and 8 mmol kg(-1) dry soil) or with maleic hydrazide, an antigerminative chemical (5, 10 and 20 MUmol kg(-1) dry soil). We concluded that the pH had no effect on the mitotic index or micronucleus frequency in the root cells of the negative controls: extreme pH values did not induce micronucleus formation in root cells. Moreover, according to our results, the Vicia-micronucleus test can be performed with pH values ranging between 3.2 and 9.0, but in the ISO 29200 "Soil quality- assessment of genotoxic effects on higher plants--V. faba micronucleus test" we recommended to use a control soil with a pH value ranging between 5 and 8 for a more accurate assessment of chemical genotoxicity. We also found that acid pH could increase the genotoxic potential of pollutants, especially heavy metals. With hydrazide maleic spiked soil, plants were placed in a situation of double stress, i.e. toxicity caused by extreme pH values and toxicity induced by the pollutant. PMID- 25440907 TI - Activation of Toll-like receptors by intestinal microflora reduces radiation induced DNA damage in mice. AB - Activation of Toll-like receptors (TLRs) signaling by intestinal microflora derived bacterial products plays a key role in injury defence for the host. We investigated the role of TLRs activated by intestinal microflora in radiation induced DNA damage in mice. We analyzed DNA damage induced by 2Gy gamma-ray radiation in an intestinal commensal bacteria-depleted mouse model (CD group), in which TLRs (TLR2/6, TLR4 and TLR5) ligand levels in serum were reduced. Chromosomal aberrations were measured in bone marrow cells and peripheral blood leukocyte comet assays were performed. DNA damage was increased in the CD group compared with the control group. Treatment of mice with TLR agonists (CBLB502, LPS and lipopeptide) 1h before radiation resulted in a significant decrease in DNA damage. Genes induced by TLR5 activation were analyzed; activation of TLRs regulated the expression of Gadd45b, Sod2, and Rad21, which are involved in DNA damage repair. In summary, our data indicate that TLRs activation by intestinal microflora reduces DNA damage induced by radiation and regulates expression of several DNA repair genes. PMID- 25440908 TI - In vivo Comet assay--statistical analysis and power calculations of mice testicular cells. AB - The in vivo Comet assay is a sensitive method for evaluating DNA damage. A recurrent concern is how to analyze the data appropriately and efficiently. A popular approach is to summarize the raw data into a summary statistic prior to the statistical analysis. However, consensus on which summary statistic to use has yet to be reached. Another important consideration concerns the assessment of proper sample sizes in the design of Comet assay studies. This study aims to identify a statistic suitably summarizing the % tail DNA of mice testicular samples in Comet assay studies. A second aim is to provide curves for this statistic outlining the number of animals and gels to use. The current study was based on 11 compounds administered via oral gavage in three doses to male mice: CAS no. 110-26-9, CAS no. 512-56-1, CAS no. 111873-33-7, CAS no. 79-94-7, CAS no. 115-96-8, CAS no. 598-55-0, CAS no. 636-97-5, CAS no. 85-28-9, CAS no. 13674-87 8, CAS no. 43100-38-5 and CAS no. 60965-26-6. Testicular cells were examined using the alkaline version of the Comet assay and the DNA damage was quantified as % tail DNA using a fully automatic scoring system. From the raw data 23 summary statistics were examined. A linear mixed-effects model was fitted to the summarized data and the estimated variance components were used to generate power curves as a function of sample size. The statistic that most appropriately summarized the within-sample distributions was the median of the log-transformed data, as it most consistently conformed to the assumptions of the statistical model. Power curves for 1.5-, 2-, and 2.5-fold changes of the highest dose group compared to the control group when 50 and 100 cells were scored per gel are provided to aid in the design of future Comet assay studies on testicular cells. PMID- 25440909 TI - Cytokinesis block micronucleus assay in field plants for monitoring radiation induced genotoxicity of the environment. AB - Effective biomonitoring for detection of radiation-induced genotoxicity of contaminants in natural environments involves testing of field plants for cytogenetic changes. To increase the efficiency and precision of cytogenetic analyses of field plants that have naturally high individual variability, an improved micronucleus assay is proposed that employs a cytokinesis block technique similar to the lymphocyte test system used in mammals. In seed embryonic meristems of the Japanese cedar, application of a methylxanthine derivative, 3-isobutyl-1-methylxanthine (IBMX), was found to be effective in inhibiting cytokinesis to make once-divided cells easily recognizable by their binucleate appearance. In the meristem of IBMX-treated seminal roots from X-ray irradiated seeds, variation in micronucleus frequency in the binucleate cell population was reduced compared to that in the total cell population. The highest efficiency of measurement of micronucleus frequencies was obtained in the root meristems where 0.2- to 1.5-mm-long seminal roots were incubated with IBMX for 24 h. This result indicated that this root elongation stage corresponded to the first divisions of the root meristematic cells, and was therefore suitable for obtaining reliable estimations of accumulated genetic damage in the seeds. This cytokinesis block assay applied specifically at the root elongation stage was then used to examine dose-response relationships in Japanese cedar seeds irradiated either acutely with X-rays or chronically with gamma-rays. The resulting dose-response curve for the acute X-ray irradiation was fitted onto a linear-quadratic regression curve, whereas the dose-response curve for the chronic gamma-irradiation matched a linear regression line better. Both dose response curves were consistent with the target theory of classical radiation biology. The good agreement of the micronucleus data to a simple dose-response model indicates the proposed accuracy of the cytokinesis block micronucleus assay for plant monitoring. PMID- 25440910 TI - Effect of tiletamine-zolazepam on the intraocular pressure of the dog. AB - OBJECTIVE: To determine the effect of tiletamine-zolazepam (TZ) on canine intraocular pressure (IOP). ANIMALS STUDIED: Six healthy dogs without ocular abnormalities were used in this study. PROCEDURES: The study was carried out as a crossover experimental trial with a 7-day interval between treatments. TZ combination was administered intravenously (IV) at a dose of 5, 10, and 20 mg/kg (TZ5, TZ10, and TZ20, respectively). Following preanesthetic baseline readings of IOP, each dog received IV TZ and then the IOP values were measured every 10 min for 40 min in all treatments. RESULTS: The baseline IOP values (mean +/- standard deviation) for TZ5, TZ10, and TZ20 were 12.7 +/- 0.8, 14.4 +/- 1.2, and 15.3 +/- 1.7 mmHg, and each IOP changed to 11.1 +/- 1.1, 13.1 +/- 1.4 and 13.5 +/- 1.7 mmHg after intravenous administration of each TZ treatment, respectively. However, there were no statistical differences between baseline and post treatment values. CONCLUSIONS: The TZ combination had no clinically significant effect on IOP of the dog. This could be an option for induction or surgical procedures in dogs with ophthalmic problems when an increase in IOP is undesirable. PMID- 25440911 TI - Male-to-male sex among men who inject drugs in Delhi, India: overlapping HIV risk behaviours. AB - BACKGROUND: HIV among people who inject drugs (PWID) is a major public health challenge in India. This paper examines PWID in Delhi who also have male-to-male sex with a focus on overlapping HIV risk behaviours and the psychosocial correlates of a history of male-to-male anal sex. METHODS: We analysed data collected in April-May of 2012 from a community-based sample of 420 male PWID in Delhi obtained using time location sampling. RESULTS: One third (37%) of the men reported a history of anal sex with men, among whom just 16% used a condom at last anal sex. Almost all (93%) participants who had a history of anal sex with men also had sex with women. Chi-square tests revealed that a history of anal sex with men was associated with a higher number of female sexual partners and sharing of needles and syringes. Additionally, unprotected sex at last sex with a male partner was significantly associated with unprotected sex at last sex with regular and paid female partners. Multivariate binary logistic regression revealed that the psychosocial correlates of a history of anal sex with other men were: being aged 18-24 (OR = 2.4, p = 0.014), illiteracy (OR = 1.9, p = 0.033), having never been married (OR = 2.6, p = 0.007), a main source of income of crime/begging (OR = 3.1, p = 0.019), a duration of injecting drug use greater than 20 years (OR = 3.4, p = 0.035) and suicidal ideation (OR = 1.7, p = 0.048). CONCLUSION: Male-to-male sex was associated with psychosocial vulnerability, including a longer history of injecting drug use, suicidal ideation and socio economic disadvantage. Given the extent of overlapping HIV risk behaviours, HIV programs for PWID would benefit from a strong focus on prevention of sexual HIV transmission, especially among male injectors who also have sex with other men. PMID- 25440912 TI - An alternative approach to the prevention of doping in cycling. AB - BACKGROUND: Framed by an overly reductionist perspective on doping in professional cycling as an individual moral failing, anti-doping policies tend to envisage a combination of education and repression as the primary intervention strategies. We offer an alternative approach, which seeks to understand doping practices as embedded in social relations, especially in relation to team organisation and employment conditions. METHODS: We undertake an in-depth analysis of the functioning of nine of the 40 world professional cycling teams, and the careers of the 2,351 riders who were or have been professionals since 2005. RESULTS: We find that anti-doping approaches rest upon questionable assumptions of doping as an individual moral fault, and have not produced the anti-doping effects expected or intended. Based on an analysis of team practices, and the ways in which riders produce their achievements, we offer an alternative perspective which emphasises doping as a product of social-economic condition. Our findings emphasise employment and business models, as well as day-to-day working conditions, as structural drivers of doping practices in which individuals and teams engage. CONCLUSION: Anti-doping requires structural as well as cultural change within the sport of professional cycling, especially in the ways teams function economically. PMID- 25440913 TI - Quality of thawed plasma inactivated with methylene blue after 48-hour storage. PMID- 25440914 TI - Human metapneumovirus pneumonia in patients with hematological malignancies. AB - BACKGROUND: Human metapneumovirus (HMPV) has recently emerged as a cause of respiratory infections in hematological patients. Clinical data are lacking to guide the management of HMPV pneumonias. OBJECTIVES: To characterize the clinical and radiographic presentation and outcome of HMPV pneumonias diagnosed in hematological patients. STUDY DESIGN: We screened the patients with a positive HMPV respiratory test in two French teaching hospitals between 2007 and 2011. Among them, the medical charts from the hematological patients who presented with HMPV pneumonia were reviewed. RESULTS: Among the 54 patients with several underlying hematological conditions who were positive for HMPV, we found 13 cases of HMPV pneumonias. HMPV could be the cause of pneumonia as a single pathogen without associated upper respiratory infection. Centrilobular nodules were constant on lung computed tomography scans. No patients died despite the absence of administration of antiviral treatments. CONCLUSIONS: Our data provide further insights in the diagnosis and management of HMPV pneumonias in this setting. PMID- 25440915 TI - Aciclovir-induced neurotoxicity: Utility of CSF and serum CMMG levels in diagnosis. AB - Aciclovir is an anti-viral frequently used for herpes virus infections. Neurotoxicity and nephrotoxicity are uncommon but serious side effects of aciclovir treatment. This case illustrates how aciclovir induced neurotoxicity can present and how it can be diagnosed using quantitative assays of aciclovir and its metabolite in the CSF and serum. PMID- 25440916 TI - Interferon and tumor necrosis factor as humoral mechanisms coupling hematopoietic activity to inflammation and injury. AB - Enhanced hematopoiesis accompanies systemic responses to injury and infection. Tumor necrosis factor (TNF) produced by injured cells and interferons (IFNs) secreted by inflammatory cells is a co-product of the process of clearance of debris and removal of still viable but dysfunctional cells. Concomitantly, these cytokines induce hematopoietic stem and progenitor cell (HSPC) activity as an intrinsic component of the systemic response. The proposed scenario includes induction of HSPC activity by type I (IFNalpha/beta) and II (IFNgamma) receptors within the quiescent bone marrow niches rendering progenitors responsive to additional signals. TNFalpha converges as a non-selective stimulant of HSPC activity and both cytokines synergize with other growth factors in promoting differentiation. These physiological signaling pathways of stress hematopoiesis occur quite frequent and do not cause HSPC extinction. The proposed role of IFNs and TNFs in stress hematopoiesis commends revision of their alleged involvement in bone marrow failure syndromes. PMID- 25440917 TI - Epidemiology and diagnosis of acute nonvariceal upper gastrointestinal bleeding. AB - Acute upper gastrointestinal bleeding (UGIB) is a common gastroenterological emergency. A vast majority of these bleeds have nonvariceal causes, in particular gastroduodenal peptic ulcers. Nonsteroidal antiinflammatory drugs, low-dose aspirin use, and Helicobacter pylori infection are the main risk factors for UGIB. Current epidemiologic data suggest that patients most affected are older with medical comorbidit. Widespread use of potentially gastroerosive medications underscores the importance of adopting gastroprotective pharamacologic strategies. Endoscopy is the mainstay for diagnosis and treatment of acute UGIB. It should be performed within 24 hours of presentation by skilled operators in adequately equipped settings, using a multidisciplinary team approach. PMID- 25440918 TI - Upper gastrointestinal bleeding: patient presentation, risk stratification, and early management. AB - The established quality indicators for early management of upper gastrointestinal (GI) hemorrhage are based on rapid diagnosis, risk stratification, and early management. Effective preendoscopic treatment may improve survivability of critically ill patients and improve resource allocation for all patients. Accurate risk stratification helps determine the need for hospital admission, hemodynamic monitoring, blood transfusion, and endoscopic hemostasis before esophagogastroduodenoscopy (EGD) via indirect measures such as laboratory studies, physiologic data, and comorbidities. Early management before the definitive EGD is essential to improving outcomes for patients with upper GI bleeding. PMID- 25440919 TI - Endoscopic management of acute peptic ulcer bleeding. AB - This review discusses the indications, technical aspects, and comparative effectiveness of the endoscopic treatment of upper gastrointestinal bleeding caused by peptic ulcer. Pre-endoscopic considerations, such as the use of prokinetics and timing of endoscopy, are reviewed. In addition, this article examines aspects of postendoscopic care such as the effectiveness, dosing, and duration of postendoscopic proton-pump inhibitors, Helicobacter pylori testing, and benefits of treatment in terms of preventing rebleeding; and the use of nonsteroidal anti-inflammatory drugs, antiplatelet agents, and oral anticoagulants, including direct thrombin and Xa inhibitors, following acute peptic ulcer bleeding. PMID- 25440920 TI - Endoscopic management of nonvariceal, nonulcer upper gastrointestinal bleeding. AB - Upper gastrointestinal bleeding (UGIB) is the most common emergency condition in gastroenterology. Although peptic ulcer and esophagogastric varices are the predominant causes, other conditions account for up to 50% of UGIBs. These conditions, among others, include angiodysplasia, Dieulafoy and Mallory-Weiss lesions, gastric antral vascular ectasia, and Cameron lesions. Upper GI cancer as well as lesions of the biliary tract and pancreas may also result in severe UGIB. This article provides an overview of the endoscopic management of these lesions, including the role of novel therapeutic modalities such as hemostatic powder and over-the-scope-clips. PMID- 25440921 TI - Emerging endoscopic therapies for nonvariceal upper gastrointestinal bleeding. AB - Several new devices and innovative adaptations of existing modalities have emerged as primary, adjunctive, or rescue therapy in endoscopic hemostasis of gastrointestinal hemorrhage. These techniques include over-the-scope clip devices, hemostatic sprays, cryotherapy, radiofrequency ablation, endoscopic suturing, and endoscopic ultrasound-guided angiotherapy. This review highlights the technical aspects and clinical applications of these devices in the context of nonvariceal upper gastrointestinal bleeding. PMID- 25440922 TI - What if endoscopic hemostasis fails? Alternative treatment strategies: interventional radiology. AB - Since the 1960s, interventional radiology has played a role in the management of gastrointestinal bleeding. What began primarily as a diagnostic modality has evolved into much more of a therapeutic tool. And although the frequency of gastrointestinal bleeding has diminished thanks to management by pharmacologic and endoscopic methods, the need for additional invasive interventions still exists. Transcatheter angiography and intervention is a fundamental step in the algorithm for the treatment of gastrointestinal bleeding. PMID- 25440923 TI - What if endoscopic hemostasis fails?: Alternative treatment strategies: surgery. AB - Management of bleeding peptic ulcers is increasingly challenging in an aging population. Endoscopic therapy reduces the need for emergency surgery in bleeding peptic ulcers. Initial endoscopic control offers an opportunity for selecting high-risk ulcers for potential early preemptive surgery. However, such an approach has not been supported by evidence in the literature. Endoscopic retreatment can be an option to control ulcer rebleeding and reduce complications. The success of endoscopic retreatment largely depends on the severity of rebleeding and ulcer characteristics. Large chronic ulcers with urgent bleeding are less likely to respond to endoscopic retreatment. Expeditious surgery is advised. PMID- 25440924 TI - Epidemiology, diagnosis and early patient management of esophagogastric hemorrhage. AB - Acute variceal bleeding (AVB) is a potentially life-threatening complication of cirrhosis and portal hypertension. Combination therapy with vasoactive drugs and endoscopic variceal ligation is the first-line treatment in the management of AVB after adequate hemodynamic resuscitation. Short-term antibiotic prophylaxis, early resuscitation, early use of lactulose for prevention of hepatic encephalopathy, targeting of conservative goals for blood transfusion, and application of early transjugular intrahepatic portosystemic shunts in patients with AVB have further improved the prognosis of AVB. This article discusses the epidemiology, diagnosis, and nonendoscopic management of AVB. PMID- 25440925 TI - Primary prophylaxis of variceal bleeding. AB - Gastroesophageal varices are present in almost half of patients with cirrhosis at the time of initial diagnosis. Variceal bleeding occurs in 25% to 35% of patients with cirrhosis. Effective and timely care can prevent variceal bleeding (primary prophylaxis). For example, clinical studies demonstrate that both beta-blockers and endoscopic variceal ligation are effective in preventing a first episode of variceal bleeding. The major challenge is to screen patients in a timely manner and institute a form of therapy that has the highest chance of success in terms of patient compliance and effectiveness. PMID- 25440926 TI - Endoscopic hemostasis in acute esophageal variceal bleeding. AB - Acute variceal bleeding (AVB) is a milestone event for patients with portal hypertension. Esophageal varices bleed because of an increase in portal pressure that causes the variceal wall to rupture. AVB in a patient with cirrhosis and portal hypertension is associated with significant morbidity and mortality. The initial management of these patients includes proper resuscitation, antibiotic prophylaxis, pharmacologic therapy with vasoconstrictors, and endoscopic therapy. Intravascular fluid management, timing of endoscopy, and endoscopic technique are key in managing these patients. This article reviews the current endoscopic hemostatic strategies for patients with AVB. PMID- 25440927 TI - Endoscopic management of gastric variceal bleeding. AB - Expert knowledge of endoscopic management of gastric varices is essential, as these occur in 20% of patients with portal hypertension. Bleeding is relatively uncommon, but carries significant mortality when this occurs. Inability to directly target intravascular injections and the potential complication related to glue embolization has resulted in the development of novel techniques. Direct visualization of the varix lumen using endoscopic ultrasound (EUS) allows targeted therapy of feeder vessels with real-time imaging. EUS-guided combination therapy with endovascular coiling and cyanoacrylate injections promise to provide reduced complication rates, increased obliteration of varices, and reduced long term rebleeding rates. PMID- 25440929 TI - Approach to the management of portal hypertensive gastropathy and gastric antral vascular ectasia. AB - Gastric antral vascular ectasia (GAVE) and portal hypertensive gastropathy (PHG) are important causes of chronic gastrointestinal bleeding. These gastric mucosal lesions are mostly diagnosed on upper endoscopy and can be distinguished based on their appearance or location in the stomach. In some situations, especially in patients with liver cirrhosis and portal hypertension, a diffuse pattern and involvement of gastric mucosa are seen with both GAVE and severe PHG. The diagnosis in such cases is hard to determine on visual inspection, and thus, biopsy and histologic evaluation can be used to help differentiate GAVE from PHG. PMID- 25440930 TI - Upper GI bleeding. PMID- 25440931 TI - Upper GI bleeding. PMID- 25440928 TI - Nonendoscopic management strategies for acute esophagogastric variceal bleeding. AB - Acute variceal bleeding is a potentially life-threatening complication of portal hypertension. Management consists of emergent hemostasis, therapy directed at hemodynamic resuscitation, protection of the airway, and prevention and treatment of complications including prophylactic use of antibiotics. Endoscopic treatment remains the mainstay in the management of acute variceal bleeding in combination with pharmacotherapy aimed at reducing portal pressure. This article intends to highlight only the current nonendoscopic treatment approaches for control of acute variceal bleeding. PMID- 25440936 TI - The concepts and applications of tissue engineering in otorhinolaryngology. AB - INTRODUCTION: Tissue engineering is a rapidly developing field that, making biological substitutes for the repair and regeneration of damaged tissues, will play an important role in the future of otorhinolaryngology. OBJECTIVE: In this article we explain the principles of regenerative medicine and its potential applications in Otorhinolaryngology. MATERIALS AND METHODS: The authors searched the published literature on this topic, chose relevant references, and extracted and systematized the data. RESULTS AND CONCLUSION: There are some exciting possibilities for future treatments in otorhinolaryngology applying the concepts of tissue engineering. PMID- 25440937 TI - Perforating pilomatricoma presenting as an ulcer in the helix of the pinna. PMID- 25440938 TI - Exostosis of the Internal Auditory Canal: 10-Year Follow-Up. PMID- 25440939 TI - Anatomy of nasal complex in the southern right whale, Eubalaena australis (Cetacea, Mysticeti). AB - The nasal region of the skull has undergone dramatic changes during the course of cetacean evolution. In particular, mysticetes (baleen whales) conserve the nasal mammalian pattern associated with the secondary function of olfaction, and lack the sound-producing specializations present in odontocetes (toothed whales, dolphins and porpoises). To improve our understanding of the morphology of the nasal region of mysticetes, we investigate the nasal anatomy, osteology and myology of the southern right whale, Eubalaena australis, and make comparisons with other mysticetes. In E. australis external deflection surfaces around the blowholes appear to divert water off the head, and differ in appearance from those observed in balaenopterids, eschrichtiids and cetotherids. In E. australis the blowholes are placed above hypertrophied nasal soft tissues formed by fat and nasal muscles, a pattern also observed in balaenopterids (rorqual mysticetes) and a cetotherid (pygmy right whale, Caperea marginata). Blowhole movements are due to the action of five nasofacial muscles: dilator naris superficialis, dilator naris profundus, depressor alae nasi, constrictor naris, and retractor alae nasi. The dilator naris profundus found in E. australis has not been previously reported in balaenopterids. The other nasofacial muscles have a similar arrangement in balaenopterids, with minor differences. A novel structure, not reported previously in any mysticete, is the presence of a vascular tissue (rete mirabile) covering the lower nasal passage. This vascular tissue could play a role in warming inspired air, or may engorge to accommodate loss of respiratory space volume due to gas compression from increased pressure during diving. PMID- 25440940 TI - A scheme for assessing the performance characteristics of small field-of-view gamma cameras. AB - Existing protocols for assessing the performance characteristics of large field of-view (LFOV) gamma cameras can be inappropriate and require modification for use with small field-of-view (SFOV) gamma camera systems. This communication proposes a generic scheme suitable for evaluating the performance characteristics of SFOV gamma cameras, based on modifications to the standard procedures of NEMA NU1-2007. Key differences in methodology between tests for LFOV and SFOV gamma cameras are highlighted along with the rationale for these changes. It is envisaged that this scheme will provide more appropriate methods for equipment characterisation, ensuring quality and consistency for all SFOV cameras. PMID- 25440941 TI - [Renal injury in Takayasu's arteritis]. AB - Renal involvement in Takayasu's arteritis is frequent and worsens the progression of the disease. This is primarily a renal artery stenosis causing renovascular hypertension. The glomerular disease is exceptional. This study was undertaken to determine the clinical, radiological, biological features and therapeutic response in patients with kidney disease associated with Takayasu arteritis. A retrospective chart review was conducted on 11 patients (five men and six females), with a mean age of 31.1 years (19-40 years). The discovery of kidney disease preceded the diagnosis of Takayasu's arteritis in eight cases. Ten patients developed hypertension. Laboratory finding showed proteinuria in five cases of which one case was due to nephrotic syndrome. Renal failure was found in six cases including four cases in stage of terminal chronic renal failure. Impairment of the renal artery was present in nine patients, proximal in seven cases and distal in two cases, bilateral in five cases and unilateral in four cases. Narrowing renal artery was found in seven cases. The renal biopsy revealed membranoproliferative glomerulonephritis in one case and nephrosclerosis in another case. Eleven patients were followed for an average period of 155 months (3-335 months). Remission of nephrotic syndrome was concomitant with the remission of the disease. Seven patients developed outbreaks of Takayasu's arteritis of which six were in care. Relapse of nephrotic syndrome was concomitant with the outbreak of the disease followed by spontaneous remission of both diseases. Improved pressure was obtained in 5 cases and worsening renal function in seven cases. Death was observed in two cases. PMID- 25440942 TI - [Current aspects of acute humoral rejection]. AB - Acute clinical antibody-mediated rejection is currently defined by (1), an acute renal failure occurring during the first months following transplantation, (2), at least a microcirculation inflammation (glomerulitis and peritubular capillaritis) on kidney biopsy and (3), the presence in peripheral blood of donor specific antibodies, mostly anti-human leukocyte antigen (HLA) antibodies. The prognosis of this rejection is scored using the severity of vascular lesions and the positivity of C4d on peritubular capillaries. Recently, a subclinical variety of antibody-mediated rejection was recognized as an entity because, as the clinical rejection, it leads to chronic antibody-mediated rejection, currently the most frequent cause of graft loss. The description of these various aspects of antibody-mediated rejection allowed a better understanding of its pathophyiology that may lead in a near future to a more specific treatment. PMID- 25440943 TI - Nursing Diagnoses in Inpatient Psychiatry. AB - PURPOSE: This study explored how well NANDA-I covers the reality of adult inpatient psychiatric nursing care. METHODS: Patient observations documented by registered nurses in records were analyzed using content analysis and mapped with the classification NANDA-I. FINDINGS: A total of 1,818 notes were examined and contained 46 different patient responses. Twenty-nine patient responses were recognizable as NANDA-I diagnoses at the level of definitions, 15 as diagnoses related factors, and 12 did not match with any NANDA-I diagnosis. CONCLUSIONS: This study demonstrates that NANDA-I describes the adult inpatient psychiatric nursing care to a large extent. Nevertheless, further development of the classification is important. IMPLICATIONS FOR NURSING PRACTICE: The results of this study will spur nursing research and further classification development. PMID- 25440944 TI - Heartworm 'lack of effectiveness' claims in the Mississippi delta: computerized analysis of owner compliance--2004-2011. AB - A retrospective medical record review was conducted to identify factors from veterinary clinic medical records that may have contributed to suspected ineffectiveness of a heartworm preventive product. Patient records of 271 dogs, comprising 301 instances of positive heartworm antigen test results while the dogs were receiving heartworm preventive were evaluated. Nineteen veterinary practices in 17 counties and parishes in Arkansas, Louisiana, Mississippi, and Tennessee participated in the study. Records were selected by the veterinary clinics as representative of cases of suspected lack of effectiveness for a heartworm preventive, and for which an owner satisfaction claim had been filed with the manufacturer. Medical record data were entered into a software program, and a graphic representation was created to facilitate analysis of whether pet owners had purchased sufficient heartworm preventive for the dog to be compliant during the period when infection with Dirofilaria immitis could have led to the positive heartworm antigen test result for that patient ("window of infection"). In 243 (80.7%) cases, there was insufficient heartworm preventive purchased, leading to a gap in protection during the "window of infection". In only five cases (1.7%) there were no purchase lapses or extenuating circumstances (underdosing of medication, multiple purchase gaps outside the established window of infection, or dogs have been diagnosed with heartworm infection more than once during the period studied). Half the cases were from multiple-dog households, and in many of these households, sharing of product between pets was acknowledged. In another 28% of the cases from multiple-dog households, more product was purchased than was needed for one dog, suggesting that the product was being shared between more than one pet. In most cases, there was at least one reason that a dog did not receive sufficient heartworm preventive product, placing the dog at risk of developing an infection with mature heartworms. Several actions were identified that veterinary clinics can take to improve heartworm disease prevention in their patients. PMID- 25440945 TI - Prevalence and seasonal variations of canine dirofilariosis in Portugal. AB - Dirofilariosis is a severe vector-borne emergent disease that is spreading worldwide and becoming a serious threat to human and veterinary public health. Portugal, a Mediterranean country, has favorable climate conditions for mosquito development and survival. At present, accurate data on the prevalence and epidemiological pattern of dirofilariosis in Portugal is scarce and outdated. To study these trends, a project was developed to assess the current prevalence of Dirofilaria immitis infection in shelter dogs as well as the prevalence of Dirofilaria species present in three coastal regions in central Portugal: Coimbra, Santarem, and Setubal. Blood samples were collected from 696 shelter dogs during three consecutive years: 2011, 2012, and 2013. A rapid immunomigration technique was performed to detect female D. immitis antigens. Concurrently, to detect and identify circulating microfilariae, a modified Knott's technique and acid phosphatase histochemical staining were also performed. Of the 696 dogs sampled, 105 were positive for D. immitis, with an overall prevalence of 15.1%. Forty of the 105 dogs were antigen negative but were positive for D. immitis microfilariae. Three animals were co-infected with D. immitis and Acanthocheilonema dracunculoides, and there was also one dog infected only with A. dracunculoides, all confirmed by polymerase chain reaction. The highest prevalence of canine heartworm during the 3-y period was in Setubal (24.8%), followed by Coimbra (13.8%), and Santarem (13.2%), with significant inter-district differences. Our results demonstrate a higher prevalence of dirofilariosis compared with findings of previous studies and show an increasing rate of infection in the southern areas of Portugal attributed, at least in part, to bioclimatic and ecological factors. The present study updates the epidemiological situation and correlates the risk of dirofilariosis transmission within each region. These findings are highly relevant to both human and veterinary public health, contributing to the general awareness of pet owners and veterinarian practitioners and reinforcing the need for effective control measures against vectors and preventive therapy in companion animals. PMID- 25440946 TI - A novel procedure for diagnosing multiple faults in rotating machinery. AB - In analyzing signals from a wind turbine gearbox this paper suggests a new signal processing procedure named as CMF-EEMD method which is formed by applying conventional EEMD to a new type of combined mode function (CMF). This CMF consists of a low frequency CMF, denoted as CL, and a high frequency CMF, denoted as Ch. Then it optimizes the amplitude of the added noise in decomposing Ch and CL using EEMD. Finally, it calculates cyclic autocorrelation function (CAF) for every characteristic IMF from EEMD. The proposed procedure is applied to analyze the multi-faults of a wind turbine gearbox and the results confirm better performances in resolving different signal components by the proposed method than that from the cyclic autocorrelation function (CAF) of a direct EEMD analysis. PMID- 25440948 TI - On computation of stabilizing loop gain and delay ranges for bi-proper delay systems. AB - A graphical method for exactly computing the stabilizing loop gain and delay ranges was proposed [Le BN, Wang Q-G, Lee T-H. Development of D-decomposition method for computing stabilizing gain ranges for general delay systems. J Process Control 2012] for a strictly proper process by determining the boundary functions which may change system's stability. A bi-proper process is rare but causes great complications for the method, due to the new phenomena that do not exist for a strictly proper process, such as a non-zero gain at infinity frequency, which may cause infinite intersections of boundary functions within a finite delay range. This paper addresses such a kind of processes and develops a general method that can produce the exact and complete set of the loop gain and delay for closed-loop stabilization, which is hard to find with analytical methods. PMID- 25440947 TI - Variable-order fuzzy fractional PID controller. AB - In this paper, a new tuning method of variable-order fractional fuzzy PID controller (VOFFLC) is proposed for a class of fractional-order and integer-order control plants. Fuzzy logic control (FLC) could easily deal with parameter variations of control system, but the fractional-order parameters are unable to change through this way and it has confined the effectiveness of FLC. Therefore, an attempt is made in this paper to allow all the five parameters of fractional order PID controller vary along with the transformation of system structure as the outputs of FLC, and the influence of fractional orders lambda and MU on control systems has been investigated to make the fuzzy rules for VOFFLC. Four simulation results of different plants are shown to verify the availability of the proposed control strategy. PMID- 25440949 TI - A new class of nonlinear Rauch-Tung-Striebel cubature Kalman smoothers. AB - In this paper, a new Rauch-Tung-Striebel type of nonlinear smoothing method is proposed based on a class of high-degree cubature integration rules. This new class of cubature Kalman smoothers generalizes the conventional third-degree cubature Kalman smoother using the combination of Genz's or Mysovskikh's high degree spherical rule with the moment matching based arbitrary-degree radial rule, which considerably improves the estimation accuracy. A target tracking problem is utilized to demonstrate the performance of this new smoother and to compare it with other Gaussian approximation smoothers. It will be shown that this new cubature Kalman smoother enhances the filtering accuracy and outperforms the extended Kalman smoother, the unscented Kalman smoother, and the conventional third-degree cubature Kalman smoother. It also maintains close performance to the Gauss-Hermite quadrature smoother with much less computational cost. PMID- 25440950 TI - Information fusion based optimal control for large civil aircraft system. AB - Wind disturbance has a great influence on landing security of Large Civil Aircraft. Through simulation research and engineering experience, it can be found that PID control is not good enough to solve the problem of restraining the wind disturbance. This paper focuses on anti-wind attitude control for Large Civil Aircraft in landing phase. In order to improve the riding comfort and the flight security, an information fusion based optimal control strategy is presented to restrain the wind in landing phase for maintaining attitudes and airspeed. Data of Boeing707 is used to establish a nonlinear mode with total variables of Large Civil Aircraft, and then two linear models are obtained which are divided into longitudinal and lateral equations. Based on engineering experience, the longitudinal channel adopts PID control and C inner control to keep longitudinal attitude constant, and applies autothrottle system for keeping airspeed constant, while an information fusion based optimal regulator in the lateral control channel is designed to achieve lateral attitude holding. According to information fusion estimation, by fusing hard constraint information of system dynamic equations and the soft constraint information of performance index function, optimal estimation of the control sequence is derived. Based on this, an information fusion state regulator is deduced for discrete time linear system with disturbance. The simulation results of nonlinear model of aircraft indicate that the information fusion optimal control is better than traditional PID control, LQR control and LQR control with integral action, in anti-wind disturbance performance in the landing phase. PMID- 25440951 TI - Delay-range-dependent chaos synchronization approach under varying time-lags and delayed nonlinear coupling. AB - This paper proposes a novel state feedback delay-range-dependent control approach for chaos synchronization in coupled nonlinear time-delay systems. The coupling between two systems is esteemed to be nonlinear subject to time-lags. Time varying nature of both the intrinsic and the coupling delays is incorporated to broad scope of the present study for a better-quality synchronization controller synthesis. Lyapunov-Krasovskii (LK) functional is employed to derive delay-range dependent conditions that can be solved by means of the conventional linear matrix inequality (LMI)-tools. The resultant control approach for chaos synchronization of the master-slave time-delay systems considers non-zero lower bound of the intrinsic as well as the coupling time-delays. Further, the delay dependent synchronization condition has been established as a special case of the proposed LK functional treatment. Furthermore, a delay-range-dependent condition, independent of the delay-rate, has been provided to address the situation when upper bound of the delay-derivative is unknown. A robust state feedback control methodology is formulated for synchronization of the time-delay chaotic networks against the L2 norm bounded perturbations by minimizing the L2 gain from the disturbance to the synchronization error. Numerical simulation results are provided for the time-delay chaotic networks to show effectiveness of the proposed delay-range-dependent chaos synchronization methodologies. PMID- 25440952 TI - Design of a robust model predictive controller with reduced computational complexity. AB - The practicality of robust model predictive control of systems with model uncertainties depends on the time consumed for solving a defined optimization problem. This paper presents a method for the computational complexity reduction in a robust model predictive control. First a scaled state vector is defined such that the objective function contours in the defined optimization problem become vertical or horizontal ellipses or circles, and then the control input is determined at each sampling time as a state feedback that minimizes the infinite horizon objective function by solving some linear matrix inequalities. The simulation results show that the number of iterations to solve the problem at each sampling interval is reduced while the control performance does not alter noticeably. PMID- 25440953 TI - Further improvement on delay-dependent robust stability criteria for neutral-type recurrent neural networks with time-varying delays. AB - This paper is concerned with the problem of improved delay-dependent robust stability criteria for neutral-type recurrent neural networks (NRNNs) with time varying delays. Combining the Lyapunov-Krasovskii functional with linear matrix inequality (LMI) techniques and integral inequality approach (IIA), delay dependent robust stability conditions for RNNs with time-varying delay, expressed in terms of quadratic forms of state and LMI, are derived. The proposed methods contain the least number of computed variables while maintaining the effectiveness of the robust stability conditions. Both theoretical and numerical comparisons have been provided to show the effectiveness and efficiency of the present method. Numerical examples are included to show that the proposed method is effective and can provide less conservative results. PMID- 25440954 TI - Food allergy in small children carries a risk of essential fatty acid deficiency, as detected by elevated serum mead acid proportion of total fatty acids. AB - BACKGROUND: Elevated serum Mead acid as a proportion of total fatty acids is an indirect marker of a deficiency of essential fatty acids (EFA). The aim of the study was to evaluate the symptoms and nutrition of food-allergic children with elevated or normal serum Mead acid. METHODS: Serum fatty acid compositions from 400 children were studied by clinical indications, mostly by suspicion of deficiency of EFA due to inadequate nutrition. A Mead acid level exceeding 0.21% (percentage of total fatty acids) was considered to be a specific sign of an insufficient EFA supply. From a total of 31 children with elevated Mead acid (MEADplus group), 23 (74%) had food allergy. The symptoms and dietary restrictions of this MEADplus group of food allergic children were compared to 54 age-and sex-matched controls with food allergy but normal Mead acid proportions (MEADminus group) before and 6 months after the serum fatty acid determination. RESULTS: At the beginning of the 6-month follow-up, 44% of the food allergic children in both MEADplus and MEADminus groups were on an elimination diet. These diets did not differ between the two groups and we were not able to document an association between the severity of elimination diet and elevated Mead acid proportion. However, the MEADplus children were on average more symptomatic than MEADminus children. In the MEADplus group, food allergy presented with skin symptoms in 100% (vs. 70% in the MEADminus group, p < 0.001) and with vomiting or diarrhea in 70% (vs. 44% in the MEADminus group, p < 0.05). Clinical suspicion of malnutrition resulted in increase in the use of vegetable oil and milk-free margarine in both groups from <50% to 65-74% during the follow-up. After 6 months, 64% of the MEADplus children with food allergy had been sent to a control serum fatty acid analysis. Of these children, Mead acid had declined to normal level in 69%, and remained elevated in 31%. CONCLUSIONS: Severe symptoms of food allergy combined with elimination diets in children may lead to insufficient nutrition presenting with elevated serum Mead acid. Adding of supplementary polyunsaturated fat to the diet should be considered in these children. PMID- 25440956 TI - In honour of the 60th birthday of Professor Jun Haginaka. PMID- 25440955 TI - Analysis of codon usage pattern in Taenia saginata based on a transcriptome dataset. AB - BACKGROUND: Codon usage bias is an important evolutionary feature in a genome and has been widely documented in many genomes. Analysis of codon usage bias has significance for mRNA translation, design of transgenes, new gene discovery, and studies of molecular biology and evolution, etc. However, the information about synonymous codon usage pattern of T. saginata genome remains unclear. T. saginata is a food-borne zoonotic cestode which infects approximataely 50 million humans worldwide, and causes significant health problems to the host and considerable socio-economic losses as a consequence. In this study, synonymous codon usage in T. saginata were examined. METHODS: Total RNA was isolated from T. saginata cysticerci and 91,487 unigenes were generated using Illumina sequencing technology. After filtering, the final sequence collection containing 11,399 CDSs was used for our analysis. RESULTS: Neutrality analysis showed that the T. saginata had a wide GC3 distribution and a significant correlation was observed between GC12 and GC3. NC-plot showed most of genes on or close to the expected curve, but only a few points with low-ENC values were below it, suggesting that mutational bias plays a major role in shaping codon usage. The Parity Rule 2 plot (PR2) analysis showed that GC and AT were not used proportionally. We also identified twenty-three optimal codons in the T. saginata genome, all of which were ended with a G or C residue. These results suggest that mutational and selection forces are probably driving factors of codon usage bias in T. saginata genome. Meanwhile, other factors such as protein length, gene expression, GC content of genes, the hydropathicity of each protein also influence codon usage. CONCLUSIONS: Here, we systematically analyzed the codon usage pattern and identified factors shaping in codon usage bias in T. saginata. Currently, no complete nuclear genome is available for codon usage analysis at the genome level in T. saginata. This is the first report to investigate codon biology in T. sagninata. Such information does not only bring about a new perspective for understanding the mechanisms of biased usage of synonymous codons but also provide useful clues for molecular genetic engineering and evolutionary studies. PMID- 25440957 TI - Correlations of lymphocyte subset infiltrates with donor-specific antibodies and acute antibody-mediated rejection in endomyocardial biopsies. AB - BACKGROUND: Acute antibody-mediated rejection (AMR) is a major complication after heart transplantation, posing a significant risk for allograft failure, cardiac allograft vasculopathy, and poor survival. While the inflammatory milieu of cellular rejection and Quilty lesions is well known, the immunologic components of AMR are not well understood. Our aim was to better define the immunophenotype of infiltrating lymphocytes in biopsies with AMR, specifically in relation to donor-specific antibodies to human leukocyte antigen (HLA) class I, II, or both. METHOD: We performed a retrospective analysis of cardiac transplant patients with concurrent endomyocardial biopsies (EMB), donor-specific antibody (DSA) measurements, and immunofluorescence for C4d at our institution (2005-2011). DSA was evaluated against HLA class I and class II specificities pre- and posttransplant using flow cytometry and/or Luminex bead assays. Acute cellular rejection (ACR) and pathologic AMR (pAMR) were based on the International Society for Heart and Lung Transplantation 2005/2013 reports. Immunohistochemical analysis for CD3, CD4, CD8, and CD79a was performed using standard immunohistochemical protocols on one formalin-fixed, paraffin-embedded EMB from each patient. The number of lymphocytes expressing each protein was enumerated microscopically at 400*. Ratios of T:B cells and CD4:CD8 T cells were then calculated for each EMB. RESULTS: Seventy-nine cardiac transplant patients who had pre- and posttransplant DSA measurements were analyzed. Of these 79 patients, 37 had DSA against HLA class I, HLA class II, or both. Of patients with DSA, the average CD4:CD8 ratio in the EMB was 0.80, while those with only ACR had a CD4:CD8 ratio of 1.49. Interestingly, the T:B cell ratio in patients with and without DSA was 5.7 and 5.5, respectively. CONCLUSION: Cardiac transplant patients with DSA against HLA have more CD8 cytotoxic T cells than CD4 helper T cells in the EMB lymphocytic infiltrate compared with patients without DSA against HLA. The inflammatory infiltrate T:B cell ratio was similar in patients both with and without DSA. The relative increase of cytotoxic T cells in EMB while the patient has DSA suggests a possible pathogenic role of these cells and may aid in the diagnosis and treatment of AMR. PMID- 25440958 TI - Claudin-5 levels are reduced from multiple cell types in human failing hearts and are associated with mislocalization of ephrin-B1. AB - Claudin-5 is transcriptionally downregulated resulting in dramatically reduced protein levels in human heart failure. Studies in mice have demonstrated that reduced claudin-5 levels occur prior to cardiac damage and far before reduced whole heart function. Therefore, claudin-5 may be a useful early therapeutic target for human heart failure. However, the cell types in which claudin-5 is localized in human heart and from which claudin-5 is reduced in heart failure is not known. The recent identification of claudin-5's interaction with ephrin-B1 in mouse hearts has also not been investigated in non-failing or failing human hearts. In this study we collected human left ventricular mid-myocardium histological samples from 7 non-failing hearts and 16 end-stage failing hearts. Immunoblots demonstrate severe reductions of claudin-5 protein in 14 of 16 failing hearts compared to non-failing controls. Claudin-5 was observed to localize to cardiomyocytes, endothelial cells, and a subset of fibroblasts in non failing human heart sections. In isolated cardiomyocytes, the transmembrane claudin-5 protein localized in longitudinal striations in lateral membranes. In failing heart, both cardiomyocyte and endothelial claudin-5 localization was severely reduced, but claudin-5 remained in fibroblasts. Absence of claudin-5 staining also correlated with the reduction of the endothelial cell marker CD31. Ephrin-B1 localization, but not protein levels, was altered in failing hearts supporting that claudin-5 is required for ephrin-B1 localization. These data support that loss of claudin-5 in cardiomyocytes and endothelial cells is prevalent in human heart failure. Investigating claudin-5/ephrin-B1 protein complexes and gene regulation may lead to novel therapies. PMID- 25440959 TI - Dysplastic nevi, cutaneous melanoma, and other skin neoplasms in patients with myotonic dystrophy type 1: a cross-sectional study. AB - BACKGROUND: Myotonic dystrophy type 1 (MD1) is reported to be associated with internal malignancies. The association of myotonic dystrophy with cutaneous tumors is not fully understood. OBJECTIVE: We sought to explore the total nevi count and the presence of atypical nevi, cutaneous melanoma, and other skin neoplasms in a representative cohort of patients with MD1 and to compare the findings with age- and sex-matched control subjects. METHODS: In all, 90 patients with MD1 and 103 age- and sex-matched control subjects were assessed for cutaneous neoplasms by clinical skin and epiluminescence examination (dermoscopy). Where indicated, subsequent excisions were performed. In patients with MD1, leukocyte n(CTG) expansion was measured. RESULTS: Patients with MD1 showed significantly higher numbers of nevi, dysplastic nevi, and melanomas despite a significantly greater proportion of the control subjects reporting sunburns. In addition, we found a significantly greater number of pilomatrixoma in patients with MD1. LIMITATIONS: Our study is limited by the fact that there is no agreed-upon standardized technique to assess for prior sun exposure. Further research in the association of cutaneous neoplasms and MD1 including vitamin D and molecular biological techniques are also recommended. CONCLUSION: MD1 itself may predispose to development of skin tumors. PMID- 25440960 TI - Likelihood of finding melanoma when removing a Spitzoid-looking lesion in patients aged 12 years or older. AB - BACKGROUND: Dermoscopy improves the recognition of melanoma and Spitz nevus but occasionally melanoma may exhibit a symmetric pattern mimicking Spitz nevus. OBJECTIVE: We sought to investigate the likelihood of finding melanoma when excising a symmetric Spitzoid-looking lesion in patients aged 12 years or older. METHODS: This study included patients aged 12 years or older with symmetric, Spitzoid-looking lesions that were diagnosed histopathologically as Spitz nevus or melanoma. Demographic, clinical, and dermoscopic variables were included in the analysis. We used chi(2) for nonparametric comparisons. Crude odds ratios and 95% confidence intervals were calculated by univariate logistic regression. RESULTS: Of 384 included lesions, 333 (86.7%) were histopathologically diagnosed as Spitz nevus and 51 (13.3%) as melanoma. The risk of melanoma significantly increased with increasing age, being 50% or higher after the age of 50 years. LIMITATIONS: Limitations are retrospective design, exclusion of patients younger than 12 years, lack of detailed histopathologic data, and limited sample size. CONCLUSION: Our results confirm the observation that melanoma may be dermoscopically indistinguishable from Spitz nevi, strongly suggesting that the only safe strategy not to miss melanoma is to excise all Spitzoid-looking lesions in patients aged 12 years or older. PMID- 25440962 TI - [Non-compaction cardiomyopathy]. PMID- 25440961 TI - [Pulmonary sequestration in the simple chest X-ray. When to suspect it and why]. PMID- 25440963 TI - [Groin pain and fever]. PMID- 25440964 TI - [Peripheral facial palsy in a patient with unilateral vesicular eruption on the face]. PMID- 25440965 TI - [Persistent elevated transaminases in the adult: A common situation like the presentation of Wilson's disease]. PMID- 25440966 TI - [Occupational disability in epilepsy. The assessment criteria]. AB - Epilepsy is a chronic disease cursing with recurrent and paroxysmal crises due to anomalies in the electrical activity of brain, and is controllable in most of the patients by using antiepileptic drugs, in single or combination therapy. Probably one of the most complex aspects of epilepsy is the assessment of disability for work of the affected person. For this purpose, multiple factors need to be taken into account for homogeneous decision-making, and according to criteria of approval and within the principle of equity inherent in the granting of Social Security disability benefits. This requires the cooperation of all professionals involved in the different specialties, with reports using common criteria and taking into account the disease itself, as well as the effects of the prescribed treatments, the effects of which can contribute to the limitations in the performance of certain professions of risk. PMID- 25440967 TI - [National implementation of the prescription]. PMID- 25440969 TI - [Wellens' syndrome]. PMID- 25440968 TI - [Viper bite treatment in Spain]. AB - Viper snake bite is, by far, the most common ophidian accident in Spain. It is responsible for between 100 and 150 hospitalizations per year in this country, although it is difficult to determine the frequency of emergency admissions due to this cause. The cornerstone to their approach rests on the correct evaluation of the possible effects derived from envenomation and the use of anti-venoms. In spite of all the controversies surrounding the use of anti-venoms, they have become a powerful therapeutic weapon ever since the serum has been highly purified and the great decrease of related anaphylactic reactions. The aim of this article is to update the emergency room procedures when viper bites are suspected, and to clarify the main therapeutic recommendations. PMID- 25440970 TI - [Colchicine and pericarditis]. PMID- 25440971 TI - [Chikungunya, an emerging viral disease. Proposal of an algorithm for its clinical management]. AB - Chikungunya fever (CHIK) is an emerging viral disease. It is caused by the Chikungunya virus, an alphavirus from the Togaviridae family. It is transmitted to humans by the bite of infected mosquitoes, mainly Aedes aegypti and Aedes albopictus. They are also involved in the transmission of dengue, malaria, etc. CHIK is now endemic in any region of Africa and Southeast-Asia. Cases of CHIK have been reported in America, the Caribbean, and Europe (France, Italy and Spain). There are reservoirs of these mosquitoes in some regions of Spain (Catalonia, Alicante, Murcia and Balearic islands). CHIK is characterized by a sudden high and debilitating fever, and severe or disabling symmetrical arthralgia. It tends to improve in days or weeks. There are severe and chronic forms of CHIK. There is no specific treatment or prophylaxis for CHIK. An algorithm is proposed for the clinical management of CHIK based in the latest guidelines. PMID- 25440972 TI - [Congresses and meetings: A species in extinction in medicine?]. PMID- 25440973 TI - [Does the use of statins modify calorie intake and fat consumption?]. PMID- 25440974 TI - [Acute myocardial infarction due to a coronary embolism and a massive pulmonary thromboembolism in a young patient. A difficult to manage combination]. PMID- 25440975 TI - Effects of immunomodulatory supplementation with Lactobacillus rhamnosus on airway inflammation in a mouse asthma model. AB - BACKGROUND: Asthma is a common allergic disease. In previous studies, probiotics improved the balance of intestinal microbes, reduced inflammation, and promoted mucosal tolerance. This study investigated whether oral administrations of Lactobacillus rhamnosus GG (LGG) inhibited allergen (ovalbumin or OVA)-induced airway inflammation in a mouse asthma model. METHODS: The allergy/asthma animal model in this study was sensitization with OVA. After intranasal challenge with OVA, the airway inflammation and hyper-responsiveness were determined by a Buxco system, bronchoalveolar lavage fluid analysis with Liu stain, and enzyme-linked immunosorbent assay. Histopathologic changes in the lung were detected by hematoxylin and eosin staining and immunohistochemistry staining. RESULTS: Both pre- and post-treatment with LGG suppressed the airway hyper-responsiveness to methacholine and significantly decreased the number of infiltrating inflammatory cells and Th2 cytokines in bronchoalveolar lavage fluid and serum compared with the OVA-sensitized mice. In addition, LGG reduced OVA-specific IgE levels in serum. Oral LGG decreased matrix metalloproteinase 9 expression in lung tissue and inhibited inflammatory cell infiltration. CONCLUSION: LGG had an anti inflammatory effect on OVA-induced airway inflammation and might be an additional or supplementary therapy for allergic airway diseases. PMID- 25440976 TI - Risk factors for microbiologic failure among Taiwanese adults with Mycobacterium abscessus complex pulmonary disease. AB - BACKGROUND: The Mycobacterium abscessus complex is a common cause of pulmonary nontuberculous mycobacteria infections in Taiwan. We examined the risk factors associated with treatment outcome in Taiwanese adults with pulmonary disease caused by the M. abscessus complex. METHODS: We retrospectively reviewed the records of all patients from a southern Taiwan medical center from 2006 to 2012 who had respiratory specimens identified as M. abscessus complex and met the American Thoracic Society criteria for pulmonary disease. RESULTS: Of the 106 included patients, females (58.5%) and nonsmokers (79.2%) predominated. The mean age of patients was 64.8 years. Sixty-three patients (59.4%) had pre-existing lung disease. Previous mycobacterial pulmonary disease (34.9%) was the most common underlying disorder. Chest radiography indicated that bronchiectasis was common (47.2%) and that cavitations were less common (14.2%). Fifty-six patients received antibiotic treatment. Clinicians were more likely to prescribe antibiotics if the initial sputum acid-fast staining was positive (p < 0.001). Treatment outcome was analyzed in 26 patients who were treated for more than 3 months; three of these patients (11.5%) had clinical failure and 18 (69.2%) experienced sputum conversion. Patients with cavitary lesions were more likely to experience microbiologic failure (p = 0.02). Nine patients had positive cultures after antibiotic treatment for > 1 year. Previous mycobacterial pulmonary disease (p = 0.011) and cavitary lesion (p = 0.034) are risk factors for persistence of M. abscessus complex. CONCLUSION: With antimicrobial therapy, previous mycobacterial disease, and cavitary lesion are associated with microbiologic failure in Taiwanese adults with M. abscessus complex pulmonary disease. PMID- 25440977 TI - Clinical efficacy and safety of primary antifungal prophylaxis with posaconazole versus fluconazole in allogeneic blood hematopoietic stem cell transplantation recipients-A retrospective analysis of a single medical center in Taiwan. AB - BACKGROUND/PURPOSE: The efficacy and safety of posaconazole compared to fluconazole as antifungal prophylaxis in patients receiving allogeneic blood hematopoietic stem cell transplantation (allo-HSCT) during the early neutropenic phase without graft-versus-host disease (GVHD) was uncertain. METHODS: The medical records of allo-HSCT recipients from a single institution, who received oral fluconazole (from January 2005 to June 2011) or oral posaconazole (from June 2011 to December 2013) during the early neutropenic phase (until engraftment), were retrospectively reviewed. RESULTS: There were 52 allo-HSCT recipients, two of whom were younger than 18 years of age. Twelve cases received posaconazole and 40 cases received fluconazole as primary antifungal prophylaxis. The two groups had similar transplant characteristics, conditioning, and GVHD prophylaxis regimens. The fluconazole group had a higher risk for development of invasive fungal infections within 90 days after allo-HSCT (43% vs. 8.3%, p = 0.039). Kaplan-Meier analysis indicated that the cumulative incidence of invasive fungal infection for 90 days after allo-HSCT was higher in the fluconazole group (log rank test, p = 0.047). Early discontinuation of antifungal prophylaxis for intolerance was significantly lower in the posaconazole group (8.3% vs. 50%, p = 0.017). Both groups had similar rates of impaired liver function. CONCLUSION: Analysis of primary fungal prophylaxis during the early neutropenic phase following allo-HSCT indicated that posaconazole was more effective and was better tolerated than fluconazole. Both drugs had similar safety profiles. PMID- 25440978 TI - Gene-expression analysis of cold-stress response in the sexually transmitted protist Trichomonas vaginalis. AB - BACKGROUND: Trichomonas vaginalis is the etiologic agent of trichomoniasis, the most common nonviral sexually transmitted disease in the world. This infection affects millions of individuals worldwide annually. Although direct sexual contact is the most common mode of transmission, increasing evidence indicates that T. vaginalis can survive in the external environment and can be transmitted by contaminated utensils. We found that the growth of T. vaginalis under cold conditions is greatly inhibited, but recovers after placing these stressed cells at the normal cultivation temperature of 37 degrees C. However, the mechanisms by which T. vaginalis regulates this adaptive process are unclear. METHODS: An expressed sequence tag (EST) database generated from a complementary DNA library of T. vaginalis messenger RNAs expressed under cold-culture conditions (4 degrees C, TvC) was compared with a previously published normal-cultured EST library (37 degrees C, TvE) to assess the cold-stress responses of T. vaginalis. RESULTS: A total of 9780 clones were sequenced from the TvC library and were mapped to 2934 genes in the T. vaginalis genome. A total of 1254 genes were expressed in both the TvE and TvC libraries, and 1680 genes were only found in the TvC library. A functional analysis showed that cold temperature has effects on many cellular mechanisms, including increased H2O2 tolerance, activation of the ubiquitin-proteasome system, induction of iron-sulfur cluster assembly, and reduced energy metabolism and enzyme expression. CONCLUSION: The current study is the first large-scale transcriptomic analysis in cold-stressed T. vaginalis and the results enhance our understanding of this important protist. PMID- 25440979 TI - Aeromonas stool isolates from individuals with or without diarrhea in southern Taiwan: Predominance of Aeromonas veronii. AB - BACKGROUND: Although aeromonads are important pathogens causing invasive infections in southern Taiwan, Aeromonas-associated intestinal infections have been rarely mentioned. PURPOSE: The aim of this study was to understand the frequency of isolation and clinical significance of aeromonads recovered from adult stool samples in southern Taiwan. METHODS: During a 15-month study period, 514 adults with diarrhea and 167 asymptomatic controls were prospectively screened for the presence of aeromonads in stools. The identity of Aeromonas species was determined by the rpoD sequencing. Clinical information was retrieved from medical records, and in vitro cytotoxicity assay and polymerase chain reaction detection of putative virulent genes were performed. RESULTS: Thirteen (2.5 %) of 514 diarrheal patients and six (3.6%) of 167 asymptomatic controls had Aeromonas isolates in their stools. Of 11 diarrheal patients with available clinical information, Aeromonas veronii, the predominant species, was noted in six patients, and another potential enteropathogen was present in four patients. The cytotoxicity of A. veronii isolates to the HT-29 cell line was more potent in the isolates from diarrheal patients than those from asymptomatic controls (p = 0.015). The cytotoxicity of A. veronii isolates was more potent than that of A. caviae from symptomatic patients (p = 0.001). Putative virulence markers, including AHCYTONE, ascV, ascF-ascG, and aexT, were detected exclusively in A. veronii. The presence of the ascV gene was associated with cytotoxicity in A. veronii isolates. All Aeromonas isolates were susceptible to varied antimicrobial agents, except ampicillin/sulbactam. CONCLUSION: A. veronii is the predominant species in stools from individuals with or without diarrhea in southern Taiwan. PMID- 25440980 TI - Highly active antiretroviral therapy-related hepatotoxicity in human immunodeficiency virus and hepatitis C virus co-infected patients with advanced liver fibrosis in Taiwan. AB - BACKGROUND: The prevalence of patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is higher in Taiwan than in Western countries. This study aimed to analyze the frequency and risk factors for highly active antiretroviral therapy (HAART)-related liver toxicity in patients co infected with HIV and HCV with advanced liver fibrosis in Taiwan. METHODS: This retrospective cohort study included 228 HAART-experienced and HAART-naive patients who were co-infected with HIV and HCV from January 2013 to December 2013 in Taiwan. Transaminase elevation (TE) was defined by grades. Fibrosis 4 score and aspartate-to-platelet ratio index were used to evaluate liver fibrosis. Cox proportional hazard regression model was used to analyze the risk factors for time to TE events. RESULTS: A total of 228 patients were included. Only two episodes (1.28%) of high-grade TE were observed. The overall prevalence rate of TE was 16%, and the incidence was 1.38 cases/100 patient-months. Two predictive factors of TE were the initiation of HAART during the study period and CD4 cell count less than 350 cells/mm(3). Subgroup analysis showed that HAART improved liver fibrosis status in patients who had advanced liver fibrosis at baseline (p = 0.033). CONCLUSION: The frequency of HAART-related TE in HIV and HCV co infected patients in Taiwan was much lower than that observed in previous studies. Pre-existing advanced liver fibrosis had no influence on the frequency of TE. The use of HAART showed benefits on liver fibrosis progression in patients with underlying advanced liver fibrosis. PMID- 25440981 TI - Dietary sunflower oil modulates milk fatty acid composition without major changes in adipose and mammary tissue fatty acid profile or related gene mRNA abundance in sheep. AB - There are very few studies in ruminants characterizing mammary and adipose tissue (AT) expression of genes and gene networks for diets causing variations in milk fatty acid (FA) composition without altering milk fat secretion, and even less complementing this information with data on tissue FA profiles. This work was conducted in sheep in order to investigate the response of the mammary gland and the subcutaneous and perirenal AT, in terms of FA profile and mRNA abundance of genes involved in lipid metabolism, to a diet known to modify milk FA composition. Ten lactating Assaf ewes were randomly assigned to two treatments consisting of a total mixed ration based on alfalfa hay and a concentrate (60 : 40) supplemented with 0 (control diet) or 25 (SO diet) g of sunflower oil/kg of diet dry matter for 7 weeks. Milk composition, including FA profile, was analysed after 48 days on treatments. On day 49, the animals were euthanized and tissue samples were collected to analyse FA and mRNA abundance of 16 candidate genes. Feeding SO did not affect animal performance but modified milk FA composition. Major changes included decreases in the concentration of FA derived from de novo synthesis (e.g. 12:0, 14:0 and 16:0) and increases in that of long-chain FA (e.g. 18:0, c9-18:1, trans-18:1 isomers and c9,t11-CLA); however, they were not accompanied by significant variations in the mRNA abundance of the studied lipogenic genes (i.e. ACACA, FASN, LPL, CD36, FABP3, SCD1 and SCD5) and transcription factors (SREBF1 and PPARG), or in the constituent FA of mammary tissue. Regarding the FA composition of AT, the little influence of SO did not appear to be linked to changes in gene mRNA abundance (decreases of GPAM and SREBF1 in both tissues, and of PPARG in the subcutaneous depot). Similarly, the great variation between AT (higher contents of saturated FA and trans-18:1 isomers in the perirenal, and of cis-18:1, c9,t11-CLA and n-3 PUFA in the subcutaneous AT) could not be related to differences in gene mRNA abundance due to tissue site (higher LPL and CD36, and lower SREBF1 in perirenal than in subcutaneous AT). Overall, these results suggest a marginal contribution of gene expression to the nutritional regulation of lipid metabolism in these tissues, at least with the examined diets and after 7 weeks on treatments. It cannot be ruled out, however, that the response to SO is mediated by other genes or post transcriptional mechanisms. PMID- 25440983 TI - Doing with less: hominin brain atrophy. AB - In contrast to hominin encephalization, the final Pleistocene and Holocene reduction in cranial volume has attracted very little attention and remains unexplained. Here it is examined in the light of current neuroscientific and archaeological understanding, and it is shown that the most parsimonious explanation is via the domestication hypothesis of recent humans. Accordingly, rapid atrophy of the brain is partly explained by the culturally based process of sexual selection, first detectable in late robust Homo sapiens perhaps 40,000 years ago. Furthermore it is suggested that this deleterious process of neotenization and brain atrophy was compensated for by the concurrent development of exograms, i.e. means of storing memory outside the brain. Consequently most of human memory and cultural information is now stored external to the brain, which has altered that organ significantly and facilitated a cultural complexity that would be impossible to maintain by biological memory alone. The escalating use of exograms, neotenization and reduction in cranial volume all appear to co-occur with numerous other changes to the human genome. PMID- 25440982 TI - Implementing a national approach to universal child and family health services in Australia: professionals' views of the challenges and opportunities. AB - Australia has a well-accepted system of universal child and family health (CFH) services. However, government reports and research indicate that these services vary across states and territories, and many children and families do not receive these services. The aim of this paper was to explore professionals' perceptions of the challenges and opportunities in implementing a national approach to universal CFH services across Australia. Qualitative data were collected between July 2010 and April 2011 in the first phase of a three-phase study designed to investigate the feasibility of implementing a national approach to CFH services in Australia. In total, 161 professionals participated in phase 1 consultations conducted either as discussion groups, teleconferences or through email conversation. Participants came from all Australian states and territories and included 60 CFH nurses, 45 midwives, 15 general practitioners (GPs), 12 practice nurses, 14 allied health professionals, 7 early childhood education specialists, 6 staff from non-government organisations and 2 Australian government policy advisors. Data were analysed thematically. Participants supported the concept of a universal CFH service, but identified implementation barriers. Key challenges included the absence of a minimum data set and lack of aggregated national data to assist planning and determine outcomes; an inconsistent approach to transfer of information about mothers and newborns from maternity services to CFH nursing services or GPs; poor communication across disciplines and services; issues of access and equity of service delivery; workforce limitations and tensions around role boundaries. Directions for change were identified, including improved electronic data collection and communication systems, reporting of service delivery and outcomes between states and territories, professional collaboration, service co-location and interprofessional learning and development. PMID- 25440984 TI - Neurogenetic disorders in the Basque population. AB - In the molecular era, the study of neurogenetic disorders in relict populations provides an opportunity to discover new genes by linkage studies and to establish clearer genotype-phenotype correlations in large cohorts of individuals carrying the same mutation. The Basque people are one of the most ancient populations living in Europe and represent an excellent resource for this type of analysis in certain genetic conditions. Our objective was to describe neurogenetic disorders reported in the Basque population due to the presence of ancestral mutations or an accumulation of cases or both. We conducted a search in PubMed with the terms: Basque, neurogenetic disorders, genetic risk, and neurological disorders. We identified nine autosomal and two recessive disorders in the Basque population attributable to ancestral mutations (such as in PNRP, PARK8, FTDP-TDP43, LGMD2A, VCP, c9ORF72, and CMT4A), highly prevalent (DM1) or involving unique mutations (PARK1 or MAPT). Other genes were reported for their role as protective/risk factors in complex diseases such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease. At the present time, when powerful sequencing techniques are identifying large numbers of genetic variants associated with unique phenotypes, the scrutiny of these findings in genetically homogeneous populations can help analyze genotype-phenotype correlations. PMID- 25440985 TI - Urinary diversion: how experts divert. AB - OBJECTIVE: To determine the rates of the available urinary diversion options for patients treated with radical cystectomy for bladder cancer in different settings (pioneering institutions, leading urologic oncology centers, and population based). METHODS: Population-based data from the literature included all patients (n = 7608) treated in Sweden during the period 1964-2008, from Germany (n = 14,200) for the years 2008 and 2011, US patients (identified from National Inpatient Sample during 1998-2005, 35,370 patients and 2001-2008, 55,187 patients), and from Medicare (n = 22,600) for the years 1992, 1995, 1998, and 2001. After the International Consultation on Urologic Diseases-European Association of Urology International Consultation on Bladder Cancer 2012, the urinary diversion committee members disclosed data from their home institutions (n = 15,867), including the pioneering institutions and the leading urologic oncology centers. They are the coauthors of this report. RESULTS: The receipt of continent urinary diversion in Sweden and the United States is <15%, whereas in the German high-volume setting, 30% of patients receive a neobladder. At leading urologic oncology centers, this rate is also 30%. At pioneering institutions up to 75% of patients receive an orthotopic reconstruction. Anal diversion is <1%. Continent cutaneous diversion is the second choice. CONCLUSION: Enormous variations in urinary diversion exist for >2 decades. Increased attention in expanding the use of continent reconstruction may help to reduce these disparities for patients undergoing radical cystectomy for bladder cancer. Continent reconstruction should not be the exclusive domain of cystectomy centers. Efforts to increase rates of this complex reconstruction must concentrate on better definition of the quality-of-life impact, technique dissemination, and the centralization of radical cystectomy. PMID- 25440986 TI - Magnetic resonance-invisible versus magnetic resonance-visible prostate cancer in active surveillance: a preliminary report on disease outcomes. AB - OBJECTIVE: To assess the association between magnetic resonance (MR) appearance of prostate cancer on a baseline multiparametric prostate (MP) MR imaging (MRI) and biopsy outcome in men with favorable-risk prostate cancer managed with active surveillance (AS). MATERIALS AND METHODS: Ninety-six consecutive men (mean age, 67.8 years) who had a baseline MP MRI within 1 year of AS enrollment were included in the study. MP MRI results were analyzed to identify men with MR invisible tumor defined as no signal abnormality on T2-weighted images, no focal restricted diffusion, and no perfusion abnormality on dynamic contrast-enhanced images. Patients with (n = 84) or without (n = 12) MR-visible tumor were compared and the impact of MR-invisibility of tumor on the risk of adverse biopsy pathology based on the Epstein criteria was investigated with a median follow-up of 23 months. RESULTS: Adverse biopsy pathology occurred in 36.5% (35 of 96) of patients. There was no significant difference in the fulfillment of AS criteria at enrollment, prostate-specific antigen level or density, prostate volume, and number of biopsies (total or after MRI) between the 2 groups of patients. A total of 8.3% (1 of 12) of men with MR-invisible tumor had adverse biopsy pathology as compared with 40.5% (34 of 84) of men with MR-visible tumors. The MR-invisibility of tumor was associated with a lower risk of adverse biopsy pathology (crude relative risk = 0.35; 95% confidence interval, 0.10-1.25; prostate-specific antigen density-adjusted relative risk = 0.21; 95% confidence interval, 0.03 1.32). CONCLUSION: The MR-invisibility of tumor on MP MRI could be of prognostic significance in monitoring men in AS with potential benefit of tailoring the frequency of surveillance biopsies and reducing the number of unnecessary biopsies. PMID- 25440987 TI - Reduced radiation tolerance of penile structures associated with dose-escalated hypofractionated prostate radiotherapy. AB - OBJECTIVE: To investigate the effect of hypofractionated external beam radiation therapy (RT) on sexual function in patients treated for localized prostate cancer, and also to determine the effect of radiation dose to the penile bulb or crura of the corpus cavernosum on sexual function outcome. MATERIALS AND METHODS: Forty-one patients treated with hypofractionated RT without androgen deprivation were prescribed 67.6-70.2 Gy to the prostate, delivered in 26-28 fractions. The primary endpoint was erectile dysfunction (ED) category based on the Sexual Health Inventory for Men (SHIM) score closest to 2 years from RT. The penile bulb and crura were contoured and mean radiation dose calculated for each structure. RESULTS: The mean pretreatment SHIM score was 19.8, and the mean posttreatment SHIM score was 15.1. The ED category was decreased by >= 2 in 50% of patients with a mean penile bulb of >20 Gy compared with that in 9% of patients with a mean penile bulb dose of <= 20 Gy (P = .003). Mean dose to the crura was highly correlated with mean dose to the penile bulb (Pearson correlation = 0.842; P <.001) but did not reach statistical significance as a predictor of ED after radiation. CONCLUSION: Radiation dose to the penile bulb is predictive of posttreatment ED in patients treated with dose-escalated hypofractionated prostate RT. The cutpoint at which this effect was observed with this treatment is substantially lower than the previous reports. PMID- 25440988 TI - Surgical outcomes after cytoreductive nephrectomy with inferior vena cava thrombectomy. AB - OBJECTIVE: To determine postoperative outcomes in patients with metastatic renal cell carcinoma (mRCC) and level II through IV inferior vena cava (IVC) thrombus (IVCT), and their ability to receive systemic therapy. MATERIALS AND METHODS: We reviewed medical records of all patients with mRCC and level II through IV IVCT who underwent surgery between January 1990 and December 2012 at our institution. Complications within 30 days of surgery were recorded according to the Clavien Dindo system. Survival was calculated according to the Kaplan-Meier method, and intergroup comparisons were performed with the log-rank statistics. RESULTS: Seventy-six patients were identified, of which 30 (40%), 31 (41%), and 15 (20%) patients had a level II, III, and IV IVCT, respectively. Perioperative mortality was 6.6%. The overall postoperative complication rate was 37%, of which 7.8% (n = 6) were classified as major postoperative complications (Clavien grade 3-5). Follow-up information was available in 60 patients, of whom 90% received a postoperative systemic therapy. Four patients chose expectant management, and 2 patients died of progressive disease before receiving systemic therapy. Overall median survival was 14 months and was significantly related to postoperative treatment with targeted molecular therapies and number of prognostic risk factors, but was not influenced by the level of IVC tumor thrombus. CONCLUSION: Cytoreductive nephrectomy and IVC thrombectomy can be performed with acceptable complication rates and should be considered as an integral part of the treatment approach for patients with mRCC and IVC tumor thrombi. PMID- 25440989 TI - Trends in the management of male urethral stricture disease in the veteran population. AB - OBJECTIVE: To evaluate the relative use of urethral dilation, urethrotomy, and urethroplasty for male stricture disease in the Veterans Affairs (VA) population and examine trends over time in this cohort. METHODS: A retrospective chart review was performed using the VA Informatics and Computing Infrastructure database to access the Corporate Data Warehouse. The current procedural terminology codes were used to define a cohort of all men who underwent procedures for urethral stricture disease between October 1999 and August 2013. RESULTS: A total of 92,448 procedures were performed: 50,875 urethral dilations (55.03%), 39,785 urethrotomies (43.03%), and 1788 urethroplasties (0.19%). Over the course of the study, there was a shift in the management of male stricture disease. The relative percentage of urethral dilations performed decreased in each quintile (71.27, 58.03, 45.61, 44.39, and 38.67). The relative percentage of urethrotomies increased in each quintile (27.89, 40.80, 52.18, 53.04, and 56.95) as did the relative percentage of urethroplasties performed (0.85, 1.17, 2.21, 2.57, and 4.38). A total of 80.4% of these urethroplasties were performed in locations with a residency program. CONCLUSION: Although urethroplasty is still underused, there is a trend toward increased use of urethroplasty for male urethral stricture disease in the VA population. The majority of urethroplasties were performed at VA medical centers in locations with a residency program. We predict continued increases in utilization of urethroplasty for male urethral stricture disease as the number of fellowship-trained reconstructive urologists increases. PMID- 25440990 TI - Day case laparoscopic nephrectomy with vaginal extraction: initial experience. AB - OBJECTIVE: To assess the feasibility of laparoscopic nephrectomy with vaginal extraction in an ambulatory setting. METHODS: Two patients underwent a laparoscopic (1 was robot assisted) nephrectomy with vaginal extraction for a nonfunctioning kidney in an ambulatory setting. Both interventions were performed by the same surgical team comprising a urologic surgeon and a gynecologic surgeon. The operative specimen was vaginally extracted via an incision in the posterior fornix at the end of the intervention. Patients had to respect very strict socioenvironmental and clinical criteria. Anesthesia was achieved using short-acting agents. Only first- and second-step analgesics were used (morphine free protocol). The main judgment criteria were visual analog scale assessment for postoperative pain, the Clavien-Dindo classification for surgical complications, and the hospital readmission rate. RESULTS: Two female patients (37 and 41 years old) have been successfully operated with this technique. No major perioperative or postoperative complications (Clavien-Dindo grade >2) were reported, and no patient readmission was required. Postoperative pain was well managed with visual analog scale scores <= 5. Both patients operated in the ambulatory setting had Chung scores of 10 before their discharge. CONCLUSION: Laparoscopic or robotic nephrectomy with vaginal extraction can be performed in an ambulatory setting in carefully selected patients. The association of fast track surgical techniques and vaginal extraction by eliminating the abdominal wound extraction source of postoperative pain allows performing this operation in this setting with a high level of satisfaction. PMID- 25440991 TI - A new subtype of crossed fused ectopia of the kidneys. AB - Crossed fused renal ectopia is a rare congenital anomaly; here, we report a new subtype of crossed fused renal ectopia associated with the retroiliac megaureter and thoracic scoliosis deformity. It is beyond the traditional classification of crossed fused renal ectopia. There are 2 kidneys in the left and hydronephrosis of the upper kidney, the right kidney crossed over and fused with the lower kidney of the left. It is never seen in previous reports. Recurrent infection was cured by resecting the hydronephrosis of the upper kidney and retroiliac megaureter. PMID- 25440992 TI - A nephropleural fistula complicated by distal ureteral obstruction results in tension hydrothorax after percutaneous nephrostolithotomy. AB - We present the case of a patient with nephrocalcinosis and chronic kidney disease who underwent percutaneous nephrostolithotomy via a mid-pole access. After nephroureteral stent removal, the patient developed a tension hydrothorax due to the rare combination of a nephropleural fistula and ipsilateral distal ureteral obstruction. This complication was managed by percutaneous nephrostomy and thoracostomy placement and subsequent thoracoscopic surgery without further sequelae. PMID- 25440993 TI - Youth participation in disaster risk reduction through science clubs in the Philippines. AB - With the UN-led celebration of the International Year of Youth from August 2010 to August 2011 there has been a renewed interest in young people and the vital role they can play in important issues, such as disaster risk reduction (DRR). This study aims to examine the potential of science clubs as a vehicle for youth participation in DRR in the Philippines. A questionnaire survey was conducted to obtain quantitative and qualitative data. A total of 658 science club members from different provinces of the Philippines participated in the survey. The result of the survey is used to explain how the major barriers to youth participation in DRR can be overcome. Through science clubs, the youth can become a link between their school, home and community and can contribute to spreading knowledge about disaster prevention, preparedness and response learned inside and outside the classroom. PMID- 25440994 TI - MRI for local staging of endometrial carcinoma: Is endovenous contrast medium administration still needed? AB - PURPOSE: To compare the diagnostic performance of T2-weighted images (T2 WI)+contrast-enhanced T1-weighted images (CE T1-WI) with the one of T2 WI+diffusion-weighted images (DWI) in the assessment of myometrial and cervical stromal infiltration by endometrial carcinoma (EC). MATERIALS AND METHODS: Institutional review board approved our retrospective study; requirement for informed consent was waived. 56 patients with histologically proven EC who underwent preoperative MRI and surgery at our Institution over a 34 months period were included. Two radiologists independently evaluated T2-WI+CE T1-WI and T2 WI+DWI of each patient. Confidence in imaging evaluation (0-3), depth of myometrial invasion (=50%) and presence of cervical stromal infiltration (Yes/No) were assessed. MRI findings were compared with pathological ones. RESULTS: Confidence in imaging evaluation was higher for T2-WI+CE T1-WI (2.83/3) than for T2-WI+DWI (2.62/3). T2-WI+DWI showed a better diagnostic performance than T2-WI+CE T1-WI in recognizing deep myometrial infiltration by EC (accuracy, sensitivity and specificity of 0.89, 0.89 and 0.89 vs. 0.86, 0.84, 0.86; p>0.05) whereas both imaging sequences combinations showed the same diagnostic performance in recognizing cervical stromal infiltration (accuracy, sensitivity and specificity of 0.95, 0.98 and 0.80, p>0.05). CONCLUSION: T2-WI+DWI can reliably replace the "classical" combination T2-WI+CE T1-WI for local staging of endometrial carcinoma. PMID- 25440995 TI - Effect of Bidens pilosa on infection and drug resistance of Eimeria in chickens. AB - Extensive use of current anti-coccidial drugs together with drug resistance and residue has raised concerns about public health and poultry development. Here, we studied the anti-coccidial properties of Bidens pilosa. A phytochemical approach was developed for analysis of B. pilosa utilized as a feed additive. The protective effects of B. pilosa supplemented chicken diet were evaluated chickens infected with Eimeria tenella. B. pilosa, at doses of 0.5%, 1% and 5% of the chicken diet, significantly protected against E.tenella as measured by reduction in mortality, weight loss, fecal oocyst excretion and gut pathology in chickens. Finally, drug resistance of E. tenella to B. pilosa was assessed in chickens using the anti-coccidial index. This index showed that B. pilosa induced little, if any, drug resistance to Eimeria in chickens. Collectively, this work suggests that B. pilosa may serve as a novel, natural remedy for coccidiosis with low drug resistance in chickens. PMID- 25440996 TI - Serum concentration of high density lipoproteins (HDLs) in leishmaniotic dogs. AB - In order to assess whether the concentration of high density lipoproteins (HDLs) changes in leishmaniotic dogs before and after treatment, HDL cholesterol (HDL Chol and HDL%), C reactive protein (CRP) and activity of the antioxidant enzyme paraoxonase (PON-1) were measured in sera from 10 controls and 10 leishmaniotic dogs. Seven of these latter were sampled also 3, 7, 14, 21 and 28 days after treatment with antimonials and allopurinol. HDL-chol, and PON-1 were low in leishmaniotic dogs at admission and increased after treatment. HDL-chol and HDL% correlated positively with PON-1 and negatively with CRP suggesting that HDLs decrease through an oxidative mechanism. Therefore, HDLs may be used to monitor the magnitude of oxidation associated with inflammation in leishmaniotic dogs. PMID- 25440997 TI - XerC-mediated DNA inversion at the inverted repeats of the UU172-phase-variable element of Ureaplasma parvum serovar 3. AB - Phase variation of the UU172 phase-variable element of Ureaplasma parvum is governed by a DNA inversion event that takes place at short inverted repeats. The putative tyrosine recombinase XerC of Ureaplasma has been suggested as a mediator in the proposed site-specific recombination event. Here, we provide evidence that XerC mediates DNA inversion at the inverted repeats located on a synthetic locus that was introduced into the model organism Escherichia coli. Synthetic loci were created by exchanging the genes UU171 and UU172 with the two reporter genes gfp (green fluorescent protein) and mrfp1 (monomeric red fluorescent protein 1) either containing or missing the inverted repeats of the UU172 phase-variable element. E. coli was transformed with these loci and also co-transformed with the expression vector pBAD24 that contained the xerC gene behind the arabinose inducible pBAD promoter. Upon XerC expression, DNA inversion was observed only in the locus that contained the inverted repeat regions. We also demonstrate that XerC can process the recombination event with both an N-terminal maltose binding protein tag and a C-terminal 6*His tag in E. coli. A XerC mutant, where the proposed catalytic tyrosine residue 228 was exchanged with an alanine, did not process the recombination event. PMID- 25440998 TI - Antibacterial activity and genotypic-phenotypic characteristics of bacteriocin producing Bacillus subtilis KKU213: potential as a probiotic strain. AB - The antimicrobial activity and probiotic properties of Bacillus subtilis strain KKU213, isolated from local soil, were investigated. The cell-free supernatant (CFS) of a KKU213 culture containing crude bacteriocins exhibited inhibitory effects on Gram-positive bacteria, including Bacillus cereus, Listeria monocytogenes, Micrococcus luteus, and Staphylococcus aureus. The antibacterial activity of the CFS precipitated with 40% ammonium sulfate (AS) remained even after treatment at 60 and 100 degrees C, at pH 4 and 10 and with proteolytic enzymes, detergents and heavy metals. When analyzed by SDS-PAGE and overlaid with the indicator strains B. cereus and S. aureus, the 40% AS precipitate exhibited inhibitory activity on proteins smaller than 10 kDa. However, proteins larger than 25 kDa and smaller than 10 kDa were still observed on a native protein gel. Purified subtilosin A was prepared by Amberlite XAD-16 bead extraction and HPLC and analyzed by Nano-LC-QTOF-MS. Its molecular mass was found to be 3.4 kDa, and it retained its antibacterial activity. These results are consistent with the detection of the anti-listerial subtilosin A gene of the sbo/alb cluster in the KKU213 strain, which is 100% identical to that of B. subtilis subsp. subtilis 168. In addition to stable and cyclic subtilosin A, a mixture of many extracellular antibacterial peptides was also detected in the KKU213 culture. The KKU213 strain produced extracellular amylase, cellulase, lipase and protease, is highly acid-resistant (pH 2) when cultured in inulin and promotes health and reduces infection of intestinally colonized broiler chickens. Therefore, we propose that bacteriocin-producing B. subtilis KKU213 could be used as a potential probiotic strain or protective culture. PMID- 25440999 TI - Comparative effect of telmisartan vs lisinopril on blood pressure in patients of metabolic syndrome. AB - OBJECTIVE: The present study was planned to focus on comparative effects of telmisartan vs lisinopril on blood pressure in patients of metabolic syndrome METHODS: The study was carried out on 62 patients of metabolic syndrome from Dec 2010 to Oct 2012 in OPD of Institute. There were two groups, A and B. Group A- Telmisartan (31 patients) and Group B- Lisinopril (31 patients) receiving Telmisartan 40 mg and lisinopril 5 mg orally once a day respectively for 12 weeks. The diagnosis of essential hypertension was made by the physician based on two measurements of blood pressure on two different occasions using auscultatory method and was done at initial stage and repeated after 6 weeks and 12 weeks of treatment in Group A and Group B patients. KEY FINDINGS: Our study found that telmisartan or lisinopril treatment for 12 weeks leads to statistically significant (p<0.001) reduction in both SBP and DBP at 6 and 12 weeks when compared with baseline, whereas comparison between telmisartan and lisinopril treatment failed to show any statistically significant effect. CONCLUSION: Treatment of metabolic patients with telmisartan or lisinopril for the management of hypertension reduced both Systolic blood pressure (SBP) as well as Diastolic blood pressure (DBP) statistically significantly during 12 weeks treatment. However, telmisartan and lisinopril treatment were found effective. PMID- 25441000 TI - Mitral valve repair in asymptomatic patients with severe mitral regurgitation: pushing past the tipping point. AB - Degenerative mitral valve regurgitation (MR) is the one of the most frequent valvular heart conditions in the Western world and is increasingly recognized as an important preventable cause of chronic heart failure. This condition also represents the most common indication for mitral surgery and is of particular interest because the mitral valve can be repaired in most patients with very low surgical risk. Historical single-center studies have supported the performance of "early mitral valve repair" in asymptomatic patients with severe degenerative MR to normalize survival and improve late outcomes. Emerging recent evidence further indicates for the first time that the prompt surgical correction of severe MR due to flail mitral leaflets within 3 months following diagnosis in asymptomatic patients without classical Class I indications (symptoms or left ventricular dysfunction) conveys a 40% decrease in the risk of late death and a 60% diminution in heart failure incidence. A 10-point rationale based on the weight of rapidly accumulating clinical data, supports the performance of early mitral valve repair even in the absence of symptoms, left ventricular dysfunction, or guideline-based triggers; when effective operations can be provided using conventional or minimally invasive techniques at very low surgical risk. PMID- 25441001 TI - The current status of neoadjuvant therapy for esophageal cancer. AB - Through the contribution of a very large number of single-arm phase II trials and many less randomized phase III trials, the standard of care for locally advanced esophageal cancer has evolved to either combination chemotherapy plus radiation or combination chemotherapy. In this review, we focus on the key findings of these studies and selected meta-analyses that have led to this evolution. We note differences in outcomes for adenocarcinomas of the esophagus when compared to squamous cell esophageal cancers. Despite progress in developing a consensus for therapy, the outcome for patients with locally advanced remains poor. We complete the review by noting newer areas of investigation seeking to provide targeted and more personalized therapy to patients with esophageal cancer. PMID- 25441002 TI - Anomalous aortic origin of a coronary artery: toward a standardized approach. AB - Anomalous aortic origin of a coronary artery (AAOCA) is a congenital abnormality of the origin or course of a coronary artery that arises from the aorta. It is the second most common cause of sudden cardiac death in young athletes. Its exact prevalence, the pathophysiological mechanisms that cause sudden cardiac death, the actual risk of death for the different types of AAOCA, the optimal way to evaluate these patients, and whether any treatment strategies decrease the risk of sudden cardiac death in patients diagnosed with AAOCA are unknown. This article analyzes what is currently known and unknown about this disease. It also describes the creation of a dedicated multidisciplinary coronary anomalies program and the development of a framework in an initial attempt to standardize the evaluation and management of these patients. PMID- 25441003 TI - Current understandings and approach to the management of aortic intramural hematomas. AB - Intramural hematoma is the most enigmatic of the 3 lethal entities comprising acute aortic syndrome. Despite being identified almost 100 years ago, there is considerable controversy surrounding the definition, etiology, management, and the very existence of intramural hematoma. The following review outlines these controversies and discusses their effect on management strategies. PMID- 25441005 TI - Current readings: radiologic interpretation of the part-solid nodule: clinical relevance and novel technologies. AB - Persistent subsolid nodules, part-solid or pure ground-glass attenuation, are associated with primary lung adenocarcinoma, recently redefined by the International Association for the Study of Lung Cancer-American Thoracic Society European Respiratory Society in 2011 and include newly categorized entities of adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant adenocarcinoma. Awareness of the relationship of the subsolid nodule with adenocarcinoma has emerged in the era of high-resolution multidetector computed tomography (CT). This article highlights the role of noninvasive CT for subsolid nodules with an emphasis on the potential for quantitative measures to predict adenocarcinoma subtypes and their longitudinal behavior. Of particular importance is the knowledge that an increase in solid components on CT is an indication of progression. Continued experience in evaluating quantitative measures in combination with morphologic features, including margin contour, internal architecture, and nodule size, will further aid in guiding crucial decisions pertaining to the use of CT surveillance vs more invasive approaches including biopsy and surgical resection. PMID- 25441004 TI - Current readings: long-term management of patients undergoing successful pediatric cardiac surgery. AB - As of 2000, more adults than children are alive with congenital heart disease. Each year, more of these adults with congenital heart disease undergo surgery. Adults with congenital heart disease require lifelong surveillance, follow-up imaging, and clinical decision making by appropriately trained and familiar physicians and extenders. Three common challenges facing adults with congenital heart disease are the neglected patient, weak programmatic infrastructure, and the planning and management of pregnancy in the adult with congenital heart disease. Many challenges must be overcome in order to establish and maintain a comprehensive medical and surgical program for adults with congenital heart disease. Three common and challenging groups of adults with congenital heart disease who may require surgery are adults requiring tricuspid valve surgery for Ebstein's malformation, those requiring reoperation for failing Fontan circulation, and those requiring pulmonary valve replacement (PVR). Surgery for Ebstein's anomaly is now offered to older patients at low risk and with good late outcome. The operation includes tricuspid valve repair or replacement and frequent concomitant procedures such as atrial septal defect closure, arrhythmia surgery (the Maze procedure), and coronary artery bypass grafting. Patients undergoing previous iterations of the Fontan operation are especially prone to arrhythmia and failing circulation. Fontan conversion with arrhythmia surgery and pacemaker therapy was developed by Constantine Mavroudis, Barbara Deal, and Carl Backer to treat these challenging patients, with the first such operation performed in 1994. Fontan conversion involves: (1) conversion of the previously created atriopulmonary connection to a total cavopulmonary connection (TCPC), extracardiac Fontan; (2) arrhythmia surgery, typically with a modified biatrial Maze procedure along with placement of an antitachycardia, dual-chamber pacemaker with steroid-eluting epicardial leads in all patients; and (3) concomitant procedures to treat associated lesions. The need for pulmonary valve replacement is increasing for many adults with congenital heart disease. In the past, chronic pulmonary regurgitation following repair of tetralogy of Fallot was considered benign. Current evidence demonstrates that chronic pulmonary regurgitation causes significant morbidity by producing right ventricular dilatation and dysfunction, exercise intolerance, arrhythmias, and sudden death. Multiple options exist for pulmonary valve replacement including several recent developments such as pulmonary valve replacement with a hand-sewn polytetrafluoroethylene bicuspid valve and percutaneous pulmonary valve replacement. Reoperative cardiac surgery is common in adults with congenital heart disease. Although a history of previous cardiac surgery does not independently confer a significant incremental risk of operative mortality, patients with the greatest number of previous surgeries appear to be a higher risk group. Multi-institutional data about adults with congenital heart disease from The Society of Thoracic Surgeons Congenital Heart Surgery Database can be used to estimate prognosis and council patients and their families. The six manuscripts reviewed in this article have been selected to give a flavor of the state of the art in the domain of caring for adults with congenital heart disease and to provide important information about the long term management of patients undergoing successful pediatric cardiac surgery. PMID- 25441007 TI - The postintensive care syndrome of survivors of critical illness and their families. PMID- 25441006 TI - Solitary pulmonary nodules. PMID- 25441008 TI - Safety of supervised exercise therapy in patients with intermittent claudication. AB - BACKGROUND: Supervised exercise therapy (SET) is recommended as the primary treatment for patients with intermittent claudication (IC). However, there is concern regarding the safety of performing SET because IC patients are at risk for untoward cardiovascular events. The Dutch physical therapy guideline advocates cardiac exercise testing before SET, if indicated. Perceived uncertainties concerning safety may contribute to the underuse of SET in daily practice. The objective of this review was to analyze the safety of supervised exercise training in patients with IC. METHODS: Two authors independently studied clinical trials investigating SET. Data were obtained from MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials. Complication rates were calculated and expressed as number of events per number of patient-hours. The usefulness of cardiac screening before SET was evaluated in a subanalysis. RESULTS: Our search strategy revealed 2703 abstracts. We selected 121 articles, of which 74 met the inclusion criteria. Studies represent 82,725 hours of training in 2876 IC patients. Eight adverse events were reported, six of cardiac and two of noncardiac origin, resulting in an all-cause complication rate of one event per 10,340 patient-hours. CONCLUSIONS: SET can safely be prescribed in patients with IC because an exceedingly low all-cause complication rate was found. Routine cardiac screening before commencing SET is not required. Our results may diminish perceived uncertainties regarding safety and will possibly increase the use of SET in daily practice. PMID- 25441009 TI - Outcomes and risk factors of cardiac arrest after vascular surgery procedures. AB - BACKGROUND: Despite increased awareness of the value of discussing patients' goals of care, advance directives, and code status as part of the surgical informed consent process, the actual outcomes and risks of cardiopulmonary resuscitation (CPR) remain poorly defined among some subsets of surgical patients. Thus, in an effort to generate an evidence base for communication about shared decision making and informed consent for vascular surgery patients and their surrogates, we defined the incidence, risks, and outcomes of postoperative cardiac arrest after primary vascular surgery procedures. METHODS: The 2007 to 2010 National Surgical Quality Improvement Program data were queried to develop a multi-institutional database of patients undergoing vascular surgery (N = 123,581). Univariate analyses and multivariate logistic regression were used to identify crude and adjusted risk factors for postoperative cardiac arrest requiring CPR and to assess outcomes. RESULTS: Postoperative cardiac arrest requiring CPR was seen in 1234 of 123,581 patients (1.0%) after vascular surgery at a mean of 7.2 +/- 2 days. The 30-day mortality was 73.4% compared with 2.7% among patients who did not arrest (P < .001). Of CPR survivors, 102 (12.1%) were still hospitalized at 30 days. Patient variables that were most predictive of postoperative cardiac arrest included dependent functional status (odds ratio [OR], 2.9; 95% confidence interval [CI], 2.3-3.6; P < .001), dialysis dependence (OR, 2.7; 95% CI, 2.3-3.2; P < .001), emergent case (OR, 2.2; 95% CI, 1.9-2.5; P < .001), and preoperative ventilator dependence (OR, 2.0; 95% CI, 1.5-2.7; P < .001). Procedures associated with the highest risk included thoracic aortic surgery (OR, 6.9; 95% CI, 4.8-9.9; P < .001), open abdominal procedures (OR, 3.7; 95% CI, 3.1-4.4; P < .001), axillary-femoral bypass (OR, 2.1; 95% CI, 1.3-3.2; P = .001), and peripheral embolectomy (OR, 1.5; 95% CI, 1.2-1.9; P = .002). At least one major complication preceded cardiac arrest in 47.7% of patients including sepsis (23.5%), renal failure (14.5%), and myocardial infarction (12.1%). Patients with do not resuscitate orders were significantly less likely to undergo CPR (OR, 0.59; 95% CI, 0.39-0.93; P = .021). CONCLUSIONS: Patients undergoing vascular surgery who suffer a postoperative cardiac arrest frequently die in spite of receiving CPR; for those who survive, there is likely to be prolonged hospitalization and significant morbidity. These data provide an evidence base for discussing goals of care, advance directives, and code status with vascular surgery patients and their surrogates. Further research into how to best communicate risk, to elicit patient preferences, and to engage in shared decision making is needed. PMID- 25441010 TI - Follow-up compliance after endovascular abdominal aortic aneurysm repair in Medicare beneficiaries. AB - OBJECTIVE: Lifelong imaging follow-up is essential to the safe and appropriate management of patients who undergo endovascular abdominal aortic aneurysm repair (EVAR). We sought to evaluate the rate of compliance with imaging follow-up after EVAR and to identify factors associated with being lost to imaging follow-up. METHODS: We identified a 20% sample of continuously enrolled Medicare beneficiaries who underwent EVAR between 2001 and 2008. Using data through 2010 from Medicare Inpatient, Outpatient, and Carrier files, we identified all abdominal imaging studies that may have been performed for EVAR follow-up. Patients were considered lost to annual imaging follow-up if they did not undergo any abdominal imaging study within their last 2 years of follow-up. Multivariable models were constructed to identify independent factors associated with being lost to annual imaging follow-up. RESULTS: Among 19,962 patients who underwent EVAR, the incidence of loss to annual imaging follow-up at 5 years after EVAR was 50%. Primary factors associated with being lost to annual imaging follow-up were advanced age (age 65-69 years, reference; age 75-79 years: hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.15-1.32; age 80-85 years: HR, 1.45; 95% CI, 1.35-1.55; age >85 years: HR, 2.03; 95% CI, 1.88-2.20) and presentation with an urgent/emergent intact aneurysm (HR, 1.27; 95% CI, 1.20-1.35) or ruptured aneurysm (HR, 1.84; 95% CI, 1.63-2.08). Additional independent factors included several previously diagnosed chronic diseases and South and West regions of the United States. CONCLUSIONS: Annual imaging follow-up compliance after EVAR in the United States is significantly below recommended levels. Quality improvement efforts to encourage improved compliance with imaging follow-up, especially in older patients with multiple comorbidities and in those who underwent EVAR urgently or for rupture, are necessary. PMID- 25441011 TI - Current state in tracking and robotic navigation systems for application in endovascular aortic aneurysm repair. AB - OBJECTIVE: This study reviewed the current developments in manual tracking and robotic navigation technologies for application in endovascular aortic aneurysm repair (EVAR). METHODS: EMBASE and MEDLINE databases were searched for studies reporting manual tracking or robotic navigation systems that are able to manipulate endovascular surgical tools during abdominal or thoracic aortic aneurysm repair. Reports were grouped by the navigation systems and categorized into phantom, animal, and clinical studies. First, the general characteristics of each system were compared. Second, target registration error and deployment error were used to compare the accuracy of the tracking systems. Third, all systems were reviewed for fluoroscopy time (FT), radiation dose, and contrast volumes, if reported, in rigid and nonrigid studies. Fourth, vascular cannulation performance of the systems was compared, studying cannulation time, Imperial College Complex Cannulation Scoring Tool score, and the number of wall hits and catheter movements within rigid studies. RESULTS: Of 721 articles and references found, 18 studies of four different navigation systems were included: the Aurora (Northern Digital, Waterloo, Ontario, Canada) tracking system, the StealthStation (Medtronic Inc, Minneapolis, Minn) tracking system, an ultrasound localization tracking system, and the Sensei (Hansen Medical, Mountain View, Calif) steerable remote-controlled robotic navigation system. The mean tracking accuracy averaged 1 mm for the three manual tracking systems measured in a rigid environment. An increase of target registration error reaching >3 mm was reported when measured in a nonrigid experimental environment or due to external distortion factors. Except within small-animal studies or case studies, no evidence was found on reduction of clinical outcome parameters, such as FT, radiation dose, and contrast volumes, within clinical EVAR. A comparison of vascular cannulation performance in rigid studies revealed that the Sensei robotic system might have an advantage during advanced cannulation compared with standard cannulation within complex cannulations tasks. CONCLUSIONS: This review summarizes the current studies on manual tracking and robotic navigation systems for application in EVAR. The main focus of these systems is improving aortic vessel cannulation, required in complex EVAR, in which the robotic system with the improved steerability is favored over manual tracking systems or conventional cannulation. All reviewed tracking systems still require X-ray for anatomic imaging, stent graft deployment, and device registration. Although the current reviewed endovascular navigation systems have shown their potential in phantom and animal studies, clinical trials are too limited to conclude that these systems can improve EVAR outcomes or that they can systematically reduce FTs, radiation doses, and contrast volumes during (complex) EVAR. PMID- 25441012 TI - Care of patients undergoing vascular surgery at safety net public hospitals is associated with higher cost but similar mortality to nonsafety net hospitals. AB - OBJECTIVE: This study compared in-hospital mortality and resource utilization among vascular surgical patients at safety net public hospitals (SNPHs) with those at nonsafety net public hospitals (nSNPHs). METHODS: The National Inpatient Sample (2003-2011) was queried to identify surgical patients with peripheral arterial disease (PAD), carotid stenosis, or nonruptured abdominal aorta aneurysm based on International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic and procedure codes. The cohort was then divided into SNPH and nSNPH groups according to the definition of SNPH used by the National Association of Public Hospitals. Clinical characteristics, length of stay, in hospital mortality, and hospital charges were compared between groups. Advanced PAD was defined as that associated with rest pain or tissue loss. Statistical methods included bivariate chi(2) tests for categoric variables, t-tests for continuous variables, and multivariable linear and logistic regression to adjust for confounding variables (in-hospital mortality). RESULTS: We identified 306,438 patients operated on for PAD, carotid stenosis, and abdominal aortic aneurysm. Patients at SNPHs were younger, the percentage of female and minority patients was higher, and patients had a higher Elixhauser comorbidity index (P < .001). Nonelective admissions were more common among SNPH patients who presented with more advanced PAD (P > .05) and symptomatic carotid stenosis (P < .05). Patients at SNPHs had a significantly longer length of stay, higher hospital charges, and higher in-hospital mortality (P < .05 for all variables). Crude odds of mortality at SNPHs were 1.28 higher than at nSNPHs (95% confidence interval, 1.13-1.46; P < .001), but adjusted analyses revealed no statistically significant difference between the odds of in-hospital mortality at both hospital groups. CONCLUSIONS: Patients undergoing vascular surgery at SNPHs, despite being younger, had higher comorbidities, presented more urgently with more advanced disease, and incurred higher costs than the SNPH cohort despite similar adjusted odds of in-hospital mortality. Delayed presentation and higher comorbidities are most likely related to poor access to routine and preventive health care for the SNPH patients. PMID- 25441013 TI - Discovery of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3 carboxamide (VX-770, ivacaftor), a potent and orally bioavailable CFTR potentiator. AB - Quinolinone-3-carboxamide 1, a novel CFTR potentiator, was discovered using high throughput screening in NIH-3T3 cells expressing the F508del-CFTR mutation. Extensive medicinal chemistry and iterative structure-activity relationship (SAR) studies to evaluate potency, selectivity, and pharmacokinetic properties resulted in the identification of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4 dihydroquinoline-3-carboxamide (VX-770, 48, ivacaftor), an investigational drug candidate approved by the FDA for the treatment of CF patients 6 years of age and older carrying the G551D mutation. PMID- 25441014 TI - Editorial. PMID- 25441016 TI - The film festival "AUSNAHME|ZUSTAND" (State of Emergency)--do feature films and documentaries on mental health reduce stigma and influence help-seeking attitudes? AB - The study aims at evaluating the impact of the Germany-wide film festival "AUSNAHME|ZUSTAND" on social distance and help-seeking attitudes of the adolescent audience. The festival, on the subject of mental health, was staged for the second time, aiming to give a podium to the topic mental health and to inform and entertain an adolescent audience that has not been in close contact with the subject before. A pre-post test was carried out to look for the effect of feature films and documentaries on social distance of the audience towards people with mental illness and on the change in help-seeking attitudes. A total of 532 young people with a mean age of 15.6 were questioned during the film festival in Leipzig. As the results show, the effect on the viewers' social distance and their help-seeking attitudes strongly depend on the content of the feature films and documentaries. Two films improved attitudes - one both social distance and help-seeking, one only help-seeking. One film increased social distance, and two films did not affect either outcome. Age, gender, and knowing someone with mental health problems also turned out to be decisive factors influencing the development of social distance and help-seeking attitudes. Feature films or documentaries about mental illness can reduce social distance or influence help-seeking attitudes, but effects strongly depend on the particular film. PMID- 25441017 TI - Excess length of stay and mortality due to Clostridium difficile infection: a multi-state modelling approach. AB - BACKGROUND: The burden of healthcare-associated infections, such as healthcare acquired Clostridium difficile (HA-CDI), can be expressed in terms of additional length of stay (LOS) and mortality. However, previous estimates have varied widely. Although some have considered time of infection onset (time-dependent bias), none considered the impact of severity of HA-CDI; this was the primary aim of this study. METHODS: The daily risk of in-hospital death or discharge was modelled using a Cox proportional hazards model, fitted to data on patients discharged in 2012 from a large English teaching hospital. We treated HA-CDI status as a time-dependent variable and adjusted for confounders. In addition, a multi-state model was developed to provide a clinically intuitive metric of delayed discharge associated with non-severe and severe HA-CDI respectively. FINDINGS: Data comprised 157 (including 48 severe) HA-CDI cases among 42,618 patients. HA-CDI reduced the daily discharge rate by nearly one-quarter [hazard ratio (HR): 0.72; 95% confidence interval (CI): 0.61-0.84] and increased the in hospital death rate by 75% compared with non-HA-CDI patients (HR: 1.75; 95% CI: 1.16-2.62). Whereas overall HA-CDI resulted in a mean excess LOS of about seven days (95% CI: 3.5-10.9), severe cases had an average excess LOS which was twice (~11.6 days; 95% CI: 3.6-19.6) that of the non-severe cases (about five days; 95% CI: 1.1-9.5). CONCLUSION: HA-CDI contributes to patients' expected LOS and risk of mortality. However, when quantifying the health and economic burden of hospital-onset of HA-CDI, the heterogeneity in the impact of HA-CDI should be accounted for. PMID- 25441015 TI - Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies. AB - Posttraumatic stress disorder (PTSD) may involve over-consolidated emotional memories of the traumatic event. Reactivation (RP) can return a memory to an unstable state, from which it must be restabilized (reconsolidated) if it is to persist. Pharmacological agents administered while the memory is unstable have been shown to impair reconsolidation. The N-methyl-d-aspartate (NMDA) partial agonist d-cycloserine (DCS) may promote memory destabilization. In the three studies reported here, we investigated whether the beta-adrenergic blocker propranolol or the glucocorticoid (GR) antagonist mifepristone, given at the time of traumatic memory reactivation, could reduce PTSD symptoms and physiological responding during subsequent traumatic imagery. Individuals with PTSD were randomized as follows: Study One: propranolol with memory reactivation (n=10) or without reactivation (n=8); Study Two: reactivation mifepristone (n=13), non reactivation (NRP) mifepristone (n=15), or double placebo (PL) (n=15); Study Three: reactivation mifepristone plus d-cycloserine (n=16), or two placebos (n=15). Subjects underwent memory retrieval by describing their traumatic event. A week later they engaged in script-driven traumatic mental imagery, while heart rate (HR), skin conductance (SC), and facial electromyogram (EMG) responses were measured. There were no significant group differences in physiological responsivity or change in PTSD symptoms in any of the studies. These results do not support successful blockade of reconsolidation of traumatic memories in PTSD. PMID- 25441018 TI - [Flagellate dermatitis caused by shiitake]. PMID- 25441019 TI - [Usefulness of a diagnostic algorithm hyperferritinemia: A case report of a Spanish family with hereditary hemochromatosis and mutation in SLC40A1 gene]. PMID- 25441020 TI - [Growth hormone deficiency secondary to pituitary iron deposition in a pyruvate kinase deficient patient]. PMID- 25441021 TI - [Groove sign and thickened fascia in eosinophilic fasciitis]. PMID- 25441022 TI - [Usefulness of measuring cardiovascular risk at 30 years and vascular age]. PMID- 25441023 TI - [Vogt-Koyanagi-Harada syndrome]. PMID- 25441024 TI - [Don't forget to walk at least 30 minutes per day 5 days a week. Why and how to prescribe physical exercise in chronic obstructive pulmonary disease]. PMID- 25441025 TI - [Mesocardiac scars as the substrate of ventricular tachycardia in patients with normal ventricular size and function]. PMID- 25441026 TI - [Primary cardiovascular prevention with statins in type 2 diabetes mellitus]. PMID- 25441027 TI - [Vaccination of patients with hereditary hemorrhagic telangiectasia]. PMID- 25441028 TI - Mapping the deubiquitination module within the SAGA complex. AB - The molecular organization of the yeast transcriptional coactivator Spt-Ada-Gcn5 acetyltransferase (SAGA) was analyzed by single-particle electron microscopy. Complete or partial deletion of the Sgf73 subunit disconnects the deubiquitination (DUB) module from SAGA and favors in our conditions the cleavage of the C-terminal ends of the Spt7 subunit and the loss of the Spt8 subunit. The structural comparison of the wild-type SAGA with two deletion mutants positioned the DUB module and enabled the fitting of the available atomic models. The localization of the DUB module close to Gcn5 defines a chromatin-binding interface within SAGA, which could be demonstrated by the binding of nucleosome core particles. The TATA-box binding protein (TBP)-interacting subunit Spt8 was found to be located close to the DUB but in a different domain than Spt3, also known to contact TBP. A flexible protein arm brings both subunits close enough to interact simultaneously with TBP. PMID- 25441029 TI - Structural basis of a Kv7.1 potassium channel gating module: studies of the intracellular c-terminal domain in complex with calmodulin. AB - Kv7 channels tune neuronal and cardiomyocyte excitability. In addition to the channel membrane domain, they also have a unique intracellular C-terminal (CT) domain, bound constitutively to calmodulin (CaM). This CT domain regulates gating and tetramerization. We investigated the structure of the membrane proximal CT module in complex with CaM by X-ray crystallography. The results show how the CaM intimately hugs a two-helical bundle, explaining many channelopathic mutations. Structure-based mutagenesis of this module in the context of concatemeric tetramer channels and functional analysis along with in vitro data lead us to propose that one CaM binds to one individual protomer, without crosslinking subunits and that this configuration is required for proper channel expression and function. Molecular modeling of the CT/CaM complex in conjunction with small angle X-ray scattering suggests that the membrane proximal region, having a rigid lever arm, is a critical gating regulator. PMID- 25441031 TI - Correlation analysis of hypothalamic mRNA levels of appetite regulatory neuropeptides and several metabolic parameters in 28-day-old layer chickens. AB - Various lines of evidence suggest that appetite-related neuropeptides in the hypothalamus are regulated by adiposity signals such as leptin and insulin in mammals. In the present study, we examined age-dependent changes in the weight of abdominal fat and hypothalamic mRNA levels of neuropeptide Y (NPY, an orexigenic neuropeptide) and proopiomelanocortin (POMC, a precursor of anorexigenic neuropeptides) in growing chickens at 7, 14, 21 and 28 days of age. Hypothalamic NPY mRNA levels were significantly (P < 0.05) decreased after 14 days of age, whereas hypothalamic POMC mRNA levels were significantly (P < 0.05) increased at 28 days of age. The percentage of abdominal fat was significantly increased after 14 days of age in chickens. We next examined the correlation of hypothalamic NPY and POMC mRNA levels and several parameters at 28 days of age. There were no significant correlations between hypothalamic mRNA levels of NPY or POMC and the percentage of abdominal fat. These findings suggest that the gene expressions of NPY and POMC do not depend on adiposity in chickens, at least in 28-day-old layer chickens. PMID- 25441030 TI - B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1(+) neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1beta levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1beta and IL-17A dependent. BAFF was required for rIL-17A induced lung fibrosis and augmented IL-17A production by CD3(+) T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1beta, BAFF and IL-17A. PMID- 25441032 TI - Shock. AB - Critically ill patients with undifferentiated shock are complex and challenging cases in the ED. A systematic approach to assessment and management is essential to prevent unnecessary morbidity and mortality. The simplified, systematic approach described in this article focuses on determining the presence of problems with cardiac function (the pump), intravascular volume (the tank), or systemic vascular resistance (the pipes). With this approach, the emergency physician can detect life-threatening conditions and implement time-sensitive therapy. PMID- 25441033 TI - Early identification and management of patients with severe sepsis and septic shock in the emergency department. AB - Severe sepsis and septic shock have great relevance to Emergency Medicine physicians because of their high prevalence, morbidity, and mortality. Treatment is time-sensitive, depends on early identification risk stratification, and has the potential to significantly improve patient outcomes. In this article, we review the pathophysiology of, and evidence basis for, the emergency department management of severe sepsis and septic shock. PMID- 25441034 TI - Assessment and treatment of the trauma patient in shock. AB - High-volume crystalloid resuscitation is associated with increased length of stay, ICU and ventilator days, and organ failure and infection rates. Rapid evaluation of a hemodynamically unstable trauma patient is vital to diagnosis and treatment of the cause of shock. CT scanning should be used liberally in trauma patients to effect decreased mortality. Nonoperative management and catheter based interventions are becoming the standard of care in appropriately selected patients with solid organ injuries. PMID- 25441035 TI - Hemorrhage and coagulopathy in the critically ill. AB - Bleeding is the second leading cause of death after trauma. Initial care of the patient with hemorrhage focuses on restoring circulating blood volume and reversing coagulopathy. Trauma and injury can initiate the coagulation cascade. Patients with massive bleeding should be resuscitated with goal-directed therapy. Hemostatic resuscitation in conjunction with ratio-based transfusion and massive transfusion protocols should be utilized while awaiting hemorrhage control. The military initiated massive transfusion protocols in the battlefield. We discuss the coagulation cascade, recent recommendations of goal-directed therapy, massive transfusion protocols, fixed ratios, and the future of transfusion medicine. PMID- 25441036 TI - Assessing volume status. AB - Shock is a physiologic state associated with high morbidity and mortality rates. The clinician has several tools available to evaluate volume status. Each modality has its benefits and limitations but, to date, no one test can indicate with 100% accuracy which patients will be truly volume responsive. Although the search for the Holy Grail of a perfect intravascular monitor continues, we must remember the importance of early, aggressive, and goal-directed interventions for patients in shock. Finally, there is no substitute for the most important intervention-the frequent presence of the physician at the patient's bedside. PMID- 25441037 TI - Pressors and inotropes. AB - To effectively treat an aging and increasingly complex patient population, emergency physicians and other acute-care providers must be comfortable with the use of vasopressors, inotropes, and chronotropes. These medicines are used to augment the cardiovascular function of critically ill patients. Each class of medication produces a different hemodynamic effect. Some agents produce only one of these actions, whereas others have multiple effects. For the emergency physician, these agents are used with the explicit goal of preserving vital organ perfusion during acute and severe illness. This article reviews the physiologic receptors targeted by such drugs, common agents used, and specific clinical indications for their use. PMID- 25441038 TI - Emergency department antimicrobial considerations in severe sepsis. AB - Severe sepsis and septic shock are common problems in the emergency department patient population and require expert clinical skill by members of the emergency department team to maximize optimal patient outcomes. Although various guidelines have been developed for the management of these patients, issues around antimicrobial-related considerations in critically ill patients require further evidence-based attention. In this review article, important factors related to patient illness, microorganism, timing of antimicrobial administration, and source control are discussed. PMID- 25441039 TI - Mechanical circulatory support. AB - The role for temporary and durable mechanical circulatory support is rapidly expanding. As the use of these technologies continues to grow, the emergency physician has an increasing opportunity to participate in the advancement of these potentially life-saving technologies. This review discusses the current role of the intra-aortic balloon pump in cardiogenic shock, describes the complications and management strategies for the critically ill patient with a left ventricular assist device, and explores the emerging role of ECMO in the emergency department for patients presenting in refractory cardiogenic shock and cardiac arrest. PMID- 25441040 TI - Lung-protective ventilation strategies and adjunctive treatments for the emergency medicine patient with acute respiratory failure. AB - Respiratory failure is a frequent disease process encountered in the emergency department. There is significant need for improvement in the care of patients on mechanical ventilation. If not contraindicated, lung-protective ventilation strategies should be used. It is important to consider pathophysiology (shunting, dead space ventilation, and low venous admixture) when formulating treatment strategies in patients who are difficult to oxygenate or ventilate or when Pao2, Paco2, and pH can only be maintained at unsafe ventilator settings. PMID- 25441041 TI - Neurotrauma. AB - Neurotrauma continues to be a significant cause of morbidity and mortality. Prevention of primary neurologic injury is a critical public health concern. Early and thorough assessment of the patient with neurotrauma with high index of suspicion of traumatic spinal cord injuries and traumatic vascular injuries requires a multidisciplinary approach involving prehospital providers, emergency physicians, neurosurgeons, and neurointensivists. Critical care management of the patient with neurotrauma is focused on the prevention of secondary injuries. Much research is still needed for potential neuroprotection therapies. PMID- 25441042 TI - Critical care ultrasonography. AB - Resuscitative ultrasonography provides rapid, repeatable, and multisystem assessment to guide diagnosis and management of critically ill patients in the emergency department (ED). Cardiac ultrasonography offers new anatomic and hemodynamic information, previously unavailable in an ED setting, whereas other applications match or exceed the speed and utility of existing tests such as chest radiograph (thoracic ultrasonography) or central venous pressure determination (inferior vena cava ultrasonography). Evolving areas of resuscitative ultrasonography include neurologic applications and transesophageal echocardiography, which promise to further enhance the role of ultrasonography in managing critical illness in the ED. PMID- 25441043 TI - Select topics in neurocritical care. AB - Neurocritical care aims to improve outcomes in patients with life-threatening neurologic illness. The scope of neurocritical care extends beyond the more commonly encountered and important field of cerebrovascular disease, as described previously. This article focuses on neuromuscular, neuroinfectious, and neuroimmunologic conditions that are significant causes of morbidity and mortality in the acutely neurologically ill patient. As understanding continues to increase regarding the physiology of these conditions and the best treatment, rapid identification, triage, and treatment of these patients in the emergency department is paramount. PMID- 25441044 TI - Pediatric critical care. AB - Care of the ill and injured child requires knowledge of unique pediatric anatomic and physiologic differences. Subtleties in presentation and pathophysiologic differences impact management. This article discusses pediatric resuscitation, the presentation and management of common childhood illness, pediatric trauma, and common procedures required in the critically ill child. PMID- 25441046 TI - Critical care emergencies. PMID- 25441045 TI - End of life/palliative care/ethics. AB - Palliative and end-of-life care, once the purview of oncologists and intensivists, has also become the responsibility of the emergency physician. As our population ages and medical technology enables increased longevity, it is essential that all medical professionals know how to help patients negotiate the balance between quantity and quality of life. Emergency physicians have the opportunity to educate patients and their loved ones on how to best accomplish their goals of care while also enhancing quality of life through treatment of symptoms. The emergency physician must be aware of the ethical and medico-legal parameters that govern decision making. PMID- 25441047 TI - Critical care. PMID- 25441048 TI - From the bench to modeling--R0 at the interface between empirical and theoretical approaches in epidemiology of environmentally transmitted infectious diseases. AB - For environmentally transmitted infectious diseases (ETIDs), which spread through the contaminated environment (such as foods, surfaces and fomites), there is a lack of consensus about the mathematical approach to derive R0, leading to inconsistent predictions about the spread and control of these infections in their host populations. The objective of this study was to explain three current, though conflicting, approaches to derive a theoretical expression for R0 for ETIDs and assess their validity through comparison with available empirical data. Salmonella Typhimurium in laboratory mice was used as a theoretical and empirical model system. The three conflicting theoretical expressions for R0 were derived using the next generation matrix approach according to three unverified hypotheses about the role of the environmental phase in the transmission of ETIDs. The hypotheses assume that the environment contaminated with a pathogen is: (H1) an extension of the host's infectious period, (H2) a reservoir for the infectious agent, or (H3) has both of these characteristics. For the parameter values describing the empirical model system, the theoretical values of R0 corresponding to the hypotheses H2 and H3 were very similar (1.38 and 1.62, respectively) and their values were approximately half of the value of R0 for hypothesis H1 (2.94). The theoretical R0 values were compared with an empirical R0 (1.58, 95% confidence interval: 1.14, 2.02) estimated using a Martingale method from published experimental data on Salmonella Typhimurium transmission in mice. The results of the comparison suggested that hypothesis H1 is unlikely to hold true but it could not be rejected with confidence because of uncertainty in the value of the pathogen growth rate in the environment. The hypotheses H2 and H3 were both equally strongly supported with the empirical data suggesting that either of them could be valid. A sensitivity analysis identified critical information gaps about the indirect transmission rate of infection and the pathogen growth rate in the environment. Moreover, we identified experimental conditions for which the theoretical R0 predictions based on the hypotheses H2 and H3 differ greatly, which would assist their discrimination and conclusive validation against future empirical studies. Once a valid theoretical R0 is identified for Salmonella Typhimurium in mice, its generalizability to other host pathogen-environment systems should be tested. The present study may serve as a template for integrated empirical and theoretical research of R0 in the epidemiology of ETIDs. PMID- 25441049 TI - Future risk of bovine tuberculosis recurrence among higher risk herds in Ireland. AB - Within the Irish national bovine tuberculosis (bTB) eradication programme, controls are tighter on higher risk herds, known as H-herds. These H-herds are defined as herds that have previously had a bTB restriction (also known as a bTB episode), with at least 2 animals positive to the single intradermal comparative tuberculin test (SICTT) or with a bTB lesion detected at slaughter. Such herds are considered at higher risk of recurrence following the end of the bTB episode. In this study, we examined if, and when, the future bTB risk of H-herds returned to a similar level comparable to herds with no history of bTB. In addition, the proportion of bTB episodes in 2012 that could be attributed to the recent introduction of an infected animal was also estimated, providing an update of earlier work. The study population consisted of all Irish herds that were not bTB restricted at the start of 2012 and with at least one whole-herd SICTT in 2012, with the herd being the unit of interest. The outcome measure was a bTB restriction, defined as any herd where at least 1 standard SICTT reactor or an animal with a bTB lesion at slaughter in 2012 was identified. A logistic regression model was used to model the probability of a herd being restricted in 2012. Herds that were previously restricted had significantly higher odds of being restricted in 2012 compared to herds that had not. Similarly, the odds of being restricted in 2012 decreased as the time since the previous restriction increased, but increased as the severity of the previous restriction increased. Odds of being restricted also increased with an increase (although not linear) in herd size, the number of animals greater than 1 year of age purchased in 2011, the county incidence rate and the proportion of cows in the herd. The recent introduction of an infected animal accounted for 7.4% (6.7-8.2) of herd restrictions. This study confirms the key role of past bTB history in determining the future risk of Irish herds, with the odds related to both the severity of and time since the previous restriction. It also illustrates the difficulty in clearly defining H-herds, noting that risk persists for extended periods following a bTB restriction, regardless of breakdown severity. There is a need for robust controls on H-herds for an extended period post de-restriction. PMID- 25441050 TI - Objectively measured physical activity in Danish after-school cares: Does sport certification matter? AB - Inactivity and more sedentary time predominate the daily activity level of many of today's children. In Denmark, certified sport after-school cares have been established in order to increase children's daily physical activity (PA) level. This cross-sectional study aimed to investigate the activity level among participants in certified sport after-school cares vs regular after-school cares. The study was carried out in 2011 in 10 after-school cares (5 sport/5 regular) throughout Denmark, whereof 475 children aged 5-11 years participated. PA level was assessed using Actigraph GT3X and GT3X+ activity monitors worn by the children for at least 8 consecutive days. Anthropometry and cardiorespiratory fitness were measured as well. A multivariate regression analysis was carried out to check for the differences in the PA level across the two care systems. However, there did not appear to be any differences in overall PA or in time specific day parts (e.g., during after-school care). The activity levels were quite similar across after-school cares and were mutually high during time spent in the care facility. PMID- 25441051 TI - Early menarche increases the risk of Type 2 diabetes in young and middle-aged Korean women. AB - AIMS: To investigate the association between early menarche (menarche age < 12 years) and Type 2 diabetes mellitus in young and middle-aged Korean women. METHODS: We analysed data for 4657 women aged 20-50 years from the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV) (2007-2009). RESULTS: The prevalence of Type 2 diabetes was 2.8%. Women with early menarche had a higher prevalence of impaired fasting glucose than did women with later menarche (age >= 12 years) in the 20-30 age group (7.4% vs. 3.0%), and a higher prevalence of diabetes in the 30-40 (6.3% vs. 1.7%) and 40-50 (18.5% vs. 4.4%) age groups. The odds ratio (OR) of Type 2 diabetes in women with early menarche was 3.61 [95% confidence interval (CI), 1.90-6.88] after adjusting for age. In multivariate regression, the OR of Type 2 diabetes decreased to 2.52 (95% CI, 1.29-4.94) after further adjusting for BMI. However, the OR decreased to 2.04 (95% CI, 0.95-4.39) without significance after adjusting for HOMA-IR. CONCLUSIONS: Early menarche increased the risk of Type 2 diabetes in young and middle-aged Korean women although adulthood adiposity attenuated the relationship. Knowledge of age at menarche is important in identifying women at risk for diabetes. PMID- 25441052 TI - Primary radical therapy selection in high-risk non-metastatic prostate cancer. AB - As the incidence of prostate cancer rises, the detection and management of men with high-risk non-metastatic prostate cancer is becoming increasingly important. The benefits of radical treatment have been clearly shown in this group from a number of publications. The current mainstays of treatment are radical prostatectomy (with selective use of adjuvant radiation) and radical radiotherapy with concurrent androgen deprivation. The outcomes from these two approaches seem to be remarkably similar and are considered equally valid options for primary treatment. The choice of therapy is critically dependent on a number of factors, but ultimately left to the decision of the patients with advice from clinicians. Clinicians themselves, however, are known to be biased towards their particular skill set and experiences. Attempts at randomised comparisons between these two modalities have so far failed and are confounded by patient-clinician bias, the continual advances in therapy as well as the long natural history of the disease. In the lack of level 1 comparable evidence, this article explores the existing literature as to the key factors that should be considered in radical treatment selection for high-risk prostate cancer. These factors include disease aggressiveness, comorbidity and life expectancy, functional outcomes and the consequences of therapy failure with regards to salvage treatment. We propose that these factors may be useful in developing a decision guide for rationale radical therapy selection in the light of two apparently equally effective treatments. Ultimately, however, there is an urgent need for added clinical and biological markers that can provide a more precise approach to therapy selection. PMID- 25441053 TI - Predicting Cognitive, Functional, and Diagnostic Change over 4 Years Using Baseline Subjective Cognitive Complaints in the Sydney Memory and Ageing Study. AB - OBJECTIVE: There is limited understanding of the usefulness of subjective cognitive complaint(s) (SCC) in predicting longitudinal outcome because most studies focus solely on memory (as opposed to nonmemory cognitive) complaints, do not collect data from both participants and informants, do not control for relevant covariates, and have limited outcome measures. Therefore the authors investigate the usefulness of participant and informant SCCs in predicting change in cognition, functional abilities, and diagnostic classification of mild cognitive impairment or dementia in a community-dwelling sample over 4 years. METHODS: Nondemented participants (N = 620) in the Sydney Memory and Ageing Study aged between 70 and 90 years completed 15 memory and 9 nonmemory SCC questions. An informant completed a baseline questionnaire that included 15 memory and 4 nonmemory SCC questions relating to the participant. Neuropsychological, functional, and diagnostic assessments were carried out at baseline and again at 4-year follow-up. Cross-sectional and longitudinal analyses were carried out to determine the association between SCC indices and neuropsychological, functional, and diagnostic data while controlling for psychological measures. RESULTS: Once participant characteristics were controlled for, participant complaints were generally not predictive of cognitive or functional decline, although participant memory-specific complaints were predictive of diagnostic conversion. Informant related memory questions were associated with global cognitive and functional decline and with diagnostic conversion over 4 years. CONCLUSION: Informant memory complaint questions were better than participant complaints in predicting cognitive and functional decline as well as diagnoses over 4 years. PMID- 25441054 TI - What Makes Residents Interested in Geriatric Psychiatry? A Pan-Canadian Online Survey of Psychiatry Residents. AB - OBJECTIVES: In spite of a rapidly increasing need, there remains a shortage of geriatric psychiatrists in North America. The factors associated with psychiatric residents' interest in geriatric psychiatry have not yet been examined in a nationally representative sample. DESIGN: Cross-sectional study. SETTING: Web based online survey of Canadian psychiatry residents. PARTICIPANTS: 207 psychiatry residents (24.3% response rate). MEASUREMENTS: The main outcome was interest in becoming a geriatric psychiatrist. Bivariate and multivariate analyses were performed to better understand what demographic, educational, and vocational variables were associated with interest in becoming a geriatric psychiatrist. RESULTS: A number of respondents had an interest in becoming a geriatric psychiatrist (29.0%, N = 60); in doing a geriatric psychiatry fellowship (20.3%, N = 42); or an interest in doing geriatric psychiatry as a part of the clinical practice (60.0%, N = 124). Demographic characteristics (age, gender, ethnicity) did not correlate with interest in geriatric psychiatry. The variables most robustly associated with interest in geriatric psychiatry were: 1) completion of geriatric psychiatry rotation(s) before the third year of residency (OR: 5.13, 95% CI: 1.23-21.4); 2) comfort working with geriatric patients and their families (OR: 18.6, 95% CI: 2.09-165.3); 3) positive experiences caring for older adults prior to medical school (OR: 12.4, 95% CI: 1.07-144.5); and 4) the presence of annual conferences in the resident's field of interest (OR: 4.50, 95% CI: 1.12-18.2). CONCLUSION: Exposing medical students and junior psychiatry residents to clinical geriatric psychiatry rotations that increase comfort in working with older adults may be potential future strategies to improve recruitment of geriatric psychiatrists. PMID- 25441055 TI - Does cognition predict treatment response and remission in psychotherapy for late life depression? AB - OBJECTIVES: To identify cognitive predictors of geriatric depression treatment outcome. METHOD: Older participants completed baseline measures of memory and executive function, health, and baseline and post-treatment Hamilton Depression Scales (HAM-D) in a 12-week trial comparing psychotherapies (problem-solving vs. supportive; N = 46). We examined cognitive predictors to identify treatment responders (i.e., HAM-D scores reduced by >=50%) and remitters (i.e., post treatment HAM-D score <=10). RESULTS: Empirically derived decision trees identified poorer performance on switching (i.e., Trails B), with a cut-score of >=82 predicting psychotherapy responders. No other cognitive or health variables predicted psychotherapy outcomes in the decision trees. CONCLUSIONS: Psychotherapies that support or improve the executive skill of switching may augment treatment response for older patients exhibiting executive dysfunction in depression. If replicated, Trails B has potential as a brief cognitive tool for clinical decision-making in geriatric depression. PMID- 25441057 TI - Can small field diode correction factors be applied universally? AB - BACKGROUND AND PURPOSE: Diode detectors are commonly used in dosimetry, but have been reported to over-respond in small fields. Diode correction factors have been reported in the literature. The purpose of this study is to determine whether correction factors for a given diode type can be universally applied over a range of irradiation conditions including beams of different qualities. MATERIALS AND METHODS: A mathematical relation of diode over-response as a function of the field size was developed using previously published experimental data in which diodes were compared to an air core scintillation dosimeter. Correction factors calculated from the mathematical relation were then compared those available in the literature. RESULTS: The mathematical relation established between diode over response and the field size was found to predict the measured diode correction factors for fields between 5 and 30 mm in width. The average deviation between measured and predicted over-response was 0.32% for IBA SFD and PTW Type E diodes. Diode over-response was found to be not strongly dependent on the type of linac, the method of collimation or the measurement depth. CONCLUSIONS: The mathematical relation was found to agree with published diode correction factors derived from Monte Carlo simulations and measurements, indicating that correction factors are robust in their transportability between different radiation beams. PMID- 25441056 TI - Longitudinal Association of Dementia and Depression. AB - OBJECTIVES: Depression is an important precursor to dementia, but less is known about the role dementia plays in altering the course of depression. We examined whether depression prevalence, incidence, and severity are higher in those with dementia versus those with mild cognitive impairment (MCI), or normal cognition. DESIGN: Prospective cohort study using the longitudinal Uniform Data Set of the National Alzheimer's Coordinating Center (2005-2013). SETTING: 34 Alzheimer Disease research centers. PARTICIPANTS: 27,776 subjects with dementia, MCI, or normal cognition. MEASUREMENTS: Depression status was determined by a clinical diagnosis of depression within the prior 2 years and by a Geriatric Depression Scale-Short Form score >5. RESULTS: Rates of depression were significantly higher in subjects with MCI and dementia compared with those with normal cognition at index visit. Controlling for demographics and common chronic conditions, logistic regression analysis revealed elevated depression in those with MCI (OR: 2.40 [95% CI: 2.25, 2.56]) or dementia (OR: 2.64 [95% CI: 2.43, 2.86]) relative to those with normal cognition. In the subjects without depression at the index visit (N = 18,842), those with MCI and dementia had higher probabilities of depression diagnosis 2 years post index visit than those with normal cognition: MCI = 21.7%, dementia = 24.7%, normal cognition = 10.5%. CONCLUSION: MCI and dementia were associated with significantly higher rates of depression in concurrent as well as prospective analyses. These findings suggest that efforts to effectively engage and treat older adults with dementia will need also to address co-occurring depression. PMID- 25441059 TI - Evaluation of the distribution of Paclitaxel by immunohistochemistry and nuclear magnetic resonance spectroscopy after the application of a drug-eluting balloon in the porcine ureter. AB - BACKGROUND AND PURPOSE: The urothelium represents "the tightest and most impermeable barrier in the body." We investigated the distribution of paclitaxel (PTX) in the ureteral wall after the inflation of a paclitaxel-eluting balloon (PEB) in an attempt to elucidate the possibility of clinical application of PEBs in the ureter. MATERIALS AND METHODS: Nine domestic pigs were used. Nine PEBs and nine conventional percutaneous angioplasty balloons (CB) were inflated in the right and left ureter of each animal, respectively. The ureter treated by CB was the control for the contralateral ureter. Specimens were removed: Immediately after inflation (group A), after 12 hours (group B), and after 24 hours (group C). Two samples were obtained from each ureter of groups A, B and C. One sample was investigated by nuclear magnetic resonance spectroscopy (NMR), the other by histology and immunohistochemistry (IHC) using a specific for PTX polyclonal antibody. RESULTS: Reduced inflammation was observed in the group B and C samples in comparison with their controls. PTX was distributed mostly in the urothelium and submucosal layer in group A (IHC). The agent was present in the urothelial, submucosal, and muscle layer in groups B and C. The concentration of PTX (NMR) has been reduced in group C compared with the tissue extracts of group B. CONCLUSION: The distribution of PTX includes the urothelial, submucosal, and smooth muscle layers. Inflammation was reduced in the case of drug-eluting balloons. PMID- 25441058 TI - Multi-institutional phase I study of low-dose ultra-fractionated radiotherapy as a chemosensitizer for gemcitabine and erlotinib in patients with locally advanced or limited metastatic pancreatic cancer. AB - PURPOSE: Gemcitabine (G) has been shown to sensitize pancreatic cancer to radiotherapy but requires lower doses of G and thus delays aggressive systemic treatment, potentially leading to distant failure. We initiated a phase I trial combining ultra-fractionated low-dose radiotherapy with full dose G and erlotinib in the treatment of patients with advanced pancreatic cancer. METHODS: Patients with locally advanced or metastatic pancreatic cancer confined to the abdomen and an ECOG performance status (PS) of 0-1 who had received 0-1 prior regimens (without G or E) and no prior radiotherapy were eligible. Patients were treated in 21 day cycles with G IV days 1 & 8, E once PO QD, and twice daily RT fractions separated by at least 4h on days 1, 2, 8, and 9. Whole abdominal RT fields were used. Primary endpoint was to define dose limiting toxicity (DLT) and the maximum tolerated dose (MTD). RESULTS: 27 patients (median age 64 years and 15 male) were enrolled between 11/24/08 and 4/12/12. 1 patient withdrew consent prior to receiving any protocol therapy. 17 patients had a PS of 1. The majority of patients were stage IV. One DLT was noted out of 7 patients at dose level (DL) 1. Subsequently no DLTs were noted in 3 patients each enrolled at DL2-4 or 11 patients in the expansion cohort. The majority of grade 3 toxicities were hematologic with 1 grade 5 bowel perforation in dose level 1 in cycle 4. Best response in 24 evaluable patients: PR (8), stable (15), PD 1. Median survival for the entire group was 9.1 months. CONCLUSION: This phase I study combining low dose ultra-fractionated RT as a sensitizer to full dose G plus E was well tolerated with encouraging efficacy. This represents a novel strategy worthy of further investigation in advanced pancreatic cancer patients. PMID- 25441060 TI - Green Web or megabiased clock? Plant fossils from Gondwanan Patagonia speak on evolutionary radiations. AB - Evolutionary divergence-age estimates derived from molecular 'clocks' are frequently correlated with paleogeographic, paleoclimatic and extinction events. One prominent hypothesis based on molecular data states that the dominant pattern of Southern Hemisphere biogeography is post-Gondwanan clade origins and subsequent dispersal across the oceans in a metaphoric 'Green Web'. We tested this idea against well-dated Patagonian fossils of 19 plant lineages, representing organisms that actually lived on Gondwana. Most of these occurrences are substantially older than their respective, often post-Gondwanan molecular dates. The Green Web interpretation probably results from directional bias in molecular results. Gondwanan history remains fundamental to understanding Southern Hemisphere plant radiations, and we urge significantly greater caution when using molecular dating to interpret the biological impacts of geological events. PMID- 25441061 TI - Molecular mechanism of DNA damage induced by titanium dioxide nanoparticles in toll-like receptor 3 or 4 expressing human hepatocarcinoma cell lines. AB - BACKGROUND: Titanium dioxide nanoparticles (TiO2 NPs) are widely used in the biological sciences. The increasing use of TiO2 NPs increases the risk of humans and the environment being exposed to NPs. We previously showed that toll-like receptors (TLRs) play an important role in the interactions between NPs and cells. Our previous results indicated that TLR4 increased the DNA damage response induced by TiO2 NPs, due to enhanced NP uptake into the cytoplasm, whereas TLR3 expression decreased the DNA damage response induced by TiO2 NPs because of NP retention in the endosome. In this study, we explored the molecular mechanism of the DNA damage response induced by TiO2 NPs using TLR3 or TLR4 transfected cells. We examined the effect of TLR3 or TLR4 over-expression on oxidative stress and the effect of DNA damage induced by TiO2 NPs on gene expression levels. RESULTS: Our results showed evidence for elevated oxidative stress, including the generation of reactive oxygen species (ROS), with increased hydrogen peroxide levels, decreased glutathione peroxidase, and reduced glutathione and activated caspase-3 levels in cells exposed for 48 h to 10 MUg/ml TiO2 NPs. These effects were enhanced by TLR4 and reduced by TLR3 over-expression. Seventeen genes related to DNA double-strand breaks and apoptosis were induced, particularly IP6K3 and ATM. CONCLUSION: Our results indicated that TiO2 NPs induced ROS, and the above molecules are implicated in the genotoxicity induced by TiO2 NPs. PMID- 25441062 TI - Human Dobrava-Belgrade hantavirus infection, Kosovo. AB - Here we describe an acute Dobrava-Belgrade virus (DOBV) infection that presented as severe hemorrhagic fever with renal syndrome (HFRS) in an active-duty U.S. soldier. The infection was acquired in northern Kosovo in spring 2013. Amplification of DOBV genome segments directly from the patient's serum sample was successfully performed. Phylogenetic analysis demonstrated that the strain belong to DOBV genotype Dobrava and is closely related to strains circulating in Southeast Europe and Slovakia. Thus, our case confirms that DOBV genotype Dobrava is able to cause a severe form of HFRS, especially when compared to the other less pathogenic DOBV genotypes. PMID- 25441064 TI - Ring-reinforced Sano conduit at Norwood stage I reduces proximal conduit obstruction. AB - BACKGROUND: Reinterventions for proximal conduit obstruction or on the pulmonary arteries are frequent after the Sano-modified stage I Norwood palliation of hypoplastic left heart syndrome. We report our initial experience with a modified Sano technique using a ring-reinforced graft inserted transmurally through the right ventricle with a limited ventriculotomy. METHODS: All patients who underwent the Sano-modified stage I Norwood procedure using a modified "dunked" technique from September 2010 to September 2012 at our institution were reviewed. An historical control group consisted of patients undergoing the traditional Sano right ventricle-to-pulmonary artery conduit anastomosed to the epicardium. The primary outcome measures included death, reintervention on the Sano and pulmonary arteries, and ventricular function. RESULTS: The study included 29 patients. No patients required intervention on the Sano conduit, pulmonary arteries, or aortic arch before discharge after the stage I procedure. During a median follow-up of 20 months (range, 26 days to 3.3 years), survival was estimated at 96.6% +/- 3.4% at 1 month and 86.2% +/- 6.4% at the latest follow-up. One patient underwent heart transplantation. No interstage intervention was required on the proximal or distal Sano conduit. Intervention was required on the midportion of the conduit in 1 patient and on the pulmonary arteries in 3 patients. At the time of the bidirectional Glenn anastomosis, freedom from conduit and pulmonary artery intervention was estimated at 92.3% +/- 7.4% and 90.1% +/- 8.7%, respectively, and global right ventricular dysfunction was mild or less in 84% (16 of 19) of patients. CONCLUSIONS: The ring-reinforced right ventricle-to-pulmonary artery Sano conduit transmurally inserted into the right ventricle provides acceptable results, with a low incidence of interstage reinterventions in patients undergoing stage I palliation. PMID- 25441063 TI - Microdissection testicular sperm extraction in men with Sertoli cell-only testicular histology. AB - OBJECTIVE: To study the outcomes of microdissection testicular sperm extraction (microTESE) among men with pure Sertoli cell-only histology on diagnostic testicular biopsy. DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENT(S): Six hundred forty patients with pure Sertoli cell-only histology on testicular biopsy who underwent microTESE by a single surgeon. INTERVENTION(S): MicroTESE. MAIN OUTCOME MEASURE(S): Sperm retrieval rates. RESULT(S): Overall, 44.5% of patients with Sertoli cell only had sperm retrieved with microTESE. No difference was noted in sperm retrieval rates based on testis volume (>=15 mL vs. <15 mL, 35.3% vs. 46.1%, respectively). Patients with >=15 mL testicular volume and FSH 10-15 mU/mL had the worst prognosis, with a sperm retrieval rate of 6.7%. CONCLUSION(S): Patients with previous testicular biopsy demonstrating Sertoli cell-only histology can be counseled that they have a reasonable likelihood of sperm retrieval with the contemporary delivery of microTESE. Given this finding, the utility of testicular biopsy before microTESE is further questioned. PMID- 25441065 TI - A randomized multicenter trial of minimally invasive rapid deployment versus conventional full sternotomy aortic valve replacement. AB - BACKGROUND: Minimally invasive surgical procedures (MIS) may offer several advantages over conventional full sternotomy (FS) aortic valve replacement (AVR). A novel class of aortic valve prostheses has been developed for rapid-deployment AVR (RDAVR). We report a randomized, multicenter trial comparing the outcomes for MIS-RDAVR with those of conventional FS-AVR. METHODS: A total of 100 patients with aortic stenosis were enrolled in a prospective, multicenter, randomized comparison trial (CADENCE-MIS). Exclusion criteria included ejection fraction below 25%, AVR requiring concomitant procedures, and recent myocardial infarction or stroke. Patients were randomized to undergo MIS-RDAVR through an upper hemisternotomy (n = 51) or AVR by FS with a conventional stented bioprosthesis (n = 49). Three patients were excluded before the procedure, and 3 more patients who were randomized to undergo RDAVR were excluded because of their anatomy. Procedural, early clinical outcomes, and functional outcomes were assessed for the remaining 94 patients. Hemodynamic performance was assessed by an echocardiography core laboratory. RESULTS: Implanted valve sizes were similar between groups (22.9 +/- 2.1 vs 23.0 +/- 2.1 mm, p = 0.9). MIS-RDAVR was associated with significantly reduced aortic cross-clamp times compared with FS AVR (41.3 +/- 20.3 vs 54.0 +/- 20.3 minutes, p < 0.001), although cardiopulmonary bypass times were similar (68.8 +/- 29.0 vs 74.4 +/- 28.4 minutes, p = 0.21). Early clinical outcomes were similar between the two groups, including quality of life measures. The RDAVR patients had a significantly lower mean transvalvular gradient (8.5 vs 10.3 mm Hg, p = 0.044) and a lower prevalence of patient prosthesis mismatch (0% vs 15.0%, p = 0.013) 3 months postoperatively compared with the FS-AVR patients. CONCLUSIONS: RDAVR by the MIS approach is associated with significantly reduced myocardial ischemic time and better valvular hemodynamic function than FS-AVR with a conventional stented bioprosthesis. Rapid deployment valves may facilitate the performance of MIS-AVR. PMID- 25441066 TI - Determination of vitamin C in foods: current state of method validation. AB - Vitamin C is one of the most important vitamins, so reliable information about its content in foodstuffs is a concern to both consumers and quality control agencies. However, the heterogeneity of food matrixes and the potential degradation of this vitamin during its analysis create enormous challenges. This review addresses the development and validation of high-performance liquid chromatography methods for vitamin C analysis in food commodities, during the period 2000-2014. The main characteristics of vitamin C are mentioned, along with the strategies adopted by most authors during sample preparation (freezing and acidification) to avoid vitamin oxidation. After that, the advantages and handicaps of different analytical methods are discussed. Finally, the main aspects concerning method validation for vitamin C analysis are critically discussed. Parameters such as selectivity, linearity, limit of quantification, and accuracy were studied by most authors. Recovery experiments during accuracy evaluation were in general satisfactory, with usual values between 81 and 109%. However, few methods considered vitamin C stability during the analytical process, and the study of the precision was not always clear or complete. Potential future improvements regarding proper method validation are indicated to conclude this review. PMID- 25441067 TI - Effects of packing density, flow and humidity on the performance of needle trap devices. AB - Needle trap devices (NTDs) have become a promising alternative to solid-phase microextraction (SPME) due to their robustness and exhaustive sampling while maintaining all the advantages of SPME. This study investigates the compromise required in packing NTDs starting from the hypothesis that their diameter makes perfect packing impractical. The most limiting parameter of NTDs is the small amount of sorbent that can be fitted in the trap. On evaluating packing density, it is found that the densest packing cannot practically be achieved with NTDs. This poor packing leads to oscillations in the fluid flow profiles and so sampling flows up to 10-15 mL min(-1) are recommended for this methodology. The limited amount of sorbent materials inside the needles makes breakthrough another limiting aspect of NTDs. However, one of the most significant advantages of these devices is that they have a large preconcentration factor, which results in method detection limits in the pptv range with sample volumes <100 mL. This methodology gives promising results in the analysis of water saturated samples as the limited amount of sorbents reduces water retention. Moreover, it is desirable for a small amount of water to be retained with NTDs as this improves the desorption of the retained compounds in the GC injector and allows sharper injection band-widths to be obtained. PMID- 25441068 TI - Determination of perfluorinated carboxylic acids in fish fillet by micro-solid phase extraction, followed by liquid chromatography-triple quadrupole mass spectrometry. AB - In the current study, a simple, fast and efficient combination of protein precipitation and micro-solid phase extraction (MU-SPE) followed by liquid chromatography-triple quadrupole tandem mass spectrometry (LC-MS/MS) was developed for the determination of perfluorinated carboxylic acids (PFCAs) in fish fillet. Ten PFCAs with different hydrocarbon chain lengths (C5-C14) were analysed simultaneously using this method. Protein precipitation by acetonitrile and MU-SPE by surfactant-incorporated ordered mesoporous silica were applied to the extraction and concentration of the PFCAs as well as for removal of interferences. Determination of the PFCAs was carried out by LC-MS/MS in negative electrospray ionization mode. MS/MS parameters were optimized for multiple reaction monitoring of the analytes. (13)C mass labelled PFOA as a stable isotopic internal standard, was used for calibration. The detection limits of the method ranged from 0.97 ng/g to 2.7 ng/g, with a relative standard deviation of between 5.4 and 13.5. The recoveries were evaluated for each analyte and were ranged from 77% to 120%. The t-test at 95% confidence level showed that for all the analytes, the relative recoveries did not depend on their concentrations in the explored concentration range. The effect of the matrix on MS signals (suppression or enhancement) was also evaluated. Contamination at low levels was detected for some analytes in the fish samples. The protective role of the polypropylene membrane used in MU-SPE in the elimination of matrix effects was evaluated by parallel experiments in classical dispersive solid phase extraction. The results evidently showed that the polypropylene membrane was significantly effective in reducing matrix effects. PMID- 25441069 TI - Simultaneous determination of free and bonded forms of odor-active carbonyls in wine using a headspace solid phase microextraction strategy. AB - This paper presents a new strategy for the direct evaluation of odor-active carbonyls in the wine headspace and for the simultaneous estimation of their amounts in odorless bonded forms. In the final developed strategy, 25 mL of wine are spiked with internal and surrogate standards and let to equilibrate for at least 12 h in an oxygen-free chamber. Ten milliliter of the sample are then transferred to a standard headspace vial. Carbonyls in the headspace are preconcentrated on a PDMS/DVD fiber keeping the sample unstirred at 45 degrees C for just 10 min and are further analyzed on a GC-MS equipped with a quadrupole in SIM mode. Normalized peak analyte areas interpolated in calibration plots built with synthetic wines give estimations of the concentrations of free forms, while the ratios of the areas of surrogates observed in wines to those observed in synthetic wine make it possible to get estimations of the proportion of each analyte present in bonded non-volatile form. The validity of this approach has been demonstrated both via standard recovery experiments and via the analysis of samples previously incubated with glyoxal in order to break aldehyde-bisulfite complexes. In general, method detection limits (below 1 MUg L(-1)), precision (RSD (%)<10%) and accuracy are satisfactory for 12 studied carbonyls. Results demonstrate that wine contain relevant amounts of aldehydes (more than 95% in some cases) in the form of reversible odorless complexes, supporting a previous observation about the potential implication of these complexes on the development of oxidized aroma. PMID- 25441070 TI - Sample preservation for the analysis of antibiotics in water. AB - This paper describes a stability study performed for 56 antibiotics belonging to 9 different groups--macrolides, tetracyclines, fluoroquinolones, quinolones, penicillins, cephalosporines, lincosamides, sulfonamides and nitroimidazole antibiotics--in purified water samples fortified with the selected compounds at 10 ng/ml. For this purpose, three different sample preservation modes were tested with the aim of avoiding biotic and abiotic degradation: (i) storage at -20 degrees C, (ii) storage at -20 degrees C with 0.1% of EDTA and (iii) pre concentration in a solid phase extraction cartridge (SPE), which was afterwards stored at -20 degrees C. Concentrations of antibiotics in the samples preserved using the different protocols were monitored after 0, 1, 2 and 12 weeks. The results showed that, for the accurate determination of all compounds they should be analyzed right after sampling. However, if this is not possible, most of the antibiotics can be analyzed within the 1st week after sampling and preservation at -20 degrees C (with or without EDTA) or in a SPE cartridges at -20 degrees C. Nonetheless, some antibiotics found extensively in the environment, such as sulfamethoxazole, ciprofloxacin, ofloxacin, erythromycin, azithromycin and clarithromycin exhibited low stability after 1 week preservation and, therefore, they should be analyzed within this time. PMID- 25441071 TI - High-throughput hydrophilic interaction chromatography coupled to tandem mass spectrometry for the optimized quantification of the anti-Gram-negatives antibiotic colistin A/B and its pro-drug colistimethate. AB - Colistin is a last resort's antibacterial treatment in critically ill patients with multi-drug resistant Gram-negative infections. As appropriate colistin exposure is the key for maximizing efficacy while minimizing toxicity, individualized dosing optimization guided by therapeutic drug monitoring is a top clinical priority. Objective of the present work was to develop a rapid and robust HPLC-MS/MS assay for quantification of colistin plasma concentrations. This novel methodology validated according to international standards simultaneously quantifies the microbiologically active compounds colistin A and B, plus the pro-drug colistin methanesulfonate (colistimethate, CMS). 96-well micro-Elution SPE on Oasis Hydrophilic-Lipophilic-Balanced (HLB) followed by direct analysis by Hydrophilic Interaction Liquid Chromatography (HILIC) with Ethylene Bridged Hybrid--BEH--Amide phase column coupled to tandem mass spectrometry allows a high-throughput with no significant matrix effect. The technique is highly sensitive (limit of quantification 0.014 and 0.006 MUg/mL for colistin A and B), precise (intra-/inter-assay CV 0.6-8.4%) and accurate (intra /inter-assay deviation from nominal concentrations -4.4 to +6.3%) over the clinically relevant analytical range 0.05-20 MUg/mL. Colistin A and B in plasma and whole blood samples are reliably quantified over 48 h at room temperature and at +4 degrees C (<6% deviation from nominal values) and after three freeze-thaw cycles. Colistimethate acidic hydrolysis (1M H2SO4) to colistin A and B in plasma was completed in vitro after 15 min of sonication while the pro-drug hydrolyzed spontaneously in plasma ex vivo after 4 h at room temperature: this information is of utmost importance for interpretation of analytical results. Quantification is precise and accurate when using serum, citrated or EDTA plasma as biological matrix, while use of heparin plasma is not appropriate. This new analytical technique providing optimized quantification in real-life conditions of the microbiologically active compounds colistin A and B offers a highly efficient tool for routine therapeutic drug monitoring aimed at individualizing drug dosing against life-threatening infections. PMID- 25441072 TI - Dual-ligand affinity systems with octapeptide ligands for affinity chromatography of hIgG and monoclonal antibody. AB - This work reports the development of affinity systems with dual octapeptide ligands for affinity adsorption and purification of human IgG (hIgG) and monoclonal antibody (mAb). The three octapeptide ligands, FYWHCLDE (1), FYCHWALE (2), and FYCHTIDE (3), identified earlier by the biomimetic design strategy were used; any two of the three were mixed and coupled to Sepharose gel, leading to the formation of three dual-ligand affinity systems. Research emphasis was first placed on hIgG adsorption isotherms and the results were compared to the three single-ligand affinity systems. It was found that there was synergistic effect of the two peptide ligands in a dual-ligand system, so the affinity of a dual-ligand resin for hIgG was higher than those of its counterparts, single-ligand resins. Of the three dual-ligand systems, the FYWHCLDE (1)-FYCHTIDE (3) resin showed the highest affinity, so it was selected for investigating the effects of ligand density and molar ratio on hIgG adsorption equilibrium. It was found that the synergistic effect increased with increasing the total ligand density of the two peptides in the dual-ligand affinity system. Moreover, the FYWHCLDE (1)-FYCHTIDE (3) system at a molar ratio of 2:1 displayed the highest affinity for hIgG (0.69 MUM at a total ligand density of 31.1 MUmol/mL), indicating that the synergistic effect reached the maximum at this ratio. This dual-ligand affinity column was then used for the purification of hIgG and mAb by affinity chromatography, resulting in over 95% pure hIgG and mAb at recovery yield over 90%. Molecular docking of the two peptides to the Fc fragment simultaneously showed that FYWHCLDE (1) stood still but FYCHTIDE (3) shifted aside the CH2CH3 inter-domain. Molecular dynamics simulation of the binding process of the two octapeptides to Fc revealed that both the peptide ligands kept stable interactions with Fc. The synergistic effect of the dual-ligand affinity system was thus elucidated by the molecular simulations. PMID- 25441073 TI - "Measure Your Gradient": a new way to measure gradients in high performance liquid chromatography by mass spectrometric or absorbance detection. AB - The gradient produced by an HPLC is never the same as the one it is programmed to produce, but non-idealities in the gradient can be taken into account if they are measured. Such measurements are routine, yet only one general approach has been described to make them: both HPLC solvents are replaced with water, solvent B is spiked with 0.1% acetone, and the gradient is measured by UV absorbance. Despite the widespread use of this procedure, we found a number of problems and complications with it, mostly stemming from the fact that it measures the gradient under abnormal conditions (e.g. both solvents are water). It is also generally not amenable to MS detection, leaving those with only an MS detector no way to accurately measure their gradients. We describe a new approach called "Measure Your Gradient" that potentially solves these problems. One runs a test mixture containing 20 standards on a standard stationary phase and enters their gradient retention times into open-source software available at www.measureyourgradient.org. The software uses the retention times to back calculate the gradient that was truly produced by the HPLC. Here we present a preliminary investigation of the new approach. We found that gradients measured this way are comparable to those measured by a more accurate, albeit impractical, version of the conventional approach. The new procedure worked with different gradients, flow rates, column lengths, inner diameters, on two different HPLCs, and with six different batches of the standard stationary phase. PMID- 25441074 TI - Evaluation and comparison of the kinetic performance of ultra-high performance liquid chromatography and high-performance liquid chromatography columns in hydrophilic interaction and reversed-phase liquid chromatography conditions. AB - An intrinsic performance comparison is made of the reduction in analysis time that can be obtained when switching from HPLC to UHPLC column formats in HILIC and reversed-phase conditions. A detailed overview of the packing characteristics of both stationary phase types is given first. It is demonstrated that HILIC columns demonstrate higher external porosity values than their reversed-phase counterparts resulting in lower flow resistance values. Column total porosity values determined from the elution time of a small marker molecule are shown to depend strongly on the composition of the mobile phase. To omit errors that might arise from an over- or underestimation of the column void time, all plate height and kinetic plot data are therefore expressed as a function of the interstitial velocity. Although only a limited number of columns are evaluated in this study, it is shown that the column efficiency of the HILIC columns is lower than that of their reversed-phase counterparts, at least for the compounds evaluated here. Despite this lower efficiency, the kinetic performance of both stationary phase types is similar, due to the much lower viscosity of the mobile phases typically used in HILIC conditions. Finally, it is demonstrated that a similar, yet slightly larger reduction in analysis time can be obtained when switching from HPLC column formats to UHPLC formats in HILIC compared to reversed-phase conditions. PMID- 25441075 TI - Diagnostic application of the exponentially modified Gaussian model for peak quality and quantitation in high-throughput liquid chromatography-tandem mass spectrometry. AB - Typical area calculation for a chromatographic peak assumes the observed signal strength at every measurement is an exactly accurate count of the signal. We compared that approach to one using the exponentially modified Gaussian (EMG) in an automated, clinical production setting. Peak areas in a 47 analyte high throughput clinical production liquid chromatography-tandem mass spectrometry assay were compared across four months of production data to determine trends over the lifespan of a chromatographic column. The EMG parameters were superior to traditional quality control methods for monitoring data reproducibility, accuracy and precision. Because the EMG calculations are performed for every peak in the system, a constant monitor of system health is integrated into the operational workflow. Parameter trends confirmed the need for column replacement, and indicated the opportunity for a reduced schedule of preventive and routine maintenance. PMID- 25441076 TI - Salt-independent hydrophobic displacement chromatography for antibody purification using cyclodextrin as supermolecular displacer. AB - Hydrophobic interaction chromatography (HIC) offers an orthogonal selectivity to ion exchange chromatography and the combination of the two processes can provide a potential cost-effective alternative to protein A chromatography in industrial antibody purification. However, the application of HIC is limited by its close dependence on high concentrations of kosmotropic salts to achieve desired separation. These salts can cause antibody precipitation and induce the corrosion of manufacturing facilities. Here, we report a new strategy of salt-independent HIC, which can capture antibody at the physiological salt concentration and allow the recovery of bound proteins through cyclodextrin (CD)-based displacement elution. Hydrophobicity-intensified HIC media with different coupling amount of phenyl ligands were prepared and assessed for their antibody binding capacity and selectivity. beta-CD was investigated for its supermolecular interaction with phenyl ligands and elution capacity as a displacer. The results clarified a nearly linear correlation between binding capacity of human immunoglobulin G (IgG) and phenyl coupling density in the range of 44-159 MUmol/mL. The host-guest interaction between beta-CD and the phenyl ligands revealed a modest binding strength (Ka=4.1*10(3) M(-1)), and 15 mM beta-CD solution showed a general effectiveness as displacement eluent for these HIC media, with IgG recovery varying with the ligand density. This strategy allowed the direct purification of human IgG from serum with satisfactory purity. The whole procedure of this method, including loading and elution, can be performed under physiological conditions. We expect such a salt-independent mode of HIC could be used as a capture or intermediate step in industrial antibody purification. PMID- 25441077 TI - A single step reversed-phase high performance liquid chromatography separation of polar and non-polar lipids. AB - This paper reports a simple chromatographic system to separate lipids classes as well as their molecular species. By the use of phenyl coated silica as stationary phase in combination with a simple mobile phase consisting of methanol and water, all tested lipid classes elute within 30 min. Furthermore, a method to accurately predict retention times of specific lipid components for this type of chromatography is presented. Common detection systems were used, namely evaporative light scattering detection (ELSD), charged aerosol detection (CAD), electrospray mass spectrometry (ESI-MS), and UV detection. PMID- 25441078 TI - Preparation and evaluation of dextran-grafted agarose resin for hydrophobic charge-induction chromatography. AB - Hydrophobic charge-induction chromatography (HCIC) is a new and effective technology for antibody separation. In the present work, HCIC resin MMI-B-XL was prepared with dextran-grafted agarose gel as the matrix and 2-mercapto-1-methyl imidazole (MMI) as the functional ligand. The preparation procedures were optimized, and the maximum ligand density could reach as high as 200 MUmol/g gel. The adsorption isotherms and kinetics on new resins were investigated with human immunoglobulin G (hIgG) as the model protein, which were compared with non grafted HCIC resin MMI-B-6FF. It was found that the saturated adsorption capacity (Qm) increased with the increase of ligand density for MMI-B-XL. Moreover, the effective diffusivity (De) could be dramatically enhanced with the increase of ligand density for MMI-B-XL, and the De for MMI-B-XL with the ligand density of 200 MUmol/g gel was 18-40 times higher than that for MMI-B-6FF. The breakthrough experiments indicated that new resins with the ligand density of 200 MUmol/g gel could be used for high superficial velocity and high dynamic adsorption could be obtained. The results indicated that dextran-grafted layer on the resin could increase the ligand density, enhance the mass transport in the pore, and improve the dynamic adsorption at high velocity, which showed a potential application for large-scale antibody purification. PMID- 25441079 TI - The impact of flow distribution on column performance: a computational fluid dynamics study. AB - In this manuscript, the band broadening contribution of a generic flow distributor and collector has been calculated using computational fluid dynamics (CFD). The effects of distributor design and operating conditions on distributor performance have been studied. The non uniform flow fields in the distributor cause band deformation and an increase in volumetric band variance (sigmav(2)). This volumetric band variance was calculated to be about 0.2 MUl(2) at the inlet of a 4.6 mm ID column and 0.3 MUl(2) at the outlet for a flow rate of 2 ml/min. For a 2.1 mm column the volumetric band variance is about 0.002 MUl(2) for a flow rate of 0.41 ml/min. For current column performance the measured contributions are negligible in practice, probably because designs have been empirically improved together with improving column performance. None the less, the simulations show that bad distributor design can be detrimental for column performance. PMID- 25441080 TI - Simultaneous determination of total nitrogen and total phosphorus in environmental waters using alkaline persulfate digestion and ion chromatography. AB - An ion chromatography (IC) method was developed for the simultaneous determination of total nitrogen and total phosphorus after alkaline persulfate digestion. This study takes advantage of advances in construction of high resolution, high-capacity anion-exchange columns that can better tolerate the matrices typically encountered when a determination of total nitrogen and total phosphorous is required. Here, we used an electrolytically generated hydroxide eluent combined with a high-capacity, hydroxide-selective, anion-exchange column for the determination of total nitrogen (as nitrate-N) and total phosphorus (as phosphate-P) in environmental samples by IC. This method yielded LODs for nitrate N and phosphate-P of 1.0 and 1.3 MUg/L, respectively. The LOQs determined for these analytes were 3.4 and 4.2 MUg/L, respectively. Due to the dilution factor required and the blank nitrate-N concentration after the persulfate digestion, the quantification limits increased for nitrate-N and phosphate-P to 171 and 63 MUg/L, respectively. The suitability of the method was evaluated by determining the nitrogen and phosphorus concentrations from known concentrations of organic containing nitrogen and phosphorus compounds. In addition, environmental samples consisting of six different wastewaters and 48 reservoir samples were evaluated for total nitrogen and phosphorus. The recoveries of nitrogen and phosphorus from the organic-containing compounds ranged from 93.1 to 100.1% and 85.2 to 97.1%, respectively. In addition, good correlation between results obtained by the colorimetric method and IC was also observed. The linearity, accuracy, and evaluation of potential interferences for determining TN and TP will be discussed. PMID- 25441082 TI - Quantitative and qualitative analysis of hemicellulose, cellulose and lignin bio oils by comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry. AB - Thermal and catalytic pyrolysis are efficient processes for the transformation of biomass to bio-oil, a liquid energy carrier and a general source of chemicals. The elucidation of the bio-oil's composition is essential for a rational design of both its production and utilization process. However, the complex composition of bio-oils hinders their complete qualitative and quantitative analysis, and conventional chromatographic techniques lack the necessary separation power. Two dimensional gas chromatography with time-of-flight mass spectrometry (GC*GC ToFMS) is considered a suitable technique for bio-oil analysis due to its increased separation and resolution capacity. This work presents the tentative qualitative and quantitative analysis of bio-oils resulting from the thermal and catalytic pyrolysis of standard xylan, cellulose, lignin and their mixture by GC*GC-ToFMS. Emphasis is placed on the development of the quantitative method using phenol-d6 as internal standard. During the method development, a standard solution of 39 compounds was used for the determination of the respective Relative Response Factors (RRF) employing statistical methods, ANOVA and WLSLR, for verification of the data. The developed method was applied to the above mentioned bio-oils and their detailed analysis is presented. The different compounds produced and their diverse concentration allows for an elucidation of the pyrolysis mechanism and highlight the effect of the catalyst. PMID- 25441081 TI - Comprehensive characterization of the halogenated dibenzo-p-dioxin and dibenzofuran contents of residential fire debris using comprehensive two dimensional gas chromatography coupled to time of flight mass spectrometry. AB - A comprehensive approach was taken to characterize the polyhalogenated dibenzo-p dioxin and dibenzofuran contents of fire debris. Household and electronics fire simulations were performed to create samples representative of those firefighters most typically come in contact with. Sample analysis was performed using GC*GC TOFMS to provide a comprehensive profile of the halogenated dioxins and furans present among the two types of fire debris. Both the household fire and electronics fire simulations produced a significant amount of polybrominated dibenzofurans. Only the electronics rich fire simulation produced mixed halogenated (Br/Cl) dibenzofurans in amounts above the limit of detection of the analytical method. Of the mixed halogenated dibenzofurans identified, a majority were those having no commercially available standard to allow for specific congener identification. GC*GC-TOFMS was extremely beneficial for the identification of compound classes due to the manner in which compounds classify in the two-dimensional chromatographic plane, thus aiding data reduction for these materials. PMID- 25441083 TI - Development of quantitative method for determination of gamma-glutamyl peptides by capillary electrophoresis tandem mass spectrometry: an efficient approach avoiding matrix effect. AB - Serum gamma-glutamyl di- and tripeptides have proven to be useful biomarkers to accurately predict nine different forms of liver disease. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with multiple reaction monitoring (MRM), serum and liver samples spiked with gamma-glutamyl peptide standards were analyzed to estimate accuracy. Unexpectedly, the recovery rates for several gamma-glutamyl peptides in the serum samples were quite low, whereas values for some gamma-glutamyl peptides in the liver samples were highly elevated. Most of these peptides were barely retained on the reverse-phase column, resulting in significant ion suppression or enhancement. In contrast, a capillary electrophoresis tandem mass spectrometry (CE-MS/MS) method with MRM was minimally affected by matrix effects. Of the 39 tested compounds, most of gamma glutamyl peptides that did not contain a thiol substituent in its structure gave acceptable recoveries (70-120%), and limits of detection for the analytes were between 3.6 and 800 nmol/l with pressure injection at 5 kPa for 10 s (ca. 10 nl). The CE-MS/MS method provided high resolution and proved to be highly selective and sensitive, its utility being demonstrated by the determination of gamma glutamyl di- and tripeptides in serum and liver samples. PMID- 25441084 TI - Supermacroporous polymer monolith prepared with polymeric porogens via viscoelastic phase separation for capillary electrochromatography. AB - Supermacroporous poly(methacrylic acid-butyl methacrylate-ethylene glycol dimethacrylate) monoliths with the pore size up to 5-10 MUm were successfully prepared in a ternary polymeric porogens utilizing viscoelastic effect. High concentration (over 20 mg/mL) of polystyrene (PS) in porogen was used to achieve the desirable characteristics of the monolithic capillary. Modification of the co porogen composition, i.e., the content of dimethyl sulfoxide and isooctane, enabled tailoring of the supermacropore structure with a wide range of pore size. The effects of the amount of polymer porogen and molecular weights of PS on the formation of supermacropore were also studied. In preliminary applications, the separations of alkyl phenones and alkylbenzenes were achieved on the supermacropore columns using a mode of capillary electrochromatography. The study demonstrated successfully the ability of polymer porogen to form supermacropore monolith via viscoelastic phase separation. PMID- 25441085 TI - Ultrathin-shell boron nitride hollow spheres as sorbent for dispersive solid phase extraction of polychlorinated biphenyls from environmental water samples. AB - Boron nitride hollow spheres with ultrathin-shells were synthesized and used as sorbents for dispersive solid-phase extraction of aromatic pollutants at trace levels from environmental water samples. Polychlorinated biphenyls (PCBs) were selected as target compounds. Sample quantification and detection were performed by gas chromatography-tandem mass spectrometry. Extraction parameters influencing the extraction efficiency were optimized through response surface methodology using the Box-Behnken design. The proposed method achieved good linearity within the concentration range of 0.15-250 ng L(-1) PCBs, low limits of detection (0.04 0.09 ng L(-1), S/N=3:1), good repeatability of the extractions (relative standard deviation, <12%, n=6), and satisfactory recoveries between 84.9% and 101.0% under optimal conditions. Real environmental samples collected from rivers, local lakes, rain and spring waters were analyzed using the developed method. Results demonstrated that the hexagonal boron nitride-based material has significant potential as a sorbent for organic pollutant extraction from environmental water samples. PMID- 25441086 TI - Off-line sample preparation by electrophoretic concentration using a micropipette and hydrogel. AB - An off-line electrophoretic sample concentration technique for charged analytes in aqueous samples is presented. As a demonstration, nine anions including inorganic ions, a dye and benzenesulfonate derivatives were enriched from a 10 mL sample solution into 20 MUL electrolyte inside a glass micropipette. A hydrogel was placed at one end of the micropipette while the other end was immersed in the sample. The electric field caused the movement and concentration of anions into the high conductivity electrolyte. The technique was applied to purified, drinking and river water and was optimised by changing applied voltage and voltage application time. The LODs after analysis by capillary electrophoresis was 1-19 ng/mL, 4-133 ng/mL and 18-80 ng/mL for purified, drinking and river water, respectively. The linear range was 0.002-0.048 to 0.1-2.4 MUg/mL (R(2) of 0.993-0.999), 0.02-0.24 to 1.0-24 MUg/mL (R(2) of 0.995-0.999) and 0.02-0.24 to 1.0-24 MUg/mL (R(2) of 0.998-1.000), correspondingly. The intraday and interday repeatability (%RSD, n=6) was <=7.4% and 14.0%, respectively. The concentration factor was from one to two orders of magnitude. The technique was directly compatible with a liquid phase analytical technique, thus eliminated the additional steps (e.g., evaporation, elution and/or reconstitution) which are typically performed in sample preparation (e.g., liquid and solid phase extraction). PMID- 25441087 TI - Equivalence between the equilibrium dispersive and the transport model in describing band broadening in analytical gradient liquid chromatography. AB - It is shown that the transport (TR) model may be equivalent to the equilibrium dispersive (ED) model in analytical gradient liquid chromatography when the column efficiency is not small. This result is obtained by assuming that the gradient profile is not distorted, the injection is an impulse, and the apparent axial dispersion coefficient (Da) of the ED model or the lumped kinetic coefficient (kfL) of the TR model varies with mobile phase composition. According to this equivalence, the plate height equation derived from the TR model in our previous work (Eq. (91) in Hao et al., 2013) is also suited for the ED model. This conclusion is confirmed by comparing the equation with the results obtained by Gritti and Guiochon from the ED model (Gritti and Guiochon, 2012). PMID- 25441088 TI - Placental transfer of IgG antibodies specific to Klebsiella and Pseudomonas LPS and to group B Streptococcus in twin pregnancies. AB - Group B Streptococcus (GBS), Klebsiella spp. and Pseudomonas spp. are important aetiological agents of neonatal infections in Brazil. There is a lack of data in the literature regarding the specific transport of immunoglobulin G (IgG) against these pathogens in multiple pregnancies. Maternal (n = 55) and umbilical cord (n = 110) blood samples were prospectively collected at birth from 55 twin pregnancies. The factors associated with cord levels and transfer ratios of IgG against GBS, Klebsiella and Pseudomonas were examined. The IgG umbilical cord serum levels specific to GBS, Klebsiella LPS and Pseudomonas LPS were significantly associated with maternal-specific IgG concentrations and the presence of diabetes. The anti-Klebsiella IgG cord serum concentrations were also related to birthweight and the presence of hypertension. The transfer ratios against GBS and Pseudomonas LPS were associated with maternal-specific IgG concentrations. The transfer ratios for GBS and Pseudomonas LPS were associated with gestational age at delivery and the presence of diabetes, respectively. None of the examined parameters were related to Klebsiella LPS transfer ratios. We conclude that in twin pregnancies, specific maternal IgG serum concentrations and diabetes were the parameters associated with umbilical cord serum IgG concentrations reactive with the three pathogens investigated. All the other parameters investigated showed different associations with neonatal-specific IgG levels according to the antigen studied. There was no uniformity of the investigated parameters regarding association with placental IgG transfer ratios against the GBS, Pseudomonas LPS and Klebsiella LPS. PMID- 25441089 TI - Core geometry in perspective. AB - Research on animals, infants, children, and adults provides evidence that distinct cognitive systems underlie navigation and object recognition. Here we examine whether and how these systems interact when children interpret 2D edge based perspectival line drawings of scenes and objects. Such drawings serve as symbols early in development, and they preserve scene and object geometry from canonical points of view. Young children show limits when using geometry both in non-symbolic tasks and in symbolic map tasks that present 3D contexts from unusual, unfamiliar points of view. When presented with the familiar viewpoints in perspectival line drawings, however, do children engage more integrated geometric representations? In three experiments, children successfully interpreted line drawings with respect to their depicted scene or object. Nevertheless, children recruited distinct processes when navigating based on the information in these drawings, and these processes depended on the context in which the drawings were presented. These results suggest that children are flexible but limited in using geometric information to form integrated representations of scenes and objects, even when interpreting spatial symbols that are highly familiar and faithful renditions of the visual world. PMID- 25441090 TI - Molecular typing of antibiotic-resistant Staphylococcus aureus in Nigeria. AB - BACKGROUND: Antibiotic-resistant Staphylococcus aureus including methicillin resistant strains (MRSA) are a major concern in densely populated urban areas. Initial studies of S. aureus in Nigeria indicated existence of antibiotic resistant S. aureus strains in clinical and community settings. METHODS: 73 biological samples (40 throat, 23 nasal, 10 wound) were collected from patients and healthcare workers in three populations in Nigeria: Lagos University Teaching Hospital, Nigerian Institute of Medical Research, and Owerri General Hospital. RESULTS: S. aureus was isolated from 38 of 73 samples (52%). Of the 38 S. aureus samples, 9 (24%) carried the Panton-Valentine leukocidin gene (PVL) while 16 (42%) possessed methicillin resistance genes (mecA). Antibiotic susceptibility profiles indicated resistance to several broad-spectrum antibiotics. CONCLUSION: Antibiotic-resistant S. aureus isolates were recovered from clinical and community settings in Nigeria. Insight about S. aureus in Nigeria may be used to improve antibiotic prescription methods and minimize the spread of antibiotic resistant organisms in highly populated urban communities similar to Lagos, Nigeria. PMID- 25441091 TI - Pulse electron paramagnetic resonance studies of the interaction of methanol with the S2 state of the Mn4O5Ca cluster of photosystem II. AB - The binding of the substrate analogue methanol to the catalytic Mn4CaO5 cluster of the water-oxidizing enzyme photosystem II is known to alter the electronic structure properties of the oxygen-evolving complex without retarding O2 evolution under steady-state illumination conditions. We report the binding mode of (13)C-labeled methanol determined using 9.4 GHz (X-band) hyperfine sublevel correlation (HYSCORE) and 34 GHz (Q-band) electron spin-echo electron nuclear double resonance (ESE-ENDOR) spectroscopies. These results are compared to analogous experiments on a mixed-valence Mn(III)Mn(IV) complex (2-OH-3,5-Cl2 salpn)2Mn(III)Mn(IV) (salpn = N,N'-bis(3,5-dichlorosalicylidene)-1,3-diamino-2 hydroxypropane) in which methanol ligates to the Mn(III) ion ( Larson et al. (1992) J. Am. Chem. Soc. , 114 , 6263 ). In the mixed-valence Mn(III,IV) complex, the hyperfine coupling to the (13)C of the bound methanol (Aiso = 0.65 MHz, T = 1.25 MHz) is appreciably larger than that observed for (13)C methanol associated with the Mn4CaO5 cluster poised in the S2 state, where only a weak dipolar hyperfine interaction (Aiso = 0.05 MHz, T = 0.27 MHz) is observed. An evaluation of the (13)C hyperfine interaction using the X-ray structure coordinates of the Mn4CaO5 cluster indicates that methanol does not bind as a terminal ligand to any of the manganese ions in the oxygen-evolving complex. We favor methanol binding in place of a water ligand to the Ca(2+) in the Mn4CaO5 cluster or in place of one of the waters that form hydrogen bonds with the oxygen bridges of the cluster. PMID- 25441094 TI - Dietary flavonoids added to pharmacological antihypertensive therapy are effective in improving blood pressure. AB - Epidemiological studies have suggested that the daily intake of flavonoids is associated with a decreased risk of developing cardiovascular disease. Our purpose was to evaluate the effect of the addition of dietary flavonoids (DF) to antihypertensive treatment (AHT), based on telmisartan (Tms) or captopril (Cpr), on blood pressure (BP), body mass index (BMI), waist/hip ratio, leptin, lipid profile and inflammation in hypertensive young patients. An open-label, randomized, controlled trial was performed among 79 patients aged 20-55 years with grade I or grade II systemic arterial hypertension. The subjects were assigned to one of four groups for AHT plus DF during 6 months: Cpr (n = 14), Cpr + DF (n = 19), Tms (n = 25) and Tms + DF (n = 21). DF consisted of dark chocolate, dehydrated red apple and green tea in an infusion to obtain a daily dose of 425.8 +/- 13.9 mg epicatechin equivalents. The BP and anthropometric parameters were measured every 2 weeks. Lipid profile, leptin and hsCRP were determined by standard methods. The combination AHT-DF produced an additional and significant reduction in (i) SBP/DBP of -5/-4 mmHg, being -7/-5 for Cpr + DF and 4/-3 for Tms + DF; (ii) triglyceride levels (-30.6%) versus AHT alone (-9.6%); and (iii) leptin: Cpr + DF versus Tms + DF (p < 0.005). Finally, C-reactive protein plasma levels were reduced significantly in all groups independently of the applied treatment. We conclude that the addition of flavonoids to pharmacological antihypertensive therapy shows additional benefits on BP, lipid profile, leptin, obesity and inflammation. PMID- 25441095 TI - Comparing thin slices of verbal communication behavior of varying number and duration. AB - OBJECTIVE: The aim of this study was to assess the accuracy of thin slices to characterize the verbal communication behavior of counselors and patients engaged in Motivational Interviewing sessions relative to fully coded sessions. METHODS: Four thin slice samples that varied in number (four versus six slices) and duration (one- versus two-minutes) were extracted from a previously coded dataset. In the parent study, an observational code scheme was used to characterize specific counselor and patient verbal communication behaviors. For the current study, we compared the frequency of communication codes and the correlations among the full dataset and each thin slice sample. RESULTS: Both the proportion of communication codes and strength of the correlation demonstrated the highest degree of accuracy when a greater number (i.e., six versus four) and duration (i.e., two- versus one-minute) of slices were extracted. CONCLUSION: These results suggest that thin slice sampling may be a useful and accurate strategy to reduce coding burden when coding specific verbal communication behaviors within clinical encounters. PRACTICE IMPLICATIONS: We suggest researchers interested in using thin slice sampling in their own work conduct preliminary research to determine the number and duration of thin slices required to accurately characterize the behaviors of interest. PMID- 25441096 TI - An evaluation of a self-management program for patients with long-term conditions. AB - OBJECTIVE: To evaluate a group-based self-management program (SMP) delivered as part of a quality improvement program, Co-Creating Health, for patients living with one of four long-term conditions (LTCs): chronic obstructive pulmonary disease, depression, diabetes, and musculoskeletal pain. METHODS: The 7 week SMP was co-delivered by lay and health professional tutors. Patients completed self reported outcome measures at pre-course and 6 months follow-up. RESULTS: 486 patients completed (attended >=5 sessions) the SMP and returned pre-course and 6 months follow up data. Patients reported significant improvements in patient activation (ES 0.65, p<0.001), with 53.9% of all patients reporting a meaningful >=4 point improvement. Health-related quality of life (ES 0.06, p=0.04), and health status (ES 0.33, p<0.001) were also significantly improved. Patients' anxiety (ES 0.37, p<0.001) and depression (ES 0.31, p<0.001) significantly improved. Patients also reported significant improvements in their self management skills (p values from p<0.001 to p=0.028). CONCLUSION: Attending the SMP led to improvements in a range of outcomes. Improvement in patient activation is important, as activated patients are more likely to perform self-care activities. PRACTICE IMPLICATIONS: Co-delivered SMPs provide meaningful improvements in activation for >50% of those who complete and are a useful addition to self-management support provision. PMID- 25441097 TI - Looking beyond the face: a training to improve perceivers' impressions of people with facial paralysis. AB - OBJECTIVE: Healthcare providers and lay people alike tend to form inaccurate first impressions of people with facial movement disorders such as facial paralysis (FP) because of the natural tendency to base impressions on the face. This study tested the effectiveness of the first interpersonal sensitivity training for FP. METHODS: Undergraduate participants were randomly assigned to one of two training conditions or an untrained control. Education raised awareness about FP symptoms and experiences and instructed participants to form their impressions based on cues from the body and voice rather than the face. Education+feedback added feedback about the correctness of participants' judgments. Subsequently, participants watched 30s video clips of people with FP and rated their extraversion. RESULTS: Participants' bias and accuracy in the two training conditions did not significantly differ, but they were significantly less biased than controls. Training did not improve the more challenging task of accurately detecting individual differences in extraversion. CONCLUSION: Educating people improves bias, but not accuracy, of impressions of people with FP. PRACTICE IMPLICATIONS: Information from the education condition could be delivered in a pamphlet to those likely to interact with this population such as healthcare providers and educators. PMID- 25441098 TI - Blood pressure, gait speed, and mortality in very old individuals: a population based cohort study. AB - OBJECTIVES: Clinical trials and observational studies have produced contradictory results regarding the association of blood pressure (BP) and mortality in people aged 80 years or older. Gait speed at usual pace has been shown to moderate this association in a population of noninstitutionalized people aged 65 years or older. The aims of this study were to investigate the association of BP with all cause mortality in a representative sample of people aged 85 years or older and to assess whether gait speed moderates this association. DESIGN, SETTING, AND PARTICIPANTS: A total of 806 participants in the population-based prospective Umea 85+/GERDA study aged 85, 90, and 95 years or older. MEASUREMENTS: Gait speed at usual pace was measured over 2.4 m. The main outcome was hazard ratios (HRs) for all-cause mortality according to systolic and diastolic BP categories in the total sample and in faster-walking (>=0.5 m/s, n = 312) and slower-walking (<0.5 m/s, n = 433) subcohorts; the latter also included habitually nonwalking participants. Comprehensive adjustments were made for sociodemographic and clinical characteristics associated with death. RESULTS: Mean age and baseline systolic and diastolic BP were 89.6 +/- 4.6 years, 146.8 +/- 23.9 mm Hg, and 74.8 +/- 11.1 mm Hg, respectively. Most (n = 561 [69%]) participants were women, 315 (39%) were care facility residents, and 566 (70%) were prescribed BP-lowering drugs. Within 5 years, 490 (61%) participants died. In the total sample and slower-walking subcohort, systolic BP appeared to be inversely associated with mortality, although not independent of adjustments. Among faster-walking participants, mortality risk after adjustment was more than 2 times higher in those with systolic BP of 140 to 149 mm Hg (HR = 2.25, 95% confidence interval [CI] = 1.03-4.94) and 165 mm Hg or higher (HR = 2.13, 95% CI = 1.01-4.49), compared with systolic BP of 126 to 139 mm Hg. Mortality risk was also independently higher in faster-walking participants with diastolic BP higher than 80 mm Hg, compared with diastolic BP of 75 to 80 mm Hg (HR = 1.76, 95% CI = 1.07 2.90). CONCLUSION: The gait speed threshold of 0.5 m/s may be clinically useful for the distinction of very old people with and without increased all-cause mortality risk due to elevated systolic and diastolic BP. PMID- 25441099 TI - Factors associated with short-term functional recovery in elderly people with a hip fracture. Influence of cognitive impairment. AB - OBJECTIVES: To assess factors associated with functional recovery and determine the influence of cognitive impairment. DESIGN: Prospective cohort study. SETTING: Orthogeriatric rehabilitation ward. PARTICIPANTS: A total of 314 older adults (>=65 years) admitted for rehabilitation after a hip operation. MEASUREMENTS: Patients were stratified according to the Mini Mental State Examination into the following categories: severe cognitive impairment, scores 0 to 15; mild cognitive impairment, scores 16 to 23; and no cognitive impairment, scores >=24. Their functional status, in terms of activities of daily living (ADLs), was recorded, and their ability to walk was measured with the Functional Ambulation Categories at 3 points in time: basal, on admission, and on discharge. We considered recovery of ADLs and ability to walk to be positive responses to rehabilitation treatment. RESULTS: Of the patients included, 285 finished the study (16 patients were moved to another hospital and 13 patients died) and 280 received rehabilitation treatment, with all 3 groups achieving functional gain (P < .01). Fifty-eight percent of patients recovered both the autonomy in ADLs they had before the fracture and the ability to walk (73.7% without cognitive impairment, 50% mild cognitive impairment, and 5% severe cognitive impairment) (P < .001). Previous walking ability (odds ratio [OR] 5.57, 95% confidence interval [CI] 2.41 12.74) together with the presence of pressure ulcers (OR 11.12, 95% CI 2.88 43.29) and delirium (OR 3.20, 95% CI 1.07-9.52) are sturdier predictive factors for functional recovery than the degree of cognitive impairment (OR 1.12, 95% CI 1.04-1.22). CONCLUSION: Previous walking ability and the presence of complications, such as pressure ulcers or delirium, play a greater role in functional recovery than cognitive impairment. Not considering these aspects could lead to an overestimation of the impact of cognitive impairment in the recovery of these patients. PMID- 25441100 TI - Integrating palliative care in the nursing home: an interprofessional opportunity. PMID- 25441101 TI - Case report: herpes simplex esophagitis in a frail elderly patient. PMID- 25441102 TI - Personalized treatments of cancer patients: a reality in daily practice, a costly dream or a shared vision of the future from the oncology community? AB - Therapies targeting activated oncogenes have been associated with several successes in the last decades that are described in this review, together with their limits and related unsolved questions. Most of the tumours will eventually develop drug resistance potentially due to intratumor heterogeneity and selection of additional molecular events. Moreover, studies in the field of molecular characterisation of cancers have shown that most tumors include large number of rare genomic events. Developing new drugs requires the use of large-scale molecular screening programs to enrich phase I/II trials with patients presenting the genetic alterations to treat them with the appropriate drug(s). Administering one single drug will incur in non-durable results, so the future is to cleverly combine drugs. Development of personalized immunotherapeutics and/or anti angiogenic agents could change the natural history of several cancers. Finally, other systems including DNA repair and metabolism have become targetable. These considerations justify the development of molecular medicine with the characterisation of each tumour to assess defects in all the systems previously mentioned to propose a unique combination of therapies to each patient. Current drug development is clearly not appropriate, and studies with drugs given in relevant combinations should be favoured by new relationships between academia and industry. New organisational and medico-economics approaches are required to minimize the financial burden of personalized medicine by considering the foreseen decrease of the costs of new technologies, and the money saved by avoiding the use of many costly, useless but nonetheless toxic treatments given after failure of standard therapy. PMID- 25441103 TI - Monoclonal gammopathy of renal significance with light-chain deposition disease diagnosed postrenal transplant: a diagnostic and therapeutic challenge. AB - Patients with light-chain deposition disease (LCDD) frequently do not meet criteria for myeloma. In such cases, despite low tumor burden, the circulating monoclonal immunoglobulins cause renal damage, are responsible for post transplant recurrence, and are rightly categorized as monoclonal gammopathy of renal significance (MGRS) requiring chemotherapy. A 65-year male with uncharacterized nodular glomerulopathy presented with proteinuria 3 years postrenal transplant. His allograft biopsies were diagnostic of light-chain deposition disease (likely recurrent), and in the absence of myeloma, he was labeled as MGRS. Based on the limited literature available, he was treated with bortezomib which resulted in normalization of serum-free light-chain ratios and resolution of proteinuria. He, however, later succumbed to complications of chemotherapy. This case highlights the diagnostic difficulties in LCDD, the importance of an accurate pretransplant diagnosis, and treatment of the malignant clone, in the absence of which post-transplant management of recurrence is challenging with poor outcomes. PMID- 25441104 TI - Eliminating treatable deaths due to acute kidney injury in resource-poor settings. AB - Acute kidney injury (AKI) is imposing a severe burden of morbidity and mortality both in developed and developing countries. Also AKI has a major economic impact on healthcare expenditure. This is particularly so in poor countries where AKI especially impacts young productive people, imposing severe penury upon their families. The mission is to lessen the high burden in terms of death consequent to this disorder in low-resource regions, which in many cases is preventable and treatable with simple measures. The International Society of Nephrology has launched a long-term program, called "0 by 25", which advocates that zero people should die of untreated AKI in the poorest part of Africa, Asia, and Latin America by 2025. This paper illustrates how the project will be developed. PMID- 25441105 TI - Allergic contact dermatitis caused by undisclosed thiurams in a patch test tubular net. PMID- 25441109 TI - Serum free light chain response after 2 courses of induction chemotherapy predicts prognosis in myeloma patients. AB - BACKGROUND: The aim of this study was to investigate the prognostic effect of serum free light chain (sFLC) response after 2 cycles of first-line chemotherapy (CT) in multiple myeloma (MM) patients. MATERIALS AND METHODS: The data of 78 newly diagnosed MM patients who had sFLC levels at diagnosis and after 2 cycles of first-line CT were included in the study. The prognostic effect of sFLCs were evaluated with normalization of sFLC kappa/lambda ratio after 2 cycles of CT and involved/uninvolved (i/u) sFLCs. RESULTS: At the end of follow-up the probability of overall survival (OS) was 95.7% versus 68.5% in patients with and without normalized sFLC kappa/lambda ratio, respectively (P = .072). The probability of OS with i/u sFLC assessment was 97.4% versus 55.8% with regard to i/u sFLC <= 10 and > 10, respectively (P = .001). In univariate and multivariate analysis including sFLC ratio, age, sex, and International Staging System, i/u sFLC ratio > 10 after 2 cycles of CT was identified as an independent risk factor for OS (P = .015; hazard ratio [HR], 13.2; 95% confidence interval [CI], 1.668-104.65 vs. P = .011; HR, 15.17; 95% CI, 1.85-123.89). CONCLUSION: Early response assessment in terms of sFLC after 2 courses of induction CT seems to have a prognostic effect in MM patients. The methodology and timing of the evaluation based on sFLCs needs to be validated in prospective studies. PMID- 25441108 TI - A phase I/II study of the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with relapsed or refractory acute myeloid leukemia. AB - BACKGROUND: Ruxolitinib is a potent and specific JAK1/JAK2 inhibitor recently approved for the treatment of myelofibrosis. PATIENTS AND METHODS: We conducted a single-center phase I/II clinical study testing 3 dose levels (50 mg b.i.d. [n = 4], 100 mg b.i.d. [n = 5], and 200 mg b.i.d. [n = 18]). We enrolled 27 patients older than 14 years with relapsed or refractory acute myeloid leukemia (n = 26) or acute lymphoid leukemia (n = 1). RESULTS: The median age was 66 (range, 25-88) years. Thirteen patients were evaluable for dose-limiting toxicities. The most common Grade 3 or 4 nonhematologic event was infection (n = 26 events; most frequently pneumonia; 15 of 26; 58%). One patient with multiple relapses after 7 lines of therapy had a CRp at a ruxolitinib dose of 200 mg b.i.d. CONCLUSION: In this cohort of heavily pretreated patients with relapsed or refractory acute leukemias, ruxolitinib was overall reasonably well tolerated, with 1 patient achieving CRp. PMID- 25441111 TI - Multiple myeloma: a rare case in an 8-year-old child. PMID- 25441112 TI - West nile virus and equine encephalitis viruses: new perspectives. AB - Mosquito-borne diseases affect horses worldwide. Mosquito-borne diseases generally cause encephalomyelitis in the horse and can be difficult to diagnose antemortem. In addition to general disease, and diagnostic and treatment aspects, this review article summarizes the latest information on these diseases, covering approximately the past 5 years, with a focus on new equine disease encroachments, diagnostic and vaccination aspects, and possible therapeutics on the horizon. PMID- 25441110 TI - Progress in acute myeloid leukemia. AB - Significant progress has been made in the treatment of acute myeloid leukemia (AML). Steady gains in clinical research and a renaissance of genomics in leukemia have led to improved outcomes. The recognition of tremendous heterogeneity in AML has allowed individualized treatments of specific disease entities within the context of patient age, cytogenetics, and mutational analysis. The following is a comprehensive review of the current state of AML therapy and a roadmap of our approach to these distinct disease entities. PMID- 25441113 TI - Equine viral arteritis. AB - Equine arteritis virus (EAV), the causative agent of equine viral arteritis (EVA), is a respiratory and reproductive disease that occurs throughout the world. EAV infection is highly species-specific and exclusively limited to members of the family Equidae, which includes horses, donkeys, mules, and zebras. EVA is an economically important disease and outbreaks could cause significant losses to the equine industry. The primary objective of this article is to summarize current understanding of EVA, specifically the disease, pathogenesis, epidemiology, host immune response, vaccination and treatment strategies, prevention and control measures, and future directions. PMID- 25441114 TI - Equine infectious anemia in 2014: live with it or eradicate it? AB - In the absence of an effective vaccine, the success of the test and removal approach for the control of equine infectious anemia (EIA) cannot be overstated, at least in those areas where testing has been traditionally routine. This article addresses 4 main aspects: what has been learned about EIA virus, host control of its replication, and inapparent carriers; international status regarding the control of EIA; diagnostic and laboratory investigation; and reducing the spread of blood-borne infections by veterinarians. An attempt is made to put these issues into practical contemporary perspectives for the equine practitioner. PMID- 25441115 TI - Equine protozoal myeloencephalitis. AB - Equine protozoal myeloencephalitis (EPM) can be caused by either of 2 related protozoan parasites, Sarcocystis neurona and Neospora hughesi, although S. neurona is the most frequent etiologic pathogen. Horses are commonly infected, but clinical disease occurs infrequently; the factors influencing disease occurrence are not well understood. Risk factors for the development of EPM include the presence of opossums and prior stressful health-related events. Attempts to reproduce EPM experimentally have reliably induced antibody responses in challenged horses but have not consistently produced acute neurologic disease. Diagnosis and options for treatment of EPM have improved over the past decade. PMID- 25441117 TI - A farewell and thanks. PMID- 25441116 TI - Infectious diseases of working equids. AB - Most working equids reside in low-income countries where they have an essential role in the livelihoods of their owners. Numerous infectious diseases negatively impact the health and productivity of these animals. There are considerable technical, social-behavioral, and institutional impediments globally to reducing the burden of infectious diseases on working equids. One the greatest remaining challenges is the lack of funding for research, resulting from the low priority assigned to working equids by funding bodies. Changing the attitudes of decision makers will require data-driven advocacy, and global networks of collaborators have a vital role in building this more robust evidence base. PMID- 25441118 TI - New perspectives in infectious diseases. PMID- 25441119 TI - Discrimination of biomechanically possible and impossible hand movements at birth. AB - The development of human body perception has long been investigated, but little is known about its early origins. This study focused on how a body part highly relevant to the human species, namely the hand, is perceived a few days after birth. Using a preferential-looking paradigm, 24- to 48-hr-old newborns watched biomechanically possible and impossible dynamic hand gestures (Experiment 1, N = 15) and static hand postures (Experiment 2, N = 15). In Experiment 1, newborns looked longer at the impossible, compared to the possible, hand movement, whereas in Experiment 2 no visual preference emerged. These findings suggest that early in life the representation of the human body may be shaped by sensory-motor experience. PMID- 25441120 TI - Up-regulation of HP1gamma expression during neuronal maturation promotes axonal and dendritic development in mouse embryonic neocortex. AB - Immature neurons undergo morphological and physiological changes including axonal and dendritic development to establish neuronal networks. As the transcriptional status changes at a large number of genes during neuronal maturation, global changes in chromatin modifiers may take place in this process. We now show that the amount of heterochromatin protein 1gamma (HP1gamma) increases during neuronal maturation in the mouse neocortex. Knockdown of HP1gamma suppressed axonal and dendritic development in mouse embryonic neocortical neurons in culture, and either knockdown or knockout of HP1gamma impaired the projection of callosal axons of superficial layer neurons to the contralateral hemisphere in the developing neocortex. Conversely, forced expression of HP1gamma facilitated axonal and dendritic development, suggesting that the increase of HP1gamma is a rate limiting step in neuronal maturation. These results together show an important role for HP1gamma in promoting axonal and dendritic development in maturing neurons. PMID- 25441121 TI - Ulcerated Spitz nevus masquerading as a juvenile xanthogranuloma. AB - We report a case of ulcerated atypical Spitz nevi that demonstrated a yellow to light orange background under dermoscopy, which can be seen in juvenile xanthogranuloma (JXG) and is referred to as the "setting sun" appearance. This yellow to orange appearance was due to serous crusting and not histiocytic infiltration, which is seen in JXG. This case highlights overlapping dermatoscopic features between the two skin lesions and polymorphous vascular structures, which are unique to atypical Spitz nevi. PMID- 25441129 TI - Lung resection in patients with marginal pulmonary function. AB - The advent of MIS or VATS techniques, better perioperative anesthesia management, and better postoperative care enables thoracic surgeons to operate on marginal patients, with less risk than previously established. Careful preoperative decision making in a multidisciplinary setting should insure that all patients are given the best potential curative option. PMID- 25441130 TI - Surgical resection of lung cancer in the elderly. AB - Assessment for thoracic surgery in elderly patients should be based on physiologic rather than chronologic age. Thoracic surgery has been shown to be safe in selected elderly patients, and age should not be a contraindication to a therapy that offers the best chance of cure for patients with early-stage cancer. A targeted preoperative assessment can help individualize the risk of morbidity and mortality for each patient, and thus provide both surgeon and patient with the information needed for operative decision making. Operative interventions in the elderly require coordinated attention to the specific requirements of the aged. Specialized multidisciplinary care provided by primary care physicians, geriatric specialists, cardiologists, oncologists, surgeons, anesthetists, nurses, physical therapists, and nutrition specialists optimizes care for the elderly patient undergoing thoracic surgery. Careful selection of patients for surgery has contributed to the improvement in operative mortality over time, and refinements in preoperative testing should continue this trend in the future. The goal is to provide surgery to the maximum number of patients at the minimal cost of mortality and loss of independence. PMID- 25441131 TI - Extended chest wall resection and reconstruction in the setting of lung cancer. AB - Reconstruction of large chest wall defects after resection remains a significant undertaking. Obtaining a negative margin is of paramount importance for long-term survival. While reconstructing the chest wall, recreating a stable chest wall with adequate functional capacity and reasonable cosmesis are always the end goals. Morbidity from these procedures is significant, and mortality continues to hover around 5%. With continued advancement in reconstructive techniques and improved perioperative management, these procedures will continue to result in improved outcomes for patients. PMID- 25441132 TI - The management of non-small cell lung cancer with oligometastases. AB - In the absence of persuasive findings from the trials outlined earlier, the available evidence supports treating patients with a solitary site of M1 disease with induction chemotherapy followed by resection of all sites of disease as long as patients understand that this multimodality approach has not been proven to be superior to either surgery alone or chemotherapy alone. PMID- 25441133 TI - Surgery for small cell lung cancer. AB - Small-cell lung cancer (SCLC) comprises approximately 14% of all lung cancer cases. Most patients present with locally advanced or metastatic disease and are therefore treated nonoperatively with chemotherapy, radiotherapy, or both. A small subset of patients with SCLC present with early-stage disease and will benefit from surgical resection plus chemotherapy. The rationale for radiotherapy in these patients remains controversial. PMID- 25441134 TI - Bronchial and arterial sleeve resection after induction therapy for lung cancer. AB - Lobectomy with reconstruction of the bronchus and pulmonary artery is a viable therapeutic option for patients with centrally located non-small cell lung cancer. Preoperative chemotherapy or chemoradiotherapy may represent an additional risk factor for postoperative complications because of increased difficulty in surgical dissection and potential impairment of bronchial healing. Although limited data are available in the literature in this setting, a few published studies have reported the possibility of performing even complex bronchovascular reconstructions after neoadjuvant treatment with no increased morbidity and mortality. This article discusses the main technical details and data from the literature. PMID- 25441135 TI - Advanced lung cancer: aggressive surgical therapy vertebral body involvement. AB - The NOMS considerations provide a dynamic decision framework to determine the optimal combination of systemic and radiation therapies and surgery. Generally, NSCLC metastases to the spine require SRS because cEBRT usually fails to provide consistent long-term local control. Patients with spinal cord compression secondary to NSCLC require surgical decompression to safely undergo SRS and to reduce the risk of radiation-induced spinal cord injury. Separation surgery allows spinal cord decompression and spinal stabilization using the posterior approach and, in combination with SRS, has been shown to provide reliable local control with low risk of wound complication or spinal hardware fracture. PMID- 25441137 TI - Superior vena caval resection in lung cancer. AB - Lung cancer with involvement of the SVC is uncommon but presents a unique management challenge. Discovery of N2 disease should be given its due diligence and these patients should undergo induction therapy. Patients can attain favorable long-term outcomes with surgery, but they need to be carefully selected at specialized centers. PMID- 25441136 TI - Pulmonary resection after pneumonectomy. AB - Limited lung resection for second primary lung cancer after pneumonectomy is a worthwhile procedure in appropriately selected patients because it carries a low operative risk and allows for longterm survival with good quality of life. Operations for metachronous cancers had a survival benefit that approximated the expected survival for primary lung cancer. The prognosis is poor for patients with N2 status and for those treated by second surgery earlier than 2 years after the first procedure. Careful selection of potential candidates for remaining lung surgery with special attention to functional cardiopulmonary reserve and lung cancer extension is mandatory for optimal early postoperative results and a long term beneficial effect. Wedge resection with negative margins is the preferred procedure for peripheral tumors. Central tumors would benefit more from segmentectomy. With the exception of middle lobectomy, lobectomy should be avoided because of its negative impact on cardiopulmonary reserve and outcomes. In highly selected patients, surgical resection of a second primary NSCLC after pneumonectomy following these principles may achieve a 5-year survival rate of up to 63%. SBRT has shown promising early results as an alternative to surgical resection in inoperable patients. PMID- 25441138 TI - Surgical resection of non-small cell lung cancer with N2 disease. AB - Mediastinal node involvement is the primary determinant for IIIA disease in NSCLC. It is locally advanced disease and curable, but remains a significant treatment challenge. There is no single treatment paradigm appropriate for all patients. The role for surgery is dictated by the ability to perform an R0 resection and by the extent of mediastinal node involvement. For most patients with N2 disease, induction therapy is recommended and survival is closely linked to the response to that treatment. Many believe that a trimodality approach using a combination of chemotherapy, radiation, and surgery provides the best hope for cure, but safety and success is highly dependent on careful patient selection and meticulous treatment delivery. PMID- 25441139 TI - Extended resections of non-small cell lung cancers invading the aorta, pulmonary artery, left atrium, or esophagus: can they be justified? AB - T4 tumors that invade the heart, great vessels, or esophagus comprise a heterogenous group of locally invasive lung cancers. Prognosis depends on nodal status; this relationship has been consistently demonstrated in many of the small series of extended resection. Current National Comprehensive Cancer Network guidelines do not recommend surgery for T4 extension with N2-3 disease (stage IIIB). However, biopsy-proven T4 N0-1 (stage IIIA) may be operable. Localized tumors with invasion of the aorta, pulmonary artery, left atrium, or esophagus represent a small subset of T4 disease. Acquiring sufficient randomized data to provide statistical proof of a survival advantage for patients undergoing extended resections for these neoplasms will likely never be possible.Therefore, we are left to critically analyze current documented experience to make clinical decisions on a case-by-case basis.It is clear that the operative morbidity and mortality of extended resections for locally advanced T4 tumors have significantly improved over time,yet the risks are still high. The indications for such procedures and the anticipated outcomes should be clearly weighed in terms of potential perioperative complications and expertise of the surgical team. Patients with T4 N0-1 have the best prognosis and with complete resection may have the potential for cure. The use of induction therapy and surgery for advanced T4 tumors may improve survival. Current data suggest that for tumors that invade the aorta, pulmonary artery,left atrium, or esophagus, resection should be considered in relation to multidisciplinary care.For properly selected patients receiving treatment at high volume, experienced centers, extended resections may be warranted. PMID- 25441140 TI - Video-assisted thoracoscopic (VATS) lobectomy after induction therapy. AB - Concerns regarding the sequelae of neoadjuvant chemotherapy or chemoradiotherapy on the pleural space and tissue planes had previously deterred the application of video-assisted thoracoscopic (VATS) lobectomy for patients who underwent neoadjuvant therapy. As experience with VATS has increased, however, its application toward more technically demanding operations has also expanded. The diminished impact on pulmonary function associated with the VATS approach may make pulmonary resection more tolerable in compromised patients. This article describes an approach designed for maximal safety on carefully selected patients who have undergone induction therapy. PMID- 25441141 TI - Extrapleural pneumonectomy for pleural malignancies. AB - Although originally performed on patients with refractory tuberculosis and malignant pleural mesothelioma, extrapleural pneumonectomy may be used to treat patients with pleural dissemination of other malignancies, including thymoma and NSCLC. Patients who present with stage IV NSCLC caused by malignant pleural effusion may be considered for EPP following induction chemotherapy if they demonstrate no mediastinal nodal or distant metastases and have adequate cardiopulmonary reserve. EPP for NSCLC should be performed by experienced teams at experienced centers to minimize the morbidity and mortality associated with this radical procedure. Additional prospective studies are needed to better characterize the role of EPP in the multimodality treatment of patients with pleural dissemination of malignancy, including NSCLC. PMID- 25441142 TI - Carinal resection. AB - Carinal resections and reconstructions, with or without lung resection, are challenging operations that may be indicated in less than 1% of operable patients with NSCLC or benign lesions involving the carina. These operations are completed in only a few centers worldwide, likely because of their technical complexity and the general opinion about their limited patient benefit. However, good survival results can be expected in pN0 or pN1 patients so that, in experienced hands, these operations are effective options. The risk of postoperative complications can be minimized by several intraoperative and postoperative precautions. PMID- 25441143 TI - Lung transplantation for multifocal lung adenocarcinoma (multifocal lung carcinoma). AB - Lung transplantation is an acceptable treatment option in highly selected patients with lung limited AIS or MIA. Aside from the cancer diagnosis, ideal candidates should not possess any absolute or relative contraindications to lung transplantation as described by the ISHLT. Confirmation of lung-limited disease and AIS/MIA with lepidic histology and the absence of carcinoma metastatic to mediastinal lymph nodes will optimize outcomes. Those patients with multifocal minimally invasive lung ACA and respiratory insufficiency from severe bronchorrhea may enjoy the best palliation of their disease and have high enough LAS to facilitate transplantation. The role of targeted therapies for those patients with EGFR or ALK-activating mutations and might favorably AIS/MIA has yet to be determined and impact survival and augment (or supplant) lung transplantation for these patients. PMID- 25441144 TI - Advanced lung cancer: radical surgical therapy. PMID- 25441145 TI - The neuroscience of psychological treatments. AB - The series of articles in this issue of Behavior Research and Therapy presages a new field of translational research that could be called "the neuroscience of psychological treatments". After a brief retrospective on the origins and promise of this focus of study several cautions are adumbrated. As in any new field of scientific endeavor, close collaboration among stakeholders with interest in this field and the integration of a healthy scientific skepticism will best ensure the continued development of ever more powerful psychological treatments. PMID- 25441149 TI - The Swiss Continence Foundation Award: promoting the next generation in neuro urology and functional urology. PMID- 25441150 TI - Extracts of Actinidia arguta stems inhibited LPS-induced inflammatory responses through nuclear factor-kappaB pathway in Raw 264.7 cells. AB - The inflammatory response protects our body from bacteria and tumors, but chronic inflammation driven by the persistent activation of macrophages can lead to serious adverse effects including gastrointestinal problems, cardiac disorders, and a sore throat. Part of the ongoing research is focused on searching for antiinflammatory compounds from natural sources, so we investigated the effects of hardy kiwis (Actinidia arguta, Lauraceae) stems on inflammation induced by lipopolysaccharide (LPS) in Raw 264.7 cells to test the hypothesis that antiinflammatory effects of A. arguta stems were exerted through the inhibition of the nuclear factor (NF)-kappaB pathway. The methanol extract of A. arguta (20 MUg/mL) stems lowered nitric oxide production in LPS-stimulated Raw 264.7 cells by 40%. It was then partitioned with hexane, chloroform, ethyl acetate, butanol, and water based on the polarity of each compound. Among the 5 layers, the chloroform layer had the greatest inhibitory effect on LPS-stimulated nitric oxide production and inducible nitric oxide synthase mRNA expression in Raw 264.7 cells. However, the levels of prostaglandin E2 and cyclooxygease 2 were not altered. On the other hand, treatment of cells with the chloroform layer of A. arguta before LPS stimulation also reduced them RNA expression of proinflammatory cytokines including tumor necrosis factor alpha and interleukin 1beta. Nuclear translocation of NF-kappaB p50 and p65 subunits induced by LPS was also inhibited by treatment with the chloroform layer of A. arguta. This was accompanied with the reduced phosphorylation of mitogen-activated protein kinases including extracellular signal-regulated protein kinase 1/2, c-Jun N-terminal protein kinase, and p38. Taken together, these results suggest that chloroform layer of A. arguta exerted antiinflammatory effects by the inhibition of mitogen-activated protein kinase phosphorylation and nuclear translocation of NF-kappaB. PMID- 25441151 TI - Induction of labour and intrapartum care in obese women. AB - The rising incidence of obesity in pregnancy has a significant impact on the provision of health services around the world. Due to the pathophysiological processes associated with the condition, the obese pregnant woman is at increased risks of induction of labour, caesarean section, post-partum haemorrhage, infection, longer hospital stay, macrosomia and higher perinatal morbidity and mortality. Labour is more likely to be prolonged and dysfunctional, leading to the requirements for higher doses of oxytocin and increased risks of operative deliveries and morbidity. A multidisciplinary approach to the planning of antenatal, intrapartum and postnatal care is vital to ensure a safe outcome for the obese pregnant woman and her baby. The need for supervision and attendance by senior obstetric staff is increased, emphasising the need to identify the appropriate place of birth for this high-risk group of women, placing a significant strain on the resources of health-care providers. PMID- 25441152 TI - Inhibition-induced plasticity in tinnitus patients after repetitive exposure to tailor-made notched music. AB - OBJECTIVE: Notch-filtered music has been shown to induce frequency-specific inhibition. Here, we investigated which cortical structures are affected by tailor-made notched music (TMNM) in tinnitus patients and how this inhibition induced plasticity develops over time. METHODS: Nine subjects suffering from chronic tonal tinnitus listened to music passing through a notch-filter centered at the patient's individual tinnitus frequency (TMNM) for three hours on three consecutive days. Before and after each listening session, a tone at the tinnitus frequency and a control tone of 500 Hz were presented in the magnetoencephalograph. Subjective tinnitus loudness was measured via visual analog scales. RESULTS: TMNM exposure reduced subjective tinnitus loudness and neural activity evoked by the tinnitus tone in temporal, parietal and frontal regions within the N1m time interval. Reduction of temporal and frontal activation correlated significantly with tinnitus loudness decline. Reduction of tinnitus related neural activity persisted and accumulated over three days. CONCLUSIONS: Inhibition-induced plasticity occurs in a cortical network, known to be crucial for tinnitus perception. This cortical reorganization evolves fast and accumulates across sessions. SIGNIFICANCE: This study extends previous work on inhibition-induced plasticity, as it demonstrates the involvement of parietal and frontal areas and discovers a cumulative effect of cortical reorganization in tinnitus patients. PMID- 25441154 TI - Monitoring electrochemical reactions in situ using steady-state free precession (13)C NMR spectroscopy. AB - All attempts to use in situ(13)C NMR in spectroelectrochemical studies, using static cells and unlabeled substrates, have failed due to the very long average time (several hours). In this paper, we demonstrated that steady-state free precession (SSFP) pulse sequence can enhance signal to noise ratio and reduces the average time of (13)C NMR signals by more than one order of magnitude. The results showed that each (13)C NMR spectrum during the electrochemical reduction of 9-chloroanthracene, in a static cell, can be acquired in eleven minutes. This short averaging time allowed the analysis of the reaction every 30min during 3h. The phase and truncation anomalies present in SSFP spectra were minimized using Traff apodization function and Krylov basis diagonalization method (KBDM). PMID- 25441153 TI - Probability distributions of the electroencephalogram envelope of preterm infants. AB - OBJECTIVE: To determine the stationary characteristics of electroencephalogram (EEG) envelopes for prematurely born (preterm) infants and investigate the intrinsic characteristics of early brain development in preterm infants. METHODS: Twenty neurologically normal sets of EEGs recorded in infants with a post conceptional age (PCA) range of 26-44 weeks (mean 37.5 +/- 5.0 weeks) were analyzed. Hilbert transform was applied to extract the envelope. We determined the suitable probability distribution of the envelope and performed a statistical analysis. RESULTS: It was found that (i) the probability distributions for preterm EEG envelopes were best fitted by lognormal distributions at 38 weeks PCA or less, and by gamma distributions at 44 weeks PCA; (ii) the scale parameter of the lognormal distribution had positive correlations with PCA as well as a strong negative correlation with the percentage of low-voltage activity; (iii) the shape parameter of the lognormal distribution had significant positive correlations with PCA; (iv) the statistics of mode showed significant linear relationships with PCA, and, therefore, it was considered a useful index in PCA prediction. CONCLUSION: These statistics, including the scale parameter of the lognormal distribution and the skewness and mode derived from a suitable probability distribution, may be good indexes for estimating stationary nature in developing brain activity in preterm infants. SIGNIFICANCE: The stationary characteristics, such as discontinuity, asymmetry, and unimodality, of preterm EEGs are well indicated by the statistics estimated from the probability distribution of the preterm EEG envelopes. PMID- 25441155 TI - Recent advances in sample preparation techniques and methods of sulfonamides detection - A review. AB - Sulfonamides (SAs) have been the most widely used antimicrobial drugs for more than 70 years, and their residues in foodstuffs and environmental samples pose serious health hazards. For this reason, sensitive and specific methods for the quantification of these compounds in numerous matrices have been developed. This review intends to provide an updated overview of the recent trends over the past five years in sample preparation techniques and methods for detecting SAs. Examples of the sample preparation techniques, including liquid-liquid and solid phase extraction, dispersive liquid-liquid microextraction and QuEChERS, are given. Different methods of detecting the SAs present in food and feed and in environmental, pharmaceutical and biological samples are discussed. PMID- 25441156 TI - Sarcosine oxidase composite screen-printed electrode for sarcosine determination in biological samples. AB - As the prostate cancer (PCa) progresses, sarcosine levels increase both in tumor cells and urine samples, suggesting that this metabolite measurements can help in the creation of non-invasive diagnostic methods for this disease. In this work, a biosensor device was developed for the quantification of sarcosine via electrochemical detection of H2O2 (at 0.6V) generated from the catalyzed oxidation of sarcosine. The detection was carried out after the modification of carbon screen printed electrodes (SPEs) by immobilization of sarcosine oxidase (SOX) on the electrode surface. The strategies used herein included the activation of the carbon films by an electrochemical step and the formation of an NHS/EDAC layer to bond the enzyme to the electrode, the use of metallic or semiconductor nanoparticles layer previously or during the enzyme immobilization. In order to improve the sensor stability and selectivity a polymeric layer with extra enzyme content was further added. The proposed methodology for the detection of sarcosine allowed obtaining a limit of detection (LOD) of 16nM, using a linear concentration range between 10 and 100nM. The biosensor was successfully applied to the analysis of sarcosine in urine samples. PMID- 25441157 TI - A label-free and high sensitive aptamer biosensor based on hyperbranched polyester microspheres for thrombin detection. AB - In this paper, we have synthesized hyperbranched polyester microspheres with carboxylic acid functional groups (HBPE-CA) and developed a label-free electrochemical aptamer biosensor using thrombin-binding aptamer (TBA) as receptor for the measurement of thrombin in whole blood. The indium tin oxide (ITO) electrode surface modified with HBPE-CA microspheres was grafted with TBA, which has excellent binding affinity and selectivity for thrombin. Binding of the thrombin at the modified ITO electrode surface greatly restrained access of electrons for a redox probe of [Fe(CN)6](3-/4-). Moreover, the aptamer biosensor could be used for detection of thrombin in whole blood, a wide detection range (10fM-100nM) and a detection limit on the order of 0.90fM were demonstrated. Control experiments were also carried out by using bull serum albumin (BSA) and lysozyme in the absence of thrombin. The good stability and repeatability of this aptamer biosensor were also proved. We expect that this demonstration will lead to the development of highly sensitive label-free sensors based on aptamer with lower cost than current technology. The integration of the technologies, which include anticoagulant, sensor and nanoscience, will bring significant input to high-performance biosensors relevant to diagnostics and therapy of interest for human health. PMID- 25441158 TI - A novel poly(3,4-ethylenedioxythiophene)-ionic liquid composite coating for the headspace solid-phase microextraction and gas chromatography determination of several alcohols in soft drinks. AB - A novel poly(3,4-ethylenedioxythiophene)-ionic liquid (i.e., 1-hydroxyethyl-3 methyl imidazolium-bis[(trifluoromethyl)sulfonyl]imide) composite film was electrodeposited on a Pt wire for headspace solid-phase microextraction. The film showed nodular structure and had large specific surface. In addition, it displayed high thermal stability (up to 300 degrees C) and durable property (could be used for more than 200 times). Coupled with gas chromatography-flame ionization detection, the resulting fiber was applied to the headspace solid phase microextraction and determination of several alcohols (i.e., linalool, nonanol, terpineol, geraniol, decanol and dodecanol). It presented higher extraction capability in comparison with the poly(3,4-ethylenedioxythiophene) and commercial polydimethylsiloxane/divinylbenzene fiber. Under the optimized conditions, the linear ranges exceeded three magnitudes with correlation coefficients above 0.9952 and the low limits of detection were 34.2-81.3ng L(-1). For different alcohols the repeatabilities (defined as RSD) were <5.8% and <7.8% for single fiber (n=5) and fiber-to-fiber (n=4), respectively. The proposed method was applied to the determination of these alcohols in real samples with acceptable recoveries from 81.1% to 106.6%. PMID- 25441159 TI - A novel hierarchical nanobiocomposite of graphene oxide-magnetic chitosan grafted with mercapto as a solid phase extraction sorbent for the determination of mercury ions in environmental water samples. AB - New mercapto-grafted graphene oxide-magnetic chitosan (GO-MC) has been developed as a novel biosorbent for the preconcentration and extraction of mercury ion from water samples. A facile and ecofriendly synthesis procedure was also developed for modification of GO-MC with 3-mercaptopropyltrimethoxysilane. The prepared nanocomposite material (mercapto/GO-MC) was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR) and energy-dispersive X-ray spectroscopy (EDX). The mercury analysis was performed by continuous-flow cold vapor atomic absorption spectrometry. The parameters affecting the extraction and preconcentration processes were carried out. The optimum conditions were found to be 60mg of sorbent, pH of 6.5, 10min for adsorption time, 3mL of HCl (0.1mol L(-1))/thiourea (2% w/v) as the eluent and 250mL for breakthrough volume. An excellent linearity was achieved in the range of 0.12-80ng mL(-1) (R(2)=0.999) at a preconcentration factor of 80. The limit of detection and quantification were achieved as 0.06ng mL(-1) and 0.12ng mL(-1), respectively. A good repeatability was obtained with the relative standard deviation (RSD) of 4.7%. Furthermore, real water samples were analyzed and good recoveries were obtained from 95 to 100%. PMID- 25441161 TI - Expanding the linear dynamic range for quantitative liquid chromatography-high resolution mass spectrometry utilizing natural isotopologue signals. AB - The linear dynamic range (LDR) for quantitative liquid chromatography-mass spectrometry can be extended until ionization saturation is reached by using a number of target isotopologue ions in addition to the normally used target ion that provides the highest sensitivity. Less abundant isotopologue ions extend the LDR: the lower ion abundance decreases the probability of ion detector saturation. Effectively the sensitivity decreases and the upper limit of the LDR increases. We show in this paper that the technique is particularly powerful with a high resolution time of flight mass spectrometer because the data for all ions are automatically acquired, and we demonstrated this for four small organic molecules; the upper limits of LDRs increased by 25-50 times. PMID- 25441160 TI - Multi-detection method for five common microalgal toxins based on the use of microspheres coupled to a flow-cytometry system. AB - Freshwater and brackish microalgal toxins, such as microcystins, cylindrospermopsins, paralytic toxins, anatoxins or other neurotoxins are produced during the overgrowth of certain phytoplankton and benthic cyanobacteria, which includes either prokaryotic or eukaryotic microalgae. Although, further studies are necessary to define the biological role of these toxins, at least some of them are known to be poisonous to humans and wildlife due to their occurrence in these aquatic systems. The World Health Organization (WHO) has established as provisional recommended limit 1MUg of microcystin-LR per liter of drinking water. In this work we present a microsphere-based multi detection method for five classes of freshwater and brackish toxins: microcystin LR (MC-LR), cylindrospermopsin (CYN), anatoxin-a (ANA-a), saxitoxin (STX) and domoic acid (DA). Five inhibition assays were developed using different binding proteins and microsphere classes coupled to a flow-cytometry Luminex system. Then, assays were combined in one method for the simultaneous detection of the toxins. The IC50's using this method were 1.9+/-0.1MUg L(-1) MC-LR, 1.3+/-0.1MUg L(-1) CYN, 61+/-4MUg L(-1) ANA-a, 5.4+/-0.4MUg L(-1) STX and 4.9+/-0.9MUg L(-1) DA. Lyophilized cyanobacterial culture samples were extracted using a simple procedure and analyzed by the Luminex method and by UPLC-IT-TOF-MS. Similar quantification was obtained by both methods for all toxins except for ANA-a, whereby the estimated content was lower when using UPLC-IT-TOF-MS. Therefore, this newly developed multiplexed detection method provides a rapid, simple, semi quantitative screening tool for the simultaneous detection of five environmentally important freshwater and brackish toxins, in buffer and cyanobacterial extracts. PMID- 25441162 TI - A sensitive and selective detection method for thiol compounds using novel fluorescence probe. AB - In this work, a sensitive and selective detection method based on fluorescence resonance energy transfer (FRET) was developed for analyzing thiol compounds by using a novel fluorescent probe. The new fluorescent probe contains a disulfide bond which selectively reacts with nucleophilic thiolate through the thiol disulfide exchange reaction. An obvious fluorescence recovery can be observed upon addition of the thiol compound in the fluorescent probe solution due to the thiol-disulfide exchange reaction and the destruction of FRET. This novel probe was successfully used to determine dithiothreitol (DTT), glutathione (GSH) and cysteine (Cys). The limits of detection (LOD) were 2.0MUM for DTT, 0.6MUM for GSH, and 0.8MUM for Cys. This new detection method was further investigated in the analysis of compound amino acid injection. PMID- 25441163 TI - Ag nanoclusters as probes for turn-on fluorescence recognition of TpG dinucleotide with a high selectivity. AB - CpG dinucleotide in DNA has a great tendency to mutate to TpG dinucleotide and this transition can cause some serious diseases. In this work, fluorescent Ag nanoclusters (Ag NCs) were employed as useful inorganic fluorophores for the potential of selectively discriminating TpG dinucleotide from CpG dinucleotide. Opposite the base Y of interest in YpG dinucleotide (Y=C or T), a bulge site was introduced so as to make the base Y to be unpaired and ready for Ag(+) binding. Such that the unpaired Y and context base pairs can provide a specific space suitable for creating fluorescent Ag NCs. We found that in comparison with CpG dinucleotide, TpG dinucleotide is much more efficient in growing fluorescent Ag NCs. Therefore, mutation of CpG dinucleotide to TpG can be identified by a turn on fluorescence response and a high selectivity. More interestingly, Ag NCs exhibit a better performance in the TpG recognition over the other dinucleotides (Y=A and G) than the previously used organic fluorophores. Additionally, the effectiveness of the bulge site design in discriminating these dinucleotides was evidenced by control DNAs having the abasic site structure. We expect that a practical method for TpG dinucleotide recognition with a high selectivity can be developed using the bulge site-grown fluorescent Ag NCs as novel probes. PMID- 25441164 TI - Early diagnosis of blast fungus, Magnaporthe oryzae, in rice plant by using an ultra-sensitive electrically magnetic-controllable electrochemical biosensor. AB - As one of the most destructive and widespread disease of rice, Magnaporthe oryzae (also called Magnaporthe grisea) has a significant negative impact on rice production. Therefore, it is still in high demand to develop extremely sensitive and accurate methods for the early diagnosis of Magnaporthe oryzae (M. oryzae). In this study, we developed a novel magnetic-controllable electrochemical biosensor for the ultra sensitive and specific detection of M. oryzae in rice plant by using M. oryzae's chitinases (Mgchi) as biochemical marker and a rice (Oryza sativa) cDNA encoding mannose-binding jacalin-related lectin (Osmbl) as recognition probe. The proposed biosensor combined with the merits of chronoamperometry, electrically magnetic-controllable gold electrode and magnetic beads (MBs)-based palladium nano-particles (PdNPs) catalysis amplification, has an ultra-high sensitivity and specificity for the detection of trace M. oryzae in rice plant. It could be used to detect M. oryzae in rice plant in the initial infection stage (before any symptomatic lesions were observed) to help farmers timely manage the disease. In comparison with previous methods, the proposed method has notable advantages such as higher sensitivity, excellent specificity, short analysis time, robust resistibility to complex matrix and low cost etc. The success in this study provides a reliable approach for the early diagnosis and fast screening of M. oryzae in rice plant. PMID- 25441165 TI - Quantification of residual solvents in antibody drug conjugates using gas chromatography. AB - The detection and quantification of residual solvents present in clinical and commercial pharmaceutical products is necessary from both patient safety and regulatory perspectives. Head-space gas chromatography is routinely used for quantitation of residual solvents for small molecule APIs produced through synthetic processes; however residual solvent analysis is generally not needed for protein based pharmaceuticals produced through cultured cell lines where solvents are not introduced. In contrast, antibody drug conjugates and other protein conjugates where a drug or other molecule is covalently bound to a protein typically use solvents such as N,N-dimethylacetamide (DMA), N,N dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or propylene glycol (PG) to dissolve the hydrophobic small molecule drug for conjugation to the protein. The levels of the solvent remaining following the conjugation step are therefore important to patient safety as these parental drug products are introduced directly into the patients bloodstream. We have developed a rapid sample preparation followed by a gas chromatography separation for the detection and quantification of several solvents typically used in these conjugation reactions. This generic method has been validated and can be easily implemented for use in quality control testing for clinical or commercial bioconjugated products. PMID- 25441166 TI - Effectiveness of extracorporeal shock wave lithotripsy to treat dystrophic calcinosis cutis ulcers. PMID- 25441170 TI - Cognitive behavioural treatment for the chronic post-traumatic headache patient: a randomized controlled trial. AB - BACKGROUND: Chronic post-traumatic headache (CPTH) after mild head injury can be difficult to manage. Research is scarce and successful interventions are lacking.To evaluate the effect of a group-based Cognitive Behavioural Therapy (CBT) intervention in relation to headache, pain perception, psychological symptoms and quality of life in patients with CPTH. METHODS: Ninety patients with CPTH according to ICHD-2 criteria were enrolled from the Danish Headache Center into a randomized, controlled trial. Patients were randomly assigned to either a waiting list group or to a nine-week CBT group intervention. At baseline and after 26 weeks all patients completed the Rivermead Post Concussion Symptoms Questionnaire, SF-36, SCL-90-R and a headache diary. RESULTS: The CBT had no effect on headache and pressure pain thresholds and only a minor impact on the CPTH patients' quality of life, psychological distress, and the overall experience of symptoms. The waiting-list group experienced no change in headache but, opposed to the treatment group, a significant decrease in somatic and cognitive symptoms indicating a spontaneous remission over time. CONCLUSIONS: Our primarily negative findings confirm that management of patients with CPTH still remains a considerable challenge. Psychological group therapy with CBT might be effective in an earlier stage of CPTH and in less severely affected patients but our findings strongly underline the need for randomized controlled studies to test the efficacy of psychological therapy. PMID- 25441171 TI - Estimation of skull table thickness with clinical CT and validation with microCT. AB - Brain injuries resulting from motor vehicle crashes (MVC) are extremely common yet the details of the mechanism of injury remain to be well characterized. Skull deformation is believed to be a contributing factor to some types of traumatic brain injury (TBI). Understanding biomechanical contributors to skull deformation would provide further insight into the mechanism of head injury resulting from blunt trauma. In particular, skull thickness is thought be a very important factor governing deformation of the skull and its propensity for fracture. Current computed tomography (CT) technology is limited in its ability to accurately measure cortical thickness using standard techniques. A method to evaluate cortical thickness using cortical density measured from CT data has been developed previously. This effort validates this technique for measurement of skull table thickness in clinical head CT scans using two postmortem human specimens. Bone samples were harvested from the skulls of two cadavers and scanned with microCT to evaluate the accuracy of the estimated cortical thickness measured from clinical CT. Clinical scans were collected at 0.488 and 0.625 mm in plane resolution with 0.625 mm thickness. The overall cortical thickness error was determined to be 0.078 +/- 0.58 mm for cortical samples thinner than 4 mm. It was determined that 91.3% of these differences fell within the scanner resolution. Color maps of clinical CT thickness estimations are comparable to color maps of microCT thickness measurements, indicating good quantitative agreement. These data confirm that the cortical density algorithm successfully estimates skull table thickness from clinical CT scans. The application of this technique to clinical CT scans enables evaluation of cortical thickness in population-based studies. PMID- 25441172 TI - Admission blood glucose predicted haemorrhagic shock in multiple trauma patients. AB - INTRODUCTION: Admission blood glucose is known to be a predictor for outcome in several disease patterns, especially in critically ill trauma patients. The underlying mechanisms for the association of hyperglycaemia and poor outcome are still not proven. It was hypothesised that hyperglycaemia upon hospital admission is associated with haemorrhagic shock and in-hospital mortality. METHODS: Data was extracted from an observational trauma database of the level 1 trauma centre at Innsbruck Medical University hospital. Trauma patients (>=18 years) with multiple injuries and an Injury Severity Score >=17 were included and analysed. RESULTS: In total, 279 patients were analysed, of which 42 patients (15.1%) died. With increasing blood glucose upon hospital admission, the rate of patients with haemorrhagic shock rose significantly [from 4.4% (glucose 4.1-5.5mmol/L) to 87.5% (glucose >15mmol/L), p<0.0001]. Mortality was also associated with initial blood glucose [<=5.50mmol/L 8.3%; 5.51-7.50mmol/L 10.9%, 7.51-10mmol/L 12.4%; 10.01 15mmol/L 32.0%; >=15.01mmol/L 12.5%, p=0.008]. Admission blood glucose was a better indicator for haemorrhagic shock (cut-off 9.4mmol/L, sensitivity 67.1%, specificity 83.9%) than haemoglobin, base excess, bicarbonate, pH, lactate, or vital parameters. Regarding haemorrhagic shock, admission blood glucose is more valuable during initial patient assessment than the second best predictive parameter, which was admission haemoglobin (cut-off value 6.5mmol/L (10.4g/dL): sensitivity 61.3%, specificity 83.9%). CONCLUSIONS: In multiple trauma, non diabetic patients, admission blood glucose predicted the incidence of haemorrhagic shock. Admission blood glucose is an inexpensive, rapidly and easily available laboratory value that might help to identify patients at risk for haemorrhagic shock during initial evaluation upon hospital admission. PMID- 25441173 TI - Restoration of the volar cortex: predicting instability after manipulation of distal radial fractures. AB - INTRODUCTION: Distal radial fractures are one of the most common fractures that are presented to the emergency department (ed). The management of non-emergent cases often involves closed reduction and immobilisation before referral to orthopaedic services. Surgical intervention is offered based on the criteria for instability. This can be predicted from the initial and post-manipulation radiographs. The purpose of this study was to assess the role of various predictors of instability in the requirement for surgery, based on specific evidence-based criteria. PATIENTS AND METHOD: We audited 87 consecutive distal radial fractures that had been manipulated by the ED and analysed what factors predicted instability. RESULTS: The most significant predictor of instability and hence further surgery was the failure to anatomically restore the volar cortex (VC) (p = 0.002) during the manipulation. Other significant factors were increasing age (p = 0.006) and fracture of the ulna styloid (p = 0.028). If the VC was restored or remained intact during the manipulation, only 38% required further surgery. If the VC was displaced or not restored, 65% required further surgery. CONCLUSION: The restoration or maintenance of volar cortical alignment during the manipulation of distal radial fractures offers patients the best chance of avoiding the need for further surgery. This factor should be taken into account in the decision-making process for these fractures. PMID- 25441174 TI - Quadriceps tendon rupture in maintenance haemodialysis patients: results of surgical treatment and analysis of risk factors. AB - BACKGROUND: Reports of spontaneous quadriceps ruptures in end-stage renal disease (ESRD) patients are scarce, and the assessment of risk factors for tendon rupture is poorly addressed in the majority of the studies. The purpose of the present study is to report a series of patients on haemodialysis with spontaneous quadriceps tendon ruptures operated at our institution. The results of the surgical treatment are described and the potential risk factors associated with the rupture are analyzed. METHODS: Our study consisted of retrospective analysis of patient's charts. Clinical and laboratory findings of the operated group were compared to the ones of a control group of haemodialysis patients matched by age, gender, and time on haemodialysis, but without tendon rupture. RESULTS: Between 1998 and 2010, six ESRD patients with 11 spontaneous ruptures of the quadriceps tendon were treated at our institution. On postoperative evaluation all patients were able to walk without crutches after six months of follow-up, and there were no new ruptures. Positive serology for Hepatitis C was present in two cases (33%) but in none of the controls (p = 0.034). Mean serum levels of intact parathormone (iPTH) and alkaline phosphatase were both higher in cases (p = 0.013 and p = 0.034, respectively). In contrast, mean serum levels of albumin, ferritin and haemoglobin were all lower in cases (p = 0.008, p = 0.043 and p = 0.016, respectively). CONCLUSION: Reconstructive surgery is a good way to restore knee function in ESRD patients with quadriceps tendon ruptures. Our cases exhibited higher levels of iPTH and alkaline phosphatase than control patients, reinforcing the role of secondary hyperparathyroidism in tendon weakening. They also had a higher frequency of hepatitis C and lower levels of albumin and haemoglobin compared to controls, possibly implicating chronic inflammation as a potential risk factor for tendon rupture. PMID- 25441175 TI - Elevated serum creatine phosphokinase is associated with mortality and inotropic requirement in critically injured adults. AB - BACKGROUND: Hemeproteins such as free myoglobin can undergo autoxidation and catalyse lipid peroxidation, increasing oxidative stress. Creatine phosphokinase (CPK) elevation is a marker for free myoglobin after myocyte damage. Since oxidative injury is a key mechanism of injury-related organ dysfunction, we hypothesised that serum CPK levels correlate with mortality and need for inotropic medication and duration of inotropic support, i.e. shock, among critically injured patients. METHODS: We conducted a retrospective review of 17,847 patients admitted to a single Trauma Intensive Care Unit over 9 years. 2583 patients with serum CPK levels were included in the analysis. Patient data were collected continuously into an electronic ICU repository. Univariate analysis was accomplished using Spearman correlation and the Mann-Whitney U test. Propensity score adjustment models accounting for potential confounders were used to assess the independent effect of CPK level on mortality, need for inotropic support, and duration of inotropic support. RESULTS: Median CPK was significantly higher in patients who died (916 [IQR 332, 2472] vs. 711 [253, 1971], p = 0.004) and in those who required inotropic medications (950 [353, 2525] vs. 469 [188, 1220], p < 0.001). After adjusting for propensity score and potential confounders the odds of mortality increased by 1.10 (95% CI 1.02-1.19, p = 0.020) and the odds of inotropic medication use increased by 1.30 (95% CI 1.22-1.38, p < 0.001) per natural log unit increase in CPK. There was a significant association between CPK level and duration of inotropic support (Spearman's rho .237, p < 0.001) that remained significant in a propensity score-adjusted model. CONCLUSION: In critically injured patients, elevated serum CPK level is independently associated with mortality, need for inotropic medication, and duration of inotropic support. This study is the first to evaluate the relationship of CPK level and mortality in addition to surrogate measures of shock in a population of critically injured patients. If these associations are verified prospectively, there may be a role for treatment with hemeprotein reductants, such as paracetamol, to mitigate the effects of shock and end-organ dysfunction. PMID- 25441176 TI - Lentiviral vector-mediated RBM5 overexpression downregulates EGFR expression in human non-small cell lung cancer cells. AB - BACKGROUND: RNA binding motif 5 (RBM5) is a tumor suppressor gene that modulates apoptosis through the regulation of alternative splicing of apoptosis-related genes. Our previous studies suggested that RBM5 expression was negatively correlated with the expression of epidermal growth factor receptor (EGFR) in non small cell lung cancer (NSCLC) tissues. This study was aimed at determining whether RBM5 is able to regulate EGFR expression. METHODS: Both in vitro and in vivo studies were carried out to determine the effect of RBM5 on the expression of EGFR. Lentiviral vector-mediated RBM5 overexpression was employed in lung adenocarcinoma cell line A549. A549 xenograft mice were treated with recombinant RBM5 plasmid carried by attenuated Salmonella typhi Ty21a. Real-time quantitative polymerase chain reaction and Western blot were carried out to detect RBM5 and EGFR expression. RESULTS: Both in vivo and in vitro studies indicated that the expression of EGFR mRNA and protein was decreased significantly in the RBM5 overexpression group compared to control groups as shown by real-time PCR and Western blot analysis. We identified that RBM5 overexpression inhibited EGFR expression both in A549 cells and in A549 xenograft mice model. CONCLUSIONS: Our study demonstrated that EGFR expression is regulated by RBM5 in lung adenocarcinomas cells either in a direct or indirect way, which might be meaningful with regards to target therapy in lung cancer. PMID- 25441179 TI - The medium and the message of Ebola. PMID- 25441177 TI - Recent and projected future climatic suitability of North America for the Asian tiger mosquito Aedes albopictus. AB - BACKGROUND: Since the 1980s, populations of the Asian tiger mosquito Aedes albopictus have become established in south-eastern, eastern and central United States, extending to approximately 40 degrees N. Ae. albopictus is a vector of a wide range of human pathogens including dengue and chikungunya viruses, which are currently emerging in the Caribbean and Central America and posing a threat to North America. METHODS: The risk of Ae. albopictus expanding its geographic range in North America under current and future climate was assessed using three climatic indicators of Ae. albopictus survival: overwintering conditions (OW), OW combined with annual air temperature (OWAT), and a linear index of precipitation and air temperature suitability expressed through a sigmoidal function (SIG). The capacity of these indicators to predict Ae. albopictus occurrence was evaluated using surveillance data from the United States. Projected future climatic suitability for Ae. albopictus was obtained using output of nine Regional Climate Model experiments (RCMs). RESULTS: OW and OWAT showed >90% specificity and sensitivity in predicting observed Ae. albopictus occurrence and also predicted moderate to high risk of Ae. albopictus invasion in Pacific coastal areas of the Unites States and Canada under current climate. SIG also well predicted observed Ae. albopictus occurrence (ROC area under the curve was 0.92) but predicted wider current climatic suitability in the north-central and north-eastern United States and south-eastern Canada. RCM output projected modest (circa 500 km) future northward range expansion of Ae. albopictus by the 2050s when using OW and OWAT indicators, but greater (600-1000 km) range expansion, particularly in eastern and central Canada, when using the SIG indicator. Variation in future possible distributions of Ae. albopictus was greater amongst the climatic indicators used than amongst the RCM experiments. CONCLUSIONS: Current Ae. albopictus distributions were well predicted by simple climatic indicators and northward range expansion was predicted for the future with climate change. However, current and future predicted geographic distributions of Ae. albopictus varied amongst the climatic indicators used. Further field studies are needed to assess which climatic indicator is the most accurate in predicting regions suitable for Ae. albopictus survival in North America. PMID- 25441180 TI - A new Lancet Commission on Essential Medicines. PMID- 25441178 TI - Linear and undulating periodized strength plus aerobic training promote similar benefits and lead to improvement of insulin resistance on obese adolescents. AB - The present study compares the effectiveness of three types of physical training for obesity control in adolescents submitted to a long-term interdisciplinary therapy. Forty-five post-puberty obese adolescents (15-18yo) were randomly placed in three different groups of physical trainings: aerobic training (AT n=20), aerobic plus strength training with linear periodization (LP n=13) and aerobic plus strength training with daily undulating periodization (DUP n=12). The body composition was evaluated by air-displacement plethysmography; the rest metabolic rate was measured by indirect calorimetry; serum analysis was collected after an overnight fasting. The most important finding of this study was that both LP and DUP groups improved lipid profile, insulin sensitivity and adiponectin concentration (p<0.01). The linear regression showed a negative association between delta (%) adiponectin and delta (%) insulin (p<0.05). Each group presented a significant reduction in body mass, body mass index and fat mass (kg) after short and long-term intervention (p<0.01). However, the AT group reduced the fat-free mass after short-term intervention (p<0.01) and enhanced protein oxidation (p<0.01), whereas only LP group was able to increase the fat-free mass and maintain the rest metabolic rate (RMR). There was a negative correlation between percentage of protein oxidation and RMR (r=-0.75) in all groups. The interdisciplinary therapy models that included aerobic plus strength training were more effective than only aerobic training to improve lipid profile and insulin sensitivity, as well as the inflammatory state by increasing adiponectin. In all groups were observed an improvement on anthropometric profile. PMID- 25441181 TI - Young adults' health warrants greater attention and action. PMID- 25441182 TI - The changing role of the British state and its citizens. PMID- 25441183 TI - Refugees and health: lessons from World War 1. PMID- 25441184 TI - Disability and socioeconomic inclusion after World War 1. PMID- 25441185 TI - Dysentery in World War 1: Shigella a century on. PMID- 25441187 TI - Adrian Hill: accelerating the pace of Ebola vaccine research. PMID- 25441188 TI - Randomisation is essential in Ebola drug trials. PMID- 25441189 TI - Delayed cord clamping. PMID- 25441190 TI - Delayed cord clamping. PMID- 25441191 TI - Delayed cord clamping. PMID- 25441192 TI - Delayed cord clamping - Authors' reply. PMID- 25441193 TI - Positive end-expiratory pressure during surgery. PMID- 25441194 TI - Positive end-expiratory pressure during surgery. PMID- 25441195 TI - Positive end-expiratory pressure during surgery - Authors' reply. PMID- 25441196 TI - Primary care research. PMID- 25441197 TI - Public health--the bigger picture. PMID- 25441198 TI - Stillbirth in France. PMID- 25441200 TI - How World War 1 changed global attitudes to war and infectious diseases. AB - World War 1 was a key transition point towards scientific medicine. Medical officers incorporated Louis Pasteur's discoveries into their understanding of microorganisms as the cause of infectious diseases, which were therefore susceptible to rational control and treatment measures even in the pre-antibiotic era. Typhoid vaccination led to the successful evasion of the disastrous epidemics of previous wars. The incidence of tetanus was probably decreased by giving millions of doses of horse antitoxin to wounded soldiers. Quinine treated but could not control malaria; its use required mass compulsion. Tuberculosis was not a great military problem during World War 1, although mortality in civilian populations increased substantially. Treatment of sexually transmitted infections remained a matter of aversive conditioning, with invasive antiseptics used in the absence of antibiotics. Pandemic influenza in 1918-19 killed more people than died during the entire war, showing how much remained beyond the capability of the scientists and doctors who fought infectious diseases during World War 1. PMID- 25441199 TI - The extant World War 1 dysentery bacillus NCTC1: a genomic analysis. AB - BACKGROUND: Shigellosis (previously bacillary dysentery) was the primary diarrhoeal disease of World War 1, but outbreaks still occur in military operations, and shigellosis causes hundreds of thousands of deaths per year in developing nations. We aimed to generate a high-quality reference genome of the historical Shigella flexneri isolate NCTC1 and to examine the isolate for resistance to antimicrobials. METHODS: In this genomic analysis, we sequenced the oldest extant Shigella flexneri serotype 2a isolate using single-molecule real time (SMRT) sequencing technology. Isolated from a soldier with dysentery from the British forces fighting on the Western Front in World War 1, this bacterium, NCTC1, was the first isolate accessioned into the National Collection of Type Cultures. We created a reference sequence for NCTC1, investigated the isolate for antimicrobial resistance, and undertook comparative genetics with S flexneri reference strains isolated during the 100 years since World War 1. FINDINGS: We discovered that NCTC1 belonged to a 2a lineage of S flexneri, with which it shares common characteristics and a large core genome. NCTC1 was resistant to penicillin and erythromycin, and contained a complement of chromosomal antimicrobial resistance genes similar to that of more recent isolates. Genomic islands gained in the S flexneri 2a lineage over time were predominately associated with additional antimicrobial resistances, virulence, and serotype conversion. INTERPRETATION: This S flexneri 2a lineage is a well adapted pathogen that has continued to respond to selective pressures. We have created a valuable historical benchmark for shigellae in the form of a high-quality reference sequence for a publicly available isolate. FUNDING: The Wellcome Trust. PMID- 25441201 TI - Battle for the mind: World War 1 and the birth of military psychiatry. AB - The 100th anniversary of the outbreak of World War 1 could be viewed as a tempting opportunity to acknowledge the origins of military psychiatry and the start of a journey from psychological ignorance to enlightenment. However, the psychiatric legacy of the war is ambiguous. During World War 1, a new disorder (shellshock) and a new treatment (forward psychiatry) were introduced, but the former should not be thought of as the first recognition of what is now called post-traumatic stress disorder and the latter did not offer the solution to the management of psychiatric casualties, as was subsequently claimed. For this Series paper, we researched contemporary publications, classified military reports, and casualty returns to reassess the conventional narrative about the effect of shellshock on psychiatric practice. We conclude that the expression of distress by soldiers was culturally mediated and that patients with postcombat syndromes presented with symptom clusters and causal interpretations that engaged the attention of doctors but also resonated with popular health concerns. Likewise, claims for the efficacy of forward psychiatry were inflated. The vigorous debates that arose in response to controversy about the nature of psychiatric disorders and the discussions about how these disorders should be managed remain relevant to the trauma experienced by military personnel who have served in Iraq and Afghanistan. The psychiatric history of World War 1 should be thought of as an opportunity for commemoration and in terms of its contemporary relevance-not as an opportunity for self-congratulation. PMID- 25441202 TI - "Doomed to go in company with miserable pain": surgical recognition and treatment of amputation-related pain on the Western Front during World War 1. AB - The principal feature of injuries from World War 1 was musculoskeletal trauma and injury to peripheral nerves as a result of damage to the upper and lower limbs caused by gunshot wounds and fragments of artillery munitions. Amputation was used as a treatment in field hospitals to save lives; limb conservation was a secondary consideration. A century later, the principal feature of injuries to soldiers in today's wars in Iraq and Afghanistan is also musculoskeletal trauma and injury to the peripheral nerves caused by improvised explosive devices. Common to both types of injury is postamputation pain. We searched The Lancet's archives in this Series paper to show the efforts of surgeons in World War 1 to understand and treat postamputation pain in its own right both during and immediately after the war. Despite unprecedented patient numbers and levels of civilian medical expertise, little progress was made in providing relief from this type of pain, a grave concern to the surgeons treating these soldiers. Today postamputation pain is understood beyond a surgical context but remains a complex and poorly understood condition with few effective treatments. PMID- 25441203 TI - Bacillary dysentery from World War 1 and NCTC1, the first bacterial isolate in the National Collection. PMID- 25441204 TI - Linguistic complex networks: rationale, application, interpretation, and directions: reply to comments on "approaching human language with complex networks". PMID- 25441205 TI - [The influence of sleep and emotional states on childhood body mass index]. AB - INTRODUCTION: By using path analysis, the aim of this study iso show how anxiety, low self-esteem and a decrease in hours of sleep interact to lead to an increase in overweight in children. METHOD: A random sample of 291 schoolchildren was included. A cross-sectional design was used, measuring their body mass index (BMI) and applying the State-Trait Anxiety inventory for Children and the Children' Depression Inventory. RESULTS: The mean sleep time was 9 hours and 50 minutes. There was an inverse relationship between hours of sleep and BMI. Similarly, anxiety and low self-esteem were predictors of the number of hours of sleep. CONCLUSIONS: These data allow it to be concluded that, on one hand, the population studied sleeps less than the 10 or 11 hours recommended for their age. On the other hand, it has been demonstrated how certain emotional states can encourage increased BMI in children, but this relationship is associated with reduced sleep. PMID- 25441206 TI - [Use of benzodiazepines in prolonged seizures and status epilepticus in the community]. AB - Prolonged seizures and status epilepticus are common neurological medical emergencies. Early and appropriate treatment is essential to reduce morbidity and mortality. Most seizures occur in the community, so parents and caregivers must be prepared for their management. Benzodiazepines (BZD) are the first-line drugs used, with rectal diazepam (DZPr) being the most commonly used in pre-hospital treatment in Spain. In September 2011, the European Medicines Agency (EMA) authorized the use of oromucosal midazolam (MDZb) for the treatment of prolonged acute convulsive seizures in patients aged 3 months to <18 years. MDZb has a rapid onset, short duration of effect, and avoids first-pass hepatic metabolism. MDZb has shown to be at least as or more effective than DZPr to stop the seizures. Buccal administration is easier and more socially accepted, especially in adolescents and adults. It is a safe drug with similar effects to other BZD; MDZb improves the overall cost-effectiveness of seizures management. PMID- 25441207 TI - [Advances in the treatment of secondary osteoporosis]. AB - Osteoporosis is being increasingly recognised in paediatric practice as a consequence of the increasing life expectancy of children who suffer from chronic diseases and other factors. There are many non-pharmacological measures that can improve children' bone health, for example, avoiding inflammatory activity and osteotoxic treatments; increasing sun exposure and weight-bearing exercise, and maintaining an adequate nutritional status. Vitamin D and calcium supplements have been proposed as a measure to increase bone mass, but their effect and therapeutic indications are not completely clear. On the other hand, bisphosphonates are currently the only pharmacological alternative for the patients with infantile secondary osteoporosis. However, more studies are required on the therapeutic indications, posology, and long term secondary effects of biphosphonates. The aim of this article is to analyze the scientific evidence of the effectiveness of the therapeutic alternatives for childhood secondary osteoporosis and their safety in children. PMID- 25441208 TI - [Kearns-Sayre syndrome: ophthalmic manifestations]. AB - The clinical case and genetic diagnosis of Kearns-Sayre syndrome (KSS) is described in a young patient. The findings included: ptosis, ocular motility disturbances, pigmentary retinopathy, as well as mitral insufficiency. A muscle biopsy revealed mitochondrial cytopathyand heteroplasmic mitochondrial DNA deletions. KSS is a rare neuromuscular disorder defined by a characteristic triad of progressive external ophthalmoplegia, pigmentary retinopathy and atrioventricular block. Early detection is essential to avoid potential cardiac complications. PMID- 25441209 TI - [Amanita phalloides poisoning]. PMID- 25441210 TI - [Influence of school health promotion on the life habits of schoolchildren]. AB - INTRODUCTION: In recent decades, attention has been directed at global theories that attempt to prevent childhood obesity by exposing them to healthy environments. The aim of this study was to analyze the influence of health promoting environments in primary schools in Logrono (La Rioja, Spain) on the habits of school children. METHODS: The directors of the 31 primary schools in the city completed a questionnaire which examined the health promotion activities of their schools. In addition, anthropometric measurements, adherence to the Mediterranean diet, and sedentary and physical activity habits were recorded from a representative sample of 329 schoolchildren in the sixth year of primary education (11-12 year-olds). RESULTS: The majority of schools had developed nutritional and/or physical activity programs (77.4% and 61.3%, respectively); however, teachers had generally not received specific training in that area. Guidelines regarding healthy habits were not formally included in the School Educational Project. Physical activity, which was greater amongst boys (P<.001), was mostly promoted after school hours. The major influences on school children's physical activity and dietary habits of the children were training of teachers, existence of guidelines, and access to sports grounds (P<.05). CONCLUSIONS: Although further research is required, this study shows that certain modifiable aspects in the organizational or school environment can influence the habits of school children at a fundamental stage of their development. PMID- 25441211 TI - [Satisfaction with weight and characteristics of eating disorders in high school]. AB - INTRODUCTION: The prevalence of diseases related to eating behaviour disorders has increased among adolescents. The objective of this study is to analyse the satisfaction with body weight of schoolchildren as regards their body mass index and the strategies used to control the diet. METHOD: A total of 1197 students from secondary education (12-18 years) answered a questionnaire on eating habits and body weight control. Their weight and height was measured and body mass index was calculated. RESULTS: More than two-thirds (68.1%) of students who had an adequate BMI were satisfied with their weight. Greater dissatisfaction with the weight is associated with overweight (OR=10.23) and obesity (OR=16.60). Students with overweight are on a diet consulting an expert such as a physician or even the family, whereas among schoolchildren with normal weight there is a large percentage on a diet on their own. A 13.87% of the schoolchildren have been undertaken Compensatory activities before excessive eating has been undertaken by 13.87% of the schoolchildren. An overweight BMI is associated, with more than twice the risk (OR>2.00), with the use of measures such as physical activity, vomiting, or fasting to compensate an excessive intake. CONCLUSIONS: Overweight and obese schoolchildren are more likely to be dissatisfied with their body, and are more likely to use ploys such as vomiting, in order to compensate for the excess intake. PMID- 25441212 TI - [Delayed haemolytic anemia due to intravenous artesunate]. PMID- 25441213 TI - [Insomnia, melatonin and prudence]. PMID- 25441214 TI - [Growth charts: Impact on the prevalence of nutritional disorders]. AB - INTRODUCTION: The references used to assess child growth in Spain are the graphs of the Orbegozo Foundation and the charts of the World Health Organization (WHO). The objective of this study is to analyze the differences between the two charts for weight, height and body mass index, and assess their relevance to identify growth or nutritional problems. MATERIAL AND METHODS: The values of the extreme percentiles of height, weight and body mass index for each sex from 0 to 10 years in both charts are compared. For each value Absolute differences and Z scores are calculated for each value. To evaluate the impact on the prevalence of the various nutritional or growth disorders the location of the value of the respective percentiles of in each of the charts were assessed. RESULTS: Significant differences were observed between the 3th percentile of height and weight, 97th of weight, and 85th and 97th of body mass index. Marked differences were observed for the extreme values of body mass index. During the first years, the Orbegozo charts overestimate the prevalence of malnutrition (between 2% and 19% depending on age and sex) compared to the WHO charts. In subsequent ages Orbegozo underestimates WHO between 0.7% and 2.89%. Orbegozo underestimates the prevalence of overweight (between 2.5% and 14.8%) compared to the WHO charts. The 97th percentile of Body mass index in the Orbegozo charts corresponds in most cases with WHO percentiles above 99.99%. CONCLUSION: The two charts analyzed have significant differences from a clinical and the public health point of view, in the estimation of overweight/obesity and malnutrition. PMID- 25441215 TI - Towards Building a Bridge between Community Engagement in Research (CEnR) and Comparative Effectiveness Research (CER). AB - A major national priority is establishing an effective infrastructure for translation of scientific discoveries into the community. Knowledge and practice continue to accelerate in health research yet healthcare recommendation adoption remains slow for practitioners, patients, and communities. Two areas of research placed in the later stages of the translational research spectrum, Community Engagement in Research and Comparative Effectiveness Research, are ideal for approaching this challenge collaboratively. The Clinical and Translational Science Institute of Southeastern Wisconsin convened academics and community based organizations familiar with these fields of research in a 1-day workshop to establish an initial dialogue on similarities and differences with a goal of exploring ways to operationalize a collective effort. Participants represented four academic institutions and twelve other healthcare and community-based service organizations. Primary fields of study included community engaged research, comparative effectiveness research, psychology, clinical research, administration, nursing, public health, education, and other professionals. This initial report outlines the results of this diverse discussion and provides insights into the priorities, diverging issues, and areas for future examination and practice. Key discoveries reveal clear crosscutting issues, value in philosophical and provocative discussions among investigators, a need for practice and lessons learned, and bidirectional exchange with community representation. PMID- 25441216 TI - Further results on global state feedback stabilization of high-order nonlinear systems with time-varying delays. AB - This paper considers the problem of global stabilization by state feedback for a class of high-order nonlinear systems with time-varying delays. Comparing with the existing relevant literature, the systems under investigation allow more uncertainties, to which the existing control methods are inapplicable. By introducing sign function and necessarily modifying the method of adding a power integrator, a state feedback controller is successfully constructed to preserve the equilibrium at the origin and guarantee the global asymptotic stability of the resulting closed-loop system. Finally, two simulation examples are provided to illustrate the effectiveness of the proposed approach. PMID- 25441217 TI - Distributed model predictive control for constrained nonlinear systems with decoupled local dynamics. AB - This paper considers the distributed model predictive control (MPC) of nonlinear large-scale systems with dynamically decoupled subsystems. According to the coupled state in the overall cost function of centralized MPC, the neighbors are confirmed and fixed for each subsystem, and the overall objective function is disassembled into each local optimization. In order to guarantee the closed-loop stability of distributed MPC algorithm, the overall compatibility constraint for centralized MPC algorithm is decomposed into each local controller. The communication between each subsystem and its neighbors is relatively low, only the current states before optimization and the optimized input variables after optimization are being transferred. For each local controller, the quasi-infinite horizon MPC algorithm is adopted, and the global closed-loop system is proven to be exponentially stable. PMID- 25441218 TI - A frequency response model matching method for PID controller design for processes with dead-time. AB - In this paper, a PID controller design method for the integrating processes based on frequency response matching is presented. Two approaches are proposed for the controller design. In the first approach, a double feedback loop configuration is considered where the inner loop is designed with a stabilizing gain. In the outer loop, the parameters of the PID controller are obtained by frequency response matching between the closed-loop system with the PID controller and a reference model with desired specifications. In the second approach, the design is directly carried out considering a desired load-disturbance rejection model of the system. In both the approaches, two low frequency points are considered for matching the frequency response, which yield linear algebraic equations, solution of which gives the controller parameters. Several examples are taken from the literature to demonstrate the effectiveness and to compare with some well known design methods. PMID- 25441219 TI - Programmable logic controller performance enhancement by field programmable gate array based design. AB - PLC, the core element of modern automation systems, due to serial execution, exhibits limitations like slow speed and poor scan time. Improved PLC design using FPGA has been proposed based on parallel execution mechanism for enhancement of performance and flexibility. Modelsim as simulation platform and VHDL used to translate, integrate and implement the logic circuit in FPGA. Xilinx's Spartan kit for implementation-testing and VB has been used for GUI development. Salient merits of the design include cost-effectiveness, miniaturization, user-friendliness, simplicity, along with lower power consumption, smaller scan time and higher speed. Various functionalities and applications like typical PLC and industrial alarm annunciator have been developed and successfully tested. Results of simulation, design and implementation have been reported. PMID- 25441220 TI - Stabilization strategies of a general nonlinear car-following model with varying reaction-time delay of the drivers. AB - In this paper, the stabilization strategies of a general nonlinear car-following model with reaction-time delay of the drivers are investigated. The reaction-time delay of the driver is time varying and bounded. By using the Lyapunov stability theory, the sufficient condition for the existence of the state feedback control strategy for the stability of the car-following model is given in the form of linear matrix inequality, under which the traffic jam can be well suppressed with respect to the varying reaction-time delay. Moreover, by considering the external disturbance for the running cars, the robust state feedback control strategy is designed, which ensures robust stability and a smaller prescribed Hinfinity disturbance attenuation level for the traffic flow. Numerical examples are given to illustrate the effectiveness of the proposed methods. PMID- 25441221 TI - High HDL-C prevalence is common in type 1 diabetes and increases with age but is lower in Hispanic individuals. AB - High HDL-cholesterol (HDL-C) based on the 85th percentile of the 2009-2010 National Health and Education Survey (NHANES) was present in more than a third of 194 unselected subjects with type 1 diabetes (T1D). Age was associated with an increase and Hispanic ethnicity with a decrease in the prevalence of high HDL-C. PMID- 25441223 TI - Exploring identity in the 'figured worlds' of cancer care-giving and marriage in Australia. AB - Following changes in the structure and funding of the Australian medical system, patients have become 'consumers' or 'clients'. Family and friends have become 'carers' or 'caregivers', signifying their increased responsibilities as patients move from hospitals to communities. While policy makers embrace the term 'carer', some argue that the title is not widely recognised and has disempowering connotations. This paper examines spouses' reflections on the term 'carer' based on qualitative interviews with 32 Australians caring for a spouse with cancer from a study conducted between 2006 and 2009. Recruitment involved survey and snowball sampling. Following a grounded theory approach, data collection and analysis were performed simultaneously. Using Holland and colleagues' sociocultural 'identity as practice' theory and a thematic approach to analysis, findings depict identification with the 'spouse' and 'carer' label as relationally situated and dependent on meaningful interaction. Although others argue that the term 'carer' is a 'failure', these findings depict identification with the label as contextual, positional and enacted, not fixed. Furthermore, and of most significance to practitioners and policy makers, the title has value, providing carers with an opportunity to position themselves as entitled to inclusion and support, and providing health professionals with a potential indicator of a spouse's increased burden. PMID- 25441222 TI - The predictive role of markers of Inflammation and endothelial dysfunction on the course of diabetic retinopathy in type 1 diabetes. AB - AIMS: This study was undertaken to determine whether levels of inflammation and endothelial dysfunction biomarkers in serum samples collected at baseline in the Diabetes Control and Complications Trial (DCCT) cohort could predict the development of retinopathy. METHODS: Levels of clotting/fibrinolysis, inflammation and endothelial dysfunction biomarkers were measured in 1391 subjects with type 1 diabetes to determine whether their levels predicted increased risk to develop or accelerate progression of retinopathy during 16years of follow-up. RESULTS: Using regression models adjusted for DCCT treatment group, duration of diabetes, baseline retinopathy scores, HbA1c and albumin excretion rate, the baseline levels of sE-selectin and PAI-1 (active) were significantly associated with increased risk of a 3-step progression in retinopathy score in the primary prevention cohort (PPC). After adjusting for additional covariates (e.g., ACE/ARB and statin therapy), this association persisted. Levels of active and total PAI-1 in the same group were also significantly associated, after similar adjustments, with the time to progress to severe non-proliferative retinopathy during the follow-up period (54 and 29%, respectively of increased risk). No associations were observed in the secondary intervention cohort for any of the outcomes. CONCLUSIONS: High levels of sE-selectin and PAI-1 are associated with the development of retinopathy in patients with uncomplicated type 1 diabetes. PMID- 25441224 TI - Identification of six novel mutations in ZEB1 and description of the associated phenotypes in patients with posterior polymorphous corneal dystrophy 3. AB - Posterior polymorphous corneal dystrophy 3 (PPCD3) is a rare autosomal dominant disorder caused by mutations in ZEB1. To date all identified disease-causing variants were unique to the studied families, except for c.1576dup. We have detected six novel ZEB1 mutations; c.1749_1750del; p.(Pro584*) and c.1717_1718del; p.(Val573Phefs*12) in two Czech families, c.1176dup; p.(Ala393Serfs*19), c.1100C>A; p.(Ser367*), c.627del; p.(Phe209Leufs*11) in three British families and a splice site mutation, c.685-2A>G, in a patient of Sri Lankan origin. An additional British proband had the c.1576dup; p.(Val526Glyfs*3) mutation previously reported in other populations. Clinical findings were variable and included bilateral congenital corneal opacity in one proband, development of opacity before the age of 2 years in another individual and bilateral iris flocculi in yet another subject. The majority of eyes examined by corneal topography (10 out of 16) had an abnormally steep cornea (flat keratometry 46.5-52.7 diopters, steep keratometry 48.1-54.0 diopters). One proband underwent surgery for cryptorchidism. Our study further demonstrates that PPCD3 can present as corneal edema in early childhood, and that an abnormally steep keratometry is a common feature of this condition. As cryptorchidism has been previously observed in two other PPCD3 cases, its association with the disease warrants further investigation. PMID- 25441225 TI - Assessing the impact of microfinance programming on children: an evaluation from post-tsunami Aceh. AB - This paper presents an evaluation of the long-term impact of microfinance programmes on Acehnese children during the post-tsunami recovery. The study, conducted from June to August 2010, examined the impact of microfinance programming six years after the tsunami. The sample consisted of 185 microfinance participants, with a comparison group of 192 individuals who did not participate in microfinance programmes. All respondents were parents, interviewed through a structured survey. The study used four child protection indicators-diet, health, childcare and education-in contrast to traditional repayment rate indicators. The primary results were insignificant with respect to all four child protection indicators, suggesting that, with respect to these indicators, there was no long term difference between the impact of microfinance on beneficiaries' children and non-beneficiaries' children. These findings signify a need for microfinance actors to move beyond traditional indicators of economic success to evaluate the social changes microfinance programmes are presumed to effect. PMID- 25441226 TI - [Pulse contour analysis calibrated by Trans-pulmonar thermodilution (Picco Plus((r))) for the perioperative management of a caesarean section in a patient with severe cardiomyopathy]. AB - BACKGROUND: The delivery of cardiac patients is a challenge for the anaesthesiologist, to whom the welfare of both the mother and the foetus is a main issue. In case of caesarean section, advanced monitoring allows to optimize haemodynamic condition and to improve morbidity and mortality. OBJECTIVE: To describe the use of pulse contour analysis calibrated by Trans-pulmonar thermodilution (Picco Plus((r))) for the perioperative management of a caesarean section in a patient with severe cardiomyopathy. CASE REPORT: We describe the case of a 28-year-old woman with a congenital heart disease who was submitted to a caesarean section under general anaesthesia for maternal pathology and foetal breech presentation. Intra- and post-operative management was optimized by advanced haemodynamic monitorization obtained by pulse contour wave analysis and thermodilution calibration (Picco Plus((r)) monitor). The information about preload, myocardial contractility and postcharge was useful in guiding the fluid therapy and the use of vasoactive drugs. CONCLUSION: This case report illustrates the importance of advanced haemodynamic monitoring with an acceptably invasive device in obstetric patients with high cardiac risk. The increasing experience in advanced haemodynamic management will probably permit to decrease morbidity and mortality of obstetric patients in the future. PMID- 25441228 TI - Characteristics of nitrate removal in a bio-ceramsite reactor by aerobic denitrification. AB - A newly aerobic denitrifying bacterial strain, Pseudomonas sp. X31, which was isolated from activated sludge, was added to a newly developed aerobic denitrification bio-ceramsite reactor as an inoculum to treat nitrate-polluted water and the denitrification activities of this system under different air-water ratio, hydraulic loading, and C/N (carbon/nitrogen ratio) conditions were investigated. It demonstrated excellent capability for denitrification in the bio ceramsite reactor at air-water ratios that varied from 6.5:1 to 8:1. The optimal hydraulic loading for the bio-ceramsite reactor was 0.75 m/h with the optimum denitrification efficiency of 95.18%. The optimal C/N was 4.5:1 with a maximum nitrate removal efficiency of 98.48%. COD could be completely removed under the most appropriate condition (air-water ratio 6.5:1-8:1, hydraulic loading 0.75 m/h, and C/N 4.5:1). The quantity of the biomass in the reactor decreased along with flow, which was in accordance with the variety of the available substrate concentrations in the water. However, the biofilm activity was not proportional to the biomass in the bio-ceramsite reactor, but increased with the quantity of the biomass up to a peak value and then decreased. PMID- 25441227 TI - High iron level in early pregnancy increased glucose intolerance. AB - High iron stores in pregnancy are essential in preventing negative outcomes for both infants and mothers; however the risk of gestational diabetes mellitus (GDM) might also be increased. We intend to study the relationship between increased iron stores in early pregnancy and the risk of glucose intolerance and GDM. This prospective, observational, single-hospital study involved 104 non-anemic pregnant women, divided into 4 groups based on the quartile values for ferritin at the first trimester of pregnancy. All participants were screened for GDM with 75-g oral glucose tolerance test (OGTT) at 24-28 weeks' gestation. We observed that ferritin levels at early pregnancy were significantly correlated to glucose level after OGTT at 1-h and 2-h (rho=0.21, p<0.05; rho=0.43, p<0.001 respectively). Furthermore, in the higher quartile for ferritin (>38.8MUg/L) glycemia at 2-h OGTT was significantly higher than in the others quartiles (p=0.002). In multivariate regression analysis, serum ferritin was a significant determinant of glycemia at 2-h OGTT. Although we did not find a significant association in the incidence of GDM in women with higher serum ferritin levels, probably in reason to the limit power of our study, our data demonstrated that the role of iron excess is tightly involved in the pathogenesis of glucose intolerance. We report for the first time that high ferritin values in early pregnancy are predictors of impaired glucose tolerance in non-anemic women. Individual iron supplementation should be evaluated in order to minimize glucose impairment risk in women with high risk of diabetes. PMID- 25441229 TI - Construct validity and reliability of the Chinese version of the Disaster Preparedness Evaluation Tool in Taiwan. AB - AIMS AND OBJECTIVES: To develop a Chinese version of the Disaster Preparedness Evaluation Tool and validate its psychometric properties. BACKGROUND: An adequate disaster preparation programme for nurses has not been developed in Taiwan. To develop an exhaustive and effective educational programme on disaster preparation for nurses, a multidimensional instrument is required for assessing the disaster preparation level of nurses. DESIGN: A cross-sectional study was conducted. METHODS: In total, 1550 of 2226 public health nurses in 15 counties completed the self-administrated questionnaire. We randomly selected 805 samples to examine the factor structure and factor model by using exploratory factor analysis and confirmatory factor analysis. The convergent validity was measured using the average variance extracted and composite reliability. RESULTS: Five factors, namely postdisaster management, skills, knowledge of self-preparation in a disaster, knowledge to respond in the community, and knowledge to respond in the workplace, were extracted, and explained 65.13% of the total variance. An acceptable model fit was identified using confirmatory factor analysis. The Cronbach's alpha coefficient of the Chinese version of the Disaster Preparedness Evaluation Tool was 0.97. Significant values of the average variance extracted greater than 0.5 indicated convergent validity. CONCLUSION: The Chinese version of the Disaster Preparedness Evaluation Tool is a reliable and valid instrument for measuring disaster preparation. RELEVANCE TO CLINICAL PRACTICE: The Chinese version of the Disaster Preparedness Evaluation Tool provides reliable and valid measures that can be used to evaluate the disaster preparedness of nurses. The items in the instrument can be used to identify the dimension of disaster management in all stages, and can form the essential foundation of an education and training programme for public health nurses to reduce the harm of disasters and promote community resilience. PMID- 25441230 TI - Improving injury prevention through health information technology. AB - Health information technology is an emerging area of focus in clinical medicine with the potential to improve injury and violence prevention practice. With injuries being the leading cause of death for Americans aged 1-44 years, greater implementation of evidence-based preventive services, referral to community resources, and real-time surveillance of emerging threats is needed. Through a review of the literature and capturing of current practice in the field, this paper showcases how health information technology applied to injury and violence prevention can lead to strengthened clinical preventive services, more rigorous measurement of clinical outcomes, and improved injury surveillance, potentially resulting in health improvement. PMID- 25441231 TI - Child-directed marketing inside and on the exterior of fast food restaurants. AB - BACKGROUND: Children who eat fast food have poor diet and health outcomes. Fast food is heavily marketed to youth, and exposure to such marketing is associated with higher fast food consumption. PURPOSE: To examine the extent of child directed marketing (CDM) inside and on the exterior of fast food restaurants. METHODS: Data were collected from 6,716 fast food restaurants located in a nationally representative sample of public middle- and high-school enrollment areas in 2010, 2011, and 2012. CDM was defined as the presence of one or more of seven components inside or on the exterior of the restaurant. Analyses were conducted in 2014. RESULTS: More than 20% of fast food restaurants used CDM inside or on their exterior. In multivariate analyses, fast food restaurants that were part of a chain, offered kids' meals, were located in middle- (compared to high)-income neighborhoods, and in rural (compared to urban) areas had significantly higher odds of using any CDM; chain restaurants and those located in majority black neighborhoods (compared to white) had significantly higher odds of having an indoor display of kids' meal toys. Compared to 2010, there was a significant decline in use of CDM in 2011, but the prevalence increased close to the 2010 level in 2012. CONCLUSIONS: CDM inside and on the exterior of fast food restaurants is prevalent in chain restaurants; majority black communities, rural areas, and middle-income communities are disproportionately exposed. The fast food industry should limit children's exposure to marketing that promotes unhealthy food choices. PMID- 25441232 TI - Racial/ethnic workplace discrimination: association with tobacco and alcohol use. AB - BACKGROUND: Experiences of discrimination are associated with tobacco and alcohol use, and work is a common setting where individuals experience racial/ethnic discrimination. Few studies have evaluated the association between workplace discrimination and these behaviors, and none have described associations across race/ethnicity. PURPOSE: To examine the association between workplace discrimination and tobacco and alcohol use in a large, multistate sample of U.S. adult respondents to the Behavioral Risk Factor Surveillance System survey Reactions to Race Module (2004-2010). METHODS: Multivariable logistic regression analyses evaluated cross-sectional associations between self-reported workplace discrimination and tobacco (current and daily smoking) and alcohol use (any and heavy use, and binge drinking) among all participants and stratified by race/ethnicity, adjusting for relevant covariates. Data were analyzed in 2013. RESULTS: Among respondents, 70,080 completed the workplace discrimination measure. Discrimination was more common among black non-Hispanic (21%), Hispanic (12%), and other race respondents (11%) than white non-Hispanics (4%) (p<0.001). In the total sample, discrimination was associated with current smoking (risk ratio [RR]=1.32, 95% CI=1.19, 1.47), daily smoking (RR=1.41, 95% CI=1.24, 1.61), and heavy drinking (RR=1.11, 95% CI=1.01, 1.22), but not binge or any drinking. Among Hispanics, workplace discrimination was associated with increased heavy and binge drinking, but not any alcohol use or smoking. Workplace discrimination among black non-Hispanics and white Non-Hispanics was associated with increased current and daily smoking, but not alcohol outcomes. CONCLUSIONS: Workplace discrimination is common, associated with smoking and alcohol use, and merits further policy attention, given the impact of these behaviors on morbidity and mortality. PMID- 25441233 TI - Primary care physician supply, insurance type, and late-stage cancer diagnosis. AB - BACKGROUND: Understanding the joint effects of insurance type and primary care physician density on stage at diagnosis is essential to elucidating the healthcare access and late-stage cancer relationship. PURPOSE: To determine if the relationship between primary care physician density and odds of late-stage cancer are modified by insurance type at diagnosis. METHODS: Case patients were Ohio adults diagnosed between 1996 and 2008 with cancer of one of the following sites: female breast, cervix, colon/rectum, lung/bronchus, melanoma of the skin, oral cavity and pharynx, or prostate (N=376,425). County-level physician density was obtained from the Ohio Department of Health. Multilevel logistic regression models estimated odds ratios of late-stage cancer diagnosis associated with increases in primary care physician density by insurance type. Analyses were conducted in 2014. RESULTS: Decreases in late-stage diagnosis of cancers of the breast, prostate, melanoma of the skin, oral cavity and pharynx, or lung/bronchus associated with increases in primary care physician density were strongest among those with private insurance, whereas those with Medicare (prostate, oral cavity and pharynx, lung/bronchus), Medicaid (lung/bronchus), uninsured (prostate), and other/unknown (prostate, oral cavity and pharynx, lung/bronchus) did not benefit as greatly, or experienced significant increases in late-stage cancer diagnosis (other/unknown [female breast], Medicaid [melanoma of the skin], and uninsured [colon/rectum]). CONCLUSIONS: As primary care physician density increases, those with private insurance consistently benefit the most in terms of late-stage cancer diagnosis, whereas those with several other insurance types experience flatter decreases or significantly higher odds of late-stage cancer diagnosis. PMID- 25441235 TI - Racial Disparities in Access to Care Under Conditions of Universal Coverage. AB - BACKGROUND: Racial disparities in access to regular health care have been reported in the U.S., but little is known about the extent of disparities in societies with universal coverage. PURPOSE: To investigate the extent of racial disparities in access to care under conditions of universal coverage by observing the association between race and regular access to a doctor in Canada. METHODS: Racial disparities in access to a regular doctor were calculated using the largest available source of nationally representative data in Canada--the Canadian Community Health Survey. Surveys from 2000-2010 were analyzed in 2014. Multinomial regression analyses predicted odds of having a regular doctor for each racial group compared to whites. Analyses were stratified by immigrant status--Canadian-born versus shorter-term immigrant versus longer-term immigrants -and controlled for sociodemographics and self-rated health. RESULTS: Racial disparities in Canada, a country with universal coverage, were far more muted than those previously reported in the U.S. Only among longer-term Latin American immigrants (OR=1.90, 95% CI=1.45, 2.08) and Canadian-born Aboriginals (OR=1.34, 95% CI=1.22, 1.47) were significant disparities noted. Among shorter-term immigrants, all Asians were more likely than whites, and among longer-term immigrants, South Asians were more like than whites, to have a regular doctor. CONCLUSIONS: Universal coverage may have a major impact on reducing racial disparities in access to health care, although among some subgroups, other factors may also play a role above and beyond health insurance. PMID- 25441234 TI - State Medicaid expansion decisions and disparities in women's cancer screening. AB - BACKGROUND: There are substantial disparities in breast and cervical cancer screening that stem from lack of health insurance. Although the Affordable Care Act (ACA) expands insurance coverage to many Americans, there are differences in availability of Medicaid coverage across states. PURPOSE: To understand the potential impact of Medicaid expansions on disparities in preventive care for low income women by assessing pre-ACA breast and cervical cancer screening across states currently expanding and not expanding Medicaid to low-income adults. METHODS: Data from the 2012 Behavioral Risk Factor Surveillance System (analyzed in 2014) were used to consider differences in demographics among women for whom screening is recommended, including income and race/ethnicity, across expansion and nonexpansion states. Self-reported screening was compared by state expansion status overall, for the uninsured, and for low-income women. Logistic regressions were estimated to assess differences in self-reported screening across expansion and nonexpansion states controlling for demographics. RESULTS: Women in states that are not expanding Medicaid had significantly lower odds of receiving recommended mammograms (OR=0.87, 95% CI=0.79, 0.95) or Pap tests (OR=0.87, 95% CI=0.79, 0.95). The difference was larger among the uninsured (OR=0.72, 95% CI=0.56, 0.91 for mammography; OR=0.78, 95% CI=0.65, 0.94 for Pap tests). CONCLUSIONS: As women in nonexpansion states remain uninsured and others gain coverage, existing disparities in cancer screening by race and socioeconomic status are likely to widen. Health risks and associated costs to underserved populations must be taken into account in ongoing debates over expansion. PMID- 25441236 TI - Vision 2020 measures University of New Mexico's success by health of its state. AB - The University of New Mexico Health Sciences Center (UNMHSC) adopted a new Vision to work with community partners to help New Mexico make more progress in health and health equity than any other state by 2020. UNMHSC recognized it would be more successful in meeting communities' health priorities if it better aligned its own educational, research, and clinical missions with their needs. National measures that compare states on the basis of health determinants and outcomes were adopted in 2013 as part of Vision 2020 target measures for gauging progress toward improved health and health care in New Mexico. The Vision focused the institution's resources on strengthening community capacity and responding to community priorities via pipeline education, workforce development programs, community-driven and community-focused research, and community-based clinical service innovations, such as telehealth and "health extension." Initiatives with the greatest impact often cut across institutional silos in colleges, departments, and programs, yielding measurable community health benefits. Community leaders also facilitated collaboration by enlisting University of New Mexico educational and clinical resources to better respond to their local priorities. Early progress in New Mexico's health outcomes measures and state health ranking is a promising sign of movement toward Vision 2020. PMID- 25441237 TI - The steps to health randomized trial for arthritis: a self-directed exercise versus nutrition control program. AB - BACKGROUND: Despite the established benefits of exercise for adults with arthritis, participation is low. Safe, evidence-based, self-directed programs, which have the potential for high reach at a low cost, are needed. PURPOSE: To test a 12-week, self-directed, multicomponent exercise program for adults with arthritis. DESIGN: Randomized controlled trial. Data were collected from 2010 to 2012. Data were analyzed in 2013 and 2014. SETTING/PARTICIPANTS: Adults with arthritis (N=401, aged 56.3 [10.7] years, 85.8% women, 63.8% white, 35.2% African American, BMI of 33.0 [8.2]) completed measures at a university research center and participated in a self-directed exercise intervention (First Step to Active Health((r))) or nutrition control program (Steps to Healthy Eating). INTERVENTION: Intervention participants received a self-directed multicomponent exercise program and returned self-monitoring logs for 12 weeks. MAIN OUTCOME MEASURES: Self-reported physical activity, functional performance measures, and disease-specific outcomes (arthritis symptoms and self-efficacy) assessed at baseline, 12 weeks, and 9 months. RESULTS: Participants in the exercise condition showed greater increases in physical activity than those in the nutrition control group (p=0.01). Significant improvements, irrespective of condition, were seen in lower body strength, functional exercise capacity, lower body flexibility, pain, fatigue, stiffness, and arthritis management self-efficacy (p values<0.0001). More adverse events occurred in the exercise than nutrition control condition, but only one was severe and most were expected with increased physical activity. CONCLUSIONS: The exercise program improves physical activity, and both programs improve functional and psychosocial outcomes. Potential reasons for improvements in the nutrition control condition are discussed. These interventions have the potential for large-scale dissemination. This study is registered at Clinicaltrials.gov NCT01172327. PMID- 25441239 TI - Use of psychology and behavioral economics to promote healthy eating. AB - Understanding the psychology of how people make decisions can shed light on important factors contributing to the cause and maintenance of public health problems like obesity. This knowledge can and should inform the design of government and private-sector public health interventions. Several insights from psychology and behavioral economics that help explain why people are particularly vulnerable to the current food environment are discussed. These insights fall into the following categories: the influence of starting points (status quo bias and anchoring effects); communicating health information (simplicity and framing); and unintended consequences of policy interventions (compensation, substitution, and the peanuts effect). The paper discusses opportunities for improving the design of food policies and interventions by altering default options, providing the public with simple and meaningful nutrition information, carefully constructing the framing of public health messages, and designing food policies to minimize unintended consequences, such as compensation and substitution. PMID- 25441238 TI - Risk factors for accident death in the U.S. Army, 2004-2009. AB - BACKGROUND: Accidents are one of the leading causes of death among U.S. active duty Army soldiers. Evidence-based approaches to injury prevention could be strengthened by adding person-level characteristics (e.g., demographics) to risk models tested on diverse soldier samples studied over time. PURPOSE: To identify person-level risk indicators of accident deaths in Regular Army soldiers during a time frame of intense military operations, and to discriminate risk of not-line of-duty from line-of-duty accident deaths. METHODS: Administrative data acquired from multiple Army/Department of Defense sources for active duty Army soldiers during 2004-2009 were analyzed in 2013. Logistic regression modeling was used to identify person-level sociodemographic, service-related, occupational, and mental health predictors of accident deaths. RESULTS: Delayed rank progression or demotion and being male, unmarried, in a combat arms specialty, and of low rank/service length increased odds of accident death for enlisted soldiers. Unique to officers was high risk associated with aviation specialties. Accident death risk decreased over time for currently deployed, enlisted soldiers and increased for those never deployed. Mental health diagnosis was associated with risk only for previous and never-deployed, enlisted soldiers. Models did not discriminate not-line-of-duty from line-of-duty accident deaths. CONCLUSIONS: Adding more refined person-level and situational risk indicators to current models could enhance understanding of accident death risk specific to soldier rank and deployment status. Stable predictors could help identify high risk of accident deaths in future cohorts of Regular Army soldiers. PMID- 25441240 TI - Effects of ovariectomy on the inflammatory responses of female rats to the central injection of lipopolysaccharide. AB - It has been reported that obesity leads to more marked inflammatory responses in a site-specific manner. As has been seen in other animal models of obesity, ovariectomized rodents exhibit obesity and exacerbated fever and anorectic responses to the systemic injection of lipopolysaccharide (LPS). Furthermore, they also display increased pro-inflammatory cytokine expression in several central and peripheral tissues. Interestingly, the alterations observed in the hypothalamus are more marked than those seen in other peripheral tissues. In this study, the effects of ovariectomy on hypothalamic inflammatory responses were evaluated using the central LPS injection method. LPS was intracerebroventricularly (i.c.v.) injected into ovariectomized and gonadally intact female rats, and the immune responses of the two groups were compared. The ovariectomized rats exhibited heavier body weights than the gonadally intact rats. In addition, the ovariectomized rats displayed stronger febrile responses than the gonadally intact rats. After the i.c.v. injection of LPS, the hypothalamic interleukin (IL)-1beta, IL-6, and cyclooxygenase 2 mRNA levels of the ovariectomized rats were significantly higher than those of the gonadally intact rats. The effects of estradiol supplementation on the rats' immune responses were also examined. However, the febrile responses and hypothalamic IL 1beta, IL-6, and TNF-alpha mRNA levels of estradiol-supplemented ovariectomized rats and body weight matched oil-administered (control) rats did not differ after the i.c.v. injection of LPS. These results indicate that hypothalamic sensitivity to LPS is increased in ovariectomized rats and that this change is induced by the indirect effects of gonadal steroid deficiency. As is seen in other obese animal models, ovariectomy-induced obesity might play important roles in the exacerbated inflammatory responses observed in ovariectomized rats. PMID- 25441241 TI - Risk factors for cisplatin-induced long-term nephrotoxicity in pediatric cancer survivors. AB - BACKGROUND: The aim of this study was to compare the nephrotoxicity risk of cisplatin (CPL) and ifosfamide (IFO) combination treatment (CT) with that of CPL alone and to evaluate the prevalence of CPL-induced long-term nephrotoxicity in pediatric cancer survivors (CS). METHODS: A total of 33 patients with pediatric solid tumors who have been cured of their disease were included in the study. They were divided into two groups based on the type of chemotherapeutics, either CPL (n = 21) or CT (n = 12), given during cancer treatment and were evaluated for glomerular and tubular function using the Skinner grading system. RESULTS: Nephrotoxicity was found in 15 CS (45.4%): seven (21.3%) of those had moderate, six (18.2%) had mild, and two (6.1%) had severe nephrotoxicity. Neither the rates of overall nephrotoxicity, glomerular toxicity and tubular toxicity, nor the mean overall, glomerular and tubular toxicity scores differed significantly among the CPL and CT groups (P > 0.05 for all parameters). Cumulative IFO dose and age at treatment were found to be independent risk factors for both development and severity of CPL-induced nephrotoxicity (P = 0.025 and P = 0.036 for development of nephrotoxicity; P = 0.004 and P = 0.050 for severity of nephrotoxicity, respectively). CONCLUSIONS: Although CPL-induced long-term nephrotoxicity was found in half of the pediatric CS of solid tumors, clinically significant nephrotoxicity was detected only in a minority of them. Both higher cumulative IFO dose and younger age at treatment were found to be independent risk factors for both development and severity of CPL-induced nephrotoxicity. PMID- 25441243 TI - What is the most effective treatment for relieving the pain of a jellyfish sting? PMID- 25441242 TI - Accuracy of reduced-dose computed tomography for ureteral stones in emergency department patients. AB - STUDY OBJECTIVE: Reduced-dose computed tomography (CT) scans have been recommended for diagnosis of kidney stone but are rarely used in the emergency department (ED) setting. Test characteristics are incompletely characterized, particularly in obese patients. Our primary outcome is to determine the sensitivity and specificity of a reduced-dose CT protocol for symptomatic ureteral stones, particularly those large enough to require intervention, using a protocol stratified by patient size. METHODS: This was a prospective, blinded observational study of 201 patients at an academic medical center. Consenting subjects underwent both regular- and reduced-dose CT, stratified into a high and low body mass index (BMI) protocol based on effective abdominal diameter. Reduced dose CT scans were interpreted by radiologists blinded to regular-dose interpretations. Follow-up for outcome and intervention was performed at 90 days. RESULTS: CT scans with both regular and reduced doses were conducted for 201 patients, with 63% receiving the high BMI reduced-dose protocol. Ureteral stone was identified in 102 patients (50.7%) of those receiving regular-dose CT, with a ureteral stone greater than 5 mm identified in 26 subjects (12.9%). Sensitivity of the reduced-dose CT for any ureteral stone was 90.2% (95% confidence interval [CI] 82.3% to 95.0%), with a specificity of 99.0% (95% CI 93.7% to 100.0%). For stones greater than 5 mm, sensitivity was 100% (95% CI 85.0% to 100.0%). Reduced dose CT identified 96% of patients who required intervention for ureteral stone within 90 days. Mean reduction in size-specific dose estimate was 18.6 milligray (mGy), from 21.7 mGy (SD 9.7) to 3.4 mGy (SD 0.9). CONCLUSION: CT with substantial dose reduction was 90.2% (95% CI 82.3% to 95.0%) sensitive and 98.9% (95% CI 85.0% to 100.0%) specific for ureteral stones in ED patients with a wide range of BMIs. Reduced-dose CT was 96.0% (95% CI 80.5% to 99.3%) sensitive for ureteral stones requiring intervention within 90 days. PMID- 25441244 TI - Do Intravenous Nitrates Improve Dyspnea in Acute Heart Failure Syndromes More Than Alternative Pharmacologic Interventions? PMID- 25441245 TI - Does endovascular therapy benefit patients with acute ischemic stroke? PMID- 25441246 TI - Syncope and presyncope: same mechanism, causes, and concern. PMID- 25441247 TI - Randomized, double-blinded, clinical trial of propofol, 1:1 propofol/ketamine, and 4:1 propofol/ketamine for deep procedural sedation in the emergency department. AB - STUDY OBJECTIVE: We compare the frequency of airway and respiratory adverse events leading to an intervention between propofol with 1:1 and 4:1 mixtures of propofol and ketamine (ketofol). METHODS: We performed a randomized, double blinded trial in which emergency department adults undergoing deep sedation received propofol, 1:1 propofol and ketamine, or 4:1 propofol and ketamine. Our primary outcome was the frequency of airway and respiratory adverse events leading to an intervention. Other outcomes included sedation depth, efficacy, procedure and recovery time, patient satisfaction, pain, and procedural recall. RESULTS: Two hundred seventy-one subjects completed the trial, 90 receiving propofol, 85 receiving 1:1 propofol and ketamine, and 96 receiving 4:1 propofol and ketamine. Airway or respiratory adverse events leading to an intervention were similar between groups: 29%, 19%, and 32%, respectively (P=.21). There were no serious adverse events in any group. Secondary outcomes were generally similar between groups, with greater recovery agitation observed in the 1:1 ketofol group (8%, 21%, and 10%, respectively). CONCLUSION: We found a similar frequency of airway and respiratory adverse events leading to intervention between propofol alone and either 1:1 or 4:1 ketofol. PMID- 25441248 TI - Pediatric cervical spine injury evaluation after blunt trauma: a clinical decision analysis. AB - STUDY OBJECTIVE: Although many adult algorithms for evaluating cervical spine injury use computed tomography (CT) as the initial screening modality, this may not be appropriate in low-risk children, considering radiation risks. We determine the optimal initial evaluation strategy for cervical spine injury in pediatric blunt trauma. METHODS: We constructed a decision analysis tree for a hypothetical population of patients younger than 19 years with blunt trauma, using 3 strategies: clinical stratification, screening radiographs followed by focused CT if the radiograph result was positive, and CT. For the model inputs, we used the current literature to determine the probabilities of cervical spine injury and estimate the long-term risks of malignancy after CT, as well as test characteristics of radiographic imaging. We used published utilities and conducted 1- and 2-way sensitivity analyses to determine the optimal strategy for evaluation of pediatric cervical spine injury. RESULTS: In our model of a population with blunt trauma, the expected value of a clinical stratification strategy was the highest of the 3 strategies, making it the overall preferred management. One-way sensitivity analysis of several contributing factors revealed that the only independent factor that altered the dominant strategy was the sensitivity of clinical clearance criteria, lowering the threshold at which screening-radiograph strategy is optimal. Within the patient population considered as having non-negligible risk by clinical stratification and thus requiring imaging, the preferred imaging modality was screening radiograph/focused CT. The probability of cervical spine injury above which CT became the preferred strategy was 24.9%. CONCLUSION: The model highlights that clinical clearance and screening radiographs in a hypothetical trauma pediatric population are preferred strategies, whereas CT scanning is rarely the initial optimal evaluation. PMID- 25441249 TI - Accuracy of ultrasonography for determining successful realignment of pediatric forearm fractures. AB - STUDY OBJECTIVE: The primary objective of this study is to assess the accuracy of point-of-care ultrasonography compared with blinded orthopedic assessment of fluoroscopy in determining successful realignment of pediatric forearm fractures. The secondary objective is to determine the rate of agreement of ultrasonography and fluoroscopy in real-time by the treating physician. METHODS: A cross sectional study was conducted in children younger than 18 years and presenting to an academic emergency department with forearm fractures requiring realignment of a single bone. Physicians performed closed reductions with ultrasonographic assessment of realignment until the best possible reduction was achieved. Fluoroscopy was then immediately performed and images were saved. A positive test result was defined as an inadequately reduced fracture on fluoroscopy by a blinded pediatric orthopedic surgeon (reference standard) and on ultrasonography (index test) and fluoroscopy in real-time by the treating physician. RESULTS: One hundred patients were enrolled (median age 12.1 years; 74% male patients); the radius was involved in 98%, with 27% involving the growth plate. The sensitivity, specificity, positive predictive value, and negative predictive value were 50% (95% confidence interval [CI] 15.4% to 84.6%), 89.1% (95% CI 82.8% to 95.5%), 28.6% (95% CI 4.9% to 52.2%), and 95.3% (95% CI 90.9% to 99.8%), respectively. The treating physicians' agreement rate of the real-time images was 98%. CONCLUSION: Point-of-care ultrasonography can help emergency physicians determine when pediatric forearm fractures have been adequately realigned, but inadequate reductions should be confirmed by other imaging modalities. PMID- 25441250 TI - Greater occipital nerve block for postdural puncture headache (PDPH): a prospective audit of a modified guideline for the management of PDPH and review of the literature. AB - STUDY OBJECTIVE: To perform a prospective audit of the modified guideline for the management postdural puncture headache (PDPH) and present the results at 6 months. DESIGN: Prospective single-center audit. SETTING: University hospital. PATIENTS: 24 adult, ASA physical status 1, 2, and 3 patients presenting with PDPH in both the obstetric and nonobstetric setting. INTERVENTIONS: Epidural blood patch (EBP) and bilateral greater occipital nerve blocks (GONB) were administered. MEASUREMENTS: Headache scores, nausea scores, presence and severity of neck stiffness, tinnitus, photophobia, and any complications with either technique. RESULTS: 24 patients were audited. Nineteen patients failed conservative management and were offered both GONB and EBP. One patient chose the EBP and was successfully treated. Of the 18 patients who received the GONB, headache resolved in 12 patients (66%). Six patients had a partial response to nerve block and were treated with an EBP. CONCLUSION: Greater occipital nerve block with dexamethasone may have a role in the management of patients presenting with PDPH, who have failed conservative management. We present the results of our prospective audit and review the literature on GONB in the management of PDPH. PMID- 25441251 TI - Effect of soy nuts and equol status on blood pressure, lipids and inflammation in postmenopausal women stratified by metabolic syndrome status. AB - OBJECTIVE: Soy has been associated with lower risk of cardiovascular disease in Asian countries which consume daily soy. Our study examined whether production of equol, an estrogen metabolite, affected the ability of soy nuts to improve cardiovascular risk factors. MATERIALS/METHODS: Sixty postmenopausal women participated in a randomized, controlled, crossover trial of a Therapeutic Lifestyle Changes (TLC) diet alone and a TLC diet in which 0.5 cup of soy nuts (25 g of soy protein and 101 mg of aglycone isoflavones) replaced 25 g of nonsoy protein daily. Each diet was followed for 8 weeks at the end of which blood pressure (BP), lipid levels, adhesion molecules and inflammatory markers were measured. RESULTS: Women with MetS had significantly higher baseline body mass index (BMI), BP, triglycerides (TG), and soluble intercellular adhesion molecule (sICAM) than women without MetS. In women with MetS on the soy diet, significant reductions in diastolic BP (7.7%; P=0.02), TG (22.9%; P=0.02), C-reactive protein (CRP) (21.4%; P=0.01) and sICAM (7.3%; P=0.03) were noted among equol producers compared to levels on the TLC diet. No significant changes were noted in equol nonproducers. Similarly, in women without MetS, only equol producers had significant reductions in diastolic BP (3.3%, P=0.02) and CRP (30%, P=0.04). In contrast to women with MetS, TG and sICAM levels were not affected in women without MetS, a finding possibly related to lower baseline levels. CONCLUSIONS: Cardiovascular risk reduction with soy nuts is not uniform and may be greater among producers of equol. PMID- 25441252 TI - Excessive daytime sleepiness and metabolic syndrome: a cross-sectional study. AB - OBJECTIVE: Excessive daytime sleepiness (EDS) has been associated with singular independent symptoms of metabolic syndrome, such as insulin resistance and diabetes. The aim of this study was to assess whether this relationship is sustained among individuals who meet criteria for the whole syndrome. MATERIALS/METHODS: 994 Women aged 21-94 years (median 50.2 years, IQR 34-65) and 840 men aged 24-92 years (median 60.4 years, IQR 47-73) who resided in the Barwon Statistical Division, South-Eastern Australia, and participated in the Geelong Osteoporosis Study (GOS) between the years of 2001 and 2008. Anthropometric measurements, lifestyle, mood, demographic and health-related factors were obtained. Sleep duration was categorized as short (<6 h), average (6-9 h) and long (>9 h). Sleepiness was assessed using the Epworth Sleepiness Scale (ESS), and scores of >= 10 indicated EDS. The presence of metabolic syndrome was assessed using a modified version of criteria as outlined by the International Diabetics Federations recommendations (2005). RESULTS: Women: 138 (14.0%) of the women reported EDS; those with EDS were heavier, had a greater body mass index (BMI) and were more likely to have metabolic syndrome. The association between EDS and metabolic syndrome was sustained following adjustment for age and hours sleep (adjusted OR=1.90, 95% CI 1.16-3.09), however BMI attenuated the relationship (adjusted OR=1.64, 95% CI =1.05-2.57). These findings were independent of smoking status, alcohol intake, medication use, socioeconomic status, physical activity and current diagnosis of a depressive illness. Men: 111 (13.2%) of the men reported EDS; those with EDS had a greater waist circumference and were more likely to have metabolic syndrome. Analysis of age-stratified data (<60 years vs. >=60 years) revealed that the older men with EDS were more likely to have metabolic syndrome (OR=1.71, 95% CI 1.01-2.92), however, age explained this association (age adjusted OR=1.51, 95% CI 0.88-2.60). In the younger age group, no association was detected between EDS and metabolic syndrome. For both men and women, the prevalence of combined EDS and metabolic syndrome increased progressively with age. CONCLUSION: For women, the association between EDS and metabolic syndrome appears to be driven by adiposity measures; while for men, the association is somewhat attributed to older age. Additional research is required to assess temporal associations with underlying sleep pathology. PMID- 25441253 TI - Thalidomide controls adipose tissue inflammation associated with high-fat diet induced obesity in mice. AB - INTRODUCTION: Immunosuppressant agents modulate the activity of the immune system and control adipose tissue inflammatory responses associated with obesity. Controlling adipose tissue inflammation represents an interesting option for inhibiting the low-grade inflammatory state in obese subjects and for preventing obesity-associated pathologies. In this work, we assessed the effects of thalidomide on the inflammatory response in adipose tissue as well as on systemic inflammatory marker expression in the well-established high-fat diet-induced obesity mouse model. METHODS: Swiss male mice were fed a high-fat diet (60% kcal from fat) for 12 weeks and received thalidomide for the last 10 days (100 mg.kg 1). Adipokine levels were measured in serum and adipose tissue by EIA and real time quantitative PCR, respectively. Adipose tissue infiltrating macrophages were identified by immunohistochemistry and western blot analysis of F4/80 marker expression. Other inflammatory markers, such as c-Jun N-terminal kinase (JNK) phosphorylation and monocyte chemoattractant protein-1 (MCP-1) production, were also evaluated by western blot analysis. In vitro assays using 3T3-L1 adipocytes were also conducted to evaluated adipokine release. RESULTS: In obese mice, thalidomide administration induced a reduction in adiposity accompanied by a reduction of tumor necrosis factor-alpha (TNF-alpha), leptin and MCP-1 adipose tissue production, macrophage infiltration and JNK activation. TNF-alpha and leptin serum levels were also reduced by thalidomide treatment in obese mice. In vitro, the release of basal TNF-alpha and lipopolysaccharide (LPS)-induced MCP-1 was inhibited in 3T3-L1 cells. SIGNIFICANCE: Our results suggest that drugs that can modulate the inflammatory status as well as control adipose tissue expansion could represent an interesting approach in the management of obesity, highlighting the need for further development of such compounds. PMID- 25441254 TI - In vivo radioactive metabolite analysis for individualized medicine: a basic study of a new method of CYP activity assay using (123)I-IMP. AB - INTRODUCTION: (123)I-N-isopropyl-p-iodoamphetamine ((123)I-IMP) is metabolized and converted to (123)I-p-iodoamphetamine ((123)I-PIA) by CYP2C19 in humans. Since variations in (123)I-PIA levels reflect variations in CYP2C19 activity, CYP2C19 activity can be estimated by quantitative analysis of (123)I-PIA levels. Thus, (123)I-IMP administration can provide diagnostic information not only regarding cerebral blood flow (rCBF) but also regarding metabolic function. The aim of the present study was to detect variations in CYP activity in mice using metabolite analysis. METHODS: Metabolism of (125)I-IMP in pooled homogenates of mouse liver (MLH) was analyzed by high-performance liquid chromatography (HPLC) in the presence or absence of NADPH. The amount of (125)I-PIA generated was calculated as the normalized peak area of the chromatogram. Inhibition of (125)I IMP metabolism was evaluated using the inhibitor SKF-525A. A biodistribution study of (125)I-IMP was performed to determine the organ distribution of (125)I IMP/(125)I-IMP metabolites and the effect of SKF-525A. Variations in CYP activity in vivo were detected by administration of (123)I-IMP and/or SKF-525A to mice. The liver and the kidney were then excised, homogenized and analyzed using HPLC. RESULTS: (125)I-IMP was metabolized by MLH in the presence of NADPH, and the production of (125)I-PIA was inhibited by SKF-525A. SKF-525A did not greatly affect the biodistribution of (125)I-IMP/(125)I-IMP metabolites in vivo. Both (123)I-IMP and (123)I-PIA were detected in organs of control mice. However, (123)I-PIA was not detected in the livers or kidneys of mice treated with SKF 525A. CONCLUSIONS: CYP activity in vivo was inhibited by SKF-525A treatment. Variations in CYP activity could be detected in the blood, liver and kidney as changes in the peak area of (123)I-PIA. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: (123)I-IMP metabolite analysis has the potential to provide beneficial information for prediction of the effect of medicines, in addition to its contribution to more accurate rCBF diagnosis that reflects individual CYP activity. PMID- 25441255 TI - The effect of PPAR-gamma agonist on (18)F-FDG PET imaging for differentiating tumors and inflammation lesions. AB - INTRODUCTION: (18)F-2-deoxy-2-fluoro-d-glucose ((18)F-FDG) positron emission tomography (PET) has been used for imaging human cancers for several decades. Despite its extensive use, (18)F-FDG PET imaging has limitations in the tumor findings. The goal of this study was to investigate the potential of a PPAR-gamma agonist pioglitazone (PIO) to distinguish tumors and inflammatory lesions in (18)F-FDG PET imaging. METHODS: Studies of cellular uptake of (18)F-FDG and Western blot were performed in macrophage (RAW264.7) and three tumor cell lines (A549, KB, and MDA-MB-231) after treatment with PIO. In vivo microPET/CT imaging and biodistribution were performed in animal models. RESULTS: The uptake of (18)F FDG in the macrophages was decreased and uptake of (18)F-FDG in the tumor cells was increased when these cells were treated with PIO. Western blot showed that the expression of Glut1 was reduced by treatment of PIO in the macrophage cells, whereas the expression of Glut1 in the tumor cells was increased. In vivo PET/CT imaging revealed that (18)F-FDG uptake (%ID/g) in the tumors was enhanced from 4.05+/-1.46 to 5.28+/-1.92 for A549, from 3.9+/-0.5 to 4.9+/-0.2 for KB, and from 9.14+/-0.86 to 13.48+/-2.07 for MDA-MB-231 tumors after treatment with PIO. Unlike tumors, the RAW264.7 xenograft model showed the reduced (18)F-FDG uptake in the inflammatory lesion from 11.74+/-1.19 to 6.50+/-1.47. The results of biodistribution also showed that (18)F-FDG uptake in the tumors were increased after treatment of PIO. However, the uptake of inflammation lesions was reduced. CONCLUSIONS: In this study, we demonstrated the effect of a PPAR-gamma agonist PIO on (18)F-FDG uptake in tumors and inflammation in vitro and in vivo. PIO has potential to differentiate tumors and inflammatory lesions on (18)F-FDG PET imaging. PMID- 25441256 TI - Denitrification by cystic fibrosis pathogens - Stenotrophomonas maltophilia is dormant in sputum. AB - OBJECTIVE: Chronic Pseudomonas aeruginosa lung infection is the most severe complication for cystic fibrosis (CF) patients. Infected endobronchial mucus of CF patients contains anaerobic zones mainly due to the respiratory burst of polymorphonuclear leukocytes. We have recently demonstrated ongoing denitrification in sputum from patients infected with P. aeruginosa. Therefore we aimed to investigate, whether the pathogenicity of several known CF pathogens is correlated to their ability to perform denitrification. METHODS: We measured denitrification with N(2)O microsensors in concert with anaerobic growth measurements by absorbance changes and colony counting in isolates from 32 CF patients chronically infected with the highly pathogenic bacteria P. aeruginosa, Achromobacter xylosoxidans, Burkholderia multivorans or the less pathogenic bacterium Stenotrophomonas maltophilia. Consumption of NO(3)(-) and NO(2)(-) was estimated by the Griess Assay. All isolates were assayed during 2 days of incubation in anaerobic LB broth with NO(3)(-) or NO(2)(-). PNA FISH staining of 16S rRNA was used to estimate the amount of ribosomes per bacterial cells and thereby the in situ growth rate of S. maltophilia in sputum. RESULTS: Supplemental NO(3)(-) caused increased production of N(2)O by P. aeruginosa, A. xylosoxidans and B. multivorans and increased growth for all pathogens. Growth was, however, lowest for S. maltophilia. NO(3)(-) was metabolized by all pathogens, but only P. aeruginosa was able to remove NO(2)(-). S. maltophilia had limited growth in sputum as seen by the weak PNA FISH staining. CONCLUSIONS: All four pathogens were able to grow anaerobically by NO(3)(-) reduction. Denitrification as demonstrated by N(2)O production was, however, not found in S. maltophilia isolates. The ability to perform denitrification may contribute to the pathogenicity of the infectious isolates since complete denitrification promotes faster anaerobic growth. The inability of S. maltophilia to proliferate by denitrification and therefore grow in the anaerobic CF sputum may explain its low pathogenicity in CF patients. PMID- 25441257 TI - A comparative study of zinc protoporphyrin IX-forming properties of animal by products as sources for improving the color of meat products. AB - The objective of this study was to obtain fundamental data for improving the color of meat products by using animal by-products. We investigated zinc protoporphyrin IX (ZnPP)-forming properties of various internal organs from pigs and chickens. ZnPP was formed in the liver, heart and kidney, whereas the porcine spleen and bile, which are involved in the metabolism of heme, did not have ZnPP forming properties. The optimum pH values were different among the internal organs and the ZnPP-forming properties of porcine organs were better than those of chicken organs. The porcine liver showed the greatest ZnPP-forming properties among all of the internal organs investigated in this study. The optimum pH value for ZnPP formation in the liver was lower than that of skeletal muscle. Oxygen did not inhibit the formation of ZnPP in the liver, unlike in skeletal muscle. Animal by-products such as the liver have good ability for the formation of ZnPP and might be useful for improving the color of meat products. PMID- 25441258 TI - Exploring 'new' bioactivities of polymers at the nano-bio interface. AB - A biological system is essentially an elegant assembly of polymeric nanostructures. The polymers in the body, biomacromolecules, are both building blocks and versatile messengers. We propose that non-biologically derived polymers can be potential therapeutic candidates with unique advantages. Emerging findings about polycations, polysaccharides, immobilised multivalent ligands, and biomolecular coronas provide evidence that polymers are activated at the nano-bio interface, while emphasising the current theoretical and practical challenges. Our increasing understanding of the nano-bio interface and evolving approaches to establish the therapeutic potential of polymers enable the development of polymer drugs with high specificities for broad applications. PMID- 25441259 TI - Validity and reliability of global operative assessment of laparoscopic skills (GOALS) in novice trainees performing a laparoscopic cholecystectomy. AB - PURPOSE: Global Operative Assessment of Laparoscopic Skills (GOALS) assessment has been designed to evaluate skills in laparoscopic surgery. A longitudinal blinded study of randomized video fragments was conducted to estimate the validity and reliability of GOALS in novice trainees. METHODS: In total, 10 trainees each performed 6 consecutive laparoscopic cholecystectomies. Sixty procedures were recorded on video. Video fragments of (1) opening of the peritoneum; (2) dissection of Calot's triangle and achievement of critical view of safety; and (3) dissection of the gallbladder from the liver bed were blinded, randomized, and rated by 2 consultant surgeons using GOALS. Also, a grade was given for overall competence. The correlation of GOALS with live observation Objective Structured Assessment of Technical Skills (OSATS) scores was calculated. Construct validity was estimated using the Friedman 2-way analysis of variance by ranks and the Wilcoxon signed-rank test. The interrater reliability was calculated using the absolute and consistency agreement 2-way random-effects model intraclass correlation coefficient. RESULTS: A high correlation was found between mean GOALS score (r = 0.879, p = 0.021) and mean OSATS score. The GOALS score increased significantly across the 6 procedures (p = 0.002). The trainees performed significantly better on their sixth when compared with their first cholecystectomy (p = 0.004). The consistency agreement interrater reliability was 0.37 for the mean GOALS score (p = 0.002) and 0.55 for overall competence (p < 0.001) of the 3 video fragments. CONCLUSION: The validity observed in this randomized blinded longitudinal study supports the existing evidence that GOALS is a valid tool for assessment of novice trainees. A relatively low reliability was found in this study. PMID- 25441260 TI - Outcomes registries: an untapped resource for use in surgical education. AB - OBJECTIVE: To examine the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) for use in profiling the aggregated resident operative experience by postgraduate training year and to demonstrate the extent to which a surgical registry could be used to examine resident exposure to adverse events. BACKGROUND: Independent data regarding the operative experience and clinical effectiveness across residency programs remain elusive. In the absence of reliable data, the ability to standardize surgical education and reduce variation in practice remains an unachievable goal. METHODS: We identified general surgery cases using the ACS NSQIP Participant Use File 2011. Resident participation was defined according to postgraduate year (PGY). Descriptive statistical analyses were performed regarding procedure type and clinical outcomes. RESULTS: Of the total general surgery cases, a PGY 1 to 5 resident participated in 87% (45,423), and 28% (n = 14,559) were performed with PGY 5 residents. Interns were involved with 10% (n = 5448) of the cases. The type of procedures performed varied by PGY, but cholecystectomy was the most common. Overall, 11% (4773) of cases were associated with an adverse event or mortality or both, with a mortality rate of 0.8% (374). The most common adverse event was bleeding (5%). CONCLUSIONS: The ACS NSQIP captures the breadth of the resident experience in operative case mix and exposure to adverse events. Although the program was originally designed to uncover areas for quality improvement, the findings of our study demonstrate the utility of an outcomes registry as a guide for the development of future educational content in the resident curriculum. PMID- 25441262 TI - Use of human patient simulation and validation of the Team Situation Awareness Global Assessment Technique (TSAGAT): a multidisciplinary team assessment tool in trauma education. AB - OBJECTIVE: Situation awareness (SA) is a vital construct for decision making in intense, dynamic environments such as trauma resuscitation. Human patient simulation (HPS) allows for a safe environment where individuals can develop these skills. Trauma resuscitation is performed by multidisciplinary teams that are traditionally difficult to globally assess. Our objective was to create and validate a novel tool to measure SA in multidisciplinary trauma teams using a HPS -the Team Situation Awareness Global Assessment Technique (TSAGAT). SETTING: Memorial University Simulation Centre. DESIGN/PARTICIPANTS: Using HPS, 4 trauma teams completed 2 separate trauma scenarios. Student, junior resident, senior resident, and attending staff teams each had 3 members (trauma team leader, nurse, and airway manager). Individual SAGATs were developed by experts in each respective field and contained shared and complimentary knowledge questions. Teams were assessed with SAGAT in real time and with traditional checklists using video review. TSAGAT was calculated as the sum of individual SAGAT scores and was compared with the traditional checklist scores. RESULTS: Shared, complimentary, and TSAGAT scores improved with increasing team experience. Differences between teams for TSAGAT and complimentary knowledge were statistically significant (p < 0.05). Mean checklist differences between teams also reached statistical significance (p < 0.05). TSAGAT scores correlated strongly with traditional checklist scores (Pearson correlation r = 0.996). Interrater reliability for the checklist tool was high (Pearson correlation r = 0.937). CONCLUSION: TSAGAT is the first valid and reliable assessment tool incorporating SA and HPS for multidisciplinary team performance in trauma resuscitation. TSAGAT could compliment or improve on current assessment methods and curricula in trauma and critical care and provides a template for team assessment in other areas of surgical education. PMID- 25441263 TI - Young athletes' awareness and monitoring of anti-doping in daily life: Does motivation matter? AB - This study was a preliminarily investigation into the prevention of unintentional doping on the basis of self-determination theory (SDT). Specifically, we examined the relationship between athletes' motives for doping avoidance and their behavior when offered an unfamiliar food product. Participants were young Australian athletes (n = 410) that were offered a free lollipop prior to completing a questionnaire. It was noted whether participants refused to take or eat the lollipop and whether they read the ingredients of the lollipop. The questionnaire assessed autonomous and controlled forms of motivation, amotivation, doping intentions, and adherence regarding doping avoidance behaviors. The results showed that young athletes who adopted controlled reasons to avoid doping in sport (e.g., not getting caught) tended to report higher adherence to behaviors related to avoiding and monitoring banned substances, whereas those who adopted autonomous reasons (e.g., anti-doping being consistent with life goals) appeared to be more willing to read the ingredients of the provided food. The significant interaction effect between autonomous and controlled motivation indicated that autonomous motivation was more predictive to doping intention for athletes with low controlled motivation. It is concluded that SDT may help understand the motivational processes of the prevention of unintentional doping in sport. PMID- 25441261 TI - Estimating minimum program volume needed to train surgeons: when 4 * 15 really equals 90. AB - INTRODUCTION: Work-hour restrictions have decreased flexibility in scheduling and reduced exposure to certain operative cases. These restrictions may affect a resident's ability to meet certification requirements, particularly for rare, unscheduled cases (e.g., cardiothoracic transplants). We developed a computer based simulation model using variables such as case volume and program size to demonstrate the influence of these factors on the likelihood of certifying a set of residents on rare cases. METHODS: We built a simulator to predict the probability of attaining certification for surgical residents, using cardiothoracic transplants as a test case. Inputs to the model included operating times, call schedules, and procurement travel times, as well as information on the distribution of times between transplants. RESULTS: We simulated 100 years of schedules using our current system parameters of an average of 33 heart and 31 lung transplants per year, and assuming an Accreditation Council for Graduate Medical Education-compliant daily-rotating call schedule. Despite having enough transplants to certify all residents for lungs if all opportunities were distributed equally among residents, the certification rate achieved when constrained by arrival time (and call schedules) and work restrictions was only 55%. Our calculations show that meeting minimum transplant-certification requirements for all residents would require at least 1.5 times the expected number of annual transplants. CONCLUSIONS: Our model enables analysis of a given program's ability to certify its residents based on program size and volume. These results could be used to design alternative scheduling paradigms to improve certification rates, without requiring reductions in certification requirements or program size. PMID- 25441264 TI - Long-term changes in body weight are associated with changes in blood pressure levels. AB - BACKGROUND AND AIMS: Hypertension and obesity are highly prevalent in Western societies. We investigated the associations of changes in body weight with changes in blood pressure and with incident hypertension, incident cardiovascular events, or incident normalization of blood pressure in patients who were hypertensive at baseline, over a 5-year period. METHODS AND RESULTS: Data of men and women aged 20-81 years of the Study of Health in Pomerania were used. Changes in body weight were related to changes in blood pressure by linear regression (n = 1875) adjusted for cofounders. Incident hypertension, incident cardiovascular events, or incident blood pressure normalization in patients who were hypertensive at baseline were investigated using Poisson regression (n = 3280) models. A change of 1 kg in body weight was positively associated with a change of 0.45 mm Hg (95% confidence interval (CI): 0.34-0.55 mm Hg) in systolic blood pressure, 0.32 mm Hg (95% CI: 0.25-0.38 mm Hg) in diastolic blood pressure, and 0.36 mm Hg (95% CI: 0.29-0.43 mm Hg) in mean arterial pressure (all p-values <0.001). A 5% weight loss reduced the relative risk (RR) of incident hypertension (RRs 0.84 (95% CI: 0.79-0.89)) and incident cardiovascular events (RRs 0.81 (95% CI: 0.68-0.98)) and increased the chance of incident blood pressure normalization in patients who were hypertensive at baseline by 15% (95% CI: 7-23%). CONCLUSIONS: Absolute and relative changes in body weight are positively associated with changes in blood pressure levels and also affect the risk of cardiovascular events. PMID- 25441265 TI - Intraoperative value of the thompson test. AB - The purpose of the present study was to assess the validity of the Thompson sign and determine whether the deep flexors of the foot can produce a falsely intact Achilles tendon.Ten unmatched above-the-knee lower extremity cadaveric specimens were studied. In group 1, the Achilles tendon was sectioned into 25% increments. The Thompson maneuver was performed after each sequential sectioning of the Achilles tendon, including after it had been completely sectioned. If the Thompson sign was still intact after complete release of the Achilles tendon, we proceeded to release the tendon, and tendon flexor hallucis longus, flexor digitorum longus, and posterior tibial tendons. The Thompson test was performed after the release of each tendon. In group 2, the tendon releases were performed in a reverse order to that of group 1, with the Thompson test performed after each release. In group 1, the Thompson sign remained intact in all specimens after sectioning of 25%, 50%, and 75% of the tendon. After complete (100%) release of the tendon, the Thompson sign was absent in all specimens. In group 2, the Thompson sign remained intact after sectioning of the posterior tibial, flexor digitorum longus, and flexor hallucis longus tendons in all specimens. The Thompson sign remained intact in all specimens after sectioning of 25%, 50%, and 75% of the Achilles tendon. After complete release of the tendon, the Thompson sign was absent in all specimens.The Thompson test is an accurate clinical test for diagnosing complete Achilles tendon ruptures. However, it might not be a useful test for diagnosing partial Achilles tendon ruptures. Our findings also call into question the usefulness of the Thompson test in the intraoperative setting. PMID- 25441266 TI - Oncogenic Osteomalacia From a Primary Phosphaturic Mesenchymal Tumor of the Toe: A Case Report. AB - Oncogenic osteomalacia is an acquired, rare paraneoplastic syndrome characterized by renal phosphate wasting and subsequent hypophosphatemic osteomalacia. The condition is usually associated with a phosphaturic mesenchymal tumor, which produces fibroblast growth factor 23, the primary circulating factor responsible for reduced tubular phosphate reabsorption. Clinically, adult patients typically present with bone pain, myalgia, recurrent and/or multiple stress fractures, and fatigue, with serum levels typified by low 1,25-(OH)2 vitamin D3, increased alkaline phosphatase, and normal calcium, parathyroid hormone, calcitonin, 25-OH vitamin D3, and 25,25-(OH)2 vitamin D3 levels. The tumor in question is typically benign and can be of little clinical significance apart from its role in causing hypophosphatemic osteomalacia. Detection of the tumor, therefore, can often be delayed and requires an astute index of suspicion. PMID- 25441268 TI - Limb Salvage in Secondary Chondrosarcoma of the Metatarsus. AB - Malignant transformation of metatarsal osteochondroma into chondrosarcoma is a rare entity. The most optimal line of treatment, salvage procedure or amputation, continues to be debated. Both of these treatments have varied in popularity. We report the case of a 24-year-old male with chondrosarcoma secondary to differentiation of an osteochondroma in the second and third metatarsals. Wide resection of the tumor mass and reconstruction of the second and third metatarsals was performed using a simple and biologic approach. This was accomplished with an autologous nonvascularized fibular graft to reconstruct the longitudinal arch of the foot. The foot was successfully salvaged, with good anatomic, functional, and aesthetic results. At 1 year postoperatively, the patient was able to walk without any orthotic devices and had returned to his routine work. No evidence of local recurrence or metastasis was observed. PMID- 25441267 TI - An Unusual Ankle Injury: The Bosworth-Pilon Fracture. AB - The Bosworth injury occurs when the distal fibula becomes entrapped posterior to the posterior tibial tubercle, usually as a result of a supination external rotation injury. This uncommon occurrence is a recognized cause of an irreducible ankle dislocation. A pilon fracture is usually a high-energy injury caused by the talus being driven upward into the tibial plafond. The resulting bone and soft tissue injuries often require a staged approach to management. The present report is the first in the medical data to describe a Bosworth injury complicating a pilon fracture. We also discuss a management approach for this rare fracture. PMID- 25441269 TI - A Method of Open Reduction of an Irreducible Hawkins Type III Fracture of the Talar Neck. AB - Hawkins type III fracture talar neck may sometimes be a nightmare for surgeons to reduce, even intraoperatively. It is difficult to reduce as the talar body is locked into its dislocated posteromedial position out of both the ankle and subtalar joint. Maneuvers of reduction have been described both in dorsiflexion and plantarflexion of ankle, but these are complicated and not tissue friendly. Further, various methods of grasping and pushing the dislocated talar body by use of joysticks and distractors have been advocated. To accomplish this intraoperatively, we present a convenient and utilitarian method using only 2 smooth 1.5-mm Kirschner wires and a JESS distractor clamp. Two key concepts to keep in mind while reducing such fracture dislocations are also highlighted. This was done in a 22-year-old male with 7-day-old Hawkins type III fracture of the left talar neck and a right Pilon fracture with good results at 2 year follow-up. PMID- 25441270 TI - Fact or fiction? Iatrogenic hallux abducto valgus secondary to tibial sesamoidectomy. AB - First ray function and hallux misalignment after isolated tibial sesamoidectomy have been topics of debate. Although sesamoidectomy has been proved to be effective in the relief of sesamoid pain, many foot and ankle surgeons remain hesitant to perform the procedure fearing a possible joint perturbation. To our knowledge, the present study is the first to evaluate both laboratory and clinical evidence of the association between isolated tibial sesamoidectomy and hallux abducto valgus deformity. The bench study consisted of 10 cadaveric limbs that were dissected and prepared for testing. Controlled valgus loads were applied before and after tibial sesamoidectomy. No significant difference was found in the joint position after sesamoidectomy in both the rectus (p = .36) and the dorsiflexed (p = .062) positions. The clinical evaluation consisted of a retrospective cohort of 5 females; all of whom underwent isolated tibial sesamoidectomy. The pre- and postoperative radiographs and self-reported pain scores (visual analog scale) were compared. None of the patients developed a postoperative hallux abducto valgus deformity. Neither the hallux abductus angle (p = .180) nor the intermetatarsal angle 1-2 (p = .180) changed significantly in the postoperative setting. The visual analog scale pain scores changed from a mean of 6.8 to 1, a significant difference (p = .042). Based on our observations and clinical experience, we believe that isolated tibial sesamoidectomy does not have a significant effect on the position of the first metatarsophalangeal joint when meticulous surgical technique is used to excise the sesamoid. Isolated tibial sesamoidectomy can provide substantial pain relief and appears to be a safe treatment for a variety of conditions affecting the tibial sesamoid. PMID- 25441271 TI - Outcomes are favorable after arthroscopic treatment of osteochondritis dissecans of the talus. AB - Arthroscopic treatment of osteochondritis dissecans (OCD) of the talus has resulted in outcomes as good as, or better than, those after arthrotomy. We noted a lack of prospective studies investigating the outcomes of arthroscopic treatment. As such, we conducted a prospective study investigating the functional outcomes, pain scores, patient satisfaction, and expectation scores of patients undergoing arthroscopic treatment of OCD of the talus, hypothesizing that these patients would have good outcomes and satisfaction. A total of 61 patients underwent arthroscopic chondroplasty, removal of loose bodies, and microfracture for OCD of the talus and completed >=1 year of follow-up. We evaluated patients pre- and postoperatively at 6 and 12 months using the Ankle-Hindfoot score, visual analog scale for pain, and Medical Outcomes Study short-form 36 questionnaires. We also evaluated the patients' expectations and satisfaction. The mean Ankle-Hindfoot score improved significantly from 53.0 +/- 14.3 points preoperatively to 77.8 +/- 19.1 at 6 months and 83.1 +/- 18.3 at 12 months after arthroscopic treatment (p < .001). The overall scores at the final follow-up visit were excellent for 30 (49%), good for 6 (10%), fair for 18 (30%), and poor for 7 (11%). The patients also experienced significant improvement in the visual analog scale score and physical component score of the short-form 36 questionnaire (p < .001). Of the 61 patients, 67% had their expectations fulfilled and 74% were satisfied with their surgery at 12 months of follow-up. Arthroscopic treatment of OCD of the talus continues to be a successful procedure to alleviate pain and loss of function. It is also associated with improvements to quality of life and good patient satisfaction. PMID- 25441272 TI - Reconstruction of weightbearing forefoot defects with digital artery flaps. AB - Reconstruction of a defect of the weightbearing forefoot region remains a challenging problem owing to the limited alternatives available. The digital artery flap can be used for coverage of defects in the weightbearing forefoot. The present study reports our results using a digital artery flap for reconstruction of soft tissue defects of the weightbearing forefoot in 8 patients. The mean patient age was 35 +/- 11.3 years. The etiology of the soft tissue defects included 4 (50%) traumatic events, 2 (25%) dysfunctional scars, and 2 (25%) neuropathic ulcerations. The mean postoperative follow-up duration was 22 +/- 11.1 months (range 12 months to 4 years). All 8 flaps survived successfully. The complications included 1 case of delayed healing of a neuropathic ulceration. The digital artery flap is a good alternative for soft tissue defects of the weightbearing forefoot. The surgical techniques for harvesting the flaps are easy to manage. PMID- 25441273 TI - Missed Medial Malleolar Fracture Associated With Achilles Tendon Rupture: A Case Report and Literature Review. AB - A 45-year-old man sustained an Achilles tendon rupture while playing futsal. A concomitant medial malleolar fracture was not diagnosed until the patient underwent an operation for Achilles tendon repair. A routine postoperative radiograph showed a minimally displaced medial malleolar fracture. Conservative treatment was chosen for the fracture. The function of the Achilles tendon recovered well, and the fracture was united. A medial malleolar fracture can be missed when an Achilles tendon rupture occurs simultaneously. Thus, surgeons should consider the possibility of medial malleolar fracture associated with an Achilles tendon rupture. PMID- 25441274 TI - Use of an all-suture anchor for re-creation of the anterior talofibular ligament: a case report. AB - The lateral ankle ligament complex is typically injured during athletic activity caused by an inversion force on a plantar flexed foot. Numerous open surgical procedures to reconstruct the lateral ankle complex have been described. In contrast, we present a case report in which an all-suture anchor was used arthroscopically to re-create the anterior talofibular ligament in conjunction with ankle arthroscopy. A retrospective analysis of a 55-year-old male with a work-related inversion ankle sprain was performed with 14 months of follow-up. Objective and subjective assessments were obtained using range of motion measures, a strength assessment, and the Foot Function Index. An all-suture anchor was deployed through the anterolateral portal and secured in both the fibula and talus, re-creating the anterior talofibular ligament at its origin and insertion. Active range of motion physical therapy began at 2 weeks postoperatively. The patient started a neuromuscular re-education program at 5 weeks with minimal pain or discomfort. A return to full duty was achieved at 3 months postoperatively. To our knowledge, the use of an all-suture anchor has not been previously reported for lateral ankle complex re-creation. It is hoped that this approach to anterior talofibular ligament repair will decrease the incidence of complications and improve outcomes. PMID- 25441275 TI - Early minimally invasive percutaneous fixation of displaced intra-articular calcaneal fractures with a percutaneous angle stable device. AB - The Minimally Invasive Reduction and Osteosynthesis System((r)) (MIROS) is a percutaneous angle stable device for the treatment of fractures. The aim of the present study was to evaluate the clinical and radiographic results of an early minimally invasive osteosynthesis with the MIROS device. A total of 40 consecutive patients were treated for an intra-articular fracture of the calcaneus. We evaluated the clinical and radiographic outcomes after treatment of intra-articular calcaneal fractures with the MIROS hardware. Soft tissue damage was noted. The patients completed the American Orthopaedic Foot and Ankle Society survey at 12 and 24 months and underwent radiologic evaluations. A statistically significant association between the American Orthopaedic Foot and Ankle Society score and type of soft tissue lesion. A Sanders type II, III, and IV fracture was found in 15, 20, and 15 of 50 fractures, respectively. Postoperatively, restoration of the posterior facet was reached in 13 of 15, 18 of 20, and 11 of 15 with a type II, III, and IV fracture, respectively. The American Orthopaedic Foot and Ankle Society scale mean score was 85 at the final follow-up visit. No significant association was found between the score and the preoperative variables (p > .09), although patients with bilateral fractures had a significantly lower score. The MIROS device for early treatment of intra articular calcaneus fractures resulted in excellent clinic and radiologic results. The standardized technique we have reported, with the elastic wires acting as a girder for the fractured and displace subtalar joint and the collapsed lateral calcaneal wall, has permitted early weightbearing with positive stimuli for the bone healing. The drainage effect of the percutaneous wires likely prevented compartment syndrome when applied within the first hours after the trauma. PMID- 25441276 TI - Comparison of wedge resection (Winograd procedure) and wedge resection plus complete nail plate avulsion in the treatment of ingrown toenails. AB - The present retrospective study compared the efficacy of wedge resection (Winograd procedure) and wedge resection plus complete nail plate avulsion for the treatment of ingrown toenails (onychocryptosis). Two surgical methods were performed in 95 patients with a stage 2 or 3 ingrown toenail. Each patient was examined weekly until healing and then at 1, 6, and 12 months of follow-up. The outcomes measured were surgical duration, healing time, recurrence rate, the incidence of postoperative infection, and cosmetic appearance after surgery. Of the 95 patients (115 ingrown toenails) included in the present study, 39 (41.1%) underwent wedge resection (Winograd procedure) and 56 (59%), wedge resection plus complete nail plate avulsion. The mean surgical duration for wedge resection (Winograd procedure) and wedge resection plus complete nail plate avulsion was 14.9 +/- 2.4 minutes and 15.1 +/- 3.2 minutes, respectively (p = .73). The corresponding healing times were 2.8 +/- 1.2 weeks and 2.7 +/- 1.3 weeks (p = .70). Recurrence developed in 3 (3.2%) patients after wedge resection (Winograd procedure) and in 4 (4.2%) after wedge resection plus complete nail plate avulsion. In addition, postoperative infection occurred in 3 (3.2%) patients after wedge resection (Winograd procedure) and 2 (2.1%) after wedge resection plus complete nail plate avulsion. Both of the surgical procedures were practical and appropriate for the treatment of ingrown toenails, being simple and associated with low morbidity and a high success rate. However, cosmetically, wedge resection (Winograd procedure) would be the better choice because the nail plate remains intact. PMID- 25441277 TI - Posterior tibial tendon entrapment within an intact ankle mortise: a case report. AB - The present case report demonstrates a rare finding associated with irreducible ankle fracture dislocations. To our knowledge, posterior tibial tendon entrapment with an intact ankle mortise has not yet been documented in published studies. In the case of our patient, a high-energy, 12-ft fall resulted in a comminuted intra articular fracture of the medial malleolus, confirmed by the initial radiographs. Preoperative magnetic resonance imaging showed the Achilles tendon to be ruptured and the posterior tibial tendon to be both displaced and entrapped between the medial malleolar fracture fragments, preventing initial closed reduction. At operative repair for the ruptured Achilles tendon and the medial malleolus fracture, the posterior tibial tendon was removed from the fracture site and was found to be intact with no evidence of laceration or rupture. The tendon was returned back to its anatomic position, and the tendon sheath was reapproximated. Although uncommon, it is important that entrapment of the posterior tibial tendon be considered in cases of irreducible ankle fracture. This injury type can be addressed during open reduction internal fixation to achieve reduction. PMID- 25441278 TI - Tarsal Tunnel Syndrome Secondary to an Unreported Ossicle of the Talus: A Case Report. AB - Tarsal tunnel syndrome (TTS) is a compression neuropathy of the posterior tibial nerve in the tarsal tunnel. In about 80% of patients, a specific cause can be identified for TTS. We present a case of TTS secondary to an ossicle in close relation to the talus that, to our knowledge, has not previously been reported. A 26-year-old male presented with left ankle and foot pain that increased with activity and playing football. He had a tingling sensation and paresthesia in the sole and medial border of the foot along the distribution of the medial and lateral plantar nerves. Clinically, he had hard swelling at the floor of the tarsal tunnel, and Tinel's sign was positive. Computed tomography showed an accessory ossicle articulating with the posteromedial aspect of the talus, separating the flexor digitorum longus and flexor hallucis longus tendons, with tenosynovitis of the tibialis posterior, flexor digitorum longus and flexor hallucis longus tendons. Surgical release of the tarsal tunnel and excision of the ossicle were performed. Postoperatively, the patient showed dramatic improvement and had no complications or recurrence of symptoms after 8 months of follow-up. More interestingly, to the best of our knowledge, this ossicle has not been previously reported to cause TTS. PMID- 25441280 TI - Intraosseous Gouty Tophus in the Talus: A Case Report. AB - Isolated intraosseous gouty invasion is a rare presentation of gout. Although most patients will have a history of gouty arthritis or hyperuricemia, others will have an insidious onset of local pain, tenderness without significant swelling, or inflammation. Surgical debridement is the mainstay of treatment for intraosseous tophus formation. PMID- 25441279 TI - Multifocal bilateral metatarsal tuberculosis: a rare presentation. AB - Tuberculosis, or phthisis (consumption) as it was popularly known in the Greek era, has been endemic in Southeast Asia and Sub-Saharan Africa; however, the human immunodeficiency virus epidemic has seen the re-emergence of this disease in the areas in which it was not very commonly reported. With this, the need for understanding and treatment of rare presentations of tuberculosis has become of paramount importance to achieve the World Health Organization millennium goal of a "reversal of incidence by 2015." Foot involvement has been reported in 0.1% to 0.3% of extrapulmonary cases. Multifocal lesions have an incidence of <10% in osteoarticular tuberculosis. Bilateral feet involvement in multifocal tuberculosis has not yet been reported in either children or adults in published studies. We report a case of tuberculosis with lesions in the bilateral metatarsals, the occurrence of which is very rare. The diagnosis was mainly histopathologic owing to the paucibacillary nature of the disease. Early identification and treatment with antitubercular drugs will normally result in a good cosmetic and functional result. PMID- 25441281 TI - Relationship of the dorsalis pedis artery to the tarsal navicular. AB - When undertaking surgical maneuvers about the midfoot, caution must be used to avoid injury to the dorsalis pedis artery, which courses along the dorsum of the foot on the dorsolateral aspect of the tarsal navicular. In an effort to better understand the relationship of the course of the dorsalis pedis artery relative to the tarsal navicular, 128 embalmed feet (31 [48.4%] female and 33 [51.6%] male cadavers aged 15 to 91 years) were measured. The dorsalis pedis artery was dissected from its origin to its termination (i.e., the first dorsal metatarsal artery and the deep plantar perforating artery), and the distance from the medial cortex of the navicular tuberosity to the medial margin of the artery and the location of the artery as a percentage of the medial-to-lateral width of the navicular were measured. In the male cadaver specimens, the distance from the navicular tuberosity to the dorsalis pedis was 23.75 +/- 3.1 mm, the width of the navicular was 37.41 +/- 5.0 mm, and the location of the artery as a percentage of the width of the navicular was 64.34% +/- 13.1%. In the female cadaver specimens, the distance from the navicular tuberosity to the dorsalis pedis was 22.81 +/- 5.5 mm, the width of the navicular was 36.11 +/- 4.0 mm, and the location of the artery as a percentage of the width of the navicular was 63.29% +/- 9.9%. For the right foot specimens, the distance from the navicular tuberosity to the dorsalis pedis artery was 20.29 +/- 3.3 mm, and the width of the navicular was 37.21 +/- 4.4 mm. For the left foot specimens, the distance from the navicular tuberosity to the dorsalis pedis was 21.40 +/- 2.5 mm, and the width of the navicular was 35.92 +/- 4.4 mm. The statistical comparisons between the males and females showed no statistically significant differences. In contrast, those between the right and left feet showed significant differences in the distance from the navicular tuberosity to the dorsalis pedis artery and the location of the dorsalis pedis artery as a percentage of the width of the navicular. Knowledge of these distances and the location of the dorsalis pedis artery relative to the width of the tarsal navicular should aid surgeons in preparation for, and during, dissection of the midfoot. PMID- 25441282 TI - Surgical treatment of calcaneal fractures of Sanders type II and III by a minimally invasive technique using a locking plate. AB - The aim of the present study was to investigate the outcomes of surgical treatment of calcaneal fractures of Sanders type II and III using a minimally invasive technique and a locking plate. We reviewed 33 feet in 33 consecutive patients with Sanders type II and III calcaneal fractures who had undergone a minimally invasive technique using percutaneous reduction and locking plates. All operations were performed by the same surgeons. The postoperative evaluation included radiographs, determination of restoration of Bohler's angle and Gissane's angle, and administration of the American Orthopaedic Foot and Ankle Society ankle-hind foot scale, Maryland Foot Score, and visual analog scale of pain. The mean visual analog scale score was 1.6 +/- 1.4 when radiographic fracture healing was observed. The median functional score of the 33 patients (33 feet) reached 82 (interquartile range 80 to 99) at the last follow-up evaluation according to the American Orthopaedic Foot and Ankle Society ankle-hind foot scale and 89 (interquartile range 80 to 99) according to Maryland Foot Score. All cases achieved restoration of a normal Bohler's angle and Gissane's angle. Postoperative superficial infections occurred in 2 patients, subtalar arthritis developed in 2, and no soft tissue necrosis was observed. For Sanders type II and III fractures of the calcaneus bone, treatment with a minimally invasive technique combining percutaneous reduction and locking plate fixation provided satisfactory clinical results, with a lower incidence of complications. However, longer term studies with a larger sample size and more randomized controlled trials are required to define the superiority of our minimally invasive technique compared with conventional surgical treatment of calcaneal fractures. PMID- 25441283 TI - Autogenous capsular interpositional arthroplasty surgery for painful hallux rigidus: assessing changes in range of motion and postoperative foot health. AB - The autogenous capsular interpositional arthroplasty procedure can be a motion sparing alternative to arthrodesis for the treatment of recalcitrant hallux rigidus deformity. Previous studies have reported positive results; however, many had small samples or lacked comparable preoperative measures. The present study used a prospective cohort study to assess the benefit of this technique for increasing range of motion, and comparative data to assess the reduction of pain and improvements in perceived foot health status for a consecutively drawn sample of patients. Thirty-four patients (44 feet) reviewed using a long-arm goniometer at a mean of 3.75 years after surgery experienced a significant increase in dorsiflexion (preoperative mean 11.09 degrees +/- 10.13 degrees ; postoperative mean 26.64 degrees +/- 10.07 degrees ; p < .001); plantar flexion remained unchanged. Additionally, 15 of 17 patients for whom the hallux abductus angle was initially greater than the normal range was within the normal range postoperatively. The postoperative patient perceptions of foot pain were significantly better than those from a comparable sample of patients presenting for a surgical opinion (t[69] = 6.80), just as were the perceptions of foot function, foot health, and footwear comfort (p < .001 for all). The postoperative perceptions of foot pain were comparable with the postoperative results from a range of previously published studies. These results have shown, with improvements in range of motion and reduction in pain, that autogenous capsular interpositional arthroplasty is a useful, motion-sparing technique in the treatment of painful hallux rigidus and should be considered for classification as a clinical practice guideline. PMID- 25441284 TI - Effect of obesity on arthroscopic treatment of anterolateral impingement syndrome of the ankle. AB - The present case series study was performed to evaluate the effect of obesity on the arthroscopic findings and the functional outcome after arthroscopic treatment of anterolateral impingement syndrome of the ankle. The study was conducted on 36 patients (26 were classified as obese [body mass index >=30 kg/m(2)] and 10 as not obese [body mass index <25 kg/m(2)]) who had previously undergone arthroscopic treatment of anterolateral impingement syndrome of the ankle. The arthroscopic findings and demographic features were recorded. The patients were examined postoperatively at 6 and 12 months postoperatively, and AOFAS scores were obtained. Our data showed that obese patients had the same arthroscopic findings as nonobese patients, except for chondral lesions. At 1 year of follow up after performing arthroscopy, the presence of obesity had no effect on the functional outcome of arthroscopic treatment of anterolateral impingement syndrome of the ankle.Obesity has no effect on the effectiveness of arthroscopic treatment. PMID- 25441285 TI - A ligament reattachment technique for high-demand athletes with chronic ankle instability. AB - The present prospective study was conducted to evaluate the clinical outcomes of the new ligament reattachment procedure for chronic lateral ankle instability in high-demand athletes. A total of 24 athletes <30 years old were followed for >2 years after undergoing the modified Brostrom procedure using the suture bridge technique. The clinical evaluation included the Karlsson score, the Sefton grading system, and the period to return to exercise. As an evaluation of mechanical stability, the talar tilt angle and anterior talar translation were measured on stress radiographs. The Karlsson score had improved significantly from a preoperative average of 43.5 points to 92.2 points. Using the Sefton grading system, 22 (91.7%) patients achieved satisfactory results. The period to return to exercise was as follows: a mean of 8.4 weeks for jogging, 12.5 weeks for spurt running, 10.5 weeks for jumping, 9.2 weeks for 1 leg standing for >1 minute, 10.6 weeks for walking on uneven ground, and 11.2 weeks for going downstairs. The talar tilt angle and anterior talar translation had improved significantly from the preoperative average of 15.4 degrees and 13.3 mm to 3.8 degrees and 4.2 mm at 2 months postoperatively and 4.9 degrees and 4.8 mm at the final follow-up visit, respectively. The modified Brostrom procedure using the suture bridge technique resulted in satisfactory clinical outcomes comparable to those with conventional ligament reattachment techniques. The suture bridge technique appears to be an effective treatment option for chronic ankle instability in high-demand athletes. PMID- 25441287 TI - Is our current paradigm for evaluation and management of the bunion deformity flawed? A discussion of procedure philosophy relative to anatomy. AB - Of the >100 procedures that have been proposed to treat hallux valgus or the "bunion" deformity, most have focused on correction through metatarsal osteotomies at various levels combined with soft tissue balancing procedures at the first metatarsophalangeal joint. This paradigm of metatarsal osteotomy and soft tissue balancing has been so commonplace, any argument for a fundamental change to the approach becomes uncomfortable and seems unwarranted to most foot and ankle surgeons. However, the simple fact that so many procedures exist, with so many modifications of these procedures, can be interpreted as a failure of our basic paradigm of metatarsal osteotomy and soft tissue balancing. We have observed that failure to recognize frontal plane rotation of the first metatarsal and our willingness to ignore deformity correction principles and create osteotomies outside the center of rotation of angulation are factors that can result in inconsistent outcomes. Our current multiprocedural mindset drives the search for yet more procedures and modifications in an attempt to reduce the incidence of complications. We present an anatomic analysis of hallux abducto valgus and metatarsus primus adducto valgus and critically analyze some of the shortcomings of currently popular corrective procedures. We also review the available data regarding frontal plane rotation of the first metatarsal and propose a new paradigm that considers frontal plane rotation of the first metatarsal as a priority in choosing the most appropriate procedure for bunion correction. PMID- 25441286 TI - Delayed Union of a Jones Fracture in a Patient With Rothmund-Thomson Syndrome: A Case Report and Review of the Literature. AB - Rothmund-Thomson syndrome is a rare autosomal recessive genodermatosis, characterized by poikiloderma, small stature, juvenile cataracts, sparse hair, skeletal abnormalities, and a predisposition to osteogenic sarcomas and skin cancers. Although numerous skeletal abnormalities have been described in patients with Rothmund-Thomson syndrome, to our knowledge, only 1 study has shown evidence of delayed fracture healing in a patient with Rothmund-Thomson syndrome. We present the case of a 13-year-old female diagnosed with Rothmund-Thomson syndrome who demonstrated delayed union of her fifth metatarsal after a Jones fracture. She was treated conservatively for 6 weeks with non-weightbearing cast immobilization and was then transitioned to a controlled ankle motion walker for an additional 4 weeks. Two months later, however, she continued to experience pain, and, on radiographic examination, the fracture remained unchanged. Therefore, with her guardian's consent, the patient elected to undergo open reduction and internal fixation of the fifth metatarsal fracture. At 8 weeks postoperatively, the patient reported a subsidence of symptoms and had returned to normal activity. With our report, we hope to increase practitioner awareness that delayed bone healing could be a possibility in patients with Rothmund Thomson syndrome and encourage consideration of routine imaging and supplementation with calcium and vitamin D. Additionally, the present findings suggest that patients with Rothmund-Thomson syndrome could benefit from early surgical intervention, given their poor bone healing capacity and high likelihood of nonunion. Although the association between impaired bone healing and Rothmund Thomson syndrome is rational, additional studies are needed to determine the prevalence of chronic nonunion in this patient population. PMID- 25441288 TI - A prospective study of surgical outcomes and quality of life in severe foot trauma and associated compartment syndrome after fasciotomy. AB - The purpose of the present prospective study was to analyze the predictors of outcome and review the quality of life of patients who underwent emergency fasciotomy for foot compartment syndrome after blunt trauma. A total of 14 patients were identified and followed for an average of 24 (range 14 to 33) months. The mean interval from initial presentation to decompressive fasciotomy was 5.8 (range 3 to 11) hours. The follow-up data from our patients revealed satisfactory functional and quality of life outcomes, with 11 of 14 (78.6%) able to return to work. Two (14.3%) patients developed claw-toe deformities and 3 (21.4%) patients had sensory deficits directly attributed to compartment syndrome. Finally, 4 (28.6%) patients required modified shoes or shoe inserts for comfortable ambulation. Our findings suggest that earlier fasciotomy results in better quality of life scores, American Orthopaedic Foot and Ankle Society scale scores, and visual analog scale pain scores and a greater likelihood of being able to wear all shoes comfortably, ambulate independently, and return to work. A shorter interval to fasciotomy, younger age, the absence of bony injury, the absence of other concomitant injuries, and a low velocity crush injury all tended to be predictors of good outcomes at the final review. PMID- 25441289 TI - Changes in peanut allergy prevalence in different ethnic groups in 2 time periods. PMID- 25441290 TI - Environmental lead exposure and increased risk for total and allergen-specific IgE in US adults. PMID- 25441292 TI - Clinical relevance of house dust mite immunotherapy. PMID- 25441291 TI - Thymic stromal lymphopoietin signaling in CD4(+) T cells is required for TH2 memory. AB - BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a key factor in the development of allergic asthma. Numbers of TH2 memory cells gradually increase in allergic patients with the progression of disease and persist in the lungs during remission, although the mechanism is not clear. OBJECTIVE: We sought to define the role of TSLP in TH2 memory cell generation and maintenance in vivo. METHODS: Adoptive transfer of wild-type and thymic stromal lymphopoietin receptor (TSLPR) deficient ovalbumin-specific CD4(+) T cells before TH2 sensitization was used to define T cell-specific TSLP effects. Atopic dermatitis and increased serum TSLP concentrations were induced by topical application of the vitamin D3 analog MC903. Memory cells in peripheral blood were monitored weekly with flow cytometry. Memory recall was tested after intranasal ovalbumin challenge. RESULTS: TSLP signaling in CD4(+) T cells is required for the generation/maintenance of memory cells after in vivo priming. TSLPR-deficient CD4(+) T cells have no defects in proliferation but do not survive 1 week after sensitization, and increased TSLP expression during sensitization significantly increased the frequency of memory cells. Although in vitro-differentiated TSLPR deficient TH2 cells develop into memory cells with equal efficiency to wild-type cells, the recall response to airway antigen challenge is impaired. Moreover, after antigen challenge of mice with established TH2 memory, TSLP signaling in CD4(+) T cells significantly affects memory cell generation/maintenance from secondary effector cells. CONCLUSION: TSLP signaling in CD4(+) T cells is required for not only TH2 memory cell formation in vivo but also the recall response of the memory cells to local antigen challenge. PMID- 25441293 TI - Reply: To PMID 24679845. PMID- 25441294 TI - EXCELS study results do not rule out potential cancer risk with omalizumab. PMID- 25441295 TI - Peripheral airways dysfunction in obesity reflects increased bronchomotor tone. PMID- 25441296 TI - Food allergy in patients with primary immunodeficiency diseases: prevalence within the US Immunodeficiency Network (USIDNET). PMID- 25441297 TI - Reply: To PMID 24388010. PMID- 25441298 TI - In utero priming by worms protects against respiratory allergies. PMID- 25441299 TI - Rate of asthma trial outcomes reporting on ClinicalTrials.gov and in the published literature. PMID- 25441300 TI - The natural history of peanut sensitization and allergy in a birth cohort. PMID- 25441301 TI - Fc-sialylated IgGs in intravenous immunoglobulins are not responsible for induction of regulatory T cells. PMID- 25441302 TI - Reply: To PMID 24210883. PMID- 25441303 TI - Aggregated and complementary: symmetric proliferation, overyielding, and mass effects explain fine-root biomass in soil patches in a diverse temperate deciduous forest landscape. AB - Few studies describe root distributions at the species level in diverse forests, although belowground species interactions and traits are often assumed to affect fine-root biomass (FRB). We used molecular barcoding to study how FRB of trees relates to soil characteristics, species identity, root diversity, and root traits, and how these relationships are affected by proximity to ecotones in a temperate forest landscape. We found that soil patch root biomass increased in response to soil resources across all species, and there was little belowground vertical or horizontal spatial segregation among species. Root traits and species relative abundance did not explain significant variation in FRB after correcting for soil fertility. A positive relationship between phylogenetic diversity and FRB indicated significant belowground overyielding attributable to local root diversity. Finally, variation in FRB explained by soil fertility and diversity was reduced near ecotones, but only because of a reduction in biomass in periodically anoxic areas. These results suggest that symmetric responses to soil properties are coupled with complementary species traits and interactions to explain variation in FRB among soil patches. In addition, landscape-level dispersal among habitats and across ecotones helps explain variation in the strength of these relationships in complex landscapes. PMID- 25441304 TI - When insomnia is not just insomnia: the deeper correlates of disturbed sleep with reference to DSM-5. AB - Recent scientific evidences have brought a paradigm shift in our approach towards the concepts of insomnia and its management. The differentiation between primary and secondary insomnia was proved more hypothetical than actual and based upon the current evidences insomnia subtypes described in earlier system have been lumped into one-insomnia disorder. Research in this field suggests that insomnia occurring during psychiatric or medical disorders has a bidirectional and interactive relationship with and coexisting medical and psychiatric illnesses. The new approach looks to coexist psychiatric or medical disorders as comorbid conditions and hence specifies two coexisting conditions. Therefore, the management and treatment plans should address both the conditions. A number of sleep disorders may present with insomnia like symptoms and these disorders should be treated efficiently in order to alleviate insomnia symptoms. In such cases, a thorough history from the patient and his/her bed-partner is warranted. Moreover, some patients may need polysomnography or other diagnostic tests like actigraphy to confirm the diagnosis of the underlying sleep disorder. DSM-5 classification system of sleep-wake disorders has several advantages, e.g., it has seen insomnia across different dimensions to make it clinically more useful; it focuses on the assessment of severity and guides the mental health professional when to refer a patient of insomnia to a sleep specialist; lastly, it may encourage the psychiatrists to opt for sleep medicine as a career. PMID- 25441305 TI - Severity of suicidal intent, method and behaviour antecedent to an act of self harm: a cross sectional study of survivors of self-harm referred to a tertiary hospital in Mysore, south India. AB - BACKGROUND: Rates of self harm are high in south India, but little is known about the relationship between antecedent behaviour, suicidal intent and method. Aims: To identify clinical, social and behavioural antecedents preceding an act of self harm. METHODS: 200 participants, consecutively presenting with deliberate self harm to a hospital in south India,were interviewed. Socio-demographic and clinical characteristics were recorded, together with behaviours preceding self harm. The Pierce Suicidal Intent Scale and Mini International Neuropsychiatric Inventory were administered. RESULTS: Pesticide poisoning was the most common method, especially amongst men, in rural areas, and amongst professionals. No particular antecedent behaviour or activity appears to be associated with higher levels of suicidal intent. Absenteeism from work was the most commonly reported change of behaviour in the month preceding an act of self-harm. Unskilled labourers and professionals had significantly greater suicidal intent (adjusted for age, gender and method) than skilled labourers and the unemployed. There were no differences in suicidal intent between different methods. Rural dwellers had significantly greater suicidal intent compared to urban dwellers, irrespective of the method. Major Depressive Disorder was associated with significantly greater suicidal intent compared with other diagnoses and no diagnosis. CONCLUSIONS: Amongst people who harm themselves in south India, professionals and unskilled labourers, rural residents, and people with current major depressive disorder have higher levels of suicidal intent. Severity of suicidal intent does not appear to influence choice of method of self-harm. Behaviours predictive of self harm in the west may not be relevant in south India. PMID- 25441306 TI - Shell Shock and the Kloppe: war neuroses amongst British and Belgian troops during and after the First World War. AB - During the First World War combatants of all armies were prey to nervous disorders or psychological breakdown. These war neuroses were a response to the highly-industrialised nature of the warfare as well as to the fatigue engendered over four years of intense conflict. Yet while fear and mental breakdown were universal, national responses varied. A comparison of British and Belgian shell shock indicates that men suffered in very similar ways but that symptoms met with rather different responses: in Britain treatment and diagnostic regimes stressed the importance of class difference and shell shock was often linked to cowardice. These issues were not of overriding importance in the Belgian army. In the longer term shell shock became, and remained, a topic of political and social concern in Britain whereas in Belgium men suffering from kloppe (extreme fear) tended to be forgotten and the topic has not excited much popular interest or scholarly attention. Yet despite these differences one overarching theme remains clear, namely that despite the extensive experience of war neuroses during and after the First World War, there still remains a fierce stigma about the mental wounds of war. PMID- 25441307 TI - Pathology and genetics of pancreatic neoplasms with acinar differentiation. AB - Pancreatic neoplasms with acinar differentiation, including acinar cell carcinoma, pancreatoblastoma, and carcinomas with mixed differentiation, are distinctive pancreatic neoplasms with a poor prognosis. These neoplasms are clinically, pathologically, and genetically unique when compared to other more common pancreatic neoplasms. Most occur in adults, although pancreatoblastomas usually affect children under 10 years old. All of these neoplasms exhibit characteristic histologic features including a solid or acinar growth pattern, dense neoplastic cellularity, uniform nuclei with prominent nucleoli, and granular eosinophilic cytoplasm. Exocrine enzymes are detectable by immunohistochemistry and, for carcinomas with mixed differentiation, neuroendocrine or ductal lineage markers are also expressed. The genetic alterations of this family of neoplasms largely differ from conventional ductal adenocarcinomas, with only rare mutations in TP53, KRAS, and p16, but no single gene or neoplastic pathway is consistently altered in acinar neoplasms. Instead, there is striking genomic instability, and a subset of cases has mutations in the APC/beta-catenin pathway, mutations in SMAD4, RAF gene family fusions, or microsatellite instability. Therapeutically targetable mutations are often present. This review summarizes the clinical and pathologic features of acinar neoplasms and reviews the current molecular data on these uncommon tumors. PMID- 25441309 TI - Serous cystic neoplasms of the pancreas: clinicopathologic and molecular characteristics. AB - We herein summarize the pathology and most recent advances in the molecular genetics of serous cystic neoplasms of the pancreas. They typically present as relatively large, well-demarcated tumors (mean size, 6cm), predominantly occurring in females. Pre-operative diagnosis remains challenging; imaging findings and cyst fluid analysis often prove non-specific and fine-needle aspiration often does not yield diagnostic cells. Pathologically, they are characterized by a distinctive cytology referred to as "serous." Although they have ductal differentiation, they distinctly lack the mucin production that characterizes most other pancreatic ductal tumors, including ductal adenocarcinoma and its variants, intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). They instead produce abundant glycogen (glycogen-rich adenoma). Serous cystadenomas also lack the molecular alterations that characterize ductal neoplasms, such as mutation of KRAS (high prevalence in most mucinous ductal neoplasms), inactivation of SMAD4 (seen in ductal adenocarcinomas), and mutations in GNAS (seen in some IPMNs) and RNF43 (detected in MCNs and IPMNs). Instead, new molecular and immunohistochemical observations place serous pancreatic tumors closer to "clear cell neoplasms" seen in various other organs that are associated with the von Hippel-Lindau (VHL) pathway, such as clear cell renal cell carcinomas and capillary hemangioblastomas. Patients with VHL syndrome have an increased risk of developing serous pancreatic tumors and somatic mutations of the VHL gene are common in these tumors along with modification of its downstream effectors including hypoxia-inducible factor (HIF1), glucose uptake and transporter-1 (GLUT-1), a common factor in clear cell (glycogen-rich) tumors, as well as expression of vascular endothelial growth factor (VEGF), thought to be a factor in the striking capillarization of serous cystadenomas and other non-pancreatic clear cell tumors. VEGF may prove to be of significant diagnostic value since its elevation in cyst fluid has recently been found highly sensitive and specific for serous neoplasms. These molecular alterations establish serous tumors as prototypes of clear cell tumorigenesis and angiogenesis and may prove helpful both as diagnostic and non-surgical therapeutic targets. PMID- 25441308 TI - Adenocarcinoma of the pancreas. AB - Infiltrating ductal adenocarcinoma of the pancreas is a real enigma. On one hand, it is one of the most deadly of all of the solid malignancies. On the other hand, the neoplastic glands can be remarkably well-differentiated, and it can be difficult to distinguish between a reactive non-neoplastic gland and a gland of invasive adenocarcinoma. In this review, we will present diagnostic criteria that one can "hang your hat on" when establishing the diagnosis of infiltrating ductal adenocarcinoma of the pancreas. We will also review clinically important features of the disease, and, with the impending incorporation of molecular genetics into everyday practice, we will emphasize clinical applications of cancer genetics. PMID- 25441310 TI - Mucinous cystic neoplasms of the pancreas: update on the surgical pathology and molecular genetics. AB - Mucinous cystic neoplasms (MCNs) of the pancreas are primary pancreatic cyst forming neoplasms that can be a precursor to invasive adenocarcinoma of the pancreas. MCNs occur almost exclusively in the distal pancreas of middle-aged women. MCNs typically show a "cyst-in-cyst" pattern of growth and are well encapsulated by a thick fibrous wall. MCNs are composed of mucin-producing neoplastic epithelial cells and "ovarian-type" subepithelial stroma. The epithelium is dysplastic and the grade can range from low to high grade; some MCNs have an associated invasive carcinoma. It is this associated invasive carcinoma that determines prognosis. MCNs harbor several characteristic genetic and epigenetic alterations, some of which are shared with conventional invasive pancreatic ductal adenocarcinoma. Furthermore, several studies reveal characteristic patterns of gene expression in the ovarian-type stroma that suggest steroidogenesis in the ovarian-type stroma. Better knowledge of the molecular alterations could help in the management of patients with this type of precursor of invasive carcinoma. PMID- 25441311 TI - Pancreatic neuroendocrine tumors: pathologic and molecular characteristics. AB - Pancreatic neuroendocrine neoplasms include mainly well-differentiated neuroendocrine tumors but also rare poorly differentiated neuroendocrine carcinomas. Molecular mechanisms underlying pancreatic neuroendocrine tumorigenesis have recently been elucidated. While alterations in the chromatin remodeling and PI3K/Akt/mTOR pathways are present in most well-differentiated pancreatic neuroendocrine tumors, mutations in TP53 and RB may contribute to the development of pancreatic poorly differentiated neuroendocrine carcinomas. With these discoveries, new molecular targeted therapies have become available and show promise in some patients with pancreatic well-differentiated neuroendocrine tumor. PMID- 25441312 TI - Introduction. PMID- 25441313 TI - The social dynamics of healthy food shopping and store choice in an urban environment. AB - To respond to the high prevalence of obesity and its associated health consequences, recent food research and policy have focused on neighborhood food environments, especially the links between health and retail mix, proximity of food outlets, and types of foods available. In addition, the social environment exerts important influences on food-related behaviors, through mechanisms like role-modeling, social support, and social norms. This study examined the social dynamics of residents' health-related food-shopping behaviors in 2010-11 in urban Philadelphia, where we conducted 25 semi-structured resident interviews-the foundation for this paper-in addition to 514 structured interviews and a food environment audit. In interviews, participants demonstrated adaptability and resourcefulness in their food shopping; they chose to shop at stores that met a range of social needs. Those needs ranged from practical financial considerations, to fundamental issues of safety, to mundane concerns about convenience, and juggling multiple work and family responsibilities. The majority of participants were highly motivated to adapt their shopping patterns to accommodate personal financial constraints. In addition, they selectively shopped at stores frequented by people who shared their race/ethnicity, income and education, and they sought stores where they had positive interactions with personnel and proprietors. In deciding where to shop in this urban context, participants adapted their routines to avoid unsafe places and the threat of violence. Participants also discussed the importance of convenient stores that allowed for easy parking, accommodation of physical disabilities or special needs, and integration of food shopping into other daily activities like meeting children at school. Food research and policies should explicitly attend to the social dynamics that influence food-shopping behavior. In our social relationships, interactions, and responsibilities, there are countless opportunities to influence-and also to improve-health. PMID- 25441314 TI - Newborn care practices in rural Bangladesh: Implications for the adaptation of kangaroo mother care for community-based interventions. AB - Bangladesh has one of the world's highest rates of low birth weight along with prevalent traditional care practices that leave newborns highly vulnerable to hypothermia, infection, and early death. We conducted formative research to explore existing newborn care practices in rural Bangladesh with an emphasis on thermal protection, and to identify potential facilitators, barriers, and recommendations for the community level delivery of kangaroo mother care (CKMC). Forty in-depth interviews and 14 focus group discussions were conducted between September and December 2012. Participants included pregnant women and mothers, husbands, maternal and paternal grandmothers, traditional birth attendants, village doctors, traditional healers, pharmacy men, religious leaders, community leaders, and formal healthcare providers. Audio recordings were transcribed and translated into English, and the textual data were analyzed using the Framework Approach. We find that harmful newborn care practices, such as delayed wrapping and early initiation of bathing, are changing as more biomedical advice from formal healthcare providers is reaching the community through word-of-mouth and television campaigns. While the goal of CKMC was relatively easily understood and accepted by many of the participants, logistical and to a lesser extent ideological barriers exist that may keep the practice from being adopted easily. Women feel a sense of inevitable responsibility for household duties despite the desire to provide the best care for their new babies. Our findings showed that participants appreciated CKMC as an appropriate treatment method for ill babies, but were less accepting of it as a protective method of caring for seemingly healthy newborns during the first few days of life. Participants highlighted the necessity of receiving help from family members and witnessing other women performing CKMC with positive outcomes if they are to adopt the behavior themselves. Focusing intervention messages on building a supportive environment for CKMC practice will be critical for the intervention's success. PMID- 25441315 TI - The impending globalization of ADHD: notes on the expansion and growth of a medicalized disorder. AB - Attention Deficit Hyperactivity Disorder (ADHD) has been medicalized in the United States since the 1960s. Primarily used in North America until the 1990s, ADHD diagnosis and treatment have increasingly been applied internationally. After documenting the expansion of ADHD in a global context, this paper presents five brief international examples examining ADHD usage and expansion: the United Kingdom, Germany, France, Italy and Brazil. We then identify and describe several vehicles that facilitate the migration of the ADHD diagnosis: the transnational pharmaceutical industry; the influence of western psychiatry; moving from ICD to DSM diagnostic criteria; the role of the Internet including the related advent of easily accessible online screening checklists; and advocacy groups. Finally, we discuss what this globalization of a diagnosis reflects about the potential global medicalization of other conditions. PMID- 25441316 TI - 'Every bone of my body:' domestic violence and the diagnostic body. AB - Diagnostic categories for domestic violence have shifted over time, transforming from a disorder of psychological passivity and acute injury into a chronic and somatically invasive condition. This paper links these changing diagnoses to constructions of the abused body and to victim-blaming narratives. Based on an analysis of medical journal articles, this research identifies two logics that undergird domestic violence diagnoses, the body, and victim-blaming: 1) the logic of injury (1970s-1980s); and 2) the logic of health (late 1980s-present). The logic of injury is associated with overt victim-blaming, a temporally bounded and injured body, and psychological passivity. Once the feminist anti-violence movement gained mainstream credibility, however, the logic of injury fell out of favor as an explanation for domestic violence. What surfaced next was the logic of health, which is associated with chronic diagnoses and what the author calls a temporally extended body. The temporally extended body is flexible and layered, linking up past, present, and future states of disordered embodiment. The author suggests that, rather than ushering in hope and possibility via the logic of health's somatic flexibility, this abused body creates spaces into which new forms of blame and self-responsibility can take shape. PMID- 25441317 TI - Leadership networks in Catholic parishes: implications for implementation research in health. AB - Through two case studies of Catholic parishes in Massachusetts, this study explores the implications of leader-centered versus distributed leadership in Catholic parishes for the implementation of evidence-based health interventions. The two parishes involved in the study differ from each other in several ways. In the first, parishioners are less engaged in leadership activities at the decision making level in the parish. A small group of lay volunteers work with the parish priest and other ordained leaders on parish activities. In the second parish, a large and active lay volunteer leadership have forged an organizational structure that allows more independence from the pastor's direct oversight. In this parish, lay volunteer leaders are the prime drivers of organizational programs and events. In 2012-2013, three types of networks were assessed at each parish: discussion, collaboration, and outside-of-parish ties. The contrasts between each parish include differences in density of collaboration, in frequency of discussion, and network centrality of the respective parish priests. We further identified key actors in the network structures at each parish. We discuss the implications of these findings for understanding organizational capacity in the context of health program implementation. PMID- 25441318 TI - Healthcare organization-education partnerships and career ladder programs for health care workers. AB - Increasing concerns about quality of care and workforce shortages have motivated health care organizations and educational institutions to partner to create career ladders for frontline health care workers. Career ladders reward workers for gains in skills and knowledge and may reduce the costs associated with turnover, improve patient care, and/or address projected shortages of certain nursing and allied health professions. This study examines partnerships between health care and educational organizations in the United States during the design and implementation of career ladder training programs for low-skill workers in health care settings, referred to as frontline health care workers. Mixed methods data from 291 frontline health care workers and 347 key informants (e.g., administrators, instructors, managers) collected between 2007 and 2010 were analyzed using both regression and fuzzy-set qualitative comparative analysis (QCA). Results suggest that different combinations of partner characteristics, including having an education leader, employer leader, frontline management support, partnership history, community need, and educational policies, were necessary for high worker career self-efficacy and program satisfaction. Whether a worker received a wage increase, however, was primarily dependent on leadership within the health care organization, including having an employer leader and employer implementation policies. Findings suggest that strong partnerships between health care and educational organizations can contribute to the successful implementation of career ladder programs, but workers' ability to earn monetary rewards for program participation depends on the strength of leadership support within the health care organization. PMID- 25441319 TI - Standardization as situation-specific achievement: regulatory diversity and the production of value in intercontinental collaborations in stem cell medicine. AB - The article examines the role and challenges of scientific self-governance and standardization in inter-continental clinical research partnerships in stem cell medicine. The paper shows that - due to a high level of regulatory diversity - the enactment of internationally recognized standards in multi-country stem cell trials is a complex and highly situation-specific achievement. Standardization is imposed on a background of regulatory, institutional and epistemic-cultural heterogeneity, and implemented exclusively in the context of select clinical projects. Based on ethnographic data from the first trans-continental clinical trial infrastructure in stem cell medicine between China and the USA, the article demonstrates that locally evolved and international forms of experimental clinical research practices often co-exist in the same medical institutions. Researchers switch back and forth between these schemas, depending on the purposes of their research, the partners they work with, the geographic scale of research projects, and the contrasting demands for regulatory review, that result from these differences. Drawing on Birch's analysis of the role of standardization in international forms of capital production in the biosciences, the article argues that the integration of local knowledge institutions into the global bioeconomy does not necessarily result in the shutting down of localized forms of value production. In emerging fields of medical research, that are regulated in highly divergent ways across geographical regions, the coexistence of distinct modes of clinical translation allows also for the production of multiple forms of economic value, at varying spatial scales. This is especially so in countries with lenient regulations. As this paper shows, the long-standing absence of a regulatory framework for clinical stem cell applications in China, permits the situation-specific adoption of internationally recognized standards in some contexts, while enabling the continuation of localized forms of value production in others. PMID- 25441320 TI - Do institutional logics predict interpretation of contract rules at the dental chair-side? AB - In quasi-markets, contracts find purchasers influencing health care providers, although problems exist where providers use personal bias and heuristics to respond to written agreements, tending towards the moral hazard of opportunism. Previous research on quasi-market contracts typically understands opportunism as fully rational, individual responses selecting maximally efficient outcomes from a set of possibilities. We take a more emotive and collective view of contracting, exploring the influence of institutional logics in relation to the opportunistic behaviour of dentists. Following earlier qualitative work where we identified four institutional logics in English general dental practice, and six dental contract areas where there was scope for opportunism; in 2013 we surveyed 924 dentists to investigate these logics and whether they had predictive purchase over dentists' chair-side behaviour. Factor analysis involving 300 responses identified four logics entwined in (often technical) behaviour: entrepreneurial commercialism, duty to staff and patients, managerialism, public good. PMID- 25441321 TI - Politics drives human functioning, dignity, and quality of life. AB - Too little is known about human functioning amidst chronic adversity. We addressed that need by studying adult Palestinians in the occupied Palestinian territories (oPt), a population that has experienced longstanding economic and political hardships. Fourteen group interviews were conducted in February, 2010 in Arabic by local fieldworkers with 68 participants representing the main stratifications of Palestinian society: gender, region, refugee status, and political affiliation. Interview tasks included each participant: describing someone doing well and not well, free listing domains of functioning, and prioritizing domains to the three most important. Thematic analyses highlighted the dominating role of the political domain of functioning (e.g., political structures, constraints, effects, identity, and activism) and the degree to which political conditions impacted all other realms of functioning (economic, education, family, psychological, etc.). The discussion links the findings to relevant theory and empirical work that has called attention to the need to include the political in frameworks of quality of life. It also emphasized that values, such as justice, rights, dignity and self-determination, that underlie political structures and policies, are key elements of human functioning. This is the case not only in the oPt, but in any society where power imbalances marginalize segments of the population. PMID- 25441322 TI - The National Health Insurance Scheme in Ghana's Upper West Region: a gendered perspective of insurance acquisition in a resource-poor setting. AB - Ghana's National Health Insurance Scheme (NHIS) was designed as a pro-poor strategy to create wider access to health care. While recent studies have shown that wealth is an important factor in enrolment in the scheme, there is little understanding of its interlinkages with the geographical divisions and deep seated deprivation in the northern region. In response to the nexus of poverty, gender and access to health care, this research took place in Ghana's Upper West Region (UWR), one of the poorest regions and yet paradoxically touting the highest enrolment rates. Using data from a population survey (n = 2119) collected between May to December 2011, we used multinomial regression to examine factors that influence enrolment, controlling for theoretically relevant covariates. Findings reveal that although wealth and desire for health insurance are contributing factors, education was the primary determinant in both never enrolling and in dropping out, and that these factors impact men and women differently. The study also shows that Muslims were less likely to enrol and also women living in non-nuclear households were far more likely to dropout. Our results demonstrate clear gendered divisions in accessing the NHIS, and raised serious equity concerns in the UWR. By focussing on the context of the UWR, we show the importance of understanding intra-household bargaining and resource allocation via the gender dynamics related to health insurance procurement and maintenance, and discuss associated policy implications. PMID- 25441323 TI - How do dual practitioners divide their time? The cases of three African capital cities. AB - Health professionals dual practice has received increasing attention, particularly in the context of the universal health coverage movement. This paper explores the determinants of doctors' choices to become a dual practitioner and of dual practitioners' choices to allocate time to the private sector in the capital cities of Mozambique, Guinea Bissau and Cape Verde. The data are drawn from a survey conducted in 2012 among 329 physicians. We use a two-part model to analyse the decision of both public and private practitioners to become dual practitioners, and to allocate time between public and private sectors. We impute potential earnings in public and private practice by using nearest-neighbour propensity score matching. Our results show that hourly wage in the private sector, number of dependents, length of time as a physician, work outside city, and being a specialist with or without technology all have a positive association with the probability of being a dual physician, while number of dependents displays a negative sign. Level of salaries in the public sector are not associated with dual practice engagement, with important implications for attempts aimed at retaining professionals in the public sector through wage increases. As predicted by theory that recognises doctors' role in price setting, earnings rates are not significant predictors of private sector time allocation; personal characteristics of physicians appear more important, such as age, number of dependents, specialist without technology, specialist with technology, and three reasons for not working more hours in the private sector. Answers to questions about the factors that limit working hours in the private sector have significant predictive power, suggesting that type of employment in the private sector may be an underlying determinant of both dual practice engagement and time allocation decisions. PMID- 25441324 TI - Racial/ethnic residential segregation, neighborhood poverty and urinary biomarkers of diet in New York City adults. AB - Consuming less sodium and more potassium are components of a healthy diet and reduced cardiovascular disease risk. Racial/ethnic segregation and poverty are both associated with dietary habits, but data linking dietary intake to neighborhood characteristics are limited, particularly in Hispanic and Asian American ethnic enclaves. This study presents relationships between neighborhood level segregation, poverty and biologic indicators of sodium and potassium consumption. Data were from the 2010 Heart Follow-Up Study, a cross-sectional health survey, which included 24-h urine collections and self-reported health status (n = 1656). Black, Hispanic, and Asian segregated areas and neighborhood poverty were defined for aggregated zip-code areas. Multivariable models assessed the association between neighborhood segregation and poverty and sodium and potassium intake, after adjustment for individual-level covariates. In unadjusted models, potassium intake (a marker of fruit and vegetable consumption) was lower in high-versus low-Hispanic segregated neighborhoods, and the sodium-potassium ratio was higher in high-versus low black and Hispanic segregated neighborhoods, and in high-versus low-poverty neighborhoods; the sodium-potassium ratio was lower in high-versus low Asian segregated neighborhoods. Segregation and poverty were not independently associated with nutrition biomarkers after adjustment for demographics and for each other; however, practical consideration of neighborhood race/ethnic composition may be useful to understand differences in consumption. PMID- 25441325 TI - Public engagement in priority-setting: results from a pan-Canadian survey of decision-makers in cancer control. AB - Decision-makers are challenged to incorporate public input into priority-setting decisions. We conducted a pan-Canadian survey of decision-makers in cancer control to investigate the types of evidence, especially evidence supplied by the public, that are utilized in health care priority-setting. We further examined how normative attitudes and contextual factors influence the use of public engagement as evidence at the committee level. Administered between November and December 2012, 67 respondents from 117 invited individuals participated in the survey. The results indicated that public engagement was infrequently utilized compared to clinical effectiveness evidence or cost evidence. General positive agreement between normative attitudes towards the use of evidence and the frequency of evidence utilization was observed, but absence of correlative agreement was found for the types of evidence that are supplied by the general public and for cost-effectiveness inputs. Regression analyses suggested that public engagement was unevenly utilized between jurisdictions and that educational background and barriers to implementing public input may decrease the odds of using public engagement as evidence. We recommend that institutions establish a link between committee members' normative attitudes for using public engagement and its real-world utilization. PMID- 25441326 TI - Contextualizing online human milk sharing: structural factors and lactation disparity among middle income women in the U.S. AB - Women in the U.S. face significant structural constraints in attempting to breastfeed as recommended in the first six months of their child's life. Internet facilitated human milk sharing is an emergent response to breastfeeding challenges. Little is known about the demographic characteristics of milk sharing donors and recipients and the ways structural factors circumscribe the biocultural context of lactation in milk sharing practices. Data regarding demographic characteristics, reproductive history, lactation history, and levels of social support and health care provider support for breastfeeding were collected via an online survey September 2013-March 2014. Statistical tests were executed to ascertain whether significant differences exist between donors and recipients. A total of 867 respondents (661 donors, 206 recipients) met the eligibility criteria for the study. Respondents were U.S. residents and primarily White, middle-class, well educated, and employed women. Both donors and recipients reported higher than the national average for household income, maternal educational attainment, breastfeeding exclusivity 0-6 months, and breastfeeding duration. Differences in lactation sufficiency and breastfeeding outcomes between donors and recipients were associated with both structural and biocultural factors. Donors reported significantly higher income, education, and support for breastfeeding from spouse/partner, other family, employers, and pediatricians. Donors also reported significantly higher rates of full term birth for child of most recent lactation. This study provides a foundation for understanding how milk sharing reflects a broader political economy of breastfeeding in the U.S. PMID- 25441327 TI - Adult children's socioeconomic positions and their parents' mortality: a comparison of education, occupational class, and income. AB - Recent research has shown that the parents of well-educated children live longer than do other parents and that this association is only partly confounded by the parent's own socioeconomic position. However, the relationships between other aspects of children's socioeconomic position (e.g., occupational class and economic resources) and parental mortality have not been examined. Using the Swedish Multi-generation Register that connects parents to their children, this paper studies the associations of children's various socioeconomic resources (education, occupation, and income) and parents' mortality. The models are adjusted for a range of parental socioeconomic resources and include the resources of the parents' partners. In addition to all-cause mortality, five causes of death are analyzed separately (circulatory disease mortality, overall cancer, lung cancer, breast cancer, and prostate cancer). The results show net associations between all included indicators of children's socioeconomic position and parents' mortality risk, with the clearest association for education. Children's education is significantly associated with all of the examined causes of death except prostate cancer. Breast cancer mortality is negatively related to offspring's education but not the mothers' own education. To conclude, children's education seems to be a key factor compared with other dimensions of socioeconomic position in the offspring generation. This finding suggests that explanations linked to behavioral norms or knowledge are more plausible than those linked to access to material resources. However, it is possible that children's education - to a greater degree than class and income - captures unmeasured parental characteristics. The cause-specific analyses imply that future research should investigate whether offspring's socioeconomic position is linked to the likelihood of developing diseases and/or the chances of treating them. A broader family perspective in the description and explanations of social inequalities in health that includes the younger generation may increase our understanding of why these inequalities persist across the life course. PMID- 25441328 TI - Identifying errors and inconsistencies in real time while using facilitated echocardiographic reporting. AB - BACKGROUND: Facilitated reporting using a discrete set of finding codes (FCs) is a common method of generating echocardiographic reports. METHODS: The investigators developed a tool that allows echocardiographic reports to be evaluated in real time for errors, omissions, and inconsistencies on the basis of a defined group of "rules" applied to the FCs present in the report. At the time of report finalization, conflicts were displayed for the interpreting physicians, and their responses to each rule conflict were logged. RESULTS: Over the course of 1 year, 7,986 transthoracic echocardiographic reports were analyzed prospectively during study interpretation. Overall, 30 +/- 4.7 FCs were used to generate finalized reports. An average of 2.4 +/- 2.0 conflicts were detected per finalized study. Eighty-three percent of studies had at least one conflict identified. There was no significant correlation between physician experience and conflict rates, but time of day (earlier) and rate at which studies were being finalized (faster) were both correlated with increased conflict rate. Overall, physicians ignored identified conflicts 52% of the time and altered their readings to eliminate the conflicts 48% of the time. Overall, at least one change was made in 54% of all finalized studies. There was a small but significant trend for physicians to produce more conflicts over time as the tool was used. CONCLUSIONS: This study demonstrates that facilitated reporting of echocardiographic studies, using a discrete set of FCs, allows the generation of rules that can be used to identify discrepancies in echocardiographic reports before finalization. Conflicts are common in clinical practice, and the identification of these conflicts in real time allowed readers to review their interpretations and frequently resulted in alterations to echocardiographic reports. PMID- 25441329 TI - Echocardiographic prediction of pre- versus postcapillary pulmonary hypertension. AB - BACKGROUND: The differential diagnosis between pre- and postcapillary pulmonary hypertension (PH) is of major therapeutic relevance and thus requires optimal clinical probability assessment with echocardiography. METHODS: We prospectively analyzed 152 consecutive patients referred to a PH center over a 1-year period undergoing quasi-simultaneous (within 1 hour) echocardiography and right heart catheterization. Echocardiography was performed as usually recommended for the assessment of PH and left heart conditions. PH was defined as a mean pulmonary artery pressure >= 25 mm Hg. Postcapillary PH was diagnosed on the basis of a pulmonary capillary wedge pressure >15 mm Hg. RESULTS: Ten of 152 patients (7%) had no PH, 81 of 152 (53%) had precapillary PH, and 61 of 152 (40%) had postcapillary PH. The following five echocardiographic variables were found to predict precapillary PH: right heart chamber larger than the left (P = .0018), left ventricular eccentricity index > 1.2 (P = .0039), dilated inferior vena cava without inspiratory collapse (P = .0076), E/e' ratio <= 10 (P = .00001), and the right ventricle forming the heart apex (P = .0144). Beta coefficients from multiple logistic regression were significant for dilated inferior vena cava without inspiratory collapse (P = .0464) and E/e' ratio <= 10 (P = .0002). The score based on beta coefficients, ranging from 3 to 34 points, resulted in optimal discrimination at >5, with a positive predictive value of 67.9% and a negative predictive value of 77.5% for precapillary PH. CONCLUSION: Echocardiography enables a clinically satisfactory differential diagnosis between pre- and postcapillary PH. PMID- 25441330 TI - Symptoms in severe aortic stenosis are associated with decreased compensatory circumferential myocardial mechanics. AB - BACKGROUND: Symptomatic patients with severe aortic stenosis (AS) demonstrate abnormal left ventricular (LV) mechanics. The aim of this study was to compare mechanics in asymptomatic and symptomatic patients with severe AS using two dimensional myocardial strain imaging. METHODS: One hundred fifty-four patients with severe AS (aortic valve area <= 1.0 cm(2)) referred to a heart valve clinic from 2004 to 2011 were studied. Thirty patients were asymptomatic, with normal LV ejection fractions (>= 55%), without other significant valvular disease or wall motion abnormalities. Thirty-two symptomatic patients who underwent early aortic valve replacement, with similar age, gender, LV ejection fraction, and aortic valve area, were selected for comparison. Both groups were also compared with 32 healthy subjects with similar age and gender distributions and normal echocardiographic results who served as controls. LV longitudinal and circumferential strain and rotation were measured using speckle-tracking software applied to archived echocardiographic studies. Conventional echocardiographic and myocardial mechanical parameters were compared among the study subgroups. RESULTS: Patients with asymptomatic severe AS demonstrated smaller reductions in longitudinal strain, higher (supernormal) apical circumferential strain (-38 +/- 6% vs -35 +/- 4%, P < .05), and extreme (supernormal) apical rotation (12.2 +/- 4.9 degrees vs 2.9 +/- 1.7 degrees , P < .0005) compared with symptomatic patients. Apical rotation < 6 degrees was the single significant predictor of symptoms in logistic regression analysis of clinical, echocardiographic, and mechanical parameters. Twelve asymptomatic patients underwent eventual aortic valve replacement and showed decreases in strain and apical rotation compared with baseline values. CONCLUSIONS: Longitudinal strain was uniformly low in patients with severe AS and lower in those with symptoms. Compensatory circumferential myocardial mechanics (increased apical circumferential strain and rotation) were absent in symptomatic patients. Thus, myocardial mechanics may help in the follow-up of patients with severe AS and timing of valve surgery. PMID- 25441331 TI - Patterns of left ventricular diastolic function in Olympic athletes. AB - BACKGROUND: Whether morphologic left ventricular (LV) changes in elite athletes are associated with altered diastolic properties is undefined. The aim of this study was to investigate LV diastolic properties in a large population of Olympic athletes compared to untrained controls. METHODS: A total of 1,145 Olympic athletes (61% men), and 154 controls, free of cardiovascular disease, underwent two-dimensional echocardiography, Doppler echocardiography, and Doppler tissue imaging. RESULTS: Athletes had similar E velocities (87 +/- 15 vs 89 +/- 16 cm/sec, P = .134) but significantly decreased A velocities (47 +/- 10 vs 56 +/- 12 cm/sec, P < .001) compared with controls, with increased E/A ratios (1.93 +/- 0.50 vs 1.63 +/- 0.35, P < .001) and values ranging up to 4.8. Isovolumic relaxation (83 +/- 13 vs 71 +/- 16 msec, P < .001) and deceleration times (203 +/ 40 vs 181 +/- 36 msec, P < .001) were longer in athletes compared with controls. Doppler tissue imaging e' (13.8 +/- 2.2 vs 16.2 +/- 3.7 cm/sec, P < .001) and a' (7.2 +/- 1.8 vs 8.5 +/- 2.1 cm/sec, P < .001) were lower in athletes than in controls, but their ratio was not different between groups; E/e' ratios (6.37 +/- 1.2 vs 5.72 +/- 1.33, P < .001) were mildly higher in athletes. Subgroup analysis for type of sport showed that endurance athletes had the lowest A and a' velocities and the largest E/A ratios. Gender analysis revealed that men had significantly lower E and A velocities, as well as e', e'/a' ratios, and E/e' ratios (P < .01), compared with women. CONCLUSION: This study provides normal values for Doppler echocardiographic and Doppler tissue imaging parameters describing diastolic function in elite athletes, which may be implemented as reference values in the clinical assessment of athlete's heart and prove useful in understanding the physiologic limits of cardiac adaptations in athletes. PMID- 25441332 TI - Long-term follow-up in repaired tetralogy of fallot: can deformation imaging help identify optimal timing of pulmonary valve replacement? AB - BACKGROUND: Novel echocardiographic techniques based on myocardial deformation have not been extensively evaluated to assess right ventricular (RV) and left ventricular (LV) response after pulmonary valve replacement (PVR) in patients with repaired tetralogy of Fallot. METHODS: Between 2003 and 2012, 133 patients undergoing first-time PVR after tetralogy of Fallot repair underwent echocardiographic assessment at Mayo Clinic. The last echocardiogram before PVR and 1 year after surgery were retrospectively analyzed with Velocity Vector Imaging. RESULTS: Mean age at PVR was 35.5 +/- 16.2 years (54% women). Longitudinal peak systolic strain and strain rate before PVR were low: for the left ventricle, -14.8 +/- 3.5% and -0.8 +/- 0.2 sec(-1), and for the right ventricle, -16.2 +/- 4.1% and -0.9 +/- 0.3 sec(-1), respectively. There was no significant change in either parameter after surgery. A close correlation between LV and RV deformational parameters was found before PVR and was maintained after surgery. In the multivariate analysis, patients with better LV and RV peak systolic strain preoperatively were found to have better LV and RV peak systolic strain after surgery (P = .004 and P = .006, respectively). However, patients with the most improvement in deformation were those with worse RV function preoperatively (P = .002). Mean New York Heart Association class at early follow up improved from 2.2 +/- 0.8 to 1.2 +/- 0.6 (P < .0001); RV peak systolic strain was the only factor associated with symptomatic improvement. CONCLUSION: LV and RV systolic and diastolic deformational parameters were decreased in patients with repaired tetralogy of Fallot undergoing PVR, and there was no significant change after surgery. However, preoperative systolic deformational parameters were predictive of postoperative ventricular function and New York Heart Association class after PVR and may be helpful to identify optimal timing for surgical intervention in this cohort. PMID- 25441333 TI - Authors' reply. PMID- 25441334 TI - Nagy, Zoltan, A.: A history of modern immunology: the path toward understanding. AB - This book provides a detailed survey of the major advances made in the field of immunology in a period corresponding approximately to the last third of the twentieth century. In the first chapter, referred to as Pre-History, the Author, an experienced senior immunologist, briefly summarizes the preceding era often called "immunological revolution", in which the foundations of a new science, immunobiology, were laid down. The subsequent chapters (The History) then deal in detail with a number of topics within immunobiology, such as, the generation of antibody diversity, monoclonal antibodies, the major histocompatibility complex, antigen presentation, T cell biology, self tolerance, and autoimmunity. The fact that the Author contributed himself to most of these topics lends the text more depth and authenticity. This article is protected by copyright. All rights reserved. PMID- 25441335 TI - Infants' use of social partnerships to predict behavior. AB - The experiences of social partners are important motivators of social action. Can infants use such experiences to make predictions about how social agents will behave? Sixteen-month-old infants were introduced to two social pairs. Initial events established within-pair cooperation as well as between-pair conflict involving an individual from each pair. Following these events, infants looked longer when between-pair members who had never previously interacted now cooperated - instead of conflicted - with each other. Thus, infants tracked the third-person allegiances and inferred that the conflict would generalize across social partnerships. These findings demonstrate a critical feature of early social cognition and promote needed, further research on the role of social allegiances in social cognition across development. PMID- 25441336 TI - Targeting alpha4beta2 nicotinic acetylcholine receptors in central nervous system disorders: perspectives on positive allosteric modulation as a therapeutic approach. AB - The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels broadly involved in regulating neurotransmission in the central nervous system (CNS) by conducting cation currents through the membrane of neurons. Many different nAChR subtypes exist with each their functional characteristics, expression pattern and pharmacological profile. The focus of the present MiniReview is on the heteromeric alpha4beta2 nAChR, as activity at this subtype contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders, for example schizophrenia and Alzheimer's disease. Additionally, the alpha4beta2 nAChR provides an extra layer of molecular complexity by existing in two different stoichiometries determined by the subunit composition. Such findings have founded the rationale that pharmacological modulation of the alpha4beta2 nAChR may be used as a treatment approach in various CNS disorders. As subtype-selective agonists and other cholinergic ligands have only shown limited therapeutic success, the focus of recent drug development endeavours has largely shifted to positive allosteric modulators (PAMs). By potentiating the action of an agonist through binding to an allosteric site, a PAM can enhance cholinergic neurotransmission, thus compensating for compromised neuronal communication in a pathophysiological setting. The pharmacological advantages of PAMs compared to other types of ligands include minimal interference with spatial and temporal aspects of neurotransmission as well as higher subtype selectivity, hypothetically resulting in high clinical efficacy with minimal adverse effects. In this MiniReview, we describe the currently identified compounds, which potentiate the effects of agonists at the alpha4beta2 nAChR. The potential clinical advantages and concerns of PAMs are discussed in the light of the role of alpha4beta2 nAChRs as key regulators of fast synaptic transmission. PMID- 25441338 TI - New methods and technologies for measuring uremic toxins and quantifying dialysis adequacy. AB - This publication reviews the currently available methods to identify uremic retention solutes, to determine their biological relevance and to quantify their removal. The analytical methods for the detection of uremic solutes have improved continuously, allowing the identification of several previously unknown solutes. Progress has been accelerated by the development of comprehensive strategies such as genomics, proteomics and the latest "omics" area, metabolomics. Those methodologies will be further refined in future. Once the concentration of solutes of interest is known based on targeted analysis, their biological relevance can be studied by means of in vitro, ex vivo, or animal models, provided those are representative for the key complications of the uremic syndrome. For this to come to pass, rigid protocols should be applied, e.g., aiming at free solute concentrations conform those found in uremia. Subsequently, the decrease in concentration of relevant solutes should be pursued by nondialysis (e.g., by influencing nutritional intake or intestinal generation, using sorbents, modifying metabolism, or preserving renal function) and dialysis methods. Optimal dialysis strategies can be sought by studying solute kinetics during dialysis. Clinical studies are necessary to assess the correct impact of those optimized strategies on outcomes. Although longitudinal studies of solute concentration and surrogate outcome studies are first steps in suggesting the usefulness of a given approach, ultimately hard outcome randomized controlled trials are needed to endorse evidence-based therapeutic choices. The nonspecificity of dialysis removal is however a handicap limiting the chances to provide proof of concept that a given solute or group of solutes has definite biological impact. PMID- 25441337 TI - A role for innate immunity in the development of hypertension. AB - Clinically, angiotensin II (Ang II) has been implicated in some forms of hypertension and linked to vascular injury. Experimentally, chronic Ang II infusion leads to an increase in blood pressure, resulting in impaired endothelial function and vascular hypertrophy. Ang II also upregulates the activity and expression of a number of inflammatory molecules, including nuclear factor kappa B (NFkappaB) and pro-inflammatory cytokines, such as interleukin-6 (IL-6). More recently, it has been reported that Ang II is associated with upregulation of toll-like receptor TLR expression, specifically TLR4. Classical TLR4 signaling is mediated in large part by the effector protein myeloid differentiation factor 88 (MyD88), with resultant activation of NFkappaB, a transcription factor that promotes expression of a number of inflammatory gene products, including IL-6. A role for IL-6 has been previously implicated in the vascular dysfunction associated with Ang II-dependent hypertension. It is not known whether the MyD88 signaling pathway represents a cellular mechanism by which Ang II promotes endothelial dysfunction via NFkappaB activation and increases in IL-6. Taken together, we propose to mechanistically elucidate the role of innate immune signaling in Ang II-dependent hypertension. We hypothesize MyD88-deficiency will prevent the activation and transcription of NFkappaB related gene products, including IL-6, thereby limiting Ang II-dependent hypertension and vascular complications. PMID- 25441339 TI - Applications of liquid-phase microextraction techniques in natural product analysis: a review. AB - Over the last years, liquid-phase microextraction (LPME) as a simple, rapid, practical and effective sample-preparation technique, coupled with various instrumental analytical methods, has been increasingly and widely used to research and determine trace or ultra-micro-levels of both inorganic and organic analytes from different matrix-complex samples. In this review, different kinds of LPMEs such as single drop liquid-phase microextraction, dispersive liquid liquid microextraction, and hollow fibre liquid-phase microextraction are summarized and recent applications of LPMEs in trace compounds in vivo and in vitro from different natural product matrice analysis such as tea, vegetables, seeds, herbs, and galenical are also discussed. Finally, future developments and applications of LPMEs in complex sample analysis are prospected. PMID- 25441340 TI - Graphene oxide-based microspheres for the dispersive solid-phase extraction of non-steroidal estrogens from water samples. AB - A modified Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) method based on the dispersive solid-phase extraction (dSPE) combined with high performance liquid chromatography (HPLC) was developed for the determination of non-steroidal estrogens in water samples. In this study, graphene oxide-based silica microspheres (SiO2@GO) were used as dSPE material for the preconcentration of analytes. HPLC was used for the separation and detection. This was the first time that the synthesized SiO2@GO microspheres were used as stationary phases for the off-line preconcentration of the non-steroidal estrogens in dSPE. dSPE parameters, such as sample pH, volume and type of eluent were optimized. Application of the developed method to analyze spiked lake, reservoir and tap water samples resulted in good recoveries values ranging from 70 to 106% with relative standard deviation values lower than 7.0% in all cases. Limits of detection were in the range of 0.2-6.1 MUg/L. The combined data obtained in this study recommended that the proposed method is very fast, simple, repeatable and accurate for the detection of non-steroidal estrogens. Furthermore, the SiO2@GO microspheres application could potentially be expanded to extract and pre concentrate other compounds in various matrices. PMID- 25441341 TI - Assessment of dispersive liquid-liquid microextraction conditions for gas chromatography time-of-flight mass spectrometry identification of organic compounds in honey. AB - The suitability of the dispersive liquid-liquid microextraction (DLLME) technique for gas chromatography (GC) characterization of minor organic compounds in honey samples is evaluated. Under optimized conditions, samples were pre-treated by liquid-liquid extraction with acetonitrile followed by DLLME using carbon tetrachloride (CCl4, 0.075 mL) as extractant. The yielded settled phase was analyzed by GC using high resolution time-of-flight (TOF) mass spectrometry (MS). The whole sample preparation process is completed in approximately 10 min, with a total consumption of organic solvents below 4 mL, relative standard deviations lower than 12% and with more than 70 organic compounds, displaying linear retention index in the range from 990 to 2900, identified in the obtained extracts. In comparison with HS SPME extraction, higher peak intensities were attained for most volatile and semi-volatile compounds amenable to both extraction techniques. Furthermore, other species such as highly polar and water soluble benzene acids, long chain fatty acids, esters and flavonoids, which are difficult to concentrate by HS SPME, could be identified in DLLME extracts. Some of the compounds identified in DLLME extracts have been proposed as useful for samples classification and/or they are recognized as markers of honeys from certain geographic areas. PMID- 25441342 TI - A new graphene oxide/polypyrrole foam material with pipette-tip solid-phase extraction for determination of three auxins in papaya juice. AB - A new material, graphene oxide/polypyrrole (GO/Ppy), was synthesized by mixing graphene oxide and polypyrrole in a specific proportion. It possesses a unique structure similar to that of foam. A homemade pipette-tip solid-phase extraction (PT-SPE) device, which is more simple and convenient than traditional devices, was used for saving reagents and operation time. When GO/Ppy was used as the adsorbent of PT-SPE for determining three auxins (indole-3-propionic acid, indole 3-butyric acid, and 1-naphthaleneacetic acid) present in trace amounts in papaya juice, it showed high affinity and adsorption capacity for all the three auxins. GO/Ppy-PT-SPE also had a significant capacity for eliminating the interferences from the papaya juice matrix. Under optimized conditions, a good linearity of auxins was obtained in the range 16.3-812.5 ng g(-1); the average recoveries at the three spiked levels of the three auxins ranged from 89.4% to 105.6% with the relative standard deviations <= 3.0%. Meanwhile, six papaya juice samples with different growth stages were analyzed under optimum conditions, and trace auxins in the range 18.3-100.6 ng g(-1) were observed. Because of its high selectivity, simplicity, and reliability, the GO/Ppy-PT-SPE method developed herein can be potentially applied for determining trace auxins in complex biological samples. PMID- 25441343 TI - Molecularly imprinted polymers with synthetic dummy template for simultaneously selective removal and enrichment of ginkgolic acids from Ginkgo biloba L. leaves extracts. AB - Dummy molecularly imprinted polymers (DMIPs) for simultaneously selective removal and enrichment of ginkgolic acids (GAs) during the processing of Ginkgo biloba leaves have been prepared. Two dummy template molecule with similar structural skeleton to GAs, 6-methoxysalicylic acid (MOSA, DT-1) and 6-hexadecyloxysalicylic acid (HOSA, DT-2), have been designed and synthesized. The performance of the DMIPs and NIPs were evaluated including selective recognition capacity, adsorption isotherm, and adsorption kinetics. The selective recognition capacity of the three GAs with four analogues on the sorbents illustrated that the DMIPs sorbents have high specificity for GAs. An efficient method based on DMIP-HOSA coupled with solid-phase extraction (SPE) was developed for simultaneously selective removal and enrichment of ginkgolic acids (GAs) during the processing of Ginkgo biloba leaves. The method showed excellent recoveries (82.5-88.7%) and precision (RSD 0.5-2.6%, n=5) for licorice extracts, Gastrodia elata extracts and pepper extracts spiked at three concentration levels each (50, 100, 200 MUg mL( 1)). The results indicated that GAs and standardized Ginkgo biloba leaves extracts could be obtained simultaneously through the DMIP-SPE. PMID- 25441344 TI - Programmable flow-based dynamic sorptive microextraction exploiting an octadecyl chemically modified rotating disk extraction system for the determination of acidic drugs in urine. AB - A novel automatic sorptive microextraction approach combining sequential injection-based programmable flow with rotating disk sorptive extraction (RDSE) is proposed for the clean-up and concentration of low polarity organic species in urine samples. Non-steroidal anti-inflammatory drugs (NSAIDs), namely, ketoprofen, naproxen, diclofenac and ibuprofen, were selected as model analytes in a proof-of-concept design, and they were further determined by liquid chromatographic (LC) assays. The extracting phase consisted of octadecyl (C18) chemically bonded silica embedded in a polytetrafluoroethylene (PTFE) substrate. The thin film was immobilized onto the surface of an in-house prepared rotating PTFE disk in a dedicated flow-through chamber. The programmable flow-based microextraction method operates under kinetic principles and features software controlled sample loading and dynamic sorptive unidirectional-flow microextraction for as little as 10 min, followed by matrix clean-up and in-line elution with methanol. The hydrophobic thin-film extracting phase was demonstrated to be reusable for at least 15 consecutive extractions in urine without removing or changing the disk. The relative recoveries of the NSAIDs in urine ranged from 101 to 106% using a matrix-matched calibration curve, with extraction efficiencies of 30-38% using a dynamic regime, an enrichment factor of approximately 17 for 10 mL sample and relative standard deviations (RSD) between 3 and 6%. The detection limits (3 * S/N ratio) of the in-line sample preparation method coupled to LC-UV detection ranged from 0.022 to 0.044 mg L(-1). Using NSAID monitored in urine from individuals who received oral administration of ibuprofen and diclofenac, the automatic sample handling method was proven to be efficient for urine clean-up and the determination of acidic drugs at biologically relevant levels. PMID- 25441345 TI - High resolution mass spectrometry in the identification of transformation products and metabolites from beta-lactam antibiotics in thermally treated milk. AB - Antibiotics such as beta-lactam derivatives (penicillins and cephalosporins) are frequently used in veterinary medicine. The presence of these antibiotics together with their metabolites and/or products produced in subsequent treatments at which milk is submitted (sterilization, pasteurization), may be responsible for bacterial resistance, allergy and/or toxicity on sensitive individuals. In this study, liquid chromatography coupled with high resolution mass spectrometry (LC-HRMS) is used to identify transformation products (TPs) from four beta-lactam antibiotics (amoxicillin (AMOX), cephapirin (PIR), ceftiofur (TIO) and penicillin G (PENG)) in thermally treated cow milk. In addition, milk from cows medicated with PENG has also been analogously treated and studied. The detected TPs come mainly from hydrolysis and decarboxylation reactions. Products more strongly degraded respect to parent compounds (of lower molecular weight) were obtained after treating milk at higher temperatures. Products identified in milk from cows medicated with PENG have been classified as TPs when coming from chemical/thermal degradation, and metabolites when resulting from the biological drug metabolism. While TPs are the result of hydrolysis and decarboxylation processes, as already indicated, an enzymatic conjugation with amino acids is suggested to be involved in the formation of metabolites. PMID- 25441346 TI - Evaluation of the impact of peak description on the quantitative capabilities of comprehensive two-dimensional liquid chromatography. AB - Comprehensive, two-dimensional liquid chromatography (LC * LC) is a powerful technique for the separation of complex mixtures. Most studies using LC * LC are focused on qualitative efforts, such as increasing peak capacity. The present study examined the use of LC * LC-UV/vis for the separation and quantitation of polycyclic aromatic hydrocarbons (PAHs). More specifically, this study evaluated the impact of different peak integration approaches on the quantitative performance of the LC * LC method. For well-resolved three-dimensional peaks, parameters such as baseline definition, peak base shape, and peak width determination did not have a significant impact on accuracy and precision. For less-resolved peaks, a dropped baseline and the summation of all slices in the peak improved the accuracy and precision of the integration methods. The computational approaches to three-dimensional peak integration are provided, including fully descriptive, select slice, and summed heights integration methods, each with its own strengths and weaknesses. Overall, the integration methods presented quantify each of the PAHs within acceptable precision and accuracy ranges and have comparable performance to that of single dimension liquid chromatography. PMID- 25441347 TI - Folding fan mode counter-current chromatography offers fast blind screening for drug discovery. Case study: finding anti-enterovirus 71 agents from Anemarrhena asphodeloides. AB - A new application of counter-current chromatography (CCC) in drug discovery, called folding fan mode (FFM), is designed to eliminate the extensive and time consuming calculation of the partition coefficients of some preset compounds in conventional CCC separation. Careful reading of reports in the literature reveals that, when two-phase solvent systems are listed in a polarity-increasing sequence, the isolates also show a similar trend in polarity. The relationship between the two-phase solvent system and the isolates is like that between the folds and the picture of a folding fan. We can directly select a two-phase solvent system to separate fractions having similar polarity, just as opening a fan reveals a picture. The solvent ratio of two-phase solvent systems can be adjusted according to the polarity and weight ratio of active fractions rather than the partition coefficients. Without preset compounds, FFM-CCC not only requires no measurement of partition coefficients, but also achieves true blind screening. This paper reports the method's first success in drug discovery: six anti-EV71 saponins were found from the mixture (9.13 g) of ethanol extract and water extract of Anemarrhena asphodeloides after a total of four CCC separations, using hexan/ethyl acetate/methanol/butanol/water as the model solvent system. Among these saponins, timosaponin B-II displayed a comparable IC50 (4.3 +/- 2.1 MUM) and a 40-fold higher selective index (SI=92.9) than the positive control (IC50=361.7 +/- 104.6 MUM, SI=2.4), ribavirin. The structure-activity relationship (SAR) of these compounds was also studied. PMID- 25441348 TI - Use of individual retention modeling for gradient optimization in hydrophilic interaction chromatography: separation of nucleobases and nucleosides. AB - In this study, the separation of twelve nucleobases and nucleosides was optimized via chromatogram simulation (i.e., prediction of individual retention times and estimation of the peak widths) with the use of an empirical (reversed-phase) non linear model proposed by Neue and Kuss. Retention time prediction errors of less than 2% were observed for all compounds on different stationary phases. As a single HILIC column could not resolve all peaks, the modeling was extended to coupled-column systems (with different stationary phase chemistries) to increase the separation efficiency and selectivity. The analytical expressions for the gradient retention factor on a coupled column system were derived and accurate retention time predictions were obtained (<2% prediction errors in general). The optimized gradient (predicted by the optimization software) included coupling of an amide and an pentahydroxy functionalized silica stationary phases with a gradient profile from 95 to 85%ACN in 6 min and resulted in almost baseline separation of the twelve nucleobases and nucleosides in less than 7 min. The final separation was obtained in less than 4h of instrument time (including equilibration times) and was fully obtained via computer-based optimization. As such, this study provides an example of a case where individual retention modeling can be used as a way to optimize the gradient conditions in the HILIC mode using a non-linear model such as the Neue and Kuss model. PMID- 25441349 TI - A metabolomic approach to quality determination and authentication of raw plant material in the fragrance field. Iris rhizomes: a case study. AB - This study aimed to discriminate 22 samples of commercial Iris rhizomes (orris root) by species and origin (Iris germanica (Morocco), I. albicans (Morocco), I. pallida (Morocco), I. pallida (China), I. pallida (Italy)) by applying a strategy derived from those adopted in metabolomics. The specimens' fingerprints from conventional analysis methods (LC-UV and/or LC-MS) were unable to provide clear discrimination. A strategy combining UHPLC/TOF-HRMS, in positive and negative modes, with multivariate statistical methods was therefore applied. Exact mass/retention time (EMRT) pairs obtained by UHPLC-TOF/HRMS were successfully submitted to statistical processing by principal component analysis (PCA), partial least square discriminant analysis (PLS-DA), and then orthogonal partial least square-discriminant analysis (OPLS-DA), to extract the discriminating EMRT pairs through their trend views. 146 EMRT pairs were selected on the basis of their trend views, because they significantly varied, and 104 of them were included to discriminate between species and origins. 32 of them were tentatively identified as discriminating markers (flavonoids, isoflavonoids, triterpenoids, benzophenone derivatives and related glycosides ...) from the reference database created on the basis of Iris genus components reported in the literature: eight of them specific for I. albicans, four for I. germanica, five for I. pallida (Italy), five for I. pallida (China), and ten for I. pallida (Morocco). The reliability of this strategy was confirmed by identifying species and origin of two unknown samples submitted to the same analytical procedure. PMID- 25441350 TI - Two-stage chromatographic separation of aggregates for monoclonal antibody therapeutics. AB - Aggregates of monoclonal antibody (mAb) therapeutics, due to their perceived impact on immunogenicity, are recognized as a critical quality attribute by the regulatory authorities as well as the industry. Hence, removal of aggregates is a key objective of bioprocessing. At present, this is achieved by a combination of two or more orthogonal chromatographic steps with possible modalities of ion exchange, hydrophobic interaction and mixed mode. A two-stage chromatographic purification process consisting of ion-exchange and hydrophobic interaction modes is proposed in this paper for effective and efficient control of aggregates for a mAb therapeutic. The proposed scheme does not require any intermediate processing of the process stream. Further, baseline separation is achieved for monomer and aggregates resulting in robust performance. This was possible because the proposed operational scheme allowed for an addition of selectivities of the two chromatography modes vs. the traditional two column scheme where part of the separation of aggregates achieved by the first column is lost upon pooling. The proposed process scheme yielded improved separation of aggregates (0% vs. 1-2%) at >95% recovery and reduced overall process time (6h vs. 14 h) for a typical application. Further, clearance of host cell proteins was also shown to have improved with the suggested process scheme. Successful implementation of the proposed scheme has been demonstrated for two different monoclonal antibody therapeutic products. PMID- 25441351 TI - Are sub-2 MUm particles best for separating small molecules? An alternative. AB - Superficially porous particles (SPP) in the 2.5-2.7 MUm range provide almost the same efficiency and resolution of sub-2 MUm totally porous particles (TPP), but at one-half to one-third of the operating pressure. The advantage of SPP has led to the introduction of sub-2 MUm SPP as a natural extension of this technology. While short columns of both SPP and TPP sub-2 MUm particles allow very fast separations, the efficiency advantages of these very small particles often are not realized nor sufficient to overcome some of the practical limitations and disadvantages of such small particles. Advantages and disadvantages of columns packed with sub-2 MUm particles are described for comparison with the characteristics of larger particles. The authors conclude that while sub-2 MUm particles have utility in research studies, columns of larger particles are often better suited for most applications. A suggested 2.0 MUm superficially porous particle diameter retains many of the advantages of sub-2 MUm particles, but minimizes some of the disadvantages. The characteristics of these new 2.0 MUm SPP are described in studies comparing some present sub-2 MUm SPP commercial columns for efficiency, column bed homogeneity and stability. PMID- 25441352 TI - Pharmaceutical-grade pre-miR-29 purification using an agmatine monolithic support. AB - MicroRNA-based therapeutic applications have fostered a growing interest in the development of microRNAs purification processes in order to obtain the final product with high purity degree, good quality and biologically active. The pre miR-29 deficiency or overexpression has been associated to a number of clinically important diseases, and its therapeutic application can be considered. Monolithic columns emerged as a new class of chromatographic supports used in the plasmid DNA purification platforms, being an interesting alternative to the conventional particle-based columns. Thus, the current work describes, for the first time, a new affinity chromatography method that combines the high selectivity of agmatine ligands with the versatility of monoliths to specifically and efficiently purify pre-miR-29 from other small RNA species and Rhodovulum sulfidophilum impurities. The effect of different flow rates on pre-miR-29 separation was also evaluated. Moreover, breakthrough experiments were designed to study the effect of different RNA concentrations on the modified monolithic support binding capacity, being verified that the dynamic binding capacity for RNA molecules is dependent of the feed concentration. In order to achieve higher efficiency and selectivity, three different binding and elution strategies based on increased sodium chloride (1.75 3M) or arginine (100mM) and decreased ammonium sulfate (2.4-0M) stepwise gradients are described to purify pre-miR-29. As a matter of fact, by employing elution strategies using sodium chloride or arginine, an improvement in the final pre-miR-29 yields (97.33 and 94.88%, respectively) as well as purity (75.21 and 90.11%, respectively) were obtained. Moreover, the quality control analysis revealed that the level of impurities (proteins, endotoxins, sRNA) in the final pre-miR-29 sample was negligible. In fact, this new monolithic support arises as a powerful instrument on the microRNA purification to be used in further clinical applications, providing a more rapid and economical purification platform. PMID- 25441353 TI - Retention time prediction in temperature-programmed, comprehensive two dimensional gas chromatography: modeling and error assessment. AB - In this paper we present a model relating experimental factors (column lengths, diameters and thickness, modulation times, pressures and temperature programs) with retention times. Unfortunately, an analytical solution to calculate the retention in temperature programmed GC * GC is impossible, making thus necessary to perform a numerical integration. In this paper we present a computational physical model of GC * GC, capable of predicting with a high accuracy retention times in both dimensions. Once fitted (e.g., calibrated), the model is used to make predictions, which are always subject to error. In this way, the prediction can result rather in a probability distribution of (predicted) retention times than in a fixed (most likely) value. One of the most common problems that can occur when fitting unknown parameters using experimental data is overfitting. In order to detect overfitting situations and assess the error, the K-fold cross validation technique was applied. Another technique of error assessment proposed in this article is the use of error propagation using Jacobians. This method is based on estimation of the accuracy of the model by the partial derivatives of the retention time prediction with respect to the fitted parameters (in this case entropy and enthalpy for each component) in a set of given conditions. By treating the predictions of the model in terms of intervals rather than as precise values, it is possible to considerably increase the robustness of any optimization algorithm. PMID- 25441354 TI - Application of inverse gas chromatography in physicochemical characterization of phenolic resin adhesives. AB - One of the most important stages during production of abrasive tools is their hardening. The degree of hardening is very important and influence toughness of the final product. During hardening process the cross-linking of the phenolic resins, used as a binder, occurs. Nowadays, there is no standard, accurate and simple method for the estimation of the hardening degree of abrasive tools. The procedure of the determination of hardening degree of the binder (phenolic resins) by means of inverse gas chromatography (IGC) was presented in this paper. Results obtained by use of IGC derived method was verified by Soxhlet extraction and by FTIR method. Good agreement was found for results from IGC and Soxhlet extraction whereas those from FTIR were much lower. FTIR method supplies data concerning bulk properties not the surface as in case of IGC and Soxhlet methods. These results indicate that resins are more cross-linked on the surface than inside the material. PMID- 25441355 TI - Gas chromatography for in situ analysis of a cometary nucleus V. Study of capillary columns' robustness submitted to long-term reduced environmental pressure conditions. AB - With the European Space Agency's Rosetta space mission to comet 67P/Churyumov Gerasimenko, a gas chromatograph, part of the COmetary Sampling And Composition (COSAC) experiment, travelled for about 10 years in the interplanetary medium before operating at the surface of the cometary nucleus in November 2014. During its journey in space, the instrument was exposed to the constraining conditions of the interplanetary medium, including reduced environmental pressures. In order to estimate the potential influence of this severe condition on the chromatographic capillary columns, their stationary phase and the subsequent separation capability, a set of flight spare columns were kept under reduced environmental pressure in the laboratory for the same duration as the probe sent to the comet. The columns' analytical performances were evaluated recently and compared to the original ones obtained just before the launch of the Rosetta probe. The results presented here show that the chromatographic performances of the spare chromatographic columns were not altered in time. From this result, it can be expected that the flight instrument will perform nominally for the analysis of the first cometary nucleus sample to be collected ever, and that the preparation of the interpretation of the data to be taken at the cometary surface nucleus can be done through calibration of these spare columns, and other spare components of the instrument. PMID- 25441356 TI - Speciation analysis of inorganic tin by on-column complexation ion chromatography with inductively coupled plasma mass spectrometry and electrospray mass spectrometry. AB - Inductively coupled plasma-mass spectrometry (ICP-MS) and electrospray mass spectrometry (ESI-MS) were used as complementary methods to identify Sn pentaacetic acid (DTPA) complex formation. ESI-MS was used to initially confirm the formation of [Sn(DTPA)](3-) and [Sn(DTPA)](1-) and their MS spectra suggest these tin complexes were stable in solution. On-column complexation of tin with DTPA and the separation of [Sn(DTPA)](3-) and [Sn(DTPA)](1-) was performed on anion-exchange chromatography with an mobile phase containing 20mM NH4NO3 and 3mM DTPA at pH 6.0, and the subsequent detection of [Sn(DTPA)](3-) and [Sn(DTPA)](1-) was achieved by ICP-MS. Linear plots were obtained in a concentration range of 1.0-1000 MUg L(-1) with detection limits ranging from 0.1 to 0.3 MUg L(-1). The developed procedure allows the simultaneous determination of [Sn(DTPA)](3-) and [Sn(DTPA)](1-) in less than 5 min with a RSD between 2.1 and 2.7%. The recoveries of [Sn(DTPA)](3-) and [Sn(DTPA)](1-) were found to be 96.8 and 99.4%, respectively, when the sample was spiked with 20 MUg L(-1) standard. Finally, the proposed procedure was used for the determination of tin species in contaminated water. PMID- 25441357 TI - Sol-gel transition of charged fibrils composed of a model amphiphilic peptide. AB - We characterized the sol-gel transition of positively charged fibrils composed of the model amphiphilic peptide RADARADARADARADA (RADA 16-I) using a combination of microscopy, light scattering, microrheology and rheology techniques, and we investigated the dependence of the hydrogel formation on fibril concentration and ionic strength. The peptide is initially present as a dispersion of short rigid fibrils with average length of about 100 nm. During incubation, the fibrils aggregate irreversibly into longer fibrils and fibrillar aggregates. At peptide concentrations in the range 3-6.5 g/L, the fibrillar aggregates form a weak gel network which can be destroyed upon dilution. Percolation occurs without the formation of a nematic phase at a critical peptide concentration which decreases with increasing ionic strength. The gel structure can be well described in the frame of the fractal gel theory considering the network as a collection of fibrillar aggregates characterized by self-similar structure with a fractal dimension of 1.34. PMID- 25441358 TI - Ethanol chemiresistor with enhanced discriminative ability from acetone based on Sr-doped SnO2 nanofibers. AB - We demonstrated a new metal oxides based chemiresistor (MOC), which exhibits fast response/recovery behavior, large sensitivity, and good selectivity to ethanol, enabled by Sr-doped SnO2 nanofibers via simple electrospinning and followed by calcination. Transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectra (XPS) were carefully used to characterize their morphology, structure, and composition. The ethanol sensing performances based on Sr-doped SnO2 nanofibers were investigated. Comparing with the pristine SnO2 nanofibers, enhanced ethanol sensing performances (more rapid response/recovery behavior and larger response values) have been achieved owing to the basic SnO2 surface caused by Sr-doping, whereas the acetone sensing performances have been weakened. Thus, good discriminative ability to ethanol from acetone has been realized. Additionally, Sr-doped SnO2 nanofibers also exhibit good selectivity. PMID- 25441359 TI - Modeling of microbubble dissolution in aqueous medium. AB - A mathematical model for microbubble dissolution in an aqueous medium containing dissolved gases is presented. None of the models available in the literature take into account the influence of shell elasticity (Es), variation in surface tension (sigma) at the gas-liquid interface and shell resistance (Omega) on the kinetics of microbubble dissolution. Moreover, values of these shell parameters are not known/available and hence arbitrary values for these variables have been assumed in many of the reports for estimation of dissolution kinetics. Therefore, in this work, a mathematical model is developed to describe microbubble dissolution which takes into account the effect of shell elasticity (Es), shell resistance (Omega), surface tension (sigma) and their variation, on the microbubble dissolution. The values of these shell parameters have then been estimated using the proposed model and the experimental data available in literature. The proposed model accurately predicts the experimental microbubble dissolution data using estimated values of shell parameters. Analysis of the results further show that the surface tension and shell resistances change drastically during the microbubble dissolution process and the variation in these parameters during the dissolution process is highly dependent on the shell elasticity which in turn affects the microbubble dissolution times. The methodology developed in this work can be used to estimate shell parameters for any microbubble formulation, to accurately predict in-vitro/in-vivo dissolution of microbubbles, and hence to design a microbubble system with desired characteristics and performance. PMID- 25441360 TI - Spontaneous deposition of polylysine on surfaces: role of the secondary structure to optimize noncovalent coating strategies. AB - Understanding the factors that governs spontaneous molecular transfer from solution to solid surface is fundamental to control noncovalent surface functionalization strategies, both in term of robustness and reproducibility. The comprehension of the nature of interaction involved in the mechanism of spontaneous adsorption will allow for a fine modulation of the deposition process. Herein, we provide experimental evidences to demonstrate that poly lysine secondary structure represents a crucial factor profoundly influencing the outcome of its spontaneous deposition on quartz surfaces. In particular, random coil to alpha-helix transition is required to drive an effective transfer of the poly-l-lysine at the liquid-solid interface. beta-sheet deposition requires longer times to be accomplished, while random-coil deposition is highly unfavored. Accordingly, polylysine deposition on quartz and silicon is effective when alpha-helix is formed in solution (pH>10). This surface noncovalent functionalization represents a simple strategy to fabricate hybrid organic inorganic or biocompatible materials. In fact, the proposed methodology is proven robust and repeatable and compatible for combination with solution or vapor phases (i.e. MOCVD) nanomaterial deposition approaches. PMID- 25441361 TI - Graphene oxide caged in cellulose microbeads for removal of malachite green dye from aqueous solution. AB - A simple sol-gel method using non-toxic and cost-effective precursors has been developed to prepare graphene oxide (GO)/cellulose bead (GOCB) composites for removal of dye pollutants. Taking advantage of the combined benefits of GO and cellulose, the prepared GOCB composites exhibit excellent removal efficiency towards malachite green (>96%) and can be reused for over 5 times through simple filtration method. The high-decontamination performance of the GOCB system is strongly dependent on encapsulation amount of GO, temperature and pH value. In addition, the adsorption behavior of this new adsorbent fits well with the Langmuir isotherm and pseudo-second-order kinetic model. PMID- 25441362 TI - Catalytic performance of carbon nanotubes in H2O2 decomposition: experimental and quantum chemical study. AB - The catalytic performance of multi-walled carbon nanotubes (MWCNTs) with different surface chemistry was studied in the decomposition reaction of H2O2 at various values of pH and temperature. A comparative analysis of experimental and quantum chemical calculation results is given. It has been shown that both the lowest calculated activation energy (~18.9 kJ/mol) and the highest rate constant correspond to the N-containing CNT. The calculated chemisorption energy values correlate with the operation stability of MWCNTs. Based on the proposed quantum chemical model it was found that the catalytic activity of carbon materials in electron transfer reactions is controlled by their electron donor capability. PMID- 25441363 TI - Two-dimensional colloidal crystal assisted formation of conductive porous gold films with flexible structural controllability. AB - Two-dimensional (2D) colloidal crystals of polystyrene (PS) particles were used as a structure-controlling template to fabricate conductive Au films with an ordered array of nanoholes. The fabrication mainly involved the functionalization of the supporting substrate with polyelectrolyte (PE) functional layers, self assembly of Au nanoparticles, and electroless deposition of gold. The self assembly of Au nanoparticles and electroless deposition of gold were macroscopically monitored using ultraviolet-visible (UV-vis) spectroscopy based on the changes in both the extinction spectra of Au nanoparticles and the optical responses of ordered arrays of PS particles. By scanning electron microscopy (SEM) characterization, it was found that Au nanoparticles were assembled into a film structure with orderly dispersed nanoholes and the deposition of gold was confined to the preformed Au nanoparticle films. During the formation of Au films, PE layer structure, Au nanoparticle size and heating treatment applied to the PS template could influence the structures of conductive porous Au films such as the hole diameter, film thickness, and hole diameter/wall thickness ratio (D/W). In addition, this paper also described electrochemical cyclic voltammetry (CV) employed to demonstrate the porosity of the ultimate Au films. PMID- 25441364 TI - Surface loading effects on orthophosphate surface complexation at the goethite/water interface as examined by extended X-ray Absorption Fine Structure (EXAFS) spectroscopy. AB - To investigate the effect of P surface loading on the structure of surface complexes formed at the goethite/water interface, goethite was reacted with orthophosphate at P concentrations of 0.1, 0.2, and 0.8 mmol L(-1) at pH 4.5 for 5 days. The P concentrations were chosen to ensure that P loadings at the surface would allow one to follow the transition between adsorption and surface precipitation. Extended X-ray Absorption Fine Structure (EXAFS) spectra were collected in fluorescence mode at the P K-edge at 2150 eV. The structural parameters were obtained through the fits of the sorption data to single and multiple scattering paths using Artemis. EXAFS analysis revealed a continuum among the different surface complexes, with bidentate mononuclear ((2)E), bidentate binuclear ((2)C) and monodentate mononuclear ((1)V) surface complexes forming at the goethite/water interface under the studied conditions. The distances for P-O (1.51-1.53A) and P-Fe (3.2-3.3A for bidentate binuclear and around 3.6A for mononuclear surface complexes) shells observed in our study were consistent with distances obtained via other spectroscopic techniques. The shortest P-Fe distance of 2.83-2.87A was indicative of a bidentate mononuclear bonding configuration. The coexistence of different surface complexes or the predominance of one sorption mechanism over others was directly related to surface loading. PMID- 25441365 TI - Free-standing porous manganese dioxide/graphene composite films for high performance supercapacitors. AB - A simple hard template method and hydrothermal process have been employed to fabricate a self-standing hierarchical porous MnO2/graphene film. Thus constructed electrode materials for binder-free supercapacitors exhibit a high specific capacitance of 266.3 F g(-1) at the density of 0.2 A g(-1). Moreover, the two-electrode device demonstrates an excellent rate capability and cycling stability with capacitance retention of 85.1% after 2000 charge-discharge cycles at a current density of 1 A g(-1). The porous nanostructured design can effectively improve the specific surface areas and account for the shorter relaxation time for the electrodes, resulting in a high electrochemical performance. PMID- 25441366 TI - Shape separation of gold nanoparticles using a pH-responsive amphiphilic dendrimer according to their shape anisotropy distinction. AB - We present a novel method for shape-selective separation of nanoparticles in aqueous media utilizing an amphiphilic cationic dendrimer (C18N5) through regulation of the pH of the dispersion medium. This amphiphilic dendrimer (C18N5) bears a poly(amidoamine) dendron with four terminal amine groups and one hydrophobic long alkyl chain, and it can strongly adsorb to the surface of gold nanoparticles at low pH and promote their aggregation at high pH. During aggregation, isotropic NPs with smaller inter-particle contact area have much better solution stability than anisotropic NPs. Therefore, isotropic NPs remain stable in the supernatant, while anisotropic NPs are subject to aggregation and subsequent precipitation. As a result of this simple separation strategy, gold nanoplates with a purity level of 97% (in number density) can be rapidly and conveniently achieved. PMID- 25441367 TI - Magnetic core-shell iron(II,III) oxide@layered double oxide microspheres for removal of 2,5-dihydroxybenzoic acid from aqueous solutions. AB - Magnetic core-shell Fe3O4@layered double oxide (Fe3O4@LDO) microspheres were synthesized and utilized as adsorbent in the removal of 2,5-dihydroxybenzoic acid (2,5-DHBA) from aqueous samples. Due to the "memory effect", the microspheres showed higher adsorption capacity compared with Fe3O4@layered double hydroxide. The Fe3O4@LDO microspheres were easily recovered after the experiment via the application of a magnetic force. The effect of mass of Fe3O4@LDO, temperature and time on adsorption efficiency were investigated using batch experiments. Adsorption was in conformance with the Langmuir model, with a maximum adsorption capacity of 188.7 mg/g. Recyclability experiments indicated that adsorption efficiency did not decrease noticeably after 3 cycles of adsorption-calcination. The Fe3O4@LDO microspheres were evaluated by considering matrix-matched aqueous samples spiked with 2,5-DHBA. Under optimized conditions, 98.4% of the 2,5-DHBA analyte in the sample can be effectively removed from an aqueous solution within 4 h. The results indicate that Fe3O4@LDO microspheres have the potential to be employed as highly efficient, convenient, and low-cost magnetic adsorbents in the removal of 2,5-DHBA from water. PMID- 25441368 TI - Expression of matrix metalloproteinases (MMP-2, MMP-9) and their inhibitors (TIMP 1, TIMP-2) in canine testis, epididymis and semen. AB - This study aims to investigate the role of matrix metalloproteinases (MMPs) in determining semen quality and to evaluate the expression and cellular localization of MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 in the testes, epididymis and ejaculated spermatozoa. Gelatinase activities between normal (n = 21) and abnormal (n = 25) semen samples showed a significant, sixfold increase in proMMP-2 and MMP-2 activity in high than low sperm concentration samples (p < 0.001). ProMMP-9 and MMP-9 levels were significantly elevated in samples with low sperm counts compared to those with high sperm density (p < 0.001). High levels of proMMP-2 and MMP-2 were associated with high sperm motility (>=70%, p < 0.001). Sperm-rich fraction showed significantly (eight-fold) higher proMMP-9 enzymatic activity compared with prostatic fraction. The mRNA expressions of MMP-2, MMP-9, TIMP-1 and TIMP-2 were confirmed in testicular and epididymal tissues. Immunohistochemical staining illustrated the MMP-2-specific strong immunoreactivity in the head of mature spermatids during spermatogenesis, whereas MMP-9, TIMP-1 and TIMP-2 were absent in these cells. Matrix metalloproteinase-9 immunoreactivity was observed in the spermatocyte and round spermatid, whereas TIMP-1 was only exhibited in the residual bodies. Immunolabeling of epididymal and ejaculated sperm demonstrated MMP-2 localization along acrosomal region of sperm, while MMP-9, TIMP-1 and TIMP 2 localization was merely limited to the flagella. In conclusion, spermatozoa initially acquire MMP-2 during their formation at testicular level, and the presence of this protein persists through the epididymal transit and up to ejaculate. The enzymatic activity of MMP-2 and MMP-9 may serve as an alternative biomarker in determining semen quality. PMID- 25441369 TI - Friends, friendlessness, and social cognition. AB - I applaud the methods and findings of the target article by Fink and colleagues (Brit. J. Dev. Psychol, 2015; 33, 1-17) who demonstrate an important link between theory of mind and children's social lives. In particular, enhanced theory of mind in preschool buffers children from friendlessness in the transition to school. Going further, I suggest needed steps for the field to experimentally demonstrate causal links between children's theory of mind and their social actions and interactions. PMID- 25441370 TI - SIDS symposium--a perspective for future research. PMID- 25441371 TI - Infectious causes of sudden infant death syndrome. AB - Investigators have long suspected the role of infection in sudden infant death syndrome (SIDS). Evidence of infectious associations with SIDS is accentuated through the presence of markers of infection and inflammation on autopsy of SIDS infants and isolates of some bacteria and viruses. Several observational studies have looked into the relation between seasonality and incidence of SIDS, which often showed a winter peak. These all may suggest an infectious aetiology of SIDS. In this review we have summarised the current literature on infectious aetiologies of SIDS by looking at viral, bacterial, genetic and environmental factors which are believed to be associated with SIDS. PMID- 25441375 TI - Azo pigments and quinacridones induce delayed hypersensitivity in red tattoos. AB - BACKGROUND: Induction of delayed hypersensitivity reactions by red tattoos has been occasionally reported. Little is known about the inks used. Azo pigments have been implicated in some instances, but there is only one reported case involving quinacridones. OBJECTIVES: To describe the clinical and pathological features and outcome of skin reactions induced by red tattoo pigments. PATIENTS, MATERIALS, AND METHODS: Six patients with a cutaneous reaction induced by a red tattoo pigment underwent biopsy and prick and patch testing with the inks supplied. RESULTS: We observed seven reactions in the 6 patients. Histology showed various patterns: three lichenoid, two eczematous, and two pseudolymphomatous. Five reactions occurred with azo pigments, and two with quinacridones, in both cases with Violet 19 and Red 122. Four inks were tested. Only one patch test gave a positive result at a late reading (day 7). Prick tests gave negative results. The reactions required various treatments, including laser treatment for 2 patients. Activation of the reaction in 1 case was transient. CONCLUSION: Azo pigments and quinacridones both triggered reactions with similar clinical aspects but with varying histological findings. Patch and prick test results were disappointing with both. Reactions occurred following laser use in 1 case. PMID- 25441383 TI - 50 Years ago in the Journal of Pediatrics: the syndrome of pancreatic insufficiency and bone marrow dysfunction. PMID- 25441382 TI - Patching the pipeline: creation and retention of the next generation of physician scientists for child health research. PMID- 25441384 TI - 50 Years ago in the Journal of Pediatrics: congenital heart disease in the neonatal period. PMID- 25441385 TI - 50 Years ago in the Journal of Pediatrics: the startle response and serum enzyme profile in early detection of Tay-Sachs' disease. PMID- 25441386 TI - 50 Years ago in the Journal of Pediatrics: a 5-year clinical evaluation of therapeutic program for patients with cystic fibrosis. PMID- 25441387 TI - 50 Years ago in the Journal of Pediatrics: brain tumors in early infancy- probably congenital in origin. PMID- 25441389 TI - Vaccine promotion messages may not encourage vaccination. PMID- 25441388 TI - Differentiating skin-limited and multisystem Langerhans cell histiocytosis. AB - OBJECTIVE: To identify features associated with multisystem involvement and therapeutic failure in patients with skin Langerhans cell histiocytosis (LCH). STUDY DESIGN: We reviewed medical records of 71 consecutive patients with LCH with skin involvement evaluated at Texas Children's Hospital and analyzed clinical features, laboratory results, and the presence of circulating cells with the BRAF-V600E mutation with respect to initial staging and clinical outcomes. RESULTS: Skin disease in patients older than 18 months of age at diagnosis was associated with the presence of multisystem disease (OR, 9.65; 95% CI, 1.17 79.4). Forty percent of patients referred for presumed skin-limited LCH had underlying multisystem involvement, one-half of these with risk-organ involvement. Patients with skin-limited LCH had a 3-year progression-free survival of 89% after initial therapy, and none developed multisystem disease. Patients with skin/multisystem involvement had a 3-year progression-free survival of 44% with vinblastine/prednisone therapy, and risk-organ involvement did not correlate with failure to achieve nonactive disease. Circulating cells with BRAF V600E were detected at higher frequency in patients with multisystem involvement (8 of 11 skin/multisystem vs 1 of 13 skin-limited; P = .002). CONCLUSION: Skin limited LCH necessitates infrequent therapeutic intervention and has a lower risk of progression relative to skin plus multisystem LCH. The less-aggressive clinical course and lack of circulating cells with the BRAF-V600E mutation in skin-limited LCH suggest a different mechanism of disease origin compared with multisystem or risk-organ disease. PMID- 25441390 TI - Completion of circumcision when distal hypospadias is discovered intra procedurally and its effect on subsequent hypospadias repair. PMID- 25441391 TI - Childhood psychosocial stimulation in Jamaica enhances later wage earnings. PMID- 25441392 TI - The BATiC score to rule out traumatic intra-abdominal injury. PMID- 25441393 TI - Substantial lifelong cost of autism spectrum disorder. PMID- 25441394 TI - The quality of hereditary haemochromatosis guidelines: a comparative analysis. AB - BACKGROUND AND OBJECTIVES: Hereditary haemochromatosis (HH) is the most prevalent genetic liver disease, with an incidence of 1/200 to 1/400 in the Caucasian population. HH patients are treated by family physicians as well as different specialists. When left untreated or insufficiently treated, the complications can become life threatening. To support and evaluate qualitative care for HH, we evaluated and compared the available structured guidelines on screening, diagnosis and management of HH patients. METHODS: Seven appraisers systematically reviewed the retrieved guidelines. The Appraisal of Guidelines Research and Evaluation II (AGREE II) was used to score and discuss the quality and reach consensus. The content of recommendations and the evidence behind them, were evaluated. RESULTS: Three guidelines, developed by the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL) and a DUTCH guideline were found. Fifty-seven percent of the recommendations were not shared between the guidelines, pointing to inconsistency of their content. Only two references supporting the recommendations were shared between all three guidelines. The AASLD guideline contains no information about management and follow-up. Moreover, the methodological quality of the AASLD guideline was rated insufficient, except for 'clarity and presentation' (77%). Applicability of the guidelines was scored very low in all three (AASLD: 31%, EASL: 23%, DUTCH: 35%). The DUTCH guideline was judged best. CONCLUSIONS: Very poor consistency between available guidelines for HH hampers qualitative care and its evaluation. An updated high-quality and evidence-based guideline that covers follow-up and management of patients with HH is needed. PMID- 25441395 TI - Enhancing the executive functions of 3-year-olds in the Dimensional Change Card Sort task. AB - Executive functions enable flexible thinking, something young children are notoriously bad at. For instance, in the dimensional change card sort (DCCS) task, 3-year-olds can sort cards by one dimension (shape), but continue to sort by this dimension when asked to switch (to color). This study tests a prediction of a dynamic neural field model that prior experience with the postswitch dimension can enhance 3-year-olds' performance in the DCCS. In Experiment 1A, a matching game was used to preexpose 3-year-olds (n = 36) to color. This facilitated switching from sorting by shape to color. In , 3-year-olds (n = 18) were preexposed to shape. This did not facilitate switching from sorting by color to shape. The model was used to explain this asymmetry. PMID- 25441396 TI - Long-Term Learning in a Short-Term Study Abroad Program: "Are We Really Truly Helping the Community?". AB - OBJECTIVE: To discover long-term learning outcomes in a short-term study abroad program. Students worked directly with community members to identify health issues, implement educational workshops addressing those issues, and evaluate health outcomes. DESIGN AND SAMPLE: This is a qualitative, descriptive study. Thematic analysis was conducted using a written questionnaire completed one or more years postimmersion. The sample was 41 nursing students who participated in a 10-day immersion experience in remote Honduras. RESULTS: Four themes emerged revealing evidence of long-term learning. Three of these themes, Embracing Other, Gaining Cultural Competencies, and Experiencing an Ethnocentric Shift, are supported in the literature. The fourth theme, Negotiating Ethical Dilemmas, offers a new finding. CONCLUSION: Although educators have questioned ethical consequences of study abroad programs, there is a paucity of literature indicating that students are the ones doing the questioning. Implications for educators and community members alike include facilitating dialog about collective worldviews related to global health ethics when designing study abroad programs. PMID- 25441398 TI - Medical futility and nonbeneficial interventions: an algorithm to aid clinicians. PMID- 25441397 TI - Atorvastatin reduces T-cell activation and exhaustion among HIV-infected cART treated suboptimal immune responders in Uganda: a randomised crossover placebo controlled trial. AB - OBJECTIVE: T-cell activation independently predicts mortality, poor immune recovery and non-AIDS illnesses during combination antiretroviral therapy (cART). Atorvastatin showed anti-immune activation effects among HIV-infected cART-naive individuals. We investigated whether adjunct atorvastatin therapy reduces T-cell activation among cART-treated adults with suboptimal immune recovery. METHODS: A randomised double-blind placebo-controlled crossover trial, of atorvastatin 80 mg daily vs. placebo for 12 weeks, was conducted among individuals with CD4 increase <295 cells/MUl after seven years of suppressive cART. Change in T-cell activation (CD3 + CD4 + /CD8 + CD38 + HLADR+) and in T-cell exhaustion (CD3 + CD4 + /CD8 + PD1 + ) was measured using flow cytometry. RESULTS: Thirty patients were randomised, 15 to each arm. Atorvastatin resulted in a 28% greater reduction in CD4 T-cell activation (60% reduction) than placebo (32% reduction); P = 0.001. Atorvastatin also resulted in a 35% greater reduction in CD8-T-cell activation than placebo (49% vs. 14%, P = 0.0009), CD4 T-cell exhaustion (27% vs. 17% in placebo), P = 0.001 and CD8 T-cell exhaustion (27% vs. 16%), P = 0.004. There was no carry-over/period effect. Expected adverse events were comparable in both groups, and no serious adverse events were reported. CONCLUSION: Atorvastatin reduced T-cell immune activation and exhaustion among cART-treated adults in a Ugandan cohort. Atorvastatin adjunct therapy should be explored as a strategy to improve HIV treatment outcomes among people living with HIV in sub-Saharan Africa. PMID- 25441399 TI - Comparative efficacy of biologic therapy in biologic-naive patients with Crohn disease: a systematic review and network meta-analysis. AB - OBJECTIVE: To study the comparative efficacy of biologic therapy in the management of biologic-naive patients with Crohn disease (CD). PATIENTS AND METHODS: We conducted a systematic review of randomized controlled trials published from January 1, 1985, through September 30, 2013, comparing biologic agents (infliximab [IFX], adalimumab [ADA], certolizumab pegol, natalizumab, vedolizumab, and ustekinumab) with each other or placebo for inducing and maintaining clinical remission in adults with moderate to severe CD. To increase comparability across trials, we focused on a subset of biologic-naive patients for the induction end point and on responders to induction therapy for the maintenance end point. We followed a Bayesian network meta-analysis approach. RESULTS: We identified 17 randomized controlled trials of good methodological quality comparing 6 biologic agents with placebo, with no direct comparison of biologic agents. In network meta-analysis, we observed that IFX (relative risk [RR], 6.11; 95% credible interval [CrI], 2.49-18.29) and ADA (RR, 2.98; 95% CrI, 1.12-8.18), but not certolizumab pegol (RR, 1.48; 95% CrI, 0.76-2.93), natalizumab (RR, 1.36; 95% CrI, 0.69-2.86), vedolizumab (RR, 1.40; 95% CrI, 0.63 3.28), and ustekinumab (RR, 0.61; 95% CrI, 0.15-2.49), were more likely to induce remission than placebo. Similar results were observed for maintenance of remission. Infliximab had the highest probability of being ranked as the most efficacious agent for induction (86%) and ADA for maintenance of remission (48%). CONCLUSION: On the basis of network meta-analysis, IFX may be most efficacious agent for inducing remission in CD in biologic-naive patients. In the absence of head-to-head treatment comparison, the confidence in these estimates is low. Future comparative efficacy studies are warranted. PMID- 25441400 TI - Relationship between exercise heart rate and age in men vs women. AB - OBJECTIVE: To analyze a large cohort of patients who underwent exercise testing and also report sex differences in other exercise heart rate (HR) parameters to determine whether separate sex-based equations to predict peak HR are indicated. PATIENTS AND METHODS: Patients aged 40 to 89 years who performed treadmill exercise tests (Bruce protocol) from September 21, 1993, to December 20, 2010, were included. Patients with cardiovascular disease or taking HR-attenuating drugs were excluded. After analyses on preliminary cohort, peak HR-modifying factors were eliminated to obtain a pure data set. Analysis of variance was used to test difference in HR responses by sex with age adjustment. RESULTS: A total of 37,010 patients (67.3% men) were included in the preliminary cohort. Men had higher peak HR (166+/-17 vs 163+/-16 beats/min [bpm]; P<.001), HR reserve (90+/ 19 vs 84+/-17 bpm; P<.001), and HR recovery (19+/-8 vs 18+/-9 bpm; P<.03). Poor exercise capacity, current smoking, diabetes, and obesity had significant peak HR lowering effects (all P<.001). In a pure cohort of 19,013 patients (51.3% of full cohort) without these factors, regression lines approximated more closely the traditional line of 220 - age. For men, the regression line in our final cohort was peak HR = 220 - 0.95 * age. For women, both slope (0.79 bpm/y) and intercept (210 bpm) were still substantially different from those obtained with the traditional formula. CONCLUSION: The HR responses to exercise are different in men and women. The HR response of men was close to that obtained with the traditional formula, but peak HR in women had a lower intercept and decreased more slowly with age. A separate formula for peak HR in women appears to be appropriate. PMID- 25441401 TI - Mitigating the safety risks of drugs with a focus on opioids: are risk evaluation and mitigation strategies the answer? AB - Approximately 40% of all newly approved drugs are subject to safety restrictions inclusive of Risk Evaluation and Mitigation Strategies (REMS), which were created with the US Food and Drug Administration Amendments Act of 2007. This law expanded Food and Drug Administration (FDA) authority to require REMS of manufacturers but left implementation to the FDA. As a result, the potential access to medications that are effective but not without safety concerns has improved, yet the converse is also true because access may be restricted due to REMS requirements (eg, physician or patient registration). With the July 2012 reauthorization of the Prescription Drug User Fee Act, the FDA was given additional authorities and mandates for enhancing and modernizing the drug safety system-specifically, measuring the effectiveness of REMS as well as standardizing and better integrating REMS into the overall health care system. So, are REMS, which were conceived as a tool to improve medication safety, working? Specifically, are REMS achieving their intended outcomes (mitigating safety risks of effective drugs) without causing unintended consequences (creating a burden to the health care system and physicians and/or diminishing patient access to drugs)? Sitting squarely in the crosshairs, the approved shared REMS for extended release/long-acting opioid analgesics provide a lens through which this question can be examined. This article discusses the current status, stakeholders, and key policy issues for clinicians with a focus on the shared REMS for opioids, as well as the anticipated role of clinicians in optimizing patient care in the new world of REMS. PMID- 25441402 TI - New-onset heart failure in association with severe hypertension during trastuzumab therapy. AB - Heart failure is a dreaded complication of trastuzumab therapy in women with breast cancer overexpressing the human epidermal growth factor receptor (HER)-2. Experimental studies have pointed out that the HER-2 signaling pathway is important in the adaptation to high afterload conditions and its inactivation leads to cardiac decompensation. Herein, we report on 2 patients with breast cancer who were receiving trastuzumab monotherapy and required hospital admission for new-onset heart failure. This occurred at a time of unprecedented blood pressure elevations, in one case due to cessation of antihypertensive medications and in the other case due to a scleroderma crisis. Although trastuzumab may not have been the precipitating factor for blood pressure dyscontrol in these patients, severe, uncontrolled hypertension may have been the precipitating factor for trastuzumab-related acute heart failure. These 2 cases add to previous reports recognizing systemic hypertension as a risk factor for the development of trastuzumab cardiotoxicity and translate experimental observations of the significance of the HER-2 signaling pathway to the bedside. Pending further confirmation, the present observations may raise awareness of the need for appropriate monitoring and control of systemic hypertension in patients receiving trastuzumab, or potentially any other HER-2-targeted therapy. PMID- 25441406 TI - Report of the editors, 2014. AB - The editors of Revista Clinica Espanola(Rev Clin Esp) inform on their editorial activity during the last 12 months: (a) Objectives and attainments in 2014, (b) Editorial activity, 2014, and (c) 2013 impact factor. In 2014 we achieved the 5 planned objectives. We have published the 9 programmed issues and 103% of the planned papers according to the usual fixed sections. We emphasize the publication of 29 editorials, 21 of which are signed by prestigious foreign authors. From the first January to the 30th September 2014 we received 421 manuscripts (46.8 manuscripts per month), a slight lower figure to that obtained in 2013 (50.9 manuscripts per month). The acceptance rate of the 404 manuscripts whose editorial process has been concluded was 32.3% (originals, 22.4%). We asked for 315 revisions to 240 reviewers and we received 53.3% revisions in less than two weeks (10.4 days). The mean time to adopt an editorial decision for all manuscripts ("accepted"/"rejected") has been 18,3 (less than half than in 2009). For "originals" this figure has dropped from 56,6 days in 2009 to 26.6 days in 2014. The mean time elapsed from manuscript reception to its on-line publication was 103 days. In 2014 the collaboration with the working groups from the Internal Medicine Spanish Foundation (FEMI) has reported 11 published manuscripts. In July 2014 we were informed that the Journal Citation Reports gave Rev Clin Esp an Impact Factor of 1,314 (year 2013). This Impact Factor without self-citations would have been 0.705 (in 2009 the global impact factor was 0,584). With the Editorial Committee farewell we welcome the new editorial team and we sincerely thank the SEMI Steering Committee, our colleagues, journal officers, reviewers, readers and authors that since 2009 have trusted on our editorial work. PMID- 25441407 TI - Amyloidosis: Is there hope? PMID- 25441408 TI - A randomised, open-label phase II trial of afatinib versus cetuximab in patients with metastatic colorectal cancer. AB - PURPOSE: This randomised phase II trial aimed to compare efficacy of the irreversible ErbB family blocker, afatinib, with cetuximab in patients with KRAS wild-type metastatic colorectal adenocarcinoma (mCRC) with progression following oxaliplatin- and irinotecan-based regimens. Efficacy in patients with KRAS mutations was also evaluated. PATIENTS AND METHODS: Patients with KRAS wild-type tumours were randomised 2:1 to afatinib (40 mg/day, increasing to 50 mg/day if minimal toxicity) or cetuximab weekly (400 mg/m2 loading dose, then 250 mg/m2/week) according to number of previous chemotherapy lines. All patients with KRAS-mutated tumours received afatinib. Primary end-points were objective response (OR) for the wild-type group and disease control for the KRAS-mutated group. Secondary end-points were progression-free survival (PFS) and overall survival (OS). RESULTS: Patients with KRAS wild-type tumours (n=50) received afatinib (n=36) or cetuximab (n=14). Unconfirmed and confirmed ORs were 3% and 0% for afatinib versus 20% and 13% for cetuximab (odds ratio: 0.122 [P=0.0735] and <0.001, respectively). Median PFS was 46.0 and 144.5 days for afatinib and cetuximab, respectively. Median OS was 355 days with afatinib but not reached for cetuximab. In the KRAS-mutated group (n=41), five (12%) patients achieved confirmed disease control (stable disease; P=0.6394 [comparison versus 10%]); no ORs were reported. Median PFS and OS were 41.0 and 173days, respectively. Most frequent treatment-related adverse events were diarrhoea and rash across groups. CONCLUSIONS: The efficacy of afatinib was inferior to cetuximab in patients with KRAS wild-type mCRC. In patients with KRAS-mutated tumours, disease control was modest with afatinib. Afatinib had a manageable safety profile. PMID- 25441409 TI - 2,6-Diaminopyridine-imprinted polymer and its potency to hair-dye assay using graphene/ionic liquid electrochemical sensor. AB - A new analytical approach for detecting diaminopyridine derivatives has been constructed using a molecular imprinting-electrochemical sensor. Opposed to the conventional strategy of employing diaminopyridine as the functional monomer and uracil derivatives as the target analyte, in the current study, the 2,6 Diaminopyridine-imprinted core-shell nanoparticles were synthesized with 2,6 Diaminopyridine as the template molecule and 6-aminouracil as the functional monomer. Graphene and ionic liquid which can assist 2,6-Diaminopyridine-imprinted core-shell nanoparticles in electrochemical reaction kinetics by increasing conductivity have been introduced to form one of the electrode modified layers. The proposed analytical method has been applied in 2,6-Diaminopyridine detection in hair-dyes and demonstrated appropriate sensitivity and selectivity, with a linear range of 0.0500-35.0 mg kg(-1) and a detection limit as low as 0.0275 mg kg(-1). PMID- 25441410 TI - A DNA-templated silver nanocluster probe for label-free, turn-on fluorescence based screening of homo-adenine binding molecules. AB - A novel, label-free, turn-on fluorescence strategy to detect molecules that bind to adenine-rich DNA sequences has been developed. The probe employs DNA-templated silver nanoclusters (DNA-AgNCs) as the key detection component. The new strategy relies on the formation of non-Watson-Crick homo-adenine DNA duplex, triggered by strong interactions with homo-adenine binding molecules, which brings a guanine rich sequence in one strand close to DNA-AgNCs located on the opposite strand. This phenomenon transforms weakly fluorescent AgNCs into highly emissive species that display bright red fluorescence. Finally, we have shown that the new fluorescence turn-on strategy can be employed to detect coralyne, the most representative homo-adenine binding molecule that triggers formation of a non Watson-Crick homo-adenine DNA duplex. PMID- 25441411 TI - A miniature porous aluminum oxide-based flow-cell for online water quality monitoring using bacterial sensor cells. AB - The use of live bacterial reporters as sensing entities in whole-cell biosensors allows the investigation of the biological effects of a tested sample, as well as the bioavailability of its components. Here we present a proof of concept for a new design for online continuous water monitoring flow-cell biosensor, incorporating recombinant reporter bacteria, engineered to generate an optical signal (fluorescent or bioluminescent) in the presence of the target compound(s). At the heart of the flow-cell is a disposable chip made of porous aluminum oxide (PAO), which retains the sensor microorganisms on its rigid planar surface, while its high porosity allows an undisturbed access both to the sample and to essential nutrients. The ability of the bacterial reporters to detect model toxic chemicals was first demonstrated using a "naked" PAO chip placed on solid agar, and later in a chip encased in a specially designed flow-through configuration which enables continuous on-line monitoring. The applicability of the PAO chip to simultaneous online detection of diverse groups of chemicals was demonstrated by the incorporation of a 6-member sensor array into the flow-through chip. The selective response of the array was also confirmed in spiked municipal wastewater effluents. Sensing activity was retained by the bacteria after 12-weeks storage of freeze-dried biochips, demonstrating the biochip potential as a simple minimal maintenance "plug-in" cartridge. This low-cost and easy to handle PAO-based flow cell biosensor may serve as a basis for a future platform for water quality monitoring. PMID- 25441412 TI - Disposable and reliable electrochemical magnetoimmunosensor for Fumonisins simplified determination in maize-based foodstuffs. AB - An electrochemical magnetoimmunosensor involving magnetic beads and disposable carbon screen-printed electrode (CSPE) for Fumonosins (FB1, FB2 and FB3) has been developed and evaluated through a certified reference material (CRM) and beer samples. Once the immunochemical reactions took place on the magnetic beads solution, they were confined on the surface of CSPE, where electrochemical detection is achieved through the addition of suitable substrate and mediator for enzymatic tracer (Horseradish peroxidase--HRP). A remarkable detection limit of 0.33 MUg L(-1), outstanding repeatability and reproducibility (RSD(intraday) of 5.6% and 2.9%; RSD(interday) of 6.9% and 6.0%; both for 0 and 5 MUg L(-1) FB1 respectively), and excellent accuracy with recovery rate of 85-96% showed the suggested approach to be a very suitable screening tool for the analysis of Fumonisin B1 and B2 in food samples. A simultaneous simplified calibration and analysis protocol allows a fast and reliable determination of Fumonisin in beer samples with recovery rate of 87-105%. This strategy enhanced the analytical merits of immunosensor approach towards truly disposable tools for food-safety monitoring. PMID- 25441413 TI - A portable low-cost long-term live-cell imaging platform for biomedical research and education. AB - Time-resolved visualization and analysis of slow dynamic processes in living cells has revolutionized many aspects of in vitro cellular studies. However, existing technology applied to time-resolved live-cell microscopy is often immobile, costly and requires a high level of skill to use and maintain. These factors limit its utility to field research and educational purposes. The recent availability of rapid prototyping technology makes it possible to quickly and easily engineer purpose-built alternatives to conventional research infrastructure which are low-cost and user-friendly. In this paper we describe the prototype of a fully automated low-cost, portable live-cell imaging system for time-resolved label-free visualization of dynamic processes in living cells. The device is light-weight (3.6 kg), small (22 * 22 * 22 cm) and extremely low cost ( .05). In patients with HER2(-) and HR(-) disease, trastuzumab combined with chemotherapy did not significantly improve (P > .05) ORR or PFS. Targeted therapies also increased the overall risk of adverse events. So far, there is a lack of published results for everolimus and trastuzumab emtansine trials in patients with previously untreated MBC. The addition of targeted therapy to chemotherapy or endocrine therapy using HER2 and HR status significantly improved ORR, PFS, and OS in patients with previously untreated MBC. PMID- 25441422 TI - Acceleration of heat shock-induced collagen breakdown in human dermal fibroblasts with knockdown of NF-E2-related factor 2. AB - Heat shock increases skin temperature during sun exposure and some evidence indicates that it may be involved in skin aging. The antioxidant response mediated by the transcription factor NF-E2-related factor 2 (Nrf2) is a critically important cellular defense mechanism that serves to limit skin aging. We investigated the effects of heat shock on collagenase expression when the antioxidant defense system was downregulated by knockdown of Nrf2. GSH and collagenases were analyzed, and the expression of inducible Nrf2, HO-1, and NQO1 was measured. HS68 cells were transfected with small interfering RNA against Nrf2. Heat shock induced the downregulation of Nrf2 in both the cytosol and nucleus and reduced the expression of HO-1, GSH, and NQO1. In addition, heat exposed Nrf2-knockdown cells showed significantly increased levels of collagenase protein and decreased levels of procollagen. Our data suggest that Nrf2 plays an important role in protection against heat shock-induced collagen breakdown in skin. PMID- 25441423 TI - Synergistic effect of curcumin on epigallocatechin gallate-induced anticancer action in PC3 prostate cancer cells. AB - Epigallocatechin gallate (EGCG) and curcumin are well known to naturally occurring anticancer agents. The aim of this study was to verify the combined beneficial anticancer effects of curcumin and EGCG on PC3 prostate cancer cells, which are resistant to chemotherapy drugs and apoptosis inducers. EGCG showed weaker inhibitory effect on PC3 cell proliferation than two other prostate cancer cell lines, LNCaP and DU145. Co-treatment of curcumin improved antiproliferative effect of EGCG on PC3 cells. The protein expressions of p21 were significantly increased by the co-treatment of EGCG and curcumin, whereas it was not changed by the treatment with each individual compound. Moreover, treatments of EGCG and curcumin arrested both S and G2/M phases of PC3 cells. These results suggest that the enhanced inhibitory effect of EGCG on PC3 cell proliferation by curcumin was mediated by the synergic up-regulation of p21-induced growth arrest and followed cell growth arrest. PMID- 25441424 TI - Physiological functions of the TRPM4 channels via protein interactions. AB - Transient Receptor Potential, Melastatin-related, member 4 (TRPM4) channels are Ca2(+)-activated Ca2(+)-impermeable cation channels. These channels are expressed in various types of mammalian tissues including the brain and are implicated in many diverse physiological and pathophysiological conditions. In the past several years, the trafficking processes and regulatory mechanism of these channels and their interacting proteins have been uncovered. Here in this minireview, we summarize the current understanding of the trafficking mechanism of TRPM4 channels on the plasma membrane as well as heteromeric complex formation via protein interactions. We also describe physiological implications of protein TRPM4 interactions and suggest TRPM4 channels as therapeutic targets in many related diseases. PMID- 25441425 TI - Molecular epidemiology of norovirus in South Korea. AB - Norovirus is a major cause of viral gastroenteritis and a common cause of foodborne and waterborne outbreaks. Norovirus outbreaks are responsible for economic losses, most notably to the public health and food industry field. Norovirus has characteristics such as low infectious dose, prolonged shedding period, strong stability, great diversity, and frequent genome mutations. Besides these characteristics, they are known for rapid and extensive spread in closed settings such as hospitals, hotels, and schools. Norovirus is well known as a major agent of food-poisoning in diverse settings in South Korea. For these reasons, nationwide surveillance for norovirus is active in both clinical and environmental settings in South Korea. Recent studies have reported the emergence of variants and novel recombinants of norovirus. In this review, we summarized studies on the molecular epidemiology and nationwide surveillance of norovirus in South Korea. This review will provide information for vaccine development and prediction of new emerging variants of norovirus in South Korea. PMID- 25441426 TI - Structure and apoptotic function of p73. AB - p73 is a structural and functional homologue of the p53 tumor suppressor protein. Like p53, p73 induces apoptosis and cell cycle arrest and transactivates p53 responsive genes, conferring its tumor suppressive activity. In addition, p73 has unique roles in neuronal development and differentiation. The importance of p73 induced apoptosis lies in its capability to substitute the pro-apoptotic activity of p53 in various human cancer cells in which p53 is mutated or inactive. Despite the great importance of p73-induced apoptosis in cancer therapy, little is known about the molecular basis of p73-induced apoptosis. In this review, we discuss the p73 structures reported to date, detailed structural comparisons between p73 and p53, and current understanding of the transcription-dependent and independent mechanisms of p73-induced apoptosis. PMID- 25441431 TI - Narrowing the focus: what we now know (and still don't know) about antibiotic prophylaxis for children with vesicoureteral reflux. PMID- 25441432 TI - Myoglobin cast nephropathy in a kidney transplant patient with normal creatine kinase. AB - Delayed graft function in kidney transplant recipients is a known complication associated with increased risk of acute rejection and reduced transplant survival after 1 year. There are multiple risk factors, including prolonged cold ischemia time, donor age, and cause of donor's death. Major causes of delayed graft function are acute kidney injury in the donor, often from prolonged terminal ischemia, reflected by acute tubular injury in the recipient. However, the differential diagnosis of delayed graft function includes acute rejection, recurrence of the primary glomerular diseases, and other less commonly encountered conditions. A transplant kidney biopsy usually is required to elucidate the correct cause and initiate the right treatment, which is crucial for transplant survival. We report a case of a transplant recipient who developed delayed graft function due to an uncommon cause. After correct diagnosis, the patient's transplant function improved. PMID- 25441433 TI - Complement in kidney disease: core curriculum 2015. PMID- 25441434 TI - Intratubular hemoglobin casts in hemolysis-associated acute kidney injury. AB - Kidney injury is a complication of intravascular hemolysis associated with many forms of hemolytic disease. Reports of kidney biopsy findings in patients with hemolysis-related kidney injury have focused primarily on the accumulation of hemosiderin pigment within proximal tubular epithelial cells (hemosiderosis), a feature of chronic hemolysis. The nephrotoxic effects of hemoglobin include direct cytotoxicity to tubular cells, but hemoglobin also can precipitate in distal nephron segments, forming obstructive casts. We present a case of hemolysis-associated tubular injury, characterized by acute onset of intravascular hemolysis followed by acute kidney injury with acute tubular injury and abundant intratubular casts containing hemoglobin. PMID- 25441436 TI - Adverse technical events in home hemodialysis. AB - BACKGROUND: There is a growing interest in home hemodialysis because of its clinical benefits. However, given that patients are responsible for performing a complex medical procedure at home, adverse-event reporting is important to ensure patient safety. The purpose of this study was to describe adverse technical events in a large cohort of home hemodialysis patients. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: All consecutive patients undergoing home hemodialysis at a large tertiary-care center from 1999 through 2011 (last follow-up, July 2012). OUTCOMES: Overall rate of adverse technical events and number/rate of severe adverse events (defined as those requiring intervention). RESULTS: The cohort consisted of 202 patients with total follow-up of 757 patient-years. The cohort underwent a median of 5 dialysis treatments per week and 8 hours per session. 22 first adverse events and 7 recurrent events were identified. Adverse event rates were 0.049 per arteriovenous fistula access-year, 0.015 per arteriovenous graft access-year, and 0.022 per dialysis catheter access year. Event rates per 1,000 dialysis treatments were 0.208, 0.068, and 0.087 for arteriovenous fistula, arteriovenous graft, and dialysis catheter access, respectively. Most adverse events were related to needle dislodgement (n=18) or air embolism (n=6). 8 adverse events resulted in emergency department visits and 5 required hospital admission. The rate of severe adverse events was 0.009 per patient-year of home hemodialysis and 0.038 per 1,000 dialysis treatments. Interventions included 3 blood transfusions, 2 catheter changes, 1 use of intravenous fluids, and 1 need for urgent dialysis. Attempts were made to retrain or review the technique in all patients with a first adverse event. LIMITATIONS: Events that were not severe may have been under-reported by patients. CONCLUSIONS: Serious adverse technical events in home hemodialysis are relatively rare. Strategies to further prevent these events may include patient retraining and periodic vascular access technique audit. PMID- 25441435 TI - Estimating time to ESRD using kidney failure risk equations: results from the African American Study of Kidney Disease and Hypertension (AASK). AB - BACKGROUND: Planning for renal replacement therapy, such as referral for arteriovenous fistula placement and transplantation, often is guided by level of estimated glomerular filtration rate (eGFR). The use of risk equations might enable more accurate estimation of time to end-stage renal disease (ESRD), thus improving patient care. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 1,094 participants in the African American Study of Kidney Disease and Hypertension (AASK) cohort. PREDICTOR: Age, sex, urine protein-creatinine ratio >= 1g/g, APOL1 high-risk status, and 3-year antecedent eGFR decline. OUTCOME: Cumulative incidence of ESRD from 5 different starting points: eGFR of 30 and 15mL/min/1.73m(2) and 1-year ESRD risk of 5%, 10%, and 20%, estimated by a published 4-variable kidney failure risk equation. RESULTS: 566 participants developed eGFR of 30mL/min/1.73m(2), 244 developed eGFR of 15mL/min/1.73m(2), and 437, 336, and 259 developed 1-year ESRD risks of 5%, 10%, and 20%, respectively. The 1-year cumulative incidence of ESRD was 4.3% from eGFR of 30mL/min/1.73m(2), 49.0% from eGFR of 15mL/min/1.73m(2), 6.7% from 5% ESRD risk, 15.0% from 10% ESRD risk, and 29% from 20% ESRD risk. From eGFR of 30mL/min/1.73m(2), there were several risk factors that predicted ESRD risk. From eGFR of 15mL/min/1.73m(2), only level of proteinuria did; median time to ESRD was 9 and 19 months in those with higher and lower proteinuria, respectively. Median times were less variable from corresponding ESRD risk thresholds. For example, median times to ESRD from 20% ESRD risk were 22 and 25 months among those with higher and lower proteinuria, respectively. LIMITATIONS: Relatively homogeneous population of African Americans with hypertensive kidney disease. CONCLUSIONS: Results of the present study suggest the potential benefit of incorporating kidney failure risk equations into clinical care, with selection of a specific threshold guided by its intended use. PMID- 25441437 TI - GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. AB - The US Food and Drug Administration currently accepts halving of glomerular filtration rate (GFR), assessed as doubling of serum creatinine level, as a surrogate end point for the development of kidney failure in clinical trials of kidney disease progression. A doubling of serum creatinine level generally is a late event in chronic kidney disease (CKD); thus, there is great interest in considering alternative end points for clinical trials to shorten their duration, reduce sample size, and extend their conduct to patients with earlier stages of CKD. However, the relationship between lesser declines in GFR and the subsequent development of kidney failure has not been well characterized. The National Kidney Foundation and Food and Drug Administration sponsored a scientific workshop to critically examine available data to determine whether alternative GFR-based end points have sufficiently strong relationships with important clinical outcomes of CKD to be used in clinical trials. Based on a series of meta analyses of cohorts and clinical trials and simulations of trial designs and analytic methods, the workshop concluded that a confirmed decline in estimated GFR of 30% over 2 to 3 years may be an acceptable surrogate end point in some circumstances, but the pattern of treatment effects on GFR must be examined, specifically acute effects on estimated GFR. An estimated GFR decline of 40% may be more broadly acceptable than a 30% decline across a wider range of baseline GFRs and patterns of treatment effects on GFR. However, there are other circumstances in which these end points could lead to a reduction in statistical power or erroneous conclusions regarding benefits or harms of interventions. We encourage careful consideration of these alternative end points in the design of future clinical trials. PMID- 25441438 TI - GFR decline as an alternative end point to kidney failure in clinical trials: a meta-analysis of treatment effects from 37 randomized trials. AB - BACKGROUND: There is increased interest in using alternative end points for trials of kidney disease progression. The currently established end points of end stage renal disease and doubling of serum creatinine level, equivalent to a 57% decline in estimated glomerular filtration rate (eGFR), are late events in chronic kidney disease (CKD), requiring large clinical trials with long follow up. As part of a comprehensive evaluation of lesser declines in eGFR as alternative end points, we describe the consistency of treatment effects of intervention on the alternative and established end points in past trials. STUDY DESIGN: Diagnostic test study. SETTING & POPULATION: 9,488 participants from 37 randomized controlled trials of CKD progression across 5 intervention types. INDEX TEST: Alternative end points including percentage change in eGFR from baseline (20%, 30%, 40%, and 57%) throughout study duration and to 12, 18, and 24 months. eGFR change confirmed versus nonconfirmed at the next visit. REFERENCE TEST: The historically established end point of time to composite of treated kidney failure (end-stage renal disease), untreated kidney failure (GFR<15mL/min/1.73m(2)), or doubling of serum creatinine level throughout study duration. RESULTS: Over a median of 3.62 years' follow-up, there were 3,070 established end points. Compared to the established end point, the number of alternative end points was greater for smaller versus larger declines in eGFR and longer versus shorter follow-up intervals. There was a general trend toward attenuation of the treatment effect with end points defined by a lesser eGFR decline, with greater attenuation with nonconfirmed end points, except for the low-protein-diet intervention, for which a stronger treatment effect was observed. The ratio (95% credible interval) of the HR for the alternative to established end point for the 5 intervention types ranged from 0.91 (0.64-1.43) to 1.12 (0.89-1.40) for 40% decline and from 0.88 (0.63-1.39) to 1.15 (0.88-1.54) for 30% decline for the overall study duration, indicating consistency of treatment effects. LIMITATIONS: Limited variety of interventions tested and low statistical power for many CKD clinical trials. CONCLUSIONS: These results provide some support for the use of lesser eGFR declines as a surrogate end point, with stronger support for the 40% than 30% decline. PMID- 25441439 TI - GFR decline and subsequent risk of established kidney outcomes: a meta-analysis of 37 randomized controlled trials. AB - BACKGROUND: The currently established end points for clinical trials of progression of chronic kidney disease (CKD) are end-stage renal disease and doubling of serum creatinine level, which approximates a 57% decline in estimated glomerular filtration rate (eGFR). There is increased interest in using alternative end points in clinical trials to shorten trial duration and reduce sample size. As part of an evaluation of using lesser declines in GFR as alternative end points, we examined the associations of various levels of eGFR decline with the subsequent development of established end points and assess the consistency of alternate levels of eGFR decline across varying clinical manifestations of kidney disease and interventions. STUDY DESIGN: Observational analysis of randomized controlled trials. SETTING & PARTICIPANTS: 9,488 participants in 37 randomized controlled trials in CKD. PREDICTOR: Alternative end points, defined as 30% and 40% declines in eGFR from baseline to month 12. Effect modification by baseline eGFR, proteinuria, cause of disease, and interventions. OUTCOMES: Established end point, defined as end-stage renal disease, eGFR<15mL/min/1.73m(2), or doubling of serum creatinine level. RESULTS: From baseline to 12 months, 16.1% and 7.8% of participants had eGFR declines of >=30% or >=40%, respectively. Over a median follow-up of 2.0 (IQR, 1.2-3.1) years after the 12-month baseline period, 2,661 established end points were observed. A strong linear association was observed between eGFR decline and subsequent established end points. HRs for the established end point for 30% and 40% decreases in eGFR compared to a 0% decline were 9.6 (95% CI, 7.3-12.6) and 20.3 (95% CI, 14.1-29.3), respectively. The associations were consistent regardless of baseline eGFR, proteinuria, causes of disease, and interventions. LIMITATIONS: Observational study subject to residual confounding. CONCLUSIONS: The strong associations between lesser declines in eGFR and the subsequent development of established end points were consistent across different clinical characteristics of kidney disease and interventions and support implementation of alternative end points in clinical trials of CKD progression. PMID- 25441440 TI - Utility and validity of estimated GFR-based surrogate time-to-event end points in CKD: a simulation study. AB - BACKGROUND: There is interest in surrogate end points for clinical trials of chronic kidney disease progression because currently established end points-end stage renal disease (ESRD) and doubling of serum creatinine level-are late events, requiring large clinical trials with long follow-up. Doubling of serum creatinine level is equivalent to a 57% decline in estimated glomerular filtration rate (eGFR). We evaluated type 1 error and required sample size for clinical trials using surrogate end points based on lesser eGFR declines. STUDY DESIGN: Simulation study. SETTING & PARTICIPANTS: Simulations evaluating 3,060 scenarios representative of 19 treatment comparisons in 13 chronic kidney disease clinical trials. INDEX TESTS: Surrogate end points defined as composite end points based on ESRD and either 30% or 40% eGFR declines. REFERENCE TEST: Clinical outcome (ESRD) for type 1 error. Established end point (composite of ESRD and 57% eGFR decline) for required sample size. RESULTS: Use of the 40% versus 57% eGFR decline end point consistently led to a reduction in sample size > 20% while maintaining risk for type 1 error < 10% in the presence of a small acute effect (<1.25mL/min/1.73m(2)) for: (1) 2-, 3-, or 5-year trials with a high mean baseline eGFR (67.5mL/min/1.73m(2)), and (2) 2-year trials with an intermediate mean baseline eGFR (42.5mL/min/1.73m(2)). Use of the 30% versus the 40% eGFR decline end point often led to moderately larger reductions in sample size in the absence of an acute effect, but not in the presence of acute effects. LIMITATIONS: The complexity of eGFR trajectories prevented evaluation of all scenarios for clinical trials. CONCLUSIONS: Use of end points based on 30% or 40% eGFR declines is an appropriate strategy to reduce sample size in certain situations. However, risk for type 1 error is increased in the presence of acute effects, particularly for 30% eGFR declines. The decision to use these end points should be made after thorough evaluation of their expected performance under the conditions of specific clinical trials. PMID- 25441441 TI - Identification of glycosyl hydrolases from a metagenomic library of microflora in sugarcane bagasse collection site and their cooperative action on cellulose degradation. AB - Lignocellulose decomposition is a natural process involving the cooperative action of various glycosyl hydrolases (GH) on plant cell wall components. In this study, a metagenomic library was constructed to capture the genetic diversity of microbes inhabiting an industrial bagasse collection site. A variety of putative genes encoding GH families 2, 3, 5, 9, 11, and 16 were identified using activity based screening, which showed low to moderate homology to various cellulases and hemicellulases. The recombinant GH9 endoglucanase (Cel9) and GH11 endo-xylanase (Xyn11) were thermophilic with optimal activity between 75 degrees C and 80 degrees C and the maximal activity at slightly acidic to neutral pH range. The enzymes exhibited cooperative activity with Trichoderma reesei cellulase on the degradation of lignocellulosic substrates. Mixture design showed positive interactions among the enzyme components. The optimal combination was determined to be 41.4% Celluclast, 18.0% Cel9, and 40.6% Xyn11 with the predicted relative reducing sugar of 658% when compared to Celluclast alone on hydrolysis of alkaline-pretreated bagasse. The work demonstrates the potential of lignocellulolytic enzymes from a novel uncultured microbial resource for enhancing efficiency of biomass-degrading enzyme systems for bio-industries. PMID- 25441442 TI - Gene dynamics of core transcription factors for pluripotency in embryonic stem cells. AB - Embryonic stem cell (ESC) pluripotency is maintained by core transcription factors (TFs). Although the expression of these TFs is well documented, their expression dynamics is poorly evaluated. Here, we visualized the dynamics of Nanog and Oct3/4 expression in ESC using fluorescent reporters and found that expression of these TFs change dramatically during culture. PMID- 25441444 TI - Construction of transformation system in Penicillium purpurogenum. AB - Penicillium purpurogenum attracts attention in the food industry and biomass degradation. We expressed green fluorescent protein (GFP) with pBPE, a novel vector, and constructed a transformation system for P. purpurogenum. The accumulation of GFP was confirmed by fluorescence microscopy. In future, this system may prove useful for the genetic modification of P. purpurogenum. PMID- 25441443 TI - Exploration of three heterotrophic nitrifying strains from a tilapia pond for their characteristics of inorganic nitrogen use and application in aquaculture water. AB - Three heterotrophic nitrifying bacterial strains, HLf01, HBf01 and HHf01, were isolated from a pond where genetically improved farmed tilapia (GIFT) (Oreochromis niloticus) was intensively cultured during the annual peak breeding period. Analysis of biochemical, morphological characteristics and sequences analysis of 16S rDNA identified strains HLf01 and HBf01 as Pseudomonas sp., and strain HHf01 as Acinetobacter baumannii. Further analysis of heterotrophic nitrifying medium inorganic nitrogen used showed that most of the ammonia nitrogen was removed after 48 h. Strains HBf01 and HHf01 removed 67.9% and 76.7% of the total ammonia nitrogen after 24 h, recording the mass ratio of carbon to nitrogen used as 10.6 to 1 and 11.7 to 1, respectively. Strain HLf01 used a C:N ratio of 22.7 to 1 with a total of 43.8% ammonia nitrogen removed. In denitrifying media, strains HBf01 and HHf01 may have used nitrate and nitrite as the sole nitrogen source by strain HLf01. Generally, all the three strains used nitrogen in the order ammonia > nitrite > nitrate when all the three nitrogen forms were recorded present. Although the bacterial strains consumed dissolved organic carbon, it was limited when ammonia was the main source of nitrogen compared with other forms of inorganic nitrogen. Also, the test of the three strains on aquaculture water showed similar results of efficiency of ammonia nitrogen removal with the test of inorganic nitrogen use. PMID- 25441445 TI - Effects of temperature on the astaxanthin productivity and light harvesting characteristics of the green alga Haematococcus pluvialis. AB - The green alga Haematococcus pluvialis, which accumulates astaxanthin at an optimal temperature of 20 degrees C, was cultivated under temperatures of 20 degrees C, 23.5 degrees C, 27 degrees C, and 30.5 degrees C, in order to assess the effects on algal metabolism during the growth phase. The culture growth rate declined with above-optimal increases in temperature, and the final maximum cell concentration at 30.5 degrees C reached only 35% of that attained at 20 degrees C. On the contrary, the biomass productivity was increased under all the high temperature conditions, probably reflecting the metabolism switch from cell duplication to energy accumulation that is typically observed in algal cultures subjected to environmental stress. Moreover, an increase in the light-harvesting capability of the alga was observed by means of the total pigment balance and the photosynthesis-intensity (PI) curve measured under the different cultivation conditions. Cultures kept at higher temperatures were able to better harvest and utilize the impinging light due to photo-acclimation. Finally, the differences in the astaxanthin metabolism were elucidated by subjecting the cultures to nitrogen starvation at 20 degrees C and 27 degrees C. In the culture at 27 degrees C, a 1.4-fold increase in the astaxanthin productivity was observed when compared to that at 20 degrees C, and the latter required almost two-fold more energy for the astaxanthin production compared with the 27 degrees C culture. PMID- 25441446 TI - Inhibition effects of benzylideneacetone, benzylacetone, and 4-phenyl-2-butanol on the activity of mushroom tyrosinase. AB - Tyrosinase (EC 1.14.18.1) is the key enzyme of melanin synthesis and fruit vegetable browning. The inhibition of benzylideneacetone, benzylacetone, and 4 phenyl-2-butanol on mushroom tyrosinase was first investigated. The results shown that these three compounds could effectively inhibit the enzyme activity sharply and the inhibitory effects were determined to be reversible. Their inhibitor concentrations leading to 50% activity lost values were determined to be 1.5, 2.8, and 1.1 mM for monophenolase and 2.0, 0.6, and 0.8 mM for diphenolase, respectively. For the monophenolase activity, all of these three compounds were mixed-type inhibitors, however, only 4-phenyl-2-butanol obviously lengthened the lag time. For the diphenolase activity, benzylideneacetone and benzylacetone were mixed-type inhibitors, while 4-phenyl-2-butanol was a noncompetitive type inhibitor. In conclusion, these compounds exhibited potent antityrosinase activities. This research would provide scientific evidence for the use of benzylideneacetone, benzylacetone, and 4-phenyl-2-butanol as antityrosinase agents. PMID- 25441447 TI - High resolution surface plasmon resonance imaging for single cells. AB - BACKGROUND: Surface plasmon resonance imaging (SPRI) is a label-free technique that can image refractive index changes at an interface. We have previously used SPRI to study the dynamics of cell-substratum interactions. However, characterization of spatial resolution in 3 dimensions is necessary to quantitatively interpret SPR images. Spatial resolution is complicated by the asymmetric propagation length of surface plasmons in the x and y dimensions leading to image degradation in one direction. Inferring the distance of intracellular organelles and other subcellular features from the interface by SPRI is complicated by uncertainties regarding the detection of the evanescent wave decay into cells. This study provides an experimental basis for characterizing the resolution of an SPR imaging system in the lateral and distal dimensions and demonstrates a novel approach for resolving sub-micrometer cellular structures by SPRI. The SPRI resolution here is distinct in its ability to visualize subcellular structures that are in proximity to a surface, which is comparable with that of total internal reflection fluorescence (TIRF) microscopy but has the advantage of no fluorescent labels. RESULTS: An SPR imaging system was designed that uses a high numerical aperture objective lens to image cells and a digital light projector to pattern the angle of the incident excitation on the sample. Cellular components such as focal adhesions, nucleus, and cellular secretions are visualized. The point spread function of polymeric nanoparticle beads indicates near-diffraction limited spatial resolution. To characterize the z-axis response, we used micrometer scale polymeric beads with a refractive index similar to cells as reference materials to determine the detection limit of the SPR field as a function of distance from the substrate. Multi-wavelength measurements of these microspheres show that it is possible to tailor the effective depth of penetration of the evanescent wave into the cellular environment. CONCLUSION: We describe how the use of patterned incident light provides SPRI at high spatial resolution, and we characterize a finite limit of detection for penetration depth. We demonstrate the application of a novel technique that allows unprecedented subcellular detail for SPRI, and enables a quantitative interpretation of SPRI for subcellular imaging. PMID- 25441448 TI - Wetting properties of phospholipid dispersion on tunable hydrophobic SiO2-glass plates. AB - We study the wetting properties of very small droplets of salty aqueous suspensions of unilamellar liposomes of DMPC (dimyristoylphosphatidylcholine), situated on SiO2-glass surfaces with different levels of hydrophobicity. We evaluated two different measures of hydrophobicity of solid surfaces - receding contact angles and the thickness of wetting films trapped between an air bubble and the solid surface at different levels of hydrophobicity. We established a good correlation between methods which differ significantly in measurement difficulty and experimental setup. We also reveal details of the mechanism of wetting of different surfaces by the DMPC liposome suspension. Hydrophilic surfaces with water contact angles in the range of 0 degrees to 35 degrees are readily hydrophobized by the liposomes and only showed corresponding contact angles in the range 27 degrees -43 degrees . For same range of surface hydrophobicities, there was a clear reduction of the thickness of the wetting films between the surface and a bubble, reaching a minimum in the 35 degrees -40 degrees range. At higher levels of hydrophobicity both pure water and the liposome suspension show similar contact angles, and the thickness of wetting films between a bubble and those surfaces increases in parallel. Our analysis showed that the only force able to stabilize the film under these experimental conditions is steric repulsion. The latter suggests that nanobubbles adsorbed on hydrophobic parts of the surface, and coated with a DMPC layer, may be the cause of the 40-70 nm thickness of wetting films we observe. PMID- 25441449 TI - Use of microcapsules as controlled release devices for coatings. AB - Biofouling of surfaces is a considerable problem in many industrial sectors and for the public community in general. The problem is usually approached by the use of functional coatings and most of such antifouling coatings rely on the effect of biocides. However, a substantial drawback is the poor control over the release of the biocide as well as its degradation in the paint. Encapsulation of the biocides in microcapsules is a promising approach that may overcome some of the problems associated with the more traditional ways of incorporating the antifouling agent into the formulation. In this review, we summarize more than a decade of microcapsule research from our lab as well as from other groups working on this topic. Focus will be on two coacervation-based encapsulation techniques; the internal phase separation method and the double emulsion method, which together enable the encapsulation of a broad spectrum of biocides with different physicochemical properties. The release of the biocide from core-shell particles and from encapsulated biocides in coatings is treated in detail. The release behaviour is interpreted in terms of the physicochemical properties of the core shell particle and the coating matrix. In addition, special attention is given to the experimental release methodology and the implementation of proper diffusion models to describe the release. At the end of the review examples of antifouling properties of some coatings against common biofoulers are presented. PMID- 25441450 TI - A new point mutation in the iron-sulfur subunit of succinate dehydrogenase confers resistance to boscalid in Sclerotinia sclerotiorum. AB - Research has established that mutations in highly conserved amino acids of the succinate dehydrogenase (SDH) complex in various fungi confer SDH inhibitor (SDHI) resistance. For Sclerotinia sclerotiorum (Lib.) de Bary, a necrotrophic fungus with a broad host range and a worldwide distribution, boscalid resistance has been attributed to the mutation H132R in the highly conserved SdhD subunit protein of the SDH complex. In our previous study, however, only one point mutation, A11V in SdhB (GCA to GTA change in SdhB), was detected in S. sclerotiorum boscalid-resistant (BR) mutants. In the current study, replacement of the SdhB gene in a boscalid-sensitive (BS) S. sclerotiorum strain with the mutant SdhB gene conferred resistance. Compared with wild-type strains, BR and GSM (SdhB gene in the wild-type strain replaced by the mutant SdhB gene) mutants were more sensitive to osmotic stress, lacked the ability to produce sclerotia and exhibited lower expression of the pac1 gene. Importantly, the point mutation was not located in the highly conserved sequence of the iron-sulfur subunit of SDH. These results suggest that resistance based on non-conserved vs. conserved protein domains differs in mechanism. In addition to increasing our understanding of boscalid resistance in S. sclerotiorum, the new information will be useful for the development of alternative antifungal drugs. PMID- 25441451 TI - A review of 33 years (1980-2013) of data indicating a rise in ectopic pregnancy in Saudi Arabia. AB - OBJECTIVE: To assess the trend in ectopic pregnancy (EP) at a single center in Saudi Arabia and to compare the data with those from the rest of Saudi Arabia. METHODS: In a retrospective study, data were analyzed from patients admitted to King Fahd Hospital of the University, Al Khobar, Saudi Arabia, with a diagnosis of EP between January 2011 and December 2013. The prevalence of EP was calculated as a percentage of the number of live births during the study period. A 30-year review of publications on EP in Saudi Arabia was done via search engines. RESULTS: During the study period, there were 58 EPs among 3818 deliveries, giving an overall incidence of 1.5% at the study center; the incidence of EP in the rest of the country during this period was 0.5%. Between 2002 and 2004, the country's incidence was 0.6% as compared with 1% at the study center. CONCLUSION: The incidence of EP in Saudi Arabia has increased in the past few decades. PMID- 25441452 TI - Blood salvage device for use during ruptured ectopic pregnancy in low-resource countries. PMID- 25441453 TI - [Kinetic and organization of granulocytes transfusion: a case report]. AB - BACKGROUND: Therapeutic granulocyte transfusion remains an indication for neutropenic sepsis associated with prolonged neutropenia. However, harvest complexity and lack of proved efficacy mark the limits of its development. CASE REPORT: A 58-year old man received allogeneic stem cell transplantation for osteomyelofibrosis. Six months later, after a transplant rejection, he presented with perineal cellulitis from hemorrhoid origin, without any microbiological documentation. The evolution was unfavorable despite antibiotic and antifungal therapy. A set of seven granulocytes transfusions was initiated. Re-circulation of granulocytes analysis showed an initial increase (H2) followed by a decrease (H8) reaching the basal rate at H16. No toxicity has been reported during or following the transfusions. Clinical improvement has been reported five days after the first transfusion, scaring over at D15, without any neutrophil recovery. CONCLUSION: In 2014, granulocyte transfusion therapy is indicated for severe infection associated with long-term neutropenia. Minimal circulation of transfused cells in our observation and fast clinical improvement suggest the concentration of granulocytes on the infected area. PMID- 25441454 TI - [Delayed hemolytic transfusion reaction in sicle cell disease patients: a new challenge for the Hemovigilance network]. AB - Delayed hemolytic reaction transfusion in patients with sickle cell disease (SCD) is a serious and still under diagnosed event. Clinical and biological presentation mimics an acute SCD complication. It is a life-threatening event, especially in hyperhemolysis syndrome (HS) characterized by a massive destruction of both the donor's and patient's red blood cells. The main cause is related to the presence of alloantibodies directed against red blood cell antigens, more rarely autoantibodies. In approximately a third of the cases, no new antibody is highlighted. Pathophysiological hypotheses are still under debate but most of the authors agree on the role played by the SCD inflammatory state. Several therapeutic approaches are used but the data are still insufficient to estimate their efficiency. It is admitted that a new transfusion may exacerbate the phenomenon and the benefit-risk of any transfusion must be carefully evaluated. Measures limiting alloimmunization and rigorous follow-up of SCD patients and their immunohematologic status can prevent some of these accidents. The Hemovigilance network has a role to play in the recognition and the description of this risk. A first analysis realized on the French national Hemovigilance database of the French National Agency for Medicines and Health Products Safety (ANSM) over the period 2000-2013, shows us interesting information but some inadequacies, described here, must be taken into account to strengthen these data and insure in the future a better reporting quality. PMID- 25441455 TI - [Organization for the coverage of the transfusional needs of patients with hemoglobinopathy at the Etablissement francais du sang Bretagne]. AB - Brittany is a low prevalence region for hemoglobinopathies. Despite of that, the number of patients is increasing each year. In 2013, 140 patients were known at the EFS Bretagne, and medical consultations are growing for 50% each year since 2011. The consequence is an increase of needs of 22% of compatible packed red blood cells. To anticipate the announced progress, various actions were implemented as study groups, creation of a new informatic prescription for red blood cells phenotyping, promotion of donation, transfusion organisation. RESULTS: Fifthty-nine percent of the 400 ABO RH-KELL, FY, JK, MNS 3, 4, red blood cells were realised on the basis of this new informatic prescription, as the 99% of the packed red blood cells identified Fy (a- b-). So, 92% of the compatible transfused packed red blood cells were already in stock when the patients needed them. CONCLUSIONS: In Brittany, that organisation leads to assume qualitative and quantitative transfusion for sickle cell disease in more than 90% of cases, with fast distribution. In the same time promotion of donation is done to increase the diversity of donors. PMID- 25441456 TI - [How do I assess requirement of a blood bank and its kind for a healthcare establishment?]. AB - Access to blood components is required for healthcare establishments, particularly for emergency situation and hospital blood bank was often a response to this requirement. However, the complexity of regulation and economic pressures lead healthcare establishment to review regularly their need for a blood bank. This assessment requires analysis of need for transfusions in terms of delay, quantity and clinical situations to which they must respond. When a blood bank is required, three kinds could be under consideration: emergency blood bank, intermediate blood bank and issuance blood bank. According to requirements, advantages and disadvantages of each kind, healthcare establishments would select the most suitable one. PMID- 25441457 TI - Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics. AB - The impact of thiopurine methyltransferase (TPMT) genotype on thiopurine dose intensity, myelosuppression and treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia (ALL) trial ALL97. TPMT heterozygotes had significantly more frequent cytopenias and therefore required dose adjustments below target levels significantly more often than TPMT wild-type patients although the average dose range was similar for both genotypes. Event free survival (EFS) for patients heterozygous for the more common TPMT*1/*3A variant allele (n = 99, 5-year EFS 88%) was better than for both wild-type TPMT*1/*1 (n = 1206, EFS 80%, P = 0.05) and TPMT*1/*3C patients (n = 17, EFS 53%, P = 0.002); outcomes supported by a multivariate Cox regression analysis. Poor compliance without subsequent clinician intervention was associated with a worse EFS (P = 0.02) and such non-compliance may have contributed to the poorer outcome for TPMT*1/*3C patients. Patients prescribed escalated doses had a worse EFS (P = 0.04), but there was no difference in EFS by dose intensity or duration of cytopenias. In contrast to reports from some USA and Nordic trials, TPMT heterozygosity was not associated with a higher rate of second cancers. In conclusion, TPMT*1/*3A heterozygotes had a better EFS than TPMT wild-type patients. Thiopurine induced cytopenias were not detrimental to treatment outcome. PMID- 25441459 TI - Regulation of biologic oncology products in the FDA's Center for Biologics Evaluation and Research. AB - In the United States, cancer vaccines and immunotherapies, including cell and gene therapies and peptides and proteins used as therapeutic vaccines, are regulated by the Food and Drug Administration's Center for Biologics Evaluation and Research in the Office of Cellular, Tissue, and Gene Therapies (OCTGT). Center for Biologics Evaluation and Research has licensed two immunotherapy products for urologic indications: bacillus Calmette-Guerin for superficial bladder cancer and sipuleucel-T for advanced prostate cancer. OCTGT places a high priority on scientific and regulatory activities that promote the development of safe and effective cancer therapy products. OCTGT has published guidance documents and developed innovative tools that are designed to aid the rapid development of biologic products for patient use. The success of immunotherapeutic products for urologic malignancies stands as an example for ongoing and future therapeutic research and discovery. PMID- 25441458 TI - Evaluation of blood and bone marrow in selected canine vector-borne diseases. AB - BACKGROUND: Bone marrow (BM) is a major hematopoietic organ that can harbour a variety of vector-borne pathogens; however, knowledge of BM pathological changes in dogs infected with vector-borne pathogens is limited. Thus, the aim of the present study was to assess the pathological changes in canine BM associated with natural infections by four vector-borne pathogens, as well as to determine the relationships between such changes and abnormalities of the peripheral blood. METHODS: Cytological disorders and pathological changes of the BM of 83 dogs naturally-infected with one or more of four vector-borne pathogens (i.e., Anaplasma platys, Leishmania infantum, Babesia vogeli and Hepatozoon canis) were evaluated and compared with the corresponding hematological findings. RESULTS: Dysgranulopoiesis and dysmegakaryocytopoiesis were the most frequently observed BM abnormalities in infected dogs. Erythroid suppression, and lymphocytic, monocytic and macrophage hyperplasia were also observed. Interestingly, associations between suppression and hyperplasia of specific cell lines in the marrow and corresponding changes in numbers of circulating peripheral blood cells were not observed. CONCLUSIONS: Infections with one or more of the vector-borne pathogens examined in this study should be considered as differential diagnoses for secondary dysmyelopoiesis. PMID- 25441460 TI - Achievements in health equity: nesting an NIMHD center of excellence within a CTSA. PMID- 25441461 TI - Enhancing social networks: a qualitative study of health and social care practice in UK mental health services. AB - People with severe mental health problems such as psychosis have access to less social capital, defined as resources within social networks, than members of the general population. However, a lack of theoretically and empirically informed models hampers the development of social interventions which seek to enhance an individual's social networks. This paper reports the findings of a qualitative study, which used ethnographic field methods in six sites in England to investigate how workers helped people recovering from psychosis to enhance their social networks. This study drew upon practice wisdom and lived experience to provide data for intervention modelling. Data were collected from 73 practitioners and 51 people who used their services in two phases. Data were selected and coded using a grounded theory approach to depict the key themes that appeared to underpin the generation of social capital within networks. Findings are presented in four over-arching themes - worker skills, attitudes and roles; connecting people processes; role of the agency; and barriers to network development. The sub-themes which were identified included worker attitudes; person-centred approach; equality of worker-individual relationship; goal setting; creating new networks and relationships; engagement through activities; practical support; existing relationships; the individual taking responsibility; identifying and overcoming barriers; and moving on. Themes were consistent with recovery models used within mental health services and will provide the basis for the development of an intervention model to enhance individuals' access to social capital within networks. PMID- 25441462 TI - Red face revisited: II. PMID- 25441463 TI - Facial bacterial infections: folliculitis. AB - Facial bacterial infections are most commonly caused by infections of the hair follicles. Wherever pilosebaceous units are found folliculitis can occur, with the most frequent bacterial culprit being Staphylococcus aureus. We review different origins of facial folliculitis, distinguishing bacterial forms from other infectious and non-infectious mimickers. We distinguish folliculitis from pseudofolliculitis and perifolliculitis. Clinical features, etiology, pathology, and management options are also discussed. PMID- 25441464 TI - Viral infections of the face. AB - Viral infections affecting the face may cause significant morbidity, cosmetic disfigurement, and psychological distress. The success of therapy needs whole and correct evaluation of the clinical signs and symptoms. Some viruses such as Papillomaviridae, Herpesviridae, and Polyomaviridae primarily infect the facial skin, whereas others affect the face infrequently, as in parapox virus infections. Sometimes, involvement of the face can be a part of more generalized eruption and systemic symptoms in viral infections caused by Todaviridae, Flaviviridae, Arenaviridiae, and Flaviviridae. Clinical diagnosis can be challenging in various viral diseases when they occur in nonendemic geographic areas. The objective of this review was to concentrate on epidemiologic and clinical characteristics of the viral illnesses with facial skin involvement. PMID- 25441465 TI - Red face and fungi infection. AB - Red face syndrome is characterized by an erythematous dermatitis that is produced by different entities. These include rosacea, seborrheic dermatitis, contact dermatitis, atopic dermatitis, psoriasis, cutaneous lupus, photodermatosis, post topical steroid dermatosis, demodicosis, borderline borderline (BB) leprosy, mastocytosis, carcinoid, postneoplasia flushing, cutaneous lymphoma, tineas, ulerythema ophryogenes, and psychosomatic flushing. Red face is a relatively common dermatologic manifestation. Our goal is to review tinea corporis and other fungi that affect this region causing facial erythema and its therapeutic management. PMID- 25441466 TI - Demodex mites. AB - Demodex mites are normal inhabitants of human hair follicles. D folliculorum is found predominantly in the follicular infundibulum of facial skin and is typically present in small groups. D brevis, the smaller of the two species, predominates on the trunk, typically as solitarily mites within the sebaceous glands and ducts. In a wide variety of animals, Demodex mites are recognized as a cause of mange. The role of Demodex mites as agents of human disease has been more controversial, but evidence favors their involvement in acneiform eruptions, folliculitis, and a range of eruptions in immunosuppressed patients. PMID- 25441468 TI - Chronic actinic damage of facial skin. AB - Chronic actinic damage of the skin manifests itself as extrinsic skin aging (photoaging) and photocarcinogenesis. During the last decade, substantial progress has been made in understanding cellular and molecular mechanisms of photoaging. DNA photodamage and ultraviolet-generated reactive oxygen species are the initial events that lead to most of the typical histologic and clinical manifestations of chronic photodamage of the skin. Chronic actinic damage affects all layers of the skin. Keratinocytes, melanocytes, fibroblasts, and endothelial cells are altered by ultraviolet radiation and can result in numerous changes in human skin, particularly the skin of fair-skinned individuals. These changes include actinic keratosis, thickening and wrinkling, elastosis, telengiectasia, solar comedones, diffuse or mottled hyperpigmentation, and skin cancers. There are many options in the treatment of changes caused by chronic actinic damage. The most effective measure of prevention of the photoaging and photocarcinogenesis is sun protection. PMID- 25441467 TI - Rarely seen infections. AB - There are many rare cutaneous infections of the face. This phrase seems irrelevant, because rare infections in certain parts of the world are common in others. This is more apparent if applied to different sites of the body (eg, face). For instance, cutaneous leishmaniasis (CL) is common in Central and South America and uncommon in the United States. Because most medical practitioners in this country have never seen a case, it is easy for them to miss a diagnosis. Cutaneous leishmaniasis, a protozoan infection transmitted by phlebotomine sand flies, is typically divided into two forms: one found in the Middle East, Asia, Africa, and southern Europe, called Old World leishmaniasis, and one found in Latin and Central America, called New World leishmaniasis. Also atypical mycobacterial infection has been described in the medical literature since the mid-1950s. The development and introduction of a rapid radiometric mycobacterial detection system has advanced the field of mycobacteriology over the past 20 years. This method has allowed the distinction of Mycobacterium tuberculosis from other mycobacteria and enabled the performance of antimicrobial susceptibility testing of mycobacteria. The increased frequency of atypical mycobacterial infection stems from advances in the diagnostic procedures concerning the infection paired with the prevalence of mycobacterial disease in immunocompromised patients infected with HIV. Erysipelas and facial cellulitis are covered briefly in this paper. PMID- 25441469 TI - Psychologic factors in the development of facial dermatoses. AB - In medical literature, as well as in daily practice, some common facial dermatoses are considered to be influenced or triggered by emotional factors. The main damager is stress, but depression and anxiety may play a role, among other factors. Some patients may experience a vicious cycle: Their facial dermatosis is triggered or worsened by stress, and in turn, the exacerbation itself is a major stressogenic stimulus. It appears that clinical wisdom and experience preceded clinical investigation in this field. Although patients testify that their emotional state may sometimes influence their facial condition, only limited experimental data exist so far, and only a few facial dermatoses were investigated. PMID- 25441470 TI - Psychologic consequences of facial dermatoses. AB - The attractiveness of the human body has always been an important issue in the fields of sociology, psychology, and psychiatry and also in the field of dermatology. In psychodermatology, one often discovers how all these fields intermingle to produce elaborate situations and extreme human difficulties. Perfect skin is widely adored in literature, poetry, and biblical texts, as well as in advertisements, movies, and television. Because in most societies the face is the body part that is visible, imperfections of the skin are also visible; therefore, its flawed appearance bears the potential to become a source of misery to some. PMID- 25441471 TI - Facial involvement in genodermatoses. AB - Facial involvement represents a characteristic feature of a wide range of genodermatoses. Specific facial findings often help point to the correct diagnosis, which improves counseling and management. In particular, this can facilitate the identification and treatment of associated extracutaneous disease. The highly visible nature of facial lesions in genodermatoses and facial birthmarks can result in stigmatization and frequently leads to particular concern in patients and their family members. It is therefore critical for dermatologists to be aware of the broad spectrum of facial manifestations in genetic skin disease, especially when these findings have important implications with regard to monitoring and treatment. In this contribution, facial involvement in genodermatoses is divided into five morphologic categories based on the most prominent feature: Papules, scaling, photosensitivity/findings associated with aging (eg, telangiectasias, atrophy, lentigines), blisters/erosions, and birthmarks. Hopefully, this will provide a practical and clinically useful approach to a large and diverse assortment of genetic skin conditions. PMID- 25441472 TI - Red face revisited: Disorders of hair growth and the pilosebaceous unit. AB - This paper reviews the recent literature on the diseases of the hair and pilosebaceous unit that may cause a red face. We discuss the epidemiology, clinicals, pathogenesis, and therapy of lichen planopilaris with its variants, discoid lupus erythematosus, folliculitis decalvans, dissecting folliculitis, acne keloidalis nuchae, pseudofolliculitis barbae, tinea capitis, tinea barbae, folliculitis of diverse causative factors and inflammatory follicular keratotic syndromes, ulerythema ophryogenes, atrophoderma vermiculatum, keratosis follicularis spinulosa decalvans, and folliculitis spinulosa decalvans. PMID- 25441473 TI - Red face revisited: Flushing. AB - The term red face is reserved for lesions located exclusively or very predominantly on the face that result from changes in cutaneous blood flow triggered by multiple different conditions. Facial erythema may not only present clinically as a distinct entity, but can also be a sign of other diseases. Patients with a red face challenge clinicians to consider a broad differential diagnosis. Diagnosis is based on date and mode of appearance, characteristics of the erythema, functional signs, and associated systemic manifestations. In most cases, the cause is a benign disease such as rosacea, contact dermatitis, photodermatosis, and climacterium, and a thorough history and physical examination is enough to make a diagnosis; facial erythema may also present as a symptom of drug allergies, cardiac disease, carcinoid syndrome, pheochromocytoma, mastocytosis, and anaphylaxis, as well as some rare causes such as medullary carcinoma of the thyroid, pancreatic cell tumor, and renal carcinoma where further laboratory, radiologic, or histopathologic studies are required. In this review, the mechanisms of flushing, its clinical differential diagnosis, and management of various conditions that cause flushing are discussed. PMID- 25441474 TI - Facial skin care products and cosmetics. AB - Facial skin care products and cosmetics can both aid or incite facial dermatoses. Properly selected skin care can create an environment for barrier repair aiding in the re-establishment of a healing biofilm and diminution of facial redness; however, skin care products that aggressively remove intercellular lipids or cause irritation must be eliminated before the red face will resolve. Cosmetics are an additive variable either aiding or challenging facial skin health. PMID- 25441475 TI - Camouflage therapy in aesthetic surgery. AB - The use of makeup has been traced back to antiquity. Today, there are multiple reasons that makeup constitutes an important part of, and is a driving force in, almost every woman's life. The idea of using cosmetics for camouflage therapy, especially in the postoperative period, originates from the illusionary effect, which is thought to diminish the post-traumatic stress frequently seen after facial operations. The patients will feel better following cosmetic application, as they will see themselves better. PMID- 25441476 TI - Nasal septal ulceration. AB - Nasal septal ulceration can have multiple etiologies. Determining the exact cause depends on who the consulting specialist is, who could either be the ENT surgeon or the dermatologist. The common causes are infections (tuberculosis, leprosy, leishmaniasis), vasculitis (Wegener's granulomatosis and Churg-Strauss syndrome), and lupus erythematosus. Traumatic causes and malignancy can also be seen in tertiary referral centers. The diagnosis often requires thorough investigations and multiple tissue specimens from various sites, and in chronic cases, a suspicion of lymphoma should be considered. Apart from disease-specific therapy, a multidisciplinary approach is required in most cases to tackle the cosmetic disfigurement. PMID- 25441477 TI - Palatal ulceration. AB - Palatal ulcers are a common presentation and can be conveniently divided into developmental and acquired causes, the latter of which is subdivided into acute and chronic causes. Most commonly seen dermatologic causes have associated skin manifestations. Acute and multiple ulcers are usually infectious or drug induced in origin. Recurrent ulcers are largely dominated by aphthosis, while chronic ulcers are seen in immunocompromised patients and can occasionally be malignant. It is essential to involve the oral and maxillofacial surgeons early in the therapeutic management to tackle the inevitable complications that may ensue in the chronic cases. PMID- 25441478 TI - Follicular disorders of the face. AB - Follicular disorders are possibly a commonly seen, though rarely reported, group of disorders, which are localized around follicles and appendages and clinically present as small papules. Classically, clinicopathological follicular plugging is seen in the "true" follicular disorders, which are appropriately referred to as follicular keratosis. Another subtype is folliculitis (infectious or noninfectious) and the follicular mimickers that clinically resemble "true" follicular disorders without the follicular keratoses. Acne vulgaris has an amalgamation of all the above lesion types. Our review is aimed at describing all the follicular disorders and gives an algorithm for diagnosing the common follicular disorders. PMID- 25441479 TI - How to prepare and deliver a great talk. PMID- 25441480 TI - CT training of nuclear medicine residents in the United States, 2013-2014. AB - PURPOSE: In 2011, the ACGME Nuclear Medicine (NM) Residency Review Committee revised the NM program requirements, which increased CT training for NM residents. This article examines the effect of this revision. METHODS: Requests were e-mailed to all NM program directors asking that their residents be given the opportunity to complete an online survey regarding their CT training. Subsequently, an identical online survey regarding CT training was e-mailed directly to all members of the NM Residents Organization of the American College of NM asking that they complete the survey regarding their CT training if they had not already done so. RESULTS: Resident responses, compared with those from a similar 2011 survey, indicate a perception that CT training and CT expertise gained in ACGME-accredited NM programs have improved. However, some NM residents are not provided with the opportunity to develop critical skills in interpreting and dictating CT scans during their time on dedicated CT services. The survey indicates that experience gained during NM residency in head and neck/neuroradiology, emergency, and musculoskeletal CT is marginal at best. A slight majority felt that CT training should be further increased. CONCLUSIONS: Compared with a 2011 survey of NM residents and the 2011 implementation of expanded CT training requirements, a follow-up survey seems to indicate improvement in CT training for most NM residents. Nevertheless, an opportunity clearly remains to further improve the breadth and depth of CT skills during NM residency. However, whether such an improvement will result in a reversal of multiyear downward trends in the number of NM residents and training programs in the United States is not clear. PMID- 25441481 TI - Radiologist compliance with institutional guidelines for use of nonroutine communication of diagnostic imaging results. AB - PURPOSE: The aim of this study was to evaluate radiologist compliance with institutional guidelines for nonroutine communication of diagnostic imaging results. METHODS: From July 2012 through September 2013, 7,401 completed advanced imaging cases were retrospectively reviewed by groups of 3 or more radiologists. The reviewing radiologists were asked to reach consensus on two questions related to nonroutine communication: (1) "Does the report describe a finding which requires nonroutine communication to the patient's physicians?" and if so, (2) "Were the department's guidelines for nonroutine communication followed?" Consensus judgments were aggregated and analyzed on the basis of subspecialty, level of acuity per the guidelines, and type of communication used. RESULTS: Of the 7,401 studies reviewed, 960 (13.0%) were deemed to require nonroutine results communication. The need for nonroutine communication was most frequent with CT (16.6%), followed by MRI (11.1%) and ultrasound (3.4%). For the divisions studied, nonroutine communication was most frequently needed in thoracic (37.9%), followed by neurologic (17.3%), emergency (15.8%), cardiac (13.7%), musculoskeletal (4.4%), and abdominal (0.7%) imaging. Of the cases requiring nonroutine communication, 39 (4%) yielded consensus that the guidelines were not appropriately followed: 21% (n = 8) involved level 1 findings (critical), 41% (n = 16) involved level 2 findings (acute), and 38% (n = 15) involved level 3 findings (nonacute). Failures of communication involving level 1 findings primarily involved neurologic imaging, including 4 cases of new cerebral infarct and 3 cases of new intracranial hemorrhage. CONCLUSIONS: Established guidelines for nonroutine communication are appropriately applied and durable, underscoring the high yield of formalizing and implementing these guidelines across practice settings. PMID- 25441482 TI - Value management program: performance, quantification, and presentation of imaging value-added actions. AB - Health care is in a state of transition, shifting from volume-based success to value-based success. Hospital executives and referring physicians often do not understand the total value a radiology group provides. A template for easy, cost effective implementation in clinical practice for most radiology groups to demonstrate the value they provide to their clients (patients, physicians, health care executives) has not been well described. A value management program was developed to document all of the value-added activities performed by on-site radiologists, quantify them in terms of time spent on each activity (investment), and present the benefits to internal and external stakeholders (outcomes). The radiology value-added matrix is the platform from which value-added activities are categorized and synthesized into a template for defining investments and outcomes. The value management program was first implemented systemwide in 2013. Across all serviced locations, 9,931.75 hours were invested. An annual executive summary report template demonstrating outcomes is given to clients. The mean and median individual value-added hours per radiologist were 134.52 and 113.33, respectively. If this program were extrapolated to the entire field of radiology, approximately 30,000 radiologists, this would have resulted in 10,641,161 uncompensated value-added hours documented in 2013, with an estimated economic value of $2.21 billion. PMID- 25441483 TI - The health care value transparency movement and its implications for radiology. AB - The US health care system is in the midst of disruptive changes intended to expand access, improve outcomes, and lower costs. As part of this movement, a growing number of stakeholders have advocated dramatically increasing consumer transparency into the quality and price of health care services. The authors review the general movement toward American health care value transparency within the public, private, and nonprofit sectors, with an emphasis on those initiatives most relevant to radiology. They conclude that radiology, along with other "ancillary services," has been a major focus of early efforts to enhance consumer price transparency. By contrast, radiology as a field remains in the "middle of the pack" with regard to quality transparency. There is thus the danger that radiology value transparency in its current form will stimulate primarily price based competition, erode provider profit margins, and disincentivize quality. The authors conclude with suggested actions radiologists can take to ensure that a more optimal balance is struck between quality transparency and price transparency, one that will enable true value-based competition among radiologists rather than commoditization. PMID- 25441484 TI - Clinical imaging guidelines part 1: a proposal for uniform methodology. AB - Inappropriate imaging can lead to unnecessary medical radiologic exposures and cost and may not answer the clinical question. Imaging referral guidelines inform the justification of radiologic procedures and facilitate the choice of the best test first, but their acceptance by referrers, use, and value may be limited by shortcomings in the methodology of development. Focusing on common, essential elements of methodology will help guideline developers. In 2012 and 2013, the International Atomic Energy Agency hosted Technical Meetings on Radiation Protection of Patients Through the Development of Appropriateness Criteria in Diagnostic Imaging. Participants identified and agreed on issues concerning development of imaging referral guidelines. Items based on the Appraisal of Guidelines for Research and Evaluation II instrument were amended with additional items including development and consensus group composition. Consensus was sought on 28 items, 18 of which were agreed should be uniform, and 10 should allow for regional differences. Further work is required to encourage, provide, and identify higher quality evidence and to agree on a grading system for recommendations. Many key areas are common to guideline developers globally, opening the way for international collaboration to help demystify, simplify, and justify. PMID- 25441486 TI - Effect of soy isoflavone supplementation on endothelial dysfunction and oxidative stress in equol-producing postmenopausal women. AB - Dietary isoflavones are considered to be cardioprotective because of their structural similarity to estrogen. Equol is a metabolite of daidzein that is more potent than daidzein itself. The effect of equol on endothelial function and oxidative stress remains unclear. The objective of this study was to determine the effect of 100 mg/day soy isoflavone supplementation on the following markers: vascular cell adhesion molecule-1 (VCAM-1) and nitric oxide (NO) as markers of vascular endothelial function, and malonyldialdehyde (MDA) as oxidative stress marker in equol-producing postmenopausal women. A stratified randomized double blind controlled trial was conducted among 190 postmenopausal Indonesian women aged 47 to 60 years. They were stratified into equol producers and equol nonproducers. The random allocation of intervention was carried out separately in each stratum. The intervention group received tablets consisting of 100 mg soy isoflavones and calcium carbonate 500 mg, and the control group received 500 mg calcium carbonate. The concentrations of VCAM-1, NO and MDA were measured at baseline and post-supplementation at 6 months. After 6 months of supplementation the MDA concentrations were significantly lower in the soy-isoflavone equol producers compared with equol nonproducers (p=0.021). Similar results were also found for VCAM-1 and NO concentrations, but these were statistically not significant (p = 0.413 and p= 0.724, respectively). This study demonstrates that isoflavone supplementation in postmenopausal women with equol-producer status had a more beneficial effect by decreasing the MDA concentration, but did not improve VCAM-1 and NO concentrations. PMID- 25441485 TI - Comparing morbidities of testing with a new index: screening colonoscopy versus core-needle breast biopsy. AB - PURPOSE: Focusing on outcomes of care alone may be too restrictive. Patients can experience morbidity that is important to them from health care processes themselves. However, many processes, such as testing and screening, have been little evaluated. This study's purpose was to assess the construct validity of a new preference-based index, the Testing Morbidities Index (TMI), by comparing two common cancer-related procedures in prior publications: screening colonoscopy and core-needle breast biopsy. METHODS: Women evaluating their breast biopsies (n = 100) were compared with men and women who had undergone screening colonoscopy (n = 109) after both groups completed the TMI. The TMI addresses physical and mental or emotional quality of life affected by test-specific aspects occurring before, during, or after any test. It has 7 domains and survey items. TMI scores can be scaled in various ways, including multi-attribute value theory-based patient or societal preferences, where 0 = dead and 1.0 = full health, as used here. RESULTS: There was significantly greater morbidity from breast biopsy (mean, 0.84) than from screening colonoscopy (mean, 0.88) comparing overall TMI preference scores (P < .0001). Breast biopsy showed significantly worse morbidity (P = .005 to P < .0001) in most domains. Pain or discomfort before testing was worse for colonoscopy because of bowel preparation. The TMI showed no floor effect and an acceptable ceiling effect. CONCLUSIONS: The TMI provides the first objective evidence comparing the morbidity of one cancer-related testing procedure with another. The TMI may be useful in assessments of medical care processes informative to institutions and imaging departments, shared decision making scenarios, and economic analyses. PMID- 25441487 TI - Impact of contact precautions on falls, pressure ulcers and transmission of MRSA and VRE in hospitalized patients. AB - BACKGROUND: Hospitals use contact precautions to prevent the spread of meticillin resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). There is concern that contact precautions may have adverse effects on the safety of isolated patients. In November 2010, the infection control policy at an academic medical centre was modified, and contact precautions were discontinued for patients colonized or infected with MRSA or VRE (MRSA/VRE patients). AIM: To assess the rates of falls and pressure ulcers among MRSA/VRE patients and other adult medical-surgical patients, as well as changes in MRSA and VRE transmission before and after the policy change. METHODS: A single-centre retrospective hospital-wide cohort study was performed from 1st November 2009 to 31st October 2011. FINDINGS: Rates of falls and pressure ulcers were significantly higher among MRSA/VRE patients compared with other adult medical-surgical patients before the policy change (falls: 4.57 vs 2.04 per 1000 patient-days, P < 0.0001; pressure ulcers: 4.87 vs 1.22 per 1000 patient-days, P < 0.0001) and after the policy change (falls: 4.82 vs 2.10 per 1000 patient-days, P < 0.0001; pressure ulcers: 4.17 vs 1.19 per 1000 patient-days, P < 0.0001). No significant differences in the rates of falls and pressure ulcers among MRSA/VRE patients were found after the policy change compared with before the policy change. There was no overall change in MRSA or VRE hospital-acquired transmission. CONCLUSION: MRSA/VRE patients had higher rates of falls and pressure ulcers compared with other adult medical-surgical patients. Rates were not affected by removal of contact precautions, suggesting that other factors contribute to these complications. Further research is required among this population to prevent complications. PMID- 25441488 TI - Combined epithelial-mesenchymal transition with cancer stem cell-like marker as predictors of recurrence after radical resection for gastric cancer. AB - BACKGROUND: The aim of the study was to identify the incidence and the predictors of recurrence after curative resection and the clinical significance of epithelial-mesenchymal transition (EMT) and stem cell-like phenotypes in gastric cancer. METHODS: In a total of 1,463 patients that underwent curative resection for gastric cancer between January 2001 and January 2008 at Drum Tower Hospital, 402 (27.5%) experienced recurrence. They were divided into early recurrence (within two years) and late recurrence (more than two years). The clinicopathological characteristics, including five EMT-related proteins (Snail 1, ZEB-1, E-cadherin, vimentin, and beta-catenin) and the gastric cancer stem cell markers CD44 and CD54, therapeutic modalities, survival time after recurrence, and recurrence patterns were compared between the two groups. RESULTS: Loss of E-cadherin expression and aberrant expression of vimentin and the known gastric cancer stem cell maker CD44 were significantly associated with aggressive clinicopathologic features. Multivariate analysis showed that stage III gastric cancer patients with early recurrence had larger tumors and more lymph node metastasis, coupled with aberrant expression EMT and cancer stem cell marker, than patients with late recurrence. Early recurrence was associated with more distant metastasis than late recurrence and patients tended to die within two years of recurrence. CONCLUSIONS: Combined EMT with cancer stem cell-like marker is a predictor of recurrence after radical resection for gastric cancer. Advanced TNM stage was associated with early cancer death after recurrence. PMID- 25441490 TI - Giant baker' cyst. Differential diagnosis of deep vein thrombosis. PMID- 25441489 TI - Extra-articular disease in patients with spondyloarthritis. Baseline characteristics of the spondyloarthritis cohort of the AQUILES study. AB - OBJECTIVES: To describe the prevalence of extra-articular disease (uveitis, psoriasis and inflammatory bowel disease [IBD]), in a cohort of patients with spondyloarthritis (SpA). PATIENTS AND METHODS: AQUILES is an observational, prospective and multicentric study of three cohorts of patients with one of the following immune-mediated inflammatory diseases (IMID): SpA, psoriasis, or IBD. In the present cohort, patients >=18 years of age with SpA were enrolled from Rheumatology clinics. The main objective was to assess the coexistence of these diseases and of uveitis, based on the patients' clinical history up to the study entry. RESULTS: A total of 601 patients with SpA (men: 63.1%; women: 36.9%) were enrolled. The specific diagnoses were: ankylosing spondylitis (55.1%), psoriatic arthritis (25.1%), undifferentiated spondyloarthritis (16.1%), enteropathic arthritis (2.5%), and others (1.3%). In 43.6% (95% CI: 39.7-47.6) of the patients, at least one of the three abovementioned diseases was encountered, predominantly psoriasis (prevalence 27.8%, 95% CI: 24.4-31.5), uveitis (13.6%, CI 95%: 11.1-16.6) and IBD (5.1%, 95% CI: 3.7-7.2). In patients with ankylosing spondylitis the proportion of other disease was 25.3% (IBD: 3.9%, psoriasis: 5.4%, uveitis: 19.0%) whilst it was 94.7% in psoriatic arthritis, due to the presence of psoriasis (94.0%). The coexistence of these diseases was associated with age, female gender and the presence of other extra-articular manifestations associated with SpA. CONCLUSIONS: Extra-articular disease in patients with SpA is common and, in this study, it was associated to age, female gender and the presence of other SpA-related extra-articular manifestations. PMID- 25441491 TI - Osteonecrosis in systemic lupus erythematosus. AB - OBJECTIVES: To define the proportion of osteonecrosis (ON) in our patient population with lupus and to identify factors associated with the development of ON in systemic lupus erythematosus, as well as to carry out a descriptive analysis of ON cases. MATERIALS AND METHODS: Observational retrospective study of 158 patients with SLE (ACR 1982 criteria). Demographic and laboratory data, clinical manifestations, SLICC, SLEDAI, cytotoxic and steroid treatments were compared. In patients with ON, we analyzed time of disease progression and age at ON diagnosis, form of presentation, joints involved, diagnostic methods, Ficat Arlet classification, and treatment. To compare the means, t-test or Mann Whitney's test were employed and the cHi-2 test or Fisher's exact test, as appropriate, were used to measure the equality of proportions. RESULTS: ON was present in 15 out 158 patients (9.5%), 13 women and 2 men, with a mean age of 30 (r: 16-66) at diagnosis and 35 months of evolution until diagnosis (r: 1-195). Among the 15 patients, 34 joints presented ON, 23 were symptomatic and 22 were diagnosed by magnetic resonance images. Twenty-six occurred in hips (24 bilateral), 4 in knees and 4 in shoulders. In 13 patients, ON involved 2 or more joints. At onset, 28 joints were in stage i-ii, one in stage iii and 5 had no data and; in the end, 14 were in stage iii-iv, 5 in stage i-ii and 15 had no data. Twenty-nine underwent conservative treatment with rest and 8 hips required joint replacement. ON progression was associated with Cushing's syndrome (P=0.014) OR 4.16 (95% CI 1.4-12.6) and 2nd year SLICC (P=0.042). No relation with clinical manifestations, lab results, cytotoxic treatment, steroid treatment (total accumulated dose, mean daily dose and duration) metilprednisolone pulses, nor activity was found. All patients with ON received antimalarials, in contrast to 77% of those without ON. CONCLUSIONS: The proportion of ON was 9.5%, mainly in women, 76% in hips (26) and 92% bilaterally. They were associated significantly with Cushing's syndrome and accumulated damage at second year. PMID- 25441492 TI - Thrombotic manifestations in SAPHO syndrome. Review of the literature. AB - SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome is a cluster of osteo-cutaneous manifestations that can lead to serious complications such as thrombosis of the subclavian vein or superior vena cava, mainly in patients with significant inflammatory involvement of the anterior-chest-wall. The objective of this study was to review the cases published in the medical literature related with the presence of thrombotic complications in patients diagnosed with SAPHO syndrome and to try to determine their possible pathogenic mechanism and risk factors. We analyzed 11 published reports of isolated clinical cases or case series, a total of 144 patients, which described a total of 15 cases of venous thrombosis. The clinical characteristics of these patients, evaluated to determine whether they meet the ASAS criteria for axial and peripheral spondyloarthritis, is analyzed the need for early diagnosis and treatment is highlighted. PMID- 25441493 TI - Parvovirus B19 chronic monoarthritis in a patient with common variable immunodeficiency. PMID- 25441494 TI - Schnitzler syndrome. PMID- 25441496 TI - Novel method for comparing coverage by future methods of ballistic facial protection. AB - The wearing of eye protection by United Kingdom soldiers in Afghanistan has reduced the morbidity caused by explosive fragments. However, the remaining face remains uncovered because there is a lack of evidence to substantiate the procurement of methods to protect it. Using a new computerised tool we entered details of the entry sites of surface wounds caused by explosive fragments in all UK soldiers who were injured in the face between 1 January 2010 and 31 December 2011. We compared clinical and predicted immediate and long term outcomes (as defined by the Abbreviated Injury Score (AIS) and the Functional Capacity Index (pFCI), respectively). We also used the tool to predict how additional protection in the form of a visor and mandible guard would affect outcomes. A soldier wearing eye protection was 9 times (1.03/0.12) less likely to sustain an eye injury than one without. However, 38% of soldiers in this series were not wearing eye protection at the time of injury. There was no significant difference between the AIS and pFCI scores predicted by the tool and those found clinically. There is limited evidence to support the use of a mandible guard; its greatest asset is better protection of the nose, but a visor would be expected to reduce long-term morbidity more than eye protection alone, and we recommend future trials to assess its acceptability to users. We think that use of this novel tool can help in the selection of future methods of ballistic facial protection. PMID- 25441497 TI - Use of computer-assisted semen analysis for evaluation of Rosy-faced lovebird (Agapornis roseicollis) semen collected in different periods of the year. AB - The seminal characteristics of the Rosy-faced lovebird (Agapornis roseicollis) were analyzed, both in and out of season, using a computer-aided sperm analyzer. Avian semen collection and artificial insemination techniques have great potential for captive breeding programs, and computer-aided sperm analyzer allows an objective and quantitative assessment of sperm motility and kinetics. Although Agapornis roseicollis is a largely diffuse species, its seminal parameters have never been fully investigated. Using the massage technique, 38 ejaculates were collected in the breeding season, and 6 ejaculates were collected outside of the breeding season. Semen color, volume, degree of contamination, spermatozoa concentration, total and progressive motility, and kinetics parameters were recorded. Seasonal significant differences were found in the ejaculate volume (1.6 +/- 0.6 and 1.1 +/- 0.2 mL in and out season, respectively, P < 0.01) and spermatozoa concentration (7194.0 +/- 6735.1 x 10(6) and 327.5 +/- 314.0 x 10(6) spermatozoa/mL, P < 0.01); among the motility parameters, only beat cross frequency, indicating the frequency of flagellar beats, was significantly higher out of the reproductive season (29.8 +/- 2.6 vs. 24.5 +/- 3.8 Hz, P < 0.01). There was very large individual variation in semen characteristics that could qualify a male as a potentially good or bad semen donor for future assisted reproduction in captivity. PMID- 25441495 TI - Secondary macrophage activation syndrome due to autoimmune, hematologic, infectious and oncologic diseases. Thirteen case series and review of the literature. AB - OBJECTIVE: Describe the demographic characteristics and disorders of patients with diagnosis of Macrophage Activation Syndrome (MAS) in the December 2008 - January 2014 period. METHODS: Medical records were reviewed from diagnosis of MAS and after discharge until January 2014. Patients were divided into 4 groups according to the primary disease: Autoimmune (AI), Hemato - oncologic (HO), Infectious (Inf) and Oncologic (Onc). The variables were analyzed among the 4 groups and between AI and HO. RESULTS: Thirteen patients [7 men, with a median of 54 years (32-63)] were studied. The etiologies were: 5 AI, 5 HO, 2 Inf. and 1 Onc. disease. Hemophagocitc cells were found in the ascitic fluid of one patient. A patient with MAS secondary to IgG4-related disease was found. CONCLUSIONS: Mortality, prognosis and disease progression may be influenced by the delay in diagnosis, treatment initiation and etiology of MAS. HO ill patients had a worse prognosis. PMID- 25441498 TI - Effect of glycerol on the viability and fertility of cooled bovine semen. AB - The aim of the present study was to compare the viability and fertility of bovine semen diluted in Botu-Bov (BB) commercial extender with and without the cryoprotectant glycerol then cooled at 5 degree C for 24 hours in the Botu-Flex passive cooling system and of semen diluted in BB with glycerol then frozen. One ejaculate of 30 Nelore Bos Taurus indicus bulls between 24 and 30 months of age was used for in vitro analysis. Sperm kinetics and cell viability were analyzed using computer-assisted sperm analysis and flow cytometry, respectively. Three Nelore bulls approximately 30 month old were used for in vivo test using fixed time artificial insemination for the fertility analysis. The ejaculates were divided into three experimental groups: semen in BB extender with 7% glycerol cooled at 5 degrees C for 24 hours (cooled semen with cryoprotectant), semen in BB without glycerol cooled at 5 degrees C for 24 hours (cooled semen without cryoprotectant), and semen diluted in BB with 7% glycerol then subsequently frozen rather than cooled (frozen semen). For the fertility analysis, 762 Nelore cows (B taurus indicus) were randomly inseminated using fixed-time artificial insemination. For the groups corresponding to cooled semen with cryoprotectant, cooled semen without cryoprotectant, and frozen semen, 278, 268, and 216 cows were inseminated, respectively, and the resulting conception rates were 51% a, 44%ab and 41%b (P < 0.05), respectively. In conclusion, the fertility rates improved, when samples were cooled with glycerol at 5 degrees C for 24 hours compared with the frozen samples. PMID- 25441499 TI - Adjuvant effects of therapeutic glycolipids administered to a cohort of NKT cell diverse pigs. AB - CD1d-restricted natural killer T (NKT) cells are a unique lymphocyte population that makes important contributions to host defense against numerous microbial pathogens. The powerful immunomodulatory effects of these cells can be exploited in mice by cognate antigens for multiple therapeutic purposes, including for protection from infectious diseases and as adjuvants to improve vaccines against microbial organisms. These applications have potential to treat and prevent infectious diseases in livestock species that express NKT cells, including pigs. In this study, immune tissues from commercial swine of mixed genetic background were compared for NKT cell frequency, cytokine secretion and subset ratios. Pigs were also injected with the model antigen hen-egg lysozyme (HEL) in conjunction with one of three glycosphingolipids, alpha-galactosylceramide (alphaGC), OCH and C-glycoside that selectively activate NKT cells, to assess the adjuvant potential of each. There was significant variation between individual pigs for all NKT cell parameters measured. The NKT cell agonists elicited HEL-specific immune responses of different quality, but only alphaGC increased the systemic concentration of NKT cells. Peripheral blood NKT cell frequency measured prior to treatment was a poor predictor of how individual animals responded to NKT cell therapy. However, our results show that although NKT cells vary considerably between pigs, there exists considerable potential to harness these cells to protect swine from infectious diseases. PMID- 25441500 TI - Blood oxygen level dependent functional magnetic resonance imaging for presurgical planning. AB - Functional magnetic resonance imaging (fMRI) has become a common tool for presurgical sensorimotor mapping, and is a significant preoperative asset for tumors located adjacent to the central sulcus. fMRI has changed surgical options for many patients. This noninvasive tool allows for easy display and integration with other neuroimaging techniques. Although fMRI is a useful preoperative tool, it is not perfect. Tumors that affect the normal vascular coupling of neuronal activity will affect fMRI measurements. This article discusses the usefulness of blood oxygen level dependent (BOLD) fMRI with regard to preoperative motor mapping. PMID- 25441502 TI - Memory assessment in the clinical context using functional magnetic resonance imaging: a critical look at the state of the field. AB - The use of functional magnetic resonance imaging to map language and sensorimotor regions in the brain is rapidly becoming a clinical standard in neurosurgical centers. Despite a wealth of cognitive neuroscience data showing focal medial temporal activation elicited by memory encoding and retrieval tasks in controls, translating such findings to generate reliable metrics for clinical use has been slow. The current review documents some of the successes that have been achieved, using both activation and resting-state functional connectivity in the clinical context of temporal lobe epilepsy, and discusses some of the challenges that remain to be addressed. PMID- 25441501 TI - Visual mapping using blood oxygen level dependent functional magnetic resonance imaging. AB - Functional magnetic resonance imaging (fMRI) is used clinically to map the visual cortex before brain surgery or other invasive treatments to achieve an optimal balance between therapeutic effect and the avoidance of postoperative vision deficits. Clinically optimized stimuli, behavioral task, analysis, and displays permit identification of cortical subregions supporting high-acuity central vision that is critical for reading and other essential visual functions. Emerging techniques such as resting-state fMRI may facilitate the use of fMRI based vision mapping in a broader range of patients. PMID- 25441503 TI - Preoperative diffusion tensor imaging: improving neurosurgical outcomes in brain tumor patients. AB - Preoperative mapping has revolutionized neurosurgical care for brain tumor patients. Maximizing resections has improved diagnosis, optimized treatment algorithms, and decreased potentially devastating postoperative deficits. Although mapping has multiple steps and complimentary localization sources, diffusion tensor imaging (DTI) excels in its essential role in depicting white matter tracts. A thorough understanding of DTI, data visualization methods, and limitations with mastery of functional and dysfunctional white matter anatomy is necessary to realize the potential of DTI. By establishing spatial relationships between lesion borders and functional networks preoperatively and intraoperatively, DTI is central to high-risk neurosurgical resections and becoming the standard of care. PMID- 25441504 TI - Diffusion tensor imaging for brain malformations: does it help? AB - In this article, the basics of diffusion-weighted imaging/diffusion tensor imaging (DTI) are discussed, including a short historical perspective on the fiber dissection technique, followed by a review of selected brain malformations in which DTI and tractography have contributed to a better understanding of the malformations, and by a clinical case in which DTI showed a disorder of the internal neuroarchitecture that could not be correctly appreciated by conventional anatomic magnetic resonance imaging. PMID- 25441505 TI - Pretherapeutic functional magnetic resonance imaging in children. AB - In this article, some specificities of functional magnetic resonance imaging (fMRI) in children (eg, blood-oxygen-level-dependent response and brain maturation, paradigm design, technical issues, feasibility, data analysis) are reviewed, the main knowledge on presurgical cortical mapping in children (motor, language, reading, memory) is summarized, and the emergence of resting state fMRI in presurgical cortical mapping is discussed. PMID- 25441507 TI - Applications of blood-oxygen-level-dependent functional magnetic resonance imaging and diffusion tensor imaging in epilepsy. AB - The lifetime prevalence of epilepsy ranges from 2.7 to 12.4 per 1000 in Western countries. Around 30% of patients with epilepsy remain refractory to antiepileptic drugs and continue to have seizures. Noninvasive imaging techniques such as functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) have helped to better understand mechanisms of seizure generation and propagation, and to localize epileptic, eloquent, and cognitive networks. In this review, the clinical applications of fMRI and DTI are discussed, for mapping cognitive and epileptic networks and organization of white matter tracts in individuals with epilepsy. PMID- 25441506 TI - Resting-state blood oxygen level-dependent functional magnetic resonance imaging for presurgical planning. AB - Resting-state functional MR imaging (rsfMR imaging) measures spontaneous fluctuations in the blood oxygen level-dependent (BOLD) signal and can be used to elucidate the brain's functional organization. It is used to simultaneously assess multiple distributed resting-state networks. Unlike task-based functional MR imaging, rsfMR imaging does not require task performance. This article presents a brief introduction of rsfMR imaging processing methods followed by a detailed discussion on the use of rsfMR imaging in presurgical planning. Example cases are provided to highlight the strengths and limitations of the technique. PMID- 25441508 TI - Technical considerations for functional magnetic resonance imaging analysis. AB - Clinical application of functional magnetic resonance imaging (fMRI) based on blood oxygenation level-dependent (BOLD) effect has increased over the past decade because of its ability to map regional blood flow in response to brain stimulation. This mapping is primarily achieved by exploiting the BOLD effect precipitated by changes in the magnetic properties of hemoglobin. BOLD fMRI has utility in neurosurgical planning and mapping neuronal functional connectivity. Conventional echo planar imaging techniques are used to acquire stimulus-driven fMR imaging BOLD data. This article highlights technical aspects of fMRI data analysis to make it more accessible in clinical settings. PMID- 25441509 TI - Special considerations/technical limitations of blood-oxygen-level-dependent functional magnetic resonance imaging. AB - In this review, limitations affecting the results of presurgical mapping with blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) are discussed. There is a great need to standardize fMRI acquisition and analysis methods and establish guidelines to address quality control issues. Several national and international organizations are formulating guidelines and standards for both clinical and research applications of BOLD fMRI. Consensus regarding management of these issues will likely both improve the clinical standard of care and enhance future research applications of fMRI. PMID- 25441510 TI - The economics of functional magnetic resonance imaging: clinical and research. AB - It is difficult to justify maintaining a clinical functional magnetic resonance imaging (fMRI) program based solely on revenue generation. The use of fMRI is, therefore, based mostly in patient care considerations, leading to better outcomes. The high costs of the top-of-the-line equipment, hardware, and software needed for state-of-the-art fMRI and the time commitment by multiple professionals are not adequately reimbursed at a representative rate by current payor schemes for the Current Procedure Terminology codes assigned. PMID- 25441511 TI - Neuroimaging Clinics of North America. Clinical applications of functional MRI. Foreword. PMID- 25441512 TI - Clinical applications of functional MRI. PMID- 25441514 TI - A 55-year-old woman with an abrupt onset of weakness. PMID- 25441516 TI - It's good to be the king. PMID- 25441515 TI - Coagulation: part 2. PMID- 25441517 TI - 2014 critical care transport workplace and salary survey. AB - This 2014 survey polled critical care transport industry leaders, programs, and caregivers about workplace and salary information. Beyond descriptive information and salary data, the article details specific experience, education, and scope of practice within the critical care transport industry. PMID- 25441518 TI - Paramedic specialization: a strategy for better out-of-hospital care. AB - Demographic, economic, and political forces are driving significant change in the US health care system. Paramedics are a health profession currently providing advanced emergency care and medical transportation throughout the United States. As the health care system demands more team-based care in nonacute, community, interfacility, and tactical response settings, specialized paramedic practitioners could be a valuable and well-positioned resource to meet these needs. Currently, there is limited support for specialty certifications that demand appropriate education, training, or experience standards before specialized practice by paramedics. A fragmented approach to specialty paramedic practice currently exists across our country in which states, regulators, nonprofit organizations, and other health care professions influence and regulate the practice of paramedicine. Multiple other medical professions, however, have already developed effective systems over the last century that can be easily adapted to the practice of paramedicine. Paramedicine practitioners need to organize a profession-based specialty board to organize and standardize a specialty certification system that can be used on a national level. PMID- 25441520 TI - Placement of a central venous catheter in the antecubital vein using a modified seldinger technique. AB - PURPOSE: To describe a case of a patient requiring inotropic support without central venous access in which the central venous catheter (CVC) was placed in the antecubital vein using a modified seldinger technique. BACKGROUND: Placement of CVC in the field in retrieval medicine can be time consuming and is not without risk of complication. Minimizing time in the field can lead to better outcomes for patients who are seriously medically ill or traumatically injured. The ED also offers a more controlled environment for the safe and accurate placement of CVCs. However, there are times in the prehospital environment when more secure access than peripheral is needed in order to administer the appropriate treatment. Herein, a modified seldinger technique is described for the peripheral placement of a CVC. CASE REPORT: A 53-year-old man presented to a remote health clinic in the outback of Australia with complaints of weakness, persistent vomiting and chest pain. He subsequently arrested for a brief period (~3 minutes) from suspected hyperkalemia complicated by MI and upon resuscitation was bradycardic, obtunded and hypotensive. Clinic staff were only able to gain an 18G left antecubital IV. The patient required an adrenaline infusion, IVF and other medications. Using the angiocatherter already in place, a guide wire was placed through and a quadruple lumen CVC was placed without complication allowing for infusion of medications (adrenaline drip, meropenem) and IVF. The catheter was removed after a CVC was placed under US guidance and sterile conditions in the ICU 12 hours later. CONCLUSION: This case represents a dilemma faced in the prehospital environment by retrieval teams and offers a novel technique as a temporizing solution until appropriate CVC access can be gained. PMID- 25441519 TI - Ethical considerations for conducting a randomized controlled trial in transport. AB - Although recent studies support the rapid transfer of patients experiencing time sensitive emergencies, limited data exist to support the use of air transport for nonurgent patient transfers. The nature of medical transport and the heterogeneity of patients who are transferred present unique challenges in designing and conducting clinical research trials that could contribute to the evidence-based decision making for patient care and transport. The current regulatory framework presents several barriers to conducting such research in the medical transport setting. We present a hypothetic study that randomizes patients to either ground or air transport as an exemplar. We discuss informed consent, risk, and the impracticality of conducting community consultations in a medical transport setting. Finally, recommendations for potential changes to current regulations are presented. These are directed at facilitating the conduct of emergency research through a system of oversight that integrates characteristics of quality improvement and health services research. PMID- 25441521 TI - In-flight auscultation during medical air evacuation: comparison between traditional and amplified stethoscopes. AB - OBJECTIVES: The aim of this study was to evaluate the capacity of a traditional stethoscope versus an electronically amplified one (expected to reduce background and ambient noise) to assess heart and respiratory sounds during medical transport. MATERIALS AND METHODS: It was a prospective, double-blinded, randomized performed study. One traditional stethoscope (Littmann Cardiology III; 3M, St Paul, MN) and 1 electronically amplified stethoscope (Littmann 3200, 3M) were used for our tests. Heart and lung auscultation during real medical evacuations aboard a medically configured Falcon 50 aircrafts were studied. The quality of auscultation was ranged using a numeric rating scale from 0 to 10 (0 corresponding to "I hear nothing" and 10 to "I hear perfectly"). Data collected were compared using a t-test for paired values. RESULTS: A total of 40 comparative evaluations were performed. For cardiac auscultation, the value of the rating scale was 4.53 +/- 1.91 and 7.18 +/- 1.88 for the traditional and amplified stethoscope, respectively (paired t-test: P < .0001). For respiratory sounds, quality of auscultation was estimated at 3.1 +/- 1.95 for a traditional stethoscope and 5.10 +/- 2.13 for the amplified one (paired t-test: P < .0001). CONCLUSIONS: This study showed that practitioners would be better helped in hearing cardiac and respiratory sounds with an electronically amplified stethoscope than with a traditional one during air medical transport in a medically configured Falcon 50 aircraft. PMID- 25441522 TI - Review of respiratory management of extremely premature neonates during transport. AB - INTRODUCTION: The objective was to evaluate the respiratory management of neonates of 23 to 26 weeks' gestation transported after birth outside a tertiary center. Another objective was to collect data regarding survival, intraventricular hemorrhage (IVH), and chronic lung disease. METHODS: This was a retrospective study of transports from a statewide dedicated neonatal and pediatric transport service over a 3-year period. Data were collected from the local databases. Neonates with and without transcutaneous carbon dioxide (TcCO2) monitoring were compared. Outcomes were compared with the inborn group from the same period. RESULTS: A total of 43 mechanically ventilated neonates were included. Significant hypocarbia and/or hypercarbia were seen in 49%. Hyperoxia was noted in 46.5%. Despite the moderate correlation between PCO2 and TcCO2 readings, no clinical benefit was seen with TcCO2 monitoring. Survival was 65.1%. Rates of IVH were 60% for any IVH and 27.5% for severe IVH. IVH was more common in the study cohort. CONCLUSIONS: Neonates born at 23 to 26 weeks' gestation outside tertiary centers have high rates of mortality and morbidity. The avoidance of hypocarbia, hypercarbia, and hyperoxia is challenging in the transport environment. Transcutaneous monitoring is an imperfect tool for following PCO2 levels. PMID- 25441523 TI - Introduction of a physician-staffed helicopter emergency medical service in eastern Shizuoka prefecture in Japan. AB - OBJECTIVE: To analyze the operating situation of a physician-staffed helicopter emergency medical service in eastern Shizuoka prefecture. METHODS: A retrospective analysis was performed using the conveyance records reported by staff members of the physician-staffed helicopter. A comparison between 2007 (n = 619) and 2012 (n = 678) was performed. RESULTS: There were no significant differences between the 2 groups with regard to the sex, ratio of cardiopulmonary arrest, and survival ratio. In contrast, the duration from the request of dispatch to arrival at the hospital in 2007 was significantly longer than that in 2012 (53.7 vs 48.2 minutes, P < 0.0001). The average age in 2007 was significantly younger than in 2012 (55.7 vs 59.4 years, P < 0.01). The ratio of trauma case in the 2012 was higher than that in 2007 (47 vs 37%, P < 0.001). The ratio of severe cases in 2007 was higher than in 2012 (45 vs 39%, P < 0.05). CONCLUSION: Japan is an aging society. In eastern Shizuoka prefecture, the increase in the number of trauma and minor injury cases may have increased due to the emphasis on the importance of early medical intervention by the fire department. PMID- 25441524 TI - Helicopter emergency medical service patient transport safe at night? AB - OBJECTIVE: Dutch helicopter emergency medical services are available 24/7. Working without daylight brings additional challenges, both in patient care and in-flight operation. We retrospectively evaluated the safety of this nighttime helicopter transportation of patients. METHODS: Our helicopter emergency medical service database was reviewed for all patients transported by helicopter during nighttime. Both interhospital transports and patients transported from the accident location to a hospital were included. The time traveled by helicopter was compared with the time that road transportation of these patients would have taken. RESULTS: In total, 513 patients were transported by helicopter. Of these patients, 72 were transported during nighttime (14%); the median age was 25.3 years (range, 1.1-73.9 years). The median flight time to the hospital was 16 minutes (range, 5-42 minutes). To travel by road, this would have taken a median of approximately 44 minutes (range, 23-100 minutes). When comparing these travel times, a significantly faster transport time by helicopter during nighttime was observed (P < .001). Three non-flight-specific incidents were noted. CONCLUSION: We conclude that helicopter transportation of patients without daylight is safe and fast in a Dutch setting. PMID- 25441525 TI - Benefit of mechanical chest compression devices in mountain HEMS: lessons learned from 1 year of experience and evaluation. AB - INTRODUCTION: Pre-hospital care of cardiac arrest patients in the mountain environment is one of the most challenging problems for helicopter medical emergency services (HEMS) teams. To provide high-quality chest compression with minimal hand s-off-time is very demanding in the alpine area. METHODS: We used and evaluated mechanical chest compression devices (Lucas and AutoPulse) and investigated if these are good and useful tools in the alpine HEMS. Over a period of 12 months we performed 7 CPRs in remote alpine terrain. CONCLUSION: On the strength of our past experience, CPR under special circumstances like deep hypothermia, in which a prolonged CPR is essential, the use of the Lucas and/or AutoPulse was an easy and sufficient tool even in difficult alpine terrain which requires special rescue missions like winch or MERS evacuation. PMID- 25441526 TI - In-flight breech delivery in Finnish lapland. AB - Although medical crews may initially approach obstetric transport requests with (at least internal) trepidation, it has been shown that the risk of an in-flight delivery occurring is extremely low, even among patients considered high risk.(1 4) Nevertheless, the greatest concern of helicopter emergency medical service (HEMS) personnel remains the potential for in-flight delivery.(5) Finland is a Northern European country, with a land area almost equivalent to that of the US state of New Mexico. The Finnish HEMS system is managed by FinnHEMS, and there are 6 HEMS units in Finland. The northernmost HEMS unit, FinnHEMS 51, is based at Rovaniemi Airport in Finnish Lapland, which is located within the Arctic Circle; it operates over a remote and sparsely habited area. Finnish Lapland accounts for almost 30% of Finland by area; however, the density of population is low (only 2.0 persons per square kilometer), and the average annual year-round temperature is only -1 degrees C (30 degrees F).(6) So far, there has been only 1 reported in flight delivery; in 1939, a baby girl was born in an airplane operated by the Finnish Border Guard.(7.) PMID- 25441527 TI - Air medical retrieval of acute psychiatric patients. AB - BACKGROUND: The aim of this study is to review the characteristics of acute psychiatric patients requiring air medical retrieval across the Northern Territory (NT) of Australia, to assess the sedation requirements and incidence of in-flight complications when retrieving such patients, and to review the optimal flight crew composition required for safe retrieval. METHODS: Retrospective data were collected for all psychiatric patients retrieved by an air medical retrieval service of the NT of Australia over a 12-month period between February 1, 2012, and January 31, 2013. RESULTS: Two hundred sixty-two patients were retrieved using fixed wing transport; 90% were indigenous. Eighty-one percent of retrievals occurred during the day, averaging approximately 4.5 hours. A flight doctor was tasked with a nurse to retrieve 79% of patients. Eighty-nine percent of patients received sedation in the health care center before flight, whereas 39% of total patients required further in-flight sedation. Only 8 patients required intubation before transport. The only in-flight complication was hypotension occurring in 6% of patients; these cases predominantly involved the use of propofol, and the hypotension was rapidly corrected without further incident. CONCLUSIONS: This review highlights the characteristics of psychiatric patients retrieved by an air medical retrieval service in the NT of Australia. The majority of patients retrieved had a background psychiatric history and also a history of violence. Given the nature of the retrieval and the risk to crew and aircraft, a flight doctor was tasked on a high number of cases. The complication rate was negligible. Further analysis of patient history and characteristics of violence could lead to a risk assessment tool for the retrieval of such patients. PMID- 25441528 TI - Mexico City's Petroleos Mexicanos explosion: disaster management and air medical transport. AB - Mexico City is the largest metropolitan area in the Americas and 1 of the largest in the world; its geographic location and uncontrolled population and industrial growth make this metropolis prone to natural and human-made disasters. Mass casualty disaster responses in Mexico City tend to have complications from multiple logistical and operational challenges. This article focuses on the experiences and lessons learned from an explosion that occurred in a government building in Mexico City and the current status of mass casualty disaster risks and response strategies in Mexico City as well as air medical evacuation, which is a critical component and was shown to be extremely useful in the evacuation of 15 critically ill and polytraumatized patients (Injury Severity Score > 15). Several components of the public and privately owned emergency medical services and health care systems among Mexico City pose serious logistical and operational complications, which finally will be addressed by a joint emergency preparedness council to unify criteria in communications, triage, and incident/disaster command post establishment. PMID- 25441529 TI - Helicopter patient transportation service on the Ulleung Island, South Korea. AB - INTRODUCTION: Despite numerous studies of helicopter emergency medical services, few reports have examined the outcomes of patients transported by helicopter across the sea from isolated islands. We analyzed helicopter transportation from the isolated Ulleung Island, which lies to the east of the South Korean mainland. METHODS: This study included 284 patients transported from the Ulleung Island to mainland hospitals between January 2007 and March 2013. Emergency Severity Index and Injury Severity Score were calculated. Hospital stay time and flight duration was measured. Data were analyzed using Student's t-test. RESULTS: The mean age of the patients was 53.5 years. Of the transported patients, 19.0% were visitors to the island and 29.6% were traumatically injured. The mortality rate after transportation was 11.6% (33 patients). CONCLUSION: Helicopter transportation has been very beneficial for the treatment of emergency patients on Ulleung Island. A national level of interest and investment is required to improve this service. PMID- 25441530 TI - Characteristics of nontrauma scene flights for air medical transport. AB - INTRODUCTION: Little is known about the use of air medical transport for patients with medical, rather than traumatic, emergencies. This study describes the practices of air transport programs, with respect to nontrauma scene responses, in several areas throughout the United States and Canada. METHODS: A descriptive, retrospective study was conducted of all nontrauma scene flights from 2008 and 2009. Flight information and patient demographic data were collected from 5 air transport programs. Descriptive statistics were used to examine indications for transport, Glasgow Coma Scale Scores, and loaded miles traveled. RESULTS: A total of 1,785 nontrauma scene flights were evaluated. The percentage of scene flights contributed by nontraumatic emergencies varied between programs, ranging from 0% to 44.3%. The most common indication for transport was cardiac, nonST-segment elevation myocardial infarction (22.9%). Cardiac arrest was the indication for transport in 2.5% of flights. One air transport program reported a high percentage (49.4) of neurologic, stroke, flights. CONCLUSION: The use of air transport for nontraumatic emergencies varied considerably between various air transport programs and regions. More research is needed to evaluate which nontraumatic emergencies benefit from air transport. National guidelines regarding the use of air transport for nontraumatic emergencies are needed. PMID- 25441531 TI - Use of arterial catheters in the management of acute aortic dissection. AB - PURPOSE: The aim of this study was to investigate the relationship between the use of invasive arterial blood pressure (IBP) monitoring and reaching established aggressive medical management goals in acute aortic dissection. METHODS: Data were collected through a retrospective chart review of patients diagnosed with acute aortic syndromes of the thoracic cavity who required transport to tertiary care over a 28-month period. The 2010 American Heart Association medical management goals of thoracic aortic disease were used as hemodynamic end points. RESULTS: A total of 208 patients were included, with 113 (54%) diagnosed at least in part with acute Stanford Type A aortic dissections and the remaining 95 (46%) having isolated Stanford Type B dissections. Emergency departments made up 158 (76%) of transfer departments; 129 (62%) patients had IBP catheters placed. The highest mean systolic blood pressures (SBPs) recorded were 165 mm Hg in the IBP group versus 151 mm Hg when noninvasive blood pressure (NIBP) cuffs were used (P < .01). The mean decrease in SBP during transport was 51 mm Hg in the IBP group versus 34 mm Hg in the NIBP group (P < .001). The difference between the last reported NIBP and the first IBP was noted as 19 mm Hg higher. The IBP group met the SBP goal more frequently than the NIBP group (P < .05) when the SBP was noted as greater than 140 mm Hg during transport. Bedside time increased only 6 minutes with IBP placement (P < .007). CONCLUSION: Patients with IBP catheters were noted to be more aggressively managed with antihypertensive medications, met hemodynamic goals more frequently, and had only 6 minutes longer bedside times. These findings support the placement of IBP catheters by emergency departments and critical care transport (CCT) teams in patients with acute aortic syndromes requiring interfacility transport to definitive care. PMID- 25441532 TI - Successful airtraq use in an air medical transport system. AB - INTRODUCTION: There is a large body of literature that shows that the AirTraq device achieves equal or superior rates of successful intubation in all classes of user. A recent prospective human trial of the device questioned the first pass success rate and whether effective training could occur outside the Operating Room (OR). The purpose of this study was to investigate the first pass success rate for intubation with the AirTraq (AT) device utilizing only mannequin training in an air ambulance setting from Aug. 1 2009 to Aug. 1 2012 and compare it to direct laryngoscopy (DL). HYPOTHESIS: We hypothesize that the AirTraq device will be as effective overall as direct laryngoscopy, and that this requires no OR training to achieve. METHODS: A retrospective chart review of 161 intubations by air ambulance flight nurses from Aug. 1, 2009 to Aug. 1, 2012 was conducted. Data regarding date of service, devices used, number of attempts, rescue device use, and complications was gathered and analyzed. The generalized estimating equation and the chi-squared test were used to evaluate the data. RESULTS: 161 intubations were reviewed. 135 met inclusion criteria. Overall first pass success rate for AT was 82% (68/83) and DL was 74% (35/47). Overall first use success rate for AT was 79% (71/90) and DL was 70% (43/61). The overall success rate of intubation for any patient in which either AT or DL was attempted is 96% (130/135). CONCLUSION: AirTraq was shown to be as effective as direct laryngoscopy. All air crew training for the AirTraq device was performed on mannequins. The successof the device compared to DL shows that mannequin training is sufficient to implement the AirTraq device for pre-hospital intubation. PMID- 25441534 TI - Consanguinity and late fertility: spatial analysis reveals positive association patterns. AB - The role of consanguinity on human complex traits is an important and controversial issue. In this work we focused on the Sardinian population and examined the effect of consanguineous unions on late female fertility. During the last century the island has been characterized by a high incidence of marriages between relatives, favoured by socio economic conditions and geographical isolation, and by high fertility despite a widespread tendency to delay reproduction. Through spatial analysis techniques, we explored the geographical heterogeneity of consanguinity and late fertility, and identified in Central Eastern Sardinia a common area with an excess of both traits, where the traits are positively associated. We found that their association did not significantly affect women's fertility in the area, despite the expected negative role of both traits. Intriguingly, this critical zone corresponds well to areas reported by previous studies as being peculiar for a high frequency of centenarians and for lower risk in pregnancy outcome. The proposed approach can be generally exploited to identify target populations on which socioeconomic, biodemographic and genetic data can be collected at the individual level, and deeper analyses carried out to disentangle the determinants of complex biological traits and to investigate their association. PMID- 25441535 TI - Unreported clinical deterioration in emergency department patients: a point prevalence study. AB - BACKGROUND: Formal processes for recognising and responding to deteriorating emergency department (ED) patients are variable despite features of the ED context that may increase the risk of unrecognised or unreported clinical deterioration. The aim of this study was to determine the frequency and nature of unreported clinical deterioration in emergency care. METHODS: A prospective, exploratory descriptive design was used. Data were collected during nine point prevalence surveys (PPS) from 1 May to 30 June 2009 at an urban district hospital in Melbourne Australia. Patients present in ED cubicles during the PPS (n=186) were included in the study. RESULTS: Unreported clinical deterioration occurred in 12.9% of patients (n=24/186). Unreported clinical deterioration was more common when: (i) patients aged >=65 years comprised >50% of patients within the ED; (ii) occupancy of the resuscitation, monitored or general adult cubicles was >50%; and (iii) the proportion of patients requiring treatment within 30 min (Australasian Triage Category 1, 2 or 3) was <=50% of the total ED population. CONCLUSIONS: Unreported clinical deterioration is an important quality indicator of emergency care. The effect of the collective ED patient group on the frequency and nature of adverse events for individual ED patients is poorly understood and warrants further investigation. PMID- 25441536 TI - Fabrication and evaluation of Au-Pd core-shell nanocomposites for dechlorination of diclofenac in water. AB - Nanocomposites with core-shell structure usually exhibit excellent catalytic properties due to unique interfaces and synergistic effect among composites. In this study, Au-Pd bimetallic nanoparticles (NPs) with core-shell structure (Au-Pd cs) by using Au NPs as core and Pd as shell were successfully fabricated and, for the first time, were used to investigate the dechlorination of diclofenac (DCF) at H2 atmosphere in water at room temperature. The degradation products were studied as well by using HPLC/Q-ToF MS/MS. The operational factors such as pH and composition of the Au-Pd cs were also studied. The results showed that nearly 100% of DCF (30 mg L(-1), 50 mL, pH=7) was dechlorinated in 4.5 h by 10 mL of 56 mg L(-1) of Au-Pd cs. Ninety per cent of DCF was degraded in 6.5 h by the mixture of Au and Pd NPs. However, the individual Au NPs had no obvious effect in degrading DCF and the monometallic Pd NPs with comparable concentration only degraded less than 20% of DCF. Furthermore, the reaction mechanism of this catalytic process was studied in detail. It was found that the degradation was a second-order exponential reaction. The two main degradation products were obtained by cleaving the carbon-halogen bond of DCF and this made the degradation products more environmentally friendly. PMID- 25441537 TI - Thirst in chronic heart failure: a review. AB - AIMS AND OBJECTIVES: This review will (1) explore factors related to thirst in chronic heart failure and (2) describe interventions to alleviate thirst in chronic heart failure patients. BACKGROUND: Thirst is a common and troublesome symptom of chronic heart failure. Despite the burden and prevalence of this symptom, there are limited strategies to assist in its management. DESIGN: This is a review of literature on the burden of thirst, contributors to thirst and potential management strategies of thirst in patients with chronic heart failure. METHODS: Medline, Cumulative Index for Nursing and Allied Health, PubMed and Scopus were searched using the key words thirst, chronic heart failure, angiotensin II, fluid restriction and intervention. Of the 165 citations yielded, nine studies (n = 9) were included. The eligibility criteria included participants with confirmed diagnosis of chronic heart failure, randomised controlled studies or any studies with thirst as primary or secondary outcome, in humans and in English. There was no limit to the years searched. RESULTS: Factors related to thirst in chronic heart failure were condition; prolonged neurohormonal activation, treatment; pharmacological interventions and fluid restriction and emotion. No intervention studies were found in chronic heart failure patients. Interventions such as artificial saliva and chewing gum have been investigated for their effectiveness as a thirst reliever in haemodialysis patients. CONCLUSION: Thirst is a frequent and troublesome symptom for individuals with chronic heart failure. It is highly likely that this contributes to poor adherence with fluid restrictions. Chewing gum can help alleviate thirst, but investigation in people with heart failure is needed. RELEVANCE TO CLINICAL PRACTICE: Increasing awareness of thirst and interventions to relieve it in clinical practice is likely to improve the quality of care for people with chronic heart failure. PMID- 25441538 TI - Feed analyses and their interpretation. AB - Compositional analysis is central to determining the nutritional value of feedstuffs for use in ration formulation. The utility of the values and how they should be used depends on how representative the feed subsample is, the nutritional relevance and analytical variability of the assays, and whether an analysis is suitable to be applied to a particular feedstuff. Commercial analyses presently available for carbohydrates, protein, and fats have improved nutritionally pertinent description of feed fractions. Factors affecting interpretation of feed analyses and the nutritional relevance and application of currently available analyses are discussed. PMID- 25441539 TI - Carbohydrate nutrition: managing energy intake and partitioning through lactation. AB - The objective of this article is to discuss the effects of dietary carbohydrates on energy intake and partitioning as cows progress through lactation. Understanding how diet interacts with the physiologic state as it changes through lactation is critical to maximize productivity, efficiency of production, and health of lactating dairy cows. PMID- 25441540 TI - Nonnutritional factors influencing response to the nutritional program. AB - In this article, the important role of the cow's environment is addressed, namely, the facilities that provide opportunities to eat, sleep, drink water, and socially interact. Research and anecdotal observation suggest that cow comfort is a critical factor to success of any nutritional program. PMID- 25441541 TI - Neck burn reconstruction with pre-expanded scapular free flaps. AB - BACKGROUND: The reconstruction of neck contracture deformities after severe burns is challenging. This is due to insufficient tissue to resurface the large defect after local flap transfer as well as the poor functional and cosmetic results after traditional methods such as skin grafting. We employed free transfer of pre expanded scapular flaps to reconstruct postburn neck deformities. METHODS: In the first stage, skin expansion was performed with tissue expanders ranging from 400 to 800 mL according to the neck defect size and expanders were filled to their end volumes. In the second stage, the contracture in the neck was released and the unstable scar was resected. The pre-expanded scapular flap was then harvested and transferred to the neck defect. Flap revisions were performed 3-12 months after flap transfer. RESULTS: A total of 12 flaps (100%) were successful. The contour, colour, and texture of flaps matched well to the nearby skin. The range of motion of the neck was significantly improved. The donor defects were closed directly except for one case, which required skin grafting. CONCLUSIONS: The free tissue transfer of pre-expanded scapular flap is a valuable tool in neck burn reconstruction. It can be used safely and effectively with minimal morbidity in selected patients. PMID- 25441542 TI - Pilot project in rural western Madhya Pradesh, India, to assess the feasibility of using LED and solar-powered lanterns to remove kerosene lamps and related hazards from homes. AB - BACKGROUND: Globally, 300,000 deaths are estimated to occur annually and the incidence is far greater as a large majority of burns are small and go unreported. Ninety-five percent of the global burden of burns is found in low- and middle-income countries; however, there is relatively little in the literature regarding effective primary prevention in these areas. Flame is the most common cause of burn in Madhya Pradesh, the central state of India. The most common demographic among the burn unit inpatient of Choithram hospital Indore, is young women from 21 to 40 years of age, whose burns are primarily caused by kerosene lamps. A non electrical source of illumination is essential for every household in rural areas due to the infrequent and poor power supply. At the baseline, 23 kerosene lamp burns were reported by villagers in the past 5 years among the study population of this pilot project. METHOD: A pilot project to investigate the strategies for reducing the incidence of domestic burns in rural villages around the city of Indore was performed, by replacing kerosene lamps with safer and more sustainable alternatives, including solar-powered and light emitting diode (LED) lamps. A total of 1042 households were randomly chosen from 18 villages within the Malwa region of Madhya Pradesh (population of 28,825) to receive the alternative light source (670 LED and 372 solar lamps). We investigated the efficacy of this strategy of reducing the incidence of burns, measured the social acceptance by villagers, and quantified the cost implications and availability of LED lamps in rural communities with a high incidence of burns. RESULTS: Replacing kerosene lamps with LED and solar alternatives was deemed socially acceptable by 99.34% of the participants and reduced the cost of lighting for impoverished rural villagers by 85% over 1 year. We successfully demonstrated a significant decrease in the use of kerosene lamps (p<0.01). More evidence is required to investigate the efficacy of this strategy in reducing burns. CONCLUSION: This pilot study highlights the viability of the approach of replacing kerosene lamps as an effective primary prevention strategy for reducing burns in rural areas. However, barriers remain to the wider adoption of these lamps, including accessibility and availability for the populations of rural India. PMID- 25441544 TI - Perforator detection with a hand-held Doppler device: importance of the learning curve. PMID- 25441543 TI - Quality of life of individuals treated in an outpatient burn treatment centre: application of the BSHS-R. AB - BACKGROUND: Burns are injuries that affect individuals' physical and emotional health and may impair their quality of life (QOL). This study aimed to evaluate the QOL of individuals from an outpatient burn treatment centre in southern Brazil, according to the Burn Specific Health Scale-Revised (BSHS-R), and to determine the relationships between sociodemographic variables, burns history and the mean domains of BSHS-R. METHODS: A cross-sectional study was carried out with 107 participants from July 2012 to January 2013 by administering the BSHS-R scale and a questionnaire to collect sociodemographic data and the participants' history of burns. Statistical analyses were performed comparing the scores obtained in the domains of the BSHS-R. Multiple linear regressions with the stepwise method were used to obtain a model that allowed the prediction of BSHS-R as a function of independent variables. RESULTS: A negative impact on the individuals' quality of life was revealed for the domains Simple Functional Ability, Work, Affect and Body Image and Interpersonal Relationships. Predictors of a poorer BSHS-R total score were: environment of trauma occurrence (reg. coefficient -0.39 95% CI -0.77;-0.01), gender (reg. coefficient -0.52 95% CI 0.82;-0.21), occupation (reg. coefficient -0.52 95% CI -0.86;-0.18) and place of residence (reg. coefficient -0.52 95% CI -0.83;-0.13). CONCLUSIONS: Sociodemographic determinants have the greatest effect on determining the QOL of individuals who have suffered burns. Therefore, actions to promote education on preventing burns in workplaces and homes are needed. PMID- 25441545 TI - In view of standardization: comparison and analysis of initial management of severely burned patients in Germany, Austria and Switzerland. AB - INTRODUCTION: Initial treatment of severely injured patients in German speaking trauma centers follows precise sequences. Several guidelines and training courses ensure a constant quality in providing evidence-based treatment for these patients. Similar standards, algorithms and guidelines for the treatment of severely burned patients are lacking. This raises the question about the current standard of care for burn victims in German speaking burn centers. In order to achieve standardization, as a first step this study surveys principles of burn room organization and management in these burn centers. MATERIAL AND METHODS: A questionnaire including 40 questions regarding burn room organization, personnel structure and qualification, infrastructural conditions and quality management was developed and sent to 21 level one burn centers in Germany, Austria and Switzerland. RESULTS: The rate of returned questionnaires was 81%. The analysis revealed varying personnel and infrastructural conditions in participating burn centers. Indications for admission to the burn room and admission procedures itself are different throughout surveyed hospitals. Individual standard operating procedure (SOP) for burn trauma admissions was available in most burn centers and nearly all participants register their burn trauma cases using an in-house burn register. CONCLUSION: The survey suggests a lack of standardization in personnel structure, infrastructure and treatment approach for the initial clinical care of severely burned patients in burn centers across the German speaking countries. Further evaluation of existing protocols and international standards in burn care is inevitable to develop standardized guidelines for burn care and to improve quality of care. PMID- 25441546 TI - Reply to: perforator detection with a hand-held Doppler device: importance of the learning curve. PMID- 25441547 TI - Identification of methicillin-resistant Staphylococcus aureus (MRSA) strains isolated from burn patients by multiplex PCR. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin resistant coagulase-negative staphylococci (MRCoNS) as important human pathogens are causes of nosocomial infections worldwide. Burn patients are at a higher risk of local and systemic infections with these microorganisms. OBJECTIVE: A screening method for MRSA by using a multiplex polymerase chain reaction (PCR) targeting the 16S ribosomal RNA (rRNA), mecA, and nuc genes was developed. The aim of the present study was to investigate the potential of this PCR assay for the detection of MRSA strains in samples from burn patients. METHODS: During an 11-month period, 230 isolates (53.11%) of Staphylococcus spp. were collected from burn patients. The isolates were identified as S. aureus by using standard culture and biochemical tests. DNA was extracted from bacterial colonies and multiplex PCR was used to detect MRSA and MRCoNS strains. RESULTS: Of the staphylococci isolates, 149 (64.9%) were identified as S. aureus and 81 (35.21%) were described as CoNS. Among the latter, 51 (62.97%) were reported to be MRCoNS. From the total S. aureus isolates, 132 (88.6%) were detected as MRSA and 17 (11.4%) were methicillin-susceptible S. aureus (MSSA). The presence of the mecA gene in all isolates was confirmed by using multiplex PCR as a gold standard method. CONCLUSION: This study presented a high MRSA rate in the region under investigation. The 16S rRNA-mecA-nuc multiplex PCR is a good tool for the rapid characterization of MRSA strains. This paper emphasizes the need for preventive measures and choosing effective antimicrobials against MRSA and MRCoNS infections in the burn units. PMID- 25441548 TI - Home hydrotherapy in the postoperative rehabilitation phase of the burn patients. PMID- 25441549 TI - Evaluation of two glucose meters and interference corrections for screening neonatal hypoglycemia. AB - BACKGROUND: Many neonatal intensive care and maternal units still use self monitoring of blood glucose (SMBG) devices as a tool to aid diagnosis despite the introduction of point-of-care testing (POCT) devices, which are known to have higher accuracy. We evaluated the performance of two glucose meters, the StatStrip (Nova Biomedical), a POCT device, and the Medisafe Mini (Terumo), an SMBG device, to detect hypoglycemia in neonates. In addition, we evaluated the interference of hematocrit, acetaminophen and ascorbic acid. METHODS: Whole blood samples were drawn from neonates who were at risk of hypoglycemia and analyzed with the StatStrip and Medisafe Mini. The results were further confirmed with blood gas analyzers ABL825 and BM6050. To evaluate the interference of hematocrit, acetaminophen and ascorbic acid, concentrated solutions of glucose and interfering substances were gravimetrically prepared and analyzed. RESULTS: Among the 222 blood samples analyzed, results from the StatStrip were more closely aligned to those of the ABL825 at all levels of glucose than the Medisafe Mini. CONCLUSION: StatStrip appears to be unaffected by hematocrit, ascorbic acid or acetaminophen. We recommend its use in neonates in hospital. Further studies are required to identify other interference effects. PMID- 25441550 TI - [Risks acceptability related to obstetrical epidural analgesia]. AB - OBJECTIVES: Evaluation of the acceptability of complications related to obstetrical epidural analgesia in two populations, parturients and anesthesiologists. STUDY DESIGN: Prospective, transversal, single center study. MATERIALS AND METHODS: Evaluation of the acceptability of complications associated with obstetric epidural analgesia performed using a questionnaire of six clinical scenarii in two populations: parturients cared at the University maternity of Nancy and anesthesiologists of Lorraine. Patients were interviewed by an anesthesiologist, physicians via Internet. Acceptability was assessed using two tools, the absolute acceptability with a visual analog scale and the relative acceptability obtained by classifying clinical scenario against each other, in ascending order of acceptability. RESULTS: One hundred and forty-six parturients and 87 anesthetists assessed the acceptability of the different scenarios. The three less serious scenarios (hypotension, failure, dural tap) were acceptable for both populations. One case (spinal hematoma) was unacceptable for parturients. Three cases of varying severity (failure, dural tap, plexus injury with sequelae) were judged significantly less acceptable by patients than physicians (5.9 vs. 7.9 [P<0.001], 5.75 vs. 8.1 [P<0.01], 4.1 vs. 5.1 [P=0.035]). Multivariate analysis did not show any predictive factor of acceptability in both populations. CONCLUSION: In this study, the overall acceptability of the inherent complications of epidural analgesia was good in the two populations. It was essentially based on the notion of severity and preventability. A large interindividual variability was observed and a better acceptance by the anesthesiologists. PMID- 25441551 TI - Why does methylene blue reduce methemoglobin in benzocaine poisoning but beneficially oxidize hemoglobin in cyanide poisoning? PMID- 25441552 TI - Glossary of terms for information technology and pearls of wisdom for implementation and use. AB - This glossary of terms is a primer on the vocabulary information technology professionals use and with which infection preventionists should be familiar. The author's comments are in italics. PMID- 25441553 TI - Reconciling reintegration: the complexity of economic and social reintegration of ex-combatants in Burundi. AB - The extent to which disarmament, demobilisation and reintegration (DDR) programmes initiated by state or multilateral agencies can realise the reintegration of ex-combatants remains debated. While some consider that DDR should have the ambition to result in long-term reintegration, others argue that DDR should focus on short-term goals. This paper explores experiences with the reintegration of ex-combatants in Burundi. It shows the interconnectedness of economic and social reintegration processes, and demonstrates that the reintegration of ex-combatants cannot be seen in isolation from the wider recovery and development context in which DDR is taking place. Moreover, the case demonstrates that reconciliation and social reintegration are deeply interconnected, to the extent that social reintegration may fail if reconciliation is not taken into account. Rather than a debate between long- and short-term goals, the focus should therefore be on increasing the understanding of reintegration processes and finding ways in which programmes can contribute to those. PMID- 25441554 TI - A new concept for tuberosity repair in hemiarthroplasty for fracture: use of a clamp and underlying ledge to form a trapdoor. AB - BACKGROUND: Sutures are the most common method for tuberosity repair in hemiarthroplasty for fracture. Despite numerous suggested patterns, tuberosity repair remains a weak point leading to poor functional results. This study mechanically tested a new mechanism that avoids difficulties sutures may engender. The hallmark of the prosthesis is a "trapdoor" effect. Low-profile metallic clamps with undersurface stoppers are screwed across the tuberosity tendon junction to an underlying ledge, creating a fixed metallic space. With cuff contraction, the tuberosities are too large to pull through this space. MATERIALS AND METHODS: Tests were carried out in line with the U.K. Human Tissue Authority regulations. Four-part fractures in 8 cadavers repaired with this method were subjected to simultaneous cyclic tension of 350N and passive glenohumeral motion for 8000 cycles. Both before and after machine stress, repairs were assessed by clasping each tuberosity with a forceps and attempting to displace it in a variety of directions. No movement was present before stressing. Any post-stress movement was considered a failure and recorded in millimeters. RESULTS: Six specimens after machine stress showed 0-mm movement (95% confidence interval, 34.9%-96.8%). Isolated movements of a single tuberosity occurred in 2 specimens. CONCLUSION AND DISCUSSION: The trapdoor completely withstood challenging elements of cyclic load and passive motion in 75% of cases. The device may represent an alternative to sutures. PMID- 25441555 TI - Prospective evaluation of clinical and radiologic factors predicting return to activity within 6 months after arthroscopic rotator cuff repair. AB - BACKGROUND: This study aimed to report the outcome of patients who underwent arthroscopic rotator cuff repair (ARCR) and to determine the factors associated with return to work and activity. MATERIALS: Three hundred sixty-five patients who underwent ARCR were prospectively evaluated. The cohort was divided into 2 groups based on clinical results at 6 months. Group A consisted of patients who were considered to have a satisfactory outcome based on return to their previous professional or spare-time activities. Group B consisted of patients with an unsatisfactory outcome based on a lack of return to normal work or activities. RESULTS: Of the patients, 305 had a satisfactory outcome (group A) and 60 were categorized as having an unsatisfactory outcome (group B). On multivariate analysis, preoperative factors associated with group B included female gender and heavy manual labor. Postoperative bursitis on ultrasound at 6 months was associated with being in group B. Lack of tendon healing was not associated with group B. However, if a patient without healing had persistent pain at 6 months, the pain persisted at 9 months. CONCLUSION: ARCR is an effective procedure that leads to significant improvement in pain, function, and tendon healing in most cases. However, in 1 of 5 cases, patients were unable to resume normal activity at 6 months postoperatively. Persistent limitation at 6 months was associated with female gender, heavy manual workers, and the presence of postoperative persistent bursitis. PMID- 25441556 TI - Does bony increased-offset reverse shoulder arthroplasty decrease scapular notching? AB - BACKGROUND: The purpose of this cohort study was to compare scapular notching rates, range of motion, and functional outcomes between patients who underwent a standard Grammont-style reverse shoulder arthroplasty (RSA) and patients who underwent bony increased-offset reverse shoulder arthroplasty (BIO-RSA) at a minimum of 2 years' follow-up. We hypothesized that the BIO-RSA cohort would have lower notching rates and improved rotational range of motion; however, validated outcome scores between cohorts would be no different. METHODS: A comparative cohort study was designed after a sample size calculation. A total of 40 patients were studied with 20 in each cohort (RSA vs BIO-RSA). All patients underwent an interview and physical examination. Outcomes included range of motion; shoulder strength; Disabilities of the Arm, Shoulder and Hand (DASH) score; American Shoulder and Elbow Surgeons score; Simple Shoulder Test score; Constant score; and Global Rating of Change scale score. Radiographs were obtained for all patients and examined for scapular notching. RESULTS: When we compared demographic characteristics between the standard RSA and BIO-RSA cohorts, including age, sex, and follow-up duration, there were no significant differences between groups (P > .05). In addition, there were no significant differences between cohorts when we compared forward elevation (P = .418); external rotation (P = .999); internal rotation (P = .071); strength (P > .376); Disabilities of the Arm, Shoulder and Hand score (P = .229); American Shoulder and Elbow Surgeons score (P = .579); Simple Shoulder Test score (P = .522); Constant score (P = .917); or Global Rating of Change scale score (P = .167). The frequency of scapular notching, however, was significantly higher (P = .022) in the RSA cohort than in the BIO-RSA cohort: 75% versus 40%. CONCLUSIONS: Although the scapular notching rate was significantly higher in the standard RSA group, no other outcome measures were statistically different, including range of motion, strength, and validated outcome scores. PMID- 25441557 TI - Comparative analysis of anatomic and reverse total shoulder arthroplasty: in hospital outcomes and costs. AB - BACKGROUND: The rate of shoulder arthroplasty has continued to increase at an exponential rate during the past decade in large part owing to approval by the Food and Drug Administration of reverse shoulder arthroplasty. Whereas reverse shoulder arthroplasty has resulted in expanded surgical indications, there are numerous reports of relatively high complication rates. The increased prevalence of both anatomic and reverse shoulder arthroplasty underscores the need to elucidate whether perioperative outcomes are influenced by type of total shoulder arthroplasty. The purpose of this study was to determine the impact of shoulder arthroplasty type, anatomic or reverse, with respect to perioperative adverse events, in-hospital death, prolonged hospital stay, nonroutine disposition, and hospital charges in a nationally representative sample. METHODS: By use of the Nationwide Inpatient Sample database from 2011, the first year that reverse total shoulder arthroplasty received a unique International Classification of Diseases, Ninth Revision procedure code, an estimated 51,052 patients undergoing total shoulder arthroplasty were separated into anatomic total shoulder arthroplasty (58%) and reverse total shoulder arthroplasty (43%). Comparisons of early outcome measures between anatomic and reverse total shoulder cohorts were performed by bivariate and multivariable analyses with logistic regression modeling. RESULTS: Compared with anatomic shoulder arthroplasty recipients, patients undergoing reverse shoulder replacement were at higher risk for in-hospital death, multiple perioperative complications, prolonged hospital stay, increased hospital cost, and nonroutine discharge. CONCLUSION: Despite the expanding indications for reverse shoulder arthroplasty, it is an independent risk factor for inpatient morbidity, mortality, and hospital costs and should perhaps be offered more judiciously and performed in the hands of appropriately trained shoulder specialists. PMID- 25441558 TI - Accuracy of the glenohumeral subluxation index in nonpathologic shoulders. AB - BACKGROUND: Correction of posterior humeral subluxation, measured by the humeral subluxation index (HSI) according to Walch, is necessary in total shoulder arthroplasty to prevent early loosening. The 3-dimensional (3D) measurement of the shoulder is becoming well accepted and common practice as it overcomes positional errors to which 2-dimensional (2D) glenohumeral measurements are prone. The first objective was to describe the HSI in a nonpathologic population with the 2D HSI according to Walch and a newly described 3D HSI method. The second objective was to compare both measuring methods with each other. METHODS: In 151 nonpathologic shoulders, the 2D HSI was measured on the midaxial computed tomography scan cut of the scapula. The 3D HSI, based on the native glenoid plane, was defined as [formula in text], in which X is the projection of the center of the humeral head to the anteroposterior axis of the glenoid fossa and R is the radius of the humeral head. Both measuring methods were compared with each other. Correlation was determined. Interobserver and intraobserver reliability of the 3D HSI was measured. RESULTS: The mean 3D HSI (51.5% +/- 2.7%) was significantly (P < .001) more posterior than the mean 2D HSI (48.7% +/- 5.2%), with a mean difference of 2.9% +/- 5.6%. No correlation was found between the 2D and 3D HSI. The interobserver and intraobserver reliability was excellent. CONCLUSION: The 2D HSI seems to underestimate the humeral subluxation compared with a 3D reliable equivalent. PMID- 25441559 TI - Effects of osteoarthritis on load transfer after cemented total shoulder arthroplasty. AB - BACKGROUND: Total shoulder arthroplasty is commonly performed to treat glenohumeral osteoarthritis (OA); however, little is understood of the mechanics of the reconstructed OA shoulder. We sought to establish the effects of OA induced changes in bone density and retroversion angle on load transfer and stress distribution in the bone-implant system of the scapula. METHODS: We developed finite element models of reconstructed healthy and OA scapulas with a virtually implanted glenoid prosthesis design. For the OA scapula, models with uncorrected and corrected retroversion were created. Loads were applied at the center or posteriorly on the glenoid surface. RESULTS: Our results suggest that with reconstruction of the corrected glenoid with a contemporary implant, cement stresses increase and the load transfer pattern changes with eccentric loads. The load transfer and local stresses in the bone-implant system in the retroverted glenoid are less sensitive to changes in loading location. Furthermore, the load transfer in the OA glenoid is less sensitive to the effect of peg proximity to the cortical shell than in the healthy glenoid. CONCLUSION: We provided evidence of how load sharing is altered among healthy, corrected OA, and retroverted OA glenoids. We demonstrated that correction of retroversion in OA glenoids may actually increase the risk for stress shielding and cement failure compared with retroverted glenoids, and OA patients can accommodate shorter pegs because of the higher glenoid bone stiffness in the OA glenoid. PMID- 25441560 TI - Which parameters affect medium- to long-term results after angular stable plate fixation for proximal humeral fractures? AB - BACKGROUND: Very little information on medium- to long-term results is available for surgically treated proximal humeral fractures. The aim of this prospective treatment study was to present long-term results after angular stable plate fixation of displaced proximal humeral fractures and to detect which specific patient- and fracture-related parameters affect the clinical outcome. METHODS: We performed a prospective clinical and radiologic evaluation of 77 patients with a displaced proximal humeral fracture (28 Neer 2-part, 38 3-part, and 11 4-part fractures; 28 AO A fractures, 30 AO B fractures, and 19 AO C fractures) treated with angular stable plate fixation after a mean follow-up period of 96 months (range, 74-133 months). We assessed outcomes with the Constant, University of California-Los Angeles (UCLA), and Disabilities of the Arm, Shoulder, and Hand (DASH) scores and evaluated specific patient- and fracture-related parameters including complications. RESULTS: The mean Constant, University of California-Los Angeles (UCLA), and Disabilities of the Arm, Shoulder, and Hand (DASH) scores were 79, 31, and 12 points. Reasons for revisions were implant-related impingement (n = 13), screw perforation (n = 10), infection (n = 4), and secondary fracture displacement (n = 1). There was a significant association between worse score results and occurrence of secondary fracture displacement, screw perforation, residual bone deformities, and a rotator cuff defect at follow up. CONCLUSIONS: Good medium- to long-term results after angular stable plate fixation of displaced proximal humeral fracture can be expected. A reconstruction within a range of 15 degrees in both anteroposterior and axillary views and <5 mm tuberosity displacement should be the aim of head-preserving surgery to prevent complications, such as secondary fracture displacement and screw perforation, and a less favorable long-term result. PMID- 25441561 TI - Outcomes of staged bilateral reverse shoulder arthroplasties for rotator cuff tear arthropathy. AB - BACKGROUND: The purpose of this study was to evaluate outcomes in patients with rotator cuff tear arthropathy after staged bilateral reverse shoulder arthroplasties (RSAs) and to compare them with an age-, gender-, and diagnosis matched control group with a unilateral RSA. METHODS: We identified 11 patients with bilateral RSAs for rotator cuff tear arthropathy with a minimum of 2-year follow-up in a prospective shoulder arthroplasty registry. The bilateral group was matched to a control group of 19 patients with a unilateral RSA. Shoulder function scores, mobility, patient satisfaction, and activities of daily living were assessed preoperatively and at final follow-up. RESULTS: There was no statistical difference between the first RSA or second RSA and the control group regarding age, gender, or follow-up. No group differences were noted preoperatively for shoulder function scores or mobility (P > .10). All groups significantly improved on all shoulder function scores (Constant score, American Shoulder and Elbow Surgeons score, Western Ontario Osteoarthritis of the Shoulder index, Single Assessment Numeric Evaluation score) and mobility at final follow up (all P < .01). There were no significant differences in shoulder function scores or mobility between the first and second RSA in the bilateral group or between either shoulder in the bilateral group and the unilateral group (all P > .10). Patient satisfaction improved and patients were successfully able to perform many important activities of daily living after bilateral RSAs. CONCLUSIONS: Patients with bilateral rotator cuff tear arthropathy can be advised that staged bilateral RSAs can be successful when indicated. Improvements in shoulder function scores, patient satisfaction, and mobility are possible for both the first RSA and the second RSA. PMID- 25441562 TI - Upper limb kinematics after arthroscopic and open shoulder stabilization. AB - BACKGROUND: Shoulder joint stability mediated by proprioception is often quantified by arm repositioning tests (i.e., static end-position accuracy), overlooking ongoing movement quality. This study assessed movement quality by adopting smoothness-related kinematic descriptors. We compared performance of healthy controls with that of patients in arthroscopic shoulder stabilization and open shoulder stabilization groups. We hypothesized that arm kinematics after arthroscopic intervention would more closely resemble healthy movements compared with patients after open shoulder stabilization surgery. METHODS: Healthy controls (N = 14) were compared with patients after arthroscopic shoulder stabilization (N = 10) and open shoulder stabilization (N = 12). Right-hand dominant subjects (the affected side in patients) performed 135 unconstrained 3 dimensional pointing movements toward visual targets (seen through pinhole goggles; i.e., no arm vision). Arm kinematic data were recorded and offline analyzed to obtain hand tangential velocity profiles further used to compute the acceleration-to-movement time ratio, peak-to-mean velocity ratio, and number of velocity peaks ("symmetry," "proportion," and "fragmentation" features, respectively). Parametric and nonparametric statistics were used for comparisons (P <= .05). RESULTS: Control and arthroscopic shoulder stabilization groups presented similar acceleration-to-movement time ratio and peak-to-mean velocity ratio. Both groups differed from the open shoulder stabilization group (P = .001). Distributions of velocity peaks for control and arthroscopic shoulder stabilization groups were similar, whereas open shoulder stabilization and control subjects differed significantly (P = .028). CONCLUSIONS: Movement quality mediated by proprioception in arthroscopic shoulder stabilization patients matches that of healthy controls, whereas performance in open shoulder stabilization patients seems inferior compared with that in healthy controls, as assessed by smoothness-related measures (less symmetrical, more fragmented movements). PMID- 25441563 TI - Results of closed management of acute dislocation after reverse shoulder arthroplasty. AB - BACKGROUND: Postoperative instability continues to be one of the most common complications limiting outcomes of reverse shoulder arthroplasty (RSA). The optimal management of this complication remains unknown. The purpose of this study was to evaluate the outcomes of patients with postoperative dislocation after RSA managed with closed reduction. METHODS: All patients who were treated with a closed reduction for dislocation after RSA in the period between May 2002 and September 2011 were identified and retrospectively reviewed. Final outcomes including recurrent instability, need for revision surgery, American Shoulder and Elbow Surgeons outcome score, and range of motion were evaluated. RESULTS: A total of 21 patients were identified. Nearly 50% of cases (10 of 21) had previous surgery, with 80% (8 of 10) of these being previous arthroplasty. The average time to first dislocation was 200 days, with 62% (13 of 21) occurring in the first 90 days. At average follow-up of 28 months, 62% of these shoulders remained stable (13 of 21), 29% required revision surgery (6 of 21), and 9% remained unstable (2 of 21). The average American Shoulder and Elbow Surgeons score was 68.0 for patients treated with closed reduction for instability and 62.7 for those treated with revision surgery (P = .64). DISCUSSION: This study shows that an initial dislocation episode after RSA with use of this implant can be successfully managed with closed reduction and temporary immobilization in more than half of cases. Given that outcomes after revision surgery are not different from those after closed treatment, we would continue to recommend an initial attempt at closed reduction in the office setting in all cases of postoperative RSA dislocation. PMID- 25441564 TI - Reverse total shoulder arthroplasty: a biomechanical evaluation of humeral and glenosphere hardware configuration. AB - BACKGROUND: Various reverse total shoulder arthroplasty (rTSA) implant options are available for the humeral and glenosphere components. This study used a cadaveric biomechanical shoulder simulator to evaluate how hardware configurations in 2 common rTSA systems affect (1) abduction/adduction range of motion (ROM), (2) rotational ROM, and (3) forces to elevate the arm. METHODS: Seven pairs of shoulders were tested on a biomechanical shoulder simulator before and after rTSA implantation. The Aequalis Reverse Shoulder (Tornier, Edina, MN, USA) and the Reverse Shoulder Prosthesis (RSP; DJO Surgical, Austin, TX, USA) were implanted in opposing shoulders. Aequalis implant options included humeral polymer insert thickness and eccentricity and glenosphere tilt. RSP implant options included glenosphere diameter and lateralization, humeral shell offset, and polymer insert depth. RESULTS: Both the RSP and Aequalis shifted the center of rotation inferior and medially compared with native shoulders (P < .001). Increased Aequalis insert thickness reduced adduction (P < .003) and internal/external (P < .028) passive ROM. The 10 degrees inferiorly tilted glenosphere increased deltoid abduction forces (P < .032). In the RSP, smaller glenosphere diameter (P < .012), a semiconstrained humeral insert (P < .023), and a neutral humeral shell offset (P < .002) all decreased adduction deficit, whereas lateral glenosphere offset increased passive abduction ROM (P < .028). Increased humeral shell offset decreased passive internal/external rotation ROM (P < .050). DISCUSSION: Hardware configurations in rTSA have different effects on passive ROM and deltoid forces required for abduction. Identifying these changes may guide surgical decision making during rTSA placement. PMID- 25441565 TI - The impact of faulty posture on rotator cuff tears with and without symptoms. AB - HYPOTHESIS: We hypothesized that the prevalence of rotator cuff tears would be higher among individuals with poor posture, regardless of the presence of symptoms. METHODS: The study initially comprised 525 residents of a mountain village who participated in an annual health check. Participants completed a background questionnaire, and physical examinations were performed to evaluate shoulder function. Ultrasonographic examinations were also performed to identify rotator cuff tears, and participants were grouped according to the presence or absence of tears. Posture was classified by 2 observers into 4 types according to the classification of Kendall, as follows: ideal alignment, kyphotic-lordotic posture, flat-back posture, and sway-back posture. Univariate analyses were performed to compare differences in background characteristics between groups, then multivariate analysis was performed to identify those factors associated with rotator cuff tears. RESULTS: Final analysis was performed for 379 participants (135 men, 244 women; mean age, 62.0 years; range, 31-94 years) showing the same posture classification from both observers. Of these, 93 (24.5%) showed rotator cuff tear in one shoulder and 45 (11.9%) showed tears in both. Prevalence of rotator cuff tears was 2.9% with ideal alignment, 65.8% with kyphotic-lordotic posture, 54.3% with flat-back posture, and 48.9% with sway-back posture. Logistic regression analysis identified increased age, abnormal posture, and past pain as factors associated with rotator cuff tears. CONCLUSIONS: Postural abnormality represented an independent predictor of both symptomatic and asymptomatic rotator cuff tears. These results may help define preventive measures for rotator cuff tears and in design ing rehabilitation therapies for shoulder disease. PMID- 25441566 TI - Graft osteolysis and recurrent instability after the Latarjet procedure performed with bioabsorbable screw fixation. AB - HYPOTHESIS AND BACKGROUND: The Latarjet procedure is a reliable treatment of recurrent anterior shoulder instability. The coracoid process is usually fixed with metallic screws; however, these can lead to irritation and the necessity for hardware removal and also can produce artifacts on imaging studies. The use of resorbable screws could avoid these complications. The purpose of this study was to assess the clinical results of the Latarjet procedure performed with bioabsorbable screws in addition to healing of the graft and resorption of the screws. METHODS: In 2009, we performed a prospective study (case series, LEVEL OF EVIDENCE: IV) of 11 patients (12 shoulders) who underwent a Latarjet procedure fixed with resorbable screws. Each patient was observed clinically and had a computed tomography scan at 3 months and 2 years of follow-up. RESULTS: Every graft healed at 3-month follow-up. At 2-year follow-up, 4 patients had at least one instability episode, and one underwent a revision surgery. Three of these 4 patients were unhappy or disappointed. The Walch-Duplay score was excellent or good for 7 shoulders and medium or poor for 5. Screw resorption appeared complete in every case. No drill hole enlargement was observed. Every drill hole was partially filled with bone. Of 12 shoulders, 8 (66.67%) were associated with a severe osteolysis and an almost complete disappearance of the graft. CONCLUSION: Coracoid graft osteolysis, previously reported after the Latarjet procedure, appears to be exacerbated with a risk of complete disappearance of the graft when the procedure is performed with the bioabsorbable screws used in this study. PMID- 25441567 TI - Extracorporeal shockwave therapy improves short-term functional outcomes of shoulder adhesive capsulitis. AB - BACKGROUND: The treatment of adhesive capsulitis is a dilemma for orthopaedic rehabilitation specialists. In this study, we assessed whether extracorporeal shockwave therapy (ESWT) improves the functional outcome of primary shoulder adhesive capsulitis. METHODS: In this prospective, randomized, controlled, single blind clinical trial, we enrolled 40 patients with primary adhesive capsulitis to assess whether ESWT can improve the functional outcome of primary adhesive capsulitis better than oral steroid therapy. Patients were allocated to the oral steroid group or ESWT group with randomization. Functional outcome evaluations were performed using the Constant Shoulder Score (CSS) and Oxford Shoulder Score. RESULTS: Both groups showed significant improvement in the Oxford Shoulder Score evaluation throughout the study period. In the ESWT group, the total CSS and range of motion (ROM) parameter of the CSS in the ESWT group showed significant improvement from the fourth week that was better than that in the steroid group; the activities-of-daily living (ADL) parameter of the CSS achieved significance and was better than that in the steroid group at the sixth week. For the steroid group, pain was significantly reduced from baseline to the fourth week of the study; ADL and ROM improved at the fourth to 12th week. For the ESWT group, ADL and ROM improvements were significant from baseline to the sixth week. CONCLUSION: Our results showed that ESWT can be an alternative treatment, at least in the short-term, for primary adhesive capsulitis of the shoulder. In addition, all of the side effects of ESWT were transient and tolerable. PMID- 25441569 TI - Unique application of a metacarpophalangeal joint implant as a radial head prosthesis. PMID- 25441568 TI - A systematic review and pooled analysis of the prevalence of rotator cuff disease with increasing age. AB - Hypothesis and background: Abnormalities of the rotator cuff are more common with age, but the exact prevalence of abnormalities and the extent to which the presence of an abnormality is associated with symptoms are topics of debate. Our aim was to review the published literature to establish the prevalence of abnormalities of the rotator cuff and to determine if the prevalence of abnormalities increases with older age in 10-year intervals. In addition, we assessed prevalence in 4 separate groups: (1) asymptomatic patients, (2) general population, (3) symptomatic patients, and (4) patients after shoulder dislocation. METHODS: We searched PubMed, EMBASE, and the Cochrane Library up to February 24, 2014, and included studies reporting rotator cuff abnormalities by age. Thirty studies including 6112 shoulders met our criteria. We pooled the individual patient data and calculated proportions of patients with and without abnormalities per decade (range, younger than 20 years to 80 years and older). RESULTS: Overall prevalence of abnormalities increased with age, from 9.7% (29 of 299) in patients aged 20 years and younger to 62% (166 of 268) in patients aged 80 years and older (P < .001) (odds ratio, 15; 95% confidence interval, 9.6-24; P < .001). There was a similar increasing prevalence of abnormalities regardless of symptoms or shoulder dislocation. DISCUSSION AND CONCLUSION: The prevalence of rotator cuff abnormalities in asymptomatic people is high enough for degeneration of the rotator cuff to be considered a common aspect of normal human aging and to make it difficult to determine when an abnormality is new (e.g., after a dislocation) or is the cause of symptoms. PMID- 25441570 TI - Reconstruction of active elbow flexion in patients with radial ray deficiency: report of two cases. PMID- 25441571 TI - Total elbow arthroplasty: a prospective clinical outcome study of Discovery Elbow System with a 4-year mean follow-up. AB - BACKGROUND: Total elbow arthroplasty (TEA) is increasingly used for the treatment of advanced elbow conditions to reduce pain and improve function. However, TEA is still associated with a higher complication rate than total hip and knee arthroplasty despite advances in the design and surgical techniques. This prospective clinical study reports the outcome of the Discovery Elbow System (Biomet, Warsaw IN, USA), which has been in clinical use in the United Kingdom since 2003. METHODS: The study included a total of 100 Discovery Elbows (April 2003 to January 2010) with a minimum 2-year follow-up, including 75 primary and 25 revisions (60% women and 40% men; mean age, 62 years). Outcome was assessed by means of the Liverpool Elbow Score, pain experience, patient satisfaction, range of motion, and radiographic imaging. RESULTS: The mean follow-up period was 48.5 months (range, 24-108 months). The Liverpool Elbow Score improved from 3.79 to 6.36 (P < .001). The percentage of pain-free patients was substantially increased from 7% preoperatively to 64% at the final follow-up. The patient satisfaction rate was over 90%. The flexion-extension arc and pronation-supination arc increased from 72 degrees to 93 degrees and from 86 degrees to 111 degrees , respectively (P < .001). Major postoperative complications included deep infection (2%), progressive aseptic loosening requiring revision (primary, 5%; revision 12%), persistent ulnar neuropathy (3%), and periprosthetic fracture (primary, 6.8%; revision, 8%). CONCLUSION: The Discovery Elbow System resulted in improved function, reduced pain, and high patient satisfaction. Long-term results are required to assess the survivorship of this system. PMID- 25441572 TI - Distal peripheral neuropathy after open and arthroscopic shoulder surgery: an under-recognized complication. AB - HYPOTHESIS: Distal peripheral neuropathy (DPN) is an under-reported complication after anatomic total shoulder arthroplasty (TSA), reverse shoulder arthroplasty (RSA), and arthroscopic rotator cuff repair (RCR). METHODS: We conducted a retrospective review of patients undergoing shoulder arthroplasty or arthroscopic RCR by 4 shoulder surgeons during a 2-year period. The primary outcome measure was the diagnosis of DPN, defined as carpal tunnel syndrome, cubital tunnel syndrome, ulnar tunnel syndrome, and distal radial sensory neuropathy. Patient demographics and clinical course of DPN were recorded. Mean follow-up was 21, 15, and 12 months for TSA, RSA, and RCR, respectively. RESULTS: Postoperatively, 6 of 85 TSA (7.1%), 7 of 57 RSA (12.3%), and 21 of 753 RCR (2.79%) patients were diagnosed with DPN. The most common neuropathy was cubital tunnel syndrome for TSA and RSA and carpal tunnel syndrome for RCR. The risk of DPN was higher for shoulder arthroplasty (TSA and RSA) compared with the RCR group. After nonsurgical treatment of DPN, complete resolution of symptoms occurred in 33.3% of TSA, 42.86% of RSA, and 71.43% of RCR patients. However, 16.7% of TSA, 14.3% of RSA, and 4.76% of RCR patients with DPN required surgical decompression; 100% of the patients undergoing surgical decompression had complete resolution of symptoms. CONCLUSION: DPN is a relatively common complication after shoulder surgery. When it occurs, DPN will often resolve with nonoperative management. Surgical decompression is an effective treatment option in refractory cases. PMID- 25441573 TI - Patient perception of physician reimbursement in elective shoulder surgery. AB - BACKGROUND: A previous study revealed that patients perceived physician reimbursement to be much higher than current Medicare schedules for hip and knee replacement. The purpose of this study was to evaluate patient perception of surgeon reimbursement for total shoulder replacement (TSA) and rotator cuff repair (RCR). METHODS: The study surveyed 250 patients. Patients were asked what they believe a surgeon should be reimbursed for performing TSA and RCR. Patients were then asked to estimate what Medicare reimbursed for each of these procedures. We then revealed the Medicare reimbursement rate for TSA and RCR, and patients were asked to comment. Finally, patients were asked whether surgeons with advanced shoulder training should receive additional payments. RESULTS: Patients thought that surgeons should receive $13,178 for TSA and $8459 for RCR. Patients estimated actual Medicare reimbursement was $7177 for TSA and $4692 for RCR. Eighty percent of patients stated that Medicare reimbursement was too low for TSA, 75% thought that payment for RCR was lower than what it should be. Less than 1% of patients felt that it was higher than it should be. A total of 87% of patients thought that surgeons with advanced shoulder training should be reimbursed at a higher rate. CONCLUSION: Patients perceived the values of TSA and RCR were much higher than current Medicare schedules. This is in agreement with prior surveys. Continued decreases in Medicare reimbursements may force surgeons to not participate in Medicare and create a potential access issue. Further investigation should focus on identifying how many surgeons may opt out. PMID- 25441574 TI - Biomechanics of reverse total shoulder arthroplasty. AB - Reverse total shoulder arthroplasty is an effective procedure for treatment of glenohumeral joint disease among patients with severe rotator cuff deficiency. Improvements in prosthetic design are the result of an evolved understanding of both shoulder and joint replacement biomechanics. Although modern generations of the reverse shoulder prosthesis vary in specific design details, they continue to adhere to Grammont's core principles demonstrated by his original Delta III prosthesis. This review article discusses the biomechanics of reverse total shoulder arthroplasty with a focus on elements of implant design and surgical technique that may affect stability, postoperative complications, and functional outcomes. PMID- 25441575 TI - Measuring illness beliefs in patients with lower extremity injuries: reliability and validity of the Dutch version of the Somatic Pre-Occupation and Coping questionnaire (SPOC-NL). AB - INTRODUCTION: Positive coping strategies, illness perceptions and recovery expectations are associated with better clinical outcomes and earlier return to work after injuries. The Somatic Pre-Occupation and Coping (SPOC) questionnaire captures illness beliefs and coping towards recovery of physical function and return to work after surgical treatment of tibial shaft fractures. The aim of this study was to translate and culturally adapt the SPOC into Dutch (SPOC-NL) and evaluate its reliability and validity in patients with lower extremity injuries. MATERIALS: The SPOC-NL contains four subscales: Somatic complaints, Coping, Energy, and Optimism. Patients treated for lower extremity injuries (N=106) completed the SPOC-NL, Short Form-36 and Short Musculoskeletal Function Assessment (SMFA-NL) questionnaire, and reported their current work status and self-perceived work ability. To assess test-retest reliability, 56 patients completed the SPOC-NL for a second time two weeks after the first administration of the SPOC-NL. We calculated Cronbach's Alpha, intraclass correlation coefficients (ICCs) and G coefficients to measure internal consistency and overall reliability, and used the Bland and Altman method to assess bias between test and retest SPOC-NL scores. To determine construct validity, we explored 16 a priori hypotheses regarding correlations between SPOC-NL scores and subscale scores and SF-36, SMFA-NL, work status and work ability. RESULTS: Internal consistency was good to excellent, with Cronbach's Alpha values ranging between 0.79 and 0.94 and G coefficients ranging between 0.77 and 0.95. Test-retest reliability was also good, since high ICCs (0.72-0.91) and G coefficients (0.82 0.94) were found. Construct validity of the SPOC-NL was good, as 75% of the predefined hypotheses were confirmed. Compared to participants who were on sick leave or receiving disability benefits, participants with a paid job had significantly higher scores on the total score and the subscales Somatic complaints and Energy of the SPOC-NL. Participants with high work ability also had significantly higher scores on the total score and all subscales than participants with low work ability. DISCUSSION AND CONCLUSIONS: The SPOC-NL is a reliable and valid measure for the assessment of illness beliefs and coping towards recovery and it is strongly related to work status and self-perceived ability to work in patients with lower extremity injuries. PMID- 25441576 TI - Commercially available gaming systems as clinical assessment tools to improve value in the orthopaedic setting: a systematic review. AB - INTRODUCTION: Commercially available gaming systems (CAGS) such as the Wii Balance Board (WBB) and Microsoft Xbox with Kinect (Xbox Kinect) are increasingly used as balance training and rehabilitation tools. The purpose of this review was to answer the question, "Are commercially available gaming systems valid and reliable instruments for use as clinical diagnostic and functional assessment tools in orthopaedic settings?" and provide a summary of relevant studies, identify their strengths and weaknesses, and generate conclusions regarding general validity/reliability of WBB and Xbox Kinect in orthopaedics. MATERIALS AND METHODS: A systematic search was performed using MEDLINE (1996-2013) and Scopus (1996-2013). Inclusion criteria were minimum of 5 subjects, full manuscript provided in English or translated, and studies incorporating investigation of CAG measurement properties. Exclusion criteria included reviews, systematic reviews, summary/clinical commentaries, or case studies; conference proceedings/presentations; cadaveric studies; studies of non-reversible, non orthopaedic-related musculoskeletal disease; non-human trials; and therapeutic studies not reporting comparative evaluation to already established functional assessment criteria. All studies meeting inclusion and exclusion criteria were appraised for quality by two independent reviewers. Evidence levels (I-V) were assigned to each study based on established methodological criteria. RESULTS: 3 Level II, 7 level III, and 1 Level IV studies met inclusion criteria and provided information related to the use of the WBB and Xbox Kinect as clinical assessment tools in the field of orthopaedics. Studies have used the WBB in a variety of clinical applications, including the measurement of center of pressure (COP), measurement of medial-to-lateral (M/L) or anterior-to-posterior (A/P) symmetry, assessment anatomic landmark positioning, and assessment of fall risk. However, no uniform protocols or outcomes were used to evaluate the quality of the WBB as a clinical assessment tool; therefore a wide range of sensitivities, specificities, accuracies, and validities were reported. CONCLUSION: Currently it is not possible to make a universal generalization about the clinical utility of CAGS in the field of orthopaedics. However, there is evidence to support using the WBB and the Xbox Kinect as tools to obtain reliable and valid COP measurements. The Wii Fit Game may specifically provide reliable and valid measurements for predicting fall risk. PMID- 25441577 TI - Early tracheostomy in trauma patients saves time and money. AB - INTRODUCTION: Patients suffering traumatic brain and chest wall injuries are often difficult to liberate from the ventilator yet best timing of tracheostomy remains ill-defined. While prior studies have addressed early versus late tracheostomy, they generally suffer from the use of historical controls, which cannot account for variations in management over time. Propensity scoring can be utilized to identify controls from the same patient population, minimizing impact of confounding variables. The purpose of this study was to determine outcomes associated with early versus late tracheostomy by application of propensity scoring. METHODS: Patients requiring intubation within 48h and receiving tracheostomy from January 2010 to June 2012 were identified. Early tracheostomy (ET) was a tracheostomy performed by the fifth hospital day. ET patients were matched to late tracheostomy patients (LT, tracheostomy after day 5) using propensity scoring and compared for multiple outcomes. Cost for services was calculated using average daily billing rates at our institution. RESULTS: One hundred and six patients were included, 53 each in the ET (mean day tracheostomy=4) and the LT (mean day tracheostomy=10) cohorts. The average age was 47 years and 94% suffered blunt injury, with an average NISS of 23.7. Patients in the ET group had significantly shorter TICU LOS (21.4 days vs. 28.6 days, p<0.0001) and significantly fewer ventilator days (16.7 days vs. 21.9, p<0.0001) compared to the LT group. ET patients also had significantly less VAP (34% vs. 64.2%, p=0.0019). CONCLUSION: In the current era of increased health care costs, early tracheostomy significantly decreased both pulmonary morbidity and critical care resource utilization. This translates to an appreciable cost savings, at minimum $52,173 per patient and a potential total savings of $2.8million/year for the entire LT cohort. For trauma patients requiring prolonged ventilator support, early tracheostomy should be performed. PMID- 25441578 TI - UK Triage the validation of a new tool to counter an evolving threat. AB - INTRODUCTION: Major Incidents (MI) occur frequently and their unpredictable nature makes prospective research difficult and largely unethical. A key step in MI management is triage; the identification of the critically injured. Within a MI environment this is commonly performed using simple physiological 'tools', such as the Triage Sieve (TS). However the most commonly used tools appear to lack an evidence base. In a previous study, the authors used a military population to compare the performance of the TS to the Military Sieve (MS) at predicting need for Life-Saving Intervention (LSI). The MS differs only with the addition of a measurement of consciousness. The outcome from this study was that the MS outperformed the TS, but could be further improved with small changes to its physiological parameters, the Modified Military Sieve (MMS). MATERIALS AND METHODS: Physiological data and interventions performed within the Emergency Department (ED) and Operating Theatre were prospectively collected for consecutive adult trauma patients (>18years) presenting to the ED at Camp Bastion, Afghanistan between March and September 2011. All patients receiving a LSI were considered Gold Standard Priority One. Patients were triaged using the TS, MS, MMS, START (ST) and Careflight (CF) triage tools. Sensitivities and specificities were estimated with 95% confidence intervals and differences were checked for statistical significance using a McNemar test with Bonferroni correction. RESULTS: 482 patients presented to the ED during the study period, sufficient data was recorded for 335 (71%) with 199 (59%) P1s. The MMS (sensitivity 68.3%, specificity 79.4%) showed an absolute increase in sensitivity over existing tools ranging from 5.0% (MS) to 23.6% (CF). There was a statistically significant difference (P = 0.0005) between the MMS and MS. DISCUSSION: A key limitation to this study, is the use of a military cohort to validate the MMS, a tool which itself was developed using military data. The mechanism of injury also is unlikely to translate fully to the civilian population. CONCLUSIONS: Within a military population, the MMS outperforms existing MI triage tools. Before it is recommended as a replacement to the existing TS in UK civilian practice, it needs to be tested in a civilian environment. PMID- 25441579 TI - Management of infected non-union of the proximal femur: a combination of therapeutic techniques. AB - A challenging case of a nonunion of the proximal femur complicated by infection attributed to microbial and fungal pathogens requiring a combination of novel surgical techniques to achieve eradication of infection, preservation of the native hip joint, and restoration of function. PMID- 25441580 TI - Re. "Association of fructose consumption and components of metabolic syndrome in human studies: a systematic review and meta-analysis". PMID- 25441582 TI - Re. "Review on emu products for use as complementary and alternative medicine". PMID- 25441581 TI - Pregestational maternal obesity impairs endocrine pancreas in male F1 and F2 progeny. AB - OBJECTIVE: The aim of this study was to evaluate the effects of maternal obesity on pancreas structure and carbohydrate metabolism in early adult life, focusing on the F1 and F2 generations after F0 maternal pregestational, gestation, and lactation high-fat diet (HF). METHODS: C57 BL/6 female mice (F0) were fed standard chow (SC) or an HF diet for 8 wk before mating and during the gestation and lactation periods to provide the F1 generation (F1-SC and F1-HF). At 3 mo old, F1 females were mated to produce the F2 generation (F2-SC and F2-HF). The male offspring from all groups were evaluated at 3 mo old. RESULTS: F0-HF and F1 HF dams were overweight before gestation and had a higher body mass gain and energy intake during gestation, although only F0-HF dams presented pregestational hyperglycemia. The F1-HF offspring had higher body mass, energy intake, fasting glucose levels, and were glucose intolerant compared with F1-SC offspring. These parameters were not significantly altered in F2-HF offspring. Both F1-HF and F2 HF offspring showed hyperinsulinemia, hyperleptinemia, decreased adiponectin levels, increased pancreatic mass, and islet volume density with elevated alpha- and beta-cell mass, hypertrophied islet characterized by an altered distribution of alpha- and beta-cells and weak pancreatic-duodenal homeobox (Pdx)1 immunoreactivity. CONCLUSIONS: Maternal HF diet consumed during the preconception period and throughout the gestation and lactation periods in mice promotes metabolism and pancreatic programming in F1 and F2 male offspring, implying intergenerational effects. PMID- 25441583 TI - Energy expenditure in women with breast cancer. AB - OBJECTIVE: To assess the energy expenditure of women with breast cancer and the effectiveness of available predictive equations (PEs) for the estimation of energy requirements in these subjects. METHODS: Women with breast cancer and healthy women controls underwent indirect calorimetry and nutritional assessment. The estimation of energy requirements included PEs (Harris-Benedict [HB], corrected by injury and activity factors), the Mifflin St. Jeor, and the quick formula of 25 kcal/kg of body weight (BW). Statistical analyses, including Student's t test, a paired t test, Bland-Altman analysis, and backward multivariate linear regression, were performed using the SPSS 17.0 software. Statistical significance was set at P < 0.05. RESULTS: Seventeen women with breast cancer and 19 healthy women were evaluated. Analysis of nutritional status revealed 64.7% of the patients were overweight/obese, and 88.2% had an excess of body fat mass. The resting energy expenditure (REE) of the breast cancer patients was similar to that of the healthy women, even after adjustment for fat free mass (FFM) (P < 0.05). The resting and total energy requirements estimated by the predictive equations widely varied, and the quick formula was the most accurate at determining total energy needs. CONCLUSIONS: The REE of women with breast cancer was similar to that of healthy women. The energy requirements of these patients may be calculated based on the quick formula of 25 kcal/kg of BW. Nonetheless, this estimation should be used cautiously as it results in wide variations when used alone. PMID- 25441584 TI - Curcumin: a pleiotropic phytonutrient in diabetic complications. AB - Curcumin is the major polyphenolic constituent of an indigenous herb, Curcuma longa, found to have a wide range of applications right from its kitchen use as a spicy ingredient to therapeutic and medicinal applications in various diseases. Curcumin has been identified to have a plethora of biologic and pharmacologic properties owing to its antioxidant and anti-inflammatory activities. This pleiotropic regulation of redox balance of cell and inflammation might be the basis of curcumin's beneficial activities in various pathologic conditions including diabetic complications. This review summarizes various in vitro, in vivo studies done on curcumin and its therapeutic utility in diabetic micro vascular complications. This review also emphasizes the importance of curcumin in addition to the existing therapeutic modalities in diabetic complications. PMID- 25441585 TI - Review on emu products for use as complementary and alternative medicine. AB - Emu (Dromaius novaehallandiae), the flightless bird native to Australia and found in many countries, is receiving much attention for its nutritional benefits as well as its medicinal value. Emu oil contains high amounts of polyunsaturated fatty acids and antioxidants. It has potent anti-inflammatory actions and thus can be used topically and orally to treat conditions such as mucositis, inflammatory bowel syndrome, and auricular inflammation, and to prevent chemotherapy-induced bone loss. Emu oil also has a hypocholesterolemic effect, transdermal penetration-enhancing activity, cosmetic and insect repellent activity, and so on. However, its mechanism(s) of actions are unclear and have not, to our knowledge, been studied to date. Previous studies suggest that the fatty acids of the omega-9, omega-6, and omega-3 series, which are present in emu oil, may act on cyclooxygenase, lipoxygenase, and lipoxin pathways to bring about its anti-inflammatory and other beneficial actions. The aim of this review was to provide a brief summary of the current knowledge of research on emu products, mainly emu oil, for the possible use as a complementary and alternative natural medicine for various chronic diseases. In this review we also highlighted the future research scope of emu oil for its possible antidiabetic activity. Thus, emu oil is an attractive pharmacologic agent to further explore for its therapeutic activity to treat various ailments. PMID- 25441586 TI - Substituting sugar-sweetened beverages with water or milk is inversely associated with body fatness development from childhood to adolescence. AB - OBJECTIVE: The aim of this study was to examine the association between different types of beverage intake and substitution of sugar-sweetened beverages (SSBs) by water, milk, or 100% fruit juice in relation to 6-y change in body fatness. METHODS: A cohort of 9-y-old children (N = 358) who participated in the Danish part of the European Youth Heart Study was followed for development of body fatness over 6 y. Multivariate linear regression was used to examine the associations between beverage intake at baseline and change in body fatness (body mass index z score [BMIz]), waist circumference (WC), and sum of four skinfolds (Sigma4SF) over 6 y with adjustment for potential confounders. Substitution models were used to evaluate various beverages as alternatives to SSBs. RESULTS: SSB intake at age 9 y, but not intake of other beverages, was directly associated with subsequent 6-y changes in BMIz (beta = 0.05; P = 0.02) and Sigma4SF (beta = 0.86; P = 0.02). Daily substitution of 100 g water for 100 g SSB was inversely associated with changes in BMIz (beta = -0.04; P = 0.02), WC (beta =-0.29; P = 0.04), and Sigma4SF (beta = -0.91; P = 0.02) over 6 y. Daily substitution of 100 g milk for 100 g SSB was also inversely associated with changes in BMIz (beta = 0.05; P = 0.02), WC (beta = -0.33; P = 0.046), and Sigma4SF (beta = -0.79; P = 0.06). No effect was observed for substitution of SSB by 100% fruit juice. CONCLUSION: Our results suggest that SSB intake is associated with long-term changes in body fatness in children, and replacing SSBs with water or milk, but not 100% fruit juice, is inversely associated with body fatness development. PMID- 25441587 TI - Association between ferritin and hepcidin levels and inflammatory status in patients with type 2 diabetes mellitus and obesity. AB - OBJECTIVE: The aim of this study was to determine the association between iron parameters and inflammation in obese individuals with and without type 2 diabetes mellitus (T2DM). METHODS: We studied 132 obese individuals (OB), 60 individuals with T2DM, 106 obese individuals with T2DM (T2DOB), and 146 controls (C). All of were men aged >30 y. Biochemical, iron nutrition, and oxidative stress parameters were determined. Peripheral mononuclear cells were isolated and total RNA was extracted to quantify tumor necrosis factor (TNF)-alpha, nuclear factor (NF) kappaB, interleukin (IL)-6, toll-like receptor (TLR)-2/4 and hepcidin by quantitative reverse transcription polymerase chain reaction. RESULTS: OB, T2DM, and T2DOB individuals had higher ferritin, retinol-binding protein 4, and thiobarbituric acid reactive substance (TBAR) levels than controls. T2DOB and T2DM individuals showed high high-sensitivity C-reactive protein (hsCRP) levels and OB with and without T2DM had elevated levels of serum hepcidin. Heme oxygenase activity was high in OB and T2DM and there were no differences observed in superoxide dismutase and glutathione parameters. A correlation between TBARS and ferritin in T2DOB was observed (r = 0.31; P < 0.006). Multiple linear regression analysis showed an association between diabetes and obesity with ferritin, TBARS, and hsCRP levels. The upper quartiles of ferritin, TBARS and hepcidin showed an adjusted odd ratio for T2DM of 1.782, 2.250, and 4.370, respectively. TNF-alpha, IL-6, hepcidin, NF-kappaB, TLR-2/4 mRNA abundances were increased in T2DM and T2DOB. CONCLUSION: Elevated hsCRP and hepcidin levels, and increased gene expression of TNF-alpha, IL-6, NF-kappaB, and TLR-2/4 in patients with diabetes, obesity, or both exacerbate and perpetuate the insulin resistance and inflammatory state. PMID- 25441589 TI - Vitamin A and anthropometric status of South African preschool children from four areas with known distinct eating patterns. AB - OBJECTIVE: The aim of this study was to assess the vitamin A and anthropometric status of South African preschool children from four areas with known distinct eating patterns. METHODS: Serum retinol, anthropometric indicators, and dietary intake were determined for randomly selected preschool children from two rural areas, i.e. KwaZulu-Natal (n = 140) and Limpopo (n = 206); an urban area in the Northern Cape (n = 194); and an urban metropolitan area in the Western Cape (n = 207). RESULTS: Serum retinol <20 MUg/dL was prevalent in 8.2% to 13.6% children. Between 3% (urban-Northern Cape) and 44.2% (rural-Limpopo) children had received a high-dose vitamin A supplement during the preceding 6 mo. Vitamin A derived from fortified bread and/or maize meal ranged from 65 MUg retinol activity equivalents (24%-31% of the Estimated Average Requirement) to 160 MUg retinol activity equivalents (58%-76% Estimated Average Requirement). Fortified bread and/or maize meal contributed 57% to 59% of total vitamin A intake in rural children, and 28% to 38% in urban children. Across the four areas, stunting in children ranged from 13.9% to 40.9%; and overweight from 1.2% to 15.1%. CONCLUSION: Prevalence of vitamin A deficiency was lower than national figures, and did not differ across areas despite differences in socioeconomics, dietary intake, and vitamin A supplementation coverage. Rural children benefited more from the national food fortification program in terms of vitamin A intake. Large variations in anthropometric status highlight the importance of targeting specific nutrition interventions, taking into account the double burden of overnutrition and undernutrition. PMID- 25441588 TI - Hypoglycemia in noncritically ill patients receiving total parenteral nutrition: a multicenter study. (Study group on the problem of hyperglycemia in parenteral nutrition; Nutrition area of the Spanish Society of Endocrinology and Nutrition). AB - OBJECTIVE: Hypoglycemia is a common problem among hospitalized patients. Treatment of hyperglycemia with insulin is potentially associated with an increased risk for hypoglycemia. The aim of this study was to determine the prevalence and predictors of hypoglycemia (capillary blood glucose <70 mg/dL) in hospitalized patients receiving total parenteral nutrition (TPN). METHODS: This prospective multicenter study involved 19 Spanish hospitals. Noncritically ill adults who were prescribed TPN were included, thus enabling us to collect data on capillary blood glucose and insulin dosage. RESULTS: The study included 605 patients of whom 6.8% (n = 41) had at least one capillary blood glucose <70 mg/dL and 2.6% (n = 16) had symptomatic hypoglycemia. The total number of hypoglycemic episodes per 100 d of TPN was 0.82. In univariate analysis, hypoglycemia was significantly associated with the presence of diabetes, a lower body mass index (BMI), and treatment with intravenous (IV) insulin. Patients with hypoglycemia also had a significantly longer hospital length of stay, PN duration, higher blood glucose variability, and a higher insulin dose. Multiple logistic regression analysis showed that a lower BMI, high blood glucose variability, and TPN duration were risk factors for hypoglycemia. Use of IV insulin and blood glucose variability were predictors of symptomatic hypoglycemia. CONCLUSIONS: The occurrence of hypoglycemia in noncritically ill patients receiving PN is low. A lower BMI and a greater blood glucose variability and TPN duration are factors associated with the risk for hypoglycemia. IV insulin and glucose variability were predictors of symptomatic hypoglycemia. PMID- 25441590 TI - Preliminary evaluation of the prevalence of sarcopenia in obese patients from Southern Italy. AB - OBJECTIVES: Sarcopenic obesity has not yet been widely defined. The aim of this study was to evaluate the prevalence of sarcopenia in a group of severely obese adults from southern Italy by using two different indexes: percentage of skeletal muscle mass (SMP) and skeletal muscle mass normalized for height (SMI); and to determine SMP and SMI cutoff points in a southern Italy reference population. METHODS: Skeletal muscle mass of 131 consecutive obese adult outpatients (51 men and 80 women; ages 45-67 y; body mass index 44.6 +/- 7.7 kg/m(2)), was assessed by bioimpedance analysis. SMP and SMI cutoff points to identify moderate and severe sarcopenia were calculated in a reference group of 500 young southern Italy adults (100 men and 400 women; ages 18-40 y; body mass index 25.2 +/- 5.6 kg/m(2)) and applied to assess the prevalence of sarcopenia in the study population. RESULTS: SMP cutoff points to identify moderate and severe sarcopenia were, 28.8% to 35.6% and <= 28.7% in men and 23.1% to 28.4% and <= 23% in women, respectively. The corresponding values for SMI were 8.44 to 9.53 kg/m(2) and <= 8.43 kg/m(2) in men, 6.49 to 7.32 kg/m(2) and <= 6.48 kg/m(2) in women. According to SMP, 23 of 51 (45.1%) men and 19 of 80 (23.8%) women were moderately sarcopenic; 28 of 51 (54.9%) men and 61 of 80 (76.3%) women met the definition of severe sarcopenia. Based on SMI, only 2 of 51 (3.9%) men were moderately sarcopenic. CONCLUSIONS: This study confirms that sarcopenia rates vary widely in obese patients depending on the criteria used. SMP as a screening tool to identify a sarcopenia at-risk population. PMID- 25441591 TI - Effects of brown and golden flaxseed on the lipid profile, glycemia, inflammatory biomarkers, blood pressure and body composition in overweight adolescents. AB - BACKGROUND: Flaxseed is a promising alternative to reduce the risk of diseases associated with body weight excess because it is rich in a-linolenic acid, lignans, and dietary fiber. Flaxseed (Linum usitatissimum) can be found in brown and golden varieties; however, questions have arisen as to whether the variety may influence the health effects. OBJECTIVE: The objective of this study was to compare the effects of brown and golden flaxseeds on lipid profile, glycemia, blood pressure, inflammatory status,body weight, and body composition in overweight adolescents. METHODS: Seventy-five overweight adolescents (33 boys, 42 girls; age 13.7 ! 2.1 y), from Alegre-ES, Brazil, were randomized to one of the three groups (n 1/4 25) on a parallel, single-blind clinical trial. They received 28 g/d of brown flaxseed (BF), golden flaxseed (GF), or the equivalent amount of wheat bran (Control, CG) in different preparations at school from Monday to Friday for 11 wk. Blood pressure, anthropometric evaluation, and the analyses of blood total cholesterol, lipoproteins, glucose, and inflammatory markers were performed at the beginning and at the end of the intervention. The data were analyzed by ANCOVA at 5% significance. RESULTS: The groups who consumed brown and golden flaxseed showed significant reduction in diastolic blood pressure. Brown and golden flaxseed did not differentially affect plasma lipid responses, plasma glucose and inflammatory profile, although all groups (BF, GF, and CG) showed increased levels of TNF-a. CONCLUSIONS: The adolescents consumed about half the daily amount provided, which may not have been sufficient to exert the health benefits of flaxseed reported in the literature, concerning the lipid profile, inflammation biomarkers and body composition. PMID- 25441592 TI - Diet and its relationship to sarcopenia in community dwelling Iranian elderly: a cross sectional study. AB - OBJECTIVES: Sarcopenia is associated with frailty and disability among the elderly and imposes significant costs on health care systems. We tested whether adherence to a particular dietary pattern was associated with sarcopenia among the elderly in a district of Tehran, Iran. METHODS: We used a semiquantitative Food Frequency Questionnaire to assess the dietary intake of 300 randomly selected elderly men and women (at least 55 y old) living in the sixth district of Tehran; and the dietary patterns of the subjects were obtained using principal component analysis. We performed a logistic regression to measure the effect of adherence to each dietary pattern on the odds of sarcopenia. RESULTS: Subjects in the highest tertile of the Mediterranean dietary pattern, characterized by a higher consumption of olive oil, fruits, vegetables, fish, and nuts, had a lower odds ratio for sarcopenia than those in the lowest tertile (OR = 0.42; 95% CI = 0.18-0.97; P for trend = 0.04). In contrast, adherence to the Western dietary pattern, characterized by a high consumption of sugar, soy, and fast foods, was not associated with sarcopenia (OR = 0.51; 95% CI = 0.21-1.24; P for trend = 0.13). Similarly, adherence to the Mixed dietary pattern, characterized by a high consumption of animal proteins, potatoes, and refined grains, did not affect the odds of sarcopenia (OR = 1.45; 95% CI = 0.66-3.19; P for trend = 0.95). CONCLUSIONS: This study suggests that adherence to the Mediterranean diet is associated with lower odds of sarcopenia among the Iranian elderly. PMID- 25441593 TI - Recovery of nutritional metabolism after liver transplantation. AB - OBJECTIVE: Perioperative nutritional assessment is critically important to reflect nutritional management because liver transplantation (LTx) often is undertaken in patients with poor nutritional status. The aim of this study was to evaluate nutritional status, including the non-protein respiratory quotient (npRQ), resting energy expenditure (REE), nitrogen balance, and blood biochemical parameters in patients before and after LTx. METHODS: Fourteen patients undergoing LTx and 10 healthy controls were enrolled in this study. The npRQ and REE were measured using indirect calorimetry before LTx and at 2, 3, and 4 wk after the procedure. Blood biochemistry and nitrogen balance calculated by 24-h urine collection were performed concurrently with indirect calorimetric measurement; the results were compared between the two groups. RESULTS: Before LTx, npRQ was significantly lower and serum non-esterified fatty acid levels were significantly higher in the patients than in the controls. Furthermore, a negative nitrogen balance was observed in the patients. These, however, improved significantly at 4 wk after LTx. REE did not significantly increase compared with the preoperative values in recipients. Blood biochemistry showed gradually increasing levels of serum cholinesterase and albumin. These failed to reach to normal levels by 4 wk post-transplant. CONCLUSIONS: The findings revealed that improvement of nutritional metabolism after LTx may require 4 wk. Additional nutritional strategies, therefore, may be needed to minimize catabolic state during the early post-transplant period. Adequate, individualized nutritional guidance before and after LTx should be performed in these patients. PMID- 25441594 TI - Early oral refeeding based on hunger in moderate and severe acute pancreatitis: a prospective controlled, randomized clinical trial. AB - OBJECTIVE: Early enteral nutrition is beneficial for acute pancreatitis (AP), but the optimal timing and criteria remain unclear. The aim of this study was to explore the feasibility and safety of early oral refeeding (EORF) based on hunger in patients with moderate or severe AP. METHODS: In a prospective, single-center, controlled, randomized clinical trial (ChiCTR-TRC-12002994), eligible patients with moderate or severe AP were randomized to either EORF or conventional oral refeeding (CORF). Patients in the EORF group restarted an oral diet when they felt hungry, regardless of laboratory parameters. Those in the CORF group restarted an oral diet only when clinical and laboratory symptoms had resolved. Clinical outcomes were compared between the two groups. RESULTS: In all, 146 eligible patients with moderate or severe AP were included and randomized to the EORF (n = 70) or CORF (n = 76) group. There were eight dropouts after randomization (three in EORF group; five in CORF group). The groups had similar baseline characteristics. The total length of hospitalization (13.7 +/- 5.4 d versus 15.7 +/- 6.2 d; P = 0.0398) and duration of fasting (8.3 +/- 3.9 d versus 10.5 +/- 5.1 d; P = 0.0047) were shorter in the EORF group than in the CORF group. There was no difference in the number of adverse events or complications between the two groups. The mean blood glucose level after oral refeeding was higher in the EORF group than in the CORF group (P = 0.0030). CONCLUSIONS: This controlled, randomized clinical trial confirmed the effectiveness and feasibility of EORF based on hunger in patients with moderate or severe AP. EORF could shorten the length of hospitalization in patients with moderate or severe AP. PMID- 25441595 TI - Sarcopenia impairs prognosis of patients with liver cirrhosis. AB - OBJECTIVE: Sarcopenia is characterized by the loss of skeletal muscle mass, and is reported to appear in patients with liver cirrhosis (LC). The aim of this study was to investigate the prevalence of sarcopenia in patients with LC, and to test the association between sarcopenia and patient outcomes. We also analyzed the effect of branched-chain amino acid (BCAA) supplementation on sarcopenic LC. METHODS: Clinical and blood biochemical data of 130 patients with LC who underwent abdominal computed tomography scan were analyzed in this retrospective study. The cross-sectional area of skeletal muscles was measured at the level of the third lumbar vertebra on the scan. The skeletal muscle index was calculated to identify sarcopenia. Cirrhotic patients who were treated with BCAA supplementation of 12 g/d for >= 1 y were defined as the BCAA group, and the effect of BCAA on sarcopenic LC was evaluated. RESULTS: Sixty-eight percent of all patients (82% of men and 50% of women) were diagnosed with sarcopenia. Male sex (P = 0.01) and body mass index (P < 0.0001) were predictors of sarcopenia. The multivariate Cox proportional hazards model found BCAA supplementation (hazard ratio [HR], 0.38; P = 0.01), sarcopenia (HR, 3.03; P < 0.01), and Child Pugh classes B (HR, 2.39; P = 0.03) and C (HR, 5.49; P < 0.001) to be independently associated with mortality. The mortality of sarcopenic LC was significantly higher than that of non-sarcopenic LC (P = 0.01). Moreover, BCAA supplementation improved the survival of sarcopenic patients in subgroup analysis (P < 0.01). CONCLUSIONS: Sarcopenia is significantly associated with mortality in patients with LC. BCAA supplementation might be associated with improved survival of such patients. PMID- 25441596 TI - Long-term (15 mo) dietary supplementation with pomegranates from Oman attenuates cognitive and behavioral deficits in a transgenic mice model of Alzheimer's disease. AB - OBJECTIVE: Transgenic (Tg) mice, which possess an amyloid precursor protein (APP) gene mutation, develop extracellular amyloid beta (Abeta) deposition in the brain, and severe memory and behavioral deficits with age. These mice serve as an important animal model for testing the efficacy of novel drug candidates for the treatment and management of symptoms of Alzheimer's disease (AD). Several reports have suggested that oxidative stress is the underlying cause of Abeta neurotoxicity in AD. Pomegranates contain very high levels of antioxidants and several medicinal properties that may be useful for improving quality of life in individuals with AD. The aim of this study was to investigate the effect of dietary supplementation of Omani pomegranate extract on memory, anxiety, and learning skills in an AD mouse model possessing the double Swedish APP mutation (APPsw/Tg2576). METHODS: The experimental groups of APP-Tg mice from the age of 4 mo were fed a custom mixed diet (pellets) containing 4% pomegranate. We assessed spatial memory and learning ability, psychomotor coordination, and anxiety related behavior in Tg and wild-type mice at the age of 4 to 5 mo and 18 to 19 mo using the Morris water maze test, rotarod performance test, elevated plus-maze test, and open field test. RESULTS: APPsw/Tg2576 mice that were fed a standard chow diet without pomegranates showed significant memory deficits, increased anxiety-related behavior, and severe impairment in spatial learning ability, position discrimination learning ability, and motor coordination compared with the wild-type mice on the same diet, at the age of 18 to 19 mo. In contrast, APPsw/Tg2576 mice that were fed a diet containing 4% pomegranates showed significant improvements in memory, learning, locomotor function, as well as reduction in anxiety, compared with APPsw/Tg2576 mice fed the standard chow diet. CONCLUSION: Our results suggest that dietary supplementation with pomegranates may slow the progression of cognitive and behavioral impairments in AD. PMID- 25441597 TI - Predictors of dietary gluten avoidance in adults without a prior diagnosis of celiac disease. AB - OBJECTIVE: Prior studies have shown that dietary gluten avoidance (DGA) is relatively common in children without previously diagnosed celiac disease (CD), and several clinical predictors of DGA have been found. However, available data on predictors of DGA in adults without diagnosed CD are limited. The aim of this study was to determine the independent predictors of DGA in this population. METHODS: We performed a structured medical record review of 376 patients, ages >= 20 y, who had never been formally diagnosed with CD, presenting for an initial CD evaluation (ICD-9-CM 579.0) between January 2000 and December 2010 at two large Boston teaching hospitals. We collected data including demographic characteristics, medical history, history of CD serology before referral, and self-reported DGA. Predictors of DGA were determined using multivariable logistic regression. RESULTS: Mean age was 47 (SD = 17) years. We found that 41 patients (10.9%; 95% confidence interval [CI], 7.9-14.5) had avoided gluten at some time in their lives. Most patients had subjective abdominal complaints or bowel movement changes. History of CD seropositivity before referral was noted in 14%. Independent predictors of DGA (P < 0.05) were lactose intolerance (odds ratio [OR], 2.8; 95% CI, 1.1-7.5), food allergy (OR, 3.8; 95% CI, 1.04-13.7), and history of positive serology of less-specific CD markers before the referral (OR, 3.2; 95% CI, 1.3-7.9). CONCLUSIONS: Gluten avoidance is common in a clinic population of adults without prior CD diagnosis. The recognized predictors suggest that DGA may associate with conditions presenting with nonspecific gastrointestinal complaints and perhaps with the perceived benefits of DGA among patients with prior history of positive CD serology. PMID- 25441599 TI - Invited commentary on Clostridium difficile increases the risk for venous thromboembolism. PMID- 25441598 TI - Anatomy, physiology and neurobiology of the nociception: a focus on low back pain (part A). AB - INTRODUCTION: The treatment of Failed Back Surgery Syndrome (FBSS) remains a challenge for pain medicine due to the complexity in the interactions between [1] a residual mechanical pain after surgery and, [2] a progressive transition into chronic pain involving central nervous system plasticity and molecular reorganization. The aim of this paper is to provide a fundamental overview of the pain pathway supporting the nociceptive component of the back pain. METHODS: Literature searches included an exhaustive review of 643 references and 74 book chapters updated by searching the major electronic databases from 1930 to August 2013. RESULTS: Pain input is gathered by the peripheral fibre from the innervated tissue's environment and relayed by two contiguous central axons to the brain, via the spinal cord. At this level, it is possible to characterize physical pain and emotional pain. These are supported by two different pathways, encoding two dimensions of pain perception: In Neo-spino-thalamic pathway, the wide dynamic range neuron system is able to provide the information needed for mapping the "sensory-discriminative" dimension of pain. The second projection system (Paleo spino-thalamic pathway) also involves the ventromedial thalamus but projects to the amygdala, the insula and the anterior cingulate cortex. These areas are associated with emotionality and affect. CONCLUSION: The mechanical component of FBSS cannot be understood unless the functioning of the pain system is known. But ultimately, the highly variable nature of back pain expression among individuals would require a careful pathophysiological dissection of the potential generators of back pain to guide pain management strategies. PMID- 25441600 TI - Implementation of the acute care surgery model provides benefits in the surgical treatment of the acute appendicitis. AB - BACKGROUND: Several reports have indicated the benefits of the acute care surgery (ACS) model in surgical outcomes. We tried to delineate the impact of the ACS model on surgical efficiency and quality. METHODS: Before the ACS model was implemented, abdominal surgical emergencies were evaluated by an on-call nontrauma general surgeon (pre-ACS model). An in-house trauma surgeon treated all patients with trauma or nontrauma abdominal surgical emergencies after the ACS model. Patients with acute appendicitis who underwent appendectomies were included. We conducted a pre- and poststudy to compare the time patients were in the emergency department and surgical qualities. RESULTS: There were 146 and 159 patients enrolled in the pre-ACS model and ACS model, respectively. The overall ED length of stay in the ACS model was significantly shorter than that in the pre ACS model (300.3 +/- 61.7 vs 719.1 +/- 339.0 minutes, P < .001). Hospital LOS was also significantly shorter in the ACS model than in the pre-ACS model (2.44 +/- 1.39 vs 3.83 +/- 2.21 days, P = .022). CONCLUSION: The ACS model may improve abdominal surgical efficiency and quality. Our study results echoed the benefits of the implementation of the ACS model shown in North America. PMID- 25441601 TI - The dtd gene from Bacillus amyloliquefaciens encodes a putative D-tyrosyl-tRNATyr deacylase and is a selectable marker for Bacillus subtilis. AB - Genetically engineered microbes are of high practical importance due to their cost-effective production of valuable metabolites and enzymes, and the search for new selectable markers for genetic manipulation is of particular interest. Here, we revealed that the soil bacterium Bacillus amyloliquefaciens A50 is tolerant to the non-canonical amino acid D-tyrosine (D-Tyr), in contrast to the closely related Bacillus strain B. subtilis 168, which is a widely used "domesticated" laboratory strain. The gene responsible for resistance to D-Tyr was identified. The resistance was associated with the activity of a potential D-tyrosyl tRNA(Tyr) deacylase. Orthologs of this enzyme are capable of hydrolyzing the ester bond and recycling misacetylated D-aminoacyl-tRNA molecules into free tRNAs and D-amino acids. This gene, yrvI (dtd), is applicable as a convenient, small selectable marker for non-antibiotic resistance selection in experiments aimed at genome editing of D-Tyr-sensitive microorganisms. PMID- 25441602 TI - Hearing loss in syndromic craniosynostoses: otologic manifestations and clinical findings. AB - OBJECTIVE: This review addresses hearing loss as it occurs and has been reported in Muenke syndrome as well as six additional FGFR related craniosynostosis syndromes (Apert syndrome, Pfeiffer syndrome, Crouzon syndrome, Beare-Stevenson syndrome, Crouzon syndrome with acanthosis nigricans, and Jackson-Weiss syndrome. DATA SOURCES: Pub-Med, Medline, Cochrane Database, Science Direct, NLM Catalog. REVIEW METHODS: A Medline search was conducted to find all reported cases of the 7 FGFR related syndromic craniosynostosis. Special attention was paid to literature that reported hearing findings and the audiology literature. RESULTS: Hearing loss occurs in variable percentage as a component part of all FGFR related craniosynostosis syndromes. Our literature review revealed the following incidences of hearing loss in FGFR craniosynostoses: 61% in Muenke syndrome, 80% in Apert Syndrome, 92% in Pfeiffer syndrome, 74% in Crouzon syndrome, 68% in Jackson Weiss syndrome, 4% in Beare Stevenson syndrome and 14% in Crouzon syndrome with Acanthosis Nigricans. The majority of the hearing loss is a conductive hearing loss, with the exception of Muenke syndrome where the majority of patients have a sensorineural hearing loss and Crouzon syndrome where almost half of patients have a pure or component of sensorineural hearing loss. CONCLUSION: This manuscript presents a diagnostic and management algorithm for patients with syndromic craniosynostosis. It will aid clinicians in treating these patients and further, the recognition of a possible syndrome in patients with hearing loss who also have syndromic features. PMID- 25441603 TI - Clinical relevance of speaking voice intensity effects on acoustic jitter and shimmer in children between 5;0 and 9;11 years. AB - BACKGROUND: Current voice assessment recommendations for dysphonic children comprise instrumental acoustic measurements of the perturbation parameters jitter and shimmer. In healthy adults and children changes in speaking voice sound pressure level (voice SPL) have significant confounding effects on both parameters. In adults these effects were considerably reduced in phonations with controlled voice SPL >80dBA (10cm distance). However, it is unclear if these findings apply to children and if children are able to control for their own voice intensity. OBJECTIVE: This cross-sectional single cohort study investigates voice SPL effects on jitter and shimmer in children between 5;0 and 9;11 years phonating at individually "medium" (modeling "comfortable" loudness of the usual clinical protocol), "soft" and "loud" voice and a prescribed intensity level of ">80dBA" (10cm distance, with visual control). Further both their ability to phonate at a prescribed voice intensity level and the effect on SPL related confounding effects were studied. SUBJECTS AND METHODS: A total of 68 healthy children (39 f/29m) aged 5;0 to 9;11 years were included. All phonated the vowel/a/for 5s, three times at four defined voice intensity levels (soft/medium/loud/>80dBA) each. Jitter (%), shimmer (%) and voice SPL (dBA) were determined using PRAAT. Voice intensity level effects were assessed by descriptive statistics, Analysis of Variance (ANOVA) and Linear Mixed Models (LMM). RESULTS: There were significant differences for jitter and shimmer between all voice tasks (p<.01). Jitter and shimmer were lowest and showed the smallest spread in controlled phonations ">80dBA". 19 children below 7;0 years could not perform the voice tasks and were excluded from the study. CONCLUSIONS: This practical study demonstrated a significant effect of voice loudness and task on jitter and shimmer in children. Since the observed confounding effects were large compared to treatment effects, jitter and shimmer may not be meaningful without adequate control of voice SPL. In phonations at ">80dBA" (10cm distance) voice SPL related effects were considerably reduced. However, this assessment protocol was suitable only for children above 7;0 years. Application of this task to future studies of dysphonic children may yield clinically valuable information. PMID- 25441604 TI - Important points for primary cleft palate repair for speech derived from speech outcome after three different types of palatoplasty. AB - OBJECTIVE: This study was performed to investigate speech outcomes after three different types of palatoplasty for the same cleft type. The objective of this study was to investigate the surgical techniques that are essential for normal speech on the basis of each surgical characteristic. METHODS: Thirty-eight consecutive nonsyndromic patients with unilateral complete cleft of the lip, alveolus, and palate were enrolled in this study. Speech outcomes, i.e., nasal emission, velopharyngeal insufficiency, and malarticulation after one-stage pushback (PB), one-stage modified Furlow (MF), or conventional two-stage MF palatoplasty, were evaluated at 4 (before intensive speech therapy) and 8 (after closure of oronasal fistula/unclosed hard palate) years of age. RESULTS: Velopharyngeal insufficiency at 4 (and 8) years of age was present in 5.9% (0.0%), 0.0% (0.0%), and 10.0% (10.0%) of patients who underwent one-stage PB, one-stage MF, or two-stage MF palatoplasty, respectively. No significant differences in velopharyngeal function were found among these three groups at 4 and 8 years of age. Malarticulation at 4 years of age was found in 35.3%, 10.0%, and 63.6% of patients who underwent one-stage PB, one-stage MF, and two-stage MF palatoplasty, respectively. Malarticulation at 4 years of age was significantly related to the presence of a fistula/unclosed hard palate (P<0.01). One-stage MF palatoplasty that was not associated with postoperative oronasal fistula (ONF) showed significantly better results than two-stage MF (P<0.01). Although the incidences of malarticulation at 8 years of age were decreased in each group compared to at 4 years of age, the incidence was still high in patients treated with two-stage MF (45.5%). On the whole, there was a significant correlation between ONF/unclosed hard palate at 4 years of age and malarticulation at 8 years of age (P<0.05). CONCLUSION: Appropriate muscle sling formation can compensate for a lack of retropositioning of the palate for adequate velopharyngeal closure. Early closure of the whole palate and the absence of a palatal fistula were confirmed to be essential for normal speech. To avoid fistula formation, multilayer repair of the whole palate may be critical. PMID- 25441605 TI - Characterization of middle-ear condition of Oporto daycare children up-to 3 years old: a cross sectional study. AB - OBJECTIVE: The aim of this study was to determine tympanometric values of children who attend Oporto daycare centers and further analyze any relations with host and environmental factors. METHODS: Cross sectional study in a randomly selected sample of 117 daycare children up-to 3-years old from Oporto. Tympanometric measures were collected. RESULTS: Children presented in left ear (LE) a mean peak pressure (PP) of -156.53daPa and a mean compliance of 0.16cm(3). Right ear (RE) revealed a PP of -145.61daPa and a compliance of 0.19cm(3). Normal tympanograms (type A) had a lower frequency than abnormal tympanograms (type B and type C). There was a positive association between age and compliance (LE: p=0.016; RE: p=0.013) and between the presence of rhinorrhea and PP (LE: p=0.002; RE: p<0.05). Abnormal tympanograms were more frequent in Spring (RE: p=0.009), in younger children (LE: p=0.03) and in children that had rhinorrhea (LE: p=0.002; RE: p=0.044). Healthy children had a mean PP of -125.19daPa and a mean compliance of 0.21cm(3) in LE and a mean PP of -144.27daPa and a mean compliance of 0.22cm(3) in RE. CONCLUSION: Tympanometric measures presented in this paper may be applicable to Oporto daycare children up-to 3 years-old. Most of daycare children revealed abnormal tympanograms. Age, rhinorrhea and season influenced children's middle-ear condition. PMID- 25441606 TI - Assessment of ototoxicity of tea tree oil in a chinchilla animal model. AB - OBJECTIVE: The aim of the present study is to examine the effects of tea tree oil on hearing function and cochlear morphology after intratympanic administration in a chinchilla animal model. METHODS: Nine chinchillas received intratympanic injection of 3% tea tree oil dissolved in olive oil in one ear, whereas the contralateral control ear received olive oil only. Outcome measures included auditory brainstem responses conducted before treatment and at 10 days and 30 days following the injection. Post-mortem cochlear morphology was assessed using scanning electron microscopy. RESULTS: At 10 and 30 days following the injection, there was no significant change in auditory brain response thresholds at 8, 16, 20 or 25kHz. Scanning electron microscopy imaging showed no damage to auditory hair cells. CONCLUSION: Tea tree oil (3%) does not appear to be ototoxic in a chinchilla animal model. Future preclinical and clinical studies are required to establish the effectiveness of TTO in treating otitis. PMID- 25441607 TI - Airway laser procedures in children and the American Society of Anesthesiologists' Practice Advisory: a survey among pediatric anesthesiologists. AB - BACKGROUND AND OBJECTIVES: Recognizing the risk of fire during laser procedures involving the airway, the American Society of Anesthesiologists (ASA) developed recommendations designed to promote safe practice and reduce burn injuries. The aim of this study was to identify how reported anesthetic management of airway laser endoscopies in pediatric patients aligns with the ASA Practice Advisory (ASA-PA). METHODS: An online survey was created in an iterative process, pilot tested, and distributed using the Society for Pediatric Anesthesia's (SPA) membership email list. Responses were analyzed using descriptive statistics. RESULTS: Responses from 322 respondents were included, 296 (92%) of whom participated in pediatric laser airway procedures. Fifty-nine respondents (20%) reported the use of an inspired fraction of oxygen (FiO2) of 90% or greater during laser activation in patients with a native airway, and 101 (34%) reported not waiting after the reduction of the FiO2 and laser activation in the airway. Sixty-four (36%) of respondents reporting the use of a non-laser-safe tube during laser airway cases did so due to a lack of availability of a laser specific tube or size limitations. Six respondents (2%) reported an airway fire during a laser procedure in a child under their care. CONCLUSIONS: Our results indicate that, in general, pediatric anesthesiologists do not adhere to the ASA-PA in several important aspects. Possible explanations might be knowledge deficiencies about the Practice Advisory or a perceived limited clinical applicability in the pediatric setting. Regardless, airway fires during laser airway surgeries in this population do occur, emphasizing the need for safe practice standards for both anesthesiologists and surgeons. PMID- 25441608 TI - Lipoid proteinosis: rare case confirmed by ECM1 mutation detection. PMID- 25441609 TI - Randomized trial on radiotherapy for paediatric diffuse intrinsic pontine glioma (DIPG). PMID- 25441610 TI - Rectal toxicity after intensity modulated radiotherapy for prostate cancer: which rectal dose volume constraints should we use? AB - BACKGROUND: To define rectal dose volume constraints (DVC) to prevent ?grade2 late rectal toxicity (LRT) after intensity modulated radiotherapy (IMRT) for prostate cancer (PC). MATERIAL AND METHODS: Six hundred thirty-seven PC patients were treated with primary (prostate median dose: 78Gy) or postoperative (prostatic bed median dose: 74Gy (adjuvant)-76Gy (salvage)) IMRTwhile restricting the rectal dose to 76Gy, 72Gy and 74Gy respectively. The impact of patient characteristics and rectal volume parameters on ?grade2 LRT was determined. DVC were defined to estimate the 5% and 10% risk of developing ?grade2 LRT. RESULTS: The 5-year probability of being free from ?grade2 LRT, non-rectal blood loss and persisting symptoms is 88.8% (95% CI: 85.8-91.1%), 93.4% (95% CI: 91.0-95.1%) and 94.3% (95% CI: 92.0-95.9%) respectively. There was no correlation with patient characteristics. All volume parameters, except rectal volume receiving ?70Gy (R70), were significantly correlated with ?grade2 LRT. To avoid 10% and 5% risk of ?grade2 LRT following DVC were derived: R40, R50, R60 and R65 <64-35%, 52-22%, 38-14% and 5% respectively. CONCLUSION: Applying existing rectal volume constraints resulted in a 5-year estimated risk of developing late ?grade2 LRT of 11.2%. New rectal DVC for primary and postoperative IMRT planning of PC patients are proposed. A prospective evaluation is needed. PMID- 25441611 TI - Impact of inadequate respiratory motion management in SBRT for oligometastatic colorectal cancer. AB - PURPOSE: Stereotactic body radiotherapy (SBRT) in oligometastatic colorectal cancer (CRC) resulted in a disappointing 1-year local control rate of 54% in our experience. We aimed to determine the root cause(s). METHODS: 47 oligometastatic CRC patients were treated with SBRT by helical tomotherapy to a dose of 40 or 50Gy in 10 fractions, without specific respiratory motion management and PTV margins of 10-10-12mm in all patients. The local recurrences (LRs) were delineated on diagnostic PET-CT scans and co-registered with initial planning CTs. LRs were classified as in-field or marginal with respect to the initial dose distribution, and predictors for LR were determined. RESULTS: Out of 105 irradiated metastases, LR modeling yielded 15 in-field and 15 marginal failures. Metastases in moving organs (liver and lung) exhibited a local control of 53% at 1-year (95% confidence interval (CI): 38-67%), compared to 79% for lymph nodes (95% CI: 32-95%). The first group exhibited a sixfold increased risk compared to the latter on multivariate analysis (p=0.01). CONCLUSIONS: The nature and locations of LR indicated that dose prescription and methodology were both inadequate for liver and lung metastases. This study demonstrates the need for individual respiratory motion management and a biological effective dose of >75Gy. PMID- 25441612 TI - Prognostic implication of pulmonary function at the beginning of postoperative radiotherapy in non-small cell lung cancer. AB - PURPOSE: The purpose of this study was to investigate the prognostic effect of pulmonary function at the beginning of postoperative radiotherapy (PORT) in non small cell lung cancer (NSCLC). MATERIALS AND METHODS: From January 2002 to December 2012, 115 patients with NSCLC who underwent PORT and took the forced expiratory volume in 1 second (FEV1) at the beginning of PORT were analysed. PORT began within 4-6weeks following surgery, and the 3-dimensional conformal technique was used with conventional fractionation. The high and low FEV1 groups were divided by the median absolute value of FEV1 at the beginning of PORT, and we compared the clinical factors and survival between two groups. RESULTS: The median absolute value of FEV1 at the beginning of PORT was 1.68L (range, 0.83 3.89), and patients were divided into low and high FEV1 groups (<1.68L versus ?1.68L). Patients in the low FEV1 group showed a lower preoperative FEV1 (mean, 1.94L versus 2.73L, p<0.001) and received more pneumonectomy (36.8% versus 8.6%, p<0.001) compared to the high FEV1 group. The overall median follow-up time was 31months (range, 3-110), and 5-year locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were 52.4%, 48.9%, and 45.9%, respectively. Five-year OS of the low FEV1 group was significantly lower than that of the high FEV1 group (35.4% versus 56.9%, p=0.002), and no significant differences were found in LRRFS and DMFS. In a multivariate analysis, the difference of OS between the low and high FEV1 groups remained significant (Hazard Ratio=2.04, CI, 1.18-3.55, p=0.011). CONCLUSIONS: The FEV1 at the beginning of PORT was an independent significant prognostic factor in patients with NSCLC who received PORT. Considering this analysis was limited to only patients receiving PORT, further studies are warranted to compare the survival effect of postoperative pulmonary function between groups with/without PORT. PMID- 25441613 TI - Muscle enzyme and fiber type-specific sarcomere protein increases in serum after inertial concentric-eccentric exercise. AB - Muscle damage induced by inertial exercise performed on a flywheel device was assessed through the serum evolution of muscle enzymes, interleukin 6, and fiber type-specific sarcomere proteins such as fast myosin (FM) and slow myosin (SM). We hypothesized that a model of muscle damage could be constructed by measuring the evolution of serum concentration of muscle proteins following inertial exercise, according to their molecular weight and the fiber compartment in which they are located. Moreover, by measuring FM and SM, the type of fibers that are affected could be assessed. Serum profiles were registered before and 24, 48, and 144 h after exercise in 10 healthy and recreationally active young men. Creatine kinase (CK) and CK-myocardial band isoenzyme increased in serum early (24 h) and returned to baseline values after 48 h. FM increased in serum late (48 h) and remained elevated 144 h post-exercise. The increase in serum muscle enzymes suggests increased membrane permeability of both fast and slow fibers, and the increase in FM reveals sarcomere disruption as well as increased membrane permeability of fast fibers. Consequently, FM could be adopted as a fiber type specific biomarker of muscle damage. PMID- 25441615 TI - There is no bubble, but there are conflicts of interests. Efforts to improve the credibility of the scientific process. PMID- 25441614 TI - Leaf morphology of 40 evergreen and deciduous broadleaved subtropical tree species and relationships to functional ecophysiological traits. AB - We explored potential of morphological and anatomical leaf traits for predicting ecophysiological key functions in subtropical trees. We asked whether the ecophysiological parameters stomatal conductance and xylem cavitation vulnerability could be predicted from microscopy leaf traits. We investigated 21 deciduous and 19 evergreen subtropical tree species, using individuals of the same age and from the same environment in the Biodiversity-Ecosystem Functioning experiment at Jiangxi (BEF-China). Information-theoretic linear model selection was used to identify the best combination of morphological and anatomical predictors for ecophysiological functions. Leaf anatomy and morphology strongly depended on leaf habit. Evergreen species tended to have thicker leaves, thicker spongy and palisade mesophyll, more palisade mesophyll layers and a thicker subepidermis. Over 50% of all evergreen species had leaves with multi-layered palisade parenchyma, while only one deciduous species (Koelreuteria bipinnata) had this. Interactions with leaf habit were also included in best multi-predictor models for stomatal conductance (gs ) and xylem cavitation vulnerability. In addition, maximum gs was positively related to log ratio of palisade to spongy mesophyll thickness. Vapour pressure deficit (vpd) for maximum gs increased with the log ratio of palisade to spongy mesophyll thickness in species having leaves with papillae. In contrast, maximum specific hydraulic conductivity and xylem pressure at which 50% loss of maximum specific xylem hydraulic conductivity occurred (Psi50 ) were best predicted by leaf habit and density of spongy parenchyma. Evergreen species had lower Psi50 values and lower maximum xylem hydraulic conductivities. As hydraulic leaf and wood characteristics were reflected in structural leaf traits, there is high potential for identifying further linkages between morphological and anatomical leaf traits and ecophysiological responses. PMID- 25441616 TI - Human amniotic membrane-derived stromal cells (hAMSC) interact depending on breast cancer cell type through secreted molecules. AB - Human amniotic membrane-derived stromal cells (hAMSC) are candidates for cell based therapies. We examined the characteristics of hAMSC including the interaction between hAMSC and breast cancer cells, MCF-7, and MDA-MB-231. Human amniotic membrane-derived stromal cells showed typical MSC properties, including fibroblast-like morphology, surface antigen expression, and mesodermal differentiation. To investigate cell-cell interaction via secreted molecules, we cultured breast cancer cells in hAMSC-conditioned medium (hAMSC-CM) and analyzed their proliferation, migration, and secretome profiles. MCF-7 and MDA-MB-231 cells exposed to hAMSC-CM showed increased proliferation and migration. However, in hAMSC-CM, MCF-7 cells proliferated significantly faster than MDA-MB-231 cells. When cultured in hAMSC-CM, MCF-7 cells migrated faster than MDA-MB-231 cells. Two cell types showed different profiles of secreted factors. MCF-7 cells expressed much amounts of IL-8, GRO, and MCP-1 in hAMSC-CM. Human amniotic membrane-derived stromal cells interact with breast cancer cells through secreted molecules. Factors secreted by hAMSCs promote the proliferation and migration of MCF-7 breast cancer cells. For much safe cell-based therapies using hAMSC, it is necessary to study carefully about interaction between hAMSC and cancer cells. PMID- 25441617 TI - Quantitative analysis of development and aging of genital corpuscles in glans penis of the rat. AB - The aim of the present postnatal developmental study was to determine densities of unique genital corpuscles (GCs) in glans penis of developing and aged rats. GCs were identified as corpuscular endings consisting of highly branched and coiled axons with many varicosities, which were immunoreactive for protein gene product 9.5. In addition, GCs were immunoreactive for calcitonin gene-related peptide and substance P, but not for vasoactive intestinal polypeptide and neuropeptide Y. GCs were not found in the glans penis of 1 week old rats. Densities of GCs were low at 3 weeks, significantly increased at 5 and 10 weeks, reached the peak of density at 40 weeks, and tended to decrease at 70 and 100 weeks. Sizes of GCs were small in 3 weeks old rats, increased at 5 and 10 weeks, reached the peak-size at 40 weeks and reduced in size at 70 and 100 weeks. Considering sexual maturation of the rat, the results reveal that GCs of the rat begins to develop postnatal and reaches to the peak of their development after puberty and continues to exist until old age, in contrast to prenatal and early postnatal development of other sensory receptors of glabrous skin. PMID- 25441618 TI - Establishment and characterization of a bovine rectal myxoma cell line. AB - A new bovine cell line was developed from tumor biopsy material of rectum obtained from clinical case of 7 years old cattle with tumor mass obliterating the rectal opening. Histopathology of tumor revealed scattered stellate cells arranged singly or in clusters in loose mucinous ground substance, simulating myxoma. The cells obtained from tumor mass have been cultured for more than 36 months in DMEM supplemented with 10% fetal bovine serum (FBS). The population doubling time of this cell line was about 20.64 h. The cytogenetic analysis revealed several chromosomal abnormalities with bizarre karyotype. The origin of the cell line was confirmed by PCR amplification of 1086 bp fragment of 16s rRNA using bovine species specific primers. The new cell line would act as in vitro model to study many aspect of cancer biology such as tumor development, differentiation and therapeutics regimen to combat cancer. PMID- 25441619 TI - A new rolling culture-based in vitro fertilization system capable of reducing polyspermy in porcine oocytes. AB - The high incidence of polyspermy is one of the major obstacles during in vitro fertilization (IVF) in pigs. To overcome this, we developed a novel IVF method, which involves constant rotation. Oocytes matured in vitro were mixed with spermatozoa (0.2 * 10(5) sperm/mL) in an IVF medium (200 MUL) using a 200 MUL PCR tube. This tube was then rotated at 1 rpm for 6 h at 38.5 degrees C in a rotation mixer (experimental group). A second PCR tube was simultaneously cultured without rotation (control group). The rate of polyspermy was evaluated 12 h after insemination and was significantly (P < 0.05; 21.0% vs. 48.3%) lower in the experimental group than in the control group. Sperm penetration rate was similar in oocytes from the experimental and control groups (75.2% vs. 83.1%). However, monospermic fertilization rate of the oocytes was significantly (P < 0.05; 44.8% vs. 21.2%) higher in the experimental group than in the control group. Furthermore, the rate of blastocyst formation (30.1% vs. 20.8%) increased in the experimental group, as compared to the control group. This present system will contribute to increase the efficacy of blastocyst production through reduction of polyspermic penetration. PMID- 25441620 TI - The XV International Congress of the World Apheresis Association (WAA) was held in San Francisco in April. Introduction. PMID- 25441622 TI - Extracellular hemoglobin - mediator of inflammation and cell death in the choroid plexus following preterm intraventricular hemorrhage. AB - BACKGROUND: Intraventricular hemorrhage (IVH) with post-hemorrhagic ventricular dilatation (PHVD) is a major cause of neurodevelopmental impairment and mortality in preterm infants. The mechanisms leading to PHVD and brain damage remain largely unknown. The choroid plexus and the ependyma, which constitute an essential part of the blood-brain barrier (BBB), are the first structures to encounter the damaging effects of extravasated blood. The breakdown of the BBB is a critical upstream event leading to brain damage following IVH. In this study we investigated the impact of hemorrhage and hemoglobin (Hb) metabolites on the choroid plexus epithelium. METHODS: Using a preterm rabbit pup model of IVH, the structural and functional integrity, cellular, inflammatory and oxidative response of the choroid plexus, at 24 and 72 hours following IVH + PHVD, were investigated. In order to further characterize cellular and molecular mechanisms, primary human choroid plexus epithelial cells were exposed to cerebrospinal fluid (CSF) from preterm infants with IVH as well as to Hb-metabolites. Finally, the blocking effects of the Hb-scavenger haptoglobin (Hp) were investigated both in vivo and in vitro. RESULTS: Following IVH + PHVD, an up-regulation of mRNA for the receptor-related genes TLR-4, IL1R1, FAS, the transcription factor NF Kappabeta and for the pro-inflammatory and chemotactic effector molecules, IL 1beta, TNFalpha, MCP-1, IL-8, and IL-6 was observed in the choroid plexus at 24 and 72 hours. This was associated with structural disintegration, caspase activation and cell death in the choroid plexus epithelium. In vitro characterization of choroid plexus epithelial cells, following exposure to hemorrhagic CSF and to the Hb-metabolites metHb and heme, displayed apoptotic and necrotic cell death and an up-regulation of receptor-related and inflammatory effector molecules similar to that observed in vivo following IVH + PHVD. Intraventricular injection of the Hb-scavenger Hp in vivo and co-incubation with Hp in vitro reversed or reduced the cellular activation, inflammatory response, structural damage and cell death. CONCLUSION: Hb-metabolites are important causal initiators of cell death following IVH and removal or scavenging of Hb metabolites may present an efficient means to reduce the damage to the immature brain following IVH. PMID- 25441623 TI - Ability of Lactobacillus plantarum MON03 to mitigate aflatoxins (B1 and M1) immunotoxicities in mice. AB - Aflatoxin B1 (AFB1) and M1 (AFM1) are mycotoxins produced by numerous Aspergillus species in pre- or post-harvest cereals and milk. AFB1 and AFM1 display a potent economic loss in livestock and also cause severe immunological problems. The aims of this study were to: evaluate a new AFB1 and AFM1-binding/degrading micro organism for biological detoxification; examine its ability to degrade AFB1 and AFM1 in liquid medium; and evaluate its potential for in vivo preventative effects against AFB1- and AFM1-induced immunomodulation in mice. Lactobacillus plantarum MON03 (LP) isolated from Tunisian artisanal butter was found to display significant binding ability to AFB1 and AFM1 in PBS (i.e. 82% and 89%, respectively) within 24 h of incubation and able to tolerate gastric acidity, have strongly hydrophilic cells surface properties, and adhere efficacy to Caco-3 cells in vitro. The in vivo study was conducted using Balb/c mice that received by oral gavage vehicle (control), LP only (2 * 10(9) CFU/L, ~2 g/kg BW), AFB1 or AFM1 alone (0.25 and 0.27 mg/kg, respectively), or AFB1 + LP or AFM1 + LP daily for 15 days. Compared to in control mice, treatments with AFB1 and AFM1 led to significantly decreased body weight gains, histopathological changes, and decrements in all hematologic and immune parameters assessed. Co-treatment with LP strongly reduced the adverse effects of each mycotoxin. In fact, the mice receiving AFB1 + LP or AFM1 + LP co-treatment displayed no significant differences in the assayed parameters as compared to the control mice. By itself, the bacteria alone had no adverse effects in the mice. From these data, it is concluded that the tested bacteria could be beneficial in biotechnology detoxification of contaminated food and feed for humans and animals. PMID- 25441621 TI - Homologous recombination and retention of a single form of most genes shape the highly chimeric mitochondrial genome of a cybrid plant. AB - The structure and evolution of angiosperm mitochondrial genomes are driven by extremely high rates of recombination and rearrangement. An excellent experimental system for studying these events is offered by cybrid plants, in which parental mitochondria usually fuse and their genomes recombine. Little is known about the extent, nature and consequences of mitochondrial recombination in these plants. We conducted the first study in which the organellar genomes of a cybrid - between Nicotiana tabacum and Hyoscyamus niger - were sequenced and compared to those of its parents. This cybrid mitochondrial genome is highly recombinant, reflecting at least 30 crossovers and five gene conversions between its parental genomes. It is also surprisingly large (41% and 64% larger than the parental genomes), yet contains single alleles for 90% of mitochondrial genes. Recombination produced a remarkably chimeric cybrid mitochondrial genome and occurred entirely via homologous mechanisms involving the double-strand break repair and/or break-induced replication pathways. Retention of a single form of most genes could be advantageous to minimize intracellular incompatibilities and/or reflect neutral forces that preferentially eliminate duplicated regions. We discuss the relevance of these findings to the surprisingly frequent occurrence of horizontal gene - and genome - transfer in angiosperm mitochondrial DNAs. PMID- 25441624 TI - New treatment modalities for brain tumors in dogs and cats. AB - Despite advancements in standard therapies, intracranial tumors remain a significant source of morbidity and mortality in veterinary and human medicine. Several newer approaches are gaining more widespread acceptance or are currently being prepared for translation from experimental to routine therapeutic use. Clinical trials in dogs with spontaneous brain tumors have contributed to the development and human translation of several novel therapeutic brain tumor approaches. PMID- 25441625 TI - Altered states of consciousness in small animals. AB - Impaired states of consciousness can be relatively easily identified, although it can occasionally be difficult to assess whether there is a pure disorder of wakefulness or awareness. Regardless, such impairments represent dysfunction of the brainstem and or cerebrum. Acute and severe impairments of consciousness can require immediate assessment, in part currently performed using the modified Glasgow coma scoring system, and emergency stabilization. The prognosis is always guarded and highly sensitive to the underlying etiology. PMID- 25441626 TI - Canine hereditary ataxia. AB - The hereditary ataxias are a group of neurodegenerative diseases that cause a progressive (or episodic) cerebellar ataxia. A large number of different disorders have been described in different breeds of purebred dog, and in some instances, more than one disorder occurs in a single breed, creating a confusing clinical picture. The mutations associated with these disorders are being described at a rapid rate, potentially changing our ability to prevent, diagnose, and treat affected dogs. A breed-related neurodegenerative process should be suspected in any pure bred dog with slowly progressive, symmetric signs of ataxia. PMID- 25441627 TI - Canine paroxysmal movement disorders. AB - Paroxysmal dyskinesias are episodic movement disorders characterized by muscle hypertonicity that can produce involuntary movements. Signs emanate from the central nervous system; consciousness is not impaired, ictal electroencephalography is normal, and there are no autonomic signs, distinguishing them from seizure disorders. In humans they are classified into 3 groups, each responding to different therapies. A mutation in the gene for brevican (BCAN) has been identified as the cause of Episodic Falling in Cavalier King Charles spaniels. Further elucidation of the genetic causes will enhance our ability to identify and treat these canine diseases. PMID- 25441629 TI - Acute spinal cord injury: tetraplegia and paraplegia in small animals. AB - Spinal cord injury (SCI) is a common problem in animals for which definitive treatment is lacking, and information gained from its study has benefit for both companion animals and humans in developing new therapeutic approaches. This review provides an overview of the main concepts that are useful for clinicians in assessing companion animals with severe acute SCI. Current available advanced ancillary tests and those in development are reviewed. In addition, the current standard of care for companion animals following SCI and recent advances in the development of new therapies are presented, and new predictors of recovery discussed. PMID- 25441630 TI - Acute lower motor neuron tetraparesis. AB - Flaccid nonambulatory tetraparesis or tetraplegia is an infrequent neurologic presentation; it is characteristic of neuromuscular disease (lower motor neuron [LMN] disease) rather than spinal cord disease. Paresis beginning in the pelvic limbs and progressing to the thoracic limbs resulting in flaccid tetraparesis or tetraplegia within 24 to 72 hours is a common presentation of peripheral nerve or neuromuscular junction disease. Complete body flaccidity develops with severe decrease or complete loss of spinal reflexes in pelvic and thoracic limbs. Animals with acute generalized LMN tetraparesis commonly show severe motor dysfunction in all limbs and severe generalized weakness in all muscles. PMID- 25441628 TI - Aging in the canine and feline brain. AB - Aging dogs and cats show neurodegenerative features that are similar to human aging and Alzheimer disease. Neuropathologic changes with age may be linked to signs of cognitive dysfunction both in the laboratory and in a clinic setting. Less is known about cat brain aging and cognition and this represents an area for further study. Neurodegenerative diseases such as lysosomal storage diseases in dogs and cats also show similar features of human aging, suggesting some common underlying pathogenic mechanisms and also suggesting pathways that can be modified to promote healthy brain aging. PMID- 25441631 TI - Inherited neurologic disorders in the dog: the science behind the solutions. AB - Canine inherited neurologic diseases are clinically varied and can be congenital, neonatal, or late onset as well as progressive or stationary. Modern genetic technologies are revolutionizing the speed and efficiency with which mutations responsible for inherited neurologic disease are being identified. Clinically similar disorders can be caused by different mutations, even within a single breed, and are thus genetically distinct. DNA tests can be used by dog breeders to reduce the prevalence of inherited neurologic disorders in specific breeds and help the veterinarian diagnose disease. PMID- 25441632 TI - Fibrocyte trafficking in patients with chronic obstructive asthma and during an acute asthma exacerbation. AB - BACKGROUND: Fibrocytes express several chemokine receptors (CCR7 and CXCR4) that regulate their recruitment and trafficking into tissue-damage sites in response to specific chemokine gradients (CCL19 and CXCL12). OBJECTIVE: We investigated whether these chemoattractants and S100A9, through the receptor for advanced glycation end-products (RAGE; ie, its receptor), are involved in fibrocyte trafficking in patients with chronic obstructive asthma (COA) and during an acute exacerbation (AE) in patients without airflow obstruction (Asthma AE group). METHODS: We collected peripheral blood from 14 asthmatic patients with normal pulmonary function, 14 patients with COA, 11 patients in the Asthma AE group, and 14 healthy subjects. Isolated circulating fibrocytes were used for migration assay. Expression of CCR7, CXCR4, S100A9, and RAGE in fibrocytes was measured by using flow cytometry. CCL19 and CXCL12 expression in bronchial tissues was determined by using immunohistochemistry and RT-PCR. RESULTS: There were higher numbers of circulating fibrocytes in patients in the Asthma AE group and patients with COA. The expression of CXCL12 in bronchial tissues and CXCR4 in circulating fibrocytes was higher in the Asthma AE group and, to a lesser extent, in patients with COA. The expression of CCL19 in bronchial tissues and CCR7 in fibrocytes was higher in patients with COA. CXCL12/CXCR4 and CCL19/CCR7 enhanced fibrocyte transmigration in the Asthma AE group and in patients with COA, respectively. The upregulated expression of S100A9 and RAGE in fibrocytes of patients in the Asthma AE group and those with COA contributes to the enhanced basal migratory motility of fibrocytes. CONCLUSION: The CXCR4/CXCL12 axis contributes to chemotaxis of fibrocytes in patients in the Asthma AE group, whereas the CCR7/CCL19 axis plays an important role in patients with COA. S100A9 enhances the basal migratory motility of fibrocytes from patients in the Asthma AE group and patients with COA. PMID- 25441633 TI - Ramipril and metoprolol intake aggravate human and murine anaphylaxis: evidence for direct mast cell priming. AB - BACKGROUND: Cofactors contribute to the elicitation of anaphylaxis. beta-Blockers and angiotensin-converting enzyme (ACE) inhibitors are widely used cardiovascular drugs. We specially designed a mouse model to further analyze the cofactor potential of these drugs. OBJECTIVE: We sought to test the hypothesis that beta blockers and ACE inhibitors alter the risk for severe anaphylaxis and to pinpoint the associated mechanism. METHODS: The risk factor potency of cardiovascular drugs on the severity of anaphylaxis in patients from German-speaking countries was analyzed. In vivo interaction of the cardiovascular drugs metoprolol (beta blocker) and ramipril (ACE inhibitor) with the anaphylactic response was determined. Mast cell (MC) mediators (histamine, serotonin, leukotriene C4, prostaglandin D2, and mouse mast cell protease 1) were quantified in serum. Bone marrow-derived cultured MCs served to identify whether the therapeutics targeted MCs directly. RESULTS: Our anaphylaxis database indicated a higher risk of severe anaphylaxis after monotherapy with beta-blockers or ACE inhibitors, which was more pronounced when both drugs were combined. This was confirmed in our mouse model. While single therapeutics had either no significant (ramipril) or a modestly aggravating (metoprolol) effect, their combined administration exacerbated anaphylactic symptoms potently and simultaneously enhanced MC mediators, hinting at MCs as direct targets. In fact, FcepsilonRI-mediated MC histamine release was synergistically increased by metoprolol/ramipril or metoprolol/bradykinin (the latter increased after ACE inhibitor intake), whereas the substances had no significant effect on their own. MC priming was particularly pronounced when FcepsilonRI aggregation was in the suboptimal range, reflecting common clinical settings. CONCLUSION: beta-Blockers and ACE inhibitors synergistically aggravate anaphylaxis at least partly by decreasing the threshold of MC activation. PMID- 25441635 TI - Effect of ingested H1 antihistamines on methacholine challenge. PMID- 25441636 TI - Anaphylaxis: Unique aspects of clinical diagnosis and management in infants (birth to age 2 years). AB - In this rostrum we aim to increase awareness of anaphylaxis in infancy in order to improve clinical diagnosis, management, and prevention of recurrences. Anaphylaxis is increasingly reported in this age group. Foods are the most common triggers. Presentation typically involves the skin (generalized urticaria), the respiratory tract (cough, wheeze, stridor, and dyspnea), and/or the gastrointestinal tract (persistent vomiting). Tryptase levels are seldom increased because of infant anaphylaxis, although baseline tryptase levels can be increased in the first few months of life, reflecting mast cell burden in the developing immune system. The differential diagnosis of infant anaphylaxis includes consideration of age-unique entities, such as food protein-induced enterocolitis syndrome with acute presentation. Epinephrine (adrenaline) treatment is underused in health care and community settings. No epinephrine autoinjectors contain an optimal dose for infants weighing 10 kg or less. After treatment of an anaphylactic episode, follow-up with a physician, preferably an allergy/immunology specialist, is important for confirmation of anaphylaxis triggers and prevention of recurrences through avoidance of confirmed specific triggers. Natural desensitization to milk and egg can occur. Future research should include validation of the clinical criteria for anaphylaxis diagnosis in infants, prospective longitudinal monitoring of baseline serum tryptase levels in healthy and atopic infants during the first year of life, studies of infant comorbidities and cofactors that increase the risk of severe anaphylaxis, development of autoinjectors containing a 0.1-mg epinephrine dose suitable for infants, and inclusion of infants in prospective studies of immune modulation to prevent anaphylaxis recurrences. PMID- 25441637 TI - The prevalence of severe refractory asthma. AB - BACKGROUND: Severe asthma is characterized by difficulty to achieve disease control despite high-intensity treatment. However, prevalence figures of severe asthma are lacking, whereas longstanding estimates vary between 5% and 10% of all asthmatic patients. Knowing the exact prevalence of severe refractory asthma as opposed to difficult-to-control asthma is important for clinical decision making, drug development, and reimbursement policies by health authorities. OBJECTIVE: We sought to estimate the prevalence of severe refractory asthma as defined by the Innovative Medicine Initiative consensus. METHODS: Adult patients with a prescription for high-intensity treatment (high-dose inhaled corticosteroids and long-acting beta2-agonists or medium- to high-dose inhaled corticosteroids combined with oral corticosteroids and long-acting beta2-agonists) were extracted from 65 Dutch pharmacy databases, representing 3% of the population (500,500 inhabitants). Questionnaires were sent to 5,002 patients, of which 2,312 were analyzed. The diagnosis of asthma and degree of asthma control were derived from questionnaires to identify patients with difficult-to-control asthma. Inhalation technique was assessed in a random sample of 60 adherent patients (prescription filling, >=80%). Patients with difficult-to-control asthma, adherence to treatment, and a correct inhalation technique were qualified as having severe refractory asthma. Results were mirrored to the Dutch population. RESULTS: Of asthmatic adults, 3.6% (95% CI, 3.0% to 4.1%) qualified for a diagnosis of severe refractory asthma, representing 10.4 patients per 10,000 inhabitants. CONCLUSION: The prevalence of severe refractory asthma might be lower than estimated by expert opinion. This implies that currently recognized severe asthma subphenotypes could meet the criteria of rare diseases. PMID- 25441634 TI - Development and characterization of a recombinant, hypoallergenic, peptide-based vaccine for grass pollen allergy. AB - BACKGROUND: Grass pollen is one of the most important sources of respiratory allergies worldwide. OBJECTIVE: This study describes the development of a grass pollen allergy vaccine based on recombinant hypoallergenic derivatives of the major timothy grass pollen allergens Phl p 1, Phl p 2, Phl p 5, and Phl p 6 by using a peptide-carrier approach. METHODS: Fusion proteins consisting of nonallergenic peptides from the 4 major timothy grass pollen allergens and the PreS protein from hepatitis B virus as a carrier were expressed in Escherichia coli and purified by means of chromatography. Recombinant PreS fusion proteins were tested for allergenic activity and T-cell activation by means of IgE serology, basophil activation testing, T-cell proliferation assays, and xMAP Luminex technology in patients with grass pollen allergy. Rabbits were immunized with PreS fusion proteins to characterize their immunogenicity. RESULTS: Ten hypoallergenic PreS fusion proteins were constructed, expressed, and purified. According to immunogenicity and induction of allergen-specific blocking IgG antibodies, 4 hypoallergenic fusion proteins (BM321, BM322, BM325, and BM326) representing Phl p 1, Phl p 2, Phl p 5, and Phl p 6 were included as components in the vaccine termed BM32. BM321, BM322, BM325, and BM326 showed almost completely abolished allergenic activity and induced significantly reduced T-cell proliferation and release of proinflammatory cytokines in patients' PBMCs compared with grass pollen allergens. On immunization, they induced allergen specific IgG antibodies, which inhibited patients' IgE binding to all 4 major allergens of grass pollen, as well as allergen-induced basophil activation. CONCLUSION: A recombinant hypoallergenic grass pollen allergy vaccine (BM32) consisting of 4 recombinant PreS-fused grass pollen allergen peptides was developed for safe immunotherapy of grass pollen allergy. PMID- 25441638 TI - Transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitor-reversible allergic inflammation. AB - BACKGROUND: Esophageal eosinophilia can be proton pump inhibitor (PPI) resistant or responsive, representing 2 entities known as eosinophilic esophagitis (EoE) and PPI-responsive esophageal eosinophilia (PPI-REE), respectively. Although they present with similar clinical features, EoE is accepted to be an antigen-driven, TH2-associated allergic disorder, whereas the cause of PPI-REE remains a mystery. OBJECTIVE: In this study, our aim was to investigate the pathogenesis of PPI-REE by using a recently described EoE diagnostic panel (EDP) composed of a set of 94 esophageal transcripts and to determine whether PPI therapy reverses any esophageal transcriptional abnormalities. METHODS: We evaluated the EDP signature in biopsy samples obtained from adult and pediatric patients with PPI-REE from 4 institutions and compared the pre- and post-PPI therapy expression profiles of these subjects with those of patients with active EoE. RESULTS: The EDP differentiated patients with EoE from control subjects with 100% accuracy among the 4 clinical sites. Bioinformatics analysis revealed largely overlapping transcriptomes between patients with PPI-REE and those with EoE, including the genes for eosinophil chemotaxis (eotaxin 3, CCL26), barrier molecules (desmoglein 1, DSG1), tissue remodeling (periostin, POSTN), and mast cells (carboxypeptidase A, CPA3). PPI monotherapy alone almost completely reversed the allergic inflammatory transcriptome of patients with PPI-REE. Furthermore, we identified a set of candidate genes to differentiate patients with EoE from those with PPI-REE before treatment. CONCLUSION: These findings provide definitive evidence that PPI REE is a disease entity with significant molecular overlap with EoE, suggesting that many patients with PPI-REE represent a continuum of the same pathogenic allergic mechanisms that underlie EoE and thus might constitute a subphenotype of patients with EoE. The ability of PPI therapy to nearly entirely reverse gene expression associated with PPI-REE, particularly that associated with classic features of allergic inflammation, provides new insight into potential disease etiology and management strategies for patients with significant esophageal eosinophilia. PMID- 25441639 TI - The Xolair Pregnancy Registry (EXPECT): the safety of omalizumab use during pregnancy. AB - BACKGROUND: For many asthma medications, pregnancy safety data remains insufficient. OBJECTIVE: The omalizumab pregnancy registry, EXPECT, evaluates maternal, pregnancy, and infant outcomes after exposure to omalizumab, including incidence of congenital anomalies. METHODS: EXPECT is a prospective, observational study of pregnant women exposed to >=1 dose of omalizumab within 8 weeks prior to conception or at any time during pregnancy. Primary outcome measures include rates of live births, elective terminations, stillbirths, and congenital anomalies. Data were collected at enrollment, each trimester, birth, and every 6 months up to 18 months post-delivery. RESULTS: As of November 2012, 188 of 191 pregnant women were exposed to omalizumab during their first trimester. Of 169 pregnancies with known outcomes (median exposure during pregnancy, 8.8 months), there were 156 live births of 160 infants (4 twin pairs), 1 fetal death/stillbirth, 11 spontaneous abortions, and 1 elective termination. Among 152 singleton infants, 22 (14.5%) were born prematurely. Of 147 singleton infants with weight data, 16 (10.9%) were small for gestational age. Among 125 singleton full-term infants, 4 (3.2%) had low birth weights. Overall, 20 infants had congenital anomalies confirmed, 7 (4.4%) of whom had 1 major defect. No pattern of anomalies was observed. CONCLUSIONS: To date, proportions of major congenital anomalies, prematurity, low birth weight, and small size for gestational age observed in the EXPECT registry are not inconsistent with findings from other studies in this asthma population. Recognizing the small sample size available, no apparent increased birth prevalence of major anomalies or patterns of major anomalies has been observed. PMID- 25441641 TI - An acute cough-specific quality-of-life questionnaire for children: Development and validation. AB - BACKGROUND: Patient-relevant outcome measures are essential for high-quality clinical research, and quality-of-life (QoL) tools are the current standard. Currently, there is no validated children's acute cough-specific QoL questionnaire. OBJECTIVE: The objective of this study was to develop and validate the Parent-proxy Children's Acute Cough-specific QoL Questionnaire (PAC-QoL). METHODS: Using focus groups, a 48-item PAC-QoL questionnaire was developed and later reduced to 16 items by using the clinical impact method. Parents of children with a current acute cough (<2 weeks) at enrollment completed 2 validated cough score measures, the preliminary 48-item PAC-QoL, and 3 other questionnaires (the State Trait Anxiety Inventory [STAI], the Short-Form 8-item 24-hour recall Health Survey [SF-8], and the Depression, Anxiety, and Stress 21 item Scale [DASS21]). All measures were repeated on days 3 and 14. RESULTS: The median age of the 155 children enrolled was 2.3 years (interquartile range, 1.3 4.6). Median cough duration at enrollment was 3 days (interquartile range, 2-5). The reduced 16-item scale had high internal consistency (Cronbach alpha = 0.95). Evidence for repeatability and criterion validity was shown by significant correlations between the domains and total PAC-QoL scores and the SF-8 (r = -0.36 and -0.51), STAI (r = -0.27 and -0.39), and DASS21 (r = -0.32 and -0.41) scales on days 0 and 3, respectively. The final PAC-QoL questionnaire was sensitive to change over time, with changes significantly relating to changes in cough score measures (P < .001). CONCLUSION: The 16-item PAC-QoL is a reliable and valid outcome measure that assesses QoL related to childhood acute cough at a given time point and reflects changes in acute cough-specific QoL over time. PMID- 25441640 TI - Overweight children report qualitatively distinct asthma symptoms: analysis of validated symptom measures. AB - BACKGROUND: Past studies of asthma in overweight/obese children have been inconsistent. The reason overweight/obese children commonly report worse asthma control remains unclear. OBJECTIVE: To determine qualitative differences in symptoms between lean and overweight/obese children with early-onset, atopic asthma. METHODS: We conducted a cross-sectional analytic study of lean (20% to 65% body mass index) and overweight/obese (>=85% body mass index) 10- to 17-year old children with persistent, early-onset asthma. Participants completed 2 to 3 visits to provide a complete history, qualitative and quantitative asthma symptom characterization, and lung function testing. We determined associations between weight status and symptoms using multivariable linear and logistic regression methods. RESULTS: Overweight/obese and lean asthmatic children displayed similar lung function. Despite lower fraction of exhaled nitric oxide (30.0 vs 62.6 ppb; P = .037) and reduced methacholine responsiveness (PC20FEV1 1.87 vs 0.45 mg/mL; P < .012), overweight/obese children reported more than thrice frequent rescue treatments (3.7 vs 1.1 treatments/wk; P = .0002) than did lean children. Weight status affected the child's primary symptom reported with loss of asthma control (Fisher exact test; P = .003); overweight/obese children more often reported shortness of breath (odds ratio = 11.8; 95% CI, 1.41-98.7) and less often reported cough (odds ratio = 0.26; 95% CI, 0.08-0.82). Gastroesophageal reflux scores were higher in overweight/obese children (9.6 vs 23.2; P = .003) and appear to mediate overweight/obesity-related asthma symptoms. CONCLUSIONS: Overweight/obese children with early-onset asthma display poorer asthma control and a distinct pattern of symptoms. Greater shortness of breath and beta-agonist use appears to be partially mediated via esophageal reflux symptoms. Overweight children with asthma may falsely attribute exertional dyspnea and esophageal reflux to asthma, leading to excess rescue medication use. PMID- 25441642 TI - Dynamic transcriptional and epigenomic reprogramming from pediatric nasal epithelial cells to induced pluripotent stem cells. AB - BACKGROUND: Induced pluripotent stem cells (iPSCs) hold tremendous potential, both as a biological tool to uncover the pathophysiology of disease by creating relevant human cell models and as a source of cells for cell-based therapeutic applications. Studying the reprogramming process will also provide significant insight into tissue development. OBJECTIVE: We sought to characterize the derivation of iPSC lines from nasal epithelial cells (NECs) isolated from nasal mucosa samples of children, a highly relevant and easily accessible tissue for pediatric populations. METHODS: We performed detailed comparative analysis on the transcriptomes and methylomes of NECs, iPSCs derived from NECs (NEC-iPSCs), and embryonic stem cells (ESCs). RESULTS: NEC-iPSCs express pluripotent cell markers, can differentiate into all 3 germ layers in vivo and in vitro, and have a transcriptome and methylome remarkably similar to those of ESCs. However, residual DNA methylation marks exist, which are differentially methylated between NEC-iPSCs and ESCs. A subset of these methylation markers related to epithelium development and asthma and specific to NEC-iPSCs persisted after several passages in vitro, suggesting the retention of an epigenetic memory of their tissue of origin. Our analysis also identified novel candidate genes with dynamic gene expression and DNA methylation changes during reprogramming, which are indicative of possible roles in airway epithelium development. CONCLUSION: NECs are an excellent tissue source to generate iPSCs in pediatric asthmatic patients, and detailed characterization of the resulting iPSC lines would help us better understand the reprogramming process and retention of epigenetic memory. PMID- 25441644 TI - Prostaglandin D2 and leukotriene E4 synergize to stimulate diverse TH2 functions and TH2 cell/neutrophil crosstalk. AB - BACKGROUND: Prostaglandin D2 (PGD2) and cysteinyl leukotrienes (cysLTs) are lipid mediators derived from mast cells, which activate TH2 cells. The combination of PGD2 and cysLTs (notably cysteinyl leukotriene E4 [LTE4]) enhances TH2 cytokine production. However, the synergistic interaction of cysLTs with PGD2 in promoting TH2 cell activation is still poorly understood. The receptors for these mediators are drug targets in the treatment of allergic diseases, and hence understanding their interaction is likely to have clinical implications. OBJECTIVE: We aimed to comprehensively define the roles of PGD2, LTE4, and their combination in activating human TH2 cells and how such activation might allow the TH2 cells to engage downstream effectors, such as neutrophils, which contribute to the pathology of allergic responses. METHODS: The effects of PGD2, LTE4, and their combination on human TH2 cell gene expression were defined by using a microarray, and changes in specific inflammatory pathways were confirmed by means of PCR array, quantitative RT-PCR, ELISA, Luminex, flow cytometry, and functional assays, including analysis of downstream neutrophil activation. Blockade of PGD2 and LTE4 was tested by using TM30089, an antagonist of chemoattractant receptor homologous molecule expressed on TH2 cells, and montelukast, an antagonist of cysteinyl leukotriene receptor 1. RESULTS: PGD2 and LTE4 altered the transcription of a wide range of genes and induced diverse functional responses in TH2 cells, including cell adhesion, migration, and survival and cytokine production. The combination of these lipids synergistically or additively enhanced TH2 responses and, strikingly, induced marked production of diverse nonclassical TH2 inflammatory mediators, including IL-22, IL-8, and GM-CSF, at concentrations sufficient to affect neutrophil activation. CONCLUSIONS: PGD2 and LTE4 activate TH2 cells through different pathways but act synergistically to promote multiple downstream effector functions, including neutrophil migration and survival. Combined inhibition of both PGD2 and LTE4 pathways might provide an effective therapeutic strategy for allergic responses, particularly those involving interaction between TH2 cells and neutrophils, such as in patients with severe asthma. PMID- 25441646 TI - Patients with positive skin test results to penicillin should not undergo penicillin or amoxicillin challenge. PMID- 25441645 TI - Consumption of unprocessed cow's milk protects infants from common respiratory infections. AB - BACKGROUND: Breast-feeding is protective against respiratory infections in early life. Given the co-evolutionary adaptations of humans and cattle, bovine milk might exert similar anti-infective effects in human infants. OBJECTIVE: To study effects of consumption of raw and processed cow's milk on common infections in infants. METHODS: The PASTURE birth cohort followed 983 infants from rural areas in Austria, Finland, France, Germany, and Switzerland, for the first year of life, covering 37,306 person-weeks. Consumption of different types of cow's milk and occurrence of rhinitis, respiratory tract infections, otitis, and fever were assessed by weekly health diaries. C-reactive protein levels were assessed using blood samples taken at 12 months. RESULTS: When contrasted with ultra-heat treated milk, raw milk consumption was inversely associated with occurrence of rhinitis (adjusted odds ratio from longitudinal models [95% CI]: 0.71 [0.54 0.94]), respiratory tract infections (0.77 [0.59-0.99]), otitis (0.14 [0.05 0.42]), and fever (0.69 [0.47-1.01]). Boiled farm milk showed similar but weaker associations. Industrially processed pasteurized milk was inversely associated with fever. Raw farm milk consumption was inversely associated with C-reactive protein levels at 12 months (geometric means ratio [95% CI]: 0.66 [0.45-0.98]). CONCLUSIONS: Early life consumption of raw cow's milk reduced the risk of manifest respiratory infections and fever by about 30%. If the health hazards of raw milk could be overcome, the public health impact of minimally processed but pathogen-free milk might be enormous, given the high prevalence of respiratory infections in the first year of life and the associated direct and indirect costs. PMID- 25441643 TI - DNA-dependent protein kinase inhibition blocks asthma in mice and modulates human endothelial and CD4+ T-cell function without causing severe combined immunodeficiency. AB - BACKGROUND: We reported that DNA-dependent protein kinase (DNA-PK) is critical for the expression of nuclear factor kappaB-dependent genes in TNF-alpha-treated glioblastoma cells, suggesting an involvement in inflammatory diseases. OBJECTIVE: We sought to investigate the role of DNA-PK in asthma. METHODS: Cell culture and ovalbumin (OVA)- or house dust mite-based murine asthma models were used in this study. RESULTS: DNA-PK was essential for monocyte adhesion to TNF alpha-treated endothelial cells. Administration of the DNA-PK inhibitor NU7441 reduced airway eosinophilia, mucus hypersecretion, airway hyperresponsiveness, and OVA-specific IgE production in mice prechallenged with OVA. Such effects correlated with a marked reduction in lung vascular cell adhesion molecule 1 expression and production of several cytokines, including IL-4, IL-5, IL-13, eotaxin, IL-2, and IL-12 and the chemokines monocyte chemoattractant protein 1 and keratinocyte-derived chemokine, with a negligible effect on IL-10/IFN-gamma production. DNA-PK inhibition by gene heterozygosity of the 450-kDa catalytic subunit of the kinase (DNA-PKcs(+/-)) also prevented manifestation of asthma-like traits. These results were confirmed in a chronic model of asthma by using house dust mite, a human allergen. Remarkably, such protection occurred without causing severe combined immunodeficiency. Adoptive transfer of TH2-skewed OT-II wild-type CD4(+) T cells reversed IgE and TH2 cytokine production but not airway hyperresponsiveness in OVA-challenged DNA-PKcs(+/-) mice. DNA-PK inhibition reduced IL-4, IL-5, IL-13, eotaxin, IL-8, and monocyte chemoattractant protein 1 production without affecting IL-2, IL-12, IFN-gamma, and interferon-inducible protein 10 production in CD3/CD28-stimulated human CD4(+) T cells, potentially by blocking expression of Gata3. These effects occurred without significant reductions in T-cell proliferation. In mouse CD4(+) T cells in vitro DNA-PK inhibition severely blocked CD3/CD28-induced Gata3 and T-bet expression in CD4(+) T cells and prevented differentiation of TH1 and TH2 cells under respective TH1- and TH2-skewing conditions. CONCLUSION: Our results suggest DNA-PK as a novel determinant of asthma and a potential target for the treatment of the disease. PMID- 25441648 TI - Knowledge of the literature is crucial for meta-analyses. PMID- 25441647 TI - Prenatal and infant exposure to acetaminophen and ibuprofen and the risk for wheeze and asthma in children. AB - BACKGROUND: Several studies have reported an association between use of over-the counter antipyretics during pregnancy or infancy and increased asthma risk. An important potential limitation of these observational studies is confounding by indication. OBJECTIVES: We investigated the association of antipyretic intake during pregnancy and during the first year of life (infancy) with asthma-related outcomes before and after controlling for early-life respiratory tract infections. METHODS: We included 1490 mother-child pairs in Project Viva, a longitudinal prebirth cohort study. We categorized prenatal acetaminophen exposure as the maximum intake (never, 1-9 times, or >=10 times) in early pregnancy or midpregnancy and ibuprofen intake as presence or absence in early pregnancy. We expressed intake of antipyretics in infancy as never, 1 to 5 times, 6 to 10 times, or more than 10 times. We examined the associations of acetaminophen and ibuprofen (per unit increase in exposure category) during pregnancy and infancy with wheeze, asthma, and allergen sensitization in early childhood (3-5 years of age, n = 1419) and midchildhood (7-10 years of age, n = 1220). RESULTS: Unadjusted models showed an increased asthma risk in early childhood for higher infant acetaminophen (odds ratio [OR], 1.21; 95% CI 1.04 1.41) and ibuprofen (OR, 1.35; 95% CI, 1.19-1.52) intake. Controlling for respiratory tract infections attenuated estimates for acetaminophen (OR, 1.03; 95% CI, 0.88-1.22) and ibuprofen (OR, 1.19; 95% CI, 1.05-1.36). Prenatal acetaminophen was associated with increased asthma (OR, 1.26; 95% CI, 1.02-1.58) in early childhood but not midchildhood. CONCLUSIONS: Adjustment for respiratory tract infections in early life substantially diminished associations between infant antipyretic use and early childhood asthma. Respiratory tract infections should be accounted for in studies of antipyretics and asthma to mitigate bias caused by confounding by indication. PMID- 25441649 TI - Introducing an environmental assessment and intervention program in inner-city schools. AB - Home-based environmental interventions have demonstrated clinical benefit for children with asthma. Although much is known about school-based exposures, few studies have comprehensively examined the role the school environment plays in asthma and how effectively changing the environment might reduce morbidity when adjusting for exposures in the home. This review summarizes the importance and common challenges of school-based environmental assessment and intervention studies linked to health effects. We focus on the key components of study development and the challenges and benefits to implementation. PMID- 25441651 TI - Learning trajectories of children with special health care needs across the severity spectrum. AB - OBJECTIVE: A significant proportion of school-aged children experience special health care needs (SCHN) and seek care from pediatricians with a wide range of condition types and severity levels. This study examines the learning pathways of children with established (already diagnosed at school entry) and emerging (teacher identified) SHCN from school entry through the elementary school years. METHODS: The Longitudinal Study of Australian Children (LSAC) is a nationally representative clustered cross-sequential sample of 2 cohorts of Australian children which commenced in May 2004. Data were analyzed from the LSAC kindergarten cohort (n = 4,983), as well as a subsample of 720 children for whom teachers also completed the Australian Early Development Index checklist, a measure of early childhood development at school entry that includes SHCN. RESULTS: Latent class analysis was utilized to establish 3 academic trajectories from 4-5 to 10-11 years: high (24.3%), average (49.8%), and low (23.6%). Descriptive statistics revealed a trend for both children with established and emerging SHCN to fall into weaker performing learning pathways. Multinomial logistic regression focusing on those children with emerging SHCN confirmed this pattern of results, even after adjustment for covariates (relative risk 3.06, 95% confidence interval 1.03-9.10). Children who additionally had low socioeconomic standing were particularly at risk. CONCLUSIONS: Even children with less complex SCHN are at risk for academic failure. Early identification, together with integrated health and educational support, may promote stronger pathways of educational attainment for these children. Achieving these better outcomes will require the involvement of both educational and health practitioners. PMID- 25441650 TI - Maternal allergy increases susceptibility to offspring allergy in association with TH2-biased epigenetic alterations in a mouse model of peanut allergy. AB - BACKGROUND: Although maternal atopy is a risk factor for the development of peanut allergy, this phenomenon has not been well characterized experimentally, and the mechanisms underlying offspring risk are unclear. OBJECTIVE: We sought to determine whether offspring of mothers with peanut allergy (O-PAM mice) are more susceptible to peanut allergy than offspring of naive mothers (O-NM mice) in a murine model and, if so, whether the susceptibility is linked to TH2-biased epigenetic alterations. METHODS: Five-week-old O-PAM and O-NM mice were intragastrically sensitized to and challenged with peanut. Serum peanut-specific IgE levels, plasma histamine levels, anaphylactic reactions, and splenocyte and MLN cell cytokine production were measured. DNA methylation levels of the Il4 gene promoter from splenocytes and MLN cells from sensitized offspring and splenocytes from unsensitized neonatal offspring were determined by means of pyrosequencing. RESULTS: O-PAM mice exhibited 3-fold higher peanut-specific IgE levels after peanut sensitization, as well as 5-fold higher histamine levels and significantly higher anaphylactic symptom scores after challenge than O-NM mice (P < .05-.01). Cultured splenocytes and MLNs from O-PAM mice produced significantly more TH2 cytokines than cells from O-NM mice (P < .05-.01). Cells from O-PAM mice exhibited significantly reduced DNA methylation at CpG sites of the Il4 gene promoter than cells from O-NM mice. DNA methylation levels were inversely correlated with IL-4 and IgE production. O-PAM neonatal splenocyte hypomethylation of the Il4 gene promoter was also present. CONCLUSION: This study is the first to demonstrate that increased susceptibility to peanut allergy in O PAM mice is associated with epigenetic alteration of the Il4 gene promoter. This finding might provide insight into preventing the development of early-life allergy. PMID- 25441652 TI - Media violence exposure and physical aggression in fifth-grade children. AB - OBJECTIVE: To examine the association of media violence exposure and physical aggression in fifth graders across 3 media types. METHODS: We analyzed data from a population-based, cross-sectional survey of 5,147 fifth graders and their parents in 3 US metropolitan areas. We used multivariable linear regression and report partial correlation coefficients to examine associations between children's exposure to violence in television/film, video games, and music (reported time spent consuming media and reported frequency of violent content: physical fighting, hurting, shooting, or killing) and the Problem Behavior Frequency Scale. RESULTS: Child-reported media violence exposure was associated with physical aggression after multivariable adjustment for sociodemographics, family and community violence, and child mental health symptoms (partial correlation coefficients: TV, 0.17; video games, 0.15; music, 0.14). This association was significant and independent for television, video games, and music violence exposure in a model including all 3 media types (partial correlation coefficients: TV, 0.11; video games, 0.09; music, 0.09). There was a significant positive interaction between media time and media violence for video games and music but not for television. Effect sizes for the association of media violence exposure and physical aggression were greater in magnitude than for most of the other examined variables. CONCLUSIONS: The association between physical aggression and media violence exposure is robust and persistent; the strength of this association of media violence may be at least as important as that of other factors with physical aggression in children, such as neighborhood violence, home violence, child mental health, and male gender. PMID- 25441653 TI - Diagnosis of attention-deficit/hyperactivity disorder by developmental pediatricians in academic centers: A DBPNet study. AB - OBJECTIVE: To describe the developmental-behavioral pediatricians (DBPs), patients, and clinical practices used in the diagnostic assessments of attention deficit/hyperactivity disorder (ADHD) within all 12 academic medical centers comprising Developmental-Behavioral Pediatrics Research Network (DBPNet). METHODS: Between December 2011 and June 2012, all DBPs who evaluated children with ADHD or autism spectrum disorders were asked to complete a diagnostic encounter survey form for up to 10 consecutive new cases that resulted in the diagnosis of ADHD or autism spectrum disorder. Fifty-two clinicians returned one or more forms for children diagnosed with ADHD (n = 211). RESULTS: DBPs were generally experienced full-time academics. Children were 76.3% male, 62.3% white, 24.5% African American, and 20.7% Hispanic. Mean child age was 8.0 + 3.1 years. DBPs reviewed parent ratings of behavior in 84.4% and teacher ratings in 69.2% of cases. They reviewed or completed at least one developmental assessment in 79.2% of cases: intelligence (60.2%), academic (57.8%), fine motor or visual motor (39.3%), speech/language (34.6%), or adaptive skills (28.9%). They made the diagnosis of coexisting conditions in 82.7% of cases, including learning disabilities (31.8%), speech/language disorders (31.8%), anxiety (14.2%), externalizing disorders (10.9%), and sleep disorders (9.5%). Among 146 children not medicated before the visit, stimulant medications were initiated in 15 children (10.2%). CONCLUSIONS: Within DBPNet, DBPs were highly likely to complete comprehensive assessments of ADHD that went beyond the requirements of primary care practice guidelines. They typically identified coexisting developmental and learning conditions. They did not typically prescribe medication at the end of diagnostic encounters. PMID- 25441654 TI - Trajectories of Adverse Childhood Experiences and Self-Reported Health at Age 18. AB - OBJECTIVE: Despite growing evidence of links between adverse childhood experiences (ACEs) and long-term health outcomes, there has been limited longitudinal investigation of such links in youth. The purpose of these analyses was to describe the patterns of exposure to ACEs over time and their links to youth health. METHODS: The current analyses used data from LONGSCAN, a prospective study of children at risk for or exposed to child maltreatment, who were followed from age 4 to age 18. The analyses focused on 802 youth with complete data. Cumulative exposure to ACEs between 4 and 16 was used to place participants in 3 trajectory-defined groups: chronic ACEs, early ACEs only, and limited ACEs. Links to self-reported health at age 18 were examined using linear mixed models after controlling for earlier health status and demographics. RESULTS: The chronic ACEs group had increased self-reported health concerns and use of medical care at 18 but not poorer self-rated health status. The early ACEs only group did not significantly differ from limited ACEs on outcomes. CONCLUSIONS: In addition to other negative outcomes, chronic ACEs appear to affect physical health in emerging adulthood. Interventions aimed at reducing exposure to ACEs and early mitigation of their effects may have lasting and widespread health benefits. PMID- 25441655 TI - The effectiveness of interventions to increase physical activity among adolescent girls: a meta-analysis. AB - BACKGROUND: Research has shown that a clear decline in physical activity among girls starting in early adolescence. Therefore, adolescent girls have been identified as a key target population for physical activity behavior change. The quantification of intervention effectiveness for this group has not been previously reported in a meta-analysis, and this therefore was the objective of the current meta-analysis. STUDY SELECTION: Included were interventions in which the main component, or 1 of the components, was aimed at promoting physical activity through behavior change in any setting. Interventions had to include a non-physical activity control group or comparison group, and include a quantitative outcome assessment of physical activity behavior in girls aged 12 to 18 years. DATA SOURCES: Science Direct, PubMed, PsychINFO, Web of Science, Cochrane Libraries, and EPPI Centre databases were searched up to and including May 2013. DATA EXTRACTION AND SYNTHESIS: Forty-five studies (k = 34 independent samples) were eligible from an initial 13,747 references. A random-effects meta analysis was conducted. RESULTS: The average treatment effect for adolescent girls involved in physical activity interventions was significant but small (g = 0.350, 95% confidence interval 0.12, 0.58, P < .001). Moderator analyses showed larger effects for interventions that were theory based, performed in schools, were girls only, with younger girls, used multicomponent strategies, and involved targeting both physical activity and sedentary behavior. CONCLUSIONS: Interventions to increase physical activity in adolescent girls show small but significant effects, suggesting that behavior change may be challenging. Results suggest some approaches that appear to be successful. PMID- 25441656 TI - Nonspecific abdominal pain in pediatric primary care: evaluation and outcomes. AB - OBJECTIVE: To describe the characteristics of children with nonspecific abdominal pain (AP) in primary care, their evaluation, and their outcomes. METHODS: Between 2007 and 2009, a retrospective cohort of children from 5 primary care practices was followed from an index visit with AP until a well-child visit 6 to 24 months later (outcome visit). Using International Classification of Disease, 9th Revision (ICD-9), codes and chart review, we identified afebrile children between 4 and 12 years old with AP. Use of diagnostic testing was assessed. Multivariable logistic regression was used to model the association of index visit clinical and demographic variables with persistent pain at the outcome visit, and receipt of a specific diagnosis. RESULTS: Three hundred seventy-five children presented with AP, representing 1% of the total population of 4- to 12-year-olds during the study period. Eighteen percent of children had persistent pain, and 70% of the study cohort never received a specific diagnosis for their pain. Seventeen percent and 14% of children had laboratory and radiology testing at the index visit, respectively. Only 3% of laboratory evaluations helped to yield a diagnosis. Among variables considered, only preceding pain of more than 7 days at the index visit was associated with persistent pain (odds ratio 2.15, 95% confidence interval 1.19-3.89). None of the variables considered was associated with receiving a specific diagnosis. CONCLUSIONS: Most children with AP do not receive a diagnosis, many have persistent pain, and very few receive a functional AP diagnosis. Results support limited use of diagnostic testing and conservative management consistent with national policy statements. PMID- 25441657 TI - Dental caries development among African American children: results from a 4-year longitudinal study. AB - OBJECTIVE: To examine dental caries development and caries risk factors among preschool African American children from low-income families in Detroit, Michigan, over a 4-year window. METHODS: Data came from a representative sample of 1021 children (0-5 years) and their caregivers in Detroit. The baseline participants in 2002-2003 (W1) were re-examined in 2004-2005 (W2) and 2007 (W3). Caries was measured using the International Caries Detection and Assessment System. Bivariate and multivariate analyses for repeated data were conducted to explore associations between caries increment outcomes and demographics, access to dental care, oral health-related behaviours, and social and physical environments. RESULTS: The mean number of new noncavitated caries lesions (NCCL) was 2.8 between W1 and W2 and 2.6 between W2 and W3, while the mean number of new cavitated caries lesions (CCL) was 2.0 and 2.0, respectively, during the same time periods. In younger children (<3 years old in W1), higher number of new NCCL than new CCL was observed in both W1-W2 and W2-W3. The risk of new NCCL was associated with child's soda intake and caregiver's age. For the risk of new CCL, significant risk factors included baseline NCCL, baseline CCL, as well as child's age. Baseline caries and child's soda intake were also associated with the risk of developing new decayed, missing and filled tooth surfaces. CONCLUSIONS: Higher number of new NCCL relative to CCL was developed among low-income African American children during early childhood. New caries development was associated with baseline caries and child's soda intake. PMID- 25441658 TI - Nitric oxide as a regulatory factor for aquaporin-1 and 4 gene expression following brain ischemia/reperfusion injury in rat. AB - Although the role of aquaporin-4 (AQP4) and aquaporin-1 (AQP1) channels in ischemia-induced brain edema has been previously reported, nitric oxide (NO) modulation of these channels has not been investigated. The aim of this study was to evaluate the NO modulation of AQPs gene expression after brain ischemia/reperfusion (I/R) in rats. The experiment was performed in three groups of rats: sham, control ischemic and L-NAME pretreated (1 mg/kg). Brain ischemia was induced by 60 min middle cerebral artery occlusion (MCAO) under continuous recording of regional cerebral blood flow (rCBF) followed by 12 h reperfusion. Brain edema was assessed by dry/wet method, and Quantitative RT-PCR was used for assessment of mRNA levels of AQPs. There was 80% reduction in rCBF during MCAO. Brain cerebral ischemia elevated the brain water content from 78.66+/-0.17% to 81.93+/-0.60%, and inhibition of NO production by L-NAME significantly reduced this elevation (79.74+/-0.79%). The mRNA expression of AQP1 increased, but AQP4 decreased in response to I/R. l-NAME pretreatment significantly decreased AQP1 mRNA and prevented the reduction of AQP4 mRNA. The findings of this study indicated that brain I/R injury provokes brain edema by alterations of AQPs expression, and the NO is the main signaling factor that modulates gene expression of these channels. PMID- 25441659 TI - Reduction of immunity in HIV-infected individuals: can fibrosis induce hypoplasia in palatine and lingual tonsils of individuals with HIV infection? AB - The role of tonsils in oral immunity has been described. However, the pathogenesis of HIV infection in these organs is still unclear. The aim of this study is to perform histological and immunohistochemical analysis of the palatine and lingual tonsils of autopsied individuals with or without HIV infection. Twenty-six autopsied individuals with HIV infection (HI) (n=13) and without HIV infection (CO) (n=13) were selected. Palatine and lingual tonsil fragments were collected for histological and immunohistochemical analysis. We found in the HI group a higher frequency of hyaline degeneration in both palatine and lingual tonsils; smaller follicle areas, and a higher percentage of collagen in comparison with the CO group. In the HI group, there was higher density of blood vessels in palatine tonsils than in the CO group. In the HI group, there were significant positive correlations between palatine and lingual tonsils and the area of lymphoid follicles, and between the percentage of blood vessels and collagen in palatine tonsils. In addition, there was a significant negative correlation between the percentage of collagen and lymphoid follicle area in both palatine and lingual tonsils in the HI group. These findings suggest that the immune functions of these tonsils are prejudiced by fibrosis. Therapies to reduce the neoformation of collagen are required to improve immune function of organs against pathogens. PMID- 25441660 TI - Staging of thymic epithelial neoplasms: thymoma and thymic carcinoma. AB - Thymic epithelial neoplasms are uncommon tumors that have been the subject of interest in the last few decades with regard to their histogenesis, histopathologic classification, treatment and prognosis. These tumors are a group of heterogenous neoplasms that are often difficult to subtype and the value of such subclassification with regard to prognosis remains obscure. One factor, however, that appears strongly associated with clinical behavior is tumor staging. The focus of this review will be an overview of the different staging systems for thymic epithelial neoplasms that have been presented in the literature over the years. Particular emphasis is paid to the latest developments in this context. PMID- 25441662 TI - Ultrastructural changes in rat airway epithelium in asthmatic airway remodeling. AB - OBJECTIVES: To explore asthmatic rat airway epithelial cells mitochondrial ultrastructure changes. METHODS: Six female Wistar rats of the same weight (60-80 g) were randomly divided into two groups: the asthmatic group and the control group. According to the OVA inhaled method, the asthmatic airway remodeling rat model was established. Epithelial tissue of the rat trachea was taken from the two groups for transmission electron microscopy (TEM); we counted the number of mitochondria and observed the airway ciliated epithelium, intercellular collagen deposition in the two rat groups and mitochondrial ultrastructure change. RESULTS: Airway multilayer ciliated epithelium develops, with cilia fallen off; goblet cells increased and irregular, mitochondrial basement membrane density is decreased, mitochondrial crista is reduced, and the nucleus has more incisures and irregular shape in asthmatic rats; airway epithelial cell matrix collagen deposition increased; and lamellar body and mitochondrial cavity formation. CONCLUSIONS: In the asthmatic rat airway, epithelial cells undergo apoptosis and the numbers of mitochondria increased compared with the ones in normal rat airway but lose normal structure. PMID- 25441661 TI - Increased VEGFR2 and MMP9 protein levels are associated with epithelial dysplasia grading. AB - The present study aimed to compare levels of VEGFR2 and MMP-9 among control, epithelial dysplasia (ED) and oral squamous cell carcinoma (OSCC) groups. We analyzed 48 patients with oral leukoplakia (OL), 20 patients with OSCC and 21 patients without OL and OSCC. Immunohistochemistry of VEGFR2 and MMP9 were performed and compared among groups. Analysis of tissue immunolocalization of VEGFR2 and MMP-9 assumed non-parametrical distribution and comparison between groups was performed using the Mann-Whitney and Kruskal-Wallis statistical tests. VEGFR2 and MMP9 immunoexpression appeared to correlate with the degree of dysplasia and was observed to increase in lesions with more severe dysplasia as compared to those with lower degrees of dysplasia. Immunoreactivity of MMP-9 was lower in the OL samples compared to the OSCC samples (p = 0.004). We observed no difference in VEGFR2 protein levels between OL and OSCC samples. A positive correlation was found between VEGFR2 and MMP-9 in OL samples (r = +0.452, p = 0.001), however, no correlation was found in OSCC samples (r = -0.042, p = 0.861). In conclusion, the results of the current study suggest that expression of MMP9 and VEGFR2 is associated with ED grading and MMP9 levels are increased in OSCC. PMID- 25441663 TI - Monitoring vegetation change and dynamics on U.S. Army training lands using satellite image time series analysis. AB - Given the significant land holdings of the U.S. Department of Defense, and the importance of those lands to support a variety of inherently damaging activities, application of sound natural resource conservation principles and proactive monitoring practices are necessary to manage military training lands in a sustainable manner. This study explores a method for, and the utility of, analyzing vegetation condition and trends as sustainability indicators for use by military commanders and land managers, at both the national and local levels, in identifying when and where vegetation-related environmental impacts might exist. The BFAST time series decomposition method was applied to a ten-year MODIS NDVI time series dataset for the Fort Riley military installation and Konza Prairie Biological Station (KPBS) in northeastern Kansas. Imagery selected for time series analysis were 16-day MODIS NDVI (MOD13Q1 Collection 5) composites capable of characterizing vegetation change induced by human activities and climate variability. Three indicators related to gradual interannual or abrupt intraannual vegetation change for each pixel were calculated from the trend component resulting from the BFAST decomposition. Assessment of gradual interannual NDVI trends showed the majority of Fort Riley experienced browning between 2001 and 2010. This result is supported by validation using high spatial resolution imagery. The observed versus expected frequency of linear trends detected at Fort Riley and KPBS were significantly different and suggest a causal link between military training activities and/or land management practices. While both sites were similar with regards to overall disturbance frequency and the relative spatial extents of monotonic or interrupted trends, vegetation trajectories after disturbance were significantly different. This suggests that the type and magnitude of disturbances characteristic of each location result in distinct post-disturbance vegetation responses. Using a remotely-sensed vegetation index time series with BFAST and the indicators outlined here provides a consistent and relatively rapid assessment of military training lands with applicability outside of grassland biomes. Characterizing overall trends and disturbance responses of vegetation can promote sustainable use of military lands and assist land managers in targeting specific areas for various rehabilitation activities. PMID- 25441664 TI - The metabolic syndrome and sexual function in climacteric women: a cross sectional study. AB - INTRODUCTION: Studies have associated the metabolic syndrome with poor sexual function; the results, however, are controversial. AIMS: To evaluate the relationship between the metabolic syndrome and sexual function and to identify the factors associated with poor sexual function. METHODS: A secondary analysis of a cross-sectional cohort study including 256 women of 40-60 years of age receiving care at the outpatient department of a university teaching hospital. MAIN OUTCOME MEASURES: A specific questionnaire was applied to collect sociodemographic and behavioral data, and the Short Personal Experience Questionnaire was used to evaluate sexual function, with a score <= 7 being indicative of poor sexual function. Anthropometric measurements, blood pressure, fasting glucose, high-density lipoprotein, total cholesterol, triglycerides, follicle-stimulating hormone and thyroid stimulating hormone levels were determined. RESULTS: The prevalence of the metabolic syndrome, as defined by the International Diabetes Federation, was 62.1%, and the prevalence of poor sexual function was 31.4%. The only factor related to female sexual function that was associated with the metabolic syndrome was sexual dysfunction in the woman's partner. The factors associated with poor sexual function in the bivariate analysis were age >50 years (P=0.003), not having a partner (P<0.001), being postmenopausal (P=0.046), the presence of hot flashes (P=0.02), poor self perception of health (P=0.04), partner's age >= 50 years, and time with partner >= 21 years. Reported active (P=0.02) and passive (P=0.01) oral sex was associated with an absence of sexual dysfunction. In the multiple regression analysis, the only factor associated with poor sexual function was being 50 years of age or more. CONCLUSIONS: The prevalence of the metabolic syndrome was high and was not associated with poor sexual function in this sample of menopausal women. The only factor associated with poor sexual function was being over 50 years of age. PMID- 25441668 TI - Staple aneurysmorrhaphy to salvage autogenous arteriovenous fistulas with aneurysm-related complications. AB - OBJECTIVE: Aneurysm-related complications could lead to loss of a functioning arteriovenous fistula (AVF). We report our midterm and long-term results with the staple aneurysmorrhaphy technique to repair and preserve aneurysmal AVFs. METHODS: We retrospectively reviewed our surgical treatment of patients with aneurysmal autogenous AVF complicated by skin erosion, bleeding, infection, pain, and difficulty with needle access from 2007 through 2014. We identified 52 patients, 40 (77%) of whom underwent repair with the staple aneurysmorrhaphy technique. The operation involved mobilizing the entire aneurysmal segments. A TA (Covidien, Norwalk, Conn) or Endo GIA (Covidien, Mansfield, Mass) stapler was used to resect the redundant aneurysm wall to create a 6- to 8-mm-diameter conduit. A subcutaneous skin flap was created after excising compromised skin. The remodeled vein was repositioned underneath the subcutaneous flap, with the staple line rotated laterally to avoid needle puncture. RESULTS: We attempted staple aneurysmorrhaphy in 40 patients with complicated AVF aneurysms, of which 38 repairs (95%) were successful. Median patient age was 66 years (range, 29-88 years). Median AVF age was 63 months (range, 12-136 months). Median follow-up was 20 months (range, 5-81 months). At 1 year, primary patency was 67%, assisted primary patency was 88%, and secondary patency was 91%. At 2 years, primary patency was 59%, assisted primary patency was 84%, and secondary patency was 91%. At 3 years, primary patency was 46%, assisted primary patency was 69%, and secondary patency was 85%. Surgery was performed under local-regional anesthesia in 28 patients (70%) and under general anesthesia in the remaining 12 (30%). Proximal venous outflow stenoses were detected in 19 of 40 AVFs (48%) preoperatively and in 11 of 38 AVFs (29%) postoperatively. Aneurysm recurrence occurred in two repaired AVFs. CONCLUSIONS: Our experience with staple aneurysmorrhaphy shows that it is an effective, safe, and durable procedure to preserve a functioning autogenous AVF with complicated aneurysmal degeneration. Key principles are to reduce the vein to normal adjacent diameter and to provide healthy skin coverage. The remodeled AVF has a low aneurysm recurrence rate and maintains the beneficial properties of superior patency and low infection. It is important to aggressively monitor for and treat proximal outflow venous stenoses to prevent aneurysm recurrence. The surgery can be done safely under local anesthesia in selected patients. PMID- 25441669 TI - Identification of a potential proinflammatory genetic profile influencing carotid plaque vulnerability. AB - OBJECTIVE: Atherosclerosis and vascular remodeling after injury are driven by inflammation and mononuclear cell infiltration. Unstable atherosclerotic plaques are characterized by a large necrotic core. In this study we investigated the distribution and interaction between gene polymorphisms encoding proinflammatory molecules in an Italian population with internal carotid artery stenosis (ICAS). We also evaluated whether reciprocal interaction between these gene polymorphisms increased the risk of plaque vulnerability. METHODS: In this genetic association study, 11 proinflammatory gene polymorphisms were analyzed in 933 individuals comprising 344 patients with ICAS who underwent carotid endarterectomy and 589 controls without ultrasound evidence of atherosclerosis or intimal thickening. RESULTS: We found that interleukin (IL) 6 (IL-6), IL-1beta, monocyte chemoattractant protein-1 (CCL2) macrophage inflammatory protein-1alpha (CCL3), E selectin (SELE), intercellular adhesion molecule 1 (ICAM1), and matrix metalloproteinase-3 (MMP-3), and 9 (MMP-9) gene variants were independently and significantly associated with ICAS. The association remained significant even after the Bonferroni correction. We also found a genetic profile associated with different risks for ICAS, depending on the number of high-risk genotypes simultaneously present in an individual. Furthermore, proinflammatory genetic profiles are significantly more common in individuals with unstable carotid plaque. CONCLUSIONS: Our study shows, for the first time, a reciprocal interaction between proinflammatory genotypes for the development and progression of ICAS. PMID- 25441670 TI - Selective renal blood perfusion induces renal tubules injury in a porcine model. AB - OBJECTIVE: Extracorporeal circulation is routinely used in thoracoabdominal aortic aneurysm repair to preserve blood perfusion. Despite this protective measure, acute and chronic kidney disorders can develop. Therefore, the aim of this study was to establish a new large-animal model to assess the efficacy of selective renal perfusion (SRP) with extracorporeal circulation in a setting of thoracoabdominal aortic aneurysm repair. METHODS: Eighteen pigs underwent a thoracolaparotomy, during with the aorta and renal arteries were exposed. The animals were divided into three cohorts of six pigs each: cohort I--control; cohort II--thoracic aortic clamping with distal aortic perfusion (DAP) using a roller pump; and cohort III--thoracic aortic clamping with DAP plus SRP. Kidney metabolism, kidney injury, and red blood cell damage were measured by oxygen extraction ratio (O2ER), neutrophil gelatinase-associated lipocalin, a marker for acute kidney damage, and serum free hemoglobin. RESULTS: With normal mean arterial blood pressures, flow rates in the renal arteries during perfusion decreased to 75% (group II) with DAP and to 50% (group III) with SRP compared with the control animals (group I; P = .0279 for I vs II; P = .0002 for I vs III). Microcirculation, measured by microspheres, did not differ significantly among the groups. In contrast, O2ER (P = .0021 for I vs III) and neutrophil gelatinase-associated lipocalin (P = .0083 for I vs III) levels were significantly increased in group III, whereas free hemoglobin was increased in groups II and III (P = .0406 for I vs II; P = .0018 for I vs III). CONCLUSIONS: SRP with a roller pump induces kidney tubule injury. Thus, distal aortic and SRP in our model does not provide adequate kidney protection. Furthermore, the perfusion system provokes red blood cell damage with increased free hemoglobin. Hence, the SRP perfusion technique should be revised and tested. PMID- 25441671 TI - Matrix metalloproteinase 10 is associated with disease severity and mortality in patients with peripheral arterial disease. AB - OBJECTIVE: Peripheral arterial disease (PAD) is associated with poor prognosis in terms of cardiovascular (CV) morbidity and mortality. Matrix metalloproteinases (MMPs) contribute to vascular remodeling by degrading extracellular matrix components and play a role in atherosclerosis as demonstrated for MMP-10 (stromelysin-2). This study analyzed MMP-10 levels in PAD patients according to disease severity and CV risk factors and evaluated the prognostic value of MMP-10 for CV events and mortality in lower limb arterial disease after a follow-up period of 2 years. METHODS: MMP-10 was measured by enzyme-linked immunosorbent assay in 187 PAD patients and 200 sex-matched controls. RESULTS: PAD patients presented with increased levels of MMP-10 (702 +/- 326 pg/mL control vs 946 +/- 473 pg/mL PAD; P < .001) and decreased levels of tissue inhibitor of matrix metalloproteinase 1 (312 +/- 117 ng/mL control vs 235 +/- 110 ng/mL PAD; P < .001) compared with controls. Among PAD patients, those with critical limb ischemia (n = 88) showed higher levels of MMP-10 (1086 +/- 478 pg/mL vs 822 +/- 436 pg/mL; P < .001) compared with those with intermittent claudication (n = 99), whereas the MMP-10/tissue inhibitor of matrix metalloproteinase 1 ratio remained similar. The univariate analysis showed an association between MMP-10, age (P = .015), hypertension (P = .021), and ankle-brachial index (P = .006) in PAD patients that remained significantly associated with PAD severity after adjustment for other CV risk factors. Patients with the highest MMP-10 tertile had an increased incidence of all-cause mortality and CV mortality (P < .03). CONCLUSIONS: Our results suggest that MMP-10 is associated with severity and poor outcome in PAD. PMID- 25441672 TI - Vascular reconstruction plays an important role in the treatment of pancreatic adenocarcinoma. AB - OBJECTIVE: Previous studies have proved the feasibility of performing a pancreaticoduodenectomy (Whipple operation) in patients with portal vein-superior mesenteric vein and hepatic artery invasion. We report our institutional experience with the use of a variety of vascular reconstructive methods during pancreatic resections for adenocarcinoma. METHODS: A retrospective review was performed identifying all patients undergoing a Whipple operation or total pancreatectomy procedure from January 2003 to December 2013. All venous (portal vein-superior mesenteric vein) and arterial (superior mesenteric artery-hepatic artery) reconstructions were extracted and reviewed to determine survival and perioperative complications. RESULTS: During the 10-year study period, 270 Whipple and total pancreatectomy procedures were performed, of which 183 were for adenocarcinoma of the pancreas. Of the 183 operations, a total of 60 (32.8%) vascular reconstructions were found, 49 venous and 11 arterial. Venous reconstruction included 37 (61.7%) primary repairs, four (6.7%) reconstructions with CryoVein (CryoLife, Inc, Kennesaw, Ga), three (5.0%) repairs with autologous vein patch, three (5.0%) autologous saphenous reconstructions, and two (3.33%) portacaval shunts. In addition, there were 11 (18.3%) arterial reconstructions (seven hepatic artery and four superior mesenteric artery). The 1-year survival for all reconstructions was 71.1%, which is equivalent to T3 lesions that did not receive vascular reconstruction (70.11%), with a median survival time of 575.28 days and 12 patients still alive. Survival time was comparable with each type of venous reconstruction, averaging 528 days (11 of 49 patients still alive). There was a total thrombosis rate of seven of 60 (11.6%), all of which were portal vein thrombosis: three in the primary repair group and four delayed thromboses seen in primary repair, CryoVein repair, and vein patch repair. There was no thrombosis in any patients after arterial reconstruction. CONCLUSIONS: An aggressive approach for stage II pancreatic cancers with venous or arterial invasion can be performed with comparable results when it is executed by an experienced institution with skilled oncologic and vascular surgeons. PMID- 25441673 TI - Clinical outcome after infrapopliteal bypass surgery in chronic hemodialysis patients with critical limb ischemia. AB - OBJECTIVE: Lower extremity bypass surgery has been widely performed to treat critical limb ischemia (CLI) in patients on hemodialysis (HD). However, the clinical outcome still remains unclear. We investigated the limb salvage rate after infrapopliteal bypass surgery in HD patients with CLI. METHODS: From April 2006 to January 2013, 226 patients with 236 limbs who electively underwent bypass surgery for treatment of CLI due to infrapopliteal disease were enrolled. Patients were grouped by those who were on HD (n = 177) and those who were not (n = 49). They were monitored for 5 years or until December 2013 if the follow-up period was <5 years. Amputation-free survival, defined as freedom from major amputation or all-cause death, was primarily evaluated. Incidence of reintervention was also analyzed. RESULTS: Ulcer/gangrene was present in 206 patients (91.2%), and 233 limbs (98.7%) were treated using autogenous vein. Age was younger (67 +/- 9 vs 72 +/- 9 years; P = .0011) and ulcer/gangrene was more prevalent (93.8% vs 81.6%, P = .0080) in HD patients than in non-HD patients. During the follow-up period (median, 28 months), 33 (14.6%) major amputations and 28 reinterventions (12.4%) occurred, and 65 patients (28.8%) died. The 5-year amputation-free survival rate was significantly lower in HD patients than in non HD patients (43.6% vs 78.8%, P = .0033), and the adjusted hazard ratio (HR) for amputation or death for HD patients was 2.36 (95% confidence interval [CI], 1.13 4.92; P = .022). Compared with non-HD patients, the status of HD was similarly an independent risk of major amputation (72.4% vs 92.5%; adjusted HR, 4.36; 95% CI, 1.04-18.3; P = .045) and mortality (56.9% vs 83.2%; adjusted HR, 2.81; 95% CI, 1.30-6.09; P = .0085). However, freedom from reintervention was comparable between the two groups (84.3% vs 86.8%; P = .89). In HD patients, body mass index (HR, 0.86; 95% CI, 0.76-0.96; per 1 kg/m(2) increase; P = .014) and C-reactive protein (HR, 1.06; 95% CI, 1.01-1.11; P = .014) independently predicted major amputation. Elevated C-reactive protein levels were also associated with death (HR, 1.04; 95% CI, 1.01-1.09; P = .047). CONCLUSIONS: The clinical outcome after infrapopliteal bypass surgery was poorer in HD patients with CLI compared with non-HD patients. Malnutrition or chronic inflammation was associated with poor outcome in HD patients with CLI due to infrapopliteal occlusive disease. PMID- 25441674 TI - Contemporary comparison of aortic arch repair by endovascular and open surgical reconstructions. AB - OBJECTIVE: This study analyzed total aortic arch reconstruction in a contemporary comparison of current open and endovascular repair. METHODS: Endovascular (group 1) and open arch procedures (group 2) performed during 2007 to 2013 were entered in a prospective database and retrospectively analyzed. Endovascular repair (proximal landing zones 0-1), with or without a hybrid adjunct, was selected for patients with a high comorbidity profile and fit anatomy. Operations involving coverage of left subclavian artery only (zone 2 proximal landing: n = 41) and open hemiarch replacement (n = 434) were excluded. Early and midterm mortality and major complications were assessed. RESULTS: Overall, 100 (78 men; mean age, 68 years) consecutive procedures were analyzed: 29 patients in group 2 and 71 in group 1. Seven group 1 patients were treated with branched or chimney stent graft, and 64 with partial or total debranching and straight stent graft. The 29 patients in group 2 were younger (mean age, 61.9 vs 70.3; P = .005), more frequently females (48.2% vs 11.3; P < .001) with less cardiac (6.9% vs 38.2%; P = .001), hypertensive (58.5% vs 88.4%; P = .002), and peripheral artery (0% vs 16.2%; P = .031) disease. At 30 days, there were six deaths in group 1 and four in group 2 (8.5% vs 13.8%; odds ratio, 1.7; 95% confidence interval, 0.45-6.66; P = .47), and four strokes in group 1 and one in group 2 (odds ratio, 0.59; 95% confidence interval, 0.06-5.59; P = 1). Spinal cord ischemia occurred in two group 1 patients and in no group 2 patients. Three retrograde dissections (1 fatal) were detected in group 1. During a mean follow-up of 26.2 months, two type I endoleaks and three reinterventions were recorded in group 1 (all for persistent endoleak), and one reintervention was performed in group 2. According to Kaplan Meier estimates, survival at 4 years was 79.8% in group 1 and 69.8% in group 2 (P = .62), and freedom from late reintervention was 94.6% and 95.5%, respectively (P = .82). CONCLUSIONS: Despite the older age and a higher comorbidity profile in patients with challenging aortic arch disease suitable and selected for endovascular arch repair, no significant differences were detected in perioperative and 4-year outcomes compared with the younger patients undergoing open arch total repair. An endovascular approach might also be a valid alternative to open surgery in average-risk patients with aortic arch diseases requiring 0 to 1 landing zones, when morphologically feasible. However, larger concurrent comparison and longer follow-up are needed to confirm this hypothesis. PMID- 25441675 TI - The effect of hospital factors on mortality rates after abdominal aortic aneurysm repair. AB - BACKGROUND: Patient factors that contribute to mortality from abdominal aortic aneurysm (AAA) repair have been previously described, but few studies have delineated the hospital factors that may be associated with an increase in patient mortality after AAA. This study used a large national database to identify hospital factors that affect mortality rates after open repair (OAR) and endovascular AAA repair (EVAR) of elective and ruptured AAA. METHODS: A retrospective analysis was completed using the Nationwide Inpatient Sample from 1998 to 2011. International Classification of Disease, Ninth Revision codes were used to identify patients who underwent elective or ruptured AAA repair by OAR or EVAR. The association between mortality and hospital covariates, including ownership, bed size, region, and individual hospital volume for these patients was statistically delineated by analysis of variance, chi(2), and Mann-Kendall trend analysis. RESULTS: A total of 128,232 patients were identified over the 14 year period, of which 88.5% were elective procedures and 11.5% were performed acutely for rupture. Most hospitals that complete elective OAR do between one and 50 cases, with mortality between 0% and 40%. Hospitals with mortality >40% uniformly complete fewer than five elective OAR cases annually and fall in the bottom 2.5% of all hospitals for mortality. Most hospitals that complete elective EVAR do between one and 70 cases, with mortality between 0% and 13%. Hospitals with mortality >13% uniformly complete fewer than eight elective EVAR cases annually and fall in the bottom 2.5% of all hospitals for mortality. The majority of hospitals that complete OAR or EVAR for ruptured AAA have between 0% to 100% for mortality, indicative of the high mortality risk associated with rupture. CONCLUSIONS: Hospitals that complete fewer than five OARs or eight EVARs annually have significantly greater mortality compared with their counterparts. Improved implementation of best practices, more detailed informed consent to include hospital mortality data, and better regional access to health care may improve survival after elective AAA repair. PMID- 25441676 TI - Failure to rescue trends in elective abdominal aortic aneurysm repair between 1995 and 2011. AB - OBJECTIVE: Factors affecting mortality after abdominal aortic aneurysm (AAA) repair have been extensively studied, but little is known about the effects of the shift to endovascular aneurysm repair (EVAR) vs open repair on failure to rescue (FTR). This study examines the impact of treatment modalities on FTR for elective AAA surgery during the years 1995 to 2011. METHODS: Data for 491,779 patients undergoing elective AAA surgery were collected from Medicare files. Patient demographics, comorbidities, hospital volume, and repair type were collected. Primary outcome was FTR: the percentage of deaths in patients who had a complication within 30 days of surgery. Data were analyzed by univariate and multivariate analysis. RESULTS: Patients undergoing AAA surgery have become progressively more complex, with 84.96%, 89.33%, 93.76%, and 95.72% presenting with one or more comorbidities in 1995, 2000, 2005, and 2011, respectively. Despite this, overall FTR after AAA surgery was stable from 1995 to 2000 (P = .38) and decreased from 2.68% to 1.58% between 2000 and 2011 (P < .001). In addition, FTR in EVAR decreased from 1.70% to 0.58% from 2000 to 2006 (P = .03) and then stabilized at 0.88% +/- 0.9% after 2007 (P = .45). Unlike for EVAR, FTR for open repair remained stable at 3.06% +/- 0.17% to 2.74% +/- 0.16% from 1995 to 2000 (P = .38) but increased to 4.51% +/- 0.21% in 2011 (P < .001). Mortality was highest after transfusion (20.86%), prolonged ventilation (17.37%), and respiratory complications (29.78%) for all AAA surgeries. Of note, high-volume hospitals had lower FTR rates than low-volume hospitals for both open (2.73% vs 5.66%; P < .001) and endovascular (0.7% vs 1.69%; P < .001) repair. Multivariate analysis showed that high annual volume hospital status (odds ratio, 0.6; confidence interval, 0.58-0.63) and endovascular repair (odds ratio, 0.3; confidence interval, 0.28-0.31) were associated with decreased FTR. CONCLUSIONS: The success in AAA surgery of rescuing patients from 30-day mortality after a complication is associated with increased volume of EVAR. This increased success can also be attributed to the improved FTR outcomes and complication rates when surgeries are performed at high-volume hospital centers. PMID- 25441677 TI - Outcomes after false lumen embolization with covered stent devices in chronic dissection. AB - OBJECTIVE: Persistent retrograde false lumen perfusion is a common mode of failure after thoracic endovascular aortic repair (TEVAR) for chronic dissection. Objectives were to describe a novel endovascular approach for false lumen occlusion and assess outcomes. METHODS: From 2009 to 2013, 21 patients (mean age, 64 +/- 11 years) with chronic thoracoabdominal dissection underwent adjunctive false lumen embolization using covered stent devices for persistent retrograde perfusion. Eight patients had type B dissection, 13 had residual dissection after prior type A repair, and all were deemed high risk for open operation. False lumen embolization in 17 patients was an adjunct at the initial TEVAR or extension, including two as elephant trunk completion. In the other four, this was done as an isolated procedure, and three had previously undergone TEVAR sparing the celiac artery. Covered stent devices included iliac plugs in 18, nitinol embolization plugs in two, and occluded stent graft in one. More than one device was used in 15 patients. RESULTS: There was one hospital death due to left subclavian artery aneurysm rupture but no patient had stroke, paraplegia, myocardial infarction, or renal failure. Mean follow-up was 25 +/- 19 months. During surveillance computed tomography imaging, false lumen thrombosis was noted in all patients, but four required further embolization because the thrombosis was incomplete. Mean maximum aortic diameter decreased from 64 +/- 14 to 59 +/- 15 mm. There was one late death from intracranial hemorrhage and no aortic ruptures. CONCLUSIONS: Adjunctive false lumen embolization with a covered stent device promotes thrombosis and remodeling after stent grafting the true lumen for chronic dissection. Further study of this strategy is warranted. PMID- 25441678 TI - Outcomes of nonelective weekend admissions for lower extremity ischemia. AB - OBJECTIVE: A "weekend effect" has been demonstrated for a number of diagnoses, including many cardiovascular pathologies. Whether patients with lower extremity ischemia admitted over the weekend have inferior outcomes compared with those admitted on a weekday is unknown. METHODS: Nonelective admissions for critical limb ischemia (CLI) and acute limb ischemia (ALI) from lower extremity thrombosis or embolism were identified in the 2005 to 2010 Nationwide Inpatient Sample, and outcomes were compared based on weekend vs weekday admission by using multiple logistic and linear regression. RESULTS: Of the 63,768 patients identified with lower extremity vascular emergencies, 15.4% were admitted during the weekend. Patients admitted on the weekend were less likely to have CLI than those admitted on a weekday (51.2% vs 65.4%; P < .001) and were more likely to have ALI than patients admitted during a weekday (48.8% vs 34.5%; P < .001). Weekend admission was independently associated with a lower likelihood of revascularization (adjusted odds ratio [aOR], 0.90; 95% confidence interval [CI], 0.85-0.95; P < .001), a longer time until revascularization (3.09 days vs 2.75 days; P < .001), an increased likelihood of major amputation (aOR, 1.35; 95% CI, 1.19-1.53; P < .001), in-hospital complications (aOR, 1.18; 95% CI, 1.11-1.25; P < .001), and discharge to a skilled nursing facility (aOR, 1.15; 95% CI, 1.06-1.25; P = .001), and a longer predicted length of stay (10.1 days vs 9.5 days; P < .001). There was no statistically significant association between weekend admission and in hospital mortality (aOR, 1.15; 95% CI, 1.06-1.25; P = .10). CONCLUSIONS: Patients admitted on the weekend for lower extremity vascular emergencies are significantly more likely to experience adverse outcomes, including major amputation, than patients admitted on a weekday, independent of their presenting diagnosis with ALI or CLI. Further investigation into the etiologies of these differences is needed to address this disparity. These data raise questions about the proper staffing models to optimize urgent treatment of lower extremity vascular emergencies. PMID- 25441680 TI - Adequacy and complication rates with 14- vs. 16-gauge automated needles in percutaneous renal biopsy of native kidneys. AB - In performing percutaneous renal biopsy (PRB) of native kidneys, an increasing use of 16-gauge automated biopsy needles has been observed. We compare the adequacy and safety of PRBs in adults performed with a 14-gauge (n = 82) vs. 16 gauge (n = 55) automated needle using real-time ultrasound (US) from 1/2010 to 12/2013. Baseline clinical and laboratory data along with outcome data (renal US 1-hour postbiopsy, biopsy adequacy, and safety) were collected prospectively. There was no difference in age, gender, blood pressure, serum creatinine, or pre PRB hemoglobin at baseline for PRBs performed with a 14- vs. 16-gauge needle. The number of glomeruli obtained per biopsy was similar (29 +/- 11 vs. 31 +/- 14, p = 0.6) and adequate tissue for diagnosis was obtained in 99% and 100% of biopsies. The clinical complication (8.5% vs. 9.1%, p = 1.0), transfusion (7.3% vs. 7.2%, p = 1.0), and embolization (3.7% vs. 1.8%, p = 0.6) rates were not significantly different for 14- vs. 16-gauge needles, but by routine renal US 1-hour post-PRB, a perinephric hematoma was demonstrated more often in biopsies done with the 14 gauge needle (39% vs. 22%, P 0.04). Thus, while the success of PRB of native kidneys is similar for both needle gauges, the potential for complication may be less using a 16-gauge automated needle. PMID- 25441679 TI - Relationship between kidney disease and endothelial function in peripheral artery disease. AB - OBJECTIVE: We have previously shown that peripheral artery disease (PAD) is associated with marked impairment of endothelial function (EF). Given that poor EF is associated with functional status of PAD patients as well as with increased morbidity and mortality in patients undergoing vascular procedures, determination of factors associated with poor EF in a PAD cohort is important. We hypothesized that decreased kidney function is associated with impaired EF in patients with PAD. METHODS: This was a cross-sectional study of PAD patients presenting to a vascular surgery outpatient clinic at the San Francisco Veterans Affairs Medical Center including patients enrolled in the OMEGA-PAD I trial (NCT01310270) and the OMEGA-PAD Cohort. Brachial artery flow-mediated vasodilation was performed to assess EF. Kidney function was characterized by estimated glomerular filtration rate with the abbreviated Modification of Diet in Renal Disease formula. Linear regression was performed to assess the relationship between EF and kidney function in claudicants. RESULTS: Ninety-seven patients with intermittent claudication participated in this study. Mean age was 69 +/- 8 years, 97% were male, and 79% were white. Comorbidities included hypertension (91%), dyslipidemia (87%), coronary artery disease (42%), and diabetes mellitus (38%). Mean ankle brachial index was 0.73 +/- 0.14 and mean flow-mediated vasodilation was 7.0% +/- 3.8%, indicating impaired EF. Linear regression showed an association between kidney function and EF (by 10 mL/min/1.73 m(2); beta, 0.12; confidence interval, 0.05-0.20; P = .001). After multivariable regression adjusting for age, race, log tumor necrosis factor alpha, hypertension, dyslipidemia, and diabetes, estimated glomerular filtration rate remained significantly associated with EF (P = .033). CONCLUSIONS: In patients with PAD, decreased kidney function is associated with endothelial dysfunction. Further longitudinal studies are needed to better understand the impact of kidney function on PAD progression and the role of endothelial dysfunction in this process. PMID- 25441681 TI - Resolving clinical diagnoses for syndromic cleft lip and/or palate phenotypes using whole-exome sequencing. AB - Individuals from three families ascertained in Bogota, Colombia, showing syndromic phenotypes, including cleft lip and/or palate, were exome-sequenced. In each case, sequencing revealed the underlying causal variation confirming or establishing diagnoses. The findings include very rare and novel variants providing insights into genotype and phenotype relationships. These include the molecular diagnosis of an individual with Nager syndrome and a family exhibiting an atypical incontinentia pigmenti phenotype with a missense mutation in IKBKG. IKBKG mutations are typically associated with preterm male death, but this variant is associated with survival for 8-15 days. The third family exhibits unusual phenotypic features and the proband received a provisional diagnosis of Pierre Robin sequence (PRS). Affected individuals share a novel deleterious mutation in IRF6. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndrome and contribute to nonsyndromic cleft lip phenotypes but have not previously been associated with a PRS phenotype. Exome sequencing followed by in silico screening to identify candidate causal variant(s), and functional assay in some cases offers a powerful route to establishing molecular diagnoses. This approach is invaluable for conditions showing phenotypic and/or genetic heterogeneity including cleft lip and/or palate phenotypes where many underlying causal genes have not been identified. PMID- 25441682 TI - A novel three-component system-based regulatory model for D-xylose sensing and transport in Clostridium beijerinckii. AB - D-Xylose is the most abundant fermentable pentose in nature and can serve as a carbon source for many bacterial species. Since D-xylose constitutes the major component of hemicellulose, its metabolism is important for lignocellulosic biomass utilization. Here, we report a six-protein module for D-xylose signaling, uptake and regulation in solvent-producing Clostridium beijerinckii. This module consists of a novel 'three-component system' (a putative periplasmic ABC transporter substrate-binding protein XylFII and a two-component system LytS/YesN) and an ABC-type D-xylose transporter XylFGH. Interestingly, we demonstrate that, although XylFII harbors a transmembrane domain, it is not involved in D-xylose transport. Instead, XylFII acts as a signal sensor to assist the response of LytS/YesN to extracellular D-xylose, thus enabling LytS/YesN to directly activate the transcription of the adjacent xylFGH genes and thereby promote the uptake of D-xylose. To our knowledge, XylFII is a novel single transmembrane sensor that assists two-component system to respond to extracellular sugar molecules. Also of significance, this 'three-component system' is widely distributed in Firmicutes, indicating that it may play a broad role in this bacterial phylum. The results reported here provide new insights into the regulatory mechanism of D-xylose sensing and transport in bacteria. PMID- 25441683 TI - High frequency of rare structural chromosome abnormalities at relapse of cytogenetically normal acute myeloid leukemia with FLT3 internal tandem duplication. AB - FLT3 internal tandem duplication (ITD) mutations are present in acute myeloid leukemia (AML) in 30% of patients with acute myeloid leukemia (AML), most commonly in those with a normal karyotype, and are associated with short relapse free survival. Both in vitro and in vivo studies of FLT3-ITD cell lines have demonstrated reactive oxygen species-mediated DNA double-strand breaks and associated error-prone DNA repair as a mechanism of genomic instability, and we hypothesized that genomic instability might be manifested by cytogenetic changes at relapse of FLT3-ITD AML. We retrospectively reviewed charts of patients with cytogenetically normal (CN) FLT3-ITD AML treated at the University of Maryland Greenebaum Cancer Center, with attention to metaphase analysis results at relapse. Cytogenetic data were available from first and, when applicable, subsequent relapses for 15 patients diagnosed with CN FLT3-ITD AML. Among 12 patients with documented FLT3-ITD at first and, when applicable, subsequent relapse, 10 had cytogenetic changes, including nine with rare structural abnormalities. The high frequency of rare structural chromosome abnormalities at relapse in our case series supports a role of genomic instability in the genesis of relapse, and suggests that reactive oxygen species-generating and DNA repair pathways might be therapeutic targets in FLT3-ITD AML. PMID- 25441684 TI - Knockdown of ZFX suppresses renal carcinoma cell growth and induces apoptosis. AB - The ZFX (zinc finger protein, X-linked) gene located on the human X chromosome controls the self-renewal of embryonic and hematopoietic stem cells as a transcriptional regulator. Recently, studies have affirmed that ZFX is associated with several human cancers, including lymphoma, laryngeal squamous cell carcinoma, prostate cancer, and liver cancer, which suggests ZFX as a potential therapeutic target in cancer. However, the functional role of ZFX in human renal cancer remains unclear. Herein, we detected the expression of ZFX in 42 patients with renal cancer and found the expression of ZFX was specifically upregulated in cancer tissues at the mRNA and protein levels. Moreover, we employed lentivirus mediated short hairpin RNA (shRNA) to knock down ZFX expression in two human renal cell carcinoma cell lines, 786-0 and ACHN. Functional analysis indicated that ZFX silencing significantly inhibited renal cell carcinoma cell proliferation and cell cycle progression, probably because of suppression of CDK4 and cyclin D1, and induced apoptosis via activation of Bax, Caspase 3, and PUMA in a p53-dependent manner. Our findings suggest that knockdown of ZFX by shRNA may be a potential therapeutic approach for the treatment of renal cancer. PMID- 25441685 TI - Effect of telomerase inhibition on preclinical models of malignant rhabdoid tumor. AB - Novel treatment approaches are desperately needed for malignant rhabdoid tumor (MRT). Telomerase is an attractive therapeutic target because it is specific to cancer and critical for cancer cell immortality. We evaluated the effect of the telomerase inhibitor imetelstat in preclinical models of MRT. Three MRT cell lines, BT-12, G401, and RT-peri, were treated with the telomerase inhibitor imetelstat. The effects of imetelstat on telomere length, DNA damage response, and cell proliferation were assessed. The efficacy of imetelstat in vivo was evaluated in subcutaneous xenografts derived from each of the cell lines. Treatment with imetelstat resulted in inhibition of telomerase activity, marked telomere shortening, and activation of the DNA damage response pathway, as measured by formation of gamma-H2AX nuclear foci, phosphorylation of ATM, and phosphorylation of TP53. Imetelstat-treated G401 cells underwent complete growth arrest after 16 passages. The other two cell lines exhibited growth inhibition. Imetelstat resulted in 40-50% growth inhibition compared to placebo-treated controls in all three xenograft models. The activity of imetelstat as a single agent suggests that further studies of telomerase inhibitors in combination with other agents may be warranted. PMID- 25441686 TI - Population-based characterization of the genetic landscape of chronic lymphocytic leukemia patients referred for cytogenetic testing in British Columbia, Canada: the role of provincial laboratory standardization. AB - Detection of recurrent chromosome abnormalities by fluorescence in situ hybridization (FISH) is an essential component of care in chronic lymphocytic leukemia (CLL) patients. In the province of British Columbia (BC), Canada, population 4.6 million, CLL patients receive uniform evaluation and therapy with FISH testing performed in three jurisdictions. The aims of this study were to (i) validate CLL-FISH testing among the BC cytogenetic laboratories to ensure standardization of results and (ii) characterize population-level CLL-FISH abnormalities by pooling provincial data. From 2004 to 2011, 585 consecutive patients underwent pretreatment CLL-FISH testing at laboratory A (50.1%), laboratory B (32.3%), or laboratory C (17.6%). For validation purposes, 26 CLL FISH abnormalities were tested by each laboratory's protocol, with 91% result concordance. Discordant results involved percent abnormalities at or near cutoff values; therefore, a 10% universal cutoff was established when pooling results. Applying the universal cutoff to the provincial cohort, CLL-FISH abnormalities were detected in 74.9%: 54.9% 13q-, 18.8% +12, 8.5% 11q-, and 7.7% 17p-. In this large population-based cohort of patients referred for CLL-FISH testing, frequencies of abnormalities detected by FISH analysis were highly consistent with those reported in single-institution and clinical trial populations. Provinces or districts that work together to care for CLL patients can effectively pool data with appropriate laboratory validation to ensure standardization of results. PMID- 25441687 TI - Ewing sarcoma mimicking atypical carcinoid tumor: detection of unexpected genomic alterations demonstrates the use of next generation sequencing as a diagnostic tool. AB - Increasingly, tumors are being analyzed for a variety of mutations and other genomic changes, with the goals of guiding personalized therapy and directing patients to appropriate clinical trials based on genotype, as well as identifying previously unknown genomic changes in different tumor types and thereby providing new insights into the pathogenesis of human cancers. Next generation sequencing is a powerful research tool now gaining traction in the clinic. In this report, we demonstrate the utility of next generation sequencing assays in providing diagnostic information when evaluating tumor specimens. This is illustrated by a case previously thought to represent an atypical carcinoid tumor, in which an EWSR1-ERG translocation was detected during next generation sequencing using a hybrid capture approach, leading to a revised diagnosis of Ewing sarcoma. The role of translocation detection in these assays is also discussed. PMID- 25441688 TI - Chronic lymphocytic leukemia with a FGFR3 translocation: case report and literature review of an uncommon cytogenetic event. AB - The t(4;14) (p16; q32) with fusion of the IGH (immunoglobulin heavy chain) and FGFR3 (fibroblast growth factor receptor 3) genes are rarely present in patients with chronic lymphocytic leukemia (CLL), with only two previously reported cases. We herein describe a unique case of CLL with the occurrence of a t(4;14) (p16;q32), trisomy 12, and deletion of 11q13-q23 in the same clonal cells. In contrast to myeloma, in which FGFR3 translocations are a common early cytogenetic hit, FGFR3 rearrangement in CLL appears to occur later in the disease course. PMID- 25441689 TI - The fentanyl story. AB - Fentanyl, introduced more than 50 years ago, has become the most often used opioid for intraoperative analgesia. Since the early 1990s the fentanyl patch has been available for management of chronic pain of all forms of cancer as well as the persistent, intense pain from many noncancerous maladies. More than a half dozen rapid-onset transmucosal fentanyl preparations have been developed, approved, launched, and popularized for "breakthrough" pain syndromes in the past 20 years. The purpose of this article is to describe why this opioid has become so important in the treatment of pain in modern clinical practice. The data indicate that fentanyl's popularity has occurred because it has minimal cardiovascular effects, does not result in increases in plasma histamine, is relatively short in onset of action and duration of effect, is easy and inexpensive to synthesize and prepare for the marketplace, and is now familiar to clinicians working in pain and perioperative medicine throughout the world. PMID- 25441691 TI - Discussion. PMID- 25441690 TI - Results of the endovascular abdominal aortic aneurysm repair using the Anaconda aortic endograft. AB - OBJECTIVE: The objective of this study was to evaluate early and late results of the Anaconda aortic endograft (Vascutek, Terumo, Inchinnan, Scotland) in a single center experience. METHODS: From September 2005 to March 2012, patients underwent endovascular aortic repair for abdominal aortic aneurysm (AAA) with Anaconda endograft were prospectively enrolled in a dedicated database. Demographic and aortoiliac morphological data were considered. Preoperative planning was based on thoracoabdominal and pelvic computed tomography angiography. Follow-up included duplex ultrasound or computed tomography angiography at 1, 6, and 12 months and yearly thereafter. Primary end points were technical success, early and late primary and primary assisted clinical success (CS), overall and AAA-related survival and freedom from reinterventions. Secondary end points were endoleaks (ELs), steno-obstructive iliac leg complications, and AAA shrinkage. RESULTS: An Anaconda endograft was implanted in 177 patients (male 94%; mean age, 73.3 +/- 7.4 years; American Society of Anesthesiologists class III-IV, 85% and 9%, respectively). The mean AAA diameter, neck length, and diameter were 55 +/- 9.7 mm, 26.7 +/- 10 mm, and 23 +/- 2.3 mm, respectively. There was an aortic neck angle >60 degrees in 44 (25%) patients. Iliac angles >90 degrees were observed in 152 (43%) iliac axes. Technical success was 98.9%. Early CS was 96%. Mean follow-up was 33 +/- 23.3 months. Late assisted CS was 97.7%. Survival at 12, 24, and 36 months was 96.4%, 89%, and 86.2%, respectively. There was only one case of late AAA-related mortality. Freedom from reintervention was 94%, 92%, and 85% at 12, 24, and 36 months, respectively. Three (1.7%) conversions occurred during follow-up. There were 14.1% ELs at the completion angiography (EL Ia, 1.1%; EL II, 13%). Late ELs were 20.2% (EL Ia, 1.1%; EL Ib, 2.2%; EL II, 16.9%). Iliac leg complications occurred in 5.6% of the cases. An AAA shrinkage >5 mm was observed in 130 (73.4%) patients. In 7 (4%) cases there was an AAA enlargement >5 mm. CONCLUSIONS: Data in our series demonstrate that the Anaconda endograft has good early and late results in the treatment of AAAs. PMID- 25441692 TI - Invited commentary. PMID- 25441693 TI - Extracranial internal carotid artery aneurysm. PMID- 25441694 TI - Antithrombotic therapy after infrainguinal bypass. AB - OBJECTIVE: Bypass surgery is regularly performed for the treatment of critical limb ischemia, but the risk of occlusion remains significant. Antiplatelet therapy in patients with arterial disease is useful for secondary cardiovascular and bypass occlusion prevention. However, despite the common use of an antiplatelet agent, especially aspirin, which became the standard of care, the risk of graft occlusion persists. The best antithrombotic treatment for bypass patency therefore remains a matter of debate. METHODS: We conducted a systematic literature search to identify studies and consensus reporting the use of antithrombotic treatment to prevent bypass occlusion. We excluded case reports and clinical trials with a placebo arm. RESULTS: Aspirin remains the mainstay of treatment to improve infrainguinal bypass patency; however, the effect differs according to the bypass material used. The greatest beneficial effect of antiplatelet agents was observed with prosthetic bypasses. In such cases, the addition of clopidogrel to aspirin, for at least 1 year, in patients who benefited from a below-knee bypass graft significantly improved bypass patency (occlusion 32% vs 47% for aspirin alone; P = .02) and the amputation rate (9.4% vs 19.2% for aspirin alone; P = .03), without increasing the incidence of major hemorrhage. In contrast, antiplatelet regimens were less efficacious for autologous vein bypasses. The addition of a vitamin K antagonist (VKA) is not routinely proposed because of the increased incidence of associated major hemorrhage. The use of VKA alone, instead of aspirin, should probably be discussed in selected patients, and a combination of VKA and antiplatelet agents should be discussed in patients with venous infrainguinal bypasses considered to be at a high risk for occlusion. CONCLUSIONS: Although aspirin remains the first line treatment to prevent infrainguinal bypass occlusion, future studies are needed to define stronger recommendations. PMID- 25441695 TI - Custom-made versus off-the-shelf multibranched endografts for endovascular repair of thoracoabdominal aortic aneurysms. PMID- 25441696 TI - Reply: To PMID 24461866. PMID- 25441697 TI - Regarding "Cavernous hemangioma of the external carotid artery". PMID- 25441698 TI - Cochran's Q test was useful to assess heterogeneity in likelihood ratios in studies of diagnostic accuracy. AB - OBJECTIVES: Empirical evaluations have demonstrated that diagnostic accuracy frequently shows significant heterogeneity between subgroups of patients within a study. We propose to use Cochran's Q test to assess heterogeneity in diagnostic likelihood ratios (LRs). STUDY DESIGN AND SETTING: We reanalyzed published data of six articles that showed within-study heterogeneity in diagnostic accuracy. We used the Q test to assess heterogeneity in LRs and compared the results of the Q test with those obtained using another method for stratified analysis of LRs, based on subgroup confidence intervals. We also studied the behavior of the Q test using hypothetical data. RESULTS: The Q test detected significant heterogeneity in LRs in all six example data sets. The Q test detected significant heterogeneity in LRs more frequently than the confidence interval approach (38% vs. 20%). When applied to hypothetical data, the Q test would be able to detect relatively small variations in LRs, of about a twofold increase, in a study including 300 participants. CONCLUSION: Reanalysis of published data using the Q test can be easily performed to assess heterogeneity in diagnostic LRs between subgroups of patients, potentially providing important information to clinicians who base their decisions on published LRs. PMID- 25441699 TI - Mobile health data collection at primary health care in Ethiopia: a feasible challenge. AB - OBJECTIVES: Feasibility assessment of mobile health (mHealth) data collection at primary health care in Ethiopia. STUDY DESIGN AND SETTING: A total of 14 health workers were recruited from 12 primary health care facilities to use smartphones, installed with customized data collection application and electronic maternal health care forms for assessing pregnant women's health for 6 months. Qualitative approaches comprising in-depth interviews and field notes were used to document the users' perception and experience in using the application and forms. RESULTS: All health workers had never had previous exposure to smartphones and electronic forms, but they got used to them easily. Over 6 months, all health workers completed a total of 952 patient records using the forms on smartphones. Health workers' acceptability and demand for the application and forms were high. In introducing the application, nontechnical challenges were more difficult to solve than technical challenges. CONCLUSION: Introducing an mHealth application at primary health care for routine collection of health data relevant to maternal health at a small scale was feasible. Nonetheless, implementing a system of assigning unique and consistent patient identifier, standardization of health services, and improving mobile network coverage would be prerequisites for scaled up usage of such an application. PMID- 25441700 TI - Meaningful changes for the Oxford hip and knee scores after joint replacement surgery. AB - OBJECTIVES: To present estimates of clinically meaningful or minimal important changes for the Oxford Hip Score (OHS) and the Oxford Knee Score (OKS) after joint replacement surgery. STUDY DESIGN AND SETTING: Secondary data analysis of the NHS patient-reported outcome measures data set that included 82,415 patients listed for hip replacement surgery and 94,015 patients listed for knee replacement surgery was performed. RESULTS: Anchor-based methods revealed that meaningful change indices at the group level [minimal important change (MIC)], for example in cohort studies, were ~ 11 points for the OHS and ~ 9 points for the OKS. For assessment of individual patients, receiver operating characteristic analysis produced MICs of 8 and 7 points for OHS and OKS, respectively. Additionally, the between group minimal important difference (MID), which allows the estimation of a clinically relevant difference in change scores from baseline when comparing two groups, that is, for clinical trials, was estimated to be ~ 5 points for both the OKS and the OHS. The distribution-based minimal detectable change (MDC90) estimates for the OKS and OHS were 4 and 5 points, respectively. CONCLUSION: This study has produced and discussed estimates of minimal important change/difference for the OKS/OHS. These estimates should be used in the power calculations and the interpretation of studies using the OKS and OHS. The MDC90 (~ 4 points OKS and ~ 5 points OHS) represents the smallest possible detectable change for each of these instruments, thus indicating that any lower value would fall within measurement error. PMID- 25441701 TI - Mixture models in diagnostic meta-analyses--clustering summary receiver operating characteristic curves accounted for heterogeneity and correlation. AB - OBJECTIVES: Bivariate linear and generalized linear random effects are frequently used to perform a diagnostic meta-analysis. The objective of this article was to apply a finite mixture model of bivariate normal distributions that can be used for the construction of componentwise summary receiver operating characteristic (sROC) curves. STUDY DESIGN AND SETTING: Bivariate linear random effects and a bivariate finite mixture model are used. The latter model is developed as an extension of a univariate finite mixture model. Two examples, computed tomography (CT) angiography for ruling out coronary artery disease and procalcitonin as a diagnostic marker for sepsis, are used to estimate mean sensitivity and mean specificity and to construct sROC curves. RESULTS: The suggested approach of a bivariate finite mixture model identifies two latent classes of diagnostic accuracy for the CT angiography example. Both classes show high sensitivity but mainly two different levels of specificity. For the procalcitonin example, this approach identifies three latent classes of diagnostic accuracy. Here, sensitivities and specificities are quite different as such that sensitivity increases with decreasing specificity. Additionally, the model is used to construct componentwise sROC curves and to classify individual studies. CONCLUSION: The proposed method offers an alternative approach to model between study heterogeneity in a diagnostic meta-analysis. Furthermore, it is possible to construct sROC curves even if a positive correlation between sensitivity and specificity is present. PMID- 25441702 TI - A systematic review identifies valid comorbidity indices derived from administrative health data. AB - OBJECTIVES: To conduct a systematic review of studies reporting on the development or validation of comorbidity indices using administrative health data and compare their ability to predict outcomes related to comorbidity (ie, construct validity). STUDY DESIGN AND SETTING: We conducted a comprehensive literature search of MEDLINE and EMBASE, until September 2012. After title and abstract screen, relevant articles were selected for review by two independent investigators. Predictive validity and model fit were measured using c-statistic for dichotomous outcomes and R(2) for continuous outcomes. RESULTS: Our review includes 76 articles. Two categories of comorbidity indices were identified: those identifying comorbidities based on diagnoses, using International Classification of Disease codes from hospitalization or outpatient data, and based on medications, using pharmacy data. The ability of indices studied to predict morbidity-related outcomes ranged from poor (C statistic <= 0.69) to excellent (C statistic >0.80) depending on the specific index, outcome measured, and study population. Diagnosis-based measures, particularly the Elixhauser Index and the Romano adaptation of the Charlson Index, resulted in higher ability to predict mortality outcomes. Medication-based indices, such as the Chronic Disease Score, demonstrated better performance for predicting health care utilization. CONCLUSION: A number of valid comorbidity indices derived from administrative data are available. Selection of an appropriate index should take into account the type of data available, study population, and specific outcome of interest. PMID- 25441703 TI - External validation of new risk prediction models is infrequent and reveals worse prognostic discrimination. AB - OBJECTIVES: To evaluate how often newly developed risk prediction models undergo external validation and how well they perform in such validations. STUDY DESIGN AND SETTING: We reviewed derivation studies of newly proposed risk models and their subsequent external validations. Study characteristics, outcome(s), and models' discriminatory performance [area under the curve, (AUC)] in derivation and validation studies were extracted. We estimated the probability of having a validation, change in discriminatory performance with more stringent external validation by overlapping or different authors compared to the derivation estimates. RESULTS: We evaluated 127 new prediction models. Of those, for 32 models (25%), at least an external validation study was identified; in 22 models (17%), the validation had been done by entirely different authors. The probability of having an external validation by different authors within 5 years was 16%. AUC estimates significantly decreased during external validation vs. the derivation study [median AUC change: -0.05 (P < 0.001) overall; -0.04 (P = 0.009) for validation by overlapping authors; -0.05 (P < 0.001) for validation by different authors]. On external validation, AUC decreased by at least 0.03 in 19 models and never increased by at least 0.03 (P < 0.001). CONCLUSION: External independent validation of predictive models in different studies is uncommon. Predictive performance may worsen substantially on external validation. PMID- 25441704 TI - Inhomogeneous Longitudinal Cardiac Rotation and Impaired Left Ventricular Longitudinal Strain in Children and Young Adults with End-Stage Renal Failure Undergoing Hemodialysis. AB - BACKGROUND: Cardiac dysfunction frequently complicates the clinical course of patients with end-stage renal failure (ESRF). Recently, we observed abnormal longitudinal cardiac rotation (LR) among patients with ESRF. In this study, we sought to quantify LR mechanics in patients undergoing hemodialysis (HD). METHODS: Twenty-four subjects, 12 ESRF patients (58% male; age 17.5 +/- 4.4 years) receiving HD, and 12 aged-matched controls, were prospectively studied. Patients underwent echocardiographic studies before and after HD. LR mechanics were quantified with two-dimensional speckle tracking echocardiography. Peak systolic left ventricular (LV) longitudinal strain and displacement measurements were obtained in all subjects. RESULTS: LR mechanics were successfully quantified in all subjects using 5 key echocardiographic features of LR. We identified two different inhomogeneous LR motion patterns in 41.7% of ESRF patients, characterized by a delayed timing of LR or increased segmental apical rotation. Inhomogeneous LR patterns were not found in controls. Timing of early-systolic counterclockwise LR increased after HD (P = 0.006). In patients, late-systolic clockwise LR occurred earlier (P = 0.043), and showed a significant prolongation after HD (P = 0.003). Longitudinal strain was significantly impaired in patients (P = 0.015), and further decreased after HD (P < 0.0001). Strong correlations were observed between strain and displacement parameters and LR mechanics. CONCLUSIONS: Quantifying LR using speckle tracking echocardiography was feasible, easy, and reproducible. Inhomogeneous LR motion patterns were demonstrated in a large proportion of patients with ESRF. LV dysfunction seems the most important determinant of inhomogeneous LR. Further studies are required to validate these findings. PMID- 25441705 TI - Characterization of fosA5, a new plasmid-mediated fosfomycin resistance gene in Escherichia coli. AB - A clinical strain of extended-spectrum beta-lactamase-producing Escherichia coli E265, with a fosfomycin MIC of 512 MUg ml(-1), was isolated from an inpatient with hospital-acquired pneumonia. This strain was negative for known fos genes, had no mutation in the target enzyme by polymerase chain reaction amplification and had functional transport systems for fosfomycin uptake. Fosfomycin resistance could be transferred from strain E265 to E. coli J53 azide(R) by conjugation. The DNA fragment containing fosfomycin resistance determinants was cloned into E. coli TOP10. The minimal inhibitory concentrations of fosfomycin for the transconjugant and transformant were 512 and 1024 MUg ml(-1). By sequencing, a plasmid-mediated fosA subtype, designated fosA5, was found and characterized. The fosA5 gene was 420 bp in length and encoded a 139-amino-acid protein that shared 69 to 80% identity with FosA, FosA2, FosA3 and FosA4, and 31, 14 and 25% identity with FosB, FosC and FosX, respectively. The analysis of genetic environment of fosA5 suggested that a strain such as Klebsiella pneumoniae CG4 might be the origin of plasmid-mediated fosA5, with IS10 playing an important role in its mobilization. SIGNIFICANCE AND IMPACT OF THE STUDY: This study aimed to clone and characterize a plasmid-mediated fosA subtype gene, fosA5, in a clinical strain of ESBL-producing Escherichia coli, which confers fosfomycin resistance. Detection of the fosA5 gene clarified the mechanism of fosfomycin resistance in a strain that was negative for known fosfomycin resistance genes. Monitoring and surveillance will be important to follow the changes in fosfomycin resistance and prevent further dissemination of fos genes. PMID- 25441706 TI - Dietary models of insulin resistance. AB - Insulin resistance is a significant factor in the development of type 2 diabetes mellitus, however the connection between the Western diet and the development of insulin resistance has not been fully explained. Dietary macronutrient composition has been examined in a number of articles, and diets enriched in saturated fatty acids, and possibly in fructose, appear to be most consistently associated with the development of insulin resistance. However, mechanistic insights into the metabolic effects of such diets are lacking, and merit further study. PMID- 25441707 TI - Tectal plate tumours. Our experience with a paediatric surgical series. AB - INTRODUCTION: Exophytic tectal plate tumours are a particular kind of brain stem tumour that can be treated with microsurgical resection. This paper reports our surgical experience with a paediatric series stressing and underlines the fact that this surgery can be possible because the rate of surgical mortality is low in experienced hands with acceptable morbidity. MATERIAL AND METHODS: From 1997 to 2010, 27 patients were treated for exophytic tectal plate tumours. The clinical symptomatology was characterized by an intracranial hypertensive syndrome in 77% of cases, visual disorders in 36% of cases and a Parinaud's syndrome in 12% of cases. All patients were studied using a pre-operative cranio spinal MRI with and without gadolinium. Hydrocephalus was present in 20 cases treated with a VP shunt in 6 cases and an ETV in the other cases. The surgical removal was total in 60% of cases, partial in 28% of cases and only a large biopsy in 12% of cases. From an histological point of view benign gliomas were diagnosed in 84% of cases and in 16% of cases were classified as WHO grade II and III. Eight patients needed complementary treatment, four with chemotherapy and four with chemotherapy associated to radiotherapy. As a surgical complication two patients had hydrocephalus, one patient had a sub-dural acute haematoma, two patients had an infectious complication requiring surgical treatment and antibiotic therapy, and 5 patients a mechanical shunt dysfunction. No post surgical mortality was observed. RESULTS: The most recent results after a median survival of 4.3 years show that 22 patients are still alive while 5 patients died of a progressive disease. Twenty patients in school age continue to follow a normal school programme but 10 patients need assistance. CONCLUSION: Exophytic tectal plate tumours can be treated based on a microsurgical approach in paediatric patients. In experienced hands surgery can be performed with an acceptable morbidity and with zero percent mortality. In our experience, the sub occipital transtentorial approach permits a wide view of the region and safe surgical removal. PMID- 25441708 TI - [Variability in decision-making for treatment choice of intracranial aneurysms]. AB - OBJECTIVES: To measure the variability in choosing treatment options in different clinical situations involving intracranial aneurysms. MATERIALS AND METHODS: A questionnaire regarding 25 clinical cases was presented via visual projection, to attendees of the Congres de la Societe francaise de neurochirurgie et de la Societe de langue francaise de neurochirurgie held in Toulouse from May 9th to May 12th, 2012. The audience (n=59) consisted of 58 neurosurgeons and one neuroradiologist. A minority of them (29.2%) stated that they specialized in vascular neurosurgery. The questionnaire dealt with 25 illustrative clinical cases, in which age, gender, and clinical context were provided along with the corresponding angiographic image of the aneurysm. The questionnaire asked whether the physician would have proposed treatment, and if so, which type of treatment (clip, coil or other). In addition, the physician had to indicate, on a scale of one to ten, the degree of confidence they had in their decision. RESULTS: For one third of the cases, there was at least 10% of the respondents who opted for a decision opposite to the one of the majority. For 41.7% of the cases, the proportion of respondents who opted for the clip was not significantly different from the proportion of those who opted for the coil. CONCLUSION: Even in a relatively homogenous group of physicians, there were significantly diverging opinions regarding the management of cerebral aneurysms. This demonstrates the need for evidence-based data from controlled randomized studies. PMID- 25441709 TI - [Intracranial empyemas: Epidemiological, clinical, radiological and therapeutic aspects. Retrospective study of 100 observations]. AB - INTRODUCTION: Intracranial empyema is a frequent complication of ear-nose-throat (ENT) infections. Limited studies have been carried-out on cerebral empyema during recent years in Senegal. Despite new imaging techniques, diagnostic and therapeutic problems as well as outcome still remain in our regions. We report our experience compared to that of the literature. The study focused on epidemiological aspects, difficulties in diagnosis and treatment as well as prognosis of this condition. METHODS: This was a retrospective study conducted from January 2008 to December 2011 of 100 clinical cases. Diagnosis was made based on contrast CT-scan. Twenty-one percent of patients received medical treatment alone, while 79% underwent surgery. The duration of the treatment varied from 4 to 8 weeks. The follow-up was clinical and radiological with a mean follow-up time of 12 months. RESULTS: Cerebral empyema represented 44.4 % of all intracranial suppuration cases and the mean age was 21 years. The etiology was ENT in 35%, meningitis 10%, unknown 25%. Localization was sub-dural in 57%, extra dural in 22%, inter-hemispheric in 10% of the cases. Empyema was associated with an abscess in 7 cases. One case was located in the posterior fossa. The evolution was favorable in 78% of the cases and in 12.5% some neurologic sequelae were observed. Eleven patients died and 3% of the patients had recurrences. CONCLUSION: The frequency of intracranial empyema is still high in Senegal. Difficulties in diagnosis, therapeutics and low economic incomes account for the gravity of intracranial empyema. In spite of these risks, early stage and effective treatment is necessary to reduce the morbi-mortality, especially in young aged children. PMID- 25441710 TI - Neurological form of Erdheim-Chester disease : Case report and review of the literature. AB - OBJECTIVE: Report an unusual presentation of Erdheim-Chester disease revealed by a severe hypothalamic syndrome due to a hypothalamic infiltration and a review of the literature. METHODS: A 28-year-old man was admitted for a previous three month history of asthenia, weight loss, and polyuria-polydipsia. Magnetic resonance imaging on gadolinium T1-weighted sequence revealed a contrast enhancing hypothalamic mass extending to the floor of the fourth ventricle. Cerebrospinal fluid examination was not suggestive of a germinal lesion. Lung nodules were found on thoracic CT-scan but due to their small size, brain stereotactic biopsies were required. RESULTS: Histological examination revealed a diffuse polymorphic inflammatory infiltrate including numerous foamy histiocytes which displayed large eosinophilic CD68-positive, CD1a-negative cytoplasms, and collagen deposition, characteristic of Erdheim-Chester disease. Despite symptomatic and etiologic treatment, death occurred within twelve months. CONCLUSION: Erdheim-Chester disease is a rare multisystem non-Langerhans cell histiocytosis which typically affects long bones, lung, retroperitoneal and orbital spaces and less frequently primary central nervous system. The pathogenesis of the disease remains unknown and no significant prognostic factor has been correlated with survival time. The recently reported BRAF V600E mutation suggests that specific therapeutics (BRAF inhibitors) should be considered. PMID- 25441711 TI - Need for certification of household water treatment products: examples from Haiti. AB - OBJECTIVE: To evaluate four household water treatment (HWT) products currently seeking approval for distribution in Haiti, through the application of a recently developed national HWT product certification process. METHODS: Four chemical treatment products were evaluated against the certification process validation stage by verifying international product certifications confirming treatment efficacy and reviewing laboratory efficacy data against WHO HWT microbiological performance targets; and against the approval stage by confirming product composition, evaluating treated water chemical content against national and international drinking water quality guidelines and reviewing packaging for dosing ability and usage directions in Creole. RESULTS: None of the four evaluated products fulfilled validation or approval stage requirements. None was certified by an international agency as efficacious for drinking water treatment, and none had data demonstrating its ability to meet WHO HWT performance targets. All product sample compositions differed from labelled composition by >20%, and no packaging included complete usage directions in Creole. CONCLUSIONS: Product manufacturers provided information that was inapplicable, did not demonstrate product efficacy, and was insufficient to ensure safe product use. Capacity building is needed with country regulatory agencies to objectively evaluate HWT products. Products should be internationally assessed against WHO performance targets and also locally approved, considering language, culture and usability, to ensure effective HWT. PMID- 25441712 TI - Strategic test-day recording regimes to estimate lactation yield in tropical dairy animals. AB - BACKGROUND: In developing dairy sectors, genetic improvement programs have limited resources and recording of herds is minimal. This study evaluated different methods to estimate lactation yield and sampling schedules with fewer test-day records per lactation to determine recording regimes that (1) estimate lactation yield with a minimal impact on the accuracy of selection and (2) optimise the available resources. METHODS: Using Sahiwal cattle as a tropical dairy breed example, weekly milk records from 464 cows were used in a simulation study to generate different shaped lactation curves. The daily milk yields from these simulated lactation curves were subset to equally spaced (weekly, monthly and quarterly) and unequally spaced (with four, five or six records per lactation) test-day intervals. Lactation yield estimates were calculated from these subsets using two methods: the test-interval method and Wood's (Nature 216:164-165, 1967) lactation curve model. Using the resulting lactation yields, breeding values were predicted and comparisons were made between the sampling regimes and estimation methods. RESULTS: The results show that, based on the mean square error of prediction, use of Wood's lactation curve model to estimate total yield was more accurate than use of the test-interval method. However, the differences in the ranking of animals were small, i.e. a 1 to 5% difference in accuracy. Comparisons between the different test-day sampling regimes showed that, with the same number of records per lactation (for example, quarterly and four test-days), strategically timed test-days can result in more accurate estimates of lactation yield than test-days at equal intervals. CONCLUSIONS: An important outcome of these results is that combining Wood's model for lactation yield estimation and as few as four, five or six strategically placed test-day records can produce estimates of lactation yield that are comparable with estimates based on monthly test-day records using the test-interval method. Furthermore, calculations show that although using fewer test-days results in a decrease in the accuracy of selection, it does provide an opportunity to progeny test more sires. Thus, using strategically timed test-days and Wood's model to estimate lactation yield, can lead to a more efficient use of the allocated resources. PMID- 25441716 TI - Introduction. PMID- 25441713 TI - Viruses infecting marine picoplancton encode functional potassium ion channels. AB - Phycodnaviruses are dsDNA viruses, which infect algae. Their large genomes encode many gene products, like small K(+) channels, with homologs in prokaryotes and eukaryotes. Screening for K(+) channels revealed their abundance in viruses from fresh-water habitats. Recent sequencing of viruses from marine algae or from salt water in Antarctica revealed sequences with the predicted characteristics of K(+) channels but with some unexpected features. Two genes encode either 78 or 79 amino acid proteins, which are the smallest known K(+) channels. Also of interest is an unusual sequence in the canonical alpha-helixes in K(+) channels. Structural prediction algorithms indicate that the new channels have the conserved alpha-helix folds but the algorithms failed to identify the expected transmembrane domains flanking the K(+) channel pores. In spite of these unexpected properties electophysiological studies confirmed that the new proteins are functional K(+) channels. PMID- 25441717 TI - Biodiesel production by combined fatty acids separation and subsequently enzymatic esterification to improve the low temperature properties. AB - The poor low-temperature properties of biodiesel, which provokes easy crystallization at low temperature, can cause fuel line plugging and limits its blending amount with petro-diesel. This work aimed to study the production of biodiesel with a new process of improving the low temperature performance of biodiesel. Waste cooking oil was first hydrolyzed into fatty acids (FAs) by 60g immobilized lipase and 240g RO water in 15h. Then, urea complexation was used to divide the FAs into saturated and unsaturated components. The conditions for complexation were: FA-to-urea ratio 1:2 (w/w), methanol to FA ratio 5:1 (v/v), duration 2h. The saturated and unsaturated FAs were then converted to iso-propyl and methyl esters by lipase, respectively. Finally, the esters were mixed together. The CFPP of this mixture was decreased from 5 degrees C to -3 degrees C. Hydrolysis, urea complexation and enzymic catalyzed esterification processes are discussed in this paper. PMID- 25441718 TI - Is an appropriate wheelchair becoming out of reach? - Part 2. PMID- 25441719 TI - Electrodiagnostic testing before surgery for spinal stenosis. PMID- 25441721 TI - [Cuff pressure control at the intersinve care unit: influence of nursing professionals' training]. AB - OBJETIVE: To analyze proper control of endotracheal cuff pressure in an intensive care unit. The specific objective is to verify whether training of nursing professionals improves monitoring endotracheal cuff pressure. BASIC PROCEDURES: the study type is descriptive, observational and retrospective. All patients were admitted to the Critical Unit II of the Clinico San Carlos Hospital between May 2010-November 2011, requiring either a tracheal tube or tracheal cannula. Studied variables were: number of in range measures, number of intubated patients, or with tracheal cannula and register. Four cuts were made on all admitted patients admitted during the study period in order to measure endotracheal cuff pressure. Two cuts were performed before the professional nurses training and the other two cuts after a specific training with respect to endotracheal cuff pressure and Zero pneumonia. RESULTS: There were 74 measurements. The first cut obtained 40.74% of measures in range. In the second cut 61.90% of measures were identified in range. In the third cut, it was found that 85.7% of measures were in range and in the fourth court, it was noted the 89.47% of measures were in range. CONCLUSIONS: Monitoring of the endotracheal cuff pressure was inadequate before specific training of professionals. Nursing professionals training facilitates the correct measurement of the endotracheal cuff pressure, which improves patient safety. PMID- 25441722 TI - [Analysis of compliance of 2 prevention measures for ventilator-associated pneumonia (raised head of bed and cuff pressure control)]. AB - OBJECTIVES: To quantify the hours of mechanical ventilation in patients with head of bed elevation>=30 degrees . Determining compliance of cuff measurement every 6h. METHOD: Descriptive longitudinal study. Measured: time head of bed elevation>=30 degrees , <30 degrees and reasons for non compliance, as well as cuff control every 6h. RESULTS: One hundred and seventy-two records of head of bed elevation and 584 of cuff pressure. Daily average head<30 degrees for care or procedures: 2h (1h19'). The theoretical average number of hours that patients should remain at>=30 degrees was 21h15' (3h) and actual 14h (5h) (P<.001). Registration of cuff was 76,7%. Cuffs between 20-30cmH2O were 75.9%. The 20% of cuff pressure were measured every 6h<20cmH2O and 33.7% when the interval was higher (P=.04). CONCLUSIONS: A third of the day patients are<30 degrees without justification. Cuff pressure registration and percentage of therapeutic range are high. Control every 6h decreases the cuff with pressure<20cmH2O. PMID- 25441723 TI - [High-flow nasal cannula oxygen therapy in critical patients. Prospective study]. AB - OBJECTIVE: To analyze the incidence of use of high-flow nasal cannula oxygen (HFNC) in intensive care and evaluate the procedure. BASIC PROCEDURES: descriptive prospective study. INCLUSION CRITERIA: all participants were patients admitted to the intensive care units of the hospital Clinico San Carlos November 2012 - January 2013 that required HFNC. VARIABLES: socio-demographic; indications, complications, objectives and flows of the therapy. Statistical analysis with average, standard deviation and percentages, with the statistical program SPSS ver18.0. RESULTS: 12 cases of which 58.3% were men, with a mean age 68.66 (+/- 12) and with NEMS 33.25 (+/-7). The incidence of HFNC was 0.95%. The indication of HFNC was: 75% moderate respiratory failure or need for oxygen supply greater than 40%, 58.3% hypoxemia without hypercapnia, the 41.7% withdrawal and/or employment with non-invasive mechanical ventilation, the 25% support post-extubation, the 16.7% exacerbations of heart failure, the 16.7% improve respiratory work and the 8.3% acute lung edema. The main complications of the HFNC were: mouth-breathing (8.3%), nasal injury (8.3%) and abundant secretions (8.3%). In the fulfilment of the objectives of the HFNC, there was a 91.7% improvement of oxygen therapy, and in 50% of the cases orotracheal intubation was averted. CONCLUSIONS: There is a low incidence of HFNC in the unit. The main indication is the moderate respiratory failure or the high need for oxygen supply. Almost all patients have improved with oxygen therapy, although it has not been possible to avoid intubation. PMID- 25441720 TI - Long noncoding RNAs: an emerging link between gene regulation and nuclear organization. AB - Mammalian genomes encode thousands of long noncoding RNAs (lncRNAs) that play important roles in diverse biological processes. As a class, lncRNAs are generally enriched in the nucleus and, specifically, within the chromatin associated fraction. Consistent with their localization, many lncRNAs have been implicated in the regulation of gene expression and in shaping 3D nuclear organization. In this review, we discuss the evidence that many nuclear-retained lncRNAs can interact with various chromatin regulatory proteins and recruit them to specific sites on DNA to regulate gene expression. Furthermore, we discuss the role of specific lncRNAs in shaping nuclear organization and their emerging mechanisms. Based on these examples, we propose a model that explains how lncRNAs may shape aspects of nuclear organization to regulate gene expression. PMID- 25441724 TI - Pain reduction after percutaneous vertebroplasty for myeloma-associated vertebral fractures. AB - INTRODUCTION: Percutaneous vertebroplasty (PVP) is a minimally invasive procedure with cement augmentation of vertebral fractures. It was introduced in 1987 as a treatment for painful haemangiomas and is today mostly used for painful osteoporotic fractures of the spine. Two randomised, double-blinded trials published in 2009 have raised a debate about the efficiency of the PVP treatment. The aim of this study was to assess the safety and efficacy of PVP for vertebral body fractures in myeloma patients. METHODS: A consecutive group of patients with multiple myeloma who underwent PVP were reviewed. A total of 64 levels were treated on 17 patients during 24 sessions. All procedures were performed in local anaesthesia; no patients complained about discomfort during the procedure. RESULTS: The median preoperative visual analogue scale (VAS) score was 7.6. Improvement was observed in all patients. The median VAS pain score decreased to 3.2 at the three-month follow-up. The results are statistically significant. No complications were observed either during or after the treatment. We observed cement leakage in 12.5% of the patients, but no patients with cement leakage had clinical symptoms. CONCLUSION: PVP is a safe and efficient procedure in the treatment of painful vertebral fractures in patients with multiple myeloma. The main advantages are the immediate stabilisation of the fractured vertebral body, reduction of the pain level and the fact that the patient can be discharged after two hours. The procedure can be repeated for several levels, and the pain relieving effect seems to be permanent. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25441725 TI - Recurrence and survival after neck dissections in cutaneous head and neck melanoma. AB - INTRODUCTION: An important prognostic factor in head and neck melanoma is the status of the regional lymph nodes since the presence of metastatic disease in the nodes greatly aggravates the prognosis. There is no consensus on the surgical treatment algorithm for this group. Our aim was to study if there is a difference in nodal recurrence and survival after radical, modified or selective neck dissection. METHODS: A total of 57 patients treated for regional meta-stases of head and neck melanoma were analysed retrospectively with respect to type of neck dissection, use of sentinel node biopsy, nodal recurrence and survival. RESULTS: After a median 127-month (range: 22-290) follow-up period, we showed that there was no significant difference in nodal recurrence between three different dissection groups (11% for radical node dissection, 24% for modified radical node dissection and 23% for selective node dissection, p > 0.05). No significant difference in five-year survival was observed between the dissection types (56% for radical node dissection, 61% for modified radical node dissection and 48% for selective node dissection, p = 0.613). Multivariate and univariate analysis revealed that patients with metastatic deposits in sentinel nodes had a better survival than patients with clinically palpable nodes (five-year survival rate: 70% versus 36%, p = 0.008). CONCLUSION: The extent of neck dissection does not significantly influence the rate of recurrence or survival. This study indicates that there is a survival benefit for patients who undergo completion lymph node dissection following a positive sentinel node biopsy. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25441726 TI - The dose of levothyroxine in pregnant women with hypothyroidism should be increased by 20-30% in the first trimester. AB - INTRODUCTION: Severe hypothyroidism in pregnancy is associated with maternal and foetal complications, and in less severe cases impaired neuropsychological foetal development is seen. The aim of the present study was to evaluate the efficiency of the clinical control suggested in the guidelines. METHODS: This was a retrospective study of 93 consecutive pregnant women with hypothyroidism who were followed at Herlev Hospital in 2012. The thyroid function was evaluated upon confirmation of pregnancy and thereafter every fourth week. The aim of the treatment was a concentration of serum thyroid-stimulating hormone (S-TSH) less than 2.5 mU/l. RESULTS: The frequency of an S-TSH of more than 4.1 mU/l was 39%. In 27% of all patients, a single measurement was made of a slight increase in S TSH during the pregnancy, and only 12% had several increased S-TSH measurements exceeding 4.1 mU/l. Furthermore, 62% had a minimum of one S-TSH measurement above 2.5 mU/l. The pregnant women with increased S-TSH levels in the beginning of their pregnancy had a tendency to be overtreated later in their pregnancy. CONCLUSION: Although a careful follow-up was performed, we found a high number of patients with a single occurrence of S-TSH outside of the recommended range during their first trimester. The high S-TSH values were registered during the first weeks of the pregnancy, but hereafter corrected, and the number of pregnancy complications recorded did not seem to differ from the number of complications in patients with a normal thyroid function. We recommend increased attention and monitoring of fertile women with hypothyroidism who are planning pregnancy. FUNDING: not relevant. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02094079. PMID- 25441727 TI - Psychotropic medication in a randomly selected group of citizens receiving residential or home care. AB - INTRODUCTION: Treatment with one or more psychotropic medications (PMs), especially in the elderly, is associated with risk, and the effects of treatment are poorly validated. The aim of this article was to describe the use of PM in a population of citizens receiving either residential care or home care with focus on the prevalence of drug use, the combination of different PMs and doses in relation to current recommendations. METHODS: The medication lists of 214 citizens receiving residential care (122) and home care (92) were collected together with information on age, gender and residential status. RESULTS: Two thirds of the citizens (64.5%) used one or more PMs (antipsychotics 15.9%, antidepressants 43.5%, anxiolytics/hypnotics 27.1% and anti-dementia drugs 16.4%). Citizens treated with antipsychotics were also prescribed antidepressants (52.9%), anxiolytics/hypnotics (35.3%) and anti-dementia drugs (20.9%). Citizens treated with anti-dementia drugs were also prescribed antipsychotics (20.0%) and antidepressants (54.3%). Doses over 20 mg and 10 mg of citalopram and escitalopram, respectively, were given to 28.0% of the citizens treated with these antidepressants. CONCLUSION: Compared to previous studies, we observed improvements with regard to doses and choice of drug, but the use of PMs among the elderly is still not sufficiently in accordance with current recommendations. FUNDING: not relevant. TRIAL REGISTRATION: The Danish Data Protection Agency approved the project with journal number 2007-58-0015. PMID- 25441728 TI - Benefit of physiotherapeutic treatment in children with torticollis. AB - INTRODUCTION: The incidence of torticollis, which is often accompanied by some degree of plagiocephaly in infants, has remained increased since the introduction of the supine sleeping position to prevent sudden infant death. Recently, instruments allowing quantitative measurement of torticollis and related pathology have been developed and validated. The aim of the present study was to monitor a cohort of children with torticollis using a standardised protocol including valid and reliable measurements. METHODS: A total of 136 infants diagnosed with torticollis and referred to physiotherapeutic treatment in four paediatric departments were included (October 2009-April 2011). Trained and calibrated physiotherapists assessed their cervical range of motion (ROM), cervical muscle function and severity of plagiocephaly prior to and after the treatment period. RESULTS: The infants' median age was three months at inclusion and seven months at the end of the treatment period that comprised a median of five treatment sessions. Initially, 52% and 54% presented with ROM deficits in rotation and lateral flexion, respectively. After treatment, these parts were reduced to 6% and 14%, and the magnitudes of the remaining ROM deficits were substantially reduced. Plagiocephaly improved in 82, remained unchanged in 18 and deteriorated in five of 105 infants with complete follow-up. Symmetrical or almost symmetrical muscle function was achieved in 93% (n = 101). CONCLUSION: A successful outcome was achieved in the majority (90%) of children with torticollis with less than ten physiotherapeutic treatment sessions. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25441729 TI - Limited success in patients treated with transanal haemorrhoidal dearterialisation. AB - INTRODUCTION: Transanal haemorrhoidal dearterialisation (THD) is a novel non excisional technique based on suture closure of the haemorrhoidal arterial flow feeding the haemorrhoidal plexus. The primary objective of this study was to report the first Danish experience with THD. METHODS: The study was a single centre, non-controlled retrospective study that comprised consecutive patients from a two-year period. Prior to the study start, THD was introduced in our surgical department as the standard treatment of Grade III-IV haemorrhoids. All patients were clinically examined 4-6 weeks post-operatively. Additionally, a structured telephone interview was conducted within two years after the THD operation. RESULTS: During the study period (from January 2011 to January 2013), 93 patients underwent a THD procedure. Twenty patients were exluded from the study which left 73 patients for analysis. Treatment success was obtained in 47 patients (64%) after a median follow-up period of nine months (range 1-24 months). CONCLUSION: We found a relatively low success rate of 64% in patients undergoing THD. Our findings may, in part, reflect a learning curve, patient selection, or that a low success rate is associated with the use of THD per se. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25441730 TI - Low risk of pelvic sepsis after intersphincteric proctectomy in patients with low rectal cancer. AB - INTRODUCTION: Pelvic sepsis after Hartmann's procedure for low rectal cancer is a frequent complication. It has been reported at a frequency of 12.2-17.2% and has even reached 33% when the transection level of the rectum is <= 2 cm from the anal verge. The aim of this study was to examine whether intersphincteric proctectomy reduces the frequency of pelvic sepsis in patients operated with an extended Hartmann's procedure for rectal cancer. METHODS: Patients undergoing elective extended Hartmann's procedure with an intersphincteric proctectomy from 2010 until 2014 were reviewed retrospectively. Patient characteristics and post operative complications were obtained and analysed. RESULTS: A total of 50 patients were included in this analysis. Sixteen were female, the median age was 73 years, and the median BMI was 26 kg/m2. Furthermore, the American Society of Anesthesiologists (ASA) scores were as follows: ASA 1 (28%), ASA 2 (60%), and ASA 3 (12%); their tumour-node-metastasis (TNM) staging was TNM: <= T2 (30%), T3 (50%), and T4 (20%); and 26% had received neoadjuvant radiotherapy, whereas 40% had received chemotherapy. A total of three patients (6%) developed a post operative pelvic sepsis. The median length of post-operative hospitalisation was 9.5 days. Overall mortality was 4% (n = 50). The most frequent surgical complication to intersphincteric proctectomy was perineal wound infection, occurring in 20%. DISCUSSION: This study suggests a reduction in the frequency of pelvic sepsis when intersphincteric proctectomy is performed in patients who undergo extended Hartmann's procedure. The frequency is, however, larger than that reported herein when the rectal stump is left long. Intersphincteric proctectomy should therefore primarily be reserved for low cancers with short rectal stumps. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25441731 TI - Increased risk of post-operative complications in patients with Crohn's disease treated with anti-tumour necrosis factor alpha agents - a systematic review. AB - INTRODUCTION: Tumour necrosis factor alpha (TNF-alpha) plays a role in the immune defence, angiogenesis and collagen synthesis. Inhibition of these pathways may increase the risk of infections and impair wound healing in patients after surgery. Biologic treatments including anti-TNF-alpha agents are increasingly used in the treatment of inflammatory bowel disease. Taking into consideration the biologics' mechanism of action, fears have been expressed that they might increase the rate of post-operative complications. Results from 18 retrospective studies were conflicting, and meta-analyses based on these studies did not agree. The objective of this study was to review data from present reviews and meta analyses in an attempt to come to conclusions for the use of anti-TNF-alpha in Crohn's disease patients in clinical practice. METHODS: Literature search using both electronic and manual searches was conducted according to a pre-defined protocol. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied. RESULTS: Two systematic reviews and six meta analyses were found. Meta-analyses that included a large number of patients and applied quality assessment showed an increased risk of overall post-operative complications and an increased rate of infectious or anastomosis-related complications in patients receiving anti-TNF-alpha. CONCLUSION: The use of anti TNF-alpha agents in Crohn's disease patients is associated with an increased risk of post-operative complications after abdominal surgery. PMID- 25441732 TI - Parental questionnaire as a screening instrument for motor function at age five. AB - INTRODUCTION: No standardised method is used to determine motor function in children in general practice in Denmark. Our aim was to evaluate the correlation between a parental questionnaire assessing motor function at the age of five years and the clinical test Movement Assessment Battery for Children (M-ABC), and to assess whether one or more questions could be used to screen for motor problems at the age of five years. METHODS: This study was based on a parental questionnaire containing ten questions. The M-ABC was used as the gold standard. n = 755 children. The Mann-Whitney rank sum test, Pearson's chi(2)-test, logistic regression analyses and sensitivity and specificity were used to assess the correlation between the questionnaire and the M-ABC test. RESULTS: The best screening tool was six questions in combination: sensitivity 39.8%, specificity 87.1%. Asking if a health professional ever expressed concern about the childs motor development had a sensitivity of 17.0% and a specificity of 93.9%. CONCLUSION: A parental questionnaire used as a screening instrument to identify children with motor problems has a reasonable specificity, but a low sensitivity. The six questions can be used to identify children who do not have motor function difficulties with a relatively high certainty, and it can fairly well identify children with motor function problems. FUNDING: This study was primarily supported by the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA. Additional support was obtained from The Danish Health and Medicines Authority, the Lundbeck Foundation, Ludvig & Daara Elsass Foundation, the Augustinus Foundation, and Aase & Ejnar Danielsens Foundation. The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the Danish National Birth Cohort is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Foundation. TRIAL REGISTRATION: Approved by the Danish National Birth Cohort (DNBC) Board of Directors, the DNBC Steering Committee, the Regional Ethics Committee, the Danish Data Protection Agency and the CDC Institutional Review Board. PMID- 25441733 TI - Management of anal fistula by ligation of the intersphincteric fistula tract - a systematic review. AB - INTRODUCTION: Ligation of the intersphincteric fistula tract (LIFT) is a sphincter-preserving procedure for treatment of anal fistulas described in 2007 by Rojanasakul et al. Several studies have since then assessed the procedure with varied results. This review assesses the relevant literature on this topic. METHODS: The primary endpoints were healing rates, length of follow-up, time to recurrence and post-operative complications. The secondary endpoints were details of the operative technique. A search was made in the PubMed and Embase electronic databases. Reports where LIFT was combined with other fistula treatment techniques were excluded. Only reports in English were included. Most reports were case studies with no control groups. One report could not be retrieved. RESULTS: A total of 19 original reports were assessed. Details concerning preoperative assessment, antibiotic usage and tract ligation methods varied considerably. Primary healing was achieved in 432 out of 612 (70.6%) patients, and no sphincter function impairments were reported. However, ten out of 19 reports did not include an objective assessment of pre- and post-operative continence. No apparent correlation between length of follow-up and healing rate was found, and the longest time to recurrence was eight months. CONCLUSION: LIFT is a safe procedure that provided a mean healing of 70.6% with no reports of impairment of the sphincter function. Future reports should include a follow-up length of a minimum of eight months. It remains uncertain whether the outcome may be improved by prior seton suture insertion. PMID- 25441734 TI - Choice of osteoporosis guideline has important implications for the treatment decision in elderly women referred to a fall clinic. AB - INTRODUCTION: Different guidelines are used worldwide to make decisions on treating osteoporosis. Some are based on fracture risk calculations, whereas others use criteria based on bone mineral density (BMD) T-scores, risk factors, or fragility fractures. The aim of this study was to explore how osteoporosis treatment decisions in a group of elderly women with falls would be affected if fracture risk-based guidelines were used as compared to guidelines based on BMD T scores. METHODS: We studied 88 women attending a falls clinic. Dual energy X-ray absorptiometry and vertebral fracture assessment were performed and clinical risk factors were identified. We calculated the percentage of women recommended for treatment using five guidelines: Danish Bone Society (DBS-DK), UK National Osteoporosis Guideline Group (NOGG-UK), US National Osteoporosis Foundation (NOF US); and we applied a 20% cut-off to fracture risk calculations by the Garvan Fracture Risk Calculator and Q-fracture 2012. Agreement was calculated using kappa statistics. RESULTS: The median age (interquartile range) was 81 years (75 85.5 years). The proportion of women (95% confidence interval) recommended for treatment was DBS-DK 56% (44.7-66.3%), NOGG-UK 51% (40.1-62.1%), NOF-US 88% (78.5 93.5%), Garvan 91% (82.9-96.0%), Q-fracture 58% (47.0-68.4%). The guidelines agreed on treatment recommendations for 23 (26%) of the 88 women studied. The kappa score was 0.13 (p < 0.0001). CONCLUSION: This study showed that the choice of guideline has a major impact on the treatment decisions in elderly women with falls. FUNDING: not relevant. TRIAL REGISTRATION: ClinicalTrial.gov (NCT01600547). PMID- 25441735 TI - Procalcitonin and C-reactive protein as markers of bacterial infection in patients with solid tumours. AB - INTRODUCTION: The diagnosis of bacterial infections in patients with solid tumours can be difficult as both the tumour and its treatment can cause symptoms and signs similar to those of infections. Many patients with solid tumours therefore receive antibiotic treatment without having a bacterial infection. In this prospective study, we wanted to investigate the value of procalcitonin (PCT) compared with C-reactive protein (CRP) as an indicator of bacterial infection in adult patients with solid tumours. METHODS: A total of 41 patients with solid tumours admitted to hospital due to fever or clinical signs of infection had their PCT and CRP levels measured on and during admission. The patients were classified as having a microbio-logically verified infection, a radiologically verified infection or no infection. PCT and CRP were also measured in a control group of 34 out-patients with solid tumours, but with no signs of infection. RESULTS: Of the 41 admitted patients, 25 were classified as having an infection (either microbiologically or radioo-gically verified). Among the 25 cases with infection, PCT was within the normal range in 11 cases and only elevated in 14. As nearly half of the patients with infection had PCT within the normal range, PCT is not suited to exclude an infection. CRP was elevated in 20 patients out of the 25. CONCLUSION: PCT within the normal range cannot exclude an infection and does not appear to be superior to CRP to exclude an infection in patients with solid tumours. FUNDING: not relevant. TRIAL REGISTRATION: Clinicaltrials.Gov, NCT01227109. PMID- 25441736 TI - Coagulation changes following traumatic brain injury and shock. AB - In these studies, we have shown that coagulation and innate immunity pathways respond to trauma within minutes. Furthermore, the appearance of dysfunction of platelets as well as activation of the endothelium is rapidly manifested. Interestingly, many of these changes were attenuated by treatment with valproic acid (VPA). These most notably included coagulation and endothelial activation as well as platelet dysfunction. These results add to the growing body of evidence indicating a protective effect of VPA following trauma, and suggests that this may in part be mediated through an attenuation of the above-mentioned pathways. Furthermore, these results indicate that VPA treatment may be effective in other pathological settings such as coagulopathy following trauma or sepsis. PMID- 25441737 TI - Assessment of mechanical dyssynchrony in cardiac resynchronization therapy. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) significantly reduces morbidity and mortality in patients with symptomatic severe heart failure and evidence of interventricular conduction delay by ECG. Unfortunately, one third of patients do not respond to CRT and selection criteria may need to be improved. Assessment of mechanical dyssynchrony by echocardiography has been suggested to add value in selection of CRT candidates. However, current methods for dyssynchrony analysis may not accurately reflect an activation delay amenable to CRT and controversy remains for the role of mechanical dyssynchrony. HYPOTHESIS: This thesis was based on the assumption that benefit from treatment with CRT requires a significant activation delay of the left ventricle (LV). It was hypothesized that echocardiographic methods for evaluation of mechanical dyssynchrony, reflecting this fundamental pathophysiologic change, could predict response to CRT. In addition, it was hypothesized that this approach would provide improved diagnostic value with regards to dyssynchrony analysis compared to conventional time-to-peak measurements. METHODS: Three studies were performed and consisted of: 1) A prospective study in 67 consecutive patients who fulfilled standard criteria for CRT and had left bundle branch block (LBBB) by ECG. Patients underwent 2D-strain echocardiography (speckle tracking analysis) one day prior to CRT, at day one and six months after implantation and the mechanics behind CRT-response was studied. Strain patterns thought to reflect a complete LBBB were characterized and the predictive ability of this approach was tested with regards to echocardiographic response at six months (> 15% reduction in LVESV) and compared to current time-to-peak indices. 2) A retrospective study in 131 consecutive patients from two centers. Patients all had a Tissue Doppler Imaging (TDI)-dyssynchrony study prior to implantation. Baseline mechanical dyssynchrony was determined by cross-correlation analysis (XCA), a more quantitative method for comparison of contraction patterns, and the association with long-term outcome (survival free from LVAD or heart transplantation after four years) was determined and compared to current time-to-peak indices. In addition, subgroup analysis of the relation to QRS-duration was performed. 3) A prospective study of 33 consecutive CRT-recipients. Patients were VV-optimized at day one after implantation. At six months, TDI and 2D-strain analysis were performed at six different interventricular pacing intervals in steps of 20 ms to investigate the performance of different indices of mechanical dyssynchrony (time to-peak indices and XCA, respectively) and the relation between mechanical dyssynchrony and hemodynamic performance by LVOT VTI. RESULTS: 1) An LBBB-related strain pattern was highly predictive of LV re-modeling response to CRT at six months and significantly added to other known predictors of outcome (etiology and QRS > 150 ms). A reversal in strain-ratio between the early and late-activated myocardial regions was observed at day 1 only among responders suggestive of an important role in promotion of remodeling. 2) Mechanical dyssynchrony at baseline measured by XCA was independently associated with improved long-term outcome in CRT-recipients. Patients with lack of mechanical dyssynchrony and QRS between 120 150 ms showed particularly poor outcome. 3) VV-optimization after six months of CRT was beneficial in both responders and non-responders. Improvements in mechanical synchrony by any method translated into improved hemodynamics. XCA showed the best feasibility, reproducibility and correlation to hemodynamic performance. In all three studies, new methods for dyssynchrony assessment performed better compared to conventional indices. CONCLUSIONS: This thesis confirms the importance of mechanical dyssynchrony for outcome to CRT and demonstrates the value of dyssynchrony assessment for prediction of response to CRT as well as in optimization of device programming. New methods, which better reflect a significant LV activation delay, provides an improved tool for dyssynchrony analysis compared to conventional techniques. PMID- 25441742 TI - Abnormal secretion of melatonin and cortisol in relation to sleep disturbances in children with Williams syndrome. AB - OBJECTIVE: A high rate of sleep disturbances has been reported in individuals with Williams syndrome (WS) but the underlying aetiology has yet to be identified. Melatonin and cortisol levels display circadian rhythmicity and are known to affect and regulate sleep/wake patterns. The current study examined the levels of these two endocrine markers and explored a possible relationship with sleep patterns in children with WS. METHODS: Twenty-five children with WS and 27 typically developing age- and gender-matched comparison children were recruited. Saliva was collected from each child at three time points: 4-6 pm, before natural bedtime, and after awakening. The levels of salivary melatonin and cortisol were analysed by specific enzyme-linked immunoassays. Sleep patterns were examined using actigraphy and the Children's Sleep Habit Questionnaire. RESULTS: The WS group had shallower drops in cortisol and less pronounced increase in melatonin at bedtime compared to the controls. Furthermore, they also had significantly higher levels of cortisol before bedtime. CONCLUSIONS: Increased bedtime cortisol and less pronounced rise in melatonin levels before sleep may play a role in the occurrence of sleep disturbances, such as delayed sleep onset, observed in children with WS. As both markers play a significant role in our circadian rhythm and sleep/wake cycle, it is necessary to examine sleep using multi-system analysis. PMID- 25441743 TI - Apnea burden: efficacy versus effectiveness in patients using positive airway pressure. AB - BACKGROUND: Modern continuous positive airway pressure (PAP) machines track hours of use and residual respiratory events while on treatment. A substantial portion of sleep apnea patients are partially compliant, emphasizing the need to distinguish between PAP efficacy and PAP effectiveness in chronic management of patients with sleep apnea. METHODS: We used a combination of three data sources to estimate the sleep apnea burden in a convenience cohort of PAP users from our clinics that were compliant based on Medicare criteria: self-reported habitual total sleep time, and PAP usage times with residual apnea-hypopnea index (AHI) from compliance downloads. RESULTS: Assuming that the off-PAP time consists of baseline AHI severity, an estimated apnea burden was calculated to estimate PAP effectiveness. Whereas 70% of patients in our cohort showed machine AHI values <5/h, the apnea burden calculations revealed that only one-third of patients are predicted to have an effective AHI <5. CONCLUSION: Estimating PAP effectiveness through the concept of apnea burden has implications for clinical care as well as research trials. PMID- 25441744 TI - Associations of self-reported sleep disturbance and duration with academic failure in community-dwelling Swedish adolescents: sleep and academic performance at school. AB - OBJECTIVE: To examine associations of self-reported sleep disturbance and short sleep duration with the risk for academic failure. METHODS: A cohort of ~40,000 adolescents (age range: 12-19 years) who were attending high school grades 7, 9, and 2nd year of upper secondary school in the Swedish Uppsala County were invited to participate in the Life and Health Young Survey (conducted between 2005 and 2011 in Uppsala County, Sweden). In addition to the question how many subjects they failed during the school year (outcome variable), subsamples of adolescents also answered questions related to subjective sleep disturbance (n = 20,026) and habitual sleep duration (n = 4736) (exposure variables). Binary logistic regression analysis was utilized to explore if self-reported sleep disturbances and habitual short sleep duration (defined as less than 7-8 h sleep per night) increase the relative risk to fail subjects during the school year (controlled for possible confounders, e.g. body-mass-index). RESULTS: Adolescents with self reported sleep disturbances had an increased risk for academic failure (i.e., they failed at least one subject during the school year; OR: boys, 1.68; girls, 2.05, both P < 0.001), compared to adolescents without self-reported sleep disturbances. In addition, adolescents who reported short sleep duration on both working and weekend days were more likely to fail at least one subject at school than those who slept at least 7-8 h per night (OR: boys, 4.1; girls, 5.0, both P < 0.001). CONCLUSION: Our findings indicate that reports of sleep disturbance and short sleep duration are linked to academic failure in adolescents. Based on our data, causality cannot be established. PMID- 25441745 TI - The effects of chronotype, sleep schedule and light/dark pattern exposures on circadian phase. AB - BACKGROUND: Chronotype characterizes individual differences in sleep/wake rhythm timing, which can also impact light exposure patterns. The present study investigated whether early and late chronotypes respond differently to controlled advancing and delaying light exposure patterns while on a fixed, advanced sleep/wake schedule. METHODS: In a mixed design, 23 participants (11 late chronotypes and 12 early chronotypes) completed a 2-week, advanced sleep/wake protocol twice, once with an advancing light exposure pattern and once with a delaying light exposure pattern. In the advancing light exposure pattern, the participants received short-wavelength light in the morning and short-wavelength restricting orange-tinted glasses in the evening. In the delaying light exposure pattern, participants received short-wavelength-restricting orange-tinted glasses in the morning and short-wavelength light in the evening. Light/dark exposures were measured with the Daysimeter. Salivary dim light melatonin onset (DLMO) was also measured. RESULTS: Compared to the baseline week, DLMO was significantly delayed after the delaying light intervention and significantly advanced after the advancing light intervention in both groups. There was no significant difference in how the two chronotype groups responded to the light intervention. CONCLUSIONS: The present results demonstrate that circadian phase changes resulting from light interventions are consistent with those predicted by previously published phase response curves (PRCs) for both early and late chronotypes. PMID- 25441746 TI - Sleep, but not other daily routines, mediates the association between maternal employment and BMI for preschool children. AB - BACKGROUND: It has been established that the more time mothers spend working outside of the home, the more likely their preschool-aged children are to be overweight. However, the mechanisms explaining this relationship are not well understood. Our objective was to explore child sleep, dietary habits, TV time, and family mealtime routines as mediators of the relationship between maternal employment status (full-time, part-time, and no or minimal employment) and child body mass index (BMI) percentile. METHODS: Data were drawn from waves 1 and 2 of STRONG Kids, a prospective panel study examining childhood obesity among parent preschooler dyads (n = 247). Mothers reported their own work hours, their child's hours of nighttime sleep, dietary habits, TV time, and mealtime routines. Trained staff measured child height and weight. RESULTS: Compared to working 0-19 h/week, both full-time (>35 h/week) and part-time (20-34 h/week) employment predicted higher child BMI percentile 1 year later. Hours of child nighttime sleep partially mediated the association between maternal full-time employment and child BMI percentile. Adjusting for individual and family characteristics, children whose mothers were employed full time were less likely to sleep longer hours than children whose mothers were employed 0-19 h/week (b = -0.49, p < 0.04). Shorter child nighttime sleep was associated with higher BMI percentile (b = -7.31, p < 0.001). None of the other mediation pathways tested were significant. CONCLUSIONS: These findings add to the growing literature on the importance of adequate sleep for young children's health. PMID- 25441748 TI - Response to intravenous iron in patients with iron deficiency anemia (IDA) and restless leg syndrome (Willis-Ekbom disease). AB - OBJECTIVES: Iron deficiency anemia (IDA) engenders restless legs syndrome (RLS, aka Willis-Ekbom disease). Intravenous (IV) iron can rapidly reverse IDA and would be expected to similarly reverse RLS caused by IDA. This is the first consecutive case series evaluating the effects of IV iron therapy on RLS occurring with IDA (RLS-IDA). METHODS: RLS-IDA patients were evaluated before and 7-12 months after a 1000-mg IV infusion of low-molecular-weight iron dextran (INFeD(@)) using validated questionnaires and standardized telephone interview. Patients were classified as respondent versus nonrespondent for RLS improvement. RESULTS: Follow-up data were obtained on 42 (70%) of 60 consecutive RLS-IDA patients. The symptoms of RLS were reduced in 76% (32/42) with 47% (20/42) showing an extended response lasting >6 months. The response did not relate to age or gender, but tended to be less among African-Americans than Whites (40% (2/5) vs. 81% (30/37), p = 0.078). White respondents versus nonrespondents had higher hemoglobin levels after treatment (12.1 vs. 11.3 g/dl, p = 0.03). CONCLUSIONS: RLS-IDA is reduced after administration of IV iron in most cases, but the 24% failing to respond was higher than expected. The nonrespondents all showed below-normal hemoglobin levels (<12.5 g/dl) suggesting a failure of adequate treatment of the iron deficiency. IV iron treatment of the RLS with IDA likely requires ensuring more than minimally adequate body iron stores to support iron delivery to the brain. For some, this may require a dose higher than the customary 1000-mg IV iron used for the treatment of either IDA or RLS alone. PMID- 25441747 TI - Sleep efficiency (but not sleep duration) of healthy school-age children is associated with grades in math and languages. AB - OBJECTIVE: The objective of this study was to examine the associations between objective measures of sleep duration and sleep efficiency with the grades obtained by healthy typically developing children in math, language, science, and art while controlling for the potential confounding effects of socioeconomic status (SES), age, and gender. STUDY DESIGN: We studied healthy typically developing children between 7 and 11 years of age. Sleep was assessed for five week nights using actigraphy, and parents provided their child's most recent report card. RESULTS: Higher sleep efficiency (but not sleep duration) was associated with better grades in math, English language, and French as a second language, above and beyond the contributions of age, gender, and SES. CONCLUSION: Sleep efficiency, but not sleep duration, is associated with academic performance as measured by report-card grades in typically developing school-aged children. The integration of strategies to improve sleep efficiency might represent a successful approach for improving children's readiness and/or performance in math and languages. PMID- 25441749 TI - The Children's Report of Sleep Patterns: validity and reliability of the Sleep Hygiene Index and Sleep Disturbance Scale in adolescents. AB - OBJECTIVE: Sleep is critical for adolescent health and well-being. However, there are a limited number of validated self-report measures of sleep for adolescents and no well-validated measures of sleep that can be used across middle childhood and adolescence. The Children's Report of Sleep Patterns (CRSP) has been validated in children aged 8-12 years. The purpose of this study was to examine the psychometric properties of the CRSP, a multidimensional, self-report sleep measure for adolescents. METHODS: The participants included 570 adolescents 13-18 years, 60% female, recruited from pediatricians' offices, sleep clinics, children's hospitals, schools, and the general population. A multi-method, multi reporter approach was used to validate the CRSP. Along with the CRSP, a subset of the sample completed the Adolescent Sleep Hygiene Scale (ASHS), with a different subset of adolescents undergoing polysomnography. RESULTS: The CRSP demonstrated good reliability and validity. Group differences on the CRSP were found for adolescents presenting to a sleep or medical clinic (vs. a community sample), for older adolescents (vs. younger adolescents), for those who regularly napped (vs. infrequently napped), and for those with poor sleep quality (vs. good sleep quality). Self-reported sleep quality in adolescents was also associated with higher apnea-hypopnea index scores from polysomnography. Finally, the CRSP Sleep Hygiene Indices were significantly correlated with indices of the ASHS. CONCLUSIONS: The CRSP is a valid and reliable measure of adolescent sleep hygiene and sleep disturbances. With a parallel version for middle childhood, the CRSP likely provides clinicians and researchers the ability to measure self-reported sleep across development. PMID- 25441750 TI - Sleep, executive functioning and behaviour in children and adolescents with type 1 diabetes. AB - OBJECTIVE: The aim of the study was to examine sleep, neurocognitive and behavioural functioning in children and adolescents with type 1 diabetes (T1D) compared to controls and to test whether sleep quality mediates the relationship between diabetes and neurocognitive and behavioural deficits. METHODS: Participants include 49 children and adolescents with T1D (recruited from a hospital clinic) and 36 healthy controls (age range = 6-16 years). Parents completed a survey consisting of the Sleep Disturbances Scale for Children, the Behavior Rating Inventory of Executive Functions, and the Behavior Assessment System for Children-2. Diabetic and demographic parameters were collated from medical records. The survey was posted to participants. RESULTS: Children with T1D compared to controls reported a higher frequency of sleep problems, and mild deficits in executive and behavioural functioning. Mediational analyses revealed that sleep quality fully mediated metacognitive functioning, externalised problematic behaviour, and internalised problematic behaviour, but not behavioural regulation. CONCLUSIONS: Rather than the direct impact of T1D on daytime functioning, it is the consequent impact of T1D on sleep and the resulting sleep disruption which can explain much of the neurocognitive and behavioural deficits reported in children with T1D. Maintaining good nocturnal glycaemic control may play a much larger role than previously thought in regulating daytime functioning in children with T1D. PMID- 25441752 TI - Attempters, adherers, and non-adherers: latent profile analysis of CPAP use with correlates. AB - STUDY OBJECTIVES: To examine whether subtypes of continuous positive airway pressure (CPAP) user profiles could be identified, and to determine predictors of CPAP subgroup membership. DESIGN: A retrospective, correlational approach was used. Subjects attended clinic where a CPAP download was performed and questionnaires were completed. Additional information was obtained from the electronic medical record. SETTING: Miami VA Sleep Clinic. PARTICIPANTS: Obstructive sleep apnea patients (N = 207). MEASUREMENTS: Three adherence variables comprised the profile: % of nights of CPAP use, % of nights of CPAP use > 4 hours and average nightly use in minutes. Predictors included age, AHI, time since CPAP therapy was initiated, CPAP pressure, residual AHI, BMI, social cognitive variables, insomnia, sleepiness, and psychiatric and medical comorbidities. RESULTS: Latent profile analysis was used to identify CPAP user profiles. Three subgroups were identified and labeled "Non-Adherers," "Attempters," and "Adherers". Non-Adherers (37.6% of the sample) used CPAP for an average of 37 minutes nightly, used CPAP 18.2% of nights and used CPAP > 4 hour 6.2 % of nights. Attempters (32.9%) used CPAP for 156 minutes on average, used CPAP 68.2% of nights and used CPAP > 4 hour 29.3% of nights. Adherers (29.5%) used CPAP for 392 minutes, used CPAP 95.4% of nights and used CPAP >4 hour 86.2% of nights. Self-efficacy, insomnia, AHI, time since CPAP was initiated, and CPAP pressure predicted CPAP subgroup membership. CONCLUSION: Sixty-seven percent of users (Non-Adherers, Attempters) had suboptimal adherence. Understanding CPAP use profiles and their predictors enable identification of those who may require additional intervention to improve adherence. PMID- 25441751 TI - Predictors of shift work disorder among nurses: a longitudinal study. AB - BACKGROUND: Shift work is associated with sleep problems and impaired health. The main aim of the present study was to explore predictors of developing shift work disorder (SWD) among Norwegian nurses using a longitudinal design. METHODS: A total of 1533 nurses participating in a survey on shift work, sleep and health responded to questionnaires at baseline and at follow-up about two years later. SWD was defined as problems of excessive sleepiness and/or complaints of insomnia related to the work schedule. RESULTS AND CONCLUSIONS: There was a significant reduction (p < 0.001) in the prevalence of SWD from baseline to follow-up, from 35.7% to 28.6%. Logistic regression analyses showed significant risks of having SWD at follow-up and the following variables measured at baseline: number of nights worked the last year (OR = 1.01, 95% CI = 1.01-1.02), having SWD (OR = 5.19, 95% CI = 3.74-7.20), composite score on the Epworth Sleepiness Scale (OR = 1.08, 95% CI = 1.04-1.13), use of melatonin (OR = 4.20, 95% CI = 1.33-13.33), use of bright light therapy (OR = 3.10, 95% CI 1.14-8.39), and symptoms of depression measured by the Hospital Anxiety and Depression Scale (OR = 1.07, 95% CI = 1.00 1.14). In addition, leaving night work between baseline and follow-up was associated with a significantly reduced risk of SWD at follow-up (OR = 0.12, 95% CI = 0.07-0.22). PMID- 25441753 TI - "Rebound" is not an appropriate criterion for withdrawal insomnia. PMID- 25441754 TI - The effects of dummy/pacifier use on infant blood pressure and autonomic activity during sleep. AB - BACKGROUND: Dummy/pacifier use is protective for sudden infant death syndrome (SIDS); however, the mechanism/s for this are unknown. As impaired cardiovascular control may be the underlying cause of SIDS, we assessed the effects of dummy/pacifier use on cardiovascular control during sleep within the first 6 months of life. METHODS: Term infants, divided into dummy/pacifier users and non dummy/pacifier users, were studied at 2-4 weeks (n = 27), 2-3 months (n = 35) and 5-6 months (n = 31) using daytime polysomnography. Heart rate, blood pressure (BP), heart rate variability (HRV), blood pressure variability (BPV), and baroreflex sensitivity (BRS) were measured in triplicate 1-2-min epochs during quiet and active sleep in the supine and prone positions. RESULTS: Overall, during the non-sucking periods, in the prone position, the BP was higher (10-22 mmHg) in dummy/pacifier users compared to non-users at 2-4 weeks and 5-6 months (p < 0.05 for both). HRV and BRS were higher in dummy/pacifier users compared to non-users at 2-4 weeks (p < 0.05). Active sucking increased HRV and BPV, consistent with increased sympathetic activity in dummy/pacifier users. CONCLUSIONS: Higher BP and HRV in dummy/pacifier users indicate increased sympathetic tone, which may serve as a protective mechanism against possible hypotension leading to SIDS; however, these effects were not apparent at 2-3 months, when the risk of SIDS is highest. PMID- 25441755 TI - Transcriptome structure variability in Saccharomyces cerevisiae strains determined with a newly developed assembly software. AB - BACKGROUND: RNA-seq studies have an important role for both large-scale analysis of gene expression and for transcriptome reconstruction. However, the lack of software specifically developed for the analysis of the transcriptome structure in lower eukaryotes, has so far limited the comparative studies among different species and strains. RESULTS: In order to fill this gap, an innovative software called ORA (Overlapped Reads Assembler) was developed. This software allows a simple and reliable analysis of the transcriptome structure in organisms with a low number of introns. It can also determine the size and the position of the untranslated regions (UTR) and of polycistronic transcripts. As a case study, we analyzed the transcriptional landscape of six S. cerevisiae strains in two different key steps of the fermentation process. This comparative analysis revealed differences in the UTR regions of transcripts. By extending the transcriptome analysis to yeast species belonging to the Saccharomyces genus, it was possible to examine the conservation level of unknown non-coding RNAs and their putative functional role. CONCLUSIONS: By comparing the results obtained using ORA with previous studies and with the transcriptome structure determined with other software, it was proven that ORA has a remarkable reliability. The results obtained from the training set made it possible to detect the presence of transcripts with variable UTRs between S. cerevisiae strains. Finally, we propose a regulatory role for some non-coding transcripts conserved within the Saccharomyces genus and localized in the antisense strand to genes involved in meiosis and cell wall biosynthesis. PMID- 25441757 TI - Basic statistical reporting for articles published in biomedical journals: the "Statistical Analyses and Methods in the Published Literature" or the SAMPL Guidelines. PMID- 25441758 TI - Childhood atopic dermatitis: a cross-sectional study of relationships between child and parent factors, atopic dermatitis management, and disease severity. AB - BACKGROUND: Successful management of atopic dermatitis poses a significant and ongoing challenge to parents of affected children. Despite frequent reports of child behaviour problems and parenting difficulties, there is a paucity of literature examining relationships between child behaviour and parents' confidence and competence with treatment. OBJECTIVES: To examine relationships between child, parent, and family variables, parents' self-efficacy for managing atopic dermatitis, self-reported performance of management tasks, observed competence with providing treatment, and atopic dermatitis severity. DESIGN: Cross-sectional study design. Participants A sample of 64 parent-child dyads was recruited from the dermatology clinic of a paediatric tertiary referral hospital in Brisbane, Australia. METHODS: Parents completed self-report questionnaires examining child behaviour, parents' adjustment, parenting conflict, parents' relationship satisfaction, and parents' self-efficacy and self-reported performance of key management tasks. Severity of atopic dermatitis was assessed using the Scoring Atopic Dermatitis index. A routine home treatment session was observed, and parents' competence in carrying out the child's treatment assessed. RESULTS: Pearson's and Spearman's correlations identified significant relationships (p<.05) between parents' self-efficacy and disease severity, child behaviour difficulties, parent depression and stress, parenting conflict, and relationship satisfaction. There were also significant relationships between each of these variables and parents' self-reported performance of management tasks. More profound child behaviour difficulties were associated with more severe atopic dermatitis and greater parent stress. Using multiple linear regressions, significant proportions of variation in parents' self-efficacy and self-reported task performance were explained by child behaviour difficulties and parents' formal education. Self-efficacy emerged as a likely mediator for relationships between both child behaviour and parents' education, and self-reported task performance. Direct observation of treatment sessions revealed strong relationships between parents' treatment competence and parents' self-efficacy, outcome expectations, and self-reported task performance. Less competent task performance was also associated with greater parent-reported child behaviour difficulties, parent depression and stress, parenting conflict, and relationship dissatisfaction. CONCLUSION: This study revealed the importance of child behaviour to parents' confidence and practices in the context of atopic dermatitis management. Children with more severe atopic dermatitis are at risk of presenting with challenging behaviour problems and their parents struggle to manage the condition successfully. PMID- 25441759 TI - Basic statistical reporting for articles published in biomedical journals: classic methods paper. PMID- 25441760 TI - [PARP inhibitors and radiotherapy: rational and prospects for a clinical use]. AB - Poly(ADP-ribosyl)ation is a ubiquitous protein modification involved in the regulation of many cellular processes that is carried out by the poly(ADP-ribose) polymerase (PARP) family. The PARP-1, PARP-2 and PARP-3 are the only PARPs known to be activated by DNA damage. The absence of PARP-1 and PARP-2, that are both activated by DNA damage and participate in DNA damage repair processes, results in hypersensitivity to ionizing radiation and alkylating agents. PARP inhibitors that compete with NAD(+) at the enzyme's activity site can be used in BRCA deficient cells as single agent therapies acting through the principle of synthetic lethality exploiting these cells deficient DNA double-strand break repair. Preclinical data showing an enhancement of the response of tumors to radiation has been documented for several PARP inhibitors. However, whether this is due exclusively to impaired DNA damage responses or whether tumor re oxygenation contributes to this radio-sensitization via the vasoactive effects of the PARP inhibitors remains to be fully determined. These promising results have paved the way for the evaluation of PARP inhibitors in combination with radiotherapy in phase I and phase II clinical trials for malignant glioma, head and neck, and breast cancers. A number of challenges remain that are also reviewed in this article, including the optimization of treatment schedules for combined therapies and the validation of biomarkers that will identify which patients will most benefit from either PARP inhibitors in combination with radiotherapy. PMID- 25441761 TI - Immunodeficiency-associated renal Burkitt lymphoma. PMID- 25441756 TI - Annual research review: Growth connectomics--the organization and reorganization of brain networks during normal and abnormal development. AB - BACKGROUND: We first give a brief introduction to graph theoretical analysis and its application to the study of brain network topology or connectomics. Within this framework, we review the existing empirical data on developmental changes in brain network organization across a range of experimental modalities (including structural and functional MRI, diffusion tensor imaging, magnetoencephalography and electroencephalography in humans). SYNTHESIS: We discuss preliminary evidence and current hypotheses for how the emergence of network properties correlates with concomitant cognitive and behavioural changes associated with development. We highlight some of the technical and conceptual challenges to be addressed by future developments in this rapidly moving field. Given the parallels previously discovered between neural systems across species and over a range of spatial scales, we also review some recent advances in developmental network studies at the cellular scale. We highlight the opportunities presented by such studies and how they may complement neuroimaging in advancing our understanding of brain development. Finally, we note that many brain and mind disorders are thought to be neurodevelopmental in origin and that charting the trajectory of brain network changes associated with healthy development also sets the stage for understanding abnormal network development. CONCLUSIONS: We therefore briefly review the clinical relevance of network metrics as potential diagnostic markers and some recent efforts in computational modelling of brain networks which might contribute to a more mechanistic understanding of neurodevelopmental disorders in future. PMID- 25441764 TI - Involvement as inclusion? Shared decision-making in social work practice in Israel: a qualitative account. AB - Shared decision-making (SDM), a representation of shared knowledge and power between social workers and their clients, is gaining popularity and prevalence in social services around the world. In many senses, SDM reflects values traditionally associated with social work and service provision, such as equality and anti-discrimination. In the complex context of social problem-solving, however, the relationship between SDM, social workers and their clients is multi faceted and deserves particular attention. The current study examined SDM and the dilemmas it entails through interviews conducted in 2012 with 77 Israeli social workers and policy makers whose responses were analysed according to the guiding principles of descriptive phenomenological content analysis and dialogical commonality. Participants' responses represent notions of hope, change, identity and choice. Findings are discussed in correspondence with current and recent trends in Israeli social services, and the social work profession in Israel. PMID- 25441763 TI - MOR1 expression in gastric cancer: a biomarker associated with poor outcome. AB - BACKGROUND: At present, the expression of MOR1 and its function in gastric cancer remains unclear with evidence suggesting that it is to be involved in tumor progression and metastasis. The study was to assess the clinicopathologic relevance and prognostic value of MOR1 expression in gastric cancer. METHODS: Real-time quantitative RT-PCR and immunohistochemical staining were used to detect MOR1 expression in primary gastric cancerous surgical specimens and adjacent nontumorous tissues. RESULTS: High MOR1 expression was detected in cancerous tumor compared with their adjacent nontumorous tissues. In addition, the chi-square test revealed that high MOR1 expression was significantly correlated with depth of invasion (p = 0.006), lymph node metastasis (p = 0.001), distant metastasis (p = 0.017), and TNM staging (p = 0.027). Moreover, Kaplan Meier analysis revealed a significant association between MOR1 expression and overall survival. High expression of MOR1 was identified as an independent and significant predictor gene of reduced postoperative survival. CONCLUSION: We conclude that MOR1 expression may be a useful biomarker for better prediction of the clinical outcome and management of gastric cancer patients. PMID- 25441762 TI - Pathogens in ticks collected from dogs in Berlin/Brandenburg, Germany. AB - BACKGROUND: Tick-borne diseases are a major health risk for humans and dogs. In addition to collection and analysis of questing ticks, analysis of host associated ticks for the presence of pathogens is a valuable method to gain insight into transmission patterns of tick-borne diseases. METHODS: Ticks were collected from dogs living in the Berlin/Brandenburg area. The three tick species Ixodes ricinus, Ixodes hexagonus and Dermacentor reticulatus were examined for the presence of Babesia spp., Borrelia spp., Rickettsia spp. and Anaplasmataceae. Conventional PCR followed by sequencing was used for pathogen detection and characterization. RESULTS: Babesia spp. were found in 2.5% and 3% of I. ricinus and I. hexagonus, respectively. Sequencing revealed the presence of Babesia microti, Babesia capreoli and Babesia venatorum. D. reticulatus were free of Babesia canis. Rickettsia spp. were detected in 61% of I. ricinus, 44% of I. hexagonus and 39% of D. reticulatus. Specifically detected were Rickettsia raoulti in D. reticulatus and I. hexagonus, Rickettsia helvetica in I. ricinus and I. hexagonus and Rickettsia monacensis in I. hexagonus. Anaplasma phagocytophilum and Candidatus Neoehrlichia mikurensis have been reported previously in I. ricinus (6.5% and 4.3%, respectively) and I. hexagonus (3.9% and 5.9%). Borrelia spp. were found in 11.6% of I. ricinus and 11.2% of I. hexagonus. Subsequent genospecies analysis revealed Borrelia afzelii, Borrelia garinii, Borrelia burgdorferi sensu stricto and Borrelia miyamotoi. Simultanous presence of more than one pathogen was found in 20% of I. ricinus and in 59% of I. hexagonus whereas the total frequency of any pathogen was 65% in I. ricinus, 59% in I. hexagonus and 64% in D. reticulatus. Ticks in which A. phagocytophilum was detected had a significantly increased risk of also containing Rickettsia. Ticks harbouring a pathogen had significantly higher scutal indices than ticks without presence of any pathogen. CONCLUSIONS: Frequencies of potential human or canine pathogens in ticks were considerable and DNA of all four groups of pathogens was detected. Differences in scutal indices might suggest that pathogens are frequently taken up by ticks when feeding on dogs in Berlin/Brandenburg. PMID- 25441765 TI - Expression of secretory leukocyte protease inhibitor detected by immunohistochemistry correlating with prognosis and metastasis in colorectal cancer. AB - BACKGROUND: The potential of secretory leukocyte protease inhibitor (SLPI) as a biomarker for colorectal cancer was studied. A prospective, randomized, controlled, clinical trial was conducted in 2013 and 2014 to confirm whether the expression of SLPI correlates with prognosis and metastasis in colorectal cancer patients. METHODS: Immunohistochemistry was used to detect SLPI expression in colorectal cancer. The expression of SLPI was scored by two pathologists independently. Statistical analysis of the data was performed using a Chi2 test to investigate the influence of SLPI on the pathologic characteristics of colorectal cancer. RESULTS: Compared with normal tissue, SLPI was overexpressed in colorectal cancer tissue. Overexpression of SLPI correlated with different grades (moderate or good differentiation: 2.7% low expression versus 97.3% high expression, low differentiation: 41.7% low expression versus 58.3% high expression), TNM stage (I or II: 4.2% low expression versus 95.8% high expression; III or IV: 19.7% low expression versus 80.3% high expression), lymphatic metastasis (18.6% low expression versus 81.4% high expression) and distal metastasis (86.5% low expression versus 13.5% high expression), but not with patient age or sex (P=0.613, P=0.871). CONCLUSIONS: Upregulated SLPI correlates with aggressive pathologic characteristics of colorectal cancer; SLPI could be used as an indicator of progression and metastasis in patients with colorectal cancer. PMID- 25441766 TI - A tale of two populations: addressing pediatric needs in the continuum of emergency care. AB - Nearly 27% of all annual emergency department (ED) visits are pediatric related, a relatively small percentage in comparison to the number of visits from the adult population. The majority of the 31 million children and adolescents access care in nonpediatric facilities and have different clinical presentations and needs than adults. Administered by the Health Resources and Services Administration within the Department of Health and Human Services, the Emergency Medical Services for Children (EMSC) program is a federal entity that aims to ensure that pediatric care is well integrated into the entire emergency medical services system so that no matter where a child lives or travels, he or she can receive appropriate and timely care. The objective of this article is to describe the role of the EMSC program in the development of the pediatric emergency care system. The program is striving to improve pediatric emergency care in a number of ways: EMSC State Partnership grant performance measures address the ability of the out-of-hospital and hospital settings to care for children; the National Pediatric Readiness project works with EDs to ensure that essential resources are present to care for children; regionalization grants focus on the challenges of geographic isolation, access to specialty care, and limited resources; and the targeted issue grants focus on the care of the child in the out-of-hospital setting in which there is a paucity of evidence-based knowledge. PMID- 25441769 TI - Induction of dental pulp-derived induced pluripotent stem cells in the absence of c-Myc for differentiation into neuron-like cells. AB - BACKGROUND: A recent research breakthrough has demonstrated that the ectopic expression of four genes is sufficient to reprogram human fibroblasts into inducible pluripotent stem cells (iPSCs). However, whether human dental pulp cells (DPCs) could be reprogrammed into iPSCs remains an open question. In this study, we demonstrated that DPCs from deciduous and permanent teeth can be reprogrammed into iPSCs without c-Myc and had the capacity to differentiate into neuron-like cells. METHODS: DPCs were obtained from donors and reprogrammed into iPSCs using retroviral transduction with SOX2, OCT4, and KLF4. Then, these iPSCs were differentiated into neuron-like cells. Microarray and bioinformatics were used to compare the gene expression profile among these iPSCs and iPSC-derived neuron-like cells. RESULTS: The DPCs displayed a high vitality and capability to quickly restart proliferation and expressed elevated pluripotency similar to mesenchymal stem cells. According to our results, DPC-derived iPSC colonies that could be subcultured and propagated were established as early as 10 days after transduction, in comparison with the skin fibroblast (DPC-derived iPSCs) without c-Myc presented embryonic stem cell-like properties and the pluripotent potential to differentiate into neuron-like cells, which resemble neurons both morphologically and functionally. CONCLUSION: The human DPCs from deciduous and permanent teeth can undergo reprogramming to establish pluripotent stem cell lines without c-Myc. These surgical residues, usually regarded as medical waste, can be used as an alternative source of pluripotent stem cells for personalized medicine. PMID- 25441767 TI - Efficacy of methylene blue in an experimental model of calcium channel blocker induced shock. AB - STUDY OBJECTIVE: Calcium channel blocker poisonings account for a substantial number of reported deaths from cardiovascular drugs. Although supportive care is the mainstay of treatment, experimental therapies such as high-dose insulin euglycemia and lipid emulsion have been studied in animal models and used in humans. In the most severe cases, even aggressive care is inadequate and deaths occur. In both experimental models and clinical cases of vasodilatory shock, methylene blue improves hemodynamic measures. It acts as a nitric oxide scavenger and inhibits guanylate cyclase that is responsible for the production of cyclic guanosine monophosphate (cGMP). Excessive cGMP production is associated with refractory vasodilatory shock in sepsis and anaphylaxis. The aim of this study is to determine the efficacy of methylene blue in an animal model of amlodipine induced shock. METHODS: Sprague-Dawley rats were anesthetized, ventilated, and instrumented for continuous blood pressure and pulse rate monitoring. The dose of amlodipine that produced death within 60 minutes was 17 mg/kg per hour (LD50). Rats were divided into 2 groups: amlodipine followed by methylene blue or amlodipine followed by normal saline solution, with 15 rats in each group. Rats received methylene blue at 2 mg/kg during 5 minutes or an equivalent amount of normal saline solution in 3 intervals from the start of the protocol: minutes 5, 30, and 60. The animals were observed for a total of 2 hours after the start of the protocol. Mortality risk and survival time were analyzed with Fisher's exact test and Kaplan-Meier survival analysis with the log rank test. RESULTS: Overall, 1 of 15 rats (7%) in the saline solution-treated group survived to 120 minutes compared with 5 of 15 (33%) in the methylene blue-treated group (difference -26%; 95% confidence interval [CI] -54% to 0.3%). The median survival time for the normal saline solution group was 42 minutes (95% CI 28.1 to 55.9 minutes); for the methylene blue group, 109 minutes (95% CI 93.9 to 124.1 minutes). Pulse rate and mean arterial pressure (MAP) differences between groups were analyzed until 60 minutes. Pulse rate was significantly higher in the methylene blue-treated group beginning 25 minutes after the start of the amlodipine infusion (95% CI 30 to 113 minutes) that was analyzed until 60 minutes. MAP was significantly higher in the methylene blue-treated group starting 25 minutes after the amlodipine infusion (95% CI 2 to 30 minutes) that was analyzed until 60 minutes. CONCLUSION: Methylene blue did not result in a significant difference in mortality risk. There was an increased pulse rate, MAP, and median survival time in the methylene blue group. PMID- 25441768 TI - Emergency Department Patients With Atrial Fibrillation or Flutter and an Acute Underlying Medical Illness May Not Benefit From Attempts to Control Rate or Rhythm. AB - STUDY OBJECTIVE: Although the management and outcomes of emergency department (ED) patients with atrial fibrillation or flutter have been explored, such studies have typically excluded patients with acute underlying medical illnesses. We seek to describe the ED treatment and outcomes of these complex patients with atrial fibrillation or flutter. METHODS: This retrospective descriptive cohort study used an ECG database from 2 urban EDs to identify consecutive ED patients with an ECG demonstrating atrial fibrillation or flutter from January 1, 2009, to December 31, 2009. We categorized patients with atrial fibrillation or flutter as "complex" according to prespecified criteria and then grouped them as being managed with rate or rhythm control attempts, or not. The primary outcome was safety of rate or rhythm control, measured by whether patients had a predefined adverse event or not. The secondary outcome was the success of rate or rhythm control, defined as rate control decreasing the pulse rate by 20 beats/min and successful rhythm control, both within 4 hours of treatment initiation. Descriptive statistics were used to compare the 2 groups. RESULTS: Four hundred sixteen complex patients with atrial fibrillation or flutter were identified. Patients managed with rate or rhythm control were similar in all baseline characteristics and illness distribution to patients who were not managed in this manner. The 135 patients with attempted rate control (105) or rhythm control (30) had 55 adverse events (40.7%; 95% confidence interval [CI] 32.5% to 49.5%), whereas the 281 patients not managed with rate or rhythm control had 20 adverse events (7.1%; 95% CI 4.5% to 10.9%), for a risk difference of 33.6% (95% CI 24.3% to 42.5%) and a relative risk of 5.7 (95% CI 3.6 to 9.1). Twenty of 105 patients (19.1%; 95% CI 12.3% to 28.1%) were successfully rate controlled, whereas 4 of 30 (13.3%; 95% CI 4.4% to 31.6%) were successfully rhythm controlled. CONCLUSION: In ED patients with complex atrial fibrillation or flutter, attempts at rate and rhythm control are associated with a nearly 6-fold higher adverse event rate than that for patients who are not managed with rate or rhythm control. Success rates of rate or rhythm control attempts appear low. PMID- 25441770 TI - Standardized analysis of laparoscopic and robotic-assisted partial nephrectomy complications with Clavien classification. AB - BACKGROUND: Laparoscopic partial nephrectomy (LPN) and robotic-assisted partial nephrectomy (RPN) are accepted as alternatives of open partial nephrectomy for managing renal tumors. However, LPN and RPN are technically challenging procedures. This report analyzed, according to the Clavien classification, the complications after LPN and RPN. METHODS: We analyzed consecutive LPN (n = 85) and RPN (n = 93) cases at our institution between April 1994 and December 2012. The data were retrospectively reviewed from a prospectively collected database. All complications that occurred within 3 months postoperatively were recorded and classified according to the modified Clavien classification system. RESULTS: The mean tumor size was 3.90 +/- 1.77 cm. The mean operative time was 255.0 +/- 83.5 minutes, and the mean warm ischemia time was 31.6 +/- 22.0 minutes. The overall complication rate was 18.5%. Clavien Grades I, II, IIIa, and IIIb complications accounted for 3.93%, 11.2%, 2.81%, and 1.69% of patients, respectively. The most common complication was perioperative hemorrhage that required blood transfusion. Delayed bleeding occurred in seven patients, and four patients underwent angiographic embolization. The proportions of intermediate and high PADUA (Preoperative Aspects and Dimensions Used for an Anatomical) score (>= 8) and RENAL (Radius/Exophytic/Nearness to collecting system/Anterior/Location) score (>= 7) were 70.8% and 74.2%, respectively. A higher PADUA or RENAL score was associated with a significantly greater complication rate (p = 0.024 and p = 0.02, respectively). CONCLUSION: The overall complication rate in the present study was comparable to that reported in previous studies, although our patients had a larger mean tumor size and higher-complexity procedures. PMID- 25441771 TI - The immediate effects of foot orthoses on hip and knee kinematics and muscle activity during a functional step-up task in individuals with patellofemoral pain. AB - BACKGROUND: Evidence shows that anti-pronating foot orthoses improve patellofemoral pain, but there is a paucity of evidence concerning mechanisms. We investigated the immediate effects of prefabricated foot orthoses on (i) hip and knee kinematics; (ii) electromyography variables of vastus medialis oblique, vastus lateralis and gluteus medius during a functional step-up task, and (iii) associated clinical measures. METHODS: Hip muscle activity and kinematics were measured during a step-up task with and without an anti-pronating foot orthoses, in people (n=20, 9 M, 11 F) with patellofemoral pain. Additionally, we measured knee function, foot posture index, isometric hip abductor and knee extensor strength and weight-bearing ankle dorsiflexion. FINDINGS: Reduced hip adduction (0.82 degrees , P=0.01), knee internal rotation (0.46 degrees , P=0.03), and decreased gluteus medius peak amplitude (0.9mV, P=0.043) were observed after ground contact in the 'with orthoses' condition. With the addition of orthoses, a more pronated foot posture correlated with earlier vastus medialis oblique onset (r=-0.51, P=0.02) whilst higher Kujala scores correlated with earlier gluteus medius onset (r=0.52, P=0.02). INTERPRETATION: Although small in magnitude, reductions in hip adduction, knee internal rotation and gluteus medius amplitude observed immediately following orthoses application during a task that commonly aggravates symptoms, offer a potential mechanism for their effectiveness in patellofemoral pain management. Given the potential for cumulative effects of weight bearing repetitions completed with a foot orthoses, for example during repeated stair ascent, the differences are likely to be clinically meaningful. PMID- 25441772 TI - Potentially dangerous patients: a review of the duty to warn. PMID- 25441773 TI - Nonprofit foundations spur translational research. AB - Every year, hundreds of promising basic discoveries in the pharmacological field are lost and will never have a chance to be exploited for patients due to difficulties in clinical translation. This is especially true for most neurodegenerative disorders lacking disease-modifying therapies. Here we present the current scenario and our vision of a 'collective-impact' multistakeholder approach to expedite the development of new drugs. PMID- 25441774 TI - Prodrug-based nanoparticulate drug delivery strategies for cancer therapy. AB - Despite the rapid developments in nanotechnology and biomaterials, the efficient delivery of chemotherapeutic agents is still challenging. Prodrug-based nanoassemblies have many advantages as a potent platform for anticancer drug delivery, such as improved drug availability, high drug loading efficiency, resistance to recrystallization upon encapsulation, and spatially and temporally controllable drug release. In this review, we discuss prodrug-based nanocarriers for cancer therapy, including nanosystems based on polymer-drug conjugates, self assembling small molecular weight prodrugs and prodrug-encapsulated nanoparticles (NPs). In addition, we discuss new trends in the field of prodrug-based nanoassemblies that enhance the delivery efficiency of anticancer drugs, with special emphasis on smart stimuli-triggered drug release, hybrid nanoassemblies, and combination drug therapy. PMID- 25441775 TI - Integrins: therapeutic targets in airway hyperresponsiveness and remodelling? AB - Integrins are a group of transmembrane heterodimeric proteins that mediate cell cell and cell-extracellular matrix (ECM) interactions. Integrins have been under intense investigation for their role in inflammation in asthma. Clinical trials investigating integrin antagonists, however, have shown that these compounds are relatively ineffective. Airway remodelling is another pathological feature of asthma that is thought to make an important contribution to airway hyperresponsiveness (AHR) and lung function decline. Recent studies have identified integrins as important players in this process, with a particular role for beta1 and alphav integrins. Here we review the role of these integrins in airway remodelling and hyperresponsiveness in obstructive airway disease and their potential as pharmacological targets for future treatment. PMID- 25441776 TI - Towards a better understanding of readmissions after stroke: partnering with stroke survivors and caregivers. AB - AIMS AND OBJECTIVES: To describe the experience of readmission from the perspective of the stroke survivor and family caregiver. BACKGROUND: Older stroke survivors are at an increased risk for readmission with approximately 40% being readmitted in the first year after stroke. Patients and their families are best positioned to provide information about factors associated with readmission, yet their perspectives have rarely been elicited. DESIGN: Descriptive qualitative study. METHODS: This study included older stroke survivors who were readmitted to acute care from home in the six months following stroke, and their family caregivers. Participants were interviewed by telephone at approximately two weeks after discharge and a sub-set was also interviewed in person during the readmission. Interviews were audio-taped and content analysis was used to identify themes. RESULTS: From the 29 semi-structured interviews conducted with 20 stroke survivors and/or their caregivers, the following themes were identified: preparing to go home after the stroke, what to expect at home, complexity of medication management, support for self-care in the community and the influence of social factors. CONCLUSIONS: This study provides the critical perspective of the stroke survivor and family caregiver into furthering our understanding of readmissions after stroke. Participants identified several areas for intervention including better discharge preparation and the need for support in the community for medication management and self-care. The findings suggest that interventions designed to reduce readmissions after stroke should be multifaceted in approach and extend across the continuum of care. RELEVANCE TO CLINICAL PRACTICE: The hospital level has been the focus of interventions to reduce preventable readmissions, but the results of this study suggest the importance of community-level care. The individual nature of each situation must be taken into account, including the postdischarge environment and the availability of social support. PMID- 25441777 TI - Tranexamic acid in brain injury: the devil in the detail. PMID- 25441778 TI - Paroxysmal sympathetic hyperactivity after near-hanging. PMID- 25441779 TI - Identification and molecular characterization of HNF1B gene mutations in Indian diabetic patients with renal abnormalities. AB - Heterozygous mutations of the HNF1B gene (HNF1B-MODY or MODY5) are associated with a wide clinical spectrum of renal and extrarenal disease without clear genotype-phenotype correlation. In this study, we investigated the prevalence of HNF1B gene mutations in young Indian diabetic patients with various renal abnormalities. Fifty unrelated young diabetic patients, who also had renal abnormalities, were selected from the electronic records of a large diabetes centre in Chennai, in southern India. All patients were sequenced for HNF1B gene mutations. The whole or partial gene deletion was analyzed by MLPA. Functional characterization of the novel variant (Asn321Asp) was also performed using transcriptional activation and subcellular localization assays. We identified six different HNF1B gene mutations which included four previously reported (-67C>T, Arg165His, IVS2nt+2insT, Met1_Trp557del) and two novel variations (Asn321Asp, IVS3nt-4C>G). The functional study revealed that the novel variation Asn321Asp in both the heterozygous and homozygous state showed similar transcriptional activity, expression levels and normal transportation of protein to the nucleus similar to wild type, suggesting that it is not likely to be pathogenic. This is the first major study of HNF1B-MODY from India and shows that about 10% of young diabetic subjects with renal abnormalities seen at a tertiary diabetes centre harbor HNF1B gene mutations. PMID- 25441781 TI - Invited commentary. PMID- 25441780 TI - Invited commentary. PMID- 25441782 TI - Invited commentary. PMID- 25441783 TI - Invited commentary. PMID- 25441784 TI - Invited commentary. PMID- 25441785 TI - Invited commentary. PMID- 25441786 TI - Invited commentary. PMID- 25441787 TI - Invited commentary. PMID- 25441788 TI - Invited commentary. PMID- 25441789 TI - Image-based decision-making treatment of degenerated mitroflow and trifecta prostheses. AB - PURPOSE: In the present report we describe our clinical experience using specific image-based decision making and anatomic considerations for transcatheter valve in-valve (ViV) implantation in degenerated xenografts with their pericardial leaflets externally mounted around the stent (Mitroflow [SORIN Group, Milan, Italy] or Trifecta [St. Jude Medical, St Paul, MN]). This design seems to increase the risk of coronary ostia obstruction after ViV procedures. DESCRIPTION: We report 5 patients with degenerated Mitroflow or Trifecta xenografts in whom different anatomic considerations led to different treatment strategies. EVALUATION: One patient underwent conventional redo aortic valve replacement, 2 patients underwent transcatheter ViV implantation with first generation prostheses, and 2 patients underwent transcatheter ViV implantation using the Engager prosthesis (Medtronic, Minneapolis, MN). All patients were discharged alive in good clinical condition and were alive at 30 days after the procedure. CONCLUSIONS: Transcatheter ViV procedures can be performed safely in degenerated Mitroflow and Trifecta prostheses, if the anatomy of the aortic root is taken into consideration. Precise preoperative image-based decision making is mandatory. The Engager prosthesis may allow for ViV procedures even in patients with smaller aortic roots. PMID- 25441790 TI - Heart transplantation after longest-term support with ventricular assist devices. AB - The use of mechanical circulatory support devices to keep patients alive until transplantation has become essential in the face of an increasing organ shortage. We report successful heart transplantations after 841 days of left ventricular assist device (LVAD) support in a child with hypoplastic left heart syndrome, and after 547 days of biventricular assist device (BVAD) support in another child with cardiomyopathy. To our knowledge, this report is the first on the longest term (841 days) LVAD and the longest-term (547 days) BVAD support in children who were mobile and awake during the support, as a most effective bridge to heart transplantation. PMID- 25441791 TI - Giant right atrium: an extreme case of idiopathic dilation of the right atrium. AB - An adult with a grossly dilated right atrium of unknown etiology is presented. The right atrial volume was estimated at more than 1,900 mL, with normal sized left atrium and ventricles. She presented in atrial fibrillation and right ventricular failure. She underwent subsequent reduction atrioplasty of the right atrium and tricuspid valve ring annuloplasty. Atrioplasty alone was unsuccessful in controlling the atrial fibrillation. Postoperatively, her course was complicated by pericardial space problems, eventually requiring a partial pericardiectomy. At her 2-year follow-up she was asymptomatic, although still in atrial fibrillation. PMID- 25441792 TI - Myxoid fibrosarcoma of the left atrium and ventricle in pregnancy. AB - Myxoid fibrosarcoma is rare in adults, and presentation during pregnancy is extremely rare. We report a woman who presented at 20+1 weeks of gestation with a 1-month history of swollen legs, exertional dyspnea, and cough with frothy sputum. Dual-source computed tomography and transthoracic echocardiography showed a left atrial mass. The dead fetus was delivered by caesarean section. Two weeks later, she underwent resection of the intracardiac mass and mitral valve replacement. Histopathologic examination showed myxoid fibrosarcoma. The patient refused postoperative adjuvant chemotherapy and radiotherapy. After 1 year, she had no apparent complications, and echocardiography showed no evidence of recurrence. PMID- 25441793 TI - Surgical treatment of giant left atrial diverticulum in an adult. AB - Giant left atrial diverticulum is a rare congenital abnormality that is most commonly diagnosed in childhood. Here, we report the case of an 18-year-old woman who presented with chest tightness. Contrast-enhanced computed tomography imaging revealed a 12-cm*7-cm left atrial diverticulum. After transesophageal echocardiography was used to exclude left atrial thrombus and mitral regurgitation, an isolated left atrial diverticulum resection was performed. The patient had an uneventful recovery. PMID- 25441794 TI - Subacute endocarditis of an atrial septal closure device in a patient with a patent foramen ovale. AB - The role of transcatheter closure of a patent foramen ovale for cryptogenic stroke remains controversial. The most common complications include atrial arrhythmia and bleeding. Infectious complications are exceedingly rare. We describe a 37-year-old man with a history of transient ischemic attacks and a patent foramen ovale who underwent transcatheter closure, complicated by subacute endocarditis of the completely endothelialized device 2 years after placement. PMID- 25441795 TI - Percutaneous closure of a poorly tolerated post-transcatheter aortic valve implantation ventricular septal defect. AB - We report the case of a 78-year-old woman with severe aortic valve stenosis that was successfully treated with transcatheter aortic valve implantation, with initial good hemodynamic results and clinical improvement of the patient. After 3 weeks, her clinical condition worsened, with progressive heart failure. Transthoracic echocardiography revealed an iatrogenic large subaortic ventricular septal defect with important left-to right shunt (Qp/Qs 3:1). The patient underwent successful transcatheter closure of the ventricular septal defect with a 14-mm Amplatzer mVSD Occluder (AGA Medical, Plymouth, MN), resulting in dramatic clinical improvement. PMID- 25441796 TI - Tricuspid valve replacement with a melody stented bovine jugular vein conduit. AB - Atrioventricular valve replacement options are limited in infants and small children. The Melody stented bovine jugular vein conduit is being used with increasing frequency for percutaneous pulmonary valve replacement. The Melody valve can be serially dilated over time to accommodate the somatic growth of pediatric patients. We report the initial experience of using the Melody valve as a surgical tricuspid valve replacement in an infant. PMID- 25441797 TI - Pulmonary valve replacement through a left minithoracotomy: an alternate approach. AB - We present a case of an isolated pulmonary valve endocarditis in a 23-year-old woman with a history of heavy oxycodone abuse. She presented with fever and positive cultures for methicillin-sensitive Staphylococcus aureus. A transesophageal echocardiogram demonstrated a 3-cm vegetation of the pulmonary valve. Antibiotic therapy was started but she continued to have fever and the vegetation size did not change. In view of ongoing fever and risk of embolization, a left minithoracotomy was performed, and the pulmonary valve was replaced with a bioprosthesis using warm cardiopulmonary bypass, with a beating heart technique. The patient had an uneventful postoperative course and was discharged home. To the best of our knowledge, this is the first case of a pulmonary valve replacement through this approach. PMID- 25441798 TI - Pituitary apoplexy after surgical treatment of lung cancer. AB - Pituitary apoplexy is a rare but potentially life-threatening condition caused by the sudden enlargement of a pituitary adenoma secondary to infarction and hemorrhage. Surgical stress is 1 cause of pituitary apoplexy, but asymptomatic pituitary adenomas are difficult to diagnose preoperatively. Here we report a case of a 78-year-old male who had postoperative pituitary apoplexy after surgery for lung cancer. He underwent right upper and middle lobectomy and lymph node dissection for squamous cell carcinoma with obstructive pneumonia. On the sixth postoperative day he developed sudden-onset fever, respiratory distress, and polyuria. Brain magnetic resonance imaging revealed an enlarged, hemorrhagic pituitary gland. He was treated with steroid hormone replacement. Subsequent endocrine hormone stress tests revealed recovery of his pituitary function. Based on his clinical course, the patient was diagnosed with acute adrenal insufficiency and diabetes insipidus due to pituitary apoplexy. PMID- 25441800 TI - Multiple cavernous hemangiomas of the lung. AB - We present a rare case of multiple cavernous hemangiomas. A 19-year-old girl was seen with dyspnea and fatigue. Thoracic computed tomography showed multiple nodule shadows scattered in the lung. Lung biopsy was carried out. Postoperative histopathologic study identified the nodules as pulmonary cavernous hemangiomas. PMID- 25441799 TI - Invasive pulmonary mucormycosis with concomitant lung cancer presented with massive hemoptysis by huge pseudoaneurysm of pulmonary artery. AB - Pulmonary mucormycosis is a rare opportunistic invasive fungal infection involving the pulmonary vasculature in immunocompromised patients. Pseudoaneurysm of pulmonary artery in mucormycosis is a rare fatal complication after invasion and rupture of a pulmonary artery. We report a patient with diabetes mellitus and incidental lung cancer who developed massive hemoptysis because of a huge pseudoaneurysm of the left pulmonary artery by mucormycosis. Although the patient had been managed by amphotericin B followed by left pneumonectomy for persistent hemoptysis, he died from septic shock and multiorgan failure after surgery. Histologic analysis of a surgical specimen revealed concomitant squamous cell lung cancer. PMID- 25441801 TI - Successful lung transplantation after donor lung reconditioning with urokinase in ex vivo lung perfusion system. AB - Acute pulmonary embolism is considered a contraindication to lung donation for transplantation as it might result in graft dysfunction. Ex vivo lung perfusion (EVLP) is a novel method to assess and recondition a questionable donor graft before transplantation. In this report we present a case of successful bilateral lung transplant after donor lung assessment and treatment with a fibrinolytic agent, urokinase, during EVLP. PMID- 25441802 TI - Pneumothorax as the initial manifestation of idiopathic hypereosinophilic syndrome. AB - We report a case of hypereosinophilic syndrome in a 47-year-old man who had acute pneumothorax as the initial presentation. Peripheral blood eosinophil count increased continuously over a period of 1 month and was associated with pulmonary changes and appearance of skin lesions on the right chest wall. Idiopathic hypereosinophilic syndrome was confirmed by bone marrow aspiration biopsy and skin lesion biopsy after exclusion of all possible secondary etiologies. The clinical status and chest radiographs showed marked improvement after treatment with corticosteroids. PMID- 25441803 TI - Aneurysm of the pulmonary vein: an unusual cause of stroke. AB - This clinical report deals with a giant true pulmonary venous aneurysm, which was partially thrombosed. The overall incidence of pulmonary venous aneurysms is unknown, and they are reported only occasionally. We present the case of a previously healthy man with acute onset of ischemic cerebral stroke. The cause was a thrombus in a huge aneurysm of the left superior pulmonary vein. The patient subsequently underwent uncomplicated therapy for stroke, including thrombolysis followed by excision of the giant pulmonary venous aneurysm. As curative therapy we recommend complete resection of this rare entity. PMID- 25441804 TI - Extraesophageal saline during endoscopic submucosal dissection in a patient with early esophageal squamous cell carcinoma. AB - Saline submucosal injection (SSI) is an indispensable procedure before endoscopic submucosal dissection (ESD) in patients with early esophageal squamous cell carcinoma. Successful SSI should create a saline cushion in the submucosa rather than elsewhere. However, saline outside the esophagus was detected incidentally by endoscopic ultrasonography during ESD in a patient with early esophageal cancer. In this case, saline separated the esophageal adventitia from adjacent tissues, and there were no complications during or after ESD. This finding indicates that it is possible to use interventional extraesophageal saline injection to help differentiate advanced esophageal cancer of Stage T3 from Stage T4 by endoscopic ultrasonography. PMID- 25441805 TI - A 25-cm angiomyxoma of the right atrium extending toward the right ventricle and pulmonary artery terminated to the right pulmonary hilum. PMID- 25441806 TI - Recurrent spontaneous pneumothorax hiding a rare pulmonary tumor in a 4-year-old girl. PMID- 25441807 TI - Giant costal chondrosarcoma in a patient with hereditary multiple exostoses. PMID- 25441808 TI - Plastic bronchitis complicating primary graft dysfunction after lung transplantation. PMID- 25441809 TI - Pulmonary cusp and annular extension technique for reconstruction of right ventricular outflow in tetralogy of Fallot. AB - An alternative pulmonary valve-sparing technique for primary repair of tetralogy of Fallot is presented. Reconstruction of the right ventricular outflow tract was accomplished by augmentation of the anterior facing pulmonary cusp, the pulmonary annulus, and the main pulmonary artery using a single autologous pericardial patch. This valve-sparing technique preserves the coaptation and suspension mechanisms of the native pulmonary cusp and therefore may minimize pulmonary insufficiency in the long term. PMID- 25441810 TI - Using near-infrared spectroscopy to monitor lower extremities in patients on venoarterial extracorporeal membrane oxygenation. AB - Patients on peripheral extracorporeal membrane oxygenation (ECMO) are at risk for lower extremity ischemia. Effective monitoring is needed to identify complications quickly and allow timely correction. Near-infrared spectroscopy has been used extensively in cerebral monitoring during cardiac surgery. We present its use in monitoring lower extremity perfusion in patients on ECMO. Five patients on ECMO had near-infrared spectroscopy monitors placed on the calf of both lower extremities. Continuous real-time tissue oxygen saturation data (stO2) was displayed and recorded. Two patients had lower extremity complications in the leg with the arterial cannula. The patients with complications had lower stO2 in the cannulated leg at the time of ECMO insertion, larger differences in stO2 between the legs at the time of insertion, lower nadir stO2s, and larger peak differences in stO2 between the legs than patients without limb complications. The use of near-infrared spectroscopy for continuous monitoring of tissue oxygenation in the lower extremities in patients on ECMO may allow early identification of patients with lower extremity complications. PMID- 25441811 TI - Video-assisted thoracoscopic implantation of cardioverter-defibrillator systems. AB - Implantation of cardioverter-defibrillators in patients with limited venous access due to recurrent infections, thrombosis, or congenital anomalies can be challenging. For this subset of patients, we performed a video-assisted thoracoscopic intrapericardial implantation using standard shock electrodes and epicardial leads. The pulse generator was placed in pectoral or subcostal position. All pacing and sensing parameters and defibrillation thresholds were satisfactory and stable in time. No major complications were reported. Our limited experience suggests that this technique is a potential alternative in patients where endocardial implantation should be avoided. PMID- 25441812 TI - Valve-sparing aortic root replacement in the presence of coronary anomalies. AB - Aortic root replacement in the presence of coronary anomalies can be challenging. Because the anomalous coronary often arises close to a commissure, reconstruction with traditional buttons can be technically difficult without compromising either the leaflets or the coronary artery. A method of valve sparing root surgery termed "aortic valve and root restoration," using aortic ring annuloplasty and formal valve repair, and then incorporating the anomalous coronary into the commissural suture line, may offer a simple solution to this problem. PMID- 25441813 TI - Laparoscopy with left chest collis gastroplasty: a simplified technique for shortened esophagus. AB - Axial shortening of the esophagus is caused by repetitive esophageal injury from gastroesophageal reflux disease resulting in esophagitis, submucosal fibrosis, and esophageal dysmotility. A short esophagus (<2 cm of intraabdominal length after type II mediastinal dissection) is encountered in 20% to 63% of patients undergoing paraesophageal hernia repair. An esophageal lengthening procedure can be a useful adjunct to fundoplication to reduce the 50% recurrence rate reported at 5 years. We describe a simplified Collis gastroplasty technique that negates the need for wedge fundectomy, potentially saving operating room time and cost, while hypothetically reducing morbidity. PMID- 25441814 TI - Ultrasound-guided extrapleural Nuss procedure for pectus excavatum repair. AB - The minimally invasive Nuss procedure has been widely utilized to treat pectus excavatum. In the present study, intraoperative ultrasonography to guide placement of a Nuss bar, instead of thoracoscopy, is described. This technique may be a simple and safe method to avoid cardiac injury. PMID- 25441815 TI - Definition of the inclusion criteria of Poland's syndrome. PMID- 25441816 TI - The left thoracotomy approach for esophagectomy. PMID- 25441817 TI - Reply: To PMID 24792260. PMID- 25441818 TI - Reply: To PMID 24650587. PMID- 25441819 TI - The approach to a critical aortic stenosis patient with severely depressed left ventricular function. PMID- 25441820 TI - Percutaneous coronary intervention versus coronary artery bypass grafting in severe left ventricle dysfunction. PMID- 25441821 TI - Reply: To PMID 24182911. PMID- 25441822 TI - About the impact of extracardiac vascular disease on vein graft failure. PMID- 25441823 TI - Reply: To PMID 23968761. PMID- 25441824 TI - United States Food and Drug Administration perspectives on the update to the objective performance criteria for surgically implanted heart valve prostheses. PMID- 25441825 TI - Reply: To PMID 24360877. PMID- 25441826 TI - Beating-heart surgery for hypoplastic left heart syndrome with coronary artery fistulas. AB - The presence of ventriculocoronary connections in patients with hypoplastic left heart syndrome and mitral stenosis-aortic atresia is a suggested risk factor for myocardial ischemia after surgical palliation. We describe a neonate with this anatomic variant of hypoplastic left heart syndrome who underwent a successful beating-heart Norwood operation, with continuous coronary perfusion. The ventricular condition could be visually confirmed during the procedure, and a postoperative echocardiogram showed preserved ventricular function. This technique is considered an effective option for minimizing myocardial damage in this patient subtype. PMID- 25441827 TI - Treatment of cardiogenic shock in severe aortic stenosis with the Edwards INTUITY valve. AB - We report the first known cases of successful implantation of the Edwards INTUITY (Edwards Lifesciences LLC, Irvine, CA) rapid-deployment valve in 3 patients with aortic stenosis presenting under emergency cardiogenic shock. At the 6-month follow-up, the 3 patients showed improved left ventricular function and improved functional capacity. PMID- 25441828 TI - Ventricular assist device implantation late after double switch operation for L transposition of the great arteries. AB - We provided a left ventricular assist device (LVAD) for a 22-year-old man with congenital L-transposition of the great arteries after anatomic repair at the age of 7 years. He was hospitalized for progressive low-output syndrome caused by intractable biventricular failure. He received LVAD in his morphologic left ventricle with a concomitant pulmonary valve replacement. After the surgery, critical multiorgan failure with severe right heart failure occurred. It took three postoperative months to normalize all organ function following improvement of morphologic right ventricular function. He has remained stable with LVAD support for 1.5 years. PMID- 25441829 TI - Benign metastasizing leiomyomatosis of the lungs presenting a miliary pattern. AB - Benign metastasizing leiomyomatosis is a very rare and significantly interesting pathology of the lungs. It is a challenge to clinicians when presenting a miliary pattern in preoperative radiologic imaging because it could be any other interstitial disease or infectious in etiology such as miliary tuberculosis. We report a case of innumerable tiny nodular densities spread evenly throughout both lungs in a patient with history of hysterectomy for a fibroid uterus. PMID- 25441830 TI - Lung transplantation for pleuroparenchymal fibroelastosis after chemotherapy. AB - We report the youngest patient ever reported in the literature to exhibit pleuroparenchymal fibroelastosis (PPFE) as a late-onset pulmonary toxicity after treatment with anticancer chemotherapy. The patient was diagnosed with mature B cell leukemia at age 14. He was successfully treated with intensive chemotherapy; however, 7 years later, he experienced recurrent pneumothoraces. He was clinically diagnosed with upper lobe pulmonary fibrosis. At age 28, he underwent single left lung transplantation. Histologic examination of the resected lung revealed PPFE in the upper lobe and constrictive bronchiolitis obliterans in the lower lobe, which implied a close relationship between PPFE and constrictive bronchiolitis obliterans. PMID- 25441831 TI - Video-assisted thoracoscopic conservative repair of postoperative lobar torsion. AB - Postoperative lobar torsion is a rare and life-threatening complication. Several previous cases have been treated with completion lobectomy. We report successful surgical repair of middle lobar torsion after upper lobectomy. On postoperative day 4, the middle lobe was rotated approximately 150 degrees counterclockwise. The surface of the middle lobe appeared congestive, but its surface color, elasticity, and compliance improved 1 h after detorsion. We preserved the middle lobar function and prescribed warfarin for pulmonary vein thrombosis. When preserving a twisted lobe, it is important to consider the damage to the twisted lung, risk of thrombosis, and residual pulmonary function. PMID- 25441832 TI - Esophageal sarcomatoid carcinoma presenting as a Fever with elevated serum leukocytes. AB - The study presented a case of esophageal cancer presenting as intermittent fever with markedly elevated serum leukocyte and C-reactive protein. The patient's symptoms had not improved with antibiotic treatment. However, after thoracic esophagectomy, the fever faded and leukocyte serum levels rapidly normalized. PMID- 25441834 TI - Development and Structural Modifications of Cholinesterase Reactivators against Chemical Warfare Agents in Last Decade: A Review. AB - Organophosphate (OP) pesticides and nerve agents are responsible for suicidal and accidental poisonings. The acute toxicity of nerve agents leads to progressive inhibition of the enzyme acetylcholinesterase (AChE) by phosphylation of serine residue at the active site of gorge. The recent massive destruction of Syrian civilians by nerve gas sarin, has again renewed the research attention of global science fraternity towards nerve agents, their mode of action and most prominently their therapeutic treatment. This review is principally focused on nerve agent intoxication. The common approach to deal with OP-intoxication is, application of antimuscarinic drug (atropine), anticonvulsant drug (diazepam) and clinically used oximes (pralidoxime, trimedoxime, obidoxime and asoxime). However, the existing therapeutic approach is arguable and has several failings to cure all kinds of nerve agent poisonings. Considering this issue, numerous oximes have been synthesized and screened through various in-vitro and in-vivo studies in last decade to overcome the downsides. At present, only a few oximes (bis pyridinum-oximes) exhibit sound efficacy against selective OPs. In spite of extensive efforts, till date no oxime is available as a universal antidote against all the classes of OPs. This review is centered on the recent developments and structural modification of AChE reactivators against nerve agent toxicity. In particular, a deeper look has been taken into chemical modifications of the reactivators by incorporation of different structural moieties targeted towards the increased reactivation affinity and improved blood brain barrier (BBB) penetration. PMID- 25441833 TI - Anaerobic digestion of alkaline bleaching wastewater from a kraft pulp and paper mill using UASB technique. AB - Anaerobic digestion of alkaline kraft elemental chlorine-free bleaching wastewater in two mesophilic, lab-scale upflow anaerobic sludge bed reactors resulted in significantly higher biogas production (250+/-50 vs. 120+/-30 NmL g [Formula: see text]) and reduction of filtered total organic carbon (fTOC) (60+/ 5 vs. 43+/-6%) for wastewater from processing of hardwood (HW) compared with softwood (SW). In all cases, the gas production was likely underestimated due to poor gas separation in the reactors. Despite changes in wastewater characteristics, a stable anaerobic process was maintained with hydraulic retention times (HRTs) between 7 and 14 h. Lowering the HRT (from 13.5 to 8.5 h) did not significantly affect the process, and the stable performance at 8.5 h leaves room for further decreases in HRT. The results show that this type of wastewater is suitable for a full-scale implementation, but the difference in methane potential between SW and HW is important to consider both regarding process dimensioning and biogas yield optimization. PMID- 25441835 TI - Chemical glycan conjugation controls the biodistribution and kinetics of proteins in live animals. AB - The biodistributions and in vivo kinetics of chemically prepared neoglycoproteins have been examined previously and are reviewed here. A variety of mono- and oligosaccharides may be conjugated onto a protein surface using chemical methods. The kinetics and organ-specific accumulation profiles of these glycoconjugates, introduced through intravenous injection, have been analyzed using conventional dissection studies as well as noninvasive methods, such as SPECT, PET, or fluorescence imaging. These studies have revealed glycan-dependent protein distribution kinetics that may be useful for pharmacological and diagnostic applications. PMID- 25441836 TI - Morton's foot and pyridoxal 5'-phosphate deficiency: genetically linked traits. AB - Vitamin B6 is an essential vitamin needed for many chemical reactions in the human body. It exists as several vitamins forms but pyridoxal 5'-phosphate (PLP) is the phosphorylated form needed for transamination, deamination, and decarboxylation. PLP is important in the production of neurotransmitters, acts as a Schiff base and is essential in the metabolism of homocysteine, a toxic amino acid involved in cardiovascular disease, stroke, thrombotic and Alzheimer's disease. This report announces the connection between a deficit of PLP with a genetically linked physical foot form known as the Morton's foot. Morton's foot has been associated with fibromyalgia/myofascial pain syndrome. Another gene mutation methylenetetrahydrofolate reductase (MTHFr) is now being recognized much commonly than previous with chronic fatigue, chronic Lyme diseases and as "the missing link" in other chronic diseases. PLP deficiency also plays a role in impaired glucose tolerance and may play a much bigger role in the obesity, diabetes, fatty liver and metabolic syndrome. Without the Schiff-base of PLP acting as an electron sink, storing electrons and dispensing them in the mitochondria, free radical damage occurs! The recognition that a phenotypical expression (Morton's foot) of a gene resulting in deficiency of an important cofactor enzyme pyridoxal 5'-phosphate will hopefully alert physicians and nutritionist to these phenomena. Supplementation with PLP, L5-MTHF, B12 and trimethylglycine should be used in those patients with hyperhomocysteinemia and/or MTHFR gene mutation. PMID- 25441837 TI - Possible target for preventing fibrotic scar formation following acute myocardial infarction. AB - Bone morphogenetic protein 1 (BMP1) was originally isolated from bone with other BMPs due to its affinity for heparin. While all other BMPs are members of the Transforming Growth Factor beta (TGFbeta) superfamily of growth factors, BMP1 is not an authentic member of the BMP protein family. Together with mammalian Tolloid Like protein 1 (mTLL-1) and mTLL-2, BMP1 comprise a small group of zinc- and calcium-dependent proteinases. Acute myocardial infarction (AMI) is the leading cause of death in developed countries which accounts for 13% of deaths worldwide. It was recently shown that inhibition of BMP1-3 reduces progression of fibrosis in chronic kidney disease and suggested that BMP1-3 is an important molecule for fibrogenesis. We hypothesize that inhibition of BMP1-3 represents future of therapeutic interventions in the heart tissue fibrosis following AMI. This novel approach aims to acquire the first candidate specific treatment for recuperating the heart function in patients with AMI. PMID- 25441838 TI - Could DNA-reactive B lymphocytes be activated through HIV-1 DNA-stimulation involving BCR/TLR-9 pathway to yield antibodies targeting viral DNA? AB - This paper discusses potential avenues to abate the last bulwark to the HIV-1 eradication i.e. viral reservoirs in the body, consisting mainly of viral DNA hidden, in latent form, into long-lived memory CD4+ T-cells, resulting unaffected by either drugs or immune system. Activation of the innate immune system is necessary for the induction of adaptive immune responses against invading pathogens. In part, this is achieved by recognition of molecules associated with infection by a plethora of pattern recognition receptors comprising Toll-like receptors (TLRs) which are express on numerous cells of immune system such as, dendritic cells and B cells, and are activated by some TLR ligands. TLR-9, localized in endosomal compartment, specifically recognizes unmethylated oligonucleotide sequences containing CpG motifs which are particularly abundant in microbial genome, including HIV-1 DNA. Naive B cells are activated following antigen binding to the B cell receptor (BCR). The complex antigen/BCR, internalises and synergises with TLR leading to hyper activation of B cells and antibodies production. Cross-link of the BCR with TLR9, followed by upregulation of TLR-9, in response to self DNA-containing antigens, on DNA-specific B lymphocytes lead to the development of DNA-specific autoantibodies. This occur in systemic autoimmune disorders, such as, systemic lupus erythematosus (SLE). Although such DNA-specific B lymphocytes, are usually present in B cell repertoire at low frequency, they normally do not produce autoantibodies, they can be activated by antigen BCR ligation, with plasmacytoid dendritic cells (pDCs) providing helper signals. The hypothesis here derives by insight that stimulation of BCR, by exogenously added HIV-1 DNA, on potentially reactive HIV-1 DNA-specific B cells, from HIV-1 and/or HIV-1/SLE patients, co-cultured with autologous viral DNA-stimulated pDCs, could lead to desirable in vitro production of antibodies direct against HIV-1 DNA by involving BCR/TLR9 pathway. These antibodies, suitably delivered into infected or uninfected CD4(+) T-cells, by a carrier, such as, peptide transduction domain of Tat, could selectively recognize viral nucleic acid, rich in CpG motifs, respect to host DNA, both in productively than latently infected T cells. Because HIV-1 DNA into latently infected cells is heavily methylated and deacetylated, co-treatment with a small molecule inhibitor of DNA methylation, such as 5-aza-2'-deoxycytidine (aza-Cdr), and histone deacetylase inhibitors (HDACi), they would favor higher accessibility by antibodies to viral DNA, which is harbored into human chromosomes. The in vitro production of anti-HIV-1 DNA antibodies and their in vivo reintroduction, could find future application as interesting strategy to pave the way to an eventual cure to decrease and/or eliminate viral reservoirs from the body, and providing possible therapeutic applications not only for HIV-1/AIDS, but also for other infectious diseases. PMID- 25441839 TI - HLA associated type 1 diabetes risk in children of Pakistani migrants to Norway. AB - Type 1 diabetes (T1D) results from poorly defined interaction between susceptibility genes and environmental factors. The objective was to investigate Human Leukocyte Antigens (HLA) associated T1D risk among Pakistani newborns in Norway based on what published globally. DNA samples from 189 newborns, whose parents were first generation migrants from Pakistan, were analyzed. The hypothesis was tested using high resolution HLA genotyping for the -DRB1 and DQB1 loci and high/intermediate for the -DQA1 locus. We identified 28 different DRB1, 13 DQB1 and 9 DQA1 alleles. Of the 39 different haplotypes identified, only five have been reported to confer T1D susceptibility. Among these the DR3-DQ2 (DRB1*03:01:01-DQA1*05-DQB1*02:01:01) haplotype was found in 18.5% (n=70) of the newborns, and 18.6% (n=13) of these were homozygotes. A diverse range of HLA haplotypes were identified amongst an ethnically homogenous group of newborns, with only a small proportion associated with T1D risk. The incidence of T1D among immigrants form South/East Asia is the lowest in the Norwegian Type 1 Diabetes Registry. The few included so far, are children of first generation immigrants. If incidence of T1D rises in the Norwegian Pakistani childhood population, as observed in the UK, then environmental triggers rather than genetic susceptibility will be the explanation. PMID- 25441840 TI - Commentary on 'A randomized controlled trial of the fascia suture technique compared with a suture-mediated closure device for femoral arterial closure after endovascular aortic repair'. PMID- 25441841 TI - Nurses' knowledge and comfort levels using the Physician Orders for Life sustaining Treatment (POLST) form in the progressive care unit. AB - Many patients are admitted to the hospital with an active Physician Orders for Life-sustaining Treatment (POLST) Form; however, not all registered nurses (RNs) are familiar with the form or comfortable with initiating a discussion about end of-life care. Evidence indicates that an education program increases RNs' knowledge and utilization of the POLST form. The purpose of this evidence-based practice project was to answer the question: among the RNs in a progressive care unit (PCU), does implementing a formal evidence-based practice POLST program compared to current practice increase RNs' knowledge and comfort level using the POLST form? A pre-post education survey was used. Results indicated a POLST education program increased PCU RNs' knowledge and comfort level in using the POLST form. It is recommended to include POLST form education for PCU RNs in workplace education programs. PMID- 25441842 TI - Explaining implementation behaviour of the National Incident Management System (NIMS). AB - This paper explains the perceived implementation behaviour of counties in the United States with respect to the National Incident Management System (NIMS). The system represents a massive and historic policy mandate designed to restructure, standardise and thereby unify the efforts of a wide variety of emergency management entities. Specifically, this study examined variables identified in the NIMS and policy literature that might influence the behavioural intentions and actual behaviour of counties. It found that three key factors limit or promote how counties intend to implement NIMS and how they actually implement the system: policy characteristics related to NIMS, implementer views and a measure of local capacity. One additional variable-inter-organisational characteristics was found to influence only actual behaviour. This study's findings suggest that the purpose underlying NIMS may not be fulfilled and confirm what disaster research has long suggested: the potential for standardisation in emergency management is limited. PMID- 25441843 TI - [Paronychia]. AB - Paronychia is an inflammation of the folds of tissue surrounding the nail; proximal and/or lateral nail folds. Acute paronychia is mainly due to bacterial infection, Staphyloccus aureus or Streptococcus sometimes viral infection (herpetic whitlow). Chronic paronychia is the result of numerous conditions in which the main factor is the disappearance of the cuticle. On fingers, etiology is often a contact dermatitis; bacterial or mycological infections are secondary colonizations. Onychomycosis due to moulds (Fusarium) or dematiae (Scytalidium dimitiadum) are often associated with paronychia. Paronychia is a frequent side effect of chemotherapies and targeted therapies. Paronychia is a common complication of lateral or proximal (retronychia) ingrown nail and systemic antibiotics are ineffective unless infection is proved. Do not use systematically systemic antibiotics. PMID- 25441844 TI - Flaxseed oil enhances the effectiveness of trastuzumab in reducing the growth of HER2-overexpressing human breast tumors (BT-474). AB - Flaxseed oil (FSO) reduces breast tumorigenesis and HER2 expression in animal models of luminal breast cancer. The primary treatment for HER2-overexpressing tumors is trastuzumab (TRAS). We aimed to determine the effect of 4% FSO alone and combined with TRAS on HER2-overexpressing tumor (BT-474) growth and to explore potential mechanisms with a specific focus on HER2, mitogen-activated protein kinase (MAPK) and Akt signaling and fatty acid profile. Athymic mice with established tumors were fed the basal diet (control) or 4% FSO diet, with or without TRAS (1 or 2.5 mg/kg) treatment for 4 weeks. Tumor growth, HER2 signaling biomarkers (mRNA and protein) and fatty acid profile were measured. Tumors treated with FSO alone showed no difference in tumor growth compared to control; however, compared to TRAS2.5 and other groups, FSO+TRAS2.5 caused significantly lower tumor growth and cell proliferation and higher apoptosis and the greatest lowering of signaling biomarker expressions (MAPK2, HER2 mRNA; pHER2 protein). Both TRAS and FSO had main effects of reducing the phosphorylated/total expression of Akt and MAPK protein expression. Dietary FSO altered the tumor fatty acid profile. In conclusion, 4% dietary FSO alone does not affect BT-474 tumor growth but enhances the tumor-reducing effect of TRAS (2.5 mg/kg). FSO*TRAS interactive effect may be modulated by their combined reductions of HER2 signaling through the Akt and MAPK pathways leading to reduced cell proliferation and increased apoptosis. FSO alters tumor fatty acid profile that likely contributes to effects on signaling pathways. This supports FSO as a complementary treatment for HER2+ breast cancer treated with TRAS. PMID- 25441845 TI - "Jumping stump" phenomenon. AB - Myoclonic spasm of an amputated extremity can be problematic for amputees and requires recognition and understanding by surgeons encountering the phenomenon. In the present brief report, we describe the condition in a female amputee after below-the-knee amputation. Our aim is to increase awareness of this condition among foot and ankle surgeons. PMID- 25441846 TI - Excision of Elephantiasis Nostras Verrucosa Lesions in a Patient With Hereditary Lymphedema: Case Report and Review of the Literature. AB - Elephantiasis nostras verrucosa (ENV) is a rare cutaneous sequela of chronic lymphedema. Treatment of ENV remains poorly elucidated but has historically involved conservative management aimed at relieving the underlying lymphedema, with a few cases managed by surgical intervention. We report a case of a 27-year old male with primary lymphedema complicated by large painful ENV lesions on his left foot that we excised surgically with good functional and cosmetic results as validated by the patient. To our knowledge, this is the first report of a case of ENV with a pedunculated morphology and the presence of a deep invasive stalk. PMID- 25441847 TI - Validity, reliability, and responsiveness of the Korean version of American Academy of Orthopedic Surgeons Foot and Ankle questionnaire. AB - The American Academy of Orthopaedic Surgeons Foot and Ankle Questionnaire (AFAQ) reflects patients' subjective disorder due to foot and ankle conditions. We evaluated the validity, reliability, and responsiveness of the Korean version of the AFAQ, after translation and transcultural adaptation of the original AFAQ into the Korean language. A total of 206 patients were enrolled, including 152 with chronic problems (experimental group) and 54 with acute problems (control group). We used the intraclass correlation coefficient to assess the test-retest reliability and Cronbach's alpha to assess internal reliability. Pearson's correlation coefficient was used to assess the criterion validity by correlating the Korean AFAQ scores with those from other validated scales (American Orthopaedic Foot and Ankle Society Hallux-Metatarsophalangeal-Interphalangeal scale, American Orthopaedic Foot and Ankle Society Ankle-Hindfoot scale, and visual analog scale for pain). To analyze discriminant validity, we evaluated the difference between the experimental and control groups using the Student t test. Of the 152 patients in the experimental group, 29 revisited our clinic postoperatively and repeated the Korean AFAQ. To analyze responsiveness, we used paired t tests to evaluate postoperative changes. In terms of test-retest reliability, the intraclass correlation coefficient ranged from 0.979 to 0.999. In terms of internal reliability, Cronbach's alpha was 0.528 for the stiffness and swelling subscale and greater than 0.7 for all other subscales. In terms of criterion validity, Pearson's correlation coefficient ranged from 0.492 to 0.699. The probability of the null hypothesis for discriminant validity and responsiveness was statistically significant (p < .001 and p = .021, respectively). These results showed that the Korean version of the AFAQ had the same concept and intention as the original version and is reliable, valid, and responsive. PMID- 25441848 TI - A passing glance? Differences in eye tracking and gaze patterns between trainees and experts reading plain film bunion radiographs. AB - Eye tracking and gaze pattern studies have been used to evaluate human behavior for decades. This is because of its ability to reveal conscious and subconscious behaviors when subjects are tasked with observation, decision making, and surgical performance. Many have popularized the use of this technology for radiographic assessment while evaluating radiologist behaviors, but little has been described for surgeon behavior patterns when evaluating preoperative deformities by radiograph. Because the radiographic assessment strongly influences surgical selection, the present study was designed to evaluate the differences between groups of novice and experienced surgeons' gaze patterns when tasked to describe hallux valgus deformities. The subjects were asked to rate the deformity as "none," "mild," "moderate," or "severe." Using an externally mounted eye tracking system, our study assessed saccades, fixations, overall time spent per radiograph, and the subjects' chosen bunion rating. Both the novice and advanced groups of foot and ankle surgeons were tasked to evaluate 25 total anteroposterior radiographs from patients who presented with a primary complaint of bunion pain. These patients were chosen at random, such that all participating surgeons had no previous patient familiarization. Statistically significant differences were observed with regard to the activity and rating of the moderate bunion films. The experience of surgeons does appear to modify gaze behavior with respect to time and attention, such that less overall time spent per image is needed by the advanced group, with improved efficiency. Future academic curriculum and training techniques could be developed to reflect these potential technical differences in search behavior, diagnostic technique, and surgical selection strategy. PMID- 25441849 TI - Evaluation of Hallux Interphalangeal Joint Arthroplasty Compared With Nonoperative Treatment of Recalcitrant Hallux Ulceration. AB - Patients with chronic diabetes can develop plantar hallux ulcerations secondary to neuropathy, increased pressure, and deformity. The present retrospective study evaluated the efficacy of hallux interphalangeal joint (HIPJ) arthroplasty to address recalcitrant ulceration. Two groups of patients with diabetes were compared: a surgical group of 13 patients and a nonsurgical standard therapy group of 13 patients. The patients in the surgical group underwent HIPJ arthroplasty. All the patients in the standard therapy group received local wound care and offloading. The mean duration of follow-up was 19.5 (range 1.2 to 47.9) months, and the mean age was 55 +/- 13.0 years. Statistical significance was found in the surgical group for faster time to healing (3.5 weeks [2.5, 4.25] vs 9 weeks [2, 17.29], p = .033) and lower incidence of ulcer recurrence (8% +/- 7.69 vs 54% +/- 53.85, p = .031). There were also fewer amputations in the surgical group (0% +/- 0 vs 38% +/- 38.6, p = .063). To our knowledge, only 1 other published study has evaluated HIPJ arthroplasty as a treatment of recalcitrant hallux ulceration. The present study adds comparison data from a nonoperative standard therapy group and found that HIPJ arthroplasty is an effective curative treatment option to address chronic plantar hallux ulcerations in diabetic patients with neuropathy. PMID- 25441850 TI - Management of complex fibular fractures: double plating of fibular fractures. AB - Complex fibular fractures as a result of either high-energy mechanisms or advanced age can be difficult to manage as significant comminution can preclude standard operative techniques. Furthermore, the maintenance of osseous reduction postoperatively throughout convalescence can present an equivalent challenge. Strict weightbearing restrictions in the elderly and the noncompliant postoperatively convey an additional risk of potential failure. We present a technique that has offered additional reassurance in these instances. We retrospectively evaluated 25 consecutive patients who had undergone this fibular double plating technique and evaluated the patient outcomes to determine whether this technique conferred any additional risk when weighed against its benefits. All 25 patients underwent benign postoperative courses. No additional operations were performed as a result of this technique. No patient undergoing this technique complained of any hardware irritation, and no hardware removal was required. This double plating technique may confer additional stability to fracture patterns that are inherently unstable. It does not appear to increase the incidence of hardware removal or irritation, and patient morbidity remained low. Based on our results, we advocate this technique especially for comminuted fracture patterns. PMID- 25441851 TI - Giant Cell Tumors of the Foot and Ankle Bones: High Recurrence Rates After Surgical Treatment. AB - Giant cell tumor (GCT) of the bone is a benign primary bone tumor most often treated with intralesional surgery. Most cases occur around the knee; however, rarely, GCT of bone can occur in the foot and ankle. Limited data exist about the outcomes after treatment of GCT in this location. We retrospectively reviewed an orthopedic oncology database from 1970 to 2010 for cases of GCT of the bone, specifically within the foot and ankle bones. After exclusionary criteria were applied, a total of 19 disease sites in 18 patients were included for analysis. Of the 19 disease sites, 10 recurred. Patients, on average, required 1.7 operations per disease site. Of the 18 patients, 10 required >=2 operations, 3 required >=3 operations, and 1 required 4 operations. A total of 4 amputations were performed, including 2 below the knee amputations. Of the 10 patients with recurrence, 2 also had evidence of metastatic disease. The recurrence rates of GCT in the foot and ankle bones appear to be greatest after intralesional curettage without the use of cement. Although the recurrence rates are high, intralesional operations with multiple adjuvant therapy can eventually result in cure. PMID- 25441852 TI - Isolated calcaneofibular ligament injury: a report of two cases. AB - Injury to the lateral ankle ligaments is very common among both athletes and nonathletes alike. Although anterior talofibular ligament injuries and combination anterior talofibular ligament and calcaneofibular ligament injuries are considerably common, an isolated injury to the calcaneofibular ligament has rarely been reported. We present the case reports of 2 patients, both of whom had sustained an isolated calcaneofibular ligament injury. In both patients, the diagnosis was obtained from the clinical examination and magnetic resonance imaging. Also, in 1 patient, formal open surgical inspection was performed. We advocate conservative treatment initially using the same protocols used for common lateral ankle ligament injuries and, if necessary, surgical intervention to address this unique and rare pathologic entity. PMID- 25441853 TI - Screw placement relative to the calcaneal fracture constant fragment: an anatomic study. AB - Placement of a screw from the lateral wall of the calcaneus into the constant sustentaculum tali fragment can be difficult when surgically repairing a calcaneal fracture. This screw serves to compress the fracture fragments and support the posterior facet. This difficulty results from the small landing zone of the sustentaculum tali with its nearby vulnerable soft tissue structures. We present an anatomic study of 10 cadavers to determine a starting point and angle of screw advancement when placing a constant fragment screw. PMID- 25441854 TI - The fifth metatarsal base: anatomic evaluation regarding fracture mechanism and treatment algorithms. AB - Fractures occurring within the 1.5-cm proximal portion of the fifth metatarsal are commonly considered avulsion fractures. The exact mechanisms of such fractures are controversial. The present study focused on determining the likely mechanism of fracture according to the exact anatomy to allow for more successful treatment. The research sample included 10 frozen cadaveric specimens. The lateral band of the plantar fascia, peroneus brevis, and articular surface were identified and separated from their attachments, thereby splitting the fifth metatarsal base into zones A, B, and C. In zone A, the attachment of the plantar fascia was 6.6 +/- 2.2 mm from the inferior aspect, 9.5 +/- 2.9 mm from the proximal aspect, and 11.5 +/- 0.9 mm from the lateral aspect. In zone B, the attachment of the peroneus brevis was 12.0 +/- 2.2 mm from the inferior aspect, 10.2 +/- 2.2 mm from the proximal aspect, and 11.5 +/- 0.9 mm from the lateral aspect. Zone C was measured from the border of zone B and encompassed the articulation of the fifth metatarsal to the cuboid. We propose that fractures occurring in the most proximal end of the fifth metatarsal, zone A, are caused by a lateral band of plantar fascia and might be able to be treated conservatively by immobilization with weightbearing. We also propose that fractures occurring in zones B and C result from traumatic tension on peroneus brevis and might need to be treated with strict immobilization and non-weightbearing or open reduction internal fixation. PMID- 25441855 TI - Role of Fixation and Postoperative Regimens in the Long-Term Outcomes of Distal Chevron Osteotomy: A Randomized Controlled Two-by-Two Factorial Trial of 100 Patients. AB - The necessity of chevron osteotomy fixation is controversial and evidence for the effectiveness of postoperative regimens is limited. In a prospective, randomized study, we compared the long-term results of 2 operative techniques (osteotomy fixation versus no fixation) and 2 postoperative regimens (a soft cast versus an elastic bandage) in 100 patients who underwent surgery for hallux valgus. Clinical evaluations with the American Orthopaedic Foot and Ankle Society (AOFAS) scale scoring were performed at baseline and 6 weeks, 6 months, 1 year, and a mean of 7.9 years postoperatively. The mean AOFAS function score were better in the group treated without osteotomy fixation and with an elastic bandage at 6 weeks postoperatively, but the differences then disappeared. The total AOFAS scores improved significantly in all 4 subgroups during the first 12 months; however, in the long term, some deterioration occurred. In the AOFAS scores, the average function, alignment, and total points were significantly worse when the preoperative hallux valgus angles exceeded 30 degrees . The incidence of complication was low (1%); there was 1 superficial wound infection. The AOFAS score did not differ statistically among the groups in our population. An elastic bandage for postoperative treatment is recommended. The risk of recurrence is greater and functional result worse if the preoperative hallux valgus angle exceeds 30 degrees . PMID- 25441856 TI - Treatment of Longitudinal Epiphyseal Bracket by Excision and Polymethylmethacrylate Insertion at the Preossified Disease Stage. AB - Longitudinal epiphyseal bracket is a rare ossification anomaly involving the tubular bones of the hand or foot that have a proximal epiphysis, which becomes deformed as a result of the bracket. Untreated, the deformity becomes worse with age, because longitudinal growth cannot occur. The present report discusses the use of polymethylmethacrylate at the preossified disease stage in 2 patients with first metatarsal involvement. A medical record and radiographic review was performed for 2 children (3 feet), aged 1 year and 2 years and 5 months, who were treated with insertion of polymethylmethacrylate after excision of the aberrant epiphyseal bracket. Two different radiographic parameters (i.e., the intraosseous angulation and the metadiaphyseal length index) were used to measure the effect of treatment on the subsequent longitudinal growth of the metatarsals. An excellent clinical result after a long follow-up period was observed in 2 feet, and a good result was documented in 1 foot, which developed hallux valgus angulation. The use of polymethylmethacrylate as an interposition material after excision of the aberrant metatarsal epiphyseal bracket appeared to be an effective method of treatment during the preossified first stage of the disease, despite the general recommendation to use a cement spacer during the third ossified stage. Normal longitudinal growth of the metatarsals was noted without complications or risk of deformity recurrence. PMID- 25441857 TI - Vital registration and under-reporting of maternal mortality in Jamaica. AB - OBJECTIVE: To identify why vital registration under-reports maternal deaths in Jamaica. METHODS: A cross-sectional study was undertaken to identify all maternal deaths (during pregnancy or <=42 days after pregnancy ended) occurring in 2008. Data sources included vital registration, hospital records, forensic pathology records, and an independent maternal mortality surveillance system. Potential cases were cross-referenced to registered live births and stillbirths, and hospital records to confirm pregnancy status, when the pregnancy ended, and registration. Medical certificates were inspected for certification, transcription, and coding errors. Maternal mortality ratios (MMRs) for registered and/or unregistered deaths were calculated. RESULTS: Of 50 maternal deaths identified, 10 (20%) were unregistered. Eight unregistered deaths were coroners' cases. Among 40 registered deaths, pregnancy was undocumented in 4 (10%). Among the other 36, 24 (67%) had been misclassified (59% direct and 89% indirect deaths). Therefore, only 12 (30%) registered maternal deaths had been coded as maternal deaths, yielding an MMR of 28.3 per 100 000 live births (95% confidence interval [CI] 12.3-48.3), which was 76% lower than the actual MMR of 117.8 (95% CI 85.2-150.4). CONCLUSION: Under-reporting of maternal deaths in Jamaica in 2008 was attributable to delayed registration of coroners' cases and misclassification. Timely registration of coroners' cases and training of nosologists to recognize and code maternal deaths is needed. PMID- 25441858 TI - The state of routine and emergency obstetric and neonatal care in Southern Province, Zambia. AB - OBJECTIVE: To evaluate the capacity of health facilities in Southern Province, Zambia, to perform routine obstetric care and emergency obstetric and neonatal care (EmONC). METHODS: Surveys were completed at 90 health centers and 10 hospitals between September 1, 2011, and February 28, 2012. An expanded set of signal functions for routine care and EmONC was used to assess the facilities' capacity to provide obstetric and neonatal care. RESULTS: Interviews were completed with 172 health workers. Comprehensive EmONC was available in only six of 10 hospitals; the remaining four hospitals did not perform all basic EmONC signal functions. None of the 90 health centers performed the basic set of EmONC signal functions. Performance of routine obstetric care functions, health worker EmONC training, and facility infrastructure and staffing varied. CONCLUSION: Assessment of the indicators for routine care revealed that several low-cost interventions are currently underused in Southern Province. There is substantial room for improvement in emergency and routine obstetric and neonatal care at the surveyed facilities. Efforts should focus on improving infrastructure and supplies, EmONC training, and adherence to the UN guidelines for routine and emergency obstetric care. PMID- 25441859 TI - Risk of respiratory syncytial virus infection in infants with congenital cystic lung disease. AB - BACKGROUND: Congenital cystic lung disease (CCLD), which includes congenital cystic adenomatoid malformation, bronchopulmonary sequestration, and congenital lobar emphysema, has been reported to increase the risk of recurrent respiratory infection. In particular, respiratory syncytial virus (RSV) causes severe lower respiratory tract disease in high-risk infants. The objective of this study was to investigate the risk of severe RSV infection in infants with CCLD. METHODS: Infants antenatally diagnosed as having CCLD and admitted to a neonatal intensive care unit at the National Center for Child Health and Development in Tokyo between September 2002 and October 2011 were included in this study. We investigated retrospectively whether the infants were hospitalized with RSV infection by 24 months of age using their medical records. RESULTS: Forty-eight infants were antenatally diagnosed as having CCLD. Of the 48 infants, four (8.3%) were hospitalized with RSV infection by 24 months of age. CONCLUSIONS: Infants with CCLD have increased risk of severe RSV infection. PMID- 25441860 TI - VEGF transfer based on gene-modified fibroblasts using a hypoxia-induced vector to modulate neoangiogenesis in ischaemic regions of myocutaneous transplants. AB - The effect of a hypoxia-inducible VEGF-expressing on wound healing in an ischaemic hind leg rat model was evaluated in this study. 180 Wistar rats were assigned randomly to three groups. After ligation of the femoral artery, group 1 received pRTP801-VEGF165, group 2 untransfected fibroblasts, group 3 saline; injection was into the subcutaneous tissue, proximal and distal to the artery ligation. Biopsy specimens were obtained on days 3, 5, 7, 14 after implementation. VEGF transgene expression, vessel architecture, the amount and total area of vessel formation were investigated. Results showed a significantly higher level of VEGF protein expression in group 1 compared to group 2 (P<=0.001) throughout the investigational period. Group 1 exhibited a significant growth of CD31-positive blood vessels in the subcutaneous tissue on day 14 compared to groups 2 and 3 (P<=0.001) (group 1, 62.20+/-1.92; group 2, 20.60+/-1.67; group 3, 12.40+/-1.14). Alpha-SMA-positive staining also showed significant vessel growth in group 1 on day 5 (group 1, 27.00+/-1.87; group 2, 7.20+/-1.48; group 3, 10.00+/-1.73). These results were confirmed in the distal muscle tissue. No significant results were obtained for the proximal muscle tissue. The subcutaneous application of pRTP801-VEGF165 showed a long-lasting effect, with an increased expression of VEGF over the entire observation period. It appears that the use of fibroblasts transfected with VEGF is a promising way to increase early angiogenesis in ischaemic tissue. PMID- 25441861 TI - Surgical safety distances in the infratemporal fossa: three-dimensional measurement study. AB - The wedge-shaped infratemporal fossa is a constricted space and has long been a surgical challenge, mainly due to difficulties in access. Three-dimensional (3D) reconstruction of the skull, internal carotid artery (ICA), and internal jugular vein (IJV) was carried out using enhanced computed tomography (CT) data, to measure the safety distances in relation to infratemporal fossa surgery. Fifty enhanced CT datasets were selected to reconstruct 3D images by segmentation technique. The anatomical routes of the ICA, IJV, and the styloid process (SP) were observed. The following were measured: SP length, height of the pterygoid plates (PP height), distances from the pterygoid process (antero-inferior and anterosuperior border) to the leading edge of the ICA (PP-ICA (inferior), PP-ICA (superior)), and distance between the most prominent point of the zygomatic arch and the medial pterygoid plate (Zyg-MPP). The mean measurements of SP length, PP height, and the distances PP-ICA (inferior), PP-ICA (superior), and Zyg-MPP were 30.64 mm, 26.61 mm, 31.16 mm, 34.37 mm, and 51.37 mm, respectively. No significant differences were observed by age group, except the distance of PP-ICA (inferior) on the left side. In centres without intraoperative navigation facilities, proper knowledge of the anatomy, particularly of bony landmarks and the safe distances to nearby neurovascular structures, can provide useful information to ensure safe operations. PMID- 25441863 TI - Metastasis to the jaws as a first manifestation of hepatocellular carcinoma: report of a case and analysis of 41 cases. AB - INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Local metastasis is common but metastasis to the jaw is rare with 40 reported cases in the English language literature. REPORT OF CASE: We describe a case of a 54-year-old man who, for the past two months, had noticed a rapidly growing facial mass in the posterior mandibular area. The patient was known to be a hepatitis C virus carrier and suffered from liver cirrhosis but the presence of HCC was unknown. METHODS AND RESULTS: The English language literature was searched for documented cases of HCC metastasis to the jaw, applicable data was evaluated. The literature analysis revealed 41 reported cases (including the present case). In most cases (81%) the jaw lesion was the only known metastasis at the time of HCC diagnosis. Clinical presentation occurred up to 2 years before discovery of the jaw metastasis. Patients with HCC jaw metastasis have a poor survival rate with an average of 6.1 months between diagnosis and death. CONCLUSIONS: This study shows that an isolated jaw mass may be the initial presentation of HCC and therefore must be considered in the differential diagnosis, especially in the presence of known liver cirrhosis or chronic viral hepatitis. PMID- 25441864 TI - Clinical and genetic study on 356 Brazilian patients with a distinct phenotype of cleft lip and palate without alveolar ridge involvement. AB - Oral clefts include cleft lip (CL), cleft lip with cleft palate (CLP) and cleft palate (CP), with wide variations in clinical presentation and degree of severity. We described a sample of individuals with CL and CP without alveolar arch involvement (CL + CP) to verify if the characteristics of this group are distinct from those with CL with or without CP (CL/P) described in literature. The sample was composed of 356 patients with CL + CP, registered at HRCA-USP, Bauru-SP-Brazil. The following characteristics were investigated: sex ratio, parental age at the time of conception, parental consanguinity, familial recurrence, laterality of the cleft and associated anomalies. A subgroup of 30 individuals with microforms of CL and CP were taken from the sample and compared with the remaining cases. Statistical differences were found between this CL + CP sample and the literature data for groups with CL/P regarding laterality, sex ratio, consanguinity, familial recurrence, and the presence of associated anomalies. The microform sample showed a statistical difference in paternal age. In most evaluated aspects, this sample presents similar characteristics to the consulted literature data for CL/P; as do the group of microform cleft cases when compared with the remaining CL + CP sample in this study. Microforms of cleft can represent a target group for investigation into the embryogenetic mechanisms of oral clefts and their phenotypic variability. PMID- 25441865 TI - Skeletal stability and condylar position related to fixation method following mandibular setback with bilateral sagittal split ramus osteotomy. AB - PURPOSE: To investigate postoperative intersegmental displacement and relapse following bilateral sagittal split ramus osteotomy (BSSRO) by comparing three different fixation methods: group A (sliding plate), group B (miniplate) and group C (bicortical screws). MATERIALS AND METHODS: The present retrospective study included 55 patients with mandibular prognathism who were treated with BSSRO. To evaluate skeletal changes, cone-beam computed tomography was taken before surgery (T0), three days after surgery (T1), and 6 months after surgery (T2). Differences among the three groups were assessed using a one-way analysis of variance, where P < 0.05 was accepted as statistically significant. RESULTS: There were no significant differences among the three groups in demographic data and the amount of mandibular setback. In skeletal changes and condylar axis changes, there were no statistically significant differences among the three groups. However, there were statistically significant postoperative skeletal changes in group C (bicortical screws) at all landmarks. The mean horizontal relapse rate was 1.9% in group A (sliding plate); 4.8% in group B (miniplate); and 15.4% in group C (bicortical screws). CONCLUSION: The sliding plate system has good adaptability to the proximal segment after mandibular setback with BSSRO, and behaves according to semi-rigid fixation principles. PMID- 25441866 TI - Diffuse sclerosing osteomyelitis (DSO) of the mandible in SAPHO syndrome: a novel approach with anti-TNF therapy. Systematic review. AB - Diffuse sclerosing osteomyelitis of the mandible is now considered a local manifestation of SAPHO syndrome. This rare condition is thought to be of auto inflammatory origin. The myriad of treatments shown in the literature, are basically empirical and reflect its unknown origin. We present a clinical case of refractory DSO treated with an anti-TNF drug (etanercept) with complete clinical remission. We advise against radical surgery and an interdisciplinary approach is recommended. A systematic literature review was also conducted. PMID- 25441868 TI - Accuracy assessment of a marker-free method for registration of CT and stereo images applied in image-guided implantology: a phantom study. AB - To assess the accuracy of a proposed marker-free registration method as opposed to the conventional marker-based method using an image-guided dental system, and investigating the best configurations of anatomical landmarks for various surgical fields in a phantom study, a CT-compatible dental phantom consisting of implanted targets was used. Two marker-free registration methods were evaluated, first using dental anatomical landmarks and second, using a reference marker tool. Six implanted markers, distributed in the inner space of the phantom were used as the targets; the values of target registration error (TRE) for each target were measured and compared with the marker-based method. Then, the effects of different landmark configurations on TRE values, measured using the Parsiss IV Guided Navigation system (Parsiss, Tehran, Iran), were investigated to find the best landmark arrangement for reaching the minimum registration error in each target region. It was proved that marker-free registration can be as precise as the marker-based method. This has a great impact on image-guided implantology systems whereby the drawbacks of fiducial markers for patient and surgeon are removed. It was also shown that smaller values of TRE could be achieved by using appropriate landmark configurations and moving the center of the landmark set closer to the surgery target. Other common factors would not necessarily decrease the TRE value so the conventional rules accepted in the clinical community about the ways to reduce TRE should be adapted to the selected field of dental surgery. PMID- 25441867 TI - Augmented reality as an aid in maxillofacial surgery: validation of a wearable system allowing maxillary repositioning. AB - AIM: We present a newly designed, localiser-free, head-mounted system featuring augmented reality as an aid to maxillofacial bone surgery, and assess the potential utility of the device by conducting a feasibility study and validation. METHODS: Our head-mounted wearable system facilitating augmented surgery was developed as a stand-alone, video-based, see-through device in which the visual features were adapted to facilitate maxillofacial bone surgery. We implement a strategy designed to present augmented reality information to the operating surgeon. LeFort1 osteotomy was chosen as the test procedure. The system is designed to exhibit virtual planning overlaying the details of a real patient. We implemented a method allowing performance of waferless, augmented-reality assisted bone repositioning. In vitro testing was conducted on a physical replica of a human skull, and the augmented reality system was used to perform LeFort1 maxillary repositioning. Surgical accuracy was measured with the aid of an optical navigation system that recorded the coordinates of three reference points (located in anterior, posterior right, and posterior left positions) on the repositioned maxilla. The outcomes were compared with those expected to be achievable in a three-dimensional environment. Data were derived using three levels of surgical planning, of increasing complexity, and for nine different operators with varying levels of surgical skill. RESULTS: The mean error was 1.70 +/- 0.51 mm. The axial errors were 0.89 +/- 0.54 mm on the sagittal axis, 0.60 +/ 0.20 mm on the frontal axis, and 1.06 +/- 0.40 mm on the craniocaudal axis. The simplest plan was associated with a slightly lower mean error (1.58 +/- 0.37 mm) compared with the more complex plans (medium: 1.82 +/- 0.71 mm; difficult: 1.70 +/- 0.45 mm). The mean error for the anterior reference point was lower (1.33 +/- 0.58 mm) than those for both the posterior right (1.72 +/- 0.24 mm) and posterior left points (2.05 +/- 0.47 mm). No significant difference in terms of error was noticed among operators, despite variations in surgical experience. Feedback from surgeons was acceptable; all tests were completed within 15 min and the tool was considered to be both comfortable and usable in practice. CONCLUSION: We used a new localiser-free, head-mounted, wearable, stereoscopic, video see-through display to develop a useful strategy affording surgeons access to augmented reality information. Our device appears to be accurate when used to assist in waferless maxillary repositioning. Our results suggest that the method can potentially be extended for use with many surgical procedures on the facial skeleton. Further, our positive results suggest that it would be appropriate to proceed to in vivo testing to assess surgical accuracy under real clinical conditions. PMID- 25441869 TI - Combination of Tessier clefts 3 and 4: case report of a rare anomaly with 12 years' follow-up. AB - Tessier cleft types 3 and 4 are both rare craniofacial anomalies. Here we present the first case of a girl born with a combined anomaly of Tessier clefts 3 and 4 with severe bilateral cleft lip, a displaced premaxilla, and three-dimensional underdevelopment of the hard and soft tissues of the maxilla and zygoma. This type of rare facial cleft poses a major operative challenge. Over a period of years, presurgical alveolar molding with an active appliance was followed by seven operations. A satisfactory esthetic outcome was obtained. A multidisciplinary approach to treatment with a plastic surgeon in charge of the operations and an orthodontist in charge of the cleft deformity is essential. PMID- 25441870 TI - Sialendoscopy-assisted transfacial surgical removal of parotid stones. AB - Minimally invasive surgical approaches to parotid stones (such as extra-corporeal shockwave lithotripsy and sialendoscopy) have proved to be effective in a high percentage of cases, although success depends on factors such as the localisation of the stone, its size and its mobility. The failure rate of 10% is largely due to large and impacted stones and, in such cases, a combined external and sialendoscopic approach can be used to avoid morbidity and the risks of more invasive superficial parotidectomy. We treated eight patients with large parotid stones (>7 mm) using a sialendoscopy-assisted transfacial surgical approach that was effective in all but one case, which was successfully solved by combining this procedure with extra-corporeal lithotripsy and operative sialendoscopy. Our results confirm that the combined approach is a valid alternative to parotidectomy for large parotid stones and should be added to other minimally invasive techniques aimed at restoring the function of the affected parotid gland. PMID- 25441871 TI - Crisscross pulmonary arteries with partial anomalous pulmonary venous drainage on multislice cardiac CT. AB - Criss cross pulmonary arteries is a rare entity characterized by classic malposition of pulmonary arteries. It may be associated with other conotruncal malformations and genetic syndromes. This report describes a case of crisscross pulmonary arteries associated with anomalous pulmonary venous return, an association which has never been reported before in literature. PMID- 25441872 TI - Capillary electrophoresis methods for microRNAs assays: a review. AB - MicroRNAs (miRNAs) are short noncoding RNAs that conduct important roles in many cellular processes such as development, proliferation, differentiation, and apoptosis. In particular, circulating miRNAs have been proposed as biomarkers for cancer, diabetes, cardiovascular disease, and other illnesses. Therefore, determination of miRNA expression levels in various biofluids is important for the investigation of biological processes in health and disease and for discovering their potential as new biomarkers and drug targets. Capillary electrophoresis (CE) is emerging as a useful analytical tool for analyzing miRNA because of its simple sample preparation steps and efficient resolution of a diverse size range of compounds. In particular, CE with laser-induced fluorescence detection is a promising and relatively rapidly developing tool with the potential to provide high sensitivity and specificity in the analysis of miRNAs. This paper covers a short overview of the recent developments and applications of CE systems in miRNA studies in biological and biomedical areas. PMID- 25441873 TI - Direct determination of total mercury in phosphate rock using alkaline fusion digestion. AB - The aim of this work was to develop a new method to determine the mercury (Hg) concentrations in phosphate rock using a dedicated analytical instrument (the DMA80 Tricell by Milestone) that employs an integrated sequence of thermal decomposition followed by catalyst conversion, amalgamation and atomic absorption spectrophotometry. However, this instrument underestimates Hg concentrations when phosphorite and apatite rocks are investigated with a classic thermal decomposition treatment that complies with US EPA method 7473. Therefore, to improve the recovery of total Hg, we performed alkaline fusion digestion (AFD) directly inside the furnace of the instrument, using BCR(32) as a certified reference material (Moroccan phosphate rock--phosphorite). The salts used for the AFD were a mixture of Na2CO3, K2CO3 and Li2CO3, which melt at about 400 degrees C, due to their ability to form a ternary eutectic and to decompose the phosphorite matrices at 700 degrees C. By adopting this analytical approach, the Hg recovery in BCR(32) was about 100%, compared to 40% when the reference material was analysed without using the alkaline fusion salt. We suggest that the AFD allowed the decomposition of the sample matrix and that some Hg compounds linked with other functional groups may be transformed in carbonates that sublimate at lower temperatures than other Hg compounds. This original method was tested on a number of different geological samples to compare the differences between the AFD method and the thermal treatment in order to verify the working range and to check the robustness of the new approach. PMID- 25441874 TI - Crosslinked plastic scintillators: a new detection system for radioactivity measurement in organic and aggressive media. AB - The measurement of radioactive solutions containing organic or aggressive media may cause stability problems in liquid and plastic scintillation (PS) techniques. In the case of PS, this can be overcome by adding a crosslinker to the polymer structure. The objectives of this study are to synthesise a suitable crosslinked plastic scintillator (C-PS) for radioactivity determination in organic and aggressive media. The results indicated that an increase in the crosslinker content reduces the detection efficiency and a more flexible crosslinker yields higher detection efficiency. For the polymer composition studied, 2,5 diphenyloxazole (PPO) is the most adequate fluorescent solute and an increase in its concentration causes little change in the detection efficiency. The inclusion of a secondary fluorescent solute 1,4-bis-2-(5-phenyloxazolyl) benzene (POPOP) improves the C-PS radiometrical characteristics. For the final composition chosen, the synthesis of the C-PS exhibits good reproducibility with elevated yield. The obtained C-PS also displays high stability in different organic (toluene, hydrotreated vegetable oil (HVO) and methanol) and aggressive media (hydrochloric acid, nitric acid and hydrogen peroxide). Finally, the C-PS exhibits high detection efficiency both in water and in aggressive media and can also be applied in organic media showing similar or even higher detection efficiency values. PMID- 25441875 TI - Firefly as a novel swarm intelligence variable selection method in spectroscopy. AB - A critical step in multivariate calibration is wavelength selection, which is used to build models with better prediction performance when applied to spectral data. Up to now, many feature selection techniques have been developed. Among all different types of feature selection techniques, those based on swarm intelligence optimization methodologies are more interesting since they are usually simulated based on animal and insect life behavior to, e.g., find the shortest path between a food source and their nests. This decision is made by a crowd, leading to a more robust model with less falling in local minima during the optimization cycle. This paper represents a novel feature selection approach to the selection of spectroscopic data, leading to more robust calibration models. The performance of the firefly algorithm, a swarm intelligence paradigm, was evaluated and compared with genetic algorithm and particle swarm optimization. All three techniques were coupled with partial least squares (PLS) and applied to three spectroscopic data sets. They demonstrate improved prediction results in comparison to when only a PLS model was built using all wavelengths. Results show that firefly algorithm as a novel swarm paradigm leads to a lower number of selected wavelengths while the prediction performance of built PLS stays the same. PMID- 25441876 TI - A highly sensitive electrochemical sensor for simultaneous determination of hydroquinone and bisphenol A based on the ultrafine Pd nanoparticle@TiO2 functionalized SiC. AB - A titanium dioxide-silicon carbide nanohybrid (TiO2-SiC) with enhanced electrochemical performance was successfully prepared through a facile generic in situ growth strategy. Monodispersed ultrafine palladium nanoparticles (Pd NPs) with a uniform size of ~2.3 nm were successfully obtained on the TiO2-SiC surface via a chemical reduction method. The Pd-loaded TiO2-SiC nanohybrid (Pd@TiO2-SiC) was characterized by transmission electron microscopy and X-ray diffractometry. A method for the simultaneous electrochemical determination of hydroquinone (HQ) and bisphenol A (BPA) using a Pd@TiO2-SiC nanocomposite-modified glassy carbon electrode was established. Utilizing the favorable properties of Pd NPs, the Pd@TiO2-SiC nanohybrid-modified glassy carbon electrode exhibited electrochemical performance superior to those of TiO2-SiC and SiC. Differential pulse voltammetry was successfully used to simultaneously quantify HQ and BPA within the concentration range of 0.01-200 MUM under optimal conditions. The detection limits (S/N=3) of the Pd@TiO2-SiC nanohybrid electrode for HQ and BPA were 5.5 and 4.3 nM, respectively. The selectivity of the electrochemical sensor was improved by introducing 10% ethanol to the buffer medium. The practical application of the modified electrode was demonstrated by the simultaneous detection of HQ and BPA in tap water and wastewater samples. The simple and straightforward strategy presented in this paper are important for the facile fabrication of ultrafine metal NPs@metal oxide-SiC hybrids with high electrochemical performance and catalytic activity. PMID- 25441877 TI - Highly accessible Pt nanodots homogeneously decorated on Au nanorods surface for sensing. AB - Some nanostructures are reported to possess enzyme-mimetic activities similar to those of natural enzymes. Herein, highly-dispersed Pt nanodots on Au nanorods (HD PtNDs@AuNRs) with mimetic peroxidase activity were designed as an active electrode modifier for fabrication of a hydrogen peroxide (H2O2) electrochemical sensor. The HD-PtNDs@AuNRs were synthesized by a seed-mediated growth approach and confirmed by scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, and UV-vis spectroscopy. The electrochemical and catalytical performances of HD-PtNDs@AuNRs towards H2O2 reduction were investigated in detail by cyclic voltammetry and amperometry. The HD-PtNDs@AuNRs modified electrode displayed a high catalytic activity to H2O2 at 0.10 V (versus SCE), a rapid response within 5 s, a wide linear range of 2.0 3800.0 MUM, a detection limit of 1.2 MUM (S/N=3), and a high sensitivity of 181 MUA mM(-1) cm(-2). These results suggested a promising potential of fabricating H2O2 electrochemical sensor using HD-PtNDs@AuNRs. PMID- 25441879 TI - Highly sensitive determination of mercury using copper enhancer by diamond electrode coupled with sequential injection-anodic stripping voltammetry. AB - A highly sensitive determination of mercury in the presence of Cu(II) using a boron-doped diamond (BDD) thin film electrode coupled with sequential injection anodic stripping voltammetry (SI-ASV) was proposed. The Cu(II) was simultaneously deposited with Hg(II) in a 0.5 M HCl supporting electrolyte by electrodeposition. In presence of an excess of Cu(II), the sensitivity for the determination of Hg(II) was remarkably enhanced. Cu(II) and Hg(II) were on-line deposited onto the BDD electrode surface at -1.0 V (vs. Ag/AgCl, 3 M KCl) for 150 s with a flow rate of 14 MUL s(-1). An anodic stripping voltammogram was recorded from -0.4 V to 0.25 V using a frequency of 60 Hz, an amplitude of 50 mV, and a step potential of 10 mV at a stopped flow. Under the optimal conditions, well-defined peaks of Cu(II) and Hg(II) were found at -0.25 V and +0.05 V (vs. Ag/AgCl, 3 M KCl), respectively. The detection of Hg(II) showed two linear dynamic ranges (0.1-30.0 ng mL(-1) and 5.0-60.0 ng mL(-1)). The limit of detection (S/N=3) obtained from the experiment was found to be 0.04 ng mL(-1). The precision values for 10 replicate determinations were 1.1, 2.1 and 2.9% RSD for 0.5, 10 and 20 ng mL(-1), respectively. The proposed method has been successfully applied for the determination of Hg(II) in seawater, salmon, squid, cockle and seaweed samples. A comparison between the proposed method and an inductively coupled plasma optical emission spectrometry (ICP-OES) standard method was performed on the samples, and the concentrations obtained via both methods were in agreement with the certified values of Hg(II), according to the paired t-test at a 95% confidence level. PMID- 25441878 TI - Ultrasensitive and simultaneous detection of heavy metal ions based on three dimensional graphene-carbon nanotubes hybrid electrode materials. AB - A green and facile method was developed to prepare a novel hybrid nanocomposite that consisted of one-dimensional multi-walled carbon nanotubes (MWCNTs) and two dimensional graphene oxide (GO) sheets. The as-prepared three-dimensional GO MWCNTs hybrid nanocomposites exhibit excellent water-solubility owing to the high hydrophilicity of GO components; meanwhile, a certain amount of MWCNTs loaded on the surface of GO sheets through pi-pi interaction seem to be "dissolved" in water. Moreover, the graphene(G)-MWCNTs nanocomposites with excellent conductivity were obtained conveniently by the direct electrochemical reduction of GO-MWCNTs nanocomposites. Seeing that there is a good synergistic effect between MWCNTs and graphene components in enhancing preconcentration efficiency of metal ions and accelerating electron transfer rate at G-MWCNTs/electrolyte interface, the G-MWCNTs nanocomposites possess fast, simultaneous and sensitive detection performance for trace amounts of heavy metal ions. The electrochemical results demonstrate that the G-MWCNTs nanocomposites can act as a kind of practical sensing material to simultaneously determine Pb(2+) and Cd(2+) ions in terms of anodic stripping voltammetry (ASV). The linear calibration plots for Pb(2+) and Cd(2+) ranged from 0.5 MUg L(-1) to 30 MUg L(-1). The detection limits were determined to be 0.2 MUg L(-1) (S/N=3) for Pb(2+) and 0.1 MUg L(-1) (S/N=3) for Cd(2+) in the case of a deposition time of 180 s. It is worth mentioning that the G-MWCNTs modified electrodes were successfully applied to the simultaneous detection of Cd(2+) and Pb(2+) ions in real electroplating effluent samples containing lots of surface active impurities, showing a good application prospect in the determination of trace amounts of heavy metals. PMID- 25441880 TI - An electrochemical sensor for sodium dodecyl sulfate detection based on anion exchange using eosin Y/polyethyleneimine modified electrode. AB - A simple and effective method for the detection of electrochemically inactive sodium dodecyl sulfate (SDS) has been designed, based on different binding affinity of polyethyleneimine (PEI) toward electrochemically active eosin Y and electrochemically inactive SDS. The stronger binding affinity of the PEI toward SDS than eosin Y results in the decrease of the redox peak current of surface confined eosin Y and provides a quantitative readout for the SDS. The difference in value of the cathodic peak current showed a linear relationship with SDS concentration in a concentration range from 1 to 40 MUg mL(-1), and a detection limit of 0.9 MUg mL(-1) for SDS was obtained. Furthermore, the method has been successfully applied to the detection of SDS in real samples. The developed approach provided a simple and reliable detection for SDS and might have potential applications in electrochemical methods for inactive molecules. PMID- 25441881 TI - An electrochemiluminescence sensor for bromate assay based on a new cationic polythiophene derivative. AB - A sensitive electrochemiluminescence (ECL) sensor was fabricated for bromate assay based on a cationic polythiophene derivative, poly[3-(1,1'-dimethyl-4 piperidinemethylene)thiophene-2,5-diyl chloride] (PTh-D)/nafion modified Au electrode. Bromate was used as the coreactant as well as detecting analyte in the ECL sensor for the first time. The prepared PTh-D exhibited excellent solubility, strong and stable cathodic ECL activity. PTh-D can be immobilized on the surface of Au electrode via AuS bonding and nafion and chitosan were also used to immobilize PTh-D. The fabricated sensor exhibited a good linear relationship between the ECL intensities and the concentrations of BrO3(-) ranging from 1 MUM to 0.1 M with a detection limit of 1 MUM. This proposed method not only expands the application of PTh-D, but also opens new doors toward the detection of BrO3( ). PMID- 25441882 TI - Determination of picomolar beryllium levels in seawater with inductively coupled plasma mass spectrometry following silica-gel preconcentration. AB - A robust and rapid method for the determination of natural levels of beryllium (Be) in seawater was developed to facilitate mapping Be concentrations in the ocean. A solid-phase extraction method using a silica gel column was applied for preconcentration and purification of Be in seawater prior to determination of Be concentrations with inductively coupled plasma mass spectrometry (ICP-MS). Be was quantitatively adsorbed onto silica gel from solutions with pH values ranging from 6.3 to 9, including natural seawater. The chelating agent ethylenediamine tetraacetic acid was used to remove other ions in the seawater matrix (Na, Mg, and Ca) that interfere with the ICP-MS analysis. The reproducibility of the method was 3% based on triplicate analyses of natural seawater samples, and the detection limit was 0.4 pmol kg(-1) for 250 mL of seawater, which is sufficient for the analysis of seawater in the open ocean. The method was then used to determine the vertical profile of Be in the eastern North Pacific Ocean, which was found to be a recycled-type profile in which the Be concentration increased with depth from the surface (7.2 pmol kg(-1) at <200 m) to deep water (29.2 pmol kg(-1) from 3500 m to the bottom). PMID- 25441883 TI - Simultaneous determination of bromine and chlorine in coal using electrothermal vaporization inductively coupled plasma mass spectrometry and direct solid sample analysis. AB - A new method for the direct analysis of coal using electrothermal vaporization inductively coupled plasma mass spectrometry and direct solid sample analysis was developed, aiming at the determination of Br and Cl. The procedure does not require any significant sample pretreatment and allows simultaneous determination of both elements to be carried out, requiring small mass aliquots of sample (about 0.5 mg). All operating parameters, including carrier gas flow-rate and RF power, were optimized for maximum sensitivity. The use of modifiers/aerosol carriers (Pd, Pd+Al and Pd+Ca) was evaluated, and the mixture of Pd and Ca was chosen, allowing pyrolysis and vaporization temperatures of 700 degrees C and 1900 degrees C, respectively. Chlorine was accurately determined using calibration against solid standards, whereas Br could also be determined using calibration against aqueous standard solutions. The limits of quantification were 0.03 MUg g(-1) for Br and 7 MUg g(-1) for Cl, and no spectral interferences were observed. PMID- 25441884 TI - A novel magnetic ionic liquid modified carbon nanotube for the simultaneous determination of aryloxyphenoxy-propionate herbicides and their metabolites in water. AB - A reliable, sensitive, rapid and environmentally friendly analysis procedure for the simultaneous determination of the analytes with a wide range of polarity in the environmental water was developed by coupling dispersive magnetic solid-phase extraction (d-MSPE) with high-performance liquid chromatography (HPLC)-diode array detector (DAD) and ultra-high pressure liquid chromatography (UHPLC)-triple quadrupole mass spectrometer (MS/MS), in this work. Magnetic ionic liquid modified multi-walled carbon nanotubes (m-IL-MWCNTs) were prepared by spontaneous assembly of magnetic nanoparticles and imidazolium-modified carbon nanotubes, and used as the sorbent of d-MSPE to simultaneously extract aryloxyphenoxy-propionate herbicides (AOPPs) and their polar acid metabolites due to the excellent pi-pi electron donor-acceptor interactions and anion exchange ability. The factors, including the amount of sorbent, pH of the sample solution, extraction time and the volume of elution solvent were investigated. Under the optimized conditions, the proposed d-MSPE coupling to HPLC-DAD system had a satisfactory performance, the limits of detection (LODs, defined as the signal to noise ratio of 3) and the limits of quantification (LOQs, defined as the signal to noise ratio of 10) for analytes in Milli-Q water were in the range of 2.8-14.3 and 9.8-43.2 MUg L(-1) respectively. Calibration curves were linear (r(2)>0.998) over the concentration range from 0.02 to 1 mg L(-1). The recoveries of the eight analytes ranged from 66.1 to 89.6% with the RSDs less than 8.6%. In order to extend the method in extremely low concentration analysis, d-MSPE-UHPLC-MS/MS was investigated, which showed better performance in terms of limit of detection and analysis time. PMID- 25441885 TI - A new simple, low-cost approach for generation of the PM10 fraction from soil and related materials: application to human health risk assessment. AB - A new simple, robust and low-cost wet laboratory method for the generation of the <10 MUm (PM10) particle size fraction is reported. A sedimentation method is directly compared with a centrifugation method for generation of the PM10 fraction. Both approaches are based on an integrated form of Stokes' law. Subsequently the sedimentation method was adopted. The results from the sedimentation method were corroborated using particle size distribution measurements. This approach for the generation of the PM10 fraction was applied to soil and mine waste samples from Mitrovica, Kosovo as part of an investigation in to the human risk assessment from inhalation of the PM10 fraction containing potentially harmful elements (PHEs). The average daily dose for Cd from the inhalation of suspended soil particles was calculated to be 0.021 and 0.010 MUg kg(-1) BW d(-1) for a child and an adult, respectively. This corresponded to an inhalation dose of 0.50 and 0.70 MUg Cdd(-1) for a child (20 kg) and an adult (70 kg), respectively. PMID- 25441886 TI - Chemometrics-assisted excitation-emission fluorescence spectroscopy on nylon attached rotating disks. Simultaneous determination of polycyclic aromatic hydrocarbons in the presence of interferences. AB - This work presents a green and very simple approach which enables the accurate and simultaneous determination of benzo[a]pyrene, dibenz[a,h]anthracene, benz[a]anthracene, and chrysene, concerned and potentially carcinogenic heavy polycyclic aromatic hydrocarbons (PAHs) in interfering samples. The compounds are extracted from water samples onto a device composed of a small rotating Teflon disk, with a nylon membrane attached to one of its surfaces. After extraction, the nylon membrane containing the concentrated analytes is separated from the Teflon disk, and fluorescence excitation-emission matrices are directly measured on the nylon surface, and processed by applying parallel factor analysis (PARAFAC), without the necessity of a desorption step. Under optimum conditions and for a sample volume of 25 mL, the PAHs extraction was carried out in 20 min. Detection limits based on the IUPAC recommended criterion and relative errors of prediction were in the ranges 20-100 ng L(-1) and 5-7%, respectively. Thanks to the combination of the ability of nylon to strongly retain PAHs, the easy rotating disk extraction approach, and the selectivity of second-order calibration, which greatly simplifies sample treatment avoiding the use of toxic solvents, the developed method follows most green analytical chemistry principles. PMID- 25441887 TI - Analysis of endocrine disruptor compounds in marine sediments by in cell clean up pressurized liquid extraction-liquid chromatography tandem mass spectrometry determination. AB - A less time-, solvent- and sorbent-consuming analytical methodology for the determination of bisphenol A and alkylphenols (4-tert-octylphenol, 4-octylphenol, 4-n-nonylphenol, nonylphenol) in marine sediment was developed and validated. The method was based on selective pressurized liquid extraction (SPLE) with a simultaneous in cell clean up combined with liquid chromatography-electrospray ionization tandem mass spectrometry in negative mode (LC-ESI-MS/MS). The SPLE extraction conditions were optimized by a Plackett-Burman design followed by a central composite design. Quantitation was performed by standard addition curves in order to correct matrix effects. The analytical features of the method were satisfactory: relative recoveries varied between 94 and 100% and repeatability and intermediate precision were <6% for all compounds. Uncertainty assessment of measurement was estimated on the basis of an in-house validation according to EURACHEM/CITAC guide. Quantitation limits of the method (MQL) ranged between 0.17 (4-n-nonylphenol) and 4.01 ng g(-1) dry weight (nonylphenol). Sensitivity, selectivity, automaticity and fastness are the main advantages of this green methodology. As an application, marine sediment samples from Galicia coast (NW of Spain) were analysed. Nonylphenol and 4-tert-octylphenol were measured in all samples at concentrations between 20.1 and 1409 ng g(-1) dry weight, respectively. Sediment toxicity was estimated and no risk to aquatic biota was found. PMID- 25441888 TI - Cu2+-assisted two dimensional charge-mass double focusing gel electrophoresis and mass spectrometric analysis of histone variants. AB - Abundant isoforms and dynamic posttranslational modifications cause the separation and identification of histone variants to be experimentally challenging. To meet this need, we employ two-dimensional electrophoretic gel separation followed by mass spectrometric detection which takes advantage of the chelation of Cu(2+) with amino acid residues exposed on the surfaces of the histone proteins. Acid-extracted rat liver histones were first mixed with CuSO4 solution and then separated in one dimension with triton-acid-urea (TAU) gel electrophoresis and in a second dimension using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The separations result from both the changes in charge and mass upon Cu(2+) chelation. Identities of each separated gel bands were obtained by using matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS). It was found that the migration of H3 histone isoforms of rat liver is markedly affected by the use of Cu(2+) ions. PMID- 25441889 TI - Effects of the temperature and beam parameters on depth profiles in X-ray photoelectron spectrometry and secondary ion mass spectrometry under C60(+)-Ar(+) cosputtering. AB - Polymethylmethacrylate (PMMA) is widely used in various fields, including the semiconductor, biomaterial and microelectronic fields. Obtaining the correct depth profiles of PMMA is essential, especially when it is used as a thin-film. There have been many studies that have used earlier generation of cluster ion (SF5(+)) as the sputtering source to profile PMMA films, but few reports have discussed the use of the more recently developed C60(+) in the PMMA sputtering process. In this study, X-ray photoelectron spectroscopy (XPS) and dynamic secondary ion mass spectroscopy (D-SIMS) were used concurrently to monitor the depth profiles of PMMA under C60(+) bombardment. Additionally, the cosputtering technique (C60(+) sputtering with auxiliary, low-kinetic-energy Ar(+)) was introduced to improve the analytical results. The proper cosputtering conditions could eliminate the signal enhancement near the interface that occurred with C60(+) sputtering and enhance the sputtering yield of the characteristic signals. Atomic force microscopy (AFM) was also used to measure the ion-induced topography. Furthermore, the effect of the specimen temperature on the PMMA depth profile was also examined. At higher temperatures (+120 degrees C), the depolymerization reaction that corresponded to main-chain scission dominated the sputtering process. At lower temperatures (-120 degrees C), the cross-linking mechanism was retarded significantly due to the immobilization of free radicals. Both the higher and lower sample temperatures were found to further improve the resulting depth profiles. PMID- 25441891 TI - IRMS detection of testosterone manipulated with 13C labeled standards in human urine by removing the labeled 13C. AB - Isotope ratio mass spectrometry (IRMS) is applied to confirm testosterone (T) abuse by determining the carbon isotope ratios (delta(13)C value). However, (13)C labeled standards can be used to control the delta(13)C value and produce manipulated T which cannot be detected by the current method. A method was explored to remove the (13)C labeled atom at C-3 from the molecule of androsterone (Andro), the metabolite of T in urine, to produce the resultant (A nor-5alpha-androstane-2,17-dione, ANAD). The difference in delta(13)C values between Andro and ANAD (Deltadelta(13)CAndro-ANAD, 0/00) would change significantly in case manipulated T is abused. Twenty-one volunteers administered T manipulated with different (13)C labeled standards. The collected urine samples were analyzed with the established method, and the maximum value of Deltadelta(13)CAndro-ANAD post ingestion ranged from 3.00/00 to 8.80/00. Based on the population reference, the cut-off value of Deltadelta(13)CAndro-ANAD for positive result was suggested as 1.20/00. The developed method could be used to detect T manipulated with 3-(13)C labeled standards. PMID- 25441890 TI - Detection of boldenone, its conjugates and androstadienedione, as well as five corticosteroids in bovine bile through a unique immunoaffinity column clean-up and two validated liquid chromatography-tandem mass spectrometry analyses. AB - The presence of beta-boldenone II phase metabolites and prednisolone in urine samples, owing to endogenous or natural origin or illicit treatment, is under debate within the European Union. The detection of beta-boldenone conjugates, alpha-boldenone conjugates at concentrations higher than 2 ng mL(-1) and prednisolone above the cut-off level of 5 ng mL(-1) in urine have been, until now, critical in deciding if illegal drug use has occurred. The use of urine sometimes is not entirely satisfactory, especially when the drug is administrated at low doses or when its metabolic conversion is very fast. This subsequently would hamper its detection in urine. The introduction of a new, advantageous matrix where the illicit treatment can be investigated would be highly appreciated. In this study, we have developed and validated a simple and unique immunoaffinity clean-up procedure, which was applied to bovine bile samples, followed by two different analytical liquid chromatography-electrospray-tandem mass spectrometry methods. The first method tests androstadienedione, alpha- and beta-boldenone sulphate, glucuronate and related free forms, while the other method assays prednisolone, prednisone, dexamethasone, cortisone, and cortisol. The methods were validated according to European Commission Decision 2002/657/EC. The evaluated parameters were linearity, specificity, precision (repeatability and intra-laboratory reproducibility), recovery, decision limit and detection capability. The decision limits (CCalpha) were between 0.38 and 0.45 ng mL(-1) for anabolic steroids, and 0.13 and 0.15 ng mL(-1) as far as corticosteroids were concerned. Intra- and inter-day repeatability was below 15.8 and 19.9% for all analytes, respectively. The methods were applied to the analysis of some bile samples collected from untreated young bulls in order to investigate the presence of the studied steroids in this matrix. PMID- 25441892 TI - Graphene/TiO2 nanocomposite based solid-phase extraction and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for lipidomic profiling of avocado (Persea americana Mill.). AB - Phospholipids possess important physiological, structural and nutritional functions in biological systems. This study described a solid-phase extraction (SPE) method, employing graphene and titanium dioxide (G/TiO2) nanocomposite as sorbent, for the selective isolation and enrichment of phospholipids from avocado (Persea americana Mill.). Based on the principal that the phosphoryl group in the phospholipid can interact with TiO2 via a bridging bidentate mode, an optimum condition was established for SPE, and was successfully applied to prepare avocado samples. The extracts were monitored by matrix-assisted laser desorption ionization time-of-flight/tandem mass spectrometry (MALDI-TOF/MS) in both positive-ion and negative-ion modes. Results showed that phospholipids could be efficiently extracted in a clean manner by G/TiO2 based SPE. In addition, the signals of phospholipids were enhanced while the noise was reduced. Some minor peaks became more obvious. In conclusion, the nanocomposite material of G/TiO2 was proved to be a promising sorbent for selective separation of phospholipids from crude lipid extract. PMID- 25441893 TI - Sensitive determination of fluoride in biological samples by gas chromatography mass spectrometry after derivatization with 2-(bromomethyl)naphthalene. AB - A gas chromatography-mass spectrometric method was developed in this study in order to determine fluoride in plasma and urine after derivatization with 2 (bromomethyl)naphthalene. 2-Fluoronaphthalene was chosen as the internal standard. The derivatization of fluoride was performed in the biological sample and the best reaction conditions (10.0 mg mL(-1) of 2-(bromomethyl)naphthalene, 1.0 mg mL(-1) of 15-crown-5-ether as a phase transfer catalyst, pH of 7.0, reaction temperature of 70 degrees C, and heating time of 70 min) were established. The organic derivative was extracted with dichloromethane and then measured by a gas chromatography-mass spectrometry. Under the established condition, the detection limits were 11 MUg L(-1) and 7 MUg L(-1) by using 0.2 mL of plasma or urine, respectively. The accuracy was in a range of 100.8-107.6%, and the precision of the assay was less than 4.3% in plasma or urine. Fluoride was detected in a concentration range of 0.12-0.53 mg L(-1) in six urine samples after intake of natural mineral water containing 0.7 mg L(-1) of fluoride. PMID- 25441894 TI - Ultra-sensitive determination of cyanide in surface water by gas chromatography tandem mass spectrometry after derivatization with 2-(dimethylamino)ethanethiol. AB - A gas chromatography-tandem mass spectrometric (GC-MS/MS) method has been established for the determination of cyanide in surface water. This method is based on the derivatization of cyanide with 2-(dimethylamino)ethanethiol in surface water. The following optimum reaction conditions were established: reagent dosage, 0.7 g L(-1) of 2-(dimethylamino)ethanethiol; pH 6; reaction carried out for 20 min at 60 degrees C. The organic derivative was extracted with 3 mL of ethyl acetate, and then measured by using GC-MS/MS. Under the established conditions, the detection and quantification limits were 0.02 MUg L(-1) and 0.07 MUg L(-1) in 10-mL of surface water, respectively. The calibration curve had a linear relationship relationship with y=0.7140x+0.1997 and r(2)=0.9963 (for a working range of 0.07-10 MUg L(-1)) and the accuracy was in a range of 98-102%; the precision of the assay was less than 7% in surface water. The common ions Cl( ), F(-), Br(-), NO3(-), SO4(2-), PO4(3-), K(+), Na(+), NH4(+), Ca(2+), Mg(2+), Ba(2+), Mn(4+), Mn(2+), Fe(3+), Fe(2+) and sea water did not interfere in cyanide detection, even when present in 1000-fold excess over the species. Cyanide was detected in a concentration range of 0.07-0.11 MUg L(-1) in 6 of 10 surface water samples. PMID- 25441895 TI - Carbon dots from tryptophan doped glucose for peroxynitrite sensing. AB - Tryptophan doped carbon dots (Trp-CD) were microwave synthesized. The optimum conditions of synthesizing of the Trp-CD were established by response surface multivariate optimization methodologies and were the following: 2.5 g of glucose and 300 mg of tryptophan diluted in 15 mL of water exposed for 5 min to a microwave radiation of 700 W. Trp-CD have an average size of 20 nm, were fluorescent with a quantum yield of 12.4% and the presence of peroxynitrite anion (ONOO(-)) provokes quenching of the fluorescence. The evaluated analytical methodology for ONOO(-) detection shows a linear response range from 5 to 25 MUM with a limit of detection of 1.5 MUM and quantification of 4.9 MUM. The capability of the ONOO(-) quantification was evaluated in standard solutions and in fortified serum samples. PMID- 25441896 TI - Graphene-palladium nanowires based electrochemical sensor using ZnFe2O4-graphene quantum dots as an effective peroxidase mimic. AB - We proposed an electrochemical DNA sensor by using peroxidase-like magnetic ZnFe2O4-graphene quantum dots (ZnFe2O4/GQDs) nanohybrid as a mimic enzymatic label. Aminated graphene and Pd nanowires were successively modified on glassy carbon electrode, which improved the electronic transfer rate as well as increased the amount of immobilized capture ssDNA (S1). The nanohybrid ZnFe2O4/GQDs was prepared by assembling the GQDs on the surface of ZnFe2O4 through a photo-Fenton reaction, which was not only used as a mimic enzyme but also as a carrier to label complementary ssDNA (S3). By synergistically integrating highly catalytically activity of nano-sized GQDs and ZnFe2O4, the nanohybrid possessed highly-efficient peroxidase-like catalytic activity which could produce a large current toward the reduction of H2O2 for signal amplification. Thionine was used as an excellent electron mediator. Compared with traditional enzyme labels, the mimic enzyme ZnFe2O4/GQDs exhibited many advantages such as environment friendly and better stability. Under the optimal conditions, the approach provided a wide linear range from 10(-16) to 5*10(-9) M and low detection limit of 6.2*10(-17) M. The remarkable high catalytic capability could allow the nanohybrid to replace conventional peroxidase-based assay systems. The new, robust and convenient assay systems can be widely utilized for the identification of other target molecules. PMID- 25441898 TI - Fluorogenic ratiometric dipodal optode containing imine-amide linkages: exploiting subtle thorium (IV) ion sensing. AB - The (13E,19E)-N1',N3'-bis[4-(diethylamino)-2-hydroxybenzylidene]malonohydrazide (L) has been developed for the detection of Th(4+) ions using dual channel signalling system. The UV-vis absorbance and fluorescence spectroscopic data revealed the formation of L-Th(4+) complex in 1:1 equilibrium. The density functional theory (DFT) also confirms the optimum binding cavity for the recognition of metal ion. The binding constant computed from different mathematical models for an assembly of L-Th(4+). The detection limit of L for Th(4+) recognition is to a concentration down to 0.1 MUM (0.023 MUg g(-1)). The present sensing system is also successfully applied for the detection of Th(4+) ion present in soil near nuclear atomic plants. PMID- 25441897 TI - Visual and fluorescent detection of acetamiprid based on the inner filter effect of gold nanoparticles on ratiometric fluorescence quantum dots. AB - In this work, we develop a simple and rapid sensing method for the visual and fluorescent detection of acetamiprid (AC) based on the inner-filter effect (IFE) of gold nanoparticles (AuNPs) on ratiometric fluorescent quantum dots (RF-QDs). The RF-QDs based dual-emission nanosensor was fabricated by assembling green emissive QDs (QDs539nm, lambdaem=539 nm) on the surface of red emissive QDs (QDs661nm, lambdaem=661 nm)-doped silica microspheres. The photoluminescence (PL) intensity of RF-QDs could be quenched by AuNPs based on IFE. Acetamiprid can adsorb on the surface of AuNPs due to its cyano group that has good affinity with gold, which could induce the aggregation of AuNPs accompanying color change from red to blue. Thus, the IFE of AuNPs on RF-QDs was weakened and the PL intensity of RF-QDs was recovered accordingly. Under the optimized conditions, the PL intensity of the RF-QDs/AuNPs system was proportional to the concentration of AC in the range of 0.025-5.0 MUg mL(-1), with a detection limit of 16.8 MUg L(-1). The established method had been used for AC detection in environmental and agricultural samples with satisfactory results. PMID- 25441899 TI - Colorimetric and fluorometric dual-modal probes for cyanide detection based on the doubly activated Michael acceptor and their bioimaging applications. AB - In this study, we synthesized CTB and CB probes based on doubly activated Michael acceptors to selectively detect cyanide (CN(-)) anions through a one-step condensation reaction of coumarinyl acrylaldehyde with the corresponding derivatives of malonyl urea (thiourea). Through the conjugated addition of CN(-) to the beta-site of the Michael acceptor, both probes displayed colorimetric and fluorometric dual-modal responses that were highly reactive and selective. CTB generates an active fluorescent response, whereas CB displays a ratiometric fluorescent response. The fluorescent signal of the probes reached its maximum given only 1 CN(-) equivalent and the signal change was linearly proportional to CN(-) concentrations ranging from 0 to 5 MUM with the detection limits 18 and 23 nM, respectively. The reaction rate of the probes is highly dependent on the methylene acidity of malonyl urea derivatives. Thus, the response rate of CTB to CN(-) is 1.2-fold faster than that of CB, and the response rate of CB to CN(-) is 1.2-fold faster than that of the previously examined CM. We then verified the highly reactive nature of the beta-site of the probes through density functional reactivity theory calculations. In addition, according to proof-of-concept experiments, these probes may be applied to analyze CN(-) contaminated water and biomimetic samples. Finally, cell cytotoxicity and bioimaging studies revealed that the probes were cell-permeable and could be used to detect CN(-) with low cytotoxicity. PMID- 25441901 TI - Colorimetric detection of sulfide based on target-induced shielding against the peroxidase-like activity of gold nanoparticles. AB - Colorimetric recognition and sensing of sulfide with high sensitivity was proposed based on target-induced shielding against the peroxidase-like activity of bare gold nanoparticles. Significant features of the new assay system are its simplicity and cost-effectiveness. The recognition of sulfide by bare gold nanoparticles can be fulfilled in a few seconds and the assay can be accomplished in about 10 min. Furthermore, the new assay system does not require surface modification of GNPs to obtain the specificity for sulfide, and a salt-induced aggregation step is not needed. The detection limit of this method for sulfide was 80 nM. These features make this sensor a potentially powerful tool for the quantitative determination of sulfide in water samples. PMID- 25441902 TI - Silver ion imprinted polymer nanobeads based on a aza-thioether crown containing a 1,10-phenanthroline subunit for solid phase extraction and for voltammetric and potentiometric silver sensors. AB - A new nano-sized silver(I) ion-imprinted polymer (IIP) was prepared via precipitation copolymerization using ethyleneglycol dimethacrylate, as a cross linking agent in the presence of Ag(+) and an aza-thioether crown containing a 1,10-phenanthroline subunit as a highly selective complexing agent. The imprint silver(I) ion was removed from the polymeric matrix using a 1.0M HNO3 solution. The resulting powder material was characterized using IR spectroscopy and scanning electron microscopy. The SEM micrographs showed colloidal nanoparticles of about 52 nm and 75 nm in diameter and slightly irregular in shape for leached and unleached IIPs, respectively. The optimal pH for quantitative enrichment was 6.0 and maximum sorbent capacity of the prepared IIP for Ag(+) was 18.08 MUmol g( 1). The relative standard deviation and limit of detection (LOD=3Sb/m) for flame atomic absorption spectrometric determination of silver(I) ion, after its selective extraction by the prepared IIP nanobeads, were evaluated as 2.42% and 2.2*10(-8) M, respectively. The new Ag(+)-IIP was also applied as a suitable sensing element to the preparation of highly selective and sensitive voltammetric and potentiometric sensors for ultra trace detection of silver(I) ion in water samples, with limits of detection of 9.0*10(-10) and 1.2*10(-9) M, respectively. PMID- 25441903 TI - Multiplex sensor for detection of different metal ions based on on-off of fluorescent gold nanoclusters. AB - In this study, a multiplex fluorescence sensor for successive detection of Fe(3+), Cu(2+) and Hg(2+) ions based on "on-off" of fluorescence of a single type of gold nanoclusters (Au NCs) is described. Any of the Fe(3+), Cu(2+) and Hg(2+) ions can cause quenching fluorescence of Au NCs, which established a sensitive sensor for detection of these ions respectively. With the introduction of ethylene diamine tetraacetic acid (EDTA) to the system of Au NCs and metal ions, a restoration of fluorescence may be found with the exception of Hg(2+). A highly selective detection of Hg(2+) ion is, thus, achieved by masking Fe(3+) and Cu(2+). On the other hand, the masking of Fe(3+) and Cu(2+) leads to the enhancement of fluorescence of Au NCs, which in turn provides an approach for successive determination of Fe(3+) and Cu(2+) based on "on-off" of fluorescence of Au NCs. Moreover, this assay was applied to the successful detection of Fe(3+), Cu(2+) and Hg(2+) in fish, a good linear relationship was found between these metal ions and the degree of quenched fluorescent intensity. The dynamic ranges of Hg(2+), Fe(3+) and Cu(2+) were 1.96*10(-10)-1.01*10(-9), 1.28*10(-7) 1.27*10(-6) and 1.2*10(-7)-1.2*10(-6) M with high sensitivity (the limit of detection of Fe(3+) 2.0*10(-8) M, Cu(2+) 1.9*10(-8) M and Hg(2+) 2*10(-10) M). These results indicate that the assay is suitable for sensitive detection of these metal ions even under the coexistence, which can not only determine all three kinds of metal ions successively but also of detecting any or several kinds of metal ions. PMID- 25441900 TI - Quantification of 5-methylcytosine, 5-hydroxymethylcytosine and 5 carboxylcytosine from the blood of cancer patients by an enzyme-based immunoassay. AB - BACKGROUND: Genome-wide aberrations of the classic epigenetic modification 5 methylcytosine (5mC), considered the hallmark of gene silencing, has been implicated to play a pivotal role in mediating carcinogenic transformation of healthy cells. Recently, three epigenetic marks derived from enzymatic oxidization of 5mC namely 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), have been discovered in the mammalian genome. Growing evidence suggests that these novel bases possess unique regulatory functions and may play critical roles in carcinogenesis. METHODS: To provide a quantitative basis for these rare epigenetic marks, we have designed a biotin avidin mediated enzyme-based immunoassay (EIA) and evaluated its performance in genomic DNA isolated from blood of patients diagnosed with metastatic forms of lung, pancreatic and bladder cancer, as well as healthy controls. The proposed EIA incorporates spatially optimized biotinylated antibody and a high degree of horseradish-peroxidase (HRP) labeled streptavidin, facilitating signal amplification and sensitive detection. RESULTS: We report that the percentages of 5mC, 5hmC and 5caC present in the genomic DNA of blood in healthy controls as 1.025+/-0.081, 0.023+/-0.006 and 0.001+/-0.0002, respectively. We observed a significant (p<0.05) decrease in the mean global percentage of 5hmC in blood of patients with malignant lung cancer (0.013+/-0.003%) in comparison to healthy controls. CONCLUSION: The precise biological roles of these epigenetic modifications in cancers are still unknown but in the past two years it has become evident that the global 5hmC content is drastically reduced in a variety of cancers. To the best of our knowledge, this is the first report of decreased 5hmC content in the blood of metastatic lung cancer patients and the clinical utility of this observation needs to be further validated in larger sample datasets. PMID- 25441904 TI - Label-free and enzyme-free sensitive fluorescent detection of human immunodeficiency virus deoxyribonucleic acid based on hybridization chain reaction. AB - A label-free and enzyme-free sensitive fluorescent detection of human immunodeficiency virus (HIV) deoxyribonucleic acid (DNA) based on isothermal hybridization chain reaction (HCR) was developed. A G-quadruplex sequence which was incorporated into one of the two hairpin probes was inactive in the absence of target DNA. However, at the presence of target DNA numerous G-quadruplexes along DNA nanowires were self-assembled through HCR. Using N-methyl mesoporphyrin IX (NMM) as the fluorophore, a "turn-on" fluorescent response would be achieved and detected as low as 0.5 nmol L(-1) of HIV DNA. This proposed method was applied to detect HIV DNA in biologic samples with satisfactory results. PMID- 25441905 TI - Molecularly imprinted polymer coated magnetite nanoparticles as an efficient mefenamic acid resonance light scattering nanosensor. AB - In this work, a mefenamic acid (MFA) nanosensor was synthesized by the aid of molecularly imprinted polymer (MIP) technique. MIP layer was coated on magnetite nanoparticles as magnetic nano-carriers. Synthesized nanoparticles were characterized using various measurements techniques. Light scattering properties of the synthesized nanoparticles in the presence or absence of MFA have been selected as the detection signal. In this regard, resonance light scattering has been used as the detection method. Various factors that can potentially affect light scattering efficiency (i.e., pH, ultrasonication time and nanoparticle dosage) were optimized using "one-at-a-time" method. A linear dynamic range was established from 100.0 to 2000.0 ng L(-1) of MFA and the limit of detection was found to be 50.0 ng L(-1) using the proposed method. PMID- 25441906 TI - Gas chromatographic retention index as a basis for predicting evaporation rates of complex mixtures. AB - Models that predict the fate of petroleum fuels in the environment are often required for effective remediation of fuel-contaminated sites. In this research, an environmental fuel spill was simulated by means of a diesel/water microcosm, in which the temporal changes in composition were assessed during evaporation by gas chromatography-mass spectrometry (GC-MS). First-order kinetic rate constants were calculated for 51 selected compounds and utilized to develop predictive models for evaporation rate constants, using GC retention indices on a nonpolar stationary phase. Models were initially developed to predict rates of evaporation of compounds from individual classes (normal alkane, branched alkane, alkyl benzene, and polycyclic hydrocarbon) and then expanded to include all compounds (comprehensive model). Using the comprehensive model, the rate constants were predicted with a mean absolute percent error (MAPE) of 10%, whereas the class specific models resulted in less error (4-8%). These models were employed to predict the fraction remaining of the total fuel (6% error) as well as the fraction remaining of individual compounds (13% MAPE). Accurate models such as these will facilitate remediation of environmental releases of petroleum products. PMID- 25441907 TI - Towards high peak capacity separations in normal pressure nanoflow liquid chromatography using meter long packed capillary columns. AB - Single shot proteomics is a promising approach to high throughput proteomics analysis. In this strategy, long capillary columns are needed to perform long and shallow gradients to achieve high peak capacity and good peak width for informative mass spectrometric detection. Herein, we report that meter long capillary columns, packed with 5 MUm particulate material, can be facilely fabricated based on single particle fritting technology. The long columns could reliably generate high peak capacities of 800 in 10 h long gradients for protein digest separations. The operation was within the pressure range (40 MPa) of the most widely used normal pressure nanoLC systems. Due to the excellent life time (>100 injections) and inter-column performance consistency, the meter long capillary columns reported here should be of practical usefulness in single shot proteomics without the need for ultra-high pressure instrumentation. PMID- 25441908 TI - A real-time decoding sequencing based on dual mononucleotide addition for cyclic synthesis. AB - We propose a real-time decoding sequencing strategy in which a template is determined without directly measuring base sequence but by decoding two sets of encodings obtained from two parallel sequencing runs. This strategy relies on adding a mixture of different two-base pair, A+G, C+T, A+C, G+T, A+T or C+G (abbreviated as AG, CT, AC, GT, AT, or CG), into the reaction each time. When a template is cyclically interrogated twice with any two kinds of dual mononucleotide addition (AG/CT, AC/GT, and AT/CG), two sets of encodings are obtained sequentially. The two sets of encodings allow for the bases to be sequentially decoded, moving from first to last, in a deterministic manner. This strategy applies fewer cycles to obtain longer read length compared to the traditional real-time sequencing strategy. Partial rnpB gene was applied to verify the applicability of the decoding strategy via pyrosequencing. The results indicated that the sequence could be reconstructed by decoding two sets of encodings. Moreover, streptococcal strains could be differentiated by comparing signal intensity in each cycle and encoding size of each template. This strategy is likely to be applied to differentiate nucleic acid sequence as encoding size and signal intensity in each cycle vary with the base size and composition. Furthermore, it has the potential in building a promising strategy that could be utilized as an alternative to conventional sequencing systems. PMID- 25441909 TI - Zirconium silicate assisted removal of residual proteins after organic solvent deproteinization of human plasma, enhancing the stability of the LC-ESI-MS response for the bioanalysis of small molecules. AB - An efficient blood plasma clean-up method was developed, where methanol protein precipitation was applied, followed by zirconium silicate assisted exclusion of residual proteins. A strong binding of zirconium (IV) silicate to the proteins enabled the elimination of remaining proteins after solvent deproteinization through a rapid solid-phase extraction (SPE) procedure. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI/TOF MS) was used for monitoring the proteins during clean-up practice applied to human plasma samples. The proteins were quantified by colorimetric detection using the bicinchoninic acid (BCA) assay. The presented analytical strategy resulted in the depletion of >99.6% proteins from human plasma samples. Furthermore, high performance liquid chromatography hyphenated to diode-array and electrospray ionization mass spectrometric detection (HPLC-DAD/ESI MS) was applied for qualitative and quantitative analysis of the caffeoylquinic acids (CQAs) and their metabolites in human plasma. The procedure demonstrated high recoveries for the standard compounds spiked at different concentrations. Cynarin and chlorogenic acid were recovered in the range of 81-86% and 78-83%, respectively. Caffeic acid was extracted in the excess of 89-92%, while ferulic acid and dihydroxyhydrocinnamic acid showed a recovery of 87-91% and 92-95%, respectively. The method was partially validated in accordance with FDA-Industry Guidelines for Bioanalytical Method Validation (2001). The presented scheme improves the clean up efficacy of the methanol deproteinization, significantly reduces the matrix effects and provides a great analytical tool for the isolation of small molecules from human plasma. PMID- 25441920 TI - Evaluation of the effects of phototherapy on cochlear function in newborns. AB - OBJECTIVE: This study aimed to evaluate any potential effects of phototherapy on cochlear function in newborns using transient evoked otoacoustic emissions (TEOAEs). METHODS AND MATERIALS: Fifty-seven newborns, undergoing phototherapy for hyperbilirubinemia without any other risk factors, and a control group of 53 healthy newborns, were administered the TEOAE test prior to and following phototherapy. In the newborns undergoing phototherapy, otoacoustic emission (OAE) measurements obtained at baseline and following phototherapy were compared. Moreover, pre-phototherapy OAE measurements obtained in the newborns undergoing phototherapy were compared with the OAE measurements of the control group. RESULTS: In newborns undergoing phototherapy, there was no significant difference between pre- and post-phototherapy TEOAE amplitudes, nor in the reproducibility ratios. Similarly, no difference was found in the pre-treatment measurements of amplitude and reproducibility ratios between phototherapy-receiving newborns and controls (p>0.05). CONCLUSION: The normal TEOAE results observed in the newborns undergoing phototherapy suggest that phototherapy does not exert negative effects on the cochlea. PMID- 25441922 TI - Emerging strategies for high-risk and relapsed/refractory acute myeloid leukemia: novel agents and approaches currently in clinical trials. AB - High-risk acute myeloid leukemia (AML) is defined by clinical and biologic features that predict for poor response to induction chemotherapy and high risk of relapse. Despite even the most aggressive and well-developed strategies for care, most patients succumb to the disease. No currently available treatment has demonstrated consistent efficacy in terms of remission induction or long-term survival. This review will highlight some of the emerging strategies to treat high-risk AML with an emphasis on clinical trials of novel strategies currently enrolling patients. Targeted molecular therapies, novel cytotoxics, and immune based therapies are under investigation for the management of high-risk AML. Some of the agents covered include tyrosine kinase inhibitors targeted to AML specific oncoproteins, nanoparticle formulations of existing drugs, nucleoside analogs, monoclonal antibodies, chimeric antigen receptors, bispecific T-cell engaging antibodies, and vaccines. As our understanding of the biology of AML has improved, targeted therapy for AML has emerged, offering to change not only response rate, but also the nature of response. Differentiation, rather than necrosis or apoptosis, is often seen in response to targeted agents and may be seen more frequently in the future. Interventions that might be more widely used in the near future include FLT3 inhibitors and nanoparticle formulations of drugs already known to have activity in the disease. Long term immune therapy holds significant promise. PMID- 25441921 TI - The curious case of the orange coloured tonsils. AB - Tangier disease is an extremely rare and severe form of high density lipoprotein deficiency. Even though there is no specific therapy for patients with Tangier disease, it is important to recognize the clinical presentation as patients are at an increased risk of developing atherosclerosis and subsequent CVD. The case discussed in this report, illustrates the importance of recognizing that orange discoloured tonsils are an indication that the patient could be suffering from Tangier's disease. PMID- 25441923 TI - Increases in body mass index following initiation of methadone treatment. AB - Despite the clear efficacy of methadone for opioid dependence, one less desirable phenomenon associated with methadone may be weight gain. We examined changes in body mass index (BMI) among patients entering methadone treatment. A retrospective chart review was conducted for 96 patients enrolled in an outpatient methadone clinic for >= 6 months. The primary outcome of BMI was assessed at intake and a subsequent physical examination approximately 1.8 +/- 0.95 years later. Demographic, drug use and treatment characteristics were also examined. There was a significant increase in BMI following intake (p<0.001). Mean BMIs increased from 27.2 +/- 6.8 to 30.1 +/- 7.7 kg/m(2), translating to a 17.8-pound increase (10% increase in body weight) in the overall patient sample. Gender was the strongest predictor of BMI changes (p < 0.001), with significantly greater BMI increases in females than males (5.2 vs. 1.7 kg/m(2), respectively). This translates to a 28-pound (17.5%) increase in females vs. a 12-pound (6.4%) increase in males. In summary, methadone treatment enrollment was associated with clinically significant weight gain, particularly among female patients. This study highlights the importance of efforts to help patients mitigate weight gain during treatment, particularly considering the significant health and economic consequences of obesity for individuals and society more generally. PMID- 25441925 TI - Oxidation of nanoscale zero-valent iron under sufficient and limited dissolved oxygen: Influences on aggregation behaviors. AB - Oxidations of nanoscale zero-valent iron (nZVI) under aerobic (dissolved oxygen~8mgL(-1)) and anaerobic (dissolved oxygen <3mgL(-1)) conditions were simulated, and their influences on aggregation behaviors of nZVI were investigated. The two oxidation products were noted as HO-nZVI (nZVI oxidized in highly oxygenated water) and LO-nZVI (nZVI oxidized in lowly oxygenated water) respectively. The metallic iron of the oxidized nZVI was almost exhausted (Fe(0)~8+/-5%), thus magnetization mainly depended on magnetite content. Since sufficient dissolved oxygen led to the much less magnetite (~15%) in HO-nZVI than that in LO-nZVI (>90%), HO-nZVI was far less magnetic (Ms=88kAm(-1)) than LO-nZVI (Ms=365kAm(-1)). Consequently, HO-nZVI formed small agglomerates (228+/-10nm), while LO-nZVI tended to form chain-like aggregations (>1MUm) which precipitated rapidly. Based on the EDLVO theory, we suggested that dissolved oxygen level determined aggregation morphologies by controlling the degree of oxidation and the magnitude of magnetization. Then the chain-like alignment of LO-nZVI would promote further aggregation, but the agglomerate morphology of HO-nZVI would eliminate magnetic forces and inhibit the aggregation while HO-nZVI remained magnetic. Our results indicated the fine colloidal stability of HO-nZVI, which might lead to the great mobility in the environment. PMID- 25441924 TI - Evaluation of non-invasive screening measures to identify individuals with prediabetes. AB - AIMS: Because blood-based screening to identify those with prediabetes to take part in Diabetes Prevention Program (DPP) translation efforts can be costly and time-consuming, non-invasive methods are needed. The aims of this paper are to evaluate the ability of the American Diabetes Association (ADA) risk test in identifying individuals with prediabetes, as well as the use of body composition measures for this purpose. In addition the utility of these alternate methods to ascertain the presence of the metabolic syndrome was assessed. METHODS: Potential participants were recruited from a worksite and three community centers to take part in a DPP translation study. Participants completed onsite screening where anthropometric measures, fasting lipids and glucose, and hemoglobin A1c were assessed. Those with a BMI >=24 kg/m(2) and prediabetes and/or the metabolic syndrome were eligible to participate. Non-invasive screening methods were evaluated for their ability to identify those with prediabetes and the metabolic syndrome based on clinically measured values. RESULTS: All non-invasive methods were highly sensitive (68.9% to 98.5%) in the detection of prediabetes, but specificity was low (6.7% to 44.5%). None of the alternatives evaluated achieved acceptable discrimination levels in ROC analysis. Similar results were noted in identifying the metabolic syndrome. CONCLUSIONS: The non-invasive methods evaluated in this study effectively identify participants with prediabetes, but would also allow for enrollment of a large number of individuals who do not have prediabetes. Deciding whether to use these alternatives, blood-based measures, or a combination of both will ultimately depend on the purpose of the program and the level of flexibility regarding participant eligibility. PMID- 25441926 TI - Specific component comparison of extracellular polymeric substances (EPS) in flocs and granular sludge using EEM and SDS-PAGE. AB - Extracellular polymeric substances (EPS) plays an important role in the formation of bioaggregates such as flocs, biofilm and granular sludge. However, the role of their specific components in sludge flocculation and granulation is still unclear. Three sludge samples including the flocs, aerobic and anaerobic granular sludge were investigated in this study and the specific components in different EPS structures of loosely bound-EPS (LB-EPS) and tightly bound-EPS (TB-EPS) were analyzed. Results showed that the protein (PN) contents in LB-EPS and TB-EPS of the aerobic and anaerobic granular sludge were 33.6+/-9.7 and 96.8+/-11.9, 27.1+/ 2.8 and 61.6+/-4.2 mg g(-1)VSS, respectively, which were both higher than the flocs of 8.5+/-1.5 and 43.1+/-2.7 mg g(-1)VSS. But the polysaccharide (PS) contents in the three sludges were all about 30 mg g(-1)VSS. The analysis of sludge surface charge indicated that they had a linear correlation with the PN content, which implied that PN significantly contributed to the formation of granular sludge. The results of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated that the molecular weight of PN in flocs was mainly distributed in 14.3-66.2 kDa, while it was 20.1-97.4 kDa in the granular sludge, which indicated that the proteins with high molecular weight favors the sludge granulation. According to the three-dimensional fluorescence (EEM) results, the aromatic protein-like and tryptophan protein-like substances were more abundant in the granular sludge than that in flocs, suggesting they are the key components in the structural stability of granular sludge. PMID- 25441927 TI - Sacrificial hydrogen generation from aqueous triethanolamine with Eosin Y sensitized Pt/TiO2 photocatalyst in UV, visible and solar light irradiation. AB - In this paper, we have studied Eosin Y-sensitized sacrificial hydrogen generation with triethanolamine as electron donor in UV, visible, and solar light irradiation. Aeroxide TiO2 was loaded with platinum metal via solar photo deposition method to reduce the electron hole recombination process. Photocatalytic sacrificial hydrogen generation was influenced by several factors such as platinum loading (wt%) on TiO2, solution pH, Eosin Y to Pt/TiO2 mass ratio, triethanolamine concentration, and light (UV, visible and solar) intensities. Detailed reaction mechanisms in visible and solar light irradiation were established. Oxidation of triethanolamine and formaldehyde formation was correlated with hydrogen generation in both visible and solar lights. Hydrogen generation kinetics followed a Langmuir-type isotherm with reaction rate constant and adsorption constant of 6.77*10(-6) mol min(-1) and 14.45 M(-1), respectively. Sacrificial hydrogen generation and charge recombination processes were studied as a function of light intensities. Apparent quantum yields (QYs) were compared for UV, visible, and solar light at four different light intensities. Highest QYs were attained at lower light intensity because of trivial charge recombination. At 30 mW cm(-2) we achieved QYs of 10.82%, 12.23% and 11.33% in UV, visible and solar light respectively. PMID- 25441928 TI - Perinatal exposure to di-(2-ethylhexyl) phthalate affects anxiety- and depression like behaviors in mice. AB - Di-(2-ethylhexyl) phthalate (DEHP) is an environmental endocrine disrupter. The present study investigated the effect of DEHP on emotional behavior of mice following perinatal exposure (10, 50, and 200 mg kg(-1) d(-1)) from gestation day 7 through postnatal day 21. The results showed that, in pubertal males (6-w-old), DEHP decreased the time spent in the open arms and the number of entries into them in elevated plus maze and decreased the time in the mirrored chamber and in the light-box; in pubertal females, DEHP decreased the time spent in the open arms and the number of entries into them, suggesting that DEHP exposure made a anxiogenic effect in pubertal offspring regardless of sex. While DEHP effect on anxiety of adult (12-w-old) displayed sex differences, with decreased time spent in the open arms in the adult females. Perinatal exposure to DEPH significantly extended the time of immobility in forced swim task of pubertal offspring and adulthood regardless of sex. Furthermore, DEHP down-regulated the expressions of androgen receptor (AR) in pubertal male hippocampus and of estrogen receptor (ER) beta in pubertal female and adult hippocampus of both sexes and inhibited the phosphorylation of ERK1/2 of hippocampus in pubertal mice and adult males. These results suggest that exposure to DEHP early in life affected the anxiety- and depressive-like behaviors of pubertal offspring and even adult. The disruption of gonadal hormones' modulation of behaviors due to down-regulation of AR or ERbeta in the hippocampus may be associated with the aggravated anxiety- and depression like status induced by DEHP. PMID- 25441929 TI - Increased ecological risk due to the hyperaccumulation of As in Pteris cretica during the phytoremediation of an As-contaminated site. AB - Ecological risk due to the hyperaccumulation of As in Pteris cretica during phytoremediation was evaluated at an abandoned As-contaminated site. Five receptor groups representing terrestrial invertebrates, avian insectivores, small mammals, herbivores, and omnivores were selected as potentially affected ecological receptors. Soil and food ingestion were considered as major exposure pathways. Phytoremediation was performed with P.cretica only and with both P.cretica and siderophores to enhance plant uptake of As. Ecological hazard index (EHI) values for the small mammal greatly exceeded 1.0 even after three weeks of growth regardless of siderophore application, probably due to its limited home range. For the mammalian herbivore, which mainly consumes plant foliage, the EHI values were greater than 5.73 after seven weeks without siderophore application, but the value increased sharply to 29.3 at seven weeks when siderophores were applied. This increased risk could be attributed to the facilitated translocation of As from roots to stems and leaves in P.cretica. Our results suggest that, when a phytoremediation strategy is considered for metals remediation, its ecological consequences should be taken into account to prevent the spread of hyperaccumulated heavy metals throughout the food chain of ecological receptors. Uncertainties involved in the ecological risk assessment process were also discussed. PMID- 25441932 TI - Fair and reasonable judgments of cost-effectiveness of medicines. PMID- 25441930 TI - Persistent organic pollutants and semen quality: The LIFE Study. AB - Growing evidence suggests that persistent environmental chemicals such as polychlorinated biphenyls may adversely affect human fecundity. The purpose of this study was to evaluate associations between persistent environmental chemicals and semen quality among 501 male partners of couples discontinuing contraception for purposes of becoming pregnant. Men provided a blood specimen and two fresh semen samples collected approximately a month apart that underwent next day analysis for 35 semen quality endpoints. Serum samples were analyzed for 36 polychlorinated biphenyls (congeners #18, 28, 44, 49, 52, 66, 74, 87, 99, 101, 114, 118, 128, 138, 146, 149, 151, 153, 156, 157, 167, 170, 172, 177, 178, 180, 183, 187, 189, 194, 195, 196, 201, 206, 209); 1 polybrominated biphenyl (#153); 9 organochlorine pesticides; and 10 polybrominated diphenyl ethers (congeners #17, 28, 47, 66, 85, 99, 100, 153, 154183) using high resolution mass spectrometry. To estimate the effect of chemicals on semen quality, we regressed each semen marker on each chemical while adjusting for research site, age, body mass index, serum lipids, and cotinine levels. Males with chemical concentrations in the fourth quartile, as compared to the first quartile, showed significant associations for several individual chemicals in each chemical class and type of semen quality parameter indicating negative and positive associations with semen quality. Polybrominated diphenyl ethers in particular were associated with several measures of increased abnormal morphology. These exploratory results highlight the role of environmental influences on male fecundity, and are of particular interest given the ubiquitous exposures to these compounds. PMID- 25441931 TI - Effect of diet, location and sampling year on bioaccumulation of mercury, selenium and cadmium in pelagic feeding seabirds in Svalbard. AB - Hepatic concentrations of mercury (Hg), selenium (Se) and cadmium (Cd) were determined in black-legged kittiwakes (Rissa tridactyla) and little auks (Alle alle) from two fjords in Svalbard (Kongsfjorden; 78 degrees 57'N, 12 degrees 12'E and Liefdefjorden; 79 degrees 37'N, 13 degrees 20'E). The inflow of Arctic and Atlantic water differs between the two fjords, potentially affecting element accumulation. Trophic positions (TP) were derived from stable nitrogen isotope ratios (delta(15)N), and stable carbon isotope ratios (delta(13)C) were assessed to evaluate the terrestrial influence on element accumulation. Mercury, Cd, TP and delta(13)C varied significantly between locations and years in both species. Trophic position and feeding habits explained Hg and Cd accumulation in kittiwakes, but not in little auks. Biomagnification of Hg and Cd were found in the food webs of both the Atlantic and the Arctic fjord, and no inter-fjord differences were detected. The delta(13)C were higher in the seabirds from Kongsfjorden than in Liefdefjorden, but this did not explain variations in element accumulation. Selenium concentrations were not influenced by Hg accumulation in kittiwakes, indicating baseline levels of Se in this species. In contrast, correlations between Hg and Se and lower Se:Hg ratios in little auks from Kongsfjorden than in Liefdefjorden indicate a more pronounced influence of Se-Hg complex formation in little auks feeding in Atlantic waters. PMID- 25441933 TI - Surgical management of lobular carcinoma from a national screening program: a retrospective analysis. AB - OBJECTIVE: To compare the surgical outcomes of women diagnosed with invasive ductal and lobular carcinoma of the breast. BACKGROUND: The role of Breast Conserving Surgery (BCS) for invasive cancers of the breast is well established; however its role for invasive lobular carcinoma is less well defined. Concerns exist regarding the need for re-excision of margins and the eventual need for mastectomy in women with Invasive Lobular Carcinoma (ILC) compared with Ductal Carcinoma (IDC). In this study we compare the surgical results of these two groups examining BCS from a national breast cancer screening program. METHODS: Analysis of mammographically detected ILC and IDC tumours obtained from the national breast cancer screening program of the Republic of Ireland (BreastCheck) was performed. BreastCheck offers biannual screening mammograms to women throughout the Republic of Ireland between 50 and 65 years of age. We examined and pooled the data across 4 screening zones from 2005 to 2010. CONCLUSIONS: We observed similar success rates and trends in both the ILC and IDC groups where BCS was attempted. Patients selected for BCS with ILC were statistically more likely to have successful surgery compared with IDC as tumour size increased. There however was no statistical difference in a pooled analysis of successful treatment across all tumour sizes in comparing the two groups. We conclude that BCS is an appropriate and acceptable treatment option for women diagnosed with ILC. PMID- 25441934 TI - Variations in the management of the axilla in screen-detected ductal carcinoma in situ: evidence from the UK NHS breast screening programme audit of screen detected DCIS. AB - The diagnosis and surgical management of screen-detected Ductal Carcinoma In Situ (DCIS) remains controversial including a range of axillary approaches and consequent morbidity. This study examined the management of the axilla in all patients with DCIS presenting through the United Kingdom National Health Service Breast Screening Programme (UK NHS BSP). Retrospective analysis of the UK NHS BSP identified 26,696 women initially diagnosed with DCIS over the 8 years 1 April 2003-31 March 2011. The final breast pathology of these women was upgraded to invasive ductal cancer in 5564 (20.8%) women or micro-invasive cancer in 1031 (3.9%) women. At first operation, 5290 (26.3%) of the 20,094 women who had a final post-operative diagnosis of DCIS only underwent axillary surgery (72.4% at the time of mastectomy, 23.8% breast conservation surgery, 3.8% axillary surgery alone). Performance of axillary surgery reflected increasing tumour size, micro invasion or increasing nuclear grade for the final diagnosis of DCIS. More extensive nodal surgery was performed in those undergoing mastectomy; 10.8% of women had more than 8 nodes removed. Overall, 12.0% of women with invasive cancer, 1.7% with micro-invasion, and 0.2% with DCIS alone, were ultimately node positive. Improved pre-operative sampling of DCIS, axillary assessment by ultrasound with needle biopsy for suspected metastases, risk stratification for sentinel node biopsy (for high grade or extensive DCIS) and avoiding axillary clearance for a pre-operative diagnosis of DCIS alone should reduce unnecessary axillary surgery. Standards using such criteria for axillary surgery in screen detected DCIS should be integrated into the NHS BSP. PMID- 25441935 TI - Impact of rhinosinusitis symptoms on patients' self-esteem before and after FESS. AB - INTRODUCTION: Chronic rhinosinusitis (CRS) is one of the most common diseases in Polish society. According to the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2012 the incidence of CRS among European and US citizens varies from 5 to 16%. Its treatment is based on pharmacotherapy or surgical procedure. The aim of the study was to evaluate the correlation between general health condition of the patients with CRS with each symptom of the disease before and after Functional Endonasal Sinus Surgery (FESS) procedure. MATERIALS AND METHODS: The study was conducted on 100 patients, who evaluated symptoms and general health condition twice - before and after FESS, by means of visual analogue scale (VAS). RESULTS: Before FESS the highest severity among all symptoms concerned the nasal blockade and olfactory disorders, while after the procedure this ratio was found to be the opposite. All results were statistically significant (p<0.05). CONCLUSIONS: The authors emphasize a great role of general health assessment in patients with CRS as the element of proper diagnosis and better comprehension of patients' needs. They indicate that the patient's estimation of the disease and its symptoms differs from the clinician's interpretation to much extent. PMID- 25441936 TI - [Internal and external chordectomy via laryngofissure with the use of CO2 laser]. AB - INTRODUCTION: The aim of this work was to evaluate the therapy results of patients with glottic carcinoma in the T1NoMo advanced clinical stage on internal or external chordectomy via the thyroid cartilage with the use of CO2 laser. MATERIAL AND METHODS: The study was conducted in 110 patients, including 7 women aged 52-68 and 103 men aged 52-73, who were treated in the Department of Otolaryngology and Laryngological Oncology, Military Medical Academy Teaching Hospital in Lodz, during the years 2010-2012, due to laryngeal carcinoma (T1N0M0). RESULTS: The studied material was subjected to external chordectomy via laryngofissure in 51 men (46.4%), and internal chordectomy with the use of CO2 laser in 52 men (47.2%) and 7 women (6.4%). In the patients operated via laryngofissure, the following types of external chordectomy were performed: IV - in 25 cases (49.0%), Vc - in 12 cases (23.6%), and Vb and Vd - in 7 cases each (13.7% each). Internal chordectomy was conducted with the use of the following types: III - in 31 cases (52.5%), IV - in 15 cases (25.4%) and Vd - in 13 cases (22.1%). During the post-operative follow-up of 1-3 years, no recurrence of carcinoma was observed. CONCLUSIONS: The place and size of carcinoma are often dependent on the type of internal and external chordectomy, which is preceded by tracheotomy and is usually dependent on a patient's consent. Too short post operative follow-up does not allow for the comparison of effective therapies of the two surgical methods. PMID- 25441937 TI - [Neoplastic tumors in patients with unilateral inflammations qualified for endoscopic surgery]. AB - INTRODUCTION: The aim of this work was to analyze the occurrence and type of neoplasm in unilateral pathological lesions within the nose and paranasal sinuses in patients who underwent endoscopic surgery, in own material. MATERIAL AND METHODS: Between 2006 and 2012 2295 patients, including 1006 women aged 15-84 and 1289 men aged 17-87, were operated on due to diseases of paranasal sinuses in the Department of Otolaryngology and Laryngological Oncology. The patients underwent surgery after a medical interview, physical examination, 3D CT of paranasal sinuses and laboratory tests. The removed lesions were histopathologically investigated. The studied group included the patients with only unilateral lesions and histopathologically recognized neoplastic lesion. RESULTS: In the studied material, neoplastic lesions occurred in 9.8% cases, out of which 5.4% were inverted papillomas, 3.1% osteomas, and 1.5% malignant tumors. However, in the patients who were operated due to hypertrophic changes within paranasal sinuses, neoplasm was found in 1.3% cases, while inverted papilloma in 0.7%, osteoma in 0.4% and malignant tumors in 0.1%, which altogether amounts to 8 times higher occurrence of neoplastic lesions in unilateral changes. RESULTS: Unilateral changes within paranasal sinuses require highly inquisitive pre operative diagnostics, peri-operative analysis and histopathological evaluation. PMID- 25441938 TI - [Long-term results and cause of failure analysis in larynx cancer patients irradiated conventionally and with accelerated fractionation schedules in 1995 1998]. AB - The clinical material consists of 217 patients with squamous cell carcinoma in supraglottic and glottic larynx in clinical stage T1-3N0M0 irradiated radically in Warsaw Oncology Centre in 1995-1998. All patients were treated with Co-60, according to two schedules of fractionation, with maintenance of the consistent therapeutic protocol. The same team of doctors worked on the treatment of patients and on the follow-up as well. The clinical material is a part of a three phased clinical trial KBN 0295. In the course of observation, the progression of cancer was not observed in 157 patients, among whom, 66% were treated conventionally and 79% with accelerated fractionation method. 60 cases of loco regional recurrences were noted, among which 55 were regional. The majority of failure cases was observed until the 30(th) of the month after the radiotherapy ended. In conventional fractionation treatment, recurrences in T1 were 8/31 (26%), in T2 22/59 (37%) and in T3 8/20 (40%). In patients treated with AF, recurrences were T1 5/39 (13%), T2 15/55 (27%) and T3 2/13 (15%) respectively. The percentage of primary site tumour recurrences for each localization and kind of treatment was analysed. In CF 28/78 (37%) of glottic tumour recurrences and 10/34 (29%) of supraglottic tumour, recurrences were observed. In AF, 12/71 (17%) and 10/36 (28%) were observed respectively. In 48 cases salvage surgery was used, and 12 patients were not qualified because of tumour massive progression or because they refused to have a surgery. Among 34 cases (16%) of the second primary tumour or distant methastases, 25 were observed with glottic cancer, among which 23 were observed in early stages, and 9 cases with supraglottic cancer, among which, 6 showed early stage of tumour. In only 3 cases out of all the patients, distant methastases were confirmed in histopatology examination. The main cause of failure in larynx cancer patients in stage T1 is that 3N0M0 are local recurrences. Second primary or distant methastases constitute 16% of the patients in this paper. PMID- 25441939 TI - Giant cystic primary mucoepidermoid carcinoma of mandible: a rare case and literature review. AB - Primary intra-osseous mucoepidermoid carcinoma arising from jaw is an extremely rare condition accounting to less than 2% of all mucoepidermoid carcinomas. In the jaw, it occurs more commonly in mandible than maxilla. They are low-grade cancers and affect jaw as uni- or multi-locular radiographic lesions. Here we discuss a rare case of giant cystic primary intra-cystic mucoepidermoid carcinoma of the mandible which was excised in toto. Here we discuss the clinical features, radiological and histological characteristics of this rare lesion, and review the literature. PMID- 25441940 TI - A neglected giant parotid gland mass: excision and reconstruction with facial nerve preservation. AB - Carcinoma ex pleomorphic adenoma (CXPA) is a malignant transformed variant of pleomorphic adenoma (PA). Generally it presents with a rapidly growing mass in the parotid gland within a preexisting PA or following surgical resection of PA. Mainstream treatment modality is surgical resection followed by radiotherapy if necessary. Facial nerve preservation and complete resection of the tumor are the main principles of the operation. Giant malignant derivates are not seen frequently and constitute a challenging task for surgeons to achieve the main principles of resection. Prognosis of CXPA is poor and aggressive treatment should be performed immediately after the diagnosis. We present a 82-year-old woman with a giant malignant parotid gland mass who was successfully treated with surgery without any facial nerve injury. PMID- 25441941 TI - Cystic squamous cell carcinoma of the neck: could a second metastatic focus help? AB - Squamous cell carcinoma of the neck presenting clinically as predominantly cystic lesion has often been considered as branchiogenic carcinoma in the past. However, such cystic lesions presently constitute a distinct form of head-neck metastasis, and a co-existent second metastatic focus could supposedly help distinguish them from branchiogenic carcinoma. We here present a case where, although the primary remained elusive, the associated spinal metastasis precluded us from diagnosing a cystic squamous cell carcinoma as branchiogenic carcinoma. Thus a second metastatic focus, if found, could add to the existing knowledge to distinguish between a cystic squamous cell carcinoma and the so-called branchiogenic carcinoma, especially when the primary could not be found. PMID- 25441942 TI - Cancer-related fatigue: still an enigma to be solved quickly. AB - Fatigue is the most common symptom in patients with advanced cancer and its prevalence ranges between 50% to 90% overall. In cancer survivors, approximately 30% of patients will experience persistent fatigue for a number of years after treatment. This complex, multidimensional symptom causes disruption in many aspects of quality of life and becomes particularly problematic in the frail and elderly patients. However, cancer-related fatigue is still less investigated and undertreated by the clinicians. Recent guidelines focus on the importance to investigate this distressing symptom at the baseline visit and then at regular intervals. There is no certainty on aetiology and pathogenesis, but it seems that proinflammatory cytokine network is involved both during or after a therapy for cancer. After addressing reversible or treatable contributing risk factors, the treatment can be pharmacologic and non-pharmacologic or combined but it is still largely inadequate especially in case of moderate-severe cancer-related fatigue. Interventions should be tailored to each patient's specific needs. Finally, cancer-related fatigue has societal and economic costs with increased cancer care. PMID- 25441943 TI - Antimicrobial sensitivity pattern of bacterial pathogens in urinary tract infections in South Delhi, India. AB - Seventy-four bacterial proven cases of urinary tract infections were studied, and identified by Mac Conkey agar and blood agar medium separately; all the isolates were subjected to antimicrobial sensitivity testing by Stokes technique. Ninty six percent of total isolated organisms were found to be gram negative while remaining 4% were gram positive. Among gram negatives, E. coli and gram positive S. aureus were the most prevalent organisms. The percentage of gram negative isolates were as follows, E. coli (79.7%) followed by Klebsiella (9.5%), Pseudomonas, Acinetobacter were (2.7% each), Proteus constituted (1.4%). and among gram positive S. aureus (4%). The antibiotic resistance of identified organisms was carried out by disc-diffusion method with commercially available disc of thirteen antibiotics having different mode of actions such as inhibition of cell wall synthesis, membrane permeability alternatives, inhibition of protein synthesis and DNA synthesis inhibitors. Gram negatives showed more resistance to these antibiotics as compared to gram positive organisms. The most effective antibiotic for gram negative UTI isolates is amikacin showing 63% efficacy followed by Cefotaxime 55% efficacy, Amoxicillin and Ciprofloxacin with (49% each) efficacy. Among gram positives, Chloramphenicol, Co-trimoxazole, Gentamicin, Amikacin, Ciprofloxacin and Cefotaxime are most effective with (66.6% each) efficacy, then Ampicillin, Amoxicillin, Tetracycline and norfloxacin with (33.3% each) efficacy. PMID- 25441944 TI - Anti-HER2 therapy in elderly breast cancer patients. AB - Targeting anti-HER-2 therapy, trastuzumab, Lapatinib, T-DM1, and Pertuzumab is a standard therapy for HER-2-overexpressing breast cancer. But there are less data available related to anti-HER-2 therapy in elderly patients because they have been consistently underrepresented in clinical trials. Anti- HER-2 therapy among an elderly population was reviewed including approaches for making treatment effective. PMID- 25441946 TI - Effects of acupuncture at Zu-San-Li (ST36) on the activity of the hypothalamic- pituitary--adrenal axis during ethanol withdrawal in rats. AB - The current study investigated the effects of acupuncture at Zu-San-Li (ST36) on the hypothalamic-pituitary-adrenal axis during ethanol withdrawal in rats. Rats were intraperitoneally treated with 3 g/kg/day of ethanol or saline for 28 days. Following 24 hours of ethanol withdrawal, acupuncture was applied at bilateral ST36 points or non-acupoints (tail) for 1 minute. Plasma levels of corticosterone (CORT) and adrenocorticotropic hormone (ACTH) were measured by radioimmunoassay (RIA), and the corticotropin-releasing factor (CRF) protein levels in the paraventricular nucleus of the hypothalamus were also examined by RIA 20 minutes after the acupuncture treatment. RIA showed significantly increased plasma levels of CORT and ACTH in the ethanol-withdrawn rats compared with the saline-treated rats, which were inhibited significantly by the acupuncture at the acupoint ST36 but not at the non-acupoint. Additionally, ethanol withdrawal promoted CRF protein expressions in the paraventricular nucleus of the hypothalamus, which were also blocked by the acupuncture at ST36. These findings suggest that acupuncture at the specific acupoint ST36 can inhibit ethanol withdrawal-induced hyperactivation of hypothalamic-pituitary-adrenal axis, and it may be mediated via the modulation of hypothalamic CRF. PMID- 25441945 TI - Homology modeling and explicit membrane molecular dynamics simulation to delineate the mode of binding of thiazolidinediones into FFAR1 and the mechanism of receptor activation. AB - Free fatty acid receptor 1 (FFAR1) is a member of a previously characterized cluster of orphan G protein-coupled receptors (GPCRs). Later, this orphan receptor was identified as a target of medium- to long-chain free fatty acids in beta-cells of the pancreas. Administration of FFAR1 agonists has been proved to potentiate glucose-stimulated insulin secretion from pancreatic beta-cells. It was reported that some thiazolidinediones (TZDs), the best studied PPARgamma agonists, are also able to stimulate FFAR1 in a dose-dependent manner. In the present study, a homology model of the human FFAR1 was constructed and inserted into a pre-equilibrated DPPC/TIP3P membrane system. This system was then simulated for 20 ns in complex with the FFAR1 agonist GW9085, as well as rosiglitazone and pioglitazone. We noticed that the salt bridge between Glu172 and Arg258 and the H bond between Glu145 and His153 could be responsible for the stabilization of the receptor in the inactive state. Moreover, we described for the first time the binding mode of TZDs in the binding site of FFAR1. The thiazolidinedione head forms a hydrogen bonding network with the critical polar residues in the binding site, Arg258 and Asn244, while the rest of the molecule is embedded into the receptor hydrophobic pocket. Based on this modeling study, we arrived at a proposal of the pharmacophore required for binding to both PPARgamma and FFAR1. Insights gained from this investigation should provide future directions for the design of novel dual acting antidiabetic agents. PMID- 25441947 TI - Electromyographic and strength analyses of activation patterns of the wrist flexor muscles after acupuncture. AB - This study analyzed the electromyographic and strength responses of the flexor muscles of the wrist following stimulation of acupuncture points. A total of 52 participants were randomly divided into four groups: local (heart 3, HT3), distant (heart 4, HT4), control (bladder 60, BL60), and naive control groups. To obtain the root mean square electromyographic activity, we placed surface electrodes over the wrist flexors. To obtain kilogram force (kgf) values, we attached a force transducer to the floor and to the hands of participants. Both values were recorded over three repetitions of maximal isometric wrist flexion contractions. Data were analyzed using one-way analyses of variance, followed by Dunnett's post-hoc tests. We found reductions in electromyographic activity contralateral to the stimulated point in the distant group 10 minutes after removal of the needles (F(3,48) = 3.25; p < 0.05). Regarding muscle strength, ipsilateral and contralateral stimulation in the distant group produced kgf levels prior to and 10 minute and 20 minutes after withdrawal of the acupuncture needle that were lower than that obtained prior to insertion of the needle (F(3,48) = 5.82; p < 0.05). Thus, stimulation of the acupuncture points distant from the wrist flexors reduced ipsilateral and contralateral muscle strength and decreased the root mean square values contralateral to the site of stimulation. PMID- 25441948 TI - Influence of electroacupuncture on thermal changes in a soft tissue defect. AB - This study investigated thermal changes in the skin at locations where soft tissue defects existed and acupuncture needles stimulated by using bipolar electroacupuncture (EA) had been inserted. Under general anesthesia (GA), experimental defects were made at the dorsum site of five New Zealand rabbits. Bipolar EA was used for 20 minutes to stimulate the experimental defects, and the skin temperature was monitored at the sites where the acupuncture needles had been inserted and the soft tissue defects existed. The initial thermography of those defects had the same trend as that of the negative pole of EA stimulation at the first acupoint. Skin thermography during the first 3 minutes of bipolar EA indicated a centrifugal vasoconstriction and a vasodilatation at the negative and positive poles, respectively. After that, the thermal change in soft tissue undergoing EA stimulation was not modified by a different EA polarity. The local temperature at the defect and its surroundings under both positive and negative electric loads was increased by 0.2-0.3 degrees C for vasodilatation. This study indicates that EA influences sympathetic modulation of soft tissue defects and that selective sympathetic modulation caused by bipolar EA is responsible for the clinical perception. PMID- 25441949 TI - Influence of electroacupuncture on the soft tissue healing process. AB - The aim of this study was to determine the effect of bipolar electroacupuncture (EA) on a soft tissue defect in rabbits. Ten clinically healthy New Zealand white rabbits were divided into two groups: the control group (Group C, n = 5) and the experimental (EA) group (Group T, n = 5). During neuroleptanalgesia, defects of soft tissue (skin and muscle) were made at the dorsum site on the rabbits in both groups, and those defects were stimulated using EA. The biopsy samples were collected on Day 2, Day 4, and Day 6, prepared for histology, and examined microscopically. On the 2(nd) day, in Group C, the inflammatory degree was higher than it was in Group T; on subsequent days, low or identical degrees of inflammation were observed in both groups. Proliferative fibrous activity was increased on Day 4 for Group T and identical for both groups on Day 6. The dynamics of the epidermal thickness were characterized by a high rate on Day 2, Day 4, and Day 6 for Group T. EA facilitates a low tissue mechanical stress and has a positive effect on the healing of muscular defects. EA enhances the healing process, with no side effects. PMID- 25441950 TI - Electromagnetic acupuncture to enhance the effects of manual acupuncture on recovery from muscle fatigue of the quadriceps. AB - The aim of this study was to investigate a new method of manual acupuncture that used a magnetic field to stimulate only one acupoint vertically. We developed an eight-channel electromagnetic acupuncture (EMA) system that uses a solenoid-type electrode to insert the manual acupuncture needle into a hole in an electrode. We used a manual acupuncture needle for magnetic induction in order to penetrate vertically and deeply into tissues. In order to confirm the usefulness of EMA, we investigated the effects of treatment on muscle fatigue after strenuous knee extension/flexion exercises that had been performed by three groups: the nonstimulation, the manual acupuncture, and the EMA groups. Electromyograms showed that the median frequency (MF) in the EMA group had rapidly recovered after 4 minutes (p = 0.608), but that the peak torque had not recovered to the normal state (p < 0.05). Thus, we confirmed that compared with manual acupuncture, EMA resulted in better recovery from muscle fatigue. PMID- 25441951 TI - Treatment of an elderly patient with acute abdominal pain with traditional Korean medicine. AB - Abdominal pain in elderly patients leads to challenge due to diagnostic difficulty and high incidence of complications. This case report presents an elderly patient with acute and severe abdominal pain, who did not respond to Western treatments. The patient was diagnosed to have abdominal pain by Yang deficiency of spleen (???). Acupuncture (mainly at LI4 and LR3), indirect moxibustion (CV4 and CV8), and a herbal drug [DaehwangBuja-Tang (?????)] were given to the patient; the abdominal pain and related symptoms disappeared completely within 3 days. This study proved the potential use of traditional Korean medicine for treating abdominal pain in elderly patients. PMID- 25441952 TI - The successful treatment of pain associated with scar tissue using acupuncture. AB - In this case report, a 48-year-old female who had suffered severe scar pain for 3 months was treated with acupuncture using the Wei Ci technique (surrounding the dragon). Scar tissue usually forms after deep trauma, such as piercings, burns, and surgery, to the dermis. In Chinese Medicine, scar tissue causes local Qi and blood stagnation which lead to pain. The Wei Ci technique (surrounding the dragon) and distal points Hegu-LI-4, Taichong-LIV-3, Zusanli-ST-36 were used. The patient received a total of eight treatments in 5 weeks. The scar pain decreased from 7 to 1 or 2 on a Likert scale of 0-10, with 0 being no pain and 10 being the worst pain. Acupuncture may have a good short-term pain-relieving effect on scar pain but its long-term scar-pain-relieving effects are still unclear. PMID- 25441953 TI - A study of Sa-Ahm's thoughts on the four-needle acupuncture technique with the five-element theory. AB - In order to study Sa-Ahm's underlying thoughts on the basis of Yin-Yang and the five-element theory, the 12 acupuncture meridian systems and eight extra meridian systems were investigated in detail. The clinical acupuncture points for Sa-Ahm's four-needle acupuncture technique were also reviewed. The forms of the combinations using the five Shu acupuncture points, which are based on the promotion and control cycles with tonification and sedation, were shown to connect to the acupuncture points, which represent the meridian system itself. However, not all of Sa-Ahm's clinical cases were fully explained by this doctrine, so the five correlations among the meridian systems and the acupuncture points that affect the clinical treatment and the occurrence of disease were determined. The mutual efficacies for Sa-Ahm's clinical cases can be analyzed and explained with correlativity diagrams that include five interrelations. PMID- 25441955 TI - Image-assisted dietary assessment: a systematic review of the evidence. AB - Images captured during eating episodes provide objective information to assist in the assessment of dietary intake. Images are captured using handheld devices or wearable cameras, and can support traditional self-report or provide the primary record of dietary intake. A diverse range of image-assisted methods have been developed and evaluated but have not been previously examined together. Therefore, a review was undertaken to examine all studies that have evaluated or validated image-assisted methods of dietary assessment for assessing dietary energy intake. Identified image-assisted methods that employ similar methodologies were grouped for comparison. English-language full-text research articles published between January 1998 and November 2013 were searched using five electronic databases. A search of reference lists and associated websites was also conducted. Thirteen studies that evaluated 10 unique image-assisted methods among adults aged 18 to 70 years were included. Ten studies used handheld devices and three studies used wearable cameras. Eight studies evaluated image based food records, two studies explored the use of images to enhance written food records, and three studies evaluated image-assisted 24-hour dietary recalls. Results indicate images enhance self-report by revealing unreported foods and identify misreporting errors not captured by traditional methods alone. Moreover, when used as the primary record of dietary intake, images can provide valid estimates of energy intake. However, image-assisted methods that rely on image analysis can be prone to underestimation if users do not capture images of satisfactory quality before all foods are consumed. Further validation studies using criterion measures are warranted. The validity among children, adolescents, and elderly persons as well as the feasibility of using image-assisted methods in large samples needs to be examined. Additional research is also needed to better understand the potential applications and pitfalls of wearable cameras. PMID- 25441954 TI - Dietary fat increases vitamin D-3 absorption. AB - BACKGROUND: The plasma 25-hydroxyvitamin D response to supplementation with vitamin D varies widely, but vitamin D absorption differences based on diet composition is poorly understood. OBJECTIVES: We tested the hypotheses that absorption of vitamin D-3 is greater when the supplement is taken with a meal containing fat than with a fat-free meal and that absorption is greater when the fat in the meal has a higher monounsaturated-to-polyunsaturated fatty acid ratio (MUFA:PUFA). DESIGN: Open, three-group, single-dose vitamin D-3 comparative absorption experiment. PARTICIPANTS/SETTING: Our 1-day study was conducted in 50 healthy older men and women who were randomly assigned to one of three meal groups: fat-free meal, and a meal with 30% of calories as fat with a low (1:4) and one with a high (4:1) MUFA:PUFA. After a 12-hour fast, all subjects took a single 50,000 IU vitamin D-3 supplement with their test breakfast meal. MAIN OUTCOME MEASURES: Plasma vitamin D-3 was measured by liquid chromatography-mass spectrometry before and 10, 12 (the expected peak), and 14 hours after the dose. STATISTICAL ANALYSES PERFORMED: Means were compared with two-tailed t tests for independent samples. Group differences in vitamin D-3 absorption across the measurement time points were examined by analysis of variance with the repeated measures subcommand of the general linear models procedure. RESULTS: The mean peak (12-hour) plasma vitamin D-3 level after the dose was 32% (95% CI 11% to 52%) greater in subjects consuming fat-containing compared with fat-free meals (P=0.003). Absorption did not differ significantly at any time point in the high and low MUFA and PUFA groups. CONCLUSIONS: The presence of fat in a meal with which a vitamin D-3 supplement is taken significantly enhances absorption of the supplement, but the MUFA:PUFA of the fat in that meal does not influence its absorption. PMID- 25441956 TI - Relative validity and reproducibility of a food frequency questionnaire for identifying the dietary patterns of toddlers in New Zealand. AB - BACKGROUND: Dietary patterns provide insight into relationships between diet and disease. Food frequency questionnaires (FFQs) can identify dietary patterns in adults, but similar analyses have not been performed for toddlers. OBJECTIVE: The aim of the Eating Assessment in Toddlers study was to evaluate the relative validity and reproducibility of dietary patterns from an FFQ developed for toddlers aged 12 to 24 months. DESIGN/SETTING: Participants were 160 toddlers aged 12 to 24 months and their primary caregiver who completed an FFQ twice, approximately 5 weeks apart (FFQ1 and FFQ2). A 5-day weighed food record was collected on nonconsecutive days between FFQ administrations. STATISTICAL ANALYSIS: Principal component analysis identified three major dietary patterns similar across FFQ1, FFQ2, and the 5-day weighted food record. RESULTS: The sweet foods and fries pattern was characterized by high intakes of sweet foods, fries and roast potato and kumara (sweet potato), butter and margarines, processed meat, sweet drinks, and fruit or milk drinks. The vegetables and meat pattern was characterized by high intakes of vegetables, meat, eggs and beans, and fruit. The milk and fruit pattern was characterized by high intakes of milk and milk products and fruit, and low intakes of breastmilk and infant and follow-up formula. The FFQ (FFQ1) correctly classified 43.1% to 51.0% of toddlers into the same quartile of pattern score as the 5-day weighted food record, and Pearson correlations ranged from 0.56 to 0.68 for the three patterns. Reliability coefficients ranged from 0.71 to 0.72 for all three dietary patterns. CONCLUSIONS: the Eating Assessment in Toddlers study FFQ shows acceptable relative validity and high reproducibility for identifying dietary patterns in toddlers. PMID- 25441957 TI - Relationship of 6-n-propylthiouracil taste intensity and chili pepper use with body mass index, energy intake, and fat intake within an ethnically diverse population. AB - BACKGROUND: One of the weight-loss strategies that has attracted attention is the use of spicy foods. It has been suggested that spicy food preference is related to a genetically predetermined sensitivity to the bitter compound 6-n propylthiouracil (PROP). OBJECTIVE: Our aim was to examine the relationship of PROP taste intensity and hot chili pepper use with body mass index (BMI), energy intake, and fat intake. DESIGN: This study utilized a cross-sectional design. PARTICIPANTS/SETTING: The sample included 350 subjects (154 male, 196 female) ages 18 to 55 years living in the New York City area. MAIN OUTCOME MEASURES: BMI was calculated by measuring weight and height, and the sensitivity to PROP was evaluated using the PROP filter paper method. Subjects also rated the frequency of usage and preference for hot chili pepper using a chili pepper questionnaire. Their daily energy and fat intake were assessed using a food frequency questionnaire. STATISTICAL ANALYSES PERFORMED: An independent sample t-test compared subject characteristics between groups based on sex, PROP status, and hot chili pepper user status for the continuous variables, and the chi(2) test was used for categorical variables. One-way analysis variance examined the differences in subject characteristics across four ethnicities. To predict BMI, energy intake, and fat intake, multiple linear regression models were fit with the covariates of age, sex, ethnicity, chili pepper score, and PROP mean. RESULTS: The values for BMI, energy intake, and fat intake of PROP tasters were significantly lower than those of PROP nontasters (P=0.03, P<0.001, and P<0.001, respectively). The energy intake of chili pepper nonusers was significantly lower than that of chili pepper users (P=0.02), while there was no significant difference in fat intake between chili pepper users and nonusers. CONCLUSIONS: This study suggests that PROP taste sensitivity contributes more to the prediction of energy and fat intake than chili pepper use. PMID- 25441958 TI - An approach to monitor food and nutrition from "factory to fork". AB - BACKGROUND: Accurate, adequate, and timely food and nutrition information is necessary in order to monitor changes in the US food supply and assess their impact on individual dietary intake. OBJECTIVE: Our aim was to develop an approach that links time-specific purchase and consumption data to provide updated, market representative nutrient information. METHODS: We utilized household purchase data (Nielsen Homescan, 2007-2008), self-reported dietary intake data (What We Eat in America [WWEIA], 2007-2008), and two sources of nutrition composition data. This Factory to Fork Crosswalk approach connected each of the items reported to have been obtained from stores from the 2007-2008 cycle of the WWEIA dietary intake survey to corresponding food and beverage products that were purchased by US households during the equivalent time period. Using nutrition composition information and purchase data, an alternate Crosswalk based nutrient profile for each WWEIA intake code was created weighted by purchase volume of all corresponding items. Mean intakes of daily calories, total sugars, sodium, and saturated fat were estimated. RESULTS: Differences were observed in the mean daily calories, sodium, and total sugars reported consumed from beverages, yogurts, and cheeses, depending on whether the Food and Nutrient Database for Dietary Studies 4.1 or the alternate nutrient profiles were used. CONCLUSIONS: The Crosswalk approach augments national nutrition surveys with commercial food and beverage purchases and nutrient databases to capture changes in the US food supply from factory to fork. The Crosswalk provides a comprehensive and representative measurement of the types, amounts, prices, locations and nutrient composition of consumer packaged goods foods and beverages consumed in the United States. This system has potential to be a major step forward in understanding the consumer packaged goods sector of the US food system and the impacts of the changing food environment on human health. PMID- 25441959 TI - Case-based learning facilitates critical thinking in undergraduate nutrition education: students describe the big picture. AB - BACKGROUND: The vision of dietetics professions is based on interdependent education, credentialing, and practice. Case-based learning is a method of problem-based learning that is designed to heighten higher-order thinking. Case based learning can assist students to connect education and specialized practice while developing professional skills for entry-level practice in nutrition and dietetics. OBJECTIVE: This study examined student perspectives of their learning after immersion into case-based learning in nutrition courses. DESIGN: The theoretical frameworks of phenomenology and Bloom's Taxonomy of Educational Objectives triangulated the design of this qualitative study. PARTICIPANTS/SETTING: Data were drawn from 426 written responses and three focus group discussions among 85 students from three upper-level undergraduate nutrition courses. MAIN OUTCOME MEASURES: Coding served to deconstruct the essence of respondent meaning given to case-based learning as a learning method. The analysis of the coding was the constructive stage that led to configuration of themes and theoretical practice pathways about student learning. RESULTS: Four leading themes emerged. Story or Scenario represents the ways that students described case-based learning, changes in student thought processes to accommodate case-based learning are illustrated in Method of Learning, higher cognitive learning that was achieved from case-based learning is represented in Problem Solving, and Future Practice details how students explained perceived professional competency gains from case-based learning. CONCLUSIONS: The skills that students acquired are consistent with those identified as essential to professional practice. In addition, the common concept of Big Picture was iterated throughout the themes and demonstrated that case-based learning prepares students for multifaceted problems that they are likely to encounter in professional practice. PMID- 25441960 TI - The use of technology for delivering a weight loss program for adolescents with intellectual and developmental disabilities. AB - Adolescents with intellectual and developmental disabilities (IDD) are at an increased risk of obesity, with up to 55% considered overweight and 31% obese. However, there has been minimal research on weight management strategies for adolescents with IDD. The purpose of this study was to compare the effectiveness of two weight loss diets, an enhanced Stop Light Diet (eSLD) and a conventional diet (CD), and to determine the feasibility of using tablet computers as a weight loss tool in overweight and obese adolescents with IDD. A 2-month pilot intervention was conducted. All participants were randomized to the eSLD or CD and were given a tablet computer that they used to track daily dietary intake and physical activity. Participants and parents met weekly with a registered dietitian nutritionist via video chat on the tablet computer to receive diet and physical activity feedback and education. Twenty participants (45% female, aged 14.9+/-2.2 years) were randomized and completed the intervention. Participants in both diets were able to lose weight, and there were no significant differences between the eSLD and CD (-3.89+/-2.66 kg vs -2.22+/-1.37 kg). Participants were able to use the tablet computer to track their dietary intake 83.4%+/-21.3% of possible days and to attend 80.0% of the video chat meetings. Both dietary interventions appear to promote weight loss in adolescents with IDD, and the use of tablet computers appears to be a feasible tool to deliver a weight loss intervention in adolescents with IDD. PMID- 25441961 TI - What is your nutrition program missing? Finding answers with the guide for Effective Nutrition Interventions and Education (GENIE). PMID- 25441962 TI - Use of sodium information on the nutrition facts label in New York City adults with hypertension. AB - The Nutrition Facts (NF) label was established to help individuals monitor their nutrient intake and select healthier foods. This tool is particularly useful for individuals for whom dietary improvements are recommended, such as those with hypertension. Study objectives were to examine the independent association between hypertension and frequency of use of the NF label for sodium information and determine whether frequent use in individuals with hypertension was associated with differences in mean sodium intake assessed through 24-hour urine samples. Data came from the New York City Community Health Survey Heart Follow-Up Study, a cross-sectional study conducted in 2010 in a representative sample of New York City adults (n=1,656). Participants were asked questions regarding frequency of checking the NF label and also had 24-hour urine samples collected to assess actual sodium intake. Results indicated that hypertension was associated with frequent use of the NF label for sodium information (adjusted odds ratio 1.71, 95% CI 1.07 to 2.73). In individuals with hypertension, sodium intake did not differ between frequent vs nonfrequent use of the NF label for sodium information (3,084 mg/day vs 3,059 mg/day; P=0.92). Although individuals with hypertension compared to those with no hypertension had 71% higher odds of frequently using the NF label for sodium information, suggesting they may be interested in decreasing sodium intake, sodium intake did not differ by frequency of NF label use among those with hypertension. Future research should explore strategies to ensure that when nutrition information is used, it is translated into meaningful results, especially in individuals with health concerns such as hypertension. PMID- 25441963 TI - Rheological characteristics of cold thickened beverages containing xanthan gum based food thickeners used for dysphagia diets. AB - Cold beverages are commonly thickened with commercial gum-based food thickeners for consumption by patients with dysphagia. In this study, the rheological properties of a thickened water and five thickened beverages (orange juice, apple juice, grape juice, whole milk, and a sport drink) that were prepared with four commercial instant xanthan gum-based thickeners (coded A-D) were investigated at a 3% thickener concentration. All thickened samples showed high shear-thinning behavior with yield stress at the serving temperature of 8 degrees C. The magnitudes of apparent viscosity (etaa,50), consistency index (K), storage modulus (G'), and loss modulus (G'') of the thickened beverages, except for water, with food thickener A were significantly higher compared with other thickeners (B, C, and D) (P<0.05). The largest increases in K values for thickened beverages were observed at 1-hour storage, and at longer times their K values, except for milk, remained approximately constant. Rheological parameters demonstrated statistically significant differences in flow and dynamic behaviors between the cold thickened beverages prepared with the xanthan gum-based food thickeners (P<0.05), indicating that their rheological properties are strongly influenced by the dispersing medium, the type of food thickener, and storage time. In particular, appropriately selecting a commercial food thickener for preparing thickened beverages seems to be of importance for managing dysphagia. PMID- 25441965 TI - The United States food supply is not consistent with dietary guidance: evidence from an evaluation using the Healthy Eating Index-2010. AB - The US food system is primarily an economic enterprise, with far-reaching health, environmental, and social effects. A key data source for evaluating the many effects of the food system, including the overall quality and extent to which it provides the basic elements of a healthful diet, is the Food Availability Data System. The objective of the present study was to update earlier research that evaluated the extent to which the US food supply aligns with the most recent federal dietary guidance, using the current Healthy Eating Index-2010 (HEI-2010) and food supply data extending through 2010. The HEI-2010 was applied to 40 years of food supply data (1970-2010) to examine trends in the overall food supply as well as specific components related to a healthy diet, such as fruits and vegetables. The HEI-2010 overall summary score hovered around half of optimal for all years evaluated, with an increase from 48 points in 1970 to 55 points (out of a possible 100 points) in 2010. Fluctuations in scores for most individual components did not lead to sustained trends. Our study continues to demonstrate sizable gaps between federal dietary guidance and the food supply. This disconnect is troublesome within a context of high rates of diet-related chronic diseases among the population and suggests the need for continual monitoring of the quality of the food supply. Moving toward a food system that is more conducive to healthy eating requires consideration of a range of factors that influence food supply and demand. PMID- 25441964 TI - Disparities persist in nutrition policies and practices in Minnesota secondary schools. AB - Access to healthy foods among secondary school students is patterned by individual-level socioeconomic status, but few studies have examined how school nutrition policies and practices are patterned by school-level characteristics. The objective of our study was to examine school nutrition policies and practices by school characteristics (eg, location, racial/ethnic composition, and free/reduced priced lunch eligibility) in Minnesota secondary schools between 2008 and 2012. Data from the 2008 to 2012 Minnesota School Health Profiles survey were used to assess school nutrition policies and practices, and National Center for Educational Statistics data were used for school characteristics (n=505 secondary schools). Nutrition policies and practices included the availability of low-nutrient, energy dense (LNED) items, strategies to engage students in healthy eating, and restrictions on advertisements of LNED products in areas around the school. Among school-level characteristics, school location was most strongly related to school nutrition policies. Across all years, city schools were less likely than town/rural schools to have vending machines/school stores (prevalence difference [PD] -13.7, 95% CI -25.0 to -2.3), and less likely to sell sport drinks (PD -36.3, 95% CI -51.8 to -20.7). City schools were also more likely to prohibit advertisements for LNED products in school buildings (PD 17.7, 95% CI 5.5 to 29.9) and on school grounds (PD 15.6, 95% CI 1.7 to 29.5). Between 2008 and 2012, the prevalence of some healthy eating policies/practices (eg, limiting salty snacks, offering taste testing, and banning unhealthy food advertisements in school publications) declined in city schools only, where these policies/practices had previously been more common. Monitoring of these trends is needed to understand the influence of these policies on student outcomes across school settings. PMID- 25441966 TI - Changing beverage consumption patterns have resulted in fewer liquid calories in the diets of US children: National Health and Nutrition Examination Survey 2001 2010. AB - BACKGROUND: Beverage consumption patterns have been linked to obesity and chronic disease risk. Although the consumption of sugar-sweetened beverages (SSBs) has decreased recently, little is known about the parallel trends in intake of other beverages. OBJECTIVE: To describe recent trends in consumption of all commonly consumed beverages among US children aged 2 to 19 years. DESIGN: Twenty-four-hour dietary recalls from 18,541 participants in the National Health and Nutrition Examination Survey from 2001-2010 were used to assess beverage intake, including SSBs (ie, sodas, fruit-flavored drinks, sport and energy drinks, fruit juices, coffees/teas, and other [nondairy] sugar-sweetened drinks); milks (ie, plain whole, reduced fat, and low-/nonfat, sweetened, other milks/milk-based drinks, and milk alternatives); 100% juices (ie, fruit, and vegetable/mixed without added sugar); low-/no-calorie beverages (ie, unsweetened or artificially sweetened: sodas, coffees/teas, flavored waters, diet sport/energy drinks, and other low/no calorie drinks); alcohol-containing; and plain water (during 2005-2010 only). Weighted mean intakes (percent total energy and total ounces) and consumption prevalence were estimated. Regression models and analytical procedures that account for the complex sampling methods were used to test trends. RESULTS: Between 2001-2002 and 2009-2010, total daily beverage consumption (excluding water) decreased from 24.4% to 21.1% energy (32.0 to 27.9 oz). Significant decreases (P<0.05) occurred in sugar-sweetened sodas (13.5% to 10.2% energy), whole milk (2.7% to 1.6% energy), fruit juices with sugar added (2.3% to 2.1% energy), and fruit-flavored drinks (1.6% to 0.8% energy). Significant increases occurred for sweetened coffees/teas, energy drinks, sport drinks, and unsweetened juices though the contribution of each to total energy intake remained <1%. Low /no-calorie drink consumption also increased, rising from 0.2 to 1.3 oz/day. CONCLUSIONS: Changing beverage consumption patterns reflect positive trends in the form of reduced intake of SSBs, whole milk, and total calories from beverages. Although the consumption of sport drinks, energy drinks, and low calorie beverages have increased, their contribution to total beverage intake remains small. PMID- 25441967 TI - Secular trend of serum docosahexaenoic acid, eicosapentaenoic acid, and arachidonic acid concentrations among Japanese-a 4- and 13-year descriptive epidemiologic study. AB - Cross-sectional studies have shown age-related increases in blood docosahexaenoic and eicosapentaenoic acid and decreases in arachidonic acid. We describe serum docosahexaenoic, eicosapentaenoic, and arachidonic acid concentrations over 13 years (1997-2012) across four study waves and serum fatty acid composition over 4 years (2006-2012) between two study waves according to age groups by sex in the same subjects. We included 443 men and 435 women aged 40-79 years at baseline. Serum arachidonic acid concentrations increased in all sex and age groups over 13 years, and eicosapentaenoic or docosahexaenoic acid concentrations increased in males and females who were younger and middle-aged at baseline. Only serum arachidonic acid composition increased over 4 years in men and women who were 40 69 years at baseline, even after adjustment for arachidonic acid intake. These findings suggest a secular increase trend in serum arachidonic acid levels over 13 years among randomly selected community-dwelling middle-aged and elderly Japanese. PMID- 25441968 TI - Nurse practitioners: who we are, and who we are not. PMID- 25441969 TI - Impact of Affordable Care Act on children's oral health: states hold the key. PMID- 25441970 TI - Vitamin D deficiency and acute lower respiratory infections in children younger than 5 years: identification and treatment. AB - INTRODUCTION: Acute lower respiratory infection (ALRI) is a leading cause of childhood mortality. Research suggests that vitamin D deficiency (VDD) puts children at risk for ALRI. The purpose of this review is to examine ALRI and VDD in children 5 years and younger. Common etiologies, diagnosis, prevention, treatment of ALRI, and recommendations for vitamin D supplementation are summarized. METHOD: Databases were searched for studies investigating VDD and ALRI in children. Independent reviewers assessed the internal validity of the studies. RESULTS: Of 18 studies examined, VDD was found to be associated with increased risk or severity of ALRI in 13 studies; associations were not found in 4 studies. In one study it was found that high maternal vitamin D levels was associated with ALRI in infants. DISCUSSION: Vitamin D supplementation is a low cost, low-risk intervention that providers should consider for children, especially those at high risk for ALRI. Practitioners should follow current recommendations when prescribing vitamin D supplementation for infants and children. PMID- 25441971 TI - Clearing the cervical spine in Plato's cave. PMID- 25441972 TI - Nonoperative care or noncare for thoracolumbar spine fractures? Questioning the unthinkable. PMID- 25441973 TI - Current evidence on catastrophizing and fear avoidance beliefs in low back pain patients. PMID- 25441974 TI - Moral responsibility and free will: A meta-analysis. AB - Fundamental beliefs about free will and moral responsibility are often thought to shape our ability to have healthy relationships with others and ourselves. Emotional reactions have also been shown to have an important and pervasive impact on judgments and behaviors. Recent research suggests that emotional reactions play a prominent role in judgments about free will, influencing judgments about determinism's relation to free will and moral responsibility. However, the extent to which affect influences these judgments is unclear. We conducted a meta-analysis to estimate the impact of affect. Our meta-analysis indicates that beliefs in free will are largely robust to emotional reactions. PMID- 25441975 TI - Scaling sporting equipment for children promotes implicit processes during performance. AB - This study investigated whether children who used scaled equipment compared to full size equipment during a motor task demonstrated reduced conscious involvement in performance. Children (9-11 years) performed a tennis hitting task in two attention conditions (single-task and dual-task) using two types of equipment (scaled and full size). A more skilled group and a less skilled group were formed using hitting performance scores. The more skilled group displayed greater working memory capacity than the less skilled group. For both groups, hitting performance and technique were better when scaled equipment was used. Hitting performance when using scaled equipment was not disrupted in either group by a cognitively demanding secondary task; however, performance was disrupted in the less skilled group when using full size equipment. We conclude that equipment scaling may reduce working memory engagement in motor performance and discuss the findings in the context of implicit motor learning theory. PMID- 25441976 TI - Iconic memory for the gist of natural scenes. AB - Does iconic memory contain the gist of multiple scenes? Three experiments were conducted. In the first, four scenes from different basic-level categories were briefly presented in one of two conditions: a cue or a no-cue condition. The cue condition was designed to provide an index of the contents of iconic memory of the display. Subjects were more sensitive to scene gist in the cue condition than in the no-cue condition. In the second, the scenes came from the same basic-level category. We found no difference in sensitivity between the two conditions. In the third, six scenes from different basic level categories were presented in the visual periphery. Subjects were more sensitive to scene gist in the cue condition. These results suggest that scene gist is contained in iconic memory even in the visual periphery; however, iconic representations are not sufficiently detailed to distinguish between scenes coming from the same category. PMID- 25441977 TI - Effects of an 8-week meditation program on the implicit and explicit attitudes toward religious/spiritual self-representations. AB - Explicit self-representations often conflict with implicit and intuitive self representations, with such discrepancies being seen as a source of psychological tension. Most of previous research on the psychological effects of mindfulness meditation has assessed people's self-attitudes at an explicit level, leaving unknown whether mindfulness-meditation promotes changes on implicit self representations. Here, we assessed the changes in implicit and explicit self related religious/spiritual (RS) representations in healthy participants following an 8-week mindfulness-oriented meditation (MOM) program. Before and after meditation, participants were administered implicit (implicit association test) and explicit (self-reported questionnaires) RS measures. Relative to control condition, MOM led to increases of implicit RS in individuals whit low pre-existing implicit RS and to more widespread increases in explicit RS. On the assumption that MOM practice may enhance the clarity of one's transcendental thoughts and feelings, we argued that MOM allows people to transform their intuitive feelings of implicit RS as well as their explicit RS attitudes. PMID- 25441978 TI - Osseous resective surgery with and without fibre retention technique in the treatment of shallow intrabony defects: a split-mouth randomized clinical trial. AB - AIM: The aim of this split-mouth clinical trial was to compare the effectiveness of Apically Positioned Flap with Fibre Retention Osseous Resective Surgery (FibReORS) or Osseous Resective Surgery (ORS) in the treatment of periodontal pockets associated with intrabony defects <= 3 mm at posterior natural teeth. MATERIALS AND METHODS: Twenty-six posterior sextants requiring osseous resective surgery were selected in 13 chronic periodontitis patients: 13 sextants were randomly assigned to ORS and 13 to FibReORS. Clinical evaluation of probing depth (PD), gingival recession and clinical attachment level was performed at baseline, 6 and 12 months postoperatively. Periapical radiographs were taken prior and after surgical treatment, at 6- and 12-month follow-up. RESULTS: Ostectomy amounted to 1.0 +/- 0.3 mm in the ORS group and to 0.4 +/- 0.2 mm in the FibReORS group. At 12-month examination PD changes did not significantly differ between the experimental groups. ORS group showed significantly (p < 0.001) greater clinical attachment loss (2.2 +/- 1.0 mm versus 1.0 +/- 0.6 mm), radiographic bone resorption (0.43 +/- 0.08 mm versus 0.13 +/- 0.09 mm) and post-operative patient discomfort compared to FibReORS. CONCLUSION: FibReORS resulted in similar PD reduction, but less ostectomy, clinical attachment loss and patient morbidity compared to ORS. PMID- 25441981 TI - In vitro antifilarial activity of Azadirachta indica aqueous extract through reactive oxygen species enhancement. AB - OBJECTIVE: To evaluate an aqueous preparation from the Azadirachta indica leaves (AEA) against Setaria cervi (S. cervi), a model filarial parasite. METHOD: In vitro efficacy of AEA was evaluated against S. cervi through estimation of relative motility value, dye exclusion test and MTT assay. Visible morphological alterations were monitored using conventional microscopic techniques in microfilariae and haematoxylin-eosin stained sections of AEA-treated adults. RESULTS: Enhancement of reactive oxygen species in S. cervi treated with AEA was established through alteration in the activity of glutathione S-transferase, superoxide dismutase, catalase, peroxidase and level of superoxide anion and reduced glutathione. CONCLUSION: In vitro filaricidal activity of AEA is possibly through disturbing redox homeostasis by down-regulating and altering the level of some key antioxidants and regulatory enzymes like reduced glutathione, glutathione S-transferase, superoxide dismutase, catalase and glutathione peroxidase of S. cervi. PMID- 25441980 TI - The prevalence and the risk factors of testosterone deficiency in newly diagnosed and previously known type 2 diabetic men. AB - INTRODUCTION: While the epidemiology of testosterone deficiency has been well described in men with previously known type 2 diabetes mellitus (T2DM), it was less reported in those with untreated, newly diagnosed T2DM. AIM: The aim of this study was to investigate the prevalence and the risk factors of testosterone deficiency of men with newly diagnosed T2DM. METHODS: The cross-sectional study included 105 men (mean age: 61.2 +/- 6.8 years) with previously known T2DM and another 81 (57.8 +/- 8.8 years) with newly diagnosed T2DM. All received health checkup and sex hormone measurement at our institute in 2009. MAIN OUTCOME MEASURES: We calculated the prevalence and explored the risk factors of low total (<300 ng/dL) and free (<6 ng/dL) testosterone in men with newly diagnosed and previously known T2DM. RESULTS: Men with previously known T2DM were older and had higher diastolic pressure and greater fasting glucose. There was no significant difference in total (358.0 [155.0] ng/dL vs. 363.0 [154.0] ng/dL, P=0.68) and free (7.2 [2.5] ng/dL vs. 7.4 [2.4]ng/dL, P=0.84) testosterone and sex-hormone binding globulin (SHBG) (27.3 [22.3]nmol/L vs. 28.7 [14.9]nmol/L, P=0.46). The prevalence of low total and free testosterone was 28.4% and 21.0%, respectively, in men with newly diagnosed T2DM, and was 26.7% and 19.0% in those with previously known T2DM. In men with previously known T2DM, better glycemic control (HbA1c <7%) was associated with a higher level of total testosterone and a lower risk of low total testosterone. Men with newly diagnosed and previously known T2DM shared similar risk factors of low total testosterone, including high HbA1c (>= 7%), low SHBG (<20 nmol/L), obesity, hyperuricemia, hypertriglycemia, and metabolic syndrome. Elevated prostate-specific antigen was a protective factor of low total testosterone. However, none of these factors was associated with low free testosterone. CONCLUSIONS: The prevalence and the risk factors of testosterone deficiency are similar between newly diagnosed and previously known type 2 diabetic men. PMID- 25441979 TI - T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases. AB - Neuroinflammation is involved in several neurodegenerative disorders and emerging evidence indicates that it constitutes a critical process that is required for the progression of neurodegeneration. Microglial activation constitutes a central event in neuroinflammation. Furthermore, microglia can not only be activated with an inflammatory and neurotoxic phenotype (M1-like phenotype), but they also can acquire a neurosupportive functional phenotype (M2-like phenotype) characterised by the production of anti-inflammatory mediators and neurotrophic factors. Importantly, during the past decade, several studies have shown that CD4(+) T cells infiltrate the central nervous system (CNS) in many neurodegenerative disorders, in which their participation has a critical influence on the outcome of microglial activation and consequent neurodegeneration. In this review, we focus on the analysis of the interplay of the different sub-populations of CD4(+) T-cells infiltrating the CNS and how they participate in regulating the outcome of neuroinflammation and neurodegeneration in the context of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. In this regard, encephalitogenic inflammatory CD4(+) T-cells, such as Th1, Th17, GM CSF-producer CD4(+) T-cells and gammadeltaT-cells, strongly contribute to chronic neuroinflammation, thus perpetuating neurodegenerative processes. In contrast, encephalitogenic or meningeal Tregs and Th2 cells decrease inflammatory functions in microglial cells and promote a neurosupportive microenvironment. Moreover, whereas some neurodegenerative disorders such as multiple sclerosis, Parkinson's disease and Alzheimer's disease involve the participation of inflammatory CD4(+) T-cells 'naturally', the physiopathology of other neurodegenerative diseases, such as amyotrophic lateral sclerosis, is associated with the participation of anti-inflammatory CD4(+) T-cells that delay the neurodegenerative process. Thus, current evidence supports the hypothesis that the involvement of CD4(+) T-cells against CNS antigens constitutes a key component in regulating the progression of the neurodegenerative process. PMID- 25441982 TI - Immune stimulatory activity of BRP-4, an acidic polysaccharide from an edible plant, Basella rubra L. AB - OBJECTIVE: To evaluated the immunomodulatory effect of BRP-4, an acidic polysaccharide from Basella rubra (B. rubra) L on the macrophage activity. METHODS: Phagocytic activity was determined by the ingestion of Latex Beads Rabbit IgG-FITC using the fluorescent microscopy and flow cytometry analysis and nitric oxide production was measured using Griess reaction assay. RESULTS: An enhanced production of NO was observed at 10 and 100 MUg/mL of BRP-4. The phagocytic activity of macrophage was enhanced in BRP-4 treated RAW264.7 cells. BRP-4 combined with concanavalin A (Con A) provided obvious promotion and strengthening of the proliferation of the splenocytes. CONCLUSIONS: BRP-4, polysaccharide isolated from B. rubra, is suggested to activate macrophage function and stimulate splenocyte proliferation. The strong immunomodulatory activity of BRP-4 confirmed its good potential as an immunotherapeutic adjuvant. PMID- 25441983 TI - Specific primers design based on the superoxide dismutase b gene for Trypanosoma cruzi as a screening tool: Validation method using strains from Colombia classified according to their discrete typing unit. AB - OBJECTIVE: To classify 21 new isolates of Trypanosoma cruzi (T. cruzi) according to the Discrete Typing Unit (DTU) which they belong to, as well as tune up a new pair of primers designed to detect the parasite in biological samples. METHODS: Strains were isolated, DNA extracted, and classified by using three Polymerase Chain Reactions (PCR). Subsequently this DNA was used along with other isolates of various biological samples, for a new PCR using primers designed. Finally, the amplified fragments were sequenced. RESULTS: It was observed the predominance of DTU I in Colombia, as well as the specificity of our primers for detection of T. cruzi, while no band was obtained when other species were used. CONCLUSIONS: This work reveals the genetic variability of 21 new isolates of T. cruzi in Colombia.Our primers confirmed their specificity for detecting the presence of T. cruzi. PMID- 25441984 TI - Phospholipase C from Pseudomonas aeruginosa and Bacillus cereus; characterization of catalytic activity. AB - OBJECTIVE: To study characteristics of phospholipases C (PLCs), their importance for producing microorganisms as well as the potential of their use for industrial purposes. METHOD: PLC from Bacillus cereus (B. cereus) D101 was selected as an example of Gram-positive PLCs and PLC from Pseudomonas aeruginosa (P. aeruginosa) D183 of Gram-negative ones. Enzymes were partially purified by ammonium sulfate precipitation followed by membrane dialysis. Partially purified preparations were used to study effect of different factors on activities as well as in substrate specificity tests which were conducted using a turbidimetric assay method. RESULTS: Maximum activity was at pH 7 and 8 and 40 degrees C for P. aeruginosa PLC, and pH 8-10 and 37 degrees C for B. cereus PLC. Both PLCs were inhibited by Pi at 5 mM or higher, whereas, PLC from B. cereus only was inhibited by EDTA. Activity of P. aeruginosa PLC was not affected by removing Zn(2+) ions from reaction mixture or their replacement with Ca(2+), Ba(2+), Mg(2+) or Mn(2+) ions. Vis-a-vis, activity of B. cereus PLC was found to be metal ion dependent. PLCs from both isolates were relatively thermostable and showed maximum affinity toward phosphatidylcholine. Sphingomyelin and phosphatidylethanolamine were not good substrates and phosphatidylinositol, phosphatidylserine, phosphatidylglycerol and cardiolipin could be considered non-substrates. CONCLUSION: Human body physiological conditions could favor activity of P. aeruginosa and B. cereus PLCs. These enzymes may participate in phosphate scavenging and virulence of producing isolates but not in autolysis. PLCs from both isolates are potential candidates for industrial use. PMID- 25441985 TI - Inhibitive effect of IL-24 gene on CD133(+) laryngeal cancer cells. AB - OBJECTIVE: To explore the inhibitive and apoptosis inductive effect of IL-24 genes on CD133(+) laryngeal cancer cells in Hep-2 line. METHODS: Human peripheral blood monocytes were isolated. The total RNA was extracted by using Trizol method and reverse transcripted into cDNA using RT-PCR method. Primers P1 and P2 was designed for the amplification of human IL-24 genes. After confirmation of agarose gel electrophoresis tests, TA was cloned into pMD19-T simple vector. Nhe I and Xho I double digesting human IL-24 and pIRES2-ZsGreen1 and eukaryotic expression vector were used to establish the pIRES2-ZsGreen1-hIL-24 vector, and detected by enzyme digestion and gene sequencing methods. Flow cytometry (FCM) was used to isolate CD133(+) cells from Hep-2 cells. CD133(+) cells were transfected with pIRES2-ZsGreen1-hIL-24 through liposome 2000. After detection, MTT and FCM were used to observe the effect of IL-24 gene on CD133(+) laryngeal cancer Hep-2 cells. RESULTS: Lipotin mediated transfection of recombinant pIRES2 ZsGreen1-hIL-24 plasmid into CD133(+) Hep-2 could expressed IL-24 gene in cells stably. MTT results showed that IL-24 transfected group was significantly suppressed compared to empty vector group and control group (P<0.05); FCM results showed that the apoptosis rate of experimental group increased significantly compared to empty vector group and control group (P<0.05). CONCLUSIONS: IL-24 gene expressions can inhibit proliferation of CD133(+) laryngeal cells in Hep-2 line and promote their apoptosis. PMID- 25441986 TI - Adenovirus-mediated NDRG2 inhibits the proliferation of human renal cell carcinoma cell line OS-RC-2 in vitro. AB - OBJECTIVE: To investigate the inhibitory effects of adenovirus-mediated NDRG2 on the proliferation of human renal cell carcinoma cell line OS-RC-2 in vitro. METHOD: NDRG2 was harvested by RT-PCR, confirmed by DNA sequencing, and then cloned into the eukaryotic expression vector pIRES2-EGFP, which encodes green fluorescent protein (GFP), to construct pIRES2-EGFP-NDRG2 plasmid. OS-RC-2 cells with NDRG2 negative expression were transfected with pIRES2-EGFP-NDRG2 plasmid. The growth of transfected OS-RC-2 cells was observed under light and fluorescence microscopes. After colony-forming cell assays, cell proliferation detection and MTT assays, the growth curves of cells in each group were plotted to investigate the inhibitory effects of adenovirus-mediated NDRG2 on the proliferation of OS-RC 2 cells. Cell cycle was determined by flow cytometry. Confocal laser scanning microscopy showed that NDRG2 protein was specifically located on subcellular organelle. RESULTS: A eukaryotic expression vector pIRES2-EGFP-NDRG2 was successfully constructed. After NDRG2 transfection, the growth of OS-RC-2 cells was inhibited. Flow cytometry showed that cells were arrested in S phase but the peak of cell apoptosis was not present, and confocal laser scanning microscopy showed that NDRG2 protein was located in mitochondrion. CONCLUSIONS: NDRG2 can significantly inhibit the proliferation of OS-RC-2 cells in vitro and its protein is specifically expressed in the mitochondrion. PMID- 25441987 TI - Monitoring of prostate cancer growth and metastasis using a PSA luciferase report plasmid in a mouse model. AB - OBJECTIVE: To construct a PSA luciferase report plasmid and monitor the growth and metastasis of prostate cancer after emasculation in SCID mice. METHODS: PSA promoter sequence and luciferase gene were amplified by PCR and subsequently inserted into pZsGreen1-1 vector to construct pPSA-FL-Luc vector. LNCaP cells that were stably transfected with pPSA-FL-Luc were used to establish a SCID mouse xenograft model. Then, the growth and metastasis of prostate cancer were monitored via living imaging. RESULTS: We successfully constructed a PSA luciferase plasmid, pPSA-FL-Luc. DHT enhanced luciferase activity in a concentration-dependent manner in 293T cells with pPSA-FL-Luc transfection. Prostate cancer SCID mouse model was established with pPSA-FL-Luc transfected LNCaP cells. In tumor bearing mice with or without emasculation, pPSA-FL-Luc plasmid was applied to monitored tumor growth and metastasis based on bioluminescence imaging. CONCLUSIONS: We construct a pPSA-FL-Luc plasmid, which stably expresses luciferase and can be applied to monitor tumor development in a prostate SCID mouse model. PMID- 25441988 TI - RhoA/ROCK pathway regulates hypoxia-induced myocardial cell apoptosis. AB - OBJECTIVE: To observe the regulatory effects of RhoA/ROCK pathway on the apoptosis of cardiac myocyte induced by anoxia and its mechanism. METHODS: The model of cardiac myocyte anoxia was established. The beat pulsations and apoptosis rates after 1 h, 3 h, 6 h, 9 h and 12 h of anoxia were recorded and the expressions of RhoA, ROCK1/2, p-PI3K, p-AKT and caspae-3 were detected, too. The apoptosis and the expressions of related proteins were detected after RNAi of RhoA and the inhibition of ROCK by Y-27632. RESULTS: The beat pulsations after 1 h, 3 h, 6 h, 9 h and 12 h decreased gradually but the apoptosis rates increased gradually, and the expressions of RhoA, ROCK1/2, p-PI3K, p-AKT and caspase-3 were increasing along with the increasing duration of anoxia. The apoptotic rates after 1 h, 3 h, 6 h, 9 h and 12 h of anoxia were (4.360.98)%, (8.362.12)%, (15.323.62)%, (18.684.83)% and (24.566.22)%, respectively and decreased more significantly than control group in different time points of anoxia (P<0.05), and the expressions of RhoA, ROCK1/2, p-PI3K, p-AKT and caspase-3 decreased significantly (P<0.05). The apoptosis rate and the expressions of RhoA, ROCK1/2, p-PI3K, p-AKT and caspase-3 decreased significantly (P<0.05) after the inhibition of ROCK by Y-27632 (P<0.05). CONCLUSIONS: RhoA/ROCK pathway plays a critical role in the regulation of the apoptosis of cardiac myocyte induced by anoxia, which may be accompanied by regulating the activity of PI3K/AKT/Caspase-3 pathway. PMID- 25441989 TI - Transcellular transport characteristics of huperzine alone or in combination with ginkgolide B across Caco-2 and Madin-Darby canine kidney cell monolayer. AB - OBJECTIVE: To study the various processes involved in transcellular transport (TT) of huperzine A alone or in combination with ginkgolide B in Caco-2 and Madin Darby canine renal (MDCK) cell monolayer. METHODS: The transepithelial passage was assayed in the apical-to-basolateral (AP to BL) direction and opposite direction (BL to AP) in both cell lines. The determination of huperzine A and ginkgolide B were performed by high performance liquid chromatography (HPLC). The passage rates of huperzine A and ginkgolide B were calculated. Bi-directional TT (absorption and secretion) were taken in huperzine A and ginkgolide B in Caco-2 and MDCK cell monolayer. RESULTS: TT absorption and secretion kinetics of huperzine A and ginkgolide B across two cells existed at the same time. The passage rates of huperzine A were increased significantly with adding different concentrations of ginkgolide B. CONCLUSIONS: The compound preparations of HA in combination with GB for dementia caused by cerebral ischemic have synergistic effects on the pharmacodynamics, and improve the bioavailability through BBB. PMID- 25441990 TI - Effect of recombinant human bone morphogenetic protein 2/poly-lactide-co-glycolic acid (rhBMP-2/PLGA) with core decompression on repair of rabbit femoral head necrosis. AB - OBJECTIVE: To observe the effect of recombinant human bone morphogenetic protein 2/poly-lactide-co-glycolic acid (rhBMP-2/PLGA) with core decompression on repair of rabbit femoral head necrosis. METHOD: Bilateral femoral head necrosis models of rabbit were established by steroid injection. A total of 48 rabbits (96 femoral head necrosis) were randomly divided into 4 groups: Group A, control group with12 rabbits, 24 femoral head necrosis; Group B, treated with rhBMP 2/PLGA implantation after core depression, with 12 rabbits, 24 femoral head necrosis; Group C, treated with rhBMP-2 implantation after core depression, with 12 rabbits, 24 femoral head necrosis; Group D treated with core depression group without implantation, with 12 rabbits, 24 femoral head necrosis. All animals were sacrificed after 12 weeks. The ability of repairing bone defect was evaluated by X-ray radiograph. Bone mineral density analysis of the defect regions were used to evaluate the level of ossification. The morphologic change and bone formation was assessed by HE staining. The angiogenesis was evaluated by VEGF immunohistochemistry. RESULTS: The osteogenetic ability and quality of femoral head necrosis in group B were better than those of other groups after 12 weeks by X-ray radiograph and morphologic investigation. And the angiogenesis in group B was better than other groups. Group C had similar osteogenetic quality of femoral head necrosis and angiogenesis with group D. CONCLUSION: The treatment of rhBMP 2/PLGA implantation after core depression can promote the repair of rabbit femoral head necrosis. It is a promising and efficient synthetic bone material to treat the femoral head necrosis. PMID- 25441991 TI - Effect of alprostadil combined with Diammonium glycyrrhizinate on renal interstitial fibrosis in SD rats. AB - OBJECTIVE: To observe effect of alprostadil combined with Diammonium glycyrrhizinate on renal interstitial fibrosis in SD rats. METHODS: A total of 75 SD rats were randomly divided into A, B, C, D, E groups with 15 in each group. Rats in group A served as the control group received just only but tissue separation without modeling operation, while model of unilateral ureteral obstruction (UUO) was established in B, C, D, E groups. Rats in A, B group were given saline lavage placebo treatment, while rats in C, D, E groups were given diammonium glycyrrhizinate and alprostadil injection. Five rats were sacrificed 1, 2, 3 weeks after modeling, serum creatinine level of femoral venous blood was determined. Transforming growth factor - beta1 (TGF - beta1) and concentration of connective tissue growth factor (CTGF) were also detected by using ELISA. Line renal interstitial tissue was taken after HE staining, renal interstitial TGF - beta1 and CTGF expression were detected by using immunohistochemical method. RESULTS: Serum creatinine levels of B, C, D, E group at different time points in were significantly higher than that of group A (P<0.05); serum creatinine levels in group B were significantly higher than that of C, D, E group at each time point (P<0.05). Serum creatinine level of Group E was significantly lower than C, D group after 2, 3 weeks (P<0.05). Rats in A group at each time point showed no significant changes in TGF - beta1 and CREA concentration in serum and kidney tissues (P>0.05); while serum and kidney tissue TGF - beta1, concentration of CREA, expression of rats in B, C, D, E groups showed a gradual increasing trend over time. TGF - beta1 and CREF of Group B in serum and kidney tissues at each time point were significantly higher than that of the other groups (P<0.05). TGF beta1 and CREF of Group E in serum and kidney tissues at each time point were significantly lower than that of B, C, D group at all time points in serum and kidney tissues (P<0.05). CONCLUSIONS: Alprostadil combined with diammonium glycyrrhizinate can significantly lower the expression of TGF - beta1 and CTGF in serum and tissues of SD rat with renal interstitial fibrosis, thus inhibit rat renal interstitial fibrosis process. It has synergy protective effect. PMID- 25441992 TI - Effect of captopril on serum TNF-alpha level in acute lung injury rats induced by HCL. AB - OBJECTIVE: To observe the effect of captopril on the tumor necrosis factor-alpha (TNF-alpha) level and arterial blood gases in acute lung injury (ALI) induced by HCL in rats, and to analyze its protective mechanism. METHODS: Fifty Wistar rats were selected and randomly divided into three groups, with 20 rats in Group I and II, respectively and 10 animals in Group III. ALI model was constructed by intratracheal injection of diluted hydrochloric acid (pH=1.25, 1.2 mL/kg). Group I rats received not any treatment after construction of ALI model. Group II rats were treated with captopril (5 mg/kg, i.p.) 5 min after induction of ALI. Group III served as normal control without any treatment. Ninety minutes after construction of ALI model, all the rats were sacrificed. Blood was withdrawn for detection of TNF-alpha level and arterial blood gases index. And lung tissue slices of the three groups were prepared for observation of pathologic histology changes. RESULTS: TNF-alpha level in serum of Group I and II rats was significantly higher than that in Group III (P<0.05), while TNF-alpha level in serum of Group II was significantly lower in Group I (P<0.05). PaCO2 level was significantly higher (P<0.05), while PaO2 was significantly lower (P<0.05) in Group I and II rats than those in Group III. PaCO2 was significantly lower (P<0.05) and PaO2 was significantly higher (P<0.05) in Group II than those in Group I. Histological observation showed diffuse congestion and severe edema of lung tissue, obvious thickening and structure damage of alveolar walls and a large amount of neutrophil infiltration in Group I rats. Group II rats showed mild edema of lung tissue; only a small portion of alveolar walls showed thickening and only a few of neutrophil infiltration could be observed. The degree of injury was remarkably slighter than that of Group I rats. Group III rats showed clear lung tissue structure and normal morphology; alveolar walls were uniform and the margin was smooth and few neutrophil could be observed. CONCLUSIONS: Captopril can significantly reduce serum TNF-alpha level, elevate PaO2 and reduce PaCO2 in rats with ALI. It has a protective effect on ALI rats. PMID- 25441993 TI - Seroepidemiology and genetic characterization of hepatitis E virus in western Yunnan Province. AB - OBJECTIVE: To investigate the seroepidemiology and genetic characterization of hepatitis E virus (HEV) in western Yunnan Province. METHODS: Questionnaire survey was conducted among 1638 residents in western Yunnan Province using stratified sampling method. Enzyme-linked immunosorbent assay was used to detect serum anti HEV IgG and IgM. HEV RNA was extracted from patients with serum anti-HEV IgM positive. The open reading flame 2 (ORF2) of HEV that was amplified by nested RT PCR was sequenced and compared with standard HEV genotypes 1-4. RESULTS: Serum anti-HEV positive was found in 13.92% (228/1638) residents. The HEV infection rate in males was significantly higher than that in females with a ratio of 1.47 (P<0.01). 20-30 and 30-40 years old young men showed the highest incidence, 20.57% and 20.78%, respectively. While 10-20 and 20-30 years old young women exhibited the highest infection rate, 11.85% and 15.60%, respectively. According to occupation, the highest HEV infection rate was observed in farmers (20.35%) and migrants (16.50%). We isolated 10 individual HEV isolates from 31 patients with serum anti-HEV IgM positive. Homology analysis and phylogenetic analysis indicated that these 10 HEV isolates belonged to HEV genotype 4 with the homology of 78.65%-94.71%. CONCLUSIONS: The HEV infection rate is high in western Yunnan Province. HEV genotype 4 is the leading cause of HEV infection and young farmers and migrants are the main infected population. PMID- 25441994 TI - Curative effect of BCG-polysaccharide nuceic acid on atopic dermatitis in mice. AB - OBJECTIVE: To explore the effect of bacilli Galmette-Gurin (BCG)-polysaccharide nuceic acid on atopic dermatitis in mice and its mechanism. METHOD: Forty NC/Nga mice were selected and randomly divided into Group A (model group), Group B (dexamethasone treatment group), Group C (BCG polysaccharide nucleic acid treatment group) and Group D (control group) with 10 mice in each group. Atopic dermatitis model were constructed by applying 2, 4-dinitrochlorobenzene on the skin of the mice. Mice in Group D were treated with acetone solution (100 MUL) on the foot pad and abdomen after hair removal at the age of 7 weeks, then on ear skin at the age of 8-13 weeks. For mice in A, B and C groups, 100 MUL of acetone solution containing 2, 4-dinitrochlorobenzene was applied to the foot pad and the abdomen at the age of 7 weeks, then on ear skins at the age of 8 to 13 weeks. At the age of 7-13 weeks, mice in Group A and Group D were treated with 100 MUL saline (i.p.); mice were given dexamethasone (0.1 mL/kg, i.p.) every other day for 7 weeks in Group B; mice were treated with BCG polysaccharide nucleic acid (0.5 mg/kg, i.p.) every other day for 7 weeks in Group C. The ear thickness was measured every week and the scratching frequency was recorded 1 times for 10 min a week. The mice were sacrificed after the last administration of drugs. IgE, IL 4, IL-10, IL-12 and IFN-gamma in the plasma were detected using ELISA, and RT-PCR method was employed to detect the concentrations of IL-4, IL-10, IL-12 and IFN gamma proteins. After HE staining, the lesion degree of inflammation in ear tissue was observed microscopically. RESULTS: The ear thickness and scratching frequency of Group A were significantly higher than those in group B, C and D (P<0.05), and there was no significant difference between Group B and C (P>0.05); the concentrations of IgE, IL-4 and IL-10 in the plasma and the expression of IL 4, IL-10 mRNA in the spleen tissues of Group A, B and C were all significantly higher than those of Group D (P<0.05); the concentrations of plasma IL-12 and IFN gamma, and spleen protein expression of IL-12 and IFN-gamma in Group C mice were significantly higher than those of Group A (P<0.05). Histological observation showed obvious ear tissue exudation, erythema, swelling, desquamation of skin, and scabbing in Group A. Histopathology of the skin lesion also showed hyperkeratosis, focal-parakeratosis, stratum spinosum hypertrophy, mild sponge like edema, a large number of lymphocytes along with plasma cell infiltration in dermis, angiectasis and hyperemia in Group A, while degree of ear skin lesion in Group B and D mice was significantly lighter than that of Group A. CONCLUSIONS: BCG polysaccharide nucleic acid can significantly reduce the serum IgE concentrations, increase the expression of IL-12, IFN-gamma protein, correct the imbalance of Thl/Th2 in atopic dermatitis mice, and has obvious inhibitory effect on atopic dermatitis in NC/Nga mice. PMID- 25441995 TI - Effect of ulinastatin combined rivaroxaban on deep vein thrombosis in major orthopedic surgery. AB - OBJECTIVE: To explore the effect of ulinastatin (UTI) continuous infusion combined Rivaroxaban on the deep vein thrombosis in patients undergoing major orthopedic surgery. METHODS: Forty-five patients undergoing major orthopedic surgery were randomly divided into three groups:ulinastatin continuous infusion (Uc) group, ulinastatin single injection (Us) group and control (C) group. All patients received patient-controlled intravenous analgesia (PCIA) after operation, and took Rivaroxaban 10 mg orally 12 hours after operation. Ulinastatin (5 000 U/kg) was given intravenously to both Uc and Us groups preoperatively. Group C was given isometric normal saline, group Uc was pumped UTI continuous intravenously at the end of surgery (10 000 U/kg) to 48 hours through PCIA pump. The values of hematocrit (HCT), thrombomodulin (TM), Interleukin (IL-6), thrombin-antithrombin complex (TAT), D-Dimer (D-D) were normally tested before surgery (T1), at the end of the surgery (T2), 12 hours (T3), 24 hours (T4) and 48 hours (T5) after surgery. RESULTS: Compared with T1, there was an upward tendency in TM, IL-6, TAT, and D-D after operation in group C group (P<0.05). The values of them were significantly increased from nearly 24 hour after surgery in Us group (P<0.05). In group Uc, there were no significant changes in these indices after operation (P>0.05). CONCLUSIONS: During the perioperative period, ulinastatin continuous infusion combined Rivaroxaban can correct blood hypercoagulability through different approaches in patients undergoing major orthopedic surgery. PMID- 25441996 TI - Cardiac cystic echinococcosis: Report of three cases. AB - We present a retrospective analysis of three cases of cardiac hydatidosis, who underwent surgery between 2010 and 2012. Two patients had a lesion in the interventricular septum, whereas one patient had the lesion in apicoinferior wall of LV. The diagnosis was made by echocardiography, but magnetic resonance imaging was utilized to assess cyst activity and extend of disease. All patients were placed on cardiopulmonary bypass. No postoperative complication or death occurred. The patients discharged uneventfully and all of them were free from hydatid disease at two years follow-up. We concluded that cardiac hydatid cysts should be removed surgically regardless of their location or extent, even in asymptomatic patients. PMID- 25441998 TI - Takotsubo cardiomyopathy and chronic obstructive pulmonary disease--reply. PMID- 25441997 TI - Takotsubo cardiomyopathy and chronic obstructive pulmonary disease. PMID- 25441999 TI - Functional assessment of coronary artery disease by intravascular ultrasound and computational fluid dynamics simulation. AB - Clinical trials have shown that functional assessment of coronary stenosis by fractional flow reserve (FFR) improves clinical outcomes. Intravascular ultrasound (IVUS) complements conventional angiography, and is a powerful tool to assess atherosclerotic plaques and to guide percutaneous coronary intervention (PCI). Computational fluid dynamics (CFD) simulation represents a novel method for the functional assessment of coronary flow. A CFD simulation can be calculated from the data normally acquired by IVUS images. A case of coronary heart disease studied with FFR and IVUS, before and after PCI, is presented. A three-dimensional model was constructed based on IVUS images, to which CFD was applied. A discussion of the literature concerning the clinical utility of CFD simulation is provided. PMID- 25442000 TI - Short QT syndrome presenting as syncope: how short is too short? AB - We report the case of a 52-year-old man who presented to our emergency department (ED) after three episodes of syncope in the seven hours before admission. During his stay in the ED he had recurrent ventricular tachycardia (VT) requiring external electrical cardioversion. A 12-lead electrocardiogram (ECG) showed a short QT (SQT) interval (270 ms, QTc 327 ms), with frequent R-on-T extrasystoles triggering sustained polymorphic VT. After exclusion of other precipitating causes, the patient was diagnosed as having SQT syndrome (SQTS) according to the Gollob criteria. To our knowledge, this is the first known documentation of an SQT-caused arrhythmic episode on a 12-lead ECG, as well as the first reported case of SQTS in Portugal. The patient received an implantable cardioverter defibrillator and was discharged. At a follow-up assessment 14 months later he was symptom-free, interrogation of the device showed no arrhythmic events, and the ECG showed a QT interval of 320 ms (QTc 347 ms). PMID- 25442001 TI - Atrial tachycardia treated by coil embolization of a giant coronary artery fistula. AB - Coronary artery fistulas are the second most frequently seen coronary anomaly following abnormalities of coronary artery origin and distribution. A coronary fistula is defined as a direct communication between a coronary artery and any cardiac chamber or vessel. Treatment options include percutaneous embolization and surgical intervention. Herein, we present a case of a giant coronary artery fistula and right atrial tachycardia that was induced during a diagnostic electrophysiologic study but was not inducible after the successful treatment of the fistula. This is the first case indicating this association. PMID- 25442002 TI - A pharmacogenetic determinant of mu-opioid receptor antagonist effects on alcohol reward and consumption: evidence from humanized mice. AB - BACKGROUND: It has been proposed that therapeutic responses to naltrexone in alcoholism are moderated by variation at the mu-opioid receptor gene locus (OPRM1). This remains controversial because human results vary and no prospectively genotyped studies have been reported. We generated humanized mice carrying the respective human OPRM1 A118G alleles. Here, we used this model system to examine the role of OPRM1 A118G variation for opioid antagonist effects on alcohol responses. METHODS: Effects of naltrexone on alcohol reward were examined using intracranial self-stimulation. Effects of naltrexone or nalmefene on alcohol intake were examined in continuous access home cage two-bottle free choice drinking and operant alcohol self-administration paradigms. RESULTS: Alcohol lowered brain stimulation reward thresholds in 118GG mice in a manner characteristic of rewarding drugs, and this effect was blocked by naltrexone. Brain stimulation reward thresholds were unchanged by alcohol or naltrexone in 118AA mice. In the home cage, increased alcohol intake emerged in 118GG mice with increasing alcohol concentrations and was 33% higher at 17% alcohol. At this concentration, naltrexone selectively suppressed alcohol intake in 118GG animals to a level virtually identical to that of 118AA mice. No effect of naltrexone was found in the latter group. Similarly, both naltrexone and nalmefene were more effective in suppressing operant alcohol self-administration in 118GG mice. CONCLUSIONS: In a model that allows close experimental control, OPRM1 A118G variation robustly moderates effects of opioid antagonism on alcohol reward and consumption. These findings strongly support a personalized medicine approach to alcoholism treatment that takes into account OPRM1 genotype. PMID- 25442003 TI - Inhibiting Lateral Habenula Improves L-DOPA-Induced Dyskinesia. AB - BACKGROUND: A systematic search of brain nuclei putatively involved in L-3,4 dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson's disease shed light, notably, upon the lateral habenula (LHb), which displayed an overexpression of the ?FosB, ARC, and Zif268 immediate-early genes only in rats experiencing abnormal involuntary movements (AIMs). We thus hypothesized that LHb might play a role in LID. METHODS: ?FosB immunoreactivity, 2-deoxyglucose uptake, and firing activity of LHb were studied in experimental models of Parkinson's disease and LID. DeltaFosB-expressing LHb neurons were then targeted using the Daun02-inactivation method. A total of 18 monkeys and 55 rats were used. RESULTS: LHb was found to be metabolically modified in dyskinetic monkeys and its neuronal firing frequency significantly increased in ON L-DOPA dyskinetic 6 hydroxydopamine-lesioned rats, suggesting that increased LHb neuronal activity in response to L-DOPA is related to AIM manifestation. Therefore, to mechanistically test if LHb neuronal activity might affect AIM severity, following induction of AIMs, 6-hydroxydopamine rats were injected with Daun02 in the LHb previously transfected with beta-galactosidase under control of the FosB promoter. Three days after Daun02 administration, animals were tested daily with L-DOPA to assess LID and L-DOPA-induced rotations. Inactivation of ?FosB-expressing neurons significantly reduced AIM severity and also increased rotations. Interestingly, the dopaminergic D1 receptor was overexpressed only on the lesioned side of dyskinetic rats in LHb and co-localized with DeltaFosB, suggesting a D1 receptor mediated mechanism supporting the LHb involvement in AIMs. CONCLUSIONS: This study highlights the role of LHb in LID, offering a new target to innovative treatments of LID. PMID- 25442004 TI - Enhancement of stress resilience through histone deacetylase 6-mediated regulation of glucocorticoid receptor chaperone dynamics. AB - BACKGROUND: Acetylation of heat shock protein 90 (Hsp90) regulates downstream hormone signaling via the glucocorticoid receptor (GR), but the role of this molecular mechanism in stress homeostasis is poorly understood. We tested whether acetylation of Hsp90 in the brain predicts and modulates the behavioral sequelae of a mouse model of social stress. METHODS: Mice subjected to chronic social defeat stress were stratified into resilient and vulnerable subpopulations. Hypothalamic-pituitary-adrenal axis function was probed using a dexamethasone/corticotropin-releasing factor test. Measurements of Hsp90 acetylation, Hsp90-GR interactions, and GR translocation were performed in the dorsal raphe nucleus. To manipulate Hsp90 acetylation, we pharmacologically inhibited histone deacetylase 6, a known deacetylase of Hsp90, or overexpressed a point mutant that mimics the hyperacetylated state of Hsp90 at lysine K294. RESULTS: Lower acetylated Hsp90, higher GR-Hsp90 association, and enhanced GR translocation were observed in dorsal raphe nucleus of vulnerable mice after chronic social defeat stress. Administration of ACY-738, a histone deacetylase 6 selective inhibitor, led to Hsp90 hyperacetylation in brain and in neuronal culture. In cell-based assays, ACY-738 increased the relative association of Hsp90 with FK506 binding protein 51 versus FK506 binding protein 52 and inhibited hormone-induced GR translocation. This effect was replicated by overexpressing the acetylation-mimic point mutant of Hsp90. In vivo, ACY-738 promoted resilience to chronic social defeat stress, and serotonin-selective viral overexpression of the acetylation-mimic mutant of Hsp90 in raphe neurons reproduced the behavioral effect of ACY-738. CONCLUSIONS: Hyperacetylation of Hsp90 is a predictor and causal molecular determinant of stress resilience in mice. Brain-penetrant histone deacetylase 6 inhibitors increase Hsp90 acetylation and modulate GR chaperone dynamics offering a promising strategy to curtail deleterious socioaffective effects of stress and glucocorticoids. PMID- 25442006 TI - Maternal immune activation in nonhuman primates alters social attention in juvenile offspring. AB - BACKGROUND: Sickness during pregnancy is associated with an increased risk of offspring neurodevelopmental disorders. Rodent models have played a critical role in establishing causal relationships and identifying mechanisms of altered brain and behavior development in pups prenatally exposed to maternal immune activation (MIA). We recently developed a novel nonhuman primate model to bridge the gap between human epidemiological studies and rodent models of prenatal immune challenge. Our initial results demonstrated that rhesus monkeys given the viral mimic synthetic double-stranded RNA (polyinosinic:polycytidylic acid stabilized with poly-l-lysine) during pregnancy produce offspring with abnormal repetitive behaviors, altered communication, and atypical social interactions. METHODS: We utilized noninvasive infrared eye tracking to further evaluate social processing capabilities in a subset of the first trimester MIA-exposed offspring (n = 4) and control animals (n = 4) from our previous study. RESULTS: As juveniles, the MIA offspring differed from control animals on several measures of social attention, particularly when viewing macaque faces depicting the fear grimace facial expression. Compared with control animals, MIA offspring had a longer latency before fixating on the eyes, had fewer fixations directed at the eyes, and spent less total time fixating on the eyes of the fear grimace images. CONCLUSIONS: In the rhesus monkey model, exposure to MIA at the end of the first trimester results in abnormal gaze patterns to salient social information. The use of noninvasive eye tracking extends the findings from rodent MIA models to more human-like behaviors resembling those in both autism spectrum disorder and schizophrenia. PMID- 25442007 TI - Clinical and electrophysiological effects of D-serine in a schizophrenia patient positive for anti-N-methyl-D-aspartate receptor antibodies. PMID- 25442008 TI - Quantitative computed tomography-based finite element analysis predictions of femoral strength and stiffness depend on computed tomography settings. AB - The aim of the present study was to compare proximal femur strength and stiffness obtained experimentally with estimations from Finite Element Analysis (FEA) models derived from Quantitative Computed Tomography (QCT) scans acquired at two different scanner settings. QCT/FEA models could potentially aid in diagnosis and treatment of osteoporosis but several drawbacks still limit their predictive ability. One potential reason is that the models are still sensitive to scanner settings which could lead to changes in assigned material properties, thus limiting their results accuracy and clinical effectiveness. To find the mechanical properties we fracture tested 44 proximal femora in a sideways fall-on the-hip configuration. Before testing, we CT scanned all femora twice, first at high resolution scanner settings, and second at low resolution scanner settings and built 88 QCT/FEA models of femoral strength and stiffness. The femoral set neck bone mineral density, as measured by DXA, uniformly covered the range from osteoporotic to normal. This study showed that the femoral strength and stiffness values predicted from high and low resolution scans were significantly different (p<0.0001). Strength estimated from high resolution QCT scans was larger for osteoporotic, but smaller for normal and osteopenic femora when compared to low resolution scans. In addition, stiffness estimated from high resolution scans was consistently larger than stiffness obtained from low resolution scans over the entire femoral dataset. While QCT/FEA techniques hold promise for use in clinical settings we provided evidence that further improvements are required to increase robustness in their predictive power under different scanner settings and modeling assumptions. PMID- 25442005 TI - Imaging biomarkers associated with cognitive decline: a review. AB - In evaluating disease changes, it is critical to have measurements that are sensitive, specific, and reliable. Cognitive decline, particularly in the context of Alzheimer's disease, is an area that has attracted numerous recent studies, and the proposed biomarkers used in these investigations need to be validated. In this review, we highlight studies with important implications about the role of imaging biomarkers in cognitive decline and dementia as well as in distinguishing preclinical dementia before evidence of cognitive decline. Structural changes determined on cross-sectional and longitudinal magnetic resonance imaging provide early prediction of dementia, particularly when combined with other measures. Molecular imaging using positron emission tomography and single photon emission computed tomography tracers quantify the presence or activity of receptors, transporters, enzymes, metabolic pathways, and proteins. The newest developments in molecular imaging are described, and methods are compared. Distinguishing features of imaging biomarkers among dementias and the spectrum of preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease are described. Appropriate use criteria for positron emission tomography with amyloid tracers are delineated. Although these efforts are still in the early phase of development, there is great promise for further development in structural magnetic resonance imaging and positron emission tomography technologies. PMID- 25442009 TI - Promoting increased mechanical properties of tissue engineered neocartilage via the application of hyperosmolarity and 4alpha-phorbol 12,13-didecanoate (4alphaPDD). AB - Osteoarthritis, a degenerative disease of the load-bearing joints, greatly reduces quality of life for millions of Americans and places a tremendous cost on the American healthcare system. Due to limitations of current treatments, tissue engineering of articular cartilage may provide a promising therapeutic option to treat cartilage defects. However, cartilage tissue engineering has yet to recapitulate the functional properties of native tissue. During normal joint loading, cartilage tissue experiences variations in osmolarity and subsequent changes in ionic concentrations. Motivated by these known variations in the cellular microenvironment, this study sought to improve the mechanical properties of neocartilage constructs via the application of hyperosmolarity and transient receptor potential vanilloid 4 (TRPV4) channel activator 4alpha-phorbol 12,13 didecanoate (4alphaPDD). It was shown that 4alphaPDD elicited significant increases in compressive properties. Importantly, when combined, 4alphaPDD positively interacted with hyperosmolarity to modulate its effects on tensile stiffness and collagen content. Thus, this study supports 4alphaPDD-activated channel TRPV4 as a purported mechanosensor and osmosensor that can facilitate the cell and tissue level responses to improve the mechanical properties of engineered cartilage. To our knowledge, this study is the first to systematically evaluate the roles of hyperosmolarity and 4alphaPDD on the functional (i.e., mechanical and biochemical) properties of self-assembled neotissue. Future work may combine 4alphaPDD-induced channel activation with other chemical and mechanical stimuli to create robust neocartilages suitable for treatment of articular cartilage defects. PMID- 25442011 TI - Removal of Mycobacterium avium subspecies hominissuis (MAH) from drinking water by coagulation, flocculation and sedimentation processes. AB - There has been a growing concern over human exposure to Mycobacterium avium subspecies hominissuis (MAH) through drinking water due to its ubiquitous presence in natural waters and remarkable resistance to both chemical and physical disinfectants in drinking water treatment processes. However, little is known about the effectiveness of physico-chemical water treatment processes to remove MAH. Therefore, we determined the removal of MAH by alum coagulation, flocculation and sedimentation processes in optimized drinking water treatment conditions using standard jar test equipment. Contrary to the prevailing hypothesis, the results of this study show that removal of MAH by coagulation, flocculation and sedimentation processes was only moderate (approx. 0.65 log10) under low turbidity treatment conditions and the removal of MAH was actually lower than that of Escherichia coli (reference bacterium) in all the waters tested. Overall, the results of this study suggested that coagulation, flocculation and sedimentation processes may not be a reliable treatment option for removing MAH, and more efforts to find an effective control measures against MAH should be made to reduce the risk of MAH infection from drinking water. SIGNIFICANCE AND IMPACT OF THE STUDY: Despite a growing concern over human exposure to Mycobacterium avium subspecies hominissuis (MAH) through drinking water and its remarkable resistance to water disinfectants, little is known about the effectiveness of physico-chemical water treatment processes to remove MAH. Contrary to the prevailing hypothesis, the results of this study suggest that coagulation, flocculation and sedimentation processes may not be a reliable treatment option for MAH removal. As these processes have been the last remaining conventional drinking water treatment processes that might be effective against MAH, more efforts should be urgently made to find an effective control measures against this important waterborne pathogen. PMID- 25442010 TI - Identification and examination of a novel 9-bp insert/deletion polymorphism on porcine SFTPA1 exon 2 associated with acute lung injury using an oleic acid-acute lung injury model. AB - The pulmonary surfactant-associated protein (SFTPA1, SP-A) gene has been studied as a candidate gene for lung disease resistance in humans and livestock. The objective of the present study was to identify polymorphisms of the porcine SFTPA1 gene coding region and its association with acute lung injury (ALI). Through DNA sequencing and the PCR-single-strand conformation polymorphism method, a novel 9-bp nucleotide insertion (+) or deletion (-) was detected on exon 2 of SFTPA1, which causes a change in three amino acids, namely, alanine (Ala), glycine (Gly) and proline (Pro). Individuals of three genotypes (-/-, +/- and +/+) were divided into equal groups from 60 Rongchang pigs that were genotyped. These pigs were selected for participation in the oleic acid (OA)-ALI model by 1-h and 3-h injections of OA, and there were equal numbers of pigs in the control and injection groups. The lung water content, a marker for acute lung injury, was measured in this study; there is a significant correlation between high lung water content and the presence of the 9-bp indel polymorphism (P < 0.01). The lung water content of the OA injection group was markedly higher than that of the control group and lung water content for the +/+ genotype was significantly higher than that of the others in the 1-h group (P < 0.01). No differences in the expression of the SFTPA1 gene were found among individuals with different SFTPA1 genotypes, indicating that the trait is not caused by a linked polymorphism causing altered expression of the gene. The individuals with the -/- genotype showed lower lung water content than the +/+ genotype pigs, which suggests that polymorphism could be a potential marker for lung disease resistant pig breeding and that pig can be a potential animal model for human lung disease resistance in future studies. PMID- 25442012 TI - Identification of CROWN ROOTLESS1-regulated genes in rice reveals specific and conserved elements of postembryonic root formation. AB - In monocotyledons, the root system is mostly composed of postembryonic shoot borne roots called crown roots. In rice (Oryza sativa), auxin promotes crown root initiation via the LOB-domain transcription factor (LBD) transcription factor CROWN ROOTLESS1 (CRL1); however, the gene regulatory network downstream of CRL1 remains largely unknown. We tested CRL1 transcriptional activity in yeast and in planta, identified CRL1-regulated genes using an inducible gene expression system and a transcriptome analysis, and used in situ hybridization to demonstrate coexpression of a sample of CRL1-regulated genes with CRL1 in crown root primordia. We show that CRL1 positively regulates 277 genes, including key genes involved in meristem patterning (such as QUIESCENT-CENTER SPECIFIC HOMEOBOX; QHB), cell proliferation and hormone homeostasis. Many genes are homologous to Arabidopsis genes involved in lateral root formation, but about a quarter are rice-specific. Our study reveals that several genes acting downstream of LBD transcription factors controlling postembryonic root formation are conserved between monocots and dicots. It also provides evidence that specific genes are involved in the formation of shoot-derived roots in rice. PMID- 25442013 TI - The boundaries of care work: a comparative study of professionals and volunteers in Denmark and Australia. AB - This paper explores the manner in which two hospices--one located in Denmark and one in Australia--negotiate and determine the boundaries of volunteer workers vis a-vis paid staff. A comparative case study approach was used to juxtapose organisations with similar activity fields located in different welfare state systems, i.e. a social democratic welfare state and a liberal welfare state. This study involved non-participant observation of volunteers at work and unstructured interviews with volunteers, staff and management in the hospices (n = 41). Data were collected between August 2012 and February 2013. Data were managed using NVivo and analysed thematically. A key finding is that volunteers in the Danish hospice were excluded from all direct care work due to the effective monopoly of the professional care providers, whereas the Australian volunteers participated in the provision of care to the extent that risk could be eliminated or mitigated to an acceptable level. The findings suggest two different models of the roles of volunteers in tension with professional care providers. Both models recognise that volunteers add to the level of care delivered by the organisations and allow for a discussion that moves away from the normative discussions of 'not taking somebody's job', while also recognising that volunteers must be more than just the 'nice extra' if they are to be of any real value to the organisation and to care receivers. PMID- 25442014 TI - Calretinin immunohistochemistry for the diagnosis of Hirschprung disease in rectal biopsies. AB - In this study we aimed to evaluate the usability of calretinin staining in the diagnosis and exclusion of HD in 36 rectal biopsies. Through immunohistochemical examination, in of a total of 21 pediatric patients in whom ganglion cells were detected in first rectal biopsies and in re-biopsies, ganglion cells were seen through nuclear and cytoplasmic staining. In the lamina propria and superficial submucosa, staining of nerve fibers was detected in a granular pattern in varying intensities. Out of a total of 5 biopsies (including one re-biopsy) of non-HD patients, where ganglion cells could not be seen, the nerve fibers were all stained. On the other hand, in 10 HD patients, diagnosed by a colon pull through operation, calretinin staining was not detected in any area of the rectal biopsies except for the mast cells. We conclude that calretinin immunostaining for the diagnosis of HD is an easy and reliable method for use in daily practice. PMID- 25442015 TI - Characterization of cathepsin X in colorectal cancer development and progression. AB - The lysosomal cysteine carboxypeptidase cathepsin X (CTSX), localized predominantly in immune cells, has been associated with the development and progression of cancer. To determine its specific role in colorectal carcinoma (CRC), we analyzed CTSX expression in non-malignant mucosa and carcinoma of 177 patients as well as in 111 adenomas and related it with clinicopathological parameters. Further, the role of CTSX in the adhesion and invasion of the colon carcinoma cell lines HT-29 and HCT116 was investigated in an in vitro culture cell system with fibroblasts and monocytes, reflecting the situation at the tumor invasion front. Epithelial CTSX expression significantly increased from normal mucosa to adenoma and carcinoma, with highest expression levels in high grade intraepithelial neoplasia and in early tumor stages. Loss of CTSX occurred with tumor progression, and correlated with advanced local invasion, lymph node and distal metastasis, lymphatic vessel and vein invasion, tumor cell budding and poorer overall survival of patients with CRC. The subcellular distribution of CTSX changed from vesicular paranuclear expression in the tumor center to submembranous expression in cells of the invasion front. Peritumoral macrophages showed highest expression of CTSX. In vitro assays identified CTSX as relevant factor for cell-cell adhesion and tumor cell anchorage to fibroblasts and basal membrane components, whereas inhibition of CTSX caused increased invasiveness of colon carcinoma cells in mono- and co-culture. In conclusion, CTSX is involved in early tumorigenesis and in the stabilization of tumor cell formation in CRC. The results suggest that loss of CTSX may be needed for tumor cell detachment, local invasion and tumor progression. In addition, CTSX in tumor-associated macrophages indicates a role for CTSX in the anti-tumor immune response. PMID- 25442016 TI - Temporal analysis of prostaglandin F2alpha receptor, caspase 3, and cyclooxygenase 2 messenger RNA expression and prostaglandin F2alpha receptor and cyclooxygenase 2 protein expression in endometrial tissue from multiparous Nelore (Bos taurus indicus) cows treated with cloprostenol sodium during puerperium. AB - The use of cloprostenol sodium in puerperium is questionable, as both favorable and unfavorable responses during the uterine involution process have been reported in the literature. This study is based on the hypothesis that cloprostenol sodium promotes modifications in the prostaglandin F2alpha receptor (FP), caspase 3 (CASP-3), and cyclooxygenase 2 (COX-2) mRNA expression that may favor the process of postpartum uterine involution in multiparous Nelore (Bos taurus indicus) females. Additionally, we aimed to describe the presence and immunolocalization of the FP and COX-2 protein in endometrial tissue at different postpartum time points in these females. Multiparous Nelore cows (n = 24) were treated with cloprostenol sodium (n = 12) or saline solution (n = 12) on postpartum Days 1 and 4 (Day 0 = birth), and endometrial biopsies were performed with a Yomann biopsy instrument and collected on Days 1, 7, 14, 28, and 42 postpartum. The mRNA expression from samples on the Days 1, 7, 14, 28, and 42 and the protein expression from samples on the Days 1, 14, 28, and 42 were then analyzed. The treated cows had altered FP and CASP-3 mRNA expression, and FP and COX-2 protein were observed in the endometrial surface epithelium, the stroma, and the glandular epithelium, with cytoplasmic immunolocalization. Although we attribute the change in CASP-3 mRNA expression to physiological phenomena, the results obtained for FP mRNA expression opens new doors for the study of hormonal protocols associated with cloprostenol sodium in the puerperium of Zebu females. PMID- 25442017 TI - Functional status of STAT3 and MAPK3/1 signaling pathways in granulosa cells during bovine follicular deviation. AB - Follicle development is coordinated by gonadotropins, steroids, and growth factors, which activate multiple signaling pathways. Phosphorylated-MAPK (pMAPK) level was indicated as an early marker of follicle dominance, whereas phosphorylated STAT3 (pSTAT3) was increased in granulosa cells of hypophysectomized rats. We hypothesized that MAPK3/1 and STAT3 pathways are regulated in granulosa cells during follicle deviation in cattle. Cyclic beef cows were synchronized and ovariectomized to recover the two largest follicles. Follicular diameter did not differ on Day 2 but was significantly greater in dominant follicles (DFs) than that in subordinate follicles (SFs) on Days 3 and 4 of the follicular wave. The elevated abundance of CYP19A1 mRNA expression in granulosa cells of DFs and cleaved caspase 3 in Day-4 SFs further validated our in vivo model. Before deviation, pMAPK3/1 levels were significantly higher in granulosa cells of the future DF. STAT3 mRNA and total protein (tSTAT3) were higher in granulosa cells of SFs collected on Day 4. Furthermore, levels of pSTAT3 were dramatically increased in granulosa cells of Day-4 SFs. In conclusion, pMAPK3/1 was increased in the future DF, but such differential abundance between the DF and SF was not evident after deviation. The higher abundance of pSTAT3 in granulosa cells of SFs after deviation suggests that this pathway may be involved in granulosa cell death and follicular atresia. PMID- 25442018 TI - Effects of coculture with cumulus-derived somatic cells on in vitro maturation of porcine oocytes. AB - In the process of IVM, cumulus-oocyte complexes (COCs) separate from the follicular microenvironment, leading to the loss of endocrine interactions between follicular mural somatic cells and COCs. To restore the microenvironment, a coculture system was established using cumulus-derived somatic cells (CSCs) for IVM. The CSCs were cultured in Dulbecco's modified Eagle's medium for 48 hours with varying numbers of CSCs (0.0, 2.5 * 10(4), 5.0 * 10(4), and 10.0 * 10(4)) and then cultured in tissue culture medium 199 (TCM 199) for 4 hours before adding the oocytes. Cumulus-oocyte complexes from 3- to 6-mm follicles were matured in 500 MUL of TCM 199 with eCG and hCG for 22 hours and then cultured in TCM 199 without hormones for 22 hours. After IVM, the group with 2.5 * 10(4) CSCs showed a significant increase in intracellular glutathione levels compared with the control group. In the evaluation of sperm penetration, efficient fertilization was increased in the groups with 2.5 * 10(4) and 5.0 * 10(4) CSCs compared with controls (44.9 and 46.5 vs. 32.1, respectively). The mRNA expression pattern analysis in matured COCs showed a significant upregulation of PCNA, COX-2, Has2, Ptx3, and Nrf2 in the 2.5 * 10(4) CSC group compared with controls. During COC maturation at 0, 11, 22, 33, and 44 hours, the 2.5 * 10(4) and 5.0 * 10(4) CSC groups showed a significantly altered mRNA expression of BMP15 and GDF9. The developmental competence of the matured oocytes in all groups was evaluated after IVF and parthenogenetic activation (PA). After IVF, the 2.5 * 10(4) CSC group showed significantly higher cleavage, blastocyst formation rate, and total cell numbers compared with controls (60.0%, 35.7%, and 127.3 vs. 43.2%, 21.1%, and 89.3, respectively). After PA, the 2.5 * 10(4) CSC group had significantly higher blastocyst formation rate and total cell number than the control group (52.0% and 120.4 vs. 35.4% and 90.9, respectively). In conclusion, these results suggest that the presence of a population of 2.5 * 10(4) CSCs during IVM synergistically improved the developmental potential of IVF- and PA derived porcine embryos by increasing the intracellular glutathione level via changing of a specific gene expression pattern during oocyte maturation. PMID- 25442019 TI - Increasing the cAMP concentration during in vitro maturation of pig oocytes improves cumulus maturation and subsequent fertilization in vitro. AB - Porcine IVF faces various problems such as incomplete cytoplasmic maturation of the oocyte and polyspermy. Previous studies proved the importance of cAMP in regulating nuclear and cytoplasmic maturation of oocytes. This study investigated the effect of the cAMP-modulating agents 3-isobutyl-1-methylxanthine (IBMX) and dibutyryl cAMP sodium salt (dbcAMP) on several parameters during in vitro production of porcine embryos. First, we wanted to see if oocyte collection in IBMX could meiotically arrest oocytes and, as such, improve synchronization of nuclear and cytoplasmic maturation. To this end, cumulus-oocyte complexes (COCs) were collected from gilts in HEPES-buffered Tyrode balanced salt solution medium with 0.5-mM IBMX or without IBMX. At the end of oocyte collection, the effect of IBMX on chromatin configuration was evaluated. However, no differences could be observed in nuclear configuration between IBMX- and IBMX+ oocytes (P > 0.05). Second, we added dbcAMP during IVM to improve cytoplasmic maturation and evaluated cumulus expansion (lack of adhesion), a disintegrin and metalloproteinase with thrombospondin-like repeats (ADAMTS-1) levels in cumulus cells, fertilization, and blastocyst rates. Cumulus-oocyte complexes were matured in modified North Carolina State University medium 37 with or without 1-mM dbcAMP. Frozen-thawed, epididymal, boar spermatozoa were used for IVF. After IVF, presumed zygotes were cultured for 7 days in North Carolina State University medium 23. Penetration rate decreased in dbcAMP+ (57.3%) compared with dbcAMP- (67.8%), but the polyspermy rate also decreased (43.3% vs. 53.4%, respectively) leading to an increased normal fertilization rate (56.7% vs. 46.6%, respectively; P < 0.05). Only 7.2% of the COCs showed adhesion in dbcAMP+ which was lower than 15.7% in dbcAMP- (P < 0.05) probably because of an upregulation of the ADAMTS-1 protein by dbcAMP. When the adherent oocytes were removed during maturation, no difference could be detected between the blastocyst rate of dbcAMP- and dbcAMP+ (17.1% and 21.0% on Day 7, respectively; P > 0.05). In conclusion, the use of IBMX during collection did not cause a meiotic arrest. Using dbcAMP during IVM caused a greater normal fertilization rate, a lower rate of adherent COCs during IVM, higher levels of ADAMTS-1 in cumulus cells, and an equal blastocyst rate after screening out adherent COCs. These findings contribute to a better understanding of cAMP involvement in porcine oocyte maturation and provide a basis to develop an improved system with less polyspermy and higher blastocyst rates. PMID- 25442020 TI - Effect of preoperative simvastatin treatment on transplantation of cryopreserved warmed mouse ovarian tissue quality. AB - After the ovarian tissue (OT) transplantation, the ischemia-reperfusion injury causes depletion and apoptosis of follicle. Recent reports stated that simvastatin reduces ischemic damage. Therefore, we used the mouse whole ovarian vitrification and autotransplantation models to investigate the effects of simvastatin. Five-week-old B6D2F1 mice were randomly divided into four groups. Three groups were given simvastatin orally (5 mg/kg) before ovariectomy, either 2 hours before (2H Tx) or once a day for 3 or 7 days. The control group was given saline 2 hours before ovariectomy. All ovaries were cryopreserved by vitrification, held in liquid nitrogen for 1 week before being warmed, and autotransplanted. The grafts were collected for analysis on 2, 7, or 21 days after transplantation. Ovarian follicle morphology and apoptosis were assessed by hematoxylin and eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Vessel integrity in ovary was evaluated by immunohistochemistry using anti-CD31 antibody. Serum FSH level was measured to estimate the transplanted ovarian reserve. The proportion of morphologically normal (G1) follicles at 7 and 21 days and the percentage of CD31 (+) tissue at 21 days was significantly higher in the 2H Tx group than that in the control group. In addition, the 2H Tx group showed a significantly increased intact primordial follicle ratio at 2 and 21 days after OT transplantation. Administration of simvastatin 2 hours before ovariectomy could improve the quality after transplantation of cryopreserved mouse OT. PMID- 25442021 TI - Magnetic resonance imaging of the meniscus. AB - The treatment of meniscal tears has evolved secondary to a better understanding of the essential roles that the menisci play in the normal function of the knee, including load transmission, stress distribution, shock absorption, joint lubrication, resistance to capsular and synovial impingement, and maintenance of joint congruity. Imaging evaluation of the menisci requires an understanding of the normal anatomy, the imaging criteria necessary to accurately diagnose a meniscal tear, meniscal tear patterns, and awareness of common diagnostic pitfalls. PMID- 25442022 TI - Magnetic resonance imaging of the postoperative meniscus: resection, repair, and replacement. AB - Meniscus surgery is common, and surgical indications and techniques continue to evolve. After highlighting relevant anatomy and emerging magnetic resonance (MR) imaging techniques, this article reviews the current indications and techniques used for meniscus surgery, evaluates the use of MR imaging protocols with and without arthrography, and focuses on MR imaging interpretation of the postoperative meniscus, with particular attention to clinical outcomes and diagnostic criteria. PMID- 25442023 TI - MR imaging of cruciate ligaments. AB - Cruciate ligament injuries, and in particular injuries of the anterior cruciate ligament (ACL), are the most commonly reconstructed ligamentous injuries of the knee. As such, accurate preoperative diagnosis is essential in optimal management of patients with cruciate ligament injuries. This article reviews the anatomy and biomechanics of the ACL and posterior cruciate ligament (PCL) and describes the magnetic resonance (MR) imaging appearances of complete and partial tears. Normal postoperative appearances of ACL and PCL reconstructions as well as MR imaging features of postoperative complications will also be reviewed. PMID- 25442024 TI - Posterolateral and posteromedial corner injuries of the knee. AB - Posterolateral (PLC) and posteromedial (PMC) corners of the knee represent complex anatomic regions because of intricate soft tissue and osseous relationships in small areas. Concise knowledge of these relationships is necessary before approaching their evaluation at imaging. Magnetic resonance imaging offers an accurate imaging diagnostic tool to establish normal anatomy and diagnose and characterize soft tissue and osseous injury. It is important to carefully evaluate the PLC and PMC structures on magnetic resonance imaging before planned surgical intervention to avoid potential complications resulting from occult injury. PMID- 25442025 TI - Magnetic resonance imaging of the extensor mechanism. AB - Anterior knee pain is associated with many different causes. The clinical diagnosis may be unclear when the patient initially presents for evaluation. Magnetic resonance (MR) imaging is a valuable modality with high diagnostic accuracy in the evaluation of extensor mechanism pathology, which commonly presents with anterior knee pain. The most common disorders include patellar fracture, patellofemoral tracking abnormalities, tendon trauma and degeneration. These injuries manifest with characteristic patterns on MR imaging. This article discusses normal anatomy, common injuries, and diagnostic pitfalls on MR imaging. PMID- 25442026 TI - A biomechanical approach to interpreting magnetic resonance imaging of knee injuries. AB - This article discusses common injury mechanisms and the subsequent constellation of magnetic resonance (MR) imaging findings in the knee following trauma in the context of instability, as distinguished by the degree of knee flexion and tibial rotation at the time of initial injury, in addition to the direction and magnitude of the responsible force vectors. Using 3-dimensional imaging, common injury mechanisms are illustrated and correlated with MR imaging findings of the resulting osteochondral, ligamentous, meniscal, and musculotendinous lesions. The most common classification and grading systems for these individual lesions and their subsequent treatment implications are discussed. PMID- 25442027 TI - Quantitative magnetic resonance imaging of the articular cartilage of the knee joint. AB - Osteoarthritis is characterized by a decrease in the proteoglycan content and disruption of the highly organized collagen fiber network of articular cartilage. Various quantitative magnetic resonance imaging techniques have been developed for noninvasive assessment of the proteoglycan and collagen components of cartilage. These techniques have been extensively used in clinical practice to detect early cartilage degeneration and in osteoarthritis research studies to monitor disease-related and treatment-related changes in cartilage over time. This article reviews the role of quantitative magnetic resonance imaging in evaluating the composition and ultrastructure of the articular cartilage of the knee joint. PMID- 25442028 TI - Magnetic resonance imaging of cartilage repair procedures. AB - Cartilage injuries in the knee are common and can be a persistent source of pain or dysfunction. Many new surgical strategies have been developed to treat these lesions. It is important for the radiologist to have an understanding of these procedures and their appearance on magnetic resonance (MR) imaging. This article provides the radiologist with an overview of the surgical strategies for repairing cartilage lesions in the knee followed by a discussion of their postoperative appearance on MR imaging in normal and abnormal cases. Guidelines for adequate reporting of the MR imaging findings after cartilage repair in the knee are also included. PMID- 25442029 TI - MR imaging assessment of arthritis of the knee. AB - The magnetic resonance (MR) imaging presentations of arthritis of the knee are important for radiologists to recognize because these disorders are often clinically unsuspected. When they are known or clinically suspected, knowledge of imaging features allows for the confirmation and characterization of the extent of disease. This article reviews the fundamental MR imaging manifestations of rheumatologic disorders of the knee and their presentation in specific arthropathies. PMID- 25442030 TI - MR imaging of extrasynovial inflammation and impingement about the knee. AB - The knee has unique anatomy regarding the relationship between the synovial and capsular layers, with interposed fat pads at certain locations. The extrasynovial impingement and inflammation syndromes about the knee are underdiagnosed and should be included in the differential diagnosis of anterior knee pain. MR imaging is the best imaging modality for evaluation of the anatomy and disorders of these extrasynovial compartments. PMID- 25442031 TI - Magnetic resonance imaging of the pediatric knee. AB - In pediatric patients, the high resolution and excellent soft-tissue contrast of magnetic resonance (MR) imaging allows for complete evaluation of osseous and soft-tissue structures around the knee joint, and its lack of ionizing radiation makes it a preferred modality for advanced imaging. Older children and adolescents are most commonly imaged to evaluate athletic and traumatic injuries, whereas in infants and school age children MR imaging is used to evaluate developmental conditions such as Blount disease or assess for causes of atraumatic pain such as infection or inflammatory arthritis. A thorough understanding of normal skeletal development is necessary to avoid misdiagnoses. PMID- 25442032 TI - Imaging the knee in the setting of metal hardware. AB - Magnetic resonance (MR) imaging is an established modality for the evaluation of musculoskeletal structures, including the knee. Metallic implants are increasingly used and techniques to minimize artifacts are continuously improving. This article reviews the general principles behind the effects of metal on MR imaging, various MR imaging techniques that are available or have been recently described in the literature, and abnormalities that can be encountered during MR imaging of patients related to knee arthroplasty, hardware after internal fixation, or hardware used for soft tissue fixation. PMID- 25442033 TI - MRI of the knee. PMID- 25442034 TI - MR imaging of the knee. PMID- 25442035 TI - Recovering from disasters: a study of livelihoods in post-quake villages in northern Pakistan. AB - The October 2005 earthquake in northern Pakistan severely affected the livelihoods of 1.5 million people. With the destruction of material assets and communications infrastructure, the quake had a devastating impact on people's way of life in this remote mountainous region. This paper explores livelihood revival interventions undertaken during the earthquake response, and considers how differentiated livelihood outcomes were achieved. In addressing this objective the paper examines livelihood rehabilitation schemes in terms of structural aspects, working strategies, key factors, strengths of interventions and the role of human agency in influencing livelihood trajectories of quake-affected communities. Primary data for this study was gathered in northern Pakistan between October 2008 and January 2009. The study identifies structural shortcomings and strengths of the programmes attempting to revive the livelihoods of poor and vulnerable households. It identifies how households in two villages made the most of opportunities to improve their lives and move towards favourable outcomes. PMID- 25442036 TI - Long-term results from the Contura multilumen balloon breast brachytherapy catheter phase 4 registry trial. AB - PURPOSE: To describe the long-term outcomes from a completed, multi-institutional phase 4 registry trial using the Contura multilumen balloon (CMLB) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI) in patients with early-stage breast cancer. METHODS AND MATERIALS: Three hundred forty-two evaluable patients were enrolled by 23 institutions between January 2008 and February 2011. All patients received 34 Gy in 10 fractions, delivered twice daily. Rigorous target coverage and normal tissue dose constraints were observed. RESULTS: The median follow-up time was 36 months (range, 1-54 months). For the entire patient cohort of 342 patients, 10 patients experienced an ipsilateral breast tumor recurrence (IBTR). Eight of these IBTR were classified as true recurrences/marginal miss (TRMM), and 2 were elsewhere failures (EF). Local recurrence-free survival was 97.8% at 3 years. For the entire cohort, 88% of patients had good to excellent overall cosmesis. The overall incidence of infection was 8.5%. Symptomatic seroma was reported in only 4.4% of patients. A separate analysis was performed to determine whether improved outcomes would be observed for patients treated at high-volume centers with extensive brachytherapy experience. Three IBTR were observed in this cohort, only 1 of which was classified as a TRMM. Local recurrence-free survival at high-volume centers was 98.1% at 3 years. Overall cosmetic outcome and toxicity were superior in patients treated at high-volume centers. In these patients, 95% had good to excellent overall cosmesis. Infection was observed in only 2.9% of patients, and symptomatic seroma was reported in only 1.9%. CONCLUSION: Use of the CMLB for APBI delivery is associated with acceptable long-term local control and toxicity. Local recurrence-free survival was 97.8% at 3 years. Significant (grade 3) toxicity was uncommon, and no grade 4 toxicity was observed. Treatment at high volume centers was associated with decreased late toxicity. PMID- 25442037 TI - The modern role of radiation therapy in treating advanced-stage retinoblastoma: long-term outcomes and racial differences. AB - PURPOSE/OBJECTIVE(S): To evaluate the effects of various patient characteristics and radiation therapy treatment variables on outcomes in advanced-stage retinoblastoma. METHODS AND MATERIALS: This was a retrospective review of 41 eyes of 30 patients treated with external beam radiation therapy between June 1, 1992, and March 31, 2012, with a median follow-up time of 133 months (11 years). Outcome measures included overall survival, progression-free survival, local control, eye preservation rate, and toxicity. RESULTS: Over 90% of the eyes were stage V. Definitive external beam radiation therapy (EBRT) was delivered in 43.9% of eyes, adjuvant EBRT in 22% of eyes, and second-line/salvage EBRT in 34.1% of eyes. A relative lens sparing (RLS) technique was used in 68.3% of eyes and modified lens sparing (MLS) in 24.4% of eyes. Three eyes were treated with other techniques. Doses >=45 Gy were used in 68.3% of eyes. Chemotherapy was a component of treatment in 53.7% of eyes. The 10-year overall survival was 87.7%, progression-free survival was 80.5%, and local control was 87.8%. White patients had significantly better overall survival than did African-American patients in univariate analysis (hazard ratio 0.09; 95% confidence interval 0.01-0.84; P=.035). Toxicity was seen in 68.3% of eyes, including 24.3% with isolated acute dermatitis. CONCLUSIONS: External beam radiation therapy continues to be an effective treatment modality for advanced retinoblastoma, achieving excellent long-term local control and survival with low rates of treatment-related toxicity and secondary malignancy. PMID- 25442038 TI - Outcomes of proton therapy for the treatment of uveal metastases. AB - PURPOSE/OBJECTIVE(S): Radiation therapy can be used to treat uveal metastases with the goal of local control and improvement of quality of life. Proton therapy can be used to treat uveal tumors efficiently and with expectant minimization of normal tissue injury. Here, we report the use of proton beam therapy for the management of uveal metastases. METHODS AND MATERIALS: A retrospective chart review was made of all patients with uveal metastases treated at our institution with proton therapy between June 2002 and June 2012. Patient and tumor characteristics, fractionation and dose schemes, local control, and toxicities are reported. RESULTS: Ninety patients were identified. Of those, 13 were excluded because of missing information. We report on 77 patients with 99 affected eyes with available data. Patients were 68% female, and the most common primary tumor was breast carcinoma (49%). The median age at diagnosis of uveal metastasis was 57.9 years. Serous retinal detachment was seen in 38% of treated eyes. The median follow-up time was 7.7 months. The median dose delivered to either eye was 20 Gy(relative biological effectiveness [RBE]) in 2 fractions. Local control was 94%. The median survival after diagnosis of uveal metastases was 12.3 months (95% confidence interval, 7.7-16.8). Death in all cases was secondary to systemic disease. Radiation vasculopathy, measured decreased visual acuity, or both was observed in 50% of evaluable treated eyes. The actuarial rate of radiation vasculopathy, measured decreased visual acuity, or both was 46% at 6 months and 73% at 1 year. The 6 eyes with documented local failure were successfully salvaged with retreatment. CONCLUSIONS: Proton therapy is an effective and efficient means of treating uveal metastases. Acutely, the majority of patients experience minor adverse effects. For longer-term survivors, the risk of retinal injury with vision loss increases significantly over the first year. PMID- 25442039 TI - Stereotactic ablative body radiation therapy for primary kidney cancer: a 3 dimensional conformal technique associated with low rates of early toxicity. AB - PURPOSE: To describe our 3-dimensional conformal planning approaches and report early toxicities with stereotactic body radiation therapy for the management of primary renal cell carcinoma. METHODS AND MATERIALS: This is an analysis of a phase 1 trial of stereotactic body radiation therapy for primary inoperable renal cell carcinoma. A dose of 42 Gy/3 fractions was prescribed to targets >=5 cm, whereas for <5 cm 26 Gy/1 fraction was used. All patients underwent a planning 4 dimensional CT to generate a planning target volume (PTV) from a 5-mm isotropic expansion of the internal target volume. Planning required a minimum of 8 fields prescribing to the minimum isodose surrounding the PTV. Intermediate dose spillage at 50% of the prescription dose (R50%) was measured to describe the dose gradient. Early toxicity (<6 months) was scored using the Common Terminology Criteria for Adverse Events (v4.0). RESULTS: From July 2012 to August 2013 a total of 20 patients (median age, 77 years) were recruited into a prospective clinical trial. Eleven patients underwent fractionated treatment and 9 patients a single fraction. For PTV targets <100 cm(3) the median number of beams used was 8 (2 noncoplanar) to achieve an average R50% of 3.7. For PTV targets >100 cm(3) the median beam number used was 10 (4 noncoplanar) for an average R50% value of 4.3. The R50% was inversely proportional to decreasing PTV volume (r=-0.62, P=.003) and increasing total beams used (r=-0.51, P=.022). Twelve of 20 patients (60%) suffered grade <=2 early toxicity, whereas 8 of 20 patients (40%) were asymptomatic. Nausea, chest wall pain, and fatigue were the most common toxicities reported. CONCLUSION: A 3-dimensional conformal planning technique of 8-10 beams can be used to deliver highly tolerable stereotactic ablation to primary kidney targets with minimal early toxicities. Ongoing follow-up is currently in place to assess long-term toxicities and cancer control. PMID- 25442040 TI - Low interrater reliability in grading of rectal bleeding using National Cancer Institute Common Toxicity Criteria and Radiation Therapy Oncology Group Toxicity scales: a survey of radiation oncologists. AB - PURPOSE: To measure concordance among genitourinary radiation oncologists in using the National Cancer Institute Common Toxicity Criteria (NCI CTC) and Radiation Therapy Oncology Group (RTOG) grading scales to grade rectal bleeding. METHODS AND MATERIALS: From June 2013 to January 2014, a Web-based survey was sent to 250 American and Canadian academic radiation oncologists who treat prostate cancer. Participants were provided 4 case vignettes in which patients received radiation therapy and developed rectal bleeding and were asked for management plans and to rate the bleeding according to NCI CTC v.4 and RTOG late toxicity grading (scales provided). In 2 cases, participants were also asked whether they would send the patient for colonoscopy. A multilevel, random intercept modeling approach was used to assess sources of variation (case, respondent) in toxicity grading to calculate the intraclass correlation coefficient (ICC). Agreement on a dichotomous grading scale (low grades 1-2 vs high grades 3-4) was also assessed, using the kappa statistic for multiple respondents. RESULTS: Seventy-two radiation oncologists (28%) completed the survey. Forty-seven (65%) reported having either written or been principal investigator on a study using these scales. Agreement between respondents was moderate (ICC 0.52, 95% confidence interval [CI] 0.47-0.58) when using NCI CTC and fair using the RTOG scale (ICC 0.28, 95% CI 0.20-0.40). Respondents who chose an invasive management were more likely to select a higher toxicity grade (P<.0001). Using the dichotomous scale, we observed moderate agreement (kappa = 0.42, 95% CI 0.40-0.44) with the NCI CTC scale, but only slight agreement with the RTOG scale (kappa = 0.19, 95% CI 0.17-0.21). CONCLUSION: Low interrater reliability was observed among radiation oncologists grading rectal bleeding using 2 common scales. Clearer definitions of late rectal bleeding toxicity should be constructed to reduce this variability and avoid ambiguity in both reporting and interpretation. PMID- 25442041 TI - [(18)F]FDG-PET standard uptake value as a metabolic predictor of bone marrow response to radiation: impact on acute and late hematological toxicity in cervical cancer patients treated with chemoradiation therapy. AB - PURPOSE: To quantify the relationship between bone marrow (BM) response to radiation and radiation dose by using (18)F-labeled fluorodeoxyglucose positron emission tomography [(18)F]FDG-PET standard uptake values (SUV) and to correlate these findings with hematological toxicity (HT) in cervical cancer (CC) patients treated with chemoradiation therapy (CRT). METHODS AND MATERIALS: Seventeen women with a diagnosis of CC were treated with standard doses of CRT. All patients underwent pre- and post-therapy [(18)F]FDG-PET/computed tomography (CT). Hemograms were obtained before and during treatment and 3 months after treatment and at last follow-up. Pelvic bone was autosegmented as total bone marrow (BMTOT). Active bone marrow (BMACT) was contoured based on SUV greater than the mean SUV of BMTOT. The volumes (V) of each region receiving 10, 20, 30, and 40 Gy (V10, V20, V30, and V40, respectively) were calculated. Metabolic volume histograms and voxel SUV map response graphs were created. Relative changes in SUV before and after therapy were calculated by separating SUV voxels into radiation therapy dose ranges of 5 Gy. The relationships among SUV decrease, radiation dose, and HT were investigated using multiple regression models. RESULTS: Mean relative pre-post-therapy SUV reductions in BMTOT and BMACT were 27% and 38%, respectively. BMACT volume was significantly reduced after treatment (from 651.5 to 231.6 cm(3), respectively; P<.0001). BMACT V30 was significantly correlated with a reduction in BMACT SUV (R(2), 0.14; P<.001). The reduction in BMACT SUV significantly correlated with reduction in white blood cells (WBCs) at 3 months post-treatment (R(2), 0.27; P=.04) and at last follow-up (R(2), 0.25; P=.04). Different dosimetric parameters of BMTOT and BMACT correlated with long term hematological outcome. CONCLUSIONS: The volumes of BMTOT and BMACT that are exposed to even relatively low doses of radiation are associated with a decrease in WBC counts following CRT. The loss in proliferative BM SUV uptake translates into low WBC nadirs after treatment. These results suggest the potential of intensity modulated radiation therapy to spare BMTOT to reduce long-term hematological toxicity. PMID- 25442042 TI - Neoadjuvant sandwich treatment with oxaliplatin and capecitabine administered prior to, concurrently with, and following radiation therapy in locally advanced rectal cancer: a prospective phase 2 trial. AB - PURPOSE: Systemic failure remains the major challenge in management of locally advanced rectal cancer (LARC). To optimize the timing of neoadjuvant treatment and enhance systemic control, we initiated a phase 2 trial to evaluate a new strategy of neoadjuvant sandwich treatment, integrating induction chemotherapy, concurrent chemoradiation therapy, and consolidation chemotherapy. Here, we present preliminary results of this trial, reporting the tumor response, toxicities, and surgical complications. METHODS AND MATERIALS: Fifty-one patients with LARC were enrolled, among which were two patients who were ineligible because of distant metastases before treatment. Patients were treated first with one cycle of induction chemotherapy consisting of oxaliplatin, 130 mg/m2 on day 1, with capecitabine, 1000 mg/m2 twice daily for 14 days every 3 weeks (the XELOX regimen), followed by chemoradiation therapy, 50 Gy over 5 weeks, with the modified XELOX regimen (oxaliplatin 100 mg/m2), and then with another cycle of consolidation chemotherapy with the XELOX regimen. Surgery was performed 6 to 8 weeks after completion of radiation therapy. Tumor responses, toxicities, and surgical complications were recorded. RESULTS: All but one patent completed the planned schedule of neoadjuvant sandwich treatment. Neither life-threatening blood count decrease nor febrile neutropenia were observed. Forty-five patents underwent optimal surgery with total mesorectal excision (TME). Four patients refused surgery because of clinically complete response. There was no perioperative mortality in this cohort. Five patients (11.1%) developed postoperative complications. Among the 45 patients who underwent TME, pathologic complete response (pCR), pCR or major regression, and at least moderate regression were achieved in 19 (42.2%), 37 (82.2%), and 44 patients (97.8%), respectively. CONCLUSIONS: Preliminary results suggest that the strategy of neoadjuvant sandwich treatment using XELOX regimen as induction, concomitant, and consolidation chemotherapy to the conventional radiation is well tolerated. The strategy is highly effective in terms of pCR and major regression, which warrants further investigation. PMID- 25442043 TI - Impact of intrafraction and residual interfraction effect on prostate proton pencil beam scanning. AB - PURPOSE: To quantitatively evaluate the impact of interplay effect and plan robustness associated with intrafraction and residual interfraction prostate motion for pencil beam scanning proton therapy. METHODS AND MATERIALS: Ten prostate cancer patients with weekly verification CTs underwent pencil beam scanning with the bilateral single-field uniform dose (SFUD) modality. A typical field had 10-15 energy layers and 500-1000 spots. According to their treatment logs, each layer delivery time was <1 s, with average time to change layers of approximately 8 s. Real-time intrafraction prostate motion was determined from our previously reported prospective study using Calypso beacon transponders. Prostate motion and beam delivering sequence of the worst-case scenario patient were synchronized to calculate the "true" dose received by the prostate. The intrafraction effect was examined by applying the worst-case scenario prostate motion on the planning CT, and the residual interfraction effect was examined on the basis of weekly CT scans. The resultant dose variation of target and critical structures was examined to evaluate the interplay effect. RESULTS: The clinical target volume (CTV) coverage was degraded because of both effects. The CTV D99 (percentage dose to 99% of the CTV) varied up to 10% relative to the initial plan in individual fractions. However, over the entire course of treatment the total dose degradation of D99 was 2%-3%, with a standard deviation of <2%. Absolute differences between SFUD, intensity modulate proton therapy, and one-field-per day SFUD plans were small. The intrafraction effect dominated over the residual interfraction effect for CTV coverage. Mean dose to the anterior rectal wall increased approximately 10% because of combined residual interfraction and intrafraction effects, the interfraction effect being dominant. CONCLUSIONS: Both intrafraction and residual interfraction prostate motion degrade CTV coverage within a clinically acceptable level. One-field-per-day SFUD delivered twice is as robust as the bilateral SFUD plan treated daily over the course of treatment. PMID- 25442044 TI - Institutional patient-specific IMRT QA does not predict unacceptable plan delivery. AB - PURPOSE: To determine whether in-house patient-specific intensity modulated radiation therapy quality assurance (IMRT QA) results predict Imaging and Radiation Oncology Core (IROC)-Houston phantom results. METHODS AND MATERIALS: IROC Houston's IMRT head and neck phantoms have been irradiated by numerous institutions as part of clinical trial credentialing. We retrospectively compared these phantom results with those of in-house IMRT QA (following the institution's clinical process) for 855 irradiations performed between 2003 and 2013. The sensitivity and specificity of IMRT QA to detect unacceptable or acceptable plans were determined relative to the IROC Houston phantom results. Additional analyses evaluated specific IMRT QA dosimeters and analysis methods. RESULTS: IMRT QA universally showed poor sensitivity relative to the head and neck phantom, that is, poor ability to predict a failing IROC Houston phantom result. Depending on how the IMRT QA results were interpreted, overall sensitivity ranged from 2% to 18%. For different IMRT QA methods, sensitivity ranged from 3% to 54%. Although the observed sensitivity was particularly poor at clinical thresholds (eg 3% dose difference or 90% of pixels passing gamma), receiver operator characteristic analysis indicated that no threshold showed good sensitivity and specificity for the devices evaluated. CONCLUSIONS: IMRT QA is not a reasonable replacement for a credentialing phantom. Moreover, the particularly poor agreement between IMRT QA and the IROC Houston phantoms highlights surprising inconsistency in the QA process. PMID- 25442045 TI - A real-time safety and quality reporting system: assessment of clinical data and staff participation. AB - PURPOSE: To report on the use of an incident learning system in a radiation oncology clinic, along with a review of staff participation. METHODS AND MATERIALS: On September 24, 2010, our department initiated an online real-time voluntary reporting system for safety issues, called the Radiation Oncology Quality Reporting System (ROQRS). We reviewed these reports from the program's inception through January 18, 2013 (2 years, 3 months, 25 days) to assess error reports (defined as both near-misses and incidents of inaccurate treatment). RESULTS: During the study interval, there were 60,168 fractions of external beam radiation therapy and 955 brachytherapy procedures. There were 298 entries in the ROQRS system, among which 108 errors were reported. There were 31 patients with near-misses reported and 27 patients with incidents of inaccurate treatment reported. These incidents of inaccurate treatment occurred in 68 total treatment fractions (0.11% of treatments delivered during the study interval). None of these incidents of inaccurate treatment resulted in deviation from the prescription by 5% or more. A solution to the errors was documented in ROQRS in 65% of the cases. Errors occurred as repeated errors in 22% of the cases. A disproportionate number of the incidents of inaccurate treatment were due to improper patient setup at the linear accelerator (P<.001). Physician participation in ROQRS was nonexistent initially, but improved after an education program. CONCLUSIONS: Incident learning systems are a useful and practical means of improving safety and quality in patient care. PMID- 25442046 TI - Adaptive replanning to account for lumpectomy cavity change in sequential boost after whole-breast irradiation. AB - PURPOSE: To evaluate the efficiency of standard image-guided radiation therapy (IGRT) to account for lumpectomy cavity (LC) variation during whole-breast irradiation (WBI) and propose an adaptive strategy to improve dosimetry if IGRT fails to address the interfraction LC variations. METHODS AND MATERIALS: Daily diagnostic-quality CT data acquired during IGRT in the boost stage using an in room CT for 19 breast cancer patients treated with sequential boost after WBI in the prone position were retrospectively analyzed. Contours of the LC, treated breast, ipsilateral lung, and heart were generated by populating contours from planning CTs to boost fraction CTs using an auto-segmentation tool with manual editing. Three plans were generated on each fraction CT: (1) a repositioning plan by applying the original boost plan with the shift determined by IGRT; (2) an adaptive plan by modifying the original plan according to a fraction CT; and (3) a reoptimization plan by a full-scale optimization. RESULTS: Significant variations were observed in LC. The change in LC volume at the first boost fraction ranged from a 70% decrease to a 50% increase of that on the planning CT. The adaptive and reoptimization plans were comparable. Compared with the repositioning plans, the adaptive plans led to an improvement in target coverage for an increased LC case (1 of 19, 7.5% increase in planning target volume evaluation volume V95%), and breast tissue sparing for an LC decrease larger than 35% (3 of 19, 7.5% decrease in breast evaluation volume V50%; P=.008). CONCLUSION: Significant changes in LC shape and volume at the time of boost that deviate from the original plan for WBI with sequential boost can be addressed by adaptive replanning at the first boost fraction. PMID- 25442048 TI - Multiple histidines in the periplasmic domain of the Salmonella enterica sensor kinase SsrA enhance signaling in response to extracellular acidification. AB - The two-component regulatory system SsrA-SsrB in Salmonella enterica controls expression of a virulence gene program required for intracellular survival in host cells. SsrA signaling is induced within the acidic host vacuole in which the bacteria reside; however, the mechanism by which SsrA senses this intracellular environment is unknown. Here, we show that the periplasmic sensor domain of SsrA is enriched in histidine residues that increase SsrA signaling below external pH of 6. While no single histidine accounted for the full acid-responsiveness of SsrA, we localized the acid-responsiveness principally to five histidines in the C-terminal end of the periplasmic sensor domain, with input from additional histidines in the N-terminal end of the senor. A sensor mutant lacking critical pH-responsive histidines was defective for acid-promoted activity, yet retained basal activity similar to wild type at neutral pH, indicating that the role of these histidines is to enhance signaling in response to acidification. In support of this, a pH-blind mutant was insensitive to the vacuole acidification blocking activity of bafilomycin, and was attenuated for competitive fitness during infection of mice. Our data demonstrate that SsrA contains a histidine-rich periplasmic sensor that enhances signaling in response to the innate host defense of vacuolar acidification. PMID- 25442047 TI - Retrospective reconstructions of active bone marrow dose-volume histograms. AB - PURPOSE: To present a method for calculating dose-volume histograms (DVH's) to the active bone marrow (ABM) of patients who had undergone radiation therapy (RT) and subsequently developed leukemia. METHODS AND MATERIALS: The study focuses on 15 patients treated between 1961 and 1996. Whole-body RT planning computed tomographic (CT) data were not available. We therefore generated representative whole-body CTs similar to patient anatomy. In addition, we developed a method enabling us to obtain information on the density distribution of ABM all over the skeleton. Dose could then be calculated in a series of points distributed all over the skeleton in such a way that their local density reflected age-specific data for ABM distribution. Dose to particular regions and dose-volume histograms of the entire ABM were estimated for all patients. RESULTS: Depending on patient age, the total number of dose calculation points generated ranged from 1,190,970 to 4,108,524. The average dose to ABM ranged from 0.3 to 16.4 Gy. Dose-volume histograms analysis showed that the median doses (D50%) ranged from 0.06 to 12.8 Gy. We also evaluated the inhomogeneity of individual patient ABM dose distribution according to clinical situation. It was evident that the coefficient of variation of the dose for the whole ABM ranged from 1.0 to 5.7, which means that the standard deviation could be more than 5 times higher than the mean. CONCLUSIONS: For patients with available long-term follow-up data, our method provides reconstruction of dose-volume data comparable to detailed dose calculations, which have become standard in modern CT-based 3-dimensional RT planning. Our strategy of using dose-volume histograms offers new perspectives to retrospective epidemiological studies. PMID- 25442050 TI - Current state of anterior cruciate ligament registers. AB - PURPOSE: The purpose of this work was to report the main characteristics and results of all active anterior cruciate ligament (ACL) reconstruction registers along with the differences between them. METHODS: We systematically searched on Google and Medline via PubMed to identify ACL registers. National or regional registers were included if they were active and took into account ACL reconstructions. The main results and characteristics, namely the number of inclusions, exhaustivity, data collection methods and results dissemination methods were determined. The collected information was then submitted to each register for validation. RESULTS: Four registers (3 national, 1 regional) were identified that routinely included every ACL reconstruction procedure. Register data were collected either through dedicated websites or on paper forms. All the registers used the same two outcome measures, namely the revision rate and a subjective patient score (KOOS score). Register results were made available through scientific publications or annual reports. The main differences between registers were in the graft choice and presence of associated meniscus and cartilage injuries. CONCLUSIONS: Although there are only a few ACL reconstruction specific registers, their scientific contribution is undeniable thanks to the quality of the collected data and the organization and collaboration between registers. Their impact on health care and science should grow in the future. PMID- 25442049 TI - Effect of impaired renal function on the maintenance dose of warfarin in Japanese patients. AB - BACKGROUND: Chronic kidney disease (CKD) alters dose-effect relationship not only of drugs eliminated by the kidney but also of some drugs metabolized by the liver and not renally excreted. It is not known whether impaired renal function alters dose-effect relationship of warfarin in Asian patients. It is also unknown whether the maintenance dose of warfarin can be predicted more accurately by incorporating renal function in Asians. METHODS: This was a cross-sectional study of patients receiving constant doses of warfarin who had PT-INR within 1.5-3.0 for 3 months or longer. RESULTS: In a total of 137 participants, the estimated creatinine clearance (eCrCl) was 62.5+/-25.5 [ml/min] and the warfarin dose was 3.21+/-1.46 [mg/day] (both mean+/-standard deviation). There was a significant correlation between warfarin dose and eCrCl (p<0.0001, r(2)=0.23). In a stepwise linear regression with the maintenance dose of warfarin as the dependent variable, eCrCl as well as age, body weight, intra-individual average prothrombin time/international normalized ratio (PT-INR), and genotype of VKORC1 -1639 G>A polymorphism were chosen as independent variables. The coefficient of determination (r(2)) of this formula was 0.47. A regression equation with all the same explanatory variables except for eCrCl had an r(2) of 0.41. CONCLUSIONS: The maintenance warfarin dose was positively correlated with kidney function as represented by eCrCl in Japanese patients. Incorporating eCrCl improved accuracy of predicting warfarin maintenance dose in this population. PMID- 25442051 TI - Adolescent idiopathic scoliosis correction achieved by posteromedial translation using polyester bands: A comparative study of subtransverse process versus sublaminar fixation. AB - PURPOSE: Sublaminar polyester bands have been used in hybrid construct to achieve correction of adolescent idiopathic scoliosis since 2003. Despite the reported safety of the bands, some surgeons remain reluctant at the idea of approaching the canal because of the potential neurological complications reported with the Luque wiring. Sub transverse bands might be an alternative. The present study is the first to compare sublaminar polyester band fixation to fixation of polyester bands around the transverse processes in hybrid constructs used to treat AIS. METHODS: Two cohorts of consecutive patients treated for thoracic AIS were retrospectively reviewed, with a minimum 2-year follow-up. Posteromedial translation was used for main curve correction in all cases. Sublaminar polyester bands were used in group 1 (20 patients). In group 2 (20 patients), the same implant was used, but the bands were passed around the transverse process instead of the lamina. Radiographic analysis included frontal Cobb angle measurements for each curve, thoracic kyphosis and rotation of the apical vertebra (RVA). RESULTS: Mean operative time was similar in groups 1 and 2 (235+/-35 and 240+/-30minutes, respectively). Mean frontal correction achieved for the main curve was similar in both groups, 62.5+/-17.4% in group 1 and 54.1+/-19.4% in group 2. Sagittal correction was similar, with a final mean thoracic kyphosis of 30.9 degrees +/ 9.7 degrees and 27.8 degrees +/- 6.8 degrees in group 1 and 2, respectively. Correction of RVA was similar in both groups postoperatively, 65.8% (+/-29.1) and 54.4% (+/-42.7) in group 1 and 2 respectively. No transverse process or lamina fracture was observed during insertion of the bands or curve correction in any of the groups. CONCLUSION: This study confirms that anchorage of Universal clamps (UCs) around transverse processes is a safe and efficacious technique in both the frontal and sagittal planes, providing a useful alternative for the correction of moderate AIS. UCs attached to transverse processes can achieve correction of moderate AIS similar to that obtained with sublaminar UCs while further reducing risks of vertebral canal complications. LEVEL OF EVIDENCE: Level IV. PMID- 25442052 TI - Scoring of medical publications with SIGAPS software: Application to orthopedics. AB - SIGAPS is a bibliometric software tool developed in France to identify and analyze Medline-indexed publications that are produced by a researcher or research group. This measurement takes into account the author's ranking on the paper along with the journal's prestige according to its impact factor within the research field. However, use of this impact factor is the primary limitation of SIGAPS. SIGAPS analysis results are used to assign a financial value to hospital facilities. The impact of the journal Revue de Chirurgie Orthopedique and its successor-Orthopaedics & Traumatology: Surgery & Research-was compared using the Medline-based ISI (SIGAPS) and SCOPUS-based SCImago journal rankings. PMID- 25442053 TI - Therapeutic options in high-risk non-muscle-invasive bladder cancer during the current worldwide shortage of bacille Calmette-Guerin. AB - Optimal management of high-risk non-muscle-invasive bladder cancer during the current bacillus Calmette-Guerin (BCG) shortage is challenging. Although no evidence-based guidelines exist for this specific situation, current management options can be adapted for when BCG supplies are limited or when BCG is unavailable. PMID- 25442054 TI - Reply from authors re: Camillo Porta, Sergio Bracarda, Romano Danesi. Steroids in prostate cancer: the jury is still out... and even more confused. Eur Urol 2015;67:680-1: Corticosteroids in prostate cancer: known benefits versus potential risks. PMID- 25442055 TI - Towards semantic-driven high-content image analysis: an operational instantiation for mitosis detection in digital histopathology. AB - This study concerns a novel symbolic cognitive vision framework emerged from the Cognitive Microscopy (MICO(1)) initiative. MICO aims at supporting the evolution towards digital pathology, by studying cognitive clinical-compliant protocols involving routine virtual microscopy. We instantiate this paradigm in the case of mitotic count as a component of breast cancer grading in histopathology. The key concept of our approach is the role of the semantics as driver of the whole slide image analysis protocol. All the decisions being taken into a semantic and formal world, MICO represents a knowledge-driven platform for digital histopathology. Therefore, the core of this initiative is the knowledge representation and the reasoning. Pathologists' knowledge and strategies are used to efficiently guide image analysis algorithms. In this sense, hard-coded knowledge, semantic and usability gaps are to be reduced by a leading, active role of reasoning and of semantic approaches. Integrating ontologies and reasoning in confluence with modular imaging algorithms, allows the emergence of new clinical-compliant protocols for digital pathology. This represents a promising way to solve decision reproducibility and traceability issues in digital histopathology, while increasing the flexibility of the platform and pathologists' acceptance, the one always having the legal responsibility in the diagnosis process. The proposed protocols open the way to increasingly reliable cancer assessment (i.e. multiple slides per sample analysis), quantifiable and traceable second opinion for cancer grading, and modern capabilities for cancer research support in histopathology (i.e. content and context-based indexing and retrieval). Last, but not least, the generic approach introduced here is applicable for number of additional challenges, related to molecular imaging and, in general, to high-content image exploration. PMID- 25442056 TI - Changes in the pattern of breast cancer burden among African American women: evidence based on 29 states and District of Columbia during 1998 to 2010. AB - PURPOSE: Assessment of breast cancer (BC) pattern in individual states with respect to ethnicity. METHODS: Population-based cancer registries from the Cancer Incidence in Five Continents databases (1998-2007) supplemented with Surveillance, Epidemiology, and End Results data from 2008 to 2010 were used. RESULTS: The age-specific burden showed a clear convergence of BC burden among African American (AA) and Caucasian American (CA) in most states. This was primarily because of a decrease in the BC rate among CA aged 50 years or older and an increase among AA of the same age group. The 2003-2007/1998-2002 rate ratio for CA was 0.91 (95% confidence interval [CI], 0.90-0.91) in the South, whereas it was 1.06 (95% CI, 1.04-1.08) for AA. This convergence was confirmed in states with available data for the period 2008 to 2010. The AA/CA rate ratio among women aged younger than 40 years was 0.99 (95% CI, 0.99-1.04) in the Northeast, 1.29 (95% CI, 1.25-1.33) in the South, and 1.10 (95% CI, 1.04-1.17) in the West. This pattern correlates with the estrogen receptor positive and progesterone receptor positive pattern. The strongest disparity in estrogen receptor negative was observed in Louisiana which with Detroit, have had the highest rates of estrogen receptor negative. CONCLUSIONS: The changes in postmenopausal hormone use and mammography screening might have played a role in the observed convergence. PMID- 25442057 TI - How does stress-induced activation of the kappa opioid system increase addiction risk? PMID- 25442058 TI - Reductions of p11 and 5-HT1B receptor availability in limbic brain regions in cocaine dependence. PMID- 25442059 TI - More cocaine-more glutamate-more addiction. PMID- 25442061 TI - D2cm3/DICRU ratio as a surrogate of bladder hotspots localizations during image guided adaptive brachytherapy for cervical cancer: assessment and implications in late urinary morbidity analysis. AB - PURPOSE: To evaluate the efficiency and potential implications of the lowest dose evaluated in the maximally exposed 2cm(3) of the bladder/dose evaluated at the International Commission for Radiation Units and Measurements (ICRU) bladder point (D2cm(3)/DICRU) ratio as surrogate to locate the D2cm(3) in patients treated with MRI-guided adaptive brachytherapy for cervical cancer. METHODS AND MATERIALS: The D2cm(3) area of the bladder was located in 69 patients, using the Digital Imaging and Communications in Medicine coordinates of its barycenter, with respect to the ICRU bladder point. The D2cm(3)/DICRU ratio was correlated with the longitudinal coordinate of the D2cm(3). Afterward, the ratio was used in a retrospective cohort of 216 patients to evaluate its impact in dose-effect analyses for late urinary incontinence. RESULTS: The mean position of the D2cm(3) was 1.73+/-0.98 cm cranially, 0.59+/-0.65 cm backwardly, and 0.02+/-0.89 cm to the right of the ICRU point. It was located above the ICRU point in 95.7% of the patients. Its position was lower in patients with vaginal involvement at diagnosis (p=0.03). The D2cm(3)/DICRU ratio was correlated with the position of the D2cm(3) (R2=0.716, p<10(-6)). In speculating that a ratio greater than one would predict a D2cm(3) located above the ICRU point, the sensibility, specificity, positive, and negative predictive values were 95.2%, 100%, 100%, and 66.8%, respectively. Among the retrospective cohort, 85 patients had a ratio lower than 1.1, reflecting a D2cm(3) located in the lower bladder. In these patients, analyses showed significant dose relationship with Grade 2-4 incontinence (p=0.017), whereas no correlation was demonstrated in the remaining patients. CONCLUSIONS: The D2cm(3)/DICRU ratio is a relevant surrogate to estimate the localization of the D2cm(3). Significant dose-effect correlations for incontinence were established in patients with low values for this ratio. PMID- 25442062 TI - Hypoplasia, pseudocoarctation and coarctation of the aorta - a systematic review. AB - Aortic arch abnormalities are uncommon and may be seen in association with other congenital cardiac anomalies. Coarctation, pseudocoarctation and hypoplastic aortic arch are known aortic arch abnormalities, with the former being well studied, whilst for the latter two, much less is known. There are similarities and differences that are important to distinguish among these three conditions in order to avoid errors in diagnosis that may result in unnecessary investigations, which may in turn result in physical or emotional harm to the patient. For this reason, we present a systematic review of the published literature providing an evidence-based overview that may be helpful to clinicians when faced with this diagnostic dilemma. PMID- 25442063 TI - Hybrid repair of an aortic arch aneurysm rupture in a redo sternotomy. AB - PURPOSE: To report a case of operative intervention for an aortic arch aneurysm rupture via a hybrid approach. METHODS AND RESULTS: Ten years after successful open repair of an acute type A aortic dissection a male presented with a rupture of his distal aortic arch aneurysm. A hybrid procedure was carried out which involved debranching of the innominate and left common carotid arteries and stent graft deployment landing proximally into the ascending aorta and distally into the descending thoracic aorta. CONCLUSIONS: Ruptured aortic arch aneurysms present a challenging and complex surgical dilemma. Open repair carries high mortality and pure endovascular repair is unfeasible; hence a hybrid repair presents an attractive solution. PMID- 25442064 TI - Association of arteriosclerosis index and oxidative stress markers in school children. AB - BACKGROUND: Recent years have seen increased numbers of children with conditions that contribute strongly to atherosclerotic disease, such as passive smoking, obesity, and dyslipidemia. In the present study, we evaluated the utility of non invasive urinary markers in preventing lifestyle-related diseases by comparing lipid metabolism-related parameters with oxidative stress markers in school children. METHODS: Subjects were 85 first-grade students. The variables examined included the smoking in subjects' household; exercise habits; height and weight; blood pressure; and plasma total cholesterol, high-density lipoprotein cholesterol, triglyceride, leptin, blood sugar, urinary cotinine, 8-hydroxy-2' deoxyguanosine (8-OHdG), and 8-isoprostaglandin F2alpha (IsoP). RESULTS: Of the subjects, 10.6% were obese (% overweight >= 20%), 3.5% had a high-risk arteriosclerosis index (AI; 3 <= AI < 5), and 29.4% were passive smokers. No significant differences were seen between boys and girls for any of the measurement parameters. Both urinary 8-OHdG (6.8-24.5 ng/mg creatinine) and IsoP (0.9-7.4 ng/mg creatinine) were detected in all subjects, and a significant positive correlation was seen between the two markers. On multiple regression analysis using AI as an objective variable and all non-invasive markers as explanatory variables, urinary IsoP correlated most strongly with AI (P <= 0.01). CONCLUSIONS: Risk factors for atherosclerosis in adults, such as obesity and hypercholesterolemia, are associated with oxidative stress and inflammation. The present findings of the strongest correlation between urinary IsoP and AI suggest that urinary IsoP may serve as a non-invasive and effective early marker in predicting risk in children of developing lifestyle-related diseases. PMID- 25442065 TI - Is American College of Surgeons NSQIP organ space infection a surrogate for pancreatic fistula? AB - BACKGROUND: In the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP), pancreatic fistula has not been monitored, although organ space infection (OSI) data are collected. Therefore, the purpose of this analysis was to determine the relationship between ACS NSQIP organ space infection and pancreatic fistulas. STUDY DESIGN: From 2007 to 2011, 976 pancreatic resection patients were monitored via ACS NSQIP at our institution. From this database, 250 patients were randomly chosen for further analysis. Four patients were excluded because they underwent total pancreatectomy. Data on OSI were gathered prospectively. Data on pancreatic fistulas and other intra abdominal complications were determined retrospectively. RESULTS: Organ space infections (OSIs) were documented in 22 patients (8.9%). Grades B (n = 26) and C (n = 5) pancreatic fistulas occurred in 31 patients (12.4%); grade A fistulas were observed in 38 patients (15.2%). Bile leaks and gastrointestinal (GI) anastomotic leaks each developed in 5 (2.0%) patients. Only 17 of 31 grade B and C pancreatic fistulas (55%), and none of 38 grade A fistulas were classified as OSIs in ACS NSQIP. In addition, only 2 of 5 bile leaks (40%) and 2 of 5 GI anastomotic leaks (40%) were OSIs. Moreover, 3 OSIs were due to bacterial peritonitis, a chyle leak, and an ischemic bowel. CONCLUSIONS: This analysis suggests that the sensitivity (55%) and specificity (45%) of organ space infection (OSI) in ACS NSQIP are too low for OSI to be a surrogate for grade B and C pancreatic fistulas. We concluded that procedure-specific variables will be required for ACS NSQIP to improve outcomes after pancreatectomy. PMID- 25442066 TI - Long-term favorable surgical results of laparoscopic hepatic resection for hepatocellular carcinoma in patients with cirrhosis: a single-center experience over a 10-year period. AB - BACKGROUND: We first performed laparoscopic hepatic resection (Lap-Hx) for hepatocellular carcinoma (HCC) in 1994. Here we review the long-term surgical results of Lap-Hx for HCC in patients with cirrhosis over a 10-year period at a single institution. STUDY DESIGN: Between January 2000 and December 2013, 99 patients with cirrhosis underwent open hepatic resection (Open-Hx) and 63 underwent Lap-Hx for primary HCC within the Milan criteria. We compared the operative outcomes and patient survival between the 2 groups. RESULTS: There were no significant differences regarding patient background characteristics or tumor related factors between the 2 groups. The morbidity rate of the Lap-Hx group was significantly lower than that of the Open-Hx group (26% vs 10%; p = 0.0459), and the complication rate of ascites was significantly lower (7% vs 0%; p = 0.0077). The mean duration of hospital stay of the Lap-Hx group was significantly shorter than that of the Open-Hx group (16 vs 10 days; p = 0.0008). There were no significant between-group differences regarding overall or disease-free survival. CONCLUSIONS: Laparoscopic-Hx for HCC in patients with cirrhosis is associated with less morbidity and shorter hospital stays, with no compromise in patient survival. It may be time to consider changing the standard operation for primary HCC within the Milan criteria to Lap-Hx in patients with cirrhosis. PMID- 25442067 TI - Standardizing a control group for comparing open with laparoscopic major liver resection in observational studies: reducing the need for correction of clinical heterogeneity. AB - BACKGROUND: The results of comparative observational trials of liver resections can be problematic because of the large number of covariates that need to be balanced by complex statistical methods. Our purpose was to examine a cohort of patients whose outcomes were specifically representative of a major open hepatectomy, therefore reducing the number of covariates requiring statistical correction in future comparative observational trials. STUDY DESIGN: The cohort was restricted to a single major common liver resection-open right hepatectomy. Subsequent restrictions eliminated covariates whose effects were not due to the liver resection, such as concomitant procedures. Variability was further reduced by including only NSQIP-based data for complications. The Modified Accordion Severity Grading System was used to quantify the complications. RESULTS: Of 114 patients in the NSQIP database, 70 met eligibility criteria. The mean operative time was 243 minutes and 19% of patients were transfused. The most common diagnosis was colorectal metastases, and the R0 resection rate in this group was 94%. One patient (1.4%) died postoperatively, and 25% of patients developed complications. Organ space infection, unplanned intubation, and on ventilator more than 48 hours had the highest fractional burden of complications. The Postoperative Morbidity Index was 0.089. Mean length of stay was 7.7 days. CONCLUSIONS: This study displays results for a cohort of patients who are specifically reflective of a major open liver resection. Use of NSQIP data allows rigorous collection of complication data in a quantifiable manner. This methodology should facilitate comparative observational trials using laparoscopic techniques by reducing the need for statistical correction of unbalanced covariates. PMID- 25442068 TI - Demonstrating the benefits of transversus abdominis plane blocks on patient outcomes in laparoscopic colorectal surgery: review of 200 consecutive cases. AB - BACKGROUND: Quality improvement in colorectal surgery (CRS) requires implementation of tools to improve patient and financial outcomes, and assessment of results. Our objective was to evaluate the durability of transversus abdominis plane (TAP) blocks and a standardized enhanced recovery protocol (ERP) on a large series of laparoscopic colorectal resections. STUDY DESIGN: Two hundred consecutive laparoscopic CRS patients received TAP blocks under laparoscopic guidance at the end of their operation. All were managed with a standardized ERP. Demographic, perioperative, and postoperative outcomes variables were analyzed. The main outcomes measures were length of stay (LOS), readmission, reoperation, morbidity, and mortality rates. RESULTS: Of 200 cases, 194 were elective and 6 emergent. The main diagnosis was colorectal cancer (45%). The mean patient age was 61.2 years, mean body mass index was 29.2 kg/m(2), and the majority (63%) were American Society of Anesthesiologists (ASA) class III. The main procedure performed was a segmental colectomy (64%). Mean operative time was 181 minutes. Nine cases (4.5%) were converted to open. The median LOS was 2 days (range 1 to 8 days). Twenty-one percent were discharged by postoperative day (POD) 1, 41% by POD 2, and 77% by POD 3. By POD 7, 99% were discharged. Twelve percent (n = 24) had complications, and 6.5% (n = 13) were readmitted. There were 3 unplanned reoperations and no mortalities. Comparing the first and second groups of 100 consecutive patients further tested the consistency of the TAP block benefit. With comparable demographics, there were no significant differences in readmission, complication, or reoperation rates over the entire series. CONCLUSIONS: Adding TAP blocks to an ERP facilitated shorter LOS with low readmission and reoperation rates when compared to previously published series. The effect appears durable and consistent in a large case series. Transversus abdominis plane blocks may be an efficient, cost-effective method for improving laparoscopic CRS results. PMID- 25442069 TI - Foods from black market at EU border as a neglected route of potential methicillin-resistant Staphylococcus aureus transmission. AB - The illegal entrance of foods to EU through black markets at the EU borders can constitute a neglected route of dissemination of foodborne pathogens, and in particular of methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have assessed the presence of MRSA in foods sold in a black market at an EU border (the southeast part of Romania, on the border with Republic of Moldavia). We performed a search for MRSA among 200 food samples collected from 2012 to 2013. All S. aureus were studied by pulsed-field gel electrophoresis (PFGE) and antimicrobial susceptibility testing. MRSA isolates were further characterized by multilocus sequence typing (MLST) and SCCmec typing, and tested for the presence of Panton-Valentine leukocidin (PVL) virulence factors. Overall, 32 S. aureus isolates were recovered from 16 food samples (8%). One isolate detected in a pork lard sample was MRSA (0.5%). PFGE with the restriction enzyme SmaI revealed 12 genotypes among the 32 S. aureus isolates. The MRSA isolate belonged to sequence type 398, harbored SCCmec type V, tested negative for the presence of the PVL genes and was resistant to ciprofloxacin, tetracycline and cefazolin, besides all beta-lactams. Among 31 methicillin-sensitive S. aureus (MSSA), 29% were resistant to penicillin, 9.7% to tetracycline and 3.2% to ciprofloxacin. In conclusion, in this study we report the presence of livestock-associated MRSA in foods sold in a black market at an EU border: ST398-MRSA-V. These results confirm the potential role of food in the dissemination of MRSA lineages among population, and the potential role of illegally introduced food to EU in the prevalence and evolution of MRSA clones in the community. PMID- 25442070 TI - Effects of alendronate on osteoclast formation and activity in vitro. AB - INTRODUCTION: Root resorption is a common complication after replantation following traumatic dental avulsion. Endodontic therapy combined with local and intracanal medications aims to avoid osteoclastic activity. In such cases, the application of alendronate (ALN), a bisphosphonate widely used for the treatment of bone disorders, could be of clinical relevance. This study evaluated alendronate biocompatibility on periodontal ligament cells as well as its effects on an in vitro osteoclastogenesis model. METHODS: Alendronate cytotoxicity (10( 3) to 10(-9) mol/L) in human periodontal ligament fibroblasts, human osteogenic sarcoma cells, and murine osteoclastic precursors (RAW 264.7) was analyzed using cell number determination, cell viability, and proliferation assays. ALN (10(-6) to 10(-12) mol/L) effects on RANKL-induced osteoclastogenesis of RAW cells were assessed by tartrate-resistant acid phosphatase (TRAP) staining and activity and real-time polymerase chain reaction. RESULTS: ALN at higher concentrations was cytotoxic for all cell types, inhibiting significantly the proliferation of human osteogenic sarcoma cells and human periodontal ligament fibroblasts (>=10(-5) mol/L). TRAP activity and expression of the osteoclast markers TRAP and cathepsin K by RAW-derived osteoclasts decreased significantly with ALN at low concentrations, reaching the maximum effect at 10(-10) mol/L. CONCLUSIONS: We showed that ALN at very low concentrations is an effective inhibitor of RANKL generated osteoclasts, without causing cytotoxic effects on their precursors or periapical cells. ALN at such concentrations might be useful to prevent replacement resorption in avulsed teeth. PMID- 25442071 TI - Efficacy of 3 different irrigation systems on removal of calcium hydroxide from the root canal: a scanning electron microscopic study. AB - INTRODUCTION: The purpose of this study was to evaluate the effectiveness of different irrigation systems on removing calcium hydroxide (Ca[OH]2) from the root canal by using a scanning electron microscope. METHODS: Forty extracted single-rooted teeth were divided randomly into 4 groups. Canal instrumentation was done, and the teeth were filled with Ca(OH)2 paste. One week later, 4 techniques were used for Ca(OH)2 removal. In the first group, the canals were cleaned with a master apical file. The second, third, and fourth groups were irrigated using the EndoVac (Discus Dental, Culver City, CA), EndoActivator (Dentsply Tulsa Dental Specialties, Tulsa, OK), and ProUltra (Dentsply Tulsa, Tulsa, OK) systems, respectively. All the groups were irrigated with 3 mL (18%) EDTA and 3 mL (1%) NaOCl for 1 minute. The canal walls were viewed, and the remaining amount of Ca(OH)2 was evaluated using a scanning electron microscope. A scoring system was used to assess the amount of residue Ca(OH)2 on each third of the canal. The obtained data for comparisons between the conventional irrigation needle and each device were statistically analyzed using the Mann-Whitney U test. RESULTS: To compare the 4 devices, the results were statistically analyzed using the analysis of variance test. CONCLUSIONS: None of the investigated techniques removed the Ca(OH)2 dressing completely. However, the EndoActivator System showed better results in removing Ca(OH)2 in each third of the root canals in comparison with the other techniques. PMID- 25442072 TI - A cine-EPID based method for jaw detection and quality assurance for tracking jaw in IMRT/VMAT treatments. AB - A new tool with the potential to verify and track jaw position during delivery has been developed. The method should be suitable for independent quality assurance for jaw position during jaw tracking dynamic IMRT and VMAT treatments. The jaw detection and tracking algorithm developed consists of five main steps. Firstly, the image is enhanced by removing a normalised predicted EPID image (that does not include the collimator transmission) from each cine EPID image. Then, using a histogram clustering technique a global intensity threshold level was determined. This threshold level was used to classify each pixel of the image as either under the jaws or under the MLC. Additionally, the collimator angle was automatically detected and used to rotate the image to vertical direction. Finally, this rotation allows the jaw positions to be determined using vertical and horizontal projection profiles. Nine IMRT fields (with static jaws) and a single VMAT clinical field (with dynamic jaws) were tested by determining the root mean square difference between planned and detected jaw positions. The test results give a detection accuracy of +/-1 mm RMS error for static jaw IMRT treatments and +/-1.5 mm RMS error for the dynamic jaw VMAT treatment. This method is designed for quality assurance and verification in modern radiation therapy; to detect the position of static jaws or verify the position of tracking jaws in more complex treatments. This method uses only information extracted from EPID images and it is therefore independent from the linear accelerator. PMID- 25442073 TI - Incisional hernia repair after caesarean section: a population-based study. AB - BACKGROUND: Incisional hernias occur at surgical abdominal incision sites, but the association with caesarean section (CS) has not been examined. AIM: To determine whether CS is a risk factor for incisional hernia repair. MATERIALS AND METHODS: Population-based cohort study in Australia using linked birth and hospital data for women who gave birth from 2000 to 2011. Survival analysis was used to explore the association between CS and subsequent incisional hernia repair. Analyses were adjusted for confounding factors, including other abdominal surgery. The main outcome measure was surgical repair of an incisional hernia. RESULTS: Of 642,578 women, 217,555 (33.9%) had at least one CS and 1,554 (0.2%) women had a subsequent incisional hernia repair. The rate of incisional hernia repair in women who had ever had a caesarean section was 0.47%, compared to 0.12% in women who never had a caesarean section. After controlling for the duration of follow-up and known explanatory variables (eg other abdominal surgery, parity and multiple pregnancy), the adjusted hazard ratio (aHR) was 2.73 (95% confidence interval (CI) 2.45-3.06, P < 0.001). Incisional hernia repair risk increased with number of caesarean sections: women with two CS had a threefold increased risk of incisional hernia repair, which increased to sixfold after five CS (aHR = 6.29, 95% CI 3.99-9.93, P < 0.001) compared to women with no CS. CONCLUSIONS: There was a strong association between maternal CS and subsequent incisional hernia repair, which increased as the number of CSs increased, but the absolute risk of incisional hernia repair was low. PMID- 25442074 TI - Genomic microarray analysis on formalin-fixed paraffin-embedded material for uveal melanoma prognostication. AB - Cytogenetic alterations are strong outcome prognosticators in uveal melanoma (UVM). Monosomy 3 (-3) and MYC amplification at 8q24 are commonly tested by fluorescence in situ hybridization (FISH). Alternatively, microarray analysis provides whole genome data, detecting partial chromosome loss, loss of heterozygosity (LOH), or abnormalities unrepresented by FISH probes. Nonfixed frozen tissue is conventionally used for microarray analysis but may not always be available. We assessed the feasibility of genomic microarray analysis for high resolution interrogation of UVM using formalin-fixed paraffin-embedded tissue (FFPET) as an alternative to frozen tissue (FZT). Enucleations from 44 patients (clinical trial NCT00952939) yielded sufficient DNA from FFPET (n = 34) and/or frozen tissue (n = 41) for comparative genomic hybridization and select single nucleotide polymorphism analysis (CGH/SNP) on Roche-NimbleGen OncoChip arrays. CEP3 FISH analysis was performed on matched cytology ThinPrep material. CGH/SNP analysis was successful in 30 of 34 FFPET and 41 of 41 FZT samples. Of 27 paired FFPET/FZT samples, 26 (96.3%) were concordant for at least four of six major recurrent abnormalities (-3, +8q, -1p, +6p, -6q, -8p), and 25 of 27 (92.6%) were concordant for -3. Results of CGH/SNP were concordant with the CEP3 FISH results in 27 of 30 (90%) FFPET and 38 of 41 (92.6%) FZT cases; partial -3q was detected in two CEP3 FISH-negative cases and whole chromosome 3, 4, and 6 SNP-LOH in one case. CGH detection of -3, +8q, -8p on FFPET and FZT showed significant correlation with the clinical outcome measures (metastasis development, time to progression, survival). Results of the UVM genotyping by CGH/SNP on FFPET are highly concordant with those of the FZT analysis and with those of the CEP3 FISH analysis, and therefore CGH/SNP is a practical method for UVM prognostication. Genome-wide coverage provides additional data with potential relevance to UVM biology, diagnosis, and prognosis. PMID- 25442075 TI - Chemoradiation in elderly patients with head and neck cancers: a single institution experience. AB - AIMS: To evaluate the efficacy and toxicity of concurrent chemoradiation in patients with head and neck cancers aged 65 and older. MATERIALS AND METHODS: Thirty-two elderly patients were treated with radical chemoradiation. Twenty-six (81.3%) out of thirty-two patients had stage III-IV disease. Twenty-nine (90.6%) patients received concurrent weekly cisplatin or carboplatin, 3 (9.4%) patients received concurrent cetuximab or nimotuzumab. Total dose of radiotherapy ranged from 66Gy to 70Gy. RESULTS: Twenty-nine patients (90.6%) completed at least 5cycles of concurrent chemotherapy. Twenty-four (77.6%) patients achieved complete response. Fourteen (45.2%) patients experienced grade 3 mucositis. None of our patients developed grade 3 or above hematological toxicity. Loco-regional control and overall survival at 2year were 71.6% and 88.9%, respectively. CONCLUSIONS: Chemoradiation in elderly patients with high precision radiotherapy is a feasible option. PMID- 25442076 TI - Anchor technique: prevention of intraluminal stent migration with the help of loop and clips. PMID- 25442077 TI - Challenging EMR for the definite diagnosis of submucosal tumor in the small bowel by using double-balloon endoscopy. PMID- 25442078 TI - Failed attempt at duodenal perforation closure with over-the-scope clip. PMID- 25442079 TI - Blue rubber bleb nevus syndrome: treatment of lesions in the small intestine with repeated injection of lauromacrogol. PMID- 25442080 TI - Risk factors for post-ERCP pancreatitis in wire-guided cannulation for therapeutic biliary ERCP. AB - BACKGROUND: Wire-guided cannulation (WGC) was reported to decrease post-ERCP pancreatitis (PEP), but risk factors for PEP in WGC are not fully elucidated. OBJECTIVE: To evaluate the incidence and risk factors of PEP in WGC. DESIGN: Single-center retrospective study. SETTING: Academic center. PATIENTS: A total of 800 consecutive patients with a native papilla. INTERVENTIONS: Biliary therapeutic ERCP by using WGC. MAIN OUTCOME MEASUREMENTS: The rate of PEP and its risk factors. RESULTS: Biliary cannulation was successful by using WGC alone in 70.5%, and the final cannulation rate was 96.1%. Unintentional guidewire insertion and contrast material injection into the pancreatic duct (PD) during cannulation occurred in 55.3% and 21.8%, respectively. The incidence of PEP was 9.5% (mild 5.6%, moderate 2.9%, severe 1.0%). Multivariate analysis revealed a common bile duct (CBD) diameter of <9 mm (odds ratio [OR] 2.03; P = .006) and unintentional guidewire insertion into the PD (OR 2.25; P = .014) as risk factors for PEP. PD opacification was not a risk factor for PEP (OR 1.15; P = .642), but the incremental increase of the PEP rate was seen in patients with CBDs <9 mm: 4.6% without any PD manipulation, 8.3% with contrast material alone, 16.9% with guidewire alone, and 22.1% with both contrast material and guidewire. LIMITATIONS: Retrospective design in a single center. CONCLUSION: Unintentional PD manipulation was not uncommon in WGC. Guidewire insertion into the PD and a small CBD were risk factors for PEP in biliary therapeutic ERCP with the use of WGC. PMID- 25442081 TI - Mechanical lithotriptor-assisted endoscopic removal of an eroded gastric lap band. PMID- 25442082 TI - In vivo histopathology using endocytoscopy for non-neoplastic changes in the gastric mucosa: a prospective pilot study (with video). AB - BACKGROUND: Endocytoscopy (EC), as a novel ultrahigh magnification technology, enables in vivo histopathological diagnoses of the GI tract. EC is particularly exceptional when comparing dysplastic and neoplastic tissue with normal tissue. There are, however, no detailed data for minute or minimal changes in the gastric mucosa. OBJECTIVE: To describe non-neoplastic EC patterns of the gastric mucosa correlated with histopathological findings and to determine any relationship with Helicobacter pylori (HP) infection. DESIGN: A pilot prospective study. SETTING: Tertiary care referral center. PATIENTS: Sixty-four participants undergoing upper endoscopy for various indications. METHODS: Antral mucosal patterns on EC were divided into 4 categories: type 1 (normal), each papilla/pit has round smooth structure; type 2 (gastritis), extended, notched, and distorted structure with some necrotic tissue; type 3(atrophy), neighboring papilla/pit take on a lobulated appearance; type 4 (intestinal metaplasia [IM]), goblet cells are identified in a completely stained crypt. Target biopsy specimens were obtained from the region identified with these patterns, and multiple HP tests were performed. RESULTS: HP positivity was 0%, 40.9%, 50.0%, and 58.3% in types 1, 2, 3, and 4, respectively. The sensitivity and specificity of types 2+3+4 for HP positivity were 100% and 42.5%, respectively. The positive predictive values of type 1 for normal, type 2 for chronic gastritis, type 3 for atrophic gastritis, and type 4 for IM were 100%, 62.5%, 40.0%, and 100%, respectively. The sensitivity and specificity of types 3+4 for atrophic gastritis to IM were 87.0% and 95.1%, respectively. LIMITATIONS: Small, single-center, pilot study. CONCLUSIONS: EC can differentiate gastric mucosal patterns of minimal, non neoplastic change and appears to reliably exclude HP infection. PMID- 25442084 TI - Early metal stent insertion fails to prevent stricturing after single-stage complete Barrett's excision for high-grade dysplasia and early cancer. AB - BACKGROUND: Barrett's esophagus with high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) can be effectively treated by single-session EMR, resulting in complete Barrett's excision (CBE). CBE provides accurate histology for staging and clinical confirmation of neoplasia eradication but is limited by a high risk of esophageal stricture formation. OBJECTIVE: To evaluate the effectiveness of prophylactic temporary esophageal stenting to prevent post-CBE stricture formation. DESIGN AND SETTING: Single-center, investigator-initiated feasibility study. PATIENTS: Circumferential, short-segment Barrett's esophagus (<=C3<=M5) with HGD or IMC. INTERVENTION: Single-stage CBE and insertion of a fully covered metal esophageal stent at 10 days that was removed at 8 weeks. Patients were followed for a minimum of 2 surveillance endoscopies. MAIN OUTCOME MEASUREMENT: Symptomatic esophageal stricture formation. RESULTS: At the end of the follow-up period, 8 patients (57.1%) required esophageal dilation for symptomatic CBE related (n = 7) or stent-related (n = 4) strictures. A median of 3 surveillance endoscopies were performed over a median endoscopic follow-up of 17 months (range 4-25 months). Single-stage CBE successfully eliminated Barrett's intestinal metaplasia and neoplasia in 71.4% and 92.9% of patients, respectively. Four patients were admitted to the hospital, and 4 patients had early stent removal because of pain or dysphagia. LIMITATIONS: Single-center feasibility study. CONCLUSIONS: In a prospective study evaluating prophylactic esophageal stent insertion after single-stage CBE, esophageal strictures formed in more than of half the study cohort, and stents were associated with significant morbidity. An alternative method to reduce stricture formation is required. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01554280.). PMID- 25442083 TI - Plastic biliary stent patency in patients with locally advanced pancreatic adenocarcinoma receiving downstaging chemotherapy. AB - BACKGROUND: Plastic stents in patients with biliary obstruction caused by pancreatic adenocarcinoma are typically exchanged at 3-month intervals. Plastic stents may have reduced durability in patients receiving chemotherapy. OBJECTIVE: To determine the duration of plastic biliary stent patency in patients undergoing chemotherapy for pancreatic adenocarcinoma. DESIGN: Retrospective, multicenter cohort study. SETTING: Three tertiary academic referral centers. PATIENTS: A total of 173 patients receiving downstaging chemotherapy for locally advanced or borderline resectable pancreatic adenocarcinoma from 1996 to 2013. INTERVENTIONS: Placement of 10F or larger plastic biliary stents. MAIN OUTCOME MEASUREMENTS: Primary outcome was overall duration of stent patency. Secondary outcomes included the incidence of premature stent exchange (because of cholangitis or jaundice) and hospitalization rates. RESULTS: A total of 233 plastic stents were placed, and the overall median duration of stent patency was 53 days (interquartile range [IQR] 25-99 days). Eighty-seven stents were removed at the time of surgical resection, and 63 stents were exchanged routinely per protocol. The remaining 83 stent exchanges were performed for worsening liver function test results, jaundice, or cholangitis, representing a 35.6% rate of premature stent exchange. The median stent patency duration in the premature stent exchange group was 49 days (IQR 25-91 days) with a 44.6% hospitalization rate. The overall rate of cholangitis was 15.0% of stent exchanges, occurring a median of 56 days after stent placement (IQR 26-89 days). LIMITATIONS: Retrospective study. CONCLUSIONS: Plastic biliary stents placed during chemotherapy/chemoradiation for pancreatic adenocarcinoma have a shorter-than-expected patency duration, and a substantial number of patients will require premature stent exchange. Consideration should be given to shortening the interval for plastic biliary stent exchange. PMID- 25442085 TI - Differentiation of pancreatic ductal adenocarcinoma from other neoplastic solid pancreatic lesions: a tertiary oncology center experience. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), pancreatic neuroendocrine tumors (pNET), and metastatic lesions (pMET) are the most common neoplastic solid pancreatic lesions (SPLs). Early diagnosis enables prompt treatment. OBJECTIVE: To identify factors differentiating PDAC from non-PDAC lesions and assess the accuracy of EUS-guided FNA. DESIGN AND SETTING: Retrospective tertiary center. PATIENTS AND INTERVENTION: Consecutive patients referred for EUS evaluation of SPLs from 2004 to 2011. MAIN OUTCOME MEASUREMENTS: Pretest (preceding EUS-guided FNA [EUS-FNA]) predictors of PDAC among neoplastic SPLs and accuracy of EUS-FNA. RESULTS: A total of 1333 EUS scans with 1108 EUS-FNAs were performed for pancreatic lesions. Of the 672 patients with neoplastic SPLs, 528 had PDAC and 144 non-PDAC. The sensitivity, specificity, positive predictive value, and accuracy of EUS-FNA for the diagnosis of PDAC were 97.3%, 99.3%, 99.8%, and 97.8%, respectively. Years of EUS experience significantly correlated with fewer needle passes (Rs = -0.18, P < .001). Controlling for all potential confounders, multivariable regression analysis demonstrated that patients with PDAC compared with pNETs and pMETs were older (odds ratio [OR] 4.42; 95% confidence interval [CI], 2.1-9.5; P < .001), had weight loss (OR 3.0; 95% CI, 1.6-5.4; P < .001), hyperbilirubinemia (OR 3.7; 95% CI, 1.8-7.5; P < .001), elevated CA19-9 (OR 6.9; 95% CI, 2.4-20.3; P < .01), evidence of arterial invasion (OR 6.5; 95% CI, 2.7 15.4; P < .001), and PD dilation (OR 3.3; 95% CI, 1.8-5.9; P < .001). LIMITATIONS: Retrospective design, single center. CONCLUSIONS: When evaluating neoplastic SPLs, demographic, clinical, laboratory, and imaging characteristics can reliably discern and suggest PDAC. In addition, EUS-FNA is exceedingly sensitive and specific for PDAC. PMID- 25442086 TI - Learning curve for EUS in gastric cancer T staging by using cumulative sum analysis. AB - BACKGROUND: EUS is an operator-dependent procedure and requires more technical and cognitive skills than a routine endoscopic procedure. The learning curve for the staging of gastric cancer, however, has not been evaluated. OBJECTIVE: To evaluate the threshold number of EUS examinations for gastric cancer T staging. DESIGN: Retrospective study. SETTING: University-affiliated tertiary care hospital in the Republic of Korea. PATIENTS: Four trainees with no previous EUS experience. INTERVENTION: Analyzing performance of EUS trainees in gastric cancer T staging by using cumulative sum (CUSUM) analysis. MAIN OUTCOME MEASUREMENTS: CUSUM plot and a minimal number of procedures for reaching a plateau. RESULTS: A total of 553 initial EUS examinations for treatment-naive gastric cancers, performed by trainees, were enrolled in the study. The final T stage was determined by experts by using EUS in 332 gastric cancer cases, whereas the T stage of the other 221 lesions was determined by trainees by using EUS. The accuracy of EUS examinations performed by trainees and experts was 72.6% and 84.3%, respectively. The number of EUS examinations required to reach the first plateau in each trainee was 20, 41, 60, and 65. LIMITATIONS: Retrospective study with a relatively small number of trainees. CONCLUSION: The CUSUM scores of all of 4 trainees in the study reached a plateau by the 65th examination. PMID- 25442087 TI - Drainage of infected pancreatic necrosis by using 2 lumen-apposing metal stents, a nasocystic drain, and hydrogen peroxide. PMID- 25442088 TI - Diagnostic performance of EUS in predicting advanced cancer among patients with Barrett's esophagus and high-grade dysplasia/early adenocarcinoma: systematic review and meta-analysis. AB - BACKGROUND: The role of EUS among patients with Barrett's esophagus (BE) with high-grade dysplasia (HGD) or suspected mucosal carcinoma is controversial. OBJECTIVE: To define the role of EUS in detecting advanced disease among patients with BE. DESIGN: Systematic review and meta-analysis. SETTING: MEDLINE, Embase, Web of Science, and Cochrane Central databases. PATIENTS: Patients with BE and HGD or esophageal adenocarcinoma (EAC) who were referred for endoscopic evaluation and underwent EUS. INTERVENTIONS: EUS. MAIN OUTCOME MEASUREMENTS: Pooled proportion of patients with advanced EAC identified by EUS among patients with BE who are referred for HGD or EAC (with or without visible lesions). Forest plots were used to contrast effect sizes in each of the studies and random effect models when tests of heterogeneity were significant (I(2) > 50% or P < .1 for the Q statistic). RESULTS: Of 1278 articles, 47 were reviewed in full text, and 11 articles met the inclusion criteria, including a total of 656 patients. Based on a random-effects model, the proportion of patients with advanced disease detected on EUS was 14% (95% confidence interval, 8%-22%; P < .0001). In a subanalysis, the pooled proportion of patients with advanced disease on EUS in the absence of nodules was 4% (95% confidence interval, 2%-6%, P < .0001). LIMITATIONS: Significant heterogeneity among studies. CONCLUSIONS: EUS will result in a change in the therapeutic approach among in a significant minority of patients with BE who are referred for HGD or EAC. PMID- 25442089 TI - Antibiotic prophylaxis for GI endoscopy. PMID- 25442090 TI - Cholangioscopic evaluation of a sectoral biliary stricture. PMID- 25442091 TI - High-definition and high-magnification endoscopes. PMID- 25442092 TI - Confocal laser endomicroscopy. PMID- 25442093 TI - Absent microsurface pattern is characteristic of early gastric cancer of undifferentiated type: magnifying endoscopy with narrow-band imaging. PMID- 25442094 TI - Spine surgery training: is it time to consider categorical spine surgery residency? PMID- 25442095 TI - Influence of feeding mixture composition in batch anaerobic co-digestion of stabilized municipal sludge and waste from dairy farms. AB - Waste anaerobic co-digestion applications are particularly useful in Southern Mediterranean areas where large quantities of agricultural waste materials and waste from agro-industries are produced. This waste can be added to urban waste together with the sludge produced by wastewater treatment processes, which, when combined, guarantee the supply of organic matrixes for treatment throughout the year. The implementation of facilities to service vast areas of the agricultural economy and which are heterogeneous in terms of production can provide a good solution. We present an experimental investigation into the anaerobic co digestion of municipal sludge and bio-waste produced in the Mediterranean area. We conducted anaerobic treatability tests, with measures of biogas production and pH of the mixture in digestion. Our main aims were to identify an optimal mix of substrates for the production of biogas, and to analyse the influence on the composition of biogas and the variation in pH values of the substrates. This analysis was conducted considering the variation of the input, in particular due to the addition of waste acids, such as biological sewage sludge. PMID- 25442104 TI - Influence of initial pH on thermophilic anaerobic co-digestion of swine manure and maize stalk. AB - The contradictions between the increasing energy demand and decreasing fossil fuels are making the use of renewable energy the key to the sustainable development of energy in the future. Biogas, a renewable clean energy, can be obtained by the anaerobic fermentation of manure waste and agricultural straw. This study examined the initial pH value had obvious effect on methane production and the process in the thermophilic anaerobic co-digestion. Five different initial pH levels with three different manure ratios were tested. All digesters in different initial pH showed a diverse methane production after 35 days. The VFA/alkalinity ratio of the optimum reaction condition for methanogens activity was in the range of 0.1-0.3 and the optimal condition that at the 70% dung ratio and initial pH 6.81, was expected to achieve maximum total biogas production (146.32 mL/g VS). PMID- 25442105 TI - Quantification of methane emissions from 15 Danish landfills using the mobile tracer dispersion method. AB - Whole-site methane emissions from 15 Danish landfills were assessed using a mobile tracer dispersion method with either Fourier transform infrared spectroscopy (FTIR), using nitrous oxide as a tracer gas, or cavity ring-down spectrometry (CRDS), using acetylene as a tracer gas. The landfills were chosen to represent the different stages of the lifetime of a landfill, including open, active, and closed covered landfills, as well as those with and without gas extraction for utilisation or flaring. Measurements also included landfills with biocover for oxidizing any fugitive methane. Methane emission rates ranged from 2.6 to 60.8 kg h(-1), corresponding to 0.7-13.2 g m(-2)d(-1), with the largest emission rates per area coming from landfills with malfunctioning gas extraction systems installed, and the smallest emission rates from landfills closed decades ago and landfills with an engineered biocover installed. Landfills with gas collection and recovery systems had a recovery efficiency of 41-81%. Landfills where shredder waste was deposited showed significant methane emissions, with the largest emission from newly deposited shredder waste. The average methane emission from the landfills was 154 tons y(-1). This average was obtained from a few measurement campaigns conducted at each of the 15 landfills and extrapolating to annual emissions requires more measurements. Assuming that these landfills are representative of the average Danish landfill, the total emission from Danish landfills were calculated at 20,600 tons y(-1), which is significantly lower than the 33,300 tons y(-1) estimated for the national greenhouse gas inventory for 2011. PMID- 25442096 TI - Regulatory mechanisms of testosterone-stimulated song in the sensorimotor nucleus HVC of female songbirds. AB - BACKGROUND: In male birds, influence of the sex steroid hormone testosterone and its estrogenic metabolites on seasonal song behavior has been demonstrated for many species. In contrast, female song was only recently recognized to be widespread among songbird species, and to date, sex hormone effects on singing and brain regions controlling song development and production (song control nuclei) have been studied in females almost exclusively using domesticated canaries (Serinus canaria). However, domesticated female canaries hardly sing at all in normal circumstances and exhibit only very weak, if any, song seasonally under the natural photoperiod. By contrast, adult female European robins (Erithacus rubecula) routinely sing during the winter season, a time when they defend feeding territories and show elevated circulating testosterone levels. We therefore used wild female European robins captured in the fall to examine the effects of testosterone administration on song as well as on the anatomy and the transcriptome of the song control nucleus HVC (sic). The results obtained from female robins were compared to outcomes of a similar experiment done in female domesticated canaries. RESULTS: Testosterone treatment induced abundant song in female robins. Examination of HVC transcriptomes and histological analyses of song control nuclei showed testosterone-induced differentiation processes related to neuron growth and spacing, angiogenesis and neuron projection morphogenesis. Similar effects were found in female canaries treated with testosterone. In contrast, the expression of genes related to synaptic transmission was not enhanced in the HVC of testosterone treated female robins but was strongly up regulated in female canaries. A comparison of the testosterone-stimulated transcriptomes indicated that brain-derived neurotrophic factor (BDNF) likely functions as a common mediator of the testosterone effects in HVC. CONCLUSIONS: Testosterone-induced singing of female robins correlated with cellular differentiation processes in the HVC that were partially similar to those seen in the HVC of testosterone-treated female canaries. Other modes of testosterone action, notably related to synaptic transmission, appeared to be regulated in a more species-specific manner in the female HVC. Divergent effects of testosterone on the HVC of different species might be related to differences between species in regulatory mechanisms of the singing behavior. PMID- 25442106 TI - Hydrogen and waste: illusions, challenges and perspectives. PMID- 25442107 TI - Foundations of invasion genetics: the Baker and Stebbins legacy. AB - Invasion genetics is a relatively new discipline that investigates patterns of genetic variation in populations of invasive species and their ecological and evolutionary consequences. Evolutionary biologists have a long-standing interest in colonizing species, owing to their short life cycles and widespread distributions, but not until publication of The Genetics of Colonizing Species (1965), edited by H.G. Baker and G.L. Stebbins, was a synthesis on the genetics and evolution of colonizers available. Here, I make the case that the Baker and Stebbins volume is the foundational document for invasion genetics, and in conjunction with the increased use of genetic markers and development of invasion biology, resulted in the birth of this new field over the past two decades. I consider the historical origins and legacy of the Baker and Stebbins volume and review some of the key issues that were addressed. I provide biographical sketches of the two editors, emphasizing their contrasting backgrounds and personalities. I review examples from my own work on plant invasions that are relevant to issues discussed by contributors to the volume. These include the following: determinants of invasion success, life history trade-offs, generalist vs. specialist strategies, general-purpose genotypes, adaptive phenotypic plasticity, mating systems and the influence of bottlenecks on genetic variation. I conclude by posing several key questions in invasion genetics and argue that one of the main challenges that the area faces is to integrate experimental field studies of the ecology and demography of populations with the largely descriptive approaches that have tended to dominate most research to date. PMID- 25442108 TI - Intralesional vs. contact cryosurgery in treatment of keloids: a clinical and immunohistochemical study. AB - BACKGROUND: Cryosurgery is a safe and effective treatment of keloids. Intralesional cryosurgery has been shown to bring about significant improvement in keloids. The histopathological and immunohistochemical changes in keloids following cryosurgery are not well-assessed. METHODS: Twenty-three patients with 66 keloids were treated with either the contact (cryoprobe) method or intralesional cryosurgery. Keloid specimens were obtained before treatment and after two sessions of treatment for evaluation of keloid pathology and immunohistochemical changes in expression of vascular endothelial growth factor (VEGF) and tenascin C induced by both cryosurgical techniques. RESULTS: A better therapeutic response was detected after intralesional cryosurgery (excellent response [ER], 87%) than contact cryosurgery (ER, 60%; P < 0.05). The intralesional technique achieved higher rates of flattening after the first two sessions (ER in 61.3% and 22.9%, respectively; P < 0.05) and caused fewer side effects compared with the contact method. Both cryosurgical methods resulted in a significant decrease in VEGF and tenascin C expression in keloids. CONCLUSIONS: Intralesional cryosurgery is superior to contact cryosurgery in terms of efficacy and safety. Both techniques may have beneficial effects on keloids, at least partially, through the modulation of VEGF and tenascin C expression. PMID- 25442109 TI - Renal impairment in HIV-infected patients initiating tenofovir-containing antiretroviral therapy regimens in a Primary Healthcare Setting in South Africa. AB - OBJECTIVE: Long-term use of tenofovir disoproxil fumarate is associated with declines in glomerular function and chronic kidney disease in HIV-infected patients. We aimed to assess the prevalence and incidence of renal impairment in a primary care setting in sub-Saharan Africa. METHODS: We analysed data from 1092 HIV-infected patients initiating tenofovir at a primary care clinic in Cape Town, South Africa. Renal function was assessed for the first 12 months on ART by estimating glomerular filtration rate (eGFR) calculated using the Cockroft-Gault equation categorised into normal, mild, moderate and severe reduction in renal function based on values >90, 60-89, 30-59 and <30 ml/min/1.73 m(2) , respectively. Associations were assessed using logistic regression, and average GFR trajectory over time was modelled using linear mixed-effects models. RESULTS: The cohort consisted of 62% women; median age was 34 years (IQR 29; 41 years). The majority had normal renal function pre-ART (79%), 19% had mildly reduced GFR, and 2% had moderate renal impairment. Older age, more advanced WHO stage and anaemia were independently associated with prevalent renal impairment. On average, estimated glomerular function improved over the first year on tenofovir [1.10 ml/min/1.73 m(2) average increase over 12 months (95% CI: 0.80; 1.40)]. Male gender, anaemia and immunosuppression (WHO Stage III/IV and CD4 cell counts <100 cells/mm(3) ) were associated with lower average eGFR levels over time. Overall, 3% developed eGFR <50 ml/min/1.73 m(2) during this period. Serum creatinine tests conducted before 4 months on ART had low predictive value for predicting change in eGFR after a year on ART. CONCLUSION: Generally, renal function improved in HIV-infected adults initiating ART in this primary healthcare setting during the first year on ART. While monitoring of renal function is recommended in the first 4 months on ART, renal impairment appears uncommon during the first 12 months of tenofovir-containing ART in primary care populations. PMID- 25442110 TI - Characterization of DNA G-quadruplex species forming from C9ORF72 G4C2-expanded repeats associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. AB - The G4C2 hexanucleotide repeat expansion, located in the first intron of the C9ORF72 gene, represents a major genetic hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Several hypotheses have been proposed on how the transcribed repeat RNA leads to the development of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. However, despite their importance, factors affecting the transcription of expanded-repeat RNA are not well known. As transcription is dependent on the DNA containing the expanded repeats, it is crucial to understand its structure. G-quadruplexes are known to affect expression on the level of DNA, therefore whether they form on the expanded-repeat DNA constitutes an important biological question. Using nuclear magnetic resonance and circular dichroism spectroscopy we show that DNA G4C2 with varying number of repeats d(G4C2)n form planar guanine quartets characteristic of G-quadruplexes. Additionally, we show DNA G-quadruplexes can form inter- and intra-molecularly in either parallel or anti-parallel orientation, based on d(G4C2) sequence length. This potential structural heterogeneity of longer disease-relevant repeats should therefore be taken into account when studying their role in disease pathogenesis. PMID- 25442111 TI - Human secreted tau increases amyloid-beta production. AB - The interaction of amyloid-beta (Abeta) and tau in the pathogenesis of Alzheimer's disease is a subject of intense inquiry, with the bulk of evidence indicating that changes in tau are downstream of Abeta. It has been shown however, that human tau overexpression in amyloid precursor protein transgenic mice increases Abeta plaque deposition. Here, we confirm that human tau increases Abeta levels. To determine if the observed changes in Abeta levels were because of intracellular or extracellular secreted tau (eTau for extracellular tau), we affinity purified secreted tau from Alzheimer's disease patient-derived cortical neuron conditioned media and analyzed it by liquid chromatography-mass spectrometry. We found the extracellular species to be composed predominantly of a series of N-terminal fragments of tau, with no evidence of C-terminal tau fragments. We characterized a subset of high affinity tau antibodies, each capable of engaging and neutralizing eTau. We found that neutralizing eTau reduces Abeta levels in vitro in primary human cortical neurons where exogenously adding eTau increases Abeta levels. In vivo, neutralizing human tau in 2 human tau transgenic models also reduced Abeta levels. We show that the human tau insert sequence is sufficient to cause the observed increase in Abeta levels. Our data furthermore suggest that neuronal hyperactivity may be the mechanism by which this regulation occurs. We show that neuronal hyperactivity regulates both eTau secretion and Abeta production. Electrophysiological analysis shows for the first time that secreted eTau causes neuronal hyperactivity. Its induction of hyperactivity may be the mechanism by which eTau regulates Abeta production. Together with previous findings, these data posit a novel connection between tau and Abeta, suggesting a dynamic mechanism of positive feed forward regulation. Abeta drives the disease pathway through tau, with eTau further increasing Abeta levels, perpetuating a destructive cycle. PMID- 25442112 TI - Stimulation of the mineralocorticoid receptor improves memory in young and elderly healthy individuals. AB - Glucocorticoids play an important role in cognitive function and act on glucocorticoid receptors and mineralocorticoid receptors (MRs) in the brain. Previously, the blockade of the MR has been shown to impair visuospatial and working memory in healthy young men. Here, we investigated the effects of the MR agonist fludrocortisone on memory in young and elderly healthy individuals. Thirty-one young (mean age 25.4 +/- 4.6 years) and 22 elderly (mean age 63.2 +/- 8.2 years) healthy participants received the MR agonist fludrocortisone (0.4 mg) or placebo at least 3 days apart in a randomized, double-blind within-subject cross-over design. We measured verbal memory (auditory verbal learning test), nonverbal memory (Rey/Taylor complex figure test), and working memory (digit-span task). As expected, young participants performed significantly better than elderly individuals in visuospatial memory (effect of group: F = 42.7, p < 0.01), verbal memory (F = 33.1, p < 0.01), and working memory (digit-span backward: F = 4.5, p = 0.04). For visuospatial memory (F = 5.0, p = 0.03) and short-term and working memory (digit-span forward: F = 4.2, p = 0.05), we found a significant treatment effect indicating better memory performance after fludrocortisone compared with placebo across groups. In concert with the previous studies, our data suggest a role of the MR in memory function. A cognitive enhancing effect by MR stimulation warrants future studies. PMID- 25442114 TI - Abeta and NMDAR activation cause mitochondrial dysfunction involving ER calcium release. AB - Early cognitive deficits in Alzheimer's disease (AD) seem to be correlated to dysregulation of glutamate receptors evoked by amyloid-beta (Abeta) peptide. Abeta interference with the activity of N-methyl-d-aspartate receptors (NMDARs) may be a relevant factor for Abeta-induced mitochondrial toxicity and neuronal dysfunction. To evaluate the role of mitochondria in NMDARs activation mediated by Abeta, we followed in situ single-cell simultaneous measurement of cytosolic free Ca(2+)(Cai(2+)) and mitochondrial membrane potential in primary cortical neurons. Our results show that direct exposure to Abeta + NMDA largely increased Cai(2+) and induced immediate mitochondrial depolarization, compared with Abeta or NMDA alone. Mitochondrial depolarization induced by rotenone strongly inhibited the rise in Cai(2+) evoked by Abeta or NMDA, suggesting that mitochondria control Ca(2+) entry through NMDARs. However, incubation with rotenone did not preclude mitochondrial Ca(2+) (mitCa(2+)) retention in cells treated with Abeta. Abeta-induced Cai(2+) and mitCa(2+) rise were inhibited by ifenprodil, an antagonist of GluN2B-containing NMDARs. Exposure to Abeta + NMDA further evoked a higher mitCa(2+) retention, which was ameliorated in GluN2B(-/-) cortical neurons, largely implicating the involvement of this NMDAR subunit. Moreover, pharmacologic inhibition of endoplasmic reticulum (ER) inositol-1,4,5 triphosphate receptor (IP3R) and mitCa(2+) uniporter (MCU) evidenced that Abeta + NMDA-induced mitCa(2+) rise involves ER Ca(2+) release through IP3R and mitochondrial entry by the MCU. Altogether, data highlight mitCa(2+) dyshomeostasis and subsequent dysfunction as mechanisms relevant for early neuronal dysfunction in AD linked to Abeta-mediated GluN2B-composed NMDARs activation. PMID- 25442115 TI - Functional complementation in Drosophila to predict the pathogenicity of TARDBP variants: evidence for a loss-of-function mechanism. AB - The human TAR DNA binding protein 43 (TDP-43), encoded by the gene TARDBP, plays a central role in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. TDP-43 inclusions are also found in up to approximately 60% of Alzheimer's disease (AD) brains. Although ALS-causing TARDBP mutations cluster in the C-terminal glycine-rich region of the protein, the pathogenic nature of the atypical missense variants p.A90V (located between the bipartite nuclear localization signal) and p.D169G (located in the first RNA-binding domain) is unclear. In addition, whether causal ALS mutations represent gain or loss-of function alleles remains unknown. We recently reported that loss-of-function of the highly conserved TARDBP ortholog in Drosophila (called TBPH) leads to death of bursicon neurons resulting in adult maturation and wing expansion defects. Here, we compared wild-type TARDBP, 2 typical ALS-causing mutations (p.G287S and p.A315T) and 2 atypical variants (p.A90V and p.D169G), for their ability to complement neuronal TBPH loss-of-function. Although p.D169G rescued organismal pupal lethality and neuronal loss to a similar extent as wild-type TARDBP, p.A90V, p.G287S, and p.A315T were less efficient. Accordingly, p.A90V, p.G287S, and p.A315T but not p.D169G or wild-type protein promoted a shift of TDP-43 from the nucleus to the cytoplasm in approximately 12%-14% of bursicon neurons. Finally, we found that the carrier frequency of rare variant p.A90V was higher in French-Belgian AD cases (5/1714, 0.29%) than in controls of European descent (5/9436, 0.05%) (odds ratio = 5.5; 95% confidence interval, 1.6-19.0; p = 0.009). We propose that pathogenic TARDBP mutations have partial loss-of-function properties and that TARDBP p.A90V may increase AD risk by the same mechanism. PMID- 25442113 TI - Inhibition of phosphodiesterase 2 reverses impaired cognition and neuronal remodeling caused by chronic stress. AB - Chronic stress and neuronal vulnerability have recently been recognized as factors contributing to cognitive disorders. One way to modify neuronal vulnerability is through mediation of phosphodiesterase 2 (PDE2), an enzyme that exerts its action on cognitive processes via the control of intracellular second messengers, cGMP and, to a lesser extent, cAMP. This study explored the effects of a PDE2 inhibitor, Bay 60-7550, on stress-induced learning and memory dysfunction in terms of its ramification on behavioral, morphologic, and molecular changes. Bay 60-7550 reversed stress-induced cognitive impairment in the Morris water maze, novel object recognition, and location tasks (object recognition test and/or object location test), effects prevented by treatment with 7-NI, a selective inhibitor of neuronal nitric oxide synthase; MK801, a glutamate receptor (NMDAR) inhibitor; myr-AIP, a CaMKII inhibitor; and KT5823, a protein kinase G inhibitor. Bay 60-7550 also ameliorated stress-induced structural remodeling in the CA1 of the hippocampus, leading to increases in dendritic branching, length, and spine density. However, the neuroplasticity initiated by Bay 60-7550 was not seen in the presence of 7-NI, MK801, myr-AIP, or KT5823. PDE2 inhibition reduced stress-induced extracellular-regulated protein kinase activation and attenuated stress-induced decreases in transcription factors (e.g., Elk-1, TORC1, and CREB phosphorylation) and plasticity-related proteins (e.g., Egr-1 and brain-derived neurotrophic factor). Pretreatment with inhibitors of NMDA, CaMKII, neuronal nitric oxide synthase, and protein kinase G (or protein kinase A) blocked the effects of Bay 60-7550 on cGMP or cAMP signaling. These findings indicate that the effect of PDE2 inhibition on stress induced memory impairment is potentially mediated via modulation of neuroplasticity-related NMDAR-CaMKII-cGMP/cAMP signaling. PMID- 25442116 TI - Sleep spindles in Parkinson's disease may predict the development of dementia. AB - Sleep disturbances and cognitive impairment are common non-motor manifestations of Parkinson's disease (PD). Recent studies suggest that sleep spindles and slow waves play a role in brain plasticity mechanisms and are associated with cognitive performance. However, it remains unknown whether these sleep parameters could serve as markers of cognitive decline in PD. Therefore, we examined whether alterations in sleep spindles and slow waves at baseline visit were associated with increased likelihood of developing dementia at follow-up in PD. Sixty-eight nondemented PD patients (64.9 +/- 8.8 years old; 46 men) participated in the study, along with 47 healthy individuals (65.0 +/- 10.6 years old; 30 men). All participants underwent baseline polysomnographic recording and a comprehensive neuropsychological assessment. Sleep spindles (12-15 Hz) and slow waves (>75 MUV and <4 Hz) were automatically detected on all-night non-rapid eye movement sleep electroencephalography. At follow-up (mean: 4.5 years later), 18 PD patients developed dementia (70.2 +/- 7.6 years old; 13 men) and 50 remained dementia-free (63.0 +/- 8.5 years old; 33 men). Sleep spindle density and amplitude were lower in PD patients who converted to dementia compared with both patients who remained dementia-free and controls, mostly in posterior cortical regions (p < 0.05). Dementia-free PD patients were intermediate between dementia patients and controls, with lower baseline sleep spindle density in all cortical areas compared with controls (p < 0.01). In demented PD patients, lower sleep spindle amplitude in parietal and occipital areas was associated with poorer visuospatial abilities. Although slow wave amplitude was lower in PD patients compared with controls (p < 0.0001), no difference was observed between those who developed or did not develop dementia. Results demonstrate non-rapid eye movement sleep electroencephalographic abnormalities in PD patients. Sleep spindle activity was particularly impaired in PD patients who developed dementia, with a more posterior topographic pattern. Sleep spindle alterations are associated with later development of dementia in PD, and thus may serve as an additional marker of cognitive decline in these patients. PMID- 25442117 TI - Mutation scanning of the COQ2 gene in ethnic Chinese patients with multiple system atrophy. AB - Multiple-system atrophy (MSA) is a fatal neurodegenerative disorder with unknown etiology. It is widely considered to be a nongenetic disorder, but accumulating evidence suggests that several genes are linked to MSA. Recently, functionally impaired variants in the coenzyme Q2 4-hydroxybenzoate polyprenyltransferase (COQ2) gene have been reported to increase the risk of MSA in familial and sporadic Japanese patients. In this study, we investigated the mutation spectrum of COQ2 and analyzed the association between the common variant Val393Ala in exon 7 of COQ2 and MSA in a Chinese population. This study included 312 sporadic MSA patients from the Department of Neurology, West China Hospital of Sichuan University. All 7 exons of COQ2 in all the patients and exon 7 in 598 healthy controls (HCs) were directly sequenced. Novel candidate mutations and variations were confirmed by direct sequencing in 300 HCs. Two novel nonsynonymous variants, including p.R173H and p.N386I, and a reported missense variant, p.L162F, were found in 4 patients (p.R173H in 2 patients). However, the Val393Ala variant was not detected in the above 4 patients. Thirteen MSA patients (4.17%) and 18 controls (3.01%) had the heterozygous variant (Val393Ala/NM) of COQ2. No significant differences existed in the genotype frequency and minor allele frequency of Val393Ala between patients and controls or between MSA characterized predominantly by cerebellar ataxia and by pakinsonism groups. The mutation frequency of COQ2 is 1.28% in a Chinese MSA population. The common variant Val393Ala in COQ2 does not appear to be associated with MSA in ethnic Chinese. PMID- 25442119 TI - Second-generation Irish genome-wide association study for amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a heritable neurological disease for which the underlying genetic etiology is only partially understood. In Ireland, 83%-90% of cases are currently unexplained. Through large international collaborations, genome-wide association studies (GWASs) have succeeded in identifying a number of genomic loci that contribute toward ALS risk and age at onset. However, for the large proportion of risk that remains unexplained, population specificity of pathogenic variants could interfere with the detection of disease-associated loci. Single-population studies are therefore an important complement to larger international collaborations. In this study, we conduct a GWAS for ALS risk and age at onset in a large Irish ALS case-control cohort, using genome-wide imputation to increase marker density. Despite being adequately powered to detect associations of modest effect size, the study did not identify any locus associated with ALS risk or age at onset above the genome-wide significance threshold. Several speculative associations were, however, identified at loci that have been previously implicated in ALS. The lack of any clear association supports the conclusion that ALS is likely to be caused by multiple rare genetic risk factors. The findings of the present study highlight the importance of ongoing genetic research into the cause of ALS and its likely future challenges. PMID- 25442121 TI - Molecular pathogenesis of alpha-1-antitrypsin deficiency. AB - Alpha-1 antitrypsin (alpha1-AT) is the most abundant circulating protease inhibitor. The common severe Z allele of alpha1-AT (Glu342Lys) causes the protein to form ordered polymers that are retained within the endoplasmic reticulum of hepatocytes. These polymers form the periodic acid-Schiff positive inclusions that are associated with cirrhosis. The lack of circulating alpha1-AT predisposes the Z alpha1-AT homozygote to early onset emphysema. We review here the molecular basis of alpha1-AT deficiency and show how understanding the liver disease provides new insights in the pathobiology of the associated emphysema. The mechanism of alpha1-AT deficiency provides a paradigm for a wider group of conditions that we have termed the serpinopathies. We also examine the strategies that are being pursued to develop novel therapies for alpha1-AT deficiency. This review considers our understanding of the pathobiology of alpha1-AT deficiency and then illustrate the therapeutic possibilities that can ensue once we understand basic mechanisms of disease. PMID- 25442122 TI - [Programming and implementation a meningitis vaccination campaign in Africa]. PMID- 25442120 TI - Effects of 12 weeks of probiotic supplementation on quality of life in colorectal cancer survivors: a double-blind, randomized, placebo-controlled trial. AB - BACKGROUND: Probiotics may help resolve bowel symptoms and improve quality of life. We investigated the effects of 12 weeks of probiotics administration in colorectal cancer patients. METHODS: We conducted a double-blind, randomized, placebo-controlled trial. The participants took probiotics (Lacidofil) or placebo twice a day for 12 weeks. The cancer-related quality of life (FACT), patient's health-9 (PHQ-9), and bowel symptom questionnaires were completed by each participant. RESULTS: We obtained data for 32 participants in the placebo group and 28 participants in the probiotics group. The mean ages of total participants were 56.18 +/- .86 years and 58.3% were male. Administration of probiotics significantly decreased the proportion of patients suffering from irritable bowel symptoms (0 week vs. 12 week; 67.9% vs. 45.7%, p=0.03), improved colorectal cancer-related FACT (baseline vs. 12 weeks: 19.79 +/- 4.66 vs. 21.18 +/- 3.67, p=0.04) and fatigue-related FACT (baseline vs. 12 weeks: 43.00 (36.50-45.50) vs. 44.50 (38.50-49.00), p=0.02) and PHQ-9 scores (0 weeks vs. 12 weeks; 3.00 (0 8.00) vs. 1.00 (0-3.00), p=0.01). We found significant differences in changes of the proportion of patients with bowel symptoms (p<0.05), functional well-being scores (p=0.04) and cancer-related FACT scores (p=0.04) between the two groups. CONCLUSION: Probiotics improved bowel symptoms and quality of life in colorectal cancer survivors. PMID- 25442118 TI - Occipital sources of resting-state alpha rhythms are related to local gray matter density in subjects with amnesic mild cognitive impairment and Alzheimer's disease. AB - Occipital sources of resting-state electroencephalographic (EEG) alpha rhythms are abnormal, at the group level, in patients with amnesic mild cognitive impairment (MCI) and Alzheimer's disease (AD). Here, we evaluated the hypothesis that amplitude of these occipital sources is related to neurodegeneration in occipital lobe as measured by magnetic resonance imaging. Resting-state eyes closed EEG rhythms were recorded in 45 healthy elderly (Nold), 100 MCI, and 90 AD subjects. Neurodegeneration of occipital lobe was indexed by weighted averages of gray matter density, estimated from structural MRIs. EEG rhythms of interest were alpha 1 (8-10.5 Hz) and alpha 2 (10.5-13 Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography. Results showed a positive correlation between occipital gray matter density and amplitude of occipital alpha 1 sources in Nold, MCI, and AD subjects as a whole group (r = 0.3, p = 0.000004, N = 235). Furthermore, there was a positive correlation between the amplitude of occipital alpha 1 sources and cognitive status as revealed by Mini Mental State Examination score across all subjects (r = 0.38, p = 0.000001, N = 235). Finally, amplitude of occipital alpha 1 sources allowed a moderate classification of individual Nold and AD subjects (sensitivity: 87.8%; specificity: 66.7%; area under the receiver operating characteristic curve: 0.81). These results suggest that the amplitude of occipital sources of resting state alpha rhythms is related to AD neurodegeneration in occipital lobe along pathologic aging. PMID- 25442124 TI - [What is the scientific basis of our surgical beliefs?]. AB - The purpose of the study is to assess the validity of surgical beliefs and their application in the operating room... An exhaustive revue of literature was performed using PubMed and the Cochrane Library. We found over 400 articles, and chose to select the 135 most pertinent ones. Antiseptic hand washing and the use of sterile gloves are the main elements of SSI prevention. In this field, use of hydroalcoholic solutions and chlorhexidine seem to be the more efficient. Regarding the surgical gown, the use of masks and surgical hands contamination. Antiseptic pre-operative shower has no advantage over a simple soap shower. Also depilation has no influence. Regarding the surgery in itself, cutaneous preparation is more efficient with alcoholic antiseptics or with chlorhexidine. After the surgery, no wound dressing has shown to ease the healing when compared to the use of regular water. There are two types of attitudes in surgery: those that have a proven benefit for the patient and/or the surgeon and those based on good intentions or beliefs but that have no scientific ground. PMID- 25442125 TI - [Introduction.] PMID- 25442123 TI - [Should we drain after pre-pectoral breast implants? Analysis of a cohort of 400 patients operated for breast augmentation with pre-pectoral silicone implants]. AB - AIM OF THE STUDY: During breast augmentation, surgical drainage remains a source of debate. The objective of the study was to determine the interest of the drainage after pre-pectoral breast implants pre, analyzing the risk of hematoma and capsular contracture. PATIENTS AND METHODS: We retrospectively analyzed a cohort of 400 patients who underwent a first aesthetic breast augmentation by pre pectoral silicone gel implants. Patients were followed with a maximum of nine years and a minimum of one year. RESULTS: The mean age of patients was 37 years (18-64). Ninety-two percent (368 cases) had no drainage (patients "low risk of bleeding") and 8% (32 cases) underwent a bilateral drainage (patients "high risk of bleeding"). We recorded 1.75% hematoma (7 cases) and 2% of capsular contracture (8 cases). CONCLUSION: We believe that the drainage should not be systematic for pre-pectoral breast implants. In patients at high risk of bleeding that we drained, it does not prevent the occurrence of a possible hematoma. In patients at low risk of bleeding that we have not drained, we do not observed more hematoma or capsular contracture than data published for drained patients. PMID- 25442126 TI - [Acknowledgements.] PMID- 25442127 TI - Branchial cleft anomalies and thymic cysts. AB - Branchial cleft anomalies are a common cause of congenital neck masses and can present as a cyst, sinus, or fistula. A comprehensive understanding of the embryologic basis of these anomalies aids in diagnosis and surgical excision. Fistulas tend to present at an earlier age than sinuses or cysts, with most lesions presenting as either a neck mass, draining sinus, or recurrent infections. The eventual management of each is complete surgical excision, which is curative. A history of recurrent preoperative infections leads to a higher rate of recurrence. PMID- 25442128 TI - Malignant cervical masses in children. AB - The timely diagnosis of malignant cervical masses in children necessitates a high level of suspicion. The care of children with malignant cervical masses requires a multidisciplinary approach. Staging systems provide a basis for counseling, risk stratification, and treatment planning for children with cervical malignancies. Recent advances in molecular genetics, tumor biology, and treatment strategies are changing the management of head and neck malignancies in children. PMID- 25442129 TI - Pediatric maxillary and mandibular tumors. AB - Pediatric maxillary and mandibular tumors offer considerable challenges to otolaryngologists, oral surgeons, pathologists, and radiologists alike. Because of the close proximity to vital structures, appropriate steps toward a definitive diagnosis and treatment plan are of paramount importance. This article reviews the most common causes of pediatric jaw masses and discusses diagnostic and therapeutic considerations and recommendations. PMID- 25442130 TI - Prenatal diagnosis of obstructive head and neck masses and perinatal airway management: the ex utero intrapartum treatment procedure. AB - Advances in prenatal imaging in the last 20 years have enabled prenatal diagnosis of obstructive head and neck masses. These advances, coupled with improvements in maternal-fetal anesthesia, have made possible the development of the ex utero intrapartum treatment (EXIT) procedure for management of obstructive head and neck masses, during which the airway is managed in a controlled fashion while maintaining fetal circulation for oxygenation. This review addresses the preoperative and perioperative assessment and management of patients with prenatally diagnosed airway obstruction, indications and contraindications for the EXIT procedure, technical details of the procedure, and outcomes. PMID- 25442131 TI - Risk factors for pneumothorax complicating radiofrequency ablation for lung malignancy: a systematic review and meta-analysis. AB - PURPOSE: To assess the potential risk factors for pneumothorax secondary to pulmonary radiofrequency (RF) ablation. MATERIALS AND METHODS: Six electronic databases were searched from inception to February 2014 for studies assessing potential patient-related, tumor-related, or treatment-related risk factors for pneumothorax during pulmonary RF ablation. Study selection, data collection, and quality assessment were done by three independent reviewers. RESULTS: Among 771 studies identified in the search, 10 retrospective cohort studies met inclusion criteria. There were 981 patients (61.5% male) with a mean age of 64.2 years included (259 primary lung tumors, 722 metastatic tumors). The prevalence of pneumothorax was 37% (95% confidence interval [CI], 29%-46%) in 1,916 RF ablation sessions. The potential patient-related and tumor-related risk factors for pneumothorax were increased age (mean difference [MD], 2.09; 95% CI [0.11-4.06]; I(2) = 0%), male gender (unadjusted odds ratio [OR], 2.20; 95% CI [1.49-3.27]; I(2) = 0%), no history of lung surgery (unadjusted OR, 0.29; 95% CI [0.19-0.44]; I(2) = 0%), and a greater number of tumors ablated (MD, 0.50; 95% CI [0.27-0.73]; I(2) = 0%). CONCLUSION: Based on available observational studies, the results suggest risk factors for pneumothorax secondary to pulmonary RF ablation may include increased age, male gender, no history of lung surgery, number of tumors ablated, and increased length of the aerated lung traversed by the electrode. The findings from this systematic review should be interpreted with caution because of the inherent limitations of the retrospective observational design. PMID- 25442133 TI - Image-guided tumor ablation: standardization of terminology and reporting criteria--a 10-year update: supplement to the consensus document. PMID- 25442132 TI - Image-guided tumor ablation: standardization of terminology and reporting criteria--a 10-year update. AB - Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes. PMID- 25442134 TI - Radiation-induced cholecystitis after hepatic radioembolization: do we need to take precautionary measures? AB - Controversy exists over the need to take precautionary measures during hepatic radioembolization to minimize the risk of radiation-induced cholecystitis. Strategies for a variety of clinical scenarios are discussed on the basis of a literature review. Precautionary measures are unnecessary in the majority of patients and should be taken only when single photon-emission computed tomography (CT; SPECT)/CT shows a significant concentration of technetium-99m macroaggregated albumin in the gallbladder wall. In this case report with quantitative SPECT analysis, it is illustrated how an adjustment of the catheter position can effectively reduce the absorbed dose of radiation delivered to the gallbladder wall by more than 90%. PMID- 25442135 TI - Radioembolization and the cystic artery. PMID- 25442137 TI - Quality improvement guidelines for uterine artery embolization: an evolution in patient selection. PMID- 25442136 TI - Quality improvement guidelines for uterine artery embolization for symptomatic leiomyomata. PMID- 25442138 TI - Particle embolization: factors affecting arterial distribution. PMID- 25442139 TI - Variant adrenal vein anatomy: free with sample. PMID- 25442140 TI - IR--demystifying the "black box". PMID- 25442141 TI - Management of type II endoleak after endovascular repair of arteriocaval fistula complicating aortoiliac aneurysm: case report and literature review. AB - Endovascular treatment for arteriocaval fistula (ACF) has become the preferred alternative to open repair. However, endoleaks sometimes occur and maintain the ACF. A 64-year-old man presented with persistent fistula after placement of a bifurcated stent-graft for ACF complicating an aortoiliac aneurysm that was maintained by endoleaks from the inferior mesenteric and lumbar arteries. Transarterial embolization of the aneurysm sac and inferior mesenteric artery successfully resolved the problem without any complications observed over 16 months of follow-up. A literature review and discussion of the management options for this entity are presented. A combination of inflow and outflow control is important to obtain better long-term outcomes. PMID- 25442142 TI - Endovascular treatment of symptomatic vestibular aqueduct dehiscence as a result of jugular bulb abnormalities. AB - A new endovascular treatment consisting of stent-assisted coil implantation is described for jugular bulb abnormalities causing symptomatic vestibular aqueduct dehiscence. Three patients presenting with vertigo associated with pulsatile tinnitus or hearing loss were treated. This technique cured the vertigo and pulsatile tinnitus in all patients and preserved normal cerebral venous drainage with no side effects. PMID- 25442143 TI - Ethylene-vinyl alcohol copolymer endobiliary obliteration of hepatic segments in a patient with isolated bile leaks. AB - A 54-year-old woman with a symptomatic giant hepatic hemangioma underwent an extended left hepatic trisegmentectomy complicated by 250-350 mL/d postoperative bilious drainage. After 5 months of therapy, drainage was unabated, and the patient was no longer a surgical candidate. Sinography revealed three distinct isolated bile duct leaks involving segments 6, 7, and 8. Endobiliary segmentectomy was achieved by obliterating the isolated systems with ethylene vinyl alcohol copolymer (Onyx; ev3, Plymouth, Minnesota) during three fluoroscopic procedures. Bilious leaks were successfully eliminated, and compensatory hypertrophy of noninvolved liver occurred. At 2 years from the last embolization procedure, the patient remained asymptomatic with no bilious leak. PMID- 25442144 TI - Re: Double coaxial microcatheter technique for transarterial aneurysm sac embolization of type II endoleaks after endovascular abdominal aortic repair. PMID- 25442145 TI - Technique in port catheter repositioning. PMID- 25442146 TI - Transvenous biopsy of retroperitoneal tumoral masses: value of cone-beam CT guidance. PMID- 25442147 TI - Iliac stent-graft placement for treatment of a cutting balloon-induced ureteroiliac vein fistula. PMID- 25442148 TI - Creation of an artificial hydromediastinum for radiofrequency ablation of lung tumor: a report of two cases. PMID- 25442149 TI - Extraluminal left brachiocephalic vein superior vena cava (SVC) confluence reconstruction using a radiofrequency wire to treat SVC syndrome. PMID- 25442150 TI - Re: Microwave ablation of pulmonary metastases associated with perioperative Takotsubo cardiomyopathy. PMID- 25442151 TI - Reply to: 'Re: "Microwave ablation of pulmonary metastases associated with perioperative Takotsubo cardiomyopathy"'. PMID- 25442152 TI - A negative pilot study of daily bimodal transcranial direct current stimulation in schizophrenia. AB - BACKGROUND: A small number of studies conducted to date have suggested that transcranial direct current stimulation (tDCS) applied to the temporoparietal cortex may reduce auditory hallucinations in patients with schizophrenia. Prefrontal brain stimulation with other methods, has also been shown to potentially improve the negative symptoms of this disorder. OBJECTIVE: To investigate the therapeutic potential of daily bimodal tDCS: anodal stimulation to the prefrontal cortex and cathodal stimulation to the temporoparietal junction in patients with persistent hallucinations and negative symptoms of schizophrenia. METHODS: We conducted two small randomized double-blind controlled trials comparing bimodal tDCS to sham stimulation. In one study, stimulation was provided unilaterally, in the second study it was provided bilaterally. RESULTS: Neither unilateral nor bilateral tDCS resulted in a substantial change in either hallucinations or negative symptoms. Stimulation was well tolerated without side effects. CONCLUSION: Daily tDCS does not appear to have substantial potential in the treatment of hallucinations or negative symptoms and further research should investigate higher doses of stimulation or more frequently applied treatment schedules. PMID- 25442154 TI - Neurosensory effects of transcranial alternating current stimulation. AB - BACKGROUND: Electrical brain stimulation can elicit neurosensory side effects that are unrelated to the intended stimulation effects. This presents a challenge when designing studies with blinded control conditions. OBJECTIVE: The aim of this research was to investigate the role of different transcranial alternating current stimulation (tACS) parameters, i.e. intensity, frequency, and electrode montage, on the probability, duration and intensity of elicited neurosensory side effects. METHODS: In a first study, we examined the influence of tACS on sensations of phosphenes, dizziness, pressure, and skin sensation in fifteen healthy subjects, during 8 s of stimulation with different amplitudes (1500 MUA, 1000 MUA, 500 MUA, 250 MUA), frequencies (2 Hz, 4 Hz, 8 Hz, 16 Hz, 32 Hz, 64 Hz), and montages (F3/F4, F3/C4, F3/P4, P3/F4, P3/C4, P3/P4). In a second study, ten healthy subjects were exposed to 60 s of tACS (1000 MUA, 2 Hz versus 16 Hz, F3/F4 versus P3/P4) and were asked to rate the intensity of sensations every 12 s. RESULTS: The first study showed that all stimulation parameters had an influence on the probability and intensity of sensations. Phosphenes were most likely and strongest for frontal montages and higher frequencies. Dizziness was most likely and strongest for parietal montages and at stimulation frequency of 4 Hz. Skin sensations and pressure was more likely when stimulation was performed across central regions and at posterior montages, respectively. The second study also revealed that the probability and the intensity of sensations were neither modified during more extended periods of stimulation nor affected by carry-over effects. CONCLUSION: We demonstrated that the strength and the likelihood of sensations elicited by tACS were specifically modulated by the stimulation parameters. The present work may therefore be instrumental in establishing effective blinding conditions for studies with tACS. PMID- 25442155 TI - Evaluation and treatment of the concussed athlete - update. AB - Athletes with sports related concussions are increasingly seeking medical care for management and guidance for return to play. This article aims to provide an updated review of the management of youth sports concussions including preseason planning, on the field identification of concussion, clinical management of acute concussion, and discussion of prolonged symptoms including headache. PMID- 25442156 TI - Return to play considerations for cervical spine injuries in athletes. AB - Injuries to the cervical spine during sports are relatively common, depending on the specific sport. Given the adjacent neurovascular structures, any injury to the cervical spine must be evaluated with caution to assess its severity. With proper management, most injuries resolve quickly and allow for rapid return to play (RTP). The purpose of this article is to synthesize the current literature on the most common cervical spine injuries in athletes, including injury prevalence, mechanisms of injury, and RTP decision-making processes. PMID- 25442153 TI - The effect of vagus nerve stimulation on CSF monoamines and the PTZ seizure threshold in dogs. AB - BACKGROUND: Vagus nerve stimulation (VNS) is an established treatment for refractory epilepsy in humans, but the precise mechanism of action (MOA), predictive responsive factors and the optimal stimulation parameters remain to be elucidated. OBJECTIVE: We aimed to investigate the effect of two rapid cycling VNS paradigms on CSF monoamine levels and the seizure threshold in the canine pentylenetetrazole (PTZ) model. METHODS: Eight Beagle dogs, implanted with a VNS Therapy((r)) System, participated in a cross-over study. Levels of serotonin (5HT), norepinephrine (NE) and dopamine (DA) were quantified in the CSF after 1 h of sham, standard and microburst VNS with a wash-out period of 1 month. One week after the CSF experiment, the PTZ seizure threshold was determined after the same stimulation paradigm. As a positive control, the PTZ seizure threshold was determined after a single oral dose of phenobarbital. RESULTS: Rapid cycling standard and microburst VNS caused a significant increase of NE levels in the CSF (P = 0.03 and P = 0.02 respectively). No significant changes in 5HT or DA levels were detected. Rapid cycling standard and microburst VNS did not cause significant changes in the PTZ seizure threshold compared to sham. CONCLUSIONS: VNS induces an increase of NE in the canine brain, which supports previous findings indicating that VNS influences the locus coeruleus-NE (LC/NE) system. Importantly, this study demonstrates that this increase in NE is measurable in the CSF. One hour of VNS did not affect seizure threshold in the canine PTZ model. Therefore, the role of NE in the antiepileptic effect of VNS in dogs remains to be elucidated. PMID- 25442158 TI - Low back pain in the adolescent athlete. AB - Clinicians must have knowledge of the growth and development of the adolescent spine and the subsequent injury patterns and other spinal conditions common in the adolescent athlete. The management and treatment of spinal injuries in adolescent athletes require a coordinated effort between the clinician, patients, parents/guardians, coaches, therapists, and athletic trainers. Treatment should not only help alleviate the current symptoms but also address flexibility and muscle imbalances to prevent future injuries by recognizing and addressing risk factors. Return to sport should be a gradual process once the pain has resolved and the athlete has regained full strength. PMID- 25442157 TI - Understanding and evaluating shoulder pain in the throwing athlete. AB - Shoulder pain in the throwing athlete can present at any age and in any level of sport and can lead to dysfunction. A thorough evaluation of the throwing athlete can often determine the cause of symptoms, which is frequently multifactorial. Although the pathophysiology leading to pain in the shoulder of the throwing athlete is not entirely known, nonoperative modalities remain the mainstay of treatment. In general, surgical intervention should be reserved as a last resort. Effective treatment often requires collaboration among trainers, players, physicians, and therapists to determine an appropriate course of action. PMID- 25442159 TI - Managing hip pain in the athlete. AB - Hip and groin pain is commonly experienced by athletes. The differential diagnosis should include both intra-articular and extra-articular sources for pain and dysfunction. A comprehensive history and physical examination can guide the evaluation of hip pain and the potential need for further diagnostics. Treatment of athletes with hip disorders includes education, addressing activities of daily living, pain-modulating medications or modalities, exercise and sports modification, and therapeutic exercise. Surgical techniques for prearthritic hip disorders are expanding and can offer appropriate patients a successful return to athletic endeavors when conservative measures are not effective. PMID- 25442160 TI - Anterior cruciate ligament injury: mechanisms of injury and strategies for injury prevention. AB - Anterior cruciate ligament (ACL) injury is a common sports injury which can have severe negative consequences. Neuromuscular factors that increase risk, such as knee landing kinematics, may be ameliorated through training. Effective ACL injury prevention programs exist, although the ideal program is yet to be determined. It is recommended that athletes engaged in high-risk sports participate in an ACL injury prevention program to reduce the risk of sustaining this injury. PMID- 25442161 TI - Foot and ankle problems in dancers. AB - The dancer's foot and ankle are subjected to high forces and unusual stresses in training and performance. Injuries are common in dancers, and the foot and ankle are particularly vulnerable. Ankle sprains, ankle impingement syndromes, flexor hallucis longus tendonitis, cuboid subluxation, stress fractures, midfoot injuries, heel pain, and first metatarsophalangeal joint problems including hallux valgus, hallux rigidus, and sesamoid injuries will be reviewed. This article will discuss these common foot and ankle problems in dancers and give typical clinical presentation and diagnostic and treatment recommendations. PMID- 25442162 TI - Evaluation and treatment of injury and illness in the ultramarathon athlete. AB - Participation in ultramarathon races and knowledge of these athletes continues to increase as the sport becomes more popular. Physicians and athletes need to better understand the impact of the unique aspects of ultramarathon races, such as race environment (temperature, humidity, and altitude), race distance, race stages, nutritional requirements and equipment, on athlete injuries and illness. Proper treatment of injuries and illnesses during an ultramarathon race is important for avoiding long-term medical issues. In this article, the evaluation and treatment of common musculoskeletal injuries and medical illnesses in ultramarathon runners are reviewed. PMID- 25442163 TI - Treatment of tendinopathies with platelet-rich plasma. AB - Pain and dysfunction related to tendinopathy are often refractory to traditional treatments and offer a unique challenge to physicians, because no gold standard treatment exists. Injectable biologics may represent a new modality in conjunction with a multifaceted treatment approach. Platelet-rich plasma (PRP) injections are not associated with the systemic or tendon degradation risks of corticosteroids or the inherent risks of surgery. Studies are promising but have not been replicated with high-powered evidence at the clinical level. Further evidence to expand understanding of the role of PRP in the treatment of tendinopathy is needed. PMID- 25442164 TI - The role of regenerative medicine in the treatment of sports injuries. AB - Traditional treatment of sports injuries includes use of the PRICE principle (Protection, Rest, Ice, Compression, Elevation), nonsteroidal anti inflammatories, physical therapy modalities, and corticosteroid injections. Recent evidence has raised concerns over this traditional treatment approach regarding the use of anti-inflammatories and injectable corticosteroids. More recent treatments, known as regenerative medicine, include platelet-rich plasma and stem cell therapies. Evidence for their efficacy in a variety of sports injuries has emerged, ranging from tendinopathy and muscle tears to ligament and chondral injuries. This article reviews the literature regarding established treatments for sports injuries and these more innovative treatments. PMID- 25442165 TI - Performance-enhancing drugs: understanding the risks. AB - To help clinicians understand the risks associated with performance-enhancing drugs, this overview covers prohibited lists of substances and methods, therapeutic use exemptions, the legitimate indications and adverse effects, including for megadose and polypharmacy doping of stimulants, anabolic steroids, erythropoiesis-stimulating agents, and growth hormone and ways in which physicians or patients risk committing anti-doping rule violations inadvertently. PMID- 25442167 TI - Sports medicine. Foreword. PMID- 25442166 TI - Psychosocial factors in sports injury rehabilitation and return to play. AB - This article discusses the principles and practices that guide psychological intervention with injury, and encourages a psychological approach to injury for clinicians. Part 1 reviews the research literature, and serves as a foundation for the review of clinical practices in part 2. Examination of the research literature highlights 4 areas: (1) psychological factors influencing rehabilitation, (2) social factors affecting rehabilitation, (3) performance concerns among returning athletes, and (4) tools/inventories for assessing psychological readiness to return. A synopsis of an injury intervention plan is provided, and the influence of pain and fear in the rehabilitation process is described. PMID- 25442168 TI - Sports medicine. Preface. PMID- 25442169 TI - Differences in the acute inflammatory and glucose regulatory responses between small-sided games and cycling in sedentary, middle-aged men. AB - OBJECTIVES: This study compared the acute inflammatory and glucose regulatory response within and between rugby specific small-sided games and stationary cycling in sedentary, middle-aged Caucasian men. DESIGN: Nine middle-aged, sedentary men who were free from disease participated in 2 * 40 min exercise conditions (stationary cycling and small-sided games) in a randomised, cross-over design. METHODS: Heart rate and Rating of Perceived Exertion were collected during each bout. Venous blood was collected at fasting, 0, 30, 60 and 240 min post-exercise for measurement of glucose, insulin, cortisol and inflammatory markers including tumour necrosis factor-alpha, interleukin-1 beta, interleukin 6, interleukin-1 receptor agonist and C-reactive protein. RESULTS: No significant differences existed between conditions for heart rate and Rating of Perceived Exertion (p > 0.05). Interleukin-6 was increased immediately post-exercise in both conditions (p < 0.05), but greater in small-sided games at 240 min post exercise compared with stationary cycling (p < 0.05). Glucose was lower in small sided games than stationary cycling at 30 and 240 min post-exercise (p < 0.05). Interleukin-1 receptor agonist, insulin and cortisol showed an exercise-induced increase (p < 0.05), with no significant differences between conditions (p > 0.05). Results for C-reactive protein, tumour necrosis factor-alpha and interleukin-1 beta showed no significant exercise-induced changes within or between conditions (p > 0.05). CONCLUSIONS: Both small-sided games and stationary cycling conditions were sufficient to stimulate an acute anti-inflammatory response as indicated by the post-exercise elevation of interleukin-6, interleukin-1 receptor agonist and cortisol. The novel findings are that an acute bout of small-sided games bout is capable of maintaining an elevated post exercise interleukin-6 response and lowered blood glucose concentration, compared with intensity- and duration-matched stationary cycling condition. PMID- 25442170 TI - Development of EST-based SNP and InDel markers and their utilization in tetraploid cotton genetic mapping. AB - BACKGROUND: Availability of molecular markers has proven to be an efficient tool in facilitating progress in plant breeding, which is particularly important in the case of less researched crops such as cotton. Considering the obvious advantages of single nucleotide polymorphisms (SNPs) and insertion-deletion polymorphisms (InDels), expressed sequence tags (ESTs) were analyzed in silico to identify SNPs and InDels in this study, aiming to develop more molecular markers in cotton. RESULTS: A total of 1,349 EST-based SNP and InDel markers were developed by comparing ESTs between Gossypium hirsutum and G. barbadense, mining G. hirsutum unigenes, and analyzing 3' untranslated region (3'UTR) sequences. The marker polymorphisms were investigated using the two parents of the mapping population based on the single-strand conformation polymorphism (SSCP) analysis. Of all the markers, 137 (10.16%) were polymorphic, and revealed 142 loci. Linkage analysis using a BC1 population mapped 133 loci on the 26 chromosomes. Statistical analysis of base variations in SNPs showed that base transitions accounted for 55.78% of the total base variations and gene ontology indicated that cotton genes varied greatly in harboring SNPs ranging from 1.00 to 24.00 SNPs per gene. Sanger sequencing of three randomly selected SNP markers revealed discrepancy between the in silico predicted sequences and the actual sequencing results. CONCLUSIONS: In silico analysis is a double-edged blade to develop EST SNP/InDel markers. On the one hand, the designed markers can be well used in tetraploid cotton genetic mapping. And it plays a certain role in revealing transition preference and SNP frequency of cotton genes. On the other hand, the developmental efficiency of markers and polymorphism of designed primers are comparatively low. PMID- 25442191 TI - Emotion regulation in autism spectrum disorder: evidence from parent interviews and children's daily diaries. AB - BACKGROUND: Although emotion dysregulation is not a defining feature of Autism Spectrum Disorder (ASD), there is a growing consensus that emotional problems play a prominent role in this disorder. METHODS: The present study examined a wide range of emotion regulation (ER) strategies in 32 individuals with ASD compared to 31 group-matched typically developing (TD) participants in three emotional domains (anger, anxiety, and amusement). Parents of individuals with ASD and TD individuals were interviewed about their child's emotional experience and the use and efficacy of 10 ER strategies. In addition, participants filled out daily diaries on experience and regulation in the same emotional domains. RESULTS: Compared to TD individuals, parents reported that individuals with ASD experienced more anger and anxiety and less amusement, made less frequent use of a variety of adaptive ER strategies (e.g. problem solving, cognitive reappraisal), and made more frequent use of maladaptive strategies (e.g. repetitive behavior). Moreover, individuals with ASD were less effective at utilizing adaptive ER strategies. Self-reports showed differences in experience of amusement and in ER strategies for anger and anxiety, but not in experience of anger and anxiety. CONCLUSIONS: This study provides evidence that individuals with ASD less frequently use adaptive - but more frequently use maladaptive - ER strategies. Implications for ASD treatments that focus on increasing the use of adaptive strategies are discussed. PMID- 25442171 TI - Sleep and circadian contributions to adolescent alcohol use disorder. AB - Adolescence is a time of marked changes across sleep, circadian rhythms, brain function, and alcohol use. Starting at puberty, adolescents' endogenous circadian rhythms and preferred sleep times shift later, often leading to a mismatch with the schedules imposed by secondary education. This mismatch induces circadian misalignment and sleep loss, which have been associated with affect dysregulation, increased drug and alcohol use, and other risk-taking behaviors in adolescents and adults. In parallel to developmental changes in sleep, adolescent brains are undergoing structural and functional changes in the circuits subserving the pursuit and processing of rewards. These developmental changes in reward processing likely contribute to the initiation of alcohol use during adolescence. Abundant evidence indicates that sleep and circadian rhythms modulate reward function, suggesting that adolescent sleep and circadian disturbance may contribute to altered reward function, and in turn, alcohol involvement. In this review, we summarize the relevant evidence and propose that these parallel developmental changes in sleep, circadian rhythms, and neural processing of reward interact to increase risk for alcohol use disorder (AUD). PMID- 25442209 TI - Ultrasound-assisted periconal ocular blockade in rabbits. AB - OBJECTIVE: This study aimed to evaluate the benefit and specifically the feasibility of using ultrasound in ophthalmologic periconal block, and the occurrence of complications. STUDY DESIGN: Prospective experimental study. ANIMALS: Ten healthy New Zealand White rabbits (6-8 months of age), weighing 2.0 3.5 kg. METHODS: Rabbits were anesthetized by intramuscular injection of acepromazine (1 mg kg(-1)), ketamine (30 mg kg(-1)) and xylazine (3 mg kg(-1)). Ultrasound-assisted periconal block with lidocaine was performed on 18 eyes. Intraocular pressure was measured by applanation tonometry whereas corneal sensitivity was assessed using an esthesiometer, before and after each periconal anesthesia. RESULTS: In all 18 eyes, it was possible to adequately visualize the needle shaft within the periconal space, as well as muscular cone, optic nerve and local anesthetic solution spread. Lidocaine 2% without epinephrine (0.79 +/- 0.19 mL) was injected into the periconal space. There was no statistical difference between the intraocular pressure (mean +/- SD) measured before (10.9 +/- 2.9 mmHg) and after (11.9 +/- 3.8 mmHg) the periconal anesthesia (p = 0.38). The effectiveness of the ultrasound-assisted technique was shown according to the values for corneal sensitivity, assessed before and after periconal anesthesia (p < 0.0001). Complications were not observed in this study. CONCLUSIONS: Eye ultrasonography allowed visualization of all anatomic structures necessary to perform a periconal block, as well as the needle insertion and anesthetic spread in real time. Further studies are required to prove the real potential of ultrasound for reducing the incidence of complications associated with ophthalmic blocks, especially when anatomic disorders of the eye could potentially increase the risk. CLINICAL RELEVANCE: Ultrasonography is a painless, noninvasive tool that may improve safety of ophthalmic regional blocks, potentially by reducing the prevalence of globe perforation or penetration of the optic nerve associated with the needle-based techniques. PMID- 25442192 TI - Novel mouse hemostasis model for real-time determination of bleeding time and hemostatic plug composition. AB - INTRODUCTION: Hemostasis is a rapid response by the body to stop bleeding at sites of vessel injury. Both platelets and fibrin are important for the formation of a hemostatic plug. Mice have been used to uncover the molecular mechanisms that regulate the activation of platelets and coagulation under physiologic conditions. However, measurements of hemostasis in mice are quite variable, and current methods do not quantify platelet adhesion or fibrin formation at the site of injury. METHODS: We describe a novel hemostasis model that uses intravital fluorescence microscopy to quantify platelet adhesion, fibrin formation and time to hemostatic plug formation in real time. Repeated vessel injuries of ~ 50-100 MUm in diameter were induced with laser ablation technology in the saphenous vein of mice. RESULTS: Hemostasis in this model was strongly impaired in mice deficient in glycoprotein Ibalpha or talin-1, which are important regulators of platelet adhesiveness. In contrast, the time to hemostatic plug formation was only minimally affected in mice deficient in the extrinsic tissue factor (TF(low)) or the intrinsic factor IX coagulation pathways, even though platelet adhesion was significantly reduced. A partial reduction in platelet adhesiveness obtained with clopidogrel led to instability within the hemostatic plug, especially when combined with impaired coagulation in TF(low) mice. CONCLUSIONS: In summary, we present a novel, highly sensitive method to quantify hemostatic plug formation in mice. On the basis of its sensitivity to platelet adhesion defects and its real-time imaging capability, we propose this model as an ideal tool with which to study the efficacy and safety of antiplatelet agents. PMID- 25442218 TI - Accurate identification of Culicidae at aquatic developmental stages by MALDI-TOF MS profiling. AB - BACKGROUND: The identification of mosquito vectors is generally based on morphological criteria, but for aquatic stages, morphological characteristics may be missing, leading to incomplete or incorrect identification. The high cost of molecular biology techniques requires the development of an alternative strategy. In the last decade, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) profiling has proved to be efficient for arthropod identification at the species level. METHODS: To investigate the usefulness of MALDI-TOF MS for the identification of mosquitoes at aquatic stages, optimizations of sample preparation, diet, body parts and storage conditions were tested. Protein extracts of whole specimens from second larval stage to pupae were selected for the creation of a reference spectra database. The database included a total of 95 laboratory-reared specimens of 6 mosquito species, including Anopheles gambiae (S form), Anopheles coluzzi (M form), Culex pipiens pipiens, Culex pipiens molestus, Aedes aegypti and 2 colonies of Aedes albopictus. RESULTS: The present study revealed that whole specimens at aquatic stages produced reproducible and singular spectra according to the mosquito species. Moreover, MS protein profiles appeared weakly affected by the diet provided. Despite the low diversity of some MS profiles, notably for cryptic species, clustering analyses correctly classified all specimens tested at the species level followed by the clustering of early vs. late aquatic developmental stages. Discriminant mass peaks were recorded for the 6 mosquito species analyzed at larval stage 3 and the pupal stage. Querying against the reference spectra database of 149 new specimens at different aquatic stages from the 6 mosquito species revealed that 147 specimens were correctly identified at the species level and that early and late developmental stages were also distinguished. CONCLUSIONS: The present work highlights that MALDI-TOF MS profiling may be useful for the rapid and reliable identification of mosquito species at aquatic stages. With this proteomic tool, it becomes now conceivable to survey mosquito breeding sites prior to the mosquitoes' emergence and to adapt anti-vectorial measures according to the mosquito fauna detected. PMID- 25442220 TI - Editorial: cell movement. AB - Cell movement is a fundamental process of normal cellular physiology and pathophysiology. Abnormal regulation of cell migration is a common denominator of many medical disorders, including cancer metastasis, autoimmune disease and inflammation. Increased interest in the targeting of cell migration and invasion, which has potential for therapeutic intervention in many diseases are behind this special themed issue. Thus, the focus of this issue is centred on the control of cellular cytoskeletal dynamics and cellular or tissue microenvironment sensors. Novel therapeutic opportunities targeting regulation of cell migration are discussed including the emerging roles of tetraspanins, phosphoinositides, transient receptor potential cation channels, stromal interaction molecules and calcium release-activated calcium modulators. Better understanding of these regulatory factors will hopefully bring greater attention to strategically targeting aberrant cell migration, which has many therapeutic implications for common human diseases. LINKED ARTICLES: This article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-24 PMID- 25442219 TI - Case-control study of breast cancer and exposure to synthetic environmental chemicals among Alaska Native women. AB - BACKGROUND: Exposure to environmental chemicals may impair endocrine system function. Alaska Native (AN) women may be at higher risk of exposure to these endocrine disrupting chemicals, which may contribute to breast cancer in this population. OBJECTIVE: To measure the association between exposure to select environmental chemicals and breast cancer among AN women. DESIGN: A case-control study of 170 women (75 cases, 95 controls) recruited from the AN Medical Center from 1999 to 2002. Participants provided urine and serum samples. Serum was analyzed for 9 persistent pesticides, 34 polychlorinated biphenyl (PCB) congeners, and 8 polybrominated diethyl ether (PBDE) congeners. Urine was analyzed for 10 phthalate metabolites. We calculated geometric means (GM) and compared cases and controls using logistic regression. RESULTS: Serum concentrations of most pesticides and 3 indicator PCB congeners (PCB-138/158; PCB 153, PCB-180) were lower in case women than controls. BDE-47 was significantly higher in case women (GM=38.8 ng/g lipid) than controls (GM=25.1 ng/g lipid) (p=0.04). Persistent pesticides, PCBs, and most phthalate metabolites were not associated with case status in univariate logistic regression. The odds of being a case were higher for those with urinary mono-(2-ethylhexyl) phthalate (MEHP) concentrations that were above the median; this relationship was seen in both univariate (OR 2.16, 95% CI 1.16-4.05, p=0.02) and multivariable (OR 2.43, 95% CI 1.13-5.25, p=0.02) logistic regression. Women with oestrogen receptor (ER) /progesterone receptor (PR)-tumour types tended to have higher concentrations of persistent pesticides than did ER+/PR+ women, although these differences were not statistically significant. CONCLUSIONS: Exposure to the parent compound of the phthalate metabolite MEHP may be associated with breast cancer. However, our study is limited by small sample size and an inability to control for the confounding effects of body mass index. The association between BDE-47 and breast cancer warrants further investigation. PMID- 25442221 TI - Social network analysis to assess the impact of the CTSA on biomedical research grant collaboration. AB - Success of the Clinical Translational Science Award (CTSA) program implicitly demands team science efforts and well-orchestrated collaboration across the translational silos (T1-T4). Networks have proven to be useful abstractions of research collaborations. Networks provide novel system-level insights and exhibit marked changes in response to external interventions, making them potential evaluation tools that complement more traditional approaches. This study is part of our ongoing efforts to assess the impact of the CTSA on Biomedical Research Grant Collaboration (BRGC). Collaborative research grants are a complex undertaking and an outcome of sustained interaction among researchers. In this report, BRGC networks representing collaborations among CTSA-affiliated investigators constructed from grants management system data at the University of Kentucky across a period of six years (2007-2012) corresponding to pre- and post CTSA are investigated. Overlapping community structure detection algorithms, in conjunction with surrogate testing, revealed the presence of intricate research communities rejecting random graphs as generative mechanisms. The deviation from randomness was especially pronounced post-CTSA, reflecting an increasing trend in collaborations and team-science efforts potentially as a result of CTSA. Intercommunity cross talk was especially pronounced post-CTSA. PMID- 25442222 TI - Prospective immunohistochemical analysis of BRAF V600E mutation in melanoma. AB - The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation is the most common activating genetic alteration of this oncogene and a predictive marker for the therapeutic use of BRAF inhibitors in melanoma. Our aim was to evaluate the performance of BRAF V600E mutation-specific monoclonal antibody (VE1) in a prospective diagnostic setting of melanoma patients (n = 102). All 41 cases (40.2%) that showed a V600E mutation in the cyclic minisequencing analysis of the DNA were also initially scored immunopositive. Two cases that were scored as BRAF V600E mutation positive by immunohistochemistry were negative in the DNA based mutation analysis and determined to be immunonegative in a repeated staining with more representative specimens. Thus, BRAF V600E mutation detection using immunohistochemistry was 100% sensitive and 96.8% specific, when compared with the analysis of the DNA. None of the BRAF V600K mutations was detected by the VE1 antibody (n = 7). However, the VE1 antibody detected a rare V600E2 mutation. We also studied the role of BRAF V600E mutation in a set of melanoma patients who had been investigated for sentinel node metastasis. Melanoma lymph node metastases were diagnosed in 21.8% (12/55) of the sentinel nodes, and BRAF V600E immunopositivity was detected in 34.5% (19/55) of the cases. BRAF V600E mutation status did not correlate with any clinicopathological parameters. In conclusion, analysis of BRAF V600E mutation in melanoma by immunohistochemistry is a sensitive and specific method, which can be used to identify BRAF inhibitor sensitive melanoma patients as a first-line method due to its rapid and affordable nature. PMID- 25442223 TI - Cost-benefit analysis simulation of a hospital-based violence intervention program. AB - BACKGROUND: Violent injury is a major cause of disability, premature mortality, and health disparities worldwide. Hospital-based violence intervention programs (HVIPs) show promise in preventing violent injury. Little is known, however, about how the impact of HVIPs may translate into monetary figures. PURPOSE: To conduct a cost-benefit analysis simulation to estimate the savings an HVIP might produce in healthcare, criminal justice, and lost productivity costs over 5 years in a hypothetical population of 180 violently injured patients, 90 of whom received HVIP intervention and 90 of whom did not. METHODS: Primary data from 2012, analyzed in 2013, on annual HVIP costs/number of clients served and secondary data sources were used to estimate the cost, number, and type of violent reinjury incidents (fatal/nonfatal, resulting in hospitalization/not resulting in hospitalization) and violent perpetration incidents (aggravated assault/homicide) that this population might experience over 5 years. Four different models were constructed and three different estimates of HVIP effect size (20%, 25%, and 30%) were used to calculate a range of estimates for HVIP net savings and cost-benefit ratios from different payer perspectives. All benefits were discounted at 5% to adjust for their net present value. RESULTS: Estimates of HVIP cost savings at the base effect estimate of 25% ranged from $82,765 (narrowest model) to $4,055,873 (broadest model). CONCLUSIONS: HVIPs are likely to produce cost savings. This study provides a systematic framework for the economic evaluation of HVIPs and estimates of HVIP cost savings and cost-benefit ratios that may be useful in informing public policy decisions. PMID- 25442224 TI - Effect of body mass index on insulin secretion or sensitivity and diabetes. AB - BACKGROUND: Although the association between obesity and diabetes is well known, the factors predisposing to diabetes in non-obese Asians are less clearly characterized. PURPOSE: To investigate the effects of impaired insulin secretion (IIS) and insulin resistance (IR) according to BMI on the incidence of diabetes in the Saku Study. METHODS: This 4-year cohort study involved 3,083 participants aged 30-69 years without diabetes at baseline (2006-2007). Participants were stratified by BMI (<23.0, 23.0-24.9, and >=25). Based on insulinogenic index and homeostasis model of IR values, participants were classified into four categories: normal; isolated IIS (i-IIS); isolated IR (i-IR); and IIS plus IR. All data were collected in 2006-2011 and analyzed in 2013-2014. RESULTS: For participants with BMI <23.0, the risk of developing diabetes was higher in the i IIS (adjusted hazard ratio=6.6; 95% CI=3.7, 11.6) and IIS plus IR groups (9.4; 3.1, 28.4) than in the normal group. For participants with BMI 23.0-24.9, risk was higher in the i-IIS (9.9; 4.4, 22.1); i-IR (3.4; 1.2, 9.5); and IIS plus IR (23.4; 9.3, 58.9) groups. Among participants with BMI >=25, risk was higher in the i-IIS (16.9; 6.0, 47.7); i-IR (7.9; 2.8, 22.6); and IIS plus IR (26.9; 9.0, 80.8) groups. BMI was negatively associated with incidence of IIS but positively associated with IR incidence. CONCLUSIONS: Individuals with normal BMI may develop diabetes mainly through IIS, whereas individuals with high BMI may develop diabetes primarily through IR. PMID- 25442225 TI - Twelve-month physical activity outcomes in Latinas in the Seamos Saludables trial. AB - BACKGROUND: Physical activity interventions designed for Latinas have shown short term behavior change, but longer-term change and maintenance is rarely measured. PURPOSE: To assess physical activity change at 12 months, following 6-month tapered completion of an RCT of a physical activity intervention for Latinas. METHODS: Two hundred sixty-six underactive (<60 minutes/week physical activity) Latinas were randomized to an individually tailored, culturally and linguistically adapted physical activity intervention, or a wellness contact control. Participants received the materials through the mail for 6 months, then received booster doses at 8, 10, and 12 months. Minutes per week of moderate to vigorous physical activity were measured by the 7-Day Physical Activity Recall interview at baseline and 6 and 12 months. Data were collected at Brown University between 2009 and 2013, and analyses were conducted in 2013. RESULTS: At 12 months, increases in moderate to vigorous physical activity were significantly greater in the intervention than in the wellness group (mean difference=52 minutes/week, SE=9.38, p<0.01), with both groups showing slight increases in moderate to vigorous physical activity from 6 to 12 months. Intervention participants were also more likely to meet national moderate to vigorous physical activity guidelines (OR=3.14, p=0.01). CONCLUSIONS: The intervention was more effective than the wellness control at 12 months, and physical activity increases from baseline to 6 months were maintained, suggesting the intervention may lead to sustainable behavior change. TRIAL REGISTRATION: This study is registered at Clinicaltrials.gov NCT01583140. PMID- 25442226 TI - Overweight and obesity trends among active duty military personnel: a 13-year perspective. AB - BACKGROUND: The U.S. population has shown increasing rates of overweight and obesity in recent years, but similar analyses do not exist for U.S. military personnel. It is important to understand these patterns in the military because of their impact on fitness and readiness. PURPOSE: To assess prevalence and trends in overweight/obesity among U.S. service members and to examine the associations of sociodemographic characteristics, exercise, depression, and substance use with these patterns. METHODS: Analyses performed in 2013 used five large population-based health-related behavior surveys conducted from 1995 to 2008. Main outcome measures were overweight and obesity among active duty military personnel based on BMI. RESULTS: Combined overweight and obesity (BMI>=25) increased from 50.6% in 1995 to 60.8% in 2008, primarily driven by the rise in obesity (BMI>=30) from 5.0% to 12.7%. For overweight, military women showed the largest increase. For obesity, all sociodemographic groups showed significant increases, with the largest among warrant officers, senior enlisted personnel, and people aged 36-45 years. Adjusted multinomial logit analyses found that service members aged 26 years and older, men, non-Hispanic blacks and Hispanics, enlisted personnel, married personnel, and heavy drinkers had the highest risk both for overweight and obesity. CONCLUSIONS: Combined overweight and obesity in active duty personnel rose to more than 60% between 1995 and 2008, primarily because of increased obesity. The high prevalence of overweight and obesity needs attention and has implications for Department of Defense efforts to improve the health, fitness, readiness, and quality of life of the Active Forces. PMID- 25442227 TI - Youth indoor tanning and skin cancer prevention: lessons from tobacco control. AB - Youth use of ultraviolet-emitting indoor tanning beds represents a present and emerging public health crisis. Nearly 30% of white female high school students report tanning indoors, and a quarter of high school tanners have used a tanning bed more than 20 times in the past year. Despite the significant health risks of tanning beds, including potentially deadly melanoma and eye problems, limited actions have been taken in the U.S. to protect youth. Tobacco control policies and campaigns, which have sharply reduced youth smoking, may provide a useful framework to control indoor tanning among young people. This article describes several evidence-based tobacco control strategies with potential applicability to indoor tanning within the context of the U.S. Further, current tobacco control policies and current indoor tanning policies in the U.S. are compared, and recommendations on how to curtail youth indoor tanning are discussed. PMID- 25442228 TI - Receipt of diabetes preventive services differs by insurance status at visit. AB - BACKGROUND: Lack of insurance is associated with suboptimal receipt of diabetes preventive care. One known reason for this is an access barrier to obtaining healthcare visits; however, little is known about whether insurance status is associated with differential rates of receipt of diabetes care during visits. PURPOSE: To examine the association between health insurance and receipt of diabetes preventive care during an office visit. METHODS: This retrospective cohort study used electronic health record and Medicaid data from 38 Oregon community health centers. Logistic regression was used to test the association between insurance and receipt of four diabetes services during an office visit among patients who were continuously uninsured (n=1,117); continuously insured (n=1,466); and discontinuously insured (n=336) in 2006-2007. Generalized estimating equations were used to account for within-patient correlation. Data were analyzed in 2013. RESULTS: Overall, continuously uninsured patients had lower odds of receiving services at visits when due, compared to those who were continuously insured (AOR=0.73, 95% CI=0.66, 0.80). Among the discontinuously insured, being uninsured at a visit was associated with lower odds of receipt of services due at that visit (AOR=0.77, 95% CI=0.64, 0.92) than being insured at a visit. CONCLUSIONS: Lack of insurance is associated with a lower probability of receiving recommended services that are due during a clinic visit. Thus, the association between being uninsured and receiving fewer preventive services may not be completely mediated by access to clinic visits. PMID- 25442229 TI - Prevalence and costs of skin cancer treatment in the U.S., 2002-2006 and 2007 2011. AB - BACKGROUND: Skin cancer, the most common cancer in the U.S., is a major public health problem. The incidence of nonmelanoma and melanoma skin cancer is increasing; however, little is known about the economic burden of treatment. PURPOSE: To examine trends in the treated prevalence and treatment costs of nonmelanoma and melanoma skin cancers. METHODS: This study used data on adults from the 2002-2011 Medical Expenditure Panel Survey full-year consolidated files and information from corresponding medical conditions and medical event files to estimate the treated prevalence and treatment cost of nonmelanoma skin cancer, melanoma skin cancer, and all other cancer sites. Analyses were conducted in January 2014. RESULTS: The average annual number of adults treated for skin cancer increased from 3.4 million in 2002-2006 to 4.9 million in 2007-2011 (p<0.001). During this period, the average annual total cost for skin cancer increased from $3.6 billion to $8.1 billion (p=0.001), representing an increase of 126.2%, while the average annual total cost for all other cancers increased by 25.1%. During 2007-2011, nearly 5 million adults were treated for skin cancer annually, with average treatment costs of $8.1 billion each year. CONCLUSIONS: These findings demonstrate that the health and economic burden of skin cancer treatment is substantial and increasing. Such findings highlight the importance of skin cancer prevention efforts, which may result in future savings to the healthcare system. PMID- 25442230 TI - Association of body mass index with cardiovascular disease biomarkers. AB - BACKGROUND: Few studies have examined the underweight-morbidity relationship, and those that have were conducted in non-U.S. populations and limited in their evaluation of cardiovascular disease (CVD) risk factors. PURPOSE: To examine the associations among underweight (along with overweight and obese) and various CVD risk factors in a national sample of U.S. adults (aged >=20 years). METHODS: Ten years of data (1999-2010) from the National Health and Nutrition Examination Survey were used (analyzed in 2014). Underweight (tertiles); overweight (25 29.9); and obesity (three classes: 30-34.9, 35-39.9, and >=40) were assessed from measured BMI. The evaluated biological and anthropometric markers included waist circumference; mean arterial pressure; C-reactive protein (CRP); fasting low density lipoprotein (LDL) cholesterol; total cholesterol; fasting triglycerides; and fasting glucose. RESULTS: After adjustments, underweight adults had significantly (p<0.005) lower levels of CRP (beta=-0.12, Tertile 2); total cholesterol (beta=-17.7 and -12.2, Tertiles 1 and 3); total cholesterol to high density lipoprotein cholesterol ratio (beta=-0.39 and -0.46, Tertiles 2 and 3); LDL cholesterol (beta=-20.7, Tertile 1); and triglycerides (beta=-37.1 and -18.0, Tertiles 1 and 3) compared to normal-weight individuals. The severely underweight and obese were less likely to be physically active than normal-weight adults (p<0.001). Adults in each of the overweight and obese groups had higher levels for each biomarker compared to normal-weight individuals. CONCLUSIONS: Underweight adults have lower (i.e., more favorable) levels of various CVD biomarkers. PMID- 25442231 TI - A bibliometric analysis of U.S.-based research on the Behavioral Risk Factor Surveillance System. AB - BACKGROUND: Since Alan Pritchard defined bibliometrics as "the application of statistical methods to media of communication" in 1969, bibliometric analyses have become widespread. To date, however, bibliometrics has not been used to analyze publications related to the U.S. Behavioral Risk Factor Surveillance System (BRFSS). PURPOSE: To determine the most frequently cited BRFSS-related topical areas, institutions, and journals. METHODS: A search of the Web of Knowledge database in 2013 identified U.S.-published studies related to BRFSS, from its start in 1984 through 2012. Search terms were BRFSS, Behavioral Risk Factor Surveillance System, or Behavioral Risk Survey. The resulting 1,387 articles were analyzed descriptively and produced data for VOSviewer, a computer program that plotted a relevance distance-based map and clustered keywords from text in titles and abstracts. RESULTS: Topics, journals, and publishing institutions ranged widely. Most research was clustered by content area, such as cancer screening, access to care, heart health, and quality of life. The American Journal of Preventive Medicine and American Journal of Public Health published the most BRFSS-related papers (95 and 70, respectively). CONCLUSIONS: Bibliometrics can help identify the most frequently published BRFSS-related topics, publishing journals, and publishing institutions. BRFSS data are widely used, particularly by CDC and academic institutions such as the University of Washington and other universities hosting top-ranked schools of public health. Bibliometric analysis and mapping provides an innovative way of quantifying and visualizing the plethora of research conducted using BRFSS data and summarizing the contribution of this surveillance system to public health. PMID- 25442232 TI - Health problems of partner violence victims: comparing help-seeking men to a population-based sample. AB - BACKGROUND: National population-based studies show that 40%-50% of physical partner violence victims in a 1-year time period are men. However, studies assessing the health concerns related to partner violence victimization tend to focus on women, and none have assessed the health of male physical partner violence victims who sought help for their victimization. PURPOSE: To understand men's mental and physical health concerns that may be related to partner violence victimization. METHODS: In 2012-2013, two samples of men-611 physical partner violence victims who sought help and 1,601 men from a population-based sample completed online questionnaires on their demographics, various types of partner violence victimization, physical health, mental health, and other risks. Data were analyzed using logistic regression, log binomial models, and robust Poisson models in 2013. RESULTS: In comparison to the population-based sample of men, male partner violence victims who sought help had significantly poorer health, particularly with regard to post-traumatic stress disorder, depression, high blood pressure, sexually transmitted diseases, and asthma. These differences remained after controlling for sample differences in demographics, substance use, previous traumatic exposure, and social support. CONCLUSIONS: Practitioners should assess for health problems among partner violence victims and for partner violence victimization among men presenting with health problems. PMID- 25442233 TI - Home and workplace built environment supports for physical activity. AB - BACKGROUND: Physical inactivity has been associated with obesity and related chronic diseases. Understanding built environment (BE) influences on specific domains of physical activity (PA) around homes and workplaces is important for public health interventions to increase population PA. PURPOSE: To examine the association of home and workplace BE features with PA occurring across specific life domains (work, leisure, and travel). METHODS: Between 2012 and 2013, telephone interviews were conducted with participants in four Missouri metropolitan areas. Questions included sociodemographic characteristics, home and workplace supports for PA, and dietary behaviors. Data analysis was conducted in 2013; logistic regression was used to examine associations between BE features and domain-specific PA. RESULTS: In home neighborhoods, seven of 12 BE features (availability of fruits and vegetables, presence of shops and stores, bike facilities, recreation facilities, crime rate, seeing others active, and interesting things) were associated with leisure PA. The global average score of home neighborhood BE features was associated with greater odds of travel PA (AOR=1.99, 95% CI=1.46, 2.72); leisure PA (AOR=1.84, 95% CI=1.44, 2.34); and total PA (AOR=1.41, 95% CI=1.04, 1.92). Associations between workplace neighborhoods' BE features and workplace PA were small but in the expected direction. CONCLUSIONS: This study offers empirical evidence on BE supports for domain-specific PA. Findings suggest that diverse, attractive, and walkable neighborhoods around workplaces support walking, bicycling, and use of public transit. Public health practitioners, researchers, and worksite leaders could benefit by utilizing worksite domains and measures from this study for future BE assessments. PMID- 25442235 TI - Preventive care utilization among the uninsured by race/ethnicity and income. AB - BACKGROUND: Health insurance status affects access to preventive services. Effective use of preventive services is a key factor in the reduction of important health concerns and has the potential to enable adults to live longer, healthier lives. PURPOSE: To analyze the use of U.S. Preventive Services Task Force (USPSTF)-recommended preventive services among uninsured adults, with a focus on variation across race, ethnicity, and household income. METHODS: Using pooled 2004-2011 Medical Expenditure Panel Survey data, this study conducted multivariate logistic regressions to estimate variation in receipt of eight USPSTF-recommended preventive services by race/ethnicity among adults aged 18 years and older uninsured in the previous year. Stratified analyses by household income were applied. Data were analyzed in 2013. RESULTS: Uninsured adults received preventive services far below Healthy People 2020 targets. Among the uninsured, African Americans had higher odds of receiving Pap tests, mammograms, routine physical checkups, and blood pressure checks according to guidelines than whites. Moreover, compared to whites, Hispanics had higher odds of receiving Pap tests, mammograms, influenza vaccinations, and routine physical checkups and lower odds of receiving blood pressure screening and advice to quit smoking. When results were stratified by household income, racial/ethnic differences persisted except for the highest income levels (>=400% Federal Poverty Level), where they were largely non-significant. CONCLUSIONS: Generally, uninsured African American and Hispanic populations fare better than uninsured whites in preventive service utilization. Future research should examine reasons behind these racial/ethnic differences to inform policy interventions aiming to increase preventive service utilization among the uninsured. PMID- 25442234 TI - Worksite neighborhood and obesogenic behaviors: findings among employees in the Promoting Activity and Changes in Eating (PACE) trial. AB - BACKGROUND: Understanding mechanisms linking neighborhood context to health behaviors may provide targets for increasing lifestyle intervention effectiveness. Although associations between home neighborhood and obesogenic behaviors have been studied, less is known about the role of worksite neighborhood. PURPOSE: To evaluate associations between worksite neighborhood context at baseline (2006) and change in obesogenic behaviors of adult employees at follow-up (2007-2009) in a worksite randomized trial to prevent weight gain. METHODS: Worksite property values were used as an indicator of worksite neighborhood SES (NSES). Worksite neighborhood built environment attributes associated with walkability were evaluated as explanatory factors in relationships among worksite NSES, diet, and physical activity behaviors of employees. Behavioral data were collected at baseline (2005-2007) and follow-up (2007-2009). Multilevel linear and logistic models were constructed adjusting for covariates and accounting for clustering within worksites. Product-of coefficients methods were used to assess mediation. Analyses were performed after study completion (2011-2012). RESULTS: Higher worksite NSES was associated with more walking (OR=1.16, 95% CI=1.03, 1.30, p=0.01). Higher density of residential units surrounding worksites was associated with more walking and eating five or more daily servings of fruits and vegetables, independent of worksite NSES. Residential density partially explained relationships among worksite NSES, fruit and vegetable consumption, and walking. CONCLUSIONS: Worksite neighborhood context may influence employees' obesogenic behaviors. Furthermore, residential density around worksites could be an indicator of access to dietary and physical activity-related infrastructure in urban areas. This may be important given the popularity of worksites as venues for obesity prevention efforts. PMID- 25442236 TI - Emergency epinephrine use for food allergy reactions in Chicago Public Schools. AB - BACKGROUND: Given the increase in childhood food allergy, national and local policies have been developed to encourage schools to stock undesignated epinephrine auto-injectors in case of an anaphylactic emergency. PURPOSE: To describe the use of epinephrine auto-injectors in Chicago Public Schools during the 2012-2013 school year, specifically for food-induced allergic reactions. METHODS: District-issued epinephrine auto-injectors were distributed to all public and charter schools in Chicago prior to the start of the 2012-2013 school year. Data on their use were collected, and frequencies were computed in the autumn of 2013. RESULTS: Thirty-eight district-issued epinephrine auto-injectors were administered during the inaugural year of the Chicago Public Schools initiative. Epinephrine auto-injectors were administered to students (92.1%) and school staff (7.9%). Most district-issued epinephrine auto-injectors were administered in elementary schools (63.2%) and on Chicago's North-Northwest Side (36.8%). More than half (55.0%) of all district-issued epinephrine auto-injectors were administered for first-time anaphylactic events. Food-induced reactions accounted for more than half (55.3%) of all reactions requiring epinephrine auto injector use, whereas the trigger of more than one third (34.2%) of all reactions requiring the use of an epinephrine auto-injector remained unknown. CONCLUSIONS: Chicago Public Schools is the first large, urban school district in the U.S. to develop and implement the District-Issued Emergency Epinephrine Initiative, which helped 38 students and staff avoid potential morbidity and mortality. The impact of this initiative during its first year underscores the need for stocking undesignated epinephrine in schools across the country. PMID- 25442237 TI - Number of warning information sources and decision making during tornadoes. AB - BACKGROUND: Taking proper protective action upon receiving tornado warnings is critical to reducing casualties. With more warning information sources becoming available, how the number of such information sources affects decision making should be quantitatively investigated. PURPOSE: To examine how the number of warning information sources affected individuals' decisions to take protective action during tornadoes. METHODS: A telephone survey using random sampling was conducted in 2012 with residents in Tuscaloosa AL and Joplin MO, resulting in a working sample of 782 respondents. Both cities were struck by violent tornadoes (Enhanced Fujita Scale [EF]4 and EF5) in 2011. The analysis was conducted in 2013. RESULTS: Logistic regression analysis showed that relative to having only one warning information source, having two and three or more warning information sources significantly increased the odds of taking protective action in Joplin but not in Tuscaloosa; having three or more sources had a significantly stronger effect on taking protective action in Joplin than in Tuscaloosa. Having an emergency preparation plan in both cities and being white in Tuscaloosa significantly increased the odds of taking protective action, whereas being divorced in Joplin reduced these odds. CONCLUSIONS: Receiving warnings from more warning information sources might be more beneficial in places with less previous exposure to tornadoes and for populations with lower awareness of a potential tornado and higher probability of receiving no warnings. Emergency management agencies and public health officials should give priority to these places and populations when formulating disaster mitigation decisions and policies. PMID- 25442238 TI - Infectious agents and inflammation in donated hearts and dilated cardiomyopathies related to cardiovascular diseases, Chagas' heart disease, primary and secondary dilated cardiomyopathies. AB - BACKGROUND: Clinical and experimental conflicting data have questioned the relationship between infectious agents, inflammation and dilated cardiomyopathy (DCM). OBJECTIVES: The aim of this study was to determine the frequency of infectious agents and inflammation in endomyocardial biopsy (EMB) specimens from patients with idiopathic DCM, explanted hearts from different etiologies, including Chagas' disease, compared to donated hearts. METHODS: From 2008 to 2011, myocardial samples from 29 heart donors and 55 patients with DCMs from different etiologies were studied (32 idiopathic, 9 chagasic, 6 ischemic and 8 other specific etiologies). Inflammation was investigated by immunohistochemistry and infectious agents by immunohistochemistry, molecular biology, in situ hybridization and electron microscopy. RESULTS: There were no differences regarding the presence of macrophages, expression of HLA class II and ICAM-I in donors and DCM. Inflammation in Chagas' disease was predominant. By immunohistochemistry, in donors, there was a higher expression of antigens of enterovirus and Borrelia, hepatitis B and C in DCMs. By molecular biology, in all groups, the positivity was elevated to microorganisms, including co-infections, with a higher positivity to adenovirus and HHV6 in donors towards DCMs. This study was the first to demonstrate the presence of virus in the heart tissue of chagasic DCM. CONCLUSIONS: The presence of inflammation and infectious agents is frequent in donated hearts, in the myocardium of patients with idiopathic DCM, myocardial dysfunction related to cardiovascular diseases, and primary and secondary cardiomyopathies, including Chagas' disease. The role of co-infection in Chagas' heart disease physiopathology deserves to be investigated in future studies. PMID- 25442239 TI - Ovarian reserve markers and assisted reproductive technique (ART) outcomes in women with advanced endometriosis. AB - BACKGROUND: The role of ovarian reserve markers as predictors of the controlled ovarian stimulation (COS) response in intracytoplasmic sperm injection (ICSI) cycles in women with endometriosis has been much debated. The aim of the present study is to assess the predictability of ovarian reserve markers for the number of mature oocytes (MII) retrieved and to assess the pregnancy rate and live birth rate in women with advanced endometriosis. METHODS: Two hundred eighty-five infertile women who had laparoscopy followed by a first ICSI cycle were recruited in this prospective study. One hundred ten patients were diagnosed with endometriosis stage III-IV (group 1), and 175 patients had no endometriosis (group II). Sixty-three patients in group 1 had no history of previous endometrioma surgery (group Ia), and 47 patients had a history of previous endometrioma surgery (group Ib). RESULTS: The number of mature oocytes retrieved was significantly lower in women with advanced endometriosis than in women with no endometriosis. The number of mature oocytes retrieved in women with and without endometriosis was best predicted by antral follicle count (AFC) and age, whereas only AFC was a predictor in women with previous endometrioma surgery (odds ratio: 0.49; 95% confidence interval: 0.13-0.60). Women with endometriosis had a lower rate of live births than the control group, but this difference was not statistically significant; the number of live births was significantly lower in those with previous endometrioma surgery. CONCLUSIONS: The best predictor of the COS response in ICSI was AFC, followed by age. Women receiving ICSI following surgery for ovarian endometrioma had a poorer clinical outcome and lower rate of live births compared with those with endometriosis but no previous surgery and the control group. PMID- 25442240 TI - Metabolic alterations, HFE gene mutations and atherogenic lipoprotein modifications in patients with primary iron overload. AB - Iron overload (IO) has been associated with glucose metabolism alterations and increased risk of cardiovascular disease (CVD). Primary IO is associated with mutations in the HFE gene. To which extent HFE gene mutations and metabolic alterations contribute to the presence of atherogenic lipoprotein modifications in primary IO remains undetermined. The present study aimed to assess small, dense low-density lipoprotein (LDL) levels, chemical composition of LDL and high density lipoprotein (HDL) particles, and HDL functionality in IO patients. Eighteen male patients with primary IO and 16 sex- and age-matched controls were recruited. HFE mutations (C282Y, H63D and S65C), measures of insulin sensitivity and secretion (calculated from the oral glucose tolerance test), chemical composition and distribution profile of LDL and HDL subfractions (isolated by gradient density ultracentrifugation) and HDL functionality (as cholesterol efflux and antioxidative activity) were studied. IO patients compared with controls exhibited insulin resistance (HOMA-IR (homoeostasis model assessment estimated insulin resistance): +93%, P< 0.001). Metabolic profiles differed across HFE genotypes. C282Y homozygotes (n=7) presented a reduced beta-cell function and insulin secretion compared with non-C282Y patients (n=11) (-58% and 73%, respectively, P< 0.05). In addition, C282Y homozygotes featured a predominance of large, buoyant LDL particles (C282Y: 43+/-5; non-C282Y: 25+/-8; controls: 32+/-7%; P< 0.001), whereas non-C282Y patients presented higher amounts of small, dense LDL (C282Y: 23+/-5; non-C282Y: 39+/-10; controls: 26+/-4%; P< 0.01). HDL particles were altered in C282Y homozygotes. However, HDL functionality was conserved. In conclusion, metabolic alterations and HFE gene mutations are involved in the presence of atherogenic lipoprotein modifications in primary IO. To what extent such alterations could account for an increase in CVD risk remains to be determined. PMID- 25442241 TI - Nursing care in a high-technological environment: Experiences of critical care nurses. AB - OBJECTIVES: Management of technical equipment, such as ventilators, infusion pumps, monitors and dialysis, makes health care in an intensive care setting more complex. Technology can be defined as items, machinery and equipment that are connected to knowledge and management to maximise efficiency. Technology is not only the equipment itself, but also the knowledge of how to use it and the ability to convert it into nursing care. The aim of this study is to describe critical care nurses' experience of performing nursing care in a high technology healthcare environment. RESEARCH METHODOLOGY: Qualitative, personal interviews were conducted during 2012 with eight critical care nurses in the northern part of Sweden. Interview transcripts were analysed using qualitative content analysis. FINDINGS: Three themes with six categories emerged. The technology was described as a security that could facilitate nursing care, but also one that could sometimes present obstacles. The importance of using the clinical gaze was highlighted. CONCLUSION: Nursing care in a high technological environment must be seen as multi-faceted when it comes to how it affects CCNs' experience. The advanced care conducted in an ICU could not function without high-tech equipment, nor could care operate without skilled interpersonal interaction and maintenance of basal nursing. That technology is seen as a major tool and simultaneously as a barrier to patient-centred care. PMID- 25442242 TI - The role of perioperative chewing gum on gastric fluid volume and gastric pH: a meta-analysis. AB - STUDY OBJECTIVE: To determine if preoperative gum chewing affects gastric pH and gastric fluid volume. DESIGN: Systematic review and meta-analysis. METHODS: Data sources included Cochrane, PubMed, and EMBASE databases from inception to June 2012 and reference lists of known relevant articles without language restriction. Randomized controlled trials in which a treatment group that chewed gum was compared to a control group that fasted were included. Relevant data, including main outcomes of gastric fluid volume and gastric pH, were extracted. RESULTS: Four studies involving 287 patients were included. The presence of chewing gum was associated with small but statically significant increases in gastric fluid volume (mean difference = 0.21 mL/kg; 95% confidence interval, 0.02-0.39; P = .03) but not in gastric pH (mean difference = 0.11 mL/kg; 95% confidence interval, -0.14 to 0.36; P = .38). Gastric fluid volume and gastric pH remained unchanged in subgroup analysis by either sugar or sugarless gum type. CONCLUSIONS: Chewing gum in the perioperative period causes small but statically significant increases in gastric fluid volume and no change in gastric pH. The increase in gastric fluid most likely is of no clinical significance in terms of aspiration risk for the patient. Elective surgery should not necessarily be canceled or delayed in healthy patients who accidentally chew gum preoperatively. PMID- 25442243 TI - Amoxicillin/clavulanic acid 2000/125 mg to prevent complications due to infection following completely bone-impacted lower third molar removal: a clinical trial. AB - OBJECTIVE: The purpose of this study was to determine the effect of amoxicillin/clavulanic acid to prevent infection following completely bone impacted lower third molar removal. STUDY DESIGN: A random, double-blind placebo controlled clinical trial including 118 adults randomly allocated to placebo (60 patients) or antibiotic treatment (58 patients): 2 g amoxicillin/125 mg clavulanic acid 2 hours before the surgery and post-operatively twice a day for 4 days. Infection was clinically assessed until 8 weeks after surgery. Adverse events, as well as clinical and surgical variables, were recorded. Analysis was by intention to treat. RESULTS: Infections developed in five patients in the placebo group, all in the first postoperative week, and in two in the antibiotic group, both after the first week, the difference not being statistically significant (P = .278, number needed to treat 19 [8-infinity]). There were no relationships between any variables studied and infection. No serious adverse events were reported. CONCLUSION: There is insufficient evidence to recommend routine use of this antibiotic treatment. PMID- 25442244 TI - Lack of evidence for increased postoperative bleeding risk for dental osteotomy with continued aspirin therapy. AB - OBJECTIVE: Dental osteotomy, the removal of an impacted, ankylosed, or severely destroyed tooth requiring an osteotomy, is more invasive than other minor dental procedures and therefore also has a higher bleeding risk. A considerable number of patients under antiplatelet therapy interrupt their therapy perioperatively, which, however, increases the risk of thromboembolism. STUDY DESIGN: This retrospective study assessed postoperative bleeding incidence for a total of 297 dental osteotomies with continued aspirin therapy, compared with that of 179 similar procedures on patients who were not on any anticoagulation or anti platelet therapy. All procedures were carried out on an outpatient basis. RESULTS: Postoperative bleeding event was rare in both groups, 5 (1.7%) and 2 (1.1%), respectively, and the difference was not significant (P = .7). CONCLUSIONS: Continued aspirin therapy in patients undergoing dental osteotomies has no effect on the incidence of postoperative bleeding and should not be interrupted. PMID- 25442245 TI - Giant life-threatening external carotid artery pseudoaneurysm caused by a mandibular condylar fracture. AB - OBJECTIVE: Vascular lesions are rare complications associated to mandibular condylar fractures. This paper aims to describe a case of a giant pseudoaneurysm involving the external carotid artery (ECA) caused by a condylar fracture. CASE REPORT: A 33-year-old man was the victim of traffic accident and presented with a panfacial fracture, including a bilateral condylar fracture. The condylar fracture was treated by closed reduction, and 4 weeks after treatment, the patient developed facial edema, which suggested postoperative infection. An attempt at draining it resulted in intensive bleeding. A computed tomographic angiography showed a huge pseudoaneurysm originating from the ECA. The patient was treated with surgery with ligation of the ECA and drainage of the pseudoaneurysm. CONCLUSION: Vascular complications associated with condylar fractures are rare, but surgeons should be aware of this type of complication, especially because of the high risk of serious damage, including death. The use of computed tomographic angiography is very helpful in the diagnosis of vascular lesions and also guides treatment. PMID- 25442246 TI - Broken dental needle retrieval using a surgical navigation system: a case report and literature review. AB - This paper reports a case of fractured needle retrieval in the pterygomandibular space using the Medtronic surgical navigation system. Current literature on needle fracture and retrieval in the oral cavity was also reviewed. A literature search was conducted in the following databases: PubMed, MDConsult, The Cochrane Library, and Google. A variety of keywords were used, including "needle fracture," "broken dental needle," "needle injuries in dentistry," "foreign body retrieval," and "dental needle retrieval." Articles published after 1980 were reviewed. Seventeen articles that involved broken dental needle retrieval were selected. PMID- 25442247 TI - Craniofacial manifestations of beta-thalassemia major. AB - Hemoglobinopathies are by far the most common genetic diseases, affecting millions worldwide with a prevalence for natives of Iran, Southeast Asia, and the Caspian Sea, as part of the so-called Thalassemia Belt, and an overall incidence ranging approximately from 3 to 100 patients per 100,000 population. beta Thalassemia major is of particular significance, providing bad outcomes despite aggressive therapeutic approaches. We report a case of beta-thalassemia in a 5 year-old Persian boy who presented with classical diagnostic features of the disease and who did not survive despite an aggressive management approach. A review of the clinical, radiographic, laboratory, and therapeutic characteristics as well as diagnostic tests of this disease is also presented. The multifactorial challenges that face clinicians in the management of this serious disease are also reviewed. PMID- 25442248 TI - Keratinizing odontogenic cyst with verrucous pattern featuring negative human papillomavirus status by polymerase chain reaction. AB - Verrucous odontogenic cysts (OCs) are extremely rare. Here, we report the clinicopathologic features of this unusual entity and investigate the role of human papillomavirus (HPV) by p16INK4A immunohistochemistry and HPV-DNA polymerase chain reaction (PCR). A 32-year-old male presented with a 8.3 * 4.0 cm, multilocular radiolucency of the left ascending ramus of the mandible. Microscopically, the cystic cavity was lined by hyperplastic stratified squamous epithelium demonstrating marked verrucous morphology with multiple sharp or blunt projections. Mild dysplastic features were also identified. A final diagnosis of keratinizing OC with verrucous hyperplasia and epithelial dysplasia was rendered. Immunohistochemically, the verrucous OC showed foci of moderate-to-intense and diffuse, nuclear, and cytoplasmic p16INK4A positivity as well as weak or absent p53 immunopositivity in the p16INK4A labeled areas. The Ki-67 expression was increased. Interestingly, HPV-DNA PCR failed to reveal transcriptionally active HPV genotypes. Complete surgical excision was performed, with no recurrences seen during a 66-month follow-up. PMID- 25442249 TI - mTOR inhibitor-associated stomatitis (mIAS) in three patients with cancer treated with everolimus. AB - Mammalian targets of rapamycin inhibitors (mTOR inhibitors, mTORI) are indicated for the management of several cancer types, including hormone receptor--positive or HER2-negative breast cancer, advanced renal cell carcinoma, advanced neuroendocrine tumors of pancreatic origin, and tuberous sclerosis complex related tumors. Among the most common adverse events of mTORI medication are discrete, large, solitary or multiple, superficial ulcers, almost exclusively situated on nonkeratinized oral mucosa, described as mTORI-associated stomatitis (mIAS). We describe the clinical presentation, course, and management of mIAS in three patients receiving the mTORI everolimus (Afinitor, Novartis, East Hanover, NJ). In two patients, mIAS manifested 9 and 30 days after first using everolimus, respectively, whereas in the third patient, it recurred 3 months after re introduction of everolimus. Oral rinses with a "magic mouthwash" solution (dexamethasone oral drops solution 2 mg/mL * 10 mL, lidocaine gel 2% * 30 g, doxycycline suspension 50 mg/5 mL * 60 mL, and sucralfate oral suspension 1000 mg/5 mL * 150 mL, dissolved in sodium chloride 0.9% * 2000 mL) four times daily proved helpful in alleviating the symptoms, and the ulcers healed in 4 to 15 days. No side effects were recorded, and dose reduction or discontinuation of everolimus was not necessitated in two cases. PMID- 25442250 TI - Hypomaturation amelogenesis imperfecta caused by a novel SLC24A4 mutation. AB - In this case report of autosomal recessive pigmented hypomaturation amelogenesis imperfecta (AI), we identify a novel homozygous missense mutation (g.165151 T>G; c.1317 T>G; p.Leu436 Arg) in SLC24A4, a gene encoding a potassium-dependent sodium-calcium exchanger that is critical for hardening dental enamel during tooth development. PMID- 25442251 TI - Mucocutaneous leishmaniasis must be included in the differential diagnosis of midline destructive disease: two case reports. AB - Midline destructive lesions have multiple possible etiologies, which can be grouped into neoplastic, infectious, or vasculitis-associated. The purpose of these case reports and literature review was to highlight the need to include mucocutaneous leishmaniasis in the diagnosis of midfacial lesions in any patient who has lived in Leishmania-endemic areas because this entity meets all of the clinical criteria to be considered a form of midline destructive lesion. We present two cases of mucocutaneous leishmaniasis that occurred in a Bolivian male immigrant and a European male traveler to Panama, in whom lesions were misdiagnosed as different midline destructive lesions with different causes (Wegener, vasculitis, and natural killer or T-cell lymphoma [NKTL]). The conclusion of our work is that all patients with midline destructive lesions should undergo histologic and molecular studies to be evaluated for mucosal leishmaniasis, particularly patients whose clinical history suggests this possibility. In cases of uvular involvement, biopsy of this region might be a possible alternative to nasal biopsy. PMID- 25442252 TI - Adverse drug events in the oral cavity. AB - Adverse reactions to medications are common and may have a variety of clinical presentations in the oral cavity. Targeted therapies and the new biologic agents have revolutionized the treatment of cancers, autoimmune diseases, and inflammatory and rheumatologic diseases but have also been associated with adverse events in the oral cavity. Some examples include osteonecrosis, seen with not only bisphosphonates but also antiangiogenic agents, and the distinctive ulcers caused by mammalian target of rapamycin inhibitors. As newer therapeutic agents are approved, it is likely that more adverse drug events will be encountered. This review describes the most common clinical presentations of oral mucosal reactions to medications, namely, xerostomia, lichenoid reactions, ulcers, bullous disorders, pigmentation, fibrovascular hyperplasia, white lesions, dysesthesia, osteonecrosis, infection, angioedema, and malignancy. Oral health care providers should be familiar with such events, as they will encounter them in their practice. PMID- 25442253 TI - Trigeminal neuralgia: differences in magnetic resonance imaging characteristics of neurovascular compression between symptomatic and asymptomatic nerves. AB - OBJECTIVES: Neurovascular compression (NVC) of the trigeminal nerve is the primary cause of trigeminal neuralgia (TN) but is known to occur in both symptomatic and asymptomatic nerves. The purposes of this study were to evaluate the relationship between the magnetic resonance imaging (MRI) findings regarding the site of NVC and the manifestation of TN symptoms. METHODS: In 147 patients with unilateral TN, the presence or absence of NVC was evaluated on MRI in both symptomatic and asymptomatic nerves. In cases with NVC, the shortest distance from the trigeminal nerve root to the responsible vessel was measured. RESULTS: The mean distance from the trigeminal nerve root to the site of NVC in asymptomatic nerves (3.85 +/- 2.69 mm) was significantly greater than that in symptomatic nerves (0.94 +/- 1.27 mm). When the distance was 3 mm or less, the rate of the manifestation of TN symptoms was 83.1% (103/124). On the other hand, it was only 19.6% (9/46) in cases with a distance of greater than 3 mm. CONCLUSIONS: Whether or not NVC of the trigeminal nerve was symptomatic was closely related to the distance from the trigeminal nerve root to the responsible blood vessel. PMID- 25442254 TI - Swelling of the hard and soft palates. PMID- 25442255 TI - Childhood mycosis fungoides with a CD8+ CD56+ cytotoxic immunophenotype. AB - Primary cutaneous T-cell lymphomas mostly occur in patients of middle and higher age. Their rarity and an oftentimes atypical clinical presentation in childhood as well as the reluctance of taking biopsies in children are reasons for a delayed diagnosis. We report the case of an 11-year-old boy with a 7-year history of slowly progressive CD8+CD56+ mycosis fungoides of the cytotoxic immunophenotype. His trunk and extremities were affected by extensive pale erythematous patches and plaques with fine scaling. In addition, several poikilodermatous lesions were present on his thighs. Improvement was achieved by topical mometasone furoate treatment. On the basis of our observation, a brief review on cutaneous T-cell lymphomas in childhood and on CD8+ subtypes in particular is given. Clinicopathological correlation is crucial for establishing the correct diagnosis and for estimation of the prognosis. PMID- 25442256 TI - Letter to the Editor in response to "Adulteration of Ginkgo biloba products and a simple method to improve its detection" by Wohlmuth et al. PMID- 25442257 TI - Pueraria mirifica extract and puerarin enhance proliferation and expression of alkaline phosphatase and type I collagen in primary baboon osteoblasts. AB - Phytoestrogen-rich Pueraria mirifica (PM) tuberous extract is a promising candidate for the development of anti-osteoporosis drugs for postmenopausal women, but its action has never been validated in humans or in non-human primates, which are more closely related to humans than rodents. In vitro study of non-human primate osteoblasts is thus fundamental to prepare for in vivo studies of phytoestrogen effects on primate bone. This study aimed to establish a culture system of baboon primary osteoblasts and to investigate the effects of PM extract and its phytoestrogens on these cells. Primary osteoblasts from adult baboon fibulae exhibited osteoblast characteristics in regard to proliferation, differentiation, mineralization, and estrogen receptor expression. They responded to 17beta-estradiol by increased proliferation rate and mRNA levels of alkaline phosphatase (ALP), type I collagen, and osteocalcin. After being exposed for 48 h to 100 MUg/ml PM extract, 1000 nM genistein, or 1000 nM puerarin, primary baboon osteoblasts markedly increased the rate of proliferation and mRNA levels of ALP and type I collagen without changes in Runx2, osterix, or osteocalcin expression. PM extract, genistein, and puerarin also decreased the RANKL/OPG ratio, suggesting that they could decrease osteoclast-mediated bone resorption. However, neither PM extract nor its phytoestrogens altered calcium deposition in osteoblast culture. In conclusion, we have established baboon primary osteoblast culture, which is a new tool for bone research and drug discovery. Furthermore, the present results provide substantial support for the potential of PM extract and its phytoestrogens to be developed as therapeutic agents against bone fragility. PMID- 25442259 TI - In-vivo antinociceptive, anti-inflammatory and antipyretic activity of pistagremic acid isolated from Pistacia integerrima. AB - The current study was designed to explore the antinociceptive, antiinflammatory and antipyretic activity of pistagremic acid (PA), isolated from Pistacia integerima bark in various animal paradigms. The results illustrated significant inhibition of noxious stimulation in acetic acid induced writhing test with maximum effect of 68% at 10mg/kg i.p. In tail immersion test, pretreatment with PA demonstrated marked activity during various assessment times in a dose dependent manner. The maximum pain inhibition was 59.46% at 10mg/kg i.p. after 90 min of PA treatment. However, the injection of naloxone did not antagonize this induced effect. PA significantly ameliorated post carrageenan induced edema dose dependently during various stages of inflammation. The effect was most dominant (60.02%) after 3(rd) h of drug administration when examined for 5h. Similarly, it provoked dose dependent antipyretic effect in febrile mice with maximum of 60.04% activity at 10mg/kg i.p. after 3rd hour of PA post treatment. Furthermore, molecular docking was carried out to understand the binding mode of PA. From the docking study it was observed that PA fits well in the active site of COX-2 enzyme due to hydrogen and hydrophobic moiety interactions to the important active site of molecule. In conclusion, PA possesses strong peripheral and central antinociceptive activity independent of opioidergic effect which was augmented by its anti-inflammatory and antipyretic activities. PMID- 25442258 TI - Portulaca oleracea reduces triglyceridemia, cholesterolemia, and improves lecithin: cholesterol acyltransferase activity in rats fed enriched-cholesterol diet. AB - PURPOSE: The effects of Portulaca oleracea (Po) lyophilized aqueous extract were determined on the serum high-density lipoproteins (HDL2 and HDL3) amounts and composition, as well as on lecithin: cholesterol acyltansferase (LCAT) activity. METHODS: Male Wistar rats (n = 12) were fed on 1% cholesterol-enriched diet for 10 days. After this phase, hypercholesterolemic rats (HC) were divided into two groups fed the same diet supplemented or not with Portulaca oleracea (Po-HC) (0.5%) for four weeks. RESULTS: Serum total cholesterol (TC) and triacylglycerols (TG), and liver TG values were respectively 1.6-, 1.8-, and 1.6-fold lower in Po HC than in HC group. Cholesterol concentrations in LDL-HDL1, HDL2, and HDL3 were respectively 1.8, 1.4-, and 2.4-fold decreased in Po-HC group. HDL2 and HDL3 amounts, which were the sum of apolipoproteins (apos), TG, cholesteryl esters (CE), unesterified cholesterol (UC), and phospholipids (PL) contents, were respectively 4.5-fold higher and 1.2-fold lower with Po treatment. Indeed, enhanced LCAT activity (1.2-fold), its cofactor-activator apo A-I (2-fold) and its reaction product HDL2-CE (2.1-fold) were observed, whereas HDL3-PL (enzyme substrate) and HDL3-UC (acyl group acceptor) were 1.2- and 2.4-fold lower. CONCLUSION: Portulaca oleracea reduces triglyceridemia, cholesterolemia, and improves reverse cholesterol transport in rat fed enriched-cholesterol diet, contributing to anti-atherogenic effects. PMID- 25442260 TI - Synergistic property of cordycepin in cultivated Cordyceps militaris-mediated apoptosis in human leukemia cells. AB - Cordyceps militaris is a well-known Chinese traditional medicinal mushroom frequently used for tonics and recently of a potential interest for cancer intervention. Here, we explored the cancer cell killing activity of the hot water extracts of C. militaris cultured mycelia (CM(MY)) and cultivated fruiting bodies (CM(FB)). We found that CM(FB) exhibited a greater cytotoxic effect against various cancer cells over CM(MY). Apoptotic phenotypes including apoptotic body formation, DNA laddering, caspase 3 activation and cleavage of PARP proteins were induced by CM(FB) treatment but only slightly induced by same concentration of CM(MY) treatment in human HL-60 leukemia cells. Cordycepin in CM(FB) (10.47 mg/g) is significantly higher (~ 15.2 times) than that of CM(MY) (0.69 mg/g). Using isobolographic analysis, the synergy of cytotoxicity was observed across different combined concentrations of CM(MY) and cordycepin. By complementing cordycepin into CM(MY) to the level comparable with CM(FB), we observed that CM(MY) (500 MUg/ml) with cordycepin (4.8 MUg/ml) induced apoptosis to a level similar to that induced by CM(FB) (500 MUg/ml). Together, our results suggest that cordycepin possesses a synergistic cytotoxic effect with Cordyceps militaris mediated apoptosis in human leukemia cells and therefore explaining a better anti proliferating activity of CM(FB) over CM(MY). PMID- 25442261 TI - Cytotoxicity of the bisphenolic honokiol from Magnolia officinalis against multiple drug-resistant tumor cells as determined by pharmacogenomics and molecular docking. AB - A main problem in oncology is the development of drug-resistance. Some plant derived lignans are established in cancer therapy, e.g. the semisynthetic epipodophyllotoxins etoposide and teniposide. Their activity is, unfortunately, hampered by the ATP-binding cassette (ABC) efflux transporter, P-glycoprotein. Here, we investigated the bisphenolic honokiol derived from Magnolia officinalis. P-glycoprotein-overexpressing CEM/ADR5000 cells were not cross-resistant to honokiol, but MDA-MB-231 BRCP cells transfected with another ABC-transporter, BCRP, revealed 3-fold resistance. Further drug resistance mechanisms analyzed study was the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR). HCT116 p53(-/-) did not reveal resistance to honokiol, and EGFR transfected U87.MG EGFR cells were collateral sensitive compared to wild-type cells (degree of resistance: 0.34). To gain insight into possible modes of collateral sensitivity, we performed in silico molecular docking studies of honokiol to EGFR and EGFR-related downstream signal proteins. Honokiol bound with comparable binding energies to EGFR (-7.30 +/- 0.01 kcal/mol) as the control drugs erlotinib (-7.50 +/- 0.30 kcal/mol) and gefitinib (-8.30 +/- 0.10 kcal/mol). Similar binding affinities of AKT, MEK1, MEK2, STAT3 and mTOR were calculated for honokiol (range from -9.0 +/- 0.01 to 7.40 +/- 0.01 kcal/mol) compared to corresponding control inhibitor compounds for these signal transducers. This indicates that collateral sensitivity of EGFR-transfectant cells towards honokiol may be due to binding to EGFR and downstream signal transducers. COMPARE and hierarchical cluster analyses of microarray-based transcriptomic mRNA expression data of 59 tumor cell lines revealed a specific gene expression profile predicting sensitivity or resistance towards honokiol. PMID- 25442262 TI - Bergenia crassifolia (L.) Fritsch--pharmacology and phytochemistry. AB - PURPOSE: Bergenia crassifolia (L.) Fritsch, a species in the Bergenia genus belongs to the family Saxifragaceae, is valuated for its medicinal application. The review focuses on the medicinal uses, phytochemistry, and the biological activities of B. crassifolia to explore its benefits and potential uses. METHODS: In this review, we summarized data, published in Russia and in other countries related to B. crassifolia. RESULTS: Rhizomes and leaves of this plant are in use as traditional remedies for the treatment of different disorders in the folk medicine systems of Russia and Asia. The plant is a potential source of tannins, benzanoids, flavonoids, polysaccharides and other active compounds. Due to the presence of a multitude of bioactives, a wide array of pharmacological activities have been ascribed to different parts of this herb and individual compounds, which include adaptogenic, antiinflammatory, antihypertensive, antimicrobial, antioxidant, antiobesity, antitussive, cerebro-protective, hepatoprotective, immunomodulating, and diuretic. CONCLUSION: The review highlights the potential of B. crassifolia for further development of herbal medicines on its base. PMID- 25442263 TI - Synergistic effect of the interaction between curcumin and diclofenac on the formalin test in rats. AB - The association of non-steroidal anti-inflammatory drugs with certain plant extracts can increase antinociceptive activity, permitting the use of lower doses and thus limiting side effects. Therefore, the aim objective of the current study was to examine the effects of curcumin on the nociception and pharmacokinetics of diclofenac in rats. Antinociception was assessed using the formalin test. Diluted formalin was injected subcutaneously into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection, and a reduction in formalin-induced flinching was interpreted as an antinociceptive response. Rats were treated with oral diclofenac (1-31 mg/kg), curcumin (3.1-100 mg/kg) or the diclofenac-curcumin combination (2.4-38.4 mg/kg). To determine the possibility of a pharmacokinetic interaction, the oral bioavailability of diclofenac (10 mg/kg) was studied in presence and the absence of curcumin (31 mg/kg). Diclofenac, curcumin, or diclofenac-curcumin combination produced an antinociceptive effect on the formalin test. ED30 values were estimated for the individual drugs, and an isobologram was constructed. The derived theoretical ED30 for the antinociceptive effect (19.2 mg/kg) was significantly different from the observed experimental ED30 value (9.8 mg/kg); hence, the interaction between diclofenac and curcumin that mediates the antinociceptive effect was synergistic. Notwithstanding, the interaction does not appear to involve pharmacokinetic mechanisms, as oral curcumin failed to produce any significant alteration in oral diclofenac bioavailability. Data suggest that the diclofenac-curcumin combination can interact at the systemic level and may have therapeutic advantages for the clinical treatment of inflammatory pain. PMID- 25442264 TI - Effect of chito-oligosaccharide on the intestinal absorptions of phenylethanoid glycosides in Fructus Forsythiae extract. AB - Phenylethanoid glycosides, the main active ingredients in Fructus Forsythiae extract possesses strong antibacterial, antioxidant and antiviral effects, and their contents were higher largely than that of other ingredients such as lignans and flavones, but their absolute bioavailability orally was significantly low, which influenced clinical efficacies of its oral preparations seriously. In the present study, the absorption mechanism of phenylethanoid glycosides was studied using in vitro Caco-2 cell model. And the effect of chito-oligosaccharide (COS) on the intestinal absorption of phenylethanoid glycosides in Fructus Forsythiae extract was investigated using in vitro, in situ and in vivo models. The pharmacological effects such as antiviral activity improvement by COS were verified by MDCK cell damage inhibition rate after influenza virus propagation. The observations from in vitro Caco-2 cell showed that the absorption of phenylethanoid glycosides in Fructus Forsythiae extract so with that in monomers was mainly restricted by the tight junctions, and influenced by efflux transporters (P-gp and MRP2). Meanwhile, the absorption of phenylethanoid glycosides in Fructus Forsythiae extract could be improved by COS. Besides, COS at the same low, medium and high concentrations caused a significant, concentration-dependent increase in the Papp-value for phenylethanoid glycosides compared to the control group (p<0.05), and was all safe for the Caco-2 cells. The observations from single-pass intestinal perfusion in situ model showed that the intestinal absorption of phenylethanoid glycosides can be enhanced by COS. Meanwhile, the absorption enhancing effect of phenylethanoid glycosides might be saturable in different intestine sites. In pharmacokinetics study, COS at dosage of 25mg/kg improved the bioavailability of phenylethanoid glycosides in Fructus Forsythiae extract to the greatest extent, and was safe for gastrointestine from morphological observation. In addition, treatment with Fructus Forsythiae extract with COS at dosage of 25mg/kg prevented MDCK cell damage upon influenza virus propagation better than that of control. All findings above suggested that COS at dosage of 25mg/kg might be safe and effective absorption enhancer for improving the bioavailability of phenylethanoid glycosides and the antiviral activity in vitro in Fructus Forsythiae extract. PMID- 25442265 TI - Naturally occurring bioactive Cyclobutane-containing (CBC) alkaloids in fungi, fungal endophytes, and plants. AB - This article focuses on the occurrence and biological activities of cyclobutane containing (CBC) alkaloids obtained from fungi, fungal endophytes, and plants. Naturally occurring CBC alkaloids are of particular interest because many of these compounds display important biological activities and possess antitumour, antibacterial, antimicrobial, antifungal, and immunosuppressive properties. Therefore, these compounds are of great interest in the fields of medicine, pharmacology, medicinal chemistry, and the pharmaceutical industry. Fermentation and production of CBC alkaloids by fungi and/or fungal endophytes is also discussed. This review presents the structures and describes the activities of 98 CBC alkaloids. PMID- 25442266 TI - The vasodilating effect of a Hintonia latiflora extract with antidiabetic action. AB - In the present study, it is shown for the first time that an extract of Hintonia latiflora (HLE) which is used as an antidiabetic herbal medicine, is not only able to decrease blood glucose concentration but additionally exerts a vasodilating effect. Accordingly, this extract might have a positive influence on diabetes-associated dysfunction of blood vessels. The vasodilating effect was demonstrated in vitro in aortic rings of guinea pigs as well as in vivo in rabbits. Aortic rings pre-contracted with noradrenaline (NA) could completely be relaxed by HLE (EC50: 51.98 mg/l). In contrast, potassium-induced contractions were not diminished by HLE. Therefore, it can be suggested that the vasodilating effect of HLE is primarily the result of an inhibition of G protein-induced increase in intracellular calcium and not of a blockade of voltage-operated L type calcium channels. The neoflavonoid coutareagenin (COU), a constituent of HLE which in part is responsible for the blood glucose-lowering effect of HLE, also relaxed NA-induced contractions of aortic rings (EC50: 32.55 mg/l) and only weakly inhibited potassium-induced contractions. Experiments in aortic rat cells revealed that calcium transients evoked by vasopressin were suppressed by 60 mg/l COU supporting the idea of an inhibition of G protein-induced intracellular calcium release by a constituent of HLE. To study the effect of HLE on vascular tone under in vivo conditions, ultrasound measurements were carried out in conscious rabbits which received a single oral dose of HLE. Under the influence of HLE, a vasodilation combined with a lowering of blood flow velocity could be observed in the abdominal aorta and the common carotid artery. Additionally, a decrease in blood glucose concentration in the HLE group occurred. The combination of a blood glucose-lowering with a vasodilating effect may be helpful for reducing angiopathies, typical long-term complications in patients with diabetes mellitus. PMID- 25442268 TI - Biotransformation of monoterpenoids and their antimicrobial activities. AB - Biotransformation is an economically and ecologically viable technology which has been used extensively to modify the structures of many classes of biologically active products. The discovery of novel antimicrobial metabolites from biotransformation is an important alternative to overcome the increasing levels of drug resistance by plant and human pathogens. Monoterpenes, the main constituents of essential oils, are known for their antimicrobial activities. In 2004, Farooq, Atta-Ur-Rahman and Choudhary published a review on fungal transformation of monoterpenes which covers papers published up to 2002. The present review not only updates the previous one but also discusses the antimicrobial activities (antibacterial, antifungal and antiviral) of biotransformed compounds. PMID- 25442267 TI - Combining metabolomic analysis and microarray gene expression analysis in the characterization of the medicinal plant Chelidonium majus L. AB - BACKGROUND AND OBJECTIVE: Even though herbal medicines have played an important role in disease management and health for many centuries, their present frequent use is challenged by the necessity to determine their complex composition and their multitarget mode of action. In the present study, modern methods were investigated towards their potential in the characterization of herbal substances. As a model the herbal substance Chelidonii herba was used, for which several reports on liver toxicities exist. Extracts of Chelidonii herba with different solvents were characterized phytochemically and functionally by experiments with HepG2 liver cells. METHODS: Chelidonii herba was extracted with four solvents of different polarity (dichloromethane, water, ethanol, and ethanol 50% (V/V); four replicates each). The different extracts were characterized metabolomically by (1)H-NMR fingerprinting analysis and principal component analysis (PCA). The content of alkaloids was additionally determined by RP-HPLC. Functional characterization was achieved by the determination of cell proliferation and by transcriptomics techniques (Whole Genome Gene Expression Microarrays v2, Agilent Technologies) in HepG2 cells after exposure to the different extracts (four experimental replicates each). RESULTS: Based on data from (1)H-NMR fingerprints and RP-HPLC analyses the different extracts showed a divergent composition of constituents depending on the solvent used. HepG2 liver cells responded differentially to the four extracts. Microarray analysis revealed a significant regulation of genes and signal cascades related to biotransformation. Also liver-toxic signal cascades were activated. Neither the activated genes nor the proliferation response could be clearly related to the differing alkaloid content of the extracts. CONCLUSION: Different manufacturing processes lead to different herbal preparations. A systems biology approach combining a metabolomic plant analysis with a functional characterization by gene expression profiling in HepG2 cells is an appropriate strategy to characterize variations in plant extracts. Safety assessments of herbal substances may benefit from such complementary analyses. PMID- 25442269 TI - Encapsulation and modified-release of thymol from oral microparticles as adjuvant or substitute to current medications. AB - The aim of this study was to encapsulate, thymol, in natural polymers in order to obtain (i) taste masking effect and, then, enhancing its palatability and (ii) two formulations for systemic and local delivery of herbal drug as adjuvants or substitutes to current medications to prevent and treat several human and animal diseases. Microspheres based on methylcellulose or hydroxypropyl methylcellulose phthalate (HPMCP) were prepared by spray drying technique. Microparticles were in vitro characterized in terms of yield of production, drug content and encapsulation efficiency, particle size, morphology and drug release. Both formulations were in vivo orally administered and pharmacokinetic analysis was carried out. The polymers used affect the release and, then, the pharmacokinetic profile of thymol. Encapsulation into methylcellulose microspheres leads to short half/life but bioavailability remarkably increases compared to the free thymol. In contrast, enteric formulation based on HPMCP shows very limited systemic absorption. These formulations could be proposed as alternative or adjuvants for controlling pathogen infections in human or animal. In particular, methylcellulose microspheres can be used for thymol systemic administration at low doses and HPMCP particles for local treatment of intestinal infections. PMID- 25442270 TI - Synergistic inhibitory effect of Icariside II with Icaritin from Herba Epimedii on pre-osteoclastic RAW264.7 cell growth. AB - Increasing evidence shows the therapeutic superiority of herbal extracts in comparison to isolated single constituents. One of the reasons may be attributed to the synergy effect of compound combinations. Flavonoids from Herba Epimedii have been shown to have therapeutic effect against bone loss. Our previous study showed that Icariside II inhibited pre-osteoclast RAW264.7 growth. The aim of this study was to investigate whether the activity of Icariside II is synergized by other components of Herba Epimedii. The inhibitory activity of Icariside II was significantly enhanced in the presence of the extract of Herba Epimedii (EHE) at the ratio of 1:1, 1:5 and 1:10. Icaritin, another flavonoid constituent, was shown here to inhibit RAW264.7 growth in a dose-dependent manner. Further, we found that Icariside II, together with Icaritin, synergistically inhibited RAW264.7 growth. The synergistic effect is significant when the ratio of Icariside II and Icaritin was 10:1, 5:1, 1:1, 1:2, and 1:5, respectively. In conclusion, Icaritin were an active component. The inhibitory activity of Icariside II on pre-osteoclast RAW264.7 growth was synergized by Icaritin, which maybe contribute to the efficiency of Herba Epimedii extract on curing bone related diseases, such as osteoporosis. PMID- 25442271 TI - Anti-malarial drug artesunate protects against cigarette smoke-induced lung injury in mice. AB - Cigarette smoking is the primary cause of chronic obstructive pulmonary disease (COPD), which is mediated by lung infiltration with inflammatory cells, enhanced oxidative stress, and tissue destruction. Anti-malarial drug artesunate has been shown to possess anti-inflammatory and anti-oxidative actions in mouse asthma models. We hypothesized that artesunate can protect against cigarette smoke induced acute lung injury via its anti-inflammatory and anti-oxidative properties. Artesunate was given by oral gavage to BALB/c mice daily 2h before 4% cigarette smoke exposure for 1h over five consecutive days. Bronchoalveolar lavage (BAL) fluid and lungs were collected for analyses of cytokines, oxidative damage and antioxidant activities. Bronchial epithelial cell BEAS-2B was exposed to cigarette smoke extract (CSE) and used to study the mechanisms of action of artesunate. Artesunate suppressed cigarette smoke-induced increases in BAL fluid total and differential cell counts; levels of IL-1beta, MCP-1, IP-10 and KC; and levels of oxidative biomarkers 8-isoprostane, 8-OHdG and 3-nitrotyrosine in a dose-dependent manner. Artesunate promoted anti-oxidant catalase activity and reduced NADPH oxidase 2 (NOX2) protein level in the lungs from cigarette smoke exposed mice. In BEAS-2B cells, artesunate suppressed pro-inflammatory PI3K/Akt and p44/42 MAPK signaling pathways, and increased nuclear Nrf2 accumulation in response to CSE. Artesunate possesses anti-inflammatory and anti-oxidative properties against cigarette smoke-induced lung injury, probably via inhibition of PI3K and p42/22 MAPK signaling pathways, augmentation of Nrf2 and catalase activities, and reduction of NOX2 level. Our data suggest that artesunate may have therapeutic potential for treating COPD. PMID- 25442272 TI - In vitro effect of important herbal active constituents on human cytochrome P450 1A2 (CYP1A2) activity. AB - This study was designed to investigate eight herbal active constituents (andrographolide, asiaticoside, asiatic acid, madecassic acid, eupatorin, sinensetin, caffeic acid, and rosmarinic acid) on their potential inhibitory effects on human cytochrome P450 1A2 (CYP1A2) activity. A fluorescence-based enzyme assay was performed by co-incubating human cDNA-expressed CYP1A2 with its selective probe substrate, 3-cyano-7-ethoxycoumarin (CEC), in the absence or presence of various concentrations of herbal active constituents. The metabolite (cyano-hydroxycoumarin) formed was subsequently measured in order to obtain IC50 values. The results indicated that only eupatorin and sinensetin moderately inhibited CYP1A2 with IC50 values of 50.8 and 40.2 MUM, while the other active compounds did not significantly affect CYP1A2 activity with IC50 values more than 100 MUM. Ki values further determined for eupatorin and sinensetin were 46.4 and 35.2 MUM, respectively. Our data indicated that most of the investigated herbal constituents have negligible CYP1A2 inhibitory effect. In vivo studies however may be warranted to ascertain the inhibitory effect of eupatorin and sinensetin on CYP1A2 activity in clinical situations. PMID- 25442273 TI - Cytotoxicity and modes of action of 4'-hydroxy-2',6'-dimethoxychalcone and other flavonoids toward drug-sensitive and multidrug-resistant cancer cell lines. AB - INTRODUCTION: Resistance of cancer to chemotherapy is a main cause in treatment failure. Naturally occurring chalcones possess a wide range of biological activities including anti-cancer effects. In this work, we evaluated the antiproliferative activity of three chalcones [4'-hydroxy-2',6'-dimethoxychalcone (1), cardamomin (2), 2',4'-dihydroxy-3',6'-dimethoxychalcone (3)], and four flavanones [(S)-(-)-pinostrobin (4), (S)-(-)-onysilin (5) and alpinetin (6)] toward nine cancer cell lines amongst which were multidrug resistant (MDR) types. METHODS: The resazurin reduction assay was used to detect the antiproliferative activity of the studied samples whilst flow cytometry for the mechanistic studies of the most active molecule (1). RESULTS: IC50 values in a range of 2.54 MUM against CEM/ADR5000 leukemia cells to 58.63 MUM toward hepatocarcinoma HepG2 cells were obtained with 1. The lowest IC50 values of 8.59 MUM for 2 and 10.67 MUM for 3 were found against CCRF-CEM cells leukemia cells, whilst the corresponding values were above 80 MUM for 4 and 6. P-glycoprotein-expressing and multidrug-resistant CEM/ADR5000 cells were much more sensitive toward compound 1 than toward doxorubicin and low cross-resistance or even collateral sensitivity was observed in other drug-resistent cell lines to this compound. Normal liver AML12 cells were more resistant to the studied compounds than HepG2 liver cancer cells, indicating tumor specificity at least to some extent. Compound 1 arrested the cell cycle between Go/G1 phase, strongly induced apoptosis via disrupted mitochondrial membrane potential (MMP) and increased production of reactive oxygen species (ROS) in the studied leukemia cell line. CONCLUSIONS: Chalcone 1 was the best tested cytotoxic molecule and further studies will be performed in order to envisage its possible use in the fight against multifactorial resistant cancer cells. PMID- 25442274 TI - Polygonatum odoratum lectin induces apoptosis and autophagy via targeting EGFR mediated Ras-Raf-MEK-ERK pathway in human MCF-7 breast cancer cells. AB - Polygonatum odoratum lectin (POL), a mannose-binding GNA-related lectin, has been reported to display remarkable anti-proliferative and apoptosis-inducing activities toward a variety of cancer cells; however, the precise molecular mechanisms by which POL induces cancer cell death are still elusive. In the current study, we found that POL could induce both apoptosis and autophagy in human MCF-7 breast cancer cells. Subsequently, we found that POL induced MCF-7 cell apoptosis via the mitochondrial pathway. Additionally, we also found that POL induces MCF-7 cell apoptosis via EGFR-mediated Ras-Raf-MEK-ERK pathway, suggesting that POL may be a potential EGFR inhibitor. Finally, we used proteomics analyses for exploring more possible POL-induced pathways with EGFR, Ras, Raf, MEK and ERK, some of which were consistent with our in silico network prediction. Taken together, these results demonstrate that POL induces MCF-7 cell apoptosis and autophagy via targeting EGFR-mediated Ras-Raf-MEK-ERK signaling pathway, which would provide a new clue for exploiting POL as a potential anti neoplastic drug for future cancer therapy. PMID- 25442275 TI - Synergistic effect of Myrtus communis L. essential oils and conventional antibiotics against multi-drug resistant Acinetobacter baumannii wound isolates. AB - Acinetobacter baumannii is a rapidly emerging, highly resistant clinical pathogen with increasing prevalence. In recent years, the limited number of antimicrobial agents available for treatment of infections with multi-drug resistant (MDR) strains reinforced tendency for discovery of novel antimicrobial agents or treatment strategies. The aim of the study was to determine antimicrobial effectiveness of three Myrtus communis L. essential oils, both alone and in combination with conventional antibiotics, against MDR A. baumannii wound isolates. The results obtained highlighted the occurrence of good antibacterial effect of myrtle oils when administered alone. Using checkerboard method, the combinations of subinhibitory concentrations of myrtle essential oils and conventional antibiotics, i.e. polymixin B and ciprofloxacine were examined. The results proved synergism among M. communis L. essential oils and both antibiotics against MDR A. baumannii wound isolates, with a FIC index under or equal 0.50. Combination of subinhibitory concentrations of essential oils and ciprofloxacin most frequently reduced bacterial growth in synergistic manner. The similar has been shown for combination with polymyxin B; furthermore, the myrtle essential oil resulted in re-sensitization of the MDR wound isolates, i.e. MICs used in combination were below the cut off for the sensitivity to the antibiotic. Time kill curve method confirmed efficacy of myrtle essential oil and polymyxin B combination, with complete reduction of bacterial count after 6h. The detected synergy offers an opportunity for future development of treatment strategies for potentially lethal wound infections caused by MDR A. baumannii. PMID- 25442276 TI - A novel compound T7 (N-{4'-[(1E)-N-hydroxyethanimidoyl]-3',5,6-trimethoxybiphenyl 3-yl}-N'-[4-(3-morpholin-4-ylpropoxy)phenyl]urea) screened by tissue angiogenesis model and its activity evaluation on anti-angiogenesis. AB - A tissue model for angiogenesis that imitated new blood vessels formation in vivo had been established in the previous study. Here, it was used to screen and evaluate a series of synthesized compounds and the results indicated that compound T7 (N-{4'-[(1E)-N-hydroxyethanimidoyl]-3',5,6-trimethoxybiphenyl-3-yl} N'-[4-(3-morpholin-4-ylpropoxy)phenyl]urea) could effectively inhibit the blood vessels formation. Then the anti-angiogenic potential of T7 and its related molecular mechanisms against lung carcinoma in vitro and in vivo were investigated. Treatment with T7 significantly inhibited human umbilical vein endothelial cells and A549 cells proliferation and migration. T7 reduced human umbilical vein endothelial cells tube formation as well. Western blotting analysis of cell signaling molecules indicated that T7 reduced phosphorylation of KDR and its downstream signaling players AKT and ERK1/2 activation in endothelial cells and A549 cells. Moreover, T7 inhibited tumor growth in A549 xenografted model of athymic mice and reduced CD34 expression levels in tumor-bearing mice by immunohistochemistry. In sum, our findings showed that T7 was a candidate of tumor angiogenesis inhibitors, and it functioned by interrupting the autophosphorylation of KDR, AKT and ERK1/2. PMID- 25442277 TI - Determination of pharmacological interactions of uliginosin B, a natural phloroglucinol derivative, with amitriptyline, clonidine and morphine by isobolographic analysis. AB - Uliginosin B is a natural phloroglucinol derivative, obtained from Hypericum species native to South America. Previous studies have shown that uliginosin B presents antidepressant-like and antinociceptive effects. Although its mechanism of action is still not completely elucidated, it is known that it involves the activation of monoaminergic neurotransmission. The aim of the current study was to further investigate the antinociceptive mechanism of action of uliginosin B by combining it with different drugs used for treating pain in clinical practice. The intraperitoneal administration of uliginosin B, morphine, amitriptyline and clonidine, alone or in mixture, produced a dose-dependent antinociceptive effect in the hot-plate assay in mice. The effect of the mixtures of drugs was studied using an adapted isobologram analysis at the effect level of 50% of the maximal effect observed. The analysis showed that the interactions between uliginosin B and morphine was synergistic, while the interactions between uliginosin B and amitriptyline or clonidine were additive. These findings point to uliginosin B as a potential adjuvant for pain pharmacotherapy, especially for opioid analgesia. PMID- 25442278 TI - In vitro effects of triterpenic acids from olive leaf extracts on the mitochondrial membrane potential of promastigote stage of Leishmania spp. AB - Protozoan diseases, such as leishmaniasis, are a cause of considerable morbidity throughout the world, affecting millions every year. In this study, two triterpenic acids (maslinic and oleanolic acids) were isolated from Tunisian olive leaf extracts and their in vitro activity against the promastigotes stage of Leishmania (L.) infantum and Leishmania (L.) amazonensis was investigated. Maslinic acid showed the highest activity with an IC50 of 9.32 +/- 1.654 and 12.460 +/- 1.25 MUg/ml against L. infantum and L. amazonensis, respectively. The mechanism of action of these drugs was investigated by detecting changes in the phosphatidylserine (PS) exposure, the plasma membrane permeability, the mitochondrial membrane potential and the ATP level production in the treated parasites. By using the fluorescent probe SYTOX(r) Green, both triterpenic acids showed that they produce a time-dependent plasma membrane permeabilization in the treated Leishmania species. In addition, spectrofluorimeteric data revealed the surface exposure of PS in promastigotes. Both molecules reduced the mitochondrial membrane potential and decreased the ATP levels to 15% in parasites treated with IC90 for 24h. We conclude that the triterpenic acids tested in this study, show potential as future therapeutic alternative against leishmaniasis. Further studies are needed to confirm this. PMID- 25442279 TI - Pharmacological insight into the anti-inflammatory activity of sesquiterpene lactones from Neurolaena lobata (L.) R.Br. ex Cass. AB - PURPOSE: Neurolaena lobata is a Caribbean medicinal plant used for the treatment of several conditions including inflammation. Recent data regarding potent anti inflammatory activity of the plant and isolated sesquiterpene lactones raised our interest in further pharmacological studies. The present work aimed at providing a mechanistic insight into the anti-inflammatory activity of N. lobata and eight isolated sesquiterpene lactones, as well as a structure-activity relationship and in vivo anti-inflammatory data. METHODS: The effect of the extract and its compounds on the generation of pro-inflammatory proteins was assessed in vitro in endothelial and monocytic cells by enzyme-linked immunosorbent assay. Their potential to modulate the expression of inflammatory genes was further studied at the mRNA level. In vivo anti-inflammatory activity of the chemically characterized extract was evaluated using carrageenan-induced paw edema model in rats. RESULTS: The compounds and extract inhibited LPS- and TNF-alpha-induced upregulation of the pro-inflammatory molecules E-selectin and interleukin-8 in HUVECtert and THP-1 cells. LPS-induced elevation of mRNA encoding for E-selectin and interleukin-8 was also suppressed. Furthermore, the extract inhibited the development of acute inflammation in rats. CONCLUSIONS: Sesquiterpene lactones from N. lobata interfered with the induction of inflammatory cell adhesion molecules and chemokines in cells stimulated with bacterial products and cytokines. Structure-activity analysis revealed the importance of the double bond at C-4-C-5 and C-2-C-3 and the acetyl group at C-9 for the anti-inflammatory activity. The effect was confirmed in vivo, which raises further interest in the therapeutic potential of the compounds for the treatment of inflammatory diseases. PMID- 25442280 TI - Ethanolic extract of Coelogyne cristata Lindley (Orchidaceae) and its compound coelogin promote osteoprotective activity in ovariectomized estrogen deficient mice. AB - Coelogyne cristata Lindley (CC) family Orchidaceae is an Indian medicinal plant used for the treatment of fractured bones in folk-tradition of Kumaon region, Uttarakhand, India. In continuation of our drug discovery program, feeding of ethanolic extract to ovariectomized estrogen deficient mice led to significant restoration of trabecular micro architecture in both femoral and tibial bones, better bone quality and also devoid of any uterine estrogenicity. Subsequently, coelogin, a pure compound was isolated from ethyl acetate fraction of C. cristata and evaluated in in vitro osteoblast cell cultures. Treatment of coelogin to osteoblasts led to enhanced ALP activity (a marker of osteoblast differentiation), mineral nodule formation and mRNA levels of osteogenic markers like BMP-2, Type 1 Collagen and RUNX-2. Based on these results, we propose that ethanolic extract of C. cristata and its pure compound coelogin have potential in the management of post menopausal osteoporosis. PMID- 25442281 TI - Comparison of solid-state-cultured and wood-cultured Antrodia camphorata in anti inflammatory effects using NF-kappaB/luciferase inducible transgenic mice. AB - PURPOSE: Antrodia camphorata (AC), a highly valued polypore mushroom native only to Taiwan, has been traditionally used as a medicine for the treatment of food and drug intoxication, diarrhea, abdominal pain, hypertension, skin itching, and cancer. In this study, both of solid-state-cultured AC (S-AC) and wood-cultured AC (W-AC) were evaluated the anti-inflammatory effects on hyperoxia-induced lung injury in NF-kappaB-luciferase(+/+) transgenic mice. METHODS: The homozygous transgenic mice (NF-kappaB-luciferase(+/+)) were randomly assigned to four groups for treatment (n = 6) including Normoxia/DMSO group, Hyperoxia/DMSO group, Hyperoxia/S-AC group, and Hyperoxia/W-AC group. After 72 h of hyperoxia, we examined the bioluminescence images, reactive oxygen species (ROS), the mRNA and protein expression levels of inflammation factors, and histopathological analyses of the lung tissues. RESULTS: Hyperoxia-induced lung injury significantly increased the generation of ROS, the mRNA levels of IL-6, TNF-alpha, IL-1beta and IL-8, and the protein expression levels of IKKalpha/beta, iNOS and IL-6. Pulmonary edema and alveolar infiltration of neutrophils was also observed in the hyperoxia-induced lung tissue. However, treatment with either S-AC or W-AC obviously decreased hyperoxia-induced generation of ROS and the expression of IL 6, TNF-alpha, IL-1beta, IL-8, IKKalpha/beta and iNOS compared to hyperoxia treatment alone. Lung histopathology also showed that treatment with either S-AC or W-AC significantly reduced neutrophil infiltration and lung edema compared to treatment with hyperoxia treated alone. To find out their major compounds, eburicoic acid and dehydroeburicoic acid were both isolated and identified from S AC and W-AC by using HPLC, MS, and NMR spectrometry. CONCLUSIONS: These results demonstrated that methanolic extracts both of S-AC and W-AC have excellent anti inflammatory activities and thus have great potential as a source for natural health products. PMID- 25442282 TI - Effects of anti-proliferative lichen metabolite, protolichesterinic acid on fatty acid synthase, cell signalling and drug response in breast cancer cells. AB - BACKGROUND: The lichen compound (+)-protolichesterinic acid (+)-PA, isolated from Iceland moss, has anti-proliferative effects on several cancer cell lines. The chemical structure of (+)-PA is similar to a known fatty acid synthase (FASN) inhibitor C75. AIMS: To test whether the anti-proliferative activity of (+)-PA is associated with effects on FASN and HER2 (human epidermal growth factor receptor 2) and major signalling pathways. Synergism between (+)-PA and lapatinib, a HER2 active drug, was also evaluated. MATERIALS AND METHODS: Pure compound was isolated by preparative high-performance liquid chromatography (HPLC) and purity of (+)-PA analyzed by analytical HPLC. Cell viability was assessed using Crystal violet staining. FASN and HER2 expression was estimated by immunofluorescence. The Meso Scale Discovery (MSD)((r)) assay was used to measure activation of ERK1/2 and AKT. Synergism was estimated by the CalcuSyn software. RESULTS: Treatment with (+)-PA increased FASN expression in SK-BR-3 cells, which overexpress FASN and HER2, implying a compensatory response to inhibition of FASN activity. HER2 expression was decreased suggesting secondary downregulation. ERK1/2 and AKT signalling pathways were inhibited, probably due to reduced levels of HER2. No effects were observed in T-47D cells. Synergism between (+)-PA and lapatinib was observed in the SK-BR-3 cells. CONCLUSION: Results suggest that the primary effect of (+)-PA is inhibition of FASN activity. Synergistic effects with lapatinib were seen only in SK-BR-3 cells, and not T-47D cells, further supporting the notion that (+)-PA acts by inhibiting FASN with secondary effects on HER2 expression and signalling. (+)-PA could therefore be a suitable agent for further testing, alone or in combination treatment against HER2-overexpressing breast cancer. PMID- 25442283 TI - Salvianolic acid A reverses paclitaxel resistance in human breast cancer MCF-7 cells via targeting the expression of transgelin 2 and attenuating PI3 K/Akt pathway. AB - Chemotherapy resistance represents a major problem for the treatment of patients with breast cancer and greatly restricts the use of first-line chemotherapeutics paclitaxel. The purpose of this study was to investigate the role of transgelin 2 in human breast cancer paclitaxel resistance cell line (MCF-7/PTX) and the reversal mechanism of salvianolic acid A (SAA), a phenolic active compound extracted from Salvia miltiorrhiza. Western blotting and real-time quantitative polymerase chain reaction (qRT-PCR) indicated that transgelin 2 may mediate paclitaxel resistance by activating the phosphatidylinositol 3-kinase (PI3 K)/Akt signaling pathway to suppress MCF-7/PTX cells apoptosis. The reversal ability of SAA was confirmed by MTT assay and flow cytometry, with a superior 9.1-fold reversal index and enhancement of the apoptotic cytotoxicity induced by paclitaxel. In addition, SAA effectively prevented transgelin 2 and adenosine triphosphate binding cassette transporter (ABC transporter) including P glycoprotein (P-gp), multidrug resistance associated protein 1 (MRP1), and breast cancer resistance protein (BCRP) up-regulation and exhibited inhibitory effect on PI3 K/Akt signaling pathway in MCF-7/PTX cells. Taken together, SAA can reverse paclitaxel resistance through suppressing transgelin 2 expression by mechanisms involving attenuation of PI3 K/Akt pathway activation and ABC transporter up regulation. These results not only provide insight into the potential application of SAA in reversing paclitaxel resistance, thus facilitating the sensitivity of breast cancer chemotherapy, but also highlight a potential role of transgelin 2 in the development of paclitaxel resistance in breast cancer. PMID- 25442284 TI - Oroxylin A, a constituent of Oroxylum indicum inhibits adipogenesis and induces apoptosis in 3T3-L1 cells. AB - Oroxylin A (OA) is a flavonoid found in Oroxylum indicum, a medicinal plant with multiple biological activities. This study was taken up to investigate the effect of OA, on adipogenesis, lipolysis and apoptosis in 3T3 L1 cells. Pre-adipocytes were treated with 10-40 MUM OA on various days of adipogenesis treatment schedule. Mature adipocytes were treated with OA for lipolysis and apoptosis studies. In maturing pre-adipocytes, 10 MUM OA suppressed intracellular lipid accumulation by 42.19% which was confirmed by lipidTox imaging of cells. In addition, OA decreased the nuclear translocation of PPARgamma and mRNA expression of its downstream genes (FAS and LPL) along with adiponectin secretion. In mature adipocytes, 40 MUM of OA decreased cell viability by 30% of control. Annexin V/PI staining showed induction of apoptosis which was further confirmed by enhanced levels of pro-apoptotic proteins Bax, cyt c, AIF and chromatin condensation. OA enhanced TNF-alpha secretion, lipolysis and decreased Akt phosphorylation in mature adipocytes. Findings suggest that OA possibly exerts its anti-obesity effect by affecting adipocyte life cycle at critical points of differentiation and maturity. When we compared the potency of OA with non-methoxylated flavonoids morin, naringenin and kaempferol on adipocyte life cycle OA was far more potent. Thus, study clearly indicates a new role for oroxylin A as regulator of adipocyte life cycle. In addition, study also suggested a specific role of methoxylated group in exerting lipolysis and cytotoxic effects in mature adipocytes. PMID- 25442285 TI - Baicalein protects against hypertension associated with diabetes: effect on vascular reactivity and stiffness. AB - The present work investigated the possible protective effect of baicalein, a natural lipoxygenase enzyme inhibitor, on both insulin deficiency (ID) and insulin resistance (IR)-induced macro-vascular impairment. ID and IR were induced by STZ or fructose for 8 or 12 weeks respectively while baicalein was administered in the last six weeks. Blood pressure (BP) was recorded and isolated aorta reactivity to phenylephrine (PE) and acetylcholine (ACh) were studied. Blood levels of glucose, insulin, advanced glycation end products (AGEs) and tumour necrosis factor-alpha (TNF-alpha) were determined. Aortic nuclear transcription factor-kappaB (NF-kappaB) activation was assessed. Both models resulted in elevated BP, increased vasoconstriction and impaired relaxation KCl, elevated TNF-alpha and AGEs, NF-kappaB activation, marked infiltration of leukocytes in the adventitia, pyknosis of endothelial cells and marked collagen deposition. Baicalein ameliorated elevations in BP in models, prevented exaggerated vasoconstriction IR model and improved relaxation in ID model. Baicalein reduced AGEs and TNF-alpha level, decreased NF-kappaB activation and inhibited histopathological changes in both models. Baicalein offsets the hypertensive and the vascular impairment associated with both diabetic models via ameliorating functional and structural derangements of blood vessels. PMID- 25442286 TI - Hispolon from Phellinus linteus possesses mediate caspases activation and induces human nasopharyngeal carcinomas cells apoptosis through ERK1/2, JNK1/2 and p38 MAPK pathway. AB - Hispolon, a phenol compound isolated from Phellinus linteus (PL), possesses anti inflammatory, antiproliferative, and antioxidant effects. However, the effects of hispolon on human nasopharyngeal carcinomas have yet to be evaluated. Here, the molecular mechanism by which hispolon anticancer effects in human nasopharyngeal carcinomas cells was investigated. The results showed that hispolon significantly inhibited cell proliferation of HONE-1 and NP-039 cell lines. Furthermore, hispolon induced apoptosis through caspases-3, -8, and -9 activations and PARP cleavage in dose- and time-dependent manner in HONE-1 and NP-039 cells. Moreover, hispolon also showed that increase phosphorylation of ERK1/2, p38 MAPK and JNK1/2 in dose- and time-dependent manner by western blot analysis. However, hispolon induced activation of the caspase-3, -8 and -9 significantly abolished by inhibition of p38 MAPK and JNK1/2 specific inhibitors. In this study, we determine that the effects of hispolon on the apoptosis and related regulation mechanism in HONE-1 and NPC-039 cells takes place. Our findings revealed that hispolon may be a useful candidate as a chemotherapeutic agent for NPC therapy. PMID- 25442287 TI - 25 years of ESCOP--a story of success. PMID- 25442288 TI - Identification and genomic characterization of a novel porcine parvovirus (PPV6) in China. AB - BACKGROUND: Parvoviruses are classified into two subfamilies based on their host range: the Parvovirinae, which infect vertebrates, and the Densovirinae, which mainly infect insects and other arthropods. In recent years, a number of novel parvoviruses belonging to the subfamily Parvovirinae have been identified from various animal species and humans, including human parvovirus 4 (PARV4), porcine hokovirus, ovine partetravirus, porcine parvovirus 4 (PPV4), and porcine parvovirus 5 (PPV5). METHODS: Using sequence-independent single primer amplification (SISPA), a novel parvovirus within the subfamily Parvovirinae that was distinct from any known parvoviruses was identified and five full-length genome sequences were determined and analyzed. RESULTS: A novel porcine parvovirus, provisionally named PPV6, was initially identified from aborted pig fetuses in China. Retrospective studies revealed the prevalence of PPV6 in aborted pig fetuses and piglets(50% and 75%, respectively) was apparently higher than that in finishing pigs and sows (15.6% and 3.8% respectively). Furthermore, the prevalence of PPV6 in finishing pig was similar in affected and unaffected farms (i.e. 16.7% vs. 13.6%-21.7%). This finding indicates that animal age, perhaps due to increased innate immune resistance, strongly influences the level of PPV6 viremia. Complete genome sequencing and multiple alignments have shown that the nearly full-length genome sequences were approximately 6,100 nucleotides in length and shared 20.5%-42.6% DNA sequence identity with other members of the Parvovirinae subfamily. Phylogenetic analysis showed that PPV6 was significantly distinct from other known parvoviruses and was most closely related to PPV4. CONCLUSION: Our findings and review of published parvovirus sequences suggested that a novel porcine parvovirus is currently circulating in China and might be classified into the novel genus Copiparvovirus within the subfamily Parvovirinae. However, the clinical manifestations of PPV6 are still unknown in that the prevalence of PPV6 was similar between healthy pigs and sick pigs in a retrospective epidemiological study. The identification of PPV6 within the subfamily Parvovirinae provides further insight into the viral and genetic diversity of parvoviruses. PMID- 25442289 TI - Interaction of antimicrobial cyclic lipopeptides from Bacillus subtilis influences their effect on spore germination and membrane permeability in fungal plant pathogens. AB - Bacillus subtilis cyclic lipopeptides are known to have various antimicrobial effects including different types of interactions with the cell membranes of plant pathogenic fungi. The various spectra of activities of the three main lipopeptide families (fengycins, iturins, and surfactins) seem to be linked to their respective mechanisms of action on the fungal biomembrane. Few studies have shown the combined effect of more than one family of lipopeptides on fungal plant pathogens. In an effort to understand the effect of producing multiple lipopeptide families, sensitivity and membrane permeability of spores from four fungal plant pathogens (Alternaria solani, Fusarium sambucinum, Rhizopus stolonifer, and Verticillium dahliae) were assayed in response to lipopeptides, both individually and as combined treatments. Results showed that inhibition of spores was highly variable depending on the tested fungus-lipopeptide treatment. Results also showed that inhibition of the spores was closely associated with SYTOX stain absorption suggesting effects of efficient treatments on membrane permeability. Combined lipopeptide treatments revealed additive, synergistic or sometimes mutual inhibition of beneficial effects. PMID- 25442290 TI - Interspecific variability of class II hydrophobin GEO1 in the genus Geosmithia. AB - The genus Geosmithia Pitt (Ascomycota: Hypocreales) comprises cosmopolite fungi living in the galleries built by phloeophagous insects. Following the characterization in Geosmithia species 5 of the class II hydrophobin GEO1 and of the corresponding gene, the presence of the geo1 gene was investigated in 26 strains derived from different host plants and geographic locations and representing the whole phylogenetic diversity of the genus. The geo1 gene was detected in all the species tested where it maintained the general organization shown in Geosmithia species 5, comprising three exons and two introns. Size variations were found in both introns and in the first exon, the latter being due to the presence of an intragenic tandem repeat sequence corresponding to a stretch of glycine residues in the deduced proteins. At the amino acid level the deduced proteins had 44.6 % identity and no major differences in the biochemical parameters (pI, GRAVY index, hydropathy plots) were found. GEO1 release in the fungal culture medium was also assessed by turbidimetric assay and SDS-PAGE, and showed high variability between species. The phylogeny based on the geo1 sequences did not correspond to that generated from a neutral marker (ITS rDNA), suggesting that sequence similarities could be influenced by other factors than phylogenetic relatedness, such as the intimacy of the symbiosis with insect vectors. The hypothesis of a strong selection pressure on the geo1 gene was sustained by the low values (<1) of non synonymous to synonymous nucleotide substitutions ratios (Ka/Ks), which suggest that purifying selection might act on this gene. These results are compatible with either a birth-and-death evolution scenario or horizontal transfer of the gene between Geosmithia species. PMID- 25442291 TI - Control of yeast-mycelium dimorphism in vitro in Dutch elm disease fungi by manipulation of specific external stimuli. AB - Dutch elm disease (DED) fungi exhibit yeast-mycelium dimorphism both in planta and in vitro. However, previously published data on the transition between these two growth forms in vitro were mostly obtained from a single strain. We examined the effect of six factors on yeast-mycelium dimorphism in vitro in ten strains of Ophiostoma ulmi, Ophiostoma novo-ulmi and Ophiostoma himal-ulmi. Nitrogen sources, calcium, and yeast extract, altogether with inhibitors of phosphodiesterase (caffeine) and dioxygenases (propyl gallate and salicylic acid) were tested in defined culture media. Morphological response to manipulation of several of these factors varied according to the strain of Ophiostoma being analysed. Responses ranged from no statistical differences in morphological transitions to stimulation or reversion of yeast-mycelium dimorphism with the treatments that were tested. These results suggest that different mechanisms and pathways operate in the control of the yeast-mycelium transition in DED pathogens. Oxylipins could be involved in the yeast-to-mycelium transition, since the addition of a dioxygenase inhibitor, salicylic acid, reduced mycelium production in all strains that were tested. PMID- 25442292 TI - Complementation of a manganese-dependent superoxide dismutase-deficient yeast strain with Pneumocystis carinii sod2 gene. AB - Manganese-dependent superoxide dismutase (MnSOD) is one of the key enzymes involved in the cellular defense against oxidative stress. Previously, the Pneumocystis carinii sod2 gene (Pcsod2) was isolated and characterized. Based on protein sequence comparison, Pcsod2 was suggested to encode a putative MnSOD protein likely to be targeted into the mitochondrion. In this work, the Pcsod2 was cloned and expressed as a recombinant protein in EG110 Saccharomyces cerevisiae strain lacking the MnSOD-coding gene (Scsod2) in order to investigate the function and subcellular localization of P. carinii MnSOD (PcMnSOD). The Pcsod2 gene was amplified by PCR and cloned into the pYES2.1/V5-His-TOPO((r)) expression vector. The recombinant construct was then transformed into EG110 strain. Once its expression had been induced, PcMnSOD was able to complement the growth defect of EG110 yeast cells that had been exposed to the redox-cycling compound menadione. N-term sequencing of the PcMnSOD protein allowed identifying the cleavage site of a mitochondrial targeting peptide. Immune-colocalization of PcMnSOD and yeast CoxIV further confirmed the mitochondrial localization of the PcMnSOD. Heterologous expression of PcMnSOD in yeast indicates that Pcsod2 encodes an active MnSOD, targeted to the yeast mitochondrion that allows the yeast cells to grow in the presence of reactive oxygen species (ROS). PMID- 25442293 TI - Evolution of ketosynthase domains of polyketide synthase genes in the Cladonia chlorophaea species complex (Cladoniaceae). AB - Lichen-forming fungi synthesize a diversity of polyketides, but only a few non reducing polyketide synthase (PKS) genes from a lichen-forming fungus have been linked with a specific polyketide. While it is a challenge to link the large number of PKS paralogs in fungi with specific products, it might be expected that the PKS paralogs from closely related species would be similar because of recent evolutionary divergence. The objectives of this study were to reconstruct a PKS gene phylogeny of the Cladonia chlorophaea species complex based on the ketosynthase domain, a species phylogeny of the complex, and to explore the presence of PKS gene paralogs among members of the species complex. DNA was isolated from 51 individuals of C. chlorophaea and allies to screen for the presence of 13 PKS paralogs. A 128 sequence PKS gene phylogeny using deduced amino acid sequences estimated from the 13 PKS paralogs and sequences subjected to BLASTx comparisons showed losses of each of two PKS domains (reducing and methylation). This research provided insight into the evolution of PKS genes in the C. chlorophaea group, species evolution in the group, and it identified potential directions for further investigation of polyketide synthesis in the C. chlorophaea species complex. PMID- 25442295 TI - Molecular characterisation of an endornavirus from Rhizoctonia solani AG-3PT infecting potato. AB - Rhizoctonia solani (teleomorph: Thanatephorus cucumeris) is a soil-borne plant pathogenic fungus that has a broad host range, including potato. In this study, the double-stranded RNA (dsRNA) profiles were defined for 39 Rhizoctonia solani isolates representative of two different anastomosis groups (AGs) associated with black scurf of potato in New Zealand. A large dsRNA of c. 12 kb-18 kb was detected in each of the isolates, regardless of AG or virulence on potato. Characterisation of the large dsRNA from R. solani AG-3PT isolate RS002, using random amplification of total dsRNA and analyses of overlapping cDNA sequences, resulted in the assembly of a consensus sequence of 14 694 nt. A single, large open reading frame was identified on the positive strand of the assembled sequence encoding a putative polypeptide of at least 4893 amino acids, with a predicted molecular mass of 555.6 kDa. Conserved domains within this polypeptide included those for a viral methyltransferase, a viral RNA helicase 1 and an RNA dependent RNA polymerase. The domains and their sequential organisation revealed the polyprotein was very similar to those encoded by dsRNA viruses of the genus Endornavirus, in the family Endornaviridae. This is the first report of an endornavirus in R. solani, and thus the putative virus is herein named Rhizoctonia solani endornavirus - RS002 (RsEV-RS002). Partial characterisation of the large dsRNAs in five additional AG-3PT isolates of R. solani also identified them as probable endornaviruses, suggesting this family of viruses is widespread in R. solani infecting potato. The ubiquitous nature of endornaviruses in this plant pathogen implies they may have an important, but yet uncharacterised, role in R. solani. PMID- 25442294 TI - Melampsora rust species on biomass willows in central and north-eastern Germany. AB - Melampsora willow rusts are the most important fungal pathogens in short rotation coppices of biomass willows. In the past, breeding programmes for rust resistant biomass willows concentrated on the distinction of races within the forma specialis Melampsora larici-epitea f. sp. larici-epitea typica that colonized Salix viminalis and related clones. In a new breeding program that is based on a wider range of willow species it is necessary to identify further Melampsora species and formae specialis that are pathogens of willow species other than S. viminalis. Therefore, three stock collections with Salix daphnoides, Salix purpurea, and other shrub willow species (including S. viminalis) species were sampled in north-eastern Germany. A fourth stock collection in central Germany contributed rusts of tree willows (Salix fragilis and Salix alba) and the large shrub Salix caprea. Out of 156 rust samples, 149 were successfully sequenced for ITS rDNA. A phylogenetic analysis combining Neighbour-Joining, Maximum-Likelihood and Bayesian analysis revealed six species: Melampsora ribesii-purpureae, Melampsora allii-salicis-albae, Melampsora sp. aff. allii-fragilis, Melampsora larici-pentandrae, Melampsora larici-caprearum, and Melampsora larici-epitea. The first four species were found exclusively on the expected hosts. Melampsora larici-caprearum had a wider host range comprising S. caprea and S. viminalis hybrids. Melampsora larici-epitea can be further differentiated into two formae speciales. The forma specialis larici-epitea typica (59 samples) colonized Salix viminalis clones, Salix purpurea, Salix*dasyclados, and Salix*aquatica. In contrast to this relatively broad host range, f. sp. larici-daphnoides (65 samples) was found exclusively on Salix daphnoides. With the distinction and identification of the rust species/formae speciales it is now possible to test for race-specific resistances in a more targeted manner within the determined pairings of rust and willow species. PMID- 25442296 TI - Metabolite secretion, Fe(3+)-reducing activity and wood degradation by the white rot fungus Trametes versicolor ATCC 20869. AB - Trametes versicolor is a promising white-rot fungus for the biological pretreatment of lignocellulosic biomass. In the present work, T. versicolor ATCC 20869 was grown on Pinus taeda wood chips under solid-state fermentation conditions to examine the wood-degrading mechanisms employed by this fungus. Samples that were subjected to fungal pretreatment for one-, two- and four-week periods were investigated. The average mass loss ranged from 5 % to 8 % (m m( )(1)). The polysaccharides were preferentially degraded: hemicellulose and glucan losses reached 13.4 % and 6.9 % (m m(-)(1)) after four weeks of cultivation, respectively. Crude enzyme extracts were obtained and assayed using specific substrates and their enzymatic activities were measured. Xylanases were the predominant enzymes, while cellobiohydrolase activities were marginally detected. Endoglucanase activity, beta-glucosidase activity, and wood glucan losses increased up to the second week of biodegradation and remained constant after that time. Although no lignin-degrading enzyme activity was detected, the lignin loss reached 7.5 % (m m(-)(1)). Soluble oxalic acid was detected in trace quantities. After the first week of biodegradation, the Fe(3+)-reducing activity steadily increased with time, but the activity levels were always lower than those observed in the undecayed wood. The progressive wood polymer degradation appeared related to the secretion of hydrolytic enzymes, as well as to Fe(3+) reducing activity, which was restored in the cultures after the first week of biodegradation. PMID- 25442297 TI - Criterion validity of the International Physical Activity Questionnaire Short Form (IPAQ-SF) for use in patients with rheumatoid arthritis: comparison with the SenseWear Armband. AB - OBJECTIVES: The International Physical Activity Questionnaire Short Form (IPAQ SF) is a self-report questionnaire commonly used in patients with rheumatoid arthritis (RA) to measure physical activity. However, despite its frequent use in patients with RA, its validity has not been ascertained in this population. The aim of this study was to examine the criterion validity of energy expenditure from physical activity recorded with the IPAQ-SF in patients with RA compared with the objective criterion measure, the SenseWear Armband (SWA) which has been validated previously in this population. DESIGN: Cross-sectional criterion validation study. SETTING: Regional hospital outpatient setting. PARTICIPANTS: Twenty-two patients with RA attending outpatient rheumatology clinics. INTERVENTIONS: Subjects wore an SWA for 7 full consecutive days and completed the IPAQ-SF. MAIN OUTCOME MEASURES: Energy expenditure from physical activity recorded by the SWA and the IPAQ-SF. RESULTS: Energy expenditure from physical activity recorded by the IPAQ-SF and the SWA showed a small, non-significant correlation (r=0.407, P=0.60). The IPAQ-SF underestimated energy expenditure from physical activity by 41% compared with the SWA. This was corroborated using Bland and Altman plots, as the IPAQ-SF was found to overestimate energy expenditure from physical activity in nine of the 22 individuals, and underestimate energy expenditure from physical activity in the remaining 13 individuals. CONCLUSION: The IPAQ-SF has limited use as an accurate and absolute measure for estimating energy expenditure from physical activity in patients with RA. PMID- 25442299 TI - Muscular activity during isometric incisal biting. AB - This study attempted to estimate TMJ loading during incisal loading using a custom load-cell device and surface electromyographic (sEMG) recordings of the main jaw closers to assess the outcome correlation. Study participants were 23 healthy volunteers. The incisal loads having submaximal and mean intensity were recorded using a calibrated electronic load cell; simultaneously, surface electromyography (sEMG) of the right and left masseter and temporalis muscles was recorded. Readings of the resting, clenching in maximal and submaximal intercuspal positions and mean (50%) incisal loads were recorded. Clenching sEMG activity was used as a reference for normalization. The mean (SD) submaximal incisal load recorded was 498 (305.78)N, and the mean at 50% of the submaximal load was 268.93 (147.37)N. Mean (SD) sEMG activity during submaximal clenching was 141.23 (87.76)MUV, with no significant differences between the four muscles. During submaximal voluntary incisal loading, the normalized mean sEMG activity was 49.99 (34.54)uV %, and 27.17(15.29)uV % during mean (50%) effort. The incisal load was generated mainly by the masseter muscles, as these showed a positive correlation during mean but not during submaximal effort. In the edge-to-edge jaw position, the mean incisal load effort seems to be physiological, but excessive TMJ loads can be expected from chronic or excessive incisal loading. In conclusion, incisal loads require the activity of the masseter muscles, which show a positive correlation between sEMG activity and effective incisal loads during mean, but not during submaximal, effort, and the masseter muscles are dominant over the temporalis muscles during submaximal incisal biting. PMID- 25442298 TI - Upper extremity impairments, pain and disability in patients with diabetes mellitus. AB - OBJECTIVES: To determine the severity of, and relationships between, upper extremity impairments, pain and disability in patients with diabetes mellitus, and to compare upper extremity impairments in patients with diabetes with non diabetic controls. DESIGN: Case-control, cross-sectional design. SETTING: University-based, outpatient diabetes centre and physical therapy research clinic. PARTICIPANTS: Two hundred and thirty-six patients with diabetes attending an outpatient diabetes clinic completed the Shoulder Pain and Disability Index (SPADI) questionnaire. A detailed shoulder and hand examination was conducted on a subgroup of 29 volunteers with type 2 diabetes, and 27 controls matched for age, sex and body mass index. INTERVENTIONS: None. MAIN OUTCOME MEASURES: SPADI score, passive shoulder range of motion (ROM) and strength, grip strength, hand sensation, dexterity and limited joint mobility of the hand. RESULTS: Sixty-three percent (149/236) of patients with diabetes reported shoulder pain and/or disability [median SPADI score 10.0 (interquartile range 0.0 to 39.6)]. Compared with the control group, the subgroup of patients with diabetes had substantial reductions in shoulder ROM, shoulder muscle strength, grip and key pinch strength (P<0.05). Patients with diabetes had a greater prevalence of decreased sensation (26/27 vs 14/27) and limited joint mobility of the hand (17/27 vs 4/27) compared with the control group. Total SPADI score was negatively correlated (P<0.05) with shoulder ROM (r=-0.42 to -0.74) and strength measures (r=-0.44 to -0.63) in patients with diabetes. CONCLUSIONS: Upper extremity impairments in this sample of patients with diabetes were common, severe and related to complaints of pain and disability. Additional research is needed to understand the unique reasons for upper extremity problems in patients with diabetes, and to identify preventative treatments. PMID- 25442300 TI - Ginsenoside Rg3 improves erectile function in streptozotocin-induced diabetic rats. AB - INTRODUCTION: Ginsenoside Rg3 is one of the active ingredients isolated from Panax ginseng C.A. Meyer. Previous studies demonstrated that Rg3 has antioxidant and neuroprotective abilities. AIM: The purpose of this study was to evaluate the protective effect of Rg3 on erectile function in streptozotocin (STZ)-induced diabetic rats. METHODS: Two-month-old Sprague-Dawley male rats received a one time intraperitoneal (IP) STZ (60 mg/kg) or vehicle injection after a 16-hour fast. Three days later, rats were randomly divided into four groups and were treated with daily gavage feedings of a mix of distilled saline water and 0.5% carboxymethylcellulose or Rg3 dissolved in the mix at doses of 10 mg/kg and 100 mg/kg for 3 months. A sham group underwent IP injection of saline followed by daily gavage of the above mix for 3 months. MAIN OUTCOME MEASURE: Erectile function was assessed by cavernosal nerve electrostimulation at 3 months. The penis was then harvested and deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was performed. Western blot was performed to examine cleaved caspase-3, platelet endothelial cell adhesion molecule (PECAM)-1, and smooth muscle actin (SMA). Neural regeneration was measured by nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were detected by colorimetry. RESULTS: In the negative control group, the functional evaluation showed a lower mean intracavernosal pressure (ICP) with cavernosal nerve stimulation than in the sham group; there was a significant change in the expression of cleaved caspase-3, bcl 2, bcl-xl, PECAM-1, and SMA, as well as in the SOD and MDA production in the corpus cavernosum. Histological analysis of specimens stained for NADPH showed a significant change in the staining quality of the neurons in the dorsal nerves; TUNEL showed a greater apoptotic index in corpus cavernosum cells. With daily oral gavage with 100 mg/kg Rg3, the ICP/mean arterial pressure value was significantly higher than in the controls. The level of cleaved caspase-3, bcl-2, bcl-xl, PECAM-1, and SMA and the number of positively stained nerve fibers tended to revert to normal after Rg3 treatment. The apoptotic index in corpus cavernosum cells was lowered. CONCLUSION: Oral gavage with Rg3 appears to both prevent degeneration of neurons in the dorsal nerves and exert an antioxidant effect in the corpus cavernosum of rats. PMID- 25442301 TI - New silibinin glyco-conjugates: synthesis and evaluation of antioxidant properties. AB - New silibinin glyco-conjugates have been synthesized by efficient method and in short time. Exploiting our solution phase strategy, several structurally diverse silibinin glyco-conjugates (gluco, manno, galacto, and lacto-) were successfully realized in very good yields and in short time. In preliminary study to evaluate their antioxidant and neuroprotective activities new derivatives were subjected to DPPH free radical scavenging assay and the Xanthine oxidase (XO) inhibition models assay. Irrespective of the sugar moiety examined, new glyco-conjugates are more than 50 times water-soluble of silibinin. In the other hand they exhibit a radical scavenging activities slightly higher than to silibinin and XO inhibition at least as silibinin. PMID- 25442302 TI - Phosphocalyculin C as a pyrophosphate protoxin of calyculin C in the marine sponge Discodermia calyx. AB - Calyculin C, a minor derivative of the calyculins, has an additional methyl group on C32 of calyculin A. A recent biosynthetic study of calyculins revealed that an end product of calyculin biosynthesis is the pyrophosphate form, phosphocalyculin A. However, the pyrophosphate counterpart derived from calyculin C had not been reported. We isolated phosphocalyculin C as a minor pyrophosphate derivative, by a detailed investigation of an extract from the sponge Discodermia calyx. The treatment of phosphocalyculin C with the D. calyx cell-free extract significantly enhanced its cytotoxicity, providing molecular evidence for its role as the protoxin of calyculin C. PMID- 25442303 TI - Synthesis and antitumor activities of novel hybrid molecules containing 1,3,4 oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety. AB - A series of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4 thiadiazole bearing Schiff base moiety were designed, synthesized and evaluated for their in vitro antitumor activities against SMMC-7721, MCF-7 and A549 human tumor cell lines by CCK-8 assay. The bioassay results demonstrated that most of the tested compounds showed potent antitumor activities, and some compounds exhibited stronger effects than positive control 5-fluorouracil (5-FU) against various cell lines. Among these compounds, compound 8d showed the best inhibitory effect against SMMC-7721 cells, with IC50 value of 2.84 MUM. Compounds 8k and 8 n displayed highly effective antitumor activities against MCF-7 cells, with IC50 values of 4.56 and 4.25 MUM, respectively. Compounds 8a and 8 n exhibited significant antiproliferative activity against A549 cells, with IC50 values of 4.11 and 4.13 MUM, respectively. The pharmacological results suggest that the substituents of phenyl ring on the 1,3,4-oxadiazole are vital for modulating antiproliferative activities against various tumor cell lines. PMID- 25442304 TI - Bioactive triterpenoid saponins and phenolic compounds against glioma cells. AB - A total of 54 natural origin compounds were evaluated for their activity in inhibiting the proliferation of glioma cells. Results showed that four Aesculus polyhydroxylated triterpenoid saponins (3-6), six Gleditsia triterpenoid saponins (7-12), and five phenolic compounds (43-46, 51) had dose-dependent activity suppressing the proliferation of both C6 and U251 cells. Structure-activity relationship analysis suggested that the acetyl group at C-28 for the Aesculus saponins and the monoterpenic acid moiety for the Gleditsia saponins could be critical for the activity of these active compounds. Aesculioside H (4), gleditsioside A (7), and feuric acid 3,4-dihydroxyphenethyl ester (FADPE, 46) were the three most active compounds from the different types of the active compounds and induced apoptosis and necrosis in glioma cells. PMID- 25442305 TI - Bioactive compounds from the insect Aspongopus chinensis. AB - Recent studies focusing on unveiling the biological agents of Aspongopus chinensis have led to the identification of four new norepinephrine derivatives (1-4), three new sesquiterpenoids (5-7), and one new lactam (8). In addition, twenty-three known compounds have been identified, most of which were isolated from this insect for the first time. Selected members of insect-derived substances were evaluated for their biological activities against renal protection in high-glucose-induced mesangial cells and COX-2 inhibition. PMID- 25442306 TI - Synthesis and identification of alpha-cyano bis(indolyl)chalcones as novel anticancer agents. AB - Microwave-assisted synthesis of 23 alpha-cyano bis(indolyl)chalcones (6a-w) and their in vitro anticancer activity against three human cancer cell lines have been discussed. Among the synthesized chalcones, compound 6n was found to be the most potent and selective against A549 lung cancer cell line (IC50 = 0.8 MUM). In a preliminary mechanism of action studies some alpha-cyano bis(indolyl)chalcones were found to enhance tubulin polymerization suggesting these compounds could act as microtubule stabilizing agents. PMID- 25442307 TI - Design and synthesis of novel 5-(3,4,5-trimethoxybenzoyl)-4-aminopyrimidine derivatives as potent and selective phosphodiesterase 5 inhibitors: scaffold hopping using a pseudo-ring by intramolecular hydrogen bond formation. AB - 5-(3,4,5-Trimethoxybenzoyl)-4-amimopyrimidine derivatives were found as a novel chemical class of potent and highly selective phosphodiesterase 5 inhibitors. A pseudo-ring formed by an intramolecular hydrogen bond constrained the conformation of 3-chloro-4-methoxybenzylamino and 3,4,5-trimethoxybenzoyl substituents and led to the discovery of T-6932 (19a) with a potent PDE5 inhibitory activity (IC50 = 0.13 nM) and a high selectivity over PDE6 (IC50 ratio: PDE6/PDE5 = 2400). Further modification at the 2-position of T-6932 resulted in the finding of 26, which exhibited potent relaxant effects on isolated rabbit corpus cavernosum (EC30 = 11 nM) with a high PDE5 selectivity over PDE6 (IC50 ratio: PDE6/PDE5 = 2800). PMID- 25442308 TI - Design, synthesis and molecular docking of substituted 3-hydrazinyl-3-oxo propanamides as anti-tubercular agents. AB - Based on the anti-mycobacterial activity of various acid hydrazides, a series of substituted 3-hydrazinyl-3-oxo-propanamides has been designed. The target compounds have been synthesized from diethylmalonate using substituted amines and hydrazine hydrate in ethanol. Computational studies and anti-tubercular activity screenings were undertaken to test their inhibitory effect on protein kinase PknB from Mycobacterium tuberculosis. Binding poses of the compounds were energetically favorable and showed good interactions with active site residues. Designed molecules obey the Lipinski's rule of 5 and gave moderate to good drug likeness score. Among the sixteen compounds (1-16) taken for in silico and in vitro studies, 3 compounds (11, 12 and 15) have shown good binding energies along with exhibiting good anti-tubercular activity and thus may be considered as a good inhibitors of PknB. PMID- 25442309 TI - Carbonic anhydrase inhibitory activity of sulfonamides and carboxylic acids incorporating cyclic imide scaffolds. AB - A series of sulfonamides incorporating cyclic imide moieties were investigated as inhibitors of several human alpha-carbonic anhydrase (hCA, EC 4.2.1.1) isoforms. Several carboxylic acids possessing the same scaffolds as the sulfonamides were also included in the study, since the sulfonamidate and the carboxylate are among the frequently used zinc-binding groups (ZBGs) for obtaining zinc enzymes inhibitors. The cytosolic isoform hCA I was moderately inhibited by most of the 30 investigated derivatives; many low nanomolar hCA II inhibitors were detected, whereas some of these compounds were low nanomolar/subnanomolar inhibitors of the transmembrane, tumor-associated isoforms hCA IX and XII. In this series of compounds the SO(2)NH(-) and the COO(-) ZBGs showed similar efficacy for obtaining potent inhibitors, although some carboxylates had isoform-selective inhibition profiles for the transmembrane CAs. PMID- 25442310 TI - Synthesis and cytotoxic evaluation of novel ester-triazole-linked triterpenoid AZT conjugates. AB - Betulinic acid and analogous naturally occurring triterpenoid acids were transformed into the corresponding propargyl esters and subsequently deployed as substrates for a click chemistry-mediated coupling with azidothymidine (AZT) en route to novel 1,2,3-triazole-tethered triterpenoid-AZT conjugates. Twelve new hybrids were thus prepared and assessed in terms of their cytotoxic activity, revealing an interesting anticancer activity of five triterpenoid-AZT hybrids on KB and Hep-G2 tumor cell lines. PMID- 25442311 TI - The identification of GPR3 inverse agonist AF64394; the first small molecule inhibitor of GPR3 receptor function. AB - The identification of the novel and selective GPR3 inverse agonist AF64394, the first small molecule inhibitor of GPR3 receptor function, is described. Structure activity relationships and syntheses based around AF64394 are reported. PMID- 25442312 TI - Cytotoxic 1,5-diaryl-3-oxo-1,5-pentadienes: an assessment and comparison of membrane permeability using Caco-2 and MDCK monolayers. AB - A number of cytotoxic conjugated unsaturated ketones were screened for their membrane permeability characteristics using Caco-2 and MDCK cells with the view of finding promising leads for in vivo evaluations. 3b-e and 4a-b demonstrated high permeability characteristics. In particular, 4a emerged as a promising lead which showed excellent apparent permeability (P(app): 54.70) and efflux ratio (ER: 0.15) values. In general, the relative apparent permeabilities of these enones are similar in both bioassays. PMID- 25442313 TI - Inhibiting prolyl isomerase activity by hybrid organic-inorganic molecules containing rhodium(II) fragments. AB - A small molecule containing a rhodium(II) tetracarboxylate fragment is shown to be a potent inhibitor of the prolyl isomerase FKBP12. The use of small molecules conjugates of rhodium(II) is presented as a general strategy for developing new protein inhibitors based on distinct structural and sequence features of the enzyme active site. PMID- 25442314 TI - Synthesis and in vitro stability of amino acid prodrugs of 6-beta-naltrexol for microneedle-enhanced transdermal delivery. AB - A small library of amino acid ester prodrugs of 6-beta-naltrexol (NTXOL, 1) was prepared in order to investigate the candidacy of these prodrugs for microneedle enhanced transdermal delivery. Six amino acid ester prodrugs were synthesized (6a f). 6b, 6d, and 6 e were stable enough at skin pH (pH 5.0) to move forward to studies in 50% human plasma. The lead compound (6 e) exhibited the most rapid bioconversion to NTXOL in human plasma (t1/2 = 2.2 +/- 0.1h). PMID- 25442315 TI - Synthesis of new bioisosteric hemiasterlin analogues with extremely high cytotoxicity. AB - In this Letter, the synthesis and the evaluation of the cytotoxicity of new hemiasterlin analogues were reported. The indole moiety was replaced respectively by benzofurane, naphthalene and 4-bromobenzene groups. Most of these derivatives possess strong cytotoxic activity on two human tumour cell lines (KB and Hep-G2), and some analogues showed comparable cytotoxic activity to that observed for paclitaxel and ellipticine, against KB and Hep-G2 cancer cell lines. PMID- 25442317 TI - Design, synthesis, anti-TMV, fungicidal, and insecticidal activity evaluation of 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid derivatives based on virus inhibitors of plant sources. AB - By drawing the creation ideas of botanical pesticides, a series of tetrahydro beta-carboline-3-carboxylic acid derivatives were designed and synthesized, and first evaluated for their anti-TMV, fungicidal and insecticidal activities. Most of these derivatives exhibited good antiviral activity against TMV both in vitro and in vivo. Especially, the activities of compounds 8 and 15 in vivo were higher than that of ribavirin. The compound 8 exhibited more than 70% fungicidal activities against Cercospora arachidicola Hori, Alternaria solani, Bipolaris maydis, and Rhizoctonia solani at 50mg/kg, compounds 16 and 20 exhibited more than 60% insecticidal activities against Mythimna separate and Ostrinia nubilalis. PMID- 25442316 TI - Design, synthesis and evaluation of [(3)H]PF-7191, a highly specific nociceptin opioid peptide (NOP) receptor radiotracer for in vivo receptor occupancy (RO) studies. AB - Herein we report the identification of (+)-N-(2-((1H-pyrazol-1-yl)methyl)-3 ((1R,3r,5S)-6'-fluoro-8-azaspiro[bicyclo[3.2.1]octane-3,1'-isochroman]-8 yl)propyl)-N-[(3)H]-methylacetamide {[(3)H]PF-7191 [(+)-11]} as a promising radiotracer for the nociceptin opioid peptide (NOP) receptor. (+)-11 demonstrated high NOP binding affinity (Ki = 0.1 nM), excellent selectivity over other opioid receptors (>1000*) and good brain permeability in rats (C(b,u)/C(p,u) = 0.29). Subsequent characterization of [(3)H](+)-11 showed a high level of specific binding and a brain bio-distribution pattern consistent with known NOP receptor expression. Furthermore, the in vivo brain binding of [(3)H](+)-11 in rats was inhibited by a selective NOP receptor antagonist in a dose-responsive manner. This overall favorable profile indicated that [(3)H](+)-11 is a robust radiotracer for pre-clinical in vivo receptor occupancy (RO) measurements and a possible substrate for carbon-11 labeling for positron emission tomography (PET) imaging in higher species. PMID- 25442318 TI - 6-Hydroxyquinolinium salts differing in the length of alkyl side-chain: synthesis and antimicrobial activity. AB - Quaternary ammonium salts substituted with a long alkyl chain exemplify a trustworthy group of medicinal compounds frequently employed as antifungal and antibacterial agents. A great asset of these surfactants underlying their widespread use is low local and system toxicity in humans. In this Letter, a series of novel quaternary 6-hydroxyquinolinium salts with varying length of N alkyl chain (from C10 to C18) was synthesized and tested for in vitro activity against pathogenic bacterial and fungal strains. 6-Hydroxyquinolinium salt with C12 alkyl chain seems to be very interesting candidate due to a high antimicrobial efficacy and cytotoxic safety. PMID- 25442319 TI - Synthesis and SAR studies of bis-chromenone derivatives for anti-proliferative activity against human cancer cells. AB - A novel family of 3-((4-oxo-4H-chromen-3-yl)methyl)-4H-chromen-4-one (bis chromone) derivatives were designed, synthesized and studied for their anti cancer activity using the XTT assay for the growth inhibition against various human cancer cells. Among them, 3-((5-(cyclohexylmethoxy)-4-oxo-4H-chromen-3 yl)methyl)-7-methoxy-4H-chromen-4-one and 3-((5-(cyclohexylmethoxy)-4-oxo-4H chromen-3-yl)methyl)-7-hydroxy-4H-chromen-4-one showed micromolar level of in vitro anti-proliferative activity against human cancer cell lines. The SAR studies indicated bis-chromone as a basic scaffold to design anticancer agents. The 5-cyclohexylmethoxy on the first chromenone ring and electron donating group such as CH3, OCH3 or hydrogen bonding group (OH) on the other chromenone ring of bis-chromone increased the activity. However, saturation of one of chromenone to chromanone in bis-chromones decreased the activity. PMID- 25442320 TI - Anti-inflammatory secoiridoid glycosides from Gentianella azurea. AB - A phytochemical investigation on crude extract of Gentianella azurea led to the isolation of ten new (1-10) and one known (11) secoiridoid glycosides. Their structures were unambiguously elucidated by analysis of 1D and 2D NMR. Compounds 2, 5 and 11 were found to inhibit nitric oxide (NO) production in RAW 264.7 macrophages with IC50 values of 52.78 +/- 8.61, 0.69 +/- 0.23 and 5.18 +/- 1.33, respectively, while indomethacin, the positive control, showed an IC50 value of 1.25 +/- 0.52 MUM. PMID- 25442321 TI - Synthesis and structure-activity relationship of novel cinnamamide derivatives as antidepressant agents. AB - Cinnamamide 3a, a leading compound with antidepressant-like activity, and its derivatives were synthesized and their antidepressant activity and structure activity relationship were investigated. Most of the compounds with trifluoromethyl group in methylenedioxyphenyl moiety (3f, 4b-c and 6a-b) exhibited significant antidepressant activity, measured in terms of percentage decrease in immobility duration by tail suspension test. In addition, the dose dependent antidepressant effect of the most potent compound 3f was subsequently confirmed in tail suspension test and forced swim test. The test results showed that 3f was equal to or more effective than the standard drug fluoxetine at a concentration of 10mg/kg. Furthermore, compound 3f did not show any central nervous system stimulant properties in the open-field test and the preliminary results were promising enough to warrant further detailed antidepressant research around this scaffold. PMID- 25442322 TI - Novel benzenesulfonylureas containing thiophenylpyrazoline moiety as potential antidiabetic and anticancer agents. AB - In the present study a library of twenty six benzenesulfonylureas containing thiophenylpyrazoline moiety has been synthesized. All the compounds were docked against PPAR-gamma target. Most of the compounds displayed higher dock score than standard drugs, glibenclamide and rosiglitazone. All the synthesized compounds were primarily evaluated for their antidiabetic effect by oral glucose tolerance test. Further assessment of antidiabetic potential of sixteen active compounds was then done on STZ induced diabetic model. The results of in vivo activity by both the methods were found to be consistent with each other as well as with docking studies. Change in body weight of STZ induced animals post treatment was also assessed at the end of study. In vitro PPAR-gamma transactivation assay was performed on active compounds in order to validate docking results and the most active compound 3 k was also shown to elevate gene expression of PPAR-gamma. Furthermore, the compounds were screened by National Cancer Institute, Bethesda for anticancer effect and two compounds 3h and 3 i were selected at one dose level since they exhibited sensitivity towards tumor cell lines (mainly melanoma). PMID- 25442323 TI - Inhibition of microbial beta-N-acetylhexosaminidases by 4-deoxy- and galacto analogues of NAG-thiazoline. AB - NAG-thiazoline is a well-established competitive inhibitor of two physiologically relevant glycosidase families-beta-N-acetylhexosaminidases (GH20) and beta-N acetylglucosaminidases (GH84). Based on the different substrate flexibilities of these enzyme groups, we designed and synthesized the 4-deoxy derivative of NAG thiazoline aiming at the selective inhibition of GH20 beta-N acetylhexosaminidases. One GH84 and two GH20 microbial glycosidases were employed as model enzymes for the inhibition assays. Surprisingly, the new compound 4 deoxy-thiazoline exhibited no activity inhibition with either of the enzyme families of interest. Unlike with the substrates, the 4-hydroxyl group of the inhibitor's sugar ring seems to be crucial for binding the inhibitor to the active sites of these enzymes. PMID- 25442324 TI - Risk factors for colorectal neoplasia in persons aged 30 to 39 years and 40 to 49 years. AB - BACKGROUND: Very little is known about risk factors associated with colorectal neoplasia in persons aged <50 years. In particular, there has been no study thus far focusing on the risk factors for colorectal neoplasia in persons aged 30 to 39 years. OBJECTIVE: To investigate risk factors for colorectal neoplasia in persons aged 30 to 39 years and 40 to 49 years and to compare those data with those of persons aged 50 to 59 years. DESIGN: Cross-sectional observational study. SETTING: Screening center in a university hospital in Korea. PATIENTS: A cohort of 28,504 Korean adults (13,678 aged 30-39 years, 12,507 aged 40-49 years, and 2319 aged 50-59 years) who underwent colonoscopy as part of their routine preventive health care. INTERVENTIONS: Colonoscopy. MAIN OUTCOME MEASUREMENTS: Risk factors for colorectal neoplasia in persons aged 30 to 39 years and 40 to 49 years. RESULTS: In the 30-to-39-years group, male sex, smoking, fatty liver, metabolic syndrome (MetS), obesity, elevated fasting blood glucose levels, and elevated triglyceride levels were associated with overall neoplasia, whereas for advanced neoplasia, the independent risk factors were smoking, fatty liver, and elevated triglyceride levels. Moreover, the prevalence of overall neoplasia in men aged 30 to 39 years exhibiting all risk factors was not lower than that in average-risk women aged >50 years (20.8% vs 18.8%; P = .546). The risk factors of overall neoplasia in the 40-to-49-years group were similar to those in the 30-to 39-years group. For advanced neoplasia, the independent risk factors in the 40-to 49-years group were male sex, smoking, MetS, and obesity. LIMITATIONS: Selection bias may exist for participants of ethnic Korean heritage in 2 centers. CONCLUSION: Obese male smokers with fatty liver and MetS might benefit from screening colonoscopy starting before age 50 years. PMID- 25442325 TI - Effects of hypothalamic dopamine on growth hormone-releasing hormone-induced growth hormone secretion and thyrotropin-releasing hormone-induced prolactin secretion in goats. AB - The aim of the present study was to clarify the effects of hypothalamic dopamine (DA) on the secretion of growth hormone (GH) in goats. The GH-releasing response to an intravenous (i.v.) injection of GH-releasing hormone (GHRH, 0.25 MUg/kg body weight (BW)) was examined after treatments to augment central DA using carbidopa (carbi, 1 mg/kg BW) and L-dopa (1 mg/kg BW) in male and female goats under a 16-h photoperiod (16 h light, 8 h dark) condition. GHRH significantly and rapidly stimulated the release of GH after its i.v. administration to goats (P < 0.05). The carbi and L-dopa treatments completely suppressed GH-releasing responses to GHRH in both male and female goats (P < 0.05). The prolactin (PRL) releasing response to an i.v. injection of thyrotropin-releasing hormone (TRH, 1 MUg/kg BW) was additionally examined in male goats in this study to confirm modifications to central DA concentrations. The treatments with carbi and L-dopa significantly reduced TRH-induced PRL release in goats (P < 0.05). These results demonstrated that hypothalamic DA was involved in the regulatory mechanisms of GH, as well as PRL secretion in goats. PMID- 25442326 TI - Miniaturized planar chromatography using office peripherals--office chromatography. AB - Office chromatography (OC) harnesses the novel combination of miniaturized planar separation science and modern print & media technologies. Interdisciplinary knowledge is the essence: Printing of solutions on powerful miniaturized planar separation materials in combination with image capturing and evaluation tools enables an innovative analytical online system. Site-specific printing as lines or areas on defined sections of the layer comprises important steps like application of samples, feeding of the mobile phase as well as supply of the derivatization reagent. Also printing of bioassays can be combined for effect directed detections and the homogeneous printing of the ultrathin layer itself, enabling tailor-made gradient-layer or multi-layer plates. OC exploits image giving miniaturized chromatograms being captured and processed with a flatbed scanner or mini-camera. Thus, miniaturized separation materials are the core of OC. Monolithic, electrospun, nanostructured glancing angle deposition and carbon nanotube-templated microfabricated layers or even pillar arrays or polymer brush coated sub-MUm silica particles were demonstrated, showing promising results. Layer thicknesses from 50 MUm down to few micrometers were explored. A high throughput capacity is given through the parallel development of as many as possible tiny-printed samples on the separation material. The migration time was reduced to a few minutes and the calculated analysis time per sample lasted few seconds. Considering a substantially reduced solvent consumption at short run times for parallel analysis of numerous samples at the same time, OC is an appropriate analytical technique for green chemistry. OC facilitates the whole planar separation process to be performed with no other equipment but a combined device of printer and flatbed scanner or mini-camera. At the same time, OC can be expected to become a widespread and economical technique with the user friendliness of high-end office tools, appealing to users. PMID- 25442328 TI - Three explanations for biodiversity hotspots: small range size, geographical overlap and time for species accumulation. An Australian case study. AB - To understand the generation and maintenance of biodiversity hotspots, we tested three major hypotheses: rates of diversification, ecological limits to diversity, and time for species accumulation. Using dated molecular phylogenies, measures of species' range size and geographical clade overlap, niche modelling, and lineages through-time plots of Australian Fabaceae, we compared the southwest Australia Floristic Region (SWAFR; a global biodiversity hotspot) with a latitudinally equivalent non-hotspot, southeast Australia (SEA). Ranges of species (real and simulated) were smaller in the SWAFR than in SEA. Geographical overlap of clades was significantly greater for Daviesia in the SWAFR than in SEA, but the inverse for Bossiaea. Lineage diversification rates over the past 10 Myr did not differ between the SWAFR and SEA in either genus. Interaction of multiple factors probably explains the differences in measured diversity between the two regions. Steeper climatic gradients in the SWAFR probably explain the smaller geographical ranges of both genera there. Greater geographical overlap of clades in the SWAFR, combined with a longer time in the region, can explain why Daviesia is far more species-rich there than in SEA. Our results indicate that the time for speciation and ecological limits hypotheses, in concert, can explain the differences in biodiversity. PMID- 25442327 TI - A Threshold Shear Force for Calcium Influx in an Astrocyte Model of Traumatic Brain Injury. AB - Traumatic brain injury (TBI) refers to brain damage resulting from external mechanical force, such as a blast or crash. Our current understanding of TBI is derived mainly from in vivo studies that show measurable biological effects on neurons sampled after TBI. Little is known about the early responses of brain cells during stimuli and which features of the stimulus are most critical to cell injury. We generated defined shear stress in a microfluidic chamber using a fast pressure servo and examined the intracellular Ca(2+) levels in cultured adult astrocytes. Shear stress increased intracellular Ca(2+) depending on the magnitude, duration, and rise time of the stimulus. Square pulses with a fast rise time (~2 ms) caused transient increases in intracellular Ca(2+), but when the rise time was extended to 20 ms, the response was much less. The threshold for a response is a matrix of multiple parameters. Cells can integrate the effect of shear force from repeated challenges: A pulse train of 10 narrow pulses (11.5 dyn/cm(2) and 10 ms wide) resulted in a 4-fold increase in Ca(2+) relative to a single pulse of the same amplitude 100 ms wide. The Ca(2+) increase was eliminated in Ca(2+)-free media, but was observed after depleting the intracellular Ca(2+) stores with thapsigargin suggesting the need for a Ca(2+) influx. The Ca(2+) influx was inhibited by extracellular Gd(3+), a nonspecific inhibitor of mechanosensitive ion channels, but it was not affected by the more specific inhibitor, GsMTx4. The voltage-gated channel blockers, nifedipine, diltiazem, and verapamil, were also ineffective. The data show that the mechanically induced Ca(2+) influx commonly associated with neuron models for TBI is also present in astrocytes, and there is a viscoelastic/plastic coupling of shear stress to the Ca(2+) influx. The site of Ca(2+) influx has yet to be determined. PMID- 25442330 TI - Formal home-care utilisation by older adults in Ireland: evidence from the Irish Longitudinal Study on Ageing (TILDA). AB - The aim of this study was to provide a population-based estimate of the utilisation of publicly financed formal home care by older adults in Ireland and to identify the principal characteristics of those utilising formal home care. Data were collected through computer-aided personal interviews from a representative sample of community living older adults in Ireland. The interviews were conducted between 2009 and 2011 as part of the first wave of the Irish Longitudinal Study on Ageing (TILDA). The study is cross-sectional in design and limited to participants aged 65 years and older (n = 3507). Results reveal that 8.2% (95% CI 7.1%-9.3%) of participants utilised publicly financed formal home care in the form of home help and/or personal care. Key determinants of formal home-care utilisation were Instrumental Activity of Daily Living (IADL) difficulty (Adj OR 3.8, 95% CI 2.7-5.3), older age (Adj OR 3.4, 95% CI 2.4-4.8) and living alone (Adj OR 2.6, 95% CI 1.9-3.8). Almost half of those utilising formal care did not self-report an Activity of Daily Living (ADL) difficulty or an IADL difficulty. Government policy aims to reduce the need for long-term residential care by providing formal home care for older adults with low to moderate levels of dependency. This requires an increasing emphasis on personal care provision in the home. No evidence was found in this study to suggest that a shift in emphasis from formal domestic to personal care is taking place in Ireland. The absence of standardised assessment and eligibility criteria are deemed to be barriers to reorientation of the system. From a health services perspective, the current situation is not sustainable into the future and requires a focused policy response. PMID- 25442329 TI - Multiple-locus variable-number tandem-repeat analysis of Francisella tularensis from Quebec, Canada. AB - Francisella tularensis is ubiquitous in the Northern Hemisphere. Yet, little is known about the disease and its ecology within Canada as few serological studies have shown exposure to the disease and fewer case studies have been reported. This report is the first to describe the molecular subtyping of F. tularensis isolates within eastern Canada using multiple-locus variable-number tandem-repeat analysis. From 1998 to 2011, a total of 73 specimens were isolated from unique human and animal sources. As expected, F. tularensis subsp. tularensis AI and F. tularensis subsp. holarctica subtypes were observed, corresponding to the known geographical division within this species. The majority of human isolates (78%) and all animal (hare) isolates were of the more virulent, AI type. Half of the B isolates were isolated from patients living in a region of Quebec where muskrat densities are known to be high. A relatively high level of marker diversity was found, suggestive of multiple introductions of the organism to the region, or more likely ongoing endemicity. There was no evidence of ongoing outbreaks or transmission, and the bulk of cases were likely due to interaction between human activity and the environment (e.g. hunting/trapping activities). SIGNIFICANCE AND IMPACT OF THE STUDY: This study reveals the diversity of Francisella tularensis in eastern Canada using multiple-locus variable-number tandem-repeat analysis. It was initiated to further the understanding of the species within North America as previous studies elucidating the diversity and phylogeography of the species have consisted mostly of specimens from the United States. Type A tularaemia, the most life-threatening subtype of the species and a Category A biothreat agent, is restricted to North America, and this study serves to broaden the knowledge of the epidemiology and diversity of the organism. PMID- 25442331 TI - An Asian Woman with Upper Arm Burns. PMID- 25442332 TI - More accurate definition of clinical target volume based on the measurement of microscopic extensions of the primary tumor toward the uterus body in international federation of gynecology and obstetrics Ib-IIa squamous cell carcinoma of the cervix. AB - PURPOSE: To more accurately define clinical target volume for cervical cancer radiation treatment planning by evaluating tumor microscopic extension toward the uterus body (METU) in International Federation of Gynecology and Obstetrics stage Ib-IIa squamous cell carcinoma of the cervix (SCCC). PATIENTS AND METHODS: In this multicenter study, surgical resection specimens from 318 cases of stage Ib IIa SCCC that underwent radical hysterectomy were included. Patients who had undergone preoperative chemotherapy, radiation, or both were excluded from this study. Microscopic extension of primary tumor toward the uterus body was measured. The association between other pathologic factors and METU was analyzed. RESULTS: Microscopic extension toward the uterus body was not common, with only 12.3% of patients (39 of 318) demonstrating METU. The mean (+/-SD) distance of METU was 0.32 +/- 1.079 mm (range, 0-10 mm). Lymphovascular space invasion was associated with METU distance and occurrence rate. A margin of 5 mm added to gross tumor would adequately cover 99.4% and 99% of the METU in the whole group and in patients with lymphovascular space invasion, respectively. CONCLUSION: According to our analysis of 318 SCCC specimens for METU, using a 5-mm gross tumor volume to clinical target volume margin in the direction of the uterus should be adequate for International Federation of Gynecology and Obstetrics stage Ib-IIa SCCC. Considering the discrepancy between imaging and pathologic methods in determining gross tumor volume extent, we recommend a safer 10-mm margin in the uterine direction as the standard for clinical practice when using MRI for contouring tumor volume. PMID- 25442333 TI - Valvular abnormalities detected by echocardiography in 5-year survivors of childhood cancer: a long-term follow-up study. AB - PURPOSE: To determine the prevalence of valvular abnormalities after radiation therapy involving the heart region and/or treatment with anthracyclines and to identify associated risk factors in a large cohort of 5-year childhood cancer survivors (CCS). METHODS AND MATERIALS: The study cohort consisted of all 626 eligible 5-year CCS diagnosed with childhood cancer in the Emma Children's Hospital/Academic Medical Center between 1966 and 1996 and treated with radiation therapy involving the heart region and/or anthracyclines. We determined the presence of valvular abnormalities according to echocardiograms. Physical radiation dose was converted into the equivalent dose in 2-Gy fractions (EQD2). Using multivariable logistic regression analyses, we examined the associations between cancer treatment and valvular abnormalities. RESULTS: We identified 225 mainly mild echocardiographic valvular abnormalities in 169 of 545 CCS (31%) with a cardiac assessment (median follow-up time, 14.9 years [range, 5.1-36.8 years]; median attained age 22.0 years [range, 7.0-49.7 years]). Twenty-four CCS (4.4%) had 31 moderate or higher-graded abnormalities. Most common abnormalities were tricuspid valve disorders (n=119; 21.8%) and mitral valve disorders (n=73; 13.4%). The risk of valvular abnormalities was associated with increasing radiation dose (using EQD2) involving the heart region (odds ratio 1.33 per 10 Gy) and the presence of congenital heart disease (odds ratio 3.43). We found no statistically significant evidence that anthracyclines increase the risk. CONCLUSIONS: Almost one-third of CCS treated with potentially cardiotoxic therapy had 1 or more asymptomatic, mostly mild valvular abnormalities after a median follow-up of nearly 15 years. The most important risk factors are higher EQD2 to the heart region and congenital heart disease. Studies with longer follow-up are necessary to investigate the clinical course of asymptomatic valvular abnormalities in CCS. PMID- 25442334 TI - Adoption of intensity modulated radiation therapy for early-stage breast cancer from 2004 through 2011. AB - PURPOSE: Intensity modulated radiation therapy (IMRT) is a newer method of radiation therapy (RT) that has been increasingly adopted as an adjuvant treatment after breast-conserving surgery (BCS). IMRT may result in improved cosmesis compared to standard RT, although at greater expense. To investigate the adoption of IMRT, we examined trends and factors associated with IMRT in women under the age of 65 with early stage breast cancer. METHODS AND MATERIALS: We performed a retrospective study of early stage breast cancer patients treated with BCS followed by whole-breast irradiation (WBI) who were <=65 years old in the National Cancer Data Base from 2004 to 2011. We used logistic regression to identify factors associated with receipt of IMRT (vs standard RT). RESULTS: We identified 11,089 women with early breast cancer (9.6%) who were treated with IMRT and 104,448 (90.4%) who were treated with standard RT, after BCS. The proportion of WBI patients receiving IMRT increased yearly from 2004 to 2009, with 5.3% of WBI patients receiving IMRT in 2004 and 11.6% receiving IMRT in 2009. Further use of IMRT declined afterward, with the proportion remaining steady at 11.0% and 10.7% in 2010 and 2011, respectively. Patients treated in nonacademic community centers were more likely to receive IMRT (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.30-1.43 for nonacademic vs academic center). Compared to privately insured patients, the uninsured patients (OR, 0.81; 95% CI, 0.70-0.95) and those with Medicaid insurance (OR, 0.87; 95% CI, 0.79-0.95) were less likely to receive IMRT. CONCLUSIONS: The use of IMRT rose from 2004 to 2009 and then stabilized. Important nonclinical factors associated with IMRT use included facility type and insurance status. PMID- 25442335 TI - Hemithoracic intensity modulated radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma: toxicity, patterns of failure, and a matched survival analysis. AB - PURPOSE: To investigate safety, efficacy, and recurrence after hemithoracic intensity modulated radiation therapy after pleurectomy/decortication (PD-IMRT) and after extrapleural pneumonectomy (EPP-IMRT). METHODS AND MATERIALS: In 2009 2013, 24 patients with mesothelioma underwent PD-IMRT to the involved hemithorax to a dose of 45 Gy, with an optional integrated boost; 22 also received chemotherapy. Toxicity was scored with the Common Terminology Criteria for Adverse Events v4.0. Pulmonary function was compared at baseline, after surgery, and after IMRT. Kaplan-Meier analysis was used to calculate overall survival (OS), progression-free survival (PFS), time to locoregional failure, and time to distant metastasis. Failures were in-field, marginal, or out of field. Outcomes were compared with those of 24 patients, matched for age, nodal status, performance status, and chemotherapy, who had received EPP-IMRT. RESULTS: Median follow-up time was 12.2 months. Grade 3 toxicity rates were 8% skin and 8% pulmonary. Pulmonary function declined from baseline to after surgery (by 21% for forced vital capacity, 16% for forced expiratory volume in 1 second, and 19% for lung diffusion of carbon monoxide [P for all = .01]) and declined still further after IMRT (by 31% for forced vital capacity [P=.02], 25% for forced expiratory volume in 1 second [P=.01], and 30% for lung diffusion of carbon monoxide [P=.01]). The OS and PFS rates were 76% and 67%, respectively, at 1 year and 56% and 34% at 2 years. Median OS (28.4 vs 14.2 months, P=.04) and median PFS (16.4 vs 8.2 months, P=.01) favored PD-IMRT versus EPP-IMRT. No differences were found in grade 4-5 toxicity (0 of 24 vs 3 of 24, P=.23), median time to locoregional failure (18.7 months vs not reached, P not calculable), or median time to distant metastasis (18.8 vs 11.8 months, P=.12). CONCLUSIONS: Hemithoracic intensity modulated radiation therapy after pleurectomy/decortication produced little high grade toxicity but led to progressive declines in pulmonary function; OS and PFS were better in PD-IMRT compared with EPP-IMRT. PMID- 25442337 TI - Toxicity after central versus peripheral lung stereotactic body radiation therapy: a propensity score matched-pair analysis. AB - PURPOSE: To compare toxicity after stereotactic body radiation therapy (SBRT) for "central" tumors-within 2 cm of the proximal bronchial tree or with planning tumor volume (PTV) touching mediastinum-versus noncentral ("peripheral") lung tumors. METHODS AND MATERIALS: From November 2005 to January 2011, 229 tumors (110 central, 119 peripheral; T1-3N0M0 non-small-cell lung cancer and limited lung metastases) in 196 consecutive patients followed prospectively at a single institution received moderate-dose SBRT (48-60 Gy in 4-5 fractions [biologic effective dose=100-132 Gy, alpha/beta=10]) using 4-dimensional planning, online image-guided radiation therapy, and institutional dose constraints. Clinical adverse events (AEs) were graded prospectively at clinical and radiographic follow-up using Common Terminology Criteria for Adverse Events version 3.0. Pulmonary function test (PFT) decline was graded as 2 (25%-49.9% decline), 3 (50.0%-74.9% decline), or 4 (>=75.0% decline). Central/peripheral location was assessed retrospectively on planning CT scans. Groups were compared after propensity score matching. Characteristics were compared with chi(2) and 2-tailed t tests, adverse events with chi(2) test-for-trend, and cumulative incidence using competing risks analysis (Gray's test). RESULTS: With 79 central and 79 peripheral tumors matched, no differences in AEs were observed after 17 months median follow-up. Two-year cumulative incidences of grade >=2 pain, musculoskeletal, pulmonary, and skin AEs were 14%, 5%, 6%, and 10% (central) versus 19%, 10%, 10%, and 3% (peripheral), respectively (P=.31, .38, .70, and .09). Grade >=2 cardiovascular, gastrointestinal, and central nervous system AEs were rare (<1%). Two-year incidences of grade >=2 clinical AEs (28% vs 25%, P=.79), grade >=2 PFT decline (36% vs 34%, P=.94), grade >=3 clinical AEs (3% vs 7%, P=.48), and grade >=3 PFT decline (0 vs 10%, P=.11) were similar for central versus peripheral tumors, respectively. Pooled 2-year incidences of grades 4 and 5 AEs were <1% and 0%, respectively, in both the prematched and matched groups. CONCLUSION: Moderate-dose SBRT with these techniques yields a similarly safe toxicity profile for both central and peripheral lung tumors. PMID- 25442336 TI - Epidermal growth factor receptor mutation is associated with longer local control after definitive chemoradiotherapy in patients with stage III nonsquamous non small-cell lung cancer. AB - PURPOSE: To determine the frequency and clinical significance of epidermal growth factor receptor (EGFR) mutations in patients with potentially curable stage III non-small-cell lung cancer (NSCLC) who are eligible for definitive chemoradiotherapy (CRT). PATIENTS AND METHODS: Between January 2001 and December 2010, we analyzed the EGFR mutational status in consecutive NSCLC patients who were treated by CRT. The response rate, relapse-free survival, 2-year relapse free rate, initial relapse sites, and overall survival of the patients were investigated. RESULTS: A total of 528 patients received CRT at our hospital during the study period. Of these, 274 were diagnosed as having nonsquamous NSCLC. Sufficient specimens for mutational analyses could be obtained from 198 of these patients. The proportion of patients with EGFR activating mutations was 17%. In addition to the well-known characteristics of patients carrying EGFR mutations (female, adenocarcinoma, and never/light smoker), the proportion of cases with smaller primary lesions (T1/2) was found to be higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with EGFR mutations showed similar response rate, relapse-free survival, and 2-year relapse-free rates as compared to patients with wild-type EGFR. Local relapses as the site of initial relapse occurred significantly less frequently in patients with EGFR mutation (4% vs 21%; P=.045). Patients with EGFR mutations showed longer local control (adjusted hazard ratio 0.49; P=.043). After disease progression, a majority of the patients with EGFR mutations received EGFR tyrosine kinase inhibitors (62%), and these patients showed longer postprogression survival than those with wild-type EGFR. CONCLUSIONS: Our study is the first to show radiosensitive biology of EGFR-mutated tumors in definitive CRT with curative intent. This finding could serve as a credible baseline estimate of EGFR-mutated population in stage III nonsquamous NSCLC. PMID- 25442338 TI - Rectal toxicity after proton therapy for prostate cancer: an analysis of outcomes of prospective studies conducted at the university of Florida Proton Therapy Institute. AB - PURPOSE: Study goals were to characterize gastrointestinal effects of proton therapy (PT) in a large cohort of patients treated for prostate cancer, identify factors associated with rectal bleeding (RB), and compare RB between patients receiving investigational protocols versus those in outcome-tracking protocols. METHODS AND MATERIALS: A total of 1285 consecutive patients were treated with PT between August 2006 and May 2010. Potential pre-existing clinical and treatment related risk factors for rectal toxicity were recorded. Common Terminology Criteria for Adverse Events version 3.0 was used to score toxicity. RESULTS: Transient RB was the predominant grade 2 or higher (GR2+) toxicity after PT, accounting for 95% of gastrointestinal events. GR1 RB occurred in 217 patients (16.9%), GR2 RB in 187 patients (14.5%), and GR3 in 11 (0.9%) patients. There were no GR4 or GR5 events. Univariate analyses showed correlations between GR2+ RB and anticoagulation therapy (P=.008) and rectal and rectal wall dose-volume histogram (DVH) parameters (P<.001). On multivariate analysis, anticoagulation therapy (P=.0034), relative volume of rectum receiving 75 Gy (V75; P=.0102), and relative rectal wall V75 (P=.0017) were significant predictors for G2+ RB. Patients treated with investigational protocols had toxicity rates similar to those receiving outcome-tracking protocols. CONCLUSIONS: PT was associated with a low rate of GR2+ gastrointestinal toxicity, predominantly transient RB, which was highly correlated with anticoagulation and rectal DVH parameters. Techniques that limit rectal exposure should be used when possible. PMID- 25442339 TI - Standard (60 Gy) or short-course (40 Gy) irradiation plus concomitant and adjuvant temozolomide for elderly patients with glioblastoma: a propensity matched analysis. AB - PURPOSE: To evaluate 2 specific radiation schedules, each combined with temozolomide (TMZ), assessing their efficacy and safety in patients aged >=65 years with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS: Patients aged >=65 years with Karnofsky performance status (KPS) >=60 who received either standard (60 Gy) or short-course (40 Gy) radiation therapy (RT) with concomitant and adjuvant TMZ between June 2004 and October 2013 were retrospectively analyzed. A propensity score analysis was executed for a balanced comparison of treatment outcomes. RESULTS: A total of 127 patients received standard RT-TMZ, whereas 116 patients underwent short-course RT-TMZ. Median overall survival and progression-free survival times were similar: 12 months and 5.6 months for the standard RT-TMZ group and 12.5 months and 6.7 months for the short-course RT-TMZ group, respectively. Radiation schedule was associated with similar survival outcomes in either unadjusted or adjusted analysis. O(6)-methylguanine-DNA methyltransferase promoter methylation was the most favorable prognostic factor (P=.0001). Standard RT-TMZ therapy was associated with a significant rise in grade 2 and 3 neurologic toxicity (P=.01), lowering of KPS scores during the study (P=.01), and higher posttreatment dosing of corticosteroid (P=.02). CONCLUSIONS: In older adults with GBM, survival outcomes of standard and short course RT-TMZ were similar. An abbreviated course of RT plus TMZ may represent a reasonable therapeutic approach for these patients, without loss of survival benefit and acceptable toxicity. PMID- 25442341 TI - Implementation of a novel algorithm for generating synthetic CT images from magnetic resonance imaging data sets for prostate cancer radiation therapy. AB - PURPOSE: To describe and evaluate a method for generating synthetic computed tomography (synCT) images from magnetic resonance simulation (MR-SIM) data for accurate digitally reconstructed radiograph (DRR) generation and dose calculations in prostate cancer radiation therapy. METHODS AND MATERIALS: A retrospective evaluation was performed in 9 prostate cancer patients who had undergone MR-SIM in addition to CT simulation (CT-SIM). MR-SIM data were used to generate synCT images by using a novel, voxel-based weighted summation approach. A subset of patients was used for weight optimization, and the number of patients to use during optimization was determined. Hounsfield unit (HU) differences between CT-SIM and synCT images were analyzed via mean absolute error (MAE). Original, CT-based treatment plans were mapped onto synCTs. DRRs were generated, and agreement between CT and synCT-generated DRRs was evaluated via Dice similarity coefficient (DSC). Dose was recalculated, and dose-volume metrics and gamma analysis were used to evaluate resulting treatment plans. RESULTS: Full field-of-view synCT MAE across all patients was 74.3 +/- 10.9 HU with differences from CTs of 2.0 +/- 8.1 HU and 11.9 +/- 46.7 HU for soft tissue structures (prostate, bladder, and rectum) and femoral bones, respectively. Calculated DSCs for anterior-posterior and lateral DRRs were 0.90 +/- 0.04 and 0.92 +/- 0.05, respectively. Differences in D99%, mean dose, and maximum dose to the clinical target volume from CT-SIM dose calculations were 0.75% +/- 0.35%, 0.63% +/- 0.34%, and 0.54% +/- 0.33%, respectively, for synCT-generated plans. Gamma analysis (2%/2 mm dose difference/distance to agreement) revealed pass rates of 99.9% +/- 0.1% (range, 99.7%-100%). CONCLUSION: Generated synCTs enabled accurate DRR generation and dose computation for prostate MR-only simulation. Dose recalculated on synCTs agreed well with original planning distributions. Further validation using a larger patient cohort is warranted. PMID- 25442340 TI - Multi-institutional feasibility study of a fast patient localization method in total marrow irradiation with helical tomotherapy: a global health initiative by the international consortium of total marrow irradiation. AB - PURPOSE: To develop, characterize, and implement a fast patient localization method for total marrow irradiation. METHODS AND MATERIALS: Topographic images were acquired using megavoltage computed tomography (MVCT) detector data by delivering static orthogonal beams while the couch traversed through the gantry. Geometric and detector response corrections were performed to generate a megavoltage topogram (MVtopo). We also generated kilovoltage topograms (kVtopo) from the projection data of 3-dimensional CT images to reproduce the same geometry as helical tomotherapy. The MVtopo imaging dose and the optimal image acquisition parameters were investigated. A multi-institutional phantom study was performed to verify the image registration uncertainty. Forty-five MVtopo images were acquired and analyzed with in-house image registration software. RESULTS: The smallest jaw size (front and backup jaws of 0) provided the best image contrast and longitudinal resolution. Couch velocity did not affect the image quality or geometric accuracy. The MVtopo dose was less than the MVCT dose. The image registration uncertainty from the multi-institutional study was within 2.8 mm. In patient localization, the differences in calculated couch shift between the registration with MVtopo-kVtopo and MVCT-kVCT images in lateral, cranial caudal, and vertical directions were 2.2 +/- 1.7 mm, 2.6 +/- 1.4 mm, and 2.7 +/- 1.1 mm, respectively. The imaging time in MVtopo acquisition at the couch speed of 3 cm/s was <1 minute, compared with >=15 minutes in MVCT for all patients. CONCLUSION: Whole-body MVtopo imaging could be an effective alternative to time consuming MVCT for total marrow irradiation patient localization. PMID- 25442342 TI - Defining the optimal planning target volume in image-guided stereotactic radiosurgery of brain metastases: results of a randomized trial. AB - PURPOSE: To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (SRS) of brain metastases, minimizing toxicity and local recurrence. METHODS AND MATERIALS: Adult patients with 1 to 3 brain metastases less than 4 cm in greatest dimension, no previous brain radiation therapy, and Karnofsky performance status (KPS) above 70 were eligible for this institutional review board-approved trial. Individual lesions were randomized to 1- or 3- mm uniform expansion of the GTV defined on contrast-enhanced magnetic resonance imaging (MRI). The resulting planning target volume (PTV) was treated to 24, 18, or 15 Gy marginal dose for maximum PTV diameters less than 2, 2 to 2.9, and 3 to 3.9 cm, respectively, using a linear accelerator-based image-guided system. The primary endpoint was local recurrence (LR). Secondary endpoints included neurocognition Mini-Mental State Examination, Trail Making Test Parts A and B, quality of life (Functional Assessment of Cancer Therapy-Brain), radionecrosis (RN), need for salvage radiation therapy, distant failure (DF) in the brain, and overall survival (OS). RESULTS: Between February 2010 and November 2012, 49 patients with 80 brain metastases were treated. The median age was 61 years, the median KPS was 90, and the predominant histologies were non-small cell lung cancer (25 patients) and melanoma (8). Fifty-five, 19, and 6 lesions were treated to 24, 18, and 15 Gy, respectively. The PTV/GTV ratio, volume receiving 12 Gy or more, and minimum dose to PTV were significantly higher in the 3-mm group (all P<.01), and GTV was similar (P=.76). At a median follow-up time of 32.2 months, 11 patients were alive, with median OS 10.6 months. LR was observed in only 3 lesions (2 in the 1 mm group, P=.51), with 6.7% LR 12 months after SRS. Biopsy-proven RN alone was observed in 6 lesions (5 in the 3-mm group, P=.10). The 12-month DF rate was 45.7%. Three months after SRS, no significant change in neurocognition or quality of life was observed. CONCLUSIONS: SRS was well tolerated, with low rates of LR and RN in both cohorts. However, given the higher potential risk of RN with a 3-mm margin, a 1-mm GTV expansion is more appropriate. PMID- 25442343 TI - Patient-specific quality assurance for the delivery of (60)Co intensity modulated radiation therapy subject to a 0.35-T lateral magnetic field. AB - PURPOSE: This work describes a patient-specific dosimetry quality assurance (QA) program for intensity modulated radiation therapy (IMRT) using ViewRay, the first commercial magnetic resonance imaging-guided RT device. METHODS AND MATERIALS: The program consisted of: (1) a 1-dimensional multipoint ionization chamber measurement using a customized 15-cm(3) cube-shaped phantom; (2) 2-dimensional (2D) radiographic film measurement using a 30- * 30- * 20-cm(3) phantom with multiple inserted ionization chambers; (3) quasi-3D diode array (ArcCHECK) measurement with a centrally inserted ionization chamber; (4) 2D fluence verification using machine delivery log files; and (5) 3D Monte Carlo (MC) dose reconstruction with machine delivery files and phantom CT. RESULTS: Ionization chamber measurements agreed well with treatment planning system (TPS)-computed doses in all phantom geometries where the mean +/- SD difference was 0.0% +/- 1.3% (n=102; range, -3.0%-2.9%). Film measurements also showed excellent agreement with the TPS-computed 2D dose distributions where the mean passing rate using 3% relative/3 mm gamma criteria was 94.6% +/- 3.4% (n=30; range, 87.4% 100%). For ArcCHECK measurements, the mean +/- SD passing rate using 3% relative/3 mm gamma criteria was 98.9% +/- 1.1% (n=34; range, 95.8%-100%). 2D fluence maps with a resolution of 1 * 1 mm(2) showed 100% passing rates for all plan deliveries (n=34). The MC reconstructed doses to the phantom agreed well with planned 3D doses where the mean passing rate using 3% absolute/3 mm gamma criteria was 99.0% +/- 1.0% (n=18; range, 97.0%-100%), demonstrating the feasibility of evaluating the QA results in the patient geometry. CONCLUSIONS: We developed a dosimetry program for ViewRay's patient-specific IMRT QA. The methodology will be useful for other ViewRay users. The QA results presented here can assist the RT community to establish appropriate tolerance and action limits for ViewRay's IMRT QA. PMID- 25442344 TI - An image-guided study of setup reproducibility of postmastectomy breast cancer patients treated with inverse-planned intensity modulated radiation therapy. AB - PURPOSE: To calculate planning target volume (PTV) margins for chest wall and regional nodal targets using daily orthogonal kilovolt (kV) imaging and to study residual setup error after kV alignment using volumetric cone-beam computed tomography (CBCT). METHODS AND MATERIALS: Twenty-one postmastectomy patients were treated with intensity modulated radiation therapy with 7-mm PTV margins. Population-based PTV margins were calculated from translational shifts after daily kV positioning and/or weekly CBCT data for each of 8 patients, whose surgical clips were used as surrogates for target volumes. Errors from kV and CBCT data were mathematically combined to generate PTV margins for 3 simulated alignment workflows: (1) skin marks alone; (2) weekly kV imaging; and (3) daily kV imaging. RESULTS: The kV data from 613 treatment fractions indicated that a 7 mm uniform margin would account for 95% of daily shifts if patients were positioned using only skin marks. Total setup errors incorporating both kV and CBCT data were larger than those from kV alone, yielding PTV expansions of 7 mm anterior-posterior, 9 mm left-right, and 9 mm superior-inferior. Required PTV margins after weekly kV imaging were similar in magnitude as alignment to skin marks, but rotational adjustments of patients were required in 32% +/- 17% of treatments. These rotations would have remained uncorrected without the use of daily kV imaging. Despite the use of daily kV imaging, CBCT data taken at the treatment position indicate that an anisotropic PTV margin of 6 mm anterior posterior, 4 mm left-right, and 8 mm superior-inferior must be retained to account for residual errors. CONCLUSIONS: Cone-beam CT provides additional information on 3-dimensional reproducibility of treatment setup for chest wall targets. Three-dimensional data indicate that a uniform 7-mm PTV margin is insufficient in the absence of daily IGRT. Interfraction movement is greater than suggested by 2-dimensional imaging, thus a margin of at least 4 to 8 mm must be retained despite the use of daily IGRT. PMID- 25442345 TI - Cytogenetic low-dose hyperradiosensitivity is observed in human peripheral blood lymphocytes. AB - PURPOSE: The shape of the ionizing radiation response curve at very low doses has been the subject of considerable debate. Linear-no-threshold (LNT) models are widely used to estimate risks associated with low-dose exposures. However, the low-dose hyperradiosensitivity (HRS) phenomenon, in which cells are especially sensitive at low doses but then show increased radioresistance at higher doses, provides evidence of nonlinearity in the low-dose region. HRS is more prominent in the G2 phase of the cell cycle than in the G0/G1 or S phases. Here we provide the first cytogenetic mechanistic evidence of low-dose HRS in human peripheral blood lymphocytes using structural chromosomal aberrations. METHODS AND MATERIALS: Human peripheral blood lymphocytes from 2 normal healthy female donors were acutely exposed to cobalt 60 gamma rays in either G0 or G2 using closely spaced doses ranging from 0 to 1.5 Gy. Structural chromosomal aberrations were enumerated, and the slopes of the regression lines at low doses (0-0.4 Gy) were compared with doses of 0.5 Gy and above. RESULTS: HRS was clearly evident in both donors for cells irradiated in G2. No HRS was observed in cells irradiated in G0. The radiation effect per unit dose was 2.5- to 3.5-fold higher for doses <=0.4 Gy than for doses >0.5 Gy. CONCLUSIONS: These data provide the first cytogenetic evidence for the existence of HRS in human cells irradiated in G2 and suggest that LNT models may not always be optimal for making radiation risk assessments at low doses. PMID- 25442346 TI - miR-15a/16 enhances radiation sensitivity of non-small cell lung cancer cells by targeting the TLR1/NF-kappaB signaling pathway. AB - PURPOSE: Many miRNAs have been identified as essential issues and core determining factors in tumor radiation. Recent reports have demonstrated that miRNAs and Toll-like receptors could exert reciprocal effects to control cancer development in various ways. However, a novel role of miR-15a/16 in enhancing radiation sensitivity by directly targeting TLR1 has not been reported, to our knowledge. METHODS AND MATERIALS: Bioinformatic analyses, luciferase reporter assay, biochemical assays, and subcutaneous tumor establishment were used to characterize the signaling pathways of miRNA-15a/16 in response to radiation treatment. RESULTS: First, an inverse correlation between the expression of miR 15a/16 and TLR1 protein was revealed in non-small cell lung cancer (NSCLC) and normal lung tissues. Next, we corroborated that miR-15a/16 specifically bound to TLR1 3'UTR and inhibited the expression of TLR1 in H358 and A549 cells. Furthermore, miR-15a/16 downregulated the activity of the NF-kappaB signaling pathway through TLR1. In addition, overexpression of miR-15a/16 inhibited survival capability and increased radiation-induced apoptosis, resulting in enhancement of radiosensitivity in H358 and A549 cells. Finally, subcutaneous tumor bearing NSCLC cells in a nude mice model was established, and the results showed that combined groups (miR-15a/16 + radiation) inhibited tumor growth more significantly than did radiation alone. CONCLUSIONS: We mainly elucidate that miRNA-15a/16 can enhance radiation sensitivity by regulating the TLR1/NF-kappaB signaling pathway and act as a potential therapeutic approach to overcome radioresistance for lung cancer treatment. PMID- 25442348 TI - A simple and efficient methodology to improve geometric accuracy in gamma knife radiation surgery: implementation in multiple brain metastases. AB - PURPOSE: To propose, verify, and implement a simple and efficient methodology for the improvement of total geometric accuracy in multiple brain metastases gamma knife (GK) radiation surgery. METHODS AND MATERIALS: The proposed methodology exploits the directional dependence of magnetic resonance imaging (MRI)-related spatial distortions stemming from background field inhomogeneities, also known as sequence-dependent distortions, with respect to the read-gradient polarity during MRI acquisition. First, an extra MRI pulse sequence is acquired with the same imaging parameters as those used for routine patient imaging, aside from a reversal in the read-gradient polarity. Then, "average" image data are compounded from data acquired from the 2 MRI sequences and are used for treatment planning purposes. The method was applied and verified in a polymer gel phantom irradiated with multiple shots in an extended region of the GK stereotactic space. Its clinical impact in dose delivery accuracy was assessed in 15 patients with a total of 96 relatively small (<2 cm) metastases treated with GK radiation surgery. RESULTS: Phantom study results showed that use of average MR images eliminates the effect of sequence-dependent distortions, leading to a total spatial uncertainty of less than 0.3 mm, attributed mainly to gradient nonlinearities. In brain metastases patients, non-eliminated sequence-dependent distortions lead to target localization uncertainties of up to 1.3 mm (mean: 0.51 +/- 0.37 mm) with respect to the corresponding target locations in the "average" MRI series. Due to these uncertainties, a considerable underdosage (5%-32% of the prescription dose) was found in 33% of the studied targets. CONCLUSIONS: The proposed methodology is simple and straightforward in its implementation. Regarding multiple brain metastases applications, the suggested approach may substantially improve total GK dose delivery accuracy in smaller, outlying targets. PMID- 25442347 TI - Automated segmentation of the parotid gland based on atlas registration and machine learning: a longitudinal MRI study in head-and-neck radiation therapy. AB - PURPOSE: To develop an automated magnetic resonance imaging (MRI) parotid segmentation method to monitor radiation-induced parotid gland changes in patients after head and neck radiation therapy (RT). METHODS AND MATERIALS: The proposed method combines the atlas registration method, which captures the global variation of anatomy, with a machine learning technology, which captures the local statistical features, to automatically segment the parotid glands from the MRIs. The segmentation method consists of 3 major steps. First, an atlas (pre-RT MRI and manually contoured parotid gland mask) is built for each patient. A hybrid deformable image registration is used to map the pre-RT MRI to the post-RT MRI, and the transformation is applied to the pre-RT parotid volume. Second, the kernel support vector machine (SVM) is trained with the subject-specific atlas pair consisting of multiple features (intensity, gradient, and others) from the aligned pre-RT MRI and the transformed parotid volume. Third, the well-trained kernel SVM is used to differentiate the parotid from surrounding tissues in the post-RT MRIs by statistically matching multiple texture features. A longitudinal study of 15 patients undergoing head and neck RT was conducted: baseline MRI was acquired prior to RT, and the post-RT MRIs were acquired at 3-, 6-, and 12-month follow-up examinations. The resulting segmentations were compared with the physicians' manual contours. RESULTS: Successful parotid segmentation was achieved for all 15 patients (42 post-RT MRIs). The average percentage of volume differences between the automated segmentations and those of the physicians' manual contours were 7.98% for the left parotid and 8.12% for the right parotid. The average volume overlap was 91.1% +/- 1.6% for the left parotid and 90.5% +/- 2.4% for the right parotid. The parotid gland volume reduction at follow-up was 25% at 3 months, 27% at 6 months, and 16% at 12 months. CONCLUSIONS: We have validated our automated parotid segmentation algorithm in a longitudinal study. This segmentation method may be useful in future studies to address radiation induced xerostomia in head and neck radiation therapy. PMID- 25442350 TI - Embedded wisdom or rooted problems? Aid workers' perspectives on local social and political infrastructure in post-tsunami Aceh. AB - This paper analyses the role of local social, cultural, and political institutions in post-disaster reconstruction projects. It contends that such institutions are important considerations within community-driven reconstruction initiatives, but are often viewed with ambivalence by external aid organisations. This paper draws upon in-depth qualitative interviews with aid workers involved in the post-tsunami reconstruction in Aceh, Indonesia, to establish: (i) what roles community institutions were suited to play in the reconstruction; (ii) what were the limitations of community institutions when engaging with external aid agencies; (iii) how did external aid agencies engage with local community institutions; and (iv) how did external aid agencies perceive community institutions. PMID- 25442349 TI - Modelling the impact of fractionation on late urinary toxicity after postprostatectomy radiation therapy. AB - PURPOSE: To fit urinary toxicity data of patients treated with postprostatectomy radiation therapy with the linear quadratic (LQ) model with/without introducing a time factor. METHODS AND MATERIALS: Between 1993 and 2010, 1176 patients were treated with conventional fractionation (1.8 Gy per fraction, median 70.2 Gy, n=929) or hypofractionation (2.35-2.90 Gy per fraction, n=247). Data referred to 2004-2010 (when all schemes were in use, n=563; conventional fractionation: 316; hypofractionation: 247) were fitted as a logit function of biological equivalent dose (BED), according to the LQ model with/without including a time factor gamma (fixing alpha/beta = 5 Gy). The 3-year risks of severe urethral stenosis, incontinence, and hematuria were considered as endpoints. Best-fit parameters were derived, and the resulting BEDs were taken in multivariable backward logistic models, including relevant clinical variables, considering the whole population. RESULTS: The 3-year incidences of severe stenosis, incontinence, and hematuria were, respectively, 6.6%, 4.8%, and 3.3% in the group treated in 2004 2010. The best-fitted alpha/beta values were 0.81 Gy and 0.74 Gy for incontinence and hematuria, respectively, with the classic LQ formula. When fixing alpha/beta = 5 Gy, best-fit values for gamma were, respectively, 0.66 Gy/d and 0.85 Gy/d. Sensitivity analyses showed reasonable values for gamma (0.6-1.0 Gy/d), with comparable goodness of fit for alpha/beta values between 3.5 and 6.5 Gy. Likelihood ratio tests showed that the fits with/without including gamma were equivalent. The resulting multivariable backward logistic models in the whole population included BED, pT4, and use of antihypertensives (area under the curve [AUC] = 0.72) for incontinence and BED, pT4, and year of surgery (AUC = 0.80) for hematuria. Stenosis data could not be fitted: a 4-variable model including only clinical factors (acute urinary toxicity, pT4, year of surgery, and use of antihypertensives) was suggested (AUC = 0.73). CONCLUSIONS: The unexpected impact of moderate hypofractionation on severe incontinence and hematuria after postprostatectomy radiation therapy may be explained by a bladder alpha/beta value <1 Gy or, radiobiologically more plausible, by introducing a time factor likely to represent a previously hypothesized consequential component of late effect. PMID- 25442351 TI - Why academic radiologists should use social media. PMID- 25442353 TI - Dual-energy CT colonography for preoperative "one-stop" staging in patients with colonic neoplasia. AB - RATIONALE AND OBJECTIVES: To evaluate the benefits of dual-energy computed tomography (CT) colonography (DECTC) as a preoperative staging tool in patients with clinically suspected colorectal cancer (CRC). MATERIALS AND METHODS: Twenty two patients with colorectal neoplasia underwent preoperative abdominal DECTC on a dual-source scanner (SOMATOM Definition Flash; Siemens) operated at tube potentials of Sn140/100 kVp. Scans were evaluated for local tumor stage and the presence of synchronous intracolonic and extracolonic findings using dual-energy color-coded images. An enhancement >=25 Hounsfield units (HU) was defined to indicate malignancy. Patients' effective doses were calculated. RESULTS: Preoperative DECTC allowed for complete bowel evaluation in all patients, including subjects with stenosing CRC. DECTC revealed 22 carcinomas (mean enhancement, 47 +/- 12 HU). In total, 22 synchronous intracolonic lesions were detected, including 19 adenomas (mean enhancement, 51 +/- 19 HU). Benign structures showed enhancement <25 HU. Comparing DECTC to histopathology, 95% carcinomas and 71% synchronous lesions proximal to stenosing CRC could be verified. Mean estimated effective dose was 13.0 +/- 5.2 mSv. CONCLUSIONS: Preoperative DECTC can be used as an accurate and dose-efficient primary-staging examination. Especially after incomplete optical colonoscopy, virtual colonoscopy enables full preoperative colonic assessment on the same day. Dual-energy CT enables distinction between neoplasia and non-neoplastic findings within and outside the colon. Therefore, DECTC can be regarded as a promising "one-stop" staging examination in patients with clinically suspected CRC. PMID- 25442352 TI - Prediction of aortic enhancement on coronary CTA images using a test bolus of diluted contrast material. AB - RATIONALE AND OBJECTIVES: The purpose of our study was to compare test bolus techniques using undiluted or diluted contrast material for their ability to predict aortic enhancement on coronary computed tomographic angiography (c-CTA) images. MATERIALS AND METHODS: We divided 200 consecutive patients who underwent c-CTA on a 64-MDCT scanner into two groups. In group A (n = 100), we used a test bolus of undiluted contrast material and in group B (n = 100), the contrast material was diluted. The injection volume was body weight * 0.2 (contrast material 100%) in group A and body weight * 0.7 (contrast material 30%, saline 70%) in group B. We then compared the CT number in the ascending aorta on c-CTA images obtained with undiluted and diluted contrast media to the CT number on c CTA images. RESULTS: The mean CT number in the ascending aorta was significantly higher in group B than group A (217.1 vs. 157.4 HU, P < .001). There was a significant difference in the correlation between the CT number of the ascending aorta on c-CTA images and on images acquired with the test bolus using undiluted or diluted test bolus (P < .001). In group B, the correlation had a strong positive linear relationship (r = 0.72, P < .001), whereas in group A the positive linear relationship was weak (r = 0.36). CONCLUSIONS: The test bolus with diluted contrast material was useful for predicting aortic enhancement before c-CTA scanning. PMID- 25442354 TI - Development of a personalized training system using the Lung Image Database Consortium and Image Database resource Initiative Database. AB - RATIONALE AND OBJECTIVES: The aim of this study was to develop a personalized training system using the Lung Image Database Consortium (LIDC) and Image Database resource Initiative (IDRI) Database, because collecting, annotating, and marking a large number of appropriate computed tomography (CT) scans, and providing the capability of dynamically selecting suitable training cases based on the performance levels of trainees and the characteristics of cases are critical for developing a efficient training system. MATERIALS AND METHODS: A novel approach is proposed to develop a personalized radiology training system for the interpretation of lung nodules in CT scans using the Lung Image Database Consortium (LIDC) and Image Database Resource Initiative (IDRI) database, which provides a Content-Boosted Collaborative Filtering (CBCF) algorithm for predicting the difficulty level of each case of each trainee when selecting suitable cases to meet individual needs, and a diagnostic simulation tool to enable trainees to analyze and diagnose lung nodules with the help of an image processing tool and a nodule retrieval tool. RESULTS: Preliminary evaluation of the system shows that developing a personalized training system for interpretation of lung nodules is needed and useful to enhance the professional skills of trainees. CONCLUSIONS: The approach of developing personalized training systems using the LIDC/IDRL database is a feasible solution to the challenges of constructing specific training program in terms of cost and training efficiency. PMID- 25442355 TI - Stickiness and educational effectiveness. PMID- 25442356 TI - Understanding and using fluoroscopic dose display information. AB - Fluoroscopically guided procedures are an area of radiology in which radiation exposure to the patient is highly operator dependent. Modern fluoroscopy machines display a variety of information, including technique factors, field of view, operating geometry, exposure mode, fluoroscopic time, air kerma at the reference point (RAK), and air kerma area-product. However, the presentation of this information is highly vendor specific, and many users are unaware of how to interpret this information and use it to perform a study with the minimum necessary dose. A conceptual framework for understanding the radiation dose readout during a procedure is to compare it to the dashboard of an automobile, where the rate at which radiation is being applied (the RAK rate [mGy/min]) is the dose "speed" and the cumulative amount of radiation applied (cumulative RAK [mGy]) is the dose "odometer." This analogy can be used as a starting point to improve knowledge of these parameters, including how RAK is measured, how RAK correlates with skin dose, and how parameters are displayed differently during fluoroscopy and fluorography. Awareness of these factors is critical to understanding how dose parameters translate to patient risk and the consequences of high-dose studies. With this increased awareness, physicians performing fluoroscopically guided procedures can understand how to use built-in features of the fluoroscopic equipment (pulse rate, beam filtration, and automatic exposure control) and fluoroscopic techniques (procedure planning, patient positioning, proper collimation, and magnification) to reduce patient radiation dose, thereby improving patient safety. PMID- 25442357 TI - Encoding of point of view during action observation in the local field potentials of macaque area F5. AB - The discovery of mirror neurons compellingly shows that the monkey premotor area F5 is active not only during the execution but also during the observation of goal-directed motor acts. Previous studies have addressed the functioning of the mirror-neuron system at the single-unit level. Here, we tackled this research question at the network level by analysing local field potentials in area F5 while the monkey was presented with goal-directed actions executed by a human or monkey actor and observed either from a first-person or third-person perspective. Our analysis showed that rhythmic responses are not only present in area F5 during action observation, but are also modulated by the point of view. Observing an action from a subjective point of view produced significantly higher power in the low-frequency band (2-10 Hz) than observing the same action from a frontal view. Interestingly, an increase in power in the 2-10 Hz band was also produced by the execution of goal-directed motor acts. Independently of the point of view, action observation also produced a significant decrease in power in the 15-40 Hz band and an increase in the 60-100 Hz band. These results suggest that, depending on the point of view, action observation might activate different processes in area F5. Furthermore, they may provide information about the functional architecture of action perception in primates. PMID- 25442358 TI - Comparative assessment of antimicrobial susceptibility testing for tigecycline and colistin against Acinetobacter baumannii clinical isolates, including multidrug-resistant isolates. AB - Acinetobacter baumannii has become a serious concern in clinical practice owing to its multiple resistance to antimicrobial agents. Tigecycline and colistin may be used as alternative therapies, although they lack practical susceptibility testing guidelines. This study assessed the reliability of commonly used methods (disc diffusion, Etest and VITEK((r)) 2) for testing sensitivity to both agents compared with the reference broth microdilution (BMD) method against 290 A. baumannii clinical isolates, including multidrug-resistant isolates. For tigecycline, essential agreement and categorical agreement (CA) of minimum inhibitory concentration (MIC) testing were most correlated with BMD when using a breakpoint of susceptible (S)<=1/resistant (R)>2 mg/L; 94.8% and 84.5% (Etest) and 99.3% and 75.5% (VITEK 2), respectively. A disc diffusion zone diameter breakpoint of S>=17/R<=12 mm showed good agreement. All three methods did not show major errors or very major errors. For colistin, a BMD MIC breakpoint of S<=2/R>4 mg/L was proposed. The disc diffusion method was highly reproducible with a zone diameter breakpoint of S>=12/R<=9 mm. However, Etest results showed a different MIC range, and the MIC breakpoint should be modified to S<=0.5/R>2 mg/L, whilst a similar MIC breakpoint to BMD could be applied for VITEK 2. Both Etest and VITEK 2 showed a high CA for isolates with colistin-susceptible and resistant results. We recommend that disc diffusion, Etest and VITEK 2 may be used with caution for testing tigecycline and colistin based on our proposed breakpoints. The reliability of individual methods will be discussed. PMID- 25442359 TI - Identification of the first imported KPC-3 Klebsiella pneumoniae from the USA to Taiwan. AB - Establishment of KPC-associated genes into a new region usually requires travellers with hospital admission and their carriage into the communities. In this report, a worldwide spreading clone carrying KPC-3 was isolated from the sputum of a hospitalised patient with a serious infection who had just come from the USA and had been admitted to a New York hospital. By genetic comparison with a strain isolated from New Jersey (NJ-KPC-21), this isolate from the traveller was genetically related. The blaKPC-3 gene was harboured on a large plasmid with a complex structure of a Tn3-based transposon, Tn4401a. The KPC-3-carrying plasmid was very similar (>99.9% identity) to the 113 637-bp blaKPC-3-encoding plasmid pKpQIL that originated from the 2006 epidemic carbapenem-resistant Klebsiella pneumoniae outbreak in Israel. With the first recognition of KPC-2 in 2011 and continuing spread, physicians should be aware of the coming of KPC-3 K. pneumoniae in Taiwan. PMID- 25442360 TI - Comparison of the reduction in the antibacterial potency of a fluoroquinolone conferred by a single mutation in the quinolone resistance-determining region or by the inoculum size effect. PMID- 25442361 TI - Stress and dietary behaviour among first-year university students in Australia: sex differences. AB - OBJECTIVE: The aim of this study was to examine the relationship between stress and food selection patterns by sex among first-year undergraduate students studying in an Australian university. METHODS: Participating in this cross sectional study were 728 (331 men and 397 female students) first-year students, ages >18 y, attending the Gold Coast Campus of Griffith University. Data were collected using a self-administered questionnaire consisting of three sections: sociodemographic information, stress measures, and a 7-d food frequency questionnaire. RESULTS: More than half (52.9%) of the participants were found to suffer from some level of stress, with relatively more female students (57.4%) suffering than men (47.4%). Men who experienced mild to moderate levels of stress were two to three times more likely to eat cereal foods (P < 0.01), fish/seafood (P < 0.001), and protein powder (P < 0.05). They also tended to eat more meat alternatives (P < 0.05), highly processed foods (P < 0.05), and to drink more alcohol (P < 0.05) than unstressed male students. However, they were less likely to consume vegetables and fruit (P < 0.05) compared with their unstressed counterparts. The trend analysis results indicated significant dose-response patterns in the relationship between stress level and consumption of cereal food, meat alternatives, vegetables and fruit (negative trend), highly processed food, protein powder, beverages and alcoholic beverages (all P < 0.05). Female students who experienced mild to moderate stress were 2.22 times more likely to eat processed food (P < 0.01) than unstressed female students. Female students who experienced severe stress were less likely to consume meat alternatives (P < 0.05) than their unstressed counterparts. Significant dose-response trends were found in the relationship between stress levels and the consumption of meat alternatives, vegetables and fruit (both negative trends), and processed food (all P < 0.01). CONCLUSION: These results demonstrate a clear difference in food selection patterns between stressed male and female students, with stress being a more significant predictor of unhealthy food selection among male students. Further research is needed using a qualitative approach to understand how stress and eating behavior are related in university students. PMID- 25442362 TI - Is primary visual cortex necessary for visual awareness? AB - Influential models propose that conscious experience of extrastriate activity requires the integrity of primary visual cortex (V1). A new study challenges this view by demonstrating that when V1 is lesioned, visual qualia can be induced when transcranial magnetic stimulation (TMS) is applied over the patients' ipsilesional hemisphere. PMID- 25442363 TI - HIV sexual risk behavior in older black women: a systematic review. AB - BACKGROUND: Human immunodeficiency virus (HIV) is a major public health concern in the United States, particularly among older Black women who comprise approximately 40% of the newly diagnosed cases among women. This systematic review sought to answer the research question: What are the sexual practices in older Black women associated with HIV risk? METHODS: CINAHL, PubMed, MEDLINE, and Web of Knowledge electronic databases were searched for English-language research studies published between 2003 and 2013 that focused on the HIV sexual risk practices of Black women over the age of 50. Using PRISMA guidelines, two reviewers independently reviewed and appraised the quality of relevant articles; agreement of select studies was achieved by consensus. RESULTS: Among the 3,167 articles surveyed, 9 met inclusion criteria. The majority (88%) were quantitative, observational studies. All nine articles addressed at least one of three factors that contribute to HIV sexual risk: Behavioral (inconsistent condom use and multiple sexual partners), psychological (risk perception, depression/stress, trauma, and self-esteem issues), and social factors (economics, education, and drugs/alcohol use). Outcome measures varied across studies. CONCLUSION: Although this systematic review appraised few studies, findings suggest that many older Black women are engaged in HIV risk-taking practices. Clinicians and researchers need to be aware of the HIV risk practices of older Black women to improve health outcomes through education, effective communication and risk appraisal. PMID- 25442364 TI - Serious psychological distress as a barrier to cancer screening among women. AB - BACKGROUND: The purposes of the study were to examine the association of serious psychological distress (SPD) and cancer-screening utilization in a nationally representative sample of women aged 40 to 74 years and to identify barriers and facilitating factors to breast and cervical cancer screening among women with SPD. METHODS: Women aged 40 to 74 (n = 17,770) were selected from the Household Component of Medical Expenditure Panel Survey series of 2007, 2009, and 2011. SPD was defined as a score of 13 of higher on the Kessler Psychological Distress Scale-6 items (K6 scale) of nonspecific psychological distress. Logistic regression was conducted to examine the association between SPD and up-to-date cancer screening. FINDINGS: Women with SPD had significantly lower rates of up-to date clinical breast examination (67.56% vs. 81.93%), mammography (59.94% vs. 75.56%), and Pap smear (72.27% vs. 85.37%). In multivariate logistic regression analyses adjusting for sociodemographics, insurance, health behaviors, comorbidity, and service utilization, SPD was associated with nearly 40% decreased odds of being up to date with all three screening tests. Having a usual place of care, being physically active, and a greater number of past-year medical visits were strongly associated with higher odds of screening utilization among women with SPD. CONCLUSIONS: Women with mental health problems have substantial risk for low use of routine breast and cervical cancer screenings. The K6 may be a useful tool to screen this risk factor. Frequent contact with the health care system among women with mental health problems opens up opportunities to reduce the mental illness-related disparities in utilization of cancer screening. PMID- 25442367 TI - Birthmarks and reincarnation. PMID- 25442365 TI - Understanding disparities in lipid management among patients with type 2 diabetes: gender differences in medication nonadherence after treatment intensification. AB - BACKGROUND: Gender differences in dyslipidemia are widely documented, but the contributors to these differences are not well understood. This study examines whether differences in quality of care, intensity of lipid-lowering medication regimen, and medication adherence can explain this disparity. METHODS: Secondary analysis of medical records data and questionnaires collected from adult patients with type 2 diabetes (n = 1,369) from seven outpatient clinics affiliated with an academic medical center as part of the Reducing Racial Disparities in Diabetes: Coached Care (R2D2C2) study. Primary outcome was low-density lipoprotein (LDL) cholesterol. FINDINGS: Women had higher LDL cholesterol levels than men (mean [SD], 101.2 [35.2] vs. 92.3 [33.0] mg/dL; p < .001), but were no less likely to receive recommended processes of diabetes care, to attain targets for glycemic control and blood pressure, or to be on intensive medication regimens. More women than men reported medication nonadherence related to cost (32.7% vs. 24.2%; p = .040) and related to side effects (47.2% vs. 36.8%; p = .024). For all patients, regimen intensity (p < .05) and nonadherence related to side effects (p < .01) were each associated with higher LDL cholesterol levels. The addition of a new lipid-lowering agent was associated with subsequent nonadherence related to side effects for women (p < .001), but not for men (p = .45; test for interaction p = .048). CONCLUSIONS: Despite comparable quality of diabetes care and regimen intensity for lipid management, women with diabetes experienced poorer lipid control than men. Medication nonadherence seemed to be a major contributor to dyslipidemia, particularly for women because of side effects associated with intensifying the lipid-lowering regimen. PMID- 25442366 TI - Gender differences in the impact of warfare exposure on self-rated health. AB - BACKGROUND: This study examined gender differences in the impact of warfare exposure on self-reported physical health. METHODS: Data are from the 2010 National Survey of Veterans, a nationally representative survey of veterans from multiple eras of service. Regression analyses assessed gender differences in the association between warfare exposure (deployment to a war zone, exposure to casualties) and health status and functional impairment, adjusting for sociodemographics. FINDINGS: Women reported better health status but greater functional impairment than men. Among men, those who experienced casualties only or both casualties and deployment to a war zone had worse health compared with those who experienced neither stressor or deployment to a war zone only. Among women, those who experienced casualties only or both stressors reported worse health than those who experienced war zone only, who did not differ from the unexposed. No association was found between warfare exposure and functional impairment in women; in men, however, those who experienced exposure to casualties or both stressors had greater odds of functional impairment compared with those who experienced war zone only or neither stressor. CONCLUSIONS: Exposure to casualties may be more predictive of health than deployment to a war zone, especially for men. We did not find a stronger association between warfare exposure and health for women than men. Given that the expansion of women's military roles has allowed them to serve in direct combat, their degree and scope of warfare exposure is likely to increase in the future. PMID- 25442368 TI - Unique barriers and needs in weight management for obese women with fibromyalgia. AB - RESEARCH QUESTION: The aim of this study was to identify barriers, needs, and preferences of weight management intervention for women with fibromyalgia (FM). THEORETICAL FRAMEWORK: Obesity appears in higher rates in women with fibromyalgia compared to the population at large, and no study to date has taken a qualitative approach to better understand how these women view weight management in relation to their disease and vice versa. METHODOLOGY: We designed a qualitative interview study with women patients with FM and obesity. CONTEXT: Women (N = 15) were recruited by their participation in a fibromyalgia treatment program (FTP) within the year prior. SAMPLE SELECTION: The women approached for the study met the following inclusion criteria: confirmed diagnosis of FM, age between 30 and 60 years (M = 51 +/- 6.27), and body mass index (BMI) >= 30 (M = 37.88 +/- 4.87). DATA COLLECTION: Patients completed questionnaire data prior to their participation in focus groups (N = 3), including weight loss history, physical activity data, the Revised Fibromyalgia Impact Questionnaire (FIQR), and the Patient Health Questionnaire 9-item (PHQ-9). Three focus group interviews were conducted to collect qualitative data. ANALYSIS AND INTERPRETATION: Consistent themes were revealed within and between groups. Patients expressed the complex relationships between FM symptoms, daily responsibilities, and weight management. Weight was viewed as an emotionally laden topic requiring compassionate delivery of programming from an empathetic leader who is knowledgeable about fibromyalgia. Patients view themselves as complex and different, requiring a specifically tailored weight management program for women with FM. MAIN RESULTS: Women with FM identify unique barriers to weight management, including the complex interrelationships between symptoms of FM and health behaviors, such as diet and exercise. They prefer a weight management program for women with FM that consists of an in-person, group-based approach with a leader but are open to a tailored conventional weight management program. Feasibility may be one of the biggest barriers to such a program both from an institutional and individual perspective. PMID- 25442370 TI - The association between a living wage and subjective social status and self-rated health: a quasi-experimental study in the Dominican Republic. AB - Poverty, both absolute and relative, is associated with poorer health. This is of particular concern in middle- and low-income countries facing a significant and growing burden of disease. There has been limited research specifically on whether interventions that increase income may foster better health outcomes. The establishment of a "living wage" apparel factory in the Dominican Republic provided a minimum income standard for factory workers, thus creating a natural experiment through which to study the effects of increased income on health indicators. The primary component of the intervention was a 350% wage increase, but apparel workers in the intervention factory also received education and professional development and were exposed to an enhanced occupational health and safety program. Workers at the intervention factory (n = 99) were compared with workers at a matched apparel factory (n = 105). Data were collected via in-person interviews in July and August of 2011, which was 15-16 months after workers were initially hired at the intervention site. Primary analyses used employment at the intervention factory as the independent variable and examined associations with two dependent variables: subjective social status and self-rated health. Results showed that receiving a 350% higher wage was associated with substantially higher subjective social status scores, as well as higher global and comparative self rated health scores; effects were strongest in women. Subjective social status and self-rated health are associated with future health outcomes, so these results indicate that income increases for apparel workers may have positive long term health outcomes, particularly for women. PMID- 25442371 TI - Do employment protection policies reduce the relative disadvantage in the labour market experienced by unhealthy people? A natural experiment created by the Great Recession in Europe. AB - Unhealthy persons are more likely to lose their jobs than those who are healthy but whether this is affected by recession is unclear. We asked how healthy and unhealthy persons fared in labour markets during Europe's 2008-2010 recessions and whether national differences in employment protection helped mitigate any relative disadvantage experienced by those in poor health. Two retrospective cohorts of persons employed at baseline were constructed from the European Statistics of Income and Living Conditions in 26 EU countries. The first comprised individuals followed between 2006 and 2008, n = 46,085 (pre-recession) and the second between 2008 and 2010, n = 85,786 (during recession). We used multi-level (individual- and country-fixed effects) logistic regression models to assess the relationship (overall and disaggregated by gender) between recessions, unemployment, and health status, as well as any modifying effect of OECD employment protection indices measuring the strength of policies against dismissal and redundancy. Those with chronic illnesses and health limitations were disproportionately affected by the recession, respectively with a 1.5- and 2.5-fold greater risk of unemployment than healthy people during 2008-2010. During severe recessions (>7% fall in GDP), employment protections did not mitigate the risk of job loss (OR = 1.06, 95% CI: 0.94-1.21). However, in countries experiencing milder recessions (<7% fall in GDP), each additional unit of employment protection reduced job loss risk (OR = 0.72, 95% CI: 0.58-0.90). Before the recession, women with severe health limitations especially benefited, with additional reductions of 22% for each unit of employment protection (AORfemale = 0.78, 95% CI: 0.62-0.97), such that at high levels the difference in the risk of job loss between healthy and unhealthy women disappeared. Employment protection policies may counteract labour market inequalities between healthy and unhealthy people, but additional programmes are likely needed to protect vulnerable groups during severe recessions. PMID- 25442372 TI - Health-related quality of life and sense of coherence among partners of women with breast cancer in Israel. AB - PURPOSE: To compare HRQOL of husbands of women with non-metastatic breast cancer to husbands of healthy women. Additionally, to examine the impact of Sense of Coherence (SOC), socio-demographic, and clinical variables, on HRQOL of spouses in both groups. METHOD: This study used a comparative, matched, convenience sample. Husbands of women with non-metastatic breast cancer (n = 50), undergoing chemotherapy during 3-6 months after diagnoses and spouses of healthy women (n = 50) participated in a study. HRQOL was measured using the Medical Outcomes Study (MOS SF-36), and coping characteristics were measured using the Short Sense of Coherence scale. Socio-demographic factors, cancer stage, and treatments were collected. The groups were matched by age, education, employment (working/not working). The physical and mental component summary scores were dependent variables in the regression analysis. RESULT: Physical and Mental Component Summary indexes in the study group were significantly lower than in the control group. Higher education level, greater income, or more daily working hours were associated with better physical health index (added 30% to explaining the variance). The only personal variable predicting the mental component of QOL was financial situation (added 7%). Higher SOC was associated with higher HRQOL. Disease and treatment characteristics were found to have no influence upon the husbands' QOL. CONCLUSIONS: While the main influence found in this study of a woman's breast cancer on her partner's quality of life is on the mental component, the partner's physical health should also be taken into account. PMID- 25442373 TI - Effects of patient and personal demographic, clinical and psychosocial characteristics on the burden of family members caring for patients with advanced cancer in Greece. AB - PURPOSE: Caregiving burden affects the lives of family members providing care to patients with advanced cancer, with a host of factors possibly contributing to this. The aim of this study was to explore the effects of patient and caregiver variables on the perceptions of burden in families caring for a loved one living with advanced cancer in Greece. METHODS: A convenience sample of 100 pairs of patients receiving palliative radiotherapy for advanced cancer and their respective primary family caregivers were consecutively recruited at one radiotherapy centre. Patients and caregivers completed a set of questionnaires during face-to-face interviews. Correlational and multiple regression analyses were performed to identify potential predictors of caregiving burden. RESULTS: Caregiving burden was linked to both patient (gender, age, past surgery or chemotherapy treatment, depression and impact of cancer-related symptoms) and caregiver variables (gender, family status, education, place of residence, previous experience of care, employment status, difficulty of caregiving, anxiety and depression). In multiple regression analyses, caregiving burden was significantly predicted by caregivers' depressed mood, perceived difficulty of caregiving, family status, employment status, as well as by patients' past surgery, in a model that explained 49% of the total variance. CONCLUSIONS: Greek family caregivers reporting greater depressive mood and difficulty with caregiving tasks, those married, those not employed, and those who cared for patients who had not undergone surgery were found at greater distress and disadvantage. Systematic assessment and intervention strategies are required to identify these vulnerable carers and help them cope when sharing in patient's cancer experience. PMID- 25442374 TI - Targeting bacterial central metabolism for drug development. AB - Current antibiotics, derived mainly from natural sources, inhibit a narrow spectrum of cellular processes, namely DNA replication, protein synthesis, and cell wall biosynthesis. With the worldwide explosion of drug resistance, there is renewed interest in the investigation of alternate essential cellular processes, including bacterial central metabolic pathways, as a drug target space for the next generation of antibiotics. However, the validation of targets in central metabolism is more complex, as essentiality of such targets can be conditional and/or contextual. Bearing in mind our enhanced understanding of prokaryotic central metabolism, a key question arises: can central metabolism be bacteria's Achilles' heel and a therapeutic target for the development of new classes of antibiotics? In this review, we draw lessons from oncology and attempt to address some of the open questions related to feasibility of targeting bacterial central metabolism as a strategy for developing new antibacterial drugs. PMID- 25442375 TI - Recent progress in the design, study, and development of c-Jun N-terminal kinase inhibitors as anticancer agents. AB - The c-Jun N-terminal kinase (JNK) family, with its three members JNK1, JNK2, and JNK3, is a subfamily of mitogen-activated protein kinases. Involved in many aspects of cellular processes, JNK has been also associated with pathological states such as neurodegenerative diseases, inflammation, and cancers. In oncology, each isoform plays a distinct role depending on the context of the targeted tissue/organ, the tumor stage, and, most likely, the signaling pathway activated upstream. Consequently, the current challenge in finding new successful anti-JNK therapies is to design isoform-selective inhibitors of the JNKs. In this review, a particular focus is given to the JNK inhibitors that have been developed thus far when examining 3D structures of various JNK-inhibitor complexes. Using current data regarding structure-activity relationships and medicinal chemistry approaches, our objective is to provide a better understanding of the design and development of selective JNK inhibitors in the present and future. PMID- 25442376 TI - Korean public opinion on alcohol control policy: a cross-sectional International Alcohol Control study. AB - OBJECTIVE: To examine Korean public opinions toward alcohol control measures on availability, advertisement, drink-driving and pricing policy, and how the views on alcohol control policy vary by demographics, drinking patterns and attitude to drinking environments. METHODS: The study used national-based, cross-sectional data collected in 2012 as part of the International Alcohol Control study. 2510 people (M: 1163, F: 1261) aged 15-65 and living in geographically diverse regions of Korea completed the questionnaire asking the support of 12 alcohol control measures. RESULTS: Generally, targeted measures (purchase age of 20 and drink driving) were more popular than universal (availability, advertisement and price) among Koreans. Gender, age, marital status, drinking patterns and attitude to drinking environments related to alcohol use of young and heavy drinkers were strong predictors of the opinions on most of the alcohol control measures. It was daily/weekly drinkers who opposed most restrictions on alcohol availability and price and the support from individuals who are more aware of problems with drinking in public place was outstanding in every control measure. CONCLUSION: These findings should be taken into account by Korean policy-makers as they formulate an alcohol policy for the country. PMID- 25442377 TI - Food intolerance and mucosal inflammation. AB - Most infants are immunologically active and are able to develop a tolerance to oligoclonal antigens by producing IgA, along with activation of regulatory T cells, in early infancy. Cytokines and their signaling molecules are important mediators in the intestine, regulating both oral tolerance and mucosal inflammation. This system works efficiently in most individuals, but for an as yet undefined reason, some people react to food and other proteins as though they were pathogens, with induction of chronic inflammation in the mucosa. The adverse reaction caused by ingested foods is defined as food intolerance. The clinical features of food intolerance include vomiting, diarrhea, bloody stool, eczema, failure to thrive, and a protean range of other symptoms. Intolerance can be divided into two categories depending on whether or not they are immunologically mediated. Food intolerance and mucosal inflammation are deeply related because tolerance cannot be established when there is an inflammation in the intestinal mucosa. Mast cells, eosinophils, mucosal lymphocytes, and epithelial cells are deeply involved and related to each other in the development of mucosal inflammation. Meanwhile, rectal bleeding in infancy is related to lymphoid hyperplasia with eosinophil infiltration into the colonic mucosa facilitated by C C motif ligand 11 (CCL11, known as eotaxin-1) and C-X-C motif chemokine ligand 13 (CXCL13). Rectal bleeding in infancy may not be simply caused by allergic reactions against specific antigens, but may be due to migrated lymphocytes developing immunological tolerance; including IgA synthesizing, in the intestinal mucosa. PMID- 25442378 TI - Severe nutritional risk predicts decreased long-term survival in geriatric patients undergoing pancreaticoduodenectomy for benign disease. AB - BACKGROUND: Weight loss and malnutrition are poorly tolerated by geriatric patients, and pancreaticoduodenectomy (PD) can result in chronic malabsorption and weight loss. We sought to determine how preoperative severe nutritional risk (SNR), as defined by the American College of Surgeons National Surgical Quality Improvement Program/American Geriatric Society Best Practice Guidelines, affects long-term survival after PD for benign disease among geriatric and nongeriatric patients. STUDY DESIGN: All patients undergoing PD for nonmalignant conditions at a single center between 1995 and 2013 were followed for survival, excluding patients who died within 90 days of surgery. Survival of geriatric (age >=65 years) and nongeriatric (age <65 years) patients with and without SNR was compared using Kaplan Meier methods. Cox regression was performed. RESULTS: There were 320 patients who underwent PD for benign disease. Over the course of the study, the proportion of geriatric patients undergoing PD for benign conditions increased from 25% to 46%. In addition to being older, geriatric patients undergoing PD for benign disease were significantly more likely to have coronary artery disease (CAD) and hypertension. Geriatric patients with preoperative SNR had significantly decreased long-term survival after PD for benign disease (p < 0.001), with roughly 1 in 3 patients dead at 5 years compared with 1 in 14 patients without SNR. Survival was not significantly different among nongeriatric patients with and without SNR. In geriatric patients, age, CAD, and SNR were significantly associated with decreased survival on both univariate and multivariate analysis. CONCLUSIONS: Severe nutritional risk can be a useful predictor of long-term survival in geriatric patients undergoing PD, and could improve patient risk stratification preoperatively. Nonoperative management should be strongly considered in geriatric patients with SNR, when malignancy is not suspected. PMID- 25442380 TI - [Mold infections in lung transplants]. AB - Invasive infections by molds, mainly Aspergillus infections, account for more than 10% of infectious complications in lung transplant recipients. These infections have a bimodal presentation: an early one, mainly invading bronchial airways, and a late one, mostly focused on lung or disseminated. The Aspergillus colonization at any time in the post-transplant period is one of the major risk factors. Late colonization, together with chronic rejection, is one of the main causes of late invasive forms. A galactomannan value of 0.5 in bronchoalveolar lavage is currently considered a predictive factor of pulmonary invasive infection. There is no universal strategy in terms of prophylaxis. Targeted prophylaxis and preemptive treatment instead of universal prophylaxis, are gaining more followers. The therapeutic drug monitoring level of azoles is highly recommended in the treatment. Monotherapy with voriconazole is the treatment of choice in invasive aspergillosis; combined antifungal therapies are only recommended in severe, disseminated, and other infections due to non-Aspergillus molds. PMID- 25442381 TI - [Immunopathogenesis of invasive mould infections]. AB - Invasive fungal infections caused by filamentous fungi are devastating diseases that occur in patients with a variety of immunosuppressive conditions. This review focuses on the pathogenesis of the most important invasive mycosis in the human being caused by the filamentous fungi Aspergillus, Fusarium, Scedosporium and mucorales. The first contact between the mould and the patient, the host defense to different fungi, including the role of mucosa in the innate immune system, the whole innate immune recognition receptors, and the pathways connecting innate and adaptive immunity, as well as the virulence factors of fungi, are discussed in this paper. PMID- 25442379 TI - Choledochal cysts: presentation, clinical differentiation, and management. PMID- 25442382 TI - [Pharmacology of the antifungals used in the treatment of aspergillosis]. AB - The treatment of invasive aspergillosis requires the use of drugs that characteristically have complex pharmacokinetic properties, the knowledge of which is essential to achieve maximum efficacy with minimal risk to the patient. The lipid-based amphotericin B formulations vary significantly in their pharmacokinetic behaviour, with very high plasma concentrations of the liposomal form, probably related to the presence of cholesterol in their structure. Azoles have a variable absorption profile, particularly in the case of itraconazole and posaconazole, with the latter very dependent on multiple factors. This may also lead to variations in voriconazole, which requires considering the possibility of monitoring plasma concentrations. The aim of this article is to review some of the most relevant aspects of the pharmacology of the antifungals used in the prophylaxis and treatment of the Aspergillus infection. For this reason, it includes the most relevant features of some of the azoles normally prescribed in this infection (itraconazole, posaconazole and voriconazole) and the amphotericin B formulations. PMID- 25442383 TI - [Invasive fungal disease due to Scedosporium, Fusarium and mucorales]. AB - The number of emerging organisms causing invasive fungal infections has increased in the last decades. These etiological agents include Scedosporium, Fusarium and mucorales. All of them can cause disseminated, virulent, and difficult-to treat infections in immunosuppressed patients, the most affected, due to their resistance to most available antifungal agents. Current trends in transplantation including the use of new immunosuppressive treatments, the common prescription of antifungal agents for prophylaxis, and new ecological niches could explain the emergence of these fungal pathogens. These pathogens can also affect immunocompetent individuals, especially after natural disasters (earthquakes, floods, tsunamis), combat wounds or near drowning. All the invasive infections caused by Scedosporium, Fusarium, and mucorales are potentially lethal and a favourable outcome is associated with rapid diagnosis by direct microscopic examination of the involved tissue, wide debridement of infected material, early use of antifungal agents including combination therapy, and an improvement in host defenses, especially neutropenia. PMID- 25442384 TI - Molecular cloning, sequencing, and distribution of feline GnRH receptor (GnRHR) and resequencing of canine GnRHR. AB - GnRH receptors play vital roles in mammalian reproduction via regulation of gonadotropin secretion, which is essential for gametogenesis and production of gonadal steroids. GnRH receptors for more than 20 mammalian species have been sequenced, including human, mouse, and dog. This study reports the molecular cloning and sequencing of GnRH receptor (GnRHR) cDNA from the pituitary gland of the domestic cat, an important species in biomedical research. Feline GnRHR cDNA is composed of 981 nucleotides and encodes a 327 amino acid protein. Unlike the majority of mammalian species sequenced so far, but similar to canine GnRHR, feline GnRHR protein lacks asparagine in position three of the extracellular domain of the protein. At the amino acid level, feline GnRHR exhibits 95.1% identity with canine, 93.8% with human, and 88.9% with mouse GnRHR. Comparative sequence analysis of GnRHRs for multiple mammalian species led to resequencing of canine GnRHR, which differed from that previously published by a single base change that translates to a different amino acid in position 193. This single base change was confirmed in dogs of multiple breeds. Reverse transcriptase PCR analysis of GnRHR messenger RNA in different tissues from four normal cats indicated the presence of amplicons of varying lengths, including full-length as well as shortened GnRHR amplicons, pointing to the existence of truncated GnRHR transcripts in the domestic cat. This study is the first insight into molecular composition and expression of feline GnRHR and promotes better understanding of receptor organization, and distribution in various tissues of this species. PMID- 25442385 TI - Effect of progesterone supplementation on fertility responses of lactating dairy cows with corpus luteum at the initiation of the Ovsynch protocol. AB - The objectives of this study were to determine the effects of supplemental progesterone on fertility responses of lactating dairy cows with a CL at the initiation of the timed artificial insemination (AI) program. Holstein cows were subjected to the Ovsynch protocol (Day -10 GnRH, Day -3 PGF2alpha, Day -0.7 GnRH, and Day 0 timed AI). Ovaries were scanned by ultrasonography on Day -10 and cows with CL were blocked by pen and assigned randomly to receive no supplemental progesterone (control, n = 863) or to receive a controlled internal drug-release (CIDR) insert containing progesterone from Days -10 to -3 (1CIDR, n = 862). Cows were observed for signs of estrus beginning on Day -9 based on removal of tail chalk and those in estrus received AI on the same day. Blood sampled from a subset of cows was analyzed for progesterone concentrations on Days -10, -9, -7, 5, -3, 0, 6, 13, and 19. Pregnancy was diagnosed on Days 32 and 60 after AI. Supplementation increased (P < 0.01) progesterone concentrations between Day -9 and -3 compared with control (7.5 vs. 6.2 ng/mL). Treatment had no effect on the ovulatory response to the first and final GnRH injections of the Ovsynch protocol, the proportion of cows that maintained their CL until the day of PGF2alpha injection, or the diameter of the ovulatory follicle before AI. Although the overall proportion of cows in estrus at AI did not differ between treatments, progesterone supplementation prevented (P < 0.01) cows from coming into estrus from Days -9 to -3 (0.0% vs. 4.7%), whereas it increased (P = 0.02) the proportion of cows inseminated in estrus from Days -2 to -1 (7.1% vs. 4.5%). Pregnancy per AI (P/AI) tended to be reduced (P = 0.06) by supplemental progesterone on Day 32 (40.5% vs. 45.0%), but not on Day 60 after AI (36.6% vs. 39.7%). A tendency for an interaction (P = 0.09) between treatment and the presence of CL at the PGF2alpha injection was observed for P/AI on Day 32 in cows that received timed AI because progesterone supplementation reduced P/AI in cows that maintained their CL until Day -3 (40.3% vs. 46.7%); however, it increased P/AI in those that did not have a CL at PGF2alpha (38.1% vs. 27.7%). Treatment did not affect pregnancy loss between Days 32 and 60 of gestation. In conclusion, incorporating a single intravaginal insert to the timed AI program increased progesterone concentrations in plasma by 1.3 ng/mL, but did not benefit fertility in dairy cows that have CL at the initiation of the synchronization protocol. PMID- 25442386 TI - Effect of GnRH treatment on ovarian activity and reproductive performance of low prolific Rahmani ewes. AB - This study was designed to evaluate the effect of GnRH treatment during different times of the reproductive cycle on ovarian activity, progesterone (P4) concentration, and subsequent fertility of low-prolific, subtropical, Rahmani ewes during breeding season. Forty-five ewes were synchronized for estrus using a double injection of 0.5 mL of PGF2alpha agonist (125-MUg cloprostenol), 11 days apart. Ewes showing estrus (Day 0) were treated with 1 mL of GnRH agonist (4-MUg buserelin) on the day of estrus (GnRH0, n = 12) or 7 days post-mating (GnRH7, n = 10) or on both days (GnRH0+7, n = 11) or not (control, n = 12). Ovarian response to the treatment and diagnosis of pregnancy were ultrasonographically monitored. Also, serum P4 concentration was determined weekly throughout 28 days post mating. Results showed that neither total number of follicles nor their populations were changed on Day 0 or 7 days post-mating by the GnRH treatment. GnRH treatment on Day 0 or Day 7 post-mating or both days did not enhance ovulation rate compared with the control. The mean numbers of accessory CL increased (P < 0.05) in the GnRH7 group than those in the control and GnRH0 groups, whereas it was intermediate in the GnRH0+7 group. The greatest (P < 0.05) overall mean of serum P4 concentration was for the GnRH7 and GnRH0+7 groups, followed by the GnRH0 and control groups. Serum P4 concentration increased (P < 0.05) on Day 14 post-mating and continued higher (P < 0.05) until Day 28 post mating in the GnRH7 and GnRH0+7 groups compared with the control. Regardless of the time of GnRH administration, GnRH treatment reduced (P < 0.05) pregnancy loss from Day 40 post-mating to parturition and tended to enhance (P < 0.20) lambing rate compared with the control. In conclusion, a single dose of GnRH at the time of estrus or 7 days post-mating could be used as an effective protocol to decrease pregnancy loss from Day 40 after mating to parturition in low-prolific Rahmani ewes. PMID- 25442387 TI - Circulating nitric oxide metabolites during luteolysis and the effect of luteinizing hormone on circulating nitric oxide metabolites in heifers. AB - Temporal relationships among circulating concentrations of nitric oxide metabolites (NOM), progesterone (P4), and luteinizing hormone (LH) within the hours of a PGFM pulse were studied during luteolysis in heifers. The peak of a PGFM pulse was designated Hour 0. All of the following increases and decreases were significant. Within a spontaneous PGFM pulse (experiment 1; n = 7), concentrations of P4 and LH decreased between Hours -1 and 0 and increased between Hours 0 and 1; NOM increased between Hours -1 and 2. In experiment 2, PGFM pulses were simulated by intrauterine infusion of PGF2alpha (PGF group, n = 6), and another group was also treated with acyline to inhibit LH secretion (acyline-PGF group, n = 6). Averaged over the two groups, concentration of P4 decreased between Hours -2 and 0, increased (rebounded) between Hours 0 and 1, and decreased after Hour 2. In the PGF group, concentration of LH decreased between Hours -2 and -0.5 and increased between Hour 0 and Hour 1.5 to a maximum at Hour 1.5; NOM decreased between Hours -2 and -1.5 and increased between Hours 0 and 1.5. In the acyline-PGF group, the effect of hour was not significant for concentrations of LH and NOM. The absence of an increase in NOM concentration when LH was inhibited is a novel finding. The hypotheses were supported that concentrations of LH and NOM are temporally related, and LH has a role in the increase in NOM within the hours of a PGFM pulse. PMID- 25442388 TI - Daily exposure to summer circadian cycles affects spermatogenesis, but not fertility in an in vivo rabbit model. AB - Heat stress (HS) in mammals is a determining factor in the deterioration of spermatogenesis and can cause infertility. The aim of this study was to evaluate the effect of continuous summer circadian cycles on semen production, sperm cell features, fertility, prolificacy, and fecal cortisol metabolites from rabbits kept under an in vivo HS model. We split randomly 60 New Zealand White rabbits into two temperature-controlled rooms: The control group was maintained at comfort temperature (18 degrees C-22 degrees C) and an HS group, where the environmental temperature was programmed to increase from 22 degrees C to 31 degrees C and be maintained for 3 hours to this temperature at the central part of the day. Fecal cortisol metabolites were assessed to evaluate the stress conditions. Seminal parameters were analyzed. Although animals exposed to HS showed higher values of fecal cortisol metabolites (P = 0.0003), no differences were detected in fertility or prolificacy. Semen samples from HS males showed a significant decrease (P < 0.05) with respect to the controls in the percentage of viable spermatozoa (80.71% vs. 74.21%), and a significant (P <= 0.01) increase in the percentage of acrosomic abnormalities (22.57% vs. 36.96%) and tailless spermatozoa (7.91% vs. 12.83). Among motility parameters, no differences were found. This study describes a model of HS simulating a continuous summer daily cycle that allows periods of time to recover as it occurs under natural conditions. Although negative effects have been detected in several sperm parameters, fertility and prolificacy were not affected, suggesting a recovery of the reproductive function when normal conditions are reestablished. PMID- 25442389 TI - Comparison between primary sex ratio in spermatozoa of bulls and secondary sex ratio in the deriving offspring. AB - The objectives of the present work were to compare the primary sex ratio in sperm with the secondary sex ratio recorded in the offspring produced by artificial insemination (AI) with the same sperm and assess whether the primary sex ratio is influenced by sperm survival and motility after thawing. Calving data of 98 Holstein Friesian bulls used in AI were collected during 4 years, and commercial semen of the same bulls was analyzed immediately after thawing and after swim-up using a real-time polymerase chain reaction method developed and validated in our laboratory. Calving data relative to single bulls did not reveal any significant deviation between genders from the theoretical 1:1 for none of the bulls, being the mean values of male and female calves born 52.1 +/- 2.80% and 47.9 +/- 2.71%, respectively. Thereafter, calving events of bulls were classified and analyzed according to four classes of years: 2009 (n = 13,261), 2010 (n = 21,551), 2011 (n = 24,218), and 2012 (n = 41,726), and seasons categorized as winter, spring, summer, and fall. When data aggregated per years were analyzed, the difference between the two sexes was significant (P < 0.005) in favor of the male gender, whereas no influence of the season was evidenced. Real-time polymerase chain reaction did not evidence any difference between the mean values of frequency of Y chromosome-bearing sperm detected in three sperm batches of the same bulls analyzed immediately after thawing (51.1 +/- 2.1), nor a difference with respect to the theoretical 1:1 ratio was reported after sperm analysis of one batch of sperm of the bulls analyzed after swim-up and immediately after thawing (50.1 +/- 2.1 and 49.8 +/- 1.8, respectively). The results are consistent with the observation of the farmers who often report a skewed sex ratio of the calves being born with AI in favor of the male gender. However, we have not evidenced differences in the primary sex ratio with respect to the theoretical 1:1 ratio both at thawing and after swim-up, thus demonstrating that the freezing procedure itself does not impact selectively on the survival of the X or Y chromosome bearing sperm. Therefore, we hypothesize that the difference between genders observed after AI is more likely due to the events occurring after fertilization, which can comprise an impaired function of the X- or Y-bearing sperm with consequences on embryo development or a maternal influence. PMID- 25442390 TI - Effect of seminal plasma on Atlantic salmon (Salmo salar) sperm vitrification. AB - This study was designed to test a vitrification method in Atlantic salmon spermatozoa and determine the capacity of seminal plasma (SP) to protect these cells from cryoinjuries. The vitrification medium consisted of a standard buffer for fish spermatozoa (Cortland medium) + 10% DMSO + 2% BSA + 0.13-M sucrose + SP at concentrations of 30% (G30), 40% (G40), or 50% (G50). Fresh sperm was used as a control. To freeze the samples, 30-MUL suspensions of spermatozoa from each group were dropped directly into liquid nitrogen. The resulting spheres were placed in cryotubes for storage in liquid nitrogen. The cryotubes with the vitrified spermatozoa were thawed by placing them in a water bath at 37 degrees C for 45 seconds. After thawing, the following sperm quality parameters were determined by flow cytometry: DNA fragmentation (terminal deoxynucleotidyl transferase dUTP nick end labeling), plasma membrane integrity (SYBR-14/PI, staining technique), and mitochondrial membrane potential (JC-1 staining). An optical microscope was used to assess subjectively sperm motility, whereas fertility was determined by the presence of neurulation using five replicates per treatment in a sample of 30 eggs. Spermatozoa quality variables were preserved best when the highest concentration of SP (50%) was used (DNA fragmentation, 9.2%; plasma membrane integrity, 98.6%; mitochondrial membrane integrity, 47.2%; motility, 44.1%; and fertility, 46.2%). PMID- 25442391 TI - Individual bovine in vitro embryo production and cumulus cell transcriptomic analysis to distinguish cumulus-oocyte complexes with high or low developmental potential. AB - Studying cumulus cell (CC) transcriptome is of great interest as it could provide a noninvasive method to assess oocyte quality. In cattle, the search for quality markers has not been done with cumulus-oocyte complexes (COCs) cultured individually from maturation to blastocyst stage. Here, differences between high- and low-potential COCs were examined by transcriptomic analysis of CC biopsies obtained from COCs of 2 to 6 mm follicles (n = 249; eight replicates) before individual in vitro maturation, fertilization, and culture until Day 8 after fertilization. Each COC was individually tracked and categorized based on his fate: embryo at blastocyst stage (CC-Blast) or embryo arrested at 2- to 8-cell stage (CC-2-8-cells). Average blastocyst rates were 27.7% for individual culture and 31.2% for group control (not significantly different). For transcriptomic analysis, five cumulus biopsies per replicate were pooled for each fate. Three CC replicates underwent transcriptomic analysis using RNA microarray assay. Some clear differences in gene expression between the CC-Blast and the CC-2-8-cell groups were identified. Considering a 1.5-fold change (P < 0.05), 68 genes were differentially expressed between the CC-Blast and CC-2-8-cells. Quantitative reverse transcription-polymerase chain reaction validations were performed for 12 selected genes: six upregulated genes for each COC fate. Higher expression of 1 acylglycerol-3-phosphate O-acyltransferase 9 (AGPAT9) (lipid metabolism), Chloride intracellular channel 3 (CLIC3), Keratin 8 (KRT8), and Lumican (LUM) (molecular transport) was observed in CC-2-8-cells (P < 0.05). The CC-Blast fate analysis revealed a significantly higher expression of Glycine amidinotransferase (L-arginine:glycine amidinotransferase) (GATM) (posttranslational modification, amino acid metabolism, and free radical scavenging). This newly identified set of genes could provide new markers to distinguish COCs associated with good quality embryos from COCs with limited developmental potential. PMID- 25442392 TI - Diagnostic double-guarded low-volume uterine lavage in mares. AB - Endometritis constitutes a major problem in the management of broodmares; hence, diagnostic tests with a high sensitivity and specificity are highly appreciated. The aim of this study was to compare the results from endometrial, cytologic, and bacteriologic examinations obtained by a newly developed, double-guarded, flushing technique versus standard diagnostic tests, the double-guarded swab and biopsy. The described double-guarded flush technique requires the use of a disposable uterine flushing tube, a sanitary sleeve, a sterile steel speculum, and a 250 mL fluid bag. Endometrial biopsies, swabs, and low-volume lavage samples were obtained from 34 research mares at six different time points in four estrous cycles and were evaluated cytologically and bacteriologically. Endometrial biopsies from the first cycle (n = 34) were examined for the presence of polymorphonuclear neutrophils (PMNs) in the stratum compactum and stratum spongiosum and used as a gold standard for calculation of diagnostic sensitivity and specificity. In all samples, Escherichia coli was most frequently isolated (lavage, 30%; swab, 21%; and biopsy, 12%) followed by beta-hemolytic streptococci (lavage, 11%; swab, 8%; and biopsy, 7%). Positive cytology was less likely to occur when E coli was isolated from the diagnostic tests compared with the growth of beta-hemolytic streptococci. Isolation of pathogens from uterine samples was highly associated with the presence of PMNs in the stratum compactum and straum spongiosum on histology. Using the presence of PMNs in the tissue specimens as the gold standard for diagnosing endometritis, the sensitivity of low-volume lavage culture was 0.75 and the specificity was 0.72. In conclusion, the double guarded, low-volume, lavage technique was a rapid and accurate method for diagnosing mares with endometritis, and the risk of false-positive samples is considered to be minimal compared with other flushing techniques described. PMID- 25442393 TI - Sperm motility of externally fertilizing fish and amphibians. AB - We review the phylogeny, sperm competition, morphology, physiology, and fertilization environments of the sperm of externally fertilizing fish and amphibians. Increased sperm competition in both fish and anurans generally increases sperm numbers, sperm length, and energy reserves. The difference between the internal osmolarity and iconicity of sperm cells and those of the aquatic medium control the activation, longevity, and velocity of sperm motility. Hypo-osmolarity of the aquatic medium activates the motility of freshwater fish and amphibian sperm and hyperosmolarity activates the motility of marine fish sperm. The average longevity of the motility of marine fish sperm (~550 seconds) was significantly (P < 0.05) greater than that of freshwater fish sperm (~150 seconds), with the longevities of both marine and freshwater fish being significantly (P < 0.05) lower than that of anuran sperm (~4100 seconds). The average velocity of anuran sperm (25 MUm/s) was significantly (P < 0.05) lower than that of marine fish (140 MUm/s) or freshwater fish (135 MUm/s) sperm. The longevity of the sperm of giant salamanders (Cryptobranchoidea) of approximately 600 seconds was greater than that of freshwater fish sperm but much lower than anuran sperm. Our research and information from the literature showed that higher osmolarities promote greater longevity in anuran sperm, and some freshwater fish sperm, and that anuran and cryptobranchid sperm maintained membrane integrity long after the cessation of motility, demonstrating a preferential sharing of energy reserves toward the maintenance of membrane integrity. The maintenance of the membrane integrity of anuran sperm in fresh water for up to 6 hours showed an extremely high osmotic tolerance relative to fish sperm. The very high longevity and osmotic tolerance of anuran sperm and high longevity of cryptobranchid sperm, relative to those of freshwater fish, may reflect the complex fertilization history of amphibian sperm in general and anurans reversion from internal to external fertilization. Our findings provide a greater understanding of the reproductive biology of externally fertilizing fish and amphibians, and a biological foundation for the further development of reproduction technologies for their sustainable management. PMID- 25442394 TI - Collateral benefit of screening patients for methicillin-resistant Staphylococcus aureus at hospital admission: isolation of patients with multidrug-resistant gram negative bacteria. AB - BACKGROUND: Surveillance at hospital admission for multidrug-resistant (MDR) gram negative bacteria (GNB) is not often performed, potentially leaving patients carrying these organisms unrecognized and not placed in transmission precautions until they develop infection. Veterans Affairs (VA) facilities screen all admissions for methicillin-resistant Staphylococcus aureus (MRSA) and place positive patients in contact precautions. We assessed how often patients with MDR GNB in clinical cultures obtained within 30 days following admission would have been in contact precautions because of a positive MRSA admission screen. METHODS: MRSA screening and MDR GNB culture results were extracted from a database of patients admitted to all VA acute care medical facilities from January 2009 December 2012. RESULTS: Of patients with MDR GNB-positive cultures within 30 days following admission, up to 44.3% (dependent on bacterial species) would have been in contact precautions because of a clinical positive admission MRSA nasal screen. Admissions with a positive MRSA screen had odds for MDR GNB in a culture 2.5 times greater than those with a negative screen (95% confidence interval [CI], 2.4-2.6). Odds ratios were 2.4 (95% CI, 2.3-2.5) for MDR Enterobacteriaceae, 2.7 (95% CI, 2.5-2.9) for MDR Pseudomonas aeruginosa, and 4.3 (95% CI, 3.8-4.8) for MDR Acinetobacter spp. CONCLUSIONS: Patients may be serendipitously placed in contact precautions for MDR GNB when isolated for a positive admission MRSA screen. PMID- 25442395 TI - Outbreak of hepatitis C virus infection associated with narcotics diversion by an hepatitis C virus-infected surgical technician. AB - BACKGROUND: Drug diversion by health care personnel poses a risk for serious patient harm. Public health identified 2 patients diagnosed with acute hepatitis C virus (HCV) infection who shared a common link with a hospital. Further investigation implicated a drug-diverting, HCV-infected surgical technician who was subsequently employed at an ambulatory surgical center. METHODS: Patients at the 2 facilities were offered testing for HCV infection if they were potentially exposed. Serum from the surgical technician and patients testing positive for HCV but without evidence of infection before their surgical procedure was further tested to determine HCV genotype and quasi-species sequences. Parenteral medication handling practices at the 2 facilities were evaluated. RESULTS: The 2 facilities notified 5970 patients of their possible exposure to HCV, 88% of whom were tested and had results reported to the state public health departments. Eighteen patients had HCV highly related to the surgical technician's virus. The surgical technician gained unauthorized access to fentanyl owing to limitations in procedures for securing controlled substances. CONCLUSIONS: Public health surveillance identified an outbreak of HCV infection due to an infected health care provider engaged in diversion of injectable narcotics. The investigation highlights the value of public health surveillance in identifying HCV outbreaks and uncovering a method of drug diversion and its impacts on patients. PMID- 25442396 TI - Effectiveness of stringent decontamination of computer input devices in the era of electronic medical records and bedside computing: a randomized controlled trial. AB - Bedside computing may lead to increased hospital-acquired infections mediated by computer input devices handled immediately after patient contact. We compared 2 decontamination methods in 2 types of wards. We found high baseline contamination rates, which decreased following decontamination, but the rates remained unacceptably high. Decontamination was more effective in intensive care units compared with medical wards and when using alcohol-based impregnated wipes compared with quaternary ammonium-based impregnated wipes. PMID- 25442397 TI - Stickers used for identification of intravenous lines may be a source of contamination. AB - This study assessed in an in vitro model the effect of 2% alcohol clorhexidine for the disinfection of stickers used for intravenous line identification. Nonadhesive sticker sides were associated with higher numbers of colony-forming units when manipulation was performed without 2% alcohol clorhexidine disinfection. Future clinical studies are needed to validate these data and design policies for daily sticker disinfection. PMID- 25442398 TI - From Gil Brogdon to modern post-mortem imaging. PMID- 25442399 TI - Convergence analysis of the alternating RGLS algorithm for the identification of the reduced complexity Volterra model. AB - In this paper we provide a convergence analysis of the alternating RGLS (Recursive Generalized Least Square) algorithm used for the identification of the reduced complexity Volterra model describing stochastic non-linear systems. The reduced Volterra model used is the 3rd order SVD-PARAFC-Volterra model provided using the Singular Value Decomposition (SVD) and the Parallel Factor (PARAFAC) tensor decomposition of the quadratic and the cubic kernels respectively of the classical Volterra model. The Alternating RGLS (ARGLS) algorithm consists on the execution of the classical RGLS algorithm in alternating way. The ARGLS convergence was proved using the Ordinary Differential Equation (ODE) method. It is noted that the algorithm convergence canno't be ensured when the disturbance acting on the system to be identified has specific features. The ARGLS algorithm is tested in simulations on a numerical example by satisfying the determined convergence conditions. To raise the elegies of the proposed algorithm, we proceed to its comparison with the classical Alternating Recursive Least Squares (ARLS) presented in the literature. The comparison has been built on a non-linear satellite channel and a benchmark system CSTR (Continuous Stirred Tank Reactor). Moreover the efficiency of the proposed identification approach is proved on an experimental Communicating Two Tank system (CTTS). PMID- 25442400 TI - Generalizing PFD formulas of IEC 61508 for KooN configurations. AB - Detailed formulas are given in IEC 61508 for calculating Probability of Failure on Demand for 1oo1, 1oo2, 2oo2, 2oo3 and 1oo3 systems. Simplified PFD formulas are also derived for general k-out-of-n combinations, without incorporating all the elements utilized in IEC 61508 formulas. While there have been other studies on IEC 61508 formulas and the simplified k-out-of-n equations, none have proposed an inclusive generalized form of IEC 61508 formulas to replicate all the specific combinations covered by the standard. This paper uses a detailed analysis to derive a generalized PFD formula based on IEC 61508.6-2011 that can be applied to all k-out-of-n combinations. The proposed formula is verified against both IEC 61508 and the simplified formulas, and its application is demonstrated by a real life example. PMID- 25442401 TI - Robust structured controllers for piezoelectric microactuators. AB - This paper introduces a new control scheme which incorporates the concept of shaping filter together with the use of the nu-gap metric and the robust design of a structured controller. The main motivation in doing this is related to the development of efficient control laws for small size actuators. Designing a structured controller is known to be computationally intractable via the traditional Hinfinity method. This is mainly due to the non-convexity of the resulting control problem which is of fixed order or structure type. To solve this kind of control problem easily and directly, without using any complicated mathematical manipulations and without using too many "user defined" parameters, we utilize the heuristic Kalman algorithm (HKA) for the resolution of the underlying constrained non-convex optimization problem. The experimental results validate the proposed technique and demonstrate its convenience for the development of fast and precise positioning systems. PMID- 25442402 TI - Application of Petri nets to performance evaluation of subsea blowout preventer system. AB - This paper presents an application of deterministic and stochastic Petri nets (DSPN) to evaluate the performance of subsea blowout preventer (BOP) system. The overall subsea BOP system is comprised of five mechanical subsystems and five electrical subsystems, which can be viewed as a series-parallel system. In regard to common cause failures, TimeNET 4.0 toolkit is utilized to develop and analyze the DSPN models. Availability and reliability of the subsea BOP system and its subsystems are obtained. Besides, the effects of failure rate and repair time of each component on system performance are researched. PMID- 25442403 TI - Seasonal influenza vaccine dose distribution in 157 countries (2004-2011). AB - Globally there are an estimated 3-5 million cases of severe influenza illness every year, resulting in 250,000-500,000 deaths. At the World Health Assembly in 2003, World Health Organization (WHO) resolved to increase influenza vaccine coverage rates (VCR) for high-risk groups, particularly focusing on at least 75% of the elderly by 2010. But systematic worldwide data have not been available to assist public health authorities to monitor vaccine uptake and review progress toward vaccination coverage targets. In 2008, the International Federation of Pharmaceutical Manufacturers and Associations Influenza Vaccine Supply task force (IFPMA IVS) developed a survey methodology to assess global influenza vaccine dose distribution. The current survey results represent 2011 data and demonstrate the evolution of the absolute number distributed between 2004 and 2011 inclusive, and the evolution in the per capita doses distributed in 2008-2011. Global distribution of IFPMA IVS member doses increased approximately 86.9% between 2004 and 2011, but only approximately 12.1% between 2008 and 2011. The WHO's regions in Eastern Mediterranean (EMRO), Southeast Asian (SEARO) and Africa (AFRO) together account for about 47% of the global population, but only 3.7% of all IFPMA IVS doses distributed. While distributed doses have globally increased, they have decreased in EURO and EMRO since 2009. Dose distribution can provide a reasonable proxy of vaccine utilization. Based on the dose distribution, we conclude that seasonal influenza VCR in many countries remains well below the WHA's VCR targets and below the recommendations of the Council of the European Union in EURO. Inter- and intra-regional disparities in dose distribution trends call into question the impact of current vaccine recommendations at achieving coverage targets. Additional policy measures, particularly those that influence patients adherence to vaccination programs, such as reimbursement, healthcare provider knowledge, attitudes, practices, and communications, are required for VCR targets to be met and benefit public health. PMID- 25442404 TI - Degradation of toluene-2,4-diamine by persulphate: kinetics, intermediates and degradation pathway. AB - In this study, the degradation of toluene-2,4-diamine (TDA) by persulphate (PS) in an aqueous solution at near-neutral pH was examined. The result showed that the degradation rate of TDA increased with increasing PS concentrations. The optimal dosage of PS in the reaction system was determined by efficiency indicator (I) coupling in the consumption of PS and decay half-life of TDA. Calculation showed that 0.74 mM of PS was the most effective dosage for TDA degradation, at that level the maximum I of 24.51 was obtained. PS can oxidize TDA for an extended reaction time period. Under neutral condition without activation, four degradation intermediates, 2,4-diamino-3-hydroxy-5 sulfonicacidtoluene, 2,4-diaminobenzaldehyde, 2,4-bis(vinylamino)benzaldehyde and 3,5-diamino-4-hydroxy-2-pentene, were identified by high-performance liquid chromatography-mass spectrometry. The tentative degradation pathway of TDA was proposed as well. It was found that hydroxyl radical played an important role in degradation of TDA with the activation of Fe2+, whereas PS anion and sulphate radicals were responsible for the degradation without activation of Fe2+. PMID- 25442406 TI - [Primary flexor tendons repair in zone 2]. AB - Primary flexor tendon repair is still challenging even in the most experienced hands. With atraumatic surgery, the goal is to suture the tendon in a way that it will be strong enough to allow for tendon gliding without the risk of rupture or adhesions during the 12 weeks needed for the tendon to heal. After reviewing the zone 2 anatomy, the authors describe the state of art for flexor tendon repair along with their personal preferences. Although suture methods and postoperative rehabilitation programs are not universal, most specialized teams now use multistrand suturing techniques with at least 4 stands along with protected and controlled early active mobilization. Although the published rates of failure of the repair or postoperative adhesions with stiffness have decreased, these complications are still a concern. They will continue to pose a challenge for scientists performing research into the mechanics and biology of flexor tendon repairs, especially in zone 2. PMID- 25442405 TI - Transcriptome analysis of ripe and unripe fruit tissue of banana identifies major metabolic networks involved in fruit ripening process. AB - BACKGROUND: Banana is one of the most important crop plants grown in the tropics and sub-tropics. It is a climacteric fruit and undergoes ethylene dependent ripening. Once ripening is initiated, it proceeds at a fast rate making postharvest life short, which can result in heavy economic losses. During the fruit ripening process a number of physiological and biochemical changes take place and thousands of genes from various metabolic pathways are recruited to produce a ripe and edible fruit. To better understand the underlying mechanism of ripening, we undertook a study to evaluate global changes in the transcriptome of the fruit during the ripening process. RESULTS: We sequenced the transcriptomes of the unripe and ripe stages of banana (Musa accuminata; Dwarf Cavendish) fruit. The transcriptomes were sequenced using a 454 GSFLX-Titanium platform that resulted in more than 7,00,000 high quality (HQ) reads. The assembly of the reads resulted in 19,410 contigs and 92,823 singletons. A large number of the differentially expressed genes identified were linked to ripening dependent processes including ethylene biosynthesis, perception and signalling, cell wall degradation and production of aromatic volatiles. In the banana fruit transcriptomes, we found transcripts included in 120 pathways described in the KEGG database for rice. The members of the expansin and xyloglucan transglycosylase/hydrolase (XTH) gene families were highly up-regulated during ripening, which suggests that they might play important roles in the softening of the fruit. Several genes involved in the synthesis of aromatic volatiles and members of transcription factor families previously reported to be involved in ripening were also identified. CONCLUSIONS: A large number of differentially regulated genes were identified during banana fruit ripening. Many of these are associated with cell wall degradation and synthesis of aromatic volatiles. A large number of differentially expressed genes did not align with any of the databases and might be novel genes in banana. These genes can be good candidates for future studies to establish their role in banana fruit ripening. The datasets developed in this study will help in developing strategies to manipulate banana fruit ripening and reduce post harvest losses. PMID- 25442407 TI - [Flexor tendons repair in zones 3, 4 and 5]. AB - Surgical repair of zones 1 and 2 flexor tendon injuries is a technically demanding procedure. Surgical repair of zones 3 to 5 lacerated flexor tendons is less demanding. The associated vascular and neural damage will impact the functional outcome. The surgical techniques used to repair flexor tendons in zones 3, 4 and 5 are described, along with the strategy used to treat any associated lesions. PMID- 25442423 TI - Local adaptation despite high gene flow in the waterfall-climbing Hawaiian goby, Sicyopterus stimpsoni. AB - Environmental heterogeneity can promote the emergence of locally adapted phenotypes among subpopulations of a species, whereas gene flow can result in phenotypic and genotypic homogenization. For organisms like amphidromous fishes that change habitats during their life history, the balance between selection and migration can shift through ontogeny, making the likelihood of local adaptation difficult to predict. In Hawaiian waterfall-climbing gobies, it has been hypothesized that larval mixing during oceanic dispersal counters local adaptation to contrasting topographic features of streams, like slope gradient, that can select for predator avoidance or climbing ability in juvenile recruits. To test this hypothesis, we used morphological traits and neutral genetic markers to compare phenotypic and genotypic distributions in recruiting juveniles and adult subpopulations of the waterfall-climbing amphidromous goby, Sicyopterus stimpsoni, from the islands of Hawai'i and Kaua'i. We found that body shape is significantly different between adult subpopulations from streams with contrasting slopes and that trait divergence in recruiting juveniles tracked stream topography more so than morphological measures of adult subpopulation differentiation. Although no evidence of population genetic differentiation was observed among adult subpopulations, we observed low but significant levels of spatially and temporally variable genetic differentiation among juvenile cohorts, which correlated with morphological divergence. Such a pattern of genetic differentiation is consistent with chaotic genetic patchiness arising from variable sources of recruits to different streams. Thus, at least in S. stimpsoni, the combination of variation in settlement cohorts in space and time coupled with strong postsettlement selection on juveniles as they migrate upstream to adult habitats provides the opportunity for morphological adaptation to local stream environments despite high gene flow. PMID- 25442424 TI - Noise spectroscopy as an efficient tool for impedance based sub-femtomolar toxin detection in complex mixture using nanoporous silicon oxide. AB - In this paper we demonstrate an efficient and non-interfering computational method for sub-femtomolar food toxin detection in complex mixture based on nanoporous silicon oxide impedance immunosensor by employing noise spectroscopy analysis at the peak frequency. It has been observed that the peak frequency (fp) values obtained from steady state impedance measurements cannot distinguish between solution with only the specific toxin, which is aflatoxin B1 (AfB1) and mixture of AfB1 with other non-specific toxins (NSTs), thus leading to erroneous quantification of AfB1 in complex mixture. On the other hand, the first cut-off frequency (fc) ranges obtained from noise spectroscopy analysis can qualitatively differentiate between solution containing only AfB1, AfB1 and NSTs and no AfB1. However fc values being very close for different concentration of AfB1 in pure solution and being overlapping for different mixtures cannot quantify AfB1 either in pure solution or in complex mixture. To address this problem, the proposed computational method first clusters the fp and fc values in 11 categories each using k-means clustering algorithm and then applies a simple combinational digital logic on the clusters of fps and fcs to obtain the final output, realizable with standard NAND-NOR gates. The output digital word differs only with AfB1 concentration and not with concentration of NSTs and is found to be capable of detecting sub-femtomolar AfB1 range down to 0.1 fg/ml not only in pure solution but also in complex mixture with as high as 1000 ng/ml NSTs. This is the most sensitive and selective report so far on electrochemical food toxin immunosensors. PMID- 25442425 TI - Enantioselective pharmacodynamic and pharmacokinetic analysis of two chiral CNS active carbamate derivatives of valproic acid. AB - OBJECTIVE: 2-Ethyl-3-methylbutyl-carbamate (EMC) and 2-isopropylpentyl-carbamate (IPC) are among the most potent anticonvulsant carbamate derivatives of valproic acid. EMC and IPC are chiral compounds. Consequently, the aim of the current study was to comparatively evaluate the pharmacokinetic (PK) and pharmacodynamic (PD anticonvulsant activity) profile of EMC and IPC individual enantiomers. METHODS: The anticonvulsant activity of EMC and IPC individual enantiomers was evaluated in several anticonvulsant rodent models including maximal electroshock (MES), 6 Hz psychomotor, subcutaneous (pentylenetetrazole) (scMet), and the pilocarpine-induced and soman-induced status epilepticus (SE). The PK-PD relationship of EMC and IPC individual enantiomers was evaluated following intraperitoneal administration (50 mg/kg) to rats. Induction of neural tube defects (NTDs) was evaluated in a mouse strain that was highly susceptible to teratogen-induced NTDs. RESULTS: In mice and rats, (2S)-EMC exhibited anticonvulsant activity similar to that of racemic EMC in the MES and scMet tests, whereas in the 6 Hz test, racemic EMC was more potent than its two individual enantiomers. Racemic EMC exhibited a potent activity in the soman induced SE model when administered 5 and 20 min after seizure onset with median effective dose (ED50 ) values of 33 and 48 mg/kg, respectively. (2R)-IPC and (2S) IPC exhibited ED50 values similar to those of racemic IPC in the mouse and rat MES and scMet models. (2R)-IPC had similar ED50 values on the 6 Hz tests. Racemic IPC had an ED50 value of 107 mg/kg in the pilocarpine-induced SE model when given 30 min after seizure onset. Racemic EMC and IPC and their enantiomers had similar clearance (3.8-5.5 L/h/kg) and short half-life (<1 h). EMC and its enantiomers did not cause NTDs at doses 3-10 times higher than their anticonvulsant ED50 values. SIGNIFICANCE: EMC and IPC did not exhibit enantioselective PK, a fact that may contribute to their nonenantioselective activity in any of the anticonvulsant models. The nonsignificant difference between racemic EMC and racemic IPC and their enantiomers, suggests that their wide spectrum of anticonvulsant activity is likely to be caused by multiple mechanisms of action. PMID- 25442426 TI - A model to investigate the mechanisms underlying the emergence and development of independent sitting. AB - When infants first begin to sit independently, they are highly unstable and unable to maintain upright sitting posture for more than a few seconds. Over the course of 3 months, the sitting ability of infants drastically improves. To investigate the mechanisms controlling the development of sitting posture, a single-degree-of-freedom inverted pendulum model was developed. Passive muscle properties were modeled with a stiffness and damping term, while active neurological control was modeled with a time-delayed proportional-integral derivative (PID) controller. The findings of the simulations suggest that infants primarily utilize passive muscle stiffness to remain upright when they first begin to sit. This passive control mechanism allows the infant to remain upright so that active feedback control mechanisms can develop. The emergence of active control mechanisms allows infants to integrate sensory information into their movements so that they can exhibit more adaptive sitting. PMID- 25442427 TI - The mini-STAR technique in chronic total occlusions: maximizing the interventional toolbox. PMID- 25442428 TI - Left main coronary artery percutaneous coronary intervention in high-risk patients: hopes for improvement and limitations of randomized trials. PMID- 25442429 TI - Serum uric acid concentration and left atrial thrombus: biomarker, pathophysiological indicator, or innocent bystander? PMID- 25442431 TI - Human embryonic stem cells vs human induced pluripotent stem cells for cardiac repair. AB - Human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) have the capacity to differentiate into any specialized cell type, including cardiomyocytes. Therefore, hESC-derived and hiPSC-derived cardiomyocytes (hESC-CMs and hiPSC-CMs, respectively) offer great potential for cardiac regenerative medicine. Unlike some organs, the heart has a limited ability to regenerate, and dysfunction resulting from significant cardiomyocyte loss under pathophysiological conditions, such as myocardial infarction (MI), can lead to heart failure. Unfortunately, for patients with end-stage heart failure, heart transplantation remains the main alternative, and it is insufficient, mainly because of the limited availability of donor organs. Although left ventricular assist devices are progressively entering clinical practice as a bridge to transplantation and even as an optional therapy, cell replacement therapy presents a plausible alternative to donor organ transplantation. During the past decade, multiple candidate cells were proposed for cardiac regeneration, and their mechanisms of action in the myocardium have been explored. The purpose of this article is to critically review the comprehensive research involving the use of hESCs and hiPSCs in MI models and to discuss current controversies, unresolved issues, challenges, and future directions. PMID- 25442433 TI - Regenerative cell imaging in cardiac repair. AB - Heart disease continues to be a leading cause of death in the Western world. Although strides have been made in prevention and management of coronary artery disease, lost myocardium after an ischemic event remains at the core of the morbidity and the mortality. Poor regenerative capacity of the myocardium has led to the study of cell-based therapies to restore anatomical, functional, and viable myocardium. To that end, stem cells are undifferentiated cells that are self-renewing, clonogenic, and pluripotent and therefore ideal for the restorative job. However, to refine the technique of cell-based therapy, in vivo molecular assessment is imperative to monitor cell survival and their effect on myocardial restoration. Direct imaging of the behaviour of cells after implantation into living subjects can offer great insight into their mechanisms of action, and their therapeutic efficacy. In this article we explore current knowledge of various imaging modalities that have been used to assess in vivo cellular and molecular events after administration of stem cells in injured myocardium. The goal of the article is to provide a comprehensive overview of the literature, highlight various imaging modalities, and suggest some of the key concepts on the horizon in cardiac stem cell imaging. PMID- 25442430 TI - The heart: mostly postmitotic or mostly premitotic? Myocyte cell cycle, senescence, and quiescence. AB - The concept of myocyte division and myocyte-mediated regeneration has re-emerged in the past 5 years through development of sophisticated transgenic mice and carbon-dating of cells. Although recently, a couple of studies have been conducted as an attempt to intervene in myocyte division, the efficiency in adult animals remains discouragingly low. Re-enforcing myocyte division is a vision that has been desired for decades, leading to years of experience in myocyte resistance to proproliferative stimuli. Previous attempts have indeed provided a platform for basic knowledge on molecular players and signalling in myocytes. However, natural biological processes such as hypertrophy and binucleation provide layers of complexity in interpretation of previous and current findings. A major hurdle in mediating myocyte division is a lack of insight in the myocyte cell cycle. To date, no knowledge is gained on myoycte cell cycle progression and/or duration. This review will include an overview of previous and current literature on myocyte cell cycle and division. Furthermore, the limitations of current approaches and basic questions that might be essential in understanding myocardial resistance to division will be discussed. PMID- 25442434 TI - Transforming the promise of pluripotent stem cell-derived cardiomyocytes to a therapy: challenges and solutions for clinical trials. AB - Despite advances in coronary artery disease treatment and prevention, myocardial damage due to acute myocardial infarction (MI) remains a major cause of morbidity and mortality in the population. Cell-based clinical trials to treat MI have focused on cells derived from the bone marrow or those potentially possessing functional similarities such as skeletal myoblasts or cardiac progenitors isolated from heart biopsies. Any benefits provided by these cells in improving heart function, left ventricular ejection fraction, or extending life expectancy after MI have been credited mostly to paracrine effects. Functional restoration of damaged myocardium will require a functional cell type with similar phenotype and characteristics of the damaged tissue that can also integrate, survive, and electrically couple to the host. Human pluripotent stem cells (hPSCs) have the ability to differentiate into multiple cell types of the adult body. hPSC-derived cardiomyocytes represent a promising target population for cell-based therapies for MI because they are scalable and the product can be defined with a specific set of release criteria. The purpose of this article is to review the rationale for cell therapy in heart disease, discuss the properties of hPSC cardiomyocytes that define their usefulness for regenerative therapy, consider manufacturing issues and preclinical investigation, and finally examine the steps required to establish effective clinical implementation. Pluripotent stem cell-derived cardiomyocyte-based therapies have enormous potential to revolutionize the management of heart disease; expedient but careful development is needed to ensure that this potential is fully realized. PMID- 25442435 TI - Regenerative cell and tissue-based therapies for pulmonary arterial hypertension. AB - Within the span of 2 decades, cell-based regenerative therapies for pulmonary arterial hypertension have progressed from bench-side hypotheses to clinical realities. Promising preclinical investigations that examined the therapeutic potential of endothelial progenitor cell and mesenchymal stem cell populations have demonstrated the safety and efficacy of these cell types and provided the foundation for first-in-man clinical trials. Moreover, these studies have improved our understanding of the therapeutic mechanisms by which stem/progenitor cells exert their regenerative functions. Ultimately, these discoveries have led to new applications for stem and progenitor cells including the autologous cell reseeding of decellularized or synthetic lung scaffolds. In this review, an overview of established and emerging cell and tissue regenerative therapies for pulmonary lung diseases are presented, along with discussion of recent advancements in the emerging field of repopulating decellularized or bioengineered lung scaffolds with stem/progenitor cells for allogeneic transplant. PMID- 25442432 TI - The role of tissue engineering and biomaterials in cardiac regenerative medicine. AB - In recent years, the development of 3-dimensional engineered heart tissue (EHT) has made large strides forward because of advances in stem cell biology, materials science, prevascularization strategies, and nanotechnology. As a result, the role of tissue engineering in cardiac regenerative medicine has become multifaceted as new applications become feasible. Cardiac tissue engineering has long been established to have the potential to partially or fully restore cardiac function after cardiac injury. However, EHTs may also serve as surrogate human cardiac tissue for drug-related toxicity screening. Cardiotoxicity remains a major cause of drug withdrawal in the pharmaceutical industry. Unsafe drugs reach the market because preclinical evaluation is insufficient to weed out cardiotoxic drugs in all their forms. Bioengineering methods could provide functional and mature human myocardial tissues, ie, physiologically relevant platforms, for screening the cardiotoxic effects of pharmaceutical agents and facilitate the discovery of new therapeutic agents. Finally, advances in induced pluripotent stem cells have made patient-specific EHTs possible, which opens up the possibility of personalized medicine. Herein, we give an overview of the present state of the art in cardiac tissue engineering, the challenges to the field, and future perspectives. PMID- 25442436 TI - The effect of infrequent low-dose rosuvastatin on the lipid profile. AB - We retrospectively studied 21 patients who had difficulty tolerating daily or alternating-day statins. Patients received rosuvastatin at a mean frequency of 1.7 doses per week, and a mean dose of 11.7 mg per week. We assessed lipid profiles at baseline and after at least 3 months of therapy. We found that total and low-density lipoprotein cholesterol were reduced by 2.03 +/- 2.04 and 1.31 +/ 0.83 mmol/L (27.9% and 31.5%), respectively, from baseline (both P < 0.001). Thus, in patients with statin intolerance, infrequent low-dose rosuvastatin significantly improved low-density lipoprotein cholesterol and was well tolerated over the long term. PMID- 25442437 TI - Superiority of ticagrelor over clopidogrel in patients after cardiac arrest undergoing therapeutic hypothermia. AB - Current guidelines suggest that patients undergoing percutaneous coronary intervention (PCI) receive dual-antiplatelet therapy. There are limited data on the pharmacodynamics of P2Y12 inhibitors in patients with cardiac arrest and return of spontaneous circulation (ROSC) undergoing PCI and therapeutic hypothermia (TH). Accordingly, we compared inhibition of platelet reactivity in patients undergoing TH receiving clopidogrel or ticagrelor. Notably, clopidogrel was ineffective in lowering platelet reactivity, with ticagrelor providing a more rapid (within 4 hours) and sustained reduction (6 days) in platelet reactivity. Pending outcome-based studies, ticagrelor should be used preferentially in patients who have ROSC and are undergoing PCI and TH. PMID- 25442438 TI - Long-term clinical and angiographic outcomes of the mini-STAR technique as a bailout strategy for percutaneous coronary intervention of chronic total occlusion. AB - BACKGROUND: A promising variant of the subintimal tracking and re-entry (STAR) technique, called "mini-STAR," has been recently described as a successful rescue technique after revascularization failure by conventional techniques for coronary chronic total occlusion (CTO). METHODS: The current study enrolled patients with CTO who underwent successful revascularization by the mini-STAR technique as a bailout strategy. Two-year clinical follow-up and angiographic control procedures were performed. RESULTS: From March 2009-September 2011, 100 of 117 patients (mean age, 61.4 +/- 10.9 years) underwent successful recanalization of CTO by the mini-STAR technique as a bailout strategy. Drug-eluting stents (DESs) were implanted in all cases. At 2-year follow-up, the major adverse cardiac events (MACE)-free survival was 89.2%, with a target lesion revascularization (TLR) rate of 6.5%. Angiographic follow-up was performed in 72% of patients. CTO target lesion restenosis was observed in 25% of patients, whereas the reocclusion rate was 12.5%. At multivariate Cox analysis, final thrombolysis in myocardial infarction (TIMI) flow < grade 3 was related to occurrence of MACE (hazard ratio, 5.9; 95% confidence interval [CI], 1.4-24.4; P = 0.013). Final TIMI flow < grade 3 (odds ratio [OR], 5.41; 95% CI, 1.05-27.73; P = 0.043) and CTO stent length (OR, 0.96; 95% CI, 0.93-0.99; P = 0.017) were independent predictors of reocclusion. The independent variables related to restenosis were first generation DESs (OR, 4.10; 95% CI, 1.23-13.64; P = 0.022) and CTO stent length (OR, 0.97; 95% CI, 0.95-0.99; P = 0.027). CONCLUSIONS: As bailout strategy for CTO revascularization, the mini-STAR technique shows low MACE and TLR rates at long-term follow-up. PMID- 25442439 TI - Long-term outcome of unprotected left main stenting: a Canadian tertiary care experience. AB - BACKGROUND: Coronary stenting is increasingly used to treat unprotected left main disease in selected patients. However, there is a paucity of data on the long term outcome of these patients in a Canadian context outside of clinical trials. METHODS: We retrospectively reviewed all provincially-insured patients undergoing left main coronary stenting at a large tertiary referral centre from 2000-2011. Pre-procedural angiograms were reviewed to identify the location of left main disease, and extent of concomitant coronary disease quantified by calculating Synergy Between Percutaneous Coronary Intervention With TAXUS Drug-Eluting Stent and Cardiac Surgery (SYNTAX) scores for each patient. In-hospital death and major adverse cardiac event (MACE) rates were evaluated as were long-term death and MACE rates obtained via linkage of our institutional registry with the Ontario health claims database. RESULTS: Two hundred twenty-one patients underwent unprotected left main stenting with 29 (13.1%) in-hospital death and 34 (15.4%) a MACE. At an average follow-up of 3.1 +/- 2.8 years, 109 patients (49.3%) died and 151 (68.3%) experienced a MACE. Higher SYNTAX tertile and use of bare metal rather than drug-eluting stents was associated with increased rates of in hospital and long-term death. CONCLUSIONS: This study reports, to our knowledge, the largest Canadian cohort of unprotected left main stenting over more than a decade. Coronary stenting was associated with acceptable in-hospital event rates, but poor long-term outcomes, reflecting the higher-risk population traditionally selected for this procedure. PMID- 25442440 TI - Serum uric acid and risk of left atrial thrombus in patients with nonvalvular atrial fibrillation. AB - BACKGROUND: Serum uric acid (SUA) is a simple and independent marker of morbidity and mortality in a variety of cardiovascular diseases. In this study we aimed to investigate SUA and the risk of left atrial (LA) thrombus in patients with nonvalvular atrial fibrillation (AF). METHODS: In this retrospective study, 1359 consecutive patients undergoing transesophageal echocardiography before catheter ablation of AF were enrolled. Sixty-one of the 1359 patients (4.5%) had LA thrombus. RESULTS: SUA levels in patients with LA thrombus were significantly greater (413.5 +/- 98.8 MUmol/L vs 366.7 +/- 94.3 MUmol/L; P < 0.001). Hyperuricemia was defined as SUA >= 359.8 MUmol/L in women and >= 445.6 MUmol/L in men determined according to receiver operating characteristic curve. The incidence of LA thrombus was significantly greater in patients with hyperuricemia than in those with a normal SUA level in women (12.1% vs 1.9%; P < 0.001) and in men (8.5% vs 2.8%; P < 0.001). Hyperuricemia had a negative predictive value of 98.1% in women and 97.1% in men for identifying LA thrombus. Hyperuricemia was associated with significantly greater risk of LA thrombus among Congestive Heart Failure, Hypertension, Age >= 75 Years, Diabetes Mellitus, Stroke, Vascular Disease, Age 65 to 74 Years, Sex Category (CHA2DS2-VASc) score = 0, 1, and >= 2 groups with odds ratios of 7.19, 4.05, and 3.25, respectively. In multivariable analysis, SUA was an independent risk factor of LA thrombus (odds ratio, 1.004; 95% confidence interval, 1.000-1.008; P = 0.028). CONCLUSIONS: Hyperuricemia was a modest risk factor for LA thrombus, which might refine stratification of LA thrombus in patients with nonvalvular AF. PMID- 25442441 TI - The quality of cardiac rehabilitation in Canada: a report of the Canadian Cardiac Rehab Registry. AB - Cardiac rehabilitation (CR) significantly reduces morbidity and mortality compared with usual care. CR quality indicators (QIs) have recently been established in Canada. This article presents an assessment of real-world CR program achievement of process and outcome QIs in Canada, using the Canadian Cardiac Rehab Registry (CCRR). The CR QIs were developed through the Canadian Cardiovascular Society's Best Practice Methodology. After reconciling the QI with CCRR definitions, it was identified that 14 (46.7%) of the 30 QIs could be assessed through the CCRR. There were 5447 patient records from 11 CR programs in the CCRR. Wait times exceeded the 30-day QI target, at a median of 84 days from referral to enrollment. Assessment of QIs of blood pressure (90%) and adiposity (85%) were high, however assessment of QIs for lipids (41%), blood glucose among patients with diabetes (23%), and depression overall (13%) were low. A majority of the participants (68%) achieved the half metabolic equivalent increase in the exercise capacity QI from CR program entry to exit. Of smokers, only 61% were offered smoking cessation therapy. Thirty percent of participants were offered stress management. The CR program completion QI was met in 90% of patients. Areas for care and quality improvement have been identified for the CR community in Canada. Efforts to engage more CR programs assess a greater number of QIs, and to feed back the findings to participating programs quarterly are currently under way. PMID- 25442443 TI - Successful recycling of a previously transplanted heart: another option for limited resources. AB - We report a case of successful reuse of a previously transplanted heart. The organ was retransplanted 16 days after the initial transplantation into a 60-year old man who had previously received a left ventricular assist device. PMID- 25442442 TI - Healthy food procurement policy: an important intervention to aid the reduction in chronic noncommunicable diseases. AB - In 2010, unhealthy diets were estimated to be the leading risk for death and disability in Canada and globally. Although important, policies aimed at improving individual's skills in selecting and eating healthy foods has had a limited effect. Policies that create healthy eating environments are strongly recommended but have not yet been effectively and/or broadly implemented in Canada. Widespread adoption of healthy food procurement policies are strongly recommended in this policy statement from the Hypertension Advisory Committee with support from 15 major national health organizations. The policy statement calls on governments to take a leadership role, but also outlines key roles for the commercial and noncommercial sectors including health and scientific organizations and the Canadian public. The policy statement is based on a systematic review of healthy food procurement interventions that found them to be almost uniformly effective at improving sales and purchases of healthy foods. Successful food procurement policies are nearly always accompanied by supporting education programs and some by pricing policies. Ensuring access and availability to affordable healthy foods and beverages in public and private sector settings could play a substantive role in the prevention of noncommunicable diseases and health risks such as obesity, hypertension, and ultimately improve cardiovascular health. PMID- 25442444 TI - First case of left posterior fascicle in a bystander circuit of idiopathic left ventricular tachycardia. AB - We describe a case of idiopathic left ventricular tachycardia in which the left posterior fascicle was clearly delineated to be a bystander in a re-entry circuit, with participation of the left interventricular myocardium as the retrograde limb instead. To the best of our knowledge, this is the first case report that has directly proven the left posterior fascicle to be a bystander during idiopathic left ventricular tachycardia. PMID- 25442446 TI - Automatic implantable cardioverter defibrillator lead dislodgement resulting in sudden cardiac death: a case report. AB - A 39-year-old subject with nonischemic dilated cardiomyopathy experienced sudden cardiac death 13 days after automatic implantable cardioverter defibrillator (AICD) implant. A hitherto unreported cause of death secondary to AICD lead dislodgement is presented along with a brief review of the literature on this subject. This case highlights the need for intensive monitoring of subjects at high risk of AICD lead dislodgement for early detection and intervention. PMID- 25442445 TI - Optimal duration of dual antiplatelet therapy after implantation of bioresorbable vascular scaffolds: lessons from optical coherence tomography. AB - The current case report demonstrates the interesting finding of incomplete bioresorbable vascular scaffold (BVS) strut coverage at 18 months after implantation for a chronic total occlusion of the left anterior descending coronary artery. In this case, local differences in shear stress could explain the simultaneous presence of well covered and uncovered BVS strut segments in the same optical coherence tomography frame. Even though current standard practice suggests dual antiplatelet therapy for 12 months after BVS implantation, further studies are required to establish optimal duration of dual antiplatelet therapy, particularly when tackling complex lesions. PMID- 25442447 TI - Spontaneous coronary artery dissection treated with bioresorbable vascular scaffolds guided by optical coherence tomography. AB - Spontaneous coronary artery dissection (SCAD) is an uncommon cause of acute coronary syndromes. We report the first case, to our knowledge, of SCAD in an active fit man. We treated this patient with novel bioresorbable vascular scaffold, guided by optical coherence tomography. PMID- 25442448 TI - MitraClip for papillary muscle rupture in patient with cardiogenic shock. AB - We report the successful use of the MitraClip device (Abbott Vascular, Santa Clara, CA) in a 68-year-old man with posterolateral ST-elevation myocardial infarction complicated by papillary muscle rupture and cardiogenic shock. PMID- 25442449 TI - Progressive increase in peridevice leakage after the implantation of the watchman device on long-term serial echocardiographic follow-up. AB - Percutaneous left atrial appendage (LAA) occlusion using the Watchman device (Atritech, Plymouth, MN) is suggested as an alternative modality to warfarin for stroke prevention in patients with nonvalvular atrial fibrillation (AF). However, peridevice leakage resulting from incomplete LAA occlusion remains 1 of the most frequent limitations. We report a case of progressive increase in peridevice leakage after Watchman device implantation on long-term transesophageal echocardiographic follow-up accompanied by stroke. PMID- 25442450 TI - Balloon in the septum: imaging presentation of septal pseudoaneurysm and therapeutic considerations. AB - Coronary pseudoaneurysm is a rare complication of coronary intervention. We present a case with progression of coronary pseuodoaneurysm after a retrograde coronary intervention. According to the previous literature, conservative treatment with imaging follow-up is often adequate as an initial management of septal collateral perforation or pseudoaneurysm. However, in our case, the follow up echocardiography and coronary angiography demonstrated rapid progression of the coronary pseudoaneurysm as a balloon-like cavity within the septum. Close imaging follow-up would be beneficial in case of complex coronary intervention to allow early treatment in case of pseudoaneurysm progression. PMID- 25442451 TI - Proximal optimization technique and kissing balloon inflations with the bioresorbable vascular scaffold for coronary bifurcation percutaneous coronary intervention. AB - Proximal optimization technique and final kissing balloon inflations with noncompliant balloons facilitate success with coronary bifurcation intervention. The use of bioresorbable vascular scaffolds has been postulated to reduce the risk of in-stent restenosis, a particular problem with bifurcation intervention. We present a case of bifurcation intervention in a 49-year-old woman, using for the first time, proximal optimization and kissing balloon inflation within bioresorbable vascular scaffolds, using optical coherence tomography guidance. PMID- 25442452 TI - First direct aortic retrievable transcatheter aortic valve implantation in humans. AB - We describe 2 cases in which transcatheter aortic valve implantation was performed with a Portico prosthesis (St Jude Medical, St Paul, MN) through a direct aortic approach. In 1 of the cases, prosthesis retrieval was needed during the procedure and was essential to the successful outcome. This is the first report, to our knowledge, of direct aortic Portico prosthesis implantation, and it highlights the significance of the retrievable nature of this device. PMID- 25442453 TI - First reported human case of native mitral infective endocarditis caused by Streptococcus canis. AB - A 65 year-old woman was admitted for acute heart failure and severe sepsis revealing definite mitral infective endocarditis with severe regurgitation, complicated by multiple embolisms. Three blood cultures yielded a group G Streptococcus canis strain. Urgent surgery was performed with bioprosthetic valve replacement. Polymerase chain reaction analysis of the valve found S canis DNA. Amoxicillin and gentamicin were given for 2 weeks followed by 4 weeks of amoxicillin alone. She reported contact with a dog without bite. S canis has been reported to cause zoonotic septicemia but to our knowledge, this is the first human case of native valve infective endocarditis. PMID- 25442454 TI - Invasive cardiac aspergillosis with postinfectious left ventricular aneurysm in a patient with acute myeloid leukemia. PMID- 25442455 TI - Issues about knowledge and risk of heart disease in women. PMID- 25442456 TI - Osteoprotegerin is associated with subclinical left ventricular systolic dysfunction in diabetic hypertensive patients: a speckle tracking study. AB - BACKGROUND: Recently, the role of osteoprotegerin (OPG) in the pathogenesis of heart failure through different mechanisms has received much attention. Subclinical changes in left ventricular (LV) function can be identified using quantification of myocardial strain, and global longitudinal strain (GLS) is a superior predictor of outcomes than ejection fraction. We hypothesized that increased OPG levels could predict subclinical LV systolic dysfunction in treated diabetic hypertensive patients with preserved LV ejection fraction. METHODS: The study was composed of 86 diabetic hypertensive and 30 nondiabetic hypertensive patients. All patients underwent echocardiography and venous blood samples were taken for determination of OPG. The relation between OPG levels and LV GLS was investigated using 2-dimensional speckle tracking echocardiography. RESULTS: Diabetic hypertensive patients had higher diastolic peak early/early diastolic tissue velocity and lower systolic tissue velocity, GLS, GLS rate systolic, and GLS rate early diastolic than nondiabetic hypertensive patients (P = 0.009, P = 0.049, P < 0.001, P = 0.004, and P < 0.001, respectively). Diabetic hypertensive patients were divided into 2 groups according to median GLS value (> 18.5 and <= 18.5). The patients with GLS <= 18.5 had higher diastolic blood pressure (mm Hg; P = 0.048), OPG (pmol/L; P < 0.001), and hemoglobin A1c (%; P = 0.042) values than those with GLS > 18.5. In multivariate logistic regression analysis, OPG was found to be an independent predictor of impaired GLS (P = 0.001). Receiver operating characteristic curve analysis revealed that OPG values of > 6.45 (pmol/L) identified the patients with GLS <= 18.5. CONCLUSIONS: Plasma OPG values could predict subclinical LV systolic dysfunction in diabetic hypertensive patients. PMID- 25442457 TI - Lymphocytes infiltrate the quadriceps muscle in lymphocytic myocarditis patients: a potential new diagnostic tool. AB - BACKGROUND: Diagnosing lymphocytic myocarditis (LM) is challenging because of the large variation in clinical presentation and the limitations inherent in current diagnostic tools. The objective of this study was to analyze infiltration of inflammatory cells in quadriceps skeletal muscle of LM patients and investigate the potential diagnostic value of assaying infiltrating inflammatory cells. METHODS: Quadriceps muscle tissue, obtained at autopsy from control patients (n = 9) and LM patients (n = 21), was analyzed using immunohistochemistry for infiltration of lymphocytes (CD45), macrophages (CD68), neutrophilic granulocytes (myeloperoxidase), and several lymphocyte subtypes (CD3, CD4, CD8, CD20) and using polymerase chain reaction for a panel of myocarditis-associated viruses. Additionally, quadriceps muscle from mice with acute coxsackievirus B3-induced myocarditis and control mice was analyzed for presence of lymphocytes and virus. RESULTS: In quadriceps muscle of LM patients the number of infiltrating lymphocytes were significantly increased and LM was diagnosed with specificity of 100% and sensitivity of 71%. Parvovirus B19 was the primary virus found in our patient groups, found in quadriceps tissue of 3 LM patients (although it was also found in 1 control patient). In the mice, enteroviral RNA was present in the quadriceps muscle, although enteroviral capsid proteins and lymphocyte infiltration were found primarily in the adipose tissue within and directly adjacent to the myocyte tissue, rather than in the myocyte tissue itself. CONCLUSIONS: LM is associated with lymphocyte infiltration and viral presence in quadriceps muscle. This indicates that skeletal muscle biopsy/lymphocyte quantification might be a potential diagnostic tool for LM patients. PMID- 25442458 TI - Excellent outcomes for transcatheter aortic valve replacement within 1 year of opening a low-volume centre and consideration of requirements. AB - BACKGROUND: After the approval of transcatheter aortic valve replacement (TAVR) for high-risk or inoperable patients with severe aortic stenosis (AS), many low- and moderate-volume TAVR programs were initiated. Contemporary outcomes from these newly initiated centres remain unknown. METHODS: In March 2013, our institution was authorized by the Quebec Ministry of Health to perform 30 TAVR procedures. After thorough clinical screening and imaging evaluation, suitable patients underwent transfemoral TAVR with the balloon-expandable SAPIEN XT (Edwards Lifesciences, Irvine, CA) transcatheter heart valve (THV). In-hospital and 30-day outcomes were prospectively collected and reported according to Valve Academic Research Consortium 2 guidelines. RESULTS: From April 2013 to January 2014, 30 consecutive high-risk (n = 16 [53.3%]) or inoperable (n = 14 [46.7%]) patients (mean age, 84.6 years; mean Society of Thoracic Surgery score, 7) with symptomatic severe AS underwent transfemoral TAVR. No catastrophic intraprocedural complications such as annulus rupture, valve embolization, aortic dissection, or coronary occlusion occurred, and there were no deaths at 30 days. Disabling stroke occurred in 1 (3.3%) patient 48 hours after THV implantation. Major vascular complications and major bleeding occurred in 1 (3.3%) patient. No moderate or severe paravalvular leak was observed. The median length of stay was 2 (1-3) days, with 8 (26.7%) patients discharged within 24 hours after the procedure. CONCLUSIONS: Excellent outcomes can be achieved in newly initiated relatively low-volume centres, which compares favorably to previously published large series. Important considerations include appropriate team training, rigorous patient screening, use of multimodality imaging techniques, a heart team approach, constant integration of lessons learned from larger published experiences, and maintaining a recommended minimum volume of 25 cases per year. PMID- 25442459 TI - Percutaneous intervention of circumflex chronic total occlusions is associated with worse procedural outcomes: insights from a Multicentre US Registry. AB - BACKGROUND: We sought to determine whether outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) vary according to CTO target vessel: left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA). METHODS: We evaluated the clinical and angiographic characteristics and procedural outcomes of 636 patients who underwent CTO PCI at 6 high-volume centres in the United States between January 2012 and March 2014. RESULTS: The CTO target vessel was the RCA in 387 cases (61%), LAD in 132 (21%), and LCX in 117 (18%). LCX lesions were more tortuous and RCA lesions had greater occlusion length and Japanese Chronic Total Occlusion (J-CTO) score, but were less likely to have a side branch at the proximal cap and had more developed collateral circulation. The rate of procedural success was lower in LCX CTOs (84.6%), followed by RCA (91.7%), and LAD (94.7%) CTOs (P = 0.016). Major complications tended to occur more frequently in LCX PCI (4.3% vs 1.0% for RCA vs 2.3% for LAD; P = 0.07). LCX and RCA CTO PCI required longer fluoroscopy times (45 [interquartile range (IQR), 30-74] minutes vs 45 [IQR, 21-69] minutes for RCA vs 34 [IQR, 20-60] minutes for LAD; P = 0.018) and LCX CTOs required more contrast administration (280 [IQR, 210-370] mL vs 250 [IQR, 184-350] mL for RCA and 280 [IQR, 200-400] mL for LAD). CONCLUSIONS: In a contemporary, multicentre CTO PCI registry, LCX was the least common target vessel. Compared with LAD and RCA, PCI of LCX CTOs was associated with a lower rate of procedural success, less efficiency, and a nonsignificant trend for higher rates of complications. PMID- 25442460 TI - Common carotid intima-media thickness as a risk factor for outcomes in Asian patients with acute ST-elevation myocardial infarction. AB - BACKGROUND: Carotid intima-media thickness (CIMT) is associated with an increased risk of cardiovascular disease. We studied whether CIMT predicts the prognosis of Asian patients with acute ST-elevation myocardial infarction (STEMI). METHODS: A total of 345 patients with STEMI (men, 82.9%; age, 59 +/- 13 years) treated with emergent revascularization were prospectively investigated. In all patients, common CIMT was measured with high-resolution ultrasonography. The patients were followed for a median period of 583 days, and the primary end point was major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death, heart failure, nonfatal recurrent MI, revascularization, and stroke. RESULTS: Mean CIMT of the patients with STEMI was 0.77 +/- 0.14 mm. Of the total patients, 20.6% had carotid plaque and 11.0% experienced MACE. Killip class, left ventricular (LV) function, and carotid plaque were associated with 30-day MACE, whereas CIMT and carotid plaque were related to overall MACE. After adjusting for age, the event rate was 19.0% in the third-tertile CIMT (>= 0.83 mm) group, 12.1% in the second-tertile (0.70-0.82 mm) group, and 4.3% in the first-tertile (<= 0.69 mm) group (P = 0.01). Carotid plaque was independently associated with a higher incidence of MACE (adjusted odds ratio [OR], 3.7; 95% confidence interval [CI], 1.327-10.234; P = 0.012). Area under the receiver operating characteristic (ROC) curve for CIMT tertile (0.69 +/- 0.05) was significantly larger compared with those for door-to-balloon time (0.55 +/- 0.05), LV ejection fraction (LVEF) (0.49 +/- 0.05), and Killip class (0.48 +/- 0.05) (P < 0.001). CONCLUSIONS: CIMT was a useful prognosticator to predict future cardiovascular events (CVEs) in Asian patients with STEMI. PMID- 25442462 TI - Embolus from probable Takotsubo cardiomyopathy: a bedside diagnosis. AB - A 59-year-old woman with stroke and thromboembolic aortoiliac disease in the setting of profound stress was found to have severe left ventricular (LV) systolic dysfunction and large mobile clot on focused cardiac ultrasonography (FCU). Marked recovery of LV function and thrombus resolution within 4 days suggested resolving Takotsubo cardiomyopathy. The role of FCU in early diagnosis and treatment is outlined here. PMID- 25442461 TI - T1 measurements for detection of expansion of the myocardial extracellular volume in chronic obstructive pulmonary disease. AB - BACKGROUND: We aimed to assess whether chronic obstructive pulmonary disease (COPD) is associated with expansion of the myocardial extracellular volume (ECV) using T1 measurements. METHODS: Adult COPD patients Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2 or higher and free of known cardiovascular disease were recruited. All study patients underwent measures of pulmonary function, 6-minute walk test, serum measures of inflammation, overnight polysomnography, and a contrast cardiac magnetic resonance study. RESULTS: Eight patients with COPD were compared with 8 healthy control subjects. The mean predicted forced expiratory volume at 1 second of COPD subjects was 68%. Compared with control subjects, patients had normal left ventricular (LV) and right ventricular size, mass, and function. However, compared with control subjects, the LV remodelling index (median, 0.87; interquartile range [IQR], 0.71-1.14; vs median, 0.62; IQR, 0.60-0.77; P 1/4 0.03) and active left atrial emptying fraction was increased (median, 46; IQR, 41-49; vs median, 38; IQR, 33-43; P 1/4 0.005), and passive left atrial emptying fraction was reduced (median, 24; IQR, 20-30; vs median, 44; IQR, 31-51; P 1/4 0.007). The ECV was increased in patients with COPD (median, 0.32; IQR, 0.05; vs median, 0.27; IQR, 0.05; P = 0.001). The ECV showed a strong positive association with LV remodelling (r = 0.72; P = 0.04) and an inverse association with the 6-minute walk duration (r = -0.79; P = 0.02) and passive left atrial emptying fraction (r = -0.68; P = 0.003). CONCLUSIONS: Expansion of the ECV, suggestive of diffuse myocardial fibrosis, is present in COPD and is associated with LV remodelling, and reduced left atrial function and exercise capacity. PMID- 25442463 TI - [Clinical Psychology in Primary Care: A Descriptive Study of One Year of Operation]. AB - OBJECTIVE: Our aim is to present the first year of operation of a Clinical Psychology service in a Primary Care setting. MATERIAL AND METHOD: A descriptive study was performed by analysing the requests and the care intervention of the Psychology Service, in collaboration with 36 general practitioners (33% of the staff), belonging to 6 health centres. Within the one year period, 171 outpatients from 15 years and older were referred with mild psychological disorders (> 61 in the global assessment functioning scale, APA, 2002). RESULTS: A total of 111 outpatients received psychological care. The main diagnoses were adaptation disorder, affective disorder, and anxiety. More than half (54.82%) of them achieved a full recovery. After a year follow up, a drop of 25.19% was observed in medicines use. CONCLUSIONS: The Primary Care Psychology team is a halfway unit between Primary Care practitioners and specialised units in order to deal with mild mental symptomatology which otherwise could be undertreated. It represents an important support for practitioners. Secondly, the early intervention can prevent mental problems becoming chronic, as shown by the drop in medication use. In spite of the not very high agreement between the practitioner's diagnoses and those made by the Psychology unit, it has set up an important means of communication and with direct and immediate interdisciplinary action. This should eventually lead to savings in economic resources and human suffering. PMID- 25442464 TI - [Bariatric surgery versus intensive treatment in the patient with type 2 diabetes: A follow-up of 3 years]. PMID- 25442466 TI - [A review of multiple sclerosis (2). Diagnosis and treatment]. AB - Multiple sclerosis is a major demyelinating disease of the central nervous system. It has a significant economic and social impact. Its etiology is unclear, although there are several hypotheses, such as infections or genetics. In its pathophysiology, it seems that immune activation attacks the myelin sheath, causing a progressive and irreversible axonal degeneration. The disease produces a variety of symptoms, and diagnosis requires fulfilling a number of criteria and the exclusion of other possible causes. The role of neuroimaging is very important, especially Magnetic Resonance Imaging. Despite the availability of disease-modifying drugs, none of them are able to halt its progress, and the most useful drugs are those designed to alleviate the symptoms of outbreaks. Overall, multiple sclerosis requires a significant effort in research to clarify not only why and how it occurs, as well as the development of new measures to improve quality of life of affected patients. PMID- 25442465 TI - [Palliative care needs in the inmobilized population of a Primary Care area in Vigo Spain]. AB - GENERAL OBJECTIVE: To determine palliative care needs in a sample of people with mobility problems in the area of the C.S. Matama by using the NECPAL instrument (identification and integral-integrated care of people with advanced chronic diseases in social and healthcare provision services). MATERIAL AND METHODS: Descriptive and cross-sectional study of patients immobilized in a health centre in Vigo (87 subjects overall). RESULTS: The average age of our patients is 84.34 years and 82% are women. The most frequent immobilization type was the patient's inability to leave their home (64%). The result of this test was positive in 38% of cases (33 patients), most of whom have chronic diseases and only 1 patient has been diagnosed with cancer. There is a significant negative association between the score obtained on the Barthel scale and the ratio of positives to the test. Concerning the use of resources there are important differences regarding hospital admissions and PHC depending on the outcome of the test. These differences were statistically significant with regard to PHC and emergency consultations. CONCLUSIONS: An immobilized patient is not synonymous with a patient in need of palliative care; the tool used has been proved to be useful to detect this need, which concerns a third of our patients. The results of the questionnaire of need for care palliative (NECPAL) relate well to the basic activities of daily living (Barthel scale score) and to indicators of use of health services. PMID- 25442467 TI - [Hematuria and palpable mass in the right upper quadrant: Usefulness of ultrasonography in primary care]. PMID- 25442468 TI - [Difficult-to-diagnose melanomas: a key role for the dermatologist]. PMID- 25442469 TI - [Desmoplastic melanoma: a study of 23 cases at 3 centres in the Bouches-du-Rhone region]. AB - BACKGROUND: Desmoplastic melanoma (DM) is a rare form of melanoma, often with atypical and potentially misleading aspects that result in difficult and late diagnosis. Because of the high likelihood of local relapse, practitioners must have a good knowledge of such tumours. PATIENTS AND METHODS: A retrospective study of the activities of 3 centres in the Bouches-du-Rhone region between 1998 and 2010 enabled us to collate 23 cases of DM and analyse the clinical and histological features of the disease as well as patient survival. RESULTS: Fifteen of the 23 patients (65.2%) were male with a median age of 64.4 years. Mean Breslow thickness was 7.56 mm. The numbers of AJCC (American Joint Committee for Cancer) stages I, II, III, IV were respectively 4.1, 66.7, 20.8 and 4.1%. Thirteen patients presented relapse, with a mean time to onset of 21 months. The initial relapse involved the skin in 1 case, the lymph nodes in 2 cases, the organs in 5 cases, the organs and subcutaneous region in 1 case, the organs and lymph nodes in 2 cases, and the organs, lymph nodes and skin in 1 case. DISCUSSION: While DM presents a higher rate of local relapse than classical melanoma, this trend appears to subside in the case of thick DM, in which relapse also involves the lymph nodes and/or organs. PMID- 25442470 TI - [Frequency of lymphoscintigraphic anomalies in the contralateral limb and progression of unilateral primary lymphedema in children]. AB - BACKGROUND: Primary lymphoedema (LE) is the consequence of lymphatic insufficiency, usually associated with hypoplasia of the lymph vessels and/or nodes. Lymphoscintigraphy allows early diagnosis. OBJECTIVES: To assess the frequency of contralateral LE by lymphoscintigraphy in children with unilateral primary LE of one limb; to assess facets of clinical bilateralization of LE. METHODS: This retrospective single-centre study included children with unilateral LE followed up at the Tours university hospital centre between 2004 and 2014. Parents were contacted by phone to obtain follow-up data. RESULTS: Of the 13 children included, 6 (46%) displayed bilateral lymphatic anomalies on lymphoscintigraphy. Within a median follow-up period of 6 years, clinical bilateralization was observed in one girl after progression of her LE for 7 years; in her case, bilateral lymphatic insufficiency was detected at the initial lymphoscintigraphy. CONCLUSION: While contralateral subclinical lymphatic insufficiency is frequent in children with unilateral primary LE of the limbs, clinical bilateralization appears only rarely. PMID- 25442471 TI - [Mechanisms of resistance to anti-BRAF treatments]. AB - CONTEXT: In patients with melanoma positive for the BRAF V600 mutation, clinical response to specific BRAF inhibitors is usually rapid and striking, with significant benefits in terms of progression-free survival and overall survival. However, resistance to treatment almost invariably arises, typically within a median timeframe of 6 months. Indeed, very few patients exhibit long-lasting response to these targeted therapies. AIMS: It is essential to better understand the mechanisms of resistance to targeted anti-BRAF therapies in order to increase both response rates and the duration of clinical response to treatment. This literature review describes the signaling pathways involving BRAF and presents recent data from clinical trials with these molecules. Furthermore, we aim to describe the main resistance mechanisms linked with targeted anti-BRAF therapies. METHODS: The keywords (resistance, BRAF, melanoma, targeted therapy, vemurafenib, and dabrafenib) were used to extract relevant articles in the Medline/Pubmed database published before 31 January 2014. DISCUSSION: Improved knowledge and understanding of the mechanisms of resistance to targeted anti-BRAF therapies should enable the development of new therapeutic strategies in order to overcome such resistance and allow more significant and sustained response rates to be achieved among melanoma patients. PMID- 25442472 TI - [Phlegmasia cerulea dolens]. AB - BACKGROUND: Herein we report a case of phlegmasia cerulea dolens, a form of venous thrombosis complicated by arterial ischaemia. PATIENTS AND METHODS: A 69 year-old man presented a bilateral trophic condition of the lower limbs that had appeared 3 weeks earlier. The patient had a history of metastatic urothelial bladder carcinoma and arteritis. Clinical examination revealed right leg ulcers with massive bilateral oedema of the lower limbs, cyanosis and local ischaemia. Doppler ultrasound revealed bilateral and proximal deep vein thrombosis (sural and superficial femoral veins of the right leg; sural and iliac veins of the left leg) without any distal arterial flow. We concluded on a diagnosis of bilateral phlegmasia cerulea dolens. DISCUSSION: Phlegmasia cerulea dolens is a particular type of deep venous thrombosis in which a proximal venous thrombus is combined with arterial ischaemic signs due to brutal and massive oedema and slowing down of arterial flow. In most cases, the lower limbs are involved, with malignancy being the most common cause. It should be suspected in the presence of the classical triad of "pain, oedema and cyanosis", with confirmation by Doppler ultrasound. There is no general consensus regarding standard management. Traditionally, systemic anticoagulation has been the mainstay of treatment for this condition. Endovascular surgery may be a possibility in some cases. Prompt diagnosis and rapid treatment initiation are paramount in order to improve the prognosis of this severe condition with ominous prospects. PMID- 25442473 TI - [Acanthosis nigricans in children and Crouzon syndrome]. AB - BACKGROUND: Crouzon syndrome with acanthosis nigricans is a rare form of Crouzon syndrome in which craniosynostosis and facial dysmorphism are associated with acanthosis nigricans. PATIENTS AND METHODS: Cutaneous examination of a 9-year-old child presenting bicoronal craniosynostosis revealed acanthosis nigricans of the cervical, axillar, inguinal and popliteal regions which appeared at the age of two. He had a dysmorphic face including a large forehead, hypertelorism, mid-face hypoplasia, prognathism and low-set ears. These clinical anomalies suggested a case of Crouzon syndrome with acanthosis nigricans, which was later confirmed by the finding of a mutation in the FGFR3 gene. DISCUSSION: Acanthosis nigricans in children is often a cutaneous marker of insulin resistance. However, it may also form part of diverse diseases, notably those of genetic origin. The association of craniosynostosis and acanthosis nigricans allows incrimination of the FGFR3 gene from the outset and diagnosis of Crouzon syndrome with acanthosis nigricans. In the present case, dermatological examination allowed an aetiology of craniosynostosis to be determined. PMID- 25442474 TI - [Acantholytic dermatosis in patients treated by vemurafenib: 2 cases]. AB - BACKGROUND: Acantholytic dyskeratosis under BRAF inhibitors are dermatological diseases rarely reported to date. PATIENTS AND METHODS: We report 2 cases of acantholytic dyskeratosis, reaching the trunk and the seborrheic zones, not itchy, appeared one month after the introduction of vemurafenib. The histological analysis was typical of a "Grover-like rash" for the 2 patients. DISCUSSION: The appearance of acantholytic dyskeratosis under vemurafenib, a BRAF inhibitor, seems related with a paradoxical activation of the MAP-kinases pathway and with a growth acceleration of lesions in which RAS mutations of keratinocytes. Theses dermatoses seem also to occur with dabrafenib. CONCLUSION: The patients treated by BRAF inhibitors (vemurafenib and dabrafenib) can present acantholytic dyskeratosis. The arisen of this mild dermatosis does not question, of course, the continuation of the treatment. These cutaneous manifestations can be managed with emollients. PMID- 25442475 TI - [The value of elastography in detection of nodal melanoma metastasis]. PMID- 25442476 TI - [Mastocytosis]. PMID- 25442477 TI - [Bullous lesions on the wrists]. PMID- 25442478 TI - [Mucosal advancement flap in the repair of vermilionectomy defects of the lower lip]. PMID- 25442479 TI - [Vampirism and medicine]. PMID- 25442480 TI - [The announcement of bad news in dermatology]. PMID- 25442481 TI - [Trichofolliculoma of the scalp]. PMID- 25442482 TI - [Neutrophilic eccrine hidradenitis and azathioprine hypersensitivity syndrome]. PMID- 25442483 TI - Endobronchial valve therapy in prolonged air leak. PMID- 25442484 TI - Apparent diffusion coefficient value of gastric cancer by diffusion-weighted imaging: correlations with the histological differentiation and Lauren classification. AB - OBJECTIVE: The purpose of this study was to evaluate the correlations between histological differentiation and Lauren classification of gastric cancer and the apparent diffusion coefficient (ADC) value of diffusion weighted imaging (DWI). MATERIALS AND METHODS: Sixty-nine patients with gastric cancer lesions underwent preoperative magnetic resonance imaging (MRI) (3.0T) and surgical resection. DWI was obtained with a single-shot, echo-planar imaging sequence in the axial plane (b values: 0 and 1000s/mm(2)). Mean and minimum ADC values were obtained for each gastric cancer and normal gastric walls by two radiologists, who were blinded to the histological findings. Histological type, degree of differentiation and Lauren classification of each resected specimen were determined by one pathologist. Mean and minimum ADC values of gastric cancers with different histological types, degrees of differentiation and Lauren classifications were compared. Correlations between ADC values and histological differentiation and Lauren classification were analyzed. RESULTS: The mean and minimum ADC values of gastric cancers, as a whole and separately, were significantly lower than those of normal gastric walls (all p values <0.001). There were significant differences in the mean and minimum ADC values among gastric cancers with different histological types, degrees of differentiation and Lauren classifications (p<0.05). Mean and minimum ADC values correlated significantly (all p<0.001) with histological differentiation (r=0.564, 0.578) and Lauren classification (r= 0.493, -0.481). CONCLUSIONS: The ADC values may be helpful as a noninvasive tool for evaluating the histological features of gastric cancer, such as histological type, degree of differentiation and Lauren classification. PMID- 25442485 TI - Intermediate care pathways for musculoskeletal conditions--are they working? A systematic review. AB - BACKGROUND: Musculoskeletal condition assessment and management is increasingly delivered at the primary to secondary care interface, by inter-disciplinary triage and treat services. OBJECTIVES: This review aimed to describe Intermediate Care pathways, evaluate effectiveness, describe outcomes and identify gaps in the evidence. DATA SOURCES: PubMed, ISI Web of Science, EMBASE, Ovid Medline, PEDro, Google Scholar to October 2013. STUDY SELECTION/ELIGIBILITY CRITERIA: Studies in English that evaluated relevant services were considered for inclusion. Studies evaluating paediatric or emergency medicine and self-referral were excluded. RESULTS: Twenty-three studies were identified. Between 72% and 97% of patients could be managed entirely within Intermediate Care with a 20% to 60% resultant reduction in orthopaedic referral rate. Patient reported outcome measures typically showed significant symptom improvements. Knee conditions were most commonly referred on to secondary care (35% to 56%), with plain films (5% to 23%) and MRI (10% to 18%) the commonest investigations. Physiotherapists' clinical decision making and referral accuracy were comparable to medical doctors in 68% to 96% of cases. Intermediate Care consistently leads to significantly reduced orthopaedic waiting times and high patient satisfaction. LIMITATIONS: These findings are not based on strong evidence and there is an urgent need for high quality, prospective, comprehensive evaluation of Intermediate Care provision, including cost-effectiveness and impact on other services. FUNDING: Part funded by EPSRC and AXA-PPP. CONCLUSION: Intermediate Care consistently improves patient outcome, typically results in appropriate referral and management, reduces waiting times and increases patient satisfaction. There is a case for wider provision of Intermediate Care services to effectively manage non-surgical musculoskeletal patients. PMID- 25442486 TI - Vitamin D deficiency in mycosis fungoides and Sezary syndrome patients is similar to other cancer patients. AB - BACKGROUND: The purpose of this study was to determine the prevalence of vitamin D deficiency in CTCL patients and whether supplementation corrects vitamin D deficiency or treatment outcome. PATIENTS AND METHODS: Three hundred eleven CTCL patients including 27/311 (8.7%) with Sezary syndrome (SS), 169 cancer controls, and 69 normal controls from the M.D. Anderson clinics had 25(OH)D3 levels determined and categorized as deficient (< 20 ng/mL),insufficient (20-29 ng/mL), or sufficient (>= 30 ng/mL). Clinical response was determined according to a change in percent body surface area involvement. RESULTS: Low 25(OH)D3 (< 30 ng/mL) levels were present in 76.9% of mycosis fungoides/SS patients, 75.2% of cancer controls, and 66.7% of healthy controls (P 1/4 .05, .07) and in 30% to 39% of historical normal controls. Correction of deficiency was successful in 35% or 55 of 156 patients who were given dealer's choice of either vitamin D2 at 50,000 IU orally (p.o.) biweekly or D3 1000 IU p.o. daily. Correction of vitamin D levels was noted in 27 of 100 (27%) patients given D3 and 28 of 56 (50%) given D2. Responses to standard CTCL therapy was similar among patients with corrected and persistently low levels (P 1/4 .51). CONCLUSION: To our knowledge,this is the first study of vitamin D status in CTCL patients. Vitamin D deficiency was present in CTCL and other cancer patients compared with normal and historical controls. Correction of vitamin D deficiency and type of vitamin D supplementation used did not affect the overall clinical disease response. PMID- 25442487 TI - Multidimensional approach to classifying chronic pain conditions--less is more. PMID- 25442488 TI - The ACTTION-APS Pain Taxonomy initiative: response to Henriques et al. PMID- 25442489 TI - Etiology of facial fractures in elderly Finns during 2006-2007. AB - OBJECTIVE: The purpose of the present study was to clarify the trauma mechanisms and resulting facial fractures in geriatric patients and to compare them with those of younger adults. STUDY DESIGN: A cohort of 117 geriatric patients was compared with 136 patients aged 20 to 50 years. The statistical significance of differences between the age groups was evaluated with chi(2) tests. RESULTS: Falls on the ground were significantly more frequent among geriatric patients (P < .001), whereas assault was more frequent in controls (P < .001). Accident rates in geriatric patients were significantly higher during the winter months (P = .04). Fractures of the midface in general (P = .001) and of the nasal bone (P = .004) and orbit (P = .015) in particular were more frequent in geriatric patients. CONCLUSIONS: Age-related factors and preexisting medical problems predispose the elderly to falls and subsequent fractures. Footwear traction devices are recommended during the cold season. Orbital fractures should be strongly suspected in the elderly. PMID- 25442490 TI - Long-term outcomes of endoscopic neck dissection in the treatment of early-stage oral cancer: a pilot study. AB - OBJECTIVE: This study aimed to investigate the feasibility and safety of endoscopic neck dissection in the treatment of early-stage oral cancer and to evaluate the long-term clinical outcomes. STUDY DESIGN: Six patients with early stage oral cancer were enrolled in this pilot study from December 2006 to May 2007. All the patients underwent endoscopic selective neck dissection (levels I IV) of the ipsilateral neck and partial glossectomy or hemiglossectomy as the primary treatment. RESULTS: All endoscopic procedures were successfully performed, with important neck structures identified and preserved. All the patients survived with no persistent or recurrent disease during the 76- to 83 month follow-up. CONCLUSIONS: Our preliminary results indicated that endoscopic neck dissection is a technically feasible and safe technique for treating early stage oral cancer. The oncologic indications and validation should be further confirmed in patients with clinically positive neck lymph nodes in a future study. PMID- 25442491 TI - In vitro activity of terpenes against Candida albicans and ultrastructural alterations. AB - OBJECTIVE: The purpose of this study was to investigate the in vitro activity of terpene blends combined with tissue conditioner against Candida albicans and the effect on its morphology and sub-micro structure. STUDY DESIGN: The minimal inhibitory concentration (MIC) of terpenes, obtained from a by-product of kraft pulping, was determined using broth microdilution against C. albicans strains, and the activity of terpenes combined with Coe-Comfort tissue conditioner was assessed. Cell morphologic alterations were evaluated using scanning electronic microscopy and transmission electronic microscopy. Data was analyzed using Student's t test P < .05. RESULTS: The MIC of terpene blends fluctuated between 0.097% and 0.39% (v/v). Coe-Comfort tissue conditioner mixed with terpenes exhibited a total inhibition of C. albicans (P < .05). Terpenes induced ultrastructural alterations, even at the MIC value, including an increase in size, shape modification, cell wall damage with perforations, pronounced disconnection between cell wall and cytoplasm, and cytoplasmic vacuoles. CONCLUSIONS: Terpenes had pronounced effects against C. albicans alone and in combination with Coe-Comfort tissue conditioner, which mainly resulted in cell wall damage. PMID- 25442492 TI - Oral cancer in young Jordanians: potential association with frequency of narghile smoking. AB - OBJECTIVE: The aim of this study was to investigate the relationship between narghile (water-pipe) smoking and the age of patients when diagnosed with oral cancer. STUDY DESIGN: Patients with oral cancer registered in the Jordanian National Cancer Registry were asked about frequency of cigarette, narghile, and alcohol use. Relationship between age at diagnosis and risk factors was assessed using multiple regression analysis. RESULTS: In this sample, 66% of patients were cigarette smokers, and 36% and 17% were narghile smokers and alcohol drinkers, respectively. The multivariate regression analysis adjusted for sex, cigarette smoking, and alcohol drinking found that narghile smokers were significantly younger when diagnosed with oral cancer compared with nonsmokers. CONCLUSIONS: Narghile smoking is an independent risk factor associated with the development of oral cancer at a younger age. Prospective studies of its effect on the earlier development of oral cancer are needed to establish a cause-effect relationship. PMID- 25442493 TI - Viral infection and oral habits as risk factors for oral squamous cell carcinoma in Yemen: a case-control study. AB - OBJECTIVE: The role of qat chewing, tobacco (shammah) dipping, smoking, alcohol drinking, and oral viral infection as risk factors for oral squamous cell carcinoma (OSCC) in Yemen was assessed. STUDY DESIGN: A total of 60 cases of OSCC and 120 age- and gender-matched controls were analyzed with respect to demographic data, history of oral habits, and the presence of human papillomavirus (HPV)-16, HPV-18, or Epstein-Barr virus (EBV) as determined by Taqman quantitative polymerase chain reaction. Logistic regression analysis was used to identify independent predictors of the disease. RESULTS: Shammah use was the only risk factor for OSCC, with an odds ratio of 12.6 (CI, 3.3-48.2) and 39 (CI, 14-105) for the ex-users and current users, respectively. The association of shammah use alone with OSCC exceeded that of shammah use in combination with qat chewing, smoking, or both. EBV infection, smoking, and qat chewing showed no association with OSCC, while neither HPV-16 nor HPV-18 were detected in any sample. CONCLUSIONS: Shammah use is a major risk factor for oral cancer in Yemen. PMID- 25442494 TI - Benefits of an intraoral stent in decreasing the irradiation dose to oral healthy tissue: dosimetric and clinical features. AB - OBJECTIVE: To determine whether an intraoral stent may decrease radiation dose to health tissues during intensity-modulated radiotherapy (IMRT) and to evaluate the effect on mucositis. STUDY DESIGN: A total of 33 patients with tongue or floor of the mouth cancer were retrospectively evaluated and divided into 2 groups: group 1 (with stent, n = 19) and group 2 (without stent, n = 14). Data were collected on dosimetric and mucositis outcomes. RESULTS: The mean dose to the maxilla was significantly lower in group 1 (20.9 Gy) than in group 2 (35.8 Gy) (P = .05). The mean dose to the ipsilateral parotid was 35.0 Gy in group 1 vs 41.8 Gy in group 2 (P = .05). No difference was seen in the severity of mucositis between groups (P = .82). However, grade III mucositis was present in group 1 at 4 weeks after IMRT, 1 week after its occurrence in group 2. CONCLUSIONS: A stent was effective in decreasing doses to healthy structures and delaying the emergence of mucositis. PMID- 25442496 TI - Adenoid dysplasia of the oral mucosa. AB - OBJECTIVE: To describe an unusual variant of oral epithelial dysplasia and to provide an appraisal of its immunohistochemical profile. STUDY DESIGN: An unusual form of epithelial dysplasia, which we have termed adenoid dysplasia, was evaluated for staining of cytokeratins AE1/AE3, vimentin, E-cadherin, and beta catenin. The immunohistochemical results were compared with those observed in moderate epithelial dysplasia, moderately differentiated squamous cell carcinoma, and acantholytic squamous cell carcinoma. RESULTS: The immunoprofile of adenoid dysplasia was similar to that of acantholytic squamous cell carcinoma. Cytokeratin positivity within the acantholytic dysplastic cells confirmed their epithelial nature, and upregulation of vimentin was suggestive of epithelial mesenchymal transition. The most distinctive finding was a loss of E-cadherin expression within the discohesive cells, accompanied by increased cytosolic expression of beta-catenin. CONCLUSIONS: This report presents the histomorphologic features of a unique form of oral epithelial dysplasia, termed adenoid dysplasia. PMID- 25442495 TI - The highly prevalent H3F3A mutation in giant cell tumours of bone is not shared by sporadic central giant cell lesion of the jaws. AB - OBJECTIVE: Central giant cell lesion (CGCL) and giant cell tumour (GCT) are bone lesions that share similar microscopic features. Recently, it was reported that 90% of bone GCT exhibit either p.Gly34 Trp or p.Gly34 Leu in H3F3A, one of two genes for histone H3.3 located on chromosome 1. We aimed to test whether sporadic CGCL of the jaws share the H3F3A mutations reported in GCT of other bones. METHODS: Nine samples of CGCL of the jaws were included in the study, and mutations were assessed by direct sequencing. RESULTS: None of the CGCL samples presented the recurrent p.Gly34 Trp or p.Gly34 Leu mutations in the H3F3A gene. CONCLUSION: On the basis of our findings, H3F3A p.Gly34 Trp or p.Gly34 Leu mutations are not a frequent event in CGCL. If these alterations are confirmed to be exclusive of GCT, the assessment of H3F3A mutations may help in the differential diagnosis of GCT and CGCL of the jaws. PMID- 25442497 TI - Cone beam computed tomography for the diagnosis of vertical root fractures: a systematic review of the literature and meta-analysis. AB - OBJECTIVE: The aim of this review was to compare the efficiency of cone beam computed tomography (CBCT) and conventional intraoral radiography for the detection of vertical root fractures (VRFs). STUDY DESIGN: Data from comparative and noncomparative studies investigating CBCT, conventional radiography, or both for the diagnosis of VRFs were searched. The main outcome variables were sensitivity, specificity, and accuracy of the techniques. Data were separated into 4 groups: in vivo, ex vivo/untreated teeth, ex vivo/treated teeth, and ex vivo with post. The weighted mean of each parameter was estimated. RESULTS: Twelve articles were considered for the analysis. There was a large heterogeneity of the characteristics of the studies and a wide variability in outcome variables. No significant differences were found between radiographic techniques. CONCLUSIONS: No superiority of CBCT compared with conventional radiography was found for VRF detection. Adequate choice of voxel size seems to be important when diagnosing VRFs. PMID- 25442498 TI - A phantom for simplified image quality control of dental cone beam computed tomography units. AB - OBJECTIVE: The purpose of this work was to develop an inexpensive phantom for simplified image quality assurance (IQA) together with algorithms for objective evaluation of image quality parameters and to integrate these components into an easy-to-use software package. This should help make quality control of dental cone beam computed tomography (CBCT) units accessible, easy, and affordable for any specialist or general practitioner. STUDY DESIGN: Our study developed an inexpensive polymethyl methacrylate (Plexiglas) phantom containing objects and structures for objective quantification of the most important image-quality parameters in CBCT imaging. It also paired the phantom with a software package, based on open-source software, for automatic processing and analysis. RESULTS: The software produces objectively measured IQA data for low- and high-contrast resolution, uniformity, noise characteristics, and geometric linearity. CONCLUSIONS: The authors consider the phantom and methods presented in this article to be a step toward helping clinical dental personnel perform regular quality assurance on CBCT units. PMID- 25442499 TI - Prevalence of carotid artery calcification in patients with chronic renal disease identified by panoramic radiography. AB - OBJECTIVE: This study aimed to evaluate the prevalence of carotid artery calcification (CAC) in the panoramic radiographs of patients with chronic renal disease and to ascertain the medical parameters. STUDY DESIGN: A total of 100 panoramic radiographs were observed. The division of patients according to renal disease was as follows: 37 in early-stage renal disease (ESG), 32 in predialysis (PDG), and 31 in hemodialysis (HDG). RESULTS: There were 21 images with opacities suggestive of CAC (6 from ESG, 7 from PDG, and 8 from HDG). The medical parameters were as follows: Triglyceride levels were significantly higher (P < .0001) in patients with CAC compared with those without CAC; potassium levels were higher in the group with CAC compared with the group without CAC (P < .0001); and the calcium levels were lower in the group with CAC compared with the group without CAC (P < .0001). CONCLUSIONS: The patients with renal injury and changes in triglyceride and potassium levels had a higher prevalence of CAC on panoramic radiography. PMID- 25442500 TI - Influence of an object's z-axis location and location on the axial plane on the voxel value representation and uniformity in cone beam computed tomography. AB - OBJECTIVE: This study aimed to determine the influence of an object's z-axis location and location on the axial plane on the voxel values in cone beam computed tomography. STUDY DESIGN: The CTP401 and CTP486 of the Catphan 500 phantom were scanned with an Alphard-3030 at 6 locations in the z-axis. RESULTS: In CTP401, the voxel values of 3 inserts showed the lowest values when the center of the radiation field corresponded to under 2 or 4 cm of the z-axis center of CTP401. In CTP486, the voxel values showed the lowest values when the center of the radiation field corresponded to under 2 or 4 cm of the z-axis center of CTP486. On the same axial plane, the voxel values at the center showed significantly lower values than the off-center locations (P = .002). CONCLUSIONS: The voxel values in the Alphard-3030 changed based on the z-axis location of the radiation field and were nonuniform on the same axial plane. PMID- 25442501 TI - Systemic delivery of human bone marrow embryonic-like stem cells improves motor function of severely affected dystrophin/utrophin-deficient mice. AB - BACKGROUND AIMS: Embryonic-like stem cells (ELSCs) express embryonic stem cell specific marker genes, such as SSEA-4, Oct-4 and Nanog, and can be induced to differentiate into cells of all 3 germ layers. Our preliminary data showed that ELSCs isolated from human bone marrow express multipotent antigen markers and differentiate into multinucleated myotube-like cells more efficiently than do mesenchymal stromal cells (MSCs) isolated from the same source. We investigated the therapeutic effect of ELSCs in dystrophin/utrophin double knock-out (dko) mice, one of the Duchenne muscular dystrophy animal models, by systemically transplanting them through tail-vein injection. METHODS: ELSCs and MSCs were both isolated from human bone marrow. Two months after equal amounts of ELSCs or MSCs were injected through tail-vein injection, we evaluated skeletal muscle motor function and serum creatine kinase activity and measured dystrophin expression by means of immunostaining, Western blotting and semi-quantitative reverse transcriptase-polymerase chain reaction. RESULTS: ELSCs positive for Oct-4 and Nanog-3 expressed higher levels of SSEA-4, FZD-9 and CD105 and were induced to differentiate into myotube-like cells more efficiently than did MSCs in vitro. Transplantation of ELSCs through the tail vein improved motor function and decreased serum creatine kinase activity at 2 months after cell transplantation. In addition, dystrophin protein and messenger RNA were upregulated and the skeletal muscle histology was improved in these dko mice transplanted with ELSCs. CONCLUSIONS: ELSCs could be more efficiently induced to differentiate into myotubes than were MSCs in vitro, and systematically transplanting ELSCs improved muscle motor function and muscle histology in dko mice. PMID- 25442503 TI - Osteosarcomas in the upper distal extremities: are their oncological outcomes similar to other sites? AB - AIMS: To investigate whether the oncological outcomes of patients with osteosarcomas in the upper distal extremity are similar to other sites and assess if limb-salvage surgery is safe in this location. METHODS: The centre database was used to identify all patients with osteosarcomas in the lower humerus and distally between 1985 and 2012. Patient, tumor, treatment and outcome data was collected. RESULTS: Twenty-six patients were included in this study. There were 9 males and 17 females with a mean age of 33 years (9-90). Seventeen osteosarcomas were located in the forearm bones (65%), six in the distal humerus (23%), and three (12%) in the hand. The three most common sub-diagnoses were parosteal 7/21 (33%), fibroblastic 4/21 (19%) and osteoblastic osteosarcomas 3/21 (14%). 2 patients (8%) had Paget's disease and 19 patients (73%) had high-grade tumors. Local excision was carried out in 12 patients (48%), 4 patients underwent endoprosthetic replacement (16%) and 9 underwent amputation (36%). The overall risk of local recurrence was 4% in our series. The five-year overall survival rate was 67%, with low tumor grade and parosteal type of osteosarcoma being positive predictors of survival. CONCLUSION: This series has shown that patients with high-grade osteosarcomas of the upper distal extremities have a higher amputation risk than other limb sites but have favorable outcomes with limb salvage surgery, comparable to other anatomical sites. Parosteal osteosarcomas in particular have a good prognosis. PMID- 25442508 TI - Letter commenting on: Panjwani, C. and Caraher, M. (2014). The Public Health Responsibility Deal: brokering a deal for public health, but on whose terms? Health Policy, 114(2), pp. 163-173. PMID- 25442502 TI - De novo prediction of cis-regulatory elements and modules through integrative analysis of a large number of ChIP datasets. AB - BACKGROUND: In eukaryotes, transcriptional regulation is usually mediated by interactions of multiple transcription factors (TFs) with their respective specific cis-regulatory elements (CREs) in the so-called cis-regulatory modules (CRMs) in DNA. Although the knowledge of CREs and CRMs in a genome is crucial to elucidate gene regulatory networks and understand many important biological phenomena, little is known about the CREs and CRMs in most eukaryotic genomes due to the difficulty to characterize them by either computational or traditional experimental methods. However, the exponentially increasing number of TF binding location data produced by the recent wide adaptation of chromatin immunoprecipitation coupled with microarray hybridization (ChIP-chip) or high throughput sequencing (ChIP-seq) technologies has provided an unprecedented opportunity to identify CRMs and CREs in genomes. Nonetheless, how to effectively mine these large volumes of ChIP data to identify CREs and CRMs at nucleotide resolution is a highly challenging task. RESULTS: We have developed a novel graph theoretic based algorithm DePCRM for genome-wide de novo predictions of CREs and CRMs using a large number of ChIP datasets. DePCRM predicts CREs and CRMs by identifying overrepresented combinatorial CRE motif patterns in multiple ChIP datasets in an effective way. When applied to 168 ChIP datasets of 56 TFs from D. melanogaster, DePCRM identified 184 and 746 overrepresented CRE motifs and their combinatorial patterns, respectively, and predicted a total of 115,932 CRMs in the genome. The predictions recover 77.9% of known CRMs in the datasets and 89.3% of known CRMs containing at least one predicted CRE. We found that the putative CRMs as well as CREs as a whole in a CRM are more conserved than randomly selected sequences. CONCLUSION: Our results suggest that the CRMs predicted by DePCRM are highly likely to be functional. Our algorithm is the first of its kind for de novo genome-wide prediction of CREs and CRMs using larger number of transcription factor ChIP datasets. The algorithm and predictions will hopefully facilitate the elucidation of gene regulatory networks in eukaryotes. All the predicted CREs, CRMs, and their target genes are available at http://bioinfo.uncc.edu/mniu/pcrms/www/. PMID- 25442509 TI - Decreased left ventricular (LV) function is associated with hip-fractures. AB - BACKGROUND: Several risk factors for falls and hip-fractures have been recognized, but controversy still exists toward the importance of structural cardiac abnormalities as a potentially modifiable risk factor for recurrent falls. Aim of this study was to determine the association between echocardiographic abnormalities and hip-fractures. METHODS: Design case-control study within consecutive patients undergoing hip-surgery in an academic hospital. CASES: patients with traumatic hip-fractures. CONTROLS: patients undergoing planned hip surgery (non-traumatic). INCLUSION CRITERIA: age>=50 years, presence of pre-operative echocardiogram. EXCLUSION CRITERIA: high energy trauma, pathological and/or previous hip-fracture. OUTCOME: echocardiographic abnormalities (ventricular function, atrial enlargement, valve stenosis and/or regurgitation, pulmonary hypertension (pulmonary artery pressure (PAP) >=35mmHg)). Multivariate logistic regression was performed to calculate odds ratios (OR) and to correct for confounders. RESULTS: We included 197 patients (141 cases). Mean age was 77 years (SD), 65% female. After adjustment for potential confounders, decreased LV systolic function was associated with hip fractures (OR 3.2 [95%CI 1.1-9.1]). Increasing severity of LV dysfunction was also associated with hip-fractures (p for trend=0.012). DISCUSSION: In conclusion, patients with traumatic hip-fracture had greater risk of decreased LV function than patients who underwent planned hip-surgery. Possibly, decreased LV function is an underestimated risk factor for injurious falls. PMID- 25442510 TI - A new anti-forensic scheme--hiding the single JPEG compression trace for digital image. AB - To prevent image forgeries, a number of forensic techniques for digital image have been developed that can detect an image's origin, trace its processing history, and can also locate the position of tampering. Especially, the statistical footprint left by JPEG compression operation can be a valuable source of information for the forensic analyst, and some image forensic algorithm have been raised based on the image statistics in the DCT domain. Recently, it has been shown that footprints can be removed by adding a suitable anti-forensic dithering signal to the image in the DCT domain, this results in invalid for some image forensic algorithms. In this paper, a novel anti-forensic algorithm is proposed, which is capable of concealing the quantization artifacts that left in the single JPEG compressed image. In the scheme, a chaos-based dither is added to an image's DCT coefficients to remove such artifacts. Effectiveness of both the scheme and the loss of image quality are evaluated through the experiments. The simulation results show that the proposed anti-forensic scheme can verify the reliability of the JPEG forensic tools. PMID- 25442511 TI - Sub-segmental pulmonary embolism in three academic teaching hospitals: a review of management and outcomes. AB - BACKGROUND: The availability of computed tomography pulmonary angiography (CTPA) has led to an increase in the diagnosis of sub-segmental pulmonary embolism (SSPE). Current clinical practice guidelines do not make any treatment distinctions for SSPE, though the benefits of anticoagulation for SSPE have not been established. OBJECTIVES: To review the frequency of pulmonary embolism and sub-segmental pulmonary embolism identified through CTPA as well as their management. METHODS: Cross-sectional review of the charts of 2213 patients who underwent CTPA in three Hamilton teaching hospitals from 2009 to 2011. In-depth review of the charts of patients with SSPE was undertaken to determine the frequency with which patients received anticoagulation therapy for SSPE, as well as bleeding complications and recurrent thrombosis. RESULTS: A total of 2216 CTPAs were reviewed. The frequency of PE was 24.8% (n = 550). The most frequent filling defect was SSPE in 82 patients (3.9% of total scans and 15.0% of identified PEs). In 55 of these 82 SSPEs, an alternative diagnosis to PE was identified on CT to explain the patients' symptoms. Approximately 52.4% (n = 43) received anticoagulation for SSPE. Major life-threatening bleeding complications occurred in two of the 43 who received anticoagulation for SSPE. There was no documented recurrent thrombosis in any patients with SSPE, with or without anticoagulation. SUMMARY/CONCLUSIONS: A substantial proportion of patients received anticoagulation for SSPE (52%) and two developed life-threatening bleeding complications. Randomized controlled trial data are needed to further investigate the risks and benefits of anticoagulation in patients with SSPE. PMID- 25442512 TI - Computed tomographic scan mapping of gastric wall perfusion and clinical implications. AB - BACKGROUND: Several postoperative gastrointestinal complications are attributed to ischemia. We herein evaluate the gastric wall perfusion using computed tomography (CT) scan perfusion index on trial to address the etiology of ischemic complication after sleeve gastrectomy. METHODS: A retrospective study of 205 patients undergoing CT scan of the abdomen to evaluate the pattern of gastric vascular perfusion was performed. The perfusion index of the gastric mucosa was measured at 5 gastric points using CT perfusion scanning. RESULTS: Gastric perfusion at the angle of His (AOH) (53.51 +/- 14.38) was statistically significantly lower (P < .001) than that at the other gastric points studied: fundus, greater curvature, lesser curvature, incisura angularis, and mid gastric points (76.16 +/- 15.21, 73.27 +/- 16.55, 76.12 +/- 16.12, and 75.24 +/- 14.9, respectively). Gastric perfusion was significantly lower at all the gastric points (and especially so at the AOH) among obese patients (33 cases) compared with nonobese patients (18 cases). Gastric perfusion at all the points studied showed a decrease as the body mass index increases. Hypertensive patients had a better gastric perfusion compared with nonhypertensive patients. CONCLUSIONS: Gastric wall perfusion is statistically significantly decreased at the AOH and gastric fundus compared with perfusion at other gastric points. Gastric perfusion at all the gastric points studied decreased with the increase in body mass index. Gastric leakage in obese patients following sleeve gastrectomy could be attributed to a decrease in the blood supply at AOH. PMID- 25442513 TI - Outcome reporting in bariatric surgery: an in-depth analysis to inform the development of a core outcome set, the BARIACT Study. AB - Outcome reporting in bariatric surgery needs a core outcome set (COS), an agreed minimum set of outcomes reported in all studies of a particular condition. The aim of this study was to summarize outcome reporting in bariatric surgery to inform the development of a COS. Outcomes reported in randomized controlled trials (RCTs) and large non-randomized studies identified by a systematic review were listed verbatim and categorized into domains, scrutinizing the frequency of outcome reporting and uniformity of definitions. Ninety studies (39 RCTs) identified 1,088 separate outcomes, grouped into nine domains with most (n = 920, 85%) reported only once. The largest outcome domain was 'surgical complications', and overall, 42% of outcomes corresponded to a theme of 'adverse events'. Only a quarter of outcomes were defined, and where provided definitions, which were often contradictory. Percentage of excess weight loss was the main study outcome in 49 studies, but nearly 40% of weight loss outcomes were heterogeneous, thus not comparable. Outcomes of diverse bariatric operations focus largely on adverse events. Reporting is inconsistent and ill-defined, limiting interpretation and comparison of published studies. Thus, we propose and are developing a COS for the surgical treatment of severe and complex obesity. PMID- 25442515 TI - Seasonal cercarial emergence patterns of Opisthorchis viverrini infecting Bithynia siamensis goniomphalos from Vientiane Province, Lao PDR. AB - BACKGROUND: Snail intermediate hosts play a pivotal role in maintaining the life cycles of trematodes, including Opisthorchis viverrini. We investigated the emergence patterns of O. viverrini cercariae infecting Bithynia siamensis goniomphalos at foci in an endemic area in Vientiane Province, Lao PDR. FINDINGS: Samples of B. s. goniomphalos collected during the hot-dry, rainy and cool-dry seasons were examined for O. viverrini infection by cercarial shedding. Emergence of cercariae from O. viverrini-positive snails was monitored daily from 06:00 18:00 h for seven consecutive days at 2 hourly intervals. Snail infections varied seasonally, being highest in the cool-dry season. Peak cercarial emergence was not consistent in different seasons, occurring between 08.00-10.00 h during the hot-dry season and between 12.00-14.00 h during the rainy and cool-dry seasons. The cercarial output was highest in the hot-dry season. The prevalence of infection and the emergence of cercariae were strongly dependent on snail size. CONCLUSIONS: This study shows that size of snails and environmental factors (such as season) may affect the emergence patterns of cercariae of O. viverrini in snails. These results have both fundamental and applied implications for opisthorchiasis epidemiology and control. PMID- 25442516 TI - Influence of drying method on steviol glycosides and antioxidants in Stevia rebaudiana leaves. AB - The application of different drying conditions (hot air drying at 100 degrees C and 180 degrees C, freeze drying and shade drying) on steviol glycosides (stevioside, dulcoside A, rebaudioside A and rebaudioside C) and antioxidants in Stevia leaves was evaluated. Stevioside, the major glycoside found in fresh leaves (81.2mg/g), suffered an important reduction in all cases, although shade drying was the least aggressive treatment. Considering the antioxidant parameters (total phenols, flavonoids and total antioxidants), the most suitable drying method was hot air at 180 degrees C, since it substantially increased all of them (76.8 mg gallic acid, 45.1mg catechin and 126 mg Trolox, all equivalent/g Stevia, respectively), with respect to those present in fresh leaves (44.4, 2.5 and 52.9 mg equivalent/g). Therefore, the ideal method for drying Stevia leaves depends on their final use (sweetener or antioxidant), although, hot air at 180 degrees C is the most recommendable if only one treatment has to be chosen. PMID- 25442517 TI - Optimisation of ultrasound-assisted extraction of oil from papaya seed by response surface methodology: oil recovery, radical scavenging antioxidant activity, and oxidation stability. AB - The present study aimed to investigate the effects of ultrasound-assisted extraction (UAE) condition on the yield, antioxidant activity and stability of the oil from papaya seed. The studied ultrasound variables were time, temperature, ultrasound power and solvent to sample ratio. The main goal was to optimise UAE condition providing the highest recovery of papaya seed oil with the most desirable antioxidant activity and stability. The interaction of ultrasound variables had the most and least significant effects on the antioxidant activity and stability, respectively. Ultrasound-assisted extraction provided a relatively high oil recovery (~ 73%) from papaya seed. The strongest antioxidant activity was achieved by the extraction at the elevated temperature using low solvent to sample ratio. The optimum ultrasound extraction was set at the elevated temperature (62.5 degrees C) for 38.5 min at high ultrasound power (700 W) using medium solvent to sample ratio (~ 7:1 v/w). The optimum point was practically validated. PMID- 25442518 TI - Incorporation of phenolic compounds, rutin and epicatechin, into soy protein isolate films: mechanical, barrier and cross-linking properties. AB - Edible films prepared from soy protein isolate (SPI), with and without the phenolic compounds, rutin and epicatechin, as cross linking agents, were tested for their mechanical, optical and water vapour barrier properties. The addition of rutin significantly increased puncture strength (9.3N) over SPI alone (6.4N) whereas epicatechin had no effect. Tensile strengths of SPI films with rutin and epicatechin were similar (35.1 MPa and 22.1 MPa, respectively) and significantly stronger than films without added phenolics (9.3 MPa). SPI films without phenolics showed the greatest flexibility, as measured by tensile elongation. The addition of epicatechin was found to increase water vapour permeability significantly to 2.3 g mm/m(2)h kPa from 1.7 g mm/m(2)h kPa for SPI alone whereas rutin decreased water vapour permeability to 1.2 g mm/m(2)h kPa. Films without phenolics had lower opacity values than had those with phenolics. Findings indicate that rutin and epicatechin may be used as a natural means for improving specific properties of SPI films. PMID- 25442519 TI - Nafion covered lead film electrode for the voltammetric determination of caffeine in beverage samples and pharmaceutical formulations. AB - This paper presents a sensitive, selective and low-cost voltammetric method for the determination of caffeine using a Nafion covered lead film electrode. The sensor was prepared on a glassy carbon electrode modified with lead film recovered by a Nafion layer. Caffeine was accumulated and then oxidised at the modified electrode surface to produce two anodic peaks at 0.86 and 1.40 V (vs. Ag/AgCl) in 0.1 mol L(-1) H2SO4 medium. The obtained detection limits for caffeine following 120 s of accumulation time were equal to 1.7 * 10(-8) mol L( 1) (for peak 1) and 2.2 * 10(-7) mol L(-1) (for peak 2). The method was successfully applied to determination of caffeine in tea, coffee, soft and energy drink samples as well as pharmaceutical formulation and the contents closely corresponded to those quoted by the manufacturer and those obtained by the reported spectrophotometric method. PMID- 25442520 TI - Metabolic study of enrofloxacin and metabolic profile modifications in broiler chicken tissues after drug administration. AB - In this work, the identification and distribution of the metabolites from enrofloxacin (ENR) in liver, kidney and muscle tissues from broiler chickens subjected to a pharmacological treatment was studied. In addition, qualitative analyses of changes in the metabolic profile in those tissues after drug administration were also investigated. As a result, a total of 31 different metabolites from ENR were identified, which ciprofloxacin (CIP) and desethylene ENR were the major metabolites. After four days of withdrawal period, most of the metabolites were excreted, but residues of ENR and CIP still persisted in tissues at a concentration under the permitted maximum residue limit (MRL). Non medicated, medicated and post-treatment samples of chicken tissues were clearly clustered according to their metabolite profile by principal component analysis and partial least squares discriminant analysis, which indicates that endogenous metabolites have not returned to their original levels after the withdrawal period. A total of 22 relevant mass features contributing to this separation as potential markers of chicken samples were tentatively identified. PMID- 25442521 TI - Effect of different format-solvent rosemary extracts (Rosmarinus officinalis) on frozen chicken nuggets quality. AB - Three kinds of Rosmarinus officinalis extract (powder-acetone, liquid-methanol, liquid-acetone) were used to examine the effects of format-solvent on the active compounds extracted (total phenolic, carnosol and carnosic acid content) and antioxidant activity (FRAP, ABTS). The results showed that both, as the format but also the solvent used, had significant effect on the parameters analyzed (p < 0.05). The highest antioxidant activity was found for the powder-acetone extract followed by the liquid methanol and liquid acetone extracts (p < 0.05). The effect of the three different extracts on the physical-chemical and sensory quality of frozen chicken nuggets was evaluated. At the dose proposed by the European Union Directive 2010/69/EU for the carnosic and carnosol compounds [150 ppm (mg/kg fat basic)], the format-solvent combination of the rosemary extracts used did not modify the chicken nuggets quality characteristics (pH, colour, sensory quality) and still underlines the effectiveness of these extracts. PMID- 25442522 TI - Effects of temperature and photoperiod on sensory quality and contents of glucosinolates, flavonols and vitamin C in broccoli florets. AB - Broccoli is grown around the world at a wide range of photoperiods and temperatures, which may influence both sensory quality and phytochemical contents. Florets produced in phytotron and at two semi-field sites (70 degrees N and 58 degrees N) were examined for effects of contrasting temperatures and photoperiods on sensory quality and contents of glucosinolates, flavonols and vitamin C. Growth conditions associated with high northern latitudes of low temperature and long photoperiods, produced bigger floral buds, and florets with sweeter taste and less colour hue than more southern conditions. The contents of vitamin C did not vary, while the response of individual glucosinolates varied with temperature and day length, and contents of quercetin and kaempferol were lower in phytotron than under semi-field conditions. Thus, our results show that contrasting temperatures and photoperiods influence the sensory quality of broccoli florets, while contents of different bioactive phytochemicals are not influenced in a unidirectional pattern. PMID- 25442523 TI - Photocontrolled solid-phase extraction of guanine from complex samples using a novel photoresponsive molecularly imprinted polymer. AB - A novel photoresponsive molecularly imprinted polymer (MIP) was developed for the selective extraction of guanine from complex samples. The photoresponsive MIP was fabricated using guanine as the template, water-soluble 5-[(4 (methacryloyloxy)phenyl)diazenyl]isophthalic acid as the functional monomer, and water-soluble triethanolamine trimethacrylate as the cross-linker. The MIP displayed good selectivity toward guanine with a dissociation constant of (2.70 +/- 0.16) * 10(-5) mol L(-1) in aqueous media. The density of the guanine specific receptor sites in the MIP material was (4.49 +/- 0.22)MUmol g(-1). Quantitatively release and uptake of guanine by the MIP occurred with irradiation at 365 and 440 nm, respectively. The MIP could efficiently extract guanine from beer and then release it into aqueous media under photocontrol. This method could be used for selective separation and subsequent determination of a specific analytes from complex samples. PMID- 25442524 TI - NMR metabolomics of ripened and developing oilseed rape (Brassica napus) and turnip rape (Brassica rapa). AB - The oilseeds of the commercially important oilseed rape (Brassica napus) and turnip rape (Brassica rapa) were investigated with (1)H NMR metabolomics. The compositions of ripened (cultivated in field trials) and developing seeds (cultivated in controlled conditions) were compared in multivariate models using principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA). Differences in the major lipids and the minor metabolites between the two species were found. A higher content of polyunsaturated fatty acids and sucrose were observed in turnip rape, while the overall oil content and sinapine levels were higher in oilseed rape. The genotype traits were negligible compared to the effect of the growing site and concomitant conditions on the oilseed metabolome. This study demonstrates the applicability of NMR-based analysis in determining the species, geographical origin, developmental stage, and quality of oilseed Brassicas. PMID- 25442525 TI - Anti-inflammatory and antioxidative activity of anthocyanins from purple basil leaves induced by selected abiotic elicitors. AB - This paper investigates changes in the anti-inflammatory and antioxidative activity of anthocyanins from purple basil (Ocimum basilicum L.) leaves induced by arachidonic acid (AA), jasmonic acid (JA) and beta-aminobutyric acid (BABA). The anthocyanins content was significantly increased by all elicitors used in this study; however, no increase was observed in the antioxidant activity of the analyzed extracts. Additionally, a significant decrease by about 50% in the ability to chelate Fe(II) was noted. Further, an increase in the potential anti inflammatory activity of basil anthocyanins was observed after treatment with each the abiotic elicitor. The IC50 value for lipoxygenase inhibition was almost twice as low after elicitation as that of the control. Also, cyclooxygenase inhibition by anthocyanins was stimulated by abiotic elicitors, except for JA sample. Additionally, HPLC-analysis indicated that elicitation with AA, JA and BABA caused increases in content most of all anthocyanin compounds. PMID- 25442526 TI - Natural compounds from grape by-products enhance nutritive value and reduce formation of CML in model muffins. AB - This study had the objective of determining the effects of the addition of different ingredients and grape by-products (GP) to muffins on CML content. It was found that ingredients, such as salt, baking powder and protein-rich components, reduced CML from 50% to 86%. The use of all ingredients simultaneously caused the highest reduction in CML, suggesting synergistic effects in the muffin formula. Raw cane sugar produced higher amounts of CML than refined sucrose, probably due to metal-ion mediated degradation of fructoselysine. The CML content was correlated with the level of oleic acid at 0.829 and with the level of linoleic acid at 0.913. Muffins enriched with appropriate levels of GP (20%) showed a lowering of the CML level and no significant changes in the sensory profile. GP added to the model system with protein-rich ingredients resulted in the weakest inhibitory effects, probably due to the polyphenol-protein binding mechanism. PMID- 25442527 TI - Comparative assessment of sugar and malic acid composition in cultivated and wild apples. AB - Soluble sugar and malic acid contents in mature fruits of 364 apple accessions were quantified using high-performance liquid chromatography (HPLC). Fructose and sucrose represented the major components of soluble sugars in cultivated fruits, whilst fructose and glucose were the major items of sugars in wild fruits. Wild fruits were significantly more acidic than cultivated fruits, whilst the average concentration of total sugars and sweetness index were quite similar between cultivated and wild fruits. Thus, our study suggests that fruit acidity rather than sweetness is likely to have undergone selection during apple domestication. Additionally, malic acid content was positively correlated with glucose content and negatively correlated with sucrose content. This suggests that selection of fruit acidity must have an effect on the proportion of sugar components in apple fruits. Our study provides information that could be helpful for future apple breeding. PMID- 25442528 TI - Physicochemical properties and digestibility of hydrothermally treated waxy rice starch. AB - Waxy rice starch was subjected to annealing (ANN) and heat-moisture treatment (HMT). These starches were also treated by a combination of ANN and HMT. The impact of single and dual modifications (ANN-HMT and HMT-ANN) on the molecular weight (M(w)), crystalline structure, thermal properties, and the digestibility were investigated. The relative crystallinity and short-range order on the granule surface increased on ANN, whereas decreased on HMT. All treated starches showed lower M(w) than that of the native starch. Gelatinization onset temperature, peak temperature and conclusion temperature increased for both single and dual treatments. Increased slowly digestible starch content was found on HMT and ANN-HMT. However, resistant starch levels decreased in all treated starches as compared with native starch. The results would imply that hydrothermal treatment induced structural changes in waxy rice starch significantly affected its digestibility. PMID- 25442529 TI - Validation of an Ultraviolet-visible (UV-Vis) technique for the quantitative determination of curcumin in poly(L-lactic acid) nanoparticles. AB - Curcumin is a natural yellow-orange pigment extracted from turmeric and is a potential substitute of health-dangerous artificial dyes. Nanoencapsulation in biodegradable polymers is a promising alternative to improve curcumin stability and water solubility but curcumin concentration inside the nanoparticles must be precisely known. A reliable method to determine the actual curcumin concentration must be validated since the validation procedures warrant that the method is adequate and sufficient for the specific application involved. This work describes the validation parameters given by the International Conference on Harmonisation (ICH) guidelines to adopt an analytical method based on Ultraviolet visible spectroscopy for the quantitative determination of curcumin encapsulated in poly(l-lactic acid) nanoparticles. This method was validated in respect to linearity, detection limit, quantification limit, accuracy and precision. Studies on the analytical procedure validation warranted safety in final results obtained for the curcumin concentration in the nanoparticles. PMID- 25442531 TI - In vivo degradation of alginate in the presence and in the absence of resistant starch. AB - This study evaluated the intestinal degradability of alginate during 74 days intake in pigs as models for humans. Diets contained pregelatinized starch, retrograded starch, alginate, or a mix of retrograded starch and alginate. Faeces were collected on day 1, 3, 7, 14, 39 and 74. Clear trends in intestinal alginate degradation were observed. Up to day 39, the total tract digestibility of alginate was limited (0.52 +/- 0.10), and was lower with the inclusion of retrograded starch in the diet (0.34 +/- 0.02). More than 90% of the faecal alginate was insoluble in water, which may explain the low digestibility of the alginate. The digestibility of mannuronic acid (M) was 2-3 times higher than that of guluronic acid (G). The changes of G:M ratio and the relative amounts of alginate oligosaccharides between day 39 and 74 indicated that the microbiota needed more than 39 days to adapt to alginate. This study demonstrated that in depth analyses of dietary fibres are valuable in understanding the fate of the dietary fibres in the large intestine as it was shown that degradation of a dietary fibre depends not only on the properties of the fibre itself, but also on the other dietary fibres present in the diet and the adaptation time. PMID- 25442530 TI - Integrated and comparative proteomics of high-oil and high-protein soybean seeds. AB - We analysed the global protein expression in seeds of a high-oil soybean cultivar (Jiyu 73, JY73) by proteomics. More than 700 protein spots were detected and 363 protein spots were successfully identified. Comparison of the protein profile of JY73 with that of a high-protein cultivar (Zhonghuang 13, ZH13) revealed 40 differentially expressed proteins, including oil synthesis, redox/stress, hydrolysis and storage-related proteins. All redox/stress proteins were less or not expressed in JY73, whereas the expression of the major storage proteins, nitrogen and carbon metabolism-related proteins was higher in ZH13. Biochemical analysis of JY73 revealed that it was in a low oxidation state, with a high content of polyunsaturated fatty acids and vitamin E. Vitamin E was more active than antioxidant enzymes and protected the soybean seed in a lower oxidation state. The characteristics of high oil and high protein in soybean, we revealed, might provide a reference for soybean nutrition and soybean breeding. PMID- 25442532 TI - Yeast mannoproteins improve thermal stability of anthocyanins at pH 7.0. AB - Anthocyanins are food colourants with strong antioxidant activities, but poor thermal stability limits their application in neutral foods. In the present study, impacts of yeast mannoproteins on the thermal stability of anthocyanins were studied at pH 7.0. The degradation of anthocyanins at 80 and 126 degrees C followed first order kinetics, and the addition of mannoproteins reduced the degradation rate constant and increased the half-life by 4 to 5-fold. After heating at 80 and 126 degrees C for 30 min, mannoproteins improved the colour stability of anthocyanins by 4 to 5-fold and maintained the antioxidant capacity of anthocyanins. Visible light absorption, fluorescence spectroscopy, and zeta potential results suggest that anthocyanins bound with the protein moiety of mannoproteins by hydrophobic interactions, and that the inclusion of anthocyanins in complexes effectively reduced the thermal degradation at pH 7.0. Therefore, mannoproteins may expand the application of anthocyanins as natural colours or functional ingredients. PMID- 25442533 TI - Unique variability of tocopherol composition in various seed oils recovered from by-products of apple industry: rapid and simple determination of all four homologues (alpha, beta, gamma and delta) by RP-HPLC/FLD. AB - The tocochromanol profile was studied in seed oils recovered from by-products of fruit industry, five dessert and seven crab apple varieties grown in Eastern Europe (Latvia). The seed oils obtained from dessert apples were characterized by higher contents of tocopherols (191.05-379.08 mg/100g oil) when compared to seed oils recovered from crab apples (130.55-202.54 mg/100g oil). The predominant homologues of tocopherol in all the studied samples were alpha and beta over gamma and delta. However, seed oils recovered from the apple cultivars 'Antej' and 'Beforest' had a unique profile of four tocopherol homologues (alpha:beta:gamma:delta) 91.41:80.55:72.46:79.03 and 114.55:112.84:78.69:73.00 mg/100g oil, respectively. A single dilution of seed oils in 2-propanol facilitated the direct use samples in the DPPH assay as well as injection into the RP-HPLC system containing a PFP (pentafluorophenyl) column, which resulted in a rapid separation of all four tocopherol homologues with excellent repeatability and reproducibility. PMID- 25442534 TI - Phenolic compounds in blackcurrant (Ribes nigrum L.) leaves relative to leaf position and harvest date. AB - Blackcurrant leaves are an essential source of phenolic compounds and this study investigated their variation relative to leaf positions and harvest date. The phenolic content varied between harvest dates, although leaf position on the shoot and interactions also played an important role. The contents of quercetin malonyl-glucoside, kaempferol-malonyl-glucoside isomer and kaempferol-malonyl glucoside were higher than that of the other identified phenolic compounds, whereas epigallocatechin was the lowest for all investigated leaf positions and harvest dates. The content of several of the compounds was highest in June, while quercetin-glucoside, kaempferol-glucoside and total phenols, increased towards the end of the season. Leaf position influenced the content of myricetin-malonyl glucoside, myricetin-malonyl-glucoside isomer, quercetin-malonyl-glucoside and kaempferol-glucoside at the end of the season. Knowledge relating to the influence of ontogenetic and harvest time on the content of specific phenolic compounds might contribute in tailoring functional foods or pharmaceutical products using blackcurrant leaves as natural ingredients. PMID- 25442535 TI - Interaction of ochratoxin A with quaternary ammonium beta-cyclodextrin. AB - Ochratoxin A (OTA) is a widely spread nephrotoxic food contaminant mycotoxin. Unfortunately, attenuation or prevention of the toxic effects of OTA is still an unresolved problem. Molecular inclusion of OTA by cyclodextrins (CDs) results in complexes with low stability. In the human organism, OTA exists mostly in the dianionic state (OTA(2-)). Therefore, our major goal was to develop a chemically modified cyclodextrin which gives a more stable complex with OTA than the previously published derivatives and which shows stronger preference towards OTA(2-). In our fluorescence spectroscopic study we demonstrate that quaternary ammonium beta-cyclodextrin (QABCD) fulfils both of these requirements. The calculated stability constant of the QABCD-OTA(2-) complex was 28,840 M(-1) (about 200-fold higher than that of the beta-CD-OTA(2-) complex). We hypothesize, that QABCD may be a suitable tool for the decontamination of different OTA contaminated drinks; furthermore, for alleviation of the toxic effects of OTA, such complex formation may reduce its absorption from the intestine. PMID- 25442536 TI - Synthesis of galactosyl glycerol from guar gum by transglycosylation of alpha galactosidase from Aspergillus sp. MK14. AB - A guar gum-hydrolyzing strain, Aspergillus sp. MK14, secreted alpha-galactosidase selectively in liquid culture. Its alpha-galactosidase activity (0.820 U/ml) was much higher than its beta-mannosidase and beta-mannanase activities (0.027 and 0.050 U/ml, respectively). The molecular weight was estimated to be 59,000 Da by SDS-PAGE. The optimal pH was 5 and it was active from pH 2.2 to 6.2. The optimal temperature was 60 degrees C and the activity was stable below 50 degrees C. Enzyme activity toward melibiose was much lower than that with pNP-alpha-D galactopyranoside. The activities toward 6(1)-alpha-D-galactosyl-mannobiose and 6(3),6(4)-alpha-D-galactosyl-mannopentaose were relatively high (86.2% and 48.4% relative to pNP-alpha-D-galactopyranoside, respectively). MK14 crude enzyme released only the monosaccharides, galactose and mannose (Gal/Man: 0.64) from guar gum. When glycerol was added to the reaction mixture, the transglycosylation proceeded efficiently, and the synthesis of galactosyl glycerol was 76.6 mg/g of guar gum. MK14 alpha-galactosidase could use guar gum as a good substrate (donor) in the transglycosylation. PMID- 25442537 TI - Fat-soluble vitamin intestinal absorption: absorption sites in the intestine and interactions for absorption. AB - The interactions occurring at the intestinal level between the fat-soluble vitamins A, D, E and K (FSVs) are poorly documented. We first determined each FSV absorption profile along the duodenal-colonic axis of mouse intestine to clarify their respective absorption sites. We then investigated the interactions between FSVs during their uptake by Caco-2 cells. Our data show that vitamin A was mostly absorbed in the mouse proximal intestine, while vitamin D was absorbed in the median intestine, and vitamin E and K in the distal intestine. Significant competitive interactions for uptake were then elucidated among vitamin D, E and K, supporting the hypothesis of common absorption pathways. Vitamin A also significantly decreased the uptake of the other FSVs but, conversely, its uptake was not impaired by vitamins D and K and even promoted by vitamin E. These results should be taken into account, especially for supplement formulation, to optimise FSV absorption. PMID- 25442538 TI - Magnetic stirrer induced dispersive ionic-liquid microextraction for the determination of vanadium in water and food samples prior to graphite furnace atomic absorption spectrometry. AB - A new dispersive liquid-liquid microextraction, magnetic stirrer induced dispersive ionic-liquid microextraction (MS-IL-DLLME) was developed to quantify the trace level of vanadium in real water and food samples by graphite furnace atomic absorption spectrometry (GFAAS). In this extraction method magnetic stirrer was applied to obtained a dispersive medium of 1-butyl-3 methylimidazolium hexafluorophosphate [C4MIM][PF6] in aqueous solution of (real water samples and digested food samples) to increase phase transfer ratio, which significantly enhance the recovery of vanadium - 4-(2-pyridylazo) resorcinol (PAR) chelate. Variables having vital role on desired microextraction methods were optimised to obtain the maximum recovery of study analyte. Under the optimised experimental variables, enhancement factor (EF) and limit of detection (LOD) were achieved to be 125 and 18 ng L(-1), respectively. Validity and accuracy of the desired method was checked by analysis of certified reference materials (SLRS-4 Riverine water and NIST SRM 1515 Apple leaves). The relative standard deviation (RSD) for 10 replicate determinations at 0.5 MUg L(-1) of vanadium level was found to be <5.0%. This method was successfully applied to real water and acid digested food samples. PMID- 25442539 TI - Preparative purification of polyphenols from sweet potato (Ipomoea batatas L.) leaves by AB-8 macroporous resins. AB - In this study, the adsorption properties of AB-8 macroporous resin for sweet potato leaf polyphenols was investigated. The adsorption mechanism was elaborated by the Langmuir and Freundlich equations, and the purification parameters were optimised by adsorption and desorption tests. The constituents and their contents of the purified products were analysed, and the antioxidant activities were determined. The results showed that the optimal processing parameters were as follows: an initial polyphenol concentration of 2.0mg chlorogenic acid equivalent (CAE)/ml, pH 3.0, an ethanol desorption solution concentration of 70% (v/v) and a flow rate for feeding and elution of 1BV/h. The purified products mainly contained eight phenolic constituents and the contents of three di-caffeoylquinic acids were relatively higher than the other constituents. The purified products possessed strong antioxidant activities. In conclusion, purification by AB-8 macroporous resin was highly efficient, economic and environmentally friendly and has a great industrial production potential. PMID- 25442540 TI - Anthocyanin and antioxidant activity of snacks with coloured potato. AB - Coloured-fleshed potatoes of four varieties were used as raw material for coloured flour and fried snack production. The effects of thermal processes traditionally used in dried potato processing and in snack pellet manufacturing on anthocyanin profiles, total polyphenols and antioxidant properties of obtained half- and ready products were studied. There was a significant influence of potato variety on the experimental flour and snack properties. Flours with the highest antioxidant activities were obtained from Salad Blue and Herbie 26 potatoes; however, the flour prepared from the Blue Congo exhibited a much higher total polyphenol and anthocyanin content. Snacks produced with coloured flour had 2-3 times higher antioxidant activities, 40% higher contents of polyphenols, attractive colour and better expansion compared to control samples. The lowest losses of anthocyanins during snack processing were in snacks with flour from the purple-fleshed Blue Congo and red-fleshed Herbie 26. PMID- 25442541 TI - Effect of glycosylation patterns of Chinese eggplant anthocyanins and other derivatives on antioxidant effectiveness in human colon cell lines. AB - In this study, we compared the scavenging ROS of anthocyanins from Chinese eggplant var. Niu Jiao Qie and other delphinidin derivatives with different glycosylation patterns in HT-29 and HCT-116 cell lines. The eggplant anthocyanins were isolated and identified using LC-MSn and (1)H/(13)C NMR as delphinidin-3 [(4"-trans-p-coumaroyl)-rhamnosyl (1 -> 6)glucoside]-5-glucoside, also known as nasunin. Delphinidin derivatives with glycosylation only on C3 (delphinidin-3 glucoside, 3-sambubioside, or 3-rutinoside) exhibited greater effects on ROS reduction as compared to delphinidin derivatives that have glycosylation on C3 and C5 (delphinidin-3,5-diglucoside>delphinidin-3-rutinoside-5-glucoside). Nasunin has glycosylation on C3 and C5 and an acyl group (p-coumaric acid), demonstrated the least effect on ROS reduction. Meanwhile, their ROS reduction activities were consistent with glutathione reductase protein expression levels in HT-29. Although not potent in ROS reduction, nasunin and its deacylated derivatives protected cells from DNA damage in a dose-dependent manner. Taken together, our results suggest that the anthocyanins isolated from Chinese eggplant var. Niu Jiao Qie and other delphinidin have antioxidant activities in colon cancer cells and also protect cells from DNA damage. PMID- 25442542 TI - The nutrient composition of European ready meals: protein, fat, total carbohydrates and energy. AB - Despite the increasing social importance of ready meals, only few studies have been conducted on their nutrient composition. Therefore, 32 chilled, frozen and heat-treated ready meals (only main dishes) from the continental European market were analysed for protein, fat, total carbohydrate and energy. Half of the meals were nutritionally imbalanced by providing elevated fat (>30% of energy) and low carbohydrate levels (<50% of energy). Protein was generally above recommendations and ranged from 8.0 to 47.2g per serving. The inter-package variation was high, reaching 19.04 +/- 2.90 g/package for fat. After proposing understandable guidelines to improve nutritional quality for the food industry, seven "nutritionally optimised" ready meals were created at the European level and analysed, however success was limited. If product labelling is to be useful for consumers, our results also indicate a need for better quality control to reduce the differences between content and labelling. PMID- 25442543 TI - Characterisation of novel fungal and bacterial protease preparations and evaluation of their ability to hydrolyse meat myofibrillar and connective tissue proteins. AB - The catalytic capability of four commercially available food-grade fungal and bacterial protease preparations (AFP, FPII, F60K and HT) was evaluated over a range of pH, temperature and substrate conditions using esterase and caseinolytic activity assays and time course hydrolysis over 120 and 60 min of myofibrillar and connective tissue proteins, respectively. The protease preparations displayed similar casein hydrolysis kinetics and were active in hydrolysing BODIPY-FL casein to varying extents at postmortem aging meat pH (5.0-6.0). All of the four proteases exhibited selective hydrolytic activity towards meat myofibrillar proteins including myosin and actin. Significant hydrolysis of two meat tenderisation protein markers troponin T and desmin by the four proteases was detected by western blot. The results obtained indicate that the new fungal protease preparations AFP and FPII, bacterial protease preparation HT and the new source of fungal protease preparation F60K have potential for use in meat tenderising applications. PMID- 25442544 TI - Infrared spectroscopy as a rapid tool to detect methylglyoxal and antibacterial activity in Australian honeys. AB - Methylglyoxal (2-oxopropanal) is a compound known to contribute to the non peroxide antimicrobial activity of honeys. The feasibility of using infrared spectroscopy as a predictive tool for honey antibacterial activity and methylglyoxal content was assessed. A linear relationship was found between methylglyoxal content (279-1755 mg/kg) in Leptospermum polygalifolium honeys and bacterial inhibition for Escherichiacoli (R(2) = 0.80) and Staphylococcusaureus (R(2) = 0.64). A good prediction of methylglyoxal (R(2) 0.75) content in honey was achieved using spectroscopic data from the mid infrared (MIR) range in combination with partial least squares regression. These results indicate that robust predictive equations could be developed using MIR for commercial application where the prediction of bacterial inhibition is needed to 'value' honeys with methylglyoxal contents in excess of 200mg/kg. PMID- 25442545 TI - Determination of sulphur in various vegetables by solid sampling high-resolution electrothermal molecular absorption spectrometry. AB - Sulphur was determined in various vegetables via molecular absorption of carbon monosulphide (CS) at 258.056 nm using a solid sampling high resolution continuum source electrothermal atomic absorption spectrometer (SS HR-CS ETAAS). Samples were dried, ground and directly introduced into the ruthenium coated graphite furnace as 0.05 to 0.50mg. All determinations were performed using palladium+citric acid modifier and applying a pyrolysis temperature of 1000 degrees C and a volatilisation temperature of 2400 degrees C. The results were in good agreement with certified sulphur concentrations of various vegetal CRM samples applying linear calibration technique prepared from thioacetamide. The limit of detection and characteristic mass of the method were 7.5 and 8.7 ng of S, respectively. The concentrations of S in various spinach, leek, lettuce, radish, Brussels sprouts, zucchini and chard samples were determined. It was showed that distribution of sulphur in CRM and grinded food samples were homogeneous even in micro-scale. PMID- 25442546 TI - Selenium containing conducting polymer based pyranose oxidase biosensor for glucose detection. AB - A novel amperometric pyranose oxidase (PyOx) biosensor based on a selenium containing conducting polymer has been developed for the glucose detection. For this purpose, a conducting polymer; poly(4,7-bis(thieno[3,2-b]thiophen-2 yl)benzo[c][1,2,5] selenadiazole) (poly(BSeTT)) was synthesized via electropolymerisation on gold electrode to examine its matrix property for glucose detection. For this purpose, PyOx was used as the model enzyme and immobilised via physical adsorption technique. Amperometric detection of consumed oxygen was monitored at -0.7 V vs Ag reference electrode in a phosphate buffer (50 mM, pH 7.0). K(M)(app), Imax, LOD and sensitivity were calculated as 0.229 mM, 42.37 nA, 3.3 * 10(-4)nM and 6.4 nA/mM cm(2), respectively. Scanning electron microscopy (SEM), Electrochemical Impedance Spectroscopy (EIS) and cyclic voltammetry (CV) techniques were used to monitor changes in surface morphologies and to run electrochemical characterisations. Finally, the constructed biosensor was applied for the determination of glucose in beverages successfully. PMID- 25442547 TI - Tomato waste: Carotenoids content, antioxidant and cell growth activities. AB - The carotenoid content, antioxidant and cell growth activities of tomato waste extracts, obtained from five different tomato genotypes, was investigated. High performance liquid chromatography was used to identify and quantify the main carotenoids present in tomato waste extracts. The antioxidant activity of tomato waste extracts was tested using spectrophotometric methods, 2,2-diphenyl-1 picrylhydrazyl (DPPH) free radical scavenging activity and reducing power assay. The highest DPPH scavenging activity (IC50 = 0.057 mg/ml) was obtained for Backa extract. The Knjaz extract showed the best reducing power (IC50 = 2.12 mg/ml). Cell growth effects were determined in HeLa, MCF7 and MRC-5 cell lines by sulforhodamine B test. Anti-proliferative effects were observed in all cell lines at higher concentrations (? 0.125 mg/ml). The carotenoid contents exhibited a strong correlation with antioxidant and anti-proliferation activity. The results obtained indicated that tomato waste should be regarded as potential nutraceutic resource and may be used as a functional food ingredient. PMID- 25442548 TI - Comparison of three spectrophotometric methods for analysis of egg yolk carotenoids. AB - Carotenoids accumulated in the egg yolk are of importance for two reasons. Firstly they are important pigments influencing customer acceptance and secondly they are essential components with positive health effects either as antioxidants or as precursor of vitamin A. Different analytical methods are available to quantitatively identify carotenoids from egg yolk such as spectrophotometric methods described by AOAC (Association of Official Analytical Chemists) and HPLC (High Performance Liquid Chromatography). Both methods have in common that they are time consuming, need a laboratory environment and well trained technical operators. Recently, a rapid lab-independent spectrophotometric method (iCheck, BioAnalyt GmbH, Germany) has been introduced that claims to be less time consuming and easy to operate. The aim of the current study was therefore to compare the novel method with the two standard methods. Yolks of 80 eggs were analysed as aliquots by the three methods in parallel. While both spectrometric methods are only able measure total carotenoids as total beta-carotene, HPLC enables the determination of individual carotenoids such lutein, zeaxanthin, canthaxanthin, beta-carotene and beta-apocarotenoic ester. In general, total carotenoids levels as obtained by AOAC were in average 27% higher than those obtained by HPLC. Carotenoid values obtained by the reference methods AOAC and HPLC are highly correlated with the iCheck method with r(2) of 0.99 and 0.94 for iCheck vs. AOAC and iCheck vs. HPLC, respectively (both p<0.001). Bland Altman analysis showed that the novel iCheck method is comparable to the reference methods. In conclusion, the novel rapid and portable iCheck method is a valid and effective tool to determine total carotenoid of egg yolk under laboratory independent conditions with little trained personal. PMID- 25442549 TI - Mineral profile of Spanish commercial baby food. AB - Commercial baby foods are an important part of the daily intake of babies from 6 to 12 months. The mineral profile of commercial baby foods in Spain was determined to establish levels of essential and non-essential elements, and their contribution to adequate intake (AI) and estimated average requirement (EAR). Thirty-five jars of commercial foods containing meat, fish, vegetables and fruit were obtained from the Spanish market and the mineral composition determined for 14 elements. In general, the baby foods analysed were sufficient for an adequate mineral intake, but contributions to AI and EAR for iron, zinc and calcium were very low (5-20%, 10-60% and 10-70%, respectively). This deficiency could be associated with growth problems or diseases in adulthood, and fortification of commercial products is recommended. PMID- 25442550 TI - Synergistic effect of different dietary fibres in pasta on in vitro starch digestion? AB - Pasta is traditionally manufactured using only durum wheat semolina, but it is possible to incorporate other flours or ingredients into pasta in order to increase its nutritional value to the consumer, compared to conventional pasta. For this reason, pasta was prepared substituting durum wheat semolina with 15% of enriched dietary fibre flours (Glucagel, inulin Raftiline(r) HPX, inulin Raftiline(r) GR, psyllium and oat). Moreover, all dietary fibres (excluded Glucagel) were added in combination in order to evaluate their possible antagonistic or synergic effect on predicted glycaemic response. In general, all enriched dietary fibre pasta sample showed a significant decrease (except for pasta containing a combination of 7.5% inulin Raftiline(r) GR and 7.5% oat bran flour) in reducing sugars released and standardised AUC values compared to control pasta. However, this study showed that the combination of dietary fibres in pasta formulation led to an antagonistic effect on the predicted glycaemic response. PMID- 25442551 TI - A new comprehensive index for discriminating adulteration in bovine raw milk. AB - This paper proposes a new comprehensive index, called Q, which can effectively discriminate artificial adulterated milk from unadulterated milk. Both normal and adulterated samples of bovine raw milk were analysed by Fourier transform infrared spectroscopic instrument to measure the traditional indices of quality, including fat (FAT), protein (PRO), lactose (LAC), total solids (TS), non-fat solid (NFS), freezing point (FP) and somatic cell counts (SCC). From these traditional indices, this paper elaborates a method to build the index Q. First, correlated analysis and principle component analysis were used to select parameter pairs TS-FAT and FP-LAC as predominant variables. Second, linear regression analysis and residual analysis are applied to determine the index Q and its discriminating ranges. The verification and two-blind trial results suggested that index Q could accurately detect milk adulteration with maltodextrin and water (as low as 1.0% of adulteration proportions), and with other nine kinds of synthetic adulterants (as low as 0.5% of adulteration proportions). PMID- 25442552 TI - Purification of barley dimeric alpha-amylase inhibitor-1 (BDAI-1) and avenin-like protein-a (ALP) from beer and their impact on beer foam stability. AB - Foam stability is a key factor of beer quality for consumers and brewers. Recent beer proteome analyses have suggested that barley dimeric alpha-amylase inhibitor 1 (BDAI-1) and avenin-like protein-a (ALP) derived from barley are important for beer foam stability. In this study, BDAI-1 and ALP were purified from a Japanese commercial beer sample using salt precipitation and column chromatography. The purification level was verified using two-dimensional gel electrophoresis, mass spectrometry, and database searches. Purified BDAI-1 and ALP were added to a beer sample to compare the foam stability to that of a control beer sample. As a result, beer foam stability was significantly improved by BDAI-1 but not by ALP, thereby suggesting that BDAI-1 affects beer foam stability whereas ALP does not. PMID- 25442553 TI - Modelling of pepsin digestibility of myofibrillar proteins and of variations due to heating. AB - Digestibility of myofibrillar proteins by pepsin was determined by in vitro trials and mathematical modelling. A primary model was developed to predict in vitro digestion kinetics, and a secondary model based on the mechanisms of protein denaturation was then added to take into account the effect of meat heating. Model predictions agreed with measurements in the pH and pepsin concentration ranges 1.8-3.8 and 6-50 U mg(-1) respectively. The utility of the model is illustrated by a simple example where meat is assumed to be heated homogeneously, and myofibrillar proteins to be directly in contact with pepsin. The combined effects of heating time, temperature, enzyme concentration and pH modified the digestibility value, which also depends on residence time in the stomach. PMID- 25442554 TI - Study of mango endogenous pectinases as a tool to engineer mango puree consistency. AB - The objective of this work was to evaluate the possibility of using mango endogenous pectinases to change the viscosity of mango puree. Hereto, the structure of pectic polysaccharide and the presence of sufficiently active endogenous enzymes of ripe mango were determined. Pectin of mango flesh had a high molecular weight and was highly methoxylated. Pectin methylesterase showed a negligible activity which is related to the confirmed presence of a pectin methylesterase inhibitor. Pectin contained relatively high amounts of galactose and considerable beta-galactosidase (beta-Gal) activity was observed. The possibility of stimulating beta-Gal activity during processing (temperature/pressure, time) was investigated. beta-Gal of mango was rather temperature labile but pressure stable relatively to the temperature and pressure levels used to inactivate destructive enzymes in industry. Creating processing conditions allowing endogenous beta-Gal activity did not substantially change the consistency of mango puree. PMID- 25442555 TI - Differentiation of fresh and frozen-thawed fish samples using Raman spectroscopy coupled with chemometric analysis. AB - The potential of Raman spectroscopy was investigated in terms of its capability to discriminate the species of the fish samples and determine their freshness according to the number of freezing/thawing cycles they exposed. Species discrimination analysis was carried out on sixty-four fish samples from six different species, namely horse mackerel (Trachurus trachurus), European anchovy (Engraulis encrasicolus), red mullet (Mullus surmuletus), Bluefish (Pomatamus saltatrix), Atlantic salmon (Salmo salar) and flying gurnard (Trigla lucerna). Afterwards, fish samples were exposed to different numbers of freezing/thawing cycles and separated into three batches, namely (i) fresh, (ii) once frozen thawed (OF) and (iii) twice frozen-thawed (TF) samples, in order to perform the freshness analysis. Raman data collected were used as inputs for chemometric analysis, which enabled us to develop two main PCA models to successfully terminate the studies for both species discrimination and freshness determination analysis. PMID- 25442556 TI - Mineral profile of kaki fruits (Diospyros kaki L.). AB - The main objective of this study was the determination of the mineral profile of 167 kaki fruit (Diospyros kaki L.) samples produced from different regions of Spain, including samples with the protected designation of origin (PDO) 'Kaki Ribera del Xuquer' Valencia (Spain). Samples were analysed by inductively coupled plasma optical emission spectroscopy (ICP-OES) and inductively coupled plasma mass spectrometry (ICP-MS). Consumption of one piece of kaki fruit (200-400 g) would give a mineral intake providing 1-10% of the recommended daily allowance (RDA) for calcium, 1-30% for copper and potassium, 1-15% from iron and magnesium, up to 1% of sodium, and up to 4% of zinc. ANOVA analysis indicates differences between samples from different Spanish region, thus offering a way for authentication of PDO sample origin. PMID- 25442557 TI - Fabrication, stability and efficacy of dual-component antimicrobial nanoemulsions: essential oil (thyme oil) and cationic surfactant (lauric arginate). AB - The influence of a cationic surfactant (lauric arginate, LAE) on the physical properties and antimicrobial efficacy of thyme oil nanoemulsions was investigated. Nanoemulsions prepared from pure thyme oil were highly unstable due to Ostwald ripening, but they could be stabilized by adding a ripening inhibitor (corn oil) to the oil phase prior to homogenisation. The loading capacity and antimicrobial efficacy of thyme oil nanoemulsions were significantly increased by adding LAE. In the absence of LAE, at least 60 wt% corn oil had to be added to the lipid phase to inhibit Ostwald ripening; but in the presence of 0.1 wt% LAE, only 30 wt% corn oil was needed. LAE addition substantially increased the antimicrobial efficacy of the thyme oil nanoemulsions: 200 MUg/ml thyme oil was needed to inhibit growth of a spoilage yeast (Zygosaccharomyces bailii) if LAE was added, whereas ? 400 MUg/ml was needed in the absence of LAE. PMID- 25442558 TI - High-quality Italian rice cultivars: chemical indices of ageing and aroma quality. AB - The volatile fractions of six Italian high-quality rice cultivars were investigated by HS-SPME-GC-MS to define fingerprinting and identify chemical markers and/or indices of ageing and aroma quality. In particular, four non aromatic (Carnaroli, Carnise, Cerere and Antares) and two aromatic (Apollo and Venere) rices, harvested in 2010 and 2011, were monitored over 12months. Twenty five aroma components were considered and, despite considerable inter-annual variability, some of them showed similar trends over time, including 2-(E) octenal as a marker of ageing for all cultivars, and heptanal, octanal and 2 ethyl hexanol as cultivar-specific indicators. The area ratios 2-acetyl-1 pyrroline/1-octen-3-ol, for Venere, and 3-methyl-1-butanol/2-methyl-1-butanol, for Apollo, were also found to act as ageing indices. Additional information on release of key-aroma compounds was also obtained from quantitation and its dependence on grain shape and chemical composition. Heptanal/1-octen-3-ol and heptanal/octanal ratios were also defined as characterising the aroma quality indices of the six Italian rice cultivars investigated. PMID- 25442559 TI - Practical method for the confirmation of authentic flours of different types of cereals and pseudocereals. AB - Gas chromatography with mass spectrometry was used to perform a qualitative analysis of the liposoluble flour extract of different types of cereals (bread wheat and spelt) and pseudocereals (amaranth and buckwheat). In addition to major fatty acids, the liposoluble extract also contained minor fatty acids with more than 20 carbon atoms, higher hydrocarbons and phytosterols. TMSH (trimethylsulfonium hydroxide, 0.2 mol/l in methanol) was used as a trans esterification reagent. In a trans-esterification reaction, triglycerides esterified from acilglycerols to methyl-esters. SIM (selected ion monitoring) was applied to isolate fatty acid methyl esters on TIC (total ion current) chromatograms, using the 74 Da fragment ion, which originated from McLafferty rearrangement, and is typical for methyl-esters. GC-MS system was used for the trans-esterification of triglycerides to fatty acid methyl esters in the gas chromatographic injector. This eliminated laboratory preparation for fatty acid methyl esters. Cluster analysis was applied to compare the liposoluble flour extract from different types of cereals and pseudocereals. Statistical data showed the liposoluble extract analysis enabled determination of flour origin and, because the results were unambiguous, this approach could be used for quality control. PMID- 25442560 TI - Electrochemical tomato (Solanum lycopersicum L.) characterisation using contact probe in situ voltammetry. AB - An in situ electrochemical contact probe methodology for characterising tomato samples is proposed. It is based on the record of the voltammetric response of antioxidant compounds when glassy carbon electrodes are inserted into the pericarp of fresh tomato specimens cut in half. The absence of pretreatment and in situ sampling avoid sample contamination and the oxidation of air-sensitive compounds thus increasing the representativity of the analytical data relative to conventional electrochemical analysis. Characteristic voltammetric responses recorded for such compounds, including rutin, chlorogenic acid, naringenin, naringenin chalcone and ascorbic acid have been obtained. A positive correlation between the (total phenolic compounds)/(ascorbic acid) ratio and peak intensity ratios has been found when analysing the voltammograms. This fact led us to differentiate between diverse tomato varieties and also tomatoes sample growth under different agronomic conditions and harvested at two ripeness stages. PMID- 25442561 TI - A new HPLC method for the detection of iodine applied to natural samples of edible seaweeds and commercial seaweed food products. AB - Rich in micronutrients and considered to contain high iodine levels, seaweeds have multiple applications as food/supplements and nutraceuticals with potential health implications. Here, we describe the development and validation of a new analytical method to quantify iodine as iodide (I(-)) using an isocratic HPLC system with UV detection; algal iodine was converted to I(-) via dry alkaline incineration. The method was successfully applied to 19 macroalgal species from three taxonomic groups and five commercially available seaweed food products. Fesh kelps contained highest levels, reaching >1.0% per dry weight (DW), but concentrations differed amongst thallus parts. In addition to kelps, other brown (Fucales: ~ 0.05% DW) and some red species (~ 0.05% DW) can also serve as a rich source of iodine; lowest iodine concentrations were detected in green macroalgae (~ 0.005% DW), implying that quantities recommended for seaweed consumption may require species-specific re-evaluation to reach adequate daily intake levels. PMID- 25442562 TI - Multilayer graphene-gold nanocomposite modified stem-loop DNA biosensor for peanut allergen-Ara h1 detection. AB - In this study, we developed an electrochemically-amplified, stem-loop DNA biosensor to detect the peanut allergen Ara h1. Specifically, we electrodeposited a multilayer graphene-gold nanocomposite onto a glassy carbon electrode and then immobilised a thiolated hairpin DNA-biotin probe onto the modified electrode surface. The multilayer graphene-gold composite has good dispersion ability, and can amplify the electrochemical signal due to its high electron-transfer efficiency. The probe was switched to an "off" state in the presence of target DNA. The prepared biosensor demonstrated a linear response ranging from 10(-16) to 10(-13)M, with an ultrasensitive detection limit of 0.041 fM. Moreover, the biosensor showed excellent selectivity, as well as the ability to discriminate between a complementary target and a one-base mismatch or non-complementary sequence. Results show that this prepared DNA biosensor can be successfully used to detect the peanut allergen Ara h1 in a peanut milk beverage. Findings can be applied to the prevention of allergic reactions, thus improving human health and safety. PMID- 25442563 TI - Fermentation enhances the content of bioactive compounds in kidney bean extracts. AB - The influence of solid (SSF) or liquid state fermentation (LSF) for 48 and 96 h on the production of water soluble extracts from kidney beans was investigated. SSF was carried out by Bacillus subtilis, whilst LSF was performed either by natural fermentation (NF) or by Lactobacillus plantarum strain (LPF). SSF extracts showed high soluble phenolic compound content (31-36 mg/g) and antioxidant activity (508-541 MUg trolox equivalents/g), whilst LSF extracts exhibited potential antihypertensive activity due to their large gamma aminobutyric acid (GABA) content (6.8-10.6 mg/g) and angiotensin converting enzyme inhibitory (ACEI) activity (>90%). Therefore, fermentation can be considered as a valuable process to obtain bioactive ingredients from kidney beans, which could encourage their utilisation in the formulation of added-value functional foods. PMID- 25442564 TI - Effect of lime concentration on gelatinized maize starch dispersions properties. AB - Maize starch was lime-cooked at 92 degrees C with 0.0-0.40% w/w Ca(OH)2. Optical micrographs showed that lime disrupted the integrity of insoluble remnants (ghosts) and increased the degree of syneresis of the gelatinized starch dispersions (GSD). The particle size distribution was monomodal, shifting to smaller sizes and narrower distributions with increasing lime concentration. X ray patterns and FTIR spectra showed that crystallinity decreased to a minimum at lime concentration of 0.20% w/w. Lime-treated GSD exhibited thixotropic and viscoelastic behaviour. In the linear viscoelastic region the storage modulus was higher than the loss modulus, but a crossover between these moduli occurred in the non-linear viscoelastic region. The viscoelastic properties decreased with increased lime concentration. The electrochemical properties suggested that the amylopectin-rich remnants and the released amylose contained in the continuous matrix was firstly attacked by calcium ions at low lime levels (<0.20% w/w), disrupting the starch gel microstructure. PMID- 25442565 TI - Improved bioavailability of vitamin D3 using a beta-lactoglobulin-based coagulum. AB - Vitamin D3 (D3) was encapsulated within a water-soluble matrix, formed by promoting the betalg/D3 complex by acidification. The capacity of the betalg based coagulum to increase the long term stability of D3 in cold storage, upon exposure to intensive UV-light, and in the presence and absence of intestinal proteases, was evaluated. Additionally, the impact of the sequestration of D3 within the matrix of betalg-based coagulum on its bioavailability was determined in vivo with force-fed rats. The water solubility, long-term storage and UV-light stability of D3 were significantly increased (p < 0.0001) due to the high encapsulation efficiency (94.5 +/- 1.8%). The betalg-based coagulum was not rapidly disrupted by the proteases in the intestines, leading to a slow release of D3, increased uptake of D3 and subsequent enhancement of the bioavailability of D3 in rats. PMID- 25442566 TI - RP-HPLC method using 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate incorporated with normalization technique in principal component analysis to differentiate the bovine, porcine and fish gelatins. AB - The amino acid compositions of bovine, porcine and fish gelatin were determined by amino acid analysis using 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate as derivatization reagent. Sixteen amino acids were identified with similar spectral chromatograms. Data pre-treatment via centering and transformation of data by normalization were performed to provide data that are more suitable for analysis and easier to be interpreted. Principal component analysis (PCA) transformed the original data matrix into a number of principal components (PCs). Three principal components (PCs) described 96.5% of the total variance, and 2 PCs (91%) explained the highest variances. The PCA model demonstrated the relationships among amino acids in the correlation loadings plot to the group of gelatins in the scores plot. Fish gelatin was correlated to threonine, serine and methionine on the positive side of PC1; bovine gelatin was correlated to the non-polar side chains amino acids that were proline, hydroxyproline, leucine, isoleucine and valine on the negative side of PC1 and porcine gelatin was correlated to the polar side chains amino acids that were aspartate, glutamic acid, lysine and tyrosine on the negative side of PC2. Verification on the database using 12 samples from commercial products gelatin-based had confirmed the grouping patterns and the variables correlations. Therefore, this quantitative method is very useful as a screening method to determine gelatin from various sources. PMID- 25442567 TI - Evaluation of a dual-probe real time PCR system for detection of mandarin in commercial orange juice. AB - A dual-probe real time PCR assay, based on the simultaneous detection of two TaqMan(r) probes, was evaluated for the detection of mandarin in orange juice. A single conserved polymorphism, located at the 314 position of intron belongs to chloroplast trnL gene, was confirmed by sequencing in 30 mandarin, 28 orange cultivars and 13 hybrids. The assay was also successfully evaluated in a blind trial against analysing 60 samples from different industrial processes in different countries around the world. The detection limit of the assay was established in 1% presence of mandarin detectable in processed orange juice and with a 100% precision. The quantitative application of the assay on citrus mixtures was also investigated, pointing out that the number of chloroplast DNA copies is too variable for its possible use as quantitative analysis. This assay can be employed as a routine methodology to control the accidental mixing during industrial processes and to deter intentional fraud. PMID- 25442568 TI - Vortex-assisted hollow fibre liquid-phase microextraction technique combined with high performance liquid chromatography-diode array detection for the determination of oestrogens in milk samples. AB - A rapid, simple, sensitive and environmentally friendly method has been developed for the determination of three oestrogens (17beta-estradiol (17beta-E2), estrone (E1), and diethylstilbestrol (DES)) in milk samples by using vortex-assisted hollow fibre liquid-phase microextraction (VA-HF-LPME) and high performance liquid chromatography. Method is based on the microextraction of oestrogens from sample solution into 15 MUL of nonanoic acid as extracting agent, which is placed inside the hollow fibre followed by vortex-mixing. Vortex provided effective and mild mixing of sample solution and increased the contact between analytes and boundary layers of the hollow fibre, thereby enhancing mass transfer rate and leading to high recovery of target analytes. The extraction equilibrium is achieved within 2 min. Parameters influencing the recovery were investigated and optimized. The proposed technique provided good linearity (>0.9984), repeatability (RSD = 2.56-4.38), low limits of detection (0.06-0.17 ng mL(-1)), and high enrichment factor (330). PMID- 25442569 TI - Influence of partial replacement of NaCl with KCl on profiles of volatile compounds in dry-cured bacon during processing. AB - This study investigated the influence of partial substitution of NaCl with KCl on the formation of volatile compounds in bacons during processing using a purge and trap dynamic headspace GC/MS system. Three substitutions were 0% KCl (I), 40% KCl (II), and 70% KCl (III). The profiles of the volatile compounds significantly changed during processing, particularly during the drying/ripening. At the end of process, the bacons from substitution III formed significantly higher levels of lipid-derived volatiles, such as straight chain aldehydes, hydrocarbons than bacons from substitution I and II, whereas the latter formed higher levels of volatiles from amino acid degradation such as 3-methylbutanal. There were very few differences in volatile formation between 0% and 40% KCl application. These results suggest that K(+) substitution of Na(+) by more than 40% may significantly change profiles of volatiles in finished dry-cured bacons and therefore would result in changes in the product aroma and/or flavour. PMID- 25442570 TI - Purification and identification of dipeptidyl peptidase (DPP) IV inhibitory peptides from the macroalga Palmaria palmata. AB - Dipeptidyl peptidase (DPP)-IV inhibitory peptides were purified and identified from an aqueous Palmaria palmata protein extract hydrolysed with Corolase PP. The hydrolysate was fractionated by solid phase extraction (SPE) using a C18 matrix followed by semi-preparative reverse phase-high performance liquid chromatography (SP RP-HPLC). IC50 values of 1.47 +/- 0.09, 0.54 +/- 0.03 and 0.36 +/- 0.03 mg/ml were obtained for the hydrolysate, the 25%--acetonitrile (ACN) SPE fraction and the most active SP RP-HPLC peptide fraction (SP RP-HPLC 25_F28), respectively. Thirteen peptide sequences were identified following UPLC-ESI MS/MS analysis of SP RP-HPLC 25_F28. Three novel DPP-IV inhibitory peptides, Ile-Leu-Ala-Pro, Leu Leu-Ala-Pro and Met-Ala-Gly-Val-Asp-His-Ile, with IC50 values in the range 43-159 MUM were identified. The results indicate that P. palmata derived peptides may have potential as functional food ingredients in the prevention and management of type 2 diabetes. PMID- 25442571 TI - Effect of hydrolysis time on the physicochemical and functional properties of corn glutelin by Protamex hydrolysis. AB - The physicochemical and functional properties, such as surface hydrophobicity, disulphide bond content, thermal properties, molecular weight distribution, antioxidant properties, of corn glutelin hydrolysates catalysed by Protamex at different hydrolysis times were evaluated. The hydrolysis influenced the properties of corn glutelin significantly, and not only decreased its molecular weight and disulphide bond content, but also eventually transformed its insoluble native aggregates to soluble aggregates during the hydrolysis process. Corn glutelin hydrolysates were found to have a higher solubility, which was associated with their relatively higher foaming and emulsifying properties compared to the original glutelin. Corn glutelin and its hydrolysates maintained a high thermal stability. In addition, the hydrolysates exhibited excellent antioxidant properties measured through in vitro assays, namely DPPH and OH radical scavenging activity, Fe(2+)-chelating capacity and reducing power; the values were 58.86%, 82.64%, 29.92% and 0.236% at 2.0mg/mL, respectively. PMID- 25442572 TI - Antioxidant activities of Vine Tea (Ampelopsis grossedentata) extract and its major component dihydromyricetin in soybean oil and cooked ground beef. AB - Antioxidant activities of Ampelopsis grossedentata extract (EXT) and its major component dihydromyricetin (DHM) were analysed and compared with BHA in two model systems, soybean oil and cooked ground beef. Oxidation of soybean oil samples was measured using peroxide value, anisidine value, headspace volatiles and headspace oxygen content. TBARS (thiobarbituric acid reactive substances) test was used to measure the oxidation of cooked beef. DHM was more potent than BHA in preventing soybean oil oxidation. EXT was not as effective as BHA or DHM in soybean oil. In cooked beef, all three antioxidants significantly lowered oxidation compared to control, but there were no differences between the three. Mechanisms and potentials of EXT and DHM as natural food antioxidants need to be studied on a case-by-case basis. PMID- 25442573 TI - Development of pressurised hot water extraction (PHWE) for essential compounds from Moringa oleifera leaf extracts. AB - Pressurised hot water extraction (PHWE) is a "green" technology which can be used for the extraction of essential components in Moringa oleifera leaf extracts. The behaviour of three flavonols (myricetin, quercetin and kaempferol) and total phenolic content (TPC) in Moringa leaf powder were investigated at various temperatures using PHWE. The TPC of extracts from PHWE were investigated using two indicators. These are reducing activity and the radical scavenging activity of 2,2-diphenyl-1-picrylhydrazyl (DPPH). Flavonols content in the PHWE extracts were analysed on high performance liquid chromatography with ultra violet (HPLC UV) detection. The concentration of kaempferol and myricetin started decreasing at 150 degrees C while that of quercetin remained steady with extraction temperature. Optimum extraction temperature for flavonols and DPPH radical scavenging activity was found to be 100 degrees C. The TPC increased with temperature until 150 degrees C and then decreased while the reducing activity increased. PMID- 25442574 TI - Application of PCDA/SPH/CHO/Lysine vesicles to detect pathogenic bacteria in chicken. AB - During the course of infection, Salmonella must successively survive the harsh acid stress of the stomach and multiply into a mild acidic compartment within macrophages. Inducible amino acid decarboxylases are known to promote adaptation to acidic environments, as lysine decarboxylation to cadaverine. The idea of Salmonella defenses responses could be employed in systems as polydiacetylene (PDA) to detect this pathogen so important to public health system. Beside that PDA is an important substance because of the unique optical property; that undergoes a colorimetric transitions by various external stimuli. Therefore 10,12 pentacosadyinoic acid (PCDA)/Sphingomyelin(SPH)/Cholesterol(CHO)/Lysine system was tested to determine the colorimetric response induced by Salmonella choleraesuis. PCDA/SPH/CHO/Lysine vesicles showed a colour change even in low S. choleraesuis concentration present in laboratory conditions and in chicken meat. Thus, this work showed a PCDA/SPH/CHO/Lysine vesicle application to simplify routine analyses in food industry, as chicken meat industry. PMID- 25442575 TI - Physicochemical properties of starches from diverse rice cultivars varying in apparent amylose content and gelatinisation temperature combinations. AB - The physicochemical properties of starches isolated from 14 rice cultivars produced in China were investigated. These rice starches showed a non-random combination of AAC and GT. Rice starches showed a typical A-type diffraction pattern with the degree of crystallinity ranging from 32.3% (a high AAC rice) to 45.5% (a waxy rice). AAC was significantly correlated with the pasting, thermal and textural properties. The positive correlations were found with PV, HPV, CPV, SB and HD (p<0.05), while the negative corrections were found with SP, ADH, COH, T(o), T(p), T(c) and DeltaH (p<0.05). However, AAC had no correlations with BD, PTime and percentage of retrogradation (R%). The degree of crystallinity and GT had a positive correlation with the retrogradation properties. It could be concluded that although AAC was the major factor affecting the physicochemical properties of rice starch, the retrogradation property of rice starch was mainly determined by the degree of crystallinity and GT. PMID- 25442576 TI - Antihypertensive effect of the bovine casein-derived peptide Met-Lys-Pro. AB - The antihypertensive effect of the bovine casein-derived peptide Met-Lys-Pro (MKP) was examined in vitro and in vivo. MKP showed angiotensin I-converting enzyme (ACE)-inhibitory activity in vitro (IC50 = 0.43 MUM). An in vivo kinetics study using radiolabeled Met-[1-(14)C]Lys-Pro ((14)C-MKP) showed that orally administered (14)C-MKP to spontaneously hypertensive rats (SHRs) was absorbed and moved into the plasma. In vitro vasoconstriction of thoracic aorta preparations, which was induced by adding angiotensin I, was reduced by prior exposure of MKP. A single oral dose of MKP lowered systolic blood pressure (SBP) of SHRs, and repeated oral administration of MKP for 28 days significantly lowered SBP of SHRs. The results obtained in the present study suggest that orally administrated MKP can be absorbed into the plasma and its ACE-inhibitory activity may contribute to induce the antihypertensive effect in vivo. PMID- 25442578 TI - Microextraction method of medium and long chain fatty acids from milk. AB - The aim of this research was to develop a method for microextraction and quantification of long and medium chain fatty acids from milk. The proposed method was carried out on three steps: (1) lipids extraction from 10 MUL of whole or skimmed milk containing omega-3 fatty acids (FAs) during 12, 24, 48, 72 and 96 h, in 2 mL chloroform: methanol mixture (2:1); (2) acid methylation of FAs; and (3) quantification of FAs methyl esters by gas chromatography. Using this method, the percentage recovery of FAs was higher (67% for whole and 85% for skimmed milk) compared with AOAC method 905.02 recovery (49% and 83%, respectively). Good reproducibility and repeatability (<3%) were obtained. The method developed can be useful for researching and in routine quality control. Additionally, it is simpler, faster and cheaper than the reference procedure since it requires minimum sample and solvents volume as well as fewer steps. PMID- 25442577 TI - Protein modifications in cooked pork products investigated by a proteomic approach. AB - To evaluate process-induced protein modifications in cooked ham and emulsion sausages, the proteomes of whole-cut (Parma and "Praga" cooked hams) and comminuted pork (mortadella and wurstel) products were compared to raw pork using two-dimensional gel electrophoresis (2-DE) coupled to image analysis and mass spectrometry (MS). Other than heat-induced breakdown of part of the myosin heavy chains, the 2-DE pattern of cooked ham was substantially similar to that of raw pork. However, the MS-based analysis showed minor modifications, including the extensive oxidation of methionines. In contrast, likely due to emulsification, comminuted sausages were characterized by an abundant insoluble protein fraction (IPF). Interestingly, tropomyosin and myosin light chains in comminuted sausages were exclusively found in the IPF. Our results indicate that the protein aggregation systems of cooked hams and emulsion sausages reflect the processing conditions and are definitely different, the former being characterized mainly by disulphide bridges and the latter by additional covalent inter-protein links. PMID- 25442579 TI - Brazilian fruit pulps as functional foods and additives: evaluation of bioactive compounds. AB - Eight tropical fruit pulps from Brazil were simultaneously characterised in terms of their antioxidant and antimicrobial properties. Antioxidant activity was screened by DPPH radical scavenging activity (126-3987 mg TE/100g DW) and ferric reduction activity power (368-20819 mg AAE/100g DW), and complemented with total phenolic content (329-12466 mg GAE/100g DW) and total flavonoid content measurements (46-672 mg EE /100g DW), whereas antimicrobial activity was tested against the most frequently found food pathogens. Acerola and acai presented the highest values for the antioxidant-related measurements. Direct correlations between these measurements could be observed for some of the fruits. Tamarind exhibited the broadest antimicrobial potential, having revealed growth inhibition of Pseudomonas aeruginosa. Escherichia coli, Listeria monocytogenes, Salmonella sp. and Staphylococcus aureus. Acai and tamarind extracts presented an inverse relationship between antibacterial and antioxidant activities, and therefore, the antibacterial activity cannot be attributed (only) to phenolic compounds. PMID- 25442580 TI - Simultaneous determination of 15 phenolic compounds and caffeine in teas and mate using RP-HPLC/UV detection: method development and optimization of extraction process. AB - A reversed-phase high performance liquid chromatographic coupled to ultraviolet detection (RP-HPLC/UV) method was developed for simultaneous determination of 15 phenolic compounds and caffeine in TEAS (green tea, oolong tea, black tea and mate). Furthermore, the extraction process of total phenolic contents (TPC) from TEAS were optimized using response surface methodology (RSM) based on a central composite design (CCD) and then applied to extraction of TEAS. The best conditions obtained using the model were as follow: green tea--extraction time of 123 min, extraction temperature of 70 degrees C and ethanol concentration of 75%, oolong tea--extraction time of 98 min, extraction temperature of 70 degrees C and ethanol concentration of 69%, black tea--extraction time of 105 min, extraction temperature of 71 degrees C and ethanol concentration of 63%, and mate--extraction time of 103 min, extraction temperature of 71 degrees C and ethanol concentration of 61%. Among the extraction methods used in this study, heat-reflux extraction was found to result in the highest values of TPC. The chromatographic peaks of the 16 studied compounds were successfully identified by comparing their retention time and UV spectra with the reference standards. Method validation was performed by means of linearity, sensitivity, selectivity, accuracy and precision. The developed method was found to be simple, specific and reliable and is suited for routine analysis of phenolic compounds and caffeine in TEAS. PMID- 25442581 TI - Effect of water content on the acid-base equilibrium of cyanidin-3-glucoside. AB - Laser Flash Photolysis was employed to measure the deprotonation and reprotonation rate constants of cyanidin 3-monoglucoside (kuromanin) in water/methanol mixtures. It was found that the deprotonation rate constant kd decreases with decreasing water content, reflecting the lack of free water molecules around kuromanin, which may accommodate and stabilize the outgoing protons. On the other hand, the reprotonation rate constant, kp, increases with the decrease in water concentration from a value of kp = 2 * 10(10) l mol(-1) s( 1) in water up to kp = 6 * 10(10) l mol(-1) s(-1) at 5.6M water concentration in the mixture. The higher value of kp at lower water concentrations reflects the fact that the proton is not freely escaping the solvation shell of the molecule. The deprotonation rate constant decreases with decreasing water content, reflecting the lack of free water molecules around kuromanin that can accommodate the outgoing protons. Overall, the acidity constant of the flavylium cation decreases with the decrease in water concentration from pKa values of 3.8 in water to approximately 4.8 in water-depleted media, thus shifting the equilibrium towards the red-coloured form, AH(+), at low water contents. The presence, or lack, of water, will affect the colour shade (red to blue) of kuromanin. This is relevant for its role as an intrinsic food component and as a food pigment additive (E163). PMID- 25442582 TI - Presence of galactooligosaccharides and furosine in special dairy products designed for elderly people. AB - An evaluation of the formation of prebiotic carbohydrates during lactose hydrolysis has been carried out in industrially elaborated dairy preparations designed for elderly people. Due to the hydrolysis of lactose, high levels of galactose and glucose were found together with galactooligosaccharides (GOS), mainly allolactose, 6-galactobiose and 6'-galactosyl lactose. Total GOS content was between 7.1% and 13.4% of total carbohydrates, depending on lactose hydrolysis extent. In addition, the determination of furosine as indicator of lysine loss during the Maillard reaction (MR) has been also studied. The high content of monosaccharides promoted the progress of the MR during UHT processing, as reflected by the levels of furosine found in samples. After storage at 20 degrees C for 4 months the content of furosine increased by 74-90%. These results underline the importance of controlling lactose hydrolysis, and processing and storage conditions to preserve the quality and increase the bioactivity of dairy preparations designed for elderly people. PMID- 25442583 TI - The combined impact of vineyard origin and processing winery on the elemental profile of red wines. AB - The combined effects of vineyard origin and winery processing have been studied in 65 red wines samples. Grapes originating from five different vineyards within 40 miles of each other were processed in at least two different wineries. Sixty three different elements were determined with inductively coupled-plasma mass spectrometry (ICP-MS), and wines were classified according to vineyard origin, processing winery, and the combination of both factors. Vineyard origin as well as winery processing have an impact on the elemental composition of wine, but each winery and each vineyard change the composition to a different degree. For some vineyards, wines showed a characteristic elemental pattern, independent of the processing winery, but the same was found for some wineries, with similar elemental pattern for all grapes processed in these wineries, independent of the vineyard origin. Studying the combined effects of grapegrowing and winemaking provides insight into the determination of geographical origin of red wines. PMID- 25442584 TI - Process optimization of microencapsulation of curcumin in gamma-polyglutamic acid using response surface methodology. AB - The aim of this study was to develop an optimal microencapsulation method for an oil-soluble component (curcumin) using gamma-PGA. The results show that Span80 significantly enhances the encapsulation efficiency (EE) of gamma-Na(+)-PGA microcapsules. Therefore, the effects of gamma-Na(+)-PGA, curcumin and Span80 concentration on EE of gamma-Na(+)-PGA microcapsules were studied by means of response surface methodology (RSM). It was found that the optimal microencapsulation process is achieved by using gamma-Na(+)-PGA 6.05%, curcumin 15.97% and Span80 0.61% with a high EE% (74.47 +/- 0.20%). Furthermore, the models explain 98% of the variability in the responses. gamma-Na(+)-PGA seems to be a good carrier for the encapsulation of curcumin. In conclusion, this simple and versatile approach can potentially be applied to the microencapsulation of various oil-soluble components for food applications. PMID- 25442585 TI - Effect of laboratory milling on properties of starches isolated from different flour millstreams of hard and soft wheat. AB - The properties of starch from different flour millstreams are very important for the production of specific flours used in different wheat-based food products. The present study aimed at characterising starches from different flour millstreams by Buhler laboratory mill and flour from Brabender senior mill. Damaged starch content increased from 3.4% to 15.7% and from 1.8% to 6.0% for flour from B1 to R3 millstream of Beijing 0045 and Zhongmai 175, respectively. Milling resulted in the fragmentation of starch granules, but did not induce significant changes in the relative crystallinity. Starches from different flour millstreams presented similar swelling power values. Except onset temperature of starches from Beijing 0045, no significant differences were observed in thermal transition parameters of starches from Beijing 0045 or Zhongmai 175. Pasting and in vitro digestion profiles of starches from different flour millstreams showed significant differences. This study showed that laboratory milling induces variable differences in functional properties without changing starch crystalline structure. PMID- 25442586 TI - Effect of organic acid pretreatment on some physical, functional and antioxidant properties of flour obtained from three unripe banana cultivars. AB - Unripe banana flour (UBF) obtained from organic acid pretreatment of pulp from three non-commercial cultivars were profiled for physical, functional and antioxidant properties. UBF showed marked significant differences (p<0.05) in colour (CIEL(*)a(*)b(*) and CIELCH) and water holding capacity with no significant difference in oil holding capacity. The total polyphenol content (TPC) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) differed significantly with M-red UBF recording high TPC (1130.39 +/- 27.26 mg GAE/100g d.w.) at 10 g/L citric acid pretreatment. Correlation analysis between TPC and DPPH showed very strong positive correlation for Mabonde UBF in citric and lactic acid pretreatment (r = 0.999, p < 0.01; r = 0.985, p < 0.01), while inverse correlation was recorded in M-red UBF for ascorbic and lactic acid pretreatment (r = -0.031; r = -0.137). Organic acid pretreatment enhances the physical and antioxidant properties of UBF hitherto absent in composite food formulations. PMID- 25442587 TI - Applicability of stable C and N isotope analysis in inferring the geographical origin and authentication of commercial fish (Mackerel, Yellow Croaker and Pollock). AB - Globalisation of seafood and aquaculture products and their convenient marketing worldwide, increases the possibility for the distribution of mislabelled products; thereby, underlining the need to identify their origin. Stable isotope analysis is a promising approach to identify the authenticity and traceability of seafood and aquaculture products. In this investigation, we measured carbon and nitrogen stable isotope ratios (delta(13)C and delta(15)N) of three commercial fish, viz. Mackerel, Yellow Croaker and Pollock, originating from various countries. Apart from the species-dependent variation in the isotopic values, marked differences in the delta(13)C and delta(15)N ratios were also observed with respect to the country of origin. This suggests that C and N isotopic signatures could be reliable tools to identify and trace the origin of commercial fish. PMID- 25442589 TI - Over-evaluation of total flavonoids in grape skin extracts containing sulphur dioxide. AB - Sulphur dioxide (SO2) proved to increase absorbance at 280 nm of grape skin and seed extracts containing it, diluted with ethanol-HCl to assess total flavonoids and anthocyanins in the same analysis. Additional absorbance at 280 nm was also observed in acetone:H2O extracts, if the acetone had not completely evaporated before the extracts were diluted with a solvent. Flavonoids were correctly quantified in the extracts when SO2 or acetone were removed by solid-phase extraction with a C18 RP as sorbent and methanol as eluting solvent. PMID- 25442588 TI - Quality traits analysis and protein profiling of field pea (Pisum sativum) germplasm from Himalayan region. AB - The grain and flour characteristics of different field pea (FP) accessions were evaluated. Accessions with higher grain weight had less compact structure with a greater proportion of large-sized starch granules. Accessions with higher protein content had lower starch content, blue value and lambda(max) whereas accessions with higher amylose showed higher resistant starch (RS) and final viscosity and lower rapidly digestible starch (RDS). Ca, Zn, K and Fe content vary significantly amongst different accessions and creamish green and white seeds accessions showed higher Fe and Zn content. Yellow coloured accessions (1.36 3.71%) showed lower antioxidant activity as compared to brownish and green coloured accessions (4.06-9.30%). Out of 21 major polypeptides observed (9-100 kDa), 11 showed differential trypsin inhibitory activity (TIA) under non-reducing conditions. Polypeptides of 68, 46, 33 and 22 kDa showed prominent TIA. PMID- 25442590 TI - Optimisation of ultrasonic-assisted extraction of phenolic compounds, antioxidants, and anthocyanins from sugar beet molasses. AB - Response surface methodology was used to optimise experimental conditions for ultrasonic-assisted extraction (UAE) of functional components from sugar beet molasses. The central composite design (CCD) was used for the optimisation of extraction parameters in terms of total phenolic contents, antioxidant activities and anthocyanins. Result suggested the optimal conditions obtained by RSM for UAE from sugar beet molasses were as follows: HCl concentration 1.55-1.72 mol/L, ethanol concentration 57-63% (v/v), extraction temperature 41-48 degrees C, and extraction time 66-73 min. In the optimal conditions, the experimental total phenolic contents were 17.36 mg GAE/100mL, antioxidant activity was 16.66 mg TE/g, and total anthocyanins were 31.81 mg/100g of the sugar beet molasses extract, which were well matched the predicted values. Teen compounds, i.e. gallic acid, vanillin, hydroxybenzoic acid, syringic acid, cyanidin-3-O rutinoside, cyanidin-3-O-glucoside, catechin, delphinidin-3-O-rutinoside, delphinidin-3-O-glucuronide and ferulic acid were determined by HPLC-DAD-MS/MS in sugar beet molasses. PMID- 25442591 TI - Endogenous proteolytic enzymes--a study of their impact on cod (Gadus morhua) muscle proteins and textural properties in a fermented product. AB - The aim of this study was to investigate endogenous proteolytic activities in a cod product and their impact on muscle proteins and textural properties during fermentation and storage. The result of specific proteolytic activities showed that cathepsins, especially cathepsin B, had the highest activities during fermentation and storage. SDS-PAGE indicated more degradation of myofibrillar proteins by cathepsin L than other proteases and that the hydrolysis by cathepsins was pronounced in the last stage of fermentation. Texture analysis showed that cathepsins had a negative impact on gel strength and this impact increased in the last stage of fermentation. However the product still had a firm texture. During storage (4 degrees C) for one week, no significant changes were seen in the gel strength. In conclusion, cathepsins had more impact on muscle proteins and textural properties than other proteases during fermentation but had little impact on gel strength during storage at 4 degrees C. PMID- 25442592 TI - Use of near infrared hyperspectral tools for the screening of extractable polyphenols in red grape skins. AB - Hyperspectral images of intact grapes were recorded at harvest time using a near infrared hyperspectral imaging system (900-1700 nm). Spectral data have been correlated with red grape skin extractable polyphenols (total phenolic, anthocyanins and flavanols) by modified partial least squares regression (MPLS) using a number of spectral pretreatments. The obtained results (coefficient of determination (RSQ) and standard error of prediction (SEP), respectively) for the developed models were: 0.82 and 0.92 mg g(-1) of grape skin for extractable total phenolic content, 0.79 and 0.63 mg g(-1) of grape skin for extractable anthocyanin content, 0.82 and 0.45 mg g(-1) of grape skin for extractable flavanol content. The obtained results present a good potential for a fast and reasonably inexpensive screening of the extractable polyphenolic compounds in intact grapes. Moreover, the heterogeneity of extractable polyphenols within the ripeness stage has been also evaluated using the proposed method. PMID- 25442593 TI - Evolution of phenolic compounds and sensory in bottled red wines and their co development. AB - This study aimed to assess the correspondence between the evolution of phenolic compounds and the development of appearance and mouthfeel in Cabernet Sauvignon (Vitis vinifera L. cv.) dry red wines during 18-month aging in bottle. The wines were sealed with six types of bottle stoppers. The results showed that phenolic compounds presented four evolution patterns along with wine aging in bottle, mainly depending on their chemical nature. Most of the anthocyanins had significant differences in concentration amongst the wines sealed with the six bottle stoppers at the 18-month point. Analysis of partial least squares (PLS) revealed that wine appearance quality was positively correlated with the levels of malvidin-3-O-(6-O-acetyl)-glucoside-4-vinylguaiacol, gallocatechin and dihydrokaempferol-3-O-rhamnos, while the development of mouthfeel properties was positively associated with the evolutions of malvidin-3-O-glucoside-ethyl (epi)catechin, peonidin-3-O-(6-O-acetyl)-glucoside, malvidin-3-O-(6-O-coumaryl) glucoside-pyruvic acid and peonidin-3-O-glucoside-4-vinylphenol. No obvious association was observed between the development of wine sensory characteristics and the evolution of dissolved oxygen in wine. PMID- 25442594 TI - Characterisation of phenolic compounds in processed fibres from the juice industry. AB - The content of phenolic compounds was determined in nine industrially processed fibres derived from the juice industry. Apple, peach, and pear as non-citrus fruit fibres were examined, as well as orange peel and flesh, tangerine peel and flesh, and lemon flesh as citrus fruit fibres, and carrot as vegetable fibre. The extractable phenolic profile of all fibres was obtained by UPLC-PDA-FLR-MS/MS. Forty phenolic compounds were identified and their concentrations determined. In addition, bound phenolic acids and proanthocyanidins were measured in solid residues in order to determine the phenolic compounds remaining. Also, to allow the comparison of the profiles and contents in the fresh fruit and fibres, we analysed extractable and bound phenolic compounds in lyophilized peel and pulp from fresh fruit. The profile and phenolic content of the fibres was similar to that of the fresh fruit, except for flavan-3-ols, which registered lower values. PMID- 25442595 TI - Development, validation and determination of multiclass pesticide residues in cocoa beans using gas chromatography and liquid chromatography tandem mass spectrometry. AB - An efficient and rapid method for the analysis of pesticide residues in cocoa beans using gas and liquid chromatography-tandem mass spectrometry was developed, validated and applied to imported and domestic cocoa beans samples collected over 2 years from smallholders and Malaysian ports. The method was based on solvent extraction method and covers 26 pesticides (insecticides, fungicides, and herbicides) of different chemical classes. The recoveries for all pesticides at 10 and 50 MUg/kg were in the range of 70-120% with relative standard deviations of less than 20%. Good selectivity and sensitivity were obtained with method limit of quantification of 10 MUg/kg. The expanded uncertainty measurements were in the range of 4-25%. Finally, the proposed method was successfully applied for the routine analysis of pesticide residues in cocoa beans via a monitoring study where 10% of them was found positive for chlorpyrifos, ametryn and metalaxyl. PMID- 25442596 TI - A novel reliable method of DNA extraction from olive oil suitable for molecular traceability. AB - Extra virgin olive oil production has a worldwide economic impact. The use of this brand, however, is of great concern to Institutions and private industries because of the increasing number of fraud and adulteration attempts to the market products. Here, we present a novel, reliable and not expensive method for extracting the DNA from commercial virgin and extra virgin olive oils. The DNA is stable overtime and amenable for molecular analyses; in fact, by carrying out simple sequence repeats (SSRs) markers analysis, we characterise the genetic profile of monovarietal olive oils. By comparing the oil-derived pattern with that of the corresponding tree, we can unambiguously identify four cultivars from Samnium, a region of Southern Italy, and distinguish them from reference and more widely used varieties. Through a parentage statistical analysis, we also identify the putative pollinators, establishing an unprecedented and powerful tool for olive oil traceability. PMID- 25442598 TI - Native and enzymatically modified wheat (Triticum aestivum L.) endogenous lipids in bread making: a focus on gas cell stabilization mechanisms. AB - Lipopan F and Lecitase Ultra lipases were used in straight dough bread making to study how wheat lipids affect bread loaf volume (LV) and crumb structure setting. Lipase effects on LV were dose and dough piece weight dependent. The bread quality improving mechanisms exerted by endogenous lipids were studied in terms of gluten network strengthening, which indirectly stabilizes gas cells, and in terms of direct interfacial gas cell stabilization. Unlike diacetyl tartaric esters of mono- and diacylglycerols (DATEM, used as control), lipase use did not impact dough extensibility. The effect on dough extensibility was therefore related to its lipid composition at the start of mixing. Both lipases and DATEM strongly increase the levels of polar lipids in dough liquor and their availability for and potential accumulation at gas cell interfaces. Lipases form lysolipids that emulsify other lipids. We speculate that DATEM competes with (endogenous) polar lipids for interacting with gluten proteins. PMID- 25442597 TI - Transcript profiling analysis of Rhodosporidium paludigenum-mediated signalling pathways and defense responses in mandarin orange. AB - To investigate the basis of inducible resistance response in postharvest mandarin orange, cDNA microarray and high-performance liquid chromatography were performed to study transcriptional and metabolic changes in Rhodosporidium paludigenum strain treated fruit. The microarray data mining revealed that R. paludigenum activated transcription of genes important for plant hormones, signalling transduction, stress and defensive responses in orange peel tissue. Moreover, up regulation of phenylalanine and tyrosine metabolism, phenylpropanoids biosynthesis, and alkaloid biosynthesis I, were observed at the transcription level. Conversely, large amounts of genes involved in starch metabolism, oligosaccharide and glycoside metabolism were markedly repressed by R. paludigenum treatment. Activation of phenylpropanoids biosynthesis pathway was correlated with the increasing production of phenolic acids and their subsequent metabolite lignin, indicating antifungal metabolites indeed contributed to biocontrol yeast enhanced fruit protection. Our findings provide an important basis for understanding the mechanisms of resistance induction in mandarin orange, as well as for reducing postharvest losses. PMID- 25442599 TI - An on-line HPLC-FRSD system for rapid evaluation of the total antioxidant capacity of Citrus fruits. AB - An on-line high performance liquid chromatography-free radical scavenging detection (HPLC-FRSD) system was developed for rapidly evaluating the total antioxidant capacity (TAC) of Citrus fruits. With the system, all samples can be analyzed within 5 min. The on-line HPLC-FRSD system has low limits of detection (0.001-0.010 mg mL(-1)) and quantification (0.005-0.020 mg mL(-1)), excellent recovery rate (90.44-115.72%), stability (RSD < 15.80%), reproducibility (RSD < 2%), and precision (RSD < 2%). Using a guard column instead of an analytic column, this new on-line HPLC-FRSD system performed better than the existing on line HPLC methods in the analysis of the TAC of Citrus. Compared with the conventional off-line 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3 ethylbenzthiozoline-6)-sulphonic acid (ABTS) radical scavenging methods, our newly developed system is faster and more robust. The methodology can be a good alternative for analysis TACs of Citrus fruits and potentially for other plants and plant-based products. PMID- 25442600 TI - Phenolic compounds and antioxidant properties of breeding lines between the white and black rice. AB - Advanced breeding lines made from the cross between the black and white rice as parents were collected to evaluate phenolic levels and antioxidant properties. No free phenolic acid was found in the soluble fraction, while p-coumaric acid, ferulic acid, isoferulic acid and vanillic acid were identified in insoluble bound fractions. Of noteworthy, is isoferulic acid which has rarely been reported to occur in cereal grains. Phenolic dehydrodimers were only observed in the insoluble bound fractions, which mainly consisted of 8-5'-coupled diferulic acids and 5-5'-coupled diferulic acids. Cyanidin 3-glucoside, peonidin 3-glucoside and cyanidin occurred in black and some light-purple rice samples. The breeding line YF53 has the highest total phenolic content (23.3mg ferulic acid equiv./g), total anthocyanin content (2.07 mg cyanidin-3-glu equiv./g), and antioxidant activities. The results indicate that it is possible to develop advanced breeding lines for improvement of the phenolic profiles and antioxidant capacity with high yield. PMID- 25442602 TI - Physico-chemical parameters, bioactive compounds and microbial quality of thermo sonicated carrot juice during storage. AB - Thermosonication has been successfully tested in food for microbial inactivation; however, changes in bioactive compounds and shelf-life of treated products have not been thoroughly investigated. Carrot juice was thermo-sonicated (24 kHz, 120 MUm amplitude) at 50 degrees C, 54 degrees C and 58 degrees C for 10 min (acoustic power 2204.40, 2155.72, 2181.68 mW/mL, respectively). Quality parameters and microbial growth were evaluated after processing and during storage at 4 degrees C. Control and sonicated treatments at 50 degrees C and 54 degrees C had 10, 12 and 14 d of shelf-life, respectively. Samples sonicated at 58 degrees C had the best quality; microbial growth remained low at around 3-log for mesophiles, 4.5-log for yeasts and molds and 2-log for enterobacteria after 20 d of storage. Furthermore, thermo-sonicated juice at 58 degrees C retained >98% of carotenoids and 100% of ascorbic acid. Phenolic compounds increased in all stored, treated juices. Thermo-sonication is therefore a promising technology for preserving the quality of carrot juice by minimising the physicochemical changes during storage, retarding microbial growth and retaining the bioactive compounds. PMID- 25442601 TI - Hydroxyl radical reactions and the radical scavenging activity of beta-carboline alkaloids. AB - beta-Carbolines are bioactive pyridoindole alkaloids occurring in foods, plants and the human body. Their activity as hydroxyl radical (OH) scavengers is reported here by using three different methods: deoxyribose degradation, hydroxylation of benzoate and hydroxylation of 2'-deoxyguanosine to give 8 hydroxy-2'-deoxyguanosine (8-OHdG) as assessed by RP-HPLC (MS). Fenton reactions (Fe(2+)/Fe(3+) plus H2O2) were used for OH generation, and the radical increased in the presence of ascorbic acid or 6-hydroxydopamine as pro-oxidants. beta Carbolines were scavengers of OH in the three assays and in the presence of pro oxidants. Tetrahydro-beta-carboline-3-carboxylic acids were active against the hydroxylation of 2'-deoxyguanosine. beta-Carbolines reacted with hydroxyl radicals (OH) affording hydroxy-beta-carbolines, whereas tetrahydro-beta carbolines gave oxidative and degradation products. On the basis of IC50 and reaction rates (k), beta-carbolines (norharman and harman), and tetrahydro-beta carbolines (tetrahydro-beta-carboline, 1-methyltetrahydro-beta-carboline and pinoline) were good OH radical scavengers and their activity was comparable to that of the indole, melatonin, which is an effective hydroxyl radical scavenger and antioxidant. PMID- 25442603 TI - Self-enhancement of GABA in rice bran using various stress treatments. AB - Gamma-aminobutyric acid (GABA) may be synthesized in plant tissues when the organism is under stressful conditions. Rice bran byproduct obtained from the milling of brown rice was treated under anaerobic storage with nitrogen at different temperatures (20-60 degrees C) and moisture contents (10-50%) up to 12h. For the GABA synthesis, the storage at 30% moisture content and 40 degrees C appeared optimal. Utilisation of an electrolyzed oxidizing water (EOW, pH 3.3) for moisture adjustment and addition of glutamic acid increased the GABA content in rice bran. The maximum GABA content in rice bran (523 mg/100g) could be achieved by the anaerobic storage at 30% EOW for 5h at 40 degrees C after an addition of glutamic acid (5mM). This amount was approximately 17 times higher than that in the control (30 mg/100g). The use of EOW also prevented bacterial growth by decreasing the colony counts almost by half. PMID- 25442604 TI - A novel solid phase extraction--ultra high performance liquid chromatography tandem mass spectrometry method for the quantification of ochratoxin A in red wines. AB - A novel and advanced technology on solid phase extraction column prior to liquid chromatography coupled to tandem mass spectrometry has been used for the determination of ochratoxin A in red wine samples. Due to the need of a reliable and rugged method according to current regulations and with the aim of minimize heuristic efforts associated with analytical method development, the statistical design of experiment was employed. On other hand, the method validation according to European Commission 2002/657/EC was achieved. The values obtained for decision limit (CCalpha), detection capability (CCbeta), limits of detection and quantification were 0.07 MUg L(-1), 0.14 MUg L(-1), 0.13 MUg L(-1) and 0.41 MUg L(-1), respectively. The recoveries values were ranged from 95.7% to 107.2%. These values were compatible with the 2.0 MUg L(-1) maximum allowable concentration limit established by different international regulations. PMID- 25442605 TI - Detection of honey adulteration with starch syrup by high performance liquid chromatography. AB - According to saccharide profile comparison between starch syrups and pure honeys analysed through high performance liquid chromatography (HPLC), a characteristic peak was found at 15.25 min retention time in HPLC chromatogram of syrup, but no peak was observed at the same retention time in chromatogram of pure honeys. This characteristic peak for syrup was identified as an overlapping peak of oligosaccharides with more than 5 degree of polymerisation (DP) based on HPLC chromatogram comparison between starch syrup and a series of standard mono-, di- and oligosaccharides of 3-7 DP. Additionally syrup content correlated linearly with the height of the characteristic peak of syrup under different slope in two ranges 2.5-7.5% and 10-100%, respectively. Therefore, the characteristic peak at 15.25 min retention time can serve as a syrup indicator in HPLC analysis of the adulterated honeys. This new HPLC method for honey adulteration detection was further applied in an authenticity inspection on more than 100 commercial honeys. In addition to the improved accuracy of honey adulteration detection, the proposed HPLC method was simple, low cost and easy practice for honey product quality control by government department considering the popularity of HPLC device and technology. PMID- 25442606 TI - Development of complete hydrolysis of pectins from apple pomace. AB - Enzymatically extracted pectins have a more complex structure than those obtained by conventional methods. As a result, they are less susceptible to hydrolysis, which makes the precise determination of their composition difficult. The aim of the study was to develop a method of complete hydrolysis of enzymatically extracted apple pectins. Substrates were pectins isolated from apple pomace by the use of xylanase and multicatalytic preparation Celluclast and apple pomace. Hydrolysis was performed by a chemical method with 2M TFA at 100 degrees C and 120 degrees C and a combined acidic/enzymatic method. After hydrolysis, the contents of galacturonic acid and neutral sugars were measured by HPLC. Complete hydrolysis of polygalacturonic acid occurred after 2.5h incubation with 2M TFA at 120 degrees C. The efficient hydrolysis of neutral sugars in pectins was performed with 2M TFA at 100 degrees C for 2.5h. Monomers most susceptible to concentrated acid were rhamnose, mannose and arabinose. PMID- 25442607 TI - Rapid measurement of free cyanide in liquor by ion chromatography with pulsed amperometric detection. AB - This study investigated the measurement of free cyanide in liquor by ion chromatography coupled with pulsed amperometric detection (IC-PAD). Eluent concentration, interferent evaluation and method performance were discussed. Results show that free cyanide in liquor can be rapidly determined by the optimised IC-PAD method. A sample requires only 1:100 dilution and simple filtration before being subjected to IC-PAD. The linear range is 1-5000 MUg/L with an R value of 0.9998. The detection limit is 1 MUg/L for a 25 MUL injection loop. The overall relative standard deviation (RSD) of the method is less than 5%, and the recovery range is from 98.1% to 105.0%. This study has been proven significant and may have potential applications in liquors analysis. PMID- 25442608 TI - Effect of ultrasound treatment, oil addition and storage time on lycopene stability and in vitro bioaccessibility of tomato pulp. AB - This study was performed to investigate the influence of ultrasound processing on tomato pulp containing no sunflower oil, or increasing amounts (i.e. 2.5%, 5% and 10%), on lycopene concentration and in vitro bioaccessibility at time zero and during storage at 5 degrees C. Results confirmed previous findings in that ultrasonication was responsible for cell breakage and subsequent lycopene release in a highly viscous matrix. Neither the ultrasound process nor oil addition affected lycopene concentration. A decrease of approximately 35% lycopene content occurred at storage times longer than 15 days, due to isomerisation and oxidation reactions. No differences in lycopene in vitro bioaccessibility were found between the untreated and ultrasonically treated samples; this parameter decreased as a consequence of oil addition. Losses of lycopene in vitro bioaccessibility ranging between 50% and 80% occurred in the untreated and ultrasonically treated tomato pulps with and without oil during storage, mainly due to carotenoid degradation. PMID- 25442609 TI - Fumigation with essential oils improves sensory quality and enhanced antioxidant ability of shiitake mushroom (Lentinus edodes). AB - Several naturally occurring essential oils were evaluated for their effectiveness in maintaining sensory quality and increasing antioxidant levels and activities in shiitake (Lentinus edodes) mushrooms. Freshly harvested mushrooms were fumigated with 5 MUl l(-)(1) clove, cinnamaldehyde and thyme oils at 10 degrees C for 1.5h and the antioxidant activities determined using assays of H2O2 content, O2(-) production rate, DPPH, and ABTS radical scavenging activity. The results showed that the antioxidant activities of the mushrooms fumigated with cinnamaldehyde were significantly increased when compared to the controls. Moreover, cinnamaldehyde fumigation significantly delayed losses of phenolic compounds and enhanced flavonoid content. The essential oil fumigation treatment also increased the antioxidant enzyme activities of CAT, SOD, APX and GR throughout the storage periods. All the fumigation treatments were effective in retarding mushroom sensory deterioration. These results indicate that postharvest application of essential oil fumigation can extend the shelf life and enhance the antioxidant capacity of shiitake mushrooms. PMID- 25442610 TI - Bioactive and yield potential of jelly palms (Butia odorata Barb. Rodr.). AB - In this descriptive study, Butia odorata genotypes were evaluated for yield, fruit number, pulp yield, bioactive content (including phenolic compounds, carotenoid, anthocyanin, L-ascorbic acid, and fibre content), antioxidant potential, and phenotypic characteristics. Genotype 117 was the highest yielding, with an estimated fruit yield of 22,000 kg ha(-1) and pulp yield of 12,000 kg ha( 1). On the other hand, the lowest yielding genotype, accession 49, showed an estimated fruit yield of 8400 kg ha(-1). Jelly palm fruit were generally rich in phenolic content (280.50-398.50 mg 100(-1)g), carotenoid content (2.80-4.08 mg 100 g(-1)), and L-ascorbic acid content (34.63-63.84 mg 100g(-1)). While the highest yielding genotype was not the richest in bioactive content, the lowest yielding genotype showed the highest l-ascorbic acid content. Although fruit yield and phytochemical composition are desirable attributes in jelly palm fruit, none of the genotypes evaluated showed high levels of both. Therefore, fruit yield and bioactive phytochemical content appear to be inversely proportional. PMID- 25442612 TI - Effect of solvents on the fractionation of high oleic-high stearic sunflower oil. AB - Solvent fractionation of high oleic-high stearic (HOHS) sunflower oil was studied to determine the best solvent to use (hexane or acetone) in terms of the operational parameters and properties of the final stearins. Acetone fractionation on two types of HOHS sunflower oils (N17 and N20) was carried out at temperatures from 5 to 10 degrees C using micelles with different oil/solvent ratios. Acetone was more suitable than hexane as a solvent for HSHO sunflower oil fractionation because it allowed the oil to be fractionated at higher temperatures and at lower supercooling degrees. Likewise, a sunflower soft stearin obtained by dry fractionation of HOHS sunflower oil was also used to produce high-melting point stearins by acetone or hexane fractionation. The fractionation of these stearins could be performed at higher temperatures and gave higher yields. The combination of dry and solvent fractionation to obtain tailor-made stearins is discussed. PMID- 25442611 TI - Effect of light on quality and bioactive compounds in postharvest broccoli florets. AB - The effect of light treatment (fluorescent and light-emitting diode (LED) green light) on shelf life, visual quality and bioactive compounds in broccoli florets was investigated. The results showed that light treatment extended shelf life and inhibited the decrease of H value and chlorophyll contents in broccoli florets stored at 25 degrees C. The content of total phenols and glucosinolates were markedly increased by LED green light, but no effect on sulforaphane. Fluorescent and LED green light treatment significantly increased DPPH radical scavenging activity in broccoli, but little effect was found between the two light treatments. These results indicated that LED green light could be a useful technique for extending shelf life, maintaining visual quality and preventing decrease of bioactive compounds in broccoli florets. PMID- 25442614 TI - Validation of HPLC and CE methods for determination of organic acids in sour cassava starch wastewater. AB - Fast and efficient analytical methods to determine the concentrations of lactic, acetic, propionic and butyric acids in sour cassava starch wastewater using reversed-phase high performance liquid chromatography (HPLC) and capillary electrophoresis (CE), were developed and validated. Good linearity (R(2) > 0.999) and significance with F > 25,000 for all acids was showed. The matrix effect was not detected. The coefficient of variation values indicated good repeatability. The limits of detection (LOD) ranged from 1.0 to 3.7 and 2.0 to 3.0, and the limits of quantification (LOQ) from 3.1 to 12.2, and 8.0 to 12.5mg/L for HPLC and CE, respectively. The quantification of the samples did not reveal significant differences between the methods for all compounds analyzed. However, the benefits of CE in relation to HPLC, such as lower costs and less waste generation, along with shorter analysis times, need to be taken into consideration. PMID- 25442613 TI - Enantioselective chromatography in analysis of triacylglycerols common in edible fats and oils. AB - Enantiomers of racemic triacylglycerol (TAG) mixtures were separated using two chiral HPLC columns with a sample recycling system and a UV detector. A closed system without sample derivatisation enabled separation and identification by using enantiopure reference compounds of eleven racemic TAGs with C12-C22 fatty acids with 0-2 double bonds. The prolonged separation time was compensated for by fewer pretreatment steps. Presence of one saturated and one unsaturated fatty acid in the asymmetric TAG favoured the separation. Enantiomeric resolution, at the same time with stronger retention of TAGs, increased with increasing fatty acid chain length in the sn-1(3) position. Triunsaturated TAGs containing oleic, linoleic or palmitoleic acids did not separate. The elution order of enantiomers was determined by chemoenzymatically synthesised enantiopure TAGs with a co injection method. The method is applicable to many natural fats and oils of low unsaturation level assisting advanced investigation of lipid synthesis and metabolism. PMID- 25442615 TI - Omics integrating physical techniques: aged Piedmontese meat analysis. AB - Piedmontese meat tenderness becomes higher by extending the ageing period after slaughter up to 44 days. Classical physical analysis only partially explain this evidence, so in order to discover the reason of the potential beneficial effects of prolonged ageing, we performed omic analysis in the Longissimus thoracis muscle by examining main biochemical changes through mass spectrometry-based metabolomics and proteomics. We observed a progressive decline in myofibrillar structural integrity (underpinning meat tenderness) and impaired energy metabolism. Markers of autophagic responses (e.g. serine and glutathione metabolism) and nitrogen metabolism (urea cycle intermediates) accumulated until the end of the assayed period. Key metabolites such as glutamate, a mediator of the appreciated umami taste of the meat, were found to constantly accumulate until day 44. Finally, statistical analyses revealed that glutamate, serine and arginine could serve as good predictors of ultimate meat quality parameters, even though further studies are mandatory. PMID- 25442616 TI - Chemical transformations of characteristic hop secondary metabolites in relation to beer properties and the brewing process: a review. AB - The annual production of hops (Humulus lupulus L.) exceeds 100,000 mt and is almost exclusively consumed by the brewing industry. The value of hops is attributed to their characteristic secondary metabolites; these metabolites are precursors which are transformed during the brewing process into important bittering, aromatising and preservative components with rather low efficiency. By selectively transforming these components off-line, both their utilisation efficiency and functionality can be significantly improved. Therefore, the chemical transformations of these secondary metabolites will be considered with special attention to recent advances in the field. The considered components are the hop alpha-acids, hop beta-acids and xanthohumol, which are components unique to hops, and alpha-humulene and beta-caryophyllene, sesquiterpenes which are highly characteristic of hops. PMID- 25442617 TI - In vitro digestibility and physicochemical properties of milled rice. AB - Rice is a staple diet as well as a major ingredient in many processed foods. The physicochemical and supra-molecular structure of eight rice varieties with amylose content from 9% to 19% were studied to elucidate the factors responsible for variation in enzymatic digestibility of raw and cooked rice. Parboiled rice had a digestion rate coefficient almost 4.5 times higher than the least digestible Low GI rice. The rate coefficient was found to be independent of helical structure and long range molecular order, possibly attributed to the effect of rice flour architecture. Strong swelling and pasting behaviour and lower gelatinisation temperature were linked with apparently higher in vitro digestibility but the relationship was statistically insignificant. It is concluded that the enzymatic susceptibility of rice flours are independent of supra-molecular structure and are most likely controlled by external factors not limited to particle size, presence of intact cell wall and other non-starch polymers. PMID- 25442618 TI - Nutritional quality of rice bran protein in comparison to animal and vegetable protein. AB - Rice bran protein (RBP) was prepared by alkali extraction and isoelectric precipitation from defatted rice bran. The protein quality of RPB was evaluated and compared to two vegetable proteins [soy protein (ISP) and rice endosperm protein (REP)] and two animal proteins [whey protein (WPI) and casein]. RPB contained 74.93% of protein and its pepsin digestibility and KOH solubility were 89.8% and 91.5%, respectively. In Sprague-Dawley rats, RBP showed protein efficiency ratio, net protein ratio, net protein utilisation, and biological value of 2.39, 3.77, 70.7, and 72.6, which were comparable to the qualities of animal proteins. The true digestibility of RBP (94.8%) was significantly higher than that of REP (90.8%), ISP (91.7%) and WPI (92.8%) and the same as that of casein. Protein digestibility corrected amino acid score (PDCAAS) of RBP was 0.90. These results suggest that rice bran protein appears to be a promising protein source with good biological values and digestibility. PMID- 25442619 TI - Effect of cooking on the concentration of bioactive compounds in broccoli (Brassica oleracea var. Avenger) and cauliflower (Brassica oleracea var. Alphina F1) grown in an organic system. AB - Brassica vegetables have been shown to have antioxidant capacities due to the presence of carotenoids, flavonoids and vitamins. This study evaluates the influence of different processing conditions (boiling, steaming, microwaving and sous vide) on the stability of flavonoids, carotenoids and vitamin A in broccoli and cauliflower inflorescences grown in an organic system. Results indicated that sous vide processing resulted in greater antioxidant capacity and that all processes contributed in some way to an increased content of antioxidant compounds in both cauliflower and broccoli. PMID- 25442620 TI - Antioxidant activity and phenolic profile of various morphological parts of underutilised Baccaurea angulata fruit. AB - Baccaurea angulata is an underutilised tropical fruit of Borneo Island of Malaysia. The effect of solvents was examined on yield, total phenolic (TPC), total flavonoids (TFC), total carotene content (TCC), free radical scavenging activities and lipid peroxidation inhibition activities. The results indicated that the pulp (edible portion) had the highest yield, while methanol extracts were significantly (p < 0.01) found to contain higher TPC, TFC and TCC than phosphate buffered saline (PBS) extracts for all the fruits parts. The methanol extracts also showed remarkable antiradical activity and significant lipid peroxidation inhibition activities, with their IC50 results highly comparable to that of commercial blueberry. The variations in the results among the extracts suggest different interactions, such as negative or antagonistic (interference), additive and synergistic effect interactions. The study indicated that B. angulata like other underutilised tropical fruits contained remarkable primary antioxidants. Thus, the fruit has the potential to be sources of antioxidant components. PMID- 25442621 TI - Predicting the anthocyanin content of wine grapes by NIR hyperspectral imaging. AB - The aim of this study was to demonstrate the capability of hyperspectral imaging in predicting anthocyanin content changes in wine grapes during ripening. One hundred twenty groups of Cabernet Sauvignon grapes were collected periodically after veraison. The hyperspectral images were recorded by a hyperspectral imaging system with a spectral range from 900 to 1700 nm. The anthocyanin content was measured by the pH differential method. A quantitative model was developed using partial least squares regression (PLSR) or support vector regression (SVR) for calculating the anthocyanin content. The best model was obtained using SVR, yielding a coefficient of validation (P-R(2)) of 0.9414 and a root mean square error of prediction (RMSEP) of 0.0046, higher than the PLSR model, which had a P R(2) of 0.8407 and a RMSEP of 0.0129. Therefore, hyperspectral imaging can be a fast and non-destructive method for predicting the anthocyanin content of wine grapes during ripening. PMID- 25442622 TI - A novel citrate selective electrode based on surfactant modified nano clinoptilolite. AB - A citrate-selective sensor was prepared by modification of a PVC membrane with modified nano-clinoptilolite particles by hexadecyltrimethyl ammonium surfactant (SMZ). A Nernstian slope of 29.9 +/- 0.2 mV per decade of citrate concentration was obtained over the concentration range of 5.0 * 10(-5)-5.0 * 10(-2) mol L(-1) of citrate. The electrode showed a fast response time (? 10 s) and a detection limit of 1.3 * 10(-5) mol L(-1) of citrate. The linear range and detection limit were respectively changed to 1.0 * 10(-4)-5.0 * 10(-2) mol L(-1) and 1.0 * 10(-4) mol L(-1) of citrate when the micronized clinoptilolite particles were used. PMID- 25442624 TI - Rheological and kinetic study of the ultrasonic degradation of xanthan gum in aqueous solutions. AB - The effectiveness of ultrasound to degrade the molecular weight of xanthan gum in aqueous solutions was investigated for sonication times up to 60 min at 20 degrees C and for polymer concentrations up to 0.1g/dl. The Huggins equation was found to be applicable to the intrinsic viscosity of xanthan gum prior to sonication, while a truncated form was found to be adequate for estimating the intrinsic viscosity of the degraded xanthan. To better understand the influence of salting-in and salting-out salts (classified on the basis of the Hofmeister series) on degradation, xanthan-gum solutions were pre-mixed with 0.1, 10(-2), 10(-3), or 10(-4)M NaCl or Na2SO4, prior to ultrasonication. A kinetic model was developed and successfully applied to quantify and predict the degradation rates and efficiency. The various reaction rate constants and reaction orders were found to correlate with the different salt species and concentrations used, suggesting that salting-in and salting-out salts could increase or inhibit ultrasonic degradation by adjusting the molecular conformation of the xanthan. PMID- 25442623 TI - Formation of advanced glycation endproducts in ground beef under pasteurisation conditions. AB - Advanced glycation endproducts (AGEs) in food products may pose health risks, and thermal processing of foods accelerates the formation of AGEs. The effects of heat treatments (65-100 degrees C, 0-60 min) on the formation of AGEs including N(epsilon)-carboxymethyllysine (CML) and N(epsilon)-carboxyethyllysine (CEL) in ground beef were investigated. The levels of CML and CEL in ground beef steadily increased with heating time and heating temperature. A strong linear relationship (r(2) = 0.920) between the amounts of CML (2.76-19.96 mg/kg) and CEL (2.32-11.89 mg/kg) in raw and thermally treated beef was found. The formations of both CML and CEL in ground beef during heat treatments basically fitted zero-order reactions (CML: r(2) = 0.851-0.995, rate constant = 0.031-0.224 mg kg(-1) min( 1); CEL: r(2) = 0.907-0.971, rate constant = 0.044-0.118 mg kg(-1) min(-1)) with an activation energy of 61.01 kJ/mol for CML and 29.21 kJ/mol for CEL. PMID- 25442625 TI - Critical analysis of current methods for assessing the in vitro antioxidant and antibacterial activity of plant extracts. AB - Natural product research is an active branch of science, driven by the increased value placed on individual health and well-being. Many naturally-occurring phytochemicals in plants, fruits and vegetables have been reported to exhibit antioxidant and antibacterial activity; often touted as being beneficial for human health. In vitro screening is a common practice in many research laboratories as a means of rapidly assessing these properties. However, the methods used by many are not necessarily optimal; a result of poor standardization, redundant assays and/or outdated methodology. This review primarily aims to give a better understanding in the selection of in vitro assays, with emphasis placed on some common assays such as the total phenolic content assay, free radical scavenging activity, disc-diffusion and broth microdilution. This includes a discussion on the reasons for choosing a particular assay, its strengths and weaknesses, ways to improve the accuracy of results and alternative assays. PMID- 25442626 TI - Proof of concept of using chromogenic arrays as a tool to identify blue cheese varieties. AB - A new chromogenic array for the identification and classification of blue cheeses has been developed. It is based on the response of a chromogenic array composed of five sensing materials prepared by the incorporation of pH indicators to MCM 41 and alumina. Four blue cheeses were tested: Roquefort, Blue Stilton, blue cheese with leaves and blue cheese spread. The colour modulations of the chromogenic array were processed by the principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). The statistical PCA analysis showed different responses to each cheese. PLS-DA models were developed by incorporating the data measured at diverse times, and this approach allowed us to obtain a perfect classification of all five cheeses in 5.5h. The results suggest that chromogenic arrays and optoelectronic noses can be a suitable approach to develop simple systems to classify blue cheeses and of potential use for the detection of food fraud. PMID- 25442627 TI - The major factors influencing the formation of sediments in reconstituted green tea infusion. AB - The effects of Ca(2+), caffeine and polyphenols on the formation of reversible tea sediments (RTS) and irreversible tea sediments (IRS) in green tea infusion were studied. Adding Ca(2+) (2 mmol/l) was found to increase the formation of RTS by 8% and IRS by 92%, while adding chelating ions of Na2EDTA significantly decreased the amount of RTS by 14.6%, but not the amount of IRS. Under acid conditions, Ca(2+) combined with oxalic ions to form indissoluble oxalate that is the principal constituent of IRS, despite the existence of the chelating ions. Decaffeination largely inhibited the formation of RTS (73%) and IRS (60%), even in the presence of Ca(2+). The amount of sediment could be reduced by removing polyphenols using polyvinyl-polypyrrolidone. The results suggest that sediment formation in green tea infusions can be inhibited by lowering the concentration of Ca(2+), caffeine or polyphenols. PMID- 25442628 TI - Effects of alkaline pretreatments and acid extraction conditions on the acid soluble collagen from grass carp (Ctenopharyngodon idella) skin. AB - This study investigated the effects of alkaline pretreatments and acid extraction conditions on the production of acid-soluble collagen (ASC) from grass carp skin. For alkaline pretreatment, 0.05 and 0.1M NaOH removed non-collagenous proteins without significant loss of ASC at 4, 10, 15 and 20 degrees C; while 0.2 and 0.5M NaOH caused significant loss of ASC, and 0.5M NaOH caused structural modification of ASC at 15 and 20 degrees C. For acid extraction at 4, 10, 15 and 20 degrees C, ASC was partly extracted by 0.1 and 0.2M acetic acid, while 0.5 and 1.0M acetic acid resulted in almost complete extraction. The processing conditions involving 0.05-0.1M NaOH for pretreatment, 0.5M acetic acid for extraction and 4-20 degrees C for both pretreatment and extraction, produced ASC with the structural integrity being well maintained and hence were recommended to prepare ASC from grass carp skin in practical application. PMID- 25442629 TI - Immobilisation of Fenugreek beta-amylase on chitosan/PVP blend and chitosan coated PVC beads: a comparative study. AB - A Box-Behnken design of Response Surface Methodology (RSM) was utilised for optimisation of parameters affecting immobilisation of Fenugreek beta-amylase on chitosan coated PVC (polyvinyl chloride) beads and beads made from chitosan/PVP (polyvinylpyrrolidone) blend, which resulted in 85.2% and 81% immobilisation efficiency, respectively. Immobilisation resulted in shift of pH optima while the optimum temperature remained unaffected. Enhancement in thermal stability of the enzyme was observed on conjugation with both the matrices. The immobilised enzyme appeared suitable for industrial applications due to the non-toxic nature of chosen matrices, ease of immobilisation procedure, enhanced stability and reusability with retention of 72% and 60% residual activity after 10 uses for the enzyme immobilised on chitosan coated PVC beads and on the beads of chitosan/PVP blend, respectively. PMID- 25442630 TI - Identification and quantification of glucosinolate and flavonol compounds in rocket salad (Eruca sativa, Eruca vesicaria and Diplotaxis tenuifolia) by LC-MS: highlighting the potential for improving nutritional value of rocket crops. AB - Liquid chromatography mass spectrometry (LC-MS) was used to obtain glucosinolate and flavonol content for 35 rocket accessions and commercial varieties. 13 glucosinolates and 11 flavonol compounds were identified. Semi-quantitative methods were used to estimate concentrations of both groups of compounds. Minor glucosinolate composition was found to be different between accessions; concentrations varied significantly. Flavonols showed differentiation between genera, with Diplotaxis accumulating quercetin glucosides and Eruca accumulating kaempferol glucosides. Several compounds were detected in each genus that have only previously been reported in the other. We highlight how knowledge of phytochemical content and concentration can be used to breed new, nutritionally superior varieties. We also demonstrate the effects of controlled environment conditions on the accumulations of glucosinolates and flavonols and explore the reasons for differences with previous studies. We stress the importance of consistent experimental design between research groups to effectively compare and contrast results. PMID- 25442631 TI - Phenolic profiles of 20 Canadian lentil cultivars and their contribution to antioxidant activity and inhibitory effects on alpha-glucosidase and pancreatic lipase. AB - Phenolic extracts from 20 Canadian lentil cultivars (Lens culinaris) were evaluated for total phenolic contents and composition, antioxidant activities (DPPH, FRAP, ORAC), and inhibitory properties against alpha-glucosidase and pancreatic lipase. Twenty one phenolic compounds were identified in the present study, with the majority being flavonoids, including kaempeferol glycosides, catechin/epicatechin glucosides and procyanidins. These phenolic compounds not only contributed significantly to the antioxidant activities, but they were also good inhibitors of alpha-glucosidase and lipase, two enzymes, respectively, associated with glucose and lipid digestion in the human intestine, thus contributing significantly to the control of blood glucose levels and obesity. More interestingly, it was the flavonols, not the flavanols, which showed the inhibitory activities against alpha-glucosidase and pancreatic lipase. Our result provides supporting information for developing lentil cultivars and functional foods with improved health benefits and suggests a potential role of lentil consumption in managing weight and control of blood glucose. PMID- 25442632 TI - Ultrasensitive and simultaneous determination of the isomers of Amaranth and Ponceau 4R in foods based on new carbon nanotube/polypyrrole composites. AB - In the present work, a novel strategy based on new carbon nanotube (CNT) and polypyrrole (ppy) composite modified electrode for the simultaneous determination of the isomers of Amaranth (E123) and Ponceau 4R (E124) was proposed. Due to the increasing dispersibility and effective surface area of the CNT caused by decoration of ppy to the CNT, the proposed electrode exhibited excellent electrochemical sensitivity and high selectivity toward the oxidation of Amaranth and Ponceau 4R. The linear response ranges for Amaranth and Ponceau 4R were 5.0 * 10(-9)M-5.0 * 10(-7)M, and 8 * 10(-9)M-1 * 10(-6)M and corresponding detection limits as low as 5.0 * 10(-10)M and 1.0 * 10(-9)M, respectively. This proposed method was successfully applied in the detection of Ponceau 4R and Amaranth in fruit drink samples. PMID- 25442633 TI - Fourier Transform Near-Infrared Spectroscopy for rapid and simple determination of phytic acid content in green gram seeds (Vigna radiata). AB - The feasibility of measuring phytic acid content in green gram (Vigna radiata) seeds was investigated by Fourier Transform Near-Infrared (FT-NIR) spectroscopic technique. Pure phytic acid standards of varying concentrations were scanned using FTNIR spectroscopy. The spectra were measured in diffused reflectance mode by keeping 100-1500 mg/100g standard of pure phytic acid in small sample cuvette. A calibration model was developed using pure phytic acid standards of varying concentrations in the near-infrared region (4000-12,000 cm(-1)). FT-NIR spectroscopy with chemometrics, using the first derivative plus vector normalisation method could predict the phytic acid content in green gram seeds samples. The developed model was validated using cross-validation technique. Maximum coefficient of determination (R(2)) value of 0.97 was obtained for the calibration model developed. The developed model was applied to predict phytic acid content in green gram seeds samples within 1-2 min. The developed procedure was further validated by recovery studies by comparing with UV spectroscopic method of phytic acid determination. PMID- 25442634 TI - Effect of stevia and citric acid on the stability of phenolic compounds and in vitro antioxidant and antidiabetic capacity of a roselle (Hibiscus sabdariffa L.) beverage. AB - Plant infusions are consumed due to their beneficial effects on health, which is attributed to their bioactive compounds content. However, these compounds are susceptible to degradation during processing and storage. The objective of this research was to evaluate the effect of stevia and citric acid on the stability of phenolic compounds, antioxidant capacity and carbohydrate-hydrolysing enzyme inhibitory activity of roselle beverages during storage. The optimum extraction conditions of roselle polyphenolic compounds was of 95 degrees C/60 min, which was obtained by a second order experimental design. The incorporation of stevia increased the stability of colour and some polyphenols, such as quercetin, gallic acid and rosmarinic acid, during storage. In addition, stevia decreased the loss of ABTS, DPPH scavenging activity and alpha-amylase inhibitory capacity, whereas the incorporation of citric acid showed no effect. These results may contribute to the improvement of technological processes for the elaboration of hypocaloric and functional beverages. PMID- 25442635 TI - Trans- and cis-urocanic acid, biogenic amine and amino acid contents in ikan pekasam (fermented fish) produced from Javanese carp (Puntius gonionotus) and black tilapia (Oreochromis mossambicus). AB - Ikan pekasam is a fermented fish product produced in Malaysia and is usually made from freshwater fish with ground roasted uncooked rice as the main source of carbohydrate. In this study, the amino acid, biogenic amine, and trans- and cis urocanic acid (UCA) contents of fifteen commercial samples of Ikan pekasam made from Javanese carp and black tilapia, that had undergone either natural or acid assisted fermentation, were quantified. The latter includes either tamarind (Tamarindus indica) pulp or dried slices of Garcinia atroviridis fruit in the fermentation process. Results showed that there are no significant differences in most of the biogenic amines including histamine, while there are significant differences in total UCA content, and trans- and cis-UCA contents between the two samples. Differences in the amino acid contents were largely fish-dependent. PMID- 25442636 TI - Tocochromanols and carotenoids in sorghum (Sorghum bicolor L.): diversity and stability to the heat treatment. AB - The content and stability (retention) to dry heat in a conventional oven (DHCO) and extrusion of tocochromanols and carotenoids in sorghum genotypes were evaluated. One hundred sorghum genotypes showed high variability in tocochromanol content (280.7-2962.4 MUg/100g in wet basis) and 23% of the genotypes were classified as source of vitamin E. The total carotenoid varied from 2.12 to 85.46 MUg/100g in one hundred sorghum genotypes. According to the genetic variability for carotenoids and tocochromanols, the 100 genotypes were grouped into 7 groups. The retention of the total tocochromanols and alpha-tocopherol equivalent decreased after extrusion (69.1-84.8% and 52.4-85.0%, respectively) but increased after DHCO (106.8-114.7% and 109.9-115.8%, respectively). Sorghum carotenoids were sensitive to extrusion (30.7-37.1%) and DHCO (58.6-79.2%). In conclusion, the tocochromanols profile in sorghum varied widely and the genotypes presented high genetic variability for carotenoids and tocochromanols. Sorghum was a source of tocochromanols, which increased after DHCO and decreased after extrusion. The carotenoid content in sorghum decreased after DHCO and extrusion. PMID- 25442638 TI - Comments on the recently published study: "Compositional differences in soybeans on the market: glyphosate accumulates in Roundup Ready GM soybeans", by T. Bohn, M. Cuhra, T. Traavik, M. Sanden, J. Fagan and R. Primicerio (Food Chemistry 2014, 153: 207-215). PMID- 25442637 TI - Determination of heat-induced changes in the protein secondary structure of reconstituted livetins (water-soluble proteins from hen's egg yolk) by FTIR. AB - This study characterized the impact of technological treatments on the protein secondary structure of a newly developed egg yolk livetin formulation and its components alpha-livetin, which is identical with chicken serum albumin, and gamma-livetin, the bioactive antibody immunoglobulin Y. Fourier transform infrared (FTIR) spectroscopy at 25 degrees C revealed that the largest proportion of conformal elements comprised intramolecular (native) beta-sheets (60-80%) in gamma-livetin, and alpha-helices/random coils (60.59%) in alpha livetin. In reconstituted freeze-dried livetins, the main protein conformations were also intramolecular (native) beta-sheets (55.08%) and alpha-helices/random coils (30.51%), but upon heating from 25 to 95 degrees C, the former decreased sigmoidally at the onset-of-denaturation temperature (TOD (FTIR)) of 69.5 degrees C, concomitant with a sigmoidal increase in intermolecular (denatured) beta-sheets at a TOD (FTIR) of 72.4 degrees C and a sigmoidal decrease in IgY activity at TOD (ELISA) of 67.5 degrees C. Reconstituted spray-dried livetins showed less native beta-sheets and significantly lower TOD (FTIR) values than freeze-dried livetins. PMID- 25442639 TI - Reply to letter to the editor. PMID- 25442640 TI - Molecular imaging to identify tumor recurrence following chemoradiation in a hostile surgical environment. AB - Surgical biopsy of potential tumor recurrence is a common challenge facing oncologists, surgeons, and cancer patients. Imaging modalities have limited ability to accurately detect recurrent cancer in fields affected by previous surgery, chemotherapy, or radiation. However, definitive tissue diagnosis is often needed to initiate treatment and to direct therapy. We sought to determine if a targeted fluorescent intraoperative molecular imaging technique could be applied in a clinical setting to assist a surgical biopsy in a "hostile" field. We describe the use of a folate-fluorescein conjugate to direct the biopsy of a suspected recurrent lung adenocarcinoma invading the mediastinum that had been previously treated with chemoradiation. We found that intraoperative imaging allowed the identification of small viable tumor deposits that were otherwise indistinguishable from scar and necrosis. Our operative observations were confirmed by histology, fluorescence microscopy, and immunohistochemistry. Our results demonstrate one possible application and clinical value of intraoperative molecular imaging. PMID- 25442641 TI - The influence of a triclosan toothpaste on adverse events in patients with cardiovascular disease over 5-years. AB - Adverse effects of long-term usage of triclosan-containing toothpaste in humans are currently unknown. We assessed the effect of long-term use of 0.3% triclosan toothpaste on serious adverse events (SAEs) in patients with cardiovascular disease (CVD). 438 patients with a history of stable CVD were entered into the 5 year longitudinal Cardiovascular and Periodontal Study at Prince Charles Hospital, Brisbane, Australia and randomised into test (triclosan) or placebo groups. There were no significant differences in demographics or clinical features between the groups. Patients were examined at baseline, and annually for 5-years. SAEs were classified according to the System Organ Classes defined by MedDRA (Medical Dictionary for Regulatory Activities). Results were analysed using chi square and Kaplan Meier analysis. Overall, 232 patients (123 in the triclosan group; 109 in the placebo group) experienced 569 SAEs (288 in the triclosan group and 281 in the placebo group). There was no significant difference between the groups in numbers of patients experiencing SAEs (p=0.35) or specific cardiovascular SAEs (p=0.82), nor in time to the first SAE or first cardiovascular SAE, irrespective of gender, age or BMI after adjusting for multiple comparisons (p>0.05). The adjusted odds of experiencing an SAE were estimated to increase by 2.7% for each year of age (p=0.02) and the adjusted odds of experiencing a cardiovascular SAE were estimated to increase by 5.1% for each unit increase in BMI (p=0.02). Most cardiovascular events were related to unstable angina or myocardial infarcts, 21 were associated with arrhythmia and 41 were vascular events such as aortic aneurysm and cerebrovascular accident. Within the limitations of the present study the data suggest that the use of triclosan toothpaste may not be associated with any increase in SAEs in this CVD population. The long-term impact of triclosan on hormone-related disease, such as cancer, in humans remains to be determined. PMID- 25442642 TI - Distant drivers or local signals: where do mercury trends in western Arctic belugas originate? AB - Temporal trends of contaminants are monitored in Arctic higher trophic level species to inform us on the fate, transport and risk of contaminants as well as advise on global emissions. However, monitoring mercury (Hg) trends in species such as belugas challenge us, as their tissue concentrations reflect complex interactions among Hg deposition and methylation, whale physiology, dietary exposure and foraging patterns. The Beaufort Sea beluga population showed significant increases in Hg during the 1990 s; since that time an additional 10 years of data have been collected. During this time of data collection, changes in the Arctic have affected many processes that underlie the Hg cycle. Here, we examine Hg in beluga tissues and investigate factors that could contribute to the observed trends after removing the effect of age and size on Hg concentrations and dietary factors. Finally, we examine available indicators of climate variability (Arctic Oscillation (AO), the Pacific Decadal Oscillation (PDO) and sea-ice minimum (SIM) concentration) to evaluate their potential to explain beluga Hg trends. Results reveal a decline in Hg concentrations from 2002 to 2012 in the liver of older whales and the muscle of large whales. The temporal increases in Hg in the 1990 s followed by recent declines do not follow trends in Hg emission, and are not easily explained by diet markers highlighting the complexity of feeding, food web dynamics and Hg uptake. Among the regional-scale climate variables the PDO exhibited the most significant relationship with beluga Hg at an eight year lag time. This distant signal points us to consider beluga winter feeding areas. Given that changes in climate will impact ecosystems; it is plausible that these climate variables are important in explaining beluga Hg trends. Such relationships require further investigation of the multiple connections between climate variables and beluga Hg. PMID- 25442644 TI - Arthroscopic treatment of mild to moderate deformity after slipped capital femoral epiphysis: intra-operative findings and functional outcomes. AB - PURPOSE: To identify intra-articular pathology during arthroscopic osteochondroplasty for slipped capital femoral epiphysis (SCFE)-related femoroacetabular impingement and determine functional outcomes after treatment. METHODS: Nine hips in 9 patients (6 male and 3 female patients; mean age, 17.5 years; age range, 13.5 to 26.9 years) underwent hip arthroscopy for femoroacetabular impingement after in situ pinning of the SCFE. Medical records, radiographs, and intraoperative images were reviewed to determine the severity of disease and damage to the hip joints. For all patients, we obtained the modified Harris Hip Score and Hip Outcome Score (HOS) preoperatively and at a minimum of 12 months postoperatively, as well as a Likert scale of perceived change in physical activity. RESULTS: All 9 treated patients had some degree of labral or acetabular cartilage injury at the time of arthroscopy, which was a mean of 58.6 months (range, 18 to 169 months) after in situ pinning. The alpha angle improved from 75 degrees preoperatively to 46 degrees postoperatively (P < .001). The mean follow-up period was 28.6 months (range, 12.6 to 55.6 months). The mean modified Harris Hip Score improved from 63.6 preoperatively to 91.4 postoperatively (P = .005). Similarly, the mean HOS activities-of-daily living scale improved from 70.2 to 93.3 (P = .010), and the HOS sports scale improved from 53.4 to 88.9 (P = .004). Most patients reported significant improvement on a physical-activity Likert scale, with 4 reporting much improved, 3 reporting improved, and 1 reporting slightly improved physical activity. One patient reported an unchanged activity level. No patients reported a worse activity level after surgery. CONCLUSIONS: Post-SCFE cartilage and/or labral damage develops in patients with symptomatic mild to moderate SCFE deformity, and arthroscopic treatment improved functional outcomes in a small cohort of patients at short term follow-up. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25442643 TI - Arthroscopic management of chronic unstable scaphoid nonunions: effects on restoration of carpal alignment and recovery of wrist function. AB - PURPOSE: The purpose of this study was to assess the effects of arthroscopically assisted reduction and osteosynthesis on restoration of carpal alignment and recovery of clinical wrist function in patients with unstable scaphoid nonunion. METHODS: Thirty-six patients who underwent arthroscopically assisted osteosynthesis with or without bone grafting for unstable scaphoid nonunion between July 2006 and January 2012 were enrolled. The average time from injury to surgery was 51 +/- 78.3 months. Radiographic and clinical evaluations were assessed on preoperative and postoperative days, and follow-up evaluation took place at a minimum of 24 months. RESULTS: Union was achieved in 86% (31 of 36) of patients at a mean of 11 +/- 2.7 weeks. Scaphoid axial length (SAL), lateral intrascaphoid angle (ISA), scapholunate angle (SLA), and reversed carpal height ratio (CHR) was significantly improved after surgery, and those correction ratios averaged 66% +/- 46.8%, 74% +/- 58.2%, 81% +/- 59.8%%, and 94% +/- 46%, respectively. The range of wrist motion was unchanged after surgery, but the grip strength improved from 74% +/- 22.1% preoperatively to 89% +/- 13.7% postoperatively compared with the contralateral side (P = .042). Mean Disabilities of the Arm, Shoulder, and Hand (DASH) and Patient-Related Wrist Evaluation (PRWE) scores improved significantly (P < .001) from 44 and 51 preoperatively to 13 and 23 postoperatively, respectively. The radiological parameters of the scaphoid and carpal alignment in patients who achieved bony union did not correlate with clinical wrist function. CONCLUSIONS: Arthroscopic reduction and osteosynthesis of chronic unstable scaphoid nonunion is limited for restoration of normal carpal alignment but has positive effects on the recovery of clinical wrist function. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25442646 TI - Effect of knee brace type on braking response time during automobile driving. AB - PURPOSE: To assess driving ability (brake response time [BRT]) with commonly used knee braces. METHODS: Sixty-four healthy participants (32 women and 32 men) participated in our study. BRT was assessed using a custom-made driving simulator. We assessed BRT for 5 different commonly used knee braces (right leg) used in 9 different settings: without a knee brace (control group); with a typical postoperative knee brace with adjustable range of motion (ROM) and the settings of 0 degrees to 30 degrees , 0 degrees to 60 degrees , 0 degrees to 90 degrees , and 20 degrees to 90 degrees (extension and flexion); and with an unloading knee brace for moderate to severe unicompartmental osteoarthritis, an orthosis for ligament instabilities, a knee brace for patellofemoral disorders, and an elastic knee bandage. RESULTS: The 64 participants (mean age, 33.5 years) showed significantly impaired BRT with the typical postoperative brace set at an ROM of 0 degrees to 30 degrees (673 milliseconds, P < .001), ROM of 0 degrees to 60 degrees (629 milliseconds, P < .001), ROM of 0 degrees to 90 degrees (607 milliseconds, P = .001), and ROM of 20 degrees to 90 degrees (602 milliseconds, P = .005) compared with the control group. However, no such impaired BRT was found for any other investigated knee brace. CONCLUSIONS: Right sided ROM-restricting knee braces involve significant impairment of BRT in healthy participants. No such prolonged BRT was found for a patellofemoral realignment brace, a ligament brace, a valgus/osteoarthritis brace, or an elastic knee bandage. However, our findings should be viewed in light of the limitations of the study, which are (1) the lack of a defined decrease in BRT that could lead to an accident and (2) uncertainty of whether the statistical differences are also clinically important. LEVEL OF EVIDENCE: Level II, lesser-quality randomized controlled trial. PMID- 25442645 TI - Clinical outcomes of rotator cuff repair with arthroscopic capsular release and manipulation for rotator cuff tear with stiffness: a matched-pair comparative study between patients with and without stiffness. AB - PURPOSE: To compare clinical outcomes after surgical treatment between rotator cuff tears with and without shoulder stiffness and evaluate the serial changes in pain intensity, functional scores, and range of motion (ROM). METHODS: The study comprised 26 patients with preoperative stiffness (stiff group) and 26 patients without stiffness (non-stiff group). The stiff group underwent arthroscopic or mini-open rotator cuff repair with arthroscopic capsular release and manipulation. The non-stiff group with rotator cuff repair only was matched for age and sex with the stiff group. The visual analog scale (VAS) pain score; University of California, Los Angeles (UCLA) score; American Shoulder and Elbow Surgeons (ASES) score; and ROM were evaluated preoperatively; 3, 6, and 12 months after surgery; and at final follow-up. RESULTS: Both groups had significant improvements in the VAS pain score, UCLA score, ASES score, and ROM at final follow-up. There were no significant differences between the 2 groups regarding VAS pain score, UCLA score, and ASES score at any period after surgery. In the stiff group, mean forward flexion was significantly lower than that in the non stiff group at 3 months after surgery (143.1 degrees v 154.2 degrees , P = .003). Mean external rotation and internal rotation were significantly lower than those in the non-stiff group at 3 months after surgery (37.9 degrees v 44.2 degrees , P = .043, and 15.8 v 13.9, P < .001, respectively) and 6 months after surgery (49.1 degrees v 57.3 degrees , P = .002, and 13.2 v 12.0, P = .033, respectively). CONCLUSIONS: Overall satisfactory clinical outcomes could be achieved in both the stiff and non-stiff groups, although the stiff group had slower postoperative recovery of ROM until 6 months after surgery. LEVEL OF EVIDENCE: Level III, retrospective comparative study, prognosis study. PMID- 25442647 TI - Comparison of functional gains after arthroscopic rotator cuff repair in patients over 70 years of age versus patients under 50 years of age: a prospective multicenter study. AB - PURPOSE: To assess rotator cuff rupture characteristics and evaluate healing and the functional outcome after arthroscopic repair in patients older than 70 years versus patients younger than 50 years. METHODS: We conducted a multicenter, prospective, comparative study of 40 patients younger than 50 years (group A) and 40 patients older than 70 years (group B) treated with arthroscopic rotator cuff repair. Patients older than 70 years were operated on only if symptoms persisted after 6 months of conservative treatment, whereas patients younger than 50 years were operated on regardless of any persistent symptoms. Imaging consisted of preoperative magnetic resonance imaging and postoperative ultrasound. Preoperative and postoperative function was evaluated with Constant and modified Constant scores. Patient satisfaction was also assessed. The evaluations were performed at least 1 year postoperatively. RESULTS: No patient was lost to follow up. The incidence of both supraspinatus and infraspinatus tears was greater in group B. Greater retraction in the frontal plane and greater fatty infiltration were observed in group B. The Constant score was significantly improved in both groups (51 +/- 12.32 preoperatively v 77.18 +/- 11.02 postoperatively in group A and 48.8 +/- 10.97 preoperatively v 74.6 +/- 12.02 postoperatively in group B, P < .05). The improvement was similar in both groups. The modified Constant score was also significantly improved in both groups (57.48 +/- 18.23 preoperatively v 81.35 +/- 19.75 postoperatively in group A and 63.09 +/- 14.96 preoperatively v 95.62 +/- 17.61 postoperatively in group B, P < .05). The improvement was greater for group B (P < .05). Partial rerupture of the rotator cuff occurred in 2 cases in group A and 5 cases in group B. Complete rerupture was observed in 2 patients in group B. In group A, 29 patients (72.5%) were very satisfied, 8 (20%) were satisfied, and 3 (7.5%) were less satisfied. In group B, 33 patients (82.5%) were very satisfied, 6 (15%) were satisfied, and only 1 (2.5%) was less satisfied. CONCLUSIONS: Rotator cuff tears are characterized by greater retraction in the frontal plane and greater fatty infiltration in patients older than 70 years compared with patients younger than 50 years. After arthroscopic repair, healing is greater for patients younger than 50 years. Functional gain is at least equal between the 2 groups. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25442648 TI - Effect of sagittal allograft position on coronal extrusion in lateral meniscus allograft transplantation. AB - PURPOSE: This study assessed the incidence of graft extrusion on the sagittal plane on magnetic resonance imaging (MRI) and evaluated the correlation between the sagittal position of the allograft and coronal graft extrusion. METHODS: The study involved 99 patients who underwent lateral meniscus allograft transplantation (LMAT) for knees that had undergone total meniscectomy and 50 sex and age-matched control patients who underwent MRI for evaluation of knee pain and had no intra-articular lesions. Graft extrusion and sagittal graft position parameters, including the distance from the articular cartilage center to the anterior meniscus (CAMD), the distance from the articular cartilage center to the posterior meniscus, the distance from the anterior articular cartilage margin to the anterior horn (ACMD), or the distance from the posterior articular cartilage margin to the posterior horn, were assessed on immediate postoperative MRI studies (2 days after surgery) and compared between the LMAT and control groups. In the LMAT group, correlations between graft extrusion and MRI parameters were analyzed, and multiple linear regression analysis was performed to identify predictors of graft extrusion. RESULTS: The mean CAMD and mean ACMD were significantly greater and the mean distance from the articular cartilage center to the posterior meniscus and the mean distance from the posterior articular cartilage margin to the posterior horn were significantly smaller in the LMAT group than in the normal control group (P < .001 for each). CAMD (r = 0.294, P = .015) and ACMD (r = 0.244, P = .041) correlated with relative extrusion, and CAMD (r = 0.288, P = .013) correlated with absolute extrusion. CAMD was the only predictor independently associated with both absolute (beta = 0.248, P = .013) and relative (beta = 0.244, P = .015) extrusion. CONCLUSIONS: Transplanted lateral meniscal allografts were located more anteriorly on the sagittal plane than normal lateral menisci. More anterior allograft placement correlated with a greater degree of graft extrusion on the coronal plane. LEVEL OF EVIDENCE: Level III, retrospective case-control study. PMID- 25442649 TI - Biceps muscle fatty infiltration and atrophy. A midterm review after arthroscopic tenotomy of the long head of the biceps. AB - PURPOSE: Pathology of the long head of the biceps (LHB) tendon is commonly treated by tenotomy. High levels of clinical function and patient satisfaction are reported in the short-term. The purpose of this study was to investigate the midterm effects of tenotomy on biceps fatty infiltration and atrophy in active working-age male patients. METHODS: Twenty-five men (mean age, 57 years) were evaluated at a mean follow-up of 6.7 years after tenotomy. Bilateral magnetic resonance imaging (MRI) was performed, and fatty infiltration of the biceps was assessed relative to the ipsilateral triceps. Seventeen participants had an intact contralateral LHB tendon. To assess atrophy, anterior muscle compartment volume was measured by serial cross-sectional area measurements on MRI. The tenotomized side was then compared to the healthy side in these 17 participants. Clinical scores were obtained using the QuickDASH and Oxford Elbow Score, and the occurrence of a Popeye sign and residual pain were recorded. RESULTS: Good clinical function was maintained at a mean follow-up time of 6.7 years (range, 4 to 10 years) (QuickDASH score of 7.1; standard error [SE], 1.8) and Oxford Elbow Score of 97.9 [SE 1.2]). Eleven of the 25 participants had a Popeye deformity. Four participants showed signs of fatty infiltration, and all were minor (grade 1). The mean decrease in total volume of the anterior musculature was 3.6%. In participants without a Popeye deformity, it was 3.3%, whereas it was 4.1% in participants with a Popeye sign (P = .8). CONCLUSIONS: In the midterm, LHB tenotomy in active men of working age does not result in fatty degeneration or substantial atrophy in the anterior musculature of the arm. Clinical function remains good. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25442650 TI - Arthroscopic proximal biceps tenodesis at the articular margin: evaluation of outcomes, complications, and revision rate. AB - PURPOSE: The purpose of this study was to evaluate the incidence of residual pain, outcomes, and the revision rate of arthroscopic proximal biceps tenodesis high in the groove at the articular margin of the humeral head by interference screw fixation. METHODS: Seven surgeons pooled data on patients who underwent an arthroscopic biceps tenodesis at the articular margin by interference screw fixation. All patients had a minimum of 50 weeks' follow-up. Preoperative and postoperative patient data including visual analog scale scores (obtained by all surgeons), objective shoulder scores (Simple Shoulder Test and University of California, Los Angeles scores obtained by 2 and 4 surgeons, respectively), and need for revision surgery (obtained by all surgeons) were retrospectively analyzed, the results are reported, and statistical analysis was performed. RESULTS: After the application of our exclusion criteria, 1,083 patients were included in the analysis. The mean follow-up period was 136 weeks. The overall revision surgery rate for this group was 4.1% (44 of 1,083). Revision for biceps tenodesis-related issues was needed in only 4 cases (for a biceps tenodesis related revision rate of 0.4%). Pain scores improved from 6.47 preoperatively to 1.08 postoperatively (P < .0001). University of California, Los Angeles scores improved from 14.9 preoperatively to 30.1 postoperatively (P < .0001), and Simple Shoulder Test scores improved from 2.7 preoperatively to 10.2 postoperatively (P < .0001). CONCLUSIONS: Arthroscopic biceps tenodesis performed at the articular margin results in a low surgical revision rate, a low rate of residual pain, and significant improvement in objective shoulder outcome scores. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25442651 TI - Arthroscopic debridement and capsular release for the treatment of shoulder osteoarthritis. AB - PURPOSE: The purpose of this study was to evaluate patients who underwent isolated arthroscopic debridement and capsular release without any other procedures for primary glenohumeral osteoarthritis to determine clinical and functional outcomes and time until conversion to shoulder arthroplasty. METHODS: We performed a retrospective review of 33 patients who underwent arthroscopic debridement and capsular release for shoulder osteoarthritis at our institution between 2006 and 2011. All procedures were performed by a single surgeon (K.Y.). Patients were evaluated for intraoperative arthritis grade, preoperative and postoperative range or motion, American Shoulder and Elbow Surgeons (ASES) score, pain score self-assessments, radiographic evaluation, and conversion to total shoulder arthroplasty. Clinical follow-up was on average 40.3 weeks postoperatively and telephone interview follow-up was performed at a minimum of 2 years postoperatively in all patients. RESULTS: There was an initial improvement in range of motion and pain scores; however, patients in our study returned to preoperative levels approximately 3.8 months after debridement and capsular release. Twenty patients (60.6%) reported that they were not satisfied with the outcome of the procedure. Total shoulder arthroplasty was undertaken in 14 (42.4%) patients an average of 8.8 months after arthroscopy. Among the 19 (57.6%) patients who did not go on to have total shoulder arthroplasty, ASES scores (42.2 to 50.8; P = .41) and visual analog scale pain scores (7.8 to 7.4; P = .59) were similar preoperatively and at final telephone follow-up. CONCLUSIONS: Isolated arthroscopic debridement and capsular release without any other procedures were associated with only temporary pain relief and improvement in motion. Although there are limited nonarthroplasty surgical options available for glenohumeral arthritis, isolated arthroscopic debridement and capsular release may not provide substantial benefit to justify its use in most patients. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25442652 TI - Capsular closure does not affect development of heterotopic ossification after hip arthroscopy. AB - PURPOSE: The purpose of this study was to evaluate the role of capsular closure after hip arthroscopy in reduction of the incidence of heterotopic ossification (HO). METHODS: One hundred (50 study group, 50 control group) consecutive hip arthroscopy procedures with radiographic follow-up of more than 9 weeks were included in the study. The study group consisted of 50 patients in whom capsular closure with 2 No. 1 polydioxanone (PDS) sutures was performed, and a control group consisted of 50 patients in whom the capsule remained open after capsulotomy. HO was assessed by radiographs using the Brooker classification. Statistical analysis of the data was carried out with the chi-square or Fisher exact test and Student t test, when appropriate, at a significance level of .05. RESULTS: Thirty-six (36%) patients had radiographic evidence of postoperative HO (14 patients in the capsular closure group). No significant difference was found regarding sex, side of operation, age, or HO rate between the study and the control groups (P = .778, P = .123, P = .744, and P = .144, respectively). Furthermore, no significant difference was found in the rate of HO with potential clinical significance (Brooker classification > I) between the control and study groups (P = .764). CONCLUSIONS: Capsular closure did not seem to alter the rate of HO when compared with a control group of patients in whom the capsulotomy was not repaired. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 25442654 TI - Closure of patellar tendon defect in anterior cruciate ligament reconstruction with bone-patellar tendon-bone autograft: systematic review of randomized controlled trials. AB - PURPOSE: This study aimed to systematically review the highest level of evidence on anterior cruciate ligament (ACL) reconstruction with bone-patellar tendon-bone (BPTB) autografts with patellar tendon defect closure versus no closure after surgery. METHODS: We performed a systematic review of multiple medical databases using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Level I and Level II randomized controlled trials comparing patellar tendon defect closure to no closure during ACL reconstruction with BPTB autografts were included. Two independent reviewers analyzed all studies. Descriptive statistics were calculated. Study methodological quality was analyzed using the Modified Coleman Methodology Score (MCMS) and Jadad scale. RESULTS: Four studies with a combined 221 patients (154 male patients and 67 female patients) with an average age of 26.6 +/- 2.4 years (range, 17 to 54 years) were included. All studies randomized patients before surgery into ACLR with BPTB autografts either with patellar tendon defect closure or without closure. There were no differences in clinical outcomes (Lysholm score, Tegner scale, International Knee Documentation Committee [IKDC] classification, modified Larsen score, and Lauridsen rating) between groups. There were no significant differences in knee pain between groups. All studies reported imaging findings of the patellar tendon defect, with 2 studies showing no difference in appearance between groups, one study showing excessive scar formation with defect repair, and one study showing improved restoration of normal tendon appearance with defect repair. The overall quality of the studies was poor, with all studies scoring less than 46 (average, 40.5 +/- 4.7) on the MCMS and scoring 1 on the Jadad scale. CONCLUSIONS: Based on this systematic review of 4 randomized trials, there are no statistically significant or clinically relevant differences in outcomes between patients who have the patellar tendon defect closed and those who have it left open after ACLR with BPTB autografts. The methodology of the included studies limits the interpretation of the data, as evidenced by low MCMS and Jadad scores. LEVEL OF EVIDENCE: Level II, systematic review of Level I and Level II studies. PMID- 25442653 TI - Biomechanical evaluation of an all-inside suture-based device for repairing longitudinal meniscal tears. AB - PURPOSE: A device for all-inside suture-based meniscal repairs has been introduced (NovoStitch; Ceterix, Menlo Park, CA) that passes the suture vertically through the meniscus, thereby encircling the tear, and does not require an additional incision or extra-capsular anchors. Our aim was to compare this all-inside suture-based repair with an inside-out suture repair and an all inside anchor-based repair (FasT-Fix 360 degrees ; Smith & Nephew, Andover, MA). METHODS: Longitudinal tears were created in 36 fresh-frozen porcine menisci. Repairs were performed using an all-inside suture-based meniscal repair device, an all-inside anchor-based repair, and an inside-out suture repair. They were tested with cyclic loading and load-to-failure testing. The displacement, response to cyclic loading (100, 300, and 500 cycles), and mode of failure were recorded. The stiffness of the constructs was calculated as well. RESULTS: The all-inside suture-based repairs and the inside-out repairs showed significantly higher loads to failure than the all-inside anchor-based repairs. The stiffness values for the 3 repairs were not different. There were no differences in initial displacement. After 100, 300, and 500 cycles, the inside-out repair had higher gap formation (displacement) than the other 2 groups. Suture failure was the predominant mode of failure across all repair techniques. CONCLUSIONS: The all inside suture-based repairs and inside-out repairs did not exhibit different load to-failure values. In addition, the all-inside suture-based repairs and the all inside anchor-based repairs did not exhibit different displacement values during cyclic loading. CLINICAL RELEVANCE: When addressing a longitudinal meniscal tear, surgeons should consider biomechanical data of various repair devices and techniques in their decision-making process to maximize the mechanical strength and healing probability of the repair. PMID- 25442655 TI - Smoking and unstable hinge fractures cause delayed gap filling irrespective of early weight bearing after open wedge osteotomy. AB - PURPOSE: The purpose of this study was to examine the osteotomy gap filling rate with new bone after open wedge high tibial osteotomy (HTO) without bone graft and the effects of smoking, lateral hinge fracture, and early full weight bearing. METHODS: A prospective series (N = 70) of open wedge HTOs with the TomoFix plate (DePuy Synthes, Umkirch, Germany) was performed. Radiologic follow-up examinations took place postoperatively, after 6 and 12 weeks, and after 6, 12, and 18 months to measure osteotomy gap filling at each follow-up. Bone healing was compared in smokers versus nonsmokers who underwent open wedge HTOs with intact lateral hinges. Fractured lateral hinges were classified according to the Takeuchi classification and separately analyzed regarding bone healing. Patients were randomly assigned to undergo early (11 days) or standard (6 weeks) full weight-bearing rehabilitation. RESULTS: A delay in the osteotomy gap filling rate between smokers and nonsmokers could be observed at all follow-up periods, but differences were not significant. A fracture of the lateral hinge was found in 39% of the patients. A type I fracture was observed in 14% of patients, a type II fracture was observed in 13%, and a type III fracture was found in 6%. The highest increase in the osteotomy gap filling rate was observed between 12 weeks and 6 months after surgery in patients with intact lateral hinges. For patients with unstable type II fractures, the highest increase in the gap filling rate was delayed until 6 to 12 months. Early full weight bearing had no effect on the gap filling rate in any of the patient groups evaluated. CONCLUSIONS: This study shows that osteotomy gap filling after open wedge HTO is delayed in smokers and in patients in whom opening of the gap resulted in unstable lateral hinge fractures. Early full weight bearing did not have a significant effect on the gap filling rate. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 25442656 TI - Quantification of the learning curve for arthroscopic suprascapular nerve decompression: an evaluation of 300 cases. AB - PURPOSE: This study aimed to quantify the learning curve for arthroscopic suprascapular nerve decompression (SSND) using the log-linear model. METHODS: Three hundred consecutive patients underwent arthroscopic SSND by release of the transverse scapular ligament at the suprascapular notch by a single surgeon. Cases with a bony suprascapular nerve foramen were excluded. The arthroscopic SSND time was defined as the time from the beginning of shaving the soft tissue medial to the acromioclavicular joint until the completion of the transverse scapular ligament release. Regression analysis was applied to predict the time required for SSND on the basis of the cumulative case volume after logarithmic transformation of both statistics. RESULTS: The mean SSND time decreased from the first 50 cases (mean, 29.5 minutes) to the last 50 cases (mean, 6.2 minutes). The estimated SSND times of the first and last 50 cases were 25.1 minutes and 5.5 minutes, respectively. A significant linear correlation was observed between the SSND time and the cumulative volume of cases after logarithmic transformation (r(2) = 0.481, P < .01), and the best-fit linear equation was calculated as log y = -0.52 log x + 4.6, where y represents the estimated SSND time and x represents the cumulative volume of cases, resulting in an estimated learning rate of 69.7% (which equals 2(-0.52)). CONCLUSIONS: This study presents the overall time reduction in arthroscopic SSND in support of a learning-curve effect. Furthermore, this study quantifies the learning rate, estimated as approximately 70%, indicating that the time required for arthroscopic SSND can decrease by up to 30% when the cumulative volume of cases doubles. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 25442657 TI - Outcomes of hip arthroscopy in patients aged 50 years or older compared with a matched-pair control of patients aged 30 years or younger. AB - PURPOSE: Age has been suggested as a negative prognostic factor for hip arthroscopy. The purpose of this study was to compare patient characteristics and outcomes after hip arthroscopy in patients aged 50 years or older with a matched control group of patients aged 30 years or younger at a minimum postoperative follow-up of 2 years. METHODS: Between September 2008 and March 2010, data were prospectively collected on all patients aged 50 years or older undergoing primary hip arthroscopy. Fifty-two patients met our inclusion and matching criteria, of whom all 52 (100%) were available for follow-up at a minimum of 2 years. This cohort was compared with a matched-pair control group of patients aged 30 years or younger who underwent similar procedures. RESULTS: The mean age of the study group was 54.8 years (range, 50 to 69 years), and that of the control group was 20.3 years (range, 13 to 30 years). The groups were matched at a 1:1 ratio, including 18 male patients (34.6%) and 34 female patients (65.4%) in each group, with a mean follow-up period of 32 months (range, 24 to 54 months). In the younger control group, the score improvement from preoperatively to 2 years' follow-up was 62.9 to 84.2 for the modified Harris Hip Score, 60.5 to 84.2 for the Non-Arthritic Hip Score, 63.1 to 86.5 for the Hip Outcome Score-Activities of Daily Living, and 42.2 to 72.7 for the Hip Outcome Score-Sport-Specific Subscale. In the older study group, the score improvement from preoperatively to 2 years' follow-up was 61.2 to 82.2 for the modified Harris Hip Score, 59.9 to 80.4 for the Non-Arthritic Hip Score, 63.9 to 83 for the Hip Outcome Score-Activities of Daily Living, and 41.2 to 64.6 for the Hip Outcome Score-Sport-Specific Subscale. All improvements in both groups were statistically significant at the 2-year postoperative follow-up (P < .001). There was no significant difference for all patient-reported outcome (PRO) scores at final follow-up between both groups. When we compared the change in PRO scores (Delta) from preoperatively to 2 years postoperatively, there was no significant difference between both groups. The overall survivorship rate was 98.1% for the younger control group and 82.7% for the older study group. CONCLUSIONS: Survivors aged 50 years or older show similar improvement to patients aged 30 years or younger in PRO and patient satisfaction scores. The 2-year survivorship rate was 98.1% for the younger control group and 82.7% for the older study group. Therefore we believe that hip arthroscopy should be considered a valid treatment option when treating hip pain in patients aged 50 years or older with a Tonnis arthritic grade of 0 or 1. Older patients should be counseled on the possibility of later conversion to total hip arthroplasty. Future work may include development of a decision-making tool to assess for prognosis to better delineate the indications for hip arthroscopy in the older population. LEVEL OF EVIDENCE: Level III, therapeutic case-control study. PMID- 25442658 TI - Direct bursoscopic ossicle resection in young and active patients with unresolved Osgood-Schlatter disease. AB - PURPOSE: The aim of this study was to determine the outcomes of bursoscopic ossicle excision in young and active patients with unresolved Osgood-Schlatter disease. METHODS: This retrospective study included 18 male military recruits. A direct bursoscopic ossicle excision was performed using low anterolateral and low anteromedial portals. Outcomes were evaluated using the Lysholm knee score, pain score on a visual analog scale (VAS) (from 0 to 10), and Tegner activity scale score. In addition, patients were asked whether they could kneel or squat and whether they were able to return to their duty after surgery. Patient satisfaction was evaluated using the VAS and by asking whether patients thought that the prominence of the tibial tuberosity was reduced and whether they would recommend the same surgical treatment to others. Complications after surgery were also evaluated. RESULTS: The mean Lysholm knee score was 71 preoperatively and improved to 99 after surgery. The mean VAS pain score was 6.5 in the preoperative period and decreased to 0.9 after surgery. In addition, the mean Tegner activity scale score improved from 2.7 preoperatively to 6.2 at final follow-up. However, 4 patients were not able to return to their duty, and 4 patients still had difficulties with kneeling after surgery. A superficial infection occurred in 1 patient, and a recurrent ossicle formation was found in 1 patient. Of 18 patients, 17 were satisfied with their surgical outcomes, and the mean VAS score for patient satisfaction was 8.8. Furthermore, all but 1 patient would recommend the same surgical treatment to others. However, 6 patients did not believe that the prominence of the tibial tuberosity was reduced. CONCLUSIONS: Bursoscopic ossicle excision showed satisfactory outcomes in selective young and active patients with persistent symptoms. However, bursoscopic surgery showed limitation in reducing the prominence of the tibial tuberosity. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25442659 TI - Surgeon-rated visualization in shoulder arthroscopy: a randomized blinded controlled trial comparing irrigation fluid with and without epinephrine. AB - PURPOSE: The objective of the current study was to compare surgeon-rated visualization in shoulder arthroscopy using irrigation fluid with and without epinephrine. METHODS: Eighty-three patients were randomized to receive irrigation fluid with (44 patients) or without (39 patients) epinephrine during their arthroscopic shoulder procedures. After each procedure, the blinded senior author (G.F.C.) evaluated visualization based on a visual analog scale (VAS), and all clinically important procedure variables were recorded. RESULTS: Eighty-three arthroscopic shoulder procedures were included in the study. Fifty-four of these procedures were arthroscopic rotator cuff repairs, allowing a subset analysis of this specific procedure. There was a significant difference, with improved visualization in the epinephrine group versus the group without epinephrine when comparing all procedures (P < .0001) and when comparing only rotator cuff repairs (P < .0001). However, there was no statistical difference in other clinically important variables, including operative time and amount of irrigation fluid used. CONCLUSIONS: The addition of epinephrine to irrigation fluid significantly improves surgeon-rated visualization in shoulder arthroscopy. Without an observed significant difference in operative time or volume of irrigation fluid used, the clinical significance of this improved visualization is unclear, and the use of irrigation fluid without epinephrine remains a viable option in the hands of an experienced surgeon. LEVEL OF EVIDENCE: Level I, high-quality randomized controlled trial with statistically significant difference. PMID- 25442660 TI - Implant failure after biodegradable screw fixation in osteochondritis dissecans of the knee in skeletally immature patients. AB - PURPOSE: The primary purpose of this study was to retrospectively assess the incidence of bioabsorbable screw failure in skeletally immature patients treated for osteochondritis dissecans (OCD) of the knee. The second purpose was to assess implant degradation, focusing on differential breakdown of the intraosseous and extraosseous parts of the screw on magnetic resonance imaging (MRI). METHODS: In this retrospective study, 24 patients (30 knees) with MRI-confirmed OCD were treated with a total of 61 biodegradable screws and followed up for a minimum of 2 years or until the onset of new symptoms. MRI scans were performed every 6 months to assess differences in signal intensity between the head and body of the screw. The angle between the surface of the head and the body of the screw was measured, with an angle greater than 90 degrees interpreted as indicating a broken screw (i.e., failed implant). RESULTS: Seven screws (all 2.7 mm, 11.5% of all screws) in 5 patients were considered broken screws. The implant failed completely in an additional 4 patients with breakage of 7 of 9 screws; 3 patients were considered late failures, occurring after more than 6 months. Altogether, 14 of a total of 61 screws (23%) were broken. CONCLUSIONS: Screw breakage is a surprisingly frequent cause of failure in resorbable OCD fixation in skeletally immature patients. MRI data showed differential decomposition of the screw within and outside of bone as a possible cause. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25442661 TI - Biological knee reconstruction for combined malalignment, meniscal deficiency, and articular cartilage disease. AB - PURPOSE: The aim of this study was to analyze patient-reported outcomes in those undergoing the triad of simultaneous osteotomy, meniscal transplantation, and articular cartilage repair. METHODS: Patients undergoing simultaneous meniscal transplantation, distal femoral or proximal tibial osteotomy, and articular cartilage surgery by a single surgeon (B.J.C.) were analyzed. Meniscal transplantation was performed using bone-in-slot techniques. Distal femoral and high tibial osteotomies were performed for valgus and varus malalignment, respectively. Microfracture, autologous chondrocyte implantation, and osteochondral autograft or allograft were performed for articular cartilage disease. Validated patient-reported and surgeon-measured outcomes were collected. Preoperative and postoperative outcomes and medial versus lateral disease were compared using Student t tests. RESULTS: Eighteen participants (mean age, 34 +/- 7.8 years; symptomatic patients, 7.4 +/- 5.6 years; 2.4 +/- 1.0 surgical procedures before study enrollment; mean follow-up, 6.5 +/- 3.2 years) were analyzed. Two thirds of participants had medial compartment pathologic conditions and one third had lateral compartment pathologic processes. At final follow-up, there were statistically significant clinically meaningful improvements in International Knee Documentation Committee (IKDC) subjective classification, Lysholm score, and 4 Knee Injury and Osteoarthritis Outcome Score (KOOS) subscores. Postoperative 12-item short form (SF-12) physical and mental component scores were not significantly different from preoperative scores. The Kellgren Lawrence classification grade was 1.5 +/- 1.1 at 2.5 +/- 3.0 years after surgery. There was a significantly higher preoperative SF-12 physical composite score (PCS) in participants with lateral compartment pathologic conditions (v medial compartment conditions) (P = .011). Although there were 13 reoperations in 10 patients (55.5% reoperation rate), only one patient was converted to knee arthroplasty (5.6%) and one to revision cartilage surgery and meniscal transplantation (5.6% revision rate). The most common complication was arthrofibrosis (16.7%). CONCLUSIONS: Statistically significant and clinically meaningful improvements in validated patient-reported clinical outcome scores at long-term follow-up were observed in 18 participants undergoing combined meniscal transplantation, osteotomy, and articular cartilage surgery. Although there was a low rate of cartilage or meniscal revision (or both) and total knee arthroplasty, there was a high rate of reoperation. There was no significant difference in outcomes between participants with medial versus lateral pathologic conditions. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25442662 TI - Subscapularis tendon tear classification based on 3-dimensional anatomic footprint: a cadaveric and prospective clinical observational study. AB - PURPOSE: The purpose of this study was to define the subscapularis tendon footprint anatomy in 3-dimensional (3D) perspective, report the incidence of tears, and classify the tear patterns prospectively during shoulder arthroscopic surgery. METHODS: The cadaveric study consisted of a pilot study that revealed 4 different bony facets by simple observation at the subscapularis attachment. The 3D footprint anatomy was digitally evaluated in 39 cadavers. The clinical study was conducted from 2011 to 2013 and was based on 3D footprint anatomy. All consecutive arthroscopic shoulder operations were prospectively evaluated for subscapularis tendon integrity. A new classification system was developed with 5 categories: (1) type I-fraying or longitudinal split of the subscapularis tendon leading edge; (2) type IIA-less than 50% subscapularis tendon detachment of the first facet; (3) type IIB-greater than 50% detachment without complete disruption of the lateral hood, which is approximately a one-quarter to one-third tear of the entire subscapularis tendon's superior-inferior length; (5) type III-entire first facet with complete-thickness tear (lateral hood tear), (5) type IV-first and second facets are exposed with much medial retraction of the tendon (approximately a two-thirds tear of the entire footprint; entire tendinous portion), and (6) type V-complete subscapularis tendon involving the muscular portion (rare). RESULTS: The medial-lateral and superior-inferior dimensions of the first facet dimensions were 13.8 * 13.5 mm, respectively; its surface area was 34% of the entire footprint. From superior to inferior, the facet's medial lateral dimensions and surface area decreased. The fourth facet was 77 mm(2) from medial to lateral and encompassed 15% of the footprint. Clinically, among 821 shoulder arthroscopies performed over a 29-month-period, the incidence of subscapularis tears was 415 (50.5%). The most common tear was type IIB (29.4%) or a one-quarter to one-third tear of the entire subscapularis footprint length. However, the incidence between types I, IIA, and IIB did not show a statistically significant difference, indicating an equal distribution. The mean ages of the torn group versus the intact subscapularis group showed a difference. CONCLUSIONS: The first facet of the subscapularis tendon footprint consists of approximately one third of the entire footprint, and the first 2 facets consist of 60% of the entire footprint. The probability of finding any extension of the subscapularis tendon tear occurs in approximately 50% of the patients who undergo shoulder arthroscopy for all forms of shoulder disease. Among those subscapularis tendon tears, less than or equal to 80% are first facet tears. LEVEL OF EVIDENCE: Level II, diagnostic study. PMID- 25442663 TI - Clinical results of hip arthroscopy for labral tears: a comparison between intraoperative platelet-rich plasma and bupivacaine injection. AB - PURPOSE: The purpose of this prospective comparative study was to evaluate the effect of intraoperative platelet-rich plasma (PRP) injection on the outcomes of patients undergoing hip arthroscopy for labral treatment. METHODS: During the period from November 2010 through March 2012, all patients undergoing hip arthroscopy for labral tears were considered for this study. The study group received intra-articular PRP at the end of the operation, and the control group received an intra-articular injection of 0.25% bupivacaine. Selection for the study group was based on the day of the week on which the patient underwent surgery. The protocol included administration of 4 hip-specific patient-reported outcome tools. Patients also reported their pain score on a visual analog scale from 0 to 10. Scores were recorded at the preoperative visit and at 3 months and 2 years postoperatively. RESULTS: A minimum of 2 years' follow-up was available for 306 patients. Thirteen patients (4.2%) underwent conversion to total hip arthroplasty and 24 patients (7.8%) underwent revision hip arthroscopy, which left 91 patients in the study group and 180 patients in the control group. The study group had slightly higher pain scores than the control group (3.4 v 2.5) 2 years after surgery (P = .005). No difference in pain scores was identified at 3 months postoperatively. The 2-year modified Harris Hip Score was slightly lower in the study group (78.6) than in the control group (82.6) (P = .049). No significant difference was observed for the Hip Outcome Score-Activities of Daily Living, Hip Outcome Score-Sport-Specific Subscale, or Non-Arthritic Hip Score at any time point. There was no significant difference between groups for conversion to total hip arthroplasty or revision surgery. CONCLUSIONS: On the basis of the results of this study, intraoperative PRP injection does not appear to improve the clinical results of patients undergoing hip arthroscopy for labral treatment. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 25442664 TI - Arthroscopic versus mini-open rotator cuff repair: an up-to-date meta-analysis of randomized controlled trials. AB - PURPOSE: The aim of this meta-analysis was to compare the clinical outcomes of arthroscopic and mini-open rotator cuff repairs based on recently published Level I randomized controlled trials (RCTs). METHODS: We systematically searched electronic databases to identify RCTs that compared arthroscopic and mini-open rotator cuff repairs from 1980 to October 2013. The clinical outcome scores, including the University of California, Los Angeles score and the Constant-Murley score, were converted to a common 100-point outcome score for further analysis. The results of the pooled studies were analyzed in terms of surgery time, weighted 100-point score, pain on a visual analog scale (VAS), and range of motion. Study quality was assessed and relevant data were extracted independently by 2 reviewers. RESULTS: Five RCTs, including 166 patients in the arthroscopic repair group and 163 patients in the mini-open repair group, were included in this meta-analysis. The results of the meta-analysis showed that there were no significant differences in surgery time (P = .11), weighted 100-point score (P = .65), VAS pain score (P = .87), or range of motion (P = .29 for forward flexion and P = .82 for external rotation). CONCLUSIONS: On the basis of current literature, no differences in surgery time, functional outcome score, VAS pain score, and range of motion were found at the end of follow-up between the arthroscopic and mini-open rotator cuff repair techniques. In addition, there was no significant difference in VAS pain score in the early phase between the 2 repairs. LEVEL OF EVIDENCE: Level I, meta-analysis of Level I studies. PMID- 25442665 TI - The sagittal plane angle and tunnel-related complications in double-bundle anterior cruciate ligament reconstruction using the transportal technique: an in vivo imaging study. AB - PURPOSE: To evaluate the relation between the tunnel angle in the 3 orthogonal planes, especially the sagittal plane, which can be influenced by knee flexion during drilling, and the incidence of complications from the transportal technique using in vivo imaging data. METHODS: Fifty-one patients who underwent anatomic double-bundle anterior cruciate ligament reconstruction by the transportal technique were evaluated retrospectively. A 3-dimensional surface model was made using an axial computed tomography scan obtained after anterior cruciate ligament reconstruction. The tunnel length, posterior cortical damage, proximity between the outer orifice of the tunnel and lateral collateral ligament (LCL) origin, and medial femoral condyle cartilage damage were evaluated on a 3 dimensional computed tomography scan and 3-T magnetic resonance imaging. Correlations between those parameters and the tunnel angle in the coronal, axial, and sagittal planes were analyzed. RESULTS: A tunnel length of less than 30 mm developed in 4 cases (8%) in the anteromedial tunnel and in 1 case (2%) in the posterolateral (PL) tunnel. Posterior cortical damage developed in 12 cases (23%). A distance from the outer orifice of the tunnel to the LCL origin of less than 3 mm occurred in 18 cases (35.2%) in the PL tunnel. Medial femoral condyle cartilage damage was detected in 3 cases (6%). A positive correlation was observed between the sagittal angle and anteromedial tunnel length (P = .002, r = 0.547). The sagittal angle in the group with posterior cortical damage was lower than that in the group with no posterior cortical damage (P = .002). A negative correlation was observed between the distance from the outer orifice of the PL tunnel to the LCL origin and the sagittal angle (P = .002, r = -0.55). CONCLUSIONS: Drilling at a higher angle in the sagittal plane decreased the incidence of posterior cortical damage and a short anteromedial tunnel. However, drilling at a higher angle shortened the distance to the LCL origin for the PL tunnel. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25442666 TI - Outcomes after primary open or endoscopic abductor tendon repair in the hip: a systematic review of the literature. AB - PURPOSE: The purpose of this study was to systematically appraise the evidence on primary open and endoscopic abductor tendon repair. METHODS: A systematic review of the literature was performed to (1) identify the demographic undergoing abductor tendon repair, (2) summarize the overall outcomes after primary surgical abductor tendon repair, (3) identify the type of tear most commonly encountered intraoperatively, (4) summarize the repair methods used, and (5) identify the published complication and tendon retear rates. RESULTS: A total of 8 articles were identified as eligible for inclusion. All studies were Level IV Evidence. Of the patients undergoing surgical repair, 90% were women. As assessed by a variety of outcome measures, most patients reported good to excellent functional outcomes and pain reduction after open or endoscopic repair. Intraoperatively, tears of the gluteus medius and partial-thickness tears were encountered most often. Tears involving both the gluteus medius and minimus occurred 29% of the time. Complication rates were low for both the open and endoscopic approaches. No tendon retears were documented after endoscopic repair, whereas the retear rate after open repair was 9%. CONCLUSIONS: Patients undergoing surgical repair for partial- and full-thickness tears are mostly women. Intraoperatively, tears almost always include the gluteus medius, with concomitant tearing of the gluteus minimus in approximately one-third of cases. Both open and endoscopic techniques are viable surgical approaches to repairing abductor tendon tears in the hip that produce good to excellent functional results and reduce pain; however, endoscopic repair appears to result in fewer postoperative complications including tendon retear. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies. PMID- 25442667 TI - Global inventory, long-range transport and environmental distribution of dicofol. AB - The uncertainties on whether dicofol can be identified as a persistent organic pollutant (POP) in terms of its long-range transport (LRT) potential and global distribution, are always a controversial topic during international regulation deliberations. The lack of monitoring data in remote background regions necessitates a model-based evaluation approach for assessing the global distribution of dicofol. However, few model simulations are available at present, as there is no inventory available for global historical usage of dicofol that has sufficiently high spatial and temporal resolution. To describe the current status of global emission, we first developed an inventory of global dicofol usage for the period of 2000-2012 at 1 degrees * 1 degrees latitude/longitude resolution. We then assessed the LRT potential of dicofol by calculating its Arctic Contamination Potential using the Globo-POP model. In addition, we simulated the global mass distribution and the fate of dicofol in the environment using the BETR-Global model at 15 degrees * 15 degrees latitude/longitude resolution. Our estimated inventory established that over the period of 13 years, a total of 28.2 kilo tonnes (kt) of dicofol was applied and released into the environment. East and Southeast Asia, the Mediterranean Coast, and Northern and Central America were identified as hotspots of usage and release. Dicofol exhibited a higher Arctic Contamination Potential than several confirmed Arctic contaminants, and a larger current volume of consumption than most existing POPs. The results of our BETR-Global simulation suggest that (i) dicofol can indeed be transported northward, most likely driven by both atmospheric and oceanic advections from source regions at midlatitudes, and (ii) dicofol will be enriched in remote background regions. Continuous use of dicofol in source regions will result in exposure both locally and in remote regions, and the examination of the potential for adverse effects is therefore of paramount importance. Proactive restrictions at the international level may be warranted. PMID- 25442668 TI - MIC gene polymorphism and haplotype diversity in Li nationality of Southern China. AB - Here, we report for the first time the polymorphisms of MICA and MICB in a healthy Li population of 344 unrelated individuals. By using polymerase chain reaction-sequence specific priming (PCR-SSP) and sequence-based typing (PCR-SBT), 17 MICA-sequence alleles and 5 MICA-STR (short tandem repeats, STR) alleles, as well as 17 MICB alleles were detected, among which MICA*010, MICA*A4 and MICB*005:02 were the most frequent alleles. In addition, linkage disequilibrium was investigated and the most common two-locus haplotypes were MICB*005:02 MICA*010 and MICB*008-MICA*002:01. These results present informative genetic markers for the investigation of possible origins and the evolution of MHC class I haplotypes in the Li population. PMID- 25442669 TI - Normative data for arm swing asymmetry: how (a)symmetrical are we? AB - Arm swing asymmetry during gait may be a sensitive sign for early Parkinson's disease. There is only very limited information about how much asymmetry can be considered to be physiological. To assess the normal range of arm swing asymmetry, we investigated 60 healthy subjects. The influence of age, gender, and additional mental tasks (dual-tasking) on arm swing asymmetry was assessed. Limb kinematics of 60 healthy persons in three age groups (between 40 and 75 years) were measured with an ultrasound motion capture system while subjects walked on a treadmill. Treadmill velocity was varied (3 steps) and mental loads (2 different tasks) were applied in different trials. Additionally, a group of 7 patients with early Parkinson's disease was investigated. Arm swing amplitude as well as arm swing asymmetry varied considerably in the healthy subjects. Elderly subjects swung their arms more than younger participants. Only the more demanding mental load caused a significant asymmetry, i.e., arm swing was reduced on the right side. In the patient group, asymmetry was considerably higher and even more enhanced by mental loads. Our data indicate that an asymmetry index above 50 (i.e., one side has twice the amplitude of the other) may be considered abnormal. Evaluation of arm swing asymmetry may be used as part of a test battery for early Parkinson's disease. Such testing may become even more important when disease modifying drugs become available for Parkinson's disease. PMID- 25442670 TI - Detection of gait cycles in treadmill walking using a Kinect. AB - Treadmill walking is commonly used to analyze several gait cycles in a limited space. Depth cameras, such as the low-cost and easy-to-use Kinect sensor, look promising for gait analysis on a treadmill for routine outpatient clinics. However, gait analysis is based on accurately detecting gait events (such as heel strike) by tracking the feet which may be incorrectly recognized with Kinect. Indeed depth images could lead to confusion between the ground and the feet around the contact phase. To tackle this problem we assume that heel-strike events could be indirectly estimated by searching for extreme values of the distance between knee joints along the walking longitudinal axis. To evaluate this assumption, the motion of 11 healthy subjects walking on a treadmill was recorded using both an optoelectronic system and Kinect. The measures were compared to reference heel-strike events obtained with vertical foot velocity. When using the optoelectronic system to assess knee joints, heel-strike estimation errors were very small (29+/-18ms) leading to small cycle durations errors (0+/-15ms). To locate knees in depth map (Kinect), we used anthropometrical data to select the body point located at a constant height where the knee should be based on a reference posture. This Kinect approach gave heel strike errors of 17+/-24ms (mean cycle duration error: 0+/-12ms). Using this same anthropometric methodology with optoelectronic data, the heel-strike error was 12+/-12ms (mean cycle duration error: 0+/-11ms). Compared to previous studies using Kinect, heel-strike and gait cycles were more accurately estimated, which could improve clinical gait analysis with such sensor. PMID- 25442671 TI - Maternal hydroxytyrosol administration improves neurogenesis and cognitive function in prenatally stressed offspring. AB - Prenatal stress is known to induce emotional and cognitive dysfunction in the offspring of both humans and experimental animals. Hydroxytyrosol (HT), a major polyphenol in olive oil with reported ability modulating oxidative stress and mitochondrial function, was performed to investigate its preventive effect on prenatal stress-induced behavioral and molecular alterations in offspring. Rats were exposed to restraint stress on days 14-20 of pregnancy. HT was given at doses of 10 and 50 mg/kg/day. The spontaneous alternation performance and Morris water maze confirmed the impaired learning capacity and memory performance induced by prenatal stress in both male and female offspring, and these effects were markedly restored in the HT supplement groups. Through tissue analysis of the hippocampi of male offspring, we found that the stress-induced downregulation of neural proteins, including BDNF, GAP43, synaptophysin, NMDAR1, NMDANR2A and NMDANR2B, was prevented by HT. Prenatal stress-induced low expression of glucocorticoid receptor was also increased by HT, although basal fetal serum corticosterone levels were not different among the four groups. Oxidative stress and mitochondrial dysfunction in prenatally stressed rats were confirmed with changes in protein oxidation, SOD activity, the expression of mitochondrial complexes and mitochondrial DNA copy number. Meanwhile, HT significantly increased transcription factors FOXO1 and FOXO3, as well as phase II enzyme related proteins, including Nrf2 and HO-1, which may contribute to the decreased oxidative stress and increased mitochondrial function shown with HT supplementation. Taken together, these findings suggest that HT is an efficient maternal nutrient protecting neurogenesis and cognitive function in prenatally stressed offspring. PMID- 25442672 TI - The impact of cortical remapping interventions on pain and disability in chronic low back pain: a systematic review. AB - BACKGROUND: Cortical change, in the manner of cortical remapping is a common feature of and potential driver for chronic low back pain (CLBP). Novel interventions such as graded motor imagery (GMI) and mirror visual feedback (MVF) have been shown to facilitate correction of cortical changes and improve symptoms in other chronic pain states. However, little is known regarding the effectiveness of these treatment approaches in CLBP. OBJECTIVE: To identify and assess the current evidence regarding the effectiveness of interventions which target cortical remapping in the management of CLBP. DATA SOURCES: The electronic databases Medline, Embase, CINAHL, AMED, OVID, PEDro, BNI, PsycINFO, HMIC, and Cochrane library were systematically searched. STUDY SELECTION: Of 11 potential citations identified, 5 articles were identified for inclusion and critiqued. These comprised 3 randomised controlled trials (RCTs), 1 randomised cross-over study, and 1 multiple case study design. RESULTS: Visualisation of lumbar movement may significantly improve movement-related pain severity and duration. A combined sensorimotor retraining approach has been shown to produce short-term improvements in both pain and disability outcomes in CLBP. The relative effectiveness of individual interventions and their long-term efficacy have yet to be established. CONCLUSIONS: There is a paucity of robust literature which has examined the application and efficacy of these novel treatments in the management of CLBP. Results from the few CLBP studies which are available are encouraging. Further, robust research is needed to optimise treatment protocols and establish their long-term effectiveness in CLBP. PMID- 25442673 TI - A randomized controlled trial comparing McKenzie therapy and motor control exercises on the recruitment of trunk muscles in people with chronic low back pain: a trial protocol. AB - OBJECTIVE: To investigate if McKenzie exercises when applied to a cohort of patients with chronic LBP who have a directional preference demonstrate improved recruitment of the transversus abdominis compared to motor control exercises when measurements were assessed from ultrasound images. DESIGN: A randomized blinded trial with a 12-month follow-up. SETTING: The Physiotherapy department of Concord Hospital a primary health care environment. PARTICIPANTS: 70-adults with greater than three-month history of LBP who have a directional preference. INTERVENTIONS: McKenzie techniques or motor control exercises for 12-sessions over eight weeks. MAIN OUTCOME MEASURES: Transversus abdominus thickness measured from real time ultrasound images, pain, global perceived effect and capacity to self-manage. DISCUSSION: This study will be the first to investigate the possible mechanism of action that McKenzie therapy and motor control exercises have on the recruitment of the transversus abdominus in a cohort of low back pain patients sub-classified with a directional preference. Patients receiving matched exercises according to their directional preference are believed to have better outcomes than those receiving unmatched exercises. A better understanding of the mechanism of action that specific treatments such as motor control exercises or McKenzie exercises have on patients classified with a directional preference will allow therapist to make a more informed choice about treatment options. PMID- 25442674 TI - Distinct signaling mechanisms of mTORC1 and mTORC2 in glioblastoma multiforme: a tale of two complexes. AB - Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that functions via two multiprotein complexes, namely mTORC1 and mTORC2, each characterized by different binding partners that confer separate functions. mTORC1 function is tightly regulated by PI3-K/Akt and is sensitive to rapamycin. mTORC2 is sensitive to growth factors, not nutrients, and is associated with rapamycin-insensitivity. mTORC1 regulates protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. Also, mTORC2 is thought to modulate growth factor signaling by phosphorylating the C terminal hydrophobic motif of some AGC kinases such as Akt and SGK. Recent evidence has suggested that mTORC2 may play an important role in maintenance of normal as well as cancer cells by virtue of its association with ribosomes, which may be involved in metabolic regulation of the cell. Rapamycin (sirolimus) and its analogs known as rapalogues, such as RAD001 (everolimus) and CCI-779 (temsirolimus), suppress mTOR activity through an allosteric mechanism that acts at a distance from the ATP-catalytic binding site, and are considered incomplete inhibitors. Moreover, these compounds suppress mTORC1-mediated S6K activation, thereby blocking a negative feedback loop, leading to activation of mitogenic pathways promoting cell survival and growth. Consequently, mTOR is a suitable target of therapy in cancer treatments. However, neither of these complexes is fully inhibited by the allosteric inhibitor rapamycin or its analogs. In recent years, new pharmacologic agents have been developed which can inhibit these complexes via ATP-binding mechanism, or dual inhibition of the canonical PI3 K/Akt/mTOR signaling pathway. These compounds include WYE-354, KU-003679, PI-103, Torin1, and Torin2, which can target both complexes or serve as a dual inhibitor for PI3-K/mTOR. This investigation describes the mechanism of action of pharmacological agents that effectively target mTORC1 and mTORC2 resulting in suppression of growth, proliferation, and migration of tumor and cancer stem cells. PMID- 25442676 TI - Polio: is the end in sight? PMID- 25442675 TI - BRAF V600E analysis for the differentiation of papillary craniopharyngiomas and Rathke's cleft cysts. AB - AIMS: The differential diagnosis of cystic epithelial masses of the sellar region, especially the histopathological differentiation of craniopharyngiomas and Rathke's cleft cysts, poses a challenge even to experienced diagnosticians. Recently, BRAF V600E mutations have been described as a genetic hallmark of papillary craniopharyngiomas. We investigated a series of 33 Rathke's cleft cysts to determine the frequency of BRAF V600E mutations and its suitability as an additional diagnostic marker for the differentiation of cystic lesions of the sellar region. METHODS: Thirty-three Rathke's cleft cysts and 18 papillary craniopharyngiomas were analysed for BRAF mutational status by immunohistochemistry using a monoclonal antibody (VE1) that selectively recognizes the BRAF V600E mutant epitope and additional BRAF pyrosequencing in a subset of samples. RESULTS: Thirty of 33 specimens diagnosed as Rathke's cleft cysts were negative by VE1 immunohistochemistry and pyrosequencing, whereas in three cysts and in all the 18 papillary craniopharyngiomas, a BRAF V600E mutation was detected. Clinical and histological re-evaluation of the three BRAF V600E mutated cases formerly diagnosed as Rathke's cleft cysts revealed unusual presentations. Two of them were rediagnosed as papillary craniopharyngiomas. The patient of the third case had a history of craniopharyngioma operated 14 years before, and reoperation showed a cystic epithelial lesion with unclear histology. CONCLUSIONS: The determination of BRAF mutational status is recommended in any cystic sellar lesion and can in most cases be provided by VE1 immunohistochemistry even in specimens of low cellularity. Confirmation by (pyro )sequencing should be attempted whenever sufficient epithelium is available due to variable staining results. PMID- 25442677 TI - Ending preventable child deaths: addressing the high-risk days after birth. PMID- 25442678 TI - Is targeting access to sanitation enough? PMID- 25442679 TI - Transient benefits in young children of a nutrition intervention during pregnancy. PMID- 25442680 TI - Prevention of syphilis: another positive benefit of male circumcision. PMID- 25442681 TI - Planning adaptive health systems: the climate challenge. PMID- 25442682 TI - Inactivated polio vaccine launch in Nepal: a public health milestone. PMID- 25442683 TI - Defining and targeting high-risk populations in Buruli ulcer. PMID- 25442684 TI - Defining and targeting high-risk populations in Buruli ulcer--authors' reply. PMID- 25442685 TI - Representativeness of the UN post-2015 national consultations. PMID- 25442686 TI - The World Bank: can it learn from Silicon Valley? PMID- 25442687 TI - Confusing drug packaging contributes to death of 15 children. PMID- 25442688 TI - Estimation of daily risk of neonatal death, including the day of birth, in 186 countries in 2013: a vital-registration and modelling-based study. AB - BACKGROUND: The days immediately after birth are the most risky for human survival, yet neonatal mortality risks are generally not reported by day. Early neonatal deaths are sometimes under-reported or might be misclassified by day of death or as stillbirths. We modelled daily neonatal mortality risk and estimated the proportion of deaths on the day of birth and in week 1 for 186 countries in 2013. METHODS: We reviewed data from vital registration (VR) and demographic and health surveys for information on the timing of neonatal deaths. For countries with high-quality VR we used the data as reported. For countries without high quality VR data, we applied an exponential model to data from 206 surveys in 79 countries (n=50,396 deaths) to estimate the proportions of neonatal deaths per day and used bootstrap sampling to develop uncertainty estimates. FINDINGS: 57 countries (n=122,757 deaths) had high-quality VR, and modelled data were used for 129 countries. The proportion of deaths on the day of birth (day 0) and within week 1 varied little by neonatal mortality rate, income, or region. 1.00 million (36.3%) of all neonatal deaths occurred on day 0 (uncertainty range 0.94 million to 1.05 million), and 2.02 million (73.2%) in the first week (uncertainty range 1.99 million to 2.05 million). Sub-Saharan Africa had the highest risk of neonatal death and, therefore, had the highest risk of death on day 0 (11.2 per 1000 livebirths); the highest number of deaths on day 0 was seen in southern Asia (n=392,300). INTERPRETATION: The risk of early neonatal death is very high across a range of countries and contexts. Cost-effective and feasible interventions to improve neonatal and maternity care could save many lives. FUNDING: Save the Children's Saving Newborn Lives programme. PMID- 25442689 TI - Effectiveness of a rural sanitation programme on diarrhoea, soil-transmitted helminth infection, and child malnutrition in Odisha, India: a cluster-randomised trial. AB - BACKGROUND: A third of the 2.5 billion people worldwide without access to improved sanitation live in India, as do two-thirds of the 1.1 billion practising open defecation and a quarter of the 1.5 million who die annually from diarrhoeal diseases. We aimed to assess the effectiveness of a rural sanitation intervention, within the context of the Government of India's Total Sanitation Campaign, to prevent diarrhoea, soil-transmitted helminth infection, and child malnutrition. METHODS: We did a cluster-randomised controlled trial between May 20, 2010, and Dec 22, 2013, in 100 rural villages in Odisha, India. Households within villages were eligible if they had a child younger than 4 years or a pregnant woman. Villages were randomly assigned (1:1), with a computer-generated sequence, to undergo latrine promotion and construction or to receive no intervention (control). Randomisation was stratified by administrative block to ensure an equal number of intervention and control villages in each block. Masking of participants was not possible because of the nature of the intervention. However, households were not told explicitly that the purpose of enrolment was to study the effect of a trial intervention, and the surveillance team was different from the intervention team. The primary endpoint was 7-day prevalence of reported diarrhoea in children younger than 5 years. We did intention-to-treat and per-protocol analyses. This trial is registered with ClinicalTrials.gov, number NCT01214785. FINDINGS: We randomly assigned 50 villages to the intervention group and 50 villages to the control group. There were 4586 households (24,969 individuals) in intervention villages and 4894 households (25,982 individuals) in control villages. The intervention increased mean village-level latrine coverage from 9% of households to 63%, compared with an increase from 8% to 12% in control villages. Health surveillance data were obtained from 1437 households with children younger than 5 years in the intervention group (1919 children younger than 5 years), and from 1465 households (1916 children younger than 5 years) in the control group. 7-day prevalence of reported diarrhoea in children younger than 5 years was 8.8% in the intervention group and 9.1% in the control group (period prevalence ratio 0.97, 95% CI 0.83 1.12). 162 participants died in the intervention group (11 children younger than 5 years) and 151 died in the control group (13 children younger than 5 years). INTERPRETATION: Increased latrine coverage is generally believed to be effective for reducing exposure to faecal pathogens and preventing disease; however, our results show that this outcome cannot be assumed. As efforts to improve sanitation are being undertaken worldwide, approaches should not only meet international coverage targets, but should also be implemented in a way that achieves uptake, reduces exposure, and delivers genuine health gains. FUNDING: Bill & Melinda Gates Foundation, International Initiative for Impact Evaluation (3ie), and Department for International Development-backed SHARE Research Consortium at the London School of Hygiene & Tropical Medicine. PMID- 25442692 TI - Why we should improve attendance at the annual meeting poster and abstract sessions. PMID- 25442690 TI - Effect of antenatal multiple micronutrient supplementation on anthropometry and blood pressure in mid-childhood in Nepal: follow-up of a double-blind randomised controlled trial. AB - BACKGROUND: In 2002-04, we did a randomised controlled trial in southern Nepal, and reported that children born to mothers taking multiple micronutrient supplements during pregnancy had a mean birthweight 77 g greater than children born to mothers taking iron and folic acid supplements. Children born to mothers in the study group were a mean 204 g heavier at 2.5 years of age and their systolic blood pressure was a mean 2.5 mm Hg lower than children born to mothers in the control group. We aimed to follow up the same children to mid-childhood (age 8.5 years) to investigate whether these differences would be sustained. METHODS: For this follow-up study, we identified children from the original trial and measured anthropometry, body composition with bioelectrical impedance (with population-specific isotope calibration), blood pressure, and renal dimensions by ultrasound. We documented socioeconomic status, household food security, and air pollution. Main outcomes of the follow-up at 8 years were Z scores for weight-for age, height-for-age, and body-mass index (BMI)-for-age according to WHO Child Growth Standards for children aged 5-19 years, and blood pressure. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN88625934. FINDINGS: Between Sept 21, 2011, and Dec 7, 2012, we assessed 841 children (422 in the control group and 419 in the intervention group). Unadjusted differences (intervention minus control) in Z scores were 0.05 for weight-for-age (95% CI -0.09 to 0.19), 0.02 in height-for-age (-0.10 to 0.15), and 0.04 in BMI-for-age (-0.09 to 0.18). We recorded no difference in blood pressure. Adjusted differences were similar for all outcomes. INTERPRETATION: We recorded no differences in phenotype between children born to mothers who received antenatal multiple micronutrient or iron and folate supplements at age 8.5 years. Our findings did not extend to physiological differences or potential longer-term effects. FUNDING: The Wellcome Trust. PMID- 25442693 TI - Aspirin exacerbated respiratory disease: the search for a biomarker. PMID- 25442694 TI - Food allergy quality of life. PMID- 25442691 TI - Association between male circumcision and incidence of syphilis in men and women: a prospective study in HIV-1 serodiscordant heterosexual African couples. AB - BACKGROUND: Male circumcision is a primary HIV-1 prevention intervention for men, but whether the procedure reduces the risk of syphilis among men and their female partners is uncertain. We aimed to assess whether male circumcision was associated with incident syphilis in men and in their female partners. METHODS: In this large prospective cohort study, participants were members of Kenyan and Ugandan HIV-1 serodiscordant heterosexual couples enrolled in a randomised safety and efficacy clinical trial of pre-exposure prophylaxis for HIV-1 prevention (the Partners PrEP Study). Participants attended monthly or quarterly follow-up visits for up to 36 months. Annually, syphilis serology testing was done and male circumcision status was assessed. We used multivariate Andersen-Gill survival methods, adjusted for age, sexual behaviour, and plasma HIV RNA levels of the HIV infected partner. FINDINGS: 4716 HIV-1 serodiscordant couples (38%) with a man with HIV were followed for a median of 2.75 years. At enrolment, 1575 (53%) men with HIV and 560 (32%) men without HIV were circumcised; an additional 69 (4%) men with HIV and 132 (5%) men without HIV were circumcised during study follow up. 221 incident syphilis infections were reported: 46 (21%) in men with HIV (incidence 1.10 per 100 person-years), 76 (34%) in men without HIV (1.09), 54 (24%) in women with HIV (0.77), and 45 (24%) in women without HIV (1.11). Male circumcision was associated with a 42% reduction in incident syphilis in men (adjusted hazard ratio [aHR] 0.58, 95% CI 0.37-0.91) including a 62% reduction in men with HIV (0.38, 0.18-0.81), and a non-significant reduction in incident syphilis in men without HIV (0.64, 0.36-1.11). In women, circumcision of their male partners was associated with a 59% reduction in incident syphilis (aHR 0.41, 95% CI 0.25-0.69), including a 75% reduction in women without HIV (0.25, 0.08 0.76) and a 48% reduction in women with HIV (0.52, 0.27-0.97). INTERPRETATION: Male circumcision was associated with decreased risk of incident syphilis in men and women. If confirmed, these results suggest that medical male circumcision could substantially reduce incidence of syphilis and its sequelae. FUNDING: Bill & Melinda Gates Foundation and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. PMID- 25442695 TI - Potential benefit of omalizumab in respiratory diseases. AB - OBJECTIVE: To provide an overview of primary and secondary mechanisms associated with anti-IgE therapy and their relation to other potential indications in diseases affecting the respiratory tract. DATA SOURCES: Literature from PubMed searches for publications providing insight into secondary mechanisms resulting from anti-IgE therapy and publications reporting on the use of omalizumab to treat conditions that affect the respiratory tract, other than severe atopic asthma. STUDY SELECTIONS: Clinical trials or case reports were identified for asthma in patients without atopy, allergic rhinitis, nasal polyposis, and allergic bronchopulmonary aspergillosis. RESULTS: There is substantial evidence from controlled trials supporting a benefit for allergic rhinitis. Case reports and series on more than 50 patients with allergic bronchopulmonary aspergillosis have been published, including patients with or without cystic fibrosis; most have reported benefits in terms of decreased steroid use, exacerbation rates, and, in patients with cystic fibrosis, improvement in lung function. Several small controlled studies on nasal polyposis have shown equivocal results. One small controlled trial in patients with nonatopic asthma showed a significant improvement for lung function but not in exacerbation rate or asthma scores. CONCLUSION: Recent insight into the immunopathology of respiratory diseases should be used to identify patient populations likely to respond to anti-IgE therapy. Controlled clinical trials are needed to confirm efficacy and determine the clinical significance of the effects of omalizumab in these populations. PMID- 25442696 TI - Attitudes toward allergy: what do the pediatricians think? AB - BACKGROUND: In 1971, we published a survey regarding pediatricians' attitudes toward the field of allergy/immunology (A/I). Results indicated general attitudes and practices fell short of what most allergist-immunologists would hope. We revisited this in 1998 to determine how pediatricians' attitudes toward A/I had changed nearly 3 decades later. Despite some advances, results from 1998 revealed that A/I remained a misunderstood specialty. With the increasing incidence of atopic disorders and improving awareness of primary immunodeficiency, it is more important today than ever before that pediatricians and general practitioners have a strong appreciation for the scope of disorders the subspecialty of A/I encompasses. OBJECTIVE: To reevaluate attitudes and practices of pediatricians toward A/I 40 years after the initial study and 13 years after this topic was last addressed. METHODS: A 25-question survey was mailed to 293 pediatricians in the St Louis area. Surveys were completed confidentially. Pearson correlation and chi(2) analyses were performed. RESULTS: Of 293 pediatricians polled, 135 (46%) responded. Referrals to allergist-immunologists for urticaria have increased. Fewer pediatricians are referring asthma and atopic dermatitis patients to allergist-immunologists. Personal experience referring to an allergist immunologist remains the greatest influence on current attitudes toward A/I. Prior exposure to A/I during medical education continues to have the least influence on pediatricians' attitudes toward A/I. CONCLUSION: Increased appropriate referrals and improved patient outcomes could result from efforts to enhance A/I education during medical school and residency, maintain effective communication with referring physicians, and break down referral barriers to improve physicians' attitudes toward A/I. PMID- 25442697 TI - Allergen of the month--Chinese elm. PMID- 25442698 TI - 'Autoimmunity cutting edge at the 21st century. Representation of the 9th International Congress of Autoimmunity, Nice, France 2014'. PMID- 25442700 TI - Assessment and numerical search for minimal Taylor-Aris dispersion in micro machined channels of nearly rectangular cross-section. AB - A mathematical procedure using the Matlab(r) PDE toolbox to calculate the numerical constant appearing in the general Taylor-Aris expression for the dispersion in a laminar flow through open-tubular conduits with a variety of quasi-rectangular cross-sectional shapes is described. The procedure has been applied to assess the effect of some of the most frequently occurring etching imperfections (linear or curved tapering of the inter-pillar distance along the depth coordinate, occurrence of local notches) in etched pillar array columns. In addition, covering a broad range of possible geometries, a number of new shapes and optimal geometries to minimize the dispersion in open-tubular microchannels and pillar array columns have been proposed. Making a full shape-sensitivity study, it was also found that, whereas the proposed designs can theoretically reduce the dispersion up to a factor of 8, relatively small deviations from this ideal shape can however again dramatically increase the dispersion. Designers should therefore be very careful before implementing an optimized shape and should first aim at solving the etching imperfection problems. PMID- 25442699 TI - Ultrafine carbon particle mediated cardiovascular impairment of aged spontaneously hypertensive rats. AB - BACKGROUND: Studies provide compelling evidences for particulate matter (PM) associated cardiovascular health effects. Elderly individuals, particularly those with preexisting conditions like hypertension are regarded to be vulnerable. Experimental data are warranted to reveal the molecular pathomechanism of PM related cardiovascular impairments among aged/predisposed individuals. Thus we investigated the cardiovascular effects of ultrafine carbon particles (UfCP) on aged (12-13 months) spontaneously hypertensive rats (SHRs) and compared the findings with our pervious study on adult SHRs (6-7 months) to identify age related predisposition events in cardiovascular compromised elderly individuals. METHODS: Aged SHRs were inhalation exposed to UfCP for 24 h (~180 MUg/m3) followed by radio-telemetric assessment for blood pressure (BP) and heart rate (HR). Bronchoalveolar lavage (BAL) fluid cell differentials, interleukin 6 (IL-6) and other proinflammatory cytokines; serum C-reactive protein (CRP) and haptoglobin (HPT); and plasma fibrinogen were measured. Transcript levels of hemeoxygenase 1 (HO-1), endothelin 1 (ET1), endothelin receptors A, B (ETA, ETB), tissue factor (TF), and plasminogen activator inhibitor-1 (PAI-1) were measured in the lung and heart to assess oxidative stress, endothelial dysfunction and coagulation cascade. RESULT: UfCP exposed aged SHRs exhibited increased BP (4.4%) and HR (6.3%) on 1(st) recovery day paralleled by a 58% increase of neutrophils and 25% increase of IL-6 in the BAL fluid. Simultaneously higher CRP, HPT and fibrinogen levels in exposed SHRs indicate systemic inflammation. HO-1, ET1, ET A, ET-B, TF and PAI-1 were induced by 1.5-2.0 folds in lungs of aged SHRs on 1(st) recovery day. However, in UfCP exposed adult SHRs these markers were up regulated (2.5-6 fold) on 3(rd) recovery day in lung without detectable pulmonary/systemic inflammation. CONCLUSIONS: The UfCP induced pulmonary and systemic inflammation in aged SHRs is associated with oxidative stress, endothelial dysfunction and disturbed coagulatory hemostasis. UfCP exposure increased BP and HR in aged SHRs rats which was associated with lung inflammation, and increased expression of inflammatory, vasoconstriction and coagulation markers as well as systemic changes in biomarkers of thrombosis in aged SHRs. Our study provides further evidence for potential molecular mechanisms explaining the increased risk of particle mediated cardiac health effects in cardiovascular compromised elderly individuals. PMID- 25442701 TI - The influence of sexual orientation and sexual role on male grooming-related injuries and infections. AB - AIM: Pubic hair grooming is a common practice in the United States and coincides with prevalence of grooming-related injuries. Men who have sex with men (MSM) groom more frequently than men who have sex with women (MSW). We aim to characterize the influence of sexual orientation and sexual role on grooming behavior, injuries, and infections in men in the United States. METHODS: We conducted a nationally representative survey of noninstitutionalized adults aged 18-65 residing in the United States. We examined the prevalence and risk factors of injuries and infections that occur as a result of personal grooming. RESULTS: Of the 4,062 men who completed the survey, 3,176 (78.2%) report having sex with only women (MSW), 198 (4.9%) report sex with men (MSM), and 688 (16.9%) report not being sexually active. MSM are more likely to groom (42.5% vs. 29.0%, P < 0.001) and groom more around the anus, scrotum, and penile shaft compared with MSW. MSM receptive partners groom more often (50.9% vs. 26.9%, P = 0.005) and groom more for sex (85.3% vs. 51.9%, P < 0.001) compared with MSM insertive partners. MSM report more injuries to the anus (7.0% vs. 1.0%, P < 0.001), more grooming-related infections (7.0% vs. 1.0%, P < 0.001) and abscesses (8.8% vs. 2.5%, P = 0.010), as well as lifetime sexually transmitted infections (STIs) (1.65 vs. 1.45, P = 0.038) compared with MSW. More receptive partners report grooming at the time of their STI infection (52.2% vs. 14.3%, P < 0.001) compared with insertive partners. CONCLUSIONS: Sexual orientation, and in particular sexual role, may influence male grooming behavior and impact grooming-related injuries and infections. Anogenital grooming may put one at risk for an STI. Healthcare providers should be aware of different grooming practices in order to better educate safe depilatory practices (i.e., the use of electric razors for anogenital grooming) in patients of all sexual orientations. PMID- 25442702 TI - Declining HIV incidence among women in the United States. PMID- 25442703 TI - Intimate partner violence and safety strategy use: frequency of use and perceived effectiveness. AB - BACKGROUND: There is a need for effective interventions that enable women in current or past violent relationships to reduce their risk of revictimization. One approach that can be taken is safety planning, where advocates and women talk about strategies that theoretically increase the women's safety. Although this process is common, there is little empirical research focusing on the effectiveness of the safety strategies. METHODS: This systematic review examines the frequency with which women report using safety strategies and their effectiveness at reducing risk of revictimization. RESULTS: Nine studies reviewed confirm prior research, namely, that women in intimate partner violence situations are using a variety of safety strategies at varying frequencies to protect themselves. Results from two studies looking at whether use of safety strategies reduces a woman's risk of future violence provide modest support for a greater risk of revictimization among women who used resistance strategies. Seven studies examined the perceived helpfulness of the strategies. Women who involved other individuals reported that interaction as helpful. There are several limitations to this review, including the focus on perceived helpfulness. What is reported here is not an objective assessment of safety strategy effectiveness. We were also not able to determine whether strategies women reported using were actually discussed during safety planning. CONCLUSION: There is a dearth of literature focusing on the effectiveness of safety strategies. Women and advocates talk about safety strategies we know very little about. Additional research examining the consequences of using safety strategies is needed because what is known now is preliminary and limited. PMID- 25442704 TI - Women know best--findings from a thematic analysis of 5,214 surveys of abortion care experience. AB - OBJECTIVE: Patient experience is an essential component of quality care. Few studies have comprehensively evaluated patient experiences of abortion care. The objectives of this study were to describe women's experiences of abortion care in their own words, and to determine themes across patient experiences. STUDY DESIGN: Data for this thematic analysis, a qualitative method that allows for the identification, analysis, and report of patterns or themes within data, come from a larger study of safety and quality of aspiration abortion care across 22 clinical sites. Participants completed an abortion experience survey including fixed choice questions and an open-ended question: "Is there anything you would like to tell us about your experience?" The data were then categorized by responses to another survey question: "Overall, was your experience about, better, or worse than you expected?" RESULTS: A total of 5,214 responses were analyzed. Women reported positive abortion care experiences with the majority of women rating their experience as better than expected (n = 3,600). Two major themes that emerged from the data include clinic- and patient-level factors that impact how patients rate their experiences. Analysis of the responses categorized in the worse than expected group (n = 136) found that women primarily faulted clinic-level factors for their negative experiences, such as pain control and management, and wait time for appointments and in clinic. CONCLUSION: This analysis highlights specific areas of abortion care that influence patients' experience. The few women who were disappointed by care in the clinic tended to fault readily modifiable clinical factors, and provided suggested areas of improvement to enhance positive experiences related to their abortion care. PMID- 25442705 TI - Unit support protects against sexual harassment and assault among national guard soldiers. AB - OBJECTIVE: Despite concerns about increased sexual harassment and assault after the 2013 legislation repealing the ban on women in combat, little research has examined military factors that could prevent sexual harassment and assault during deployment. This study examined whether unit support, which reflects the quality of service members' relationships within their unit, protects against sexual harassment and assault during deployment. METHODS: Participants were 1,674 Ohio Army National Guard service members who reported at least one deployment during a telephone survey conducted in 2008 and 2009. Participants completed measures of sexual harassment/assault, unit support, and psychosocial support. Logistic regression was used to model odds of sexual harassment/assault. RESULTS: Approximately 13.2% of men (n = 198) and 43.5% of women (n = 74) reported sexual harassment, and 1.1% of men (n = 17) and 18.8% of women (n = 32) reported sexual assault during their most recent deployment. Greater unit support was associated with decreased odds of sexual harassment and assault. CONCLUSIONS: A substantial proportion of men and women reported sexual harassment/assault. Greater unit support was associated with diminished odds of sexual harassment/assault during deployment. Programming designed to improve unit cohesion has the potential to reduce sexual harassment and assault. PMID- 25442706 TI - Association between women veterans' experiences with VA outpatient health care and designation as a women's health provider in primary care clinics. AB - BACKGROUND: Women veterans comprise a small percentage of Department of Veterans Affairs (VA) health care users. Prior research on women veterans' experiences with primary care has focused on VA site differences and not individual provider characteristics. In 2010, the VA established policy requiring the provision of comprehensive women's health care by designated women's health providers (DWHPs). Little is known about the quality of health care delivered by DWHPs and women veterans' experience with care from these providers. METHODS: Secondary data were obtained from the VA Survey of Healthcare Experience of Patients (SHEP) using the Consumer Assessment of Healthcare Providers and Systems (CAHPS) patient-centered medical home (PCMH) survey from March 2012 through February 2013, a survey designed to measure patient experience with care and the DWHPs Assessment of Workforce Capacity that discerns between DWHPs versus non-DWHPs. FINDINGS: Of the 28,994 surveys mailed to women veterans, 24,789 were seen by primary care providers and 8,151 women responded to the survey (response rate, 32%). A total of 3,147 providers were evaluated by the SHEP-CAHPS-PCMH survey (40%; n = 1,267 were DWHPs). In a multivariable model, patients seen by DWHPs (relative risk, 1.02; 95% CI, 1.01-1.04) reported higher overall experiences with care compared with patients seen by non-DWHPs. CONCLUSIONS: The main finding is that women veterans' overall experiences with outpatient health care are slightly better for those receiving care from DWHPs compared with those receiving care from non DWHPs. Our findings have important policy implications for how to continue to improve women veterans' experiences. Our work provides support to increase access to DWHPs at VA primary care clinics. PMID- 25442707 TI - Health indicators associated with falls among middle-aged and older women enrolled in an evidence-based program. AB - BACKGROUND: Evidence-based fall prevention programs primarily attract older women, who are increasingly burdened by fall-related injuries. However, little is known about the relationship between older female participants' baseline health status and self-reported falls over the course of fall prevention interventions. Using data from A Matter of Balance/Volunteer Lay Leader Model (AMOB/VLL) workshops, this study examines female participants' sociodemographics and health indicators associated with self-reported falls at baseline and postintervention. METHODS: Data were analyzed from 837 older women (M = 76.2 years) collected during the statewide AMOB/VLL dissemination in Texas. Longitudinal Poisson regression models, using the generalized estimating equation method, were used to investigate the associations of personal characteristics and health indicators with and reductions in the number of self-reported falls from baseline to postintervention. FINDINGS: Approximately 21% of participants reported falling at baseline, and the number of reported falls significantly decreased from baseline to postintervention (beta = -0.443). At baseline, more unhealthy physical days (beta = 0.022), more unhealthy mental days (beta = 0.018), and lower Falls Efficacy Scale scores (beta = -0.052) were significantly associated with more falls reported at baseline. More falls at baseline was also associated with worse program attendance (beta = -0.069). Greater improvements in Falls Efficacy Scale Scores (beta = -0.069) and decreases in unhealthy physical health days (beta = 0.026) over the course of the intervention were significantly associated with greater reductions in reported falls at postintervention, respectively. CONCLUSIONS: Findings have implications for identifying at-risk older women upon enrollment, expanding the reach of AMOB/VLL, and leveraging AMOB/VLL to refer participants to other evidence-based exercise, disease management, and mental health interventions. PMID- 25442708 TI - Subjective social status and depression symptoms: a prospective study of women with noncancerous pelvic problems. AB - OBJECTIVE: Subjective social status (SSS) may be a stronger determinant of health than objective measures of socioeconomic status. We sought to examine the effect of community and national SSS on symptoms of depression in a racially/ethnically diverse sample of adult women with noncancerous uterine conditions. METHODS: We conducted a secondary analysis of data obtained from 634 women who enrolled in the Study of Pelvic Problems, Hysterectomy, and Intervention Alternatives (SOPHIA) in 2003 and 2004. SOPHIA was a longitudinal study of women aged 31 to 54 who were experiencing abnormal uterine bleeding, symptomatic fibroids, or pelvic pain. The primary outcome for this analysis consisted of symptoms suggesting major or other depressive disorder, as measured by the Patient Health Questionnaire-9, 2 years after study enrollment. We hypothesized that women who had low community and national SSS at baseline, as measured by the MacArthur SSS ladder, would be at higher risk of experiencing symptoms of depression at follow up. RESULTS: Women with low community SSS had an increased odds of experiencing depression symptoms 2 years later compared with women with high SSS, after adjusting for age, pelvic problem impact and baseline depression (odds ratio, 2.93; 95% CI, 1.11-7.77). Odds remained elevated after further adjusting for income and education. Results for the national ladder were not significant. CONCLUSION: Low perceived community social status is predictive of symptoms suggestive of major or other depressive disorder among women with noncancerous uterine conditions. Asking about perceived community social status can help clinicians to identify patients who may be at increased risk for depressive disorders. Asking about perceived national social status does not seem to add value beyond that provided by income and education. PMID- 25442709 TI - Accuracy of reduction and early clinical outcome in acetabular fractures treated by the standard ilio-inguinal versus the Stoppa/iliac approaches. AB - In acetabular fractures, the correct choice of the surgical approach is mandatory to achieve accurate reduction and to avoid complications. Anterior approaches include the ilio-inguinal, the Stoppa, the ilio-femoral and the para-rectal exposures. The first two are the most commonly used approaches nowadays. The aim of this study was to compare these two approaches. The standard three window ilio inguinal approach was compared to the intra-pelvic Stoppa approach with an added iliac window. The study enrolled 54 patients. Patients were divided into two groups. The first group consisted of 33 patients presented with acetabular fractures and had ORIF starting with an ilio-inguinal exposure. This group was compared to a second group of 21 patients who were treated with the Stoppa/iliac window approach. All patients were treated by one surgical team. The accuracy of reduction, the early clinical results and the approach related complications were compared. PMID- 25442710 TI - The relationship between socioeconomic status and fracture in a fracture clinic setting: data from the Nottingham Fracture Liaison Service. AB - BACKGROUND: This study aims to better understand the relationship between socioeconomic status (SES), fractures in those that attend an outpatient fracture clinic and a diagnosis of osteoporosis. This will further aid our ability to risk stratify patients' with fractures for further investigation and secondary management of their bone health. METHOD: This is a cross sectional analysis using data from the Nottingham Fracture Liaison Service of patients attending the outpatient fracture clinic from 1/01/08 to 31/12/11. Logistic regression adjusted for age and gender were used to investigate SES, fractures and a diagnosis of osteoporosis. Fisher's exact test was used to compare DXA attendance in those living in most deprived and least deprived area. A cut off of 65 years was used to conduct subset analysis of a younger and an older group. RESULTS: 6362 patients (1346 male, 5016 female; mean (SD) age, 69 (12)) were included in the study. There was no relationship between SES, proportion of fracture types and having a diagnosis of osteoporosis. Prevalence of osteoporosis in each SES quintile from 1 (most deprived) to 5 (least deprived) was 26.68%, 29.04%, 24.83%, 25.67% and 26.68% respectively. The least deprived quintile compared with the most deprived was not associated with a diagnosis of osteoporosis (OR 0.97; 95% CI 0.76-1.25, p=0.837). Those living in the most deprived area were less likely to attend their bone density scan appointment compared to those living in the least deprived area (OR 0.56; 95% CI 0.44-0.7, p<0.0001). CONCLUSION: This study has shown that there is no relationship between SES, fracture types and a diagnosis of osteoporosis in those that present to the fracture clinic. SES should not be used to risk stratify patients for further bone health management after fractures. Those living in the most deprived areas are less likely to attend their bone density scan and efforts need to be made to improve attendance in this group. PMID- 25442711 TI - Effects of beet pulp supplementation on growth performance, fecal moisture, serum hormones and litter performance in lactating sows. AB - This study was conducted to evaluate effects of beet pulp supplementation on growth performance, fecal moisture, serum hormones and litter performance in lactating sows. Ninety primiparous sows (Landrace * Yorkshire) were randomly allotted to one of three dietary treatments in a 21-day trial starting 3 days before parturition. The three dietary treatments were supplemented with 0, 10 and 20% beet pulp, respectively. Backfat loss and fecal moisture content were increased (P < 0.05), where cortisol and norepinephrine levels were decreased (P < 0.05) in sows fed beet pulp supplementation diets compared with control diet, but there was no difference between 10% and 20% beet pulp supplementation treatments. No effect was observed on bodyweight, average daily intake, weaning to estrus interval, epinephrine level in sows and litter weight, litter size, survivability in piglets among dietary treatments. Taken together, beet pulp supplementation has no significant effect of growth performance of lactating sows and piglets with decreased cortisol and norepinephrine levels in lactating sows, but it can increase fecal moisture content which is beneficial for sow feces excretion. PMID- 25442713 TI - Response to comment on "James K. Beattie, Alex M. Djerdjev, Angus Gray-Weale, Nikola Kallay, Johannes Lutzenkirchen, Tajana Preocanin, Atida Selmani, pH and the surface tension of water" [J. Colloid Interface Sci. 422 (1) (2014), 54-58]. PMID- 25442714 TI - A comment on "pH and the surface tension of water" (J. K. Beattie, A. M. Djerdjev, A. Gray-Weale, N. Kallay, J. Lutzenkirchen, T. Preocanin, A. Selmani, J. Colloid Interface Sci. 422 (2014) 54.). PMID- 25442712 TI - Electrochemical synthesis of nanostructured gold film for the study of carbohydrate-lectin interactions using localized surface plasmon resonance spectroscopy. AB - Localized surface plasmon resonance (LSPR) spectroscopy is a label-free chemical and biological molecular sensing technique whose sensitivity depends upon development of nanostructured transducers. Herein, we report an electrodeposition method for fabricating nanostructured gold films (NGFs) that can be used as transducers in LSPR spectroscopy. The NGF was prepared by electrodepositing gold from potassium dicyanoaurate solution onto a flat gold surface using two sequential controlled potential steps. Imaging by scanning electron microscopy reveals a morphology consisting of randomly configured block-like nanostructures. The bulk refractive index sensitivity of the prepared NGF is 100+/-2 nmRIU(-1) and the initial peak in the reflectance spectrum is at 518+/-1 nm under N2(g). The figure of merit is 1.7. In addition, we have studied the interaction between carbohydrate (mannose) and lectin (Concanavalin A) on the NGF surface using LSPR spectroscopy by measuring the interaction of 8-mercaptooctyl-alpha-d mannopyranoside (alphaMan-C8-SH) with Concanavalin A by first immobilizing alphaMan-C8-SH in mixed SAMs with 3,6-dioxa-8-mercaptooctanol (TEG-SH) on the NGF surface. The interaction of Con A with the mixed SAMs is confirmed using electrochemical impedance spectroscopy. Finally, the NGF surface was regenerated to its original sensitivity by removing the SAM and the bound biomolecules. The results from these experiments contribute toward the development of inexpensive LSPR based sensors that could be useful for studying glycan-protein interactions and other bioanalytical purposes. PMID- 25442715 TI - Nanocapsules loaded with iron-saturated bovine lactoferrin have antimicrobial therapeutic potential and maintain calcium, zinc and iron metabolism. AB - AIM: This study aimed to evaluate the potential antimicrobial efficacy of alginate gel-encapsulated ceramic nanocarriers loaded with iron-saturated bovine lactoferrin (Fe-bLf) nanocarriers/nanocapsules (AEC-CP-Fe-bLf NCs). MATERIALS & METHODS: The antimicrobial activities of non-nanoformulated apo (iron free), Fe bLf and native forms of Australian bLf against pathogenic Salmonella typhimurium (wild strain) were studied in vitro. The efficacy of AEC-CP-Fe-bLf NCs were checked in vivo using Balb/c mice model. RESULTS: The study revealed that native bLf is more effective in combating infection than the conventional drug ciprofloxacin (0.4 mg/ml). The efficacy of the drug was also revealed in vivo when BALB/c mice that, after being challenged with S. typhimurium (200 MUl of 10(8) CFU/ml suspension), were fed orally with a nanoformulated bLf diet and the infection was observed to be eliminated. However, chronic infection developed in the group of infected mice that did not receive any drug treatment, as well as the mice treated with ciprofloxacin. The immune response to bacterial infection and to various drug treatments thereafter was studied in the mice. CONCLUSION: The study concludes that bLf and nanoformulated Fe-bLf are more effective in the treatment of Salmonella-infected mice than ciprofloxacin. PMID- 25442716 TI - BURSTING POLLEN is required to organize the pollen germination plaque and pollen tube tip in Arabidopsis thaliana. AB - Pollen germination may occur via the so-called germination pores or directly through the pollen wall at the site of contact with the stigma. In this study, we addressed what processes take place during pollen hydration (i.e. before tube emergence), in a species with extra-poral pollen germination, Arabidopsis thaliana. A T-DNA mutant population was screened by segregation distortion analysis. Histological and electron microscopy techniques were applied to examine the wild-type and mutant phenotypes. Within 1 h of the start of pollen hydration, an intine-like structure consisting of cellulose, callose and at least partly de esterified pectin was formed at the pollen wall. Subsequently, this 'germination plaque' gradually extended and opened up to provide passage for the cytoplasm into the emerging pollen tube. BURSTING POLLEN (BUP) was identified as a gene essential for the correct organization of this plaque and the tip of the pollen tube. BUP encodes a novel Golgi-located glycosyltransferase related to the glycosyltransferase 4 (GT4) subfamily which is conserved throughout the plant kingdom. Extra-poral pollen germination involves the development of a germination plaque and BUP defines the correct plastic-elastic properties of this plaque and the pollen tube tip by affecting pectin synthesis or delivery. PMID- 25442717 TI - Genetic variation in Vibrio parahaemolyticus isolated from the aquacultural environments. AB - Environmental strains of Vibrio parahaemolyticus, a foodborne pathogen, were isolated from milkfish and grouper aquaculture facilities in southern Taiwan and characterized by pulsed-field gel electrophoresis (PFGE) and polymerase chain reaction targeting on the virulence-associated and genomic island (VPaI) marker genes. Analyses of 62 environmental isolates, including two putative pathogenic isolates, by NotI-PFGE revealed 11 pulse-type clusters with a similarity of 85%. Some of the T3SS2alpha-associated genes (vopB2, vopC and vopT) were not present in all of these two putative pathogenic isolates. Marker genes of VPaI-1 (MTase gene), VPaI-2 (VP0636) and VPaI-3 (VP1073 and VP1077) were detected in 14-100% of the environmental isolates examined, and the VP1073 and VP1077 of VPaI-3 marker genes were not detected. This study confirmed the high genetic variability of the environmental isolates including the putative pathogenic strains and identified some marker genes of VPaI in the environmental V. parahaemolyticus isolates. SIGNIFICANCE AND IMPACT OF THE STUDY: Vibrio parahaemolyticus is a prevalent seafood-borne enteropathogen with the appearance of pandemic O3:K6 strains in 1996. This study characterized the environmental nontoxigenic and toxigenic isolates by pulsed-field gel electrophoresis and the presence of marker genes of genomic islands. Results showed that the T3SS2alpha-associated genes are not present in all environmental tdh(+) isolates, and the presence of movable elements may contribute to genetic variation in the environmental V. parahaemolyticus isolates. PMID- 25442718 TI - Changing homelessness services: revanchism, 'professionalisation' and resistance. AB - This paper argues that the increasing international salience of homelessness can be partially explained by reference to the revanchist thesis (involving processes of coerced exclusion and abjection), but the situation on the ground is more complex. It reports on interviews with 18 representatives of 11 homelessness service providers in one city in England. As Cloke et al. found, these providers tended to be either larger, more 'professional', 'insider' services or smaller, more 'amateur', 'outsider' services. However, this does not mean that the former were necessarily more revanchist and the latter less so. Rather, the actions of both types of organisation could, in some cases, be construed as both advancing and counteracting a revanchist project. PMID- 25442719 TI - Application of resin adhesive on the surface of a silanized glass fiber reinforced post and its effect on the retention to root dentin. AB - INTRODUCTION: In this study, the effect of different post surface treatments on the retention of glass fiber-reinforced post to root dentin was evaluated. The hypotheses tested were (1) post silanization would not improve its retention and (2) the application of silane plus resin adhesive on the post would enhance its retention. METHODS: After root canal preparation, 4 different protocols (n = 5) of post surface treatment were evaluated, combined with or without silane (Silane coupling agent) and adhesive (Scotchbond Multipurpose): silane + adhesive (S/A), only silane, only adhesive, or no treatment (control). RelyX ARC was used for post cementation. Next, specimens were subjected to push-out bond strength testing, and data were analyzed by two-way analysis of variance and Tukey test (P < .05). RESULTS: S/A showed higher bond strength than other protocols in the middle and coronal root regions (P < .001). Only silane did not enhance post retention compared with control (P > .05). The root dentin region influenced bond strength results only in the S/A group. CONCLUSIONS: Whereas silanization as the only post surface treatment did not improve retention, the combination of silane plus resin adhesive enhanced post retention to dentin in the middle and coronal root regions. PMID- 25442720 TI - Prevalence of middle mesial canals in mandibular molars after guided troughing under high magnification: an in vivo investigation. AB - INTRODUCTION: A limited number of in vivo studies have discussed the prevalence of middle mesial canals in root canal systems of mandibular molars. The reported results have varied between 1% and 25%, with no detailed description of the depth and direction of troughing needed to identify such small canal orifices. The objective of the present study was to determine (1) the prevalence of a middle mesial canal before and after troughing by using a standardized troughing technique, (2) the pathway of the middle mesial canal in relation to the mesiobuccal (MB) and mesiolingual (ML) canals, and (3) its correlation with the patient's age. METHODS: Ninety-one mandibular molars from 87 patients were included in this study. The patient's age and tooth number were recorded. After access cavity preparation, a standardized troughing technique was performed between MB and ML canals to search for a middle mesial canal by using a dental operating microscope. If a middle mesial canal was located, it was recorded as separate or as joining the MB or the ML canals. Results were statistically analyzed by using Z test and logistic regression. RESULTS: A middle mesial canal was found in 42 of 91 mandibular molars (46.2%). Six middle mesial canals were located after conventional access preparation (6.6%). The other 36 were located after standardized troughing (39.6%). The results were statistically significant (P < .001). There was a higher tendency to locate the middle mesial canal in second molars (60%) versus first molars (37.5%). Younger patients had a significantly higher incidence of a middle mesial canal (P = .004). CONCLUSIONS: The middle mesial canal was present in 46.2% of mandibular molars. High magnification, troughing, and patient's age appeared to be determining factors in accessing the middle mesial canal. PMID- 25442721 TI - In vitro cytotoxicity of calcium silicate-containing endodontic sealers. AB - INTRODUCTION: The cytotoxicity of 2 novel calcium silicate-containing endodontic sealers to human gingival fibroblasts was studied. METHODS: EndoSequence BC (Brasseler, Savannah, GA), MTA Fillapex (Angelus Industria de Produtos Odontologicos S/A, Londrina, PR, Brazil) and a control sealer (AH Plus; Dentsply DeTrey GmbH, Konstanz, Germany) were evaluated. Human gingival fibroblasts were incubated for 3 days both with the extracts from fresh and set materials in culture medium and cultured on the surface of the set materials in Dulbecco modified Eagle medium. Fibroblasts cultured in Dulbecco-modified Eagle medium were used as a control group. Cytotoxicity was evaluated by flow cytometry, and the adhesion of the fibroblasts to the surface of the set materials was assessed using scanning electron microscopy. The data of cell cytotoxicity were analyzed statistically using a 1-way analysis of variance test at a significance level of P < .05. RESULTS: Cells incubated with extracts from BC Sealer showed higher viabilities at all extract concentrations than cells incubated with extracts from freshly mixed AH Plus and fresh and set MTA Fillapex, esspecially for the high extract concentrations (1:2 and 1:8 dilutions). Extracts from set MTA Fillapex of 2 weeks and older were more cytotoxic than extracts from freshly mixed and 1-week old cement. With extract concentrations of 1:32 and lower, MTA Fillapex was no longer cytotoxic. After setting, AH Plus was no longer cytotoxic, and the fibroblast cells grew on set AH Plus equally as well as on BC Sealer. CONCLUSIONS: BC Sealer and MTA Fillapex, the 2 calcium silicate-containing endodontic sealers, exhibited different cytotoxicity to human gingival fibroblasts. PMID- 25442722 TI - Effect of sodium bicarbonate-buffered lidocaine on the success of inferior alveolar nerve block for teeth with symptomatic irreversible pulpitis: a prospective, randomized double-blind study. AB - INTRODUCTION: The purpose of this prospective, randomized, double-blind study was to compare the anesthetic efficacy of buffered with nonbuffered 2% lidocaine with 1:80,000 epinephrine solution for inferior alveolar nerve (IAN) block in patients with mandibular posterior teeth experiencing symptomatic irreversible pulpitis. METHODS: Eighty adult patients diagnosed with symptomatic irreversible pulpitis of a mandibular posterior tooth were selected. The patients received 2 cartridges of either 2% lidocaine with 1:80,000 epinephrine buffered with 0.18 mL 8.4% sodium bicarbonate or 2% lidocaine with 1:80,000 epinephrine with 0.18 mL sterile distilled water using conventional IAN block injections. Endodontic access preparation was initiated 15 minutes after injection. Lip numbness was required for all the patients. Success was determined as no or mild pain on the basis of Heft-Parker visual analog scale recordings upon access cavity preparation or initial instrumentation. Data were analyzed by the t, Mann-Whitney, and chi square tests. RESULTS: The success rates were 62.5% and 47.5% for buffered and nonbuffered groups, respectively, with no significant differences between the two groups (P = .381). CONCLUSIONS: Buffering the 2% lidocaine with 1:80,000 epinephrine with 8.4% sodium bicarbonate did not improve the success of the IAN block in mandibular molars in patients with symptomatic irreversible pulpitis. PMID- 25442723 TI - In situ assessment of the setting of tricalcium silicate-based sealers using a dentin pressure model. AB - INTRODUCTION: EndoSequence BC Sealer (Brasseler, Savannah, GA) is a premixed tricalcium silicate-based root canal sealer that requires moisture from the root dentin to hydrate. The aim of this study was to investigate the setting of EndoSequence BC Sealer and other sealers in contact with human dentin in a simulated clinical environment. METHODS: EndoSequence BC Sealer, MTA Fillapex (Angelus, Londrina, Brazil), Septodont Sealer (Septodont, Saint Maur-des-Fosses, France), and Apexit Plus (Ivoclar, Schaan, Lichtenstein) were assessed. Caries free lower premolars extracted for orthodontic purposes in patients aged 13-16 years were standardized to a 10-mm root length and were filled with test sealers and set up in a dentin pressure model for 14 days. In addition, set sealers immersed in physiologic solution for 14 days were also assessed. The set materials in solution and materials retrieved from the dentin pressure setup were characterized by scanning electron microscopy and X-ray diffraction analysis. The setting time and radiopacity were assessed using ISO 6876:2002 specifications. Furthermore, mineral ion leaching was evaluated by inductively coupled plasma mass spectrometry. RESULTS: All the sealers tested exhibited formation of a calcium phosphate phase when in contact with physiologic solution. Septodont Sealer and Apexit Plus did not exhibit the formation of a calcium phosphate phase in the dentin pressure setup. The fluid in the system was enough to allow the setting of EndoSequence BC Sealer, which did not set in a dry environment. All materials leached calcium with the Septodont Sealer, exhibiting double the calcium ion leaching compared with EndoSequence BC Sealer. CONCLUSIONS: Using the dentinal fluid pressure system resulted in an adequate flow of dentinal fluid that allowed EndoSequence BC Sealer to set inside the root canal. Although the sealers tested were tricalcium silicate based, the hydration reaction and bioactivity in the presence of dentinal fluid were different to hydration in vitro. Thus, clinically, material bioactivity cannot be assumed. PMID- 25442724 TI - Evaluation of the Gow-Gates and Vazirani-Akinosi techniques in patients with symptomatic irreversible pulpitis: a prospective randomized study. AB - INTRODUCTION: Few studies have evaluated the effectiveness of the Gow-Gates and Vazirani-Akinosi techniques in patients presenting with symptomatic irreversible pulpitis. Therefore, the purpose of this prospective, randomized study was to evaluate the anesthetic efficacy of the Gow-Gates and Vazirani-Akinosi techniques using 3.6 mL 2% lidocaine with 1:100,000 epinephrine in mandibular posterior teeth in patients presenting with symptomatic irreversible pulpitis. METHODS: One hundred twenty-five emergency patients diagnosed with symptomatic irreversible pulpitis randomly received either a Gow-Gates or Vazirani-Akinosi injection using 3.6 mL 2% lidocaine with 1:100,000 epinephrine to block the inferior alveolar nerve before endodontic access. Subjective lip numbness was recorded. Pulpal anesthetic success of the injection was defined as no pain or mild pain upon endodontic access and instrumentation as measured on a visual analog scale. RESULTS: Subjective lip numbness was obtained 92% of the time with the Gow-Gates technique and 63% of the time with the Vazirani-Akinosi technique. The difference was statistically significant (P = .0001). For the patients achieving lip numbness, successful pulpal anesthesia was obtained 35% of the time with the Gow Gates technique and 16% of the time with the Vazirani-Akinosi technique. The difference was statistically significant (P = .0381). CONCLUSIONS: We concluded that for patients who achieved lip numbness neither the Gow-Gates technique nor the Vazirani-Akinosi technique provided adequate pulpal anesthesia for mandibular posterior teeth in patients presenting with symptomatic irreversible pulpitis. Both injections would require supplemental anesthesia. PMID- 25442725 TI - Does acetaminophen/hydrocodone affect cold pulpal testing in patients with symptomatic irreversible pulpitis? A prospective, randomized, double-blind, placebo-controlled study. AB - INTRODUCTION: The purpose of this prospective randomized, double-blind, placebo controlled study was to determine the effects of a combination dose of 1000 mg acetaminophen/10 mg hydrocodone on cold pulpal testing in patients experiencing symptomatic irreversible pulpitis. METHODS: One hundred emergency patients in moderate to severe pain diagnosed with symptomatic irreversible pulpitis of a mandibular posterior tooth randomly received, in a double-blind manner, identical capsules of either a combination of 1000 mg acetaminophen/10 hydrocodone or placebo. Cold testing with Endo-Ice (1,1,1,2 tetrafluoroethane; Hygenic Corp, Akron, OH) was performed at baseline and every 10 minutes for 60 minutes. Pain to cold testing was recorded by the patient using a Heft-Parker visual analog scale. Patients' reaction to the cold application was also rated. RESULTS: Cold testing at baseline and at 10 minutes resulted in severe pain for both the acetaminophen/hydrocodone and placebo groups. Although pain ratings decreased from 20-60 minutes, the ratings still resulted in moderate pain. Patient reaction to cold testing showed that 56%-62% had a severe reaction. Although the reactions decreased in severity over the 60 minutes, 20%-34% still had severe reactions at 60 minutes. Regarding pain and patients' reactions to cold testing, there were no significant differences between the combination acetaminophen/hydrocodone and placebo groups at any time period. CONCLUSIONS: A combination dose of 1000 mg of acetaminophen/10 mg of hydrocodone did not statistically affect cold pulpal testing in patients presenting with symptomatic irreversible pulpitis. Patients experienced moderate to severe pain and reactions to cold testing. PMID- 25442727 TI - Evaluation of the breakage of orthograde endodontic ultrasonic tips. AB - INTRODUCTION: The objective of this study was to compare the breakage of 3 endodontic ultrasonic tips when removing dentin from extracted molars. METHODS: Three tips were tested (n = 10): BUC 1A (Obtura Spartan, Fenton, MO), CPR 5D (Obtura Spartan), and EDS 5E (Essential Dental Systems, South Hackensack, NJ). Extracted molars were prepared and mounted to a slow-speed alternating-current motor of a custom testing apparatus, which provided a 5-mm linear movement at an approximate rate of 4 mm/s. A 20-g axial force was applied to the tooth specimens. The MiniEndo II Ultrasonic Unit (SybronEndo, Orange, CA) was used to operate the ultrasonic tips in 20-second cycles with 10 seconds of rest between each cycle. The process was repeated until breakage was observed or 10 minutes had elapsed. The time to breakage was recorded for each sample. Tips that did not break were assigned a breakage time of 10 minutes. RESULTS: There was a statistically significant difference in breakage as a function of tip type (P = .0002). No EDS 5E tips were observed to break after 10 minutes of instrumentation. CONCLUSIONS: Based on the results of the investigation, the EDS 5E tip is significantly more resistant to breakage than the other tips tested. PMID- 25442726 TI - Comparison of pH changes induced by calcium enriched mixture and those of calcium hydroxide in simulated root resorption defects. AB - INTRODUCTION: External resorption usually occurs after dental trauma and the loss of root cementum. Because it has the ability to induce alkaline pH, calcium hydroxide is used in treatment of external resorption, which is reportedly not free from disadvantages. Driven by such understanding, the aim of this in vitro study was to compare the pH changes induced by calcium enriched mixture (CEM) and those of calcium hydroxide in simulated root resorption defects. METHODS: Twenty one paired extracted human premolars were cut to the length of 14 mm. Root canal preparation was performed by using ProTaper rotary system. Cavities of 0.7-mm depth and 1.4-mm diameter were prepared on the external root surface, 5 mm from the apex. Half of the teeth were filled with CEM and the other half with calcium hydroxide. Five premolars were also assigned as the negative control group and filled with normal saline. To be assured of the filling quality, a radiograph was obtained from each tooth. Subsequently, pH of the cavity was measured with a microelectrode at 20-minute, 3-hour, and 1-, 7-, 14-, 21-, and 28-day intervals after filling. RESULTS: Mean pH in the CEM and in the calcium hydroxide groups were significantly varied during the study period, with pH of the calcium hydroxide group significantly higher than that of CEM in all of the measurements. However, no significant difference was observed between the pH of the calcium hydroxide group and that of the control group at the 7-day and 14-day measurements and between those of the CEM group and the control group at days 7, 21, and 28. CONCLUSIONS: In comparison with calcium hydroxide, CEM hardly maintained alkaline pH during the first month of use, and so CEM may be an inappropriate material in treatment of external root resorption. PMID- 25442728 TI - Reciprocating versus rotary systems for root filling removal: assessment of the apically extruded material. AB - INTRODUCTION: This study was designed to quantitatively evaluate the amount of apically extruded debris by comparing the ProTaper Universal Retreatment system (Dentsply Maillefer, Ballaigues, Switzerland) with 2 reciprocating single-file systems (Reciproc [VDW, Munich, Germany] and WaveOne [Dentsply Maillefer]) during endodontic retreatment. METHODS: Forty-five mandibular premolars with a single canal were prepared with the ProTaper Universal system and then obturated. The specimens were divided into 3 groups (n = 15) according to the system used for filling removal: ProTaper Universal Retreatment system associated with the ProTaper Universal system (until file F4 40/0.06]), Reciproc system (Reciproc R40 [40/0.06]), and WaveOne system (WaveOne Large [40/0.08]). Sodium hypochlorite was used as an irrigant, and the apically extruded debris was collected in glass vials and then dried. The mean weight of debris was assessed with a microbalance and statistically analyzed using 1-way analysis of variance and post hoc Tukey multiple comparison tests (P < .05). RESULTS: The ProTaper Universal Retreatment system produced significantly more debris compared with the Reciproc and WaveOne systems (P < .01). The reciprocating systems showed no significant difference between them (P > .05). CONCLUSIONS: Under the conditions of the present study, all systems caused apical debris extrusion. Reciprocating systems were associated with less debris extrusion when compared with a conventional rotary retreatment system. PMID- 25442729 TI - Computed tomographic imaging of renal and ureteral emergencies. AB - A variety of renal and ureteral pathologies are encountered on computed tomographic scans performed in the emergency department. Although these are often suspected based on the patient's clinical presentation, they may also be fortuitous or incidental findings. Stone disease is the most common genitourinary condition seen in the acute setting; however, other conditions such as infection, hemorrhage, acute ischemic disease, and iatrogenic and traumatic injuries may also occur. We review the computed tomographic features of the spectrum of these conditions. PMID- 25442730 TI - Breast lesions on chest computed tomography: pictorial review with mammography and ultrasound correlation. AB - This pictorial review demonstrates computed tomography (CT) features with mammogram and, in some instances, ultrasound and positron emission tomography scan correlation of a wide spectrum of both malignant and benign findings on breast evaluation. Characterization of the margins, shape, pattern of enhancement, density, and associated findings is essential for accurate assessment of breast lesions during CT examination. Spiculated margins, irregular shape, and the presence of enhancement have a high predictive pattern for malignancy. The associated findings that could be seen include skin thickening, lymphadenopathy, architectural distortion, or chest wall or skin invasion. Nearly all detected breast calcifications on chest CT scans are benign. However, any breast masses and calcifications seen need further evaluation by other modalities, such as mammography or ultrasound or both. PMID- 25442731 TI - Identifying and Referring Youths at Risk for Suicide Following Participation in School-Based Gatekeeper Training. AB - Gatekeeper training is a core strategy of the Garrett Lee Smith Memorial Suicide Prevention Act of 2004. Using data gathered from school-based gatekeeper trainings implemented by GLS grantees, this analysis examines training and gatekeeper factors associated with (1) identification and referral patterns and (2) services at-risk youths receive. Time spent interacting with youths was positively correlated with the number of gatekeeper identifications and knowledge about service receipt. Gatekeepers who participated in longer trainings identified proportionately more at-risk youths than participants in shorter trainings. Most gatekeeper trainees referred the identified youths to services regardless of training type. PMID- 25442732 TI - Atrial fibrillation and dementia. AB - Emerging evidence has shown a consistent association between AF and risk of dementia, including Alzheimer's disease. It is likely that a constellation of various mechanisms combine to cause dementia in AF patients. Both AF and dementia share multiple common risk factors, and as such these may be targets of early prevention strategies to reduce risk. In patients with AF, choices regarding type and duration of anticoagulation as well as rhythm- and rate-control strategies can influence dementia risk. PMID- 25442733 TI - New cholesterol guidelines and primary prevention in women. AB - Cardiovascular disease (CVD) remains the leading cause of death for women in the United States. The role of primary prevention of CVD is a necessary focus of healthcare, given the overall prevalence of CVD and its risk factors in women. In 2013, the American College of Cardiology and the American Heart Association released new guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk (ASCVD) in adults that were based on results of randomized controlled trials. These guidelines apply to both men and women. Achievement of a target cholesterol level is no longer part of the guidelines. Rather, the guidelines recommend an appropriate and fixed intensity of a statin based on calculation of an individual's risk of ASCVD or in diabetics or those with severely elevated LDL-C for primary prevention. The new guidelines emphasize statin therapy over other lipid-lowering therapy. The new guidelines are evidence based, coming from randomized control trials that have clearly demonstrated improved outcomes using statin therapy in those with ASCVD and those at high risk of ASCVD, not based on LDL targets but rather LDL lowering. This evidence-based approach to ASCVD prevention should be used in women. There were no specific sex differences in the new guidelines, and the focus of this article is to provide the evidence to support the use of these guidelines in women. PMID- 25442734 TI - MY APPROACH to selecting cardiac computed tomography vs cardiac magnetic resonance imaging vs echocardiography. PMID- 25442736 TI - MY APPROACH to treatment of the congenital long QT syndromes. PMID- 25442735 TI - Insights into cardiac conduction system formation provided by HCN4 expression. AB - Specialized myocytes of the cardiac conduction system (CCS) are essential to coordinate sequential contraction of cardiac atria and ventricles. Anomalies of the CCS can result in lethal cardiac arrhythmias, including sick sinus syndrome and atrial or ventricular fibrillation. To develop future therapies and regenerative medicine aimed at cardiac arrhythmias, it is important to understand formation and function of distinct components of the CCS. Essential to this understanding is the development of CCS-specific markers. In this review, we briefly summarize available mouse models of CCS markers and focus on those involving the hyperpolarization cation-selective nucleotide-gated cation channel, HCN4, which selectively marks all components of the specialized CCS in adult heart. Recent studies have revealed, however, that HCN4 expression during development is highly dynamic in cardiac precursors. These studies have offered insights into the contributions of the first and second heart field to myocyte and conduction system lineages and suggested the timing of allocation of specific conduction system precursors during development. Altogether, they have highlighted the utility of HCN4 as a cell surface marker for distinct components of the CCS at distinct stages of development, which can be utilized to facilitate purification and characterization of CCS precursors in mouse and human model systems and pave the way for regenerative therapies. PMID- 25442737 TI - Clinical aspects of inherited J-wave syndromes. AB - Presence of J-point elevation with rapidly ascending ST segment in the anterior leads of the 12-lead electrocardiogram has been generally considered a benign phenomenon. The concept of benign nature of J-waves has changed as data emerged on variants of J-waves that were associated with the increased risk of sudden cardiac death. Two specific inherited arrhythmia syndromes, such as Brugada syndrome and early repolarization syndrome, have been recognized that carry an increased risk for ventricular fibrillation. The current review is aimed at discussing the clinical aspects of these syndromes and the implications of incidental recognition of the J-waves in a randomly recorded electrocardiogram of asymptomatic subjects. PMID- 25442738 TI - Multiple Ca2+ channel-dependent components in growth hormone secretion from rat anterior pituitary somatotrophs. AB - The involvement of L-type Ca(2+) channels in both 'basal' and 'stimulated' growth hormone (GH) secretion is well established; however, knowledge regarding the involvement of non-L-type Ca(2+) channels is lacking. We investigated whether non L-type Ca(2+) channels regulate GH secretion from anterior pituitary (AP) cells. To this end, GH secretion was monitored from dissociated AP cells, which were incubated for 15 min with 2 mm K(+) ('basal' secretion) or 60 mm K(+) ('stimulated' secretion). The role of non-L-type Ca(2+) influx was investigated using specific channel blockers, including omega-agatoxin-IVA, omega-conotoxin GVIA or SNX-482, to block P/Q-, N- or R-type Ca(2+) channels, respectively. Our results demonstrate that P/Q-, N- and R-type Ca(2+) channels contributed 21.2 +/- 1.9%, 20.2 +/- 7.6% and 11.4 +/- 1.8%, respectively, to 'basal' GH secretion and 18.3 +/- 1.0%, 24.4 +/- 5.4% and 14.2 +/- 4.8%, respectively, to 'stimulated' GH secretion. After treatment with a 'cocktail' that comprised the previously described non-L-type blockers, non-L-type Ca(2+) channels contributed 50.9 +/- 0.4% and 45.5 +/- 2.0% to 'basal' and 'stimulated' GH secretion, respectively. Similarly, based on the effects of nifedipine (10 MUM), L-type Ca(2+) channels contributed 34.2 +/- 3.7% and 54.7 +/- 4.1% to 'basal' and 'stimulated' GH secretion, respectively. Interestingly, the relative contributions of L-type/non L-type Ca(2+) channels to 'stimulated' GH secretion were well correlated with the relative contributions of L-type/non-L-type Ca(2+) channels to voltage-gated Ca(2+) influx in AP cells. Finally, we demonstrated that compartmentalisation of Ca(2+) channels is important for GH secretion. Lipid raft disruption (methyl-beta cyclodextrin, 10 mm) abrogated the compartmentalisation of Ca(2+) channels and substantially reduced 'basal' and 'stimulated' GH secretion by 43.2 +/- 3.4% and 58.4 +/- 4.0%, respectively. In summary, we have demonstrated that multiple Ca(2+) channel-dependent pathways regulate GH secretion. The proper function of these pathways depends on their compartmentalisation within AP cell membranes. PMID- 25442739 TI - Bony defect of palate and vomer in submucous cleft palate patients. AB - The aim of this study was to visualize bony defects of the palate and vomer in submucous cleft palate patients (SMCP) by three-dimensional (3D) computed tomography (CT) reconstruction and to classify the range of bony defects. Forty eight consecutive non-operated SMCP patients were included. Diagnosis was based on the presence of at least one of three classical signs of SMCP: bifid uvula, a translucent zone in the midline of the soft palate, and a palpable 'V' notch on the posterior border of the bony palate. Patients were imaged using spiral CT. 3D reconstruction models were created of the palate and vomer. The sagittal extent of the bony cleft in SMCP was classified into four types: type I, no V-shaped hard palate cleft (8.3%); type II, cleft involving the partial palate (43.8%); type III, cleft involving the complete palate and extending to the incisive foramen (43.8%); type IV, cleft involving the complete palate and the alveolar bone (4.2%). The extent of the vomer defect was classified into three types: type A, vomer completely fused with the palate (8.3%); type B, vomer partially fused with the palate (43.8%); type C, vomer not fused with the palate up to the incisive foramen (47.9%). Significant variability in hard palate defects in SMCP is the rule rather than the exception. The association of velopharyngeal insufficiency with anatomical malformations may be complex. PMID- 25442740 TI - Complications of mandibular distraction osteogenesis for developmental deformities: a systematic review of the literature. AB - A systematic review of English and non-English articles on the complications of mandibular distraction osteogenesis (MDO) for patients with developmental deformities was performed, in accordance with the PRISMA statement. Search terms expressing distraction osteogenesis were used in 'AND' combination with search terms comprising 'mandible' and terms for complication, failure, and morbidity. A search using PubMed (National Library of Medicine, NCBI), EMBASE, and Cochrane Controlled Trials Register yielded 644 articles published between 1966 and mid October 2013. Clinical articles that reported complications related to MDO in developmental deformities were included. Two hundred and fifty articles were eligible and were screened in detail. A total of 32 articles reporting the cases of 565 patients were finally included. Patients underwent mandibular lengthening and transverse widening. A total of 211 complications were reported (37.4%); these were classified according to an index that indicates the clinical impact. Inferior alveolar nerve (IAN) neurosensory disturbances, minor infection, device failure, anterior open bite, permanent dental damage, and skeletal relapse were most represented. Complications that resolved spontaneously (type I) were seen in 11.0%, medically or technically manageable complications, without hospitalization, were seen in 10.8% (type II), and permanent complications (type VI) were seen in 9.6%. PMID- 25442741 TI - The role of diffusion-weighted magnetic resonance imaging in the diagnosis, lymph node staging and assessment of treatment response of head and neck cancer. AB - Standard magnetic resonance imaging (MRI) and computed tomography continue to be the imaging modalities of choice in staging and reviewing patients with head and neck cancer. Diffusion-weighted MRI (DW-MRI) is an advanced imaging modality that records the molecular diffusion of protons and thus provides an opportunity to further assess tissue character. Interest in DW-MRI of the head and neck continues to grow, especially its application to the assessment and treatment of head and neck cancer. We highlight the potential role of DW-MRI in the delineation, characterization, and lymph node staging of head and neck tumours. Furthermore, we discuss the ability of DW-MRI to provide a real opportunity to differentiate post-treatment tumour recurrence from chemoradiotherapy-induced local tissue changes. The future impact of these findings upon the clinical practice of the head and neck surgeon is discussed. PMID- 25442742 TI - Computer-assisted surgical planning and intraoperative navigation in the treatment of condylar osteochondroma. AB - Mandibular condylar osteochondroma (OC) results in asymmetric prognathism with facial morphology and functional disturbances. The aim of this study was to explore the feasibility of computer-assisted surgical planning combined with intraoperative navigation in the treatment of condylar OC. Five patients with mandibular condylar OC were enrolled in this study. Surgical planning and simulation was performed based on a computed tomography reconstruction model using SurgiCase software. Under the guidance of navigation, a condylar OC resection and conservative condylectomy was carried out via intraoral approach. Simultaneous orthognathic surgery was used to correct the facial asymmetry and malocclusion. All patients healed uneventfully. No facial nerve injury or salivary fistula occurred. Facial symmetry and morphology were greatly improved and stable occlusion was obtained in all cases. Good matching between preoperative planning and postoperative results was achieved. Patients showed no signs of recurrence or temporomandibular joint ankylosis during follow-up of 12 30 months. Computer-assisted surgical planning and intraoperative navigation is a valuable option in the treatment of mandibular condylar OC. PMID- 25442743 TI - Lipopolysaccharide aggravates bisphosphonate-induced osteonecrosis in rats. AB - The pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is highly controversial. We have previously reported the development of osteonecrosis by periodontal pathogenic stimulation in the jaw and femur of rats treated with bisphosphonate. Since the major toxicity factor of Gram-negative bacteria is lipopolysaccharide (LPS), the present study aimed to evaluate the relationship between osteonecrosis and LPS in a rat model of BRON-like lesions. Seventeen male rats were injected subcutaneously with zoledronic acid weekly for 4 weeks and divided into three groups: LPS (LPS administered into the bone marrow of the mandible and femur) and LPS plus polymyxin B (PMB) and saline groups (given neutralized LPS with PMB or saline, respectively, using the same protocol). At 4 weeks after the procedure, harvested specimens were analyzed using histomorphology (n=5 from each group) and histochemistry (n=1 each from LPS and LPS plus PMB groups). There was a significantly wider area of osteonecrosis in the LPS group as compared to the saline and LPS plus PMB groups in both the mandible (P=0.030 and P=0.009, respectively) and femur (P=0.002 and P=0.020, respectively). Our results indicate that LPS stimulation is deeply involved in the development and promotion of BRON. PMID- 25442744 TI - Performance of cone beam computed tomography in comparison to conventional imaging techniques for the detection of bone invasion in oral cancer. AB - Detecting bone invasion in oral cancer is crucial for therapy planning and the prognosis. The present study evaluated cone beam computed tomography (CBCT) for detecting bone invasion in comparison to standard imaging techniques. A total of 197 patients with diagnoses of oral cancer underwent CBCT as part of preoperative staging between January 2007 and April 2013. The sensitivity, specificity, and accuracy of CBCT were compared with panoramic radiography (PR), multi-slice computed tomography (CT) or magnetic resonance imaging (MRI), and bone scintigraphy (BS) using McNemar's test. Histopathology and clinical follow-up served as references for the presence of bone invasion. CBCT and BS (84.8% and 89.3%, respectively), as well as CBCT and CT/MRI (83.2%), showed comparable accuracy (P = 0.188 and P = 0.771). CBCT was significantly superior to PR, which was reconstructed based on a CBCT dataset (74.1%, P = 0.002). In detecting bone invasion, CBCT was significantly more accurate than PR and was comparable to BS and CT/MRI. However, each method has certain advantages, and the best combination of imaging methods must be evaluated in prospective clinic trials. PMID- 25442745 TI - Commentary on "reattachment of flexor digitorum profundus avulsion: biomechanical performance of 3 techniques". Zone I flexor tendon repairs: more strength not worth altered joint kinematics. PMID- 25442746 TI - Closed flexor tendon ruptures. AB - We review different causes, diagnoses, and treatment options of closed flexor tendon disruptions in the hand. A classification of closed tendon ruptures based on their mechanism includes traumatic tendon avulsion, spontaneous midsubstance rupture, attrition rupture, infiltrative tenosynovial rupture, and iatrogenic. Certain conditions result in tendon disruption inflicted by more than 1 of these etiologies. In rheumatoid arthritis, tendon rupture may result from attrition on an exposed rough surface, proliferative tenosynovial tendon infiltration, or steroid use. PMID- 25442747 TI - Physical examination of the hand. AB - Examination of the hand is an essential piece of a hand surgeon's skill set. This current concepts review presents a systematic process of performing a comprehensive physical examination of the hand including vascular, sensory, and motor assessments. Evaluations focused on specific hand diseases and injuries are also discussed. This information can be useful for any health care provider treating patients with hand conditions. PMID- 25442748 TI - Are hamate fractures common? Letter regarding "carpal fractures" article. PMID- 25442749 TI - In reply. PMID- 25442750 TI - Letter regarding "a stepwise algorithm for surgical treatment of type II displaced pediatric phalangeal neck fractures". PMID- 25442751 TI - In reply. PMID- 25442752 TI - Gentle manual reduction for traumatic bowing/plastic deformation of the ulna with radial head dislocation. PMID- 25442753 TI - A simple technique for confirmation of complete release in surgical treatment of pediatric trigger thumb. PMID- 25442754 TI - Pre-hospital stroke management: an Australian perspective. PMID- 25442755 TI - Mandatory reporting of impaired doctors: protecting the community or increasing the risk? PMID- 25442756 TI - Mandatory notification of impaired doctors. AB - Mandatory reporting of impaired doctors is compulsory in Australasia. Australian Health Practitioner Regulation Agency guidelines for notification claim high benchmark though the Royal Australasian College of Surgeons and the Royal Australasian College of Physicians suggest they still obstruct doctors seeking help. Western Australia excludes mandatory reporting of practitioner-patients. This study examines reporting, consequences and international experiences with notification. Depressed doctors avoid diagnosis and treatment, fearing consequences, yet are more prone to marital problems, substance dependence and needing psychotherapy. South African research confirms isolation of impaired doctors and delayed seeking help with definable characteristics of those at risk. New Zealand data acknowledge: errors occur; questionable contribution from mandatory reporting; issues concerning competence assessment; favouring reporting to senior colleagues or self-intervention to compliance with mandatory reporting. UK found an anaesthetist guilty of professional misconduct for not reporting and sanctioned doctors regarding Harold Shipman. Australians are reluctant to report, fearing legalistic intrusion into care. Australian research confirmed definable characteristics for doctors with psychiatric illness or alcohol abuse. Exposure to legal medicine evokes personal disenchantment for doctors involved. Medicine poses barriers for impaired doctors. Spanish and UK doctors do not use general practitioners and may have suboptimal care. US and European doctors self-medicate using samples. US drug-dependent doctors also prescribe for spouses. Junior doctors are losing empathy with the profession. UK doctors favour private care, avoiding public scrutiny. NZ and Brazil created specific services for doctors, which appear effective. Mandatory reporting may be counterproductive requiring reappraisal. PMID- 25442757 TI - Mandatory reporting of impaired medical practitioners: protecting patients, supporting practitioners. AB - Taking action to protect patients from impaired colleagues is a long-standing ethical and professional obligation. In 2010, this responsibility was codified in law with the introduction, across Australia, of a new mandatory reporting regimen. While several concerns remain to be addressed, mandatory reporting has the potential not only to reinforce the primacy of patient safety, but also to open internal dialogue about the profession's response to concerns about practitioner health and well-being. Four years after the introduction of the scheme, key challenges include ensuring the reporting threshold is appropriately defined and clearly understood, improving access to evidence-based health programmes for practitioners, and strengthening upstream protections to prevent and minimise impairment at its roots. PMID- 25442758 TI - Vanishing bile duct syndrome and immunodeficiency preceding the diagnosis of Hodgkin lymphoma. AB - Vanishing bile duct syndrome (VBDS) in association with Hodgkin lymphoma (HL) is well described but not well understood. We report an unusual case of a 75-year old patient presenting with biopsy-proven VBDS and immunodeficiency, without identifiable cause, which showed a waxing and waning course, culminating in the development of HL 18 months later. To our knowledge, this is the first adult case in which VBDS preceded the diagnosis of HL by such a long period. PMID- 25442759 TI - Melioidosis in a patient on monoclonal antibody therapy for psoriatic arthritis. AB - Melioidosis is caused by the environmental bacterium Burkholderia pseudomallei and can present with severe sepsis. Predisposing risk factors are present in 80% of cases. Monoclonal antibodies are increasingly prescribed for varied medical conditions. This report describes the first known case of melioidosis in a patient whose only risk factor for disease is treatment with a monoclonal antibody. Prescribers of monoclonal antibodies and other immunosuppressants should ensure that their patients are aware of the potential risk of melioidosis prior to travel and the precautions that should be taken. PMID- 25442760 TI - Detection of bacteria and analyses of Chlamydia trachomatis viability in patients with postvenereal reactive arthritis. AB - Postvenereal reactive arthritis is an inflammatory form of arthritis that commonly develops after urogenital infection, predominantly in human leucocyte antigen-B27-positive men in the third decade of life. In our hospital, patients underwent synovectomy before a 4-month course of antibiotics (ciprofloxacin, tetracycline and roxithromicin). The clinical remission was achieved in approximately 70% patients. At molecular level, the remission was associated with the negative polymerase chain reaction findings of bacteria. PMID- 25442761 TI - Arise the systems physician. AB - Healthcare in Australia faces significant challenges. Variations in care, suboptimal safety and reliability, fragmentation of care and unsustainable cost increases are compounded by substantial overuse and underuse of clinical interventions. These problems arise not from intentional actions of individual clinicians, but from deficiencies in the design, operations and governance of systems of care. Physicians play an important role in optimising systems of care and, in doing so, must rely on enhanced skills in a range of domains. These include: how to evaluate and improve quality and safety of clinical processes; analyse and interpret clinical and administrative data in ways that can be used to enhance care delivery; build and lead cohesive multidisciplinary teams capable of solving operational defects and inefficient workarounds; and implement new and effective innovations in clinical service delivery. While clinical skills are essential in individual patient care, skills that improve systems of care targeting whole patient populations will become increasingly desirable and recognised as core skills. PMID- 25442762 TI - Prolonged echocardiography-guided resuscitation of pulseless electrical activity cardiac arrest due to Prinzmetal angina. PMID- 25442763 TI - Neutropenic fever rates with adjuvant docetaxel and cyclophosphamide in early breast cancer: audit from regional cancer centre in New South Wales. PMID- 25442764 TI - Autoimmune haemolytic anaemia as an initial presentation of primary Sjogren syndrome. PMID- 25442765 TI - Stroke thrombolysis remains unproven: per ardua, ad astra ... PMID- 25442766 TI - Author reply: To PMID 24528811. PMID- 25442767 TI - Divergent understanding of health professionals regarding correct subsequent management of an asymptomatic patient with a positive faecal occult blood test and negative colonoscopy with resultant cost implications. PMID- 25442768 TI - Radial nerve injuries. AB - Radial nerve injuries continue to challenge hand surgeons. The course of the nerve and its intimate relationship to the humerus place it at high risk for injury with humerus fractures. We present a review of radial nerve injuries with emphasis on their etiology, workup, diagnosis, management, and outcomes. PMID- 25442769 TI - Soft tissue stabilization for palmar midcarpal instability using a palmaris longus tendon graft. AB - PURPOSE: To report the results of a technique of soft tissue stabilization for palmar midcarpal instability using a palmaris longus graft. METHODS: In patients' symptomatic wrists with palmar midcarpal instability that had failed conservative management, we used a dorsal approach and stabilized the hamate and triquetrum by reconstructing the dorsal triquetrohamate ligament. The palmaris longus tendon graft was fixed with bone anchors. Seven wrists in 6 patients were available for follow-up at a mean of 28 months (range, 17-37 mo). RESULTS: There was an overall meaningful improvement in function (mean preoperative Disabilities of the Arm, Shoulder, and Hand score, 49 preoperatively, 28 postoperatively). There was a significant increase in grip strength from 15 to 21 kg. At final follow-up, 2 patients had moderate pain. The others had mild or no pain. Four patients returned to their previous occupation or activity. Patients retained full pronation and supination. When compared with the normal side, flexion was reduced to 71%, extension to 81%, radial deviation to 90%, and ulnar deviation to 65% of the opposite side. Although the mean results show an improvement, one patient had a poor result with deterioration in Disabilities of the Arm, Shoulder, and Hand score in spite of a clinically stable wrist, and another had clinical evidence of recurrent instability during pregnancy. One patient had residual symptoms from a prominent bone anchor. CONCLUSIONS: Overall, this technique showed good medium term results in most of our patients. It retained some midcarpal mobility, eliminated clunking in most patients, and provided a noteworthy improvement in grip strength and function. We continue to use this technique for patients with symptomatic midcarpal instability, but it requires further evaluation with larger patient numbers and a longer follow-up to assess its overall value. PMID- 25442770 TI - Management of ulnar nerve injuries. AB - Injuries to the ulnar nerve result in both sensory and motor deficits within the hand. Functional outcomes following repair of this nerve have not performed as well as outcomes following repair of the median or radial nerves. Advances in imaging modalities may provide earlier means of identifying and diagnosing closed nerve injuries. Early neurorrhaphy of acute nerve injuries provides the best outcome, but consideration should also be given to performing distal motor nerve transfers to preserve hand intrinsic motor function when injuries occur at or above the proximal forearm. This article attempts to summarize the most recent trends within ulnar nerve repair. PMID- 25442771 TI - Delayed reconstruction of a flexor digitorum profundus tendon lacerated during cesarean delivery: case report. AB - We present a case of primary tendon grafting in a 14-month-old infant for an index finger flexor digitorum profundus tendon laceration sustained during cesarean section with excellent functional results at 2-year follow-up. PMID- 25442772 TI - Treatment of distal humerus fractures in adults: a historical perspective. AB - Nonsurgical treatment was the mainstay of management of distal humerus fractures for centuries and nonunions and malunions were common. The 19th century featured the recognition of distinct injury patterns. With advances in radiology, anesthesia, antisepsis, and hardware technology, surgical treatment is now generally preferred, yet loss of elbow joint mobility can still be a vexing problem. PMID- 25442773 TI - Acquired Hypothyroidism as a Predictive Marker of Outcome in Patients With Metastatic Renal Cell Carcinoma Treated With Tyrosine Kinase Inhibitors: A Literature-Based Meta-Analysis. AB - Hypothyroidism in patients with metastatic renal cell carcinoma (mRCC) during treatment with the tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib is a well-established side effect. Furthermore, the potential role of hypothyroidism as predictive marker of outcome has been studied but with conflicting results. The aim of the present meta-analysis was to assess the predictive value of hypothyroidism for progression-free (PFS) and overall survival (OS) in patients with mRCC during TKI therapy. We searched PubMed and the electronic abstract databases of the major international congresses' proceedings to identify all eligible studies that reported a correlation between the development of hypothyroidism during TKI treatment and outcome in patients with mRCC. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS and OS were obtained from these publications and pooled in a meta-analysis. Eleven studies with a total of 500 patients fulfilled the inclusion criteria. We found no statistical significant difference in PFS between patients who developed hypothyroidism during sunitinib therapy and unaffected patients (HR, 0.82; 95% CI, 0.59-1.13; P = .22; 6 studies; 250 patients). The HR for OS was 0.52 (95% CI, 0.31-0.87; P = .01) for patients who developed hypothyroidism during sunitinib therapy compared with patients who did not (4 studies; 147 patients). The development of hypothyroidism during TKI therapy is not clearly shown to be predictive of efficacy in patients with mRCC. The observed advantage in OS for the patients with acquired hypothyroidism should be interpreted with caution. PMID- 25442778 TI - New opportunities for quantitative and time efficient 3D MRI of liquid and solid electrochemical cell components: Sectoral Fast Spin Echo and SPRITE. AB - The ability to image electrochemical processes in situ using nuclear magnetic resonance imaging (MRI) offers exciting possibilities for understanding and optimizing materials in batteries, fuel cells and supercapacitors. In these applications, however, the quality of the MRI measurement is inherently limited by the presence of conductive elements in the cell or device. To overcome related difficulties, optimal methodologies have to be employed. We show that time efficient three dimensional (3D) imaging of liquid and solid lithium battery components can be performed by Sectoral Fast Spin Echo and Single Point Imaging with T1 Enhancement (SPRITE), respectively. The former method is based on the generalized phase encoding concept employed in clinical MRI, which we have adapted and optimized for materials science and electrochemistry applications. Hard radio frequency pulses, short echo spacing and centrically ordered sectoral phase encoding ensure accurate and time-efficient full volume imaging. Mapping of density, diffusivity and relaxation time constants in metal-containing liquid electrolytes is demonstrated. 1, 2 and 3D SPRITE approaches show strong potential for rapid high resolution (7)Li MRI of lithium electrode components. PMID- 25442776 TI - Zero field splitting fluctuations induced phase relaxation of Gd3+ in frozen solutions at cryogenic temperatures. AB - Distance measurements using double electron-electron resonance (DEER) and Gd(3+) chelates for spin labels (GdSL) have been shown to be an attractive alternative to nitroxide spin labels at W-band (95GHz). The maximal distance that can be accessed by DEER measurements and the sensitivity of such measurements strongly depends on the phase relaxation of Gd(3+) chelates in frozen, glassy solutions. In this work, we explore the phase relaxation of Gd(3+)-DOTA as a representative of GdSL in temperature and concentration ranges typically used for W-band DEER measurements. We observed that in addition to the usual mechanisms of phase relaxation known for nitroxide based spin labels, GdSL are subjected to an additional phase relaxation mechanism that features an increase in the relaxation rate from the center to the periphery of the EPR spectrum. Since the EPR spectrum of GdSL is the sum of subspectra of the individual EPR transitions, we attribute this field dependence to transition dependent phase relaxation. Using simulations of the EPR spectra and its decomposition into the individual transition subspectra, we isolated the phase relaxation of each transition and found that its rate increases with |ms|. We suggest that this mechanism is due to transient zero field splitting (tZFS), where its magnitude and correlation time are scaled down and distributed as compared with similar situations in liquids. This tZFS induced phase relaxation mechanism becomes dominant (or at least significant) when all other well-known phase relaxation mechanisms, such as spectral diffusion caused by nuclear spin diffusion, instantaneous and electron spin spectral diffusion, are significantly suppressed by matrix deuteration and low concentration, and when the temperature is sufficiently low to disable spin lattice interaction as a source of phase relaxation. PMID- 25442780 TI - A double-component Anderson-Weiss approach for describing NMR signals of mobile SIn units: application to constant-time DIPSHIFT experiments. AB - A composed Gaussian local field is proposed to describe the effect of molecular motions on NMR signals of SIn units (e.g., CHn or NHn), based upon the well-know Anderson-Weiss (AW) approximation. The approach is exemplified on constant-time recoupled dipolar chemical-shift correlation (tC-recDIPSHIFT) experiments, providing an analytical formula that can be used as a fitting function in studies of intermediate-regime motions. By comparison of analytical tC-recDIPSHIFT curves and dynamic spin dynamics simulations, we show that for heteronuclear spin pairs (SI system), the AW treatment assuming the usual Gaussian local field is accurate. However, the approximation fails for the case of SIn spin systems for motional rates higher than a few kHz. Based on earlier work of Terao et al., who proposed a decomposition of CHn dipolar powder patterns into to 2(n) spin-pair type patterns, we propose an AW approach based upon a double-Gaussian local field. We derive an analytical formula for tC-recDIPSHIFT signals, and demonstrate its accuracy by comparison with simulations of several motional geometries and rates, and with experimental results for a model sample. The approach is not limited to the tC-recDIPSHIFT experiment and should be of general use in dipolar-coupling based experiments probing (partially) mobile SIn molecular moieties. PMID- 25442777 TI - Time-shared experiments for efficient assignment of triple-selectively labeled proteins. AB - Combinatorial triple-selective labeling facilitates the NMR assignment process for proteins that are subject to signal overlap and insufficient signal-to-noise in standard triple-resonance experiments. Aiming at maximum amino-acid type and sequence-specific information, the method represents a trade-off between the number of selectively labeled samples that have to be prepared and the number of spectra to be recorded per sample. In order to address the demand of long measurement times, we here propose pulse sequences in which individual phase shifted transients are stored separately and recombined later to produce several 2D HN(CX) type spectra that are usually acquired sequentially. Sign encoding by the phases of (13)C 90 degrees pulses allows to either select or discriminate against (13)C' or (13)C(alpha) spins coupled to (15)N. As a result, (1)H-(15)N correlation maps of the various isotopomeric species present in triple selectively labeled proteins are deconvoluted which in turn reduces problems due to spectral overlap. The new methods are demonstrated with four different membrane proteins with rotational correlation times ranging from 18 to 52 ns. PMID- 25442779 TI - Rotation operator propagators for time-varying radiofrequency pulses in NMR spectroscopy: applications to shaped pulses and pulse trains. AB - The propagator for trains of radiofrequency pulses can be directly integrated numerically or approximated by average Hamiltonian approaches. The former provides high accuracy and the latter, in favorable cases, convenient analytical formula. The Euler-angle rotation operator factorization of the propagator provides insights into performance that are not as easily discerned from either of these conventional techniques. This approach is useful in determining whether a shaped pulse can be represented over some bandwidth by a sequence tau1 Rphi(beta)-tau2, in which Rphi(beta) is a rotation by an angle beta around an axis with phase phi in the transverse plane and tau1 and tau2 are time delays, allowing phase evolution during the pulse to be compensated by adjusting time periods prior or subsequent to the pulse. Perturbation theory establishes explicit formulas for tau1 and tau2 as proportional to the average transverse magnetization generated during the shaped pulse. The Euler-angle representation of the propagator also is useful in iterative reduction of pulse-interrupted-free precession schemes. Application to Carr-Purcell-Meiboom-Gill sequences identifies an eight-pulse phase alternating scheme that generates a propagator nearly equal to the identity operator. PMID- 25442781 TI - Two-dimensional EPR imaging with the rapid scan and rotated magnetic field gradient. AB - A new method for fast 2D Electron Paramagnetic Resonance Imaging (EPRI) is presented. To reduce the time of projections acquisition we propose to combine rapid scan of Zeeman magnetic field using high frequency sinusoidal modulation with simultaneously applied magnetic field gradient, whose orientation is changed at low frequency. The correctness of the method is confirmed by studies carried out on a phantom consisting of two LiPc samples. The images from the acquired data are reconstructed using iterative algorithms. The proposed method allows to reduce the image acquisition time up to 10 ms for 2D EPRI, and to detect the sinogram with infinitesimal angular step between projections. PMID- 25442782 TI - Optimization of the AC-gradient method for velocity profile measurement and application to slow flow. AB - This work presents a spectroscopic method to measure slow flow. Within a single shot the velocity distribution is acquired. This allows distinguishing rapidly between single velocities within the sampled volume with a high sensitivity. The technique is based on signal acquisition in the presence of a periodic gradient and a train of refocussing RF pulses. The theoretical model for trapezoidal bipolar pulse shaped gradients under consideration of diffusion and the outflow effect is introduced. A phase correction technique is presented that improves the spectral accuracy. Therefore, flow phantom measurements are used to validate the new sequence and the simulation based on the theoretical model. It was demonstrated that accurate parabolic flow profiles can be acquired and flow variations below 200 MUm/s can be detected. Three post-processing methods that eliminate static background signal are also presented for applications in which static background signal dominates. Finally, this technique is applied to flow measurement of a small alder tree demonstrating a typical application of in vivo plant measurements. PMID- 25442783 TI - Frequency of contact with non-cohabitating adult children and risk of depression in elderly: a community-based three-year longitudinal study in Korea. AB - PURPOSE: Our study aimed to assess the longitudinal association of frequency of contact with non-cohabitating adult children and risk of depression in the elderly. METHODS: Elderly aged >=60 years were included from Living Profiles of Older People Survey (LPOPS) in Korea. The baseline assessment, Wave 1, was conducted in 2008, and follow-up assessment, Wave 2, was conducted in 2011. We included participants who completed both waves and excluded those who met the following criteria: no adult children, living with adult children, cognitive impairment at either waves, and depression at baseline (n=4398). We defined infrequent contact as <1 time per month face-to-face contact or <1 time per week phone contact and classified participants into four groups based on contact method and frequency. Depression was measured using the 15-item geriatric depression scales (SGDS-K). RESULTS: In multivariable logistic regression analysis, infrequent face-to-face and phone contact group had adjusted odds ratio (OR) of 1.86 (95% CI, 1.44-2.42) when compared with frequent face-to-face and phone contact group. Frequent face-to-face contact with infrequent phone contact group and infrequent face-to-face contact with frequent phone contact group had adjusted OR of 1.49 (95% CI, 1.12-1.98) and 1.44 (95% CI, 1.15-1.80), respectively, when compared with frequent face-to-face and phone contact group. CONCLUSION: These results propose that the risk of subsequent depression in elderly is associated with frequency of contact with non-cohabitating adult children. Moreover, the efficacy of face-to-face contact and that of phone contact were similar, while the group lacking both types of contact demonstrated the highest risk of depression. PMID- 25442784 TI - Depressive symptoms and adverse outcomes from hospitalization in older adults: secondary outcomes of a trial of falls prevention education. AB - Depression is common in older people and symptoms of depression are known to substantially increase during hospitalization. There is little known about predictors of depressive symptoms in older adults or impact of common interventions during hospitalization. This study aimed to describe the magnitude of depressive symptoms, shift of depressive symptoms and the impact of the symptoms of depression among older hospital patients during hospital admission and identify whether exposure to falls prevention education affected symptoms of depression. Participants (n=1206) were older adults admitted within two Australian hospitals, the majority of participants completed the Geriatric Depression Scale - Short Form (GDS) at admission (n=1168). Participants' mean age was 74.7 (+/-SD 11) years and 47% (n=551) were male. At admission 53% (619 out of 1168) of participants had symptoms of clinical depression and symptoms remained at the same level at discharge for 55% (543 out of 987). Those exposed to the low intensity education program had higher GDS scores at discharge than those in the control group (low intensity vs control n=652, adjusted regression coefficient (95% CI)=0.24 (0.02, 0.45), p=0.03). The only factor other than admission level of depression that affected depressive symptoms change was if the participant was worried about falling. Older patients frequently present with symptoms of clinical depression on admission to hospital. Future research should consider these factors, whether these are modifiable and whether treatment may influence outcomes. PMID- 25442786 TI - Discarded Wharton jelly of the human umbilical cord: a viable source for mesenchymal stromal cells. AB - Mesenchymal stromal cells (MSCs) are multi-potent cells that have the capability of differentiating into adipogenic, osteogenic, chondrogenic and neural cells. With these multiple capabilities, MSCs have been highly regarded as an effective transplantable cell source for regenerative medicine. A large bank of these cells can be found in several regions of the human umbilical cord, including the umbilical cord lining, the subendothelial layer, the perivascular zone and, most important, in Wharton jelly (WJ). These cells, all umbilical cord-derived MSCs, are durable, have large loading capacities and are considered ethical to harvest because the umbilical cord is often considered waste. These logistical advantages make WJ as appealing source of stem cells for transplant therapy. In particular, WJ is a predominantly good source of cells because MSCs in WJ are maintained in an early embryologic phase and therefore have retained some of the primitive stemness properties. WJ-MSCs can easily differentiate into a plethora of cell types leading to a variety of applications. In addition, WJ-MSCs are slightly easier to harvest compared with other MSCs (such as bone marrow-derived MSCs). The fascinating stemness properties and therapeutic potential of WJ-MSCs provide great promise in many aspects of regenerative medicine and should be considered for further investigations as safe and effective donor cells for transplantation therapy in many debilitating disorders, which are discussed here. We previously reviewed the therapeutic potential of WJ-MSCs and now provide an update on their recent preclinical and clinical applications. PMID- 25442787 TI - Restorative benefits of transplanting human mesenchymal stromal cells overexpressing arginine decarboxylase genes after spinal cord injury. AB - BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) promote functional recovery in central nervous system (CNS) injury. Neuroprotective effects of MSCs are being tested in clinical trials for the treatment of CNS injury; however, the underlying mechanisms remain unclear. Arginine decarboxylase (ADC) is a rate limiting enzyme of agmatine synthesis and is known to exist in the CNS of mammals. The present study investigated whether transplantation of ADC overexpressing human MSCs (ADC-hMSCs) after spinal cord injury (SCI) could increase the production of neurotrophic factors and promote cell survival, differentiation, axonal regeneration and the restoration of functional recovery. METHODS: Retroviral human ADC was constructed with the use of an LXSN vector. After compression injury in thoracic level 9, PKH26-labeled ADC-hMSCs were transplanted into the dorsolateral funiculus 1 mm rostral and caudal to the lesion site. The tissues were sampled at 2, 4 and 10 weeks after SCI. RESULTS: Behavioral analysis revealed that locomotor functions of the ADC-hMSC group were significantly restored. Histological analysis showed that the fibrotic scar volume was smaller in the ADC-hMSC-injected group than in any other group. Brain derived neurotrophic factor level was significantly higher in the ADC-hMSC injected group than in any other group throughout 10 weeks. Terminal deoxynucleotidyl transferase-mediated nick-end labeling assay showed decreased cell death, and co-localization analysis showed significant increase in the number of neurons and oligodendrocytes originating from transplanted hMSCs when they had been transduced with the ADC gene. CONCLUSIONS: The results suggested that ADC-hMSCs are a more suitable candidate than hMSCs for stem cell therapy after SCI. PMID- 25442788 TI - Stem cells in animal asthma models: a systematic review. AB - BACKGROUND AIMS: Asthma control frequently falls short of the goals set in international guidelines. Treatment options for patients with poorly controlled asthma despite inhaled corticosteroids and long-acting beta-agonists are limited, and new therapeutic options are needed. Stem cell therapy is promising for a variety of disorders but there has been no human clinical trial of stem cell therapy for asthma. We aimed to systematically review the literature regarding the potential benefits of stem cell therapy in animal models of asthma to determine whether a human trial is warranted. METHODS: The MEDLINE and Embase databases were searched for original studies of stem cell therapy in animal asthma models. RESULTS: Nineteen studies were selected. They were found to be heterogeneous in their design. Mesenchymal stromal cells were used before sensitization with an allergen, before challenge with the allergen and after challenge, most frequently with ovalbumin, and mainly in BALB/c mice. Stem cell therapy resulted in a reduction of bronchoalveolar lavage fluid inflammation and eosinophilia as well as Th2 cytokines such as interleukin-4 and interleukin-5. Improvement in histopathology such as peribronchial and perivascular inflammation, epithelial thickness, goblet cell hyperplasia and smooth muscle layer thickening was universal. Several studies showed a reduction in airway hyper-responsiveness. CONCLUSIONS: Stem cell therapy decreases eosinophilic and Th2 inflammation and is effective in several phases of the allergic response in animal asthma models. Further study is warranted, up to human clinical trials. PMID- 25442789 TI - Infusion of human embryonic kidney cell line conditioned medium reverses kainic acid induced hippocampal damage in mice. AB - BACKGROUND AIMS: Hippocampal neurodegeneration is one of the hallmarks in neurological and neurodegenerative diseases such as temporal lobe epilepsy and Alzheimer disease. Human embryonic kidney (HEK) cells are a mixed population of cells, including neurons, and their conditioned medium is enriched with erythropoietin (EPO). Because EPO is a known neuroprotectant, we hypothesized that infusion of HEK cells or HEK-conditioned medium (HEK-CM) may provide neuroprotection against kainic acid (KA)-induced hippocampal damage in mice. METHODS: Adult CF1 mice were treated with KA to induce hippocampal damage. On 3rd and 5th days after KA treatment, HEK cells or HEK-CM was infused intravenously through the tail vein. On the 7th and 8th days after KA treatment, all groups of mice were subjected to cognitive and depression assessment by use of a novel object recognition test and a forced swim test, respectively. Subsequent to this assessment, mice were killed and the brain samples were used to assess the histopathology and messenger RNA expression for EPO and B-cell lymphoma-2 (Bcl 2). RESULTS: We found that infusion of HEK cells/HEK-CM improves cognitive function and alleviates symptoms of depression. Histological assessment demonstrates complete neuroprotection against KA-mediated excitotoxicity, and the hippocampal cytoarchitecture of HEK cells/HEK-CM treated mice was comparable to normal control mice. HEK cells/HEK-CM treatment could provide neuroprotection by upregulating the endogenous EPO and Bcl-2 in KA-treated mice. CONCLUSIONS: Our present data demonstrate for the first time that infusion of HEK cells/HEK-CM can prevent excitotoxic hippocampal damage and alleviate consequent behavioral abnormalities. PMID- 25442791 TI - Treatment-Resistant Depression and Aquaporin-4 Autoantibodies: Is There a Link? PMID- 25442790 TI - Aversive stimuli drive drug seeking in a state of low dopamine tone. AB - BACKGROUND: Stressors negatively impact emotional state and drive drug seeking, in part, by modulating the activity of the mesolimbic dopamine system. Unfortunately, the rapid regulation of dopamine signaling by the aversive stimuli that cause drug seeking is not well characterized. In a series of experiments, we scrutinized the subsecond regulation of dopamine signaling by the aversive stimulus, quinine, and tested its ability to cause cocaine seeking. Additionally, we examined the midbrain regulation of both dopamine signaling and cocaine seeking by the stress-sensitive peptide, corticotropin releasing factor (CRF). METHODS: Combining fast-scan cyclic voltammetry with behavioral pharmacology, we examined the effect of intraoral quinine administration on nucleus accumbens dopamine signaling and hedonic expression in 21 male Sprague-Dawley rats. We tested the role of CRF in modulating aversion-induced changes in dopamine concentration and cocaine seeking by bilaterally infusing the CRF antagonist, CP 376395, into the ventral tegmental area (VTA). RESULTS: We found that quinine rapidly reduced dopamine signaling on two distinct time scales. We determined that CRF acted in the VTA to mediate this reduction on only one of these time scales. Further, we found that the reduction of dopamine tone and quinine-induced cocaine seeking were eliminated by blocking the actions of CRF in the VTA during the experience of the aversive stimulus. CONCLUSIONS: These data demonstrate that stress-induced drug seeking can occur in a terminal environment of low dopamine tone that is dependent on a CRF-induced decrease in midbrain dopamine activity. PMID- 25442792 TI - Prefrontal cortical gamma-aminobutyric acid transmission and cognitive function: drawing links to schizophrenia from preclinical research. AB - Cognitive dysfunction in schizophrenia is one of the most pervasive and debilitating aspects of the disorder. Among the numerous neural abnormalities that may contribute to schizophrenia symptoms, perturbations in markers for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), particularly within the frontal lobes, are some of the most reliable alterations observed at postmortem examination. However, how prefrontal GABA dysfunction contributes to cognitive impairment in schizophrenia remains unclear. We provide an overview of postmortem GABAergic perturbations in the brain affected by schizophrenia and describe circumstantial evidence linking these alterations to cognitive dysfunction. In addition, we conduct a survey of studies using neurodevelopmental, genetic, and pharmacologic rodent models that induce schizophrenia-like cognitive impairments, highlighting the convergence of these mechanistically distinct approaches to prefrontal GABAergic disruption. We review preclinical studies that have directly targeted prefrontal cortical GABAergic transmission using local application of GABAA receptor antagonists. These studies have provided an important link between GABA transmission and cognitive dysfunction in schizophrenia because they show that reducing prefrontal inhibitory transmission induces various cognitive, emotional, and dopaminergic abnormalities that resemble aspects of the disorder. These converging clinical and preclinical findings provide strong support for the idea that perturbations in GABA signaling drive certain forms of cognitive dysfunction in schizophrenia. Future studies using this approach will yield information to refine further a putative "GABA hypothesis" of schizophrenia. PMID- 25442793 TI - State of structured reporting in radiology, a survey. AB - RATIONALE AND OBJECTIVES: To survey North American radiologists on current practices in structured reporting and language. MATERIALS AND METHODS: An e-mail invitation was sent to the Association of University Radiologists membership (comprising 910 members) to participate in an online survey that addressed development, use, and experience of structured reporting, language, and imaging classification or reporting systems and personal dictation styles. RESULTS: Of the 910 members e-mailed, 265 (29.1%) responded, 90.6% of whom were from academic teaching hospitals. There were no significant differences in responses based on group size or region of practice. Of all the respondents, 51.3% come from groups that developed structured reporting for at least half of their reports and only 10.9% for none. A significantly fewer 13% of respondents used rigid unmodifiable structures or checklists rather than adaptable outlines; 59.5% respondents report being satisfied or very satisfied with their structured reports, whereas a significantly fewer 13% report being dissatisfied or very dissatisfied. Structured reports were reportedly significantly more likely to be required, appreciated, and to decrease errors in departments using many structured reports compared to groups with less widespread use. CONCLUSIONS: Most academic radiology departments are using or experimenting with structured reports. Although radiologist satisfaction with standardization is significant, there are strong opinions about their limitations and value. Our survey suggests that North American radiologists are invested in exploring structured reporting and will hopefully inform future study on how we define a standard report and how much we can centralize this process. PMID- 25442796 TI - Visual search in abdominopelvic CT interpretation: accuracy and time efficiency between coronal MPR and axial images. AB - RATIONALE AND OBJECTIVES: The objective of this study was to compare reader accuracy and time efficiency between coronal reformats of abdominopelvic computed tomography (CT) and axial images, by means of a visual search task. MATERIALS AND METHODS: In this experimental crossover study, a novel visual search task, containing targets placed on actual CT images, was constructed to assess reader performance on both planes. Six trials were shown to participants in each plane, at a fixed time of 0.5 seconds per slice. The task was presented to 43 junior doctors. On each trial, participants were assessed for accuracy and confidence in finding the target on a five-point scale. Statistical analysis was performed using the Wilcoxon signed rank test, and Fleiss kappa. RESULTS: Coronal images took 40% less time to view overall. No significant difference was found in reader accuracy or reader confidence between the two planes. Interrater agreement was observed as fair, across a very large number of raters (43). CONCLUSIONS: Target identification in the coronal plane is extremely similar to the axial plane on abdominopelvic CT in this study and offers a substantial time benefit. A perceptual limit to visual processing of CT images may contribute to this similarity. Greater use of coronal reformats in day-to-day practice could substantially improve radiologist workflow. PMID- 25442795 TI - The application of dynamic contrast-enhanced MRI and diffusion-weighted MRI in patients with maxillofacial tumors. AB - RATIONALE AND OBJECTIVES: To elucidate the characteristics of four types of tumors, including squamous cell carcinoma (SCC), malignant lymphoma (ML), malignant salivary gland tumors (MSGTs), and pleomorphic adenoma (Pleo), in the maxillofacial region using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted MRI (DW-MRI)data. MATERIALS AND METHODS: A total of 59 tumors were included in this research. DCE-MRI and DW-MRI were performed. We applied the Tofts and Kermode model (TK model) for the DCE-MRI data and obtained three dependent parameters: the influx forward volume transfer constant into the extravascular extracellular space from the plasma (K(trans)), the fractional volume of extravascular extracellular space per unit volume of tissue (ve), and the fractional volume of plasma (vp). RESULTS: Among the K(trans) values, there were no significant differences between the three types of malignant tumors; however, there was a significant difference between the SCC and Pleo (P = .0099). The ve values of the Pleo were highest, with significant differences compared to the other categories (SCC, P = .0012; ML, P = .0017; and MSGT, P = .041). The ML had the lowest ve values, and there were significant differences between ML and the other two types of malignant tumors (SCC, P = .0278 and MSGT, P = .0062). In 14 (24%) cases, apparent diffusion coefficient (ADC) could not be measured because of poor image quality. The ADC values of the ML were lowest, whereas those of Pleo were highest, similar to that observed for ve. CONCLUSIONS: The Pleo tumors had lower K(trans) values and higher ve values, which are useful for differentiating them from the malignant tumors. Moreover, the ve was also useful for establishing a diagnosis of ML. PMID- 25442794 TI - Parametric response mapping monitors temporal changes on lung CT scans in the subpopulations and intermediate outcome measures in COPD Study (SPIROMICS). AB - RATIONALE AND OBJECTIVES: The longitudinal relationship between regional air trapping and emphysema remains unexplored. We have sought to demonstrate the utility of parametric response mapping (PRM), a computed tomography (CT)-based biomarker, for monitoring regional disease progression in chronic obstructive pulmonary disease (COPD) patients, linking expiratory- and inspiratory-based CT metrics over time. MATERIALS AND METHODS: Inspiratory and expiratory lung CT scans were acquired from 89 COPD subjects with varying Global Initiative for Chronic Obstructive Lung Disease (GOLD) status at 30 days (n = 13) or 1 year (n = 76) from baseline as part of the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) clinical trial. PRMs of CT data were used to quantify the relative volumes of normal parenchyma (PRM(Normal)), emphysema (PRM(Emph)), and functional small airways disease (PRM(fSAD)). PRM measurement variability was assessed using the 30-day interval data. Changes in PRM metrics over a 1-year period were correlated to pulmonary function (forced expiratory volume at 1 second [FEV1]). A theoretical model that simulates PRM changes from COPD was compared to experimental findings. RESULTS: PRM metrics varied by ~6.5% of total lung volume for PRM(Normal) and PRM(fSAD) and 1% for PRM(Emph) when testing 30 day repeatability. Over a 1-year interval, only PRM(Emph) in severe COPD subjects produced significant change (19%-21%). However, 11 of 76 subjects showed changes in PRM(fSAD) greater than variations observed from analysis of 30-day data. Mathematical model simulations agreed with experimental PRM results, suggesting fSAD is a transitional phase from normal parenchyma to emphysema. CONCLUSIONS: PRM of lung CT scans in COPD patients provides an opportunity to more precisely characterize underlying disease phenotypes, with the potential to monitor disease status and therapy response. PMID- 25442797 TI - Building for tomorrow today: opportunities and directions in radiology resident research. AB - RATIONALE AND OBJECTIVES: With rapid scientific and technological advancements in radiological research, there is renewed emphasis on promoting early research training to develop researchers who are capable of tackling the hypothesis-driven research that is typically funded in contemporary academic research enterprises. This review article aims to introduce radiology residents to the abundant radiology research opportunities available to them and to encourage early research engagement among trainees. MATERIALS AND METHODS: To encourage early resident participation in radiology research, we review the various research opportunities available to trainees spanning basic, clinical, and translational science opportunities to ongoing research in information technology, informatics, and quality improvement research. CONCLUSIONS: There is an incredible breadth and depth of ongoing research at academic radiology departments across the country, and the material presented herein aspires to highlight both subject matter and opportunities available to radiology residents eager to engage in radiologic research. The opportunities for interested radiology residents are as numerous as they are broad, spanning the basic sciences to clinical research to informatics, with abundant opportunities to shape our future practice of radiology. PMID- 25442798 TI - Improving our PRODUCT: a quality and safety improvement project demonstrating the value of a preprocedural checklist for fluoroscopy. AB - RATIONALE AND OBJECTIVES: To implement a preprocedural checklist in gastrointestinal (GI)/genitourinary (GU) fluoroscopy suites to assist radiology residents in performing studies with optimal fluoroscopic technique with a goal to lower radiation dose delivered to patients and operators. MATERIALS AND METHODS: We introduced a preprocedural checklist in the form of a mnemonic to first-year resident fluoroscopy operators. The checklist was augmented by teaching sessions at the fluoroscopy tower. Fluoroscopy time (FT) was collected for GI/GU fluoroscopy studies performed by first-year residents who did not use the checklist (year 1) and compared with FT from first-year residents who used the checklist for one full academic year (year 2). Residents in both groups were surveyed to assess their knowledge of radiation safety at the end of their respective radiology 1 (R1) academic years. RESULTS: A total of 778 examinations were analyzed from year 1, and 941 total examinations from year 2. After implementation of the checklist, mean FT for all studies decreased by 41.1 seconds (P < .0001) in year 2 residents. Multivariate linear regression confirmed that year of examination was the strongest independent predictor of FT when other covariates such as resident age, gender, and experience and patient age and gender were included. Radiation safety knowledge was similar in both groups but self-reported confidence in safe fluoroscopy tower operation increased slightly in year 2 (P = .144). CONCLUSIONS: A visual preprocedural radiation safety checklist in GI/GU fluoroscopy was associated with a reduction in mean FT and may contribute to a culture of radiation safety awareness. PMID- 25442799 TI - Entrepreneurship in the academic radiology environment. AB - RATIONALE AND OBJECTIVES: Innovation and entrepreneurship in health care can help solve the current health care crisis by creating products and services that improve quality and convenience while reducing costs. MATERIALS AND METHODS: To effectively drive innovation and entrepreneurship within the current health care delivery environment, academic institutions will need to provide education, promote networking across disciplines, align incentives, and adapt institutional cultures. This article provides a general review of entrepreneurship and commercialization from the perspective of academic radiology departments, drawing on information sources in several disciplines including radiology, medicine, law, and business. CONCLUSIONS: Our review will discuss the role of universities in supporting academic entrepreneurship, identify drivers of entrepreneurship, detail opportunities for academic radiologists, and outline key strategies that foster greater involvement of radiologists in entrepreneurial efforts and encourage leadership to embrace and support entrepreneurship. PMID- 25442801 TI - CT density distribution analysis in patients with cystic fibrosis: correlation with pulmonary function and radiologic scores. AB - RATIONALE AND OBJECTIVES: The progressive changes in lung morphology observed in cystic fibrosis (CF) can potentially affect the statistical distribution of computed tomography (CT) density values. This study aimed to characterize the lung CT density distributions by quantifying indices of the kurtosis and skewness of the lung density distribution and to compare these indices to radiologic scores and lung function parameters in children and young adults with CF. MATERIALS AND METHODS: CT scans and lung function of 26 patients with CF were retrospectively examined. The Bhalla radiologic scoring was performed separately, in random order, by two expert radiologists, blinded to the patient's identity, age, clinical status, results of lung function tests, and the other paired observer's score. RESULTS: Positive relations were evidenced between the log indices of lung density distribution kurtosis (iKurtosis) and the overall radiologic scores (RS) of both observers (R = 0.58; P < .001 vs RS1 and R = 0.71; P < .001 vs RS2). A similar relationship was evidenced with the log index of the degree of distribution asymmetry (iSkewness; R = 0.62; P < .001 vs RS1 and R = 0.62; P < .001 vs RS2). Log-iKurtosis and log-iSkewness were related to FEV1 (R = -0.56; P < 10(-5) and R = -0.55; P < 10(-5)) and to residual volume (R = 0.40; P < .001 and R = 0.45; P < .001, respectively). Both radiologic scores showed significant relation with lung function. The correlation between RS1 and RS2 was excellent (R = 0.93), with a Cohen weighted kappa of 0.43. CONCLUSIONS: Characteristic indices of lung CT density distribution are correlated to lung function and radiologic scores in patients with CF and merit further evaluation as part of more comprehensive automated methods for quantifying CF lung CT data. PMID- 25442802 TI - Descriptive epidemiology of children hospitalized for inflammatory bowel disease in Japan: Inpatient database analysis. AB - BACKGROUND: Inflammatory bowel disease (IBD) - Crohn's disease (CD) and ulcerative colitis (UC) - are chronic inflammatory disorders of the intestine. Patients with IBD are at risk of hospitalization for disease exacerbation or IBD associated complications. In the pediatric population, however, there are limited data on IBD hospitalizations. We therefore investigated the descriptive epidemiology of hospitalizations relevant to pediatric IBD. METHODS: The national inpatient claims database in Japan was searched for children (<= 18 years old) with a diagnosis of IBD. The study period was 2007-2010. Data on demographic characteristics and descriptive statistics of the hospital course were extracted and analyzed. RESULTS: A total of 3559 admissions of 2175 patients met the definition of pediatric IBD: there were 1999 admissions for CD and 1560 admissions for UC. Internists were responsible for patient care in 56.6% of admissions, followed by pediatricians (27.5%). Of 3559 admissions, unscheduled hospitalizations accounted for 79.7%, and 7.6% of hospitalizations were attributable to complications of IBD, including intestinal, extraintestinal and other manifestations. The median age at first admission was 16 years (IQR, 13-17 years), in both the CD and UC groups. Compared with UC patients, CD patients had a higher number of hospitalizations (P < 0.001), but hospital stay was shorter (median: 6 vs 16 days, P < 0.001). There were seven fatal cases of IBD, accounting for 0.32% in the present series, and sepsis was the cause in five. CONCLUSIONS: This study provides a description of pediatric inpatients with IBD and their hospital course in Japan. PMID- 25442800 TI - Clinical utility of quantitative imaging. AB - Quantitative imaging (QI) is increasingly applied in modern radiology practice, assisting in the clinical assessment of many patients and providing a source of biomarkers for a spectrum of diseases. QI is commonly used to inform patient diagnosis or prognosis, determine the choice of therapy, or monitor therapy response. Because most radiologists will likely implement some QI tools to meet the patient care needs of their referring clinicians, it is important for all radiologists to become familiar with the strengths and limitations of QI. The Association of University Radiologists Radiology Research Alliance Quantitative Imaging Task Force has explored the clinical application of QI and summarizes its work in this review. We provide an overview of the clinical use of QI by discussing QI tools that are currently used in clinical practice, clinical applications of these tools, approaches to reporting of QI, and challenges to implementing QI. It is hoped that these insights will help radiologists recognize the tangible benefits of QI to their patients, their referring clinicians, and their own radiology practice. PMID- 25442803 TI - Assessing the appropriateness of outpatient abdominopelvic CT and MRI examinations using the American College of Radiology Appropriateness Criteria. AB - RATIONALE AND OBJECTIVES: To retrospectively assess the appropriateness of outpatient abdominal and pelvic computed tomography (CT) and magnetic resonance imaging (MRI) examinations using the American College of Radiology Appropriateness Criteria (AC). MATERIALS AND METHODS: A total of 570 adult outpatient abdominopelvic CT (304) and MRI (266) studies performed in a 1-month period with available documentation of the clinical encounter generating the imaging order were included. On the basis of review of the imaging report and patient record, examinations were classified in terms of match to a specific AC variant, appropriateness score, and the presence of a significant result. Data were analyzed using Fisher's exact test. RESULTS: Forty-five percent of examinations matched an AC variant: 52% of CT and 38% of MRI (P < .001). Ninety two percent of examinations matching the AC were appropriate: 96% of CT and 86% of MRI (P = .009). Appropriate examinations were more likely to provide a significant result than not appropriate studies (48% vs. 24%, P = .041). Although a significant result was related to the primary study indication more frequently in appropriate than not appropriate examinations, this difference was not significant (93% vs. 80%, respectively, P = .204). The most common indications not matching an AC were colon cancer follow-up (n = 14) and melanoma follow-up (n = 14) among CT, and hepatocellular carcinoma screening (n = 31) and elevated prostate-specific antigen (PSA) without prior biopsy (n = 14) among MRI. CONCLUSIONS: Most examinations matching the AC were appropriate, and appropriate examinations were more likely to have a significant result. However, most examinations, including 62% of MRI, had no relevant clinical condition, highlighting a critical area for future AC expansion and modification. PMID- 25442804 TI - Development of the AMSER standardized examinations in radiology for medical students. AB - RATIONALE AND OBJECTIVES: The variability in medical imaging evaluation across US medical schools inspired leading radiology student educators to develop the Alliance of Medical Student Educators in Radiology (AMSER) Standardized Exam (SE). This examination tests the understanding of essential material and concepts which are endorsed by the AMSER National Medical Student Curriculum in Radiology. MATERIALS AND METHODS: The AMSER Electronics Committee developed and deployed the AMSER SE using Radiology ExamWeb (REW), a previously-developed databank of imaging questions. The Committee created an examination blueprint that placed emphasis on effective use of medical imaging and less emphasis on image interpretation. Question items correlating to the blueprint were used from the REW databank to draft AMSER SE version 1, which was piloted in early 2012. Item performance was then analyzed, and the exam was revised. After national deployment, a subsequent revision was performed 1 year later. AMSER SE version 2, developed in a similar manner, was released in early 2013 and will go through a similar process of revision. A 20-question Practice Exam was also developed. RESULTS: Since national deployment, more than 1400 students, in over 22 institutions, have taken the AMSER SEs. CONCLUSIONS: The collaborative project of the AMSER Electronics Committee has resulted in the successful national deployment of two examinations using questions that have been validated and based on the AMSER peer-reviewed national curriculum. We hope that this assessment tool will help drive a more uniform approach to curriculum development, promoting more effective and safe use of medical imaging. This step should also help promote the value radiologists bring to the patient care arena. PMID- 25442805 TI - The ultrastructure of fibronectin fibers pulled from a protein monolayer at the air-liquid interface and the mechanism of the sheet-to-fiber transition. AB - Fibronectin is a globular protein that circulates in the blood and undergoes fibrillogenesis if stretched or under other partially denaturing conditions, even in the absence of cells. Stretch assays made by pulling fibers from droplets of solutions containing high concentrations of fibronectin have previously been introduced in mechanobiology, particularly to ask how bacteria and cells exploit the stretching of fibronectin fibers within extracellular matrix to mechano regulate its chemical display. Our electron microscopy analysis of their ultrastructure now reveals that the manually pulled fibronectin fibers are composed of densely packed lamellar spirals, whose interlamellar distances are dictated by ion-tunable electrostatic interactions. Our findings suggest that fibrillogenesis proceeds via an irreversible sheet-to-fiber transition as the fibronectin sheet formed at the air-liquid interface of the droplet is pulled off by a sharp tip. This far from equilibrium process is driven by the externally applied force, interfacial surface tension, shear-induced fibronectin self association, and capillary force-induced buffer drainage. The ultrastructural characterization is then contrasted with previous FRET studies that characterized the molecular strain within these manually pulled fibers. Particularly relevant for stretch-dependent binding studies is the finding that the interior fiber surfaces are accessible to nanoparticles smaller than 10 nm. In summary, our study discovers the underpinning mechanism by which highly hierarchically structured fibers can be generated with unique mechanical and mechano-chemical properties, a concept that might be extended to other bio- or biomimetic polymers. PMID- 25442806 TI - Efficacy and safety of metronidazole injection for the treatment of infectious peritonitis, abdominal abscess and pelvic inflammatory diseases in Japan. AB - Although metronidazole (MNZ) has been used worldwide for more than 4 decades as a standard therapy for trichomoniasis, anaerobic and amebic infections, resistance to MNZ is still low. MNZ is available as oral, intravenous, and vaginal formulations, but the intravenous formulation of MNZ has not been approved in Japan. We conducted a phase 3 study to evaluate the efficacy and safety of intravenous MNZ combined with ceftriaxone (CTRX) in Japanese subjects with infectious peritonitis, abdominal abscess or pelvic inflammatory diseases (PIDs) to obtain regulatory approval. A combination of MNZ/CTRX at doses of 500 mg 3 or 4 times a day/1 or 2 g twice a day was administered intravenously to a total of 38 hospitalized subjects. MNZ/CTRX was well tolerated and exhibited excellent clinical and bacteriological efficacy with clinical efficacy rates of 100% (20/20) in infectious peritonitis or abdominal abscess subjects and 90.0% (9/10) in PID subjects, and the eradication rates in infectious peritonitis or abdominal abscess subjects and PID subjects were 100% (16/16) and 100% (4/4), respectively, at the test of cure. MNZ/CTRX was effective in 1 subject in whom a metallo-beta lactamase-producing Bacteroides fragilis strain (MIC of MNZ, 2 MUg/ml) was identified. The most common treatment-related adverse event was diarrhea (23.7%), followed by nausea (5.3%). No new safety signals were identified. MNZ/CTRX demonstrated excellent efficacy and was well tolerated in Japanese infectious peritonitis, abdominal abscess and PID subjects. This treatment regimen can be useful for anaerobic infections. Clinical registration number: NCT01473836. PMID- 25442807 TI - An adolescent female having hepatocellular carcinoma associated with hepatitis B virus genotype H with a deletion mutation in the pre-S2 region. AB - The genotypes of hepatitis B virus (HBV) have a distinct geographical distribution, with HBV genotype H being very rare in East Asia, including Japan. We herein report the case of a 12-year-old Japanese female with hepatocellular carcinoma (HCC) who exhibited HBV genotype H. Notably, the HBV isolated from the patient had a deletion mutation in the pre-S2 region. The genome of HBV genotype H in the patient with HCC has not been analyzed in detail. The deletion mutations in the pre-S2 region, which may play an important role in hepatocarcinogenesis in children, can also present in genotype H. PMID- 25442808 TI - Differentiating Between DKA and HHS. PMID- 25442809 TI - The 5-gallon bucket. PMID- 25442811 TI - Estimation of tibial shaft defect volume using standard radiographs: development and validation of a novel technique. AB - BACKGROUND: No simple clinical technique with which to measure the volume of bone gaps in the treatment of open fractures or nonunions of the tibia is currently available. It is difficult to compare the three-dimensional magnitude of bone defects in research studies on bone grafting without such a tool, and clinicians have no way of determining the magnitude of defects in clinical practice. The purposes of this study were to develop and to validate a technique with which to accurately measure bone gap volumes of the tibial shaft by using only simple measurements on already available clinical radiographs and a simple equation. We hypothesized that a technique could be developed using anteroposterior- and lateral-view radiographs of the tibia to accurately determine the volume of a tibial shaft fracture. METHODS: We created standardized fracture gap models using 45 synthetic tibiae cut in different locations and orientations, rendering 135 gaps. We developed and validated a hydrostatic suspension technique to determine the volume of each bone, which underwent anteroposterior- and lateral-view radiography after each cut. Radiographic measurements were used to calculate defect volumes based on a simple equation. Predicted volumes were compared with measured volumes. RESULTS: The triangular prism equation matched well with the actual volumes. Linear regression analysis showed a slope of 0.92 and R(2) of 0.97. CONCLUSION: The equation provides a simple technique with which to calculate three-dimensional gap volumes based on standard radiographs. The simplicity of the equation and availability of standard radiographs make this a practical research and perhaps clinical tool that might be useful in quantifying volumes of the tibial shaft defect. PMID- 25442810 TI - Home visits by care providers--influences on health outcomes for caregivers of homebound older adults with dementia. AB - Homebound older adults benefit from provider home visits and there is an increasing need for these visits. A study was conducted to evaluate the effect of provider (MD, NP) visits on the caregivers of homebound older adults. Fifty-five caregivers were interviewed to determine any difference in health measures between those whose care recipients had access to a provider and those that did not. The participants completed the SF-36, questionnaires on demographics and access and one opened ended question. Analysis revealed statistically significant differences between the two groups of caregivers. The caregivers whose care recipients did not have access to a provider showed poorer health measures. Providers may have a positive impact on caregiver's health as well as that of the homebound. Developing new and innovative ways to support caregivers while providing care for our patients will be even more important as the population ages and the numbers of available caregivers decrease. PMID- 25442812 TI - The effects of palliative chemotherapy in metastatic colorectal cancer patients with an ECOG performance status of 3 and 4. AB - BACKGROUND: Although chemotherapy is standard for patients with mCRC and ECOG PS of 0/1, the real benefit for patients with ECOG PS > 2 remains uncertain, because they are generally excluded from clinical trials. Our objectives were to compare the survival and safety of ECOG PS 3/4 patients who were administered chemotherapy with those who received BSC only. PATIENTS AND METHODS: We retrospectively analyzed all consecutive mCRC patients who started first-line chemotherapy at our institution in a 4-year period. A multivariable Cox regression model was used to adjust for prognostic factors and logistic regression, to identify predictive factors of Grade 3/4 toxicity. RESULTS: From June 2008 to June 2012, 240 consecutive patients were included: 100 (41.7%) had an ECOG PS of 0/1, 75 (31.3%) ECOG PS of 2, and 65 (27%) ECOG PS of 3/4. Median survival for patients treated with chemotherapy was 18.4 months for patients with ECOG PS of 0/1, 10.8 months for those with ECOG PS of 2, and 6.8 months for patients with ECOG PS of 3/4. Among those with ECOG PS of 3/4, chemotherapy use led to a nonsignificant survival gain (median, 6.8 vs. 2.3 months for BSC; P = .13). Factors significantly associated with worse survival in an adjusted analysis were right-sided tumors (hazard ratio [HR], 2.97; P = .005) and ECOG PS status (ECOG PS 2 vs. 0/1; HR, 1.67; P = .025, and ECOG PS 3/4 vs. 0/1; HR, 2.67; P < .0001). The rate of Grade >= 3 toxicities during the first cycle did not differ significantly across ECOG groups; likely because 40% of ECOG PS 3/4 patients received upfront dose-reduced therapy. The rates of treatment-related hospitalization were similar across all ECOG groups. All deaths were disease associated. CONCLUSION: Our retrospective study suggests that chemotherapy might benefit selected mCRC patients with poor PS. With up-front dose reduction and close monitoring for toxicity, the risk of serious adverse events is minimized. PMID- 25442813 TI - Prognostic factors for patients with advanced colorectal cancer and symptomatic brain metastases. AB - BACKGROUND: Increased rates of long-term survival after CRC diagnosis are accompanied by increases in the incidence of BMs. Here, we retrospectively evaluated the outcomes of patients with BMs from CRC. MATERIALS AND METHODS: We reviewed the records of 1364 patients with CRC treated between January 1999 and December 2010 at Kinki University Hospital in Japan. Twenty-five of these patients developed BMs. Log-rank tests and Cox regression analyses were used to assess potential prognostic factors for survival. RESULTS: Among the patients with BMs, BMs developed a median of 25.3 (range, 11.4-111) months after primary CRC surgery. There was a median of 2 BMs per patient. Eleven patients had solitary BMs. Concomitant extracerebral metastases, particularly lung metastases, were found in 23 patients. Twenty-three patients were receiving systemic chemotherapy at the time of diagnosis with BMs. After the development of BMs, the median survival time (MST) was 2.8 months. The MST was 4.8 months among patients who underwent neurosurgical resection (n = 6) or stereotactic surgery (n = 9, including combined therapy in 2 patients) and 1.5 months among patients who underwent whole-brain radiotherapy only or best supportive care (n = 12). In multivariate analysis, single BMs and additional systemic chemotherapy after BMs diagnosis were significantly associated with overall survival (P = .022 and .023, respectively). CONCLUSION: Our results suggest that advancements in continuing systemic chemotherapy prolong survival among patients with BMs from CRC. Clinicians should be especially aware of BMs in patients with lung metastases. PMID- 25442814 TI - FOLFIRINOX for locally advanced or metastatic pancreatic ductal adenocarcinoma: the Royal Marsden experience. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) has a very poor prognosis. Treatment with FOLFIRINOX has been shown to improve outcomes, but can be associated with significant toxicity. MATERIALS AND METHODS: A retrospective review was performed of all patients with locally advanced or metastatic PDA treated with FOLFIRINOX at the Royal Marsden between November 2010 and November 2013. Efficacy, tolerability, and potential prognostic factors were evaluated. RESULTS: Twenty-seven patients with metastatic PDA and 22 patients with locally advanced PDA were treated with FOLFIRINOX. Patients received a median of 9 cycles (range, 1-26) of FOLFIRINOX. The overall response rate was 41% (20 patients), and a further 17 patients (35%) had stable disease. Thirty-five patients (71%) received FOLFIRINOX in the first-line setting, with a median progression-free survival and overall survival, respectively, of 12.9 months and 18.4 months for patients with locally advanced disease; and 8.4 months and 12.2 months for patients with metastatic disease. The most frequently occurring Grade 3/4 toxicities were neutropenia (29%), fatigue (18%), febrile neutropenia (14%), thromboembolism (12%), and thrombocytopenia (10%). In a univariate analysis, reduction in CA 19-9 of >50% (P < .001), normalization of CA19-9 (P < .001), surgery after FOLFIRINOX (P = .004), and use of prophylactic pegfilgrastim (P = .005) were prognostic for overall survival. CONCLUSION: The efficacy and tolerability of FOLFIRINOX for PDA at our institution is similar to that reported in clinical trials. Careful selection of patients and monitoring of response (according to CA19-9) and toxicities can help maximize advantage in this patient population. PMID- 25442815 TI - CA 19-9 as a marker in addition to CEA to monitor colorectal cancer. AB - BACKGROUND: Carcinoembryonic antigen is the commonly used tumor marker in patients with colorectal cancer, and CA 19-9 might be an additional marker. The aim of this retrospective study was to investigate whether CA 19-9 levels can be used to monitor the disease process in patients with colorectal cancer who had no elevated CEA levels. The secondary aim was to determine if preoperative increased levels of CEA and CA 19-9 were associated with mortality. MATERIALS AND METHODS: Two sets of data from patients with histologically confirmed colorectal cancer, were included in a single-center study. First, patients with a minimum of 3 serial measurements of CA 19-9 and CEA tumor markers were related to the clinical course of their disease. Second, patients with preoperative levels of CEA and CA 19-9 were related to survival. RESULTS: In patients with colorectal cancer and 3 serial measurements of tumor markers, 7.3% had only increased CA 19-9 levels without increased CEA levels, and 55.4% of the patients had an increase of CA 19 9 and CEA levels. In the patients with available preoperative markers, patients with only an increase of CA 19-9 had a significantly decreased 5-year survival compared with patients with an increase of only CEA (P = .013). CONCLUSION: CA 19 9 can be used as additional marker to follow the disease process in patients with colorectal cancer without an increase in CEA level. Patients with preoperative increased CA 19-9 level had a poorer 5-year survival than patients with preoperative increased CEA levels. PMID- 25442816 TI - Colonic metastasis from gastric cancer. PMID- 25442817 TI - Oxaliplatin-induced Lhermitte sign. A case report and review of literature. PMID- 25442818 TI - State of science: mental workload in ergonomics. AB - Mental workload (MWL) is one of the most widely used concepts in ergonomics and human factors and represents a topic of increasing importance. Since modern technology in many working environments imposes ever more cognitive demands upon operators while physical demands diminish, understanding how MWL impinges on performance is increasingly critical. Yet, MWL is also one of the most nebulous concepts, with numerous definitions and dimensions associated with it. Moreover, MWL research has had a tendency to focus on complex, often safety-critical systems (e.g. transport, process control). Here we provide a general overview of the current state of affairs regarding the understanding, measurement and application of MWL in the design of complex systems over the last three decades. We conclude by discussing contemporary challenges for applied research, such as the interaction between cognitive workload and physical workload, and the quantification of workload 'redlines' which specify when operators are approaching or exceeding their performance tolerances. PMID- 25442820 TI - [Have female flight attendants an over-risk of breast cancer?]. AB - OBJECTIVE: The aim of this revue was to estimate the level of breast cancer risk among female flight attendants. MATERIAL AND METHODS: The selected articles were taken from the PUBMED database, between January 1st 1995 and December 31st 2013 by the means of the following keywords: "breast cancer", "flight attendants", "airline cabin crew" and "flight personnel". Seventeen articles were finally selected. RESULTS: The incidence of breast cancer is significantly higher among female flights attendants [standardized incidence ratio (SIR) 1.04-5.24, 95% CI 1.00-17.38]. However, no studies have demonstrated a significant increase of mortality by breast cancer [standardized mortality ratio (SMR) 1.0-1.28, 95% CI 0.54-3.7]. The circadian rhythm disruption through night work and time zones leading to disorder of melatonin secretion just as exposure to cosmic radiation could account for this increase of risk. DISCUSSION AND CONCLUSION: A medical supervision concerning breast cancer for flight attendants is recommended. Additional studies seem to be necessary in order to estimate the additional role of other risk factors, in particular hormonal factor. PMID- 25442819 TI - BIIDXI, the At4g32460 DUF642 gene, is involved in pectin methyl esterase regulation during Arabidopsis thaliana seed germination and plant development. AB - BACKGROUND: DUF642 proteins constitute a highly conserved family of proteins that are associated with the cell wall and are specific to spermatophytes. Transcriptome studies have suggested that members of this family are involved in seed development and germination processes. Previous in vitro studies have revealed that At4g32460- and At5g11420-encoded proteins interact with the catalytic domain of pectin methyl esterase 3 (AtPME3, which is encoded by At3g14310). PMEs play an important role in plant development, including seed germination. The aim of this study was to evaluate the function of the DUF642 gene At4g32460 during seed germination and plant development and to determine its relation to PME activity regulation. RESULTS: Our results indicated that the DUF642 proteins encoded by At4g32460 and At5g11420 could be positive regulators of PME activity during several developmental processes. Transgenic lines overexpressing these proteins showed increased PME activity during seed germination, and improved seed germination performance. In plants expressing At4g32460 antisense RNA, PME activity was decreased in the leaves, and the siliques were very short and contained no seeds. This phenotype was also present in the SALK_142260 and SALK_054867 lines for At4g32460. CONCLUSIONS: Our results suggested that the DUF642 family contributes to the complexity of the methylesterification process by participating in the fine regulation of pectin status during plant development. PMID- 25442821 TI - [Robotic-assisted laparoscopy for deep infiltrating endometriosis: the Register of the Society of European Robotic Gynaecological Surgery]. AB - OBJECTIVES: To assess the interest of robotic-assisted laparoscopy in the context of deep infiltrating endometriosis and to investigate perioperative results. PATIENTS AND METHODS: From November 2008 to April 2012, 164 women with stage IV endometriosis who underwent robotic-assisted laparoscopy (DA VINCI Intuitive Surgical System((r))) were included by eight international participating clinical centers. Patients were divided in 4 groups according to the localization of the nodule(s): rectum (n=88), bladder (n=23), ureter and uterosacral ligaments (n=115) et hysterectomy (n=28). We evaluated the procedures performed, the duration of intervention, the complications, the recurrence and the impact on fertility. RESULTS: In the rectum group, there was a laparotomy conversion, 2 sutured rectal injuries and a red cells blood transfusion. In the bladder group, there was a vesicovaginal hematoma and a prolongated intermittent self catheterization. In the ureter and uterosacral ligaments group, there was 2 ureteral fistulas and there was no complication in the hysterectomy group. DISCUSSION AND CONCLUSION: This study is the largest series published in the literature on robotic-assisted laparoscopy for deep infiltrating endometriosis. The interest of robotic-assisted laparoscopy in deep infiltrating endometriosis seems to be promising while no increase in surgical time, blood loss, and intra- and postoperative complications were observed. PMID- 25442822 TI - [Predictors of failed trial of labor in obese nulliparous]. AB - OBJECTIVES: To identify predictors of failed trial of labour (TOL) in obese nulliparous at term. PATIENTS AND METHODS: Retrospective study about 213 nulliparous with a body mass index (BMI) greater than 30kg/m(2) who delivered a vertex singleton after 37 weeks of gestation (WG). Planned caesarean sections were excluded. Maternal, sonographic, per-partum and neonatal characteristics were analyzed according to the mode of entry into labor and delivery route. Univariate and multivariate logistic regression analysis were performed. RESULTS: The cesarean delivery rate was 28%. Induction of labor (aOR=4.3 [1.8-10.7]), prolonged pregnancy (aOR=10.8 [1.7-67.6]), macrosomia (aOR=5.6 [1.1-27.3]), meconium-stained amniotic fluid (aOR: 2.57 [1.03-6.42]), use of trinitrine (aOR=5.5 [1.39-21.6]) and neonatal head circumference greater than 35cm (aOR=3.1 [1.2-8.0]) were predictors of failed TOL. There was no significant correlation between failed TOL and preconceptional BMI. Univariate analysis revealed an association between excessive weight gain and failed TOL. DISCUSSION AND CONCLUSION: Predictors of failed TOL are the same in obese and non-obese women. Preconceptional BMI does not predict failed TOL in this nulliparous obese population. PMID- 25442823 TI - [Reluctances in organized breast cancer screenig in Yvelines]. AB - OBJECTIVES: Women's participation in organized screening of breast cancer was 52% in France and 40% in the Ile de France in 2010. We wanted to investigate the reasons for non-participation in the screening program and the reluctance of women to it at the level of a department in Ile de France. MATERIALS AND METHODS: An anonymous questionnaire was sent to non-respondents in organized screening for breast cancer in the Yvelines department in September 2011 on the occasion of the event "Octobre Rose", month of national mobilization for mass screening for breast cancer. The analysis of these questionnaires was used to determine the causes of non-adherence to organized screening and reluctance to it. We compared the questionnaire responses in the characteristics of patients attending an individual screening with those of patients without any screening. RESULTS: Two thousand nine hundred and ninety-two questionnaires were sent and 3026 responses received (10%). Two thousand six hundred and fifteen women (86%) reported regular screening and make mammograms every two years while 411 (14%) reported occasional or no screening. About the reluctance to conduct the review, the lack of time, the bad memories of a previous mammogram and the fear of pain were the predominant brakes. Nearly 50% of women do not participate in screening because they did not consider themselves at risk for various reasons (lack of symptoms, healthy lifestyle and no family history) and 22% of women surveyed had an attitude of denial cope with the disease. The typical profile of women performing individual or organized screening of breast cancer was that young, single, working, of low socio-professional category and rarely attending their general practitioner or gynaecologist. Health-care professionals seem most likely to cause adherence to screening for breast cancer. DISCUSSION AND CONCLUSION: Focusing on the poor communication and promote organized screening instead of individual screening by health-care professionals themselves could increase adherence to organized screening in the Yvelines. PMID- 25442824 TI - [Effects of artificial shrinkage prior to vitrification in a closed system: a randomized controlled trial]. AB - OBJECTIVE: To evaluate the effect of induced blastocoele shrinkage before vitrification in a closed carrier device. PATIENTS AND METHODS: Prior to vitrification, blastocyst cavity was artificially shrinked by laser pulse or not treated according to a 2:1 randomized procedure. A total of 185 warming cycles from April 2011 to March 2013 have been analyzed. Clinical pregnancy rate and survival rate were compared between the two groups. The mean (+/-SD) women age was 33.5+/-5.7 years for both groups. RESULTS: The pregnancy rate in the group with artificial reduction of the cavity was higher ([32/67] 47.7%) than in the control group but not significantly ([43/113] 38%). The survival rate in the artificial shrinkage group was significantly higher compared with the control group : 99% (102/103) and 91.8% (168/183) respectively (P=0.01). DISCUSSION AND CONCLUSION: This study reveals that artificial shrinkage of blastocoelic cavity by laser pulse before vitrification in a closed carrier device improves survival rate after warming. PMID- 25442825 TI - [New targeted therapies in breast cancer]. AB - Trastuzumab improves care of patients with HER2+ breast cancer and allows a major gain in terms of survival. T-DM1 and pertuzumab are two new treatments, which give very encouraging results in metastatic breast cancer. Their place in neo adjuvant and adjuvant setting still remains to be defined. Bevacizumab have its place in metastatic breast cancer. In adjuvant setting, results are disappointing and in neo-adjuvant setting, we need more studies on subgroups, which can benefit more. Development of the PARP inhibitors was slowed down by recent negative results in metastatic breast cancer but studies continue with more targeted patient's. Finally, everolimus, inhibitor of mTOR, allows to by pass the hormono resistance in metastatic phase. Its toxicity must be taken into account in particular in adjuvant setting. PMID- 25442842 TI - Assessing the impact of evolving evidence in renal cell carcinoma treatment: an update of the Renal Cell Carcinoma Appropriateness-based Treatment Toolkit (ReCATT). AB - The appropriateness of the numerous therapeutic options available for patients with advanced or metastatic renal cell carcinoma (RCC) was evaluated in 2011, using the RAND/University of California, Los Angeles (UCLA) appropriateness methodology to match treatment suitability to a range of patient scenarios. However, the RCC therapeutic area evolves rapidly and a body of new clinical data has accrued in the intervening years; as a result the exercise was repeated in 2013 using the same methodology, expert panel and patient scenarios. The aim of the updated assessment was to update the guidance to clinicians and use it to develop an interactive web-based application, the Renal Cell Carcinoma Appropriateness-based Treatment Toolkit (ReCATT). This round of assessment achieved greater concordance concerning the appropriateness of treatments/interventions for the clinical scenarios tested; this higher level of agreement is likely to reflect the body of scientific evidence accrued since the previous assessment exercise. Many of the areas of disagreement in 2011 related to the suitability of pazopanib or sunitinib treatment; in the 2013 assessment both agents were considered appropriate treatment options for many of the clinical scenarios assessed. Uncertain scenarios often are related to the optimal management of metastatic RCC with clear cell histology. The use of the RAND/UCLA RCC assessment findings to develop the ReCATT support tool will help to disseminate expert opinion concerning best treatment practice and guide the clinical management of RCC patients treated in the community setting. PMID- 25442828 TI - Deciphering life history transcriptomes in different environments. AB - We compared whole transcriptome variation in six pre-adult stages and seven adult female ages in two populations of cactophilic Drosophila mojavensis reared on two host plants to understand how differences in gene expression influence standing life history variation. We used singular value decomposition (SVD) to identify dominant trajectories of life cycle gene expression variation, performed pairwise comparisons of stage and age differences in gene expression across the life cycle, identified when genes exhibited maximum levels of life cycle gene expression, and assessed population and host cactus effects on gene expression. Life cycle SVD analysis returned four significant components of transcriptional variation, revealing functional enrichment of genes responsible for growth, metabolic function, sensory perception, neural function, translation and ageing. Host cactus effects on female gene expression revealed population- and stage specific differences, including significant host plant effects on larval metabolism and development, as well as adult neurotransmitter binding and courtship behaviour gene expression levels. In 3- to 6-day-old virgin females, significant upregulation of genes associated with meiosis and oogenesis was accompanied by downregulation of genes associated with somatic maintenance, evidence for a life history trade-off. The transcriptome of D. mojavensis reared in natural environments throughout its life cycle revealed core developmental transitions and genome-wide influences on life history variation in natural populations. PMID- 25442843 TI - Thalamic stimulation to improve level of consciousness after seizures: evaluation of electrophysiology and behavior. AB - OBJECTIVE: Understanding the neural mechanisms that support human consciousness is an important frontier in neuroscience and medicine. We previously developed a rodent model of temporal lobe seizures that recapitulates the human electroencephalography (EEG) signature of ictal and postictal neocortical slow waves associated with behavioral impairments in level of consciousness. The mechanism of slow-wave production in epilepsy may involve suppression of the subcortical arousal systems including the brainstem and intralaminar thalamic nuclei. We hypothesized that intralaminar thalamic stimulation may lead to electrophysiologic and functional rescue from postictal slow waves and behavioral arrest. METHODS: We electrically stimulated the central lateral thalamic nucleus (a member of the intralaminar nuclei) under anesthesia and after electrically induced hippocampal seizures in anesthetized and in awake-behaving animal model preparations. RESULTS: We demonstrated a proof-of-principle restoration of electrophysiologic and behavioral measures of consciousness by stimulating the intralaminar thalamic nuclei after seizures. We measured decreased cortical slow waves and increased desynchronization and multiunit activity in the cortex with thalamic stimulation following seizures. Functionally, thalamic stimulation produced resumption of exploratory behaviors in the postictal state. SIGNIFICANCE: Targeting of nodes in the neural circuitry of consciousness has important medical implications. Impaired consciousness with epilepsy has dangerous consequences including decreased school/work performance, social stigmatization, and impaired airway protection. These data suggest a novel therapeutic approach for restoring consciousness after seizures. If paired with responsive neurostimulation, this may allow rapid implementation to improve level of consciousness in patients with epilepsy. PMID- 25442844 TI - Ensemble perception of size in 4-5-year-old children. AB - Groups of objects are nearly everywhere we look. Adults can perceive and understand the 'gist' of multiple objects at once, engaging ensemble-coding mechanisms that summarize a group's overall appearance. Are these group perception mechanisms in place early in childhood? Here, we provide the first evidence that 4-5-year-old children use ensemble coding to perceive the average size of a group of objects. Children viewed a pair of trees, with each containing a group of differently sized oranges. We found that, in order to determine which tree had the larger oranges overall, children integrated the sizes of multiple oranges into ensemble representations. This pooling occurred rapidly, and it occurred despite conflicting information from numerosity, continuous extent, density, and contrast. An ideal observer analysis showed that although children's integration mechanisms are sensitive, they are not yet as efficient as adults'. Overall, our results provide a new insight into the way children see and understand the environment, and they illustrate the fundamental nature of ensemble coding in visual perception. PMID- 25442845 TI - Amygdala: eyes wide open. PMID- 25442846 TI - Biofilms: five-star accommodations for the aerobically challenged. PMID- 25442847 TI - Cellular energetics: actin and myosin abstain from ATP during starvation. PMID- 25442848 TI - Neuronal mitophagy: long-distance delivery or eating locally? PMID- 25442849 TI - Tumor microenvironment: unleashing metalloproteinases to induce a CAF phenotype. PMID- 25442851 TI - Strigolactones. PMID- 25442852 TI - Adipocytes. PMID- 25442854 TI - Aging: manipulating sex differences. PMID- 25442853 TI - Polyphasic feedback enables tunable cellular timers. AB - Cellular 'timers' provide an important function in living cells. Timers help cells defer their responses to stimuli, often for time intervals extending over multiple cell cycles (Figure 1A, left). For example, mammalian oligodendrocyte precursors typically proliferate for ~ 7 divisions before differentiating during neural development. The bacterium Bacillus subtilis can respond to sudden nutrient limitation by transforming into a dormant spore after ~ 5 cell cycles. Timers can balance proliferation with differentiation to control the sizes of various cell populations. Some timers appear to operate in a largely cell autonomous fashion, but the underlying genetic circuit mechanisms that enable this remain poorly understood. Protein dilution poses stringent challenges to timer circuits by continually diluting out timer components in proliferating cells (Figure 1A, right). Recent work suggests that pulsatile or oscillatory dynamics can facilitate timer functions [3,4]. Here, we show how polyphasic positive feedback - a pulsed architecture that breaks a feedback signal into temporally distinct phases - counteracts protein dilution to facilitate timer behavior. PMID- 25442850 TI - Moving sensory adaptation beyond suppressive effects in single neurons. AB - How an object is perceived depends on the temporal context in which it is encountered. Sensory signals in the brain also depend on temporal context, a phenomenon often referred to as adaptation. Traditional descriptions of adaptation effects emphasize various forms of response fatigue in single neurons, which grow in strength with exposure to a stimulus. Recent work on vision, and other sensory modalities, has shown that this description has substantial shortcomings. Here we review our emerging understanding of how adaptation alters the balance between excitatory and suppressive signals, how effects depend on adaptation duration, and how adaptation influences representations that are distributed within and across multiple brain structures. This work points to a sophisticated set of mechanisms for adjusting to recent sensory experience, and suggests new avenues for understanding their function. PMID- 25442855 TI - Microtubule recognition: a curvy attraction. PMID- 25442856 TI - Hepatitis B virus infection and replication in a new cell culture system established by fusing HepG2 cells with primary human hepatocytes. AB - BACKGROUND: Hepatitis B virus (HBV) infection is strictly species and tissue specific, therefore none of the cell models established previously can reproduce the natural infection process of HBV in vitro. The aim of this study was to establish a new cell line that is susceptible to HBV and can support the replication of HBV. METHODS: A hybrid cell line was established by fusing primary human hepatocytes with HepG2 cells. The hybrid cells were incubated with HBV positive serum for 12 hours. HBV DNA was detected by quantitative fluorescence polymerase chain reaction (QF-PCR). HBsAg (surface antigen) and HBeAg (extracellular form of core antigen) were observed by electrochemiluminescence (ECL). HBcAg (core antigen) was detected by the indirect immunofluorescence technique. HBV covalently closed circular DNA (cccDNA) was analyzed by Southern blot hybridization and quantified using real-time PCR. RESULTS: A new cell line was established and named HepCHLine-7. The extracellular HBV DNA was observed from Day 2 and the levels ranged from 9.80 (+/- 0.32) * 10(2) copies/mL to 3.12 (+/- 0.03) * 10(4) copies/mL. Intracellular HBV DNA was detected at Day 2 after infection and the levels ranged from 7.92 (+/- 1.08) * 10(3) copies/mL to 5.63 (+/- 0.11) * 10(5) copies/mL. HBsAg in the culture medium was detected from Day 4 to Day 20. HBeAg secretion was positive from Day 5 to Day 20. HBcAg constantly showed positive signals in approximately 20% (+/- 0.82%) of hybrid cells. Intracellular HBV cccDNA could be detected as early as 2 days postinfection and the highest level was 15.76 (+/- 0.26) copies/cell. CONCLUSION: HepCHLine-7 cells were susceptible to HBV and supported the replication of HBV. They are therefore suitable for studying the complete life cycle of HBV. PMID- 25442857 TI - Comparisons of etiology and diagnostic tools of lower respiratory tract infections in hospitalized young children in Southern Taiwan in two seasons. AB - BACKGROUND: Lower respiratory tract infections (LRTIs) play an important role in pediatric diseases; however, there are limited data about LRTIs in Southern Taiwan. This study aimed to investigate the clinical and epidemiological data of LRTIs in this area. METHODS: Children aged under 5 years who were hospitalized at a medical center in Southern Taiwan with acute LRTIs from July 2010 to October 2010 (summer) and from March 2011 to May 2011 (spring) were prospectively enrolled. Nasopharyngeal aspirates were obtained and sent for viral cultures, multiplex polymerase chain reaction (PCR), and traditional quick tests. The clinical features, laboratory data, and imaging findings were recorded and analyzed. RESULTS: A total of 90 children were enrolled, 70 of whom had detectable pathogens. The positive rate of conventional viral and bacterial cultures was 25.6%, which increased to 77.77% after combining with the two multiplex PCR methods. Adenovirus and enterovirus were the most common viral etiologies identified (26.5% of cases) and Streptococcus pneumoniae was the leading bacterial etiology (46.4%). The seasonal trend of viral infections in Southern Taiwan was different from Northern Taiwan. There were no differences in demographic data, severity of disease, or hospital stay between single and mixed infections. A similar result was found between nonpneumococcal and pneumococcal infections. CONCLUSION: Viral infections were the main etiologies of LRTIs in young children. Multiplex PCR methods are rapid assays that can increase the diagnostic yield rate. Mixed infections do not seem to affect the severity of disease. Early detection may aid clinicians in appropriate decision-making and treatment. PMID- 25442858 TI - Prevalence of latent tuberculosis infection in persons with and without human immunodeficiency virus infection using two interferon-gamma release assays and tuberculin skin test in a low human immunodeficiency virus prevalence, intermediate tuberculosis-burden country. AB - BACKGROUND: The risk of tuberculosis (TB) is higher in human immunodeficiency virus (HIV)-infected patients and intravenous drug users (IDUs). We determined the prevalence and risk factors of latent TB infection (LTBI) in individuals with or without HIV infection, including IDUs, in a country with a low HIV prevalence, an intermediate TB burden, and a high Bacillus Calmette-Guerin (BCG) vaccine coverage using two interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST). METHODS: For this prospective, cross-sectional study, HIV infected and -uninfected patients from a regional hospital and medical center in Taiwan were enrolled. Results of the two IGRAs [QuantiFERON-TB Gold (QFT-G) and QuantiFERON-TB Gold In-Tube (QFT-GIT)] and the TST were compared. Risk factors for positivity were analyzed. RESULTS: We recruited 233 patients [198 (85%) men; mean age, 39.4 years]. Most patients (74%) were BCG vaccinated. The prevalence of LTBI was estimated to be 22.8% by TST, 15.9% by QFT-G, and 20.6% by QFT-GIT. HIV infected individuals had fewer positive QFT-GIT [7.0% vs. 28.6%, p < 0.001, adjusted odds ratio (aOR) = 0.28, p = 0.05] and TST results, and more indeterminate QFT-G responses (9.3% vs. 0.7%, p = 0.002). Concordance between IGRAs and TST was very poor in HIV-infected patients (kappa < 0.05). Independent risk factors for IGRA positivity were increasing age (QFT-G: aOR = 1.98, p = 0.03; QFT-GIT: aOR = 2.00, p = 0.01) and IDUs (aOR = 4.33, p = 0.05 by QFT-G). CONCLUSION: HIV-infected persons had a significantly lower response to both IGRAs and TST. High discordance was found between the two generations of IGRAs and between IGRAs and TST. Increasing age, a known risk factor for LTBI, was significantly associated with IGRAs, but not with TST. PMID- 25442859 TI - Analysis of codon usage preference in hemagglutinin genes of the swine-origin influenza A (H1N1) virus. AB - BACKGROUND: The swine-origin influenza A (H1N1) virus (S-OIV) has come to the forefront since 2009 and was identified as a new reassortant strain. The hemagglutinin (HA) glycoprotein mediates virus binding, contains antigenic regions recognized by neutralizing antibodies, and is associated with viral cross species infection and adaption. The comparison study of codon usage preferences in influenza viral genomes was less extensive. In this study, we used codon usage pattern analyses to validate the adaption and origins of S-OIV. METHODS: Codon usage pattern was used to estimate the host adaption of S-OIVs. Phylogenetic analysis of the HA gene was conducted to understand the phylogeny of H1N1 viruses isolated from different hosts. Amino acid signature pattern on antigenic sites of HA was analyzed to understand the antigenic characteristics. RESULTS: Results of phylogenetic analyses of HA gene indicate that S-OIVs group in identical clusters. The synonymous codon usage pattern analyses indicate that the effective number of codons versus GC content at the third codon position in the HA1 gene slightly differ from those in swine H1N1 and gradually adapted to human. Our data indicate that S-OIV evolution occurred according to positive selection within these antigenic regions. A comparison of antigenic site amino acids reveals similar signature patterns between S-OIV and 1918 human influenza strains. CONCLUSION: This study proposes a new and effective way to gain a better understanding of the features of the S-OIV genome and evolutionary processes based on the codon usage pattern. It is useful to trace influenza viral origins and cross-species virus transmission. PMID- 25442860 TI - Prevalence of aminoglycoside modifying enzyme and 16S ribosomal RNA methylase genes among aminoglycoside-resistant Escherichia coli isolates. AB - Aminoglycoside resistance determinants among 188 aminoglycoside-resistant blood culture Escherichia coli isolates from a tertiary hospital in Hong Kong, from 2004 to 2010 were investigated. Overall, 91% had aac(3)-II, 12.2% had aac(6') Ib/Ib-cr, and 5.4% had the methylase genes (rmtB, armA). Aminoglycoside-resistant isolates with aac(')-Ib/Ib-cr, rmtB, and armA often had coresistance to multiple other antibiotics. PMID- 25442861 TI - Analysis of clinical outcomes in pediatric bacterial meningitis focusing on patients without cerebrospinal fluid pleocytosis. AB - BACKGROUND: Cerebrospinal fluid (CSF) cell count and biochemical examinations and cultures form the basis for the diagnosis of bacterial meningitis. However, some patients do not have typical findings and are at a higher risk of being missed or having delayed treatment. To better understand the correlation between CSF results and outcomes, we evaluated CSF data focusing on the patients with atypical findings. METHODS: This study enrolled CSF culture-proven bacterial meningitis patients aged from 1 month to 18 years in a medical center. The patients were divided into "normal" and "abnormal" groups for each laboratory result and in combination. The correlations between the laboratory results and the outcomes were analyzed. RESULTS: A total of 175 children with confirmed bacterial meningitis were enrolled. In CSF examinations, 16.2% of patients had normal white blood cell counts, 29.5% had normal glucose levels, 24.5% had normal protein levels, 10.2% had normal results in two items, and 8.6% had normal results in all three items. In logistic regression analysis, a normal CSF leukocyte count and increased CSF protein level were related to poor outcomes. Patients with meningitis caused by Streptococcus pneumoniae and hyponatremia were at a higher risk of mortality and the development of sequelae. CONCLUSIONS: In children with bacterial meningitis, nontypical CSF findings and, in particular, normal CSF leukocyte count and increased protein level may indicate a worse prognosis. PMID- 25442862 TI - Recent trends in antibiotic prescriptions for acute respiratory tract infections in pediatric ambulatory care in Taiwan, 2000-2009: A nationwide population-based study. AB - BACKGROUND: Antibiotic resistance is a global problem, and the inappropriate overuse of antibiotics is the major cause. Among children seeking medical help, acute respiratory tract infections (ARTIs) are the most common tentative diagnosis made by physicians and the leading condition for which antibiotics are prescribed. This study aimed to examine the trends of prescribing antibiotics in pediatric ambulatory care in Taiwan over a 10-year period. METHODS: Children younger than 18 years old and being diagnosed as having ARTIs [International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 460, 465, and 466] during ambulatory visits from 2000 to 2009 were retrieved from the systematic random sampling datasets of the National Health Insurance Research Database (NHIRD) in Taiwan. The annual and monthly case numbers were recorded and the children's demographic characteristics, including sex, age, seasonality, location, level of medical institution, physician specialty, and their ambulatory prescriptions of antibiotics were collected and analyzed. RESULTS: Among 565,065 enrolled ambulatory children, 39,324 were prescribed antibiotics. The average antibiotics prescription rate was 7.0% during the 10-year period. There were marked descending trends in case numbers and antibiotic dispensing rates from 2000 to 2009. Female patients, elder ages (>=6 years old), summer and autumn, middle and southern areas of Taiwan, medical centers and regional hospitals, and physicians of pediatric specialty were associated with significantly lower antibiotic dispensing rates than other conditions (p < 0.05). CONCLUSION: The 10-year antibiotics prescription rate in ambulatory children with ARTIs was 7.0% and it decreased gradually from 2000 to 2009 in Taiwan. Through understanding the annual trends in antibiotic prescriptions, it may be possible to design interventions to improve the judicious use of antibiotics in children. PMID- 25442863 TI - Seroepidemiology for measles among elementary school children in Northern Taiwan. AB - BACKGROUND: Despite the high vaccination coverage in Taiwan, sporadic cases or small cluster of measles still occur every year. Nevertheless, few studies provided information about the serostatus for measles in recent years. This cross sectional survey aimed to establish the seroepidemiologic data of measles among elementary school children in New Taipei City, Taiwan during 2012-2013. METHODS: A multistage stratified sampling design using 14 variables was employed to obtain samples. All selected schoolchildren were bled for the serologic tests of measles by both chemiluminescence immunoassay (CLIA) and enzyme immunoassay (EIA). RESULTS: A total of 856 schoolchildren from 14 schools were recruited in this study. Among these individuals, the overall seropositive rates for measles were 82.24% and 92.17% by the Liaison and NovaLisa assays, respectively. For schoolchildren in each grade, the seropositive rates were > 90% for Grade 1, and then decreased gradually to 70-80% for Grade 6 (p < 0.001 for both methods). A decay of measles-specific immunoglobulin G titers was also observed with the maximum drop between Grade 1 and Grade 2 (declining trend of p < 0.001 for both). CONCLUSION: Although the seropositive rate of measles was > 90% for Grade 1, the rate for Grade 6 was only in the range of 70-80%, which may be a challenge to prevent outbreaks of measles in the future and should be monitored meticulously. PMID- 25442864 TI - Changes in the six most common sequence types of Neisseria gonorrhoeae, including ST4378, identified by surveillance of antimicrobial resistance in northern Taiwan from 2006 to 2013. AB - BACKGROUND: There has been no longitudinal study of drug susceptibility in Neisseria gonorrhoeae in Taiwan since 2006. METHODS: We collected 1090 gonococcal isolates from Taipei City Hospital, Taiwan from April 2006 to August 2013. We used a disk diffusion assay to determine the susceptibility to five antibiotics and an E-test to determine the minimum inhibitory concentrations for cefixime and ceftriaxone in isolates with resistance. Neisseria gonorrhoeae-multi Antigen Sequence Typing and DNA sequencing of the por and tbpB genes were used to identify sequence types. RESULTS: Among the 1090 isolates, the resistances to penicillin, ciprofloxacin, cefpodoxime, cefixime, and ceftriaxone were 61.01%, 83.39%, 9.63%, 6.70%, and 2.39%, respectively. The highest minimum inhibitory concentrations of cefixime and ceftriaxone were 0.19 mg/L and 0.50 mg/L, respectively. There were 327 sequence types. The four most common sequence types in homosexuals were ST4378, ST359, ST4654, and ST547; the two most common sequence types in heterosexuals were ST421 and ST419. Each of these sequence types had more than 25 isolates. There were significant differences in the sequence types in patients with different sexual orientations (p < 0.001). CONCLUSION: Oral cefixime or ceftriaxone injections were used as first-line drugs for the treatment of gonorrhea from 2006 to 2013 because gonorrhea isolates had low minimum inhibitory concentrations for these two drugs. The abrupt emergence of ST4378 (closely related to the notorious ST1407) since 2009 is a cause for alarm. Changes in sexual behavior, including an increase in sexual activity without the use of condoms, may have contributed to the peak in gonorrhea in 2010. Further molecular epidemiological investigations are required. PMID- 25442865 TI - The roles of noncoding RNA Rli60 in regulating the virulence of Listeria monocytogenes. AB - BACKGROUND: Listeria monocytogenes (LM) is an important zoonotic foodborne pathogen. Noncoding RNA (ncRNA) has an important role in regulating its virulence. As a member of ncRNA, however, the function of Rli60 in regulating LM virulence remain unclear. The aim of this study was to investigate the role of Rli60 in regulating LM virulence. METHODS: Using a homologous recombination method, a LM EGD-e rli60 gene deletion strain (LM-Deltarli60) was constructed and compared with a LM EGD-e strain in the following respects: (1) adhesiveness, invasion ability, intracellular survival, proliferation, and transcription of virulence genes in the mouse macrophage cell line RAW264.7; (2) 50% lethal dose (LD50) to the BALB/c mouse; and (3) the amount in the mouse liver and spleen and the effects on pathology of mouse liver, spleen, and kidney after inoculation. RESULTS: The LM-Deltarli60 strain had a significantly higher adhesion rate and lower invasion rate with significantly lower intracellular survival and proliferation rates in the RAW264.7 cell line, compared to the LM EGD-e strain. Inoculation with LM-Deltarli60 strain significantly affected the transcription of virulence genes. The LD50 of LM-Deltarli60 to BALB/c mouse was increased by 2.12 logarithmic magnitude, which indicated that the virulence in LM-Deltarli60 is significantly decreased (p < 0.05). The amount of LM-Deltarli60 in the liver and spleen was significantly lower than the amount of LM EGD-e in these organs (p < 0.05). The pathological damage due to LM-Deltarli60 infection in the mouse liver, spleen, and kidney was lower than the damage due to LM EGD-e infection. CONCLUSION: This study confirmed that the rli60 deletion could significantly affect LM virulence, adhesion, invasion, survival, and proliferation. This suggests that Rli60 has an important role in regulating LM virulence. PMID- 25442866 TI - Clinical outcomes of septic patients with diabetic ketoacidosis between 2004 and 2013 in a tertiary hospital in Taiwan. AB - BACKGROUND: Infection is the most common predisposing factor for diabetic ketoacidosis (DKA); however, studies are rare that have investigated the clinical outcomes of septic patients with infection-precipitated DKA. METHODS: A retrospective cohort study was conducted at a tertiary hospital from 2004 to 2013. Patients with DKA in whom the presence of a predisposing infection was confirmed were enrolled. Characteristics at initial presentation, primary infection sources, and causative microorganisms were compared between the nonacute kidney injury (non-AKI) group and acute kidney injury (AKI) group at each stage. Risk factors for the development of failure-stage AKI and its outcomes were also analyzed. RESULTS: One hundred and sixty DKA episodes were assessed. The most common infection sites were the urinary and respiratory tracts. The leading causative microorganism was Escherichia coli, followed by Klebsiella pneumoniae. A complicated/severe infection state [odds ratio (OR), 15.27; p < 0.001] and a high level of C-reactive protein (OR, 1.012; p < 0.001) were independently associated with bacteremia. Corrected sodium (Na; OR, 1.062; p = 0.039), initial plasma glucose (OR, 1.003; p = 0.041), severe grade of DKA (OR, 13.41; p = 0.045), and the Acute Physiology and Chronic Health Evaluation (APACHE) II score (OR, 1.08; p = 0.033) were identified as independent risk factors for the development of failure-stage AKI among septic patients with infection-precipitated DKA. Patients with failure-stage AKI had a higher frequency of incomplete recovery of renal function (20.4% of patients in failure vs. 5.9% of patients in risk and injury, p = 0.009). Bacteremia independently predicted the absence of complete recovery of renal function (OR, 5.86; p = 0.038). CONCLUSION: For patients with infection-precipitated DKA, the clinician should aggressively monitor renal function if a patient presents with risk factors associated with failure-stage AKI. Furthermore, bacteremia predicts a poor renal prognosis. PMID- 25442867 TI - Pseudomonas aeruginosa infective endocarditis in patients who do not use intravenous drugs: Analysis of risk factors and treatment outcomes. AB - BACKGROUND: Infective endocarditis (IE) due to Pseudomonas aeruginosa is rare and accounts for only about 3% of all patients with this disease. Most infections are associated with the use of intravenous drugs. Patients with P. aeruginosa-related IE who do not use intravenous drugs are extremely rare. We carried out a review of the literature to identify the nature and risk factors of this disease. METHODS: Patients with IE reported between 1993 and 2013 were reviewed by searching the Medline database using the keywords "endocarditis" and "Pseudomonas aeruginosa". All of the patients included met the definition of the modified Duke criteria. RESULTS: Twenty-seven patients in 22 reports were reviewed. IE associated with health care accounted for 20 patients (74%). The mean age of the patients was 53.4 years and there was a predominance of men (81.5%). Native valve endocarditis was seen in 20 (74.1%) patients. Surgery for infection control was performed in 15 (55.6%) patients and the mortality rate in patients who underwent surgery was 33.3% (five patients). A relapse of IE after adequate treatment was seen in nine (33.3%) patients. The mortality rate in all 27 patients was 28.6% (2/7) for those with community-acquired IE and 40% (8/20) for those with IE associated with health care. Univariate analysis showed a higher mortality rate in patients aged >60 years and in those whose source of endocarditis was related to a prosthetic device. CONCLUSION: P. aeruginosa endocarditis has substantial morbidity and mortality. It is characterized by easy relapse and is highly associated with prosthetic devices. PMID- 25442868 TI - Risk factors associated with death in patients with severe respiratory syncytial virus infection. AB - BACKGROUND: Respiratory syncytial virus (RSV) infection is an important cause of viral respiratory tract infection in children. This retrospective study describes the clinical characteristics of severe RSV infection and determines the risk factors for death. METHODS: Patients were identified through a review of all patients discharged with a diagnosis of RSV lower respiratory tract infection and admitted to hospital in the pediatric intensive care unit (PICU) of a tertiary medical center between July 1, 2001 and June 30, 2010. The medical and demographic variables were recorded and analyzed. RESULTS: The 186 RSV-positive patients admitted to the PICU had a median age of 5.3 months (interquartile range 2.3-12.4 months) and included 129 boys and 57 girls. Among them, 134 had at least one underlying disease: prematurity in 92, neurological disease in 57, bronchopulmonary dysplasia in 40, congenital heart disease in 26, hematological malignancies in 11, and Down's syndrome in nine patients. The 10 patients who died from RSV-related causes had a median age of 20.8 months (interquartile range 6.6-89.2 months) and all had a comorbidity. In multivariate analysis, the risk factors for death in severe RSV infection were Down's syndrome (odds ratio 7.20, 95% confidence interval 1.13-45.76; p = 0.036) and nosocomial RSV infection (odds ratio 4.46, 95% confidence interval 1.09-18.27; p = 0.038). CONCLUSION: Down's syndrome and nosocomial RSV infection are significantly associated with death in severe RSV infections. Clinicians should be alert to these conditions. PMID- 25442869 TI - Impact of revised susceptibility breakpoints on bacteremia of Klebsiella pneumoniae: Minimum inhibitory concentration of cefazolin and clinical outcomes. AB - BACKGROUND: The Clinical and Laboratory Standards Institute (CLSI) revised the susceptibility breakpoints of cephalosporins for Enterobacteriaceae in 2010 and 2011. However, there is a lack of clinical data about the correlation of minimum inhibitory concentrations (MICs) and clinical outcome. Data for the distribution of MICs and clinical outcomes were analyzed in this study to evaluate the impact of changes in the CLSI breakpoints on the treatment of Klebsiella pneumoniae bacteremia. METHODS: Ninety-seven bacteremic K. pneumoniae isolates from Taichung Veterans General Hospital, Taichung, Taiwan were collected for study during the period 2009-2011. The cefazolin MIC was determined by the broth microdilution method according to the recommendations of the CLSI. The MIC distribution of cefazolin and the clinical responses to definitive cefazolin treatment were analyzed. RESULTS: The modal cefazolin MIC among the 97 isolates was 1 MUg/mL and accounted for 73 (75.3%) isolates. There were 18 (18.6%) isolates with a cefazolin MIC of 2 MUg/mL. The conventional dosage regimens of cefazolin (1 g every 6 hours or 8 hours) achieved a clinical cure in 70 (97.2%) of 72 patients in the group with a cefazolin MIC <=1 MUg/mL and in 14 (87.5%) of 16 patients in the group with a cefazolin MIC of 2 MUg/mL. With the conventional dose, the cumulative clinical cure rate for K. pneumoniae bacteremia with cefazolin MIC <=2 MUg/mL was 95.5% (84/88 patients). CONCLUSION: The conventional cefazolin dose still can result in satisfactory clinical cure rates for bacteremic episodes due to K. pneumoniae with cefazolin MIC <=2 MUg/mL, the revised susceptible breakpoint of CLSI 2011. PMID- 25442870 TI - Hepatitis A virus seroepidemiology of elementary school children in New Taipei City in Taiwan. AB - BACKGROUND: To establish the seroepidemiologic data of hepatitis A virus (HAV) vaccine-preventable HAV diseases among school children (7-12 years old) attending elementary schools in New Taipei City, Taiwan. This is a pilot study of an ongoing nationwide study, and will be the reference for a national immunization program. METHODS: The school children were selected for samplings, based on a multistage stratified sampling method that included 14 variables (4 socioeducational variables, 4 socioeducational variables, and 6 medical facilities' variables). The 29 administrative districts of New Taipei City were categorized into five strata. In total, 936 school children from 14 schools were recruited and bled for the serologic tests of HAV by enzyme-linked immunosorbent assay method. RESULTS: The seropositive rate for HAV was 8.33% among the 936 children. From each school, the difference in the seropositive rate for HAV ranged 0-18.75%. There was no significant difference between each stratum (p = 0.059) or grade (p = 0.570); however, there was a difference between schools in the first stratum (p = 0.033) that was associated with different vaccination rates. This study also revealed a significantly greater seropositive rate in the vaccination group (p < 0.001) and in females (p = 0.02). CONCLUSION: The seropositive rate for the HAV was <10% and was mostly associated with the vaccination status. Because of the low HAV vaccination rate and low seropositive rate for the HAV, an effective hepatitis A vaccine is a useful tool to prevent HAV infection. It is worthy to discuss whether to include the HAV vaccine as part of a routine vaccination program in Taiwan. PMID- 25442871 TI - Regulator of the mucoid phenotype A gene increases the virulent ability of extended-spectrum beta-lactamase-producing serotype non-K1/K2 Klebsiella pneumonia. AB - BACKGROUND: To determine whether the presence of a capsule regulator gene [i.e., regulator of mucoid phenotype A (rmpA) gene] contributes to virulence on extended spectrum beta-lactamase-producing Klebsiella pneumoniae (ESBL-KP) with serotype non-K1/K2 strains. METHODS: Twenty-eight ESBL-KP and non-ESBL-KP isolates were collected from the Tri-Service General Hospital (Taipei, Taiwan). The impact of the virulent rmpA gene in different capsular polysaccharide serotypes on ESBL-KP and non-ESBL-KP isolates was studied by a neutrophil phagocytosis reaction, a serum bactericidal assay, and an animal survival model. RESULTS: Resistance to broad spectrum antibiotics was more prevalent in ESBL-KP strains than in non-ESBL KP strains (p < 0.01). The ESBL-KP strains had different molecular patterns from non-ESBL-KP strains, based on pulsed-field gel electrophoresis. The frequency of serum-resistant isolates was the highest among ESBL-KP strains with rmpA (i.e., rmpA(+)) [71.4% (5/7)] than among of non-ESBL-KP rmpA(+) strains [42.8% (6/14)], ESBL-KP strains without rmpA (rmpA(-)) [33.3% (7/21)], and non-ESBL-KP rmpA(-) strains [14.2% (2/14)]. The most significant increase in neutrophil resistance occurred in the ESBL-KP rmpA(+) strains in comparison to the non-ESBL-KP rmpA(+), ESBL-KP rmpA(-), and non-ESBL-KP rmpA(-) strains (p < 0.01). The results of the animal survival model were compatible with the neutrophil phagocytosis reaction and serum bactericidal assay. CONCLUSION: We conclude that the pathogenic potential is greater in rmpA(+) ESBL-KP strains than in rmpA(-) ESBL-KP and non ESBL-KP strains. PMID- 25442872 TI - Treatment of recurrent complicated urinary tract infections in children with vesicoureteral reflux. AB - BACKGROUND: Urinary tract infections (UTIs) in children with vesicoureteral reflux (VUR) are often caused by uropathogens with a high rate of drug resistance and are associated with a high rate of recurrence with a single pathogen. In this study, we evaluated the incidence of recurrent UTI and the drug resistance pattern of Escherichia coli in children with VUR. We also evaluated whether combination therapy comprising fosomycin plus one other antimicrobial agent is effective for treatment of recurrent UTIs. METHODS: We retrospectively reviewed the medical records of all children with VUR who developed at least one episode of UTI during the period January 1, 2003 to December 31, 2013 at a single medical center. The effectiveness of fosfomycin plus amikicin for Enterobacteriaceae or ceftazidime for Pseudomonas aeruginosa infections was prospectively studied in six children with recurrent relapsing UTIs. RESULTS: The study population comprised 129 children (age range, from 1month to 15 years; mean +/- standard deviation, 2.37 +/- 2.91 years) with VUR who developed at least one UTI during the 10-year study period; 68 (52.7%) had recurrent UTIs. The presence of an underlying urinary tract anomaly was predictive of recurrence (p = 0.028). The rates of susceptibility of E. coli to cefazolin (p < 0.001) and cefotaxime (p < 0.001) were significantly lower in patients with recurrent UTIs. Combination therapy with fosfomycin plus amikacin or ceftazidime was shown to be an effective therapeutic option for recurrent UTIs due to a single uropathogen. CONCLUSION: The rates of susceptibility of E. coli to commonly used antimicrobials were significantly lower in children who developed more than one episode of UTI. The empiric choice of cefazolin or cefotaxime was usually ineffective. Administration of fosfomycin plus amikacin or ceftazidime was an effective therapeutic and preventive strategy in children with VUR and recurrent relapsing UTI. PMID- 25442873 TI - Multidrug-resistant Acinetobacter baumannii infection among neonates in a neonatal intensive care unit at a medical center in central Taiwan. AB - BACKGROUND: Few studies have focused on multidrug-resistant Acinetobacter baumannii (MDRAB) infection in neonates. The aim of this study was to investigate risk factors for mortality in neonates with MDRAB infection. METHODS: This retrospective case-series study was conducted at the Children's Hospital of China Medical University, Taichung, Taiwan. All patients hospitalized between January 2010 and December 2013 in the neonatal intensive care unit (NICU) with MDRAB infections were reviewed. RESULTS: A total of 67 isolates from 59 neonatal patients were positive for MDRAB. Of the 67 isolates, 38 were from blood (56.72%), 16 from sputum (23.88%), seven from pus (10.45%), three from ascites (4.48%), two from cerebrospinal fluid (2.99%), and one from pleural fluid (1.49%). There were five episodes of MDRAB clusters consisting of 28 cases during the study period. The mortality rate due to MDRAB sepsis was 20.34% (12/59). The statistically significant risk factors for mortality due to MDRAB infection were being infected with MDRAB within 7 days of admission to the NICU, use of umbilical vein catheters, absolute neutrophil count < 1500/mm(3), platelet count < 100,000/mm(3), and a delay in initiating adequate antibiotic treatment. CONCLUSION: MDRAB infection is responsible for a high mortality rate among neonates in the NICU, especially in those who have neutropenia or thrombocytopenia. Infection control and appropriateness of the initial antimicrobial agent with colistin play an important role in reducing mortality. PMID- 25442874 TI - Role of calcium channels in cellular antituberculosis effects: Potential of voltage-gated calcium-channel blockers in tuberculosis therapy. AB - The immunity of human immune cells and their ability to inhibit Mycobacterium tuberculosis (MTB) are key factors in the anti-MTB effect. However, MTB modulates the levels and activity of key intracellular second messengers, such as calcium, to evade protective immune responses. Recent studies suggest that inhibiting L type calcium channel in immune cells using either antibodies or small interfering RNA increases calcium influx, upregulates the expression of proinflammation genes, and reduces MTB burden. First, we will review the key factors in calcium signaling pathway that may affect the immunity of immune cells to MTB infection. Second, we will focus on the role of calcium channels in regulating cellular immunity to MTB. Finally, we will discuss the possibility of using calcium channel blockers as anti-MTB chemotherapy drugs to enhance chemotherapy effects, shorten treatment period, and overcome drug resistance. PMID- 25442875 TI - Community-onset bacteremia in kidney transplant recipients: The recipients fare well in terms of mortality and kidney injury. AB - BACKGROUND: Bloodstream infection is not uncommon in kidney transplant recipients (KTRs) and is associated with mortality, graft loss, and increased medical expenses. Whether these septic patients are more vulnerable to serious complications, resistant strains, or worse clinical outcomes than other patient groups in the community-onset settings remains undetermined. METHODS: A retrospective study was conducted at a medical center in southern Taiwan. Community-onset bacteremia in the KTRs and a control population at the emergency department were identified. Demographic data, clinical characteristics, bacteremic pathogens, antimicrobial resistance, and clinical outcomes were recorded. RESULTS: Forty-one bacteremic episodes in the KTRs and 82 episodes in control patients were studied. The KTR group had younger age, fewer malignancies, more urosepsis (61% vs. 22%, p = 0.004), and fewer biliary tract infections (0% vs. 13.4%, p = 0.018). Escherichia coli was the most commonly isolated pathogen in both the groups (51.2% and 41.5%, respectively). No Klebsiella pneumoniae bacteremia was noted in the KTRs, compared with 14 (17.1%) episodes in the control group (p = 0.010). Antimicrobial resistance profiles of bacteremic pathogens were similar (all p > 0.6). The KTRs with community-onset bacteremia did not have a worse outcome (in-hospital mortality rate: 2.4% vs. 10%, p = 0.172) nor more incomplete resolution of kidney injury after acute kidney injury events (21.1% vs. 25%, p > 0.99) than the control group. CONCLUSION: KTRs with community-onset bacteremia did not fare worse in terms of clinical outcome and kidney injury. PMID- 25442876 TI - Epidemiology and clinical outcome of pyogenic liver abscess: an analysis from the National Health Insurance Research Database of Taiwan, 2000-2011. AB - BACKGROUND: The epidemiology of pyogenic liver abscess continues to change and the issue of antimicrobial therapy is controversial. This study investigated the epidemiology and clinical outcomes of antimicrobial therapy. METHODS: The annual incidence rates, demographic data, underlying diseases, complications, length of stay, mortality rates, and antimicrobial therapy were analyzed using the data retrieved from the Longitudinal Health Insurance Database 2000, Taiwan, from 2000 to 2011. RESULTS: The annual incidence of pyogenic liver abscess for all age groups increased gradually in Taiwan from 10.83 per 100,000 person-years in 2000 to 15.45 per 100,000 person-years in 2011. Pyogenic liver abscess occurred more commonly in patients with male sex, of older age (>50 years), and lower family income. Among the 1522 adult patients with pyogenic liver abscess, 537 (35.3%) patients had diabetes mellitus, 165 (10.8%) patients had complications, 234 (15.4%) patients received mechanical ventilation, and 361 (23.7%) patients had a stay in intensive care; the mortality rate was 8.2% (125/1522). There were 426 (28%) patients treated with cefazolin and 158 (10.4%) patients treated with extended-spectrum cephalosporins. There were no statistically significant differences in the length of stay and mortality rates between these two groups (20.2 days vs. 23.1 days; and 7.5% vs. 10.1%, respectively). CONCLUSION: The clinical outcomes of pyogenic liver abscess treated with cefazolin were comparable to those treated by extended-spectrum cephalosporins. Extended spectrum cephalosporins should be used for severe complications, such as meningitis and endophthalmitis. Further surveillance of epidemiology and cohort analysis of antimicrobial therapy are important. PMID- 25442878 TI - High-speed discrimination and sorting of submicron particles using a microfluidic device. AB - The size- and fluorescence-based sorting of micro- and nanoscale particles suspended in fluid presents a significant and important challenge for both sample analysis and for manufacturing of nanoparticle-based products. Here, we demonstrate a disposable microfluidic particle sorter that enables high throughput, on-demand counting and binary sorting of submicron particles and cells using either fluorescence or an electrically based determination of particle size. Size-based sorting uses a resistive pulse sensor integrated on chip, whereas fluorescence-based discrimination is achieved using on-the-fly optical image capture and analysis. Following detection and analysis, the individual particles are deflected using a pair of piezoelectric actuators, directing the particles into one of two desired output channels; the main flow goes into a third waste channel. The integrated system can achieve sorting fidelities of better than 98%, and the mechanism can successfully count and actuate, on demand, more than 60,000 particles/min. PMID- 25442877 TI - Role of aerosolized colistin methanesulfonate therapy for extensively-drug resistant Acinetobacter baumannii complex pneumonia and airway colonization. AB - BACKGROUND: Aerosolized colistin methanesulfonate (CMS) has been used for the treatment of extensively drug-resistant Acinetobacter baumannii (XDRAB) pneumonia and eradication of XDRAB colonization in the respiratory tract. The aims of this study were to compare the efficacy, adverse effects, clinical outcomes, and microbiological eradication of the cases of XDRAB pneumonia or colonization. METHODS: We retrospectively reviewed the medical records of patients who received aerosolized CMS for the treatment of pneumonia and airway colonization due to XDRAB. RESULTS: Clinical data from 118 patients were studied. The mean age of 57 patients in the pneumonia group was 79.4 years, and that of 61 patients in the colonization group was 80.0 years. Patients with XDRAB pneumonia were more likely to be ventilator-dependent than colonized patients (46.5% vs. 21.3%; p = 0.005), receive steroid therapy (49.1% vs. 31.1%; p = 0.046), and be admitted to an intensive care unit (ICU) at the time of aerosolized CMS treatment (56.1% vs. 32.8%; p = 0.011). The in-hospital mortality rate was higher in the pneumonia group than the colonization group (50.9% vs. 33.3%; p = 0.05). Microbiological eradication of XDRAB in airway samples was achieved in 75% (89 of 118) patients. In pneumonia patients, XDRAB eradication was associated with resolution or improvement of presenting symptoms and signs of infection by the end of treatment relative to the noneradicated group (57.8% vs. 25%; p = 0.044), but had no influence on 30-day mortality. In colonized patients, no difference in clinical outcomes was noted between the eradicated and noneradicated groups. CONCLUSION: Aerosolized CMS therapy has acceptable efficacy for XDRAB pneumonia, but no proven efficacy for XDRAB airway colonization. PMID- 25442879 TI - Ocular methicillin-resistant Staphylococcus aureus. PMID- 25442880 TI - Sutureless intrascleral fixation of a custom-tailored iris prosthesis with an intraocular lens. AB - We describe a technique for sutureless intrascleral fixation of a 3-piece intraocular lens (IOL) and custom silicone iris prosthesis complex to address the optical and functional issues of aphakia and aniridia, as well as to restore excellent cosmesis. The 3-piece IOL is anchored to the iris prosthesis using the belt-loop technique. We believe the intrascleral haptic fixation is overall a more robust fixation method in patients with aphakia and aniridia, who are often younger and require a long-lasting anterior segment reconstruction. FINANCIAL DISCLOSURE: Dr. Ahmed is a consultant to Alcon Laboratories, Inc., and Abbott Medical Optics, Inc. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 25442881 TI - Pre-surround division technique: precise cracks surrounding the posterior opacity prior to phacoemulsification in posterior polar cataract surgery. AB - Three methods are currently used for posterior polar cataract surgery: intracapsular cataract extraction, posterior approach, and anterior approach. A high level of skill is required to divide the lens in the anterior approach, and few studies have investigated safer or simpler division methods. We focused on the division method in posterior polar cataract and developed a pre-surround division technique that divides the nucleus and avoids the posterior opacity. This technique creates precise cracks that surround the posterior opacity prior to phacoemulsification and does not cause intraoperative complications, resulting in successful intraocular lens implantation in all eyes. This pre-surround division method is a safe and easy technique that can be used in patients with posterior polar cataract. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 25442882 TI - Corneal coupling of astigmatism applied to incisional and ablative surgery. AB - PURPOSE: To redefine measures of corneal coupling for use with incisional and ablation procedures for astigmatism. SETTING: Private clinics, Melbourne, Victoria, Australia. DESIGN: Retrospective nonrandomized study. METHODS: The measures known as the coupling ratio (CR) and coupling constant (CC) were redefined to ensure validity in most cases of incisional procedures and laser vision correction procedures. In addition, a new measure--the coupling adjustment (CAdj)--was developed to quantify the amount of spherical adjustment that must be applied to compensate for coupling that occurs as a result of astigmatism treatment. These quantitative measures of coupling were applied to retrospective data to show their applicability. RESULTS: Pure myopic, compound myopic, and compound hyperopic astigmatism excimer laser treatments showed a CR close to zero, a CC close to 0.5, and a CAdj close to zero. Incision LRIs showed a CR close to 1.0 and a CC close to zero. In all cases, the coupling measures were consistent for treatments with a larger astigmatic component (>1.0 diopter) but variable when the astigmatic component of the treatment was smaller. CONCLUSIONS: The revised definitions of CR and CC can be used with incisional and ablative surgery. Incorporating the CAdj into the planning of spherocylindrical treatments allows one to factor in the effect of the astigmatic treatment on the spherical component and thus to more accurately target the desired spherical equivalent. FINANCIAL DISCLOSURE: Dr. Alpins and Mr. Stamatelatos have a financial interest in the Assort software program. Dr. Ong is an employee of Assort. PMID- 25442883 TI - New equivalent keratometry reading calculation with a rotating Scheimpflug camera for intraocular lens power calculation after myopic corneal surgery. AB - PURPOSE: To calculate the keratometric (K) reading in corneas modified by myopic keratorefractive surgery using the total corneal refractive power (TCRP) of the Pentacam rotating Scheimpflug camera. SETTING: University hospitals and private clinics, South Korea DESIGN: Evaluation of diagnostic test or technology. METHODS: The study comprised healthy eyes, eyes having myopic keratorefractive surgery, and eyes having cataract surgery after myopic keratorefractive surgery. The conversion equation from the TCRP in the central 4.0 mm zone (TCRP4) to a K reading was derived in normal corneas. This equation was rechecked and its application range extended in corneas modified by myopic keratorefractive surgery. Then, the predictability of the TCRP method, combining the K reading derived from the TCRP4 and the Holladay 2 formula, was evaluated in a case series of cataract surgery patients who had previous myopic keratorefractive surgery. RESULTS: The K reading derived from the TCRP4 was obtained by adding 0.7 diopter (D). This conversion factor was applicable after myopic keratorefractive surgery because changes in TCRP4 were equal to changes in refraction in the 4.0 mm zone. The TCRP method predicted intraocular lens power within +/- 0.5 D in 83% and within +/- 1.0 D in 94% of eyes having cataract surgery after myopic keratorefractive surgery. CONCLUSION: The TCRP4 of the rotating Scheimpflug camera was successfully converted into the equivalent K reading, and the TCRP method showed good predictability in corneas modified by myopic keratorefractive surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25442885 TI - Current knowledge about and recommendations for ocular methicillin-resistant Staphylococcus aureus. AB - Staphylococcus aureus is the most important and common pathogen that infects patients following cataract surgery, laser in situ keratomileusis, and photorefractive keratectomy. It is reported to be the second most common pathogen causing bacterial keratitis around the world. Of special concern are increasing reports of postoperative methicillin-resistant S aureus (MRSA) infection. For example, MRSA wound infections have been reported with clear corneal phacoemulsification wounds, penetrating keratoplasty, lamellar keratoplasty, and following ex vivo epithelial transplantation associated with amniotic membrane grafts. These and other data suggest that MRSA has become increasingly prevalent worldwide. In this article, we review the current medical literature and describe the current challenge of ocular MRSA infections. Recommendations are made based on an evidence-based review to identify, treat, and possibly reduce the overall problem of this organism. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25442884 TI - Hyaluronan protection of corneal endothelial cells against extracellular histones after phacoemulsification. AB - PURPOSE: To determine the effect of histones on corneal endothelial cells generated during cataract surgery. SETTING: Kagoshima University Hospital, Kagoshima, Japan. DESIGN: Experimental study. METHODS: Standard phacoemulsification was performed on enucleated pig eyes. Histones in the anterior segment of the eye were determined by immunohistochemistry. Cultured human corneal endothelial cells were exposed to histones for 18 hours, and cell viability was determined by 2-(2-methoxy-4-nitrophenyl)-3-(4-nitro-phenyl)-5-(2,4 disulfophenyl)-2H-tetrazolium, monosodium salt assay. The concentration of interleukin-6 (IL-6) in the culture medium of human corneal endothelial cells was measured using enzyme-linked immunosorbent assay. The effects of signal inhibitors U0126, SB203580, and SP600125 were evaluated. The protective effect of hyaluronan against histones was evaluated in human corneal endothelial cells with and without hyaluronan. RESULTS: Cellular debris containing histones was observed in the anterior chamber of pig eyes after phacoemulsification. Exposure of human corneal endothelial cells to 50 MUg/mL of histones or more led to cytotoxic effects. The IL-6 concentration was significantly increased dose dependently after exposure of human corneal endothelial cells to histones (P<.01). The histone-induced IL-6 production was significantly decreased by extracellular signal-regulated kinases 1/2 and p-38 mitogen-activated protein kinase inhibitors (P<.01). Co-incubation of hyaluronan and histones caused formation of histone aggregates, decreased the cytotoxic effects of the histones, and blocked the increase in IL-6 (P<.01). CONCLUSIONS: Histones were released extracellularly during phacoemulsification and exposure of human corneal endothelial cells to histones increased the IL-6 secretion. The intraoperative use of hyaluronan may decrease the cytotoxic effects of histones released during cataract surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25442886 TI - Customizing femtosecond laser-assisted cataract surgery in a patient with a traumatic corneal scar and cataract. PMID- 25442887 TI - Iris chafing syndrome after scleral-fixated intraocular lens implantation. PMID- 25442888 TI - Inadvertent intracorneal triamcinolone injection during cataract extraction. PMID- 25442889 TI - Cataract surgical problem: November consultation #1. PMID- 25442890 TI - November consultation #2. PMID- 25442891 TI - November consultation #3. PMID- 25442892 TI - November consultation #4. PMID- 25442893 TI - November consultation #5. PMID- 25442894 TI - November consultation #6. PMID- 25442895 TI - November consultation #8. PMID- 25442896 TI - November consultation #7. PMID- 25442897 TI - November consultation #9. PMID- 25442898 TI - November consultation #10. PMID- 25442899 TI - Safety of intracameral antibiotic use after cataract surgery. PMID- 25442900 TI - Reply: To PMID 24957443. PMID- 25442901 TI - Accuracy of statistical analysis of posterior corneal stability after LASIK. PMID- 25442902 TI - Reply: To PMID 24857434. PMID- 25442903 TI - Effectiveness of corneal collagen crosslinking in vivo for corneal stiffening. PMID- 25442904 TI - Indirect evidence of cataract surgery in ancient Egypt. PMID- 25442905 TI - Incidental Findings on Bedside Ultrasonography: Detection Rate and Accuracy of Resident-Performed Examinations in the Acute Setting. AB - BACKGROUND: Bedside ultrasonography has become a valuable tool in the emergent care setting for triage and rapid evaluation of patients who are acutely ill. Given the cross-sectional nature of ultrasound technology, incidental findings are frequently encountered during imaging. These can impact clinical management and can pose a diagnostic dilemma for emergency medicine (EM) physicians and EM residents. PURPOSE: Our retrospective study was designed to evaluate the prevalence and detection rate of incidental findings on bedside ultrasound examinations performed by EM residents. We also sought to identify types of incidental findings encountered and the diagnostic accuracy of those findings. MATERIALS AND METHODS: Board-certified radiologists retrospectively reviewed bedside ultrasonography examinations performed and interpreted by EM residents at a large urban academic hospital. Our sample included patients who presented with traumatic and nontraumatic symptoms in the acute setting. Findings were defined as incidental only if they were previously unknown and not related to a patients presenting symptoms. The results were corroborated with electronic medical records and additional pertinent imaging when available. RESULTS: Of 196 examinations analysed, EM residents identified incidental findings on 26% of the studies, which mostly involved the renal and biliary system. Radiologist review detected incidental findings in 20.9% but was more accurate when supplemental imaging was available. EM residents detected incidental findings at rates similar to that published previously and had moderate interobserver agreement with radiologist review. Worrisome and indeterminate findings were confirmed by additional work-up and further imaging. CONCLUSION: Incidental findings are frequently encountered on bedside ultrasonography and have the potential to alter clinical management. Expertise in detection and knowledge of the presence and spectrum of these incidental findings is essential for appropriate triage, patient management, and follow-up. PMID- 25442906 TI - Plasmacytoid urothelial carcinoma of the bladder with peritoneal spread. Cytological diagnosis in ascitic fluid. PMID- 25442907 TI - Insulin-Like growth factor 1 related pathways and high-fat diet promotion of transgenic adenocarcinoma mouse prostate (TRAMP) cancer progression. AB - INTRODUCTION: We aimed to investigate the role of IGF-1 related pathway in high fat diet (HFD) promotion of TRAMP mouse PCa progression. METHODS: TRAMP mice were randomly divided into two groups: HFD group and normal diet group. TRAMP mice of both groups were sacrificed and sampled on the 20th, 24th and 28th week respectively. Serum levels of insulin, IGF-1 and IGF-2 were tested by ELISA. Prostate tissue of TRAMP mice was used for both HE staining and immunohistochemical staining of IGF-1 related pathway proteins, including IGF 1Ralpha, IGF -1Rbeta, IGFBPs and AKT. RESULTS: The mortality of TRAMP mice from HFD group was significantly higher than that of normal diet group (23.81% and 7.14%, p=.035). The tumor incidence of HFD TRAMP mice at 20(th) week was significantly higher than normal diet group (78.57% and 35.71%, p=.022). Serum IGF-1 level of HFD TRAMP mice was significantly higher than that of normal diet TRAMP mice. Serum IGF-1 level tended to increase with HFD TRAMP mice's age. HFD TRAMP mice had higher positive staining rate of IGF-1Ralpha, IGF-1Rbeta, IGFBP3 and Akt than normal diet TRAMP mice. CONCLUSIONS: IGF-1 related pathway played an important role in high-fat diet promotion of TRAMP mouse PCa development and progression. PMID- 25442908 TI - Adherence to fesoterodine in women with overactive bladder in routine clinical practice. AB - OBJECTIVES: To assess the short-term compliance with fesoterodine treatment and to identify the reasons for lack of adherence and discontinuation in routine clinical practice. The secondary aim was to estimate the patient-reported outcomes. METHODS: This was an observational retrospective, multicenter study conducted in a sample of women with overactive bladder on fesoterodine treatment for at least three months. Adherence to medication was assessed using the Morisky Green test. Patient-reported outcomes were assessed using the Incontinence Questionnaire Short Form (ICIQ-SF), Overactive Bladder Questionnaire Short Form (OAB-qSF), and Treatment Benefit Scale (TBS). RESULTS: One hundred and twenty women with a mean age [standard deviation (SD)] of 62.2 (12.0) years with severe OAB [mean (SD) ICIQ-SF score 13.2 (4.0)] were included. 42.1% of the patients were considered compliant with fesoterodine treatment. The main causes for non compliance/discontinuation stated by the remaining 57.9% of the patients were adverse events (62.2%) and lack of clinical benefits (20.0%). The illness status as well as the patient-perceived bother occasioned by the OAB symptoms and their impact on the quality of life improved significantly after three months on fesoterodine treatment (p<0.0001). Most of the patients stated that the current state of their urinary problems had greatly improved/ improved. CONCLUSION: In routine clinical practice, a high percentage of patients were adherent to fesoterodine and perceived the benefit that the treatment provided them three months after starting treatment. However, more than half of the study population failed to comply or discontinued the treatment mainly due to intolerance or lack of efficacy. PMID- 25442909 TI - Complications of percutaneous nephrolithotomy in the prone position according with modified Clavien-Dindo grading system. AB - INTRODUCTION: Clavien-Dindo classification system has been proposed to grade perioperative complications in percutaneous nephrolithotomy. The complications of this technique that have taken place in the last 2 years are reported in this paper according Clavien-Dindo classification. MATERIALS AND METHODS: Between 2011 and 2012 a total of 255 percutaneous nephrolithotomy were performed at our center for stones more than 2 cm in size. In order to determine the incidence of complications classified in the modified Clavien-Dindo system, statistical analysis of the data obtained was carried out. RESULTS: During the period analyzed, 255 percutaneous nephrolithotomy were performed in 249 patients, 41% of the right side, 57% of the left side and 2% bilateral and simultaneous. 137 and 112 patients were males and females, respectively. The most prevalent comorbidities were: hypertension (AHT) in 101 patients (40.6%), BMI>30 in 81 patients (32%), diabetes mellitus in 46 patients (18.5%) and coagulation abnormalities in 24 patients (9.6%). A total of 70 cases (27.4%) were distributed according to Clavien-Dindo classification: grade i, 8.4%, grade ii 8.4%, grade iiia 4.4%, grade iiib 6% grade iva .8%, grade ivb: 0% and grade v 0%. CONCLUSIONS: A graded classification scheme for reporting the complications of percutaneous nephrolithotomy is useful for monitoring and reporting outcomes. We propose a standardized use of this classification in order to make the results comparable among different centers performing the technique. PMID- 25442910 TI - Corynanthean, eburnan, secoleuconoxine, and pauciflorine alkaloids from Kopsia pauciflora. AB - Eleven indole alkaloids, comprising four corynanthean, two eburnane, one aspidofractinine, one secoleuconoxine, one andranginine, and two pauciflorine type alkaloids were isolated from the stem-bark and leaf extracts of Kopsia pauciflora. Their structures were determined using NMR and MS analyses. The catharinensine type alkaloid kopsirensine B and the secoleuconoxine alkaloid arboloscine A showed moderate to weak activity in reversing MDR in vincristine resistant KB cells. The alkaloid content was markedly different compared to that of a sample from Malaysian Borneo. PMID- 25442911 TI - Candida kefyr as a cause of bloodstream infection and adjunctive role of biomarkers in its diagnosis. AB - A rare case of bloodstream infection caused by Candida kefyr is described. The diagnosis was established by repeatedly isolating the yeast in blood cultures and by detecting C. kefyr-specific DNA in serum samples. Demonstration of elevated serum levels of beta-D-glucan and Candida mannan also provided additional diagnostic evidence. The identity of the isolates was confirmed by PCR sequencing of the ITS region of rDNA. This is the first report of C. kefyr candidemia from Kuwait and the Middle East. The report highlights emerging clinical significance of rare Candida spp. in etiology of candidemia and reinforces the adjunctive role of biomarkers in diagnosis. PMID- 25442912 TI - [Cryptococcosis: a potential aetiology of facial ulceration]. AB - Cutaneous cryptococcosis is an uncommon aetiology of chronic facial ulceration but which may be associated to a potentially lethal focus of cryptococcosis. OBSERVATION: A 35-year-old AIDS patient under antiretroviral therapy, presented with a chronic facial ulceration. Histopathological examination of a biopsy of the facial ulceration showed an inflammatory granuloma and masses of yeasts. Mycological culture of the cerebrospinal fluid revealed Cryptococcus neoformans. The diagnosis of AIDS-related cutaneous cryptococcosis of the face and cryptococcal meningitis was concluded. DISCUSSION: Cryptococcosis should be thought as a potential aetiology of a chronic facial ulceration in an AIDS patient. Screening of other foci of the cryptococcosis such as that of the central nervous system is mandatory. Mycological examinations are of great interest for the diagnosis in rare resources setting. PMID- 25442913 TI - In vitro susceptibility profile of 200 recent clinical isolates of Candida spp. to topical antifungal treatments of vulvovaginal candidiasis, the imidazoles and nystatin agents. AB - OBJECTIVE: Topical antifungal treatment of vulvovaginal candidiasis is widely recommended. The most commonly recommended topical antifungals (the imidazoles clotrimazole, miconazole and econazole and the polyene nystatin) have been on the market for more than 30 years. There are only a few recent data available on the susceptibility of different Candida species to these antifungals, especially of non-albicans Candida species which appear to be less responsive to treatment with imidazoles. The study aimed to determine the in vitro susceptibility profile of a large number of recent clinical isolates of Candida spp. to the most commonly recommended topical antifungals. MATERIALS AND METHODS: An antifungal susceptibility test was performed according to the CLSI M27-A3 broth microdilution method, and minimal inhibitory concentrations were determined for econazole, miconazole, clotrimazole and nystatin. RESULTS: The clinical isolates comprised of: 113 Candida albicans, 54 Candida glabrata, 11 Candida krusei, 11 Candida tropicalis and 11 Candida parapsilosis. The three azoles agents exhibited MIC90 values of 0.06 mg/L against C. albicans isolates, while nystatin exhibited a MIC90 of 4 mg/L. For non-albicans Candida isolates, MIC90 values ranged from 0.5 to 8 mg/L, from 1 to 4 mg/L and from 0.12 to 4 mg/L, for econazole, miconazole, clotrimazole, respectively. Nystatin MIC90 remained at 4 mg/L for all non-albicans Candida species tested. CONCLUSION: These results confirmed the susceptibility of C. albicans to the most frequently used topical agents and may support the use of alternative agents to imidazoles, such as nystatin, to treat vulvovaginal candidiasis caused by non-albicans Candida species. PMID- 25442914 TI - Effects of ascorbic acid and alpha-tocopherol on the therapeutic index of amphotericin B. AB - Amphotericin B (AmB) remains the antifungal polyene of choice in deep fungal infections, but its high toxicity to mammalian cells limits its use. This toxicity is partly due to lipid peroxidation exerted by amphotericin B in cell membranes. The work we have undertaken focused on the one part the evaluation of the efficacy of amphotericin B in the presence of some antioxidants vitamins (vitamin C "ascorbic acid" and vitamin E "alpha-tocopherol") against the yeast Candida albicans ATCC 10231. Secondly, we have tested the cytotoxicity of these formulations on human red blood cells. The results showed a significant improvement in the efficiency of our formulations tested from 7% to 12% compared with amphotericin B alone at therapeutic concentrations. Furthermore, the addition of vitamin C and vitamin E protects human red blood cells against the cytotoxicity induced by amphotericin B with 17%. This is due may be to the antioxidant power of vitamins which confer protection against the autoxidation of the molecule of amphotericin B. On the other hand, it is noticed that the yeast regrows after 24h whatever in complex with vitamin C or vitamin E of the stock solution. On completion of this study, the incorporation of antioxidant vitamins that we propose to the reaction medium of antifungal improved the therapeutic index of amphotericin B. PMID- 25442915 TI - Immunomodulatory efficacy of ethanol extract of propolis on tumor-bearing mice with disseminated candidiasis. AB - OBJECTIVE: This study was aimed at investigating the effect of propolis on immunosurveillance by measuring the levels of serum interleukin (IL)-4, IL-10, IL 17, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in tumor-bearing mice with disseminated candidiasis. METHODS: The ethanol extract of propolis was selected for this study. Balb/C female mice were infected with Candida albicans (C. albicans) and inoculated with spontaneous mouse mammary tumor (SMMT). The serum levels of tissue inhibitor of metalloproteinase-1(TIMP-1) were assessed by enzyme- linked immunosorbent assay (ELISA). Mice were treated daily with propolis solution (100mg/kg, 0.1 mL, orally) for 3 days before IV challenge with C. albicans and SC challenge with SMMT and continued for 10 days. The rates of survival and tumor growth of understudy mice were investigated as well. The levels of TNF-alpha, IFN-gamma, IL-4, IL-10 and IL-17 cytokines in culture supernatants were determined by ELISA. RESULTS: The mean tumor size was significantly increased in tumor-bearing mice infected with C. albicans (16.98 +/ 0.49 mm(2)) as compared to other mice groups (P<0.05). The results showed a significant decline of IL-4 and IL-10 levels after propolis administration to tumor-bearing mice infected with C. albicans (53.41 pg/mL, 156.81 pg/mL and 63.45 pg/mL) (P < 0.05). The increment of TNF-alpha (433.85 pg/mL) and IFN-gamma (120.43 pg/mL) levels were also observed. CONCLUSION: Data revealed that propolis has remarkable immunomodulatory effect, which provides a scientific validation for the popular use of this natural substance, and further investigation will help to understand propolis usefulness during immunosuppressive conditions. PMID- 25442916 TI - Anti-Candida and anti-Cryptococcus antifungal produced by marine microorganisms. AB - In order to search for antifungal from biological origin, we performed a screening of marine microorganisms isolated from seawater, seaweed, sediment and marine invertebrates collected from different coastal areas of the Moroccan Atlantic Ocean. The antifungal activities of these isolates were investigated against the pathogenic yeasts involved in medical mycology. Whole cultures of 34 marine microorganisms were screened for antifungal activities using the method of agar diffusion against four yeasts. The results showed that among the 34 isolates studied, 13 (38%) strains have antifungal activity against at least one out of four yeast species, 11 isolates have anti-Candida albicans CIP 48.72 activity, 12 isolates have anti-C. albicans CIP 884.65 activity, 13 isolates have anti Cryptococcus neoformans activity and only 6 isolates are actives against Candida tropicalis R2 resistant to nystatin and amphotericin B. Nine isolates showed strong fungicidal activity. Fourteen microorganisms were identified and assigned to the genera Acinetobacter, Aeromonas, Alcaligenes, Bacillus, Chromobacterium, Enterococcus, Pantoea, and Pseudomonas. Due to a competitive role for space and nutrient, the marine microorganisms could produce more antimicrobials; therefore these marine microorganisms were expected to be potential resources of natural products such as those we research: anti-Candida and anti-Cryptococcus fungicides. PMID- 25442917 TI - An ancient plant Lawsonia inermis (henna): determination of in vitro antifungal activity against dermatophytes species. AB - World is endowed with a rich wealth of medicinal plants. There is a widespread belief that green medicines are healthier and more harmless or safer than synthetic ones. Medicinal plants have been used to cure a number of diseases. The ancient plant Lawsonia inermis or henna is used as medicinal plant because of its attributed strong fungicidal, anti-inflammatory, analgesic, antibacterial, virucidal, antiparasitic, antiamoebiasis, astringent, antihemorrhagic, hypotensive, sedative, anticancer effect and possible anti-sweating properties. In this study, we investigated antifungal activity of L. inermis against clinical dermatophytes species. This study was carried out using 70 clinical isolates of dermatophytes representing six different species; 44 Trichophyton rubrum, 8 Trichophyton mentagrophytes, 6 Microsporum canis, 6 Trichophyton tonsurans, 4 Epidermophyton floccosum, and 2 Trichophyton violaceum. The antifungal activity of L. inermis (henna) was determined by agar diffusion method and henna was used as paste form. Henna paste showed the high antifungal activity against all dermatophytes species (20 to 50mm inhibition zone). PMID- 25442918 TI - Evaluation of antifungal activities of the essential oil and various extracts of Nigella sativa and its main component, thymoquinone against pathogenic dermatophyte strains. AB - OBJECTIVE: Plant extracts and plant-derived compounds are valuable sources as folk medicine for the treatment and prevention of a wide range of diseases including infectious diseases. In the present study, the antifungal activities of the essential oil and various extracts Nigella sativa and its active principle, thymoquinone against Trichophyton mentagrophytes, Microsporum canis and Microsporum gypseum as pathogenic dermatophyte strains have been evaluated. In addition, the cytotoxic effects of N. sativa against murine macrophage cells were determined. MATERIALS AND METHODS: In this study, the antifungal activity was studied by disk diffusion method and assessment of minimum inhibitory concentration (MIC) of extracts using broth macrodilution method. In addition, the cytotoxic activity of N. sativa was evaluated by colorimetric assay (MTT). The components of the N. sativa essential oil were also identified by gas chromatography/mass spectroscopy (GC/MS) analysis. RESULTS: The results showed that the essential oil and various extracts of N. sativa particularly thymoquinone have potent antifungal effects on T. mentagrophytes, M. canis and M. gypseum as pathogenic dermatophyte strains. In the assessment of the cytotoxicity activity, it could be observed that N. sativa had no significant cytotoxicity in the murine macrophages at low concentrations. While, thymoquinone in comparison with essential oil and various extracts of N. sativa showed higher cytotoxicity on murine macrophage cells. In the GC/MS analysis, thymoquinone (42.4%), p-cymene (14.1%), carvacrol (10.3%) and longifolene (6.1%) were found to be the major components of N. sativa essential oil. CONCLUSION: The findings of this study suggest a first step in the search of new antidermatophytic drugs and aid the use of N. sativa seeds in the traditional medicine for dermatophytic infections. PMID- 25442919 TI - Comparative effects of hypoxia and hypoxia mimetic cobalt chloride on in vitro adhesion, biofilm formation and susceptibility to amphotericin B of Candida glabrata. AB - OBJECTIVES: Candida glabrata has emerged as potent pathogen in nosocomial infections. The objective of this study is to investigate the effects of hypoxia (an important host factor) and hypoxia mimetic cobalt chloride upon growth, in vitro adhesion, biofilm formation and susceptibility to amphotericin B of Candida glabrata. MATERIALS AND METHODS: Growth was checked by spotting assays. Expression of TDH3, a gene of glycolytic pathway was analyzed as intracellular hypoxia marker by reverse transcription PCR. In vitro adhesion, biofilm development and susceptibility of biofilm to amphotericin B were performed on polystyrene plates and quantified by XTT assay in RPMI 1640 and YNB media. Experiments were performed in triplicates and Student's t-test was used for statistical analysis. RESULTS: Hypoxia did not compromise the growth of C. glabrata unlike CoCl2. Hypoxia and CoCl2 upregulated TDH3 expression. Adhesion was reduced upon exposure to hypoxia and CoCl2. Biofilm activity remained unchanged in the presence of CoCl2 in both media. In comparison to normoxia control, hypoxia increased biofilm activity to 259.33 +/- 22.05% in RPMI 1640, while hypoxia reduced it to 70.99 +/- 2.99% in YNB. Biofilm susceptibility to amphotericin B was significantly decreased in RPMI 1640 and remained unaffected in YNB in hypoxia. CONCLUSIONS: C. glabrata grows well even under hypoxia but not upon CoCl2 exposures. CoCl2 mimics hypoxia like expression of TDH3 but affects the virulence properties unlike hypoxia. Both, hypoxia and CoCl2 affects adhesion adversely. Hypoxia increases biofilm development and reduces the susceptibility of biofilm to amp B in RPMI 1640 but not in YNB. PMID- 25442920 TI - Isolation of keratinophilic fungi from selected soils of Sanjay Gandhi National Park, Mumbai (India). AB - One hundred and twenty-five samples were collected from eight different sites in the vicinity of Sanjay Gandhi National Park (SGNP) and screened for the presence of keratinophilic fungi using hair baiting technique for isolation. Seventy-three isolates were recovered and identified. The cultures were identified using macro- and micro-morphological features. Their identification was also confirmed by the BLAST search of sequences of the ITS1-5.8S-ITS2 rDNA region against the NCBI/Genbank data and compared with deposited sequences for identification purpose. Thirteen species of nine genera were isolated viz. Aphanoascus durus (2.4%), Arthroderma corniculatum (1.6%), Auxarthron umbrinum (0.8%), Chrysosporium evolceanui (1.6%), Chrysosporium indicum (16.0%), Chrysosporium tropicum (2.4%), Chrysosporium zonatum (4.0%), Chrysosporium states of Arthroderma tuberculatum (0.8%), Chrysosporium state of Ctenomyces serratus (11.2%), Gymnascella dankaliensis (3.2%), Microsporum gypseum (12.0%), Myriodontium keratinophilum (0.8%) and Trichophyton mentagrophytes (1.6%). Representative of all thirteen species can release the protein in the range of 152.2-322.4 MUg/mL in liquid media when grown on human hair in shake flask culture and also decompose 18.4-40.2% of human hair after four weeks of incubation. This study indicates that the soils of SGNP, Mumbai may be significant reservoirs of certain keratinophilic fungi. The keratinolytic activity of these fungi may be playing significant role in superficial infections to man and animals and recycling of keratinic material of this environment. PMID- 25442922 TI - [Cerebral aspergillosis and liver transplantation: about one case]. AB - Cerebral invasive aspergillosis is a rare but serious infection. Mortality is still high despite appropriate treatment. We report the case of a patient with liver transplantation in the context of alcoholic cirrhosis and transplanted back seven years later consequently to an ischemic cholangitis. Following an acquired active viral infection by HCV and treated by antiviral combination therapy the patient presented six months after this second operation a cerebral aspergillosis of tumour-like presentation. It rapidly evolved to an unfavourable outcome with intracranial hypertension state. If the therapeutic management is well established, the diagnosis is difficult. This observation allows us to discuss the various diagnostic criteria of cerebral aspergillosis. PMID- 25442921 TI - [Catheterization and fungal infection risk in the University Hospital of Tlemcen: epidemiology and susceptibility to antifungals]. AB - Fungal infections are a major cause of morbidity and mortality, and are frequently associated with the implantation of vascular catheters, especially in immune-compromised patients. Unfortunately, the therapeutic arsenal available for the treatment of these infections, caused generally by the yeasts of the genus Candida is still limited because of the toxicity and/or of the emergence of resistance against some antifungal agents. That is why we have undertaken this study, which is to determine the incidence and the degree of sensitivity of Candida spp., isolated from peripheral venous catheters at the University Hospital of Tlemcen (Algeria) to caspofungin and amphotericin B. The results show that the rate of colonization of vascular catheters was 19 % by yeasts of Candida spp., of which 60 % are Candida parapsilosis, 20 % Candida albicans, 14.3 % Candida glabrata and 5.7 % Candida famata. The minimum inhibitory concentrations (MIC) for amphotericin B are between 0.5 and 2 MUg/mL and for caspofungin, they are between 0.125 and 2 MUg/mL. PMID- 25442924 TI - Epidemiological profile of fungal keratitis in Sfax (Tunisia). AB - Fungal keratitis is responsible for a significant burden of blinding disease in the developing world. OBJECTIVE: The aim of this study was to determine the etiological agents, predisposing factors and therapy of keratomycosis in our region. METHODS: Retrospective study of 60 patients with clinically and cultured confirmed fungi keratitis, who were attended at department of mycology in Sfax (1995 to 2012). RESULTS: The mean age of patients was 47.2 years (sex ratio: 1.58). At least, one presumed predisposing factor was identified in 83.3% of cases. Corneal traumatism was established as the most common predisposing factor (61.6%) with vegetative matter (42.4%). Patients had corneal ulcer in 40% or abscess in 47.6%. All cases were positive on direct microscopy and 93% of cultures were positive. Filamentous fungi form the major etiologic agents (83%): Fusarium species (49% with F. solani [66%]), Aspergillus sp. (22%), Alternaria (5%), Scedosporium sp. (2%); and non-identified mold in (5%). Yeast were identified in 17% of cases. Topical agents were used in 97% of cases: ketoconazole 2%, amphotericin B (0.5%). Fluconazole per os was administrated for 11% of cases, itraconazole (2 cases) and voriconazole (one case). Keratoplasty was indicated for 27% of cases. The outcome was favorable in 16% of patients. Among the patients, 71% had persistent corneal deposit sequelae. Four patients lost the eyeball. CONCLUSION: Corneal traumatism was the principal risk factor for fungal keratitis in young and middle-aged farmers. Fusarium solani is the predominant cause in Sfax. Early diagnosis, coupled with appropriate treatment, is crucial for increasing the chance of complete recovery. PMID- 25442923 TI - The comparative study of antifungal activity of Syzygium aromaticum, Punica granatum and nystatin on Candida albicans; an in vitro study. AB - AIM: Candida species are opportunistic fungi, among which, Candida albicans is the most important species responsible for infections in immunocompromised patients with invasive fungal disease. Resistance of Candida species to antifungal drugs has led scientists to pay more attention to traditional medicine herbs. Due to the limitations in the treatment of fungal diseases such as shortages, high prices, antifungal side effects and drug resistance or reduced susceptibility to fungal drugs we decided to study the antifungal effects of herbal extracts of Syzygium aromaticum and Punica granatum. METHODS: Twenty-one isolates of oral C. albicans in patients with denture stomatitis referred to prosthesis department, Dental faculty of Tehran University of Medical Sciences were prepared and cultured. Plant extracts were prepared from the herbs market. Tests on patient samples and standard strains 5027ATCC (PTCC10231) yeast C. albicans were performed via well diffusion method. In addition, nystatin and methanol were used as positive and negative control, respectively. Finally, the antifungal effect of extracts using Statistical Repeated measurement ANOVA test was investigated. RESULTS: Both S. aromaticum and P. granatum showed noticeable antifungal activity in well method. Syzygium aromaticum showed better anti candida activity than nystatin (P<0.001). CONCLUSION: Due to increasing problems with fungal diseases, these findings suggest that the plant extracts of S. aromaticum and P. granatum showed good antifungal effects (P-value<0.001). S. aromaticum (inhibition zone diameter: 29.62) showed better antifungal effects than nystatin (inhibition zone diameter: 28.48). PMID- 25442926 TI - Bridging the gap. PMID- 25442925 TI - Congenital multifocal rhabdoid tumor: a case with peculiar biological behavior and different response to treatment according to location (central nervous system and kidney). AB - Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system and malignant rhabdoid tumor of the kidney (MRTK) may present with different responses to chemotherapy and outcomes. We describe the case of an infant with multifocal rhabdoid tumor with different behavior and response to treatment, depending on the anatomic site. PMID- 25442927 TI - NINDS translational programs: priming the pump of neurotherapeutics discovery and development. AB - The National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH) recently issued a new suite of funding opportunities for neurotherapeutics development. The goals are to build a contiguous bridge from basic science, accelerate the advancement of promising projects to clinical testing with the contributions of multidisciplinary teams, and enhance hand-off to subsequent funders. PMID- 25442928 TI - Collaboration in translational neuroscience: a call to arms. AB - Neurological and psychiatric disorders present an immediate and growing challenge. The scale and complexity of this unmet need calls for a concomitantly large and sophisticated response. Here the author discusses just one element of such a response, the power of collaboration, and presents a personal account of how a variety of collaborative structures can advance science. PMID- 25442929 TI - Transforming our approach to translational neuroscience: the role and impact of charitable nonprofits in research. AB - From mental health to rare diseases, charitable nonprofits and foundations are bringing energy, perspective, and leadership to the process of translational research. In challenging researchers to become more connected-to each other and to patients-charities are helping neuroscience deliver innovation that is relevant to real people in the real world. PMID- 25442930 TI - Public-private partnership: a new engine for translational research in neurosciences. AB - We have made little recent progress developing effective new treatments for neuropsychiatric and neurodevelopmental disorders. Novel molecular mechanisms have been identified, but have not translated into the clinic. We suggest an alternative: combinations of treatments targeting different aspects of final common pathways in biologically defined clinical subgroups. This will require integrated translational neuroscience and international public-private partnerships. PMID- 25442931 TI - Translating human genetics into novel treatment targets for schizophrenia. AB - Human genetics is a rational starting point for target identification in drug discovery, yet this approach has found little application in neuroscience. Recent large-scale analyses have begun to identify robust genetic loci for schizophrenia, providing an opportunity to derive novel drug targets. Here, we summarize a strategy for applying human genetics to neuroscience drug discovery. PMID- 25442932 TI - Found in translation: training the next generation of translational neuroscientists. AB - Integrated, multidisciplinary programs for training physicians and scientists in translational science have become essential in efforts to meet the demand for more effective translation of basic science discoveries into new clinical applications. PMID- 25442933 TI - Improving and accelerating drug development for nervous system disorders. AB - Advances in the neurosciences have placed the field in the position where it is poised to significantly reduce the burden of nervous system disorders. However, drug discovery, development, and translation for nervous system disorders still pose many unique challenges. The key scientific challenges can be summarized as follows: mechanisms of disease, target identification and validation, predictive models, biomarkers for patient stratification and as endpoints for clinical trials, clear regulatory pathways, reliability and reproducibility of published data, and data sharing and collaboration. To accelerate nervous system drug development, the Institute of Medicine's Forum on Neuroscience and Nervous System Disorders has hosted a series of public workshops that brought together representatives of industry, government (including both research funding and regulatory agencies), academia, and patient groups to discuss these challenges and offer potential strategies to improve the translational neuroscience. PMID- 25442934 TI - Medicines for the mind: policy-based "pull" incentives for creating breakthrough CNS drugs. AB - Several large pharmaceutical companies have selectively downsized their neuroscience research divisions, reflecting a growing view that developing drugs to treat brain diseases is more difficult and often more time-consuming and expensive than developing drugs for other therapeutic areas, and thus represents a weak area for investment. These withdrawals reduce global neuroscience translational capabilities and pose a serious challenge to society's interests in ameliorating the impact of nervous system diseases. While the path forward ultimately lies in improving understandings of disease mechanisms, many promising therapeutic approaches have already been identified, and rebalancing the underlying risk/reward calculus could help keep companies engaged in making CNS drugs. One way to do this that would not require upfront funding is to change the policies that regulate market returns for the most-needed breakthrough drugs. The broader neuroscience community including clinicians and patients should convene to develop and advocate for such policy changes. PMID- 25442936 TI - Rigor or mortis: best practices for preclinical research in neuroscience. AB - Numerous recent reports document a lack of reproducibility of preclinical studies, raising concerns about potential lack of rigor. Examples of lack of rigor have been extensively documented and proposals for practices to improve rigor are appearing. Here, we discuss some of the details and implications of previously proposed best practices and consider some new ones, focusing on preclinical studies relevant to human neurological and psychiatric disorders. PMID- 25442935 TI - New approaches to psychiatric diagnostic classification. AB - Recent findings in psychiatric genetics have crystallized concerns that diagnostic categories used in the clinic map poorly onto the underlying biology. If we are to harness developments in genetics and neuroscience to understand disease mechanisms and develop new treatments, we need new approaches to patient stratification that recognize the complexity and continuous nature of psychiatric traits and that are not constrained by current categorical approaches. Recognizing this, the National Institute for Mental Health (NIMH) has developed a novel framework to encourage more research of this kind. The implications of these recent findings and funding policy developments for neuroscience research are considerable. PMID- 25442937 TI - How clinical development can, and should, inform translational science. AB - There is an urgent need for preclinical translational efforts to be realized as breakthroughs in therapy for the many patients with life-altering conditions affecting the CNS. Despite intensive efforts, few transformative therapies have emerged, and many new potential therapies that looked promising in preclinical development have failed in the clinic. In this Perspective, we suggest that if preclinical scientists partner early with clinical scientists, they can begin to envision the pathway forward for their work through clinical trials. Options might include determining the populations to be treated, issues of dose selection, timing of intervention, duration of intervention, and the availability of biomarkers. In addition, understanding other factors that impact the likelihood that a proof-of-concept trial can be performed, as well as other critical issues, will altogether increase the attractiveness of the project to investors and partners and will also increase the likelihood that the intervention will succeed in the clinic. PMID- 25442940 TI - Placebo effects: from the neurobiological paradigm to translational implications. AB - Today we are witnessing a new science of placebo, a complex discipline that encompasses several experimental approaches and translational implications. Modern neurobiological tools have been used to answer important questions in placebo research, such as the top-down modulation of sensory and motor systems as well as the influence of cognition, emotions, and learning on symptoms, diseases, and responses to treatments. What we have learned is that there is not one single placebo effect, but many. This review highlights the translational implications of this new knowledge, ranging from clinical trial design to medical practice to social and ethical issues. PMID- 25442938 TI - Unbiased approaches to biomarker discovery in neurodegenerative diseases. AB - Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia have several important features in common. They are progressive, they affect a relatively inaccessible organ, and we have no disease-modifying therapies for them. For these brain-based diseases, current diagnosis and evaluation of disease severity rely almost entirely on clinical examination, which may be only a rough approximation of disease state. Thus, the development of biomarkers-objective, relatively easily measured, and precise indicators of pathogenic processes-could improve patient care and accelerate therapeutic discovery. Yet existing, rigorously tested neurodegenerative disease biomarkers are few, and even fewer biomarkers have translated into clinical use. To find new biomarkers for these diseases, an unbiased, high-throughput screening approach may be needed. In this review, I will describe the potential utility of such an approach to biomarker discovery, using Parkinson's disease as a case example. PMID- 25442939 TI - The evolution of preclinical Alzheimer's disease: implications for prevention trials. AB - As the field begins to test the concept of a "preclinical" stage of neurodegenerative disease, when the pathophysiological process has begun in the brain, but clinical symptoms are not yet manifest, a number of intriguing questions have already arisen. In particular, in preclinical Alzheimer's disease (AD), the temporal relationship of amyloid markers to markers of neurodegeneration and their relative utility in the prediction of cognitive decline among clinically normal older individuals remains to be fully elucidated. Secondary prevention trials in AD have already begun in both genetic at-risk and amyloid at-risk cohorts, with several more trials in the planning stages, and should provide critical answers about whether intervention at this very early stage of disease can truly bend the curve of clinical progression. This review will highlight recent progress in cognitive, imaging, and biomarker outcomes in the field of preclinical AD, and the remaining gaps in knowledge. PMID- 25442942 TI - A fast and sensitive coupled enzyme assay for the measurement of l-threonine and application to high-throughput screening of threonine-overproducing strains. AB - Amino acids are important fermentation products that are used in the food, animal feed, pharmaceutical, and cosmetics industries. Development of a better quantitation assay to measure amino acid levels will facilitate research and application in medical and industrial fields. Here we report the development of an assay that allows the rapid measurement of threonine concentration. l threonine aldolase (LTA) catalyzes the cleavage of threonine to glycine and acetaldehyde. The resulting acetaldehyde is further converted into ethanol by alcohol dehydrogenase accompanying NADH reduction. Therefore, monitoring the changes in NADH concentration can serve as a readout for the amount of threonine present within certain range. This LTA assay can distinguish a 0.5mM difference in threonine concentration in some certain mediums. We successfully utilized this assay to measure l-threonine levels in industrial fermentation samples. Moreover, we were able to scale up this assay to 96-well format and use it in high throughput screening of threonine-overproducing strains. We show this assay is simple, accurate, specific and suitable for determination of threonine concentration in large numbers of samples. PMID- 25442943 TI - Enhanced free fatty acid production by codon-optimized Lactococcus lactis acyl ACP thioesterase gene expression in Escherichia coli using crude glycerol. AB - Fatty acid production and composition are determined by the type of acyl-acyl carrier protein thioesterases (acyl-ACP TEs) expressed in Escherichia coli. Bacterial acyl-ACP TEs from Lactococcus lactis (SGJS47), Enterococcus faecalis (SGJS49), and Burkholderia cepacia (SGJS50) were codon-optimized and expressed in E. coli for enhanced fatty acid production. Samples were extracted at the lag, log, and stationary phases of cell growth, and gene expression levels of the codon optimized acy-ACP TEs as well as fatty acid production were monitored. At 24h after initiation of gene expression, the OPLlTE expression level and fatty acid production in SGJS47 increased up to 15.8-fold and 3.2-fold compared to the control and other recombinant strains, respectively. Additionally, in SGJS47, improvement in free fatty acid (FFA) composition, high-specificity production of short-chain fatty acids (C8, C10) and unsaturated fatty acids (C16:1) was achieved in crude glycerol medium condition. Compared with control strain, the percentage of FFAs (C8 and C10) was enhanced by approximately 16- to 21-fold, C16:1 FFA ratio increased approximately 18-fold. Observation of codon-optimized acyl-ACP TE genes expression level in E. coli may be useful for understanding mechanisms towards improving fatty acid production. Engineered strains have the potential to overproduce specific FFAs and thereby reduce the cost of fatty acid production by using industrially inexpensive carbon sources. PMID- 25442941 TI - Computational psychiatry. AB - Psychiatric disorders such as autism and schizophrenia, arise from abnormalities in brain systems that underlie cognitive, emotional, and social functions. The brain is enormously complex and its abundant feedback loops on multiple scales preclude intuitive explication of circuit functions. In close interplay with experiments, theory and computational modeling are essential for understanding how, precisely, neural circuits generate flexible behaviors and their impairments give rise to psychiatric symptoms. This Perspective highlights recent progress in applying computational neuroscience to the study of mental disorders. We outline basic approaches, including identification of core deficits that cut across disease categories, biologically realistic modeling bridging cellular and synaptic mechanisms with behavior, and model-aided diagnosis. The need for new research strategies in psychiatry is urgent. Computational psychiatry potentially provides powerful tools for elucidating pathophysiology that may inform both diagnosis and treatment. To achieve this promise will require investment in cross disciplinary training and research in this nascent field. PMID- 25442944 TI - Trpac1, a pH response transcription regulator, is involved in cellulase gene expression in Trichoderma reesei. AB - Fungi grow over a relatively wide pH range and adapt to extracellular pH through a genetic regulatory system mediated by a key component PacC, which is a pH transcription regulator. The cellulase production of the filamentous fungi Trichoderma reesei is sensitive to ambient pH. To investigate the connection between cellulase expression regulation and ambient pH, an ortholog of Aspergillus nidulans pacC, Trpac1, was identified and functionally characterized using a target gene deletion strategy. Deleting Trpac1 dramatically increased the cellulase production and the transcription levels of the major cellulase genes at neutral pH, which suggested Trpac1 is involved in the regulation of cellulase production. It was further observed that the expression levels of transcription factors xyr1 and ace2 also increased in the DeltaTrpac1 mutant at neutral pH. In addition, the DeltaTrpac1 mutant exhibited conidiation defects under neutral and alkaline pH. These results implied that Trpac1 in involved in growth and development process and cellulase gene expression in T. reesei. PMID- 25442945 TI - Activation of immobilized enzymes by acoustic wave resonance oscillation. AB - Acoustic wave resonance oscillation has been used successfully in the development of methods to activate immobilized enzyme catalysts. In this study, resonance oscillation effects were demonstrated for enzyme reactions on galactose oxidase (GAD), D-amino acid oxidase (DAAO), and L-amino acid oxidase (LAAO), all of which were immobilized covalently on a ferroelectric lead zirconate titanate (PZT) device that could generate thickness-extensional resonance oscillations (TERO) of acoustic waves. For galactose oxidation on immobilized GAD in a microreactor, TERO generation immediately increased enzyme activity 2- to 3-fold. Eliminating TERO caused a slight decrease in the activity, with ~90% of the enhanced activity retained while the reaction proceeded. Contact of the enhanced enzyme with a galactose-free solution caused almost complete reversion of the activity to the original low level before TERO generation, indicating that, not only TERO-induced GAD activation, but also preservation of the increased activity, required a galactose substrate. Similar activity changes with TERO were observed for enzyme reactions on DAAO and LAAO. Kinetic analysis demonstrated that TERO helped strengthen the interactions of the immobilized enzyme with the reactant substrate and promoted formation of an activation complex. PMID- 25442946 TI - Transesterification of plant oils using Staphylococcus haemolyticus L62 lipase displayed on Escherichia coli cell surface using the OmpA signal peptide and EstAbeta8 anchoring motif. AB - Staphylococcus haemolyticus L62 (SHL62) lipase was displayed on the outer membrane of Escherichia coli using the OmpA signal peptide and the autotransporter EstAbeta8 protein. Localization of SHL62 lipase on the outer membrane of E. coli was confirmed using immunofluorescence microscopy and flow cytometry analysis. Lipase activity of the displayed SHL62 lipase was also measured using spectrophotometry and pH titration. SHL62 lipase activity of whole cells reached 2.0U/ml culture (OD600nm of 10) when it was measured by the p nitrophenyl caprylate assay after being induced with 1mM IPTG for 24h. The optimum temperature and pH for the lipase was 45 degrees C and 10, respectively. Furthermore, it maintained more than 90% of maximum lipase activity at up to 50 degrees C and in a pH range of 5-9. The hydrolytic activity assay conduted with various substrates confirmed that p-nitrophenyl caprylate and corn oil were preferred substrates among various synthetic and natural substrates, respectively. The displayed SHL62 lipase produced fatty acid esters from various alcohols and plant oils through transesterification. PMID- 25442947 TI - Influence of some formulation and process parameters on the stability of lysozyme incorporated in corn flour- or corn starch-based extruded materials prepared by melt blending processing. AB - In order to obtain an antimicrobial biodegradable material, corn flour was extruded with 1% of lysozyme. Since the limited stability of natural preservatives such as lysozyme is a common bottleneck to the elaboration of active biomaterials by melt blending processes, the influence of formulation and of extrusion processing temperature on its residual enzymatic activity was investigated. To assess the contribution of process parameters such as temperature, shear stress and of related formulation parameters such as glycerol and moisture contents, the stability of lysozyme following its extrusion or its thermoforming with plasticized corn starch or thermal treatments in aqueous glycerol solutions was also studied. Increasing glycerol content from 25% to 30% significantly limited inactivation of lysozyme during extrusion, while increasing initial moisture content of the mixture from 14.5% to 28.5% had the opposite effect. These observations open the possibility to prepare active materials retaining more than 60+/-7% of initial lysozyme activity. PMID- 25442948 TI - Identification of a beta-glucosidase from the Mucor circinelloides genome by peptide pattern recognition. AB - Mucor circinelloides produces plant cell wall degrading enzymes that allow it to grow on complex polysaccharides. Although the genome of M. circinelloides has been sequenced, only few plant cell wall degrading enzymes are annotated in this species. We applied peptide pattern recognition, which is a non-alignment based method for sequence analysis to map conserved sequences in glycoside hydrolase families. The conserved sequences were used to identify similar genes in the M. circinelloides genome. We found 12 different novel genes encoding members of the GH3, GH5, GH9, GH16, GH38, GH47 and GH125 families in M. circinelloides. One of the two GH3-encoding genes was predicted to encode a beta-glucosidase (EC 3.2.1.21). We expressed this gene in Pichia pastoris KM71H and found that the purified recombinant protein had relative high beta-glucosidase activity (1.73U/mg) at pH5 and 50 degrees C. The Km and Vmax with p-nitrophenyl-beta-d glucopyranoside as substrate was 0.20mM and 2.41U/mg, respectively. The enzyme was not inhibited by glucose and retained 84% activity at glucose concentrations up to 140mM. Although zygomycetes are not considered to be important degraders of lignocellulosic biomass in nature, the present finding of an active beta glucosidase in M. circinelloides demonstrates that enzymes from this group of fungi have a potential for cellulose degradation. PMID- 25442949 TI - Less is more, greener microbial synthesis of silver nanoparticles. AB - Microbial nano-synthesis has been well established as a green method for the sustainable development of nanotechnology. However, the mechanism of this biotechnology has to be reconsidered with the increasing realization that microorganism culture broth plays a vital role during the synthesis, which may obviate the dependence on microbes. Here, we demonstrate that silver nanoparticles (AgNPs) could be synthesized in several types of microorganism culture broth (an aqueous solution abundant in peptone, yeast extract from Saccharomyces cerevisiae, dextrose and other reducing and stabilizing agents) without any specific living microbe involvement. Light and high pH values of broth were identified as two critical factors in ensuring pure AgNPs formation. In broths containing NaCl at high concentration (0.5wt%), silver chloride was identified as the major intermediate and could be converted to AgNPs via one-pot photoreduction. Our broth alone strategy dramatically simplifies the conventional microbial nano-synthesis process by cutting the use of microorganisms and thus provides a more eco-friendly way for nano-Ag preparation. The fundamental understanding of the microbial synthesis mechanisms and implementing of complete green methods to fabricate technologically important nanomaterials will be further promoted by this study. PMID- 25442951 TI - Enhanced activity of immobilized pepsin nanoparticles coated on solid substrates compared to free pepsin. AB - In the present work nanoparticles (NPs) of pepsin were generated in an aqueous solution using high-intensity ultrasound, and were subsequently immobilized on low-density polyethylene (PE) films, or on polycarbonate (PC) plates, or on microscope glass slides. The pepsin NPs coated on the solid surfaces have been characterized by HRSEM, TEM, FTIR, XPS and DLS. The amount of enzyme introduced on the substrates, the leaching properties, and the catalytic activity of the immobilized enzyme on the three surfaces are compared. Catalytic activities of pepsin deposited onto the three solid surfaces as well as free pepsin, without sonication, and free pepsin NPs were compared at various pH levels and temperatures using a hemoglobin assay. Compared to native pepsin, pepsin coated onto PE showed the best catalytic activity in all the examined parameters. Pepsin immobilized on glass exhibited better activity than the native enzyme, especially at high temperatures. Enzyme activity of pepsin immobilized on PC was no better than native enzyme activity at all temperatures at pH 2, and only over a narrow pH range at 37 degrees C was the activity improved over the native enzyme. A remarkable observation is that immobilized pepsin on all the surfaces was still active to some extent even at pH 7, while free pepsin was completely inactive. The kinetic parameters, Km and Vmax were also calculated and compared for all the samples. Relative to the free enzyme, pepsin coated PE showed the greatest improvement in kinetic parameters (Km=15g/L, Vmax=719U/mg versus Km=12.6g/L and Vmax=787U/mg, respectively), whereas pepsin coated on PC exhibited the most unfavorable kinetic parameters (Km=18g/L, Vmax=685U/mg). The values for the anchored enzyme-glass were Km=19g/L, Vmax=763U/mg. PMID- 25442952 TI - Effects and action mechanisms of sodium fluoride (NaF) on the growth and cephalotaxine production of Cephalotaxus mannii suspension cells. AB - To explore the effects of NaF on the growth and cephalotaxine production of Cephalotaxus mannii suspension cells, NaF was added into the C mannii cell suspension cultures at day 15 of culture time. It is documented that NaF suppressed cell growth but enhanced cephalotaxine production. The largest yield obtained of cephalotaxine reached to 9.57mg/L when the cultures were treated with an appropriate dosage of 15mg/L NaF, which was 3.7 times that of the control cultures (2.58mg/L). Additionally, NaF markedly enhanced the activity of glucose 6-phosphate dehydrogenase (G6PDH) and reduced the level of hydrogen peroxide (H2O2) of cells. It was also found that NaF weakened the oxidative damage of cell membrane and led to lower content of malonyl dialdehyde (MDA) in NaF-treated cells compared with the control cells. The MDA content of NaF-treated cells decreased 91% compared to the controls. Although lower membrane lipid peroxidation in NaF-treated cells, its membrane permeability was higher than the control cells and showed a high product secret rate. What is more, NaF boosted the activity of phenylalanine ammonium-lyse (PAL), but did not burst a peak of PAL activity in the time curve of PAL activity. These results indicated NaF acted as an inhibitor of the Enbden Parnas (EMP) pathway, not as an elicitor to promote cephalotaxine production. PMID- 25442950 TI - Purification and functional characterization of the first stilbene glucoside specific beta-glucosidase isolated from Lactobacillus kimchi. AB - This study aimed to develop viable enzymes for bioconversion of resveratrol glucoside into resveratrol. Out of 13 bacterial strains tested, Lactobacillus kimchi JB301 could completely convert polydatin into resveratrol. The purified enzyme had an optimum temperature of 30-40 degrees C and optimum pH of pH 5.0 against polydatin. This enzyme showed high substrate specificities towards different substrates in the following order: isorhaponticin>>polydatin>>mulberroside A>oxyresveratrol-3-O-glucoside. Additionally, it rarely hydrolyzed astringin and desoxyrhaponticin. Based on these catalytic specificities, we suggest this enzyme be named stilbene glucoside specific beta-glucosidase. Furthermore, polydatin extracts from Polygonum cuspidatum were successfully converted to resveratrol with a high yield (of over 99%). Stilbene glucoside-specific beta-glucosidase is the first enzyme isolated from lactic acid bacteria capable of bio-converting various stilbene glucosides into stilbene. PMID- 25442953 TI - Design of a novel chimeric tissue plasminogen activator with favorable Vampire bat plasminogen activator properties. AB - Fibrinolytic agents are widely used in treatment of the thromboembolic disorders. The new generations like recombinant tissue plasminogen activator (t-PA, alteplase) are not showing promising results in clinical practice in spite of displaying specific binding to fibrin in vitro. Vampire bat plasminogen activator (b-PA) is a plasminogen activator with higher fibrin affinity and specificity in comparison to t-PA resulting in reduced probability of hemorrhage. b-PA is also resistant to plasminogen activator inhibitor-1 (PAI-1) showing higher half-life compared to other variants of t-PA. However, its non-human origin was a driving force to design a human t-PA with favorable properties of b-PA. In the present study, we designed a chimeric t-PA with desirable b-PA properties and this new molecule was called as CT-b. The construct was prepared through kringle 2 domain removal and replacement of t-PA finger domain with b-PA one. In addition, the KHRR sequence at the initial part of protease domain was replaced by four alanine residues. The novel construct was integrated in Pichia pastoris genome by electroporation. Catalytic activity was investigated in the presence and absence of fibrin. The purified protein was analyzed by western blot. Fibrin binding and PAI resistance assays were also conducted. The activity of the recombinant protein in the presence of fibrin was 1560 times more than its activity in the absence of fibrin, showing its higher specificity to fibrin. The fibrin binding of CT-b was 1.2 fold more than t-PA. In addition, it was inhibited by PAI enzyme 44% less than t-PA. Although the presented data demonstrate a promising in vitro activity, more in vivo studies are needed to confirm the therapeutic advantage of this novel plasminogen activator. PMID- 25442954 TI - Consent, common adverse events, and post-adverse event actions in endoscopy. AB - Endoscopy constitutes a wide range of procedures with many indications. Esophagogastroduodenoscopy, colonoscopy, endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography, and enteroscopy comprise the most commonly performed procedures. These examinations all carry risk to the patient, and incumbent in this is some legal risk with regard to how the procedure is conducted, decisions made based on the intraprocedure findings, and the postprocedure results, in addition to events that occur following the procedure. This article provides an overview of consent and complications of endoscopy. PMID- 25442955 TI - Foregut and colonic perforations: practical measures to prevent and assess them. AB - Acute endoscopic perforations of the foregut and colon are rare but can have devastating consequences. There are several principles and practices that can lower the risk of perforation and guide the endoscopist in early assessment when they do occur. Mastery of these principles will lead to overall improved patient outcomes. PMID- 25442956 TI - Closing perforations and postperforation management in endoscopy: esophagus and stomach. AB - Luminal perforation after endoscopy is a dreaded complication that is associated with significant morbidity and mortality, longer and more costly hospitalization, and the specter of potential future litigation. The management of such perforations requires a multidisciplinary approach. Until recently, surgery was required. However, nowadays the endoscopist has a burgeoning armamentarium of devices and techniques that may obviate surgery. This article discusses the approach to endoscopic perforations in the esophagus and stomach. PMID- 25442957 TI - Closing perforations and postperforation management in endoscopy: duodenal, biliary, and colorectal. AB - Early recognition of adverse events arising from endoscopy is essential. In some cases the injury can be viewed clearly during the procedure, and immediate action should be taken to repair the defect endoscopically if feasible. If perforation is unclear, imaging can be used to confirm the diagnosis. Surgical intervention is not always necessary; however, a surgical consultation for backup is essential. Selective cases can be managed conservatively or endoscopically with successful outcomes. Early recognition and intervention, input from specialist colleagues, and communication with the patient and family are keys to successfully managing the event. PMID- 25442959 TI - Adverse events associated with percutaneous enteral access. AB - Placement of percutaneous endoscopic gastrostomy or jejunostomy is a safe procedure with low periprocedural mortality, but overall mortality rates are high because of underlying disease conditions. These procedures are also associated with postprocedure complications. The clinically significant adverse events related to the procedures include infection (at tube site and peritonitis), bleeding, and aspiration. More rare associated events include buried bumpers, injury to adjacent viscera with subsequent fistula formation, and tumor seeding. There is a lack of guidelines about these procedures other than those concerning the use of antibiotics and the management of antithrombotics and anticoagulation before the procedure. PMID- 25442958 TI - Adverse events related to colonic endoscopic mucosal resection and polypectomy. AB - Colonoscopy is a commonly performed procedure. The rate of adverse events is 2.8 per 1000 screening colonoscopies. These adverse events include cardiovascular and pulmonary events, abdominal pain, hemorrhage, perforation, postpolypectomy syndrome, infection, and death. Serious adverse events, such as hemorrhage and perforation, occur most frequently when colonoscopy is performed with polypectomy. This article highlights the prevention and management of adverse events associated with polypectomy and endoscopic mucosal resection of colonic lesions. PMID- 25442960 TI - Complications of enteroscopy: how to avoid them and manage them when they arise. AB - Deep small bowel enteroscopy is a safe procedure that has revolutionized the strategy for diagnosis and treatment of small bowel diseases. However, enteroscopy-associated adverse events are more common compared with standard endoscopy. Prevention, early detection, and effective intervention are crucial in reducing the adverse event severity and improving outcomes. In this article, how to safely perform enteroscopy, avoid adverse events, detect adverse events early, and accomplish effective treatments are discussed. This knowledge can serve as a continuing quality improvement process to reduce the risk of future adverse events and improve the overall quality of endoscopy. PMID- 25442961 TI - Endoscopic retrograde cholangiopancreatography-related adverse events: general overview. AB - Endoscopic retrograde cholangiopancreatography (ERCP) represents a monumental advance in the management of patients with pancreaticobiliary diseases, but is a complex and technically demanding procedure with the highest inherent risk of adverse events of all routine endoscopic procedures. Overall adverse event rates for ERCP are typically reported as 5-10%. The most commonly reported adverse events include post-ERCP pancreatitis, bleeding, perforation, infection (cholangitis), and cardiopulomary or "sedation related" events. This article evaluates patient-related and procedure-related risk factors for ERCP-related adverse events, and discusses strategies for the prevention, diagnosis and management of these events. PMID- 25442962 TI - Endoscopic retrograde cholangiopancreatography (ERCP)-related adverse events: post-ERCP pancreatitis. AB - Post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP), and not uncommonly is the reason behind ERCP-related lawsuits. Patients at high risk for PEP include young women with abdominal pain, normal liver tests, and unremarkable imaging. Procedure-related factors include traumatic and persistent cannulation attempts, multiple injections of the pancreatic duct, pancreatic sphincterotomy, and, possibly, use of precut sphincterotomy. Aggressive hydration, use of rectal indomethacin, and prophylactic pancreatic stenting can diminish the risk (and likely severity) of PEP. Though hugely beneficial, these measures do not supersede careful patient selection and technique. PMID- 25442963 TI - Achieving hemostasis and the risks associated with therapy. AB - Acute gastrointestinal bleeding is a common cause for hospitalization. Endoscopic hemostasis plays a central role in the management of lesions with active bleeding or high-risk stigmata for rebleeding. The efficacy and safety of endoscopic hemostasis rely on the identification of lesions suitable for endoscopic therapy, selection of the appropriate hemostatic devices, attention to technique, and prompt recognition and management of procedure-related adverse events. In this article, practical applications of hemostatic devices and pitfalls related to endoscopic hemostasis are discussed. PMID- 25442964 TI - Sedation-related complications in gastrointestinal endoscopy. AB - Defining the risk of procedural sedation for gastrointestinal endoscopic procedures remains a vexing challenge. The definitions as to what constitutes a cardiopulmonary unplanned event are beginning to take focus but the existing literature is an amalgam of various definitions and subjective outcomes, providing a challenge to patient, practitioner, and researcher. Gastrointestinal endoscopy when undertaken by trained personnel after the appropriate preprocedural evaluation and in the right setting is a safe experience. However, significant challenges exist in further quantifying the sedation risks to patients, optimizing physiologic monitoring, and sublimating the pharmacoeconomic and regulatory embroglios that limit the scope of practice and the quality of services delivered to patients. PMID- 25442965 TI - New devices and techniques for handling adverse events: claw, suture, or cover? AB - Increasingly invasive therapeutic endoscopic procedures and laparoscopic surgeries have resulted in endoscopists being challenged more frequently with perforations, fistulas, and anastomotic leakages, for which nonsurgical closure is desired. Devices and techniques are available and in development for endoscopic closure of gastrointestinal wall defects. Currently available devices with excellent clinical success rates include the over-the-scope clip and an endoscopic suturing system. Another device, the cardiac septal defect occluder, has been adapted for use in the gastrointestinal tract. Extensive endoscopic knowledge, a highly trained endoscopy team, and the availability of devices and equipment are required to manage complications endoscopically. PMID- 25442966 TI - Comprehensive review of adverse events associated with GI endoscopy. PMID- 25442967 TI - Minimizing, recognizing, and managing endoscopic adverse events. PMID- 25442968 TI - Genomic selection accuracies within and between environments and small breeding groups in white spruce. AB - BACKGROUND: Genomic selection (GS) may improve selection response over conventional pedigree-based selection if markers capture more detailed information than pedigrees in recently domesticated tree species and/or make it more cost effective. Genomic prediction accuracies using 1748 trees and 6932 SNPs representative of as many distinct gene loci were determined for growth and wood traits in white spruce, within and between environments and breeding groups (BG), each with an effective size of Ne ~ 20. Marker subsets were also tested. RESULTS: Model fits and/or cross-validation (CV) prediction accuracies for ridge regression (RR) and the least absolute shrinkage and selection operator models approached those of pedigree-based models. With strong relatedness between CV sets, prediction accuracies for RR within environment and BG were high for wood (r = 0.71-0.79) and moderately high for growth (r = 0.52-0.69) traits, in line with trends in heritabilities. For both classes of traits, these accuracies achieved between 83% and 92% of those obtained with phenotypes and pedigree information. Prediction into untested environments remained moderately high for wood (r >= 0.61) but dropped significantly for growth (r >= 0.24) traits, emphasizing the need to phenotype in all test environments and model genotype-by environment interactions for growth traits. Removing relatedness between CV sets sharply decreased prediction accuracies for all traits and subpopulations, falling near zero between BGs with no known shared ancestry. For marker subsets, similar patterns were observed but with lower prediction accuracies. CONCLUSIONS: Given the need for high relatedness between CV sets to obtain good prediction accuracies, we recommend to build GS models for prediction within the same breeding population only. Breeding groups could be merged to build genomic prediction models as long as the total effective population size does not exceed 50 individuals in order to obtain high prediction accuracy such as that obtained in the present study. A number of markers limited to a few hundred would not negatively impact prediction accuracies, but these could decrease more rapidly over generations. The most promising short-term approach for genomic selection would likely be the selection of superior individuals within large full-sib families vegetatively propagated to implement multiclonal forestry. PMID- 25442970 TI - Reprint of: "This is the medicine:" a Kenyan community responds to a sexual concurrency reduction intervention. AB - We report the results of the first study designed to evaluate the feasibility and acceptability of an HIV prevention intervention focused on concurrent sexual partnerships. Mathematical models and longitudinal studies of stable couples indicate concurrency plays a critical role in sustaining generalized HIV epidemics in heterosexual populations, and East and Southern African nations identified concurrency reduction as a priority for HIV prevention. "Know Your Network" (KYN) is a single-session community-level concurrency awareness intervention designed to address this need. It is rooted in traditional social network research, but takes advantage of new network methodology and years of participatory action research with communities living in a region of Kenya with the highest HIV prevalence nationally. KYN combines didactic presentation, interactive exercises, high-impact graphics, and a network survey with immediate visualization of the results, to prompt a community conversation about sexual norms. We combined focus group discussions and the traditional east African baraza to evaluate the feasibility and acceptability of KYN for use with adults living in rural Nyanza Province, Kenya. We were able to implement KYN with fidelity to its components. Participants understood the intervention's messages about concurrency and its role in HIV transmission through sexual networks. They agreed to provide anonymous egocentric data on their sexual partnerships, and in return we successfully simulated a representation of their local network for them to view and discuss. This launched a dynamic conversation about concurrency and sexual norms that persisted after the intervention. The concurrency message was novel, but resonant to participants, who reported sharing it with their children, friends, and sexual partners. With clear evidence of KYN's feasibility and acceptability, it would be appropriate to evaluate the effectiveness of the intervention using a community-randomized trial. If effective, KYN would offer an inexpensive complement to ongoing comprehensive HIV prevention efforts in generalized epidemic settings. PMID- 25442971 TI - Reprint of: The myth of conformity: adolescents and abstention from unhealthy drinking behaviors. AB - Adolescent peer groups with pro-drinking group norms are a well-established source of influence for alcohol initiation and use. However, classic experimental studies of social influence, namely 'minority influence', clearly indicate social situations in which an individual can resist conforming to the group norm. Using the National Longitudinal Study of Adolescent Health ("Add Health"), a nationally representative sample of adolescents, we find evidence that being a non-drinking adolescent does not unilaterally put youth at risk for drinking onset when faced with a friendship network where the majority of friends drink. Our results also show that a non-drinking adolescent with a majority of drinking friends is significantly less likely to initiate alcohol abuse if he or she has a minority of non-drinking friend(s). Furthermore, a drinking adolescent with a majority of friends who drink has a decreased probability of continuing to drink and has overall lower levels of consumption if he or she has a minority of friends who do not drink. Our findings recognize that adolescent in-group friendships are a mix of behavioral profiles and can perhaps help adolescents continue or begin to abstain alcohol use even when in a friendship group supportive of alcohol use. PMID- 25442969 TI - Social networks and health: a systematic review of sociocentric network studies in low- and middle-income countries. AB - In low- and middle-income countries (LMICs), naturally occurring social networks may be particularly vital to health outcomes as extended webs of social ties often are the principal source of various resources. Understanding how social network structure, and influential individuals within the network, may amplify the effects of interventions in LMICs, by creating, for example, cascade effects to non-targeted participants, presents an opportunity to improve the efficiency and effectiveness of public health interventions in such settings. We conducted a systematic review of PubMed, Econlit, Sociological Abstracts, and PsycINFO to identify a sample of 17 sociocentric network papers (arising from 10 studies) that specifically examined health issues in LMICs. We also separately selected to review 19 sociocentric network papers (arising from 10 other studies) on development topics related to wellbeing in LMICs. First, to provide a methodological resource, we discuss the sociocentric network study designs employed in the selected papers, and then provide a catalog of 105 name generator questions used to measure social ties across all the LMIC network papers (including both ego- and sociocentric network papers) cited in this review. Second, we show that network composition, individual network centrality, and network structure are associated with important health behaviors and health and development outcomes in different contexts across multiple levels of analysis and across distinct network types. Lastly, we highlight the opportunities for health researchers and practitioners in LMICs to 1) design effective studies and interventions in LMICs that account for the sociocentric network positions of certain individuals and overall network structure, 2) measure the spread of outcomes or intervention externalities, and 3) enhance the effectiveness and efficiency of aid based on knowledge of social structure. In summary, human health and wellbeing are connected through complex webs of dynamic social relationships. Harnessing such information may be especially important in contexts where resources are limited and people depend on their direct and indirect connections for support. PMID- 25442972 TI - Reprint of: Results from using a new dyadic-dependence model to analyze sociocentric physician networks. AB - Professional physician networks can potentially influence clinical practices and quality of care. With the current focus on coordinated care, discerning influences of naturally occurring clusters and other forms of dependence among physicians' relationships based on their attributes and care patterns is an important area of research. In this paper, two directed physician networks: a physician influential conversation network (N = 33) and a physician network obtained from patient visit data (N = 135) are analyzed using a new model that accounts for effect modification of the within-dyad effect of reciprocity and inter-dyad effects involving three (or more) actors. The results from this model include more nuanced effects involving reciprocity and triadic dependence than under incumbent models and more flexible control for these effects in the extraction of other network phenomena, including the relationship between similarity of individuals' attributes (e.g., same-gender, same residency location) and tie-status. In both cases we find extensive evidence of clustering and triadic dependence that if not accounted for confounds the effect of reciprocity and attribute homophily. Findings from our analysis suggest alternative conclusions to those from incumbent models. PMID- 25442977 TI - Uncertain diagnosis of Fabry disease: consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance. AB - BACKGROUND: Screening in subjects with left ventricular hypertrophy (LVH) reveals a high prevalence of Fabry disease (FD). Often, a diagnosis is uncertain because characteristic clinical features are absent and genetic variants of unknown significance (GVUS) in the alpha-galactosidase A (GLA) gene are identified. This carries a risk of misdiagnosis, inappropriate counselling and extremely expensive treatment. We developed a diagnostic algorithm for adults with LVH (maximal wall thickness (MWT) of >12 mm), GLA GVUS and an uncertain diagnosis of FD. METHODS: A Delphi method was used to reach a consensus between FD experts. We performed a systematic review selecting criteria on electrocardiogram, MRI and echocardiography to confirm or exclude FD. Criteria for a definite or uncertain diagnosis and a gold standard were defined. RESULTS: A definite diagnosis of FD was defined as follows: a GLA mutation with <= 5% GLA activity (leucocytes, mean of reference value, males only) with >= 1 characteristic FD symptom or sign (neuropathic pain, cornea verticillata, angiokeratoma) or increased plasma (lyso)Gb3 (classical male range) or family members with definite FD. Subjects with LVH failing these criteria have a GVUS and an uncertain diagnosis. The gold standard was defined as characteristic storage in an endomyocardial biopsy on electron microscopy. Abnormally low voltages on ECG and severe LVH (MWT>15 mm) <20 years exclude FD. Other criteria were rejected due to insufficient evidence. CONCLUSIONS: In adults with unexplained LVH and a GLA GVUS, severe LVH at young age and low voltages on ECG exclude FD. If absent, an endomyocardial biopsy with electron microscopy should be performed. PMID- 25442978 TI - Acute effect of ambient air pollution on heart failure in Guangzhou, China. AB - BACKGROUND: Heart failure (HF) is a global public health problem of increasing importance. The association between acute exposure to air pollution and HF has been well established in developed countries, but little evidence was available in developing countries where air pollution levels were much higher. We conducted a time-series study to investigate the short-term association between air pollution and overall emergency ambulance dispatches (EAD) due to HF in Guangzhou, China. METHODS: Daily data of EAD due to HF from 1 January 2008 to 31 December 2012 were obtained from Guangzhou Emergency Center. We applied the over dispersed Poisson generalized addictive model to analyze the associations after controlling for the seasonality, day of the week and weather conditions. RESULTS: We identified a total of 3375 EAD for HF. A 10-MUg/m(3) increase in the present day concentrations of particulate matter with an aerodynamic diameter of less than 10 MUm, sulfur dioxide and nitrogen dioxide corresponded to increases of 3.54% [95% confidence interval (CI): 1.35%, 5.74%], 5.29% (95% CI: 2.28%, 8.30%) and 4.34% (95% CI: 1.71%, 6.97%) in daily EAD for HF, respectively. The effects of air pollution on acute HF were restricted on the concurrent day and in the cool seasons. CONCLUSIONS: Our results provided the first population-based evidence in Mainland China that outdoor air pollution could trigger the exacerbation of HF. PMID- 25442979 TI - Serum transaminase determined in the emergency room predicts outcomes in patients with acute ST-segment elevation myocardial infarction who undergo primary percutaneous coronary intervention. AB - BACKGROUND: Elevated serum aspartate and alanine aminotransferase (AST and ALT) are often observed in patients with acute ST-segment elevation myocardial infarction (STEMI) and the condition is ascribed to liver hypoperfusion. We evaluated the prevalence and prognostic implication of hypoxic liver injury (HLI) in STEMI. METHODS: Patients with STEMI and no preexisting liver disease who underwent primary percutaneous coronary intervention (PCI) were enrolled. A blood test was performed at the time of presentation and transthoracic echocardiography was performed after the index PCI. We reviewed medical records and contacted families of the patients by telephone to assess outcomes. RESULTS: Of 456 patients (age 60 +/- 13 years, 370 males), 31 patients (7%) died during follow-up (duration: 754 +/- 540 days). Those patients were older (72 +/- 10 vs. 59 +/- 13 years), had higher AST (179 +/- 224 vs. 64 +/- 103 U/L), ALT (56 +/- 79 vs. 35 +/ 33 U/L), blood urea nitrogen (25 +/- 15 vs. 17 +/- 7 mg/dL), uric acid (6.9 +/- 2.9 vs. 5.8 +/- 1.6 mg/dL), creatine kinase-myocardial band isoenzyme (76 +/- 104 vs. 41 +/- 79 ng/mL), troponin I (19.9 +/- 23.0 vs. 10.8 +/- 19.1 ng/mL), and lower albumin (4.0 +/- 0.5 vs. 4.2 +/- 0.4 g/dL) at the time of presentation (p<0.05 for all). Particularly, AST independently predicted all-cause mortality (per 10 U/L increase, hazard ratio: 1.06, 95% confidence interval: 1.02-1.10, p=0.007), whereas cardiac markers did not. HLI (>2-fold elevation of AST or ALT upper normal limits) showed close correlation with reduced left ventricular ejection fraction (beta=-0.12, p=0.03) and patients with the condition (n=100 [20%]) had poorer survival than the others (Log-Rank, p=0.005). CONCLUSION: The presence of HLI predicts mortality in patients with STEMI who undergo successful primary PCIs. PMID- 25442980 TI - Facial tissue depths in children with cleft lip and palate. AB - Cleft lip and palate (CLP) is a craniofacial malformation affecting more than seven million people worldwide that results in defects of the hard palate, teeth, maxilla, nasal spine and floor, and maxillodental asymmetry. CLP facial soft tissue depth (FSTD) values have never been published. The purpose of this research is to report CLP FSTD values and compare them to previously published FSTD values for normal children. Thirty-eight FSTDs were measured on cone beam computed tomography images of CLP children (n = 86; 7-17 years). MANOVA and ANOVA tests determined whether cleft type, age, sex, and bone graft surgical status affect tissue depths. Both cleft type (unilateral/bilateral) and age influence FSTDs. CLP FSTDs exhibit patterns of variation that differ from normal children, particularly around the oronasal regions of the face. These differences should be taken into account when facial reconstructions of children with CLP are created. PMID- 25442981 TI - The novel ADAMTS13-p.D187H mutation impairs ADAMTS13 activity and secretion and contributes to thrombotic thrombocytopenic purpura in mice. AB - BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP) is characterized by mutations in the ADAMTS13 gene, which either impair protein secretion or influence ADAMTS13 (A Disintegrin-like And Metalloprotease domain with ThromboSpondin type-1 motif, member 13) activity. Phenotypic consequences of these mutations have not yet been evaluated in animal models for TTP. OBJECTIVES: To identify the in vitro effect of a novel ADAMTS13 mutation and to investigate whether this mutation induces TTP in vivo. METHODS: All 29 ADAMTS13 exons with exon-intron boundaries of a patient with pregnancy-onset TTP were sequenced. Wild type and mutant ADAMTS13 proteins were both transiently and stably expressed in human embryonic kidney cells, and their activity was evaluated in vitro using fluorescence resonance energy transfer and flow assays. Molecular dynamics simulations were performed to study Ca(2+) stability. Adamts13(-/-) mice were hydrodynamically injected with wild-type and mutant expression plasmids and triggered with recombinant human von Willebrand factor. RESULTS: We identified a novel heterozygous c.559G>C mutation in exon 6 of the proposita's ADAMTS13 gene. This mutation resulted in a p.Asp187His substitution (p.D187H), which was located in the high affinity Ca(2+) -binding site in the metalloprotease domain of ADAMTS13. The homozygous p.D187H mutation down-regulated ADAMTS13 activity in vitro. Impaired proteolytic activity was linked to unstable Ca(2+) binding as visualized using a molecular dynamics simulation. In addition, the p.D187H mutation affects protein secretion in vitro. In Adamts13(-/-) mice, the homozygous p.D187H mutation reduced ADAMTS13 secretion and activity and contributed to TTP when these mice were triggered with recombinant human von Willebrand factor. CONCLUSIONS: Our data indicate that the p.D187H mutation impairs ADAMTS13 activity and secretion and is responsible for TTP onset in mice. PMID- 25442982 TI - Determinants of left ventricular dysfunction after repair of chronic asymptomatic mitral regurgitation. AB - BACKGROUND: The evidence supporting early surgical intervention in patients with chronic asymptomatic mitral regurgitation (MR) is steadily accumulating. Although left ventricular (LV) enlargement and preoperative pulmonary hypertension are considered when deciding on surgical intervention, the threshold above which these factors influence clinical outcomes remains poorly defined. METHODS: One hundred fifty asymptomatic patients of aged 59.3 +/- 13.4 years underwent mitral valve repair of severe MR caused by myxomatous degeneration between 2001 and 2012. Mean preoperative left atrial diameter, LV end-systolic diameter (LVESD), and right ventricular systolic pressure were 41.2 +/- 6.9 mm, 34.6 +/- 5.4 mm, and 38.4 +/- 11.8 mm Hg, respectively. Preoperative LV ejection fraction (LVEF) was greater than 60% in 136 (91%) patients, and none had preoperative atrial fibrillation. Clinical and echocardiographic follow-up averaged 3.3 years and extended to 9.1 years. RESULTS: There were no perioperative deaths. Five-year survival and freedom from recurrent MR greater than or equal to 2+ were 93.4% +/- 3.2% and 94.0% +/- 3.2%, respectively. A threshold LVESD indexed to body surface area greater than 19 mm/m(2) (hazard ratio [HR], 3.5 +/- 2.0; p = 0.03) and a preoperative right ventricular systolic pressure greater than 45 mm Hg (HR, 3.8 +/- 12.1; p = 0.01) were independently associated with postoperative LV dysfunction, defined as a LVEF less than 60%. CONCLUSIONS: Mitral valve repair can be performed with favorable early and late outcomes in patients with asymptomatic severe MR. The presence of minimal LV enlargement and preoperative pulmonary hypertension were associated with postoperative LV dysfunction in this otherwise healthy population. Mitral valve repair may be considered in asymptomatic patients with an indexed LVESD (ILVESD) greater than 19 mm/m(2) or preoperative right ventricular systolic pressure greater than 45 mm Hg. PMID- 25442983 TI - A defined management strategy improves early outcomes after the Fontan procedure: the PORTLAND protocol. AB - BACKGROUND: Patients undergoing the Fontan procedure may have extended hospital stay due to various postoperative factors including prolonged chest tube drainage. Our aim was to determine the efficacy of our Fontan management protocol in reducing chest tube drainage and length of stay. METHODS: Patients who underwent a Fontan procedure at our institution from June 2008 to September 2013 were analyzed (n = 42). We currently manage our patients according to the PORTLAND protocol: Peripheral vasodilation, Oxygen, Restriction of fluids, Technique of surgery, Low-fat diet, Anticoagulation (including antithrombin III management), No ventilator, and Diuretics. Group A (n = 28) had surgery prior to initiation of this protocol; group B (n = 14) had surgery during the current protocol era. RESULTS: The median number of chest tube days was lower in group B (6 vs 11 days, p < 0.001) as was the total indexed drainage (126 vs 259 mL/kg, p < 0.001). Patients in group B had shorter intensive care unit length of stay (4 vs 7 days, p = 0.004) and hospital length of stay (8 vs 13 days, p = 0.001). Group B had higher preoperative common atrial pressures (7.0 vs 5.8 mm Hg, p = 0.017), end-diastolic pressures (9 vs 7 mm Hg, p = 0.026), and trended toward higher pulmonary artery pressures (11.5 vs 9.5 mm Hg, p = 0.077). There was no statistically significant difference in age, weight, transpulmonary gradient, or pulmonary vascular resistance between groups. CONCLUSIONS: The PORTLAND protocol has improved early outcomes after the Fontan procedure. Chest tube drainage and duration, and both intensive care unit and hospital length of stay have been reduced since initiation of this protocol. PMID- 25442984 TI - Survival predictors in acute respiratory distress syndrome with extracorporeal membrane oxygenation. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) can be used as a salvage therapy, but the effectiveness is controversial. The aim of this study was to investigate the predictors of mortality and the influence of organ dysfunction scores in severe acute respiratory distress syndrome (ARDS) patients treated with ECMO. METHODS: The records of adult severe ARDS patients receiving ECMO support from May 2006 to December 2011 at Chang Gung Memorial Hospital were retrospectively analyzed. RESULTS: The records of 65 patients with severe ARDS who received venovenous ECMO were analyzed. The hospital survival rate was 47.7%. Survivors were younger than nonsurvivors (41.4 +/- 15.4 versus 54.1 +/- 16.9 years, respectively; p = 0.002) and had shorter duration of mechanical ventilation before ECMO (52.7 +/- 51.1 versus 112.1 +/- 101.0 hours, respectively; p = 0.01). Before ECMO, Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, and Multiple Organ Dysfunction scores were significantly lower for survivors than for nonsurvivors. Mortality rate increased with rising predictive score. During 7 days of ECMO use, organ dysfunction scores were significantly lower for survivors than nonsurvivors. CONCLUSIONS: Severe ARDS patients who are younger, have shorter duration of mechanical ventilation, and lower organ dysfunction scores before ECMO initiation have more favorable survival outcome. Early application of ECMO, especially if predictive score is below 2, may improve survival. Organ dysfunction scores before and during ECMO support are correlated with survival. PMID- 25442986 TI - Contemporary real-world outcomes of surgical aortic valve replacement in 141,905 low-risk, intermediate-risk, and high-risk patients. AB - BACKGROUND: The introduction of transcatheter aortic valve replacement mandates attention to outcomes after surgical aortic valve replacement (SAVR) in low-risk, intermediate-risk, and very high-risk patients. METHODS: The study population included 141,905 patients who underwent isolated primary SAVR from 2002 to 2010. Patients were risk-stratified by Society of Thoracic Surgeons (STS) predicted risk of mortality (PROM) <4% (group 1, n = 113,377), 4% to 8% (group 2, n = 19,769), and >8% (group 3, n = 8,759). The majority of patients were considered at low risk (80%), and only 6.2% were categorized as being at high risk. Outcomes were analyzed based on two time periods: 2002 to 2006 (n = 63,754) and 2007 to 2010 (n = 78,151). RESULTS: The mean age was 65 years in group 1, 77 in group 2, and 77 in group 3 (p < 0.0001). The median STS PROM for the entire population was 1.84: 1.46% in group 1, 5.24% in group 2, and 11.2% in group 3 (p < 0.0001). Compared with PROM, in-hospital mean mortality was lower than expected in all patients (2.5% vs 2.95%) and when analyzed within risk groups was as follows: group 1 (1.4% vs 1.7%), group 2 (5.1% vs 5.5%), and group 3 (11.8% vs 13.7%) (p < 0.0001). In the most recent surgical era, operative mortality was significantly reduced in group 2 (5.4% vs 6.4%, p = 0.002) and group 3 (11.9% vs 14.4%, p = 0.0004) but not in group 1. CONCLUSIONS: Nearly 80% of patients undergoing SAVR have outcomes that are superior to those by the predicted risk models. In the most recent era, early results have further improved in medium-risk and high-risk patients. This large real-world assessment serves as a benchmark for patients with aortic valve stenosis as therapeutic options are further evaluated. PMID- 25442985 TI - Bridge to removal: a paradigm shift for left ventricular assist device therapy. AB - Ventricular assist devices have become standard therapy for patients with advanced heart failure either as a bridge to transplantation or destination therapy. Despite the functional and biologic evidence of reverse cardiac remodeling, few patients actually proceed to myocardial recovery, and even fewer to the point of having their device explanted. An enhanced understanding of the biology and care of the mechanically supported patient has redirected focus on the possibility of using ventricular assist devices as a bridge to myocardial recovery and removal. Herein, we review the current issues and approaches to transforming myocardial recovery to a practical reality. PMID- 25442987 TI - Hospital readmission is associated with poor survival after esophagectomy for esophageal cancer. AB - BACKGROUND: Hospital readmissions are costly and associated with inferior patient outcomes. There is limited knowledge related to readmissions after esophagectomy for malignancy. Our aim was to determine the impact on survival of readmission after esophagectomy. METHODS: This cohort study utilizes Surveillance, Epidemiology, and End Results-Medicare data (2002 to 2009). Survival, length of stay, 30-day readmissions, and discharge disposition were determined. Multivariate logistic regression models were created to examine risk factors associated with readmission. RESULTS: In all, 1,744 patients with esophageal cancer underwent esophagectomy: 80% of patients (1,390) were male, and mean age was 73 years; 71.8% of tumors (1,251) were adenocarcinomas, and 72.5% (1,265) were distal esophageal tumors; 38% of patients (667) received induction therapy. Operative approach was transthoracic in 52.6% of patients (918) and transhiatal in 37.4% (653), and required complex reconstruction (intestinal interposition) in 9.9% (173). Stage distribution was as follows: stage I, 35.3% (616); stage II, 32.5% (566); stage III, 27.9% (487); and stage IV, 2.3% (40). Median length of stay was 13 days, hospital mortality was 9.3% (158 patients), and 30-day readmission rate was 18.6% (212 of 1,139 home discharges); 25.4% of patients (443) were discharged to institutional care facilities. Overall survival was significantly worse for patients who were readmitted (p < 0.0001, log rank test). Risk factors for readmission were comorbidity score of 3+, urgent admission, and urban residence. CONCLUSIONS: Hospital readmissions after esophagectomy for cancer occur frequently and are associated with worse survival. Improved identification of patients at risk for readmission after esophagectomy can inform patient selection, discharge planning, and outpatient monitoring. Optimization of such practices may lead to improved outcomes at reduced cost. PMID- 25442988 TI - Localization of pulmonary nodules using navigation bronchoscope and a near infrared fluorescence thoracoscope. AB - BACKGROUND: Video-assisted thoracoscopic wedge resection of multiple small, non visible, and nonpalpable pulmonary nodules is a clinical challenge. We propose an ultra-minimally invasive technique for localization of pulmonary nodules using the electromagnetic navigation bronchoscope (ENB)-guided transbronchial indocyanine green (ICG) injection and intraoperative fluorescence detection with a near-infrared (NIR) fluorescence thoracoscope. METHODS: Fluorescence properties of ICG topically injected into the lung parenchyma were determined using a resected porcine lung. The combination of ENB-guided ICG injection and NIR fluorescence detection was tested using a live porcine model. An electromagnetic sensor integrated flexible bronchoscope was geometrically registered to the three dimensional chest computed tomographic image data by way of a real-time electromagnetic tracking system. The ICG mixed with iopamidol was injected into the pulmonary nodules by ENB guidance; ICG fluorescence was visualized by a near infrared (NIR) thoracoscope. RESULTS: The ICG existing under 24-mm depth of inflated lung was detectable by the NIR fluorescence thoracoscope. The size of the fluorescence spot made by 0.1 mL of ICG was 10.4 +/- 2.2 mm. An ICG or iopamidol spot remained at the injected point of the lung for more than 6 hours in vivo. The ICG fluorescence spot injected into the pulmonary nodule with ENB guidance was identified at the pulmonary nodule with the NIR thoracoscope. CONCLUSIONS: The ENB-guided transbronchial ICG injection and intraoperative NIR thoracoscopic detection is a feasible method to localize multiple pulmonary nodules. PMID- 25442989 TI - Unilateral versus bilateral cerebral perfusion for acute type A aortic dissection. AB - BACKGROUND: Antegrade cerebral perfusion (ACP) is standard treatment for complex aortic pathology and includes both unilateral (u-ACP) and bilateral (b-ACP) techniques. Focusing on proximal acute aortic dissection, we investigated the clinical effect of u-ACP versus b-ACP. METHODS: From January 2005 to May 2013, 157 consecutive patients presented with acute type A aortic dissection. Antegrade cerebral perfusion was used in 153 patients (97.4%). Ninety patients (58.8%) received u-ACP, and 63 (41.2%) received b-ACP. No retrograde cerebral perfusion was used. The target systemic hypothermia temperature during ACP was 22 degrees to 24 degrees C. The mean ACP, cardiopulmonary bypass, and cardiac ischemia times were 34.6 +/- 18.0, 125.6 +/- 48.0, and 92.6 +/- 34.1 minutes, respectively. RESULTS: The p values from logistic regression models indicated that in both groups combined, the ACP, cardiopulmonary bypass, and cardiac ischemia times predicted hospital mortality (p = 0.035, p = 0.0033, and p = 0.035, respectively) but not stroke. The operative mortality was 13.3% (n = 12) with u-ACP and 12.7% (n = 8) with b-ACP (p = 0.91). Of the survivors, 13 of 88 u-ACP patients (14.8%) and 8 of 62 b-ACP patients (12.9%) had a postoperative stroke (p = 0.75). A circulatory arrest time of >30 minutes was associated with stroke (p = 0.031). Temporary neurologic dysfunction was present in 10 u-ACP (11.4%) and 5 b-ACP (8.2%) patients (p = 0.53). Postoperative renal failure occurred in 10 u-ACP (11.4%) and 10 b-ACP patients (16.1%) (p = 0.40). Antegrade stent delivery in the descending thoracic aorta did not affect the ACP, cardiac ischemia, circulatory arrest, or cardiopulmonary bypass times. CONCLUSIONS: As one of the largest single-center studies of the efficacy of u-ACP and b-ACP in patients with type A aortic dissection, operative mortality, stroke, temporary neurologic dysfunction, and renal failure rates were similar in both. In this intrinsically complex disease, survival is the most important outcome; u-ACP may provide cardiac surgeons with valuable technical simplicity during challenging procedures, and b ACP may be justified for circulatory arrest times of more than 30 minutes. PMID- 25442990 TI - Operative mortality and complication risk model for all major cardiovascular operations in Japan. AB - BACKGROUND: The Japan Cardiovascular Surgery Database (JCVSD) is a nationwide benchmarking project to improve the quality of cardiovascular surgery in Japan. This study aimed to develop new JACVD risk models not only for operative mortality but also for each postoperative complication for coronary artery bypass grafting (CABG) operations, valve operations, and thoracic aortic operations. METHODS: We analyzed 24,704 isolated CABG operations, 26,137 valve operations, and 18,228 thoracic aortic operations. Risk models were developed for each operation for operative death, permanent stroke, renal failure, prolonged ventilation (>24 hours), deep sternal wound infection, and reoperation for bleeding. The population was divided into an 80% development sample and a 20% validation sample. The statistical model was constructed by multiple logistic regression analysis. Model discrimination was tested using the area under the receiver operating characteristic curve (C index). RESULTS: The 30-day mortality rates for isolated CABG, valve, and thoracic aortic operations were 1.5%, 2.5%, and 6.0%, respectively, and operative mortality rates were 2.4%, 3.8%, and 8.4%, respectively. The C indices for the end points of isolated CABG, valve, and aortic thoracic operations were 0.6358 for (deep sternal infection) to 0.8655 (operative mortality), 0.6114 (reoperation for bleeding) to 0.8319 (operative death), and 0.6311 (gastrointestinal complication) to 0.7591 (operative death), respectively. CONCLUSIONS: These risk models increased the discriminatory power of former models. Thus, our models can be said to reflect the current state of Japan. With respect to major complications, useful feedback can now be provided through the Japan Cardiovascular Surgery Database Web-based system. PMID- 25442991 TI - Neoadjuvant treatment response in negative nodes is an important prognosticator after esophagectomy. AB - BACKGROUND: The current American Joint Committee on Cancer Seventh Edition (AJCC7) pathologic staging for esophageal adenocarcinoma (EAC) is derived from data assessing the outcomes of patients having undergone esophagectomy without neoadjuvant treatment and has unclear significance in patients who have received multimodality therapy. Lymph nodes with evidence of neoadjuvant treatment effect without residual cancer cells may be observed and are not traditionally considered in pathologic reports, but may have prognostic significance. METHODS: All patients who underwent esophagectomy after completing neoadjuvant therapy for EAC at our institution between 2006 and 2012 were reviewed. Slides of pathologic specimens were reexamined for locoregional treatment-response nodes lacking viable cancer cells but with evidence of acellular mucin pools, central fibrosis, necrosis, or calcifications suggesting prior tumor involvement. Kaplan-Meier survival functions were estimated, and Cox proportional hazards regression models were used to compare staging models. RESULTS: Ninety patients (82 men) underwent esophagectomy after neoadjuvant therapy for EAC (mean age, 61.8 +/- 8.9 years). All patients received preoperative chemotherapy, and 50 patients also underwent preoperative radiotherapy. Median Kaplan-Meier survival was 55.6 months, and 5 year survival was 35% (95% confidence interval, 19% to 62%). A total of 100 treatment-response nodes were found in 38 patients. For patients with limited nodal disease (62 ypN0-N1), the presence of treatment-response nodes was associated with significantly worse survival (p = 0.03) compared with patients lacking such nodes. Adjusting for patient age and AJCC7 pathologic stage showed the presence of treatment-response nodes significantly increased the risk of death (hazard ratio, 2.7; 95% confidence interval, 1.1 to 6.9; p = 0.04). When stage-adjusted survival was modeled, counting treatment-response nodes as positive nodes offered a better model fit than ignoring them. CONCLUSIONS: Treatment-response lymph nodes detected from esophagectomy specimens in patients having undergone neoadjuvant chemotherapy or combined chemoradiation for EAC provide valuable prognostic information, particularly in patients with limited nodal disease. The current practice of considering lymph nodes lacking viable cancer cells, but with evidence of tumor necrosis, as pathologically negative likely results in understaging. Future efforts at revising the staging system for EAC should consider incorporating treatment-response lymph nodes in the analysis. PMID- 25442992 TI - Postoperative atrial fibrillation impacts on costs and one-year clinical outcomes: the Veterans Affairs Randomized On/Off Bypass Trial. AB - BACKGROUND: New-onset postoperative atrial fibrillation (POAF) after coronary artery bypass graft surgery (CABG) is associated with worse in-hospital morbidity and mortality, extended hospital stays, and higher costs. Beyond the initial hospital discharge, the cost and outcomes of POAF have not been well studied. METHODS: For CABG patients with and without new-onset POAF, a retrospective propensity-matched, multivariable regression analysis was performed to compare 1 year outcomes (including health-related quality of life [HRQoL] scores and mortality rates) and costs (standardized to 2010 dollars). Regression models controlled for site and patient factors, with propensity matching used to adjust for differences in POAF versus no-POAF patients' risk profiles. RESULTS: Using the existing CABG trial database, 2,096 patient records were analyzed, including POAF patients (n = 549) versus no-POAF patients (n = 1,547). For the index CABG hospitalization, POAF patients had longer postoperative length of stay (+3.9 days) and higher discharge costs (+$13,993) than no-POAF patients. At 1 year, POAF patients had more than twice the adjusted odds of dying (p < 0.01), with higher 1-year total cumulative costs. This 1-year cost difference (+$15,593) was largely attributable to hospital-based costs during the index surgery hospitalization. There was no difference in 1-year HRQoL scores (or HRQoL score changes) between POAF patients and no-POAF patients. CONCLUSIONS: Compared with no-POAF patients, POAF patients had higher discharge and 1-year costs along with higher 1-year mortality rates, but no differences were observed in 1-year HRQoL scores. Additional research appears warranted to improve the longer-term survival rates for POAF CABG patients, targeting future POAF-specific postdischarge interventions. PMID- 25442993 TI - Outcomes of surgery for chronic type A aortic dissection. AB - BACKGROUND: Data on outcomes of surgery for chronic Stanford type A aortic dissection are limited. We investigated the primary surgery and long-term results in patients with chronic dissection of the native ascending aorta. METHODS: Between 1993 and 2013, among 696 patients (median age, 61 years [first quartile, 50; third quartile 73 years]; 64% males) who underwent surgery for type A dissection, 67 (10%) had chronic dissection by traditional criteria (>14 days). Median follow-up was 4.1 years (first quartile, 1.9; third quartile, 7.3 years; 3,105 patient-years). RESULTS: Patients with chronic dissection more frequently had undergone previous cardiac surgery (37% versus 9%; p < 0.001) and more frequently had bicuspid aortic valve syndrome (19% versus 7%; p < 0.001) and larger ascending aortic diameter (6.0 cm [first quartile 5.2; third quartile 7.2 cm] versus 4.9 cm [first quartile, 4.5; third quartile, 5.7 cm]; p < 0.001). Aortic dissection extended beyond the aortic arch less frequently in chronic dissection patients (27% versus 70%; p < 0.001). Moderate to severe aortic insufficiency rate was higher in chronic group (65% versus 36%; p < 0.001); they required aortic root replacement more frequently (42% versus 18%; p < 0.001) and had lower in-hospital mortality (4.5% versus 13.2%; p = 0.062). Resection of all dissected aortic tissue was achieved in 73% chronic and 30% acute dissection patients. Overall survival was better in the chronic group with 80% +/- 5% versus 68% +/- 2% at 5 years and 64% +/- 13% versus 49% +/- 3% at 10 years (log rank p = 0.021). CONCLUSIONS: Patients with chronic and acute type A dissection differ substantially in presentation, management, and outcome. Replacement of all dissected aortic tissue can be performed safely in the majority of patients with chronic type A dissection. PMID- 25442994 TI - Pathologic evaluation of 28 Mitroflow pericardial valves: a 12-year experience. AB - BACKGROUND: Mitroflow pericardial valves (model A12) are used for aortic valve replacement with favorable hemodynamic results, and are ideal for patients with a small aortic annulus as the pericardium is mounted outside the stent frame. We report the morphologic findings in explanted Mitroflow valves from our institution and demonstrate pathologic changes leading to explantation. METHODS: From 2001 to 2013, 28 Mitroflow valves were analyzed at our institution. Demographic data was recorded. The excised valves were analyzed by gross and microscopic examination. After pathologic examination, mode of failure was determined. RESULTS: During the 12-year period, 28 valves were explanted. The 28 patients, with a mean age at implant of 72.2 +/- 5.7 years (range, 60 to 81 years), included 16 males (57%). The mean interval between index surgery and explantation was 4.5 +/- 3.4 years (range, 3 months to 11 years). Structural valve deterioration was seen in 18 (64%) patients; mean age at implantation was 72.1 +/- 5.69 years with an implant duration of 6.25 +/- 2.6 years. Findings in patients with structural valve deterioration included cusp thickening (n = 18), tears (n = 17), pannus deposition (n = 17), and calcification (n = 14). Nonstructural valve deterioration and endocarditis was seen in 1 (4%) and 7 patients (25%), respectively. One valve explanted at post mortem did not contribute to the patient's death. CONCLUSIONS: Structural valve deterioration was seen in 18 of 19 explanted valves with implant durations of at least 30 months, and is related to valve design. It appears that clinicians should carefully consider Mitroflow valve implantation in all patients, even in patients older than 65 years old, given the early presence of structural valve deterioration. PMID- 25442995 TI - Prophylactic atrial arrhythmia surgical procedures with congenital heart operations: review and recommendations. AB - Specific congenital heart anomalies significantly increase the risk for late atrial arrhythmias, raising the question whether prophylactic arrhythmia operations should be incorporated into reparative open heart procedures. Currently no consensus exists regarding standard prophylactic arrhythmia procedures. Questions remain concerning the arrhythmia-specific lesions to perform, energy sources to use, need for atrial appendectomy, and choosing a right, left, or biatrial Maze procedure. These considerations are important because prophylactic arrhythmia procedures are performed without knowing if the patient will actually experience an arrhythmia. This review identifies congenital defects with a risk for the development of atrial arrhythmias and proposes standardizing lesion sets for prophylactic arrhythmia operations. PMID- 25442996 TI - Adult aortic valve interstitial cells have greater responses to toll-like receptor 4 stimulation. AB - BACKGROUND: Aortic valve interstitial cells (AVICs) have been implicated in the pathogenesis of calcific aortic valve disease. Signal transducer and activator of transcription 3 (Stat3) possesses antiinflammatory effects. Given that calcification occurs in adult valves, we hypothesized that AVICs from adult valves more likely undergo a proosteogenic phenotypic change than those from pediatric valves and that may be related to different Stat3 activation in the response of those two age groups to toll-like receptor 4 (TLR4). METHODS: AVICs from healthy human aortic valve tissues were treated with TLR4 agonist lipopolysaccharide. Cellular levels of TLR4, intercellular adhesion molecule 1, bone morphogenetic protein 2, and alkaline phosphatase, as well as phosphorylation of p-38 mitogen-activated protein kinase (MAPK), nuclear factor kappabeta (NF-kappabeta), and Stat3, were analyzed. RESULTS: Toll-like receptor 4 protein levels were comparable between adult and pediatric AVICs. Adult cells produce markedly higher levels of the above markers after TLR4 stimulation, which is negatively associated with phosphorylation of Stat3. Inhibition of Stat3 enhanced p-38 MAPK and NF-kappabeta phosphorylation and exaggerated the expression of the above markers in pediatric AVICs after TLR4 stimulation. CONCLUSIONS: Adult AVICs exhibit greater inflammatory and osteogenic responses to TLR4 stimulation. The enhanced responses in adult AVICs are at least partly due to lower levels of Stat3 activation in response to TLR4 stimulation relative to pediatric cells. Stat3 functions as a negative regulator of the TLR4 responses in human AVICs. The results suggest that Stat3 activation (tyrosine phosphorylation) may be protective and that TLR4 inhibition could be targeted pharmacologically to treat calcific aortic valve disease. PMID- 25442997 TI - Heart valve culture and sequencing to identify the infective endocarditis pathogen in surgically treated patients. AB - BACKGROUND: Testing excised valves in surgically treated infective endocarditis (IE) patients provides an opportunity to identify the microbial etiology of IE. Microbial sequencing (universal bacterial, mycobacterial, or fungal polymerase chain reaction followed by DNA sequencing) of valves can identify microorganisms accurately, but the value it adds beyond information provided by blood and valve cultures has not been adequately explored. METHODS: Three hundred fifty-six patients who underwent surgery for active IE from January 1, 2010, to January 1, 2013, were identified from our cardiovascular information registry and outpatient parenteral antibiotic therapy registry. Their records were reviewed to identify 174 patients whose valves were sent for sequencing. The microbial etiology of IE was defined using comprehensive clinical, pathologic, and microbiological criteria. Blood culture, valve culture, and valve sequencing were examined to determine how frequently they identified the definitive cause of IE. RESULTS: Of the 174 patients, 162 (93%) had acute inflammation on histopathologic examination of their valves. Valve sequencing was significantly more sensitive than valve culture in identifying the causative pathogen (90% versus 31%, p < 0.001), and yielded fewer false positive results (3% versus 33%, p <0.001). The pathogen would not have been identified in 25 patients (15%) had it not been for valve sequencing. All the value provided by sequencing was attributable to bacterial DNA sequencing; mycobacterial and fungal sequencing provided no additional information beyond that provided by blood culture, histopathology, and valve culture. CONCLUSIONS: Valve sequencing, not valve culture, should be considered the primary test for identifying bacteria in excised cardiac valves. PMID- 25442998 TI - Roux-en-Y near esophagojejunostomy for failed antireflux operations: outcomes in more than 100 patients. AB - BACKGROUND: Intractable gastroesophageal reflux disease (GERD) after antireflux operations presents a challenge-particularly in obese patients and patients with esophageal dysmotility-and increases the complexity of the redo operation. This study evaluated the results of Roux-en-Y near esophagojejunostomy (RNYNEJ) in the management of recurrent GERD after antireflux operations. METHODS: We conducted a retrospective review of overweight patients with intractable GERD who underwent RNYNEJ for failed antireflux operations. We evaluated perioperative outcomes, dysphagia (ranging from 1 = no dysphagia to 5 = unable to swallow saliva), and quality of life (QOL) (assessed using the GERD health-related quality-of-life instrument (HRQOL). RESULTS: Over a 12-year period, 105 patients with body mass index (BMI) greater than 25 underwent RNYNEJ for failed antireflux operations. Most were obese (BMI > 30; 82 patients [78%]); esophageal dysmotility was demonstrated in more than one-third of patients. Forty-eight (46%) patients had multiple antireflux operations before RNYNEJ, and 27 patients had undergone a previous Collis gastroplasty. There was no perioperative mortality. Major complications, including anastomotic leak requiring surgical intervention (n = 3 [2.9%]), were noted in 25 patients (24%).The median length of stay was 6 days. During follow-up (mean, 23.39 months), median BMI decreased from 35 to 27.6 (p < 0.0001), and the mean dysphagia score decreased from 2.9 to 1.5 (p < 0.0001). The median GERD HRQOL score, assessed in a subset of patients, was 9 (classified as excellent). CONCLUSIONS: RNYNEJ for persistent GERD after antireflux operations in appropriately selected patients can be performed safely with good results in experienced centers. RNYNEJ should be considered an important option for the treatment of intractable recurrent symptoms after antireflux operations, particularly in obese patients. PMID- 25442999 TI - Differential outcomes with early and late repeat transplantation in the era of the lung allocation score. AB - BACKGROUND: Rates of repeat lung transplantation have increased since implementation of the lung allocation score (LAS). The purpose of this study is to compare survival between repeat (ReTx) and primary (LTx) lung transplant recipients in the LAS era. METHODS: We extracted data from 9,270 LTx and 456 ReTx recipients since LAS implementation, from the United Network for Organ Sharing registry. Propensity scoring was used to match ReTx and LTx recipients. Kaplan Meier analysis compared survival between LTx and ReTx groups, with and without stratification based on time between first and second transplant. Multivariable Cox models estimated predictors of survival in lung recipients. RESULTS: Comparing all ReTx to LTx demonstrates a survival advantage for LTx that is diminished with propensity score matching (p = 0.174). Considering LTx against ReTx greater than 90 days after the initial procedure, there are similar survival results (p < 0.067). In contrast, ReTx within 90 days was associated with a survival disadvantage that persisted despite matching (p = 0.011). In ReTx populations, factors conferring worse outcomes include intensive care unit admission, unilateral transplantation, poor functional status, and primary graft dysfunction as the indication for retransplantation (p < 0.05). CONCLUSIONS: Late lung retransplantation appears to be as beneficial as primary transplantation in propensity-matched patients. However, survival is severely diminished in those retransplanted less than 90 days after primary transplantation. The utility of early retransplantation needs to be carefully weighed in light of risks. PMID- 25443000 TI - The effect of prior pneumonectomy or lobectomy on subsequent lung transplantation. AB - BACKGROUND: Lung transplantation in patients with prior lobectomy or pneumonectomy is not well understood. Using the United Network for Organ Sharing (UNOS) database, we address the impact of prior major lung resection on lung transplantation outcomes. METHODS: Retrospective review of adult lung transplants from October 1999 to December 2011 in the UNOS database identified 15,300 lung transplants; 102 patients had undergone major lung resection, defined as prior pneumonectomy (n = 22) or lobectomy (n = 80). Propensity match with nonparametric 3:1 nearest-neighbor matching algorithm adjusted for treatment-level differences. After matching, the primary outcome (90-day mortality) and secondary outcome (airway dehiscence, need for dialysis, length of stay more than 25 days) were assessed with univariable and multivariable methods. Subanalysis of pneumonectomy and lobectomy individually compared with matched nonresection patients was done in a similar manner. The Kaplan-Meier method estimated long-term survival. RESULTS: After matching, no significant differences were noted between groups for recipient, donor, or operative characteristics. There were 10 double lung and 12 single lung transplants after pneumonectomy and 51 double lung and 29 single lung transplants after lobectomy. Mortality at 90 days was 13.9% (n = 14) for the resection group and 8.6% (n = 1,247) for the nonresection group (p = 0.09). After matching, a significant increase was noted in 90-day mortality (p = 0.017) and perioperative dialysis (p = 0.039) for the resection versus nonresection patients. Dialysis was significantly higher among pneumonectomy patients (p = 0.03). No long-term survival difference was observed (p = 0.514). CONCLUSIONS: After propensity-matching, resection was associated with increased 90-day mortality and dialysis. Careful patient selection is necessary with patients who have undergone prior major lung resection, given their increased risk of perioperative mortality and dialysis. PMID- 25443001 TI - Survival benefit of lung transplantation for chronic obstructive pulmonary disease in Sweden. AB - BACKGROUND: Lung transplantation (LTx) is a therapeutic option for patients with life-threatening chronic obstructive pulmonary disease (COPD) that is refractory to conventional therapies. The survival benefit of LTx for COPD is difficult to assess. The aim of this study was to evaluate the Swedish series of LTx performed to treat COPD and to identify differences in outcome between COPD related to severe alpha-1-antitrypsin deficiency (AATD) and COPD with normal alpha-1 antitrypsin (AAT) levels. METHODS: We retrospectively reviewed the data of 342 patients (128 AATD and 214 non-AATD) receiving lung transplants for end stage COPD from 1990 through 2012. RESULTS: The majority (71%) of patients received a single lung transplant. The median survival time after LTx for all COPD patients was 9 years (95% confidence interval [CI]: 8 to 10). Non-AATD recipients had a shorter survival time than AATD recipients, 6 years (95% CI: 5.0 to 8.8) versus 12 years (95% CI: 9.6 to 13.5, p = 0.000). Mortality was higher among non-AATD recipients after adjusting for age, pack-years of smoking, body mass index, oxygen therapy use, exercise capacity, donor age, cytomegalovirus mismatch, and transplant type (hazard ratio 1.70, 95% CI: 1.02 to 2.82). The 5-year and 10-year survival rates for the AATD recipients were 75% and 59%, respectively, compared with 60% and 31% for the non-AATD recipients. Early deaths were mainly due to cardio/cerebrovascular accidents and sepsis, and late deaths to bronchiolitis obliterans syndrome and pulmonary infections. CONCLUSIONS: Survival after LTx is significantly better for patients with severe AATD and end stage COPD than for the patients with COPD related to cigarette smoking. PMID- 25443002 TI - Outcomes of intraoperative venoarterial extracorporeal membrane oxygenation versus cardiopulmonary bypass during lung transplantation. AB - BACKGROUND: The intraoperative use of cardiopulmonary bypass (CPB) in lung transplantation has been associated with increased rates of pulmonary dysfunction and bleeding complications. More recently, extracorporeal membrane oxygenation (ECMO) has emerged as a valid alternative method of support and has been our preferred method of support since March 2012. We compared early and midterm outcomes of these 2 support methods. METHODS: Between July 2007 and April 2013, 271 consecutive patients underwent lung transplant using CPB (n = 222) or ECMO (n = 49). We retrospectively reviewed the outcomes of these patients requiring CPB or ECMO during lung transplant. RESULTS: The CPB and ECMO groups had comparable demographic and operative characteristics; however, the ECMO group had higher mean lung allocation scores (73 vs 52, p < 0.001). In the CPB group, more patients required reintubation (35.6% vs 20.4%, p = 0.04) or temporary tracheostomy (44.6% vs 28.6%, p = 0.05). Patients in the CPB group had a higher rate of renal failure requiring dialysis than the ECMO group (22.1% vs 8.2 %, p = 0.028). There were no differences in severe PGD requiring postoperative circulatory support (p = 0.83) or the need for perioperative red blood cell transfusions (p = 0.64) between the groups. No differences in 30-day (5% CPB vs 4.1% ECMO) or 6-month mortality (14.4% CPB vs 14.3% ECMO) were noted. CONCLUSIONS: The use of ECMO in lung transplant is safe and in our experience was associated with decreased rates of pulmonary and renal complications, as compared with CPB. Extracorporeal membrane oxygenation has become our preferred method of intraoperative support during lung transplantation. PMID- 25443003 TI - Predictors of mortality after surgical management of lung cancer in the National Cancer Database. AB - BACKGROUND: Surgical resection represents the standard of care for locoregionally confined non-small cell lung cancer (NSCLC); however, surgical complications may compromise the overall outcome. Adverse events after lung cancer surgery have been studied extensively, yet available databases have significant limitations (with respect to size, provider, patient age, and so forth). The National Cancer Database (NCDB) is the largest cancer registry in the world, capturing 67% of newly diagnosed NSCLC in the United States. We studied surgically managed NSCLC patients in the NCDB to more accurately assess factors that influence perioperative outcomes. METHODS: Patients diagnosed with NSCLC from 2004 to 2009 in the NCDB who were managed with surgical resection were included (n = 119,146). Primary endpoints included death within 30 days of surgery and extended length of stay (more than 14 days). RESULTS: Overall 30-day mortality rate was 3.4% and varied by procedure: lobectomy/bilobectomy (2.6%), wedge resection (4.2%), extended lobectomy/bilobectomy (4%), and pneumonectomy (8.5%). By multivariable analysis, increasing age, male sex, increasing comorbidities, and decreased facility volume were associated with higher 30-day mortality. Of patients who underwent lobectomy, 9.1% had an extended length of stay. On multivariable analysis, increasing age, male sex, increasing comorbidities, decreasing facility volume, and right-sided tumors were associated with increased incidence of extended length of stay. CONCLUSIONS: Adverse events after the surgical treatment of NSCLC in the NCDB occur with a similar frequency and are predicted by similar patient, procedural, and facility variables as have been identified by more restricted data resources. The NCDB appears to be a valuable resource to study NSCLC in the United States. PMID- 25443004 TI - Incidence and management of anastomotic complications after bronchial resection: a retrospective study. AB - BACKGROUND: Bronchial resection and reimplantation in surgical management of lung cancer is intended to spare lung parenchyma, with curative intent. We studied the incidence and management of anastomotic complications after such procedures. METHODS: We retrospectively reviewed charts of patients referred to our center for lung tumors who underwent bronchial resection and reimplantation from 1992 to 2011. RESULTS: A total of 108 patients were included. Sixty-eight percent were male, and mean age was 58 years. Sleeve lobectomies were performed in 100 patients, bronchial resections without lung parenchymal resection in 8 patients. Squamous cell carcinoma represented 46.3% of cases, carcinoid tumors 22.2%, and adenocarcinoma 18.5%. Mean time between surgery and first bronchoscopic examination was 4.47 days. During the follow-up, anastomotic abnormalities were detected in 23 patients (21.3%): malacic or fibrotic bronchial stenoses in 9 cases (39.1%), dehiscences in 7 (30.4%), obstructive granulomas in 4 (17.4%), and bronchopleural fistulas in 3 (13.0%). Endoscopic treatment was indicated in 14 patients (13%) and consisted of stent placement in 6 cases (26%), mechanical dilations in 3 (13%), laser treatment for 1 case of bronchomalacia (4.3%), and resection of granulomas in 4 (17.4%). No risk factors were identified as predisposing for bronchial complications. There was a trend toward lower 1-year survival in patients with bronchial complications compared with those without (71.9% versus 83.4%; p = 0.114). CONCLUSIONS: Bronchial resection and reimplantation is a surgical procedure associated with an anastomotic complication rate of 21.3%, but only 13% required endoscopic management. Regular endoscopic surveillance is advised to detect and treat early complications. PMID- 25443005 TI - Surgical treatment for synchronous primary lung adenocarcinomas. AB - BACKGROUND: Surgical treatment has become the mainstay of treatment for multiple primary lung cancers. In particular, the prevalence of synchronous primary lung adenocarcinomas (SPLA) has recently increased, but few studies have evaluated surgical outcomes of patients with SPLA. We reviewed the clinicopathologic features and surgical outcomes of SPLA to identify factors related to survival. METHODS: Data on 2,041 consecutive patients with primary non-small cell carcinoma who underwent surgical resection in our hospital from 1995 through 2009 were retrospectively analyzed. RESULTS: The SPLA was pathologically diagnosed in 93 patients, including 26 with bilateral tumors. The rates of overall survival and recurrence-free survival at 5 years were 87.0% and 81.8%, respectively. There was no surgical mortality at 30 days. On univariate analysis, lymph node metastasis (p = 0.0000), nonlepidic predominant histologic subtype (p = 0.0018), and a solid appearance of the largest tumor on computed tomography (p = 0.0088) were significantly related to poor overall survival. On multivariate analysis, bilateral distribution of tumors (p = 0.031), lymph node metastasis (p = 0.004), and sublobar resection (p = 0.042) were independent predictors of poor survival. CONCLUSIONS: Surgery has good outcomes and should be aggressively performed for patients with SPLA. The evaluation of lymph node status has an important role in deciding whether surgery is indicated. Bilateral tumors are a predictor of poor outcomes, requiring that caution be exercised. Lobectomy has a high cure rate and should be performed whenever possible. However, sublobar resection should be considered for patients likely to have poor residual lung function postoperatively. PMID- 25443006 TI - Nonintubated uniportal thoracoscopic surgery for peripheral lung nodules. AB - BACKGROUND: Uniportal video-assisted thoracoscopic surgery (VATS) has recently been introduced for various thoracic diseases. However, management of peripheral lung nodules by uniportal VATS without tracheal intubation has rarely been attempted. We evaluated the feasibility and safety of nonintubated uniportal VATS for peripheral lung nodules. METHODS: From January to March 2014, 32 patients with indeterminate peripheral lung nodules underwent uniportal VATS without tracheal intubation using a combination of intercostal nerve block, intrathoracic vagal block, and target-controlled sedation. Computed tomography-guided dye localization was sometimes used to identify small or ground-glass opacity lesions. RESULTS: A definite diagnosis was obtained in all 32 patients. A wedge resection was performed in 31 patients and a lobectomy in 1. Conversion to nonintubated multiport VATS was required in 4 patients (13%), in 3 because of primary lung cancer requiring further resection for adequacy of margins and in 1 because of difficulty in identifying a small nodule. Conversion to intubated 1 lung ventilation was required in 1 patient (3%) because of vigorous mediastinal movement. Operative complications developed in 2 patients who had air leaks for more than 3 days postoperatively. The median durations of postoperative chest tube drainage and hospital stay were 1 and 3 days, respectively. Postoperative neuralgia that required occasional use of analgesics occurred in only 1 patient (3%), and 97% of patients were very satisfied or satisfied with the resulting scars at 1 month. CONCLUSIONS: Nonintubated uniportal VATS is technically feasible and safe for selected patients and is a less invasive alternative in managing indeterminate peripheral lung nodules. PMID- 25443008 TI - Thoracic surgical resident education: a costly endeavor. AB - BACKGROUND: We sought to define an accurate measure of thoracic surgical education costs. METHODS: Program directors from six distinct and differently sized and geographically located thoracic surgical training programs used a common template to provide estimates of resident educational costs. These data were reviewed, clarifying questions or discrepancies when noted and using best estimates when exact data were unavailable. Subsequently, a composite of previously published cost-estimation products was used to capture accurate cost data. Data were then compiled and averaged to provide an accurate picture of all costs associated with thoracic surgical education. RESULTS: Before formal accounting was performed, the estimated average for all programs was approximately $250,000 per year per resident. However, when formal evaluations by the six programs were performed, the annual cost of resident education ranged from $330,000 to $667,000 per year per resident. The average cost of $483,000 per year was almost double the initial estimates. Variability was noted by region and size of program. Faculty teaching costs varied from $208,000 to $346,000 per year. Simulation costs ranged from $0 to $80,000 per year. Resident savings to program ranged from $0 to $135,000 per year and averaged $37,000 per year per resident. CONCLUSIONS: Thoracic surgical education costs are considerably higher than initial estimates from program directors and probably represent an unappreciated source of financial burden for cardiothoracic surgical educational programs. PMID- 25443007 TI - Staple line coverage after bullectomy for primary spontaneous pneumothorax: a randomized trial. AB - BACKGROUND: Thoracoscopic wedge resection is generally accepted as a standard surgical procedure for primary spontaneous pneumothorax. Because of the relatively high recurrence rate after surgery, additional procedures such as mechanical pleurodesis or visceral pleural coverage are usually applied to minimize recurrence, although mechanical pleurodesis has some potential disadvantages. The aim of this study was to clarify whether an additional coverage procedure on the staple line after thoracoscopic bullectomy prevents postoperative recurrence compared with additional pleurodesis. METHODS: A total of 1,414 patients in 11 hospitals with primary spontaneous pneumothorax undergoing thoracoscopic bullectomy were enrolled. After bullectomy with staplers, patients were randomly assigned to either the coverage group (n = 757) or the pleurodesis group (n = 657). In the coverage group, the staple line was covered with absorbable cellulose mesh and fibrin glue. The pleurodesis group underwent additional mechanical abrasion on the parietal pleura. RESULTS: The coverage group and the pleurodesis group showed comparable surgical outcomes. After a median follow-up of 19.5 months, the postoperative 1-year recurrence rate was 9.5% in the coverage group and 10.7% in the pleurodesis group. The 1-year recurrence rate requiring intervention was 5.8% in the coverage group and 7.8% in the pleurodesis group. The coverage group showed better recovery from pain. CONCLUSIONS: In terms of postoperative recurrence rate, visceral pleural coverage after thoracoscopic bullectomy was not inferior to mechanical pleurodesis. Visceral pleural coverage may potentially replace mechanical pleurodesis, which has potential disadvantages such as disturbed normal pleural physiology. PMID- 25443010 TI - Early experiences with a new three-dimensional annuloplasty ring for the treatment of functional tricuspid regurgitation. AB - BACKGROUND: Various techniques and devices have been proposed for tricuspid valve (TV) repair in patients with tricuspid regurgitation (TR). However, residual or recurrent TR is not uncommon occurring in 20% to 30% of patients. This study reports first experiences with a new three-dimensional annuloplasty ring. METHODS: We retrospectively reviewed 200 consecutive patients who underwent TV repair for functional TR with the Contour 3D annuloplasty ring (Medtronic, Minneapolis, MN) from December 2010 to February 2013 at our institution. The follow-up is 98% complete (mean 1.0 +/- 0.7 years; cumulative total 189 patient years). RESULTS: Mean age was 70.4 +/- 9.1 years and the median logistic European system for cardiac operative risk was 7%. Sixty-nine percent of the patients were in New York Heart Association class III/IV. Echocardiography documented moderate or severe TR in 97.5% of the patients, with a mean annulus diameter of 45.1 +/- 4.9 mm; 93.5% of the patients underwent a combined procedure, and 20.5% an urgent or emergent operation. The 30-day mortality was 6%. The preoperative TR grade was reduced from 2.45 +/- 0.53 to 0.77 +/- 0.54 (p < 0.001). At hospital discharge residual II TR or greater was present in 4.3% of the patients. Freedom from recurrent II TR or greater at 2 years was 90.9% +/- 4.2% and freedom from TV related reoperations at 2 years was 98.5% +/- 1.0%. No case of ring dehiscence occurred. Fourteen patients (7%) required a permanent pacemaker implantation for atrioventricular block. CONCLUSIONS: Tricuspid valve repair with the Contour 3D annuloplasty ring can be performed with a low rate of residual TR at hospital discharge, a low reoperation rate, and with an excellent early functional outcome. PMID- 25443009 TI - The association of transcatheter aortic valve replacement availability and hospital aortic valve replacement volume and mortality in the United States. AB - BACKGROUND: Whether the introduction of transcatheter aortic valve replacement (TAVR) has affected hospitals' surgical aortic valve replacement (SAVR) and overall aortic valve replacement (AVR) case volumes and outcomes in the United States is unknown. METHODS: We utilized data from The Society of Thoracic Surgeons (STS) adult cardiac surgery database and the STS/American College of Cardiology (ACC) transcatheter valve therapies registry to examine SAVR and TAVR procedures. Temporal trends in total case volume (SAVR plus TAVR), and observed and risk-adjusted in-hospital mortality rates were assessed among low-risk cases (STS predicted risk of operative mortality < 4%), intermediate-risk cases (4% to 8%), and high-risk cases (> 8%). A contemporary control was provided by non-TAVR centers. RESULTS: From 2008 to 2013, the total annual volume of AVR among 246 TAVR-performing hospitals increased from 19,578 to 33,004, with a 22% growth in SAVR volumes; non-TAVR hospital (n = 555) increases were more modest (16,563 to 19,134; 16% growth). Expanded volumes at TAVR hospitals included increased SAVR use in low- and intermediate-risk cases, and TAVR use in high-risk cases. In parallel, in-hospital mortality for all AVR procedures at TAVR sites declined from 3.4% to 2.9% (observed to expected [O:E] ratio 0.75 to 0.58, p < 0.001); the greatest declines were among intermediate- and high-risk SAVR patients. Owing to reduced SAVR mortality, TAVR centers experienced a significantly greater decline in O:E ratio for high-risk patient in-hospital mortality than non-TAVR centers (TAVR center O:E ratio, 0.81 to 0.61; non-TAVR center O:E ratio, 0.85 to 0.76; p < 0.001). After approval of TAVR for clinical use, a trend toward higher in hospital mortality rates and O:E ratios for TAVR procedures was observed at new (but not at established) TAVR centers (O:E ratio, 0.41 to 0.67; p = 0.08). CONCLUSIONS: Since the introduction of TAVR, the total volume of AVR procedures, including higher overall use of SAVR, at TAVR sites has significantly increased in the United States. Overall, in-hospital survival of patients undergoing treatment for aortic valve stenosis continues to improve. PMID- 25443011 TI - The association of chronic lung disease with early mortality and respiratory adverse events after aortic valve replacement. AB - BACKGROUND: We studied the association between components of chronic lung disease (CLD) assessment and operative outcomes in patients undergoing aortic valve replacement (AVR) for aortic stenosis. METHODS: From 2011 to 2012, 9,177 patients included in The Society of Thoracic Surgeons (STS) Cardiac Surgery Database underwent AVR for aortic stenosis with complete pulmonary function tests (PFT) and CLD data (31% of AVRs). We evaluated markers of CLD and their association with operative mortality, pulmonary morbidity, and length of hospital stay using multivariable logistic regression analysis. RESULTS: In a selected population of AVR patients with PFTs, CLD was prevalent in 50% (mild, 25.6%; moderate, 13.2%; severe, 11.2%). Predicted forced expiratory volume in 1 second (FEV1) was obtained in all patients and diffusion capacity of the lung for carbon monoxide (DLCO), arterial oxygen tension (PaO2), and arterial carbon dioxide tension (PaCO2) in 31%. The STS predicted risk of operative mortality, mortality, pulmonary morbidity, and hospital stay increased with severity of CLD and with low FEV1, DLCO, and PaO2. Moderate and severe CLD were independently associated with operative mortality (odds ratio [OR] 2.88, 95% confidence interval [CI]: 2.0 4.5), pulmonary morbidity (OR 2.33, 95% CI: 1.93-2.8), and prolonged hospital stay (OR 2.73, 95% CI: 2.17-3.45). Low FEV1 was independently associated with pulmonary morbidity and prolonged hospital stay. Low PaO2 and DLCO were independently associated with a combined mortality and pulmonary morbidity endpoint. CONCLUSIONS: CLD is associated with adverse operative outcomes in selected patients with aortic stenosis undergoing AVR. FEV1, DLCO, and PaO2 may add important information to current risk adjustment models beyond the broad CLD classification. PMID- 25443012 TI - Experimental evaluation of complete endovascular arch reconstruction by in situ retrograde fenestration. AB - BACKGROUND: The aim of this experimental study was to assess the feasibility of complete endovascular arch reconstruction by in situ retrograde fenestration and to investigate the impact of stent-graft material on stent-graft fenestrations. METHODS: The experiments were performed using 8 cadaveric human thoracic aortas (aortic arch) using 2 different stent-graft types: woven polyester (Valiant Captivia; Medtronic Vascular, Santa Rosa, CA) and expanded polytetrafluoroethylene (conformable [C]-TAG; W.L. Gore & Associates, Flagstaff, AZ). A benchtop aortic pulsatile flow model was used. Stent-grafts were deployed into the aortic arch, covering the ostia of the supraaortic trunks. A 5-mm 30 degree angioscope was introduced into the ascending aorta to monitor the procedure. Retrograde fenestration and deployment of the balloon expandable stent graft was performed sequentially for each supraaortic trunk. Subsequent to stent graft explantation, macroscopic evaluation of each fenestration was performed. RESULTS: All attempts to fenestrate the C-TAG and Valiant stent-grafts and implant the covered stent through the supraaortic trunks were successful. In all cases, branch stents were patent and no endoleak was evident. The Valiant stent graft was easier to puncture because of the higher radial force of the stent graft providing better counterpressure; however, stent-graft material had no impact on the quality of fenestrations. CONCLUSIONS: Total endovascular repair of the aortic arch through in situ retrograde fenestration of stent-grafts is feasible. The behavior of the 2 types of stent-graft was significantly different while the fenestrations were fashioned, but stent-graft material had no impact on the quality of fenestrations. PMID- 25443013 TI - Evaluation of the organ care system in heart transplantation with an adverse donor/recipient profile. AB - BACKGROUND: A severe shortage of available donor organs has created an impetus to use extended criteria organs for heart transplantation. Although such attempts increase donor organ availability, they may result in an adverse donor-recipient risk profile. The TransMedics Organ Care System (OCS) (TransMedics, Inc, Boston) allows preservation of the donor heart by perfusing the organ at 34 degrees C in a beating state, potentially reducing the detrimental effect of cold storage and providing additional assessment options. We describe a single-center experience with the OCS in high-risk heart transplant procedures. METHODS: Thirty hearts were preserved using the OCS between February 2013 and January 2014, 26 of which (86.7%) were transplanted. Procedures were classified as high risk based on (1) donor factors, ie, transport time more than 2.5 hours with estimated ischemic time longer than 4 hours, left ventricular ejection fraction (LVEF) less than 50%, left ventricular hypertrophy (LVH), donor cardiac arrest, alcohol/drug abuse, coronary artery disease or (2) recipient factors, ie, mechanical circulatory support or elevated pulmonary vascular resistance (PVR), or both. RESULTS: Donor and recipient age was 37 +/- 12 years and 43 +/- 13 years, respectively. Allograft cold ischemia time was 85 +/- 17 minutes and OCS perfusion time was 284 +/- 90 minutes. The median intensive care unit stay was 6 days. One death (3.8%) was observed over the follow-up: 257 +/- 116 (109-445 days). There was preserved allograft function in 92% of patients, with a mean LVEF of 64% +/- 5%. CONCLUSIONS: Use of the OCS is associated with markedly improved short-term outcomes and transplant activity by allowing use of organs previously not considered suitable for transplantation or selection of higher risk recipients, or both. PMID- 25443014 TI - Characterizing cardiac donation after circulatory death: implications for perfusion preservation. AB - BACKGROUND: Donation after circulatory determination of death (DCDD) involves variable definitions of death among hospitals, and DCDD hearts are not generally considered for transplantation. The definition can affect ischemic times, and machine perfusion preservation appears promising for recovery of DCDD hearts. The purpose of the current study was to investigate the agonal phase of DCDD donors and evaluate retrograde perfusion preservation of DCDD donor hearts in a large animal model of cardiac transplantation. METHODS: Ten canines were anesthetized and then disconnected from mechanical ventilation. Time to loss of pulse (systolic blood pressure <50 mm Hg), loss of pressure, and asystole or fibrillation were recorded. Five minutes after asystole, hearts were exposed and arrested with 1 L of University of Wisconsin Machine Perfusion Solution. Eight hearts were cold preserved for 4 hours by retrograde machine perfusion or static storage (n = 4/group), then reimplanted and reperfused for 6 hours. The preload recruitable stroke work was used to measure myocardial function. RESULTS: The agonal phase was similar between groups. Loss of pulse and pressure were consistent between animals (7.9 +/- 0.5 minutes [range, 5 to 11 minutes], 10.2 +/ 0.4 minutes [range, 9 to 13 minutes], respectively). Electrical silence was variable at 26.9 +/- 3.8 minutes (range, 11 to 43 minutes). All perfused hearts separated and remained off cardiopulmonary bypass. Three of four static hearts initially separated from cardiopulmonary bypass, but two returned by the end of the reperfusion period. The preload recruitable stroke work was significantly higher in perfused hearts. CONCLUSIONS: Protocols for DCDD have implications on ischemic times of donor hearts. Machine perfusion preservation can recover DCDD hearts more consistently than static storage. PMID- 25443015 TI - Cardiac transplantation for radiation-induced cardiomyopathy: the Mayo Clinic experience. AB - BACKGROUND: High-dose radiotherapy to the mediastinum for the treatment of malignancies causes injury to the intrathoracic organs. Coronary artery disease, valvular dysfunction, cardiomyopathy, and chronic constrictive pericarditis are common cardiovascular sequelae during long-term follow-up. Cardiac transplantation is indicated for the surgical treatment of heart failure due to radiation-induced end-stage cardiac disease. METHODS: A retrospective study of radiation-induced cardiomyopathy requiring cardiac transplantation was undertaken from December 1992 to August 2010. RESULTS: Twelve patients (7 men, 5 women), with a mean age of 47.4 years, underwent orthotopic cardiac transplantation. Redo cardiac operations were performed in 9 patients. Lymphoma was the primary malignancy in all patients. Adjuvant chemotherapy was used in 9 patients, and splenectomy was performed in 7. Restrictive cardiomyopathy (n = 8) was the predominant diagnosis. Restrictive lung disease was present in 10 patients (83%). Postoperative chronic kidney injury developed in 3 patients (25%). Hospital mortality was 8.3%. Survival at 1, 5, and 10 years was 91.7%, 75%, and 46.7%, respectively. The overall mean follow-up was 7.7 years (median, 6.1; range, 1.8 to 16.4 years). Late respiratory failure accounted for 3 deaths. CONCLUSIONS: Cardiac transplantation provides satisfactory medium-term to long-term outcome in patients with radiation-induced cardiomyopathy. Secondary malignancies, kidney injury, and respiratory failure contribute to significant postoperative morbidity and death. PMID- 25443016 TI - Durable ventricular assist device support for failing systemic morphologic right ventricle: early results. AB - BACKGROUND: The systemic morphologic right ventricle (RV) in congenitally corrected transposition of the great arteries or after atrial switch for transposition of the great arteries is associated with late ventricular failure. Although the role of the left ventricular assist device (LVAD) in supporting the failing LV is established, the indications and outcomes of using LVAD in a systemic RV remain unclear. We assessed the role of a third-generation LVAD for systemic RV support. METHODS: Seven patients (mean age, 36 years) received the HeartWare (HeartWare International Inc, Framingham, MA) VAD for systemic RV failure (congenitally corrected transposition of the great arteries in 1 and after atrial switch in 6). Four patients (57%) had severe subpulmonic LV failure, and aggressive perioperative diuresis with or without hemofiltration was used to offload the subpulmonic LV. The indications of VAD were (1) bridge to transplant in 3 and (2) bridge to decision for a high transpulmonary gradient in 4. Transplantation outcome was compared with systemic RV failure without VAD bridge in 19 patients (years 1989 to 2013). RESULTS: Systemic RV support alone was achieved in all patients, with no early deaths (<=30 days). Overall, 6 (86%) returned home, 3 (44%) received a transplant, 2 (28%) died of noncardiac causes, and 2 (28%) continue on VAD support (median support, 232 days). Repeat catheterization (n = 4) showed an improved median transpulmonary gradient in 3 patients (median 18.5 mm Hg pre-VAD vs 8.0 mm Hg post-VAD). Two bridge-to decision patients received transplants at 640 and 685 days. The stroke rate on VAD support was 43% (2 thromboembolic and 1 hemorrhagic; 3 with satisfactory recovery). De novo aortic regurgitation was 29% (n = 2; 1 valve replacement). All patients (n = 3) survived transplantation (vs 10.5% early mortality without VAD bridge; p = 1.00) and were well at follow-up (range, 53 to 700 days). CONCLUSIONS: The third-generation VAD provides durable support for systemic RV failure as a bridge to transplant and as a strategy to reduce pulmonary vascular resistance. Although concomitant subpulmonic LV failure is common, systemic RV support alone was achieved in all patients. PMID- 25443017 TI - Induced pluripotent stem cell transplantation in the treatment of porcine chronic myocardial ischemia. AB - BACKGROUND: This study was designed to test the effects of induced pluripotent stem cell (iPSC) in the treatment of chronic myocardial ischemia. METHODS: The reprogramming of passage 3 myocardial fibroblasts was performed by using the lentiviral vector containing 4 human factors: OCT4, SOX2, KLF4, and c-MYC. The iPSC colonies at P12-17 were allogeneically transplanted into ischemic myocardium of 10 swine by direct injection. Cohorts of 2 animals were sacrificed at 2, 4, 6, 8, and 12 weeks after injection. RESULTS: No signs of graft versus host disease were evident at any time points. At 2 weeks, clusters of SSEA-4-positive iPSCs were detected in the injected area. At 4 to 8 weeks, these cells started to proliferate into small spheres surrounded by thin capsules. At 12 weeks the cell clusters still existed, but decreased in size and numbers. The cells inside these masses were homogeneous with no sign of differentiation into any specific lineage. Increased smooth muscle actin or vWF positive cells were found inside and around the iPSC clusters, compared with non-injected areas. By real-time polymerase chain reaction, the levels of VEGF, basic FGF, and ANRT expression were significantly higher in the iPSC-treated myocardium compared with untreated areas. These results suggest that iPSCs contributed to angiogenesis. CONCLUSIONS: Allogeneically transplanted pig iPSCs proliferated despite an ischemic environment in the first 2 months and survived for at least 3 months in immunocompetent hosts. Transplanted iPSCs were also proangiogenic and thus might have beneficial effects on the ischemic heart diseases. PMID- 25443019 TI - Pediatric recipient survival beyond 15 post-heart transplant years: a single center experience. AB - BACKGROUND: We evaluated late survival among pediatric heart transplant patients who have lived more than 15 years. METHODS: This is a retrospective chart review of the pediatric patients who underwent heart transplantation (HTx) between 1985 and 1998. Multivariate and univariate analyses were examined. RESULTS: There were 183 recipients, of whom 151 are currently alive. Age at HTx ranged from 0 days to 17.48 years (median 56 days). Pretransplant diagnoses included congenital heart disease 142 (77.6%), cardiomyopathy 38 (20.8%), and tumor 3 (1.6%). Pretransplant renal dysfunction was present in 58 patients (31.7%). Perioperative peritoneal dialysis was instituted in 15 patients, all recovered. During the follow-up period (median 20.2 years), 17 (9.3%) have had renal transplants, and 2 require hemodialysis. There were 32 deaths from the following: cardiac allograft vasculopathy (CAV); 11 (34.3%); posttransplant lymphoproliferative disease 6 (18.8%); acute rejection 4 (12.5%); sepsis 2 (6.3%); multiorgan failure 1 (3.1%); and unknown 8 (25%). Immunosuppressive therapy for the living patients consists of monotherapy 25 (17.7%), dual therapy 87 (61.7%), triple therapy 24 (17%), quadruple therapy 5 (3.5%), and 10 unknown. Cardiac re-Tx was required for CAV in 30 patients and for graft failure in 6 patients. Four patients required a third transplant for CAV. For those who survived more than 15 years after HTx, actuarial survival to 20 years and 25 years is 82% and 78%, respectively. CONCLUSIONS: Pediatric HTx provides acceptable long-term survival. Cardiac re-Tx and renal transplantation offer reasonable palliation for recipients who develop CAV and renal dysfunction. PMID- 25443018 TI - Epidemiology and outcomes after in-hospital cardiac arrest after pediatric cardiac surgery. AB - BACKGROUND: Multicenter data regarding cardiac arrest in children undergoing heart operations are limited. We describe epidemiology and outcomes associated with postoperative cardiac arrest in a large multiinstitutional cohort. METHODS: Patients younger than 18 years in the Society of Thoracic Surgeons Congenital Heart Surgery Database (2007 through 2012) were included. Patient factors, operative characteristics, and outcomes were described for patients with and without postoperative cardiac arrest. Multivariable models were used to evaluate the association of center volume with cardiac arrest rate and mortality after cardiac arrest, adjusting for patient and procedural factors. RESULTS: Of 70,270 patients (97 centers), 1,843 (2.6%) had postoperative cardiac arrest. Younger age, lower weight, and presence of preoperative morbidities (all p < 0.0001) were associated with cardiac arrest. Arrest rate increased with procedural complexity across common benchmark operations, ranging from 0.7% (ventricular septal defect repair) to 12.7% (Norwood operation). Cardiac arrest was associated with significant mortality risk across procedures, ranging from 15.4% to 62.3% (all p < 0.0001). In multivariable analysis, arrest rate was not associated with center volume (odds ratio, 1.06; 95% confidence interval, 0.71 to 1.57 in low- versus high-volume centers). However, mortality after cardiac arrest was higher in low volume centers (odds ratio, 2.00; 95% confidence interval, 1.52 to 2.63). This association was present for both high- and low-complexity operations. CONCLUSIONS: Cardiac arrest carries a significant mortality risk across the stratum of procedural complexity. Although arrest rates are not associated with center volume, lower-volume centers have increased mortality after cardiac arrest. Further study of mechanisms to prevent cardiac arrest and to reduce mortality in those with an arrest is warranted. PMID- 25443020 TI - Twenty-four hour in-hospital congenital cardiac surgical coverage improves perioperative ECMO support outcomes. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) support is often required in the management of perioperative congenital heart surgery (CHS) patients. However, 24-hour in-hospital congenital cardiac surgical coverage (24-CCSC) is not available at all institutions. The purpose of this study is to evaluate the effect of 24-CCSC on perioperative ECMO outcomes in CHS patients. METHODS: An institutional review board approved, retrospective review of 128 perioperative CHS ECMO patients at a single, quaternary care children's hospital between January 2003 and December 2012 was performed. Primary endpoints evaluated were mortality in children supported with ECMO after undergoing cardiac surgery and ECMO-related morbidity after initiation of 24-CCSC with advanced congenital cardiac surgical fellows. Patients were divided into 2 groups based on whether 24 CCSC was absent (cohort 1: January 2003 to July 2007) or present (cohort 2: August 2007 to December 2012) at the time of ECMO management. RESULTS: The surgical procedures performed were similar in both cohorts based on STAT Mortality Categories (5 Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Mortality Categories). The overall mortality rate in children supported with ECMO after undergoing cardiac surgery was 53%. This mortality was significantly reduced from 68% to 43% (p = 0.007) with 24-CCSC. Multivariate logistic regression analysis revealed that 24 CCSC (p = 0.009) and lower STAT Mortality Category (p = 0.042) were independent predictors of operative survival. Cardiac arrhythmias (36% to 16%; p = 0.012) and pulmonary complications (32% to 8%; p < 0.001) were significantly reduced with 24 CCSC. CONCLUSIONS: The presence of 24-CCSC significantly decreased the rate of mortality in children supported with ECMO after undergoing cardiac surgery, as well as cardiac arrhythmias and pulmonary complications for perioperative CHS patients receiving ECMO support. This study demonstrates that CHS programs would benefit from 24-CCSC in the care of this critically ill patient population. PMID- 25443021 TI - Association of center volume with outcomes: analysis of verified data of European Association for Cardio-Thoracic Surgery Congenital Database. AB - BACKGROUND: The relation between surgical volumes and outcome in congenital heart surgery (CHS) was investigated with no clear conclusions. We sought to quantify the relationship between surgical volume and surgical performance defined as the relation between outcome and Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery Congenital Heart Surgery (STAT) Mortality Score and The Society of Thoracic Surgeons (STS) Morbidity Score. METHODS: We have used only the verified data of the European Association for Cardio-Thoracic Surgery Congenital Database. The verified dataset consists of 17,861 procedures performed in 23 congenital heart surgery centers between 2003 and 2011. The centers were divided into 4 volume-related groups with annual caseload of below 150, 150 to 250, 250 to 350, and over 350. Stepwise logistic regression was used to calculate the ratio between volume and mortality, as well as between volume and onset of complications. The relations between volume and STAT Mortality Score, and STS Morbidity Score were evaluated using the analysis of variance test. The performance was calculated as the following: 100 - observed mortality/STAT Mortality Score; and 100 - observed complications/STS Morbidity Score. RESULTS: The study showed no relation between volume and raw mortality (p = 0.94) and between volume and complications (p = 0.6). The STAT Mortality Score and STS Morbidity Score were higher in larger volume centers (p < 0.001). Surgical performances measured as related to mortality and morbidity were higher at high volume centers (R(2) = 0.95 and R(2) = 0.92). CONCLUSIONS: Our analysis suggests that after adjustment for case mix higher programmatic volume is associated with lower rates of mortality and morbidity. The small- and medium-volume centers have higher rates of major complications. When complications occurred the chance of rescue is higher in large-volume centers. PMID- 25443022 TI - Early primary repair of tetralogy of Fallot does not lead to increased postoperative resource utilization. AB - BACKGROUND: Although early primary repair of tetralogy of Fallot has gained wider acceptance, there is some speculation that repair at a younger age may be associated with increased morbidity and resource utilization. METHODS: A retrospective review of all consecutive patients undergoing tetralogy of Fallot repair between September 2004 and December 2011 was performed. Primary end points were hospital charges, and surrogates of postoperative hospital resource utilization, including ventilation time, intensive care unit (ICU) stay, and hospital stay. The secondary end point was operative death. Logistic regression analysis was used to determine factors associated with increased postoperative hospital resource utilization. RESULTS: Among 164 patients in the study, there was 1 hospital death (0.6%). After excluding 9 patients who had palliative procedures before their repair, 155 comprised the primary repair group. Multivariate linear regression analysis revealed prematurity (p = 0.018), a nonelective operation (p < 0.001), and major extracardiac anomalies (p = 0.003) were independent predictors of increased postoperative hospital charges. Prematurity (p < 0.002), low birth weight (p = 0.047), and major extracardiac anomalies (p < 0.001) were significant predictors of increased ventilation time. Prematurity (p < 0.001), a nonelective operation (p < 0.001), and low birth weight (p = 0.048) significantly increased ICU length of stay. A nonelective operation (p = 0.025) and major extracardiac anomalies (p < 0.001) were predictors of an increased hospital stay. Younger age at repair was not associated with any increase in ventilation time, ICU stay, hospital stay, or with an increase in hospital charges. CONCLUSIONS: Extracardiac anomalies, prematurity, low birth weight, and nonelective surgical intervention are predictors of increased morbidity and increased hospital resource utilization and impose a significant cost burden to the care of these patients. Early primary repair of tetralogy of Fallot can be safely performed without any increase in morbidity or increased hospital resource utilization. PMID- 25443024 TI - Impact of bilateral superior venae cavae on outcome of staged Fontan procedure. AB - BACKGROUND: The presence of bilateral superior venae cavae may add complexity to the performance of a bidirectional Glenn procedure (BDG). Stagnation of blood flow between the two cavopulmonary anastomoses may increase the risk of thrombosis and impair central pulmonary artery growth. METHODS: Forty patients underwent BDG from January 2004 to April 2011. The cohort was divided into two groups: those receiving bilateral BDG (b-BDG, n = 13) and those receiving unilateral BDG (u-BDG, n = 27). Operative, angiographic, and follow-up data were analyzed retrospectively. RESULTS: None of the patients experienced thrombosis. There was no difference in actuarial survival rate (u-BDG vs b-BDG, 100% vs 92% at 5 years, p = 0.15). On follow-up angiography, no difference in central pulmonary artery index was noted (78.4 +/- 45.5 vs 60.4 +/- 32.1, p = 0.24). Central pulmonary artery stenosis was detected in 6 patients (4 with u-BDG and 2 with b-BDG), 4 of whom (2 from each group) underwent balloon pulmonary artery plasty before the Fontan procedure. There was no difference in freedom from reintervention for central pulmonary artery stenosis (93% vs 85% at 1 year, p = 0.59). The rate of Fontan completion was comparable between groups, with similar operative variables and satisfactory outcomes. CONCLUSIONS: Bilateral BDG did not increase the risks of thrombosis and central pulmonary artery hypoplasia and can be performed safely without altering the outcome of the Fontan procedure. PMID- 25443023 TI - The modified Fontan procedure with use of extracardiac conduit in adults: analysis of 32 consecutive patients. AB - BACKGROUND: Uncommonly, adults with functionally univentricular hearts are becoming candidates for a Fontan procedure. The purpose of this study was to evaluate the course of patients undergoing the modified Fontan procedure with an extracardiac conduit in recent years. METHODS: Between January 2003 and December 2013, 32 adult patients (17 female and 15 male) underwent total cavopulmonary connection (TCPC) with extracardiac conduit. The median age at procedure was 24.5 years (interquartile range [IQR] 20 to 33 years). The diagnoses included double inlet left ventricle (DILV) in 10 patients (31.2%), tricuspid atresia in 8 patients (25%), double-outlet right ventricle in 4 patients (12.5%), heterotaxia in 4 patients (12.5%), and mitral atresia in 2 patients (6.2%). Seventy-eight percent of patients had undergone at least one prior palliative procedure; the most common procedures were Blalock-Taussig shunt (16 patients), superior cavopulmonary shunt (12 patients), and pulmonary artery banding (6 patients). All patients underwent cardiac catheterization preoperatively. Aortic cross-clamping was necessary in 15 patients for intracardiac procedures. Fenestration was required in 9 patients (28%). Four concomitant intraoperative cryoablation procedures were performed. RESULTS: There was no hospital mortality. One patient (3.1%) died 6 months after undergoing TCPC. Morbidities included prolonged pleural effusion lasting more than 7 days in 20 patients (62.5%), atrial arrhythmias in 4 patients (12.5%), and permanent pacemakers in 3 patients (9.3%). The median follow-up time was 33 months (interquartile range [IQR], 10.5 to 50 months). Actuarial survival was 91.83% (95% confidence limits, 71.07 to 97.89) at 1 year and 5 years. Ninety-two percent of patients were in New York Heart Association class I or II at follow-up. The median postoperative oxygen saturation was 95% (IQR, 93% to 95.5%). Cardiac arrhythmia occurred in 4 patients. Systolic ventricular function improved during follow-up for all patients except 1 patient, who underwent cardiac transplantation 7 months after the TCPC. CONCLUSIONS: The modified Fontan procedure with use of an extracardiac conduit can be performed in adults with encouraging early and midterm results. The majority of late survivors had improved quality of life. The incidence of late death, reoperation, arrhythmias, and thromboembolic events was low during follow-up. PMID- 25443025 TI - Technical issues in the use of the radial artery as a coronary artery bypass conduit. AB - The clinical and angiographic benefits related to the use of the radial artery (RA) as a bypass conduit have extensively been proven. However, due to its morpho functional features and its anatomic position, successful use of the RA requires careful consideration of several technical issues. We herein summarize the current evidence on all the technical aspects related to the RA use in coronary surgery such as the preoperative evaluation of ulnar compensation, the different means of intraoperative vasodilatation, and the various harvesting techniques. PMID- 25443026 TI - Ring or suture annuloplasty for tricuspid regurgitation? A meta-analysis review. AB - We performed a meta-analysis of early and long-term outcomes after tricuspid repair to compare the results of suture-based and prosthetic ring annuloplasty with the employment of an algorithm that derives the original patient time-to event data. There was an advantage in early but not in long-term survival with the use of the annuloplasty ring. The freedom from moderate tricuspid regurgitation was significantly better in patients with ring annuloplasty (78.9% +/- 5.0% at 15 years vs 60.0% +/- 4.2%, log-rank p = 0.0107). The ring annuloplasty is associated to better outcomes, being a protective factor for early mortality and long-term recurrence of tricuspid regurgitation after surgery. PMID- 25443027 TI - Peer review at the Health Information and Libraries Journal. AB - At its best, peer review can mean receiving constructive feedback to help you make the most of your writing. At the Health Information and Libraries Journal, we strive to make the peer review a positive process for both authors and referees. We adopt a process of double-blind peer review. To receive two reviews in a timely manner, three referees are initially invited for each article submitted. The referees are asked to submit their review noting errors, areas of ambiguity or clarification required before the editor and editorial team consider the manuscript ready for publication. As with most journals, it's unlikely that your writing will be accepted in its original form; a typical outcome will be for a recommendation for major or minor revisions. This is good! It means the editorial team has seen something of likely interest to their readership and wants to help you develop it to a publishable standard. There can be a surprising amount of development and change in a manuscript from original submission through to publication. While you may be experienced in your field, you may not have much experience of writing for publication. As a referee, you get an intriguing insight into the shape of manuscripts in their original form. PMID- 25443028 TI - An investigation into the feasibility of designing a framework for the quantitative evaluation of the Clinical Librarian service at an NHS Trust in Brighton, UK. AB - This feature presents research undertaken by Archana Deshmukh for her MA dissertation at the University of Brighton. She worked closely with Tom Roper, the Clinical Librarian at Brighton and Sussex University Hospitals NHS Trust, in a project to explore the feasibility of applying quantitative measures to evaluate the Clinical Librarian service. The investigation used an innovative participatory approach and the findings showed that although an exclusively quantitative approach to evaluation is not feasible, using a mixed methods approach is a way forward. Agreed outputs and outcomes could be embedded in a marketing plan, and the resulting framework could provide evidence to demonstrate overall impact. Archana graduated in July 2014, gaining a Distinction in the MA in Information Studies, and she is currently looking for work in the health information sector. PMID- 25443029 TI - International trends in health science librarianship part 12: South Asia (India, Pakistan and Sri Lanka). AB - This is the 12th in a series of articles exploring international trends in health science librarianship. This issue describes developments in health science librarianship in the first decade of the 21st century in South Asia. The three contributors report on challenges facing health science librarians in India, Pakistan and Sri Lanka. There is consensus as to the need for education, training and professional development. Starting in the next issue, the focus will turn to Africa, starting with countries in southern Africa. JM. PMID- 25443030 TI - The information experience and learning needs of couples living with HIV in Malawi. AB - In this feature, guest writer Kondwani Wella presents an overview of his PhD - a study which investigated the information experience of serodiscordant couples with HIV and AIDS in Malawi. In particular, for this article, he considers the information behaviour of people who need HIV- and AIDS-specific information and the role of the librarian in helping to deliver what is needed to support engagement in relevant learning. H.S. PMID- 25443031 TI - [Diabetic foot: what is the most appropriate therapeutic approach?]. PMID- 25443033 TI - Death from AIDS is preventable, so why are people still dying of AIDS in Europe? PMID- 25443034 TI - Ten years after Dublin: principal trends in HIV surveillance in the EU/EEA, 2004 to 2013. AB - In 2004, the 31 countries of the European Union and European Economic Area (EU/EEA) adopted the Dublin Declaration on Partnership to Fight HIV/AIDS in Europe and Central Asia. In 2013, 29,157 persons were diagnosed with HIV in 30 EU/EEA countries (adjusted rate: 6.2/100,000); new diagnoses have increased by 33% since 2004 among men who have sex with men and late diagnosis remains common. Evidence-based prevention measures and efforts towards earlier testing need to be expanded. PMID- 25443032 TI - Defensins from the tick Ixodes scapularis are effective against phytopathogenic fungi and the human bacterial pathogen Listeria grayi. AB - BACKGROUND: Ixodes scapularis is the most common tick species in North America and a vector of important pathogens that cause diseases in humans and animals including Lyme disease, anaplasmosis and babesiosis. Tick defensins have been identified as a new source of antimicrobial agents with putative medical applications due to their wide-ranging antimicrobial activities. Two multigene families of defensins were previously reported in I. scapularis. The objective of the present study was to characterise the potential antimicrobial activity of two defensins from I. scapularis with emphasis on human pathogenic bacterial strains and important phytopathogenic fungi. METHODS: Scapularisin-3 and Scapularisin-6 mature peptides were chemically synthesised. In vitro antimicrobial assays were performed to test the activity of these two defensins against species of different bacterial genera including Gram-positive bacteria Staphylococcus aureus, Staphylococcus epidermidis, and Listeria spp. as well as Gram-negative bacteria Escherichia coli, Pseudomonas aeruginosa along with two plant-pathogenic fungi from the genus Fusarium. In addition, the tissue-specific expression patterns of Scapularisin-3 and Scapularisin-6 in I. scapularis midgut, salivary glands and embryo-derived cell lines were determined using PCR. Finally, tertiary structures of the two defensins were predicted and structural analyses were conducted. RESULTS: Scapularisin-6 efficiently killed L. grayi, and both Scapularisin-3 and Scapularisin-6 caused strong inhibition (IC50 value: ~1 MUM) of the germination of plant-pathogenic fungi Fusarium culmorum and Fusarium graminearum. Scapularisin-6 gene expression was observed in I. scapularis salivary glands and midgut. However, Scapularisin-3 gene expression was only detected in the salivary glands. Transcripts from the two defensins were not found in the I. scapularis tick cell lines ISE6 and ISE18. CONCLUSION: Our results have two main implications. Firstly, the anti-Listeria and antifungal activities of Scapularisin-3 and Scapularisin-6 suggest that these peptides may be useful for (i) treatment of antibiotic-resistant L. grayi in humans and (ii) plant protection. Secondly, the antimicrobial properties of the two defensins described in this study may pave the way for further studies regarding pathogen invasion and innate immunity in I. scapularis. PMID- 25443036 TI - Trends in HIV testing, prevalence among first-time testers, and incidence in most at-risk populations in Spain: the EPI-VIH Study, 2000 to 2009. AB - During 2000 to 2009, data on people undergoing HIV testing and on those newly diagnosed with HIV were collected in a network of 20 Spanish clinics specialising in sexually transmitted infections and/or HIV testing and counselling. The number of tests performed, overall and disaggregated by different variables, was obtained. HIV prevalence among first-time testers and HIV incidence among repeat testers were calculated. To evaluate trends, joinpoint regression models were fitted. In total, 236,939 HIV tests were performed for 165,745 individuals. Overall HIV prevalence among persons seeking HIV testing was 2.5% (95% CI: 2.4 to 2.6). Prevalence was highest in male sex workers who had sex with other men (19.0% (95% CI: 16.7 to 21.4)) and was lowest in female sex workers (0.8% (95% CI: 0.7 to 0.9)). Significant trends in prevalence were observed in men who have sex with men (MSM) (increasing) and heterosexual individuals (decreasing). The incidence analysis included 30,679 persons, 64,104 person-years (py) of follow-up and 642 seroconversions. The overall incidence rate (IR) was 1.0/100 py (95% CI: 0.9/100 to 1.1/100). Incidence was significantly higher in men and transgender females than in women (1.8/100 py (95% CI: 1.6 to 1.9), 1.2/100 py (95% CI: 0.5 to 2.8) and 0.1/100 py (95% CI: 0.09 to 0.2) respectively) and increased with age until 35-39 years. IRs in MSM and people who inject drugs were significantly greater than in heterosexual individuals (2.5/100 py (95% CI: 2.3 to 2.7), 1.6/100 py (95% CI: 1.1 to 2.2) and 0.1/100 py (95% CI: 0.09 to 0.2) respectively), and an upward trend was observed in MSM. Our results call for HIV prevention to be reinforced in MSM and transgender women in Spain. PMID- 25443035 TI - Continuous increase in HIV-1 incidence after the year 2000 among men who have sex with men in Rome: insights from a 25-year retrospective cohort study. AB - To assess trends in HIV-1 incidence and risk factors for seroconversion among men who have sex with men (MSM) resident in Rome, Italy, a retrospective longitudinal cohort study was conducted over 25 years. Incidence rates and trends were modelled using Poisson regression and risk factors were assessed by multivariate Cox models. Of 1,862 HIV-1-negative individuals, 347 seroconverted during follow up. HIV-1 incidence rates increased from 5.2/100 persons/year (p/y) in 1986 (95% confidence interval (CI): 2.3-11.5) to 9.2/00 p/y in 1992 (95% CI: 6.4-13.0), decreased to 1.3/100 p/y in 2001 and increased until 2009 (11.7/100 p/y; 95% CI: 7.4-18.6). The risk of HIV-1 seroconversion increased during the study period in younger MSM (incidence rate ratio (IRR) = 17.18; 95% CI: 9.74-30.32 in 16-32 year olds and IRR = 5.09; 95% CI: 2.92-8.87 in 33-41 year-olds) and in those who acquired syphilis (IRR = 7.71; 95% CI: 5.00-11.88). In contrast, the risk of seroconversion decreased among highly educated MSM (IRR = 0.54; 95% CI: 0.35 0.82) and those without Italian citizenship (IRR = 0.45; 95% CI: 0.28-0.71). The HIV epidemic in MSM living in Rome continues to expand. Targeted prevention programmes against sexually transmitted infections to enhance knowledge transfer and behavioural skills are urgently required. PMID- 25443037 TI - HIV testing and counselling in Estonian prisons, 2012 to 2013: aims, processes and impacts. AB - We present data from an observational cohort study on human immunodeficiency virus (HIV) prevention and control measures in prisons in Estonia to assess the potential for HIV transmission in this setting. HIV testing and retesting data from the Estonian prison health department were used to estimate HIV prevalence and incidence in prison. Since 2002, voluntary HIV counselling and testing has routinely been offered to all prisoners and has been part of the new prisoners health check. At the end of 2012, there were 3,289 prisoners in Estonia, including 170 women: 28.5% were drug users and 15.6% were infected with HIV. Of the HIV-positive inmates, 8.3% were newly diagnosed on prison entry. In 2012, 4,387 HIV tests (including retests) were performed in Estonian prisons. Among 1,756 initially HIV-negative prisoners who were in prison for more than one year and therefore tested for HIV twice within 12 months (at entry and annual testing), one new HIV infection was detected, an incidence of 0.067 per 100 person-years (95% confidence interval (CI): 0.025-5.572). This analysis indicates low risk of HIV transmission in Estonian prisons. Implementation of HIV management interventions could impact positively on the health of prisoners and the communities to which they return. PMID- 25443039 TI - [Out-of-hospital equipment of emergency medical services for hemorrhagic shock management: can do better!]. AB - INTRODUCTION: Hemorrhagic shock is an emergency, which may benefit from a medicalized prehospital care. Our goal was to survey the means available in the 370 French prehospital medicalized emergency services (SMUR) for hemorrhagic situations. METHODS: Multicenter descriptive observational study by email then phone with all the 370 French SMUR leaders. The questionnaire was created by investigators of the project through a Delphi method, and was about service protocols concerning hemorrhagic patient care, hemorrhagic parameters measure equipment available, intravenous solutes and drugs as well as various medical devices useful or perceived to be useful to support prehospital hemorrhagic shock. The results are expressed in numbers and percentages. RESULTS: The overall response rate was 48% (n=178). Protocols were established in between 43% (n=76) and 47% (n=83) according to etiology, measuring devices were available in 5% (n=9) of the Smur for hemostasis up to 89% (n=158) for hemoglobin measurement. Available intravenous solutes were mainly isotonic salty serum (95%, n=169), hydroxylethylstarch (83%, n=148) and Ringer lactate (73%, n=130). Tranexamic acid was available in 84 (47%) Smur. The teams had access to erythrocytes concentrates, fresh frozen plasma and platelets in 84% (n=150), 44% (n=79) and 23% (n=41) respectively. Eighty-one (46%) Smur had tourniquets and 127 (71%) anti shock trousers. Finally, 57 (32%) had a pelvic restraint belt. CONCLUSION: There is a great disparity in the means available in the French Smur for the support of prehospitalization bleeding. The majority the Smur physicians can transfuse in a prehospital setting. On the other hand, a minority of teams can actively warm patients, employ tranexamic acid or use pelvic restraint belts. PMID- 25443040 TI - [A rare complication of severe acute asthma: Perthes syndrome]. PMID- 25443041 TI - [Subarachnoid haemorrhage and electronic gun]. PMID- 25443042 TI - [Rapid hemodynamic recovery after early epinephrine and sugammadex co administration during rocuronium-induced anaphylactic reaction]. PMID- 25443043 TI - Implementing an early childhood school-based mental health promotion intervention in low-resource Ugandan schools: study protocol for a cluster randomized controlled trial. AB - BACKGROUND: Children in Sub-Saharan Africa (SSA) are burdened by significant unmet mental health needs, but this region has limited access to mental health workers and resources to address these needs. Despite the successes of numerous school-based interventions for promoting child mental health, most evidence-based interventions are not available in SSA. This study will investigate the transportability of an evidence-based program from a developed country (United States) to a SSA country (Uganda). The approach includes task-shifting to early childhood teachers and consists of professional development (five days) to introduce strategies for effective behavior management and positive teacher student interactions, and group-based consultation (14 sessions) to support adoption of effective practices and tailoring to meet the needs of individual students. METHODS/DESIGN: The design of this study is guided by two implementation frameworks, the Consolidated Framework for Implementation Research and the Teacher Training Implementation Model, that consider multidimensional aspects of intervention fidelity and contextual predictors that may influence implementation and teacher outcomes. Using a cluster randomized design, 10 schools in Uganda will be randomized to either the intervention group (five schools) or the waitlist control group (five schools). A total of 80 to 100 early childhood teachers will be enrolled in the study. Teacher utilization of evidence based strategies and practices will be assessed at baseline, immediate post intervention (six months after baseline), and at seven months post-intervention (during a new academic year). Fidelity measures will be assessed throughout the program implementation period (during professional development and consultation sessions). Individual teacher and contextual factors will be assessed at baseline. Data will be collected from multiple sources. Linear mixed-effect modeling, adjusting for school nesting, will be applied to address study questions. DISCUSSION: The study will produce important information regarding the value of an evidence-based early intervention, and a theory-guided implementation process and tools designed for use in implementing early childhood evidence-based programs in SSA countries or resource-constrained community settings. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (registration number: NCT097115) on 15 May 2013. PMID- 25443044 TI - Whitey crumbles. AB - Despite scientific evidence to the contrary, cultural notions that incorrectly aggrandize genetic differences between ethnicities persist. New work on the genetic makeup of Europeans now shows even more definitively how false those notions are. PMID- 25443045 TI - Psoriasis improvement after bariatric surgery. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disease known to be associated with obesity and metabolic syndrome. Single case reports and small series suggest remission or improvement after bariatric surgery, hypothetically through a GLP-1 mediated mechanism. The objective of this study was to investigate on the effect of bariatric surgery on the clinical behavior of psoriasis in obese patients. METHODS: A total of 33 morbidly obese individuals with psoriasis who were on active medical treatment were identified. Demographic characteristics and follow-up data were extracted from our database. Medication usage and percentage of affected body surface area (%ABSA) were recorded preoperatively and at least 6 months after bariatric surgery. RESULTS: Nine (27.2%) patients were on systemic therapy at baseline. At a mean follow-up time of 26.2+/-20.3 months, a mean excess weight loss (EWL) of 48.7+/- 26.6% was achieved. This was associated with improvement of psoriasis based on downgrade of medication and %ABSA in 30.3% and 26.1% of patients, respectively. In total, 13 of 33 patients (39.4%) had improvement based on either criteria. Eight (24.2%) patients were not on any psoriasis medication at the latest follow-up (P = .001). Older age at the time of surgery (54.8+/-8.1 versus 48.1+/-10.4 years, P = .047), Roux-en-Y gastric bypass versus nonbypass procedures (52.4% versus 16.7%, P = .043), and greater EWL (64.2+/-26.0% versus 43.4+/- 23.6%, P = .036) predicted improvement. Only 1 (3%) patient experienced worsening after surgery. CONCLUSION: Almost 40% of our cohort showed improvement of psoriasis several months after bariatric surgery. Improvement is directly related to the degree of postoperative weight loss and is associated with the Roux-en-Y configuration. PMID- 25443046 TI - How to create a diverting ileostomy in the obese. PMID- 25443047 TI - Comment on: laparoscopic gastric plication in morbidly obese adolescents: a prospective study. PMID- 25443048 TI - Frequency of abnormal esophageal acid exposure in patients eligible for bariatric surgery. AB - BACKGROUND: Obesity and gastroesophageal reflux disease (GERD) are both high prevalence diseases in developed nations. Obesity has been identified as an important risk factor in the development of GERD. The objective of this study was to determine the frequency of abnormal esophageal acid exposure in patients candidate for bariatric surgery and its relationship with any clinical and endoscopic findings before surgery. METHODS: Data collected from a group of 88 patients awaiting bariatric surgery included a series of demographic variables and symptoms typical of GERD. The tests patients underwent included manometry, pH monitoring, and upper gastrointestinal endoscopy. Univariate and multivariate analyses were conducted on the variables related to the onset of reflux. RESULTS: Esophageal pH monitoring tests were positive in 65% of the patients. Manometries showed lower esophageal sphincter hypotonia in 46%, while 20% returned abnormal upper endoscopy results. Out of the 45% of patients who were asymptomatic or returned normal endoscopies, half returned positive esophageal pH tests. In turn, among the 55% of patients who had symptoms or an abnormal upper endoscopy, three quarters had pH tests that diagnosed reflux. pH tests were also positive in 80% of symptomatic patients and 100% of patients with esophagitis (P<.042). No statistically significant relationship was found between body mass index, sex, age, manometry, or hiatus hernia and the positive pH monitoring. CONCLUSION: Frequency of abnormal esophageal acid exposure among obese patients is high. There is a relationship between the presence of symptoms and reflux. But the absence of symptoms does not rule out the presence of abnormal esophageal function tests. PMID- 25443049 TI - Comment on: Influence of median surgeon operative duration on adverse outcomes in bariatric surgery. PMID- 25443050 TI - Changes in inflammatory markers after sleeve gastrectomy in patients with impaired glucose homeostasis and type 2 diabetes. AB - BACKGROUND: Bariatric surgery is an effective treatment for morbid obesity. Obesity and type 2 diabetes are associated with chronic inflammation. There is lack of data examining the effects of sleeve gastrectomy (SG) on inflammatory biomarkers. Our aim was to study the effects of SG on specific cytokines associated with obesity including interleukin-6 (IL-6), interleukin-10 (IL-10), leptin, adiponectin, and C-reactive protein (CRP) preoperatively, 1 and 6 months after surgery. METHODS: A nonrandomized prospective study comprising of 22 participants with impaired glucose homeostasis and type 2 diabetes undergoing SG (body mass index 50.1 kg/m(2), glycated hemoglobin [HbA1c] 53 mmol/mol). Serial measurements of IL-6, IL-10, leptin, adiponectin, and CRP were performed during oral glucose tolerance testing preoperatively, 1 and 6 months postoperatively. RESULTS: We observed significant improvements at 1 and 6 months in leptin (P<=.001) and CRP (P = .003) after SG. We also observed a significant reduction in IL-6 at 6 months (P = .001). No statistically significant differences were observed for adiponectin and IL-10. CONCLUSION: This study is the first to examine the detailed changes in the inflammatory cytokines after SG. Our study shows significant improvements in the inflammatory biomarkers after SG in patients with impaired glucose homeostasis and type 2 diabetes. PMID- 25443051 TI - Quality of life before and after laparoscopic sleeve gastrectomy. A prospective cohort study. AB - BACKGROUND: There is a lack of adequate prospective data on quality-of-life (QOL) and its predictors in patients undergoing laparoscopic sleeve gastrectomy (LSG). The aim of this study was to assess longitudinal changes in QOL after LSG with the use of the obesity-specific Moorehead-Ardelt II questionnaire (MAII) and to identify clinical parameters associated with QOL outcome. METHODS: Morbidly obese patients consecutively admitted for LSG, over a 30-month period, were prospectively studied. QOL was assessed using the validated Greek version of the MAII questionnaire and a visual analogueue scale (VAS), preoperatively and at 6, 12, and 24 months postoperatively. Anthropometric data and obesity-related co morbidities were recorded. RESULTS: A total of 111 patients with a mean age 36.8+/-9.2 years were included. Mean preoperative body mass index (BMI) was 49.1+/-7.5 kg/m2. Percentage excess BMI loss (%EBL) was 51.1+/-14.9, 64.2+/-17.9 and 66.4+/-18.0 at 6, 12, and 24 months, respectively. Postoperatively, all obesity-related co-morbidities were significantly improved. MAII score increased from -.40+/-1.30 preoperatively to 1.75+/-.83, 2.18+/-.80, and 1.95+/-.71 at 6, 12, and 24 months postoperatively (trend P<.001). Preoperative median (interquartile range) VAS was 3 (1) increasing to 9 (2), 10 (1), and 9 (1) at 6, 12, and 24 months postoperatively (P<.001). %EBL and reduction in obesity-related co-morbidities, especially resolution of diabetes and sleep apnea, correlated significantly with higher QOL during the course of the study. CONCLUSION: LSG, a safe and effective bariatric operation, results in sustained weight loss and significant improvements in QOL. Both weight loss and amelioration of co morbidities contribute to higher level of postsurgical QOL. PMID- 25443052 TI - The skinny on psoriasis and weight loss. PMID- 25443053 TI - Is sleeve gastrectomy the magic bullet? PMID- 25443054 TI - Predictors of hospital stay following laparoscopic gastric bypass: analysis of 9,593 patients from the National Surgical Quality Improvement Program. AB - BACKGROUND: Bariatric centers face pressure to reduce hospitalization to contain costs, and some centers have sought to develop "fast-track" protocols. There is limited data to identify which patients require a longer hospital stay after gastric bypass, and therefore would be inappropriate for fast tracking. The objectives of this study were to determine (1) whether most patients in the United States who underwent laparoscopic gastric bypass required>1 day of hospitalization to recover; (2) whether hospital length of stay can be predicted by factors known before or after the operation. METHODS: We reviewed all laparoscopic gastric bypass operations reported to the American College of Surgeons National Surgical Quality Improvement Program in 2011. Revision and open procedures were excluded. Patient and procedural characteristics, length of stay, readmissions, and 30-day morbidity and mortality were reviewed. Predictors of longer hospitalization (defined as>=3 days) were identified by multivariate analysis. RESULTS: Of 9,593 laparoscopic gastric bypass operations, median length of stay was 2 days (range 0-544) and 26% of patients required>=3 days of hospitalization. In multivariate analysis, longer hospitalization was predicted by diabetes, chronic obstructive pulmonary disease, bleeding diathesis, renal insufficiency, hypoalbuminemia, prolonged operating time, and resident involvement with the procedure, but not by patient age, sex, body mass index, and other co-morbidities. CONCLUSION: Patient characteristics and operative details predict length of hospitalization after laparoscopic gastric bypass. Such data can be used to identify patients inappropriate for fast-track protocols. PMID- 25443055 TI - Sleeve gastrectomy is also anti-inflammatory, but why? PMID- 25443056 TI - Commentary on: Bariatric surgery in the elderly: 2009-2013. PMID- 25443057 TI - Gastroesophageal reflux disease and bariatric surgery: many questions, few answers. PMID- 25443058 TI - Laparoscopic adjustable gastric banded plication: case-matched study from a single U.S. center. AB - BACKGROUND: Laparoscopic adjustable gastric banded plication (LAGBP) is a novel technique for weight loss surgery. This study evaluates the safety and short-term efficacy of LAGBP in a U.S. population. The setting was an academic medical center in the United States. METHODS: Patients who underwent LAGBP between 2012 and 2013 were reviewed retrospectively. Demographic characteristics, pre and perioperative details, body mass index (BMI), and percent excess weight loss (%EWL) were analyzed and compared to case-matched cohorts that had laparoscopic adjustable gastric banding (LAGB) or laparoscopic sleeve gastrectomy (LSG) during the same time period. RESULTS: Seventeen patients (14 females) underwent LAGBP during the study period and were case-matched based on age, sex, race, and preoperative BMI with patients having LAGB and LSG. Mean age and preoperative BMI for LAGBP cohort were 42.5+/-11.6 years and 47.7+/-6.5 kg/m2, respectively. Mean operative time and estimated blood loss were 72+/-16 minutes and 23+/-23 mL, respectively, compared to 49+/-16 minutes (P=.002) and 15+/-23 mL for LAGB, and 66+/-18 minutes and 36+/-22 mL for LSG. There were no perioperative deaths. Hospital length of stay was 1.1+/-.3 days for LAGBP, versus .7+/-.3 days (P=.004) for LAGB, and 2.7+/-1.4 days (P<.001) for LSG. At 12-month follow-up, patients in the LAGBP and LAGB groups had undergone similar number of band adjustments (4.7 versus 5.1; P=.68). The %EWL was 46.1+/-14.8% for the LAGBP cohort, compared to 38.9+/-20.6% for LAGB, and 57.7+/-16% for LSG. CONCLUSION: LAGBP is technically feasible and safe, and offers weight loss results positioned between LAGB and LSG at 1 year. To date, this is the largest U.S. series to compare this novel technique to more traditional weight loss procedures. PMID- 25443059 TI - Reproductive health counseling and practices: a cross-sectional survey of bariatric surgeons. AB - BACKGROUND: Nearly 50% of bariatric surgery patients are women of reproductive age. Both obstetric and gynecology and surgery professional guidelines recommend a delay of fertility 1-2 years postbariatric surgery. METHODS: We sought to assess bariatric surgeons' perioperative reproductive counseling and contraceptive provision for women of reproductive age. We conducted a cross sectional, national 32-question mail survey of bariatric surgeons. Survey topics included demographic factors, contraceptive counseling and provision, and method preference. Descriptive statistics were reported and Chi2 tests compared results among respondent demographic characteristics. RESULTS: A total of 574 of 1,935 physicians returned surveys (30%). After excluding 41 surveys due to missing data, we analyzed 533 (27%) surveys. Mean respondent age was 48.1 years. Most respondents were male (89%), white (78%), and completed residency training >=10 years ago (72%). The majority of respondents' bariatric surgery patients were female (77%), 63% of which were of reproductive age. Most respondents recommended that their female patients delay pregnancy 12-24 months (87%). Whereas 70% of respondents did not require preoperative contraception, 52% always required postoperative contraceptive use. Although the majority of respondents (64%) referred patients to an obstetrician-gynecologist or primary care physician to obtain contraception, 35% did not know how their female patients obtained contraception. Female respondents were more likely than male respondents to always require a medicine consultation and preoperative contraception, P<.05. CONCLUSION: Despite consistently recommending a delay in pregnancy, bariatric surgeons inconsistently address perioperative contraceptive needs of women of reproductive age. These findings highlight the need for greater collaboration between bariatric surgeons and women's healthcare providers to address the reproductive health needs of women having bariatric surgery. PMID- 25443060 TI - Laparoscopic adjustable gastric banding (LAGB) with gastric plication: short-term results and comparison with LAGB alone and sleeve gastrectomy. AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is the safest type of bariatric surgery but is less effective than other bariatric surgeries. Combining LAGB with gastric plication (LAGB-P) may increase weight loss compared to LAGB alone. METHODS: In this study, we report our short-term experience with this novel technique and compare the data for the first 42 consecutive patients with the data for LAGB alone and LSG. Forty-two morbidly obese patients underwent LAGB P and were followed for 12 months. Operative complications, weight loss, and late complications were followed and compared with matched groups of LAGB alone and laparoscopic sleeve gastrectomy (LSG). The setting was a university hospital in Taiwan. RESULTS: The study consisted of 42 patients, specifically 21 males and 21 females with an average age of 32.6+/-9.7 years (range 18 to 58) and a mean body mass index of 40.7+/-6.1 kg/m2 (range 31.5 to 56.4). The mean operation time was 141.9+/-24.8 minutes (range 105 to 190), and the mean hospital stay was 2.3+/-1.9 days. Two (4.8%) major complications were encountered and resolved by laparoscopic revision surgery. There was 1 (2.4%) major complication in the LSG group and none in the LAGB group. The operation time for LAGB-P was longer than for LAGB and LSG (75.6+/-17.9 and 110.5+/-22.3 minutes; P<.001). The mean body mass index of the LAGB-P group decreased from 40.7 to 29.4 kg/m2 at 1 year after surgery, with an excess weight loss of 62.6%. This result is similar to the 67.2% excess weight loss in the LSG group, but is higher than the 31.7% excess weight loss of the LAGB group. At follow-up, revision surgery was required in 2 (4.8%) patients in the LAGBP group, none (0%) in the LAGB group, and 1 (2.4%) in the LSG group. More patients in the LSG group still required proton pump inhibitor treatment at 1 year after surgery than the other 2 groups CONCLUSION: By combining LAGB with gastric plication, LAGB-P can augment the weight loss of LAGB and is similar to LSG but may increase risk. PMID- 25443061 TI - Longitudinal trends in food cravings following Roux-en-Y gastric bypass in an adolescent sample. AB - BACKGROUND: Food cravings are more prevalent and potentially problematic for many individuals with obesity. Initial evidence suggests that bariatric surgery has some short-term beneficial effects on cravings in adults, but little is known about the effect on adolescents or the trajectory beyond 6 months. METHODS: The purpose of the present study was to determine the longitudinal effect of Roux-en Y gastric bypass (RYGB) on food cravings in a sample of adolescents with severe obesity (body mass index (BMI)>=40 kg/m2). Sixteen adolescents were recruited and underwent RYGB. Participants completed the Food Craving Inventory before RYGB, and 3, 6, 12, 18, and 24 months postoperatively. The present study took place in a single pediatric tertiary care hospital. RESULTS: RYGB produced a negative (cravings decreased as time increased) nonlinear trend for total food cravings as well as for each individual subscale (sweets, high fat foods, carbohydrates, fast food) over the 24-month study period. This means that while cravings decrease postsurgically, there is a decline in the slope with the line reaching asymptote at approximately 18 months. BMI change was not a significant predictor of food cravings, but low statistical power may account for this lack of significance. CONCLUSION: These findings provide preliminary evidence that RYGB decreases food cravings in adolescents. PMID- 25443062 TI - The perfect storm: a foreign body and splenic infarct mimicking a sleeve gastrectomy leak. PMID- 25443063 TI - Comment on: Predictors of hospital stay following laparoscopic gastric bypass: analysis of 9,593 patients from the National Surgical Quality Improvement Program. PMID- 25443064 TI - Reply to commentary "laparoscopic gastric plication in morbidly obese adolescents: a prospective study". PMID- 25443065 TI - Comment on: revisional surgery after failed gastric banding: results of one-stage conversion to RYGB in 195 patients. PMID- 25443066 TI - Pre-surgical cortical activation to food pictures is associated with weight loss following bariatric surgery. AB - BACKGROUND: Recent research suggests that preintervention functional magnetic resonance imaging (fMRI) data may predict weight loss outcomes among patients who participate in a behavioral weight loss plan. No study has examined whether presurgical brain activation can predict outcomes following bariatric surgery. METHOD: The aim of the present study was to determine if brain activations during a presurgical fMRI food-motivation paradigm are associated with weight loss 3 and 6 months following laparoscopic adjustable gastric banding (LAGB). Nineteen participants viewed food and nonfood pictures from a well-established food motivation paradigm during an fMRI scanning session before LAGB surgery. Weight was assessed presurgery and 3 and 6 months postsurgery; data for all participants was available at each time point. fMRI data were analyzed using the BrainVoyager QX statistical package. Whole brain voxelwise correlations of presurgery (food nonfood) brain activation and weight, corrected for multiple comparisons, were performed to analyze the relationship between presurgical brain activation and subsequent weight loss. The settings were a medical university brain imaging center and 2 surgical weight loss centers in a major metropolitan area. RESULTS: Increased activity in frontal regions associated with cognitive control (medial, middle, superior frontal gyrus) and posterior cingulate cortex was associated with weight loss following LAGB. CONCLUSION: We found that neural activity in previously established regions associated with cognitive and behavioral self regulation predicts weight loss following bariatric surgery. These preliminary findings highlight the role of neural circuitry in the success and maintenance of weight loss and suggest a possible future use of fMRI in screening LAGB surgery candidates. PMID- 25443067 TI - Claims to the patient insurance after bariatric surgery in Sweden 2000-2012. AB - BACKGROUND: Since 2000, the annual number of bariatric procedures has increased more than 10-fold in Sweden, and in 2012, 94% of these procedures were primary laparoscopic gastric bypass. METHODS: We studied claims from the national Patient Insurance (Landstingens Omsesidiga Forsakringsbolag, LOF) to evaluate if the number of adverse events (AEs) from a patient perspective had increased unproportionally. All claims related to bariatric surgery from January 2000 to March 2012 were identified by ICD-10 codes and divided into 3 main groups: (1) procedure-related AEs (occurring within 30 days), (2) late AEs, and (3) nonsurgical AEs. Logistic regression was used to study the change in claim rate over time. The setting was a university hospital in Sweden. RESULTS: In total, 359 claims were included, corresponding to 14 claims per 1,000 bariatric procedures (laparoscopic 59%, open 24%, revision 17%). Numbers correlated with the expansion of bariatric surgery and type of procedure routinely performed. Of the procedure-related claims (74% of all claims), postoperative leaks or bleedings were most common. In this group, patients frequently needed additional surgery (69%) and intensive care (42%). Half of the late AEs (69 in total) were related to abdominal pain or malnutrition, including 5 cases of Wernicke's encephalopathy. In total 2% died. Of 344 settled claims, economical compensation was given to 29%. CONCLUSION: In this cohort of patients with insurance claims after bariatric surgery (1.4% of all procedures), procedure-related AEs were severe, with a large amount of patients requiring reoperation and intensive care. No change in claim rate was seen, in spite of the 10-fold increase of bariatric surgery. PMID- 25443068 TI - Prevalence and characteristics of individuals without diabetes and hypertension who underwent bariatric surgery: lessons learned about metabolically healthy obese. AB - BACKGROUND: Recent studies describe a unique subset of obese individuals with normal metabolic profiles despite having excess weight called "metabolically healthy but obese (MHO)". Our aim was to determine the prevalence of individuals without diabetes and hypertension and risk factors associated with the MHO phenotype among bariatric surgery patients. METHODS: We conducted a retrospective study of 710 adults who underwent bariatric surgery at Johns Hopkins between 2008 and 2010. In the first analysis of 523 individuals, we identified 150 individuals without diabetes and hypertension; in the second analysis of 260 individuals, we identified 44 individuals without diabetes, hypertension and hypertriglyceridemia. We used multivariable logistic regression to examine the association between each group and potential risk factors including age, sex, race, body mass index, and presence of liver disease on liver biopsy. RESULTS: The prevalence of individuals without diabetes and hypertension was 28.7%; among these individuals 88.7% had liver steatosis, 7.3% nonalcoholic steatohepatitis (NASH), and 19.3% liver fibrosis. These individuals were significantly more likely to be white OR=1.9 (95% CI: 1.1-3.1), younger OR=4.1 (95% CI=2.6-6.3), and female OR=2.1, (95% CI=1.2-3.6) and less likely to have liver steatosis OR=0.4 (95% CI=0.2-0.9) or NASH OR=0.3 (95% CI=0.2-0.6). CONCLUSION: Among bariatric surgery patients, almost a third of patients do not have diabetes and hypertension and could be probably considered "MHO" and were more likely to be white, young, female, and have less liver injury. The high prevalence of liver steatosis in MHO individuals among bariatric surgery patients challenges the notion of MHO as a truly metabolically healthy entity. PMID- 25443070 TI - Comment on: mechanisms of type 2 diabetes resolution after Roux-en-Y gastric bypass. PMID- 25443069 TI - Self-report of gastrointestinal side effects after bariatric surgery. AB - BACKGROUND: Data on gastrointestinal (GI) side effects of bariatric surgery are limited because of incomplete reporting, cross-sectional samples, and nonstandardized assessments. OBJECTIVE: To report on GI side effects over the first 6 months after Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB). SETTING: Academic medical center, United States. METHODS: One hundred forty-four patients completed a standardized clinical interview 6 months after operation, including questions on the occurrence and frequency of episodes of dumping syndrome, vomiting, and plugging for each of the past 6 months; monthly rates were stable, so results were averaged over the entire period. Although data were collected as part of a randomized controlled trial, randomization group and the interaction of group by surgical procedure were not related to GI side effects. Thus, results are reported by procedure only (RYGB, n = 87; LAGB, n = 56). RESULTS: RYGB patients had a higher preoperative body mass index (BMI) than LAGB patients (46.8+/-6.8 versus 43.5+/-4.8 kg/m(2), respectively; P = .001), were more likely to report dumping (45.7% versus 4.7%, P<.0001), and were less likely to report plugging (45.7% versus 79.1%, P = .0005). Vomiting did not differ significantly by procedure (68.6% versus 65.1%, P = .7). Most patients experienced each GI side effect less than once per week. CONCLUSION: Although self-reported GI side effects were common over the first 6 months after operation, the frequency of episodes was relatively low. Longer-term follow-up is needed to determine whether symptoms worsen or improve over time. PMID- 25443071 TI - Malignant gastric carcinoid tumor and morbid obesity. PMID- 25443072 TI - A retrospective comparison of early results of conversion of failed gastric banding to sleeve gastrectomy or gastric bypass. AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is associated with high long-term failure rates requiring conversion to alternative procedures. Operative conversion to laparoscopic sleeve gastrectomy (LSG) or laparoscopic Roux-en-Y gastric (LRYGB) bypass is associated with higher complication rates than primary procedures. OBJECTIVES: To compare results for converting failed LAGB to LSG versus LRYGB. SETTING: University Hospital, United Kingdom, National Health Service. METHODS: All patients undergoing conversion of LAGB to LRYGB and LSG from July 2006 to September 2012 were included. A retrospective analysis of our prospectively maintained database was performed to identify differences in death rates, complication rates, length of hospital stay, and weight loss. Within this study LRYGB was the preferred choice for conversion and LSG was only considered in the presence of significant intraabdominal adhesions, because of patient choice, or in patients with contraindications to LRYGB. RESULTS: Eighty nine patients with failed LAGB underwent conversional surgery within this period. Of these, 64 patients underwent conversion to LRYGB and 25 underwent conversion to LSG. There was no statistical difference in percentage of excess weight loss at 1 or 2 years after conversional surgery to LSG or LRYGB. Conversion to LRYGB was carried out as a single procedure in 51/64 (80%) compared with 10/25 (40%) for conversion to LSG (P = .003). One postoperative complication occurred requiring reoperation after conversion to LRYGB. CONCLUSION: There was no difference in complication rates, hospital stay, and early weight loss when converting failed LAGB to LRYGB or LSG. Both procedures are appropriate for conversion from LAGB, although a staged approach is often needed, especially for LSG. PMID- 25443073 TI - Are laparoscopic bariatric procedures feasible in morbidly obese patients with situs inversus? A report of 2 cases and a brief review. PMID- 25443074 TI - Effects of laparoscopic Roux-en-Y gastric bypass on bone mineral density and markers of bone turnover. AB - BACKGROUND: Despite multiple beneficial effects of weight loss after laparoscopic Roux-en-Y gastric bypass (LRYGB), the influence on bone mineral density (BMD) remains largely unknown. Our objective was to evaluate the changes in BMD and serum/urine bone markers after LRYGB. METHODS: Thirty-four women undergoing LRYGB were prospectively enrolled and underwent bone densitometry and serum/urine analysis preoperatively and 1 year postoperative. Changes>=.025 g/cm(2) in hip, femoral neck, and spine BMD and decreases>2% in total BMD were considered significant. Statistical analysis included paired t tests and McNemar's test. RESULTS: Mean age was 44.6 years. Body mass index at the preoperative and 1-year postoperative intervals were 46.7 and 29.6 kg/m(2), respectively. Mean hip, femoral neck, and spine (L1-L4) BMD was 1.191 versus 1.087 g/cm(2) (P< .001), 1.105 versus 1.032 g/cm(2) (P< .001), and 1.323 versus 1.277 g/cm(2) (P< .001) at the preoperative and 1 year postoperative intervals, respectively. Mean total BMD decreased from 1.328 preoperatively to 1.251 g/cm(2) at 1 year postoperative (P<.001). The decreases in BMD were 5.8%, 6.5%, 3.5%, and 8.8% for hip, femoral neck, spine (L1-L4) and total BMD from preoperative to 1 year postoperative. The proportion of patients with low vitamin D levels decreased from 55% preoperatively to 21% at 1 year postoperative (P = .004). Elevated osteocalcin and bone alkaline phosphatase was observed in 4% and 63% (P<.001), and 14% and 41% (P = .011) of patients preoperatively and at 1 year postoperative, respectively. CONCLUSION: BMD and bone markers changed significantly after LRYGB. Current recommendations for supplementation in post-LRYGB women may need to be reevaluated. PMID- 25443075 TI - Revisional surgery after failed gastric banding: results of one-stage conversion to RYGB in 195 patients. AB - BACKGROUND: The most performed restrictive bariatric procedure is the laparoscopic adjustable gastric band (LAGB). With many patients still receiving a LAGB in Europe and the United States, inevitably, the number of complications also increases. For many complications revisional bariatric surgery is necessary. In this study, the outcomes of one-stage LAGB conversion to a Roux-en-Y gastric bypass (RYGB) at our institution are presented. The objective of this study was to investigate the safety and efficiency of RYGB performed as a one-stage procedure after failed LAGB. METHODS: Patients were retrospectively selected using a prospectively collected database. The gastric band had to be in situ for at least 1 year and minimum postoperative follow-up was 12 months. The revisional RYGB had to be performed as a 1-step procedure. RESULTS: A total of 195 patients were included while 3 were lost to follow up. Overall, 178 (91%) procedures were performed without perioperative complications, and only 8 (4%) patients required reoperation within 30 days. The mean follow-up was 40 months (+/-24) after RYGB. Mean excess weight loss (EWL) increased from 25% (+/-26/-50- 120%) to 60% (+/ 21.2/0- 130), 65% (+/-23.5/0- 131), 63% (+/-24.2/2- 132), 60% (+/-24.1/0- 111) and 53% (+/-28.7/-39- 109) in the first 5 postoperative years. CONCLUSION: Converting a gastric band to a RYGB in a one-stage procedure is safe and feasible, with acceptable complication rates when performed in a specialized institution. The RYGB conversion results in a good EWL of 65% after 2 years. However, proper patient selection is of the utmost importance. PMID- 25443076 TI - Phytobezoar: an unexpected cause of bowel obstruction in a pregnant woman with a history of Roux-en-Y gastric bypass. PMID- 25443077 TI - Mechanisms of type 2 diabetes resolution after Roux-en-Y gastric bypass. AB - BACKGROUND: Bariatric surgery is the most effective treatment for the reduction of weight and resolution of type 2 diabetes mellitus (T2 DM). The objective of this study was to longitudinally assess hormonal and tissue responses after RYGB. METHODS: Eight patients (5 with T2 DM) were studied before and after RYGB. A standardized test meal (STM) was administered before and at 1, 3, 6, 9, 12, and 15 months. Separately, a 2-hour hyperinsulinemic-euglycemic clamp (E-clamp) and a 2-hour hyperglycemic clamp (H-clamp) were performed before and at 1, 3, 6, and 12 months. Glucagon-like peptide-1 (GLP-1) was infused during the last hour of the H clamp. Body composition was assessed with DXA methodology. RESULTS: Enrollment body mass index was 49+/-3 kg/m(2) (X+/-SE). STM glucose and insulin responses were normalized by 3 and 6 months. GLP-1 level increased dramatically at 1, 3, and 6 months, normalizing by 12 and 15 months. Insulin sensitivity (M of E-clamp) increased progressively at 3-12 months as fat mass decreased. The insulin response to glucose alone fell progressively over 12 months but the glucose clearance/metabolism (M of H-clamp) did not change significantly until 12 months. In response to GLP-1 infusion, insulin levels fell progressively throughout the 12 months. CONCLUSION: The early hypersecretion of GLP-1 leads to hyperinsulinemia and early normalization of glucose levels. The GLP-1 response normalizes within 1 year after surgery. Enhanced peripheral tissue sensitivity to insulin starts at 3 months and is associated with fat mass loss. beta-cell sensitivity improves at 12 months and after the loss of ~33% of excess weight. There is a tightly controlled feedback loop between peripheral tissue sensitivity and beta-cell and L-cell (GLP-1) responses. PMID- 25443079 TI - A novel classification system of lumbar disc degeneration. AB - The Pfirrmann and modified Pfirrmann grading systems are currently used to classify lumbar disc degeneration. These systems, however, do not incorporate variables that have been associated with lumbar disc degeneration, including Modic changes, a high intensity zone, and a significant reduction in disc height. A system that incorporates these variables that is easy to apply may be useful for research and clinical purposes. A grading system was developed that incorporates disc structure and brightness, presence or absence of Modic changes, presence or absence of a high intensity zone, and reduction in disc height (disc height less than 5mm). MRI of 300 lumbar discs in 60 patients were analyzed twice by two neurosurgeons. Intra and inter-observer reliabilities were assessed by calculating Cohen's kappa values. There were 156 grade zero ("normal"), 50 grade one, 57 grade two, 26 grade three, 10 grade four, and one grade five ("worst") discs. Inter-observer reliability was substantial (kappa = 0.66 to 0.77) for disc brightness/structure, Modic changes, and disc height. Inter-observer reliability was moderate (kappa = 0.41) for high intensity zone. Intra-observer reliability was moderate to excellent (kappa = 0.53 to 0.94) in all categories. Agreement on the total grade between reviewers occurred 71% of the time and a difference of one grade occurred in an additional 25% of cases. Lumbar disc degeneration can be graded reliably by this novel system. The advantage of this system is that it incorporates disc brightness/structure, Modic changes, high intensity zone, and a rigid definition of loss of disc height. This system might be useful in research studies evaluating disc degeneration. Further studies are required to demonstrate possible clinical utility in predicting outcomes after spinal treatments such as fusion. PMID- 25443078 TI - Older age does not limit postbariatric surgery cognitive benefits: a preliminary investigation. AB - BACKGROUND: Bariatric surgery is associated with cognitive benefits, but the nature of such gains may be variable across demographically and clinically diverse persons. Older adults achieve less weight loss and resolution of fewer medical co-morbidities after surgery compared to younger patients and are also at heightened risk for nutritional deficiencies. However, no study has examined the influence of age on cognitive improvements after bariatric surgery. The objective of this study was to determine the effects of age on cognitive function postbariatric surgery. METHODS: A total of 95 participants enrolled in the Longitudinal Assessment for Bariatric Surgery completed a computerized cognitive test battery before bariatric surgery and at 12-weeks and 12-months postoperatively. RESULTS: Baseline cognitive impairments were common. Significant improvements were found in attention/executive function and memory abilities 12 weeks and 12-months after surgery. Age was not associated with baseline cognitive test performance. Separate multivariable regression analyses controlling for baseline attention/executive function and memory also showed that age was not a significant predictor of 12-week or 12-month performances in these domains (P>.05 for all). CONCLUSION: The present study provides preliminary evidence suggesting that older age does not preclude postbariatric surgery cognitive benefits. Prospective studies in more age diverse samples (i.e., up to 70 yr) are needed to determine whether bariatric surgery can reduce risk of age-related neurologic conditions like Alzheimer's disease and stroke. PMID- 25443080 TI - Four-year follow-up results of transforaminal lumbar interbody fusion as revision surgery for recurrent lumbar disc herniation after conventional discectomy. AB - This study investigated the safety, effectiveness, and clinical and radiological outcomes of transforaminal lumbar interbody fusion (TLIF) for recurrent lumbar disc herniation (rLDH) following previous lumbar spine surgery. Seventy-three consecutive patients treated for rLDH between June 2005 and May 2012 were included in the study. The previous surgical procedures included percutaneous discectomy, discectomy with laminotomy, discectomy with unilateral laminectomy, and discectomy with bilateral laminectomy. The level of rLDH was L4-L5 in 51 patients, L5-S1 in 19 patients, and L3-L4 in three patients. All patients underwent reoperation using the TLIF technique. Outcomes were evaluated using the Oswestry disability index (ODI), visual analogue scale (VAS) scores for low back pain and leg pain, and the Japanese Orthopaedic Association (JOA) score, based on the results of physical examinations and questionnaires. The range of motion and disc height index of the operative segment were compared between preoperative and postoperative radiographs. The mean follow-up period was 4.1 years. The VAS scores for low back pain and leg pain, ODI, and JOA score improved significantly between the preoperative and final follow-up evaluations. The mean recovery rate of the JOA score was 89.0%. The disc space height and stability at the fused level were significantly improved after surgery. The fusion rate at the final follow-up was 93.2%. There were no major complications. These results indicate that TLIF can be considered an effective, reliable, and safe alternative procedure for the treatment of rLDH. PMID- 25443081 TI - Human cytomegalovirus viral load in tumor and peripheral blood samples of patients with malignant gliomas. AB - Malignant gliomas are the most common primary brain tumors in adults. The disease has no known etiology, progresses rapidly, and is fatal despite current therapies. Human cytomegalovirus (HCMV) is a beta herpes virus that is trophic for glial cells and infects 50% to 90% of the adult human population. HCMV mediated disease in immunosuppressed patients has highlighted the possible role of this virus in the development of other diseases, particularly inflammatory diseases such as vascular diseases, autoimmune diseases, and certain malignancies. Sensitive detection of viral DNA, mRNA, and antigens in tumor tissues, as well as seroepidemiologic evidence, suggest a link between HCMV and several human malignancies. HCMV gene products are proposed to dysregulate multiple cellular pathways involved in oncogenesis, such as cell cycle regulation, apoptosis, migration, and angiogenesis. These theories, currently being researched, suggest that HCMV acts as an oncomodulator in malignancies. We investigated the association between HCMV infection and reactivation, and malignant gliomas. An open, matched case-control, parallel group pilot study was performed in a tertiary referral center. The HCMV viral load in peripheral blood and tumor samples of 19 patients newly diagnosed with glioblastoma multiforme was compared with a matched control cohort comprising 19 patients newly diagnosed with non-malignant brain tumors. There was no significant correlation between peripheral blood and tumor tissue HCMV viral load in patients with glioblastoma multiforme compared to the control cohort. The findings of the present study did not support an oncomodulatory role for HCMV in malignant gliomas. PMID- 25443082 TI - Long-term follow-up results of linear accelerator-based radiosurgery for vestibular schwannoma using serial three-dimensional spoiled gradient-echo MRI. AB - We examined the characteristic changes in vestibular schwannoma (VS) volume after treatment with linear accelerator-based radiosurgery (LBRS) and the long-term therapeutic effects, by performing three-dimensional (3D) MRI evaluations of tumor volumes. We included 44 patients in whom tumor volume changes could be observed using 3D-spoiled gradient-echo MRI for at least 5 years. Examinations were performed every 3-4 months for the first 2 years after treatment and every 6 12 months thereafter. Enlargement or shrinkage was determined as a change of at least 20% from the volume at the time of treatment. The median observation period was 13.8 years (range, 5.5-19.5 years). The tumor control rates at 5 and 10 years after treatment and at the final MRI were 90.9%, 90.0%, and 88.6%, respectively. Tumor volume changes were categorized into the following four patterns: enlargement, five patients (11.4%); stable, three patients (6.8%); transient enlargement, 24 patients (54.5%); and direct shrinkage, 12 patients (27.3%). Bimodal peaks were observed in three of the 24 patients with transient enlargement. Tumor volume changes from 5 and 10 years post-LBRS to the final observation point were observed in 27 (64.2%) and 10 patients (33.3%), respectively. The long-term tumor volume changes observed after LBRS suggest that radiation exerts long-term effects on tumors. Furthermore, while transient enlargements in tumor volume were characteristic, true tumor enlargements should be characterized by increased volumes of more than two-fold and continued growth for at least 2 years. PMID- 25443083 TI - Performance of SPECT in the differential diagnosis of glioma recurrence from radiation necrosis. AB - Radiation necrosis (RN) may be a confounder in the diagnosis of glioma recurrence. Several functional imaging techniques, including single photon emission computed tomography (SPECT) and positron emission tomography (PET), have been used to differentiate RN from glioma recurrence. However, to our knowledge the efficacy of SPECT has not been evaluated quantitatively. This meta-analysis evaluated the diagnostic ability of SPECT in differentiating glioma recurrence from RN. PubMed and EMBASE were systematically searched for studies published up to 1 March 2014 that evaluated SPECT in the differential diagnosis of glioma recurrence from RN. The data from eligible studies were evaluated by heterogeneity and threshold effect tests, and the sensitivity, specificity, and areas under the summary receiver-operating characteristic curve (SROC) were calculated. Twenty-eight studies in 24 articles, which included 893 patients (1163 scans) with suspected glioma recurrence after radiotherapy, met all inclusion and exclusion criteria, and were included in the meta-analysis. Their pooled sensitivity and specificity were 0.89 (95% confidence interval [CI]: 0.87, 0.91) and 0.88 (95% CI: 0.84, 0.91), respectively, and the area under the SROC was 0.9403. This meta-analysis showed that SPECT had good diagnostic performance for differentiating glioma recurrence from RN. PMID- 25443084 TI - Surgical treatment of patients with unruptured intracranial aneurysms. AB - We present our experience with elective microsurgical clipping of unruptured intracranial aneurysms (UIA) and analyze this management. A total of 150 patients with UIA were reviewed and data were collected with regard to age, sex, presence of symptoms, location and size of the aneurysms, surgical complications and postoperative 1 year outcomes. Aneurysm size was assessed either by three dimensional CT angiography or digital subtraction angiogram. Glasgow Outcome Scale was used to assess clinical outcomes. One hundred and fifty patients with 165 aneurysms were treated in this series. The mean size of the UIA was 5.6mm. Eighty aneurysms (48.5%) were less than 5mm in size, and 73 (44.2%) were from 5 to 10mm. Ten (6.1%) of the aneurysms were large and two (1.2%) were giant. One hundred and forty-three were asymptomatic and seven were symptomatic before surgery. The outcome was good in 147 patients (98%), and only three patients (2%) had a treatment-related unfavorable outcome. Five patients experienced transient neurological deficits and one patient experienced permanent neurological deficits. Overall 98.7% of the treated aneurysms were satisfactorily obliterated. Wound complications were seen only in three patients. In conclusion, UIA pose a significant challenge for neurosurgeons, where a delicate balance between benefits and possible risks must be weighed. If the requisite expertise is available, they can be treated surgically with low morbidity and a good outcome at specialized neurovascular centers. PMID- 25443085 TI - Anti-Ri-associated paraneoplastic brainstem cerebellar syndrome with coexisting limbic encephalitis in a patient with mixed large cell neuroendocrine lung carcinoma. AB - Paraneoplastic neurologic syndromes (PNS) can be the first manifestations of occult malignancies. If left untreated, PNS often lead to significant morbidity and mortality. Anti-Ri (anti-neuronal nuclear antibody type 2 [ANNA-2]) autoantibodies are commonly associated with breast and small cell lung cancers. Cases of anti-Ri paraneoplastic cerebellar degeneration are reported, but few describe severe nausea and coexisting limbic encephalitis as the major presenting features. We report a 75-year-old woman with medically-intractable emesis, encephalopathy, diplopia, vertigo, and gait ataxia for 3 months. Examination revealed rotary nystagmus, ocular skew deviation, limb dysmetria, and gait ataxia. After two courses of intravenous immunoglobulin, there was minimal improvement. Anti-Ri antibodies were positive in serum only. CT scan identified a 2.0 cm left lung mass, and histopathology revealed large cell neuroendocrine carcinoma with admixed adenocarcinoma non-small cell lung carcinoma (NCSLC). Though the patient achieved nearly complete clinical recovery after tumor resection, anti-Ri levels remained high at 20 months post-resection. To our knowledge this is the first report of a paraneoplastic brainstem cerebellar syndrome with coexisting limbic encephalitis involving anti-Ri positivity and associated mixed neuroendocrine/NSCLC of the lung with marked improvement after tumor resection. PMID- 25443086 TI - Brainstem lymphoma in a myasthenia gravis patient on azathioprine. AB - Azathioprine is used for immunosuppression in myasthenia gravis (MG). We report a patient with seropositive MG who developed a brainstem lymphoma 4 years after being treated with azathioprine and review the literature on the occurrence of lymphoma in this patient population. An 82-year-old man with ocular MG who had been on azathioprine for 4 years developed subacute worsening of bulbar symptoms including diplopia, dysarthria and dysphagia mimicking MG exacerbation. Neuroimaging followed by biopsy showed brainstem diffuse large B-cell lymphoma (DLBCL). To our knowledge this is the first reported patient with brainstem DLBCL after azathioprine treatment in MG. Lymphoma has been reported in MG patients treated with azathioprine, although the incidence is unknown. We suggest reduction of azathioprine dose and subsequent discontinuation, if possible, in MG patients who are in remission. Special caution should be taken with elderly patients and Epstein-Barr virus serology prior to initiation may be useful in this population, but this requires further study. PMID- 25443087 TI - Clinical presentation and imaging characteristics of occult lung cancer associated ischemic stroke. AB - We investigated the clinical and imaging characteristics of initial and recurrent strokes in patients with occult lung cancer associated ischemic stroke (OLCA stroke). A retrospective review of all ischemic stroke patients with occult lung cancer in the absence of conventional stroke etiologies between 2005 and 2013 was conducted. We compared the initial and recurrent lesion patterns on diffusion weighted MRI in patients with OLCA-stroke, with respect to vascular territory involved, number and size of lesions, clinical presentation, cancer subtypes, recurrences and fatalities, and outcome of survivors. Thirteen patients with confirmed OLCA-stroke were identified. All had elevated D-dimer levels, six had central lung cancer and seven had peripheral lung cancer. Eight (62%) had adenocarcinoma, and nine (69%) had metastasis. Ten (77%) patients had multiple lesions in multiple vascular territories. Twelve (92%) patients suffered recurrent strokes. Multiple small and large disseminated lesions in multiple vascular territories were more frequent in recurrent strokes in comparison with initial strokes. The middle cerebral artery was most frequently involved in recurrent strokes, followed by the posterior circulation territory and anterior cerebral artery, which were of similar frequency as initial strokes. Overall, 58% of patients had their first recurrent stroke within the first month, and 69% had a poor outcome, especially for those with multiple recurrent strokes and metastases. Occult cancer should be considered in the setting of multiple and recurrent embolic strokes within the short term in the absence of conventional stroke etiologies. The severity of malignancy and cancer treatments and stroke influenced the recurrences and outcome. PMID- 25443088 TI - Study of cerebral aneurysms in a modified rat model: from real-time imaging to histological analysis. AB - Cerebral aneurysm (CA) is a life-threatening condition with a pathogenesis that remains unclear. Previous hypotheses have primarily been based on in vitro examinations of animal models. Therefore, we attempted to observe CA in living rats and to establish a multi-level evaluation system. The rat model was produced by deoxycorticosterone-acetate (DOCA; Sigma Aldrich, St. Louis, MO, USA) induced hypertension and a single injection of elastase into the basal cistern. The animals were assessed 35 days later. At the endpoint, we induced well-developed CA in 41.7% of the surviving rats. Using synchrotron radiation angiography (SRA), we observed the experimental aneurysms and their surrounding arteries dynamically in the living model. Further anatomical and histological analyses demonstrated the typical degenerative changes of the mural structure and a major infiltration of macrophages into the aneurysmal wall. In conclusion, we visualised well developed experimental CA in living rats using SRA and demonstrated the associated degenerative histological changes and macrophage involvement; thus, we have provided an effective model for the study of dynamic multi-level changes associated with CA in a rat model. PMID- 25443090 TI - The New Zealand Neuromuscular Disease Registry: rate of diagnoses confirmed by molecular testing. AB - The New Zealand Neuromuscular Disease Registry (NZ NMD Registry) is part of the TREAT NMD Alliance, an international network that provides infrastructure ensuring the most promising new therapies reach neuromuscular patients as quickly as possible. Its main aim is to ensure that the most promising new therapies reach patients as quickly as possible. From the perspective of researchers interested in trialling treatments it is useful to have data on the pool of potential research participants. From a patient's perspective it is important to know what trials they can take part in. Both of these require a confirmed molecular diagnosis in the patient. Some therapeutic strategies not only require knowledge of which gene is affected but are targeted at specific mutations within the gene. In reviewing data held in the NZ NMD Registry it was noted that, of those diagnosed with a genetic condition, only 51% have a confirmed molecular genetic diagnosis. This low rate of genetic diagnosis is a potential barrier to research participation but can be removed with improved genetic technology and with changes in knowledge about and attitudes towards genetic testing. PMID- 25443089 TI - Clinical characteristics and long-term outcomes of moyamoya syndrome associated with neurofibromatosis type 1. AB - Moyamoya syndrome (MMS) associated with neurofibromatosis type 1 (NF1) has rarely been reported anywhere in the world, particularly in Asia. Because of the rarity of this disorder, its natural history, clinical symptoms, management, and follow up findings remain unclear. The objective of this study was to evaluate the clinical presentation, neurological imaging, and long-term outcomes of patients with this disease by reviewing Chinese patients with MMS associated with NF1. A retrospective review was conducted from the moyamoya disease (MMD) and MMS patient database of our hospital. Six patients who were diagnosed with MMS associated with NF1 between January 2003 and October 2013 were identified. The clinical symptoms were transient ischemic attack (TIA, three patients), headache (one patient), intracerebral hemorrhage (one patient), and cerebral infarction (one patient). The mean age of diagnosis for NF1 and MMS was 2.7 +/- 2.1 years (range, 1-6 years) and 11.4 +/- 8.3 years (range, 3.5-23 years), respectively. Five of six patients (nine hemispheres) underwent revascularization surgery, and their clinical symptoms were stable during a 46.3 +/- 36.1 month (range, 18-108 month) follow-up. One non-surgical patient had a new infarct that resulted in visual field deficits during follow-up. Three patients had radiographic follow up, and the postoperative angiograms showed successful revascularizations in the operated hemispheres. To conclude, the clinical and radiographic features for MMS NF1 are similar to those of typical MMD. Routine vascular screening for NF1 patients is necessary for the early identification of MMS and other cerebral arteriopathies. Revascularization surgery may prevent the progression of clinical symptoms and reduce the risk of subsequent strokes. PMID- 25443092 TI - Contribution of arsenic species in unicellular algae to the cycling of arsenic in marine ecosystems. AB - This review investigates the arsenic species produced by and found in marine unicellular algae to determine if unicellular algae contribute to the formation of arsenobetaine (AB) in higher marine organisms. A wide variety of arsenic species have been found in marine unicellular algae including inorganic species (mainly arsenate--As(V)), methylated species (mainly dimethylarsenate (DMA)), arsenoribosides (glycerol, phosphate, and sulfate) and metabolites (dimethylarsenoethanol (DMAE)). Subtle differences in arsenic species distributions exist between chlorophyte and heterokontophyte species with As(V) commonly found in water-soluble cell fractions of chlorophyte species, while DMA is more common in heterokontophyte species. Additionally, different arsenoriboside species are found in each phyla with glycerol and phosphate arsenoribosides produced by chlorophytes, whereas glycerol, phosphate, and sulfate arsenoribosides are produced by heterokontophytes, which is similar to existing data for marine macro-algae. Although arsenoribosides are the major arsenic species in many marine unicellular algal species, AB has not been detected in unicellular algae which supports the hypothesis that AB is formed in marine animals via the ingestion and further metabolism of arsenoribosides. The observation of significant DMAE concentrations in some unicellular algal cultures suggests that unicellular algae-based detritus contains arsenic species that can be further metabolized to form AB in higher marine organisms. Future research establishing how environmental variability influences the production of arsenic species by marine unicellular algae and what effect this has on arsenic cycling within marine food webs is essential to clarify the role of these organisms in marine arsenic cycling. PMID- 25443091 TI - Endovascular treatment of severe acute basilar artery occlusion. AB - Severe acute basilar artery occlusion (BAO) has a high mortality rate but as yet no effective treatment has been developed. This study aimed to evaluate the feasibility and safety of combined mechanical thrombectomy, intra-arterial thrombolysis, and emergent stent placement for patients with severe acute BAO. Eighteen patients who were unconscious after confirmed onset of BAO and who were given arterial interventional treatment from March 2011 to June 2013 at our department were included in this study. The mean age was 59.56 years (range: 31 76 years) and patients were in a critical physical condition upon admission, and had a mean National Institutes of Health Stroke Scale (NIHSS) score of 25.94 (range: 18-35). All patients were treated with mechanical thrombectomy, 10 of whom received mechanical thrombectomy only. Of the others, eight were also treated with intra-arterial thrombolysis, three were treated with emergent stent placement, and 17 were treated with recanalization with an achieved recanalized rate of 94.4%. The average number of passes through the stent was 1.5 (range: 1 3) and five patients died (27.8%). Thirteen patients survived, and the mean NIHSS score was 6.54 (range: 0-16). Seven patients showed a modified Rankin Scale score ? 2, and the rate of good prognoses was 38.9%. In the treatment of patients with severe acute BAO, intra-arterial mechanical thrombectomy combined with thrombolysis or stent placement are effective strategies to restore blood flow and preserve life, and these strategies have a low incidence of complications. PMID- 25443093 TI - Ligand affinity: multivalency counterbalances PEGylation. PMID- 25443094 TI - Transpulmonary pressure and lung elastance can be estimated by a PEEP-step manoeuvre. AB - BACKGROUND: Transpulmonary pressure is a key factor for protective ventilation. This requires measurements of oesophageal pressure that is rarely used clinically. A simple method may be found, if it could be shown that tidal and positive end-expiratory pressure (PEEP) inflation of the lungs with the same volume increases transpulmonary pressure equally. The aim of the present study was to compare tidal and PEEP inflation of the respiratory system. METHODS: A total of 12 patients with acute respiratory failure were subjected to PEEP trials of 0-4-8-12-16 cmH2O. Changes in end-expiratory lung volume (DeltaEELV) following a PEEP step were determined from cumulative differences in inspiratory-expiratory tidal volumes. Oesophageal pressure was measured with a balloon catheter. RESULTS: Following a PEEP increase from 0 to 16 cmH2O end-expiratory oesophageal pressure did not increase (0.5 +/- 4.0 cmH2O). Average increase in EELV following a PEEP step of 4 cmH2O was 230 +/- 132 ml. The increase in EELV was related to the change in PEEP divided by lung elastance (El) derived from oesophageal pressure as DeltaPEEP/El. There was a good correlation between transpulmonary pressure by oesophageal pressure and transpulmonary pressure based on El determined as DeltaPEEP/DeltaEELV, r(2) = 0.80, y = 0.96x, mean bias -0.4 +/- 3.0 cmH2 O with limits of agreement from 5.4 to -6.2 cmH2O (2 standard deviations). CONCLUSION: PEEP inflation of the respiratory system is extremely slow, and allows the chest wall complex, especially the abdomen, to yield and adapt to intrusion of the diaphragm. As a consequence a change in transpulmonary pressure is equal to the change in PEEP and transpulmonary pressure can be determined without oesophageal pressure measurements. PMID- 25443095 TI - Methodology to design a municipal solid waste generation and composition map: a case study. AB - The municipal solid waste (MSW) management is an important task that local governments as well as private companies must take into account to protect human health, the environment and to preserve natural resources. To design an adequate MSW management plan the first step consists in defining the waste generation and composition patterns of the town. As these patterns depend on several socio economic factors it is advisable to organize them previously. Moreover, the waste generation and composition patterns may vary around the town and over the time. Generally, the data are not homogeneous around the city as the number of inhabitants is not constant nor it is the economic activity. Therefore, if all the information is showed in thematic maps, the final waste management decisions can be made more efficiently. The main aim of this paper is to present a structured methodology that allows local authorities or private companies who deal with MSW to design its own MSW management plan depending on the available data. According to these data, this paper proposes two ways of action: a direct way when detailed data are available and an indirect way when there is a lack of data and it is necessary to take into account bibliographic data. In any case, the amount of information needed is considerable. This paper combines the planning methodology with the Geographic Information Systems to present the final results in thematic maps that make easier to interpret them. The proposed methodology is a previous useful tool to organize the MSW collection routes including the selective collection. To verify the methodology it has been successfully applied to a Spanish town. PMID- 25443096 TI - Compost in plant microbial fuel cell for bioelectricity generation. AB - Recycling of organic waste is an important topic in developing countries as well as developed countries. Compost from organic waste has been used for soil conditioner. In this study, an experiment has been carried out to produce green energy (bioelectricity) by using paddy plant microbial fuel cells (PMFCs) in soil mixed with compost. A total of six buckets filled with the same soil were used with carbon fiber as the electrodes for the test. Rice plants were planted in five of the buckets, with the sixth bucket containing only soil and an external resistance of 100 ohm was used for all cases. It was observed that the cells with rice plants and compost showed higher values of voltage and power density with time. The highest value of voltage showed around 700 mV when a rice plant with 1% compost mixed soil was used, however it was more than 95% less in the case of no rice plant and without compost. Comparing cases with and without compost but with the same number of rice plants, cases with compost depicted higher voltage to as much as 2 times. The power density was also 3 times higher when the compost was used in the paddy PMFCs which indicated the influence of compost on bio electricity generation. PMID- 25443097 TI - Investigations regarding the wet decontamination of fluorescent lamp waste using iodine in potassium iodide solutions. AB - With the rising popularity of fluorescent lighting, simple and efficient methods for the decontamination of discarded lamps are needed. Due to their mercury content end-of-life fluorescent lamps are classified as hazardous waste, requiring special treatment for disposal. A simple wet-based decontamination process is required, especially for streams where thermal desorption, a commonly used but energy demanding method, cannot be applied. In this study the potential of a wet-based process using iodine in potassium iodide solution was studied for the recovery of mercury from fluorescent lamp waste. The influence of the leaching agent's concentration and solid/liquid ratio on the decontamination efficiency was investigated. The leaching behaviour of mercury was studied over time, as well as its recovery from the obtained leachates by means of anion exchange, reduction, and solvent extraction. Dissolution of more than 90% of the contained mercury was achieved using 0.025/0.05 M I2/KI solution at 21 degrees C for two hours. The efficiency of the process increased with an increase in leachant concentration. 97.3 +/- 0.6% of the mercury contained was dissolved at 21 degrees C, in two hours, using a 0.25/0.5M I2/KI solution and a solid to liquid ratio of 10% w/v. Iodine and mercury can be efficiently removed from the leachates using Dowex 1X8 anion exchange resin or reducing agents such as sodium hydrosulphite, allowing the disposal of the obtained solution as non-hazardous industrial wastewater. The extractant CyMe4BTBP showed good removal of mercury, with an extraction efficiency of 97.5 +/- 0.7% being achieved in a single stage. Better removal of mercury was achieved in a single stage using the extractants Cyanex 302 and Cyanex 923 in kerosene, respectively. PMID- 25443098 TI - Onsite survey on the mechanism of passive aeration and air flow path in a semi aerobic landfill. AB - The semi-aerobic landfill is a widely accepted landfill concept in Japan because it promotes stabilization of leachates and waste via passive aeration without using any type of mechanical equipment. Ambient air is thought to be supplied to the landfill through a perforated pipe network made of leachate collection pipe laid along the bottom and a vertically erected gas vent. However, its underlying air flow path and driving forces are unclear because empirical data from real world landfills is inadequate. The objective of this study is to establish scientific evidence about the aeration mechanisms and air flow path by an on-site survey of a full-scale, semi-aerobic landfill. First, all passive vents located in the landfill were monitored with respect to temperature level and gas velocity in different seasons. We found a linear correlation between the outflow rate and gas temperature, suggesting that air flow is driven by a buoyancy force caused by the temperature difference between waste in the landfill and the ambient temperature. Some vents located near the landfill bottom acted as air inflow vents. Second, we conducted a tracer test to determine the air flow path between two vents, by injecting tracer gas from an air sucking vent. The resulting slowly increasing gas concentration at the neighboring vent suggested that fresh air flow passes through the waste layer toward the gas vents from leachate collection pipes, as well as directly flowing through the pipe network. Third, we monitored the temperature of gas flowing out of a vent at night. Since the temperature drop of the gas was much smaller than that of the environment, the air collected at the gas vents was estimated to flow mostly through the waste layer, i.e., the semi-aerobic landfill has considerable aeration ability under the appropriate conditions. PMID- 25443099 TI - Heterogeneity in health seeking behaviour for treatment, prevention and urgent care in four districts in western Kenya. AB - OBJECTIVES: The impact of effective, life-saving health interventions is limited by access to and use of health services. Health seeking behaviour is likely to vary geographically and by type of health concern. However, little is known about the extent of this heterogeneity. STUDY DESIGN: A representative cluster randomized sample of households in four districts in western Kenya was interviewed using a structured, interviewer-administered survey. GPS coordinates of all households and all local health facilities were also collected. METHODS: Household surveys measured health seeking behaviour for three distinct health needs: family planning which is a form of prevention, delivery which is an urgent care need but can be planned in advance, and childhood febrile illness which is an unexpected and potentially life-threatening concern. Logistic regression models were used to explore the relationship between seeking health services and maternal and household characteristics, with special attention to geographic and financial access to care. RESULTS: Use of health services for these three different health issues varied between the districts and also differed from national estimates. Place of delivery was most strongly correlated with the type of health services available to the family, whereas family planning was correlated with the relationship of the mother to the head of household. There was no strong interaction between socio-economic status and distance to services. CONCLUSIONS: The level of services available nearest to households rather than the distance to travel influences treatment-seeking behaviour, particularly for urgent care. Maternal factors and household wealth were often important but, even within the same households, their effect changes based on the type of health concern. Generalizing from nationwide surveys may obscure important local heterogeneity, particularly in delivery location and fever treatment. PMID- 25443100 TI - The effects of homelessness on Veterans' health care service use: an evaluation of independence from comorbidities. AB - OBJECTIVES: This study evaluates the prevalence of Multiple Comorbid Chronic Disease (MCCD) within homeless and non-homeless Veterans and the association between MCCD and inpatient medical care. METHODS: All individuals seen in the VA North Texas Health Care System between October 1, 2009 and September 30, 2010 (n = 102,034) were evaluated. Homelessness during the year and the number of common chronic diseases were evaluated for an association with likelihood of medical and psychiatric hospitalizations, bed days of care, inpatient substance treatment, rehabilitation admissions, and emergency department visits. RESULTS: Homeless Veterans had higher all-cause mortality rates and rates of use of almost all resources after controlling for chronic disease burden using the Charlson Comorbidity Index, psychiatric illnesses, substance use disorders, and demographic variables. CONCLUSIONS: Homelessness Veterans are vulnerable to a high use of resources and mortality, independent of medical and psychiatric conditions. This finding should focus additional attention on reducing homelessness. PMID- 25443101 TI - Descriptive epidemiology of school outbreaks of seasonal influenza B during 2012/2013 in the Thames Valley, United Kingdom. PMID- 25443102 TI - The debate on climate change and health in the context of ecological public health: a necessary corrective to Costello et al.'s 'biggest global health threat', or co-opted apologists for the neoliberal hegemony? AB - The threat posed to global health by climate change has been widely discussed internationally. The United Kingdom public health community seem to have accepted this as fact and have called for urgent action on climate change, often through state interventionist mitigation strategies and the adoption of a risk discourse. Putting aside the climate change deniers' arguments, there are critics of this position who seem to accept climate change as a fact but argue that the market and/or economic development should address the issue. Their view is that carbon reduction (mitigation) is a distraction, may be costly and is ineffective. They argue that what is required is more economic development and progress even if that means a warmer world. Both positions however accept the fact of growth based capitalism and thus fail to critique neoliberal market driven capitalism or posit an alternative political economy that eschews growth. Ecological public health, however, appears to be a way forward in addressing not only social determinants of health but also the political and ecological determinants. This might allow us to consider not just public health but also planetary health and health threats that arise from growth based capitalism. PMID- 25443103 TI - Homelessness and discharge delays from an urban safety net hospital. PMID- 25443104 TI - Addressing inequalities in eye health with subsidies and increased fees for General Ophthalmic Services in socio-economically deprived communities: a sensitivity analysis. AB - OBJECTIVES: Poor knowledge of eye health, concerns about the cost of spectacles, mistrust of optometrists and limited geographical access in socio-economically deprived areas are barriers to accessing regular eye examinations and result in low uptake and subsequent late presentation to ophthalmology clinics. Personal Medical Services (PMS) were introduced in the late 1990 s to provide locally negotiated solutions to problems associated with inequalities in access to primary care. An equivalent approach to delivery of optometric services could address inequalities in the uptake of eye examinations. STUDY DESIGN: One-way and multiway sensitivity analyses. METHODS: Variations in assumptions were included in the models for equipment and accommodation costs, uptake and length of appointments. The sensitivity analyses thresholds were cost-per-person tested below the GOS1 fee paid by the NHS and achieving break-even between income and expenditure, assuming no cross-subsidy from profits from sales of optical appliances. RESULTS: Cost per test ranged from L 24.01 to L 64.80 and subsidy required varied from L 14,490 to L 108,046. Unused capacity utilised for local enhanced service schemes such as glaucoma referral refinement reduced the subsidy needed. CONCLUSIONS: In order to support the financial viability of primary eye care in socio-economically deprived communities, income is required from additional subsidies or from sources other than eye examinations, such as ophthalmic or other optometric community services. This would require a significant shift of activity from secondary to primary care locations. The subsidy required could also be justified by the utility gain from earlier detection of preventable sight loss. PMID- 25443105 TI - Does closure of children's medical home impact their immunization coverage? AB - OBJECTIVES: Little is known about the impact closing a health care facility has on immunization coverage of children utilizing that facility as a medical home. The authors assessed the impact of closing a Medicaid managed care facility in Philadelphia on immunization coverage of children, primarily low income children from racial/ethnic minority groups, utilizing that facility for routine immunizations. STUDY DESIGN: Observational longitudinal cohort case study. METHODS: Eligible children were born 03/01/05-06/30/07, present in Philadelphia's immunization information system (IIS), and were active clients of the facility before it closed in September 2007. IIS-recorded immunization coverage at ages 5, 7, 13, 16 and 19 months through January 2009 was compared between clinic children age-eligible to receive specific vaccines before clinic closing (preclosure cohorts) and children not age-eligible to receive those vaccines prior to closing (postclosure cohorts). RESULTS: Of 630 eligible children, 99 (16%) had no additional IIS-recorded immunizations. Third dose DTaP vaccine coverage at age seven months among preclosure cohorts was 54.4% vs. 40.3% among postclosure cohorts [risk ratio 1.31 (1.15,1.49)]. Fourth dose DTaP coverage at 19 months was 65.9% vs. 57.7% [risk ratio 1.24 (1.08,1.42)]. MMR coverage at 16 months was 79.5% vs. 69.9% [risk ratio 1.47 (1.22, 1.76)]. Coverage for the 431331 vaccination series at 19 months was 63.8% vs. 53.8% [risk ratio 1.28 (1.12,1.88)]. CONCLUSIONS: Immunization coverage declined at key age milestones for active clients of a Medicaid managed care that closed as compared with preclosure cohorts of clients from the same facility. When a primary health care facility closes, efforts should be made to ensure that children who had received vaccinations at that facility quickly establish a new medical home. PMID- 25443106 TI - Public policy and personal preference: a disconnect between beliefs regarding responsible drinking and the motivation to get drunk. PMID- 25443107 TI - Screening for hepatitis C in injecting and ex-injecting drug users in North East Essex. PMID- 25443108 TI - A pilot study of the feasibility of delivering a brief smoking cessation intervention in community optometric practice. PMID- 25443109 TI - Is access to alcohol associated with alcohol/substance abuse among people diagnosed with anxiety/mood disorder? AB - OBJECTIVES: To investigate the relationship between access to off-license alcohol outlets and areas with dual treatment for alcohol/drug abuse and anxiety/mood disorder compared to areas with anxiety/mood disorder only in an urban setting in New Zealand. STUDY DESIGN: Ecologic study. METHODS: Within small areas (2840 meshblocks, mean size 0.05 km(2)) in the city of Auckland, New Zealand, counts of adults receiving anxiety/mood disorder treatment (2008-9) were identified and the proportions of these individuals also receiving treatment for alcohol/drug abuse were generated. Access to off-license alcohol outlets were defined as: 1) shortest road distance from the population-weighted centroid of each small area to an outlet; 2) count of outlets within a 3 km road network buffer; and 3) relative density of outlets across Auckland (determined through kernel density estimates). To test for the relationship between access to alcohol outlets and dual diagnosis, meshblocks without any cases of anxiety/mood disorder were excluded from analyses. Remaining meshblocks were dichotomized into any or no dual diagnosis. Logistic regression was used to estimate the association between access to alcohol outlets and treatment for the dual conditions. RESULTS: Neighbourhoods with dual diagnosis were generally similar to those with anxiety/mood disorder only, in terms of ethnic and gender/age composition. Regression analyses indicated statistically significant decreased risk of dual diagnosis for those areas with the lowest density (using a buffer) of alcohol outlets (OR = 0.75, P-value = 0.027) compared with areas with the highest density, after adjustment for deprivation and population density. All access measures also indicated significant linear trends where dual diagnosis was more likely in areas with greater access. CONCLUSIONS: Generally, decreased access to alcohol outlets was associated with decreased odds of dual diagnosis of alcohol/drug abuse and anxiety/mood disorder. Measures to control access to alcohol outlets may be an important area for alcohol/substance abuse intervention, particularly for vulnerable sub-populations. PMID- 25443110 TI - A neuronal DNA damage response is detected at the earliest stages of Alzheimer's neuropathology and correlates with cognitive impairment in the Medical Research Council's Cognitive Function and Ageing Study ageing brain cohort. AB - AIMS: Population-based studies have shown that approximately 20% of the ageing population (aged 65 years and over) with dementia have little or no classical Alzheimer-type neuropathology. Cumulative DNA damage and a reduced capacity of DNA repair may result in neuronal dysfunction and contribute to cognitive impairment independent of Alzheimer-type pathology in the ageing brain. METHODS: We investigated expression of the DNA damage response (DDR)-associated molecules gammaH2AX and DNA-PKcs using immunohistochemistry and western blotting, and senescence-associated beta-galactosidase in the frontal association neocortex of cases with low levels of Alzheimer-type pathology (Braak & Braak stage 0-II), and explored their relationship to cognitive impairment in a population representative sample from the Medical Research Council's Cognitive Function and Ageing Study cohort. RESULTS: Increases in both gammaH2AX(+) (r(s) = -0.36, P = 0.025) and DNA-PKcs(+) (r(s) = -0.39, P = 0.01) neuronal counts were associated with a lower Mini-Mental State Examination score. Increasing levels of senescence associated-beta-gal(+) pyramidal neurones were weakly associated with the total number of DNA-PKcs(+) neurones (P = 0.08), but not with traditional senescence associated signalling molecules, including p53 and p16. CONCLUSION: The association between the neuronal DDR and cognitive impairment, independent of AD pathology in the ageing brain, may be suggestive of a causal link via neuronal dysfunction. PMID- 25443111 TI - Race, common genetic variation, and therapeutic response disparities in heart failure. AB - Because of its comparatively recent evolution, Homo sapiens exhibit relatively little within-species genomic diversity. However, because of genome size, a proportionately small amount of variation creates ample opportunities for both rare mutations that may cause disease as well as more common genetic variations that may be important in disease modification or pharmacogenetics. Primarily because of the East African origin of modern humans, individuals of African ancestry (AA) exhibit greater degrees of genetic diversity than more recently established populations, such as those of European ancestry (EA) or Asian ancestry. Those population effects extend to differences in frequency of common gene variants that may be important in heart failure natural history or therapy. For cell-signaling mechanisms important in heart failure, we review and present new data for genetic variation between AA and EA populations. Data indicate that: 1) neurohormonal signaling mechanisms frequently (16 of the 19 investigated polymorphisms) exhibit racial differences in the allele frequencies of variants comprising key constituents; 2) some of these differences in allele frequency may differentially affect the natural history of heart failure in AA compared with EA individuals; and 3) in many cases, these differences likely play a role in observed racial differences in drug or device response. PMID- 25443113 TI - Is subclinical myocardial injury the smoking gun linking obesity with heart failure? PMID- 25443114 TI - Celebrating excellence in perioperative nursing. PMID- 25443112 TI - Obesity, subclinical myocardial injury, and incident heart failure. AB - OBJECTIVES: The study sought to evaluate the association of obesity with a novel biomarker of subclinical myocardial injury, cardiac troponin T measured with a new high-sensitivity assay (hs-cTnT), among adults without clinical cardiovascular disease (CVD). BACKGROUND: Laboratory evidence suggests a relationship between obesity and myocardial injury that may play a role in the development of heart failure (HF), but there is limited clinical data regarding this association. METHODS: We evaluated 9,507 participants in the ARIC (Atherosclerosis Risk in Communities) study without baseline CVD (Visit 4, 1996 to 1999). We assessed the cross-sectional association of body mass index (BMI) with high (>=14 ng/l) and measurable (>=3 ng/l) hs-cTnT levels after multivariable regression. We further evaluated the independent and combined associations of BMI and hs-cTnT with incident HF. RESULTS: Higher BMI was independently associated with a positive, linear increase in the likelihood of high hs-cTnT, with severe obesity (BMI >35 kg/m(2)) associated with an odds ratio of 2.20 (95% confidence interval: 1.59 to 3.06) for high hs-cTnT after adjustment. Over 12 years of follow-up, there were 869 incident HF events. Obesity and hs-cTnT were both independently associated with incident HF, and individuals with severe obesity and high hs-cTnT had a greater than 9-fold higher risk of incident HF (hazard ratio: 9.20 [95% confidence interval: 5.67 to 14.93]) than individuals with normal weight and undetectable hs-cTnT. CONCLUSIONS: Among individuals without CVD, higher BMI has an independent, linear association with subclinical myocardial injury, as assessed by hs-cTnT levels. Obesity and hs-cTnT provide independent and complementary prognostic information regarding the risk of incident HF. PMID- 25443116 TI - A few minutes with George Allen. PMID- 25443115 TI - Don't fear the red pen: AORN journal editors are here to help. PMID- 25443117 TI - Back to basics: implementing the surgical checklist. AB - Surgery is complex and technically demanding for all team members. Surgical checklists have been implemented with different degrees of success in the perioperative setting. There is a wealth of evidence that they are effective at preventing patient safety events and helping team members master the complexities of modern health care. Implementation is key to successful use of the surgical checklist in all invasive procedural settings. Key strategies for successful checklist implementation include establishing a multidisciplinary team to implement the checklist, involving surgeon leaders, pilot testing the checklist, incorporating feedback from team members to improve the process, recognizing and addressing barriers to implementation, and offering coaching and continuous feedback to team members who use the checklist. Using these strategies will give the perioperative nurse, department leaders, and surgeons the tools to implement a successful checklist. PMID- 25443118 TI - Promoting teamwork and surgical optimization: combining TeamSTEPPS with a specialty team protocol. AB - This quality improvement project was a 300-day descriptive preintervention and postintervention comparison consisting of a convenience sample of 18 gynecology surgical team members. We administered the Team Strategies & Tools to Enhance Performance and Patient Safety (TeamSTEPPS(r)) Teamwork Perception Questionnaire to measure the perception of teamwork. In addition, we collected data regarding rates of compliance (ie, huddle, time out) and measurable surgical procedure times. Results showed a statistically significant increase in the number of team members present for each procedure, 2.34 MU before compared with 2.61 MU after (P = .038), and in the final time-out (FTO) compliance as a result of a clarification of the definition of FTO, 1.05 MU before compared with 1.18 MU after (P = .004). Additionally, there was improvement in staff members' perception of teamwork. The implementation of team training, protocols, and algorithms can enhance surgical optimization, communication, and work relationships. PMID- 25443119 TI - Implementing hexaminolevulinate HCl blue light cystoscopy: a nursing perspective. AB - Hexaminolevulinate HCl is a diagnostic imaging agent used with blue light during cystoscopy to help detect non-muscle-invasive bladder cancer. Blue light cystoscopy performed using hexaminolevulinate HCl has been found to detect more papillary non-muscle-invasive bladder tumors than cystoscopy performed using standard white light. Because bladder instillation and retention requirements of hexaminolevulinate during cystoscopy can affect patient flow in the perioperative setting, this technique necessitates changes in nursing practice and care of patients with known or suspected non-muscle-invasive bladder cancer. Nursing personnel at one facility followed the AORN guidelines for preoperative patient care in the ambulatory setting to address staffing, preoperative nursing assessment, anesthesia evaluation, and preoperative teaching related to implementing blue light cystoscopy. PMID- 25443120 TI - The role of the RNFA in anterior cruciate ligament graft preparation. AB - Anterior cruciate ligament (ACL) reconstruction is one of the most commonly performed orthopedic procedures in the United States. Repair of the ACL often requires the use of autografts or allografts, and the RN first assistant (RNFA) often is the team member responsible for preparing the graft. Common grafts used in ACL repair include bone-patellar tendon-bone, hamstring, Achilles tendon, quadriceps tendon, and tibialis anterior tendon. The RNFA must be competent in preparing all of these grafts and in understanding the advantages and disadvantages of using each graft, such as the reasons for graft choice, and must ensure that all graft-related supplies and equipment are available and ready for use. The ability to prepare all graft types expands treatment options, reduces surgical time, and enhances the role of the RNFA. PMID- 25443121 TI - The relationship between direct-care RN specialty certification and surgical patient outcomes. AB - Specialty certification enhances patient safety in health care by validating that practice is consistent with standards of excellence. The purpose of this research was to explore the relationship between direct-care, specialty-certified nurses employed in perioperative units, surgical intensive care units (SICUs), and surgical units and nursing-sensitive patient outcomes in SICUs and surgical units. Lower rates of central-line-associated bloodstream infections in SICUs were significantly associated with higher rates of CPAN (certified postanesthesia nurse) (beta = -0.09, P = .05) and CNOR/CRNFA (certified nurse operating room/certified RN first assistant) (beta = -0.17, P = .00) certifications in perioperative units. Unexpectedly, higher rates of CNOR/CRNFA certification in perioperative units were associated with higher rates of hospital-acquired pressure ulcers (beta = 0.08, P = .03) and unit-acquired pressure ulcers (beta = 0.13, P = .00), possibly because of a higher risk of pressure ulcers in the patient population. Additional research is needed to clarify this relationship. Our findings lend credence to perioperative, SICU, and surgical nurses participating in lifelong learning and continuous professional development, including achievement of specialty certification. PMID- 25443122 TI - Challenging misperceptions about ASC nursing: my story. PMID- 25443123 TI - Satisfaction, press ganey, and magnet recognition. PMID- 25443124 TI - Accountability in nursing practice: why it is important for patient safety. PMID- 25443125 TI - Evidence appraisal of Joshi B, Aggarwal N, Chopra S, Taneja N. A prospective randomized controlled comparison of immediate versus late removal of urinary catheter after abdominal hysterectomy. PMID- 25443126 TI - Don't use that port: insert a PICC. PMID- 25443127 TI - Silicone/vegetable oil Janus emulsion: topological stability versus interfacial tensions and relative oil volumes. AB - Several aspects were studied of the formation and destabilization in bulk of silicone/vegetable oil, SO/VO, Janus emulsions, stabilized by Tween 80. In the formation of the emulsions, it was unexpectedly found that the dispersions tended to contain both single and flocculated drops irrespective of the emulsification intensity. Microscopy of the emulsions with no cover glass revealed flocculated drops of a large (200-500 MUm) central SO drop with many small VO drops attached. Applying a cover glass did not significantly change the drop size; instead two oil Janus drops of well-defined contact angle were found. The emulsions showed rapid creaming irrespective of the preparation method, but a few days storage did not significantly change the drop size in the creamed layer, nor was separation of the oils detected. The total interfacial free energy of the Janus drops at equilibrium was compared to the two relevant alternatives; engulfed and separate drops. The Janus drop free energies were found less for all volume ratios of the oils, when the surfactant concentrations in the aqueous phase was sufficient to prevent spreading of VO on SO. Changing the surfactant concentration to bring the interfacial tensions closer to the critical value for spreading gave declining interfacial free energy difference to that of engulfed drops. PMID- 25443128 TI - Uptake of breast screening and associated factors among Hong Kong women aged >=50 years: a population-based survey. AB - OBJECTIVE: To examine the uptake of breast screening and its associated factors among Hong Kong Chinese women aged >=50 years. STUDY DESIGN: Cross-sectional population-based survey. METHODS: A sample of Hong Kong Chinese women was recruited through telephone random-digit dialling. The survey consisted of six sections: perceived health status, use of complementary medicine, uptake of breast screening, perceived susceptibility to cancer, family history of cancer and demographic data. The factors associated with uptake of breast screening were analysed using logistic regression analysis. RESULTS: In total, 1002 women completed the (anonymous) telephone survey. The mean age was 63.5 (standard deviation 10.6) years. The uptake rate of breast screening among Hong Kong Chinese women aged >=50 years was 34%. The primary reasons for undertaking breast screening were as part of a regular medical check-up (74%), prompted by local signs and symptoms (11%) and a physician's recommendation (7%). Higher educational level, married or cohabiting, family history of cancer, frequent use of complementary therapies, regular visits to a doctor or Chinese herbalist, and the recommendation of a health professional were all independently and significantly associated with increased odds of having had a mammogram. CONCLUSIONS: This study provides community-based evidence of the need for public health policy to promote broader use of mammography services among this target population, with emphasis on the active involvement of health care professionals, through the development and implementation of appropriate evidence-based and resource-sensitive strategies. PMID- 25443129 TI - Association between colorectal cancer screening rate and motivation to quit smoking: the Fourth Korean National Health and Nutrition Examination Survey. PMID- 25443130 TI - Demographic, socio-economic and clinical characteristics: implications for time to presentation at a Nigerian tertiary ophthalmic outpatient population. AB - OBJECTIVE: To investigate the associations between time to presentation, and sociodemographic and clinical characteristics of new adult ophthalmic outpatients at the University of Nigeria Teaching Hospital (UNTH), Enugu, between March and August 2010. STUDY DESIGN: Hospital-based case-control study. METHODS: Consecutive new ophthalmic outpatients at UNTH were categorized into controls (early presenters, i.e. <3 months after onset of current eye disease) and cases (late presenters, i.e. >3 months after onset of current eye disease). Relevant data were obtained from the participants' case notes and interviews. Descriptive statistics yielded frequency distributions; bivariate and multivariate comparisons were used to test the significance of associations. P < 0.05 was considered to indicate significance. RESULTS: Eight hundred and twenty-four subjects [454 males and 370 females, mean age 39.2 (standard deviation 1.2) years, range 19-82 years] participated in this study. There were 370 early presenters and 454 late presenters. Multivariate analysis found that late presentation was significantly associated with age >50 years [odds ratio (OR) 1.34, 95% confidence interval (CI) 1.28-2.22; P < 0.01], female gender (OR 1.63, 95% CI 1.52-2.11; P < 0.01), residence >20 km from UNTH (OR 0.65, 95% CI 0.38 0.89; P = 0.0212), individual-level deprivation (OR 0.69, 95% CI 0.55-0.92; P = 0.0324) and subnormal visual acuity at presentation (OR 1.32, 95% CI 1.05-1.76; P = 0.0353). CONCLUSIONS: At UNTH, most new adult ophthalmic outpatients present >3 months after onset of their current eye disease. Measures to overcome age-, gender- and distance-related causes of late presentation, grassroots economic empowerment of the feeder population and public education about eye health are required. PMID- 25443131 TI - A telephone reminder intervention to improve breast screening information and access. AB - OBJECTIVES: In the UK, women aged 50-70 are offered breast cancer screening every three years. Screening participation rates in London have been particularly low. Low rates have been associated with low socio-economic status, and some ethnic groups have been observed to be underserved by cancer screening. This paper reports on a telephone reminder intervention in London Newham, an area of high deprivation and ethnic diversity. STUDY DESIGN: Observational study of planned intervention. METHODS: Women invited for breast screening were telephoned to confirm receipt of the invitation letter, remind invitees of their upcoming appointment, and to provide further information. Aggregate data at general practice level on invitation to and attendance at breast screening and on numbers reached by telephone were analysed by logistic regression. RESULTS: For the 29 participating GP practices (10,928 invitees) overall uptake in 2010 was higher compared to the previous screening round in 2007 (67% vs. 51%; p < 0.001). On average 59% of invitees were reached by the reminder calls. A 10% increase in women reached resulted in an 8% increase in the odds of women attending their screening appointment (95% CI: 5%-11%), after adjusting for 2007 attendance rates. Practices with a higher proportion of South Asian women were associated with a larger uptake adjusted for 2007 uptake and population reached by the telephone intervention, (4% increase in odds of attendance per 10% increase in South Asian population, CI 1%-7%, p = 0.003) while practices with a higher proportion of black women were associated with a smaller uptake similarly adjusted. (11% decrease in odds of attendance per 10% increase in black population, CI 9%-16%, p < 0.001). CONCLUSIONS: A language- and culture-sensitive programme of reminder calls substantially improved breast cancer screening uptake. PMID- 25443132 TI - Inpatient expenditures on alcohol-attributed diseases and alcohol tax policy: a nationwide analysis in Taiwan from 1996 to 2010. AB - OBJECTIVES: To assess the two opposing effects of alcohol tax policy interventions (tax rate increase in 2002 and decrease in 2009) on hospitalization in monetary terms of alcohol-attributed diseases (AADs) in Taiwan. STUDY DESIGN: An interrupted time-series analysis. METHODS: Admissions data from 1996 to 2010 were retrieved from the National Health Insurance Research Database claims file and analysed in this study. Data for 430,388 males and 34,874 females aged 15 or above who were admitted due to an AAD were collected. An interrupted time-series analysis examining the effects of the implementation of alcohol tax policy on quarterly adjusted hospital inpatient charges (HICs) for AADs was employed. RESULTS: The study showed significant (p < 0.001) changes in the adjusted HICs for AADs in 2002. Quarterly HICs showed an abrupt 14.8% decline (i.e., a 1.3 million US dollar reduction) after the first tax policy was implemented. No change in quarterly HICs for AADs was found after the alcohol tax increase. The total cost of treating these AAD inpatients over the course of the 15-year period was 640.9 million US dollars. Each inpatient with an AAD costs an average of $900 $2000 depending on the patient's sex and age with the cost increasing gradually after the two tax interventions. More than 80% of the HICs were attributed to alcoholic liver diseases. Psychoses accounted for 6%-18% of the total HICs. Alcohol abuse and alcohol poisoning accounted for less than 2% of the total HICs. CONCLUSIONS: This study provides evidence that alcohol taxation has resulted in an immediate reduction of medical expenditures related to AADs. The policy of increasing alcohol tax rates may have favourable influences on health care resources related to treating AADs. PMID- 25443133 TI - Female students receiving post-secondary education in Greece: the results of a collaborative human papillomavirus knowledge survey. AB - OBJECTIVES: Contrary to the optimistic forecasts, existing until 2008 and despite the incorporation of the vaccine into the Greek National Immunization Program, six years later, the percentage of HPV vaccination coverage in Greece remains disappointingly low. The aim of this extended study was to investigate the knowledge, behaviour and attitude of a representative sample of the initial target group; young female students of Greek higher education institutions to Pap cervical screening, biology of HPV infection and principles of HPV vaccination. STUDY DESIGN: Cross-sectional study. METHODS: One thousand two hundred ten (1210) questionnaires were completed by young female students aged 17-24 years. The survey questionnaire sought data relating to sociodemographic characteristics, health behaviour and knowledge about HPV, as well as vaccination status. RESULTS: 79.6% of the sample reported at least one annual gynaecologic examination and 92.6% were familiar with the rationale of cervical screening; however only 52.9% had undergone a Pap smear. 69.7% reported adequate knowledge about HPV and 89.3% were aware of the possible course of HPV infection. Despite most (95.9%) were aware of vaccine availability, vaccinated students represented only 33.1%. According to the multivariate analysis, vaccination status was associated with university studies (OR 1.96; 95% CI: 1.19-3.20), parental area of expertise (OR 2.77; 95% CI: 1.18-6.53, OR 2.03; 95% CI: 1.05-3.94), and adequate knowledge of the reasons for which women should undergo regular cervical screening (OR 4.23; 85% CI: 1.55-11.55). Fear of side-effects and equivocal information were the main reasons of non-vaccination (52.2% and 33.1% respectively). Finally, the majority of unvaccinated individuals showed a positive attitude towards prospective HPV vaccination, providing they received well-documented advising. CONCLUSIONS: Young women attending Greek higher education exhibit a good level of knowledge about HPV and its correlation with cervical cancer. These data highlight the need for further sensitization of the general population. PMID- 25443134 TI - Osteoporosis hospital admissions varied across sub-regions but not seasons in England: Hospital Episode Statistics, 2008-2011. PMID- 25443135 TI - Risk assessment of vector-borne diseases for public health governance. AB - OBJECTIVES: In the context of public health, risk governance (or risk analysis) is a framework for the assessment and subsequent management and/or control of the danger posed by an identified disease threat. Generic frameworks in which to carry out risk assessment have been developed by various agencies. These include monitoring, data collection, statistical analysis and dissemination. Due to the inherent complexity of disease systems, however, the generic approach must be modified for individual, disease-specific risk assessment frameworks. STUDY DESIGN: The analysis was based on the review of the current risk assessments of vector-borne diseases adopted by the main Public Health organisations (OIE, WHO, ECDC, FAO, CDC etc...). METHODS: Literature, legislation and statistical assessment of the risk analysis frameworks. RESULTS: This review outlines the need for the development of a general public health risk assessment method for vector-borne diseases, in order to guarantee that sufficient information is gathered to apply robust models of risk assessment. Stochastic (especially spatial) methods, often in Bayesian frameworks are now gaining prominence in standard risk assessment procedures because of their ability to assess accurately model uncertainties. CONCLUSIONS: Risk assessment needs to be addressed quantitatively wherever possible, and submitted with its quality assessment in order to enable successful public health measures to be adopted. In terms of current practice, often a series of different models and analyses are applied to the same problem, with results and outcomes that are difficult to compare because of the unknown model and data uncertainties. Therefore, the risk assessment areas in need of further research are identified in this article. PMID- 25443136 TI - The economic burden of diabetes in India: a review of the literature. AB - BACKGROUND: Diabetes and its complications are a major cause of morbidity and mortality in India, and the prevalence of type 2 diabetes is on the rise. This calls for an assessment of the economic burden of the disease. OBJECTIVE: To conduct a critical review of the literature on cost of illness studies of diabetes and its complications in India. METHODS: A comprehensive literature review addressing the study objective was conducted. An extraction table and a scoring system to assess the quality of the studies reviewed were developed. RESULTS: A total of nineteen articles from different regions of India met the study inclusion criteria. The third party payer perspective was the most common study design (17 articles) while fewer articles (n =2) reported on costs from a health system or societal perspective. All the articles included direct costs and only a few (n =4) provided estimates for indirect costs based on income loss for patients and carers. Drug costs proved to be a significant cost component in several studies (n =12). While middle and high-income groups had higher expenditure in absolute terms, costs constituted a higher proportion of income for the poor. The economic burden was highest among urban groups. The overall quality of the studies is low due to a number of methodological weaknesses. The most frequent epidemiological approach employed was the prevalence-based one (n =18) while costs were mainly estimated using a bottom up approach (n =15). CONCLUSION: The body of literature on the costs of diabetes and its complications in India provides a fragmented picture that has mostly concentrated on the direct costs borne by individuals rather than the healthcare system. There is a need to develop a robust methodology to perform methodologically rigorous and transparent cost of illness studies to inform policy decisions. PMID- 25443137 TI - Relaxant and antioxidant capacity of the red wine polyphenols, resveratrol and quercetin, on isolated mice corpora cavernosa. AB - INTRODUCTION: The red wine polyphenols resveratrol and quercetin are known for their vasorelaxant and antioxidant capacity, which is assumed to rely on the activation of the nitric oxide (NO)/soluble guanylyl cyclase (sGC) pathway. Vasodilators as well as antioxidants can regulate penile erection and be beneficial for the treatment of erectile dysfunction (ED). AIMS: The goal of this study was to evaluate the NO/sGC dependency of the relaxant effect of resveratrol and quercetin on mice aorta and corpora cavernosa (CC), as well as to explore their influence on oxidative stress-induced ED. METHODS: Isolated mice aorta and CC were mounted for isometric tension recordings into organ baths. Cumulative concentration-response curves were constructed for resveratrol and quercetin in the absence/presence of inhibitors of the NO/sGC pathway. In addition, in CC the effect of resveratrol and quercetin was studied on NO-mediated relaxations using acetylcholine (Ach), sodium nitroprusside (SNP), and electrical field stimulation (EFS). In certain experiments, corporal tissues were exposed to oxidative stress using palmitic acid (PA, 0.5 mM). MAIN OUTCOME MEASURES: Corporal responses to resveratrol and quercetin were measured in the presence/absence of inhibitors of different molecular pathways. The effect of resveratrol and quercetin incubation on Ach-, SNP-, or EFS-mediated responses was explored in the presence/absence of PA. RESULTS: While both polyphenols are potent vasodilators of mice aorta, only resveratrol relaxes mice CC. The relaxation response to resveratrol on aorta was diminished in sGCalpha1 (-/-) mice, but not on CC. The polyphenols did not influence Ach-, SNP-, or EFS-mediated relaxations as such. Resveratrol, but not quercetin, was able to significantly reverse PA-induced decrease of EFS relaxations. CONCLUSION: The red wine compound resveratrol, but not quercetin, relaxes isolated mice CC concentration-dependently through mechanisms independent of the NO/sGC pathway. Resveratrol is a more potent antioxidant than quercetin, being able to restore decreased neuronal NO responses in mice CC. PMID- 25443138 TI - MicroRNA-19a enhances proliferation of bronchial epithelial cells by targeting TGFbetaR2 gene in severe asthma. AB - BACKGROUND: Allergic asthma is characterized by inflammation and airway remodeling. Bronchial epithelium is considered a key player in coordinating airway wall remodeling. In mild asthma, the epithelium is damaged and fails to proliferate and to repair, whereas in severe asthma, the epithelium is highly proliferative and thicker. This may be due to different regulatory mechanisms. The purpose of our study was to determine the role of miRNAs in regulating proliferation of bronchial epithelial cells obtained from severe asthmatic subjects in comparison with cells obtained from mild asthmatics and healthy controls. METHODS: Human bronchial epithelial cells (BEC) were isolated by bronchoscopy from bronchial biopsies of healthy donors and patients with mild and severe asthma. MiRNA expression was evaluated using the TaqMan low-density arrays and qRT-PCR. Transfection studies of bronchial epithelial cells were performed to determine the target genes. Cell proliferation was evaluated by BrdU incorporation test. RESULTS: MiR-19a was upregulated in epithelia of severe asthmatic subjects compared with cells from mild asthmatics and healthy controls. Functional studies based on luciferase reporter and Western blot assays suggest that miR-19a enhances cell proliferation of BEC in severe asthma through targeting TGF-beta receptor 2 mRNA. Moreover, repressed expression of miR-19a increased SMAD3 phosphorylation through TGF-beta receptor 2 signaling and abrogated BEC proliferation. CONCLUSION: Our study uncovers a new regulatory pathway involving miR-19a that is critical to the severe phenotype of asthma and indicates that downregulating miR-19a expression could be explored as a potential new therapy to modulate epithelium repair in asthma. PMID- 25443139 TI - Children trust people who lie to benefit others. AB - The current research examined whether children consider who benefits from lies when judging the trustworthiness of liars. Across two studies (total N=214), 6- to 11-year-olds trusted individuals who lied to promote the interests of others, but not those who lied to promote their own interests. In contrast, children trusted individuals who told the truth regardless of who benefited. Trust in individuals who lied to promote the interests of others was evident even in the absence of moral approval for their actions. These results demonstrate that children take into account both the truth value of a speaker's statements and who benefits when assessing trustworthiness and that moral approval is not a prerequisite for trust. PMID- 25443140 TI - Gestational syphilis and stillbirth in Latin America and the Caribbean. AB - OBJECTIVE: To measure the association between gestational syphilis and stillbirth in Latin America and the Caribbean. METHODS: In a retrospective study, data on stillbirth and gestational syphilis extracted from the Sistema Informatico Perinatal database were analyzed for deliveries in 11 countries between January 1, 2009, and December 31, 2012. Potential confounders were examined, and binary logistic regression analysis was performed to assess the association between gestational syphilis and stillbirth. RESULTS: Among 368 151 deliveries, 3875 (1.1%) were by women with a positive syphilis test, and 1461 (0.4%) were stillbirths. Among the stillbirths, 29 (2.0%) were delivered by women with a positive syphilis test. After controlling for country, congenital anomalies, gestational age at labor, maternal age, and previous stillbirth, gestational syphilis was significantly associated with stillbirth (odds ratio 1.88, 95% confidence interval 1.25-2.83; P=0.002). CONCLUSION: Gestational syphilis contributes to stillbirth in Latin America and the Caribbean. Interventions targeting gestational syphilis are highly cost-effective and should be implemented across the region. PMID- 25443141 TI - Early-life stress selectively affects gastrointestinal but not behavioral responses in a genetic model of brain-gut axis dysfunction. AB - BACKGROUND: Early-life stress and a genetic predisposition to display an anxiety- and depressive-like phenotype are associated with behavioral and gastrointestinal (GI) dysfunction. Animals exposed to early-life stress, and those genetically predisposed to display anxiety or depressive behaviors, have proven useful tools in which to study stress-related GI disorders, such as irritable bowel syndrome (IBS). IBS is a heterogeneous disorder, and likely a consequence of both genetic and environmental factors. However, the combined effects of early-life stress and a genetic predisposition to display anxiety- and depression-like behaviors on GI function have not been investigated. METHODS: We assessed the effect of maternal separation (MS) on behavioral and GI responses in WKY animals relative to a normo anxious reference strain. KEY RESULTS: Both non-separated (NS) WKY and WKY-MS animals displayed anxiety-like responses in the open-field test and depressive like behaviors in the forced swim test relative to Sprague-Dawley rats. However, MS had no further influence on anxiety- and depressive-like behaviors exhibited by this stress-prone rat strain. Similarly, corticosterone levels measured after the OFT were insensitive to MS in WKY animals. However, WKY-MS displayed significantly increased colonic visceral hypersensitivity, fecal output, and altered colonic cholinergic sensitivity. CONCLUSIONS & INFERENCES: Our data suggest that early-life stress, on the background of a genetic predisposition to display an anxiety- and depressive-like phenotype, selectively influences GI function rather than stress-related behaviors. Thus, our findings highlight the importance of genetic predisposition on the outcome of early-life adversity on GI function. PMID- 25443142 TI - Current concepts--future needs: the 10th Annual Meeting of the International Bladder Cancer Network (IBCN) in Nijmegen, The Netherlands, September 20th to 22nd, 2012. PMID- 25443143 TI - Commentary on "economic and humanistic consequences of preventable bladder tumor recurrences in nonmuscle invasive bladder cancer cases." Lee CT, Barocas D, Globe DR, Oefelein MG, Colayco DC, Bruno A, O'Day K, Bramley T, Department of Urology, University of Michigan, Ann Arbor, MI.: J Urol 2012;188(6):2114-9. [Epub 2012 Oct 18]. doi: 10.1016/j.juro.2012.08.005. AB - PURPOSE: Perioperative intravesical chemotherapy following transurethral resection of bladder tumor has been underused despite level 1 evidence supporting its performance. The primary objective of this study was to estimate the economic and humanistic consequences associated with preventable recurrences in patients initially diagnosed with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: Using population based estimates of nonmuscle invasive bladder cancer incidence, a 2-year model was developed to estimate the number of preventable recurrences in eligible patients untreated with perioperative intravesical chemotherapy. Therapy utilization rates were obtained from a retrospective database analysis and a chart review study of 1,010 patients with nonmuscle invasive bladder cancer. Recurrence rates of nonmuscle invasive bladder cancer were obtained from a randomized clinical trial comparing transurethral resection of bladder tumor with or without perioperative mitomycin C. Costs were estimated using prevailing Medicare reimbursement rates. Quality adjusted life-year estimates and disutilities for complications were obtained from the literature. RESULTS: The model estimated that 7,827 bladder recurrences could be avoided if all patients received immediate intravesical chemotherapy. It estimated an economic savings of $3,847 per avoidable recurrence, resulting in an aggregate savings of $30.1 million. The model also estimated that 1,025 quality adjusted life-years are lost every 2 years due to preventable recurrences, resulting in 0.13 quality adjusted life-years (48 quality adjusted days) lost per avoidable recurrence. This translates into 0.02 quality adjusted life-years (8.1 quality adjusted days) lost per patient not receiving immediate intravesical chemotherapy. CONCLUSIONS: Greater use of immediate intravesical chemotherapy in the United States has the potential to substantially decrease the economic and humanistic burdens of nonmuscle invasive bladder cancer. PMID- 25443144 TI - Commentary on "the burden of depression in prostate cancer." Jayadevappa R, Malkowicz SB, Chhatre S, Johnson JC, Gallo JJ, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA.: Psychooncology 2012;21(12):1338-45. [Epub 2011 Aug 12]. doi: 10.1002/pon.2032. AB - OBJECTIVE: We sought to analyze the prevalence and incremental burden of depression among elderly with prostate cancer. METHODS: We adopted a retrospective cohort design using the Surveillance, Epidemiology and End Results Medicare linked database between 1995 and 2003. Patients with prostate cancer diagnosed between 1995 and 1998 were identified and followed retrospectively for 1 year pre-diagnosis and up to 8 years post diagnosis. In this cohort of patients with prostate cancer, depression during treatment phase (1 year after diagnosis of prostate cancer) or in the follow-up phase was identified using the International Classification of Diseases-Ninth Revision depression-related codes. Poisson, general linear (log-link) and Cox regression models were used to determine the association between depression status during treatment and follow up phases and outcomes-health resource utilization, cost and mortality. RESULTS: Of the 50,147 patients newly diagnosed with prostate cancer, 4285 (8.54%) had a diagnosis of depression. A diagnosis of depression during treatment phase was associated with higher odds of emergency room visits (odds ratio (OR) = 4.45, 95% CI = 4.13, 4.80), hospitalizations (OR = 3.22, CI = 3.08, 3.37), outpatient visits (OR = 1.71, CI = 1.67, 1.75) and excess risk of death over the course of the follow-up interval (hazard ratio = 2.82, CI = 2.60, 3.06). Health care costs associated with depression remained elevated compared with costs for men without depression, over the course of the follow-up. CONCLUSIONS: Depression during the treatment phase was associated with significant health resource utilization, costs and mortality among men with prostate cancer. These findings emphasize the need to effectively identify and treat depression in the setting of prostate cancer. PMID- 25443145 TI - Commentary on "factors associated with satisfaction with prostate cancer care: results from Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE)." Resnick MJ, Guzzo TJ, Cowan JE, Knight SJ, Carroll PR, Penson DF, VA Tennessee Valley Geriatric Research, Education and Clinical Care, Nashville, TN.: BJU Int 2013;111(2):213-20. [Epub 2012 Aug 29]. doi: 10.1111/j.1464 410X.2012.11423.x. AB - OBJECTIVE: To evaluate the impact of demographic, clinical, treatment and patient reported parameters on satisfaction with prostate cancer care. Despite the significant worldwide impact of prostate cancer, few data are available specifically addressing satisfaction with treatment-related care. PATIENTS AND METHODS: CaPSURE comprises participants from 40 US sites who were monitored during and after their treatment course. Participants who were diagnosed with clinically localized prostate cancer after 1999 underwent radical prostatectomy, radiation therapy or primary androgen deprivation, and those who also completed the satisfaction questionnaire within 2 years of treatment were included in the present study. Satisfaction was measured using a validated instrument that assesses contact with providers, confidence in providers, communication skills, humanness and overall satisfaction. Multivariable linear regression analysis were performed to evaluate the independent relationships between demographic, clinical, treatment and patient-reported parameters and satisfaction. RESULTS: Of the 3056 participants, 1927 (63%) were treated with radical prostatectomy, 843 (28%) were treated with radiation therapy and 286 (9%) were treated with primary androgen deprivation. Multivariable analysis showed that multiple patient reported factors were independently associated with satisfaction, whereas clinical, demographic and treatment parameters were not. Baseline health-related quality of life, measured by the 36-item short-form health survey, baseline fear of cancer recurrence (all P<0.01) and declines in the sexual (P = 0.03), urinary (P<0.01) and bowel (P = 0.02) function domains of the University of California Los Angeles Prostate Cancer Index were all independently associated with satisfaction. Patient-reported outcomes were more strongly associated with satisfaction in the low-risk subgroup. CONCLUSIONS: Patient-reported factors such as health-related quality of life and fear of cancer recurrence are independently associated with satisfaction with care. Pretreatment parameters should be used to identify populations at-risk for dissatisfaction to allow for intervention and/or incorporation into treatment decision-making. PMID- 25443146 TI - An update on the epidemiology and pathology of African swine fever. AB - African swine fever (ASF) is one of the most important infectious diseases of swine and has major negative consequences for affected countries. ASF is present in many sub-Saharan countries, Sardinia and several countries of eastern and central Europe, where its continuous spread has the swine industry on heightened alert. ASF is a complex disease for which no vaccine or treatment is available, so its control is based on early detection and rapid control of spread. For a robust and reliable early detection programme it is essential to be able to recognize the clinical signs and pathological changes of ASF, keeping in mind that in most cases the first introductions don't show high mortality nor characteristic clinical signs or lesions, but fever and some hemorrhagic lymph nodes. Knowledge of the main characteristics of this infection, including its current distribution and routes of transmission, is also essential for preventing and controlling ASF. This review addresses each of these topics and aims to update knowledge of the disease in order to improve early detection of ASF in the field and allow implementation of public health programmes. PMID- 25443147 TI - Age-related changes in the articular cartilage of the stifle joint in non-working and working German Shepherd dogs. AB - The aims of this study were to define age-related histological changes in the articular cartilage of the stifle joint in non-chondrodystrophic dogs and to determine whether physical activity has a positive impact on preservation of cartilage structure during ageing. Twenty-eight German shepherd dogs were included in the study. These dogs had no evidence of joint inflammation as defined by clinical assessment, radiology and synovial fluid analysis (specifically absence of synovial fluid serum amyloid A). The dogs were grouped as young working (n 1/4 4), young non-working (n 1/4 5), aged working (n 1/4 13) and aged non-working (n 1/4 6) animals. Gross changes in the stifle joints were recorded and biopsy samples of femoral and tibial articular cartilage were evaluated for thickness; chondrocyte number, density, surface area and morphology; isogenous group morphology; tidemark integrity; subchondral bone structure; presence of proteoglycans/ glycosaminoglycans; and expression of type I, II and X collagens. The major age-related changes, not related to type of physical activity, included elevated chondrocyte density and thinning of tibial cartilage and increased chondrocyte surface area in the superficial and intermediate zone of the femoral cartilage. There was also expression of type X collagen in the femoral and tibial calcified and non-calcified cartilage; however, type X collagen was not detected in the superficial zone of old working dogs. Therefore, ageing, with or without physical activity, leads to slight cartilage degeneration, while physical activity modulates the synthesis of type X collagen in the superficial cartilage zone, partially preserving the structure of hyaline cartilage. PMID- 25443148 TI - Intermittent negative-pressure therapy with antibiotic instillation for necrotizing fasciitis of the abdomen and retroperitoneum due to an infected renal hematoma. PMID- 25443149 TI - Inflammatory markers as predictors of postoperative adverse outcome in octogenarian surgical patients: an observational prospective study. AB - INTRODUCTION: The value of inflammatory proteins, interleukin-6 and alpha-1-acid glycoprotein as prognostic factors in elderly people undergoing surgery has not been determined yet. OBJECTIVE: To know whether preoperatively determined inflammatory markers may predict the postoperative outcome of elderly patients undergoing surgery. A scoring system for predicting postoperative morbidity was assessed. METHODS: Hospital-based observational prospective study, with geriatric surgical patients. Preoperative determination of following data: age, gender, scheduled or urgent operation, comorbid diseases, malignancy, physical, mental and nutritional profile. Biochemical markers of inflammation, C Reactive Protein, interleukin-6, and alpha-1-acid glycoprotein were also studied. Preoperative data and postoperative complications were recorded. Binary logistic regression analysis was used to obtain a morbidity risk prediction model. RESULTS: A total of 225 patients were included. Fifty-five patients (24.4%) had postoperative complications, with a mortality rate of 5.3%. Binary logistic regression analysis showed an independent relation between morbidity and the variables malignancy, alpha-1-acid glycoprotein and interleukin-6. The risk (R) of postoperative morbidity adjusted by age was calculated. The model showed a 22.2% sensitivity, 94.8% specificity, and a percentage of correct classification of 78.3%. The area under the ROC curve was 0.781 (95% CI: 0.703-0.858). CONCLUSIONS: An age-adjusted equation for predicting 30-day morbidity that included malignancy, serum IL-6 and alpha 1-acid glycoprotein levels may be useful for risk assessment in octogenarian surgical patients. PMID- 25443150 TI - Detection of adverse events in general surgery using the " Trigger Tool" methodology. AB - INTRODUCTION: Surgery is one of the high-risk areas for the occurrence of adverse events (AE). The purpose of this study is to know the percentage of hospitalisation-related AE that are detected by the "Global Trigger Tool" methodology in surgical patients, their characteristics and the tool validity. MATERIAL AND METHODS: Retrospective, observational study on patients admitted to a general surgery department, who underwent a surgical operation in a third level hospital during the year 2012. The identification of AE was carried out by patient record review using an adaptation of "Global Trigger Tool" methodology. Once an AE was identified, a harm category was assigned, including the grade in which the AE could have been avoided and its relation with the surgical procedure. RESULTS: The prevalence of AE was 36,8%. There were 0,5 AE per patient. 56,2% were deemed preventable. 69,3% were directly related to the surgical procedure. The tool had a sensitivity of 86% and a specificity of 93,6%. The positive predictive value was 89% and the negative predictive value 92%. CONCLUSIONS: Prevalence of AE is greater than the estimate of other studies. In most cases the AE detected were related to the surgical procedure and more than half were also preventable. The adapted "Global Trigger Tool" methodology has demonstrated to be highly effective and efficient for detecting AE in surgical patients, identifying all the serious AE with few false negative results. PMID- 25443152 TI - Accelerated treatment of concomitant empyema and lung cancer by video-assisted thoracoscopic surgery. AB - BACKGROUND: The most common cause of pleural empyema are parapneumonic effusions, and lung cancer is a rare cause of empyema. The aim of the present study is to analyse the results of the thoracoscopic treatment of empyema before definitive oncological treatment. METHODS: Retrospective descriptive study of 332 patients including different clinical variables between 2002 and 2010. RESULTS: Among 332 patients with empyema, the etiology of this disease was lung cancer in 11 patients. Ten of these patients were male and one was female (median age, 57.9 years; range, 46-76). The initial treatment was tube thoracostomy in 8 patients and video-assisted thoracoscopic surgery in 3 patients. Thoracoscopic debridement was performed in 4 patients whose tube thoracostomy underperformed because of insufficient drainage. The methods used for diagnosis of lung cancer were fiberoptic bronchoscopy and video-assisted thoracoscopic surgery. Surgical resection was performed on 7 suitable patients following infection control. Postoperative bronchopleural fistula and empyema occurred after pneumonectomy in one case. No operative mortality was observed. The mean survival time was 32.8 months for patients undergoing resection. CONCLUSIONS: Empyema could be a rare presentation of lung cancer and those suitable for surgical treatment should undergo standard treatment with reasonable results. PMID- 25443151 TI - Duodenal injuries due to trauma: Review of the literature. AB - Duodenal injuries constitute a challenge to the Trauma Surgeon, mainly due to their retroperitoneal location. When identified, they present associated with other abdominal injuries. Consequently, they have an increased morbidity and mortality. At best estimates, duodenal lesions occur in 4.3% of all patients with abdominal injuries, ranging from 3.7% to 5%, and because of their anatomical proximity to other organs, they are rarely an isolated injury. The aim of this paper is to present a concise description of the anatomy, diagnosis, surgical management and treatment of complications of duodenal trauma, and an analysis of complications and mortality rates of duodenal injuries based on a 46-year review of the literature. PMID- 25443153 TI - Laparoscopic surgery of the abdominal wall: Why has it not been implemented like other laparoscopic procedures? PMID- 25443154 TI - Total pelvic exenteration for the treatment of advanced primary or recurrent pelvic neoplasia. AB - INTRODUCTION: Complete resection with clear margins in locally advanced pelvic visceral tumors, primary or recurrent, occasionally requires total pelvic exenteration (TPE). METHODS: We reviewed the results of EFA in 34 consecutive patients operated on between June 2006 and December 2013. RESULTS: Median age was 62 (40-82) years; 24 (70%) were male. The tumor origin most frequent was advanced primary rectal tumor (APRT), with 19 cases (55.9%) and most common type of exenteration was supraelevator (61.8%). R0 resection was achieved in 24 (70.6%) patients and in 16 (85%) of the APRT. Fifteen (79%) patients had pT4 APRT, and 4 (20%) pN +. Reconstruction of the bowel and bladder was performed with two stomas in 17 cases (50%), colorectal anastomosis and Bricker in 11 (32.3%) and wet double barreled colostomy in 6 (17.6%). There was no postoperative mortality; 23 (67,5%) patients had complications, and 5 (14.6%) required a postoperative reoperation to solve them. Median follow-up was 23 (13-45) months. Overall survival (OS) and disease free survival (DFS) at 2 years were 67% and 58% respectively, and the median OS and DFS was 59 months (95% CI 26-110) and 39 months (95% CI 14-64), respectively. The DFS of R0 was significantly better (p=0.003) than R1. CONCLUSIONS: TPE is a potentially curative procedure for advanced pelvic visceral malignancies with similar morbi-mortality than other extended excisional surgery. PMID- 25443155 TI - Bilateral adrenal hemorrhagic infarction as a rare cause of acute abdominal pain in the immediate postoperative period of colonic surgery. PMID- 25443156 TI - Dynamics of asymmetrical hybridization in North American wood ferns: reconciling patterns of inheritance with gametophyte reproductive biology. AB - Hybridization is an important evolutionary force in plants, but the mechanisms underlying it have not been well studied for many groups. In particular, the drivers of non-random patterns of interspecific gene flow (asymmetrical hybridization) remain poorly understood, especially in the seed-free vascular plants. Here, we examine patterns of asymmetrical hybridization in two widespread fern hybrids from eastern North America and study the role of gametophyte ecology in the determination of hybridization bias. We characterized the maternal parentage of > 140 hybrid sporophytes by sequencing a c. 350-bp region of chloroplast DNA (cpDNA). To identify factors contributing to patterns of asymmetrical hybridization, we cultured gametophytes of the parental species and evaluated critical aspects of their reproductive biology. We found that asymmetrical hybridization was prevalent across the populations of both hybrids. Reproductive traits varied across species and suggest that selfing potential, antheridiogen responsiveness, sperm dispersal capacity and gamete size all contribute to the mediation of the direction of hybridization in this group. Our findings suggest that asymmetrical hybridization in ferns is driven by an array of reproductive traits. This study helps to sharpen and define a mechanistic understanding of patterns of hybridization in this group and demonstrates the importance of considering gametophyte biology when studying evolutionary processes in ferns. PMID- 25443157 TI - Aeromonas piscicola AH-3 expresses an extracellular collagenase with cytotoxic properties. AB - The aim of this study was to investigate the presence and the phenotypic expression of a gene coding for a putative collagenase. This gene (AHA_0517) was identified in Aeromonas hydrophila ATCC 7966 genome and named colAh. We constructed and characterized an Aeromonas piscicola AH-3::colAh knockout mutant. Collagenolytic activity of the wild-type and mutant strains was determined, demonstrating that colAh encodes for a collagenase. ColAh-collagen interaction was assayed by Far-Western blot, and cytopathic effects were investigated in Vero cells. We demonstrated that ColAh is a gluzincin metallopeptidase (approx. 100 kDa), able to cleave and physically interact with collagen, that contributes for Aeromonas collagenolytic activity and cytotoxicity. ColAh possess the consensus HEXXH sequence and a glutamic acid as the third zinc binding positioned downstream the HEXXH motif, but has low sequence similarity and distinct domain architecture to the well-known clostridial collagenases. In addition, these results highlight the importance of exploring new microbial collagenases that may have significant relevance for the health and biotechnological industries. SIGNIFICANCE AND IMPACT OF THE STUDY: Collagenases play a central role in processes where collagen digestion is needed, for example host invasion by pathogenic micro-organisms. We identified a new collagenase from Aeromonas using an integrated in silico/in vitro strategy. This enzyme is able to bind and cleave collagen, contributes for AH-3 cytotoxicity and shares low similarity with known bacterial collagenases. This is the first report of an enzyme belonging to the gluzincin subfamily of the M9 family of peptidases in Aeromonas. This study increases the current knowledge on collagenolytic enzymes bringing new perspectives for biotechnology/medical purposes. PMID- 25443158 TI - Activated microglia in ischemic stroke penumbra upregulate MCP-1 and CCR2 expression in response to lysophosphatidylcholine derived from adjacent neurons and astrocytes. AB - In acute stage of ischemic stroke, the surrounding zone of fresh infarcts is termed penumbra, where microglia are activated in response to damaged cell derived proinflammatory mediators. Rescuing penumbra by regulating inflammatory activity would minimize infarct volume, which positively correlates with functional outcome. To elucidate mechanisms by which inflammation occurs in penumbra, we performed immunohistochemical investigations using autopsied human brains affected by acute, subacute and chronic stages of cerebral infarction as well as cell culture experiments using a murine microglia-derived cell line (BV 2). In penumbra of fresh infarcts, immunoreactivity for secretory phospholipase A2 group X (sPLA2 -X), which is responsible for the production and release of the proinflammatory mediator lysophosphatidylcholine (LPC), was intensely detected in neurons and astrocytes. Furthermore, immunoreactivities for the LPC receptors G protein-coupled receptor 132 (G2A) and P2X purinoreceptor 7 (P2X7R), as well as the CC chemokine monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2, were detectable in activated microglia. Prior to cell culture experiments, it was confirmed that BV-2 cells were immunoreactive for ionized Ca(2+) -binding adaptor molecule 1 (Iba1), G2A, P2X7R, MCP-1 and CCR2. Reverse transcription quantitative polymerase chain reaction analysis revealed that MCP-1 and CCR2 mRNA expression levels were significantly increased by LPC stimulation. The LPC-driven increase in MCP-1 transcripts was lowered by blockade of G2A or P2X7R or by inhibition of Rho-associated protein kinase (ROCK) or inhibitor of kappaBalpha kinase. The LPC-driven increase in CCR2 transcripts was lowered by blockade of G2A or P2X7R or by inhibition of ROCK, phosphatidylinositide 3-kinanse, extracellular signal-regulated kinase kinase, or p38 mitogen-activated protein kinase. The present results provide in vivo and in vitro evidence that in acute stage of ischemic stroke, the sPLA2 -X enzyme product LPC is released from neurons and astrocytes and stimulates penumbra microglia via G2A and P2X7R, thereby exerting the MCP-1/CCR2-mediated neurotoxicity through distinct cell signaling pathways. PMID- 25443159 TI - Influence of composition on setting kinetics of new injectable and/or fast setting tricalcium silicate cements. AB - OBJECTIVES: New commercial tricalcium silicate based cements were elaborated to improve handling properties and setting time. The goals of the present work were: (i) to determine the composition of the new injectable and/or fast setting calcium silicate based cements, and (ii) to investigate the impact of the differences in composition on their setting kinetics. METHODS: The materials considered were Angelus MTATM, BiodentineTM, MM-MTATM, MTA-CapsTM, and ProRoot MTATM as control. Elemental composition of materials was studied by Inductively Coupled Plasma-Atomic Emission Spectroscopy and X-ray Energy Dispersive analysis, whereas phases in presence were analyzed by Micro-Raman spectroscopy and X-ray Diffraction analysis and cement surface by Scanning Electron Microscope. Setting kinetics was evaluated using rheometry. RESULTS: Elemental analysis revealed, for all cements, the presence of three major components: calcium, silicon and oxygen. Chlorine was detected in MM-MTA, MTA-Caps and Biodentine. Different radio opacifiers were identified: bismuth oxide in ProRoot MTA, Angelus MTA and MM-MTA, zirconium oxide in Biodentine and calcium tungstate (CaWO4) in MTA-Caps. All cements were composed of di- and tri-calcium silicate, except Biodentine for which only the latter was detected. Major differences in setting kinetics were observed: a modulus of 8*10(8)Pa is reached after 12min for Biodentine, 150min for MM-MTA, 230min for Angelus MTA and 320min for ProRoot MTA. The maximum modulus reached by MTA-Caps was 7*10(8)Pa after 150min. SIGNIFICANCE: Even if these cements possess some common compounds, major differences in their composition were observed between them, which directly influence their setting kinetics. PMID- 25443161 TI - Advance care planning for older people in Australia presenting to the emergency department from the community or residential aged care facilities. AB - The purpose of this retrospective, cross-sectional study was to determine the prevalence of advance care planning (ACP) among older people presenting to an Emergency Department (ED) from the community or a residential aged care facility. The study sample comprised 300 older people (aged 65+ years) presenting to three Victorian EDs in 2011. A total of 150 patients transferred from residential aged care to ED were randomly selected and then matched to 150 people who lived in the community and attended the ED by age, gender, reason for ED attendance and triage category on arrival. Overall prevalence of ACP was 13.3% (n = 40/300); over one quarter (26.6%, n = 40/150) of those presenting to the ED from residential aged care had a documented Advance Care Plan, compared to none (0%, n = 0/150) of the people from the community. There were no significant differences in the median ED length of stay, number of investigations and interventions undertaken in ED, time seen by a doctor or rate of hospital admission for those with an Advance Care Plan compared to those without. Those with a comorbidity of cerebrovascular disease or dementia and those assessed with impaired brain function were more likely to have a documented Advance Care Plan on arrival at ED. Length of hospital stay was shorter for those with an Advance Care Plan [median (IQR) = 3 days (2-6) vs. 6 days (2-10), P = 0.027] and readmission lower (0% vs. 13.7%). In conclusion, older people from the community transferred to ED were unlikely to have a documented Advance Care Plan. Those from residential aged care who were cognitively impaired more frequently had an Advance Care Plan. In the ED, decisions of care did not appear to be influenced by the presence or absence of Advance Care Plans, but length of hospital admission was shorter for those with an Advance Care Plan. PMID- 25443160 TI - Simultaneous measurement of polymerization stress and curing kinetics for photo polymerized composites with high filler contents. AB - OBJECTIVES: Photopolymerized composites are used in a broad range of applications with their performance largely directed by reaction kinetics and contraction accompanying polymerization. The present study was to demonstrate an instrument capable of simultaneously collecting multiple kinetics parameters for a wide range of photopolymerizable systems: degree of conversion (DC), reaction exotherm, and polymerization stress (PS). METHODS: Our system consisted of a cantilever beam-based instrument (tensometer) that has been optimized to capture a large range of stress generated by lightly-filled to highly-filled composites. The sample configuration allows the tensometer to be coupled to a fast near infrared (NIR) spectrometer collecting spectra in transmission mode. RESULTS: Using our instrument design, simultaneous measurements of PS and DC are performed, for the first time, on a commercial composite with ~80% (by mass) silica particle fillers. The in situ NIR spectrometer collects more than 10 spectra per second, allowing for thorough characterization of reaction kinetics. With increased instrument sensitivity coupled with the ability to collect real time reaction kinetics information, we show that the external constraint imposed by the cantilever beam during polymerization could affect the rate of cure and final degree of polymerization. SIGNIFICANCE: The present simultaneous measurement technique is expected to provide new insights into kinetics and property relationships for photopolymerized composites with high filler content such as dental restorative composites. PMID- 25443162 TI - Psychosocial-Environmental Risk Factors for Suicide Attempts in Adolescents with Suicidal Ideation: Findings from a Sample of 73,238 Adolescents. AB - We determined risk factors that discriminate between suicide attempt (SA) adolescents and suicidal ideation only (SI only) adolescents using data from the 2010 Korea Youth Risk Behavior Web-based Survey (12-19 years; N = 73,238). In males, heavy alcohol use, drug use, and high perceived sadness/hopelessness showed significant effects on the presence of SA versus the presence of SI only. In females, along with these variables, low academic achievement, poor perceived health status, high perceived stress, and unhealthy coping strategy were also significantly related to the presence of SA versus SI only. Therefore, clinical interventions targeting adolescents' psychological distress are warranted to prevent suicide. PMID- 25443163 TI - Congenital radial nerve palsy. PMID- 25443164 TI - Firework-related injuries of the hand. PMID- 25443165 TI - Aesthetic and functional results from nailfold recession following fingertip amputations. AB - PURPOSE: To analyze the aesthetic and functional results of a technique for nail salvage by recessing the nailfold to increase the exposed nail matrix after fingertip amputation. METHODS: Thirty cases of fingertip amputation with distal partial nail bed defects underwent nailfold recession and pulp reconstruction. We increased nail bed exposure by recessing a rectangle flap of eponychium and reconstructed the pulp with different local flaps depending on the injury geometry. A 0.3- to 0.4-cm-wide rectangular strip of eponychium was de epithelialized. The eponychial flap was separated from the nail matrix and slid proximally to expose more nail matrix, thereby effectively lengthening the exposed nail bed. RESULTS: The flaps survived in all patients. The exposed nail beds were lengthened 0.3 to 0.4 cm and enlarged 38% to 100%. The fingertips had smooth and natural nail plates with inconspicuous scars on both the eponychium and pulp and no deformities. The sensation and mobility of injured and uninjured contralateral fingers did not differ statistically. All patients were satisfied with the appearance and function of the reconstructed fingertips. CONCLUSIONS: Nailfold recession combined with different local flaps provided for the aesthetic and functional restoration of the fingertip after amputation with partial nail bed defect. PMID- 25443166 TI - Inter- and intrarater reliability of osteoarthritis classification at the trapeziometacarpal joint. AB - PURPOSE: To assess the reliability of the Eaton and Glickel classification for base of thumb osteoarthritis. METHODS: The interrater and intrarater reliability of this classification were assessed by comparing ratings from 6 raters using quadratic weighted kappa scores. RESULTS: Median inter-rater reliability ranged from kappa of .53 to .54; intrarater reliability ranged from kappa of .60 to .82. Using unweighted kappa interrater reliability was "slightly" reliable, and intrarater reliability was "fairly" reliable. Overall, the value of the intraclass correlation for all 6 raters was .56. CONCLUSIONS: This radiological classification does not describe all stages of carpometacarpal joint osteoarthritis accurately enough to permit reliable and consistent communication between clinicians. Therefore we believe it should be used with an understanding of its limitations when communicating disease severity between clinicians or as a tool to assist in clinical decision making. PMID- 25443167 TI - Long-term effectiveness of corticosteroid injections for trigger finger and thumb. AB - PURPOSE: To analyze the long-term response to corticosteroid injection in the management of trigger digit. METHODS: This was an observational study of a prospectively recruited series of patients with first-time diagnosis of trigger finger. Efficacy of the injections, comorbidities, digit injected, and related complications were compared and statistically analyzed. RESULTS: A total of 71 digits were included in the study. The median (interquartile range) duration of follow-up was 8 years (range, 7.0-8.3 y). At final follow-up, complete remission of symptoms was obtained in 69% of cases. There were 37 trigger thumbs (52%), with a success rate of 81% compared with 56% in the other the digits. There were 11 patients with diabetes mellitus, and 16 fingers developed trigger finger after carpal tunnel syndrome surgery. We found no complications. CONCLUSIONS: Steroid injections were an effective first-line intervention for the treatment of trigger finger. At long-term follow-up, the success incidence may be as high as 69%. In this study, the efficacy of this treatment increases when treating the thumb compared with other digits. PMID- 25443168 TI - Predicting radiographic changes at the first visit following operative repair of distal radius fractures. AB - PURPOSE: To test the hypothesis that clinical assessment reliably identifies patients with radiographic changes (including loss of reduction, hardware failure, and hardware migration) at the initial visit following operative repair of distal radius fractures. METHODS: We identified 102 patients undergoing operative repair of distal radius fractures. Radiographs and clinical notes were reviewed. RESULTS: At the initial postoperative visit, 11 patients had more than normal postoperative pain, 0 had deformity, 0 had crepitus with gentle motion, and 0 had instability at the fracture site on examination. These 11 patients were considered to have positive clinical assessments, but none had radiographic changes on x-rays taken that day. Three patients had negative clinical assessments but had radiographic changes noted at the initial postoperative visit. There were no additional radiographic changes between the series taken at the initial postoperative visit and series taken at later postoperative visits. CONCLUSIONS: These data suggest that for purposes of detecting radiographic changes, radiography at the initial visit is helpful, whereas radiography at subsequent visits may not be. Radiography at subsequent visits may be useful to monitor bony healing, which we did not investigate. PMID- 25443169 TI - Intermediate outcomes of ulnar head arthroplasty. AB - PURPOSE: To determine the survivorship and clinical outcomes of ulnar head arthroplasty. METHODS: The study design included a review of medical records and clinical assessment of all patients who had an ulnar head arthroplasty more than 2 years previously. Survivorship of 79 implants in 74 patients was determined. Forty-seven of these patients participated in a clinical review using the Patient Examination Measure, Patient-Related Wrist Examination, Wrightington Wrist Score, and EQ5D to measure outcomes. Analysis of outcomes was performed for diagnostic subgroups (inflammatory arthritis, posttraumatic, osteoarthritis/impingement, and other), primary versus revision surgery, and whether the procedure was performed for ulnar stump instability (related to either a previous Darrach or Sauve Kapandji procedure). RESULTS: The 5- and 15-year survival of the implants was 90% for both, with mean follow-up of 7 +/- 4 years. Mean age at surgery was 50 +/- 13 years (range, 24-76). Mean range of motion was within the functional range and grip strength was 67% that of the contralateral side. Patient satisfaction was generally high, but outcomes scores indicated substantial residual disability. Overall scores were 41 for the Patient Examination Measure, 52 for the Patient Related Wrist Examination, and 70 for the WWS. Patients in the "other" category had the worst scores for all measures. Patients with prior wrist surgery had poorer outcomes than those for whom the arthroplasty was a primary procedure. Patients with posttraumatic diagnoses had worse EQ5D scores and were less likely to recommend the procedure to others. CONCLUSIONS: Ulnar head arthroplasty had good long-term survival and acceptable patient satisfaction. Substantial disability remained in all groups, with the posttraumatic, "other", and revision groups faring worse. Patients should be counseled about the expected outcomes of this specialized procedure as they pertain to the patient's specific situation. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25443170 TI - Dynamic assessment of wrist after proximal row carpectomy and 4-corner fusion. AB - PURPOSE: To investigate the effect of 4-corner fusion (4CF) or proximal row carpectomy (PRC) on wrist motion, strength, and outcome for 2 different cohorts from 2 separate institutions performing either 4CF or PRC for stage 2/3 scaphoid nonunion advanced collapse and scapholunate advanced collapse. METHODS: The researchers assessed 46 subjects (24 4CF and 22 PRC), mean age 54 years, with a flexible electrogoniometer to measure maximum wrist motion and circumduction and compare it with the nonsurgical wrist. We analyzed the shape, size, rate, and smoothness of the circumduction curves. We assessed the maximum grip and sustainability of grip for 60 seconds using a digital grip analyzer. Patient evaluation measure and Michigan Hand Questionnaires measured patient-reported outcomes. RESULTS: Flexion-extension in the surgically treated wrist was 50% of the nonsurgical side after a 4CF and 65% after a PRC. The radioulnar deviation component in circumduction of the surgically treated wrist was similar but markedly decreased after either procedure. The mean area of circumduction of the surgically treated wrist was similar after a PRC and a 4CF but was 30% of the nonsurgical wrist. The center of the circumduction ellipse after a PRC was closer than after a 4CF to the opposite wrist. The orientation of the plane of circumduction was 22 degrees to the vertical flexion-extension plane after a PRC. After a 4CF, the plane was more vertical (9 degrees ). The peak grip strength and the area under the force time curve was 80% of the nonsurgical side after a PRC and 60% after a 4CF. The Michigan Hand Questionnaire result was 90% of the score for the nonsurgical hand after a PRC and 75% of score for the nonsurgical hand after a 4CF. CONCLUSIONS: The PRC provided improved flexion extension with a circumduction curve concentric with the nonsurgical wrist. The 4CF limited extension and ulnar deviation more than did a PRC. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25443171 TI - Acute, closed tendinous mallet injuries. PMID- 25443172 TI - Lower extremity function during gait in participants with first time acute lateral ankle sprain compared to controls. AB - Laboratory analyses of chronic ankle instability populations during gait have elucidated a number of anomalous movement patterns. No current research exists analysing these movement patterns in a group in the acute phase of lateral ankle sprain (LAS) injury. It is possible that participants with an acute LAS display movement patterns continuous with their chronically impaired counterparts. Sixty eight participants with acute LAS and nineteen non-injured participants completed five gait trials. 3D lower extremity temporal kinematic and kinetic data were collected from 200 ms pre- to 200 ms post-heel strike (period 1) and from 200 ms pre- to 200 ms post-toe off (period 2). During period 1, the LAS group displayed increased knee flexion with increased net extensor pattern at the knee joint, increased ankle inversion with a greater inversion moment, and reduced ankle plantar flexion, compared to the non-injured control group. During period 2, the LAS group displayed decreased hip extension with a decrease in the flexor moment at the hip, and decreased ankle plantar flexion with a decrease in the net plantar flexion moment, compared to the non-injured control group. These results indicate that participants with acute LAS display coordination strategies which may play a role in the onset of chronicity or recovery. PMID- 25443174 TI - Comments to "European Qualification in General Surgery: Quo vadis?". PMID- 25443173 TI - Photoperiodic effects on seasonal physiology, reproductive status and hypothalamic gene expression in young male F344 rats. AB - Seasonal or photoperiodically sensitive animals respond to altered day length with changes in physiology (growth, food intake and reproductive status) and behaviour to adapt to predictable yearly changes in the climate. Typically, different species of hamsters, voles and sheep are the most studied animal models of photoperiodism. Although laboratory rats are generally considered nonphotoperiodic, one rat strain, the inbred Fischer 344 (F344) rat, has been shown to be sensitive to the length of daylight exposure by changing its physiological phenotype and reproductive status according to the season. The present study aimed to better understand the nature of the photoperiodic response in the F344 rat. We examined the effects of five different photoperiods on the physiological and neuroendocrine responses. Young male F344 rats were held under light schedules ranging from 8 h of light/day to 16 h of light/day, and then body weight, including fat and lean mass, food intake, testes weights and hypothalamic gene expression were compared. We found that rats held under photoperiods of >= 12 h of light/day showed increased growth and food intake relative to rats held under photoperiods of <= 10 h of light/day. Magnetic resonance imaging analysis confirmed that these changes were mainly the result of a change in lean body mass. The same pattern was evident for reproductive status, with higher paired testes weight in photoperiods of >= 12 h of light/day. Accompanying the changes in physiological status were major changes in hypothalamic thyroid hormone (Dio2 and Dio3), retinoic acid (Crabp1 and Stra6) and Wnt/beta-Catenin signalling genes (sFrp2 and Mfrp). Our data demonstrate that a photoperiod schedule of 12 h of light/day is interpreted as a stimulatory photoperiod by the neuroendocrine system of young male F344 rats. PMID- 25443175 TI - Is it reasonable for a French general surgeon to perform a salvage craniotomy in 2014? PMID- 25443176 TI - Left ventricular end-diastolic pressure and ejection fraction correlate independently with high-sensitivity cardiac troponin-T concentrations in stable heart failure. AB - BACKGROUND: Cardiac troponin is widely accepted as a biomarker of myocyte injury in patients with myocardial ischemia. Patients with congestive heart failure are also associated with elevated cardiac troponin and it is a very sensitive prognostic marker. However, the mechanisms of troponin elevation in patients with heart failure are not fully understood. Decompensated state itself is suggested as a factor contributing to elevated cardiac troponin-T. However comparison between invasive hemodynamic parameters and cardiac troponin-T is insufficient. METHODS: Data were collected from 167 patients in stable, chronic HF, without acute coronary syndrome, recent revascularization, mitral stenoses, hemodialysis, or clinically significant right HF. We evaluated the correlations and 95% confidence intervals (CI) between invasive hemodynamic measurements and serum high-sensitivity (hs) concentrations of cTnT. RESULTS: The serum cTnT concentration was equal to or more than the detection threshold (0.003ng/ml) in all patients. The serum cTnT concentration was equal to or more than the cut-off value of 0.014ng/ml in 46% of patients. By multiple variable analysis, left ventricular (LV) end-diastolic pressure (EDP; adjusted coefficient=0.014; 95% CI 0.0003-0.029; P=0.046) was positively correlated, while hemoglobin (adjusted coefficient=-0.079; 95% CI -0.140 to -0.018; P=0.012), estimated glomerular filtration rate (adjusted coefficient=-0.008; 95% CI -0.013 to -0.003; P=0.004), and LV ejection fraction (EF; adjusted coefficient=-0.011; 95% CI -0.018 to 0.003; P=0.004) were negatively correlated with hs-cTnT concentrations. CONCLUSION: In patients with stable chronic HF, LVEDP and LVEF correlate with the serum concentrations of hs-cTnT, independently of other correlates of elevated plasma concentrations of hs-cTnT. PMID- 25443177 TI - Neural structure and social dysfunction in individuals at clinical high risk for psychosis. AB - Individuals at a clinical high risk (CHR) for psychosis have gray matter volume (GMV) abnormalities that are similar to, though less severe than, those in individuals with schizophrenia. Less GMV in schizophrenia is related to worse social cognition and social functioning, but the relationship between GMV and social functioning in CHR individuals has yet to be investigated. The aim of this study was to (1) investigate differences in GMV between healthy controls (HC) and CHR individuals, and (2) evaluate the relationship between GMV and social functioning in these two groups. Participants comprised 22 CHR and 21 HC individuals who completed a structural magnetic resonance imaging (MRI) scan as well as self-reported and interviewer-rated measures of social functioning. Processing and analysis of structural images were completed using voxel based morphometry (VBM). Results showed that the CHR group had less GMV in the left postcentral gyrus, bilateral parahippocampual gyri, and left anterior cingulate cortex. Reduced GMV in the postcentral gyrus and the anterior cingulate was related to self-reported social impairment across the whole group. This study has implications for the neurobiological basis of social dysfunction present before the onset of psychosis. PMID- 25443178 TI - Intergenerational transmission of fronto-parietal dysfunction during forethought in attention deficit/hyperactivity disorder: a pilot study. AB - There are only a few published reports of neural abnormalities within the families of children with attention deficit/hyperactivity disorder (ADHD). Functional magnetic resonance imaging was used to compare cerebral activation of ADHD and control biological parent-child dyads during forethought, a prospective function of working memory. Reduced activations in ADHD dyads were found in the inferior frontal gyrus, right superior parietal lobule and left inferior parietal lobule. This suggests that fronto-parietal abnormalities are shared within ADHD families. PMID- 25443179 TI - The human microbiome: opportunities and challenges for clinical care. AB - There is a growing appreciation of the importance of the human microbiome to our normal physiology. This complex microbial ecosystem plays a range of roles, including influencing the development and function of our immune systems, providing essential nutrients, regulating metabolism and protecting us from opportunistic infections. Our increasing understanding of these processes is due, to a large extent, to the development of high-throughput sequencing technologies, providing for the first time a means by which complex microbial dynamics can be detailed. There is also a growing recognition that disruption of commensal microbiota, a phenomenon known as dysbiosis, is associated with several common disorders, including inflammatory bowel disease, type 2 diabetes and oncogenesis. Further, where innate immunity fails to protect us, the microbial communities that colonise the external surfaces of our bodies represent a ready source of infection. This review discusses the mechanisms that govern our interaction with our resident microbiota, both in health and disease, the technological advances that allow us to gain insight into these relationships, and the way in which our growing understanding can inform clinical practice. PMID- 25443180 TI - [Congenital retinal macrovessel: an atypical presentation with low vision and macular thickening]. AB - CASE REPORT: We report a case of a 35 year old male patient with no medical history, who experienced decreased vision in his left eye that he noticed by chance. After a complete ophthalmic examination, he was diagnosed with congenital retinal macrovessel with macular thickening. DISCUSSION: Congenital retinal macrovessels are rare vascular anomalies, in which the diagnosis is usually incidental as their visual impact is minimal. In the rare cases where there is a significant visual impairment, this is due to macular hemorrhages, foveal cysts, serous macular detachment, or the course of the vessel itself through the foveal avascular zone. PMID- 25443181 TI - [A cost-effectiveness study of dexamethasone implants in macular edema]. AB - OBJECTIVE: To analyze the cost-effectiveness and benefits of a dexamethasone intravitreal implant (Ozurdex(r), Allergan, Irvine, CA, USA.) in its clinically relevant applications. MATERIAL AND METHODS: A total of 88 eyes of 86 patients with macular edema of > 300 MUm measured by optical coherence tomography (Cirrus Zeiss, Dublin, CA, USA) were included in this two-year retrospective study, with a minimum of 6 months follow-up. The patients were divide into 3 groups: group 1 with macular edema in retinal vein occlusion, group 2 with non-infectious posterior uveitis, and group 3 with diabetic macular edema. The treatment was off label but supported by the literature. Before implantation, and on days 1, 30, 60, 90 and 180, corrected visual acuity (Snellen), central retinal thickness, intraocular pressure and biomicroscopy were evaluated. The cost-benefit analysis was tabulated by line of visual acuity gained, comparing the main therapeutic alternatives and assessment of the safety profile of the dexamethasone intravitreal implant (Ozurdex(r), Allergan, Irvine, CA, USA). RESULTS: The results of this study did not differ from the published studies, in terms of visual acuity improvement in 63.3% of cases, and with central macular thickness improvement in 97% of cases. There were relapses, which occurred after 120 days on average, and the need for retreatment was 40.9%. Increased intraocular pressure >23 mm Hg was among the side effects in 29.54%, and was controlled with topical treatment, except in 1.13% requiring surgical treatment. The development of cataract was 44.7%, and 10.6% required surgery. Treatment results showed less frequent use of Ozurdex(r) than other treatments for disease control, being a cost saving option. DISCUSSION: Cost-effectiveness analyses are clinically relevant when applying treatment strategies in patients with macular edema. Dexamethasone intravitreal implant appears to be a safe and efficient therapy. PMID- 25443182 TI - [Macular atrophy in Terson's syndrome]. AB - CASE REPORT: The case is presented on a 63-year-old patient with Terson's syndrome who complained of loss of visual acuity. The optical coherence tomography showed macular atrophy. DISCUSSION: The patient developed macular atrophy probably secondary to macular hemorrhage caused by the rupture of a cerebral aneurysm. PMID- 25443183 TI - [Juvenile nasopharyngeal angiofibroma with orbital extension]. AB - CLINICAL CASE: The case is presented of a 21 year-old male with a history of left proptosis and diplopia of two weeks of onset. The MRI showed an ethmoid-orbital vascular lesion with anterior skull base invasion and orbital extension. Biopsy of the ethmoid confirmed fibrovascular tissue, which supported the diagnosis of angiofibroma. DISCUSSION: It is a benign neoplasm with local characteristics of malignancy due to its ability to invade adjacent areas. In this case, the debut presented with manifestations of orbital extension. A broad and multidisciplinary approach is needed in order to improve prognosis. PMID- 25443184 TI - Lacrimal sac lymphoproliferative lesion: case report. AB - CASE REPORT: The case is presented of a 51 year-old woman with a firm mass at the medial canthus of the right eye of five years onset. A low-grade lymphoproliferative lesion (reactive lymphoid hyperplasia) was diagnosed from an excisional biopsy DISCUSSION: Lacrimal sac tumors are rare, with a peak incidence in the fifth decade of life. The initial clinical features are epiphora and medial canthus swelling. As it mimics nasolacrimal duct obstruction, up to 40% of these tumors are misdiagnosed until undergoing surgery. PMID- 25443185 TI - Crystalline coloboma. AB - CASE REPORT: We present a seventy-three year-old female diagnosed with lens coloboma when she was going to be operated on for cataracts. DISCUSSION: The incidence of congenital coloboma of the eye is estimated to be 0.5 per 10000 newborns in Spain, 1.4 in France, 2.6 in United States, and 7.5 in China. The diagnosis is clinical by observing the defect. The visual prognosis depends on the extent and severity of the coloboma. The treatment of the cataract was by phacoemulsification with an intraocular lens using a capsular tension ring. PMID- 25443186 TI - [Management of corneal hydrops using air and micro-punctures]. AB - CASE REPORT: A 22-year- old woman with an acute hydrops and Descemet membrane detachment was managed by intracameral air injection combined with multiple corneal stromal venting incisions for the drainage of intrastromal fluid. No intraoperative complications were encountered, and the intrastromal fluid was resolved over 2 weeks. DISCUSSION: Acute corneal hydrops is a significant complication of keratoconus. If not treated, resolution usually occurs over a period of 2-4 months. The persistent oedema can cause complications, such as corneal neovascularisation, infection and corneal perforation. PMID- 25443188 TI - [Spasm of the near reflex. Treatment with botulinum toxin]. AB - CLINICAL CASE: A 38-year old female with diplopia and esotropia, with limitation of ocular abduction in both eyes, with full abduction after doll's head rotation also being observed. She was diagnosed with spasm of the near reflex. Treatment with injections of botulinum toxin in both medial rectus has temporally resolved the convergence spasm. DISCUSSION: Near reflex spasm is characterized as miosis, pseudomyopia, and convergent strabismus that lead to diplopia, blurred vision, headache, and variable, progressive, and intermittent esotropia. As the spasm worsens there will be limited ocular versions and ductions simulating a sixth nerve palsy. Botulinum toxin may be effective in some cases. PMID- 25443187 TI - Keratitis caused by Absidia corymbifera in an immunocompetent male with no corneal injuries. AB - Case Report A healthy 55-years-old male went to emergency due to a white infiltrate in the left eye without corneal trauma which partially responds to antibiotic treatment. The infiltrate worsened by the use of topical steroids. Direct microscopic evaluation and Gram stain are a valuable diagnostic tool for the detection of Absidia filaments. There is a successful treatment with anphotericin and posaconazole. Discussion Keratitis caused by Zygomicetes are unusual. This is a rare condition in healthy patients with no corneal trauma. The treatment with amphotericin and posaconazole are synergistic against filamentous fungi. PMID- 25443189 TI - Early treatment with infliximab in bilateral occlusive vasculitis as a presenting manifestation of Behcet' disease. AB - CASE REPORT: A 24 year old woman who complained of maculo-papulo rash, genital and bucal aphthous ulcers, abdominal pain, minor dyspnea and visual loss in both eyes. Funduscopy revealed a bilateral occlusive vasculitis including central vessels. Treatment was initiated with a methylprednisolone bolus (1 g/24h) and infliximab 5mg/kg/day (0-2-6 weeks and every 8 weeks). The treatment prescribed induced a fast remission. Visual acuity improved. The patient did not suffer any other relapse after one year of follow-up. DISCUSSION: An initial treatment with Infliximab should be considered in Behcet disease for serious outbreaks, such as macular occlusive vasculitis with ischemia. PMID- 25443190 TI - [Third cranial nerve palsy and Purtscher retinopathy in a child with multiple injuries]. AB - CASE REPORT: A 4 year-old girl was referred to our hospital after have suffered a severe accident. The patient was diagnosed with complete third nerve palsy in her right eye and Purtscher retinopathy in her left eye. DISCUSSION: Purtscher retinopathy is a rare condition. The diagnosis is made on clinical ground and its treatment is not well defined although it is believed that systemic steroids could improve the visual outcome. Traumatic third nerve palsy has a poor spontaneous recovery. The use of botulinum toxin might be useful in children to improve the recovery rate, maintaining binocularity, and avoiding amblyopia in other cases. PMID- 25443191 TI - [Preauricular injection of betamethasone depot and acyclovir for the treatment of acute herpes zoster ophthalmicus]. AB - CLINICAL CASES: Several treatments have been described for the management of patients with herpes zoster ophthalmicus (HZO). However, the progress of these patients is usually slow, and many of them develop postherpetic neuritis (PHN). In the present paper, three clinical cases are presented, in which a significant symptomatic improvement was obtained by using a preauricular injection of a mixture of betamethasone depot combined with acyclovir. PHN did not develop in any of them. DISCUSSION: The preauricular injection of betamethasone depot and acyclovir could be a good alternative for the management of HZO. PMID- 25443192 TI - [Goldmann-Witmer, definitive diagnosis in unifocal helicoid choroiditis]. AB - CASE REPORT: A 20 year-old healthy patient consulted due to acute loss vision in his left eye. A fundus examination showed a macular alteration compatible with unifocal helioid choroiditis, characterized by being an atypical inflammatory yellow-white, round, single lesion of approximately an optic disc in diameter. The etiology study detected low Antitoxoplasma gondii Ig G (immunoglobulin) titers. DISCUSSION: The non-specificity of the serology and the atypical characteristics of the lesion is a limitation in the diagnosis. The Goldmann Witmer coefficient may be useful in the diagnosis of atypical lesions, by comparing the concentration of IgG from the serum and aqueous humor. PMID- 25443193 TI - [SD-OCT As screening test for hydroxychloroquine retinopathy: The "flying saucer" sign]. AB - CASE REPORTS: Two asymptomatic women treated with hydroxychloroquine 200mg every day for 8 and 16 years developed retinal toxicity. DISCUSSION: Patient 1 was found to have a normal fundus and autofluorescence examination. Patient 2 was found to have a completely normal fundus examination. Fluorescein angiography shows parafoveal hyperfluorescence, and autofluorescence shows a minimal decrease in signal in the same region. In both patients the SD-OCT shows disruption of the ellipsoid zone in parafoveal region ("flying saucer" sign). SD-OCT findings in the retina can identify hydroxychloroquine retinopathy in asymptomatic patients. PMID- 25443194 TI - [Bubble mirror technique for express shunt surgery]. AB - SURGICAL TECHNIQUE: The bubble mirror technique consists of the stabilization of the anterior chamber by means of a plug made with a combination of conveniently placed air and viscoelastic material. A line arises at interface between the air and viscoelastic where the anterior chamber angle reflected can be seen as in a mirror (bubble mirror). DISCUSSION: The viscoelastic-air plug offers three advantages in glaucoma surgery with the Ex-PRESS implant: 1) plug effect of viscoelastic, giving stability to the anterior chamber and preventing it from collapsing; 2) toning effect of the air bubble; and 3) specular effect at the interface, which allows the surgeon to visually control the chamber angle during the Ex-PRESS implantation. PMID- 25443195 TI - [Recurrent neurosensory macular detachment in carotid-cavernous fistula]. AB - CASE REPORT: A 46 year-old man was seen in the emergency department complaining of vision loss and exophthalmos in his right eye. He also complained of headache, diplopia of 4 months onset, and neurosensory detachment that resolved spontaneously the month before. The study revealed tortuous conjunctival and episcleral vessels and neurosensory macular detachment in his right eye. A carotid-cavernous fistula was confirmed by computed tomography angiography. The fistula closed spontaneously during the hospitalization. One month later, the neurosensory detachment disappeared again. DISCUSSION: Carotid-cavernous fistula should be included in the differential diagnosis of neurosensory macular detachments. These neurosensory detachments can resolve spontaneously 11 the fistula is closed. PMID- 25443196 TI - Lenticonus diagnosis in Alport's syndrome: Anterior capsule apical angle calculation using Scheimpflug imagery. AB - OBJECTIVE: We describe a simplified method to detect anterior lenticonus. Three eyes of 2 patients with anterior lenticonus, plus 16 eyes from 16 healthy controls underwent Scheimpflug imaging of their anterior segment with Pentacam. The anterior capsule apex angle was manually identified and automatically measured by AutoCAD. RESULTS: The mean angle was 173.06 degrees (SD: 1.91) in healthy subjects, and 158.33 degrees (SD: 3.05) in anterior lenticonus eyes. The angle obtained from patients was more than 3 SD steeper than those from healthy subjects. CONCLUSIONS: The apical angle calculation method seems to discriminate well between normal eyes and eyes suspected of having anterior lenticonus. PMID- 25443197 TI - [Idiopathic intracranial hypertension in a patient with Chiari I malformation]. AB - CASE REPORT: The case involves a 22-year-old woman who presented with headache and decreased vision. She showed asymmetric papilledema, and a 6-mm tonsillar descent was observed in the image tests. She was diagnosed with secondary intracranial hypertension coinciding with the symptoms of a Chiari malformation (MC). DISCUSSION: Chiari malformation type I is the most common in this group of malformations, and is characterized by a greater than 5mm descent of the tonsils, being able to cause increased intracranial pressure and papilledema by blocking the flow of the cerebrospinal fluid. In this case, the MC was not the responsible for triggering the secondary intracranial hypertension, but a mere coincidence of both processes. PMID- 25443198 TI - Multidrug resistant Fusarium keratitis. AB - CASE REPORT: We report a case of keratitis in a female contact lens wearer, who developed a deep corneal abscess. The culture of a corneal biopsy scraping was positive for multiresistant Fusarium solani. The patient has a complicated clinical course and failed to respond to local and systemic antifungal treatment, requiring eye enucleation. CONCLUSION: Fusarium keratitis may progress to severe endophthalmitis. Clinical suspicion is paramount in order to start antifungal therapy without delay. Therapy is complex due to the high resistance of this organism to usual antifungal drugs. PMID- 25443199 TI - [Debut of Leber's hereditary optic neuropathy. Macular segmentation analysis using optical coherence tomography]. AB - CASE REPORT: Two clinical cases are presented of two family relatives newly diagnosed with Leber hereditary optic neuropathy (LHON) and G11778A mutation analysis by optical coherence tomography (Cirrus HD-OCT, Carl Zeiss Meditec, Dublin, California, USA) layer peripapillary fibers retina (RNFL) and ganglion cell and internal plexiform layers (GCL/IPL) using macular segmentation. DISCUSSION: The analysis of the macula by OCT segmentation (version 6.0 Cirrus OCT) allows the GCL/IPL to be evaluated without the interindividual variability of peripapillary RNFL distribution or the presence of edema of the optic disc. When an analysis of the peripapillary RNFL, it does not provide information on this neuronal damage, which itself is evidence in the study of GCL/IPL. PMID- 25443200 TI - [Charcot-Marie-Tooth disease and bilateral vitritis]. AB - CASE REPORT: We describe a patient diagnosed with Charcot-Marie-Tooth disease, with a 4 months history of bilateral decreased visual acuity and floaters. On examination, he had severe bilateral vitreous opacity and sectoral diffuse vascular sheathing. It could not be linked to some underlying aetiology and did not respond to oral steroids. CONCLUSIONS: Publications relating to ocular findings in patients with Charcot-Marie-Tooth disease exclude bilateral vitritis. In this case we were unable to test the association with another disease as the cause of vitritis. PMID- 25443201 TI - [Spontaneous expulsive choroidal hemorrhage. Case report]. AB - CLINICAL CASE: A case is presented of an 85-year-old woman living in a geriatric residence, who was admitted to the emergency department of our hospital with a spontaneous expulsive choroidal hemorrhage in her left eye. There was no a history of ophthalmic disease, and the patient only reported having intracapsular cataract surgery in both eyes 25 years ago, and that she also became blind in her left eye in the past few years. DISCUSSION: Non-surgical spontaneous expulsive choroidal hemorrhage is a very rare and disastrous clinical event. The predisposing factors involved are: advancing age, vascular illness (especially atherosclerosis), glaucoma, and severe corneal damage. PMID- 25443202 TI - [Cilioretinal artery occlusion in hemochromatosis]. AB - CLINICAL CASE: We report a case of a 31 year-old woman with a sudden visual loss due to a cilioretinal artery occlusion. The physical examinination showed hepatomegaly. Serum iron and ferritin and transferrin saturation were unusually high. The doppler scan of carotid arteries showed no relevant signs of atheromatous disease. Dilated cardiomiopaty was revealed in the B-scan with subendocardial calcium deposits. Genetic tests were positive for hemochromatosis. DISCUSSION: Subendocardial calcification due to hemochromatosis could be the embolic source in our patient. This embolic ocular disease is the first presentation of hemochromatosis in this patient. PMID- 25443203 TI - Therapeutic sectorial full-thickness sclero-keratoplasty for recurrent fungal keratitis. AB - OBJECTIVE: To report the management of a severe and recurrent fungal keratitis that required repeated penetrating keratoplasties. Despite multiple topical, intraocular and systemic antifungal treatments, superotemporal hyphal infiltration repeatedly penetrated the corneal transplant causing continuous recurrences. Cultures collected before and during surgery isolated the same organism, Fusarium spp. CONCLUSION: Corneal infection extending to the sclera and internal angle structures is the main cause of recurrence of fungal keratitis after corneal transplantation. Sectorial full-thickness sclero-keratoplasty combined with a central penetrating keratoplasty should be a surgical technique to be considered in cases where these locations are suspected to be the source of recurrence. It enables a definitive elimination of the infection, with excellent final visual acuities. No postoperative complications were reported in this case. PMID- 25443204 TI - [Dracula was right: The elixir of youth could be the young blood]. PMID- 25443205 TI - [Transposons in ophthalmology]. PMID- 25443207 TI - [Anterior uveitis in a patient with acute cytomegalovirus infection: Casualty or causality?]. PMID- 25443206 TI - Perioperative pharmacological management in patients with glaucoma. AB - REVIEWS AIM: When a phacoemulsification, a filtration surgery or a combined surgery are necessary, questions about the convenience of continuing certain antiglaucomatous drugs could appear. The aim of this review article is to unify criteria that will guide daily clinical practice and including the developing algorithms of action in the preoperative and postoperative periods of filtration surgery and/or cataract surgery. PROPOSED PROTOCOLS: In the preoperative period of cataract surgery, the use of non-steroidal anti-inflammatory drugs is at the discretion of the surgeon, with the monodose presentation being recommended. The suspension of prostaglandines a fewdays before the surgery should be considered. Preservative-free drugs ensure a better recovery of the ocular surface (OS) after cataract surgery. Once all modifying factors of the intraocular pressure (IOP) have been removed, baseline IOP should be evaluated again, choosing preservative free antiglaucomatous drugs when needed. The use of preservative-free ocular antihypertensive drugs and steroids in the preoperative period of glaucoma surgery reduces the risk of surgical failure. The interruption of prostaglandines is recommended. In the postoperative period of glaucoma surgery, steroids are the anti-inflammatory treatment of choice, the preservative-free ones being preferred. When reintroducing antiglaucomatous treatment, preservatives should be avoided to prevent scarring. The appropriate perioperative management of patients with glaucoma is essential to obtain a correct control of IOP, improve the situation of the OS, prevent complications and improve the result of the filtration surgery and cataract surgery. CONCLUSIONS: this protocol aims to unify the different lines of action in order to decrease the incidence of adverse events and maximize the surgical outcome. PMID- 25443208 TI - [Telemedicine correlation in retinopathy of prematurity between experts and non expert observers]. AB - OBJECTIVE: To study the correlation between expert and non-expert observers in the reporting images for the diagnosis of retinopathy of prematurity (ROP) in a telemedicine setting. METHODS: A cross-sectional, multicenter study, consisting of 25 sets of images of patients screened for ROP. They were evaluated by two experts in ROP and 1 non-expert and classified according to telemedicine classification, zone, stage, plus disease and Ells referral criteria. The telemedicine classification was: no ROP, mild ROP, type 2 ROP, or ROP that requires treatment. Ells referral criteria is defined as the presence at least one of the following: ROP in zone I, Stage 3 in zone I or II, or plus+ For statistical analysis, SPSS 16.0 was used. For correlation, Kappa value was performed. RESULTS: There was a high correlation between observers for the assessment of ROP stage (0.75; 0.54-0.88) plus disease (0.85; 0.71-0.92), and Ells criteria (0.89; 0.83-1.0). However, inter-observer values were low for zone (0.41; 0.27-0.54) and telemedicine classification (0.43; 0.33-0.6). CONCLUSIONS: When evaluating telemedicine images by examiners with different levels of expertise in ROP, the Ells criteria gave the best correlation. In addition, stage of disease and plus disease have good correlation among observers. In contrast, the correlation between observers was low for zone and telemedicine classification. PMID- 25443209 TI - New peripapillary findings in Alport syndrome: A case report. PMID- 25443210 TI - [AIDS-related primary CNS non-Hodgkin's lymphoma in a patient with previous Epstein-Barr virus panuveitis. A clinico-pathological report]. AB - CLINICAL CASE: Patient with AIDS and Epstein-Barr virus (EBV) uveitis. The PCR of the aqueous and vitreous humor was positive for EBV, and DNA quantification was 56.602*10(6) copies/ml in the vitreous humor, 173,400 copies/ml in the peripheral blood, and negative in the cerebrospinal fluid (CSF). The patient developed a non Hodgkin's lymphoma (NHL), diagnosed in the autopsy. CONCLUSION: The EBV is a rare cause of uveitis and it may be necessary to perform a quantitative PCR to reach the diagnosis. High amounts of EBV DNA are associated with a greater incidence of NHL. PMID- 25443211 TI - VEGF-A and VEGF-Ax: bad protein and good protein. PMID- 25443212 TI - [Corneal transplantation in keratoconus: penetrating keratoplasty versus deep anterior lamellar keratoplasty with Melles technique]. AB - OBJECTIVES: To evaluate the effectiveness of deep anterior lamellar keratoplasty (DALK) using Melles technique (technique B) in patients with advanced keratoconus versus a classic technique, penetrating keratoplasty (technique A). METHODOLOGY: Retrospective descriptive comparative study between technique A and technique B in homogeneous groups. RESULTS: Best corrected visual acuity (Snellen test decimal scale) was 0.77+/-0.32 for group A and 0.62+/-0.29 for group B, with no statistically significant differences. The mean spherical final refraction in group A was 1.73+/-5.1 diopters, and the mean spherical equivalent was -3.92+/ 5.1. Technique B group gave values -2.67+/-4.02 diopters and -4.55+/-4.08 diopters, respectively, with no statistically significant differences. The residual cylinder after removal of the sutures was 4.47+/-2.47 diopters for group A and 3.77+/-1.63 for group B, with no statistically significant differences. CONCLUSION: No statistically significant differences were found for any of the studied variables when comparing both groups using the t -test for independent samples. More studies on the homogeneity and residual stromal bed thickness could provide the key to determine whether this technique is closer to the visual acuity of penetrating keratoplasty or DALK by a descemet technique. PMID- 25443213 TI - Bilateral hypertensive retinopathy diagnostic of pheochromocytoma. PMID- 25443214 TI - [Secondary orbital lymphoma]. AB - CASE REPORT: A case is presented of an 85 year-old Caucasian female with lymphoma that recurred in the orbit (secondary ocular adnexal lymphoma). The orbital tumour was a diffuse large B-cell lymphoma according to the REAL classification (Revised European-American Lymphoma Classification). DISCUSSION: Orbital lymphomas are predominantly B-cell proliferations of a variety of histological types, and most are low-grade tumours. Patients are usually middle-aged or elderly, and it is slightly more common in women. A palpable mass, proptosis and blepharoptosis are the most common signs of presentation. PMID- 25443215 TI - [Bilateral herpetic keratouveitis in an immunocompetent patient]. AB - CASE REPORT: We report the case of an immunocompetent male who presented with a limbal-adjacent scleritis and interstitial keratitis in the left eye. A few days later a new dendritiform ulcer in his right eye and bilateral progressive worsening with granulomatous uveitis in both eyes were observed. A thorough review of systems revealed positive serum IgM titles for herpes simplex virus. DISCUSSION: In the context of a bilateral keratouveitis refractory to conventional treatment it is mandatory to rule out the herpetic origin based on the different forms of clinical presentation of this virus. PMID- 25443216 TI - N-Acetylmannosamine improves sleep-wake quality in middle-aged mice: relevance to autonomic nervous function. AB - Aging is associated with a variety of physiological changes originating peripherally and centrally, including within the autonomic nervous system. Sleep wake disturbances constitute reliable hallmarks of aging in several animal species and humans. Recent studies have been interested in N-acetylmannosamine (ManNAc) a potential therapeutic agent for improving quality of life, as well as preventing age-related cognitive decline. In this study, ManNAc (5.0 mg/ml) was administered in the drinking water of middle-aged male C57BL/6J mice (55 weeks old) for 7 days. Mice were housed under a 12:12 h light:dark cycle at 23-24 degrees C. We evaluated bio-behavioral activity using electrocardiogram, body temperature and locomotor activity recorded by an implanted telemetry transmitter. To estimate sleep-wake profile, surface electroencephalogram and electromyogram leads connected to a telemetry transmitter were also implanted in mice. Autonomic nervous activity was evaluated using power spectral analysis of heart rate variability. ManNAc-treated mice spent more time in a wakeful state and less time in slow wave sleep during the dark phase. Parasympathetic nervous activity was increased following ManNAc treatment, then the sympatho-vagal balance was shifted predominance of parasympathetic nervous system. Furthermore, improvement in sleep-wake pattern was associated with increased parasympathetic nervous activity. These results suggest that ManNAc treatment can improve bio behavioral activity and sleep-wake quality in middle-aged mice. This may have implications for improving sleep patterns in elderly humans. PMID- 25443219 TI - [In Process Citation]. PMID- 25443220 TI - [Mucosal healling: a realistic aim or marketing myth?]. AB - The classical aim of the treatment of ulcerative colitis is to induce and maintain remission. However, this aim has not been shown to prevent long-term complications. Current treatment goals attempt to prevent complications. In some studies, healing of the intestinal mucosa has been shown to improve long-term outcomes. In ulcerative colitis, mucosal healing reduces recurrence, the risk of colorectal cancer and the need for surgery, and improves patients' quality of life. The drugs for which there is greatest evidence of their efficacy in inducing and maintaining mucosal healing are salicylates and biological agents. In the near future, endoscopic monitoring may be required to evaluate response to the treatment and decisions may have to be taken according to the persistence or disappearance of these lesions. PMID- 25443221 TI - [Treatment adherence: a key element]. AB - A substantial percentage of patients fail to follow health professionals' recommendations, which affects the management of chronic diseases, reducing the effectiveness of therapeutic interventions and increasing the costs of the disease. Lack of adherence is a multidimensional phenomenon and is influenced by numerous factors that should be identified. A multiplicity of measures is available to improve adherence, such as simplifying treatment administration, but none of these measures is effective when used alone. One way of tackling lack of adherence is by identifying patients' barriers to medication and involving them in decision making. Ulcerative colitis (UC) poses a risk for lack of treatment adherence. In this disease, poor adherence correlates with poor disease control (drug effectiveness) and with higher costs. As in other chronic diseases, the causes associated with poor adherence are multiple, including psychosocial factors, the physician-patient relationship and patients' prejudices toward medication. A single dose of aminosalycylates (5-ASA) should be recommended, as this dose is as safe and effective as other regimens. However, by itself, this recommendation does not seem to improve adherence. Identifying the scale of the problem and developing strategies to involve the patient in decision making is crucial to improve treatment adherence. PMID- 25443222 TI - [No best treatment for severe outbreaks: Maintenance, the key in colitis]. AB - Several drugs are currently available to maintain remission in patients who have responded after one or other type of induction therapy, depending on the initial severity of the outbreak. Salicylates are the drugs of choice to maintain remission after a mild-to-moderate outbreak controlled by salicylates or oral corticosteroids. To maintain remission after a severe outbreak or in patients with corticosteroid dependence or resistance, thiopurines are the drugs of choice. In patients who have failed to respond to thiopurines and in those with thiopurine intolerance, biological agents, mainly infliximab, can be used to maintain remission in patients after induction therapy with infliximab for a severe outbreak. However, these scenarios may not reflect reality of gastroenterologists' daily clinical practice. Treatment will therefore be based on the patient's individual characteristics (age, clinical course, previous treatment, adverse effects and personal preferences) as well as the physician's medical art. PMID- 25443223 TI - [Mesalazine old and new]. AB - Aminosalycylates (5-ASA) are still the drugs of choice both for mild-to-moderate outbreaks of ulcerative colitis and to maintain long-term remission. The efficacy of these drugs has been widely demonstrated in placebo-controlled trials. However, when administered orally, their pharmacological characteristics hamper the desired therapeutic effect. Currently, efficiency can be optimized by exclusive or combined rectal administration. The present article reviews the available data on the efficacy of galenic preparations of 5-ASA and discusses the potential advantages of galenic forms of 5-ASA coated with a novel multi-matrix delivery system. PMID- 25443224 TI - [Role of thiopurine agents in ulcerative colitis]. AB - Thiopurine agents have been shown to be effective in maintaining remission in patients with Crohn's disease. There is less evidence for the efficacy of these treatments in ulcerative colitis. Consequently, the effect of thiopurines in the latter disease continues to be the subject of debate and controversy remains on whether these drugs are equally effective in both diseases. The present article aims to review, from a practical point of view, the evidence of the efficacy of thiopurines in ulcerative colitis, current indications for this treatment, safety in patients with inflammatory bowel disease and the treatment optimization strategies proposed. PMID- 25443225 TI - [Biological agents in ulcerative colitis. When to prescribe]. AB - Biological agents are effective both in inducing and in maintaining remission in patients with ulcerative colitis. These drugs began to be used later in ulcerative colitis than in Crohn's disease because, in addition to the possibility of surgery, other therapeutic options such as cyclosporine were available for the latter disease. Most studies and data concern infliximab, the only currently approved biological agent; however, the less than entirely satisfactory results of the first studies could also have delayed the use of this drug in Crohn's disease. Due to the results of a Scandinavian study, infliximab was initially indicated in severe, corticosteroid-resistant ulcerative colitis. Subsequently, numerous open series and observational studies have confirmed the efficacy of this drug in this subgroup of patients. However, after several years of using infliximab in colitis, clinicians are increasingly aware that its efficacy is greater in patients with corticosteroid-dependent, moderate-severe disease not requiring hospitalization than in hospitalized patients with severe disease. In the last few years, data have emerged to support the efficacy of infliximab in certain areas of ulcerative colitis refractory to other therapies, such as pediatric patients and reservoiritis. Recently, new data on another biological agent (adalimumab) in this disease have been published. The evidence indicates that this drug will soon be indicated in the treatment of ulcerative colitis. PMID- 25443227 TI - Effect of weight loss on bone mineral density determined by ultrasound of phalanges in obese women after Roux-en-y gastric bypass: conflicting results with dual-energy X-ray absorptiometry. AB - The rapid weight loss that occurs in obese patients submitted to Roux-en-y gastric bypass (RYGB) as well as the changes in dietary pattern and the intestinal malabsorption result in changes in bone mineral density (BMD). The objective of the present study was to assess the changes in BMD after the weight loss induced by RYGB using ultrasound of the phalanges and compare the results with those obtained by dual-energy X-ray absorptiometry (DXA). We conducted a 1 yr prospective longitudinal study on women with grade III obesity submitted to RYGB. Anthropometric (weight, height, body mass index, and abdominal circumference) and body composition measurements by electrical bioimpedance, assessment of food consumption by 24-h recall, biochemical evaluation, and assessment of BMD by ultrasonography of the phalanges and DXA (BMD values are from the 33% radius site) were performed during the preoperative period and 3, 6, and 12 mo after surgery. The mixed-effects linear regression model was used to analyze the effect of postoperative time on the variable of interest, and the kappa coefficient (p < 0.05) was used to compare the concordance of the methods used for BMD evaluation. Twenty-nine patients were included in the study. During the 1-yr follow-up, a reduction of 39 +/- 8 kg (71 +/- 15% of excess weight) and 29 +/- 7 kg of fat mass was observed. Calcium and zinc concentrations were reduced after 12 mo. No difference in caffeine, calcium, or sodium consumption was observed between the preoperative and postoperative periods. Analysis of BMD by ultrasonography of the phalanges 1 yr after surgery showed increased values of amplitude-dependent speed of sound (2064.6 +/- 59.4 vs 2154.7 +/- 63 m/s; p < 0.001) and ultrasound bone profile index (0.73 +/- 0.13 vs 0.76 +/- 0.14; p < 0.001). Analysis of BMD by DXA showed a reduction of BMD values (0.6 +/- 0.04 vs 0.57 +/- 0.05 g/cm3; p < 0.001) in the sixth month and maintenance of the values from the sixth to the 12th month. At the end of the study, there was no concordance between the methods for BMD analysis. This study showed improvement in bone quality and quantity assessed by ultrasonography. However, the DXA results showed a reduction in BMD after 12 mo of RYGB. Thus, the BMD measurement methods were discordant. PMID- 25443228 TI - The effects of attentional focus on jump performance and knee joint kinematics in patients after ACL reconstruction. AB - OBJECTIVES: The purpose of this study was to determine the effect of an internal and external attentional focus on single leg hop jump distance and knee kinematics in patients after ACL reconstruction (ACLR). DESIGN: Experimental. SETTING: Outpatient physical therapy facility. PARTICIPANTS: Sixteen patients after ACLR. MAIN OUTCOME MEASURES: Patients received either an instruction with an internal focus or an external focus before performing a single leg hop jump. The jump distance, knee valgus angle at initial contact, peak knee valgus angle, knee flexion angle at initial contact, peak knee flexion angle, total ROM and time to peak angles for the injured and non-injured legs were recorded. A repeated measures MANOVA was used to determine significance between the experimental conditions with the primary outcome measures as dependent variables. RESULTS: The external focus group had significant larger knee flexion angles at initial contact, peak knee flexion, total ROM and time to peak knee flexion for the injured legs. CONCLUSIONS: This study demonstrates the applicability of using an external focus during rehabilitation of patients after ACLR to enhance safer movement patterns compared to an internal focus of attention and subsequently may help to reduce second ACL injury risk. PMID- 25443229 TI - The influence of joint hypermobility on functional movement control in an elite netball population: A preliminary cohort study. AB - OBJECTIVES: To ascertain the prevalence of General Joint Hypermobility (GJH) and Joint Hypermobility Syndrome (JHS) in elite level netballers. To investigate whether GJH influences functional movement control and explore whether symptoms of dysautonomia are reported in this population. DESIGN: Observational within subject cross-sectional design. SETTING: Field based study. PARTICIPANTS: 27 elite level netballers (14-26 years). MAIN OUTCOME MEASURES: GJH and JHS were assessed using the Beighton scale, 5 point questionnaire and the Brighton Criteria. Functional movement control was measured using posturography on a force platform and the Star Excursion Balance Test (SEBT). RESULTS: The prevalence of GJH was 63% (n = 17) (Beighton score >=4/9) and JHS was 15% (n = 4). Symptoms of dysautonomia were minimally prevalent. A trend was observed in which participants with GJH demonstrated increased postural instability on the functional tests. Following Bonferroni adjustment, this was statistically significant only when comparing posturographic data between the distinctly hypermobile participants and the rest of the group for path area (p = 0.002) and velocity (p = 0.002) on the left side. CONCLUSIONS: A high prevalence of GJH was observed. A trend towards impairment of functional movement control was observed in the netballers with GJH. This observation did not reach statistical significance except for posturographic path area and velocity. PMID- 25443230 TI - High-intensity stepwise conditioning programme for improved exercise responses and agility performance of a badminton player with knee pain. AB - OBJECTIVE: To examine the effect of a high-intensity stepwise conditioning programme combined with multiple recovery measures on physical fitness, agility, and knee pain symptoms of an injured player. DESIGN: A single case study. SETTING: University-based conditioning training laboratory. PARTICIPANTS: One 26 year-old male world-class badminton player (height, 190.0 cm; weight, 79.3 kg; left dominant hand; playing experience, 16 years; former world champion) with patellar tendinosis and calcification of his left knee. HIGH-CONDITIONING STEPWISE CONDITIONING PROGRAMME: The player received seven conditioning sessions over three weeks. During the programme, there was a gradual increase in training duration and load across sessions while cold therapy, manual stretches and massage were administered after each session to minimise inflammation. MAIN OUTCOME MEASURES: The training outcome was evaluated with three different testing methods: standard step test, badminton-specific agility test, and tension-pain rating. RESULTS: The conditioning programme reduced knee pain symptoms and improved actual performance and cardiopulmonary fitness during the agility task. The player was able to return to sport and compete within a month. CONCLUSIONS: A high-intensity stepwise conditioning programme improved the physical fitness while sufficient recovery measures minimised any possible undesirable effects and promoted faster return to elite level competition. PMID- 25443231 TI - Risk factors and genetics of atrial fibrillation. AB - Atrial fibrillation (AF) is by far the most common sustained tachyarrhythmia, affecting 1% to 2% of the general population. AF prevalence and the total annual cost for treatment are alarming, emphasizing the need for an urgent attention to the problem. Thus, having up-to-date information on AF risk factors and appreciating how they promote maintenance of AF maintenance are essential. This article presents a simplified examination of AF risk factors, including emerging genetic risks. PMID- 25443233 TI - Diagnostic evaluation and follow-up of patients with atrial fibrillation. AB - In this article, a review of the diagnostic evaluation and outpatient follow-up of patients with atrial fibrillation is presented. After exploring details of symptoms, past medical history, quality of life, and physical exam findings, diagnostic tools are then discussed. Furthermore, important considerations after the initial diagnosis and treatment of patients with atrial fibrillation are discussed. PMID- 25443232 TI - Mechanisms of atrial fibrillation: rotors, ionic determinants, and excitation frequency. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia; however, therapy is suboptimal. We review recent data on dynamics of wave propagation during AF and its mechanistic link to the substrate. Data show that the dominant frequency (DF) increase during transition to persistent AF may be explained by rotor acceleration. We discuss how translation of experimentally derived understanding of the rotors may find its way into the clinic, focusing on studies analyzing spatial distribution of DF in the atria of patients with paroxysmal versus persistent AF, and how that knowledge might contribute to improve the outcome of AF ablation procedures. PMID- 25443234 TI - Rate versus rhythm control for atrial fibrillation. AB - Treatment of patients with symptomatic atrial fibrillation (AF) with antiarrhythmic drug therapy in general improves their symptom scores and exercise tolerance; however, large randomized trials have failed to show a mortality benefit with a rhythm-control compared with a rate-control strategy. Catheter ablation in patients who have failed or not tolerated medical therapy has been shown to alleviate symptoms and improve quality of life. However, catheter ablation cannot undo the structural remodeling that contributed to the arrhythmia in the first place. Patients should be alerted to modifiable factors that may decrease the likelihood of unchecked structural remodeling and AF recurrence. PMID- 25443235 TI - Antiarrhythmic drug therapy for atrial fibrillation. AB - Atrial fibrillation (AF) is the most frequently encountered arrhythmia. Prevalence increases with advancing age and so as its associated comorbidities, like heart failure. Choice of pharmacologic therapy depends on whether the goal of treatment is maintaining sinus rhythm or tolerating AF with adequate control of ventricular rates. Antiarrhythmic therapy and conversion of AF into sinus rhythm comes with the side effect profile, and we should select best antiarrhythmic therapy, individualized to the patient. New antiarrhythmic drugs are being tested in clinical trials. Drugs that target remodeling and inflammation are being tested for their use as prevention of AF or as upstream therapy. PMID- 25443236 TI - Catheter ablation of atrial fibrillation. AB - Strategies and technology related to catheter ablation for atrial fibrillation (AF) continue to advance since its inception nearly 20 years ago. Broader selections of patients are now offered ablation with a similar level of procedural outcome and safety standards. It is hoped that improved understanding of the pathophysiologic processes of the initiation and maintenance of AF will refine target selection during ablation and improve long-term procedural efficacy, particularly in patients with persistent and long-standing persistent AF. PMID- 25443238 TI - Atrioventricular junction ablation for atrial fibrillation. AB - Atrioventricular junction (AVJ) ablation is an effective therapy in patients with symptomatic atrial fibrillation who are intolerant to or unsuccessfully managed with rhythm control or medical rate control strategies. A drawback is that the procedure mandates a pacing system. Overall, the safety and efficacy of AVJ ablation is high with a majority of the patients reporting significant improvement in symptoms and quality-of-life measures. Risk of sudden cardiac death after device implantation is low, especially with an appropriate postprocedure pacing rate. Mortality benefit with AVJ ablation has been shown in patients with heart failure and cardiac resynchronization therapy devices. PMID- 25443237 TI - Surgery for atrial fibrillation. AB - Atrial fibrillation is the most common cardiac arrhythmia, and its treatment options include drug therapy or catheter-based or surgical interventions. The surgical treatment of atrial fibrillation has undergone multiple evolutions over the last several decades. The Cox-Maze procedure went on to become the gold standard for the surgical treatment of atrial fibrillation and is currently in its fourth iteration (Cox-Maze IV). This article reviews the indications and preoperative planning for performing a Cox-Maze IV procedure. This article also reviews the literature describing the surgical results for both approaches including comparisons of the Cox-Maze IV to the previous cut-and-sew method. PMID- 25443239 TI - Antithrombotic and anticoagulant therapy for atrial fibrillation. AB - As atrial fibrillation (AF) substantially increases the risk of stroke and other thromboembolic events, most AF patients require appropriate antithrombotic prophylaxis. Oral anticoagulation (OAC) with either dose-adjusted vitamin K antagonists (VKAs) (eg, warfarin) or non-VKA oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban) can be used for this purpose unless contraindicated. Therefore, risk assessment of stroke and bleeding is an obligatory part of AF management, and risk has to be weighed individually. Antiplatelet drugs (eg, aspirin and clopidogrel) are inferior to OAC, both alone and in combination, with a comparable risk of bleeding events. PMID- 25443241 TI - Postoperative atrial fibrillation: incidence, mechanisms, and clinical correlates. AB - Atrial fibrillation is the most commonly encountered arrhythmia after cardiac surgery. Although usually self-limiting, it represents an important predictor of increased patient morbidity, mortality, and health care costs. Numerous studies have attempted to determine the underlying mechanisms of postoperative atrial fibrillation (POAF) with varied success. A multifactorial pathophysiology is hypothesized, with inflammation and postoperative beta-adrenergic activation recognized as important contributing factors. The management of POAF is complicated by a paucity of data relating to the outcomes of different therapeutic interventions in this population. This article reviews the literature on epidemiology, mechanisms, and risk factors of POAF, with a subsequent focus on the therapeutic interventions and guidelines regarding management. PMID- 25443242 TI - Novel upstream approaches to prevent atrial fibrillation perpetuation. AB - The mechanisms underlying atrial fibrillation (AF) in humans are poorly understood. In particular, we simply do not understand how atrial AF becomes persistent or permanent. The objective of this brief review is to address the most important factors involved in the mechanism of AF perpetuation, including structural remodeling in the form of fibrosis and electrical remodeling secondary to ion channel expression changes. In addition, I discuss the possibility that both fibrosis and electrical remodeling might be preventable when intervening pharmacologically early enough before the remodeling process reaches a point of no return. PMID- 25443243 TI - Atrial fibrillation. Preface. PMID- 25443244 TI - Pulmonary arterial hypertension associated with congenital heart disease: recent advances and future directions. AB - Congenital heart disease (CHD), the most common inborn defect, affects approximately 1% of all newborns worldwide. Advances in its diagnosis and treatment have led to a dramatic improvement in patients' quality of life and long-term survival prospects. However, recently it has been realised that many of these patients are affected by ongoing and life-long cardiac issues, namely residual and progressive haemodynamic lesions, arrhythmia and sudden cardiac death, as well as the development of chronic heart failure and pulmonary arterial hypertension (PAH) - all of which merit tertiary care. Unfortunately, many patients with CHD are lost to follow-up, due to the assumption that their initial response to surgical and or catheter intervention in childhood led to cure. Furthermore, there are many patients with undiagnosed or unoperated CHD in the developing world coming to medical attention during adulthood. Our article focuses on advances in the management of PAH associated with CHD, a common association with an adverse impact on quality of life and survival prospects that affects approximately 10% of patients with CHD. Much of the recent progress in PAH-CHD has focused on the extreme end of the disease spectrum, namely on Eisenmenger syndrome. Herein we discuss this progress and future directions for this emerging cardiovascular field. PMID- 25443240 TI - Left atrial appendage exclusion for atrial fibrillation. AB - Percutaneous left atrial appendage (LAA) closure is being increasingly used as a treatment strategy to prevent stroke in patients with atrial fibrillation (AF) who have contraindications to anticoagulants. Several approaches and devices have been developed in the last few years, each with their own unique set of advantages and disadvantages. In this article, the published studies on surgical and percutaneous approaches to LAA closure are reviewed, focusing on stroke mechanisms in AF, LAA structure and function relevant to stroke prevention, practical differences in procedural approach, and clinical considerations surrounding management. PMID- 25443245 TI - Local and general anaesthesia do not influence outcome of transfemoral aortic valve implantation. AB - BACKGROUND: There is great variability for the type of anaesthesia used during TAVI, with no clear consensus coming from comparative studies or guidelines. We sought to detect regional differences in the anaesthetic management of patients undergoing transcatheter aortic valve implantation (TAVI) in Europe and to evaluate the relationship between type of anaesthesia and in-hospital and 1 year outcome. METHODS: Between January 2011 and May 2012 the Sentinel European TAVI Pilot Registry enrolled 2807 patients treated via a transfemoral approach using either local (LA-group, 1095 patients, 39%) or general anaesthesia (GA-group, 1712 patients, 61%). RESULTS: A wide variation in LA use was evident amongst the 10 participating countries. The use of LA has increased over time (from a mean of 37.5% of procedures in the first year, to 57% in last 6 months, p<0.01). MI, major stroke as well as in-hospital death rate (7.0% LA vs 5.3% GA, p=0.053) had a similar incidence between groups, confirmed in multivariate regression analysis after adjusting for confounders. Dividing our population in tertiles according to the Log-EuroSCORE we found similar mortality under LA, whilst mortality was higher in the highest risk tertile under GA. Survival at 1 year, compared by Kaplan-Meier analysis, was similar between groups (log-rank: p=0.1505). CONCLUSIONS: Selection of anaesthesia appears to be more influenced by national practice and operator preference than patient characteristics. In the absence of an observed difference in outcomes for either approach, there is no compelling argument to suggest that operators and centres should change their anaesthetic practice. PMID- 25443246 TI - Metabolic syndrome among children and adolescents from Southern Italy: contribution from the Calabrian Sierras Community Study (CSCS). AB - Among 1657 children and adolescents aged 6 to 14 years (787, 47% girls and 870, 53% boys) from primary and secondary schools in a 14-town Southern Italian community, HDL cholesterol (54 +/- 15 mg/dl), triglycerides (61 +/- 29 mg/dl), blood glucose (78 +/- 10 mg/dl), systolic (101 +/- 11 mm Hg) and diastolic (62 +/ 10 mm Hg) blood pressures, waist circumference (WC) (66 +/- 10 cm) and WC/height (0.46 +/- 0.006) and triglycerides/HDL cholesterol (1.31 +/- 0.99) ratios were measured. The distributions were similar in both genders. Age did not affect triglycerides/HDL cholesterol ratio, whereas there was a slightly positive correlation (p<0.00001) between WC/height and triglycerides/HDL cholesterol ratios. We present individual gender and age specific percentile distributions (as Supplementary materials). Using percentile cut-offs (<= 10th for HDL cholesterol and >= 90th for the other components), there were 183 (11%) children or adolescents with low HDL cholesterol, 162 (9.77%) with high triglycerides, 178 (10.74%) with high blood glucose, 178 (10.74%) with high WC, 244 (20.76%) with high systolic or diastolic BP and 126 (7.6%) with high systolic and diastolic BP. Abnormally high BP was seen in 470 (28.36%) children or adolescents. Using abnormal percentile values of 3 of 5 of its components, metabolic syndrome (MS) was diagnosed in 70 (4.2%) subjects, similarly in both genders. To assess out-of limit distributions of all 5 individual MS components in children and adolescents gender- and age-distributions derived from local epidemiological data should be used: these distributions are presented and they might now be used both for comparative and applicative purposes at least in Southern Europe. PMID- 25443247 TI - Optimal anticoagulation duration of unfractionated and low molecular weight heparin in non-ST elevation acute coronary syndrome: a systematic review of the literature. AB - INTRODUCTION: In this PCI era, non-invasive management for patients presenting with non-ST elevation acute coronary syndrome continues to be relevant in several clinical circumstances. The duration of anticoagulation in non-invasively treated group is not clear. The use of heparin can be associated with fatal side effects. Thus, defining the optimal duration of therapy has significant implications for patient safety and cost. METHODS: Literature search was conducted using Medline (PubMed and Ovid SP), Embase, Cochrane Central Register of Controlled Clinical Trials (CENTRAL) and Cochrane Database of Systematic Review (CDSR) from the inception of these databases till present (August 2013). Only studies on humans and in English language were included. We included only published clinical trials which used UFH or LMWH as the anticoagulation agent. RESULTS: Initial search revealed 548 studies with 182 meeting inclusion criteria for full review. The duration of therapy was reported in 20 of 182 studies with an average treatment duration of 2-8 days. There was a trend towards increased bleeding without significant improvement in cardiovascular outcomes when anticoagulation was continued for more than 5-7 days. No single trial directly analyzed the composite end point outcome or adverse events in correlation with the duration of anticoagulation. CONCLUSION: There is a lack of good quality evidence to define the optimal duration of anticoagulation in the management of NSTE ACS. Well designed, methodologically rigorous database studies are required to determine the shortest duration of therapy which achieves the benefits of anticoagulants while minimizing the costs and risks associated with prolonged anticoagulant use. PMID- 25443248 TI - Physical activity and incidence of atrial fibrillation: a systematic review and meta-analysis. AB - Whether physical activity increases or decreases the risk of atrial fibrillation (AF) remains controversial. We conducted a systematic review and meta-analysis to evaluate the relationship between AF and extent of physical activity. We searched Medline and EMBASE in June 2014 for studies that reported on the associated risk of AF according to history of physical activity. Pooled risk ratios for AF were calculated using inverse variance random effects model, and heterogeneity assessed using I(2). Subgroup analysis was performed according to the nature of the physical activity, and the quality of the studies. We identified 19 relevant studies with a total of over half a million participants (n=511,503). The pooled analysis showed no association between intensive physical activity and AF (RR 1.00 95% CI 0.82-1.22, I(2)=73%, 8 studies, 152,925 participants) with no difference considering low and moderate to high risk of bias studies. Pooled analysis of studies reporting on increasing amount of time spent on physical activities did not show a significant association with AF (RR 0.95 95% CI 0.72 1.26, I(2)=84%, 4 studies, 112,784 participants). Studies of athletes or participants with a history of sports activity which were of poor methodology quality showed a borderline significant association with AF (pooled RR 1.98 95% CI 1.00-3.94, I(2)=59%, 6 studies, 1973 participants). In conclusion, we found no significant increase in AF with a higher level of physical activity. These findings support clinical guidelines encouraging patients to exercise as there is no evidence for harm associated with increased physical activity. PMID- 25443249 TI - The association between multimorbidity and poor adherence with cardiovascular medications. AB - Multimorbidity, defined as the presence of two or more chronic conditions, leads to a substantial public health burden. This study evaluated its association with adherence with cardiovascular medications in a Chinese population. A proportional stratified sampling was adopted to draw a representative sample of residents living in Henan Province, China. Interviewer-administered surveys were conducted by trained researchers. The outcomes included the number of chronic medical conditions, adherence with long-term medications (MMAS-8), and depressive symptoms (CESD-20). Binary logistic regression analysis was conducted to evaluate if medication adherence was associated with the presence of multimorbidity. From a total of 3866 completed surveys, the proportion of subjects having 0, 1 and >=2 chronic conditions was 62.6%, 23.8% and 13.5%, respectively. Among 27.6% who were taking chronic medications, 66.6% had poor medication adherence (MMAS-8 score<=6). From binary logistic regression analysis, subjects with poor medication adherence were significantly associated with multimorbidity (adjusted odds ratio [AOR]: 1.35, 95% C.I. 1.02-1.78, p=0.037). Other associated factors included older age (AOR=1.04, 95% C.I. 1.03-1.05, p<0.001), smoking (AOR=1.63, 95% C.I. 1.16-2.30, p=0.005), family history of hypertension (AOR=1.51, 95% C.I. 1.19-1.93, p=0.001), and fair to poor self-perceived health status (AOR=2.15, 95% C.I. 1.69-2.74, p<0.001). Using medication adherence as the outcome variable, multimorbidity was significantly associated with poor drug adherence (AOR=1.34, 95% C.I. 1.02-1.77, p=0.037). Multimorbidity was associated with poorer medication adherence. This implies the need for closer monitoring of the medication taking behavior among those with multiple chronic conditions. PMID- 25443250 TI - Short-term outcomes following "full-plastic jacket" everolimus-eluting bioresorbable scaffold implantation. PMID- 25443251 TI - Letter regarding the article "acupuncture for essential hypertension". PMID- 25443252 TI - Pocket infection as a complication of a subcutaneous implantable cardioverter defibrillator. PMID- 25443253 TI - Brugada phenocopy induced by ischemia or Brugada syndrome unmasked by ischemia? PMID- 25443254 TI - Cardiac perforation of the right ventricle: a rare complication of pacemaker implantation. The importance of a collaborative vision of a multi-disciplinary treatment team. PMID- 25443255 TI - Renal denervation might be a promising treatment option for dilated cardiomyopathy. PMID- 25443256 TI - The prevalence of doctor-diagnosed angina in 4314 older adults in China and comparison with the Rose angina questionnaire: the 4 province study. PMID- 25443257 TI - Respective effects of OSA treatment and angiotensin receptor blocker on aldosterone in hypertensive OSA patients: a randomized cross-over controlled trial. PMID- 25443258 TI - Isoprostane as a promising biomarker in pulmonary arterial hypertension: preanalytical and analytical viewpoints. Response to letter to the editor. PMID- 25443259 TI - Developing a risk prediction model for survival to discharge in cardiac arrest patients who undergo extracorporeal membrane oxygenation. AB - BACKGROUND: Limited data are available on a risk model for survival to discharge after extracorporeal membrane oxygenation (ECMO)-assisted cardiopulmonary resuscitation (ECPR). We aimed to develop a risk prediction model for survival to discharge in cardiac arrest patients who undergo ECMO. METHODS: Between January 2004 and December 2012, 505 patients supported by ECMO were enrolled in a retrospective, observational registry. Among those, we studied 152 adult patients with in-hospital cardiac arrest. The primary outcome was survival to discharge. A new predictive scoring system, named the ECPR score, was developed to monitor survival to discharge using the beta coefficients of prognostic factors from the logistic model, which were internally validated. RESULTS: In-hospital death occurred in 104 patients (68.4%). In multivariate logistic regression, age <= 66, shockable arrest rhythm, CPR to ECMO pump-on time <= 38 min, post-ECMO arterial pulse pressure > 24 mmHg, and post-ECMO Sequential Organ Failure Assessment score <= 14 were independent predictors for survival to discharge. Survival to discharge was predicted by the ECPR score with a c-statistics of 0.8595 (95% confidence interval [CI], 0.80-0.92; p<0.001) which was similar to the c statistics obtained from internal validation (training vs. test set; c statistics, 0.86 vs. 0.86005; 95% CI, 0.80-0.92 vs. 0.77-0.94). The sensitivity and specificity for prediction of survival to discharge were 89.6% and 75.0%, respectively, when the ECPR score was >10. CONCLUSIONS: The new risk prediction model might be helpful for decisions about ECPR management and could provide better information regarding early prognosis. PMID- 25443260 TI - Could occupational physical activity mitigate the link between moderate kidney dysfunction and coronary heart disease? AB - BACKGROUND: Chronic kidney disease is now regarded as a risk factor for cardiovascular disease. The impact of occupational or non-occupational physical activity (PA) on moderate decreases of renal function is uncertain. OBJECTIVES: We aimed to identify the potential association of PA (occupational and leisure time) on early decline of estimated glomerular filtration rate (eGFR) and to determine the potential mediating effect of PA on the relationship between eGFR and heart disease. METHODS: From the PRIME study analyses were conducted in 1058 employed men. Energy expended during leisure, work and commuting was calculated. Linear regression analyses were used to determine the link between types of PA and moderate decrements of eGFR determined with the KDIGO guideline at the baseline assessment. Cox proportional hazards analyses were used to explore the potential effect of PA on the relationship between eGFR and heart disease, ascertained during follow-up over 10 years. RESULTS: For these employed men, and after adjustment for known confounders of GFR change, more time spent sitting at work was associated with increased risk of moderate decline in kidney function, while carrying objects or being active at work was associated with decreased risk. In contrast, no significant link with leisure PA was apparent. No potential mediating effect of occupational PA was found for the relationship between eGFR and coronary heart disease. CONCLUSION: Occupational PA (potential modifiable factors) could provide a dual role on early impairment of renal function, without influence on the relationship between early decrease of e-GFR and CHD risk. PMID- 25443261 TI - Hiccup as a major sign of aortic dissection. PMID- 25443262 TI - Left atrial enlargement causing dysphagia and weight loss: a rare contraindication for catheter ablation therapy in a patient with complex atrial arrhythmia. PMID- 25443264 TI - Transcatheter closure of a congenital subclavian arteriovenous fistula using a duct occluder. PMID- 25443263 TI - An unexpected complication during percutaneous pacemaker lead extraction unveiled by transesophageal echocardiography. PMID- 25443265 TI - The burden of skeletal-related events in patients with prostate cancer and bone metastasis. AB - BACKGROUND: To assess contemporary characteristics, hospital admissions, charges, and mortality in patients with prostate cancer (CaP) who have bone metastases and skeletal-related events in an observational study. METHODS: Relying on the Nationwide Inpatient Sample (NIS), patients with CaP with bone metastases between 1998 and 2010 were abstracted. Patients who experienced skeletal-related events were identified, and hospital charges were calculated. Generalized linear regression analyses focused on in-hospital mortality. RESULTS: Between 1998 and 2010, a weighted estimate of 443,929 CaP visits with bone metastases was recorded. Of these, 15.9% experienced at least 1 SRE. The rate of SRE decreased from 18% to 15.4% (1998-2010, estimated annual percent change [EAPC] =-1.44%, P = 0.005) and the SRE-associated mortality decreased from 8.5% to 4.7% (1998-2010, EAPC =-3.68%, P = 0.004). Nevertheless, the inflation-adjusted charges associated with hospital visits of patients with CaP with bone metastases rose by 92% to $1,512,449,106 (EAPC = +8.82%, P<0.001), and SRE charges rose by 94% to $369,256,799 (EAPC =+7.62%, P<0.001). Predictors of in-hospital mortality in patients with SRE included age (odds ratio [OR] = 1.02), comorbidities (>=3 vs. 0 1, OR = 1.72), SRE of the upper limb (OR = 1.75), SRE of the lower limb (OR = 1.35), spinal cord compression (OR = 1.48), radiation (OR = 0.68), surgery (OR = 0.32), and year of hospitalization (2010 vs. 1998, OR = 0.54; all P< 0.03). CONCLUSIONS: From 1998 to 2010, the incidence of SRE and SRE-associated mortality in patients with CaP and bone metastases decreased. However, charges for SRE associated hospitalizations have increased alarmingly. Future health care policies should strive to provide cost-effective prevention and management of SREs in this population. PMID- 25443266 TI - The effect of smoking and timing of smoking cessation on clinical outcome in non muscle-invasive bladder cancer. PMID- 25443267 TI - Treatment and survival in patients with recurrent high-risk non-muscle-invasive bladder cancer. AB - BACKGROUND: Multiple recurrences develop in patients with high-risk non-muscle invasive bladder cancer. As neither the association of recurrences with survival nor the subsequent aggressive treatment in individuals with recurrent high-grade non-muscle-invasive bladder cancer has ever been quantified, we sought to determine whether the increasing number of recurrences is associated with higher subsequent treatment and mortality rates. METHODS: Using linked Surveillance, Epidemiology, and End Results-Medicare data, we identified subjects with recurrent high-grade, non-muscle-invasive disease diagnosed in 1992 to 2002 and followed up until 2007. Using competing-risks regression analyses, we quantified the incidence of radical cystectomy, radiotherapy, and systemic chemotherapy after each recurrence. We then performed a propensity-score adjusted competing risks regression analysis to determine whether the increasing recurrences portend worse survival. RESULTS: Of 4,521 subjects, 2,694 (59.6%) had multiple recurrences within 2 years of diagnosis. Compared with patients who only had 1 recurrence, those with >= 4 recurrences were less likely to undergo radical cystectomy (hazard ratio [HR] = 0.73, 95% CI: 0.58-0.92), yet more likely to undergo radiotherapy (HR = 1.51, 95% CI: 1.23-1.85) and systemic chemotherapy (HR = 1.58, 95% CI: 1.15-2.18). For patients with >= 4 recurrences, only 25% were treated with curative intent. The 10-year cancer-specific mortality rates were 6.9%, 9.7%, 13.7%, and 15.7% for those with 1, 2, 3, and >= 4 recurrences, respectively. CONCLUSIONS: Only 25% of patients with high-risk non-muscle invasive bladder cancer who experienced recurrences at least 4 times underwent radical cystectomy or radiotherapy. Despite portending worse outcomes, increasing recurrences do not necessarily translate into higher treatment rates. PMID- 25443268 TI - Multiparametric magnetic resonance imaging vs. standard care in men being evaluated for prostate cancer: a randomized study. AB - OBJECTIVES: To assess whether the proportion of men with clinically significant prostate cancer (PCa) is higher among men randomized to multiparametric magnetic resonance imaging (mp-MRI)/biopsy vs. those randomized to transrectal ultrasound (TRUS)-guided biopsy. METHODS: In total, 1,140 patients with symptoms highly suggestive of PCa were enrolled and divided in 2 groups of 570 patients to follow 2 different diagnostic algorithms. Group A underwent a TRUS-guided random biopsy. Group B underwent an mp-MRI and a TRUS-guided targeted+random biopsy. The accuracy of mp-MRI in the diagnosis of PCa was calculated using prostatectomy as the standard of reference. RESULTS: In group A, PCa was detected in 215 patients. The remaining 355 patients underwent an mp-MRI: the findings were positive in 208 and unremarkable in 147 patients. After the second random+targeted biopsy, PCa was detected in 186 of the 208 patients. In group B, 440 patients had positive findings on mp-MRI, and PCa was detected in 417 at first biopsy; 130 group B patients had unremarkable findings on both mp-MRI and biopsy. In the 130 group B patients with unremarkable findings on mp-MRI and biopsy, a PCa Gleason score of 6 or precancerous lesions were detected after saturation biopsy. mp-MRI showed an accuracy of 97% for the diagnosis of PCa. CONCLUSIONS: The proportion of men with clinically significant PCa is higher among those randomized to mp-MRI/biopsy vs. those randomized to TRUS-guided biopsy; moreover, mp-MRI is a very reliable tool to identify patients to schedule in active surveillance. PMID- 25443269 TI - Using imaging biomarkers to improve the planning of radical prostatectomies. AB - OBJECTIVES: This exploratory pilot study aimed to evaluate whether adding imaging biomarkers to conventional staging improves complete excision rates after undergoing radical prostatectomy (RP) in the United Kingdom for patients who have not undergone population prostate specific antigen screening. We primarily considered estimates of lesion volume and location based on computer-aided analysis of ultrasound (US) raw radiofrequency (RF) data acquired during trans rectal ultrasound. The imaging analysis device used had been shown to accurately detect tumor loci within the prostate in previous studies. METHODS AND MATERIALS: US raw RF data were collected from motorized trans-rectal ultrasound of 68 consecutive men with operable prostate cancer. In this cohort (group 1), locations and volume measurements of lesions suspected of harboring cancer on US raw RF data analysis by prostate HistoScanning, were added to conventional presurgical staging.The unexposed control group comprised 100 men who underwent conventional presurgical staging only (group 2): 50 were operated before and 50 operated after group 1 recruitment. Changes to pre-operative surgical planning and positive lateral margins of RP prostate pathological specimens were the primary outcomes. Data were collected using a Microsoft Excel database and analyzed using Stata. RESULTS: Baseline demographics were comparable. In group 1, consideration of the additional imaging biomarkers led to changes in 27 (19.9%) operative surgical plans. Absolute rate reduction of a positive surgical margin (PSM) attributable to the imaging-biomarkers was 13.3% (P = 0.029). For stage pT3, PSM rate was reduced from 45.8% (n = 44) to 21.2% (n = 11) (P = 0.0028). CONCLUSIONS: Obtaining quantitative measurements of preoperative imaging biomarkers appears to improve PSM rates of patients undergoing RP. The greatest PSM rate reduction was observed for pT3 tumors. PMID- 25443270 TI - Quality of life in patients with non-muscle-invasive bladder cancer: one-year results of a multicentre prospective cohort study. AB - OBJECTIVE: Few studies describe the effect of non-muscle-invasive bladder cancer (NMIBC) on health-related quality of life (HRQL), although patients are mostly diagnosed at this stage of the disease. Taking into account this current evidence gap and the high incidence rates in Spain, we aimed to describe the evolution over time of HRQL in Spanish patients with NMIBC and to examine the clinical and treatment-related factors associated with HRQL change during the first year of management. METHODS AND MATERIALS: Observational multicenter prospective inception cohort study conducted in urology departments of 7 Spanish hospitals. A consecutive sample of 244 patients with anatomopathologically confirmed NMIBC, recruited from October 2010 to September 2011, was followed during the diagnostic process, and 6 and 12 months later. HRQL was assessed by generic and disease specific instruments: the Short Form-36 (covering physical and mental health) and the Bladder Cancer Index, measuring urinary, bowel, and sexual domains (summary scores: 0-100). Bivariate analysis was performed and generalized estimating equation models were constructed to assess HRQL score change. RESULTS: Almost 52% of the patients were diagnosed at stage I, and 84% were men. The number of patients treated only with transurethral resection (TUR) was 144, and 82 also received intravesical therapy with bacillus Calmette-Guerin (BCG) or mitomycin C. Mental health was significantly worse than Short Form-36 reference norms at diagnosis (mean of 49.7 vs. 53.3, 95% CI: 52.5-54.2). Urinary domain improved significantly from diagnosis (85.2, 95% CI: 82.9-87.4) to 12-month evaluation (90.2, 95% CI: 87.7-92.8), whereas sexual domain showed deterioration from 56.4 (95% CI: 52.8-59.9) to 53.7 (95% CI: 50.0-57.4). Adjusted HRQL score changes from baseline to 12-month follow-up estimated with generalized estimating equation models showed improvement on the following parameters: urinary domain after TUR with or without intravesical therapy (+3.9, 95% CI: 0.1-7.7), bowel domain among patients treated with TUR and BCG (+7.0, 95% CI: 2.4-11.5), and sexual domain among those treated with TUR and mitomycin C (+13.1, 95% CI: 5.9-20.2). CONCLUSIONS: For the first time, a distinctive HRQL pattern of bladder cancer treatment benefits emerges for TUR alone, and in combination with BCG or mitomycin C, which deserves further research. Treatment differences cannot be interpreted in terms of efficacy but can be useful to generate hypotheses to test in future studies. PMID- 25443271 TI - Intraventricular hemorrhage as a comorbid factor for intestinal obstruction in very low-birthweight infants. AB - BACKGROUND: In very low-birthweight infants (VLBWI), intestinal obstruction (IO) tends to increase in severity due to the immaturity of the intestine and perinatal events. We examined the clinical comorbid factors related to IO in VLBWI. METHODS: Clinical data of 160 VLBWI admitted to the neonatal intensive care unit in 2006-2011 were retrospectively reviewed. Patients were divided into two groups: IO group (n = 62) and non-IO group (n = 98). IO was defined as bile excretion via the mouth or nasogastric tube within 30 days after birth. The relationship between clinical factors and the incidence of IO was analyzed. RESULTS: On univariate analysis, gestational age, birthweight, and the incidence of chronic lung disease, patent ductus arteriosus, intraventricular hemorrhage (IVH), retinopathy of prematurity, and the postnatal use of mechanical ventilation, catecholamines, steroids, and sedatives were associated with IO. On multivariate analysis, only IVH was strongly associated with IO (OR, 4.74; P < 0.01). CONCLUSIONS: IVH is a significant comorbid factor of IO in VLBWI. PMID- 25443272 TI - Assessing functional status and the survival benefit of chemotherapy for advanced non-small cell lung cancer using administrative claims data. AB - OBJECTIVES: Borderline or poor performance status (PS) patients comprise a significant proportion of those diagnosed with advanced non-small cell lung cancer (AdvNSCLC), but are often excluded from clinical trials. It is difficult to draw conclusions about the benefit of therapy in borderline PS patients due to lack of reliable PS assessments, and small clinical trial samples. Retrospective population-based secondary analyses may allow investigators to study under represented populations in clinical trials. We hypothesized that patients with poor functional status derive benefit from chemotherapy compared good functional status, but that the magnitude of the benefit is lower compared to patients with good functional status. By utilizing a "disability status" (DS) measure as a proxy for PS, we offer a reliable mechanism for patient stratification that can be implemented in administrative claims data. METHODS: Medicare beneficiaries diagnosed with AdvNSCLC between 2001 and 2005 were selected from the Surveillance, Epidemiology and End Results database linked to Medicare claims. Disability status, a previously developed and validated claims-based proxy for baseline PS, was implemented. Patients were assigned to good versus poor DS. Cox proportional hazard models were used to examine the differential effects of chemotherapy for the two DS groups on all-cause mortality, controlling for tumor and patient characteristics. RESULTS: Most patients in the cohort (n=21,019) were >=75 years of age (59%), and non-Hispanic white (85%); 91% were assigned to good DS; 38% received chemotherapy. Chemotherapy had a strong protective effect among good DS patients (hazard ratio, 0.43; CI 0.42-0.45; p<0.001), with a slightly smaller effect for poor DS (hazard ratio, 0.50; CI 0.44-0.57). CONCLUSIONS: Chemotherapy improves survival for advanced NSCLC patients with poor DS but to a lower magnitude than for good DS patients. The DS measure opens the door to assess outcomes for cancer patients with poor functional status using insurance claims data. PMID- 25443273 TI - Pemetrexed in patients with thymic malignancies previously treated with chemotherapy. AB - PURPOSE: Thymic malignancies are rare, with limited published trials of chemotherapy activity. We performed a retrospective analysis of pemetrexed activity in patients with thymic malignancies. METHODS: Patients with unresectable histologically confirmed invasive, recurrent, or metastatic thymoma or thymic carcinoma seen at the Stanford Cancer Center between January 2005 and November 2013 were identified, and those who were treated with pemetrexed in the second-line setting and beyond were included in this analysis. RESULTS: A total of 81 thymic malignancy patients were identified, of whom 16 received pemetrexed alone (N=14) or in combination (N=2). There were 10 patients (62.5%) with thymic carcinoma and 6 patients (37.5%) with thymoma. Among the 6 patients with thymoma, best response was 1 (17%) with a partial response (PR) and 5 (83%) with stable disease (SD). At a median follow-up of 21.2 months, the median PFS in the thymoma patients was 13.8 months (95% CI, 4.9-22.6 months) and the median OS was 20.1 months (95% CI, 16.4-23.9 months). Among the 10 patients with thymic carcinoma, best response to treatment was 1 (10%) PR, 5 (50%) SD, and 4 (40%) progressive disease (PD). At a median follow-up of 13.5 months, the median PFS in patients with thymic carcinoma was 6.5 months (95% CI, 0.2-12.8 months) and the median OS was 12.7 months (95% CI, 2.9-22.5 months). CONCLUSIONS: This small retrospective study demonstrates modest pemetrexed activity and disease stabilization in thymic malignancies with a clinically meaningful duration, and supports previous reports of pemetrexed efficacy in these rare diseases. PMID- 25443275 TI - Validation of tertiary Gleason pattern 5 in Gleason score 7 prostate cancer as an independent predictor of biochemical recurrence and development of a prognostic model. AB - OBJECTIVE: To validate the biological and prognostic value of tertiary Gleason pattern 5 (TGP5) in patients with Gleason score 7 (GS 7) prostate cancer (PCa) and to develop a prognostic model to identify the high-risk group of patients with TGP5. MATERIAL AND METHODS: We retrospectively reviewed the data from 4,146 patients with localized (pT2-3 N0 M0) GS 7 PCa treated by radical prostatectomy (RP) without adjuvant therapy. The primary end point was biochemical recurrence (BCR), and the secondary one was to build a bootstrap-corrected multivariable Cox model. RESULTS: Of the 4,146 patients, 416 (10%) had a TPG5 in the RP specimen. TGP5 was associated with BCR in both univariable and multivariable analyses that adjusted for the effects of standard pathological features (P<0.001). A prognostic model based on preoperative prostate-specific antigen levels (<10 vs.>=10ng/ml), primary and secondary Gleason pattern (3+4 vs. 4+3), pathological tumor category (pT2/pT3a vs. pT3b), and surgical margin status (R0 vs. R+) stratified patients with a discrimination of 72.2%. Patients in the low-risk group had a 5-year BCR-free survival rate of 76.3% compared with only 18.5% for those in the high-risk group (P<0.001). CONCLUSIONS: Knowledge of TGP5 improves our prognostication of patients with GS 7 PCa treated with RP. We developed a statistical tool to help identify the patients with TGP5 who are at the highest risk of BCR after RP, thereby helping with the clinical decision making regarding adjuvant trials and follow-up scheduling. PMID- 25443274 TI - Novel neoadjuvant therapy paradigms for bladder cancer: results from the National Cancer Center Institute Forum. AB - OBJECTIVE: To bridge gaps in translational science and develop the concepts for 2 novel biomarker-driven clinical trials: one in the presurgical setting and the other in the setting of bladder preservation with chemoradiation. METHODS AND MATERIALS: The National Cancer Institute sponsored a forum, "Novel Neoadjuvant Therapy for Bladder Cancer," which brought leading clinical and laboratory-based scientists together with the advocacy community. RESULTS: The group designed a neoadjuvant clinical trial to compare the clinical efficacy of the two frontline chemotherapy regimens (gemcitabine plus cisplatin versus MVAC) and the ability of a gene expression profiling-based algorithm (CoXEN) to predict complete pathological response. The trial was recently opened under the leadership of the Southwest Oncology Group (SWOG, S1314), receiving support for the biomarker studies from the NCI's BISQFP resource. A second clinical trial was planned that will examine the relationship between expression of the DNA repair protein MRE11 and complete response in patients treated with concurrent 5 fluorouracil/mitomycin C plus radiation. CONCLUSION: The meeting provided a unique opportunity to launch a collective effort to establish molecular-based therapies for muscle-invasive urothelial cancer. The goal is to use this framework to develop comparable trials with immunotherapy in non-muscle invasive cancers and to exploit the neoadjuvant platform to develop targeted therapy in muscle-invasive disease. PMID- 25443276 TI - CDK1 and CDK2 activity is a strong predictor of renal cell carcinoma recurrence. AB - BACKGROUND: In renal cell carcinoma (RCC), the prediction of metastasis via tumor prognostic markers remains a major problem. The objective of our study was to evaluate the efficacy of cyclin-dependent kinase (CDK)1 and CDK2 activity as a prognostic marker in human RCC. METHODS: Surgical specimens were obtained from 125 patients with RCC without metastasis. Protein expression and kinase activity of CDKs were analyzed using a newly developed assay system named C2P (Sysmex, Kobe, Japan). We then examined the specific activities (SAs) of CDK1 and CDK2 and calculated CDK2SA-CDK1SA ratio in RCC. Also, risk score (RS) was examined. RESULTS: A total of 125 cases were tested, though 34 cases were excluded because of low sample quality (25 cases) and assay failure (9 cases). In total, 91 cases were analyzed. They included 68 male and 23 female patients, ranging in age from 19 to 83 years. At a median follow-up of 36 months (1-109M), tumor with low CDK2SA-CDK1SA ratio showed significantly better 5-year recurrence-free survival than those with high CDK2SA-CDK1SA ratio (88.7% vs. 54.7%, P = 0.00141). Also, RS enabled the classification of RCCs into high-risk and low-risk groups, and patients with tumors classified as low RS showed better recurrence-free survival than patients with tumors with high RS (88.7% vs. 54.7%, P = 0.0141). CONCLUSION: CDK1SA of tumors and the CDK2SA are both associated with recurrence and prognosis. IMPACT: CDK-based risk demonstrated is strongly associated with clinical outcome. CDK-based risk should be an accurate system for predicting recurrence and survival for planning follow-up. PMID- 25443277 TI - Ionic liquid-aqueous solution ultrasonic-assisted extraction of three kinds of alkaloids from Phellodendron amurense Rupr and optimize conditions use response surface. AB - In this paper, we chose diffident kinds of ionic liquids to optimal selection an optimal one to extract alkaloids from Phellodendron amurense Rupr. Four ionic liquids with diffident carbon chains or anions have been investigated and 1-butyl 3-methylimidazolium bromide with best productivity. Then, selections have been optimized in different conditions, including concentration of ionic liquid, time for ultrasonic treatment, ultrasonic power and solid-liquid ratio. Moreover, three conditions have been comprehensively assessment by response surface methodology, the optimal conditions were determined as follows ultrasonic power 100 W, extraction time 75 min and ratio of solvent to raw material 1:14. Under these conditions, the yield% (MIX) was 106.7% (extracted by heat reflux being defined 100%). Comparing with other methods, the advantages are saving conserving, time saving, high yield% and especially pollution-free. PMID- 25443278 TI - Characterization of drinking water treatment sludge after ultrasound treatment. AB - Ultrasonic technology alone or the combination of ultrasound with alkaline or thermal hydrolysis as pretreatment for anaerobic digestion of activated sludge has been extensively documented. However, there are few reports on ultrasound as pretreatment of drinking water treatment sludge (DWTS), and thereby the characteristic variability of sonicated DWTS has not been fully examined. This research presents a lab-scale study on physical, chemical and biological characteristics of a DWTS sample collected from a water plant after ultrasonic treatment via a bath/probe sonoreactor. By doing this work, we provide implications for using ultrasound as pretreatment of enhanced coagulation of recycling sludge, and for the conditioning of water and wastewater mixed sludge by ultrasound combined with polymers. Our results indicate that the most vigorous DWTS disintegration quantified by particles' size reduction and organic solubilization is achieved with 5 W/ml for 30 min ultra-sonication (specific energy of 1590 kWh/kg TS). The Brunauer, Emmett and Teller (BET) specific surface area of sonicated DWTS flocs increase as ultra-sonication prolongs at lower energy densities (0.03 and 1 W/ml), while decrease as ultra-sonication prolongs at higher energy densities (3 and 5 W/ml). Additionally, the pH and zeta potential of sonicated DWTS slightly varies under all conditions observed. A shorter sonication with higher energy density plays a more effective role in restraining microbial activity than longer sonication with lower energy density. PMID- 25443279 TI - A randomized controlled study of the use of ProRoot mineral trioxide aggregate and Endocem as direct pulp capping materials. AB - INTRODUCTION: The purpose of the present study was to evaluate and compare the short-term clinical outcomes of direct pulp capping using ProRoot MTA (Dentsply, Tulsa, OK) or Endocem (Maruchi, Wonju, Korea) as capping materials in a prospective randomized controlled study. MATERIALS AND METHODS: This study was conducted with subjects who were recruited from the pool of patients from the Department of Conservative Dentistry at the Dental College of Yonsei University, Seoul, Korea, between January and May 2013. Of the 48 teeth confirmed to be eligible for direct pulp capping, a total of 46 teeth were randomly assigned to either the ProRoot MTA or the Endocem group (23 teeth per group). Direct pulp capping was performed using these 2 materials, and clinical and radiographic evaluations were performed at 1, 2, 4, and 12 weeks after the treatments. Teeth with no response to pulp vitality test and those exhibiting clinical or radiographic signs and/or symptoms of irreversible pulpitis or pulp necrosis were considered to be failures. RESULTS: Thirty-two patients (43 teeth) were examined at the 3-month follow-up (patient recall rate = 91.4%); 22 of these teeth were in the ProRoot MTA group, and 21 were in the Endocem group. The overall success rate was 93%, and the success rates in the ProRoot MTA and Endocem groups were 95.5% (21/22 teeth) and 90.5% (19/21 teeth), respectively. Statistical analyses of these success rates did not reveal any significant difference between the groups (P = .522). CONCLUSIONS: In this randomized controlled study, no significant difference in the short-term clinical outcomes of direct pulp capping using ProRoot MTA or Endocem as the capping material was found. Furthermore, the favorable short-term outcome success rate of 93% indicates that direct pulp capping may be a reliable treatment for pulp exposure in adult teeth. PMID- 25443280 TI - Clinical and radiographic outcomes of traumatized immature permanent necrotic teeth after revascularization/revitalization therapy. AB - INTRODUCTION: Revascularization treatment is rapidly becoming an accepted treatment alternative for the management of endodontic pathology in immature permanent teeth with necrotic dental pulps. However, the success and timing of clinical resolution of symptoms, and radiographic outcomes of interest, such as continued hard tissue deposition within the root, are largely unknown. METHODS: In this prospective cohort study, 20 teeth were treated with a standardized revascularization treatment protocol and monitored for clinical and radiographic changes for 1 year. Standardized radiographs were collected at regular intervals, and radiographic changes were quantified. RESULTS: All 20 treated teeth survived during the 12-month follow-up period, and all 20 also met the clinical criteria for success at 12 months. As a group, the treated teeth showed a statistically significant increase in radiographic root width and length and a decrease in apical diameter, although the changes in many cases were quite small (such that the clinical significance is unclear). The within-case percent change in apical diameter after 3 months was 16% and had increased to 79% by 12 months, with 55% (11/20) showing complete apical closure. The within-case percent change in root length averaged less than 1% at 3 months and increased to 5% at 12 months. The within-case percent change in root thickness averaged 3% at 3 months and 21% at 12 months. CONCLUSIONS: Although clinical success was highly predictable with this procedure, clinically meaningful radiographic root thickening and lengthening are less predictable after 1-year of follow-up. Apical closure is the most consistent radiographic finding. PMID- 25443281 TI - Accuracy of an electronic apex locator in the retreatment of teeth obturated with plastic or cross-linked gutta-percha carrier-based materials: an ex vivo study. AB - INTRODUCTION: This ex vivo study evaluated the accuracy of the Root ZX electronic apex locator (EAL) (J Morita Corp, Kyoto, Japan) in determining the working length during retreatment of canals sealed with 2 different carrier-based obturating materials (ProTaper Obturator [Dentsply Maillefer, Ballaigues, Switzerland] and GuttaCore [Dentsply Maillefer]) and also evaluated whether they influenced its accuracy differently. METHODS: Fifty extracted single-rooted human teeth with sound apices were selected for the study. We measured canals with the direct visual technique using a #10 K-file and shaped them with ProTaper Universal instruments (Dentsply Maillefer) up to this predetermined length. After instrumentation, we determined the canal length again using the visual technique (direct length [DL]). This value was considered the "reference point." Specimens were then placed in a tooth holder (Pro-Train; Simit Dental, Mantova, Italy), and the canal length was electronically measured (electronic length 1 [EL1]). Specimens were then obturated with ProTaper Obturators (group 1, n = 25) and GuttaCore (group 2, n = 25). Seven days later, a new electronic length was determined (electronic length 2 [EL2]) during retreatment procedures in the presence of the obturating material. EL1 and EL2 values were compared with DL using the Bland and Altman method. The different influences of the tested materials on the accuracy of the EAL were calculated with repeated measures analysis of variance. RESULTS: Both EL1 and EL2 values provided a statistically significant overestimation of the actual canal length (DL [P < .05]), with the EL2 values higher from DL. The 2 different materials did not influence the accuracy of the EAL differently (P = .486). CONCLUSIONS: The measurements obtained with the EAL tested during orthograde retreatments can lead clinicians to overinstrumentation and consequent overfilling of the endodontic space. PMID- 25443282 TI - Evaluation of debris extruded apically during the removal of root canal filling material using ProTaper, D-RaCe, and R-Endo rotary nickel-titanium retreatment instruments and hand files. AB - INTRODUCTION: The aim of this study was to evaluate the amount of debris extruded apically during the removal of root canal filling material using ProTaper (Dentsply Maillefer, Ballaigues, Switzerland), D-RaCe (FKG Dentaire, La Chaux-de Fonds, Switzerland), and R-Endo (Micro-Mega, Besancon, France) nickel-titanium (NiTi) rotary retreatment instruments and hand files. METHODS: Sixty extracted single-rooted mandibular premolar teeth were prepared with K-files and filled with gutta-percha and AH Plus sealer (Dentsply DeTrey, Konstanz, Germany). The teeth were then randomly assigned to 4 groups (n = 15 for each group) for retreatment. The removal of canal filling material was performed as follows: hand files, ProTaper, D-RaCe, and R-Endo retreatment instruments. Debris extruded apically during the removal of canal filling material was collected into preweighed Eppendorf tubes. The tubes were then stored in an incubator at 70 degrees C for 5 days. The weight of the dry extruded debris was established by subtracting the preretreatment and postretreatment weight of the Eppendorf tubes for each group. The data obtained were analyzed using 1-way analysis of variance and Tukey post hoc tests. RESULTS: All retreatment techniques caused the apical extrusion of debris. Hand files produced significantly more debris when compared with ProTaper, D-RaCe, and R-Endo rotary systems (P < .05). There was no statistical difference between the ProTaper, D-RaCe, and R-Endo retreatment systems (P > .05). CONCLUSIONS: The findings showed that during the removal of root canal filling material, rotary NiTi retreatment instruments used in this study caused less apical extrusion of debris compared with hand files. PMID- 25443283 TI - Three root canals in the mesiobuccal root of maxillary molars: case reports and literature review. AB - INTRODUCTION: The knowledge of root canal anatomy is essential to ensure a successful outcome of surgical and nonsurgical root canal treatment. The aims of this article were to present 2 cases of maxillary molars with 3 mesiobuccal root canals and to review the available literature on this anatomic variation. METHODS: The first case described a nonsurgical root canal treatment of tooth #16 in a 29-year-old man with the aid of a dental operating microscope. In the second case, an extracted maxillary right first molar was scanned by a micro-computed tomographic system and reconstructed 3-dimensionally using modeling software. RESULTS: In both cases, the mesiobuccal root had 3 canals (type 3-2 in case I and type 3-3 in case II), whereas the distobuccal and palatal roots had a single canal. The literature review showed that the overall incidence of 3-canaled mesiobuccal roots in maxillary molars ranged from 1.3%-2.4% and that the most common root canal configuration was type 3-2. CONCLUSIONS: Clinicians should always anticipate the presence of extra canals in maxillary molars and use all the available tools to locate and treat these. PMID- 25443284 TI - Reduction of p75 neurotrophin receptor ameliorates the cognitive deficits in a model of Alzheimer's disease. AB - Alzheimer's disease (AD) is an extremely prevalent cause of dementia. It is characterized by progressive memory loss, confusion, and other behavioral and physiological problems. The amyloid-beta (Abeta) protein is thought to be involved in the pathogenesis of AD, and there is evidence that Abeta may act through the p75 neurotrophin receptor (p75) to mediate its pathogenic effects. This raises the possibility that reducing levels of p75 could be a treatment for AD by preventing the effects of Abeta. In this study, we have crossed the transgenic AD model mice, Tg2576, with p75(-/-) mice to generate Tg2576/p75(+/-) mice with reduced levels of p75. These mice are rescued from the deficits in learning and memory and hippocampal function which were found in the Tg2576 mice. These findings suggest that reduction of p75 can ameliorate some of the primary symptoms of AD. PMID- 25443285 TI - Rescue of impaired late-phase long-term depression in a tau transgenic mouse model. AB - Cognitive decline, the hallmark of Alzheimer's disease, and accompanying neuropsychiatric symptoms share dysfunctions of synaptic processes as a common cellular pathomechanism. Long-term potentiation has proven to be a sensitive tool for the "diagnosis" of such synaptic dysfunctions. Much less, however, is known about how long-term depression (LTD), an alternative mechanism for the storage of memory, is affected by Alzheimer's disease progression. Here, we demonstrate that impaired late LTD (>3 hours) in THY-Tau22 mice can be rescued by either inhibition of glycogen synthase kinase-3 (GSK3beta) activity or by application of the protein-phosphatase 2A agonist selenate. In line with these findings, we observed increased phosphorylation of GSK3beta at Y216 and reduced total phosphatase activity in biochemical assays of hippocampal tissue of THY-Tau22 mice. Interestingly, LTD induction and pharmacologic inhibition of GSK3beta appeared to downregulate GSK3beta activity via a marked upregulation of phosphorylation at the inhibitory Ser9 residue. Our results point to alterations in phosphorylation and/or dephosphorylation homeostasis as key mechanisms underlying the deficits in LTD and hippocampus-dependent learning found in THY Tau22 mice. PMID- 25443287 TI - Downregulation of canonical Wnt signaling in hippocampus of SAMP8 mice. AB - In the adult brain, canonical Wnt (Wnt/beta-catenin) signaling modulates neuronal function, hippocampal neurogenesis, and synaptic plasticity. Indeed, growing evidence suggests that downregulation of Wnt signaling could be involved in the cognitive decline associated with aging and also with the physiopathology of Alzheimer's disease (AD). However, the molecular basis remains unknown. At present, SAMP8 is an experimental model that has been proposed for studying age related neurodegenerative changes associated with aging and the pathogenesis of AD. Here, we examined Wnt signaling in the hippocampus of SAMP8 mice at 9 and 12 months of age, as well as in its control-strain SAMR1 mice. Our results showed increased Dickkopf-1 protein levels in SAMP8 with age, in addition to GSK-3 alpha/beta activation and hyperphosphorylated tau. Consequently, higher beta catenin phosphorylation at Ser(33,37) and Thr(41), which promotes its degradation, along with a decrease in active beta-catenin (ABC) in the nucleus, were observed in SAMP8, mainly at the age of 12 months. Moreover, nuclear levels of Dvl3 were lower in 9- and 12-month-old SAMP8 mice. Related to these findings, SAMP8 showed an increase in neuronal loss in the hippocampus that was associated with lower protein levels of the antiapoptotic protein and the Wnt target gene, Bcl-2, in addition to an increase in the proapototic protein Bax. Our results suggest a relationship between age-related downregulation of canonical Wnt signaling and neuronal loss observed in the hippocampus of SAMP8 mice. Thus, enhancing Wnt signaling may represent a novel neuroprotective strategy aimed at counteracting the cognitive decline that is associated not only with aging but also with AD. PMID- 25443286 TI - Age-related metabolic fatigue during low glucose conditions in rat hippocampus. AB - Previous reports have indicated that with aging, intrinsic brain tissue changes in cellular bioenergetics may hamper the brain's ability to cope with metabolic stress. Therefore, we analyzed the effects of age on neuronal sensitivity to glucose deprivation by monitoring changes in field excitatory postsynaptic potentials (fEPSPs), tissue Po2, and NADH fluorescence imaging in the CA1 region of hippocampal slices obtained from F344 rats (1-2, 3-6, 12-20, and >22 months). Forty minutes of moderate low glucose (2.5 mM) led to approximately 80% decrease of fEPSP amplitudes and NADH decline in all 4 ages that reversed after reintroduction of 10 mM glucose. However, tissue slices from 12 to 20 months and >22-month-old rats were more vulnerable to low glucose: fEPSPs decreased by 50% on average 8 minutes faster compared with younger slices. Tissue oxygen utilization increased after onset of 2.5 mM glucose in all ages of tissue slices, which persisted for 40 minutes in younger tissue slices. But, in older tissue slices the increased oxygen utilization slowly faded and tissue Po2 levels increased toward baseline values after approximately 25 minutes of glucose deprivation. In addition, with age the ability to regenerate NADH after oxidation was diminished. The NAD(+)/NADH ratio remained relatively oxidized after low glucose, even during recovery. In young slices, glycogen levels were stable throughout the exposure to low glucose. In contrast, with aging utilization of glycogen stores was increased during low glucose, particularly in hippocampal slices from >22 months old rats, indicating both inefficient metabolism and increased demand for glucose. Lactate addition (20 mM) improved oxidative metabolism by directly supplementing the mitochondrial NADH pool and maintained fEPSPs in young as well as aged tissue slices, indicating that inefficient metabolism in the aging tissue can be improved by directly enhancing NADH regeneration. PMID- 25443289 TI - "Preconditioning" with latrepirdine, an adenosine 5'-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1(G93A) mice. AB - Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a master regulator of energy balance. As energy imbalance is documented as a key pathologic feature of amyotrophic lateral sclerosis (ALS), we investigated AMPK as a pharmacologic target in SOD1(G93A) mice. We noted a strong activation of AMPK in lumbar spinal cords of SOD1(G93A) mice. Pharmacologic activation of AMPK has shown protective effects in neuronal "preconditioning" models. We tested the hypothesis that "preconditioning" with a small molecule activator of AMPK, latrepirdine, exerts beneficial effects on disease progression. SOD1(G93A) mice (n = 24 animals per group; sex and litter matched) were treated with latrepirdine (1 MUg/kg, intraperitoneal) or vehicle from postnatal day 70 to 120. Treatment with latrepirdine increased AMPK activity in primary mouse motor neuron cultures and in SOD1(G93A) lumbar spinal cords. Mice "preconditioned" with latrepirdine showed a delayed symptom onset and a significant increase in life span (p < 0.01). Our study suggests that "preconditioning" with latrepirdine may represent a possible therapeutic strategy for individuals harboring ALS-associated gene mutations who are at risk for developing ALS. PMID- 25443288 TI - Axonal transport declines with age in two distinct phases separated by a period of relative stability. AB - Axonal transport is critical for supplying newly synthesized proteins, organelles, mRNAs, and other cargoes from neuronal cell bodies into axons. Its impairment in many neurodegenerative conditions appears likely to contribute to pathogenesis. Axonal transport also declines during normal aging, but little is known about the timing of these changes, or about the effect of aging on specific cargoes in individual axons. This is important for understanding mechanisms of age-related axon loss and age-related axonal disorders. Here we use fluorescence live imaging of peripheral nerve and central nervous system tissue explants to investigate vesicular and mitochondrial axonal transport. Interestingly, we identify 2 distinct periods of change, 1 period during young adulthood and the other in old age, separated by a relatively stable plateau during most of adult life. We also find that after tibial nerve regeneration, even in old animals, neurons are able to support higher transport rates of each cargo for a prolonged period. Thus, the age-related decline in axonal transport is not an inevitable consequence of either aging neurons or an aging systemic milieu. PMID- 25443290 TI - Astrocytes show reduced support of motor neurons with aging that is accelerated in a rodent model of ALS. AB - Astrocytes play a crucial role in supporting motor neurons in health and disease. However, there have been few attempts to understand how aging may influence this effect. Here, we report that rat astrocytes show an age-dependent senescence phenotype and a significant reduction in their ability to support motor neurons. In a rodent model of familial amyotrophic lateral sclerosis (ALS) overexpressing mutant superoxide dismutase 1 (SOD1), the rate of astrocytes acquiring a senescent phenotype is accelerated and they subsequently provide less support to motor neurons. This can be partially reversed by glial cell line-derived neurotrophic factor (GDNF). Replacing aging astrocytes with young ones producing GDNF may therefore have a significant survival promoting affect on aging motor neurons and those lost through diseases such as ALS. PMID- 25443291 TI - R2* mapping for brain iron: associations with cognition in normal aging. AB - Brain iron accumulates during aging and has been associated with neurodegenerative disorders including Alzheimer's disease. Magnetic resonance (MR)-based R2* mapping enables the in vivo detection of iron content in brain tissue. We investigated if during normal brain aging iron load relates to cognitive impairment in region-specific patterns in a community-dwelling cohort of 336 healthy, middle aged, and older adults from the Austrian Stroke Prevention Family Study. MR imaging and R2* mapping in the basal ganglia and neocortex were done at 3T. Comprehensive neuropsychological testing assessed memory, executive function, and psychomotor speed. We found the highest iron concentration in the globus pallidus, and pallidal and putaminal iron was significantly and inversely associated with cognitive performance in all cognitive domains, except memory. These associations were iron load dependent. Vascular brain lesions and brain volume did not mediate the relationship between iron and cognitive performance. We conclude that higher R2*-determined iron in the basal ganglia correlates with cognitive impairment during brain aging independent of concomitant brain abnormalities. The prognostic significance of this finding needs to be determined. PMID- 25443292 TI - Guest editorial. Neurobiology of aging. PMID- 25443294 TI - Cannabinoid receptor 2 deficiency results in reduced neuroinflammation in an Alzheimer's disease mouse model. AB - Several studies have indicated that the cannabinoid receptor 2 (CB2) plays an important role in neuroinflammation associated with Alzheimer's disease (AD) progression. The present study examined the role of CB2 in microglia activation in vitro as well as characterizing the neuroinflammatory process in a transgenic mouse model of AD (APP/PS1 mice). We demonstrate that microglia harvested from CB2(-/-) mice were less responsive to pro-inflammatory stimuli than CB2(+/+) microglia, based on the cell surface expression of ICAM and CD40 and the release of chemokines and cytokines CCL2, IL-6, and TNFalpha. Transgenic APP/PS1 mice lacking CB2 showed reduced percentages of microglia and infiltrating macrophages. Furthermore, they showed lowered expression levels of pro-inflammatory chemokines and cytokines in the brain, as well as diminished concentrations of soluble Abeta 40/42. The reduction in neuroinflammation did not affect spatial learning and memory in APP/PS1*CB2(-/-) mice. These data suggest a role for the CB2 in Alzheimer's disease-associated neuroinflammation, independent of influencing Abeta-mediated pathology and cognitive impairment. PMID- 25443293 TI - Amyloid-beta pathology is attenuated by tauroursodeoxycholic acid treatment in APP/PS1 mice after disease onset. AB - Alzheimer's disease (AD) is a neurodegenerative disorder hallmarked by the accumulation of extracellular amyloid-beta (Abeta) peptide and intraneuronal hyperphosphorylated tau, as well as chronic neuroinflammation. Tauroursodeoxycholic acid (TUDCA) is an endogenous anti-apoptotic bile acid with potent neuroprotective properties in several experimental models of AD. We have previously reported the therapeutic efficacy of TUDCA treatment before amyloid plaque deposition in APP/PS1 double-transgenic mice. In the present study, we evaluated the protective effects of TUDCA when administrated after the onset of amyloid pathology. APP/PS1 transgenic mice with 7 months of age were injected intraperitoneally with TUDCA (500 mg/kg) every 3 days for 3 months. TUDCA treatment significantly attenuated Abeta deposition in the brain, with a concomitant decrease in Abeta1-40 and Abeta1-42 levels. The amyloidogenic processing of amyloid precursor protein was also reduced, indicating that TUDCA interferes with Abeta production. In addition, TUDCA abrogated GSK3beta hyperactivity, which is highly implicated in tau hyperphosphorylation and glial activation. This effect was likely dependent on the specific activation of the upstream kinase, Akt. Finally, TUDCA treatment decreased glial activation and reduced proinflammatory cytokine messenger RNA expression, while partially rescuing synaptic loss. Overall, our results suggest that TUDCA is a promising therapeutic strategy not only for prevention but also for treatment of AD after disease onset. PMID- 25443295 TI - Validation of the Spanish adaptation of the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V). AB - OBJECTIVE: The Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) was developed.to promote a standardised approach to evaluating and documenting auditory perceptual judgments of vocal quality. This tool was originally developed in English language and its Spanish version is still inexistent. The aim of this study was to develop a Spanish adaptation of CAPE-V and to examine the reliability and empirical validity of this Spanish version. METHOD: To adapt the CAPE-V protocol to the Spanish language, we proposed 6 phrases phonetically designed according to the CAPE-V requirements. Prospective instrument validation was performed. The validity of the Spanish version of the CAPE-V was examined in 4 ways: intra-rater reliability, inter-rater reliability and CAPE-V versus GRABS judgments. RESULTS: Inter-rater reliability coefficients for the CAPE-V ranged from 0.93 for overall severity to 0.54 for intensity; intra-rater reliability ranged from 0.98 for overall severity to 0.85 for intensity. The comparison of judgments between GRABS and CAPE-V ranged from 0.86 for overall severity to 0.61 for breathiness. CONCLUSIONS: The present study supports the use of the Spanish version of CAPE-V because of its validity and reliability. PMID- 25443296 TI - The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3. AB - The sorting of signaling receptors into and out of cilia relies on the BBSome, a complex of Bardet-Biedl syndrome (BBS) proteins, and on the intraflagellar transport (IFT) machinery. GTP loading onto the Arf-like GTPase ARL6/BBS3 drives assembly of a membrane-apposed BBSome coat that promotes cargo entry into cilia, yet how and where ARL6 is activated remains elusive. Here, we show that the Rab like GTPase IFT27/RABL4, a known component of IFT complex B, promotes the exit of BBSome and associated cargoes from cilia. Unbiased proteomics and biochemical reconstitution assays show that, upon disengagement from the rest of IFT-B, IFT27 directly interacts with the nucleotide-free form of ARL6. Furthermore, IFT27 prevents aggregation of nucleotide-free ARL6 in solution. Thus, we propose that IFT27 separates from IFT-B inside cilia to promote ARL6 activation, BBSome coat assembly, and subsequent ciliary exit, mirroring the process by which BBSome mediates cargo entry into cilia. PMID- 25443297 TI - RuvB-like ATPases function in chromatin decondensation at the end of mitosis. AB - Chromatin undergoes extensive structural changes during the cell cycle. Upon mitotic entry, metazoan chromatin undergoes tremendous condensation, creating mitotic chromosomes with 50-fold greater compaction relative to interphase chromosomes. At the end of mitosis, chromosomes reestablish functional interphase chromatin competent for replication and transcription through a decondensation process that is cytologically well described. However, the underlying molecular events and factors remain unidentified. We describe a cell-free system that recapitulates chromatin decondensation based on purified mitotic chromatin and Xenopus egg extracts. Using biochemical fractionation, we identify RuvB-like ATPases as chromatin decondensation factors and demonstrate that their ATPase activity is essential for decondensation. Our results show that decompaction of metaphase chromosomes is not merely an inactivation of known chromatin condensation factors but rather an active process requiring specific molecular machinery. Our cell-free system provides an important tool for further molecular characterization of chromatin decondensation and its coordination with concomitant processes. PMID- 25443300 TI - Factors contributing to registered nurse medication administration error: a narrative review. AB - OBJECTIVE: To explore the factors contributing to Registered Nurse medication administration error behaviour. DESIGN: A narrative review. DATA SOURCES: Electronic databases (Cochrane, CINAHL, MEDLINE, BNI, EmBase, and PsycINFO) were searched from 1 January 1999 to 31 December 2012 in the English language. 1127 papers were identified and 26 papers were included in the review. Data were extracted by one reviewer and checked by a second reviewer. REVIEW METHODS: A thematic analysis and narrative synthesis of the factors contributing to Registered Nurses' medication administration behaviour. Bandura's (1986) theory of reciprocal determinism was used as an organising framework. This theory proposes that there is a reciprocal interplay between the environment, the person and their behaviour. Medication administration error is an outcome of RN behaviour. RESULTS: The 26 papers reported studies conducted in 4 continents across 11 countries predominantly in North America and Europe, with one multi national study incorporating 27 countries. Within both the environment and person domain of the reciprocal determinism framework, a number of factors emerged as influencing Registered Nurse medication administration error behaviour. Within the environment domain, two key themes of clinical workload and work setting emerged, and within the person domain the Registered Nurses' characteristics and their lived experience of work emerged as themes. Overall, greater attention has been given to the contribution of the environment domain rather than the person domain as contributing to error, with the literature viewing an error as an event rather than the outcome of behaviour. CONCLUSION: The interplay between factors that influence behaviour were poorly accounted for within the selected studies. It is proposed that a shift away from error as an event to a focus on the relationships between the person, the environment and Registered Nurse medication administration behaviour is needed to better understand medication administration error. PMID- 25443298 TI - B-LINK: a hemicentin, plakin, and integrin-dependent adhesion system that links tissues by connecting adjacent basement membranes. AB - Basement membrane (BM), a sheet-like form of extracellular matrix, surrounds most tissues. During organogenesis, specific adhesions between adjoining tissues frequently occur; however, their molecular basis is unclear. Using live-cell imaging and electron microscopy, we identify an adhesion system that connects the uterine and gonadal tissues through their juxtaposed BMs at the site of anchor cell (AC) invasion in C. elegans. We find that the extracellular matrix component hemicentin (HIM-4), found between BMs, forms punctate accumulations under the AC and controls BM linkage to promote rapid invasion. Through targeted screening, we identify the integrin-binding cytolinker plakin (VAB-10A) and integrin (INA-1/PAT 3) as key BM-BM linkage regulators: VAB-10A localizes to the AC-BM interface and tethers hemicentin to the AC while integrin promotes hemicentin punctae formation. Together, plakin, integrin, and hemicentin are founding components of a cell-directed adhesion system, which we name a BM-LINKage (B-LINK), that connects adjacent tissues through adjoining BMs. PMID- 25443301 TI - The prevalence, prevention and multilevel variance of pressure ulcers in Norwegian hospitals: a cross-sectional study. AB - BACKGROUND: Pressure ulcers are preventable adverse events. Organizational differences may influence the quality of prevention across wards and hospitals. OBJECTIVE: To investigate the prevalence of pressure ulcers, patient-related risk factors, the use of preventive measures and how much of the pressure ulcer variance is at patient, ward and hospital level. DESIGN: A cross-sectional study. SETTING: Six of the 11 invited hospitals in South-Eastern Norway agreed to participate. PARTICIPANTS: Inpatients >=18 years at 88 somatic hospital wards (N=1209). Patients in paediatric and maternity wards and day surgery patients were excluded. METHODS: The methodology for pressure ulcer prevalence studies developed by the European Pressure Ulcer Advisory Panel was used, including demographic data, the Braden scale, skin assessment, the location and severity of pressure ulcers and preventive measures. Multilevel analysis was used to investigate variance across hierarchical levels. RESULTS: The prevalence was 18.2% for pressure ulcer category I-IV, 7.2% when category I was excluded. Among patients at risk of pressure ulcers, 44.3% had pressure redistributing support surfaces in bed and only 22.3% received planned repositioning in bed. Multilevel analysis showed that although the dominant part of the variance in the occurrence of pressure ulcers was at patient level there was also a significant amount of variance at ward level. There was, however, no significant variance at hospital level. CONCLUSIONS: Pressure ulcer prevalence in this Norwegian sample is similar to comparable European studies. At-risk patients were less likely to receive preventive measures than patients in earlier studies. There was significant variance in the occurrence of pressure ulcers at ward level but not at hospital level, indicating that although interventions for improvement are basically patient related, improvement of procedures and organization at ward level may also be important. PMID- 25443302 TI - The impact of nurse practitioner services on cost, quality of care, satisfaction and waiting times in the emergency department: a systematic review. AB - AIMS: To provide the best available evidence to determine the impact of nurse practitioner services on cost, quality of care, satisfaction and waiting times in the emergency department for adult patients. BACKGROUND: The delivery of quality care in the emergency department is emerging as one of the most important service indicators in health delivery. Increasing service pressures in the emergency department have resulted in the adoption of service innovation models: the most common and rapidly expanding of these is emergency nurse practitioner services. The rapid uptake of emergency nurse practitioner service in Australia has outpaced the capacity to evaluate this service model in terms of outcomes related to safety and quality of patient care. Previous research is now outdated and not commensurate with the changing domain of delivering emergency care with nurse practitioner services. DATA SOURCES: A comprehensive search of four electronic databases from 2006 to 2013 was conducted to identify research evaluating nurse practitioner service impact in the emergency department. English language articles were sought using MEDLINE, CINAHL, Embase and Cochrane and included two previous systematic reviews completed five and seven years ago. REVIEW METHODS: A three step approach was used. Following a comprehensive search, two reviewers assessed all identified studies against the inclusion criteria. From the original 1013 studies, 14 papers were retained for critical appraisal on methodological quality by two independent reviewers and data were extracted using standardised tools. RESULTS: Narrative synthesis was conducted to summarise and report the findings as insufficient data was available for meta-analysis of results. This systematic review has shown that emergency nurse practitioner service has a positive impact on quality of care, patient satisfaction and waiting times. There was insufficient evidence to draw conclusions regarding outcomes of a cost benefit analysis. CONCLUSION: Synthesis of the available research attempts to provide an evidence base for emergency nurse practitioner service to guide healthcare leaders, policy makers and clinicians in reform of emergency service provision. The findings suggest that further high quality research is required for comparative measures of clinical and service effectiveness of emergency nurse practitioner service. In the context of increased health service demand and the need to provide timely and effective care to patients, such measures will assist in evidence based health service planning. PMID- 25443303 TI - The role of frailty in the association between depression and somatic comorbidity: results from baseline data of an ongoing prospective cohort study. AB - BACKGROUND: Depression and physical frailty in older persons are both associated with somatic diseases, but are hardly examined in concert. OBJECTIVES: To examine whether depression and physical frailty act independently and/or synergistically in their association with somatic diseases. DESIGN: Baseline data of an ongoing observational cohort study including depressed cases and non-depressed comparison subjects. SETTINGS: Netherlands Study of Depression in Older persons (NESDO). PARTICIPANTS: 378 depressed older persons confirmed by the Composite International Diagnostic Interview (CIDI), version 2.1, and 132 non-depressed comparison subjects. METHODS: Multiple linear regression analyses adjusted for socio-demographic and life-style characteristics were conducted with the number of somatic diseases as the dependent variable and depression and physical frailty as independent variables. Physical frailty was defined as >=3 of the following characteristics, slowness, low physical activity, weight loss, exhaustion, and weakness. RESULTS: Depression and physical frailty did not interact in explaining variance in the number of somatic diseases (p=.57). Physical frailty, however, partly mediated the association between depression and somatic diseases, as the strength of this association decreased by over 10% when frailty was added to the model (B=0.47, p=.003, versus B=0.41, p=.01). The mediation effect was primarily driven by the frailty criterion exhaustion. Of the remaining frailty components, only slowness was associated with the number of somatic diseases; but this association was fully independent of depression. CONCLUSIONS: Our results suggest that depression and physical frailty have common pathways towards somatic diseases, as well as unique pathways. As no high-risk group was identified (no significant interaction), mental health nurses should regularly monitor for physical frailty within their caseload of depressed patients. PMID- 25443304 TI - How nursing home residents develop relationships with peers and staff: a grounded theory study. AB - Social support and social relationships have been repeatedly identified as essential to nursing home resident quality of life. However, little is known about ways residents develop relationships with peers or staff. OBJECTIVE: This study was conducted to explore the ways resident develop relationships with peers and staff in nursing homes. DESIGN AND METHODS: Fifteen cognitively intact nursing home residents from two facilities were interviewed for this grounded theory study. Sampling, interviewing, and analysis occurred in a cyclical process with results at each stage of the study informing decisions about data collection and analysis in the next. Unstructured interviews and field observations were conducted. Data were analyzed with open, axial, and selective coding. RESULTS: Residents developed relationships with peers and staff largely as an unintended consequence of trying to have a life in the nursing home. Having a life was a two step process. First, life motivations (Being Self and Creating a Positive Atmosphere) influenced resident preferences for daily activities and interaction goals and subsequently their strategies for achieving and establishing both. Second, the strategies residents used for achieving their required daily activities (Passing Time and Getting Needs Met) and interaction goals then influenced the nature of interaction and the subsequent peer or staff response to these interactions. Residents defined relationships as friendly or unfriendly depending on whether peers or staff responded positively or negatively. There was considerable overlap in the ways peer and staff relationships developed and the results highlight the role of peer and staff responsiveness in relationship development. IMPLICATIONS: The results provide possible explanations for the success of interventions in the literature designed to improve staff responsiveness to residents. The results suggest that adapting these kinds of interventions for use with peers may also be successful. The conceptual model also presents a number of opportunities for developing interventions for residents. PMID- 25443305 TI - Demographic and occupational predictors of stress and fatigue in French intensive care registered nurses and nurses' aides: a cross-sectional study. AB - BACKGROUND: Healthcare workers (HCWs) working in intensive-care units (ICUs) are exposed to high physical and mental demands potentially affecting their health or having repercussions on patient care. Although several studies have explored the links between some aspects of working conditions in hospitals and HCW health, the complex dynamics at play are not fully understood. OBJECTIVES: This study aimed to explore the impact of a wide array of demographic, employment and organizational factors related to fatigue and stress of French ICU HCWs. DESIGN AND SETTING: A cross-sectional study was conducted in ICUs of Paris-area hospitals between January 18, 2013 and April 2, 2013. All types of adult ICUs were included (medical, surgical and polyvalent). PARTICIPANTS: Included in the study were HCWs with patient contact (doctors, residents, registered nurses, nurse's aides and physical therapists). Participation was proposed to all eligible HCWs present during on-site visits. Temporary staff not typically assigned to the given ICU was excluded. METHODS: Data were collected using an individual questionnaire administered in interviews during day and night shifts (N=682). Stress and fatigue outcomes included the 10-item Perceived Stress Scale (PSS10), the Nottingham Health Profile sleep and energy level rubrics and the current fatigue state at the interview. Multivariate analysis was restricted to nurse and nurse's aide data (n=536). RESULTS: Doctors and residents reported fewer sleep difficulties but were more likely to report a tired current state. Female gender was associated with higher stress levels and greater fatigue for all outcomes, while greater social support of supervisor or colleagues decreased stress and fatigue. At the organizational level, longer shifts (12 h vs. 8 h) were associated with tired current state and greater sleep difficulties. Personnel on rotating shifts had lower stress and a better current state, while those on night shifts had greater sleep and energy level difficulties. CONCLUSIONS: Even when controlling for demographic factors, employment and organizational elements remained significantly associated with stress and fatigue outcomes. To improve HCW health it is important to consider simultaneously factors at the individual and organizational level. PMID- 25443306 TI - Prophylactic oral health procedures to prevent hospital-acquired and ventilator associated pneumonia: a systematic review. AB - OBJECTIVES: Given the severity of hospital-acquired pneumonia and ventilator associated pneumonia, the purpose of this systematic review was to identify various oral health procedures, in intensive care unit or nursing home setting, shown to help reduce the incidence of hospital-acquired and ventilator-associated pneumonia. DESIGN: Randomized controlled trials evaluating the efficacy of at least one prophylactic oral health procedure in reducing hospital-acquired pneumonia or ventilator-associated pneumonia were included. DATA SOURCES: MEDLINE, EMBASE, and CINAHL were searched for relevant studies. In addition, references of studies included for full-text review were examined for potentially relevant studies. Grey literature was searched for by reviewing the first 200 results obtained in Google ScholarTM. REVIEW METHODS: Two authors conducted study selection and data extraction for this review. The Cochrane risk of bias tool was applied to assess the quality of the included trials (namely sequence generation, allocation concealment, blinding, the completeness of data assessment, the lack of selective reporting, and the lack of other miscellaneous biases) based on the information in the original publications. An assessment of a high, unclear, or low risk of bias was assigned to each domain. RESULTS: Through review of the 28 trials included in this review, we found that good oral health care was suggested to be associated with a reduction in the risk for hospital-acquired and ventilator-associated pneumonia in high-risk patients. Furthermore, through the review of studies evaluating the efficacy of chlorhexidine, we found that, despite the presence of mixed results, that chlorhexidine may be a particularly effective means of lowering the risk for hospital-acquired and ventilator associated pneumonia. The efficacy of other prophylactic oral health techniques such as the use of tooth brushing or iodine swab was uncertain. CONCLUSIONS: Current evidence suggests that chlorhexidine rinses, gels and swabs may be effective oral disinfectants in patients at high risk for hospital-acquired and ventilator-associated pneumonia. The evidence supporting the effectiveness of other oral care means still remains scarce and methodologically weak. As such, efforts to promote the increase of high-quality studies and to support nursing educational efforts to promote the dissemination of evidence-based knowledge of oral prophylaxis into clinical practice are warranted. PMID- 25443308 TI - The interaction between lived experiences of older patients and their family caregivers confronted with a cancer diagnosis and treatment: a qualitative study. AB - BACKGROUND: Despite the growing incidence of cancer among older people, little is understood about how older patients and their family caregivers experience receiving a cancer diagnosis and treatment and how their experiences mutually influence each other. Such knowledge is needed to provide meaningful support for both the older person and family caregivers. OBJECTIVES: Exploring lived experiences of older cancer patients, family caregivers and their interaction. DESIGN: Qualitative interview design. SETTING: Six outpatient oncology departments at a University Hospital. PARTICIPANTS: Thirty-two patients (age range 70-86) and 19 family caregivers (age range 42-83). METHODS: Semi-structured interviews with a fairly open framework were conducted and analyzed using the constant comparative method inspired by a grounded theory approach. RESULTS: Older patients and family caregivers experience important demands when confronted with cancer. Patients feel the inherent need to search for hope, and the majority are able to do so by employing coping strategies. Because of their older age, patients anticipate getting a serious illness such as a cancer diagnosis. Family caregivers become 'a family member of an older person with cancer' and feel responsible for the patient's well-being and for providing care. If patients are able to maintain a 'positive' story, family caregivers support this ability. If not, they search for a 'positive' story and point this out to the patient. Most family caregivers perceive their care-giving as a normal process and find it difficult to request professional help for themselves. Nevertheless, knowing that professional help is available whenever they need it reassures them. Overall, life continues during the illness experience: the interaction between patients and family caregivers goes on, their relationship proceeds, the coping and care patterns continue. CONCLUSIONS: The cancer diagnosis has a major impact on patients and family caregivers. This study offers a framework for understanding what is it like to have cancer in old age and outlines the importance of listening actively to the life stories of patients and family caregivers in order to comprehend coping strategies. This may result in better tailored patient family centered care. PMID- 25443307 TI - Hospital to community transitional care by nurse practitioners: a systematic review of cost-effectiveness. AB - OBJECTIVES: To determine the cost-effectiveness of nurse practitioners delivering transitional care. DESIGN: Systematic review of randomised controlled trials. DATA SOURCES: Ten electronic databases, bibliographies, hand-searches, study authors, and websites. REVIEW METHODS: We included randomised controlled trials that compared formally trained nurse practitioners to usual care and measured health system outcomes. Two reviewers independently screened articles and assessed study quality using the Cochrane Risk of Bias and the Quality of Health Economic Studies tools. We pooled data for similar outcomes and applied the Grading of Recommendations Assessment, Development and Evaluation tool to rate the quality of evidence for each outcome. RESULTS: Five trials met the inclusion criteria. One evaluated one alternative provider nurse practitioner (154 patients) and four evaluated six complementary provider nurse practitioners (1017 patients). Two were at low and three at high risk of bias and all had weak economic analyses. The alternative provider nurse practitioner had similar patient outcomes and resource use to the physician (low quality). Complementary provider nurse practitioners scored similarly to the control group in patient outcomes except for anxiety in rehabilitation patients (MD: -15.7, 95%CI: -20.73 to -10.67, p<0.001) (very low quality) and patient satisfaction after an abdominal hysterectomy (MD: 14, 95%CI: 3.5-24.5, p<0.01) (low quality), both favouring nurse practitioner care. Meta-analyses of index re-hospitalisation up to 42 days (n=766, pooled relative risk (RR): 0.69, 95%CI: 0.34-1.43, I(2)=0%) and any re-hospitalisation up to 180 days (n=800, pooled RR: 0.87, 95%CI: 0.69 1.09, I(2)=32%) were inconclusive (low quality). Complementary provider nurse practitioners significantly reduced index re-hospitalisation over 90 days (RR: 0.55, 95%CI: 0.32-0.94, p=0.03) and 180 days (RR: 0.62, 95%CI: 0.40-0.95, p=0.03) in complex care patients (both low quality) and they significantly reduced the number and duration of rehabilitation patient-to-staff consultation calls (p<0.05). CONCLUSIONS: Given the low quality evidence, weak economic analyses, small sample sizes, and small number of nurse practitioners evaluated in each study, evidence of the cost-effectiveness of nurse practitioner-transitional care is inconclusive and further research is needed. PMID- 25443309 TI - The quality of intensive care unit nurse handover related to end of life: a descriptive comparative international study. AB - BACKGROUND: Quality ICU end-of-life-care has been found to be related to good communication. Handover is one form of communication that can be problematic due to lost or omitted information. A first step in improving care is to measure and describe it. OBJECTIVE: The objective of this study was to describe the quality of ICU nurse handover related to end-of-life care and to compare the practices of different ICUs in three different countries. DESIGN: This was a descriptive comparative study. SETTINGS: The study was conducted in seven ICUs in three countries: Australia (1 unit), Israel (3 units) and the UK (3 units). PARTICIPANTS: A convenience sample of 157 handovers was studied. METHODS: Handover quality was rated based on the ICU End-of-Life Handover tool, developed by the authors. RESULTS: The highest levels of handover quality were in the areas of goals of care and pain management while lowest levels were for legal issues (proxy and advanced directives) related to end of life. Significant differences were found between countries and units in the total handover score (country: F(2,154)=25.97, p=<.001; unit: F(6,150)=58.24, p=<.001), for the end of life subscale (country: F(2, 154)=28.23, p<.001; unit: F(6,150)=25.25, p=<.001), the family communication subscale (country: F(2,154)=15.04, p=<.001; unit: F(6,150)=27.38, p=<.001), the family needs subscale (F(2,154)=22.33, p=<.001; unit: F(6,150)=42.45, p=<.001) but only for units on the process subscale (F(6,150)=8.98, p=<.001. The total handover score was higher if the oncoming RN did not know the patient (F(1,155)=6.51, p=<.05), if the patient was expected to die during the shift (F(1,155)=89.67, p=<.01) and if the family were present (F(1,155)=25.81, p=<.01). CONCLUSIONS: Practices of end-of-life-handover communication vary greatly between units. However, room for improvement exists in all areas in all of the units studied. The total score was higher when quality of care might be deemed at greater risk (if the nurses did not know the patient or the patient was expected to die), indicating that nurses were exercising some form of discretionary decision making around handover communication; thus validating the measurement tool. PMID- 25443310 TI - Effects of shrinkage of the visual field through ageing on parking performance: a parametric manipulation of salience and relevance of contextual components. AB - The Master Activation model of attention (Michael, Vairet, and Fernandez, Capture attentionnelle en vision: La saillance, la pertinence, et la balance cortico-sous corticale. In: G. A. Michael (ed), Neuroscience cognitive de l'attention visuelle [Cognitive Neuroscience of Visual Attention], Solal, Marseille, pp. 165-201, 2007; Michael, Lete, and Ducrot, Trajectories of Attentional Development: An Exploration with the Master Activation Map Model, Developmental Psychology, 49:615-631, 2013) was used to study visual attention and driving behaviours of younger and older drivers while parking a car. The salience and the relevance of elements present in the parking environment were manipulated during parking manoeuvres. Different effects on manoeuvring were observed depending on driver characteristics such as age and the extent of the field of view (FV). It was found that the presence of a relevant element, such as a pedestrian, impaired parking performance only among older drivers with a narrower FV. The distinct effects of salience and relevance suggest that they had different statuses in attentional processing of manoeuvring drivers. PMID- 25443312 TI - Imipenem therapy for Legionnaires' disease. PMID- 25443311 TI - Transcriptional and post-transcriptional regulation of the jasmonate signalling pathway in response to abiotic and harvesting stress in Hevea brasiliensis. AB - BACKGROUND: Latex harvesting in Hevea brasiliensis amounts to strong abiotic stress that can cause a halt in production in the most susceptible clones. Although the role of jasmonic acid has been suggested in laticifer differentiation, its role in latex production and in the response to harvesting stress has received very little attention. Only a few key genes acting in the COI JAZ-MYC module have been isolated and studied at transcriptional level. RESULTS: Use of a reference transcriptome obtained on rubber clone PB 260 covering a large number of tissues under different environmental conditions enabled us to identify 24 contigs implicated in the jasmonate signalling pathway in the rubber tree. An analysis of their expression profile by qPCR, combined with hierarchical clustering, suggested that the jasmonate signalling pathway is highly activated in laticifer cells and, more particularly, in the response to harvesting stress. By comparison with their genomic sequences, the existence of regulation by alternative splicing was discovered for JAZ transcripts in response to harvesting stress. Lastly, positive transcriptional regulation of the HbJAZ_1405 gene by MYC was demonstrated. CONCLUSION: This study led to the identification of all actors of jasmonate signalling pathway and revealed a specific gene expression pattern in latex cells. In-depth analysis of this regulation showed alternative splicing that has been previously shown in Arabidopsis. Interestingly, genotypic variation was observed in Hevea clones with contrasting latex metabolism. This result suggests an involvement of jasmonate signalling pathway in latex production. The data suggest that specific variability of the JA pathway may have some major consequences for resistance to stress. The data support the hypothesis that a better understanding of transcriptional regulations of jasmonate pathway during harvesting stress, along with the use of genotypic diversity in response to such stress, can be used to improve resistance to stress and rubber production in Hevea. PMID- 25443313 TI - Relocation, high-latitude warming and host genetic identity shape the foliar fungal microbiome of poplars. AB - Micro-organisms associated with plants and animals affect host fitness, shape community structure and influence ecosystem properties. Climate change is expected to influence microbial communities, but their reactions are not well understood. Host-associated micro-organisms are influenced by the climate reactions of their hosts, which may undergo range shifts due to climatic niche tracking, or may be actively relocated to mitigate the effects of climate change. We used a common-garden experiment and rDNA metabarcoding to examine the effect of host relocation and high-latitude warming on the complex fungal endophytic microbiome associated with leaves of an ecologically dominant boreal forest tree (Populus balsamifera L.). We also considered the potential effects of poplar genetic identity in defining the reactions of the microbiome to the treatments. The relocation of hosts to the north increased the diversity of the microbiome and influenced its structure, with results indicating enemy release from plausible pathogens. High-latitude warming decreased microbiome diversity in comparison with natural northern conditions. The warming also caused structural changes, which made the fungal communities distinct in comparison with both low latitude and high-latitude natural communities, and increased the abundance of plausible pathogens. The reactions of the microbiome to relocation and warming were strongly dependent on host genetic identity. This suggests that climate change effects on host-microbiome systems may be mediated by the interaction of environmental factors and the population genetic processes of the hosts. PMID- 25443316 TI - Electrocochleography for Meniere's disease: is it reliable? AB - INTRODUCTION: Endolymphatic hydrops, the histopathological substrate of Meniere's disease, is an almost universal finding in postmortem studies of patients with this disease. The cause of hydrops is still unknown, as is the mechanism by which it causes progressive dysfunction of the sensory organs of inner ear. The fluctuating course of the disease complicates the interpretation of certain tests, such as electrocochleography; thus, for some authors its diagnostic value is questionable. OBJECTIVE: The aim of this study was to analyze the clinical applicability of electrocochleography in the diagnosis of hydrops. It is a valuable tool, but still generates conflicting opinions among otolaryngologists. METHODS: Systematic review of the literature on electrocochleography in patients diagnosed with endolymphatic hydrops. RESULTS: A total of 34 articles regarding the use of electrocochleography in patients with hydrops, from the year 2000 onwards, were selected. Of these, 15 were excluded from the review as they were not observational studies. Only one cross-sectional study addressing the clinical use of electrocochleography by otolaryngologists was included. CONCLUSION: Electrocochleography is a valuable tool in the diagnosis of hydrops, as it is a non-invasive, easy to handle procedure, which offers new techniques to increase the sensitivity of the test, and thereby assists otolaryngologists in the management of Meniere's disease. PMID- 25443317 TI - Thyroid lipoadenoma: a case report of a rare condition. PMID- 25443318 TI - Mature teratoma of the nasopharynx. PMID- 25443319 TI - Switching from reaching to navigation: differential cognitive strategies for spatial memory in children and adults. AB - Navigational and reaching spaces are known to involve different cognitive strategies and brain networks, whose development in humans is still debated. In fact, high-level spatial processing, including allocentric location encoding, is already available to very young children, but navigational strategies are not mature until late childhood. The Magic Carpet (MC) is a new electronic device translating the traditional Corsi Block-tapping Test (CBT) to navigational space. In this study, the MC and the CBT were used to assess spatial memory for navigation and for reaching, respectively. Our hypothesis was that school-age children would not treat MC stimuli as navigational paths, assimilating them to reaching sequences. Ninety-one healthy children aged 6 to 11 years and 18 adults were enrolled. Overall short-term memory performance (span) on both tests, effects of sequence geometry, and error patterns according to a new classification were studied. Span increased with age on both tests, but relatively more in navigational than in reaching space, particularly in males. Sequence geometry specifically influenced navigation, not reaching. The number of body rotations along the path affected MC performance in children more than in adults, and in women more than in men. Error patterns indicated that navigational sequences were increasingly retained as global paths across development, in contrast to separately stored reaching locations. A sequence of spatial locations can be coded as a navigational path only if a cognitive switch from a reaching mode to a navigation mode occurs. This implies the integration of egocentric and allocentric reference frames, of visual and idiothetic cues, and access to long term memory. This switch is not yet fulfilled at school age due to immature executive functions. PMID- 25443323 TI - [Intermittent abdominal distention as a form of presentation of chronic gastric volvulus]. PMID- 25443324 TI - [X-linked agammaglobulinemia: experience in a Portuguese hospital]. AB - INTRODUCTION: X-Linked agammaglobulinemia (XLA) is characterized by an arrest of B cell differentiation, leading to recurrent bacterial infections. Lifelong immunoglobulin replacement therapy (IRT) is indicated to prevent infections and their complications. MATERIAL AND METHODS: A retrospective study of patients with XLA followed in a level three hospital was performed; data was collected retrospectively by review of clinical files. RESULTS: XLA was diagnosed in 9 children. One (11%) had a positive family history with a prenatal diagnosis. Infection was the clinical presentation in all the others (89%), at an average age of 13 months; diagnosis was established at a mean age of 3.4 years. Acute otitis media (7/9) and pneumonia (5/9) were the most frequently observed. Seven (78%) presented serum immunoglobulin G (IgG) levels below 200mg/dL and all of them had CD19(+) B cells below 2%. Neutropenia was present at diagnosis in three patients (33%). Bruton tyrosine kinase (BTK) mutations were identified in all cases. Intravenous IRT was initiated, switched later to subcutaneous administration, in all. The mean time of follow-up was 10.7 years with cumulative time of 97 years. Eight children (89%) achieved IgG serum levels above 800 mg/dL. One presented lower values due to renal loss. No deaths occurred. After diagnosis the most frequent infections were acute otitis media (6/9). In spite of stable adequate IgG levels on IRT, two patients developed bronchiectasis. CONCLUSIONS: XLA overall prognosis is good, as long as patients have an early and adequate treatment. However, bronchiectasis can occur even on adequate immunoglobulin replacement therapy. PMID- 25443325 TI - [Effectiveness of a school-based program to prevent obesity]. AB - INTRODUCTION: Intervention for childhood obesity is a public health priority. The purpose of this study was to evaluate the effectiveness of an elementary school based intervention against obesity in children. MATERIAL AND METHODS: Non randomised controlled trial was conducted on children from first to fifth grade from two public schools of Aviles (Spain). The intervention lasted for 2 school years comprising healthy diet workshops, educational chats, educational meetings, informative written material, and promotion of physical activities. Primary outcome measure was body mass index z-score. Secondary outcomes included: obesity and overweight prevalence, waist circumference, dietary habits, and physical activity. RESULTS: A total of 382 (177 girls, 205 boys) out of 526 pupils of both schools were included in the study. Complete anthropometric data were obtained in 340 of the 382 individuals. Compared to children in control group, those in intervention group decreased body mass index z-score from 1.14 to 1.02 (P=.017), and improved KIDMED score from 7.33 to 7.71 points (P=.045). The percentage of students who carried on an optimal diet increased from 42.6% to 52.3% (P=.021). There were no statistical differences in the prevalence of obesity and overweight, or in waist circumference between the intervention and control groups. CONCLUSIONS: This school-based program resulted in modest beneficial changes in body mass index and diet quality. PMID- 25443326 TI - [Anti-NMDA antibody encephalitis in paediatrics: A potentially treatable condition]. PMID- 25443327 TI - Diastereoselective palladium-catalyzed arylcyanation/heteroarylcyanation of enantioenriched N-allylcarboxamides. AB - A diastereoselective Pd-catalyzed arylcyanation/heteroarylcyanation of chiral N allylcarboxamides using Zn(CN)2 as the cyanide source is reported. Nitrile containing dihydroisoquinolinone products are obtained in good to excellent yields with up to >95:5 dr and with full preseveration of enantioenrichment. By circumventing a difficult nucleophilic cyanation of a hindered neopentyl iodide, this approach represents an improvement to the previously reported formal synthesis of (+)-corynoline. PMID- 25443328 TI - [Contribution of red blood group genotyping for recipients in immune-hematology through three years of activity at the EFS Alpes-Mediterranee]. AB - AIM OF THE STUDY: Current knowledge of the molecular basis of most blood groups enables genetic testing for blood groups to overcome the limitations of agglutination. A retrospective review was carried out on genotyping assays performed between 2011 and 2013. METHODS AND PATIENTS: The Molecular Hematology Laboratory of the EFS Alpes-Mediterranee implements commercially available tools (BioArray, Gen-Probe) and other techniques (TaqMan, tetra-primer ARMS-PCR, sequencing). It provides a high-level of expertise in molecular biology, complying with regulatory requirements and standards. RESULTS: A total of 2382 genotyping assays was performed including 764 extended typings and 115 large extended typings essentially in cases involving multiple transfusion and suspected rare blood type. Phenotype discrepancies linked to the RH system accounted for 1501 genotypings. Discrepancies linked to the D and E were mainly related to an allele coding for weak antigen (weak D type 1, 2, 3 and EIV) while those linked to C, c and e antigens were related to an allele coding for a partial antigen (RN, ces(340), ceMo). A high prevalence of (C)ces haplotype in trans of a DAR allele was observed in Afro-Caribbean (54/62). CONCLUSION: In transfusion medicine, red-cell genotyping can overcome the limitations of hemagglutination. It must be used only in situations where it provides a benefit either for the patient or resource management. For implementation of appropriate transfusional practices, this technique requires a sound knowledge of the genetic characteristics of blood groups and clinically relevant variants. It also requires competency with molecular biology tools and continuously updated scientific data. PMID- 25443329 TI - Cardiac arrest every other day. PMID- 25443330 TI - Brain death organ donation potential and life support therapy limitation in neurocritical patients. AB - OBJECTIVE: To analyze the profile, incidence of life support therapy limitation (LSTL) and donation potential in neurocritical patients. STUDY DESIGN: A multicenter prospective study was carried out. SETTING: Nine hospitals authorized for organ harvesting for transplantation. PATIENTS: All patients consecutively admitted to the hospital with GCS < 8 during a 6-month period were followed-up until discharge or day 30 of hospital stay. STUDY VARIABLES: Demographic data, cause of coma, clinical status upon admission and outcome were analyzed. LSTL, brain death (BD) and organ donation incidence were recorded. RESULTS: A total of 549 patients were included, with a mean age of 59.0 +/- 14.5 years. The cause of coma was cerebral hemorrhage in 27.0% of the cases.LSTL was applied in 176 patients (32.1%). In 78 cases LSTL consisted of avoiding ICU admission. Age, the presence of contraindications, and specific causes of coma were associated to LSTL. A total of 58.1% of the patients died (n=319). One-hundred and thirty-three developed BD (24.2%), and 56.4% of these became organ donors (n=75). The presence of edema and mid-line shift on the CT scan, and transplant coordinator evaluation were associated to BD. LSTL was associated to a no-BD outcome. Early LSTL (first 4 days) was applied in 9 patients under 80 years of age, with no medical contraindications for donation and a GCS <= 4 who finally died in asystole. CONCLUSIONS: LSTL is a frequent practice in neurocritical patients. In almost one half of the cases, LSTL consisted of avoiding admission to the ICU, and on several occasions the donation potential was not evaluated by the transplant coordinator. PMID- 25443332 TI - Renal papillary carcinoma: CT and MRI features. AB - PURPOSE: To describe the CT and MRI appearances of papillary renal cell carcinoma. MATERIALS AND METHODS: Retrospective study of 102 papillary carcinomas in 79 patients, 81 tumors examined by CT and 56 by MRI. Tumor size, homogeneity and contrast enhancement were recorded. RESULTS: The most common presentation of papillary renal cell carcinoma was a small homogeneous hypovascular tumor both on CT and MRI. Eighty-nine percent of lesions were hypointense on T2 weighted images compared to the renal parenchyma. Seventeen percent of the lesions did not significantly enhance with contrast on CT. All of the lesions examined on MRI had a significant enhancement percentage. Calcifications were rare and only seen in 7% of cases (CT). The second most common presentation was a bulky necrotic tumor. In addition, atypical types of disease were found which were difficult to diagnose, including infiltrating tumors and tumors with a fatty component. CONCLUSION: A homogeneous hypovascular renal tumor which is hypointense on T2 weighted images should suggest a diagnosis of papillary carcinoma. Some papillary carcinomas do not enhance significantly on CT. MRI is then required to diagnose the renal tumor. PMID- 25443331 TI - Evaluation of head-of-bed elevation compliance in critically ill patients under mechanical ventilation in a polyvalent intensive care unit. AB - OBJECTIVES: To evaluate head-of-bed elevation (HOBE) compliance in mechanically ventilated (MV) patients during different time periods, in order to identify factors that may influence compliance and to compare direct-observation compliance with checklist-reported compliance. DESIGN AND SETTING: A prospective observational study was carried out in a polyvalent Intensive Care Unit. PATIENTS: All consecutive patients with MV and no contraindication for semi recumbency were studied. INTERVENTION AND VARIABLES: HOBE was observed during four periods of one month each for one year, the first period being blinded. HOBE was measured with an electronic device three times daily. Main variables were HOBE, type of airway device, type of bed, nursing shift, day of the week and checklist-reported compliance. No patient characteristics were collected. RESULTS: During the four periods, 2639 observations were collected. Global HOBE compliance was 24.0%, and the median angle head-of-bed elevation (M-HOBE) was 24.0 degrees (IQR 18.8-30.0). HOBE compliance and M-HOBE by periods were as follows: blinded period: 13.8% and 21.1 degrees (IQR 16.3-24.4); period 1: 25.5% and 24.3 degrees (IQR 18.8-30.2); period 2: 22.7% and 24.4 degrees (IQR 18.9 29.6); and period 3: 31.4% and 26.7 degrees (IQR 21.3-32.6) (p<0.001). An overestimation of 50-60% was found when comparing self-reported compliance using a checklist versus direct-observation compliance (p<0.001). Multivariate logistic regression analysis found the presence of an endotracheal tube (ET) and bed without HOBE measuring device to be independently associated to greater compliance (p<0.05). CONCLUSIONS: Although compliance increased significantly during the study period, it was still not optimal. Checklist-reported compliance significantly overestimated HOBE compliance. The presence of an ET and a bed without HOBE measuring device was associated to greater compliance. PMID- 25443333 TI - The usefulness of post-mortem CT angiography in injuries caused by falling from considerable heights: three fatal cases. AB - OBJECTIVE: Post-mortem computed tomography is a diagnostic tool forming part of the arsenal available to forensic pathologists today. In addition to its usefulness in detecting bone lesions, which has long been recognized, this technique has nowadays been enhanced by the development of CT angiography. The role of multiphase post-mortem computed tomography angiography (multiphase PMCTA) is primordial, improving detection of solid organ lesions and permitting vascular lesions to be visualized directly. MATERIAL AND METHODS: Our paper presents a series of three deaths by falling from a considerable height recorded since the beginning of 2012. We report the usefulness of PMCTA and the various mechanisms involved in the trauma. RESULTS: Most of the lesions were diagnosed by both PMCTA and autopsy, including the rare lesions, but the peripheral bone lesions and the hemopneumatocele were diagnosed only by PMCTA, while dislocation of vertebrae and the testicular fractures were detected solely by autopsy. CONCLUSION: PMCTA is a new, minimally-invasive technique which, combined with autopsy, provides better visualization and detection of certain lesions, particularly in the case of death by falling from a great height. PMID- 25443334 TI - A rare cause of pleural nodules: thoracic splenosis. PMID- 25443335 TI - Wrist pain. PMID- 25443336 TI - Primary infertility. PMID- 25443337 TI - Clinical characteristics and in-hospital outcome of patients with acute coronary syndromes and systemic lupus erythematosus. AB - OBJECTIVE: Due to the chronic inflammation associated with systemic lupus erythematosus (SLE), patients develop premature atherosclerosis and the disease is a risk factor for acute myocardial infarction. The best interventional treatment for acute coronary syndrome (ACS) in these patients is unclear. The objective of this study is to describe the baseline characteristics, clinical manifestations, treatment and in-hospital outcome of patients with SLE and ACS. METHODS: Eleven SLE patients with ACS were analyzed retrospectively between 2004 and 2011. The following data were obtained: age, gender, clinical and electrocardiographic characteristics, Killip class, risk factors for ACS, myocardial necrosis markers (CK-MB and troponin), creatinine clearance, left ventricular ejection fraction, inflammatory markers (C-reactive protein and erythrocyte sedimentation rate), drugs used during hospital stay, treatment (medical, percutaneous or surgical) and in-hospital outcome. The statistical analysis is presented in percentages and absolute values. RESULTS: Ten of the patients (91%) were women. The median age was 47 years. Typical precordial pain was present in 91%. Around 73% had positive erythrocyte sedimentation rate. The vessel most often affected was the anterior descending artery, in 73%. One patient underwent coronary artery bypass grafting, seven underwent percutaneous coronary intervention with bare-metal stents and three were treated medically. In hospital mortality was 18%. CONCLUSIONS: Despite the small number of patients, our findings were similar to those in the literature, showing coronary artery disease in young people with SLE due to premature atherosclerosis and a high mortality rate. PMID- 25443338 TI - Overcoming the roadblocks in hepatitis C virus infection. PMID- 25443339 TI - Management of acute and chronic HCV infection in persons with HIV coinfection. AB - Due to shared routes of transmission, acute and chronic infection with hepatitis C virus is common among persons living with HIV infection in many regions of the world. In the era of effective antiretroviral therapy, acute HCV infection has been increasingly recognized in HIV-infected persons, particularly men who have sex with men, and liver disease, including hepatocellular carcinoma, has emerged as a leading cause of morbidity and mortality in those with chronic HCV infection, particularly older adults with long-standing coinfection. Over the past decade, the foundation for the management of acute and chronic HCV infection has been interferon alfa. However, due the high burden of treatment-related side effects and low likelihood of sustained virologic response, the impact of treatment with peginterferon/ribavirin on the burden of HCV disease in has been limited. However, the anticipated availability of safe, tolerable and highly efficacious interferon-free, oral HCV direct-acting antiviral combination therapies promise to dramatically change the management of acute and chronic HCV infection in HIV-infected persons. Preliminary data from studies of such oral DAA regimens in HIV/HCV coinfected patients suggest that coinfection with HIV will not impair HCV cure with these regimens. Indeed, in the coming era of high effective oral HCV DAA treatments, the only special feature concerning treatment of acute and chronic HCV infection in HIV-infected patients may be drug interactions between the antiretroviral drugs for HIV infection and direct-acting antiviral drugs for HCV infection. PMID- 25443340 TI - Treatment options in patients with decompensated cirrhosis, pre- and post transplantation. AB - Interferon-based treatments have a poor safety profile and limited efficacy in patients with advanced liver disease and in patients with hepatitis C (HCV) recurrence after liver transplantation (LT). Despite the recent approval of the first interferon-free regimen, which will be followed by several other interferon free combinations in 2014 and 2015, data in patients with advanced cirrhosis and hepatitis C after LT are still limited. One study has already proven the concept that graft HCV infection can be prevented in a significant proportion of patients by treating them with sofosbuvir and ribavirin while awaiting LT. Two interferon free regimens have also demonstrated a high efficacy in patients with hepatitis C recurrence after transplantation. Before these treatment strategies can be implemented in clinical practice, a few issues need to be addressed: (1) safety and efficacy of new antivirals in patients with decompensated cirrhosis, (2) the impact of viral clearance on liver function, (3) the potential consequences of virological failure (and the selection of multi-drug resistant HCV strains) in patients with decompensated cirrhosis or with severe hepatitis C recurrence after LT, and (4) drug-drug interactions (DDI) profiles. Finally, in the transplant setting it is also relevant to learn which strategy is most cost-effective in minimizing the negative impact of hepatitis C: preventing graft infection by treating patients before transplantation or treating hepatitis C recurrence after LT. PMID- 25443341 TI - Simplification of antiviral hepatitis C virus therapy to support expanded access in resource-limited settings. AB - Currently, access to treatment for HCV is limited, with treatment rates lowest in the more resource-limited countries, including those countries with the highest prevalence. The use of oral DAAs has the potential to provide treatment at scale by offering opportunities to simplify drug regimens, laboratory requirements, and service delivery models. Key desirable characteristics of future HCV treatment regimens include high efficacy, tolerability, pan-genotype activity, short treatment duration, oral therapy, affordability, and availability as fixed-dose combination. Using such a regimen, HCV treatment delivery could be greatly simplified. Treatment could be initiated following confirmation of the presence of viraemia, with an initial assessment of the stage of liver disease. A combination DAA therapy that is safe and effective across genotypes could remove the need for genotyping and intermediary viral load assessments for response guided therapy and reduce the need for adverse event monitoring. Simpler, safer, shorter therapy will also facilitate simplified service delivery, including task shifting, decentralization, and integration of treatment and care. The opportunity to scale up HCV treatment using such delivery approaches will depend on efforts needed to guarantee that the new DAAs are affordable in low-income settings. This will require the engagement of all stakeholders, ranging from the companies developing these new treatments, WHO and other international organizations, including procurement and funding mechanisms, governments and civil society. PMID- 25443342 TI - Innate and adaptive immune responses in HCV infections. AB - Hepatitis C virus has been identified a quarter of a decade ago as a leading cause of chronic viral hepatitis that can lead to cirrhosis and hepatocellular carcinoma. Only a minority of patients can clear the virus spontaneously during acute infection. Elimination of HCV during acute infection correlates with a rapid induction of innate, especially interferon (IFN) induced genes, and a delayed induction of adaptive immune responses. However, the majority of patients is unable to clear the virus and develops viral persistence in face of an ongoing innate and adaptive immune response. The virus has developed several strategies to escape these immune responses. For example, to escape innate immunity, the HCV NS3/4A protease can efficiently cleave and inactivate two important signalling molecules in the sensory pathways that react to HCV pathogen-associated molecular patterns (PAMPs) to induce IFNs, i.e., the mitochondrial anti-viral signalling protein (MAVS) and the Toll-IL-1 receptor-domain-containing adaptor-inducing IFN beta (TRIF). Despite these escape mechanisms, IFN-stimulated genes (ISGs) are induced in a large proportion of patients with chronic infection. Of note, chronically HCV infected patients with constitutive IFN-stimulated gene (ISG) expression have a poor response to treatment with pegylated IFN-alpha (PegIFN alpha) and ribavirin. The mechanisms that protect HCV from IFN-mediated innate immune reactions are not entirely understood, but might involve blockade of ISG protein translation at the ribosome, localization of viral replication to cell compartments that are not accessible to anti-viral IFN-stimulated effector systems, or direct antagonism of effector systems by viral proteins. Escape from adaptive immune responses can be achieved by emergence of viral escape mutations that avoid recognition by antibodies and T cells. In addition, chronic infection is characterized by the presence of functionally and phenotypically altered NK and T cell responses that are unable to clear the virus but most likely contribute to the ongoing liver disease. In this review, we will summarize current knowledge about the role of innate and adaptive immune responses in determining the outcome of HCV infection. PMID- 25443343 TI - HCV animal models and liver disease. AB - The development and evaluation of effective therapies and vaccines for the hepatitis C virus (HCV) and the study of its interactions with the mammalian host have been hindered for a long time by the absence of suitable small animal models. Due to the narrow host tropism of HCV, the development of mice that can be robustly engrafted with human hepatocytes was a major breakthrough since they recapitulate the complete HCV life cycle. This model has been useful to investigate many aspects of the HCV life cycle, including antiviral interventions. However, studies of cellular immunity, immunopathogenesis and resulting liver diseases have been hampered by the lack of a small animal model with a functional immune system. In this review, we summarize the evolution of in vivo models for the study of HCV. PMID- 25443344 TI - Virology and cell biology of the hepatitis C virus life cycle: an update. AB - Hepatitis C virus (HCV) is an important human pathogen that causes hepatitis, liver cirrhosis and hepatocellular carcinoma. It imposes a serious problem to public health in the world as the population of chronically infected HCV patients who are at risk of progressive liver disease is projected to increase significantly in the next decades. However, the arrival of new antiviral molecules is progressively changing the landscape of hepatitis C treatment. The search for new anti-HCV therapies has also been a driving force to better understand how HCV interacts with its host, and major progresses have been made on the various steps of the HCV life cycle. Here, we review the most recent advances in the fast growing knowledge on HCV life cycle and interaction with host factors and pathways. PMID- 25443346 TI - Natural history of hepatitis C. AB - There has long been evidence that hepatitis C can lead to persistent infection in a high proportion of infected individuals, and can progress to chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). The transition from acute to chronic hepatitis C is usually sub-clinical. Accurate studies of the time course for clearance of acute hepatitis C are difficult to carry out because of the silent onset of the acute disease. The likelihood of spontaneous HCV resolution is associated with several genetic factors, including IL28B inheritance and the DQB1*0301 allele of the major histocompatibility complex class II. Most data suggest that resolution in the acute phase without progression to chronic disease is not accompanied by significant disease, but minor histological lesions have been observed in anti-HCV positive, HCV RNA negative individuals. The risk of reinfection remains a possibility after clearance of acute hepatitis C. High rates of sexually-transmitted infection are being reported in HIV positive men who have sex with men (MSM). Chronic infection with HCV is the leading cause of end-stage liver disease, hepatocellular carcinoma (HCC) and liver related death in the Western world. The natural history of the chronic disease remains incompletely defined. It is generally a slowly progressive disease characterized by persistent hepatic inflammation, leading to the development of cirrhosis in approximately 10-20% of patients over 20-30 years of HCV infection. However, the published data indicate varying progression rates to cirrhosis. Overall, once cirrhosis has developed there is a 1-5% annual risk of HCC and a 3-6% annual risk of hepatic decompensation. Following an episode of decompensation the risk of death in the following year is between 15% and 20%. The high number of chronically infected individuals, the burden of disease, and the absence of a vaccine indicates that treatment will form part of the disease control but the impact, effectiveness and outcomes of treatment in various groups remain uncertain. Several studies and meta-analysis have concluded that eradication of HCV with antiviral therapy reduces the risk of HCC in patients with chronic hepatitis C, independent of fibrosis stage, but the risk is not eliminated. PMID- 25443345 TI - A prophylactic hepatitis C virus vaccine: a distant peak still worth climbing. AB - Hepatitis C virus (HCV) infects an estimated more than 150 million people and is a leading cause of liver disease worldwide. The development of direct-acting antivirals (DAAs) will markedly improve the outcome of antiviral treatment with cure of the majority of treated patients. However, several hurdles remain before HCV infection can be considered a menace of the past: High treatment costs will most likely result in absent or limited access in middle and low resource countries and will lead to selective use even in wealthier countries. The limited efficacy of current HCV screening programs leads to a majority of cases being undiagnosed or diagnosed at a late stage and DAAs will not cure virus-induced end stage liver disease such as hepatocellular carcinoma. Certain patient subgroups may not respond or not be eligible for DAA-based treatment strategies. Finally, reinfection remains possible, making control of HCV infection in people with ongoing infection risk difficult. The unmet medical needs justify continued efforts to develop an effective vaccine, protecting from chronic HCV infection as a mean to impact the epidemic on a global scale. Recent progress in the understanding of virus-host interactions provides new perspectives for vaccine development, but many critical questions remain unanswered. In this review, we focus on what is known about the immune correlates of HCV control, highlight key mechanisms of viral evasion that pose challenges for vaccine development and suggest areas of further investigation that could enable a rational approach to vaccine design. Within this context we also discuss insights from recent HCV vaccination studies and what they suggest about the best way to go forward. PMID- 25443347 TI - Facts and fictions of HCV and comorbidities: steatosis, diabetes mellitus, and cardiovascular diseases. AB - The hepatitis C virus (HCV) is a major cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma worldwide. A significant portion of the morbidity and mortality associated with HCV is a consequence of numerous HCV-associated comorbidities. Type 2 diabetes and atherosclerosis, two known complications of the metabolic syndrome, are noteworthy, because HCV has been suggested to play a role in their pathogenesis. In addition, HCV also causes steatosis, which may increase the risk of cardiovascular events. This review summarizes the evidence supporting the association between HCV and steatosis, insulin resistance/type 2 diabetes and cardiovascular morbidity and mortality. Their diagnostic, prognostic and management aspects are discussed. PMID- 25443349 TI - Antiviral therapy with nucleotide polymerase inhibitors for chronic hepatitis C. AB - The treatment of hepatitis C virus (HCV) has made significant advances with the development of new direct-acting antivirals. Nucleotide polymerase inhibitors are one class of these new medications that have been shown to be highly effective, safe and well tolerated as part of an antiviral regimen. Sofosbuvir has become the first drug in this class to be approved for clinical use, supported by results from extensive phase II and phase III clinical trials. This review will further discuss nucleotide polymerase inhibitors, including the data supporting their use as part of interferon-free HCV treatment regimens. PMID- 25443350 TI - Interferon-free antiviral combination therapies without nucleosidic polymerase inhibitors. AB - The establishment of robust HCV cell culture systems and characterization of the viral life cycle provided the molecular basis for highly innovative, successful years in HCV drug development. With the identification of direct-acting antiviral agents (DAAs), such as NS3/4A protease inhibitors, NS5A replication complex inhibitors, nucleotide and non-nucleoside polymerase inhibitors, as well as host cell targeting agents, novel therapeutic strategies were established and competitively entered clinical testing. The first-in-class NS3/4A protease inhibitors telaprevir and boceprevir, approved in 2011, were recently outpaced by the pan-genotypic nucleotide polymerase inhibitor sofosbuvir that in combination with pegylated interferon and ribavirin, further shortens therapy durations and also offers the first interferon-free HCV treatment option. In the challenging race towards the goal of interferon-free HCV therapies, however, several oral DAA regimens without nucleotide polymerase inhibitors that combine a NS3/4A protease inhibitor, a NS5A inhibitor and/or a non-nucleoside polymerase inhibitor yielded competitive results. Second generation NS3/4A protease and NS5A inhibitors promise an improved genotypic coverage and a high resistance barrier. Results of novel DAA combination therapies without the backbone of a nucleotide polymerase inhibitor, as well as treatment strategies involving host targeting agents are reviewed herein. PMID- 25443352 TI - Electroencephalography and transcranial Doppler ultrasonography in neonatal citrullinemia. AB - The authors present a case of citrullinemia with a genotype of argininosuccinate synthetase (ASS1), c.380 G>A (p.R127Q)/c.380 G>A (p.R127Q), in two alleles. A 3 day-old female infant presented with status epilepticus and coma. Laboratory data showed hyperammonemia and marked lactic acidosis in the blood and cerebrospinal fluid; electroencephalography showed severely suppressed cerebral activity and focal paroxysmal volleys of slow and sharp waves (< 1Hz) over the left hemisphere. Real-time transcranial Doppler ultrasonography showed a brain edema and high peaked systolic and low diastolic flows in basal, anterior, and middle cerebral arteries; however, immediately after a blood exchange transfusion, systolic flows were lower and diastolic flows were higher. The resistance indices were significantly different (means: 0.58 vs. 0.37; p=0.01). The patient was placed on diet therapy. After six blood exchange transfusions and peritoneal dialysis, her neurologic examination results and serum ammonia and lactate values were normal. The authors found that electroencephalography and transcranial Doppler ultrasonography were useful for the diagnosis and follow-up treatment of neonatal citrullinemia. PMID- 25443348 TI - Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma. AB - Hepatitis C virus (HCV) is one of the major aetiologic agents that causes hepatocellular carcinoma (HCC) by generating an inflammatory, fibrogenic, and carcinogenic tissue microenvironment in the liver. HCV-induced HCC is a rational target for cancer preventive intervention because of the clear-cut high-risk condition, cirrhosis, associated with high cancer incidence (1% to 7% per year). Studies have elucidated direct and indirect carcinogenic effects of HCV, which have in turn led to the identification of candidate HCC chemoprevention targets. Selective molecular targeted agents may enable personalized strategies for HCC chemoprevention. In addition, multiple experimental and epidemiological studies suggest the potential value of generic drugs or dietary supplements targeting inflammation, oxidant stress, or metabolic derangements as possible HCC chemopreventive agents. While the successful use of highly effective direct acting antiviral agents will make important inroads into reducing long-term HCC risk, there will remain an important role for HCC chemoprevention even after viral cure, given the persistence of HCC risk in persons with advanced HCV fibrosis, as shown in recent studies. The successful development of cancer preventive therapies will be more challenging compared to cancer therapeutics because of the requirement for larger and longer clinical trials and the need for a safer toxicity profile given its use as a preventive agent. Molecular biomarkers to selectively identify high-risk population could help mitigate these challenges. Genome-wide, unbiased molecular characterization, high-throughput drug/gene screening, experimental model-based functional analysis, and systems level in silico modelling are expected to complement each other to facilitate discovery of new HCC chemoprevention targets and therapies. PMID- 25443354 TI - Comprehensive dental treatment for "meth mouth": a case report and literature review. AB - Methamphetamine-induced caries (MIC) is the rampant caries often found in methamphetamine (MA) users and is often called "meth mouth". It leads to devastating effects on dentition and is the major reason that brings patients to professional help. Dental management of these patients is challenging and the most important factor is cessation of MA use. Dentists must be aware of the signs and medical risks associated with this serious condition. If duly attended to, the dental team can help patients on many levels. Treatment plans can be simplified, so that each visit does not last too long. Finally, more attention should be paid topostoperative care. This case report presents a 40-year-old man with rampant caries caused by MA abuse with poor oral hygiene and smoking habits. He was advised to stop the drug abuse and the affected teeth underwent endodontic, restorative and prosthetic rehabilitation. One year later, the patient had some secondary caries but had stopped all drug abuse. PMID- 25443355 TI - Water-clear cell parathyroid adenoma in a patient with acute pancreatitis. PMID- 25443353 TI - Hashimoto's encephalopathy: report of three cases. AB - Both severe thyrotoxicosis and hypothyroidism may affect brain function and cause a change in consciousness, as seen with a thyroid storm or myxedema coma. However, encephalopathy may also develop in patients with autoimmune thyroid diseases independent of actual thyroid function level, and this is known as Hashimoto's encephalopathy. Although most patients are found to have Hashimoto's thyroiditis, less frequently they have Graves' disease. Clinical manifestations include epilepsy, disturbance of consciousness, cognitive impairment, memory loss, myoclonus, hallucinations, stroke-like episodes, tremor, involuntary movements, language impairment, and gait impairment. Hashimoto's encephalopathy is a relatively rare disease. As a good response can be obtained with corticosteroid therapy, early diagnosis and treatment is very beneficial for patients. Here we report three patients with Hashimoto's encephalopathy with typical manifestations of hallucinations that were associated with hypothyroidism, hyperthyroidism, and euthyroid status, respectively. They all showed a dramatic response to methylprednisolone pulse therapy. PMID- 25443356 TI - Early-onset severe donor-related Candida keratitis after descemet stripping automated endothelial keratoplasty. PMID- 25443357 TI - Type 1 leukocyte adhesion deficiency complicated by the presence of idiopathic liver cirrhosis. PMID- 25443358 TI - Anesthesia for the first successful HeartMate II left ventricular assist device implantation in Taiwan. PMID- 25443359 TI - Delayed chest wall closure for oversized donor lungs after bilateral lung transplantation. PMID- 25443360 TI - Mid-term clinical and radiographic outcomes of porous tantalum modular acetabular components for hip dysplasia. AB - It is still challenging to perform successful cementless cup fixation during total hip arthroplasty for hip dysplasia. In this multicenter study we evaluated the clinical results of porous tantalum modular acetabular cups (TM cups) in 45 dysplastic hips with a mean follow-up period of 9.8 years. The mean Japanese Orthopaedic Association hip score improved from 48.2 preoperatively to 92.1 at the most recent follow-up. All of the cups were radiographically stable with no evidence of progressive radiolucencies or osteolysis regardless of bone grafting. Sixteen hips with bone grafts showed the integration of grafted bone without any radiolucencies. There were no revisions of TM cups. The use of TM cups for dysplastic hips provided satisfactory 10-year clinical and radiographic results. PMID- 25443361 TI - Revision of unicompartmental knee arthroplasty versus primary total knee arthroplasty. AB - The risk of revision following unicompartmental arthroplasty (UKA) is greater compared with primary total knee arthroplasty (TKA). Some surgeons report that UKA revision is straightforward with outcomes comparable to TKA. We reviewed all Oxford medial UKAs and TKAs performed at our institution over a five year period. Patient reported outcomes were compared between revised UKAs, successful UKAs and primary TKAs. Out of 546 Oxford medial UKAs, twenty-nine (5.3%) were revised at a mean of 25months. The commonest indications for revision were aseptic loosening and progression of osteoarthritis. Ten patients (34%) required augments, stemmed implants or bone grafts. Outcomes following revision were poorer than those following successful UKA and primary TKA, and were a consequence of poor pre operative function rather than the complexity of surgery. PMID- 25443362 TI - Hip dislocation increases roughness of oxidized zirconium femoral heads in total hip arthroplasty: an analysis of 59 retrievals. AB - The aims of this study were to assess damage on the surface of retrieved oxidized zirconium (OxZr) metal femoral heads, to measure surface roughness of scratches, and to evaluate the extent of surface effacement using scanning electron microscopy (SEM). Ceramic zirconia-toughened alumina heads were analyzed for comparison. OxZr femoral heads explanted for recurrent dislocation had the most severe damage (P<0.001). The median surface roughness of damaged OxZr femoral heads was 1.49MUm, compared to 0.084MUm for damaged ceramic heads and 0.052MUm for undamaged OxZr (P<0.001). This may be of clinical concern because increased surface roughness has the potential to increase the wear of polyethylene liners articulating against these OxZr heads in THA. PMID- 25443363 TI - Can Dual Mobility Cups prevent Dislocation in All Situations After Revision Total Hip Arthroplasty? AB - The outcome of a single design of dual mobility cup was prospectively evaluated in a continuous series of 994 revision THAs with respect to dislocation and intra prosthetic dislocation (IPD). At a 7.3-year mean follow-up, the dislocation rate was 1.5% and the IPD rate was 0.2%. The 2 IPD occurred in acetabular-only revisions and were related to a poor head-to-neck ratio with early impingement and wear at the polyethylene mobile component chamfer. Dual mobility cups demonstrated a low dislocation rate in revision THA but did not compensate for potential perioperative technical errors. In addition, IPD did not appear to be a concern with respect to the benefit in term of instability prevention though caution is advised in acetabular-only revision associated with a poor head-to neck ratio. LEVEL OF EVIDENCE: Therapeutic study-Level IV. PMID- 25443364 TI - Oplopanax elatus (Nakai) Nakai: chemistry, traditional use and pharmacology. AB - Oplopanax elatus (Nakai) Nakai, a member of the ancient angiosperm plant family Araliaceae, is used for the treatment of different disorders in the medicine systems of China, Russia, and Korea, and was designated in Russia as a classical adaptogen. Despite extensive studies of classical adaptogens, there are comparatively few reports concerning the chemical composition and pharmacological effects of O. elatus in English. The plant is a potential source of saponins, flavonoids, anthraquinones, terpenes, and other active compounds. Experimental studies and clinical applications have indicated that O. elatus possesses a number of pharmacological activities, including adaptogenic, anti-convulsant, anti-diabetic, anti-fungal, anti-inflammatory, anti-oxidant, blood pressure modulating, and reproductive function effects. In this review, the chemistry, safety, and therapeutic potential of O. elatus are summarized and highlighted to encourage the further development of this plant. PMID- 25443365 TI - Tetramethylpyrazine protects lymphocytes from radiation-induced apoptosis through nuclear factor-kappaB. AB - AIM: Radiation induces an important apoptosis response in irradiated organs. The objective of this study was to investigate the radioprotective effect of tetramethylpyrazine (TMP) on irradiated lymphocytes and discover the possible mechanism of protection. METHOD: Lymphocytes were pretreated for 12 h with TMP (25-200 MUmol.L(-1)) and then exposed to 4 Gy radiation. Cell apoptosis and the signaling pathway were analyzed. RESULTS: Irradiation increased cell death, DNA fragmentation, activated caspase activation and cytochrome c translocation, downregulated B-cell lymphoma 2 (Bcl-2) and up-regulated Bcl-2-associated X protein (Bax). Pretreated with TMP significantly reversed this tendency. Several anti-apoptotic characteristics of TMP, including the ability to increase cell viability, inhibit caspase-9 activation, and upregulate Bcl-2 and down-regulate Bax in 4Gy-irradiated lymphocytes were determined. Signal pathway analysis showed TMP could translate nuclear factor-kappaB (NF-kappaB) from cytosol into the nucleus. CONCLUSION: The results suggest that TMP had a radioprotective effect through the NF-kappaB pathway to inhibit apoptosis, and it may be an effective candidate for treating radiation diseases associated with cell apoptosis. PMID- 25443366 TI - Gastroprotective effect of the iridoid fraction from Barleria prionitis leaves on experimentally-induced gastric ulceration. AB - AIM: To study the gastroprotective effect and in vivo antioxidant potential of a standardized iridoid fraction from B. prionitis leaves (BPE) against different gastric ulcer models in rats. METHOD: The standardized iridoid fraction from BPE at 50, 100, and 200 mg/kg body weight was administered orally, twice daily for 5 days for prevention from aspirin, ethanol, cold-restraint stress (CRS), and pylorus ligation (PL)-induced ulcers. Estimation of the antioxidant enzyme activity was carried out in a CRS-induced ulcer model, and various gastric secretion parameters including volume of gastric juice, acid output, and pH value were estimated in the PL-induced ulcer model. RESULTS: BPE showed a dose dependent ulcer protective effect in PL (18.67%-66.26% protection), aspirin (24.65%-63.25% protection), CRS (20.77%-59.42% protection), and EtOH (16.93% 77.04% protection)-induced ulcers. BPE treatment in PL-rats showed a decrease in acid-pepsin secretion, and enhanced mucin and mucosal glycoproteins. However, BPE reduced the ulcer index with significant decrease in LPO (P < 0.01-0.001), SOD (P < 0.01-0.001), and an increase in CAT (P < 0.01-0.001), activity in the CRS induced model. CONCLUSION: The data shows that the iridoid fraction from BPE possesses anti-ulcerogenic and antioxidant potential. PMID- 25443367 TI - Cytological and biochemical studies during the progression of alloxan-induced diabetes and possible protection of an aqueous leaf extract of Costus afer. AB - Some plants have proven efficacy in the management of diabetes mellitus, of which Costus afer is one. This study was designed to evaluate the cytological and biochemical properties, and comparative ameliorating effects, of an aqueous extract of Costus afer Ker Gawl. (Costaceae) leaf and glibenclamide (GBM), in liver, kidney, and pancreatic injury induced by alloxan. Thirty male albino rats were divided into six weight-matched groups. Group one served as the negative control (non-induced and non-treated, control), while groups 2-6 were alloxan induced diabetic groups. Group 2 served as a positive control (induced and non treated, IC), groups 3-5 were treated with different doses of the extract (375, 750, and 1,125 mg/kg body weight) and glibenclamide, respectively. Body weight, absolute and relative organ weights, food and fluid intake, levels of serum glucose and liver enzymes and kidney parameters were calculated and compared. Hepatocytes, renal tubules, and pancreatic cells of diabetic rats, in diabetic non-treated and treated rats were harvested and examined histopathologically. There was dose dependent amelioration on the injuries induced by alloxan on both hepatocytes, renal tubules, and pancreatic cells after treatment with Costus afer. The glucose level was reduced significantly in the Costus afer treated diabetic rats compared with the non-treated diabetic group. Costus afer leaves seem to be effective against diabetic cell injury induced in rat liver, kidney, and pancreas. PMID- 25443369 TI - Toxic effects of strychnine and strychnine N-oxide on zebrafish embryos. AB - AIM: The application of strychnine (S) is limited due to its toxicity; strychnine N-oxide (SNO) is a derivative of strychnine. The aim was to employ zebrafish embryos to investigate and compare the developmental toxicity induced by S and SNO. METHODS: The toxicity of S and SNO was examined through the hatching rate and survival rate. Morphological changes of the zebrafish were observed with a dissecting microscope. Apoptosis was detected through acridine orange (AO) staining and flow cytometry. Apoptotic genes were measured by RT-PCR. RESULTS: Embryo malformation was observed in the embryos exposed to S at 200 MUmol.L(-1). When SNO concentration was increased to 1 mmol.L(-1), scoliolosis, and pericardial edema could be seen in some embryos. Results from fluorescence microscopy and flow cytometry analysis showed that S at 200 MUmol.L(-1) induced apoptosis, whereas the apoptotic rate in the SNO-treated group (200 MUmol.L(-1)) was much lower than that in the S group. RT-PCR analysis showed that p53 mRNA expression and the ratio of Bax/Bcl-2 in the S group were significantly altered compared with the control group (*P < 0.05). Moreover, Bax mRNA expression in both S and SNO group were significantly different from that in the control group (**P < 0.01). CONCLUSION: These results lead to the conclusion that SNO has significantly lower toxicity than S in zebrafish embryos. PMID- 25443368 TI - Antidepressant-like effect of essential oil of Perilla frutescens in a chronic, unpredictable, mild stress-induced depression model mice. AB - Perilla frutescens (Perilla leaf), a garnishing vegetable in East Asian countries, as well as a plant-based medicine, has been used for centuries to treat various conditions, including depression. Several studies have demonstrated that the essential oil of P. frutescens (EOPF) attenuated the depressive-like behavior in mice. The present study was designed to test the anti-depressant effects of EOPF and the possible mechanisms in an chronic, unpredictable, mild stress (CUMS)-induced mouse model. With the exposure to stressor once daily for five consecutive weeks, EOPF (3, 6, and 9 mg.kg(-1)) and a positive control drug fluoxetine (20 mg.kg(-1)) were administered through gastric intubation to mice once daily for three consecutive weeks from the 3(rd) week. Open-field test, sucrose consumption test, tail suspension test (TST), and forced swimming test (FST) were used to evaluate the behavioral activity. The contents of 5 hydroxytryptamine (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in mouse hippocampus were determined by HPLC-ECD. Serum interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha levels were evaluated by enzyme-linked immunosorbent assay (ELISA). The results showed that CUMS significantly decreased the levels of 5-HT and 5-HIAA in the hippocampus, with an increase in plasma IL 6, IL-1beta, and TNF-alpha levels. CUMS also reduced open-field activity, sucrose consumption, as well as increased immobility duration in FST and TST. EOPF administration could effectively reverse the alterations in the concentrations of 5-HT and 5-HIAA; reduce the IL-6, IL-1beta, and TNF-alpha levels. Moreover, EOPF could effectively reverse alterations in immobility duration, sucrose consumption, and open-field activity. However, the effect was not dose-dependent. In conclusion, EOPF administration exhibited significant antidepressant-like effects in mice with CUMS-induced depression. The antidepressant activity of EOPF might be related to the relation between alteration of serotonergic responses and anti-inflammatory effects. PMID- 25443370 TI - Oral JS-38, a metabolite from Xenorhabdus sp., has both anti-tumor activity and the ability to elevate peripheral neutrophils. AB - AIM: JS-38 (mitothiolore), a synthetic version of a metabolite isolated from Xenorhabdus sp., was evaluated for its anti-tumor and white blood cell (WBC) elevating activities. METHOD: These anti-proliferative activities were assessed in vitro using a panel of ten cell lines. The anti-tumor activities were tested in vivo using B16 allograft mouse models and xenograft models of A549 human lung carcinoma and QGY human hepatoma in nude mice. The anti-tumor interactions of JS 38 and cyclophosphamide (CTX) or 5-fluorouracil (5-Fu) were studied in a S180 sarcoma model in ICR mice. Specific stimulatory effects were determined on peripheral neutrophils in normal and CTX- and 5-Fu-induced neutropenic mice. RESULTS: The IC50 values ranged from 0.1 to 2.0 MUmol.L(-1). JS-38 (1 MUmol.L( 1)) caused an increase in A549 tumor cell apoptosis. Multi-daily gavage of JS-38 (15, 30, and 60 mg.kg(-1).d(-1)) inhibited in vivo tumor progression without a significant effect on body weight. JS-38 additively enhanced the in vivo anti tumor effects of CTX or 5-Fu. JS-38 increased peripheral neutrophil counts and neutrophil rates in normal BALB/c mice almost as effectively as granulocyte colony-stimulating factor (G-CSF). In mice with neutropenia induced by CTX or 5 Fu, JS-38 rapidly restored neutrophil counts. CONCLUSION: These results suggest that JS-38 has anti-tumor activity, and also has the ability to increase peripheral blood neutrophils. PMID- 25443371 TI - Role of Ocimum sanctum leaf extract on dietary supplementation in the transgenic Drosophila model of Parkinson's disease. AB - AIM: To evaluate the effect of Ocimum sanctum leaf extract on the dietary supplementation in the transgenic Drosophila model of Parkinson's disease. METHOD: The effect of Ocimum sanctum leaf extract was studied on the transgenic Drosophila model of flies expressing normal human alpha synuclein (h-alphas) in the neurons. O. sanctum extract at final concentrations of 0.042 8 * 10(-4), 0.87 * 10(-4), and 1.85 * 10(-4) g.mL(-1) of diet were established and the flies were allowed to feed for 21 days. The climbing assay and lipid peroxidation were taken as parameters for the study. RESULTS: The supplementation of O. sanctum extract showed a dose-dependent significant delay in the loss of climbing ability and reduction in oxidative stress in the brain of PD model flies. CONCLUSION: The results of the present study showed that the O. sanctum extract is potent in reducing the PD symptoms in transgenic Drosophila model. PMID- 25443372 TI - A lignin glycoside and a nortriterpenoid from Kadsura coccinea. AB - AIM: To study the chemical constituents of the roots and stem bark of Kadsura coccinea. METHOD: Compounds were isolated by column chromatography on silica gel and Sephadex LH-20, and finally purified by prep-HPLC. Their structures were elucidated by extensive spectroscopic methods, including 1D- and 2D-NMR, and HR ESI-MS. RESULTS: Two compounds were determined as (7'S,8'S,8R)-(8beta,8'alpha) dimethyl-4,4'-dihydroxy-5,3'-dimethoxy-5'-cyclolignan glucoside (1) and micrandiactone H (2), respectively. CONCLUSION: Compunds 1 and 2 are new and neither showed inhibitory effects on nitric oxide (NO) production in lipopolysaccharide-induced RAW264.7 macrophages. PMID- 25443373 TI - Simultaneous quantitative determination of five alkaloids in Catharanthus roseus by HPLC-ESI-MS/MS. AB - AIM: To establish a method to simultaneously determine the main five alkaloids of Catharanthus roseus for trace samples, a high-performance liquid chromatography electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) analysis method was developed. METHOD: The five Catharanthus alkaloids, vinblastine, vincristine, vinleurosine, vindoline, and catharanthine were chromatographically separated on a C18 HPLC column. The mobile phase was methanol-15 nmol.L(-1) ammonium acetate containing 0.02% formic acid (65 : 35, V/V). The quantification of these alkaloids was based on the Multiple Reaction Monitoring (MRM) mode. RESULTS: This method was validated, and the results achieved the aims of the study. The intra- and inter-day precision and accuracy of the five alkaloids were within 1.2%-11.5% (RSD%) and -10.9%-10.5% (RE%). The recovery rates of the five alkaloids of samples were from 79.9% to 91.5%. The five analytes were stable at room temperature for 2 h, at 4 degrees C for 12 h, and at -20 degrees C for two weeks. The developed method was applied successfully to determine the content of the five alkaloids in three plant parts of three batches of C. roseus with a minute amount collected from three regions of China. CONCLUSION: The HPLC-ESI MS/MS method can be used for the simultaneous determination of five important alkaloids in trace C. roseus samples. PMID- 25443374 TI - A monoclonal antibody-based competitive ELISA for the determination of ruscogenin in Chinese traditional medicines and biological samples. AB - A competitive enzyme-linked immunosorbent assay (ELISA) was developed to determine ruscogenin (RUS) by using the monoclonal antibody (McAb). The monoclonal antibody against RUS, secreted from the established hybridoma cell lines, was identified as being of the IgG1 isotype. The McAb exhibited high specificity to RUS, showing a very slight cross reactivity with diosgenin (15.7%), and no cross-reactivity to sarsasapogenin, diammonium glycyrrhizinate, oleanolic acid and notoginsenoside R1. The established ELISA, at an IC50 value of 157.55 ng.mL(-1) and a detection limit (IC20) of 20.57 ng.mL(-1), was compared with HPLC analyses, and a good correlation between ELISA and HPLC-ELSD analyses of RUS in the extract of Radix Ophiopogonis was obtained. The experimental data indicated that the ELISA method exhibits more advantages over HPLC-ELSD, such as low detection limit, high specificity, low background, and no requirement for sample pre-treatment, and is more suitable for the determination of natural components in Chinese traditional medicines and in biological samples for pharmacokinetic studies. PMID- 25443375 TI - How do general dentists and orthodontists determine where to refer patients requiring oral and maxillofacial surgical procedures? AB - PURPOSE: This study investigated the influence of specific criteria on referral selection among general dentists and orthodontists in deciding referrals to oral and maxillofacial surgeons. MATERIALS AND METHODS: A cross-sectional study was designed to examine the importance of criteria used by 2 groups of practitioners, general dentists and orthodontists, for deciding on referrals to oral and maxillofacial surgeons. Data were collected by 2 multiple-choice surveys. The surveys were e-mailed to general dentists and orthodontists practicing in the state of Illinois and to graduates from the University of Illinois at Chicago (UIC) College of Dentistry and the UIC Department of Orthodontics. Participants were asked to rate referral criteria from most important to least important. Analysis of variance was used to examine the data for any differences in the importance of the criteria for each question and linear regression analysis was used to determine whether any 1 criterion was statistically meaningful within each group of practitioners. RESULTS: In total, 235 general dental practitioners and 357 orthodontists completed the survey, with a 100% completion rate. The most important criterion for referral to oral and maxillofacial surgeons in the general dentist group was the personal and professional relationship of the referring doctor to the specialist. In the orthodontist group, no single criterion was statistically meaningful. CONCLUSION: General dentists tend to develop long-term relationships with their patients, and when deciding the appropriate referrals it appears that personal and professional relationships that promote trust and open communication are key elements. General dentists favor these relationships when making referral decisions across a wide spectrum of procedures. Orthodontists do not place a substantial value on a specific criterion for referral and therefore may not develop the same relationships between patient and doctor and between doctors as general dentists. PMID- 25443376 TI - In vitro comparison of the sagittal split osteotomy with and without inferior border osteotomy. AB - PURPOSE: By adding an osteotomy of the inferior border of the mandibular body to the classic sagittal split osteotomy, the authors expected to prevent unfavorable splits and damage to the inferior alveolar nerve. MATERIALS AND METHODS: Thirty five human mandibles were used to perform 70 sagittal split osteotomies as an in vitro study. Conducted as a split-mouth model, each mandible was split at the midline. One side of the mandible was split using the traditional Obwegeser-Dal Pont technique, and the other side was split in the same manner with an additional osteotomy of the inferior mandible border. The torque used to split the mandible was measured, and the fracture line of the mandible was recorded. RESULTS: The average torque associated with the original technique was 1.38 Nm (standard deviation, 0.60 Nm), with a fracture line along the mandibular canal. The average torque required to split the hemimandible with the modified technique was 1.02 Nm (standard deviation, 0.50 Nm), a significant (P < .001) difference, with a fracture line parallel to the posterior ramus of the mandible. The fracture pattern depended significantly on the technique used (P < .001), but not on the applied torque force. CONCLUSION: By adding an osteotomy of the inferior mandibular border to the sagittal split osteotomy, less torque was needed to split the mandible. The fracture line was more predictable, even when all the surgical manipulations were performed at a safe distance from the inferior alveolar nerve. PMID- 25443377 TI - Improved apnea-hypopnea index and lowest oxygen saturation after maxillomandibular advancement with or without counterclockwise rotation in patients with obstructive sleep apnea: a meta-analysis. AB - PURPOSE: This study investigated whether patients with obstructive sleep apnea (OSA) who undergo maxillomandibular advancement (MMA) with counterclockwise (CCW) rotation compared with those who undergo MMA without CCW rotation have better outcomes. MATERIALS AND METHODS: This was a systematic review with meta-analysis. The Medline and Cochrane databases were searched for randomized controlled trials using Medical Subject Headings. The predictor variable was operative technique, namely MMA with or without CCW rotation of the maxillofacial complex. The key outcome variables were changes in pre- and postsurgical values of pharyngeal volume measured on computed tomogram or cone-beam computed tomogram and changes in Apnea-Hypopnea Index (AHI) and lowest oxygen saturation (LSAT) values after surgery. Data were subjected to a meta-analysis based on odds ratios (OR) with 95% confidence intervals (CIs) and P values lower than .05 by chi(2) test were considered significant. RESULTS: Twenty-one randomized controlled trials were identified and 4 were assessed for the variables of interest. Postoperative AHI and LSAT measurements showed vast improvement. The sample was not large enough to make a correlation between pharyngeal volume changes and surgical method used. Postoperative parameters included an AHI lower than 5 (OR = 14.9; 95% CI, 2.7 83.5; P = .002), an AHI lower than 20 (OR = 114.8; 95% CI, 23.5-561.1; P <.00001), pooled results of a 50% decrease in the AHI (OR = 6.1; 95% CI, 2.2 17.0; P = .0006), and an increase greater than 90% in LSAT measurements during sleep (OR = 6.0; 95% CI, 1.8-19.9; P = .003). The funnel plot showed no evidence of publication bias. CONCLUSION: CCW-MMA or MMA in patients with OSA results in a statistically meaningful decrease in postoperative AHI and a statistically meaningful increase in postoperative LSAT. PMID- 25443378 TI - Multimodal protocol reduces postoperative nausea and vomiting in patients undergoing Le Fort I osteotomy. AB - PURPOSE: To assess the impact of a multimodal antiemetic protocol on postoperative nausea and vomiting (PONV) after Le Fort I osteotomy. MATERIALS AND METHODS: Consecutive patients undergoing Le Fort I osteotomy with or without additional procedures at a single academic institution were recruited as the intervention cohort for an institutional review board-approved prospective clinical trial with a retrospective comparison group. The intervention cohort was managed with a multimodal antiemetic protocol, including total intravenous anesthesia; prophylactic ondansetron, steroids, scopolamine, and droperidol; gastric decompression at surgery end; opioid-sparing analgesia; avoidance of morphine and codeine; prokinetic erythromycin; and fluids at a minimum of 25 mL/kg. The comparison group consisted of consecutive patients from a larger study who underwent similar surgical procedures before protocol implementation. Data, including occurrence of PONV, were extracted from medical records. Data were analyzed in bivariate fashion with the Fisher exact and Wilcoxon rank-sum tests. Logistic regression was used to compare the likelihood of nausea and vomiting in the 2 cohorts after controlling for demographic and surgical characteristics. A P value less than .05 was considered significant. RESULTS: The intervention (n = 93) and comparison (n = 137) groups were similar in gender (58% and 65% female patients; P = .29), race (72% and 71% Caucasian; P = .85), age (median, 19 and 20 years old; P = .75), proportion of patients with known risk factors for PONV (P = .34), percentage undergoing bimaxillary surgery (60% for the 2 groups), and percentage for whom surgery time was longer than 180 minutes (63% and 59%; P = .51). Prevalence of postoperative nausea was significantly lower in the intervention group than in the comparison group (24% vs 70%; P < .0001). Prevalence of postoperative vomiting was likewise significantly lower in the intervention group (11% vs 28%; P = .0013). The likelihood that patients in the comparison group would develop nausea was 8.9 and that for vomiting was 3.7 times higher than in the intervention group. CONCLUSION: This multimodal protocol was associated with substantially decreased prevalence of PONV in patients undergoing Le Fort I osteotomy. PMID- 25443380 TI - Clinical application of the dorsalis pedis free flap for reconstruction of oral cancer defects. AB - PURPOSE: The purposes of this study were to evaluate the clinical application and efficacy of the dorsalis pedis fasciocutaneous flap in the reconstruction of oral cavity defects and to assess the associated donor-site morbidity. PATIENTS AND METHODS: From September 2009 to December 2012, 7 patients with associated oral cavity defects resulting from tumor resection underwent reconstruction with a dorsalis pedis fasciocutaneous flap. Surgical anatomy and harvesting procedure of the dorsalis pedis flap are described. Special consideration was given to the associated donor-site morbidity. RESULTS: All flaps survived without any complications. All 7 flaps were based on the dorsalis pedis artery and the greater saphenous vein for perfusion and drainage respectively. In all 7 cases, the donor site was closed with a full-thickness skin graft, with no associated healing complications or functional deficit of the foot. The resulting scar was well hidden in the lower extremity. CONCLUSIONS: The dorsalis pedis fasciocutaneous flap is a thin and pliable flap sharing many similarities with the radial forearm flap, thus making it ideal for intraoral reconstruction. Proper intraoperative and postoperative care of the donor site can result in minimal morbidity, as shown in this study. This flap may provide an ideal alternative to the radial forearm free flap, with the added advantages of a well hidden scar and a high level of patient satisfaction. PMID- 25443379 TI - Microvascular reconstruction in elderly oral cancer patients: does diabetes status have a predictive role in free flap complications? AB - PURPOSE: Flap complications still present challenges in the field of microsurgical reconstruction. The aim of this study was to explore the role of diabetes mellitus in free flap prognosis in elderly patients (>=60 years) after oral tumor resection. PATIENTS AND METHODS: The data of aged oral cancer patients who had undergone reconstructions with free flaps in our institution were gathered in this retrospective cohort study. The samples were classified into diabetic and nondiabetic groups. The predictive roles of diabetes status and other factors in free flap prognosis were analyzed. The primary outcome variable was the presence of flap complications, which was subdivided into major (requiring re-exploration or local surgery) and minor (dressing or drug treatment) groups. Major complications were defined as the second outcome variable. Univariate and multivariable analyses were used for data statistics. RESULTS: A total of 309 patients (176 men [57%] and 133 women [43%]) aged 60 years or older were included in this study. There were 105 diabetic patients (34%) and 204 nondiabetic patients (66%). A total of 75 flap complications occurred during the perioperative period, with an overall incidence of 24.3% (44 diabetic patients [41.9%] and 31 nondiabetic patients [15.2%], P <= .001). The odds of susceptibility for flap complication development in elderly diabetic patients was 3.413 times that of nondiabetic patients (odds ratio, 3.413; P <= .001). Of 75 flap complications, 43 (13.9%) were deemed major complications (24 diabetic patients [22.9%] and 19 nondiabetic patients [9.3%], P <= .001). This statistical association was further confirmed by multivariate analysis (odds ratio, 2.885; P = .002). CONCLUSIONS: Diabetes mellitus increases the risk of the development of free flap complications in elderly patients when dealing with oral reconstruction after tumor removal. PMID- 25443381 TI - Complications of sialendoscopy: personal experience, literature analysis, and suggestions. AB - PURPOSE: This article describes our experience combined with analysis of the emerging literature, presenting suggestions of how to avoid the complications that may arise during or after endoscopic or endoscopy-assisted surgery of the salivary glands. MATERIALS AND METHODS: In a retrospective study, the surgical data of 498 consecutive patients who underwent surgery for calculus removal from the parotid, submandibular, and sublingual glands from 2010 to 2012 were collected and analyzed. The analysis was concentrated on specific complications of endoscopic or endoscopy-assisted operations. RESULTS: The patients were operated on by various sialendoscopy-involved techniques that included intraductal endoscopy and an endoscopy-assisted extraductal approach. The total percentage of complications associated with endoscopy was 3.23% (n = 17). In 1 case (0.2%) (submandibular gland surgery), severe bleeding occurred that required immediate gland resection. CONCLUSIONS: At present, sialendoscopic and endoscopy assisted techniques produce a minimal number of postsurgical endoscopy-related complications, but they are not complication-free operations. Strictures, ranulas, and lingual nerve paresthesias are the most frequent of these complications. Further reduction of the number of complications is possible with careful preprocedural imaging analysis and correct endoscopic techniques. PMID- 25443382 TI - Impact of intraoperative fluid administration on length of postoperative hospital stay following orthognathic surgery. AB - PURPOSE: The purpose of this study was to evaluate whether the volume of intraoperative fluids administered to patients during routine orthognathic surgery is associated with increased length of hospital stay for postoperative convalescence. MATERIALS AND METHODS: A retrospective cohort study design was used to identify 168 patients undergoing routine orthognathic surgery at Mayo Clinic from 2010 through 2014. The primary predictor variable was total volume of intravenous fluids administered during orthognathic surgery. The primary outcome variable was the length of hospital stay in hours as measured from the completion of the procedure to patient dismissal from the hospital. Additional covariates were collected including patient demographic data, preoperative American Society of Anesthesiologists (ASA) score, type of intravenous fluid administered, complexity of surgical procedure, and duration of anesthesia. RESULTS: On univariate analysis, total fluid was significantly associated with increased length of stay (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.42 to 2.33; P < .001). After adjustment for surgical complexity and duration of anesthesia on multivariable regression analysis, the association of fluid level with length of hospital stay was no longer statistically significant (OR, 0.86; 95% CI, 0.61 to 1.22; P = .39). Duration of anesthesia remained the only covariate that was significantly associated with increased length of hospital stay in the multivariable regression model (OR, 2.21; 95% CI, 1.56 to 3.13; P < .001). CONCLUSIONS: Among surgical complexity, duration of anesthesia, and total volume of intraoperative intravenous fluids administered for routine orthognathic surgery, the duration of anesthesia has the strongest predictive value for patients requiring prolonged hospital stay for postoperative convalescence. PMID- 25443383 TI - Correlation between the Friedman Staging System and the upper airway volume in patients with obstructive sleep apnea. AB - PURPOSE: This study was designed to evaluate the correlation between computed tomography findings and data from the physical examination and the Friedman Staging System (FSS) in patients with obstructive sleep apnea (OSA). PATIENTS AND METHODS: We performed a retrospective evaluation by reviewing the medical records of 33 patients (19 male and 14 female patients) with a mean body mass index of 30.38 kg/m(2) and mean age of 49.35 years. Among these patients, 14 presented with severe OSA, 7 had moderate OSA, 7 had mild OSA, and 5 were healthy. RESULTS: The patients were divided into 2 groups according to the FSS: Group A comprised patients with FSS stage I or II, and group B comprised patients with FSS stage III. By use of the Fisher exact test, a positive relationship between the FSS stage and apnea-hypopnea index (P = .011) and between the FSS stage and body mass index (P = .012) was found. There was no correlation between age (P = .55) and gender (P = .53) with the FSS stage. The analysis of variance test comparing the upper airway volume between the 2 groups showed P = .018. CONCLUSIONS: In this sample the FSS and upper airway volume showed an inverse correlation and were useful in analyzing the mechanisms of airway collapse in patients with OSA. PMID- 25443384 TI - Effect of tranexamic acid irrigation on perioperative blood loss during orthognathic surgery: a double-blind, randomized controlled clinical trial. AB - PURPOSE: Perioperative hemorrhage is an important concern during orthognathic surgery. The purpose of this study was to assess the effect of tranexamic acid (TXA) irrigation on perioperative hemorrhage during orthognathic surgery. MATERIALS AND METHODS: In this double-blind, randomized controlled clinical trial, 56 participants who underwent orthognathic surgery were divided into 2 groups. The patients in the first group received TXA irrigation with normal saline (1 mg/mL), and the patients in the second group had normal saline for irrigation during orthognathic surgery. Age, gender, operation duration, the amount of irrigation solution used, and preoperative hemoglobin, hematocrit, and weight were the variables that were studied. The use of TXA solution for irrigation was the predictive factor of the study. RESULTS: Each group consisted of 28 patients. Group 1 consisted of 15 male patients (53.6%) and 13 female patients (46.4%) and group 2 consisted of 14 male patients (50%) and 14 female patients (50%). There was no difference in the distributions of the variables between the 2 groups, except for the duration of the operation. The mean duration of the operation was 3.94 +/- 0.61 hours in group 1 and 4.17 +/- 0.98 hours in group 2, and the difference in this respect between the 2 groups was statistically significant (P < .05). The mean intraoperative blood loss was 817.85 +/- 261.83 mL in group 1 and 575.00 +/- 286.90 mL in group 2 (P < .05). The mean volume of irrigation was 1,057.14 +/- 407.04 mL in group 1 and 843.57 +/ 275.48 mL in group 2 (P > .05). CONCLUSIONS: TXA is effective in reducing intraoperative blood loss in patients for whom substantial blood loss is anticipated. PMID- 25443385 TI - Are virtual planning and guided surgery for head and neck reconstruction economically viable? AB - PURPOSE: Virtual planning and guided surgery with or without prebent or milled plates are becoming more and more common for mandibular reconstruction with fibular free flaps (FFFs). Although this excellent surgical option is being used more widely, the question of the additional cost of planning and cutting-guide production has to be discussed. In capped payment systems such additional costs have to be offset by other savings if there are no special provisions for extra funding. Our study was designed to determine whether using virtual planning and guided surgery resulted in time saved during surgery and whether this time gain resulted in self-funding of such planning through the time saved. MATERIALS AND METHODS: All consecutive cases of FFF surgery were evaluated during a 2-year period. Institutional data were used to determine the price of 1 minute of operative time. The time for fibula molding, plate adaptation, and insetting was recorded. RESULTS: During the defined period, we performed 20 mandibular reconstructions using FFFs, 9 with virtual planning and guided surgery and 11 freehand cases. One minute of operative time was calculated to cost US $47.50. Multiplying this number by the time saved, we found that the additional cost of virtual planning was reduced from US $5,098 to US $1,231.50 with a prebent plate and from US $6,980 to US $3,113.50 for a milled plate. CONCLUSIONS: Even in capped health care systems, virtual planning and guided surgery including prebent or milled plates are financially viable. PMID- 25443386 TI - Early major medical complications after surgical management of obstructive sleep apnea: a retrospective cohort analysis and case series. AB - PURPOSE: The purpose of this study was to determine the frequency and relative risk (RR) of early postoperative major medical complications after surgery for the management of obstructive sleep apnea. PATIENTS AND METHODS: This was a retrospective cohort analysis of patients who had undergone surgery for the treatment of polysomnogram-confirmed obstructive sleep apnea at 2 hospitals in Pittsburgh, PA, between 1992 and 2013. Early postoperative major medical complications were defined as either a life-threatening complication requiring intensive care unit intervention or death within the immediate hospital course. Standard demographic data, apnea-hypopnea index, Epworth Sleepiness Score, minimum nocturnal oxygen saturation, and body mass index were collected. The 2 tailed independent t test, Fisher exact test, and RR with 95% confidence interval were used. RESULTS: A total of 267 consecutive patients who underwent surgery for obstructive sleep apnea and met the inclusion criteria were included in this study. A total of 6 patients (6 of 267, 2.2%) had early major medical postoperative complications. When stratified by surgical group (intrapharyngeal vs extrapharyngeal), there were 162 intrapharyngeal patients with 2 complications (1.2%) and 105 extrapharyngeal patients with 4 complications (3.8%). We found no statistically significant difference in frequency (2 of 162 intrapharyngeal patients [1.2%] vs 4 of 105 extrapharyngeal patients [3.8%], P = .17) or RR (3.1; 95% confidence interval, 0.58 to 16.55; P = .1885) between the groups. There were statistically significant differences for mean age, apnea-hypopnea index, Epworth Sleepiness Score, minimum nocturnal oxygen saturation, and body mass index between the surgical groups. CONCLUSIONS: The overall frequency of early major medical postoperative complications in upper airway surgery for obstructive sleep apnea is low, with no statistically significant difference in frequency and RR between intrapharyngeal and extrapharyngeal surgery. There may, however, be a clinically significance difference in RR possibly because of associated differences in risk factors between the groups. PMID- 25443388 TI - Just telling and selling: current limitations in the use of digital media in public health: a scoping review. AB - OBJECTIVE: To undertake a scoping review and to map research in the area of digital media use in public health. STUDY DESIGN: Scoping review. METHODS: PubMed, PsycINFO, Google and major textbooks of public health communication and health psychology were searched for primary studies or systematic reviews examining the use of digital media in a health context. Searches focussed on studies published between the start of 2000 and the end of June 2013. Abstracts of reviews of public health interventions were examined with respect to target groups, health topic, intervention characteristics, media used, study design, issues of quality and ethics, and outcomes. To map this area of work fully, this information was supplemented by adding information from primary studies. Areas were identified where systematic review evidence was scarce or non-existent by comparing the final map with information from the reviews analysed. RESULTS: 221 systematic reviews related to digital media use in a public health context were included. Most reviews included studies with an experimental design and general 'at risk' target populations. Specific settings were not specified in the majority of reviews. A large variety of health topics were covered. About a quarter of reviews did not specify a health topic but were concerned with broader issues of health promotion, disease prevention, or health education. Over half of the reviews focussed on eHealth and telemedicine, and another third were concerned with mass media - social marketing. Reviews most frequently reported behaviour-related outcomes or conducted some form of content analysis or analysis of the use of particular media. Research gaps were identified relating to community-based research, participation and empowerment, active media use (especially with respect to visual media und use of specific visual methodologies), and the use of salutogenic or assets-based approaches. CONCLUSION: The available research relating to digital media use in public health is dominated by studies relating to eHealth, telehealth or social marketing; emphasising the passive reception of messages and a focus on individual behaviour change approaches. Issues of quality and ethics need to be taken into account more consistently. Further research is needed with respect to more participatory methods, particularly those which would seek to use digital media as a means to harness individual and community assets. PMID- 25443387 TI - Is obesity associated with global warming? AB - OBJECTIVES: Obesity is a national epidemic that imposes direct medical and indirect economic costs on society. Recent scholarly inquiries contend that obesity also contributes to global warming. The paper investigates the relationship between greenhouse gas emissions and obesity. STUDY DESIGN: Cross sectional state-level data for the year 2010. METHODS: Multiple regression analysis using least squares with bootstrapped standard errors and quantile regression. RESULTS: States with higher rates of obesity are associated with higher CO2 and CH4 emissions (p < 0.05) and marginally associated with higher N2O emissions (p < 0.10), net of other factors. Reverting to the obesity rates of the year 2000 across the entire United States could decrease greenhouse gas emissions by about two percent, representing more than 136 million metric tons of CO2 equivalent. CONCLUSIONS: Future studies should establish clear causality between obesity and emissions by using longitudinal data while controlling for other relevant factors. They should also consider identifying means to net out the potential effects of carbon sinks, conversion of CH4 to energy, cross-state diversion, disposal, and transfer of municipal solid waste, and potentially lower energy consumption from increased sedentariness. PMID- 25443389 TI - Is violence a disease? Situating violence prevention in public health policy and practice. AB - The paper provides a review of some of the thoughts, ideas, and opinions that pervade the public health literature concerning how to classify or conceptualise violence. It is argued that violence transcends classic distinctions between communicable and non-communicable diseases, distinguishes itself from the discipline of injury control, and is influenced by wider, social determinants. Through a discussion of these varied perspectives it is concluded that a fourth revolution in public health is needed - a 'change in scope' revolution - that recognizes the influence of social justice, economics, and globalization in the aetiology of premature death and ill health, into which violence fits. However, rather than be shackled by debates of definition or classification, it is important that public health acknowledges the role it can play in preventing violence through policy and practice, and takes unified action. PMID- 25443391 TI - Parents' experiences of healthcare provider actions when their child dies: an integrative review of the literature. AB - PURPOSE: To review, critique and synthesise current research studies that examine parental perceptions of healthcare provider actions during and after the death of a child. CONCLUSIONS: Five main themes were synthesised from the literature: staff attitudes and affect; follow-up care and ongoing contact; communication; attending to the parents; and continuity of care. PRACTICE IMPLICATIONS: This review helps to identify important aspects of paediatric end-of-life care as recognised by parents, with the intention of placing the family at the centre of any future end-of-life care education or policy/protocol development. PMID- 25443394 TI - Antemortem and postmortem nonapposite data--a multidisciplinary identification strategy. AB - Identification of human remains is often achieved by comparing documented reference data with the same type of evidence obtained from the remains. We present a case of a decomposed unidentified body, whose identity was presumed but because of the low validity range of the available data, the identification process could not be completed. Antemortem radiographs of the teeth found in the house of the reputed victim could not be compared to the edentulous cadaver and the kinship between the victim and the only living relative that could provide DNA for comparison was too tenuous. Isolated teeth found at the scene, were neither a source of DNA reference information nor questioned data to be compared to the antemortem radiographs. The strategy implemented by the investigators to reallocate the status of the isolated teeth from the questioned source to the reference source of DNA to be compared with the cadaver is presented. PMID- 25443390 TI - Diversity, expression and mRNA targeting abilities of Argonaute-targeting miRNAs among selected vascular plants. AB - BACKGROUND: Micro (mi)RNAs are important regulators of plant development. Across plant lineages, Dicer-like 1 (DCL1) proteins process long ds-like structures to produce micro (mi) RNA duplexes in a stepwise manner. These miRNAs are incorporated into Argonaute (AGO) proteins and influence expression of RNAs that have sequence complementarity with miRNAs. Expression levels of AGOs are greatly regulated by plants in order to minimize unwarranted perturbations using miRNAs to target mRNAs coding for AGOs. AGOs may also have high promoter specificity sometimes expression of AGO can be limited to just a few cells in a plant. Viral pathogens utilize various means to counter antiviral roles of AGOs including hijacking the host encoded miRNAs to target AGOs. Two host encoded miRNAs namely miR168 and miR403 that target AGOs have been described in the model plant Arabidopsis and such a mechanism is thought to be well conserved across plants because AGO sequences are well conserved. RESULTS: We show that the interaction between AGO mRNAs and miRNAs is species-specific due to the diversity in sequences of two miRNAs that target AGOs, sequence diversity among corresponding target regions in AGO mRNAs and variable expression levels of these miRNAs among vascular plants. We used miRNA sequences from 68 plant species representing 31 plant families for this analysis. Sequences of miR168 and miR403 are not conserved among plant lineages, but surprisingly they differ drastically in their sequence diversity and expression levels even among closely related plants. Variation in miR168 expression among plants correlates well with secondary structures/length of loop sequences of their precursors. CONCLUSIONS: Our data indicates a complex AGO targeting interaction among plant lineages due to miRNA sequence diversity and sequences of miRNA targeting regions among AGO mRNAs, thus leading to the assumption that the perturbations by viruses that use host miRNAs to target antiviral AGOs can only be species-specific. We also show that rapid evolution and likely loss of expression of miR168 isoforms in tobacco is related to the insertion of MITE-like transposons between miRNA and miRNA* sequences, a possible mechanism showing how miRNAs are lost in few plant lineages even though other close relatives have abundantly expressing miRNAs. PMID- 25443395 TI - Estimating costs of sea lice control strategy in Norway. AB - This paper explores the costs of sea lice control strategies associated with salmon aquaculture at a farm level in Norway. Diseases can cause reduction in growth, low feed efficiency and market prices, increasing mortality rates, and expenditures on prevention and treatment measures. Aquaculture farms suffer the most direct and immediate economic losses from diseases. The goal of a control strategy is to minimize the total disease costs, including biological losses, and treatment costs while to maximize overall profit. Prevention and control strategies are required to eliminate or minimize the disease, while cost effective disease control strategies at the fish farm level are designed to reduce the losses, and to enhance productivity and profitability. Thus, the goal can be achieved by integrating models of fish growth, sea lice dynamics and economic factors. A production function is first constructed to incorporate the effects of sea lice on production at a farm level, followed by a detailed cost analysis of several prevention and treatment strategies associated with sea lice in Norway. The results reveal that treatments are costly and treatment costs are very sensitive to treatment types used and timing of the treatment conducted. Applying treatment at an early growth stage is more economical than at a later stage. PMID- 25443396 TI - Abattoir based survey of Salmonella in finishing pigs in the United Kingdom 2006 2007. AB - All European Union (EU) Member States (MSs) were required to conduct a baseline survey from October 2006 to September 2007 to estimate the prevalence of Salmonella infection in finisher pigs at slaughter. In the United Kingdom (UK), samples for microbiological culture were collected from the ileo-caecal lymph nodes, from carcass swabs and from caecal contents. Meat juice samples were also collected for testing in an enzyme-linked immunosorbent assay (MJE) to detect a serological response. Salmonella was isolated from 22% (CI95% 19-25%) of ileo caecal lymph nodes, 15% (CI95% 12-18%) of carcass swabs and 22% (CI95% 19-26%) of caecal contents. A quarter (25%, CI95% 22-29%) of MJE samples were positive for Salmonella antibodies (cut-off, S/P>=0.25). The most frequently identified serovars were Salmonella typhimurium (57%) and Salmonella derby (26%). The results were used to investigate some factors associated with Salmonella infection in slaughter pigs. The weight of the carcass was significant, with a lower probability of obtaining a positive meat juice result from pigs with a weight greater than 75 kg (p=0.03). The weight of the lymph node sample was significantly associated with Salmonella status, with a heavier sample of lymph nodes being more likely to be positive (OR=2.16 CI95% 1.07-4.39). 'Carcass weight' in two of the classes - 75-79 kg and 80-84 kg - (OR=0.44 CI95% 0.28-0.70; OR=0.64 CI95% 0.49-0.85) and 'fewer-than-1500-pigs' scheduled for slaughter on the day of sampling' (OR=0.41 CI95% 0.24-0.71) were also associated with a reduced risk of isolating Salmonella from lymph node. The model for carcass swabs showed a positive association with 'time-elapsed-since-the-start-of-the-line' indicating a higher risk of contamination as the day progressed (p<0.01). This model also showed positive association between isolation of Salmonella from a carcass swab and the occurrence of Salmonella in caecal contents from the same pig (OR=2.22 CI95% 1.38-3.59) and a negative association with time in singeing units (OR=0.88 CI95% 0.79-0.98). PMID- 25443397 TI - Low prevalence of asthma in sub Saharan Africa: a cross sectional community survey in a suburban Nigerian town. AB - BACKGROUND: Asthma remains an important cause of morbidity and mortality, especially in developing countries but the prevalence in Nigeria is not well described. METHODS: Using the European Community Respiratory Health Survey (ECRHS) standard screening questionnaire and asthma criteria, we recruited a representative sample of adults resident in a suburban community in Nigeria through a stratified three-stage cluster sampling technique. RESULTS: Out of a total of 3590 individuals contacted, 2310 responded and provided completed data (62.8% female). The prevalence of respiratory symptoms ranged from 0.4% (95% CI: 0.1-0.6) to 9.1% (95% CI: 7.6-10.6). Apart from nasal allergies, the most frequently reported symptoms were 'woken up by an attack of breathlessness at any time in the last 12 months' (2.4%, 95% CI: 1.8-3.0) and 'woken up by an attack of cough at any time in the last 12 months' (2.9%, 95% CI: 2.0-3.7). The combined proportion of respondents reporting previous asthma attack or currently taking asthma medication within the preceding 12 months (diagnosed asthma) was 1.5%, 95% CI: 1.0-2.0. The proportion with 'probable asthma' based on ECRHS criteria of any three symptoms of asthma (woken up by an attack of breathlessness or previous asthma attack or currently taking asthma medication within the preceding 12 months) was 3.1%, 95% CI: 2.0-4.3 for men and 3.3%, 95% CI: 2.4-4.2 for women. CONCLUSION: The prevalence of asthma in this suburban Nigerian population is low. Determinants of adult asthma distribution in low-income setting need further clarification. PMID- 25443398 TI - Cost of multi drug resistance tuberculosis in Germany. AB - OBJECTIVES: 4220 new cases of tuberculosis (TB) were reported in Germany in 2012; of those, 65 cases were multidrug-resistant TB (MDR-TB) or extensively multidrug resistant TB (XDR-TB) cases. However, there is only limited information on the economic consequences of drug resistance patterns on the treatment costs of MDR and XDR-TB patients. METHODS: On the basis of drug susceptibility of the single MDR-TB/XDR-TB strains the direct medical costs of suitable therapies were calculated according to the current guidelines of the World Health Organization (WHO) and those of the German Central Committee against Tuberculosis. These costs were combined with hospital and outpatients monitoring costs and followed the most recent German invoicing system and health statistics. Total drug and monitoring costs and were determined by Monte-Carlo simulation comprising all different options. RESULTS: According to this, the mean drug costs were ?51,113.22 (range ?19,586.14 to ?94,767.90). The weighted costs for hospitalization were ?26,000.76 per patient compared to only ?2,192.13 for primary outpatients; the total treatment costs of MDR-TB amounted to ?64,429.23. These are joined by the costs due to loss of productivity, varying between ?17,721.60 and ?44,304. From a societal perspective, the total cost per MDR TB/XDR-TB case reach an amount between ?82,150 and ?108,733 per case, respectively. CONCLUSION: Cost analyses based on strain resistance patterns allow more reliable estimates of the real costs of treating MDR-TB/XDR-TB than do methods that ignore this factor. Advantageously, they demonstrate the economic impact of drug-resistant TB in low-incidence countries. Costs of productivity loss is of new importance because of the length of MDR-XDR therapy, but its true share of total costs has still to be determined. PMID- 25443399 TI - Evidence of multiple mechanisms providing carbamate and organophosphate resistance in field An. gambiae population from Atacora in Benin. AB - BACKGROUND: Insecticide resistance in Anopheles gambiae s.l is a major concern to malaria vector control programmes. In West Africa, resistance is mainly due to target-site insensitivity arising from a single point mutation. Metabolic-based resistance mechanisms have also been implicated and are currently being investigated in west Africa. The aim of this study is to better understand the origins of carbamate and organophosphate resistance in An. gambiae population from Atacora, Benin in West Africa. METHODS: Anopheles mosquitoes were reared from larvae collected in two districts (Kouande and Tanguieta) of the Atacora department. Mosquitoes were then exposed to WHO impregnated papers. Four impregnated papers were used: carbamates (0.1% bendiocarb, 0.1% propoxur) and organophosphates (0.25% pirimiphos methyl, 1% fenitrothion). PCR assays were run to determine the members of the An. gambiae complex, as well as phenotypes for insensitive acetylcholinesterase (AChE1). Biochemical assays were also carried out to detect any increase in the activity of enzyme typically involved in insecticide metabolism (oxidase, esterase and glutathion-S-transferase). RESULTS: 769 female of An. gambiae mosquitoes from Kouande and Tanguieta were exposed to bendiocarb, propoxur, pirimiphos methyl and fenitrothion. Bioassays showed resistance with low mortality to bendiocarb (78.57% to 80.17%), propoxur (77.21% to 89.77%), and fenitrothion (89.74% to 92.02%). On the other hand, the same populations of An. gambiae from Kouande and Tanguieta showed high susceptibility to pirimiphos methyl with recorded mortality of 99.02% and 100% respectively. The low rate of ace-1R allele frequency (3.75% among survivors and 0.48% among dead) added to the high proportion of homozygous susceptible specimens which survived the WHO bioassays (8/28), suggest that the ace-1 mutation could not entirely explain Anopheles gambiae resistance to carbamate and organophosphate. Biochemical assays suggest that resistance in this population is mediated by metabolic resistance with elevated level of GST, MFO and NSE compared to a susceptible strain An. gambiae Kisumu. CONCLUSIONS: Anopheles gambiae populations resistance from Atacora is multifactorial and includes target-site mutation and metabolic mechanism. The co-implication of both resistance mechanisms in An. gambiae s.l may be a serious obstacle for the future success of malaria control operations based on LLINs and IRS. PMID- 25443400 TI - [Frequency and risk factors for diabetic macular edema in the wilaya of Constantine (Algeria)]. AB - We conducted an exhaustive cross-sectional descriptive study, in 2009, on type 1 diabetics residing in the wilaya of Constantine. Our objective was to assess the frequency and risk factors associated with diabetic macular edema (DME) by mydriatic non-stereoscopic fundus photographs of nine retinal fields. The frequency of DME was 8.7%. There was no gender influence on the frequency of macular edema. There were as many men (46.4%) as women (53.6%) with ME (P = 0.8). On bivariate analysis, the duration of diabetes (P = 0.001), age (P = 0.0001), hypertension (P = 0.00001), renal involvement (P = 0.00001) and hypercholesterolemia (P = 0.01) were risk factors for DME. PMID- 25443402 TI - [The alpha: a risk factor for failure of cataract surgery?]. PMID- 25443403 TI - Editorial. PMID- 25443404 TI - [Im memoriam, Donald Enlow]. PMID- 25443405 TI - [The search for excellence in adult orthodontics; an interview with Bjorn U. Zachrisson]. PMID- 25443406 TI - [Skeletal discrepancies: could we avoid surgical procedures?]. AB - Orthodontic-surgical protocols are nowadays considered as the state-of-the-art in cases of skeletal dentomaxillary dysmorphosis. However, for some reasons, it may happen that unquestionable indications for orthodontic-surgical procedures are not respected, patients being treated by orthodontics alone. This kind of mistake in the treatment planning lay the patient open to various potential complications such as: abnormal duration of the orthodontic treatment, dental root resorptions, questionable tooth extraction, unfavorable facial aesthetics, treatment instability... The authors discuss these points illustrated by clinical cases. Although orthognathic surgery protocols became considerably simplified these last two decades, orthodontic-surgical protocols are still relevantly considered as heavy both by patients and practitioners. As a consequence, their indication must be carefully weighed by a multidisciplinary team, keeping in mind that these protocols represent the ultimate functional and aesthetic treatment for dento skeletal dysmorphoses. PMID- 25443407 TI - [Class II subdivision in adults: use of miniscrews anchorage in mixed technique]. AB - Class II malocclusions represent 60% of our treatments, 50% of which are strictly unilateral or asymmetric. These require asymmetric therapeutic methods which conventional techniques answer most of the time poorly because of anchorage matters and three-dimensional control. Along with this, there is an increase in adult treatments demand requiring all together efficiency and aesthetics. The thoughtful combination of lingual and miniscrew techniques allows us to confidently treat Class II subdivision in adults. Therefore, we propose an approach which meets the esthetic needs of adults as well as treatment goals of Class II subdivision, correction of asymmetries and tilt of the occlusal plane. PMID- 25443408 TI - [Use of Cone Beam Computerized Tomography (CBCT) in orthodontic diagnosis and treatment planning in the presence of a palatally-impacted canine]. AB - Unerupted permanent canines can present orthodontists with special challenges. Conventional two-dimensional panoramic radiographs identify the presence or absence of unerupted canines and can only help approximate their locations, when used with various classification schemes in attempts to describe their locations and estimate treatment difficulties. This article suggests using three dimensional cone beam CT imaging as a direct objective method of evaluation and treatment planning, thereby eliminating the need for using a subjective system of classifying palatally-impacted permanent canines. PMID- 25443409 TI - [A particular temporomandibular disorder: the temporomandibular joint ankylosis. Basic and clinical concepts]. AB - Ankylosis of the temporomandibular joint mostly affects children and young adults. Although it is rare, it is an extremely debilitating disease whose effects on growth, morphological development and personal development are significant. To manage this disorder, it is essential to be informed about the causes, about the anatomical shapes it presents and about its symptoms. This knowledge will also help us choose the most appropriate therapy, that may nevertheless result in failures and in relapses requiring prosthetic rehabilitation. PMID- 25443414 TI - Upregulation of MAPK/Erk and PI3K/Akt pathways in ulcerative colitis-associated colon cancer. AB - An extracellular signal like a cytokine or chemokine, secreted in the inflammatory microenvironment can activate the mitogen activated protein kinase (MAPK) pathway by binding to a cytokine receptor tyrosine kinase, which further activates tyrosine kinases such as Janus Kinase-3 (Jak-3). This signal is transferred from Jak-3 to the DNA in the nucleus of the cell by a chain of kinases, ultimately activating extracellular receptor kinase (Erk/MAPK). The latter phosphorylates c-myc, an oncogene, which alters the levels and activities of many transcription factors leading to cell survival, proliferation and invasion. The oncogenic PI3K pathway plays a similar role by activating c-myc, leading to cell survival and proliferation. The present study explores the role of ulcerative colitis in colon cancer by investigating the activities of tyrosine kinase activated MAPK pathway and various components of the PI3K pathway including PI3K, PTEN, PDK1, GSK3beta, Akt, mTOR, Wnt and beta-catenin. This was done by western blot and fluorescent immunohistochemical analysis of the above mentioned proteins. Also, the morphological and histological investigation of the colonic samples from various animal groups revealed significant alterations as compared to the control in both inflammatory as well as carcinogenic conditions. These effects were reduced to a large extent by the co-administration of celecoxib, a second-generation non-steroidal anti-inflammatory drug (NSAID). PMID- 25443413 TI - Merging pathology with biomechanics using CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration): a novel, surgery-free model of traumatic brain injury. AB - BACKGROUND: Traumatic brain injury (TBI) is a major health care concern that currently lacks any effective treatment. Despite promising outcomes from many preclinical studies, clinical evaluations have failed to identify effective pharmacological therapies, suggesting that the translational potential of preclinical models may require improvement. Rodents continue to be the most widely used species for preclinical TBI research. As most human TBIs result from impact to an intact skull, closed head injury (CHI) models are highly relevant, however, traditional CHI models suffer from extensive experimental variability that may be due to poor control over biomechanical inputs. Here we describe a novel CHI model called CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration) that fully integrates biomechanical, behavioral, and neuropathological analyses. CHIMERA is distinct from existing neurotrauma model systems in that it uses a completely non-surgical procedure to precisely deliver impacts of prescribed dynamic characteristics to a closed skull while enabling kinematic analysis of unconstrained head movement. In this study, we characterized head kinematics as well as functional, neuropathological, and biochemical outcomes up to 14d following repeated TBI (rTBI) in adult C57BL/6 mice using CHIMERA. RESULTS: Head kinematic analysis showed excellent repeatability over two closed head impacts separated at 24h. Injured mice showed significantly prolonged loss of righting reflex and displayed neurological, motor, and cognitive deficits along with anxiety-like behavior. Repeated TBI led to diffuse axonal injury with extensive microgliosis in white matter from 2-14d post-rTBI. Injured mouse brains also showed significantly increased levels of TNF alpha and IL-1beta and increased endogenous tau phosphorylation. CONCLUSIONS: Repeated TBI using CHIMERA mimics many of the functional and pathological characteristics of human TBI with a reliable biomechanical response of the head. This makes CHIMERA well suited to investigate the pathophysiology of TBI and for drug development programs. PMID- 25443415 TI - Scavenging properties of neutrophil 4-hydroxyphenylpyruvate dioxygenase are based on a hypothesis that does not stand up to scrutiny. AB - It was previously reported by D'Eufemia et al. [9] that neutrophil preparations from a patient with tyrosinemia type III, i.e. with inherited deficiency of 4 hydroxyphenylpyruvate dioxygenase (HPPD), exhibited a far higher NO release than controls, when NO was estimated in terms of nitrite content in the suspending media. It was hypothesized that HPPD might participate to NO sequestration in neutrophils and that excessive NO release might reflect the lack of the scavenging action in defective cells. In recent control experiments, we found that HPPD activity in neutrophils preparations from healthy subjects is below the detection limit of the enzymatic assay (less than 3nmol product/h per mg protein). This indicates that HPPD concentration in neutrophils is very low, if any, confirming what was already suggested in literature, and rules out the possibility of a prominent role of HPPD as NO scavenger in these cells. Moreover, we found that 500MUM l-tyrosine increases nitrite release and accumulation in suspending media of U-937 cells, a human monoblast-like lymphoma cell line which displays many characteristics of macrophages, including the expression of inducible and endothelial nitric oxide synthases. We hypothesize that the increase of nitrite release by patient's neutrophils might be related to the presence of high l-tyrosine concentrations in the blood samples (426MUmol/L instead of 52.1+/-10.9MUmol/L as healthy subjects), rather than to HPPD deficiency of in these cells. PMID- 25443416 TI - Robinin modulates doxorubicin-induced cardiac apoptosis by TGF-beta1 signaling pathway in Sprague Dawley rats. AB - The study focussed on the cardioprotective effect of robinin on doxorubicin induced cardio-toxicity in Sprague Dawley rats. After the experimental period, animals were sacrificed and the various parameters such as cardiac markers, toxicity parameters, antioxidant status, ROS generation, lipid peroxidation status and inflammatory parameters were assessed. Gene expression study by RT-PCR analysis and proteins expression study by western blotting were done. Doxorubicin causes significant increase in the levels of cardiac marker enzymes, namely lactate dehydrogenase (LDH), creatine phospokinase (CPK), toxicity parameters like serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT). Antioxidant enzyme levels were decreased; lipid peroxidation products in heart tissue and inflammatory markers, namely cyclooxygenase (COX2) and lipooxygenase (LOX15) were significantly increased. Gene expression study by RT-PCR analysis of transforming growth factor-beta1 (TGF beta1), Smad2, murine double minute (Mdm2), Smad3, cyclin-dependent kinase inhibitor 2A (CDKN2A), Smad4 and Smad7 were significantly altered. The western blotting study of p53, Bcl-2 and Bax also showed altered expression. The supplementation of the Robinin along with DOX caused normalised level of all the above parameters and cardio-toxicity. This study revealed the cardioprotective nature of Robinin on doxorubicin-induced cardiac toxicity by modulating TGF-beta1 signaling pathway in Sprague Dawley rats. PMID- 25443417 TI - Dimethyl fumarate induces apoptosis of hematopoietic tumor cells via inhibition of NF-kappaB nuclear translocation and down-regulation of Bcl-xL and XIAP. AB - Dimethyl fumarate (DMF) is a fumaric acid ester that is used to treat psoriasis and multiple sclerosis. Recently, DMF was found to exhibit anti-tumor effects. However, the molecular mechanisms underlying these effects have not been elucidated. In this study, we investigated the mechanism of DMF-induced apoptosis in different human hematopoietic tumor cell lines. We found that DMF induced apoptosis in different human hematopoietic tumor cell lines but it did not affect the normal human B lymphocyte cell line RPMI 1788. We also observed a concurrent increase in caspase-3 activity and in the number of Annexin-V-positive cells. Furthermore, an examination of the survival signals, which are activated by apoptotic stimuli, revealed that DMF significantly inhibited nuclear factor kappaB (NF-kappaB) p65 nuclear translocation. In addition, DMF suppressed B-cell lymphoma extra-large (Bcl-xL) and X-linked inhibitor of apoptosis (XIAP) expression whereas Bcl-2, survivin, Bcl-2-associated X protein (Bax), and Bim levels did not change. These results indicated that DMF induced apoptosis by suppressing NF-kappaB activation, and Bcl-xL and XIAP expression. These findings suggested that DMF might have potential as an anticancer agent that could be used in combination therapy with other anticancer drugs for the treatment of human hematopoietic tumors. PMID- 25443418 TI - Sperm head ellipticity as a heat stress indicator in Australian Merino rams (Ovis aries) in Northern Patagonia, Argentina. AB - In Northern Patagonia, Argentina, the ovine mating season starts on March 15, which is the time when rams are submitted to summer temperatures. This study assessed the adaptability of 12 Australian Merino rams, six unshorn and six shorn, half of which were treated in a heat chamber for five days (09.00 hours to 17.00 hours) that gradually reached 40 degrees C. In an attempt to quantify the effects of heat stress on sperm head morphology, ellipticity was analyzed to establish the relationship between the distributions of subpopulations, light hours, temperature and humidity. Ellipticity was measured on 9224 sperm heads that were obtained over 12 weeks starting in the summer time. Four sperm head subpopulations (S) were identified by comparison with a sperm head population of ejaculates obtained in the late breeding season without the effect of heat stress (S1 = heads with ellipticity >= 2.00; S2 = sperm head with range of ellipticity between 1.80 and 1.99; S3 = sperm head with range of ellipticity from 1.60 to 1.79; and S4 = sperm head with range of ellipticity from 1.30 to 1.59). The variable sperm head ellipticity for each ejaculate was expressed as the means and frequencies of subpopulation. The results demonstrate changes in ram sperm head ellipticity in different conditions (control/treated, unshorn/shorn) throughout the experiment (P < 0.05). Treated shorn rams had a higher mean ellipticity and frequency of elliptical heads (mean ellipticity value = 2.06 and S1 frequency = 76.35%), peaking in the seventh week posttreatment (on the basis of the action of heat stress on seminiferous tubules). According to this study, unshorn rams were better adapted to heat stress than the shorn ones. PMID- 25443419 TI - Annual review of selected scientific literature: report of the Committee on Scientific Investigation of the American Academy of Restorative Dentistry. PMID- 25443420 TI - A multi-center prevalence study and randomized controlled parallel-group pragmatic trial to compare the effectiveness of standardized skin care regimens on skin health in nursing home residents: a study protocol. AB - BACKGROUND: Aged long-term residents suffer from a wide range of skin problems. Dry skin associated with severe pruritus, scratching and inflammation is the most prevalent, but exact figures are lacking. Maintaining skin and tissue health as well as enhancing the quality of life are major goals in institutional long-term care. Using mild and moisturizing skin care products is considered to improve the skin barrier and to reduce adverse events. However, the available evidence supporting particular skin care approaches is limited. OBJECTIVE: This study aims at answering two general questions: (1) What is the prevalence of skin conditions and skin diseases in aged nursing home residents and how are they associated with general person and health related characteristics? (2) Does a structured skin care regimen improve the skin health of aged nursing home residents? DESIGN AND METHODS: Using a random sample of all nursing homes of the state of Berlin, residents of seven institutions will undergo nursing, medical, and dermatological assessments. Biophysical skin parameters like transepidermal water loss or skin surface pH will be measured. Residents with dry skin will be included in a three arm randomized pragmatic trial investigating the effectiveness of two standardized skin care regimens compared to usual care. The primary outcome will be the Overall Dry Skin score. The follow-up period will be two months. SETTINGS: Institutional long-term care facilities in Berlin, Germany. PARTICIPANTS: Long term care residents being 65+ years who gave their informed consent. SAMPLE SIZE AND STATISTICAL METHODS: Due to the explorative nature of this study a formal sample size analysis is not possible. The expected sample size in the first part of the study is considered sufficiently large (n=280) to obtain precise point estimates. It is planned to allocate n=50 eligible nursing home residents in a 1:1:1 ratio per group in the intervention part. The detectable mean difference using these group sizes would be 0.32 between groups. Depending on the level of measurement variables will be described using absolute and relative frequencies, means, medians, and associated spread estimates. Possible bi- and multivariable associations will be analyzed. The primary outcome of dry skin will be described by mean differences and one-way ANOVA analysis with post-hoc pairwise two-sample t-tests. RESULTS: The study started in September 2014. The results are expected in July 2015. TRIAL REGISTRATION: The study is registered at https://clinicaltrials.gov/ct2/show/NCT02216526. PMID- 25443421 TI - Agnotology: on the varieties of ignorance, criminal negligence, and crimes against humanity. PMID- 25443422 TI - In response. PMID- 25443423 TI - Stress Management and Resiliency Training (SMART) program among Department of Radiology faculty: a pilot randomized clinical trial. AB - OBJECTIVE: To test the efficacy of a Stress Management and Resiliency Training (SMART) program for decreasing stress and anxiety and improving resilience and quality of life among Department of Radiology physicians. MATERIALS AND METHODS: The study was approved by the institutional review board. A total of 26 Department of Radiology physicians were randomized in a single-blind trial to either the SMART program or a wait-list control arm for 12 weeks. The program involved a single 90-min group session in the SMART training with two follow-up phone calls. Primary outcomes measured at baseline and week 12 included the Perceived Stress Scale, Linear Analog Self-Assessment Scale, Mindful Attention Awareness Scale, and Connor-Davidson Resilience Scale. RESULTS: A total of 22 physicians completed the study. A statistically significant improvement in perceived stress, anxiety, quality of life, and mindfulness at 12 weeks was observed in the study arm compared to the wait-list control arm; resilience also improved in the active arm, but the changes were not statistically significant when compared to the control arm. CONCLUSIONS: A single session to decrease stress among radiologists using the SMART program is feasible. Furthermore, the intervention afforded statistically significant and clinically meaningful improvement in anxiety, stress, quality of life, and mindful attention. Further studies including larger sample size and longer follow-up are warranted. PMID- 25443424 TI - Principles of therapeutic suggestions (part I) and clinical applications of therapeutic suggestions (part II). PMID- 25443425 TI - Metabolic remodelling in obesity and type 2 diabetes: pathological or protective mechanisms in response to nutrient excess? AB - Altered metabolism in tissues such as the liver, skeletal muscle and adipose tissue is observed in metabolic diseases characterized by nutrient excess and energy imbalance, such as obesity and type 2 diabetes. These alterations in metabolism can include resistance to the hormone insulin, lipid accumulation, mitochondrial dysfunction and transcriptional remodelling of major metabolic pathways. The underlying assumption has been that these same alterations in metabolism are fundamental to the pathogenesis of metabolic diseases. An alternative view is that these alterations in metabolism occur to protect cell and tissue viability in the face of constant positive energy balance. This speculative review presents evidence that many of the metabolic adaptations that occur in metabolic diseases characterized by nutrient excess can be viewed as protective in nature, rather than pathogenic per se for disease progression. Finally, we also briefly discuss the usefulness and potential pitfalls of therapeutic approaches that attempt to correct these same metabolic defects when energy balance is not altered, and the potential links between metabolic survival responses and other chronic diseases such as cancer. PMID- 25443426 TI - Allergen-specific basophil reactivity exhibits daily variations in seasonal allergic rhinitis. AB - It remains poorly understood how symptoms in allergic rhinitis are most severe during overnight or early in the morning. The circadian clock consisting of a network of several 'clock genes' including Clock drives daily rhythms in physiology. This study showed that allergen-induced surface CD203c expression on basophils in seasonal allergic rhinitis caused by Japanese cedar pollen exhibited a time-of-day-dependent variation associated with temporal variations in canonical circadian clock gene expression. We also found that bone-marrow-derived basophils (BM basophils) generated from wild-type mice exhibited a time-of-day dependent variation in IgE-mediated IL-4 and histamine production, which was not observed in BM basophils generated from Clock-mutated mice. Therefore, allergen specific basophil reactivity shows daily variations depending on the circadian clock activity in basophils, which could partly explain temporal symptomatic variations in allergic rhinitis. Additionally, circadian variations in CD203c expression should be considered for interpretation of this biomarker in clinical research. PMID- 25443427 TI - Systematic and day-to-day effects of chemical-derived population estimates on wastewater-based drug epidemiology. AB - Population size is crucial when estimating population-normalized drug consumption (PNDC) from wastewater-based drug epidemiology (WBDE). Three conceptually different population estimates can be used: de jure (common census, residence), de facto (all persons within a sewer catchment), and chemical loads (contributors to the sampled wastewater). De facto and chemical loads will be the same where all households contribute to a central sewer system without wastewater loss. This study explored the feasibility of determining a de facto population and its effect on estimating PNDC in an urban community over an extended period. Drugs and other chemicals were analyzed in 311 daily composite wastewater samples. The daily estimated de facto population (using chemical loads) was on average 32% higher than the de jure population. Consequently, using the latter would systemically overestimate PNDC by 22%. However, the relative day-to-day pattern of drug consumption was similar regardless of the type of normalization as daily illicit drug loads appeared to vary substantially more than the population. Using chemical loads population, we objectively quantified the total methodological uncertainty of PNDC and reduced it by a factor of 2. Our study illustrated the potential benefits of using chemical loads population for obtaining more robust PNDC data in WBDE. PMID- 25443428 TI - Management of patients on chemotherapeutic treatment for advanced cancer with acute conditions in the emergency department. AB - BACKGROUND: Chemotherapy is increasingly used in people with advanced cancer to palliate symptoms and improve survival. New Zealand provides medical oncology services in a Hub and Spoke model, with an increasing emphasis on delivering treatment at out-patient spoke services, where after hours and urgent care is provided by the Emergency Department (ED). This study sought to describe the factors that influenced the care and clinical decision-making of this group of patients in the ED. METHODS: Semi-structured telephone interviews were held with five ED nurses from three hospitals at the spoke. Raw data was thematically analysed via an exploratory descriptive approach. RESULTS: Care of the oncology patient in ED is determined by the presentation itself, and differs little to the care delivered to other patient groups. That the patient is on chemotherapy may have little influence on the interventions provided. Challenges arise through patient complexity, lack of oncology specialist availability and low volumes preclude the maintenance of specialist skills and knowledge. Clinical decisions are influenced by local Hospice teams rather than Oncology team providing cancer treatment. CONCLUSION: A more collaborative relationship between Oncology and ED nurses may support the provision of emergency care within the context of active cancer treatment. PMID- 25443429 TI - Initial emergency nursing management of patients with severe traumatic brain injury: development of an evidence-based care bundle for the Thai emergency department context. AB - BACKGROUND: Thai emergency nurses play a vital role in caring for patients with severe TBI, and are an important part of the healthcare team throughout the resuscitation phase. They are also responsible for continuous physiological monitoring, and detecting deterioration associated with increased intracranial pressure and preventing secondary brain injury. However, there is known variation in Thai nurses' knowledge and care practices for patients with severe TBI. In addition, there are no specific evidence-based practice guidelines available for emergency nursing management of patients with severe TBI. AIM: The aim of this paper is to describe the development of an evidence-based care bundle for initial emergency nursing management of patients with severe TBI for use in a Thai ED context. RESULTS: An evidence-based care bundle focused on seven major elements: (1) establish a secure airway along with c-spine protection, (2) maintain adequacy of oxygenation and ventilation, (3) maintain circulation and fluid balance, (4) assessment of GCS, and pupil size and reactivity, (5) maintain cerebral venous outflow, (6) management of pain, agitation, and irritability, and (7) administer for urgent CT scan. CONCLUSIONS: A care bundle is one method of promoting consistent, evidence-based emergency nursing care of patients with severe TBI, decreasing unnecessary variations in nursing care and reducing the risk of secondary brain injury from suboptimal care. Implementation of this evidence-based care bundle developed specifically for the Thai emergency nursing context has the potential to improve the care of the patients with severe TBI. PMID- 25443430 TI - A comparison of emergency triage scales in triaging poisoned patients. AB - BACKGROUND: Triage of toxicology patients presents a challenge due to their complexity, underlying psychosocial issues, and additional pharmacological considerations. Two emergency department triage systems used in Australia, the Australasian Triage Scale (ATS) and the Manchester Triage System (MTS), were compared in triaging patients presenting with poisoning and envenoming. METHODS: In this simulation-based study, 30 triage nurses from three hospitals were given 8 tabletop scenarios and asked to provide a triage category. 20 nurses from two hospitals using the ATS, and 10 nurses from a third hospital using the MTS, triaged 8 scenarios, grouped into "commonly encountered" (n=4) and "rarely encountered" (n=4). Triage systems and scenario groups were compared for median triage category and variance in scoring. Triage nurses also noted if they would seek help from toxicology services or the poisons information centre (PIC) for advice. RESULTS: Overall, MTS nurses triaged all 8 scenarios with a lower acuity triage category, though statistically significant for only 3 scenarios. ATS nurses scored higher acuity triage category in all 4 "rare" highly toxic presentations, whereas MTS nurses scored higher acuity when vital signs were abnormal. MTS showed wider variance in triage scores in both scenario groups when compared to the ATS. Triage nurses without access to local toxicology services chose to contact PIC in most cases. CONCLUSIONS: When compared to the ATS, MTS gave a lower acuity triage score for all common and rarely encountered poisoning scenario groups, which included highly toxic ingestions that appear well at triage but may progress to severe poisoning. Triage nurses should refer to information on highly toxic exposures and envenomation guidelines during their triage risk assessment. PMID- 25443431 TI - Ileal ganglioneuromatosis in a piglet: histopathological and immunohistochemical studies. AB - Ganglioneuromatosis (GNM) is a rare condition characterized by the benign proliferation of ganglion cells, nerve fibres and supporting cells of the enteric nervous system. Necropsy examination of a female piglet weighing 4 kg revealed a well-demarcated 20 cm segment of terminal ileum with thickening of the wall. Microscopically, the lamina propria was infiltrated by enteric glial cells and large ganglion cells. Within the submucosal and muscular layers, aggregates of neurons were interlaced by Schwann cells and enteric glial cells arranged in concentric rings. Immunohistochemically, the neurons were weakly labelled for S 100 and neuron-specific enolase, Schwann cells expressed S-100 and vimentin and enteric glial cells expressed glial fibrillary acidic protein and S-100. Pathological and immunohistochemical findings supported the diagnosis of ileal GNM. PMID- 25443432 TI - Anatomy of the fetal membranes using optical coherence tomography: part 1. AB - INTRODUCTION: In vitro studies on the structure of human fetal membranes have involved light or electron microscopy with fixation, dehydration, and staining. Recently, optical coherence tomography (OCT), an imaging technology, has provided high-resolution cross-sectional images of living biological tissues, with a penetration of 2-3 mm. We evaluated the use of this technology to examine the histologic features of human fetal membranes immediately after delivery. METHODS: Samples of fetal membranes of ten patients undergoing cesarean deliveries (four uncomplicated pregnancies, four with preeclampsia, and two with chorioamnionitis) and eight patients undergoing vaginal deliveries (six uncomplicated pregnancies and two with chorioamnionitis) were collected immediately after delivery. Samples were stretched across customized disks, rinsed, and analyzed using a time-domain OCT imaging system. Following OCT scanning, the samples were placed in formalin for histologic study. The OCT images were compared to histologic images of common human fetal membrane features. RESULTS: We were able to delineate the layers of the fetal membranes using bench-top time-domain OCT. The system was able to image histologic features of the fetal membranes, such as microscopic chorionic pseudocysts, ghost villi, meconium stained membranes, and chorioamnionitis. The OCT images corresponded with the histologic findings. DISCUSSION: This feasibility study demonstrates the potential of OCT technology for real-time assessment of human fetal membranes and may provide clinically useful information at delivery. PMID- 25443433 TI - Developmental differences in the expression of FGF receptors between human and mouse embryos. AB - INTRODUCTION: Fibroblast growth factor (FGF) signaling is essential for early trophoblast expansion and maintenance in the mouse, but is not required for trophectoderm specification during blastocyst formation. This signaling pathway is stably activated to expand the trophoblast stem cell compartment in vivo, while in vitro, FGFs are used for the derivation of trophoblast stem (TS) cells from blastocysts and early post-implantation mouse embryos. However, the function of FGFs during human trophoblast development is not known. METHODS: We sought to derive TS cells from human blastocysts in a number of culture conditions, including in the presence of FGFs and stem cell factor (SCF). We also investigated the expression of FGF receptors (FGFRs) in blastocysts, and the expression of FGFR2 and activated ERK1/2 in first trimester human placentae. RESULTS: We found that SCF, but not FGF2/4, improved the quality of blastocyst outgrowths, but we were unable to establish stable human TS cell lines. We observed CDX2 expression in the trophectoderm of fully blastocysts, but rarely observed transcription of FGFRs. FGFR2 protein was not detected in human blastocysts, but was strongly expressed in mouse blastocysts. However, we found robust FGFR2 expression and activated ERK1/2 in the cytotrophoblast layer of early human placenta. DISCUSSION: Our data suggests that initiation of FGF dependent trophoblast expansion may occur later in human development, and is unlikely to drive maintenance of a TS cell compartment during the peri implantation period. These findings suggest that cytotrophoblast preparations from early placentae may be a potential source of FGF-dependent human TS cells. PMID- 25443434 TI - [Critical reading of articles about diagnostic tests (part I): Are the results of the study valid?]. AB - In the era of evidence-based medicine, one of the most important skills a radiologist should have is the ability to analyze the diagnostic literature critically. This tutorial aims to present guidelines for determining whether primary diagnostic articles are valid for clinical practice. The following elements should be evaluated: whether the study can be applied to clinical practice, whether the technique was compared to the reference test, whether an appropriate spectrum of patients was included, whether expectation bias and verification bias were limited, the reproducibility of the study, the practical consequences of the study, the confidence intervals for the parameters analyzed, the normal range for continuous variables, and the placement of the test in the context of other diagnostic tests. We use elementary practical examples to illustrate how to select and interpret the literature on diagnostic imaging and specific references to provide more details. PMID- 25443435 TI - High pitch CT in triple rule-out studies: Radiation dose and image quality compared to multidetector CT. AB - OBJECTIVE: To compare the image quality and radiation dose from high pitch dual source CT (128-DSCT) versus those from retrospective acquisition with 64-row multidetector CT (64-MDCT) in triple rule-out studies. MATERIAL AND METHODS: We retrospectively studied 60 patients with acute chest pain: 30 with a retrospective EKG acquisition with 64-MDCT and 30 with high pitch 128-DSCT. We quantitatively analyzed the image quality by calculating the vascular density, muscular density (DM), noise, vascular density/noise ratio (VDNR), and contrast/noise ratio (CNR). We qualitatively evaluated the artifacts in the vena cava, aorta, and coronary arteries. We estimated the effective dose (ED) of radiation by means of the dose-length product. RESULTS: There were no significant differences between 128-DSCT and 64-MDCT in the vascular density. The VDNR and CNR were higher on 128-DSCT than on 64-MDCT in the aorta (VDNR: 28.9 +/- 11.7 vs. 20 +/- 5.5; CNR: 24.4 +/- 10.9 vs. 16.8 +/- 5.4; P<.01), in the pulmonary arteries (VDNR: 25.5 +/- 10 vs. 20.6 +/- 6.5; CNR: 24.5 +/- 5.4 vs. 17.4 +/- 6.4; P<.01), and in the coronary arteries (VDNR: 25.9 +/- 8.2 vs. 18.9 +/- 4.9; CNR: 24.9 +/- 8.2 vs. 15.6 +/- 4.6; P<.01). There were fewer artifacts in the coronary arteries on 128-DSCT than on 64-MDCT (3 vs. 34 nondiagnostic segments; P<.001), and the ED in 128-DSCT was lower than in 64-MDCT (13.77 +/- 4 vs. 2.77 +/- 0.6 mSv; P<.001). CONCLUSION: In triple rule-out studies, high pitch 128-DSCT delivers a lower dose of radiation and provides better image quality than retrospective acquisition with 64-MDCT. PMID- 25443436 TI - Efficacy and complications in the use of self-expanding colonic stents: an analysis of 15 years' experience. AB - OBJECTIVE: To analyze the efficacy and safety of the procedure for placing self expanding stents in the colon. To evaluate the factors associated with complications. To analyze the dose of radiation delivered in the procedure. MATERIAL AND METHODS: This was a retrospective descriptive study of 478 procedures done at a single center to place self-expanding metallic stents in the colon. A total of 423 nitinol stents and 79 stainless steel stents were placed. We included all colonic obstructions, of which 446 had malignant causes and 8 had benign causes. We excluded patients with intestinal perforation, severe colonic bleeding, short life expectancy, or lesions located less than 5 cm from the anus. We collected the dosimetric data and analyzed the technical success, clinical success, and complications during follow-up. RESULTS: The procedure was a technical success in 92.26% of cases (n=441) and a clinical success in 78.45% (n=375); complications occurred during follow-up in 18.5% of cases. Complications occurred more frequently with the stainless steel stents than with the nitinol stents (OR: 3.2; 95% CI: 1.8-5.7). The mean value of the dose area product was 35 Gy*cm(2). When instead of being done by the interventional radiologist working together with an endoscopist the procedure was done exclusively by the interventional radiologist, the time under fluoroscopy (p=0.001), dose area product (p=0.029), and kinetic energy released per unit mass (p=0.001) were greater. CONCLUSION: The procedure for placing self-expanding colonic stents is efficacious and safe with an acceptable rate of complications. The doses of radiation delivered were low, and the radiation doses and time under fluoroscopy were lower when the procedure was done together with an endoscopist. PMID- 25443437 TI - Influence of androgen receptor CAG polymorphism on sexual function recovery after testosterone therapy in late-onset hypogonadism. AB - INTRODUCTION: Androgen receptor (AR) CAG polymorphism has been found to influence sexual function. However, no study has evaluated its potential to condition sexual function recovery after testosterone replacement therapy (TRT) in a large cohort of hypogonadic subjects. AIM: To evaluate the role of this polymorphism in sexual function improvement after TRT in late-onset hypogonadism (LOH). METHODS: Seventy-three men affected by LOH were retrospectively considered. Evaluations were performed before TRT started (time 0) and before the sixth undecanoate testosterone injection. MAIN OUTCOME MEASURES: International Index of Erectile Function (IIEF) questionnaire (erectile function [EF], orgasmic function [OF], sexual desire [SD], intercourse satisfaction [IS], overall satisfaction [OS], and total IIEF-15 score); total and free testosterone and estradiol; AR gene CAG repeat number. RESULTS: TRT induced a significant increase in total and free testosterone and estradiol. All IIEF domains significantly improved after TRT. AR CAG repeats negatively and significantly correlated with all the variations (Delta-) of sexual function domains, except for Delta-OS. Conversely, Delta-total testosterone was found to be positively and significantly correlated with sexual function domain variations, except for Delta-IS and Delta-OS. Delta-estradiol did not correlate significantly with any of the variations of sexual function domains. After inclusion in generalized linear models, the number of AR gene CAG triplets was found to be independently and negatively associated with Delta-EF, Delta-SD, Delta-IS, and Delta-Total IIEF-15 score, whereas Delta-total testosterone was independently and positively associated with Delta-EF, Delta-OF, Delta-SD, and Delta-Total IIEF-15 score. However, after including time 0 total testosterone in the model, AR gene CAG triplets remained independently and negatively associated only with Delta-EF and Delta-Total IIEF-15 score, whereas Delta-total testosterone was independently and positively associated only with Delta-EF. CONCLUSIONS: Longer length of AR gene CAG repeat tract seems to lower TRT-induced improvement of sexual function in LOH. PMID- 25443438 TI - The experiences and needs of Chinese-Canadian stroke survivors and family caregivers as they re-integrate into the community. AB - Stroke is a leading cause of adult disability and community re-integration is a priority for stroke rehabilitation. In North America, we have a growing population of individuals whose first language is not English. Little is known about the experiences of visible minorities living in North America as they re integrate into the community post stroke or how these experiences change over time. Specifically, this research aimed to explore the experiences and needs of Chinese stroke survivors and family caregivers as they return to community living using the Timing it Right Framework as a conceptual guide. We recruited Cantonese speaking stroke survivors and family caregivers from outpatient rehabilitation programmes. Using qualitative interviews conducted in Cantonese or English, we examined their experiences and needs as they return to community living and explored the influence of culture and time on their experiences. The interviews were transcribed and translated, and then analysed using framework analysis. Using framework analysis, we coded the data corresponding to the phases of the Timing it Right framework to determine the influence of time on the themes. We interviewed five Cantonese-speaking stroke survivors and 13 caregivers in 2009. We identified two main themes: (i) Participants' education and support needs change over time and (ii) Chinese resources are needed across care environments. These resources include access to care in their preferred language, traditional Chinese medicine, and Chinese food during their recovery and rehabilitation. To optimise Chinese stroke survivors' and caregivers' community re-integration, healthcare professionals should provide timely and accessible education and be aware of the role of Chinese diet and traditional medicine in stroke survivors' rehabilitation. PMID- 25443439 TI - An evaluation of the treatment of risk and uncertainties in the IPCC reports on climate change. AB - Few global threats rival global climate change in scale and potential consequence. The principal international authority assessing climate risk is the Intergovernmental Panel on Climate Change (IPCC). Through repeated assessments the IPCC has devoted considerable effort and interdisciplinary competence to articulating a common characterization of climate risk and uncertainties. We have reviewed the assessment and its foundation for the Fifth Assessment Reports published in 2013 and 2014, in particular the guidance note for lead authors of the fifth IPCC assessment report on consistent treatment of uncertainties. Our analysis shows that the work carried out by the ICPP is short of providing a theoretically and conceptually convincing foundation on the treatment of risk and uncertainties. The main reasons for our assessment are: (i) the concept of risk is given a too narrow definition (a function of consequences and probability/likelihood); and (ii) the reports lack precision in delineating their concepts and methods. The goal of this article is to contribute to improving the handling of uncertainty and risk in future IPCC studies, thereby obtaining a more theoretically substantiated characterization as well as enhanced scientific quality for risk analysis in this area. Several suggestions for how to improve the risk and uncertainty treatment are provided. PMID- 25443440 TI - Which factors influence the development of post-traumatic stress disorder in patients with burn injuries? A systematic review of the literature. AB - INTRODUCTION: This article aims to discover which variables influence the development of post-traumatic stress disorder in patients with burn injuries. It will also consider whether it is possible to predict which burns patients will develop PTSD. BACKGROUND: Post-traumatic stress disorder is an important psychopathology for burned patients as it can affect both physical outcomes and quality of life for those affected. Research states that PTSD may be identified in up to 30% of burns patients, making it relatively common. METHODS: A systematic review of the literature was carried out using four databases. Eleven articles were identified from these searches, and were then analysed thematically to draw out common ideas. RESULTS: Gender, extraversion and neuroticism, attribution of blame, capacity for forgiveness, the event as a disaster or non disaster, alcohol consumption and peri-traumatic emotional response were all found to influence burns patients' risk of developing PTSD. CONCLUSION: While it is possible to identify the factors that put burns patients are greater risk of developing PTSD, it is not possible to accurately predict who will go on to develop PTSD due to the interplay between variables and individual differences. Focus should instead be on screening for PTSD and timely recognition of intrusive symptoms. PMID- 25443441 TI - [Comparison of effects on the oxidant/antioxidant system of sevoflurane, desflurane and propofol infusion during general anesthesia]. AB - BACKGROUND AND OBJECTIVES: Desflurane and sevoflurane are frequently used for maintenance of anesthesia and studies have shown that these anesthetics cause a variety of changes to the oxidative stress and antioxidative defense mechanisms. This study aims to compare the effects of sevoflurane, desflurane and propofol infusion anesthesia on the oxidant and antioxidant systems of patients undergoing laparoscopic cholecystectomy. METHODS: 45 patients between 18 and 50 years with planned laparoscopic cholecystectomy under general anesthetic were included in the study. Patients were divided into three groups on the way to surgery: propofol (group P, n=15), sevoflurane (group S, n=15) and desflurane (group D, n=15). All groups were given hypnotic 2mg/kg propofol IV, 1mcg/kg fentanyl IV and 0.1mg/kg vecuronium IV for induction. For maintenance of anesthesia group S were ventilated with 2% sevoflurane, group D cases were given 6% desflurane and group P were given propofol infusions of 12mg/kg/h for the first 10minutes, 9mg/kg/h for the second 10minutes and 6mg/kg/h after that. Before induction and after the operation venous blood samples were taken to evaluate the levels of glutation peroxidase, total oxidants and antioxidants. RESULTS AND CONCLUSIONS: The 45 patients included in the study were 22 male and 23 female patients. The demographic characteristics of the groups were similar. In the postoperative period we observed that while sevoflurane and propofol increased antioxidants by a statistically significant level, desflurane increased the total oxidants level by a significant amount compared to levels before the operation. PMID- 25443442 TI - [Administration of paracetamol versus dipyrone by intravenous patient-controlled analgesia for postoperative pain relief in children after tonsillectomy]. AB - BACKGROUND AND OBJECTIVE: We compared the efficacy of intravenous (IV) paracetamol versus dipyrone via patient-controlled analgesia (PCA) for postoperative pain relief in children. METHODS: The study was composed of 120 children who had undergone elective tonsillectomy after receiving general anesthesia. Patients were divided into 3 groups according to the dosage of postoperative intravenous-patient-controlled analgesia: paracetamol, dipyrone, or placebo. Pain was evaluated using a 0- to 100-mm visual analog scale and 1- to 4 pain relief score at 30min, 1, 2, 4, 6, 12, and 24h postoperatively. Pethidine (0.25mgkg(-1)) was administered intravenously to patients requiring rescue analgesia. Pethidine requirements were recorded during the first 24h postoperatively, and treatment related adverse effects were noted. RESULTS: Postoperative visual analog scale scores were significantly lower with paracetamol group compared with placebo group at 6h (p<0.05), dipyrone group compared with placebo group at 30min and 6h (p<0.05). No significant differences regarding visual analog scale values at 1, 2, 4, 12, and 24h were found. No significant differences were found between groups with respect to pain relief score (p>0.05). Postoperative pethidine requirements were significantly lower with paracetamol and dipyrone groups compared with placebo group (62.5%, 68.4% vs 90%, p<0.05). No significant differences were found between groups with respect to nausea, vomiting and the any other adverse effects of the drugs (p>0.05). CONCLUSIONS: Paracetamol and dipyrone have well tolerability profile and effective analgesic properties when administered IV-PCA for postoperative analgesia in children after tonsillectomy. PMID- 25443443 TI - [In vitro comparison of epidural bacteria filters permeability and screening scanning electron microscopy]. AB - BACKGROUND AND OBJECTIVES: Epidural catheter bacteria filters are barriers in the patient-controlled analgesia/anaesthesia for preventing contamination at the epidural insertion site. The efficiency of these filters varies according to pore sizes and materials. METHOD: The bacterial adhesion capability of the two filters was measured in vitro experiment. Adhesion capacities for standard Staphylococcus aureus (ATCC 25923) and Pseudomonas aeruginosa (ATCC 27853) strains of the two different filters (Portex and Rusch) which have the same pore size were examined. Bacterial suspension of 0.5 Mc Farland was placed in the patient-controlled analgesia pump, was filtered at a speed of 5mL/h. in continuous infusion for 48h and accumulated in bottle. The two filters were compared with colony counts of bacteria in the filters and bottles. At the same time, the filters and adhered bacteria were monitored by scanning electron microscope. RESULTS: Electron microscopic examination of filters showed that the Portex filter had a granular and the Rusch filter fibrillary structure. Colony counting from the catheter and bottle showed that both of the filters have significant bacterial adhesion capability (p<0.001). After the bacteria suspension infusion, colony countings showed that the Portex filter was more efficient (p<0.001). There was not any difference between S. aureus and P. aeruginosa bacteria adhesion. In the SEM monitoring after the infusion, it was physically shown that the bacteria were adhered efficiently by both of the filters. CONCLUSION: The granular structured filter was found statistically and significantly more successful than the fibrial. Although the pore sizes of the filters were same - of which structural differences shown by SEM were the same - it would not be right to attribute the changes in the efficiencies to only structural differences. Using microbiological and physical proofs with regard to efficiency at the same time has been another important aspect of this experiment. PMID- 25443445 TI - "Omics" at a crossroads--from integrated science to multi-sector implications. PMID- 25443444 TI - Effects of ultraviolet radiation (UVA+UVB) and copper on the morphology, ultrastructural organization and physiological responses of the red alga Pterocladiella capillacea. AB - The effect of ultraviolet (UV) radiation and copper (Cu) on apical segments of Pterocladiella capillacea was examined under two different conditions of radiation, PAR (control) and PAR+UVA+UVB (PAR+UVAB), and three copper concentrations, ranging from 0 (control) to 0.62, 1.25 and 2.50 MUm. Algae were exposed in vitro to photosynthetically active radiation (PAR) at 70 MUmol photons m(-2) s(-1) , PAR + UVB at 0.35 W m(-2) and PAR +UVA at 0.70 W m(-2) during a 12 h photocycle for 3 h each day for 7 days. The effects of radiation and copper on growth rates, content of photosynthetic pigments and photosynthetic performance were analyzed. In addition, samples were processed for light and transmission electron microscopy. The content of photosynthetic pigments decreased after exposure to radiation and Cu. Compared with PAR radiation and copper treatments modified the kinetics patterns of the photosynthesis/irradiance curve. The treatments also caused changes in the ultrastructure of cortical and subcortical cells, including increased cell wall thickness and accumulation of plastoglobuli, as well as changes in the organization of chloroplasts. The results indicate that the synergistic interaction between UV radiation and Cu in P. capillacea, led to the failure of protective mechanisms and causing more drastic changes and cellular imbalances. PMID- 25443446 TI - Interpretive visual inquiry - methodological review. PMID- 25443447 TI - Mathematical methods and models in system biomedicine. PMID- 25443450 TI - Seizure outcome in 175 patients with juvenile myoclonic epilepsy--a long-term observational study. AB - INTRODUCTION: Juvenile myoclonic epilepsy (JME) is a genetic generalized epilepsy syndrome. Under appropriate antiepileptic drugs (AED) up to 85% of patients become seizure-free, but many may have a relapse after AED withdrawal. METHODS: We retrospectively studied 242 patients with JME at the Department of Neurology, Medical University Innsbruck, Austria (1975-2006). We analyzed age at seizure onset, age at last follow up, seizure types, photosensitivity, seizure outcome and neuroimaging findings; inclusion criterion was a medical treatment period of >2 years; exclusion criteria were traumatic or infectious brain injury before the onset of JME and/or gross structural pathology on neuroimaging. RESULTS: We identified 175 patients (111 women) with a median age at seizure onset of 15 years, (range 3-46) and a median age at follow-up (FU) of 38 years (range 14-87; median FU 8 years, range 2-38). Fourteen percent showed (24/175) photosensitivity on routine EEG. Seizure outcome: 62% (109/175) were seizure-free of myoclonic seizures (MS), generalized tonic clonic seizures (GTCS) and absence seizures (AS) for >1 year, and 53% (94/175) for >2 years, including 16 patients (9%) without AEDs. Thirty-one percent (54/175) were seizure-free between 2 and 5 years, 15% (26/175) between 6 and 10, and 8% (14/175) >10 years; 38% (66/175) were not seizure-free. Not seizure-free patients had more often MS, AS and GTCS within the first year of epilepsy than those who were seizure-free at last FU (11% vs. 3%, Chi(2)=4.679, df=1, p=0.043). Seizure-free patients had more often MS and GTCS as last seizure types in the year before becoming seizure-free (37% vs. 15%, p=0.003), whereas in not seizure-free group MS only and GTCS only persisted. CONCLUSIONS: JME does not always need lifelong treatment, as a substantial minority of patients remain seizure-free without AEDs. AS, MS and GTCS at onset of the disease are indicators of poor long-term seizure control. PMID- 25443453 TI - [Analysis of complaints lodged in a health center from 2010 to 2012. Cross sectional study]. PMID- 25443451 TI - The relationship between hippocampal volumes and nonverbal memory in patients with medial temporal lobe epilepsy. AB - OBJECTIVE: To explore the involvement of medial temporal lobe structures such as the hippocampus, amygdala, and entorhinal cortex (EC) in memory consolidation by volumetric magnetic resonance imaging (MRI). METHODS: Sixty-two consecutive patients with medial temporal lobe epilepsy (MMTLE) were assessed using the Clinical Memory Scale (CMS) and MRI to measure the volumes of the hippocampus, amygdala, and EC. Participants were grouped according to MRI findings into 3 groups: left MRI-positive (abnormal hippocampal formation on the left side; n=17), right MRI-positive (abnormal hippocampal formation on the left side; n=9), and MRI-negative (normal hippocampal formation; n=36). One-way analysis of variance (ANOVA) was used to assess group differences for all volumetric data (Z scores or asymmetry indexes (AI)), memory scale scores, and clinical parameters. Post hoc analyses were done with Fisher's least significant difference (LSD) tests. AI=100*(L-R)/(L+R). "L" and "R" refer to the left and right volumes of each structure, respectively. RESULTS: The nonsense graphical recognition tests and the facial memory tests were significantly different between the three groups. Post hoc analyses showed that the right MRI-positive group performed significantly worse than the MRI-negative group on nonsense graphical recognition tests (P=0.008) and the left MRI-positive group had significantly lower scores than the MRI-negative group on facial memory tests (P=0.023). CONCLUSIONS: Nonverbal memory was correlated with the status of the right hippocampus. PMID- 25443454 TI - Prevalence of prediabetes in patients with acute coronary syndrome: impact on in hospital outcomes. AB - BACKGROUND: Prediabetes is a serious condition that is associated with an increase in cardiovascular morbidity and mortality. AIMS: We sought to explore the prevalence of prediabetes in patients admitted with acute coronary syndrome (ACS) who were not known to have diabetes and to determine the impact of prediabetes on in-hospital clinical outcomes versus non-diabetic patients. METHODS: Prospectively, we enrolled 200 patients not known to have diabetes or prediabetes, admitted with ACS. Laboratory tests included fasting plasma glucose (FPG), 2-h plasma glucose (2hPG) after 75 g glucose, HbA1c and lipid profile. Electrocardiogram and echocardiography were done. The primary end-point was in hospital major adverse cardiovascular events (MACE). RESULTS: Mean age was 50.9 +/- 6.8 years (70.5% males). The prevalence of patients with diabetes and patients with prediabetes was 24.5% and 20% respectively. Newly discovered diabetic patients were excluded. Compared with patients without diabetes, prediabetic patients had a higher body mass index (BMI) (P = 0.002) and a longer hospital stay (P = 0.09). In-hospital MACE occurred in 10 (25%) patients with prediabetes versus six (5.4%) in patients without diabetes (P = 0.001). In hospital MACE correlated with prediabetes (r = 0.28, P < 0.001), BMI (r = 0.14, P = 0.093), FPG (r = 0.19, P = 0.014), 2hPG (r = 0.19, P = 0.017) and HbA1c (r = 0.19, P = 0.019). Multivariate regression analysis identified prediabetes as the only independent predictor of in-hospital MACE. CONCLUSIONS: Prediabetes is common in patients presenting with ACS who are not previously known to have diabetes. Prediabetic patients had worse in-hospital clinical outcomes compared with patients without diabetes. PMID- 25443456 TI - Interventional radiologic management and treatment of enterocutaneous fistulae. AB - Enterocutaneous fistulae (ECFs) are abnormal sinus tract communications between the alimentary system and skin surface that can cause significant management problems and cost to the health care system. Interventional radiology can play an important role in diagnosis and treatment when conventional measures fail and additional surgery is difficult or poses a high risk. The management of patients with fistulae requires operator ingenuity and dedication, a multidisciplinary team approach, and an understanding of the pathophysiology. This article reviews the major issues in ECF management and the role of interventional radiology. PMID- 25443455 TI - Suicidal Behavior in Relatives or Associates Moderates the Strength of Common Risk Factors for Suicide. AB - The prevalence and odds ratios of different suicide risk factors were compared in three pairs of decedents: 80 suicides and 25 injury decedents with blood relatives with suicidal behavior history (biologically exposed); 259 suicides and 126 injury decedents with unrelated acquaintances with suicidal behavior history (socially exposed); and 471 suicides and 523 injury decedents with neither relatives nor acquaintances with suicidal behavior history (unexposed). Negative life events and high psychological stress were more common in socially exposed suicides than in other suicides. The adjusted odds ratios of most established suicide risk factors were higher in unexposed decedents than in biologically or socially exposed decedents, suggesting that the predictive value of established risk factors wanes in individuals who have been exposed to suicidal behavior in family or friends. PMID- 25443457 TI - Combination radiofrequency ablation and local injection of the immunostimulant bacillus Calmette-Guerin induces antitumor immunity in the lung and at a distant VX2 tumor in a rabbit model. AB - PURPOSE: To evaluate whether the combination of radiofrequency (RF) ablation and local injection of the immunostimulant Mycobacterium bovis bacillus Calmette Guerin (BCG) induces systemic antitumor immunity. MATERIALS AND METHODS: Japanese White rabbits with lung and auricle VX2 tumors were randomized into three groups: control (n = 8; no treatment), RF ablation only (n = 8; RF ablation to the lung tumor), and RF ablation with local BCG injection into the lung tumor (n = 8). Treatments were performed 1 week after tumor implantation. Survival was evaluated with Kaplan-Meier method and log-rank test. Weekly mean volume and specific growth rate (SGR) of auricle tumors were calculated, and comparisons were made by Mann-Whitney test. RESULTS: Median survival of control, RF-only, and RF/BCG groups were 23, 41.5, and 103.5 days, respectively. Survival was significantly prolonged in the RF-only and RF/BCG groups compared with the control group (P = .034 and P =.003, respectively), but no significant difference was found between the RF-only and RF/BCG groups (P = .279). Only in the RF/BCG group was mean auricle tumor volume decreased 5 weeks after implantation. No significant difference in SGR was found between the control and RF-only groups (P = .959), but SGR in the RF/BCG group was significantly lower than in the control group (P = .005). CONCLUSIONS: The combination of RF ablation and local injection of BCG resulted in distant tumor suppression compared with the control group, whereas RF ablation alone did not produce this effect. Therefore, the combination of RF ablation and local injection of BCG may induce systemic antitumor immunity. PMID- 25443458 TI - [Descemet's stripping automated endothelial keratoplasty (DEAEK). Systematic review of clinical-effectiveness and safety]. AB - OBJECTIVE: To conduct a systematic review of the efficacy/effectiveness, safety and cost of Descemet's stripping automated endothelial keratoplasty (DSAEK) technique in patients with corneal endothelial failure. METHODS: Comprehensive literature search conducted in the main biomedical databases from January-May 2012. RESULTS: Following a critical perusal of the total of 485 abstracts retrieved, 16 case series and one economic evaluation study were included. Corrected distance visual acuity and uncorrected distance visual acuity improved after treatment with DSAEK, attaining values of 0.6 to 0.8 and 0.5 respectively. The degree of post-DSAEK astigmatism was not significant with respect to baseline values. The main complications were graft dislocation-detachment (1.5-23%), primary failure (0-12%) and endothelial rejection (0.8-8.5%). CONCLUSIONS: In Fuchs' dystrophy and bullous keratopathy, data on the effectiveness of DSAEK indicate post-intervention improvement in uncorrected and corrected distance visual acuity. Astigmatism arising after DSAEK was not significant. The most significant post-DSAEK complications are linked to the viability of the graft, with the most frequent complications being dislocation-detachment and, to a lesser extent, endothelial rejection. The studies that assess DSAEK are case series, and for the most part retrospective. The quality of this type of studies is both low and limited. PMID- 25443459 TI - [Subthreshold laser for active central serous chorioretinopathy]. PMID- 25443460 TI - [Optic neuropathy in a case of recurrent idiopathic hypertrophic pachymeningitis unresponsive to steroids and immunosuppressants]. AB - CASE REPORT: A 38-year-old female patient with bilateral papilledema who presented with loss of vision in her left eye. The Magnetic Resonance Imagining (MRI) showed thickening of the dura mater, and the intracranial pressure was elevated. A cancer, infectious, and autoimmune origin was ruled out. DISCUSSION: The initial response to high doses of corticoids was satisfactory, with disappearance of the optic disc enema, with visual acuity and an improvement in the MRI. However, after one year without treatment she had a new outbreak of the disease. Despite renewed treatment with corticoids and azathioprine, the patient developed a left optic neuropathy and irreversible visual loss. PMID- 25443461 TI - [Comparison study on the efficacy and safety of bevacizumab versus mitomycin C as adjuvants in trabeculectomy]. AB - OBJECTIVE: The objective of this study is to compare the efficacy and safety of bevacizumab versus mitomycin C as an adjuvant anti-scarring agent in Trabeculectomy. METHODS: A prospective, comparative, non-randomized, interventional study was conducted on a case series. A total of 49 eyes of 45 patients with uncontrolled glaucoma were recruited: 22 eyes in the bevacizumab (BVZ) group, and 27 eyes in the mitomycin C (MMC) group. Complete success was defined as intraocular pressure (IOP) less than 18 mmHg without any antiglaucoma medications. Follow-up visits were made on 1, 7, 30, 90 and 180 days after the surgery. Visual acuity, mean IOP, number of antiglaucoma medications and additional procedures to control IOP were recorded at each follow up visit. Local and systemic complications were also noted. RESULTS: At the end of the follow-up there were no significant differences in mean IOP between groups: mean IOP was 13.4 +/- 3.5mmHg (range 8-20) in the BVZ group and 11.6 +/- 2.6 mmHg (range 7-17) in the MMC group (P=.08). Complete success was achieved in 77.2% (17 out of 22) in the BVZ group and 96.2% (26 out of 27) in the MMC group, which was a statistically significant difference (P=.024). More patients required antiglaucoma medications to control IOP in the BVZ group at the end of the study: 0.36 +/- 0.72 medications versus 0.03 +/- 0.19 medications in the MMC group (P=.018). Three patients developed avascular cystic blebs in the BVZ group. None of the patients suffered any ocular or systemic complications related to the use of these agents. CONCLUSION: Bevacizumab could be a safe and effective anti scarring agent; however IOP reduction appears to be greater with MMC, and also less antiglaucoma medications are needed with this anti-scarring agent. Bevacizumab could favor the formation of avascular cystic blebs. PMID- 25443462 TI - [Correlating cup-to-disc ratios measured by HRT-III, SD-OCT and the new color imaging Laguna ONhE procedure]. AB - OBJECTIVE: To examine correlations between cup-to-disc (C/D) ratios determined by the new Laguna ONhE (optic nerve hemoglobin) color imaging procedure, spectral domain optical coherence tomography (OCT), confocal scanning laser tomography using Heidelberg retina tomography (HRT), and examining retinal images. METHODS: C/D ratio measurements were made on 154 eyes of 154 subjects (52 healthy controls, 36 with ocular hypertension and 66 with primary open-angle glaucoma) using the Laguna ONhE, HRT-III (Heidelberg Engineering) and OCT Spectralis (Heidelberg Engineering) instruments and photographs of the optic disc were examined by a blinded observer (experienced glaucoma specialist). RESULTS: Global intraclass correlation coefficients (ICC) were: 0.379 (95% CI: 0.233-0.508) for Laguna ONhE-HRT, 0.621 (95% CI: 0.513-0.709) for Laguna ONhE-OCT, and 0.558 (95% CI: 0.398-0.678) for the Laguna ONhE-observer, indicating significant agreement in each case (P<.001). The highest ICC was recorded for OCT- observer (0.715; 95% CI: 0.605-0.795). CONCLUSIONS: C/D ratios measured using the Laguna ONhE procedure correlated well with OCT measurements and retinography measurements made by an experienced observer. Best correlation was observed for OCT versus observer measurements. Agreement was good between the Laguna ONhE, OCT and observer measurements, and was somewhat lower between HRT and the remaining procedures. PMID- 25443463 TI - [Posterior capsule opacification, capsular bag distension syndrome, and anterior capsular phimosis: A retrospective cohort study]. AB - OBJECTIVE: To determine the incidence and the risk factors involved in the development of the three main postoperative capsular complications: posterior capsule opacification (PCO), capsular bag distension syndrome (CBDS), and anterior capsular phimosis syndrome (ACP). SUBJECTS, MATERIAL AND METHODS: A retrospective cohort study was conducted on 801 patients submitted to cataract surgery in the ophthalmology unit of Hospital del Henares (Madrid) from March 2, 2009 to February 28, 2010. Computerized clinical charts were reviewed during July 2012. PCO was studied using the Kaplan-Meier method (log rank test). RESULTS: A total of 167 patients developed PCO. No association could be demonstrated between PCO and age, sex, diabetes mellitus, phaco technique, IOL model, tamsulosin intake, glaucoma, and age-related macular degeneration. Three patients developed CBDS, all of them have received and Akreos Adapt AO((r)) (Bausch & Lomb). Two of them were young men who had received surgery for posterior subcapsular cataracts. Three patients developed ACP, 2 of whom had received a MicroSlim((r)) IOL (PhysIOL). CONCLUSIONS: No association was found between PCO and any of the studied variables. Male gender, young age, subcapsular cataract and large non angulated lens such as Akreos Adapt AO((r)) could be associated with CBDS. ACP could be more frequent when microincision IOLs (like MicroSlim((r))) are implanted. PMID- 25443464 TI - [Use of intracameral triamcinolone in pediatric cataract surgery. Diagnostic and therapeutic usefulness]. PMID- 25443465 TI - [Intraoperative floppy iris syndrome after treatment with duloxetine: coincidence, association, or causality?]. AB - CASE REPORT: The case is presented of a severe Intraoperative Floppy Iris Syndrome (IFIS) in a patient that had been treated with duloxetine. DISCUSSION: Tamsulosin is the main etiological agent involved in IFIS. However several cases of IFIS, supposedly secondary to drugs of different groups have recently been reported in the literature. The authors use this case report as a means to discuss why most of these cases should be considered anecdotal evidence. PMID- 25443466 TI - Association between childhood atopic dermatitis, malnutrition, and low bone mineral density: a US population-based study. AB - BACKGROUND: Children with atopic dermatitis (AD) have multiple risk factors for low bone mineral density (BMD). METHODS: We analyzed data from 3049 children and adolescents aged 8-19 yrs from the 2005-2006 National Health and Nutrition Examination Survey, including a cross-sectional questionnaire, dual energy X-ray absorptiometry, and blood samples. RESULTS: In multivariate models that controlled for age, sex, race/ethnicity, level of education and household income, body mass index (BMI), and smoking in the household, AD was associated with lower BMD z-score for the total femur (survey linear regression; adjusted beta [95% CI]: -0.42 [0.68, -0.16]), including trochanter (-0.29 [-0.54, -0.05]) and femoral neck (-0.29 [-0.53, -0.05]) and total lumbar spine (-0.31 [-0.52, 0.11]). Children with AD had higher median levels of serum IgE (110.0 vs. 53.0 kU/l), peripheral lymphocyte (2.9 vs. 2.5 * 10(3) cells/MUl), and eosinophil counts (0.3 vs. 0.2 * 10(3) cells/MUl) (Mann-Whitney U-test, p <= 0.003 for all), but not CRP levels (0.03 vs. 0.04 mg/dl) and higher odds of 25-OH vitamin D deficiency (survey logistic regression; odds ratio [OR] [95% CI]: 4.81 [1.21, 20.81]), low calcium (2.56 [1.24, 5.28]), low alkaline phosphatase (2.56 [1.20, 5.44]), and higher tertiles of LDH (tertile 2: 6.36 [1.75, 23.18]; tertile-3: 4.57 [1.32, 15.85]), but not parathyroid hormone (PTH) or albumin. Finally, children with AD had higher rates of low BMD, that is, BMD z-score <-2, of the femur (23.4% vs. 18.4%) and spine (35.3% vs. 24.5%). In multivariate logistic regression models of low BMD of femur and/or spine using stepwise selection of the 30 sociodemographic and clinical factors, laboratory values, and medications used, AD remained a significant covariate (1.33 [1.32-1.34]). The covariates with the largest effects on low BMD were low PTH and albumin, higher basophil count, Hispanic ethnicity, and BMI <5th percentile. Among children with AD, 56.2% of those with Hispanic origin, 52.8% with BMI <5th percentile, 75.0% with low albumin, and 54.0% with low PTH had low BMD. CONCLUSIONS: Children with AD have lower BMD, particularly those with malnutrition and Hispanic ethnicity. PMID- 25443467 TI - [Contraception in breastfeeding women: place for spermicides]. AB - Any contraceptive method prescribed to a breastfeeding woman should be not only adapted to her physiological condition after delivery and to the health of her newborn, but should also meet her expectations. According to the French guidelines, combined hormonal contraception is prohibited up to 6 weeks after delivery in breastfeeding women and is not recommended within 6 months. Intrauterine devices and oral progestin alone may be utilized only from the fourth week after delivery. Spermicides have a privileged indication in breastfeeding women. Indeed, they have no restriction in national and international guidelines. In France, spermicides primarily include myristalkonium chloride and benzalkonium chloride that does not pass into maternal milk according Liebert. In addition to their safe use, the lubricant effect of some specialties can be useful. Spermicides can be used in combination with a condom as well as with the lactational amenorrhea method. The acceptability and success of spermicides in breastfeeding woman depends largely on the information of users, their motivation and understanding of the conditions of use. PMID- 25443468 TI - Research on expression and importance of p53, p16 and VEGF-C in cervical cancer. AB - OBJECTIVE: To investigate the expression of p53, p16(INK4A) and VEGF-C proteins in cervical cancer and their clinical importance. METHODS: The expression of p53, p16(INK4A) and VEGF-C proteins in 125 cases of cervical sections were detected by two-step immunohistochemical EnVision method, and analyzed combined with the clinical and pathological data. RESULTS: (1) The positive expression rates of p53, p16(INK4A) and VEGF-C proteins were 56.8%, 95.2% and 88%, respectively. (2) The positive expression rate of p53 protein was 75% in lymph node metastasis positive cases and 48.24% in lymph node metastasis-negative cases (P<0.05). The presence of difference for positive significant p53 in squamous cell carcinoma and adenocarcinoma is intensively large (P<0.01), but its expression is not much influenced by age, degree of differentiation, parametric infiltration, vascular metastasis or clinical staging (P>0.05). (3) The p16(INK4A) expression in squamous cell carcinoma is 95.65%, and it is 93.94% in adenocarcinoma, the differential expression rates bears no statistically significant, but the strong expression of squamous cell carcinoma covers 55.43% of the total number of squamous cell carcinoma, while only 15.15% rates in adenocarcinoma (P<0.01). The p16(INK4A) protein expression was not significantly correlated to age, histological type, degree of differentiation, lymph node metastasis, parametric infiltration, vascular metastasis or clinical staging (P>0.05). (4) Among the cases of lymph node metastasis, there were 100% of VEGF-C-positive expression and 82.35% of VEGF-C-negative expression, and the difference was significant (P<0.05). Among the cases of vasculature-positive samples of cervical cancer, there were 98.4% of VEGF-C-positive expression; while among the vasculature negative samples of cervical cancer, there were 76.27% of VEGF-C-positive expression; the difference was significant (P<0.01). VEGF-C protein expression was not significantly correlated to age, histological type, degree of differentiation, parametric infiltration or clinical staging (P>0.05). CONCLUSIONS: The expression of some immune enzymes in cervical cancer has a reference value for early diagnosis and prognosis of cervical cancer, and has a certain guiding significance for development of the treatment program. However, a larger sample is needed for supporting the research of its significance. PMID- 25443469 TI - Glutathione S-transferase M1 polymorphism and endometriosis susceptibility: a meta-analysis. AB - BACKGROUND: Many studies have investigated the association between glutathione S transferase M1 (GSTM1) null genotype and the risk of endometriosis. However, the effect of the GSTM1 null genotype on endometriosis is still unclear because of apparent inconsistencies among those studies. A meta-analysis was performed to characterize the relationship more accurately. PubMed, Embase, and Web of Science were searched. OBJECTIVE: To derive a more precise estimation of the relationship, a meta-analysis was performed. METHODS: We estimated the summary odds ratio (OR) with a 95% confidence interval (95% CI) to assess the association. Up to 24 case-control studies with 2,684 endometriosis cases and 3,119 control cases were included into this meta-analysis. RESULTS: Meta-analysis of the 24 studies showed that GSTM1 null genotype was associated with the risk of endometriosis (random effects OR=1.66, 95% CI 1.23 to 2.24). In the subgroup analysis by ethnicity, increased risks were found for both Caucasians (OR=1.26, 95% CI 1.04-1.51) and Asians (OR=1.28, 95% CI 1.06-1.55). No evidence of publication bias was observed. CONCLUSION: In conclusion, this meta-analysis suggests that the GSTM1 null genotype increases the overall risk of endometriosis. PMID- 25443471 TI - The p.Gly622Asp (G622D) mutation, frequently found in Reunion Island and in black populations, is associated with a wide spectrum of CF and CFTR-RD phenotypes. AB - Examination of genotype-phenotype correlations along with functional evaluation of CFTR mutations may not be straightforward. The c.1865G>A, p.Gly622Asp (G622D), located at the NBD1 C terminus of the CFTR protein, was initially reported in patients with male infertility. However, the substitution of Gly622 by an aspartic acid in vitro would perturb the local structure or even affect the CFTR folding itself. In order to determine whether p.Gly622Asp affects the risk of developing a CFTR-Related disorder (CFTR-RD) or cystic fibrosis (CF), we analyzed the phenotype of subjects bearing the p.Gly622Asp mutation. We report molecular and clinical analyses in eleven unrelated patients with CF or CFTR-RD with compound heterozygosity for the p.Gly622Asp mutation. On the basis of the clinical features presented by the eleven patients, we postulate that the p.Gly622Asp might be associated with a wide spectrum of phenotypes including classical cystic fibrosis. PMID- 25443474 TI - Future plans for the NHS. PMID- 25443473 TI - Initial evaluation of the Parent Cystic Fibrosis Questionnaire--Revised (CFQ-R) in infants and young children. AB - BACKGROUND: There is an urgent need to evaluate treatments for young children with cystic fibrosis (CF); however, efforts have been hampered by a lack of reliable, practical endpoints. To examine whether a patient-reported outcome could be reliable in children 4 to 60 months of age, we assessed the psychometric properties of the modified Parent Cystic Fibrosis Questionnaire--Revised (CFQ-R) using data from the Infant Study of Inhaled Saline (ISIS). We also characterized patterns of symptom presentation and daily functioning in children in this age range to inform future measure development. METHODS: Parents (N=314) completed the CFQ-R and Treatment Adherence Questionnaire (TAQ) at five quarterly visits, as well as a weekly Parent Symptom Diary. RESULTS: The Parent CFQ-R demonstrated good construct validity and adequate internal consistency (alpha's .58-.75). Associations with age, TAQ, and Parent Symptom Diary were observed. The Treatment Burden scale demonstrated responsiveness to change. CONCLUSIONS: Parents were reliable observers of young children's symptoms and daily functioning, and PROs show promise for this age group. Research is needed to identify key symptoms in infants and young children with CF, and to develop a parent proxy PRO according to FDA/EMA guidelines. PMID- 25443472 TI - Pseudomonas aeruginosa in CF and non-CF homes is found predominantly in drains. AB - BACKGROUND: For patients with cystic fibrosis (CF) Pseudomonas aeruginosa infection is a major contributor to progressive lung disease. While colonizing strains are thought to be primarily environmental, which environments are important in lung colonization is unclear. METHODS: We took 11,674 samples from a broad range of sites over 3-8 visits to homes with (7) and without (8) CF patients. RESULTS: Twenty-eight percent of sampled drains yielded P. aeruginosa at least once, and a general mixed linear model estimated that 6.3% of samples from drains yield P. aeruginosa. This is more than eight times the estimated recovery from any other type of household environment. CONCLUSIONS: These findings implicate drains as important potential sources of P. aeruginosa infection. They suggest that maximizing P. aeruginosa control efforts for drains would reduce exposure with minimal extra burden to CF patients and families. PMID- 25443475 TI - WHO AFRO: in need of new leadership. PMID- 25443476 TI - Violence against children in Cambodia: breaking the silence. PMID- 25443477 TI - A future vision for the NHS: the case for change. PMID- 25443478 TI - The RCP's five-point plan for the next UK Government. PMID- 25443480 TI - David Napier: cultivating the role of culture in health. PMID- 25443481 TI - Emerging arboviruses in the Pacific. PMID- 25443482 TI - The COPSI Trial: additional fidelity testing needed. PMID- 25443483 TI - Continued child survival gains will require societal change. PMID- 25443484 TI - The COPSI Trial: additional fidelity testing needed - Authors' reply. PMID- 25443485 TI - Survival in acute myocardial infarction - Authors' reply. PMID- 25443486 TI - Survival in acute myocardial infarction. PMID- 25443487 TI - Save a Child's Heart project in Israel. PMID- 25443488 TI - Bridging medical education and clinical practice. PMID- 25443489 TI - E-cigarettes in the UK: a more inclusive debate is needed. PMID- 25443491 TI - Never say never: unexpected herpes lymphadenitis. PMID- 25443490 TI - Culture and health. PMID- 25443492 TI - NAIP inflammasomes give the NOD to bacterial ligands. AB - NLRs are innate immune sensors that monitor the sanctity of the cytosolic compartment. In a recent paper in Molecular Cell, Tenthorey et al. reveal a novel ligand-sensing interface within regions of the oligomerization domain of the NAIPs, rather than within the leucine-rich repeats, as was anticipated. PMID- 25443493 TI - Serum amyloid A proteins take retinol for a ride. AB - Vitamin A plays pleiotropic roles in the immune system. A recent eLife paper by Hooper and colleagues shows that hepatic and intestinal serum amyloid A proteins, which are induced in response to infection, can transport vitamin A metabolites to tissues and thus impact immune responses both locally and systemically. PMID- 25443495 TI - Tertiary lymphoid structures in cancer and beyond. AB - Tertiary lymphoid structures (TLS) are ectopic lymphoid formations found in inflamed, infected, or tumoral tissues. They exhibit all the characteristics of structures in the lymph nodes (LN) associated with the generation of an adaptive immune response, including a T cell zone with mature dendritic cells (DC), a germinal center with follicular dendritic cells (FDC) and proliferating B cells, and high endothelial venules (HEV). In this review, we discuss evidence for the roles of TLS in chronic infection, autoimmunity, and cancer, and address the question of whether TLS present beneficial or deleterious effects in these contexts. We examine the relationship between TLS in tumors and patient prognosis, and discuss the potential role of TLS in building and/or maintaining local immune responses and how this understanding may guide therapeutic interventions. PMID- 25443496 TI - Impact of PET reconstruction algorithm and threshold on dose painting of non small cell lung cancer. AB - PURPOSE: In the current work, we investigate the impact of PET reconstruction methods (RMs) and threshold on two types of dose painting (DP) prescription strategies for non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Sixteen patients with NSCLC underwent an 18F-FDG-PET/CT examination prior to radiotherapy. Six different RMs were used. For both a dose painting by contours (DPBC) and a dose painting by numbers (DPBN) strategy, the prescribed radiation dose within the gross tumor volume (GTV) was mapped according to the spatial distribution of standardized uptake values (SUVs). SUVmax and SUVpeak were used for volume thresholding in DPBC and a linear SUV-dose scaling approach was used for DPBN. Deviations from the dose prescription as determined by the standard RM was scored by a quality factor (QF). RESULTS: For DPBC, the mean difference in thresholded boost volume between RMs was typically within 10%. The difference in dose prescription was systematically lower for thresholding based on SUVpeak (largest mean QF 2.8+/-2.0%) compared to SUVmax (largest mean QF 3.6+/-3.0%). For DPBN, the resulting dose prescriptions were less dependent on RM and threshold; the largest mean QFs were 1.3+/-0.3% both for SUVmax and SUVpeak. CONCLUSIONS: PET reconstruction algorithms will both influence DPBC and DPBN, although the impact is smaller for DPBN. For some patients, the resulting variations in dose prescriptions may result in clinically different dose distributions. SUVpeak is a more robust thresholding parameter than SUVmax. PMID- 25443494 TI - Epigenomic regulation of host-microbiota interactions. AB - The trillions of beneficial commensal microorganisms that normally reside in the gastrointestinal tract have emerged as a critical source of environmentally derived stimuli that can impact health and disease. However, the underlying cellular and molecular mechanisms that recognize commensal bacteria-derived signals and regulate mammalian homeostasis are just beginning to be defined. Highly coordinated epigenomic modifications allow mammals to alter the transcriptional program of a cell in response to environmental cues. These modifications may play a key role in regulating the dynamic relationship between mammals and their microbiota. We review recent advances in understanding the interplay between the microbiota and mammalian epigenomic pathways, and highlight emerging findings that implicate a central role for histone deacetylases (HDACs) in orchestrating host-microbiota interactions. PMID- 25443497 TI - Externally validated HPV-based prognostic nomogram for oropharyngeal carcinoma patients yields more accurate predictions than TNM staging. AB - PURPOSE: Due to the established role of the human papillomavirus (HPV), the optimal treatment for oropharyngeal carcinoma is currently under debate. We evaluated the most important determinants of treatment outcome to develop a multifactorial predictive model that could provide individualized predictions of treatment outcome in oropharyngeal carcinoma patients. METHODS: We analyzed the association between clinico-pathological factors and overall and progression-free survival in 168 OPSCC patients treated with curative radiotherapy or concurrent chemo-radiation. A multivariate model was validated in an external dataset of 189 patients and compared to the TNM staging system. This nomogram will be made publicly available at www.predictcancer.org. RESULTS: Predictors of unfavorable outcomes were negative HPV-status, moderate to severe comorbidity, T3-T4 classification, N2b-N3 stage, male gender, lower hemoglobin levels and smoking history of more than 30 pack years. Prediction of overall survival using the multi-parameter model yielded a C-index of 0.82 (95% CI, 0.76-0.88). Validation in an independent dataset yielded a C-index of 0.73 (95% CI, 0.66-0.79. For progression-free survival, the model's C-index was 0.80 (95% CI, 0.76-0.88), with a validation C-index of 0.67, (95% CI, 0.59-0.74). Stratification of model estimated probabilities showed statistically different prognosis groups in both datasets (p<0.001). CONCLUSION: This nomogram was superior to TNM classification or HPV status alone in an independent validation dataset for prediction of overall and progression-free survival in OPSCC patients, assigning patients to distinct prognosis groups. These individualized predictions could be used to stratify patients for treatment de-escalation trials. PMID- 25443498 TI - Improving the intra-fraction update efficiency of a correlation model used for internal motion estimation during real-time tumor tracking for SBRT patients: fast update or no update? AB - BACKGROUND AND PURPOSE: For tumor tracking, a correlation model is used to estimate internal tumor position based on external surrogate motion. When patients experience an internal/external surrogate drift, an update of the correlation model is required to continue tumor tracking. In this study, the accuracy of the internal tumor position estimation for both the clinical available update at discrete points in time (rebuild) and an in-house developed non-clinical online update approach was investigated. METHODS: A dynamic phantom with superimposed baseline drifts and 14 SBRT patients, treated with real-time tumor tracking (RTTT) on the Vero system, were retrospectively simulated for three update scenarios, respectively no update, clinical rebuild and 0.5 Hz automated online update of the correlation model. By comparing the target positions based on 0.5 Hz verification X-ray images with the estimated internal tumor positions regarding all three update scenarios, 95th percentile modeling errors (ME95), incidences of full geometrical coverage of the CTV by a 5 mm extended PTV (P5mm) and population-based PTV margins were calculated. Further, the treatment time reduction was estimated when switching from the clinical rebuild approach to the online correlation model update. RESULTS: For dynamic phantom motion with baseline drifts up to 0.4 mm/min, a 0.5 Hz intra-fraction update showed a similar accuracy in terms of ME95 and P5 mm compared to clinical rebuild. For SBRT patients treated on Vero with RTTT, accuracy was improved by 0.5 Hz online update compared to the clinical rebuild protocol, yielding smaller PTV margins (from 3.2 mm to 2.7 mm), reduced ME95,3D (from 4.1 mm to 3.4 mm) and an increased 5th percentile P5 mm (from 90.7% to 96.1%) for the entire patient group. Further, 80% of treatment sessions were reduced in time with on average 5.5 +/- 4.1(1 SD)min. CONCLUSION: With a fast (0.5 Hz) automated online update of the correlation model, an efficient RTTT workflow with improved geometrical accuracy was obtained. PMID- 25443499 TI - Neoadjuvant chemoradiation with IMRT in resectable and borderline resectable pancreatic cancer. AB - PURPOSE: Neoadjuvant chemoradiation is an alternative to the surgery-first approach for resectable pancreatic cancer (PDA) and represents the standard of care for borderline resectable (BLR). MATERIALS AND METHODS: All patients with resectable and BLR PDA treated with neoadjuvant chemoradiation using IMRT between 1/2009 and 11/2011 were reviewed. Patients were treated to a customized CTV which included the primary mass and regional vessels. RESULTS: Neoadjuvant chemoradiation was completed in 69 patients (39 BLR and 30 resectable). Induction chemotherapy was used in 32 (82%) of the 39 patients with BLR disease prior to chemoXRT. All resectable patients were treated with chemoXRT alone. Following neoadjuvant treatment, 48 (70%) of the 69 patients underwent successful pancreatic resection with 47 (98%) being margin negative (RO). In 30 of the BLR patients who had arterial abutment or SMV occlusion, 19 (63%) were surgically resected and all had RO resections. The cumulative incidence of local failure at 1 and 2 years was 2% (95% CI 0-6%) and 9% (95% CI 0.6-17%) respectively. The median overall survival for all patients, patients undergoing resection, and patients without resection were 20, 26 and 11 months respectively. Sixteen (23%) of the 69 patients are alive without disease with a median follow-up of 47 months (36-60). CONCLUSION: Neoadjuvant chemoXRT can facilitate a margin negative resection in patients with localized PCa. PMID- 25443500 TI - Development of a multivariable normal tissue complication probability (NTCP) model for tube feeding dependence after curative radiotherapy/chemo-radiotherapy in head and neck cancer. AB - BACKGROUND AND PURPOSE: Curative radiotherapy/chemo-radiotherapy for head and neck cancer (HNC) may result in severe acute and late side effects, including tube feeding dependence. The purpose of this prospective cohort study was to develop a multivariable normal tissue complication probability (NTCP) model for tube feeding dependence 6 months (TUBEM6) after definitive radiotherapy, radiotherapy plus cetuximab or concurrent chemoradiation based on pre-treatment and treatment characteristics. MATERIALS AND METHODS: The study included 355 patients with HNC. TUBEM6 was scored prospectively in a standard follow-up program. To design the prediction model, the penalized learning method LASSO was used, with TUBEM6 as the endpoint. RESULTS: The prevalence of TUBEM6 was 10.7%. The multivariable model with the best performance consisted of the variables: advanced T-stage, moderate to severe weight loss at baseline, accelerated radiotherapy, chemoradiation, radiotherapy plus cetuximab, the mean dose to the superior and inferior pharyngeal constrictor muscle, to the contralateral parotid gland and to the cricopharyngeal muscle. CONCLUSIONS: We developed a multivariable NTCP model for TUBEM6 to identify patients at risk for tube feeding dependence. The dosimetric variables can be used to optimize radiotherapy treatment planning aiming at prevention of tube feeding dependence and to estimate the benefit of new radiation technologies. PMID- 25443502 TI - Sporicides for Clostridium difficile-do they do what it says on the tin? PMID- 25443501 TI - Peritumoral interstitial fluid flow velocity predicts survival in cervical carcinoma. AB - BACKGROUND AND PURPOSE: High tumor interstitial fluid pressure (IFP) is associated with poor outcome in locally advanced carcinoma of the uterine cervix. We have recently developed a noninvasive assay of the IFP of tumors, and in this assay, the outward interstitial fluid flow velocity at the tumor surface (v0) is measured by Gd-DTPA-based DCE-MRI and used as a parameter for IFP. Here, we investigated the independent prognostic significance of v0 in cervical cancer patients given cisplatin-based concurrent chemoradiotherapy with curative intent. PATIENTS: The study involved 62 evaluable patients from a cohort of 74 consecutive patients (Stage IB through IIIB) with a median follow-up of 5.5 years. RESULTS: The actuarial disease-free survival (DFS) and overall survival (OS) at 5 years were 67% and 76%, respectively. Significant associations were found between v0 dichotomized about the median value and DFS and OS, both in the total patient cohort and a subcohort of 40 Stage IIB patients. Multivariate analysis involving stage, tumor volume, lymph node status, and v0 revealed that only v0 provided independent prognostic information about DFS and OS. CONCLUSION: This investigation demonstrates a strong, independent prognostic impact of the pretreatment peritumoral fluid flow velocity in cervical cancer. PMID- 25443503 TI - IL-27 and IL-27-producing CD4+ T cells in human tuberculous pleural effusion. AB - The objective of the present study was to figure out whether human IL-27 producing CD4(+) T cells represent a distinct T cell subset in tuberculosis pleural effusion (TPE). Distribution, phenotypic features of IL-27-producing CD4(+) T cells in TPE were determined. The required transcription factors and signal transductions for IL-27-producing CD4(+) T cell differentiation were explored. The immune regulation of IL-27 on pleural mesothelial cells was observed. We have determined the presence of a subset of human Th cells that infiltrated into tuberculous pleural effusion, which was characterized by the secretion of IL-27, and somehow IFN-gamma, but not of IL-4, IL-9, IL-17, or IL 22. These IL-27-producing CD4(+) T cells were effector memory cells and exhibited a transcription profile clearly separated from those of Th2, Th17, Th9, and Th22 cells. The in vitro experiments showed that IL-1beta, IL-2 and IL-12, or their various combinations could promote IL-27(+)CD4(+) T cell differentiation from naive CD4(+) T cells by means of phosphorylation of STAT3, STAT4, or/and STAT5. Transcription factors c-Fos and T-bet were required for IL-27(+)CD4(+) T cell differentiation. By activating STAT3 signaling, IL-27 not only restored a clear epithelial phenotype of pleural mesothelial cells, but also further reversed IFN gamma-induced epithelial-mesenchymal transition of pleural mesothelial cells. These data suggested that human IL-27(+)CD4(+) T cells might represent a distinct human T cell subset with unique expression profiles of transcription factors and proinflammatory cytokines, and these IL-27(+)CD4(+) T cells may play important roles in tuberculosis immunity by affecting pleural mesothelial cells. PMID- 25443505 TI - The knee anterolateral ligament. PMID- 25443504 TI - Characterisation of a putative AraC transcriptional regulator from Mycobacterium smegmatis. AB - MSMEG_0307 is annotated as a transcriptional regulator belonging to the AraC protein family and is located adjacent to the arylamine N-acetyltransferase (nat) gene in Mycobacterium smegmatis, in a gene cluster, conserved in most environmental mycobacterial species. In order to elucidate the function of the AraC protein from the nat operon in M. smegmatis, two conserved palindromic DNA motifs were identified using bioinformatics and tested for protein binding using electrophoretic mobility shift assays with a recombinant form of the AraC protein. We identified the formation of a DNA:AraC protein complex with one of the motifs as well as the presence of this motif in 20 loci across the whole genome of M. smegmatis, supporting the existence of an AraC controlled regulon. To characterise the effects of AraC in the regulation of the nat operon genes, as well as to gain further insight into its function, we generated a DeltaaraC mutant strain where the araC gene was replaced by a hygromycin resistance marker. The level of expression of the nat and MSMEG_0308 genes was down-regulated in the DeltaaraC strain when compared to the wild type strain indicating an activator effect of the AraC protein on the expression of the nat operon genes. PMID- 25443506 TI - Sham surgery studies. PMID- 25443507 TI - Editors' reply. PMID- 25443508 TI - Authors' reply. PMID- 25443509 TI - The incidence of DVT. PMID- 25443510 TI - Bilateral ossification of the auricular cartilage. PMID- 25443511 TI - Medication therapy management programs: promises and pitfalls. AB - BACKGROUND: Medication therapy management (MTM) is one form of a medication benefit program offered by public and private health providers and insurers. Although the term was first coined in 2003, MTM in its earlier forms has been used since the 1990s as a mechanism to improve health metrics for medically complex patients. Its role expanded with the passage of Medicare Part D, as a mandated component to help patients with multiple chronic conditions, high drug costs, and high utilization to improve the effectiveness and safety of their medication treatments. OBJECTIVE: To review the evidence on MTM effectiveness in order to (a) provide information on its establishment and goals and (b) summarize research findings under 3 outcomes: economic, clinical, and humanistic. METHODS: PubMed, a search engine service of the National Center for Biotechnology Information was utilized by trained research assistants to search for articles with the following key words: MTM, randomized controlled trials on MTM, evaluation of MTM, comprehensive medication review, medication action plan, special needs population, special needs plans, Medicaid, disease management, adherence, non-adherence, compliance, chronic conditions, disabling chronic conditions, and disability. Additional searches were conducted for key articles in references listed in the most recent review articles. The initial search identified nearly 300 articles. RESULTS: When evaluated, most studies found economic benefits, but the quality of research design and end point measures varied considerably across evaluations. Clinical outcomes encompassed a wide range of potential metrics, from service utilization, to individual patient and population outcomes, and quality of care. Quality measures such as provider prescribing habits and medication adherence were frequently found to improve. As noted with the economic outcomes studies, overall rigor of study design was suboptimal, and often underpowered. Few studies have focused on humanistic outcomes such as improved patient quality of life. CONCLUSIONS: Evidence suggests that MTM services are a promising way to manage complex patients, but there are gaps in the literature largely because of the limited number of studies with strong designs. Stronger evaluation of MTM programs is warranted. PMID- 25443512 TI - Sterile compounding: clinical, legal, and regulatory implications for patient safety. AB - BACKGROUND: Poor compounding practices by the New England Compounding Center resulted in the 2012-2013 fungal infections outbreak. Contaminated injectable methylprednisolone led to the diagnosis of fungal infections in 751 patients and 64 deaths. In the United States, pharmacy compounding has traditionally been regulated by state boards of pharmacy rather than the FDA. To minimize safety risks related to pharmacy compounding, the Drug Quality and Security Act (DQSA) was signed into law November 27, 2013, to improve regulation of compounding pharmacies. OBJECTIVES: To (a) review the literature regarding clinical, legal, and regulatory implications of pharmacy compounding for patient safety during the 2012-2013 fungal infections outbreak and (b) discuss strategies that managed care organizations (MCOs) can use to promote safe compounding practices. METHODS: A literature search was conducted via PubMed for original articles on fungal infections related to drug compounding published October 2012 to March 2014. Specific search terms included "drug compounding and fungal infection" and "fungal meningitis outbreak." The FDA website was also utilized for material related to the Food, Drug, and Cosmetic Act and the DQSA. RESULTS: Four articles met inclusion criteria. The 2012-2013 fungal infections outbreak was attributed to 3 lots of preservative-free methylprednisolone acetate, which comprised 17,675 vials distributed to 76 facilities across 23 states. Median incubation period (from time of last injection to initial diagnosis) was 47 days, ranging from 0 to 249 days. According to the FDA, a total of 30 recalls regarding compounded products were issued by pharmacies during March through December 2013. CONCLUSIONS: Pharmacy compounding has the potential for significant safety risks. The purpose of the DQSA is to improve regulation of compounding pharmacies. Since registration as an outsourcing facility is voluntary, uncertainty still remains regarding advancement in safe compounding practices. MCOs can employ multiple strategies to ensure patient safety and promote appropriate drug therapy. PMID- 25443513 TI - Evaluation of an integrated adherence program aimed to increase Medicare Part D star rating measures. AB - BACKGROUND: The Centers for Medicare Medicaid Services (CMS) Plan Quality and Performance Program, or Star Ratings Program, allows Medicare beneficiaries to compare quality of care among available Medicare Advantage prescription drug (MA PD) plans and stand-alone prescription drug plans (PDPs). Health plans have increased intervention efforts and applied existing care management infrastructure as an approach to improving member medication adherence and subsequent Part D star rating performance. Independent Care Health Plan (iCare), an MA-PD plan; MedImpact Healthcare Systems, Inc. (MedImpact), a pharmacy benefits manager; and US MED, a mail order pharmacy, partnered to engage and enroll iCare's dual-eligible special needs population in an intervention designed to improve patient medication adherence and health plan performance for 3 Part D patient safety outcome measures: Medication Adherence for Oral Diabetes Medications (ODM), Medication Adherence for Hypertension (HTN), and Medication Adherence for Cholesterol (CHOL). OBJECTIVES: To (a) assess the effectiveness of a coordinated member-directed medication adherence intervention and (b) determine the overall impact of the intervention on adherence rates and CMS Part D star rating adherence measures. METHODS: Administrative pharmacy claims and health plan eligibility data from MedImpact's databases were used to identify members using 3 target medication classes. Adherence was estimated by the proportion of days covered (PDC) for all members. Those members considered at high risk for nonadherence were prioritized for care management services. Risk factors were based on members' use of more than 1 target medication class, newly started therapy, and suboptimal adherence (PDC less than 80%) in the most recent 6 month period. Data files listing member adherence rates and contact information were formatted and loaded monthly into iCare's care management system, which triggered an alert for care coordinators to counsel members on the importance of adherence and offer the members an option for monthly 30-day supply medication delivery via US MED. Member adherence rates were calculated 9 months pre- and postimplementation for all members and adjusted by length of member enrollment based on CMS technical specifications. Regression analysis assessed pre-post changes in rates comparing 2 intervention groups: (1) members receiving iCare counseling only (iCare-only) and (2) members receiving counseling and medication delivery (iCare + US MED). To evaluate the overall impact of the intervention, iCare's adherence rates and iCare's measure-specific star ratings for the 2011 and 2012 calendar years (CMS measurement years) were compared with the national MA-PD plan contract average and with a health plan similar in member characteristics but without adherence intervention exposure. RESULTS: A total of 2,700 members were initially targeted for referral to iCare care management and US MED customer service specialist teams. Between April 2012 (implementation date) and January 2013, 1,302 (48.2%) members enrolled in the US MED component of the intervention. Seventy-six percent of identified members were nonadherent (PDC less than 80%) to 1 of the 3 target medication classes, and 32% of members were nonadherent to more than 1 target medication class. Pre-post absolute average adherence rates increased for the iCare-only group (ODM = 15.1, HTN = 10.1, CHOL = 13.6) and the iCare-US MED group (ODM = 30.9, HTN = 25.5, CHOL = 29.4). From 2011 to 2012, iCare adherence rates increased by absolute differences of 15.2, 9.2, and 10.1 percentage points for ODM, HTN, and CHOL measures, respectively, compared with the average MA-PD plan contract differences (1.1, 2.1, and 2.5) and the comparator health plan differences (-2.7, -1.4, and -4.1). Increases in iCare's adherence rates were associated with significant increases in iCare's 2014 adherence measure star ratings (1 star to 3 stars for ODM and CHOL, 1 star to 2 stars for HTN), which contributed to increases in the Drug Plan Quality Improvement measure (2 stars to 4 stars) and iCare's overall Part D star rating (3 to 3.5 stars). CONCLUSIONS: Members in this MA-PD plan dual-eligible population benefited from multiple points of contact to achieve increased adherence. Health plans can use network pharmacies, care management staff, and their pharmacy benefits managers to collaborate and implement interventions aimed to improve members' adherence to targeted maintenance medications and overall health plan quality performance and star ratings. PMID- 25443514 TI - Geospatial analysis of statin adherence using pharmacy claims data in the state of Michigan. AB - BACKGROUND: Research has demonstrated that variation in availability and utilization of health care resources exist on a range of scales, from regions of the United States, hospital referral regions, ZIP codes, and census tracts. Limited research using spatial analyses has found that variation in medication adherence exists across census tracts. Using spatial analysis, researchers may be able to effectively analyze geographically dispersed data to determine whether factors such as sociodemographics, local shared beliefs and attitudes, barriers to access such as availability of prescribers or pharmacies, or others are associated with variations in medication adherence in a defined geographic area. OBJECTIVES: To (a) demonstrate that medication adherence may be mapped across an entire state using medication possession ratios and (b) determine whether a geographic pattern of adherence to statins could be identified at the ZIP code level for members of a statewide insurer. METHODS: This study utilized pharmacy claims data from a statewide insurer. Insured statin users were aged greater than 30 years, had at least 1 statin prescription, and were continuously enrolled for the observation year. Patient medication possession ratios (MPR) were derived, which were then aggregated as a mean MPR for each ZIP code. ZIP codes were categorized as higher (MPR greater than 0.80) or lower (MPR less than 0.80) adherence and mapped using Arc GIS, a platform for designing and managing solutions through the application of geographic knowledge. Analysis included a determination of whether the MPRs of higher and lower adherence ZIP codes were significantly different. Hot spot analysis was conducted to identify clustering of higher, midrange, and lower adherent ZIP codes using the GetisORD Gi* Statistic. This test provides z-scores and P values to indicate where features with either high or low values cluster spatially. MPRs for these 3 categories were compared using one-way analysis of variance (ANOVA). RESULTS: Of 1,154 Michigan ZIP codes, 907 were represented by 212,783 insured statin users. The mean statin MPR by ZIP code was 0.79 +/- 0.4. The mean MPR for higher adherent ZIP codes was 0.83 +/- 0.03 and 0.76 +/- 0.03 for lower adherent ZIP codes (P less than 0.001). Significant clustering of ZIP codes by adherence levels was evident from the hot spot analysis. The mean MPR was 0.84 +/- 0.04 for high adherence areas, 0.79 +/- 0.03 for midrange areas, and 0.74 +/- 0.04 for lower adherent areas (overall P less than 0.001). CONCLUSIONS: Significant variations in adherence exist across ZIP codes at a state level. Future research is needed to determine locally relevant factors associated with this finding, which may be used to derive locally meaningful interventions. PMID- 25443515 TI - Magnitude of pharmacological nonadherence in hypertensive patients taking antihypertensive medication from a community pharmacy in Spain. AB - BACKGROUND: The most common factor associated with poor control of hypertension is treatment nonadherence to antihypertensive drug therapy. OBJECTIVE: To measure drug nonadherence and associated factors in pharmacologically treated hypertensive patients. METHODS: A prospective observational study was carried out from March 2007 to August 2009 at a community pharmacy in Spain. A pharmacist invited a convenience sample of hypertensive patients aged 50 years and older taking antihypertensive medication for at least 3 months prior to participate in the study. Drug nonadherence was analyzed by 3 separate methods: pill count, as the gold standard method, and Haynes-Sackett and Morisky-Green questionnaires. A descriptive analysis of drug nonadherence and variables associated with nonadherence was performed. Logistic regression models were used to determine the variables associated with nonadherence. RESULTS: Data were recorded from 419 patients. The drug nonadherence ratio varied depending on the method used: 62.8% by pill count, 3.1% by the Haynes-Sackett self-report test, and 36% according to the Morisky-Green test. In the multivariate model, the variable associated with a decrease in drug nonadherence was years of known hypertension (OR = 0.962, 95% CI = 0.937-0.988), and the variables associated with an increase in drug nonadherence were loose-pill combination therapy versus fixed-dose combination therapy or monotherapy (OR = 4.099, 95% CI = 2.494-6.757) and good perception of quality of life (OR = 1.276, 95% CI = 1.109-1.471). CONCLUSIONS: The magnitude of drug nonadherence varies depending on the method of measurement. The pill count method (reference method) revealed that 2 out of 3 patients with hypertension did not have good adherence. This study highlights the lack of antihypertensive drug adherence and the pharmacist's ability to detect the associated factors in order to find the best way to deal with nonadherence. PMID- 25443516 TI - Impact of specialty pharmacy on telaprevir-containing 3-drug hepatitis C regimen persistence. AB - BACKGROUND: Although the recommended treatment of hepatitis C continues to evolve as newer and more effective medications are made available, hepatitis C drug regimens consisting of a 3-drug combination of a protease inhibitor, pegylated interferon, and ribavirin were recommended by the American Association for the Study of Liver Diseases for the HCV genotype I beginning in 2011. Although more effective than the earlier standard of care, these regimens have complex dosing schedules, prolonged duration, and deleterious side effects. It has been shown that patients tend to discontinue these regimens prematurely. Specialty pharmacies offer specialized care management programs to hepatitis C patients, consisting of such services as regularly scheduled patient counseling, assessing regimen appropriateness, monitoring treatment progress, scheduling refill reminders, and coordinating patient care with prescribers. The use of specialty pharmacies by hepatitis C patients may improve persistence on the 3-drug hepatitis C regimens. OBJECTIVE: To examine the association of pharmacy dispensing channel (specialty pharmacy or retail pharmacy) and hepatitis C regimen persistence among patients on a 3-drug hepatitis C regimen containing telaprevir, a widely used hepatitis C protease inhibitor. METHODS: A retrospective, observational study was conducted using pharmacy claims data from a national pharmacy benefits manager for the period July 2011 to June 2013. Continuously eligible patients who started a new 3-drug regimen containing telaprevir were included in the study and followed for up to 12 months after the index hepatitis C claim. The study outcome was persistence to the 3-drug regimen at treatment week 24 (day 168), representing the completion of an important milestone in the regimen. Patients were defined as persistent if they filled 84 days' supply of telaprevir and 168 days' supply of pegylated interferon and ribavirin each, as required by the regimen protocol. Multivariate logistic regression was used to evaluate the association between dispensing channel and persistence, controlling for differences in demographics, medication burden, out of-pocket spend per 30-day adjusted hepatitis C prescription, and average days' supply per unadjusted hepatitis C prescription. RESULTS: The final study sample consisted of 1,475 patients-1,182 in the specialty pharmacy group and 293 in the retail pharmacy group. A significantly greater proportion of patients were persistent to the 3-drug hepatitis C regimen containing telaprevir in specialty pharmacy, compared with retail pharmacy (56.0% vs. 39.9%, P less than 0.001). After multivariate adjustment, patients in the specialty pharmacy group had 1.89 times greater odds of being persistent to 3-drug hepatitis C regimens containing telaprevir compared with patients in the retail group (95% CI=1.44-2.48). CONCLUSIONS: Patients who used a specialty pharmacy offering refill reminders, care management, and care coordination with prescribers were significantly more likely to be persistent to 3-drug hepatitis C regimens, compared with patients using a retail pharmacy. PMID- 25443517 TI - Treatment patterns and annual drug costs of biologic therapies across indications from the Humana commercial database. AB - BACKGROUND: A variety of biologic therapies are currently used for the treatment of inflammatory autoimmune diseases, including rheumatoid arthritis (RA), psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). These diseases require long-term treatment, and information regarding the use and costs of biologic therapies can be valuable in making treatment and formulary decisions for clinicians and payers. OBJECTIVE: To evaluate current utilization and annual costs of biologic therapies for treatment of RA, PsO, PsA, and AS in a real-world setting. METHODS: This retrospective observational cohort analysis utilized data from the Humana commercial claims database. Eligible patients had an index (first) claim between February 1, 2008, and September 30, 2011, for abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, or ustekinumab and a diagnosis of RA, PsO, PsA, AS, or combination of these diseases. Patients with and without a claim for their index therapy within 180 days prior to their index dates were defined as continuing and new patients, respectively. Outcomes included 1-year rates of persistence; rates of restarting, discontinuing, or switching for patients who were not persistent; and annual costs. Costs were based on dose and the October 2013 wholesale acquisition cost (WAC). Total expenditure was calculated as the (total index biologic drug utilization * WAC) + (number of administrations * Medicare fee schedule) + Sigma(biologic dose after discontinuation * associated WAC price). RESULTS: Of 2,721 patients analyzed, 1,308 (48%) were new patients, and 1,413 (52%) were continuing patients. Across approved indications, the most commonly used biologics were adalimumab, etanercept, and infliximab. Continuing patients had higher rates of persistence on index therapy than new patients. The mean annual cost [SD] per treated patient for new patients across all indications was numerically lowest for adalimumab ($20,916 [$7,572]), followed by infliximab ($22,516 [$8,460]) and etanercept ($23,567 [$8,314]). The mean annual cost [SD] per treated patient for continuing patients across all indications was numerically lowest for etanercept ($21,508 [$6,769]), followed by infliximab ($22,852 [$11,674]) and adalimumab ($24,341 [$8,906]). CONCLUSIONS: The tumor necrosis factor blockers adalimumab, etanercept, and infliximab were the most commonly used biologics across indications. New patients were less persistent than those continuing on therapy. Among new patients, adalimumab had the lowest mean annual cost per treated patient, and etanercept had the lowest mean annual cost per treated patient among those continuing on therapy. PMID- 25443518 TI - Impact of an intravenous trimethoprim/sulfamethoxazole shortage on treatment outcomes among HIV-infected patients with Pneumocystis jirovecii pneumonia. AB - BACKGROUND: Trimethoprim/sulfamethoxazole (TMP/SMX) is the recommended first-line treatment for human immunodeficiency virus (HIV)-infected patients with Pneumocystis jirovecii pneumonia (PJP).However, in June 2010, the lone manufacturer of intravenous (IV) TMP/SMX in the United States stopped production of this medication. OBJECTIVES: To (a) evaluate the impact of the national IV TMP/SMX shortage on PJP treatment outcomes between 2 groups of HIV-infected patients-those treated before the shortage and those after the shortage-and (b) compare the length of hospital stay (LOS) and PJP treatment used before and after the shortage. METHODS: A retrospective, quasi-experimental study examining 2 groups of HIV-infected adult patients with PJP was performed at an academic medical center from September 1, 2008, to June 30, 2012. Patients treated when IV TMP/SMX was available, or preshortage (PRE), were compared with patients treated when IV TMP/SMX was not available, or postshortage (POST).PRE included patients treated between September 1, 2008, and May 30, 2010, and POST included patients treated between June 1, 2010, and June 30, 2012. RESULTS: Thirty-six patients were included in the study, 18 in each group. Treatment failure, the primary outcome, included mortality or worsening clinical status (WCS) after at least 5 days of therapy. Three patients in PRE (16.7%) and 6 patients in POST (33.3%) experienced treatment failure (P = 0.248). No patients in PRE and 3 patients in POST (16.7%) experienced WCS (P = 0.035). Three patients in each group expired.In POST, 5 of the 6 treatment failures (83.3%) occurred during the first 6 months of the shortage. Median (interquartile range) LOS was 11 days (7-17) in PRE and 14 days (5-22) in POST (P = 0.800).In PRE, 7 patients (38.9%) were initiated on oral PJP treatment compared with 13 (72.2%) in POST (P = 0.042). CONCLUSIONS: The national shortage of IV TMP/SMX may have led to an immediate but temporary negative impact on treatment outcomes among HIV-infected patients with PJP at an academic medical center.Pharmacist collaboration with physicians may have helped mitigate the impact of this drug shortage on patient outcomes. PMID- 25443519 TI - Retrograde intrarenal surgery with holmium-YAG laser lithotripsy in the primary treatment of renal lithiasis. AB - INTRODUCTION: retrograde intrarenal surgery (RIRS) appears as a safe and effective technique as well as a good therapeutic alternative to extracorporeal shock wave lithotripsy (ESWL) and percutaneous nephrolithotomy (PNL). MATERIAL AND METHODS: descriptive study in 50 patients surgically treated between November 2012 and April 2013. Demographic, operative and postoperative data as well as early and late complications data were collected. The minimum follow-up of patients was one year. Surgery was performed under general anesthesia. Flexible ureteroscopy with ureteral access sheath and laser fragmentation were employed. Surgery success was defined as stone free rate in postoperative control test and at three months after surgery (simple radiography, abdominal ultrasound or CT without contrast). RESULTS: mean age was 51.1+/-15.5 years old. The highest frequency location was the lower calyceal group (26%), single stones were described in 58% of patients whilst multiple lithiasis were found in the 42%. Regarding the stone burden in 44% of the patients was low (<2 cm), and high (>3 cm) in 22% of the patients. The stone clearance rate was 89.7+/-17.5. Average surgery time was 96.6+/-35.2min. Complications were reported in 4 patients (8%), all of them early ones and minor in nature. CONCLUSIONS: RIRS is an effective and safe option whose results are comparable to ESWL and PCNL. RIRS can be considered as first-line treatment. These results are corroborated by numerous studies. To strengthen these findings, prospective studies focusing on quality of life, length of stay, complications and cost-effectiveness of different treatments are needed. PMID- 25443520 TI - Micro-ureteroscopy: Initial experience in the endoscopic treatment of pelvic ureteral lithiasis. AB - OBJECTIVES: To present to report the first case of ureteral lithiasis resolved using a new endoscopic approach, which we call microureteroscopy (m-URS) and attempts to reduce the ureteral damage caused by conventional instrumentation. MATERIAL AND METHODS: We selected a 53-year-old patient with a 16-mm calculus in the right distal ureter. For endoscopic access, we used a 4.8 Fr sheath from the microperc set and fragmented the stone with a 230-micron laser fiber. RESULTS: Complete fragmentation of the stone was achieved. We placed a JJ catheter due to significant ureteral edema. The surgical time and postsurgical stay were 156minutes and 24hours, respectively. There were no complications, the requirements for analgesia were minimal, and the patient was free of residual stones. CONCLUSIONS: The m-URS technique is feasible, simple and effective for the treatment of pelvic ureteral lithiasis in women and optimizes minimal invasion, with results that can be comparable to conventional endoscopic techniques in terms of ease of access and quality of endoscopic vision without affecting the resolution capacity. Larger studies and greater technological development is needed to define the definitive role of this procedure. Currently, its major limitations lie in the treatment of proximal ureter lithiasis and in the treatment of men. This technique could also be a viable alternative for pediatric patients. PMID- 25443521 TI - Comment to: "Efficacy and safety of fosfomycin-trometamol in the prophylaxis for transrectal prostate biopsy. Prospective randomized comparison with ciprofloxacin". PMID- 25443522 TI - Acute carotid artery occlusion. PMID- 25443524 TI - Update on screening for abdominal aortic aneurysm: a topical review. AB - OBJECTIVES: Serving as the basis for implementation of several national AAA screening programmes, four large randomised controlled trials provided evidence of a reduction in AAA mortality by ultrasound-based screening among elderly men. Recently, reports of falling AAA prevalence and mortality unrelated to AAA screening have emerged, coinciding with major additional epidemiological changes in the population, as well as improvements in AAA repair. These recent changes may individually, and in concert, affect the rationality of AAA screening. The aim of this paper was to present an up-to-date review of AAA-screening within the context of a rapidly changing AAA epidemiology. METHODS: Topical review of the literature focusing mainly on randomised controlled trials, meta-analyses, and contemporary observational AAA-screening studies. CONCLUSIONS: Summarising RCT results and recent studies; contemporary one-time screening of men for AAA appears highly cost-effective, and seems to remain an effective preventive health measure. However, several issues regarding screening need to be addressed: most importantly; the current degree of incidental detection of AAAs, the threshold diameter for follow-up, targeted screening in risk groups, and the possible need for re-screening in an elderly population with ever increasing longevity. PMID- 25443525 TI - Abdominal aortic diameter is increased in males with a family history of abdominal aortic aneurysms: results from the Danish VIVA-trial. AB - OBJECTIVE: To investigate, at a population level, whether a family history of abdominal aortic aneurysm (AAA) is independently related to increased aortic diameter and prevalence of AAA in men, and to elucidate whether the mean aortic diameter and the prevalence of AAA are different between participants with male and female relatives with AAA. DESIGN: Observational population-based cross sectional study. MATERIALS: 18,614 male participants screened for AAA in the VIVA trial 2008-2011 with information on both family history of AAA and maximal aortic diameter. METHODS: Standardized ultrasound scan measurement of maximum antero posterior aortic diameter. Family history obtained by questionnaire. Multivariate regression analysis was used to test for confounders: age, sex, smoking, comorbidity and medication. RESULTS: From the screened cohort, 569 participants had at least one first degree relative diagnosed with AAA, and 38 had AAA. Participants with a family history of AAA (+FH) had a significantly larger mean maximum aortic diameter (20.50 mm) compared with participants without family history of AAA (-FH) (19.07 mm, p < .0001), and +FH with female relatives with AAA had significantly larger mean maximum aortic diameter (21.8 mm) than +FH with male relatives (19.9 mm, p = .007). Furthermore the prevalence of AAA was significantly higher among +FH (6.7%) compared with -FH (3.0%) with an odds ratio (OR) of 2.2 (95% CI: 1.6 to 3.2, p < .001) and +FH with female relatives with AAA had a more than two and a half times increased prevalence of AAA compared with +FH with male relatives with AAA with an OR of 2.65. CONCLUSIONS: First-degree male relatives of AAA patients have wider aortas and a twofold higher prevalence of AAA compared with the age adjusted background population. The prevalence of AAA was markedly higher in participants related to female, rather than male, patients with AAA. PMID- 25443523 TI - Editor's choice - Safety of carotid endarterectomy after intravenous thrombolysis for acute ischaemic stroke: a case-controlled multicentre registry study. AB - OBJECTIVE: Few studies have been published on the safety of carotid endarterectomy (CEA) after intravenous thrombolysis (IVT). Registry reports have been recommended in order to gather large study groups. DESIGN: A retrospective, registry based, case controlled study on prospectively gathered data from Sweden, the capital region of Finland, and from Denmark, including 30 days of follow up. METHODS: The study group was a consecutive series of 5526 patients who had CEA for symptomatic carotid artery stenosis during a 4.5 year period. Among these, 202 (4%) had IVT prior to surgery, including 117 having CEA within 14 days, and 59 within 7 days of thrombolysis. IVT as well as CEA were performed following established guidelines. The median time from index symptom to CEA was 12 days (range 0-130, IQR 7-21). RESULTS: The 30 day combined stroke and death rate was 3.5% (95% CI 1.69-6.99) for those having IVT + CEA, 4.1% (95% CI 3.46-4.39) for those having CEA without previous IVT (odds ratio 0.84 [95% CI 0.39-1.81]), 3.4% (95% CI 1.33-8.39) for those having IVT + CEA within 14 days, and 5.1% (95% CI 1.74-13.91) for those having IVT + CEA within 7 days. CONCLUSION: Data on the time from symptoms to CEA in patients not having IVT, Rankin score, degree of stenosis, and cerebral imaging were not available. Despite its weaknesses, this study reasserts that CEA can be performed within the recommended 2 weeks of the onset of symptoms and IVT without increasing the risk of peri-operative stroke or death. Centres and vascular registries are recommended to continue monitoring changes in patient characteristics, lead times, and major complications after CEA in general, with a special focus on those who have undergone a prior thrombolysis. PMID- 25443526 TI - The Safe Environment for Every Kid (SEEK) Model: helping promote children's health, development, and safety: SEEK offers a practical model for enhancing pediatric primary care. PMID- 25443527 TI - Atypical hemolytic uremic syndrome: Korean pediatric series. AB - BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease with a genetic predisposition. Few studies have evaluated the disease in the Asian population. We studied a Korean pediatric cohort to delineate the clinical characteristics and genotypes. METHODS: A multicenter cohort of 51 Korean children with aHUS was screened for mutations using targeted exome sequencing covering 46 complement related genes. Anti-complement-factor-H autoantibody (anti CFH) titers were measured. Multiplex ligation-dependent probe amplification assay was performed to detect deletions in the complement factor-H related protein genes (CFHR) in the patients as well as in 100 healthy Korean controls. We grouped the patients according to etiology and compared the clinical features using Mann-Whitney U-test and chi-squared test. RESULTS: Fifteen patients (group A, 29.7%) had anti-CFH, and mutations were detected in 11 (group B, 21.6%), including one with combined mutations. The remaining 25 (group C, 49.0%) were negative for both. The prevalence of anti-CFH was higher than the worldwide level. Group A had a higher onset age than group B, although the difference was not significant. Group B had the worst renal outcome. Gene frequencies of homozygous CFHR1 deletion were 73.3%, 2.7% and 1% in group A, group B + C and the control, respectively. CONCLUSIONS: The incidence of anti-CFH in the present Korean aHUS cohort was high. Clinical outcomes largely conformed to the previous reports. Although the sample size was limited, this cohort provides a reassessment of clinicogenetic features of aHUS in Korean children. PMID- 25443529 TI - Long-term outcome of accelerated partial breast irradiation using a multilumen balloon applicator in a patient with existing breast implants. AB - PURPOSE: Accelerated partial breast irradiation is now an accepted component of breast-conserving therapy. However, data regarding long-term outcomes of patients treated with multilumen catheter systems who have existing breast implants are limited. METHODS AND MATERIALS: We report the treatment and outcome of our patient who had existing bilateral silicone subpectoral implants at the time of presentation. Ultrasound-guided core needle biopsy of the right breast showed infiltrating mucinous carcinoma. Right breast lumpectomy revealed an 8 mm area of infiltrating ductal carcinoma with mucinous features and nuclear grade 1. A 4-5 cm Contura (Bard Biopsy Systems, Tempe, AZ) device was placed, and she was treated over the course of 5 days twice daily to a dose of 34 Gy using a high dose-rate iridium-192 source. RESULTS: The planning target volume for evaluation was 73.9 cc. The percentage of the planning target volume for evaluation receiving 90%, 95%, and 100% of the prescribed dose was 99.9%, 99.3%, and 97.8%, respectively. The total implant volume was 234.5 cc and received a mean dose of 15.4 Gy and a maximum dose of 72.8 Gy. The percentage of implant volume receiving 50%, 75%, 100%, and 200% of the prescribed dose was 31.1%, 16.5%, 8.6%, 2.0%, and 0%, respectively. Maximum skin dose was 97% of the prescribed dose. With a followup of nearly 5 years, she continues to be cancer free with minimal late toxicities and good to excellent cosmetic outcome. CONCLUSIONS: Accelerated partial breast irradiation using a multilumen balloon applicator in patients with existing breast implants can safely be performed with excellent long-term cosmetic outcome. Further studies are needed to establish the absolute dosimetric tolerance of breast implants. PMID- 25443528 TI - Cost-effectiveness analysis of 3D image-guided brachytherapy compared with 2D brachytherapy in the treatment of locally advanced cervical cancer. AB - PURPOSE: Three-dimensional image-guided brachytherapy (IGBT) is a significant advance in locally advanced cervical cancer treatment. However, its cost effectiveness (C/E) is unknown. We performed a C/E analysis of IGBT compared with conventional (two-dimensional [2D]) brachytherapy in the treatment of locally advanced cervical cancer. METHODS AND MATERIALS: A Markov model was constructed to model locally advanced cervical cancer treated with five fractions of high dose-rate brachytherapy. The model captured clinical parameters, quality of life utility, and treatment costs through the literature review. Costs were 2013 Medicare reimbursement. Strategies were compared using the incremental cost effectiveness ratio (ICER), and effectiveness was measured in quality-adjusted life-years (QALYs). To account for uncertainty, one-way, two-way, and probabilistic sensitivity analyses were performed. Strategies were evaluated from a payer's perspective with a willingness-to-pay threshold of $50,000/QALY gained. RESULTS: Treatment costs for five fractions of IGBT and 2D brachytherapy were $21,374 and $17,931, respectively. In the base-case analysis, the IGBT strategy costs $3003 more than 2D brachytherapy while gaining 0.16 QALYs, resulting in an ICER of $18,634 per QALY gained. In one-way sensitivity analyses, results were most sensitive to variation of treatment costs, but the ICER remained <$50,000/QALY gained for all cost ranges. Variation of survival, local control, and complication rates was less influential. A probabilistic sensitivity analysis demonstrated that IGBT was favored in 63% of model iterations at a $50,000/QALY gained threshold. CONCLUSION: IGBT for locally advanced cervical cancer is a C/E option compared with 2D brachytherapy. These findings were robust to variation of parameter values supporting the routine use of IGBT in locally advanced cervical cancer. PMID- 25443531 TI - The new generation of learners. PMID- 25443530 TI - Salvage wide resection with intraoperative electron beam therapy or HDR brachytherapy in the management of isolated local recurrences of soft tissue sarcomas of the extremities and the superficial trunk. AB - PURPOSE: To assess the toxicity and efficacy of salvage wide resection (SWR) with intraoperative electron beam radiation therapy (IOERT) or perioperative high-dose rate brachytherapy (PHDRB) in previously unirradiated patients (PUP) vs. previously irradiated patients (PIP) with isolated local recurrence of soft tissue sarcomas (STS) of the extremities and the superficial trunk. METHODS AND MATERIALS: PUP received SWR and IOERT/PHDRB with external beam radiation therapy. PIP received SWR and IOERT/PHDRB only. RESULTS: Fifty patients were analyzed retrospectively. PUP (n = 24; 48%) received IOERT (n = 13) or PHDRB (n = 11). PIP (n = 26; 52%) received IOERT (n = 10) or PHDRB (n = 16). Reintervention because of complications was not required in PUP. Nine of 26 (34%) PIP required reintervention (p = 0.01). After a median followup of 3.7 years (range, 0.2 18.3), the 5-year rates of locoregional control, distant control, and overall survival were 54%, 66%, and 56%, respectively. Five-year locoregional control was higher in PUP than in PIP (81% vs. 26%, p = 0.01) and in the extremity locations compared with trunk locations (68% vs. 28%, p = 0.001). Five-year overall survival was superior in unifocal vs. multifocal presentations (70% vs. 36%, p = 0.03) and for tumor sizes <4 vs. >=4 cm (74% vs. 50%, p = 0.05). CONCLUSIONS: Prior irradiation is the main determinant of locoregional control in patients with isolated local recurrence of STS. The locoregional control rates in PUP were similar to those described in primary STS. In PIP, SWR + IOERT/PHDRB reirradiation yielded modest locoregional control rates and was associated with significant morbidity, especially in PHDRB cases. PMID- 25443532 TI - The importance of adding a dedicated study of congenital heart disease to the cardiac sonographer curriculum. PMID- 25443533 TI - Travel grants encourage vascular ultrasound practitioners. PMID- 25443534 TI - On feature extraction and classification in prostate cancer radiotherapy using tensor decompositions. AB - External beam radiotherapy is commonly prescribed for prostate cancer. Although new radiation techniques allow high doses to be delivered to the target, the surrounding healthy organs (rectum and bladder) may suffer from irradiation, which might produce undesirable side-effects. Hence, the understanding of the complex toxicity dose-volume effect relationships is crucial to adapt the treatment, thereby decreasing the risk of toxicity. In this paper, we introduce a novel method to classify patients at risk of presenting rectal bleeding based on a Deterministic Multi-way Analysis (DMA) of three-dimensional planned dose distributions across a population. After a non-rigid spatial alignment of the anatomies applied to the dose distributions, the proposed method seeks for two bases of vectors representing bleeding and non bleeding patients by using the Canonical Polyadic (CP) decomposition of two fourth order arrays of the planned doses. A patient is then classified according to its distance to the subspaces spanned by both bases. A total of 99 patients treated for prostate cancer were used to analyze and test the performance of the proposed approach, named CP-DMA, in a leave-one-out cross validation scheme. Results were compared with supervised (linear discriminant analysis, support vector machine, K-means, K-nearest neighbor) and unsupervised (recent principal component analysis-based algorithm, and multidimensional classification method) approaches based on the registered dose distribution. Moreover, CP-DMA was also compared with the Normal Tissue Complication Probability (NTCP) model. The CP-DMA method allowed rectal bleeding patients to be classified with good specificity and sensitivity values, outperforming the classical approaches. PMID- 25443535 TI - Operational challenges of retinal prostheses. AB - Two computational models for research on retinal implants are presented. In the first model, the electric field produced by a multi-electrode array in a uniform retina is calculated. It is shown how cross talk of activated electrodes and the resulting bunching of field lines in monopole and dipole activation prevent high resolution imaging with retinal implants. Furthermore, it is demonstrated how sequential stimulation and multipolar stimulation may overcome this limitation. In the second model a target volume, i.e., a probe cylinder approximating a bipolar cell, in the retina is chosen, and the passive Heaviside cable equation is solved inside this target volume to calculate the depolarization of the cell membrane. The depolarization as a function of time indicates that shorter signals stimulate better as long as the current does not change sign during stimulation of the retina, i.e., mono-phasic stimulation. Both computational models are equally applicable to epiretinal, subretinal, and suprachoroidal vision implants. PMID- 25443537 TI - Cohort studies of aetiology and prognosis: they're different. PMID- 25443536 TI - Wiener filtering of surface EMG with a priori SNR estimation toward myoelectric control for neurological injury patients. AB - Voluntary surface electromyogram (EMG) signals from neurological injury patients are often corrupted by involuntary background interference or spikes, imposing difficulties for myoelectric control. We present a novel framework to suppress involuntary background spikes during voluntary surface EMG recordings. The framework applies a Wiener filter to restore voluntary surface EMG signals based on tracking a priori signal to noise ratio (SNR) by using the decision-directed method. Semi-synthetic surface EMG signals contaminated by different levels of involuntary background spikes were constructed from a database of surface EMG recordings in a group of spinal cord injury subjects. After the processing, the onset detection of voluntary muscle activity was significantly improved against involuntary background spikes. The magnitude of voluntary surface EMG signals can also be reliably estimated for myoelectric control purpose. Compared with the previous sample entropy analysis for suppressing involuntary background spikes, the proposed framework is characterized by quick and simple implementation, making it more suitable for application in a myoelectric control system toward neurological injury rehabilitation. PMID- 25443538 TI - Lead, cadmium, arsenic and mercury in canned tuna fish marketed in Tehran, Iran. AB - Fifty-four canned tuna fish samples corresponding to 10 widely used different brands were purchased from local markets in Tehran, Iran during 2012-2013 and analysed on heavy metals. Mercury was determined by a direct mercury analyser without any sample preparation. For analysis of other elements samples were digested using a microwave apparatus. Lead and cadmium were determined by graphite furnace atomic absorption spectrometry and arsenic via hydride vapour generation. All samples had arsenic and mercury contamination. Arsenic levels showed a range of 0.25-1.42 mg kg(-1), which might be due to lack of national and international limits for arsenic in canned tuna fish. Lead and cadmium were measured in a small number of samples with a mean of 0.053 +/- 0.058 mg kg(-1) and 0.013 +/- 0.015 mg kg(-1), respectively. Results obtained for these heavy metals in all samples were lower than the corresponding limits, whereas arsenic and mercury contents might raise some attention. PMID- 25443539 TI - [Portal thrombosis: beyond liver cirrhosis]. PMID- 25443540 TI - Visceral leishmaniasis as an unusual infectious complication in a patient with Crohn's disease treated with infliximab. PMID- 25443541 TI - [Approach to the diagnosis and treatment of chronic anemia secondary to gastrointestinal diseases]. AB - Iron deficiency anemia is the most common type of anemia and can cause asthenia, cognitive and functional impairment, and decompensation of underlying diseases. Iron deficiency anemia is not a disease but is the result of a potentially serious medical problem. Consequently, patients should always undergo investigation of the underlying cause. In men and postmenopausal women, the condition is caused by gastrointestinal loss and malabsorption of iron. In this group, recommended procedures are gastroscopy, colonoscopy and serological testing for celiac disease. If the results of these tests are negative, repeat examinations and iron therapy should be considered. In treatment-refractory or recurrent anemia, the small intestine should be investigated. In this case, the procedure of choice is capsule endoscopy. Iron deficiency anemia should always be treated until iron deposits have returned to normal levels. A wide variety of preparations are available, in both oral and parental formulations. PMID- 25443543 TI - To eat or not to eat-international experiences with eating during hemodialysis treatment. AB - Providing food or nutrition supplements during hemodialysis (HD) may be associated with improved nutritional status and reduced mortality; however, despite these potential benefits, eating practices vary across countries, regions, and clinics. Understanding present clinic practices and clinician experiences with eating during HD may help outline best practices in this controversial area. Therefore, the objective of this study was to examine clinical practices and experiences related to eating during HD treatment. We surveyed clinicians about their clinic practices during the 2014 International Society of Renal Nutrition and Metabolism Conference. We received 73 responses from six continents. Respondents were primarily dietitians (71%) working at units housed in a hospital (63%). Sixty-one clinics (85%) allowed patients to eat during treatment, with 47 of these patients (65%) actively encouraging eating. Fifty-three clinics (73%) provided food during HD. None of the nine clinics from North America, however, provided food during treatment. The majority (47 clinics; 64%) provided supplements during treatment. Clinics in the hospital setting were more likely to provide food during treatment, whereas outpatient clinics were less likely to provide nutrition supplements (P<= 0.05 for both). We also asked clinicians about their experience with six commonly cited reasons to restrict eating during treatment using a four-point scale. Clinicians responded they observed the following conditions "rarely" or "never": choking (98%), reduced Kt/V (98%), infection control issues (96%), spills or pests (83%), gastrointestinal issues (71%), and hypotension (62%). Our results indicate that while eating is common during treatment in some areas, disparities may exist in global practices, and most of the proposed negative sequelae of eating during HD are not frequently observed in clinical practice. Whether these disparities in practice can explain global differences in albumin warrants further research to help inform decisions regarding eating during HD. PMID- 25443542 TI - Recreational drug use and risks of HIV and sexually transmitted infections among Chinese men who have sex with men: Mediation through multiple sexual partnerships. AB - BACKGROUND: Recreational drug use (RDU) may result in sexual disinhibition and higher risk for HIV and other sexually transmitted infections (STIs) among men who have sex with men (MSM) in China. We assessed whether RDU was associated with HIV, syphilis, and herpes simplex virus type 2 (HSV-2) within the context of multiple sexual partnerships and unprotected sex. METHODS: We conducted a cross sectional study among sexually-active MSM in six Chinese cities (Kunming, Jinan, Changsha, Zhengzhou, Nanjing, and Shanghai) in 2012-2013. We interviewed participants regarding RDU and sexual activity and drew blood for HIV, syphilis, and HSV-2. We fit multiple logistic regression models to assess associations of drug use and HIV, syphilis and HSV-2 infections, controlling for number of sexual partners and unprotected sex. RESULTS: Of 3830 participants, 28% reported ever using >=1 of these drugs in the past 6 months: popper (alkyl nitrites), ecstasy, ice (methamphetamine), amphetamine, tramadol, and ketamine. In the past six months, 62% of MSM reported >=2 sexual partners and 76% did not use condoms at last sexual encounter. HIV, syphilis and HSV-2 prevalences were 9.2%, 12.2%, and 10.3%, respectively.RDU was associated with HIV infection (aOR = 1.67; 95% CI, 1.31-2.13). Men with RDU were more likely to report multiple sexual partners (OR = 1.69; 95% CI, 1.44-1.98) and unprotected sex (aOR = 1.25; 95% CI, 1.05-1.49). The RDU-HIV association persisted (aOR = 1.58; 95% CI = 1.23-2.02) after adjusting for numbers of partners. CONCLUSIONS: RDU was associated with multiple sexual partnerships, unprotected sex, and HIV among Chinese MSM. It is plausible that RDU is a driver of increased sexual/HIV risk and/or may be an associated behavior with sexually risky lifestyles. Community engagement is needed. PMID- 25443544 TI - Chronic kidney disease, frailty, and unsuccessful aging: a review. AB - The global prevalence of chronic kidney disease (CKD) is rising, particularly among the elderly population. Defining aging as successful or unsuccessful has become clinically relevant in the last 15 years, with an increased recognition of the frail phenotype. Frailty has been shown to be associated with CKD and poorer outcomes, such as death or dialysis. It is likely that the mechanisms of disease in CKD such as altered protein metabolism, inflammation, oxidative stress, and anemia accelerate normal aging and lead to worsening frailty in elderly patients with CKD. PMID- 25443545 TI - The National Kidney Foundation Council on Renal Nutrition addresses the Food and Drug Administration. AB - On July 24, 2014, the Food and Drug Administration (FDA) held an open forum to review proposed changes to the Nutrition Facts Label and to allow for public comment on these changes. Lisa Gutekunst, MSEd, RD, CSR, CDN, Chair of the National Kidney Foundation Council on Renal Nutrition, lobbied the FDA to add phosphorus to the Nutrition Facts Label. This is her address to the FDA. PMID- 25443546 TI - Addressing the FDA. PMID- 25443547 TI - Patient Education. The importance of exercise for chronic kidney disease patients. PMID- 25443548 TI - Incretin-based therapy and pancreatic beta cells. AB - Type 2 diabetes (T2D) is a complex, progressive disease with life-threatening complications and one of the most serious public-health problems worldwide. The two main mechanisms of T2D pathogenesis are pancreatic beta cell dysfunction and insulin resistance. It is now recognized that pancreatic beta cell dysfunction is a necessary factor for T2D development. Traditional therapies for controlling blood glucose are suboptimal as they fail to meet target goals for many patients. Glucagon-like peptide-1 receptor agonists (GLP1RA) and dipeptidyl peptidase-4 inhibitors (DPP4I) are an attractive class of therapy because they reduce blood glucose by targeting the incretin hormone system and, in particular, have the potential to positively affect pancreatic beta cell biology. This review outlines our current understanding of pancreatic beta cell incretin system dysfunction in T2D and summarizes recent evidence of the effect of incretin-based therapies on beta cell function and mass. Incretin-based therapies have shown strong evidence for beneficial effects on beta cell function and mass in animal studies. In humans, incretin-based therapies are effective glucose-lowering agents, but further study is still required to evaluate their long-term effects on beta cell function and safety as well as beta cell mass expansion. PMID- 25443552 TI - There is no credible rational for deep brain stimulation in very early Parkinson's disease! PMID- 25443551 TI - Three sib-pairs of autopsy-confirmed progressive supranuclear palsy. AB - OBJECTIVE: To describe the clinical, pathological, and genetic features of three sib-pairs of pathologically-confirmed progressive supranuclear palsy (PSP). METHODS: We searched the Mayo Clinic neurodegenerative diseases brain bank for cases of PSP in which more than one family member had pathologically-confirmed PSP. Clinical and pathological data were reviewed and all individuals were screened for mutations in MAPT, by sequencing exons 1, 7, and 9-13. RESULTS: We identified three sib-pairs of pathologically-confirmed PSP. Sufficient information was available to suggest an autosomal dominant inheritance in two. The mean age at symptom onset was 41 years in one pair, and 76 years in the other two. The young onset pair had a p.S285R mutation in MAPT, but no mutations were detected in the other two. CONCLUSIONS: All sib-pairs had typical pathological features of PSP; however, the age at onset of the sib-pair with MAPT mutation was significantly younger than sporadic PSP. Future studies are warranted to identify a possible genetic basis for PSP associated with late onset and typical PSP pathology. PMID- 25443553 TI - Entacapone, Parkinson's disease, "functional adrenergic denervation", and Takotsubo syndrome. PMID- 25443554 TI - Response to zolpidem in oromandibular dystonia: a case report. PMID- 25443555 TI - The effectiveness of cognitive treatment in patients with Parkinson's disease: a new phase for the neuropsychological rehabilitation. PMID- 25443556 TI - Opsoclonus-myoclonus-ataxia syndrome associated with dengue virus infection. PMID- 25443557 TI - Opsoclonus-myoclonus-ataxia syndrome associated with dengue. PMID- 25443558 TI - Wearing-off detection in clinical practice: the wearing off real practice key (WORK-PD) study in Parkinson's disease. AB - OBJECTIVE: Verifying the validity and feasibility of the WOQ-19 as a useful tool in routine clinical practice and in management of patients. METHODS: 532 consecutive Parkinson's disease (PD) patients were recruited from 6 different neurological outpatient units, specialized in movement disorders, of central Italy. Inclusion criteria were diagnosis of PD and any current pharmacological treatment of PD while exclusion criteria were evident cognitive or depressive impairment, infusion with dopamine agonists or Duodopa, or Deep Brain Stimulation therapy. Patients were asked to complete the Italian version of WOQ-19 before the neurological visit. A medical form for the collection of demographic and clinical data of patients and for the evaluation of comprehensibility and usability the WOQ-19 was filled by the neurologist during the visit. RESULTS: Our data confirmed that WOQ-19 was able to identify WO in 69% of patients, a percentage similar to the recently reported in the Italian WOQ-19 validation study. Motor symptoms were more frequent than non-motor symptoms (80% vs. 20%). Patients who experienced WO had a higher age of PD onset, more severe disease, longer disease duration and were more likely to be female. CONCLUSIONS: The WOQ-19 was understandable for the patient, easily administered and suitable for routine outpatient use. It could be also particularly useful in clinical practice in the early identification of non-motor symptoms, often under reported by patients and revealed only with clinical support. PMID- 25443561 TI - Usefulness of ultrasound in Jaccoud's arthropathy. A case report. PMID- 25443560 TI - New diagnostic criteria for fibromyalgia: Here to stay? AB - OBJECTIVES: To assess the percentage of patients that fulfill the American College of Rheumatology (ACR) 1990 as well as the ACR 2010 classification criteria, to evaluate whether there is a correlation between tender points and the Widespread Pain Index (WPI) as well as signs and symptoms that predict a fibromyalgia (FM) subtype and to identify those which have greater impact on functioning. MATERIALS AND METHODS: We performed a cross-sectional comparative study of 206 patients with previous clinical diagnosis of FM. The studied variables were age, sex, years of disease, tender points, control points, WPI, Symptom Severity Score, subtype of FM, presence of other rheumatic disorders and the Fibromyalgia Impact Questionnaire (FIQ) score. RESULTS: The new diagnostic criteria of FM correctly classified 87,03% of patients who satisfied the ACR 1990 criteria. Both criteria were equally effective in assessing the impact of the disease. FM had a severe impact on the quality of life in 74,87% of patients. Somatoform disorder was the predominant subtype. Hyperalgesic FM had a significantly lower FIQ score than the somatoform disorder and depressive subtypes. CONCLUSION: The ACR 2010 criteria are a simple evaluation tool to use in the primary care setting, that incorporate both peripheral pain and somatic symptoms. New and old criteria should coexist; they enable a major comprehension and ease the management of this prevalent disease. PMID- 25443562 TI - Does the lateral plate need to overlap the stem to mitigate stress concentration when treating Vancouver C periprosthetic supracondylar femur fracture? AB - The effect of construct length on cortical strain and load to failure between locked compression plating and cemented femoral stem in a fall model was analyzed. Eight Sawbone femurs with cemented stems were instrumented with increasing fixation lengths starting 8cm distal to stem tip and progressing proximally to overlapping constructs. Uniaxial strain gauges measured cortical strain. Load to failure was performed with 8cm gap between implants, 2cm gap, and proximally overlapping configurations. Strain was significantly reduced as the 8cm gap transitioned to an overlapped construct with most comparisons. Load to failure in the overlapped construct was 273% greater compared to 2cm gap construct. Overlapping the stem with a locking compression plate resulted in reduced strain and increased load to failure. PMID- 25443563 TI - Factors which affect use of breast conservation and mastectomy in an underinsured Hispanic population. AB - BACKGROUND: Despite no difference in overall survival between breast conservation and mastectomy, significant variation exists between institutions and within populations. Less data exists about racial and ethnic minority populations. The current study was performed to evaluate variables that affect use of breast conservation and mastectomy in an underinsured Hispanic population. METHODS: A retrospective review was performed of all patients who self-identified as of Hispanic ethnicity and underwent breast cancer operations from July 2001 to February 2011 at a safety net hospital. Sociodemographic, clinical, and treatment variables were evaluated. All patients with documented contraindications to breast conservation were excluded. Univariate analysis and multivariate analysis were performed to identify variables which were associated with type of operation. RESULTS: The average age of the 219 patients included was 50 years. Most of the patients (93%) were insured with Medicaid or uninsured and 59% presented with clinical stage 2A/B cancers. Mastectomy was performed in 33% of patients and 67% had breast conservation. In adjusted multivariate analysis higher pathologic stage (p=0.01) and English speakers (p=0.03) were associated with mastectomy. By contrast, higher BMI (p=0.03) and use of preoperative chemotherapy (p=0.01) were associated with breast conservation. CONCLUSIONS: In this underinsured Hispanic population, patients with higher pathologic stage and English speaking patients were more likely to undergo mastectomy. Patients who underwent preoperative chemotherapy and who had higher BMI were more likely to undergo breast conservation. PMID- 25443564 TI - Towards a better understanding of the relationship between executive control and theory of mind: an intra-cultural comparison of three diverse samples. AB - Previous research has consistently indicated that theory of mind (ToM) is associated with executive control in the preschool years. However, interpretation of this literature is limited by the fact that most studies have focused exclusively on urbanized Western cultural samples. Consequently, it is not clear whether the association between ToM and executive control reflects the specific features of this particular cohort or instead reflects a universal pattern. The present study provides the first empirical assessment of these two constructs in three diverse groups of Iranian children. Participants were 142 preschoolers (4-5 years old) from high-socioeconomic status (SES) urban (n = 33), low-SES urban (n = 37) and rural villages (n = 77). The results show that there is a robust association between ToM and executive control in all three groups, and that executive control contributes significant unique variance to ToM understanding, even after controlling for a range of variables that have been proposed as potential confounders of this relationship. However, although the three groups were equated in ToM, significant differences in executive control were evident. Moreover, cluster analysis identified three distinct clusters that were relatively homogeneous with respect to executive control and SES. One of these clusters was characterized by both low SES and low executive functioning, and showed little evidence of ToM understanding. Taken together, these findings provide possibly the clearest evidence to date that the association between ToM and executive control is not dependent on children's previous experiences on the tasks, or their family and cultural background. PMID- 25443565 TI - Concerning limitations of food-environment research: a narrative review and commentary framed around obesity and diet-related diseases in youth. PMID- 25443566 TI - Worksite wellness: an ideal career option for nutrition and dietetics practitioners. PMID- 25443567 TI - American Society for Parenteral and Enteral Nutrition and Academy of Nutrition and Dietetics: revised 2014 standards of practice and standards of professional performance for registered dietitian nutritionists (competent, proficient, and expert) in nutrition support. AB - This 2014 revision of the Standards of Practice (SOP) and Standards of Professional Performance (SOPP) for Registered Dietitian Nutritionists (RDNs) in Nutrition Support represents an update of the 2007 Standards composed by content experts of the American Society for Parenteral and Enteral Nutrition and the Academy of Nutrition and Dietetics. The revision is based on the Revised 2012 SOP in Nutrition Care and SOPP for RDs, which incorporates the Nutrition Care Process and the following six domains of professionalism: Quality in Practice, Competence and Accountability, Provision of Services, Application of Research, Communication and Application of Knowledge, and Utilization and Management of Resources. These SOP and SOPP are designed to promote the provision of safe, effective, and efficient nutrition support services; facilitate evidence-based practice; and serve as a professional evaluation resource for RDNs who specialize in or wish to specialize in nutrition support therapy. These standards should be applied in all patient/client care settings in which RDNs in nutrition support provide care. These settings include, but are not limited to, acute care, ambulatory/outpatient care, and home and alternate site care. The standards highlight the value of the nutrition support RDN's roles in quality management, regulatory compliance, research, teaching, consulting, and writing for peer-reviewed professional publications. The standards assist the RDN in nutrition support to distinguish his or her level of practice (competent, proficient, or expert) and would guide the RDN in creating a personal development plan to achieve increasing levels of knowledge, skill, and ability in nutrition support practice. PMID- 25443568 TI - Baculovirus-induced tree-top disease: how extended is the role of egt as a gene for the extended phenotype? AB - Many parasites alter host behaviour to enhance their chance of transmission. Recently, the ecdysteroid UDP-glucosyl transferase (egt) gene from the baculovirus Lymantria dispar multiple nucleopolyhedrovirus (LdMNPV) was identified to induce tree-top disease in L. dispar larvae. Infected gypsy moth larvae died at elevated positions (hence the term tree-top disease), which is thought to promote dissemination of the virus to lower foliage. It is, however, unknown whether egt has a conserved role among baculoviruses in inducing tree-top disease. Here, we studied tree-top disease induced by the baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) in two different host insects, Trichoplusia ni and Spodoptera exigua, and we investigated the role of the viral egt gene therein. AcMNPV induced tree-top disease in both T. ni and S. exigua larvae, although in S. exigua a moulting-dependent effect was seen. Those S. exigua larvae undergoing a larval moult during the infection process died at elevated positions, while larvae that did not moult after infection died at low positions. For both T. ni and S. exigua, infection with a mutant AcMNPV lacking egt did not change the position where the larvae died. We conclude that egt has no highly conserved role in inducing tree-top disease in lepidopteran larvae. The conclusion that egt is a 'gene for an extended phenotype' is therefore not generally applicable for all baculovirus-host interactions. We hypothesize that in some baculovirus-host systems (including LdMNPV in L. dispar), an effect of egt on tree-top disease can be observed through indirect effects of egt on moulting-related climbing behaviour. PMID- 25443569 TI - Kidney failure: cardiorenal and venorenal. PMID- 25443570 TI - The need for collaboration to improve cardiovascular outcomes in patients with CKD. PMID- 25443572 TI - The management of acute coronary syndromes in patients with chronic kidney disease. AB - Coronary heart disease is highly prevalent in patients with CKD, and survival after acute coronary syndrome (ACS) is worse compared with the general population. Many trials that define guidelines for cardiovascular disease excluded patients with kidney disease, leaving a gap between the evidence base and clinical reality. The underlying pathophysiology of vascular disease appears to be different in the setting of CKD. Patients with CKD are more likely to present with myocardial infarction and less likely to be diagnosed with ACS on admission compared with the general population. Patients with CKD appear to benefit with angiography and revascularization compared with medical management alone. However, the increased risk of in-hospital bleeding and risk of contrast induced acute kidney injury are 2 factors that can limit overall benefit for some. Thus, judicious application of available therapies for the management of ACS is warranted to extend survival and reduce hospitalizations in this high-risk population. In this review, we highlight the clinical challenges and potential solutions for managing ACS in patients with CKD. PMID- 25443571 TI - Peripheral artery disease and chronic kidney disease: clinical synergy to improve outcomes. AB - Persons with CKD are at a higher risk of developing peripheral artery disease (PAD) and its adverse health outcomes than individuals in the general population who have normal renal function. Classic atherosclerosis risk factors (eg, age, smoking, diabetes, hypertension, and hyperlipidemia) are common in patients with CKD, but CKD also imposes additional unique risk factors that promote arterial disease (eg, chronic inflammation, hypoalbuminemia, and a procalcific state). Current nephrology clinical practice is adversely affected by PAD diagnostic challenges, the complexities of managing 2 serious comorbid diseases, delayed vascular specialist referral, and slow PAD treatment initiation in patients with CKD. Persons with CKD are less likely to be provided recommended "optimal" PAD care. The knowledge that both limb and mortality outcomes are significantly worse in patients with CKD, especially those on dialysis, is not just a biologic fact but can serve as a care delivery call to action. Nephrologists can facilitate positive change. This article proposes that patients with PAD and CKD be strategically comanaged by care teams that encompass the skills to create and use evidence-based care pathways. This proposed collaborative multidisciplinary approach will include vascular medicine specialists, nephrologists, wound specialists, and mid-level providers. Just as clinical care quality metrics have served as the base for ESRD and acute MI quality improvement, it is time that such quality outcomes metrics be initiated for the large PAD-CKD population. This new system will identify and resolve key gaps in the current care model so that clinical outcomes improve within a cost-effective care frame for this vulnerable population. PMID- 25443574 TI - Apparent treatment-resistant hypertension and chronic kidney disease: another cardiovascular-renal syndrome? AB - To identify patients at increased risk of cardiovascular (CV) outcomes, apparent treatment-resistant hypertension (aTRH) is defined as having a blood pressure above goal despite the use of 3 or more antihypertensive therapies of different classes at maximally tolerated doses, ideally including a diuretic. Recent epidemiologic studies in selected populations estimated the prevalence of aTRH as 10% to 15% among patients with hypertension and that aTRH is associated with elevated risk of CV and renal outcomes. Additionally, aTRH and CKD are associated. Although the pathogenesis of aTRH is multifactorial, the kidney is believed to play a significant role. Increased volume expansion, aldosterone concentration, mineralocorticoid receptor activity, arterial stiffness, and sympathetic nervous system activity are central to the pathogenesis of aTRH and are targets of therapies. Although diuretics form the basis of therapy in aTRH, pathophysiologic and clinical data suggest an important role for aldosterone antagonism. Interventional techniques, such as renal denervation and carotid baroreceptor activation, modulate the sympathetic nervous system and are currently in phase III trials for the treatment of aTRH. These technologies are as yet unproven and have not been investigated in relationship to CV outcomes or in patients with CKD. PMID- 25443573 TI - The interplay between CKD, sudden cardiac death, and ventricular arrhythmias. AB - CKD patients face an increased risk of cardiovascular disease mortality, and the risk of sudden cardiac death (SCD) increases as kidney function declines. Risk factors for SCD are poorly understood and understudied among CKD patients. In the general population, coronary heart disease-associated risk factors are the most important determinants of SCD risk, but among CKD patients, there is evidence that these factors play a much smaller role. Complex relationships between CKD specific risk factors, structural heart disease, and arrhythmic triggers contribute to the high risk of SCD and ventricular arrhythmias and modulate the effectiveness of available therapies. This review examines recent data on the epidemiology, pathophysiology, and mechanisms of SCD among CKD patients and examines current evidence regarding the use of pharmacologic and device-based therapies for management of SCD risk. PMID- 25443575 TI - Chronic kidney disease and stroke. AB - Chronic kidney disease (CKD) is associated with an increased risk of both ischemic and hemorrhagic stroke. In addition to shared risk factors, this higher cerebrovascular risk is mediated by several CKD-associated mechanisms including platelet dysfunction, coagulation disorders, endothelial dysfunction, inflammation, and increased risk of atrial fibrillation. CKD can also modify the effect of treatments used in acute stroke and in secondary stroke prevention. We review the epidemiology and pathophysiology that link CKD and stroke and the impact of CKD on stroke outcomes. Interdisciplinary collaboration between nephrologists, pharmacists, hematologists, nutrition therapists, primary care physicians, and neurologists in providing care to these subjects may potentially improve outcomes. PMID- 25443576 TI - Virtual colon flattening method based on colonic outer surface. AB - Virtual colon flattening (VF) is a minimally invasive viewing mode used to detect colorectal polyps on the colonic inner surface in virtual colonoscopy. Compared with conventional colonoscopy, inspecting a flattened colonic inner surface is faster and results in fewer uninspected regions. Unfortunately, the deformation distortions of flattened colonic inner surface impede the performance of VF. Conventionally, the deformation distortions can be corrected by using the colonic inner surface. However, colonic curvatures and haustral folds make correcting deformation distortions using only the colonic inner surface difficult. Therefore, we propose a VF method that is based on the colonic outer surface. The proposed method includes two novel algorithms, namely, the colonic outer surface extraction algorithm and the colonic outer surface-based distortion correction algorithm. Sixty scans involving 77 annotated polyps were used for the validation. The flattened colons were independently inspected by three operators and then compared with three existing VF methods. The correct detection rates of the proposed method and the three existing methods were 79.6%, 67.1%, 71.9%, and 72.7%, respectively, and the false positives per scan were 0.16, 0.32, 0.21, and 0.26, respectively. The experimental results demonstrate that our proposed method has better performance than existing methods that are based on the colonic inner surface. PMID- 25443578 TI - Making new connections: the intersection of neurendocrine and immune regulation. PMID- 25443579 TI - Spinal cord injury impacts B cell production, homeostasis, and activation. AB - Complex interactions govern the interplay of central nervous and immune systems, including the generation, homeostatic maintenance, and activation of B cells. Accordingly, spinal cord injury will likely impact all of these processes. Several laboratories have recently explored this possibility, and their observations in aggregate reveal both acute and chronic consequences that can vary based on the injury location. Acute effects include a transient cessation of bone marrow B lymphopoiesis, with a corresponding drop in the peripheral follicular and transitional B cell subsets, whereas the marginal zone subset is preserved. Despite recovery of B lymphopoiesis by 28 days post injury, follicular B cell numbers remain depressed; this may reflect reduced levels of the homeostatic cytokine BLyS. In general, the ability to mount T dependent antibody responses after injury are intact, as are pre-existing memory B cell pools and antibody levels. In contrast, T-independent responses are chronically compromised. Both glucocorticoid-dependent and -independent processes mediate these effects, but a detailed understanding of the mechanisms involved awaits further study. Nonetheless, these observations in toto strengthen the growing appreciation for bidirectional interactions between the CNS and immune system, highlighting the need for further basic and translational efforts. PMID- 25443580 TI - Paramagnetic signals in the globus pallidus as late radiographic sign of juvenile onset GM1 gangliosidosis. AB - BACKGROUND: The juvenile form of GM1 gangliosidosis lacks specific physical findings and thus is often a diagnostic challenge for clinicians. T2 hypodensity in the globus pallidus is a characteristic radiographic sign of neurodegeneration with iron accumulation in the brain that is observed in GM1 gangliosidosis, but the exact timing when this radiographic sign becomes apparent remains to be elucidated. PATIENTS: Two male siblings had normal development until 2 years of age and then developed psychomotor regression with dystonia. Their neuroimaging studies indicated progressive global cerebral atrophy. Exome sequencing identified compound heterozygous missense mutations in GLB1, leading to a diagnosis of GM1 gangliosidosis. RESULTS: A retrospective review of neuroimaging studies revealed that the two patients had strikingly similar clinical courses and radiographic progressions with cortical atrophy that preceded the T2 hypointensity in the globus pallidus. CONCLUSIONS: Paramagnetic signals in the globus pallidus become apparent relatively late during the disease course, once cerebral atrophy has already become prominent. A comprehensive diagnostic approach involving clinical, radiographic, and genetic testing is necessary for the early identification of affected individuals. PMID- 25443581 TI - Aicardi syndrome: an epidemiologic and clinical study in Norway. AB - BACKGROUND: Aicardi syndrome is a rare neurodevelopmental disorder. The main diagnostic features are agenesis of corpus callosum, chorioretinal lacunae, and infantile spasms. The outcome is in general severe, with poor cognitive development and difficult-to-treat epilepsy. The aim of this study was to perform a nationwide epidemiologic survey of patients with Aicardi syndrome and describe their clinical features. Norway is a small country with a well-developed health system, making epidemiologic studies of rare diseases feasible and reliable. METHODS: We aimed at identifying all patients diagnosed with Aicardi syndrome in Norway. Prevalence of Aicardi syndrome was calculated for January 1, 2011. All available patients were examined, and their medical records were scrutinized. RESULTS: Six females aged 7 to 27 years with the diagnosis of Aicardi syndrome were identified. With a female population of 949,578 in ages 0 to 29 years, we found an age-adjusted prevalence of 0.63 per 100,000 females. One patient never had epileptic seizures. The other five had all experienced infantile spasms, all had at some point hypsarrhythmia in electroencephalography, two had a clear picture of suppression burst, whereas three had periods of suppression. Four of the five patients with seizure disorders experienced a marked improvement with time. CONCLUSION: We found an age-adjusted prevalence of 0.63 per 100,000 females with Aicardi syndrome and that their seizure disorder appeared to improve with age. PMID- 25443582 TI - Early Wallerian degeneration in a neonate with middle carotid artery stroke. PMID- 25443583 TI - Pilocytic astrocytoma at the medulla oblongata dorsal surface presenting as intractable hiccups. PMID- 25443584 TI - Respiratory acidosis secondary to drug therapy. PMID- 25443585 TI - Following recommendations: a challenge in occupational asthma. PMID- 25443586 TI - Initial experience with real-time elastography using an ultrasound bronchoscope for the evaluation of mediastinal lymph nodes. AB - Real-time elastography performed during endoscopic ultrasonography is a relatively new method for characterizing tissue stiffness, and has been used successfully as a predictor of malignancy in mediastinal lymph nodes. This case report describes our practical experience with this technique using an ultrasound bronchoscope to examine mediastinal lymph nodes. We present a case of sectorial endobronchial ultrasound and the first published case of endoscopic ultrasound elastography using ultrasound bronchoscope in two patients with non-small cell lung carcinoma. Qualitative tissue color pattern was obtained in both cases and correlated with pathological evaluation. The initial feasibility results are promising and suggest that ultrasound bronchoscopy techniques, such as guided nodal staging, merit additional studies. It may be important to categorize the risk of malignancy to facilitate sampling decisions. PMID- 25443587 TI - Severe pneumonia caused by Rhodococcus equi with hematogenous spread to the central nervous system in an immunocompromised patient. PMID- 25443588 TI - Thoracic endometriosis: the role of imaging. PMID- 25443589 TI - Pulmonary consolidation versus splenic abscess due to Salmonella enterica. PMID- 25443590 TI - Endobronchial valves in the treatment of persistent air leak, an alternative to surgery. AB - INTRODUCTION: Persistent air leak is frustrating for both patients and physicians, above all leaks with a high risk of surgery. Insertion of endobronchial valves could be an alternative to surgery. The aim of this study is to describe our experience in these valves and analyse their efficacy in a series of patients with persistent air leaks. MATERIAL AND METHODS: The valves are inserted by means of flexible bronchoscopy under conscious sedation and local anesthesia. A preliminary bronchoscopy identifies the air leak by bronchial occlusion using a balloon catheter. A successful outcome is defined as complete disappearance of the leak following removal of the chest drain, without the need for further surgery. RESULTS: From November 2010 to December 2013, 8 patients with persistent air leaks were treated with endobronchial valves. The number of valves used ranged from 1 to 4 (median 2), with a median duration of air leak prior to placement of 15.5 days. There were no complications and the resolution of the leak was complete in 6 of 8 patients (75%). The median duration of drainage after insertion of the valves was 13 days and the median time to removal of 52.5 days. CONCLUSIONS: Insertion of endobronchial valves is a safe and effective method for treating persistent air leaks, and a valid alternative to surgery. PMID- 25443591 TI - Pneumonia as comorbidity in chronic obstructive pulmonary disease (COPD). Differences between acute exacerbation of COPD and pneumonia in patients with COPD. AB - INTRODUCTION: Pneumonia is considered an independent entity in chronic obstructive pulmonary disease (COPD), to be distinguished from an infectious exacerbation of COPD. The aim of this study was to analyze the clinical characteristics and progress of the exacerbation of COPD (ECOPD) compared to pneumonia in COPD (PCOPD) patients requiring hospitalization. PATIENTS AND METHODS: Prospective, longitudinal, observational cohort study including 124 COPD patients requiring hospital admission for lower respiratory tract infection. Patients were categorized according to presence of ECOPD (n=104) or PCOPD (n=20), depending on presence of consolidation on X-ray. Demographic, clinical, laboratory, microbiological and progress variables were collected. RESULTS: Patients with ECOPD showed more severe respiratory disease according to the degree of obstruction (P<.01) and need for oxygen therapy (P<.05). PCOPD patients showed increased presence of fever (P<.05), lower blood pressure (P<.001), more laboratory abnormalities (P<.05; leukocytosis, elevated CRP, low serum albumin) and increased presence of crepitus (P<.01). Microbiological diagnosis was achieved in 30.8% of cases of ECOPD and 35% of PCOPD; sputum culture yielded the highest percentage of positive results, predominantly Pseudomonas aeruginosa. Regarding the progress of the episode, no differences were found in hospital stay, need for ICU or mechanical ventilation. CONCLUSIONS: Our data confirm clinical and analytical differences between ECOPD and PCOPD in patients who require hospital admission, while there were no differences in subsequent progress. PMID- 25443592 TI - Multivariable analysis of anesthetic factors associated with time to extubation in dogs. AB - The purpose of this study was to identify factors that prolong the time to extubation in dogs. Anesthetic records of 900 dogs at a university teaching hospital were searched. Multiple linear regression was used to compare independent predictors (patient demographics, anesthetic and intraoperative variables) with the dependent variable (time to extubation). Induction with propofol (P < 0.025) was associated with a shorter time to extubation, while premedication with acepromazine (P = 0.000) was associated with a longer time to extubation. Time to extubation was increased by 0.311 minutes for every kilogram increase in body weight (P = 0.000), 5.924 minutes for every 1 degrees C loss in body temperature (P = 0.0000), and by 0.096 minutes for every 1 minute increase in anesthetic duration (P = 0.000). Anesthetic variables, which can be manipulated by the anesthetist, include choice of premedication and induction drugs, hypothermia, and duration of anesthesia. PMID- 25443598 TI - Photographic analyses using skin detail of the hand: a methodology and evaluation. AB - Skin features have been employed by law enforcement agencies for suspect and victim identification. Comparisons of hand have arisen in casework where images have been submitted where a face was not present but a hand was visible. This research utilizes a collection of 128 hands from employees of the U.S. Army Criminal Investigation Laboratory to examine the frequency and distribution of skin detail on the dorsal surface of the hand. To assess the location of features, the hand was segmented into 14 regions using readily discernible anatomical landmarks. Overall, 2618 pigmented lesions and 92 scars or injuries were documented. When comparing the regions with one another, Regions 1-10 had fewer pigmented lesions than Regions 11-14. There was no pattern to the distribution of scars throughout the regions. The findings presented a foundation for one possible method that may differentiate hands based on the frequency and distribution of such features. PMID- 25443593 TI - Effectiveness of a school-based academic asthma health education and counseling program on fostering acceptance of asthma in older school-age students with asthma. AB - PURPOSE: The purpose of this study was to evaluate the effectiveness of the academic asthma education and counseling Staying Healthy-Asthma Responsible and PreparedTM (SHARP) program on fostering psychosocial acceptance of asthma. DESIGN AND METHODS: This was a phase III, two-group, cluster-randomized, single-blinded, longitudinal study. Students from grades 4 and 5 (N = 205) with asthma and their caregivers completed surveys at pre-intervention and at 1-, 12-, and 24-months post-intervention. Analysis involved multilevel modeling. RESULTS: All students demonstrated significant improvement in aspects of acceptance; students in SHARP demonstrated significant improvement in openness to sharing and connectedness with teachers over students in the control condition. PRACTICE IMPLICATIONS: The SHARP program offers a well-tested, effective program for psychosocial acceptance of asthma, which is welcomed by schools. PMID- 25443599 TI - [HUCI is written with H as in HUMAN]. PMID- 25443600 TI - Yoga--a promising technique to control cardiovascular disease. PMID- 25443602 TI - Effect of a government scheme on reperfusion trends in a tertiary care centre in South India. AB - AIMS: Coronary artery disease is the leading cause of mortality and morbidity in our country, of which ST elevation myocardial infarction (STEMI) accounts for the major part of health spending. We sought to study the effect of induction of government health insurance scheme on the trends of reperfusion in patients of acute STEMI. METHODS AND RESULTS: 1133 patients presenting with acute STEMI enrolled. 1079 (95.1%) received some form of reperfusion therapy. Primary PCI was used in 60.6% of patients as the primary reperfusion modality, a six fold increase as compared to previous years. Government health insurance accounted for the one third of all. 34.5% patients underwent pharmacological reperfusion, most commonly with streptokinase. 4.9% patients of STEMI did not receive any form of reperfusion therapy in contrast to 14% during previous years. CONCLUSION: Introduction of government health insurance along with increased awareness has resulted in dramatic changes in the management of STEMI patients. PMID- 25443601 TI - Yoga based cardiac rehabilitation after coronary artery bypass surgery: one-year results on LVEF, lipid profile and psychological states--a randomized controlled study. AB - OBJECTIVE: To compare the long term effects of yoga based cardiac rehabilitation program with only physiotherapy based program as an add-on to conventional rehabilitation after coronary artery bypass grafting (CABG) on risk factors. METHODS: In this single blind prospective randomized parallel two armed active control study, 1026 patients posted for CABG at Narayana Hrudayalaya Institute of Cardiac Sciences, Bengaluru (India) were screened. Of these, 250 male participants (35-65 years) who satisfied the selection criteria and consented were randomized into two groups. Within and between group comparisons were done at three points of follow up (i.e. 6th week, 6th month, and 12th month) by using Wilcoxon's signed ranks test and Mann Whitney U test respectively. RESULTS: Yoga group had significantly (p = 0.001, Mann Whitney) better improvement in LVEF than control group in those with abnormal baseline EF (<53%) after 1 year. There was a better reduction in BMI in the yoga group (p = 0.038, between groups) in those with high baseline BMI (>=23) after 12 months. Yoga group showed significant (p = 0.008, Wilcoxon's) reduction in blood glucose at one year in those with high baseline FBS >=110 mg/dl. There was significantly better improvement in yoga than the control group in HDL (p = 0.003), LDL (p = 0.01) and VLDL (p = 0.03) in those with abnormal baseline values. There was significantly better improvement (p = 0.02, between groups) in positive affect in yoga group. Within Yoga group, there was significant decrease in perceived stress (p = 0.001), anxiety (p = 0.001), depression (p = 0.001), and negative affect (p = 0.03) while in the control group there was reduction (p = 0.003) only in scores on anxiety. CONCLUSION: Addition of yoga based relaxation to conventional post-CABG cardiac rehabilitation helps in better management of risk factors in those with abnormal baseline values and may help in preventing recurrence. PMID- 25443603 TI - Size of distal radial and distal ulnar arteries in adults of southern Rajasthan and their implications for percutaneous coronary interventions. AB - AIMS AND OBJECTIVES: Transradial interventions are gaining popularity in recent years. However the radial artery being small, there is a limitation in using interventional devices through this route. We have measured radial and ulnar arteries size in adult patients at our tertiary care cardiology center in southern Rajasthan. METHOD: Adult patients >30 years, who came for Echocardiography at a tertiary care center were included. Radial and ulnar arteries inner diameters were measured 2-3 cm above the Styloid process in both forearms with the Ultrasonography. Patient information about weight, height, diabetes and hypertension were collected. Body mass index and Body surface area were calculated. RESULTS: We studied 204 patients, which includes 60.8% males. Mean diameter was 2.325 +/- 0.4 mm mm for radial arteries and 2.358 +/- 0.39 mm for ulnar arteries (p = 0.24). Hypertensive and male patients had larger mean radial artery diameter than non hypertensive (2.383 mm v/s 2.272 mm, p = 0.006) and female patients (2.37 mm v/s 2.26 mm, p = 0.008) respectively. Diabetic patients (2.305 mm) had nonsignificantly smaller radial arteries diameters than nondiabetics (2.329 mm, p = 0.6). We calculated correlations between radial arteries diameters and Body surface area, Body mass index, height and weight of patients, none of these correlations were statistically significant (r = 0.30, r = 0.28, r = 0.07, r = 0.031 respectively). CONCLUSION: Mean radial artery diameter (2.325 +/- 0.4 mm) in the study was slightly smaller than ulnar artery (2.358 +/- 0.39 mm). Males and hypertensives had a larger mean radial artery diameter than females and non hypertensives. Radial artery inner diameter measurement by Ultrasonography may be more helpful than Allen's test for ideal selection of cases. PMID- 25443604 TI - Modified radial v/s biatrial maze for atrial fibrillation in rheumatic valvular heart surgery. AB - BACKGROUND: Atrial fibrillation (AF) is commonest sustained atrial arrhythmia producing high morbidity. Although Cox's Maze III procedure cures AF in majority, reduced atrial transport function (ATF) is a concern. Radial approach with ablation lines radial from sinus node towards atrioventricular annulii and parallel to atrial coronary arteries, has shown better ATF. METHODS: Single blind open randomized prospective study of 80 patients was undertaken in two groups (40 each) of modified Cox's maze III and modified radial approach, to evaluate conversion to normal sinus rhythm (NSR) and ATF. Patients undergoing surgery for rheumatic valvular heart disease with continuous AF were prospectively randomized. Ablation lines were created with radiofrequency (RF) bipolar coagulation with cryoablation for the isthmal lesions and coronary sinus. Results were compared at 6 months and ATF was evaluated by atrial filling fraction (AFF) and A/E ratio on echocardiography. RESULTS: The rate of conversion to NSR in both groups was statistically insignificant by Fisher's exact test (p > 0.05). ATF was better in modified radial approach compared to modified Cox's Maze III (A/E compared by unpaired t test:0.52 +/- 0.08 v/s 0.36 +/- 0.10; p < 0.05. AFF compared using Mann Whitney U test: median AFF for radial group was 23 v/s 20 for biatrial group; p < 0.05). DISCUSSION: In patients with AF undergoing rheumatic valvular surgery, radiofrequency radial approach is as effective as modified Cox's maze III for conversion to NSR with better atrial transport function. PMID- 25443605 TI - Risk scoring system to predict contrast induced nephropathy following percutaneous coronary intervention. AB - BACKGROUND: Contrast induced nephropathy (CIN) is associated with significant morbidity and mortality after percutaneous coronary intervention (PCI). The aim of this study is to evaluate the collective probability of CIN in Indian population by developing a scoring system of several identified risk factors in patients undergoing PCI. METHODS: This is a prospective single center study of 1200 consecutive patients who underwent PCI from 2008 to 2011. Patients were randomized in 3:1 ratio into development (n = 900) and validation (n = 300) groups. CIN was defined as an increase of >=25% and/or >=0.5 mg/dl in serum creatinine at 48 hours after PCI when compared to baseline value. Seven independent predictors of CIN were identified using logistic regression analysis amount of contrast, diabetes with microangiopathy, hypotension, peripheral vascular disease, albuminuria, glomerular filtration rate (GFR) and anemia. A formula was then developed to identify the probability of CIN using the logistic regression equation. RESULTS: The mean (+/-SD) age was 57.3 (+/-10.2) years. 83.6% were males. The total incidence of CIN was 9.7% in the development group. The total risk of renal replacement therapy in the study group is 1.1%. Mortality is 0.5%. The risk scoring model correlated well in the validation group (incidence of CIN was 8.7%, sensitivity 92.3%, specificity 82.1%, c statistic 0.95). CONCLUSION: A simple risk scoring equation can be employed to predict the probability of CIN following PCI, applying it to each individual. More vigilant preventive measures can be applied to the high risk candidates. PMID- 25443606 TI - Real world experience with an indigenously manufactured stent Cobal C--a retrospective study. AB - BACKGROUND: Second generation bare metal stents made of cobalt chromium alloy are superior to first generation stain less steel stents. The thin struts are shown to reduce clinical and angiographic adverse outcomes. OBJECTIVE: To study the long term clinical and angiographic outcomes in patients who underwent coronary angioplasty with an indigenously made cobalt chromium bare metal stents with thin strut Cobal+CTM (Relisys). METHODS: A total of 268 consecutive patients who underwent coronary angioplasty with Cobal+C stents were studied retrospectively. Clinical follow up was done after a minimum period of nine months through telephonic interview and angiographic follow up was done in 80 patients chosen randomly. The end points analyzed included major adverse cardiac events (MACE) at nine months and the rate of binary restenosis at follow up angiogram done between 9 and 15 months post angioplasty. RESULTS: Thirty four percent were diabetic and 33% had acute myocardial infarction. Females constituted 17%. Mean stent diameter was 2.88 +/- 0.28 and mean stent length 18.8 +/- 4.2. MACE at nine months was 4.5% with TLR 0.3%. The rate of binary restenosis was 21%. Patients with longer stent lengths and non-compliance with medications had significantly higher rates of binary restenosis. CONCLUSIONS: The use of Relisys Cobal+C stents was associated with good long term clinical and angiographic outcomes as evidenced by low incidence of MACE and binary restenosis rates for a bare metal stent. PMID- 25443607 TI - Clopidogrel resistance: the way forward. AB - Clopidogrel, a second generation thienopyridine has been the mainstay of ACS (Acute Coronary Syndrome) treatment for more than a decade. Clopidogrel Resistance has been associated with increased mortality in ACS patients with an increase in number of Stent Thrombosis. This review article tries to find out the causes of Clopidogrel Resistance, the main factors involving it, Laboratory evaluation of Clopidogrel Resistance. The overall incidence of Clopidogrel Resistance across the Globe & India has also been considered. The article also discusses the clinical significance of Clopidogrel Resistance & its relationship with adverse cardiovascular events. This review ends with the probable solutions to Clopidogrel Resistance & the new generation of antiplatelets which can be used for the same. PMID- 25443608 TI - Regression of pulmonary artery hypertension due to development of a pulmonary arteriovenous malformation. AB - Idiopathic Pulmonary Hypertension (IPAH) is characterized by elevated pulmonary arterial pressure in the absence of an identifiable underlying cause. The condition is usually relentlessly progressive with a short survival in the absence of treatment.(1) We describe a patient of IPAH in whom the pulmonary artery pressures significantly abated with complete disappearance of symptoms, following spontaneous development of a pulmonary arterio-venous malformation (PAVM). PMID- 25443609 TI - Pulmonary endarterectomy for saddling pulmonary embolism by Aspergillus fungus in an immunocompetent patient. AB - We present a case of tricuspid valve Aspergillus endocarditis with saddle shaped massive pulmonary embolism occurring in an immunocompetent host. The patient was managed uniquely by pulmonary endarterectomy (PEA) and combination antifungal chemotherapy with Liposomal amphotericin-B + caspofungin. PMID- 25443611 TI - Cardio-embolic stroke due to valve tissue embolization during percutaneous transseptal mitral commissurotomy (PTMC). AB - Percutaneous transseptal mitral commissurotomy (PTMC) has replaced surgical commissurotomy as a treatment of choice in selected patients of rheumatic mitral stenosis. Various randomized trials have shown PTMC to be equal or superior to surgical commissurotomy in terms of hemodynamic improvement as well as long term survival. Systemic embolism is one of the dreaded complications of PTMC, which is reported in 0.5-5% of cases and involves cerebral circulation in 1% of cases. Most of the time, periprocedural embolism during PTMC is caused by the mobilization of preexisting thrombus in the left atrial appendage. We report an unusual case of acute stroke due embolization of mitral valve tissue during PTMC. PMID- 25443610 TI - An unusual cause of acute cor pulmonale--significance of the 'continuous diaphragm sign'. AB - A patient presented with chest pain and clinical features of acute right heart failure. Initial work up revealed the presence of severe PAH. Acute pulmonary embolism is the commonest and most life-threatening cause for acute cor pulmonale. Even though the clinical picture suggested pulmonary embolism, a subtle sign was missed from the first chest X-ray taken in the emergency department. However on reanalysis the 'continuous diaphragm sign' later guided us towards the diagnosis. Our case represents one of the first reports of a rare etiology for acute cor pulmonale--hypersensitivity pneumonitis. Right ventricular dysfunction was caused by an acute rise in pulmonary artery pressures as well as by the compressive effects of pneumomediastinum. We emphasize the role played by a good quality chest X-ray early in the management of acute chest pain syndromes. However pulmonary embolism should be ruled out conclusively before redirecting attention to less malignant conditions. PMID- 25443612 TI - Bundle branch aberrancy in predicting mechanism of SVT. PMID- 25443613 TI - Isolated single coronary artery (RII-B type) presenting as an inferior wall myocardial infarction: a rare clinical entity. AB - Isolated single coronary artery without other congenital cardiac anomalies is very rare among the different variations of anomalous coronary patterns. The prognosis in patients with single coronary varies according to the anatomic distribution and associated coronary atherosclerosis. If the left main coronary artery travels between the aorta and pulmonary arteries, it may be a cause of sudden cardiac death. We present multimodality images of a single coronary artery, in which the whole coronary system originated by a single trunk from the right sinus of Valsalva with inter-arterial course of left main coronary artery. This rare type of single coronary artery was classified as RII-B type according to Lipton's scheme of classification. A significant flow-limiting lesions were found in the right coronary artery that was successfully treated with percutaneous coronary intervention. PMID- 25443614 TI - Ratchet-traction effect: an underdiagnosed mechanism of pacing lead dislodgement. AB - Pacing lead dislodgement contributes substantially, to the list of causes of early pacemaker failure. Reel's syndrome is a rare cause of pacemaker failure, resulting from the dislodging of pacing electrodes by manipulation of the pulse generator by the patient. We describe here an intriguing case of pacemaker lead dislodgement by a novel and frequently underdiagnosed mechanism that mimicked the fluoroscopic diagnosis of reel's syndrome. PMID- 25443615 TI - OCT during left main bifurcation PCI. PMID- 25443616 TI - Evaluation of sustained blood pressure elevation in children. PMID- 25443617 TI - Editorial comment. PMID- 25443618 TI - Economic assessment of nutritional recommendations. AB - The effect of consumers' compliance with nutritional recommendations is uncertain because of potentially complex substitutions. To lift this uncertainty, we adapt a model of consumer behaviour under rationing to the case of linear nutritional constraints. Dietary adjustments are derived from information on consumer preferences, consumption levels, and nutritional contents of foods. A calibration exercise simulates, for different income groups, how the French diet would respond to various nutrition recommendations, and those behavioural adjustments are translated into health outcomes through the DIETRON epidemiological model. This allows for the ex-ante comparison of the efficiency, equity and health effects of ten nutritional recommendations. Although most recommendations impose significant taste costs on consumers, they are highly cost-effective, with the recommendations targeting salt, saturated fat, and fruits and vegetables (F&V) ranking highest in terms of efficiency. Most recommendations are also economically progressive, with the exception of that targeting F&V. PMID- 25443619 TI - Alone but better off? Adult child migration and health of elderly parents in Moldova. AB - Increasing labor migration and simultaneous aging of societies are two important demographic developments many poor countries face. Elderly people who are left behind may experience a decrease in welfare when their children migrate. This paper investigates the effect of migration on various dimensions of elderly health using unique data from Moldova, which has one of the highest emigration rates in the world. We find positive migration effects on body mass index (BMI), mobility and self-reported health. No effects are found on depression and cognitive capacity. We find evidence that these positive outcomes are linked to an income effect which leads to improvements in diet and identify a reallocation of time use from subsistence farming to leisure and sleep which may have further beneficial effects. These positive effects seem to compensate the elderly for decreasing social contact with their migrant family members. PMID- 25443620 TI - The indole derivative NecroX-7 improves nonalcoholic steatohepatitis in ob/ob mice through suppression of mitochondrial ROS/RNS and inflammation. AB - BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is associated with cirrhosis and hepatocellular carcinoma. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play key roles in the development of the disease. However, the therapeutic target of NASH has not been fully defined and new treatments are needed. We investigated the protective effects of the antioxidant indole-derived NecroX-7 in a NASH mouse model using leptin-deficient ob/ob and methionine- and choline-deficient (MCD) diet-fed ob/ob mice. METHODS: Six-week old male mice were divided into three groups: ob/+ mice, ob/ob mice treated with vehicle and ob/ob mice treated daily with NecroX-7 (20 mg/kg) for 4 weeks. To study the effects of NecroX-7 in a fibrosis model, NASH was induced by feeding ob/ob mice an MCD diet. The effects of NecroX-7 on NASH progression were evaluated using biochemical, histological and molecular markers. RESULTS: NecroX 7-treated ob/ob mice had a marked decrease in serum aspartate aminotransferase and alanine transaminase compared with vehicle-treated controls. Interestingly, hepatic steatosis and lipid peroxidation were significantly improved by NecroX-7 treatment. NecroX-7 inhibited tert-butylhydroperoxide- and H2 O2 -induced mitochondrial ROS/RNS in primary hepatocytes and attenuated mitochondrial dysfunction in vitro and in vivo. Furthermore, NecroX-7-treated mice exhibited fewer infiltrating macrophages and reduced hepatic tumour necrosis factor-alpha expression. Hepatic fibrosis in MCD-fed ob/ob mice was significantly decreased by NecroX-7 treatment. CONCLUSIONS: NecroX-7 treatment improved hepatic steatosis and fibrosis in murine NASH models. These effects occurred through the suppression of whole-cell ROS/RNS and inflammatory responses and suggest that NecroX-7 has a potential therapeutic benefit in steatohepatitis. PMID- 25443621 TI - Correlation between microbial community and granule conductivity in anaerobic bioreactors for brewery wastewater treatment. AB - Prior investigation of an upflow anaerobic sludge blanket (UASB) reactor treating brewery wastes suggested that direct interspecies electron transfer (DIET) significantly contributed to interspecies electron transfer to methanogens. To investigate DIET in granules further, the electrical conductivity and bacterial community composition of granules in fourteen samples from four different UASB reactors treating brewery wastes were investigated. All of the UASB granules were electrically conductive whereas control granules from ANAMMOX (ANaerobic AMMonium OXidation) reactors and microbial granules from an aerobic bioreactor designed for phosphate removal were not. There was a moderate correlation (r=0.67) between the abundance of Geobacter species in the UASB granules and granule conductivity, suggesting that Geobacter contributed to granule conductivity. These results, coupled with previous studies, which have demonstrated that Geobacter species can donate electrons to methanogens that are typically predominant in anaerobic digesters, suggest that DIET may be a widespread phenomenon in UASB reactors treating brewery wastes. PMID- 25443622 TI - Rapid alkali catalyzed transesterification of microalgae lipids to biodiesel using simultaneous cooling and microwave heating and its optimization. AB - Biodiesel with improved yield was produced from microalgae biomass under simultaneous cooling and microwave heating (SCMH). Nannochloropsis sp. and Tetraselmis sp. which were known to contain higher lipid species were used. The yield obtained using this novel technique was compared with the conventional heating (CH) and microwave heating (MWH) as the control method. The results revealed that the yields obtained using the novel SCMH were higher; Nannochloropsis sp. (83.33%) and Tetraselmis sp. (77.14%) than the control methods. Maximum yields were obtained using SCMH when the microwave was set at 50 degrees C, 800W, 16h of reaction with simultaneous cooling at 15 degrees C; and water content and lipid to methanol ratio in reaction mixture was kept to 0 and 1:12 respectively. GC analysis depicted that the biodiesel produced from this technique has lower carbon components (<19 C) and has both reasonable CN and IV reflecting good ignition and lubricating properties. PMID- 25443623 TI - Correlation between biogas yield and chemical composition of energy crops. AB - The scope of this study was to investigate the influence of the chemical composition of energy crops on biogas and methane yield. In total, 41 different plants were analyzed in batch test and their chemical composition was determined. For acid detergent lignin (ADL) content below 10% of total solids, a significant negative correlation for biogas and methane yields (r~-0.90) was observed. Based on a simple regression analysis, more than 80% of the sample variation can be explained through ADL. Based on a principal component analysis and multiple regression analysis, ADL and hemicellulose are suggested as suitable model variables for biogas yield potential predictions across plant species. PMID- 25443624 TI - Rapid fingerprinting of methanogenic communities by high-resolution melting analysis. AB - Characterizing microbial community structure using molecular techniques is becoming a popular approach in studies of waste/wastewater treatment processes. A rapid and robust tool to analyze microbial communities is required for efficient process monitoring and control. In this study, a new community fingerprinting method based on high-resolution melting (HRM) analysis was developed and applied to compare methanogenic community structures of five different anaerobic digesters. The new method produced robust community clustering and ordination results comparable to the results from the commonly used denaturing gradient gel electrophoresis (DGGE) performed in parallel. This method transforms melting peak plots (MPs) of community DNA samples generated by HRM analysis to molecular fingerprints and estimates the relationships between the communities based on the fingerprints. The MP-based fingerprinting would provide a good alternative to monitor variations in microbial community structure especially when handling large sample numbers due to its high-throughput capacity and short analysis time. PMID- 25443625 TI - Leukotriene B4 activates intracellular calcium and augments human osteoclastogenesis. AB - INTRODUCTION: Bone erosion in inflammatory arthritis depends on the recruitment and activation of bone resorbing cells, the osteoclasts. Interleukin-23 (IL-23) has been primarily implicated in mediating inflammatory bone loss via the differentiation of Th17 receptor activator of nuclear factor kappaB ligand (RANKL)-producing cells. In this article, we describe a new role of IL-23 in activating the synthesis and production of leukotriene B4 (LTB4) in innate immune cells. METHODS: We utilized whole blood-derived human peripheral blood mononuclear cells (PBMCs), differentiated them towards an osteoclast lineage and then performed immunofluorescence and cytochemical staining to detect the expression of LTB4-associated receptors and enzymes such as phospholipase A2, 5 lipoxygenase and leukotriene A4 hydrolase, as well as the presence of tartrate resistant acid phosphatase (TRAP) and F-actin rings on fully mature osteoclasts. We used enzyme immunoassays to measure LTB4 levels in culture media derived from IL-23-treated human PBMCs. We used real-time calcium imaging to study the effect of leukotrienes and requirements of different calcium sources and signaling proteins in activating intracellular calcium flux using pharmacological inhibitors to phospholipase C (U73122), membrane calcium channels (2-APB) and phosphatidylinositol 3-kinase (Wortmannin) and utilized qPCR for gene expression analysis in macrophages and osteoclasts. RESULTS: Our data show that LTB4 engagement of BLT1 and BLT2 receptors on osteoclast precursors leads to activation of phospholipase C and calcium release-activated channel-mediated intracellular calcium flux, which can activate further LTB4 autocrine production. IL-23-induced synthesis and secretion of LTB4 resulted in the upregulation of osteoclast-related genes NFATC1, MMP9, ACP5, CTSK and ITGB3 and the formation of giant, multinucleated TRAP+ cells capable of F-actin ring formation. These effects were dependent on Ca2+ signaling and were completely inhibited by BLT1/BLT2 and/or PLC and CRAC inhibitors. CONCLUSIONS: In conclusion, IL-23 can initiate osteoclast differentiation independently from the RANK-RANKL pathway by utilizing Ca2+ signaling and the LTB4 signaling cascade. PMID- 25443627 TI - Cellulitis Recurrence Score: a tool for predicting recurrence of lower limb cellulitis. AB - BACKGROUND: Cellulitis is the most common skin and soft tissue infection and is associated with frequent recurrences. OBJECTIVES: An objective of our study was to identify factors for recurrence in patients who present with a first episode of lower-limb cellulitis. A secondary aim was to formulate a score based on observed clinical risk factors that might predict recurrence within a year. METHODS: Dermatology referral forms and national computerized records were reviewed from 2003 to 2012. Demographics, coexistent dermatoses, local factors, and comorbidities were reviewed. RESULTS: A total of 102 (45.3%) of 225 patients had recurrence. Multivariate analysis showed that lymphedema (P < .0005), chronic venous insufficiency (P < .0005), peripheral vascular disease (P = .002), and deep vein thrombosis (P = .008) predicted for recurrence. The Cellulitis Recurrence Score (CRS) was constructed based on these factors. CRS >= 2 was associated with a positive predictive value of 83.6% and negative predictive value of 67.5%. Model performance was good (Hosmer-Lemeshow statistic, P = .753). LIMITATIONS: This is a retrospective study limited to an inpatient cohort. CONCLUSION: Lymphedema, chronic venous insufficiency, peripheral vascular disease, and deep vein thrombosis were risk factors. CRS is reliable for predicting recurrence, and early interventions should be considered in patients with CRS >= 2. PMID- 25443626 TI - Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international panel of experts. AB - Mucous membrane pemphigoid encompasses a group of autoimmune bullous diseases with a similar phenotype characterized by subepithelial blisters, erosions, and scarring of mucous membranes, skin, or both. Although knowledge about autoimmune bullous disease is increasing, there is often a lack of clear definitions of disease, outcome measures, and therapeutic end points. With clearer definitions and outcome measures, it is possible to directly compare the results and data from various studies using meta-analyses. This consensus statement provides accurate and reproducible definitions for disease extent, activity, outcome measures, end points, and therapeutic response for mucous membrane pemphigoid and proposes a disease extent score, the Mucous Membrane Pemphigoid Disease Area Index. PMID- 25443628 TI - Association between antidiabetic drugs and psoriasis risk in diabetic patients: results from a nationwide nested case-control study in Taiwan. AB - BACKGROUND: The risk of psoriasis in diabetic patients has rarely been explored. OBJECTIVES: We sought to investigate the association between antidiabetic therapies and psoriasis. METHODS: The incidence of psoriasis was compared between a representative diabetic cohort and a matched nondiabetic cohort. We next conducted a nationwide cohort study with 1,659,727 diabetic patients using the National Health Insurance Research Database of Taiwan 1997 through 2011. Multivariate conditional logistic regression was used for nested case-control analyses. RESULTS: Incidence rates of psoriasis among diabetic patients and nondiabetic matched control subjects were 70.2 (95% confidence interval [CI] 59.5 80.9) and 42.3 (95% CI 39.5-45.5) per 100,000 person-years, respectively (P < .0001). Frequent insulin use was associated with higher risk of incident psoriasis (adjusted odds ratio 1.29, 95% CI 1.18-1.42) after adjusting for comorbidities, disease duration, and number of hospital visits. Among diabetic patients without history of insulin use, frequent use of thiazolidinedione was associated with lower risk of psoriasis (adjusted odds ratio 0.87, 95% CI 0.77 0.99). LIMITATIONS: The National Health Insurance Research Database did not contain information regarding disease severity, diet, body mass index, lifestyle, or family history. CONCLUSION: Among diabetic patients, regular insulin use is associated with psoriasis development. Frequent use of thiazolidinedione may be associated with modest reduction in psoriasis risk. PMID- 25443629 TI - Prevention of melasma relapses with sunscreen combining protection against UV and short wavelengths of visible light: a prospective randomized comparative trial. PMID- 25443630 TI - Editorial: neural and behavioral biology of intellectual disability (ID). PMID- 25443631 TI - Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis. AB - Linear Ubiquitin chain Assembly Complex (LUBAC) is an E3 ligase complex that generates linear ubiquitin chains and is important for tumour necrosis factor (TNF) signaling activation. Mice lacking Sharpin, a critical subunit of LUBAC, spontaneously develop inflammatory lesions in the skin and other organs. Here we show that TNF receptor 1 (TNFR1)-associated death domain (TRADD)-dependent TNFR1 signaling in epidermal keratinocytes drives skin inflammation in Sharpin deficient mice. Epidermis-restricted ablation of Fas-associated protein with death domain (FADD) combined with receptor-interacting protein kinase 3 (RIPK3) deficiency fully prevented skin inflammation, while single RIPK3 deficiency only delayed and partly ameliorated lesion development in Sharpin-deficient mice, showing that inflammation is primarily driven by TRADD- and FADD-dependent keratinocyte apoptosis while necroptosis plays a minor role. At the cellular level, Sharpin deficiency sensitized primary murine keratinocytes, human keratinocytes, and mouse embryonic fibroblasts to TNF-induced apoptosis. Depletion of FADD or TRADD in Sharpin-deficient HaCaT cells suppressed TNF induced apoptosis, indicating the importance of FADD and TRADD in Sharpin dependent anti-apoptosis signaling in keratinocytes. PMID- 25443633 TI - Heart failure in SAVOR-TIMI 53: The hindsight of diabetic retinopathy. PMID- 25443634 TI - [The use of nails to diagnosis diseases]. AB - For those interested in nails, a fairly good knowledge of the anatomy of the nail unit is indispensable. But nothing will replace a careful, clinical examination of the nail apparatus. The shape of the nail, surface abnormalities and coloration, with or without a magnifying glass, may well provide a medical diagnosis not only in dermatology but also for medicine in general. Pits on the surface of the nail plate may be enough to diagnose psoriasis on a limited area of scalp dandruff. Even partial detachment of the nail apparatus might lead to the suspicion of psoriatic arthritis. A triangular lunula is associated with the absence of patellas. Finally, no pulmonary examination of a smoker is complete without looking for clubbing. It is high time to pay tribute to the nail. PMID- 25443632 TI - TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice. AB - SHARPIN regulates immune signaling and contributes to full transcriptional activity and prevention of cell death in response to TNF in vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ inflammation, characterized by dermatitis, liver inflammation, splenomegaly, and loss of Peyer's patches. TNF-dependent cell death has been proposed to cause the inflammatory phenotype and consistent with this we show Tnfr1, but not Tnfr2, deficiency suppresses the phenotype (and it does so more efficiently than Il1r1 loss). TNFR1-induced apoptosis can proceed through caspase-8 and BID, but reduction in or loss of these players generally did not suppress inflammation, although Casp8 heterozygosity significantly delayed dermatitis. Ripk3 or Mlkl deficiency partially ameliorated the multi-organ phenotype, and combined Ripk3 deletion and Casp8 heterozygosity almost completely suppressed it, even restoring Peyer's patches. Unexpectedly, Sharpin, Ripk3 and Casp8 triple deficiency caused perinatal lethality. These results provide unexpected insights into the developmental importance of SHARPIN. PMID- 25443635 TI - [Management of onychomycosis]. AB - Onychomycosis accounts for half of all nail pathologies. Never prescribe a local or a systemic antifungal without confirmation of the diagnosis. The quality of the sampling is the cornerstone of mycological analysis. If the results of the mycology are negative, do not hesitate to harvest a new specimen if the clinical features are highly suggestive. Otherwise, think to another cause. Identify the clinical presentations at high risk of failure to classical treatments (thick hyperkeratosis, onycholysis, lateral disease, yellow spikes, moulds). Always eradicate as much as possible of the infected keratin (mechanically, chemically or surgically). A mycologic cure means a return to a complete normal nail with a negative culture. Prevent recurrences. PMID- 25443636 TI - [How to diagnose and treat psoriasis of the nails]. AB - Psoriasis is an inherited chronic hyper proliferative autoimmune disease. Nail involvement is common and is found in 61% of cases of cutaneous psoriasis, with lifetime incidence of 90%; 80 to 90% in patients with psoriatic arthritis. Classical manifestations on the nail apparatus are correlated with the origin site of the disease. The proximal matrix produces pitting, trachyonychia and Beau's lines, transverse grooves. The distal matrix (lunula) may appear spotted or erythematous in color. Inflammation of the mid or distal matrix causes leuconychia due to nail incorporation of parakeratotic cells. Nail bed and hyponychium can show onycholysis, oil drops (salmon patches) subungual hyperkeratosis and at the distal nail bed splinter hemorrhages. Induction or severe exacerbation of psoriasis may be due to drugs, such as beta-blockers, lithium, antimalarial agents, anti-TNF and interferon. PMID- 25443637 TI - [Severe hypercalcemia after substitution of prolonged deficiency of vitamin D in a patient with primary hyperparathyroidism]. PMID- 25443638 TI - [Letter on the article "Pericardial effusion: an unknown expression of Graves' disease"]. PMID- 25443639 TI - Myostatin in the placentae of pregnancies complicated with gestational diabetes mellitus. AB - INTRODUCTION: Gestational diabetes mellitus (GDM) is characterised by maternal glucose intolerance and insulin resistance during pregnancy. Myostatin, initially identified as a negative regulator of muscle development may also function in the regulation of placental development and glucose uptake. Myostatin expression in placentae of GDM complicated pregnancies is unknown. However, higher myostatin levels occur in placentae of pregnancies complicated with preeclampsia. We hypothesise that myostatin will be differentially expressed in GDM complicated pregnancies. METHODS: Myostatin concentrations (ELISA) were evaluated in plasma of presymptomatic women who later developed GDM and compared to plasma of normal glucose tolerant (NGT) women. Furthermore, myostatin protein expression (Western blot) was studied in placentae of pregnant women with GDM (treated with diet or insulin) compared to placentae of NGT women. RESULTS: No significant difference in myostatin concentration was seen in plasma of pre-symptomatic GDM women compared to NGT women. In placenta significant differences in myostatin protein expressions (higher precursor; p < 0.05and lower dimer: p < 0.005) were observed in GDM complicated compared to NGT pregnancies. Furthermore, placentae of GDM women treated with insulin compared to diet have higher dimer (p < 0.005) and lower precursor (p < 0.05). Compared to lean women, placentae of obese NGT women were lower in myostatin dimer expression (p < 0.05). DISCUSSION: Myostatin expression in placental tissue is altered under stress conditions (e.g. obesity and abnormal glucose metabolism) found in pregnancies complicated with GDM. We hypothesise that myostatin is active in these placentae and could affect glucose homoeostasis and/or cytokine production thereby altering the function of the placenta. PMID- 25443641 TI - Perspective of community pharmacists on their practice with patients who have an antidepressant drug treatment: findings from a focus group study. AB - BACKGROUND: Around 2/3 of patients with major depression discontinue their antidepressant drug treatment (ADT) prematurely. Community pharmacists can rely on their regular contacts with patients to identify and support those experiencing difficulties with their ADT. OBJECTIVE: The aim of this study is to describe pharmacists' perceptions with respect to their practices related to patients having an ADT. METHODS: A qualitative study was conducted based on 6 focus groups involving 43 community pharmacists in 5 regions of Quebec province, Canada. Verbatim transcripts of focus groups were analyzed using computer assisted thematic analysis. RESULTS: The discussions revealed three major aspects of the participants' pharmacy practice: convincing patients to initiate ADT, dealing with side effects in the first weeks of the treatment, and taking a reactive approach to managing the treatment for the remainder of the follow-up. Discussions also enabled participants to identify the challenges they face concerning their practice with patients who have an ADT, and voice their recommendations for improving pharmacy practice and ultimately patient adherence to ADT. CONCLUSIONS: Pharmacists wishing to help their patients to adequately manage their ADT face important barriers. Potential solutions include tools designed to help pharmacists better detect and intervene in ADT-related problems. Study findings will guide the on-going development of training and tools to support pharmacists' practice in this context. PMID- 25443640 TI - Utility of a brief screening tool for medication-related problems. AB - BACKGROUND: Medication therapy management (MTM) services position pharmacists to prevent, detect, and resolve medication-related problems (MRPs.) However, selecting patients for MTM who are most at risk for MRPs is a challenge. Using self-administered scales that are practical for use in clinical practice are one approach. OBJECTIVE: The objective of this study was to estimate the psychometric properties of a brief self-administered scale as a screening tool for MRPs. METHODS: This was a non-randomized study utilizing questionnaires administered cross-sectionally. In Phase 1, patients (n = 394) at community pharmacies and outpatient clinics completed 78 items, provided to the study team by item authors, assessing perceived MRPs. These data were used to select items for further investigation as a brief, self-administered scale, and estimate the reliability and construct validity of the resulting instrument. In Phase 2, a convenience sample of patients (n = 200) at community pharmacies completed a nine item, self-administered scale. After completion, they were engaged in a comprehensive medication review by their pharmacist who was blinded to questionnaire responses. The main outcome measure for estimating the criterion related validity of the scale was the number of pharmacist-identified medication related problems (MRPs.) Item statistics were computed as well as bivariate associations between scale scores and other variables with MRPs. A multivariate model was constructed to examine the influence of scale scores on MRPs after controlling for other significant variables. RESULTS: Higher scores on the questionnaire were positively correlated with more pharmacist-identified MRPs (r = 0.24; P = 0.001) and scores remained as a significant predictor (P = 0.031) when controlling for other relevant variables in a multivariate regression model (R(2) = 0.21; P < 0.001). CONCLUSIONS: Patient responses on the scale may have a modest role in predicting MRPs. The use of self-administered questionnaires such as this may supplement other available patient data in developing patient eligibility criteria for MTM, however, additional research is warranted. PMID- 25443642 TI - Future expectations for Japanese pharmacists as compared to the rest of the world. AB - It is important to share information about other countries' pharmacists to optimize cross-border medical cooperation. This paper examines the dispensing systems and the work done by pharmacists in the United Kingdom, Germany, France, Thailand, and Malaysia so as to compare these countries' medical practices and develop a cohesive vision for the future of Japanese pharmacists. All five of the countries have dispensing assistants. Pharmacists in Japan have duties of inventory control, drug dispensing, and providing medication advice. In contrast, assistants working in other countries are responsible for some aspects of dispensing and inventory control, allowing the pharmacists to spend their time and competency in instructing patients on how to take their medication. Because of this, pharmacists were actively involved with health promotion intervention in the United Kingdom, Germany, and France. It is hoped that work done by Japanese pharmacists would transition from primarily dispensing drugs to patient care, advice, and counseling to enrich overall health promotion and health/nutrition counseling. PMID- 25443643 TI - Sidestream dark field videomicroscopy for in vivo evaluation of vascularization and perfusion of mammary tumours in HER2/neu transgenic mice. AB - Angiogenesis plays a key role in tumour growth and the formation of metastases. Angiogenesis inhibitors and antivascular agents may prove useful in the treatment of breast cancer. A comprehensive characterization of the vasculature and perfusion of mammary tumours is a prerequisite for developing new specific drugs. We used sidestream dark field videomicroscopy to evaluate in vivo the vascular network of spontaneous mammary tumours in HER2/neu transgenic mice. The tumour masses showed higher vessel density compared with the healthy mammary gland (median (interquartile range) total vessel density 16.8 (13.4-20.5) vs 9.1 (8.1 10.9) mm/mm(2), respectively; P < 0.001). Tumor vessel density was reduced in mice treated with the anti-angiogenesis agent berberine, 12.1 (10.6-13.1) mm/mm(2). Sidestream dark field imaging is a versatile technique that may be useful for understanding the role of angiogenesis in the progression of breast cancer and its relationship with outcome. It may represent a valuable tool for dynamic monitoring of the effects of new anti-angiogenesis therapies. PMID- 25443644 TI - Thiophenes, polyacetylenes and terpenes from the aerial parts of Eclipata prostrate. AB - One new bithiophenes, 5-(but-3-yne-1,2-diol)-50-hydroxy-methyl-2,20-bithiophene (2), two new polyacetylenic glucosides, 3-O-b-D-glucopyranosyloxy-1-hydroxy-4E,6E tetradecene-8,10,12-triyne (8), (5E)-trideca-1,5-dien-7,9,11-triyne-3,4-diol-4-O b-D-glucopyranoside (9), six new terpenoid glycosides, rel-(1S,2S,3S,4R,6R)-1,6 epoxy-menthane-2,3-diol-3-O-b-D-glucopyranoside (10), rel-(1S,2S,3S,4R,6R)-3-O-(6 O-caffeoyl-b-D-glucopyranosyl)-1,6-epoxy menthane-2,3-diol (11), (2E,6E)-2,6,10 trimethyl-2,6,11-dodecatriene-1,10-diol-1-O-b-D-glucopyranoside (12), 3b,16b,29 trihydroxy oleanane-12-ene-3-O-b-D-glucopyranoside (13), 3,28-di-O-b-D glucopyranosyl-3b,16b-dihydroxy oleanane-12-ene-28-oleanlic acid (14), 3-O-b-D glucopyranosyl-(1?2)-b-D-glucopyranosyl oleanlic-18-ene acid-28-O-b-D glucopyranoside (15), along with fifteen known compounds (1, 3-7, and 16-24), were isolated from the aerial parts of Eclipta prostrata. Their structures were established by analysis of the spectroscopic data. The isolated compounds 1-9 were tested for activities against dipeptidyl peptidase IV (DPP-IV), compound 7 showed significant antihyperglycemic activities by inhibitory effects on DPP-IV in human plasma in vitro, with IC50 value of 0.51 lM. Compounds 10-24 were tested in vitro against NF-jB-luc 293 cell line induced by LPS. Compounds 12, 15, 16, 19, 21, and 23 exhibited moderate anti-inflammatory activities. PMID- 25443645 TI - Pulmonary arteriovenous malformations and their mimics. AB - Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between the pulmonary arteries and veins, which result in a right-to-left (R-L) shunt with resultant hypoxemia, the severity of which will depend upon the size and number of lesions. Most PAVMs occur in individuals with hereditary haemorrhagic telangiectasia (HHT) and are a cause of serious morbidity and mortality largely related to cerebrovascular complications secondary to paradoxical embolization. The importance of their recognition and treatment by embolization, even in the absence of symptoms, is well known. Their appearances on chest radiographs are often, but not always, characteristic and the CT appearances are diagnostic; however, there are a number of both vascular and non-vascular diseases that can cause confusion. This review serves to highlight these PAVM "mimics". PMID- 25443646 TI - Re: ultrasonographic elastography of thyroid nodules: is adding strain ratio to colour mapping better? PMID- 25443647 TI - Detection of nickel and palladium contact hypersensitivity by a flow cytometric lymphocyte proliferation test. AB - We established a flow cytometric lymphocyte proliferation test (LPT) for the detection of nickel (Ni) and palladium (Pd) sensitization. Eighty-one consecutive patients with an indication for patch test (PT) were tested by LPT with Ni (NiSO4 ) and Pd (Na2 PdCl4 and PdCl2 ) salts. The imprecision of the LPT was low (coefficient of variation 7.2%). Using PT as a diagnostic reference, the sensitivity and specificity of LPT were 74.4% and 80% for NiSO4 , 74.4% and 78.3% for Na2 PdCl4 , and 57.2% and 85.4% for PdCl2 , respectively. For both Ni and Pd, the likelihood ratio for a positive PT markedly increased with increasing LPT value. With medical history as a reference, the sensitivity and specificity were 40.6% and 82.1% for LPT and 59.4% and 89.7% for PT, respectively. Combination of LPT and PT resulted in a higher specificity of 95%, albeit lower sensitivity of 34.4%. In conclusion, flow cytometric LPT represents a reliable and useful method for the detection of Ni and Pd sensitization. LPT values correlate with PT results and, when used in combination with PT, increase test specificity. PMID- 25443648 TI - [Diagnostic performance of bone scintigraphy and (11)C-Choline PET/CT in the detection of bone metastases in patients with biochemical recurrence of prostate cancer]. AB - AIM: To compare bone scan (BS) with (11)C-Choline PET/CT for the detection of bone metastases in patients with biochemical recurrence of prostate cancer (PC). MATERIAL AND METHODS: A total of 169 patients with biochemical recurrence of PC(PSA:2.4-58 ng/ml) who were referred for both exams (0-15 days-in-between) were included. Lesion-detection-rate per patients and lesions were analyzed for both BS and (11)C-Choline PET/CT. Metastasis diagnosis was reached by: biopsy, CT/(18)F-Fluoride PET/MRI confirmation, or evidence of progression in subsequent imaging procedures. RESULTS: A total of 91 lesions were found to be active in BS and/or (11)C-choline PET/CT (40 patients), with 78 of which were metastatic. BS detected 38 blastic, 2 lytic and 10 non-CT-evident lesions. (11)C-Choline PET/CT detected 41 blastic, 4 lytic and 29 non-CT-evident lesions. BS and (11)C-Choline PET/CT sensitivities were 65.4% and 96.1%; specificities ere 38.5 and 92.3% (chi(2) 8.27, p<0.04). Both imaging techniques were negative in 118 patients. Tracer avid lesions were found in 51 patients: with 30/51 being BS and (11)C Choline PET/CT concordant; in 21/51 patients had discordant lesions (kappa 0.712, p=0.00). Lesions were absolutely discordant in 10/19 patients,: 5 FN BS, 2 FP BS (degenerative changes; dysplasia), 1 FN (11)C-Choline PET/CT (blastic), 1 FP (11)C-Choline PET/CT (degenerative), 1 out of field-of-view lesion with (11)C Choline PET/CT (tibia alone). (11)C-Choline PET/CT showed extraosseous involvement in 26/51 patients with bone metastases: 9 local recurrences, 5 infra diaphragmatic-lymph-nodes, 2 supra-diaphragmatic, 5 local and infra diaphragmatic, 4 infra- and supra-diaphragmatic, 1 supra-diaphragmatic and lung metastases. CONCLUSION: (11)C-Choline PET/CT yielded better sensitivity and specificity than BS for the detection of bone involvement in patients with biochemical recurrence of PC and allowed extraosseous restaging, with an impact in the clinical management of these patients. PMID- 25443649 TI - Aerobic capacity and upper limb strength are reduced in women diagnosed with breast cancer: a systematic review. AB - QUESTION: What are typical values of physical function for women diagnosed with breast cancer and how do these compare to normative data? DESIGN: Systematic review with meta-analysis. PARTICIPANTS: Women diagnosed with breast cancer who were before, during or after treatment. OUTCOME MEASURES: Physical function was divided into three categories: aerobic capacity, upper and lower extremity muscular fitness, and mobility. Measures of aerobic capacity included field tests (6-minute walk test, 12-minute walk tests, Rockport 1-mile test, and 2-km walk time) and submaximal/maximal exercise tests on a treadmill or cycle ergometer. Measures of upper and lower extremity muscular fitness included grip strength, one repetition maximum (bench, chest or leg press), muscle endurance tests, and chair stands. The only measure of mobility was the Timed Up and Go test. RESULTS: Of the 1978 studies identified, 85 were eligible for inclusion. Wide ranges of values were reported, reflecting the range of ages, disease severity, treatment type and time since treatment of participants. Aerobic fitness values were generally below average, although 6-minute walk time was closer to population norms. Upper and lower extremity strength was lower than population norms for women who were currently receiving cancer treatment. Lower extremity strength was above population norms for women who had completed treatment. CONCLUSION: Aerobic capacity and upper extremity strength in women diagnosed with breast cancer are generally lower than population norms. Assessment of values for lower extremity strength is less conclusive. As more research is published, expected values for sub-groups by age, treatment, and co-morbidities should be developed. [Neil Sztramko SE, Kirkham AA, Hung SH, Niksirat N, Nishikawa K Campbell KL (2014) Aerobic capacity and upper limb strength are reduced in women diagnosed with breast cancer: a systematic review.Journal of Physiotherapy60: 189-200]. PMID- 25443650 TI - Standing with electrical stimulation and splinting is no better than standing alone for management of ankle plantarflexion contractures in people with traumatic brain injury: a randomised trial. AB - QUESTION: Is a combination of standing, electrical stimulation and splinting more effective than standing alone for the management of ankle contractures after severe brain injury? DESIGN: A multi-centre randomised trial with concealed allocation, assessor blinding and intention-to-treat analysis. PARTICIPANTS: Thirty-six adults with severe traumatic brain injury and ankle plantarflexion contractures. INTERVENTION: All participants underwent a 6-week program. The experimental group received tilt table standing, electrical stimulation and ankle splinting. The control group received tilt table standing alone. OUTCOME MEASURES: The primary outcome was passive ankle dorsiflexion with a 12Nm torque. Secondary outcomes included: passive dorsiflexion with lower torques (3, 5, 7 and 9Nm); spasticity; the walking item of the Functional Independence Measure; walking speed; global perceived effect of treatment; and perceived treatment credibility. OUTCOME MEASURES were taken at baseline (Week 0), end of intervention (Week 6), and follow-up (Week 10). RESULTS: The mean between-group differences (95% CI) for passive ankle dorsiflexion at Week 6 and Week 10 were -3 degrees (-8 to 2) and -1 degrees (-6 to 4), respectively, in favour of the control group. There was a small mean reduction of 1 point in spasticity at Week 6 (95% CI 0.1 to 1.8) in favour of the experimental group, but this effect disappeared at Week 10. There were no differences for other secondary outcome measures except the physiotherapists' perceived treatment credibility. CONCLUSION: Tilt table standing with electrical stimulation and splinting is not better than tilt table standing alone for the management of ankle contractures after severe brain injury. TRIAL REGISTRATION: ACTRN12608000637347. [Leung J, Harvey LA, Moseley AM, Whiteside B, Simpson M, Stroud K (2014) Standing with electrical stimulation and splinting is no better than standing alone for management of ankle plantarflexion contractures in people with traumatic brain injury: a randomised trial.Journal of Physiotherapy60: 201-208]. PMID- 25443651 TI - Diabetes that impacts on routine activities predicts slower recovery after total knee arthroplasty: an observational study. AB - QUESTION: In the 6 months after total knee arthroplasty (TKA), what is the pattern of pain resolution and functional recovery in people without diabetes, with diabetes that does not impact on routine activities, and with diabetes that does impact on routine activities? Is diabetes that impacts on routine activities an independent predictor of slower resolution of pain and functional recovery after TKA? DESIGN: Community-based prospective observational study. PARTICIPANTS: A consecutive cohort of 405 people undergoing primary TKA, of whom 60 (15%) had diabetes. PARTICIPANTS with diabetes were also asked preoperatively whether diabetes impacted on their routine activities. PARTICIPANTS were categorised into three groups: no diabetes (n=345), diabetes with no impact on activities (n=41), and diabetes that impacted activities (n=19). OUTCOME MEASURES: Pain and function were measured using the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index within the month before surgery and 1, 3 and 6 months after surgery. Demographic, medical and surgical factors were also measured, along with depression, social support and health-related quality of life. RESULTS: No baseline differences in pain and function were seen among the three groups (p > 0.05). Adjusting for age, gender and contralateral joint involvement across the 6 postoperative months, participants with diabetes that impacted on routine activities had pain scores that were 8.3 points higher (indicating greater pain) and function scores that were 5.4 points higher (indicating lower function) than participants without diabetes. PARTICIPANTS with diabetes that doesn't impact on routine activities had similar recovery to those without diabetes. CONCLUSION: People undergoing TKA who report preoperatively that diabetes impacts on their routine activities have less recovery over 6 months than those without diabetes or those with diabetes that does not impact on routine activities. Physiotherapists could institute closer monitoring within the hospital and community settings for people undergoing TKA who perceive that diabetes impacts on their routine activities. [Amusat N, Beaupre L, Jhangri GS, Pohar SL, Simpson S, Warren S, Jones CA (2014) Diabetes that impacts on routine activities predicts slower recovery after total knee arthroplasty: an observational study.Journal of Physiotherapy60: 217-223]. PMID- 25443653 TI - ClC-5: Physiological role and biophysical mechanisms. AB - Cl(-) transport in animal cells has fundamental physiological roles and it is mediated by a variety of protein families, one of them being the CLC family of ion channels and transporters. Besides their physiological relevance, CLC proteins show peculiar biophysical properties. This review will focus on a member of the CLC protein family, the endosomal Cl(-)/H(+) antiporter ClC-5. ClC-5 mutations cause Dent's disease, a renal syndrome due to defective protein reabsorption in the proximal tubule. This established the critical function of ClC-5 for endocytosis. However, our understanding of ClC-5's molecular role in endosomes and of its biophysical properties has proved elusive in spite of important progress achieved in the last two decades. Early models in which ClC-5 would provide a shunt conductance to enable efficient endosomal acidification conflicted with the antiport activity of ClC-5 that has more recently emerged. Currently, the physiological role of ClC-5 is hotly debated and its biophysical properties are still not fully understood. PMID- 25443652 TI - Assessing organizational readiness for depression care quality improvement: relative commitment and implementation capability. AB - BACKGROUND: Depression is a major cause of morbidity and cost in primary care patient populations. Successful depression improvement models, however, are complex. Based on organizational readiness theory, a practice's commitment to change and its capability to carry out the change are both important predictors of initiating improvement. We empirically explored the links between relative commitment (i.e., the intention to move forward within the following year) and implementation capability. METHODS: The DIAMOND initiative administered organizational surveys to medical and quality improvement leaders from each of 83 primary care practices in Minnesota. Surveys preceded initiation of activities directed at implementation of a collaborative care model for improving depression care. To assess implementation capability, we developed composites of survey items for five types of organizational factors postulated to be collaborative care barriers and facilitators. To assess relative commitment for each practice, we averaged leader ratings on an identical survey question assessing practice priorities. We used multivariable regression analyses to assess the extent to which implementation capability predicted relative commitment. We explored whether relative commitment or implementation capability measures were associated with earlier initiation of DIAMOND improvements. RESULTS: All five implementation capability measures independently predicted practice leaders' relative commitment to improving depression care in the following year. These included the following: quality improvement culture and attitudes (p = 0.003), depression culture and attitudes (p <0.001), prior depression quality improvement activities (p <0.001), advanced access and tracking capabilities (p = 0.03), and depression collaborative care features in place (p = 0.03). Higher relative commitment (p = 0.002) and prior depression quality improvement activities appeared to be associated with earlier participation in the DIAMOND initiative. CONCLUSIONS: The study supports the concept of organizational readiness to improve quality of care and the use of practice leader surveys to assess it. Practice leaders' relative commitment to depression care improvement may be a useful measure of the likelihood that a practice is ready to initiate evidence-based depression care changes. A comprehensive organizational assessment of implementation capability for depression care improvement may identify specific barriers or facilitators to readiness that require targeted attention from implementers. PMID- 25443654 TI - Targeting a mitochondrial potassium channel to fight cancer. AB - Although chemotherapy is able to cure many patients with malignancies, it still also often fails. Therefore, novel approaches and targets for chemotherapeutic treatment of malignancies are urgently required. Recent studies demonstrated the expression of several potassium channels in the inner mitochondrial membrane. Among them the voltage gated potassium channel Kv1.3 and the big-potassium (BK) channel were shown to directly function in cell death by serving as target for pro-apoptotic Bax and Bak proteins. Here, we discuss the role of mitochondrial potassium channel Kv1.3 (mitoKv1.3) in cell death and its potential function in treatment of solid tumors, leukemia and lymphoma. Bax and Bak inhibit mitoKv1.3 by directly binding into the pore of the channel, by a toxin-like mechanism. Inhibition of mitoKv1.3 results in an initial hyperpolarization of the inner mitochondrial membrane that triggers the production of reactive oxygen species (ROS). ROS in turn induce a release of cytochrome c from the cristae of the inner mitochondrial membrane and an activation of the permeability transition pore, resulting in opening of the intrinsic apoptotic cell death. Since mitoKv1.3 functions downstream of pro-apoptotic Bax and Bak, compounds that directly inhibit mitoKv1.3 may serve as a new class of drugs for treatment of tumors, even with an altered expression of either pro- or anti-apoptotic Bcl-2 protein family members. This was successfully proven by the in vivo treatment of mouse melanoma and ex vivo human chronic leukemia B cells with inhibitors of mitoKv1.3. PMID- 25443656 TI - Efficient transduction of equine adipose-derived mesenchymal stem cells by VSV-G pseudotyped lentiviral vectors. AB - Equine adipose-derived mesenchymal stem cells (EADMSC) provide a unique cell based approach for treatment of a variety of equine musculoskeletal injuries, via regeneration of diseased or damaged tissue, or the secretion of immunomodulatory molecules. These capabilities can be further enhanced by genetic modification using lentiviral vectors, which provide a safe and efficient method of gene delivery. We investigated the suitability of lentiviral vector technology for gene delivery into EADMSC, using GFP expressing lentiviral vectors pseudotyped with the G glycoprotein from the vesicular stomatitis virus (V-GFP) or, for the first time, the baculovirus gp64 envelope protein (G-GFP). In this study, we produced similarly high titre V-GFP and G-GFP lentiviral vectors. Flow cytometric analysis showed efficient transduction using V-GFP; however G-GFP exhibited a poor ability to transduce EADMSC. Transduction resulted in sustained GFP expression over four passages, with minimal effects on cell viability and doubling time, and an unaltered chondrogenic differentiation potential. PMID- 25443657 TI - A novel intronic splice site deletion of the IL-2 receptor common gamma chain results in expression of a dysfunctional protein and T-cell-positive X-linked Severe combined immunodeficiency. AB - X-linked severe combined immunodeficiency is caused by mutations in the IL-2 receptor common gamma chain and classically presents in the first 6 months of life with predisposition to bacterial, viral and fungal infections. In most instances, affected individuals are lymphopenic with near complete absence of T cells and NK cells. We report a boy who presented at 12 months of age with Pneumocystis jiroveci pneumonia and a family history consistent with X-linked recessive inheritance. He had a normal lymphocyte count including the presence of T cells and a broad T-cell-receptor diversity, as well as normal surface expression of the common gamma chain (CD132) protein. He however had profound hypogammaglobulinaemia, and IL-2-induced STAT5 phosphorylation was absent. Sequencing of IL-2RG demonstrated a 12-base pair intronic deletion close to the canonical splice site of exon 5, which resulted in a variety of truncated IL2RG mRNA species. A review of the literature identified 4 other patients with T-cell positive X-SCID, with the current patient being the first associated with an mRNA splicing defect. This case raises the question of how a dysfunctional protein incapable of mediating STAT5 phosphorylation might nonetheless support T-cell development. Possible explanations are that STAT5-mediated signal transduction may be less relevant to IL7-receptor-mediated T-cell development than are other IL7R-induced intracellular transduction pathways or that a low level of STAT5 phosphorylation, undetectable in the laboratory, may be sufficient to support some T-cell development. PMID- 25443655 TI - Imaging of mitochondrial Ca2+ dynamics in astrocytes using cell-specific mitochondria-targeted GCaMP5G/6s: mitochondrial Ca2+ uptake and cytosolic Ca2+ availability via the endoplasmic reticulum store. AB - Mitochondrial Ca(2+) plays a critical physiological role in cellular energy metabolism and signaling, and its overload contributes to various pathological conditions including neuronal apoptotic death in neurological diseases. Live cell mitochondrial Ca(2+) imaging is an important approach to understand mitochondrial Ca(2+) dynamics. Recently developed GCaMP genetically-encoded Ca(2+) indicators provide unique opportunity for high sensitivity/resolution and cell type-specific mitochondrial Ca(2+) imaging. In the current study, we implemented cell-specific mitochondrial targeting of GCaMP5G/6s (mito-GCaMP5G/6s) and used two-photon microscopy to image astrocytic and neuronal mitochondrial Ca(2+) dynamics in culture, revealing Ca(2+) uptake mechanism by these organelles in response to cell stimulation. Using these mitochondrial Ca(2+) indicators, our results show that mitochondrial Ca(2+) uptake in individual mitochondria in cultured astrocytes and neurons can be seen after stimulations by ATP and glutamate, respectively. We further studied the dependence of mitochondrial Ca(2+) dynamics on cytosolic Ca(2+) changes following ATP stimulation in cultured astrocytes by simultaneously imaging mitochondrial and cytosolic Ca(2+) increase using mito GCaMP5G and a synthetic organic Ca(2+) indicator, x-Rhod-1, respectively. Combined with molecular intervention in Ca(2+) signaling pathway, our results demonstrated that the mitochondrial Ca(2+) uptake is tightly coupled with inositol 1,4,5-trisphosphate receptor-mediated Ca(2+) release from the endoplasmic reticulum and the activation of G protein-coupled receptors. The current study provides a novel approach to image mitochondrial Ca(2+) dynamics as well as Ca(2+) interplay between the endoplasmic reticulum and mitochondria, which is relevant for neuronal and astrocytic functions in health and disease. PMID- 25443658 TI - Effect of hygienization treatment on the recovery and/or regrowth of microbial indicators in sewage sludge. AB - AIMS: Escherichia coli (EC) is the primary indicator micro-organism in regulations for sewage sludge reuse. The aim of this work was to assess the ability of EC to enter and recover from a viable-but-not-culturable state (VBNC) after sludge hygienization treatments. METHODS AND RESULTS: The persistence of EC, somatic coliphages (SOMCPH), spores of sulphite-reducing clostridia (SRC) and Salmonella spp. was assessed in digested sludge after different pasteurization treatments and storage conditions. Pasteurization at 55 degrees C produced EC injured cells that were resuscitated during the first 24 h. Different sludge treatments altered the inactivation kinetics of EC, while SOMCPH and SRC did not resuscitate and showed lower die-off than EC. No regrowth was observed in stored sludge for up to 60 days. CONCLUSIONS: EC monitoring by culturable methods is not by itself a suitable method for assessing the hygienization achieved in sludge as EC can enter into VBNC from which it can recover during the first hours of storage. SIGNIFICANCE AND IMPACT OF THE STUDY: The regulations should indicate the time when monitoring of EC should be performed to avoid the period when EC can resuscitate from VBNC or add alternative microbial indicators, such as SOMCPH, which do not have a VBNC state. PMID- 25443659 TI - Societal costs of home and hospital end-of-life care for palliative care patients in Ontario, Canada. AB - In Canada, health system restructuring has led to a greater focus on home-based palliative care as an alternative to institutionalised palliative care. However, little is known about the effect of this change on end-of-life care costs and the extent to which the financial burden of care has shifted from the acute care public sector to families. The purpose of this study was to assess the societal costs of end-of-life care associated with two places of death (hospital and home) using a prospective cohort design in a home-based palliative care programme. Societal cost includes all costs incurred during the course of palliative care irrespective of payer (e.g. health system, out-of-pocket, informal care-giving costs, etc.). Primary caregivers of terminal cancer patients were recruited from the Temmy Latner Centre for Palliative Care in Toronto, Canada. Demographic, service utilisation, care-giving time, health and functional status, and death data were collected by telephone interviews with primary caregivers over the course of patients' palliative trajectory. Logistic regression was conducted to model an individual's propensity for home death. Total societal costs of end-of life care and component costs were compared between home and hospital death using propensity score stratification. Costs were presented in 2012 Canadian dollars ($1.00 CDN = $1.00 USD). The estimated total societal cost of end-of-life care was $34,197.73 per patient over the entire palliative trajectory (4 months on average). Results showed no significant difference (P > 0.05) in total societal costs between home and hospital death patients. Higher hospitalisation costs for hospital death patients were replaced by higher unpaid caregiver time and outpatient service costs for home death patients. Thus, from a societal cost perspective, alternative sites of death, while not associated with a significant change in total societal cost of end-of-life care, resulted in changes in the distribution of costs borne by different stakeholders. PMID- 25443660 TI - Equal versus differential weighting in combining forecasts. PMID- 25443661 TI - [Nocardia farcinica lung infection in a patient with cystic fibrosis and a lung transplant]. AB - Patients with cystic fibrosis have a higher risk of developing chronic respiratory infectious diseases. The Nocardia farcinica lung infection is rare in this group of patients, and there are limited publications about this topic. Its diagnosis is complex, due to the clinical and the radiology signs being non specific. Identification of the agent responsible in the sputum culture is occasionally negative. It is a slow growing organism and for this reason treatment is delayed, which can lead to an increase in complications, hospitable stays, and mortality. A case is reported on a 26 year-old woman with cystic fibrosis and chronic lung colonization by Nocardia farcinica and Aspergillus fumigatus, on long-term treatment with ciprofloxacin, trimethoprim sulfamethoxazole, and posaconazole, who was admitted to ICU after bilateral lung transplantation. The initial post-operative progress was satisfactory. After discharge, the patient showed a gradual respiratory insufficiency with new chest X-ray showing diffuse infiltrates. Initially, the agent was not seen in the sputum culture. Prompt and aggressive measures were taken, due to the high clinical suspicion of a Nocardia farcinica lung infection. Treatment with a combination of amikacin and meropenem, and later combined with linezolid, led to the disappearance of the lung infiltrates and a clinical improvement. In our case, we confirm the rapid introduction of Nocardia farcinica in the new lungs. The complex identification and the delay in treatment increased the morbimortality. There is a special need for its eradication in patients with lung transplant, due to the strong immunosuppressive treatment. PMID- 25443663 TI - Increased risk of ischaemic stroke among patients with multiple sclerosis. AB - BACKGROUND AND PURPOSE: Inflammatory processes including autoimmune diseases which ignite endothelial dysfunction and atherosclerosis may promote development of cardiovascular diseases including ischaemic stroke. This study aimed to evaluate whether multiple sclerosis (MS) increases stroke risk. METHODS: A national insurance claim data set of 22 million enrollees in Taiwan was used to identify 1174 patients with MS and 4696 randomly selected age- and gender-matched controls from 1 January 1997 to 31 December 2010. Both cohorts were followed up until the occurrence of stroke or censor. Relevant covariates, such as age, gender, hypertension, diabetes, hyperlipidaemia, coronary artery disease, congestive heart failure and pregnancy, were included for further survey. The hazard ratio (HR) of stroke was assessed using a Cox proportional hazards regression model. RESULTS: After adjusting for the relevant covariates, the MS cohort had an increased risk of stroke (adjusted HR = 12.1 for 1 year; adjusted HR = 4.69 for 2-5 years) compared with the control cohort within 5 years of follow-up. Amongst participants without comorbidities, the MS cohort was still at a greater stroke risk than the control cohort [HR 4.93, 95% confidence interval (CI) 2.85-8.55]. Moreover, in the population aged <=40, MS was associated with a significantly increased risk of stroke (HR 12.7, 95% CI 3.44-46.7). CONCLUSIONS: Multiple sclerosis is declared to be associated with an increased risk in developing stroke, which requires closer attention to this group of patients for stroke prevention, especially in the younger population. PMID- 25443662 TI - Low-level laser (light) therapy increases mitochondrial membrane potential and ATP synthesis in C2C12 myotubes with a peak response at 3-6 h. AB - Low-level laser (light) therapy has been used before exercise to increase muscle performance in both experimental animals and in humans. However, uncertainty exists concerning the optimum time to apply the light before exercise. The mechanism of action is thought to be stimulation of mitochondrial respiration in muscles, and to increase adenosine triphosphate (ATP) needed to perform exercise. The goal of this study was to investigate the time course of the increases in mitochondrial membrane potential (MMP) and ATP in myotubes formed from C2C12 mouse muscle cells and exposed to light-emitting diode therapy (LEDT). LEDT employed a cluster of LEDs with 20 red (630 +/- 10 nm, 25 mW) and 20 near infrared (850 +/- 10 nm, 50 mW) delivering 28 mW cm(2) for 90 s (2.5 J cm(2)) with analysis at 5 min, 3 h, 6 h and 24 h post-LEDT. LEDT-6 h had the highest MMP, followed by LEDT-3 h, LEDT-24 h, LEDT-5 min and Control with significant differences. The same order (6 h > 3 h > 24 h > 5 min > Control) was found for ATP with significant differences. A good correlation was found (r = 0.89) between MMP and ATP. These data suggest an optimum time window of 3-6 h for LEDT stimulate muscle cells. PMID- 25443664 TI - Gender-specific Regulatory Challenges to Product Approval: a panel discussion. AB - On May 13, 2014, a 1-hour panel discussion session titled "Gender-specific Regulatory Challenges to Product Approval" was held during the Academic Emergency Medicine consensus conference, "Gender-specific Research in Emergency Medicine: Investigate, Understand, and Translate How Gender Affects Patient Outcomes." The session sought to bring together leaders in emergency medicine (EM) research, authors, and reviewers in EM research publications, as well as faculty, fellows, residents, and students engaged in research and clinical practice. A panel was convened involving a representative from the Office of Women's Health of the U.S. Food and Drug Administration, two pharmaceutical executives, and a clinical EM researcher. The moderated discussion also involved audience members who contributed significantly to the dialogue. Historical background leading up to the session along with the main themes of the discussion are reproduced in this article. These revolve around sex- and gender-specific research, statistical analysis of sex and gender, clinical practice, financial costs associated with pharmaceutical development, adaptive design, and specific recommendations on the regulatory process as it affects the specialty of EM. PMID- 25443666 TI - Glioblastoma masquerading as herpes simplex encephalitis. PMID- 25443665 TI - Stress exposure and sensitivity in the clinical high-risk syndrome: initial findings from the North American Prodrome Longitudinal Study (NAPLS). AB - There is inconsistent evidence for increased stress exposure among individuals at clinical high risk (CHR) for psychosis. Yet similar to patients with a diagnosed psychotic illness, the preponderance of evidence suggests that CHR individuals tend to experience stressful life events (LE) and daily hassles (DH) as more subjectively stressful than healthy individuals. The present study utilizes data from the North American Prodrome Longitudinal Study Phase 2 (NAPLS-2) to test the hypotheses that (1) CHR individuals manifest higher self-reported stress in response to both LE and DH when compared to healthy controls (HC), (2) group differences in self-reported stress increase with age, (3) baseline self-reported stress is associated with follow-up clinical status, and (4) there is a sensitization effect of LE on the response to DH. In contrast to some previous research, the present findings indicate that the CHR group (N=314) reported exposure to more LE when compared to the HC group (N=162). As predicted, CHR participants rated events as more stressful, and those who progressed to psychosis reported a greater frequency of LE and greater stress from events compared to those whose prodromal symptoms remitted. There was also some evidence of stress-sensitization; those who experienced more stress from LE rated current DH as more stressful. The results indicate that the "prodromal" phase is a period of heightened stress and stress sensitivity, and elevated cumulative lifetime exposure to stressful events may increase reactions to current stressors. PMID- 25443667 TI - Human papillomavirus types detected in skin warts and cancer differ in their transforming properties but commonly counteract UVB induced protective responses in human keratinocytes. AB - In the present study, E6E7 and E6 proteins of human papillomaviruses (HPVs) associated with skin warts and cancer were compared for their transforming and carcinogenic abilities in primary human keratinocytes (PHKs). We show that E6E7 of cancer associated beta HPV types, notably 49 and 24, were able to extend the life span and enhance the clonogenic efficiency of PHKs when maintained in serum free/low calcium medium. Activities of the beta HPV E6E7 were lower than those of HPV16 E6E7. In contrast, E6 proteins from HPV types detected in skin warts or cancer, notably 10, 49 and 38, attenuated UVB induced protective responses in PHKs including cell death, proliferation arrest and accumulation of the proapoptotic proteins, p53, bax or bak. Together, this investigation revealed functional differences and commonalities between HPVs associated with skin warts and cancer, and allowed the identification of specific properties of beta HPVs supporting their involvement in skin carcinogenesis. PMID- 25443669 TI - Variants in caspase-14 gene as risk factors for xerosis and atopic dermatitis. PMID- 25443668 TI - Designing a nine cysteine-less DNA packaging motor from bacteriophage T4 reveals new insights into ATPase structure and function. AB - The packaging motor of bacteriophage T4 translocates DNA into the capsid at a rate of up to 2000 bp/s. Such a high rate would require coordination of motor movements at millisecond timescale. Designing a cysteine-less gp17 is essential to generate fluorescently labeled motors and measure distance changes between motor domains by FRET analyses. Here, by using sequence alignments, structural modeling, combinatorial mutagenesis, and recombinational rescue, we replaced all nine cysteines of gp17 and introduced single cysteines at defined positions. These mutant motors retained in vitro DNA packaging activity. Single mutant motors translocated DNA molecules in real time as imaged by total internal reflection fluorescence microscopy. We discovered, unexpectedly, that a hydrophobic or nonpolar amino acid next to Walker B motif is essential for motor function, probably for efficient generation of OH(-) nucleophile. The ATPase Walker B motif, thus, may be redefined as "beta-strand (4-6 hydrophobic-rich amino acids)-DE-hydrophobic/nonpolar amino acid". PMID- 25443670 TI - Extremophilic micro-algae and their potential contribution in biotechnology. AB - Micro-algae have potential as sustainable sources of energy and products and alternative mode of agriculture. However, their mass cultivation is challenging due to low survival under harsh outdoor conditions and competition from other, undesired, species. Extremophilic micro-algae have a role to play by virtue of their ability to grow under acidic or alkaline pH, high temperature, light, CO2 level and metal concentration. In this review, we provide several examples of potential biotechnological applications of extremophilic micro-algae and the ranges of tolerated extremes. We also discuss the adaptive mechanisms of tolerance to these extremes. Analysis of phylogenetic relationship of the reported extremophiles suggests certain groups of the Kingdom Protista to be more tolerant to extremophilic conditions than other taxa. While extremophilic microalgae are beginning to be explored, much needs to be done in terms of the physiology, molecular biology, metabolic engineering and outdoor cultivation trials before their true potential is realized. PMID- 25443671 TI - Effect of carbon sources on growth and lipid accumulation of newly isolated microalgae cultured under mixotrophic condition. AB - In order to produce microalgal lipids that can be transformed to biodiesel fuel, one isolate with high lipid content was identified as Chlorella sp. Y8-1. The growth and lipid productivity of an isolated microalga Chlorella sp. Y8-1 were investigated under different cultivation conditions, including autotrophic growth (CO2, with light), heterotrophic growth (sucrose, without light) and mixotrophic growth (organic carbon sources and CO2, with light). Mixotrophic Chlorella sp. Y8 1 showed higher lipid content (35.5+/-4.2%) and higher lipid productivity (0.01 g/L/d) than Chlorella sp. Y8-1 cultivated under autotrophic and heterotrophic conditions on modified Walne medium. Fatty acid analysis of Chlorella sp. Y8-1 showed the major presence of palmitic acid (C16:0), oleic acid (C18:1), linoleic acid (C18:2) and linolenic acids (C18:3). The main fatty acid compositions of the Chlorella sp. Y8-1 are appropriate for biodiesel production. PMID- 25443672 TI - Microbial synthesis gas utilization and ways to resolve kinetic and mass-transfer limitations. AB - Microbial conversion of syngas to energy-dense biofuels and valuable chemicals is a potential technology for the efficient utilization of fossils (e.g., coal) and renewable resources (e.g., lignocellulosic biomass) in an environmentally friendly manner. However, gas-liquid mass transfer and kinetic limitations are still major constraints that limit the widespread adoption and successful commercialization of the technology. This review paper provides rationales for syngas bioconversion and summarizes the reaction limited conditions along with the possible strategies to overcome these challenges. Mass transfer and economic performances of various reactor configurations are compared, and an ideal case for optimum bioreactor operation is presented. Overall, the challenges with the bioprocessing steps are highlighted, and potential solutions are suggested. Future research directions are provided and a conceptual design for a membrane based syngas biorefinery is proposed. PMID- 25443673 TI - Dietary management of peanut and tree nut allergy: what exactly should patients avoid? AB - Peanut and tree nut allergies are the commonest cause of life-threatening food allergic reactions and significantly affect quality of life in children and their families. Dietary nut avoidance and provision of emergency medication is currently the mainstay of treatment. Nut avoidance has consequences on both quality of life and nutrition. We review the terminology that may cause confusion and lead to unnecessary dietary restrictions. In peanut or tree nut-allergic children, introduction of specific nuts to which the child is not allergic may improve quality of life and should be considered in patients with multiple foods allergies, vegan or ethnic-specific diets, in whom nuts are an important source of protein. Nut-allergic consumers do not just need to avoid foods containing nuts as an ingredient, but also contend with pre-packed foods which frequently have precautionary allergen labelling (PAL) referring to possible nut contamination. Although the published rate of peanut contamination in 'snack' foods with PAL (see Box ) ranges from 0.9-32.4%, peanut contamination in non snack items with PAL is far less common. We propose that in some peanut-allergic patients (depending on history of reactivity to trace levels of peanut, reaction severity, other medical conditions, willingness to always carry adrenaline, etc.), consideration may be given to allow the consumption of non-snack foods containing PAL following discussion with the patient's (and their family's) specialist. More work is needed to provide consumers with clearer information on the risk of potential nut contamination in pre-packed food. We also draw attention to the change in legislation in December 2014 that require mandatory disclosure of allergens in non-pre-packed foods. PMID- 25443674 TI - Anatomic and examination considerations of the oral cavity. AB - Patients often present to their physician with complaints of dental and/or oral pain. It is important for physicians to understand the complexities of oral anatomy and how to perform a basic clinical examination of this area to evaluate and potentially manage patients with these complaints. This article discusses anatomic structures of the oral cavity and systematic clinical examination of this area. PMID- 25443675 TI - Common dental and periodontal diseases: evaluation and management. AB - Physicians may encounter patients with dental and periodontal diseases in the context of outpatient medical practice. It is important for physicians to be aware of common dental and periodontal conditions and be able to assess for the presence and severity of these diseases. This article reviews common dental and periodontal conditions, their cardinal signs and symptoms, outpatient-setting assessment techniques, as well as common methods of treatment. Physicians detecting gross abnormalities on clinical examination should refer the patient to a dentist for further evaluation and management. PMID- 25443676 TI - Common dental and orofacial trauma: evaluation and management. AB - This article reviews common dental and orofacial traumatic injuries, and provides a broad overview and general principles of the diagnosis and management of common dental and orofacial injuries. Such knowledge will aid the physician in recognition and assessment of injury, proper treatment, and appropriate referral to the specialist. Although many of these injuries warrant appropriate consultation, a sound understanding of assessment and treatment protocol is important. PMID- 25443677 TI - Normal variations of oral anatomy and common oral soft tissue lesions: evaluation and management. AB - Examination of the oral cavity can provide significant diagnostic information regarding the general health of the patient. The oral cavity is affected by a multitude of pathologic conditions of variable cause and significance; however, there are numerous normal variations of oral soft tissue structures that may resemble a pathologic state. Understanding these variations assists practitioners to discriminate between normal versus abnormal findings and determine the appropriate course of management, if necessary. PMID- 25443678 TI - Oral and oropharyngeal cancer. AB - Oral and oropharyngeal cancer (OPC) is a complex and often relentless malignancy prone to local invasion and dissemination. Despite advances in understanding of the disease and improved therapeutic interventions, it continues to be diagnosed at an advanced stage and the survival rate remains poor. The financial cost of treating OPC may be the highest of all cancers in the United States and survivors often experience major detriments to quality of life. Major risk factors for OPC are tobacco, alcohol, areca nut, and human papillomavirus infection. This article updates medical practitioners on the causes, presentation, diagnosis, and management of OPC. PMID- 25443679 TI - Oral mucosal diseases: evaluation and management. AB - Oral mucosal diseases encompass several common conditions that affect the general population. Some of these disorders present with signs and symptoms that are pathognomonic for the condition, whereas others present with similar features that can make clinical diagnosis difficult to achieve. It is important for physicians to have a clear understanding of these disorders to provide appropriate care to patients. This article reviews clinical aspects of common oral mucosal disorders, including candidiasis, herpes simplex viral infections, aphthous stomatitis, lichen planus, pemphigus vulgaris, and mucous membrane pemphigoid. PMID- 25443680 TI - Temporomandibular disorders: evaluation and management. AB - Temporomandibular disorders remain a common cause of visits to primary care physicians, internists, pediatricians, and emergency departments. Advances in the clinical diagnosis, radiographic imaging, and classification of these disorders have improved long-term management. There are several types of disorders of the masticatory muscles and the temporomandibular joint as well as associated structures and each may have a complex cause, clinical course, and response to therapy. Host susceptibility plays a role at several stages of these disorders. Future research offers greater possibility in defining this heterogeneous group of disorders and providing more focused and effective treatment strategies. PMID- 25443681 TI - Orofacial pain syndromes: evaluation and management. AB - Patients will often visit their primary medical practitioner with orofacial pain complaints. Hence, it is important to recognize and have an understanding of these conditions to properly evaluate and potentially manage these disorders. If the practitioner is uncertain or uncomfortable with these conditions, then patient referral to a knowledgeable health care practitioner should be considered for further evaluation and management. In this article, the evaluation and management of various neuropathic, neurovascular, and vascular pains are discussed. PMID- 25443682 TI - Salivary gland disorders. AB - Patients with salivary gland disease present with certain objective and/or subjective signs. An accurate diagnosis for these patients requires a range of techniques that includes the organized integration of information derived from their history, clinical examination, imaging, serology, and histopathology. This article highlights the signs and symptoms of the salivary gland disorders seen in the Salivary Gland Center, and emphasizes the methodology used to achieve a definitive diagnosis and therapy. PMID- 25443684 TI - Oral medicine: a handbook for physicians. PMID- 25443685 TI - Medical Clinics of North America. Oral medicine: a handbook for physicians. Preface. PMID- 25443686 TI - Advances in endovascular treatment of acute ischaemic stroke. AB - Over the past decade, there have been rapid advancements in ischaemic stroke reperfusion treatments. However, clear clinical benefit is yet to be shown in large clinical trials. In this review, the major studies in different types of endovascular treatments including intra-arterial thrombolysis, aspiration devices, mechanical clot retrievers and the new stent retrievers are discussed. First-generation mechanical thrombectomy devices such as the MERCI Retriever (Stryker, Kalamazoo, MI, USA) and Penumbra aspiration device (Penumbra Inc., Alameda, CA, USA) demonstrated safety and higher rates of recanalisation in the MERCI and Penumbra Pivotal Stroke Trial; however, there was no significant improvement in clinical outcome. Second-generation endovascular stent retrieval devices Solitaire (ev3 Neurovascular, Irvine, CA, USA) and Trevo (Stryker) have shown promising results. In preliminary trials, SOLITAIRE with the Intention for Thrombectomy (SWIFT) and Thrombectomy Revascularization of Large Vessel Occlusions (TREVO), both showed rates of recanalisation close to 90% and significantly improved clinical outcomes compared with the MERCI study, but the recent landmark studies for endovascular treatment (Interventional Management of Stroke (IMS III), Mechanical Retrieval and Recanalisation of Stroke Clots Using Embolectomy (MR-RESCUE) and SYNTHESIS) did not show any clinical benefit from endovascular treatment compared with standard intravenous therapy. However, moving forward, the recent Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands (MR-CLEAN) study results have shown marked improvements in recanalisation, reperfusion and functional outcome in patients receiving endovascular treatment (97% using stent retrievers) within 6 h in addition to standard medical care. Overall, although evidence regarding the efficacy of endovascular treatment in acute stroke has been equivocal, recent publications of large multicentre randomised controlled trials indicate benefit of intra-arterial stent retriever reperfusion in patients selected by appropriate imaging and treated early by experienced operators, and it will likely remain an important adjunct to established medical treatment with intravenous tPA. PMID- 25443687 TI - Malignant peripheral nerve sheath tumor of the superficial cervical plexus with parotid extension. AB - INTRODUCTION: Cervical locations of malignant peripheral nerve sheath tumor (MPNST) are rare, at less than 1% of malignant tumors of this region. CASE REPORT: A 53-year-old woman presented with a lateral cervical swelling involving the parotid region. Histology was in favor of MPNST. Adjuvant radiotherapy was indicated because of the infiltrating nature of the tumor. At 2 years' follow-up, there was no recurrence. DISCUSSION: Clinical diagnosis is difficult in cervical MPNST. Only histology with immunohistochemistry can establish the correct diagnosis. Treatment requires complete surgical resection and regular clinical follow-up. PMID- 25443688 TI - Profile of parotid gland tumours: experience of 93 cases over a period of 16 years. AB - OBJECTIVE: The pathology of the salivary glands focuses on that of the parotid gland. The purpose of this study is to clarify and explain the epidemiological features of parotid tumors in a Senegalese context, to highlight the importance of clinical examination when access to complementary investigations is limited, to discuss respective indications and finally to describe certain aspects of treatment in our context. MATERIALS AND METHODS: This retrospective study of 114 cases of parotidectomy spans 16 years, from 1992 to 2007. It was performed in the ENT department of University Hospital of Fann, Senegal. All patients operated on for chronic mass of the parotid region for whom histological results were available when initially included. Benign swellings were subsequently excluded. The study parameters were epidemiological, clinical, paraclinical and surgical. RESULTS: The 114 parotidectomies showed a predominance of benign tumours: 63 procedures (55.26%) essentially concerned pleomorphic adenoma; 30 cases (26.31%) concerned malignant tumours, mainly parotid adenocarcinoma. There were 21 cases of benign swelling (18.4%). The study focused on the series of 93 cases of benign and malignant tumours of the parotid gland. Both sexes were affected similarly. All age groups were concerned, from 5 to 89 years. A total of 97% of patients underwent surgery: conservative total parotidectomy in 75.51% of cases. CONCLUSION: Although there are features specific to the local context, the epidemiological profile of parotid tumours is well-known. Indications for complementary investigations are discussed, as availability in Senegal is restricted, highlighting the important role of clinical examination in the management of parotid tumours. PMID- 25443689 TI - The role of tonsillectomy in the initial diagnostic work-up of head and neck squamous cell carcinoma of unknown primary. AB - OBJECTIVE: The aim of the present study was to determine the value of tonsillectomy in the initial diagnostic work-up of head and neck squamous cell carcinoma of unknown primary (HNSCCUP). MATERIAL AND METHODS: A single-center retrospective study (1999-2012) included 45 patients. All cases underwent physical examination, panendoscopy and contrast-enhanced neck and chest CT scan; 27 (60%)also underwent 18-FDG PET scan. Imaging was systematically performed before panendoscopy. In 34 cases (75%), histologic tonsil samples ipsilateral to the HNSCCUP were collected (28 tonsillectomies and 6 biopsies) during panendoscopy. Categoric variables were compared on Chi-square test. RESULTS: Clinical examination and CT did not identify any primary tumor. In 13 cases (38%), invasive squamous cell carcinoma (SCC) was diagnosed on histological samples (12 tonsillectomies, 1 biopsy). For these 13 cases, lymph nodes were located in the upper or middle jugular group, and in 3 cases lymph nodes were cystic on CT scan. In 7 cases (26%), there was an abnormal tonsillar 18-FDG uptake ipsilateral to the cervical lymphadenopathy; tonsillectomy was performed, and SCC was found in 5 of these cases:i.e., 18-FDG PET showed sensitivity and specificity of respectively 55.5 and 88.8%. CONCLUSION: Tonsillectomy has a role in the initial diagnostic work-up of HNSCCUP. It is especially useful when lymph nodes are located in the upper and/or middle jugular group with a cystic aspect on CT. PMID- 25443690 TI - Primary tuberculosis of the larynx. AB - INTRODUCTION: Tuberculosis is a chronic bacterial infection caused by Mycobacterium tuberculosis, usually affecting the lung, but very rare cases of isolated laryngeal tuberculosis have been reported. PURPOSE: To demonstrate the importance of considering the diagnosis of this disease, which presents with very variable and sometimes misleading clinical and endoscopic features, but for which medical treatment is very effective. MATERIAL AND METHODS: This retrospective study was based on ten cases of laryngeal tuberculosis managed between January 2004 and December 2009. The objective of this study was to describe the epidemiology, clinical and complementary investigation findings and treatment of primary tuberculosis of the larynx in a context of endemic tuberculosis based on a review of the literature. RESULT: In this series, primary tuberculosis of the larynx essentially affected male smokers and drinkers. Clinical and endoscopic signs were totally non-specific and similar to those of laryngeal cancer. Only bacteriological and histological examinations were able to establish the diagnosis. Once the diagnosis was confirmed, antituberculosis chemotherapy was administered for a minimum duration of 6 months with excellent short-term and long-term results. CONCLUSION: Globally, the characteristics of this series are closely correlated with those reported in the literature. Due to the non-specific laryngeal signs observed on clinical examination, clinicians must consider the possibility of laryngeal tuberculosis and must not hesitate to confirm this diagnosis by bacteriological and histological examination PMID- 25443692 TI - Metabolic acidosis components in advanced chronic kidney disease: association with serum albumin and parathyroid hormone. AB - OBJECTIVE: To investigate the associations between the 2 main components of metabolic acidosis (unmeasured anions [UA] and hyperchloremia) with serum albumin and intact parathormone (iPTH) in patients with advanced chronic kidney disease. DESIGN AND METHODS: Cross-sectional study with advanced chronic kidney disease patients (estimated glomerular filtration rate <30 mL/minute/1.73 m(2)) not receiving phosphate binders, alkali therapy, or vitamin D analogs. Arterial blood sample was collected for biochemical and blood gas analysis. UA and strong ion difference (SID) were calculated according to quantitative acid-base analysis. Reduced SID was used as a measure of hyperchloremia. MAIN OUTCOME MEASURES: Serum albumin and parathormone (iPTH). RESULTS: A total of 383 patients were included with a mean age of 64.7 +/- 16.3 year and a mean estimated glomerular filtration rate of 19.9 +/- 12.1 mL/minute/1.73 m(2). Among patients with metabolic acidosis, 45.7% had metabolic acidosis exclusively because of UA and 53.7% had a hyperchloremic component (either mixed metabolic acidosis or pure hyperchloremic metabolic acidosis). Considering the main acid-base status determinants, only UA had a significant correlation with serum albumin (r = -0.278, P < .001). There was no correlation between serum albumin and SID (r = 0.083, P = .156). This is in opposition to serum iPTH, where there was no correlation with UA (r = 0.082, P = .114), but an inverse correlation between iPTH and SID was observed (r = 0.228, P < .001). Multiple linear regressions with all acid-base determinants confirmed these findings. CONCLUSIONS: Our data brings further knowledge on the associations between metabolic acidosis with bone disorders and nutritional status, suggesting that the two main metabolic acidosis components (UA and hyperchloremia) have different effects on serum parathormone and serum albumin. PMID- 25443693 TI - Rethinking the restriction on nutrition during hemodialysis treatment. AB - The annual mortality rate for patients undergoing maintenance hemodialysis (MHD) treatment in the United States is 20%, a rate higher than most other countries in the world. Poor nutrition status in MHD patients contributes to this adverse outcome as well as poor quality of life. Providing oral nutrition to MHD patients, especially during hemodialysis (HD) treatment has many potential benefits including improvements in nutrition status and attenuating HD-related muscle wasting. However, this practice is generally restricted in the United States presumably because of concerns that include worsening hemodynamic instability, reductions in treatment efficiency, and increased gastrointestinal symptoms. Despite widespread restrictions, few studies have adequately examined the effect of eating during HD on these outcomes, leaving many questions unanswered. This review outlines the current evidence regarding the effects of feeding during HD and provides potential future directions to outline the best practices in this controversial area. PMID- 25443691 TI - Cognitive and Emotion-Regulatory Mediators of the Relationship Between Behavioral Approach System Sensitivity and Nonsuicidal Self-Injury Frequency. AB - Nonsuicidal self-injury (NSSI) is highly prevalent among late adolescents and predicts the onset of suicidal ideation and behavior. Although research has established an association between the behavioral approach system (BAS) and NSSI, less research has explored mechanisms underlying this relationship. The authors examined negative and positive emotion regulation patterns, as well as the BAS relevant cognitive style of self-criticism, as potential mechanisms through which a hypersensitive BAS might be related to NSSI frequency. Late adolescents (N = 177) with high and moderate BAS levels completed measures of self-criticism, positive emotion regulation, brooding, and both lifetime and last-year frequency of NSSI. Results indicated that self-criticism and positive emotion dampening independently mediated the relationship between BAS and last-year frequency of NSSI. Self-criticism also mediated the relationship between BAS and lifetime frequency of NSSI. Results suggest that cognitive and emotion-regulatory styles may help to explain why high BAS individuals are likely to engage in NSSI. PMID- 25443694 TI - Body composition in dialysis patients: a functional assessment of bioimpedance using different prediction models. AB - OBJECTIVES: The assessment of body composition (BC) in dialysis patients is of clinical importance given its role in the diagnosis of malnutrition and sarcopenia. Bioimpedance techniques routinely express BC as a 2-compartment (2-C) model distinguishing fat mass (FM) and fat-free mass (FFM), which may be influenced by the hydration of adipose tissue and fluid overload (OH). Recently, the BC monitor was introduced which applies a 3-compartment (3-C) model, distinguishing OH, adipose tissue mass, and lean tissue mass. The aim of this study was to compare BC between the 2-C and 3-C models and assess their relation with markers of functional performance (handgrip strength [HGS] and 4-m walking test), as well as with biochemical markers of nutrition. METHODS: Forty-seven dialysis patients (30 males and 17 females) (35 hemodialysis, 12 peritoneal dialysis) with a mean age of 64.8 +/- 16.5 years were studied. 3-C BC was assessed by BC monitor, whereas the obtained resistivity values were used to calculate FM and FFM according to the Xitron Hydra 4200 formulas, which are based on a 2-C model. RESULTS: FFM (3-C) was 0.99 kg (95% confidence interval [CI], 0.27 to 1.71, P = .008) higher than FFM (2-C). FM (3-C) was 2.43 kg (95% CI, 1.70 3.15, P < .001) lower than FM (2-C). OH was 1.4 +/- 1.8 L. OH correlated significantly with DeltaFFM (FFM 3-C - FFM 2-C) (r = 0.361; P < .05) and DeltaFM (FM 3-C - FM 2-C) (r = 0.387; P = .009). HGS correlated significantly with FFM (2 C) (r = 0.713; P < .001), FFM (3-C) (r = 0.711; P < .001), body cell mass (2-C) (r = 0.733; P < .001), and body cell mass (3-C) (r = 0.767; P < .001). Both physical activity (r = 0.456; P = .004) and HGS (r = 0.488; P = .002), but not BC, were significantly related to walking speed. CONCLUSIONS: Significant differences between 2-C and 3-C models were observed, which are partly explained by the presence of OH. OH, which was related to DeltaFFM and DeltaFM of the 2-C and 3-C models, is therefore an important parameter for the differences in estimation of BC parameters of the 2-C and 3-C models. Both FFM (3-C) and FFM (2 C) were significantly related to HGS. Bioimpedance, HGS, and the 4-m walking test may all be valuable tools in the multidimensional nutritional assessment of both hemodialysis and peritoneal dialysis patients. PMID- 25443695 TI - Words of caution regarding research design when using the nutrition care process model. PMID- 25443697 TI - The heterogeneity of heart failure: will enhanced phenotyping be necessary for future clinical trial success? PMID- 25443696 TI - Clinical implications of chronic heart failure phenotypes defined by cluster analysis. AB - BACKGROUND: Classification of chronic heart failure (HF) is on the basis of criteria that may not adequately capture disease heterogeneity. Improved phenotyping may help inform research and therapeutic strategies. OBJECTIVES: This study used cluster analysis to explore clinical phenotypes in chronic HF patients. METHODS: A cluster analysis was performed on 45 baseline clinical variables from 1,619 participants in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) study, which evaluated exercise training versus usual care in chronic systolic HF. An association between identified clusters and clinical outcomes was assessed using Cox proportional hazards modeling. Differential associations between clinical outcomes and exercise testing were examined using interaction testing. RESULTS: Four clusters were identified (ranging from 248 to 773 patients in each), in which patients varied considerably among measures of age, sex, race, symptoms, comorbidities, HF etiology, socioeconomic status, quality of life, cardiopulmonary exercise testing parameters, and biomarker levels. Differential associations were observed for hospitalization and mortality risks between and within clusters. Compared with cluster 1, risk of all-cause mortality and/or all cause hospitalization ranged from 0.65 (95% confidence interval [95% CI]: 0.54 to 0.78) for cluster 4 to 1.02 (95% CI: 0.87 to 1.19) for cluster 3. However, for all-cause mortality, cluster 3 had a disproportionately lower risk of 0.61 (95% CI: 0.44 to 0.86). Evidence suggested differential effects of exercise treatment on changes in peak oxygen consumption and clinical outcomes between clusters (p for interaction <0.04). CONCLUSIONS: Cluster analysis of clinical variables identified 4 distinct phenotypes of chronic HF. Our findings underscore the high degree of disease heterogeneity that exists within chronic HF patients and the need for improved phenotyping of the syndrome. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437). PMID- 25443699 TI - Healthy lifestyles and personal responsibility. PMID- 25443698 TI - Healthy lifestyle and decreasing risk of heart failure in women: the Women's Health Initiative observational study. AB - BACKGROUND: The impact of a healthy lifestyle on risk of heart failure (HF) is not well known. OBJECTIVES: The objectives of this study were to evaluate the effect of a combination of lifestyle factors on incident HF and to further investigate whether weighting each lifestyle factor has additional impact. METHODS: Participants were 84,537 post-menopausal women from the WHI (Women's Health Initiative) observational study, free of self-reported HF at baseline. A healthy lifestyle score (HL score) was created wherein women received 1 point for each healthy criterion met: high-scoring Alternative Healthy Eating Index, physically active, healthy body mass index, and currently not smoking. A weighted score (wHL score) was also created in which each lifestyle factor was weighted according to its independent magnitude of effect on HF. The incidence of hospitalized HF was determined by trained adjudicators using standardized methodology. RESULTS: There were 1,826 HF cases over a mean follow-up of 11 years. HL score was strongly associated with risk of HF (multivariable-adjusted hazard ratio [HR] [95% confidence interval (CI)] 0.49 [95% CI: 0.38 to 0.62], 0.36 [95% CI: 0.28 to 0.46], 0.24 [95% CI: 0.19 to 0.31], and 0.23 [95% CI: 0.17 to 0.30] for HL score of 1, 2, 3, and 4 vs. 0, respectively). The HL score and wHL score were similarly associated with HF risk (HR: 0.46 [95% CI: 0.41 to 0.52] for HL score; HR: 0.48 [95% CI: 0.42 to 0.55] for wHL score, comparing the highest tertile to the lowest). The HL score was also strongly associated with HF risk among women without antecedent coronary heart disease, diabetes, or hypertension. CONCLUSIONS: An increasingly healthy lifestyle was associated with decreasing HF risk among post-menopausal women, even in the absence of antecedent coronary heart disease, hypertension, and diabetes. Weighting the lifestyle factors had minimal impact. PMID- 25443701 TI - N-terminal pro-B-type natriuretic peptide: a risk predictor for all. PMID- 25443700 TI - B-type natriuretic peptides improve cardiovascular disease risk prediction in a cohort of women. AB - BACKGROUND: Although N-terminal pro-B-type natriuretic peptide (NT-proBNP) has a strong relationship with incident cardiovascular disease (CVD), few studies have examined whether NT-proBNP adds to risk prediction algorithms, particularly in women. OBJECTIVES: This study sought to evaluate the relationship between NT proBNP and incident CVD in women. METHODS: Using a prospective case-cohort within the WHI (Women's Health Initiative) observational study, we selected 1,821 incident cases of CVD (746 myocardial infarctions, 754 ischemic strokes, 160 hemorrhagic strokes, and 161 other cardiovascular [CV] deaths) and a randomly selected reference cohort of 1,992 women without CVD at baseline. RESULTS: Median levels of NT-proBNP were higher at study entry among incident cases (120.3 ng/l [interquartile range (IQR): 68.1 to 219.5 ng/l]) than among control subjects (100.4 ng/l [IQR: 59.7 to 172.6 ng/l]; p < 0.0001). Women in the highest quartile of NT-proBNP (>=140.8 ng/l) were at 53% increased risk of CVD versus those in the lowest quartile after adjusting for traditional risk factors (1.53 [95% confidence interval (CI): 1.21 to 1.94]; p for trend <0.0001). Similar associations were observed after adjustment for Reynolds Risk Score covariables (1.53 [95% CI: 1.20 to 1.95]; p for trend <0.0001); the association remained in separate analyses of CV death (2.66 [95% CI: 1.48 to 4.81]; p for trend <0.0001), myocardial infarction (1.39 [95% CI: 1.02 to 1.88]; p for trend = 0.008), and stroke (1.60 [95% CI: 1.22 to 2.11]; p for trend <0.0001). When added to traditional risk covariables, NT-proBNP improved the c-statistic (0.765 to 0.774; p = 0.0003), categorical net reclassification (0.08; p < 0.0001), and integrated discrimination (0.0105; p < 0.0001). Similar results were observed when NT-proBNP was added to the Reynolds Risk Score. CONCLUSIONS: In this multiethnic cohort of women with numerous CV events, NT-proBNP modestly improved measures of CVD risk prediction. PMID- 25443702 TI - Dehydroepiandrosterone and its sulfate predict the 5-year risk of coronary heart disease events in elderly men. AB - BACKGROUND: The adrenal sex hormone dehydroepiandrosterone (DHEA), which is present in serum mainly as the sulfate DHEA-S, is the most abundant steroid hormone in human blood. Its levels decline dramatically with age. Despite the great amount of literature on vascular and metabolic actions of DHEA/-S, evidence for an association between DHEA/-S levels and cardiovascular events is contradictory. OBJECTIVES: This study tested the hypothesis that serum DHEA and DHEA-S are predictors of major coronary heart disease (CHD) and/or cerebrovascular disease (CBD) events in a large cohort of elderly men. METHODS: We used gas and liquid chromatography-mass spectrometry to analyze baseline levels of DHEA and DHEA-S in the prospective population-based Osteoporotic Fractures in Men study in Sweden (2,416 men, ages 69 to 81 years). Complete cardiovascular clinical outcomes were available from national Swedish registers. RESULTS: During the 5-year follow-up, 302 participants experienced a CHD event, and 225 had a CBD event. Both DHEA and DHEA-S levels were inversely associated with the age-adjusted risk of a CHD event; the hazard ratios and 95% confidence intervals per SD increase were 0.82 (0.73 to 0.93) and 0.86 (0.77 to 0.97), respectively. In contrast, DHEA/-S showed no statistically significant association with the risk of CBD events. The association between DHEA and CHD risk remained significant after adjustment for traditional cardiovascular risk factors, serum total testosterone and estradiol, C-reactive protein, and renal function, and remained unchanged after exclusion of the first 2.6 years of follow up to reduce reverse causality. CONCLUSIONS: Low serum levels of DHEA and its sulfate predict an increased risk of CHD, but not CBD, events in elderly men. PMID- 25443703 TI - Sex steroid as a new oracle to predict cardiovascular risk. PMID- 25443704 TI - Short-term results of transapical transcatheter mitral valve implantation for mitral regurgitation. AB - BACKGROUND: Mitral regurgitation (MR) is the most common valvular heart disease, and mitral valve surgery is the gold standard therapy for severe MR. Many patients with severe MR are not referred for surgery because of old age, comorbidities, or severe left ventricular dysfunction. Transcatheter mitral valve implantation may be a better therapeutic option for these high-risk patients with severe symptomatic MR. OBJECTIVES: This study sought to describe the first-in-man series of transapical mitral valve implantation for mitral regurgitation with the TIARA device. METHODS: Extensive preclinical ex vivo and animal studies were conducted with the transapical mitral valve implantation of the Tiara system. The first 2 cases of human implantation were successfully performed in a 73-year-old man and a 61-year-old woman with severe functional MR. Both patients were in New York Heart Association class IV heart failure with depressed left ventricular ejection fraction, pulmonary hypertension, and additional comorbidities. RESULTS: The valve was implanted uneventfully in both patients. General anesthesia and transapical access were used. Patients were hemodynamically stable with no need for cardiopulmonary bypass. Immediately after implantation, systemic arterial pressure and stroke volume increased and pulmonary pressure decreased dramatically. There were no intraoperative complications, and both patients were extubated in the operating room. Post-procedural echocardiograms at 48 h, 1 month, and 2 months demonstrated excellent prosthetic valve function with a low transvalvular gradient and no left ventricular outflow tract obstruction. There was a trivial paravalvular leak in the first patient at 48 h, which was completely resolved at subsequent studies; no paravalvular leak occurred in the second patient. CONCLUSIONS: Transapical transcatheter mitral valve implantation is technically feasible and can be performed safely. Early hemodynamic performance of the prosthesis was excellent. Transcatheter mitral valve implantation may become an important treatment option for patients with severe MR who are at high operative risk. PMID- 25443705 TI - Transcatheter mitral valve replacement: the next revolution? PMID- 25443706 TI - Safety and effectiveness of drug-eluting versus bare-metal stents in saphenous vein bypass graft percutaneous coronary interventions: insights from the Veterans Affairs CART program. AB - BACKGROUND: Stenosis of saphenous vein grafts (SVGs) after coronary artery bypass grafting (CABG) is common and often requires percutaneous coronary interventions (PCI) for treatment. However, data for the effectiveness of drug-eluting stents (DES) versus bare-metal stents (BMS) in SVG-PCI are unclear. OBJECTIVES: This study sought to examine the association between DES versus BMS used during SVG PCI and clinical outcomes in the national Veterans Affairs integrated healthcare system. METHODS: We studied a national cohort of 2,471 post-CABG veterans undergoing SVG-PCI between 2008 and 2011 at all Veterans Affairs hospitals and compared clinical outcomes of between those receiving DES and BMS. Clinical outcomes included procedural complications, myocardial infarction (MI), and all cause mortality. Comparisons were made in a propensity-matched cohort using Cox proportional hazards regression models. RESULTS: DES were used in 1,549 SVG-PCI patients (63%) and the use of DES increased progressively with each calendar year (50% in 2008 to 69% in 2011). Incidence of procedural complications was low and comparable in both groups (2.8% among BMS vs. 2.3% among DES patients; p = 0.54). During long-term (>2 years) follow-up, use of DES was associated with lower mortality than BMS (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.57 to 0.89) and similar rates of MI (HR: 0.94; 95% CI: 0.71 to 1.24) in the propensity-matched cohort. CONCLUSIONS: In a national cohort of veterans, we observed widespread and increasing use of DES during SVG-PCI. In long-term follow up, compared with BMS, DES use was safe and effective in SVG-PCI patients. PMID- 25443707 TI - Are drug-eluting stents safe in the long term after saphenous vein graft intervention?: lessons learned from real-world practice. PMID- 25443709 TI - Making partnerships matter. PMID- 25443708 TI - Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases? AB - Whether left ventricular noncompaction (LVNC) is a distinct cardiomyopathy or a morphologic trait shared by different cardiomyopathies remains controversial. Current guidelines from professional organizations recommend different strategies for diagnosing and treating patients with LVNC. This state-of-the-art review discusses new insights into the basic mechanisms leading to LVNC, its clinical manifestations, treatment modalities, anatomy and pathology, embryology, genetics, epidemiology, and imaging. Three markers currently define LVNC: prominent left ventricular trabeculae, deep intertrabecular recesses, and a thin compacted layer. Although new genetic data from mice and humans supports LVNC as a distinct cardiomyopathy, evidence for LVNC as a shared morphological trait is not ruled out. Criteria supporting LVNC as a shared morphological trait may depend on consensus guidelines from the multiple professional organizations. Enhanced imaging and increased use of genetics are both predicted to significantly impact our overall understanding of the basic mechanisms causing LVNC and its optimal management. PMID- 25443710 TI - Facing procedural complications as a cardiovascular trainee. PMID- 25443711 TI - Pregnancy complications in women with heart disease conceiving with fertility therapy. PMID- 25443712 TI - Reply: early intravenous beta-blockade before primary percutaneous coronary intervention gives major benefits apparently without side effects. PMID- 25443713 TI - Early intravenous beta-blockade before primary percutaneous coronary intervention gives major benefits, apparently without side effects. PMID- 25443714 TI - Zero-hour aortic sclerosis: auscultatory biomarker or imaging biomarker? PMID- 25443715 TI - Clinical image in gastroenterology. Benign esophageal perforation resolved through the placement of a fully covered self-expandable metal stent. PMID- 25443716 TI - Factors associated with asthma control in children: findings from a national Web based survey. AB - BACKGROUND: Although achieving and maintaining control of asthma is considered to be the goal of asthma treatment, determinants of asthma control are not fully understood. Our aim was to assess factors associated with asthma control among paediatric patients in the general population. METHODS: In June 2012, a Web-based survey was conducted to identify Japanese children aged 6 to 11 yr who currently have asthma and evaluate control of their disease using the Childhood Asthma Control Test (C-ACT). Associations were evaluated among uncontrolled asthma (C ACT score <20) between environmental factors, demographics and comorbid allergic diseases. RESULTS: Among the 3066 children with current asthma, 447 (14.6%) had uncontrolled asthma. Multivariable analysis identified factors such as low birthweight (adjusted OR 1.65, 95% CI 1.25-2.18), obesity (adjusted OR 1.44, 95% CI 1.05-1.99) and pet ownership before birth (adjusted OR 1.68, 95% CI 1.24-2.29) to be associated with uncontrolled disease. Comorbid allergic diseases, especially rhinitis were a significant risk of uncontrolled asthma (adjusted OR for severe rhinitis: 3.88, 95% CI 2.50-6.00). The severity of rhinitis symptoms was inversely correlated with the C-ACT score (p < 0.001). CONCLUSIONS: A population-based Web survey showed an association between several factors and the control of paediatric asthma. The assessment of these factors may help identify the children at risk with uncontrolled asthma. PMID- 25443718 TI - Antiproliferative effect induced by novel imidazoline S43126 in PC12 cells is mediated by ROS, stress activated MAPKs and caspases. AB - BACKGROUND: Some imidazoline compounds have pleiotropic effects including cell death in vitro. We examined the antiproliferative action of a novel imidazoline compound S43126, and the role of the I1-imidazoline receptor, ROS, MAPKs and caspases in S43126-induced cell death. METHODS: PC 12 cells were treated with various concentrations of S43126 in the presence or absence of several ligands, and the effects on cell proliferation, ROS levels, and apoptosis were evaluated using Trypan Blue, Alamar Blue, Western blot and microscopy. RESULTS: We showed that S43126 reduced PC12 cell proliferation by greater than 50%, increased cell death by greater than 40% and increased apoptotic body formation. These effects were reversed by I1R-antagonist, efaroxan. S43126 also increased intracellular ROS levels by greater than 2.5-fold relative to vehicle-treated control. These effects were significantly inhibited by N-acetyl-cysteine. In addition, pharmacologic inhibitors of ERK, JNK and p38 MAPK, significantly reduced S43126 induced antiproliferative activity. Caspases 3, 8 and 9 were all activated in a time-dependent manner by S43126. Pan caspase inhibitor z-VAD-fmk, ameliorated the effects of S43126 on cell death and cell proliferation. CONCLUSION: Our data showed that the effects of S43126 on PC12 cell death were partly mediated by ROS production, MAPK and caspase activation. These results further indicate an emerging role for I1R in apoptotic processes. PMID- 25443717 TI - CP55,940 attenuates spatial memory retrieval in mice. AB - BACKGROUND: Cannabinoids constitute a varied group of lipophilic substances able to infiltrate the blood-brain barrier and influence neuronal processes. Clinical observations supported by experimental data have revealed that these compounds exert a deleterious effect on cognitive processes. The present study was carried out to determine the influence of a single systemic administration of CP55,940, a potent synthetic agonist of cannabinoid receptors, on spatial memory retrieval assessed in a Morris water maze. METHODS: C57BL/6J male mice were submitted to three consecutive days of training to find a hidden platform in the water maze. CP55,940 was given intraperitoneally once, at doses of 0.025, 0.125 or 0.25mg/kg on the fourth day, 30min before testing memory retrieval, and in separate groups before testing psychomotor activity and anxiety level in a hole-board test. RESULTS: CP55,940 only at the highest dose of 0.25mg/kg significantly altered all parameters used to assess spatial memory. It increased the latency in the first crossing of the former platform location (target area), decreased the number of target area crossings and shortened the time spent in the target quadrant. Moreover, CP55,940 at doses of 0.25 and 0.125mg/kg attenuated motor and exploratory activity in hole-board test. CONCLUSION: Since the attenuated psychomotor activity after a dose of 0.125mg/kg did not interfere with memory retrieval, we assume that the impairment of spatial memory observed after the highest dose of CP55,940 (0.25mg/kg) was exerted by its influence on cognitive processes, however, the impact on locomotion could not be excluded. PMID- 25443719 TI - Chronic administration of phenytoin induces efflux transporter overexpression in rats. AB - BACKGROUND: Efflux transporters overexpression has been proposed as one of the responsible mechanism for refractory epilepsy by preventing access of the antiepileptic drug to the brain. In this work we investigated whether phenytoin (PHT), could induce efflux transporters overexpression, at different biological barriers and to evaluate the implication it could have on its pharmacokinetics and therapeutic/toxic response. METHODS: Forty-two adult females Sprague Dawley divided in five groups were treated with oral doses of 25, 50 and 75mg/kg/6h of PHT for 3 days and two additionally groups were treated with intraperitoneal (ip) doses of 25mg/kg/6h or 100mg/kg/24h. At day 4 PHT plasma concentrations were measured and, obtained several organs, brain, parotid gland, liver and duodenum in which were analyzed for the Pgp expression. At day 4 PHT plasma concentrations were measured and several tissues: brain, parotid gland, liver and duodenum were obtained in order to analyze Pgp expression. In order to evaluate the oral bioavailability of PHT, two groups were administered with oral or intraperitoneal doses of 100mg/kg and plasma level were measured. RESULTS: An induction of the expression of efflux transporter mediated by phenytoin in a concentration-and time dependent manner was found when increasing oral and ip doses of phenytoin, One week after the interruption of ip treatment a basal expression of transporters was recovered. CONCLUSIONS: Overexpression of efflux transporters can be mediated by inducer agents like PHT in a local-concentration dependent manner, and it is reversible once the substance is removed from the body. The recovery of basal Pgp expression could allow the design of dosing schedules that optimize anticonvulsant therapy. PMID- 25443720 TI - Rupatadine effectively prevents the histamine-induced up regulation of histamine H1R and bradykinin B2R receptor gene expression in the rat paw. AB - BACKGROUND: Activation of histamine H1 receptor (H1R) is a well-known hallmark of allergic and inflammatory pathology. Both types of bradykinin receptors (B1R and B2R) are also known to contribute significantly to the latter and some sort of functional interaction between them and H1R has been alluded to in the past. Here we use an experimental model of rat paw oedema formation to examine the effect of exogenously added histamine on the gene expression of H1R and bradykinin receptors B1R and B2R, alone or in combination to rupatadine, a second generation antihistamine agent. METHODS: Histamine-induced oedema formation was monitored with a plethysmometer. The gene expression of H1R, B1R and B2R was analyzed with both conventional and real-time PCR. Rupatadine fumarate was used in pure form and administered intraperitoneally, prior to histamine injection into the paw. Microscopy of haematoxylin and eosin-stained sections of paw tissue was used to examine effects on tissue architecture. RESULTS: Histamine injection into the paw resulted in significant up regulation of H1R and B2R without inducing significant cellular infiltration, but appears to affect less the expression of B1R. Rupatadine was, under the conditions used in this study, very effective in preventing this effect and in suppressing oedema formation through its antihistamine action. CONCLUSION: Rupatadine has a suppressing effect on H1R and B2R gene expression which could add to its efficacy towards allergy and allergy like conditions. PMID- 25443721 TI - Potential of metabolomics in preclinical and clinical drug development. AB - Metabolomics is an upcoming technology system which involves detailed experimental analysis of metabolic profiles. Due to its diverse applications in preclinical and clinical research, it became an useful tool for the drug discovery and drug development process. This review covers the brief outline about the instrumentation and interpretation of metabolic profiles. The applications of metabolomics have a considerable scope in the pharmaceutical industry, almost at each step from drug discovery to clinical development. These include finding drug target, potential safety and efficacy biomarkers and mechanisms of drug action, the validation of preclinical experimental models against human disease profiles, and the discovery of clinical safety and efficacy biomarkers. As we all know, nowadays the drug discovery and development process is a very expensive, and risky business. Failures at any stage of drug discovery and development process cost millions of dollars to the companies. Some of these failures or the associated risks could be prevented or minimized if there were better ways of drug screening, drug toxicity profiling and monitoring adverse drug reactions. Metabolomics potentially offers an effective route to address all the issues associated with the drug discovery and development. PMID- 25443722 TI - Role of TRPV1 and ASIC3 in formalin-induced secondary allodynia and hyperalgesia. AB - BACKGROUND: In the present study we determined the role of transient receptor potential V1 channel (TRPV1) and acid-sensing ion channel 3 (ASIC3) in chronic nociception. METHODS: 1% formalin was used to produce long-lasting secondary allodynia and hyperalgesia in rats. Western blot was used to determine TRPV1 and ASIC3 expression in dorsal root ganglia. RESULTS: Peripheral ipsilateral, but not contralateral, pre-treatment (-10min) with the TRPV1 receptor antagonists capsazepine (0.03-0.3MUM/paw) and A-784168 (0.01-1MUM/paw) prevented 1% formalin induced secondary mechanical allodynia and hyperalgesia in the ipsilateral and contralateral paws. Likewise, peripheral ipsilateral, but not contralateral, pre treatment with the non-selective and selective ASIC3 blocker benzamil (0.1 10MUM/paw) and APETx2 (0.02-2MUM/paw), respectively, prevented 1% formalin induced secondary mechanical allodynia and hyperalgesia in both paws. Peripheral ipsilateral post-treatment (day 6 after formalin injection) with capsazepine (0.03-0.3MUM/paw) and A-784168 (0.01-1MUM/paw) reversed 1% formalin-induced secondary mechanical allodynia and hyperalgesia in both paws. In addition, peripheral ipsilateral post-treatment with benzamil (0.1-10MUM/paw) and APETx2 (0.02-2MUM/paw), respectively, reversed 1% formalin-induced secondary mechanical allodynia and hyperalgesia in both paws. TRPV1 and ASIC3 proteins were expressed in dorsal root ganglion in normal conditions, and 1% formalin injection increased expression of both proteins in this location at 1 and 6 days compared to naive rats. CONCLUSIONS: Data suggest that TRPV1 and ASIC3 participate in the development and maintenance of long-lasting secondary allodynia and hyperalgesia induced by formalin in rats. The use of TRPV1 and ASIC3 antagonists by peripheral administration could prove useful to treat chronic pain. PMID- 25443723 TI - Concentration of Il-1beta, Il-2, Il-6, TNFalpha in the blood serum in children with generalized epilepsy treated by valproate. AB - BACKGROUND: The aim of the study was the comparison of concentrations of IL 1beta, IL-2, IL-6 and TNFalpha before and after valproate (VPA) treatment in blood serum in patients with generalized seizures diagnosed and treated in the Department of Developmental Neurology, Poznan University of Medical Sciences from January 2006 to May 2007. METHODS: The analysis was conducted in a group of 21 patients with well controlled, generalized seizures (mean age 7.7+/-4.7 years) before and after 4-6 months of VPA therapy. Quantitative determination IL-1beta, IL-2, IL-6 and TNFalpha were performed with method of enzyme-linked immunosorbent assay (ELISA). The serum drug concentration was determined with the use of fluorescence-polarization-immunoassay system (FPIA). RESULTS: The concentration of IL-6 in blood serum of patients decreased significantly (p<0.001) after 4-6 months of VPA therapy, but concentration of IL-1beta (p=0.732), IL-2 (p=0.865), TNFalpha (p=0.079) did not change significantly. The serum concentration of VPA in all of patients was in therapeutic range (mean 77.53+/-19.71MUg/ml). CONCLUSIONS: The serum level of pro-inflammatory IL-6 in patients with generalized epilepsy decreased in statistically significant way during VPA therapy, so the anti-inflammatory properties of VPA are also important for the effective control of seizure. Due to the incompatibility of reports on the influence of VPA on cytokine system in patients with generalized epilepsy, this problem needs more investigations, especially in the group of children. PMID- 25443724 TI - Evaluation of l-arginine on kidney function and vascular reactivity following ischemic injury in rats: protective effects and potential interactions. AB - BACKGROUND: There is an interaction between many cell types involved in the pathophysiology of ischemic acute renal failure. Nitric oxide (NO) precursors, especially l-arginine, may have protective effects on tissue ischemia/reperfusion injury (IRI); however, their molecular mechanisms are unclear. In the present study, the interaction between l-arginine, cyclo-oxygenase (COX)-2 and reactive oxygen species (ROS) in the pathogenesis of ischemic acute renal failure was investigated. METHODS: Ischemia/reperfusion injury model in rats was used and various biochemical parameters examined. The rat isolated aortic rings served as model for hypoxia/reoxygenation where endothelium dependent and independent relaxations were exerted. RESULTS: Pre-treatment of rats subjected to IRI with l arginine (125mg/kg) significantly reduced kidney MDA levels, elevated kidney SOD activity, GSH level and total NO levels at 24 and 48h after reperfusion. Kidney COX-2 level was only different in the l-arginine-treated group 48h after reperfusion compared to the IRI group. Pre-treatment with l-arginine (10(-2)M) alone or in combination with celecoxib significantly potentiated the acetylcholine (Ach)-induced relaxations in control and hypoxic rings. The effect of the combination was synergistic only in hypoxic rings. Addition of ascorbic acid to the celecoxib-arginine combination did not produce further potentiation. Sodium nitroprusside-induced relaxations in control and hypoxic rings were potentiated by l-arginine or celecoxib-arginine combination but not by ascorbic acid. CONCLUSIONS: The protective effect of l-arginine may result from the interaction between NO and ROS and increased NO bioavailability. The protective effects of combined celecoxib and l-arginine against IRI could be attributed to their antioxidant activity which exceeded that of ascorbic acid. PMID- 25443725 TI - The effect of risperidone on the mirtazapine-induced changes in extracellular monoamines in the rat frontal cortex. AB - BACKGROUND: The aim of our study was to understand the mechanism of clinical efficacy of the combination of an antidepressant and risperidone in drug resistant depression. METHODS: We studied the effect of an antidepressant (mirtazapine) and risperidone (atypical antipsychotic), given separately or jointly on extracellular levels of dopamine (DA), serotonin (5-HT) and noradrenaline (NA) in the rat frontal cortex. The animals were given a single intraperitoneal injection of risperidone (1mg/kg) and mirtazapine (10 and 20mg/kg). The release of monoamines in the rat frontal cortex was investigated using a microdialysis in freely moving animals, and monoamine levels were assayed by HPLC with coulochemical detection. RESULTS: Risperidone increased the cortical extracellular levels of DA, 5-HT and NA. Similarly, mirtazapine dose-dependently increased the cortical extracellular levels of the monoamines studied. A combination of mirtazapine either at the higher dose (20mg/kg) or at both doses (10 and 20mg/kg) with risperidone produced a significant effect on DA and NA release, respectively compared to the effect of any drug given alone. The increase in the DA (but not NA) release induced by mirtazapine plus risperidone was partly blocked by the selective 5-HT1A antagonist WAY 100635 (0.2mg/kg). CONCLUSIONS: Our data indicate that the increase of cortical extracellular levels of DA and NA by combined administration of mirtazapine and risperidone may be of crucial importance to the pharmacotherapy of drug resistant depression, and that, among other mechanisms, 5-HT1A, 5-HT2A, alpha2-adrenergic and histamine H1 receptors may play some role in this effect. PMID- 25443726 TI - Hypotensive effects of omentin-1 related to increased adiponectin and decreased interleukin-6 in intra-thoracic pericardial adipose tissue. AB - BACKGROUND: Omentin is an adipokine expressed in visceral adipose tissue (VAT). In vitro studies demonstrated that omentin induces vasorelaxation in isolated rat mesenteric arteries, and in vivo studies showed inhibition of agonist-induced increases in blood pressure, possibly mediated by nitric oxide (NO)-dependent mechanisms. METHODS: We investigated, in normotensive rats, the effects of subacute omentin-1 administration [8MUg/kg, intraperitoneally (ip), once daily for 14 days] on cardiac activity, blood pressure, plasma concentration of l citrulline (as a marker of NO production from l-arginine), and the gene expression of adiponectin, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in intra-thoracic pericardial adipose tissue (PAT). Electrocardiography (ECG), heart rate (HR), mean blood pressure (MBP), pulse pressure (PP) were monitored before and after treatment with omentin-1 or vehicle. RESULTS: With respect to baseline and vehicle, we found a significant decrease of MBP (p<0.005) and PP (p<0.05) after treatment with omentin-1, while ECG and HR were not modified. Omentin-1 significantly increased l-citrulline levels in plasma (p<0.05), and the gene expression of adiponectin in PAT (p<0.05). On the other hand, we found decreased gene expression of IL-6 (p<0.005), while TNF-alpha mRNA in PAT was not affected. CONCLUSION: We conclude that the hypotensive effects of omentin-1 could be driven by stimulated production of NO in the vascular system, possibly related to increased adiponectin and decreased IL-6 mRNA in PAT. PMID- 25443727 TI - Analgesic and anti-inflammatory activity of 7-substituted purine-2,6-diones. AB - BACKGROUND: In an effort to develop new analgesic and anti-inflammatory agents, we determined a series of 7-substituted purine-2,6-diones. METHODS: The obtained compounds (1-6) were evaluated pharmacologically in four in vivo models: the writhing syndrome, the formalin tests, the carrageenan-induced edema model and the zymosan-induced peritonitis. The influence of the investigated compounds on the phosphodiesterase (PDE) and PDE4B activity was also determined. In addition, determination of the antioxidant activity was determined by the FRAP assay. RESULTS: A majority of the tested compounds showed a significant analgesic and anti-inflammatory activity. The strongest analgesic and anti-inflammatory effect was observed for 1 and 2. The active compound 1 was more efficient than theophylline in inhibiting the PDE and more efficient than rolipram in inhibiting the PDE4B activity. The tested compounds did not show significant antioxidant properties. CONCLUSION: Active compounds (1-6) inhibited the PDE activity, while compound 1 significantly inhibited the PDE4B activity, what may suggest that this mechanism may be involved in their analgesic/anti-inflammatory properties. PMID- 25443728 TI - Integrated workflow for quantitative phosphoproteomic analysis of the selected brain structures in development of morphine dependence. AB - BACKGROUND: Phosphorylation is a key process regulating a large number of fundamental biochemical reactions in living organisms. It is known that many mechanisms of response to chronic drugs administration are regulated by phosphorylation. It can be assumed that some of the phosphorylation sites are known, but they represent only a small fraction of the regulatory phosphorylation events in this system. Therefore, it is important to investigate protein phosphorylation with high-throughput methods such as mass spectrometry, that allow for efficient global analysis. The aim of this work was to develop a robust workflow for quantitative phosphoproteomic analysis, which operates in a semi automatic manner. METHODS: The proposed approach consists of two methods of phosphopeptides enrichment (TiO2, IMAC), stable isotope methyl labeling, data dependent mass spectrometry acquisition with simultaneous CID/ETD fragmentation, and data analysis platform based on Trans-Proteomic Pipeline. We have applied our method to analyze selected brain structures from rat involved in morphine dependence. RESULTS: We have identified and quantified number of phosphoproteins that were up- or down-regulated as a result of morphine treatment. Finally, we have applied a three-step filtration process to emerge the most regulated candidates. In parallel, all of the regulated proteins were annotated with GO terms to follow global trends of protein regulation. CONCLUSIONS: The proposed MS based workflow with following data analysis is efficient method for quantitative phosphoproteomic analysis: PMID- 25443729 TI - Ligand-directed trafficking of receptor stimulus. AB - GPCRs are seven transmembrane-spanning receptors that convey specific extracellular stimuli to intracellular signalling. They represent the largest family of cell surface proteins that are therapeutically targeted. According to the traditional two-state model of receptor theory, GPCRs were considered as operating in equilibrium between two functional conformations, an active (R*) and inactive (R) state. Thus, it was assumed that a GPCR can exist either in an "off" or "on" conformation causing either no activation or equal activation of all its signalling pathways. Over the past several years it has become evident that this model is too simple and that GPCR signalling is far more complex. Different studies have presented a multistate model of receptor activation in which ligand specific receptor conformations are able to differentiate between distinct signalling partners. Recent data show that beside G proteins numerous other proteins, such as beta-arrestins and kinases, may interact with GPCRs and activate intracellular signalling pathways. GPCR activation may therefore involve receptor desensitization, coupling to multiple G proteins, Galpha or Gbetagamma signalling, and pathway activation that is independent of G proteins. This latter effect leads to agonist "functional selectivity" (also called ligand-directed receptor trafficking, stimulus trafficking, biased agonism, biased signalling), and agonist intervention with functional selectivity may improve the therapy. Many commercially available drugs with beneficial efficacy also show various undesirable side effects. Further studies of biased signalling might facilitate our understanding of the side effects of current drugs and take us to new avenues to efficiently design pathway-specific medications. PMID- 25443730 TI - Antiarrhythmic efficacy of CPUY102122, a multiple ion channel blocker, on rabbits with ischemia/reperfusion injury. AB - BACKGROUND: The antiarrhythmic potential of a novel multichannel blocker CPUY102122 (CY22) was investigated in the present study. METHODS: The effect of CY22 on rapid delayed rectifier potassium channel current (IKr) was studied using whole-cell patch clamp techniques in Chinese Hamster Ovary cells stably expressing human Ether-a-go-go-Related Gene. We further evaluated the antioxidant effects of CY22 and demonstrated the reversal of connexin down-regulation in the development of cardiac ventricular arrhythmias, which was produced using coronary ligation/reperfusion in rabbits. CY22 and Amiodarone were administered 30min prior to the procedure. Next, electrocardiograms were recorded, protein expression of left ventricular Connexin43 (Cx43), non-phosphorylation-Cx43 (np Cx43), Rac-1 and gp-91[phox] were assayed using Western blot analysis, microstructural changes in the myocardium were observed and redox system activity was assayed. RESULTS: CY22 inhibited IKr in a concentration-dependent manner with IC50 value of 2.8+/-0.8MUmol/L. CY22 treatment significantly decreased T-wave amplitude and QTc arrhythmic scores and ameliorated the shape of the infarcted myocardium compared to the model group. CY22 decreased the serum levels of creatine kinase, lactate dehydrogenase, and myocardial levels of malondialdehyde, as well as increased superoxide dismutase activity. Cx43 expression in the left ventricle was significantly increased by CY22 treatment, which significantly decreased np-43 expression, Rac-1 activity and gp-91[phox] protein expression. CONCLUSIONS: These results indicated that CY22 has both antiarrhythmic and cardiovascular protective effects partly by blocking IKr, the production of antioxidants and protection of Cx43. PMID- 25443731 TI - The effects of ifenprodil on the activity of antidepressant drugs in the forced swim test in mice. AB - BACKGROUND: According to reports in the literature, more than 30% of depressive patients fail to achieve remission. Therapy with the conventional antidepressant drugs may induce the serious adverse reactions. Moreover, its benefits may be seen at least 2-4 weeks after the first dose. Therefore, the alternative strategies for prevention and treatment of depression are sought. The main aim of our study was to assess the effects of ifenprodil given at a non-active dose (10mg/kg) on the activity of antidepressant agents from diverse pharmacological groups. METHODS: The antidepressant-like effect was assessed by the forced swim test in mice. RESULTS: Ifenprodil potentiated the antidepressant-like effect of imipramine (15mg/kg) and fluoxetine (5mg/kg) while did not reduce the immobility time of animals which simultaneously received reboxetine (2.5mg/kg) or tianeptine (15mg/kg). CONCLUSION: The concomitant administration of certain commonly prescribed antidepressant drugs that affect the serotonergic neurotransmission (i.e., typical tricyclic antidepressants and selective serotonin reuptake inhibitors) with a negative modulator selectively binding to the GluN1/N2B subunits of the NMDA receptor complex (i.e., ifenprodil) may induce a more pronounced antidepressant-like effect than monotherapy. However, these findings still need to be confirmed in further experiments. PMID- 25443732 TI - Chronotherapeutic effect of fisetin on expression of urea cycle enzymes and inflammatory markers in hyperammonaemic rats. AB - BACKGROUND: Elevated blood ammonia leads to hyperammonaemia that affects vital central nervous system (CNS) functions. Fisetin, a naturally occurring flavonoid, exhibits therapeutic benefits, such as anti-cancer, anti-diabetic, anti-oxidant, anti-angiogenic, neuroprotective and neurotrophic effects. METHODS: In this study, the chronotherapeutic effect of fisetin on ammonium chloride (AC)-induced hyperammonaemic rats was investigated, to ascertain the time point at which the maximum drug effect is achieved. The anti-hyperammonaemic potential of fisetin (50mg/kg b.w. oral) was analysed when administered to AC treated (100mg/kg b.w. i.p.) rats at 06:00, 12:00, 18:00 and 00:00h. Amelioration of pathophysiological conditions by fisetin at different time points was measured by analysing the levels of expression of liver urea cycle enzymes (carbamoyl phosphate synthetase I (CPS-I), ornithine transcarbamoylase (OTC) and argininosuccinate synthetase (ASS)), nuclear transcription factor kappaB (NF-kappaB p65), brain glutamine synthetase (GS) and inducible nitric oxide synthase (iNOS) by Western blot analysis. RESULTS: Fisetin increased the expression of CPS-I, OTC, ASS and GS and decreased iNOS and NF-kappaB p65 in hyperammonaemic rats. Fisetin administration at 00:00h showed more significant effects on the expression of liver and brain markers, compared with other time points. CONCLUSIONS: Fisetin could exhibit anti hyperammonaemic effect owing to its anti-oxidant and cytoprotective influences. The temporal variation in the effect of fisetin could be due to the (i) chronopharmacological, chronopharmacokinetic properties of fisetin and (ii) modulations in the endogenous circadian rhythms of urea cycle enzymes, brain markers, redox enzymes and renal clearance during hyperammonaemia by fisetin. However, future studies in these lines are necessitated. PMID- 25443733 TI - Ramipril/amlodipine single pill - effectiveness, tolerance and patient satisfaction with antihypertensive therapy in relation to nutritional status. AB - BACKGROUND: Overweight and obesity decrease the effectiveness of antihypertensive therapy despite the more frequent use of polytherapy. One method for improving therapy effectiveness is by decreasing non-compliance with the use of fixed-dose combinations (FDC). The aim of this study was to assess the effectiveness, tolerance, and satisfaction with ramipril/amlodipine FDC antihypertensive therapy in relation to nutritional status. METHODS: The survey enrolled 24,240 hypertensive patients recently switched to ramipril/amlodipine FDC (EGIRAMLON) at the same doses as previously prescribed separate pills. RESULTS: The effectiveness of antihypertensive therapy increased during follow-up from 32.9% to 76.5%. Overweight and obesity were associated with the increased risk of not attaining the recommended BP values [adjusted for age OR=0.74 (95% CI 0.67-0.83) and 0.70 (0.61-0.81) for overweight; 0.54 (0.47-0.60) and 0.49 (0.42-0.57) for obese, at the first and the second examination, respectively]. "Very good" or "good" the FDP tolerance was reported by 98.8%, 97.6% and 96.4%, respectively. Adverse events (AE) were reported in 0.35% of patients regardless of nutritional status. High levels of satisfaction with the FDC were reported by 57.0% of patients with normal weight, 54.5% of overweight, and 50.6% with obesity. Effectiveness and convenience were the most important for patients. CONCLUSIONS: The effectiveness of therapy with ramipril/amlodipine FDC in the study population was high, but slightly lower in overweigh and obese. This FDC was well tolerated and a significant number of patients satisfied with the therapy regardless of nutritional status. Although the perceived tolerance and satisfaction with treatment were lower in obese and overweight than in normal weight patients; the incidence of AE and perceived benefit from the use of a single-pill, compared to multiple tablets, were comparable irrespective of nutritional status. PMID- 25443734 TI - Alleviation of hepatic injury by chrysin in cisplatin administered rats: probable role of oxidative and inflammatory markers. AB - BACKGROUND: Cisplatin is an effective and extensively used chemotherapeutic agent to treat range of malignancies, but its therapeutic use is limited because of dose-dependent nephrotoxicity and hepatotoxicity. Several published reports advocate that supplementation with antioxidant can influence cisplatin induced hepatic damage. METHOD: In the present study the Wistar rats were subjected to concurrent prophylactic oral treatment of chrysin (25 and 50mg/kgb.wt.) against the hepatotoxicity induced by intraperitoneal administration of cisplatin (7.5mg/kgb.wt.). Efficacy of chrysin against the hepatotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, histopathological changes and expression levels of molecular markers of inflammation. RESULTS: Chrysin ameliorated cisplatin-induced lipid peroxidation, xanthine oxidase activity, glutathione depletion, decrease in antioxidant (catalase, glutathione reductase, superoxide dismutase, glutathione peroxidase and glucose-6 phosphate dehydrogenase) and phase-II detoxifying (glutathione-S transferase and quinone reductase) enzyme activities. Chrysin also attenuated expression of COX-2, iNOS and levels of NFkappaB and TNF-alpha, and hepatic tissue damage which were induced by cisplatin. Histological findings further supported the protective effects of chrysin against cisplatin-induced hepatic damage. CONCLUSION: The results of the present study demonstrate that oxidative stress and inflammation are closely associated with cisplatin-induced toxicity and chrysin shows the protective efficacy against cisplatin-induced hepatotoxicity possibly via attenuating the oxidative stress and inflammatory response. PMID- 25443735 TI - The anti-cancer actions of O6-methylguanine-DNA-methyltransferase in relation to colon polyps. AB - BACKGROUND: Genetic variability in DNA repair genes may contribute to differences in DNA repair capacity and susceptibility to colon polyps and cancer. In this study, we examined the role of MGMT polymorphisms in colon polyps formation. METHODS: PCR-SSCP analysis was performed included 254 patients with colon polyps and 330 controls. RESULTS: The homozygous F84F genotype was significantly more prevalent in study group than in controls. The polymorphic allele 84F was more frequent appeared in group of older patients and in group of smoking patients. On the other hand, there were no association between 84F and gender, size of polyps, cancer family history. CONCLUSIONS: We concluded that high frequency of 84F allele in the group of patients may suggest the role of the MGMT variant in colon polyps etiology. PMID- 25443736 TI - Modulating actions of NMDA receptors on pronociceptive effects of locally injected remifentanil in diabetic rats. AB - BACKGROUND: In this study, we investigated the effects of locally (intraplantar) applied remifentanil, a MU opioid receptor agonist, to the paws and tested whether locally N-methyl d-aspartate (NMDA) receptors agonist or antagonist can modify remifentanil-induced effects in diabetic rats. METHODS: Effects of locally (intraplantar) remifentanil, NMDA and MK801 or their combinations were investigated by measuring the latencies, thresholds and two biochemical parameters (malondialdehyde (MDA) and nitric oxide (NO)), in streptozotocin induced diabetic rats. RESULTS: Diabetic rats exhibited hyperalgesia and allodynia and remifentanil treatment aggravated the hyperalgesia and allodynia. The hyperalgesic and allodynic effects of remifentanil decreased in diabetic rats as compared to healthy rats. MK801 suppressed the hyperalgesic and allodynic actions of remifentanil in diabetic rats. However, hyperalgesic and allodynic actions of NMDA increased in diabetic rats. In contrast to age matched group, the combination of NMDA and remifentanil did not produce synergistic actions in diabetic rats. The levels of MDA and NO in the paw tissues of the diabetic rats significantly increased. MK801 significantly decreased NO levels, but not MDA, in diabetic rats. CONCLUSIONS: The hyperalgesic and allodynic actions of locally treated remifentanil may decrease in diabetic conditions. Increases in NMDA receptors activation, reactive oxygen species production and NO release may modify the sensitivity to remifentanil in diabetes induced neuropathic pain states. PMID- 25443737 TI - Apoptotic mechanisms of the biotechnologically produced arylnaphtalene lignan justicidin B in the acute myeloid leukemia-derived cell line HL-60. AB - BACKGROUND: The present study aimed at optimization of the biotechnological production of the lignan justicidin B by genetically transformed cultures of Linum leonii and the pharmacological evaluation of the pro-apoptotic effects of the compound in HL-60 cells. METHODS: A rapidly growing selected root line of L. leonii was grown in 2-L bioreactor for period of 40 days and the protocols for obtaining of the compound have been optimized. The pharmacological study included evaluation of the cytotoxicity of the compound in HL-60 cells (MTT-assay), its apoptogenic effects and its effects on caspase 3,8 and 9 activation. RESULTS: After 40 days of sterile run scale up of hairy root culture in bioreactor, 27.2g/L dry weight of root biomass was harvested from the bioreactor culture vessel, recording about nine times increase over initial inoculum (3.0g), with 1.55%+/-0.07 Justicidin B, greater than yields from 300ml flasks. Our findings are the first work toward the scale up of L. leonii hairy roots-based biotechnological production of Justicidin B, employing bioreactors for high biomass production to meet the industrial requirement. The results from the pharmacological evaluation have shown that the tested arylnaphtalene lignan is a potent cytotoxic and proapoptotic agent against HL-60. The induction of apoptosis proceeds via activation of the intrinsic mitochondrial cell-death signaling pathways. CONCLUSION: The potent activity at low micromolar concentration and the feasibility of biotechnological production of justicidin B implies that there is enormous scope in its further evaluation as possible antineoplastic drug candidate. PMID- 25443738 TI - Daytime sleepiness and EEG abnormalities in patients treated with second generation antipsychotic agents. AB - BACKGROUND: The aim of this study was to verify whether or not an increased prevalence of excessive daytime sleepiness (EDS) or EEG abnormalities is observed in patients with schizophrenia spectrum disorders (SSD), and to compare the effects of second generation antipsychotics (SGA) on patients' daytime sleepiness level and EEG recordings. METHODS: EEG recordings and self-reports of EDS, assessed with Epworth (ESS) and Stanford (SSS) Sleepiness Scales, were compared between 244 patients with SSD and 82 patients with anxiety, personality or behavioral disorders (non-psychotic disorders, NPD). To examine the effects of various SGA, patients treated in monotherapy with aripiprazole, olanzapine, clozapine, risperidone and sertindole were compared. RESULTS: A higher prevalence of abnormal EEG recordings was observed in SSD patients. No significant differences in average daytime sleepiness were found between patients with SSD and NPD; however, patients with SSD had longer sleep duration. Aripiprazole treatment was associated with significantly smaller and less frequent EEG abnormalities than treatment with any other SGA, while treatment with clozapine and olanzapine was related to an increased prevalence of severe EEG abnormalities. Patients with SSD treated with SGA in monotherapy were less sleepy than unmedicated patients with NPD. CONCLUSIONS: Although antipsychotics may have profound effects on EEG patients with schizophrenia do not have higher daytime sleepiness than patients with anxiety/personality disorders. Patients with schizophrenia may compensate sedative effects of antipsychotic treatment with sleep duration prolongation and report even less sleepiness than non-psychotic patients. PMID- 25443739 TI - Celecoxib prevents colitis associated colon carcinogenesis: an upregulation of apoptosis. AB - BACKGROUND: Uncontrolled cell proliferation and suppressed apoptosis are the critical events transforming a normal cell to a cancerous one wherein the inflammatory microenvironment supports this oncogenic transformation. The process of colon carcinogenesis may be aggravated in chronic inflammatory conditions such as ulcerative colitis where non-steroidal anti-inflammatory drugs (NSAIDs) may effectively prevent the cellular and molecular events. METHODS: Western blots and immunofluorescent analysis of DNA mismatch repair enzymes, cell cycle regulators and pro- and anti-apoptotic proteins were performed in dextran sulfate sodium (DSS)-induced ulcerative colitis and 1,2-dimethyl benz(a)anthracene (DMH)-induced colon cancer. Also, apoptotic studies were done in isolated colonocytes using fluorescent staining and in paraffin sections using TUNEL assay. RESULTS: An upregulation of cell cycle regulators: cyclin D1/cdk4 and cyclin E/cdk2 and anti apoptotic Bcl-2, along with the suppression of DNA repair enzymes: MLH1 and MSH2; tumour suppressors: p53, p21and Rb and pro-apoptotic proteins: Bax and Bad were observed in the DSS, DMH and DSS+DMH groups. Proliferating cell nuclear antigen (PCNA) was also overexpressed in these groups. The ultimate executioner of the apoptotic pathway; caspase-3, was suppressed in these groups. Apoptotic studies in colonocytes and paraffin sections revealed suppressed apoptosis in these groups. These effects were corrected with the administration of a second generation NSAID, celecoxib along with the treatment of DSS and DMH. CONCLUSION: The chemopreventive action of celecoxib in colitis mediated colon carcinogenesis may include the regulation of DNA mismatch repair enzymes, cell cycle check points, cell proliferation and apoptosis. PMID- 25443740 TI - Antithyroid effects of naringin, hesperidin and rutin in l-T4 induced hyperthyroid rats: possible mediation through 5'DI activity. AB - BACKGROUND: Investigations are meager on the ameliorative role of plant based active compounds in regulating hyperthyroidism. We have now explored the possible role of three flavonoids in the regulation of L-thyroxine (l-T4)-induced hyperthyroidism in rats. This investigation attempts to reveal whether rutin, naringin and hesperidin supplementation exhibit antithyroid effects in L-T4 induced hyperthyroid rats and to work out the possible involvement of free radicals in their mode of action. METHODS: Either rutin or naringin or hesperidin (50mg/kg each) was administered to L-T4-induced hyperthyroid rats for two weeks and their effects were evaluated on the alterations in levels of thyroid hormones, 5'-deiodinase I (5'DI) activity, hepatic lipid peroxidation as well as in antioxidants. RESULTS: l-T4 administration significantly enhanced the serum concentrations of thyroxine and triiodothyronine; the activities of hepatic 5'DI, serum lactate dehydrogenase and serum glutamate pyruvate transaminase along with an increase in content of malondialdehyde in hepatic tissues, but depleted the cellular antioxidants. However, on administration of the test flavonoids, these effects were more or less normalized. Electro paramagnetic resonance (EPR) spectra also indicated the suppression of the hydroxyl radicals (OH) in the hepatic tissues. CONCLUSION: Rutin, naringin and hesperidin have the potential to inhibit thyroid functions without hepatotoxicity and the effects are possibly mediated through their free radical scavenging action as evidenced by EPR study. From the comparative analyses of the results, rutin appeared to be the most effective one suggesting its better antithyroid and antioxidative potential over other two. PMID- 25443741 TI - Interactions between levetiracetam and cardiovascular drugs against electroconvulsions in mice. AB - BACKGROUND: Hypertension and heart failure belong to common comorbid conditions with epilepsy so drug interactions between antiepileptics and cardiovascular drugs are possible in clinical practice. The aim of this study was to evaluate the effects of angiotensin AT1 receptor antagonists (losartan potassium and candesartan cilexetil), angiotensin-converting enzyme (ACE) inhibitors (captopril and perindopril arginine) and diuretics (hydrochlorothiazide and ethacrynic acid) on the anticonvulsant activity of levetiracetam (LEV) in mice. METHODS: The protective action of LEV was examined in the maximal electroshock seizure threshold test. Drugs were administered intraperitoneally (ip). Additionally, combinations of cardiovascular drugs with LEV were tested for adverse effects in the passive avoidance task and the chimney test. RESULTS: Losartan potassium (50mg/kg), candesartan cilexetil (8mg/kg), captopril (50mg/kg), hydrochlorothiazide (100mg/kg) and ethacrynic acid (100mg/kg) did not affect the anticonvulsant activity of LEV. Perindopril arginine (10mg/kg) raised the convulsive threshold for LEV administered at doses of 100, 300 and 500mg/kg. This interaction could be pharmacodynamic in nature because the brain concentration of LEV remained unchanged by perindopril. The adverse effects of the combined treatment with LEV and cardiovascular drugs were not observed in the passive avoidance task or the chimney test. CONCLUSIONS: Although experimental data can be hardly extrapolated to clinical practice, it is suggested that perindopril arginine may positively influence the anticonvulsant action of LEV in epileptic patients. The use of losartan potassium, candesartan cilexetil, captopril, hydrochlorothiazide or ethacrynic acid in patients treated with LEV seems neutral regarding its anticonvulsant activity. PMID- 25443742 TI - Palmitic acid-induced lipotoxicity and protection by (+)-catechin in rat cortical astrocytes. AB - BACKGROUND: Astrocytes do not only maintain homeostasis of the extracellular milieu of the neurons, but also play an active role in modulating synaptic transmission. Palmitic acid (PA) is a saturated fatty acid which, when being excessive, is a significant risk factor for lipotoxicity. Activation of astrocytes by PA has been shown to cause neuronal inflammation and demyelination. However, direct damage by PA to astrocytes is relatively unexplored. The aim of this study was to identify the mechanism(s) of PA-induced cytotoxicity in rat cortical astrocytes and possible protection by (+)-catechin. METHODS: Cytotoxicity and endoplasmic reticulum (ER) markers were assessed by MTT assay and Western blotting, respectively. Cytosolic Ca(2+) and mitochondrial membrane potential (MMP) were measured microfluorimetrically using fura-2 and rhodamine 123, respectively. Intracellular reactive oxygen species (ROS) production was assayed by the indicator 2'-7'-dichlorodihydrofluorescein diacetate. RESULTS: Exposure of astrocytes to 100MUM PA for 24h resulted in apoptotic cell death. Whilst PA-induced cell death appeared to be unrelated to ER stress and perturbation in cytosolic Ca(2+) signaling, it was likely a result of ROS production and subsequent MMP collapse, since ascorbic acid (anti-oxidant, 100MUM) prevented PA-induced MMP collapse and cell death. Co-treatment of astrocytes with (+)-catechin (300MUM), an anti-oxidant found abundantly in green tea, significantly prevented PA-induced ROS production, MMP collapse and cell death. CONCLUSION: Our results suggest that PA-induced cytotoxicity in astrocytes may involve ROS generation and MMP collapse, which can be prevented by (+) catechin. PMID- 25443743 TI - Effect of propranolol on IL-10, visfatin, Hsp70, iNOS, TLR2, and survivin in amelioration of tumor progression and survival in Solid Ehrlich Carcinoma-bearing mice. AB - BACKGROUND: beta-Adrenergic signaling could contribute to initiation and progression of breast cancer. This research investigated some potential mechanisms of propranolol in amelioration of progression and survival in breast cancer. METHODS AND RESULTS: Solid Ehrlich Carcinoma (SEC) xenograft model was induced in 30 mice divided into 3 groups; where group I served as untreated SEC group. In groups II and III, propranolol treatment i.p. in low (5mg/kg) and high dose (10mg/kg) caused significant increase in interleukin-10 (IL-10) and decrease in heat shock protein 70 (Hsp70) and inducible nitric oxide synthase (iNOS) activity with non significant change in visfatin in tumor tissues compared to untreated SEC. In untreated SEC, tumor volume (V) exhibited significant negative correlation with IL-10 levels and toll like receptor 2 (TLR2) expression with significant positive correlation with Hsp70 levels and iNOS activity. While propranolol in either doses caused reduction of tumor volume (V), and improved percentage tumor growth inhibition (% TGI) only its high dose exhibited significant impact on survival rate. Propranolol dose-dependent effect was evident for IL-10 and Hsp70, and even only the high dose significantly increased and decreased TLR2 and survivin, respectively. This comes in favor of recommending high dose of propranolol in cancer therapy. Nonetheless, use of low dose cannot be ignored when benefit to risk balance have to be considered. CONCLUSIONS: Propranolol could provide palliative effects in progression and survival of breast cancer that are mainly mediated via direct immunomodulatory and apoptotic mechanisms and probably associated with indirect anti-angiogenic activity. PMID- 25443744 TI - The influence of amitriptyline and carbamazepine on levomepromazine metabolism in human liver: an in vitro study. AB - BACKGROUND: Joint administration of phenothiazine neuroleptics and an antidepressant or carbamazepine is applied in the therapy of many complex psychiatric disorders. The aim of the present study was to investigate possible effects of the tricyclic antidepressant drug amitriptyline and the anticonvulsant drug carbamazepine on the metabolism of the aliphatic-type phenothiazine neuroleptic levomepromazine in human liver. METHODS: The experiment was performed in vitro using human liver microsomes. The rates of levomepromazine 5 sulfoxidation and N-demethylation (levomepromazine concentrations: 5, 10, 25 and 50MUM) were assessed in the absence and presence of amitriptyline or carbamazepine added in vitro (drug concentrations: 1, 2.5, 5, 10, 25MUM). RESULTS: A kinetic analysis of levomepromazine metabolism carried out in the absence or presence of carbamazepine showed that the anticonvulsant drug potently inhibited levomepromazine 5-sulfoxidation (Ki=7.6MUM, non-competitive inhibition), and moderately decreased the rate of levomepromazine N-demethylation (Ki=15.4MUM, mixed inhibition) at therapeutic drug concentrations. On the other hand, amitriptyline weakly diminished the rate of levomepromazine 5-sulfoxidation (Ki=63MUM, mixed inhibition) and N-demethylation (Ki=47.7MUM, mixed inhibition). CONCLUSION: Regarding the central and peripheral effects of levomepromazine and some of its metabolites, the observed metabolic interaction between this neuroleptic and carbamazepine may be of pharmacological and clinical importance. PMID- 25443745 TI - On the toxicity of kynurenic acid in vivo and in vitro. AB - BACKGROUND: Kynurenic acid (KYNA), a tryptophan metabolite is an antagonist of ionotropic glutamate receptors and alpha-7 nicotinic receptor. Moreover, it is an agonist of G-protein receptor GPR35. Its neuroprotective, anticonvulsant, anti inflammatory and antioxidant activity was documented. KYNA is present in food and herbal medicines. However, the data on effects induced by a long-lasting treatment with KYNA is lacking. The aim of the study was the assessment of toxicity of a prolonged administration of KYNA in rodents. The cytotoxicity of KYNA in vitro was also examined. METHODS: Adult mice and rats were used. KYNA was administered in the drinking water in concentrations of 25 or 250mg/L for 3-21 days. The following cells were cultured in an in vitro study: mouse fibroblast (NIH/3T3), green monkey kidney cells and primary chick embryo cells (CECC). Cell viability was determined with methyl thiazol tetrazolium reduction assay, neutral red uptake assay and lactate dehydrogenase leakage assay. RESULTS: KYNA affected neither body gain nor body composition. Blood counts were also unaffected. The viability of cells in the culture was lowered at high millimolar concentrations of KYNA. An elevated viability of GMK and CECC cells was detected in the presence of KYNA in micromolar concentrations. CONCLUSIONS: The obtained results showed that a long-term application of KYNA in the drinking water is well-tolerated by rodents. No evidence of a toxic response was recorded. Achieved results indicate that diets containing a high amount of KYNA or enriched with KYNA should not cause any risk to the human health. PMID- 25443746 TI - Experimental diabetes mellitus type 1 increases hippocampal content of kynurenic acid in rats. AB - BACKGROUND: Diabetes mellitus (DM) is frequently associated with peripheral and central complications and has recently emerged as a risk factor for cognitive impairment and dementia. Kynurenic acid (KYNA), a unique tryptophan derivative, displays pleiotropic effects including blockade of ionotropic glutamate and alpha7 nicotinic receptors. Here, the influence of experimental diabetes on KYNA synthesis was studied in rat brain. METHODS: DM was induced by i.p. administration of streptozotocin (STZ). Five weeks later, KYNA content and the activity of semi-purified kynurenine aminotransferases (KATs) were measured in frontal cortex, hippocampus and striatum of diabetic and insulin-treated rats, using HPLC-based methods. RESULTS: Hippocampal but not cortical or striatal KYNA concentration was considerably increased during DM, either untreated or treated with insulin (220% and 170% of CTR, respectively). The activity of kynurenine aminotransferase I (KAT I) was not affected by DM in all of the studied structures. KAT II activity was moderately increased in cortex (145% of CTR) and hippocampus (126% of CTR), but not in striatum of diabetic animals. Insulin treatment normalized cortical but not hippocampal KAT II activity. CONCLUSIONS: A novel factor potentially implicated in diabetic hippocampal dysfunction has been identified. Observed increase of KYNA level may stem from the activation of endogenous neuroprotection, however, it may also have negative impact on cognition. PMID- 25443747 TI - L-1416, a novel MDR reversing agent with possible reduced calcium antagonism. AB - BACKGROUND: Multidrug efflux transporter P-glycoprotein (P-gp) is highly expressed on membrane of tumor cells and supposed to be implicated in the resistance to tumor chemotherapy. However, currently none of P-gp inhibitors has been approved by Food and Drug Administration not only due to toxicity but also lack of efficacy in clinical trials. METHODS: To solve the problem, our lab synthesized a novel compound named 1416 [1-(2,6-dimethylphenoxy)-3,4 dimethoxyphenylethylamino) propane hydrochloride] with the hope of high P-gp inhibition and low side effects. Caco-2 cell monolayer and tumor bearing mice were used to evaluate the P-gp inhibition of 1416 in vitro and in vivo, respectively. One of its potential side effects, calcium antagonism was also evaluated. RESULTS: Results showed that 1416 showed a similar P-gp inhibition as verapamil in Caco-2 cell monolayer. No significant difference was observed in antitumor enhancement when the optical isomers of 1416 (D-1416 and L-1416) were co-administered with vinblastine. In calcium antagonism, L-1416 showed less calcium inhibition than both D-1416 and verapamil. CONCLUSION: The novel compound 1416 could significantly increase the antitumor effects of cytotoxic drugs and one of its optical isomers, L-1416, might be more promising due to its potential low calcium antagonism. PMID- 25443748 TI - Improvement of mitochondrial NAD(+)/FAD(+)-linked state-3 respiration by caffeine attenuates quinolinic acid induced motor impairment in rats: implications in Huntington's disease. AB - BACKGROUND: Chronic quinolinic acid (QA) lesions in rats closely resemble Huntington's disease like conditions. Oxidative stress and mitochondrial dysfunction have long been implicated in the neurotoxic effects of QA acting through N-methyl-d-aspartate (NMDA) receptors. Reports suggest that inhibition of adenosine A2A receptor function elicits neuroprotective effect in QA induced neurotoxicity in rats. Caffeine, a preferential A2A receptor antagonist imitates antioxidant like actions and exerts neuroprotective effects in various neurodegenerative conditions. Thus, the present study was designed to evaluate the neuroprotective effects of caffeine against QA induced neurotoxicity in rats. METHODS: In the present study, QA (200nmol/2MUl saline) has been administered bilaterally to the striatum of rats followed by chronic caffeine (10, 20 and 40mg/kg) administration for 21 days. Motor performance of the animals was evaluated in weekly intervals and subsequently after 21 days, the animals were sacrificed and measurement of mitochondrial complexes activity, respiration rate and endogenous antioxidant levels were carried out in the striatal region. RESULTS: Single intrastriatal QA administration resulted in drastic reduction in body weight, marked motor impairment (decreased total locomotor activity in actophotometer and impaired grip strength in rotarod), increased oxidative stress, impaired mitochondrial complexes activities and decreased state 3 respiration (NAD(+)/FAD(+)-linked) in rats. However, chronic treatment of caffeine for 21 days significantly attenuated the QA induced behavioural, biochemical and mitochondrial alterations displaying neuroprotective efficacy. CONCLUSION: The study highlights the possible involvement of A2A receptor antagonism in the neuroprotective effect of caffeine against QA induced mitochondrial dysfunction and oxidative stress in rats. PMID- 25443749 TI - Human-chimpanzee alignment: ortholog exponentials and paralog power laws. AB - Genomic subsequences conserved between closely related species such as human and chimpanzee exhibit an exponential length distribution, in contrast to the algebraic length distribution observed for sequences shared between distantly related genomes. We find that the former exponential can be further decomposed into an exponential component primarily composed of orthologous sequences, and a truncated algebraic component primarily composed of paralogous sequences. PMID- 25443750 TI - Regarding the use of epinephrine auto-injectors in remote settings. PMID- 25443751 TI - Controlled hyperventilation after training may accelerate altitude acclimatization. PMID- 25443753 TI - Symptoms and treatment of acute conjunctivitis caused by skin secretions of veined tree frog (Trachycephalus venulosus). PMID- 25443752 TI - Glossopharyngeal insufflation and breath-hold diving: the more, the worse? AB - OBJECTIVE: The glossopharyngeal insufflation maneuver (lung packing) is largely performed by competitive breath-hold divers to improve their performance, despite observational evidence of fainting and loss of consciousness in the first seconds of apnea. METHODS: We describe here the time course of hemodynamic changes, induced by breath-holding with and without lung packing, in 2 world-class apnea competitors. RESULTS: When compared with apnea performed after a deep breath (100% vital capacity), lung packing leads to a decrease in cardiac output, blood pressure, and cerebral blood flow during the first seconds after the beginning of apnea. The major hemodynamic disorders were observed in diver 1, who exhibited the greater increase in pulmonary volume after lung packing (+22% for diver 1 vs +10% for diver 2). After the initial drop in both cardiac output and blood pressure, the time course of hemodynamic alterations became quite similar between the two apneas. CONCLUSIONS: Some recommendations, such as limiting the number of maneuvers and performing lung packing in the supine position, should be expressed to avoid injuries secondary to the use of glossopharyngeal insufflation. PMID- 25443754 TI - A prospective randomized blister prevention trial assessing paper tape in endurance distances (Pre-TAPED). AB - OBJECTIVE: Friction foot blisters are a common injury occurring in up to 39% of marathoners, the most common injury in adventure racing, and represent more than 70% of medical visits in multi-stage ultramarathons. The goal of the study was to determine whether paper tape could prevent foot blisters in ultramarathon runners. METHODS: This prospective randomized trial was undertaken during RacingThePlanet 155-mile (250-km), 7-day self-supported ultramarathons in China, Australia, Egypt, Chile, and Nepal in 2010 and 2011. Paper tape was applied prerace to one randomly selected foot, with the untreated foot acting as the own control. The study end point was development of a hot spot or blister on any location of either foot. RESULTS: One hundred thirty-six participants were enrolled with 90 (66%) having completed data for analysis. There were 36% women, with a mean age of 40 +/- 9.4 years (range, 25-40 years) and pack weight of 11 +/ 1.8 kg (range, 8-16 kg). All participants developed blisters, with 89% occurring by day 2 and 59% located on the toes. No protective effect was observed by the intervention (47 versus 35; 52% versus 39%; P = .22), with fewer blisters occurring around the tape on the experimental foot than under the tape (23 vs 31; 25.6% versus 34.4%), yet 84% of study participants when queried would choose paper tape for blister prevention in the future. CONCLUSIONS: Although paper tape was not found to be significantly protective against blisters, the intervention was well tolerated with high user satisfaction. PMID- 25443755 TI - Exercise-associated hyponatremic encephalopathy in an endurance open water swimmer. AB - Exercise-associated hyponatremia and its more serious form, known as exercise associated hyponatremic encephalopathy, are recognized as some of the most important medical problems seen in a variety of different forms of endurance exercise. We describe a case of exercise-associated hyponatremic encephalopathy presenting as altered conscious state and seizures in a woman who had completed a 20-km open ocean swim. Her serum sodium measured approximately 1 hour after her seizure was 119 mmol/L on point-of-care testing. With ongoing critical care support and the use of hypertonic saline, she was able to be extubated the next day, neurologically intact, and ultimately was discharged from hospital without neurological sequelae. This case emphasizes both the importance of considering exercise-associated hyponatremic encephalopathy as a cause of neurological impairment in all athletes and the pivotal role of hypertonic saline in the treatment of this condition. PMID- 25443756 TI - Epidemiology of Hunting Stand Injuries Presenting to US Emergency Departments, 2008-2013. AB - OBJECTIVE: To determine the epidemiology of injuries from hunting stands presenting to US emergency departments (EDs). METHODS: The National Electronic Injury Surveillance System (NEISS) database was queried for ED visits for the period 2008 through 2013 for hunting stand injuries and analyzed for age, diagnosis, sex, race, anatomic location of the injury, the use of alcohol, and association with a gunshot wound. RESULTS: There were an estimated 38,308 visits with an average age of 40.0 years (range, 1-83 years). The patients were predominantly male (93.3%), white (99.1%), and seen at small- or medium-size hospitals (80.6%). Disposition from the ED was admission in 20.1% and released in 79.9%. A fall occurred in 80.3%, a gunshot wound in 0.4%, and alcohol was involved in 0.6%. The most common diagnoses were a fracture (34.7%), contusion or abrasion (24.0%), strain or sprain (16.8%), laceration (7.7%), and internal organ injury (5.4%). Those injured in a fall were more frequently admitted (23.0% vs. 8.7%) and more likely to have a fracture (37.9% vs. 9.1%). Those with a fracture were older (44.6% vs. 37.9%). Those with internal organ injuries were more frequently admitted (44.8% vs 18.6%). CONCLUSIONS: This study has characterized the epidemiology of hunting stand injuries with most occurring from falls. A fracture was the most common injury with a very low alcohol intoxication rate. These baseline data can now be used to compare other studies of hunting stand injuries and guide prevention strategies, such as education regarding the need for safety measures to prevent falls. PMID- 25443757 TI - Waterfall mortality and morbidity in North Carolina, 2001-2013. PMID- 25443758 TI - A 51-year-old woman crushed by an elephant trunk. AB - Wild and exotic animal attacks are not common in the United States. Animal related injuries in the United States are usually caused by dog bites, followed by cattle and horse injuries. Exotic animal attacks can occur when the animals are provoked, depressed, or housed improperly by owners. We report the case of a 51-year-old woman who sustained multiple systemic traumatic injuries after she was pinned to a fence by an elephant's trunk. Upon arrival in the emergency department, she was hypothermic with a temperature of 35.1oC (95.1oF), hypotensive to 94/60 mm Hg after 5 L crystalloid, tachycardic at 108 beats/min, and intubated with oxygen saturation of 100%. Tranexamic acid was administered in addition to starting a massive transfusion protocol. Injuries included bilateral multiple rib fractures, left abdominal wall degloving injury, right pneumothorax, right hemothorax, left chest wall puncture wound, grade IV splenic laceration, 3 grade III liver lacerations, retroperitoneal hematoma, and degloving injuries to bilateral posterior thighs requiring more than 30 operations. Why should an emergency physician be aware of this? Several factors need to be considered when evaluating animal-related injuries, including type, age, and sex of the animal. Multisystem traumatic injuries should be assumed when a large animal is involved. Prehospital care and transport time are vital to a patient's survival in both urban and rural settings. During the initial resuscitation, administering antibiotics tailored to the specific animal can greatly decrease risk of infection and morbidity. Additionally, tetanus immunoglobulin, tetanus toxoid, and rabies immunoglobulin and vaccine may be needed, unless the victim has been previously vaccinated. PMID- 25443759 TI - Search and rescue response to a large-scale rockfall disaster. AB - OBJECTIVE: To describe the prehospital management and safety of search and rescue (SAR) teams involved in a large-scale rockfall disaster and monitor the acute and chronic health effects on personnel with severe dolomitic dust exposure. METHODS: SAR personnel underwent on-site medical screening and lung function testing 3 months and 3 years after the event. RESULTS: The emergency dispatch center was responsible for central coordination of resources. One hundred fifty SAR members from multidisciplinary air- and ground-based teams as well as geotechnical experts were dispatched to a provisionary operation center. Acute exposure to dolomite dust with detectable silicon and magnesium concentrations was not associated with (sub)acute or chronic sequelae or a clinically significant impairment in lung function in exposed personnel. CONCLUSIONS: The risk for personnel involved in mountain SAR operations is rarely reported and not easily investigated or quantified. This case exemplifies the importance of a multiskilled team and additional considerations for prehospital management during natural hazard events. Safety plans should include compulsory protective measures and medical monitoring of personnel. PMID- 25443760 TI - An itchy situation. PMID- 25443761 TI - High-intensity intermittent exercise increases pulmonary interstitial edema at altitude but not at simulated altitude. AB - OBJECTIVE: Ascent to high altitude leads to a reduction in ambient pressure and a subsequent fall in available oxygen. The resulting hypoxia can lead to elevated pulmonary artery (PA) pressure, capillary stress, and an increase in interstitial fluid. This fluid can be assessed on lung ultrasound (LUS) by the presence of B lines. We undertook a chamber and field study to assess the impact of high intensity exercise in hypoxia on the development of pulmonary interstitial edema in healthy lowlanders. METHODS: Thirteen volunteers completed a high-intensity intermittent exercise (HIIE) test at sea level, in acute normobaric hypoxia (12% O2, approximately 4090 m equivalent altitude), and in hypobaric hypoxia during a field study at 4090 m after 6 days of acclimatization. Pulmonary interstitial edema was assessed by the evaluation of LUS B-lines. RESULTS: After HIIE, no increase in B-lines was seen in normoxia, and a small increase was seen in acute normobaric hypoxia (2 +/- 2; P < .05). During the field study at 4090 m, 12 participants (92%) demonstrated 7 +/- 4 B-lines at rest, which increased to 17 +/ 5 immediately after the exercise test (P < .001). An increase was evident in all participants. There was a reciprocal fall in peripheral arterial oxygen saturations (Spo2) after exercise from 88% +/- 4% to 80% +/- 8% (P < .01). B lines and Spo2 in all participants returned to baseline levels within 4 hours. CONCLUSIONS: HIIE led to an increase in B-lines at altitude after subacute exposure but not during acute exposure at equivalent simulated altitude. This may indicate pulmonary interstitial edema. PMID- 25443762 TI - Weight cycling in bipolar disorder. AB - BACKGROUND: An association between excess weight and/or weight fluctuations and cardiovascular morbidity and mortality is amply documented. Individuals with bipolar disorder (BD) are differentially affected by overweight/obesity, chaotic eating patterns (e.g., binge eating), as well as cardiovascular morbidity and mortality. Weight cycling (WCYC) is defined as a pattern of repetitive weight loss and gain. METHODS: We sought to determine the relationship between course of illness and BD and WCYC retrospectively as well whether these co-occurring phenotypes identify a biologically distinct subpopulation on the basis of having a unique inflammatory biomarker/biosignature profile. Sociodemographic, clinical, and inflammatory markers were gathered from a well-characterized cohort of actual euthymic adults with BD (n=101) and a healthy control group (n=48). RESULTS: Individuals with BD with a history of WCYC were provided evidence of a greater frequency of prior episodes (i.e., both manic and depressed), as well as of significantly higher levels of circulating IL-6 concentrations when compared to non-WCYC individuals with BD. The association persisted after adjusting for relevant covariates (e.g., BMI, age, number of prior episodes). LIMITATIONS: Include the small control group, differing medication status and that all data relies on personal information. Nevertheless we tried to verify all data as far as clinical disclosure was available. CONCLUSION: The results of this study indicate that adults with BD excessive in weight are not only more susceptible to a relapse-prone course of illness, but also are more likely to present with WCYC. The finding of elevated pro-inflammatory cytokines in this subpopulation may identify a separate subpopulation with greater susceptibility to cardiovascular disease. The overarching aim of personalized treatment and preventive strategies in BD begins with appropriate, empirically supported patient stratification. Our results provide preliminary support for stratifying BD cardiovascular risk on the basis of anthropometrics and WCYC. PMID- 25443763 TI - Differential typology of delusions in major depression and schizophrenia. A critique to the unitary concept of 'psychosis'. AB - It is a current trend in psychiatry to discard the Kraepelinian dichotomy schizophrenia vs. manic-depressive illness and use the overinclusive label 'psychosis' to broadly indicate the whole spectrum of severe mental disorders. In this paper we show that the characteristics of psychotic symptoms vary across different diagnostic categories. We compare delusions in schizophrenia and major depression and demonstrate how these phenomena radically differ under these two psychopathological conditions. The identification of specific types of delusions is principally achieved through the differential description of subjective experiences. We will use two general domains to differentiate schizophrenic and depressive delusions, namely the intrinsic and extrinsic features of these phenomena. Intrinsic features are the form and content of delusions, extrinsic ones include the background from which delusions arise, that is, changes in the field of experience, background feelings, ontological framework of experience, and existential orientation. This kind of systematic exploration of the patients' experience may provide a useful integration to the standard symptom-based approach and can be used to establish a differential typology of the clinical manifestation of psychosis based on the fundamental alterations of the structures of subjectivity characterizing each mental disorder, particularly with respect to the Kraepelinian dichotomy schizophrenic vs. manic-depressive illness. PMID- 25443765 TI - [Psychosocial stress environment and health workers in public health: Differences between primary and hospital care]. AB - OBJECTIVE: To describe the psychosocial environment of health professionals in public health in primary and hospital care, and compare it with that of the general Spanish working population, as well as to evaluate the effect of psychosocial risk factors on symptoms related to perceived stress. DESIGN: Cross sectional study with stratified random sampling. SETTING: Health care workers in the province of Granada, distributed in 5 hospitals and 4 health districts. PARTICIPANTS: A total of 738 employees (medical and nursing staff) of the Andalusian Health Service (SAS) were invited to take part. MAIN MEASUREMENTS: CopSoQ/Istas21 questionnaire developed for the multidimensional analysis of the psychosocial work environment. Stress symptoms were measured with the Stress Profile questionnaire. RESULTS: The response rate was 67.5%. Compared with the Spanish workforce, our sample showed high cognitive, emotional, and sensory psychological demands, possibilities for development and sense of direction in their work. Primary care physicians were the group with a worse psychosocial work environment. All the groups studied showed high levels of stress symptoms. Multivariate analysis showed that variables associated with high levels of stress symptom were younger and with possibilities for social relations, role conflict, and higher emotional demands, and insecurity at work. CONCLUSIONS: Our findings support that the psychosocial work environment of health workers differs from that of the Spanish working population, being more unfavorable in general practitioners. PMID- 25443766 TI - [Evaluation of the impact of teledermatology in decreasing the waiting list in the Bages region (2009-2012)]. PMID- 25443764 TI - Pharmacologic MRI (phMRI) as a tool to differentiate Parkinson's disease-related from age-related changes in basal ganglia function. AB - The prevalence of both parkinsonian signs and Parkinson's disease (PD) per se increases with age. Although the pathophysiology of PD has been studied extensively, less is known about the functional changes taking place in the basal ganglia circuitry with age. To specifically address this issue, 3 groups of rhesus macaques were studied: normal middle-aged animals (used as controls), middle-aged animals with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced parkinsonism, and aged animals (>20 years old) with declines in motor function. All animals underwent the same behavioral and pharmacologic magnetic resonance imaging (phMRI) procedures to measure changes in basal ganglia function in response to dopaminergic drug challenges consisting of apomorphine administration followed by either a D1 (SCH23390) or a D2 (raclopride) receptor antagonist. Significant functional changes were predominantly seen in the external segment of the globus pallidus (GPe) in aged animals and in the striatum (caudate nucleus and putamen) in MPTP-lesioned animals. Despite significant differences seen in the putamen and GPe between MPTP-lesioned versus aged animals, a similar response profile to dopaminergic stimulations was found between these 2 groups in the internal segment of the GP. In contrast, the pharmacologic responses seen in the control animals were much milder compared with the other 2 groups in all the examined areas. Our phMRI findings in MPTP lesioned parkinsonian and aged animals suggest that changes in basal ganglia function in the elderly may differ from those seen in parkinsonian patients and that phMRI could be used to distinguish PD from other age-associated functional alterations in the brain. PMID- 25443767 TI - [Basic guidelines for detecting sedentarism and recommendations for physical activity in primary care]. AB - The detection of physical inactivity in adults, using simple and useful tools is primary objective in both public health and in clinical settings, since this risk factor is one of the major causes of non-communicable disease in the world, and is very prevalent in developed societies such as in Spain. Two validated instruments are described that are simple and useful for detecting and/or monitoring physical inactivity in adults: (i)the international physical activity questionnaire in its short version, and (ii)the pedometer to measure the number of steps taken in a day. Increased levels of physical activity are important for the primary prevention of some chronic diseases (coronary heart disease, type2 diabetes, osteoporosis, colon cancer) and to improve the quality of life. Medical personnel must determine the motivation level and the availability of patients and their families to change their behavior towards physical activity. Moderate intensity physical activities have hardly any contraindications and the risks are few. PMID- 25443768 TI - [Drug prescriptions study in the outpatient setting: assessment of off-label uses in children]. AB - OBJECTIVE: to evaluate the prescription profile and to assess the off-label and unlicensed uses of medicines among non-hospitalised pediatric patients. DESIGN: cross-sectional study. SETTING: pediatric units in two urban health centers and general emergency room (Hospital Materno-Infantil, Malaga). MAIN MEASUREMENTS: sociodemographics variables, reasons for consultation and information about therapeutic medications. The classification of prescriptions was established according to information requirements contained in the Summary of Products Characteristics (SPC). RESULTS: A total of 388 children were included (a subsample of 105 treated in the emergency room). Four hundred sixty-two prescriptions (involving 74 different active ingredients) were evaluated. Each infant received and average of 1,7 drugs (95% CI: 1,6-1,9). The most prescribed medicines were ibuprofen, paracetamol, amoxicillin-clavulanate and budesonide. The therapeutic group with the greatest variety of drugs was the respiratory group. 27,4% (95% CI: 23,5-31) of prescriptions were off-label and the main cause was different age (60%; 95% CI: 54,1-63), followed by different dose (21,5%; 95% CI: 18-25), different indication (12%; 95% CI: 9,2-15) and different route of administration (7%; 95% CI: 5,4-10). CONCLUSIONS: The rate of off-label uses presents intermediate figures. Around one third of the paediatric outpatients in our sample are exposed to at least one off-label or unlicensed prescription. We should, however, point out that such usage is based on scant official, quality information, although it is not necessarily incorrect. Evidence-based medicine should be encouraged to improve drug therapy in children, as well as following the rules on drugs in special situations. PMID- 25443769 TI - [An integral approach to insomnia in primary care: Non-pharmacological and phytotherapy measures compared to standard treatment]. AB - INTRODUCTION: Insomnia is a sleep disorder in which there is an inability to fall asleep or to stay asleep. At some point in life, 50% of adults suffer from it, usually in stress situations. AIM: To evaluate the impact of sleep hygiene measures, relaxations techniques, and herbal medicine to deal with insomnia, compared with standard measures (drug treatment). METHODOLOGY: An experimental, retrospective, non-randomized study was conducted by means of a review of patients diagnosed with insomnia (2008-2010). Patients in the intervention group (IG) received an integrative approach (hygiene measures, relaxation techniques, and herbal medicine) and a control group (CG) with conventional treatment. A comparison was made of the resources used in the two groups (average monthly visits pre- and post-diagnosis), type of prescribed drug therapy and total dose. Sleep quality was evaluated at 18-24 months (Epworth test). RESULTS: A total of 48 patients were included in the IG and 47 in the CG (70% women, mean age 46 years (SD: 14.3). Average monthly visit pre-diagnosis was 0.54 (SD: 0.42) in the IG and 0.53 (SD: 0.53) in the CG (P=.88). Post-diagnosis it was 0.36 (SD: 0.24) and 0.65 (SD: 0.46), respectively (P<.0001), with a statistically significant reduction being observed in the IG. More than half (52.5%) of the IG patients and 93.6% in the CG had received a benzodiazepine (P<.0001). Alprazolam and lorazepam were the most prescribed in the CG and with higher cumulative dose. In the subsequent evaluation, 17% of patients in the IG and 5% in CG did not have insomnia. Severe insomnia was present in 13% of patients in the IG and none in CG (P<.0001). CONCLUSIONS: The integrative approach to insomnia may be worthwhile as it reduces resource use and side effects, as well as dependence to benzodiazepines. PMID- 25443770 TI - The quick and easy Mongolian Rapid Baby Scale shows good concurrent validity and sensitivity. AB - AIM: In developing countries, around 200 million children with poor development cannot excel academically. Detecting children with developmental delay is fundamental in targeting early interventions. As the lack of a convenient screening tool in Mongolia remains a significant barrier, we aimed to produce an easy-to-administer developmental screening tool in Mongolia and to validate it against an internationally recognised instrument, the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III). METHODS: We developed the Mongolian Rapid Baby Scale consisting of 161 items arranged under seven developmental domains for children aged from zero months 16 days to 42 months 15 days. We recruited 150 children in Ulaanbaatar, Mongolia. After conducting face and content validity of the tool, we evaluated concurrent validity. RESULTS: Concurrent validity ranged from high correlation (r = 0.86) to very high (r = 0.97) for each of the corresponding domains between the two tests. Summary statistics showed good sensitivity (81.8%) and moderate specificity (52.3%). CONCLUSION: Our newly developed tool takes only 15 min to complete and is easy to administer. It demonstrated good concurrent validity and sensitivity for the screening of developmental status in young children. This innovative tool will be useful to identify children who may benefit from early interventions in Mongolia. PMID- 25443772 TI - Two cases of rickets presenting with poor growth, hypotonia, and respiratory problems. AB - Rickets is a rare disease in developed countries. In children, it is a disease which affects growing bone. Depending on the severity, it can present with a wide variety of symptoms. Because it is such a rare disease in developed countries, symptoms suggesting rickets are often not easily recognized. This can cause a delay in diagnosing and treating rickets. Often unnecessary and sometimes invasive investigations are performed. First leading clues to rickets on physical examination are poor growth, especially length, thickening of wrists, bow legs, and craniotabes. At further examination, special attention should be paid to osteopenia and cupping and fraying at the metaphyses on X-rays. Laboratory results suggestive for rickets are elevated alkaline phosphatase and disturbances in calcium and phosphate homeostasis. In this report, we present two cases presenting with poor growth, severe pain, and respiratory problems secondary to calcipenic rickets. PMID- 25443771 TI - Wilderness Medical Society practice guidelines for the out-of-hospital evaluation and treatment of accidental hypothermia. AB - To provide guidance to clinicians, the Wilderness Medical Society (WMS) convened an expert panel to develop evidence-based guidelines for the out-of-hospital evaluation and treatment of victims of accidental hypothermia. The guidelines present the main diagnostic and therapeutic modalities and provide recommendations for the management of hypothermic patients. The panel graded the recommendations based on the quality of supporting evidence and the balance between benefits and risks/burdens according the criteria published by the American College of Chest Physicians. The guidelines also provide suggested general approaches to the evaluation and treatment of accidental hypothermia that incorporate specific recommendations. PMID- 25443774 TI - Endovascular aneurysm repair (EVAR) follow-up imaging: the assessment and treatment of common postoperative complications. AB - Endovascular abdominal aortic aneurysm repair (EVAR) is a well-established procedure, which has long-term mortality rates similar to that of open repair. It has the additional benefit of being less invasive, making it the favoured method of treating abdominal aortic aneurysms in elderly and high-risk patients with multiple co-morbidities. The main disadvantage of EVAR is the higher rate of re intervention, due to device-related complications, including endoleaks, limb occlusion, stent migration, kinking, and infection. As a result lifelong surveillance is required. In order to avoid missing these complications, intricate knowledge of stent graft design, good-quality diagnostic ultrasound skills, multiplanar reformatting of CT images, and reproducible investigations are important. Most of these complications can be treated via an endovascular approach using cuff extensions, uncovered stents, coils, and liquid embolic agents. Open surgery is reserved for complex complications, where an endovascular approach is not feasible. PMID- 25443773 TI - Haemophilus influenzae: a forgotten cause of neonatal sepsis? AB - Due to the introduction of the conjugate vaccine against serotype b, neonatal sepsis caused by Haemophilus influenzae became very rare. There is little data in Belgium concerning the prevalence of H. influenzae early onset neonatal sepsis and articles about neonatal sepsis and H. influenzae published in the last decade are scarce. We report two invasive infections with a non-typeable H. influenzae. These cases show that neonatal sepsis caused by non-typeable H. influenzae may be underestimated and we believe that there is need for a better registration of this kind of infection. PMID- 25443775 TI - The use of cone-beam CT in assisting percutaneous translumbar catheter placement into the inferior vena cava. PMID- 25443776 TI - Ethanol ablation of predominantly cystic thyroid nodules: evaluation of recurrence rate and factors related to recurrence. AB - AIM: To evaluate recurrence rate and associated risk factors for recurrence after ethanol ablation (EA) in patients with predominantly cystic thyroid nodules. MATERIALS AND METHODS: This observational study was approved by the Ethics Committee of the Institutional Review Board and informed consent for procedures was obtained. From April 2009 to April 2013, 107 consecutive patients with predominantly cystic nodules were treated using EA. Recurrence was defined as nodules showing a residual solid portion with internal vascularity, cosmetic problems remaining, or persistent symptoms, and patients who requested additional therapy to resolve their symptomatic or cosmetic problems. Delayed recurrence was defined as treated nodules that showed no recurrent features at 1 month, but showed newly developed recurrent features during the longer follow-up period. Multivariate analysis was used for variables to demonstrate the independent factors related to volume reduction. RESULTS: One month after EA, 18.7% of patients (20/107) showed recurrence. Among 87 patients with non-recurrence, 24.1% (21/87) showed delayed recurrence. The total recurrence rate was 38.3% (41/107). Patients with recurrence (n = 41) were treated using radiofrequency ablation (n = 28), second EA (n = 4), and refused further treatment (n = 9). These patients responded well to repeat EA and radiofrequency ablation. Multivariate analysis demonstrated that the initial nodule volume (>20 ml; p < 0.036) and vascularity (grade >1; p < 0.049) were independent predictors of volume reduction at last follow-up. CONCLUSIONS: The results revealed that although EA seemed to be effective during the initial period, delayed recurrence should be considered during longer-term follow-up. The independent predictors of recurrence were initial volume (>20 ml) and vascularity. PMID- 25443777 TI - Multivoxel proton magnetic resonance spectroscopy in heat stroke. AB - AIM: To assess the role of proton MR spectroscopy (MRS) in the detection of changes in metabolite levels of the cerebellum after heat stroke (HS). MATERIALS AND METHODS: The study group consisted of eight patients after HS, with a Glasgow Coma Scale (GCS) score of 3-9. The MR studies were performed with a 1.5 T system. MR spectra were recorded from a normal-appearing cerebellum region. Spectra from patients were compared with a control group including seven age-matched healthy volunteers recorded with the same techniques. Metabolites ratios including N acetyl aspartate/creatine (NAA/Cr), N-acetyl aspartate/creatine2 (NAA/Cr2), choline/creatine (Cho/Cr), choline/creatine2 (Cho/Cr2), and N-acetyl aspartate/choline (NAA/Cho) were calculated and the differences between the two groups were evaluated using the Mann-Whitney U-test. Pearson correlation analysis was used to analyse the relationship between NAA/Cr ratios and GCS scores for eight patients after HS. RESULTS: In the cerebellum of the patients after HS, NAA/Cr ratios were found to be significantly decreased compared to normal controls (p = 0.004) and Cho/Cr ratios were found to be decreased compared to normal controls (p = 0.032). Significant positive correlation was found between NAA/Cr ratios and GCS scores for eight patients after HS (r = 0.748, p = 0.033). CONCLUSIONS: Metabolite abnormalities were seen in normal-appearing cerebellum structures in patients after HS. Proton MRS is a useful tool for evaluating major changes in metabolite levels of the cerebellum after HS and the severity of the disease can be effectively evaluated by NAA/Cr ratios. PMID- 25443779 TI - Prognostic indicators associated with early mortality of wild raptors admitted to a wildlife rehabilitation centre in Spain. AB - BACKGROUND: Assessment of the prognostic indicators of wildlife casualties is critical in wildlife rehabilitation practice, to optimize the use of economical resources, and to protect animal welfare. Few studies have been conducted in this field. OBJECTIVE: To identify the prognostic indicators associated with raptor mortality during the first week of hospitalization. ANIMALS AND METHODS: Complete medical records of 1722 wild raptor cases admitted to a wildlife rehabilitation centre from 1995 to 2007 were used. Regression models were created to determine mortality-related factors for different variables (order, sex, body condition (BC), clinical signs, and available haematological and biochemical parameters). RESULTS: In the bivariate analysis, the presence of nervous (OR = 11.9, 95%CI:5.1 27.6) or musculoskeletal (OR = 12.1, 95%CI:5.8-25.3) signs, a poor BC (OR = 32.9, 95%CI:19-81.2), and low values of packed cell volume (PCV), haemoglobin or total solids (TS), were all associated with early mortality. After adjusting variables in the multivariate model, BC was excluded due to co-linearity with other variables, and alteration of the nervous system was the only significant risk factor (OR = 4.0; 95%CI:1.9-8.8). In species specific analysis, poor prognosis was related to neurological signs in Athene noctua, poor BC in Strix aluco, trauma in Acciptiter nisus and Tyto alba, low PCV in Buteo buteo and Falco tinnunculus and low TS in Falco tinnunculus. CONCLUSIONS: Raptors with a poor BC, low values of PCV and those presenting with neurological signs, had the highest risk of dying in the first days of admittance. Thus, either medical care or humane euthanasia for poor prognosis should be performed to address animal welfare. PMID- 25443778 TI - Analysis of nucleotide-binding oligomerization domain proteins in a murine model of pneumococcal meningitis. AB - BACKGROUND: The innate immune system recognizes pathogens via its pattern recognition receptors. The objective of this study was to investigate the role of the nucleotide-binding oligomerization domain (NOD) proteins, a family of the novel bacterial pattern recognition receptors, in host responses to the gram positive bacteria Streptococcus pneumoniae. METHODS: Sprague-Dawley rats were infected via intracisternal injections of viable S. pneumoniae, and rats in the control group were injected with sterile saline. After infection, real-time PCR was performed to determine the presence of mRNAs encoding NOD1 and NOD2. Quantitative analyses of the NOD1, NOD2 and NF-kB proteins were also performed western blotting following challenge infections with viable S. pneumoniae. The TNF-alpha and IL-6 levels in brain homogenates were evaluated using enzyme-linked immunosorbent assays (ELISAs). RESULTS: The results revealed up-regulations of the mRNA and protein levels of NOD2 within the CNS of rats with S. pneumoniae meningitis. Moreover, the activation of NF-kappaB in the brain tissues following infection with live S. pneumoniae was also significantly increased, which indicates that NOD2 mediated NF-kappaB activation in experimental pneumococcal meningitis. Similarly, TNF-alpha and IL-6 levels were increased in the brain following in vivo S. pneumoniae administration. CONCLUSIONS: These results suggest that NOD2 is involved in the host response to the gram-positive bacteria S. pneumoniae in the CNS and that NOD2 might play an important role in the initiation and/or progression of CNS inflammation associated with pneumococcal meningitis. PMID- 25443780 TI - Proximal femur elastic behaviour is the same in impact and constant displacement rate fall simulation. AB - Understanding proximal femur fracture may yield new targets for fracture prevention screening and treatment. The goal of this study was to characterize force-displacement and failure behaviours in the proximal femur between displacement control and impact loading fall simulations. Twenty-one human proximal femurs were tested in two ways, first to a sub-failure load at a constant displacement rate, then to fracture in an impact fall simulator. Comparisons of sub-failure energy and stiffness were made between the tests at the same compressive force. Additionally, the impact failure tests were compared with previous, constant displacement rate failure tests (at 2 and 100mm/s) in terms of energy, yield force, and stiffness. Loading and displacement rates were characterized and related to specimen stiffness in the impact tests. No differences were observed between the sub-failure constant displacement and impact tests in the aforementioned metrics. Comparisons between failure tests showed that the impact group had the lowest absorbed energy, 24% lower maximum force and 160% higher stiffness than the 100mm/s group (p<0.01 for all), but suffered from low statistical power to differentiate the donor age and specimen BMD. Loading and displacement rates for the specimens tested using impact varied during each test and between specimens and did not show appreciable viscoelasticity. These results indicate that constant displacement rate testing may help understand sub-failure mechanical behaviour, but may not elucidate failure behaviours. The differences between the impact and constant displacement rate fall simulations have important ramifications for interpreting the results of previous experiments. PMID- 25443781 TI - Effects of low frequency cyclic mechanical stretching on osteoclastogenesis. AB - Bone cells are continuously exposed to mechanical deformations originating from movement. Mechanical stimulation at fundamental frequencies associated with most frequent normal locomotion (0.167-10Hz) has been reported to suppress differentiation of osteoclasts. However, the effects of very low frequency (0.01Hz) stimulation (which could be a frequency component of normal movement and also relevant to locomotion of movement-impaired individuals) on osteoclasts are poorly understood. We examined differentiation of osteoclasts from mouse bone marrow precursors and RAW 264.7 monocytes cultured on an extendable silicone surface that was dynamically stretched at 0.01Hz. Three stimulation regimes were applied: (i) continuously during 4 days of differentiation, (ii) non continuously, 8h/day for 4 days, and (iii) post-differentiation, when stimulation was applied for 24h after osteoclasts were noted. Low frequency mechanical stimulation did not inhibit osteoclastogenesis. Moreover, the expression of osteoclast marker genes was upregulated in mechanically stimulated cells compared to static control. Conditioned medium collected from osteoclast cultures stimulated non-continuously or post-differentiation induced differentiation of osteoclast precursors plated in standard tissue culture plates. Extracellular signal-regulated kinase (ERK) phosphorylation was increased in mechanically stimulated cultures compared to static control. Thus, low frequency mechanical stimulation has qualitatively different effects on osteoclast formation compared to stimulation associated with the fundamental frequencies of normal movement. PMID- 25443782 TI - [Zuckerkandl's tubercle: incidence and relationship with the inferior laryngeal nerve]. AB - The iatrogenal lesion of the inferior laryngeal nerve (ILN) during thyroid surgery is an incident, which can have greatest functional after-effects. Its research is recommended during cervicotomy for thyroidectomy and it can be easily found by the presence of Zuckerkandl tubercle, which is a postero-lateral excrescence of the thyroid gland. OBJECTIVES: The main objective of our study was the researching of the presence of this Zuckerkandl tubercle and appreciating the reports with the ILN. PATIENTS AND METHODS: From 1st October 2010 to 30th September 2012, we realized a continuous prospective study on a mono-operator series of 48 patients operated on for thyroidectomy. The Zuckerkandl tubercle has been researched from all the patients and classified according to the classification of Pelizzo et al. RESULTS: From 21 patients (43.75%), the Zuckerkandl tubercle has been well identified and it was grade 3 and grade 2. In those cases, the ILN was very closed to the tubercle. For the 27 other patients (56.25%), the tubercle was practically undetectable or reduced to a small glandular mound (grades 0 and 1). The connections with the nerve in this case were less evident. CONCLUSION: The zuckerkandl tubercle is comparatively frequent and is refound more than one time over 3 in our study. Its presence makes easier the identification of the ILN, which entertains a dangerous connection with the thyroid gland. PMID- 25443784 TI - [Atypical femoral fracture in patient with over 12 years of unsupervised bisphosphonate therapy]. PMID- 25443785 TI - [Physical and pharmacological restraints in geriatric and gerontology services and centers]. AB - Physical and pharmacological restraints are a controversial issue in the context of geriatric care due to their moral, ethical, social and legal repercussions and, despite this fact, no specific legislation exists at a national level. The use of restraints is being questioned with growing frequency, as there are studies that demonstrate that restraints do not reduce the number of falls or their consequences, but rather can increase them, cause complications, injuries and potentially fatal accidents. Restraints are not always used rationally, despite compromising a fundamental human right, that is, freedom, protected in the Constitution, as well as values and principles, such as dignity and personal self-esteem. There are centers where restraints are applied to more than 50% of patients, and in some cases without the consent of their legal representatives. On some occasions, restraints are used for attaining organizational or environmental objectives, such as complying with tight schedules, and for reducing or avoiding the supervision of patients who walk erratically and, at times, are used indefinitely. Even greater confusion exists with respect to the emerging concept of chemical or pharmacological restraints, since no conceptual framework exists based on scientific evidence, and with sufficient consensus for guiding healthcare workers. In this context, the Sociedad Espanola de Geriatria y Gerontologia (SEGG--Spanish Geriatrics and Gerontology Society), aware of the significance and transcendence of the issue, and in an attempt to preserve and guarantee maximum freedom, dignity and self-esteem, on the one hand, and to ensure the maximum integrity and legal certainty of the persons cared for in geriatric and gerontology services and centers, on the other, decided to create an "Interdisciplinary Committee on Restraints" made up by members from different disciplines and members of SEGG Working Groups or Committees, external health care workers, groups, organizations, and associations, who are experts in restraints, as well as the main "anti-restraint" movements. An outcome of this decision is the Consensus document on physical and pharmacological restraints, together with the Consensus on physical and pharmacological restraints, published by the SEGG, which should signify a qualitative leap forward in care for the elderly, and serving as a best practice guide for healthcare workers. PMID- 25443786 TI - [An exploratory study on the use of cognitive and neuropsychological assessessments in centres for the elderly in Galicia]. AB - INTRODUCTION: Cognitive assessment is a fundamental tool in centres for the elderly when planning individualized care and intervention. The Galician Society of Gerontology and Geriatrics (Sociedade Galega of Xerontoloxia and Xeriatria) has formed a Working Group on Cognitive and Neuropsychological Assessment, with the aim of studying the tools used and to identify the main challenges in this area. MATERIAL AND METHODS: An exploratory study was conducted via an online questionnaire with Sociedade Galega of Xerontoloxia and Xeriatria members between December 2013 and January 2014. It was completed by 49 professionals, of whom 26 were professionals in psychology and 10 medical doctors. RESULTS: Consensus was found on the use of the MMSE as a screening tool, as well as the Global Deterioration Scale for dementia. There is a wide variation in the choice of general batteries of tests for the assessment of dementia (CAMCOG-R, ADAS-Cog, abbreviated Barcelona Test), and of the use of specific tests and a severe impairment battery. CONCLUSIONS: The risk of bias in the sector is suggested, with a high percentage of general practitioners using a few tools, and a small percentage using a large number of specific tools. The need for a consensus is stressed in order to facilitate assessment, objectify training needs, maximize the relationship between assessment and cognitive intervention, and provide tools to assess change. PMID- 25443787 TI - [The editorial, a very important section]. PMID- 25443788 TI - Polymeric heart valves for surgical implantation, catheter-based technologies and heart assist devices. AB - Efficient function and long-term durability without the need for anticoagulation, coupled with the ability to be accommodated in many different types of patient, are the principal requirements of replacement heart valves. Although the clinical use of valves appeared to have remained steady for several decades, the evolving demands for the elderly and frail patients typically encountered in the developed world, and the needs of much younger and poorer rheumatic heart disease patients in the developing world have now necessitated new paradigms for heart valve technologies and associated materials. This includes further consideration of durable elastomeric materials. The use of polymers to produce flexible leaflet valves that have the benefits of current commercial bioprosthetic and mechanical valves without any of their deficiencies has been held desirable since the mid 1950s. Much attention has been focused on thermoplastic polyurethanes in view of their generally good physico-chemical properties and versatility in processing, coupled with the improving biocompatibility and stability of recent formulations. Accelerated in vitro durability of between 600 and 1000 million cycles has been achieved using polycarbonate urethanes, and good resistance to degradation, calcification and thrombosis in vivo has been shown with some polysiloxane-based polyurethanes. Nevertheless, polymeric valves have remained relegated to use in temporary ventricular assist devices for bridging heart failure patients to transplantation. Some recent studies suggest that there is a greater degree of instability in thermoplastic materials than hitherto believed so that significant challenges remain in the search for the combination of durability and biocompatibility that would allow polymeric valves to become a clinical reality for surgical implantation. Perhaps more importantly, they could become candidates for use in situations where minimally invasive transcatheter procedures are used to replace diseased valves. Being amenable to relatively inexpensive mass production techniques, the attainment of this goal could benefit very large numbers of patients in developing and emerging countries who currently have no access to treatment for rheumatic heart disease that is so prevalent in these areas. This review discusses the evolution and current status of polymeric valves in wide-ranging circumstances. PMID- 25443789 TI - UPA-sensitive ACPP-conjugated nanoparticles for multi-targeting therapy of brain glioma. AB - Now it is well evidenced that tumor growth is a comprehensive result of multiple pathways, and glioma parenchyma cells and stroma cells are closely associated and mutually compensatory. Therefore, drug delivery strategies targeting both of them simultaneously might obtain more promising therapeutic benefits. In the present study, we developed a multi-targeting drug delivery system modified with uPA activated cell-penetrating peptide (ACPP) for the treatment of brain glioma (ANP). In vitro experiments demonstrated nanoparticles (NP) decorated with cell penetrating peptide (CPP) or ACPP could significantly improve nanoparticles uptake by C6 glioma cells and nanoparticles penetration into glioma spheroids as compared with traditional NP and thus enhanced the therapeutic effects of its payload when paclitaxel (PTX) was loaded. In vivo imaging experiment revealed that ANP accumulated more specifically in brain glioma site than NP decorated with or without CPP. Brain slides further showed that ACPP contributed to more nanoparticles accumulation in glioma site, and ANP could co-localize not only with glioma parenchyma cells, but also with stroma cells including neo-vascular cells and tumor associated macrophages. The pharmacodynamics results demonstrated ACPP could significantly improve the therapeutic benefits of nanoparticles by significantly prolonging the survival time of glioma bearing mice. In conclusion, the results suggested that nanoparticles modified with uPA-sensitive ACPP could reach multiple types of cells in glioma tissues and provide a novel strategy for glioma targeted therapy. PMID- 25443790 TI - Highly stable aptamers selected from a 2'-fully modified fGmH RNA library for targeting biomaterials. AB - When developed as targeting ligands for the in vivo delivery of biomaterials to biological systems, RNA aptamers immediately face numerous obstacles, in particular nuclease degradation and post-selection 2' modification. This study aims to develop a novel class of highly stable, 2'-fully modified RNA aptamers that are ideal for the targeted delivery of biomaterials. We demonstrated the facile transcription of a fGmH (2'-F-dG, 2'-OMe-dA/dC/dU) RNA library with unexpected hydrophobicity, the direct selection of aptamers from a fGmH RNA library that bind Staphylococcus aureus Protein A (SpA) as a model target, and the superior nuclease and serum stability of these aptamers compared to 2' partially modified RNA variants. Characterizations of fGmH RNA aptamers binding to purified SpA and to endogenous SpA present on the surface of S. aureus cells demonstrate fGmH RNA aptamer selectivity and stability. Significantly, fGmH RNA aptamers were able to functionalize, stabilize, and specifically deliver aggregation-prone silver nanoparticles (AgNPs) to S. aureus with SpA-dependent antimicrobial effects. This study describes a novel aptamer class with considerable potential to improve the in vivo applicability of nucleic acid-based affinity molecules to biomaterials. PMID- 25443791 TI - Enzymes produced by autoactivation of blood factor XII in buffer: A contribution from the Hematology at Biomaterial Interfaces Research Group. AB - High-resolution electrophoresis of FXII-derived proteins produced by contact activation of FXII in buffer solutions (i.e. in absence of plasma proteins) with hydrophilic and silanized-glass activators spanning the observable range of water wettability (hydrophilic to hydrophobic), shows no evidence of proteolytic cleavage of FXII into alphaFXIIa or betaFXIIa. The autoactivation mixture contains only a single-chain protein with a molecular weight of ~80 kDa, confirming Oscar Ratnoff's previous finding of a single-chain activated form of FXII that he called 'HFea'. Functional assays have shown that these autoactivation products exhibit procoagulant potential (protease activity inducing clotting of blood) or amidolytic potential (cleaves amino bonds in s 2302 chromogen but do not cause coagulation of plasma) or both amidolytic potential and procoagulant potential. Some of these proteins also have the remarkable potential to 'suppress autoactivation' (i.e. suppress creation of enzymes with procoagulant potential). It is thus hypothesized that autoactivation of FXII in the absence of plasma proteins generates not just a single type of activated conformer, as suggested by previous researchers, but rather an ensemble of conformer products with collective activity that varies with activator surface energy used in contact activation of FXII. Furthermore, reaction of alphaFXIIa with FXII in buffer solution does not produce additional alphaFXIIa by the putative autoamplification reaction FXIIa + FXII -> 2FXIIa as has been proposed in past literature to account for the discrepancy between chromogenic and plasma coagulation assays for alphaFXIIa in buffer solution. Instead, net procoagulant activity measured directly by plasma-coagulation assays, decreases systematically with increasing FXII solution concentration. Under the same reaction conditions, chromogenic assay reveals that net amidolytic activity increases with increasing FXII solution concentration. Thus, although autoamplification does not occur it appears that there is some form of "FXII self reaction" that influences products of alphaFXIIa reaction with FXII. Electrophoretic measurements indicate that no proteolytic cleavage takes in this reaction leading us to conclude that change in activity is most likely due to change(s) in FXII conformation (with related change in enzyme activity). PMID- 25443793 TI - Diagnosis and treatment of hereditary tyrosinemia in Japan. AB - Hereditary tyrosinemia is an autosomal recessive inherited disease that manifests as three types (types I-III). We conducted a nationwide survey of this disease in Japan, and here review the results in relation to prevalence, clinical characteristics, and treatment and diagnosis. A definitive diagnosis of tyrosinemia type I is difficult to obtain based only on blood tyrosine level. Detection of succinylacetone using dried blood spots or urinary organic acid analysis, however, is useful for diagnosis. In tyrosinemia type I, dietary therapy and nitisinone (Orfandin(r)) are effective. Prognosis is greatly affected by the complications of liver cancer and hypophosphatemic rickets; even patients that are treated early with nitisinone may develop liver cancer. Long-term survival can be expected in type I if nitisinone therapy is effective. Prognosis in types II and III is relatively good. PMID- 25443792 TI - [Pyr1]-Apelin-13 delivery via nano-liposomal encapsulation attenuates pressure overload-induced cardiac dysfunction. AB - Nanoparticle-mediated sustained delivery of therapeutics is one of the highly effective and increasingly utilized applications of nanomedicine. Here, we report the development and application of a drug delivery system consisting of polyethylene glycol (PEG)-conjugated liposomal nanoparticles as an efficient in vivo delivery approach for [Pyr1]-apelin-13 polypeptide. Apelin is an adipokine that regulates a variety of biological functions including cardiac hypertrophy and hypertrophy-induced heart failure. The clinical use of apelin has been greatly impaired by its remarkably short half-life in circulation. Here, we investigate whether [Pyr1]-apelin-13 encapsulation in liposome nanocarriers, conjugated with PEG polymer on their surface, can prolong apelin stability in the blood stream and potentiate apelin beneficial effects in cardiac function. Atomic force microscopy and dynamic light scattering were used to assess the structure and size distribution of drug-laden nanoparticles. [Pyr1]-apelin-13 encapsulation in PEGylated liposomal nanocarriers resulted in sustained and extended drug release both in vitro and in vivo. Moreover, intraperitoneal injection of [Pyr1] apelin-13 nanocarriers in a mouse model of pressure-overload induced heart failure demonstrated a sustainable long-term effect of [Pyr1]-apelin-13 in preventing cardiac dysfunction. We concluded that this engineered nanocarrier system can serve as a delivery platform for treating heart injuries through sustained bioavailability of cardioprotective therapeutics. PMID- 25443798 TI - Endogenous sex steroid hormones and glucose in a South-Asian population without diabetes: the Metabolic Syndrome and Atherosclerosis in South-Asians Living in America pilot study. AB - AIMS: To examine the associations between endogenous sex steroid hormones (oestradiol, testosterone and sex hormone-binding globulin) with diabetes risk in a South-Asian population living in the USA. METHODS: We used data from the Metabolic Syndrome and Atherosclerosis in South-Asians Living in America pilot study. The analytical sample included 60 women and 45 men of Asian Indian origin living in the San Francisco Bay Area, who were free from diabetes and cardiovascular disease and did not use exogenous sex steroids. Sex steroid hormone levels were assessed by validated conventional radioimmunoassays, and visceral and hepatic adiposity were assessed by computed tomography. We used multivariable regression to examine the association between endogenous sex steroid hormone levels (log-transformed) and fasting glucose and 2-h glucose levels in a series of sex-stratified models adjusted for age, waist circumference, visceral and hepatic adiposity, and insulin resistance. RESULTS: In age-adjusted models, lower levels of sex hormone-binding globulin (beta = 0.18, 95% CI -0.30, -0.06) and higher levels of free testosterone (beta = 0.14, 95% CI 0.02, 0.26) were associated with elevated fasting glucose levels in South Asian women, whereas lower levels of sex hormone-binding globulin (beta = -0.14, 95% CI -0.26, -0.02) and lower levels of total testosterone (beta = -0.12, 95% CI -0.24, 0.00) were associated with elevated fasting glucose levels in South-Asian men. Adjustment for waist circumference, visceral adiposity and insulin resistance attenuated most of these associations, while adjustment for hepatic adiposity strengthened some of the observed associations. Similar results were found for 2-h glucose levels. CONCLUSIONS: Results were consistent with previous research, which suggests that endogenous sex steroid hormones are a risk factor for diabetes across multiple race/ethnic groups. Additional studies are needed to determine whether visceral fat is a mediator or confounder of associations between sex steroid hormone and glucose levels. PMID- 25443799 TI - NK cells and interferons. AB - The role of Natural Killer cells in host defense against infections as well as in tumour surveillance has been widely appreciated for a number of years. Upon recognition of "altered" cells, NK cells release the content of cytolytic granules, leading to the death of target cells. Moreover, NK cells are powerful producers of chemokines and cytokines, particularly Interferon-gamma (IFN-gamma), of which they are the earliest source upon a variety of infections. Despite being armed to fight against pathogens, NK cells become fully functional upon an initial phase of activation that requires the action of several cytokines, including type I IFNs. Type I IFNs are now recognized as key players in antiviral defense and immune regulation, and evidences from both mouse models of disease and in vitro studies support the existence of an alliance between type I IFNs and NK cells to ensure effective protection against viral infections. This review will focus on the role of type I IFNs in regulating NK cell functions to elicit antiviral response and on NK cell-produced IFN-gamma beneficial and pathological effects. PMID- 25443800 TI - Reduced circulating levels of TWEAK are associated with gestational diabetes mellitus. AB - BACKGROUND: To evaluate the inflammatory axis mediated by tumour necrosis factor like weak inducer of apoptosis (TWEAK) and its scavenger receptor CD163 during pregnancy and their influence on insulin sensitivity in normal pregnancy and in gestational diabetes mellitus (GDM). MATERIALS AND METHODS: One hundred and thirty seven women with one singleton pregnancy, 71 with normal glucose tolerance (NGT) and 66 with GDM were studied. Glucose metabolism was assessed by oral glucose tolerance test. Serum concentrations of soluble TWEAK (sTWEAK) and CD163 (sCD163) and insulin resistance (HOMA-IR index) were determined in maternal blood drawn at recruitment, in the early third trimester. Offspring weight and height were assessed at birth. RESULTS: Women with GDM had lower circulating sTWEAK concentrations than control NGT group (237.8 (192.1-301.0) pg/mL vs. 277.2 (206.4 355.7) pg/mL; P = 0.013). sTWEAK was negatively associated with the presence of GDM (r = -0.212; P = 0.013), HOMA-IR index (r = -0.197; P = 0.021) and ponderal index of the newborn (r = -0.196; P = 0.025), but positively with HDL cholesterol (r = 0.283; P = 0.001). In multiple regression analysis, sTWEAK concentration emerged as one of the main predictors of insulin resistance, along with BMI, triglycerides and low concentrations of HDL cholesterol (R(2) = 0.486; P < 0.001). No relationship was found between HOMA-IR index and sCD163 or sCD163/sTWEAK ratio. CONCLUSIONS: sTWEAK concentrations are lower in patients with GDM compared with healthy pregnant women, and low concentrations of sTWEAK are associated with insulin resistance. These findings suggest that insulin resistance during pregnancy is closely linked to inflammatory imbalance and sTWEAK may represent a new candidate associated with GDM. PMID- 25443801 TI - Impact of warm ischemia time on the change of split renal function after minimally invasive partial nephrectomy in Taiwanese patients. AB - BACKGROUND: Nephron-sparing surgery has become the standard treatment for T1 renal tumors. However, relevant data on the Taiwanese population are lacking, and most of the current literature uses global instead of split renal function (SRF) for postoperative renal function follow-up. We evaluated the postoperative renal function after minimally invasive partial nephrectomy in Taiwanese patients. METHODS: We retrospectively reviewed our database from April 2004 to July 2012 and enrolled patients who received laparoscopic partial nephrectomy (LPN) or robot-assisted partial nephrectomy (RPN). The estimated glomerular filtration rate (eGFR) and SRF were calculated as representatives of renal function. The preoperative and 6- and 12-month postoperative renal functions were assessed. Freidman test was used to evaluate pre- and postoperative renal function changes; Wilcoxon test was used for comparing the renal function of each period. RESULTS: The 6- and 12-month postoperative SRF values were decreased compared with the preoperative values. Multivariate analysis revealed that older age was related to a lower postoperative eGFR, and a longer warm ischemia time was related to a decreased postoperative SRF. Patients with a warm ischemia time of >30 minutes were correlated with a larger mean tumor size, higher "preoperative aspects and dimensions used for an anatomical" score, greater amount of blood loss during the operation, longer postoperative hospital stay, and lower postoperative SRF compared with patients with a warm ischemia time of <30 minutes. Patients in the RPN group had shorter warm ischemia time and higher 6-month postoperative SRF compared with patients in the LPN group. CONCLUSION: SRF is more sensitive for postoperative follow-up than eGFR. Longer warm ischemia time is associated with poorer postoperative renal function. RPN is a safe and feasible alternative to LPN. PMID- 25443802 TI - A study of renal function influence by integrating cloud-based manometers and physician order entry systems. AB - BACKGROUND: No evidence exists from randomized trials to support using cloud based manometers integrated with available physician order entry systems for tracking patient blood pressure (BP) to assist in the control of renal function deterioration. We investigated how integrating cloud-based manometers with physician order entry systems benefits our outpatient chronic kidney disease patients compared with typical BP tracking systems. METHODS: We randomly assigned 36 chronic kidney disease patients to use cloud-based manometers integrated with physician order entry systems or typical BP recording sheets, and followed the patients for 6 months. The composite outcome was that the patients saw improvement both in BP and renal function. RESULTS: We compared the systolic and diastolic BP (SBP and DBP), and renal function of our patients at 0 months, 3 months, and 6 months after using the integrated manometers and typical BP monitoring sheets. Nighttime SBP and DBP were significantly lower in the study group compared with the control group. Serum creatinine level in the study group improved significantly compared with the control group after the end of Month 6 (2.83 +/- 2.0 vs. 4.38 +/- 3.0, p = 0.018). Proteinuria improved nonsignificantly in Month 6 in the study group compared with the control group (1.05 +/- 0.9 vs. 1.90 +/- 1.3, p = 0.09). Both SBP and DBP during the nighttime hours improved significantly in the study group compared with the baseline. CONCLUSION: In pre end-stage renal disease patients, regularly monitoring BP by integrating cloud based manometers appears to result in a significant decrease in creatinine and improvement in nighttime BP control. Estimated glomerular filtration rate and proteinuria were found to be improved nonsignificantly, and thus, larger population and longer follow-up studies may be needed. PMID- 25443803 TI - Reply: To PMID 24907021. PMID- 25443804 TI - Hydrodeoxygenation processes: advances on catalytic transformations of biomass derived platform chemicals into hydrocarbon fuels. AB - Lignocellulosic biomass provides an attractive source of renewable carbon that can be sustainably converted into chemicals and fuels. Hydrodeoxygenation (HDO) processes have recently received considerable attention to upgrade biomass derived feedstocks into liquid transportation fuels. The selection and design of HDO catalysts plays an important role to determine the success of the process. This review has been aimed to emphasize recent developments on HDO catalysts in effective transformations of biomass-derived platform molecules into hydrocarbon fuels with reduced oxygen content and improved H/C ratios. Liquid hydrocarbon fuels can be obtained by combining oxygen removal processes (e.g. dehydration, hydrogenation, hydrogenolysis, decarbonylation etc.) as well as by increasing the molecular weight via C-C coupling reactions (e.g. aldol condensation, ketonization, oligomerization, hydroxyalkylation etc.). Fundamentals and mechanistic aspects of the use of HDO catalysts in deoxygenation reactions will also be discussed. PMID- 25443805 TI - Effects of crop maturity and size reduction on digestibility and methane yield of dedicated energy crop. AB - The compositional changes of Napier grass (Pennisetum purpureum) with respect to maturity (namely, 2, 4, 6, and 8 months age), and its effect on anaerobic digestion was examined under three sieving regimes (6, 10, and 20mm). Significant changes in plant composition were observed with crop maturity. The highest methane yields of 219+/-4.9 NmL/g VS added was found for biomass harvested at 2 months old compared to 189+/-7.3, 131+/-4.7, and 104+/-2.3 NmL of methane/g VS added, respectively, for 4, 6, and 8 months old biomass. For all ages, feedstock passed through a 6mm sieve resulted in significantly higher methane yields compared to biomass passed through 10 and 20mm sieves. Additionally, 2 months old biomass exhibited the highest digestibility of cellulose and hemicellulose, whereas digestibility of cellulose and hemicellulose were lowest for the biomass harvested at 8 months of maturity. PMID- 25443806 TI - Low-cost additive improved silage quality and anaerobic digestion performance of napiergrass. AB - Effects of molasses-alcoholic wastewater on the ensiling quality of napiergrass were investigated at ambient temperature, and its anaerobic digestion performance was assessed at mesophilic temperature. Results showed that the molasses alcoholic wastewater had positive effect on silage quality and anaerobic digestion performance. Lower pH values of 5.20-5.28, lower NH3-N contents of 32.65-36.60 g/kg and higher lactic acid contents of 56-61 mg/kg FM were obtained for the silage samples with molasses-alcoholic wastewater addition. Higher specific biogas yield of 273 mL/g VS was obtained for the sample with 11% molasses-alcoholic wastewater added. Therefore 11% molasses-alcoholic wastewater addition was recommended. PMID- 25443807 TI - The impacts of inbreeding, drift and selection on genetic diversity in captive breeding populations. AB - The goal of captive breeding programmes is often to maintain genetic diversity until re-introductions can occur. However, due in part to changes that occur in captive populations, approximately one-third of re-introductions fail. We evaluated genetic changes in captive populations using microsatellites and mtDNA. We analysed six populations of white-footed mice that were propagated for 20 generations using two replicates of three protocols: random mating (RAN), minimizing mean kinship (MK) and selection for docility (DOC). We found that MK resulted in the slowest loss of microsatellite genetic diversity compared to RAN and DOC. However, the loss of mtDNA haplotypes was not consistent among replicate lines. We compared our empirical data to simulated data and found no evidence of selection. Our results suggest that although the effects of drift may not be fully mitigated, MK reduces the loss of alleles due to inbreeding more effectively than random mating or docility selection. Therefore, MK should be preferred for captive breeding. Furthermore, our simulations show that incorporating microsatellite data into the MK framework reduced the magnitude of drift, which may have applications in long-term or extremely genetically depauperate captive populations. PMID- 25443808 TI - Mechanisms underlying accent accommodation in early word learning: evidence for general expansion. AB - Previous work reveals that toddlers can accommodate a novel accent after hearing it for only a brief period of time. A common assumption is that children, like adults, cope with nonstandard pronunciations by relying on words they know (e.g. 'this person pronounces sock as sack, therefore by black she meant block'). In this paper, we assess whether toddlers might additionally use a general expansion strategy, whereby they simply accept non-standard pronunciations when variability is expected. We exposed a group of 24-month-old English-learning toddlers to variability in indexical cues (very diverse voices from native English talkers), and another to variability in social cues (very diverse-looking silent actors); neither group was familiarized with the target novel accent. At test, both groups succeeded in recognizing a novel word when spoken in the novel accent. Thus, even when no lexical cues are available, variability can prepare young children for non-standard pronunciations. PMID- 25443809 TI - Just how important is a good season start? Overall team performance and financial budget of elite soccer clubs. AB - The aim of the current study was (i) to identify how important is a good season start on elite soccer teams' performance and (ii) to examine whether this impact is related to the clubs' financial budget. The match performances and annual budgets of all teams were collected from the English FA Premier League, French Ligue 1, Spanish La Liga, Italian Serie A and German Bundesliga for three consecutive seasons (2010-2011 to 2012-2013). A k-means cluster analysis classified the clubs according to their budget as High Range Budget Clubs, Upper Mid Range Budget Clubs, Lower-Mid Range Budget Clubs and Low Range Budget Clubs. Data were examined through linear regression models. Overall, the results suggested that the better the team performance at the beginning of the season, the better the ranking at the end of the season. However, the impact of the effect depended on the clubs' annual budget, with lower budgets being associated with a greater importance of having a good season start (P < 0.01). Moreover, there were differences in trends across the different leagues. These variables can be used to develop accurate models to estimate final rankings. Conversely, Lower-Mid and Lower Range Budget Clubs can benefit from fine-tuning preseason planning in order to accelerate the acquisition of optimal performances. PMID- 25443810 TI - Sarcomatoid salivary duct carcinoma of the palate: a rare case report. AB - Salivary duct carcinoma (SDC) is an uncommon neoplasm that most commonly occurs in major salivary glands, mainly the parotid gland. SDC is rarely found in the minor salivary glands of the oral cavity. This report presents an extremely rare case of sarcomatoid SDC originating in a minor salivary gland of the palate. The tumor was histologically characterized by the presence of both carcinomatous and sarcomatoid components. The patient presented with a painless mass in the right palate, which slowly increased in size over 20 years. The clinical course of the present case suggests that the tumor most probably developed as a result of malignant transformation of a preexisting benign tumor of the palatal salivary gland. This report describes the clinical and histologic features of this extremely rare case of sarcomatoid SDC with reference to the relevant literature. PMID- 25443811 TI - Carcinoma cuniculatum of the oral mucosa: a potentially underdiagnosed entity in the absence of clinical correlation. AB - OBJECTIVE: To delineate the features of carcinoma cuniculatum (CC), emphasizing potential management errors. STUDY DESIGN: A retrospective study examined archival cases of CC. An analysis of clinical, microscopic, and management parameters was performed. RESULTS: Ten cases were identified, and their clinical and microscopic features were summarized. CC exhibits a sessile pink/red mildly papillary surface. Histologically, CC presents a tortuous invasive component with a more subtle papillary appearance than verrucous carcinoma. CONCLUSIONS: CC is an uncommon variant of squamous cell carcinoma distinct from verrucous carcinoma. Diagnostic delays result from misinterpretation of superficial samples or lack of awareness of the entity. Bland cytology and unusual architecture result in underdiagnosis of CC without clinicopathologic correlation. Clinicians should submit multiple deep samples of lesions displaying a cobblestone-like surface and provide a clinical photograph to the pathologist. Pathologists can avoid underdiagnosis by thorough sampling of biopsies and requesting additional tissue as needed. PMID- 25443812 TI - Ventricular arrhythmias in super-responders to cardiac resynchronization therapy. AB - INTRODUCTION AND OBJECTIVES: Cardiac resynchronization therapy is associated with improved quality of life and reduced morbidity and mortality in patients with severe ventricular dysfunction and wide QRS. However, its role in the reduction of ventricular arrhythmias is more controversial. METHODS: We compared the incidence of ventricular arrhythmias in patients who were undergoing cardiac resynchronization therapy with an implantable cardioverter-defibrillator in terms of the degree of echocardiographic response to resynchronization. Patients were classified in 3 subgroups;super-responders, responders, and nonresponders. RESULTS: We included 196 patients who were followed up for a median 30.1 months [interquartile range, 18.0-55.1 months]. We recorded the presence of ventricular arrhythmias in 37 patients (18.8%); 3 patients (5.9%) in the super-responder group had ventricular arrhythmias vs 14 (22.2%) among the responders and 20 (24.4%) in the group of nonresponders (P = .025). In multivariate analysis, the only independent predictors of the appearance of ventricular arrhythmias were secondary-prevention device implantation (odds ratio = 4.04; 95% confidence interval, 1.52-10.75; P=.005), absence of echocardiographic super-response (odds ratio=3.81; 95% confidence interval, 1.04-13.93; P=043), QRS >160 ms (odds ratio=2.39; 95% confidence interval, 1.00-1.35; P=.049) and treatment with amiodarone (odds ratio=2.47; 95% confidence interval, 1.03-5.91; P=.041). CONCLUSIONS: The patients classified as super-responders to cardiac resynchronization therapy had a significant reduction in incidence of ventricular arrhythmias by comparison with the other patients. Despite this, arrhythmic episodes do not completely disappear in this subgroup. PMID- 25443813 TI - Outcomes of a contemporary sample of patients with atrial fibrillation taking digoxin: results from the AFBAR study. AB - INTRODUCTION AND OBJECTIVES: We aimed to assess and compare the effect of digoxin on clinical outcomes in patients with atrial fibrillation vs those under beta blockers or none of these drugs. METHODS: AFBAR is a prospective registry study carried out by a team of primary care physicians (n=777 patients). Primary endpoints were survival, survival free of admission due to any cause, and survival free of admission due to cardiovascular causes. The mean follow up was 2.9 years. Four groups were analyzed: patients receiving digoxin, beta-blockers, or digoxin plus beta-blockers, and patients receiving none of these drugs. RESULTS: Overall, 212 patients (27.28%) received digoxin as the only heart control strategy, 184 received beta-blockers (23.68%), 58 (7.46%) were administered both, and 323 (41.57%) received none of these drugs. Digoxin was not associated with all-cause mortality (estimated hazard ratio=1.42; 95% confidence interval, 0.77-2.60; P=.2), admission due to any cause (estimated hazard ratio=1.03; 95% confidence interval, 0.710-1.498; P=.8), or admission due to cardiovascular causes (estimated hazard ratio=1.193; 95% confidence interval, 0.725-1.965; P=.4). No association was found between digoxin use and all-cause mortality, admission due to any cause, or admission due to cardiovascular causes in patients without heart failure. There was no interaction between digoxin use and sex in all-cause mortality or in survival free of admission due to any cause. However, an association was found between sex and admission due to cardiovascular causes. CONCLUSIONS: Digoxin was not associated with increased all-cause mortality, survival free of admission due to any cause, or admission due to cardiovascular causes, regardless of underlying heart failure. PMID- 25443814 TI - Usefulness of 64-detector computed tomography in the diagnosis and management of patients with congenital heart disease. AB - INTRODUCTION AND OBJECTIVES: Although congenital heart defects are the most common major congenital abnormalities, the associated mortality has been decreasing due to improvements in their diagnosis and treatment. We assessed the usefulness of 64-multidetector computed tomography in the diagnosis and management of these patients. METHODS: This 5-year observational, analytical, retrospective, cohort study included a total of 222 tomographic studies of patients with congenital heart disease. Computed tomography scans were read twice and medical records were reviewed. We assessed the complexity of the disease, patient, and radiological technique, and evaluated the contribution of new data in relation to clinical suspicion and diagnostic change. A confidence interval was set at 95% and a P value of<.05 was used as the cutoff for statistical significance. RESULTS: In 35.1% of patients, the treatment procedure was performed after computed tomography without other tests. Additional diagnostic catheterization was performed in 12.5% of patients. There were new findings in 77% of patients (82.9% with complex disease), which prompted a change in patient management in 35.6%. All unexpected reports described new findings. No significant differences were found by age, sex, study period, urgency of the test order, patient complexity, or difficulty of the technique. CONCLUSIONS: Use of 64 detector computed tomography yields good diagnostic performance in congenital heart disease, prompts changes in management in more than one-third of patients, and reveals new findings in relation to the presumed diagnosis in 77% of patients. PMID- 25443815 TI - Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention and the Spanish Society of Cardiology position statement on dyslipidemia management. Differences between the European and American guidelines. AB - The publication of the 2013 American College of Cardiology/American Heart Association guidelines on the treatment of high blood cholesterol has had a strong impact due to the paradigm shift in its recommendations. The Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention and the Spanish Society of Cardiology reviewed this guideline and compared it with current European guidelines on cardiovascular prevention and dyslipidemia management. The most striking aspect of the American guideline is the elimination of the low density lipoprotein cholesterol treat-to-target strategy and the adoption of a risk reduction strategy in 4 major statin benefit groups. In patients with established cardiovascular disease, both guidelines recommend a similar therapeutic strategy (high-dose potent statins). However, in primary prevention, the application of the American guidelines would substantially increase the number of persons, particularly older people, receiving statin therapy. The elimination of the cholesterol treat-to-target strategy, so strongly rooted in the scientific community, could have a negative impact on clinical practice, create a certain amount of confusion and uncertainty among professionals, and decrease follow-up and patient adherence. Thus, this article reaffirms the recommendations of the European guidelines. Although both guidelines have positive aspects, doubt remains regarding the concerns outlined above. In addition to using risk charts based on the native population, the messages of the European guideline are more appropriate to the Spanish setting and avoid the possible risk of overtreatment with statins in primary prevention. PMID- 25443816 TI - Coronary aneurysm after paclitaxel-eluting balloon angioplasty. PMID- 25443817 TI - Bioresorbable scaffold T-stenting evaluated with optical coherence tomography. PMID- 25443818 TI - Coronary stent implantation in an infant. PMID- 25443823 TI - Cardiovascular disease in Latin America: the growing epidemic. AB - Cardiovascular diseases (CVD) produce almost a million deaths a year in Latin America (LA), becoming the main cause of death in the last years, and it is estimated that the number of deaths in the region attributable to CVD will increase in the near future. This new epidemic is a consequence of the demographic, economic and social changes observed in LA in recent years. Coronary heart disease and stroke causes 42.5% and 28.8%, respectively of the CVD mortality in the region. Chagas heart involvement and rheumatic heart disease, once a major health problem, are responsible of only 1% of the mortality each. Improving in socioeconomic status, increased life expectancy and high prevalence of risk factors for atherosclerosis have been the major determinants of this marked epidemiologic change. PMID- 25443822 TI - Peripheral artery disease and non-coronary atherosclerosis in Hispanics: another paradox? AB - Hispanic Americans (HA) are a significant and increasing segment of the population who must be considered in future health planning. HA, compared to European Americans (EA), have a lower prevalence of coronary artery disease, but higher burden of cardiovascular disease risk factors. It remains unclear if this observation termed the 'Hispanic Paradox' also exists for vascular beds outside the heart. We present a review of the literature which suggests that this paradox may also exist for arteries in the extremities and neck. PMID- 25443828 TI - Nitrate inhibits soybean nodulation by regulating expression of CLE genes. AB - Nitrogen compounds such as nitrate act as a potential inhibitor for legume nodulation. In this study, we isolated a new CLE gene, GmNIC2, from nitrate treated roots, which shares high sequence homology with nitrate-induced CLE gene GmNIC1. Similar to GmNIC1, the expression level of GmNIC2 was not significantly altered in roots by rhizobial inoculation and was much higher in young nodules than in roots. In addition, overexpression of GmNIC2 led to similar nodulation inhibition of transgenic hairy roots to that of GmNIC1, which occurred in GmNARK dependent manner and at the local level. By analyzing GmNARK loss-of-function mutant, SS2-2, it was found that expression levels of GmNIC1 and GmNIC2 in the SS2-2 roots were lower than in the wild type (WT) roots in response to nitrate. In contrast to GmNIC1 and GmNIC2, expressions of GmRIC1 and GmRIC2 genes that are related to the autoregulation of nodulation (AON) were strongly suppressed both of the soybeans during all periods of nitrate treatment and even were not induced by additional inoculation with rhizobia. Taken together, the results of this study suggest that GmNIC2, as an active homologous gene located in chromosome 13, acts locally to suppress nodulation, like GmNIC1, and nitrate inhibition of nodulation is led by fine-tuned regulation of both nitrate-induced CLEs and rhizobia-induced CLEs. PMID- 25443829 TI - Arabidopsis thaliana ICE2 gene: phylogeny, structural evolution and functional diversification from ICE1. AB - The ability to tolerate environmental stresses is crucial for all living organisms, and gene duplication is one of the sources for evolutionary novelties. Arabidopsis thaliana INDUCER OF CBF EXPRESSION1 and 2 (ICE1 and ICE2) encode MYC type bHLH (basic helix-loop-helix) transcription factors. They confer cold stress tolerance by induction of the CBF/DREB1 regulon and regulate stomata formation. Although ICE2 is closely related to ICE1, its origin and role in cold response remains uncertain. Here, we used a bioinformatics/phylogenetic approach to uncover the ICE2 evolutionary history, structural evolution and functional divergence from the putative ancestral gene. Sequence diversification from ICE1 included the gain of cis-acting elements in ICE2 promoter sequence that may provide meristem-specific and defense-related gene expression. By analyzing transgenic Arabidopsis lines with ICE2 over-expression we showed that it contributes to stomata formation, flowering time regulation and cold response. Constitutive ICE2 expression led to induced meristem freezing tolerance, resulting from activation of CBF1 and CBF3 genes and ABA biosynthesis by NCED3 induction. We presume that ICE2 gene has originated from a duplication event about 17.9MYA followed by sub- and neofunctionalization of the ancestral ICE1 gene. Moreover, we predict its role in pathogen resistance and flowering time regulation. PMID- 25443830 TI - Effects of stomatal development on stomatal conductance and on stomatal limitation of photosynthesis in Syringa oblata and Euonymus japonicus Thunb. AB - During leaf development, the increase in stomatal conductance cannot meet photosynthetic demand for CO2, thus leading to stomatal limitation of photosynthesis (Ls). Considering the crucial influences of stomatal development on stomatal conductance, we speculated whether stomatal development limits photosynthesis to some extent. To test this hypothesis, stomatal development, stomatal conductance and photosynthesis were carefully studied in both Syringa oblata (normal greening species) and Euonymus japonicus Thunb (delayed greening species). Our results show that the size of stomata increased gradually with leaf expansion, resulting in increased stomatal conductance up to the time of full leaf expansion. During this process, photosynthesis also increased steadily. Compared to that in S. oblata, the development of chloroplasts in E. japonicus Thunb was obviously delayed, leading to a delay in the improvement of photosynthetic capacity. Further analysis revealed that before full leaf expansion, stomatal limitation increased rapidly in both S. oblata and E. japonicus Thunb; after full leaf expansion, stomatal limitation continually increased in E. japonicus Thunb. Accordingly, we suggested that the enhancement of photosynthetic capacity is the main factor leading to stomatal limitation during leaf development but that stomatal development can alleviate stomatal limitation with the increase of photosynthesis by controlling gas exchange. PMID- 25443831 TI - Genomic and transcriptomic characterization of the transcription factor family R2R3-MYB in soybean and its involvement in the resistance responses to Phakopsora pachyrhizi. AB - Myb genes constitute one of the largest transcription factor families in the plant kingdom. Soybean MYB transcription factors have been related to the plant response to biotic stresses. Their involvement in response to Phakopsora pachyrhizi infection has been reported by several transcriptional studies. Due to their apparently highly diverse functions, these genes are promising targets for developing crop varieties resistant to diseases. In the present study, the identification and phylogenetic analysis of the soybean R2R3-MYB (GmMYB) transcription factor family was performed and the expression profiles of these genes under biotic stress were determined. GmMYBs were identified from the soybean genome using bioinformatic tools, and their putative functions were determined based on the phylogenetic tree and classified into subfamilies using guides AtMYBs describing known functions. The transcriptional profiles of GmMYBs upon infection with different pathogen were revealed by in vivo and in silico analyses. Selected target genes potentially involved in disease responses were assessed by RT-qPCR after different times of inoculation with P. pachyrhizi using different genetic backgrounds related to resistance genes (Rpp2 and Rpp5). R2R3 MYB transcription factors related to lignin synthesis and genes responsive to chitin were significantly induced in the resistant genotypes. PMID- 25443832 TI - Evolution of herbicide resistance mechanisms in grass weeds. AB - Herbicide resistant weeds are becoming increasingly common, threatening global food security. Here, we present BrIFAR: a new model system for the functional study of mechanisms of herbicide resistance in grass weeds. We have developed a large collection of Brachypodium accessions, the BrI collection, representing a wide range of habitats. Wide screening of the responses of the accessions to four major herbicide groups (PSII, ACCase, ALS/AHAS and EPSPS inhibitors) identified 28 herbicide-resistance candidate accessions. Target-site resistance to PSII inhibitors was found in accessions collected from habitats with a known history of herbicide applications. An amino acid substitution in the psbA gene (serine264 to glycine) conferred resistance and also significantly affected the flowering and shoot dry weight of the resistant accession, as compared to the sensitive accession. Non-target site resistance to ACCase inhibitors was found in accessions collected from habitats with a history of herbicide application and from a nature reserve. In-vitro enzyme activity tests and responses following pre treatment with malathion (a cytochrome-P450 inhibitor) indicated sensitivity at the enzyme level, and give strong support to diclofop-methyl and pinoxaden enhanced detoxification as NTS resistance mechanism. BrIFAR can promote better understanding of the evolution of mechanisms of herbicide resistance and aid the implementation of integrative management approaches for sustainable agriculture. PMID- 25443833 TI - Transcriptional regulation and functional involvement of the Arabidopsis pescadillo ortholog AtPES in root development. AB - The Pescadillo gene is highly conserved from yeasts to human and has been shown to impact on both the cell cycle and on ribosome biogenesis. However, the biological function and transcriptional regulation of the plant orthologs remain unclear. In the present study, we have implemented a combination of molecular and genetic approaches, in order to characterize the Arabidopsis thaliana pescadillo ortholog (AtPES) and its role in root development. The RNAi transgenic lines displayed severely compromised meristem structures and a reduction of the primary root length of up to 70%. The correct pattern of the cell files is distorted, whereas in the root elongation and differentiation zone the epidermal and cortex cells appear abnormally enlarged. Yeast two hybrid and BiFC experiments confirmed that AtPES interacts physically with AtPEIP1 and AtPEIP2, the orthologs of the murine Bop1 and WDR12. Promoter deletion analysis revealed that AtPES expression depends on a number of transcription factor binding sites, with the TELO-box being a crucial site for regulating its accurate tissue-specific manifestation. Our results indicate that AtPES is firmly regulated at the transcriptional level and that the corresponding protein plays a role in root developmental processes. PMID- 25443834 TI - PECTATE LYASE-LIKE 9 from Brassica campestris is associated with intine formation. AB - Brassica campestris pectate lyase-like 9 (BcPLL9) was previously identified as a differentially expressed gene both in buds during late pollen developmental stage and in pistils during fertilization in Chinese cabbage. To characterize the gene's function, antisense-RNA lines of BcPLL9 (bcpll9) were constructed in Chinese cabbage. Self- and cross-fertilization experiments harvested half seed yields when bcpll9 lines were used as pollen donors. In vivo and in vitro pollen germination assays showed that nearly half of the pollen tubes in bcpll9 were irregular with shorter length and uneven surface. Aniline blue staining identified abnormal accumulation of a specific bright blue unknown material in the bcpll9 pollen portion. Scanning electron microscopy observation verified the abnormal outthrust material to be near the pollen germinal furrows. Transmission electron microscopy observation revealed the internal endintine layer was overdeveloped and predominantly occupied the intine. This abnormally formed intine likely induced the wavy structure and growth arrest of the pollen tube in half of the bcpll9 pollen grains, which resulted in less seed yields. Collectively, this study presented a novel PLL gene that has an important function in B. campestris intine formation. PMID- 25443836 TI - Overexpression of SlREV alters the development of the flower pedicel abscission zone and fruit formation in tomato. AB - Versatile roles of REVOLUTA (REV), a Class III homeodomain-leucine zipper (HD-ZIP III) transcription factor, have been depicted mainly in Arabidopsis and Populus. In this study, we investigated the functions of its tomato homolog, namely SlREV. Overexpression of a microRNA166-resistant version of SlREV (35S::REV(Ris)) not only resulted in vegetative abnormalities such as curly leaves and fasciated stems, but also caused dramatic reproductive alterations including continuous production of flowers at the pedicel abscission zone (AZ) and ectopic fruit formation on receptacles. Microscopic analysis showed that meristem-like structures continuously emerged from the exodermises of the pedicel AZs and that ectopic carpels formed between the first and second whorl of floral buds in 35S::REV(Ris) plants. Transcriptional data suggest that SlREV may regulate genes related to meristem maintenance and cell differentiation in the development of the flower pedicel abscission zone, and modulate genes in homeodomain and MADS box families and hormone pathways during fruit formation. Altogether, these results reveal novel roles of SlREV in tomato flower development and fruit formation. PMID- 25443835 TI - Ozone-induced kiwifruit ripening delay is mediated by ethylene biosynthesis inhibition and cell wall dismantling regulation. AB - Ozone treatments are used to preserve quality during cold storage of commercially important fruits due to its ethylene oxidizing capacity and its antimicrobial attributes. To address whether or not ozone also modulates ripening by directly affecting fruit physiology, kiwifruit (Actinidia deliciosa cv. 'Hayward') were stored in very low ethylene atmosphere at 0 degrees C (95% RH) in air (control) or in the presence of ozone (0.3MULL(-1)) for 2 or 4 months and subsequently ripened at 20 degrees C (90% RH) for up to 8d. Ozone-treated kiwifruit showed a significant delay of ripening during maintenance at 20 degrees C, accompanied by a marked decrease in ethylene biosynthesis due to inhibited AdACS1 and AdACO1 expression and reduced ACC synthase (ACS) and ACC oxidase (ACO) enzyme activity. Furthermore, ozone-treated fruit exhibited a marked reduction in flesh softening and cell wall disassembly. This effect was associated with reduced cell wall swelling and pectin and neutral sugar solubilization and was correlated with the inhibition of cell wall degrading enzymes activity, such as polygalacturonase (PG) and endo-1,4-beta-glucanase/1,4-beta-glucosidase (EGase/glu). Conclusively, the present study indicated that ozone may exert major residual effects in fruit ripening physiology and suggested that ethylene biosynthesis and cell walls turnover are specifically targeted by ozone. PMID- 25443837 TI - Genome-wide identification and expression analysis of the IQD gene family in Populus trichocarpa. AB - IQD proteins are downstream targets of calcium sensors, which play important roles in development and responses to environmental cues in plants. Comprehensive analyses of IQD genes have been conducted in Arabidopsis, rice, tomato, and Brachypodium distachyon, but have not been reported from poplar. The availability of the Populus trichocarpa genome sequence allowed us to conduct phylogenetic, gene structure, chromosomal location, and microarray analyses of the predicted IQD genes in P. trichocarpa. We identified 40 IQD genes (PtIQD1-40) classified in four subfamilies (I-IV). Gene structure and protein motif analyses showed that these genes are relatively conserved within each subfamily. The 40 PtIQD genes are distributed on 18 of the 19 chromosomes, with 16 gene pairs involved in segmental duplication events. The Ka/Ks ratios of the 16 segmentally-duplicated gene pairs show that the duplicated pairs underwent purifying selection with restrictive functional divergence after the duplication events. Analyses of microarray data for 38 PtIQD genes showed tissue/organ-specific expression patterns. We also performed quantitative real-time RT-PCR (qRT-PCR) analyses of twelve selected PtIQD genes in plants treated with MeJA and PEG in order to explore their stress-related expression patterns. Our results will be valuable for further analysis of poplar IQD genes to characterize their important biological functions. PMID- 25443838 TI - Lignin and lignans in plant defence: insight from expression profiling of cinnamyl alcohol dehydrogenase genes during development and following fungal infection in Populus. AB - Cinnamyl alcohol dehydrogenase (CAD) catalyses the final step in the biosynthesis of monolignol, the main component of lignin. Lignins, deposited in the secondary cell wall, play a role in plant defence against pathogens. We re-analysed the phylogeny of CAD/CAD-like genes using sequences from recently sequenced genomes, and analysed the temporal and spatial expression profiles of CAD/CAD-like genes in Populus trichocarpa healthy and infected plants. Three fungal pathogens (Rhizoctonia solani, Fusarium oxysporum, and Cytospora sp.), varying in lifestyle and pathogenicity, were used for plant infection. Phylogenetic analyses showed that CAD/CAD-like genes were distributed in classes represented by all members from angiosperm lineages including basal angiosperms and Selaginella. The analysed genes showed different expression profiles during development and demonstrated that three genes were involved in primary xylem maturation while five may function in secondary xylem formation. Expression analysis following inoculation with fungal pathogens, showed that five genes were induced in either stem or leaves. These results add further evidence that CAD/CAD-like genes have evolved specialised functions in plant development and defence against various pest and pathogens. Two genes (PoptrCAD11 and PoptrCAD15), which were induced under various stresses, could be treated as universal markers of plant defence using lignification or lignan biosynthesis. PMID- 25443839 TI - SCI1 is a component of the auxin-dependent control of cell proliferation in Arabidopsis upper pistil. AB - To characterize the recently described SCI1 (stigma/style cell cycle inhibitor 1) gene relationship with the auxin pathway, we have taken the advantage of the Arabidopsis model system and its available tools. At first, we have analyzed the At1g79200 T-DNA insertion mutants and constructed various transgenic plants. The loss- and gain-of-function plants displayed cell number alterations in upper pistils that were controlled by the amino-terminal domain of the protein. These data also confirmed that this locus holds the functional homolog (AtSCI1) of the Nicotiana tabacum SCI1 gene. Then, we have provided some evidences the auxin synthesis/signaling pathways are required for downstream proper AtSCI1 control of cell number: (a) its expression is downregulated in yuc2yuc6 and npy1 auxin deficient mutants, (b) triple (yuc2yuc6sci1) and double (npy1sci1) mutants mimicked the auxin-deficient phenotypes, with no synergistic interactions, and (c) the increased upper pistil phenotype in these last mutants, which is a consequence of an increased cell number, was able to be complemented by AtSCI1 overexpression. Taken together, our data strongly suggests SCI1 as a component of the auxin signaling transduction pathway to control cell proliferation/differentiation in stigma/style, representing a molecular effector of this hormone on pistil development. PMID- 25443840 TI - Molecular cloning, bacterial expression and functional characterisation of cytochrome P450 monooxygenase, CYP97C27, and NADPH-cytochrome P450 reductase, CPR I, from Croton stellatopilosus Ohba. AB - The cDNAs for cytochrome P450 monooxygenase (designated as CYP97C27 by D. Nelson's group) and NADPH-cytochrome P450 reductase (designated as CPR I based on its classification) were isolated from Croton stellatopilosus leaves, which actively biosynthesise plaunotol (18-OH geranylgeraniol). CYP97C27 and CPR I contain open reading frames encoding proteins of 471 and 711 amino acids with predicted molecular masses of 53 and 79kDa, respectively. By aligning the deduced sequences of CYP97C27 and CPR I with other plant species, all functional domains of CYP97C27 (heme and oxygen binding) and CPR I (CYP- and FMN, FAD, and NADPH cofactor binding) were identified. Amino acid sequence comparison indicated that both CYP97C27 (85-93%) and CPR I (79-83%) share high sequence identities with homologous proteins in other plant species, suggesting that CYP97C27 belongs to the CYP97C subfamily and that CPR I belongs to class I of the dicotyledonous CPR. Functional characterisation of both enzymes, produced in Escherichia coli (pET32a/BL21(DE3)) as recombinant proteins, showed that simultaneous incubation of CYP97C27 and CPR I with the substrate geranylgeraniol (GGOH) and coenzyme NADPH led to formation of the product plaunotol. In C. stellatopilosus, the levels of the CYP97C27 and CPR I transcripts were highly correlated with those of several mRNAs involved in the plaunotol biosynthetic pathway, suggesting that CYP97C27 and CPR I are the enzymes that catalyse the last hydroxylation step of the pathway. PMID- 25443841 TI - Proteomic and transcriptomic analysis of rice tranglutaminase and chloroplast related proteins. AB - The recently cloned rice transglutaminase gene (tgo) is the second plant transglutaminase identified to date (Campos et al. Plant Sci. 205-206 (2013) 97 110). Similarly to its counterpart in maize (tgz), this rice TGase was localized in the chloroplast, although in this case not exclusively. To further characterise plastidial tgo functionality, proteomic and transcriptomic studies were carried out to identify possible TGO-related proteins. Some LHCII antenna proteins were identified as TGO related using an in vitro proteomic approach, as well as ATPase and some PSII core proteins by mass spectrometry. To study the relationship between TGO and other plastidial proteins, a transcriptomic in vivo Dynamic Array (FluidigmTM) was used to analyse the mRNA expression of 30 plastidial genes with respect to that of tgo, in rice plants subjected to different periods of continuous illumination. The results indicated a gene dependent tendency in the expression pattern that was related to tgo expression and to the illumination cycle. For certain genes, including tgo, significant differences between treatments, principally at the initiation and/or at the end of the illumination period, connected with the day/night cycling of gene expression, were observed. The tgo expression was especially related to plastidial proteins involved in photoprotection and the thylakoid electrochemical gradient. PMID- 25443842 TI - Characterization of three linalool synthase genes from Citrus unshiu Marc. and analysis of linalool-mediated resistance against Xanthomonas citri subsp. citri and Penicilium italicum in citrus leaves and fruits. AB - Three cDNA clones from Satsuma mandarin (Citrus unshiu Marc.) were isolated and expressed in Escherichia coli. CuSTS3-1 and CuSTS3-2 encode linalool synthases and CuSTS4 encodes a nerolidol/linalool synthase. Transcripts of CuSTS3-1, CuSTS3 2 and CuSTS4 were abundant in young fruit at 60 days after flowering (DAF), flowers and leaves, respectively. Treatments with Xanthomonas citri subsp. citri (XCC), the causal agent of citrus canker and Penicillium italicum (PI), the cause of post-harvest fruit decay, and wounding up-regulated CuSTS3-1 in fruit and mainly CuSTS4 in leaves. Linalool, citral, geraniol and citronellol showed strong antibacterial and antifungal activities against XCC and PI in vitro, while most other mono-and sesquiterpenes, including limonene and gamma-terpinene, did not. Linalool, used at levels similar to those present in resistant Ponkan mandarin (Citrus reticulata Blanco) leaves, was able to inhibit growth of XCC in vitro. Compared to other five citrus types, linalool accumulated at extraordinarily high levels in Ponkan mandarin leaves and was released at high amounts from their leaves, while it was hardly detectable in the most susceptible species, indicating that linalool biosynthesis and accumulation might be involved in plant defense against bacterial and fungal pathogens and be associated with field resistance to citrus canker. PMID- 25443843 TI - Transcription factors involved in controlling the expression of nitrate reductase genes in higher plants. AB - Nitrate reductase is a key enzyme in nitrogen assimilation, and it catalyzes the nitrate-to-nitrite reduction process in plants. A variety of factors, including nitrate, light, metabolites, phytohormones, low temperature, and drought, modulate the expression levels of nitrate reductase genes as well as nitrate reductase activity, which is consistent with its physiological role. Recently, several transcription factors involved in controlling the expression of nitrate reductase genes have been identified in Arabidopsis. NODULE-INCEPTION-like proteins (NLPs) are transcription factors responsible for nitrate-inducible expression of nitrate reductase genes. Since NLPs also control nitrate-inducible expression of genes encoding nitrate transporter, nitrite transporter, and nitrite reductase, the expression levels of nitrate reduction pathway-associated genes are coordinately modulated by NLPs in response to nitrate. LATERAL ORGAN BOUNDARIES DOMAIN (LBD) transcription factors (LBD37-LBD39) are strong candidates for transcription factors mediating negative feedback regulation in response to increases in the contents of nitrogen-containing metabolites, whereas LONG HYPOCOTYL 5 (HY5) that promotes photomorphogenesis in light may be a transcription factor involved in light-induced expression of a nitrate reductase gene. Furthermore, unidentified transcription factors likely mediate other signals and regulate the expression of nitrate reductase genes. This review presents a summary of our current knowledge of such transcription factors. PMID- 25443844 TI - Enrichment and analysis of rice seedling ubiquitin-related proteins using four UBA domains (GST-qUBAs). AB - Protein ubiquitination is a common posttranslational modification that often occurs on lysine residues. It controls the half-life, interaction and trafficking of intracellular proteins and is involved in different plant development stages and responses to environment stresses. Four Ubiquitin-Associated (UBA) domains were sequentially fused with Glutathione S-transferase (GST) tag (GST-qUBA) as bait protein in this study. A two-step affinity protocol was successfully developed and the identification of ubiquitinated proteins and their interaction proteins increased almost threefold compared to methods that directly identify ubiquitinated proteins from crude samples. A total of 170 ubiquitin-related proteins were identified in GST-qUBAs enriched samples taken from rice seedlings. There were 134 ubiquitinated proteins, 5 ubiquitin-activating enzymes (E1s), 5 ubiquitin-conjugating enzymes (E2s), 19 ubiquitin ligases (E3s) and 7 deubiquitinating enzymes (DUBs), which all contained various key factors that regulated a wide range of biological processes. Moreover, a series of novel ubiquitinated proteins and E3s were identified that had not been previously reported. This study investigated a high-efficiency method for identifying novel ubiquitinated proteins involved in biological processes and a primary mapping of the ubiquitylome during rice seedling development, which could extend our understanding of how ubiquitin modification regulates plant proteins, pathways and cellular processes. PMID- 25443845 TI - The Wall-associated Kinase gene family in rice genomes. AB - The environment is a dynamic system in which life forms adapt. Wall-Associated Kinases (WAK) are a subfamily of receptor-like kinases associated with the cell wall. These genes have been suggested as sensors of the extracellular environment and triggers of intracellular signals. They belong to the ePK superfamily with or without a conserved arginine before the catalytic subdomain VIB, which characterizes RD and non-RD WAKs. WAK is a large subfamily in rice. We performed an extensive comparison of WAK genes from A. thaliana (AtWAK), O. sativa japonica and indica subspecies (OsWAK). Phylogenetic studies and WAK domain characterization allowed for the identification of two distinct groups of WAK genes in Arabidopsis and rice. One group corresponds to a cluster containing only OsWAKs that most likely expanded after the monocot-dicot separation, which evolved into a non-RD kinase class. The other group comprises classical RD kinases with both AtWAK and OsWAK representatives. Clusterization analysis using extracellular and kinase domains demonstrated putative functional redundancy for some genes, but also highlighted genes that could recognize similar extracellular stimuli and activate different cascades. The gene expression pattern of WAKs in response to cold suggests differences in the regulation of the OsWAK genes in the indica and japonica subspecies. Our results also confirm the hypothesis of functional diversification between A. thaliana and O. sativa WAK genes. Furthermore, we propose that plant WAKs constitute two evolutionarily related but independent subfamilies: WAK-RD and WAK-nonRD. Recognition of this structural division will further provide insights to understanding WAK functions and regulations. PMID- 25443846 TI - Complexity of the transcriptional network controlling secondary wall biosynthesis. AB - Secondary walls in the form of wood and fibers are the most abundant biomass produced by vascular plants, and are important raw materials for many industrial uses. Understanding how secondary walls are constructed is of significance in basic plant biology and also has far-reaching implications in genetic engineering of plant biomass better suited for various end uses, such as biofuel production. Secondary walls are composed of three major biopolymers, i.e., cellulose, hemicelluloses and lignin, the biosynthesis of which requires the coordinated transcriptional regulation of all their biosynthesis genes. Genomic and molecular studies have identified a number of transcription factors, whose expression is associated with secondary wall biosynthesis. We comprehensively review how these secondary wall-associated transcription factors function together to turn on the secondary wall biosynthetic program, which leads to secondary wall deposition in vascular plants. The transcriptional network regulating secondary wall biosynthesis employs a multi-leveled feed-forward loop regulatory structure, in which the top-level secondary wall NAC (NAM, ATAF1/2 and CUC2) master switches activate the second-level MYB master switches and they together induce the expression of downstream transcription factors and secondary wall biosynthesis genes. Secondary wall NAC master switches and secondary wall MYB master switches bind to and activate the SNBE (secondary wall NAC binding element) and SMRE (secondary wall MYB-responsive element) sites, respectively, in their target gene promoters. Further investigation of what and how developmental signals trigger the transcriptional network to regulate secondary wall biosynthesis and how different secondary wall-associated transcription factors function cooperatively in activating secondary wall biosynthetic pathways will lead to a better understanding of the molecular mechanisms underlying the transcriptional control of secondary wall biosynthesis. PMID- 25443847 TI - Sequencing of the chloroplast genomes of cytoplasmic male-sterile and male fertile lines of soybean and identification of polymorphic markers. AB - The RN-type cytoplasmic male sterility (CMS) system used to develop Hybsoy-1, the first commercial hybrid soybean, has been subsequently applied to generate nearly all released soybean hybrids. Although more than 3 years are needed to classify sterile (S) and normal male-fertile (F) cytoplasms by conventional crossing, such classifications can be performed rapidly using organellar DNA-based molecular markers. Except for fertility, the agronomic traits of CMS hybrid soybean sterile and maintainer lines are identical. Consequently, it is difficult to distinguish them by routine visual inspection in the mixture arising in the course of field planting and harvesting during breeding. In this study, we performed next generation sequencing of chloroplast DNAs of F- and S-cytoplasmic soybeans, assembled and annotated the genomes, and identified polymorphisms distinguishing them. Chloroplast DNAs of F and S cytoplasms were very similar in size (152,215 and 152,222 base pairs) and GC contents (35.37%). Among 23 shared SNPs in gene coding regions, we identified four that could be used in conjunction with restriction endonucleases to distinguish S and F cytoplasms. Although CMS is likely associated with mitochondrial DNA, maternal transmission of mitochondrial and chloroplast DNAs allows polymorphisms in either genome to be used to classify soybean cytoplasms, aiding hybrid soybean cultivar development. PMID- 25443848 TI - RNA sequencing reveals high resolution expression change of major plant hormone pathway genes after young seedless grape berries treated with gibberellin. AB - Seedless varieties are of particular importance to the table-grape and raisin industries. Gibberellin (GA) application is widely used in the early stages of seedless berry development to increase berry size and economic value. However, the underlying mechanism of GA induction of berry enlargement is not well understood. Here, RNA-sequencing analysis of 'Centennial Seedless' (Vitis vinifera L.) berries treated with GA3 12 days after flowering is reported. Pair wise comparison of GA3-treated and control samples detected 165, 444, 463 genes with an over two-fold change in expression 1, 3, and 7 days after GA3 treatment, respectively. The number of differentially expressed genes increased with time after GA3 treatment, and the differential expression was dominated by downregulation. Significantly modulated expression included genes encoding synthesis and catabolism to manage plant hormone homeostasis, hormone transporters, receptors and key components in signaling pathways; exogenous GA3 induced multipoint cross talk with auxin, cytokinin, brassinosteroid, ABA and ethylene. The temporal gene-expression patterns of cell-wall-modification enzymes, cytoskeleton and membrane components and transporters revealed a pivotal role for cell-wall-relaxation genes in GA3-induced berry enlargement. Our results provide the first sequential transcriptomic atlas of exogenous GA3-induced berry enlargement and reveal the complexity of GA3's effect on berry sizing. PMID- 25443849 TI - Amino acids--a life between metabolism and signaling. AB - Amino acids serve as constituents of proteins, precursors for anabolism, and, in some cases, as signaling molecules in mammalians and plants. This review is focused on new insights, or speculations, on signaling functions of serine, gamma aminobutyric acid (GABA) and phenylalanine-derived phenylpropanoids. Serine acts as signal in brain tissue and mammalian cancer cells. In plants, de novo serine biosynthesis is also highly active in fast growing tissues such as meristems, suggesting a similar role of serine as in mammalians. GABA functions as inhibitory neurotransmitter in the brain. In plants, GABA is also abundant and seems to be involved in sexual reproduction, cell elongation, patterning and cell identity. The aromatic amino acids phenylalanine, tyrosine, and tryptophan are precursors for the production of secondary plant products. Besides their pharmaceutical value, lignans, neolignans and hydroxycinnamic acid amides (HCAA) deriving from phenylpropanoid metabolism and, in the case of HCAA, also from arginine have been shown to fulfill signaling functions or are involved in the response to biotic and abiotic stress. Although some basics on phenylpropanoid derived signaling have been described, little is known on recognition- or signal transduction mechanisms. In general, mutant- and transgenic approaches will be helpful to elucidate the mechanistic basis of metabolite signaling. PMID- 25443851 TI - To grow or not to grow: a stressful decision for plants. AB - Progress in improving abiotic stress tolerance of crop plants using classic breeding and selection approaches has been slow. This has generally been blamed on the lack of reliable traits and phenotyping methods for stress tolerance. In crops, abiotic stress tolerance is most often measured in terms of yield-capacity under adverse weather conditions. "Yield" is a complex trait and is determined by growth and developmental processes which are controlled by environmental signals throughout the life cycle of the plant. The use of model systems has allowed us to gradually unravel how plants grow and develop, but our understanding of the flexibility and opportunistic nature of plant development and its capacity to adapt growth to environmental cues is still evolving. There is genetic variability for the capacity to maintain yield and productivity under abiotic stress conditions in crop plants such as cereals. Technological progress in various domains has made it increasingly possible to mine that genetic variability and develop a better understanding about the basic mechanism of plant growth and abiotic stress tolerance. The aim of this paper is not to give a detailed account of all current research progress, but instead to highlight some of the current research trends that may ultimately lead to strategies for stress proofing crop species. The focus will be on abiotic stresses that are most often associated with climate change (drought, heat and cold) and those crops that are most important for human nutrition, the cereals. PMID- 25443850 TI - De novo assembly of Eugenia uniflora L. transcriptome and identification of genes from the terpenoid biosynthesis pathway. AB - Pitanga (Eugenia uniflora L.) is a member of the Myrtaceae family and is of particular interest due to its medicinal properties that are attributed to specialized metabolites with known biological activities. Among these molecules, terpenoids are the most abundant in essential oils that are found in the leaves and represent compounds with potential pharmacological benefits. The terpene diversity observed in Myrtaceae is determined by the activity of different members of the terpene synthase and oxidosqualene cyclase families. Therefore, the aim of this study was to perform a de novo assembly of transcripts from E. uniflora leaves and to annotation to identify the genes potentially involved in the terpenoid biosynthesis pathway and terpene diversity. In total, 72,742 unigenes with a mean length of 1048bp were identified. Of these, 43,631 and 36,289 were annotated with the NCBI non-redundant protein and Swiss-Prot databases, respectively. The gene ontology categorized the sequences into 53 functional groups. A metabolic pathway analysis with KEGG revealed 8,625 unigenes assigned to 141 metabolic pathways and 40 unigenes predicted to be associated with the biosynthesis of terpenoids. Furthermore, we identified four putative full-length terpene synthase genes involved in sesquiterpenes and monoterpenes biosynthesis, and three putative full-length oxidosqualene cyclase genes involved in the triterpenes biosynthesis. The expression of these genes was validated in different E. uniflora tissues. PMID- 25443852 TI - mRNA Transcript abundance during plant growth and the influence of Li(+) exposure. AB - Lithium (Li) toxicity in plants is, at a minimum, a function of Li(+) concentration, exposure time, species and growth conditions. Most plant studies with Li(+) focus on short-term acute exposures. This study examines short- and long-term effects of Li(+) exposure in Arabidopsis with Li(+) uptake studies and measured shoot mRNA transcript abundance levels in treated and control plants. Stress, pathogen-response and arabinogalactan protein genes were typically more up-regulated in older (chronic, low level) Li(+)-treatment plants and in the much younger plants from acute high-level exposures. The gene regulation behavior of high-level Li(+) resembled prior studies due to its influence on: inositol synthesis, 1-aminocyclopropane-1-carboxylate synthases and membrane ion transport. In contrast, chronically-exposed plants had gene regulation responses that were indicative of pathogen, cold, and heavy-metal stress, cell wall degradation, ethylene production, signal transduction, and calcium-release modulation. Acute Li(+) exposure phenocopies magnesium-deficiency symptoms and is associated with elevated expression of stress response genes that could lead to consumption of metabolic and transcriptional energy reserves and the dedication of more resources to cell development. In contrast, chronic Li(+) exposure increases expression signal transduction genes. The identification of new Li(+) sensitive genes and a gene-based "response plan" for acute and chronic Li(+) exposure are delineated. PMID- 25443853 TI - Light signaling and the phytohormonal regulation of shoot growth. AB - Shoot growth of dicot plants is rigorously controlled by the interactions of environmental cues with several groups of phytohormones. The signaling effects of light on shoot growth are of special interest, as both light irradiance and light quality change rapidly throughout the day, causing profound changes in stem elongation and leaf area growth. Among the several dicot species examined, we have focused on sunflower (Helianthus annuus L.) because its shoots are robust and their growth is highly plastic. Sunflower shoots thus constitute an ideal tissue for assessing responses to both light irradiance and light quality signals. Herein, we discuss the possible roles of gibberellins, auxin, ethylene, cytokinins and brassinosteroids in mediating the stem elongation and leaf area growth that is induced by shade light. To do this we uncoupled the plant's responses to changes in the red to far-red [R/FR] light ratio from its responses to changes in irradiance of photosynthetically active radiation [PAR]. Reducing each of R/FR light ratio and PAR irradiance results in increased sunflower stem elongation. However, the plant's response for leaf area growth differs considerably, with a low R/FR ratio generally promoting leaf area growth, whereas low irradiance PAR inhibits it. The increased stem elongation that occurs in response to lowering R/FR ratio and PAR irradiance is accomplished at the expense of leaf area growth. In effect, the low PAR irradiance signal overrides the low R/FR ratio signal in shade light's control of leaf growth and development. Three hormone groups, gibberellins, auxin and ethylene are directly involved in regulating these light-mediated shoot growth changes. Gibberellins and auxin function as growth promoters, with auxin likely acting as an up-regulator of gibberellin biosynthesis. Ethylene functions as a growth-inhibitor and probably interacts with gibberellins in regulating both stem and leaf growth of the sunflower shoot. PMID- 25443854 TI - Mapping infectious disease landscapes: unmanned aerial vehicles and epidemiology. AB - The potential applications of unmanned aerial vehicles (UAVs), or drones, have generated intense interest across many fields. UAVs offer the potential to collect detailed spatial information in real time at relatively low cost and are being used increasingly in conservation and ecological research. Within infectious disease epidemiology and public health research, UAVs can provide spatially and temporally accurate data critical to understanding the linkages between disease transmission and environmental factors. Using UAVs avoids many of the limitations associated with satellite data (e.g., long repeat times, cloud contamination, low spatial resolution). However, the practicalities of using UAVs for field research limit their use to specific applications and settings. UAVs fill a niche but do not replace existing remote-sensing methods. PMID- 25443855 TI - Thomas Willis: the faculties and his two cognitive frameworks. AB - Thomas Willis' 1664 study The anatomy of the brain is widely regarded as one of the first clinical studies of the brain. In Theanatomy, Thomas Willis explicitly connected the cognitive faculties and the nerves. Willis' later, 1672 work, The two discourses concerning the soul of brutes, severely undermined the materialism of Willis' first study: he affirmed dualism and cognitive immateriality; changed the anatomical locations of cognition; and reasserted a division between the rational and sensitive souls. His exact motive to return to orthodoxy is unclear, but contemporary scholarship of Willis has compounded the confusion with by relying predominantly on The soul of brutes instead of The anatomy. We trace Willis' career and examine his methodological practices, which help explain the historical practices and pressures. A closer examination of Willis' Anatomy of the brain reveals a much more materialistic account of the brain, the faculties, and nervous system. In this article, we present our own analysis of Willis' concept of rationality in the Anatomy and explain its importance for nervous physiology and understanding the analytic techniques for first defining faculty localizations. We then explain the role of the imagination and the immortal soul in the rearticulated anatomical concepts from The soulof brutes. PMID- 25443856 TI - Exposures to conducted electrical weapons (including TASER(r) devices): how many and for how long are acceptable? AB - TASER((r)) conducted electrical weapons (CEWs) are an important law-enforcement tool. The purposes of this study are a) to review recent literature regarding potential pathophysiological responses to applications of CEWs, and other related issues and b) to evaluate whether enough data exist to determine the acceptability of longer-duration (or repeated) exposures. This is a narrative review, using a multidisciplinary approach of analyzing reports from physiological, legal-medical, and police-strategy literature sources. In general, short-duration exposures to CEWs result in limited effects. Longer-duration or repeated exposures may be utilized with caution, although there are currently not enough data to determine the acceptability of all types of exposures. Data examined in the literature have inherent limitations. Appropriateness of specific types of CEW usage may be determined by individual police agencies, applying risk/benefit analyses unique to each organization. While more research is recommended, initial concepts of potential future long-duration or repeated CEW applications are presented. PMID- 25443858 TI - Innovative diagnostic tools for early detection of Alzheimer's disease. AB - Current state-of-the-art diagnostic measures of Alzheimer's disease (AD) are invasive (cerebrospinal fluid analysis), expensive (neuroimaging) and time consuming (neuropsychological assessment) and thus have limited accessibility as frontline screening and diagnostic tools for AD. Thus, there is an increasing need for additional noninvasive and/or cost-effective tools, allowing identification of subjects in the preclinical or early clinical stages of AD who could be suitable for further cognitive evaluation and dementia diagnostics. Implementation of such tests may facilitate early and potentially more effective therapeutic and preventative strategies for AD. Before applying them in clinical practice, these tools should be examined in ongoing large clinical trials. This review will summarize and highlight the most promising screening tools including neuropsychometric, clinical, blood, and neurophysiological tests. PMID- 25443857 TI - The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. AB - Although amyloid imaging with PiB-PET ([C-11]Pittsburgh Compound-B positron emission tomography), and now with F-18-labeled tracers, has produced remarkably consistent qualitative findings across a large number of centers, there has been considerable variability in the exact numbers reported as quantitative outcome measures of tracer retention. In some cases this is as trivial as the choice of units, in some cases it is scanner dependent, and of course, different tracers yield different numbers. Our working group was formed to standardize quantitative amyloid imaging measures by scaling the outcome of each particular analysis method or tracer to a 0 to 100 scale, anchored by young controls (<= 45 years) and typical Alzheimer's disease patients. The units of this scale have been named "Centiloids." Basically, we describe a "standard" method of analyzing PiB PET data and then a method for scaling any "nonstandard" method of PiB PET analysis (or any other tracer) to the Centiloid scale. PMID- 25443859 TI - Radiotherapy equipment and departments in the European countries: final results from the ESTRO-HERO survey. AB - BACKGROUND: Documenting the distribution of radiotherapy departments and the availability of radiotherapy equipment in the European countries is an important part of HERO - the ESTRO Health Economics in Radiation Oncology project. HERO has the overall aim to develop a knowledge base of the provision of radiotherapy in Europe and build a model for health economic evaluation of radiation treatments at the European level. The aim of the current report is to describe the distribution of radiotherapy equipment in European countries. METHODS: An 84-item questionnaire was sent out to European countries, principally through their national societies. The current report includes a detailed analysis of radiotherapy departments and equipment (questionnaire items 26-29), analyzed in relation to the annual number of treatment courses and the socio-economic status of the countries. The analysis is based on validated responses from 28 of the 40 European countries defined by the European Cancer Observatory (ECO). RESULTS: A large variation between countries was found for most parameters studied. There were 2192 linear accelerators, 96 dedicated stereotactic machines, and 77 cobalt machines reported in the 27 countries where this information was available. A total of 12 countries had at least one cobalt machine in use. There was a median of 0.5 simulator per MV unit (range 0.3-1.5) and 1.4 (range 0.4-4.4) simulators per department. Of the 874 simulators, a total of 654 (75%) were capable of 3D imaging (CT-scanner or CBCT-option). The number of MV machines (cobalt, linear accelerators, and dedicated stereotactic machines) per million inhabitants ranged from 1.4 to 9.5 (median 5.3) and the average number of MV machines per department from 0.9 to 8.2 (median 2.6). The average number of treatment courses per year per MV machine varied from 262 to 1061 (median 419). While 69% of MV units were capable of IMRT only 49% were equipped for image guidance (IGRT). There was a clear relation between socio-economic status, as measured by GNI per capita, and availability of radiotherapy equipment in the countries. In many low income countries in Southern and Central-Eastern Europe there was very limited access to radiotherapy and especially to equipment for IMRT or IGRT. CONCLUSIONS: The European average number of MV machines per million inhabitants and per department is now better in line with QUARTS recommendations from 2005, but the survey also showed a significant heterogeneity in the access to modern radiotherapy equipment in Europe. High income countries especially in Northern-Western Europe are well served with radiotherapy resources, other countries are facing important shortages of both equipment in general and especially machines capable of delivering high precision conformal treatments (IMRT, IGRT). PMID- 25443860 TI - Diagnostic accuracy and prognostic impact of restaging by magnetic resonance imaging after preoperative chemoradiotherapy in patients with rectal cancer. AB - BACKGROUND: The prognostic role of restaging rectal magnetic resonance imaging (MRI) in patients with preoperative CRT has not been established. The goal of this study was to evaluate the diagnostic accuracy and prognostic role of radiological staging by rectal MRI after preoperative chemoradiation (CRT) in patients with rectal cancer. METHODS: A total of 231 consecutive patients with rectal cancer who underwent preoperative CRT and radical resection from January 2008 to December 2009 were prospectively enrolled. The diagnostic accuracy and prognostic significance of post-CRT radiological staging by MRI was evaluated. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value of radiological diagnosis of good responders (ypTNM stage 0-I) were 32%, 90%, 65%, and 69%, respectively. The overall accuracy of MRI restating for good responders was 68%. The 5-year disease-free survival rates of patients with radiological and pathological TNM stage 0, stage I, and stage II-III were 100%, 94%, and 76%, respectively (P=0.037), and 97%, 87%, and 73%, respectively (P=0.007). On multivariate analysis, post-CRT radiological staging by MRI was an independent prognostic factor for disease-free survival. CONCLUSION: Radiological staging by MRI after preoperative CRT may be an independent predictor of survival in patients with rectal cancer. PMID- 25443861 TI - A dosimetric comparison of proton and intensity modulated radiation therapy in pediatric rhabdomyosarcoma patients enrolled on a prospective phase II proton study. AB - BACKGROUND: Pediatric rhabdomyosarcoma (RMS) is highly curable, however, cure may come with significant radiation related toxicity in developing tissues. Proton therapy (PT) can spare excess dose to normal structures, potentially reducing the incidence of adverse effects. METHODS: Between 2005 and 2012, 54 patients were enrolled on a prospective multi-institutional phase II trial using PT in pediatric RMS. As part of the protocol, intensity modulated radiation therapy (IMRT) plans were generated for comparison with clinical PT plans. RESULTS: Target coverage was comparable between PT and IMRT plans with a mean CTV V95 of 100% for both modalities (p=0.82). However, mean integral dose was 1.8 times higher for IMRT (range 1.0-4.9). By site, mean integral dose for IMRT was 1.8 times higher for H&N (p<0.01) and GU (p=0.02), 2.0 times higher for trunk/extremity (p<0.01), and 3.5 times higher for orbit (p<0.01) compared to PT. Significant sparing was seen with PT in 26 of 30 critical structures assessed for orbital, head and neck, pelvic, and trunk/extremity patients. CONCLUSIONS: Proton radiation lowers integral dose and improves normal tissue sparing when compared to IMRT for pediatric RMS. Correlation with clinical outcomes is necessary once mature long-term toxicity data are available. PMID- 25443862 TI - c-Myc plays part in drug resistance mediated by bone marrow stromal cells in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a malignant and aggressive disease not sensitive to chemotherapy. The dynamic interaction between AML cells and bone marrow (BM) microenvironment plays a critical role in response of this disease to chemotherapy. It is reported that mesenchymal stromal cells (MSC) are essential component of bone marrow microenvironment which affects the survival of AML cells. The aim of our research is to elucidate the mechanism of drug resistance of AML cells associated with MSC. We found that adhesion of AML cell lines U937, KG1a and primary AML cells to MSC inhibited cytotoxic drug-induced apoptosis. Western blot showed that c-Myc of AML cells cocultured with stroma was up regulated. Treatment with 10058-F4, a small molecule inhibitor of MYC-MAX heterodimerization, or c-Myc siRNA significantly induced apoptosis. Western blot analysis further showed that inhibition of c-Myc induced expression of caspases 3, cleavage of PARP and reduced expression of Bcl-2, Bcl-xL and vascular endothelial growth factor (VEGF). Thus, we conclude that MSCs protected leukemia cells from apoptosis, at least in part, through c-Myc dependent mechanisms, and that c-Myc contributed to microenvironment-mediated drug resistance in AML. In summary, we declared that c-Myc is a potential therapeutic target for overcoming drug resistance in AML. PMID- 25443864 TI - Who are the healthy active seniors? A cluster analysis. AB - BACKGROUND: This paper reports a cluster analysis of a sample recruited from a randomized controlled trial that explored the effect of using a life story work approach to improve the psychological outcomes of older people in the community. METHODS: 238 subjects from community centers were included in this analysis. After statistical testing, 169 seniors were assigned to the active ageing (AG) cluster and 69 to the inactive ageing (IG) cluster. RESULTS: Those in the AG were younger and healthier, with fewer chronic diseases and fewer depressive symptoms than those in the IG. They were more satisfied with their lives, and had higher self-esteem. They met with their family members more frequently, they engaged in more leisure activities and were more likely to have the ability to move freely. CONCLUSION: In summary, active ageing was observed in people with better health and functional performance. Our results echoed the limited findings reported in the literature. PMID- 25443863 TI - Pilot randomized trial of selective internal radiation therapy vs. chemoembolization in unresectable hepatocellular carcinoma. AB - BACKGROUND & AIMS: To compare selective internal radiation therapy (SIRT) with transarterial chemoembolization (TACE), the standard-of-care for intermediate stage unresectable, hepatocellular carcinoma (HCC), as first-line treatment. METHODS: SIRTACE was an open-label multicenter randomized-controlled pilot study, which prospectively compared primarily safety and health-related quality of life (HRQoL) changes following TACE and SIRT. Patients with unresectable HCC, Child Pugh <=B7, ECOG performance status <=2 and <=5 liver lesions (<=20 cm total maximum diameter) without extrahepatic spread were randomized to receive either TACE (at 6-weekly intervals until tumour enhancement was not observed on MRI or disease progression) or single-session SIRT (yttrium-90 resin microspheres). RESULTS: Twenty-eight patients with BCLC stage A (32.1%), B (46.4%) or C (21.4%) received either a mean of 3.4 (median 2) TACE interventions (N = 15) or single SIRT (N = 13). Both treatments were well tolerated. Despite SIRT patients having significantly worse physical functioning at baseline, at week-12, neither treatment had a significantly different impact on HRQoL as measured by Functional Assessment of Cancer Therapy-Hepatobiliary total or its subscales. Both TACE and SIRT were effective for the local control of liver tumours. Best overall response rate (RECIST 1.0) of target lesions were 13.3% and 30.8%, disease control rates were 73.3% and 76.9% for TACE and SIRT, respectively. Two patients in each group were down-staged for liver transplantation (N = 3) or radiofrequency ablation (N = 1). CONCLUSIONS: Single-session SIRT appeared to be as safe and had a similar impact on HRQoL as multiple sessions of TACE, suggesting that SIRT might be an alternative option for patients eligible for TACE. PMID- 25443865 TI - ["Patient Blood Management" in obstetric hemorrhage]. PMID- 25443866 TI - [Preoperative fasting guidelines: an update]. AB - Anesthesiology societies have issued various guidelines on preoperative fasting since 1990, not only to decrease the incidence of lung aspiration and anesthetic morbidity, but also to increase patient comfort prior to anesthesia. Some of these societies have been updating their guidelines, as such that, since 2010, we now have 2 evidence-based preoperative fasting guidelines available. In this article, an attempt is made to review these updated guidelines, as well as the current instructions for more controversial patients such as infants, the obese, and a particular type of ophthalmic surgery. PMID- 25443867 TI - Effectiveness of a school- and community-based academic asthma health education program on use of effective asthma self-care behaviors in older school-age students. AB - PURPOSE: The purpose was to evaluate the effectiveness of Staying Healthy-Asthma Responsible & Prepared, an academic asthma health education and counseling program, on fostering the use of effective asthma self-care behaviors. DESIGN AND METHODS: This was a phase III, two-group, cluster randomized, single-blinded, longitudinal design-guided study. Caregivers of 205 fourth- and fifth-grade students completed the asthma health behaviors survey at preintervention, and 1, 12, and 24 months postintervention. Analysis involved multilevel modeling. RESULTS: All students demonstrated improvement in episode management, risk reduction/prevention, and health promotion behaviors; Staying Healthy-Asthma Responsible & Prepared students demonstrated increased improvement in episode management and risk reduction/prevention behaviors. PRACTICE IMPLICATIONS: Working with schoolteachers, nurses can improve the use of effective asthma self care behaviors. PMID- 25443868 TI - Influence of bone morphogenetic protein and proportion of hydroxyapatite on new bone formation in biphasic calcium phosphate graft: two pilot studies in animal bony defect model. AB - PURPOSE: The purpose of these two pilot studies using animal bony defect models was to evaluate the influence of bone morphogenetic protein (BMP) and proportion of hydroxyapatite (HA)/beta-tricalcium phosphate (beta-TCP) in biphasic calcium phosphate (BCP) graft on new bone formation. METHODS: In this study, four kinds of synthetic osteoconductive bone materials known for bone growth scaffold, OSTEONTMII(HA:beta-TCP 30:70), OSTEONTMIII (HA:beta-TCP 20:80), OSTEONTMII Collagen, and OSTEONTMIII Collagen, were prepared as BCP graft materials. In pilot study 1, three BCP materials (OSTEONTMII, OSTEONTMIII, and OSTEONTMII Collagen) were grafted in rabbit calvarial defects after impregnating in rhBMP-2. OSTEONTMII without the rhBMP-2 impregnation was included in the study as the control. The amount of new bone was examined and measured histologically at 2, 4, and 8 weeks. In pilot study 2, four BCP materials (OSTEONTMII, OSTEONTMIII, OSTEONTMII Collagen, and OSTEONTMIII Collagen) were grafted in beagle dog mandibular defects after soaking in the rhBMP-2. The amount of total bone and new bone were measured three-dimensionally using microCT and healing process was examined histologically at 2, 4, and 8 weeks. RESULTS: In pilot study 1, rhBMP-2 impregnated groups showed more new bone formation than the rhBMP-2 free group. In pilot study 2, increased new bone formation was observed in time-dependent manner after graft of BCP and BCP-collagen (OSTEONTMII, OSTEONTMIII, OSTEONTMII Collagen, and OSTEONTMIII Collagen) impregnated with rhBMP-2. Also, BCP with a higher proportion of HA (30% HA) showed more favorable result in new bone formation and space maintenance, especially at the 8 weeks. CONCLUSION: From the results of the pilot studies, rhBMP-2 played positive roles in new bone formation and BCP could become a scaffold candidate for rhBMP-2 impregnation to induce new bone formation. Moreover, BCP with a higher proportion of HA (30% HA) could be considered more appropriate for rhBMP-2 carrier. PMID- 25443869 TI - Interval cranioplasty with patient-specific implants and autogenous bone grafts- success and cost analysis. AB - Different options exist for the reconstruction of craniectomy defects following interval cranioplasty. The standard procedure is still based on the re implantation of autogenous bone specimen which can be stored in the abdominal wall or be cryopreserved. Alternatively patient-specific implants (PSIs) can be used. We conducted a retrospective study based on 50 consecutive patients with skull bone defects of 100 cm(2) or more being operated on by the same team of surgeons. Thirty-three patients agreed to take part in the study. Seventeen patients who underwent reconstruction with PSIs (titanium and polyether ether ketone, PEEK) (follow-up, 43 months [range, 3-93]) were compared with 16 control subjects who had autogenous bone grafts re-implanted (follow-up, 32 months [range, 5-92]). Criteria analyzed were the success and complication rates, operation time, duration of hospitalization and the treatment costs. Complication rate and the rate of reoperation were significantly lower, and the hospital stay was shorter in the PSI group. The treatment costs for reconstruction with autogenous bone were considerably lower than skull bone reconstruction based on PSIs (average costs: 10849.91 ?/patient versus 15532.08 ?/patient with PSI). Due to biological reasons some of the autogenous bone implants fail due to infection and resorption and the patients have to undergo another operation with implantation of a PSI in a secondary attempt. For those patients the highest overall treatment costs must be calculated (average costs: 26086.06 ?/patient with secondary stage PSI versus 15532.08 ?/patient with primary stage PSI). CONCLUSION: High success rates and reliability of PSIs may change the treatment strategy in patients undergoing interval cranioplasty. PMID- 25443870 TI - De novo donor-specific HLA antibodies are associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation. AB - BACKGROUND: The development of human leukocyte antigen (HLA) antibody responses has been associated with worse clinical outcomes, such as bronchiolitis obliterans syndrome (BOS) and death, in lung transplant recipients (LTRs). However, the role of donor-specific HLA antibody (DSA) responses as a risk factor for poor outcomes remains controversial. METHODS: We prospectively screened 445 LTRs for DSA at our institution at the time of surveillance bronchoscopies for the first 2 years after transplantation between 2003 and 2008, and evaluated clinical outcomes. For this purpose, we used the combination of panel-reactive antibodies (PRA) by enzyme-linked immunosorbent assay (ELISA) and the Luminex single-antigen bead (SAB) assay (One Lambda, Canoga Park, CA). RESULTS: We detected de novo DSA (dnDSA) in 58 of 445 (13%) LTRs in our cohort. Freedom from BOS was significantly reduced in LTRs with dnDSA versus those without dnDSA (p < 0.001). Using a Cox proportional hazards model, the development of dnDSA was associated with a significantly increased hazard ratio (HR = 6.59 [4.53 to 9.59]; p < 0.001) for BOS and high-grade BOS (Stage >= 2) (HR = 5.76 [3.48 to 9.52]; p < 0.001). Freedom from death was significantly reduced in LTRs with dnDSA (p < 0.001), including mortality attributable to BOS (HR = 9.86 [4.91 to 19.78]; p < 0.001). CONCLUSIONS: Taken together, our findings provide evidence that dnDSA is associated with accelerated BOS kinetics and severity, as well as death due to BOS after lung transplantation. In addition, these data support regular monitoring for the development of dnDSA in LTRs and underscore the need for novel strategies to mitigate the increased risk of poor outcomes associated with dnDSA. PMID- 25443871 TI - Have risk factors for mortality after heart transplantation changed over time? Insights from 19 years of Cardiac Transplant Research Database study. AB - BACKGROUND: The Cardiac Transplant Research Database (CTRD) collected data from 26 U.S. institutions from January 1, 1990 to December 31, 2008 providing the opportunity for construction of a comprehensive multivariable model of risk for death after transplantation. We analyzed risk factors for death over 19 years of experience to determine how risk profiles have changed over time and how they interact with age. METHODS: A multivariable parametric hazard model for death was created for 7,015 patients entered into the CTRD. Variables collected over 19 years of experience were examined as potential risk factors and tested for interaction with date of transplantation to determine if their relative risk (RR) changed over time. RESULTS: The hazard for death post-transplant occurred in 2 phases: an early phase of acute risk lasting <1 year, and a late phase of relatively low, gradually increasing risk (<0.1 event/year). In the early phase, predictive models showed that ventricular assist device (VAD) at the time of transplant did not increase the RR of death for recipient transplant at 30 years of age, but the RR of death was increased by 60% (p = 0.04) at 60 years of age. Of the late-phase variables found to be risk factors, the RR of age, date of transplant and pulmonary vascular resistance changed with respect to transplant year. The overall risk of death dropped importantly over the study period, but the RR of all other variables remained unchanged. RR was 2.6 (p < 0.0001) for 25 year-old African-American (AA) versus non-AA recipients and 1.6 for 60-year-old AA recipients (p = 0.02). CONCLUSION: Over 19 years, the baseline risk of death has decreased, but the specific risk factors and the magnitudes of their RR have remained unchanged. Therefore, despite advances in clinical management and improvement in overall survival, the risk profile for death after cardiac transplantation is similar to that in 1990. PMID- 25443872 TI - Activated partial thromboplastin time overestimates anti-coagulation in left ventricular assist device patients. PMID- 25443873 TI - Gastroparesis is common after lung transplantation and may be ameliorated by botulinum toxin-A injection of the pylorus. PMID- 25443875 TI - A new mechanism of action of thienopyridine antiplatelet drugs - a role for gastric nitrosthiol metabolism? AB - This article outlines a new hypothesis that illustrates the potential role of the stomach (and subsequent chemical reactions involving nitrite therein) in modifying thienopyridines, such as clopidogrel. Gastric modification of thienopyridines can occur before standard accepted biotransformation pathways ensue. We hypothesised that thienopyridines expose the free thiol group once acidified (by the stomach) before biotransformation into active metabolites, and in the presence of nitrite (from saliva and the stomach) to form nitrosothiol derivatives (Thienopyridine induced-SNO formation). We have performed in vitro studies with each of the thienopyridines tablets/compounds confirming direct Th SNO formation from the parent (inactive) drug by the following mechanism. Thienopyridine-SH + H(+ (Stomach)) + [Formula: see text] <-> Thienopyridine-SNO + H2O Thienopyridine-SNO (an S-nitrosothiol molecule) would have the potential to participate in all the reactions expected of native nitric oxide (NO) with added benefit that the NO "moiety" is protected, transportable and largely preserved from further reactive metabolism. All these biochemical steps are present in humans and could occur prior to enzymatic biotransformation. PMID- 25443874 TI - Fasting and non-fasting triglycerides and risk of ischemic cardiovascular disease in Japanese men and women: the Circulatory Risk in Communities Study (CIRCS). AB - BACKGROUND: Non-fasting triglycerides were reported to have a greater impact on risk of ischemic cardiovascular events than fasting triglycerides. However, evidence from Asia, where the prevalence of dyslipidemia is generally lower, has been limited. METHODS: We used 1975-1986 baseline surveys to investigate cohort data of 10,659 (4264 men and 6395 women) residents aged 40-69 years, initially free from ischemic heart disease and stroke, in four Japanese communities. Serum triglyceride concentrations at baseline were obtained for 2424 fasting (>=8 h after meal) and 8235 non-fasting (<8 h after meal) participants. RESULTS: During the 22-year follow-up, 284 (165 men and 119 women) developed ischemic heart disease and 666 (349 men and 317 women) ischemic stroke. After adjustment for age, sex and known cardiovascular risk factors, multivariable hazard ratios (95%CI) of ischemic cardiovascular disease (ischemic heart disease and ischemic stroke) for the highest versus lowest quartiles of triglycerides were 1.71 (1.14 2.59), P for trend = 0.013, for fasting participants and 1.60 (1.25-2.05), P for trend <0.001, for non-fasting participants. The positive associations did not differ between fasting and non-fasting men, while they were strong for non fasting women. They were stronger for ischemic heart disease than for ischemic stroke. After further adjustment for HDL-cholesterol, these associations were slightly attenuated, but remained statistically significant. CONCLUSION: Non fasting as well as fasting triglycerides are predictive of risk of ischemic cardiovascular disease for Japanese men, as are non-fasting triglycerides for women. PMID- 25443877 TI - Previous infection and the risk of ischaemic stroke in Italy: the IN2 study. AB - BACKGROUND AND PURPOSE: There is an increasing interest in new risk factors for ischaemic stroke. Acute and chronic infections could contribute to different aetiological mechanisms of atherosclerosis that lead to cerebrovascular disease. The aim of this study was to investigate the hypothesis that previous infections and Chlamydia pneumoniae in particular increase the risk of ischaemic stroke in the population. METHODS: This was a prospective case-control study involving 11 Italian stroke units. Controls were age- and sex-matched with cases, represented by patients admitted to hospital for acute ischaemic stroke. For each participant classical vascular risk factors and previous inflammatory and infectious events up to 1 month before were registered. Blood samples were collected to analyse inflammatory markers and titres of antibodies against C. pneumoniae. RESULTS: A total of 1002 participants were included (mean age 69 years) with 749 ischaemic stroke patients. Infections occurred within 1 month previously in 12% of the entire sample with a higher prevalence in the case group (14.4% vs. 3.9%). At multivariate analysis of the seropositivity of IgA antibodies against C. pneumoniae increased the risk of stroke significantly (relative risk 2.121; 95% confidence interval 1.255-3.584) and an early previous infection (up to 7 days before the event) contributed to a rise in probability of acute cerebral ischaemia (relative risk 3.692; 95% confidence interval 1.134-6.875). CONCLUSIONS: Early previous infections and persistent chronic infection of C. pneumoniae could contribute to increase the risk of ischaemic stroke significantly, in the elderly especially. PMID- 25443876 TI - Circulating soluble LR11, a novel marker of smooth muscle cell proliferation, is enhanced after coronary stenting in response to vascular injury. AB - OBJECTIVE: Restenosis after vascular intervention remains a major clinical problem. Circulating LR11 has been shown a novel marker of intimal smooth muscle cell (SMC) proliferation in human and animal studies. The present study was performed to clarify the clinical significance of circulating LR11 in patients with stable angina pectoris after coronary stenting. METHODS AND RESULTS: We firstly investigated the circulating sLR11 levels for 28 days after arterial injury in mice, and then assessed time-dependent change in circulating sLR11 level after coronary stenting in a clinical study. Mouse sLR11 levels rapidly increased to 4.0-fold of the control value without cuff placement at postoperative day (POD) 14, and the levels gradually declined to 3.1-fold of the control value until POD 28 in mice. The circulating soluble LR11 levels were measured (before and at 14, 60 and 240 days after coronary stenting in a clinical study of 102 consecutive patients with stable angina pectoris who were treated with percutaneous coronary intervention. Circulating sLR11 levels were significantly increased on days 14 and 60 after the procedure and positively associated with the angiographic late loss index. CONCLUSIONS: Our study suggested that circulating sLR11 levels may be a potential marker for angiographic late loss in patients after coronary stenting. Further mechanistic studies are expected to know the clinical significance of sLR11 as a novel marker for intimal SMC. PMID- 25443878 TI - Death by diet: the role of food pricing interventions as a public policy response and health advocacy opportunity. PMID- 25443879 TI - Effect of in vitro chewing and bruxism events on remineralization, at the resin dentin interface. AB - The purpose of this study was to evaluate if different in vitro functional and parafunctional habits promote mineralization at the resin-dentin interface after bonding with three different adhesive approaches. Dentin surfaces were subjected to distinct treatments: demineralization by (1) 37% phosphoric acid (PA) followed by application of an etch-and-rinse dentin adhesive, Single Bond (SB) (PA+SB); (2) 0.5 M ethylenediaminetetraacetic acid (EDTA) followed by SB (EDTA+SB); (3) application of a self-etch dentin adhesive, Clearfil SE Bond (SEB). Different loading waveforms were applied: No cycling (I), cycled in sine (II) or square (III) waves, sustained loading hold for 24 h (IV) or sustained loading hold for 72 h (V). Remineralization at the bonded interfaces was assessed by AFM imaging/nano-indentation, Raman spectroscopy and Masson's trichrome staining. In general, in vitro chewing and parafunctional habits, promoted an increase of nano mechanical properties at the resin-dentin interface. Raman spectroscopy through cluster analysis demonstrated an augmentation of the mineral-matrix ratio in loaded specimens. Trichrome staining reflected a narrow demineralized dentin matrix after loading in all groups except in PA+SB and EDTA+SB samples after sustained loading hold for 72 h, which exhibited a strong degree of mineralization. In vitro mechanical loading, produced during chewing and bruxism (square or hold 24 and 72 h waveforms), induced remineralization at the resin dentin bonded interface. PMID- 25443880 TI - Effect of attachment types and number of implants supporting mandibular overdentures on stress distribution: a computed tomography-based 3D finite element analysis. AB - The objective of this study was to calculate stresses in bone tissue surrounding uncoupled and splinted implants that are induced by a bite force applied to the mandible and to determine whether the number of mandibular overdenture supporting implants in mandibular bone influence the stress distribution. A human adult edentulous mandible retrieved from a formalin fixed cadaver was used to define the geometry of finite element (FE) model and the FE model was verified with experimental measurements. Following the FE model validation, three different biting situations were simulated for the 2-, 3- and 4-implant retentive anchor as well as bar attachment overdentures under vertical loading of 100 N. As a result of the analyses, it was concluded that an increment in implant number and the splinted attachment type tended to cause lower stresses and the use of two single attachments seems to be a safe and sufficient solution for the treatment of mandibular edentulism with overdentures. PMID- 25443881 TI - Adaptation of overdenture-bars casted in different metals and their influence on the stress distribution: a laboratory and 3D FEA. AB - Adaptation at the implant/abutment interface is important to the long-term success of prosthetic rehabilitations. The aim of this study was to evaluate the adaptation of overdenture bar frameworks casted with different materials and the stress distribution of ill-fitted frameworks placement through 3-D finite element analysis (FEA). Thirty overdenture bar frameworks (n=10) were casted in different materials (Co-Cr, Ni-Cr, Ti). Vertical misfit of both abutments was examined using a single screw test and, after both screws were tightened, using a scanning electron microscope (SEM). The misfit values of each group were used to construct 3-D models, and a displacement with the same extent observed in SEM was applied to the non-tightened abutment to simulate the effect of prosthetic tightening. von Mises stress for prosthetic components, and the maximum principal stress and microstrain for bone tissue were evaluated. The misfit in the non-tightened abutment during the single screw test ranged from 145 to 211 um. Different bar framework materials did not present significant differences in regard to adaptation. An increase in the misfit values in the other abutment was observed after the final settlement of the bars in Ni-Cr and Ti frameworks. The stress values on prosthetic screw and implant were not influenced by the bar framework material. However, Ti caused lower stress in the bar framework itself and strain in the bone tissue. The bar framework material does not affect the implant/abutment adaptation. Titanium frameworks presented the best behavior for the bar framework itself and bone tissue compared to the other materials. PMID- 25443882 TI - Comparison of three methods of calculating strain in the mouse ulna in exogenous loading studies. AB - Axial compression of mouse limbs is commonly used to induce bone formation in a controlled, non-invasive manner. Determination of peak strains caused by loading is central to interpreting results. Load-strain calibration is typically performed using uniaxial strain gauges attached to the diaphyseal, periosteal surface of a small number of sacrificed animals. Strain is measured as the limb is loaded to a range of physiological loads known to be anabolic to bone. The load-strain relationship determined by this subgroup is then extrapolated to a larger group of experimental mice. This method of strain calculation requires the challenging process of strain gauging very small bones which is subject to variability in placement of the strain gauge. We previously developed a method to estimate animal-specific periosteal strain during axial ulnar loading using an image-based computational approach that does not require strain gauges. The purpose of this study was to compare the relationship between load-induced bone formation rates and periosteal strain at ulnar midshaft using three different methods to estimate strain: (A) Nominal strain values based solely on load-strain calibration; (B) Strains calculated from load-strain calibration, but scaled for differences in mid-shaft cross-sectional geometry among animals; and (C) An alternative image-based computational method for calculating strains based on beam theory and animal-specific bone geometry. Our results show that the alternative method (C) provides comparable correlation between strain and bone formation rates in the mouse ulna relative to the strain gauge-dependent methods (A and B), while avoiding the need to use strain gauges. PMID- 25443883 TI - A personalized method for estimating centre of mass location of the whole body based on differentiation of tissues of a multi-divided trunk. AB - There are several methods for obtaining location of the centre of mass of the whole body. They are based on cadaver data, using volume and density of body parts, using radiation and image techniques. Some researchers treated the trunk as a one part only, while others divided the trunk into few parts. In addition some researchers divided the trunk with planes perpendicular to the longitudinal trunk's axis, although the best approach is to obtain trunk parts as anatomical and functional elements. This procedure was used by Dempster and Erdmann. The latter elaborated personalized estimating of inertial quantities of the trunk, while Clauser et al. gave similar approach for extremities. The aim of the investigation was to merge both indirect methods in order to obtain accurate location of the centre of mass of the whole body. As a reference location a direct method based on reaction board procedure, i.e. with a body lying on a board supported on a scale was used. The location of the centre of mass using Clauser's and Erdmann's method appeared almost identical with the location obtained with a direct method. This approach can be used for several situations, especially for people of different morphology, for the bent trunk, and for asymmetrical movements. PMID- 25443884 TI - A biomechanical characterisation of acellular porcine super flexor tendons for use in anterior cruciate ligament replacement: investigation into the effects of fat reduction and bioburden reduction bioprocesses. AB - The decellularisation of xenogenic and allogeneic biological grafts offers a promising solution to replacement of the anterior cruciate ligament (ACL). The purpose of this investigation was to determine the biomechanical effects of additional fat reduction and bioburden reduction steps in the decellularisation of porcine super flexor tendon (pSFT). Study 1 investigated the use of acetone or chloroform-methanol as a fat reduction agent. The most effective of these was then carried forward into Study 2, which investigated the use of antibiotics or peracetic acid (PAA) as a bioburden reduction agent. Stress relaxation data was analysed using a Maxwell-Wiechert viscoelastic model and, in addition to classical material properties, the tangent modulus of the toe-region was determined from strength testing data. In both studies, the majority of decellularised groups demonstrated no statistical differences for material properties such as tensile strength and Young's modulus compared to native controls. Different trends were observed for many of the viscoelastic parameters, but also for the tangent modulus in the toe-region indicating a change in performance at low strains. The most severe deviations from the profile of the native tangent modulus were found to occur in Study 2 when PAA was used for bioburden reduction. Classic material properties (E, UTS etc.) are often used to compare the characteristics of native and decellularised tissues, however they may not highlight changes occurring in the tissues at low strains. In this study, this represented the physiological strains encountered by substitute acellular ACL grafts. Acetone was chosen as the fat reduction step whereas, antibiotics was preferable over PAA as a bioburden reduction step. PMID- 25443885 TI - Chronic mast cell leukemia: a novel leukemia-variant with distinct morphological and clinical features. AB - Mast cell leukemia (MCL) is a rare form of systemic mastocytosis characterized by leukemic expansion of mostly immature mast cells, organ damage, drug-resistance, and a poor prognosis. Even when treated with chemotherapy, most patients have a life-expectancy of less than one year. However, there are rare patients with MCL in whom the condition is less aggressive and does not cause organ damage within a short time. In these patients, mast cells exhibit a more mature morphology when compared to acute MCL. A recently proposed classification suggests that these cases are referred to as chronic MCL. In the present article, we discuss clinical, histopathological and morphological aspects of acute and chronic MCL. PMID- 25443886 TI - Derivation and validation of the SEER-Medicare myelodysplastic syndromes risk score (SMMRS). AB - Accruing data since 2001, the SEER-Medicare dataset is an outstanding resource for MDS-related comparative effectiveness research; however, although several MDS prognostic models exist, complete data required to calculate them are not available therein. Using SEER-Medicare as a training and internal validation set (n=9820) and clinical data at our institution as an external validation set (n=307), we created a new MDS risk score (the SMMRS) for use with SEER-Medicare. Risk stratification by the SMMRS was comparable to the IPSS (net reclassification improvement index was 0.0), demonstrating that it is a useful research tool to stratify MDS patients in studies using SEER-Medicare. PMID- 25443887 TI - Prognosis of body mass index and chemotherapy dose capping in acute myeloid leukaemia. AB - Body Mass Index (BMI) prognosis in acute myeloid leukaemia (AML) is unknown. Capping chemotherapy dose at 2m(2) of body surface area (BSA) is used without any rationale. We assessed whether both of them could be correlated with outcome in 233 AML patients. Thirty three percent were overweight, 10% obese and BSA over 2m(2) was observed in 15%. BMI and BSA>2m(2) were not associated with OS (p=0.16; p=0.39), nor with DFS (p=0.18; p=0.42), nor with CR. OS-associated factors were age (p<0.001), cytogenetic (p=0.002), FLT3-ITD (p=0.01). BMI and chemotherapy dose capping are not pejorative factors on intensively treated AML patients. PMID- 25443888 TI - Stromal cells attenuate the cytotoxicity of imatinib on Philadelphia chromosome positive leukemia cells by up-regulating the VE-cadherin/beta-catenin signal. AB - beta-Catenin is a key regulator of leukemia stem cell maintenance and drug resistance. Herein, we investigated the protective effects of the stromal cell mediated VE-cadherin-beta-catenin signal on Ph+ leukemia cells during imatinib treatment. We found stromal cells could desensitize imatinib and up-regulate VE cadherin expression on Ph+ leukemia cells (K562 and SUP-B15 cells), which further stabilized and activated beta-catenin. Knockdown of VE-cadherin with shRNA diminished the beta-catenin protein and partly resensitized Ph+ leukemia cells to imatinib despite the presence of stromal cells, suggesting VE-cadherin is a potential target in the treatment of Ph+ leukemia. PMID- 25443889 TI - Evaluation of drug-drug interactions for oncology therapies: in vitro-in vivo extrapolation model-based risk assessment. AB - AIMS: Understanding drug-drug interactions (DDI) is a critical part of the drug development process as polypharmacy has become commonplace in many therapeutic areas including the cancer patient population. The objectives of this study were to investigate cytochrome P450 (CYP)-mediated DDI profiles available for therapies used in the oncology setting and evaluate how models based on in vitro in vivo extrapolation performed in predicting CYP-mediated DDI risk. METHODS: A dataset of 125 oncology therapies was collated using drug label and approval history information, incorporating in vitro and clinical PK data. The predictive accuracy of the basic and net effect mechanistic static models was assessed using this oncology drug dataset, for both victim and perpetrator potential of CYP3A mediated DDI. RESULTS: The incidence of CYP3A-mediated interaction potential was 47%, 22% and 11% for substrates, inhibitors and inducers, respectively. The basic models for precipitants gave conservative predictions with no false negatives, whilst the mechanistic static models provided reasonable quantitative predictions (2.3-3-fold error). Further analysis revealed that incorporating DDI at the level of the intestine was in most cases over-predicting interaction magnitude due to overestimates of the rate and extent of oral absorption of the precipitant. Quantifying victim DDI potential was also demonstrated using fmCYP3A estimates from ketoconazole clinical DDI studies to predict the magnitude of interaction on co-administration with the CYP3A inducer, rifampicin (1.6-3.3 fold error). CONCLUSIONS: This work illustrates the utility and limitations of current DDI risk assessment approaches applied to a range of contemporary anti-cancer agents, and discusses the implications for therapeutic combination strategies. PMID- 25443890 TI - Mutant prevention concentrations of colistin used in combination with other antimicrobial agents against Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa clinical isolates. PMID- 25443891 TI - Emergence of novel bla(KPC-13) among carbapenem-resistant Enterobacteriaceae in Thailand. PMID- 25443892 TI - Randomized intervention for children with VesicoureReflux (RIVUR) Study: a new look at an old question? Commentary on antimicrobial prophylaxis for children with vesicoureteral reflux. PMID- 25443893 TI - The urinary catheter and its significant applications described by Avicenna (980 1037 AD) in the canon of medicine. PMID- 25443894 TI - Incidence and management of extended-spectrum beta-lactamase and quinolone resistant Escherichia coli infections after prostate biopsy. AB - OBJECTIVE: To provide an overview of the incidence, bacteriologic characteristics, and antimicrobial resistance in acute prostatitis after transrectal ultrasonography (TRUS)-guided prostate biopsy. MATERIALS AND METHODS: We reviewed the medical records of 9568 patients who underwent TRUS-guided biopsy between March 1995 and May 2013. These patients received oral quinolone and/or cephalosporin and intramuscular aminoglycoside as antibiotic prophylaxis. In patients with acute prostatitis, blood and urine cultures were obtained on hospital admission. The incidences of acute prostatitis and antimicrobial resistance were examined according to time period. RESULTS: A total of 11,345 cases of TRUS-guided biopsy were performed for 9568 patients. Acute prostatitis developed in 103 patients (0.91%). In 63 patients, the causative organism was isolated from blood and/or urine culture. The most frequent etiologic organism was Escherichia coli, which was present in 47 of 49 patients (95.9%) in blood and from 39 of 41 patients (95.1%) in urine. Extended-spectrum beta-lactamase (ESBL) producing E coli were detected continuously since 2008 and found in 10 patients (21.3%) in blood and 8 patients (20.5%) in urine. Forty-four patients (93.6%) in blood and 36 patients (92.3%) in urine of the positive cultures and all cases with ESBL-producing E coli infection showed resistance to quinolone. ESBL producing E coli were susceptible to imipenem, amikacin, and cefoxitin. CONCLUSION: In the treatment of acute prostatitis after TRUS-guided biopsy, quinolone is not an effective antimicrobial of choice. We should take into account antimicrobial-resistant patterns because of the high prevalence of quinolone resistance and emergence of an ESBL-producing strain. PMID- 25443895 TI - Editorial comment. PMID- 25443896 TI - Percutaneous nephrolithotomy during uninterrupted aspirin therapy in high cardiovascular risk patients: preliminary report. AB - OBJECTIVE: To determine the feasibility and safety of performing percutaneous nephrolithotomy (PCNL) in high-cardiovascular risk patients remaining on aspirin therapy. METHODS: We retrospectively reviewed all PCNLs performed by 3 fellowship trained endourologists at a single institution between July 2012 and January 2014. All patients remaining on aspirin for imperative indications through the day of surgery were evaluated for surgical outcomes and thromboembolic events. RESULTS: Of 281 PCNL procedures performed during the study period, 16 (5.7%) were performed in 14 patients taking aspirin, uninterrupted, through surgery. Mean surgery time was 66 minutes, mean estimated blood loss was 161 mL, and mean length of hospital stay was 2.8 days. All patients were stone free. There were no intraoperative complications. A total of 5 patients experienced a postoperative complication (n = 4, Clavien grade II; n = 1, Clavien grade IIIa). No patient experienced a perioperative thromboembolic or cardiac event. Three patients required a blood transfusion postoperatively, and none experienced delayed renal bleeding. CONCLUSION: PCNL can be performed safely and effectively in high cardiovascular risk patients continuing aspirin perioperatively. Compared with the potential sequelae of a thromboembolic or cardiac event, PCNL is associated with an acceptably low transfusion rate, and should be considered a viable treatment option for large renal stones in this population. PMID- 25443897 TI - Evaluating patients' symptoms of overactive bladder by questionnaire: the role of urgency in urinary frequency. AB - OBJECTIVE: To explain what role urinary urgency has on urinary frequency in patients with overactive bladder (OAB). MATERIALS AND METHODS: We prospectively enrolled 102 patients with OAB over a 6-week period. Patients were assessed with the OAB-q and a pilot questionnaire to identify which urinary symptoms were most bothersome and what underlying cause subjects attributed urinary frequency to. Associations between epidemiologic characteristics, OAB-q scores, and subject responses to the pilot questionnaire, were examined for statistical significance with the Pearson chi square test. RESULTS: The study population comprised 85% women and 15% men, with mean age 67.4 years and mean OAB-q score 54. Subjects reported their most bothersome symptom was: frequency 24.5%, urgency or urgency incontinence 48.0%, nocturia 27.5%. Of the patients most bothered by frequency, 64% identified the International Continence Society definition of urgency or "fear of leakage" as the underlying reason for their frequency. Overall, 82.4% and 48.0% of patients reported urgency or urgency incontinence as a symptom and most bothersome symptom respectively. However, when patients were specifically asked what drives their urinary frequency, these percentages increased to 89.2% and 63.7%. CONCLUSION: This pilot study confirms that urgency is a large factor underlying the drive to void frequently in OAB, even when patients do not admit to urgency as the most bothersome symptom. PMID- 25443898 TI - Incidence of adverse events after high doses of onabotulinumtoxinA for multiple indications. AB - OBJECTIVE: To determine the occurrence of all treatment-related adverse events (AEs), especially life-threatening AEs, after the injection of a cumulative dose of >360 units of onabotulinumtoxinA for multiple indications (neurogenic detrusor overactivity, lower limb spasticity, and so forth) within a 3-month interval. METHODS: This is a retrospective cohort study of patients who received >360 units of onabotulinumtoxinA within a 3-month interval, with at least 1 urologic indication for injection, between January 1, 2002 and January 1, 2013. The rate of treatment-related AE up to 8 days after injection and life-threatening AE up to 90 days after injection was compared between the injection sessions below and exceeding the maximum dosage recommendations. RESULTS: Thirteen patients met the study criteria. Eleven were female patients and had a diagnosis of multiple sclerosis. Sixty-five injection sessions involved >360 units of onabotulinumtoxinA administered within a 90-day interval. Median interval between injections was 54 days (interquartile range [IQR], 30-71 days) and median dose administered was 800 units (IQR, 600-1000 units). Seventy injection sessions involved <360 units of onabotulinumtoxinA administered >90 days after prior injection. Median interval between these injections was 113 days (IQR, 97-158 days) and median dose administered was 200 units (IQR, 100-300 units). The maximum cumulative dosage injected was 1900 units (1500 units for lower extremities and 400 units for bladder). This patient did not experience any AE. There was a total of 6 AEs (general and/or extremity weakness or leg pain) that occurred in 4 patients, of a total of 183 injection sessions. These AEs all eventually resolved. There were no life-threatening AEs in either group. CONCLUSION: This is the first report of patients receiving >360 cumulative units of onabotulinumtoxinA within a 3-month interval for multiple indications. There were no life-threatening AEs. This study provides preliminary data on administration of high doses of onabotulinumtoxinA for multiple indications. PMID- 25443899 TI - Processes of care and the impact of surgical volumes on cancer-specific survival: a population-based study in bladder cancer. AB - OBJECTIVE: To describe the relationships between procedure volume and late survival after cystectomy for muscle-invasive bladder cancer (MIBC) and explore variables explaining any effect. MATERIALS AND METHODS: Electronic records of treatment and surgical pathology reports were linked to a population-based registry to identify patients who underwent cystectomy during 1994-2008 in Ontario, Canada. Explanatory variables included adjuvant chemotherapy, lymph node dissection (LND), and margin status. A Cox proportional hazards regression model was used to explore associations between volume and cancer-specific survival (CSS) as well as overall survival. RESULTS: The cohort included 2802 MIBC patients treated with cystectomy. High-volume hospitals were more likely to have used adjuvant chemotherapy (25% vs 18%; P <.001), more likely to have performed an LND (83% vs 53%; P <.001), and associated with a lower 90-day mortality (6% vs 10%; P = .032). Low-volume hospitals had a lower 5-year CSS rate of 32% (28%-36%) compared with those of high-volume centers at 38% (33%-42%). Individual surgeon volume was similarly associated with both early- and long-term outcomes. In multivariate analysis, both surgeon and hospital volumes were associated with CSS and overall survival. The surgeon volume effect on long-term outcomes was modestly modified by indicators of the quality of the LND, with little effect of the other explanatory variables. CONCLUSION: Higher provider volume is associated with higher CSS in patients with MIBC in the general population. The volume effect was modestly mediated by the quality of LND. PMID- 25443900 TI - Editorial comment. PMID- 25443901 TI - Reply: To PMID 25443899. PMID- 25443903 TI - Editorial comment. PMID- 25443902 TI - Statin medications are associated with a lower probability of having an abnormal screening prostate-specific antigen result. AB - OBJECTIVE: To investigate how statin use is associated with the probability of having an abnormal screening prostate-specific antigen (PSA) result according to common PSA thresholds for biopsy (>2.5, >4.0, and >6.5 ng/mL). METHODS: We conducted a cross-sectional study of 323,426 men aged >=65 years who had a screening PSA test in 2003 at a Veterans Affairs facility. The primary predictor was the use of statin medications at the time of index screening PSA test. The main outcome was the screening PSA value. Poisson regressions were performed to calculate adjusted relative risks for having an abnormal screening PSA result according to statin usage. RESULTS: Percentages of men with PSA results exceeding commonly used thresholds of >2.5, >4.0, and >6.5 ng/mL were 21.0%, 7.6%, and 1.6%, respectively. These percentages decreased with statin use, increasing statin dose, duration of statin use, and potency of the statin. For example, after adjusting for age, the percentage of men having a PSA level >4.0 ng/mL ranged from 8.2% in non-statin users to 6.2% in men prescribed with >40 mg of simvastatin dose. Adjusted relative risks of having a PSA level >4.0 ng/mL were 0.89 (95% confidence interval [CI], 0.86-0.93), 0.87 (95% CI, 0.84-0.91), and 0.83 (95% CI, 0.80-0.87), respectively for men on simvastatin dose of 5-20, >20 40, and >40 mg vs non-statin users. CONCLUSION: Statin use is associated with a reduction in the probability that an older man will have an abnormal screening PSA result, regardless of the PSA threshold. This reduction is more pronounced with higher statin dose, longer statin duration, and higher statin potency. PMID- 25443904 TI - Reply: To PMID 25443902. PMID- 25443906 TI - Editorial comment. PMID- 25443905 TI - Technology diffusion and prostate cancer quality of care. AB - OBJECTIVE: To evaluate the association of technological capacity with prostate cancer quality of care. Technological capacity was conceptualized as a market's ability to provide prostate cancer treatment with new technology, including robotic prostatectomy and intensity-modulated radiotherapy (IMRT). METHODS: In this retrospective cohort study, we used data from the Surveillance, Epidemiology, and End Results-Medicare linked database from 2004 to 2009 to identify men with newly diagnosed prostate cancer (n = 46,274). We measured technological capacity as the number of providers performing robotic prostatectomy or IMRT per population in a health care market. We used multilevel logistic regression analysis to assess the association of technological capacity with receiving quality care according to a set of nationally endorsed quality measures, while adjusting for patient and market characteristics. RESULTS: Overall, our findings were mixed with only subtle differences in quality of care comparing high-tech with low-tech markets. High robotic prostatectomy capacity was associated with better adherence to some quality measures, such as avoiding unnecessary bone scans (79.8% vs 73.0%; P = .003) and having follow-up with urologists (67.7% vs 62.6%; P = .023). However, for most measures, neither high robotic prostatectomy nor high-IMRT capacity was associated with significant increases in adherence rates. In fact, for 1 measure (treatment by a high-volume provider), high-IMRT capacity was associated with lower performance (23.4% vs 28.5%; P <.001). CONCLUSION: Our findings suggest that new technology is not clearly associated with higher quality of care. To improve quality, more specific efforts will be needed. PMID- 25443908 TI - Editorial comment. PMID- 25443907 TI - The impact of the use of aspirin and other nonsteroidal anti-inflammatory drugs on the risk of prostate cancer detection on biopsy. AB - OBJECTIVE: To evaluate the association between nonsteroidal anti-inflammatory drug (NSAID) use and the risk of prostate cancer (PC) detection in men undergoing biopsy. METHODS: Men were identified using our academic institution's prospectively maintained prostate biopsy database. Patients were classified as aspirin (ASA) users, users of other NSAIDs, or nonusers. The primary outcome was any PC on biopsy, and the secondary outcome was clinically significant PC (CSPC; Gleason sum >=7). Multivariate logistic regression analyses were performed to adjust for a priori defined clinical confounders. RESULTS: Of 839 patients, 408 (48.6%) were diagnosed with PC and 201 (24.0%) had CSPC. A higher proportion of ASA users (63.5%) and other NSAID users (61.2%) had PC compared with nonusers (41.9%; P <.001). CSPC was more common among ASA users (34.9%; P <.001) compared with other NSAID users (20.0%) and nonusers (20.9%). In multivariate regression analyses, ASA use (odds ratio [OR] = 2.04; 95% confidence interval [CI] = 1.32 3.13; P = .001) and other NSAID use (OR = 2.42; 95% CI = 1.36-431; P = .003) were associated with higher odds of PC detection, whereas ASA use was associated with higher odds of CSPC (OR = 1.62; 95% CI = 1.00-2.62; P = .048). CONCLUSION: In men undergoing biopsy, ASA and other NSAID use were associated with increased probability of detecting PC, whereas ASA use was associated with the risk of detecting CSPC. Although NSAID use might have a protective biological effect against PC, men who develop elevated prostate-specific antigen levels while on NSAIDs may nonetheless be less likely to have an inflammatory etiology and more likely to harbor PC. It may be warranted for clinicians to consider the influence of NSAIDs when evaluating patients being considered for biopsy. PMID- 25443909 TI - Reply: To PMID 25443907. PMID- 25443910 TI - Two-port laparoscopic radical cystectomy with reusable umbilical system: a feasibility study. AB - OBJECTIVE: To describe the technique and report outcomes of laparoscopic radical cystectomy using 2 ports (2-port LRC) for muscle-invasive bladder cancer. PATIENTS AND METHODS: Prospective study was performed between November 2011 and October 2012 to standardize 2-port LRC, lymph node dissection, and urinary diversion. Twenty patients were intervened (8 ileal conduit, 12 neobladder) and followed up for >1 yr. Median follow-up was 75.5 weeks (interquartile range, 65.2 86 weeks). A reusable system placed through the umbilicus and laparoscopic curved instruments with double rotation, plus one 10-mm extra port placed in the right iliac fossa were used. Neobladder or conduit was performed extracorporeally. Preoperative, perioperative, and pathologic outcomes and long-term security data are presented. RESULTS: Median age was 69.5 years; body mass index, 27.4 kg/m(2); operative time, 335 minutes; estimated blood loss, 337 mL; hospital stay, 9 days; intraoperative transfusion rate, 10%; and visual analog pain score, 3 at day 3. Surgical margin was positive in a case (5%); 3 (15%) were pT0, 2 (10%) pT1, 5 (25%) pT2, 6 (30%) pT3a, 3 (15%) pT3b, and 1 (5%) pT4. The number of nodes removed was 18.5 (interquartile range, 16-29.2), 4 (20%) positive. Complications were major in 2 (10%; fecal peritonitis and urinary sepsis) and minor in 4 (20%; ileus and 3 postoperative transfusion) cases. No case required additional analgesia. Incision was totally hidden in the umbilicus. Continence rate in neobladders was 91.7% at daytime and 75% at nighttime. Study limitation was the absence of a comparative cohort. CONCLUSION: Umbilical 2-port LRC is feasible with good oncologic and functional outcomes, low postoperative pain, and absence of abdominal wall complications. Difficulties have slowed laparoendoscopic single site radical cystectomy, but umbilical 2-port LRC is a very acceptable alternative for minimally invasive surgery of muscle-invasive bladder cancer. PMID- 25443911 TI - Robotic-assisted laparoscopic implantation of artificial urinary sphincter in women with intrinsic sphincter deficiency incontinence: initial results. AB - OBJECTIVE: To investigate the feasibility, safety, and functional results of robotic-assisted artificial urinary sphincter (R-AUS) laparoscopic implantation in women with stress urinary incontinence due to intrinsic sphincter deficiency. PATIENTS AND METHODS: Six women underwent an R-AUS implantation between 2012 and 2013. The mean age was 65 +/- 9.6 years. Five patients had previous surgery for incontinence. The mean duration of follow-up was 14.3 months. A transperitoneal approach with a lateral positioning of the robotic arms was performed. The cuff implantation, positioning of the reservoir, and the pump were carried out similarly to the laparoscopic technique. Operative time, intraoperative occurrence of injuries of the bladder or vagina, postoperative complications, and continence (pad per day) were assessed. RESULTS: The R-AUS implantation was feasible in all cases without intraoperative injury and 1 grade 1 postoperative complication. Mean operative time, postoperative bladder catheterization, and hospitalization time were 210 +/- 32 minutes, 7 days, and 6 days, respectively. At the end of the follow-up, 83% of cases were fully continent. CONCLUSION: R-AUS implantation in incontinent women with intrinsic sphincter deficiency was feasible and safe with good functional results. More data are needed before concluding to the superiority of this new technique compared with open or laparoscopic approaches. PMID- 25443912 TI - Extraperitoneal approach for robotic-assisted simple prostatectomy. AB - OBJECTIVE: To present the experience with the extraperitoneal approach for robotic-assisted simple prostatectomy (RASP) in a technique replicating the vesicocapsular incision technique of open surgery. PATIENTS AND METHODS: RASP was performed on patients with a prostate volume of >80 cm(3) with an indication for open enucleation of the prostate. Preoperatively, all patients were evaluated by uroflowmetry, prostate-specific antigen level, and postvoid residual measurement, as well as by the International Prostate Symptom Score questionnaire. All perioperative data were recorded in a prospective database. Follow-up appointments included the aforementioned measurements and were scheduled at 1 and 6 months postoperatively. RESULTS: Ten RASP procedures were successfully performed by the extraperitoneal approach. Mean patient age and prostate volume were 63.1 years (range, 55-74 years) and 129.4 cm(3) (range, 90-170 cm(3)), respectively. Mean operative time was 122.5 minutes (range, 85-140 minutes) and represented the time from the first incision to the closure of the all incisions. The estimated blood loss was minimal (mean value, 230 mL). Transfusions were not necessary. Mean catheterization period was 7.4 days (range, 6-8 days). The symptomatology, as reported by the International Prostate Symptom Score, was improved at the follow-up appointments in comparison with the baseline values. One case of prolonged fever was noted postoperatively and managed by antibiotics. CONCLUSION: The extraperitoneal approach for RASP proved to be efficient in the management of large prostates. The results are directly comparable with the current available experience with transperitoneal RASP. The extraperitoneal RASP seems to favorably compare with the open simple prostatectomy, while the results are at least comparable with those of conventional laparoscopic approach. PMID- 25443913 TI - Impact of a single-surgeon learning curve on complications, positioning injuries, and renal function in patients undergoing robot-assisted radical prostatectomy and extended pelvic lymph node dissection. AB - OBJECTIVE: To assess the impact of a single-surgeon learning curve on complications, positioning injuries, and renal function in patients undergoing robot-assisted radical prostatectomy and extended pelvic lymph node dissection for intermediate- or high-risk clinically localized prostate cancer. METHODS: From November 2008 to October 2012, a total of 233 consecutive patients were treated by a single surgeon experienced in open and laparoscopic procedures. Four subgroups of patients (1: cases 1-59; 2: 60-117; 3: 118-175; and 4: 176-233) were compared. Complications were classified according to the modified Clavien system. Serum creatine kinase, as an indicator of tissue injury, was measured before, during, and for 5 days after surgery. Renal function monitoring was started preoperatively and ended at discharge. Minimum follow-up was 3 months. Variables were compared using chi-square and Wilcoxon tests. RESULTS: Overall, 115 complications were reported in 98 of 233 patients (42%) and significantly decreased after 175 procedures (P = .028). Minor complications (Clavien grades 1 2) represented the most frequent events (86 of 115 [75%]), with a significant drop in group 4 (P <.01). Similarly, the rate of positioning injuries (groups 1 4: 31%, 29%, 29%, and 7%, respectively) showed a significant improvement in group 4 (P = .023). Creatine kinase levels significantly decreased with increased experience (group 1 vs groups 2-4: P <.01). Renal function was unaltered postoperatively. CONCLUSION: A surgeon with extensive open and laparoscopic experience presents a safe learning curve in regard to robot-assisted radical prostatectomy and extended pelvic lymph node dissection. With increasing experience, the rates of overall and positioning-related complications significantly decrease after 175 procedures. No detrimental effect on renal function is to be expected. PMID- 25443914 TI - Penile fracture: outcomes of early surgical intervention. AB - OBJECTIVE: To report a series of penile fractures, describing preoperative evaluation, surgical repair, and long-term outcomes. PATIENTS AND METHODS: Medical records from Northwestern Memorial Hospital and Oregon Health & Science University from 2002 to 2011 were reviewed. Clinical presentation, preoperative evaluation, time from injury, mechanism and site of injury, and presence of urethral injury were assessed. Outcomes including erectile dysfunction, penile curvature, and voiding symptoms were evaluated using International Prostate Symptom Score and International Index of Erectile Function scores. RESULTS: Twenty-nine patients with 30 separate episodes of penile fractures presenting to the emergency room were identified. Mean patient age was 43 +/- 9.6 years. The time from presentation to the initiation of surgery was 5.5 +/- 4.4 hours. Mechanism of injury was intercourse in 26 of 30 fractures with the remaining attributed to masturbation or "rolling over." Immediate surgical repair was offered to all patients. Twenty-seven patients underwent surgery. Urethral injury was noted in 5 of the 27. The site of fracture was at the proximal shaft in 11, mid shaft in 12, and distal shaft in 4 patients. The mean follow-up period was 14.3 +/- 15.8 weeks. Nine patients reported new mild erectile dysfunction or penile curvature. One patient reported new irritative voiding symptoms. CONCLUSION: The most common mechanism of penile fracture was from sexual intercourse, and frequent concomitant urethral injuries were observed. The frequency of concomitant urethral injury was higher than in previous studies. Although we observed high incidence of erectile dysfunction or penile curvature with early surgical repair, we retain it as the favored approach. PMID- 25443915 TI - Efficacy of pioglitazone on erectile function recovery in a rat model of cavernous nerve injury. AB - OBJECTIVE: To examine the effect of pioglitazone on erectile function in a rat model of postprostatectomy erectile dysfunction. METHODS: Twenty adult rats were divided into 4 groups: (a) sham, (b) control--bilateral cavernosal nerve crush injury (BCNI), (c) BCNI + low-dose pioglitazone (PioL), and (d) BCNI + high-dose pioglitazone (PioH). Sham and control rats were administered phosphate-buffered saline, whereas PioL and PioH rats received 0.65 and 6.5 mg/kg of pioglitazone, respectively. All treatments were administered by oral gavage for 14 days. After treatment, animals underwent surgery for endpoint cavernosal response to define hemodynamic parameters of erectile function, reported as the ratio of intracavernosal pressure to mean arterial pressure. Corporal tissue was retrieved for histologic and molecular analysis. RESULTS: Animals treated with pioglitazone experienced dose-dependent improvements in the ratio of intracavernosal pressure to mean arterial pressure, with the PioH group achieving results similar to the sham group: sham, 0.774; BCNI, 0.421; PioL, 0.616; PioH, 0.758 (P = .0006). PioH animals demonstrated increased expression of endothelial nitric oxide (eNOS) and neuronal nitric oxide (nNOS), whereas both PioL and PioH animals had increased staining for anti--smooth muscle actin antibody and nonsignificant increases in cyclic guanosine monophosphate (cGMP). CONCLUSION: Pioglitazone improves erectile function in rats undergoing BCNI via a nitric oxide--mediated pathway. PMID- 25443916 TI - Evaluation of the prognostic significance of altered mammalian target of rapamycin pathway biomarkers in upper tract urothelial carcinoma. AB - OBJECTIVE: To evaluate the prognostic value of altered mammalian target of rapamycin (mTOR) pathway biomarkers in upper tract urothelial carcinoma (UTUC). MATERIALS AND METHODS: We performed a multi-institutional review of clinical and pathologic information on patients receiving extirpative surgery for UTUC from 1990 to 2008. Immunohistochemistry for phosphorylated-S6, mTOR, phosphorylated mTOR, PI3K, phosphorylated-4EBP1, phosphorylated-AKT, PTEN, HIF-1a, raptor, and cyclin D was performed on tissue microarrays from radical nephroureterectomy (RNU) specimens. Prognostic markers were identified and the significance of altered markers was assessed with the Kaplan-Meier analysis and the Cox regression analysis. RESULTS: Six hundred twenty patients were included. Over a median follow-up of 27.3 months, 24.6% of patients recurred and 21.8% died of UTUC. On multivariate analysis, PI3K (odds ratio, 1.28; P = .001) and cyclin D (odds ratio, 3.45; P = .05) were significant predictors of clinical outcomes. Cumulative marker score was defined as low risk (no altered markers or 1 altered marker) or high risk (cyclin D and PI3K altered). Patients with high-risk marker score had a significantly higher proportion of high-grade disease (91% vs 71%; P <.001), non-organ-confined disease (61% vs 33%; P <.001), and lymphovascular invasion (35% vs 20%; P = .001). The Kaplan-Meier analysis demonstrated a significant difference in cancer-specific mortality (CSM) based on the risk groups. On Cox regression multivariate analysis for CSM incorporating non-organ confined disease, grade, lymphovascular invasion, tumor architecture, and marker score, high-risk biomarker score was an independent predictor of CSM (hazard ratio, 1.5; 95% confidence interval, 1.04-2.3; P = .03). CONCLUSION: Alterations in mTOR pathway correlate with established adverse pathologic features and independently predict inferior oncologic outcomes. Incorporation of mTOR-based marker profiles may allow for enhanced patient counseling, risk stratification, and individualized treatment regimens. PMID- 25443918 TI - Editorial comment. PMID- 25443917 TI - Is extended pharmacologic venous thromboembolism prophylaxis uniformly safe after radical cystectomy? AB - OBJECTIVE: To quantitate the risk of clinically significant renal function deterioration after radical cystectomy (RC), which could result in supratherapeutic levels of low-molecular-weight heparin (LMWH) and increased risk of bleeding events with the use of extended pharmacologic venous thromboembolism prophylaxis (EPVTEP) after hospital discharge. METHODS: Patients undergoing RC between 2006 and 2011 were identified from the institutional registry. Estimated glomerular filtration rate (eGFR) was calculated and categorized as preoperative, discharge, and nadir. Perioperative eGFR trends in patients who would have been candidates for EPVTEP were evaluated. RESULTS: Three hundred four patients with eGFR >30 mL/min/1.73 m(2) at the time of hospital discharge were included in the analysis as potentially eligible for EPVTEP. Large portion of patients (43%) exhibited decline in eGFR after discharge. Importantly, 13.0% of patients (n = 40), who would have qualified for EPVTEP at discharge, experienced nadir GFR below the 30-mL/min/1.73 m(2) threshold value at which LMWH would have become supratherapeutic. The odds ratio for developing a GFR <30 mL/min/1.73 m(2) was 9.1 (95% confidence interval, 4.3-19.3; P <.001), comparing those with a discharge GFR >=60 mL/min/1.73 m(2) with those with a discharge GFR <60 mL/min/1.73 m(2). CONCLUSION: More than 10% experienced an eGFR, which would have rendered LMWH supratherapeutic and potentially would have placed the patient at risk for clinically significant bleeding. Although postoperative venous thromboembolic event after RC is a recognized concern, a better understanding of the risks of EPVTEP is needed before this strategy is universally adopted in patients undergoing RC. PMID- 25443919 TI - Reply: To PMID 25443917. PMID- 25443920 TI - Salvage high-intensity focused ultrasound for patients with recurrent prostate cancer after brachytherapy. AB - OBJECTIVE: To report our experience with salvage high-intensity focused ultrasound (HIFU) in patients with local failure after brachytherapy for prostate cancer. PATIENTS AND METHODS: Whole-gland HIFU was administered to prospectively recruited patients with local histologic failure after brachytherapy at 2 institutions in the United Kingdom and Canada. Functional and oncologic outcomes of the procedure were analyzed. RESULTS: Nineteen patients underwent the treatment, 12 with Gleason sum 7 and 5 with Gleason sum 8 at recurrence. Thirteen men had grade-3a or -3b complications by the Clavien system; there were no grade 4 or -5 complications. The most common postoperative complication was dysuria, which was self-limited. Three men developed rectourethral fistulae. The overall continence rate was 68.4%. At a mean follow-up of 51.6 months, all men were alive. The overall biochemical recurrence-free survival rate was 66.7% and 73.3% using the "nadir prostate-specific antigen level" +1.3 ng/mL and +2 mg/ml criteria, respectively. This study is limited by the small cohort size, relatively short follow-up period, and heterogeneity of the patient population. CONCLUSION: In this, the largest prospective series to date, we demonstrate that salvage HIFU for locally recurrent prostate cancer after failed primary brachytherapy has encouraging disease control results, albeit with a relatively high complication rate. PMID- 25443921 TI - Editorial comment. PMID- 25443922 TI - Reply: To PMID 25443920. PMID- 25443923 TI - Low percentage of free prostate-specific antigen (PSA) is a strong predictor of later detection of prostate cancer among Japanese men with serum levels of total PSA of 4.0 ng/mL or less. AB - OBJECTIVE: To investigate the effect of the percentage of free prostate-specific antigen (%fPSA) on future prostate cancer risk. MATERIALS AND METHODS: We examined serum total PSA (tPSA) and %fPSA annually in a prostate cancer-screening cohort between July 2001 and June 2011. Men with tPSA >4.0 ng/mL or tPSA of 2.0 4.0 ng/mL with %fPSA <=12% were screened as positive and were recommended to undergo a biopsy. The study population consisted of 6368 men, aged 40-79 years, who had tPSA <=4.0 ng/mL at initial screening and who subsequently underwent 1 or more screenings. We calculated the cumulative risk and hazard ratio of prostate cancer stratified by the initial %fPSA groups as quartiles of prostate cancer patients. RESULTS: During a median follow-up of 36 months, 119 men were diagnosed with prostate cancer. The lowest quartile of %fPSA (<13.3%) was associated with a 21.2-fold higher risk of having prostate cancer compared with the highest quartile (>22.2%). For the subset with an initial tPSA <=1.0 ng/mL, all men diagnosed with cancer had an initial %fPSA <=33.3% (median). For the subset with tPSA >1.0 ng/mL, men with %fPSA <=23.0% (median) had significantly higher risk for cancer than those with %fPSA >23.0% (P <.0001). Of the 114 men with prostate cancer in whom pathologic findings were available, 79 (69.3%) had a Gleason score >=3 + 4 = 7. CONCLUSION: A low %fPSA is a strong predictor of a subsequent diagnosis of prostate cancer among men with tPSA levels <=4.0 ng/mL. Measurement of %fPSA might enhance the detection of high-grade cancer that warrants aggressive treatment. PMID- 25443924 TI - Editorial comment. PMID- 25443925 TI - Histoscanning has low sensitivity and specificity for seminal vesicle invasion. AB - OBJECTIVE: To examine the accuracy of HistoScanning (HS) in detecting seminal vesicle (SV) invasion (SVI) within prostate cancer (PCa) patients. METHODS: We relied on our prospective institutional database. Patients who received HS before radical prostatectomy were included in the study cohort. An experienced HS examiner retrospectively reanalyzed the HS data blinded to patient characteristics and pathologic results. The HS results for every single SV were compared with the corresponding findings from the final pathologic report after radical prostatectomy. An area under the receiver operating characteristic curve for the prediction of SVI by HS was calculated. Depending on HS signal volume cut offs (>0, >0.2, and >0.5 mL), the sensitivity, specificity, positive predictive value, and negative predictive value for the prediction of SVI were assessed. RESULTS: Overall, 131 patients and 262 SVs were assessable. Of those, 23 (17.5%) men had SVI, and 39 (14.9%) single SVs were infiltrated by tumor overall. The area under the receiver operating characteristic curve for predicting SVI by HS was 0.54. Depending on the HS signal volume cut-offs (>0, >0.2, and >0.5 mL), the sensitivity, specificity, positive predictive value, and negative predictive value for predicting SVI were 76.9%, 10.8%, 13.1%, and 72.7%; 61.5%, 24.2%, 12.4%, and 78.3%; and 46.2%, 50.2%, 14.0%, and 84.2%, respectively. CONCLUSION: HS results did not allow a reliable prediction of SVI within PCa patients. Despite, the application of HS signal volume cut-offs (>0.2 and >0.5 mL), the prediction of SVI within PCa patients remained insufficient. PMID- 25443927 TI - Editorial comment. PMID- 25443926 TI - Reflex PCA3 messenger ribonucleic acid testing: validation of postbiopsy urine samples and correlation with prostate biopsy findings in ~2000 patients. AB - OBJECTIVE: To validate post-transrectal ultrasonography (TRUS) prostate biopsy (bx) urine samples for PCA3 messenger ribonucleic acid testing, including correlation of PCA3 score with concurrent bx findings. METHODS: From July 2008 to July 2010, 2015 patients had urine collected immediately after a TRUS-guided prostate bx. Excluded were men with history of prostate carcinoma (CaP), <6 or >=24 bx cores, and/or prostate-specific antigen (PSA) level >=50 ng/mL, resulting in 1909 included men. PCA3 and PSA messenger ribonucleic acid were quantitated using transcription-mediated amplification. A PCA3 score of >=35 was considered positive. RESULTS: Mean and median ages were 66 years. Mean and median PSA levels were 6.7 and 5.1 ng/mL, respectively. Bxs were benign in 970 (50.8%), CaP in 726 (38%), high-grade prostatic intraepithelial neoplasia (HGPIN) in 124 (6.5%), and atypical in 89 (4.7%). PCA3 test was informative in 1887 (98.8%) patients. Means +/- standard deviations (median) of PCA3 scores for benign, HGPIN, atypical, and CaP were 22.3 +/- 27.9 (12.8), 37.6 +/- 43.2 (24.1), 35.7 +/- 36.2 (25.7), and 46.9 +/- 48.1 (31.6; P <.05 benign vs CaP, benign vs HGPIN and atypical, HGPIN and atypical vs CaP). Sensitivity and specificity of PCA3 for CaP were 46.3% and 78.7%, respectively. CaP risk increased with progressively higher PCA3 score ranges from 14.8% for PCA3 <5 to 66.7% for PCA3 >100. Area under the curve (AUC) for the PCA3 receiver operating characteristics was not significantly different in men without prior bx (AUC = 0.716) compared with men with at least 1 prior nonpositive bx (AUC = 0.702). CONCLUSION: Post-TRUS bx urine is a valid sample for PCA3 testing. Patients with a negative bx and a positive PCA3 test may have a higher likelihood of unsampled CaP. PMID- 25443928 TI - Reply: To PMID 25443926. PMID- 25443929 TI - Editorial comment. PMID- 25443930 TI - Reply: To PMID 25443926. PMID- 25443931 TI - Metabolic syndrome and lower urinary tract symptoms in patients with benign prostatic enlargement: a possible link to storage symptoms. AB - OBJECTIVE: To evaluate the association between metabolic syndrome (MetS) and lower urinary tract symptoms (LUTS) in patients with benign prostatic enlargement (BPE). MATERIALS AND METHODS: From 2009 onward, a consecutive series of patients with LUTS-BPE were enrolled. Patients were evaluated using the International Prostate Symptom Score (IPSS) and ultrasonographic prostate volume. Body mass index, waist circumference, and blood pressure were measured. Blood samples were collected for prostate-specific antigen levels, fasting glucose levels, triglyceride levels, high-density lipoprotein levels, and testosterone levels. MetS was defined according to Adult Treatment Panel III (ATP III). The risk of detecting LUTS as a function of MetS was evaluated using the logistic regression analysis. RESULTS: A total of 431 patients were enrolled with a median age and prostate-specific antigen level of 67 years (61-73 years) and 3 ng/mL (2.2-4.3 ng/mL), respectively; median body mass index was 27 kg/m2 (25-29 kg/m(2)); median testosterone was 3.9 ng/mL (3.1-4.7 ng/mL); median IPSS was 8 (4-14), median prostate volume was 43 mL (35-56 mL). One hundred three of 431 patients (23.8%) presented with a MetS. Patients with MetS presented a higher IPSS storage subscore (4; interquartile range, 2-7 vs 3; interquartile range 1-7; P = .002). On multivariate analysis, the presence of MetS was associated with an increased risk of an IPSS storage subscore >=4 (odds ratio, 1.782; 95% confidence interval, 1.045-3.042; P = .030). CONCLUSION: In our single-center study, MetS is associated with an increased risk of storage symptoms in patients with BPE. Although these results should be confirmed, and the pathophysiology is yet to be understood, it can be assumed that MetS and its metabolic components should be considered as possible factors involved in LUTS-BPE pathogenesis. PMID- 25443932 TI - Late ureteral obstruction after endoscopic treatment of vesicoureteral reflux with polyacrylate polyalcohol copolymer. AB - OBJECTIVE: To investigate the incidence and presentation of ureteral obstruction after endoscopic injection of polyacrylate polyalcohol copolymer (PPC) for the treatment of vesicoureteral reflux, and to analyze its possible causes, together with histopathologic assessment. PATIENTS AND METHODS: The data of 189 patients who underwent endoscopic injection of PPC between May 2011 and December 2013 were retrospectively reviewed. After the injection, patients were followed up by urinalysis and ultrasonography monthly for 3 months. Control voiding cystouretrography was performed in the third postoperative month. Patients were then followed up by ultrasound every 3 months. If a new-onset hydroureteronephrosis (HUN) was observed, control ultrasound was performed monthly to follow the change in the degree of HUN. If a moderate or severe HUN was observed, technetium-99m mercaptoacetyltriglycine or dimercaptosuccinic acid scintigraphy was performed. For patients who needed open surgery, Cohen ureteroneocystostomy was performed. The distal 1 cm of the ureters was resected and examined histopathologically. RESULTS: One hundred eighty-nine patients with 268 refluxing ureters underwent endoscopic injection of PPC. Ureteral obstruction was observed in 3 ureters (1.1%), in 3 female patients of whom the degrees of reflux were grade 4, 5, and 5, respectively. Obstruction showed late onset in all 3 patients. Manifestations of obstruction included pain in 2 patients and recurrent febrile urinary tract infection with loss of function in scintigraphy in 1. All 3 patients underwent open ureteroneocystostomy. CONCLUSION: PPC may cause ureteral obstruction several months or even years after injection. Patients who undergo endoscopic treatment of PPC need long-term follow-up, despite reflux showing complete resolution. PMID- 25443933 TI - Beneficial effect of nifedipine on testicular torsion-detorsion injury in rats. AB - OBJECTIVE: To investigate the effect of nifedipine on testicular torsion detorsion injury. MATERIALS AND METHODS: Twenty-four adult male Sprague-Dawley rats were randomly divided into 3 groups, each containing 8 rats. Rats in the control group underwent a sham operation of the left testis. In the torsion detorsion (T/D) group, the left testis was twisted at 720 degrees for 3 hours. After 3 hours of reperfusion, at the end of the experiment, the testes were removed. Rats in the treatment group received the same surgical procedure as the T/D group, but nifedipine was administered intraperitoneally (100 MUg/kg) 30 minutes before the time of detorsion. RESULTS: Unilateral testicular torsion detorsion caused a significant increase in the malondialdehyde level and apoptosis and caused significant decreases in superoxide dismutase and glutathione peroxidase activities in ipsilateral testes. The rats treated with nifedipine had a significant decrease in malondialdehyde level and apoptosis and had significant increases in superoxide dismutase and glutathione peroxidase activities in ipsilateral testes compared with those of the T/D group. CONCLUSION: These results suggest that biochemical and histological torsion detorsion injury occurs in the ipsilateral testes after a 3-hour torsion and 3 hour detorsion and that administration of nifedipine before detorsion prevents ischemia/reperfusion cellular damage in the testicular tissue. PMID- 25443934 TI - Transumbilical single-incision laparoscopic versus conventional laparoscopic upper pole heminephroureterectomy for children with duplex kidney: a retrospective comparative study. AB - OBJECTIVE: To present our experience regarding transumbilical single-incision laparoscopic heminephroureterectomy (SILH) in children with duplex kidney anomalies, and to investigate its feasibility and safety compared with those of conventional laparoscopic heminephroureterectomy (CLH). MATERIALS AND METHODS: A matched-pair study comparing 34 SILHs and 34 CLHs performed by a single surgeon from 2007 to 2013 was presented. All SILHs were performed through a 2-cm periumbilical incision by using the port-access system, whereas CLH cases were performed via a transperitoneal 3-port approach. The groups were matched for age, gender, weight, laterality, and surgical indication of the patients. Data including demographics and perioperative and short-term outcomes of the patients were retrospectively compared. RESULTS: The 2 groups were comparable in demographics, and surgical indications of the patients (P >.05). No significant difference was observed between SILH and CLH cases in terms of median operative time (105 vs 97 minutes; P = .06), estimated blood loss (22 vs 25 mL; P = .91), interval for oral intake (12 vs 12 hours; P = .69), analgesic requirement (9 vs 6 cases; P = .38), transfusion rate (0% for both; P = 1.00), complication rate (2.9% vs 0%; P = 1.00), postoperative hospital stay (5.0 vs 4.5 days; P = .59), and renal functional loss of the operated side at 3 months after surgery (5.4% vs 5.2%; P = .60). CONCLUSION: SILH is feasible and safe in the hands of an experienced pediatric laparoscopic surgeon. Although the outcomes were comparable, better subjective cosmetic results of SILH were achieved. PMID- 25443935 TI - The role of ultrasonography in predicting vesicoureteral reflux. AB - OBJECTIVE: To evaluate the accuracy of renal and bladder ultrasonography (RBU) in predicting vesicoureteral reflux (VUR) in infants and children. MATERIALS AND METHODS: A total of 134 children who had VUR demonstrated on voiding cystourethrography (VCU) and also had RBU within 1 month of the VCU were included in the study, which took place between January 2005 and December 2012. VUR and hydronephrosis were graded with standard methods on VCU and RBU, respectively. Using VCU findings of reflux as the gold standard, diagnostic accuracy measures were performed for hydronephrosis and ureteral visualization on RBU, including sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. RESULTS: Reflux grade was significantly associated with the degree of hydronephrosis (P = .0032). The sensitivity, negative predictive value, and accuracy of ultrasonography in predicting reflux was significantly higher for grade IV+ or grade V reflux compared with lower reflux grades. Also, the specificity of ultrasonography in predicting reflux was constant and at high level across all reflux grades, suggesting that ultrasonography is a good diagnostic screening tool. CONCLUSION: Normal RBU is rare with grade IV-V reflux, and moderate to severe hydronephrosis is rare with reflux grades 18 years). MATERIALS AND METHODS: A retrospective review of the electronic medical records of patients with exstrophy-epispadias complex managed from January 2001 to December 2010 was undertaken. Patients aged >18 years at presentation, with detailed medical records were selected. They were classified into 2 groups: group A (previously untreated) and group B (residual defects or complications after childhood surgery). RESULTS: Thirty-nine patients with exstrophy-epispadias complex presented to our institution over this 10-year period. Of these 26 were adults (aged >18 years; range, 18-48 years). Detailed medical records could be obtained for 21 of them and they were included. Group A consisted of 4 patients- 2 male and 2 female. All underwent cystectomy; 2 had an ileal conduit and 2 had ureterosigmoidostomy (Mainz II). All had improved quality of life and a stable renal function at follow-up. Group B consisted of 17 patients. Mean number of surgeries attempted previously was 4.4 (range, 2-13). Presentation was varied but primarily involved incontinence of urine (n = 12). Four patients were lost to follow-up, 2 were managed conservatively, and 11 underwent a surgical procedure. All patients returned to normal activity with an improvement in the quality of life postoperatively. CONCLUSION: Exstrophy-epispadias complex is difficult to manage in resource-poor settings associated with illiteracy and poverty. However, successful rehabilitation and an improved quality of life are possible even in cases presenting in adults. PMID- 25443943 TI - Re: Crawford et al.: long-term tolerability and efficacy of degarelix: 5-year results from a phase III extension trial with a 1-arm crossover from leuprolide to degarelix (Urology 2014;83:1122-1128). PMID- 25443944 TI - Reply by the authors. PMID- 25443945 TI - Comparison between subcutaneous injection of basic fibroblast growth factor hydrogel and intracavernous injection of adipose-derived stem cells in a rat model of cavernous nerve injury. AB - OBJECTIVE: To compare the effects of subcutaneous penile injection of basic fibroblast growth factor (bFGF)-hydrogel and intracavernous injection of human adipose-derived stem cells (h-ADSCs) on improving erectile function in a rat model of cavernous nerve injury. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were randomly divided into 5 groups (n = 10 per group): age-matched control (normal group), bilateral cavernous nerve injury (BCNI group), penile subcutaneous injection of hydrogel after BCNI (hydrogel group), penile subcutaneous injection of bFGF-hydrogel after BCNI (bFGF-hydrogel group) and intracavernous injection of h-ADSCs after BCNI (ADSC group). Four weeks after the treatment, all rats underwent an erectile function test. Then, penile tissue was harvested for immunohistological analysis of bFGF, phalloidin, and cluster of differentiation (CD) 31. The cyclic guanosine monophosphate (cGMP) level of the corpus cavernosum was quantified by cGMP assay. RESULTS: From the functional test and immunohistological result, we observed that bFGF-hydrogel and h-ADSCs injection significantly elevated intracavernous pressure. The evaluation of filamentous actin content, CD31 expression, and cGMP concentration in the corpus cavernosum were meaningfully increased in the bFGF-hydrogel and ADSC groups compared with BCNI group. The bFGF released from bFGF-hydrogel prevented smooth muscle atrophy. Moreover, bFGF expression was significantly increased in bFGF hydrogel group. CONCLUSION: The subcutaneous injection of bFGF-hydrogel prevented smooth muscle atrophy, increased the intracavernous pressure, and improved erectile function like an intracavernous injection of h-ADSCs. PMID- 25443946 TI - Effects of alpha1 antagonist and cholinesterase inhibitor on cystometric parameters in lumbar canal stenosis rats with underactive bladder. AB - OBJECTIVE: To examine the lower urinary tract function of a rat lumbar canal stenosis (LCS) model by in vivo cystometry before and after alpha1 adrenoceptor antagonist or cholinesterase inhibitor administration. MATERIALS AND METHODS: One small hole was drilled at the fifth lumbar vertebral arch, and a rectangular piece of silicone rubber was inserted into the L5-L6 epidural space. Two weeks after the surgery, awake cystometry was performed before and after the oral administration of the vehicle, tamsulosin (TAM, 0.03 and 0.1 mg/kg), or distigmine (DIS, 0.3 and 1 mg/kg). We compared the awake cystometry parameters before and after drug administration. RESULTS: The LCS rats showed a large maximum cystometric capacity (MCC) and a high residual urine rate with a lower maximum bladder pressure during micturition (Pmax). TAM and DIS significantly decreased the pressure at the onset of voiding contraction, MCC, and postvoid residual urine volume. Residual urine rate was also significantly decreased by DIS at 0.3 and 1.0 mg/kg, and TAM at 0.03 mg/kg. DIS significantly increased the frequency of nonvoiding contractions per minute. Pmax was not significantly different even after administration of DIS. CONCLUSION: The LCS rats had salient characteristics of severe infra-sacral neuropathic bladder dysfunction. TAM and DIS decreased postvoid residual urine volume, but this decrease was not accompanied by an increased Pmax or increased voided volume. Rather, decreased MCC was a possible contributing factor. Moreover, increased nonvoiding contractions after administration of DIS might participate in the decreased MCC. This novel model will be useful in studying the pharmacotherapy of the underactive bladder. PMID- 25443948 TI - Penoscrotal mass: a rare presentation of herpes simplex virus infection. AB - A 55-year-old man presents with a 10-cm condylomatous penoscrotal mass. Final pathology after surgical removal reveals a rare vegetative lesion with underlying herpes simplex virus infection. Along with neoplasia, infectious causes must remain in the differential diagnosis in the immunocompromised patient who presents with an atypical lesion. PMID- 25443949 TI - Histologic confirmation of a biochemical recurrence after radical prostatectomy by performing 3-dimensional transrectal ultrasonography-guided biopsy with fusion to magnetic resonance imaging. AB - OBJECTIVE: To obtain a histologic confirmation of biochemical recurrence after radical prostatectomy, which still remains a challenge. Historically, biopsy protocols have been designed but have provided rather unsatisfactory results. We report the first case of histologic confirmation of a biochemical recurrence in the prostatectomy bed by performing 3-dimensional transrectal ultrasonography guided biopsy with fusion to magnetic resonance images. MATERIALS AND METHODS: A 66-year-old man who underwent laparoscopic prostatectomy for a localized prostate cancer of Gleason sum 3+3=6 and preoperative prostate-specific antigen (PSA) level of 8.9 ng/L was followed up yearly. Postoperative serum PSA value was <0.04 ng/L. Nine years later, the patient developed a biochemical recurrence with an elevation of serum PSA level to 1.27 ng/mL. A 3-T endorectal positron emission tomography-magnetic resonance imaging (MRI) scan showed a 5 * 3 mm nodule in the prostatectomy bed in contact with the vesicourethral anastomosis without hypermetabolism. Two biopsies of this nodule were performed by using a 3 dimensional endorectal ultrasonography probe connected to the Koelis navigation system (Urostation; Koelis, Grenoble, France) with fusion to MRI images. RESULTS: Histologic findings confirmed the presence of a recurrence of the prostate cancer of Gleason sum 4+3=7 in both biopsies, and the patient was addressed to the radio oncologist for salvage therapy. CONCLUSION: The use of a transrectal approach with 3-dimensional guidance and MRI fusion allows correct sampling of prostate cancer recurrence nodules in the prostate bed. This procedure is easily performed in the outpatient clinic but still has to be validated in a larger series. PMID- 25443950 TI - Coiling the arterial feeder: report on a successfully treated extensive hemangioma of the periprostatic venous plexus and the bladder neck. AB - Extensive hemangioma of the prostate and the bladder is rare. In most cases, patients present for hematuria, hematospermia, or lower urinary tract symptoms. Confined lesions treatable with transurethral resection are most common but large hemangiomas requiring partial cystectomy are reported as well. Endoscopic or open surgery implies the risk for postoperative functional disability that is not reasonable for young patients. We present a case of an extensive symptomatic hemangioma of the periprostatic venous plexus and the bladder neck in a 46-year old man, which was treated by superselective coiling of the arterial feeder with no recurrence at 6-month follow-up. PMID- 25443947 TI - Novel cystine ester mimics for the treatment of cystinuria-induced urolithiasis in a knockout mouse model. AB - OBJECTIVE: To assess the effectiveness of l-cystine dimethyl ester (CDME), an inhibitor of cystine crystal growth, for the treatment of cystine urolithiasis in an Slc3a1 knockout mouse model of cystinuria. MATERIALS AND METHODS: CDME (200 MUg per mouse) or water was delivered by gavage daily for 4 weeks. Higher doses by gavage or in the water supply were administered to assess organ toxicity. Urinary amino acids and cystine stones were analyzed to assess drug efficacy using several analytical methods. RESULTS: Treatment with CDME led to a significant decrease in stone size compared with that of the water group (P = .0002), but the number of stones was greater (P = .005). The change in stone size distribution between the 2 groups was evident by micro computed tomography. Overall, cystine excretion in urine was the same between the 2 groups (P = .23), indicating that CDME did not interfere with cystine metabolism. Scanning electron microscopy analysis of cystine stones from the CDME group demonstrated a change in crystal habit, with numerous small crystals. l-cysteine methyl ester was detected by ultra-performance liquid chromatography-mass spectrometer in stones from the CDME group only, indicating that a CDME metabolite was incorporated into the crystal structure. No pathologic changes were observed at the doses tested. CONCLUSION: These data demonstrate that CDME promotes formation of small stones but does not prevent stone formation, consistent with the hypothesis that CDME inhibits cystine crystal growth. Combined with the lack of observed adverse effects, our findings support the use of CDME as a viable treatment for cystine urolithiasis. PMID- 25443951 TI - Preoperative fiducial coil placement facilitates robot-assisted laparoscopic excision of retroperitoneal small solitary metastasis of kidney cancer. AB - Image-guided fiducial markers are being used in surgery, especially in spine and breast surgery, and radiotherapy, allowing localization of tumor sites precisely. We report a case of fiducial coil use in a man undergoing a robot-assisted laparoscopic resection of a metastatic nodule under the ipsilateral diaphragm after robot-assisted partial nephrectomy performed 2 years ago for a left upper pole renal tumor. The fiducial coil facilitated the localization of the lesion, which would otherwise have been challenging because of its small size and location. In addition, the fiducial coil was helpful to avoid cutting into the lesion directly. PMID- 25443952 TI - Renal subcapsular fluid collection caused by penetration of a pancreatic pseudocyst. AB - A 63-year-old man presented with left flank pain and spiked fever. Computed tomography revealed a pancreatic cyst and left renal subcapsular fluid collection that appeared to be connected to the cyst. High levels of amylase and lipase were observed in a test puncture of renal fluid collection. The cause of the fluid collection was diagnosed as penetration of the pancreatic pseudocyst. Endoscopic nasobiliary drainage was used to drain the pancreatic pseudocyst and renal subcapsular fluid collection. The present case demonstrated that renal subcapsular fluid collection may be caused by penetration of a pancreatic pseudocyst. PMID- 25443953 TI - The interplay between molecular modeling and chemoinformatics to characterize protein-ligand and protein-protein interactions landscapes for drug discovery. AB - Protein-ligand and protein-protein interactions play a fundamental role in drug discovery. A number of computational approaches have been developed to characterize and use the knowledge of such interactions that can lead to drug candidates and eventually compounds in the clinic. With the increasing structural information of protein-ligand and protein-protein complexes, the combination of molecular modeling and chemoinformatics approaches are often required for the efficient analysis of a large number of such complexes. In this chapter, we review the progress on the developments of in silico approaches that are at the interface between molecular modeling and chemoinformatics. Although the list of methods and applications is not exhaustive, we aim to cover representative cases with a special emphasis on interaction fingerprints and their applications to identify "hot spots." We also elaborate on proteochemometric modeling and the emerging concept of activity landscape, structure-based interpretation of activity cliffs and structure-protein-ligand interaction relationships. Target ligand relationships are discussed in the context of chemogenomics data sets. PMID- 25443954 TI - Computational study of putative residues involved in DNA synthesis fidelity checking in Thermus aquaticus DNA polymerase I. AB - A fidelity-checking site for DNA polymerase I has been proposed based on recent single-molecule Forster resonance energy transfer studies. The checking site is believed to ensure proper base pairing of the newly inserted nucleotide. Computational studies have been utilized to predict residues involved in this putative checking site on the Klenow and Bacillus fragments. Here, we employ energy decomposition analysis, electrostatic free energy response, and noncovalent interaction plots to identify the residues involved in the hypothesized checking site in the homologous Klenow fragment from Thermus aquaticus (Klentaq). Our results indicate multiple protein residues that show altered interactions for three mispairs compared to the correctly paired DNA dimer. Many of these residues are also conserved along A family polymerases. PMID- 25443955 TI - New strategies for integrative dynamic modeling of macromolecular assembly. AB - Data reporting on structure and dynamics of cellular constituents are growing with increasing pace enabling, as never before, the understanding of fine mechanistic aspects of biological systems and providing the possibility to affect them in controlled ways. Nonetheless, experimental techniques do not yet allow for an arbitrary level of resolution on cellular processes in situ. By consistently integrating a variety of diverse experimental data, molecular modeling is optimally poised to enhance to near-atomistic resolution our understanding of molecular recognition in large assemblies. Within this integrative modeling context, we briefly review in this chapter the recent progresses of molecular simulations at the atomistic and coarse-grained level of resolution to explore protein-protein interactions. In particular, we discuss our recent contributions in this field, which aim at providing a robust bridge between novel optimization algorithms and multiscale molecular simulations for a consistent integration of experimental inputs. We expect that, with the ever growing sampling ability of molecular simulations and the tireless progress of experimental methods, the impact of such dynamic-based approach could only be more effective with time, contributing to provide detailed description of cellular organization. PMID- 25443956 TI - Stability of amyloid oligomers. AB - Molecular simulations are now commonly used to complement experimental techniques in investigating amyloids and their role in human diseases. In this chapter, we will summarize techniques and approaches often used in amyloid simulations and will present recent success stories. Our examples will be focused on lessons learned from molecular dynamics simulations in aqueous environments that start from preformed aggregates. These studies explore the limitations that arise from the choice of force field, the role of mutations in the growth of amyloid aggregates, segmental polymorphism, and the importance of cross-seeding. Furthermore, they give evidence for potential toxicity mechanisms. We finally discuss the role of molecular simulations in the search for aggregation inhibitors. PMID- 25443958 TI - Studying allosteric regulation in metal sensor proteins using computational methods. AB - In this chapter, we describe advances made in understanding the mechanism of allosteric regulation of DNA operator binding in the ArsR/SmtB family of metal sensing proteins using computational methods. The paradigm, zinc-sensing transcriptional repressor Staphylococcus aureus CzrA represents an excellent model system to understand how metal sensor proteins maintain cellular metal homeostasis. Here, we discuss studies that helped to characterize a metal ion mediated hydrogen-bonding pathway (HBP) that plays a dominant role in the allosteric mechanism of DNA operator binding in these proteins. The chapter discusses computational methods used to provide a molecular basis for the large conformational motions and allosteric coupling free energy (~6kcal/mol) associated with Zn(II) binding in CzrA. We present an accurate and convenient means by which to include metal ions in the nuclear magnetic resonance (NMR) structure determination process using molecular dynamics (MD) constrained by NMR derived data. The method provides a realistic and physically viable description of the metal-binding site(s) and has potentially broad applicability in the structure determination of metal ion-bound proteins, protein folding, and metal template protein-design studies. Finally, our simulations provide strong support for a proposed HBP that physically connects the metal-binding residue, His97, to the DNA-binding interface through the alphaR helix that is present only in the Zn(II)-bound state. We find the interprotomer hydrogen bond interaction to be significantly stronger (~8kcal/mol) at functional allosteric metal-binding sites compared to the apo proteins. This interaction works to overcome the considerable disorder at these hydrogen-bonding sites in apo protein and functions as a "switch" to lock in a weak DNA-binding conformation once metal is bound. This interaction is found to be considerably weaker in nonresponsive metal-binding sites. These findings suggest a conserved functional role of metal-mediated second-shell coordination hydrogen bonds at allosterically responsive sites in zinc-sensing transcription regulators. PMID- 25443959 TI - Insights in the mechanism of action and inhibition of N-acylethanolamine acid amidase by means of computational methods. AB - Computer-aided approaches are widely used in modern medicinal chemistry to improve the efficiency of the discovery phase. N-Acylethanolamine acid amidase (NAAA) is a cysteine amidase belonging to the N-terminal nucleophile (Ntn) hydrolases that primarily degrades anti-inflammatory and analgesic lipid amide palmitoylethanolamide. In this chapter, we review our contribution to (i) the determination of the reaction mechanism of amide hydrolysis catalyzed by cysteine Ntn-hydrolases and (ii) the discovery and optimization of active-site-directed inhibitors of NAAA characterized by a beta-lactone warhead. The combination of different computational tools, ranging from homology modeling, docking, and mechanistic simulations based on hybrid quantum mechanics/molecular mechanics potentials, contributed to the elucidation of the mechanism of action and inhibition of NAAA enzyme and to the design of more potent inhibitors. PMID- 25443957 TI - Recent advances in transferable coarse-grained modeling of proteins. AB - Computer simulations are indispensable tools for studying the structure and dynamics of biological macromolecules. Biochemical processes occur on different scales of length and time. Atomistic simulations cannot cover the relevant spatiotemporal scales at which the cellular processes occur. To address this challenge, coarse-grained (CG) modeling of the biological systems is employed. Over the last few years, many CG models for proteins continue to be developed. However, many of them are not transferable with respect to different systems and different environments. In this review, we discuss those CG protein models that are transferable and that retain chemical specificity. We restrict ourselves to CG models of soluble proteins only. We also briefly review recent progress made in the multiscale hybrid all-atom/CG simulations of proteins. PMID- 25443961 TI - High-resolution modeling of protein structures based on flexible fitting of low resolution structural data. AB - To circumvent the difficulty of directly solving high-resolution biomolecular structures, low-resolution structural data from Cryo-electron microscopy (EM) and small angle solution X-ray scattering (SAXS) are increasingly used to explore multiple conformational states of biomolecular assemblies. One promising venue to obtain high-resolution structural models from low-resolution data is via data constrained flexible fitting. To this end, we have developed a new method based on a coarse-grained Calpha-only protein representation, and a modified form of the elastic network model (ENM) that allows large-scale conformational changes while maintaining the integrity of local structures including pseudo-bonds and secondary structures. Our method minimizes a pseudo-energy which linearly combines various terms of the modified ENM energy with an EM/SAXS-fitting score and a collision energy that penalizes steric collisions. Unlike some previous flexible fitting efforts using the lowest few normal modes, our method effectively utilizes all normal modes so that both global and local structural changes can be fully modeled with accuracy. This method is also highly efficient in computing time. We have demonstrated our method using adenylate kinase as a test case which undergoes a large open-to-close conformational change. The EM fitting method is available at a web server (http://enm.lobos.nih.gov), and the SAXS-fitting method is available as a pre-compiled executable upon request. PMID- 25443962 TI - Preface. PMID- 25443960 TI - CHARMM-GUI PDB manipulator for advanced modeling and simulations of proteins containing nonstandard residues. AB - CHARMM-GUI, http://www.charmm-gui.org, is a web-based graphical user interface to prepare molecular simulation systems and input files to facilitate the usage of common and advanced simulation techniques. Since it is originally developed in 2006, CHARMM-GUI has been widely adopted for various purposes and now contains a number of different modules designed to setup a broad range of simulations including free energy calculation and large-scale coarse-grained representation. Here, we describe functionalities that have recently been integrated into CHARMM GUI PDB Manipulator, such as ligand force field generation, incorporation of methanethiosulfonate spin labels and chemical modifiers, and substitution of amino acids with unnatural amino acids. These new features are expected to be useful in advanced biomolecular modeling and simulation of proteins. PMID- 25443963 TI - Registries and paediatric radiation oncology. PMID- 25443964 TI - Derek Oliver Berg (1926-2014). PMID- 25443967 TI - Brimonidine gel for the treatment of persistent heliotrope rash in a patient with amyopathic dermatomyositis: a case report. PMID- 25443968 TI - What outcomes are important to people with long-term neurological conditions using integrated health and social care? AB - Measuring the outcomes that are meaningful to people with long-term neurological conditions (LTNCs) using integrated health and social care services may help to assess the effectiveness of integration. Conventional outcomes tend not to be derived from service user experiences, nor are they able to demonstrate the impact of integrated working. This paper reports findings about outcomes identified as being important to people with LTNCs using integrated services. We undertook qualitative work with five community neuro-rehabilitation teams that were integrated in different ways and to different degrees. In-depth, semi structured interviews were conducted with 35 people with LTNCs using these teams. Data were collected between 2010 and 2011 and analysed using an adapted version of the Framework approach. We identified 20 outcomes across three domains: personal comfort outcomes, social and economic participation outcomes, and autonomy outcomes. Inter-relationships between outcomes, both within and across domains, were evident. The outcomes, and the inter-relationships between them, have implications for how individuals are assessed in practice. PMID- 25443969 TI - Immune-spaying as an alternative to surgical spaying in Iberian*Duroc females: effect on carcass traits and meat quality characteristics. AB - The aim of this study was to assess the effect of immune-spaying on production traits and meat quality characteristics of fresh loin (longissimus dorsi) by comparing 3 groups of Iberian*Duroc females (N=12 per batch): surgically spayed, immune-spayed and entire females. Carcass traits and physicochemical parameters, including fatty acid profile, were investigated. The only carcass trait significantly affected by castration was the ham fat thickness, where both immune spayed and surgically spayed females showed higher values against entire females (57+/-9.5mm, 62+/-2.5mm and 51+/-10.1mm, respectively; p<0.05). Furthermore, there were no significant differences in the quality parameters of fresh meat. These results are important regarding animal welfare, since in Europe, there is a plan to voluntarily end the surgical castration of pigs by 2018. Therefore, with an adequate vaccination protocol, immune-spaying might represent a good alternative to surgical spaying. The reliability of immune-spaying over long periods should be evaluated. PMID- 25443970 TI - Breeds and muscle types modulate performance of near-infrared reflectance spectroscopy to predict the fatty acid composition of bovine meat. AB - This study aims to assess near-infrared reflectance spectroscopy feasibility for predicting beef fatty acid (FA) composition. Experimental scheme included four breeds (Angus, Blond d'Aquitaine, Charolais, Limousin) and three muscles, Longissimus thoracis (LT), Rectus abdominis (RA), Semitendinosus (ST). The results showed that 1) increasing FA content variability with several breeds increased calibration model reliability (R(2)CV>0.86) for the major individual and groups of FA unless polyunsaturated FAs, 2) Longissimus thoracis FAs were better predicted than RA FAs while no ST FAs were correctly predicted (R(2)CV<0.71). This difference could be explained by FA content, FA variability or specific muscle physico-chemical characteristics. PMID- 25443971 TI - Analysis of the juice and water losses in salted and unsalted pork samples heated in water bath. Consequences for the prediction of weight loss by transfer models. AB - This study has analyzed the effect of different factors on variation of meat weight due to juice loss, and variation of water content of pork samples heated in a water bath. The weight loss (WL) was influenced by initial water content of raw meat which can be connected to meat pH, muscle type, and by pre-salting. WL was also influenced by sample thickness and by nature of the surrounding fluid. These effects were significant at 50 degrees C and in thinner samples but decreased as meat temperature and sample thickness increased. WL showed no significant difference in response to prior freezing, applying a surface constraint during heating or varying meat salt content from 0.8 to 2.0%. The results were interpreted from literature knowledge on protein denaturation, contraction and, transport phenomena. Reliably predicting WL from water content variation during heating hinges on taking into account the loss of dry matter and the possible effects of meat pH, sample size or surrounding fluid. PMID- 25443972 TI - Effects of diets supplemented with sunflower or flax seeds on quality and fatty acid profile of hamburgers made with perirenal or subcutaneous fat. AB - Steers were fed grass hay or red clover silage based diets containing flaxseed or sunflower seed as sources of 18:3n-3 and 18:2n-6 respectively. Hamburgers were made from triceps brachii and perirenal or subcutaneous fat. Perirenal-hamburgers contained more polyunsaturated fatty acids (PUFA), several PUFA biohydrogenation intermediates (BHI), and 18:0 (P<0.05). Oxidative stability was similar across hamburgers (P>0.05). Sensory differences were found due to hamburger fat source, but were < one panel unit. Within perirenal-hamburgers, feeding flaxseed increased 18:3n-3 and its BHI (P<0.05), and feeding sunflower seed increased 18:2n-6 and its BHI (P<0.05). Feeding flaxseed increased off-flavour intensity and oxidation in perirenal-hamburgers (P<0.05). Feeding oilseeds in forage based diets while using perirenal fat to make hamburgers provides opportunities to increase PUFA and BHI with potential to impact human health, but control measures need to be explored to limit oxidation and off-flavours when feeding flaxseed. PMID- 25443973 TI - Influence of level and duration of feeding polysaccharide (laminarin and fucoidan) extracts from brown seaweed (Laminaria digitata) on quality indices of fresh pork. AB - The effect of level (450 or 900 mg laminarin (L) and fucoidan (F) /kg feed) and duration (3 or 6 wks) of feeding a seaweed (Laminaria digitata) extract containing L/F on the quality of pork (longissimus thoracis et lumborum (LTL)) stored in modified atmosphere packs and on organ lipid stability was examined. Mechanisms of L/F antioxidant activity in LTL were evaluated. Plasma total antioxidant status, LTL pH, colour, microbiology and 'eating quality' sensory analysis were unaffected by dietary L/F. 'Visual' sensory descriptors (purchasing appeal and overall visual acceptability) were enhanced (p<0.05) in L/F450-3 LTL. Lipid oxidation was lower (p<0.05) in L/F450-3 and L/F900-3 LTL and reduced in L/F900-6 kidney homogenates. In cooked minced pork, lipid oxidation was not reduced by dietary L/F. Saturated fatty acids were lower (p<0.05) in L/F900-6 LTL. Results indicated L/F in pig diets for 3 weeks enhanced pork quality. PMID- 25443974 TI - Introduction to innate sensing and response to pathogens. PMID- 25443975 TI - Native and denatured egg white protein IgE tests discriminate hen's egg allergic from egg-tolerant children. AB - BACKGROUND: Accurate diagnosis of egg allergy by IgE testing is challenged by a large number of atopic subjects sensitized, but clinically tolerant to eggs. In addition, discrimination between allergy to raw only, or raw and cooked egg allergy is important. In this study, we investigate the diagnostic performance of IgE tests to native and denatured egg proteins. METHODS: According to food challenges and clinical tolerance, study subjects were randomized to the following groups: (Group A) sensitized but clinically tolerant to egg, (Group B) allergic to raw egg only, or (Group C) allergic to raw and cooked egg. Serum specific IgE to native or reduced and oxidized egg white, ovomucoid, and ovalbumin were measured. RESULTS: Increasing titers of specific IgE to the various proteins were found according to the degree of the egg allergy. Cut-off values for IgE testing to native egg could be determined to distinguish between raw egg allergic and egg-tolerant subjects (1.6 kU/l), as well as raw and cooked egg allergic and egg-tolerant subjects (4.1 kU/l). ROC curves analysis showed that native ovalbumin was the best test for the diagnosis of allergy to raw and cooked egg, and native ovomucoid was best to distinguish between allergy to raw only, and allergy to raw and cooked egg. Sequential testing improved the diagnosis, when in addition to IgE to native egg white, IgE to native ovalbumin was tested for the diagnosis of raw and cooked egg allergy, and IgE to native ovomucoid for the discrimination between allergy to raw only, or to raw and cooked eggs. CONCLUSION: The diagnosis of egg allergy can be significantly improved using a panel of IgE tests to egg proteins in the native or denatured form. The accuracy can be improved using combined IgE testing. PMID- 25443976 TI - The mass murderer history: modern classifications, sociodemographic and psychopathological characteristics, suicidal dimensions, and media contagion of mass murders. AB - Multicide and other mass killings are sufficiently dramatic to excite great interest from clinicians, criminologists and behavioral scientists. This paper revisits the history of the mass murderer, an entity that has progressively distinguished itself from the serial killer. The functional difference between mass and serial homicide is quite obvious, particularly in setting, time, victim status and modus operandi. Classification of these acts requires a number of parameters. The causes of mass murders are multiple and complex: although they rarely seem to be related to psychotic mental pathologies, they are always an expression of suffering that manifests itself in a psychological crisis that is both homicidal and suicidal. Several research teams have studied the sociodemographic and etiopathogenic characteristics of mass murderers and, in particular, the perpetrators of school killings. In addition to prevalent personality traits, these actions often jointly include suicides and homicides, which are brought together in the same psychic crisis. In keeping with the theory of little identity support, previous crimes influenced some mass murderers. Suicides and mass-murders are likely to be imitated. The media appears to play a crucial role in preventing the occurrence of imitation or copycat tragedies. The WHO recommendation regarding how to transcribe suicide and by extension, homicide, in the media is necessary. PMID- 25443977 TI - Alexithymia, a compounding factor for eating and social avoidance symptoms in anorexia nervosa. AB - Socio-affective difficulties, in particular difficulties in representing, communicating and feeling emotions, may play a critical role in anorexia nervosa (AN). The aim of this longitudinal study was to explore the links between alexithymia and two types of difficulties in AN: eating symptoms and social avoidance. Sixty adolescent girls with AN were recruited following hospitalisation in a specialised department. They completed self-administered questionnaires of alexithymia (TAS-20), of central symptoms of the eating disorders (EDI), and of anxious and depressive affects (SCL-90). Anxiety and social avoidance were assessed in the course of a standardised interview (LSAS). These measures were performed at inclusion, and at 6-, 12- and 18-months' follow up. The relationship between TAS-20 and EDI or LSAS total scale scores across the four time points was assessed using mixed-effects models, including anxiety, depression, BMI, anorexia subtype, and age as co-factors. Partial least square regression was used to refine this multivariate analysis at subscale level, at inclusion and 18 months. Robust associations between TAS-20 and EDI scores were found, independently from anxious and depressive scores, nutritional state and AN subtype. These effects appeared more particularly linked to the implication of the dimensions difficulties identifying and describing feelings, interpersonal mistrust, feelings of inadequacy and interoceptive awareness deficit. There was also a durable association between alexithymia and social anxiety and avoidance, after adjusting for the confounding effects of depression, and anxiety, and the state of starvation. Difficulties in describing feelings appeared particularly involved here. Thus alexithymia does appear as a factor in the persistence of disorders in AN, and difficulties identifying and describing feelings could compound the social difficulties and major the relational isolation of these patients. PMID- 25443978 TI - Age and gender differences in the factor structure of the Center for Epidemiological Studies Depression Scale among Japanese working individuals. AB - OBJECTIVES: Depression is a serious mental illness with a high rate of prevalence. Depressive sympotomatology is heterogeneous and is expressed as a combination of emotional, physical, cognitive, and social symptoms. The objective of this study was to examine differences in the factor structure of the Center for Epidemiologic Studies Depression Scale (CES-D) among Japanese working individuals of differing age and gender using exploratory factor analysis (EFA). METHODS: This study examined the factor structure of the CES-D in a sample of 6696 Japanese working individuals aged 20 and older. To examine within-group differences in the structural characteristics of the CES-D, the participants were stratified by age subgroup. RESULTS: The EFA with promax rotation identified three factors among the participants. These factors were labeled "depressed and negative complaints" (DEP), "somatic and apathetic complaints" (SOM), and "positive affect" (POS). Although the three factors were comparable for males in their 20-50s and females in their 20s and 30s, the content of these factors varied for other subgroups. For females in their 40s and 50s, items 15 and 19 (belonging to Radloff's original interpersonal problem factor) constituted an independent factor. For all individuals in their 60s, items that were not included in the SOM and POS factors constituted new factors that were not observed for participants in their 20s-50s. CONCLUSION: These findings indicate that age and gender could affect the factor structure of the CES-D among Japanese working individuals. Psychosocial or biological factors might contribute to the age- and gender-related differences in the factor structure of the CES-D. PMID- 25443979 TI - Interrelationship between diabetes and periodontitis: role of hyperlipidemia. AB - Diabetes mellitus and periodontitis are both common, chronic diseases. It is generally accepted that the inter-relationship between diabetes mellitus and periodontitis is a two-way relationship, i.e. the presence of one condition tends to increases the risk and severity of the other, and vice versa. Mechanisms for this two-way relationship are largely unknown. Hyperlipidemia is a group of disorders characterized by an excess of lipids in the bloodstream. Hyperlipidemia increases the risk of diabetes and peridontitis. On the other hand, diabetes and periodontitis could result in hyperlipidemia. The purposes of this review were: (1) examine the two-way relationship between diabetes mellitus and periodontitis; (2) discuss the potential synergistic interactions of hyperlipidemia to both diabetes mellitus and periodontitis; and (3) explore the mechanisms through which hyperlipidemia affects the development of both diseases. The effects of hyperlipidemia on insulin secretion and pro-inflammatory cytokines production (TNF-alpha, IL-1beta) play an important role on the pathogenesis of diabetes and periodontitis. A model is proposed suggesting the important role of hyperlipidemia in the two-way relationship between diabetes and periodontitis. As our understanding of the inter-relationship expands between hyperlipidemia, diabetes, and periodontitis, therapeutic strategies aimed at limiting hyperlipidemia should be advocated for the clinical management of diabetes and periodontitis. PMID- 25443980 TI - [Lupus nephritis: up-to-date]. AB - Renal involvement is frequent during natural history of systemic lupus erythematosus (SLE) and has a major prognostic value in this systemic disease. Screening for renal symptoms, such as proteinuria, micro-haematuria or renal failure must be performed at initial diagnosis and repeated during subsequent follow-ups. Any significant abnormality of these parameters may reveal active glomerulonephritis (GN) and should lead to a renal biopsy, which will significantly impact the therapeutic choices. Proliferative GN, defined as class III or IV by the actual histo-pathological classification, is the most severe form of SLE-associated nephropathy and can lead to end-stage renal disease (ESRD) in up to 60% of cases, according to ethnicity and follow-up duration. Standard induction treatment of active proliferative GN includes corticosteroids combined with an immunosuppressive drug, which can either be cyclophosphamide or mycophenolate mofetil (MMF). Even though, recent biotherapies have not yet proved their efficacy in the field of lupus nephritis, new protocols are expected, aiming higher remission rates and avoidance of high-dose corticosteroids regimens. When remission is achieved in proliferative GN, a maintenance therapy is required to decrease the risk of relapse, using either azathioprine or MMF. Immunosuppressive drugs are responsible for an increased risk of infectious or neoplastic complications but cardiovascular disease is actually one of the main causes of mortality among lupus patients, especially for patients with SLE related kidney disease, well before reaching ESRD. PMID- 25443981 TI - Tourette syndrome and procedures related to dental treatment: a systematic review. AB - PURPOSE: Dental treatment of patients with Tourette syndrome (TS) may present special challenges to the dentist. The aim was to systematically review the literature regarding perioperative procedures including sedation and general anaesthesia (GA) of patients with TS. MATERIALS AND METHODS: Literature searches were performed in PubMed and Embase to identify papers concerning TS in combination with dental treatment, sedation, and/or GA in order to study outcomes regarding co-morbidity, perioperative complications, and drug interactions. RESULTS: The literature search identified six publications (case reports or series) which addressed the topic. No unexpected adverse effects or drug interactions in relation to sedation or GA in TS patients and no perioperative complications were reported. CONCLUSIONS: The literature on TS is scarce and the evidence level is low. Therefore, guidelines regarding the dental treatment of patients with TS cannot be formulated at the present time. PMID- 25443982 TI - Dual-species relations between Candida tropicalis isolated from apple juice ultrafiltration membranes, with Escherichia coli O157:H7 and Salmonella sp. AB - AIMS: The objective of this study was to determine the interactions between common spoilage yeast, Candida tropicalis, isolated from ultrafiltration membranes, and Escherichia coli O157:H7 and Salmonella sp. on stainless steel surfaces. METHODS AND RESULTS: Single and dual-species attachment assays were performed on stainless steel at 25 degrees C using apple juice as culture medium. The growth of Salmonella sp. rose when it was co-cultivated with C. tropicalis in dual biofilms at 16 and 24 h; the same effect was observed for E. coli O157:H7 at 24 h. The colonization of C. tropicalis on stainless steel surfaces was reduced when it was co-cultivated with both pathogenic bacteria, reducing C. tropicalis population by at least 1.0 log unit. Visualization by SEM demonstrated that E. coli O157:H7 and Salmonella sp. adhere closely to hyphal elements using anchorage structures to attach to the surface and other cells. CONCLUSIONS: These results suggest a route for potential increased survival of pathogens in juice processing environments. These support the notion that the species involved interact in mixed yeast-bacteria communities favouring the development of bacteria over yeast. SIGNIFICANCE AND IMPACT OF THE STUDY: This study support the plausibility that pathogen interactions with strong biofilm forming members of spoilage microbiota, such as C. tropicalis, might play an important role for the survival and dissemination of E. coli O157:H7 and Salmonella sp. in food-processing environments. PMID- 25443984 TI - Transition from sinus rhythm to atrial fibrillation - a mechanism inducing or delaying pulmonary congestion and edema. AB - Cardiogenic pulmonary edema (PEd) is a life-threatening condition where fluid accumulates in the lungs due to increasing hydrostatic pressure building up in the pulmonary vasculature (PV): veins, venules and capillaries. Atrial fibrillation (AF) is accepted as an arrhythmia which triggers and promotes the pathophysiological processes leading to pulmonary congestion and its final expression: PEd. We propose a different view, where AF is actually a physiological solution temporarily protecting from PEd. We hypothesize that the compliance of the left atrium (LA) increases with the onset of AF. Thus, it is possible that even if the volume of blood within the LA increases due to loss of atrial contraction, the pressure within the LA would still be lower than that prior to AF (because of the increased LA compliance during AF). Decreased LA pressure allows more blood to flow from the PV to the LA, abating the hydrostatic pressure buildup in the PV compartment. The ratio, R, between the LA volume gained from the transition to AF provided by the greater LA compliance, and the volume of blood retained in the LA due to loss of atrial contraction, determines the instant pressure in the LA, as AF begins. If R is >1, then the LA pressure will instantly decrease with the transition to AF and this may be beneficial in delaying PEd. PMID- 25443983 TI - C-Aryl Glucosides with Substituents at the Distal Aryl Ring as Sodium-Dependent Glucose Cotransporter Inhibitors for the Treatment of Diabetes Mellitus. AB - A series of novel C-aryl glucosides with various substituents at the distal aryl ring have been synthesized and evaluated for hypoglycemic effect in normal and diabetic mice and in type 2 diabetic rats. The results indicated that introduction of electron-donating group at the distal aryl ring could improve glucose tolerance in normal mice, whereas introduction of electron-withdrawing group at this position could deteriorate. The urinary glucose excretion was significantly increased after glucose (3 g/kg) administration in normal mice with the treatment of 13c. Moreover, compound 13c could reduce fed blood glucose levels in a dose-dependent manner in type 2 diabetic rats, showed a remarkable antihyperglycemic effect with 2 weeks of treatment in diabetic mice, and might be a promising drug candidate for the treatment of diabetes mellitus. PMID- 25443985 TI - Cytodiagnosis of renal medullary carcinoma: report of a case with immunocytochemistry. PMID- 25443986 TI - Emission of methane, carbon monoxide, carbon dioxide and short-chain hydrocarbons from vegetation foliage under ultraviolet irradiation. AB - The original report that plants emit methane (CH4 ) under aerobic conditions caused much debate and controversy. Critics questioned experimental techniques, possible mechanisms for CH4 production and the nature of estimating global emissions. Several studies have now confirmed that aerobic CH4 emissions can be detected from plant foliage but the extent of the phenomenon in plants and the precise mechanisms and precursors involved remain uncertain. In this study, we investigated the role of environmentally realistic levels of ultraviolet (UV) radiation in causing the emission of CH4 and other gases from foliage obtained from a wide variety of plant types. We related our measured emissions to the foliar content of methyl esters and lignin and to the epidermal UV absorbance of the species investigated. Our data demonstrate that the terrestrial vegetation foliage sampled did emit CH4 , with a range in emissions of 0.6-31.8 ng CH4 g( 1) leaf DW h(-1) , which compares favourably with the original reports of experimental work. In addition to CH4 emissions, our data show that carbon monoxide, ethene and propane are also emitted under UV stress but we detected no significant emissions of carbon dioxide or ethane. PMID- 25443987 TI - Metaphor priming in sentence production: concrete pictures affect abstract language production. AB - People speak metaphorically about abstract concepts-for instance, a person can be "full of love" or "have a lot of love to give." Over the past decade, research has begun to focus on how metaphors are processed during language comprehension. Much of this work suggests that understanding a metaphorical expression involves activating brain and body systems involved in perception and motor control. However, no research to date has asked whether the same is true while speakers produce language. We address this gap using a sentence production task. Its results demonstrate that visually activating a concrete source domain can trigger the use of metaphorical language drawn from that same concrete domain, even in sentences that are thematically unrelated to the primes, a metaphorical priming effect. This effect suggests that conceptual metaphors play a part in language production. It also shows that activation in the perceptual system that is not part of an intended message can nevertheless influence sentence formulation. PMID- 25443988 TI - Musical metaphors: evidence for a spatial grounding of non-literal sentences describing auditory events. AB - This study investigated whether the spatial terms high and low, when used in sentence contexts implying a non-literal interpretation, trigger similar spatial associations as would have been expected from the literal meaning of the words. In three experiments, participants read sentences describing either a high or a low auditory event (e.g., The soprano sings a high aria vs. The pianist plays a low note). In all Experiments, participants were asked to judge (yes/no) whether the sentences were meaningful by means of up/down (Experiments 1 and 2) or left/right (Experiment 3) key press responses. Contrary to previous studies reporting that metaphorical language understanding differs from literal language understanding with regard to simulation effects, the results show compatibility effects between sentence implied pitch height and response location. The results are in line with grounded models of language comprehension proposing that sensory motor experiences are being elicited when processing literal as well as non literal sentences. PMID- 25443989 TI - Chief complaint-based performance measures: a new focus for acute care quality measurement. AB - Performance measures are increasingly important to guide meaningful quality improvement efforts and value-based reimbursement. Populations included in most current hospital performance measures are defined by recorded diagnoses using International Classification of Diseases, Ninth Revision codes in administrative claims data. Although the diagnosis-centric approach allows the assessment of disease-specific quality, it fails to measure one of the primary functions of emergency department (ED) care, which involves diagnosing, risk stratifying, and treating patients' potentially life-threatening conditions according to symptoms (ie, chief complaints). In this article, we propose chief complaint-based quality measures as a means to enhance the evaluation of quality and value in emergency care. We discuss the potential benefits of chief complaint-based measures, describe opportunities to mitigate challenges, propose an example measure set, and present several recommendations to advance this paradigm in ED-based performance measurement. PMID- 25443990 TI - To be blunt: are we wasting our time? Emergency department thoracotomy following blunt trauma: a systematic review and meta-analysis. AB - STUDY OBJECTIVE: The role of emergency department (ED) thoracotomy after blunt trauma is controversial. The objective of this review is to determine whether patients treated with an ED thoracotomy after blunt trauma survive and whether survivors have a good neurologic outcome. METHODS: A structured search was performed with MEDLINE, EMBASE, CINAHL, and PubMed. Inclusion criteria were ED thoracotomy or out-of-hospital thoracotomy, cardiac arrest or periarrest, and blunt trauma. Outcomes assessed were mortality and neurologic result. The articles were appraised with the system designed by the Institute of Health Economics of Canada. A fixed-effects model was used to meta-analyze the data. Heterogeneity was assessed with the I(2) statistic. RESULTS: Twenty-seven articles were included in the review. All were case series. Of 1,369 patients who underwent an ED thoracotomy, 21 (1.5%) survived with a good neurologic outcome. All 21 patients had vital signs present on scene or in the ED and a maximum duration of cardiopulmonary resuscitation of 11 to 15 minutes. Thirteen studies were included in the meta-analysis. If there were either vital signs or signs of life present in the ED, the probability of a poor outcome was 99.2% (95% confidence interval 96.4% to 99.7%). CONCLUSION: There may be a role for ED thoracotomy after blunt trauma, but only in a limited group of patients. Good outcomes have been achieved for patients who had vital signs on admission and for patients who received an ED thoracotomy within 15 minutes of cardiac arrest. The proposed guideline should be used to determine which patients should be considered for an ED thoracotomy, according to level 4 evidence. PMID- 25443991 TI - Are colloids better than crystalloids for fluid resuscitation in critically ill patients? PMID- 25443992 TI - Cost-effectiveness of the PECARN rules in children with minor head trauma. AB - STUDY OBJECTIVE: To improve the efficiency and appropriateness of computed tomography (CT) use in children with minor head trauma, clinical prediction rules were derived and validated by the Pediatric Emergency Care Applied Research Network (PECARN). The objective of this study was to conduct a cost-effectiveness analysis comparing the PECARN traumatic brain injury prediction rules to usual care for selective CT use. METHODS: We used decision analytic modeling to project the outcomes, costs, and cost-effectiveness of applying the PECARN rules compared with usual care in a hypothetical cohort of 1,000 children with minor blunt head trauma. Clinical management was directed by level of risk as specified by the presence or absence of variables in the PECARN traumatic brain injury prediction rules. Immediate costs of care (diagnostic testing, treatment [not including clinician time], and hospital stay) were derived on single-center data. Quality adjusted life-year losses related to the sequelae of clinically important traumatic brain injuries and to radiation-induced cancers, number of CT scans, number of radiation-induced cancers, number of missed clinically important traumatic brain injury, and total costs were evaluated. RESULTS: Compared with the usual care strategy, the PECARN strategy was projected to miss slightly more children with clinically important traumatic brain injuries (0.26 versus 0.02 per 1,000 children) but used fewer cranial CT scans (274 versus 353), resulted in fewer radiation-induced cancers (0.34 versus 0.45), cost less ($904,940 versus $954,420), and had lower net quality-adjusted life-year loss (-4.64 versus 5.79). Because the PECARN strategy was more effective (less quality-adjusted life year loss) and less costly, it dominated the usual care strategy. Results were robust under sensitivity analyses. CONCLUSION: Application of the PECARN traumatic brain injury prediction rules for children with minor head trauma would lead to beneficial outcomes and more cost-effective care. PMID- 25443993 TI - Eosinophilic myositis as first manifestation in a patient with type 2 myotonic dystrophy CCTG expansion mutation and rheumatoid arthritis. AB - Eosinophilic myositis is characterized by eosinophilic infiltration of skeletal muscles. In the absence of an identifiable causative factor or source (including parasitic infection, intake of drugs or L-tryptophan, certain systemic disorders as well as malignant diseases), the diagnosis of idiopathic eosinophilic myositis is usually retained. However, some muscular dystrophies have been recently identified in this subset of eosinophilic myositis. Here, we report a patient with an 8 kb CCTG expansion in intron 1 of the CNBP gene, a mutation characteristic of myotonic dystrophy type 2 (DM2), whose first manifestation was "idiopathic" eosinophilic myositis. This report suggests that in "idiopathic" eosinophilic myositis, clinicians should consider muscular dystrophies, including DM2. PMID- 25443994 TI - [Neoaortic prolapse during Ross-Konno procedure]. PMID- 25443995 TI - Social barriers to diagnosis and treatment of breast cancer in patients presenting at a teaching hospital in Ibadan, Nigeria. AB - Globally, breast cancer is the most frequent malignancy in women, and stage at diagnosis is a key determinant of outcome. In low- to middle-income countries, including Nigeria, advanced stage diagnosis and delayed treatment represent a significant problem. That social barriers contribute to delay has been noted in previous research; however, few specific factors have been studied. Using semi structured interviews, this study identifies social barriers to diagnosis and treatment for patients who presented at University College Hospital Ibadan, Nigeria. Transcripts from the interviews were coded and analysed thematically. Thirty-one patients and five physicians were interviewed. The median age of patients was 51 (range: 28 to above 80), 83% were Christian and 17% were Muslim. Preliminary analysis showed that delays in diagnosis reflected a lack of education as well as the utilisation of non-physician medical services such as pharmacists. Delays in treatment were often due to fear of unanticipated surgery and cost. The majority of women did not know the cause of their breast cancer, but some believed it was caused by a spiritual affliction. This study suggests that further education and awareness of breast cancer for both patients and providers is needed in order to increase early stage diagnosis. PMID- 25443996 TI - Exercise augmentation compared with usual care for post-traumatic stress disorder: a randomized controlled trial. AB - OBJECTIVE: To investigate the impact of a 12-week exercise programme in addition to usual care for post-traumatic stress disorder (PTSD). METHOD: An assessor blinded randomized controlled trial was conducted among 81 participants with a DSM-IV-TR diagnosis of primary PTSD. Participants were recruited after admission to an in-patient programme at a private hospital. Participants were randomized to receive either usual care (n=42), or exercise in addition to usual care (n=39). The exercise intervention involved three, 30-min resistance-training sessions/week and a pedometer-based walking programme. Usual care involved psychotherapy, pharmaceutical interventions, and group therapy. Primary outcome was PTSD symptoms assessed via the PTSD checklist-civilian version (PCL-C). Secondary outcomes included symptoms of depression, anthropometry, physical activity, mobility, strength, and sleep quality. RESULTS: Participants had a mean (SD) age of 47.8 years (12.1), 84% male. PTSD symptoms in the intervention group significantly reduced compared with the usual care group (mean difference=-5.4, 95% CI -10.5 to -0.3, P=0.04, n=58). There were significant between-group differences at follow-up for depressive symptoms, waist circumference, sleep quality, and sedentary time. CONCLUSION: This study provides the first evidence that an exercise intervention is associated with reduced PTSD and depressive symptoms, reduced waist circumference, and improved sleep quality. PMID- 25443998 TI - Quality of life paradox in gastrointestinal disorders. PMID- 25443997 TI - Comparative benefit of malaria chemoprophylaxis modelled in United Kingdom travellers. AB - BACKGROUND: Chemoprophylaxis against falciparum malaria is recommended for travellers from non-endemic countries to malarious destinations, but debate continues on benefit, especially with regard to mefloquine. Quantification of benefit for travellers from the United Kingdom (UK) was modelled to assist clinical and public health decision making. METHODS: The model was constructed utilising: World Tourism Organization data showing total number of arrivals from the UK in countries with moderate or high malaria risk; data from a retrospective UK Clinical Practice Research Datalink (CPRD) drug utilisation study; additional information on chemoprophylaxis, case fatality and tolerability were derived from the travel medicine literature. Chemoprophylaxis with the following agents was considered: atovaquone-proguanil (AP), chloroquine with and without proguanil (C +/- P), doxycycline (Dx), mefloquine (Mq). The model was validated for the most recent year with temporally matched datasets for UK travel destinations and imported malaria (2007) against UK Health Protection Agency data on imported malaria. RESULTS: The median (mean) duration of chemoprophylaxis for each agent in weeks (CPRD) was: AP 3.3 (3.5), C +/- P 9 (12.1), Dx 8 (10.3), Mq 9 (12.3): the maximum duration of use of all regimens was 52 weeks. The model correctly predicted falciparum malaria deaths and gave a robust estimate of total cases- model: 5 deaths from 1118 cases; UK Health Protection Agency: 5 deaths from 1153 cases. The number needed to take chemoprophylaxis (NNP) to prevent a case of malaria considered against the 'background' reported incidence in non-users of chemoprophylaxis deemed in need of chemoprophylaxis was: C +/- P 272, Dx 269, Mq 260, AP 252; the NNP to prevent a UK traveller malaria death was: C +/- P 62613, Dx 61923, Mq 59973, AP 58059; increasing the 'background' rate by 50% yielded NNPs of: C +/- P 176, Dx 175, Mq 171, AP 168. The impact of substituting atovaquone-proguanil for all mefloquine usage resulted in a 2.3% decrease in estimated infections. The number of travellers experiencing moderate adverse events (AE) or those requiring medical attention or drug withdrawal per case prevented is as follows: C +/- P 170, Mq 146, Dx 114, AP 103. CONCLUSIONS: The model correctly predicted the number of malaria deaths, providing a robust and reliable estimate of the number of imported malaria cases in the UK, and giving a measure of benefit derived from chemoprophylaxis use against the likely adverse events generated. Overall numbers needed to prevent a malaria infection are comparable among the four options and are sensitive to changes in the background infection rates. Only a limited impact on the number of infections can be expected if Mq is substituted by AP. PMID- 25443999 TI - Bidirectional associations between fussy eating and functional constipation in preschool children. AB - OBJECTIVE: To examine bidirectional associations between a child's fussy eating behavior and functional constipation. STUDY DESIGN: Participants were 4823 children enrolled in a prospective cohort study from pregnancy onward. We assessed fussy eating at age 4 years with the Child Eating Behavior Questionnaire, and assessed functional constipation using ROME II and III criteria with parental questionnaires at age 2, 3, 4, and 6 years. RESULTS: Higher food fussiness at age 4 years was associated with a greater risk of functional constipation at both 4 years (OR, 1.30; 95% CI, 1.20-1.42; P < .001 per 1 SD increase) and 6 years (OR, 1.12; 95% CI, 1.03-1.23; P < .05 per 1 SD increase). The converse was also observed; previous constipation predicted a greater risk of being a fussy eater at age 4 years (constipation at 2 years: OR, 2.05; 95% CI 1.43-2.94; P < .001; constipation at 3 years: OR, 1.72; 95% CI, 1.26 2.35, P < .001). Path analyses confirmed that the association between fussy eating and functional constipation was indeed bidirectional, showing that functional constipation at age 3 years predicted fussy eater classification at age 4 years (beta = 0.06; P < .001), which in turn predicted functional constipation at age 6 years (beta = 0.08: P < .001) independent of each other. CONCLUSION: A vicious cycle might develop in which children with functional constipation develop unhealthy eating behavior, which in turn increases the risk of functional gastrointestinal disease. PMID- 25444000 TI - Neonatal hemochromatosis: diagnostic work-up based on a series of 56 cases of fetal death and neonatal liver failure. AB - OBJECTIVE: To define an algorithm to improve diagnosis of neonatal hemochromatosis (NH) related to gestational alloimmune liver disease (GALD), which is diagnosed by immunohistochemistry demonstrating activated complement at hepatocytes (IDACH). STUDY DESIGN: We assessed 56 instances of fetal death or neonatal liver failure (NLF; 2006-2009), 29 (7 stillborns, 22 NLF) with NH, and 27 (5 stillborns, 22 NLF) without NH (non-NH). Immunohistochemistry was retrospectively performed in 21 cases. Cases were grouped as follows: (1) GALD as demonstrated by IDACH (n = 17); (2) indeterminate for GALD (n = 28); or (3) alternate diagnosis found (n = 11). We compared cases of immunohistochemically proven GALD with those with an alternate diagnosis. RESULTS: Of the 12 stillborns, 7 had NH because of GALD (NH-GALD), one was undeterminate, and 4 had alternate diagnoses (GALD excluded). Of the 22 newborns with NH, 6 had NH-GALD, one had mitochondrial respiratory chain disorder (MRCD), and 15 were indeterminate for GALD. Of 22 non-NH newborns, extrahepatic siderosis (EHS) was not assessed in 13 (3 GALD, 1 alternate diagnosis [MRCD] and 9 indeterminate GALD) and excluded in 9 (5 alternate diagnoses and 4 indeterminate GALD). The only clinical features found to be associated with GALD were intrafamilial recurrence, prematurity, and EHS. CONCLUSIONS: In unexplained fetal death or NLF, the diagnosis of subsets of NH requires tissue analysis (autopsy) to assess EHS. In patients with NH, if MRCD is ruled out, NH-GALD is likely. The rate of IDACH in the diagnosis of GALD in cases without NH requires further study. PMID- 25444001 TI - Birth weight and eating behaviors of young children. AB - OBJECTIVE: To evaluate the relationships prospectively between birth weight (standardized for gestational age) and problematic eating behaviors, as reported by the parents, at different ages in 3 birth cohorts: Generation XXI (Portugal), Avon Longitudinal Study of Parents and Children (United Kingdom), and Etude des Determinants pre et postnatals precoces du developpement et de la sante de l'ENfant study (France) - HabEat project. We also aimed to explore the effect of child's current body mass index (BMI) in these relationships. STUDY DESIGN: Problematic eating behaviors were assessed at 4-6, 12-15, 24, and 48-54 months, based on caregiver's perception. Children born small, appropriate, and large for gestational age were defined based on sex-specific Kramer growth references. Associations were tested by logistic regression (OR, 95% CI) adjusted for maternal age, education, BMI, smoking, breastfeeding duration, older siblings, birth type and, in a second step, for child's current BMI World Health Organization z-score. RESULTS: Parents of children born small for gestational age (compared with appropriate gestational age) reported more often feeding difficulties and poor eating patterns (eating small quantities or needing stimulation to eat) at 4-6 months (Generation XXI: OR 2.02, 95% CI 1.40-2.94; Avon Longitudinal Study of Parents and Children: OR 1.36, 95% CI 1.14-1.62; Etude des Determinants pre et postnatals precoces du developpement et de la sante de l'ENfant OR 3.24, 95% CI 1.50-6.96), but this effect was weaker at older ages. Overall, the effects decreased, after adjustment for child's BMI, but remained significant. CONCLUSIONS: Low birth weight for gestational age was related to later difficulty in eating behaviors, primarily in the first 4-6 months. PMID- 25444002 TI - Obstructive sleep apnea syndrome increases pedestrian injury risk in children. AB - OBJECTIVES: To evaluate pedestrian behavior, including reaction time, impulsivity, risk-taking, attention, and decision-making, in children with obstructive sleep apnea syndrome (OSAS) compared with healthy controls. STUDY DESIGN: Using a case control design, 8- to 16-year-olds (n = 60) with newly diagnosed and untreated OSAS engaged in a virtual reality pedestrian environment. Sixty-one healthy children matched using a yoke-control procedure by age, race, sex, and household income served as controls. RESULTS: Children with OSAS were riskier pedestrians than healthy children of the same age, race, and sex. Children with OSAS waited less time to cross (P < .01). The groups did not differ in looking at oncoming traffic or taking longer to decide to cross. CONCLUSIONS: Results suggest OSAS may have significant consequences on children's daytime functioning in a critical domain of personal safety, pedestrian skills. Children with OSAS appeared to have greater impulsivity when crossing streets. Results highlight the need for heightened awareness of the consequences of untreated sleep disorders and identify a possible target for pediatric injury prevention. PMID- 25444003 TI - Prevalence of groups A and C rotavirus antibodies in infants with biliary atresia and cholestatic controls. AB - OBJECTIVE: To analyze the prevalence of acute asymptomatic group A and C rotavirus (RV-A and RV-C) infection in neonates with cholestasis. STUDY DESIGN: Participants were infants <180 days of age with cholestasis (serum direct or conjugated bilirubin >20% of total and >=2 mg/dL) enrolled in the Childhood Liver Disease Research and Education Network during RV season (December-May). Forty infants with biliary atresia (BA), age 62 +/- 29 days (range, 4.7-13 weeks) and 38 infants with cholestasis, age 67 +/- 44 days (range, 3-15.8 weeks) were enrolled. RESULTS: At enrollment, RV-A IgM positivity rates did not differ between infants with BA (10%) vs those without (18%) (P = .349). RV-C IgM was positive in 0% of infants with BA vs 3% in those without BA (P = .49). RV-A IgG was lower in infants with BA: 51 +/- 39 vs 56 +/- 44 enzyme-linked immunoassay unit, P = .045 but this difference may lack biological relevance as maternal RV-A IgG titers were similar between groups. Infant RV-A IgM titers at 2-6 months follow-up increased markedly vs at presentation in both infants with BA (50 +/- 30 vs 9 +/- 9) and those without (43 +/- 18 vs 16 +/- 20 enzyme-linked immunoassay unit) (P < .0001), without differences between groups. CONCLUSIONS: RV-A infection in the first 6 months of life is common in infants with cholestasis of any cause. RV-A could have different pathogenetic effects by initiating different hepatic immune responses in infants with vs without BA or could lack pathogenetic significance. PMID- 25444005 TI - Exuberant varicella-zoster exanthema and pneumonia as clinical clue for HIV infection. PMID- 25444004 TI - Predictors of health-related quality of life in adolescents with tetralogy of Fallot. AB - OBJECTIVE: To assess health-related quality of life (HRQoL) of adolescents with repaired tetralogy of Fallot (TOF) and whether impairments in HRQoL domains are associated with neurocognitive and medical factors. STUDY DESIGN: Parents of subjects with TOF and healthy referents 13-16 years of age completed the Child Health Questionnaire-Parent Form 50, generating psychosocial (PsS) and physical (PhS) health summary scores. Adolescents completed the Child Health Questionnaire Child Form 87 and concurrent in-person neurocognitive testing. We analyzed relationships of PsS and PhS scores with neurocognitive performance and medical factors. RESULTS: Compared with referents (n = 85), adolescents with TOF without a genetic diagnosis (n = 66) had lower PsS (50.9 +/- 9.4 vs 57.2 +/- 4.2, P < .001) and PhS scores (49.4 +/- 9.5 vs 55.8 +/- 4.9; P < .001). Compared with a normative sample, these adolescents with TOF had similar PsS scores (P = .52) but significantly lower PhS scores (P = .01). Within adolescents with TOF without genetic disorders, lower PsS scores were highly associated with worse neurocognitive measures, particularly the parent-reported Behavior Rating Inventory of Executive Function composite (r = -0.66, P < .001) and Parent Conners' attention deficit-hyperactivity disorder Index T score (r = -0.54, P < .001), whereas associations of PhS scores with neurocognitive measures were weaker. CONCLUSIONS: Psychosocial health status in adolescents with TOF without genetic disorders was worse than in healthy referents without risk factors for brain injury but similar to a normative sample; physical health status was worse in these adolescents than in either comparison group. Within these subjects with TOF, worse psychosocial health status was most highly associated with concurrent executive dysfunction and attention deficit-hyperactivity disorder. Optimizing HRQoL constitutes another indication for attention to neurodevelopment in children with congenital heart disease. PMID- 25444006 TI - Acute hemorrhagic edema of infancy: a rare cause of purpuric exanthema. PMID- 25444007 TI - Swimming and spinal deformities: a cross-sectional study. AB - OBJECTIVE: To compare the prevalence of spinal deformities and low back pain (LBP) in adolescent competitive swimmers and normal controls. STUDY DESIGN: This was a cross-sectional study with convenience sample of 112 adolescent competitive swimmers (62 females) compared with 217 students (106 females) of the same age (12.5 years). We designed a questionnaire to collect data on LBP and measured the angle of trunk rotation with a Bunnell scoliometer to screen for scoliosis, along with the plumbline distances for kyphosis and lordosis. Clinical cutoffs defined in the literature for detection of spinal deformities were applied. Analyses were performed using the t test and chi(2) test, and ORs and 95% CIs were calculated. RESULTS: Swimming was found to increase the risk of trunk asymmetries (OR, 1.86; 95% CI, 1.08-3.20). Swimming also increased the risk of hyperkyphosis (OR, 2.26; 95% CI, 1.35-3.77) and hyperlordosis (OR, 2.24; 95% CI, 1.06-4.73), and increased LBP in females by 2.1-fold (95% CI, 1.08-4.06). CONCLUSION: Swimming is associated with an increased risk of trunk asymmetries and hyperkyphosis. Although swimming has been considered a complete sport and a treatment option for scoliosis, our data contradict that approach, and also show a higher prevalence of LBP in females. PMID- 25444008 TI - Intestinal microbiota development in preterm neonates and effect of perinatal antibiotics. AB - OBJECTIVES: To assess the establishment of the intestinal microbiota in very low birthweight preterm infants and to evaluate the impact of perinatal factors, such as delivery mode and perinatal antibiotics. STUDY DESIGN: We used 16S ribosomal RNA gene sequence-based microbiota analysis and quantitative polymerase chain reaction to evaluate the establishment of the intestinal microbiota. We also evaluated factors affecting the microbiota, during the first 3 months of life in preterm infants (n = 27) compared with full-term babies (n = 13). RESULTS: Immaturity affects the microbiota as indicated by a reduced percentage of the family Bacteroidaceae during the first months of life and by a higher initial percentage of Lactobacillaceae in preterm infants compared with full term infants. Perinatal antibiotics, including intrapartum antimicrobial prophylaxis, affects the gut microbiota, as indicated by increased Enterobacteriaceae family organisms in the infants. CONCLUSIONS: Prematurity and perinatal antibiotic administration strongly affect the initial establishment of microbiota with potential consequences for later health. PMID- 25444009 TI - Metabolic assessment and individualized nutrition in children dependent on mechanical ventilation at home. AB - OBJECTIVE: To evaluate the nutritional and metabolic status and body composition of children on long-term mechanical ventilation using a home-based model. STUDY DESIGN: Children on home mechanical ventilation, for at least 12 hours a day, were eligible. We performed anthropometry, bioelectrical impedance analysis (BIA), actual energy intake (AEI), and indirect calorimetry in the subject's home. Agreement between measured energy expenditure (MEE) from indirect calorimetry, and estimated energy expenditure by the Schofield equation and a novel volumetric carbon dioxide production-based equation was examined. Agreement between fat mass estimates from anthropometry and BIA was examined and compared with population norms. RESULTS: We enrolled 20 children, 11 (55%) male; mean age 8.4 years (SD 4.8). Mean weight for age z-score was -0.26 (SD 1.48); 9/20 had z scores <-1 or >+1. Thirteen were underfed (AEI:MEE <90%) or overfed (AEI:MEE >110%); 11 of 19 had protein intake that was less than recommended by guidelines. Fifteen subjects were hypo- or hypermetabolic. Mean (SD) fat mass % was 33.6% (8.6) by anthropometry, which was significantly greater than matched population norms (mean 23.0%, SD 6.1, P < .001). The estimated energy expenditure by a volumetric carbon dioxide production-based equation was in stronger agreement with the MEE than the Schofield equation (mean bias 0.06%, limits -15.98% to 16.16% vs mean bias -1.31%, limits -74.3% to 72%, respectively). BIA and anthropometric fat mass values were not in agreement. CONCLUSION: A majority of children on home ventilation are characterized by malnutrition, altered metabolic status, and suboptimal macronutrient intake, in particular low protein intake. A multidisciplinary home-based model facilitates individualized energy and protein delivery and may improve outcomes in this cohort. PMID- 25444010 TI - Epidemiology of overuse injuries among high-school athletes in the United States. AB - OBJECTIVE: To examine high school overuse injury rates and patterns by sex and sport. STUDY DESIGN: High school athletes participating in the High School Reporting Information Online study were examined in a descriptive epidemiologic study. Overuse injury data for the 2006/2007-2011/2012 academic years collected via High School Reporting Information Online from a large national sample of US high schools where certified athletic trainers completed detailed injury reports were evaluated. RESULTS: From 2006/2007 to 2011/2012, a total of 2834 overuse injuries were reported during 18 889 141 athletic exposures (1.50 per 10 000 athletic exposures). Girls had greater rates of overuse injury (1.88) than boys (1.26) (rate ratio 1.50, 95% CI 1.39-1.61). The greatest rates were in girls' track and field (3.82) and girls' field hockey (2.93). Overuse injuries represented 7.7% of all injuries, ranging from a low of 1.4% of all boys' ice hockey injuries to a high of 55.7% of all boys' swimming and diving injuries. Overall, overuse injuries were evenly distributed across athletes in each year of high school (freshman, 25.6%; sophomore, 25.3%; junior, 24.9%; senior, 24.3%). However, there were distinct differences by sex. The most frequent site of injury was the lower leg (21.8%). Injuries most frequently resulted in time loss of less than 1 week (50.0%), with only 7.6% resulting in time loss greater than 3 weeks. CONCLUSIONS: Overuse injury patterns differed by sex and sport. A better understanding of overuse injury patterns and criteria for return to play may help direct preventative measures and injury management. PMID- 25444011 TI - High school principals' resources, knowledge, and practices regarding the returning student with concussion. AB - OBJECTIVE: To determine high school principals' self-reported resources, knowledge, and practices regarding the management of students returning to school following concussion. STUDY DESIGN: A cross-sectional survey of public high school principals in the state of Ohio assessed respondent and school demographics, respondent concussion training, school resources, and monitoring and accommodation practices for students with concussion. RESULTS: Of the 695 eligible high school principals, 465 (66.9%) completed the survey. Over one-third of principals (37.2%) had some form of concussion training in the past year. Those with training were more likely to promote training of other school faculty (57.4% vs 30.6%, P < .001). Principals were asked to identify school personnel who are designated as case managers for students with concussion. Schools without a designated case manager were less likely to have an athletic trainer (P < .001) and had fewer students (median 424.5 vs 599) than schools with a case manager. Principals could list at least 1 faculty designee who communicates with health professionals more often for student-athletes than for nonathletes (P < .001). Most principals were willing to provide students with short-term academic accommodations, but 30.1% required a health professional's note prior to making any academic changes. Only 32% of principals reported providing families with a written academic plan following concussion. CONCLUSIONS: Schools differ in their resources and management strategies for students returning to school after concussion. Understanding these differences can help health professionals to overcome potential barriers in managing their school-aged patients with concussion. PMID- 25444013 TI - Evaluating the child with acute hip pain ("irritable hip") in a Lyme endemic region. AB - OBJECTIVES: To estimate the prevalence of Lyme infection among children presenting with acute, nontraumatic hip pain in a Lyme endemic region and to investigate predictors of Lyme disease among children with suspected transient synovitis. STUDY DESIGN: Retrospective cross-sectional study of children with unilateral hip pain who were brought to an academic pediatric emergency department. Cases were identified by specific discharge diagnoses or radiologic imaging. Lyme infection was determined by serologic criteria, and a minimum prevalence was estimated for the entire study population; maximum estimate was determined for those who had Lyme testing. Multivariate regression was used to identify discriminating clinical findings for Lyme disease among those with nonseptic arthritis. RESULTS: Three hundred eighty-five children with a median age of 5.4 years were studied; 15% of children had fever >=38.0 degrees C and 40% had pain for less than 24 hours at evaluation. Lyme infection was identified in 5.2% (95% CI 3.2%-7.9%). A maximum estimate of Lyme disease was calculated to be 8.0% (95% CI 4.9%-12.0%). Regression analysis did not identify any practical clinical predictors of Lyme infection. CONCLUSIONS: Lyme infection occurred in approximately 5% of children with acute, nontraumatic hip pain who were evaluated in a pediatric emergency department in a Lyme endemic region. Based on this estimate, we do not recommend routine Lyme testing when transient synovitis is suspected; however, Lyme testing should be considered in children having laboratory studies obtained for alternative diagnoses such as septic/pyogenic arthritis and for those with an atypical clinical course for transient synovitis. PMID- 25444012 TI - The National Spina Bifida Patient Registry: profile of a large cohort of participants from the first 10 clinics. AB - OBJECTIVE: To use data from the US National Spina Bifida Patient Registry (NSBPR) to describe variations in Contexts of Care, Processes of Care, and Health Outcomes among individuals with spina bifida (SB) receiving care in 10 clinics. STUDY DESIGN: Reported here are baseline cross-sectional data representing the first visit of 2172 participants from 10 specialized, multidisciplinary SB clinics participating in the NSBPR. We used descriptive statistics, the Fisher exact test, chi(2) test, and Wilcoxon rank-sum test to examine the data. RESULTS: The mean age was 10.1 (SD 8.1) years with slightly more female subjects (52.5%). The majority was white (63.4%) and relied upon public insurance (53.5%). One third had sacral lesions, 44.8% had mid-low lumbar lesions, and 24.9% had high lumbar and thoracic lesions. The most common surgery was ventricular shunt placement (65.7%). The most common bladder-management technique among those with bladder impairment was intermittent catheterization (69.0%). Almost 14% experienced a pressure ulcer in the last year. Of those ages 5 years or older with bowel or bladder impairments, almost 30% were continent of stool; a similar percentage was continent of urine. Most variables were associated with type of SB diagnosis. CONCLUSION: The NSBPR provides a cross section of a predominantly pediatric population of patients followed in specialized SB programs. There were wide variations in the variables studied and major differences in Context of Care, Processes of Care, and Health Outcomes by type of SB. Such wide variation and the differences by type of SB should be considered in future analyses of outcomes. PMID- 25444014 TI - The optimal postnatal growth trajectory for term small for gestational age babies: a prospective cohort study. AB - OBJECTIVES: To identify an optimal growth trajectory for term small for gestational age (SGA) babies from birth to 7-years-old. STUDY DESIGN: Data were from the Collaborative Perinatal Project, a US multicenter prospective cohort study from 1959-1976. Five weight growth trajectories of the 1957 term SGA babies were grouped by a latent class model. We selected the optimal growth pattern based on the lowest overall risks of childhood diseases. RESULTS: Compared with appropriate for gestational age children, SGA babies with no catch-up growth (439, 22.4%) had higher risks of infection in infancy (aOR 1.2, 95% CI 1.0-1.6), growth restriction (11.2, 8.6-14.6), and low IQ (2.1, 1.7-2.8) at age 7 years. Those with excessive catch-up growth (176, 8.9%) had higher risks of overweight/obesity (7.5, 5.4-10.5) and elevated blood pressure (1.7, 1.1-2.4) at age 7 years. Babies with slow catch-up growth (328, 16.8%) or regression after 4 months (285, 14.6%) were associated with higher risks of low IQ (1.6, 1.2-2.1) and growth restriction (2.2, 1.5-3.2), respectively. Only babies with appropriate catch-up growth (729, 37.3%) did not have increased risk of adverse outcomes. Further, we also tested linear growth trajectories with similar findings. CONCLUSIONS: The optimal growth trajectory for term SGA infants may be fast catch up growth to about the 30th percentile in the first several months, with modest catch-up growth thereafter, to be around the 50th percentile by 7-years-old. PMID- 25444015 TI - Population screening for von Willebrand disease in adolescents with heavy menstrual bleeding. AB - We used Ohio Medicaid data to determine frequency and predictors of laboratory screening for von Willebrand disease and other bleeding disorders in adolescents with heavy menses. Despite expert guidelines, screening was performed in only a minority of subjects (<15% of those with heavy menses and <25% of those with menstrual bleeding defined as severe), with younger adolescents and those from more urban counties more likely to undergo screening. PMID- 25444016 TI - On the need for precise, concise communication during resuscitation: a proposed solution. PMID- 25444017 TI - Heterotopic ossification in fibrodysplasia ossificans progressiva. PMID- 25444018 TI - Building Cognition: The Construction of Computational Representations for Scientific Discovery. AB - Novel computational representations, such as simulation models of complex systems and video games for scientific discovery (Foldit, EteRNA etc.), are dramatically changing the way discoveries emerge in science and engineering. The cognitive roles played by such computational representations in discovery are not well understood. We present a theoretical analysis of the cognitive roles such representations play, based on an ethnographic study of the building of computational models in a systems biology laboratory. Specifically, we focus on a case of model-building by an engineer that led to a remarkable discovery in basic bioscience. Accounting for such discoveries requires a distributed cognition (DC) analysis, as DC focuses on the roles played by external representations in cognitive processes. However, DC analyses by and large have not examined scientific discovery, and they mostly focus on memory offloading, particularly how the use of existing external representations changes the nature of cognitive tasks. In contrast, we study discovery processes and argue that discoveries emerge from the processes of building the computational representation. The building process integrates manipulations in imagination and in the representation, creating a coupled cognitive system of model and modeler, where the model is incorporated into the modeler's imagination. This account extends DC significantly, and we present some of the theoretical and application implications of this extended account. PMID- 25444019 TI - Fuzzy logic-based diagnostic algorithm plus ventricles depolarization morphology algorithm for implantable cardioverter-defibrillators. PMID- 25444020 TI - Transcatheter pulmonary valvulation: current indications and available devices. AB - Since the first transcatheter implantation of a pulmonary valve in 2000 in a twelve year-old boy with a dysfunctional right ventricle to pulmonary artery conduit by Philip Bonhoeffer and Younes Boudjemline, the Melody((r)) valve has become worldwide used. It represents an efficient alternative to open-heart surgery. We aimed in this comprehensive review to describe the current indications of percutaneous pulmonary valve implantation, the devices currently used and the clinical results. PMID- 25444021 TI - Checkpoint immunotherapy for cancer: superior survival, unaccustomed toxicities. AB - Novel cancer immunotherapy antibodies are moving from clinical trials into routine practice, delivering sustained benefits and prolonged survival to patients with melanoma, lung, kidney and other cancers. These immunostimulatory antibodies non-specifically activate the patient's own immune system by inhibiting immune system checkpoint proteins. This mechanism of action is entirely different to traditional cancer treatments, such as chemotherapy. While there are virtually no immediate toxicities, serious life-threatening autoimmune side-effects such as colitis, dermatitis, hypophysitis, pneumonitis and hepatitis can occur, sometimes starting long after the treatment has been given. Recognition, referral and prompt treatment with immunosuppressive drugs like corticosteroids can control these immune-related side-effects without compromising efficacy. This exciting new class of drugs is defining a new paradigm in cancer therapy. PMID- 25444023 TI - Interoceptive sensitivity, body image dissatisfaction, and body awareness in healthy individuals. AB - Relationships among interoceptive sensitivity (IS), body image dissatisfaction, body mass index (BMI), and self-reported body awareness were investigated in a cross-sectional study. Eighty-two Norwegian high school students and 70 Hungarian undergraduate university students participated in the study. Subjects completed two questionnaires (Body Image Ideals Questionnaire - BIQ; Body Awareness Questionnaire - BAQ) followed by the assessment of interoceptive sensitivity using the Mental Tracking Method (MTM). An inverse, medium-level relationship between body image dissatisfaction and IS was found in both the Norwegian and the Hungarian samples. The relationships between IS and self-reported body awareness, and between body image dissatisfaction and BMI were uniformly non-significant in both samples. Predictors of body image dissatisfaction were resting heart rate, gender, and IS in the regression analysis after controlling for BMI, age, and nationality. The negative relationship between IS and body image dissatisfaction described in patients with anorexia nervosa also exists in healthy individuals. There is no direct connection between IS and self-reported body awareness. PMID- 25444022 TI - A research agenda for gender and substance use disorders in the emergency department. AB - For many years, gender differences have been recognized as important factors in the etiology, pathophysiology, comorbidities, and treatment needs and outcomes associated with the use of alcohol, drugs, and tobacco. However, little is known about how these gender-specific differences affect ED utilization; responses to ED-based interventions; needs for substance use treatment and barriers to accessing care among patients in the ED; or outcomes after an alcohol-, drug-, or tobacco-related visit. As part of the 2014 Academic Emergency Medicine consensus conference on "Gender-Specific Research in Emergency Care: Investigate, Understand and Translate How Gender Affects Patient Outcomes," a breakout group convened to generate a research agenda on priority questions related to substance use disorders. PMID- 25444024 TI - Regional variations in in-hospital mortality, care processes, and spending in acute ischemic stroke patients in Japan. AB - BACKGROUND: Little is known about the regional variations in ischemic stroke care in Japan. This study investigates the regional variations and associations among outcomes, care processes, spending, and physician workforce availability in acute ischemic stroke care. METHODS: Using administrative claims data from National Claims Database, we identified National Health Insurance beneficiaries aged 65 years and older and Long Life Medical Care System beneficiaries from 9 prefectures who had been hospitalized for acute ischemic stroke between April 2010 and March 2012. Patients were grouped according to their subprefectural regions of residence known as secondary medical areas (SMAs). Performances in 8 outcome and process of care measures were analyzed in each SMA. Multilevel regression models with 2 levels (patient and regional) were used to analyze age- and sex-adjusted in-hospital mortality, hospitalization spending, and tissue plasminogen activator (tPA) utilization rate. The associations between regional supply of physicians for stroke care and the various quality measures were investigated. RESULTS: We analyzed 49,440 acute ischemic stroke patients. The regional variations among SMAs in in-hospital mortality, spending, and tPA utilization were 3.2-, 1.7-, and 5.9-fold, respectively. Higher physician supply was significantly associated with lower in-hospital mortality and higher spending. Additionally, spending had a significantly negative correlation with regional continuity of care planning rate but a significantly positive correlation with rehabilitation rate. CONCLUSIONS: The study revealed substantial regional variations in Japanese ischemic stroke care. Improving the allocative efficiency of physicians and establishing continuity of care networks may be useful in mitigating regional disparities and reconstructing the stroke care system. PMID- 25444025 TI - The application of cycling and cycling combined with feedback in the rehabilitation of stroke patients: a review. AB - Stroke is a leading cause of long-term disabilities, such as hemiparesis, inability to walk without assistance, and dependence of others in the activities of daily living. Motor function rehabilitation after stroke demands for methods oriented to the recovery of the walking capacity. Because of the similarities with walking, cycling leg exercise may present a solution to this problem. The aim of this article is to review the state of the art applications of cycling leg exercise as a (1) motor function rehabilitation method and an (2) aerobic training method for stroke patients as well as the commonly used (3) assessment tools. The cycling characteristics and applications, the applied test protocols as well as the tools used to assess the state and the recovery of patients and types of cycling devices are presented. In addition, the potential benefits of the use of other therapies, like feedback, together with cycling are explored. The application of cycling leg exercise alone and combined with feedback in stroke rehabilitation approaches has shown promising results. Positive effects on motor abilities were found in subacute and chronic patients. However, larger and normalized studies and assessments are needed because there is a high heterogeneity in the patients' characteristics, protocols and metrics. This wil allow the comparison between different studies related with cycling. PMID- 25444026 TI - Cerebral aspergillosis in a diabetic patient leading to cerebral artery occlusion and ischemic stroke: a case report and literature review. AB - Cerebral aspergillosis is a rare and highly fatal hematogenous infection most commonly found in immune compromised patients. From the onset of neurologic symptoms, the median reported rate of survival is between 5 and 9 days. Compounded with increased hemorrhagic risks and the lack of specificity in both clinical presentation and traditional imaging, a fast and noninvasive method of definitive diagnosis is necessary if there is to be any hope for positive outcomes. We describe the case of a 50-year-old female diabetic with a history of otitis media, an uncharacterized inflammatory nasopharyngeal process, and prior ischemic strokes who presented with a new cerebral infarction in the setting of an angioinvasive fungal infection of the large cerebral arteries. We also present a literature review of aspergillosis detection and treatment in hopes that future cases will be diagnosed in a timely manner and more patients may be saved. PMID- 25444028 TI - Does dabigatran increase the risk of delayed hematoma expansion in a rat model of collagenase-induced intracerebral hemorrhage? AB - BACKGROUND: Delayed hematoma expansion is common in intracerebral hemorrhage (ICH) patients using warfarin. Dabigatran induces fewer hemorrhagic complications compared with warfarin. However, the natural history of dabigatran-related ICH remains unclear. This study aims to clarify whether dabigatran increases the risk of delayed hematoma expansion in a rat ICH model. METHODS: Male Wistar rats were treated with 2 dosages of dabigatran etexilate (DE: 10 mg/kg, n = 4; 20 mg/kg, n = 3) 30 minutes before ICH induction using intraparenchymal collagenase infusion. Five rats that received saline were used as controls. Magnetic resonance imaging was performed 24 and 48 hours after ICH induction, and serial hematoma volume measurements were obtained using T2-weighted images. Expanded hematoma volumes were calculated by subtracting hematoma volumes at 48 hours from those at 24 hours; the hematoma expansion rate was defined as the ratio of the expanded hematoma volume to that at 24 hours. RESULTS: The mean hematoma volumes (mm(3)) at 24 hours were 13.3 +/- 3.3 in the control group, 14.9 +/- 2.0 in the 10 mg/kg DE group, and 18.9 +/- 7.6 in the 20 mg/kg DE group with no significant intergroup differences (P = .26). The mean hematoma volumes at 48 hours (mm(3)) were 21.7 +/- 4.9 in the control group, 22.1 +/- 5.0 in the 10 mg/kg DE group, and 23.4 +/- 5.8 in the 20 mg/kg DE group with no significant intergroup differences (P = .90). Consequently, there were no significant intergroup differences in the hematoma expansion rates (P = .33). CONCLUSIONS: This experimental study of a rat ICH model indicates that dabigatran-related ICH may not increase the risk of delayed hematoma expansion. PMID- 25444027 TI - Circulating CD133+ CD34+ progenitor cells and plasma stromal-derived factor 1alpha: predictive role in ischemic stroke patients. AB - Circulating progenitor cells and stromal-derived factor-1alpha (SDF-1alpha) have been suggested to participate in tissue repair after ischemic injury. However, the predictive role of circulating CD133+ CD34+ progenitors and plasma SDF-1alpha in ischemic stroke (IS) patients remains unknown. In this study, we recruited 95 acute IS patients, 40 at-risk subjects, and 30 normal subjects. The National Institutes of Health Stroke Scale (NIHSS), infarct volume, and carotid intima media thickness (IMT) were determined at day 1 and the modified Rankin scale (mRS) of functional outcome was assessed at day 21. The levels of circulating CD133+ CD34+ cells and plasma SDF-1alpha were determined by flow cytometry and enzyme-linked immunosorbent assay, respectively. Our data showed that: (1) the levels of CD133+ CD34+ cells were lower in at-risk subjects and IS patients at admission (day 1) when compared with normal controls; (2) the day 1 level of CD133+ CD34+ cells varied in IS subgroups and inversely correlated with NIHSS and carotid IMT and the level of SDF-1alpha inversely correlated with NIHSS and infarct volume; (3) the increment rates of circulating CD133+ CD34+ cells and plasma SDF-1alpha within the first week were correlated; and (4) patients with a higher level of CD133+ CD34+ cells at day 7 had a low mRS. The increased rate of CD133+ CD34+ cells in the first week was inversely associated with mRS. In conclusion, our findings demonstrate that the circulating CD133+ CD34+ progenitor cells and plasma SDF-1alpha can be used as predictive parameters for IS severity and outcome. PMID- 25444029 TI - Unilateral symptomatic intracranial arterial stenosis and myopathy in an adolescent with Graves disease: a case report of an high-resolution magnetic resonance imaging study. AB - Vascular and muscular involvements in Graves disease (GD) are rare. Here, we report a case of a 17-year-old patient with unilateral symptomatic middle cerebral artery stenosis concurrent with GD and myopathy. He presented with a 1 day history of acute severe right-sided hemiparesis and aphasia and a 3-week history of high metabolic syndrome. The pathogenesis of the stenosis is most likely vasculitis rather than atherosclerosis, based on contrast-enhanced high resolution magnetic resonance imaging showing concentric wall enhancement. We suggest that lipid storage myopathy is secondary to GD, and it is likely mitochondrial dysfunction or immune dysfunction induced by GD responsible for the myopathy and that magnetic resonance spectroscopy (MRS) is capable of establishing the diagnosis of myopathy. Thus, MRS can be used for follow-up evaluations of the myopathy along with the pathology biopsy. PMID- 25444030 TI - Reappearance of free-floating carotid thrombus after discontinuation of anticoagulant therapy. AB - A 73-year-old woman who suddenly developed left hemiparesis was admitted to our hospital. Ultrasonography on admission showed a free-floating thrombus (FFT) attached to an ulcerative plaque in the right common carotid artery. The FFT almost disappeared during treatment with intravenous anticoagulation therapy for acute stroke, but it reappeared when the therapy was discontinued. She underwent endarterectomy on day 13, after which she was free from stroke recurrence. PMID- 25444031 TI - Prevalence of triggering factors in acute stroke: hospital-based observational cross-sectional study. AB - BACKGROUND: Although chronic risk factors for stroke are reasonably well understood, the acute precipitants, or triggers, of stroke relatively remain understudied. Identification of particular time periods during which stroke risk is elevated could prove a valuable strategy to reduce stroke incidence through the introduction of appropriate prevention strategies during a period of vulnerability. The aim of this study was to determine the prevalence of trigger factors in acute stroke patients and to investigate the association of the presence of trigger factors with initial stroke severity at presentation (National Institutes of Health Stroke Scale (NIHSS) score in ischemic stroke patients and volume of hematoma in hemorrhagic stroke patients). METHODS: This was a hospital-based observational cross-sectional study. All consecutive patients of recent stroke (reporting within 1 week of stroke onset) were included in the study. This study examined the prevalence of 11 predefined triggers (including both well-established and potential triggers) in predefined hazard periods. RESULTS: In total, 290 patients participated in the study. Presence of any trigger factor out of 11 trigger factors studied was seen in 128 (44.2%) of 290 patients, 104 (46.4%) of 224 ischemic stroke patients and 24 (36.4%) of 66 hemorrhagic stroke patients. Psychological stress was present in 51 (17.6%) patients, among psychological stress: stressful life event in 34 (11.7%), negative affect in 17 (5.9%), acute alcohol abuse in 31 (10.7%), clinical infections in 24 (8.3%), and anger and coffee intake in 12 (4.1%) each. Sexual activity, trauma, and surgery were present in 5 (1.7%), 4 (1.4%), and 5 (1.7%) patients, respectively. None of the patients reported exposure to recreational drug abuse, startling event, and unusual vigorous physical exertion in hazard periods. Two or more trigger factors were present in 16 (5.5%) patients. Clinical variables independently associated with the presence of trigger factors in acute stroke after multivariate analysis were younger age (<60 years) and stroke severity at initial presentation (ie, higher NIHSS score and higher hematoma volume). CONCLUSIONS: Trigger factors were present in 44.2% of acute stroke patients. Psychological stress (17.6%), acute alcohol abuse (10.7%), and clinical infections (8.3%) were the most common triggers. Younger age (<60 years) and stroke severity at initial presentation were independently associated with the presence of trigger factors in acute stroke patients. However, these associations need to be further explored in community-based studies. PMID- 25444032 TI - Relation between cardiovascular disease risk markers and brain infarcts detected by magnetic resonance imaging in an elderly population. AB - BACKGROUND: Established cardiovascular risk markers, such as hypertension, are associated with increased risk of brain infarcts. The newer markers N-terminal pro-brain natriuretic peptide, troponin I, C-reactive protein, and cystatin C may affect the risk of cardiovascular events and potentially, thereby, also stroke. We investigated the association between established and new risk markers for cardiovascular disease and brain infarcts detected by magnetic resonance imaging (MRI) at age 75. METHODS: Four hundred six randomly selected subjects from the Prospective Investigation of the Vasculature in Uppsala Seniors study were examined with MRI of the brain at age 75. Blood samples, measurements, and dedicated questionnaires at age 70 were used for analysis of risk markers. A history of diseases had been obtained at age 70 and 75. MRI was evaluated regarding lacunar and cortical infarcts. Univariate associations between outcomes and risk markers were assessed with logistic regression models. RESULTS: One or more infarcts were seen in 23% of the subjects (20% had only lacunar infarcts, 1% had only cortical infarcts, and 2% had both). Hypertension (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.4, 4.7) and obesity (OR 1.3; CI 1.0, 1.8) were significantly associated with increased risk of brain infarction. The newer risk markers were not significantly associated with the brain infarcts. CONCLUSIONS: The new markers were not associated with the predominantly lacunar infarcts in our 75-year-old population, why troponin I and NT-proBNP may be associated mainly with cardioembolic infarcts as shown recently. PMID- 25444033 TI - [Congenital Horner's syndrome]. PMID- 25444034 TI - [Role of parents in paediatric emergencies: tradition, conflict or improvement]. PMID- 25444035 TI - [SEIP-SERPE-SEOP Consensus document on the treatment of uncomplicated acute osteomyelitis and septic arthritis]. AB - This is a Consensus Document of the Spanish Society of Paediatric Infectious Diseases (Sociedad Espanola de Infectologia Pediatrica), Spanish Society of Paediatric Rheumatology (Sociedad Espanola de Reumatologia Pediatrica) and the Spanish Society of Paediatric Orthopaedics (Sociedad Espanola de Ortopedia Pediatrica), on the treatment of uncomplicated acute osteomyelitis and septic arthritis. A review is presented on the medical and surgical treatment of acute osteoarticular infection, defined as a process with less than 14 days of symptomatology, uncomplicated and community-acquired. The different possible options are evaluated based on the best available scientific knowledge, and a number of evidence-based recommendations for clinical practice are provided. PMID- 25444036 TI - Can we rely on the antiretroviral treatment as the only means for human immunodeficiency virusprevention? A Public Health perspective. AB - The evidence that supports the preventive effect of combination antiretroviral treatment (cART) in HIV sexual transmission suggested the so-called 'treatment as prevention' (TAP) strategy as a promising tool for slowing down HIV transmission. As the messages and attitudes towards condom use in the context of TAP appear to be somehow confusing, the aim here is to assess whether relying on cART alone to prevent HIV transmission can currently be recommended from the Public Health perspective. A review is made of the literature on the effects of TAP strategy on HIV transmission and the epidemiology of other sexual transmitted infections (STIs) in the cART era, and recommendations from Public Health institutions on the TAP as of February 2014. The evolution of HIV and other STIs in Barcelona from 2007 to 2012 has also been analysed. Given that the widespread use of cART has coincided with an increasing incidence of HIV and other STIs, mainly amongst men who have sex with men, a combination and diversified prevention methods should always be considered and recommended in counselling. An informed decision on whether to stop using condoms should only be made by partners within stable couples, and after receiving all the up-to-date information regarding TAP. From the public health perspective, primary prevention should be a priority; therefore relying on cART alone is not a sufficient strategy to prevent new HIV and other STIs. PMID- 25444037 TI - [Usefulness of intervention programs for improving antibiotic prescribing]. PMID- 25444038 TI - Is high-dose intravenous fosfomycin safe for the treatment of patients prone to heart failure? PMID- 25444039 TI - [Usefulness of echocardiographic screening in invasive pneumococcal infections]. PMID- 25444040 TI - [Pasteurella multocida bacteremia and prosthetic joint infection]. PMID- 25444041 TI - [Safety in the Microbiology laboratory]. AB - The normal activity in the laboratory of microbiology poses different risks - mainly biological - that can affect the health of their workers, visitors and the community. Routine health examinations (surveillance and prevention), individual awareness of self-protection, hazard identification and risk assessment of laboratory procedures, the adoption of appropriate containment measures, and the use of conscientious microbiological techniques allow laboratory to be a safe place, as records of laboratory-acquired infections and accidents show. Training and information are the cornerstones for designing a comprehensive safety plan for the laboratory. In this article, the basic concepts and the theoretical background on laboratory safety are reviewed, including the main legal regulations. Moreover, practical guidelines are presented for each laboratory to design its own safety plan according its own particular characteristics. PMID- 25444042 TI - A comparative evaluation of the sensitivity of one automated and one manual nucleic acid extraction methods for the performance of the Speed-oligoTM Direct Mycobacterium Tuberculosis assay. PMID- 25444043 TI - [Infections due to Mycobacterium simiae]. AB - Mycobacterium simiae is a slow-growing photochromogenic environmental mycobacterium, first described in 1965. Rarely associated with human infections, possibly due to its limited pathogenicity, it mainly produces lung infection in immunocompetent elderly patients with underlying lung disease, and in disseminated infections in immunosuppressed young patients with AIDS. A microbiological culture is needed to confirm the clinical suspicion, and genetic sequencing techniques are essential to correctly identify the species. Treating M. simiae infections is complicated, owing to the multiple resistance to tuberculous drugs and the lack of correlation between in vitro susceptibility data and in vivo response. Proper treatment is yet to be defined, but must include clarithromycin combined with other antimicrobials such as moxifloxacin and cotrimoxazole. It is possible that M. simiae infections are undiagnosed. PMID- 25444044 TI - [Factors determining irregular attendance to follow-up visits among human immunodeficiency virus patients: results of the hospital survey of patients infected with human immunodeficiency virus]. AB - INTRODUCTION: To describe the occurrence of non-regular attendance to follow-up visits among HIV patients and to analyze the determining factors. METHODS: One day survey carried out annually (2002-2012) in public hospitals. Epidemiological, clinical and behavioral data are collected in all HIV-infected inpatients and outpatients receiving HIV-related care on the day of the survey. "Non-regular attendance to a follow-up visit" was defined as sporadic attendance to the medical appointments, according to the judgment of the attending physician. Descriptive and bivariate analyses were performed, and factors associated to non regular attendance to follow-up visits were estimated using logistic regression. RESULTS: A total of 7,304 subjects were included, of whom 13.7% did not attend medical appointments regularly. Factors directly associated with non-regular attendance were: age between 25-49 years; birth in Sub-Saharan Africa or Latin America; low educational level; being homeless or in prison; living alone or in closed institutions; being unemployed or retired; being an intravenous drug user; not using a condom at last sexual encounter, and injecting drugs in the last 30 days. Conversely, HIV diagnosis within the last year and being men who have sex with men were factors inversely associated with non-regular attendance to follow up visits. CONCLUSION: In spite of health care beings free of charge for everyone in Spain, social factors can act as barriers to regular attendance to medical appointments, which, in turn, can endanger treatment effectiveness in some population groups. This should be taken into account when planning HIV policies in Spain. PMID- 25444045 TI - Evaluation and optimization of the Sysmex UF1000i system for the screening of urinary tract infection in primary health care elderly patients. AB - OBJECTIVE: Urinary tract infections (UTIs) are a common problem in the elderly population. Urine culture is still considered the "gold standard" to diagnose infection in this population. However, urine cultures are laborious and costly, and most samples will yield no growth. METHODS: An evaluation was made of the Sysmex UF-1000i flow cytometer as a screening tool for UTI in an elderly population older than 65 years who lived in the community, using 346 urine samples submitted for culture. RESULTS: The Receiver Operating Characteristic (ROC) analysis showed a significant difference (P<0.01) between 0.98 bacteria area under the curve value and 0.82 of white blood cells (WBC). The combination of both counts for screening did not show any improvement in specificity or sensitivity. According to our data, the use of a single cut-off point of 200bacteria/MUL is suggested, in which the sensitivity and specificity were 99.11% and 91.59%, respectively, with a NPV of 99.49%. Moreover, this cut-off value could avoid 60.24% of the samples to be cultured, with a minimal false negative results rate of 0.87%. CONCLUSIONS: The stratification of age groups stratification helps in selecting a more adjusted Sysmex UF1000i cut-off limit, leading to an improvement in the screening parameters that would imply a better management of these infections, as well as a high reduction in the workload and cost savings. PMID- 25444047 TI - Hepatitis C virus infection and its relationship to certain sexual practices in men-who-have-sex-with-men in Spain: results from the European MSM internet survey (EMIS). AB - OBJECTIVES: To compare sexual practices and risk behaviours between MSM who were first diagnosed with hepatitis C (HCV) in the previous 12 months and those who were never diagnosed; and, to identify factors associated with a diagnosis of HCV. METHODS: The European-MSM-Internet-Survey (EMIS) was implemented for 3 months during 2010, mainly on websites for MSM. Data on socio-demographic characteristics, sexual behaviour, drug use, STI history, and other sexual health variables were collected. The Chi-square test and logistic regression analysis were used to analyse the data. RESULTS: Data from 13,111 respondents were analysed. The proportion of MSM who had ever been diagnosed with HCV infection was 1.9% (n=250), and of those currently infected with the virus was 0.6% (n=78). The percentage of those first diagnosed in the last 12 months was 0.4% (n=46), of whom 70% were HIV-negative and 22% had HIV coinfection. Having a first diagnosis of HCV in the last 12 months was more common among HIV-positive than among HIV negative MSM (0.9% vs 0.4%) and among MSM born abroad than among Spanish-born (0.7% vs 0.3%). MSM diagnosed with HCV in the last 12 months were more likely to have had: more than 10 sexual partners, sex abroad, receptive anal intercourse, insertive/receptive fisting, and unprotected anal intercourse with non-steady partners of unknown or discordant HIV-status. Likewise, they reported more frequent visits to sex-focused venues, higher drug use, as well as a higher proportion of STI diagnosis. In the multivariate model, visiting a public sex focused venue, practicing receptive fisting, using erection enhancing medication and having a diagnosis of syphilis were independently associated with a first diagnosis of HCV in the last 12 months. CONCLUSIONS: HCV infection does not seem to be restricted to HIV-infected MSM. Certain sexual behaviour (fisting, visiting sex-focused venues), drug use, and ulcerative STI seem to be associated with a diagnosis of HCV. PMID- 25444046 TI - [Selection of indicators for continuous monitoring of the impact of programs optimizing antimicrobial use in Primary Care]. AB - OBJECTIVES: To determine core indicators for monitoring quality prescribing in Primary Care based on the evidence, and to assess the feasibility of these indicators for monitoring the use of antibiotics. METHODS: A literature review was carried out on quality indicators for antimicrobial prescribing through an electronic search limited to the period 2001-2012. It was completed with an "ad hoc" search on the websites of public national and international health services. Finally, indicators were chosen by consensus by a multidisciplinary group of professionals dedicated to managing infections from several areas. The feasibility and applicability of these indicators was verified through the reporting and use of data in the prescription database. RESULTS: Twenty two indicators were found. The consensus group selected 16 indicators. Eleven of them measure the specific antimicrobial selection, and 5 are consumption rates. The indicators were successfully applied to the prescription database, being able to make comparisons between different geographical areas and to observe trends in prescriptions. CONCLUSION: The definition of a basic set of indicators to monitor antibiotic use adapted to local conditions is required. The results of these indicators can be used for feedback to professionals and for evaluating the impact of programs aimed at improving antimicrobial use. PMID- 25444048 TI - [Syphilis and human immunodeficiency virus infection: an endemic infection in men who have sex with men]. AB - OBJECTIVE: to analyse epidemiological, clinical, and analytical features of HIV infected men who have sex with men (MSM) diagnosed with syphilis in the Infectious Diseases Unit (Hospital Virgen de la Victoria, Malaga, Spain) during 2004-2013. PATIENTS AND METHODS: An observational study was conducted on 196 syphilis episodes in 167 MSM infected with HIV (2004-2013). Epidemiological, clinical, and analytical data were collected. Annual syphilis incidence among HIV MSM is calculated as the number of syphilis episodes among MSM in one year divided by the number of MSM followed up in that year. RESULTS: Incidence ranged from 1.2% (2007) to 7.8% (2012). There were asymptomatic episodes in 42.8% cases, and an HIV-syphilis coincident diagnosis in 28.5%. CONCLUSIONS: The annual incidence of syphilis has increased within HIV infected MSM. One third of the syphilis episodes were simultaneous to HIV diagnosis and near half of them were asymptomatic. PMID- 25444049 TI - [Microbiological diagnosis of human immunodeficiency virus infection]. AB - This document attempts to update the main tasks and roles of the Clinical Microbiology laboratory in HIV diagnosis and monitoring. The document is divided into three parts. The first deals with HIV diagnosis and how serological testing has changed in the last few years, aiming to improve diagnosis and to minimize missed opportunities for diagnosis. Technological improvements for HIV Viral Load are shown in the second part of the document, which also includes a detailed description of the clinical significance of low-level and very low-level viremia. Finally, the third part of the document deals with resistance to antiretroviral drugs, incorporating clinical indications for integrase and tropism testing, as well as the latest knowledge on minority variants. PMID- 25444050 TI - Clinical review of 95 patients with 46,XX disorders of sex development based on the new Chicago classification. AB - STUDY OBJECTIVE: The aim of our study was to determine the etiologic distribution of 46,XX disorder of sexual development (DSD) according to the new DSD classification system and to evaluate the clinical features of this DSD subgroup in our patient cohort. PARTICIPANTS: The evaluation criteria and clinical findings of 95 46,XX patients were described by clinical presentation, gonadal morphology, genital anatomy, associated dysmorphic features, presence during prenatal period with/without postnatal virilization, hormonal characteristics, and presence or absence of steroidogenic defects among 319 patients with DSD. RESULTS: Types and ratios of each presentation of our 95 patients with 46,XX DSD were as follows: 82 had androgen excess (86.3%): (74 had classical congenital adrenal hyperplasia, 2 had CAH variant possibility of P450-oxidoreductase gene defect), 6 had disorders of ovarian development (6.3%): (1 patient had gonadal dysgenesis with virilization at birth with bilateral streak gonad, 4 patients had complete gonadal dysgenesis, and 1 patient had ovotesticular DSD) and 7 had other 46,XX DSD. Two sisters, who had 46,XX complete gonadal dysgenesis,were diagnosed with Perrault Syndrome with ovarian failure due to streak gonads and associated with sensorineural deafness. CONCLUSION: 46,XX DSD are usually derived from intrauterine virilization and CAH is the most common cause of 46,XX DSD due to fetal androgen exposure. PMID- 25444051 TI - Correlates of HPV knowledge among low-income minority mothers with a child 9-17 years of age. AB - STUDY OBJECTIVE: To assess the level of HPV knowledge among low income, minority mothers with a child between the ages of 9-17 y. DESIGN: Women who sought care at a university-based clinic and had at least 1 child aged 9 to 17 years were approached. A total of 638 mothers were recruited. Only those who had heard of HPV were included in the correlation analyses (n = 468). MAIN OUTCOME MEASURES: HPV knowledge was assessed utilizing a self-administered questionnaire consisting of 20 questions. RESULTS: There were differences between those who had heard of HPV and those who had not. More of those who had not heard of HPV were Hispanic (63%), low-income (89%), and did not graduate high school (59%). Of those who had heard of HPV, the majority did not answer 50% of questions correctly. Few knew the vaccine could prevent genital warts (19.7%). Factors independently associated with HPV knowledge included age, personal history of HPV, cervical dysplasia or cervical cancer, acquiring knowledge from >= 2 sources, having known someone with HPV or cervical cancer, having seen a brochure on the vaccine, and having seen an advertisement for the vaccine. CONCLUSIONS: Knowledge regarding HPV is low among low-income women with children in the target age range for HPV vaccination. Increased awareness should focus on genital warts and other cancers, since this population has virtually no knowledge of other health outcomes related to HPV infection. Educational programs tailored to this population need to be developed to increase vaccination. PMID- 25444052 TI - Contraceptive choices pre and post pregnancy in adolescence. AB - STUDY OBJECTIVE: The main aim of this study is to evaluate the impact of adolescent pregnancy in the future contraceptive choices. A secondary aim is to verify whether these choices differ from those made after an abortion. DESIGN: Retrospective study. SETTING: Adolescent Unit of a tertiary care center. PARTICIPANTS: 212 pregnant teenagers. INTERVENTIONS: Medical records review. MAIN OUTCOME MEASURES: Intended pregnancy rate and contraceptive methods used before and after pregnancy. For contraceptive choices after pregnancy we considered: Group 1--teenagers who continued their pregnancy to delivery (n = 106) and Group 2--the same number of adolescents who chose to terminate their pregnancy. RESULTS: The intended pregnancy rate was 14.2%. Prior to a pregnancy continued to delivery, the most widely used contraceptive method was the male condom (50.9%), followed by oral combined contraceptives (28.3%); 18.9% of adolescents were not using any contraceptive method. After pregnancy, contraceptive implant was chosen by 70.8% of subjects (P < .001) and the oral combined contraceptives remained the second most frequent option (17.9%, P = .058). Comparing these results with Group 2, we found that the outcome of the pregnancy was the main factor in the choices that were made. Thus, after a pregnancy continued to delivery, adolescents prefer the use of LARC [78.4% vs 40.5%, OR: 5,958 - 95% (2.914-12.181), P < .001)], especially contraceptive implants [70.8% vs 38.7%, OR: 4.371 - 95% (2.224-8.591), P < .001], to oral combined contraceptives [17.9% vs 57.5%, OR: 0.118 - 95% CI (0.054-0.258), P < .001]. CONCLUSION: Adolescent pregnancy and its outcome constitute a factor of change in future contraceptive choice. PMID- 25444053 TI - Hysteroscopic management of congenital external cervical os stenosis using a "no touch" technique in an adolescent. AB - BACKGROUND: Congenital external cervical os stenosis, one type of congenital cervical atresia, is particularly rare, and no case has been documented so far. CASE: A 12-year-old virginal patient with a history of mild vaginal bleeding for 14 days and lower abdominal pain for 10 days during her menarche was diagnosed with congenital external cervical os stenosis. Using a "no touch" technique, the diagnosis was further confirmed through a diagnostic hysteroscopy, and the narrow external cervical os was successfully corrected by resectoscopy, leaving the hymen intact. The patient was free of any symptoms postoperatively. RESULTS AND CONCLUSION: We discuss the above-mentioned case and data already published in the literature. Congenital external cervical os stenosis in non-sexually active patients can be managed by diagnostic and operative hysteroscopy using a "no touch" technique while keeping the hymen intact. PMID- 25444054 TI - Creation of a neovagina in a patient with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome and previously corrected rectovestibular fistula concomitant with imperforate anus. AB - BACKGROUND: Congenital absence of uterus and vagina (CAUV) when associated with anorectal malformations is usually diagnosed and repaired in infancy at the time of anorectoplasty. Long-term observations of patients are scarce and do not justify early vaginal reconstruction. Question arises whether creation of a neovagina can be safely and successfully performed when the patient is mature. CASE: The patient, diagnosed with MRKH syndrome at 16 years of age, underwent repair of rectovestibular fistula and imperforate anus ("cut-back" procedure, temporal sigmostomy and sagittal anterior anorectoplasty) in infancy. At 18, modified Wharton vaginoplasty was performed with a good anatomico-functional outcome. SUMMARY AND CONCLUSIONS: Early repair of anorectal malformation and postponed vaginal reconstruction seem to be a viable option for patients with congenital rectovestibular fistula and anal atresia concomitant with CAUV. PMID- 25444055 TI - Rope swing injuries resulting in vulvar trauma. AB - BACKGROUND: River tree rope swings are popular for recreation along inland lakes and rivers, but not without hazard. In a comprehensive review of injuries related to rope swings, genital injuries accounted for nearly 3 percent. CASE: We describe significant genital injuries, with laceration and avulsion of the labia and a large vulvar hematoma in 2 young women as a consequence of rope swing use. SUMMARY AND CONCLUSIONS: Visitors to inland waterways need to be cognizant of the hazards of rope swings and health care professionals should consider this mechanism of injury when confronted with vulvar trauma. PMID- 25444056 TI - Treatment of microperforate hymen with serial dilation: a novel approach. AB - BACKGROUND: Microperforate and imperforate hymens are one of the most common causes of vaginal outflow obstruction in the adolescent population. To date, these hymen anomalies are traditionally treated by hymenectomy with a cruciate excision. CASES(S): We report 2 cases of adolescent women with a microperforate hymen who were successfully and minimally invasively treated with progressive dilation with Hegar cervical dilators until a number 23 dilator was reached under anesthesia in the OR. SUMMARY AND CONCLUSION: Minimally invasive treatment of microperforate hymen with the use of progressive cervical dilators may be an alternative technique to the traditional excisional hymenectomy. Our patients reported satisfaction and minimal postoperative pain or scarring at 2 weeks and 6 months after the procedure. This technique can be an additional option for all women, especially those with cultural beliefs in virginity. PMID- 25444057 TI - Herlyn-Werner-Wunderlich syndrome: merits of sonographic and magnetic resonance imaging for accurate diagnosis and patient management in 13 cases. AB - STUDY OBJECTIVE: To review the main sonographic and magnetic resonance imaging manifestations of Herlyn-Werner-Wunderlich syndrome, characterized by uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis, and to discuss the value of techniques for its diagnosis and treatment. PARTICIPANTS: Thirteen patients with Herlyn-Werner-Wunderlich syndrome referred to our department with acute abdomen were identified for the period from 2009-2012. DESIGN: Retrospective chart review. SETTING: Two tertiary academic centers. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The evaluation of the clinical features, ultrasonography and magnetic resonance imaging findings, and the treatment protocols. RESULTS: Ultrasonographic evaluation of didelphic or double uterus in 10 and bicornuate-bicollis uterus in 3 patients with hematocolpos or hematometrocolpos associated with agenesis of the ipsilateral kidney revealed the diagnosis. In 10 patients, magnetic resonance imaging provided extra information. In 1 patient, a 25-week pregnancy was additionally detected and follow-up was suggested. Seven patients underwent surgical excision of the septum and drainage of the obstructed vagina. Total hysterectomy and hemicolpectomy were performed in 1 patient with 2 children suffering from severe chronic pelvic pain due to pelvic inflammatory disease. CONCLUSIONS: Despite its rarity, accurate diagnosis and morphologic description of Herlyn-Werner-Wunderlich syndrome with radiologic modalities are of importance in relieving the clinical complaints by enabling the suitable surgical treatment to be identified. PMID- 25444059 TI - Experience of a Maastrich type II non heart beating donor program in a small city: preliminary results. AB - OBJECTIVE: To study the results of a non-controlled cardiac death (Maastricht type II) donor program in a city of 200,000 inhabitants. The study was initially focused on lung donation and was extended to kidney donation after 9 months. DESIGN: A prospective observational study was conducted between October 2012 and December 2013. SETTING: The Intensive Care Unit of Marques de Valdecilla University Hospital in Santander (Spain), and surrounding areas. POPULATIONS: Patients (< 55 years) who died of out-of-hospital cardiac arrest. INTERVENTIONS: All out-of-hospital cardiac arrests were treated with mechanical cardiac compression (LUCAS II). The diagnosis of death and organ preservation were performed in the ICU. RESULTS: A total of 14 calls were received, of which three were discarded. Of the 11 potential donors, 7 were effective donors with a median age of 39.5 years (range: 32-48). A total of 5 single lung transplants and four kidney transplants were performed. In addition, corneas and tissues were harvested. The non-valid donors were rejected mainly due to technical problems. There were no donation refusals on the part of the patient relatives. The lung transplant patient survival rate was 100% after one month and 80% after one year. One month after transplantation, the kidney recipients had a serum creatinine concentration of<2mg/dl. The interval from cardiac arrest to renal preservation was 80minutes (range: 71-89), and the interval from cardiac arrest to lung preservation was 84minutes (range: 77-94). CONCLUSIONS: A Maastricht type II donation program in a small city is viable for both abdominal and thoracic organs. The program was initially very cautious, but its potential is easily improvable by increasing donor and by equipping mobile ICU ambulances with mechanical cardiac compression systems. Full management of the donor in the ICU, avoiding the emergency department or operating rooms, reduces the warm ischemia time, thereby improving transplant outcomes. PMID- 25444060 TI - Characterizing the performance of the nation's hospitals in the Hospital Outpatient Quality Reporting Program's imaging efficiency measures. AB - PURPOSE: To describe the performance of the nation's hospitals in terms of the Hospital Outpatient Quality Reporting Program's imaging efficiency measures. METHODS: Data were obtained from the Hospital Compare website and reflect outpatient Medicare claims of 4,118 hospitals for 5 imaging efficiency metrics: (1) frequency of combination abdominal CT (performed with and without intravenous contrast); (2) combination chest CT (performed with and without intravenous contrast); (3) simultaneous brain/sinus CT; (4) mammography follow-up (diagnostic imaging after screening mammography); and (5) lumbar spine MRI for low back pain without prior conservative therapy. Metrics were summarized and compared with other hospital characteristics. RESULTS: Median frequency was 36.7% for lumbar spine MRI for low back pain and ranged from 1.6% to 7.8% for the remaining measures; however, extreme outliers were observed (maximal frequencies of 79.2% 95.2% for mammography follow-up and combination chest and abdominal CT). Essentially no correlation was found among measures, aside from combination abdominal and chest CT. For some measures, relatively poor performance was more commonly observed among critical access hospitals and physician-owned/proprietary hospitals, and less commonly observed among U.S. News & World Report "best" hospitals and primary residency teaching sites. Frequencies for combination abdominal and chest CT improved from 2013 to 2014 among hospitals with relatively poorer performance. CONCLUSIONS: Although the imaging efficiency measures help identify individual hospitals and hospital categories with relatively inefficient imaging practices, they do not readily identify distinctly positively performing hospitals. Excess utilization was suggested for lumbar spine MRI. Frequency of combination abdominal and chest CT examinations improved over a short time interval. PMID- 25444058 TI - [Mortality predictive factors in patients with urinary sepsis associated to upper urinary tract calculi]. AB - PURPOSE: The aims of this study were to determine the clinical characteristics of patients with urinary sepsis associated to ureteral calculi admitted to the Intensive Care Unit (ICU), and to identify predictors of mortality in the first 24 hours of admission. DESIGN: A retrospective observational study covering a 16 year period (2006-2011) was carried out. SETTING: The combined clinical/surgical ICU of a secondary-level University hospital. PATIENTS: All patients admitted to the ICU due to obstructive urinary sepsis. INTERVENTIONS: None. MAIN VARIABLES: We analyzed general clinical and laboratory test and urological data. The diagnostic technique, affected side, decompression technique, isolated microorganism and antibiotic therapy used were also considered. The assessment of risk factors was performed by multiple logistic regression analysis. RESULTS: A total of 107 patients admitted to the ICU were included in the study, with a mortality rate of 19.6%. The diagnosis was mainly established by ultrasound, and the most commonly used decompression technique was retrograde JJ stenting. Microorganisms were isolated in 48.6% of the patients. In total, 20.6% of the patients had bacteremia. Multivariate analysis found age, acute renal failure and the use of vasoactive drugs administered continuously for the first 24 hours of admission to be independently associated to mortality. CONCLUSIONS: Advanced age, acute renal failure and the need for vasoactive drugs were associated to an increased risk of mortality in patients with urinary sepsis associated to upper urinary tract calculi. PMID- 25444061 TI - Expanding roles of nurse practitioners and physician assistants as providers of nonvascular invasive radiology procedures. AB - PURPOSE: To evaluate national trends in nonvascular invasive radiology procedures performed by advanced practice providers (APPs), focusing specifically on nurse practitioners and physician assistants. METHODS: Nonvascular invasive radiology procedures commonly performed by APPs at our 2 largest hospitals were used to identify procedure groups for national trends analysis. We mapped categories of services annually to then-current Current Procedural Terminology codes from 1994 to 2012 and identified national Medicare Part B beneficiary paid claims frequency using Physician Supplier Procedure Summary Master Files. Trends were studied for APPs, radiologists, and all providers nationally for 7 categories of service: paracentesis, thoracentesis, fine-needle aspiration (FNA), superficial lymph node biopsy, abdominal biopsy, thoracic biopsy, and abdominal drainage. RESULTS: Of 1,352 nonvascular invasive procedures performed by APPs at our facilities over a 1-year period through August 2013, a total of 1,161 (85.9%) fell into the 7 defined categories. Between 1994 and 2012, national Medicare claims by APPs increased dramatically for all of these categories: paracentesis from 0 to 17,967; thoracentesis from 119 to 4,141 (+3,379%); FNA from 0 to 3,921; superficial lymph node biopsy from 0 to 251; abdominal biopsy from 1 to 1,819 (+1,818%); thoracic biopsy from 0 to 552; and abdominal drainage from 37 to 410 (+1,008%). Overall, volumes increased for both radiologists and all providers, with the total fraction of national services performed by APPs increasing from 0% to 10.7% for paracentesis, 0.1% to 5.7% for thoracentesis, 0% to 2.1% for FNA, 0% to 1.4% for superficial lymph node biopsy, 0% to 1.7% for abdominal biopsy, 0% to 1.0% for thoracic biopsy, and 0.1% to 1.2% for abdominal drainage. CONCLUSIONS: Although APPs perform a relatively small portion of commonly performed nonvascular invasive radiology procedures nationally, paid Medicare claims for those services have increased dramatically over nearly 2 decades, and at a faster pace than that for all providers as a whole. Given the multiple hurdles involved in obtaining Medicare reimbursement, that growth indicates increasing acceptance of APPs as procedure service providers at the institutional credentialing, state licensure, and payer policy levels. PMID- 25444062 TI - Acute spinal cord compression: CQI framework increases resource efficiency while promoting delivery of high-quality care. AB - PURPOSE: Literature reports indicate that advanced imaging is overutilized, especially in the emergency setting. At our institution, stat spinal MRI for suspected acute spinal cord compression (ASCC) was perceived to be excessively utilized. A continuous quality improvement process was employed to investigate this trend and improve the efficiency of this diagnosis. METHODS: Spine imaging in patients with suspected ASCC was retrospectively evaluated for appropriateness of indications and quality of imaging. Based on the results, a new institutional policy for ordering MR for suspected ASCC was implemented, concurrent with development of a new screening spine MRI protocol. Subsequently, indications, efficacy, and imaging utilization of the new strategy were analyzed for improved operational effectiveness. RESULTS: The initial retrospective study demonstrated only a 1.4% positive rate of ASCC as well as image-quality degradation due to patient motion resulting from prolonged scan times. Based on these results, a new institutional policy for ordering stat ASCC spine MRI was instituted with an updated screening MRI protocol. This policy resulted in a positive rate of ASCC of 4.4%, and decreased scan time by 50%-70%, while preserving diagnostic image quality and decreasing resource utilization. CONCLUSIONS: As suspected, stat spinal MRI for ASCC was excessively utilized at our institution. The study demonstrated that systemic improvements regarding this issue can be achieved by using a multidisciplinary approach and following a continuous quality improvement methodology. A new MRI protocol for identification of ASCC was found to preserve image quality and diagnostic confidence, while simultaneously decreasing scan time and use of valuable health care resources. PMID- 25444063 TI - Focused process improvement events: sustainability of impact on process and performance in an academic radiology department. AB - PURPOSE: To evaluate sustainability of impact of rapid, focused process improvement (PI) events on process and performance within an academic radiology department. METHODS: Our department conducted PI during 2011 and 2012 in CT, MRI, ultrasound, breast imaging, and research billing. PI entailed participation by all stakeholders, facilitation by the department chair, collection of baseline data, meetings during several weeks, definition of performance metrics, creation of an improvement plan, and prompt implementation. We explore common themes among PI events regarding initial impact and durability of changes. We also assess performance in each area pre-PI, immediately post-PI, and at the time of the current study. RESULTS: All PI events achieved an immediate improvement in performance metrics, often entailing both examination volumes and on-time performance. IT-based solutions, process standardization, and redefinition of staff responsibilities were often central in these changes, and participants consistently expressed improved internal leadership and problem-solving ability. Major environmental changes commonly occurred after PI, including a natural disaster with equipment loss, a change in location or services offered, and new enterprise-wide electronic medical record system incorporating new billing and radiology informatics systems, requiring flexibility in the PI implementation plan. Only one PI team conducted regular post-PI follow-up meetings. Sustained improvement was frequently, but not universally, observed: in the long-term following initial PI, measures of examination volume showed continued progressive improvements, whereas measures of operational efficiency remained stable or occasionally declined. CONCLUSIONS: Focused PI is generally effective in achieving performance improvement, although a changing environment influences the sustainability of impact. Thus, continued process evaluation and ongoing workflow modifications are warranted. PMID- 25444064 TI - Understanding and applying the principles of contemporary medical professionalism: illustration of a suggested approach, part 2. AB - In recent years, formal professionalism education, training, and assessment have been introduced to medical schools and accredited residency training programs. Current constructs of medical professionalism characterize it as a multidimensional competency rather than a trait. Medical professionalism is a belief system for organizing and delivering care, in which group members (medical professionals) promise patients and the public that they will self-regulate (ie, ensure that medical professionals live up to standards of competence and ethical values). Physicians who are good professionals have lapses in professionalism. Responses to professional lapses should focus on remediation. Failure of groups of professionals to enforce the standards and values can convey to patients and the public a lack of trustworthiness and thereby undermine the foundation of professionalism, the social contract. The Physician Charter sets forth the 3 fundamental principles and 10 commitments that offer guidance in some of the most challenging situations. One example is illustrated herein and is continued from Part 1 of this two-part series. PMID- 25444065 TI - Understanding and applying the principles of contemporary medical professionalism: illustration of a suggested approach, part 1. PMID- 25444066 TI - Introduction to the special issue--Quality improvement in radiology. PMID- 25444067 TI - Application of kaizen methodology to foster departmental engagement in quality improvement. AB - The Toyota Production System, also known as Lean, is a structured approach to continuous quality improvement that has been developed over the past 50 years to transform the automotive manufacturing process. In recent years, these techniques have been successfully applied to quality and safety improvement in the medical field. One of these techniques is kaizen, which is the Japanese word for "good change." The central tenant of kaizen is the quick analysis of the small, manageable components of a problem and the rapid implementation of a solution with ongoing, real-time reassessment. Kaizen adds an additional "human element" that all stakeholders, not just management, must be involved in such change. Because of the small size of the changes involved in a kaizen event and the inherent focus on human factors and change management, a kaizen event can serve as good introduction to continuous quality improvement for a radiology department. PMID- 25444068 TI - Advanced practice quality improvement: beyond the radiology department. AB - Substantial opportunity exists for radiologists to lead practice quality improvement initiatives that extend beyond the boundaries of the radiology department, especially regarding the appropriate, evidence-based utilization of radiological services by clinical colleagues. Radiologists are uniquely positioned to lead these types of interdisciplinary quality projects. An example of one such project is reviewed, with a reflection on lessons learned; specific, practical recommendations derived from past efforts are made. PMID- 25444070 TI - Telemedicine and health care IT: new guidelines and practical contractual solutions. PMID- 25444069 TI - ACR Appropriateness Criteria stage I breast cancer: initial workup and surveillance for local recurrence and distant metastases in asymptomatic women. AB - Women newly diagnosed with stage 1 breast cancer have an early-stage disease that can be effectively treated. Evidence provides little justification for performing imaging to exclude metastasis in asymptomatic women with stage I breast cancer. No differences have been found in survival or quality of life in women regardless of whether they underwent initial workup for metastatic disease. These women generally prefer intensive follow-up to detect an early recurrence. However, survival rates do not differ between women who obtain intensive screening and surveillance, with imaging and laboratory studies, and women who undergo testing only as a result of development of symptoms or findings on clinical examinations. In addition, quality of life is similar for women who undergo intensive surveillance compared with those who do not. American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines state that annual mammography is the only imaging examination that should be performed to detect a localized breast recurrence in asymptomatic patients. Additional imaging may be needed if the patient has locoregional symptoms. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review by the panel include extensive analysis of current medical literature from peer-reviewed journals and application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures. When evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 25444071 TI - Utility of medical data registries. PMID- 25444072 TI - Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. AB - OBJECTIVES: We evaluated azacitidine (Vidaza((r))) safety and efficacy in patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), in a real-life setting. Treatment response, dose, and schedule were assessed. METHODS: This non-interventional, post-marketing survey included 49/50 patients receiving azacitidine at 14 Belgian haematology centres from 2010-2012. Treatment-emergent adverse events (TEAEs), including treatment-related TEAEs, and serious TEAEs (TESAEs) were recorded throughout the study. Treatment response [complete response (CR), partial response (PR), haematological improvement (HI), stable disease (SD), treatment failure (TF)) and transfusion-independence (TI) were evaluated at completion of a 1-year observation period (1YOP) or at treatment discontinuation, and overall survival (OS), at study conclusion. RESULTS: The median age of patients was 74.7 (range: 43.9-87.8) years; 69.4% had MDS, 26.5% had primary or secondary AML, and 4.1% had CMML. Treatment-related TEAEs, grade 3-4 TEAEs, and TESAEs were reported in 67.3%, 28.6%, and 18.4% of patients, respectively. During 1YOP, patients received a median of 7 (1-12) treatment cycles. Treatment response was assessed for 38/49 patients. Among MDS and CMML patients (n = 29), 41.4% had CR, PR, or HI, 41.4% had SD, and 17.2% had TF. Among AML patients (n = 9), 44.4% had CR or PR, 33.3% had SD, and 22.2% had TF. TI was observed in 14/32 (43.8%) patients who were transfusion-dependent at baseline. Median (95% confidence interval) OS was 490 (326-555) days; 1-year OS estimate was 0.571 (0.422-0.696). CONCLUSIONS: Our data support previous findings that azacitidine has a clinically acceptable safety profile and shows efficacy. PMID- 25444073 TI - Increased placental expression of cannabinoid receptor 1 in preeclampsia: an observational study. AB - BACKGROUND: The endocannabinoid system plays a key role in female reproduction, including implantation, decidualization and placentation. In the present study, we aimed to analyze cannabinoid receptor 1 (CB1), CB2 and fatty acid amid hydrolase (FAAH) expressions and localization in normal and preeclamptic placenta, in order to determine whether placental endocannabinoid expression pattern differs between normal pregnancy and preeclampsia. METHODS: Eighteen preeclamptic patients and 18 normotensive, healthy pregnant women with uncomplicated pregnancies were involved in our case-control study. We determined CB1, CB2 and FAAH expressions by Western blotting and immunohistochemistry in placental samples collected directly after Cesarean section. RESULTS: CB1 expression semi-quantified by Western blotting was significantly higher in preeclamptic placenta, and these findings were confirmed by immunohistochemistry. CB1 immunoreactivity was markedly stronger in syncytiotrophoblasts, the mesenchymal core, decidua, villous capillary endothelial and smooth muscle cells, as well as in the amnion in preeclamptic samples compared to normal pregnancies. However, we did not find significant differences between preeclamptic and normal placenta in terms of CB2 and FAAH expressions and immunoreactivity. CONCLUSIONS: We observed markedly higher expression of CB1 protein in preeclamptic placental tissue. Increased CB1 expression might cause abnormal decidualization and impair trophoblast invasion, thus being involved in the pathogenesis of preeclampsia. Nevertheless, we did not find significant differences between preeclamptic and normal placental tissue regarding CB2 and FAAH expressions. While the detailed pathogenesis of preeclampsia is still unclear, the endocannabinoid system could play a role in the development of the disease. PMID- 25444074 TI - Co-infection of methicillin-resistant Staphylococcus epidermidis, methicillin resistant Staphylococcus aureus and extended spectrum beta-lactamase producing Escherichia coli in bovine mastitis--three cases reported from India. AB - Emergence of antimicrobial resistance among bovine mastitis pathogens is the major cause of frequent therapeutic failure and a cause of concern for veterinary practitioners. This study describes intra-mammary infection of methicillin resistant Staphylococcus epidermidis (MRSE), methicillin-resistant Staphylococcus aureus (MRSA) and extended spectrum beta-lactamase (ESBL) producing Escherichia coli in two Holstein Friesian crossbred cows with subclinical mastitis and one non-descript cow with clinical mastitis in two different districts of West Bengal, India. In total, three MRSE, one MRSA and three ESBL producing E. coli were isolated from these cases. Both the crossbreds were detected with MRSE (HFSE1 and HFSE2) and ESBL producing E. coli (HFEC1 and HFEC2), whereas, simultaneous infection of three pathogens viz. MRSA (NDSA1), MRSE (NDSE1) and ESBL producing E. coli (NDEC1) was found in the non-descript cow. The methicillin resistant isolates possessed mecA gene and exhibited resistance to various antibiotics such as amikacin, tetracycline and glycopeptides. The ESBL producers were positive for blaCTX-M and blaTEM genes; in addition, HFEC1 and HFEC2 were positive for blaSHV and possessed the genes for class I integron (int1), sulphonamide resistance (sul1), quinolone resistance (qnrS) and other virulence factors (papC, iucD and ESTA1). All the ESBL producers exhibited resistance to a variety of antibiotics tested including third- and fourth-generation cephalosporins and were also intermediately resistant to carbapenems. This is the first ever report on simultaneous occurrence of MRSE, MRSA and ESBL producing E. coli in bovine mastitis indicating a major concern for dairy industry and public health as well. PMID- 25444075 TI - Minimizing risk of hypomethylating agent failure in patients with higher-risk MDS and practical management recommendations. AB - In Europe, azacitidine is the only hypomethylating agent approved for the treatment of patients with int-2-/high-risk myelodysplastic syndromes, offering significantly improved survival compared with conventional care. However, not all patients treated with azacitidine respond to treatment, and the vast majority of responders subsequently relapse. Currently, no standard care regimens have been established for patients after failure of azacitidine. Here, we discuss treatment options after loss of response or progression on azacitidine. In addition, we briefly consider optimization of first-line treatment along with potential biomarkers for identifying and monitoring response during treatment with azacitidine. PMID- 25444076 TI - Refined medullary blast and white blood cell count based classification of chronic myelomonocytic leukemias. AB - Since 2001, chronic myelomonocytic leukemia (CMML) is classified by the WHO as myeloproliferative/myelodysplastic neoplasm. Herein we tried to better describe CMML patients with regard to hematological characteristics and prognosis using data of the Duesseldorf registry. We created 6 CMML subgroups, by dividing dysplastic and proliferative CMML at the cut-off of white blood cell count of 13,000/MUL and splitting these two groups into 3 subgroups: CMML 0 with <5% blasts (n=101), CMML I with 5-9% blasts (n=204) and CMML II with 10-19% blasts (n=81). For comparison we included patients with RCMD, RAEB I and II. The newly created CMML 0 group had better prognosis than CMML I and II, median survival times were 31 months (ms), 19ms and 13ms, respectively (p<0.001). Median survival times between the corresponding dysplastic and proliferative subgroups 0 and 1 differed significantly: CMML 0 dysplastic 48ms and CMML 0 proliferative 17ms (p=0.03), CMML I dysplastic 29ms and CMML I proliferative 15ms (p=0.008), CMML II dysplastic 17ms and CMML II proliferative 10ms (p=0.09). Outcome of CMML patients worsens with increasing medullary blasts and when presenting as proliferative type. Therefore it is justified to separate CMML with <5% medullary blasts. PMID- 25444077 TI - Measuring stages of recovery from psychosis. AB - BACKGROUND: Mental health consumers invite us to abandon the pathology model, which is tied to pessimism, and instead to embrace a model of personal recovery that goes beyond being free from symptoms, and involves self-management of the illness. The Stages of Recovery Instrument (STORI) is a measure developed from the perspective of consumers according to a conceptual five-stage model of recovery. AIMS: The main aim of this work was to study the psychometric properties of the STORI, but we also set out to compare the stages of recovery in our sample with the five-stage model in the sample with which the scale was developed. METHODS: Our sample consisted of 95 people diagnosed with schizophrenia-spectrum psychoses, with a mean age of 34.74 (SD=9.25). RESULTS: The STORI scores showed adequate psychometric properties in this sample. Cluster analysis indicated that the three-cluster model fitted the data better than the five-cluster model. Internal consistency of the STORI scores ranged between .83 and .87. STORI stages were associated with Recovery Styles Questionnaire scores. DISCUSSION: The results provide empirical validation of the STORI in other countries. Empirical evidence revealed that the stages of recovery found in our own and other clinical samples differ from those found in the samples with which the scale was developed. PMID- 25444078 TI - A proposed model of the development of suicidal ideations. AB - BACKGROUND: Suicidal ideations may precede suicide attempts. They are of particular concern in psychiatric populations because psychopathology is a major risk factor for suicide. The factors affecting the development of suicide ideations may differ among psychiatric patients with and without a previous suicide attempt and individuals without a psychiatric diagnosis. OBJECTIVES: The aim of this study is to develop a model of suicide ideation in psychiatric patients and the general population. METHOD: The study included 196 participants: 92 psychiatric patients with a previous suicide attempt ("attempters"); 47 psychiatric patients who had never attempted suicide ("non-attempters"); and 57 healthy control subjects. Data were collected on socio-demographic parameters, clinical history, and details of the suicide attempts. Participants completed a battery of psychological instruments assessing aggression-impulsivity, mental pain (including depression and hopelessness) and communication difficulties, in addition to negative life events. Findings were correlated with suicidal ideation by group. RESULTS: The correlations of the different variables with suicidal ideation differed between suicide attempters and non-attempters; therefore, the model was analyzed separately for each group. The study yielded three major findings: negative life events had a significant effect on both anger-in and impulsivity in non-attempters but not in attempters; hopelessness moderately contributed to suicidal ideations in attempters but not in non-attempters; loneliness contributed significantly to depression in non-attempters but was less distressing in attempters. CONCLUSION: The mechanism underlying suicidal ideation appears to differ between psychiatric patients who have previously attempted suicide and those who have not, supporting a dual model of suicidal ideation. Although this is only a preliminary study, these findings are important for furthering our understanding of the process of transition of suicidal thoughts to completion of suicide. These results need further replication with a larger cohort of subjects. PMID- 25444079 TI - A case of feline gastrointestinal eosinophilic sclerosing fibroplasia associated with phycomycetes. AB - Feline gastrointestinal eosinophilic sclerosing fibroplasia (FGESF) is a recently described inflammatory condition of domestic cats with unknown aetiology. A proportion of cases of FGESF are associated with bacteria, but antibiotic treatment is ineffective. It has been hypothesized that genetically predisposed cats may develop FGESF in response to the introduction of bacteria or other antigens into the intestinal wall. A 9- month-old male Persian cat presented with a history of marked acute haematemesis. A mass (10 cm diameter) was detected within the pylorus and proximal duodenum and this was not surgically accessible. On necropsy examination the duodenal wall was seen to be markedly thickened with extensive mucosal ulceration. Microscopically, there were haphazardly oriented trabecular bands of dense eosinophilic collagen, separated by wide, clear areas containing variable numbers of fibroblasts, eosinophils, mast cells, neutrophils, macrophages, lymphocytes and plasma cells. Numerous pleomorphic, non-parallel walled, sparsely septate hyphae, characteristic of phycomycetes, were present within the collagen matrix. Colonies of gram-positive and gram-negative rods were also present within the lesion. This is the first description of FGESF with intralesional fungi. PMID- 25444080 TI - Rapid acclimation of juvenile corals to CO2 -mediated acidification by upregulation of heat shock protein and Bcl-2 genes. AB - Corals play a key role in ocean ecosystems and carbonate balance, but their molecular response to ocean acidification remains unclear. The only previous whole-transcriptome study (Moya et al. Molecular Ecology, 2012; 21, 2440) documented extensive disruption of gene expression, particularly of genes encoding skeletal organic matrix proteins, in juvenile corals (Acropora millepora) after short-term (3 d) exposure to elevated pCO2 . In this study, whole-transcriptome analysis was used to compare the effects of such 'acute' (3 d) exposure to elevated pCO2 with a longer ('prolonged'; 9 d) period of exposure beginning immediately post-fertilization. Far fewer genes were differentially expressed under the 9-d treatment, and although the transcriptome data implied wholesale disruption of metabolism and calcification genes in the acute treatment experiment, expression of most genes was at control levels after prolonged treatment. There was little overlap between the genes responding to the acute and prolonged treatments, but heat shock proteins (HSPs) and heat shock factors (HSFs) were over-represented amongst the genes responding to both treatments. Amongst these was an HSP70 gene previously shown to be involved in acclimation to thermal stress in a field population of another acroporid coral. The most obvious feature of the molecular response in the 9-d treatment experiment was the upregulation of five distinct Bcl-2 family members, the majority predicted to be anti-apoptotic. This suggests that an important component of the longer term response to elevated CO2 is suppression of apoptosis. It therefore appears that juvenile A. millepora have the capacity to rapidly acclimate to elevated pCO2 , a process mediated by upregulation of specific HSPs and a suite of Bcl-2 family members. PMID- 25444081 TI - Acoustic improvements after surgical correction in congenital heart disease. AB - BACKGROUND: Hoarse or asthenic voice is frequently associated with various pediatric cardiac disorders. The aim of this study was to investigate the changes in voice physiology after surgical correction in patients with congenital heart diseases. METHODS: We performed voice analysis using induced crying of 40 infants with congenital heart disease (CHD) such as ventricular septal defect (VSD), patent ductus arteriosus (PDA), and atrial septal defect (ASD; 31 girls, 24 boys; mean age, 11 +/- 8.9 months). Cries were serially recorded immediately prior to operation, then 1 week, and 1 month after surgical correction, respectively. Acoustic parameters, fundamental frequency (F0 ), duration of cry, noise to harmonic ratio (NHR), jitter, and shimmer, were extracted using Multi-Dimensional Voice ProgramTM (MDVP) a computerized speech analysis system. Cries were compared with 30 normal healthy infants of corresponding age. RESULTS: Among the 25 infants with VSD, cry duration, jitter, and shimmer improved after the operation (P < 0.05). F0 and NHR, however, were not significantly different. F0 in patients with PDA improved, but was not statistically significant. The duration of cry, jitter, shimmer, and NHR improved in the PDA group (P < 0.05). The jitter and shimmer parameters improved significantly (P < 0.05), but F0 , cry duration, and NHR in patients with ASD did not show any significant changes. CONCLUSIONS: Deviated voice patterns in pediatric patients with CHD can normalize after surgical correction. In addition, non-invasive analysis such as MDVP can be used to identify vocal paralysis, even in the early postoperative period. PMID- 25444083 TI - Effects of long-term treatment with rotigotine transdermal system on dyskinesia in patients with early-stage Parkinson's disease. AB - PURPOSE: In two 6-month, double-blind, placebo-controlled studies, rotigotine transdermal system was well-tolerated and efficacious monotherapy in early-stage PD. This post hoc analysis of the long-term open-label extensions (NCT00594165; NCT00599196) of these studies assessed incidence and severity of dyskinesia in participants treated with rotigotine, with or without concomitant levodopa, for up to 6 years. METHODS: Open-label rotigotine was titrated to optimal dose (<=16 mg/24 h). Concomitant levodopa was permitted. Dyskinesia data, recorded using the Unified Parkinson's Disease Rating Scale Part IV, were pooled from the two open label studies. RESULTS: Of 596 participants who received open-label rotigotine, 299 (50%) remained at trial closure; no patient discontinued due to dyskinesia. In the two studies, median exposure to rotigotine was 1910 days (~5 years, 3 months), and 1564.5 days (~4 years, 3 months). During up to 6 years of open-label rotigotine, 423/596 (71%) received levodopa. Dyskinesias were reported in 115/596 (19%) participants, 90/115 (78%) of who developed dyskinesia after levodopa was added; 25 reported dyskinesia in the absence of levodopa (includes patients who never received open-label levodopa, and those who reported dyskinesia before starting concomitant levodopa). Dyskinesia severity data were available for 107 of the 115 participants. In 56/107 (52%) participants, dyskinesia was considered 'not disabling' for all occurrences; the worst-case severity was 'mildly disabling' for 33/107 (31%), and 'moderately' or 'severely disabling' for 18/107 (17%; 3% of total participants). CONCLUSION: During treatment with rotigotine in patients with PD for up to 6 years the incidence of dyskinesia was low, and the dyskinesia was generally 'not disabling' or 'mildly disabling'. PMID- 25444084 TI - Synthesis of novel pyrazole-thiadiazole hybrid as potential potent and selective cyclooxygenase-2 (COX-2) inhibitors. AB - A series of 1,3,4-trisubstituted pyrazole derivatives (3 a-f), (4 a-f), and (5 a f) have been synthesized and evaluated for their cyclooxygenase (COX-1 and COX-2) inhibitory activity. The structures of newly synthesized compounds were characterized by IR, 1H NMR, and mass spectral analysis. All of the compounds showed good inhibition of COX-2 with IC50 of 1.33-17.5 MUM. Among these derivatives, compound (5c) was the most potent and selective COX-2 inhibitor (IC50 = 1.33 MUM), with a significant selectivity index (SI > 60). Molecular docking studies were carried out in order to predict the hypothetical binding mode of these compounds to the COX-2 isoenzyme. The result of present study suggests that pyrazole-thiadiazole hybrid could be an interesting approach for the design of new selective COX-2 inhibitory agents. PMID- 25444085 TI - [Morbidity observed in a health area: Impact on professionals and funding]. AB - OBJECTIVE: To analyze morbidity, in the context of a health area, and broken down by health centre, of patients who made contact with healthcare services, in order to propose an adjustment to finance the payment per capita. DESIGN: A descriptive study of morbidity observed in citizens assigned a health area during year 2010. SITE: Health Area 9. Autonomous Community of Madrid. Formed by the municipalities of Fuenlabrada, Humanes, and Moraleja de Enmedio. All levels of health care included. PARTICIPANTS: All citizens with health card assigned to a health center in the area who has maintained contact with the public health service's own area. MEASUREMENTS: Coded contact of patients are grouped using the Population Grouping Clinical Risk 3M TM Software (CRG). Each patient is included in a homogeneous and exclusive group with a numerical morbidity and clinical sense. Through the health card is known primary care centre, physician, age and sex. RESULTS: The distribution of morbidity is obtained by primary care centre, primary care physician, age and sex analyzing differences and combinations. CONCLUSIONS: It was found that the average values of the population morbidity are different in each primary care centre. In order to maintain the principle of equity in health care, it is suggested that an adjustment is made to the per capita payment based on the morbidity rate of the population. PMID- 25444086 TI - Low transferrin saturation is associated with impaired fasting glucose and insulin resistance in the South Korean adults: the 2010 Korean National Health and Nutrition Examination Survey. AB - AIMS: The associations of transferrin saturation with diabetes have not been well evaluated and conflicting results have been reported. The purpose of this study is to examine the association of iron indices (serum ferritin and transferrin saturation) with risk of impaired fasting glucose and insulin resistance. METHODS: We conducted a cross-sectional study in 2413 individuals (1150 men and 1263 women) aged 20-50 years who participated in the 2010 Korean National Health and Nutrition Examination Survey. Participants were free of diabetes, malignancy, liver cirrhosis, chronic renal failure, anaemia, pregnancy and menopause. Fasting plasma glucose, insulin and the homeostasis model assessment of insulin resistance (HOMA-IR) were measured as the outcomes. RESULTS: Impaired fasting glucose was more prevalent in the highest compared with the lowest serum ferritin quartile among men (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.20 3.24) after adjustment for multiple covariates. Following the same adjustment, impaired fasting glucose was less prevalent in the highest compared with the lowest transferrin saturation quartile among men (OR, 0.45; 95% CI, 0.25-0.80) and women (OR, 0.33; 95% CI, 0.14-0.77). Moreover, a higher ferritin level was significantly associated with higher HOMA-IR after adjusting for confounders in men. Lower transferrin saturation was also significantly associated with higher insulin levels and HOMA-IR in both sexes. CONCLUSIONS: Lower transferrin saturations were associated with an increased risk of impaired fasting glucose and insulin resistance among general South Korean population. PMID- 25444087 TI - Familial hypocalciuric hypercalcemia associated with crystal deposition disease. AB - Chondrocalcinosis is a common disease occasionally associated with hypercalcemia in case of primary hyperparathyroidism. Familial Hypocalciuric Hypercalcemia (FHH) is a rare and almost always asymptomatic condition, due to an autosomal dominant mutation of the calcium-sensing receptor gene. We report the case of a 61-year-old female with chronic hypercalcemia and joint pain. Clinical and biological data revealed chondrocalcinosis associated with FHH. Since primary hyperparathyroidism may mimic FHH, calcium to creatinine clearance ratio should be calculated in every case to avoid a wrong diagnosis and useless parathyroid surgery. The paucity of FFH complications, including chondrocalcinosis, makes their study difficult: additional studies are needed to clearly evaluate the link between FHH and chondrocalcinosis. PMID- 25444088 TI - Packet randomized experiments for eliminating classes of confounders. AB - BACKGROUND: Although randomization is considered essential for causal inference, it is often not possible to randomize in nutrition and obesity research. To address this, we develop a framework for an experimental design-packet randomized experiments (PREs), which improves causal inferences when randomization on a single treatment variable is not possible. This situation arises when subjects are randomly assigned to a condition (such as a new roommate) which varies in one characteristic of interest (such as weight), but also varies across many others. There has been no general discussion of this experimental design, including its strengths, limitations, and statistical properties. As such, researchers are left to develop and apply PREs on an ad hoc basis, limiting its potential to improve causal inferences among nutrition and obesity researchers. METHODS: We introduce PREs as an intermediary design between randomized controlled trials and observational studies. We review previous research that used the PRE design and describe its application in obesity-related research, including random roommate assignments, heterochronic parabiosis, and the quasi-random assignment of subjects to geographic areas. We then provide a statistical framework to control for potential packet-level confounders not accounted for by randomization. RESULTS: Packet randomized experiments have successfully been used to improve causal estimates of the effect of roommates, altitude, and breastfeeding on weight outcomes. When certain assumptions are met, PREs can asymptotically control for packet-level characteristics. This has the potential to statistically estimate the effect of a single treatment even when randomization to a single treatment did not occur. CONCLUSIONS: Applying PREs to obesity-related research will improve decisions about clinical, public health, and policy actions insofar as it offers researchers new insight into cause and effect relationships among variables. PMID- 25444091 TI - Primary intraventricular central nervous system rhabdomyosarcoma. PMID- 25444090 TI - Neuromyelitis optica in an adolescent after bone marrow transplantation. AB - BACKGROUND: Central nervous system complications of bone marrow transplant are a common occurrence and the differential diagnosis is quite broad, including opportunistic infections, medications toxicities, graft versus host disease, and other autoimmune processes. PATIENT DESCRIPTION: We summarize previously reported cases of autoimmune myelitis in post-transplant patients and discuss a 17-year old boy who presented with seronegative neuromyelitis optica after a bone marrow transplant for acute myeloid leukemia. Our patient had a marked improvement in symptoms after plasmapheresis. CONCLUSION: Including our patient, there have been at least eight cases of post-transplant autoimmune myelitis presented in the literature, and at least three of these are suspicious for neuromyelitis optica. Several of these patients had poor outcomes with persistent symptoms after the myelitis. Autoimmune processes such as neuromyelitis optica should be carefully considered in patients after transplant as aggressive treatment like early plasmapheresis may improve outcomes. PMID- 25444089 TI - The brain adapts to orthography with experience: evidence from English and Chinese. AB - Using functional magnetic resonance imaging (fMRI), we examined the process of language specialization in the brain by comparing developmental changes in two contrastive orthographies: Chinese and English. In a visual word rhyming judgment task, we found a significant interaction between age and language in left inferior parietal lobule and left superior temporal gyrus, which was due to greater developmental increases in English than in Chinese. Moreover, we found that higher skill only in English children was correlated with greater activation in left inferior parietal lobule. These findings suggest that the regions associated with phonological processing are essential in English reading development. We also found greater developmental increases in English than in Chinese in left inferior temporal gyrus, suggesting refinement of this region for fine-grained word form recognition. In contrast, greater developmental increases in Chinese than in English were found in right middle occipital gyrus, suggesting the importance of holistic visual-orthographic analysis in Chinese reading acquisition. Our results suggest that the brain adapts to the special features of the orthography by engaging relevant brain regions to a greater degree over development. PMID- 25444092 TI - Perinatal arterial ischemic stroke: presentation, risk factors, evaluation, and outcome. AB - BACKGROUND: Perinatal arterial ischemic stroke is as common as large vessel arterial ischemic stroke in adults and leads to significant morbidity. Perinatal arterial ischemic stroke is the most common identifiable cause of cerebral palsy and can lead to cognitive and behavioral difficulties that are amortized over a lifetime. METHODS: The literature on perinatal arterial ischemic stroke was reviewed and analyzed. RESULTS: Risk factors for perinatal arterial ischemic stroke include those that are maternal, neonatal, and placental. The most common clinical signs at presentation are seizures and hemiparesis. Evaluation should begin with thorough history acquisition and physical examination followed by magnetic resonance imaging of the brain, with consideration of magnetic resonance angiography of the head and neck, echocardiogram, and thrombophilia evaluation. Treatment beginning early to include physical, speech, and occupational therapies including constraint-induced movement therapy and close cognitive and developmental follow-up may be beneficial. Future treatments may include transcranial magnetic stimulation, hypothermia, and erythropoietin. CONCLUSIONS: Perinatal arterial ischemic stroke comprises a group of arterial ischemic injuries that can occur in the prenatal, perinatal, and postnatal periods in term and preterm infants with different types of perinatal arterial ischemic stroke having different clinical presentations, risk factors, and long-term outcomes. PMID- 25444093 TI - Risk of subsequent asthma in children with febrile seizures: a nationwide population-based retrospective cohort study. AB - BACKGROUND: No study has reported a relationship between febrile seizures and asthma; thus, we examined the association between these two disorders. METHODS: We identified 991 cases of children with febrile seizures as the case cohort, and the control group was matched according to age, sex, urbanization level, and their parents' occupation at a 1:4 ratio. We applied the Cox proportional hazards regression model to estimate the hazard ratios and 95% confidence intervals for asthma among the children with febrile seizures. RESULTS: After 11 years of follow-up, the asthma incidence in the febrile seizure group was approximately 5% higher than that in the control group (log-rank test, P < 0.0001). The risk of asthma in the febrile seizure group was 1.41 times higher than that in the control group (95% confidence interval, 1.21-1.65; P < 0.001). Furthermore, the risk of asthma development increased (0.96 vs 3.62) in conjunction with the frequency of febrile seizure-related medical visits (one to two visits vs more than four visits; P < 0.0001). CONCLUSION: Febrile seizures may be associated with an increase in the risk of future asthma occurrence in children. We observed a significantly higher cumulative incidence of asthma occurrence in children with more febrile seizure-related medical visits. PMID- 25444094 TI - The value of 3-T magnetic resonance imaging in acute transverse myelitis. PMID- 25444095 TI - Response to Fassio and Almerigogna regarding immune function and herpes simplex encephalitis. PMID- 25444096 TI - Factors that influence utilisation of HIV/AIDS prevention methods among university students residing at a selected university campus. AB - Various studies have reported that university students, who are mostly young people, rarely use existing HIV/AIDS preventive methods. Although studies have shown that young university students have a high degree of knowledge about HIV/AIDS and HIV modes of transmission, they are still not utilising the existing HIV prevention methods and still engage in risky sexual practices favourable to HIV. Some variables, such as awareness of existing HIV/AIDS prevention methods, have been associated with utilisation of such methods. The study aimed to explore factors that influence use of existing HIV/AIDS prevention methods among university students residing in a selected campus, using the Health Belief Model (HBM) as a theoretical framework. A quantitative research approach and an exploratory-descriptive design were used to describe perceived factors that influence utilisation by university students of HIV/AIDS prevention methods. A total of 335 students completed online and manual questionnaires. Study findings showed that the factors which influenced utilisation of HIV/AIDS prevention methods were mainly determined by awareness of the existing university-based HIV/AIDS prevention strategies. Most utilised prevention methods were voluntary counselling and testing services and free condoms. Perceived susceptibility and perceived threat of HIV/AIDS score was also found to correlate with HIV risk index score. Perceived susceptibility and perceived threat of HIV/AIDS showed correlation with self-efficacy on condoms and their utilisation. Most HBM variables were not predictors of utilisation of HIV/AIDS prevention methods among students. Intervention aiming to improve the utilisation of HIV/AIDS prevention methods among students at the selected university should focus on removing identified barriers, promoting HIV/AIDS prevention services and providing appropriate resources to implement such programmes. PMID- 25444097 TI - Elastography in clinical practice. AB - Elastography is a new technique that evaluates tissue stiffness. There are two elastography methods, strain and shear wave elastography. Both techniques are being used to evaluate a wide range of applications in medical imaging. Elastography of breast masses and prostates have been shown to have high accuracy for characterizing masses and can significantly decrease the need for biopsies. Shear wave elastography has been shown to be able to detect and grade liver fibrosis and may decrease the need for liver biopsy. Evaluation of other organs is still preliminary. This article reviews the principles of elastography and its potential clinical applications. PMID- 25444098 TI - The role of ultrasonography in the evaluation of diffuse liver disease. AB - The use of ultrasonography (US) to detect and characterize diffuse liver disease can be challenging, but remains a useful tool for the diagnosis and management of many diffuse parenchymal liver diseases such as cirrhosis, steatosis, and malignancies. Newer techniques, such as elastography, are proving useful for earlier detection of hepatic parenchymal changes. The role of US in the assessment of possible biliary ductal obstruction is well established, and Doppler US may provide additional physiologic information regarding hepatic blood flow. US plays a central role in target selection and guidance of percutaneous liver biopsies. PMID- 25444099 TI - Contrast-enhanced ultrasound of the liver and kidney. AB - The clinical use of noncardiac contrast-enhanced ultrasound scan (CEUS) has been steadily gaining momentum. CEUS is a reliable and safe technique with a diverse array of applications. This article reviews the current and potential future clinical applications of CEUS. Emphasis will be placed on evaluating focal lesions with the liver and kidney. Contrast agent composition and mechanism are also briefly reviewed. PMID- 25444100 TI - Ultrasound evaluation of the first trimester. AB - Ultrasound is a valuable diagnostic test throughout the first trimester of pregnancy. Early in this trimester, it is used to distinguish between normal intrauterine, failed intrauterine, and ectopic pregnancies. Later it can be used with maternal blood tests to screen for trisomy 21 and other forms of aneuploidy, and in some centers to assess fetal anatomy and diagnose structural anomalies. First trimester sonography is also useful for accurate assessment of gestational age. This article reviews these applications, the approach to establishing diagnoses, and ways to avoid diagnostic mistakes that can lead to serious errors in patient management and adverse pregnancy outcome. PMID- 25444101 TI - Practical applications of 3D sonography in gynecologic imaging. AB - Volume imaging in the pelvis has been well demonstrated to be an extremely useful technique, largely based on its ability to reconstruct the coronal plane of the uterus that usually cannot be visualized using traditional 2-dimensional (2D) imaging. As a result, this technique is now a part of the standard pelvic ultrasound protocol in many institutions. A variety of valuable applications of 3D sonography in the pelvis are discussed in this article. PMID- 25444102 TI - Ultrasound evaluation of pelvic pain. AB - Pelvic pain is a frequent complaint in women presenting to the emergency room or to a physician's office, and ultrasound should be considered the initial imaging modality of choice in the evaluation of women with pelvic pain. This article reviews the ultrasound imaging technique and provides a thorough differential of gynecologic and nongynecologic causes of both acute and chronic pelvic pain. PMID- 25444103 TI - Ultrasonography evaluation of pelvic masses. AB - Ultrasonography is the primary imaging modality for evaluation of pelvic masses. Ultrasonography has the advantage of being inexpensive, widely available, and offering superior tissue characterization compared with computed tomography. The real-time imaging ability of ultrasonography and three-dimensional ultrasonography also has the advantage of being able to identify the organ of origin of the pelvic mass. Many pelvic masses have characteristic sonographic appearances that allow confident diagnosis and management. This article reviews the sonographic appearances and management of common pelvic masses encountered in nonpregnant women, and is organized based on anatomic location: uterus, cervix, ovaries, and fallopian tubes. PMID- 25444104 TI - Fetal CNS: a systematic approach. AB - Prenatal sonography is routinely used to evaluate fetal biometry and anatomy between 16 and 20 weeks. Ventriculomegaly is easily seen on these routine views and is commonly associated with numerous intracranial anomalies. Although ventriculomegaly can be isolated, it should always prompt a detailed search to evaluate for an underlying cause. Using a systematic approach to evaluate the intracranial structures can help the clinician arrive at a correct diagnosis for many abnormalities of central nervous system. PMID- 25444105 TI - Ultrasonography evaluation of scrotal masses. AB - Sonography is the ideal modality for evaluation and characterization of a scrotal mass. Extratesticular masses are usually benign, whereas intratesticular masses are generally malignant until proved otherwise. However, it is important to recognize the benign intratesticular conditions, thus possibly preventing orchiectomy when unwarranted, while appreciating the more significant findings of extratesticular masses that may warrant further intervention. This article reviews the anatomy and sonographic findings of scrotal masses. Normal anatomy, general imaging techniques, and assessment of intratesticular and extratesticular disorders will be discussed. PMID- 25444106 TI - The role of sonography in thyroid cancer. AB - Sonography plays several important roles in the diagnosis and management of thyroid cancer. Ultrasound (US) is used for the detection and characterization of thyroid nodules as well as a guidance modality for fine-needle aspiration biopsy of indeterminate or suspicious nodules. US is also used to help stage thyroid cancer by identifying cervical lymph nodes suspicious for metastasis so they can be biopsied prior to subsequent neck dissection. Post-thyroidectomy, routine surveillance of the neck is performed with US to identify local recurrence and/or nodal metastatic disease so that focused and limited repeat neck dissection or alcohol ablation can be accomplished. PMID- 25444107 TI - Sonographic evaluation of palpable superficial masses. AB - Palpable soft tissue masses are common and are often referred for imaging evaluation. Ultrasonography is an attractive way to image these lesions because it is inexpensive, readily available, and does not rely on ionizing radiation. Ultrasonography can easily confirm the presence of a mass, differentiate solid from cystic lesions, define the anatomic extent of the lesion, and detect vascular lesions with high sensitivity. In most cases, ultrasonography can accurately characterize the lesion, obviating biopsy and reducing unnecessary further work-up. This article reviews the capabilities of ultrasonography in evaluating superficial soft tissue lesions and the sonographic appearance of disease entities. PMID- 25444108 TI - Ultrasonographic evaluation of the renal transplant. AB - Ultrasonography is an excellent tool for evaluation of the renal transplant in the immediate postoperative period and for long-term follow-up. In this article, normal imaging findings and complications of renal transplantations are described. Disease processes are divided into vascular, perinephric, urologic and collecting system, and parenchymal abnormalities. Attention is paid to the time of occurrence of each complication, classic imaging findings, and potential pitfalls. PMID- 25444109 TI - The essentials of extracranial carotid ultrasonographic imaging. AB - In this article, the standard ultrasonographic scanning techniques and Doppler settings necessary to produce reliable and reproducible carotid imaging are discussed. The normal carotid anatomy is reviewed, including grayscale, color Doppler, and spectral Doppler imaging appearances, is reviewed. The vascular abnormalities caused by atherosclerosis are examined, including plaque morphology characterization as well as waveform and velocity changes caused by stenosis, are examined. In addition, special situations are explored, such as imaging in the presence of an arrhythmia or cardiac assist devices. Imaging after carotid intervention is discussed, including the complications associated with these procedures. PMID- 25444110 TI - A practical approach to interpreting lower extremity noninvasive physiologic studies. AB - Peripheral arterial disease (PAD) is an important manifestation of atherosclerosis, with an estimated age-adjusted prevalence of approximately 13% in people older than 50 years. Noninvasive vascular laboratory physiologic studies are indispensable tools in the initial evaluation and workup and postintervention follow-up. In this review, we describe a practical approach to the technique, interpretation, pitfalls, and limitations of these physiologic studies. We also provide an algorithmic approach for using these studies in the initial workup of patients with suspected PAD. Noninvasive techniques that primarily provide anatomic information have not been included in this review. PMID- 25444112 TI - Update in ultrasound. PMID- 25444111 TI - Update on the lower extremity venous ultrasonography examination. AB - Lower extremity venous ultrasonography is an accurate method to diagnose acute deep venous thrombosis (DVT). Recurrent DVT is often difficult diagnosis. The decision to order ultrasonography can be based on pretest risk assessment. If the ultrasonography study is negative, the report may recommend follow-up for patients whose clinical condition changes or for patients with specific risks. Lower extremity venous ultrasonography is the gold standard for diagnosis of DVT. It is accurate and objective, and because the clinical assessment of patients is limited and its potential complication, pulmonary embolism, is significant, the impact of a positive and negative test is high. PMID- 25444113 TI - Nursing students with special educational needs in Japan. AB - AIM: To reveal the prevalence of nursing students with special educational needs in Japan. METHOD: A mail survey of 833 nursing programs was conducted. Nurse educators were asked to report on their program's profiles and the number of extremely difficult students who belonged to the March 2011 class of graduates. They were also asked to fill a modified questionnaire developed by the Ministry of Education, Culture, Sports, Science and Technology about each extremely difficult student. RESULTS: Among the 14,325 students enrolled the class of 2011, 146 students (1.02%) were identified as having one or more special educational needs for "listening," "speaking," "reading," "writing," "math," "reasoning," "inattentiveness," "hyperactivity/impulsivity," or "social interaction/restricted interests." The most prevalent need was "social interaction/restricted interests," followed by "listening" and "inattentiveness." These students had the most difficulty participating in "nursing care for patients during clinical practicum." CONCLUSION: The proportion of nursing students with special educational needs is small but may have a large impact on the clinical practicum. Evaluation and support systems at multiple levels, including entrance examinations, course placement, and special educational programs, are warranted. PMID- 25444115 TI - Infiltration and evaporation of small hydrocarbon spills at gas stations. AB - Small gasoline spills frequently occur at gasoline dispensing stations. We have developed a mathematical model to estimate both the amount of gasoline that infiltrates into the concrete underneath the dispensing stations and the amount of gasoline that evaporates into the typically turbulent atmosphere. Our model shows that the fraction of infiltrated gasoline can exceed the fraction that evaporates from the sessile droplets. Infiltrated gasoline then evaporates and is slowly released to the atmosphere via slow diffusive transport in pores. Tentative experiments show that our theoretical approach captures observed experimental trends. Predictions based on independently estimated model parameters roughly describe the experimental data, except for the very slow vapor release at the end of Stage II evaporation. Our study suggests that, over the lifespan of a gas station, concrete pads underneath gas dispensing stations accumulate significant amounts of gasoline, which could eventually break through into underlying soil and groundwater. Our model also shows that lifetimes of spilled gasoline droplets on concrete surfaces are on the order of minutes or longer. Therefore contamination can be carried away by foot traffic or precipitation runoff. Regulations and guidelines typically do not address subsurface and surface contaminations due to chronic small gasoline spills, even though these spills could result in non-negligible human exposure to toxic and carcinogenic gasoline compounds. PMID- 25444114 TI - Anti-asthmatic prescription variability in children according to age. AB - INTRODUCTION: There is little research in the Spanish paediatric population about the consumption of anti-asthmatic agents. The aim of this study was to describe the current pattern of anti-asthmatic drug prescription in the paediatric population from a region of Spain, using the prescribed daily dose as a unit of measurement. METHODS: We analysed the requirements of R03 therapeutic subgroup (anti-asthmatic agents) in children less than 14 years of age in the Public Health System of Castilla y Leon from 2005 to 2010. Consumption data are presented in prescribed daily doses per thousand inhabitants per day (PDHD) and compared with defined daily doses per thousand inhabitants per day (DHD). RESULTS: 394 876 prescriptions of anti-asthmatics were given to a population of 1 580 229 persons/year. Bronchodilators, leukotriene receptor antagonists, single inhaled corticosteroids (ICS) and long-acting beta2-adrenergics associated with inhaled corticosteroids were the most commonly prescribed drugs: 7.5, 5.2, 4.9 and 2.2 PDHD, respectively. The maximum prescription of bronchodilators (15.9 PDHD/9.8 DHD) occurred in children under 12 months, with montelukast (8.9 PDHD/3.6 DHD) and single inhaled corticosteroids (7.9 PDHD/2.9 DHD) at one year of age. CONCLUSIONS: Between 2005 and 2010, children under four years received a high prescription of anti-asthmatic drugs. The use of maintenance therapy was poorly aligned with the recommendations of asthma guidelines. The PDHD was more accurate for measuring consumption than DHD, especially in younger children. PMID- 25444116 TI - Consequences of varied soil hydraulic and meteorological complexity on unsaturated zone time lag estimates. AB - The true efficacy of a programme of agricultural mitigation measures within a catchment to improve water quality can be determined only after a certain hydrologic time lag period (subsequent to implementation) has elapsed. As the biophysical response to policy is not synchronous, accurate estimates of total time lag (unsaturated and saturated) become critical to manage the expectations of policy makers. The estimation of the vertical unsaturated zone component of time lag is vital as it indicates early trends (initial breakthrough), bulk (centre of mass) and total (Exit) travel times. Typically, estimation of time lag through the unsaturated zone is poor, due to the lack of site specific soil physical data, or by assuming saturated conditions. Numerical models (e.g. Hydrus 1D) enable estimates of time lag with varied levels of input data. The current study examines the consequences of varied soil hydraulic and meteorological complexity on unsaturated zone time lag estimates using simulated and actual soil profiles. Results indicated that: greater temporal resolution (from daily to hourly) of meteorological data was more critical as the saturated hydraulic conductivity of the soil decreased; high clay content soils failed to converge reflecting prevalence of lateral component as a contaminant pathway; elucidation of soil hydraulic properties was influenced by the complexity of soil physical data employed (textural menu, ROSETTA, full and partial soil water characteristic curves), which consequently affected time lag ranges; as the importance of the unsaturated zone increases with respect to total travel times the requirements for high complexity/resolution input data become greater. The methodology presented herein demonstrates that decisions made regarding input data and landscape position will have consequences for the estimated range of vertical travel times. Insufficiencies or inaccuracies regarding such input data can therefore mislead policy makers regarding the achievability of water quality targets. PMID- 25444117 TI - Degradation kinetics of chlorinated aliphatic hydrocarbons by methane oxidizers naturally-associated with wetland plant roots. AB - Chlorinated aliphatic hydrocarbons (CAHs) are common groundwater contaminants that can be removed from the environment by natural attenuation processes. CAH biodegradation can occur in wetland environments by reductive dechlorination as well as oxidation pathways. In particular, CAH oxidation may occur in vegetated wetlands, by microorganisms that are naturally associated with the roots of wetland plants. The main objective of this study was to evaluate the cometabolic degradation kinetics of the CAHs, cis-1,2-dichloroethene (cisDCE), trichloroethene (TCE), and 1,1,1-trichloroethane (1,1,1TCA), by methane-oxidizing bacteria associated with the roots of a typical wetland plant in soil-free system. Laboratory microcosms with washed live roots investigated aerobic, cometabolic degradation of CAHs by the root-associated methane-oxidizing bacteria at initial aqueous [CH4] ~1.9mgL(-1), and initial aqueous [CAH] ~150MUgL(-1); cisDCE and TCE (in the presence of 1,1,1TCA) degraded significantly, with a removal efficiency of approximately 90% and 46%, respectively. 1,1,1TCA degradation was not observed in the presence of active methane oxidizers. The pseudo first-order degradation rate-constants of TCE and cisDCE were 0.12+/-0.01 and 0.59+/-0.07d(-1), respectively, which are comparable to published values. However, their biomass-normalized degradation rate constants obtained in this study were significantly smaller than pure-culture studies, yet they were comparable to values reported for biofilm systems. The study suggests that CAH removal in wetland plant roots may be comparable to processes within biofilms. This has led us to speculate that the active biomass may be on the root surface as a biofilm. The cisDCE and TCE mass losses due to methane oxidizers in this study offer insight into the role of shallow, vegetated wetlands as an environmental sink for such xenobiotic compounds. PMID- 25444118 TI - Influence of mineral colloids and humic substances on uranium(VI) transport in water-saturated geologic porous media. AB - Mineral colloids and humic substances often co-exist in subsurface environment and substantially influence uranium (U) transport. However, the combined effects of mineral colloids and humic substances on U transport are not clear. This study is aimed at quantifying U transport and elucidating geochemical processes that control U transport when both mineral colloids and humic acid (HA) are present. U spiked solutions/suspensions were injected into water-saturated sand columns, and U and colloid concentrations in column effluent were monitored. We found that HA promoted U transport via (i) formation of aqueous U-HA complexes, and (ii) competition against aqueous U for surface sites on transport media. Illite colloids had no influence on U transport at pH5 in the absence of HA due to low mobility of the colloids. At pH9, U desorbed from mobile illite and the presence of illite decreased U transport. At pH5, high U transport occurred when both illite colloids and HA were present, which was attributed to enhanced U adsorption to illite colloids via formation of ternary illite-HA-U surface complexes, and enhanced illite transport due to HA attachment to illite and transport media. This study demonstrates that the combined effects of mineral colloids and HA on contaminant transport is different from simple addition of the individual effect. PMID- 25444119 TI - Evaluation of leaching potential of three systemic neonicotinoid insecticides in vineyard soil. AB - Dinotefuran (DNT), imidacloprid (IMD), and thiamethoxam (THM) are commonly used neonicotinoid insecticides in a variety of agriculture operations. Although these insecticides help growers control pest infestation, the residual environmental occurrence of insecticides may cause unintended adverse ecological consequences to non-target species. In this study, the leaching behavior of DNT, IMD, and THM was investigated in soils collected from an active AgriLife Research Extension Center (AREC) vineyard. A series of column experiments were conducted to evaluate the leaching potential of insecticides under two experimental scenarios: a) individual pulse mode, and b) mixed pulse mode. In both scenarios, the breakthrough pattern of the insecticides in the mostly acidic to neutral vineyard soil clearly demonstrates medium to high leachability. Of the three insecticides studied for leaching, DNT has exhibited high leaching potential and exited the column with fewer pore volumes, whereas IMD was retained for longer, indicating lower leachability. Relative differences in leaching behavior of neonicotinoids could be attributed to their solubility with the leaching pattern IMD10-20%) and pools (Sn>20%) together accounted for almost 40% of the DNAPL mass, but only 3% of the sampled source volume. High-saturation DNAPL lenses/pools were supported by lower permeability layers, but with DNAPL still primarily present within slightly more permeable overlying units. These lenses/pools exhibited approximately linearly declining Sn profiles with increasing elevation ascribed to preferential dissolution of the uppermost DNAPL. Bi-component partitioning calculations on soil samples confirmed that the dechlorination product cDCE (cis-dichloroethene) was accumulating in the TCE DNAPL. Estimated cDCE mole fractions in the DNAPL increased towards the DNAPL interface with the uppermost mole fraction of 0.04 comparable to literature laboratory data. DNAPL dissolution yielded heterogeneous dissolved-phase plumes of TCE and its dechlorination products that exhibited orders of magnitude local concentration variation. TCE solubility concentrations were relatively localised, but coincident with high saturation DNAPL lens source areas. Biotic dechlorination in the source zone area, however, caused cDCE to be the dominant dissolved-phase plume. The conservative tracer test usefully confirmed the continuity of a permeable gravel unit at depth through the source zone. Although this unit offered significant opportunity for DNAPL bypassing and decreased timeframes for dechlorination, it still transmitted a significant proportion of the contaminant flux. This was attributed to dissolution of DNAPL mudstone aquitard associated sources at the base of the continuous gravel as well as contaminated groundwater from surrounding less permeable sand and gravel horizons draining into this permeable conduit. The cell extraction well provided an integrated metric of source zone dissolution yielding a mean concentration of around 45% TCE solubility (taking into account dechlorination) that was equivalent to a DNAPL mass removal rate of 0.4tonnes per annum over a 16m(2) cell cross sectional area of flow. This is a significant flux considering the source age and observed occurrence of much of the source mass within discrete lenses/pools. We advocate the need for further detailed field-scale studies on old DNAPL source zones that better resolve persistent pool/lens features and are of prolonged duration to assess the ageing of source zones. Such studies would further underpin the application of more surgical remediation technologies. PMID- 25444122 TI - Editorial overview: Antimicrobials: grappling with the complexities of antibiotics and resistance. PMID- 25444121 TI - What can we learn from fitness landscapes? AB - A combinatorially complete data set consists of studies of all possible combinations of a set of mutant sites in a gene or mutant alleles in a genome. Among the most robust conclusions from these studies is that epistasis between beneficial mutations often shows a pattern of diminishing returns, in which favorable mutations are less fit when combined than would be expected. Another robust inference is that the number of adaptive evolutionary paths is often limited to a relatively small fraction of the theoretical possibilities, owing largely to sign epistasis requiring evolutionary steps that would entail a decrease in fitness. Here we summarize these and other results while also examining issues that remain unresolved and future directions that seem promising. PMID- 25444123 TI - [Close relationships between microorganisms and cancer]. PMID- 25444124 TI - [Distribution of phylogenetic groups and virulence factors in CTX-M-15 beta lactamase-producing uropathogenic Escherichia coli strains isolated from patients in the community of Merida, Venezuela]. AB - In this study, the distribution of phylogenetic groups and the genetic detection of virulence factors in CTX-M-15 beta-lactamase-producing uropathogenic Escherichia coli (UPEC) strains were analyzed. Twenty eight strains were isolated between January 2009 and July 2011 from patients with urinary tract infection (UTI) who attended the Public Health Laboratory at Merida, Venezuela. Determination of phylogenetic groups and detection of six virulence genes, fimH, fyuA, kpsMTII, usp, PAI and papAH, were performed by PCR amplification. Fifteen of the 28 isolates were mainly located in the phylogenetic group A, followed by B2 (12/28) and D (1/28). No direct relationship between the severity or recurrence of UTI and the distribution of phylogroups was observed. All studied virulence factors were found in group B2 strains with the highest frequency. The prevalent virulence profile included the combination of three main genes: fimH, kpsMTII and fyuA and, to a lesser extent, the presence of other determinants such as usp, PAI and/or papAH. These results indicate that virulent UPEC incorporated three important properties: adhesion, iron uptake and evasion of phagocytosis, which favored the production of recurrent UTI. This is the first report describing the association of phylogenetic groups with the potential virulence of CTX-M-15 beta-lactamase producing UPEC strains in Venezuela. PMID- 25444126 TI - [Validation of a real time RT-PCR assay to detect foot-and-mouth disease virus and assessment of its performance in acute infection]. AB - A specific real time reverse transcription polymerase chain reaction (RT-PCRrt) for the detection of foot-and-mouth disease virus was validated using the LightCycler thermocycler 2.0 and its reagents as recommended by the World Organization for Animal Health and was assessed for the detection of the virus in acute infection of cattle experimentally vaccinated and challenged with virus A Argentina/2001 or A24 Cruzeiro. The technique proved to be robust, showing coefficients of variation lower than 4% for different ARN extractions, days or repetitions and was able to detect up to 0,4 TCID 50%, and/or up to 100 RNA molecules. In probang samples, diagnostic sensitivity was 93.1 (95% CI 86.5-96.6) and diagnostic specificity 100 (95% CI 96.3-100). The results of the challenge in vaccinated or multivaccinated bovines showed that although there were high levels of clinical protection in the vaccinated group, FMDV could be detected in all challenged groups. However, detection was 100 times lower in immunized animals. PMID- 25444125 TI - [Evaluation of vaginal dysfunction in symptomatic and asymptomatic pregnant women by using the analysis of basic vaginal states (BVS) and its comparison with the conventional microbiological study]. AB - Infections of the lower genital tract associated to maternal and perinatal complications frequently occur during pregnancy. The aim of this study was to evaluate vaginal dysfunction through the analysis of basic vaginal states (BVS) using the methodology of balance of the vaginal content (BAVACO) and to compare it with the microbiological study of candidiasis, trichomoniasis and bacterial vaginosis (BV). Pregnant patients (1238) were examined from 2010 to 2012. In asymptomatic (A) (n: 1046) and symptomatic pregnant women (S) (n: 192) BVS I was 59.5% and 26% of the patients, respectively. BVS II was observed in 19.7% of A and in 17.2% of S. BVS III was only detected in A in 0.4%. BVS IV was observed in 14.4% of A and in 38% of S. BVS V was detected in 6% of A and in 18.8% of S. Yeasts were associated to BVS I and II in 55.5% and 23.2% of A, respectively; and in 32.4% and 31% of S, respectively. Trichomonas were associated to BVS I in 50% of A, to IV in 44.4% of S and to V in 33.3% of S. BAVACO susceptibility to detect yeasts was 80.4% and 85.5% in A and S, respectively; 40% and 75% in A and S, respectively, to detect trichomonas and 100% in A and S to detect BV. BAVACO specificity was 100% for all pathogens in A and S. The study of BVS proved useful as a guide to evaluate vaginal dysfunction, regardless of symptomatology. Therefore, this study is recommended as prenatal control. PMID- 25444127 TI - [Sensitivity of the COBAS AmpliScreenTM HIV-1 test v1.5 for HIV-1 detection]. AB - The introduction of nucleic acid amplification techniques (NAT) in blood banks was intended to reduce the residual risk of transfusion-transmitted infections. Co-circulation of a great diversity of HIV-1 variants in Argentina portrays the need to assess the sensitivity of serological and molecular assays available for their detection. In this study, we evaluated the sensitivity of the COBAS AmpliScreenTM HIV-1 Test, version 1.5 (Roche) for the detection of HIV-1 RNA in plasma samples of infected individuals from Argentina. The results of this study reveal that this technique has high sensitivity for the detection of HIV-1 RNA under assay conditions: using mini-pool testing, pools >= 50 RNA copies per ml achieved >= 92 % sensitivity, whereas in the standard procedure, samples >= 207 RNA copies/ml achieved 100 % sensitivity. Moreover, the COBAS AmpliScreenTM HIV-1 Test, version 1.5 (Roche) is suitable for detecting prevailing HIV-1 variants. PMID- 25444128 TI - Genotypes of Leptospira spp. strains isolated from dogs in Buenos Aires, Argentina. AB - Leptospirosis is an infectious disease of wide global distribution, which is endemic in Argentina. The objective of this study was to obtain the genetic profiles of Leptospira spp. strains isolated from clinical cases of dogs in the province of Buenos Aires by the multiple-locus variable-number tandem repeat analysis (MLVA). Eight isolated canine strains were genotyped by MLVA, obtaining the identical profile of Leptospira interrogans serovar Canicola Hond Utrecht IV in the strains named Dogy and Mayo. The strains named Bel, Sarmiento, La Plata 4581 and La Plata 5478 were identical to the profile of the genotype of L. interrogans serovar Portlandvere MY 1039.The strain named Avellaneda was identical to the genotype profile of L. interrogans serovar Icterohaemorrhagiae RGA and the strain named SB had the same profile as the L. interrogans serovar Pomona Baires genotype and was similar to the profile of serovar Pomona Pomona genotype. It would be useful to include a larger number of isolates from different dog populations in various provinces of Argentina and to characterize the genetic profiles of the strains circulating in the country. The information obtained will be useful for the control of leptospirosis in the dog population. PMID- 25444129 TI - Diagnosis of an outbreak of Salmonella typhimurium in chinchillas (Chinchilla lanigera) by pulsed-field gel electrophoresis. AB - Adult chinchillas (Chinchilla lanigera) that had suddenly died in a commercial farm located in La Plata City, Buenos Aires Province, Argentina, in July 2012 were macroscopically, histopathologically, and microbiologically examined. Salmonella enterica serovar Typhimurium (S. Typhimurium) was isolated from the liver, spleen, heart, lungs, kidneys and intestines from each of the five animals evaluated. The five strains were susceptible to ampicillin, cephalotin, cefotaxime, nalidixic acid, gentamicin, streptomycin, chloramphenicol, fosfomycin, nitrofurantoin and trimethoprim-sulfamethoxazole, and resistant to tetracycline. Each of the five S. Typhimurium isolates was analyzed by XbaI- pulsed-field gel electrophoresis (PFGE), showing an identical electrophoretic profile with 15 defined bands, which was found to be identical to pattern ARJPXX01.0220 of the PulseNet Argentine National database of Salmonella PFGE patterns. This is the first work describing the postmortem diagnosis of an outbreak of salmonellosis in chinchillas by using molecular methods such as PFGE. PMID- 25444130 TI - beta-lactamases produced by amoxicillin-clavulanate-resistant enterobacteria isolated in Buenos Aires, Argentina: a new blaTEM gene. AB - Resistance to beta-lactam/beta-lactamase inhibitors in enterobacteria is a growing problem that has not been intensively studied in Argentina. In the present work, 54/843 enterobacteria collected in a teaching hospital of Buenos Aires city were ampicillin-sulbactam-resistant isolates remaining susceptible to second- and third-generation cephalosporins. The enzymatic mechanisms present in the isolates, which were also amoxicillin-clavulanic acid (AMC)-resistant (18/54) were herein analyzed. Sequencing revealed two different variants of blaTEM-1, being blaTEM-1b the most frequently detected allelle (10 Escherichia coli, 3 Klebsiella pneumoniae, 2 Proteus mirabilis and 1 Raoultella terrigena) followed by blaTEM-1a (1 K. pneumoniae). Amoxicillin-clavulanate resistance seems to be mainly associated with TEM-1 overproduction (mostly in E. coli) or co-expressed with OXA-2-like and/or SHV beta-lactamases (K. pneumoniae and P. mirabilis). A new blaTEM variant (TEM-163) was described in an E. coli strain having an AMC MIC value of 16/8MUg/ml. TEM-163 contains Arg275Gln and His289Leu amino acid substitutions. On the basis of the high specific activity and low IC50 for clavulanic acid observed, the resistance pattern seems to be due to overproduction of the new variant of broad spectrum beta-lactamase rather than to an inhibitor-resistant TEM (IRT)-like behavior. PMID- 25444131 TI - Rich bacterial assemblages from Maritime Antarctica (Potter Cove, South Shetlands) reveal several kinds of endemic and undescribed phylotypes. AB - Bacterial richness in maritime Antarctica has been poorly described to date. Phylogenetic affiliation of seawater free-living microbial assemblages was studied from three locations near the Argentinean Jubany Station during two Antarctic summers. Sixty 16S RNA cloned sequences were phylogenetically affiliated to Alphaproteobacteria (30/60 clones), Gammaproteobacteria(19/60 clones), Betaproteobacteria and Cytophaga-Flavobacteriia-Bacteroides (CFB), which were (2/60) and (3/60) respectively. Furthermore, six out of 60 clones could not be classified. Both, Alphaproteobacteria and Gammaproteobacteria, showed several endemic and previously undescribed sequences. Moreover, the absence of Cyanobacteria sequences in our samples is remarkable. In conclusion, we are reporting a rich sequence assemblage composed of widely divergent isolates among themselves and distant from the most closely related sequences currently deposited in data banks. PMID- 25444132 TI - [Physical and chemical methods for eliminating propagules of indigenous mycorrhizal fungi from soil samples]. AB - The objective of this work was to evaluate methods to eliminate or reduce the number of indigenous arbuscular mycorrhizal fungi (AMF) from soil samples without affecting their edaphic or microbiological properties. At an early trial we evaluated moist heat (autoclaving), dry heat (oven), sodium hypochlorite (NaClO) and formaldehyde at a range of 100.0-3.3MUl/g and 16.7-3.3MUl/g respectively. There was no germination in plants of ryegrass (Lolium multiflorum Lam.) sown on substrates receiving NaClO (100.0-33.3MUl/g), whereas autoclaving significantly increased the available soil phosphorous content. Both treatments failed to eradicate AMF colonization at 9 weeks; therefore, they were discarded. In a second trial, oven and formaldehyde (10.0MUl/g) treatments were analyzed to assess the effects of seed decontamination and AMF reinoculation. Both procedures were effective in reducing or eliminating indigenous AMF at a range of soil P availability of 12-29mg/kg. However, the time between soil treatment and AMF multiplication and safety requirements were greater in the case of formaldehyde application. PMID- 25444133 TI - [Agrobacterium rubi strains from blueberry plants are highly diverse]. AB - The diversity of a collection of Agrobacterium rubi strains isolated from blueberries from different regions of Argentina was studied by conventional microbiological tests and molecular techniques. Results from biochemical and physiological reactions, as well as from rep-PCR and RFLP analysis of PCR amplified 23S rDNA showed high phenotypic and genotypic intraspecific variation. PMID- 25444134 TI - [Networks involving quorum sensing, cyclic-di-GMP and nitric oxide on biofilm production in bacteria]. AB - Bacterial biofilms are ubiquitous in nature, and their flexibility is derived in part from a complex extracellular matrix that can be made-to-order to cope with environmental demand. Although common developmental stages leading to biofilm formation have been described, an in-depth knowledge of genetic and signaling is required to understand biofilm formation. Bacteria detect changes in population density by quorum sensing and particular environmental conditions, using signals such as cyclic di-GMP or nitric oxide. The significance of understanding these signaling pathways lies in that they control a broad variety of functions such as biofilm formation, and motility, providing benefits to bacteria as regards host colonization, defense against competitors, and adaptation to changing environments. Due to the importance of these features, we here review the signaling network and regulatory connections among quorum sensing, c-di-GMP and nitric oxide involving biofilm formation. PMID- 25444135 TI - [Microbicides for preventing sexually transmitted infections: Current status and strategies for preclinical evaluation of new candidates]. AB - Microbicides are a new tool, still under investigation, which could help prevent infection by the human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). Increasing evidence shows that the complexity of sexual transmission of viral pathogens requires the identification of compounds able to block the early events during the cycle of viral infection. In this manuscript we provide a comprehensive review of the different microbicide strategies that have been studied or are currently being considered for STI prevention, particularly emphasizing those having the potential to block HIV infection. The manuscript also reviews the complex process that is required to conduct future clinical studies in humans and concludes with a brief discussion of the strategies that could be part of the immediate future in microbicide research. PMID- 25444136 TI - Campylobacter fetus subsp. venerealis adhesion to MDBK cells. PMID- 25444137 TI - [Decreased level of consciousness, fever, and dyspnea in an HIV-infected patient]. PMID- 25444138 TI - Prognostic role of magnetic resonance imaging vs. computed tomography for hepatocellular carcinoma undergoing chemoembolization. AB - BACKGROUND & AIMS: Computed tomography (CT) and magnetic resonance imaging (MRI) play important roles in diagnosis and staging of hepatocellular carcinoma (HCC). However, prognostic roles of radiological characteristics are not yet determined. METHODS: Eighty-eight patients treated with chemoembolization were analysed. Radiological parameters at baseline were assessed in all patients using both dynamic CT and MRI. Treatment responses were assessed using modified RECIST 4 weeks after the first chemoembolization. RESULTS: Gross vascular invasion (GVI), bile duct invasion, irregular tumour margin (ITM), peripheral ragged enhancement (PRE) and satellite nodules on CT or MRI were associated with non-response (stable disease or progression) after chemoembolization respectively (all P <= 0.05). GVI, ITM and PRE on CT or MRI were also independently associated with poor overall survival (OS) respectively (all P <= 0.05). Using these results, a prognostic scoring system for CT and MRI were developed; 0, absence of all three features (GVI, ITM and PRE); 1, presence of one feature; 2, presence of two features; and 3, presence of three features. After adjusting tumour size, tumour number and alpha-foetoprotein level, both CT and MRI scores were independently associated with OS (both P < 0.001). Patients with CT or MRI score >=2 had a worse OS than those with score <2 (adjusted hazard ratios, 3.837 and 2.938 respectively). MRI-specific parameters such as signal intensity on T2- or T1 weighted images, fat signal or hyperintensity on diffusion-weighted images did not have prognostic value (all P > 0.05). CONCLUSIONS: Radiological parameters by CT and MRI may be useful in biological characterization of tumours and prognostification for HCC treated with chemoembolization. PMID- 25444139 TI - Temporal changes in interpapillary muscle dynamics as an active indicator of mitral valve and left ventricular interaction in ischemic mitral regurgitation. AB - BACKGROUND: Regional subpapillary myocardial hypokinesis may impair lateral reduction in the interpapillary muscle distance (IPMD) from diastole to systole, and adversely affect mitral valve geometry and tethering. OBJECTIVES: The goal of this study was to investigate the impact of impaired lateral shortening in the interpapillary muscle distance on mitral valve geometry and function in ischemic heart disease. METHODS: To quantify ventricular size/shape, regional myocardial contraction, lateral shortening of the IPMD, mitral valve geometry, and severity of mitral regurgitation, 67 patients with ischemic heart disease underwent cardiac magnetic resonance imaging, and a correlation analysis of measured parameters was performed. The impact of reduced IPMD shortening on mitral valve (dys)function was confirmed in swine and in a physiological computational mitral valve model. RESULTS: Lateral shortening of the IPMD from diastole to systole was severely reduced in patients with moderate/severe ischemic mitral regurgitation (9.6 +/- 2.8 mm), but preserved in mild IMR (11.5 +/- 3.4 mm). Left ventricular size and ejection fraction did not differ between the groups. In swine with subpapillary infarction and impaired IPMD, mitral regurgitation was evident within 1 week, compared to those pigs with a nonpapillary infarction and preserved IPMD. In the controlled computational valve model, IPMD had the maximal impact on regurgitation, and was exacerbated with additional annular dilation. CONCLUSIONS: By using cardiac magnetic resonance imaging in humans, we demonstrated that it is the impairment of lateral shortening between the papillary muscles, and not passive ventricular size, that governs the severity of mitral regurgitation. Loss of lateral shortening of IPMD tethers the leaflet edges and impairs their systolic closure, resulting in mitral regurgitation, even in small ventricles. Understanding the lateral dynamics of ventricular-valve interactions could aid the development of new repair techniques for ischemic mitral regurgitation. PMID- 25444140 TI - Ischemic mitral regurgitation: is mitral valve physiology moving from global to local? PMID- 25444141 TI - Clinical impact of atrial fibrillation in patients with the HeartMate II left ventricular assist device. AB - BACKGROUND: Atrial fibrillation (AF) is common in patients with the HeartMate II (HMII) left ventricular assist device (LVAD), but the impact of AF on clinical outcomes is uncertain. OBJECTIVES: This study sought to determine the effect of AF on outcomes in patients with the HMII LVAD. METHODS: Records of 106 patients who underwent HMII implantation at a single center were reviewed. The associations of paroxysmal atrial fibrillation (PAF) and persistent atrial fibrillation (PeAF) with survival, heart failure (HF) hospitalization, bleeding, and thromboembolism were examined using Kaplan-Meier survival analysis and Cox proportional hazards regression. RESULTS: Mean age was 56.6 +/- 11.4 years, 87.7% of the implants were intended as a bridge to transplantation, and median length of support was 217 days (range: 1 to 952 days). AF was present in 55 patients (51.9%); 36 patients (34.0%) had PAF and 19 (17.9%) had PeAF. Twenty-one patients (19.8%) died, and 18 (17.0%) were hospitalized for HF. There were 0.75 major bleeding events and 0.28 thromboembolic events per patient year of follow-up. PAF was not associated with increased mortality, HF hospitalization, bleeding, or thromboembolism. PeAF, however, was an independent predictor of the composite endpoint of death or HF hospitalization (hazard ratio: 3.54; 95% confidence interval: 1.52 to 8.25; p < 0.01). Although there was no increase in bleeding or thromboembolism, patients with AF had thromboembolic events at higher international normalized ratios (INRs). CONCLUSIONS: Although PAF is not associated with worse outcomes in patients with the HMII LVAD, PeAF may be associated with increased mortality and HF hospitalization. Patients with AF also may have thromboembolic events at higher INR levels. PMID- 25444142 TI - Maybe atrial fibrillation does matter in ventricular assist device patients? PMID- 25444143 TI - Impact of microvascular obstruction on the assessment of coronary flow reserve, index of microcirculatory resistance, and fractional flow reserve after ST segment elevation myocardial infarction. AB - BACKGROUND: Invasive assessment of coronary physiology (IACP) offers important prognostic insights in ST-segment elevation myocardial infarction (STEMI) but the dynamics of coronary recovery are poorly understood. OBJECTIVES: This study sought to examine the evolution of coronary flow reserve (CFR), index of microcirculatory resistance (IMR), ratio of distal coronary pressure (Pd) to mean aortic pressure (Pa), and fractional flow reserve (FFR) in patients undergoing primary percutaneous coronary intervention (PPCI). METHODS: 82 patients with STEMI underwent IACP at PPCI. Repeat IACP was performed in 61 patients (74%) at day 1 and in 46 patients (56%) at 6 months. Contrast-enhanced cardiac magnetic resonance imaging (CMR) was performed in 45 patients (55%) at day 1 and in 41 patients (50%) at 6 months. Changes in IACP were compared between patients with and without microvascular obstruction (MVO) on CMR. RESULTS: MVO was present in 21 of 45 patients (47%). Patients with MVO had lower CFR at PPCI and day 1 (p < 0.05) and a trend toward higher IMR values (p = 0.07). At 6 months, CFR and IMR were not significantly different between the groups. Baseline flow and Pd/Pa remained stable over time but FFR reduced significantly between PPCI and 6 months (p = 0.008); this reduction was mainly observed in patients with MVO (p = 0.006) but not in those without MVO (p = 0.21). CONCLUSIONS: In PPCI-treated patients with STEMI, coronary microcirculation begins to recover within 24 h and recovery progresses further by 6 months. FFR significantly reduces from baseline to 6 months. The presence of MVO indicates a highly dysfunctional microcirculation. PMID- 25444144 TI - Invasive coronary microcirculation assessment during myocardial infarction: one step forward or two steps back? PMID- 25444145 TI - Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. AB - BACKGROUND: Altered intestinal function is prevalent in patients with heart failure (HF), but its role in adverse outcomes is unclear. OBJECTIVES: This study investigated the potential pathophysiological contributions of intestinal microbiota in HF. METHODS: We examined the relationship between fasting plasma trimethylamine-N-oxide (TMAO) and all-cause mortality over a 5-year follow-up in 720 patients with stable HF. RESULTS: The median TMAO level was 5.0 MUM, which was higher than in subjects without HF (3.5 MUM; p < 0.001). There was modest but significant correlation between TMAO concentrations and B-type natriuretic peptide (BNP) levels (r = 0.23; p < 0.001). Higher plasma TMAO levels were associated with a 3.4-fold increased mortality risk. Following adjustments for traditional risk factors and BNP levels, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio [HR]: 2.2; 95% CI: 1.42 to 3.43; p < 0.001), as well as following the addition of estimated glomerular filtration rate to the model (HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.001). CONCLUSIONS: High TMAO levels were observed in patients with HF, and elevated TMAO levels portended higher long-term mortality risk independent of traditional risk factors and cardiorenal indexes. PMID- 25444146 TI - Gut feelings about heart failure. PMID- 25444148 TI - The sum of two evils: pneumonia and myocardial infarction: is platelet activation the missing link? PMID- 25444149 TI - Imaging and functional testing to assess clinical and subclinical neurological events after transcatheter or surgical aortic valve replacement: a comprehensive review. AB - Neurological events after transcatheter (TAVR) or surgical aortic valve replacement (SAVR) are potentially devastating and associated with a poor prognosis. With technological improvements and increased operator experience, their incidence is markedly declining, justifying the need for surrogate endpoints to be used in future comparative trials. Moreover, imaging studies after TAVR and SAVR suggest that neurological events are mainly embolic in nature; however, there is significant discrepancy between imaging findings and clinically overt symptoms, raising the possibility of more subtle subclinical cognitive decline. Different modalities have been used to assess both overt and subclinical neurological events after SAVR and TAVR. The purpose of this report is to systematically review and describe currently used imaging, functional, and neurocognitive testing modalities and to better understand how they could be integrated in future prospective studies. PMID- 25444150 TI - Mentoring: why it matters even after training. PMID- 25444147 TI - Platelet activation is associated with myocardial infarction in patients with pneumonia. AB - BACKGROUND: Troponins may be elevated in patients with pneumonia, but associations with myocardial infarction (MI) and with platelet activation are still undefined. OBJECTIVES: The aim of this study was to investigate the relationship between troponin elevation and in vivo markers of platelet activation in the early phase of hospitalization of patients affected by community-acquired pneumonia. METHODS: A total of 278 consecutive patients hospitalized for community-acquired pneumonia, who were followed up until discharge, were included. At admission, platelet activation markers such as plasma soluble P-selectin, soluble CD40 ligand, and serum thromboxane B2 (TxB2) were measured. Serum high-sensitivity cardiac troponin T levels and electrocardiograms were obtained every 12 and 24 h, respectively. RESULTS: Among 144 patients with elevated high-sensitivity cardiac troponin T, 31 had signs of MI and 113 did not. Baseline plasma levels of soluble P-selectin and soluble CD40 ligand and serum TxB2 were significantly higher in patients who developed signs of MI. Logistic regression analysis showed plasma soluble CD40 ligand (p < 0.001) and soluble P-selectin (p < 0.001), serum TxB2 (p = 0.030), mean platelet volume (p = 0.037), Pneumonia Severity Index score (p = 0.030), and ejection fraction (p = 0.001) to be independent predictors of MI. There were no significant differences in MI rate between the 123 patients (45%) taking aspirin (100 mg/day) and those who were not aspirin treated (12% vs. 10%; p = 0.649). Aspirin-treated patients with MIs had higher serum TxB2 compared with those without MIs (p = 0.005). CONCLUSIONS: MI is an early complication of pneumonia and is associated with in vivo platelet activation and serum TxB2 overproduction; aspirin 100 mg/day seems insufficient to inhibit thromboxane biosynthesis. (MACCE in Hospitalized Patients With Community-acquired Pneumonia; NCT01773863). PMID- 25444151 TI - T cell-based assay of pericardial fluid mononuclear cells for the diagnosis of tuberculous pericardial effusion. PMID- 25444152 TI - Circadian variations of ventricular arrhythmias and sleep-disordered breathing in HF patients. PMID- 25444153 TI - Reply: circadian variations of ventricular arrhythmias and sleep-disordered breathing in HF patients. PMID- 25444155 TI - A preliminary study for a slantwise-placed electroglottography. AB - OBJECTIVE: Slantwise-placed electroglottography (EGG) was proposed for synchronous use with an ultrasound machine in a previous work. The objective was to confirm the feasibility of this slant EGG, differentiate it from conventional EGG, and give suggestions for its applications. STUDY DESIGN AND METHODS: A synchronized system composed of an EGG device, a high-speed video, a sound level meter, and a headset was established. The same phonation conditions were acquired by training subjects to reach the target phonation frequency and intensity. Electrode position was designed, and vocal fold vibration parameters were measured from EGG waveforms recorded in each electrode position. RESULTS: Comparison showed that the characteristic points identified in slant EGG waveforms were consistent with the vibration phase shown by high-speed video images. Phonation frequency measured from slant EGG was highly accurate. EGG amplitude nonlinearly decreased with the increase of electrode distance. Compared with conventional EGG parameters, velocity ratio and glottal closed quotient measured from slant EGG were accurate when electrodes were placed symmetrically and the electrode distance was within a proper length. CONCLUSIONS: Slant EGG was proved feasible and can be considered as a useful tool to obtain comprehensive information in investigating the in vivo vocal fold dynamics when synchronized with other detecting equipment. PMID- 25444156 TI - Vocal fold nodules in school age children: attention deficit hyperactivity disorder as a potential risk factor. AB - OBJECTIVE: To evaluate the presence of symptoms of inattention and hyperactivity/impulsivity in a population of school age children affected by vocal fold nodules. METHODS: Parents and teachers of 18 children with vocal fold nodules (10 males, eight females; aged between 6 and 12 years) and 20 matched controls without dysphonia and/or vocal fold diseases (11 males, nine females; aged between 6 and 12 years) completed Attention-Deficit/Hyperactivity Disorder (ADHD) rating scale for parents (SDAG [Scala per i Disturbi di Attenzione/Iperattivita per Genitori]) and teachers (SDAI [Scala per i Disturbi di Attenzione/Iperattivita per Insegnanti) rating scales containing in two subscales items that specifically evaluate the symptoms of ADHD according to the DSM-IV. All children were subjected to videolaryngoscopy. RESULTS: The group with vocal fold nodules scored significantly higher than the controls; the difference between the two groups was statistically significant for both the subscales of both questionnaires (SDAG and SDAI) (P < 0.05). Four children in the group with vocal fold nodules who scored higher than 14 in at least one subscale were referred for psychiatric evaluation. For two of the children, both male, a diagnosis of combined ADHD was formulated. CONCLUSIONS: ADHD is a possible risk factor for the development of vocal fold nodules in childhood. SDAG and SDAI rating scales may supplement the diagnostic assessment of children with vocal fold nodules. PMID- 25444154 TI - Quantitative assessment of the asphericity of pretherapeutic FDG uptake as an independent predictor of outcome in NSCLC. AB - BACKGROUND: The aim of the present study was to evaluate the predictive value of a novel quantitative measure for the spatial heterogeneity of FDG uptake, the asphericity (ASP) in patients with non-small cell lung cancer (NSCLC). METHODS: FDG-PET/CT had been performed in 60 patients (15 women, 45 men; median age, 65.5 years) with newly diagnosed NSCLC prior to therapy. The FDG-PET image of the primary tumor was segmented using the ROVER 3D segmentation tool based on thresholding at the volume-reproducing intensity threshold after subtraction of local background. ASP was defined as the relative deviation of the tumor's shape from a sphere. Univariate and multivariate Cox regression as well as Kaplan-Meier (KM) analysis and log-rank test with respect to overall (OAS) and progression free survival (PFS) were performed for clinical variables, SUVmax/mean, metabolically active tumor volume (MTV), total lesion glycolysis (TLG), ASP and "solidity", another measure of shape irregularity. RESULTS: ASP, solidity and "primary surgical treatment" were significant independent predictors of PFS in multivariate Cox regression with binarized parameters (HR, 3.66; p<0.001, HR, 2.11; p=0.05 and HR, 2.09; p=0.05), ASP and "primary surgical treatment" of OAS (HR, 3.19; p=0.02 and HR, 3.78; p=0.01, respectively). None of the other semi quantitative PET parameters showed significant predictive value with respect to OAS or PFS. Kaplan-Meier analysis revealed a probability of 2-year PFS of 52% in patients with low ASP compared to 12% in patients with high ASP (p<0.001). Furthermore, it showed a higher OAS rate in the case of low versus high ASP (1 year-OAS, 91% vs. 67%: p=0.02). CONCLUSIONS: The novel parameter asphericity of pretherapeutic FDG uptake seems to provide better prognostic value for PFS and OAS in NCSLC compared to SUV, metabolic tumor volume, total lesion glycolysis and solidity. PMID- 25444157 TI - An aerodynamic study of labial stop consonants after laser cordectomy of types II III. AB - OBJECTIVES: The aim of this paper is to compare the aerodynamic parameters of intraoral pressure (IOP), oral airflow (OAF), and estimated transglottal pressure of 10 French patients treated by a cordectomy of types II-III with a group of 10 French healthy subjects. STUDY DESIGN: Prospective. METHODS: The collection of the aerodynamic data was conducted with EVA2. Parameters were measured using logatomes of the type CV1.CV2.CVC3 where C represents [p,b] and V is one of the vowels [a,i,u] in the positions one and two (n = 240). The maximum peaks of IOP of the plosives [p] and [b] and the maximum peaks of OAF at their releases were extracted. Finally, the transglottal pressure was estimated, necessary for the voicing of [b], to establish the difference in the IOP mean peak of [p] and [b] at the same intensity. Subsequently, the differences in IOP for both positions and each vocalic contexts, "IOP(p-b)" were calculated, and the reports of these differences for the IOP of [p], viz "IOP(p-b)/IOP(p)", were established for a normalization of the results. RESULTS: This study highlights an increase of the IOP and the OAF in voiceless contexts for both groups. The elevation of both parameters observed for the patients-confirmed by the calculation of the estimated transglottal pressure-does show some degree of laryngeal incompetence. CONCLUSIONS: The patients treated by cordectomy of types II-III maintain a relatively good voicing contrast. A certain difficulty in the execution of this articulatory feature is found. PMID- 25444158 TI - Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly. AB - BACKGROUND: Genetic haploinsufficiency of SYNGAP1/Syngap1 commonly occurs in developmental brain disorders, such as intellectual disability, epilepsy, schizophrenia, and autism spectrum disorder. Thus, studying mouse models of Syngap1 haploinsufficiency may uncover pathologic developmental processes common among distinct brain disorders. METHODS: A Syngap1 haploinsufficiency model was used to explore the relationship between critical period dendritic spine abnormalities, cortical circuit assembly, and the window for genetic rescue to understand how damaging mutations disrupt key substrates of mouse brain development. RESULTS: Syngap1 mutations broadly disrupted a developmentally sensitive period that corresponded to the period of heightened postnatal cortical synaptogenesis. Pathogenic Syngap1 mutations caused a coordinated acceleration of dendrite elongation and spine morphogenesis and pruning of these structures in neonatal cortical pyramidal neurons. These mutations also prevented a form of developmental structural plasticity associated with experience-dependent reorganization of brain circuits. Consistent with these findings, Syngap1 mutant mice displayed an altered pattern of long-distance synaptic inputs into a cortical area important for cognition. Interestingly, the ability to genetically improve the behavioral endophenotype of Syngap1 mice decreased slowly over postnatal development and mapped onto the developmental period of coordinated dendritic insults. CONCLUSIONS: Pathogenic Syngap1 mutations have a profound impact on the dynamics and structural integrity of pyramidal cell postsynaptic structures known to guide the de novo wiring of nascent cortical circuits. These findings support the idea that disrupted critical periods of dendritic growth and spine plasticity may be a common pathologic process in developmental brain disorders. PMID- 25444160 TI - A Case of Quetiapine-Induced Rapid Eye Movement Sleep Behavior Disorder. PMID- 25444159 TI - Direct regulation of diurnal Drd3 expression and cocaine reward by NPAS2. AB - BACKGROUND: Circadian gene disruptions are associated with the development of psychiatric disorders, including addiction. However, the mechanisms by which circadian genes regulate reward remain poorly understood. METHODS: We used mice with a mutation in Npas2 and adeno-associated virus-short hairpin RNA mediated knockdown of Npas2 and Clock in the nucleus accumbens (NAc). We performed conditioned place preference assays. We utilized cell sorting quantitative real time polymerase chain reaction, and chromatin immunoprecipitation followed by deep sequencing. RESULTS: Npas2 mutants exhibit decreased sensitivity to cocaine reward, which is recapitulated with a knockdown of neuronal PAS domain protein 2 (NPAS2) specifically in the NAc, demonstrating the importance of NPAS2 in this region. Interestingly, reducing circadian locomotor output cycles kaput (CLOCK) (a homologue of NPAS2) in the NAc had no effect, suggesting an important distinction in NPAS2 and CLOCK function. Furthermore, we found that NPAS2 expression is restricted to Drd1 expressing neurons while CLOCK is ubiquitous. Moreover, NPAS2 and CLOCK have distinct temporal patterns of DNA binding, and we identified novel and unique binding sites for each protein. We identified the Drd3 dopamine receptor as a direct transcriptional target of NPAS2 and found that NPAS2 knockdown in the NAc disrupts its diurnal rhythm in expression. Chronic cocaine treatment likewise disrupts the normal rhythm in Npas2 and Drd3 expression in the NAc, which may underlie behavioral plasticity in response to cocaine. CONCLUSIONS: Together, these findings identify an important role for the circadian protein, NPAS2, in the NAc in the regulation of dopamine receptor expression and drug reward. PMID- 25444161 TI - Genetics of complex traits in psychiatry. AB - Virtually all psychiatric traits are genetically complex. This article discusses the genetics of complex traits in psychiatry. The complexity is accounted for by numerous factors, including multiple risk alleles, epistasis, and epigenetic effects such as methylation. Risk alleles can individually be common or rare, and can include, for example, single nucleotide polymorphisms and copy number variants that are transmitted or are new mutations, and other kinds of variation. Many different kinds of variation can be important for trait risk, either together in various proportions or as different factors in different subjects. Until more recently, approaches to complex traits were limited, and consequently only a few variants, usually of individually minor effect, were identified. At the present time, a much richer armamentarium exists that includes the routine application of genome-wide association studies and next-generation high throughput sequencing and the combination of this information with other biologically relevant information, such as expression data. We have also seen the emergence of large meta-analysis and mega-analysis consortia. These developments are extremely important for psychiatric genetics, have advanced the field substantially, and promise formidable gains in the years to come as they are applied more widely. PMID- 25444162 TI - Neurobiological signatures of anxiety and depression in resting-state functional magnetic resonance imaging. AB - BACKGROUND: There is increasing interest in using neurobiological measures to inform psychiatric nosology. It is unclear at the present time whether anxiety and depression are neurobiologically distinct or similar processes. It is also unknown if the best way to examine these disorders neurobiologically is by contrasting categorical definitions or by examining symptom dimensions. METHODS: A cross-sectional neuroimaging study was conducted of patients with generalized anxiety disorder (GAD), major depressive disorder (MDD), comorbid GAD and MDD (GAD/MDD), or neither GAD nor MDD (control subjects). There were 90 participants, all medication-free (17 GAD, 12 MDD, 23 GAD/MDD, and 38 control subjects). Diagnosis/category and dimensions/symptoms were assessed to determine the best fit for neurobiological data. Symptoms included general distress, common to anxiety and depression, and anxiety-specific (anxious arousal) or depression specific (anhedonia) symptoms. Low-frequency (.008-.1 Hz) signal amplitude and functional connectivity analyses of resting-state functional magnetic resonance imaging data focused on a priori cortical and subcortical regions of interest. RESULTS: Support was found for effects of diagnosis above and beyond effects related to symptom levels as well as for effects of symptom levels above and beyond effects of diagnostic categories. The specific dimensional factors of general distress and anxious arousal as well as a diagnosis of MDD explained unique proportions of variance in signal amplitude or functional connectivity. CONCLUSIONS: Using resting-state functional magnetic resonance imaging, our data show that a single conceptual model alone (i.e., categorical diagnoses or symptom dimensions) provides an incomplete mapping of psychopathology to neurobiology. Instead, the data support an additive model that best captures abnormal neural patterns in patients with anxiety and depression. PMID- 25444163 TI - Autism with intellectual disability related to dynamics of head circumference growth during early infancy. AB - BACKGROUND: It is not yet definitively known whether dynamic features of head circumference growth are associated with autism. To address this issue, we carried out a nested matched case-control study using data from national well baby clinics in Finland; autism cases were identified from the Finnish Hospital and Outpatient Discharge Registry. METHODS: A nonparametric Bayesian method was used to construct growth velocity trajectories between birth and 2 years of age in autism cases and matched control subjects (n = 468 in main analyses, 1:1 matched control subjects). Estimates of odds ratios for autism risk in relation to the growth velocities were obtained using conditional logistic regression. RESULTS: Growth velocity of head circumference at 3 months of age, adjusting for gestational age at birth and maternal age, is significantly associated with autism (p = .014); the finding was observed in subjects with comorbid intellectual disability (ID) (p = .025) but not in those without ID (p = .15). Height growth velocity among subjects with autism and without ID is significantly associated with autism at 6 months (p = .007), and weight growth velocity at 18 months without ID (p = .02) and 24 months without ID (p = .042) and with ID (p = .037). CONCLUSIONS: Acceleration in head circumference growth is associated with autism with comorbid ID at 3 months but not subsequently. This association is unrelated to acceleration in height and weight, which are not strongly associated with autism until after 6 months. PMID- 25444165 TI - Early withdrawal effects in a heavy cannabis smoker during hemodialysis. PMID- 25444164 TI - Reaction time variability and related brain activity in methamphetamine psychosis. AB - BACKGROUND: This study investigated the dynamics of cognitive control instability in methamphetamine (MA) abuse, as well its relationship to substance-induced psychiatric symptoms and drug use patterns. METHODS: We used an ex-Gaussian reaction time (RT) distribution to examine intraindividual variability (IIV) and excessively long RTs (tau) in an individual's RT on a Stroop task in 30 currently drug-abstinent (3 months to 2 years) MA abusers compared with 27 nonsubstance abusing control subjects. All subjects underwent functional magnetic resonance imaging while performing the Stroop task, which allowed us to measure the relationship between IIV and tau to functional brain activity. RESULTS: Elevated IIV in the MA compared with the control group did not reach significance; however, when the MA group was divided into those subjects who had experienced MA induced psychosis (MAP+) (n = 19) and those who had not (n = 11), the MAP+ group had higher average IIV compared with the other groups (p < .03). In addition, although control subjects displayed a relationship between IIV and conflict related brain activity in bilateral prefrontal cortex such that increased IIV was associated with increased activity, the MAP+ group displayed this relationship in right prefrontal cortex only, perhaps reflecting elevated vigilance in the MAP+ group. Greater IIV did not correlate with severity of use or months MA abstinent. No group differences emerged in tau values. CONCLUSIONS: These results suggest increased cognitive instability in those MA-dependent subjects who had experienced MA-induced psychosis. PMID- 25444166 TI - Brain-derived neurotrophic factor epigenetic modifications associated with schizophrenia-like phenotype induced by prenatal stress in mice. AB - BACKGROUND: Prenatal stress (PRS) is considered a risk factor for several neurodevelopmental disorders including schizophrenia (SZ). An animal model involving restraint stress of pregnant mice suggests that PRS induces epigenetic changes in specific GABAergic and glutamatergic genes likely to be implicated in SZ, including the gene for brain-derived neurotrophic factor (BDNF). METHODS: Studying adult offspring of pregnant mice subjected to PRS, we explored the long term effects of PRS on behavior and on the expression of key chromatin remodeling factors including DNA methyltransferase 1, ten-eleven-translocation hydroxylases, methyl CpG binding protein 2, histone deacetylases, and histone methyltransferases and demethylase in the frontal cortex and hippocampus. We also measured the expression of BDNF. RESULTS: Adult PRS offspring demonstrate behavioral abnormalities suggestive of SZ and molecular changes similar to changes seen in postmortem brains of patients with SZ. This includes a significant increase in DNA methyltransferase 1 and ten-eleven-translocation hydroxylase 1 in the frontal cortex and hippocampus but not in cerebellum; no changes in histone deacetylases, histone methyltransferases and demethylases, or methyl CpG binding protein 2, and a significant decrease in Bdnf messenger RNA variants. The decrease of the corresponding Bdnf transcript level was accompanied by an enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at Bdnf gene regulatory regions. In addition, the expression of Bdnf transcripts (IV and IX) correlated positively with social approach in both PRS mice and nonstressed mice. CONCLUSIONS: Because patients with psychosis and PRS mice show similar epigenetic signature, PRS mice may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in patients with SZ. PMID- 25444167 TI - Sexual orientation modulates endocrine stress reactivity. AB - BACKGROUND: Biological sex differences and sociocultural gender diversity influence endocrine stress reactivity. Although numerous studies have shown that men typically activate stronger stress responses than women when exposed to laboratory-based psychosocial stressors, it is unclear whether sexual orientation further modulates stress reactivity. Given that lesbian, gay, and bisexual (LGB) individuals frequently report heightened distress secondary to stigma-related stressors, we investigated whether cortisol stress reactivity differs between LGB individuals and heterosexual individuals in response to a well-validated psychosocial stressor. METHODS: The study population comprised 87 healthy adults (mean age, 25 years) who were grouped according to their biological sex and their gendered sexual orientation: lesbian/bisexual women (n = 20), heterosexual women (n = 21), gay/bisexual men (n = 26), and heterosexual men (n = 20). Investigators collected 10 salivary cortisol samples throughout a 2-hour afternoon visit involving exposure to the Trier Social Stress Test modified to maximize between sex differences. RESULTS: Relative to heterosexual women, lesbian/bisexual women showed higher cortisol stress reactivity 40 min after exposure to the stressor. In contrast, gay/bisexual men displayed lower overall cortisol concentrations throughout testing compared with heterosexual men. Main findings were significant while adjusting for sex hormones (estradiol-to-progesterone ratio in women and testosterone in men), age, self-esteem, and disclosure status (whether LGB participants had completed their "coming out"). CONCLUSIONS: Our results provide novel evidence for gender-based modulation of cortisol stress reactivity based on sexual orientation that goes beyond well-established between-sex differences. This study raises several important avenues for future research related to the physiologic functioning of LGB populations and gender diversity more broadly. PMID- 25444169 TI - Dorsomedial Prefrontal Cortex Mediates the Impact of Serotonin Transporter Linked Polymorphic Region Genotype on Anticipatory Threat Reactions. AB - BACKGROUND: Excessive anticipatory reactions to potential future adversity are observed across a range of anxiety disorders, but the neurogenetic mechanisms driving interindividual differences are largely unknown. We aimed to discover and validate a gene-brain-behavior pathway by linking presumed genetic risk for anxiety-related psychopathology, key neural activity involved in anxious anticipation, and resulting aversive emotional states. METHODS: The functional neuroanatomy of aversive anticipation was probed through functional magnetic resonance imaging in two independent samples of healthy subjects (n = 99 and n = 69), and we studied the influence of genetic variance in the serotonin transporter linked polymorphic region (5-HTTLPR). Skin conductance and startle data served as objective psychophysiological indices of the intensity of individuals' anticipatory responses to potential threat. RESULTS: Threat cues signaling risk of future electrical shock activated the dorsomedial prefrontal cortex (dmPFC), anterior insula, bed nucleus of the stria terminalis, thalamus, and midbrain consistently across both samples. Threat-related dmPFC activation was enhanced in 5-HTTLPR short allele carriers in sample 1 and this effect was validated in sample 2. Critically, we show that this region mediates the increase in anticipatory psychophysiological reactions in short allele carriers indexed by skin conductance (experiment 1) and startle reactions (experiment 2). CONCLUSIONS: The converging results from these experiments demonstrate that innate 5-HTTLPR linked variation in dmPFC activity predicts psychophysiological responsivity to pending threats. Our results reveal a neurogenetic pathway mediating interindividual variability in anticipatory responses to threat and yield a novel mechanistic account for previously reported associations between genetic variability in serotonin transporter function and stress-related psychopathology. PMID- 25444168 TI - A novel anxiogenic role for the delta opioid receptor expressed in GABAergic forebrain neurons. AB - BACKGROUND: The delta opioid receptor (DOR) is broadly expressed throughout the nervous system; it regulates chronic pain, emotional responses, motivation, and memory. Neural circuits underlying DOR activities have been poorly explored by genetic approaches. We used conditional mouse mutagenesis to elucidate receptor function in GABAergic neurons of the forebrain. METHODS: We characterized DOR distribution in the brain of Dlx5/6-CreXOprd1(fl/fl) (Dlx-DOR) mice and tested main central DOR functions through behavioral testing. RESULTS: The DOR proteins were strongly deleted in olfactory bulb and striatum and remained intact in cortex and basolateral amygdala. Olfactory perception, circadian activity, and despair-like behaviors were unchanged. In contrast, locomotor stimulant effects of SNC80 (DOR agonist) and SKF81297 (D1 agonist) were abolished and increased, respectively. The Dlx-DOR mice showed lower levels of anxiety in the elevated plus maze, opposing the known high anxiety in constitutive DOR knockout animals. Also, Dlx-DOR mice reached the food more rapidly in a novelty suppressed feeding task, despite their lower motivation for food reward observed in an operant paradigm. Finally, c-fos protein staining after novelty suppressed feeding was strongly reduced in amygdala, concordant with the low anxiety phenotype of Dlx DOR mice. CONCLUSIONS: We demonstrate that DORs expressed in the forebrain mediate the described locomotor effect of SNC80 and inhibit D1-stimulated hyperactivity. Our data also reveal an unanticipated anxiogenic role for this particular DOR subpopulation, with a potential novel adaptive role. In emotional responses, DORs exert dual anxiolytic and anxiogenic roles, both of which may have implications in the area of anxiety disorders. PMID- 25444171 TI - Depression, neuroimaging and connectomics: a selective overview. AB - Depression is a multifactorial disorder with clinically heterogeneous features involving disturbances of mood and cognitive function. Noninvasive neuroimaging studies have provided rich evidence that these behavioral deficits in depression are associated with structural and functional abnormalities in specific regions and connections. Recent advances in brain connectomics through the use of graph theory highlight disrupted topological organization of large-scale functional and structural brain networks in depression, involving global topology (e.g., local clustering, shortest-path lengths, and global and local efficiencies), modular structure, and network hubs. These system-level disruptions show important correlates with genetic and environmental factors, which provide an integrative perspective on mood and cognitive deficits in depressive syndrome. Moreover, research suggests that the pathologic networks associated with depression represent potentially valuable biomarkers for early detection of this disorder and they are likely to be regulated and recalibrated by using pharmacologic, psychological, and brain stimulation therapies. These connectome-based imaging studies present new opportunities to reconceptualize the pathogenesis of depression, improve our knowledge of the biological mechanisms of therapeutic effects, and identify appropriate stimulation targets to optimize the clinical response in depression treatment. Here, we summarize the current findings and historical understanding of structural and functional connectomes in depression, focusing on graph analyses of depressive brain networks. We also consider methodological factors such as sample heterogeneity and poor test-retest reliability of recordings due to physiological, head motion, and imaging artifacts to discuss result inconsistencies among studies. We conclude with suggestions for future research directions on the emerging field of imaging connectomics in depression. PMID- 25444170 TI - Utility of Scalp Hair Follicles as a Novel Source of Biomarker Genes for Psychiatric Illnesses. AB - BACKGROUND: Identifying beneficial surrogate genetic markers in psychiatric disorders is crucial but challenging. METHODS: Given that scalp hair follicles are easily accessible and, like the brain, are derived from the ectoderm, expressions of messenger RNA (mRNA) and microRNA in the organ were examined between schizophrenia (n for first/second = 52/42) and control subjects (n = 62/55) in two sets of cohort. Genes of significance were also analyzed using postmortem brains (n for case/control = 35/35 in Brodmann area 46, 20/20 in cornu ammonis 1) and induced pluripotent stem cells (n = 4/4) and pluripotent stem cell derived neurospheres (n = 12/12) to see their role in the central nervous system. Expression levels of mRNA for autism (n for case/control = 18/24) were also examined using scalp hair follicles. RESULTS: Among mRNA examined, FABP4 was downregulated in schizophrenia subjects by two independent sample sets. Receiver operating characteristic curve analysis determined that the sensitivity and specificity were 71.8% and 66.7%, respectively. FABP4 was expressed from the stage of neurosphere. Additionally, microarray-based microRNA analysis showed a trend of increased expression of hsa-miR-4449 (p = .0634) in hair follicles from schizophrenia. hsa-miR-4449 expression was increased in Brodmann area 46 from schizophrenia (p = .0007). Finally, we tested the expression of nine putative autism candidate genes in hair follicles and found decreased CNTNAP2 expression in the autism cohort. CONCLUSIONS: Scalp hair follicles could be a beneficial genetic biomarker resource for brain diseases, and further studies of FABP4 are merited in schizophrenia pathogenesis. PMID- 25444172 TI - Patient with perinatal brain injury dystonia treated by deep brain stimulation: Management during pregnancy. PMID- 25444174 TI - Designing for our future selves. PMID- 25444173 TI - [Specificities of the logopenic variant of primary progressive aphasia]. AB - The logopenic variant of primary progressive aphasia is a syndrome with neuropsychological and linguistic specificities, including phonological loop impairment for which diagnosis is currently mainly based on the exclusion of the two other variants, semantic and nonfluent/agrammatic primary progressive aphasia. The syndrome may be underdiagnosed due (1) to mild language difficulties during the early stages of the disease or (2) to being mistaken for mild cognitive impairment or Alzheimer's disease when the evaluation of episodic memory is based on verbal material and (3) finally, it is not uncommon that the disorders are attributed to psychiatric co-morbidities such as, for example, anxiety. Moreover, compared to other variants of primary progressive aphasia, brain abnormalities are different. The left temporoparietal junction is initially affected. Neuropathology and biomarkers (cerebrospinal fluid, molecular amyloid nuclear imaging) frequently reveal Alzheimer's disease. Consequently this variant of primary progressive aphasia does not fall under the traditional concept of frontotemporal lobar degeneration. These distinctive features highlight the utility of correct diagnosis, classification, and use of biomarkers to show the neuropathological processes underlying logopenic primary progressive aphasia. The logopenic variant of primary progressive aphasia is a specific form of Alzheimer's disease frequently presenting a rapid decline; specific linguistic therapies are needed. Further investigation of this syndrome is needed to refine screening, improve diagnostic criteria and better understand the epidemiology and the biological mechanisms involved. PMID- 25444176 TI - A clinical series and literature review of the management of inguinal nodal metastases in patients with primary extramammary Paget disease of the scrotum. AB - We describe a series of five patients with extramammary Paget disease of the scrotum with inguinal nodal metastases. These patients underwent combined groin dissection. All patients experienced invasion to the dermis. One patient had invasion of the dartos muscle, another had tumor invading into the skeletal muscle and femoral vein. Four patients had positive Cloquet node involvement on frozen section and formal histology, but only one patient had positive pelvic nodal disease. Another patient with pelvic nodal metastases seen on computed tomography scan had no Cloquet node identified intraoperatively but had positive pelvic nodal metastases. The mean disease-free survival and the overall survival were 28.6 months (range: 2-60 months) and 33.4 months (range: 2-60 months), respectively, for all patients. Three patients developed distant metastases and two patients were disease free to date. No locoregional recurrences were observed. Aggressive lymphadenectomy in selected cases can provide a long-term survival benefit. The use of Cloquet node in the prediction of pelvic nodal disease should be considered. Based on the literature review, sentinel lymph node biopsy can potentially diagnose occult metastases in otherwise nonenlarged nodes. PMID- 25444175 TI - TLR3 engagement induces IRF-3-dependent apoptosis in androgen-sensitive prostate cancer cells and inhibits tumour growth in vivo. AB - Toll-like receptors (TLRs) are a family of highly conserved transmembrane proteins expressed in epithelial and immune cells that recognize pathogen associated molecular patterns. Besides their role in immune response against infections, numerous studies have shown an important role of different TLRs in cancer, indicating these receptors as potential targets for cancer therapy. We previously demonstrated that the activation of TLR3 by the synthetic double stranded RNA analogue poly I:C induces apoptosis of androgen-sensitive prostate cancer (PCa) LNCaP cells and, much less efficiently, of the more aggressive PC3 cell line. Therefore, in this study we selected LNCaP cells to investigate the mechanism of TLR3-mediated apoptosis and the in vivo efficacy of poly I:C-based therapy. We show that interferon regulatory factor-3 (IRF-3) signalling plays an essential role in TLR3-mediated apoptosis in LNCaP cells through the activation of the intrinsic and extrinsic apoptotic pathways. Interestingly, hardly any apoptosis was induced by poly I:C in normal prostate epithelial cells RWPE-1. We also demonstrate for the first time the direct anticancer effect of poly I:C as a single therapeutic agent in a well-established human androgen-sensitive PCa xenograft model, by showing that tumour growth is highly impaired in poly I:C treated immunodeficient mice. Immunohistochemical analysis of PCa xenografts highlights the antitumour role of poly I:C in vivo both on cancer cells and, indirectly, on endothelial cells. Notably, we show the presence of TLR3 and IRF-3 in both human normal and PCa clinical samples, potentially envisaging poly I:C based therapy for PCa. PMID- 25444177 TI - Effect of combined irradiation and EGFR/Erb-B inhibition with BIBW 2992 on proliferation and tumour cure in cell lines and xenografts. AB - BACKGROUND AND PURPOSE: In previous experiments an enhanced anti-proliterative effect of the EGFR/ErbB tyrosine kinase inhibitor (TKI) BIBW 2992 with single dose irradiation was observed in FaDu tumour xenografts. Aim of the present experiment was to determine if this effect can also be seen in combination with a fractionated radiotherapy. Secondly we investigate the efficacy of BIBW 2992 on local tumour control for UT-SCC-15. MATERIAL AND METHODS: Tumour pieces of FaDu, UT-SCC-14, A431, UT-SCC-15 (squamous cell carcinomas) and A7 (glioma) tumour models were transplanted onto the right hind leg of NMRI (nu/nu) nude mice. For evaluation of tumour growth mice were either treated daily orally with BIBW 2992 (30 mg/kg body weight), or carrier up to a final tumour size of 15 mm or with a fractionated radiotherapy (15f/15d, 30 Gy) with simultaneous application of BIBW 2992 or carrier. For local tumour control UT-SCC-15 tumours were treated with a fractionated radiotherapy (30f/6weeks) or received 30f/6 weeks in combination with daily orally BIBW 2992 (22.5 mg/kg b.w.) during RT. RESULTS: A significant effect on tumour growth time was observed in all tumour models for BIBW 2992 application alone. However, substantial intertumoural heterogeneity could be seen. In the UT-SCC-14, UT-SCC-15 and A431 tumour models a total regression of the tumours and no recurrence during treatment time (73 days) were determined where as for the A7 tumour only a slight effect was noticeable. For the combined treatment of fractionated radiotherapy (15f/15d) and BIBW 2992 administration a significant effect on tumour growth time was seen compared to irradiation alone for A7, UT-SCC-15 and A431 (ER 1.2 - 3.7), this advantage could not be demonstrated for FaDu and UT-SCC-14. However, the local tumour control was not altered for the UT-SCC-15 tumour model when adding BIBW 2992 to fractionated irradiation (30f/6weeks). CONCLUSION: A heterogeneous effect on tumour growth time of BIBW 2992 alone as well as in combination with fractionated irradiation could be demonstrated for all tumour models. However, the significant effect on tumour growth time did not translate into an improvement of local tumour control for the UT-SCC-15 tumour model. PMID- 25444178 TI - #SLOPCAB: is the party over? PMID- 25444179 TI - The encephalopathy of congenital heart disease. PMID- 25444180 TI - Defining and improving postoperative care. AB - Although much is known regarding the importance of postoperative care, the surveillance of patients after 30 days from the surgical procedure can be improved. It must be recognized that mortality between 30 and 90 days exceeds what is commonly considered "operative mortality"-death within 30 days of surgery. Significant effort should be dedicated to the design of predictive models to prevent readmission. More importantly, surgeons must develop better models to manage the complications that arise after readmission to prevent mortality in readmitted patients. Finally, current guidelines for oncologic surveillance are an area of controversy, and future studies are needed for better direction of resources. PMID- 25444181 TI - Novel oral anticoagulation agents: new drugs create new paradigms. PMID- 25444182 TI - Should off-pump coronary artery bypass surgery be abandoned? A potential solution. PMID- 25444183 TI - Failure to initiate statin therapy during and after percutaneous coronary interventions negatively affects coronary artery bypass graft outcomes. PMID- 25444184 TI - Arterial grafting and the risk of sternal infection: how we can learn from our experience. PMID- 25444185 TI - Do stentless valves make a difference? PMID- 25444186 TI - The importance of longitudinal assessment of valve function. PMID- 25444187 TI - "Forgotten" valve or "enigmatic" valve? Further insights into the tricuspid valve in patients undergoing mitral valve surgery. PMID- 25444188 TI - Sound arguments, true premises, and valid conclusions. PMID- 25444189 TI - Bicuspid aortopathy and the development of individualized resection strategies. PMID- 25444190 TI - Acute ascending aortic dissection: support for limited distal repair. PMID- 25444191 TI - Another approach to dissection involving the aortic arch. PMID- 25444192 TI - Leaving the nest: facing adulthood after the arterial switch operation. PMID- 25444193 TI - Predictors of 90-day mortality after congenital heart surgery: the first report of risk models from a Japanese database. AB - OBJECTIVE: The purpose of this study was to develop risk models for congenital heart surgery short-term and midterm outcomes from a nationwide integrated database drawn from hospitals in Japan. METHODS: The Japan Congenital Cardiovascular Surgery Database collects clinical information from institutions throughout Japan specializing in congenital heart surgery. Variables and definitions used in the Japan Congenital Cardiovascular Surgery Database are almost identical to those of the Society of Thoracic Surgeons-European Association for Cardiothoracic Surgery database for congenital heart surgery. We used logistic regression to develop risk models, which were then validated through spilt-sample validation. In addition to procedural complexity categories by Risk Adjustment in Congenital Heart Surgery (RACHS-1) score, we incorporated patient characteristics to predict surgical outcome. RESULTS: Among 8923 congenital heart operations performed at 69 sites with cardiac surgical programs, 30-day mortalities by RACHS-1 category were as follows: I, 0.1% (n=1319); II, 0.5% (n=3211); III, 2.2% (n=3285); IV, 4.3% (n=818); and V and VI, 8.6% (n=290). From the test data set (n=7223), we developed 3 risk models (30-day mortality, 90 day mortality, and 90-day and in-hospital mortality) with 11 variables, including age category, RACHS-1 category, preoperative risk factors, number of surgical procedures, unplanned reoperations, status of surgery, surgery type, asplenia, and prematurity (<35 weeks). For the performance metrics of the risk models, C statistic values of 30-day, 90-day, and 90-day and in-hospital mortalities for the test data set were 0.85, 0.85, and 0.84, respectively. When only the RACHS-1 score was used for discrimination, the C statistic values of 30-day, 90-day, and 90-day and in-hospital mortalities for the validation data set were 0.73, 0.73, and 0.77, respectively. CONCLUSIONS: The proposed risk scores and categories have high discrimination power for predicting mortality, demonstrating improvement relative to existing consensus-based methods. Risk models incorporating these measures may be useful for comparing mortality outcomes cross institutions or countries with mixed cases. PMID- 25444194 TI - Risk models for pediatric and congenital cardiac surgery. PMID- 25444195 TI - Utility of the technical performance score for the Norwood operation ... every score should know its limitations. PMID- 25444196 TI - Responsible innovation. PMID- 25444197 TI - The crisis of readmissions: symptom or disease? PMID- 25444198 TI - Predicting response to neoadjuvant therapy in esophageal cancer with p53 genotyping: a fortune-teller's crystal ball or a viable prognostic tool? PMID- 25444199 TI - Percutaneous versus surgical drainage of malignant pericardial effusion: Still no tiebreaker. PMID- 25444201 TI - Heart and soul. PMID- 25444200 TI - Myocardial protection isn't dead yet. PMID- 25444202 TI - An ounce of prevention is worth a pound of cure. PMID- 25444203 TI - Comparison of extracorporeal membrane oxygenation versus cardiopulmonary bypass for lung transplantation. AB - OBJECTIVE: This study compared differences in patient outcomes and operative parameters for extracorporeal membrane oxygenation (ECMO) versus cardiopulmonary bypass (CPB) in patients undergoing lung transplants. METHODS: Between January 1, 2008, and July 13, 2013, 316 patients underwent lung transplants at our institution, 102 requiring intraoperative mechanical cardiopulmonary support (CPB, n=55; ECMO, n=47). We evaluated survival, blood product transfusions, bleeding complications, graft dysfunction, and rejection. RESULTS: Intraoperatively, the CPB group required more cell saver volume (1123+/-701 vs 814+/-826 mL; P=.043), fresh-frozen plasma (3.64+/-5.0 vs 1.51+/-3.2 units; P=.014), platelets (1.38+/-1.6 vs 0.43+/-1.25 units; P=.001), and cryoprecipitate (4.89+/-6.3 vs 0.85+/-2.8 units; P<.001) than the ECMO group. Postoperatively, the CPB group received more platelets (1.09+/-2.6 vs 0.13+/-0.39 units; P=.013) and was more likely to have bleeding (15 [27.3%] vs 3 [6.4%]; P=.006) and reoperation (21 [38.2%] vs 7 [14.9%]; P=.009]. The CPB group had higher rates of primary graft dysfunction at 24 and 72 hours (41 [74.5%] vs 23 [48.9%]; P=.008; and 42 [76.4%] vs 26 [56.5%]; P=.034; respectively). There were no differences in 30-day and 1-year survivals. CONCLUSIONS: Relative to CPB, the ECMO group required fewer transfusions and had less bleeding, fewer reoperations, and less primary graft dysfunction. There were no statistically significant survival differences at 30 days or 1 year. PMID- 25444204 TI - Discussion. PMID- 25444205 TI - Reply to the editor. PMID- 25444206 TI - Intraoperative positioning to prevent driveline insulation from acting as a conduit for left ventricular assist device pocket infection. PMID- 25444207 TI - Reply to the editor. PMID- 25444208 TI - Misuse of the term "subclavian access". PMID- 25444209 TI - The aortic wall with bicuspid aortic valve: immature or prematurely aging? PMID- 25444210 TI - Reply to the editor. PMID- 25444211 TI - Minimally invasive full biatrial Cox maze IV: we are going in the right direction. PMID- 25444212 TI - Rupture of expanded polytetrafluoroethylene neochordae used for mitral valve repair: does size matter? PMID- 25444213 TI - Expanded level of sympathectomy and incidence or severity of compensatory hyperhidrosis. PMID- 25444214 TI - Reply to the editor. PMID- 25444216 TI - Recurrent cerebral embolism secondary to esophageal and atrial foreign body complicated by infective endocarditis. PMID- 25444217 TI - Familial Ebstein's anomaly, left ventricular noncompaction, and ventricular septal defect associated with an MYH7 mutation. PMID- 25444218 TI - Long-term success rates after an anterior neurectomy in patients with an abdominal cutaneous nerve entrapment syndrome. AB - BACKGROUND: Surgery occasionally is proposed in patients with chronic abdominal wall pain caused by an anterior cutaneous nerve entrapment syndrome (ACNES) who are refractory to injection therapy. An anterior neurectomy may seem successful, but follow-up is usually short and populations are small. The primary aim of this study was to determine the long-term success rate of surgery in a large ACNES population. METHODS: In this retrospective observational study, patients with ACNES >=18 years who underwent a primary anterior neurectomy between January 2004 and February 2012 in one single center were studied. Pain scores were obtained before surgery, after surgery, and at the moment of questioning using a pain intensity numeric rating scale (PI-NRS 0-10) and a 6-point verbal category rating scale. Success was defined as a >=50% PI-NRS reduction or >=2 point verbal rating scale reduction. RESULTS: Data of 181 neurectomies in 154 individuals were available for analysis (female, n = 127, 82.5%; age 47 +/- 17 years, range, 20 83). Pain before operation was severe (mean PI-NRS 8.08, SD 1.43). Short-term (1 3 months postoperative) success was 70% (127/181 procedures). Three subjects showed spontaneous remission of complaints after >=3 months. After a mean 32 months (range, 3-93) follow-up, a success rate of 61% (109/180) on the long-term was found. CONCLUSION: A 70% short-term success rate and a 61% long-term success rate after a primary anterior neurectomy in patients with chronic abdominal pain due to ACNES were attained. Surgery is the method of choice in ACNES patients who are refractory to a conservative regimen. PMID- 25444219 TI - Surgically avertable burden of digestive diseases at first-level hospitals in low and middle-income regions. AB - BACKGROUND: To quantify the burden of digestive diseases avertable by surgical care at first-level hospitals in low- and middle-income countries (LMICs). METHODS: We examined 4 digestive diseases from the Global Burden of Disease (GBD) 2010 STUDY: Appendicitis, intestinal obstruction, inguinal and femoral hernia, and gallbladder and bile duct disease. Using demographic and epidemiologic data from the GBD 2010 STUDY, we calculated the potential decrease in burden of digestive diseases if quality surgical services were available universally and accessible at first-level hospitals. The lowest case fatality rates for each age and sex grouping from all GBD regions were assumed to reflect the best possible state of full surgical coverage and treatment. These best scenario rates were applied to the GBD 2010 results from all LMIC regions to estimate surgically avertable burden. RESULTS: Overall, 4.8 million disability-adjusted life-years (DALYs) or 65% of burden related to the 4 digestive diseases are avertable potentially with first-level surgical care in LMICs. Sub-Saharan Africa has the greatest avertable burden in absolute DALYs (1.7 million) and avertable proportion (83%). Intestinal obstruction accounted for the largest portion of avertable burden among the 4 digestive diseases (2.2 million DALYs; 64% avertable). CONCLUSION: Improving the capacity of surgical services at first level hospitals is essential for averting the burden of digestive diseases in LMICs. Practicable strategies for scaling up surgical capacities in rural districts are available potentially, which must be given due attention. PMID- 25444220 TI - Tissue sealants in endoscopic applications for anastomotic leakage during a 25 year period. AB - BACKGROUND: Anastomotic leakage after gastrointestinal operation is a complication difficult to manage because conservative therapy and/or reoperation may be unsuccessful and carry the risk of increased morbidity and mortality. The endoscopic use of tissue sealants appears to be a promising alternative to avoid operation. METHOD: We present conclusively our 25-year experience with tissue sealing in a series of 63 patients referred after gastrointestinal anastomosis leakage; 48 of the upper and 15 of the lower gastrointestinal tract, experiencing a drainage volume ranging 50-2,400 mL. RESULTS: Tissue glue was applied orally in 37, anally in 10, through the fistula tract in 8, and through a combination of approximation routes in another 8 cases. Biological glue (fibrin) was used in 47, cyanoacrylate in 8, and both glue types in another 8 patients. The total volume of fibrin applied was 2-36 mL, in a median of four sessions, 0.5-4 mL for cyanoacrylate, in a median of two sessions, and, whenever a combination of glues was used, a volume of 12-40 mL of fibrin plus 1-4 mL of cyanoacrylate, in a median of nine sessions. The median hospital stay after initiation of gluing was 14 days (range 8-32). The clinical and technical success rate was 96.8% (61 of 63 patients). CONCLUSION: Tissue glue appears to be a valuable clinical tool that would prevent further operative interventions and the associated morbidity and mortality after a gastrointestinal anastomosis dehiscence. However, it must be borne in mind that repeated sessions and large volumes of sealants are necessary in many cases. PMID- 25444221 TI - The role of matrix metalloproteinases and neutrophil gelatinase-associated lipocalin in central and peripheral arterial aneurysms. AB - INTRODUCTION: An association between arterial aneurysms and matrix metalloproteinases (MMPs) has been described previously. MMPs regulate extracellular structural proteins and tissue remodeling. Neutrophil gelatinase associated lipocalin (NGAL) is involved in the regulation of MMP activity. The aim of this work was to study the relationship between the levels of MMPs and NGAL and arterial aneurysms. METHODS: In a multicenter, open-label, parallel groups, prospective study, patients with aneurysmal disease were divided into 2 groups: Group I (with ruptured aneurysm) and group II (with nonruptured aneurysm). Healthy volunteer patients were also enrolled and represented the control group (group III). RESULTS: We enrolled 307 patients (107 in group I and 200 in group II) with arterial aneurysm: 49 popliteal, 31 common femoral, 2 superficial femoral, 29 common iliac artery, 3 common carotid, and 193 abdominal aorta. Finally, 11 healthy volunteer patients (9 males and 2 females; age range, 40-70 years; median 56) were enrolled in group III. Enzyme-linked immunosorbent assay and Western blot analysis revealed greater levels of immunoreactive MMP-9 and NGAL in all patients with ruptured aneurysms, both central and peripheral aneurysms, and in the aneurismal vessels. CONCLUSION: These results provide potentially important insights to the understanding of the natural history of arterial aneurysms. MMPs and NGAL play a role in development of arterial aneurysms and may represent molecular markers for the prevention of aneurysmal rupture. PMID- 25444223 TI - Comment on: "Experimental development of an intra-abdominal chemohyperthermia model using a closed abdomen technique and a PRS-1.0 Combat CO2". PMID- 25444222 TI - Exploring ethical conflicts in emergency trauma research: the COMBAT (Control of Major Bleeding after Trauma) study experience. AB - BACKGROUND: Up to 25% of severely injured patients develop trauma-induced coagulopathy. To study interventions for this vulnerable population for whom consent cannot be obtained easily, the Food and Drug Administration issued regulations for emergency research with an exception from informed consent (ER EIC). We describe the community consultation and public disclosure (CC/PD) process in preparation for an ER-EIC study, namely the Control Of Major Bleeding After Trauma (COMBAT) study. METHODS: The CC/PD was guided by the four bioethical principles. We used a multimedia approach, including one-way communications (newspaper ads, brochures, television, radio, and web) and two-way communications (interactive in-person presentations at community meetings, printed and online feedback forms) to reach the trials catchment area (Denver County's population: 643,000 and the Denver larger metro area where commuters reside: 2.9 million). Particular attention was given to special-interests groups (eg, Jehovah Witnesses, homeless) and to Spanish-speaking communities (brochures and presentations in Spanish). Opt-out materials were available during on-site presentations or via the COMBAT study website. RESULTS: A total of 227 community organizations were contacted. Brochures were distributed to 11 medical clinics and 3 homeless shelters. The multimedia campaign had the potential to reach an estimated audience of 1.5 million individuals in large metro Denver area, the majority via one-way communication and 1900 in two-way communications. This resource intensive process cost more than $84,000. CONCLUSION: The CC/PD process is resource-intensive, costly, and complex. Although the multimedia CC/PD reached a large audience, the effectiveness of this process remains elusive. The templates can be helpful to similar ER-EIC studies. PMID- 25444224 TI - Central lymph node metastasis in papillary thyroid microcarcinoma can be stratified according to the number, the size of metastatic foci, and the presence of desmoplasia. AB - BACKGROUND: Lymph node (LN) metastasis is common in papillary thyroid microcarcinoma (PTMC). The aim of this study was to investigate the impact of LN metastasis and its risk stratification on PTMC recurrence. METHODS: We retrospectively reviewed the data of 336 patients with PTMC who underwent surgery from 2005 to 2006 at a single institution. LN metastasis was stratified according to the number of metastatic LNs, the ratio of metastatic to removed LNs, the size of metastatic foci in LNs, and the presence of extranodal extension and desmoplasia. RESULTS: Of the 336 patients, 93 (28%) had LN metastasis. During the follow-up of 5.3 years, 16 (4.8%) experienced locoregional recurrence. Among several clinicopathologic factors, LN metastasis was the most important risk factor for recurrence (P = .02). Lateral LN metastasis was correlated with recurrence-free survival (P < .01), whereas central LN metastasis was not (P = .20). When central LN metastasis was stratified, a high number of metastatic LNs (>=3), larger metastatic foci (>=0.2 cm), and the presence of desmoplasia were associated with recurrence-free survival (P < .05). CONCLUSION: The prognostic significance of central LN metastasis can differ according to the number of metastatic LNs, the size of metastatic foci, and the presence of desmoplasia. Patients with a high number of metastatic LNs, larger metastatic foci, and presence of desmoplasia in LNs should be treated aggressively and supervised carefully for PTMC recurrence. PMID- 25444226 TI - BRAF mutation in papillary thyroid cancer: A cost-utility analysis of preoperative testing. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) with BRAF mutation carries a poorer prognosis. Prophylactic central neck dissection (CND) reduces locoregional recurrences, and we hypothesize that initial total thyroidectomy (TT) with CND in patients with BRAF-mutated PTC is cost effective. METHODS: This cost-utility analysis is based on a hypothetical cohort of 40-year-old women with small PTC [2 cm, confined to the thyroid, node(-)]. We compared preoperative BRAF testing and TT+CND if BRAF-mutated or TT alone if BRAF-wild type, versus no testing with TT. This analysis took into account treatment costs and opportunity losses. Key variables were subjected to sensitivity analysis. RESULTS: Both approaches produced comparable outcomes, with costs of not testing being lower ( $801.51/patient). Preoperative BRAF testing carried an excess expense of $33.96 per quality-adjusted life-year per patient. Sensitivity analyses revealed that when BRAF positivity in the testing population decreases to 30%, or if the overall noncervical recurrence in the population increases above 11.9%, preoperative BRAF testing becomes the more cost-effective strategy. CONCLUSION: Outcomes with or without preoperative BRAF testing are comparable, with no testing being the slightly more cost-effective strategy. Although preoperative BRAF testing helps to identify patients with higher recurrence rates, implementing a more aggressive initial operation does not seem to offer a cost advantage. PMID- 25444227 TI - Risk of recurrent cervical artery dissection during pregnancy, childbirth and puerperium. AB - BACKGROUND AND PURPOSE: Hormonal and mechanical factors might increase the risk for cervical artery dissection (CAD) during pregnancy and the puerperium. There is uncertainty how to counsel women with a previous CAD regarding the risk of CAD recurrence during pregnancy and the puerperium. METHODS: In an observational study of four stroke centers, all women aged 16-45 years with primary CAD in the previous decade were asked to participate in a standardized assessment on long term follow-up with a special focus on pregnancies and recurrent CAD. RESULTS: Ninety-two women were identified and 53 of them were included in the analysis (60%). Eleven women declined to participate, 28 were untraceable. The 39 non participants did not differ from participants regarding key baseline characteristics. Average follow-up time was 72 months. Nine women (17%) had recurrent CAD after a median of 14 days (range 2 days to 117 months). Eleven women (20%) had a total of 13 completed pregnancies at a median of 44 months (range 12-84 months) after index CAD. Two of the pregnant women (18%) had suffered recurrent CAD >=18 months prior to the pregnancy. All 13 pregnancies and puerperia went without recurrent CADs or cerebrovascular events. This includes giving birth by vaginal delivery (n = 6) and caesarean section (n = 7). None of the five women with typical connective tissue disease became pregnant. CONCLUSIONS: Our observation suggests that the risk of recurrent CAD may not be greatly increased with pregnancies starting at least 12 months after CAD in women without typical connective tissue disease. PMID- 25444225 TI - Hyperparathyroidism-jaw tumor syndrome: Results of operative management. AB - BACKGROUND: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare, autosomal dominant disease secondary to germline-inactivating mutations of the tumor suppressor gene HRPT2/CDC73. The aim of the present study was to determine the optimal operative approach to parathyroid disease in patients with HPT-JT. METHODS: A retrospective analysis of clinical and genetic features, parathyroid operative outcomes, and disease outcomes in 7 unrelated HPT-JT families. RESULTS: Seven families had 5 distinct germline HRPT2/CDC73 mutations. Sixteen affected family members (median age, 30.7 years) were diagnosed with primary hyperparathyroidism (PHPT). Fifteen of the 16 patients underwent preoperative tumor localization studies and uncomplicated bilateral neck exploration at initial operation; all were in biochemical remission at most recent follow-up. Of these patients, 31% had multiglandular involvement; 37.5% of the patients developed parathyroid carcinoma (median overall survival, 8.9 years; median follow-up, 7.4 years). Long-term follow-up showed that 20% of patients had recurrent PHPT. CONCLUSION: Given the high risk of malignancy and multiglandular involvement in our cohort, we recommend bilateral neck exploration and en bloc resection of parathyroid tumors suspicious for cancer and life-long postoperative follow-up. PMID- 25444228 TI - Remote magnetic navigation for ablation of typical atrial flutter: Long-term results. AB - INTRODUCTION AND AIM: Remote magnetic navigation has proved to be effective in the ablation of most supraventricular and ventricular arrhythmias. Initial studies reported worse results with this system compared to conventional ablation for atrial flutter. The aim of this study was to assess the acute and long-term success of atrial flutter ablation with remote magnetic navigation and to retrospectively compare the results obtained with an 8-mm tip catheter versus an irrigated catheter. METHODS: We studied 38 consecutive patients, mean age 61 +/- 15 years, 28 male, who underwent ablation of typical atrial flutter with the Niobe II remote magnetic navigation system (Stereotaxis). Ablation was performed with an 8-mm tip catheter in 17 patients and with an irrigated-tip catheter in 21 patients. Acute success was defined as the presence of bidirectional isthmus block, and long-term success as absence of symptoms and atrial flutter during Holter monitoring. RESULTS: Bidirectional isthmus block was achieved in 37 patients (97%), and the success rate was similar in both groups. Total procedure time was not significantly different between the groups but fluoroscopy time was shorter in the irrigated tip group (13.4 +/- 3.7 min vs. 6 +/- 4.4 min; p<0.01). The number of applications and total radiofrequency time did not differ. There were no complications. During a follow-up of 32 +/- 19 months there were two relapses, one in each group. CONCLUSIONS: The Niobe II remote control system for ablation of typical atrial flutter is safe and effective in both the short and long term. The 8-mm and irrigated-tip catheters showed similar safety and efficacy. PMID- 25444229 TI - Cardiac imaging in pulmonary embolism: assessment of right ventricular dysfunction by tissue Doppler. PMID- 25444230 TI - A decade of cardiac transplantation in Coimbra: the value of experience. AB - INTRODUCTION AND OBJECTIVES: To analyze the experience gained in 10 years of the heart transplantation program of the University Hospital of Coimbra. METHODS: Between November 2003 and December 2013, 258 patients with a mean age of 53.0+/ 12.7 years (3-72 years) and predominantly male (78%) were transplanted. Over a third of patients had ischemic (37.2%) and 36.4% idiopathic cardiomyopathy. The mean age of donors was 34.4+/-1.3 years and 195 were male (76%), with gender difference between donor and recipient in 32% of cases and ABO disparity (non identical groups but compatible) in 18%. Harvest was distant in 59% of cases. In all cases total heart transplantation with bicaval anastomoses, modified at this center, was used. Mean ischemia time was 89.7+/-35.4 minutes. All patients received induction therapy. RESULTS: Early mortality was 4.7% (12 patients) from graft failure and stroke in five patients each, and hyperacute rejection in two. Thirteen patients (5%) required prolonged ventilation, 25 (11.8%) required inotropic support for more than 48 hours, and seven required pacemaker implantation. Mean hospital stay was 15.8+/-15.3 days (median 12 days). Ninety percent of patients were maintained on triple immunosuppressive therapy including cyclosporine, the remainder receiving tacrolimus. In 23 patients it was necessary to change the immunosuppression protocol due to renal and/or neoplastic complications and humoral rejection. All but two patients have been followed in the Surgical Center. Fifty patients (19.4%) subsequently died from infection (18), cancer (10), vascular (eight), neuropsychiatric (four), cardiac (two) or other causes (eight). Forty-six patients (17.8%) had episodes of cellular rejection (>2 R on the ISHLT classification), eight had humoral rejection (3.1%), and 22 have evidence of graft vascular disease (8.5%). Actuarial survival at 1, 5, and 8 years was 87+/-2%, 78+/-3% and 69+/-4%, respectively. CONCLUSION: This 10-year series yielded results equivalent or superior to those of centers with wider and longer experience, and have progressively improved following the introduction of changes prompted by experience. This program has made it possible to raise and maintain the rate of heart transplantation to values above the European average. PMID- 25444231 TI - What is the effect on cardiovascular events of reducing hyperuricemia with allopurinol? An evidence-based review. AB - INTRODUCTION: High levels of uric acid (UA) have been associated with cardiovascular (CV) disease, but its role as an independent risk factor is the subject of debate. Treating hyperuricemia may be useful in reducing CV risk. OBJECTIVE: To review the evidence on the effect of treatment with allopurinol in patients with hyperuricemia on reducing CV events. METHODS: We searched medical databases for randomized controlled trials (RCT), cohort studies (CS) and case control studies (CCS), meta-analyses, systematic reviews and guidelines, published between January 2002 and December 2013 in Portuguese and English. Level of evidence (LE) and strength of recommendation were graded according to the definitions used by the European Society of Cardiology. RESULTS: Out of 46 articles, one RCT, three CS and one CCS were included. In the RCT, treatment with allopurinol decreased CV events in patients with moderate chronic renal failure by 71% compared to controls (LE B). In one CS, patients treated with high doses had a greater reduction in CV events compared to low doses (LE B). The other two CS, in patients with heart failure (HF), found similar benefits in patients treated with high doses of allopurinol (LE B). In the CCS, in patients with HF and a history of gout, treatment with allopurinol reduced HF admission and all cause mortality (LE B). DISCUSSION AND CONCLUSIONS: Prolonged treatment with high doses of allopurinol may be associated with a reduction in morbidity and mortality in high CV risk populations (class of recommendation IIa). More studies evaluating the effect of therapy with allopurinol in reducing CV events in patients with and without risk are needed. PMID- 25444232 TI - Transcatheter mitral valve-in-valve implantation: role of preprocedural multidetector computed tomography. PMID- 25444233 TI - Blunted striatal responses to favorite-food cues in smokers. AB - BACKGROUND: Although tobacco-smoking is associated with relatively leaner body mass and smoking cessation with weight gain, the brain mechanisms underlying these relationships are not well understood. Smokers compared to non-smokers have shown diminished neural responses to non-tobacco rewarding stimuli (e.g., monetary rewards), but brain responses to favorite-food cues have not been investigated relative to smoking status. We hypothesized that smokers would exhibit diminished neural responses compared to non-smokers in response to favorite-food cues in motivation-reward and emotion-regulating regions of the brain. METHODS: Twenty-three smokers and 23 non-smokers matched based on body mass index (BMI), age, and gender listened to personalized favorite-food cue, stress, and neutral-relaxing audiotapes during fMRI. RESULTS: During favorite food cue exposure, smokers versus non-smokers exhibited diminished activations in the caudate, putamen, insula, and thalamus. Neural responses during stress and neutral-relaxing conditions were similar across groups. Subjective food-craving ratings were similar across groups. CONCLUSIONS: The relatively diminished neural responses to favorite-food cues in smokers may contribute to lower BMI. PMID- 25444234 TI - Nonadherence to antipsychotics: the role of positive attitudes towards positive symptoms. AB - Approximately 50-75% of all patients do not take their antipsychotic medication as prescribed. The current study examined reasons why patients continue versus discontinue antipsychotic medication. We were particularly interested to which extent positive attitudes towards psychotic symptoms foster medication nonadherence. An anonymous online questionnaire was set up to decrease response biases. After a strict selection process, 91 participants with schizophrenia spectrum disorders were retained for the final analyses. On average, 6.2 different reasons for nonadherence were reported. Side-effects (71.4%), sudden subjective symptom improvement (52.4%) and forgetfulness (33.3%) emerged as the most frequent reasons for drug discontinuation. Approximately one fourth of all participants (27.3%) reported at least one positive aspect of psychosis as a reason for nonadherence. In contrast, patients reported on average 3.5 different reasons for adherence (e.g., want to live a normal life (74.6%) and fear of psychotic symptoms (49.3%)). The belief that paranoia represents a survival strategy (subscale derived from the Beliefs about Paranoia Scale) was significantly associated with nonadherence. Patients' attitudes toward medication and the individual illness model need to be carefully considered when prescribing medication. In particular for patients who are likely to discontinue psychopharmacological treatment complementary or alternative psychological treatment should be sought because of a largely increased risk of relapse in the case of sudden drug discontinuation. PMID- 25444235 TI - Regulation of pigmentation by microRNAs: MITF-dependent microRNA-211 targets TGF beta receptor 2. AB - There is growing evidence that microRNAs are important regulators of gene expression in a variety of cell types. Using immortalized cell lines and primary neural crest cell explants, we show that microRNA-211, previously implicated in the regulation of melanoma proliferation and invasiveness, promotes pigmentation in melanoblasts and melanocytes. Expression of this microRNA is regulated by the key melanocyte transcription factor MITF and regulates pigmentation by targeting the TGF-beta receptor 2. Transfection with pre-miR-211 precursor molecules in melb-a and melan-a cells leads to a decrease in the expression of TGF-beta receptor 2 and reduces the TGF-beta signaling-mediated downregulation of two melanogenic enzymes, tyrosinase and tyrosinase-related protein 1. Conversely, downregulation of microRNA-211 using specific microRNA inhibitors has the opposite effects. It appears, therefore, that microRNA-211 serves as a negative regulator of TGF-beta signaling which is known to play a important roles in vivo in melanocyte stem cell maintenance and pigmentation. PMID- 25444236 TI - Widening horizons through alternative and augmentative communication systems for managing children with special health care needs in a pediatric dental setup. AB - PURPOSE: This study compared and evaluated the efficacy of conventional low-tech and improvised high-tech alternative and augmentative communication (AAC) software in behavior management in the dental environment and oral hygiene activities performance of children with special health care needs as well as improving their communication skills with the dentist and caretakers. METHODS: A total of 60 institutionalized children with special health care needs were divided into two groups of 30 each to be exposed to low-tech AAC and high-tech AAC systems (special smiles for special children material). Assessment of knowledge as well as behavior modification achieved before and after training was carried out on the basis of pretested proformas formatted through various peer reviewed articles. RESULTS AND CONCLUSION: Rapid and enhanced assimilation of knowledge was observed in group 2 exposed to high-tech AAC improvised software after intergroup comparison of total scores at baseline, first, second, third, sixth, and ninth month of training. Oral hygiene performance was compared using PHP (Patient Hygiene Performance) index and after training results revealed highly significant change in both groups. The subjects benefitted immensely from the programme as group 1 and group 2 children demonstrated good behavior after training compared to none at baseline. On the whole, this programme had a positive motivational impact. PMID- 25444237 TI - Gene-therapy for malaria prevention. AB - The limited number of tools for malaria prevention and the inability to eradicate the disease have required large investments in vaccine development, as vaccines have been the only foreseeable type of immunoprophylaxis against malaria. An alternative strategy named vectored immunoprophylaxis (VIP) now would allow genetically transduced host cells to assemble and secrete antibodies that neutralize the infectivity of the malaria parasite and prevent disease. PMID- 25444238 TI - Comparison of five protocols to extract DNA from paraffin-embedded tissues for the detection of human papillomavirus. AB - Formalin-fixed paraffin-embedded (FFPE) tissues are a valuable source of DNA with which to perform large retrospective studies on the epidemiology of HPV infection. Five different DNA extraction protocols were carried out to evaluate the DNA obtained from FFPE samples with polymerase chain reaction (PCR) using two primer sets to amplify a constitutive human gene, beta-globin, and two primer sets to detect the L1 and E6 HPV genes. From the five DNA extraction protocols evaluated, the best results were obtained with protocol A, corresponding to a crude extract from the sample. With the procedures described herein, we were able to amplify DNA extracted from archival paraffin blocks stored for six years. However, the amplification products were more efficiently obtained with primers that amplified shorter fragments. This result indicates that a major factor limiting the extraction process in these samples is DNA fragmentation, a factor that will naturally vary between the different specimens evaluated. Also, depending upon the extraction method, PCR amplification of a human gene does not necessarily guarantee the successful extraction of viral DNA. In conclusion, different DNA and HPV detection methods can significantly influence the results. Therefore, the DNA extraction methods and primers used for DNA amplification in fixed tissues need to be chosen carefully, depending on the specific requirements of the study being carried out. PMID- 25444239 TI - Guidelines for the specification, implementation and management of information technology systems in hospital transfusion laboratories. PMID- 25444241 TI - [Implantary surgery in 3 acts]. PMID- 25444240 TI - Pleiotropic effects of statins on the treatment of chronic periodontitis--a systematic review. AB - AIM: Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are an important group of hypolipidaemic drugs, widely used in the treatment of hypercholesterolaemia and cardiovascular disease. Some studies have shown that statins are able to modulate inflammation and alveolar bone loss. METHODS: In order to evaluate whether statins could influence periodontal treatment, improving the clinical and radiographic parameters in chronic periodontitis, a systematic review was conducted in the databases PUBMED and BIREME, searching for articles in English and Portuguese, published between the years 2004 and 2014, using the combined keywords statin, periodontal disease, periodontitis and alveolar bone. Studies regarding the treatment of chronic periodontitis in humans, blind or double-blind, retrospective cohort or randomized controlled trials that used statins topically or systemically were selected. RESULTS: Statins have important anti-inflammatory and immune effects, reducing levels of C reactive protein and matrix metalloproteinases and their intermediate products, such as tumour necrosis factor-alpha, and are also able to inhibit the adhesion and extravasation of leukocytes, which block the co-stimulation of T cells. Statins reduce bone resorption by inhibiting osteoclast formation and lead to increased apoptosis of these cells. The effect of statins on bone formation is related to the increased gene expression of bone morphogenetic protein in osteoblasts. CONCLUSION: Although we found biological mechanisms and clinical results that show lower alveolar bone loss and reduction of clinical signs of inflammation, further studies are needed to evaluate the clinical applicability of statins in the routine treatment of chronic periodontitis. PMID- 25444242 TI - [Recovery of maxillary tooth sensibility after Le Fort I osteotomy]. AB - INTRODUCTION: Upper alveolar nerves, when injured during Le Fort I osteotomies, alter maxillary tooth sensitivity. We had for aim to analyze post-operative maxillary tooth sensitivity recovery. MATERIAL AND METHODS: We conducted a prospective study in a series of patients having undergone Le Fort I osteotomy, with, or without mandibular osteotomy or intermaxillary disjunction (IMD). The direction and range of displacement of the maxillary bone were recorded. One tooth in each alveolar sector (incisivocanine, premolar, molar) was tested with an electric stimulator for each patient. The tests were performed before (D-1), and after surgery (D2 or day+2, D+15, M2 (or month +2), M3, and M6). RESULTS: Twenty-two patients were included. Among the tested teeth, 91.9 % were sensitive at D-1. At D2, only 12.7 % of teeth were sensitive. At D15, M2, M3, and M6, the sensitivity was respectively 33.3 %, 43.1 %, 50 %, and 61.8 %. The recovery of sensitivity was faster in young patients (under 35 years of age) and for upper middle and superior alveolar nerves. There was no difference regarding the direction of maxillary movement. DISCUSSION: Among the teeth that were sensitive before surgery, 87.3 % had not regained sensitivity at D2. The recovery of sensitivity increased at D15. A great displacement of the maxillary bone was an aggravating factor for loss of tooth sensitivity. PMID- 25444243 TI - [Current Nomina Anatomica for oral and maxillofacial surgery]. AB - Using the international organonymy is mandatory as well for daily clinical practice as for research and teaching our students. The international organonymy, Nomina Anatomica, is in Latin. A rather unsuccessful attempt at using a French version of the international organonymy in clinical practice has been made in France. Eponyms have been systematically contraindicated; the definitions of general anatomy are applied, as well as a systematic Gallicization of the Latin terminology. Despite a stringent observance of these rules, some terms remain inappropriate because they are misleading or inaccurate. Furthermore, using this language used worldwide remains uneasy in daily clinical practice. We had for objective to focus on the main anatomical terms used routinely in oral and maxillofacial surgery, and to justify their use in clinical practice, research, and education. PMID- 25444244 TI - [Contribution of the cervical vertebral maturation (CVM) method to dentofacial orthopedics: update]. AB - The successful orthopedic treatment of skeletal Class II malocclusions is closely related to the reasoned determination of the optimal time to initiate the treatment. This is why various methods have been proposed to assess skeletal maturation, such as a hand-wrist radiograph or the cervical vertebral maturation (CVM) method. The hand-wrist radiograph was up to now the most frequently used method to assess skeletal maturation. However, the clinical and biological limitations of this technique, as well as the need to perform an additional radiograph, were reasons to develop another method to explore the maturation stages of visible cervical vertebrae on a simple lateral cephalometric radiograph. The authors compare the 2 methods and prove the greater contribution of the CVM method compared to the hand-wrist radiograph. PMID- 25444245 TI - [Maxillary tumor revealing primary hyperparathyroidism]. AB - INTRODUCTION: Primary hyperparathyroidism can infrequently present as a giant cell tumor of the jaw. We report the case of a patient presenting with a giant cell tumor leading to the discovery of a parathyroid adenoma. OBSERVATION: A 70 year-old male patient consulted for a stiffly swollen right jaw. The radiological assessment revealed osteolytic lesions of the right maxilla. The calcium and phosphate levels were disrupted and the parathyroid hormone level was high. A neck ultrasonography revealed a parathyroid adenoma. The patient underwent excision of the maxillary mass and of the parathyroid adenoma; the outcome was marked by normalization of calcium and phosphate levels. DISCUSSION: Giant cell tumors unusually reveal primary hyperparathyroidism and their maxillary location is exceptionally rare. The diagnosis is made on parathyroid hormone level and imaging. The treatment is surgical. PMID- 25444246 TI - Altered cell wall properties are responsible for ammonium-reduced aluminium accumulation in rice roots. AB - The phytotoxicity of aluminium (Al) ions can be alleviated by ammonium (NH4(+)) in rice and this effect has been attributed to the decreased Al accumulation in the roots. Here, the effects of different nitrogen forms on cell wall properties were compared in two rice cultivars differing in Al tolerance. An in vitro Al binding assay revealed that neither NH4(+) nor NO3(-) altered the Al-binding capacity of cell walls, which were extracted from plants not previously exposed to N sources. However, cell walls extracted from NH4(+)-supplied roots displayed lower Al-binding capacity than those from NO3(-)-supplied roots when grown in non buffered solutions. Fourier-transform infrared microspectroscopy analysis revealed that, compared with NO3(-)-supplied roots, NH4(+)-supplied roots possessed fewer Al-binding groups (-OH and COO-) and lower contents of pectin and hemicellulose. However, when grown in pH-buffered solutions, these differences in the cell wall properties were not observed. Further analysis showed that the Al binding capacity and properties of cell walls were also altered by pHs alone. Taken together, our results indicate that the NH4(+)-reduced Al accumulation was attributed to the altered cell wall properties triggered by pH decrease due to NH4(+) uptake rather than direct competition for the cell wall binding sites between Al(3+) and NH4(+). PMID- 25444247 TI - Identification of Nucleoside Analogs as Inducers of Neuronal Differentiation in a Human Reporter Cell Line and Adult Stem Cells. AB - Nucleoside analogs (NSAs) were among the first chemotherapeutic agents and could also be useful for the manipulation of cell fate. To investigate the potential of NSAs for the induction of neuronal differentiation, we developed a novel phenotypic assay based on a human neuron-committed teratocarcinoma cell line (NT2) as a model for neuronal progenitors and constructed a NT2-based reporter cell line that expressed eGFP under the control of a neuron-specific promoter. We tested 38 structurally related NSAs and determined their activity to induce neuronal differentiation by immunocytochemistry of neuronal marker proteins, live cell imaging, fluorometric detection and immunoblot analysis. We identified twelve NSAs, which induced neuronal differentiation to different extents. NSAs with highest activity carried a halogen substituent at their pyrimidine nucleobase and an unmodified or 2'-O-methyl substituted 2-deoxy-beta-D ribofuranosyl residue as glyconic moiety. Cladribine, a purine nucleoside with similar structural features and in use to treat leukemia and multiple sclerosis, induced also differentiation of adult human neural crest-derived stem cells. Our results suggest that NSAs could be useful for the manipulation of neuronal cell fate in cell replacement therapy or treatment of neurodegenerative disorders. The data on the structure and function relationship will help to design compounds with increased activity and low toxicity. PMID- 25444248 TI - Derivatization oriented strategy for enhanced detection of valproic acid and its metabolites in human plasma and detection of valproic acid induced reactive oxygen species associated protein modifications by mass spectrometry. AB - Valproic acid (VA) is a branch chain fatty acid that is widely used to treat epilepsy and convulsion. Recent studies show that VA can also be used to treat migraine headaches, bipolar disorder, and other diseases such as Alzheimer disease. However, clinical treatment with VA may cause hepatotoxicity, bone marrow suppression, and hyperammonemic encephalopathy. Valproic acid is also a known human teratogen. Because of the potential cytotoxic effects of VA and its major metabolite, 2-propyl 4-pentenoic acid (4-ene VA), VA plasma concentrations must be closely monitored during clinical applications of VA in order to avoid severe side effects. This study developed a derivatization oriented strategy for increasing sensitivity in detecting VA in quantities as low as 20MUL and its metabolites in human plasma. After micro-scale liquid-liquid extraction (MLLE) and micro-scale derivatization, VA and 4-ene VA were quantitated by matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). The linear ranges were 10-1000MUM for VA and 5-500MUM for 4-ene VA. All relative standard deviation (RSD) and relative error (RE) values obtained in intra- and inter-day analyses of VA and 4-ene VA were below 8%. The structures of VA and its metabolite derivatives were further identified by nano ultra performance liquid chromatographic system (nanoUPLC) coupled with tandem mass spectrometry (MS/MS). Since protein modifications induced by VA were also identifiable by nanoUPLC-MS/MS, these modifications may be useful biological indicators of a toxic reaction during clinical applications of VA. PMID- 25444249 TI - Editorial on "Microfluidics-to-mass spectrometry: a review of coupling methods and applications" by Xue Wang, Lian Yi, Nikita Mukhitov, Adrian M. Schrell, Raghuram Dhumpa and Michael G. Roper. PMID- 25444250 TI - High throughput quantification of prohibited substances in plasma using thin film solid phase microextraction. AB - Simple, fast and efficient sample preparation approaches that allow high throughput isolation of various compounds from complex matrices are highly desired in bioanalysis. Particularly sought are methods that can, without sacrificing time, easily remove matrix interferences capable of inducing ionization suppression/enhancement, or causing detrimental effects in instrumental performance. In this work, an automated high-throughput sample preparation method using thin film solid phase microextraction (SPME) for the analysis of multiple prohibited substances in plasma is proposed. A biocompatible SPME extraction phase made of hydrophilic-lipophilic balance particles immobilized with polyacrylonitrile (PAN) demonstrated satisfactory extraction capabilities for 25 compounds of a wide range of polarities (logP from -2 to 6.8). Due to the well-known biocompatible characteristics of PAN-based SPME coatings, minimum sample handling was required. Experimental conditions for pre conditioning, extraction, wash and desorption were carefully optimized for the proposed method. By taking full advantage of the 96 thin film handling capability of the automated system, a preparation time of approximately 1.5min per sample can be achieved. Satisfactory results in terms of absolute matrix effects were found for the majority of the studied analytes, given that 24 out of 25 compounds exhibited values in the range of 100 and 120%. The method was validated in terms of linearity (R(2)>0.99), inter and intra-day accuracy (85-130%) and precision (<20%) and limits of quantitation (0.25-10ngmL(-1) for most compounds). PMID- 25444251 TI - Current state-of-the-art of nontargeted metabolomics based on liquid chromatography-mass spectrometry with special emphasis in clinical applications. AB - Metabolomics, as a part of systems biology, has been widely applied in different fields of life science by studying the endogenous metabolites. The development and applications of liquid chromatography (LC) coupled with high resolution mass spectrometry (MS) greatly improve the achievable data quality in non-targeted metabolic profiling. However, there are still some emerging challenges to be covered in LC-MS based metabolomics. Here, recent approaches about sample collection and preparation, instrumental analysis, and data handling of LC-MS based metabolomics are summarized, especially in the analysis of clinical samples. Emphasis is put on the improvement of analytical techniques including the combination of different LC columns, isotope coded derivatization methods, pseudo-targeted LC-MS method, new data analysis algorithms and structural identification of important metabolites. PMID- 25444252 TI - Molecular characterization of intergeneric hybrid between Aspergillus oryzae and Trichoderma harzianum by protoplast fusion. AB - AIMS: Protoplast fusion between Aspergillus oryzae and Trichoderma harzianum and application of fusant in degradation of shellfish waste. METHODS AND RESULTS: The filamentous chitinolytic fungal strains A. oryzae NCIM 1272 and T. harzianum NCIM 1185 were selected as parents for protoplast fusion. Viable protoplasts were released from fungal mycelium using enzyme cocktail containing 5 mg ml(-1) lysing enzymes from T. harzianum, 0.06 mg ml(-1) beta-glucuronidase from Helix pomatia and 1 mg ml(-1) purified Penicillium ochrochloron chitinase in 0.8 mol l(-1) sorbitol as an osmotic stabilizer. Intergeneric protoplast fusion was carried out using 60% polyethylene glycol as a fusogen. At optimum conditions, the regeneration frequency of the fused protoplasts on colloidal chitin medium and fusion frequency were calculated. Fusant showed higher rate of growth pattern, chitinase activity and protein content than parents. Fusant formation was confirmed by morphological markers, viz. colony morphology and spore size and denaturation gradient gel electrophoresis (DGGE). CONCLUSIONS: This study revealed protoplast fusion between A. oryzae and T. harzianum significantly enhanced chitinase activity which ultimately provides potential strain for degradation of shellfish waste. Consistency in the molecular characterization results using DGGE is the major outcome of this study which can be emerged as a fundamental step in fusant identification. SIGNIFICANCE AND IMPACT OF THE STUDY: Now it is need to provide attention over effective chitin degradation to manage shrimp processing issues. In this aspect, ability of fusant to degrade shellfish waste efficiently in short incubation time revealed discovery of potential strain in the reclamation of seafood processing crustacean bio-waste. PMID- 25444254 TI - Stopping and switching contraceptive methods: findings from Contessa, a prospective longitudinal study of women of reproductive age in England. AB - BACKGROUND: Discontinuation of, and change in, use of contraceptive methods contributes to high unplanned pregnancy rates. The aims of the Contessa study were to estimate the prevalence of and reasons for discontinuation and change and to assess the implications for preventive intervention. METHODS: Prospective cohort study of 1091 potentially fertile women aged 18-49, carried out during 2008, using a sample drawn from the Health Survey for England 2006, a random probability survey of health. We carried out a baseline survey followed by three further waves, exploring patterns of contraceptive use, characteristics of women experiencing each, and reasons for discontinuation and change. FINDINGS: A percentage of 3.7 of women were at risk of unplanned pregnancy and discontinued and/or changed a contraceptive method in a year, compared with 4.7% who were at risk of unplanned pregnancy and used no method. Compared with continuous users, stoppers and switchers were younger, better educated and more likely to be single. Women discontinued or changed their contraceptive method for reasons of ease of use, reliability, side effects or concerns over health effects. Barely a quarter of such decisions were influenced by medical staff. INTERPRETATION: Effective strategies to aid contraceptive adherence have proved elusive but, if found, could reduce unplanned pregnancy rates appreciably. Understanding of the factors contributing to successful contraceptive practice is essential to prevention of unintended pregnancy. PMID- 25444255 TI - Counseling for emergency contraception: time for a tiered approach. PMID- 25444253 TI - What happens when we routinely give doxycycline to medical abortion patients? AB - OBJECTIVES: Routine provision of antibiotics following medical abortion is common yet practitioners and professional societies differ on its utility. Our study compares the side effects experienced by women who were prescribed doxycycline following medical abortion to those who were not and assesses the adherence to one prescribed regimen. STUDY DESIGN: This was a prospective, observational, open label study from a convenience sample. Women seeking medical abortion were enrolled in nine study sites, including four clinics that routinely prescribe a seven-day course of doxycycline (Doxycycline arm) and five clinics that do not routinely prescribe any antibiotics (No Doxycycline arm). Seven to fourteen days following the administration of mifepristone, women were asked to self-administer a computer-based survey. The survey asked about side effects experienced (both arms) and adherence to the regimen (Doxycycline arm only). RESULTS: Five hundred eighty-one women were enrolled (278 in the Doxycycline arm and 303 in the No Doxycycline arm). There was a trend toward increased nausea in the Doxycycline arm (47.8% vs. 40.9%; p=.056) and a statistically significant difference in vomiting (25.2% vs. 18.5%; p=.032). Almost all women in the Doxycycline arm reported taking at least one pill, however only 28.3% reported "perfect adherence." The most common reasons reported for taking fewer pills than instructed were that participants were still taking them (beyond 7 days) or that they forgot to take them. CONCLUSION: Women who were prescribed doxycycline following medical abortion reported moderate adherence and experienced significantly more vomiting than their counterparts. IMPLICATIONS: In the absence of robust evidence that prescribing 7 days of doxycycline following medical abortion is effective at reducing serious infections, these data can assist the public health community with deciding whether routine provision is the most appropriate strategy. PMID- 25444256 TI - Use of emollients in atopic dermatitis. AB - Atopic dermatitis (AD) is a common inflammatory skin disorder that has strong financial and psychosocial impacts. Its pathogenesis is related to increased transepidermal water loss due to a defective skin epidermal barrier. Emollients serve as first-line therapy during both acute flares and remission. However, their use is poorly characterized, posing therapeutic challenges to clinicians and patients. In this article, we review available evidence to provide recommendations, aiming to standardize and optimize the use of emollients in AD. Literature search was performed using Pubmed and Google. All articles were retrieved using Pubmed. Recommendations were graded based on the British Medical Journal's Grading of Recommendations Assessment, Development and Evaluation system and the American Academy of Family Physicians' Strength of Recommendation Taxonomy. Emollients should be applied post-bathing. However, the need for immediate application is debatable. The optimal frequency for application is still undetermined, but multiple applications daily are encouraged. Ideally, a balance should be achieved between patient's compliance and clinical efficacy. Emollients hold the potential to act as steroid-sparing agents, but more well designed studies are pertinent for a definite conclusion. At present, it is recommended that 250-500 g of emollients be applied every week. Finally, primary prevention of AD by regular application of emollients in high-risk infants cannot yet be recommended. PMID- 25444257 TI - The first wheezing episode: respiratory virus etiology, atopic characteristics, and illness severity. AB - BACKGROUND: Susceptibility to early rhinovirus-induced wheezing has been recognized as an important risk factor for childhood asthma, but data on the first wheezing episode are limited. The aim of this selected population study was to investigate virus etiology, atopic characteristics, and illness severity, as well as their interrelation, among first-time wheezing children. METHODS: We studied 111 first-time wheezing children aged between 3 and 23 months (88/23 in /outpatients). The investigated factors included atopy, food, perennial and aeroallergen sensitization, eczema, atopic eczema, elevated blood eosinophil count, and parental allergic rhinitis, asthma, and smoking. Nasopharyngeal aspirates were analyzed for adenovirus, coronaviruses, enteroviruses, bocavirus-1 (also serologically confirmed), influenza viruses, metapneumovirus, parainfluenza viruses, rhinovirus, and respiratory syncytial virus using PCR methods. RESULTS: The mean age of the study patients was 12 months (standard deviation 6.0). Atopic characteristics could be found in 56%, atopic eczema in 16%, and sensitization in 23% of the cases. In all samples (100%), >=1 viruses were detected as follows: rhinovirus (76%), respiratory syncytial virus (29%), bocavirus (18%, acute infections), and other viruses <10% each. Virus coinfections occurred in 38% of the children. Rhinovirus infection was positively associated with age, blood eosinophil count, eczema, and duration of cough, as well as parental allergic rhinitis and smoking but negatively associated with virus coinfection (all p < 0.05). CONCLUSIONS: A respiratory virus infection can be detected in all first time wheezing children. Rhinovirus dominated the findings and was linked to atopic characteristics, prolonged cough, and parental smoking. PMID- 25444258 TI - Glucocorticoids in systemic sclerosis: patients' beliefs and treatment adherence. AB - OBJECTIVES: To investigate how chronic intake of glucocorticoids (GCs) is perceived by patients with systemic sclerosis (SSc) in terms of necessity and concerns, and whether such beliefs influence treatment adherence. METHOD: Ninety eight consecutive SSc patients who they had been taking oral GCs for > 3 months prior to the study were enrolled. All patients underwent a clinical evaluation and laboratory investigations, and were asked to complete four self-administered questionnaires: the Beliefs about Medicines Questionnaire (Specific-BMQ), the four-item Morisky Medication Adherence Scale (MMAS-4), the 36-item Short Form Health Survey (SF-36), and the Health Assessment Questionnaire Disability Index (HAQ-DI). Moreover, patients answered two additional questions investigating their knowledge about GC-related adverse events (AEs). RESULTS: Seventy-seven patients (83.6%) believed in the necessity of GCs for maintaining health but 72.8% also reported concerns about potential AEs to GCs. A high adherence rate was recorded in 64.1% of patients. Only about 20% of patients reported knowing that a daily GC dose and treatment duration influence the burden of GC-related AEs. Patients who believed that GC-related AEs were influenced by the dose scored lower concerns (p = 0.043) and were more frequently labelled as accepting (perceiving high necessity and low concerns) (p = 0.009). CONCLUSIONS: The majority of patients taking GCs perceived them as necessary, but high concerns about chronic GC use exist. Patients with a poorer knowledge of the factors associated with GC-related AEs and those with a poorer quality of life were the most worried about these compounds. Experimental studies assessing the efficacy of educational programmes aiming to increase the adherence to GC therapy should be planned in these patients. PMID- 25444259 TI - CIC((r)) prep tools led by the new 'Certification Study Guide': Updated 5(th) edition includes practical test preparation tools. PMID- 25444260 TI - A multifactorial action plan improves hand hygiene adherence and significantly reduces central line-associated bloodstream infections. AB - BACKGROUND: Although hand hygiene (HH) is key to reducing health care-associated infections, it is well documented that health care worker (HCW) adherence to appropriate HH protocols is relatively low. METHODS: This was a collaborative quality improvement project with multiple interventions conducted in a 570-bed academic hospital in Columbia, MO between April 2006 and September 2012. A multimodal action plan to improve HH adherence among all HCWs was developed, addressing 4 key areas: staff education, staff accountability, hand sanitizer product selection and accessibility, and organizational culture. HH adherence and central line-associated bloodstream infection (CLABSI) rates were monitored as outcome measures. RESULTS: The overall HH adherence rate increased from 58% in April 2006 to 98% in September 2012. The adherence rates increased among all hospital units and among all HCW categories; in September 2012, HH adherence was 96% for physicians, 99% for nursing staff, and 99% for food services staff. CLABSI rates decreased over the same period, from 4.08 per 1000 device-days to 0.42 per 1000 device-days. CONCLUSIONS: This multifactorial quality improvement project resulted in an institution-wide increase in HH adherence and a significant decrease in CLABSIs. PMID- 25444261 TI - Method for investigating nursing behaviors related to isolation care. AB - BACKGROUND: Although an emphasis has been placed on protecting patients by improving health care worker compliance with infection control techniques, challenges associated with patient isolation do exist. To address these issues, a more consistent mechanism to evaluate specific clinical behaviors safely is needed. METHODS: The research method described in this study used a high fidelity simulation using a live standardized patient recorded by small cameras. Immediately after the simulation experience, nurses were asked to view and comment on their performance. A demographic survey and a video recorded physical evaluation provided participant description. A questionnaire component 1 month after the simulation experience offered insight into the timing of behavior change in clinical practice. RESULTS: Errors in behaviors related to donning and doffing equipment for isolation care were noted among the nurses in the study despite knowing they were being video recorded. This simulation-based approach to clinical behavior analysis provided rich data on patient care delivery. CONCLUSION: Standard educational techniques have not led to ideal compliance, and this study demonstrated the potential for using video feedback to enhance learning and ultimately reduce behaviors, which routinely increase the likelihood of disease transmission. This educational research method could be applied to many complicated clinical skills. PMID- 25444262 TI - Attributable costs of central line-associated bloodstream infections in a pediatric hematology/oncology population. AB - BACKGROUND: Although several studies have estimated the attributable cost and length of stay (LOS) of central line-associated bloodstream infections (CLABSIs) in the pediatric intensive care unit setting, little is known about the attributable costs and LOS of CLABSIs in the vulnerable pediatric hematology/oncology population. METHODS: We studied a total of 1562 inpatient admissions for 291 pediatric hematology/oncology patients at a single tertiary care children's hospital in the mid-Atlantic region between January 2008 and May 2011. Costs were normalized to year 2011 dollars. Propensity score matching was used to estimate the effect of CLABSIs on total cost and LOS while controlling for other covariates. RESULTS: Sixty CLABSIs occurred during the 1562 admissions. Compared with the patients without a CLABSI, those who developed a CLABSI tended to be older (9.0 years vs 7.5 years; P = .026) and to have a tunneled catheter (46.7% vs 27.0%) and a peripherally inserted central catheter (20.0% vs 11.2%) as opposed to other types of catheters (P < .0001). Propensity score matching yielded matched groups without significant differences in patient characteristics. In the propensity score analysis, the attributable LOS of a CLABSI was 21.2 days (P < .0001), and the attributable cost of a CLABSI was $69,332 (P < .0001). CONCLUSIONS: Among pediatric hematology/oncology patients, CLABSI was associated with an additional LOS of 21 days and increased costs of nearly $70,000. These findings may inform decisions regarding the value of investing in efforts to prevent CLABSIs in this vulnerable population. PMID- 25444263 TI - Colonization of stickers used for the identification of intravenous lines: results from an in vitro study. AB - BACKGROUND: Clear differentiation of arterial and intravenous (IV) lines is a safety strategy recommended by the World Health Organization, and signaling stickers attached to IV lines are implemented in many institutions. However, the risk of colonization of the stickers' surface has not been evaluated. Our objective was to assess the colonization rate of stickers used for IV lines identification in an in vitro model using 3 different contamination degrees. METHODS: A set of 30 stickers used for IV lines identification were exposed to low, medium, and high contamination degrees for up to 15 days. Twice a day, a single manipulator vigorously touched the surface of the stickers simulating the daily handling. Surface cultures of all stickers were performed daily. The microorganisms recovered were counted and identified by phenotypic characteristics. RESULTS: Colonization occurred after 5 days in low and medium manipulation models and after 3 days in the high manipulation model. Nonadhesive sticker sides were associated with greater significant numbers of colony forming units when manipulation was performed without gloves. CONCLUSION: Stickers used for the identification of IV lines may become potential reservoirs of catheter colonization. Clinical studies to validate these data and design policies of stickers' changes are required. PMID- 25444264 TI - Wheelchair cleaning and disinfection in Canadian health care facilities: "That's wheelie gross!". AB - BACKGROUND: Wheelchairs are complex equipment that come in close contact with individuals at increased risk of transmitting and acquiring antibiotic-resistant organisms and health care-associated infection. The purpose of this study was to determine the status of wheelchair cleaning and disinfection in Canadian health care facilities. METHODS: Acute care hospitals (ACHs), chronic care hospitals (CCHs), and long-term care facilities (LTCFs) were contacted and the individual responsible for oversight of wheelchair cleaning and disinfection was identified. A structured interview was conducted that focused on current practices and concerns, barriers to effective wheelchair cleaning and disinfection, and potential solutions. RESULTS: Interviews were completed at 48 of the 54 facilities contacted (89%), including 18 ACHs, 16 CCHs, and 14 LTCFs. Most (n = 24) facilities had 50-200 in-house wheelchairs. Respondents were very concerned about wheelchair cleaning as an infection control issue. Specific concerns included the lack of reliable systems for tracking and identifying dirty and clean wheelchairs (71%, 34/48), failure to clean and disinfect wheelchairs between patients (52%, 25/48), difficulty cleaning cushions (42%, 20/48), lack of guidelines (35%, 27/48), continued use of visibly soiled wheelchairs (29%, 14/48) and lack of resources (25%, 12/48). CONCLUSION: Our results suggest that wheelchair cleaning and disinfection is not optimally performed at many Canadian hospitals and LTCFs. Specific guidance on wheelchair cleaning and disinfection is necessary. PMID- 25444265 TI - Long-term efficacy of a self-disinfecting coating in an intensive care unit. AB - BACKGROUND: Cleaning and disinfecting fomites can effectively remove/kill pathogens on surfaces, but studies have shown that more than one-half the time, surfaces are not adequately cleaned or are recontaminated within minutes. This study evaluated a product designed to create a long-lasting surface coating that provides continuous disinfecting action. METHODS: This study was performed in an intensive care unit (ICU) in a major hospital. Various sites within the ICU were cultured before treatment and then at 1, 2, 4, 8, and 15 weeks after application of an antimicrobial coating. Samples were cultured for total bacteria, as well as Clostridium difficile, methicillin-resistant Staphylococcus aureus, vancomycin resistant enterococcus, and carbapenemase-resistant Enterobacteriaceae. RESULTS: The average bacterial count on all treated surfaces was reduced by >99% (2 logs) for at least 8 weeks after treatment. Overall, average levels of bacteria never returned to those observed before treatment even after 15 weeks. Antibiotic resistant bacteria were found on 25% of the sites tested before treatment, but were isolated at only 1 site during the 15 weeks after treatment. CONCLUSIONS: The product assessed in this study was found to have persisted over 15 weeks in reducing the total number of bacteria and antibiotic resistant bacteria on surfaces within an ICU. PMID- 25444266 TI - Correlation between the growth of bacterial biofilm in flexible endoscopes and endoscope reprocessing methods. AB - BACKGROUND: The purpose of this article was to investigate bacterial biofilm formed on endoscopes and to explore the possible correlation between endoscope reprocessing procedures and bacterial biofilm growth on endoscope channels. METHODS: Sixty-six endoscope suction and biopsy channels and 13 water and air channels were collected from 66 hospitals throughout China. Scanning electron microscopy was used to observe biofilm growth on the internal surface of these channels. Questionnaires were mailed to 66 endoscopy centers to investigate reprocessing procedures for endoscopes. RESULTS: Obvious biofilm growth was detected on 36 suction and biopsy channels (36/66, 54.6%) and 10 water and air channels (10/13, 76.9%). The percentage of manual cleaning in group B (n = 36, without detection of biofilms) was 92.3% (33/36), whereas it was 50.0% (15/30) in group A (n = 30, with detection of biofilms). Follow-up of group A (n = 30) showed that no biofilm was detected, whereas biofilm was detected in group B. The difference was statistically significant (P = .001). The proportion of detergent reuse in group B was 92.3% (33/36), and it was 61.5% in group A (18/30) (P = .005). The proportion of alcohol-air drying in group B was 38.9% (14/36), and it was 76.7% (23/30) in group A (P = .002). CONCLUSION: The formation of endoscopic biofilm during clinical practice may be related to reuse of detergent, manual cleaning, and incomplete drying. PMID- 25444267 TI - Attitudes regarding the safety of health care provider attire. AB - The majority of medical providers, nurses, and patients agree that appearance is important for patient care. However, at our institution, concerns regarding providers' white coats as fomites are expressed primarily by providers and nurses, not by patients. We provide a framework for approaching this important issue through a structured quality-improvement process. PMID- 25444268 TI - Decreasing contamination of the anesthesia environment. AB - Until recently, anesthetists have focused on antibiotic administration and normothermia but have paid less attention to contamination in the anesthesia environment and its impact on surgical site infections. We implemented a simple intervention and tested its effect on anesthetic environment contamination between procedure start and finish. Of the baseline cases, 46% reached a critical predefined threshold of contamination compared with 12% of the intervention cases. A small behavioral change dramatically lowered contamination in the anesthesia environment. PMID- 25444269 TI - Regional differences in vancomycin-resistant Enterococcus colonization rates in critically ill veterans. AB - Screening for vancomycin-resistant Enterococcus (VRE) has not been universally implemented within the Department of Veterans Affairs (VA). A prospective study was conducted to identify the admission prevalence rate of VRE in patients admitted to the intensive care unit in 2 VA facilities. Significant regional differences were found between the 2 facilities. Further studies are needed to account for regional differences in VRE admission prevalence, to optimize infection control interventions. PMID- 25444270 TI - Routine monitoring of adenovirus and norovirus within the health care environment. AB - This study investigated the presence of adenovirus and norovirus on ward surfaces using real-time polymerase chain reaction (PCR) to assist in the development of evidence-based infection control policy. Screening was carried out weekly for 6 months in the common areas of 2 pediatric wards. Additionally, a one-off screening was undertaken for adenovirus and norovirus on a day unit and for adenovirus only in patient cubicles while occupied. Over the 6-month screening of common areas, 2.4% of samples were positive for adenovirus or norovirus. In rooms occupied with adenovirus-infected children, all cubicle screening sites and almost all swabs were contaminated with adenovirus. In the day unit, 13% of samples were positive. Cleaning and environmental interaction strategies must therefore be designed to control nosocomial transmission of viruses outside of outbreak scenarios. PMID- 25444271 TI - Infection prevention and control practices in pediatric long-term care facilities. AB - Pediatric long-term care facilities (pLTCFs) provide for children with chronic, complex medical needs and therefore face unique challenges for infection prevention and control (IP&C). At a conference in 2012, pLTCF providers reported IP&C issues of greatest concern in a survey. Major concerns included the lack of IP&C best practice guidelines, multidrug-resistant bacteria, and viral respiratory infections. Best practice guidelines for IP&C specific to pLTCF populations should be developed and evaluated. PMID- 25444272 TI - Infant pertussis prevention information on Web sites of Michigan birthing hospitals. AB - Vaccinating pregnant women and household contacts of infants is recommended for pertussis prevention. In structured abstraction of Web sites of Michigan birthing hospitals, we found only 36% contained any pertussis prevention information, and it usually required a specific search for pertussis. Hospitals should emphasize pertussis prevention as part of general information for expectant parents. PMID- 25444273 TI - Candida krusei fungemia in 7 neonates: clonality tracked to an infusate. PMID- 25444274 TI - Editorial commentary: risk assessment and prediction for health care-associated Legionnaires' disease: percent distal site positivity as a cut-point. PMID- 25444275 TI - Response to commentary on "Assessing risk of health care-acquired Legionnaires' disease from environmental sampling: the limits of using a strict percent positivity approach". PMID- 25444277 TI - Safety and efficacy of 10% imidacloprid+2.5% moxidectin for the treatment of Dirofilaria immitis circulating microfilariae in experimentally infected dogs. AB - A controlled laboratory study was conducted to establish the safety and efficacy of 10% imidacloprid+2.5% moxidectin topical solution (Advantage Multi(r) for Dogs, Bayer HealthCare, Shawnee, KS) for the treatment of circulating Dirofilaria immitis microfilariae in dogs. Twenty beagles were experimentally infected with D. immitis via surgical implantation of 10 pairs of adult worms (Pepper strain, TRS Labs) from donor dogs on Day -82. Between Days -7 and -1, physical examinations were performed, chest radiographs were taken, and blood and urine samples were collected for microfilariae counts, serum chemistry, complete blood counts, and urinalysis. Each dog was required to have a mean pretreatment count of at least 300 mf/ml of blood. On Day -1, all 20 dogs were randomized by mean pretreatment microfilarial counts to two study groups (10 animals/group). Animals in Group 1 were treated on Days 0 and 28 with 10% imidacloprid+2.5% moxidectin topical solution at the minimum label dose of 0.1 ml/kg. Group 2 animals served as negative controls and were treated on Days 0 and 28 with mineral oil at an equivalent volume as for the study solution. All dogs were observed hourly for 8h after treatment, again at 12h, and then once daily on all other study days. Blood samples for microfilarial counts were collected daily for 3 days after treatment and then weekly for 6 weeks. The percentage reduction in microfilariae was determined by comparing the geometric mean number of circulating microfilariae remaining in Group 1 dogs with the mean counts remaining in control dogs. Group 1 mean microfilarial counts were reduced 93.1% three days following the first treatment and by >99% on Days 14 through 42. Group 1 had significantly fewer (p<0.05) microfilariae compared with Group 2 counts on Days 28 and 42. In addition, log-transformed geometric mean microfilarial counts were significantly different between the two groups (p<0.05) using separate repeated measures analysis of covariance for Days 2, 3, 7, 14, 21, 28, 35, and 42. No adverse events related to treatment were reported during the study. The results of this study demonstrate that 10% imidacloprid+2.5% moxidectin topical solution is efficacious for treatment of circulating D. immitis microfilariae in heartworm positive dogs with no treatment-related adverse events observed. PMID- 25444276 TI - Balancing the innate immune system in tumor development. AB - Cells of the innate immune system have a dual role in cancer development in both tumor initiation and progression. Innate immune cells can, on the one hand, aid malignant transformation and tumor outgrowth and, on the other hand, prevent tumor progression. The innate immune system has the ability to tune the inflammatory response and is a key player in cancer-related inflammation, which can precede the development of malignancy or be induced by oncogenic changes promoting a protumor inflammatory milieu. In this review, we discuss the emerging cellular and molecular mechanisms of the innate immune system and inflammation in tumor initiation and progression, and point to the outstanding questions that remain. PMID- 25444278 TI - Analysis of the increasing prevalence of necrotising fasciitis referrals to a regional plastic surgery unit: a retrospective case series. AB - Necrotising Fasciitis is a destructive infection of the skin and subcutaneous tissues associated with significant mortality and morbidity. Survival from the condition often necessitates patient referral for appropriate reconstructive surgery and supportive medical management. The aim of our study was to identify emerging patterns, characteristics and outcomes of necrotising fasciitis in Northern Ireland. A retrospective analysis of all patients referred to the Regional Plastic Surgery Service in Belfast between 2007 and 2012 was performed. Forty-six patients were identified with clinical, intraoperative and histopathological confirmation of necrotising fasciitis. Mean patient age was 59.4 years (range 32-88) with a 25:21 male to female ratio. 13 patients died from the disease. Smoking, obesity, diabetes and immunocompromise were the most prevalent co-morbidities identified. 37 patients had no identifiable mechanism of infection initiation in the history. Painful cellulitis (44/46), skin necrosis (26/46), skin blistering (8/46) and subcutaneous emphysema (3/46) were the most common presenting features. The median LRINEC score at presentation was 7 (range 2-12). The mean serum lactate at presentation was 4.0 mmol/L (range 1.6-13.5). LRINEC scores and serum lactate at presentation exhibited diagnostic sensitivities of 65% and 90% respectively. The lower extremity was the most commonly affected anatomical site (16/46). Group A Streptococcus was the most frequently isolated causative bacterium from debrided tissue cultures (16/46). The prevalence of necrotising fasciitis in the population studied is increasing, particularly in relation to patient cases caused by Group A Streptococcal infection. Increasing bacterial virulence and levels of patient immunocompromise may explain this increasing trend. The LRINEC scoring system lacked diagnostic sensitivity. Elevated serum lactate was supported as both a diagnostic and prognostic indicator. The findings of our study are somewhat limited in their application to other regions and highlight the need for a national analysis of necrotising fasciitis in the UK. PMID- 25444280 TI - Use of irreversible hydrocolloid impression material to correct a defect in complete denture definitive impressions. PMID- 25444279 TI - Effects of repeated firing on the marginal accuracy of Co-Cr copings fabricated by selective laser melting. AB - STATEMENT OF PROBLEM: Selective laser melting (SLM) is a technique used to fabricate Co-Cr dental restorations; however, because marginal accuracy is important for the long-term success of restorations, the marginal accuracy of SLM after repeated firings must be considered. PURPOSE: The purpose of this study was to evaluate the marginal accuracy of dental Co-Cr alloy copings fabricated by SLM and to investigate the effects of repeated firing on the marginal fit of these copings. MATERIAL AND METHODS: SLM-fabricated and cast Co-Cr alloy copings (n=15) were prepared for a zirconia die. The marginal gap widths of each group were evaluated with a silicone replica technique after the first, third, fifth, and seventh firing cycle. The thickness of the reference point was measured with a stereomicroscope with *100 magnification. Analysis of variance was used to evaluate the effect of repeated firing on the marginal accuracy of the 2 alloys. The Student t test was used to compare the marginal gap widths of the SLM fabricated and cast Co-Cr alloy copings after repeated firing (alpha=.05). RESULTS: The marginal gap width values between the 2 groups at all firing periods were statistically significant (P<.05). The mean marginal gap width values for SLM-fabricated copings were 36 MUm, 37 MUm, 38 MUm, and 38 MUm after the first, third, fifth, and seventh firing, while the mean marginal gap width values for cast copings were 67 MUm, 71 MUm, 72 MUm, and 73 MUm at the same number of firings. The marginal gap width values within the 2 groups were not statistically different from each other with additional firing (P>.05). CONCLUSIONS: The SLM copings demonstrated superior marginal accuracy at all firings. Repeated firing had no significant influence on the marginal accuracy of both copings, and the marginal fit of both copings after repeated firing was within a clinically acceptable range. PMID- 25444281 TI - A surface roughening technique for maxillofacial prostheses. AB - Giving a natural surface texture to the maxillofacial prostheses is one of the major goals for the maxillofacial prosthodontists. This article describes a technique for application of an antiskid epoxy resin to the surface of the definitive mold before pouring the maxillofacial silicone elastomer. This technique produces evenly distributed and same-size pores that are more similar to the natural appearance of human skin. PMID- 25444282 TI - The shear bond strength of self-adhesive resin cements to dentin and enamel: an in vitro study. AB - STATEMENT OF PROBLEM: Clinicians continue to search for ways to simplify bonding procedures without compromising clinical efficacy. PURPOSE: The purpose of this study was to evaluate the shear strength of self-adhesive cements RelyX U100 and RelyX U200, and conventional resin cement RelyX ARC to enamel and dentin after different surface treatments. MATERIAL AND METHODS: The crowns of 120 bovine incisor teeth were separated from the roots and embedded in epoxy resin in polyvinyl chloride tubes. In each tooth, the area to be cemented was delimited with central holed adhesive tape. The teeth were distributed into 12 groups (n=10) according to the substrate; etched or not with 37% phosphoric acid; and cement type of enamel-U100, enamel-phosphoric acid-U100, enamel-U200, enamel phosphoric acid-U200, enamel-ARC, enamel-phosphoric acid-ARC, dentin-U100, dentin phosphoric acid-U100, dentin-U200, dentin-phosphoric acid-U200, dentin-ARC, and dentin-phosphoric acid-ARC. After 7 days of storage in artificial saliva, shear strength tests were performed by using a universal testing machine (0.5 mm/min). The data were analyzed with 3-way ANOVA and the Tukey test (alpha=.05). Fracture analysis was performed with a light microscope. Two specimens from each group were analyzed with a scanning electron microscope. RESULTS: In enamel, ARC (9.96 MPa) had higher shear strength (P=.038) than U100 (5.14 MPa); however, after surface etching, U100 (17.81 MPa) and U200 (17.52 MPa) had higher shear strength (P<.001). With dentin, no significant differences were observed (P=.999), except for dentin-ARC (0.34 MPa) (P=.001). Most fractures were of the adhesive type. CONCLUSIONS: U200 self-adhesive cement had similar bond strength to the ARC in enamel, but the combination with phosphoric acid had the best bond strength. For dentin, self-adhesive resin cements are equally effective alternatives to conventional resin cement. PMID- 25444283 TI - Catastrophic failure of a monolithic zirconia prosthesis. AB - Recently, monolithic zirconia restorations have received attention as an alternative to zirconia veneered with feldspathic porcelain to eliminate chipping failures of veneer ceramics. In this clinical report, a patient with mandibular edentulism received 4 dental implants in the interforaminal area, and a screw retained monolithic zirconia prosthesis was fabricated. The patient also received a maxillary complete removable dental prosthesis over 4 anterior roots. At the 18 month follow-up, all of the zirconia cylinders were seen to be fractured, and the contacting abutment surfaces had lost structural integrity. The damaged abutments were replaced with new abutments, and a new prosthesis was delivered with a computer-assisted design and computer-assisted manufacturing fabricated titanium framework with denture teeth and denture base resins. At the 6-month recall, the patient did not have any problems. Dental zirconia has excellent physical properties; however, care should be taken to prevent excessive stresses on the zirconia cylinders when a screw-retained zirconia restoration is planned as a definitive prosthesis. PMID- 25444284 TI - Prosthesis-guided implant restoration of an auricular defect using computed tomography and 3-dimensional photographic imaging technologies: a clinical report. AB - The concept of prosthesis-guided implantation has been widely accepted for intraoral implant placement, although clinicians do not fully appreciate its use for facial defect restoration. In this clinical report, multiple digital technologies were used to restore a facial defect with prosthesis-guided implantation. A simulation surgery was performed to remove the residual auricular tissue and to ensure the correct position of the mirrored contralateral ear model. The combined application of computed tomography and 3-dimensional photography preserved the position of the mirrored model and facilitated the definitive implant-retained auricular prosthesis. PMID- 25444285 TI - Studying the relationships between the outlines of the face, maxillary central incisor, and maxillary arch in Jordanian adults by using Fourier analysis. AB - STATEMENT OF THE PROBLEM: The outline shapes of the dental arch, face, and tooth are esthetic factors used to determine the proper form of artificial teeth when selected for artificial prostheses. PURPOSE: The purpose of this study was to investigate the quantitative relationships between the outlines of the face, the maxillary central incisor, and the maxillary arch by using Fourier analysis. MATERIAL AND METHODS: Frontal facial photographs and irreversible hydrocolloid impressions of the maxilla were obtained from 200 young, dentate individuals (100 men, 100 women) ages 22 to 28 years. On the resultant casts, standardized photographs were made for the dental arch and the maxillary central incisor. The outlines of the face, dental arch, and tooth were digitally traced and the digitized curved outlines were converted into X-Y coordinates with special software, which, in turn, were imported into Fourier Shape Descriptor software for harmonic analysis. The quantitative outputs of Fourier analyses were analyzed and tested with statistical software to investigate the differences across the shapes of the 3 outlines under study. RESULTS: Facial and tooth outlines were similar for each sex, although the similarity was stronger among the men. By contrast, no relationship was found between tooth and maxillary arch outlines or between face and maxillary arch outlines. CONCLUSIONS: Face and tooth forms were quantitatively related. Therefore, face form may reliably guide the selection of artificial anterior tooth form in complete denture prostheses or any complex anterior restorations. PMID- 25444286 TI - Conservative management of medication-related osteonecrosis of the maxilla with an obturator prosthesis. AB - Advanced maxillary medication-related osteonecrosis of the jaw can cause extensive hard and soft tissue destruction that results in long-term oroantral fistulae. The surgical treatment of medication-related osteonecrosis of the jaw may relieve acute symptoms and eliminate the signs of inflammation, but the primary and sustained plastic closure of these defects can challenge both the clinician and the patients. Although the use of obturator prostheses for maxillary defects after ablative oncologic surgery is well documented, studies about this treatment for similar medication-related osteonecrosis of the jaw related defects are missing. This presentation of clinical situations describes the use of obturators as a conservative alternative to repetitive surgery for the rehabilitation of selected maxillary defects with oroantral communications. PMID- 25444287 TI - Immediate loading: from biology to biomechanics. Report of the Committee on Research in fixed Prosthodontics of the American Academy of fixed Prosthodontics. AB - One of the key issues of modern implant rehabilitation is the overall shortening of treatment time. High survival rates for immediately loaded implants have been reported in many but not all treatment modalities. In recent years, considerable evidence for the successful immediate loading outcome has been documented in both animal and human studies. The mechanical force generated by immediate loading may explain the favorable biologic response of bone and surrounding tissue when the design is biomechanically sound. However, in certain treatment modalities, including but not limited to immediately placed maxillary anterior single implants, immediately placed single molar implants, unsplinted implants in overdentures, and implants in maxillary anterior partial fixed dental prostheses, loading dental implants indiscriminately and immediately is not safe because of potentially unfavorable stress distribution and a negative cellular response under such high stress during early healing. PMID- 25444288 TI - Treatment strategies for infraoccluded dental implants. AB - Single-tooth implants in the maxillary anterior region have the highest risk of esthetic complications from infrapositioning due to continuing maxillary growth and the eruption of adjacent teeth. Although the placement of anterior single tooth implants should normally be postponed, particularly girls and young women with a hyperdivergent growth pattern, if an infraposition of an implant is present, then thorough examination and strategic planning are required. According to the severity, the strategic treatment options are as follows: simple retention; adjustment or replacement of the implant restoration, possibly including adjacent teeth; surgical implant repositioning by segmental osteotomy combined with osseodistraction; or submergence or removal of the implant. With the patient presented, an interdisciplinary approach that combined orthodontic alignment, surgical segmental osteotomy, distraction osteogenesis, and restorative features offered the opportunity to realign the adjacent teeth into the arch and to harmonize the gingival contour by means of continuous soft tissue enlargement and adaptation. PMID- 25444289 TI - Quantification of the amount of blue light passing through monolithic zirconia with respect to thickness and polymerization conditions. AB - STATEMENT OF PROBLEM: Dual-polymerized luting composite resin cements would benefit from enhanced irradiance transmitted through a ceramic restoration. A quantification of the amount of transmitted light through translucent zirconia is lacking. PURPOSE: The purpose of this study was to evaluate the amount of light (360 to 540 nm) passing through translucent and conventional zirconia and a glass ceramic with respect to material thickness and different polymerizing modes. MATERIAL AND METHODS: Six translucent and a conventional zirconia (negative control) and a glass ceramic (positive control) were considered. Ten specimens of each material and thickness (.5, 1, 1.5, 2, 2.5, 3 mm) were fabricated (n=480). Zirconia materials were sintered according to manufacturers' instructions. The irradiance passing the different ceramics and thicknesses was measured with a violet-blue LED polymerizing unit in 3 polymerizing modes (plasma, high, and standard power mode) with a USB4000 Spectrometer. The polymerizing unit was placed directly on the specimen's surface. Data were analyzed with one and multivariate analysis and the Pearson correlation analysis (alpha=.05). RESULTS: In all materials, the translucency and its rate decreased exponentially according to the specimen thickness. The highest influence on the measured irradiance passing through translucent zirconia was exerted by ceramic thickness (P<.05, partial eta squared [etaP2]=.998), closely followed by polymerizing mode (etaP2=.973), while the effect of the material (P=.03, etaP2=.06) and mean grain size (P=.029, etaP2=.027) was significant but low. CONCLUSIONS: Zirconia was less translucent than the glass ceramic, but the translucency decreased more slowly with material thickness, thus approaching the translucency of glass ceramics at a specimen thicknesses of 2.5 to 3 mm. PMID- 25444290 TI - Incorporation of a vacuum-formed polyvinyl chloride sheet into an orbital prosthesis pattern. AB - Pattern formation is the most difficult and demanding step in the fabrication of a facial prosthesis. Traditionally, the pattern fabrication of an orbital prosthesis begins with the adaptation of softened base plate wax on the cast, over which the entire pattern is fabricated. However, owing to the inherent properties of wax, such as distortion and stress relaxation, incorporating discrepancies in the pattern adaptation is likely. This article describes a vacuum-formed polyvinyl chloride sheet to fabricate a durable, distortion-free base for pattern fabrication, thereby overcoming the drawbacks associated with a wax base. PMID- 25444292 TI - What is the contribution of health economic evaluations to decision-making in health care? Experiences from 7 selected countries. PMID- 25444293 TI - Revolution then evolution: the advance of health economic evaluation in Australia. AB - All governments face immense challenges in providing affordable healthcare for their citizens, and the diffusion of novel health technologies is a key driver of growth in expenditure for many. Although important methodological and process variations exist around the world, health economic evaluation is increasingly seen as an important tool to support decision-making around the introduction of new health technologies, interventions and programmes in countries of varying stages of economic development. In Australia, the assessment of the comparative cost-effectiveness of new medicines proposed for subsidy under the country's national drug subsidy programme, the Pharmaceutical Benefits Scheme, was introduced in the late 1980s and became mandatory in 1993, making Australia the first country to introduce such a requirement nationally. Since then the use of health economic evaluation has expanded and been applied to support decision making across a broader range of health technologies, as well as to programmes in public health. PMID- 25444294 TI - Health economic evaluation in England. AB - The 2010 National Health Service Constitution for England specified rights and responsibilities, including health economic evaluation for the National Institute for Health and Care Excellence (NICE) and the Joint Committee on Vaccinations and Immunisations. The National Screening Committee and the Health Protection Agency also provide advice to the Government based on health economic evaluation. Each agency largely follows the methods specified by NICE. To distinguish the methods from neoclassical economics they have been termed "extra-welfarist". Key differences include measurement and valuation of both benefits (QALYs) and costs (healthcare related). Policy on discounting has also changed over time and by agency. The debate over having NICE's methods align more closely with neoclassical economics has been prominent in the ongoing development of "value based pricing". The political unacceptability of some decisions has led to special funding for technologies not recommended by NICE. These include the 2002 Multiple Sclerosis Risk Sharing Scheme and the 2010 Cancer Drugs Fund as well as special arrangements for technologies linked to the end of life and for innovation. Since 2009 Patient Access Schemes have made price reductions possible which sometimes enables drugs to meet NICE's cost-effectiveness thresholds. As a result, the National Health Service in England has denied few technologies on grounds of cost-effectiveness. PMID- 25444295 TI - The impact of health economic evaluations in Sweden. AB - The responsibility for healthcare in Sweden is shared by the central government, county councils and municipalities. The counties and municipalities are free to make their own prioritizations within the framework of the state healthcare laws. To guide prioritization of healthcare resources in Sweden, there is consensus that cost-effectiveness constitutes one of the three principles. The objective of this paper is to describe how cost-effectiveness, and hence health economic evaluations (HEE), have a role in pricing decisions, reimbursement of pharmaceuticals as well as the overall prioritization and allocation of resources in the Swedish healthcare system. There are various organizations involved in the processes of implementing health technologies in the Swedish healthcare system, several of which consider or produce HEEs when assessing different technologies: the Dental and Pharmaceutical Benefits Agency (TLV), the county councils' group on new drug therapies (NLT), the National Board of Health and Welfare, the Swedish Council on Health Technology Assessment (SBU), regional HTA agencies and the Public Health Agency of Sweden. The only governmental agency that has official and mandatory guidelines for how to perform HEE is TLV (LFNAR 2003:2). Even though HEEs may seem to have a clear and explicit role in the decision making processes in the Swedish healthcare system, there are various obstacles and challenges in the use and dissemination of the results. PMID- 25444296 TI - Health economic evaluations in reimbursement decision making in the Netherlands: time to take it seriously? AB - Health technology assessment already informed Dutch policymaking in the early 1980s. Evidence of health economic evaluations is, however, only systematically used in drug reimbursement decision making. Outpatient drugs with an added therapeutic value and expensive specialist drugs require evidence from an economic evaluation. Due to many exemptions, however, the availability of evidence of health economic evaluations remains rather low. Although the Dutch reimbursement agency suggested a cost-effectiveness threshold range depending on the severity of the disease (i.e., ?10,000 - 80,000 per Quality Adjusted Life Year), it was never confirmed nor endorsed by the Ministry of Health. It is highly questionable whether health economic evaluations currently play a role in actual Dutch reimbursement decision making. Although the requirements exist in policy procedures, recent cases show that Dutch policymakers experience great difficulties in putting restrictions on reimbursement based on evidence from health economic evaluations. The near future will show whether the need will increase to base decisions on societal value for money, and whether Dutch policymakers show the courage to take health economic evaluations seriously. PMID- 25444297 TI - Decision making in Germany: is health economic evaluation as a supporting tool a sleeping beauty? AB - For many years, the legal situation within the statutory health insurance (SHI) system in Germany has allowed for health economic evaluations. There are various reasons why health economic evaluations have played virtually no role in decision making until now: to begin with, a method for the evaluation of the relation between benefits and costs which needed to be in accordance with the legal requirements had to be developed, the outcome of which was the efficiency frontier approach. Subsequent health care reforms have led to changing objectives and strategies. Currently, price negotiations of newly launched drugs are based on an early benefit assessment of dossiers submitted by pharmaceutical manufacturers. Other reasons might be the presently very comfortable financial situation of the statutory health insurance system as well as a historically grown societal fear and discomfort towards what is perceived to be a rationing of medicinal products. For the time being, it remains open how long the German health care system can afford to continue neglecting the benefits of health economic evaluations for drug and non-drug interventions, and when it will be time to wake this sleeping beauty. PMID- 25444298 TI - The use of economic evaluation for guiding the pharmaceutical reimbursement list in Thailand. AB - Medicines expenditure consumes a significant proportion of public health expenditure in Thailand, where Universal Health Coverage has been in place since 2002. The National List of Essential Medicines has been successfully used as a pharmaceutical benefits package for all public health plans. All patients are eligible for all medicines included in the list free of charge by law. Health economic evaluation has been employed as a tool for the development of this list, including price negotiation of medicines before inclusion, especially of high cost medicines or medicines with high budget implications. This paper illustrates the current process, mechanisms, and impact and informs of seven success factors that have contributed to the successful use of health economic evaluation in Thailand. These include strong political commitment, development of individual and institutional capacity, participation of all relevant stakeholders, establishment of standard methodological and process guidelines, consideration of several elements in the decision-making process, using evidence as a starting point rather than a deciding factor, and strong enforcement. The lessons learned from this study are likely to be applicable to other settings committed to evidence-based decision making. PMID- 25444299 TI - How health economic evaluation (HEE) contributes to decision-making in public health care: the case of Brazil. AB - The universal access to a health care system for the Brazilian population was established in 1990. Brazil is a country with no tradition in the production and use of health economic evaluation (HEE) to guide decision making in the public health system. It is only within the last two decades that HEEs using a microeconomic approach have appeared in the academic field. On a national level, HEE and Health Technology Assessment (HTA), in a wider sense, were first taken into account in 2003. Two policies deserve to be mentioned - (i) the regulation of medicines in the Brazilian market, and (ii) science, technology and innovation policy. The latter required the fostering of applied research to encourage the application of methods which employ systematic reviews and economic analyses of cost-effectiveness to guide the incorporation of technologies in the Brazilian health care system. The Ministry of Health has initiated the process of incorporating these new technologies on a federal level during the last ten years. In spite of the improvement of HEE methods at Brazilian universities and research institutes, these technologies have not yet reached the governmental bodies. In Brazil, the main challenge lies in the production, interpretation and application of HEE to all technologies within the access scheme(s), and there is limited capacity building. Setting priorities can be the solution for Brazil to be able to perform HEE for relevant technologies within the access scheme(s) while the universal coverage system struggles with a triple burden of disease. PMID- 25444300 TI - [GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations]. AB - This article describes the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to classifying the direction and strength of recommendations. The strength of a recommendation, separated into strong and weak, is defined as the extent to which one can be confident that the desirable effects of an intervention outweigh its undesirable effects. Alternative terms for a weak recommendation include conditional, discretionary, or qualified. The strength of a recommendation has specific implications for patients, the public, clinicians, and policy makers. Occasionally, guideline developers may choose to make "only-in-research" recommendations. Although panels may choose not to make recommendations, this choice leaves those looking for answers from guidelines without the guidance they are seeking. GRADE therefore encourages panels to, wherever possible, offer recommendations. PMID- 25444302 TI - Editorial: new analytical and statistical approaches for interpreting the relationships among environmental stressors and biomarkers. AB - The broad topic of biomarker research has an often-overlooked component: the documentation and interpretation of the surrounding chemical environment and other meta-data, especially from visualization, analytical and statistical perspectives. A second concern is how the environment interacts with human systems biology, what the variability is in "normal" subjects, and how such biological observations might be reconstructed to infer external stressors. In this article, we report on recent research presentations from a symposium at the 248th American Chemical Society meeting held in San Francisco, 10-14 August 2014, that focused on providing some insight into these important issues. PMID- 25444301 TI - [GRADE guidelines 15: going from evidence to recommendation - determinants of a recommendation's direction and strength]. AB - In the GRADE approach, the strength of a recommendation reflects the extent to which we can be confident that the composite desirable effects of a management strategy outweigh the composite undesirable effects. This article addresses GRADE's approach to determining the direction and strength of a recommendation. The GRADE describes the balance of desirable and undesirable outcomes of interest among alternative management strategies depending on four domains, namely estimates of effect for desirable and undesirable outcomes of interest, confidence in the estimates of effect, estimates of values and preferences, and resource use. Ultimately, guideline panels must use judgment in integrating these factors to make a strong or weak recommendation for or against an intervention. PMID- 25444303 TI - 'Dented' and 'resuscitated' masculinities: the impact of HIV diagnosis and/or enrolment on antiretroviral treatment on masculine identities in rural eastern Uganda. AB - There is limited research on the impact of HIV or its treatment on men's identity construction and gender roles in sub-Saharan Africa. Based on in-depth research with 26 men in rural Uganda, this article discusses men's vulnerabilities and shifting gender relations and sense of masculinity resulting from HIV infection or enrolment on treatment in eastern Uganda. The findings suggest two broad categories of masculinity: respectable and reputational. HIV infection and illness dented masculinity as men lost authority within the domestic sphere. A weakened provider role and over-reliance on wives and children undermined masculinity as family head, and social sanctioning of their sexual activity, undermined conventional masculine identities predicted on reputation. However, treatment led to a more reflexive approach to demonstrating masculinity, increased attentiveness to health and restored hope to father children free of HIV, resuscitating respectable masculinities. The balance between eroded and restored masculinity varied between men by their treatment history, age, family composition and state of health. HIV support agencies need to pay attention to the way HIV and antiretroviral treatment (ART) influence men's perception of their masculinity and support them to overcome the anxieties about dented or eroded masculinity, while building on the positive ways in which treatment restores masculinity to support men's adherence to HIV treatment. In particular, there is a need to support men's engagement in productive activities that bring income so that men can regain their provider roles following ART and restore their respectability in both the public and the domestic sphere. PMID- 25444304 TI - Characteristics and kinetics of cervical lymph node regression after radiation therapy for human papillomavirus-associated oropharyngeal carcinoma: quantitative image analysis of post-radiotherapy response. AB - BACKGROUND AND PURPOSE: We sought to characterize the pattern of lymph node regression and morphology following definitive radiation therapy (RT) for human papilloma virus (HPV)-associated oropharyngeal carcinoma in patients with disease control. MATERIALS AND METHODS: Radiographically positive cervical lymph nodes from patients treated with definitive RT for HPV-associated oropharyngeal carcinoma were segmented on initial pre- and subsequent post-RT contrast enhanced CT images. Pre-specified quantitative nodal parameters were calculated. Initial nodal parameter correlates of final nodal size, final nodal volume, and time to <1 cm short-axis diameter were determined. RESULTS: Sixty-six radiographically positive lymph node were analyzed in 36 patients. Lymph nodes exhibited initial volume decreases with size stabilization at ~4 months. Fifteen nodes (23%) underwent complete radiographic response (median 6.4 months following RT; range 2.9-25.6 months). On multivariate time-to-event analysis, initial hypodense/fat component, nodal volume, and short-axis diameter exhibited inverse association, while higher HU standard deviation exhibited a positive association, with reaching <1 cm short-axis diameter (all p<0.05). CONCLUSIONS: Our results showed a substantial decrease in nodal volume within the first 1-2 months following RT. These findings support our current nodal imaging paradigm, propose a quantitative methodology, and describe a reference dataset for further validation and comparison studies. PMID- 25444305 TI - Multidrug-resistant Pseudomonas aeruginosa infections pose growing threat to health care-associated infection control in the hospitals of Southern China: a case-control surveillance study. AB - BACKGROUND: Multidrug-resistant Pseudomonas aeruginosa (MDRPA) is one of the most common agents among health care-associated infections. There is a lack of data on the clinical features of MDRPA from Southern China. METHODS: A case-control surveillance study of P aeruginosa was conducted based on surveillance from July 2008-December 2012, in 5 hospitals of Guangzhou, China. Data were analyzed by univariate analysis and multivariate logistic regression using Stata 13 (StataCorp, College Station, TX). RESULTS: Of the 348 P aeruginosa strains, the prevalence of MDRPA was 54%, and it has increased over time. Isolates of P aeruginosa showed increased resistance to most antimicrobials during this time period. Independent risk factors were tracheal intubation insertion (odds ratio [OR], 2.21; 95% confidence interval [CI], 1.16-4.23; P = .02) and use of carbapenem (odds ratio [OR], 3.36; 95% confidence interval [CI], 1.75-6.47; P < .01). The distribution of MDRPA infections was uneven among the 5 hospitals (P = .01). Being infected with MDRPA strains resulted in longer duration of hospitalization (39 vs 24 days) and higher mortality (49% vs 20%). CONCLUSION: The infections of MDRPA were severe issues. More stringent measures should be applied for those with independent predictors of MDRPA infections because they may induce adverse clinical outcomes. PMID- 25444307 TI - Detection of hospital outbreaks of influenza-like illness based on excess of incidence rates compared to the community. AB - The risk of nosocomial influenza-like illness (noso-ILI) compared with that of community-acquired ILI was calculated during 3 influenza seasons (2004-2007) at a 1100-bed university hospital with a total of 21,519 hospitalized patients. Outbreaks of noso-ILI occurred in each season, although a protective effect against noso-ILI was also identified for other wards. PMID- 25444306 TI - Trends in ventilator-associated pneumonia: impact of a ventilator care bundle in an Italian tertiary care hospital intensive care unit. AB - BACKGROUND: The impact on ventilator-associated pneumonia (VAP) occurrence of a multifaceted program, including progressive strategies for VAP prevention, implemented in an Italian intensive care unit (ICU) is reported. METHODS: All adults admitted to the ICU in 2004-2010 with a length of stay >=72 hours and mechanical ventilation time >=48 hours were included in the study. Demographics, clinical information, and data on VAP were extracted from the ICU-acquired infection surveillance dataset. A standardized bundle for VAP prevention was implemented in 2004. In 2008, selective digestive tract decontamination (SDD) was added to the protocol. Changes in VAP incidence were evaluated. RESULTS: There were 1,372 subjects included in the study. Overall, 156 (11.4%) developed VAP. In the second part of the study VAP incidence decreased from 15.9% to 6.7% (P < .001). Reductions both in early-onset VAP (6.6% to 1.9%; P < .001) and late-onset VAP (9.3% to 4.7%; P = .001) incidence were observed. Multivariate analysis showed a significant reduction in the risk of developing VAP from multidrug resistant pathogens in the bundle plus SDD period as well (odds ratio, .54; 95% confidence interval, .31-.91). CONCLUSION: The implementation of a standardized approach to patient care, including a number of key reduction interventions, was associated with a significant reduction in the risk of developing VAP. PMID- 25444308 TI - Contamination of a purified water system by Aspergillus fumigatus in a new endoscopy reprocessing unit. AB - Use of purified water for the final rinse stage of disinfected endoscopes is an important element of quality control. We describe the detection and management of Aspergillus fumigatus contamination of a new reverse osmosis unit supplying 10 automated endoscope reprocessor basins. Prompt detection and reaction to this contaminant were possible because of the introduction of a comprehensive program for microbiological monitoring of rinse waters, which included total viable counts, endotoxin, conductivity, and Pseudomonas spp. PMID- 25444309 TI - Antimicrobial susceptibility profiles of Staphylococcus aureus isolates classified according to their origin in a tertiary hospital in Korea. AB - We performed a comprehensive analysis on 3,594 Staphylococcus aureus isolates from routine culture during the last 4 years. The antimicrobial susceptibilities of the isolates were analyzed according to their origin and were compared based on the type of specimens. The proportion of methicillin-resistant Staphylococcus aureus (MRSA) in community-associated (CA), health care-associated, community onset (HACO), and health care-associated (HA) isolates were 33.0%, 54.3%, and 73.3%, respectively. The MRSA rate differed significantly between specimens, with the highest rate from urine in the CA and HACO isolates, whereas the highest rate from the respiratory tract was in the HA isolates. The monitoring of the MRSA rate in CA, HACO, and HA S aureus isolates would be valuable for surveillance. The elevated rates of MRSA in urinary specimens from CA and HCA isolates need to be addressed for infection control. PMID- 25444310 TI - A case for stocking O D+ red blood cells in emergency room trauma bays. AB - BACKGROUND: AABB Standard 5.27 requires transfusion services to have a process for urgent release of blood before completion of compatibility testing. Our institution endorses a policy for the emergency release of group O, D+ red blood cells (RBC; O+ RBC) to males and females at least 50 years of age. Our emergency department (ED) stocks 4 O- RBC units. To determine if O+ RBCs can replace ED O- RBCs, we performed a retrospective review. STUDY DESIGN AND METHODS: Patients admitted to the ED between January 2001 and August 2011 and transfused emergency release O- RBCs were identified. Data were collected on sex, age, length of stay, clinical status, ABO/Rh, RBC transfusions, and RBC antibody screen results. RESULTS: A total of 498 ED O- RBC units were transfused to 268 patients (168 male, 100 female). A total of 322 units were transfused to males and 114 to females at least 50 years of age. Thirty-nine (14%) were D- with 18 receiving O+ RBCs. A total of 109 had follow-up antibody screens; one D- patient developed alloanti-D. CONCLUSIONS: The findings support the placement of O+ RBCs in the ED. The majority of ED O- RBCs (88%) went to patients who qualified for O+ RBCs; a minority (1.5%) of patients were D- females less than 50 years of age. The rate of alloimmunization was low. PMID- 25444311 TI - The Identity-Location Binding Problem. AB - The binding problem is fundamental to visual perception. It is the problem of associating an object's visual properties with itself and not with some other object. The problem is made particular difficult because different properties of an object, such as its color, shape, size, and motion, are often processed independently, sometimes in different cortical areas. The results of these separate analyses have to be combined before the object can be seen as a single coherent entity as opposed to a collection of unconnected features. Visual bindings are typically initiated and updated in a serial fashion, one object at a time. Here, we show that one type of binding, location-identity bindings, can be updated in parallel. We do this by using two complementary techniques, the simultaneous-sequential paradigm and systems factorial technology. These techniques make different assumptions and rely on different behavioral measures, yet both came to the same conclusion. PMID- 25444312 TI - Detection of medical errors in kidney transplantation: a pilot study comparing proactive clinician debriefings to a hospital-wide incident reporting system. AB - BACKGROUND: Rates of medical errors and adverse events remain high for patients who undergo kidney transplantation; they are particularly vulnerable because of the complexity of their disease and the kidney transplantation procedure. Although institutional incident-reporting systems are used in hospitals around the country, they often fail to capture a substantial proportion of medical errors. The goal of this study was to assess the ability of a proactive, web based clinician safety debriefing to augment the information about medical errors and adverse events obtained via traditional incident reporting systems. METHODS: Debriefings were sent to all individuals listed on operating room personnel reports for kidney transplantation surgeries between April 2010 and April 2011, and incident reports were collected for the same time period. The World Health Organization International Classification for Patient Safety was used to classify all issues reported. RESULTS: A total of 270 debriefings reported 334 patient safety issues (179 safety incidents, 155 contributing factors), and 57 incident reports reported 92 patient safety issues (56 safety incidents, 36 contributing factors). Compared with incident reports, more attending physicians completed the debriefings (32.0 vs 3.5%). DISCUSSION: The use of a proactive, web-based debriefing to augment an incident reporting system in assessing safety risks in kidney transplantation demonstrated increased information, more perspectives of a single safety issue, and increased breadth of participants. PMID- 25444313 TI - An analysis of whether surgeon-performed neck ultrasound can be used as the main localizing study in primary hyperparathyroidism. AB - BACKGROUND: Tc-99 sestamibi (MIBI) scan is the imaging study most frequently used in primary hyperparathyroidism (PHP). Transcutaneous cervical ultrasonography (US) is the other modality used for preoperative localization. The aim of this study was to determine whether surgeon-performed neck US can be used as the primary localizing study in PHP. METHODS: This was a prospective study of 1,000 consecutive patients with first-time, sporadic PHP who underwent parathyroidectomy at a tertiary academic center. All patients had surgeon performed neck US and MIBI before bilateral neck exploration. RESULTS: The findings at exploration were 72% single adenoma, 15% double adenoma, and 13% hyperplasia. When US suggested single-gland disease (n = 842), MIBI was concordant in 82.5%, discordant and false in 8%, negative in 7%, and discordant but correct in 2.5%. When US suggested multigland disease (n = 68), MIBI was concordant in 47%, discordant and false in 41%, and negative in 12%. When US was negative (n = 90), MIBI was positive and correct in 43%, negative in 31%, and positive but false in 26%. Surgeon-performed neck US identified unrecognized thyroid nodules in 326 patients (33%), which led to fine-needle aspiration biopsy in 161 (49%) patients and thyroid surgery in 103 (32%) patients, with a final diagnosis of thyroid cancer in 24 (7%) patients. CONCLUSION: Our results show that MIBI provides additional useful information in only a minority of patients with a positive US in PHP. Nevertheless, MIBI benefits about half of patients with a negative US. Because one-third of this patient population has unrecognized thyroid nodules as well, we propose that the most cost-effective algorithm would be to do US first and reserve MIBI for US-negative cases. PMID- 25444314 TI - Prognostic factors and staging systems in parathyroid cancer: a multicenter cohort study. AB - BACKGROUND: Parathyroid carcinoma (PC) is an uncommon disease that generally is detected postoperatively and traditionally is associated with a poor prognosis. Our purpose was to evaluate treatment outcomes, prognostic factors, and usefulness of some proposed staging systems for this disease. METHODS: A multicenter review of patients with surgically resected PC was performed, led by the Spanish Association of Surgery. All surgical units affiliated with its endocrine surgery section were invited to answer a questionnaire that collected several hospital-related, clinical, biochemical, operative, pathologic, and follow-up data. Their relationships with prognosis were assessed by both univariate and multivariate analysis, as well as the effectiveness of three staging systems for parathyroid carcinoma. RESULT: Of the 6,863 patients undergoing parathyroidectomy, 62 (0.9%) had PC. Of them, 12 (19.3%) died, in 5 cases (8%) because of disease, and 14 (22.6%) suffered recurrence, after a median follow-up of 55 months. The most predictive independent variables on tumor recurrence were intraoperative tumor rupture (hazard ratio [HR] 6.22; 95% confidence interval [CI] 1.19-32.36; P = .030); the presence of mitotic figures within tumor parenchyma cells (HR 4.76; 95% CI 1.24-18.21; P = .022); and allocation in class III according to Schulte differentiated staging classification (HR 5.23; 95% CI 1.41-19.31; P = .013). As to disease-specific survival, poor outcomes were associated with intraoperative tumor rupture (HR 58.71; 95% CI 2.39-1,439.96; P = .013) and distant recurrence (HR 38.74; 95% CI 3.44-435.62; P = .003). CONCLUSION: In addition to factors associated with tumor histopathology and stage, prognosis of PC is greatly influenced by surgeon's performance, which emphasizes the importance of preoperative diagnosis. PMID- 25444315 TI - Differential recurrent laryngeal nerve palsy rates after thyroidectomy. AB - INTRODUCTION: Recurrent laryngeal nerve (RLN) palsy is a devastating complication of thyroidectomy. Although neurapraxia is thought to be the most common cause, the underlying mechanisms are poorly understood. The objectives of this study were to examine the differential palsy rates between the left and right RLNs, and the role of intraoperative nerve swelling as a risk factor of postoperative palsy. METHODS: Thyroidectomy data were collected, including demographics, change in RLN diameter, and RLN electromyographic (EMG) reading. Left and right RLNs, as well as bilateral and unilateral subgroup analyses were performed. RESULTS: A total of 5,334 RLNs were at risk in 3,408 thyroidectomies in this study. The overall RLN palsy rate was 1.5%, greater on the right side than the left for bilateral cases (P = .025), and greater on the left side than the right for unilateral cases (P = .007). In a subgroup of 519 RLNs, the diameter and EMG amplitude were measured. The RLN diameter increased by approximately 1.5-fold (P < .001), and corresponded to increased EMG amplitude (P = .01) during the procedure. The diameter of the right RLN was larger than the left RLN, both at the beginning and end of the dissection (P = .001). CONCLUSION: The right-left differential rates of post-thyroidectomy RLN palsy seemed to be due in part to differential RLN diameters, with stretch having a more deleterious effect on RLNs with a smaller diameter; also, edema as a result of stretch might be an underlying mechanism for postoperative neurapraxia and palsy. Thyroid surgeons should be aware of the different vulnerabilities of each RLN and develop practices to avoid iatrogenic injury. PMID- 25444316 TI - Mesohepatectomy for centrally located large hepatocellular carcinoma: Indications, techniques, and outcomes. AB - BACKGROUND: Whether mesohepatectomy should be performed for large hepatocellular carcinoma (HCC) located in the central part of the liver is controversial, and the safety and long-term survival after this operation remain to be investigated. METHODS: Between January 2002 and December 2012, 696 patients with HCC located in the central part of the liver who received liver resection in our hospital were included in this study. These patients were divided into three groups: 158 patients with large HCC (tumor size >5.0 cm) and 192 patients with small HCC (tumor size <= 5.0 cm) who received mesohepatectomy were classified as the mesohepatectomy for large HCC (MHG-L) group and the mesohepatectomy for small HCC (MHG-S) groups, respectively, and 346 patients with large HCC who received hemihepatectomy or less were classified as the non-mesohepatectomy for large HCC (NMHG-L) group. The operative indications, techniques, and outcomes of the three groups were analyzed retrospectively. RESULTS: There were no substantial differences among the three groups in in-hospital mortality or postoperative complication rates. The overall survival and disease-free survival were not different between the MHG-L group and the NMHG-L group or between the MHG-L group and the MHG-S group. Univariable and multivariable analyses of the MHG-L mesohepatectomy group indicated that cirrhosis, tumor number, and vascular invasion were independent risk factors of poor long-term survival of mesohepatectomy. In the MHG-L and NMHG-L groups, solitary large hepatocellular carcinoma had better long-term survival than nodular large hepatocellular carcinoma. CONCLUSION: Mesohepatectomy is safe and efficacious for BCLC B/C patients who have centrally located large HCC, especially for solitary tumors, with good survival outcomes. PMID- 25444317 TI - Commentary on: Mesohepatectomy for centrally located large hepatocellular carcinoma: indications, techniques, and outcomes. PMID- 25444318 TI - What is the nature of pancreatic consistency? Assessment of the elastic modulus of the pancreas and comparison with tactile sensation, histology, and occurrence of postoperative pancreatic fistula after pancreaticoduodenectomy. AB - BACKGROUND: Although pancreatic consistency is a factor known to have an impact on the occurrence of postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD), it usually is assessed subjectively by the surgeon. Measurement of the elastic modulus (EM), a parameter characterizing the elasticity of a material, may be one approach for achieving objective and quantitative assessment of pancreatic consistency. This study was conducted to investigate the utility of determining the EM of the pancreas. METHODS: Fifty nine patients who underwent PD and measurement of the EM of the ex vivo pancreas were investigated. Data for EM were compared with the tactile evaluation made by surgeons, histologic findings, and the occurrence of POPF. RESULTS: The EM of the pancreas was correlated with the tactile evaluation made by the surgeon (soft pancreas, 1.4 +/- 2.1 kPa vs hard pancreas, 4.4 +/- 5.1 kPa; P < .001). An EM of >3.0 kPa was correlated with histologic findings including increased ratios of azan-Mallory positivity (P = .003) and alpha-smooth muscle actin positivity (P = .006), a decreased lobular ratio (P = .021), and an increased vessel density (P < .001). Patients with a pancreatic EM of <3.0 kPa had an increased risk of POPF (hazard ratio, 9.333; P = .002). CONCLUSION: Assessment of the EM of the resected pancreas reflects the tactile evaluation made by the surgeon and histological degree of pancreatic fibrosis, and is correlated with the occurrence of POPF after PD. PMID- 25444319 TI - Axillary reverse mapping: five-year experience. AB - BACKGROUND: We hypothesize that mapping the lymphatic drainage of the arm with blue dye (axillary reverse mapping [ARM]) during axillary lymphadenectomy decreases the likelihood of disruption of lymphatics and subsequent lymphedema. METHODS: This institutional review board-approved study involved 360 patients undergoing sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection (ALND) from May 2006 to October 2011. Technetium sulfur colloid (4 mL) was injected subareolarly, and 5 mL of blue dye was injected subcutaneously in the volar surface ipsilateral upper extremity (ARM). Data were collected on variations in lymphatic drainage, successful identification and protection of arm lymphatics, crossover, and occurrence of lymphedema. RESULTS: A group of 360 patients underwent SLNB and/or ALND, 348 of whom underwent a SLNB. Of those, 237 (68.1%) had a SLNB only, and 111 (31.9%) went on to an ALND owing to a positive axilla. An additional 12 of 360 (3.3%) axilla had ALND owing to a clinically positive axilla/preoperative core needle biopsy. In 96% of patients with SLNB (334/348), breast SLNs were hot but not blue; crossover (SLN hot and blue) was seen in 14 of 348 patients (4%). Blue lymphatics were identified in 80 of 237 SLN incisions (33.7%) and in 93 of 123 ALND (75.4%). Average follow-up was 12 months (range, 3-48) and resulted in a SLNB lymphedema rate of 1.7% (4/237) and ALND of 2.4% (3/123). CONCLUSION: ARM identified substantial lymphatic variations draining the upper extremities and facilitated preservation. Metastases in ARM identified lymph nodes were acceptably low, indicating that ARM is safe. ARM added to present-day ALND and SLNB may be useful to lesser rates of lymphedema. PMID- 25444320 TI - In response to Birgir Gudjonsson, MD. PMID- 25444321 TI - Survival calculations. PMID- 25444343 TI - Optical coherence tomography for the monitoring of neovascular age-related macular degeneration: a systematic review. AB - TOPIC: To compare the accuracy of optical coherence tomography (OCT) with alternative tests for monitoring neovascular age-related macular degeneration (nAMD) and detecting disease activity among eyes previously treated for this condition. CLINICAL RELEVANCE: Traditionally, fundus fluorescein angiography (FFA) has been considered the reference standard to detect nAMD activity, but FFA is costly and invasive. Replacement of FFA by OCT can be justified if there is a substantial agreement between tests. METHODS: Systematic review and meta analysis. The index test was OCT. The comparator tests were visual acuity, clinical evaluation (slit lamp), Amsler chart, color fundus photographs, infrared reflectance, red-free images and blue reflectance, fundus autofluorescence imaging, indocyanine green angiography (ICGA), preferential hyperacuity perimetry, and microperimetry. We searched the following databases: MEDLINE, MEDLINE In-Process, EMBASE, Biosis, Science Citation Index, the Cochrane Library, Database of Abstracts of Reviews of Effects, MEDION, and the Health Technology Assessment database. The last literature search was conducted in March 2013. We used the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) to assess risk of bias. RESULTS: We included 8 studies involving more than 400 participants. Seven reported the performance of OCT (3 time-domain [TD] OCT, 3 spectral-domain [SD] OCT, 1 both types) and 1 reported the performance of ICGA in the detection of nAMD activity. We did not find studies directly comparing tests in the same population. The pooled sensitivity and specificity of TD OCT and SD OCT for detecting active nAMD was 85% (95% confidence interval [CI], 72%-93%) and 48% (95% CI, 30%-67%), respectively. One study reported ICGA with sensitivity of 75.9% and specificity of 88.0% for the detection of active nAMD. Half of the studies were considered to have a high risk of bias. CONCLUSIONS: There is substantial disagreement between OCT and FFA findings in detecting active disease in patients with nAMD who are being monitored. Both methods may be needed to monitor patients comprehensively with nAMD. PMID- 25444344 TI - Subjective and objective screening tests for hydroxychloroquine toxicity. AB - OBJECTIVE: To compare subjective and objective clinical tests used in the screening for hydroxychloroquine retinal toxicity to multifocal electroretinography (mfERG) reference testing. DESIGN: Prospective, single center, case control study. PARTICIPANTS: Fifty-seven patients with a previous or current history of hydroxychloroquine treatment of more than 5 years' duration. METHODS: Participants were evaluated with a detailed medical history, dilated ophthalmologic examination, color fundus photography, fundus autofluorescence (FAF) imaging, spectral-domain (SD) optical coherence tomography (OCT), automated visual field testing (10-2 visual field mean deviation [VFMD]), and mfERG testing. We used mfERG test parameters as a gold standard to divide participants into 2 groups: those affected by hydroxychloroquine-induced retinal toxicity and those unaffected. MAIN OUTCOME MEASURES: We assessed the association of various imaging and psychophysical variables in the affected versus the unaffected group. RESULTS: Fifty-seven study participants (91.2% female; mean age, 55.7+/-10.4 years; mean duration of hydroxychloroquine treatment, 15.0+/-7.5 years) were divided into affected (n = 19) and unaffected (n = 38) groups based on mfERG criteria. Mean age and duration of hydroxychloroquine treatment did not differ statistically between groups. Mean OCT retinal thickness measurements in all 9 macular subfields were significantly lower (<40 MUm) in the affected group (P < 0.01 for all comparisons) compared with those in the unaffected group. Mean VFMD was 11 dB lower in the affected group (P < 0.0001). Clinical features indicative of retinal toxicity were scored for the 2 groups and were detected in 68.4% versus 0.0% using color fundus photographs, 73.3% versus 9.1% using FAF images, and 84.2% versus 0.0% on the scoring for the perifoveal loss of the photoreceptor ellipsoid zone on SD-OCT for affected and unaffected participants, respectively. Using a polynomial modeling approach, OCT inner ring retinal thickness measurements and Humphrey 10-2 VFMD were identified as the variables associated most strongly with the presence of hydroxychloroquine as defined by mfERG testing. CONCLUSIONS: Optical coherence tomography retinal thickness and 10-2 VFMD are objective measures demonstrating clinically useful sensitivity and specificity for the detection of hydroxychloroquine toxicity as identified by mfERG, and thus may be suitable surrogate tests. PMID- 25444346 TI - Clinically recognizing enlarged extraocular muscles from lymphoid origin. PMID- 25444345 TI - Longitudinal changes in quality of life and rates of progressive visual field loss in glaucoma patients. AB - PURPOSE: To evaluate the association between longitudinal changes in quality of life (QoL) and rates of progressive visual field loss in glaucoma. DESIGN: Prospective observational cohort study. PARTICIPANTS: We recruited 322 eyes of 161 patients with glaucomatous visual field loss from the Diagnostic Innovations Glaucoma Study followed for an average of 3.5+/-0.7 years. METHODS: All subjects had National Eye Institute Visual Function Questionnaire (NEI VFQ)-25 performed annually and standard automated perimetry (SAP) at 6-month intervals. Subjects were included if they had a minimum of 2 NEI VFQ-25 and >=5 SAP during follow-up. Evaluation of rates of visual field change was performed using the mean sensitivity (MS) of the integrated binocular visual field (BVF). Rasch analysis was performed to obtain final scores of disability as measured by the NEI VFQ-25. A joint longitudinal multivariate mixed model was used to investigate the association between change in NEI VFQ-25 Rasch-calibrated scores and change in BVF sensitivity. Potentially confounding socioeconomic and clinical variables also were analyzed. MAIN OUTCOME MEASURES: The relationship between change in NEI VFQ-25 Rasch-calibrated scores and change in binocular SAP MS. RESULTS: There was a significant correlation between change in the NEI VFQ-25 Rasch scores during follow-up and change in binocular SAP sensitivity. Each 1-dB change in binocular SAP MS per year was associated with a change of 2.9 units per year in the NEI VFQ 25 Rasch scores during the follow-up period (R(2) = 26%; P<0.001). Eyes with more severe disease at baseline were also more likely to have a decrease in NEI VFQ-25 scores during follow-up (P<0.001). For subjects with the same amount of change in SAP sensitivity, those with shorter follow-up times had larger changes in NEI VFQ 25 scores (P = 0.005). A multivariable model containing baseline and rate of change in binocular MS had an adjusted R(2) of 50% in predicting change in NEI VFQ-25 scores. CONCLUSIONS: Baseline severity, magnitude, and rates of change in BVF sensitivity were associated with longitudinal changes in QoL of glaucoma patients. Assessment of longitudinal visual field changes may help to identify patients at greater risk for developing disability from the disease. PMID- 25444347 TI - Pathophysiology and mechanisms of severe retinopathy of prematurity. AB - Retinopathy of prematurity (ROP) affects only premature infants, but as premature births increase in many areas of the world, ROP has become a leading cause of childhood blindness. Blindness can occur from aberrant developmental angiogenesis that leads to fibrovascular retinal detachment. To treat severe ROP, it is important to study normal developmental angiogenesis and the stresses that activate pathologic signaling events and aberrant angiogenesis in ROP. Vascular endothelial growth factor (VEGF) signaling is important in both physiologic and pathologic developmental angiogenesis. Based on studies in animal models of oxygen-induced retinopathy (OIR), exogenous factors such as oxygen levels, oxidative stress, inflammation, and nutritional capacity have been linked to severe ROP through dysregulated signaling pathways involving hypoxia-inducible factors and angiogenic factors like VEGF, oxidative species, and neuroprotective growth factors to cause phases of ROP. This translational science review focuses on studies performed in animal models of OIR representative of human ROP and highlights several areas: mechanisms for aberrant growth of blood vessels into the vitreous rather than into the retina through over-activation of VEGF receptor 2 signaling, the importance of targeting different cells in the retina to inhibit aberrant angiogenesis and promote physiologic retinal vascular development, toxicity from broad and targeted inhibition of VEGF bioactivity, and the role of VEGF in neuroprotection in retinal development. Several future translational treatments are discussed, including considerations for targeted inhibition of VEGF signaling instead of broad intravitreal anti-VEGF treatment. PMID- 25444348 TI - Relationship between induced spherical aberration and depth of focus after hyperopic LASIK in presbyopic patients. AB - OBJECTIVE: To evaluate to what extent the modification of corneal asphericity to induce spherical aberration (SA) can improve the depth of focus and to determine whether preoperative adaptive optics assessment (Voptica SL) can predict an optimal SA value for each patient. DESIGN: Comparative, prospective clinical trial with paired eye control. PARTICIPANTS: Patients >=45 years old who are hyperopic from +1.00 to +2.50 diopters (D), with eyes suitable for LASIK surgery. INTERVENTION: Bilateral hyperopic LASIK surgery using a 200-Hz Allegretto excimer laser. The dominant eye was operated using a conventional profile. The nondominant eye was programmed with an aspheric ablation profile and -0.75 D monovision. MAIN OUTCOME MEASURES: Primary outcome was the correlation between postoperative SA and depth of focus, defined as the pseudo-accommodation value (PAV = [1/reading distance {m}] - minimum addition [D]). Main secondary outcome was the comparison of depth of focus between patients with an induced SA close to the optimal one (group 1), patients with an induced SA far from the optimal one (group 2), and patients for whom SA induction did not increase the depth of focus (control group). RESULTS: We included 76 patients. Between preoperative and postoperative assessment, the mean increase of distance-corrected PAV for near vision was +0.25+/-0.64 D (P < 0.001) for dominant eyes and +0.63+/-0.55 D (P < 0.001) for nondominant eyes. As the level of negative or positive postoperative SA increased, PAV for intermediate and near vision increased. Among the 37 eyes that followed the preoperative adaptive optics assessment, the mean PAV increase at near was significantly higher (P < 0.05) in group 1 (0.93+/-0.50 D) than in group 2 (0.46+/-0.42 D) and than in the control group (0.35+/-0.32 D). The mean optimal SA value determined by the dynamic simulation procedure to optimize the depth of focus was -0.18+/-0.13 MUm at 4.5 mm. CONCLUSIONS: Aspheric hyperopic LASIK can increase the depth of focus without impairing far vision, but this benefit would be maximal and reproducible if we could define and achieve an optimal SA value determined by preoperative assessment using an adaptive optics instrument. PMID- 25444349 TI - Reduced precision of the Pentacam HR in eyes with mild to moderate keratoconus. PMID- 25444350 TI - Outpatient cataract surgery: incident and procedural risk analysis do not support current clinical ophthalmology guidelines. AB - OBJECTIVE: To evaluate whether an ophthalmologist-led, non-anesthesia-supported, limited monitoring pathway for phacoemulsification/intraocular lens cataract surgery, can be performed safely with only a medical emergency team providing support. DESIGN: Retrospective, observational, cohort study. PARTICIPANTS: All patients who underwent elective phacoemulsification/intraocular lens surgery under topical anesthesia in the ophthalmology outpatient unit between January 1, 2011, and December 31, 2012. METHODS: Cataract surgery was performed by phacoemulsification under topical anesthesia. The intake process mainly embraced ophthalmic evaluation, obtaining a medical history, and proposing the procedure. A staff ophthalmologist performed the procedure assisted by 2 registered nurses in an independent outpatient clinic operating room within the hospital. The clinical pathway was without dedicated presence of or access to anesthesia service. Perioperative monitoring was limited to blood pressure and plethysmography preoperatively and intraoperatively. Patients were offered supportive care and instructed to avoid fasting and continue all their chronic medication. MAIN OUTCOME MEASURES: The primary outcome measure was the incidence of adverse events requiring medical emergency team (MET) interventions throughout the pathway. Secondary outcome measures were surgical ocular complication rates, use of oral sedatives, and reported reasons to perform the surgery in the classical operation room complex. RESULTS: Within the cataract pathway, 6961 cases (4347 patients) were eligible for analysis. Three MET interventions related to the phacoemulsification/intraocular lens pathway occurred in the 2-year study period, resulting in an intervention rate of 0.04%. None of the interventions was intraoperative. All 3 patients were diagnosed as vasovagal collapse and recuperated uneventfully. No hospital admittance was required. Eight other incidents occurred within the general ophthalmology outpatient unit population during the study period. CONCLUSIONS: Cataract surgery can be safely performed in an outpatient clinic, in the absence of the anesthesia service and with limited workup and monitoring. Basic first aid and basic life support skills seem to be sufficient in case of an adverse event. An MET provides a generous failsafe for this low-risk procedure. PMID- 25444351 TI - Early-onset stargardt disease: phenotypic and genotypic characteristics. AB - OBJECTIVE: To describe the phenotype and genotype of patients with early-onset Stargardt disease. DESIGN: Retrospective cohort study. PARTICIPANTS: Fifty-one Stargardt patients with age at onset <=10 years. METHODS: We reviewed patient medical records for age at onset, medical history, initial symptoms, best corrected visual acuity (BCVA), ophthalmoscopy, fundus photography, fundus autofluorescence (FAF), fluorescein angiography (FA), spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinography (ffERG). The ABCA4 gene was screened for mutations. MAIN OUTCOME MEASURES: Age at onset, BCVA, fundus appearance, FAF, FA, SD-OCT, ffERG, and presence of ABCA4 mutations. RESULTS: The mean age at onset was 7.2 years (range, 1-10). The median times to develop BCVA of 20/32, 20/80, 20/200, and 20/500 were 3, 5, 12, and 23 years, respectively. Initial ophthalmoscopy in 41 patients revealed either no abnormalities or foveal retinal pigment epithelium (RPE) changes in 10 and 9 patients, respectively; the other 22 patients had foveal atrophy, atrophic RPE lesions, and/or irregular yellow-white fundus flecks. On FA, there was a "dark choroid" in 21 out of 29 patients. In 14 out of 50 patients, foveal atrophy occurred before flecks developed. On FAF, there was centrifugal expansion of disseminated atrophic spots, which progressed to the eventual profound chorioretinal atrophy. Spectral-domain OCT revealed early photoreceptor damage followed by atrophy of the outer retina, RPE, and choroid. On ffERG in 26 patients, 15 had normal amplitudes, and 11 had reduced photopic and/or scotopic amplitudes at their first visit. We found no correlation between ffERG abnormalities and the rate of vision loss. Thirteen out of 25 patients had progressive ffERG abnormalities. Finally, genetic screening of 44 patients revealed >=2 ABCA4 mutations in 37 patients and single heterozygous mutations in 7. CONCLUSIONS: In early-onset Stargardt, initial ophthalmoscopy can reveal no abnormalities or minor retinal abnormalities. Yellow-white flecks can be preceded by foveal atrophy and may be visible only on FAF. Although ffERG is insufficient for predicting the rate of vision loss, abnormalities can develop. Over time, visual acuity declines rapidly in parallel with progressive retinal degeneration, resulting in profound chorioretinal atrophy. Thus, early-onset Stargardt lies at the severe end of the spectrum of ABCA4-associated retinal phenotypes. PMID- 25444352 TI - Clinical outcomes of TECNIS toric intraocular lens implantation after cataract removal in patients with corneal astigmatism. AB - PURPOSE: To evaluate safety and effectiveness of the TECNIS toric intraocular lenses (IOLs). DESIGN: Prospective, multicenter, 2-armed, bilateral, 6-month clinical trial following the American National Standards Institute (ANSI) standard for Toric IOLs. PARTICIPANTS: Subjects implanted with a TECNIS toric IOL (n = 172) or a TECNIS 1-piece control IOL (ZCB00; n = 93). METHODS: Subjects underwent standard cataract surgery with IOL implantation. The randomized control arm consisted of subjects requiring cylinder correction of 0.75 to 1.50 diopters (D) who were implanted with either toric (ZCT150) or nontoric (ZCB00) IOLs. The open-label arm (OLA) consisted of subjects requiring cylinder correction of 1.50 to 3.62 D and implanted with ZCT225, ZCT300, or ZCT400 IOLs. MAIN OUTCOME MEASURES: Assessments were at 1 day, 1 week, and 1, 3, and 6 months and included uncorrected distance visual acuity (UCDVA) and best-corrected distance visual acuity (BCDVA), manifest refraction, keratometry, adverse events, spectacle use, and photographic documentation of IOL rotational stability. RESULTS: Mean percent reduction in cylinder (+/- standard deviation) was statistically significantly greater (P < 0.0001) for ZCT150 eyes (74.53 +/- 72.25%) versus ZCB00 eyes (31.61 +/- 78.73%). In the OLA, mean percent reduction in cylinder was 76.27 +/- 33.09%. A UCDVA of 20/20 or better was achieved by 43.6% (44/101) of ZCT150 eyes and by 23.7% (22/93) of ZCB00 eyes (P = 0.0026). In the OLA, 38.0% (27/71) achieved 20/20 or better UCDVA. Mean UCDVA was 0.10 +/- 0.14 for ZCT150 eyes and 0.16 +/- 0.16 for ZCB00 eyes (P = 0.0009); in the OLA, mean UCDVA was 0.11 +/- 0.12. The BCDVA was 20/40 or better for all eyes. Mean absolute lens rotation between visits for toric eyes pooled was less than 3 degrees . Lens rotation of 5 degrees or less occurred in 92.9% of toric eyes between 1 and 3 months and in 94.1% between 3 and 6 months, exceeding the ANSI standard for stability (>= 90% of eyes with <= 5 degrees of rotation between visits). Four lenses (2.3%) were repositioned during the study. CONCLUSIONS: The TECNIS toric IOLs successfully reduce ocular astigmatism and are a safe and effective treatment for cataract patients with corneal astigmatism. PMID- 25444353 TI - The association between ectopic fat in the pancreas and subclinical atherosclerosis in type 2 diabetes. AB - AIMS: Evidence that pancreatic fat accumulation has a role in obesity, metabolic syndrome and type 2 diabetes mellitus (DM) is emerging. However, data on the influence of pancreatic steatosis on subclinical atherosclerosis are lacking. METHODS: We examined 198 patients with type 2 DM. Pancreatic computed tomography (CT) attenuations were assessed using CT imaging. Obesity was defined as BMI >= 25 kg/m(2) according to the Asian-specific BMI cut-offs. We defined pancreatic steatosis as pancreatic attenuations below median levels. RESULTS: The pancreatic attenuations was significantly correlated with age (r=-0.302, p<0.001), visceral fat area (r=-0.194, p=0.006) and vascular stiffness (r=-0.242, p=0.001). In the non-obese group (BMI<25 kg/m(2)), pancreatic steatosis was associated with a higher prevalence of carotid artery plaque and vascular stiffness. In the non obese group, patients with pancreatic steatosis, compared with those without, had an odds ratio (OR) of 3.1 (95% CI 1.2-8.1) for carotid atherosclerosis, after adjusting for age, gender and BMI. However, significant associations between pancreatic steatosis and atherosclerosis were not found in the obese group. CONCLUSION: Ectopic fat in the pancreas is strongly associated with carotid atherosclerosis in non-obese subjects with type 2 DM. This finding highlights the importance of pancreatic fat deposits related to a higher risk of cardiovascular disease, especially in non-obese subjects. PMID- 25444355 TI - Knowledge, awareness, and behaviors of endocrinologists and dentists for the relationship between diabetes and periodontitis. AB - AIMS: This study aimed to compare the opinions of dentists and endocrinologists regarding diabetes mellitus (DM) and periodontitis, and to investigate the possible effects on their practice. METHODS: Cross-sectional data were collected from 297 endocrinologists and 134 dentists practicing in southern China using two separated questionnaires. Questions were close-ended or Likert-scaled. Statistical analyses were done by descriptive statistics, bivariate and binary logistic regression analysis. RESULTS: Compared with endocrinologists, dentists presented more favorable attitudes for the relationship of DM and periodontitis (P<0.001). 61.2% of dentists reported they would frequently refer patients with severe periodontitis for DM evaluation, while only 26.6% of endocrinologists reported they would frequently advise patients with DM to visit a dentist. Nearly all of the respondents (94.4%) agreed that the interdisciplinary collaboration should be strengthened. The logistic regression analysis exhibited that respondents with more favorable attitudes were more likely to advise a dental visit (P=0.003) or to screen for DM (P=0.006). CONCLUSIONS: Endocrinologists and dentists are not equally equipped with the knowledge about the relationship between DM and periodontitis, and there is a wide gap between their practice and the current evidence, especially for endocrinologists. It's urgent to take measures to develop the interdisciplinary education and collaboration among the health care providers. PMID- 25444356 TI - Risk stratification in early pregnancy for women at increased risk of gestational diabetes. AB - AIM: To evaluate the addition of fasting glucose and lipids to a simple, validated risk prediction tool for gestational diabetes (GDM) applied in early pregnancy. METHODS: Women at risk of developing GDM on a validated risk prediction tool were recruited in early pregnancy into a large randomised controlled trial. Outcome measures included fasting biochemical markers (glucose, lipids) at 12-15 weeks gestation and GDM diagnosis (28 weeks gestation). Multivariable logistic regression was used to identify additional predictive biochemical variables for GDM, with corresponding receiver operator characteristic (ROC) curves generated. Unadjusted and adjusted models were derived for both the Australasian Diabetes in Pregnancy (ADIPS) and the International Association for Diabetes in Pregnancy Study Group (IADPSG) GDM diagnostic criteria. RESULTS: 51 (23%) Women were diagnosed with GDM based on ADIPS criteria, with 60 (30%) diagnosed based on IADPSG criteria. In all four regression models, fasting glucose was the strongest predictor for GDM development with an odds ratio range of 4.7-6.3 (ADIPS) and 8.8-10 (IADPSG). ROC curves revealed an area under the curve of 0.79 (95% CI: 0.72-0.86) for ADIPS criteria and 0.83 (95% CI: 0.77-0.90) for IADPSG criteria for adjusted models. CONCLUSIONS: In a two-step approach, when applied with a validated risk prediction tool, fasting glucose in early pregnancy was predictive of GDM and incrementally improved risk identification, presenting potential for an early pregnancy, GDM risk screening strategy for streamlining of pregnancy care and opportunity for preventive intervention. PMID- 25444358 TI - Methods to calibrate and scale axial distances in confocal microscopy as a function of refractive index. AB - Accurate distance measurement in 3D confocal microscopy is important for quantitative analysis, volume visualization and image restoration. However, axial distances can be distorted by both the point spread function (PSF) and by a refractive-index mismatch between the sample and immersion liquid, which are difficult to separate. Additionally, accurate calibration of the axial distances in confocal microscopy remains cumbersome, although several high-end methods exist. In this paper we present two methods to calibrate axial distances in 3D confocal microscopy that are both accurate and easily implemented. With these methods, we measured axial scaling factors as a function of refractive-index mismatch for high-aperture confocal microscopy imaging. We found that our scaling factors are almost completely linearly dependent on refractive index and that they were in good agreement with theoretical predictions that take the full vectorial properties of light into account. There was however a strong deviation with the theoretical predictions using (high-angle) geometrical optics, which predict much lower scaling factors. As an illustration, we measured the PSF of a correctly calibrated point-scanning confocal microscope and showed that a nearly index-matched, micron-sized spherical object is still significantly elongated due to this PSF, which signifies that care has to be taken when determining axial calibration or axial scaling using such particles. PMID- 25444359 TI - [Osteoarticular pneumococcal infections observed in a tertiary hospital over a period of 11 years]. AB - INTRODUCTION: Osteoarticular pneumococcal infection is an infrequent complication of pneumococcal bacteremia, due to the advances in antibiotic therapy and in the pattern of immunization. METHODS: A retrospective study was conducted on patients diagnosed with osteoarticular pneumococcal infection between January 2003 and December 2013 in the University Hospital Marques de Valdecilla in Santander. RESULTS: Five out of 321 patients diagnosed with pneumococcal bacteremia had osteoarticular infection. All of them had at least one chronic underlying disease and had been immunized according to the standard vaccination schedule. Hip and vertebra were the most common joints involved. Outcome was favorable in all cases. CONCLUSIONS: The clinical findings of pneumococcal osteoarticular infection should be borne in mind. Its optimal prevention in high-risk patients should include the 13V conjugate vaccine. PMID- 25444360 TI - [Evaluation of mass spectrometry for the identification of clinically interesting yeasts]. AB - INTRODUCTION: Identification of yeasts is based on morphological, biochemical and nutritional characteristics, and using molecular methods. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, a new method for the identification of microorganisms, has demonstrated to be very useful. The aim of this study is to evaluate this new method in the identification of yeasts. METHODS: A total of 600 strains of yeasts isolated from clinical specimens belonging to 9 genera and 43 species were tested. Identification was made by sequencing of the ITS regions of ribosomal DNA, assimilation of carbon compounds (ID 32C), and mass spectrometry on a Microflex spectrometer (Bruker Daltonics GmbH, Germany). RESULTS: A total of 569 strains (94.8%) were identified to species level by ID 32C, and 580 (96.7%) by MALDI-TOF. Concordance between both methods was observed for 553 strains (92.2%), with 100% in clinically relevant species: C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and almost 100% in C. krusei. MALDI-TOF identified species requiring molecular methods: Candida dubliniensis, C. nivariensis, C. metapsilosis and C. orthopsilosis. Some irregularities were observed in the identification of arthroconidia yeast and basidiomycetes. CONCLUSION: MALDI-TOF is a rapid, effective and economic method, which enables the identification of most clinically important yeasts and the differentiation of closely related species. It would be desirable to include more species in its database to expand its performance. PMID- 25444362 TI - Serum ischemia-modified albumin and oxidized LDL in cord blood and serum of neonates born to pre-eclamptic mothers. AB - BACKGROUND: We investigated oxidized low-density lipoprotein (OxLDL) and ischemia modified albumin (IMA) in cord blood and neonatal blood of 7-day-old neonates born to pre-eclamptic and normotensive healthy mothers. METHODS: The study was performed on 30 neonates born to pre-eclamptic and 20 neonates born to normotensive mothers. IMA and OxLDL were determined on spectrophotometry and ELISA, respectively. RESULTS: IMA in cord blood was higher in the pre-eclamptic group as compared with the normotensive group, but the difference between the groups was not significant. IMA in neonate venous blood was significantly higher in the pre-eclamptic group than in the normotensive group (P < 0.001). OxLDL in both cord blood and in neonate venous blood was significantly higher in the pre eclamptic group compared with the normotensive group (P < 0.001). IMA and OxLDL were significantly decreased after delivery in both groups. CONCLUSIONS: Significantly increased cord blood OxLDL and significantly increased OxLDL and IMA 7 days after birth in neonates born to pre-eclamptic mothers might be an indicator of increased oxidative stress in pre-eclampsia. PMID- 25444363 TI - Editorial overview: Endocrine and metabolic diseases: conversations on endocrine disruptors - rising above the din. PMID- 25444361 TI - [Human immunodeficiency virus screening in primary care: Acceptance by physicians and patients]. PMID- 25444364 TI - Ectopic orbital meningioma: report of two cases and literature review. AB - Ectopic orbital meningioma is a rare tumor usually affecting the medial orbit. We present two cases that occurred in a 56-year-old woman and a 28-year-old man. The tumors in both patients were subtotally excised via orbitotomy surgery and were located in the superior quadrant in one of our patients and in the temporal quadrant in the other. Following histopathologic diagnosis, external beam radiotherapy (EBRT) was administered to one patient and intensity modulated radiotherapy to the other. We identified 12 other well-documented cases of ectopic orbital meningioma previously reported. Ectopic meningioma should be considered in the differential diagnosis of medial as well as lateral and superior orbital tumors. The tumor is usually well circumscribed but can be ill defined in imaging studies. There are intralesional calcifications and sclerosis of adjacent bone in some cases. Ectopic orbital meningioma can recur after incomplete excision. Based on the efficacy of EBRT in optic nerve sheath meningioma, we used this treatment to decrease the risk of recurrence in our two patients and found no tumor recurrence at follow-ups of 24 and 74 months, but one patient had severe vision loss from radiation retinopathy. PMID- 25444366 TI - Choroidal imaging in preterm and term infants. PMID- 25444365 TI - Primary adnexal angiosarcoma masquerading as periorbital hematoma. AB - We report an elderly woman who was anticoagulated and presented with a recent history of right-sided orbital contusion and a periorbital hematoma without clinical or radiological evidence of focal mass or orbital involvement. She was initially treated conservatively. Continued progression of adnexal swelling and erythema prompted further investigation, however. There was no improvement with surgical drainage alone; biopsy revealed angiosarcoma. The discovery of this vascular tumor underscores the importance of a reconsideration of the diagnosis in the face of counterintuitive findings. Additionally, we emphasize the need to consider malignancy in the differential diagnosis of prolonged periorbital swelling, regardless of a history of recent trauma. PMID- 25444367 TI - Sub-conjunctival lidocaine injection before intravitreal injection. PMID- 25444368 TI - Pre-transplant impedance measures of reflux are associated with early allograft injury after lung transplantation. AB - BACKGROUND: Acid reflux has been associated with poorer outcomes after lung transplantation. Standard pre-transplant reflux assessment has not been universally adopted. Non-acid reflux may also induce a pulmonary inflammatory cascade, leading to acute and chronic rejection. Esophageal multichannel intraluminal impedance and pH testing (MII-pH) may be valuable in standard pre transplant evaluation. We assessed the association between pre-transplant MII-pH measures and early allograft injury in lung transplant patients. METHODS: This was a retrospective cohort study of lung transplant recipients who underwent pre transplant MII-pH at a tertiary center from 2007 to 2012. Results from pre transplant MII-pH, cardiopulmonary function testing, and results of biopsy specimen analysis of the transplanted lung were recorded. Time-to-event analyses were performed using Cox proportional hazards and Kaplan-Maier methods to assess the associations between MII-pH measures and development of acute rejection or lymphocytic bronchiolitis. RESULTS: Thirty patients (46.7% men; age, 54.2 years) met the inclusion criteria. Pre-transplant cardiopulmonary function and pulmonary diagnoses were similar between outcome groups. Prolonged bolus clearance (hazard ratio [HR], 4.11; 95% confidence interval [CI], 1.34-12.57; p = 0.01), increased total distal reflux episodes (HR, 4.80; 95% CI, 1.33-17.25; p = 0.02), and increased total proximal reflux episodes (HR, 4.43; 95% CI, 1.14-17.31; p = 0.03) were significantly associated with decreased time to early allograft injury. Kaplan-Meier curves also demonstrated differences in time to rejection by prolonged bolus clearance (p = 0.01) and increased total distal reflux episodes (p = 0.01). Sub-group analysis including only patients with MII-pH performed off proton pump inhibitors (n = 24) showed similar results. CONCLUSIONS: Prolonged bolus clearance, increased total distal reflux episodes, and increased total proximal reflux episodes on pre-transplant MII-pH were associated with decreased time to early allograft injury after lung transplantation. Routine pre-transplant MII-pH may provide clinically relevant data regarding transplant outcomes and peri-transplant care. PMID- 25444354 TI - Continued smoking abstinence in diabetic patients in primary care: a cluster randomized controlled multicenter study. AB - AIMS: To assess the effectiveness of an intensive smoking cessation intervention based on the transtheoretical model of change (TTM) in diabetic smokers attending primary care. METHODS: A cluster randomized controlled clinical trial was designed in which the unit of randomization (intervention vs. usual care) was the primary care team. An intensive, individualized intervention using motivational interview and therapies and medications adapted to the patient's stage of change was delivered. The duration of the study was 1 year. RESULTS: A total of 722 people with diabetes who were smokers (345 in the intervention group and 377 in the control group) completed the study. After 1 year, continued abstinence was recorded in 90 (26.1%) patients in the intervention group and in 67 (17.8%) controls (p=0.007). In patients with smoking abstinence, there was a higher percentage in the precontemplation and contemplation stages at baseline in the intervention group than in controls (21.2% vs. 13.7%, p=0.024). When the precontemplation stage was taken as reference (OR=1.0), preparation/action stage at baseline showed a protective effect, decreasing 3.41 times odds of continuing smoking (OR=0.293 95% CI 0.179-0.479, p<0.001). Contemplation stage at baseline also showed a protective effect, decreasing the odds of continuing smoking (OR=0.518, 95% CI 0.318-0.845, p=0.008). CONCLUSIONS: An intensive intervention adapted to the individual stage of change delivered in primary care was feasible and effective, with a smoking cessation rate of 26.1% after 1 year. PMID- 25444369 TI - Changing outcomes after heart transplantation in patients with amyloid cardiomyopathy. AB - BACKGROUND: Amyloid cardiomyopathy (ACM) is associated with a poor prognosis. Previous reports have suggested unfavorable post-heart transplant (HT) survival in this population compared with other HT recipients. METHODS: Data from the United Network for Organ Sharing (UNOS) registry were used to study outcomes among ACM patients undergoing HT in the modern era (Era 2, 2008 to 2013) as compared with the historical era (Era 1, 1987 to 2007). RESULTS: One hundred eighty-eight ACM patients underwent primary single-organ HT. Ninety-seven patients (51.6%) were transplanted in Era 1 and 91 (48.4%) in Era 2. ACM patients undergoing HT in Era 2 were older (p < 0.0001), had higher body mass index (p = 0.008) and longer ischemic times (p = 0.02), and were more likely to be African American (p < 0.0001), UNOS Status 1A (p < 0.0001), male (p = 0.01) and highly sensitized (p < 0.0001) compared with those in Era 1. Compared with patients with other etiologies of restrictive cardiomyopathy (RCM; n = 339 in Era 1, n = 164 in Era 2), adjusted hazard ratios (HRs) for post-HT mortality of ACM were 2.08 (p < 0.0001) in Era 1 and 1.22 (p = not statistically significant) in Era 2. Adjusted HRs for mortality of ACM vs all other diagnoses (n = 36,334 in Era 1, n = 9,225 in Era 2) were 1.84 (p < 0.0001) in Era 1 and 1.38 (p = NS) in Era 2. Although post-HT survival did not change with time among non-ACM RCM patients, post-HT mortality was lower in Era 2 compared with Era 1 among ACM patients (HR 0.49, p = 0.03). CONCLUSIONS: Although historically associated with inferior survival, post HT outcomes in ACM patients in the modern era are now approaching those of non ACM patients. Changes in patients' demographics suggest that this may be related to improved patient selection, including an increased proportion of patients with transthyretin ACM. HT should be considered for appropriate candidates with ACM. PMID- 25444370 TI - Pulmonary endarterectomy in severe chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: The outcome of patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary endarterectomy (PEA) after urgent hospitalization for decompensated right heart failure (DRHF) remains unclear. METHODS: Among 120 consecutive patients undergoing PEA, 16 (13%) presented with a history of urgent hospitalization for DRHF (severe RHF group). This group was compared with the remaining 104 patients presenting with total peripheral vascular resistance (TPR) < 1,200 dynes . sec . cm(-5) (n = 78, control group) and >1,200 dynes . sec . cm(-5) (n = 26, high TPR group). RESULTS: DRHF occurred predominantly in patients with TPR > 1,200 dynes . sec . cm(-5) (prevalence of 32% vs 5% in patients with TPR < 1,200 dynes . sec . cm(-5), p < 0.0001). The overall in-hospital mortality after PEA was 4% (n = 5). All deaths occurred in patients with TPR > 1,200 dynes . sec . cm(-5) and DRHF. The proportion of patients with residual PH immediately after surgery was higher in the high TPR group (50%) and severe RHF group (56%) compared with the control group (29%; p = 0.04). In multivariate analysis, risk factors for residual PH after surgery were TPR > 1,200 dynes . sec . cm(-5), Jamieson disease Type III-IV, and female gender. A history of DRHF by itself was not a risk factor for residual PH after PEA. The overall 5-year survival was 87%. After a median follow-up of 20 months, the proportion of patients receiving medical therapy for residual PH was higher in patients with post-operative mean pulmonary artery pressure >=35 mm Hg (61% vs 9%, p = 0.0007). CONCLUSIONS: DRHF occurs more frequently in patients with TPR > 1,200 dynes . sec . cm(-5), increasing the operative risk in these patients. The outcome of patients with high TPR in the absence of DRHF is excellent. However, patients with residual mean pulmonary artery pressure >=35 mm Hg frequently receive pulmonary hypertension therapy after PEA. PMID- 25444371 TI - Effect of pulmonary hypertension on survival in patients with idiopathic pulmonary fibrosis after lung transplantation: an analysis of the United Network of Organ Sharing registry. AB - BACKGROUND: Pulmonary hypertension (PH) is a comorbidity associated with idiopathic pulmonary fibrosis (IPF). There is limited research regarding the effect on survival after lung transplantation (LTx). METHODS: To assess the effect of PH on survival in patients with IPF who received LTx, the United Network for Organ Sharing was queried for eligible patients with recorded mean (PAmean) and systolic (PAsystolic) pulmonary artery pressure. The analysis was restricted to the post-lung allocation scoring system starting May 1, 2005, to provide a cohort receiving present-day therapies and management. The last update of the data set was July 6, 2012, so a cutoff date of July 6, 2011, was chosen to allow for the possibility of at least 1 year of follow-up. Thresholds of >=25 and >=35 mm Hg were chosen for PAmean and PAsystolic, respectively, as indicators of PH. RESULTS: Of 23,951 LTxs in the UNOS data set, 2,542 met inclusion criteria, 1,234 (49%) with PAmean >= 25 mm Hg and 1,680 (66%) with PAsystolic >= 35 mm Hg. PAmean and PAsystolic were highly correlated, with an estimated correlation coefficient rho = 0.93 (p < 0.001). Patients with PH (PAmean >= 25 mm Hg or PAsystolic >= 35 mm Hg) tended to have higher ischemic times, lung allocation score values, forced vital capacity percentage predicted at LTx, and supplemental oxygen requirement at rest values. In addition, a larger proportion of patients with PH was African American, male, had diabetes, and received bilateral LTx compared with single LTx. Comparing PAmean < 25 vs >= 25 mm Hg and PAsystolic < 35 vs >= 35 mm Hg, median survival in months was 60.4 (95% confidence interval [CI], 55.2-80.4) vs 61.4 (95% CI, 56.9-66.9; log-rank p = 0.876) and 57.6 (95% CI, 50.9-68.0) vs 64.3 (95% CI, 57.5-71.3; log-rank p = 0. 247), respectively. Hazard ratios for both definitions of PH from univariable and multivariable Cox proportional hazard models were close to 1 and none were statistically significant. CONCLUSIONS: On the basis of our models and despite PH being prevalent, there is no strong evidence suggesting that PH significantly alters the risk of death in IPF patients after LTx. PMID- 25444372 TI - Outcome of cardiac transplantation in patients requiring prolonged continuous flow left ventricular assist device support. AB - OBJECTIVE: This study assessed the early and late outcomes after cardiac transplantation in patients receiving long-term continuous-flow left ventricular assist device (CF-LVAD) support. METHODS: Between April 2004 and September 2013, 192 patients underwent HeartMate II (Thoratec, Pleasanton, CA) CF-LVAD placement as a bridge to transplant at our center. Of these, 122 (63%) successfully bridged patients were retrospectively reviewed. Patients were stratified into 2 groups according to their waiting time with CF-LVAD support of <1 year or >=1 year. RESULTS: The study cohort was a mean age of 54 +/- 13 years, 79% were male, and 35% had an ischemic etiology. The mean duration of CF-LVAD support before transplantation was 296 days (range, 27-1,413 days). The overall 30-day mortality was 4.1%. Overall post-transplant survival was 88%, 84%, 78% at 1, 3, and 5 years, respectively. The 32 patients (26%) with >=1 year of CF-LVAD support (mean, 635 days) were more likely to have blood type O, a larger body size, and to have been readmitted due to recurrent heart failure and device failure requiring exchange than those with <1 year of CF-LVAD support. Patients who required prolonged support time also had worse in-hospital mortality (16% vs 6.7%, p = 0.12) and significantly lower survival at 3 years after transplantation (68% vs 88%, p = 0.049). CONCLUSIONS: The overall short-term and long-term cardiac transplant outcomes of patients supported with CF-LVAD are satisfactory. However, patients who require prolonged CF-LVAD support may have diminished post transplant survival due to adverse events occurring during device support. PMID- 25444373 TI - Biomarkers in advanced heart failure--pathophysiology leading to clinical use? PMID- 25444374 TI - Perceptions and experiences of community members on caring for preterm newborns in rural Mangochi, Malawi: a qualitative study. AB - BACKGROUND: The number of preterm birth is increasing worldwide, especially in low income countries. Malawi has the highest incidence of preterm birth in the world, currently estimated at 18.1 percent. The aim of this study was to explore the perceived causes of preterm birth, care practices for preterm newborn babies and challenges associated with preterm birth among community members in Mangochi District, southern Malawi. METHODS: We conducted 14 focus group discussions with the following groups of participants: mothers (n = 4), fathers (n = 6) and grandmothers (n = 4) for 110 participants. We conducted 20 IDIs with mothers to preterm newborns (n = 10), TBAs (n = 6) and traditional healers (n = 4). A discussion guide was used to facilitate the focus group and in-depth interview sessions. Data collection took place between October 2012 and January 2013. We used content analysis to analyze data. RESULTS: Participants mentioned a number of perceptions of preterm birth and these included young and old maternal age, heredity, sexual impurity and maternal illness during pregnancy. Provision of warmth was the most commonly reported component of care for preterm newborns. Participants reported several challenges to caring for preterm newborns such as lack of knowledge on how to provide care, poverty, and the high time burden of care leading to neglect of household, farming and business duties. Women had the main responsibility for caring for preterm newborns. CONCLUSION: In this community, the reported poor care practices for preterm newborns were associated with poverty and lack of knowledge of how to properly care for these babies at home. Action is needed to address the current care practices for preterm babies among the community members. PMID- 25444375 TI - The clinical utility of pain classification in non-specific arm pain. AB - Mechanisms-based pain classification has received considerable attention recently for its potential use in clinical decision making. A number of algorithms for pain classification have been proposed. Non-specific arm pain (NSAP) is a poorly defined condition, which could benefit from classification according to pain mechanisms to improve treatment selection. This study used three published classification algorithms (hereafter called NeuPSIG, Smart, Schafer) to investigate the frequency of different pain classifications in NSAP and the clinical utility of these systems in assessing NSAP. Forty people with NSAP underwent a clinical examination and quantitative sensory testing. Findings were used to classify participants according to three classification algorithms. Frequency of pain classification including number unclassified was analysed using descriptive statistics. Inter-rater agreement was analysed using kappa coefficients. NSAP was primarily classified as 'unlikely neuropathic pain' using NeuPSIG criteria, 'peripheral neuropathic pain' using the Smart classification and 'peripheral nerve sensitisation' using the Schafer algorithm. Two of the three algorithms allowed classification of all but one participant; up to 45% of participants (n = 18) were categorised as mixed by the Smart classification. Inter-rater agreement was good for the Schafer algorithm (k = 0.78) and moderate for the Smart classification (k = 0.40). A kappa value was unattainable for the NeuPSIG algorithm but agreement was high. Pain classification was achievable with high inter-rater agreement for two of the three algorithms assessed. The Smart classification may be useful but requires further direction regarding the use of clinical criteria included. The impact of adding a pain classification to clinical assessment on patient outcomes needs to be evaluated. PMID- 25444376 TI - Estimating Cardiovascular Risk in Spain by the European Guidelines on Cardiovascular Disease Prevention in Clinical Practice. AB - INTRODUCTION AND OBJECTIVES: There are no nationwide, population-based studies in Spain assessing overall cardiovascular risk. We aimed to describe cardiovascular risk and achievement of treatment goals following the 2012 European Guidelines on cardiovascular disease prevention strategy. We also investigated clinical characteristics (non-classical risk factors) associated with moderate risk. METHODS: Participants (n=2310, 58% women) aged 40 to 65 years from a national population-based study (Di@bet.es Study) were identified. First, a priori high/very-high risk individuals were identified. Next, total cardiovascular risk (Systematic Coronary Risk Evaluation equation including high-density lipoprotein cholesterol) was used to assess risk of a priori non-high risk individuals. Variables independently associated with moderate versus low-risk were investigated by multiple logistic regression analysis. RESULTS: Age-and-sex standardized (direct method) percentages of high/very-high, moderate, and low risk were 22.8%, 43.5%, and 33.7%, respectively. Most men were at moderate (56.2%), while 55.4% of women were at low risk. Low-density lipoprotein cholesterol (< 70,<100, < 115 mg/dL) and blood pressure (<140/90 mmHg) goals for very-high, high and moderate risk were met in 15%, 26% and 46%, and 77%, 68% and 85% of the individuals, respectively. Body mass index, high triglycerides concentrations, diastolic blood pressure, and low Mediterranean diet adherence (in women) were independently associated with moderate (versus low) risk. CONCLUSIONS: Cardiovascular risk in Spain is mainly moderate in men and low in women. Achievement of treatment goals in high-risk individuals should be improved. The prevalence of non-classical cardiovascular risk factors is elevated in subjects at moderate risk, an important aspect to consider in a population based strategy to decrease cardiovascular disease in the most prevalent group. PMID- 25444378 TI - Left ventricular pseudoaneurysm following thoracic aorta replacement. PMID- 25444377 TI - Sex-related Impact on Clinical Outcome of Everolimus-eluting Versus Bare-metal Stents in ST-segment Myocardial Infarction. Insights From the EXAMINATION Trial. AB - INTRODUCTION AND OBJECTIVES: The use of second-generation drug-eluting stents compared with bare-metal stents in patients with ST-segment elevation myocardial infarction reduces the rate of major adverse cardiac events. We aimed to evaluate the impact of sex on the performance of everolimus-eluting stents vs bare-metal stents in ST-segment elevation myocardial infarction at 2-year follow-up. METHODS: This is a sub-study of the EXAMINATION trial that randomized 1498 patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention to everolimus-eluting or bare-metal stents. Primary end point was combined all-cause death, any recurrent myocardial infarction, and any revascularization. All end points were analyzed according to sex at 2-year follow up. RESULTS: Of 1498 patients included in the trial, 254 (17.0%) were women. Women were older and had higher prevalence of hypertension and lower prevalence of smoking compared with men. In contrast with men, stent diameter was smaller in women. After multivariate analysis, the primary end point was similar between women and men (hazard ratio=0.95; 95% confidence interval, 0.66-1.37), and among women, between those treated with bare-metal vs everolimus-eluting stents (hazard ratio=2.48; 95% confidence interval, 0.95-6.46). Women showed a lower rate of repeat revascularization than men (hazard ratio=0.55; 95% confidence interval, 0.32-0.95) despite worse baseline characteristics. This difference was driven by better performance of the everolimus-eluting stent in women. CONCLUSIONS: Despite poorer baseline clinical characteristics, women with ST-segment elevation myocardial infarction treated with percutaneous coronary intervention showed outcomes similar to men. The use of everolimus-eluting stents may represent an added value in women as it showed a reduced rate of repeated revascularization compared to men. PMID- 25444379 TI - Polyphenol-enriched diet prevents coronary endothelial dysfunction by activating the Akt/eNOS pathway. AB - INTRODUCTION AND OBJECTIVES: The Mediterranean diet, rich in polyphenols, has shown to be cardioprotective. However the mechanisms involved remain unknown. We investigated whether supplementation with a pomegranate extract rich in polyphenols renders beneficial effects on coronary function in a clinically relevant experimental model and characterized the underlying mechanisms. METHODS: Pigs were fed a 10-day normocholesterolemic or hypercholesterolemic diet. Half of the animals were given a supplement of 625 mg/day of a pomegranate extract (Pomanox; 200 mg punicalagins/day). Coronary responses to escalating doses of vasoactive drugs (acetylcholine, calcium ionophore, and sodium nitroprusside) and L-NG-monomethylarginine (endothelial nitric oxide-synthase inhibitor) were measured using flow Doppler. Akt/endothelial nitric oxide-synthase axis activation, monocyte chemoattractant protein-1 expression, oxidative deoxyribonucleic acid damage in the coronary artery, and lipoprotein resistance to oxidation were evaluated. RESULTS: In dyslipidemic animals, Pomanox supplementation prevented diet-induced impairment of endothelial relaxation, reaching vasodilatory values comparable to normocholesterolemic animals upon stimulation with acetylcholine and/or calcium ionophore. These beneficial effects were associated with vascular Akt/endothelial nitric oxide-synthase activation and lower monocyte chemoattractant protein-1 expression. Pomanox supplementation reduced systemic oxidative stress (higher high-density lipoprotein-antioxidant capacity and higher low-density lipoprotein resistance to oxidation) and coronary deoxyribonucleic acid damage. Normocholesterolemic animals elicited similar drug related vasodilation regardless of Pomanox supplementation. All animals displayed a similar vasodilatory response to sodium nitroprusside and L-NG monomethylarginine blunted all vasorelaxation responses except for sodium nitroprusside. CONCLUSIONS: Pomanox supplementation hinders hyperlipemia-induced coronary endothelial dysfunction by activating the Akt/endothelial nitric oxide synthase pathway and favorably counteracting vascular inflammation and oxidative damage. PMID- 25444380 TI - Restratification at time of implantable cardioverter defibrillator replacement. PMID- 25444381 TI - Paclitaxel-eluting stents in ST-segment elevation myocardial infarction. PMID- 25444382 TI - Therapeutic strategy in patients with severe anemia admitted for non-ST-segment elevation acute coronary syndrome and prognostic impact. PMID- 25444383 TI - Early treatment of refractory cardiogenic shock with percutaneous veno-arterial ECMO implanted in the cardiac catheterization laboratory. PMID- 25444384 TI - Initial experience with a new ablation catheter using laser energy for electrical pulmonary vein isolation. PMID- 25444385 TI - Comments on Long-term results of cryoballoon ablation in the treatment of atrial fibrillation in a low-volume center. PMID- 25444386 TI - Fat phobia among first and fifth year medical students in Tijuana, Mexico. PMID- 25444387 TI - Predictors of having heard about human papillomavirus vaccination: Critical aspects for cervical cancer prevention among Colombian women. AB - OBJECTIVES: To determine whether the probability of having heard about human papillomavirus (HPV) vaccination differs by socio-demographic characteristics among Colombian women; and whether the effect of predictors of having heard about HPV vaccination varies by educational levels and rural/urban area of residence. METHODS: Data of 53,521 women aged 13-49 years were drawn from the 2010 Colombian National Demographic and Health Survey. Women were asked about aspects of their health and their socio-demographic characteristics. A logistic regression model was used to identify factors associated with having heard about HPV vaccination. Educational level and rural/urban area of residence of the women were tested as modifier effects of predictors. RESULTS: 26.8% of the women had heard about HPV vaccination. The odds of having heard about HPV vaccination were lower among women: in low wealth quintiles, without health insurance, with subsidized health insurance, and those who had children (p<0.001). Although women in older age groups and with better education had higher probabilities of having heard about HPV vaccination, differences in these probabilities by age group were more evident among educated women compared to non-educated ones. Probability gaps between non-educated and highly educated women were wider in the Eastern region. Living in rural areas decreased the probability of having heard about HPV vaccination, although narrower rural/urban gaps were observed in the Atlantic and Amazon-Orinoquia regions. CONCLUSIONS: Almost three quarters of the Colombian women had not heard about HPV vaccination, with variations by socio-demographic characteristics. Women in disadvantaged groups were less likely to have heard about HPV vaccination. PMID- 25444388 TI - [A step back in air pollution: automotive industry news]. PMID- 25444389 TI - [Physical inactivity in Galicia (Spain): trends and the impact of changes in the definition]. AB - OBJECTIVE: To estimate the prevalence of physical inactivity during leisure time in Galicia (Spain) between 2007 and 2011 and to assess the impact of including non-leisure time activities in the definition of physical inactivity. METHODS: A cross-sectional study was conducted in the population aged 16 years and older (n=19,235). Physical activity was assessed by the Minnesota Questionnaire. In 2011, inactivity was estimated by including daily activities. RESULTS: Between 2007 and 2011, the prevalence of inactivity in Galicia remained stable (p=0.249) and close to 50%. This prevalence was higher among women and those who worked or were in education. Inactivity decreased from 47% to 16% when non-leisure time activities were included in the definition. CONCLUSIONS: Between 2007 and 2011 in Galicia, the prevalence of inactivity remained high and stable. This prevalence was significantly decreased when non-leisure time activities were included in the definition. PMID- 25444390 TI - The measurement of social capital. AB - Social capital has been defined as the resources available to individuals and groups through membership in social networks. The definition is consistent with either an individualistic approach, i.e. resources (such as information or instrumental assistance) that are accessed by individuals through their network connections; or a collective approach, e.g. the benefits accruing to members of a group - such as the ability of a community to engage in collective action - as a consequence of the existence of cohesive relationships. While research often restricts itself to a single level of analysis, the benefits (and downsides) of social capital accrue to both the individual as well as to the network to which he belongs. In the Dictionary of Epidemiology both the individual and collective levels of analysis were recognized in the definition of social capital. PMID- 25444391 TI - Effectiveness of an electronic hand hygiene monitoring system on healthcare workers' compliance to guidelines. AB - Hand hygiene is a growing concern among populations and is a crucial element in ensuring patient safety in a healthcare environment. Numerous management efforts have been conducted in that regard, including education, awareness and observations. To better evaluate the possible impact of technology on a healthcare setting, we observed the impact of a particular niche technology developed as an answer to the growing hand hygiene concerns. A study was conducted at Salmaniya Medical Complex (SMC) in Bahrain on a total of 16 Coronary Care Unit (CCU) beds where the system was installed, and the hand hygiene activity of healthcare workers (HCWs) in this area was monitored for a total period of 28 days. Comments, remarks and suggestions were noted, and improvements were made to the technology during the course of the trial. While resistance to change was significant, overall results were satisfactory. Compliance with hand hygiene techniques went from 38-42% to 60% at the beginning of the trial and then increased to an average of 75% at the end of the 28-day trial. In some cases, compliance peaked at 85% or even at 100%. Our case study demonstrates that technology can be used effectively in promoting and improving hand hygiene compliance in hospitals, which is one way to prevent cross-infections, especially in critical care areas. PMID- 25444392 TI - Incidence and attributable costs of ventilator-associated pneumonia (VAP) in a tertiary-level intensive care unit (ICU) in northern India. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is the most common nosocomial infection acquired by patients in the intensive care unit (ICU). However, the economic effects of such infections remain unclear particularly in developing countries. METHODS: Patients who were mechanically ventilated for more than 48 h in the ICU were studied for the occurrence of VAP. Total drug costs and hospital costs were noted, and attributable costs were calculated after adjusting for potential confounders. RESULTS: Ninety-five (38%) patients who were ventilated for more than 48 h developed VAP, which resulted in an incidence of 40.1 VAP infections/1000 mechanical ventilation days. The patients with VAP experienced significantly longer hospital stay [21 (IQ = 14-33) days versus 11 (IQ = 6-18) days, P < 0.0001)] and incurred greater hospital costs [USD $6250.92 (IQ = 3525.39-9667.57) versus $2598.84 (IQ = 1644.33-4477.65), P < 0.0001]. Multiple regression analysis revealed that the cost-driving factors in our study population were the occurrence of VAP infections (P < 0.0001) and the duration of hospital stay (P < 0.0001). The attributable cost of VAP infection was calculated to be USD $5200 (95% CI = 3245-7152). CONCLUSION: We conclude that VAP significantly increases the costs of treatment in low-income developing countries. This study highlights the need to implement urgent measures to reduce the incidence of this disease in ICUs. PMID- 25444393 TI - 18F-FDG PET/CT imaging in blow-out metastases of clavicle from carcinoma of urinary bladder. PMID- 25444394 TI - Fever of unknown origin (FUO) due to deep-venous thrombosis: diagnostic importance of FDG PET/CT. PMID- 25444395 TI - Enterovirus D68: the unexpected guest. PMID- 25444396 TI - Emergence of a hypervirulent neonatal pathogen. PMID- 25444397 TI - Digital surveillance for enhanced detection and response to outbreaks. PMID- 25444398 TI - Investment in pneumonia and pneumococcal research. PMID- 25444399 TI - The Caribbean response to chikungunya. PMID- 25444400 TI - Hand, foot, and mouth disease in mainland China. PMID- 25444401 TI - Hand, foot, and mouth disease in mainland China. PMID- 25444402 TI - Hand, foot, and mouth disease in mainland China--authors' reply. PMID- 25444403 TI - Hand, foot, and mouth disease in mainland China. PMID- 25444404 TI - Atypical hand, foot, and mouth disease: eczema coxsackium can also occur in adults. PMID- 25444405 TI - Raltegravir and rifampicin in patients with HIV and tuberculosis. PMID- 25444406 TI - Raltegravir and rifampicin in patients with HIV and tuberculosis. PMID- 25444407 TI - Incidence of invasive group B streptococcal disease and pathogen genotype distribution in newborn babies in the Netherlands over 25 years: a nationwide surveillance study. AB - BACKGROUND: Group B streptococcus is the most common cause of neonatal infections. We studied the clinical and molecular epidemiology of invasive group B streptococcus infection in children younger than 3 months in the Netherlands over 25 years. We assessed the effect of the Dutch guidelines, introduced in 1999, for prevention of group B streptococcus, consisting of intravenous antibiotic prophylaxis during labour in cases of premature labour, prolonged rupture of membranes, or fever during delivery. METHODS: We did this nationwide surveillance study with data from 1987 to 2011, from the Netherlands Reference Laboratory for Bacterial Meningitis. We included data for patients aged 3 months or younger with positive blood culture or cerebrospinal fluid culture for group B streptococcus and Escherichia coli infection. Early onset was defined as less than 7 days after birth and late onset was defined as 7 or more days after birth. We did multilocus sequence typing of a random subset of group B streptococcus samples to assess changes in sequence type (Mann-Kendall trend test) and the distribution of clonal complexes (chi(2) and Fisher exact test) before the introduction of prevention guidelines (1987-99) and afterwards (2000-11). We compared incidences and the distribution of clonal complexes before and after the introduction of guidelines. FINDINGS: Most cases of group B streptococcus had early onset (696/1075; 65%). The incidence of invasive group B streptococcus infection increased from 0.20 per 1000 livebirths in 1987, to 0.32 per 1000 livebirths in 2011 (p<0.0001). The incidence of early-onset disease increased from 0.11 per 1000 livebirths to 0.19 per 1000 livebirths (p<0.0001). The incidence of invasive Escherichia coli infection was 0.05 in 1987, and 0.16 in 2011 (p=0.17). Early-onset group B streptococcus infection caused by isolates belonging to clonal complex 17 was more common in the post-implementation period than in the pre-implementation period (p=0.002). INTERPRETATION: The introduction of prevention guidelines for invasive group B streptococcus disease in 1999 did not reduce the incidence of disease in neonates. The guidelines should be reassessed and alternative approaches to prevent infant invasive group B streptococcus disease should be sought. FUNDING: National Institute of Public Health and the Environment, the European Union's seventh framework programme, Netherlands Organization for Health Research and Development, Academic Medical Center, and the European Research Council. PMID- 25444408 TI - A review of the neurobiological basis of dyslexia in the adult population. AB - INTRODUCTION: Adult dyslexia affects about 4% of the population. However, studies on the neurobiological basis of dyslexia in adulthood are scarce compared to paediatric studies. AIM: This review investigates the neurobiological basis of dyslexia in adulthood. DEVELOPMENT: Using PsycINFO, a database of psychology abstracts, we identified 11 studies on genetics, 9 neurostructural studies, 13 neurofunctional studies and 24 neurophysiological studies. Results from the review show that dyslexia is highly heritable and displays polygenic transmission. Likewise, adult neuroimaging studies found structural, functional, and physiological changes in the parieto-occipital and occipito-temporal regions, and in the inferior frontal gyrus, in adults with dyslexia. CONCLUSION: According to different studies, aetiology in cases of adult dyslexia is complex. We stress the need for neurobiological studies of dyslexia in languages with transparent spelling systems. PMID- 25444409 TI - Effects of morphine on brain plasticity. AB - INTRODUCTION: Morphine shares with other opiates and drugs of abuse the ability to modify the plasticity of brain areas that regulate the morphology of dendrites and spines, which are the primary sites of excitatory synapses in regions of the brain involved in incentive motivation, rewards, and learning. OBJECTIVE: In this review we discuss the impact of morphine use during the prenatal period of brain development and its long-term consequences in murines, and then link those consequences to similar effects occurring in human neonates and adults. DEVELOPMENT: Repeated exposure to morphine as treatment for pain in terminally ill patients produces long-term changes in the density of postsynaptic sites (dendrites and spines) in sensitive areas of the brain, such as the prefrontal cortex, the limbic system (hippocampus, amygdala), and caudate nuclei and nucleus accumbens. This article reviews the cellular mechanisms and receptors involved, primarily dopaminergic and glutamatergic receptors, as well as synaptic plasticity brought about by changes in dendritic spines in these areas. CONCLUSIONS: The actions of morphine on both developing and adult brains produce alterations in the plasticity of excitatory postsynaptic sites of the brain areas involved in limbic system functions (reward and learning). Doctors need further studies on plasticity in dendrites and spines and on signaling molecules, such as calcium, in order to improve treatments for addiction. PMID- 25444410 TI - [Unusual complication in a paediatric patient: Wernicke encephalopathy associated with thiamine-deficient parenteral nutrition]. PMID- 25444411 TI - Clinical evaluation of rituximab treatment for neuromyelitis optica. AB - INTRODUCTION: Neuromyelitis optica is an inflammatory and usually relapsing demyelinating autoimmune disease of the central nervous system that targets the optic nerves and spinal cord. Rituximab has been used for different neurological diseases that are probably immune-mediated or involving humoural immunity. The objective of this study is to evaluate the efficacy and safety of rituximab as treatment for neuromyelitis optica in a tertiary hospital. METHODS: Retrospective study of patients with neuromyelitis optica treated with rituximab 1000mg on days 1 and 15, repeated every 6 to 8 months. We recorded EDSS score, relapse rate, overall condition, CD19+ count, presence of anti-NMO antibodies, and possible adverse reactions. RESULTS: Six patients were treated; all were women with a median age of 46 years (range, 38-58). Anti-NMO antibodies were detected in 3 patients (50%). Baseline EDSS was 4 (range 2.0-5.5). Two patients had previously been treated with an immunomodulatory drug. Median time from the first rituximab infusion to first relapse was 3.7 years (range 1.7-6.9). Two patients had infusion reactions after the first dose of rituximab. Four patients remained relapse-free and their EDSS score did not progress during rituximab treatment, one patient showed no clinical improvement, and one patient could not be evaluated. CONCLUSION: Rituximab can be considered an attractive therapeutic alternative for patients with neuromyelitis optica as there are no approved treatments for this disease. Further studies with rituximab are needed to establish the role of this drug in treating neuromyelitis optica. PMID- 25444412 TI - Sexsomnia and sleep eating secondary to sodium oxybate consumption. PMID- 25444414 TI - Refractory neuralgia of the superior laryngeal nerve: A case study. PMID- 25444413 TI - Estimated prevalence of dementia based on analysis of drug databases in the Region of Madrid (Spain). AB - INTRODUCTION: The progressive rise in dementia prevalence increases the need for rapid methods that complement population-based prevalence studies. OBJECTIVE: To estimate the prevalence of dementia in the population aged 65 and older based on use of cholinesterase inhibitors and memantine. METHODS: Descriptive study of use and prescription of cholinesterase inhibitors and/or memantine in 2011 according to 2 databases: Farm@drid (pharmacy billing records for the Region of Madrid) and BIFAP (database for pharmacoepidemiology research in primary care, with diagnosis and prescription records). We tested the comparability of drug use results from each database using the chi-square test and prevalence ratios. The prevalence of dementia in Madrid was estimated based on the dose per 100 inhabitants/day, adjusting the result for data obtained from BIFAP on combination treatment in the general population (0.37%) and the percentage of dementia patients undergoing treatment (41.13%). RESULTS: Cholinesterase inhibitors and memantine were taken by 2.08% and 0.72% of Madrid residents aged 65 and older was respectively. Both databases displayed similar results for use of these drugs. The estimated prevalence of dementia in individuals aged 65 and older is 5.91% (95% CI%, 5.85 5.95) (52 287 people), and it is higher in women (7.16%) than in men (4.00%). CONCLUSIONS: The estimated prevalence of dementia is similar to that found in population-based studies. Analysing consumption of specific dementia drugs can be a reliable and inexpensive means of updating prevalence data periodically and helping rationalise healthcare resources. PMID- 25444415 TI - Atypical site and size of atrial myxoma. PMID- 25444416 TI - Neck arthritis pain is reduced and range of motion is increased by massage therapy. AB - BACKGROUND: The literature on the effects of massage therapy on neck arthritis pain is mixed depending on the dose level, and it is also based on self-report. In the present study an attempt was made to enhance the effects of weekly massage therapy by having the participants massage themselves daily. And in addition to self-reports on pain, range of motion (ROM) and the associated ROM pain were assessed before and after the first massage session and pre-post the last session one month later. METHODS: Staff and faculty members at a medical school who were eligible for the study if they had neck arthritis pain were randomly assigned to a massage or a waitlist control group (N = 24 per group). The massage group received moderate pressure massages weekly by a massage therapist plus daily self massages. The waitlist control group received the same schedule massages one month after being control subjects. RESULTS: The massage group showed significant short-term reductions after the first and last day massages in self-reported pain and in ROM-associated pain as well as an increase in ROM. Comparisons between the massage group (N = 23) and the control group (N = 14) on the last versus the first day data suggested significantly different changes including increased ROM and reduced ROM-associated pain for the massage group and reduced ROM and increased ROM-associated pain for the control group. These changes occurred specifically for flexion and right and left lateral flexion motions. DISCUSSION: These data highlight the importance of designing massage therapy protocols that target the most affected neck muscle groups and then assessing range of motion and related pain before and after the massage therapy. Comparisons with other studies also suggest that moderate pressure may contribute to the massage effects, and the use of daily self-massages between sessions may sustain the effects and serve as a cost-effective therapy for individuals with neck arthritis pain. PMID- 25444417 TI - Recent advances of genomic testing in perinatal medicine. AB - Rapid progress in genomic medicine in recent years has made it possible to diagnose subtle genetic abnormalities in a clinical setting on routine basis. This has allowed for detailed genotype-phenotype correlations and the identification of the genetic basis of many congenital anomalies. In addition to the availability of chromosomal microarray analysis, exome and whole-genome sequencing on pre- and postnatal samples of cell-free DNA has revolutionized the field of prenatal diagnosis. Incorporation of these technologies in perinatal pathology is bound to play a major role in coming years. In this communication, we briefly present the current experience with use of classical chromosome analysis, fluorescence in situ hybridization, and microarray testing, development of whole-genome analysis by next-generation sequencing technology, offer a detailed review of the history and current status of non-invasive prenatal testing using cell-free DNA, and discuss the advents of these new genomic technologies in perinatal medicine. PMID- 25444418 TI - Iatrogenic injury and unexpected hospital death in the newborn. AB - Neonates are unusually vulnerable to iatrogenic injury due to small body size, delicate tissues, and immature immune systems. Investigation of an unexpected neonatal death in the hospital should begin with a review of the medical record and discussion with medical staff involved in the patient's care. Postmortem investigation should include a complete and well-documented autopsy. Additional investigations, such as microbiological studies and chemical and toxicological studies of postmortem and antemortem fluid samples, may be crucial in arriving at a diagnosis. Causes of iatrogenic injury include birth trauma, medication errors and adverse drug effects, hospital-acquired infection, and medical device malfunction, incorrect placement, and misuse. Autopsy is an important tool for understanding the cause of an unexpected death, improving the quality of care, and providing closure to parents and family. PMID- 25444419 TI - Multicentre research gets into training. PMID- 25444421 TI - Opportunity cost of unavailable surgical instruments in Australian hospitals. PMID- 25444420 TI - Diagnosis from a distance: the case of J.S. Bach. PMID- 25444422 TI - Medicine in small doses. PMID- 25444424 TI - Re: Bach and His. PMID- 25444425 TI - Re: Are you and your patients safe from a surgical fire? PMID- 25444423 TI - Liver surgery in the multidisciplinary management of gastrointestinal stromal tumour. AB - BACKGROUND: After the introduction of tyrosine kinase inhibitors (TKIs), the role of surgical resection in treating liver metastasis from gastrointestinal stromal tumour (GIST) is unclear. In this study, we evaluated the outcome of patients treated with TKIs followed by surgery for metastatic GIST. METHODS: Eleven patients who underwent liver resection after downsizing TKIs therapy for metastatic GIST from 2006 until 2010 were reviewed. RESULTS: One and 2-year overall survival (OS) rates were 80.8% and 70.7%. All patients with an initially resectable tumour were still alive without recurrence. Patients operated on clinical response had a better outcome (1-year and 2-year OS rate of 100%) than those operated on disease progression (1-year and 2-year OS rates of 60% and 40%; P = 0.043). No deaths were observed among patients who achieved an R0 resection (R0 versus R1/R2, P = 0.001). CONCLUSION: R0 resection and clinical response to TKI are predictors of survival. Surgical resection should be performed as soon as feasible in responder patients. In poor responders, surgery may not add any survival benefit, except in localized progressive disease. In resectable metastatic liver disease, preoperative TKIs or upfront surgery followed by adjuvant therapy could be considered. Larger studies are needed to determine the optimum approach in patients with metastatic GIST. PMID- 25444426 TI - Trends in the management of local complications of acute pancreatitis in Australia. PMID- 25444427 TI - Re: Do medical procedures in the arm increase the risk of lymphoedema after axillary surgery? A review. PMID- 25444428 TI - Re: Utility of inguinal incision in retroperitoneoscopic live donor nephrectomy. PMID- 25444429 TI - Re: Epidemiology of traumatic head injury from a major paediatric trauma centre in New South Wales, Australia. PMID- 25444430 TI - Re: Are Australian and New Zealand trauma service resources reflective of the Australasian Trauma Verification Model Resource Criteria? PMID- 25444431 TI - [Small cell neuroendocrine carcinoma of the vulva]. AB - Neuroendocrine small cell carcinoma of the vulva is a rare and aggressive cancer with a pejorative behavior. Because it is rare, there is no consensus to date. We report the fourteenth case of a 52-year-old woman with neuroendocrine small cell carcinoma of the vulva, treated by surgery and combined chemoradiotherapy 46 Gy and cisplatinum-etoposide and adjuvant chemotherapy. Twelve months after the diagnosis, she is alive with no evidence of disease recurrence. A review of the literature on this topic is also presented. PMID- 25444432 TI - Efficacy of intravenous immunoglobulin for treatment of Lambert-Eaton myasthenic syndrome without anti-presynaptic P/Q-type voltage-gated calcium channel antibodies: a case report. AB - We evaluated the efficacy of intravenous immunoglobulin (IVIg) in a patient with Lambert-Eaton myasthenic syndrome (LEMS). Comprehensive clinical and electrophysiological testing was performed on a 34-year-old woman with progressive limb weakness, before and after IVIg treatment. Neurological examination revealed muscle weakness, predominantly in the proximal parts of the limbs. Muscle weakness improved following a short period of maximum voluntary muscle contraction. A repetitive low-rate (3-Hz) nerve stimulation test of the abductor hallucis was normal, but high-rate (20-Hz) stimulation induced an incremental response. Anti-presynaptic P/Q-type voltage-gated calcium channel (P/Q-VGCC) antibodies were absent in the patient's serum. Whole body computed tomography revealed no tumors. We diagnosed seronegative LEMS without tumor and treated the patient with IVIg. Both clinical and electrophysiological indices improved gradually after treatment. This case study indicates that treatment with IVIg is equally effective for LEMS that is seronegative or seropositive for P/Q VGCC antibodies. PMID- 25444433 TI - Implantation of a left ventricular assist device as a destination therapy in Duchenne muscular dystrophy patients with end stage cardiac failure: management and lessons learned. AB - Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, characterized by progressive skeletal muscle weakness, loss of ambulation, and death secondary to cardiac or respiratory failure. End-stage dilated cardiomyopathy (DCM) is a frequent finding in DMD patients, they are rarely candidates for cardiac transplantation. Recently, the use of ventricular assist devices as a destination therapy (DT) as an alternative to cardiac transplantation in DMD patients has been described. Preoperative planning and patient selection play a significant role in the successful postoperative course of these patients. We describe the preoperative, intraoperative and postoperative management of Jarvik 2000 implantation in 4 DMD pediatric (age range 12-17 years) patients. We also describe the complications that may occur. The most frequent were bleeding and difficulty in weaning from mechanical ventilation. Our standard protocol includes: 1) preoperative multidisciplinary evaluation and selection, 2) preoperative and postoperative non-invasive ventilation and cough machine cycles, 3) intraoperative use of near infrared spectroscopy (NIRS) and transesophageal echocardiography, 4) attention on surgical blood loss, use of tranexamic acid and prothrombin complexes, 5) early extubation and 6) avoiding the use of nasogastric feeding tubes and nasal temperature probes. Our case reports describe the use of Jarvik 2000 as a destination therapy in young patients emphasizing the use of ventricular assist devices as a new therapeutic option in DMD. PMID- 25444434 TI - A novel homozygous ISPD gene mutation causing phenotype variability in a consanguineous family. AB - Within the group of muscular dystrophies, dystroglycanopathies represent an important subgroup of recessively inherited disorders. Their severity varies from the relatively mild forms of adult-onset limb-girdle muscular dystrophy (LGMD), to the severe congenital muscular dystrophies (CMD) with cerebral and ocular involvement. We describe 2 consanguineous children of Pakistani origin, carrying a new homozygous missense mutation c.367G>A (p.Gly123Arg) in the ISPD gene. Mutations in this gene have been recently reported as a common cause of congenital and limb-girdle muscular dystrophy. Patient 1 is an 8-year-old female with an intermediate phenotype between CMD and early LGMD; patient 2 is a 20 month-old male and second cousin of patient 1, showing a CMD phenotype. Cognitive development, brain MRI, eye examination, electrocardiogram and echocardiogram were normal in both patients. To our knowledge, this is the first report on the co-occurrence of both a CMD/early LGMD intermediate phenotype and a CMD within the same family carrying a homozygous ISPD mutation. PMID- 25444439 TI - Is there a role for the development of a supra-regional network for the management of penile cancer in the Republic of Ireland? AB - INTRODUCTION: There is an average of 25 cases of penile cancer in the Republic of Ireland each year. Due to the low volume of cases, the National Institute for Clinical Excellence recommends that treatment is centralised to allow the best standardised treatment for primary tumours and nodal disease. OBJECTIVES: To determine whether outcomes for patients with penile cancer differed significantly between secondary and tertiary referral centres in the Republic of Ireland. METHODS: Between 2001 and 2014, 36 patients were treated in the Mercy University Hospital (MUH) with penile cancer. Twenty patients were treated primarily in MUH and 16 patients underwent initial management in a secondary referral centre (SRC) with subsequent referral to the MUH. A retrospective matched case-control study was performed on this patient cohort. RESULTS: There were no significant differences in length of follow-up or risk factors for the development of penile cancer between both groups (p = 0.6 and p = 0.5 respectively) Ultimately, the incidence of high risk disease, nodal metasases, high grade disease and pelvic lymph node dissection were significantly greater in patients that were initially managed in a SRC (p = 0.02, p = 0.03, p = 0.004 and p = 0.028 respectively). Patients undergoing initial treatment in a SRC had a non-significantly reduced rate of cancer specific survival (88 Vs 66%, MUH Vs SRCs, p = 0.495) and recurrence free survival (85 Vs 46%, MUH Vs SRCs, p = 0.24). CONCLUSION: Our findings suggest that managing penile cancer in special interest centres may improve oncological outcome. PMID- 25444440 TI - One Step Nucleic Acid Amplification (OSNA) positive micrometastases and additional histopathological NSLN metastases: Results from a single institution over 53 months. AB - INTRODUCTION: The role of sentinel lymph node micrometastases on histopathological analysis is controversial in axillary staging and management in clinically node negative breast cancer. Long-term studies addressing the clinical relevance of occult breast cancer in sentinel lymph nodes based on molecular analysis are lacking. One Step Nucleic Acid Amplification (OSNA), a highly sensitive assay of cytokeratin 19 mRNA, is used intra-operatively for the detection of lymph node macro- and micrometastases in breast cancer. AIM: The aim of this study is to review the rate of micrometastases and further histopathological NSLN metastases, in our unit following the introduction of OSNA in Guildford. METHODS: Data was collected prospectively from the period of introduction 01/12/2008 to 31/05/2013. All patients eligible for sentinel lymph node biopsy were offered OSNA and operations were performed by the consultant breast surgeons. Presence or absence of micro-metastases depends on the agreed cut-off point on the amplification curve. On detection of micrometastases (+) and positive but inhibited (i+) metastases, a level 1 axillary clearance (ANC) was performed and for a macrometastasis (++), a level 3 ANC was carried out. RESULTS: 66% of the patients had negative SLN (n = 672) and 34% (n = 336) had positive sentinel lymph nodes who had further axillary surgery. Of these, 45% (n = 152/336) had macrometastases, 40% (n = 136/336) had micrometastases and 15% (48/336) had positive but inhibited results. There was no difference in the patient demographics and tumour characteristics in the various positive SLN groups. In patients with micrometastases, 15% (20/136) had further positive NLSNs and a further 6% (8/136) had >4 overall positive nodes (SLN + NSLN) thus requiring adjuvant supraclavicular/chest wall radiotherapy (p < 0.05). 25% of node positive patients had further NLSN metastases (85/336) and in these patients, the ratio of positive SLN/harvested SLN (+SLN/SLN) is constant at 1:1. This shows the likelihood of further positive NSLNs if all the harvested lymph nodes are positive. This linear trend is present in both micro-and macrometastases, thus correlating with the size and number of NSLN metastases. CONCLUSION: Our study reflects the tumour burden of NSLNs based on the molecular analysis of the SLN. OSNA has the potential to accurately identify axillary micrometastases. Micro-metastases are important as some of the patients with micrometastases had overall four positive nodes [SLN + NSLN] (criteria for radiotherapy in the absence of other adverse clinicopathological features). Also, our study highlights certain factors that predict the NSLN metastases, pending validation by further prospective long-term data. This will allow accurate calculation of the axillary tumour burden, particularly in patients with micro metastases. PMID- 25444441 TI - Breast cancer in low and middle income countries (LMICs): a shifting tide in global health. AB - Cancer control planning has become a core aspect of global health, as rising rates of noncommunicable diseases in low-resource settings have fittingly propelled it into the spotlight. Comprehensive strategies for cancer control are needed to effectively manage the disease burden. As the most common cancer among women and the most likely reason a woman will die from cancer globally, breast cancer management is a necessary aspect of any comprehensive cancer control plan. Major improvements in breast cancer outcomes in high-income countries have not yet been mirrored in low-resource settings, making it a targeted priority for global health planning. Resource-stratified guidelines provide a framework and vehicle for designing programs to promote early detection, diagnosis, and treatment using existing infrastructure and renewable resources. Strategies for evaluating the current state and projecting future burden is a central aspect of developing national strategies for improving breast cancer outcomes at the national and international levels. PMID- 25444442 TI - Protective and risk factors for adolescent sleep: a meta-analytic review. AB - Teenagers need sufficient sleep to function well daily, yet consolidated evidence advising which factors protect, or harm, adolescents' sleep is lacking. Forty-one studies, published between 2003 and February, 2014, were meta-analysed. Mean weighted r values were calculated to better understand the strength of protective and risk factors for 85,561 adolescents' (age range = 12-18 y) bedtime, sleep onset latency (SOL) and total sleep time (TST). Results showed good sleep hygiene and physical activity were associated with earlier bedtimes. Video gaming, phone, computer and internet use, and evening light related to delayed bedtimes. Good sleep hygiene negatively correlated with sleep latency. Alternatively, sleep latency lengthened as a negative family environment increased. Tobacco, computer use, evening light, a negative family environment and caffeine were associated with decreased total sleep, whereas good sleep hygiene and parent-set bedtimes related to longer sleep length. Good sleep hygiene appears to be protective, whereas a negative home environment and evening light appear to be risk factors. Cautious use of technology (other than television), caffeine, tobacco and alcohol should be considered. These factors, along with pre-sleep worry, are likely to have some negative impact on sleep. Parent-set bedtimes and physical activity may be beneficial. Future research directions are discussed. PMID- 25444443 TI - Systematic chemical analysis of flavonoids in the Nelumbinis stamen. AB - The stamen of lotus, known as Nelumbinis stamen, has been used as the folk medicine and functional food for a long time, which showed good activities of anti-ulcer, anti-thrombosis, analgesic, anti-diarrhea, strengthen uterine contraction. The bioactivities of Nelumbinis stamen were attributed to the existence of flavonoids, its characteristic chemical constituents. A reliable method for comprehensive chemical analysis of flavonoids in Nelumbinis stamen by HPLC-DAD-MS was developed for the first time. The extraction protocol of flavonoids from Nelumbinis stamen was optimized by an orthogonal design. The chromatographic conditions were optimized, which exhibited similar level than that of the UHPLC platform allowing target compound identification in a shorter time with little solvent consumption. Moreover, similarity analysis, hierarchical clustering analysis and principal components analysis were successfully applied to demonstrate the variability of these Nelumbinis stamen samples. PMID- 25444444 TI - Evaluation of cytotoxicity and immune modulatory activities of soyasaponin Ab: an in vitro and in vivo study. AB - To improve the immune efficacy of protein subunit vaccines, novel adjuvants are needed to elicit a suitable protective immune response and to promote long term immunologic memory. In this work, soyasaponin Ab, a major constituent among group A soyasaponins in soybeans was purified and prepared from soy hypocotyls. The immunomodulatory effects of soyasaponin Ab both in vitro and in vivo were investigated, and its pro-immunomodulatory molecular mechanism was also studied. For in vitro assays, with mouse macrophage cell line RAW264.7 as the studying model, both cytotoxicity and immune stimulatory activity were investigated to evaluate the potential of soyasaponin Ab as the vaccine adjuvant. The results indicated that soyasaponin Ab could be significantly safer than Quillaja saponins (QS). Soyasaponin Ab showed no toxicities over the tested concentration ranges compared to QS. Soyasaponin Ab was proved able to promote releases of inflammatory cytokines like TNFalpha and IL-1beta in a dose-dependent manner. Furthermore, NF-kappaB signalling was also activated by soyasaponin Ab effectively. In addition, with TLR4 gene expression of RAW264.7 cell inhibited by RNA interference, immune stimulatory effects by soyasaponin Ab dropped down significantly. On the other hand, the in vivo experiment results showed that anti ovalbumin (OVA) IgG, IgG1, IgG2a, IgG2b were significantly enhanced by the soyasaponin Ab and QS groups (p<0.05 or p<0.01). The results suggested that compared to QS, soyasaponin Ab may represent a viable candidate for effective vaccine adjuvant. TLR4 receptor dependent pathway may be involved in immune stimulatory effects of soyasaponin Ab. PMID- 25444445 TI - DNA barcoding Chinese medicinal Bupleurum. AB - We tested 4 markers, namely nuclear internal transcribed spacer 2 (ITS2), psbA trnH, matK, and rbcL, to evaluate these candidate DNA barcodes for distinguishing Bupleuri radix (Chaihu) from its adulterants. 51 plant samples of Bupleurum representing 19 species were collected from different areas in China. Amplification and sequencing were attempted for all the 4 candidate barcode regions, whose validity was assessed in terms of the success rate of PCR amplification and sequencing, differential intra- and inter-specific divergences, DNA barcoding gap and the ability to discriminate species. The results showed that ITS2 had the best performance in identifying Bupleurum with an identification efficiency of 73.68%, which, after combining with psbA-trnH, increased to 83.33%. We further evaluated the efficiency of ITS2 for discriminating the species of Bupleurum using a large database from GenBank, which archived data of 223 samples from 74 species, and ITS2 successfully discriminated 64.13% of the samples at the species level. In conclusion, the ITS2 can serve as a potentially useful barcode for Bupleurum species, with psbA-trnH as a supplementary locus. PMID- 25444446 TI - The protective effect of the Cornus mas fruits (cornelian cherry) on hypertriglyceridemia and atherosclerosis through PPARalpha activation in hypercholesterolemic rabbits. AB - Cornelian cherry (Cornus mas L.) fruits have been used in traditional cuisine and in folk medicine in various countries. This study was conducted to evaluate the constituents and impact of cornelian cherry (C. mas L.) fruits lyophilisate on lipid levels, PPARalpha protein expression, atheromatous changes in the aorta, oxido-redox state, and proinflammatory cytokines in hypercholesterolemic rabbits. The HPLC-MS method was used for determining active constituents in cornelian cherry. In a subsequent in vivo study the protective effect of the cornelian cherry on diet-induced hyperlipidemia was studied using a rabbit model fed 1% cholesterol. Cornelian cherry (100mg/kg b.w.) or simvastatin (5mg/kg b.w.) were administered orally for 60 days. Two iridoids - loganic acid and cornuside - and five anthocyanins were identified as the main constituents of the cornelian cherry. The administering of the cornelian cherry led to a 44% significant decrease in serum triglyceride levels, as well as prevented development of atheromatous changes in the thoracic aorta. Cornelian cherry significantly increased PPARalpha protein expression in the liver, indicating that its hypolipidemic effect may stem from enhanced fatty acid catabolism. Simvastatin treatment did not affect PPAR-alpha expression. Moreover, the cornelian cherry had a significant protective effect on diet-induced oxidative stress in the liver, as well as restored upregulated proinflammatory cytokines serum levels. In conclusion, we have shown loganic acid to be the main iridoid constituent in the European cultivar of the cornelian cherry, and proven that the cornelian cherry could have protective effects on diet-induced hypertriglicerydemia and atherosclerosis through enhanced PPARalpha protein expression and via regulating oxidative stress and inflammation. PMID- 25444447 TI - [Lightning strike and lesions outside the brain: Clinical cases and a review of the literature]. AB - INTRODUCTION: Every year, 240,000 people are struck by lightning worldwide, causing injuries leading to significant handicaps. Most of the symptoms involve brain lesions; neuromuscular sequelae and myelopathy are less common. OBSERVATIONS: We describe five cases of patients struck by lightning with various clinical presentations. The first patient presented painful paresthesias in both upper limbs that disappeared 18 months later; the injury was a plexopathy. The second patient developed proximal weakness in the upper-left limb due to a myopathy. Two patients presented with various motor weaknesses in the lower limbs due to motor neuron disease and myelopathy. The last patient had a transient tetraplegy, which resolved in 5minutes; the diagnosis was keraunoparalysis. DISCUSSION: Lightning injuries can have many consequences depending on the different mechanisms involved. The clinical presentation is often due to a very focal lesion without any secondary extension. Motor neuron disease probably results from post-traumatic myelopathy. We discuss the ALS-electrocution association, frequently described in the literature. CONCLUSION: Various peripheral nerve and spinal cord lesions can be seen in lightning strike victims involving myelopathy, motor neuron, muscle and plexus. Clinical syndromes are often atypical but outcome is often favorable. PMID- 25444448 TI - Facial myokymia and autonomic synkinesis responsive to carbamazepine. PMID- 25444449 TI - The Madrid School of Neurology (1885-1939). AB - The emergence of neurology in Madrid between 1885 and 1939 had well-defined characteristics. On foundations laid by Cajal and Rio-Hortega, pioneers combined clinical practice with cutting-edge neurohistology and neuropathology research. Luis Simarro, trained in Paris, taught many talented students including Gayarre, Achucarro and Lafora. The untimely death of Nicolas Achucarro curtailed his promising career, but he still completed the clinicopathological study of the first American case of Alzheimer's disease. On returning to Spain, he studied glial cells, including rod cells. Rodriguez Lafora described progressive myoclonus epilepsy and completed experimental studies of corpus callosum lesions and clinical and neuropathology studies of senile dementia. He fled to Mexico at the end of the Spanish Civil War (1936-1939). Sanchis Banus, a sterling clinical neurologist, described the first cluster of Huntington's disease in Spain, and he and Rio-Hortega joined efforts to determine that pallidal degeneration underlies rigidity in advanced stages of the disease. Just after the war, Alberca Llorente eruditely described inflammatory diseases of the neuraxis. Manuel Peraita studied "the neurology of hunger" with data collected during the siege of Madrid. Dionisio Nieto, like many exiled intellectuals, settled in Mexico DF, where he taught neurohistological methods and neuropsychiatry in the tradition of the Madrid School of Neurology. PMID- 25444451 TI - [Prevalence and characteristics of chronic pain with neuropathic component at Parakou in northern Benin in 2012]. AB - The burden of chronic and neuropathic pain is high making it an important public health problem. The epidemiology is not well known in the general population in sub-Saharan Africa. We aimed to determine the prevalence of chronic pain with a neuropathic component at Tititou in Parakou in northeastern Benin. A cross sectional study was conducted from 1st April to 31 May 2012 and included 2314 people in a door-to-door survey. Chronic pain was defined as pain occurring for more than three months. Neuropathic pain was assessed with the DN4 score. A neurological exam was performed by a young physician for all people with chronic pain. During the interview, sociodemographic data, past medical history, weight and height were recorded. Multivariate logistic regression was performed to analyze the main associated factors. Among the 2314 people included in this survey, 49.7% were male. The mean age was 32.3 +/- 13.1 years. Nine hundred seven reported pain occurring for more than 3 months. The prevalence of chronic pain was 39.2% (CI95%: 29.3-34.7). It was more frequent in females, older people, among diabetics, people with a history of any surgery, stroke, brain trauma, and alcoholism. The prevalence of chronic pain with a neuropathic component was 6.3% (CI95%: 5.0-7.9). The main associated factors were age, matrimonial status, professional occupation, body mass index, diabetes, history of zoster, history of any surgery, brain trauma. People with neuropathic pain often reported pain with burning (87.6%), prickling (82.8%), numbness (66.9%), tingling (63.4%), and lightning pain (48.3%). The main locations were the lower limbs and low back pain. This study suggested the high frequency of chronic neuropathic pain in the general population in Parakou compared with rates reported in western countries. PMID- 25444450 TI - Depression in multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Prevalence of depression in MS is significant. Existence of mood disorders alters the patients' life quality. OBJECTIVE: To determine the prevalence of depression in MS and establish the relationship between the severity of the disease, the onset of depression and their correlation with neuroimaging. METHODS: Fifty patients with MS aged 20 to 50 years followed at the Neurology Department of Charles-Nicolle Hospital from 2008 to 2012 participated in this study. The evaluation included a neuropsychological assessment, physical examination with EDSS and MRI. RESULTS: Association between MS and depression is common and known. In our study, prevalence of depression was 65%. Coexistence of other psychiatric disorders was found in around 10% of patients. Mood disorder was inaugural in some cases and delayed in others. This suggests that depression in MS may be linked to the disease or a result of a functional disability process. Occurrence of depression was not directly related to disease severity in all cases studied. CONCLUSION: Depression is a possible manifestation of MS. This mood disorder is due to the demyelinating brain damage or to a genetic susceptibility. However, a fortuitous association cannot be excluded. PMID- 25444452 TI - [Leukoencephalopathy induced by a new cause of poisoning in young patients]. PMID- 25444453 TI - [Takayasu's arteritis: a rare cause of recurrent TIA not to ignore in a non Caucasian young subject]. PMID- 25444454 TI - Population genomics of natural and experimental populations of guppies (Poecilia reticulata). AB - Convergent evolution represents one of the best lines of evidence for adaptation, but few cases of phenotypic convergence are understood at the genetic level. Guppies inhabiting the Northern Mountain Range of Trinidad provide a classic example of phenotypic convergent evolution, where adaptation to low or high predation environments has been found for a variety of traits. A major advantage of this system is the possibility of long-term experimental studies in nature, including transplantation from high to low predation sites. We used genome scans of guppies from three natural high and low predation populations and from two experimentally established populations and their sources to examine whether phenotypic convergent evolution leaves footprints at the genome level. We used population-genetic modelling approaches to reconstruct the demographic history and migration among sampled populations. Naturally colonized low predation populations had signatures of increased effective population size since colonization, while introduction populations had signatures of decreased effective population size. Only a small number of regions across the genome had signatures of selection in all natural populations. However, the two experimental populations shared many genomic regions under apparent selection, more than expected by chance. This overlap coupled with a population decrease since introduction provides evidence for convergent selection occurring in the two introduced populations. The lack of genetic convergence in the natural populations suggests that convergent evolution is lacking in these populations or that the effects of selection become difficult to detect after a long-time period. PMID- 25444455 TI - Aspirin in the primary prevention of cardiovascular disease: current knowledge and future research needs. AB - In secondary prevention, among a very wide range of survivors of prior occlusive cardiovascular disease (CVD) events and those suffering acute myocardial infarction (MI) or occlusive stroke, aspirin decreases risks of MI, stroke, and CVD death. In these high risk patients, the absolute benefits are large and absolute risks are far smaller so aspirin should be more widely prescribed. In contrast, in primary prevention, aspirin reduces risks of first MI but the evidence on stroke and CVD death remain inconclusive. Based on the current totality of evidence from predominantly low risk subjects where the absolute benefits is low and side effects the same as in secondary prevention, any decision to prescribe aspirin for primary prevention should be an individual clinical judgment by the healthcare provider that weighs the absolute benefit in reducing the risk of a first MI against the absolute risk of major bleeding. If the ongoing trials of intermediate risks subjects show net benefits then general guidelines may be justified with several caveats. First, any decision to use aspirin should continue to be made by the healthcare provider. Second, therapeutic lifestyle changes and other drugs of life saving benefit such as statins should be considered with aspirin as an adjunct, not alternative. The more widespread and appropriate use of aspirin in primary prevention is particularly attractive, especially in developing countries where CVD is emerging as the leading cause of death. In addition, aspirin is generally widely available over the counter and is extremely inexpensive. PMID- 25444456 TI - Predictors of ICU patients' pain management satisfaction: A descriptive cross sectional survey. AB - PURPOSE: (1) To assess Jordanian ICU patients' pain characteristics (intensity and interference) and levels of pain management satisfaction; and (2) to determine potential predictors of pain management satisfaction among ICU patients. METHODS: A descriptive cross-sectional design was utilised using the American Pain Society-Patient Outcome Questionnaire to survey 139 Jordanian ICU patients from different health care sectors in Jordan. RESULTS: High levels of pain and pain interferences were reported by participants, which were higher than those reported by previous studies in other countries. However, participants were relatively satisfied with pain management approaches. Also, the results showed a predictive model of three potential predictors, which accounted for 36% of the variance in participants' satisfaction with pain management (adjusted R(2)=0.36, F=12.14, df=7129, p<0.005). The strongest predictor to participants' satisfaction with pain management was time needed to get analgesia (beta=-0.480, p<0.001), followed by average pain interference (beta=0.218, p=0.02), and being told about importance of reporting pain (beta=0.198, p=0.006). CONCLUSION: Jordanian ICU patients reported high pain levels, which supports the need for applying a caring attitude in managing patients' pain reports. Also, such a study is among the first pain management studies in Jordan aiming at setting the stage for future research studies. Finally, results can be included in planning pain management strategies and protocols within hospitals. PMID- 25444458 TI - Adding computed tomography and transcranial Doppler findings to the ABCD2 score to predict long-term risk of stroke after transient ischaemic attack or minor stroke. AB - BACKGROUND AND PURPOSE: The ABCD(2) score can predict the early risk of stroke after transient ischaemic attack or minor stroke. However, there is no simple and practical assessment method for the long-term risks. Computed tomography (CT) and transcranial Doppler (TCD) findings were added to the ABCD(2) score to build an ABCD(2) L(2) score and whether the new scoring system could improve the predictive value of the ABCD(2) score for the long-term risk of stroke was determined. METHODS: From January 2004 to December 2005, all patients with a definite diagnosis of transient ischaemic attack or minor stroke at the Prince of Wales Hospital were consecutively enrolled and followed up until August 2008. CT and TCD were performed. The areas under the curve were used to quantify the ABCD(2) and ABCD(2) L(2) scores and related items. RESULTS: All 481 patients completed the follow-up. The shortest follow-up time was 0.17 months (until death), the longest follow-up time was 55.60 months and the mean follow-up time was 40.3 +/- 11.0 months. In total, 277 (57.6%) patients showed lesions on CT scans and 195 (40.6%) patients were found with intracranial large artery atherosclerosis. Further strokes occurred in 74 (15.4%) patients, including four (0.83%) patients who died of ischaemic stroke during the follow-up period. The area under the curve increased from 0.650 (0.586-0.715) for the ABCD(2) score to 0.700 (0.637-0.764) for the ABCD(2) L(2) score. CONCLUSION: Adding CT and TCD results to the ABCD(2) score to increase its predictability for long-term risk of stroke recurrence might be a meaningful exploration. PMID- 25444457 TI - Children do not recalibrate motor-sensory temporal order after exposure to delayed sensory feedback. AB - Prolonged adaptation to delayed sensory feedback to a simple motor act (such as pressing a key) causes recalibration of sensory-motor synchronization, so instantaneous feedback appears to precede the motor act that caused it (Stetson, Cui, Montague & Eagleman, 2006). We investigated whether similar recalibration occurs in school-age children. Although plasticity may be expected to be even greater in children than in adults, we found no evidence of recalibration in children aged 8-11 years. Subjects adapted to delayed feedback for 100 trials, intermittently pressing a key that caused a tone to sound after a 200 ms delay. During the test phase, subjects responded to a visual cue by pressing a key, which triggered a tone to be played at variable intervals before or after the keypress. Subjects judged whether the tone preceded or followed the keypress, yielding psychometric functions estimating the delay when they perceived the tone to be synchronous with the action. The psychometric functions also gave an estimate of the precision of the temporal order judgment. In agreement with previous studies, adaptation caused a shift in perceived synchrony in adults, so the keypress appeared to trail behind the auditory feedback, implying sensory motor recalibration. However, school children of 8 to 11 years showed no measureable adaptation of perceived simultaneity, even after adaptation with 500 ms lags. Importantly, precision in the simultaneity task also improved with age, and this developmental trend correlated strongly with the magnitude of recalibration. This suggests that lack of recalibration of sensory-motor simultaneity after adaptation in school-age children is related to their poor precision in temporal order judgments. To test this idea we measured recalibration in adult subjects with auditory noise added to the stimuli (which hampered temporal precision). Under these conditions, recalibration was greatly reduced, with the magnitude of recalibration strongly correlating with temporal precision. PMID- 25444459 TI - Low prevalence of latent autoimmune diabetes in adults in northern India. AB - AIM: To study the frequency of islet antibodies in a large cohort of clinic- and community-based patients with Type 2 diabetes in northern India. METHODS: We measured glutamic acid decarboxylase (GAD) antibodies in 618 adults with Type 2 diabetes (378 patients with diabetes attending a hospital clinic, 240 patients diagnosed in a community survey) and in 192 healthy subjects residing in north India. Islet antigen 2 (IA2) antibodies were also studied in a proportion of the patients with diabetes (n = 492) and in a control population (n = 191). GAD and IA2 antibodies were measured by immunoprecipitation of the respective (35) S labelled recombinant antigen. RESULTS: We found that GAD antibodies were present in nine (1.5%) patients with diabetes (clinic population: 0.8%, community study: 2.5%), a prevalence similar to that among the subjects without diabetes (n = 2; 1%). IA2 antibodies were detected in seven patients with Type 2 diabetes (1.4%) and in two healthy control subjects (1.0%). The frequency of either GAD or IA2 antibodies was similar in people with and without diabetes (3.2 vs 2.1%). No subject was found to have both antibodies. Insulin requirement was higher among antibody-positive than among antibody-negative patients (GAD antibody: 33 vs 6.3%; P = 0.001; GAD or IA2 antibody: 23.1 vs 6.4%; P = 0.02); however, other clinical features were similar in the two groups. CONCLUSIONS: In the present north-Indian population with Type 2 diabetes, the overall prevalence of GAD antibodies and the prevalence of either GAD or IA2 antibodies were considerably lower than those reported in white European populations. PMID- 25444460 TI - Barriers to care and treatment for patients with chronic viral hepatitis in Europe: a systematic review. PMID- 25444461 TI - Region based stellate features combined with variable selection using AdaBoost learning in mammographic computer-aided detection. AB - In this paper, a new method is developed for extracting so-called region-based stellate features to correctly differentiate spiculated malignant masses from normal tissues on mammograms. In the proposed method, a given region of interest (ROI) for feature extraction is divided into three individual subregions, namely core, inner, and outer parts. The proposed region-based stellate features are then extracted to encode the different and complementary stellate pattern information by computing the statistical characteristics for each of the three different subregions. To further maximize classification performance, a novel variable selection algorithm based on AdaBoost learning is incorporated for choosing an optimal subset of variables of region-based stellate features. In particular, we develop a new variable selection metric (criteria) that effectively determines variable importance (ranking) within the conventional AdaBoost framework. Extensive and comparative experiments have been performed on the popular benchmark mammogram database (DB). Results show that our region-based stellate features (extracted from automatically segmented ROIs) considerably outperform other state-of-the-art features developed for mammographic spiculated mass detection or classification. Our results also indicate that combining region based stellate features with the proposed variable selection strategy has an impressive effect on improving spiculated mass classification and detection. PMID- 25444462 TI - Metastasectomy as optimal treatment for late relapsing solitary brain metastasis from testicular germ cell tumor: a case report. AB - BACKGROUND: Management of late relapse of a testicular germ cell tumor is difficult because few cases have been reported and the tumors are intractable to chemotherapy. Here we present a case with a single brain metastasis from late relapse of a testicular germ cell tumor. This is the first report of a brain metastasis that was treated successfully only by surgery. CASE PRESENTATION: A 19 year-old Japanese man presented with breathing difficulties and left testis enlargement and he was diagnosed with a yolk sac tumor following a left orchiectomy. At the time of diagnosis, multiple lung metastases were apparent on computed tomography, and serum alpha-fetoprotein level was elevated to 10,245 ng/ml. The patient received three postoperative courses of bleomycin, etoposide and cisplatin and etoposide and cisplatin respectively and a complete response was obtained. Four years after surgery, the patient was admitted to the hospital due to a sudden seizure. High alpha-fetoprotein levels (539 ng/ml) were evident and magnetic resonance imaging suggested a 45-mm single brain tumor in the right parietal lobe, for which surgery was performed. The pathological diagnosis was yolk sac tumor. The alpha-fetoprotein level remained normal at 2 months after operation. There was no recurrence 24 months post-operation. CONCLUSION: Chemoresistance and late neurotoxicity are concerns in treating brain metastasis with chemotherapy or cerebral radiotherapy. Surgery is believed to be the optimal treatment choice if the size of the brain metastasis is larger than 35-mm and the late relapse area is surgically accessible. PMID- 25444463 TI - Lipofuscin accumulation and autophagy in glaucomatous human lamina cribrosa cells. AB - BACKGROUND: Disease associated alterations in the phenotype of lamina cribrosa (LC) cells are implicated in changes occurring at the optic nerve head (ONH) in glaucoma. Lipofuscin, the formation of which is driven by reactive oxygen species (ROS), is an intralysosomal, non-degradable, auto-fluorescent macromolecule which accumulates with age and can affect autophagy - the lysosomal degradation of a cell's constituents. We aimed to compare the content of lipofuscin-like material and markers of autophagy in LC cells from normal and glaucoma donor eyes. METHODS: The number and size of peri-nuclear lysosomes were examined by transmission electron microscopy (TEM). Cellular auto-fluorescence was quantified by flow cytometry. Cathepsin K mRNA levels were assessed by PCR. Autophagy protein 5 (Atg5) mRNA and protein levels were analysed by PCR and Western blot. Protein levels of subunits of the microtubule associated proteins (MAP) 1A and 1B, light chain 3 (LC3) I and II were analysed by Western blot. Immunohistochemical staining of LC3-II in ONH sections from normal and glaucomatous donor eyes was performed. RESULTS: A significant increase in the number of peri-nuclear lysosomes [4.1 * 10,000 per high power field (h.p.f.) +/- 1.9 vs. 2.0 * 10,000 per h.p.f. +/- 1.3, p = 0.002, n = 3] and whole cell auto fluorescence (83.62 +/- 45.1 v 41.01 +/- 3.9, p = 0.02, n = 3) was found in glaucomatous LC cells relative to normal LC cells. Glaucomatous LC cells possessed significantly higher levels of Cathepsin K mRNA and Atg5 mRNA and protein. Enhanced levels of LC3-II were found in both LC cells and optic nerve head sections from glaucoma donors. CONCLUSIONS: Increased lipofuscin formation is characteristic of LC cells from donors with glaucoma. This finding confirms the importance of oxidative stress in glaucoma pathogenesis. Intracellular lipofuscin accumulation may have important effects on autophagy the modification of which could form the basis for future novel glaucoma treatments. PMID- 25444464 TI - Ganetespib, a novel Hsp90 inhibitor in patients with KRAS mutated and wild type, refractory metastatic colorectal cancer. AB - BACKGROUND: Heat shock protein 90 (Hsp90) is a cellular chaperone that is required for the maturation and stability of a variety of proteins that play key roles in colon cancer initiation and progression. The primary objective of the current study was to define the safety and efficacy of ganetespib, a novel, selective small-molecule Hsp90 inhibitor, in patients with refractory metastatic colorectal cancer. PATIENTS AND METHODS: The study was a single-arm, Simon 2 stage, phase II trial for patients with chemotherapy-refractory, metastatic colorectal cancer. Patients received ganetespib 200 mg/m(2) intravenously. Tumor tissue was collected before treatment and 48 hours after treatment for changes in expression of Hsp90 client proteins and other potential pharmacodynamics markers. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B, and phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutational status was also determined. RESULTS: Seventeen patients were treated (median age, 58; range, 44-79 years). No patients demonstrated objective regression of disease. Two patients had stable disease of 6.8 and 5.1 months duration. Serious adverse events that were potentially attributable to ganetespib included diarrhea (12%, n = 2), fatigue (17%, n = 3), and increased aspartate aminotransferase/alanine aminotransferase (12%, n = 2) and alkaline phosphatase (6%, n = 1) levels. Of the 17 evaluable patients, 9 (53%) including patients with stable disease as best response, had KRAS-mutant tumors. CONCLUSION: In this first phase II investigation of an Hsp90 inhibitor in colorectal cancer, ganetespib as a single agent did not demonstrate activity in chemotherapy-refractory metastatic colorectal cancer. However, on the basis of the drug's promising preclinical combination data and the relatively mild toxicity profile, further clinical investigation of this agent in combination with standard cytotoxic agents is planned. PMID- 25444465 TI - Squamous cell carcinoma of the sigmoid colon presenting with severe hypercalcemia. PMID- 25444466 TI - Epidemiology of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the most common histologic type of primary liver cancer, accounting for between 85% and 90% of these malignancies. The overall prognosis of patients with liver cancer is poor, and an understanding of this disease and its risk factors is crucial for screening at-risk individuals, early recognition, and timely diagnosis. Most HCCs arise in the background of chronic liver disease caused by hepatitis B virus, hepatitis C virus, and chronic excessive alcohol intake. These underlying causes are characterized by marked variations in geography, gender, and other well-documented risk factors, some of which are potentially preventable. PMID- 25444467 TI - Imaging approach to hepatocellular carcinoma, cholangiocarcinoma, and metastatic colorectal cancer. AB - Liver imaging is a highly evolving field with new imaging contrast agents and modalities. Knowledge of the different imaging options and what they have to offer in primary and metastatic liver disease is essential for appropriate diagnosis, staging, and prognosis in patients. This review summarizes the major imaging modalities in liver neoplasms and provides specific discussion of imaging hepatocellular carcinoma, cholangiocarcinoma, and colorectal liver metastases. The final sections provide an overview of presurgical imaging relevant to planning hepatectomies and ablative procedures. PMID- 25444468 TI - Prognostication systems as applied to primary and metastatic hepatic malignancies. AB - Staging systems are an attempt to incorporate the biology and therapy for cancer in a way that enables categorization and prediction of oncologic outcomes. Because of unusual disease biology and complexities related to treatment intervention, efforts to develop reliable staging systems for hepatic malignancies have been challenging. This article discusses the ways in which improved understanding of these diseases has informed the evolution of prognostication systems as applied to hepatocellular carcinoma, cholangiocarcinoma, and hepatic colorectal adenocarcinoma. PMID- 25444469 TI - Modern technical approaches in resectional hepatic surgery. AB - Techniques in liver surgery have improved considerably during the last decades, allowing for liver resections with low morbidity and mortality. Preoperative patient selection, perioperative management, and intraoperative blood-sparing techniques are the cornerstones of modern liver surgery. Multimodal treatment of colorectal liver metastases has expanded the group of patients who are potential candidates for liver resection. Adjunctive techniques, including preoperative portal vein embolization and staged hepatectomy, have facilitated the safe performance of extensive liver resection. This article provides an overview of indications for liver resection and a systematic description of the technical approach to the most commonly performed resections. PMID- 25444470 TI - Complications following hepatectomy. AB - As the number of liver resections in the United States has increased, operations are more commonly performed on older patients with multiple comorbidities. The advent of effective chemotherapy and techniques such as portal vein embolization, have compounded the number of increasingly complex resections taking up to 75% of healthy livers. Four potentially devastating complications of liver resection include postoperative hemorrhage, venous thromboembolism, bile leak, and post hepatectomy liver failure. The risk factors and management of these complications are herein explored, stressing the importance of identifying preoperative factors that can decrease the risk for these potentially fatal complications. PMID- 25444471 TI - Ablative technologies for hepatocellular, cholangiocarcinoma, and metastatic colorectal cancer of the liver. AB - A wide array of ablation technologies, in addition to the progressive sophistication of imaging technologies and percutaneous, laparoscopic, and open surgical techniques, have allowed us to expand treatment options for patients with liver tumors. In this article, technical considerations of chemical and thermal ablations and their application in hepatic oncology are reviewed. PMID- 25444472 TI - Hepatic artery infusion chemotherapy for liver malignancy. AB - To date, hepatic artery infusion (HAI) chemotherapy has primarily been investigated in the setting of colorectal cancer liver metastases (CRLM). Few studies have been conducted in North America regarding HAI chemotherapy for primary liver cancers (PLC) or noncolorectal liver metastases (non-CRLM). Despite decades of evaluation, controversy surrounding the use of HAI chemotherapy still exists. In this article the methods of HAI chemotherapy delivery, technical aspects of catheter and pump insertion, and specific complications of HAI chemotherapy are discussed. Outcomes of clinical trials and reviews of HAI chemotherapy in the setting of CRLM, PLC, and non-CRLM are evaluated. PMID- 25444473 TI - Transarterial chemoembolization for primary liver malignancies and colorectal liver metastasis. AB - Management of liver malignancies, both primary and metastatic, requires a host of treatment modalities when attempting to prolong survival. Although surgical resection and transplantation continue to offer the best chance for a cure, most patients are not amenable to these therapies because of their advanced disease at presentation. Taking advantage of the unique blood supply of the liver, transarterial chemoembolization has emerged as an alternative and effective therapy for unresectable tumors. In this article, the current role along with future perspectives of transarterial chemoembolization for hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and colorectal liver metastasis are discussed. PMID- 25444474 TI - Y90 selective internal radiation therapy. AB - Primary liver malignancies and liver metastases are affecting millions of individuals worldwide. Because of their late and advanced stage presentation, only 10% of patients can receive curative surgical treatment, including transplant or resection. Alternative treatments, such as systemic chemotherapy, ablative therapy, and chemoembolization, have been used with marginal survival benefits. Selective internal radiation therapy (SIRT), also known as radioembolization, is a compelling alternative treatment option for primary and metastatic liver malignancies with a growing body of evidence. In this article, an introduction to SIRT including background, techniques, clinical outcomes, and complications is reviewed. PMID- 25444475 TI - Systemic therapy for hepatocellular carcinoma and cholangiocarcinoma. AB - Understanding core signaling pathways in hepatic carcinogenesis has brought about a new era in the management of hepatocellular carcinoma. Sorafenib was the first molecular targeted therapy to be approved for advanced hepatocellular carcinoma and is the benchmark for all other therapies. Cytotoxic chemotherapy remains the mainstay treatment of advanced cholangiocarcinoma and there are no US Food and Drug Administration-approved molecular targeted therapies. If clinicians are able to minimize the toxicity of therapy by targeting the driving mechanism of cell proliferation, they will be able to significantly improve the survival and quality of life of patients. PMID- 25444476 TI - Integrating systemic and surgical approaches to treating metastatic colorectal cancer. AB - Multiple new treatment options for metastatic colorectal cancer have been developed over the past 2 decades, including conventional chemotherapy and agents directed against vascular endothelial growth factor and epidermal growth factor receptor. Combination regimens, integrated with surgical approaches, have led to an increase in median survival, and a minority of patients with resectable disease can survive for years. Clinical decision-making therefore requires a strategic, biomarker-based multidisciplinary approach to maximize life expectancy and quality of life. This review describes systemic approaches to the treatment of patients with metastatic colorectal cancer, including integration with liver resection, other liver-directed therapies, and primary resection. PMID- 25444477 TI - Hepatocellular cancer, cholangiocarcinoma, and metastatic tumors of the liver. PMID- 25444478 TI - Hepatocellular cancer, cholangiocarcinoma, and metastatic tumors of the liver. PMID- 25444479 TI - Oncological and functional results after the surgical treatment of parotid cancer. AB - The objective of this study was to analyze the oncological and functional outcomes after the surgical treatment of parotid cancer. We reviewed 80 primary parotid carcinomas retrospectively. A superficial parotidectomy was performed in 10 patients; 27 patients underwent total parotidectomy and 43 patients underwent radical parotidectomy. A facial-facial nerve anastomosis was chosen for the facial nerve reconstruction in eight patients, while an interpositional graft was selected in 24 patients. The overall N-positive rate of pathology was 21.3%. The rate of occult metastasis was 8.1%. High-grade carcinoma and lymphovascular emboli were independent factors for nodal metastasis. The 5-year disease-free survival and overall survival rates were 79.7% and 78.8%, respectively. Preoperative facial nerve palsy and extraparenchymal invasion were the independent factors associated with poor disease-free survival. Of the 41 patients in the facial nerve preservation group, 13 (31.7%) had transient facial nerve paresis. In the facial nerve sacrifice group of 39 cases, (sub)total recovery (House-Brackmann grade I/II) occurred in 14 (35.9%), partial recovery (House-Brackmann grade III/IV) in 13 (33.3%), and no recovery (House-Brackmann grade V) in 12 (30.8%). Facial nerve palsy upon presentation and extraparenchymal invasion indicate a grave prognosis. Facial nerve function after proper reconstruction is tolerable. PMID- 25444480 TI - Satisfaction of skeletal class III patients treated with different types of orthognathic surgery. AB - The aim of this study was to compare the satisfaction of skeletal class III patients following treatment with three different methods of orthognathic surgery. Eighty-two patients were divided into three groups according to the surgical procedure performed to correct their class III dentofacial deformity, and answered a questionnaire designed to determine the patient's opinion of the aesthetic and functional treatment outcomes. Differences in the patterns of responses to questions in the questionnaire related to satisfaction between the three clinical groups were evaluated by chi(2) and Fisher's exact tests (alpha=5%). Eighty patients (97.6%) reported being satisfied with the treatment received. There was no significant difference in response patterns among clinical groups when assessing the improvement in facial appearance, chewing, speech, and socialization. Maxillary advancement led to higher levels of improvement in breathing (P<0.0003). Class III patients treated by orthognathic surgery had high levels of satisfaction with the aesthetic and functional outcomes of their treatment. PMID- 25444481 TI - Azithromycin and congenital heart disease. PMID- 25444482 TI - Avascular necrosis of the midface secondary to disseminated intravascular coagulation. AB - To the authors' knowledge, avascular necrosis of the midface secondary to disseminated intravascular coagulation has yet to be described following a hypoxic syncopal episode secondary to 'heat stroke'. A slow, progressive loss of anterior maxillary bone and the collapse of the nasal dorsum in a healthy young man with no other known medical co-morbidities led to the diagnosis. Following debridement, a staged reconstruction of the maxilla-nasal complex was successfully performed. PMID- 25444483 TI - Tumor necrosis factor-alpha blockade and development of uveal melanoma: expected adverse effect or just coincidence? PMID- 25444484 TI - Clinical and histologic findings in patients with uveal melanomas after taking tumor necrosis factor-alpha inhibitors. AB - OBJECTIVE: To describe the progression of uveal melanocytic lesions to melanomas after initiation of tumor necrosis factor-alpha (TNF-alpha) inhibitors. PATIENTS AND METHODS: We report 3 cases of uveal melanoma occurring after treatment with TNF-alpha inhibitors, 2 from Mayo Clinic and 1 from Yale University. The study took place from February 27, 2009, through July 15, 2013. RESULTS: Two women and one man with inflammatory disease who received TNF-alpha inhibitors had subsequent development of uveal melanomas. The 2 women had inflammatory bowel disease and had been followed up for melanocytic tumors that grew markedly within 1 year after beginning treatment with TNF-alpha inhibitors to the point of requiring treatment. One had histologic confirmation of the melanoma. The male patient had rheumatoid arthritis that was being treated with TNF-alpha inhibitors. Serial ultrasonography was performed to monitor bilateral diffuse scleritis, and within 16 months of initiation of TNF-alpha inhibitor therapy, a choroidal mass was detected that continued to grow over the next 3 months. The patient elected to have enucleation, which revealed uveal melanoma and thinning of the sclera from the previous scleritis. CONCLUSION: Our 3 cases of uveal melanocytic tumors occurring after the use of TNF-alpha inhibitors add to the growing literature suggesting a correlation between TNF-alpha inhibitors and the development of malignant neoplasms. Considering the association between cutaneous melanoma and TNF-alpha inhibitors, we recommend that patients have an eye examination before initiation of TNF-alpha inhibitors, and those with preexisting nevi should be followed up at regular intervals. PMID- 25444485 TI - Increased risk of first-ever stroke in younger patients with atrial fibrillation not recommended for antithrombotic therapy by current guidelines: a population based study in an East Asian cohort of 22 million people. AB - OBJECTIVE: To assess the risk of first-ever ischemic stroke in younger patients with atrial fibrillation (AF) who have none of the CHA2DS2-VASc (congestive heart failure, hypertension, age >=75 years, diabetes mellitus, previous stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category [female sex]) risk factors (excluding female sex) by using the National Health Insurance research database in Taiwan. PATIENTS AND METHODS: From 22,842,778 insured people, we identified 24,612 hospitalized patients with newly diagnosed AF between January 1, 2002, and December 31, 2004, as the AF group and randomly selected 98,448 age- and sex-matched persons without AF as the non-AF group. Both groups were followed up until December 31, 2010, to estimate ischemic stroke incidences in relation to other stroke risk factors. RESULTS: During a follow-up period of 89,468 person-years, the stroke rate was higher in patients with AF than in those without AF (5.79 per 100 person-years vs 2.25 per 100 person years). The higher prevalence of CHA2DS2-VASc comorbidities (heart failure, hypertension, diabetes, coronary artery disease, and peripheral artery disease) in patients with AF further increased the stroke risk. In 790 patients with AF aged 30 to 55 years who had none of the CHA2DS2-VASc comorbidities at baseline and retained a "low risk," that is, those with a CHA2DS2-VASc score of 0 in men and 1 in women during follow-up, the stroke rate remained considerably higher than that in their non-AF counterparts (1.00 per 100 person-years vs 0.25 per 100 person-years), with a sex-adjusted hazard ratio of 4.09 (95% CI, 2.97-5.62). CONCLUSION: This study finds an increased risk of stroke in younger patients with AF who are not recommended for prevention of thromboembolism by current guidelines. Better stroke risk stratification tools are needed to prioritize younger patients with AF for thromboprophylactic therapy in this population. PMID- 25444486 TI - Clinical predictors of risk for atrial fibrillation: implications for diagnosis and monitoring. AB - OBJECTIVE: To create a risk score using clinical factors to determine whom to screen and monitor for atrial fibrillation (AF). PATIENTS AND METHODS: The AF risk score was developed based on the summed odds ratios (ORs) for AF development of 7 accepted clinical risk factors. The AF risk score is intended to assess the risk of AF similar to how the CHA2DS2-VASc score assesses stroke risk. Seven validated risk factors for AF were used to develop the AF risk score: age, coronary artery disease, diabetes mellitus, sex, heart failure, hypertension, and valvular disease. The AF risk score was tested within a random population sample of the Intermountain Healthcare outpatient database. Outcomes were stratified by AF risk score for OR and Kaplan-Meier analysis. RESULTS: A total of 100,000 patient records with an index follow-up from January 1, 2002, through December 31, 2007, were selected and followed up for the development of AF through the time of this analysis, May 13, 2013, through September 6, 2013. Mean +/- SD follow-up time was 3106+/-819 days. The ORs of subsequent AF diagnosis of patients with AF risk scores of 1, 2, 3, 4, and 5 or higher were 3.05, 12.9, 22.8, 34.0, and 48.0, respectively. The area under the curve statistic for the AF risk score was 0.812 (95% CI, 0.805-0.820). CONCLUSION: We developed a simple AF risk score made up of common clinical factors that may be useful to possibly select patients for long-term monitoring for AF detection. PMID- 25444487 TI - Long-term outcome of globus pallidus internus deep brain stimulation in patients with Tourette syndrome. AB - OBJECTIVE: To evaluate the effectiveness of deep brain stimulation (DBS) of the globus pallidus internus (GPi) on tic severity and common comorbidities in patients with severe Tourette syndrome that is refractory to pharmacological treatment and psychotherapy. PATIENTS AND METHODS: We retrospectively assessed the long-term clinical outcomes of 13 patients with treatment-refractory Tourette syndrome who underwent DBS targeting the GPi at the Beijing Tiantan Hospital from January 1, 2006, through May 31, 2013. The primary outcome was a change in tic severity as measured by the Yale Global Tic Severity Scale, and the secondary outcome was a change in associated behavioral disorders and mood as measured by the Gilles de la Tourette Syndrome-Quality of Life Scale assessment. RESULTS: Compared with baseline, the mean reduction in the total Yale Global Tic Severity Scale scores at last follow-up (mean, 41.9 months; range, 13-80 months) was 52.1% (range, 4.3%-83.6%), and the mean improvement rates at 1 month, 6 months, 12 months, 18 months, 24 months, 30 months, and 36 or more months were 11.8%, 20.0%, 26.8%, 36.7%, 44.7%, 49.0%, and 56.7%, respectively. A paired-sample t test revealed significant improvement of tic symptoms after 6 months of DBS programming (P<.05). The Gilles de la Tourette Syndrome-Quality of Life Scale score improved by a mean of 45.7% (range, 11.0%-77.2%). CONCLUSION: This study is currently the largest reported GPi DBS case series of patients with treatment refractory TS with the longest follow-up. Our results support the potential beneficial effect of GPi DBS on disabling tic reduction and improvement of quality of life. PMID- 25444488 TI - Severe sepsis and septic shock: clinical overview and update on management. AB - Sepsis is among the oldest themes in medicine; however, despite modern advances, it remains a leading cause of death in the United States. Every clinician should be able to recognize the signs and symptoms of sepsis, along with early management strategies, to expeditiously provide appropriate care and decrease resultant morbidity and mortality. This review addresses the definitions, pathogenesis, clinical manifestations, management, and outcomes of patients with sepsis, severe sepsis, and septic shock. PMID- 25444489 TI - 30-year-old man with chest pain and nausea. PMID- 25444491 TI - In reply--Bias and male circumcision. PMID- 25444492 TI - Bias and male circumcision. PMID- 25444490 TI - Transcranial magnetic stimulation as an antidepressant alternative in a patient with Brugada syndrome and recurrent syncope. AB - Brugada syndrome (BrS) is a common occult cause of sudden cardiac arrest in otherwise healthy-appearing adults. The pathognomonic electrocardiographic pattern may be unmasked only by certain medications, many of which are unknown. We report a case of a depressed but otherwise healthy man with an asymptomatic right bundle branch block on electrocardiography who experienced antidepressant induced BrS and ultimately recovered with transcranial magnetic stimulation (TMS). After an initial trial of nortriptyline, the patient's depressive symptoms improved; however, he experienced a syncopal event and was subsequently diagnosed as having BrS. Cross titration to bupropion, which had not previously been known to exacerbate BrS, was followed by another cardiac event. As a result, the patient was referred for TMS as a substitute for pharmacotherapy. After 31 TMS sessions over 8 weeks, the patient demonstrated significant improvement by subjective report and objective reduction in his Patient Health Questionnaire-9 scores from 10 (moderate) to 1 (minimal). Transcranial magnetic stimulation is a Food and Drug Administration-approved nonpharmacologic treatment for depression. Given the potential lethality of BrS with known and unknown psychopharmacologic agents, providers should consider TMS as first-line therapy in this patient population. Bupropion should be added to the list of agents known to exacerbate this disease. PMID- 25444493 TI - Curbside consultations: a call for more investigation into a common practice. PMID- 25444494 TI - In reply--Curbside consultations: a call for more investigation into a common practice. PMID- 25444495 TI - 78-year-old-woman with dyspnea on exertion. PMID- 25444496 TI - Pachymeningitis and aortitis in a patient with antineutrophil cytoplasmic antibody-associated vasculitis. PMID- 25444498 TI - Provocative issues in heart disease prevention. AB - In this article, new areas of cardiovascular (CV) prevention and rehabilitation research are discussed: high-intensity interval training (HIIT) and new concepts in nutrition. HIIT consists of brief periods of high-intensity exercise interspersed by periods of low-intensity exercise or rest. The optimal mode according our work (15-second exercise intervals at peak power with passive recovery intervals of the same duration) is associated with longer total exercise time, similar time spent near peak oxygen uptake (VO2 peak) VO2 peak, and lesser perceived exertion relative to other protocols that use longer intervals and active recovery periods. Evidence also suggests that compared with moderate intensity continuous exercise training, HIIT has superior effects on cardiorespiratory function and on the attenuation of multiple cardiac and peripheral abnormalities. With respect to nutrition, a growing body of evidence suggests that the gut microbiota is influenced by lifestyle choices and might play a pivotal role in modulating CV disease development. For example, recent evidence linking processed (but not unprocessed) meats to increased CV risk pointed to the gut microbial metabolite trimethylamine N-oxide as a potential culprit. In addition, altered gut microbiota could also mediate the proinflammatory and cardiometabolic abnormalities associated with excess added free sugar consumption, and in particular high-fructose corn syrup. Substantially more research is required, however, to fully understand how and which alterations in gut flora can prevent or lead to CV disease and other chronic illnesses. We conclude with thoughts about the appropriate role for HIIT in CV training and future research in the role of gut flora-directed interventions in CV prevention. PMID- 25444499 TI - Decreased expression and clinical significance of miR-148a in hepatocellular carcinoma tissues. AB - BACKGROUND: Aberrant expression of microRNA-148a (miR-148a) has been reported in several types of malignancies. However, its expression and clinicopathological significance in hepatocellular carcinoma (HCC) has not been entirely clarified. Our objective was to investigate the clinicopathological contribution of the miR 148a expression in HCC formalin-fixed paraffin-embedded (FFPE) tissues. METHODS: Eighty-nine HCC and their para-cancerous liver tissues were recruited. Total mRNA including miRNA was isolated and miR-148a expression was determined by using real time RT-qPCR. Furthermore, the relationship between the miR-148a level and clinicopathological features was explored. RESULTS: Significantly lower miR-148a expression in HCC tissues was observed than that in adjacent noncancerous hepatic tissues. miR-148a expression was also correlated to clinical TNM stage, metastasis, status of capsular infiltration and numbers of tumor nodes. CONCLUSIONS: Underexpression of miR-148a might be associated with HCC tumorigenesis and deterioration of HCC. miR-148a might act as a suppressor miRNA of HCC and it therefore has a potential role in prognosis of HCC patients. PMID- 25444500 TI - Clinical implications of congenital uterine anomalies: a meta-analysis of comparative studies. AB - The clinical implications of congenital uterine anomalies (CUA), and the benefits of hysteroscopic resection of a uterine septum, were evaluated. Studies comparing reproductive and obstetric outcome of patients with and without CUA and of patients who had and had not undergone hysteroscopic resection of a uterine septum, were evaluated. Meta-analysis of studies indicated that the pregnancy rate was decreased in women with CUA (RR 0.85, 95% CI 0.73 to 1.00; marginally significant finding, P = 0.05). The spontaneous abortion rate was increased in women with CUA (RR 1.68, 95% CI 1.31 to 2.15). Preterm delivery rates (RR 2.21, 95% CI 1.59 to 3.08), malpresentation at delivery (RR 4.75, 95% CI 3.29 to 6.84), low birth weight (RR 1.93, 95% CI 1.50 to 2.49) and perinatal mortality rates (RR 2.43, 95% CI 1.34 to 4.42) were significantly higher in women with CUA. Hysteroscopic removal of a septum was associated with a reduced probability of spontaneous abortion (RR 0.37, 95% CI 0.25 to 0.55) compared with untreated women. Presence of CUA might be associated with a detrimental effect on the probability of pregnancy achievement, spontaneous abortion and obstetric outcome. Hysteroscopic removal of a septum may reduce the probability of a spontaneous abortion. PMID- 25444501 TI - Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol). AB - Previous studies have shown that existing antral follicles in the luteal phase enable ovarian stimulation. In a pilot study, the efficacy of double stimulations during the follicular and luteal phases in women with poor ovarian response was explored (defined according to the Bologna criteria). Thirty-eight women began with mild ovarian stimulation. After the first oocyte retrieval, human menopausal gonadotrophin and letrozole were administrated to stimulate follicle development, and oocyte retrieval was carried out a second time when dominant follicles had matured. The primary outcome measured was the number of oocytes retrieved: stage one 1.7 +/- 1.0; stage two 3.5 +/- 3.2. From the double stimulation, 167 oocytes were collected and 26 out of 38 (68.4%) succeeded in producing one to six viable embryos cryopreserved for later transfer. Twenty-one women underwent 23 cryopreserved embryo transfers, resulting in 13 clinical pregnancies. The study shows that double ovarian stimulations in the same menstrual cycle provide more opportunities for retrieving oocytes in poor responders. The stimulation can start in the luteal phase resulting in retrieval of more oocytes in a short period of time. This offers new hope for women with poor ovarian response and newly diagnosed cancer patients needing fertility preservation. PMID- 25444502 TI - No adverse effects were identified on the perinatal outcomes after laser-assisted hatching treatment. AB - The aim of this study was to evaluate the safety of laser-assisted hatching (LAH) by comparing obstetric and neonatal outcomes between assisted hatching and control groups in cryopreserved embryo transfer cycles. A retrospective cohort analysis was carried out. A total of 699 women with 392 infants delivered were included. Laser- assisted hatching was carried out on D-3 thawed and warmed embryos before transfer in 480 cryopreserved embryos transfer cycles. Obstetric outcomes, neonatal outcomes, and congenital birth defects were recorded. A total of 815 cryopreserved embryo transfer cycles (480 in LAH group and 335 in control group) in 699 patients were analysed. Statistically significantly higher implantation (31.85% versus 16.95%), clinical pregnancy (53.96% versus 33.43%) and live delivery (44.58% versus 23.88%) rates were observed in the LAH group (all P < 0.001). For either singleton or multiple gestations, no statistically significant differences were found in mean gestational age, mean birth weight and mean Apgar score. Four major malformations occurred in the assisted hatching group and three malformations (one major and two minor) in the control group. This study did not identify any harmful effect of LAH on neonates, which suggested that LAH may be a safe treatment in cryopreserved embryo transfer cycles. PMID- 25444503 TI - Severe haematoperitoneum caused by ovarian bleeding after transvaginal oocyte retrieval: a retrospective analysis and systematic literature review. AB - A case series of haematoperitoneum caused by ovarian bleeding after transvaginal oocyte retrieval (TVOR) is presented and all published cases summarized. In a retrospective case series, four patients with ovarian bleeding after TVOR were included. In addition, a pooled analysis of all published cases (n = 32) who underwent surgical intervention for severe haematoperitoneum caused by ovarian bleeding after TVOR was carried out. Main outcome measures were incidence, risk factors, course and intraoperative findings. In the pooled analysis, the incidence was 0.08%. The first sign of haematoperitoneum was evident in 33.3% within the first postoperative hour, and, cumulatively, in 93.3% within 24 h. The median time between TVOR and surgical intervention was 10 h. In four patients, the ovary could not be preserved, which was associated with a longer time interval between TVOR and the onset of symptoms (median 18 h versus 2.5 h; P = 0.004) as well as between TVOR and surgical intervention (median 21.5 h versus 8.5 h; 0.004). In conclusion, severe haematoperitoneum occurs in 0.08% after TVOR. Late-onset bleeding is common. A longer time interval between TVOR and surgical intervention might put a patient at risk of ovariectomy. PMID- 25444504 TI - Effects of in-vitro or in-vivo matured ooplasm and spindle-chromosome complex on the development of spindle-transferred oocytes. AB - To study the effects of in-vitro matured ooplasm and spindle-chromosome complex (SCC) on the development of spindle-transferred oocytes, reciprocal spindle transfer was conducted between in-vivo and in-vitro matured oocytes. The reconstructed oocytes were divided into four groups according to their different ooplasm sources and SCC, artificially activated and cultured to the blastocyst stage. Oocyte survival, activation and embryo development after spindle transfer manipulation were compared between groups. Survival, activation, and cleavage rates of reconstructed oocytes after spindle transfer manipulation did not differ significantly among the four groups. The eight-cell stage embryo formation rates on day 3 and the blastocyst formation rate on day 6 were not significantly different between the in-vitro and in-vivo matured SCC groups when they were transplanted into in-vivo matured ooplasm. The rate of eight-cell stage embryo formation with in-vitro matured ooplasm was significantly lower (P < 0.05) than that of embryos with in-vivo matured ooplasm, and none of the embryos developed to the blastocyst stage. Therefore, SCC matured in vitro effectively supported the in-vitro development of reconstructed oocytes. Ooplasm matured in vitro, however, could not support the development of reconstructed oocytes, and may not be an appropriate source of ooplasm donation for spindle transfer. PMID- 25444505 TI - Pregnancy outcome of early multifetal pregnancy reduction: triplets to twins versus triplets to singletons. AB - Multifetal pregnancy reduction (MPR) of triplets to twins results in improved pregnancy outcomes compared with triplet gestations managed expectantly. Perinatal outcomes of early transvaginal MPR from triplets to twins were compared with reduction from triplets to singletons. Seventy-four trichorionic triplet pregnancies that underwent early transvaginal MPR at 6-8 weeks gestation were included. Cases were divided into two groups according to the initial procedure: reduction to twin (n = 55) or to singleton (n = 19) gestations. Infants from triplet pregnancies reduced to twins were delivered earlier (36.6 versus 37.9 weeks; P = 0.04) and had lower mean birth weights (2364 g versus 2748 g; P = 0.02) compared with those from triplets reduced to singleton gestations. The rates of pregnancy loss before 24 weeks (3.6% versus 5.3%), as well as of preterm delivery before 32 and 34 weeks of gestation (0% versus 5.3% and 7.3% versus 5.3%, respectively) were similar between the twin and singleton pregnancies. No significant difference was found in the prevalence of gestational diabetes (15.1% versus 5.6%) or gestational hypertension (24.5% versus 16.7%) between the groups. Selective reduction of triplet pregnancies to singleton rather than twin gestations is associated with improved outcomes. PMID- 25444506 TI - Obstetric outcome after oocyte vitrification and warming for fertility preservation in women with cancer. AB - Obstetric outcome of first pregnancies achieved after vitrification and warming oocytes from women being treated for cancer was evaluated. Of a total of 493 women who consulted for fertility preservation, 357 had their oocytes cryopreserved after being diagnosed with cancer, and 11 returned after being cured for assisted reproduction treatments (eight had breast cancer, one Hodgkin lymphoma, one endometrial adenocarcinoma, and one thyroid cancer). The oocyte survival rate was 92.3%, the fertilization rate was 76.6%, and the mean number of embryos transferred was 1.8 +/- 0.7. Beta-human chorionic gonadotropin was detected in seven out of the 11 embryo transfers carried out. Four ongoing pregnancies were achieved and delivered at term with normal fetal weight and no major or minor malformations. Women diagnosed with cancer who have their eggs cryopreserved before anti-cancer treatment have good assisted reproductive technology performance and good perinatal outcomes. Cryopreservation of oocytes seems to be a good alternative for fertility preservation in these women. PMID- 25444508 TI - Association between trefoil factor 3 gene variants and idiopathic recurrent spontaneous abortion. AB - Trefoil factor 3 (TFF3) gene is an inflammatory mediator expressed in human endometrium during the window of implantation. The aim of this study was to evaluate the possible genetic association of TFF3 variants in recurrent spontaneous abortion. Women with a history of recurrent spontaneous abortion (n = 164) and healthy pregnant women (n = 143) were genotyped for five TFF3 polymorphisms (rs225439 G/A, rs533093 C/T, rs225361 A/G, rs11701143 T/C and rs77436142 G/C). In addition, haplotypes formed within the gene were analysed. Within the recurrent spontaneous abortion group, women who at some point had given birth and childless women had 4.19 +/- 1.75 and 5.34 +/- 3.42 consecutive spontaneous abortions, respectively. Women who had experience recurrent spontaneous abortions had a lower allele frequency of the rs11701143 promoter region minor C allele compared with fertile women (0.02 versus 0.05, P = 0.015). Patients with rs225361 AG genotype had significantly more successful pregnancies before spontaneous abortion than those with homozygous AA and GG genotypes (P = 0.014). No significant differences in haplotype frequencies between patients and controls were detected. Possible genetic risk factors identified that might contribute to the pathogenesis of idiopathic recurrent spontaneous abortion were TFF3 gene variants. PMID- 25444509 TI - Polymorphisms in the fibrinolytic pathway genes and the risk of recurrent spontaneous abortion. AB - Impaired fibrinolytic activity is implicated in the pathogenesis of recurrent spontaneous abortion (RSA). This case-control study assessed the prevalence of polymorphisms in fibrinolytic system genes in RSA. Cases comprised 202 Sinhalese women who had experienced at least two first-trimester spontaneous abortions and had no living children; controls were 202 women with no history of spontaneous abortion and two or more living children. The groups were matched for age and ethnicity. DNA was genotyped using the Sequenom MassARRAY system. The PLAUR rs4251923 A (OR 95% CI 2.3 [1.3 to 4.0]), SERBP2 rs6098 A (OR 95% CI 1.4 [1.1 to 1.9]) and SERBP2 rs6103 C alleles (OR 95% CI 1.4 [1.1 to 1.9]) were increased in the RSA group compared with controls. The prevalence of PLAUR rs4251923/ SERBP2 rs6098/ SERBP2 rs6103 GG/AA/CC (OR 95% CI 2.4 [1.2 to 4.9], GA/GA/GC(OR 95% CI 3.9 [1.3 to 11.2]), GA/AA/CC (OR 95% CI 2.9 [1.0 to 8.6] and GA/GG/GG (OR 95% CI 21.3 [1.1 to 410.3]) genotypes were also increased in cases. Polymorphisms in the fibrinolytic system genes are associated with RSA in Sinhalese women. These likely impair implantation. PMID- 25444507 TI - Computer-automated time-lapse analysis results correlate with embryo implantation and clinical pregnancy: a blinded, multi-centre study. AB - Computer-automated time-lapse analysis has been shown to improve embryo selection by providing quantitative and objective information to supplement traditional morphology. In this multi-centre study, the relationship between such computer derived outputs (High, Medium, Low scores), embryo implantation and clinical pregnancy were examined. Data were collected from six clinics, including 205 patients whose embryos were imaged by the Eeva(TM) System. The Eeva scores were blinded and not considered during embryo selection. Embryos with High and Medium scores had significantly higher implantation rates than those with Low scores (37% and 35% versus 15%; P < 0.0001; P = 0.0004). Similar trends in implantation rates were observed in different IVF centres each using their own protocols. Further analysis revealed that patients with at least one High embryo transferred had significantly higher clinical pregnancy rates than those with only Low embryos transferred (51% versus 34%; P = 0.02), although patients' clinical characteristics across groups were comparable. These data, together with previous research and clinical studies, confirm that computer-automated Eeva scores provide valuable information, which may improve the clinical outcome of IVF procedures and ultimately facilitate the trend of single embryo selection. PMID- 25444510 TI - Evaluation of syphilis serostatus on the safety of IVF treatment. AB - An increasing number of infertile syphilis-infected individuals have turned to assisted reproductive technology; however, the safety of syphilis carrier serostatus on IVF and embryo transfer outcomes has not been evaluated. Data from 482 patients who delivered singletons were analysed. In the retrospective study, the rate of IVF and intracytoplasmic sperm injection fertilization was 79.50% +/- 17.57%/78.72% +/- 16.66% in the Treponema pallidum particle agglutination assay negative (TPPA-negative) and rapid plasma reagin negative (RPR-negative) group, 76.12% +/- 22.99%/74.05% +/- 20.31% in the TPPA-positive and RPR-negative group, and 75.66% +/- 21.72%/70.90% +/- 16.11% in the TPPA-positive and RPR-positive group. The clinical pregnancy rate was 39.79% in the TPPA-negative and RPR negative group, 46.30% in the TPPA-positive and RPR-negative group, and 36.59% in the TPPA-positive and RPR-positive group. No significant differences were found between the groups. The neonatal gestational age and mean birth weight were not significantly different between the TPPA-negative and TPPA-positive groups. Multiple linear regression analysis also showed no association between TPPA serostatus and newborn birth weight and gestational age. The present retrospective study showed that TPPA and RPR serostatus did not affect the outcomes of IVF and embryo transfer. Syphilis-infected individuals can undergo IVF and embryo transfer cycles after penicillin treatment. PMID- 25444511 TI - Knockdown of prohibitin expression promotes glucose metabolism in eutopic endometrial stromal cells from women with endometriosis. AB - In this in-vitro study, the effect of prohibitin (PHB) on glucose metabolism in eutopic endometrial stromal cells from women with endometriosis was investigated. Endometrial stromal cells were isolated from endometrium in women with endometriosis, in women without endometriosis, or from endometrioma tissues. Glucose metabolic phenotype of stromal cells were examined in vitro. Quantitative polymerase chain reaction was used to measure the mRNA expression of glycolysis related genes. Glucose consumption and lactate production were examined after knockdown of PHB expression in women with endometriosis with siRNA. In endometrioma tissue, significantly increased glucose consumption, lactate production and aberrant expression of glycolysis-related enzymes were found in women with endometriosis compared with women who do not have endometriosis (P < 0.05 versus P < 0.001). In women with endometriosis, PHB mRNA and protein were under-expressed in endometrioma tissue; in women without endometriosis, PHB mRNA and protein were over-expressed. Knockdown of PHB expression in women with endometriosis increased glucose consumption, although it had no effect on lactate production. This study suggests that aberrant expression of glycolysis-related enzymes in endometrioma tissue is associated with enhanced glycolytic metabolism. The malignant-like feature may be partially caused by low-expression of PHB gene in endometriotic stromal cells. PMID- 25444512 TI - Preoperative gemcitabine-based chemoradiation therapy for pancreatic ductal adenocarcinoma of the body and tail: impact of splenic vessels involvement on operative outcome and pattern of recurrence. AB - BACKGROUND: Among the various multimodal treatment strategies for pancreatic ductal adenocarcinoma (PDA), preoperative chemoradiation therapy (CRT) and subsequent operation is a promising strategy. The aim of this study is to evaluate the outcome of preoperative gemcitabine-based CRT for PDA of the body and tail, focusing on the associations among splenic vessel involvement, surgical outcomes, and pattern of recurrence. METHODS: A total of 99 patients with PDA of the body and tail received preoperative CRT. The status of tumor involvement of the splenic artery (SA) and vein (SV) were evaluated based on radiographical findings obtained before the initiation of preoperative CRT. We assessed the following in association with the status of SA and SV involvement: (1) resection rate, (2) survival, and (3) pattern of recurrence. RESULTS: The resection rate of SA-positive cases (71%) was significantly lesser than that of SA-negative cases (94%; P = .004), whereas SV involvement was not associated with the resection rate. The 5-year survival rates of the resected SA-negative and SA-positive cases were 76% and 20%, respectively (P < .001). The 5-year cumulative incidence of distant recurrence was significantly higher in the SA-positive patients than in the SA-negative patients (74% vs. 17%; P < .001). CONCLUSION: In preoperative CRT for PDA of the body and tail, positive SA involvement was associated with a lesser resection rate, and the survival rate for the patients with SA-positive tumors was lesser than that for patients with SA-negative tumors because of the greater incidence of distant recurrence in SA-positive patients. PMID- 25444513 TI - Biofeedback and electrostimulation: last chance or first choice for obstructed defecation? PMID- 25444515 TI - WITHDRAWN:Postoperative surgical complications after lung transplantation. AB - This article has been withdrawn for editorial reasons because the journal will be published only in English. In order to avoid duplicated records, this article can be found at http://dx.doi.org/10.1016/j.rppnen.2014.09.007. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25444514 TI - Molecular analysis of sunitinib resistant renal cell carcinoma cells after sequential treatment with RAD001 (everolimus) or sorafenib. AB - Sequential application of target drugs is standard procedure after renal cell carcinoma (RCC) patients develop resistance. To optimize the sequence, antitumour effects of the mTOR inhibitor RAD001 or the tyrosine kinase inhibitor (TKI) sorafenib on RCC cells with acquired resistance to the TKI sunitinib was evaluated. RCC cells were exposed to 1 MUM sunitinib for 24 hrs (as control) and for 8 weeks (to induce resistance) and then switched to RAD001 (5 nM) or sorafenib (5 MUM) for a further 8 weeks. Tumour cell growth, cell cycle progression, cell cycle regulating proteins and intracellular signalling were then investigated. Short-term application of sunitinib (24 hrs) induced cell growth blockade with accumulation in the G2/M phase. RCC cells became resistant to sunitinib after 8 weeks, demonstrated by accelerated cell growth along with enhanced cdk1, cdk2, loss of p27, activation of Akt, Rictor and Raptor. Switching to sorafenib only slightly reduced growth of the sunitinib resistant RCC cells and molecular analysis indicated distinct cross-resistance. In contrast, full response was achieved when the cancer cells were treated with RAD001. p19 and p27 strongly increased, phosphorylated Akt, Rictor and Raptor decreased and the tumour cells accumulated in G0/G1. It is concluded that an mTOR-inhibitor for second-line therapy could be the strategy of choice after first-line sunitinib failure. PMID- 25444516 TI - WITHDRAWN: The future of lung transplantation. AB - This article has been withdrawn for editorial reasons because the journal will be published only in English. In order to avoid duplicated records, this article can be found at http://dx.doi.org/10.1016/j.rppnen.2014.09.006. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25444517 TI - Impact of dietary n-3 polyunsaturated fatty acids on cognition, motor skills and hippocampal neurogenesis in developing C57BL/6J mice. AB - Maternal intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) is critical during perinatal development of the brain. Docosahexaenoic acid (DHA) is the most abundant n-3 PUFA in the brain and influences neuronal membrane function and neuroprotection. The present study aims to assess the effect of dietary n-3 PUFA availability during the gestational and postnatal period on cognition, brain metabolism and neurohistology in C57BL/6J mice. Female wild-type C57BL/6J mice at day 0 of gestation were randomly assigned to either an n-3 PUFA deficient diet (0.05% of total fatty acids) or an n-3 PUFA adequate diet (3.83% of total fatty acids) containing preformed DHA and its precursor alpha-linolenic acid. Male offspring remained on diet and performed cognitive tests during puberty and adulthood. In adulthood, animals underwent (31)P magnetic resonance spectroscopy to assess brain energy metabolites. Thereafter, biochemical and immunohistochemical analyses were performed assessing inflammation, neurogenesis and synaptic plasticity. Compared to the n-3 PUFA deficient group, pubertal n-3 PUFA adequate fed mice demonstrated increased motor coordination. Adult n-3 PUFA adequate fed mice exhibited increased exploratory behavior, sensorimotor integration and spatial memory, while neurogenesis in the hippocampus was decreased. Selected brain regions of n-3 PUFA adequate fed mice contained significantly lower levels of arachidonic acid and higher levels of DHA and dihomo-gamma-linolenic acid. Our data suggest that dietary n-3 PUFA can modify neural maturation and enhance brain functioning in healthy C57BL/6J mice. This indicates that availability of n-3 PUFA in infant diet during early development may have a significant impact on brain development. PMID- 25444518 TI - Plastic deformation of the forearm in adults: an analysis of 30 cases. AB - BACKGROUND: Plastic deformation of the forearm is a rare and frequently missed injury in adults that can result in a significant loss of forearm rotation. The condition is reported mainly in Western countries; however, it is not uncommon in Eastern developing countries. We conducted a retrospective study of 30 cases of forearm deformation to find common factors to increase awareness of the condition in trauma doctors. METHODS: We analyzed 30 cases of forearm plastic deformation in adult patients first diagnosed and treated at the Orthopedic Department of our hospital between January 2000 and June 2012. Patients' age, injury mechanism, therapeutic process, and forearm rotation function were recorded for further analysis. RESULTS: The average patient age was 21.3 years (range, 17-24 years), and the most common injury occurred at the right forearm in 29 patients (96.7%) when the arm became trapped in a machine with moving rollers. The remaining patient was injured while skiing. Twelve patients had a radial or ulnar fracture, 16 patients sustained no fracture, one patient had both radial and ulnar fractures, and one patient had an ipsilateral humeral fracture. Thirteen patients agreed to surgical osteotomy to reset the fracture or the distal/proximal radioulnar joint dislocation. All patients obtained good forearm function postoperatively, with an average pronation of 77 degrees and supination of 78 degrees . One patient refused surgical treatment, which led to forearm deformity and dysfunctional rotation. CONCLUSIONS: We found that adult patients with forearm plastic deformation had similar age (17-24 years) and injury mechanism (entrapment in moving rollers in machines). In cases where the resulting ulnar or radial fractures and the distal/proximal radioulnar dislocation cannot be reset, we advise surgical osteotomy. PMID- 25444519 TI - Treatment by medical compression stockings among 144 consecutive patients with non-complicated primary varicose veins: results on compliance. AB - Compression stockings are the major long-term treatment of non-complicated primary varicose veins recommended by international consensus. Nevertheless there are few data concerning the patient compliance to treatment. Hundred and forty four patients with varicose veins of primary origin were prospectively recruited and questioned about their compression therapy: 29.2% patients are wearing compression stockings, and for 10.4% on a daily basis; 32.6% do not wear their compression mainly because it is not well tolerated; 38.2% do not have compression treatment because it is not recommended or not prescribed by the physician. PMID- 25444521 TI - The first cataract surgeons in Anglo-America. AB - We tried to identify the earliest cataract surgeons in the English-speaking areas of America. In 1751, couching was performed on the Caribbean island of Montserrat by John Morphy. William Stork of England, who couched cataracts, practiced in Jamaica in 1760 and then in cities from Annapolis to Boston between 1761 and 1764. Frederick William Jericho of Germany, upon completion of his training at Utrecht, published his 1767 treatise on his preferred surgical technique of extracapsular cataract extraction. Jericho had practiced in the Leeward Islands by 1776 and then in cities from Charleston to Boston between 1783 and 1785. The French surgeon Lewis Leprilete was the first to advertise cataract extraction in the United States in 1782 and probably passed on the skill to his protege, Nathaniel Miller of Massachusetts. Leprilete was also the first to publicize Benjamin Franklin's invention of bifocals. These pioneers exposed American doctors and the public to cataract surgery. Shortly after their arrival, evidence emerges of other surgeons performing these procedures in America. PMID- 25444522 TI - Brivaracetam differentially affects voltage-gated sodium currents without impairing sustained repetitive firing in neurons. AB - AIMS: Brivaracetam (BRV) is an antiepileptic drug in Phase III clinical development. BRV binds to synaptic vesicle 2A (SV2A) protein and is also suggested to inhibit voltage-gated sodium channels (VGSCs). To evaluate whether the effect of BRV on VGSCs represents a relevant mechanism participating in its antiepileptic properties, we explored the pharmacology of BRV on VGSCs in different cell systems and tested its efficacy at reducing the sustained repetitive firing (SRF). METHODS: Brivaracetam investigations on the voltage gated sodium current (I(Na)) were performed in N1E-155 neuroblastoma cells, cultured rat cortical neurons, and adult mouse CA1 neurons. SRF was measured in cultured cortical neurons and in CA1 neurons. All BRV (100-300 MUM) experiments were performed in comparison with 100 MUM carbamazepine (CBZ). RESULTS: Brivaracetam and CBZ reduced IN a in N1E-115 cells (30% and 40%, respectively) and primary cortical neurons (21% and 47%, respectively) by modulating the fast inactivated state of VGSCs. BRV, in contrast to CBZ, did not affect I(Na) in CA1 neurons and SRF in cortical and CA1 neurons. CBZ consistently inhibited neuronal SRF by 75-93%. CONCLUSIONS: The lack of effect of BRV on SRF in neurons suggests that the reported inhibition of BRV on VGSC currents does not contribute to its antiepileptic properties. PMID- 25444523 TI - The prevalence of congenital hearing loss in neonates with Down syndrome. AB - OBJECTIVE: To determine the prevalence of hearing loss in newborns with Down syndrome. STUDY DESIGN: We performed a cross-sectional, retrospective chart review of all infants with Down syndrome born at a university-affiliated hospital (n = 77) or transferred in to the associated pediatric hospital (n = 32) following birth at an outlying hospital between 1995 and 2010. We determined the rate of failure of newborn hearing screens, the proportion of infants lost to follow-up, and the rate of confirmed hearing loss, as well as the associations of risk factors for hearing loss with confirmed hearing loss. RESULTS: Of the 109 patients with hearing screening data, 28 failed their newborn hearing screen. Twenty-seven infants were referred for audiologic evaluation, and 19 completed the evaluation. Fifteen of these 19 infants (79%) had confirmed hearing loss. The prevalence of congenital hearing loss in this sample of neonates with Down syndrome was 15%. Exposure to mechanical ventilation was the sole known risk factor associated with hearing loss. In this study, the loss to follow-up rate for infants with positive hearing screens was 32%. CONCLUSION: Newborns with Down syndrome have a higher prevalence of congenital hearing loss compared with the total neonatal population (15% vs 0.25%). Continued monitoring of hearing is needed in children with Down syndrome. PMID- 25444520 TI - Corneal lymphangiogenesis in herpetic stromal keratitis. AB - Corneal lymphangiogenesis is the extension of lymphatic vessels into the normally alymphatic cornea, a process that compromises the cornea's immune-privileged state and facilitates herpetic stromal keratitis (HSK). HSK results most commonly from infection by herpes simplex virus-1 (HSV-1) and is characterized by immune- and inflammation-mediated damage to the deep layers of the cornea. Current research demonstrates the potential of anti-lymphangiogenic therapy to decrease and prevent herpes-induced lymphangiogenesis. PMID- 25444524 TI - Evaluation of febrile, nonneutropenic pediatric oncology patients with central venous catheters who are not given empiric antibiotics. AB - OBJECTIVE: To evaluate the practice of empiric antibiotics for febrile, nonneutropenic pediatric oncology patients with a central venous catheter (CVC) in place. STUDY DESIGN: Episodes of fever without neutropenia (absolute neutrophil count [ANC] >=500 cells/mm(3)) were reviewed retrospectively in pediatric oncology patients with a CVC undergoing chemotherapy. Characteristics and symptoms were compared between patients with bacteremia and patients without bacteremia. RESULTS: A total of 392 episodes of nonneutropenic fever in 138 subjects (52 females; 38%) were reviewed. In this cohort, the median age at an episode was 7 years, and the majority of patients had a diagnosis of acute leukemia (54%). Median ANC was 3100 cells/mm(3) (IQR, 1570-5980 cells/mm(3)). Median temperature was 38.7 degrees C (IQR, 38.3-39.2 degrees C). Twenty-four infectious episodes (6%) occurred in 18 subjects, and 5 CVCs required removal; all patients requiring removal admitted and received antibiotics owing to chills. There were no significant difference in age, sex, or ANC between patients with bacteremia and those without bacteremia; however, mean temperature was higher in the patients with bacteremia (39.4 degrees C vs 38.7 degrees C; P = .003). No deaths due to sepsis occurred, and no CVCs were removed because antibiotics were not administered empirically. CONCLUSION: Our practice of observing pediatric oncology patients undergoing chemotherapy with CVCs who are not neutropenic does not appear to lead to increased serious adverse outcomes and avoids antibiotic exposure for >90% of patients without a bacterial infection. PMID- 25444525 TI - Vaccinating my way--use of alternative vaccination schedules in New York State. AB - OBJECTIVE: To identify children vaccinated following an alternative vaccine schedule using immunization information system data and determine the impact of alternative schedule use on vaccine coverage. STUDY DESIGN: Children born in New York State, outside New York City, between January 1, 2009 and August 14, 2011 were assessed for vaccination patterns consistent with use of an alternative schedule. Children who by 9 months of age had at least 3 vaccination visits recorded in the statewide mandatory immunization information system after 41 days of age were classified as either attempting to conform to the Centers for Disease Control and Prevention published recommended vaccination schedule or an alternative schedule. The number of vaccination visits and up-to-date status at age 9 months were compared between groups. RESULTS: Of the 222 628 children studied, the proportion of children following an alternative schedule was 25%. These children were significantly less likely to be up-to-date at age 9 months (15%) compared with those conforming to the routine schedule (90%, P < .05). Children following an alternative schedule on average had about 2 extra vaccine visits compared with children following a routine schedule (P < .05). CONCLUSIONS: Almost 1 in 4 children in this study appear to be intentionally deviating from the routine schedule. Intentional deviation leads to poor vaccination coverage leaving children vulnerable to infection and increasing the potential for vaccine-preventable disease outbreaks. PMID- 25444526 TI - Pulse oximetry measures a lower heart rate at birth compared with electrocardiography. AB - OBJECTIVE: To examine the effect of time after birth on heart rate (HR) measured by pulse oximetry (PO) (HRPO) and electrocardiography (ECG) (HRECG). STUDY DESIGN: HRECG and HRPO (collected at maximum sensitivity) were assessed in 53 term and preterm infants at birth. ECG electrodes and a PO sensor were attached as soon as possible and HRECG and HRPO were compared every 30 seconds from 1-10 minutes after birth. Data were compared using a Wilkinson signed-rank test. Clinical relevance (eg, HR <100 beats per minute [bpm] was tested using a McNemar test). RESULTS: Seven hundred fifty-five data pairs were analyzed. Median (IQR) gestational age was 37 (31-39) weeks. Mean (SD) starting time of PO and ECG data collection was 99 (33) vs 82 (26) seconds after birth (P = .001). In the first 2 minutes after birth, HRPO was significantly lower compared with HRECG (94 (67 144) vs 150 (91-153) bpm at 60 seconds (P < .05), 81 (60-109) vs 148 (83-170) bpm at 90 seconds (P < .001) and 83 (67-145) vs 158 (119-176) at 120 seconds (P < .001). A HR <100 bpm was more frequently observed with a PO than ECG in the first 2 minutes (64% vs 27% at 60 seconds (P = .05), 56% vs 26% at 90 seconds (P < .05) and 53% vs 21% at 120 seconds (P < .05). HR by ECG was verified by ultrasound for outflow from a subset of infants. CONCLUSIONS: In infants at birth, HRPO is significantly lower compared with ECG with clinically important differences in the first minutes. PMID- 25444528 TI - Lysosomal storage disorder screening implementation: findings from the first six months of full population pilot testing in Missouri. AB - OBJECTIVE: To evaluate the performance of a statewide full-population pilot study in Missouri on newborn blood spots for screening of lysosomal storage disorders (LSDs) using digital microfluidics. STUDY DESIGN: A full-population pilot study using a multiplexed fluorometric enzymatic assay to detect Pompe disease, Fabry disease, Gaucher disease, and mucopolysaccharidosis type I (MPS I) in the Missouri newborn population is ongoing. Provisional cutoff values were determined during a prepilot study. All newborn dried blood spots received at the Missouri State Public Health Laboratory for routine newborn screening were screened for the 4 LSDs during the pilot study. Newborns determined to be screen-positive were referred for confirmatory testing. RESULTS: The study commenced on January 11, 2013; during the first 6 months, 43,701 specimens were screened, and 27 newborns with a confirmed diagnosis of an LSD genotype (8 with Pompe disease, 1 with Gaucher disease, 15 with Fabry disease, and 3 with MPS I) were identified. These numbers correspond to detection rates of 1:5463 for Pompe disease, 1:43,701 for Gaucher disease, 1:2913 for Fabry disease, and 1:14,567 for MPS I. The positive predictive values were 47% for Pompe disease with 1 lost to follow-up, 10% for Gaucher disease, 58% for Fabry disease with 2 lost to follow-up, and 11% for MPS I with 4 pending. CONCLUSION: The first 6 months of the Missouri LSD pilot study provided the opportunity to validate the effectiveness of the digital microfluidic screening method, refine the cutoffs for detection of these LSDs, and test the entire system of infant referral, follow-up, confirmation, treatment, and screening program communication. PMID- 25444529 TI - Transcranial Doppler screening of Medicaid-insured children with sickle cell disease. AB - Transcranial Doppler screening reduces the risk of stroke in children with sickle cell disease. We tested the effect of informational letters sent to parents and doctors of Medicaid-insured children on improving screening efficiency. The letters did not improve the low baseline screening rates, suggesting the need for more aggressive outreach. Hematologist visits were correlated with increased screening rates. PMID- 25444527 TI - Ezetimibe reduces plant sterol accumulation and favorably increases platelet count in sitosterolemia. AB - OBJECTIVE: To assess if ezetimibe (EZE), a sterol-absorption inhibitor, improves platelet (PLT) count and size relative to its effect on plasma plant sterol (PS) in patients with sitosterolemia (STSL). STUDY DESIGN: Patients with STSL (5 males, 3 females, 16-56 years of age) receiving EZE intervention as part of their routine care participated in this study. EZE was discontinued for 14 weeks (off) and then resumed for another 14 weeks (on). Hematology variables along with plasma and red blood cells (RBC) PS and total cholesterol (TC) levels were measured at the end of each phase. RESULTS: EZE increased PLT count (23% +/- 9%) and decreased mean PLT volume (MPV; 10% +/- 3%, all P < .05). In patients off EZE, PLT counts inversely correlated (r = -0.96 and r = -0.91, all P < .01) with plasma and RBC PS to TC ratio (PS/TC), and MPV positively correlated (r = 0.91, P = .03 and r = 0.93, P = .02) with plasma and RBC PS/TC. EZE reduced plasma and RBC sitosterol (-35% +/- 4% and -28% +/- 3%), total PS (-37% +/- 4% and -28% +/- 3%, all P < .0001) levels, and PS/TC (-27% +/- 4% and -28% +/- 4%, P < .01). CONCLUSIONS: EZE reduces plasma and RBC PS levels, while increasing PLT count and decreasing MPV, and thereby may reduce the risk for bleeding in STSL. Plasma PS levels and ABCG5/ABCG8 genes should be analyzed in patients with unexplained hematologic abnormalities. PMID- 25444530 TI - Increased plasma incretin concentrations identifies a subset of patients with persistent congenital hyperinsulinism without KATP channel gene defects. AB - Congenital hyperinsulinism causes profound hypoglycemia, which may persist or resolve spontaneously. Among 13 children with congenital hyperinsulinism, elevated incretin hormone concentrations were detected in 2 with atypical, persistent disease. We suggest that incretin biomarkers may identify these patients, and that elevated hormone levels may contribute to their pathophysiology. PMID- 25444531 TI - Probiotics for infantile colic: a randomized, double-blind, placebo-controlled trial investigating Lactobacillus reuteri DSM 17938. AB - OBJECTIVE: To investigate the effectiveness of Lactobacillus reuteri DSM 17938 for the treatment of infantile colic in breastfed Canadian infants, compared with placebo. STUDY DESIGN: A randomized, double-blind, placebo-controlled trial was conducted involving 52 infants with colic, according to modified Wessel criteria, who were assigned at random to receive L reuteri DSM 17938 (10(8) colony-forming units) (n = 24) or placebo (n = 28) for 21 days. Daily crying and fussing times were recorded in a structured diary, and maternal questionnaires were completed to monitor changes in infant colic symptoms and adverse events. RESULTS: Total average crying and fussing times throughout the study (from baseline to day 21) were significantly shorter among infants with colic in the probiotic group compared with infants in the placebo group (1719 +/- 750 minutes [29 +/- 13 hours] vs 2195 +/- 764 minutes [37 +/- 13 hours]; P = .028) (relative risk, 0.78; 95% CI, 0.58-0.98). Infants given L reuteri DSM 17938 showed a significant reduction in daily crying and fussing times at the end of treatment period compared with those receiving placebo (median, 60 minutes/day [IQR, 64 minutes/day] vs 102 minutes/day [IQR, 87 minutes/day]; P = .045). On day 21, a significantly higher proportion of infants in the L reuteri DSM 17938 group responded to treatment with a >=50% crying time reduction compared with infants given placebo (17 vs 6, P = .035; relative risk, 3.3; 95% CI, 1.55-7.03). CONCLUSION: Administration of L reuteri DSM 17938 significantly improved colic symptoms by reducing crying and fussing times in breastfed Canadian infants with colic. PMID- 25444532 TI - A little bit of knowledge is a dangerous thing. PMID- 25444533 TI - Tuberous xanthoma as a presenting feature of familial homozygous hypercholesterolemia with aortic regurgitation. PMID- 25444534 TI - Pediatric heparin-induced thrombocytopenia: prevalence, thrombotic risk, and application of the 4Ts scoring system. AB - OBJECTIVE: To characterize heparin-induced thrombocytopenia (HIT) at a single pediatric center including the prevalence and the accuracy of the 4Ts scoring system as a predictor of HIT. STUDY DESIGN: In this retrospective cohort study, we identified 155 consecutive patients <21 years old with sufficient data for 4Ts scoring. The 4Ts scoring system is a validated pretest tool in adults that predicts the likelihood of HIT using clinical features. Hospital-wide exposure to unfractionated and low molecular weight heparin was determined by querying the hospital pharmacy database. RESULTS: The majority of patients with suspected HIT (61.2%) were on surgical services. Prediction of HIT risk using initial 4Ts scoring found 3 (2%) had high risk 4Ts scores, 114 (73%) had intermediate risk 4Ts scores, and the remaining 38 (25%) had low risk 4Ts scores. HIT was confirmed in 0/38 patients with low risk 4Ts scores, 2/114 patients with intermediate-risk 4Ts scores, and all 3 patients with high-risk 4Ts scores presented with HIT with thrombosis. Of 12 positive HIT screening tests, results were falsely positive in 66.6% of patients with intermediate risk 4Ts scores and 100% of patients with low risk 4Ts scores. The prevalence of HIT was 0.058% and HIT with thrombosis was 0.046% in pediatric patients on unfractionated heparin. CONCLUSIONS: The prevalence of HIT appears significantly lower in pediatric patients compared with adults. Application of the 4Ts system as a pretest tool may reduce laboratory evaluation for HIT in heparin-exposed children with low risk 4Ts scores, decreasing unnecessary further testing, intervention, and cost. PMID- 25444535 TI - Neural correlates of behavior therapy for Tourette's disorder. AB - Tourette's disorder, also called Tourette syndrome (TS), is characterized by motor and vocal tics that can cause significant impairment in daily functioning. Tics are believed to be due to failed inhibition of both associative and motor cortico-striato-thalamo-cortical pathways. Comprehensive Behavioral Intervention for Tics (CBIT), which is an extension of Habit Reversal Therapy (HRT), teaches patients to become more aware of sensations that reliably precede tics (premonitory urges) and to initiate competing movements that inhibit the occurrence of tics. In this study, we used functional magnetic resonance imaging (fMRI) to investigate the neural changes associated with CBIT treatment in subjects with TS. Eight subjects with TS were matched with eight healthy controls in gender, education, age, and handedness. Subjects completed the Visuospatial Priming (VSP) task, a measure of response inhibition, during fMRI scanning before and after CBIT treatment (or waiting period for controls). For TS subjects, we found a significant decrease in striatal (putamen) activation from pre- to post treatment. Change in VSP task-related activation from pre- to post-treatment in Brodmann's area 47 (the inferior frontal gyrus) was negatively correlated with changes in tic severity. CBIT may promote normalization of aberrant cortico striato-thalamo-cortical associative and motor pathways in individuals with TS. PMID- 25444538 TI - Semi-automated kinetic perimetry provides additional information to static automated perimetry in the assessment of the remaining visual field in end-stage glaucoma. AB - PURPOSE: To test the hypothesis whether semi-automated kinetic perimetry (SKP) provides additional information to static automated perimetry (SAP) in the assessment of the remaining visual field in end-stage glaucoma, as defined by disc appearance (cup-to-disc ratio worse than 0.9) and SAP criteria (MD worse than 20 dB). METHODS: Fifty eyes of 44 patients presenting with end-stage glaucoma were examined first with SAP within the central 30 degrees using stimulus size III, followed by SKP within 90 degrees using test targets III4e and V4e. RESULTS: Overall, SKP provided additional information over SAP in more than half (54%) of the cases. In 16 instances (32%), SKP revealed visual field island beyond 30 degrees that was undetected by SAP. In eight cases (16%), SKP showed both a central island and peripheral island of visual field. In three cases (6%) altitudinal scotomatous loss was found using SKP, but not in SAP. In 23 cases (46%) the central visual field island was defined both with SAP and SKP. The mean examination duration was 4 min for SAP and 9 min for SKP. CONCLUSIONS: In clinical practice, SKP with III4e and V4e test targets provides more information than 30 degrees SAP regarding the remaining peripheral VF in patients with end-stage glaucoma; however, a longer test time is required for SKP. PMID- 25444536 TI - A preliminary examination of cortical neurotransmitter levels associated with heavy drinking in posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) patients have low cortical concentrations of gamma-aminobutyric acid (GABA) and elevated glutamate (Glu) as measured by proton magnetic resonance spectroscopy ((1)H MRS). Alcohol use disorder (AUD) is highly comorbid with PTSD, but the neurobiological underpinnings are largely unknown. We wanted to determine if PTSD patients with AUD have normalized cortical GABA and Glu levels in addition to metabolite alterations common to AUD. We compared brain metabolite concentrations in 10 PTSD patients with comorbid AUD (PAUD) with concentrtations in 28 PTSD patients without AUD and in 20 trauma-exposed controls (CON) without PTSD symptoms. We measured concentrations of GABA, Glu, N acetylaspartate (NAA), creatine- (Cr) and choline-containing metabolites (Cho), and myo-Inositol (mI) in three cortical brain regions using (1)H MRS and correlated them with measures of neurocognition, insomnia, PTSD symptoms, and drinking severity. In contrast to PTSD, PAUD exhibited normal GABA and Glu concentrations in the parieto-occipital and temporal cortices, respectively, but lower Glu and trends toward higher GABA levels in the anterior cingulate cortex (ACC). Temporal NAA and Cho as well as mI in the ACC were lower in PAUD than in both PTSD and CON. Within PAUD, more cortical GABA and Glu correlated with better neurocognition. Heavy drinking in PTSD is associated with partially neutralized neurotransmitter imbalance, but also with neuronal injury commonly observed in AUD. PMID- 25444537 TI - Asbestos-related lung disease: a pictorial review. AB - Asbestos exposure can lead to a variety of adverse effects in the thorax. Although currently in the western world, levels of exposure are kept in check by strict regulations, history of previous asbestos exposure continues to have an effect on many, owing to the latent nature of the pathophysiological response of the body to the inhaled fibers. The adverse effects of asbestos generally fall under 3 categories: pleural disease, lung parenchymal disease, and neoplastic disease. Effects on the pleura include pleural effusions, plaques, and diffuse pleural thickening. In the parenchyma, rounded atelectasis, fibrotic bands, and asbestosis are observed. Differentiating asbestosis from other forms of interstitial lung diseases, such as idiopathic pulmonary fibrosis, usual interstitial pneumonia, smoking-related lung disease, and mixed interstitial lung diseases, is important because the prognosis, course of disease, and management of the patient should be tailored based on the specific etiology of the disease. In this review, imaging findings specific to asbestosis are discussed. Finally, exposure to asbestos can lead to neoplastic disease such as pleural mesothelioma, peritoneal mesothelioma, and bronchogenic carcinoma. The purpose of this article is to review the effects of asbestos exposure in the thorax, pathophysiology of these responses, and disease course. Particular emphasis is placed on the radiographic appearance of the disease, discussion of various imaging modalities and their utility, and the role of imaging in the management of patients with previous asbestos exposure and asbestos-related pulmonary disease. PMID- 25444539 TI - Profiling of triacylglycerols in plant oils by high-performance liquid chromatography-atmosphere pressure chemical ionization mass spectrometry using a novel mixed-mode column. AB - In this investigation, a rapid and high-throughput method for profiling of TAGs in plant oils by liquid chromatography using a single column coupled with atmospheric pressure chemical ionization (APCI) mass spectrometry was reported. A novel mixed-mode phenyl-hexyl chromatographic column was employed in this separation system. The phenyl-hexyl column could provide hydrophobic interactions as well as pi-pi interactions. Compared with two traditionally columns used in TAG separation - the C18 column and silver-ion column, this column exhibited much higher selectivity for the separation of TAGs with great efficiency and rapid speed. By comparison with a novel mix-mode column (Ag-HiSep OTS column), which can also provide both hydrophobic interactions as well as pi-pi interactions for the separation of TAGs, phenyl-hexyl column exhibited excellent stability. LC method using phenyl-hexyl column coupled with APCI-MS was successfully applied for the profiling of TAGs in soybean oils, peanut oils, corn oils, and sesame oils. 29 TAGs in peanut oils, 22 TAGs in soybean oils, 19 TAGs in corn oils, and 19 TAGs in sesame oils were determined and quantified. The LC-MS data was analyzed by barcodes and principal component analysis (PCA). The resulting barcodes constitute a simple tool to display differences between different plant oils. Results of PCA also enabled a clear identification of different plant oils. This method provided an efficient and convenient chromatographic technology for the fast characterization and quantification of complex TAGs in plant oils at high selectivity. It has great potential as a routine analytical method for analysis of edible oil quality and authenticity control. PMID- 25444540 TI - Quantification of intracellular and extracellular digoxin and ouabain by liquid chromatography/electrospray ionization tandem mass spectrometry. AB - A liquid chromatography/tandem mass spectrometry method for the determination of intracellular accumulation in addition to transcellular transport of digoxin and ouabain in renal epithelial HK-2 cells was developed. The solid-phase extraction Bond Elut((r)) C18 (100mg/1mL) cartridge was used for the extraction of digoxin and ouabain from extracellular (medium) and intracellular (cell lysate) matrices. Chromatographic separation was performed on a CAPCELL PAK C18 MGII column (2.0mm*150mm, 5MUm). This method covered a linear range of 0.5-1000ng/mL of concentrations in medium and 0.5-1000ng of concentrations in cell lysate for digoxin and ouabain. The intra-day precision and inter-day precision of analysis were less than 11.9%, and the accuracy was within +/-11.6%. The total run time was 16min. Our method was successfully applied to the transport experiments of digoxin and ouabain by HK-2 cell monolayers. PMID- 25444541 TI - Determination of loperamide in human plasma and saliva by liquid chromatography tandem mass spectrometry. AB - A simple and sensitive liquid chromatography-tandem mass spectrometric method for quantification of loperamide in human plasma and saliva was developed and validated, and then successfully applied in pharmacokinetic clinical study to investigate and correlate bioavailability of Imodium((r)) 2mg quartet tablet dose in both human plasma and saliva. Loperamide with labeled internal standard was extracted from its biological matrix by methanol as protein direct precipitant in single extraction step. Adequate chromatographic separation for analytes from plasma and saliva matrices was achieved using ACE C18 (50mm*2.1mm, 5MUm) column, eluted by water/methanol/formic acid (30:70:0.1%, v/v), delivered isocratically at constant flow rate of 0.75ml/min. The method validation intends to investigate specificity, sensitivity, linearity, precision, accuracy, recovery, matrix effect and stability according to European guideline, and partial validation was applied on saliva, specificity, matrix effect, recovery, sensitivity, within and between day precision and accuracy. The calibration curve was linear through the range of 20-3000pg/ml in both plasma and saliva using a 50MUl sample volume. The partial validation sections outcome in saliva was so close to those in plasma. The within and between-day precisions were all below 8.7% for plasma and below 11.4% for saliva. Accuracies ranged from 94 to 105% for both matrices. In this study, 26 healthy volunteers participated in the clinical study, and 6 of gave their saliva samples in addition to plasma at the same time schedule. The pharmacokinetic parameters of Cmax, AUC0-t and AUC0-infinity, Tmax and T1/2 in both plasma and saliva were calculated and correlated. PMID- 25444542 TI - Simultaneous determination of toltrazuril and its metabolites in chicken and pig skin+fat by UPLC-UV method. AB - A reliable method for the simultaneous determination of toltrazuril and its main metabolites (toltrazuril sulphone and toltrazuril sulphoxide) in chicken and pig skin+fat was developed and validated. Analytes were extracted from skin+fat with acetonitrile. The crude extracts were subjected to liquid-liquid extraction with n-hexane, and then further cleaned using primary secondary amine and OasisTM MAX solid phase extraction cartridges. Chromatographic separation by UPLC-UV was performed on a C18+ reversed-phase column with gradient elution. Relative recovery from the spiked samples ranged from 84.8% to 109.1%. Limits of detection and quantification for the analytes were within 25-37.5MUgkg(-1) and 50-75MUgkg( 1), respectively. The developed method has been successfully applied to the depletion study of toltrazuril drug residues in chicken skin+fat. The recommended withdrawal period with oral administration based on our research is 24.18 days. PMID- 25444543 TI - Development and validation of a rapid HPLC method for the quantification of GSE4 peptide in biodegradable PEI-PLGA nanoparticles. AB - In this work a high performance liquid chromatographic (HPLC) method has been developed and validated for the content determination of GSE4 peptide in PEI-PLGA nanoparticles. Chromatographic separation was performed on a C18 column, and a gradient elution with a mobile phase composed of methanol and 0.1% aqueous trifluoroacetic acid (TFA) solution, at a flow rate of 1ml/min, was used. GSE4 peptide identification was made by fluorescence detection at 290nm. The elution of methanol:TFA was initially maintained at (20:80, v/v) for one min and the gradient changed to (80:20, v/v) in 6min. This ratio was then followed by isocratic elution at (80:20, v/v) during another min and for further 3min it was linearly modified to (20:80, v/v). The developed method was validated according to the ICH guidelines, being specific, linear in the range 10-100MUg/ml (R(2)=0.9996), precise, exhibiting good inter-day and intra-day precision reflected by the relative standard deviation values (less than 3.88%), accurate, with a recovery rate of 100.18+/-0.95%, and stable for 48h at 5 degrees C or at RT when encapsulated in nanoparticles. The method was simple, fast, and successfully used to determine the peptide content in GSE4-loaded PEI-PLGA nanoparticles. PMID- 25444544 TI - Ultra performance liquid chromatography-tandem mass spectrometry for the determination of amicarthiazol residues in soil and water samples. AB - A reliable and rapid method has been optimized to determine the residue of amicarthiazol in soil and environmental water samples. After extraction and evaporation, the extraction was carried out with solid phase extraction (SPE) cleanup using HLB cartridge (only soil samples) and for the quantitative determination by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The resulting residues of amicarthiazol were analyzed by a gradient separation performed on a UPLC system with a C18 column, methanol and water containing 0.1% (v v(-1)) formic acid as the mobile phase in the mode of electrospray positive ionization (ESI(+)) and multiple reaction monitoring (MRM). Results showed that the recoveries for spiked samples were 74.4-97.1% and 72.1 109.9% for soil and water, respectively, with the relative standard deviation (RSD) less than 10.2% when fortified at 10, 100 and 1000MUgL(-1). The limits of detection (LODs) and the limits of quantification (LOQs) for matrix matched standards ranged from 0.073-0.425MUgL(-1) and 0.243-1.42MUgL(-1). The intra-day precision (n=5) and the inter-day precision over 10 days (n=10) for the amicarthiazol in soils and water samples spiked at 100MUgL(-1) was 7.9% and 15.9%, respectively. Results indicated that the developed method could be a helpful tool for the controlling and monitoring of the risks posed by amicarthiazol to human health and environment safety. PMID- 25444545 TI - Aqueous two-phase extraction for determination of triazine herbicides in milk by high-performance liquid chromatography. AB - A simple extraction method based on acetonitrile-K2HPO4 aqueous two-phase system was developed for separation and enrichment of five triazines in milk samples. Acetonitrile was used for extraction of analytes from milk sample and precipitation of milk protein. Deproteinization and extraction were achieved in one single step. Analytes were extracted into the upper phase of the aqueous two phase system. The parameters affecting the extraction efficiency, such as the volume of acetonitrile, the type and amount of salts, pH value of sample and extraction time were investigated. The limits of detection of atraton, desmetryn, atrazine, terbumeton and terbuthylazine were 2.1, 2.6, 2.3, 2.8 and 2.5MUg/L, respectively. When the present method was applied to the analysis of real milk samples, the recoveries of analytes ranged from 86.3 to 120.6% and relative standard deviations were lower than 7.9%. PMID- 25444546 TI - Determination of cobimetinib in human plasma using protein precipitation extraction and high-performance liquid chromatography coupled to mass spectrometry. AB - Inhibition of MAP/ERK kinase (MEK) is a promising strategy to control the growth of tumors that are dependent on aberrant signaling in the MEK pathway. Cobimetinib (GDC-0973) (S)-[3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl] ((S)-3-hydroxy-3-piperidin-2-yl-azetidin-1-yl)-methanone) inhibits proliferation of a variety of human tumor cell lines by inhibiting MEK1 and MEK2. A specific high performance liquid chromatography-mass spectrometric assay was developed and validated for the determination of cobimetinib in human plasma. The overall mean recovery using protein precipitation extraction with acetonitrile was found to be 54.1%. The calibration curve was ranged from 0.20 to 100ng/mL. The LLOQ was sensitive enough to detect terminal phase concentrations of the drug. The intra- and inter-assay precision (%CV) was within 10.3% and 9.5% for cobimetinib. The assay accuracy (%RE) was within +/-13.7% of the nominal concentration values for cobimetinib with the normal analytical QCs. The developed assay was successfully used to analyze the human plasma samples (for pharmacokinetic analysis) from clinical trials. PMID- 25444547 TI - Determination of ractopamine in animal hair: application to residue depletion in sheep and residue monitoring. AB - An ultra-performance liquid chromatography tandem mass spectrometry method to determine ractopamine (RAC) in hair samples from swine, sheep, and cattle was developed. The procedure to extract from incurred hair was optimized. The samples were extracted with 0.1mol/L HCl solution. The mixture was heated to 60 degrees C in water bath for 4h. The extracts were purified by solid-phase extraction, dried under a stream of nitrogen, and then reconstituted in mobile phase for analysis, which was performed with a Waters BEH-C18 column. The limit of detection was 0.3ng/g, the limit of quantification was 1ng/g, the recoveries were between 87% and 105%, and the coefficient of variation was less than 15%. The depletion of RAC in hair was studied in healthy sheep after administration of RAC at 1000ng/g body weight for five consecutive days. The RAC residues were still detected with 82.5+/-7.2ng/g hair 27 days after drug administration. Five samples tested positive, in which the amount of RAC detected was 13-253ng/g from 569 hair samples collected from farms and slaughterhouses. These results show that animal hair is a suitable medium to monitor the illegal use of RAC in livestock production. PMID- 25444548 TI - BCG-induced protection: effects on innate immune memory. AB - The Bacille Calmette-Guerin (BCG) vaccine is the only vaccine proved to be effective against tuberculosis and it remains the most commonly used vaccine worldwide. In addition to its effects on mycobacterial diseases, an increasing body of epidemiological evidence accumulated since its introduction in 1921 shows that BCG also exerts beneficial non-specific effects ranging from protection against non-mycobacterial diseases, decreased incidence of allergic diseases, and treatment of certain malignancies. The biological substrate of these effects is mediated partly by heterologous effects on adaptive immunity, but also on the potentiation of innate immune responses through epigenetic mechanisms, a process termed 'trained immunity'. The process of trained immunity may also play a role in the beneficial effects of BCG against tuberculosis and Mycobacterium tuberculosis infection, and this could have important consequences for our quest for improving vaccination strategies. PMID- 25444549 TI - Chemokines in tuberculosis: the good, the bad and the ugly. AB - Mycobacterium tuberculosis (Mtb) infects about one-third of the world's population, with a majority of infected individuals exhibiting latent asymptomatic infection, while 5-10% of infected individuals progress to active pulmonary disease. Research in the past two decades has elucidated critical host immune mechanisms that mediate Mtb control. Among these, chemokines have been associated with numerous key processes that lead to Mtb containment, from recruitment of myeloid cells into the lung to activation of adaptive immunity, formation of protective granulomas and vaccine recall responses. However, imbalances in several key chemokine mediators can alter the delicate balance of cytokines and cellular responses that promote mycobacterial containment, instead precipitating terminal tissue destruction and spread of Mtb infection. In this review, we will describe recent insights in the involvement of chemokines in host responses to Mtb infection and Mtb containment (the good), chemokines contributing to inflammation during TB (the bad), and the role of chemokines in driving cavitation and lung pathology (the ugly). PMID- 25444551 TI - Conversion of substrate analogs suggests a Michael cyclization in iridoid biosynthesis. AB - The core structure of the iridoid monoterpenes is formed by a unique cyclization reaction. The enzyme that catalyzes this reaction, iridoid synthase, is mechanistically distinct from other terpene cyclases. Here we describe the synthesis of two substrate analogs to probe the mechanism of iridoid synthase. Enzymatic assay of these substrate analogs along with clues from the product profile of the native substrate strongly suggest that iridoid synthase utilizes a Michael reaction to achieve cyclization. This improved mechanistic understanding will facilitate the exploitation of the potential of iridoid synthase to synthesize new cyclic compounds from nonnatural substrates. PMID- 25444550 TI - Drug-induced liver injury: results from the hospital-based Berlin Case-Control Surveillance Study. AB - AIM: Drug-induced liver injury (DILI) is often responsible for acute liver failure, drug withdrawal, boxed warnings or drug non-approval. Therefore, we conducted a case-control study to determine the hepatotoxic risk of a wide range of drugs. METHODS: The Berlin Case-Control Surveillance Study FAKOS included all 51 Berlin hospitals in a hospital network. Between 2002 and 2011, 198 patients with acute idiopathic hepatitis, 377 inpatient controls and 708 outpatient controls were ascertained. Case patients were thoroughly validated using anamnestic, clinical, laboratory and histological data. Drug exposure was obtained in a face-to-face interview. A possible drug aetiology was assessed in individual patients by applying the updated Council for International Organizations of Medical Sciences (CIOMS) scale. Drug risks were further quantified [odds ratios (OR) with 95% confidence intervals (CI)] in a case control design with unconditional logistic regression analysis. Drug intake in the last 28 days before index date was considered for the analysis. RESULTS: The study corroborated hepatotoxic risks for a number of drugs, including phenprocoumon (OR 3.3, 95% CI 1.5, 6.7), amiodarone (OR 5.5, 95% CI 1.3, 21.2), clozapine (OR 34.6, 95% CI 2.8, 824.9) and flupirtine (OR 40.2, 95% CI 5.5, 856.9). Increased risks were also suggested for less commonly reported substances such as angiotensin II receptor blockers, atypical antipsychotics and for biperiden, a drug never before reported to be hepatotoxic. CONCLUSIONS: Our study identified a large number of drugs as possible causes of hepatotoxicity. The observed risk for seldom reported substances highlights the need for further post authorization safety studies not exclusively focusing on drugs already labelled as potentially hepatotoxic. PMID- 25444552 TI - The membrane-lytic peptides K8L9 and melittin enter cancer cells via receptor endocytosis following subcytotoxic exposure. AB - We investigate the cell entry mechanism of the membrane-lytic peptides K8L9 and melittin in cancer cell lines. K8L9 and melittin interacted with the highly expressed endocytic receptors neuropilin-1, low-density lipoprotein-related protein receptor 1 (LRP1), and transferrin receptor. Silencing of these receptors by small interfering RNAs (siRNAs) attenuated the cytotoxic activity of K8L9 in four cancer cell lines. Intracellular K8L9 and melittin triggered enlargement of the lysosomal compartments and cytosolic translocation of cathepsin B. Hsc70 was identified as a melittin-interactive molecule using coimmunoprecipitation and mass spectrometry, and Hsc70-siRNA attenuated the cellular uptake of K8L9 and cytotoxic activity by K8L9 and melittin. These findings suggest that K8L9 and melittin can enter cancer cells via receptor endocytosis following subcytotoxic treatment and subsequently affect lysosomal compartments. PMID- 25444554 TI - A comparison of two methods of treatment for catheter-related bloodstream infections in patients on home parenteral nutrition. AB - BACKGROUND & AIMS: Home parenteral nutrition (HPN) enables patients who cannot eat normally to survive and function. Catheter-related bloodstream infections (CRBSIs) are the most dangerous complication, which may be fatal if left untreated or if treatment is delayed. For over 20 years CRBSIs were managed by catheter removal and implantation of a new one after completion of antibiotic treatment. However, frequent catheter replacements put the patient at risk of large vein thrombosis, which may render parenteral nutrition impossible. The management of CRBSIs evolved into antibiotic treatment without catheter removal. The effectiveness of this approach was, however, limited by the low penetration of the antibiotics into the biofilm. Filling catheters with concentrated ethanol destroys the biofilm and does not result in the emergence of drug resistance. The aim of our study was to assess the remote outcomes of CRBSI treatment using two approaches: antibiotic-ethanol lock therapy and catheter replacement. METHODS: We retrospectively analysed the treatment outcomes of CRBSI diagnosed and managed in HPN patients. During the analysed period, a total of 428 patients between 13 and 96 years of age were on HPN and a total of 181 of them suffered a total of 352 CRBSI episodes managed with one of the two approaches. RESULTS: We showed no significant differences between the two approaches in terms of survival likelihood or duration of catheter use after an episode of CRBSI caused by various bacterial species. CONCLUSION: The use of antibiotic-ethanol lock therapy in the management of CRBSI is equally effective as catheter replacement. PMID- 25444553 TI - ATF6 activation reduces the secretion and extracellular aggregation of destabilized variants of an amyloidogenic protein. AB - Systemic amyloidoses result from the aberrant secretion of destabilized, amyloidogenic proteins to the serum where they aggregate into proteotoxic soluble aggregates and amyloid fibrils. Few therapeutic approaches exist to attenuate extracellular pathologic aggregation of amyloidogenic proteins, necessitating the development of new strategies to intervene in these devastating disorders. We show that stress-independent activation of the Unfolded Protein Response associated transcription factor ATF6 increases ER quality control stringency for the amyloidogenic protein transthyretin (TTR), preferentially reducing secretion of disease-associated TTR variants to an extent corresponding to the variants' destabilization of the TTR tetramer. This decrease in destabilized TTR variant secretion attenuates extracellular, concentration-dependent aggregation of amyloidogenic TTRs into soluble aggregates commonly associated with proteotoxicity in disease. Collectively, our results indicate that increasing ER quality control stringency through ATF6 activation is a strategy to attenuate pathologic aggregation of a destabilized, amyloidogenic protein, revealing a potential approach to intervene in systemic amyloid disease pathology. PMID- 25444555 TI - Interesterified fat or palm oil as substitutes for partially hydrogenated fat in maternal diet can predispose obesity in adult male offspring. AB - BACKGROUND & AIMS: Palm oil (PO) and interesterified fat (IF) have been used to replace partially hydrogenated fat (PHF), which is rich in trans isomers, in processed foods. The purpose of this study was to investigate whether normolipidic diets containing PHF, IF, or PO consumed during pregnancy and lactation affect total body adiposity and adipose tissue morphology of adult offspring mice. METHODS: Four groups of female C57BL/6 mice were fed, during pregnancy and lactation, a control diet (control group, CG), a PHF diet (trans group, TG), a PO diet (PG group), or an IF diet (IG group). After weaning (at 21 days), male pups received the control diet for 70 days. Food intake and body weight were monitored in all groups throughout the experimental period. At 3 months of age, mice were sacrificed and the inguinal (IWAT), epididymal (EWAT), retroperitoneal (RPWAT), and mesenteric (MWAT) adipose fat pads were removed and weighed. Adiposity was quantified by micro computed tomography (micro-CT), and adipocyte areas and cell number were analyzed by histology. RESULTS: PG and IG offspring gained more weight than CG and TG groups (p < 0.01) during the first 10 weeks after weaning, resulting in higher final body weights (p < 0.05). IG mice and PG mice had respectively heavier EWAT and IWAT than TG and CG mice. Micro-CT scanning revealed that the total volumes of internal, external, and total fat depots were greater in IG animals, as compared to the other groups. Larger adipocyte areas were observed in EWAT and IWAT in IG and TG, respectively, in comparison to CG and PG mice. PG mice showed increased adipocyte numbers in IWAT. CONCLUSIONS: Maternal intake of IF and/or PO during pregnancy and lactation predisposes the offspring to the development of obesity in adult life in mice. PMID- 25444556 TI - Selenium status in pregnancy influences children's cognitive function at 1.5 years of age. AB - BACKGROUND & AIMS: Selenium deficiency has been shown to affect the neurological development in animals, but human research in this area is scarce. We aimed to assess the impact of selenium status during pregnancy on child development at 1.5 years of age. METHODS: This prospective cohort study was nested into a food and micronutrient supplementation trial (MINIMat) conducted in rural Bangladesh. Using inductively coupled plasma mass spectrometry, we measured selenium concentrations in erythrocyte fraction of blood collected from 750 mothers at gestational week 30, and calculated MUg per g hemoglobin. A revised version of Bayley Scales of Infant Development was used to assess children's mental and psychomotor development. A Bangladeshi version of MacArthur's Communicative Development Inventory was used to assess language comprehension and expression. Linear regression analyses adjusted for multiple covariates were used to assess the associations. RESULTS: Maternal erythrocyte selenium concentrations varied considerably, from 0.19 to 0.87 MUg/g hemoglobin (median 0.46 MUg/g hemoglobin), and were associated with developmental measures. An increase in erythrocyte selenium by 0.50 MUg/g hemoglobin was associated with an increase in children's language comprehension by 3.7 points (0.5 standard deviations; 95% confidence interval: 0.40, 7.1; p = 0.028). The same increase in erythrocyte selenium corresponded to an increase in the girls' psychomotor development by 12 points (0.9 standard deviation; 95% confidence interval: 4.3, 19; p = 0.002), but much less in boys. CONCLUSIONS: Low prenatal selenium status seems to be disadvantageous for children's psychomotor and language development. Further studies are needed to elucidate the underlying mechanisms of these effects. PMID- 25444557 TI - Leucine as a treatment for muscle wasting: a critical review. AB - Amino acids are potent modulators of protein turnover and skeletal muscle cells are highly sensitive to changes in amino acid availability. During amino acid abundance increased activity of mTORC1 drives protein synthesis and growth. In skeletal muscle, it has been clearly demonstrated that of all the amino acids, leucine is the most potent stimulator of mTORC1 and protein synthesis in vitro and in vivo. As such, leucine has received considerable attention as a potential pharmaconutrient for the treatment of numerous muscle wasting conditions. However, despite a multitude of studies showing enhanced acute protein synthesis with leucine or leucine-rich supplements in healthy individuals, additional leucine intake does not necessarily enhance protein synthesis during muscle wasting conditions. In addition, long-term, placebo controlled, iso-caloric studies in humans consistently show no beneficial effect of leucine supplementation on skeletal muscle mass or function. This review, critically evaluates the therapeutic potential of leucine to attenuate the skeletal muscle wasting associated with ageing, cancer and immobilization/bed rest. It also highlights the impact of inflammation on amino acid sensing, mTORC1 activation and stimulation of protein synthesis and challenges the underlying hypothesis that the acute activation of mTORC1 and stimulation of protein synthesis by leucine increases in muscle mass over time. We conclude that leucine, as a standalone nutritional intervention, is not effective in the prevention of muscle wasting. Future work should focus on identifying and utilizing other nutrients or treatments that sensitize skeletal muscle to leucine, thereby enhancing its therapeutic potential for muscle wasting conditions. PMID- 25444559 TI - Abstracts of the UK Stroke Forum 2014 Conference, 2-4 December 2014, North Yorkshire, England. PMID- 25444558 TI - Fever of unknown origin (FUO) due to Legionnaire's disease. AB - Fevers of unknown origin (FUOs) may be due to any of over 200 different disorders. We present a most unusual case of an FUO in a returning traveler from the Dominican Republic. Work-up for Q fever, Brucellosis, Bartonella, malaria and HIV were negative, but very highly elevated ESRs and ferritin levels suggested possible Legionnaire's disease. This is the third reported case of Legionnaire's disease presenting as an FUO. PMID- 25444560 TI - Vulnerability to drought-induced cavitation in poplars: synthesis and future opportunities. AB - Vulnerability to drought-induced cavitation is a key trait of plant water relations. Here, we summarize the available literature on vulnerability to drought-induced cavitation in poplars (Populus spp.), a genus of agronomic, ecological and scientific importance. Vulnerability curves and vulnerability parameters (including the water potential inducing 50% loss in hydraulic conductivity, P50) were collected from 37 studies published between 1991 and 2014, covering a range of 10 species and 12 interspecific hybrid crosses. Results of our meta-analysis confirm that poplars are among the most vulnerable woody species to drought-induced cavitation (mean P50 = -1.44 and -1.55 MPa across pure species and hybrids, respectively). Yet, significant variation occurs among species (P50 range: 1.43 MPa) and among hybrid crosses (P50 range: 1.12 MPa), within species and hybrid crosses (max. P50 range reported: 0.8 MPa) as well as in response to environmental factors including nitrogen fertilization, irradiance, temperature and drought (max. P50 range reported: 0.75 MPa). Potential implications and gaps in knowledge are discussed in the context of poplar cultivation, species adaptation and climate modifications. We suggest that poplars represent a valuable model for studies on drought-induced cavitation, especially to elucidate the genetic and molecular basis of cavitation resistance in Angiosperms. PMID- 25444562 TI - When old ways no longer work: antibiotics and drug development. PMID- 25444561 TI - Evaluation of microbial diversity in the pilot-scale beer brewing process by culture-dependent and culture-independent method. AB - AIMS: In the brewing industry, microbial management is very important for stabilizing the quality of the product. We investigated the detailed microbial community of beer during fermentation and maturation, to manage beer microbiology in more detail. METHODS AND RESULTS: We brewed a beer (all-malt) and two beerlike beverages (half- and low-malt) in pilot-scale fermentation and investigated the microbial community of them using a next-generation sequencer (454 GS FLX titanium), quantitative PCR, flow cytometry and a culture-dependent method. From 28 to 88 genera of bacteria and from 9 to 38 genera of eukaryotic micro-organisms were detected in each sample. Almost all micro-organisms died out during the boiling process. However, bacteria belonging to the genera Acidovorax, Bacillus, Brevundimonas, Caulobacter, Chryseobacterium, Methylobacterium, Paenibacillus, Polaromonas, Pseudomonas, Ralstonia, Sphingomonas, Stenotrophomonas, Tepidimonas and Tissierella were detected at the early and middle stage of fermentation, even though their cell densities were low (below approx. 10(3) cells ml(-1) ) and they were not almost detected at the end of fermentation. CONCLUSIONS: We revealed that the microbial community of beer during fermentation and maturation is very diverse and several bacteria possibly survive during fermentation. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, we revealed the detailed microbial communities of beer using next-generation sequencing. Some of the micro-organisms detected in this study were found in beer brewing process for the first time. Additionally, the possibility of growth of several bacteria at the early and middle stage of fermentation was suggested. PMID- 25444563 TI - Daptomycin in combination with other antibiotics for the treatment of complicated methicillin-resistant Staphylococcus aureus bacteremia. AB - PURPOSE: Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as one of the most important nosocomial pathogens. Resistance to antibiotic therapy has been known to emerge especially in clinically complex scenarios, resulting in challenges in determining optimal treatment of serious MRSA. Daptomycin, in combination with other antibiotics, has been successfully used in the treatment of these infections, with the aims of resulting in reducing the prevention of antimicrobial resistance and increased killing compared with daptomycin monotherapy. METHODS: This article reviews all the published studies that used daptomycin combination therapy for the treatment of bacteremia and associated complicated infections caused by gram-positive organisms, including MRSA. We discuss the rationale of combination antibiotics and the mechanisms that enhance the activity of daptomycin, with special focus on the role of beta-lactam antibiotics. FINDINGS: There are limited clinical data on the use of daptomycin in combination with other antibiotics. Most of this use was as successful salvage therapy in the setting of failing primary, secondary, or tertiary therapy and/or relapsing infection. Synergy between beta-lactams and daptomycin is associated with several characteristics, including increased daptomycin binding and beta lactam-mediated potentiation of innate immunity, but the precise molecular mechanism is unknown. IMPLICATIONS: Use of daptomycin in combination with other antibiotics, especially beta-lactams, offers a promising treatment option for complicated MRSA bacteremia in which emergence of resistance during treatment may be anticipated. Because it is currently not possible to differentiate complicated from uncomplicated bacteremia at the time of presentation, combination therapy may be considered as first-line therapy, with de-escalation to monotherapy in uncomplicated cases and cases with stable pharmacologic and surgical source control. PMID- 25444564 TI - Taking the pulse of strategic outsourcing relationships. AB - PURPOSE: Articles in peer-reviewed journals and the trade press presuppose that strategic outsourcing relationships have been formed to replace preexisting collaborative approaches with contract research organizations. They do not consider that large, fragmented pharmaceutical and biotechnology companies may be supporting competing and conflicting relationship models simultaneously. A recent Tufts Center for the Study of Drug Development study quantifies actual strategic outsourcing practices among drug development companies and sheds new light on why these relationships may be failing. METHODS: Tufts Center for the Study of Drug Development conducted an in-depth assessment of 43 Phase II and III clinical studies completed since 2012 to examine the outsourcing relationships used by 9 major pharmaceutical and biotechnology companies to support key functional areas. Descriptive statistics were assessed and t tests were performed to characterize outsourcing practices by function and to determine differences in study performance between transactional and strategic outsourcing relationships. FINDINGS: The results indicate that sponsor companies are using a variety of outsourcing relationship models to support their studies, mixing and matching the use of internal staff, and using traditional transactional and strategic outsourcing relationships simultaneously. Specifically, despite the fact that each sponsor company had entered into several strategic outsourcing relationships, in no instance did a single contract research organization manage all functional areas supporting an individual Phase II or III study. In addition, sponsor companies vary the types of outsourcing relationship models that they use on a study-by-study basis. IMPLICATIONS: The inability of pharmaceutical and biotechnology companies to consistently embrace and coordinate sourcing strategies is creating internal friction and inefficiency. As a result, the expected impact of strategic outsourcing relationships on drug development performance, quality, and cost remains elusive. PMID- 25444565 TI - The synergy of the whole: building a global system for clinical trials to accelerate medicines development. AB - PURPOSE: The pharmaceutical industry, once highly respected, productive, and profitable, is in the throes of major change driven by many forces, including economics, science, regulation, and ethics. A variety of initiatives and partnerships have been launched to improve efficiency and productivity but without significant effect because they have failed to consider the process as a system. METHODS: Addressing the challenges facing this complex endeavor requires more than modifications of individual processes; it requires a fully integrated application of systems thinking and an understanding of the desired goals and complex interactions among essential components and stakeholders of the whole. A multistakeholder collaborative effort, led by the Alliance for Clinical Research Excellence and Safety (ACRES), a global nonprofit organization operating in the public interest, is now under way to build a shared global system for clinical research. Its systems approach focuses on the interconnection of stakeholders at critical points of interaction within 4 operational domains: site development and support, quality management, information technology, and safety. The ACRES initiatives, Site Accreditation and Standards, Product Safety Culture, Global Ethical Review and Regulatory Innovation, and Quality Assurance and Safety, focus on building and implementing systems solutions. Underpinning these initiatives is an open, shared, integrated technology (site and optics and quality informatics initiative). FINDINGS: We describe the rationale, challenges, progress, and successes of this effort to date and lessons learned. The complexity and fragmentation of the intensely proprietary ecosystem of drug development, challenging regulatory climate, and magnitude of the endeavor itself pose significant challenges, but the economic, social, and scientific rewards will more than justify the effort. IMPLICATIONS: An effective alliance model requires a willingness of multiple stakeholders to work together to build a shared system within a noncompetitive space that will have major benefits for all, including better access to medicines, better health, and more productive lives. PMID- 25444566 TI - A prospective flexible-dose study of paliperidone palmitate in nonacute but symptomatic patients with schizophrenia previously unsuccessfully treated with oral antipsychotic agents. AB - PURPOSE: The goal of this study was to explore the tolerability, safety, and treatment response of flexible doses of once-monthly paliperidone palmitate (PP) in the subset of nonacute but symptomatic adult patients with schizophrenia previously unsuccessfully treated with oral antipsychotic agents in the PALMFlexS (Paliperidone Palmitate Flexible Dosing in Schizophrenia) study. METHODS: This was an interventional, single-arm, international, multicenter, unblinded, 6-month study performed in patients with schizophrenia. Patients were categorized according to reasons for switching. In patients switching because of lack of efficacy or for other reasons, primary efficacy outcomes were the proportion achieving treatment response (defined as >=20% improvement in Positive and Negative Syndrome Scale [PANSS] total score from baseline to last-observation carried-forward end point) and maintained efficacy (defined as noninferiority in the change in PANSS total score at end point versus baseline [Schuirmann's test]), respectively. FINDINGS: A total of 593 patients (intention-to-treat population) were enrolled: 63.1% were male; their mean (SD) age was 38.4 (11.8) years; and 78.6% had paranoid schizophrenia. The main reasons for transition to PP were patient's wish (n = 259 [43.7%]), lack of efficacy (n = 144 [24.3%]), lack of compliance (n = 138 [23.3%]), and lack of tolerability (n = 52 [8.8%]) with the previous oral antipsychotic medication. The recommended PP initiation regimen (150 milligram equivalents [mg eq] day 1 and 100 mg eq day 8) was administered in 93.9% of patients. Mean PANSS total score decreased from 71.5 (14.6) at baseline to 59.7 (18.1) at end point (mean change, -11.7 [15.9]; 95% CI, -13.0 to -10.5; P < 0.0001). Sixty-four percent of patients showed an improvement of >=20% in PANSS total score, and the percentage of patients rated mildly ill or less in Clinical Global Impression-Severity increased from 31.8% to 63.2%. Mean personal and social performance total score (SD) increased (ie, improved) significantly for all patients from baseline to end point (58.1 [13.4] to 66.1 [15.7]; P < 0.0001). IMPLICATIONS: The PALMFlexS study is a pragmatic interventional study compared with randomized controlled trials, conducted in a large, more representative sample of patients with schizophrenia, and designed specifically to mimic real-world clinical situations. The findings support the results from randomized controlled studies. They also demonstrate that a clinically relevant treatment response is possible in patients who are considered to be clinically stable by their physician, supporting the use of flexibly dosed PP in such patients. Clinical trials.gov number: NCT01281527. PMID- 25444568 TI - Characterization of tetracycline and methicillin resistant Staphylococcus aureus strains in a Spanish hospital: is livestock-contact a risk factor in infections caused by MRSA CC398? AB - Tetracycline-resistance (Tet(R)) has been postulated as a marker of the livestock associated methicillin-resistant Staphylococcus aureus (MRSA) lineage CC398. OBJECTIVES OF THE STUDY: to determine the spa-types and assigned MLST clonal complexes (CCs) among all 98 MRSA-Tet(R) strains recovered during 2011-2012 (from different patients) in a Spanish Hospital, analyzing the possible correlation with livestock-contact of the patients. All 98 strains were assigned to 9 CCs: CC398 (60.2%), CC1 (19.4%), CC5 (12.2%), and other CCs (8.2%). The 98 patients were classified into three groups: (A) contact with livestock-animals (n=25); (B) no-contact with livestock-animals (n=42); (C) no information about animal contact (n=31). A significant higher percentage of CC398 strains was obtained in group A (76%) than in group B (50%) (p<0.05), being the percentage in group C of 61.3%. Most of MRSA-Tet(R)-CC398 strains presented a multi-resistance phenotype, including erythromycin, clindamycin, and ciprofloxacin, and the most prevalent detected genes were tet(M) and erm(C). Three strains presented the phenotype macrolide-susceptibility/lincosamide-resistance and contained the vga(A) gene. MRSA-CC1 strains showed higher percentages of erythromycin/clindamycin resistance (95%/89%) than MRSA-CC398 strains (58%/63%), and this resistance was usually mediated by erm(C) gene. Most of MRSA-CC5 strains showed resistance to ciprofloxacin, tobramycin/kanamycin and erythromycin. None of the strains presented the genes lukF/lukS-PV, tsst-1, eta, etb or etd. All MRSA-CC398 strains lacked the genes of the immune-evasion-cluster, but MRSA-CC1 strains carried these genes (type E). In conclusion, although MRSA CC398 is detected in a significant higher proportion in patients with livestock-contact; its detection in people without this type of contact also indicates its capacity for human-to human transmission. PMID- 25444567 TI - Random insertion and gene disruption via transposon mutagenesis of Ureaplasma parvum using a mini-transposon plasmid. AB - While transposon mutagenesis has been successfully used for Mycoplasma spp. to disrupt and determine non-essential genes, previous attempts with Ureaplasma spp. have been unsuccessful. Using a polyethylene glycol-transformation enhancing protocol, we were able to transform three separate serovars of Ureaplasma parvum with a Tn4001-based mini-transposon plasmid containing a gentamicin resistance selection marker. Despite the large degree of homology between Ureaplasma parvum and Ureaplasma urealyticum, all attempts to transform the latter in parallel failed, with the exception of a single clinical U. urealyticum isolate. PCR probing and sequencing were used to confirm transposon insertion into the bacterial genome and identify disrupted genes. Transformation of prototype serovar 3 consistently resulted in transfer only of sequence between the mini transposon inverted repeats, but some strains showed additional sequence transfer. Transposon insertion occurred randomly in the genome resulting in unique disruption of genes UU047, UU390, UU440, UU450, UU520, UU526, UU582 for single clones from a panel of screened clones. An intergenic insertion between genes UU187 and UU188 was also characterised. Two phenotypic alterations were observed in the mutated strains: Disruption of a DEAD-box RNA helicase (UU582) altered growth kinetics, while the U. urealyticum strain lost resistance to serum attack coincident with disruption of gene UUR10_137 and loss of expression of a 41 kDa protein. Transposon mutagenesis was used successfully to insert single copies of a mini-transposon into the genome and disrupt genes leading to phenotypic changes in Ureaplasma parvum strains. This method can now be used to deliver exogenous genes for expression and determine essential genes for Ureaplasma parvum replication in culture and experimental models. PMID- 25444569 TI - The link between ventricular repolarization variables and arterial function. AB - AIM: To assess the relationship between repolarization variables and arterial function. METHODS: A total of 54 participants, aged 33+/-10years, underwent arteriography and standard 12-lead electrocardiography (ECG). Arteriography was performed using a noninvasive automated oscillometric method, assessing: brachial (Aix Brach) and aortic augmentation index (Aix Ao), pulse wave velocity (PWV), arterial age (AA), diastolic reflection area (DRA) and diastolic area index (DAI). Standard 12-lead ECG enabled measurement of QT and Tpeak-Tend (TpTe) intervals and TpTe/QT ratios. RESULTS: QT interval was prolonged in patients with elevated blood pressure or body mass index. Significant associations were found between electrocardiographic repolarization parameters, such as QT intervals, TpTe and TpTe/QT and arteriography variables, such as Aix Brach, Aix Ao, PWV and AA. CONCLUSION: Prolonged QTc and Tpe are associated with endothelial dysfunction, arterial stiffness, impaired coronary perfusion and accelerated arterial aging. PMID- 25444570 TI - The reproducibility of QTc changes after meal intake. PMID- 25444571 TI - Dementia and obesity paradox: reply to the letter by Dr. Moga et al. PMID- 25444572 TI - Artificial neural network and falls in community-dwellers: a new approach to identify the risk of recurrent falling? AB - BACKGROUND: Identification of the risk of recurrent falls is complex in older adults. The aim of this study was to examine the efficiency of 3 artificial neural networks (ANNs: multilayer perceptron [MLP], modified MLP, and neuroevolution of augmenting topologies [NEAT]) for the classification of recurrent fallers and nonrecurrent fallers using a set of clinical characteristics corresponding to risk factors of falls measured among community dwelling older adults. METHODS: Based on a cross-sectional design, 3289 community dwelling volunteers aged 65 and older were recruited. Age, gender, body mass index (BMI), number of drugs daily taken, use of psychoactive drugs, diphosphonate, calcium, vitamin D supplements and walking aid, fear of falling, distance vision score, Timed Up and Go (TUG) score, lower-limb proprioception, handgrip strength, depressive symptoms, cognitive disorders, and history of falls were recorded. Participants were separated into 2 groups based on the number of falls that occurred over the past year: 0 or 1 fall and 2 or more falls. In addition, total population was separated into training and testing subgroups for ANN analysis. RESULTS: Among 3289 participants, 18.9% (n = 622) were recurrent fallers. NEAT, using 15 clinical characteristics (ie, use of walking aid, fear of falling, use of calcium, depression, use of vitamin D supplements, female, cognitive disorders, BMI <21 kg/m(2), number of drugs daily taken >4, vision score <8, use of psychoactive drugs, lower-limb proprioception score <=5, TUG score >9 seconds, handgrip strength score <=29 (N), and age >=75 years), showed the best efficiency for identification of recurrent fallers, sensitivity (80.42%), specificity (92.54%), positive predictive value (84.38), negative predictive value (90.34), accuracy (88.39), and Cohen kappa (0.74), compared with MLP and modified MLP. CONCLUSIONS: NEAT, using a set of 15 clinical characteristics, was an efficient ANN for the identification of recurrent fallers in older community-dwellers. PMID- 25444574 TI - Radiofrequency catheter ablation of atrial fibrillation in patients with chronic obstructive pulmonary disease: opportunity and challenge: response to Dr. Kumar's comment. PMID- 25444573 TI - Is this elderly patient dehydrated? Diagnostic accuracy of hydration assessment using physical signs, urine, and saliva markers. AB - OBJECTIVES: Dehydration in older adults contributes to increased morbidity and mortality during hospitalization. As such, early diagnosis of dehydration may improve patient outcome and reduce the burden on healthcare. This prospective study investigated the diagnostic accuracy of routinely used physical signs, and noninvasive markers of hydration in urine and saliva. DESIGN: Prospective diagnostic accuracy study. SETTING: Hospital acute medical care unit and emergency department. PARTICIPANTS: One hundred thirty older adults [59 males, 71 females, mean (standard deviation) age = 78 (9) years]. MEASUREMENTS: Participants with any primary diagnosis underwent a hydration assessment within 30 minutes of admittance to hospital. Hydration assessment comprised 7 physical signs of dehydration [tachycardia (>100 bpm), low systolic blood pressure (<100 mm Hg), dry mucous membrane, dry axilla, poor skin turgor, sunken eyes, and long capillary refill time (>2 seconds)], urine color, urine specific gravity, saliva flow rate, and saliva osmolality. Plasma osmolality and the blood urea nitrogen to creatinine ratio were assessed as reference standards of hydration with 21% of participants classified with water-loss dehydration (plasma osmolality >295 mOsm/kg), 19% classified with water-and-solute-loss dehydration (blood urea nitrogen to creatinine ratio >20), and 60% classified as euhydrated. RESULTS: All physical signs showed poor sensitivity (0%-44%) for detecting either form of dehydration, with only low systolic blood pressure demonstrating potential utility for aiding the diagnosis of water-and-solute-loss dehydration [diagnostic odds ratio (OR) = 14.7]. Neither urine color, urine specific gravity, nor saliva flow rate could discriminate hydration status (area under the receiver operating characteristic curve = 0.49-0.57, P > .05). In contrast, saliva osmolality demonstrated moderate diagnostic accuracy (area under the receiver operating characteristic curve = 0.76, P < .001) to distinguish both dehydration types (70% sensitivity, 68% specificity, OR = 5.0 (95% confidence interval 1.7-15.1) for water-loss dehydration, and 78% sensitivity, 72% specificity, OR = 8.9 (95% confidence interval 2.5-30.7) for water-and-solute-loss dehydration). CONCLUSIONS: With the exception of low systolic blood pressure, which could aid in the specific diagnosis of water-and-solute-loss dehydration, physical signs and urine markers show little utility to determine if an elderly patient is dehydrated. Saliva osmolality demonstrated superior diagnostic accuracy compared with physical signs and urine markers, and may have utility for the assessment of both water-loss and water-and-solute-loss dehydration in older individuals. It is particularly noteworthy that saliva osmolality was able to detect water-and solute-loss dehydration, for which a measurement of plasma osmolality would have no diagnostic utility. PMID- 25444575 TI - The Study of Mental and Resistance Training (SMART) study-resistance training and/or cognitive training in mild cognitive impairment: a randomized, double blind, double-sham controlled trial. AB - BACKGROUND: Mild cognitive impairment (MCI) increases dementia risk with no pharmacologic treatment available. METHODS: The Study of Mental and Resistance Training was a randomized, double-blind, double-sham controlled trial of adults with MCI. Participants were randomized to 2 supervised interventions: active or sham physical training (high intensity progressive resistance training vs seated calisthenics) plus active or sham cognitive training (computerized, multidomain cognitive training vs watching videos/quizzes), 2-3 days/week for 6 months with 18-month follow-up. Primary outcomes were global cognitive function (Alzheimer's Disease Assessment Scale-cognitive subscale; ADAS-Cog) and functional independence (Bayer Activities of Daily Living). Secondary outcomes included executive function, memory, and speed/attention tests, and cognitive domain scores. RESULTS: One hundred adults with MCI [70.1 (6.7) years; 68% women] were enrolled and analyzed. Resistance training significantly improved the primary outcome ADAS-Cog; [relative effect size (95% confidence interval) -0.33 (-0.73, 0.06); P < .05] at 6 months and executive function (Wechsler Adult Intelligence Scale Matrices; P = .016) across 18 months. Normal ADAS-Cog scores occurred in 48% (24/49) after resistance training vs 27% (14/51) without resistance training [P < .03; odds ratio (95% confidence interval) 3.50 (1.18, 10.48)]. Cognitive training only attenuated decline in Memory Domain at 6 months (P < .02). Resistance training 18-month benefit was 74% higher (P = .02) for Executive Domain compared with combined training [z-score change = 0.42 (0.22, 0.63) resistance training vs 0.11 (-0.60, 0.28) combined] and 48% higher (P < .04) for Global Domain [z-score change = .0.45 (0.29, 0.61) resistance training vs 0.23 (0.10, 0.36) combined]. CONCLUSIONS: Resistance training significantly improved global cognitive function, with maintenance of executive and global benefits over 18 months. PMID- 25444576 TI - Four-month course of soluble milk proteins interacts with exercise to improve muscle strength and delay fatigue in elderly participants. AB - BACKGROUND: The benefit of protein supplementation on the adaptive response of muscle to exercise training in older people is controversial. OBJECTIVE: To investigate the independent and combined effects of a multicomponent exercise program with and without a milk-based nutritional supplement on muscle strength and mass, lower-extremity fatigue, and metabolic markers. DESIGN: A sample of 48 healthy sedentary men aged 60.8 +/- 0.4 years were randomly assigned to a 16-week multicomponent exercise training program with a milk-based supplement containing, besides proteins [total milk proteins 4 or 10 g/day or soluble milk proteins rich in leucine (PRO) 10 g/day], carbohydrates and fat. Body composition, muscle mass and strength, and time to task failure, an index of muscle fatigue, were measured. Blood lipid, fibrinogen, creatine phosphokinase, glucose, insulin, C reactive protein, interleukin-6, tumor necrosis factor-alpha soluble receptors, and endothelial markers were assessed. RESULTS: Body fat mass was reduced after the 4-month training program in groups receiving 10 g/day of protein supplementation (P < .01). The training program sustained with the daily 10 g/day PRO was associated with a significant increase in dominant fat free mass (+5.4%, P < .01) and in appendicular muscle mass (+4.5%, P < .01). Blood cholesterol was decreased in the trained group receiving 10 g/day PRO. The index of insulin resistance (homeostasis model assessment-insulin resistance) and blood creatine phosphokinase were reduced in the groups receiving 10 g/day PRO, irrespective of exercise. The inflammatory and endothelial markers were not different between the groups. Training caused a significant improvement (+10.6% to 19.4%, P < .01) in the maximal oxygen uptake. Increased maximum voluntary contraction force was seen in the trained groups receiving 10 g/day of proteins (about 3%, P < .05). Time to task failure was improved in the trained participants receiving a 10 g/day supplementation with PRO (P < .01). CONCLUSIONS: Soluble milk proteins rich in leucine improved time to muscle failure and increase in skeletal muscle mass and strength after prolonged multicomponent exercise training in healthy older men. PMID- 25444577 TI - Repetitive transcranial magnetic stimulation over left angular gyrus modulates the predictability gain in degraded speech comprehension. AB - Increased neural activity in left angular gyrus (AG) accompanies successful comprehension of acoustically degraded but highly predictable sentences, as previous functional imaging studies have shown. However, it remains unclear whether the left AG is causally relevant for the comprehension of degraded speech. Here, we applied transient virtual lesions to either the left AG or superior parietal lobe (SPL, as a control area) with repetitive transcranial magnetic stimulation (rTMS) while healthy volunteers listened to and repeated sentences with high- versus low-predictable endings and different noise vocoding levels. We expected that rTMS of AG should selectively modulate the predictability gain (i.e., the comprehension benefit from sentences with high predictable endings) at a medium degradation level. We found that rTMS of AG indeed reduced the predictability gain at a medium degradation level of 4-band noise vocoding (relative to control rTMS of SPL). In contrast, the behavioral perturbation induced by rTMS changed with increased signal quality. Hence, at 8 band noise vocoding, rTMS over AG versus SPL decreased the number of correctly repeated keywords for sentences with low-predictable endings. Together, these results show that the degree of the rTMS interference depended jointly on signal quality and predictability. Our results provide the first causal evidence that the left AG is a critical node for facilitating speech comprehension in challenging listening conditions. PMID- 25444578 TI - Modulation of central thalamic oscillations during emotional-cognitive processing in chronic disorder of consciousness. AB - We report on thalamic recordings in a patient with chronic disorder of consciousness (DOC). Implantation of central thalamic deep brain stimulation (CT DBS) electrodes was chosen, as this treatment has been reported to display beneficial effects with respect to behavioural responsiveness in DOC. Local field potential (LFP) oscillations were recorded from central thalamic electrodes and their changes elicited by speech stimuli consisting either of familiar voices addressing the patient or unfamiliar non-addressing phrases were studied. In response to familiar-addressing speech we observed modulation of oscillatory activity in the beta and theta band within the central thalamus accompanied by an increase in thalamocortical coherence in the theta band. Furthermore, the theta phase was coupled to the amplitude of gamma locally in the thalamus. These findings indicate a local and long-range cross-frequency response which is not only indicative of the principle involvement of the central thalamus in processing emotional and cognitive information, but also point towards intact physiological functions that may serve as a marker in diagnosing DOC patients and determining novel targets and parameters concerning therapeutic efforts. PMID- 25444579 TI - Drug eruptions induced by telaprevir in patients with chronic hepatitis C virus genotype 1 infection: a prospective study. AB - INTRODUCTION: When co-administered with interferon and ribavirin, the prescription drug telaprevir significantly improves treatment response in patients with chronic hepatitis C virus (HCV) infection. Its use, however, also increases the likelihood of adverse effects that may lead to discontinuation of treatment. Cutaneous adverse effects are particularly common. OBJECTIVE: To determine the frequency and clinical characteristics of drug eruptions induced by telaprevir in patients receiving HCV treatment and to analyze the clinical course of lesions and response to treatment. MATERIAL AND METHODS: We performed a prospective observational study of all patients who started a treatment regimen that included telaprevir between May 2012 and July 2013. We recorded the demographic characteristics of the patients who developed telaprevir-induced eruptions, and analyzed the clinical characteristics of the lesions and their clinical course following the application of guideline-based treatment recommendations. RESULTS: Twenty (46%) of the 43 patients who received triple therapy with interferon, ribavirin, and telaprevir during the study period developed drug reactions attributable to telaprevir. The reaction was classified as mild or moderate (grades 1 or 2) in 90% of cases and consisted of an exanthem with erythematous-edematous scaling plaques and papules. The rash worsened, mainly by spreading, in about one-third of cases. The skin lesions led to discontinuation of treatment in 2 patients (4.6%). Sustained viral response was achieved in 34 patients (79%). CONCLUSIONS: Telaprevir-induced eruptions are common and often progress, but they rarely require patients to discontinue treatment. PMID- 25444580 TI - Histologic features of alopecias-part I: nonscarring alopecias. AB - The diagnosis of disorders of the hair and scalp can generally be made on clinical grounds, but clinical signs are not always diagnostic and in some cases more invasive techniques, such as a biopsy, may be necessary. This 2-part article is a detailed review of the histologic features of the main types of alopecia based on the traditional classification of these disorders into 2 major groups: scarring and nonscarring alopecias. Scarring alopecias are disorders in which the hair follicle is replaced by fibrous scar tissue, a process that leads to permanent hair loss. In nonscarring alopecias, the follicles are preserved and hair growth can resume when the cause of the problem is eliminated. In the first part of this review, we describe the histologic features of the main forms of nonscarring alopecia. Since a close clinical-pathological correlation is essential for making a correct histologic diagnosis of alopecia, we also include a brief description of the clinical features of the principal forms of this disorder. PMID- 25444581 TI - Morphea following radiation therapy in a patient with breast cancer. PMID- 25444582 TI - A split-face treatment of adult colloid milium using a non-ablative, 1550-nm, erbium-glass fractional laser. PMID- 25444584 TI - Multiple Sclerosis Walking Scale-12, translation, adaptation and validation for the Persian language population. AB - The Multiple Sclerosis Walking Scale-12 (MSWS-12) is a multi-item rating scale used to assess the perspectives of patients about the impact of MS on their walking ability. The aim of this study was to examine the reliability and validity of the MSWS-12 in Persian speaking patients with MS. The MSWS-12 questionnaire was translated into Persian language according to internationally adopted standards involving forward-backward translation, reviewed by an expert committee and tested on the pre-final version. In this cross-sectional study, 100 participants (50 patients with MS and 50 healthy subjects) were included. The MSWS-12 was administered twice 7 days apart to 30 patients with MS for test and retest reliability. Internal consistency reliability was Cronbach's alpha 0.96 for test and 0.97 for retest. There were no significant floor or ceiling effects. Test-retest reliability was excellent (intraclass correlation coefficient [ICC] agreement of 0.98, 95% CI, 0.95-0.99) confirming the reproducibility of the Persian MSWS-12. Construct validity using known group methods was demonstrated through a significant difference in the Persian MSWS-12 total score between the patients with MS and healthy subjects. Factor analysis extracted 2 latent factors (79.24% of the total variance). A second factor analysis suggested the 9-item Persian MSWS as a unidimensional scale for patients with MS. The Persian MSWS-12 was found to be valid and reliable for assessing walking ability in Persian speaking patients with MS. PMID- 25444583 TI - Exercise-induced bronchospasm diagnosis in children. Utility of combined lung function tests. AB - BACKGROUND: The diagnosis of exercise-induced asthma or bronchospasm (EIB) is a complex dare in daily clinical practice. The consensus is that if bronchial hyper responsiveness (BHR) is demonstrated in a patient with symptoms consistent with EIB, then that patient can be diagnosed with exercise-induced bronchospasm. The aim of this study was to determine which BHR test is the most efficient to diagnose EIB. METHODS: Children under 16, without previous asthma diagnosis, or with stable asthma, complaining of asthma-like symptoms triggered by exercise were included. Bronchodilator, methacholine, mannitol, and exercise tests were performed on all patients, following established protocols. The performance of single and combined tests was determined. RESULTS: Of 46 patients (median age: 12 yr, ranged 8-16 y.o.) were recruited, 30 (70%) previously diagnosed of asthma. BHR was detected in 93.47% of the children. The exercise challenge test detected BHR in 11 of 46 (23.90%) patients, bronchodilator test in 10 of 46 (21.70%), mannitol in 36 of 45 (80%) and methacholine in 41 of 45 (91.11%). The total number of patients with BHR was detected using a combination of the methacholine and mannitol tests. A combination of the methacholine test performed first, followed by the mannitol test, was able to diagnose BHR in 100% of children with lower number of tests (n = 45) than if the order was reversed (n = 50). CONCLUSIONS: Methacholine and mannitol tests detect BHR in most children with suspected EIB. Bronchodilator and exercise tests show a low positivity rate. A combination of the methacholine test, followed by the mannitol test, gives the highest return to identify BHR in children for the diagnosis of EIB. PMID- 25444585 TI - [Renal amyloidosis revealing a Kartagener's syndrome]. AB - Kartagener's syndrome is a rare disease. It is a clinical variant of primary ciliary dyskinesia. It combines a situs inversus, chronic sinusitis and bronchiectasis. Glomerulopathies associated with this syndrome are rarely reported. We report the case of Kartagener's syndrome in a patient diagnosed at the age of 37 years with renal amyloidosis. PMID- 25444586 TI - Reply to the letter by Andrade. PMID- 25444587 TI - Biochemical changes in cyanobacteria during the synthesis of silver nanoparticles. AB - The methods of synthesis of silver (Ag) nanoparticles by the cyanobacteria Spirulina platensis and Nostoc linckia were studied. A complex of biochemical, spectral, and analytical methods was used to characterize biomass and to assess changes in the main components of biomass (proteins, lipids, carbohydrates, and phycobilin) during nanoparticle formation. The size and shape of Ag nanoparticles in the biomass of both types of cyanobacteria were determined. Neutron activation analysis was used to study the accumulation dynamics of the Ag quantity. The analytical results suggest that the major reduction of Ag concentration in solutions and the increase in biomass occur within the first 24 h of experiments. While in this time interval minor changes in the N. linckia and S. platensis biomass took place, a significant reduction of the levels of proteins, carbohydrates, and phycobiliproteins in both cultures and of lipids in S. platensis was observed after 48 h. At the same time, the antiradical activity of the biomass decreased. The obtained results show the necessity of determining the optimal conditions of the interaction between the biomass and the solution containing Ag ions that would allow nanoparticle formation without biomass degradation at the time of Ag nanoparticle formation by the studied cyanobacteria. PMID- 25444588 TI - Effect of transcranial static magnetic field stimulation over the sensorimotor cortex on somatosensory evoked potentials in humans. AB - BACKGROUND: The motor cortex in the human brain can be modulated by the application of transcranial static magnetic field stimulation (tSMS) through the scalp. However, the effect of tSMS on the excitability of the primary somatosensory cortex (S1) in humans has never been examined. OBJECTIVE: This study was performed to investigate the possibility of non-invasive modulation of S1 excitability by the application of tSMS in healthy humans. METHODS: tSMS and sham stimulation over the sensorimotor cortex were applied to 10 subjects for periods of 10 and 15 min. Somatosensory evoked potentials (SEPs) following right median nerve stimulation were recorded before and immediately after, 5 min after, and 10 min after tSMS from sites C3' and F3 of the international 10-20 system of electrode placement. In another session, SEPs were recorded from 6 of the 10 subjects every 3 min during 15 min of tSMS. RESULTS: Amplitudes of the N20 component of SEPs at C3' significantly decreased immediately after 10 and 15 min of tSMS by up to 20%, returning to baseline by 10 min after intervention. tSMS applied while recording SEPs every 3 min and sham stimulation had no effect on SEP. CONCLUSIONS: tSMS is able to modulate cortical somatosensory processing in humans, and thus might be a useful tool for inducing plasticity in cortical somatosensory processing. Lack of change in the amplitude of SEPs with tSMS implies that use of peripheral nerve stimulation to cause SEPs antagonizes alteration of the function of membrane ion channels during exposure to static magnetic fields. PMID- 25444589 TI - Inter-individual variation in the after-effect of paired associative stimulation can be predicted from short-interval intracortical inhibition with the threshold tracking method. AB - BACKGROUND: Paired associative stimulation (PAS), which is used to test a long term potentiation (LTP)-like effect, involves repeated pairing of peripheral somatosensory input with transcranial magnetic stimulation (TMS) given 25 ms later over M1 (PAS25). The effect is usually quantified as an increase in amplitude of motor evoked potentials evoked by single pulse TMS. However, the effect varies greatly between individuals. OBJECTIVE/HYPOTHESIS: We hypothesized that variability depends on either the individual level of GABAAergic activity in cortex, or on the proportion of late I-wave inputs that are evoked by TMS pulses during PAS25. Low levels of GABA facilitate LTP, whereas late I-waves are the site of facilitation after PAS25. METHODS: GABAAergic inhibition was quantified using SICI measured with a threshold tracking method (SICI-TT) before and after PAS25 in 18 healthy volunteers. RESULTS: The PAS25 effect correlated with the level of SICI-TT (r = 0.6) before PAS25. Contrary to the GABA hypothesis, people who had good facilitation after PAS25 had good inhibition measured by SICI-TT. On completion of the PAS25 protocol, SICI-TT was reduced by an amount correlated with the size of the PAS25 effect (r = 0.5-0.6 at an interstimulus interval of 2.5-3.0 ms). CONCLUSIONS: SICI is known to target late I-waves, thus SICI-TT will depend on the proportion of late I-waves evoked by the TMS test pulse. If the pulse recruits a large fraction of late I-waves, individuals will show good SICI TT; they will also respond well to PAS25 since this relies on facilitation of late I-waves. PMID- 25444590 TI - Auditory cortex stimulation might be efficacious in a subgroup of tinnitus patients. PMID- 25444591 TI - Mitigating cutaneous sensation differences during tDCS: comparing sham versus low intensity control conditions. AB - BACKGROUND: Cutaneous sensations at electrode sites during the administration of direct current brain stimulation may inadvertently influence participants' subjective experience and task performance. OBJECTIVE: The present study evaluated the utility of a methodological variation that substitutes sham administration with very low intensity (0.5 mA) current delivery. METHODS: We used a 4 * 1 high-definition ring electrode transcranial direct current (HD-tDCS) system to target the left dorsolateral prefrontal cortex (Brodmann's Area 9). Four stimulation conditions were compared in a repeated-measures design: sham 2.0 mA and 0.5 mA intensity, versus active 2.0 mA and 0.5 mA intensity. During stimulation participants performed a cognitive interference task that activates the cingulo-frontal-parietal network, and periodically provided perceived sensation ratings. RESULTS: We demonstrate that a relatively low intensity control condition attenuates otherwise large differences in perceived sensation between active and sham conditions. Critically, behavioral task differences maintained between the two active conditions. CONCLUSION: A low intensity control stimulation condition may prove a viable methodological alternative to conventional sham techniques used in repeated-measures designs, though important limitations are discussed. PMID- 25444592 TI - Vagus nerve stimulation has antidepressant effects in the kainic acid model for temporal lobe epilepsy. AB - BACKGROUND: Depression is the most common psychiatric comorbidity in epilepsy patients. The lack of success with current pharmacological interventions for this patient population, highlights the importance of optimizing non-pharmacological neuromodulatory treatments such as vagus nerve stimulation (VNS). Studies on the antidepressant effect of VNS in epilepsy patients may be confounded by concurrent anti-epileptic drug therapy. To date, studies in epilepsy models overcoming this problem are lacking. OBJECTIVE: We investigated whether VNS affects anhedonia, a key symptom of major depression, in the kainic acid rat model for temporal lobe epilepsy. METHODS: Anhedonia was assessed in kainic acid (KA) and saline (SAL) injected rats using the saccharin preference test (SPT). To exclude differences in taste perception, the quinine aversion test (QAT) was performed. Both groups were randomly subdivided in a VNS and a SHAM group, yielding 4 experimental arms: KA-VNS, KA-SHAM, SAL-VNS and SAL-SHAM. Both VNS groups received 2 weeks of VNS, while the SHAM groups were not stimulated. Thereafter, the SPT and QAT were repeated. RESULTS: Saccharin preference was significantly reduced in the KA compared to the SAL rats (P < 0.05), without differences in quinine aversion. Two weeks of VNS significantly increased the saccharin preference in the KA-VNS group (P < 0.05), while it had no effect on quinine aversion. No effects of VNS or SHAM were found in the other groups. CONCLUSION: The KA rats displayed anhedonia which was significantly decreased by VNS, indicating that this neuromodulatory treatment could likewise diminish depressive symptoms in patients suffering from temporal lobe epilepsy and comorbid depression. PMID- 25444593 TI - Cellular and molecular changes to cortical neurons following low intensity repetitive magnetic stimulation at different frequencies. AB - BACKGROUND: Repetitive transcranial magnetic stimulation is increasingly used as a treatment for neurological dysfunction. Therapeutic effects have been reported for low intensity rTMS (LI-rTMS) although these remain poorly understood. OBJECTIVE: Our study describes for the first time a systematic comparison of the cellular and molecular changes in neurons in vitro induced by low intensity magnetic stimulation at different frequencies. METHODS: We applied 5 different low intensity repetitive magnetic stimulation (LI-rMS) protocols to neuron enriched primary cortical cultures for 4 days and assessed survival, and morphological and biochemical change. RESULTS: We show pattern-specific effects of LI-rMS: simple frequency pulse trains (10 Hz and 100 Hz) impaired cell survival, while more complex stimulation patterns (theta-burst and a biomimetic frequency) did not. Moreover, only 1 Hz stimulation modified neuronal morphology, inhibiting neurite outgrowth. To understand mechanisms underlying these differential effects, we measured intracellular calcium concentration during LI rMS and subsequent changes in gene expression. All LI-rMS frequencies increased intracellular calcium, but rather than influx from the extracellular milieu typical of depolarization, all frequencies induced calcium release from neuronal intracellular stores. Furthermore, we observed pattern-specific changes in expression of genes related to apoptosis and neurite outgrowth, consistent with our morphological data on cell survival and neurite branching. CONCLUSIONS: Thus, in addition to the known effects on cortical excitability and synaptic plasticity, our data demonstrate that LI-rMS can change the survival and structural complexity of neurons. These findings provide a cellular and molecular framework for understanding what low intensity magnetic stimulation may contribute to human rTMS outcomes. PMID- 25444594 TI - The use of technology for urgent clinician to clinician communications: a systematic review of the literature. AB - OBJECTIVE: Urgent clinician-clinician communications require routes of contact that are fast and dependable, and allow for the exchange of complex information. Despite the increasing focus on improving healthcare delivery systems over the past decade, few studies have examined the role of technology in clinician clinician communication. The aim of this study was to review the literature examining the role of devices and technology in facilitating urgent clinician clinician communication to identify critical areas for future research. MATERIALS AND METHODS: A search of Pub Med was performed using the terms (((("Critical Care"[Mesh] OR "urgent")))) AND (((hospital communication systems[MeSH Terms]) OR health communication[MeSH Terms]) OR interdisciplinary communication[MeSH Terms]). Commentaries and editorials were excluded. RESULTS: The initial search returned 272 articles, which were reviewed to identify articles describing: (1) the role of technological support or devices in clinician-clinician communication, (2) technology-based interventions that improved clinician-to clinician communication in hospitals or acute care facilities related to critically ill patients, or (3) critical information exchange. A total of 16 articles were included in the final review. These were grouped into three categories: alphanumeric pagers, cellular and smart telephones, and novel uses of technology. DISCUSSION: Breakdowns in clinician-clinician communication are complex and cannot be solved through the implementation of devices or technologically advanced systems alone. It is essential to understand the correlation between emerging technologies, a demanding workload, and clinician clinician interaction. Enhanced communication of clinical ideas, opportunities for team discussion, and a sense of partnership and support require not just increased information, but enhanced delivery. PMID- 25444596 TI - BDNF polymorphism associates with decline in set shifting in Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder caused by nigrostriatal dopaminergic degeneration. Brain-derived neurotrophic factor (BDNF) is a key protein in brain plasticity and is particularly important for survival of dopaminergic neurons. The Val66Met polymorphism of BDNF (rs6265) has been associated with functional differences (mainly cognitive) between healthy adults and also with differences in the clinical expression of several other neuropsychiatric illnesses including PD. However, these studies used different outcome measures, have not been replicated, and were cross sectional, making it difficult to establish the role of BDNF in the clinical variability of PD. Here, a large cohort of 384 PD patients were followed up for 2 years, and associations between BDNF genotype and various clinical characteristics were examined. The BDNF Met-allele carriers showed a significantly smaller decline in set shifting during follow-up compared with the homozygous BDNF Val-allele carriers. Contrary to previous assumptions, these results indicate that mental flexibility is one of the cognitive processes that may benefit from the BDNF Met allele in PD patients. PMID- 25444598 TI - Single time point high-dimensional morphometry in Alzheimer's disease: group statistics on longitudinally acquired data. AB - Quantitative assessment of medial temporal lobe atrophy has been proposed as a biomarker for Alzheimer's disease (AD) diagnostic and prognostic in mild cognitive impairment (MCI) due to AD. We present the first results of our high dimensional morphometry technique, tracking tissue composition, and atrophy changes on T1-weighted magnetic resonance imaging at various time points. We selected 187 control subjects, 17 control subjects having progressed to MCI and/or AD, 178 subjects with stable MCI, 165 subjects with MCI having progressed to AD, and 147 AD subjects from the Alzheimer's Disease Neuroimaging Initiative study. Results show statistically significant differences between almost every diagnostic and time point comparison pairs (0-12, 12-24, and 24-36 months), including controls having progressed to either MCI or AD and trajectory dynamics that demonstrate the algorithm's ability at tracking specific pathology-related neurodegeneration. PMID- 25444597 TI - Diffusion weighted imaging-based maximum density path analysis and classification of Alzheimer's disease. AB - Characterizing brain changes in Alzheimer's disease (AD) is important for patient prognosis and for assessing brain deterioration in clinical trials. In this diffusion weighted imaging study, we used a new fiber-tract modeling method to investigate white matter integrity in 50 elderly controls (CTL), 113 people with mild cognitive impairment, and 37 AD patients. After clustering tractography using a region-of-interest atlas, we used a shortest path graph search through each bundle's fiber density map to derive maximum density paths (MDPs), which we registered across subjects. We calculated the fractional anisotropy (FA) and mean diffusivity (MD) along all MDPs and found significant MD and FA differences between AD patients and CTL subjects, as well as MD differences between CTL and late mild cognitive impairment subjects. MD and FA were also associated with widely used clinical scores. As an MDP is a compact low-dimensional representation of white matter organization, we tested the utility of diffusion tensor imaging measures along these MDPs as features for support vector machine based classification of AD. PMID- 25444599 TI - Cortical surface biomarkers for predicting cognitive outcomes using group l2,1 norm. AB - Regression models have been widely studied to investigate the prediction power of neuroimaging measures as biomarkers for inferring cognitive outcomes in the Alzheimer's disease study. Most of these models ignore the interrelated structures either within neuroimaging measures or between cognitive outcomes, and thus may have limited power to yield optimal solutions. To address this issue, we propose to use a new sparse multitask learning model called Group-Sparse Multi task Regression and Feature Selection (G-SMuRFS) and demonstrate its effectiveness by examining the predictive power of detailed cortical thickness measures toward 3 types of cognitive scores in a large cohort. G-SMuRFS proposes a group-level l2,1-norm strategy to group relevant features together in an anatomically meaningful manner and use this prior knowledge to guide the learning process. This approach also takes into account the correlation among cognitive outcomes for building a more appropriate predictive model. Compared with traditional methods, G-SMuRFS not only demonstrates a superior performance but also identifies a small set of surface markers that are biologically meaningful. PMID- 25444600 TI - Anterior and posterior MTL networks in aging and MCI. AB - Two neuroanatomically dissociable, large-scale cortical memory networks, referred to as the anterior and posterior medial temporal lobe (MTL) networks have recently been described in young adults using resting-state blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI)-based functional connectivity (fc-BOLD). They have been hypothesized to subserve distinct mnemonic and non-memory cognitive functions and are thought to be associated with differential vulnerability in neurological disorders. In this article, we demonstrate the existence of these functional networks in an older adult population and in a cohort of patients diagnosed with amnestic mild cognitive impairment (aMCI). Anatomic subregions of interest in the MTL were defined using high-resolution T2-weighted MRI and used as seeds for defining the putative networks using fc-BOLD. Although the literature has suggested that the posterior MTL network is particularly vulnerable to early Alzheimer's disease, we show that both the networks are affected in MCI, to varying degrees, compared with the control group. Furthermore, cortical thickness in the brain regions defined by these networks was reduced in MCI. PMID- 25444601 TI - Does MRI scan acceleration affect power to track brain change? AB - The Alzheimer's Disease Neuroimaging Initiative recently implemented accelerated T1-weighted structural imaging to reduce scan times. Faster scans may reduce study costs and patient attrition by accommodating people who cannot tolerate long scan sessions. However, little is known about how scan acceleration affects the power to detect longitudinal brain change. Using tensor-based morphometry, no significant difference was detected in numerical summaries of atrophy rates from accelerated and nonaccelerated scans in subgroups of patients with Alzheimer's disease, early or late mild cognitive impairment, or healthy controls over a 6- and 12-month scan interval. Whole-brain voxelwise mapping analyses revealed some apparent regional differences in 6-month atrophy rates when comparing all subjects irrespective of diagnosis (n = 345). No such whole-brain difference was detected for the 12-month scan interval (n = 156). Effect sizes for structural brain changes were not detectably different in accelerated versus nonaccelerated data. Scan acceleration may influence brain measures but has minimal effects on tensor-based morphometry-derived atrophy measures, at least over the 6- and 12 month intervals examined here. PMID- 25444603 TI - Thickness network features for prognostic applications in dementia. AB - Regional analysis of cortical thickness has been studied extensively in building imaging biomarkers for early detection of Alzheimer's disease but not its interregional covariation of thickness. We present novel features based on the inter-regional covariation of cortical thickness. Initially, the cortical labels of each subject are partitioned into small patches (graph nodes) by spatial k means clustering. A graph is then constructed by establishing a link between 2 nodes if the difference in thickness between the nodes is below a certain threshold. From this binary graph, a thickness network is computed using nodal degree, betweenness, and clustering coefficient measures. Fusing them with multiple kernel learning, it is observed that thickness network features discriminate mild cognitive impairment (MCI) converters from controls (CN) with an area under curve (AUC) of 0.83, 74% sensitivity and 76% specificity on a large subset obtained from the Alzheimer's Disease Neuroimaging Initiative data set. A comparison of predictive utility in Alzheimer's disease and/or CN classification (AUC of 0.92, 80% sensitivity [SENS] and 90% specificity [SPEC]), in discriminating CN from MCI (converters and nonconverters combined; AUC of 0.75, SENS and SPEC of 64% and 73%, respectively) and in discriminating between MCI nonconverters and MCI converters (AUC of 0.68, SENS and SPEC of 65% and 64%) is also presented. ThickNet features as defined here are novel, can be derived from a single magnetic resonance imaging scan, and demonstrate the potential for the computer-aided prognostic applications. PMID- 25444605 TI - A computational method for computing an Alzheimer's disease progression score; experiments and validation with the ADNI data set. AB - Understanding the time-dependent changes of biomarkers related to Alzheimer's disease (AD) is a key to assessing disease progression and measuring the outcomes of disease-modifying therapies. In this article, we validate an AD progression score model which uses multiple biomarkers to quantify the AD progression of subjects following 3 assumptions: (1) there is a unique disease progression for all subjects; (2) each subject has a different age of onset and rate of progression; and (3) each biomarker is sigmoidal as a function of disease progression. Fitting the parameters of this model is a challenging problem which we approach using an alternating least squares optimization algorithm. To validate this optimization scheme under realistic conditions, we use the Alzheimer's Disease Neuroimaging Initiative cohort. With the help of Monte Carlo simulations, we show that most of the global parameters of the model are tightly estimated, thus enabling an ordering of the biomarkers that fit the model well, ordered as: the Rey auditory verbal learning test with 30 minutes delay, the sum of the 2 lateral hippocampal volumes divided by the intracranial volume, followed (by the clinical dementia rating sum of boxes score and the mini-mental state examination score) in no particular order and at last the AD assessment scale cognitive subscale. PMID- 25444604 TI - Integrated cortical structural marker for Alzheimer's disease. AB - In this article, we propose an approach to integrate cortical morphology measures for improving the discrimination of individuals with and without very mild Alzheimer's disease (AD). FreeSurfer was applied to scans collected from 83 participants with very mild AD and 124 cognitively normal individuals. We generated cortex thickness, white matter convexity (aka "sulcal depth"), and white matter surface metric distortion measures on a normalized surface atlas in this first study to integrate high resolution gray matter thickness and white matter surface geometric measures in identifying very mild AD. Principal component analysis was applied to each individual structural measure to generate eigenvectors. Discrimination power based on individual and combined measures are compared, based on stepwise logistic regression and 10-fold cross-validation. Global AD likelihood index and surface-based likelihood maps were also generated. Our results show complementary patterns on the cortical surface between thickness, which reflects gray matter atrophy, convexity, which reflects white matter sulcal depth changes and metric distortion, which reflects white matter surface area changes. The classifier integrating all 3 types of surface measures significantly improved classification performance compared with classification based on single measures. The principal component analysis-based approach provides a framework for achieving high discrimination power by integrating high dimensional data, and this method could be very powerful in future studies for early diagnosis of diseases that are known to be associated with abnormal gyral and sulcal patterns. PMID- 25444602 TI - Amygdalar atrophy in symptomatic Alzheimer's disease based on diffeomorphometry: the BIOCARD cohort. AB - This article examines the diffeomorphometry of magnetic resonance imaging-derived structural markers for the amygdala, in subjects with symptomatic Alzheimer's disease (AD). Using linear mixed-effects models we show differences between those with symptomatic AD and controls. Based on template centered population analysis, the distribution of statistically significant change is seen in both the volume and shape of the amygdala in subjects with symptomatic AD compared with controls. We find that high-dimensional vertex based markers are statistically more significantly discriminating (p < 0.00001) than lower-dimensional markers and volumes, consistent with comparable findings in presymptomatic AD. Using a high field 7T atlas, significant atrophy was found to be centered in the basomedial and basolateral subregions, with no evidence of centromedial involvement. PMID- 25444608 TI - Hippocampal volume and shape in pure subcortical vascular dementia. AB - The purposes of the present study were to explore whether hippocampal atrophy exists in pure subcortical vascular dementia (SVaD) as defined by negative (11)C Pittsburg compound-B (PiB(-)) positron emission tomography and to compare hippocampal volume and shape between PiB(-) SVaD and PiB positive (PiB(+)) Alzheimer's disease (AD) dementia. Hippocampal volume and shape were compared among 40 patients with PiB(-) SVaD, 34 with PiB(+) AD, and 21 elderly with normal cognitive function (NC). The normalized hippocampal volume of PiB(-) SVaD was significantly smaller than NC but larger than that of PiB(+) AD (NC > PiB(-) SVaD > PiB(+) AD). Both PiB(-) SVaD and PiB(+) AD patients had deflated shape changes in the cornus ammonis (CA) 1 and subiculum compared with NC. However, direct comparison between PiB(-) SVaD and PiB(+) AD demonstrated more inward deformity in the subiculum of the left hippocampus in PiB(+) AD. PiB(-) SVaD patients did have smaller hippocampal volumes and inward shape change on CA 1 and subiculum compared with NC, suggesting that cumulative ischemia without amyloid pathology could lead to hippocampal atrophy and shape changes. PMID- 25444606 TI - Connectivity network measures predict volumetric atrophy in mild cognitive impairment. AB - Alzheimer's disease (AD) is characterized by cortical atrophy and disrupted anatomic connectivity, and leads to abnormal interactions between neural systems. Diffusion-weighted imaging (DWI) and graph theory can be used to evaluate major brain networks and detect signs of a breakdown in network connectivity. In a longitudinal study using both DWI and standard magnetic resonance imaging (MRI), we assessed baseline white-matter connectivity patterns in 30 subjects with mild cognitive impairment (MCI, mean age 71.8 +/- 7.5 years, 18 males and 12 females) from the Alzheimer's Disease Neuroimaging Initiative. Using both standard MRI based cortical parcellations and whole-brain tractography, we computed baseline connectivity maps from which we calculated global "small-world" architecture measures, including mean clustering coefficient and characteristic path length. We evaluated whether these baseline network measures predicted future volumetric brain atrophy in MCI subjects, who are at risk for developing AD, as determined by 3-dimensional Jacobian "expansion factor maps" between baseline and 6-month follow-up anatomic scans. This study suggests that DWI-based network measures may be a novel predictor of AD progression. PMID- 25444609 TI - Storm before the quiet: neuronal hyperactivity and Abeta in the presymptomatic stages of Alzheimer's disease. AB - Neuronal activity directly promotes the production and secretion of amyloid beta (Abeta). Interestingly, neuronal hyperactivity can be observed in presymptomatic stages of both sporadic and familial Alzheimer's disease (AD) and in several AD mouse models. In this review, we will highlight the recent evidence for neuronal hyperactivity before or during the onset of cognitive defects in mild cognitive impairment. Furthermore, we review specific molecular mechanisms through which neuronal hyperactivity affects Abeta production and degradation. With these data, we will provide more insight into the 2-faced nature of neuronal hyperactivity: does enhanced neuronal activity during the presymptomatic stages of AD provide protection against the earliest disease processes or is it a pathogenic contributor to AD? PMID- 25444607 TI - Higher homocysteine associated with thinner cortical gray matter in 803 participants from the Alzheimer's Disease Neuroimaging Initiative. AB - A significant portion of our risk for dementia in old age is associated with lifestyle factors (diet, exercise, and cardiovascular health) that are modifiable, at least in principle. One such risk factor, high-homocysteine levels in the blood, is known to increase risk for Alzheimer's disease and vascular disorders. Here, we set out to understand how homocysteine levels relate to 3D surface-based maps of cortical gray matter distribution (thickness, volume, and surface area) computed from brain magnetic resonance imaging in 803 elderly subjects from the Alzheimer's Disease Neuroimaging Initiative data set. Individuals with higher plasma levels of homocysteine had lower gray matter thickness in bilateral frontal, parietal, occipital, and right temporal regions and lower gray matter volumes in left frontal, parietal, temporal, and occipital regions, after controlling for diagnosis, age, and sex and after correcting for multiple comparisons. No significant within-group associations were found in cognitively healthy people, patients with mild cognitive impairment, or patients with Alzheimer's disease. These regional differences in gray matter structure may be useful biomarkers to assess the effectiveness of interventions, such as vitamin B supplements, that aim to prevent homocysteine-related brain atrophy by normalizing homocysteine levels. PMID- 25444610 TI - Autophagy meets fused in sarcoma-positive stress granules. AB - Mutations in fused in sarcoma and/or translocated in liposarcoma (FUS, TLS or FUS) are linked to familial cases of amyotrophic lateral sclerosis (ALS). Mutant FUS selectively accumulates into discrete cytosolic structures known as stress granules under various stress conditions. In addition, mutant FUS expression can alter the dynamics and morphology of stress granules. Although the link between mutant FUS and stress granules is well established, the mechanisms modulating stress granule formation and disassembly in the context of ALS are poorly understood. In this issue of Neurobiology of Aging, Ryu et al. uncover the impact of autophagy on the potential toxicity of mutant FUS-positive stress granules. The authors provide evidence indicating that enhanced autophagy activity reduces the number of stress granules, which in the case of cells containing mutant FUS positive stress granules, is neuroprotective. Overall, this study identifies an intersection between the proteostasis network and alterations in RNA metabolism in ALS through the dynamic assembly and disassembly of stress granules. PMID- 25444612 TI - Effectiveness of an educational intervention on the suitability of indications for cesarean delivery in a Brazilian teaching hospital. AB - OBJECTIVE: To evaluate the effectiveness of an intervention to adjust the indications for caesarean delivery in a Brazilian teaching hospital in accordance with a specific protocol. METHODS: The present before-and-after study was carried out in three stages. In stages 1 and 3, data were obtained for 160 cesarean deliveries that occurred between May 20 and July 10 in 2011 and 2012, respectively. For stage 2, the protocol was implemented for 12 months. The deliveries in stages 1 and 3 were classified as high or low risk, and as consistent or inconsistent clinical cases on the basis of the protocol. RESULTS: A total of 160 (61.1%; 95% confidence interval [CI] 55.2-67.0) of 262 deliveries in stage 1 were by cesarean, compared with 160 (71.4%; 95% CI 65.5-77.3) of 224 in stage 3 (P=0.67). In stage 1, 125 (78.1%; 95% CI 71.7-84.5) showed indications consistent with the protocol, compared with 136 (85.0%; 95% CI 79.5-90.5) in stage 3 (P=0.11). Among the low-risk cesarean deliveries, 27 (51.9%; 95% CI 38.3 65.5) of 52 were consistent with the protocol in stage 1, compared with 49 (72.1%; 95% CI 61.4-86.1) of 68 in stage 3 (P=0.02). CONCLUSION: The proposed intervention improved the suitability of indications for cesarean delivery among low-risk pregnancies only. PMID- 25444613 TI - The prevalence of sexually transmitted infections among migrant female patients in Italy. AB - OBJECTIVE: To evaluate the prevalence of several sexually transmitted infections (STIs) among migrant women incoming to Italy. METHODS: A single-center, prospective, observational study was conducted of migrant women who had attended an outpatient clinic in Messina, Italy, between January 1, 2003, and December 31, 2013. Participants underwent a gynecologic examination and a cervical smear test. Patients who showed cytologic alterations underwent human papillomavirus (HPV) typing by PCR and allele-specific hybridization. Routine tests for hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, and syphilis were done for pregnant participants. RESULTS: Overall, 724 women were enrolled, of whom 320 (44.2%) were pregnant. The mean +/- SD age was 33.1 +/- 9.8 years. Cytologic abnormalities were recorded for 76 (10.5%) participants. Among 46 who attended a follow-up clinic, 32 (69.6%) tested positive for HPV serotypes. Among the pregnant women, 9 (2.8%) had HBV infection, 3 (0.9%) had HCV infection, and 1 (0.3%) had HIV infection. No cases of syphilis were recorded. CONCLUSION: The prevalence of STIs among migrant women in Messina is similar to that among nonmigrants. PMID- 25444614 TI - A longitudinal study of unplanned pregnancy in a maternity hospital setting. AB - OBJECTIVE: To review family planning in a cohort of women who delivered a second child within 3 years of their first. METHODS: A longitudinal, observational study included women aged at least 18 years who had delivered a singleton weighing at least 500 g in 2009 after their first pregnancy at a hospital in Dublin, Ireland, and who returned to the hospital for prenatal care for a second pregnancy before January 2012. Logistic regression analyses were performed to examine the effect of maternal characteristics on pregnancy intention. RESULTS: Of 3284 primigravidas who delivered in 2009, 1220 (37.1%) returned with a second pregnancy. The second pregnancy was unplanned in 248 (20.3%) women, and both pregnancies were unplanned in 124 (10.2%). The second pregnancy was more likely to be unplanned in women whose first pregnancy was also unplanned than in those whose first was planned (adjusted odds ratio 6.5; 95% confidence interval 4.6 8.4; P<0.001). Among the 99 women with recurrent unplanned pregnancy who had not been using contraception before the first pregnancy, 85 (85.9%) were also not using contraception before the second. CONCLUSION: Women whose first pregnancy is unplanned are at increased risk of subsequent unplanned pregnancies. Postnatal contraceptive advice in this high-risk group should be prioritized. PMID- 25444611 TI - Alloimmunization in sickle cell disease: changing antibody specificities and association with chronic pain and decreased survival. AB - BACKGROUND: Alloimmunization remains a significant complication of transfusion and has been associated with multiple factors, including inflammation, an important pathophysiologic mechanism in sickle cell disease (SCD). We explored whether alloimmunization is associated with disease severity in SCD. STUDY DESIGN AND METHODS: Adult SCD patients were enrolled in a study of outcome-modifying genes in SCD. Historical records of patients with SCD at two participating institutions were reviewed for data on antigen phenotype and alloimmunization. Differences in demographic, clinical, and laboratory findings; end-organ damage; and overall disease severity were then compared between alloimmunized and nonalloimmunized patients. RESULTS: Of 319 patients, 87 (27%) were alloimmunized. Alloantibody specificities differed from those previously described, especially due to the significantly higher frequency of anti-S. Although alloimmunization was not associated with frequency of vasoocclusive episodes, a higher percentage of alloimmunized patients had chronic pain, as defined by daily use of short acting narcotics (p = 0.006), long-acting narcotics (p = 0.013), or both (p = 0.03). Additionally, alloimmunized patients had poorer survival (hazard ratio, 1.92; p = 0.01) and were more likely to have avascular necrosis (p = 0.024), end organ damage (p = 0.049), and red blood cell autoantibodies (p < 0.001), even after controlling for the effects of age, sex, and hemoglobin diagnosis. Alloimmunization was not associated with other SCD-related complications, such as acute chest syndrome or stroke. CONCLUSION: Alloimmunization in SCD may be associated with chronic pain, risk of end-organ damage, and shorter survival. These novel findings suggest new directions for the investigation of immune response-mediated pathways common to alloimmunization and chronic pain. PMID- 25444595 TI - NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases. AB - Our objective was to design a genotyping platform that would allow rapid genetic characterization of samples in the context of genetic mutations and risk factors associated with common neurodegenerative diseases. The platform needed to be relatively affordable, rapid to deploy, and use a common and accessible technology. Central to this project, we wanted to make the content of the platform open to any investigator without restriction. In designing this array we prioritized a number of types of genetic variability for inclusion, such as known risk alleles, disease-causing mutations, putative risk alleles, and other functionally important variants. The array was primarily designed to allow rapid screening of samples for disease-causing mutations and large population studies of risk factors. Notably, an explicit aim was to make this array widely available to facilitate data sharing across and within diseases. The resulting array, NeuroX, is a remarkably cost and time effective solution for high-quality genotyping. NeuroX comprises a backbone of standard Illumina exome content of approximately 240,000 variants, and over 24,000 custom content variants focusing on neurologic diseases. Data are generated at approximately $50-$60 per sample using a 12-sample format chip and regular Infinium infrastructure; thus, genotyping is rapid and accessible to many investigators. Here, we describe the design of NeuroX, discuss the utility of NeuroX in the analyses of rare and common risk variants, and present quality control metrics and a brief primer for the analysis of NeuroX derived data. PMID- 25444615 TI - Proportion of cervical excision for cervical intraepithelial neoplasia as a predictor of pregnancy outcomes. AB - OBJECTIVE: To assess how the proportion of the cervical volume/length removed during treatment for cervical intraepithelial neoplasia (CIN) varies and whether this correlates to the pregnancy duration at delivery. METHODS: The present prospective observational study included 142 women undergoing CIN treatment at a university hospital during 2009-2013. The pretreatment and post-treatment cervical dimensions and cone size were measured with magnetic resonance imaging, three-dimensional transvaginal ultrasonography, or two-dimensional transvaginal ultrasonography, and the correlation between pregnancy outcomes and the relative proportion of the cervix excised was assessed. RESULTS: Pretreatment cervical volumes and cone volumes varied substantially (range 11-40 cm(3) and 0.6-8 cm(3), respectively). The proportion of the volume excised ranged from 2.2% to 39.4%. Sixteen (11%) women conceived following treatment; 12 had a live birth (seven at term, three preterm). The pregnancy duration at delivery was significantly correlated with the proportion of the cervical volume (r=-0.9; P<0.001) and length (r=-0.7; P=0.01) excised and the cone volume (r=-0.6; P=0.04). CONCLUSION: The pretreatment cervical dimensions and the proportions of the volume/length excised vary substantially, and the latter correlates with the pregnancy duration. Assessment of the proportion excised might help to stratify women at risk who need intensive surveillance when pregnant. PMID- 25444616 TI - Temporal variations of heavy metals levels in Perna viridis, on the Chacopata Bocaripo lagoon axis, Sucre State, Venezuela. AB - Perna viridis was used as biomonitor to assess heavy metal levels in the Chacopata-Bocaripo lagoon axis, Venezuela, during rain and drought seasons. The mussels were weighed and measured. The metal concentrations were determined by atomic absorption spectrophotometry. For rain period, the order of bioavailability was: Cu>Ni>Mn>Co>Cd>Pb, and for drought: Cu>Mn>Ni>Co>Pb>Cd. The concentrations of Ni, Co, Cd and Pb showed significant differences (P<0.05) in both periods. There was higher metal accumulation during drought season, possibly related to upwelling, since it produces an increase in primary productivity, which translates more food into organisms, making metals bioavailable for mussels. Only Cu and Mn showed significant relationships between the size and metal concentration, during drought period, it may be because of the organisms need for these essential metals in different physiological processes. PMID- 25444618 TI - Eutrophication effects on phytoplankton size-fractioned biomass and production at a tropical estuary. AB - Size-fractioned phytoplankton (pico, nano and microplankton) biomass and production were estimated throughout a year at Recife harbor (NE Brazil), a shallow well mixed tropical hypereutrophic estuary with short residence times but restricted water renewal. Intense loads of P-PO4 (maximum 14 MUM) resulted in low N:P ratios (around 2:1), high phytoplankton biomass (B=7.1-72 MUg chl-a L(-1)), production (PP=10-2657 MUg C L(-1) h(-1)) and photosynthetic efficiency (P(B)=0.5 45 MUg C MUg chl-a(-1)), but no oxygen depletion (average O2 saturation: 109.6%). Nanoplankton dominated phytoplankton biomass (66%) but micro- and nanoplankton performed equivalent primary production rates (47% each). Production-biomass models indicate an export of the exceeding microplankton biomass during most of the year, possibly through grazing. The intense and constant nutrient and organic matter loading at Recife harbor is thus supporting the high microplankton productivity that is not accumulating on the system nor contributing to oxygen depletion, but supporting the whole system's trophic web. PMID- 25444617 TI - Tissue-specific Cd and Pb accumulation in Peruvian scallop (Argopecten purpuratus) transplanted to a suspended and bottom culture at Sechura Bay, Peru. AB - In order to understand the effect of different culture systems on Cd and Pb accumulation, suspended long-line and bottom cultures of Argopecten purpuratus were conducted during January until April 2010 (120 days). The Cd tissue levels were the highest at the middle of the experiment (30-d till 70-d) for suspended cultured individuals, while bottom-cultured individuals showed an increasing trend. Gonad Pb levels were also higher during the same period for all cultures, while adductor muscle exhibited no considerable variations. Cd and Pb tissue concentrations were mainly greater in deeper cultures. There were no significant differences in Cd and Pb accumulation between individual sizes. The Cd and Pb levels in edible tissue (gonad+adductor muscle) did not exceed the EU and FDA maximum levels. Based on the target hazard quotient (THQ) and the provisional tolerance weekly intake (PTWI), no risk (THQ<1 and %PTWI<30) was found for human consumption. PMID- 25444619 TI - Polycyclic aromatic hydrocarbon concentrations across the Florida Panhandle continental shelf and slope after the BP MC 252 well failure. AB - The Florida Panhandle continental shelf environment was exposed to oil from the BP oil well failure in the Gulf of Mexico during 2010. Floating mats of oil were documented by satellite, but the distribution of dissolved components of the oil in this region was unknown. Shipek(r) grab samples of sediments were taken during repeated cruises between June 2010 and June 2012 to test for selected polycyclic aromatic hydrocarbons (PAHs) as indicators of this contamination. Sediments were collected as composite samples, extracted using standard techniques, and PAHs were quantified by GC/MS-SIM. PAHs in samples from the continental slope in May 2011 were highest near to the failed well site and were reduced in samples taken one year later. PAHs from continental shelf sediments during the spill (June 2010) ranged from 10 to 165 ng g(-1). Subsequent cruises yielded variable and reduced amounts of PAHs across the shelf. The data suggest that PAHs were distributed widely across the shelf, and their subsequent loss to background levels suggests these compounds were of oil spill origin. PAH half-life estimates by regression were 70-122 days for slope and 201 days for shelf stations. PMID- 25444620 TI - Molecular phylogeny and PSP toxin profile of the Alexandrium tamarense species complex along the coast of China. AB - To explore the genetic diversity and paralytic shellfish poisoning (PSP) toxin profile of the Alexandrium tamarense species complex along the coast of China, 67 strains of A. tamarense from the China Sea were collected and genetic diversity were analyzed based on the rDNA sequences. In addition, PSP toxin compositions and contents were detected by HPLC. According to the 5.8S rDNA and ITS, and LSU rDNA D1-D2 sequence, A. tamarense in the China Sea comprises at least Group IV and Group I ribotypes. In these Chinese strains, the toxins with the highest concentration in the profile were C1/2, gonyautoxins 1/4 (GTX1/4) and neosaxitoxin (NEO). However, the toxin profiles were atypical and C1/2 toxins were not detected in some strains. No strict correlation was observed between the PSP toxins profile and the geographical distribution. PMID- 25444621 TI - Organic matter and pyritization relationship in recent sediments from a tropical and eutrophic bay. AB - The degree of pyritization (DOP) and the extension of metals incorporation into pyrite was investigated at Guanabara Bay sediments. Maximum concentrations of total organic carbon (TOC), total sulfur, biopolymers and viable bacteria cells were observed in silted stations close to discharge points of sewage and minimum concentrations at sandy stations at the entrance of the bay. Pyrite iron concentrations (Fepy) was always lower than the reactive iron and Fepy were below the detection limit at sandy stations. The same trend was found to metals, which its degree of pyritization was Mn=Cu>As=Co>Ni>Cd>Zn?Pb>Cr. The bay gathers all required factors to sulfate reduction and pyrite formation, once the C:S ratio express the reduced tendency conditions, almost half of the TOC present in its sediments is labile and both reactive sulfur and iron are available. However the degree of trace metals pyritization did not exceed 20%, consistent with the median DOP (29%). PMID- 25444622 TI - Temporal pattern in the bloom-forming macroalgae Chaetomorpha linum and Ulva pertusa in seagrass beds, Swan Lake lagoon, North China. AB - Seagrasses that are distributed over a large area of the Swan Lake, Weihai, China, support a productive ecosystem. In recent years, however, frequent macroalgal blooms have changed the ecosystem structure and threatened the seagrasses. To understand the bloom-forming macroalgae we conducted a yearly field survey of Swan Lake. Results indicated that the macroalgae Chaetomorpha linum and Ulva pertusa both exhibited a much higher productivity and attained a greater maximum biomass (of 1712+/-780gDWm(-)(2) and 1511 +/- 555 gDW m(-2), respectively) than was the case for the seagrasses. The mean annual atomic ratios of C/N, C/P and N/P in C. linum were 14.31 +/- 4.45, 402.82 +/- 130.25, and 28.12+/-2.08, respectively. The delta(15)N values (11.09 +/- 0.910/00 for C. linum; 9.27 +/- 2.830/00 for U. pertusa) indicated a land-based source of N enrichment to the macroalgal blooms. High concentrations of nitrogen and phosphorus in the lagoon, particularly near the river mouth, supported the blooms. PMID- 25444623 TI - Finite-time compressibility as an agent of frequent spontaneous patch formation in the surface layer: A case study for the Gulf of Finland, the Baltic Sea. AB - We explore the possibilities for spontaneous formation of surface patches with high concentrations of contaminants through time correlations of the convergence field and the Lagrangian transport. The test area is the Gulf of Finland, the Baltic Sea, where surface velocity fields show extensive convergence. The flow properties are extracted from 3D velocity fields simulated for 1987-1991 using the OAAS model with a resolution of 1 mile. The focus is on the spatial distribution of the areas in which the values of finite-time flow compressibility of surface velocity fields exceed the threshold for clustering of floats. The distribution of such areas is asymmetric, with likely areas of patch formation located predominantly in the southern and eastern regions of the gulf. Out of nine areas of likely patch formation, six are located along the coast in regions of frequent downwelling, while three are identified in the central region of the gulf. PMID- 25444624 TI - Diffusion of microcystins (cyanobacteria hepatotoxins) from the reservoir of Isahaya Bay, Japan, into the marine and surrounding ecosystems as a result of large-scale drainage. AB - In the artificial reservoir of the Isahaya reclaimed land, Nagasaki, Japan, algal blooms have become an annual event, dominated primarily by the microcystin (MC) producing cyanobacteria Microcystis aeruginosa. Although the majority of MCs are either degraded by bacteria or washed out to sea, some remain in the sediment of the reservoir and bay throughout the year. As a result, they also accumulate in aquatic organisms (mullet, oyster, etc.) that inhabit the reservoir and surrounding areas, as well as midge flies that spend their larval period in the bottom of the reservoir. Accordingly, MCs also accumulate in the predators of these organisms, allowing the toxin to spread from the hydrosphere to terrestrial ecosystems. The most effective method for resolving this potentially dangerous condition is to introduce seawater into the reservoir by opening the drainage gates at high tide. PMID- 25444625 TI - Distribution and transfer pattern of Polychlorinated Biphenyls (PCBs) among the selected environmental media of Ny-Alesund, the Arctic: As a case study. AB - Polychlorinated Biphenyls (PCBs) were analyzed in multi-environmental samples collected from Ny-Alesund, the Arctic to explore their legacy and transfer patterns. PCBs were ubiquitously in the environmental media, within the ranges of 1.73-6.27 and 9.18-141.1 pg m(-3) in vapor and aerosol, 2.76-10.8, 3.09-8.32, 22.5-56.3, 35.4-51.4 and 31.8-39.6 ng g(-1) (dry weight) in soil, sediment, plant, bird guano and reindeer faeces, respectively. The spatial distribution patterns exhibited a general southward decline in soil and sediment from the bay entrance to the inner bay. The concentration ratios of plants to soil inferred that no distinguished selective adsorption of PCBs congeners by plants existed and PCBs were mainly attributed to the air deposition on plant surface. The fugacity ratios among vapor, aerosol and soil indicted that the equilibrium status has not been reached and the net transferring direction was air-soil. PMID- 25444626 TI - The origin of the Ulva macroalgal blooms in the Yellow Sea in 2013. AB - Green algal blooms have occurred in the Yellow Sea for seven consecutive years from 2007 to 2013. In this study, satellite image analysis and field shipboard observations indicated that the Ulva blooms in 2013 originated in the Rudong coast. The spatial distribution of Ulva microscopic propagules in the Southern Yellow Sea also supported that the blooms originated in the Rudong coast. In addition, multi-source satellite data were used to evaluate the biomass of green algae on the Pyropia aquaculture rafts. The results showed that approximately 2784 tons of Ulva prolifera were attached to the rafts and possessed the same internal transcribed spacer and 5S rDNA sequence as the dominant species in the 2013 blooms. We conclude that the significant biomass of Ulva species on the Pyropia rafts during the harvesting season in radial tidal sand ridges played an important role in the rapid development of blooms in the Yellow Sea. PMID- 25444627 TI - Polycyclic aromatic hydrocarbons in fish from St Helena, South Atlantic, in relation to an historic wreck. AB - Concentrations of polycyclic aromatic hydrocarbons were determined in edible tissues of fish species consumed by the islanders of St Helena to assess any risk to human health posed by oil leaking from an historic wreck. Samples were collected from the vicinity of the wreck site and at two reference locations at which fishing activity occurs. Summed PAH concentrations ranged from 2.2 to 20 MUg kg(-1) wet weight, and no PAHs with more than 4 fused rings were detected. All concentrations of the four PAH used as a basis for assessment in relation to health risks to human consumers of foods within the EU (benz[a]anthracene, benzo[a]pyrene, benzo[b]fluoranthene and chrysene) were<0.1 MUg kg(-1) wet weight and raised no concerns. Additionally, concentrations were calculated as the benzo[a]pyrene toxic equivalency quotient and found to be well below the level of concern (0 to 0.05 MUg kg(-1) wet weight benzo[a]pyrene equivalents). PMID- 25444628 TI - Assessment of pollution level using Mytilus galloprovincialis as a bioindicator species: The case of the Gulf of Trieste. AB - A multidisciplinary approach was used to estimate the pollution level of the marine environment in the North Eastern Adriatic by measurement of the isotopic composition of carbon and nitrogen (delta(13)C, delta(15)N), metal/metalloids analyses (Fe, Cu, Zn, As, Se, Cd and Pb, including As speciation) in the Mytilus galloprovincialis, as well by using metallothioneins (MT) concentrations, micronuclei (MN) in gill cells and biological parameters (condition index and gonadosomatic index). Concentrations of MT were in the range from 44 to 175 MUg g(-1) wet matter tissue and were higher at the end of the winter season. The frequency of MN did not indicate an elevated level. Sewage sludge pollution was not confirmed. Elevated As concentrations in mussel are related to salinity and low nutrients concentrations and not to pollution. Elevated concentrations of Cu, Zn and Pb were found in the Bay of Koper in comparison with the Bays of Strunjan and Piran. PMID- 25444629 TI - Clinical manifestations and management of prune-belly syndrome in a large contemporary pediatric population. AB - OBJECTIVE: To review the clinical manifestations and operative management of a large contemporary pediatric cohort of patients with prune-belly syndrome (PBS). METHODS: PBS patients aged <21 years followed up in our pediatric urology clinic were identified by the International Classification of Diseases, Ninth Revision code (756.71). Demographics, concomitant diagnoses, surgical history, imaging studies, and renal or bladder function were evaluated. RESULTS: Data were available for 46 pediatric patients (44 boys and 2 girls). Mean age was 7.6 +/- 4.7 years (range, 0.9-20 years). Average length of clinical follow-up was 6.8 +/- 5 years. Forty-five children (97.8%) had hydroureteronephrosis, and 36 of them (78.3%) had vesicoureteral reflux. Five patients (10.9%) had significant pulmonary insufficiency, and 2 patients (4.3%) were oxygen dependent. Eighteen children (39.1%) had other congenital malformations, including cardiac in 4 patients (8.7%) and musculoskeletal anomalies in 10 patients (21.7%). Orchidopexy was the most common surgery, with all boys aged >=3 years having undergone the procedure. Twenty-two patients (47.8%) had a history of ureteral surgery, 22 (47.8%) had bladder surgery, 11 (23.9%) had renal surgery, and 6 (13%) had urethral procedures. Nineteen patients (41.3%) underwent abdominoplasty. Eighteen children (39.1%) had documented chronic kidney disease, and 8 children (17.4%) underwent renal transplantation. Average age at transplantation was 5.1 +/- 2.9 years. The mean nadir creatinine level for patients with end-stage renal disease was 1.4 mg/dL compared with 0.4 mg/dL for those not requiring transplantation (P <.001). CONCLUSION: Children with PBS have significant comorbidities and require frequent operative intervention, with disease heterogeneity necessitating an individualized management approach. Early end-stage renal disease is prevalent, with approximately 15% of children requiring kidney transplantation. PMID- 25444630 TI - Treatment of pouch stones after augmentation ileocystoplasty in children: is it always bothersome? AB - OBJECTIVE: To report our experience with different approaches for management of pouch stones in children with ileal-based urinary reservoir. PATIENTS AND METHODS: Charts of children who underwent ileal-based urinary reservoirs between 2000 and 2009 were retrospectively reviewed. Patients who were diagnosed with reservoir calculi were identified; medical records were reviewed for patients' demographics, diversion details, stone criteria, mode of treatment, perioperative complications, and recurrence rate. RESULTS: We identified 26 children with pouch stones after urinary diversion. There were 11 boys (42%) and 15 girls (58%). Mean age was 11 years (range, 4-16 years). Mean time for diagnosis was 42 months (24 120 months). Pouch stones were asymptomatic in 10 patients (38%). Fifteen cases were postbladder augmentation and 11 cases postcontinent cutaneous diversion. The mean stone size was 4 cm (range, 1-10 cm), and mean Hounsfield Unit was 585 (205 1090). Seventeen children (65%) had positive urine culture result, whereas 9 children were sterile. Seven children (27%) required open poucholithotomy, whereas 19 patients (73%) were managed endoscopically. Percutaneous approach was done in 5 children, whereas urethral access was used in 7 children. Mechanical extraction was performed in 12 cases, and stone disintegration was required in 7 cases. Eight children developed stone recurrence. Mean time for recurrence was 11 months (range, 3-19 months). Six children were after endoscopic disintegration, and all required redo endoscopic extraction. Stone analysis was available in 15 patients (struvite stones in 10 cases and calcium phosphate in 5 cases). CONCLUSION: Pouch stones are established long-term complication of urinary diversion. Open and endoscopic approaches are valid treatment strategies. PMID- 25444631 TI - Split-cuff nipple technique of ureteral reimplantation in children with thick walled bladders due to posterior urethral valves. AB - OBJECTIVE: To describe a novel technique of ureteral reimplantation in patients with thick-walled bladders, which addresses the technical challenges and high failure rates seen in this population. METHODS: From 1997 to 2012, 45 megaureters were reimplanted in 26 children aged 2-11 years. Key surgical modifications included ureteral trough creation within the detrusor, formation of a distal ureteral split-cuff nipple, reliance on transureteroureterostomy (TUU) when the bladder would not support the reimplantation of 2 ureters, performance of psoas vesicopexy, and judicious utilization of ureteral stump augmentation in patients undergoing TUU. Follow-up ranged from 1 to 12 years. RESULTS: Seven patients underwent unilateral and 4 underwent bilateral ureteral reimplantation; TUU was performed in 15. Psoas vesicopexy was performed in 22 patients. Voiding cystourethrography showed no reflux in all children who underwent vesicopexy. Reflux resolved in 6 of 8 bilaterally reimplanted ureters; 2 of 8 had improved reflux that later resolved with Deflux injection. No ureters obstructed. Hydronephrosis improved in 32 of 45 renal units and remained stable in 13. Seven patients continue to develop bacteriuria. Five have developed renal failure. CONCLUSION: In our experience, a long ureteral trough combined with a split-cuff nipple technique for reimplanting megaureters into thick-walled bladders yields improved results over conventional submucosal tunneling, effectively eliminating or improving reflux and preventing obstruction. TUU and psoas vesicopexy proved useful adjuncts in creating adequate intravesical trough length. The risk for continued bacteriuria and renal failure due to limited renal reserve, however, remain notable in this group. PMID- 25444632 TI - Prevalence and predictive factors of harboring fluoroquinolone-resistant and extended-spectrum beta-lactamase-producing rectal flora in Hong Kong Chinese men undergoing transrectal ultrasound-guided prostate biopsy. AB - OBJECTIVE: To study the prevalence of fluoroquinolone-resistant (FQ-resistant) and extended-spectrum beta-lactamase-producing (ESBL-producing) bacteria in the rectums of patients undergoing transrectal ultrasound-guided prostate biopsy (TRUS-Bx), identifying predictive factors for such carriage and to correlate with the microbiology of those who developed postbiopsy infection (PBI). METHODS: A total of 371 men undergoing TRUS-Bx were prospectively enrolled from August 2011 to March 2012. Rectal swab was obtained before antimicrobial prophylaxis on the day of biopsy and grown in selective media for resistant bacteria. Standard FQ prophylaxis was used without guidance from rectal swab results. Univariate and multivariate analyses were performed to identify predictive factors of either FQ resistant or ESBL-producing bacteria carriage. RESULTS: A total of 199 of 371 patients (53.6%) carried antimicrobial-resistant rectal flora, with 150 (40.4%) and 152 (41.0%) patients having FQ-resistant and ESBL-producing bacteria, respectively. Diabetes mellitus (odds ratio, 2.075; P = .028) and the use of antimicrobials within the prior 5 years (odds ratio, 1.550; P = .047) were independent predictors of rectal carriage of such flora. PBI occurred in 9 patients, of which 7 harbored prebiopsy antimicrobial-resistant bacteria, which completely matched the microbiological data collected during the patients' PBI episodes. CONCLUSION: A high prevalence of FQ-resistant and ESBL-producing rectal flora in Chinese men undergoing TRUS-Bx was found. Diabetes mellitus and prior antimicrobial use within 5 years were significant predictors for resistant bacterial carriage. Despite the high-resistant bacteria prevalence, PBI rate remained low. A targeted approach of antimicrobial prophylaxis using prebiopsy culture swab in areas with high prevalence of resistant bacteria should be further investigated. PMID- 25444633 TI - Management of non-neuropathic underactive bladder in children with voiding dysfunction by animated biofeedback: a randomized clinical trial. AB - OBJECTIVE: To assess the efficacy of animated biofeedback and pelvic floor muscle (PFM) exercise in managing children with non-neuropathic underactive bladder (UB). METHODS: A total of 50 children with UB without underlying neuropathic disease, aged 5-16 years, were included in this study. They were randomly divided into 2 equal treatment groups comprising standard urotherapy (hydration, scheduled voiding, toilet training, and diet) with (group A) or without (group B) animated biofeedback and PFM exercise. The follow-up period for each participant was 1 year. A complete voiding and bowel habit diary was recorded by participants' parents before and after 2 evaluations. In addition, uroflowmetry with electromyography and bladder ultrasound were performed before, 6 months, and 1 year after treatment. Results were compared between the 2 cohorts. RESULTS: Mean number of voiding episodes was significantly increased in group A after biofeedback therapy compared with group B with only standard urotherapy (6.6 +/- 1.6 vs 4.5 +/- 1 times a day; P <.000). Urinary tract infection did not relapse in 9 of 11 (81%) and 8 of 15 (38%) patients in groups A and B, respectively (P <.02). Postvoid residual volume and voiding time decreased considerably, whereas maximum urine flow increased significantly in group A compared with group B (17.2 +/- 4.7 vs 12.9 +/- 4.6 mL/s; P <.01). CONCLUSION: Combination of animated biofeedback and PFM exercise effectively improves sensation of bladder fullness and contractility in children with UB due to voiding dysfunction. PMID- 25444634 TI - Prostato-symphyseal fistula after photoselective vaporization of the prostate: case series and literature review of a rare complication. AB - OBJECTIVE: To report our experience with the management of prostato-symphyseal fistula (PSF) after photoselective vaporization (PVP) or transurethral resection of the prostate (TURP) and review cases of this complication in published reports. MATERIALS AND METHODS: We report the management of 3 patients with PSF after PVP at our institution. A total of 5 published cases of PSF after PVP or TURP were identified from the National Library of Medicine MEDLINE database. A total of 8 patients were reviewed. RESULTS: Overall, the mean age was 71 years (range, 50-83 years), and average follow-up was 4.3 months (range, 1-7 months). Mean prostate volume was 32 mL (range, 16-38 mL). Five patients developed PSF after PVP and 3 patients after TURP. The most common postoperative symptoms included difficulty ambulating (100%) and pelvic, groin, and/or lower abdominal pain (85%). Associated diagnoses included osteitis pubis (38%) and urinoma (50%). Infectious complications were urinary tract infection (25%), osteomyelitis (38%), and infected urinoma (38%). Average time to diagnosis of PSF was 3.5 months (range, 0.5-11 months). Operative intervention was necessary in 75% of patients. CONCLUSION: This is the first reported case series on the management of PSF after PVP or TURP. This complication can be difficult to diagnose, manage, and may cause significant patient morbidity. Management requires a multidisciplinary approach. Patients commonly present with non-urologic symptoms leading to a delay in diagnosis. Further studies are needed to assess the incidence and optimal management of this complication. PMID- 25444635 TI - Histologic evaluation of human benign prostatic hyperplasia treated by dutasteride: a study by xenograft model with improved severe combined immunodeficient mice. AB - OBJECTIVE: To evaluate histologic change in human prostate samples treated with dutasteride and to elucidate direct effects of dutasteride on human prostate tissue, the present study was conducted by using a xenograft model with improved severe combined immunodeficient (super-SCID) mice, although it is well known that dutasteride reduces prostate volume. METHODS: After establishment of a xenograft model of human benign prostatic hyperplasia in morphology and function, samples implanted into super-SCID mice with and without dutasteride were evaluated pathohistologically at 2 and 6 months after initiation of dutasteride administration. RESULTS: The proliferative index evaluated by Ki-67 staining was significantly lower in the dutasteride group than the control at 2 and 6 months after administration. Apoptotic index evaluated by the terminal transferase TdT mediated dUTP-biotin nick end labeling staining was higher in the dutasteride group than the control at 2 and 6 months after administration. Quick scores in the dutasteride group for staining of both cyclooxygenase-2 (Cox-2) and Ras homolog gene family, member A (RhoA) were significantly lower than those in the control group at 2 and 6 months after administration. CONCLUSION: Dutasteride inhibits cell proliferation and induces apoptosis of prostatic cells, causing a reduced prostate volume. Furthermore, decreased expression of Cox-2 and RhoA within benign prostatic hyperplasia tissue by dutasteride may induce an early effect on improvement of lower urinary tract symptoms, probably by attenuating inflammation reaction of the prostate and decreasing intraurethral pressure, other than the mechanism of reduced prostate volume. PMID- 25444636 TI - Factors that influence intraocular pressure changes after myopic and hyperopic LASIK and photorefractive keratectomy: a large population study. AB - PURPOSE: To describe the factors that influence the measured intraocular pressure (IOP) change and to develop a predictive model after myopic and hyperopic LASIK and photorefractive keratectomy (PRK) in a large population. DESIGN: Retrospective, observational case series. PARTICIPANTS: Patients undergoing primary PRK or LASIK with a refractive target of emmetropia between January 1, 2008, and October 5, 2011. METHODS: The Optical Express database was queried for all subjects. Data were extracted on procedure specifics, preoperative central corneal thickness (CCT), IOP (using noncontact tonometry), manifest refraction, average keratometry, age, gender, and postoperative IOP at 1 week, 1 month, and 3 months. A linear mixed methods model was used for data analysis. MAIN OUTCOME MEASURES: Change in IOP from preoperatively to 1 month postoperatively. RESULTS: A total of 174 666 eyes of 91 204 patients were analyzed. Hyperopic corrections experienced a smaller IOP decrease than myopic corrections for both PRK and LASIK (P<0.0001). Patients who underwent LASIK had a 0.94 mmHg (95% confidence interval [CI], 0.89-0.98) greater IOP decrease than patients who underwent PRK (P<0.0001), reflecting the effect of the lamellar flap. The decrease in IOP was linearly related to preoperative manifest spherical equivalent (MSE) for myopic PRK and LASIK (P<0.0001), weakly correlated with preoperative MSE after hyperopic LASIK, and not related to preoperative MSE after hyperopic PRK. The single greatest predictor of IOP change was preoperative IOP across all corrections. By using the available data, a model was constructed to predict postoperative IOP change at 1 month; this was able to explain 42% of the IOP change after myopic LASIK, 34% of the change after myopic PRK, 25% of the change after hyperopic LASIK, and 16% of the change after hyperopic PRK. CONCLUSIONS: Myopic procedures lower measured IOP more than hyperopic procedures; this decrease was proportional to the amount of refractive error corrected. Independent of the refractive correction, the creation of the lamellar LASIK flap decreased measured IOP by 0.94 mmHg. A best fit model for IOP change was developed that may allow better interpretation of post-laser vision correction IOP values. PMID- 25444637 TI - One-year outcomes with half-dose verteporfin photodynamic therapy for chronic central serous chorioretinopathy. AB - PURPOSE: To assess the 1-year outcome of half-dose verteporfin photodynamic therapy (PDT) for patients with chronic central serous chorioretinopathy (CSC). DESIGN: Retrospective, interventional case series with no controls. PARTICIPANTS: A total of 204 eyes of 204 patients with chronic CSC were studied. METHODS: Fluorescein angiography (FA) and indocyanine green angiography (ICGA) were performed before PDT. The best-corrected visual acuities (BCVAs) were measured and optical coherence tomography was performed before and 1, 3, 6, 9, and 12 months after PDT. MAIN OUTCOME MEASURES: The main outcome measures were the resolution of the serous retinal detachment (SRD), changes in BCVA, and ocular and systemic complications at 12 months. RESULTS: A total of 182 of 204 eyes (89.2%) had complete resolution of the SRD at 12 months after the PDT. Eleven eyes (5.4%) had a persistent SRD throughout the follow-up period, and 12 eyes (5.9%) had a recurrence of the SRD after an earlier resolution. One of the 12 eyes had a spontaneous resolution of the SRD 6 months after PDT. The mean+/ standard deviation BCVA in logarithm of the minimum angle of resolution (logMAR) units significantly improved from 0.11+/-0.25 before to 0.07+/-0.23 at 1 month, 0.02+/-0.23 at 3 months, 0.01+/-0.23 at 6 months, 0.00+/-0.24 at 9 months, and 0.01+/-0.22 at 12 months (P<0.0001). The eyes with an SRD at 12 months were more likely to have an intermediate hyperfluorescence on ICGA (chi-square test, P<0.001) and poorer BCVA before the half-dose PDT (Student t test, P=0.04) than those without SRD at 12 months. None of the patients developed any systemic complications or experienced any severe visual reduction after the half-dose PDT. However, polypoidal lesion appeared in 1 eye 8 months after the PDT. CONCLUSIONS: Half-dose PDT is an effective and safe method to treat eyes with chronic CSC with an SRD. The CSC resolved and the BCVA improved significantly after PDT. Half-dose PDT was less effective for cases without intense hyperpermeability on ICGA and those with lower BCVA before the PDT. PMID- 25444638 TI - Diagnostic classification of macular ganglion cell and retinal nerve fiber layer analysis: differentiation of false-positives from glaucoma. AB - PURPOSE: To investigate the rate and associated factors of false-positive diagnostic classification of ganglion cell analysis (GCA) and retinal nerve fiber layer (RNFL) maps, and characteristic false-positive patterns on optical coherence tomography (OCT) deviation maps. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: A total of 104 healthy eyes of 104 normal participants. METHODS: All participants underwent peripapillary and macular spectral-domain (Cirrus-HD, Carl Zeiss Meditec Inc, Dublin, CA) OCT scans. False-positive diagnostic classification was defined as yellow or red color-coded areas for GCA and RNFL maps. Univariate and multivariate logistic regression analyses were used to determine associated factors. Eyes with abnormal OCT deviation maps were categorized on the basis of the shape and location of abnormal color-coded area. Differences in clinical characteristics among the subgroups were compared. MAIN OUTCOME MEASURES: (1) The rate and associated factors of false-positive OCT maps; (2) patterns of false-positive, color-coded areas on the GCA deviation map and associated clinical characteristics. RESULTS: Of the 104 healthy eyes, 42 (40.4%) and 32 (30.8%) showed abnormal diagnostic classifications on any of the GCA and RNFL maps, respectively. Multivariate analysis revealed that false-positive GCA diagnostic classification was associated with longer axial length and larger fovea-disc angle, whereas longer axial length and smaller disc area were associated with abnormal RNFL maps. Eyes with abnormal GCA deviation map were categorized as group A (donut-shaped round area around the inner annulus), group B (island-like isolated area), and group C (diffuse, circular area with an irregular inner margin in either). The axial length showed a significant increasing trend from group A to C (P=0.001), and likewise, the refractive error was more myopic in group C than in groups A (P=0.015) and B (P=0.014). Group C had thinner average ganglion cell-inner plexiform layer thickness compared with other groups (group A=B>C, P=0.004). CONCLUSIONS: Abnormal OCT diagnostic classification should be interpreted with caution, especially in eyes with long axial lengths, large fovea-disc angles, and small optic discs. Our findings suggest that the characteristic patterns of OCT deviation map can provide useful clues to distinguish glaucomatous changes from false-positive findings. PMID- 25444640 TI - Glaucoma and associated visual acuity and field loss significantly affect glaucoma-specific psychosocial functioning. AB - OBJECTIVE: To examine the impact of glaucoma and visual acuity (VA) and visual field (VF) losses on psychosocial functioning (PF). DESIGN: Cross-sectional study. PARTICIPANTS: We compared PF between 192 participants with bilateral glaucoma with VA or VF losses and 40 controls from a tertiary eye hospital clinic in Singapore. METHODS: Glaucoma was defined using the Hodapp-Anderson-Parish criteria. Four psychosocial outcomes of the Glaucoma Quality of Life 36 questionnaire were psychometrically assessed using Rasch analysis. Multivariate regression was performed to determine the independent impact of glaucoma and VA and VF losses on PF. The impact of VA and VF on PF were evaluated by restricted cubic spline analysis. MAIN OUTCOME MEASURES: Anxiety, self-image, psychological well-being, and confidence in health care. RESULTS: The mean age of participants was 66.2+/-11.0 years, and 63% were male. In the better eye, VA and mean deviation were Snellen 20/25 and -8.89+/-6.52 dB, respectively. In multivariate models, glaucoma patients had 63.0% greater anxiety (95% confidence interval [CI], -66.0% to -61.2%; P<0.001), 71.0% lower self-image (95% CI, -74.1% to 68.5%; P<0.001), 38.3% less psychological well-being (95% CI, -37.4% to -39.0%; P<0.001), and 32.4% reduced confidence in health care than patients without glaucoma. The worst VA and VF categories had the most reduced PF (range, 26.0% to 81.5%; P<0.001 for all associations) compared with controls. With worsening VA, there was a linear increase in anxiety (P=0.009) and decrease in self-image (P=0.005). With worsening VF from 0 to -12.1 dB (P=0.003), anxiety increased before plateauing. Self-image decreased as VF worsened from 0 to -10 dB (P<0.001), and confidence in health care decreased when VF worsened from 0 to 9.3 dB (P=0.008). However, self-image and confidence in health care actually improved at greater levels of VF loss beyond these thresholds. CONCLUSION: Glaucoma negatively affects PF. Early stage glaucoma with mild VF loss adversely affects anxiety, self-image, and confidence in health care. As VA worsens in advanced glaucoma, anxiety further increases and self-image deteriorates. Ophthalmologists and glaucoma patients need to be aware that both VA and VF losses at different stages of glaucoma negatively impact PF. PMID- 25444639 TI - Penetrating keratoplasty for corneal amyloidosis in familial amyloidosis, Finnish type. AB - PURPOSE: To analyze the outcome of penetrating keratoplasty (PK) to the first eye for corneal amyloidosis in familial amyloidosis, Finnish type (FAF). DESIGN: Single-center, retrospective, nonrandomized, interventional, noncomparative case series. PARTICIPANTS: Thirty-one eyes of 31 patients with FAF. INTERVENTION: All patients with FAF who had their first PK in Helsinki University Eye Hospital between January 1, 1990, and August 1, 2011, were identified and a retrospective analysis of the patient charts was performed. MAIN OUTCOME MEASURES: Best spectacle-corrected visual acuity (BCVA), intraoperative and postoperative complications, graft survival, reason for graft failure, and frequency of regrafting. RESULTS: The median follow-up period was 32 months (range, 5-114). After 24 months, the median BCVA was 1.15 on a logarithm of the minimum angle of resolution scale (20/280; mean, 1.1; SD, 0.5) in comparison with the preoperative median BCVA of 1.3 (20/400; mean, 1.3; SD, 0.4). At 24 months, 3 of 18 eyes (17%) had a visual acuity of >=0.5 (20/63) and 13 of 18 grafts (72%) were clear. Rejection occurred in 6 of 31 primary grafts (19%). Graft failure occurred in 16 of 31 eyes and resulted from surface complications in 11 eyes and additionally from rejection in 5 eyes. Seven eyes needed regrafting (twice in 1 eye). Complications were frequent in the early and late postoperative periods. Presence of preoperative corneal or graft neovascularization was an indicator of a high risk of graft failure and poor visual outcome. CONCLUSIONS: In a minority of FAF patients, PK improves vision. Owing to the high failure risk and guarded visual prognosis after PK, it is important that both the surgeon and the patient have realistic expectations. It may be reasonable to limit PK to cases with bilateral advanced disease. It seems reasonable to optimize ocular surface health and to delay PK. PMID- 25444641 TI - [Quality of life in Latin American immigrant caregivers in Spain]. AB - OBJECTIVE: To describe perceived quality of life in Latin American caregivers working in Spain and how it varies in relation to certain variables shared by this group. METHODS: We used the SF-36 to measure perceived quality of life in 517 women residing in five Spanish regions: the Balearic Islands, Catalonia, the Basque Country, the Canary Islands, and Madrid. Several variables related to the socio-demographic profile and migration process were studied using Student's t test, ANOVA and linear regression models. RESULTS: The participants scored very low on the dimensions of physical and emotional roles. The factors associated with lower quality of life scores within the group were working as a live-in caregiver, lack of contract, multitasking, irregular status, and younger age. CONCLUSIONS: The vulnerability of these women can be explained by poor working conditions and other factors related to the migratory process. PMID- 25444642 TI - Dietary phytic acid modulates characteristics of the colonic luminal environment and reduces serum levels of proinflammatory cytokines in rats fed a high-fat diet. AB - Dietary phytic acid (PA; myo-inositol [MI] hexaphosphate) is known to inhibit colon carcinogenesis in rodents. Dietary fiber, which is a negative risk factor of colon cancer, improves characteristics of the colonic environment, such as the content of organic acids and microflora. We hypothesized that dietary PA would improve the colonic luminal environment in rats fed a high-fat diet. To test this hypothesis, rats were fed diets containing 30% beef tallow with 2.04% sodium PA, 0.4% MI, or 1.02% sodium PA + 0.2% MI for 3 weeks. Compared with the control diet, the sodium PA diet up-regulated cecal organic acids, including acetate, propionate, and n-butyrate; this effect was especially prominent for cecal butyrate. The sodium PA + MI diet also significantly increased cecal butyrate, although this effect was less pronounced when compared with the sodium PA diet. The cecal ratio of Lactobacillales, cecal and fecal mucins (an index of intestinal barrier function), and fecal beta-glucosidase activity were higher in rats fed the sodium PA diet than in those fed the control diet. The sodium PA, MI, and sodium PA + MI diets decreased levels of serum tumor necrosis factor alpha, which is a proinflammatory cytokine. Another proinflammatory cytokine, serum interleukin-6, was also down-regulated by the sodium PA and sodium PA + MI diets. These data showed that PA may improve the composition of cecal organic acids, microflora, and mucins, and it may decrease the levels of serum proinflammatory cytokines in rats fed a high-fat, mineral-sufficient diet. PMID- 25444644 TI - Diversity and abundance of "Pelagibacterales" (SAR11) in the Baltic Sea salinity gradient. AB - The candidate order "Pelagibacterales" (SAR11) is one of the most abundant bacterial orders in ocean surface waters and, periodically, in freshwater lakes. The presence of several stable phylogenetic lineages comprising "Pelagibacterales" correlates with the physico-chemical parameters in aquatic environments. A previous amplicon sequencing study covering the bacterial community in the salinity gradient of the Baltic Sea suggested that pelagibacteral subclade SAR11-I was replaced by SAR11-IIIa in the mesohaline region of the Baltic Sea. In this current study, we investigated the cellular abundances of "Pelagibacterales" subclades along the Baltic Sea salinity gradient using catalyzed reporter deposition fluorescence in situ hybridization (CARD FISH). The results obtained with a newly designed probe, which exclusively detected SAR11-IIIa, were compared to CARD-FISH abundances of the marine SAR11 I/II subclade and the freshwater lineage SAR11-IIIb (LD12). The results showed that SAR11-IIIa was abundant in oligohaline-mesohaline conditions (salinities 2.7 13.3), with maximal abundances at a salinity of 7 (up to 35% of total Bacteria, quantified with a universal bacterial probe EUB). As expected, SAR11-I/II was abundant (27% of EUB) in the marine parts of the Baltic Sea, whereas counts of the freshwater lineage SAR11-IIIb were below the detection limit at all stations. The shift from SAR11-IIIa to SAR11-I/II was confirmed in the vertical salinity gradient in the deeper basins of the Baltic Sea. These findings were consistent with an overlapping but defined distribution of SAR11-I/II and SAR11-IIIa in the salinity gradient of the Baltic Sea and suggested the adaptation of SAR11-IIIa for growth and survival in mesohaline conditions. PMID- 25444643 TI - Conditioned fear and extinction learning performance and its association with psychiatric symptoms in active duty Marines. AB - BACKGROUND: Posttraumatic Stress Disorder (PTSD) is a major public health concern, especially given the recent wars in Iraq and Afghanistan. Nevertheless, despite a sharp increase in the incidence of psychiatric disorders in returning veterans, empirically based prevention strategies are still lacking. To develop effective prevention and treatment strategies, it is necessary to understand the underlying biological mechanisms contributing to PTSD and other trauma related symptoms. METHODS: The "Marine Resiliency Study II" (MRS-II; October 2011-October 2013) Neurocognition project is an investigation of neurocognitive performance in Marines about to be deployed to Afghanistan. As part of this investigation, 1195 Marines and Navy corpsmen underwent a fear conditioning and extinction paradigm and psychiatric symptom assessment prior to deployment. The current study assesses (1) the effectiveness of the fear potentiated startle paradigm in producing fear learning and extinction and (2) the association of performance in the paradigm with baseline psychiatric symptom classes (healthy: n=923, PTSD symptoms: n=42, anxiety symptoms: n=37, and depression symptoms: n=12). RESULTS: Results suggest that the task was effective in producing differential fear learning and fear extinction in this cohort. Further, distinct patterns emerged differentiating the PTSD and anxiety symptom classes from both healthy and depression classes. During fear acquisition, the PTSD symptom group was the only group to show deficient discrimination between the conditioned stimulus (CS+) and safety cue (CS-), exhibiting larger startle responses during the safety cue compared to the healthy group. During extinction learning, the PTSD symptom group showed significantly less reduction in their CS+ responding over time compared to the healthy group, as well as reduced extinction of self-reported anxiety to the CS+ by the end of the extinction session. Conversely, the anxiety symptom group showed normal safety signal discrimination and extinction of conditioned fear, but exhibited increased baseline startle reactivity and potentiated startle to CS+, as well as higher self-reported anxiety to both cues. The depression symptom group showed similar physiological and self-report measures as the healthy group. DISCUSSION: These data are consistent with the idea that safety signal discrimination is a relatively specific marker of PTSD symptoms compared to general anxiety and depression symptoms. Further research is needed to determine if deficits in fear inhibition vs. exaggerated fear responding are separate biological "domains" across anxiety disorders that may predict differential biological mechanisms and possibly treatment needs. Future longitudinal analyses will examine whether poor learning of safety signals provides a marker of vulnerability to develop PTSD or is specific to symptom state. PMID- 25444645 TI - The case for characterising type-2 blindsight as a genuinely visual phenomenon. AB - Type-2 blindsight is often characterised as involving a non-visual form of awareness that blindsight subjects experience under certain presentation conditions. This paper evaluates the claim that type-2 awareness is non-visual and the proposal that it is a cognitive form of awareness. It is argued that, contrary to the standard account, type-2 awareness is best characterised as visual both because it satisfies certain criteria for being visual and because it can accommodate facts about the phenomenon that the cognitive account cannot. The conclusion is made that type-2 blindsight is best characterised as involving a form of abnormal, degraded visual awareness. PMID- 25444647 TI - Third-order aberrations in GRIN crystalline lens: a new method based on axial and field rays. AB - This paper presents a new procedure for calculating the third-order aberration of gradient-index (GRIN) lenses that combines an iterative numerical method with the Hamiltonian theory of aberrations in terms of two paraxial rays with boundary conditions on general curved end surfaces and, as a second algebraic step has been presented. Application of this new method to a GRIN human is analyzed in the framework of the bi-elliptical model. The different third-order aberrations are determined, except those that need for their calculation skew rays, because the study is made only for meridional rays. PMID- 25444648 TI - Change in intraocular pressure during scleral depression. AB - PURPOSE: Manometric studies have found that intraocular pressure (IOP) rises 116 350 mmHg during scleral depression in surgical settings. No information is available regarding the effect of scleral depression on IOP in routine clinical settings. The aim of this study is to quantify the change in IOP that occurs when scleral depression is performed on normal eyes in a routine clinical setting. METHODS: A total of 28 eyes from 28 normal subjects were included. Tono-Pen tonometry was performed while scleral depression was performed in each of the two quadrants: superotemporal (ST) and inferonasal (IN). A post-procedure IOP measurement was obtained following each scleral depression examination. Both ST and IN quadrants were tested on all eyes, with the quadrant tested first chosen at random (15 ST, 13 IN). RESULTS: The mean IOP during scleral depression was 65.3 mmHg ST and 47.8 mmHg IN, with a maximum recorded IOP of 88 mmHg. The mean change in IOP for the ST quadrant was 51.9 +/- 17.3 mmHg and 46.4 +/- 16.0 mmHg for the right and left eyes, respectively. The mean change in IOP for the IN quadrant was 45.3 +/- 22.7 mmHg and 16.8 +/- 15.8 mmHg for the right and left eyes, respectively. CONCLUSIONS: Scleral depression as performed in a routine office setting produces wide fluctuations in IOP and may impair ocular perfusion. Additional studies are needed to determine the long-term consequences of routine scleral depression. PMID- 25444650 TI - The pleiotropic role of HDL in autoimmune diseases. AB - As is widely known, the classic function of HDL is reverse cholesterol transport (RCT), thus removing cholesterol from peripheral tissues. Early epidemiological studies, such as Framingham's, stated that increased HDL levels were associated with a significant decrease in relative risk for cardiovascular disease (CVD) mortality. However, those with heightened expectations in recent years for the development of therapeutic targets to increase HDL levels have been disappointed, because efforts have demonstrated the opposite effect on cardiovascular and global mortality. However, in contrast, studies have highlighted the complexity and the intriguing role of HDL in different pathological conditions, such as infections, neoplasms, and autoimmune diseases. In this review an attempt is made to summarize some biological pathways that link HDL function with the immune system, and its possible clinical repercussions in autoimmune diseases. PMID- 25444649 TI - The association between maternal blood pressures and offspring size at birth in Southeast Asian women. AB - BACKGROUND: Maternal blood pressures in pregnancy is an important determinant of offspring size at birth. However, the relationship between maternal blood pressures and offspring's size at birth is not consistent and may vary between ethnic groups. We examined the relationship between maternal peripheral and central blood pressures and offspring size at birth in an Asian multi-ethnic cohort, and effect modifications by maternal ethnicity and obesity. METHODS: We used data from 713 participants in the Growing Up in Singapore Towards Healthy Outcomes study consisting of pregnant Chinese, Malay and Indian women recruited from two tertiary hospitals between 2009 to 2010. Peripheral systolic and diastolic blood pressures (SBP and DBP), and central SBP and pulse pressure (PP) were measured around 27 weeks of gestation. Biometric parameters at birth were collected from medical records. RESULTS: After adjusting for maternal and fetal covariates, each 1-SD increase (10.0 mmHg) in central SBP was inversely associated with birth weight (-40.52 g; 95% confidence interval (CI) -70.66 to 10.37), birth length (-0.19 cm; -0.36 to -0.03), head circumference (-0.12 cm; 0.23 to -0.02) and placental weight (-11.16 g; -20.85 to -1.47). A one-SD (11.1 mmHg) increase in peripheral SBP was also associated with lower birth weight ( 35.56 g; -66.57 to -4.54). The inverse relations between other blood pressure measures and offspring size at birth were observed but not statistically significant. Higher peripheral SBP and DBP and central SBP were associated with increased odds of low birth weight (defined as weight <2500 g) and small for gestational age (defined as <10(th) percentile for gestational age adjusted birth weight). Maternal adiposity modified these associations, with stronger inverse associations in normal weight women. No significant interactions were found with ethnicity. CONCLUSIONS: Higher second-trimester peripheral and central systolic pressures were associated with smaller offspring size at birth, particularly in normal weight women. Findings from this study reinforces the clinical relevance of antenatal blood pressure monitoring. PMID- 25444651 TI - [Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention and the Spanish Society of Cardiology position statement on dyslipidemia management. Differences between the European and American guidelines]. AB - The publication of the 2013 American College of Cardiology/American Heart Association guidelines on the treatment of high blood cholesterol has had a strong impact due to the paradigm shift in its recommendations. The Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention and the Spanish Society of Cardiology reviewed this guideline and compared it with current European guidelines on cardiovascular prevention and dyslipidemia management. The most striking aspect of the American guideline is the elimination of the low density lipoprotein cholesterol treat-to-target strategy and the adoption of a risk reduction strategy in 4 major statin benefit groups. In patients with established cardiovascular disease, both guidelines recommend a similar therapeutic strategy (high-dose potent statins). However, in primary prevention, the application of the American guidelines would substantially increase the number of persons, particularly older people, receiving statin therapy. The elimination of the cholesterol treat-to-target strategy, so strongly rooted in the scientific community, could have a negative impact on clinical practice, create a certain amount of confusion and uncertainty among professionals, and decrease follow-up and patient adherence. Thus, this article reaffirms the recommendations of the European guidelines. Although both guidelines have positive aspects, doubt remains regarding the concerns outlined above. In addition to using risk charts based on the native population, the messages of the European guideline are more appropriate to the Spanish setting and avoid the possible risk of overtreatment with statins in primary prevention. Full English text available from:www.revespcardiol.org/en. PMID- 25444646 TI - Corneal Regeneration After Photorefractive Keratectomy: A Review. AB - Photorefractive keratectomy (PRK) remodels corneal stroma to compensate refractive errors. The removal of epithelium and the ablation of stroma provoke the disruption of corneal nerves and a release of several peptides from tears, epithelium, stroma and nerves. A myriad of cytokines, growth factors, and matrix metalloproteases participate in the process of corneal wound healing. Their balance will determine if reepithelization and stromal remodeling are appropriate. The final aim is to achieve corneal transparency for restoring corneal function, and a proper visual quality. Therefore, wound-healing response is critical for a successful refractive surgery. Our goal is to provide an overview into how corneal wounding develops following PRK. We will also review the influence of intraoperative application of mitomycin C, bandage contact lenses, anti-inflammatory and other drugs in preventing corneal haze and post-PRK pain. PMID- 25444652 TI - Impact of chronic illness timing and persistence at school entry on child and parent outcomes: Australian longitudinal study. AB - OBJECTIVE: To understand the prevalence and timing of child chronic illness at school entry; associations with child learning, behavior and health-related quality of life and parent mental health at ages 6 to 7, 8 to 9, and 10 to 11 years; and cumulative health care costs. METHODS: Data were drawn from the first 4 waves of the Longitudinal Study of Australian Children. Children were aged 4 to 5 years at wave 1, with data collection every 2 years. Parent-reported timing of child chronic illness at school entry was categorized into 4 chronic illness groups based on changes between waves 1 and 2: none, resolving, incident and persistent. Child outcomes included: parent-reported quality of life, parent- and teacher-reported behavior, teacher-reported child learning, teacher-reported child-teacher relationship, directly assessed nonverbal and verbal cognition and parent self-reported mental health. Linear regression, adjusted for gender and socioeconomic position, was used to quantify longitudinal associations between chronic illness timing at school entry with outcomes at age 6 to 7 years, 8 to 9 years and 10 to 11 years. RESULTS: Of the 4983 children enrolled in the study, chronic illness data was available for 4464 children (89.6%) at both waves 1 and 2. From wave 1, 6.1% had a condition that persisted until wave 2, while 14.1% had a condition that resolved. Furthermore, 4.7% had a newly emerging condition at wave 2. Compared with the no chronic illness group, children with persistent or emerging chronic illness during school entry had the poorest outcomes (except father's mental health) at all time points, while children with resolving conditions had smaller differences. CONCLUSIONS: Child chronic illness at school entry is associated with poorer longitudinal child and maternal outcomes. Therefore, future research should aim to determine the risk and protective factors that contribute to the poorer child and parent outcomes experienced in this growing population. PMID- 25444653 TI - Annual report on health care for children and youth in the United States: national estimates of cost, utilization and expenditures for children with mental health conditions. AB - OBJECTIVE: To examine national trends in hospital utilization, costs, and expenditures for children with mental health conditions. METHODS: The analyses of children aged 1 to 17 are based on AHRQ's 2006 and 2011 Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS) and Nationwide Emergency Department Sample (NEDS) databases, and on AHRQ's pooled 2006 to 2011 Medical Expenditure Panel Survey (MEPS). All estimates are nationally representative, and standard errors account for the complex survey designs. RESULTS: Although overall all-cause children's hospitalizations did not increase between 2006 and 2011, hospitalizations for all listed mental health conditions increased by nearly 50% among children aged 10 to 14 years, and by 21% for emergency department (ED) visits. Behavioral disorders experienced a shift in underlying patterns between 2006 and 2011: inpatient stays for alcohol-related disorders declined by 44%, but ED visits increased by 34% for substance-related disorders and by 71% for impulse control disorders. Inpatient visits for suicide, suicidal ideation, and self-injury increased by 104% for children ages 1 to 17 years, and by 151% for children ages 10 to 14 years during this period. A total of $11.6 billion was spent on hospital visits for mental health during this period. Medicaid covered half of the inpatient visits, but with 50% to 30% longer length of stays in 2006 and 2011, respectively, than private payers. Medicaid's overall share of the ED visits increased from 45% in 2006 to 53% in 2011. CONCLUSIONS: These alarming trends highlight the renewed need for research on mental health care for children. This study also provides a baseline for evaluating the impact of the Affordable Care Act and the mental health parity legislation on mental health utilization and expenditures for children. PMID- 25444654 TI - Variability in inpatient management of children hospitalized with bronchiolitis. AB - OBJECTIVE: To determine the variability between hospitals in diagnostic testing and management interventions for children with bronchiolitis admitted to inpatient wards and identify its association with patient characteristics. METHODS: A prospective, multicenter (16 hospitals), multiyear (2007-2010) observational study of children (age <2 years) hospitalized with bronchiolitis. Outcomes included variability in diagnostic testing (complete blood count, chest radiographs) and medications or interventions (bronchodilator, systemic corticosteroid, antibiotic, IV placement) by hospital. A modified Respiratory Distress Severity Score was utilized to assess severity of illness. For all outcomes, intraclass correlation coefficient (ICC) was calculated from a model to estimate the random effects of hospital without added covariates and compared to ICCs from a second model that adjusted for demographic and clinical patient characteristics. A second unadjusted and adjusted model was created for age >= 2 months. RESULTS: Of 2207 subjects, 1715 were identified as admitted to inpatient wards. We observed wide variations in the proportion of patients who received diagnostic testing (complete blood count 21-75%, chest radiograph 36-85%) and medications/interventions (bronchodilators 19-91%, systemic corticosteroids 8 44%, antibiotics 17-43%, IV placement 38-93%). Adjusting for demographic and clinical patient characteristics did not materially affect the proportion of variability attributable to hospitals (differences in ICCs with and without model adjustment <4%). CONCLUSIONS: Wide variations in diagnostic test utilization and management interventions seen among children with bronchiolitis treated on the inpatient wards at 16 US hospitals were not attributable to demographic or clinical patient characteristics. These results further support efforts to standardize care for bronchiolitis through active quality improvement strategies. PMID- 25444655 TI - Pediatric primary care providers' perspectives regarding hospital discharge communication: a mixed methods analysis. AB - OBJECTIVE: Effective communication between inpatient and outpatient providers may mitigate risks of adverse events associated with hospital discharge. However, there is an absence of pediatric literature defining effective discharge communication strategies at both freestanding children's hospitals and general hospitals. The objectives of this study were to assess associations between pediatric primary care providers' (PCPs) reported receipt of discharge communication and referral hospital type, and to describe PCPs' perspectives regarding effective discharge communication and areas for improvement. METHODS: We administered a questionnaire to PCPs referring to 16 pediatric hospital medicine programs nationally. Multivariable models were developed to assess associations between referral hospital type and receipt and completeness of discharge communication. Open-ended questions asked respondents to describe effective strategies and areas requiring improvement regarding discharge communication. Conventional qualitative content analysis was performed to identify emergent themes. RESULTS: Responses were received from 201 PCPs, for a response rate of 63%. Although there were no differences between referral hospital type and PCP-reported receipt of discharge communication (relative risk 1.61, 95% confidence interval 0.97-2.67), PCPs referring to general hospitals more frequently reported completeness of discharge communication relative to those referring to freestanding children's hospitals (relative risk 1.78, 95% confidence interval 1.26-2.51). Analysis of free text responses yielded 4 major themes: 1) structured discharge communication, 2) direct personal communication, 3) reliability and timeliness of communication, and 4) communication for effective postdischarge care. CONCLUSIONS: This study highlights potential differences in the experiences of PCPs referring to general hospitals and freestanding children's hospitals, and presents valuable contextual data for future quality improvement initiatives. PMID- 25444657 TI - Enhanced protein delivery by multi-ion containing eggshell derived apatitic alginate composite nanocarriers. AB - Eggshell is an attractive natural source of calcium for the synthesis of hydroxyapatite (HA) as it contains minor amounts of biologically relevant elements such as Mg, Sr, and Si. The mineral phase of the human bone is essentially a calcium deficient hydroxyapatite (CDHA) which shows more bioactivities and absorbance than stoichiometric HA does. Hence, we have attempted to develop a protein delivery system based on eggshell derived CDHA (ECDHA) nanoparticles for bone tissue engineering. Nanoparticles with Ca/P molar ratio of 1.67, 1.61 and 1.51 to form CDHAs with compositions covering the properties of stable HA phase (Ca/P=1.67) to degradable tricalcium phosphate (TCP) phase (Ca/P=1.5) were synthesized by microwave-accelerated wet chemical synthesis using eggshell as well as synthetic calcium hydroxide as calcium precursors. The delivery profiles of bovine serum albumin (BSA), a model protein by the nanocarriers, were studied. Both eggshells derived and synthetic CDHA samples showed maximum amount of loading of 57% and 37%, respectively at a Ca/P ratio of 1.51, comparing to stoichiometric HA. ECDHA also showed a much more BSA release (25%) than synthetically derived CDHA (6.5%) did. To further improve the release profile, alginate coating was carried out on CDHA nanoparticles and the BSA release profiles were evaluated. A maximum release of 65% was observed for alginate coated ECDHA at a Ca/P ratio of 1.51 for a period of 2 days. The ECDHA nanoparticle with a Ca/P ratio similar to degradable TCP and with alginate coating seems to be an ideal protein delivery agent. PMID- 25444656 TI - Apoptosis in liver cancer (HepG2) cells induced by functionalized gold nanoparticles. AB - An ethnopharmacological approach for biosynthesis of gold nanoparticles is being demonstrated using seed coat of Cajanus cajan. Medicinal value of capping molecule investigated for anticancer activity and results disclose its greater potential. The active principle of the seed coat [3-butoxy-2-hydroxypropyl 2-(2,4 dihydroxyphenyl) acetate] is elucidated. Rapid one-step synthesis yields highly stable, monodisperse (spherical) gold nanoparticles in the size ranging from 9 to 41 nm. Anticancer activity has been studied using liver cancer cells and cytotoxic mechanism has been evaluated using MTT, Annexin-V/PI Double-Staining Assay, Cell cycle, Comet assay and Flow cytometric analysis for apoptosis. The present investigation will open up a new possibility of functionalizing gold nanoparticles for apoptosis studies in liver cancer cells. PMID- 25444659 TI - The comparison of zymosterol vs cholesterol membrane properties--the effect of zymosterol on lipid monolayers. AB - In this work systematic investigations on the influence of zymosterol (zymo), which is one of cholesterol precursors, on lipid monolayers were done. The aim of these studies was to perform thorough comparison of zymosterol vs cholesterol membrane activity and fill the gap in the studies on the effect of sterols on membranes. The Langmuir monolayers experiments combined with Brewster angle microscopy studies were performed on binary (SM:zymo, POPC:zymo, GM3:zymo) and ternary (SM:POPC:zymo, SM:GM3:zymo) films differing in the sterol content. The obtained results evidenced differences in the influence of both sterols on lipid monolayers, which was manifested in the parameters calculated based on the isotherms as well is in monolayers morphology. It was found that zymosterol is of condensing, ordering and domain promoting abilities thus this molecule can be included to the group of membrane active sterols. However, zymosterol is much less effective than cholesterol as condensing and ordering agent. These findings were attributed to the differences in the structure of both sterols and their ability to pack tightly with other lipids in the mixed systems. PMID- 25444658 TI - Interaction and enrichment of protein on cationic polysaccharide surfaces. AB - In this study, the interaction of fluorescein isothiocyanate functionalized bovine serum albumin (FITC-BSA) with cellulose surfaces decorated with trimethyl chitosan (TMC) is investigated. Two types of TMC, one exhibiting a lower and one with a higher degree of cationization are used for protein adsorption. The adsorption is carried out at different pH values and concentrations of the protein solution. The amount, morphology and wettability of FITC-BSA coating on TMC/cellulose films are determined using quartz crystal microbalance with dissipation (QCM-D), atomic force microscopy, fluorescence microscopy and contact angle measurements. A lower pH and higher concentration of protein solution resulted in a greater amount of irreversibly adsorbed material owing to the reduced solubility and minimized electrostatic repulsion. A maximum adsorption of protein is observed on cellulose surfaces functionalized with TMC carrying a higher degree of cationization compared to TMC with a lower degree of cationization and pure cellulose surfaces at all applied concentrations and pH values. BSA is a commonly used model protein and is applied in this study to better understand its interaction with cationically rendered cellulose surfaces. Such knowledge is essential for creation of multifunctional polysaccharide-based biomaterials. PMID- 25444660 TI - New evidence for TiO2 uniform surfaces leading to complete bacterial reduction in the dark: critical issues. AB - This study presents new evidence for the events leading to Escherichia coli reduction in the absence of light irradiation on TiO2-polyester (from now on TiO2 PES. By transmission electron microscopy (TEM) the diffusion of TiO2 NP's aggregates with the E. coli outer lipo-polyssacharide (LPS) layer is shown to be a prerequisite for the loss of bacterial cultivability. Within 30 min in the dark the TiO2 aggregates interact with E. coli cell wall leading within 120 min to the complete loss of bacterial cultivability on a TiO2-PES 5% TiO2 sample. The bacterial reduction was observed to increase with a higher TiO2 loading on the PES up to 5%. Bacterial disinfection on TiO2-PES in the dark was slower compared to the runs under low intensity simulated sunlight light irradiation. The interaction between the TiO2 aggregates and the E. coli cell wall is discussed in terms of the competition between the TiO2 units collapsing to form TiO2 aggregates at a physiologic pH-value followed by the electrostatic interaction with the bacteria surface. TiO2-PES samples were able to carry repetitive bacterial inactivation. This presents a potential for practical applications. X ray photoelectron spectroscopy (XPS) evidence was found for the reduction of Ti4+ to Ti3+ contributing to redox interactions between TiO2-PES and the bacterial cell wall. Insight is provided into the mechanism of interaction between the E. coli cell wall and TiO2 NP's. The properties of the TiO2-PES surface like percentage atomic concentration, TiO2-loading, optical absorption, surface charge and crystallographic phases are reported in this study. PMID- 25444661 TI - Guar gum and sesame oil based novel bigels for controlled drug delivery. AB - Bigels are novel semi-solid formulations which have been drawing attention of many research scientists due to their numerous advantages over the conventional gels. The objective of this study was to develop and characterize novel bigels by mixing guar gum hydrogel and sorbitan monostearate-sesame oil based organogel for controlled drug delivery applications. The confocal microscopy suggested the existence of both aqueous and oil phases together as bigel. Micro-scale deformation (viscometric) analysis in conjugation with macro-scale deformation studies suggested shear-thinning and viscoelastic nature of the bigels. Thermal study suggested an increase in thermal stability with the increase in organogel proportion in the bigels. The developed bigels were biocompatible in nature. The in vitro drug release study showed that the release of ciprofloxacin (lipophilic drug) increased with a decrease in the organogel content. Further analysis showed that the drug release from all the bigels followed zero order diffusion kinetics which is desirable for a controlled release system. The drug loaded gels showed good antimicrobial efficiency against Bacillus subtilis. In conclusion, the developed bigels may be tried as matrices for topical drug delivery. PMID- 25444662 TI - Effect of choline carboxylate ionic liquids on biological membranes. AB - Choline carboxylates, ChCm, with m=2-10 and choline oleate are known as biocompatible substances, yet their influence on biological membranes is not well known, and the effect on human skin has not previously been investigated. The short chain choline carboxylates ChCm with m=2, 4, 6 act as hydrotropes, solubilizing hydrophobic compounds in aqueous solution, while the longer chain choline carboxylates ChCm with m=8, 10 and oleate are able to form micelles. In the present study, the cytotoxicity of choline carboxylates was tested using HeLa and SK-MEL-28 cells. The influence of these substances on liposomes prepared from dipalmitoylphosphatidylcholine (DPPC) was also evaluated to provide insights on membrane interactions. It was observed that the choline carboxylates with a chain length of m>8 distinctly influence the bilayer, while the shorter ones had minimal interaction with the liposomes. PMID- 25444663 TI - Hygroscopicity of a sugarless coating layer formed by the interaction between mannitol and poly(vinyl alcohol) (PVA). AB - A sugarless layer that provides protection against moisture is formed on tablets when a coating solution comprising mannitol and poly(vinyl alcohol) (PVA) is applied. The objective of this study is to investigate the relationship between the formation of such a sugarless layer and the resulting hygroscopic properties in order to derive an appropriate sugarless coating. The hygroscopicity of the sugarless layer is shown to be strongly affected by the addition of PVA, and has the lowest at concentration ratios between 15:2.5 and 15:4 (w/w) of mannitol and PVA. The polymorphic form of mannitol is different in formulations with different mannitol:PVA concentration ratios. Mannitol occurs in the alpha-form at mannitol:PVA concentration ratios between 15:1 and 15:4 (w/w). Moreover, PVA affects the molecular motions in the region associated with the OH stretch, OH deformation, and CH2 wag of mannitol. In particular, the molecular motions change considerably at mannitol:PVA concentration ratio of 15:2.5 and 15:4 (w/w). In addition, the surface state of the sugarless layer depends on the amount of PVA added, and exhibits the smoothest surface at a mannitol:PVA concentration ratio between 15:2.5 and 15:4 (w/w). Thus, the hygroscopicity is related to the surface states of the sugarless layer, which, in turn, is affected by the change in the molecular motions of mannitol due to the interactions between mannitol and PVA. PMID- 25444664 TI - Improvement of quercetin protective effect against oxidative stress skin damages by incorporation in nanovesicles. AB - Quercetin was incorporated in glycerosomes, new phospholipid-glycerol vesicles, and their protective effect against oxidative stress skin damages was extensively evaluated. In particular, the concentration-dependent effect of glycerol (from 10 to 50%) on vesicle suitability as cutaneous carriers of quercetin was carefully assessed. All vesicles were unilamellar and small in size (~80-110 nm), as confirmed by cryo-TEM observation, with a drug incorporation efficiency ranging between 81 and 91%. SAXS studies, performed to investigate the bilayer arrangement, indicated a strong, dose-dependent interaction of glycerol with the polar portions of the phospholipid molecules, while quercetin did not significantly change the bilayer packing. In vitro studies on newborn pig skin underlined the concentration-dependent ability of glycerosomes to promote quercetin accumulation in the different layers, also confirmed by confocal microscopic observation of skin treated with fluorescent vesicles. Quercetin incorporated into liposomal and glycerosomal nanoformulations showed a strong ability to scavenge free radicals (DPPH test) and protect human keratinocytes in vitro against hydrogen peroxide damage. Moreover, quercetin-loaded vesicles were avidly taken up by keratinocytes in vitro. Overall, results indicate 40 and 50% glycerosomes as promising nanosystems for the improvement of cutaneous quercetin delivery and keratinocyte protection against oxidative stress damage. PMID- 25444665 TI - Spray-dried didanosine-loaded polymeric particles for enhanced oral bioavailability. AB - Didanosine (ddI) is a water-soluble antiretroviral used in the treatment of HIV that undergoes fast gastric degradation to an inactive hypoxanthine. Therefore, its oral bioavailability is relatively low (20-40%). In this work, we investigated for the first time a scalable open-loop spray-drying method with co current flow for the encapsulation of ddI (model drug) within particles of the biocompatible polyester poly(epsilon-caprolactone). The average diameter of the particles was 36-118 MUm and the morphology spherical. The encapsulation efficiency ranged from 60% to 100% with yields of up to 65%. ATR/FT-IR analysis indicated that most of the drug was encapsulated within the particles. In vitro release assays showed that the particles released the drug within 120 min. Finally, oral administration to rats led to a statistically significant 2.5-fold increase of the bioavailability with respect to a ddI aqueous solution, highlighting the potential of this technology to encapsulate efficiently other hydrophilic antiretrovirals and, by doing so, to overcome different biopharmaceutical drawbacks associated with the oral administration. PMID- 25444668 TI - Sex versus gender: a touchy subject for multiple sclerosis. PMID- 25444667 TI - Half-mirror biofeedback exercise in combination with three botulinum toxin A injections for long-lasting treatment of facial sequelae after facial paralysis. AB - OBJECTIVES/HYPOTHESIS: The present study was conducted to develop a new method for maintaining the effect of botulinum toxin treatment for facial sequelae. We used a combination strategy including the administration of botulinum toxin three times at 6-8-month intervals followed by daily newly developed half-mirror biofeedback rehabilitation for about 2 years from the first injection. STUDY DESIGN: This was a prospective study. METHODS: Seventeen patients with unilateral facial palsy for >1 year were included in the study. The amount injected per site varied from 1.5 to 3 U. The purpose of the first injection was to reduce the most inconvenient facial problem such as facial synkinesis or hyperkinetic movement at the points of the periocular area and the zygomaticus major and minor muscles with an average dosage of 17.4 +/- 13.9 U. The second injection was to enhance facial symmetry at prominent hypertrophic areas on the contralateral side with 36.5 +/- 15.4 U, and the third injection was to add cosmetic configuration at the points of deep furrows and creases caused by facial muscular hyperkinesis or atrophy with 15.6 +/- 8.4 U. RESULT: After three injections of botulinum toxin A and 2 years of half-mirror biofeedback exercises, all patients showed marked relief of facial synkinesis and facial asymmetry. Before treatment, the mean +/- standard deviation (SD) Sunnybrook (SB) score was 36.8 +/- 8.76. After the first injection, the score increased by 11.4. After the second injection, the score increased by 14.6; it further increased by 15.6 after the third injection. CONCLUSION: This facial rehabilitation strategy, consisting of three injections of botulinum toxin and half-mirror biofeedback exercises, proceeds over the course of 2 years and offers a long-lasting cure for facial synkinesis and facial symmetry as well as improved facial aesthetics. PMID- 25444666 TI - Sorafenib treatment of advanced renal cell carcinoma patients in daily practice: the large international PREDICT study. AB - BACKGROUND: Patients with advanced renal cell carcinoma in routine clinical practice can differ considerably from those in phase III studies. PATIENTS AND METHODS: PREDICT (Patient characteristics in REnal cell carcinoma and Daily practICe Treatment with sorafenib) was a prospective, noninterventional study of open-label sorafenib for the treatment of advanced RCC conducted in 18 countries. Patient characteristics, therapy duration, tumor status, and tolerability were assessed at baseline and during routine follow-up. RESULTS: Overall, 2599 patients were evaluable for safety and 2311 for efficacy. The diverse population included patients with brain metastases (5%), non-clear-cell histologies (17%), high Memorial Sloan-Kettering Cancer Center risk score (11%), poor Eastern Cooperative Oncology Group performance status (PS >= 2, 29%), and patients with no previous nephrectomy (16%) or no previous systemic therapy (37%). The median duration of sorafenib therapy was 7.3 months and was similar in clinically relevant subgroups (eg, patients with PS 2, brain metastases, or concomitant hypertension or diabetes [range, 6.7-7.0 months]). The median duration of therapy was shorter for patients with PS 3 or non-clear-cell histologies (4.6 and 4.8 months, respectively). The most common drug-related adverse events were hand-foot skin reaction (20%), diarrhea (17%), and rash (8%). CONCLUSION: Sorafenib was generally well tolerated and provided clinical benefit in a large, diverse population of patients with advanced RCC treated in routine clinical practice. PMID- 25444669 TI - Severe gastrointestinal complications in the era of image-guided high-dose-rate intracavitary brachytherapy for cervical cancer. AB - PURPOSE: The purposes of this analysis are to report a modern series of severe gastrointestinal toxic effects after definitive chemoradiotherapy in the treatment of locally advanced cervical cancer at our institution and to review the existing literature on factors that contribute to toxic effects and preventive strategies and management. METHODS: Our institution's cervical cancer cohort was evaluated for patients with late grade 3 to 4 gastrointestinal toxic effects who were retrospectively reviewed for clinical or dosimetric parameters that could have contributed to late toxic effects. A review of the published literature was performed to identify factors associated with late toxic effects, prophylactic agents, and corrective therapy. FINDINGS: Five of 85 patients were identified as having late grade 3 to 4 gastrointestinal toxic effects with a median follow-up of 13.3 months. Two of 5 patients developed late grade 3 toxic effects, and 3 of 5 developed late grade 4 toxic effects. Three of the 5 patients reviewed ultimately required permanent colostomies. Cumulative median dose (in equivalent dose in 2-Gy fractions) of clinical target volume to the hottest 90% was 107.2 Gy, rectal dose to the hottest 2 cc (D2cc) was 81.7 Gy, sigmoid D2cc was 61.7 Gy, and bladder D2cc was 79.5 Gy. No patient had evidence of disease recurrence in the pelvis. One patient developed oligometastatic disease in the suprarenal gland and was successfully salvaged with adrenalectomy. IMPLICATIONS: Despite its risk of toxic effects, intracavitary brachytherapy remains a critical component of the treatment of locally advanced cervical cancer. Even with modern radiotherapy planning and delivery techniques, extra attention is warranted to continue to strive for optimal outcomes. PMID- 25444670 TI - Five-year review of absconding in three acute psychiatric inpatient wards in Australia. AB - Absconding, where patients under an involuntary mental health order leave hospital without permission, can result in patient harm and emotional and professional implications for nursing staff. However, Australian data to drive nursing interventions remain sparse. The purpose of this retrospective study was to investigate absconding in three acute care wards from January 2006 to June 2010, in order to determine absconding rates, compare patients who did and did not abscond, and to examine incidents. The absconding rate was 17.22 incidents per 100 involuntary admissions (12.09% of patients), with no significant change over time. Being male, young, diagnosed with a schizophrenia or substance-use disorder, and having a longer hospital stay were predictive of absconding. Aboriginal and Torres Strait Islander patients had higher odds of absconding than Caucasian Australians. Over 25% of absconding patients did so multiple times. Patients absconded early in admission. More incidents occurred earlier in the year, during summer and autumn, and later in the week, and few incidents occurred early in the morning. Almost 60% of incidents lasted <=24 hours. Formulation of prospective interventions considering population demographic factors and person specific concerns are required for evidence-based nursing management of the risks of absconding and effective incident handling when they do occur. PMID- 25444672 TI - Silencing of CD59 enhanced the sensitivity of HT29 cells to 5-Fluorouracil and Oxaliplatin. AB - Complement regulatory proteins (CD55 and CD59) were known to be expressed in many tumors and tumor cell lines including colorectal carcinoma, and were proposed as immunotherapy targets, however whether knocking down of CD55 and CD59 will affect the sensitivity of HT-29 cells to chemotherapy drugs for example, 5-Fluorouracil and Oxaliplatin and their possible mechanisms haven't been studied. To address this question, SiRNAs targeting CD55 and CD59 were chemically synthesized and transfected into HT-29 cells by lipofectamine. HT-29 growth curves of CD55 and CD59 knockdown cells were detected by MTT assay, HT29 inhibition curves to chemotherapy drugs (5-Fu and Oxaliplatin) were also assayed, in addition, chemotherapy sensitivity changes of HT29 affected by CD55 and CD59 knockdown were equally detected. Complement mediated lysis was examined by calcein-AM. We found that silencing CD59 in HT-29 cells could significantly enhance their sensitivity to 5-FU (P < 0.05) and Oxaliplatin (P < 0.05), and significantly reduced their IC50 concentration. On the contrary, knocking down of CD55 could inhibit HT-29 growth (P < 0.05). Mechanisms included increasing apoptosis rate of HT-29 by CD59 knocking down and G1/G0 blocking by silencing CD55. Our results thus shed light on the novel mechanism of chemotherapy resistance and provide an alternative strategy to overcome the resistance problem. PMID- 25444671 TI - Chronic invasive sinus and intracerebral aspergillosis controlled by combination therapy with micafungin and a daily dose of 400 mg itraconazole oral solution. AB - Chronic invasive aspergillosis of the sinus is frequently fatal in the absence of early surgical and chemotherapeutic intervention because of its invasion of vascular tissue. We attempted to control a case of inoperable invasive aspergillosis of the sinus with micafungin and itraconazole oral solution. We prescribed a daily oral dose of 400 mg of itraconazole, which is twice the usual dose, and monitored the serum concentration of the drug. Finally, we were able to control the spread of the lesion. This case indicates that combination therapy with micafungin and a daily dose of 400 mg itraconazole oral solution is an alternative treatment strategy for inoperable invasive aspergillosis of the sinus. PMID- 25444674 TI - In vitro susceptibility of characterized beta-lactamase-producing Gram-negative bacteria isolated in Japan to ceftazidime-, ceftaroline-, and aztreonam-avibactam combinations. AB - Avibactam displays potent inhibition of extended-spectrum, AmpC, KPC and some OXA beta-lactamases. We examined the combinations of avibactam with ceftazidime, ceftaroline and aztreonam by the broth microdilution method against Gram-negative bacteria harboring molecularly-characterized beta-lactamase genes collected in Toho University, Japan. Bacterial isolates included: Ambler class A beta lactamase-producing Enterobacteriaceae (n = 26); class C beta-lactamase-producing Enterobacteriaceae (n = 9) and class D beta-lactamase-producing Acinetobacter baumannii (n = 9) and Enterobacteriaceae (n = 3). Ceftazidime-avibactam, ceftaroline-avibactam ands aztreonam-avibactam were active against the strains with an extended-spectrum beta-lactamase (ESBL) or AmpC enzymes, but combination with avibactam did not reduce beta-lactam MICs against A. baumannii with OXA beta lactamases including carbapenemases, such as OXA-40 and -69. PMID- 25444673 TI - Clinical features of pulmonary cryptococcosis in non-HIV patients in Japan. AB - OBJECTIVE: To clarify the clinical features of pulmonary cryptococcosis in Japanese non-HIV population. METHODS: Retrospective investigation of 151 pulmonary cryptococcosis cases between 1977 and 2012 was executed. The underlying disease (UDs), aggravating factors, radiological characteristics, and treatment were examined. RESULTS: Sixty-seven patients (44.4%) had no UDs. The common UDs were diabetes (32.1%) followed by hematologic disease (22.6%), and collagen disease (22.6%). Peripherally distributed pulmonary nodules/masses were most commonly seen. Lesions in the right middle lobe (p = 0.01) and air bronchogram (P = 0.05) were significantly more frequent, respectively, in patients with UDs than patients without them. Azoles were mainly selected for the patients without meningoencephalitis. Mean treatment duration for patients with and without UDs was 6.64 and 2.87 months, respectively. Patients whose pulmonary nodules improved after treatment continued to experience gradual reduction of cryptococcosis antigen titers, even if antigen titers were positive at the time of treatment cessation. The average time for antigen titers to become negative after treatment cessation was 13.1 and 10.7 months for patients with and without UDs, respectively. When groups were compared according to the presence of meningoencephalitis complications, deaths, and survivals, factors contributing to cryptococcosis prognosis included higher age, hypoproteinemia, hypoalbuminemia, steroid use, high C-reactive protein levels, and meningoencephalitis complications. CONCLUSIONS: It is crucial to consider the presence of UDs and meningoencephalitis for the choice of antifungals and treatment duration for cryptococcosis in non-HIV patients. Three- and six months-administration of azoles for pulmonary cryptococcosis with or without UDs, respectively is reasonable. PMID- 25444675 TI - Multidrug-resistant Acinetobactor baumannii isolated from a traveler returned from Brunei. AB - We report a case of multidrug-resistant (MDR) Acinetobactor baumannii isolates obtained from a traveler returned from Brunei. Whole-genome sequencing analysis revealed that the isolates harbored blaOxA-23 and armA. The minimum inhibitory concentrations of antibiotics against the strain were as follows: imipenem, 32 MUg/ml; meropenem, 32 MUg/ml; ciprofloxacin, 16 MUg/ml; amikacin, ? 1024 MUg/ml; arbekacin, ? 1024 MUg/ml; aztreonam, 64 MUg/ml; colistin, 4 MUg/ml. A. baumannii harboring both blaOxA-23 and armA is rarely reported in Japan, and, to the best of our knowledge, this is the second report of A. baumannii harboring both resistant genes in Japan. PMID- 25444676 TI - Evaluation of new automated syphilis test reagents 'IMMUNOTICLES AUTO3' series: performance, biochemical reactivity, and clinical significance. AB - BACKGROUND: Automated nontreponemal and treponemal test reagents based on the latex agglutination method (immunoticles auto3 RPR: ITA3RPR and immunoticles auto3 TP: ITA3TP) have been developed to improve the issues of conventional manual methods such as their subjectivity, a massive amount of assays, and so on. We evaluated these reagents in regards to their performance, reactivity to antibody isotype, and their clinical significance. METHODS: ITA3RPR and ITA3TP were measured using a clinical chemistry analyzer. Reactivity to antibody isotype was examined by gel filtration analysis. RESULTS: ITA3RPR and ITA3TP showed reactivity to both IgM- and IgG-class antibodies and detected early infections. ITA3RPR was verified to show a higher reactivity to IgM-class antibodies than the conventional methods. ITA3RPR correlated with VDRL in the high titer range, and measurement values decreased with treatment. ITA3RPR showed a negative result earlier after treatment than conventional methods. ITA3TP showed high specificity and did not give any false-negative reaction. Significant differences in the measurement values of ITA3RPR between the infective and previous group were verified. CONCLUSIONS: The double test of ITA3RPR and ITA3TP enables efficient and objective judgment for syphilis diagnosis and treatments, achieving clinical availability. PMID- 25444677 TI - Continued effectiveness of laninamivir octanate hydrate for influenza treatment in Japan: comparison between the 2011-2012 and 2012-2013 influenza seasons. AB - The clinical effectiveness of Laninamivir octanoate hydrate (laninamivir) was investigated in the Japanese 2012-2013 influenza season for comparison with that of the Japanese 2011-2012 influenza season. A total of 235 patients were enrolled, of whom 210 were evaluated for the duration of fever and other symptoms. The median durations of fever for A(H3N2) were 32.0 and 38.0 h and the median durations of symptoms for the A(H3N2) were 102.0 and 84.0 h for patients aged under 10 and 10 years or older, respectively. All four influenza B patients were 10 years or older, and their median duration of fever was 43.0 h and the median duration of symptoms was 71.0 h. There was no significant difference in the duration of fever or symptoms between the two seasons. The rates of patients A(H3N2) virus positive at day 5 were 37.2% (16/43) and 12.8% (18/141) for those aged under 10 years and 10 years or older, respectively. The virus positive rate was significantly higher for the patients under 10 years than for the patients aged 10 years or older (p < 0.0001). No significant change in IC50 value was found between days 1 and 5. Adverse drug reactions were reported by 2 of the 231 patients (0.87%), but neither was serious. These results suggest that laninamivir continued to be effective against influenza A(H3N2) with no safety issues and that it is unlikely that the clinical use of laninamivir will lead to virus resistance. PMID- 25444679 TI - Endogenous endophthalmitis in a patient with diabetes and foot osteomyelitis. AB - Endogenous endophthalmitis is a rare condition caused by the hematogenous spread of microorganisms from a remote infection site to the eye. Common predisposing conditions are intravenous drug abuse, diabetes, malignancy, immunosuppression, chronic renal failure, parenteral nutrition or invasive medical procedures. We describe a case of endogenous endophthalmitis in the setting of foot osteomyelitis in a patient with diabetes. A high index of clinical suspicion is required to diagnose this condition early in a patient with diabetes because visual symptoms commonly may be misattributed to retinopathy. Early diagnosis is important. PMID- 25444680 TI - Impaired gallbladder motility in adults with newly detected type 2 diabetes and lack of reversibility after achieving euglycemia. AB - OBJECTIVE: The effects of hyperglycemia and normoglycemia on gallbladder emptying have not been studied in detail. This prospective case-control study was designed to investigate the gallbladder ejection fraction in patients with newly detected diabetes and to assess the impact of restoring normoglycemia on gallbladder ejection fraction in such patients. METHODS: (99m)Tc-mebrofenin scintigraphy was performed in 22 patients with newly detected type 2 diabetes for measurement of gallbladder ejection fraction. The scintigraphy was performed at the time of first presentation and again 6 months after control of diabetes (glycated hemoglobin [A1C] <7%). Also, gallbladder ejection fraction was measured in 20 age and sex-matched controls without diabetes. RESULTS: Gallbladder ejection fraction was lower in patients with newly detected diabetes compared with controls (31.4%+/-5.9% vs. 70.7%+/-4.3%, p<0.001). Gallbladder ejection fraction did not improve after the treatment of diabetes mellitus (21.3%+/-5.7%, p=0.395). CONCLUSIONS: Gallbladder ejection fraction was markedly reduced in patients with newly detected diabetes compared to controls without diabetes. Control of diabetes and normalization of A1C did not reverse the motility defect. PMID- 25444678 TI - The arachidonic acid metabolome serves as a conserved regulator of cholesterol metabolism. AB - Cholesterol metabolism is closely interrelated with cardiovascular disease in humans. Dietary supplementation with omega-6 polyunsaturated fatty acids including arachidonic acid (AA) was shown to favorably affect plasma LDL-C and HDL-C. However, the underlying mechanisms are poorly understood. By combining data from a GWAS screening in >100,000 individuals of European ancestry, mediator lipidomics, and functional validation studies in mice, we identify the AA metabolome as an important regulator of cholesterol homeostasis. Pharmacological modulation of AA metabolism by aspirin induced hepatic generation of leukotrienes (LTs) and lipoxins (LXs), thereby increasing hepatic expression of the bile salt export pump Abcb11. Induction of Abcb11 translated in enhanced reverse cholesterol transport, one key function of HDL. Further characterization of the bioactive AA-derivatives identified LX mimetics to lower plasma LDL-C. Our results define the AA metabolomeasconserved regulator of cholesterol metabolism, and identify AA derivatives as promising therapeutics to treat cardiovascular disease in humans. PMID- 25444681 TI - Impact of insulin treatment in diabetic macular edema therapy in type 2 diabetes. AB - OBJECTIVE: To evaluate the impact of insulin therapy on the outcomes of diabetic macular edema (DME) treatment with vascular endothelial growth factor (VEGF) inhibitors in people with type 2 diabetes. METHODS: A retrospective consecutive case series of 95 patients with type 2 diabetes and DME who were treated with anti-VEGF therapy. We examined 2 cohorts: patients taking only oral antidiabetic agents and patients on insulin therapy. The main outcome measures were change in visual acuity and change in central subfield macular thickness measured by spectral-domain optical coherence tomography. The additional variables analyzed included glycated hemoglobin (A1C), creatinine, blood pressure and body mass index and their correlations with clinical findings. RESULTS: Both groups had a statistically significant improvement in visual acuity (oral antidiabetic agents group: 20/61 to 20/49, p=0.003; insulin therapy group: 20/76 to 20/56, p=0.005). There was no difference between groups at initial or 12-month examination (p=0.239 and p=0.489, respectively). From an anatomic standpoint, central subfield macular thickness also improved significantly in both groups: from 454.7 MUm to 354.9 MUm (p<0.001) in the oral antidiabetic agents group and from 471.5 MUm to 368.4 MUm (p<0.001) in the insulin therapy group. Again, there was no significant difference between groups at initial or 12-month follow-up examinations (p=0.586 and p=0.591, respectively). Mean A1C levels remained relatively stable during the follow up in both groups. CONCLUSION: Anti-VEGF therapy is a useful treatment for DME. This study suggests that chronic insulin therapy, compared with oral antidiabetic agents, does not modify the anatomic or functional effectiveness of DME treatment. PMID- 25444682 TI - Physiological and glycemic responses following acute ingestion of a popular functional drink in patients with type 1 diabetes. AB - OBJECTIVE: To determine the physiologic and glycemic responses to energy drinks by people with type 1 diabetes. METHODS: In a double-blind randomized comparison of Red Bull, Red Bull Light and a control drink, 16 adults (11 females; average age 31.5 years) with type 1 diabetes and an average glycated hemoglobin (A1C) of 68 mmol/mol were given 750 mL of Red Bull, Red Bull Light and Suso Orange in a random order. During 3 hours, comparisons were made of blood pressure and blood glucose and caffeine levels; 4-choice reaction time (4CRT) and a digit symbol substitution test were used to assess cognitive performance. Mood was measured using the University of Wales Institute of Science and Technology mood adjective checklist. RESULTS: Consumption of Red Bull and Suso Orange were associated with an early sustained rise in blood glucose, which was augmented by Red Bull (p=0.02). A transient rise in systolic blood pressure (115.9 mm Hg to 124.5 mm Hg and 115.8 mm Hg to 125.9 mm Hg, respectively, both p<0.01) followed consumption of Red Bull and Red Bull Light. There were less consistent changes in diastolic blood pressure and heart rate. Consumption of both energy drinks resulted in modest improvement in performance on the digit substitution test but had no effect on 4CRT. Energy arousal and hedonic tone were influenced transiently only, following the consumption of Suso Orange. CONCLUSIONS: Consumption of energy drinks can result in a significant carbohydrate load for people with diabetes, and patients must consider the need to adjust their insulin regimens appropriately. Caffeine-containing energy drinks can cause a rise in blood pressure, which may be an important consideration for individuals at risk for diabetes-related complications. PMID- 25444683 TI - Performance-based financial incentives for diabetes care: an effective strategy? AB - The use of financial incentives provided to primary care physicians who achieve target management or clinical outcomes has been advocated to support the fulfillment of care recommendations for patients with diabetes. This article explores the characteristics of incentive models implemented in the context of universal healthcare systems in the United Kingdom, Australia, Taiwan and Canada; the extent to which these interventions have been successful in improving diabetes outcomes; and the key challenges and concerns around implementing incentive models. Research in the effect of incentives in the United Kingdom demonstrates some improvements in process outcomes and achievement of cholesterol, blood pressure and glycated hemoglobin (A1C) targets. Evidence of the efficacy of programs implemented outside of the United Kingdom is very limited but suggests that physicians participating in these enhanced billing incentive programs were already completing the guideline-recommended care prior to the introduction of the incentive. A shift to pay-for-performance programs may have important implications for professionalism and patient-centred care. In the absence of definitive evidence that financial incentives drive the quality of diabetes management at the level of primary care, policy makers should proceed with caution. It is important to look beyond simply modifying physicians' behaviours and address the factors and systemic barriers that make it challenging for patients and physicians to manage diabetes in partnership. PMID- 25444689 TI - Validity of ultrasound prediction equations for total and regional muscularity in middle-aged and older men and women. AB - To test the validity of published equations, 79 Caucasian adults (40 men and 39 women) aged 50-78 y had muscle thickness (MT) measured by ultrasound at nine sites of the body. Fat-free mass (FFM), lean soft tissue mass (LM) and total muscle mass (TMM) were estimated from MT using equations previously published in the literature. Appendicular LM (aLM) was estimated using dual-energy X-ray absorptiometry (DXA) and this method served as the reference criterion. There were strong correlations (range r = 0.85-0.94) between DXA-derived aLM and estimated FFM, leg LM or TMM. Total error between DXA-derived aLM and TMM (~2 kg) was lower compared with the three other selected equations (6-10 kg). A Bland Altman plot revealed that there was no systematic bias between aLM and TMM; however, the other three equations included systematic error. Our results suggest that an ultrasound equation for TMM is appropriate and useful for evaluating skeletal muscle mass in the body. PMID- 25444690 TI - Reliability of superficial male pelvic floor structural measurements using linear array transperineal sonography. AB - This study evaluated reliability of measures for superficial structures of the male pelvic floor (PF) obtained via transperineal sonography. Two embalmed cadavers were dissected to identify positioning of muscles on and around the bulb of the penis and to confirm the PF protocol. Cross-sectional area (CSA) and linear thickness of the bulb of the penis, urethra, bulbospongiosus (BS) muscles, and ischiocavernosus (IC) muscles were measured on 38 transverse images from 20 male patients by three raters with varied study knowledge and sonographic experience. Intra- and inter-rater reliability were calculated with two-way, mixed effects intra-class correlation coefficients. Measures of the bulb of the penis had the best reliability. CSA of all muscles and sagittal thickness of the BS near the central tendon had good reliability. Reliability varied for rater identified thickest muscle region and measures of the urethra. Our study suggests that structures of the male PF can be reliably evaluated using a transperineal sonographic approach. PMID- 25444691 TI - Validation of a computer-aided diagnosis system for the automatic identification of carotid atherosclerosis. AB - Carotid atherosclerosis represents one of the most important causes of brain stroke. The degree of carotid stenosis is, up to now, considered one of the most important features for determining the risk of brain stroke. Ultrasound (US) is a non-invasive, relatively inexpensive, portable technique, which has an excellent temporal resolution. Computer-aided diagnosis (CAD) has become one of the major research fields in medical and diagnostic imaging. We studied US images of 44 patients, 22 patients with and 22 without carotid artery stenosis, by using US examination and applying a CAD system, an automatic prototype software to detect carotid plaques. We obtained 287 regions: 60 were classified as plaques, with an average signal echogenicity of 244.1 +/- 20.0 and 227 were classified as non plaques, with an average signal echogenicity of 193.8 +/- 38.6 compared with the opinion of an expert neurologist (golden test). The receiver operating characteristic (ROC) analysis revealed a highly significant area under the ROC curve difference from 0.5 (null hypothesis) in the discrimination between plaques and non-plaques; the diagnostic accuracy was 89% (95% CI: 0.85-0.92), with an appropriate cut-off value of 236.8, sensitivity was 83% and specificity reached a value of 85%. The experimental results showed that the proposed method is feasible and has a good agreement with the expert neurologist. Without the need of any user-interaction, this method generates a detection out-put that may be useful in second opinion. PMID- 25444692 TI - Semi-automated segmentation and quantification of mitral annulus and leaflets from transesophageal 3-D echocardiographic images. AB - Quantification of three-dimensional (3-D) morphology of the mitral valve (MV) using real-time 3-D transesophageal echocardiography (RT3-D TEE) has proved to be a valuable tool for the assessment of MV pathologies, but of limited use in clinical practice because it relies on user-intensive approaches. This study presents a new algorithm for the segmentation and morphologic quantification of the mitral annulus (MA) and mitral leaflets (ML) in closed valve configuration from RT3-D TEE volumes. Following initialization, the MA and the ML and the coaptation line (CL) are automatically obtained in 3-D. Validation with manual tracings was performed on 33 patients, resulting in segmentation errors in the order of 0.7 mm and 0.6 mm for the MA and ML segmentation, in addition to good intra- and inter-observer reproducibility (coefficients of variation below 12% and 15%, respectively). The ability of the algorithm to assess different MV pathologies as well as repaired valves with implanted annular rings was also explored. The reported performance of the proposed fast, semi-automated MA and ML quantification makes it promising for future applications in clinical settings such as the operating room, where obtaining results in short time is important. PMID- 25444693 TI - Quantification of elastic heterogeneity using contourlet-based texture analysis in shear-wave elastography for breast tumor classification. AB - Ultrasound shear-wave elastography (SWE) has become a valuable tool for diagnosis of breast tumors. The purpose of this study was to quantify the elastic heterogeneity of breast tumors in SWE by using contourlet-based texture features and evaluating their diagnostic performance for classification of benign and malignant breast tumors, with pathologic results as the gold standard. A total of 161 breast tumors in 125 women who underwent B-mode and SWE ultrasonography before biopsy were included. Five quantitative texture features in SWE images were extracted from the directional subbands after the contourlet transform, including the mean (Tmean), maximum (Tmax), median (Tmed), third quartile (Tqt), and standard deviation (Tsd) of the subbands. Diagnostic performance of the texture features and the classic features was compared using the area under the receiver operating characteristic curve (AUC) and the leave-one-out cross validation with Fisher classifier. The feature Tmean achieved the highest AUC (0.968) among all features and it yielded a sensitivity of 89.1%, a specificity of 94.3% and an accuracy of 92.5% for differentiation between benign and malignant tumors via the leave-one-out cross validation. Compared with the best classic feature, i.e., the maximum elasticity, Tmean improved the AUC, sensitivity, specificity and accuracy by 3.5%, 12.7%, 2.8% and 6.2%, respectively. The Tmed, Tqt and Tsd were also superior to the classic features in terms of the AUC and accuracy. The results demonstrated that the contourlet-based texture features captured the tumor's elastic heterogeneity and improved diagnostic performance contrasted with the classic features. PMID- 25444694 TI - High-frequency ultrasound as an option for scanning of prepared teeth: an in vitro study. AB - Because of its ability to non-invasively capture hard structures behind soft tissue, high-frequency ultrasound (HFUS)-assisted microscanning could be a patient-friendly and promising alternative for digitization of prepared teeth. However, intra-oral HFUS microscanners for taking digital impressions of prepared teeth are still not available in the clinical setting. Because working range, scanner size, scanning time, surface reconstruction accuracy and costs are major factors in such a system, our overall objective is to minimize hardware efforts and costs while maintaining the accuracy of the surface-reconstructed tooth model in the range 50 MUm. In the work described here, we investigated the accuracy of tooth impression taking using a single-element HFUS microscanner with only three translational degrees of freedom under the restriction that only one occlusal scan is performed per tooth. As in favor of time and scanning efforts the data density is expected to be low, the surface reconstruction process is linked to a model-based surface reconstruction approach using a thin spline robust point matching algorithm to fill data gaps. A priori knowledge for the model is generated based on the original HFUS measurement data. Three artificial teeth and one human molar were prepared and scanned using an extra-oral HFUS laboratory microscanner that was built to test and evaluate different scanning setups. A scanner with three translational degrees of freedom was used to scan the teeth from an occlusal direction. After application of the proposed thin-spline robust point matching algorithm-based reconstruction approach, reconstruction accuracy was assessed by comparing the casts with a control group scanned with an extra oral laser-scanning system. The mean difference between the reconstructed casts and the optical control group was in the range 14-53 MUm. The standard deviation was between 21 and 52 MUm. This let us assume that the suggested approach can help to decrease hardware efforts while maintaining the robustness of the 3-D surface reconstruction process for future HFUS-based intra-oral scanners. PMID- 25444695 TI - Effectiveness of the typhoid Vi vaccine in overseas travelers from England. AB - BACKGROUND: Approximately 500 cases of enteric fever, caused by Salmonella enterica serovar Typhi and Paratyphi, are reported in the UK each year. The majority are associated with travel to the Indian subcontinent. The typhoid Vi vaccine protects against S. Typhi and is available to travelers from their general practice or private clinics. The effectiveness of this vaccine has been assessed previously in endemic regions of the world but not in travelers. METHODS: Data from the enhanced surveillance scheme concerning persons in England aged >=2 years who traveled from the UK and contracted culture-confirmed enteric fever were used to calculate the effectiveness of the vaccine in travelers. A "case-case" case-control design was used, in which patients with typhoid comprised the "cases" and those with paratyphoid acted as "controls." RESULTS: The overall effectiveness of the vaccine, adjusted for age group, sex, ethnicity, birth in a typhoid-endemic country, and year (of receipt of specimen), was 65% (95% confidence interval 53%-73%). Effectiveness did not vary across subgroups of any of the factors in the model, but there was some evidence of waning effectiveness of the vaccine with increasing time since receipt (trend p = 0.05). CONCLUSIONS: The vaccine has been demonstrated to have a similar effectiveness in travelers as that found in endemic populations. It appears to be protective in all ages, including in young children (aged 2-5 years), a finding not consistently replicated in other studies. However, good hygiene practices are necessary in addition to vaccination to prevent infection. The "case-case" case control design provides a valuable method of calculating the effectiveness of this vaccine in travelers, given the availability of paratyphoid controls, a population with similar demographics and risk exposures. PMID- 25444696 TI - Recent advances in magic angle spinning solid state NMR of membrane proteins. AB - Membrane proteins mediate many critical functions in cells. Determining their three-dimensional structures in the native lipid environment has been one of the main objectives in structural biology. There are two major NMR methodologies that allow this objective to be accomplished. Oriented sample NMR, which can be applied to membrane proteins that are uniformly aligned in the magnetic field, has been successful in determining the backbone structures of a handful of membrane proteins. Owing to methodological and technological developments, Magic Angle Spinning (MAS) solid-state NMR (ssNMR) spectroscopy has emerged as another major technique for the complete characterization of the structure and dynamics of membrane proteins. First developed on peptides and small microcrystalline proteins, MAS ssNMR has recently been successfully applied to large membrane proteins. In this review we describe recent progress in MAS ssNMR methodologies, which are now available for studies of membrane protein structure determination, and outline a few examples, which highlight the broad capability of ssNMR spectroscopy. PMID- 25444697 TI - NMR structure validation in relation to dynamics and structure determination. AB - NMR spectroscopy is a key technique for understanding the behaviour of proteins, especially highly dynamic proteins that adopt multiple conformations in solution. Overall, protein structures determined from NMR spectroscopy data constitute just over 10% of the Protein Data Bank archive. This review covers the validation of these NMR protein structures, but rather than describing currently available methodology, it focuses on concepts that are important for understanding where and how validation is most relevant. First, the inherent characteristics of the protein under study have an influence on quality and quantity of the distinct types of data that can be acquired from NMR experiments. Second, these NMR data are necessarily transformed into a model for use in a structure calculation protocol, and the protein structures that result from this reflect the types of NMR data used as well as the protein characteristics. The validation of NMR protein structures should therefore take account, wherever possible, of the inherent behavioural characteristics of the protein, the types of available NMR data, and the calculation protocol. These concepts are discussed in the context of 'knowledge based' and 'model versus data' validation, with suggestions for questions to ask and different validation categories to consider. The principal aim of this review is to stimulate discussion and to help the reader understand the relationships between the above elements in order to make informed decisions on which validation approaches are the most relevant in particular cases. PMID- 25444698 TI - Solid state field-cycling NMR relaxometry: instrumental improvements and new applications. AB - The paper reviews recent progress in field cycling (FC) NMR instrumentation and its application to solid state physics. Special emphasis is put on our own work during the last 15years on instrumentation, theory and applications. As far as instrumentation is concerned we report on our development of two types of electronical FC relaxometers, a mechanical FC relaxometer and a combination of FC and one-dimensional microimaging. Progress has been achieved with respect to several parameters such as the accessible field and temperature range as well as the incorporation of sample spinning. Since an appropriate analysis of FC data requires a careful consideration of relaxation theory, we include a theory section discussing the most relevant aspects of relaxation in solids which are related to residual dipolar and quadrupolar interactions. The most important limitations of relaxation theory are also discussed. With improved instrumentation and with the help of relaxation theory we get access to interesting new applications such as ionic motion in solid electrolytes, structure determination in molecular crystals, ultraslow polymer dynamics and rotational resonance phenomena. PMID- 25444699 TI - [Uterus transplantation: tomorrow?]. PMID- 25444700 TI - [Multicentric prospective randomized and controlled study assessing effectiveness of intravaginal electrostimulation at home compared to usual care in female patients with urinary incontinence and prior perineal reeducation]. AB - OBJECTIVES: In order to maintain the benefits of perineal reeducation, patients with stress urinary incontinence need to perform self-retraining exercises of the perineal muscles at home. The aim of this randomized prospective multicentric study is to assess the effectiveness of GYNEFFIK((r)), a perineal electrostimulator, during this home-care phase. PATIENTS AND METHODS: Two parallel groups of women with stress urinary incontinence (UI) or with mixed UI (composed predominantly of stress UI), improved by physiotherapy, have followed a self-reeducation program, either with electrostimulation sessions (GYNEFFIK((r)) or home perineal electrostimulation [HPES] arm) or with usual care (UC) only, without electrostimulation. The comparison of the two groups was based on the rate of women in which the benefit of the initial perineal reeducation was maintained (defined as the ICIQ and Ditrovie scales' score not worsening) at 2, 4 and 6 months. RESULTS: A total of 161 patients were analyzed (76 in the HPES arm and 85 in the UC arm). The therapeutic benefit of the initial perineal reeducation at the last available measure (6 months for a wide majority of patients) was maintained in 81.6% in the HPES arm versus 62.4% in the UC arm (P=0.007). This significant difference reflects a significant improvement both in clinical symptomatology and in quality of life. ICIQ score was improved in 44% of patients of HPES arm while it was improved in 14% of patients of UC arm (P<0.001) and daily number of urine leakage decreased of 1.2 leakage in the HPES arm versus 0.1 leakage in UC arm (P<0.05). Likewise, improvement of quality of life was superior in the HPES arm (48% improvement of Ditrovie score versus 19% in the UC group ; P<0.05). DISCUSSION AND CONCLUSION: Investigator global impression was more favorable in the HPES arm (clinical improvement in 83% of patients versus 68% in the UC arm). At the last measure (i.e. endpoint), the benefit of initial physiotherapy was considered maintained or improved in all patients of the HPES arm while it was reported as worsened in 16.5% of the UC group. Using GYNEFFIK((r)) favorably impacts quality of life, particularly physical activity and vitality and decreases emotional consequences of UI (i.e. anxiety and depression score as assessed by HAD scale). PMID- 25444701 TI - How women with gynaecological cancer deal with treatment: issues of visibility and invisibility. AB - Through the psycho-anthropological approach study of the experiences of women affected by pelvic gynaecological cancer who undergo surgical treatment, this paper explores how these women perceive their bodily aesthetic and the impact this has on their sexuality and their relationship with their partner. Gynaecological cancers impact women in several ways, including having an effect on the way that they feel their femininity and appearance are perceived by others. Indeed, gynaecological cancer affects a part of the body intimately associated with representations of desirability that are linked to sexuality. Surgical procedures can cause scarring which can result in having a visible, physical impact on the patient, whilst also affecting their sense of body image and sexual identity. Healing treatments are too often associated with the visible, aesthetic appearance and the physicality of body, and neglect to treat questions of subjectivity. As such, women are compelled to feel like they have an integral body image, and that they are obliged to have a perfect body and need to be physically attractive to their partner. PMID- 25444702 TI - [Previa uterine leiomyoma: a rare case of bowel obstruction during pregnancy]. AB - We report the case of a massive posterior leiomyoma leading to a bowel acute obstruction and an obstructive renal failure in a 33 years old primigest woman during pregnancy. The patient underwent a urinal and an intestinal derivation during de second trimester of pregnancy as a conservative management. End of pregnancy was uneventful and she gave birth to an healthy boy (2345g) at term, by cesarean section for praevia leiomyoma. The myoma was removed 6 weeks after delivery with restoration of digestive continuity in the same time. This case report shows the morbidity of 10cm and larger leiomyoma during pregnancy. PMID- 25444703 TI - [Pseudosyndrome of Meigs revealer of an ovarian goiter]. AB - The pseudosyndrome of Meigs is caracterised by a triad, which associates a solid benign tumor of the ovary, an ascitis and a pleural effusion. Surgical extraction of the tumor entails disappearance of the symptomatology. The authors report in this study a case of an ovarian goitre revealed by this syndrom. PMID- 25444704 TI - Membrane potential regulates mitochondrial ATP-diphosphohydrolase activity but is not involved in progesterone biosynthesis in human syncytiotrophoblast cells. AB - ATP-diphosphohydrolase is associated with human syncytiotrophoblast mitochondria. The activity of this enzyme is implicated in the stimulation of oxygen uptake and progesterone synthesis. We reported previously that: (1) the detergent solubilized ATP-diphosphohydrolase has low substrate specificity, and (2) purine and pyrimidine nucleosides, tri- or diphosphates, are fully dephosphorylated in the presence of calcium or magnesium (Flores-Herrera 1999, 2002). In this study we show that ATP-diphosphohydrolase hydrolyzes first the nucleoside triphosphate to nucleoside diphosphate, and then to nucleotide monophosphate, in the case of all tested nucleotides. The activation energies (Ea) for ATP, GTP, UTP, and CTP were 6.06, 4.10, 6.25, and 5.26 kcal/mol, respectively; for ADP, GDP, UDP, and CDP, they were 4.67, 5.42, 5.43, and 6.22 kcal/mol, respectively. The corresponding Arrhenius plots indicated a single rate-limiting step for each hydrolyzed nucleoside, either tri- or diphosphate. In intact mitochondria, the ADP produced by ATP-diphosphohydrolase activity depolarized the membrane potential (DeltaPsim) and stimulated oxygen uptake. Mitochondrial respiration showed the state-3/state-4 transition when ATP was added, suggesting that ATP diphosphohydrolase and the F1F0-ATP synthase work in conjunction to avoid a futile cycle. Substrate selectivity of the ATP-diphosphohydrolase was modified by DeltaPsim (i.e. ATP was preferred over GTP when the inner mitochondrial membrane was energized). In contrast, dissipation of DeltaPsim by CCCP produced a loss of substrate specificity and so the ATP-diphosphohydrolase was able to hydrolyze ATP and GTP at the same rate. In intact mitochondria, ATP hydrolysis increased progesterone synthesis as compared with GTP. Although dissipation of DeltaPsim by CCCP decreased progesterone synthesis, NADPH production restores steroidogenesis. Overall, our results suggest a novel physiological role for DeltaPsim in steroidogenesis. PMID- 25444705 TI - Dynalets: a new method for modelling and compressing biological signals. Applications to physiological and molecular signals. AB - The biological information coming from electrophysiologic sensors like ECG, pulse sensor or from molecular signal devices like NMR spectrometry has to be visualized and manipulated in a compressed way for an efficient medical use by clinicians, if stored in scientific data bases or in personalized patient records repositories. Here, we define a new transform called Dynalet based on Lienard ordinary differential equations susceptible to model the mechanism at the source of the studied signal, and we propose to apply this new technique first to the modelling and compression of real biological periodic signals like ECG and pulse rhythm. We consider that the cardiovascular activity results from the summation of cellular oscillators located in the cardiac sinus node and we show that, as a result, the van der Pol oscillator (a particular Lienard system) fits well the ECG signal and the pulse signal. The reconstruction of the original signal (pulse or ECG) using Dynalet transform is then compared with that of Fourier, counting the number of parameters to be set for obtaining an expected signal-to-noise ratio. Then, we apply the Dynalet transform to the modelling and compression of molecular spectra obtained by protein NMR spectroscopy. The reconstruction of the original signal (peak) using Dynalet transform is again compared with that of Fourier. After reconstructing visually the peak, we propose to periodize the signal and give it to hear, the whole process being called the protein "stethoscope". PMID- 25444706 TI - Cytogenetic, cross-mating and molecular evidence of four cytological races of Anopheles crawfordi (Diptera: Culicidae) in Thailand and Cambodia. AB - Twenty-nine isolines of Anopheles crawfordi were established from wild-caught females collected from cow-baited traps in Thailand and Cambodia. Three types of X (X1, X2, X3) and four types of Y (Y1, Y2, Y3, and Y4) chromosomes were identified, according to differing amounts of extra heterochromatin. These sex chromosomes represent four metaphase karyotypes, i.e., Forms A (X1, X2, X3, Y1), B (X1, X2, X3, Y2), C (X2, Y3) and D (X2, Y4). Forms C and D are novel metaphase karyotypes confined to Thailand, whereas forms A and B appear to be common in both Thailand and Cambodia. Cross-mating experiments between the four karyotypic forms indicated genetic compatibility in yielding viable progenies and synaptic salivary gland polytene chromosomes. The results suggest that the forms are conspecific and A. crawfordi comprises four cytological races, which is further supported by very low intraspecific variation (mean genetic distance=0.000-0.018) of the nucleotide sequences in ribosomal DNA (ITS2) and mitochondrial DNA sequences (COI, COII). PMID- 25444707 TI - Neck blast disease influences grain yield and quality traits of aromatic rice. AB - A critical investigation was conducted to find out the effect of neck blast disease on yield-contributing characters, and seed quality traits of aromatic rice in Bangladesh. Both healthy and neck-blast-infected panicles of three aromatic rice cultivars (high-yielding and local) were collected and investigated at Plant Pathology Division, Bangladesh Rice Research Institute (BRRI), Gazipur, Bangladesh. All of the tested varieties were highly susceptible to neck blast disease under natural conditions, though no leaf blast symptoms appear on leaves. Neck blast disease increased grain sterility percentages, reduced grain size, yield and quality traits of seeds. The degrees of yield and seed quality reduction depended on disease severity and variety's genetic make-up. Unfilled grains were the main source of seed-borne pathogen, especially for blast in the seed lot. Transmission of blast pathogen from neck (panicle base) to seed was very poor. These findings are important, especially concerning the seed certification programme in which seed lots are certified on the basis of field inspection. Finally, controlled experiments are needed to draw more critical conclusions. PMID- 25444708 TI - Reactions by army ant workers to nestmates having had contact with sympatric ant species. AB - It was recently shown that Pheidole megacephala colonies (an invasive species originating from Africa) counterattack when raided by the army ant, Eciton burchellii. The subsequent contact permits Pheidole cuticular compounds (that constitute the "colony odour") to be transferred onto the raiding Eciton, which are then not recognised by their colony-mates and killed. Using a simple method for transferring cuticular compounds, we tested if this phenomenon occurs for Neotropical ants. Eciton workers rubbed with ants from four sympatric species were released among their colony-mates. Individuals rubbed with Solenopsis saevissima or Camponotus blandus workers were attacked, but not those rubbed with Atta sexdens, Pheidole fallax or with colony-mates (control lot). So, the chemicals of certain sympatric ant species, but not others, trigger intra colonial aggressiveness in Eciton. We conclude that prey-ant chemicals might have played a role in the evolution of army ant predatory behaviour, likely influencing prey specialization in certain cases. PMID- 25444709 TI - Immunoglobulin genes in Andalusia (Spain). Genetic diversity in the Mediterranean space. AB - Andalusia is the most densely populated region of Spain since ancient times, and has a rich history of contacts across the Mediterranean. Earlier studies have underlined the relatively high frequency of the Sub-Saharan GM 1,17 5* haplotype in western Andalusia (Huelva province, n=252) and neighbouring Atlantic regions. Here, we provide novel data on GM/KM markers in eastern Andalusians (n=195) from Granada province, where African GM*1,17 5* frequency is relatively high (0.044). The most frequent GM haplotypes in Andalusia parallel the most common in Europe. Altogether, these data allow us to gain insight into the genetic diversity of southern Iberia. Additionally, we assess population structure by comparing our Iberian samples with 41 Mediterranean populations. GM haplotype variation across the Mediterranean reflects intense and complex interactions between North Africans and South Europeans along human history, highlighting that African influence over the Iberian Peninsula does not follow an isotropic pattern. PMID- 25444710 TI - Information/education page. Preventing recurrent stroke. PMID- 25444711 TI - Looking and touching: what extant approaches reveal about the structure of early word knowledge. AB - The goal of the current study is to assess the temporal dynamics of vision and action to evaluate the underlying word representations that guide infants' responses. Sixteen-month-old infants participated in a two-alternative forced choice word-picture matching task. We conducted a moment-by-moment analysis of looking and reaching behaviors as they occurred in tandem to assess the speed with which a prompted word was processed (visual reaction time) as a function of the type of haptic response: Target, Distractor, or No Touch. Visual reaction times (visual RTs) were significantly slower during No Touches compared to Distractor and Target Touches, which were statistically indistinguishable. The finding that visual RTs were significantly faster during Distractor Touches compared to No Touches suggests that incorrect and absent haptic responses appear to index distinct knowledge states: incorrect responses are associated with partial knowledge whereas absent responses appear to reflect a true failure to map lexical items to their target referents. Further, we found that those children who were faster at processing words were also those children who exhibited better haptic performance. This research provides a methodological clarification on knowledge measured by the visual and haptic modalities and new evidence for a continuum of word knowledge in the second year of life. PMID- 25444713 TI - Curcumin protects hearts from FFA-induced injury by activating Nrf2 and inactivating NF-kappaB both in vitro and in vivo. AB - Obesity and increased free fatty acid (FFA) level are tightly linked, leading to the development of cardiovascular disorders. Curcumin is a natural product from Curcuma longa with multiple bioactivities and is known to have cardioprotective effects in several cellular and animal models. The current study was designed to evaluate the cardioprotective effects of curcumin and demonstrate the underlying mechanism in FFA-induced cardiac injury. Using cell culture studies and high fat in vivo model, we explored the mechanistic basis of anti-inflammatory and antioxidant activities of curcumin. We observed that palmitate (PA) treatment in cardiac derived H9C2 cells induced a marked increase in reactive oxygen species, inflammation, apoptosis and hypertrophy. All of these changes were effectively suppressed by curcumin treatment. In addition, oral administration of curcumin at 50mg/kg completely suppressed high fat diet-induced oxidative stress, inflammation, apoptosis, fibrosis, hypertrophy and tissue remodeling in mice. The beneficial actions of curcumin are closely associated with its ability to increase Nrf2 expression and inhibit NF-kappaB activation. Thus, both in vitro and in vivo studies showed a promising role of curcumin as a cardioprotective agent against palmitate and high fat diet mediated cardiac dysfunction. We indicated the regulatory roles of Nrf2 and NF-kappaB in obesity-induced heart injury, and suggested that they may be important therapeutic targets in the treatment of obesity-related disorders. PMID- 25444714 TI - Liquid biopsies in lung cancer: the new ambrosia of researchers. AB - In the last decades the approach to cancer patient management has been deeply revolutionized. We are moving from a "one-fits-all" strategy to the "personalized medicine" based on the molecular characterization of the tumor. In this new era it is becoming more and more clear that the monitoring of the disease is fundamental for the success of the treatment, thus there is the need of new biomarker discovery. More precisely in the last years the scientific community has started to use the term "liquid biopsy". A liquid biopsy is a liquid biomarker that can be easily isolated from many body fluids (blood, saliva, urine, ascites, pleural effusion, etc.) and, as well as a tissue biopsy, a representative of the tissue from which it is spread. In this review we will focus our attention on circulating tumor cells, circulating tumor DNA, exosomes and secretomes with the aim to underlie their usefulness and potential application in a clinical setting for lung cancer patient management. PMID- 25444715 TI - Magnesium supplementation reduces metabolic syndrome--how and why? PMID- 25444712 TI - A time to reap, a time to sow: mitophagy and biogenesis in cardiac pathophysiology. AB - Balancing mitophagy and mitochondrial biogenesis is essential for maintaining a healthy population of mitochondria and cellular homeostasis. Coordinated interplay between these two forces that govern mitochondrial turnover plays an important role as an adaptive response against various cellular stresses that can compromise cell survival. Failure to maintain the critical balance between mitophagy and mitochondrial biogenesis or homeostatic turnover of mitochondria results in a population of dysfunctional mitochondria that contribute to various disease processes. In this review we outline the mechanics and relationships between mitophagy and mitochondrial biogenesis, and discuss the implications of a disrupted balance between these two forces, with an emphasis on cardiac physiology. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease". PMID- 25444716 TI - Reply: In regard to mechanisms involved in beneficial effects of magnesium supplementation. PMID- 25444717 TI - The female condom learning curve: patterns of female condom failure over 20 uses. AB - BACKGROUND: Male and female condom (FC) functional performance failure declines with user experience. With the recent availability of a wider range of FCs, it is important to know if women with experience in using one type of FC are more proficient in using another type, even if the FC design is quite different. STUDY DESIGN: A randomized, noninferiority crossover clinical trial assessed the function of four FCs (FC2, Woman's Condom, Cupid and VA w.o.w) among 300 women in Durban, South Africa. FC functional failure (breakage, slippage, invagination and misdirection) by condom type and use period was investigated in women using five FCs of each type (20 FC uses in total). RESULTS: Of the 5364 condoms used during intercourse by 272 women, 200 clinical failures occurred in 195 condoms (190 condoms had one failure, and 5 had two failures). Total clinical failure was comparable across FC types. Of the 195 condoms in which failures occurred, the number of failures in the first condom use period was 103 (7.7%), decreasing to 43 events (3.2%) in the second, 33 (2.5%) in the third and 16 (1.2%) in the fourth. Only 2 failures were reported in the 20th use of an FC compared to 29 in the first use, irrespective of condom type. CONCLUSIONS: FC failure rates decreased markedly after use of the first five condoms regardless of FC type and continued to fall across the next three use periods. IMPLICATIONS: FC failure rates decrease over 20 uses, regardless of FC condom type used. The decrease is higher at the beginning of use, indicating that improvement is greatest after the first five uses. PMID- 25444718 TI - Selective targeting of GnRH-II neurons to block ovulation. AB - BACKGROUND: In rhesus macaques, luteinizing hormone (LH) secretion appears to be regulated by two distinct gonadotropin-releasing hormone (GnRH) neuronal populations, which can be distinguished by their unique anatomical locations and because they express different molecular forms of GnRH (GnRH-I and GnRH-II). STUDY DESIGN: The effect of estradiol on GnRH gene expression was examined. RESULTS: Estradiol inhibited GnRH-I neurons but stimulated GnRH-II neurons, suggesting that GnRH-II neurons play the dominant role in mediating estradiol positive feedback and triggering the midcycle preovulatory LH surge. CONCLUSIONS: Selective silencing of GnRH-II neurons in women could serve as a novel contraceptive, by blocking ovulation while leaving the rest of the reproductive axis relatively unperturbed. PMID- 25444719 TI - Silibinin ameliorates LPS-induced memory deficits in experimental animals. AB - Neuroinflammation is considered as one of the predisposing factor in the etiology of several neurodegenerative disorders. Therefore, the objective of the present study was to evaluate the protective effect of silibinin (SIL) in the lipopolysaccharide (LPS)-induced neuroinflammatory model. The effect of SIL on memory function was also evaluated on normal rats without LPS administration. In the first experiment, male rats were divided into five groups. Except control group animals, all rats received bilateral intracerebroventricular injection of LPS (5 MUg/5 MUl) into lateral ventricles on the first day of the experimental schedule. Control rats received bilateral intracerebroventricular injection of artificial cerebrospinal fluid into lateral ventricles. SIL in doses of 50, 100 and 200 mg/kg, p.o. was administered 1h before LPS injection and continued for 7 days. On Day-7, SIL attenuated the LPS-induced long-term and working memory loss in elevated plus and Y-maze test respectively. Further, SIL dose-dependently attenuated LPS-induced decrease in acetylcholine level and increase in the acetylcholinestrase activity in hippocampus and pre-frontal cortex. SIL ameliorated LPS-induced decrease in the mitochondrial complex activity (I, IV and V) and integrity, increase in lipid peroxidation and decrease in the activity of superoxide dismutase in both the brain regions. SIL attenuated amyloidogenesis in the hippocampus, while it decreased the LPS-induced increase in the level of NFkappaB in the pre-frontal cortex. In another study, SIL dose-dependently, enhanced memory functions in the normal rats, indicating its nootropic activity. Hence, SIL could be a potential candidate in the management of neuroinflammation related memory disorders. PMID- 25444720 TI - Repeated forced swim stress has additive effects in anxiety behavior and in cathecolamine levels of adult rats exposed to deltamethrin. AB - Deltamethrin (DTM) is a type II pyrethroid insecticide that elicits autonomic and neuroendocrine responses that indicate high levels of stress, presumably caused by the neurotoxic effect of the insecticide. This study investigated the effect of DTM exposure (10 mg/kg, p.o.) and an additional stress induced in the forced swim test (FST) in behavioral tasks related to anxiety, serum corticosterone levels, and striatal neurotransmitter levels. Open field behavior and social interaction were evaluated after DTM administration (10 mg kg(-1), p.o). DTM per se reduced rearing frequency in the open field, but no alterations in locomotion frequency or immobility duration were detected. Stress increased immobility duration compared with non-stressed animals. DTM reduced social interaction and increased corticosterone levels, and these effects were enhanced in stressed animals. Mainly stress affected dopaminergic and serotoninergic activity. In anxiety behavior and in both neurotransmitters and metabolites levels it was observed an additive effect of stress in DTM treated rat data. These results indicate that DTM enhanced the anxiogenic responses and stress had an additive effect over the DTM stress. The neurochemical data did not indicate an interaction between stress and DTM exposure. The present results maybe important for implementing pyrethroid insecticide safety standards. PMID- 25444721 TI - Propofol retards fetal neurodevelopment: does propofol have neurotoxic effects? PMID- 25444723 TI - Pediatric facial nerve rehabilitation. AB - Facial paralysis is a rare but severe condition in the pediatric population. Impaired facial movement has multiple causes and varied presentations, therefore individualized treatment plans are essential for optimal results. Advances in facial reanimation over the past 4 decades have given rise to new treatments designed to restore balance and function in pediatric patients with facial paralysis. This article provides a comprehensive review of pediatric facial rehabilitation and describes a zone-based approach to assessment and treatment of impaired facial movement. PMID- 25444722 TI - Effective response and delayed toxicities of refractory advanced diffuse large B cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells. AB - We conducted a trial testing a CD20-specific CAR coupled with CD137 and the CD3zeta moiety in patients with chemotherapy refractory advanced diffuse large B cell lymphomas (DLBCL). Seven patients were enrolled. One of the two patients with no bulky tumor obtained a 14-month durable and ongoing complete remission by cell infusion only, and another attained a 6-month tumor regression. Four of five patients with bulky tumor burden were evaluable for clinical efficacy, three of which attained 3- to 6-month tumor regression. Delayed toxicities related to cell infusion are directly correlated to tumor burden and tumor-harboring sites, and mainly included cytokine release symptoms, tumor lysis symptoms, massive hemorrhage of the alimentary tract and aggressive intrapulmonary inflammation surrounding extranodal lesions. These results show firstly that anti-CD20 CART cells can cause prolonged tumor regression in combination with debulking conditioning regimens for advanced DLBCL. This study is registered at www.clinicaltrials.gov as NCT01735604. PMID- 25444724 TI - Pediatric septorhinoplasty. AB - In the appropriately selected patient, septorhinoplasty can benefit a pediatric patient presenting with significant nasal trauma, abscess, or mass that will likely result in a progressive deformity in the growing nose or with negative functional or psychosocial effect. Clinical and experimental observations support a conservative approach to cartilage scoring and resection in pediatric patients in which septorhinoplasty is deemed necessary. PMID- 25444725 TI - Infantile hemangiomas: current management. AB - Management of infantile hemangiomas includes a combination of observation, medical therapy, laser treatments, and surgery. The nomenclature to describe these lesions has been standardized and should be adhered to. The goal of treatment is to obtain the best possible result commensurate with known developmental milestones. Current knowledge of the biology of these tumors as well as experience allows obtaining this goal. "Leave it alone, it will go away" is no longer universally acceptable advice for treatment of infantile hemangiomas. PMID- 25444726 TI - Craniofacial anomalies. AB - Craniosynostosis, in which 1 or more cranial sutures prematurely fuse, is associated with diverse environmental and genetic factors. Whereas isolated single-suture synostosis is usually sporadic and nonfamilial, FGFR mutations account for most cases of syndromic craniosynostosis. This article reviews the etiology and various clinical manifestations of the most common isolated and syndromic forms of craniosynostosis, and provides a brief overview of genetics. Past and present surgical management approaches and techniques are examined in depth. Outcomes data in the recent literature are reviewed, and controversies in the field and promising trends in craniofacial surgery discussed. PMID- 25444727 TI - Utilization of free tissue transfer for pediatric oromandibular reconstruction. AB - Head and neck tumors requiring large composite resections are rare in pediatrics. Large soft tissue and/or bony resections are usually the result of a neoplastic, traumatic, or infectious process. Sarcomas are the most common malignancy. Surgical resection is usually recommended after chemotherapy and/or radiation therapy. Free tissue transfer is safe and effective in this population, which has continued craniofacial growth and development. The surgeon must know the anatomic location of the growth centers and facial skeletal relationships because disruption results in abnormal development. Free tissue transfer can restore normal maxillomandibular occlusion and condylar-cranial articulation. PMID- 25444728 TI - Pediatric craniomaxillofacial trauma. AB - Trauma is a leading cause of death in children. The pediatric facial skeleton goes through progressive development and major changes, including change in the size ratio of the cranium to the face; change in the ratio of facial soft tissue to bone, and pneumatization of the sinuses. The main goal of maxillofacial fracture repair is to reestablish normal or preinjury structure and function. Follow-up is typically recommended until children reach skeletal maturity as trauma may affect growth of the facial skeleton. Problems not obvious immediately after the injury may become an issue later, and secondary surgery might be needed to address such issues. PMID- 25444729 TI - Cleft lip and palate. AB - Cleft lip with or without cleft palate is the most common congenital malformation of the head and neck. Orofacial clefting could significantly affect the quality of life of the child and requires multiple steps of care to obtain an optimal outcome. Each patient should be evaluated for congenital anomalies, developmental delay, neurologic disorders, and psychosocial concerns. A multidisciplinary team is necessary to ensure that every aspect of the child's care is appropriately treated and coordination between providers is achieved. This article discusses the assessment and treatment recommendations for children born with cleft lip and/or cleft palate. PMID- 25444730 TI - Starting a cleft team: a primer. AB - Facial plastic surgeons have a comprehensive understanding of the challenges that patients with cleft lip and palate encounter in form and function. Because there are areas in the United States where access to cleft care is limited, opportunities exist for facial plastic surgeons to develop cleft teams to provide greater availability of services to patients. A consensus statement has been developed by the Cleft and Craniofacial Subcommittee of the Specialty Surgery Committee of the American Academy of Facial Plastic and Reconstructive Surgery that outlines strategies for facial plastic surgeons who are prepared to assume leadership roles in domestic multidisciplinary cleft team initiatives. PMID- 25444731 TI - Surgical speech disorders. AB - Most speech disorders of childhood are treated with speech therapy. However, two conditions, ankyloglossia and velopharyngeal dysfunction, may be amenable to surgical intervention. It is important for surgeons to work with experienced speech language pathologists to diagnose the speech disorder. Children with articulation disorders related to ankyloglossia may benefit from frenuloplasty. Children with velopharyngeal dysfunction should have standardized clinical evaluation and instrumental asseessment of velopharyngeal function. Surgeons should develop a treatment protocol to optimize speech outcomes while minimizing morbidity. PMID- 25444732 TI - Pediatric esthetic otoplasty. AB - Pediatric otoplasty is generally considered to be a "simple" procedure, but an astute surgeon recognizes the challenges of this operation and is mindful of the degree of detail involved in its planning and execution. The vast number of described otoplasty methods, which are ever evolving, is a testament to the complexity of this procedure. In this article, the authors' methodology with respect to preoperative analysis and planning, surgical technique, and postoperative care, including management of complications and potential pitfalls, are highlighted. PMID- 25444733 TI - Microtia reconstruction: autologous rib and alloplast techniques. AB - Microtia represents a spectrum of maldevelopment of the external ear. Reconstructive techniques may utilize an autogenous rib cartilage framework and require 2-4 stages; alternatively, an alloplastic framework can be used and typically requires 1-2 stages. Successful reconstruction of microtia with either technique can provide a significant quality of life improvement, and both techniques are described in this article. PMID- 25444734 TI - Soft tissue trauma and scar revision. AB - Numerous techniques and treatments have been described for scar revision, with most studies focusing on the adult population. A comprehensive review of the literature reveals a paucity of references related specifically to scar revision in children. This review describes the available modalities in pediatric facial scar revision. The authors have integrated current practices in soft tissue trauma and scar revision, including closure techniques and materials, topical therapy, steroid injection, cutaneous laser therapy, and tissue expanders. PMID- 25444735 TI - Craniofacial distraction osteogenesis. AB - Distraction osteogenesis (DO) may be the most versatile tool to become available to the craniofacial surgeon in recent years. It can be used in an ever-expanding register of clinical scenarios and offers major advantages over conventional craniofacial techniques in some circumstances. Craniofacial surgery has significant complications, some of which can be mitigated but not eliminated by choosing DO over conventional approaches. Although some DO applications are in their infancy with limited data, this article provides an overview of current uses of this versatile technology. PMID- 25444736 TI - Pediatric facial plastic and reconstructive surgery. PMID- 25444737 TI - Thyroglobulin in differentiated thyroid cancer. AB - Identification of differentiated thyroid cancer (DTC) is becoming increasingly common. Patients usually have an excellent prognosis. Most undergo total thyroidectomy, radioiodine ablation and treatment with suppressive doses of levothyroxine. Patients require long term follow-up which includes measurement of serum thyroglobulin (Tg). Interpretation of serum Tg requires knowledge of the concurrent thyroid stimulating hormone (TSH) concentration, as secretion is TSH dependant, and an awareness of the limitations of the methods used to measure it. These limitations include the heterogeneity of Tg in serum, the ability of assays to recognise forms of Tg secreted by a tumour, assay biases and not least the potential for interference in immunoassays for Tg from endogenous thyroglobulin antibodies (TgAbs) in patient serum. This review considers what the clinician wants to know and how Tg results can be interpreted in light of an awareness of assay limitations. PMID- 25444738 TI - Biomarkers and physiopathology in the cardiorenal syndrome. AB - Acute cardiorenal syndrome (CRS) corresponds to an association of acute heart failure and a worsening of renal function. The detection of acute kidney injury (AKI) unfortunately occurs at a late stage of CRS, leading to an increased mortality of the patients. In this review, we described the pathophysiology of CRS and discussed the potential interest of biochemical biomarkers (namely creatinine, cystatin C, NGAL, KIM-1, fatty acid binding protein, Nacetyl-beta-D glucosaminidase and IL-18) that could potentially help to detect AKI earlier and thus reduce the morbi-mortality of the patients suffering from CRS. PMID- 25444740 TI - Hydrogen sulfide in signaling pathways. AB - For a long time hydrogen sulfide (H2S) was considered a toxic compound, but recently H2S (at low concentrations) has been found to play an important function in physiological processes. Hydrogen sulfide, like other well-known compounds - nitric oxide (NO) and carbon monoxide (CO) is a gaseous intracellular signal transducer. It regulates the cell cycle, apoptosis and the oxidative stress. Moreover, its functions include neuromodulation, regulation of cardiovascular system and inflammation. In this review, I focus on the metabolism of hydrogen sulfide (including enzymatic pathways of H2S synthesis from l- and d-cysteine) and its signaling pathways in the cardiovascular system and the nervous system. I also describe how hydrogen sulfide may be used as therapeutic agent, i.e. in the cardiovascular diseases. PMID- 25444739 TI - HDL cholesterol performance using an ultracentrifugation reference measurement procedure and the designated comparison method. AB - BACKGROUND: Accurate high-density lipoprotein cholesterol (HDL-C) measurements are important for management of cardiovascular diseases. The US Centers for Disease Control and Prevention (CDC) and Cholesterol Reference Method Laboratory Network (CRMLN) perform ultracentrifugation (UC) reference measurement procedure (RMP) to value assign HDL-C. Japanese CRMLN laboratory (Osaka) concurrently runs UC procedure and the designated comparison method (DCM). Osaka performance of UC and DCM was examined and compared with CDC RMP. METHODS: CDC RMP involved UC, heparin-MnCl2 precipitation, and cholesterol analysis. CRMLN DCM for samples containing <200 mg/dl triglycerides involved 50-kDa dextran sulfate-MgCl2 precipitation and cholesterol determination. RESULTS: HDL-C regression equations obtained with CDC (x) and Osaka (y) were y=0.992x+0.542 (R(2)=0.996) for Osaka UC and y=1.004x-0.181 (R(2)=0.998) for DCM. Pass rates within +/-1 mg/dl of the CDC target value were 91.9 and 92.1% for Osaka UC and DCM, respectively. Biases at 40 mg/dl HDL-C were +0.22 and -0.02 mg/dl for Osaka UC and DCM, respectively. CONCLUSIONS: Osaka UC and DCM were highly accurate, precise, and stable for many years, assisting manufacturers to calibrate products for clinical laboratories to accurately measure HDL-C for patients, calculate non-HDL-C, and estimate low density lipoprotein cholesterol with the Friedewald equation. PMID- 25444741 TI - Association between flavonoid intake and diabetes risk among the Koreans. AB - BACKGROUND: We investigated the association between flavonoid intake and type 2 diabetes mellitus (T2DM) risk factors including serum fasting glucose, insulin level, and insulin resistance. METHODS: A total of 4186 participants who were involved in the 2007-2009 Korean National Health and Nutrition Examination Survey were examined. The participants were divided into 2 groups by fasting plasma glucose (FPG) as follows: normal fasting glucose (NFG; FPG <100 mg/dl) and impaired fasting glucose (IFG) groups (FPG >=100 mg/dl). RESULTS: In the IFG group, body weight, body mass index, and waist circumference were increased. Fasting insulin level and homeostasis model assessment estimate of insulin resistance as markers of insulin resistance were higher in the IFG group. Intakes of energy and nutrients, including protein, fat, carbohydrate, crude fiber, vitamin C, calcium, phosphorus, and iron, did not differ between the 2 groups. For the male subjects, the energy-adjusted flavanone intake was lower in the IFG group than in the NFG group. Insulin and insulin resistance were inversely correlated with intakes of flavones and flavonols among the male subjects. CONCLUSION: These findings can provide valuable information for further development of appropriate strategies for diabetes prevention in Korea. PMID- 25444742 TI - SIRT1: role in cardiovascular biology. AB - SIRT1 (silent information regulator two protein) is a type III protein deacetylase that regulates a variety of important metabolic and physiologic processes including stress resistance, metabolism, apoptosis and energy balance. It reverses cholesterol transport and reduces risk for development of atherosclerosis and cardiovascular disease. The following review highlights the potential role of SIRT1 on cardiovascular biology and function. PMID- 25444744 TI - A mathematical procedure to estimate the impact of a change in method on discordance or misclassification at a decision limit in laboratory method comparison studies. AB - BACKGROUND: Laboratories often adopt new methods. It would be useful to have a statistical procedure to estimate the incremental impact of a change in assay. METHODS: Mathematical modeling, statistical analysis, and case example. RESULTS: We derived equations to estimate the proportion of discordant results that can be attributed to the new laboratory method. The calculations were demonstrated by comparing eGFR values based on creatinine values determined using the enzymatic method (existing method) and Jaffe method (new method). The discordance rate at the 60 ml/min eGFR decision limit was 3.15%. In this example, we estimated that 60% of the discordant results could be attributed to the Jaffe method. CONCLUSION: The sources of discordance in a laboratory method comparison study can be divided into three categories: The baseline discordance due to imprecision in the established method, the incremental discordance due to imprecision in the new method, and lack of analytical specificity. Discordance due to imprecision can be attributed to each individual method. Discordance due to bias can be attributed to individual methods if information is available to estimate the rate of biased observations in either method. Such information can be used to estimate the incremental cost effectiveness associated with the adoption of a new method. PMID- 25444743 TI - Serum HER2 in combination with CA 15-3 as a parameter for prognosis in patients with early breast cancer. AB - AIM: HER2 in breast cancer tissue is a marker of high prognostic and predictive relevance. Soluble HER2, the extracellular domain of the HER2/neu receptor (HER2 ECD), which is shed into the blood, has been suggested to be a helpful tumor marker. We investigated the relationship between the concentrations of HER2 ECD, CEA and CA 15-3, the association of these markers with clinicopathological features and the impact of HER2 ECD alone and in combination with known prognostic factors on disease free survival (DFS) and cancer specific survival (CSS) in untreated early breast cancer patients. PATIENTS AND METHODS: HER2 ECD (ADVIA, Bayer), CEA (AxSYM, Abbott) and CA 15-3 (Elecsys, Roche) were measured at time of primary diagnosis in the pre-therapeutic (pre-operative) sera of 241 breast cancer patients and were correlated with clinicopathological parameters and outcome. RESULTS: Higher HER2 ECD levels were significantly correlated with postmenopausal status (p=0.016) and tissue HER2-overexpression (p<0.0001). Higher serum levels of CA 15-3 were associated with larger tumor size (p=0.019), positive lymph nodes (p=0.019), UICC stage III (p<0.01), positive tissue HER2 overexpression (p<0.05) and negative hormone receptor status (p=0.016). In multivariate analysis, serum HER2 ECD levels, CA 15-3 levels, large tumor size and negative hormonal status were independent prognostic factors in DFS. Patients with both high levels of HER2 ECD (>15 ng/mL) and high serum levels of CA 15-3 (>24 U/mL) had the poorest prognosis with a DFS after 3 years of 50.0%. Patients without elevated serum levels had a better outcome with a DFS of 91.2%. CONCLUSIONS: In our retrospective analysis, HER2 ECD and CA 15-3 were independent and better prognostic tools than HER2 in tissue. Prospective validation is necessary to confirm their usefulness in clinical practice. PMID- 25444745 TI - Asymmetric Dimethylarginine (ADMA) in cardiovascular and renal disease. AB - BACKGROUND: Asymmetric Dimethylarginine (ADMA) is a modified amino acid formed when intracellular arginine is methylated by methyltransferases that are widely distributed throughout the body. Nitric oxide (NO) is produced from l-arginine in a reaction catalyzed by three distinct isoforms of NO synthase (NOS). NO has emerged as a mediator involved in maintenance of vascular tonus, blood pressure regulation, inhibition of platelet aggregation, leukocyte and endothelial cell interaction and vascular permeability. ADMA is an important inhibitor that competes with NOS and compromises NO synthesis. OBJECTIVE: This review aims to compile articles involving renal and cardiovascular diseases in which plasma ADMA was assessed in order to clarify its role in these diseases. CONCLUSION: Although current knowledge suggests that ADMA has a role in the onset of cardiovascular and renal diseases, its actions are poorly understood. Clarifying its biochemical mechanisms is essential for improving disease management and promoting better quality of life for these patients. PMID- 25444746 TI - Novel silent albumin variant (191Ala->Thr) detected by TOF MS of whole plasma. AB - BACKGROUND: Serum protein electrophoresis occasionally reveals multiple albumin bands referred to as bis- or alloalbuminaemia, and whilst the condition can be inherited it may also be acquired. METHODS: We present a new high resolution approach to the investigation of qualitative changes in albumin structure. The on line reverse phase time-of-flight mass spectrometry procedure (TOF MS) elaborated here requires <0.2 MUl of plasma and takes ~10 min to perform. Two plasma samples with classical bisalbuminaemia were used to verify the efficacy of the procedure for detecting genetic variants. When a novel mutation was detected, mass mapping of native unreduced albumin was used to pinpoint its location and inform targeted DNA sequencing of the albumin gene. RESULTS: Normal serum albumin showed its expected major isoform at 66,439 Da and the electrophoretic variants showed co equal expression of additional components at -14 and +744 Da respectively. Surprisingly, one of the supposed controls showed paired albumin peaks at 66,439 and 66,469 Da and this 30 Da increase in mass was localised to between Arg(114) and Arg(197) and confirmed as being due to a novel 191Ala->Thr (+30 Da) substitution through DNA sequencing. CONCLUSIONS: The electrospray TOF MS approach developed here provides a rapid, sensitive and extremely precise method of revealing minute changes in albumin primary structure. PMID- 25444747 TI - Negative feedback loop of cholesterol regulation is impaired in the livers of patients with Alagille syndrome. AB - AIM: To characterize cholesterol regulation in the liver of patients with Alagille syndrome (AGS). METHODS: Serum total cholesterol (TC) and total bile acid (TBA) levels were measured in 23 AGS patients. The expressions of genes involved in cholesterol regulation, including low-density lipoprotein receptor (LDLR), scavenger receptor class B type I (SR-BI), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), cholesterol 7alpha-hydroxylase (CYP7A1), ATP binding cassette transporter (ABC) A1, and ABCG1/5/8, were measured in liver tissues from five of these patients. Expression of regulators for these genes, including farnesoid X receptor/small heterodimer partner (SHP), liver X receptor alpha (LXRalpha) and mature Sterol regulatory element-binding protein 2 (SREBP2) was measured. The expression of mature SREBP2 protein was also examined. RESULTS: Serum TC and TBA levels were correlated in the AGS patients. Liver cholesterol was also increased compared with controls, and correlated with bile acid contents. LDLR, SR-BI, HMGCR, and ABCGs mRNA expression were upregulated, while CYP7A1 mRNA expression was downregulated in AGS livers. SHP and LXRalpha mRNA expression was also increased, but maturation of SREBP2 was not suppressed in the patients. CONCLUSIONS: The major upregulators of liver cholesterol might be increased in AGS patients, indicating an impaired negative feedback mechanism and accelerated liver cholesterol accumulation. PMID- 25444748 TI - Biomarkers for neuromyelitis optica. AB - Neuromyelitis optica (NMO) is an acquired, heterogeneous inflammatory disorder, which is characterized by recurrent optic neuritis and longitudinally extensive spinal cord lesions. The discovery of the serum autoantibody marker, anti aquaporin 4 (anti-AQP4) antibody, revolutionizes our understanding of pathogenesis of NMO. In addition to anti-AQP4 antibody, other biomarkers for NMO are also reported. These candidate biomarkers are particularly involved in T helper (Th)17 and astrocytic damages, which play a critical role in the development of NMO lesions. Among them, IL-6 in the peripheral blood is associated with anti-AQP4 antibody production. Glial fibrillary acidic protein (GFAP) in CSF demonstrates good correlations with clinical severity of NMO relapses. Detecting these useful biomarkers may be useful in the diagnosis and evaluation of disease activity of NMO. Development of compounds targeting these biomarkers may provide novel therapeutic strategies for NMO. This article will review the related biomarker studies in NMO and discuss the potential therapeutics targeting these biomarkers. PMID- 25444750 TI - PCSK9 and its modulation. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9), a newly-recognized protein, plays a key role in regulating cholesterol homeostasis. PCSK9 reduces hepatic low-density lipoprotein receptors (LDLRs) thereby increasing LDL cholesterol (LDL-C). Recently, biologic and genetic research proposed several approaches to inhibit or reduce PCSK9 to improve lipid profile and cardiovascular performance in patients with dyslipidemia, particularly hypercholesterolemia. Of note, PCSK9 is a secreted protein under tight control by multiple modulators. Therefore, elucidating the factors that influence PCSK9 would enhance our understanding of PCSK9 and potentially day-to-day management of these patients at high cardiovascular risk. This review will focus on genetic variants, physiologic processes, pharmacologic agents and pathologic conditions related to PCSK9 in order to assess current and future therapeutic strategies targeting this molecule. PMID- 25444752 TI - Calciuria determined by new NM-BAPTA calcium assay is not free from magnesium interference. PMID- 25444751 TI - Novel markers predict death and organ failure following hemorrhagic shock. AB - BACKGROUND: ADAMTS 13, sP-Selectin and HSP27 have been investigated as potential prognostic markers in patients with hemorrhagic shock. METHODS: This study was part of a double-blind, randomized, parallel-group, controlled trial and included seventeen trauma patients presented to ED with severe hemorrhagic. The sera for testing were collected from these patients at the time of admission. Investigators and laboratory personnel performing testing were blinded to the patients' identity and clinical course. RESULTS: The prognostic value of ADAMTS13, sP-Selectin, and HSP27 was compared to prognostic value of systolic blood pressure (SBP), base deficit estimation (BD), heart rate (HR), shock index (SI) and tissue oxygen saturation (StO2) by constructing the receiver operation characteristics (ROC). The area under the curve (AUC) of the ROC for HSP27 (0.92) was greater than for SBP (0.45), BD (0.89), HR (0.61), SI (0.45) and StO2 (0.46). AUC for sP-Selectin (0.86) and for ADAMTS13 antigen (0.74) were comparable with BD one, but greater than for the rest of currently used tests. CONCLUSION: Serum concentrations of ADAMTS13, HSP27 and sP-Selectin measured during the admission, appear to be comparable to or better than SBP, BD, SI, HR and StO2 in predicting MODS and death after hemorrhage from trauma. These potential new markers deserve further investigation. PMID- 25444749 TI - SULF2, a heparan sulfate endosulfatase, is present in the blood of healthy individuals and increases in cirrhosis. AB - BACKGROUND: SULF2 is an extracellular sulfatase that acts on heparan sulfate proteoglycans and modulates multiple signaling pathways. It is normally bound to the cell surface but can be released into the medium of cultured cells. SULF2 is known to be increased in cirrhotic liver compared to healthy liver. We asked whether SULF2 protein was present in the blood of healthy controls and increased in patients with liver cirrhosis. METHODS: We devised a sandwich ELISA for SULF2 using 2 novel monoclonal antibodies (mAbs) and measured its levels in sera of normal individuals and cirrhosis patients. RESULTS: SULF2 was higher in cirrhosis patients (1460 +/- 1160 pg/ml, N=34) than in healthy individuals (728 +/- 400 pg/ml, N=37). SULF2 levels increased with age in both healthy and patient groups. CONCLUSIONS: SULF2 may be a useful serologic biomarker for liver cirrhosis. PMID- 25444753 TI - Castration-resistant prostate cancer: AUA guideline amendment. AB - PURPOSE: The purpose of this amendment is to incorporate relevant newly-published literature to better provide a rational basis for the management of patients with castration-resistant prostate cancer. MATERIALS AND METHODS: The original systematic review and meta-analysis of the published literature yielded 303 articles published from 1996 through 2013. This review formed a majority of the guideline statements. Clinical Principles and Expert Opinions were used for guideline statements lacking sufficient evidence-based data. In April 2014, the CRPC guideline underwent amendment based on a second comprehensive literature search, which retrieved additional studies published between February 2013 and February 2014. Thirty-seven studies from this search provided data relevant to the specific treatment modalities for CRPC. RESULTS: Guideline statements based on six index patients developed to represent the most common scenarios encountered in clinical practice were amended appropriately. The additional literature provided the basis for an update of current supporting text as well as the incorporation of new guideline statements. Specifically, the addition of Radium-223 was placed in the guidelines related to the treatment of CRPC. CONCLUSIONS: Given the rapidly evolving nature of this field, this guideline should be used in conjunction with recent systematic literature reviews and an understanding of the individual patient's treatment goals. Patients' preferences and personal goals should be considered when choosing management strategies. The newly incorporated evidence-based statements supplement the original guideline published in 2013, which provided guidance for the treatment of men with CRPC. This guideline will be continually updated as new literature emerges in the field. PMID- 25444754 TI - Integrating the monoamine, neurotrophin and cytokine hypotheses of depression--a central role for the serotonin transporter? AB - Monoamine, in particular serotonergic neurotransmission has long been recognized as an important factor in the aetiology of depression. The serotonin transporter (SERT) is the primary regulator of serotonin levels in the brain and a key target for widely used antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs). In realising the limitations of current antidepressant therapy, depression research has branched out to encompass other areas such as synaptic plasticity, neurogenesis and brain structural remodelling as factors which influence mood and behaviour. More recently, the immune system has been implicated in the development of depression and various intriguing observations have inspired the cytokine hypothesis of depression. Over the past two decades evidence of in vitro and in vivo regulation of SERT function by pro-inflammatory cytokines as well as by mechanisms of synaptic plasticity has been accumulating, offering a mechanistic link between the monoamine, neurotrophin and cytokine theories of depression. This review will focus firstly on the interconnected roles of serotonin and neurotrophins in depression and antidepressant therapy, secondly on the impact of the immune system on serotonin transporter regulation and neurotrophin signalling and finally we propose a model of reciprocal regulation of serotonin and neurotrophin signalling in the context of inflammation-induced depression. PMID- 25444756 TI - Targeting breast cancer through its microenvironment: current status of preclinical and clinical research in finding relevant targets. AB - It is increasingly evident that not only breast cancer cells, but also the tissue embedding these cells: the tumor microenvironment, plays an important role in tumor progression, metastasis formation and treatment sensitivity. This review focuses on the current knowledge of processes by which the microenvironment affects breast cancer, including formation of the metastatic niche, metabolic stimulation, stimulation of tumor cell migration, immune modulation, angiogenesis and matrix remodeling. The number of drugs targeting key factors in these processes is expanding, and the available clinical data is increasing. Therefore current strategies for intervention and prediction of treatment response are outlined. At present, targeting the formation of the metastatic niche and metabolic stimulation by the breast cancer microenvironment, are already showing clinical efficacy. Intervening in the stimulation of tumor cell migration and immune modulation by the microenvironment upcoming fields of great research interest. In contrast, targeting microenvironmental angiogenesis or matrix remodeling appears to be of limited clinical relevance in breast cancer treatment so far. Further research is warranted to optimize intervention strategies and develop predictive tests for the relevance of targeting involved factors within the microenvironment in order to optimally personalize breast cancer treatment. PMID- 25444757 TI - Deubiquitinase inhibition as a cancer therapeutic strategy. AB - The ubiquitin proteasome system (UPS) is the main system for controlled protein degradation and a key regulator of fundamental cellular processes. The dependency of cancer cells on a functioning UPS has made this an attractive target for development of drugs that show selectivity for tumor cells. Deubiquitinases (DUBs, ubiquitin isopeptidases) are components of the UPS that catalyze the removal of ubiquitin moieties from target proteins or polyubiquitin chains, resulting in altered signaling or changes in protein stability. A number of DUBs regulate processes associated with cell proliferation and apoptosis, and as such represent candidate targets for cancer therapeutics. The majority of DUBs are cysteine proteases and are likely to be more "druggable" than E3 ligases. Cysteine residues in the active sites of DUBs are expected to be reactive to various electrophiles. Various compounds containing alpha,beta-unsaturated ketones have indeed been demonstrated to inhibit cellular DUB activity. Inhibition of proteasomal cysteine DUB enzymes (i.e. USP14 and UCHL5) can be predicted to be particularly cytotoxic to cancer cells as it leads to blocking of proteasome function and accumulation of proteasomal substrates. We here provide an overall review of DUBs relevant to cancer and of various small molecules which have been demonstrated to inhibit DUB activity. PMID- 25444758 TI - Histone deacetylases as therapeutic targets--from cancer to cardiac disease. AB - Heart failure is a major public health problem in western society. Recently, agents that inhibit histone deacetylase (HDAC) enzymes were developed and approved by the FDA as anticancer agents. This breakthrough has provided the motivation to develop more potent and more selective HDAC inhibitors and to target other pathologic conditions with these drugs. Here we review experimental evidence showing that these drugs may be beneficial in preventing cardiac hypertrophy and heart failure. Several lines of evidence show that inhibitors of Class I HDACs can blunt cardiac hypertrophy and preserve cardiac function in several small animal models. In contrast, Class IIa HDACs appear to be suppressors of hypertrophy, though experimental data with small molecule blockers of this class is largely lacking. The effects of HDAC inhibition in cardiac diseases, the cell population in the heart that is targeted by HDAC blockers, as well as the relative roles of specific HDACs are still under intense investigation. PMID- 25444759 TI - Targeting the TGFbeta pathway for cancer therapy. AB - The TGFbeta signaling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, motility and invasion, extracellular matrix production, angiogenesis, and immune response. TGFbeta signaling deregulation is frequent in tumors and has crucial roles in tumor initiation, development and metastasis. TGFbeta signaling inhibition is an emerging strategy for cancer therapy. The role of the TGFbeta pathway as a tumor-promoter or suppressor at the cancer cell level is still a matter of debate, due to its differential effects at the early and late stages of carcinogenesis. In contrast, at the microenvironment level, the TGFbeta pathway contributes to generate a favorable microenvironment for tumor growth and metastasis throughout all the steps of carcinogenesis. Then, targeting the TGFbeta pathway in cancer may be considered primarily as a microenvironment-targeted strategy. In this review, we focus on the TGFbeta pathway as a target for cancer therapy. In the first part, we provide a comprehensive overview of the roles played by this pathway and its deregulation in cancer, at the cancer cell and microenvironment levels. We go on to describe the preclinical and clinical results of pharmacological strategies to target the TGFbeta pathway, with a highlight on the effects on tumor microenvironment. We then explore the perspectives to optimize TGFbeta inhibition therapy in different tumor settings. PMID- 25444755 TI - PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer. AB - The phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (ViagraTM), vardenafil (LevitraTM), and tadalafil (CialisTM) have been developed for treatment of erectile dysfunction. Moreover, sildenafil and tadalafil are used for the management of pulmonary arterial hypertension in patients. Since our first report showing the cardioprotective effect of sildenafil in 2002, there has been tremendous growth of preclinical and clinical studies on the use of PDE5 inhibitors for cardiovascular diseases and cancer. Numerous animal studies have demonstrated that PDE5 inhibitors have powerful protective effect against myocardial ischemia/reperfusion (I/R) injury, doxorubicin cardiotoxicity, ischemic and diabetic cardiomyopathy, cardiac hypertrophy, Duchenne muscular dystrophy and the improvement of stem cell efficacy for myocardial repair. Mechanistically, PDE5 inhibitors protect the heart against I/R injury through increased expression of nitric oxide synthases, activation of protein kinase G (PKG), PKG-dependent hydrogen sulfide generation, and phosphorylation of glycogen synthase kinase-3beta - a master switch immediately proximal to mitochondrial permeability transition pore and the end effector of cardioprotection. In addition, PDE5 inhibitors enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs, including doxorubicin. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular and anti-cancer benefits. Despite mixed results of these clinical trials, there is a continuing strong interest by basic scientists and clinical investigators in exploring their new clinical uses. It is our hope that future new mechanistic investigations and carefully designed clinical trials would help in reaping additional benefits of PDE5 inhibitors for cardiovascular disease and cancer in patients. PMID- 25444761 TI - Sound transfer of active middle ear implants. AB - Implantable hearing aids are gaining importance for the treatment of sensorineural hearing loss and also for mixed hearing loss. The various hearing aid systems, combined with different middle ear situations, give rise to a wide range of different reconstructions. This article attempts to summarize the current knowledge concerning the mechanical interaction between active middle ear implants (AMEIs) and the normal or reconstructed middle ear. Some basic characteristics of the different AMEIs are provided in conjunction with the middle ear mechanics. The interaction of AMEIs and middle ear and the influence of various boundary conditions are discussed in more detail. PMID- 25444762 TI - Ear implants. Preface. PMID- 25444760 TI - Effects of eicosapentaenoic acid on peri-procedural (type IVa) myocardial infarction following elective coronary stenting. AB - OBJECTIVES: The aim of this study was to assess the effect of eicosapentaenoic acid (EPA) on peri-procedural (type IVa) myocardial infarction (MI) following elective percutaneous coronary intervention (PCI). METHODS AND RESULTS: We analyzed data from 165 of 178 consecutive patients with stable angina pectoris who underwent de novo successful stent implantation in the native coronary artery. Patients were assigned to receive statin therapy in combination with 1800mg/day of EPA or statin alone. Post-procedural index of microcirculatory resistance (IMR) values were calculated for 30 patients in the EPA group and 32 controls. In the multivariate logistic model, EPA administration, low kidney function, and the presence of slow flow/no reflow were significantly and independently associated with type IVa MI. Post-procedural IMR values were significantly lower in the EPA group [19.8 (6.4, 51.1) vs. 27.8 (8.2, 89.3), p=0.003] compared to the control group. CONCLUSIONS: Pre-treatment with EPA in addition to statins significantly reduced the incidence of type IVa MI compared to statin therapy only, which may be attributed to the ability of EPA to reduce microvascular dysfunction induced by PCI. PMID- 25444763 TI - Heart transplantation: current outlook. PMID- 25444765 TI - Pre-treatment mycobacterial sputum load influences individual on-treatment measurements. AB - Time to culture positivity (TTP) in liquid medium is now widely available as a measure of viable mycobacterial sputum load. TTP correlates well with and could replace colony-forming unit (CFU) counting in studies of antituberculosis drug effects. We investigated the influence of the pre-treatment mycobacterial sputum load on 4428 CFU measurements obtained within the first 14 days of treatment. Using a prediction model we show that pre-treatment CFU counts contribute 29% to the variation of on-treatment CFU counts and increase the precision of the prediction of on-treatment CFU from TTP by 12%. On the other hand, pre-treatment TTP contributed only 12% to the variation of on-treatment TTP and only added 2% to the prediction of TTP from CFU. We conclude pre-treatment measurements are covariates that can enhance the accuracy of statistical estimates of treatment effects, particularly when measured by CFU counts. PMID- 25444766 TI - The post-adipocytic phase of the adipose cell cycle. AB - Subcutaneous white adipose tissue harvested by liposuction has been studied with the aim to understand how the adipocytes modify their morphology when subjected to the passage in a needle for liposuction and to cryopreservation. The work try to clarify the ultrastructural aspects of adipose tissue, in the conditions described before, examining samples of body fat employed in fat graft procedures, and samples after cryopreservation. Scanning and transmission electron microscopy show that the first event that occur in the adipocytes is a lesion of mild degree detectable early in the samples fixed immediately after liposuction. The sequence of events following the adipocyte stress appeared composed by different phases: plasmatic membrane interruption, loss of lipid charge, formation of cup-like adipocytes and formation of post-adipocytes (i.e. cells that survive to traumatic events and restart to internalize lipid droplets). In conclusion, the study suggests that the loss of lipid charge in adipose cell is an active process that can be due to a small hole in the cytoplasmic membrane with the preservation of a large part of the cytoplasmatic content and that at the end of the process of lipid extrusion the cell can maintain viability. PMID- 25444764 TI - Permanent pacemaker implantation using a femoral approach. AB - We describe two cases in which a permanent pacemaker was implanted via the femoral vein, because the cephalic and subclavian veins were not patent. The technique and its indications, advantages and potential complications are reviewed. PMID- 25444767 TI - (1)H NMR analysis of the lactose/beta-galactosidase-derived galacto oligosaccharide components of Vivinal(r) GOS up to DP5. AB - Vivinal(r) GOS is a galacto-oligosaccharide (GOS) product, prepared from lactose by incubation with Bacillus circulans beta-galactosidase (EC 3.2.1.23). This complex mixture of saccharides with degree of polymerization (DP) between 1 and 8 is generally applied in infant nutrition. Here, a detailed structural description of the commercial product up to the DP5 level is given. First, Vivinal(r) GOS was subjected to DP analysis using HPLC-SEC (Rezex RSO-01 oligosaccharide Ag(+) column) and (1)H NMR analysis. Then, the product was fractionated on Bio-Gel P-2, and the obtained fractions were pooled according to DP, as indicated by MALDI-TOF MS analysis. Finally, fractions of single DP, as well as their subfractions obtained by HPAEC-PAD on CarboPac PA-1, were analyzed by 1D/2D (1)H/(13)C NMR spectroscopy and linkage analysis. In total, over 40 structures, providing a structural coverage of over 99% of the product, have been characterized. Detailed (1)H and (13)C NMR data, as well as G.U. values (glucose units; malto oligosaccharide ladder) on CarboPac PA-1 of all oligosaccharides are included. PMID- 25444768 TI - "It's Russian roulette": adulteration, adverse effects and drug use transitions during the 2010/2011 United Kingdom heroin shortage. AB - BACKGROUND: Between late 2010 and mid 2011 there was a significant heroin shortage in the United Kingdom (UK), resulting in a rapid drop in street heroin purity and increase in price. The most well documented event of this kind is the 2000-2001 Australian heroin shortage, with little published research addressing the UK context. In this paper we draw on qualitative data to explore the impact of, and responses to, the 2010/2011 shortage among London-based heroin users. METHODS: Data collection comprised longitudinal life history and narrative interviews with 37 PWID in 2010-2011. The average age of participants was 40, with a 20-year average duration of injecting. Heroin was the drug of choice for the majority of participants (25), with 12 preferring to inject a crack-cocaine and heroin mix. Recruitment took place through London drug and alcohol services and peer networks. RESULTS: The majority of participants continued to source and inject heroin despite reported decline in purity and increased adulteration. Transitions to poly-drug use during the heroin shortage were also common, increasing vulnerability to overdose and other drug related harms. Participants enacted indigenous harm reduction strategies in attempting to manage changes in drug purity and availability, with variable success. CONCLUSION: Epidemiological data gathered during periods of heroin shortage is often drawn on to emphasise the health benefits of reductions in supply. Our findings highlight the importance of understanding the ways in which heroin shortages may increase, as well as reduce, harm. There is a need for enhanced service provision during periods of drug shortage as well as caution in regard to the posited benefits of supply-side drug law enforcement. PMID- 25444769 TI - Factors influencing self-care behaviors of African Americans with heart failure: a photovoice project. AB - OBJECTIVES: The purpose of this study was to understand the influences of heart failure (HF) self-care among low income, African Americans. BACKGROUND: Compared to all other racial groups, African Americans have the highest risk of developing HF, coupled with high mortality and morbidity rates. METHODS: Using the photovoice method, participants related important lifestyle factors through photography. The participants and researcher met for reflection and discussion 2 h per week for six weeks. RESULTS: Four themes emerged: family support gives me the push I need, social interaction lifts me up, improving my mind to lift depression can improve my heart, and it is important but challenging to follow the HF diet. CONCLUSION: The findings from this study may assist policy makers, health care professionals, patients, and support systems in understanding the complexity of engaging in HF self-care. This understanding may lead to the development of appropriate patient-centered assessments and interventions. PMID- 25444770 TI - The importance of witnessed agency in chimpanzee social learning of tool use. AB - Social learning refers to individuals learning from others, including information gained through indirect social influences, such as the results of others' actions and changes in the physical environment. One method to determine the relative influence of these varieties of information is the 'ghost display', in which no model is involved, but subjects can watch the results that a model would produce. Previous research has shown mixed success by chimpanzees (Pan troglodytes) learning from ghost displays, with some studies suggesting learning only in relatively simple tasks. To explore whether the failure of chimpanzees to learn from a ghost display may be due to neophobia when tested singly or a requirement for more detailed information for complex tasks, we presented ghost displays of a tool-use task to chimpanzees in their home social groups. Previous tests have revealed that chimpanzees are unable to easily solve this tool-use task asocially, or learn from ghost displays when tested singly, but can learn after observing conspecifics in a group setting. In the present study, despite being tested in a group situation, chimpanzees still showed no success in solving the task via trial-and-error learning, in a baseline condition, nor in learning the task from the ghost display. Simply being in the presence of their group mates and being shown the affordances of the task was not sufficient to encourage learning. Following this, in an escalating series of tests, we examined the chimpanzees' ability to learn from a demonstration by models with agency: (1) a human; (2) video footage of a chimpanzee; (3) a live chimpanzee model. In the first two of these 'social' conditions, subjects showed limited success. By the end of the final open diffusion phase, which was run to determine whether this new behavior would be transmitted among the group after seeing a successful chimpanzee use the task, 83% of chimpanzees were now successful. This confirmed a marked overall effect of observing animate conspecific modeling, in contrast to the ghost condition. This article is part of a Special Issue entitled: insert SI title. PMID- 25444772 TI - The advent of canine performance science: offering a sustainable future for working dogs. AB - Working and sporting dogs provide an essential contribution to many industries worldwide. The common development, maintenance and disposal of working and sporting dogs can be considered in the same way as other animal production systems. The process of 'production' involves genetic selection, puppy rearing, recruitment and assessment, training, housing and handling, handler education, health and working life end-point management. At present, inefficiencies throughout the production process result in a high failure rate of dogs attaining operational status. This level of wastage would be condemned in other animal production industries for economic reasons and has significant implications for dog welfare, as well as public perceptions of dog-based industries. Standards of acceptable animal use are changing and some historically common uses of animals are no longer publicly acceptable, especially where harm is caused for purposes deemed trivial, or where alternatives exist. Public scrutiny of animal use appears likely to increase and extend to all roles of animals, including working and sporting dogs. Production system processes therefore need to be transparent, traceable and ethically acceptable for animal use to be sustainable into the future. Evidence-based approaches already inform best practice in fields as diverse as agriculture and human athletic performance. This article introduces the nascent discipline of canine performance science, which aims to facilitate optimal product quality and production efficiency, while also assuring evidence based increments in dog welfare through a process of research and development. Our thesis is that the model of canine performance science offers an objective, transparent and traceable opportunity for industry development in line with community expectations and underpins a sustainable future for working dogs. This article is part of a Special Issue entitled: Canine Behavior. PMID- 25444773 TI - Citizen science: a new direction in canine behavior research. AB - Researchers increasingly rely on members of the public to contribute to scientific projects-from collecting or identifying, to analyzing and disseminating data. The "citizen science" model proves useful to many thematically distinctive fields, like ornithology, astronomy, and phenology. The recent formalization of citizen science projects addresses technical issues related to volunteer participation--like data quality--so that citizen scientists can make longstanding, meaningful contributions to scientific projects. Since the late 1990s, canine science research has relied with greater frequency on the participation of the general public, particularly dog owners. These researchers do not typically consider the methods and technical issues that those conducting citizen science projects embrace and continue to investigate. As more canine science studies rely on public input, an in-depth knowledge of the benefits and challenges of citizen science can help produce relevant, high-quality data while increasing the general public's understanding of canine behavior and cognition as well as the scientific process. We examine the benefits and challenges of current citizen science models in an effort to enhance canine citizen science project preparation, execution, and dissemination. This article is part of a Special Issue entitled: Canine Behavior. PMID- 25444771 TI - Mechanisms of impulsive choice: II. Time-based interventions to improve self control. AB - Impulsive choice behavior has been proposed as a primary risk factor for other maladaptive behaviors (e.g., gambling, substance abuse). Recent research has suggested that timing processes may play a key role in impulsive choice behavior, and could provide an avenue for altering impulsive choice. Accordingly, the current experiments assessed a set of time-based behavioral interventions to increase self-control while simultaneously assessing effects on timing processes within the impulsive choice task. Three experiments assessed temporal interventions using a differential reinforcement of low rates task (Experiment 1) and exposure to either a variable or fixed interval schedule (Experiments 2-3). The efficacy of the interventions was assessed in Sprague-Dawley (Experiments 1 2) and Lewis (Experiment 3) rat strains. Impulsive choice behavior was assessed by measuring preferences of a smaller-sooner (SS) versus a larger-later (LL) reward, while timing of the SS and LL durations was measured during peak trials within the impulsive choice procedure. The rats showed an increased preference for the LL following all three time-based interventions and also displayed increased temporal precision. These results add to the increasing evidence that supports a possible role for temporal processing in impulsive choice behavior and supply novel behavioral interventions to decrease impulsive behavior. PMID- 25444774 TI - Reduced mate preference for dominant over subordinate males in old female Syrian hamsters (Mesocricetus auratus). AB - Why some females choose to mate with a 'preferred' male, whereas others choose to mate with an 'inferior' male is not always clear. Generally, the choosiness of females is thought to decline with advanced age, but relatively few studies have investigated this concept, and reports of this phenomenon in mammals are lacking. To address this deficiency, young and old female golden hamsters were evaluated for their preference for dominant vs. subordinate males. Females observed male dyads as a dominance relationship was established. Dominant and subordinate males were then placed within enclosures at the opposite ends of a Y-maze, and the first approach, scent marking, and time spent near each male were evaluated in young and old females during pro-oestrus-a time when females solicit visits by prospective mates by leaving vaginal and flank scent marks. Whereas the proportion of time spent near the dominant male was significantly greater than random for both young and old females, the proportions of vaginal and flank scent marks left for the dominant male were significantly greater than random for young females, but not for old females. Overall, these results are consistent with a decline in the preference for dominant males by old female hamsters. PMID- 25444775 TI - Landmark learning by juvenile salamanders (Ambystoma maculatum). AB - Learning to use a landmark as a beacon to locate resources is one of the simplest forms of spatial learning. We tested whether landmark learning occurs in a semifossorial salamander that migrates annually to breeding ponds as adults. Juvenile spotted salamanders (Ambystoma maculatum) were tested in square containers with a plastic feeding dish in each corner, and a piece of earthworm was placed in one randomly-chosen dish. For landmark-trained salamanders, a rock was placed beside the dish containing the prey. For control salamanders, the rock was placed beside a randomly selected feeding dish. Each salamander was trained once every 2 days for 30 days. Significantly more landmark-trained salamanders than control salamanders entered the landmark area first, and landmark-trained individuals had faster latencies to enter the landmark area and longer stay times. These results suggest that spotted salamanders are able to locate resources by associating their positions with landmarks. PMID- 25444776 TI - Mechanisms of copying behaviour in zebra finches. AB - When an individual is faced with choosing between unfamiliar food options, it may benefit initially by choosing the option chosen by other animals so avoiding potentially poisonous food. It is not clear which cues the naive forager learns from the demonstrator for choosing between food options. To determine firstly which birds (zebra finches, Taeniopygia guttata) would copy a demonstrator's choice, in Experiment 1 we presented each observer with a demonstrator feeding from one of two differently coloured feeders and then tested the observer's feeder colour preference. Of the same-sex/mixed-sex demonstrator-observer pairs tested only females copied male demonstrators. In Experiment 2, birds did not prefer either feeder colour in the absence of demonstrators confirming the social learning effect observed in Experiment 1. In Experiment 3, copying females fed significantly more at the feeder of the demonstrated colour, rather than at the location of the demonstrated feeder. These data point not just to the identity of the individual to be copied but also to the kind of information learned. PMID- 25444777 TI - Who are the bosses? Group influence on the behavior of voles following owl attack. AB - Individual members of a group must conform to the group norms, as they may otherwise become isolated from the group or the group may split. On the other hand, social groups usually comprise various social ranks and display a differential division of labor and consequently different behaviors. The present study was aimed at examining how the above factors are manifested in social voles that had experienced owl attack. Here, we reconfirm the findings of past studies: that grouped voles converge to display similar behavior after owl attack. In addition, we found that high-mass voles were more active in the open sectors of the experimental set-ups both before and after the owl attack, whereas low-mass voles dichotomized to those that increased and those that decreased their activity in the open following owl attack. Taking body mass as a proxy for social rank, it is suggested that as a consequence of their larger size and of their experience and physical strength, high-mass voles both presented an exemplary model for the low-mass voles and, accordingly, assumed leadership and stabilized their group's behavior. We also suggest a hypothetical model for the propagation of behavior in hierarchical groups. PMID- 25444778 TI - Adolescent social defeat disturbs adult aggression-related impulsivity in wild type rats. AB - Adolescence is generally considered as a developmental period during which adverse social experiences may have lasting consequences in terms of an increased vulnerability to affective disorders. This study aimed at determining the individual susceptibility to adolescent social stress using a rat model. We used rats of the Wild-type Groningen strain, which are characterized by a broad variation in adult levels of aggression and impulsivity. We hypothesized that experience of social defeat in adolescence results in heightened aggression and impulsivity levels in adulthood. In contrast to our expectation, adolescent social defeat did not lead to a difference in the average adult level of aggression and impulsivity, but the significant correlation between offensive aggression and impulsivity found in control animals was not present in animals defeated during adolescence. PMID- 25444779 TI - Effect of an immune challenge on the functional performance of male weaponry. AB - Theories of parasite-mediated sexual selection predict a positive association between immune function and the expression of sexually selected ornaments. Few studies, however, have investigated how an immune challenge affects the performance of sexually selected weaponry. Male Wellington tree weta (Hemideina crassidens) (Orthoptera: Anostostomatidae) possess enlarged mandibles that are used as weapons in fights for access to females residing in tree galleries. Intense sexual competition appears to have favoured the evolution of alternative male mating strategies in this species as males have a trimorphic phenotype in which weapon size varies across morphotype: 8th instar males have the smallest jaws, 10th instar males have the largest and 9th instar males being intermediate to the other two. After injecting males and females with either lipopolysaccharide (LPS; immune challenge) or saline (control) I measured over a 24h period each weta's body mass to assess whether they responded immunologically to the LPS and their bite force to assess the functional performance of their jaws. Both sexes responded immunologically to the immune-challenge as LPS injected individuals lost significantly more body mass than saline-injected controls with females losing more mass than males. Female bite force was significantly reduced 8h after LPS-injection whereas male bite force did not significantly decline. Both sexes regained pre-injection functional performance of their jaws 24h after the immune challenge. My results suggest that females trade-off bite force for immune function whereas males do not. This article is part of a Special Issue entitled: insert SI title. PMID- 25444780 TI - Incentive salience attribution under reward uncertainty: A Pavlovian model. AB - There is a vast literature on the behavioural effects of partial reinforcement in Pavlovian conditioning. Compared with animals receiving continuous reinforcement, partially rewarded animals typically show (a) a slower development of the conditioned response (CR) early in training and (b) a higher asymptotic level of the CR later in training. This phenomenon is known as the partial reinforcement acquisition effect (PRAE). Learning models of Pavlovian conditioning fail to account for it. In accordance with the incentive salience hypothesis, it is here argued that incentive motivation (or 'wanting') plays a more direct role in controlling behaviour than does learning, and reward uncertainty is shown to have an excitatory effect on incentive motivation. The psychological origin of that effect is discussed and a computational model integrating this new interpretation is developed. Many features of CRs under partial reinforcement emerge from this model. PMID- 25444781 TI - Vaccine Adjuvant Systems containing monophosphoryl lipid A and QS-21 induce strong humoral and cellular immune responses against hepatitis B surface antigen which persist for at least 4 years after vaccination. AB - BACKGROUND: Recombinant hepatitis B surface antigen (HBsAg) was used as a model antigen to evaluate persistence of cellular and humoral immune responses when formulated with three different Adjuvant Systems containing 3-O-desacyl-4' monophosphoryl lipid A (MPL) and QS-21, in an oil-in-water emulsion (AS02B and AS02V), or with liposomes (AS01B). METHODS: This is an open, 4-year follow-up of a previous randomised, double-blind study. Healthy subjects aged 18-40 years received three vaccine doses on a month 0, 1, 10 schedule and were initially followed for 18 months. A total of 93 subjects (AS02B: n=30; AS02V: n=28; AS01B: n=35) were enrolled in this follow-up and had an additional blood sample taken at Year 4 (NCT02153320). The primary endpoint was the frequency of HBsAg-specific CD4(+) and CD8(+) T-cells expressing cytokines upon short-term in vitro stimulation of peripheral blood mononuclear cells with HBsAg-derived peptides. Secondary endpoints were anti-HBs antibody titres and frequency of HBsAg-specific memory B-cells. RESULTS: A strong and persistent specific CD4(+) T-cell response was observed at Year 4 in all groups. HBsAg-specific CD4(+) T-cells expressed mainly CD40L and IL-2, and to a lesser extent TNF-alpha and IFN-gamma. HBsAg specific CD8(+) T-cells were not detected in any group. A high, persistent HBsAg specific humoral immune response was observed in all groups, with all subjects seroprotected (antibody titre >=10mIU/mL) at Year 4. The geometric mean antibody titre at Year 4 was above 100,000mIU/mL in all groups. A strong memory B-cell response was observed post-dose 2, which tended to increase post-dose 3 and persisted at Year 4 in all groups. CONCLUSION: The MPL/QS-21/HBsAg vaccine formulations induced persistent immune responses up to 4 years after first vaccination. These Adjuvant Systems offer potential for combination with recombinant, synthetic or highly purified subunit vaccines, particularly for vaccination against challenging diseases, or in specific populations, although additional studies are needed. PMID- 25444782 TI - Asking about human papillomavirus vaccination and the usefulness of registry validation: a study of young women recruited using Facebook. AB - BACKGROUND: Australia was the first country to implement a government-funded National Human Papillomavirus (HPV) Vaccination Programme. We assessed HPV vaccine uptake comparing self-reported and Register validated estimates, and the knowledge and attitudes of young women with regards to HPV vaccination post implementation of the programme. METHODS: Females, aged 16-25 years living in Victoria, Australia, were recruited using targeted advertising on Facebook from May to September 2010, to complete a web-based questionnaire. RESULTS: Geographic distribution, Indigenous and socio-economic status of the 278 participants were representative of the target population. Overall, 210/278 (76%) had heard of HPV vaccines, with 162/278 (58%) reporting receipt of at least one dose of vaccine, and 54 (19%) unsure. Verification of HPV vaccination status of 142 consenting participants (51%) showed 71% had received at least one dose. Main reasons for vaccination were for protection against HPV infection and cervical cancer (96%) and because it was free (87%), whereas unvaccinated women were uncertain of their eligibility (50%), concerned about adverse reactions (32%), or perceived that vaccination was not needed if they were monogamous (32%). CONCLUSION: The potential utility of a vaccination register in the context of a national programme is apparent from the large proportion of young women who were unsure of their vaccine status. HPV vaccine knowledge among participants was relatively high suggesting the national programme has successfully communicated to the majority of eligible women, the purpose and limitations of the vaccine. Vigilance is needed to ensure that young women follow through with Pap testing in vaccine eligible cohorts. The ongoing vaccination programme for pre-adolescent girls and boys should communicate to parents that those with one sexual partner can still acquire HPV and that the safety of the vaccine is now well demonstrated. PMID- 25444783 TI - Comparing the efficacy of FeLV vaccines: comment on: Stuke, K. et al. Efficacy of an inactivated FeLV vaccine compared to a recombinant FeLV vaccine in minimum age cats following virulent FeLV challenge. Vaccine 2014;32(22):2599-603. PMID- 25444785 TI - Overcoming the susceptibility gap between maternal antibody disappearance and auto-antibody production. AB - In the first 10-14 days of a chick's life, protection is conferred by maternal antibodies. Further broiler protection is achieved by active vaccination. However, the high level of maternal antibodies interferes with the induction of an effective immune response by vaccination at a young age. As a result, there is a gap between the reduction in protective maternal antibodies and elevation of self-produced antibodies following active vaccination. The major aim of this study was to test an approach consisting of passive and active vaccination to overcome this gap and to provide continuous resistance to infectious viral diseases during the broiler's growth period. Newcastle disease virus (NDV), which is one of the world's most prevalent infectious diseases of poultry, was tested as a model. Following subcutaneous injection of 18 hemagglutination-inhibiting (HI) units of anti-NDV immunoglobulin Y per 1-day-old chick, protective log2 antibody titers above 4 could be detected to at least 17 days of age. The combination of passive immunization on day 1 of age with attenuated live vaccination on day 10 led to high protective titers throughout the entire growth period, up to 41 days of age. Moreover, the HI titers in the group of birds immunized with the combined vaccination were significantly more homogeneous than those in the group vaccinated only with live virus. Thus, full protection against NDV of all broilers in flock during their entire growth period was achieved by a vaccination regime that combines passive immunization and live vaccination. PMID- 25444784 TI - Modeling the durability of ZOSTAVAX(r) vaccine efficacy in people >=60 years of age. AB - Since 2006, the vaccine, ZOSTAVAX((r)), has been licensed to prevent herpes zoster. Only limited clinical follow-up data are available to evaluate duration of protection, an important consideration when developing HZ vaccination policy recommendations. Four Poisson regression models were developed based on an integrated analysis of data from the Shingles Prevention Study and its Short Term Persistence extension to estimate the effects of years-since-vaccination and chronological-age on vaccine efficacy among people >=60 years old. The models included number of HZ cases parsed into categories by chronological-age and time since-vaccination as the dependent variable with different explanatory variables in each model. In all models, the interaction between vaccine-group and chronological-age was statistically significant indicating that vaccine efficacy decreases with the expected effects of advancing age but the interaction between vaccine-group and time-since-vaccination was not statistically significant indicating that much of the reduction in vaccine efficacy over time-since vaccination can be explained by increasing age. PMID- 25444786 TI - Childhood vaccines and Kawasaki disease, Vaccine Safety Datalink, 1996-2006. AB - BACKGROUND: Kawasaki disease is a childhood vascular disorder of unknown etiology. Concerns have been raised about vaccinations being a potential risk factor for Kawasaki disease. METHODS: Data from the Vaccine Safety Datalink were collected on children aged 0-6 years at seven managed care organizations across the United States. Defining exposure as one of several time periods up to 42 days after vaccination, we conducted Poisson regressions controlling for age, sex, season, and managed care organization to determine if rates of physician diagnosed and verified Kawasaki disease were elevated following vaccination compared to rates during all unexposed periods. We also performed case-crossover analyses to control for unmeasured confounding. RESULTS: A total of 1,721,186 children aged 0-6 years from seven managed care organizations were followed for a combined 4,417,766 person-years. The rate of verified Kawasaki disease was significantly lower during the 1-42 days after vaccination (rate ratio=0.50, 95% CL=0.27-0.92) and 8-42 days after vaccination (rate ratio=0.45, 95% CL=0.22-0.90) compared to rates during unexposed periods. Breaking down the analysis by vaccination category did not identify a subset of vaccines which was solely responsible for this association. The case-crossover analyses revealed that children with Kawasaki disease had lower rates of vaccination in the 42 days prior to symptom onset for both physician-diagnosed Kawasaki disease (rate ratio=0.79, 95% CL=0.64-0.97) and verified Kawasaki disease (rate ratio=0.38, 95% CL=0.20-0.75). CONCLUSIONS: Childhood vaccinations' studied did not increase the risk of Kawasaki disease; conversely, vaccination was associated with a transient decrease in Kawasaki disease incidence. Verifying and understanding this potential protective effect could yield clues to the underlying etiology of Kawasaki disease. PMID- 25444787 TI - Assessing genital human papillomavirus genoprevalence in young Australian women following the introduction of a national vaccination program. AB - OBJECTIVES: Following the implementation of Australia's National HPV Vaccination Program in April 2007, this study evaluated the prevalence of vaccine-targeted human papillomavirus (HPV) genotypes (HPV 6, 11, 16, 18) amongst vaccine-eligible young women. METHODS: Between September 2011 and August 2013, women from Victoria, Australia aged 18-25 were recruited through targeted advertising on the social networking website Facebook. Participants completed an online questionnaire, and sexually active women were asked to provide a self-collected vaginal swab for HPV deoxyribonucleic acid (DNA) detection and genotyping. Samples positive for HPV were genotyped using the Linear Array HPV genotyping test (Roche Diagnostics). Self-reported HPV vaccination details were verified with the National HPV Vaccination Program Register (NHVPR). RESULTS: Of 431 vaginal swabs, 24.8% were positive for HPV DNA. Vaccine-targeted HPV genotypes were detected in only seven (1.6%) samples; all HPV 16 (of the six HPV 16 positive vaccinated women, all had received the vaccine after sexual debut). There were no cases of HPV 6, 11 or 18 identified. HPV types 51, 59, 73, 84, and 89 were the most prevalent genotypes. Vaccination rates were high, with 77.3% of participants having received all three doses of the vaccine, and there was an 89.8% concordance between self-reported and registry-reported HPV vaccination status. Strong associations were observed between vaccination status, age, language spoken at home and country of birth, as well as between HPV detection and the number of male sexual partners. CONCLUSION: Preliminary data from this study demonstrate a very low prevalence of vaccine-related HPV genotypes amongst vaccine-eligible women from Victoria, Australia. We were able to use Facebook to effectively reach and recruit young women to participate in the assessment of the impact of Australia's HPV vaccination program. PMID- 25444789 TI - Response to letter by Moreira et al., regarding "PHiD-CV effectiveness against invasive pneumococcal disease caused by serotype 19A: further evidence in Colombia". PMID- 25444788 TI - The complementary roles of Phase 3 trials and post-licensure surveillance in the evaluation of new vaccines. AB - Vaccines have led to significant reductions in morbidity and saved countless lives from many infectious diseases and are one of the most important public health successes of the modern era. Both vaccines' effectiveness and safety are keys for the success of immunisation programmes. The role of post-licensure surveillance has become increasingly recognised by regulatory authorities in the overall vaccine development process. Safety, purity, and effectiveness of vaccines are carefully assessed before licensure, but some safety and effectiveness aspects need continuing monitoring after licensure; Post-marketing activities are a necessary complement to pre-licensure activities for monitoring vaccine quality and to inform public health programmes. In the recent past, the availability of large databases together with data-mining and cross-linkage techniques have significantly improved the potentialities of post-licensure surveillance. The scope of this review is to present challenges and opportunities offered by vaccine post-licensure surveillance. While pre-licensure activities form the foundation for the development of effective and safe vaccines, post licensure monitoring and assessment, are necessary to assure that vaccines are effective and safe when translated in real world settings. Strong partnerships and collaboration at an international level between different stakeholders is necessary for finding and optimally allocating resources and establishing robust post-licensure processes. PMID- 25444790 TI - Rescue of a vaccine strain of peste des petits ruminants virus: In vivo evaluation and comparison with standard vaccine. AB - Across the developing world peste des petits ruminants virus places a huge disease burden on agriculture, primarily affecting the production of small ruminant. The disease is most effectively controlled by vaccinating sheep and goats with live attenuated vaccines that provide lifelong immunity. However, the current vaccines and serological tests are unable to enable Differentiation between naturally Infected and Vaccinated Animals (DIVA). This factor precludes meaningful assessment of vaccine coverage and epidemiological surveillance based on serology, in turn reducing the efficiency of control programmes. The availability of a recombinant PPRV vaccine with a proven functionality is a prerequisite for the development of novel vaccines that may enable the development of DIVA tools for PPRV diagnostics. In this study, we have established an efficient reverse genetics system for PPRV Nigeria 75/1 vaccine strain and, further rescued a version of PPRV Nigeria 75/1 vaccine strain that expresses eGFP as a novel transcription cassette and a version of PPRV Nigeria 75/1 vaccine strain with mutations in the haemagglutinin (H) gene to enable DIVA through disruption of binding to H by the C77 monoclonal antibody used in the competitive (c) H-ELISA. All three rescued viruses showed similar growth characteristics in vitro in comparison to parent vaccine strain and, following in vivo assessment the H mutant provided full protection in goats. Although the C77 monoclonal antibody used in the cH-ELISA was unable to bind to the mutated form of H in vitro, the mutation was not sufficient to enable DIVA in vivo. PMID- 25444791 TI - Expected cost effectiveness of high-dose trivalent influenza vaccine in US seniors. AB - OBJECTIVES: Seniors are particularly vulnerable to complications resulting from influenza infection. Numerous influenza vaccines are available to immunize US seniors, and practitioners must decide which product to use. Options include trivalent and quadrivalent standard-dose inactivated influenza vaccines (IIV3 and IIV4 respectively), as well as a high-dose IIV3 (HD). Our research examines the public health impact, budget impact, and cost-utility of HD versus IIV3 and IIV4 for immunization of US seniors 65 years of age and older. METHODS: Our model was based on US influenza-related health outcome data. Health care costs and vaccine prices were obtained from the Centers for Medicare and Medicaid Services. Efficacies of IIV3 and IIV4 were estimated from various meta-analyses of IIV3 efficacy. The results of a head-to-head randomized controlled trial of HD vs. IIV3 were used to estimate relative efficacy of HD. Conservatively, herd protection was not considered. RESULTS: Compared to IIV3, HD would avert 195,958 cases of influenza, 22,567 influenza-related hospitalizations, and 5423 influenza related deaths among US seniors. HD generates 29,023 more Quality Adjusted Life Years (QALYs) and a net societal budget impact of $154 million. The Incremental Cost Effectiveness Ratio (ICER) for this comparison is $5299/QALY. 71% of the probabilistic sensitivity analysis (PSA) simulations were <$100,000/QALY. Compared to IIV4, HD would avert 169,257 cases of influenza, 21,222 hospitalizations and 5212 deaths. HD generates 27,718 more QALYs and a net societal budget impact of -$17 million and as such dominates IIV4. For this comparison, 81% of PSA simulations were <$100,000/QALY. CONCLUSIONS: HD is expected to achieve significant reductions in influenza-related morbidity and mortality. Further, HD is a cost effective alternative to both IIV3 and IIV4 in seniors. Our conclusions were robust in the face of sensitivity analyses. PMID- 25444792 TI - On birth single dose live attenuated OPV and BCG vaccination induces gut cathelicidin LL37 responses at 6 week of age: a natural experiment. AB - In a cross sectional study, we show that infants who received single dose of live attenuated OPV and BCG vaccines within 48h of birth, have higher excretion of human cathelicidin LL37 (p<0.05) in stool at 6wk of age. This response remained unchanged in multivariate analysis after adjusting for sex, mode of delivery, infant age, mother age birth weight and breast milk feeding pattern. This analysis also reveals that irrespective of vaccination, girl infants have higher human-beta-defencin2 (HBD2) and exclusively breastfed infants have higher total and anti-polio specific IgA to all three subtypes in stool (p<0.05). However, vaccination induces anti-polio IgA responses only to infants who are exclusively breastfed. Thus on-birth live attenuated vaccination may provide non-specific beneficial effect against infections while exclusive breastfeeding enhance protection by boosting vaccine induced IgA. The result also suggests that in polio endemic area, exclusive breastfeeding may be sufficient for mucosal anti polio responses during early infancy. PMID- 25444793 TI - Robust mucosal-homing antibody-secreting B cell responses induced by intramuscular administration of adjuvanted bivalent human norovirus-like particle vaccine. AB - BACKGROUND: Two major antigenically heterogenous norovirus genogroups (GI and GII) commonly infect humans and are the leading cause of foodborne, viral gastrointestinal infections in adults. METHODS: We assessed B cell responses in participants in a double-blind, placebo-controlled, dose-escalation phase 1 study of the safety and immunogenicity of an intramuscular bivalent norovirus virus like particle (VLP) vaccine. The vaccine contained a GI.1 VLP (Norwalk) and a consensus GII.4 VLP, representing the two major genotypes that cause human disease, and was administered on days 0 and 28 to healthy adults aged 18-49 years. Four separate cohorts received increasing doses of 5 MUg, 15 MUg, 50 MUg, and 150 MUg of each VLP adjuvanted in monophosphoryl lipid A and alum. PBMCs were analyzed for B cell activation and mucosal homing markers (flow cytometry) and VLP-specific and total IgG and IgA Ab-secreting cells (ASCs); and serum titers of VLP-specific IgG, IgA, and Pan-Ig were determined. RESULTS: The vaccine elicited CD27+ CD38+ plasmablasts and high frequencies of ASCs specific for both VLP antigens in the peripheral blood at 7 days after the first dose. The plasmablasts exhibited a mucosal-homing phenotype and included a high proportion of IgA ASCs. Serum antibodies increased as early as 7 days after the first immunization. CONCLUSIONS: The data suggest that a single dose of the IM bivalent norovirus vaccine is effective in activating pre-existing B cell memory. The rapid B cell response and the mucosal homing phenotype of induced ASCs are consistent with anamnestic responses in subjects primed by prior oral norovirus infection. This study is registered at ClinicalTrials.gov Identifier NCT01609257. PMID- 25444795 TI - Impact of a combined pediatric and adult pneumococcal immunization program on adult pneumonia incidence and mortality in Nicaragua. AB - BACKGROUND: In 2010, Nicaragua implemented an adult immunization program with the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and a pediatric immunization program with the 13-valent pneumococcal conjugate vaccine (PCV-13). We assessed incidence rates of ambulatory visits and hospitalizations for pneumonia and pneumonia-related mortality in adults over the age of 50 years before and after the program's implementation in the Department of Leon, Nicaragua. METHODS: We collected visit diagnoses from all 107 public health facilities between 2008 and 2012 in Leon. We compared incidence rates of ambulatory visits for pneumonia, pneumonia hospitalizations, and pneumonia related mortality in the pre-vaccine (2008-2009) and vaccine (2011-2012) periods among older adults using Poisson regression with generalized estimating equations (GEE), controlling for age group, municipality, and proportions of adults who were immunized against influenza. Exposure time was estimated by official municipality population estimates. RESULTS: We did not observe lower incidence rates of ambulatory visits or hospitalizations for pneumonia among adults during the vaccine period versus the pre-vaccine period. However, pneumonia-related mortality was lower in the vaccine period versus the pre-vaccine period, with an adjusted incidence rate ratio (IRRa) of 0.73 (0.56, 0.94) among adults aged 50-64 years, and 0.55 (0.43, 0.70) among adults aged >=65 years. CONCLUSIONS: These early results following introduction of a combined pediatric and adult pneumococcal immunization program in Nicaragua show a probable impact of the program on the reduction of pneumonia-related deaths in older adults, but a less clear impact on the reduction of health facility visits for pneumonia. PMID- 25444794 TI - What predicts postpartum pertussis booster vaccination? A controlled intervention trial. AB - BACKGROUND: 'Cocooning' aims to protect susceptible infants from pertussis via caregiver vaccination. Control trials evaluating educational interventions to promote cocooning are lacking. We evaluated the role of message-framing vs. standard health information in promoting pertussis vaccination. METHODS: We recruited postpartum women from a maternity hospital in Sydney, Australia (November 2010-July 2012). Participants self-completed a pertussis knowledge and attitudes questionnaire. We then assigned pertussis-susceptible (no pertussis vaccine <=10 years) participants to receive a gain-framed, loss-framed pamphlet or control (Government Pertussis factsheet) using weekly sequential block allocation. Next, participants were offered a pertussis vaccine (dTpa) and completed a post-questionnaire on discharge. RESULTS: A baseline questionnaire was completed for 96.4% (1433/1486) of postpartum women approached. Missing data was excluded (n=29). Next, participants (1404) were screened for vaccine status: 324 (23%) reported prior pertussis booster vaccine receipt, leaving 1080 participants requiring vaccination. Among susceptible mothers, 70% (754/1080) were vaccinated post-intervention. Rates were similar between 'gain', 'loss' or 'control' pamphlets (69.1% vs. 71.8% vs. 68.8%; p=0.62). Intention to be vaccinated (OR 2.46, p<0.001; 95% CI: 1.69-3.58), perceived vaccine benefits (OR: 1.61, p<0.001; 95% CI: 1.25-2.15) and having received a vaccine recommendation (OR 1.68; p=0.025; 95% CI: 1.07-2.65) were independent predictors of vaccine uptake. At discharge, overall pertussis vaccine coverage had increased from 23% to 77% among women screened (1078/1404). CONCLUSION: A cocooning strategy for pertussis vaccination can be highly effective when partially implemented within maternity hospitals, with information accompanied by a funded vaccine. Mothers were highly receptive to vaccination in the postnatal ward: facts about pertussis were as effective as message-framing in promoting a high uptake of 70%. Perceived vaccine benefits, intentions and vaccine recommendation were important predictors of uptake. Our intervention trial increased the existing pertussis vaccine coverage of 23-77%. PMID- 25444797 TI - Febrile seizures following measles and varicella vaccines in young children in Australia. AB - BACKGROUND: Febrile seizures (FS) are common in childhood with incidence peaking in the second year of life when measles and varicella-containing vaccines are administered. This study aimed to examine the vaccine-attributable risk of FS following separate administration of MMR and monovalent varicella vaccines (VV) prior to a planned change to MMRV as the second dose of measles-containing vaccine at 18 months of age. METHODS: All FS cases in children aged <5 years from 1st January 2012 to 30th April 2013 were identified from emergency department (ED) and inpatient databases at five Australian tertiary paediatric hospitals participating in PAEDS (Paediatric Active Enhanced Disease Surveillance). Immunization records were obtained from the Australian Childhood Immunization Register (ACIR). The relative incidence (RI) of FS following MMR dose 1 (MMR1) and VV in children aged 11-23 months was determined using the self-controlled case series (SCCS) method and used to calculate attributable risk. RESULTS: There were 2013 FS episodes in 1761 children. The peak age at FS was 18 months. The risk of FS was significantly increased 5-12 days post receipt of MMR1 at 12 months (RI=1.9 [95% CI: 1.3-2.9]), but not after VV at 18 months (RI=0.6 [95% CI: 0.3-1.2]. The estimated excess annual number of FS post MMR1 was 24 per 100,000 vaccinated children aged 11-23 months (95% CI=7-49 cases per 100,000) or 1 per 4167 doses. CONCLUSIONS: Our study detected the expected increased FS risk post MMR1 vaccine at 12 months, but monovalent varicella vaccine at age 18 months was not associated with increased risk of FS. This provides baseline data to assess the risk of FS post MMRV, introduced in Australia as the second dose of measles containing vaccine at 18 months of age in July 2013. PMID- 25444800 TI - Use of a current varicella vaccine as a live polyvalent vaccine vector. AB - Varicella-zoster virus (VZV) is the causative agent of varicella and zoster. The varicella vaccine was developed to control VZV infection in children. The currently available Oka vaccine strain is the only live varicella vaccine approved by the World Health Organization. We previously cloned the complete genome of the Oka vaccine strain into a bacterial artificial chromosome vector and then successfully reconstituted the virus. We then used this system to generate a recombinant Oka vaccine virus expressing mumps virus gene(s). The new recombinant vaccine may be an effective polyvalent live vaccine that provides protection against both varicella and mumps viruses. In this review, we discussed about possibility of polyvalent live vaccine(s) using varicella vaccine based on our recent studies. PMID- 25444798 TI - Events supposedly attributable to vaccination or immunization during pandemic influenza A (H1N1) vaccination campaigns in Latin America and the Caribbean. AB - As part of the vaccination activities against influenza A[H1N1]pdm vaccine in 2009-2010, countries in Latin American and the Caribbean (LAC) implemented surveillance of events supposedly attributable to vaccines and immunization (ESAVI). We describe the serious ESAVI reported in LAC in order to further document the safety profile of this vaccine and highlight lessons learned. We reviewed data from serious H1N1 ESAVI cases from LAC countries reported to the Pan American Health Organization/World Health Organization. We estimated serious ESAVI rates by age and target group, as well as by clinical diagnosis, and completed descriptive analyses of final outcomes and classifications given in country. A total of 1000 serious ESAVI were reported by 18 of the 29 LAC countries that vaccinated against A[H1N1]pdm. The overall reporting rate in LAC was 6.91 serious ESAVI per million doses, with country reporting rates ranging from 0.77 to 64.68 per million doses. Rates were higher among pregnant women (16.25 per million doses) when compared to health care workers (13.54 per million doses) and individuals with chronic disease (4.03 per million doses). The top three most frequent diagnoses were febrile seizures (12.0%), Guillain-Barre Syndrome (10.5%) and acute pneumonia (8.0%). Almost half (49.1%) of the serious ESAVI were reported among children aged <18 years of age; within this group, the highest proportion of cases was reported among those aged <2 years (53.1%). Of all serious ESAVI reported, 37.8% were classified as coincidental, 35.3% as related to vaccine components, 26.4% as non-conclusive and 0.5% as a programmatic error. This regional overview of A[H1N1]pdm vaccine safety data in LAC estimated the rate of serious ESAVI at lower levels than other studies. However, the ESAVI diagnosis distribution is comparable to the published literature. Lessons learned can be applied in the response to future pandemics. PMID- 25444796 TI - Prevalence of meningococcal meningitis in China from 2005 to 2010. AB - BACKGROUND: We aimed to estimate the prevalence and epidemiologic characteristics of meningococcal meningitis (MM) in mainland China (excluding Taiwan, Hong Kong, and Macau) and to provide reference data for controlling the outbreak and prevalence of MM. METHODS: Data from the National Notifiable Diseases Registry System and the MM case information reporting system from 2005 to 2010 as well as data from the MM Surveillance System were used. RESULTS: The morbidity of MM for the whole country was, on average, 0.09 cases per 100,000 (range 0.02 [2010]-0.18 [2005] cases per 100,000) from 2005 to 2010, the incidence rate was highest in the Xinjiang autonomous region (average 0.56 cases per 100,000), and the majority of cases came from Anhui province (average 0.32 cases per 100,000). Morbidity was highest in children under 1 year old (average 0.60 cases per 100,000). The proportion of laboratory-confirmed cases of serogroups A, B, and C were 37.2, 11.5 and 42.7, respectively, from 2005 to 2010. CONCLUSIONS: The incidence level declined year-to-year in mainland China. Children and students are the most at risk groups. The proportion of serogroup C cases has increased year-to-year, and new cases of serogroup W135 have been found. Controlling the epidemic of serogroup C and preventing outbreaks of serogroup B and W135 represent major future challenges. PMID- 25444799 TI - Replication of live attenuated cold-adapted H2N2 influenza virus vaccine candidates in non human primates. AB - The development of an H2N2 vaccine is a priority in pandemic preparedness planning. We previously showed that a single dose of a cold-adapted (ca) H2N2 live attenuated influenza vaccine (LAIV) based on the influenza A/Ann Arbor/6/60 (AA ca) virus was immunogenic and efficacious in mice and ferrets. However, in a Phase I clinical trial, viral replication was restricted and immunogenicity was poor. In this study, we compared the replication of four H2N2 LAIV candidate viruses, AA ca, A/Tecumseh/3/67 (TEC67 ca), and two variants of A/Japan/305/57 (JAP57 ca) in three non-human primate (NHP) species: African green monkeys (AGM), cynomolgus macaques (CM) and rhesus macaques (RM). One JAP57 ca virus had glutamine and glycine at HA amino acid positions 226 and 228 (Q-G) that binds to alpha2-3 linked sialic acids, and one had leucine and serine that binds to alpha2 3 and alpha2-6 linked residues (L-S). The replication of all ca viruses was restricted, with low titers detected in the upper respiratory tract of all NHP species, however replication was detected in significantly more CMs than AGMs. The JAP57 ca Q-G and TEC67 ca viruses replicated in a significantly higher percentage of NHPs than the AA ca virus, with the TEC67 ca virus recovered from the greatest percentage of animals. Altering the receptor specificity of the JAP57 ca virus from alpha2-3 to both alpha2-3 and alpha2-6 linked sialic acid residues did not significantly increase the number of animals infected or the titer to which the virus replicated. Taken together, our data show that in NHPs the AA ca virus more closely reflects the human experience than mice or ferret studies. We suggest that CMs and RMs may be the preferred species for evaluating H2N2 LAIV viruses, and the TEC67 ca virus may be the most promising H2N2 LAIV candidate for further evaluation. PMID- 25444801 TI - An adenoviral vector expressing lipoprotein A, a major antigen of Mycoplasma mycoides subspecies mycoides, elicits robust immune responses in mice. AB - Contagious bovine pleuropneumonia (CBPP), caused by Mycoplasma mycoides subsp. mycoides small colony type (MmmSC), is a devastating respiratory disease of cattle. In sub-Saharan Africa, where CBPP is enzootic, live attenuated vaccines are deployed but afford only short-lived protection. In cattle, recovery from experimental MmmSC infection has been associated with the presence of CD4(+) T lymphocytes that secrete interferon gamma in response to MmmSC, and in particular to the lipoprotein A (LppA) antigen. In an effort to develop a better vaccine against CBPP, a viral vector (Ad5-LppA) that expressed LppA was generated from human adenovirus type 5. The LppA-specific immune responses elicited by the Ad5 LppA vector were evaluated in mice, and compared to those elicited by recombinant LppA formulated with a potent adjuvant. Notably, a single administration of Ad5 LppA, but not recombinant protein, sufficed to elicit a robust LppA-specific humoral response. After a booster administration, both vector and recombinant protein elicited strong LppA-specific humoral and cell-mediated responses. Ex vivo stimulation of splenocytes induced extensive proliferation of CD4(+) T cells for mice immunized with vector or protein, and secretion of T helper 1-associated and proinflammatory cytokines for mice immunized with Ad5-LppA. Our study - by demonstrating the potential of a viral-vectored prototypic vaccine to elicit prompt and robust immune responses against a major antigen of MmmSC - represents a first step in developing a recombinant vaccine against CBPP. PMID- 25444802 TI - Seasonal influenza vaccination rates and reasons for non-vaccination in children with gastrointestinal disorders. AB - OBJECTIVES: Despite advances in the treatment and prevention of influenza, it is still considered an important cause of morbidity and mortality worldwide. Annual vaccination is the safest and most effective mean of prevention. Our study aims were to explore the uptake of influenza vaccination among children with gastrointestinal disorders, and to characterize non-adherent patients. METHODS: The present cross-sectional study included parents of pediatric patients attending the Gastroenterology Institute at Schneider Children's Medical Center of Israel between September and October 2011. Parents were asked to complete a questionnaire concerning demographic and clinical parameters, influenza vaccination of the child, and reasons for not vaccinating the child, when appropriate. RESULTS: The study population included 273 patients (50% female), with a median age of 10 years (range, 2-18 years). Overall, the rate of seasonal influenza vaccination was 30.8%. Higher rates were found among immunosuppressed patients (46.1%), and in patients with inflammatory bowel disease (50%). There was no significant effect of patient age, gender, ethnic origin or parental level of education on the vaccination rate. Vaccination rates were significantly associated with parents' information and knowledge of, as well as their personal beliefs regarding the vaccine (P<0.001). CONCLUSIONS: Influenza vaccination rates are relatively low in the pediatric population attending gastroenterology clinics, in both high- and low-risk groups. The importance of parental knowledge in compliance with influenza vaccination of children should prompt general pediatricians and gastroenterologists to discuss and address the common misconceptions regarding the vaccine. PMID- 25444803 TI - Safety and immunogenicity of an MF59-adjuvanted A/H1N1 pandemic influenza vaccine in children from three to seventeen years of age. AB - OBJECTIVES: This study was designed to identify the optimal dose of an MF59 adjuvanted, monovalent, A/H1N1 influenza vaccine in healthy paediatric subjects. METHODS: Subjects aged 3-8 years (n=194) and 9-17 years (n=160) were randomized to receive two primary doses of A/H1N1 vaccine containing either 3.75 MUg antigen with half a standard dose of MF59 adjuvant, 7.5 MUg antigen with a full dose of MF59, or (children 3-8 years only), a non-adjuvanted 15 MUg formulation. A booster dose of MF59-adjuvanted seasonal influenza vaccine including homologous A/H1N1 strain was given one year after priming. Immunogenicity was assessed by haemagglutination inhibition (HI) and microneutralization assays. Vaccine safety was assessed throughout the study (up to 18 months). RESULTS: A single priming dose of either MF59-adjuvanted formulation was sufficient to meet the European licensure criteria for pandemic influenza vaccines (HI titres >=1:40>70%; seroconversion>40%; and GMR>2.5). Two non-adjuvanted vaccine doses were required to meet the same licensure criteria. After first and second doses, percentage of subjects with HI titres >=1:40 were between 97% and 100% in the adjuvanted vaccine groups compared with 68% and 91% in the non-adjuvanted group, respectively. Postvaccination seroconversion rates ranged from 91% to 98% in adjuvanted groups and were 68% (first dose) and 98% (second dose) in the non adjuvanted group. HI titres >=1:330 after primary doses were achieved in 69% to 90% in adjuvanted groups compared with 41% in the non-adjuvanted group. Long-term antibody persistence after priming and a robust antibody response to booster immunization were observed in all vaccination groups. All A/H1N1 vaccine formulations were generally well tolerated. No vaccine-related serious adverse events occurred, and no subjects were withdrawn from the study due to an adverse event. CONCLUSIONS: An MF59-adjuvanted influenza vaccine containing 3.75 MUg of A/H1N1 antigen was well tolerated and sufficiently immunogenic to meet all the European licensure criteria after a single dose in healthy children 3-17 years old. PMID- 25444804 TI - Vaccination of pigs with attenuated Lawsonia intracellularis induced acute phase protein responses and primed cell-mediated immunity without reduction in bacterial shedding after challenge. AB - BACKGROUND: Lawsonia intracellularis causes porcine proliferative enteropathy and is one of the most economically important diseases in modern pig production worldwide. The Enterisol Ileitis vaccine have been shown to reduce clinical disease and to increase weight gain, however, while the natural infection with L. intracellularis can provide complete protection against re-infection, this has not been achieved by this vaccine. We therefore undertook a detailed characterization of immune responses to L. intracellularis infection in vaccinated pigs (VAC) compared to previously infected pigs (RE) in order to pinpoint immunological determinants of protection. RESULTS: The VAC pigs shed L. intracellularis to the same extent as non-vaccinated pigs after challenge, however less L. intracellularis in ileum and lymph nodes was seen post mortem. In the RE group, challenge did not lead to L. intracellularis shedding and no challenge bacteria were found post mortem. In both VAC and RE the acute phase haptoglobin response was diminished and L. intracellularis specific IgG responses were delayed and reduced compared to non-vaccinated pigs. On the other hand L. intracellularis specific IFN-gamma responses tended to develop faster in the VAC group compared to controls. CONCLUSION: Although vaccinated and non-vaccinated pigs shed L. intracellularis at similar levels after challenge, a lower number of intestinal L. intracellularis was observed in the vaccinated pigs at post mortem inspection. This might be due to the observed faster CMI responses upon challenge in vaccinated pigs. Complete protection against infection without L. intracellularis shedding, however, was only seen after a previous infection resulting in IFN-gamma production predominantly by CD8(+) and CD4(+) CD8(+) cells. Improved protective vaccines against L. intracellularis should therefore target stimulation of these T cell subsets. PMID- 25444806 TI - CD4+ T-cells, gammadelta T-cells and B-cells are associated with lack of vaccine protection in Mycobacterium avium subspecies paratuberculosis infection. AB - Vaccination is one of the strategies used to control the spread of Mycobacterium avium subspecies paratuberculosis (MAP) infection in livestock. Gudair((r)) is a widely-used vaccine in sheep and goats and is the only vaccine approved for use in sheep in Australia and New Zealand. This vaccine reduces mortality due to MAP infection by up to 90% but some sheep remain infectious by shedding MAP in faeces, despite vaccination. In this study, using an experimental infection model in sheep, our aim was to assess differences in immune parameters between vaccinated MAP-exposed sheep in which the vaccine was effective compared to those in which it failed to protect against infection. We assessed immune parameters such as MAP-specific IFNgamma, IL-10 and lymphocyte proliferative responses and serum antibody levels. At the end of the trial, 72% of non-vaccinated sheep and 24% of vaccinated sheep were infected, as defined by the detection of viable MAP in intestinal tissues when the trial was terminated at 49 weeks post exposure. There were significant differences in the proliferation of CD4(+), B and gammadelta T-cells over time in vaccinated sheep in which the vaccine failed to protect against infection compared to the non-infected vaccinated sheep. There were no significant differences in the IFNgamma response or serum antibody levels between the vaccinated infected and vaccinated non-infected sheep. These results emphasise the importance of specific lymphocyte subsets in protecting against MAP infection, especially in vaccinated sheep, and that immune parameters other than the commonly used IFNgamma and antibody tests are required when assessing vaccine efficacy. PMID- 25444805 TI - Phase II trial in adults of concurrent or sequential 2009 pandemic H1N1 and 2009 2010 seasonal trivalent influenza vaccinations. AB - BACKGROUND: During the 2009 influenza pandemic both seasonal and 2009 pandemic vaccines were recommended. We conducted a randomized trial of monovalent 2009 H1N1 vaccine and seasonal trivalent inactivated influenza vaccine (IIV3) given sequentially or concurrently to adults. METHODS: Adults randomized to 4 study groups and stratified by age (18-64 and >=65 years) received 1 dose of seasonal IIV3 or placebo and 2 doses of 2009-H1N1 vaccine or placebo in one of 4 combinations, i.e., H1N1+Placebo/H1N1+Placebo/IIV3 (HP/HP/V3), H1N1+IIV3/H1N1+Placebo/Placebo (HV3/HP/P), H1N1+Placebo/H1N1+IIV3/Placebo (HP/HV3/P), and IIV3+Placebo/H1N1+Placebo/H1N1 (V3P/HP/H). Intramuscular injections were given three times at 21 day intervals. Sera for antibody assays were obtained prior to and 21 days after each vaccination. Reactogenicity and adverse events were monitored. RESULTS: Eight hundred-five (805) adults were enrolled. All combinations of vaccines were safe and well tolerated. In general, one dose of 2009-H1N1 and one dose of IIV3, regardless of sequence or concurrency of administration, were immunogenic in adults. There were no significant differences in geometric mean titers (GMT) or the proportions of subjects with >=4-fold rise in antibody responses and titers >=40 for any vaccine group or between age strata for 2009-H1N1 after the first or second dose, although the vaccine sequence affected the titers to the IIV3 antigens. Hemagglutination inhibition antibody (HAI) GMTs against 2009-H1N1 for the combined age strata 21 days after the first 2009-H1N1 dose were 190.4, 182.1, 232.9 and 157.5 for HP/HP/V3, HV3/HP/P, HP/HV3/P and V3P/HP/H, respectively. While IIV3 GMTs were adequate they were generally lower than the 2009-H1N1 GMTs. In a subset of subjects, there was good correlation between HAI and microneutralization (MN) titers (Spearman's correlation coefficient 0.92). CONCLUSIONS: All vaccine combinations were generally well tolerated. Immune responses to one dose of 2009 H1N1 were adequate regardless of the sequence of vaccination in all age groups, but the sequence affected titers to IIV3 antigens. PMID- 25444809 TI - PHiD-CV effectiveness against invasive pneumococcal disease caused by serotype 19A. PMID- 25444808 TI - A perspective on the use of Pleurotus for the development of convenient fungi made oral subunit vaccines. AB - This review provides an outlook of the medical applications of immunomodulatory compounds taken from Pleurotus and proposes this fungus as a convenient host for the development of innovative vaccines. Although some fungal species, such as Saccharomyces and Pichia, occupy a relevant position in the biopharmaceutical field, these systems are essentially limited to the production of conventional expensive vaccines. Formulations made with minimally processed biomass constitute the ideal approach for developing low cost vaccines, which are urgently needed by low-income populations. The use of edible fungi has not been explored for the production and delivery of low cost vaccines, despite these organisms' attractive features. These include the fact that edible biomass can be produced at low costs in a short period of time, its high biosynthetic capacity, its production of immunomodulatory compounds, and the availability of genetic transformation methods. Perspectives associated to this biotechnological application are identified and discussed. PMID- 25444807 TI - Considerations for developing an immunization strategy with enterovirus 71 vaccine. AB - Enterovirus 71 (EV71) is a common pathogen for hand, foot, and mouth disease (HFMD), which has significant morbidity and mortality, and for which children aged 6-59 months age are at highest risk. Due to lack of effective treatment options, control of EV71 epidemics has mainly focused on development of EV71 vaccines. Clinical trials have been completed on 3 EV71 vaccines, with trial results demonstrating good vaccine efficacy and safety. When EV71 vaccine is approved by China's national regulatory authority, an evidence-based strategy should be developed to optimize impact and safety. An immunization strategy for EV71 vaccine should consider several factors, including the target population age group, the number of doses for primary immunization, the need for a booster dose, concomitant administration of other vaccines, economic value, program capacity and logistics, and public acceptance. Once EV71 vaccines are in use, vaccine effectiveness and safety must be monitored in large populations, and the epidemiology of HFMD must be evaluated to assure a match between vaccination strategy and epidemiology. Evaluation in China is especially important because there are no other EV71 vaccines globally. PMID- 25444810 TI - Reducing the loss of vaccines from accidental freezing in the cold chain: the experience of continuous temperature monitoring in Tunisia. AB - Accidental freezing of vaccines is a growing threat and a real risk for national immunization programs when the potency of many vaccines can be compromised if these are exposed to sub-zero temperatures in the cold chain. In Tunisia, this issue is compounded by using sub-standard domestic cold chain equipment instead of equipping the program with medical refrigerators designed specifically for storing vaccines and temperature sensitive pharmaceuticals. Against this backdrop, this paper presents the findings of a demonstration project conducted in Tunisia in 2012 that tested the impact of introducing several freeze prevention solutions to mitigate the risk of accidental freezing of vaccines. The main finding is that, despite the continued use of underperforming domestic refrigerators, continuous temperature monitoring using new technologies combined with other technological interventions significantly reduced the prevalence of accidental exposure to freezing temperatures. These improvements were noticed for cold chain storage at regional, district and health center levels, and during the transport legs that were part of the demonstration conducted in the regions of Kasserine in the South-Eastern part of Tunisia. Subsequent to introducing these freeze prevention solutions, the incidence of freeze alarms was reduced and the percent of time the temperatures dropped below the 2 degrees C recommended threshold. The incidence of freeze alarms at health center level was reduced by 40%. Lastly, the solutions implemented reduced risk of freezing during transport from 13.8% to 1.7%. Although the solution implemented is not optimal in the longer term because domestic refrigerators are used extensively in district stores and health centers, the risk of accidental freezing is significantly reduced by introducing the practice of continuous temperature monitoring as a standard. The management of the cold chain equipment was strengthened as a result which helps protect the potency of vaccines to the areas of most difficult access. PMID- 25444811 TI - Optimizing energy for a 'green' vaccine supply chain. AB - This paper describes an approach piloted in the Kasserine region of Tunisia to increase the energy efficiency of the distribution of vaccines and temperature sensitive drugs. The objectives of an approach, known as the 'net zero energy' (NZE) supply chain were demonstrated within the first year of operation. The existing distribution system was modified to store vaccines and medicines in the same buildings and to transport them according to pre-scheduled and optimized delivery circuits. Electric utility vehicles, dedicated to the integrated delivery of vaccines and medicines, improved the regularity and reliability of the supply chains. Solar energy, linked to the electricity grid at regional and district stores, supplied over 100% of consumption meeting all energy needs for storage, cooling and transportation. Significant benefits to the quality and costs of distribution were demonstrated. Supply trips were scheduled, integrated and reliable, energy consumption was reduced, the recurrent cost of electricity was eliminated and the release of carbon to the atmosphere was reduced. Although the initial capital cost of scaling up implementation of NZE remain high today, commercial forecasts predict cost reduction for solar energy and electric vehicles that may permit a step-wise implementation over the next 7-10 years. Efficiency in the use of energy and in the deployment of transport is already a critical component of distribution logistics in both private and public sectors of industrialized countries. The NZE approach has an intensified rationale in countries where energy costs threaten the maintenance of public health services in areas of low population density. In these countries where the mobility of health personnel and timely arrival of supplies is at risk, NZE has the potential to reduce energy costs and release recurrent budget to other needs of service delivery while also improving the supply chain. PMID- 25444813 TI - A systematic literature review of missed opportunities for immunization in low- and middle-income countries. AB - BACKGROUND: Missed opportunities for immunization (MOIs) may contribute to low coverage in diverse settings, including developing countries. METHODS: We conducted a systematic literature review on MOIs among children and women of childbearing age from 1991 to the present in low- and middle-income countries. We searched multiple databases and the references of retrieved articles. Meta analysis provided a pooled prevalence estimate and both univariate and multivariate meta-regression analysis was done to explore heterogeneity of results across studies. RESULTS: We found 61 data points from 45 studies involving 41,310 participants. Of the 45 studies, 41 involved children and 10 involved women. The pooled MOI prevalence was 32.2% (95% CI: 26.8-37.7) among children - with no change during the study period - and 46.9% (95% CI: 29.7 64.0%) among women of child-bearing age. The prevalence varied by region and study methodology but these two variables together accounted for only 12% of study heterogeneity. Among 352 identified reasons for MOIs, the most common categories were health care practices, false contraindications, logistic issues related to vaccines, and organizational limitations, which did not vary by time or geographic region. CONCLUSIONS: MOI prevalence was high in low- and middle income settings but the large number of identified reasons precludes standardized solutions. PMID- 25444814 TI - Measles - The epidemiology of elimination. AB - Tremendous progress has been made globally to reduce the contribution of measles to the burden of childhood deaths and measles cases have dramatically decreased with increased two dose measles-containing vaccine coverage. As a result the Global Vaccine Action Plan, endorsed by the World Health Assembly, has targeted measles elimination in at least five of the six World Health Organisation Regions by 2020. This is an ambitious goal, since measles control requires the highest immunisation coverage of any vaccine preventable disease, which means that the health system must be able to reach every community. Further, while measles remains endemic in any country, importations will result in local transmission and outbreaks in countries and Regions that have interrupted local endemic measles circulation. One of the lines of evidence that countries and Regions must address to confirm measles elimination is a detailed description of measles epidemiology over an extended period. This information is incredibly valuable as predictable epidemiological patterns emerge as measles elimination is approached and achieved. These critical features, including the source, size and duration of outbreaks, the seasonality and age-distribution of cases, genotyping pointers and effective reproduction rate estimates, are discussed with illustrative examples from the Region of the Americas, which eliminated measles in 2002, and the Western Pacific Region, which has established a Regional Verification Commission to review progress towards elimination in all member countries. PMID- 25444812 TI - Autologous aldrithiol-2-inactivated HIV-1 combined with polyinosinic polycytidylic acid-poly-L-lysine carboxymethylcellulose as a vaccine platform for therapeutic dendritic cell immunotherapy. AB - Therapeutic interventions for HIV-1 that successfully augment adaptive immunity to promote killing of infected cells may be a requisite component of strategies to reduce latent cellular reservoirs. Adoptive immunotherapies utilizing autologous monocyte-derived dendritic cells (DCs) that have been activated and antigen loaded ex vivo may serve to circumvent defects in DC function that are present during HIV infection in order to enhance adaptive immune responses. Here we detail the clinical preparation of DCs loaded with autologous aldrithiol-2 (AT 2)-inactivated HIV that have been potently activated with the viral mimic, Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (Poly-ICLC). HIV is first propagated from CD4+ T cells from HIV-infected donors and then rendered non-replicative by chemical inactivation with aldrithiol-2 (AT-2), purified, and quantified. Viral inactivation is confirmed through measurement of Tat-regulated beta-galactosidase reporter gene expression following infection of TZM-bl cells. In-process testing for sterility, mycoplasma, LPS, adventitious agents, and removal of AT-2 is performed on viral preparations. Autologous DCs are generated and pulsed with autologous AT-2-inactivated virus and simultaneously stimulated with Poly-ICLC to constitute the final DC vaccine product. Phenotypic identity, maturation, and induction of HIV-specific adaptive immune responses are confirmed via flow cytometric analysis of DCs and cocultured autologous CD4+ and CD8+ T cells. Lot release criteria for the DC vaccine have been defined in accordance with Good Manufacturing Practice (GMP) guidelines. The demonstrated feasibility of this approach has resulted in approval by the FDA for investigational use in antiretroviral (ART) suppressed individuals. We discuss how this optimized DC formulation may enhance the quality of anti-HIV adaptive responses beyond what has been previously observed during DC immunotherapy trials for HIV infection. PMID- 25444815 TI - Repeated vaccinations do not improve specific immune defenses against Hepatitis B in non-responder health care workers. AB - Hepatitis B is a major infectious occupational hazard for health care workers and can be prevented with a safe and effective vaccine. The serum titer of anti-HBsAg antibodies is the most commonly used correlate of protection and post-vaccination anti-HBsAg concentrations of >= 10 mIU/ml are considered protective. Subjects with post-vaccination anti-HBsAg titers of <10 mIU/ml 1-6 months post vaccination, who tested negative for HBsAg and anti-HBc, are defined as non responders. The question of whether non-responders should be repeatedly vaccinated is still open. The aim of the study was to (i) evaluate the distribution of lymphocyte subpopulations and the percentage of HBsAg-specific memory B cells in responders and non-responders (ii) assess whether non responders can be induced to produce antibodies after administration of a booster dose of vaccine (iii) determine whether booster vaccination increases the number of specific memory B cells in non-responders. Combining flow-cytometry, ELISPOT and serology we tested the integrity and function of the immune system in 24 health care workers, confirmed to be non-responders after at least three vaccine injections. We compared the results with those obtained in 21 responders working in the same institution. We found that the great majority of the non-responders had a functional immune system and a preserved ability to respond to other conventional antigens. Our most important findings are that the frequency of HBsAg-specific memory B cells is comparable in non-responders and controls and that booster immunization does not lead either to antibody production or memory B cell increase in non-responders. PMID- 25444816 TI - Persistent BCG bacilli perpetuate CD4 T effector memory and optimal protection against tuberculosis. AB - Tuberculosis (TB) remains one of the most important infectious diseases of man and animals, and the only available vaccine (BCG) requires urgent replacement or improvement. To facilitate this, the protective mechanisms induced by BCG require further understanding. As a live attenuated vaccine, persistence of BCG bacilli in the host may be a crucial mechanism. We have investigated the long term persistence of BCG following vaccination and the influence on the induced immune response and protection, using an established murine model. We sought to establish whether previously identified BCG-specific CD4 TEM cells represent genuine long-lived memory cells of a relatively high frequency, or are a consequence of continual priming by chronically persistent BCG vaccine bacilli. By clearing persistent bacilli, we have compared immune responses (spleen and lung CD4: cytokine producing T effector/TEM; TCR-specific) and BCG-induced protection, in the presence and absence of these persisting vaccine bacilli. Viable BCG bacilli persisted for at least 16 months post-vaccination, associated with specific CD4 T effector/TEM and tetramer-specific responses. Clearing these bacilli abrogated all BCG-specific CD4 T cells whilst only reducing protection by 1log10. BCG may induce two additive mechanisms of immunity: (i) dependant on the presence of viable bacilli and TEM; and (ii) independent of these factors. These data have crucial implications on the rational generation of replacement TB vaccines, and the interpretation of BCG induced immunity in animal models. PMID- 25444817 TI - CD4 T-cells transduced with CD80 and 4-1BBL mRNA induce long-term CD8 T-cell responses resulting in potent antitumor effects. AB - Therapeutic cancer vaccines are an attractive alternative to conventional therapies to treat malignant tumors, and more importantly, to prevent recurrence after primary therapy. However, the availability of professional antigen presenting cells (APCs) has been restricted by difficulties encountered in obtaining sufficient professional APCs for clinical use. We have prepared an alternative cellular vaccine with CD4 T-cells that can be expanded easily to yield a pure and homogeneous population in vitro. To enhance their potency as a therapeutic vaccine, in vitro expanded CD4 T-cells were transfected with RNAs encoding the costimulatory ligands CD80, 4-1BBL, or both (CD80-T, 4-1BBL-T, and CD80/4-1BBL-T-cells, respectively). We observed augmented cell vitality in CD80/4 1BBL-T-cells in vitro and in vivo. Significant CD8 T-cell responses eliciting in vivo proliferation and cytotoxicity were obtained with CD80/4-1BBL-T-cell vaccination compared to CD80-T and 4-1BBL-T-cell vaccinations. In contrast, beta2m-deficient CD80/4-1BBL-T-cells were not as effective as wile-type CD80/4 1BBL-T-cells in priming CD8 T-cells. Furthermore, CD80/4-1BBL-T-cell immunization resulted in curing established EG7 tumors, resulting in the generation of memory CD8 T-cell responses, and elicited therapeutic antitumor responses against B16 melanoma. These results suggest that CD4 T-cells endowed with costimulatory ligands allow the design of effective vaccination strategies against cancer. PMID- 25444818 TI - Progress towards measles elimination in Singapore. AB - OBJECTIVE: We describe the epidemiological trends of measles in Singapore in relation to its progress towards measles elimination and identify gaps in fulfilling the World Health Organization Western Pacific Regional Office regional measles elimination criteria. METHODS: Epidemiological data on measles maintained by the Communicable Diseases Division, Ministry of Health from 1981 to 2012 were collated and analysed. Data on measles vaccination coverage were obtained from the National Immunization Registry and School Health Services, Health Promotion Board. To assess the seroprevalence of the population, the findings of periodic seroepidemiological surveys on measles were traced and reviewed. FINDINGS: With the successful implementation of the National Childhood Immunization Programme using the monovalent measles vaccine, measles incidence declined from 88.5 cases per 100,000 in 1984 to 6.9 per 100,000 in 1991. Resurgences were observed in 1992, 1993 and 1997. A 'catch-up' vaccination programme using the trivalent measles, mumps and rubella (MMR) vaccine was conducted in 1997, followed by introduction of the two-dose vaccination schedule in January 1998. Measles incidence subsequently declined sharply to 2.9 per 100,000 in 1998. Vaccination coverage was maintained at 95% for the first dose and 92-94% for the second dose. Seroprevalence surveys showed seropositivity for measles IgG antibodies in over 95% of adults in 2004, and in 83.1% of children aged 1-17 years in 2008-2010. Sporadic cases with occasional clusters of two or more cases continued to occur among the unvaccinated population, especially children aged below 4 years. The predominant measles virus genotype has shifted from D9 to the B3 and G3 genotypes, which are endemic in neighbouring countries. CONCLUSION: Singapore has made good progress towards the elimination of endemic measles. To further eliminate sporadic cases of measles, the national immunisation schedule has recently been amended to vaccinate children with 2 doses of MMR vaccine before 2 years of age. PMID- 25444820 TI - Clinical effectiveness and cost-effectiveness of quadrivalent human papillomavirus vaccination in HIV-negative men who have sex with men to prevent recurrent high-grade anal intraepithelial neoplasia. AB - We examined the long-term clinical and economic benefits of quadrivalent human papillomavirus (qHPV) vaccine as a secondary/adjunct prevention strategy in the prevention of recurrent high-grade intraepithelial neoplasia (HGAIN) in HIV negative men who have sex with men (MSM) and are 27 years or older. We constructed a Markov model to evaluate the clinical effectiveness and cost effectiveness of two strategies: (1) no qHPV vaccine after treatment for HGAIN versus (2) qHPV vaccine after treatment for HGAIN. Model parameters, including natural history of anal cancer, vaccine efficacy measured in terms of hazard ratio (HR) (decrease in the risk of recurrent HGAIN), HGAIN treatment efficacy, utilities, and costs, were obtained from the literature. The outcomes were measured in terms of lifetime risk of anal cancer, lifetime cost, quality adjusted life years, and incremental cost-effectiveness ratios (ICERs). Sensitivity analysis was conducted on all model parameters. We found that vaccinating HIV-negative MSM reduced the lifetime risk of anal cancer by 60.77% at an ICER of US$87,240 per quality-adjusted life-year. The results were highly sensitive to vaccine efficacy, transition of HGAIN to anal cancer, cost of treatment for HGAIN, vaccine degree of protection over time, and the vaccine duration of protection and less sensitive to HPV clearance, cost of qHPV vaccine, and the transitions from normal to low-grade anal intraepithelial neoplasia (LGAIN) and normal to HGAIN. With an HR of 0.3, the ICER was well below a $50,000 willingness-to-pay threshold; with an HR of 0.5, the ICER was still below a threshold of $100,000. The most critical disease-related factor influencing the cost-effectiveness was the progression of HGAIN to anal cancer. At an annual transition probability below 0.001, the ICER was below $50,000. Vaccinating HIV negative MSM treated for HGAIN decreases the lifetime risk of anal cancer and is likely to be a cost-effective intervention. PMID- 25444819 TI - Natural killer T cell and TLR9 agonists as mucosal adjuvants for sublingual vaccination with clade C HIV-1 envelope protein. AB - The vast majority of HIV-1 infections occur at mucosa during sexual contact. It may therefore be advantageous to provide mucosal barrier protection against this entry by mucosal vaccination. While a number of mucosal routes of vaccination are possible, many like enteric oral vaccines or intranasal vaccines have significant impediments that limit vaccine efficacy or pose safety risks. In contrast, immunogens applied to the sublingual region of the mouth could provide a simple route for mucosal vaccination. While sublingual immunization is appealing, this site does not always drive strong immune responses, particularly when using protein antigens. To address this issue, we have tested the ability of two mucosal adjuvants: alpha-galactosylceramide (alphaGalCer) that is a potent stimulator of natural killer T cells and CpG-oligodeoxynucleotide (CpG-ODN) a TLR9 agonist for their ability to amplify immune responses against clade C gp140 HIV-1 envelope protein antigen. Immunization with envelope protein alone resulted in a weak T cell and antibody responses. In contrast, CD4(+) and CD8(+) T cells responses in systemic and mucosal tissues were significantly higher in mice immunized with gp140 in the presence of either alphaGalCer or CpG-ODN and these responses were further augmented when the two adjuvants were used together. While both the adjuvants effectively increased gp140-specific serum IgG and vaginal IgA antibody levels, combining both significantly improved these responses. Memory T cell responses 60 days after immunization revealed alphaGalCer to be more potent than CpG-ODN and the combination of the alphaGalCer and CpG-ODN adjuvants was more effective than either alone. Serum and vaginal washes collected 60 days after immunization with gp140 with both alphaGalCer and CpG-ODN adjuvants had significant neutralization activity against Tier 1 and Tier 2 SHIVs. These data support the utility of the sublingual route for mucosal vaccination particularly in combination with alphaGalCer and CpG-ODN adjuvants. PMID- 25444822 TI - Clearance of depot vaccine SPIO-labeled antigen and substrate visualized using MRI. AB - Immunotherapies, including peptide-based vaccines, are a growing area of cancer research, and understanding their mechanism of action is crucial for their continued development and clinical application. Exploring the biodistribution of vaccine components may be key to understanding this action. This work used magnetic resonance imaging (MRI) to characterize the in vivo biodistribution of the antigen and oil substrate of the vaccine delivery system known as DepoVax(TM). DepoVax uses a novel adjuvanted lipid-in-oil based formulation to solubilise antigens and promote a depot effect. In this study, antigen or oil were tagged with superparamagnetic iron oxide (SPIO), making them visible on MR images. This enables tracking of individual vaccine components to determine changes in biodistribution. Mice were injected with SPIO-labeled antigen or SPIO labeled oil, and imaged to examine clearance of labeled components from the vaccine site. The SPIO-antigen was steadily cleared, with nearly half cleared within two months post-vaccination. In contrast, the SPIO-oil remained relatively unchanged. The biodistribution of the SPIO-antigen component within the vaccine site was heterogeneous, indicating the presence of active clearance mechanisms, rather than passive diffusion or drainage. Mice injected with SPIO-antigen also showed MRI contrast for several weeks post-vaccination in the draining inguinal lymph node. These results indicate that MRI can visualize the in vivo longitudinal biodistribution of vaccine components. The sustained clearance is consistent with antigen up-take and trafficking by immune cells, leading to accumulation in the draining lymph node, which corresponds to the sustained immune responses and reduced tumor burden observed in vaccinated mice. PMID- 25444821 TI - Maternal immunization with pneumococcal 9-valent conjugate vaccine and early infant otitis media. AB - A randomized trial of an investigational 9-valent pneumococcal conjugate vaccine (PCV-9) or placebo given to pregnant women during the last trimester to prevent early infant otitis media (OM) was conducted. All infants received Prevnar((r)) at 2, 4, 6, and 12 months. Clinic and adverse event records were reviewed to identify OM. Variables significantly related to acute OM by age 6 months (p<0.05) were: vaccine group (9 valent or placebo), sibling history of tympanostomy tubes, upper respiratory infection, and number of clinic visits by 6 months. Infant OM rates were similar between 6 and 12 months (58% and 56%). Results suggested that immunizing pregnant women with PCV-9 increased infants' risk of acute OM in the first 6 months of life, and this correlated with decreased infant antibody responses to their infant Streptococcus pneumoniae vaccine serotypes, but did not influence antibody responses to 3 other serotypes two of which were in maternal vaccine (types 1 and 5) and one was a control (type 7F). Explanations for these results include dampening of infant antibody production by high levels of passively acquired maternal pneumococcal antibodies and/or altered B lymphocyte immune responses in infants exposed to these specific polysaccharide antigens in utero. PMID- 25444823 TI - Early indication for a reduced burden of radiologically confirmed pneumonia in children following the introduction of routine vaccination against Haemophilus influenzae type b in Nha Trang, Vietnam. AB - INTRODUCTION: Despite the global success of Hib vaccination in reducing disease and mortality, uncertainty about the disease burden and the potential impact of Hib vaccination in Southeast Asia has delayed the introduction of vaccination in some countries in the region. Hib vaccination was introduced throughout Vietnam in July 2010 without catch-up. In an observational, population based surveillance study we estimated the impact of routine Hib vaccination on all cause radiologically confirmed childhood pneumonia in Nha Trang, Vietnam. MATERIALS AND METHODS: In 2007 active hospital based surveillance was established in Khanh Hoa General Hospital, the only hospital in Nha Trang, Khanh Hoa province. Nasopharyngeal samples and chest radiographs are taken routinely from all children diagnosed with acute respiratory illness on admission. For admissions between 02/2007 and 03/2012 chest radiographs were interpreted for the presence of WHO primary endpoint pneumonia and nasopharyngeal swabs were analysed by PCR for the presence of Influenza A or B, RSV and rhinovirus. We employed Poisson regression to estimate the impact of Hib vaccination on radiologically confirmed pneumonia (RCP) while statistically accounting for potential differences in viral circulation in the post vaccination era which could have biased the estimate. RESULTS: Of 3151 cases admitted during the study period, 166 had RCP and major viruses were detected in 1601. The adjusted annual incidence of RCP in children younger than 5 years declined by 39% (12-58%) after introduction of Hib vaccination. This decline was most pronounced in children less than 2 years old, adjusted IRR: 0.52 (0.33-0.81), and no significant impact was observed in the 2-4 years old who were not eligible for vaccination, adjusted IRR: 0.96 (0.52-1.72). DISCUSSION: We present early evidence that the burden of Hib associated RCP in Nha Trang before vaccination was substantial and that shortly after introduction to the routine childhood immunisation scheme vaccination has substantially reduced that burden. PMID- 25444824 TI - Seasonal and pandemic influenza vaccine: demand, supply and vaccine availability. PMID- 25444825 TI - Varicella vaccination coverage inverse correlation with varicella hospitalizations in Spain. AB - Varicella vaccines available in Spain were marketed in 1998 and 2003 for non routine use. Since 2006 some regions included universal varicella vaccination in their regional routine vaccination programs at 15-18 months of age. Regions without universal vaccination in toddlers, but instead with the strategy of vaccinating susceptible adolescents, reached different varicella vaccination coverage through private market. This study shows the correlation between severe varicella zoster virus infections requiring hospitalization and the varicella vaccination coverage by region. A total of 3009 hospital discharges related to varicella were reported in 2009-2010. The overall annual rate of hospitalization was 3.27 cases per 100,000. In children younger than 5 years old varicella hospitalization rate was 30.73 cases per 100,000. Varicella related hospitalizations were significantly lower in the regions with universal vaccination. In those regions without universal vaccination at 15-18 months of age, those with higher coverage in private market showed lower hospitalization rates. PMID- 25444826 TI - Monitoring coverage of fully immunized children. AB - Immunization programs monitor 3rd dose of DPT-containing vaccine coverage as a principal indicator; however, this does not inform about coverage with other vaccines. A mini-survey was conducted to assess the status of monitoring coverage of fully immunized children (FIC) in Eastern and Southern African countries. We designed and distributed a structured self-administered questionnaire to all 19 national program managers attending a meeting in March 2014 in Harare, Zimbabwe. We learned that most countries already monitor FIC coverage and managers appreciate the importance of monitoring this as a national indicator, as it aligns with the full benefits of immunization. This mini-survey concluded that at national level, FIC coverage could be used as a principal indicator; however, at global level DPT3 has some additional advantages across all countries in standardizing the capacity of the immunization program to deliver multiple doses of the same vaccine to all children by 12 months of age. PMID- 25444827 TI - The use of serosurveys following emergency vaccination, to recover the status of "foot-and-mouth disease free where vaccination is not practised". AB - To eliminate incursions of foot-and-mouth disease (FMD) quickly, a combination of measures, including emergency vaccination, can help block the spread of infection. For the earliest recovery of the FMD-free status for trade, without the slaughter of uninfected vaccinated animals, a serosurvey for antibodies to FMD virus non-structural proteins (NSP) must be used to substantiate absence of occult virus infections. Areas of doubt over requirements for post-vaccination serosurveillance and its feasibility include the required and achievable confidence, the amount of sampling necessary, and the appropriate responses to and consequences of different seropositive findings. This derives largely from uncertainty over the extent of localised pockets of virus infection that may remain within vaccinated populations and the circumstances that permit this. The question therefore remains whether tests are sufficiently sensitive and specific to detect and eliminate infected animals, without excessive culling of uninfected animals, before vaccinated animals mix with non-vaccinated livestock when movement restrictions are lifted. It is recommended to change the rationale for serosurveillance after emergency vaccination. Only when emergency vaccination is used in limited outbreaks is it possible to test and cull comprehensively, an approach compatible with a three-month minimum period to recover the FMD-free status. In other situations, where emergency vaccination is used, such as dealing with large outbreaks in animal-dense regions and where the onset of vaccination has been delayed, post-vaccination serosurveys should be targeted and focus on providing an assurance to detect higher levels of infection, in case of inadequate control measures. As this provides less assurance of absence of infection, the approach would be compatible with a six-month waiting period for free-status recovery and should be complemented by other methods to provide evidence that vaccination and control measures have been effectively implemented, as these are the best guarantee against continuing virus transmission. PMID- 25444828 TI - Surveillance of congenital rubella syndrome (CRS) in tertiary care hospitals in Hanoi, Vietnam during a rubella epidemic. AB - OBJECTIVE: To describe the epidemiology and clinical features of congenital rubella syndrome (CRS) in Hanoi, Vietnam. METHODS: Prospective surveillance of CRS between May 2011 and March 2012 in Hanoi, Vietnam. CRS burden was assessed by clinical examination and collection of serum samples from infants in neonatology, cardiology and pediatric departments of two tertiary care hospitals in Hanoi. All infants born during the study period with clinical manifestations of CRS and seropositivity (IgM) for rubella were included in this study. RESULTS: During the surveillance period 113 infants were identified with confirmed CRS (clinical features and positive rubella IgM). Their mean age at diagnosis was 38.4 days (range 1-152 days) and 61% were female. Clinical manifestations of CRS included low birth weight<2500 g (86.0%), congenital heart disease (63.7%), hearing impairment (63.7%) and ophthalmological abnormalities (46.9%). Other clinical features at birth included: thrombocytopenia (85.0%), neonatal purpura (74.3%), splenomegaly (63.7%), hepatomegaly (62.8%) and blueberry muffin rash (61.1%). Among the mothers of infants with confirmed CRS none had received a rubella vaccine in the past and 88.4% gave a history of rubella contact during the pregnancy under study. In most cases (84.1%) maternal infection occurred in the first trimester. During the surveillance period the estimated annual incidence of CRS was 1.13/1000 live births (95% CI 0.92-1.34). CONCLUSIONS: These preliminary baseline data show a high burden of CRS in Hanoi, Vietnam and the urgent need for universal vaccination. Surveillance to determine and monitor the national burden of CRS is essential. PMID- 25444829 TI - Variation in exemptions to school immunization requirements among New York State private and public schools. AB - BACKGROUND AND OBJECTIVES: School immunization requirements have ensured high vaccination rates and have helped to control vaccine-preventable diseases. However, vaccine exemptions have increased in the last decade. This study compared New York State private versus public schools with respect to medical and religious exemption rates. METHODS: This retrospective study utilizes New York State Department of Health Immunization Survey data from the 2003 through 2012 academic years. Schools were categorized as private or public, the former further categorized by religious affiliation. Rates of medical and religious vaccine exemptions were compared by school category. RESULTS: From 2003 to 2012, religious exemptions increased in private and public schools from 0.63% to 1.35% and 0.17% to 0.29% (Spearman's R: 0.89 and 0.81), respectively. Among private schools, increases in religious exemption rates during the study period were observed in Catholic/Eastern Orthodox, Protestant/Other Christian, Jewish, and secular schools (Spearman's R=0.66, 0.99, 0.89, and 0.93), respectively. Exemption rate ratios in private schools compared to public schools were 1.39 (95% CI 1.15-1.68) for medical and 3.94 (95% CI: 3.20-4.86) for religious exemptions. Among private school students, all school types except for Catholic/Eastern Orthodox and Episcopal affiliates were more likely to report religious exemptions compared to children in public schools. CONCLUSIONS: Medical and religious exemption rates increased over time and higher rates were observed among New York State private schools compared to public schools. Low exemption rates are critical to minimize disease outbreaks in the schools and their community. PMID- 25444830 TI - Safety and immunogenicity of an improved oral inactivated multivalent enterotoxigenic Escherichia coli (ETEC) vaccine administered alone and together with dmLT adjuvant in a double-blind, randomized, placebo-controlled Phase I study. AB - BACKGROUND: We have developed a new oral vaccine against enterotoxigenic Escherichia coli (ETEC), which is the most common cause of bacterial diarrhea in children in developing countries and in travelers. METHODS: The vaccine was tested for safety and immunogenicity alone and together with double-mutant heat labile toxin (dmLT) adjuvant in a double-blind, placebo-controlled Phase I study in 129 Swedish adults. The vaccine consists of four inactivated recombinant E. coli strains overexpressing the major ETEC colonization factors (CFs) CFA/I, CS3, CS5, and CS6 mixed with an LT B-subunit related toxoid, LCTBA. Volunteers received two oral doses of vaccine alone, vaccine plus 10 MUg or 25 MUg dmLT or placebo. Secretory IgA antibody responses in fecal samples and IgA responses in secretions from circulating intestine-derived antibody secreting cells were assessed as primary measures of vaccine immunogenicity. RESULTS: The vaccine was safe and well tolerated; adverse events were few and generally mild with no significant differences between subjects receiving placebo or vaccine with or without adjuvant. As many as 74% of subjects receiving vaccine alone and 83% receiving vaccine plus 10 MUg dmLT showed significant mucosal IgA responses to all five primary vaccine antigens and about 90% of all vaccinees responded to at least four of the antigens. Subjects receiving vaccine plus 10 MUg dmLT responded with significantly increased intestine-derived anti-CS6 responses compared to subjects receiving vaccine alone. CONCLUSIONS: The vaccine was safe and broadly immunogenic. dmLT further enhanced mucosal immune responses to CF antigens present in low amounts in the vaccine. Based on these encouraging results, the vaccine will be tested for safety and immunogenicity in different age groups including infants in Bangladesh and for protective efficacy in travelers. PMID- 25444832 TI - Rational design of medium supplementation strategy for improved influenza viruses production based on analyzing nutritional requirements of MDCK Cells. AB - Influenza vaccine production using cell culture technology has become popular nowadays. However, to meet the ever increasing demand of influenza vaccine, it is prerequisite to improve the yield of influenza virus in cells. To achieve this, in the present study, the nutritional requirements of MDCK cells in the virus production process were analyzed and a nutrient-feeding strategy was developed accordingly. Based on the consumption rates and corresponding concentration optimization, glucose and fast metabolized amino acids were supplemented into the maintaining medium at the time of infection. Compared with the non-supplemented culture, the average cell specific death rate during 0-48 h post-infection was 0.013 h(-1), which was 40.91% lower in the nutrient-supplemented culture. Total virus titer, HA antigen protein concentration and cell-specific virus yield were (1.88+/-0.23)*10(3) HA units/50MUL, 11.70+/-0.22 MUg/mL and (10.06+/-1.16)*10(3) virions/cell, respectively, which were 84.04+/-22.50%, 31.46+/-2.87% and 86.64+/ 25.81% higher than those in the control, respectively. These data showed that the appropriate supplementation of nutrients during virus production process could reduce cell death, and improve cell-specific virus yield and total influenza virus output. This study laid foundation for the development of cell culture technology for influenza vaccine production. PMID- 25444831 TI - Factors associated with seasonal influenza immunization among church-going older African Americans. AB - OBJECTIVES: Churches and faith institutions can frequently influence health behaviors among older African Americans. The church is a centerpiece of spiritual and social life among African American congregants. We explored its influence on influenza immunization coverage during the 2012-2013 influenza season. METHODS: A cross-sectional study was conducted among congregation members ages 50-89 years from six churches in the Atlanta region in 2013-2014. We computed descriptive statistics, bivariate associations, and multivariable models to examine factors associated with immunization uptake among this population. RESULTS: Of 208 study participants, 95 (45.7%) reported receiving the influenza vaccine. Logistic regression showed that increased trust in their healthcare providers' vaccine recommendations was a positive predictor of vaccination among participants who had not experienced discrimination in a faith-based setting (OR: 14.8 [3.7, 59.8]), but was not associated with vaccination for participants who had experienced such discrimination (OR: 1.5 [0.2, 7.0]). Belief in vaccine-induced influenza illness (OR: 0.1 [0.05, 0.23]) was a negative predictor of influenza vaccination. CONCLUSION: Members of this older cohort of African Americans who expressed trust in their healthcare providers' vaccine recommendations and disbelief in vaccine-induced influenza were more likely to obtain seasonal influenza immunization. They were also more likely to act on their trust of healthcare provider's vaccine recommendations if they did not encounter negative influenza immunization attitudes within the church. Having healthcare providers address negative influenza immunization attitudes and disseminate vaccine information in a culturally appropriate manner within the church has the potential to enhance future uptake of influenza vaccination. PMID- 25444833 TI - [Psychiatry's place in physician-assisted suicide]. PMID- 25444834 TI - [Psychiatric consultation and request of physician-assisted suicide]. PMID- 25444835 TI - Self-report of sexually transmitted infections from 1994 to 2010 by adults living in France. AB - BACKGROUND: Since 1994, French population-based knowledge, attitudes, beliefs and practices surveys have enabled researchers to estimate trends in sexual behavioural indicators. METHODS: We estimated trends and prevalence of self reported sexually transmitted infections during the previous 5 years among 16,095 sexually active adults aged 18-54 through five cross-sectional telephone surveys between 1994 and 2010. We then studied the factors associated with participants' most recent sexually transmitted infections other than genital candidiasis. RESULTS: Overall, 2.5% (95% confidence interval: 2.2%-2.9%) of women reported sexually transmitted infections within the previous 5 years, increases being continuously reported between 1998 and 2010. In contrast, men reported lower prevalence of sexually transmitted infections (1.4%; 95% confidence interval: 1.1%-1.7%), which remained stable over time. General practitioners and gynaecologists managed most sexually transmitted infections. Men notified their stable partners about infection less often than women (66% vs. 84%). Self reported sexually transmitted infections were associated with younger age, multiple sexual partnerships and fear of sexually transmitted infections in both genders, with exclusively homosexual practices in men, and with a high educational level and recent HIV testing in women. CONCLUSION: Self-reported sexually transmitted infections clearly reflect risky sexual behaviours. The lower prevalence of self-reported sexually transmitted infections among men than among women may reflect less access to screening activities for sexually transmitted infections in men. PMID- 25444836 TI - [Seasonal influenza vaccination coverage of general practitioners and their patients. Practice survey of French general practitioners after vaccination campaign 2011-2012]. AB - BACKGROUND: In France, vaccination coverage against seasonal influenza for risk groups was inadequate: 55.2% of people aged 65 and older, and 33% of the 16-64 year group with chronic targeted disorders were vaccinated in March 2012. Three quarters of general practitioners were vaccinated. Our objective was to estimate the influence of the vaccination status of general practitioners on vaccine coverage of their patients at risk. METHODS: A questionnaire was sent in March 2012 to a sample of 500 general practitioners. Their professional characteristics, vaccination status against seasonal influenza and the determinants of these vaccinations were collected and compared to the vaccine coverage of their patients obtained from the French healthcare fund. RESULTS: Self-reported vaccination coverage of the 225 general practitioners respondents was 81.3%. There was a positive correlation with age greater than 50 years, high activity level, rural practice and the absence of particular mode of exercise. The doctors wanted to be vaccinated to protect themselves and protect their patients or their family. Of the 42 doctors unvaccinated, 42.5% feared the side effects of the vaccine, 40% considered influenza to be a benign illness and 32.5% considered low risk of catching or spreading it. The vaccination rate for patients aged 65 and older was 62.3% among 147 doctors vaccinated versus 58.3% in unvaccinated 31 physicians (P<0.0001). These rates were 39% versus 36.7% (P=0.29) for patients with chronic targeted disorders. CONCLUSION: This study shows a positive association between the reported vaccination of general practitioners and effective influenza vaccination of their patients aged 65 years and older. This result is less clear for patients with chronic targeted disorders. All this findings argue in favor of promoting seasonal influenza vaccination among general practitioners. PMID- 25444837 TI - [Implementation of a French cohort of children or adolescents with autism spectrum disorders: ELENA cohort]. AB - BACKGROUND: Multidisciplinary cohort studies of children with autism spectrum disorders (ASD) followed from childhood to adulthood exist abroad but not in France. The objective of the ELENA French cohort is to study the developmental trajectories of children and adolescents with ASD and their risk or protective associated factors. METHODS: This is an open, prospective and multicenter cohort study, including children and adolescents under 16 years of age with ASD recruited from services specialized in the assessment of developmental disorders. The patients will be monitored every 18 months for at least 36 months and during a maximum of 10 years. Clinical, social, environmental, and genetic data, as well as data relating to the parental quality of life will be collected. The primary endpoint will be the adaptive level in three domains of the Vineland II (communication, socialization and daily living skills). The secondary endpoints will be parental quality of life, comorbidities, interventions and severity of ASD. EXPECTED RESULTS AND PERSPECTIVES: The inclusion of 1600 patients over a 10 year period is expected. This cohort should contribute to a better knowledge of the child developing an ASD, taking into account the physical, social and familial environment, the type of interventions and some genetic components. It should also lay the foundations for a national network of professionals working in the field of autism research by offering them a common tool for promoting translational studies. PMID- 25444838 TI - What do we mean by multimorbidity? An analysis of the literature on multimorbidity measures, associated factors, and impact on health services organization. AB - BACKGROUND: Multimorbidity is a consequence of both epidemiological and demographic transition. Unlike comorbidity, it currently has no consensus definition, making it difficult to assess its epidemiological and socioeconomic burden, to organize healthcare services rationally, and to determine the skills needed for patient self-reliance. The aim of this study is to define the spectrum of multimorbidity and to discuss current implications for the organization of care. METHODS: Two independent readers analyzed the literature indexed in PubMed, Embase, CINAHL, and Scopus. RESULTS: The bibliographic search conducted on July 16, 2013, retrieved 2287 articles (670 in PubMed, 666 in Embase, 582 in Scopus, and 369 in CINAHL). Of these, 108 articles were retained. Multimorbidity is designated by a variety of terms, none of them being MeSH terms. There is no single measure of multimorbidity, as this entity is usually studied for its functional or economic impact, rather than its causes. The prevalence varies considerably, depending on the measure used and the population studied. Factors associated with multimorbidity are age, gender, and socioeconomic characteristics of the populations studied. Studies evaluating the organization-of-care are inconclusive or insufficient. CONCLUSIONS: Multimorbidity serves as an avatar for the fundamental, recurrent problems of modern medicine and the organization-of care. It may be defined by its causes or its consequences and reflects our concept of both individual health and its collective management. Tools that would allow a more appropriate measurement of this entity are available; we should use them to match medical reality to the needs of patients. PMID- 25444839 TI - [Use of social and health primary care services for older people with complex needs: Comparison of three types of gerontological coordination]. AB - BACKGROUND: Older people with complex needs live mainly at home. Several types of gerontological coordinations have been established on the French territory to meet their needs and to implement social and primary health care services. But we do not have any information on the use of these services at home as a function of the coordination method used. METHODS: We compared the use of home care services for older people with complex needs in three types of coordination with 12 months' follow-up. The three coordinations regrouped a gerontological network with case management (n=105 persons), a nursing home service (SSIAD) with a nurse coordination (n=206 persons) and an informal coordination with a non-professional caregiver (n=117 persons). RESULTS: At t0, the older people addressed to the gerontological network had less access to the services offered at home; those followed by the SSIAD had the highest number of services and of weekly interventions. Hours of weekly services were two-fold higher in those with the informal coordination. At t12, there was an improvement in access to services for the network group with case management and an overall increase in the use of professional services at home with no significant difference between the three groups. CONCLUSION: The use of social and primary health care services showed differences between the three gerontological coordinations. The one-year evolution in the use of home services was comparable between the groups without an explosion in the number of services in the network group with case management. PMID- 25444840 TI - Development, in vitro and in vivo characterization of zoledronic acid functionalized hydroxyapatite nanoparticle based formulation for treatment of osteoporosis in animal model. AB - We investigated the potential of using novel zoledronic acid (ZOL)-hydroxyapatite (HA) nanoparticle based drug formulation in a rat model of postmenopausal osteoporosis. By a classical adsorption method, nanoparticles of HA loaded with ZOL (HNLZ) drug formulation with a size range of 100-130nm were prepared. 56 female Wistar rats were ovariectomized (OVX) or sham-operated at 3months of age. Twelve weeks post surgery, rats were randomized into seven groups and treated with various doses of HNLZ (100, 50 and 25MUg/kg, intravenous single dose), ZOL (100MUg/kg, intravenous single dose) and HA nanoparticle (100MUg/kg, intravenous single dose). Untreated OVX and sham OVX served as controls. After three months treatment period, we evaluated the mechanical properties of the lumbar vertebra and femoral mid-shaft. Femurs were also tested for trabecular microarchitecture. Sensitive biochemical markers of bone formation and bone resorption in serum were also determined. With respect to improvement in the mechanical strength of the lumbar spine and the femoral mid-shaft, the therapy with HNLZ drug formulation was more effective than ZOL therapy in OVX rats. Moreover, HNLZ drug therapy preserved the trabecular microarchitecture better than ZOL therapy in OVX rats. Furthermore, the HNLZ drug formulation corrected increase in serum levels of bone specific alkaline phosphatase, procollagen type I N-terminal propeptide, osteocalcin, tartrate-resistant acid phosphatase 5b and C-telopeptide of type 1 collagen better than ZOL therapy in OVX rats. The results strongly suggest that HNLZ novel drug formulation appears to be more effective approach for treating severe osteoporosis in humans. PMID- 25444842 TI - Analysis of the impact of controlled release formulations on oral drug absorption, gut wall metabolism and relative bioavailability of CYP3A substrates using a physiologically-based pharmacokinetic model. AB - Controlled release (CR) formulations are usually designed to achieve similar exposure (AUC) levels as the marketed immediate release (IR) formulation. However, the AUC is often lower following CR compared to IR formulations. There are a few exceptions when the CR formulations have shown higher AUC. This study investigated the impact of CR formulations on oral drug absorption and CYP3A4 mediated gut wall metabolism. A review of the current literature on relative bioavailability (Frel) between CR and IR formulations of CYP3A substrates was conducted. This was followed by a systematic analysis to assess the impact of the release characteristics and the drug-specific factors (including metabolism and permeability) on oral bioavailability employing a physiologically-based pharmacokinetic (PBPK) modelling and simulation approach. From the literature review, only three CYP3A4 substrates showed higher Frel when formulated as CR. Several scenarios were investigated using the PBPK approach; in most of them, the oral absorption of CR formulations was lower as compared to the IR formulations. However, for highly permeable compounds that were CYP3A4 substrates the reduction in absorption was compensated by an increase in the fraction that escapes from first pass metabolism in the gut wall (FG), where the magnitude was dependent on CYP3A4 affinity. The systematic simulations of various interplays between different parameters demonstrated that BCS class 1 highly-cleared CYP3A4 substrates can display up to 220% higher relative bioavailability when formulated as CR compared to IR, in agreement with the observed data collected from the literature. The results and methodology of this study can be employed during the formulation development process in order to optimize drug absorption, especially for CYP3A4 substrates. PMID- 25444841 TI - Concomitant intake of alcohol may increase the absorption of poorly soluble drugs. AB - Ethanol can increase the solubility of poorly soluble and hence present a higher drug concentration in the gastrointestinal tract. This may produce a faster and more effective absorption resulting in variable and/or high drug plasma concentrations, both of which can lead to adverse drug reactions. In this work we therefore studied the solubility and absorption effects of nine diverse compounds when ethanol was present. The apparent solubility was measured using the MUDiss Profiler Plus (pION, MA) in four media representing gastric conditions with and without ethanol. The solubility results were combined with in-house data on solubility in intestinal fluids (with and without ethanol) and pharmacokinetic parameters extracted from the literature and used as input in compartmental absorption simulations using the software GI-Sim. Apparent solubility increased more than 7-fold for non-ionized compounds in simulated gastric fluid containing 20% ethanol. Compounds with weak base functions (cinnarizine, dipyridamole and terfenadine) were completely ionized at the studied gastric pH and their solubility was therefore unaffected by ethanol. Compounds with low solubility in intestinal media and a pronounced solubility increase due to ethanol in the upper gastric compartments showed an increased absorption in the simulations. The rate of absorption of the acidic compounds indomethacin and indoprofen was slightly increased but the extent of absorption was unaffected as the complete doses were readily absorbed even without ethanol. This was likely due to a high apparent solubility in the intestinal compartment where the weak acids are ionized. The absorption of the studied non-ionizable compounds increased when ethanol was present in the gastric and intestinal media. These results indicate that concomitant intake of alcohol may significantly increase the solubility and hence, the plasma concentration for non-ionizable, lipophilic compounds with the potential of adverse drug reactions to occur. PMID- 25444843 TI - Pseudocyanides of sanguinarine and chelerythrine and their series of structurally simple analogues as new anticancer lead compounds: Cytotoxic activity, structure activity relationship and apoptosis induction. AB - 6-Cyano dihydrosanguinarine (CNS) and 6-cyano dihydrochelerythrine (CNC) are respectively artificial derivatives of sanguinarine and chelerythrine, two anticancer quaternary benzo[c]phenanthridine alkaloids (QBAs) while 1-cyano-2 aryl-1,2,3,4-tetrahydroisoquinolines (CATHIQs) are a class of structurally simple analogues of CNS or CNC. This study investigated the inhibition activity of CNS, CNC and CATHIQs on cancer cells, apoptosis induction as well as their preliminary SAR. The results showed that CNS and 18 out of CATHIQs showed IC50 values of 0.53 and 0.62-2.24MUM against NB4 and 1.53 and 2.99-11.17MUM against MKN-45 cells, respectively, superior to a standard anticancer drug cis-platinum with IC50 of 2.39 and 11.36MUM. CNC showed a higher activity against NB4 cells (IC50=1.85MUM) and a moderate activity against MKN-45 cells (IC50=12.72MUM). Among all CATHIQs, 2 and 17 gave the highest activity against NB4 cells and MKN-45 cells (IC50=0.62 and 2.99MUM), respectively. DAPI staining, AO/EB staining and ultrastructure analysis of cells demonstrated that CATHIQs were able to induce apoptosis of the cells in a concentration-dependent manner. SAR showed that substitution patterns on the N-aromatic ring significantly influenced the activity of CATHIQs. The general trend was that the introduction of electron-withdrawing substituents like halogen atom, nitro, trifluoromethyl led to a significant improvement of the activity, while the presence of electron-donating groups like methyl, methoxyl caused a reduction of the activity. In most cases, the 2' site was the most favorable substitution position for the improvement of the activity. Thus, the present results strongly suggested that QBA-type pseudocyanides may serve as potential alternatives of anticancer QBAs while CATHIQs should be a class of promising lead compounds for the development of new QBA-like-type anticancer drugs. CNS exhibited the highest cytotoxicities with IC50 values of 0.53MUM on NB4 cells and 1.53MUM on MKN-45 cells. PMID- 25444844 TI - Parameterization of small intestinal water volume using PBPK modeling. AB - To facilitate accurate predictions of oral drug disposition, mechanistic absorption models require optimal parameterization. Furthermore, parameters should maintain a biological basis to establish confidence in model predictions. This study will serve to calculate an optimal parameter value for small intestinal water volume (SIWV) using a model-based approach. To evaluate physiologic fidelity, derived volume estimates will be compared to experimentally based SIWV determinations. A compartmental absorption and transit (CAT) model, created in Matlab-Simulink(r), was integrated with a whole-body PBPK model, developed in PK-SIM 5.2(r), to provide predictions of systemic drug disposition. SIWV within the CAT model was varied between 52.5mL and 420mL. Simulations incorporating specific SIWV values were compared to pharmacokinetic data from compounds exhibiting solubility induced non-proportional changes in absorption using absolute average fold-error. Correspondingly, data pertaining to oral administration of acyclovir and chlorothiazide were utilized to derive estimates of SIWV. At 400mg, a SIWV of 116mL provided the best estimates of acyclovir plasma concentrations. A similar SIWV was found to best depict the urinary excretion pattern of chlorothiazide at a dose of 100mg. In comparison, experimentally-based estimates of SIWV within adults denote a central tendency between 86 and 167mL. The derived SIWV (116mL) represents the optimal parameter value within the context of the developed CAT model. This result demonstrates the biological basis of the widely utilized CAT model as in vivo SIWV determinations correspond with model-based estimates. PMID- 25444845 TI - Statistical investigation of simulated intestinal fluid composition on the equilibrium solubility of biopharmaceutics classification system class II drugs. AB - A drug's solubility and dissolution behaviour within the gastrointestinal tract is a key property for successful administration by the oral route and one of the key factors in the biopharmaceutics classification system. This property can be determined by investigating drug solubility in human intestinal fluid (HIF) but this is difficult to obtain and highly variable, which has led to the development of multiple simulated intestinal fluid (SIF) recipes. Using a statistical design of experiment (DoE) technique this paper has investigated the effects and interactions on equilibrium drug solubility of seven typical SIF components (sodium taurocholate, lecithin, sodium phosphate, sodium chloride, pH, pancreatin and sodium oleate) within concentration ranges relevant to human intestinal fluid values. A range of poorly soluble drugs with acidic (naproxen, indomethacin, phenytoin, and piroxicam), basic (aprepitant, carvedilol, zafirlukast, tadalafil) or neutral (fenofibrate, griseofulvin, felodipine and probucol) properties have been investigated. The equilibrium solubility results determined are comparable with literature studies of the drugs in either HIF or SIF indicating that the DoE is operating in the correct space. With the exception of pancreatin, all of the factors individually had a statistically significant influence on equilibrium solubility with variations in magnitude of effect between the acidic and basic or neutral compounds and drug specific interactions were evident. Interestingly for the neutral compounds pH was the factor with the second largest solubility effect. Around one third of all the possible factor combinations showed a significant influence on equilibrium solubility with variations in interaction significance and magnitude of effect between the acidic and basic or neutral compounds. The least number of significant media component interactions were noted for the acidic compounds with three and the greatest for the neutral compounds at seven, with again drug specific effects evident. This indicates that a drug's equilibrium solubility in SIF is influenced depending upon drug type by between eight to fourteen individual or combinations of media components with some of these drug specific. This illustrates the complex nature of these fluids and provides for individual drugs a visualisation of the possible solubility envelope within the gastrointestinal tract, which may be of importance for modelling in vivo behaviour. In addition the results indicate that the design of experiment approach can be employed to provide greater detail of drug solubility behaviour, possible drug specific interactions and influence of variations in gastrointestinal media components due to disease. The approach is also feasible and amenable to adaptation for high throughput screening of drug candidates. PMID- 25444846 TI - Blood-brain barrier dysfunction, seizures and epilepsy. AB - The blood-brain barrier (BBB) is a dynamic and complex system which separates the brain from the blood. It helps to maintain the homeostasis of the brain, which is essential for normal neuronal functioning. BBB function is impaired in several neurological diseases, including epilepsy in which it may lead to abnormal and excessive neuronal firing. In this review we will discuss how BBB dysfunction can affect neuronal function and how this can lead to seizures and epilepsy. We will also summarize new therapies that aim to preserve or restore BBB function in order to prevent or reduce epileptogenesis. PMID- 25444847 TI - Sentinel lymph node metastases in cancer: causes, detection and their role in disease progression. AB - Malignant tumors of ectodermal or endodermal origin may metastasize to the sentinel lymph node, the first lymph node encountered by tumor cells that enter lymphatics in the organ of origin. This pathway is enabled by the anatomy of the disease and the causes of metastasis are the result of complex interactions that include mechanical forces within the tumor and host tissues, and molecular factors initiated by tumor cell proliferation, elaboration of cytokines and changes in the tumor microenvironment. Mechanical stresses may influence complex biochemical, genetic and other molecular events and enhance the likelihood of metastasis. This paper summarizes our understanding of interacting molecular, anatomical and mechanical processes which facilitate metastasis to SLNs. Our understanding of these interacting events is based on a combination of clinical and basic science research, in vitro and in vivo, including studies in lymphatic embryology, anatomy, micro-anatomy, pathology, physiology, molecular biology and mechanobiology. The presence of metastatic tumor in the SLN is now more accurately identifiable and, based upon prospective clinical trials, paradigm changing SLN biopsy has become the standard of clinical practice in breast cancer and melanoma. PMID- 25444848 TI - The blood-brain barrier-gatekeeper to neuronal homeostasis: clinical implications in the setting of stroke. AB - The blood-brain barrier is part of the neurovascular unit and serves as a functional and anatomical barrier between the blood and the extracellular space. It controls the flow of solutes in and out of the brain thereby providing an optimal environment for neuronal functioning. Paracellular transport between endothelial cells is restricted by tight junctions and transendothelial transport is reduced and more selective compared to capillaries of other organs. Further, the blood-brain barrier is involved in controlling blood flow and it is the site for signaling damage of the nervous system to the peripheral immune system. As an important player in brain homeostasis, blood-brain barrier dysfunction has been implicated in the pathophysiology of many brain diseases including stroke, traumatic brain injury, brain tumors, epilepsy and neurodegenerative disorders. In this article - highlighting recent advances in basic science - we review the features of the blood-brain barrier and their significance for neuronal homeostasis to discuss clinical implications for neurological complications following cerebral ischemia. PMID- 25444849 TI - Pathology in the late phase after extensive and ostial pulmonary vein ablation for atrial fibrillation: findings in 2 postmortem cases. PMID- 25444851 TI - Microscopic mechanisms for long QT syndrome type 1 revealed by single-channel analysis of I(Ks) with S3 domain mutations in KCNQ1. AB - BACKGROUND: The slowly activating delayed rectifier current IKs participates in cardiac repolarization, particularly at high heart rates, and mutations in this K(+) channel complex underlie long QT syndrome (LQTS) types 1 and 5. OBJECTIVE: The purpose of this study was to determine biophysical mechanisms of LQT1 through single-channel kinetic analysis of IKs carrying LQT1 mutations in the S3 transmembrane region of the pore-forming subunit KCNQ1. METHODS: We analyzed cell attached recordings from mammalian cells in which a single active KCNQ1 (wild type or mutant) and KCNE1 complex could be detected. RESULTS: The S3 mutants of KCNQ1 studied (D202H, I204F, V205M, and S209F), with the exception of S209F, all led to a reduction in channel activity through distinct kinetic mechanisms. D202H, I204F, and V205M showed decreased open probability (Po) compared with wild type (0.07, 0.04, and 0.12 vs 0.2); increased first latency from 1.66 to >2 seconds at +60 mV (I204F, V205M); variable-to-severe reductions in open dwell times (>=50% in V205M); stabilization of closed states (D202H); and an inability of channels to reach full conductance levels (V205M, I204F). S209F is a kinetic gain-of-function mutation with a high Po (0.40) and long open-state dwell times. CONCLUSION: S3 mutations in KCNQ1 cause diverse kinetic defects in I(Ks), affecting opening and closing properties, and can account for LQT1 phenotypes. PMID- 25444850 TI - Fractionation of electrograms is caused by colocalized conduction block and connexin disorganization in the absence of fibrosis as AF becomes persistent in the goat model. AB - BACKGROUND: Electrogram fractionation and atrial fibrosis are both thought to be pathophysiological hallmarks of evolving persistence of atrial fibrillation (AF), but recent studies in humans have shown that they do not colocalize. The interrelationship and relative roles of fractionation and fibrotic change in AF persistence therefore remain unclear. OBJECTIVE: The aim of the study was to examine the hypothesis that electrogram fractionation with increasing persistence of AF results from localized conduction slowing or block due to changes in atrial connexin distribution in the absence of fibrotic change. METHODS: Of 12 goats, atrial burst pacemakers maintained AF in 9 goats for up to 3 consecutive 4-week periods. After each 4-week period, 3 goats underwent epicardial mapping studies of the right atrium and examination of the atrial myocardium for immunodetection of connexins 43 and 40 (Cx43 and Cx40) and quantification of connective tissue. RESULTS: Despite refractoriness returning to normal in between each 4-week period of AF, there was a cumulative increase in the prevalence of fractionated atrial electrograms during both atrial pacing (control and 1, 2, and 3 months period of AF 0.3%, 1.3% +/- 1.5%, 10.6% +/- 2%, and 17% +/- 5%, respectively; analysis of variance, P < .05) and AF (0.3% +/- 0.1%, 2.3% +/- 1.2%, 14% +/- 2%, and 23% +/- 3%; P < .05) caused by colocalized areas of conduction block during both pacing (local conduction velocity <10 cm/s: 0.1% +/- 0.1%, 0.3% +/- 0.6%, 6.5% +/- 3%, and 6.9% +/- 4%; P < .05) and AF (1.5% +/- 0.5%, 2.7% +/- 1.1%, 10.1% +/- 1.2%, and 13.6% +/- 0.4%; P < .05), associated with an increase in the heterogeneity of Cx40 and lateralization of Cx43 (lateralization scores: 1.75 +/- 0.89, 1.44 +/- 0.31, 2.85 +/- 0.96, and 2.94 +/- 0.31; P < .02), but not associated with change in connective tissue content or net conduction velocity. CONCLUSION: Electrogram fractionation with increasing persistence of AF results from slow localized conduction or block associated with changes in atrial connexin distribution in the absence of fibrotic change. PMID- 25444852 TI - Isolated atrioventricular block of unknown origin in adults and anti-Ro/SSA antibodies: clinical evidence, putative mechanisms, and therapeutic implications. PMID- 25444853 TI - Effect of daily remote monitoring on pacemaker longevity: a retrospective analysis. AB - BACKGROUND: Energy demand of remote monitoring in cardiac implantable electronic devices has never been investigated. Biotronik Home Monitoring (HM) is characterized by daily transmissions that may affect longevity. OBJECTIVE: The aim of the study was to retrospectively compare longevity of a specific dual chamber pacemaker model in patients with HM on and patients with HM off. METHODS: Hospital files of 201 patients (mean age 87 +/- 10 years, 78 men) who had received a Biotronik Cylos DR-T pacemaker between April 2006 and May 2010 for standard indication were reviewed. In 134 patients (67%), HM was activated. The primary end point was device replacement due to battery depletion. RESULTS: The median follow-up period was 56.4 months (interquartile range 41.8-65.2 months). The estimated device longevity was 71.1 months (95% confidence interval [CI] 69.1 72.3 months) in the HM-on group and 60.4 months (CI 55.9-65.1 months) in the HM off group (P < .0001). The frequency of inhospital visits with significant device reprogramming was higher in the HM-on group than in the HM-off group (33.3% vs 25.0%, respectively; P = .03). Lower ventricular pulse amplitude (2.3 +/- 0.4 V vs 2.7 +/- 0.5 V; P < .0001) and pacing percentage (49% +/- 38% vs 64% +/- 38%; P = .02), both calculated as time-weighted averages, were observed with HM on as compared with HM off. Patient attrition was significantly lower in the HM-on group (9.7%; 95% CI 3.0%-28.7%) than in the HM-off group (45.6%; 95% CI 30.3% 64.3%) (P < .0001). CONCLUSION: In normal practice, energy demand of HM, if present, was overshadowed by programming optimization likely favored by continuous monitoring. Pacemakers controlled remotely with HM showed an 11-month longer longevity. Patient retention was superior. PMID- 25444854 TI - Ablation of idiopathic ventricular tachycardia arising from posterior mitral annulus in an 11-month-old infant by transapical left ventricular access via median sternotomy. PMID- 25444857 TI - Steady-state substrate specificity and O2-coupling efficiency of mouse cysteine dioxygenase. AB - Cysteine dioxygenase (CDO) is a non-heme mononuclear iron enzyme that catalyzes the oxygen-dependent oxidation of L-cysteine (Cys) to produce L-cysteine sulfinic acid (CSA). Sequence alignment of mammalian CDO with recently discovered thiol dioxygenase enzymes suggests that the mononuclear iron site within all enzymes in this class share a common 3-His first coordination sphere. This implies a similar mechanistic paradigm among thiol dioxygenase enzymes. Although steady-state studies were first reported for mammalian CDO over 45 years ago, detailed analysis of the specificity for alternative thiol-bearing substrates and their oxidative coupling efficiencies have not been reported for this enzyme. Assuming a similar mechanistic theme among this class of enzymes, characterization of the CDO substrate specificity may provide valuable insight into substrate-active site intermolecular during thiol oxidation. In this work, the substrate-specificity for wild-type Mus musculus CDO was investigated using NMR spectroscopy and LC-MS for a variety of thiol-bearing substrates. Tandem mass spectrometry was used to confirm dioxygenase activity for each non-native substrate investigated. Steady state Michaelis-Menten parameters for sulfinic acid product formation and O2 consumption were compared to establish the coupling efficiency for each reaction. In light of these results, the minimal substrate requirements for CDO catalysis and O2-activation are discussed. PMID- 25444855 TI - Targeting acidity in diseased tissues: mechanism and applications of the membrane inserting peptide, pHLIP. AB - pHLIPs are a family of soluble ~36 amino acid peptides, which bind to membrane surfaces. If the environment is acidic, a pHLIP folds and inserts across the membrane to form a stable transmembrane helix, thus preferentially locating itself in acidic tissues. Since tumors and other disease tissues are acidic, pHLIPs' low-pH targeting behavior leads to applications as carriers for diagnostic and surgical imaging agents. The energy of membrane insertion can also be used to promote the insertion of modestly polar, normally cell-impermeable cargos across the cell membrane into the cytosol of targeted cells, leading to applications in tumor-targeted delivery of therapeutic molecules. We review the biochemical and biophysical basis of pHLIPs' unique properties, diagnostic and therapeutic applications, and the principles upon which translational applications are being developed. PMID- 25444856 TI - Heme binds to an intrinsically disordered region of Bach2 and alters its conformation. AB - The transcriptional repressor Bach2 regulates humoral and cellular immunity, including antibody class switching. It possesses a basic leucine zipper domain that mediates DNA binding. Heme inhibits the DNA-binding activity of Bach2 in vitro and induces the degradation of Bach2 in B cells. However, the structural basis of the heme-Bach2 interaction has not been identified. Spectroscopic analyses revealed that Bach2(331-520) is the heme-binding domain, as it includes three Cys-Pro motifs known to be important for heme binding. Heme-titration experiments demonstrated the presence of 5- and 6-coordinated heme-binding modes. Circular dichroism measurements indicated that Bach2(331-520) exists mostly in a random-coil conformation. However, dynamic light scattering analyses showed that, upon heme binding to Bach2(331-520), this region becomes denatured at a lower temperature, as compared with unbound Bach2(331-520). In addition, small-angle X ray scattering and chemical modification analyses revealed that heme binding induces conformational alterations within the unstructured region. A GAL4-based luciferase assay in 293T cells showed that heme alters the protein interactions mediated by Bach2(331-520). These observations suggested that the unstructured region of Bach2 is important for heme binding, and consequently for its functional regulation. PMID- 25444858 TI - CRLI induces vascular smooth muscle relaxation and suggests a dual mechanism of eNOS activation by legume lectins via muscarinic receptors and shear stress. AB - Lectins are proteins able to recognize carbohydrates, without modifying their structure, via the carbohydrate-recognition domain (CRD). Here, the three dimensional structure of the mannose-binding lectin isolated from Cymbosema roseum (CRLI) was determined with X-man molecule modeled into the carbohydrate recognition domain. CRLI relaxant activity in thoracic rat aorta was also investigated, and based on the results, a molecular docking of CRLI with heparan sulfate was performed to investigate the possible interaction with mechanoreceptors involved in vasorelaxation. CRLI (IC50=12.4 MUg mL(-)(1)) elicited vasorelaxant response (96%) in endothelialized rat aorta contracted with phenylephrine. Endothelium-derived relaxant factors, extracellular calcium (Ca(2+)e) and muscarinic receptors were also evaluated as putative participants in the CRLI relaxant effect. CRLI relaxant effect was blocked by L-NAME, a nonselective inhibitor of nitric oxide synthase (NOS), and partially inhibited in a calcium-free solution (0Ca) and by atropine, but it remained unchanged in the presence of indomethacin and TEA. In summary, our data suggest interaction between CRLI and muscarinic receptors located in vascular endothelial cells leading to NOS activation triggered by a mechanism that involves Ca(2+)e along with the ability of CRLI to interact with heparan sulfate, a highly rated mechanoreceptor involved in eNOS activation. PMID- 25444859 TI - Molecular characterisation of the salmon louse, Lepeophtheirus salmonis salmonis (Kroyer, 1837), ecdysone receptor with emphasis on functional studies of female reproduction. AB - The salmon louse Lepeophtheirus salmonis (Copepoda, Caligidae) is an important parasite in the salmon farming industry in the Northern Hemisphere causing annual losses of hundreds of millions of dollars (US) worldwide. To facilitate development of a vaccine or other novel measures to gain control of the parasite, knowledge about molecular biological functions of L. salmonis is vital. In arthropods, a nuclear receptor complex consisting of the ecdysone receptor and the retinoid X receptor, ultraspiracle, are well known to be involved in a variety of both developmental and reproductive processes. To investigate the role of the ecdysone receptor in the salmon louse, we isolated and characterised cDNA with the 5'untranslated region of the predicted L. salmonis EcR (LsEcR). The LsEcR cDNA was 1608 bp encoding a 536 amino acid sequence that demonstrated high sequence similarities to other arthropod ecdysone receptors including Tribolium castaneum and Locusta migratoria. Moreover, in situ analysis of adult female lice revealed that the LsEcR transcript is localised in a wide variety of tissues such as ovaries, sub-cuticula and oocytes. Knock-down studies of LsEcR using RNA interference terminated egg production, indicating that the LsEcR plays important roles in reproduction and oocyte maturation. We believe this is the first report on the ecdysone receptor in the economically important parasite L. salmonis. PMID- 25444860 TI - Independent host switching events by digenean parasites of cetaceans inferred from ribosomal DNA. AB - Cetaceans harbour a unique fauna of digeneans whose origin and relationships have sparked considerable debate during recent decades. Disparity in the species reported indicates that they do not share close affinities, but their unusual morphology has made their taxonomic identities and phylogenetic positions uncertain. Here we use sequence data to investigate the phylogenetic relationships of the main species of flukes infecting cetaceans. We sequenced the 18S, 28S and internal transcribed spacer 2 rDNA of digenean species representing all known families reported from cetaceans: Braunina cordiformis (Brauninidae), Ogmogaster antarcticus (Notocotylidae), Pholeter gastrophilus (Heterophyidae), and Campula oblonga, Nasitrema sp. and Oschmarinella rochebruni (Brachycladiidae). The phylogenetic position of the taxa was estimated by Bayesian inference and maximum likelihood incorporating published sequences of 177 species of Digenea. Further Bayesian and maximum likelihood analyses were performed with sequences of 14 Heterophyidae and Opisthorchiidae taxa, incorporating new sequences of P. gastrophilus. Species nominally assigned to the Brachycladiidae formed a clade that was embedded among species of the Acanthocolpidae, thus making the latter family paraphyletic. Braunina cordiformis formed a sister lineage to the Strigeidae and Diplostomidae, whereas O. antarcticus was placed within the Notocotylidae, in agreement with the previous taxonomy of this genus. Similarly, P. gastrophilus was placed within the Heterophyidae as originally described. Our results suggest a paraphyletic relationship between the Heterophyidae and Opisthorchiidae, mirroring the uncertain taxonomic placement of P. gastrophilus, which has been assigned to both families in the past. The digenean families involved are parasites of fish-eating birds and mammals (i.e. Strigeidae, Diplostomidae and Heterophyidae), parasites of marine fish (i.e. Acanthocolpidae) and other herbivorous aquatic birds and mammals (i.e. Notocotylidae). The phylogenetic positions of these taxa indicate that the digenean fauna of cetaceans may have been acquired through independent host-capture events, with two clades showing subsequent diversification exclusively among marine mammals. PMID- 25444861 TI - Characterisation of polyglutamylases in trypanosomatids. AB - Microtubules are subject to post-translational modifications, which are thought to have crucial roles in the function of complex microtubule-based organelles. Among these, polyglutamylation was relatively recently discovered, and was related to centrosome stability, axonemal maintenance and mobility, and neurite outgrowth. In trypanosomatids, parasitic protozoa where microtubules constitute the essential component of the cytoskeleton, the function of polyglutamylated microtubules is unknown. Here, in order to better understand the role of this conserved but highly divergent post-translational modification, we characterised glutamylation and putative polyglutamylases in these parasites. We showed that microtubules are intensely glutamylated in all stages of the cell cycle, including interphase. Moreover, a cell cycle-dependent gradient of glutamylation was observed along the cell anteroposterior axis, which might be related to active growth of the microtubule 'corset' during the cell cycle. We also identified two putative polyglutamylase proteins (among seven analysed here) which appeared to be clearly and directly involved in microtubule polyglutamylation in in vitro activity assays. Paradoxically, in view of the importance of tubulins and of their extensive glutamylation in these organisms, RNA interference-based knockdown of all these proteins had no effect on cell growth, suggesting either functional redundancy or, more likely, subtle roles such as function modulation or interaction with protein partners. PMID- 25444862 TI - Spatial and seasonal factors are key determinants in the aggregation of helminths in their definitive hosts: Pseudamphistomum truncatum in otters (Lutra lutra). AB - Parasites are typically aggregated within their host populations. The most heavily infected hosts are frequently cited as targets for optimal disease control. Yet a heavily infected individual is not necessarily highly infective and does not automatically contribute a higher proportion of infective parasitic stages than a host with fewer parasites. Here, Pseudamphistomum truncatum (Opisthorchiida) parasitic infection within the definitive otter host (Lutra lutra) is used as a model system. The hypothesis tested is that variation in parasite abundance, aggregation and egg production (fecundity, as a proxy of host infectivity) can be explained by abiotic (season and region) or biotic (host age, sex and body condition) factors. Parasite abundance was affected most strongly by the biotic factors of age and body condition, such that adults and otters with a higher condition index had heavier infections than sub-adults or those with a lower condition index, whilst there were no significant differences in parasite abundance among the seasons, regions (ecological regions defined by river catchment boundaries) or host sexes. Conversely, parasite aggregation was affected most strongly by the abiotic factors of season and region, which were supported by four different measures of parasite aggregation (the corrected moment estimate k, Taylor's Power Law, the Index of Discrepancy D, and Boulinier's J). Pseudamphistomum truncatum was highly aggregated within otters, with aggregation stronger in the Midlands (England) and Wales than in the southwestern region of the United Kingdom. Overall, more parasites were found in fewer hosts during the summer, which coincides with the summer peak in parasite fecundity. Combined, these data suggest that (i) few otters carry the majority of P. truncatum parasites and that there are more infective stages (eggs) produced during summer; and (ii) abiotic factors are most influential when describing parasite aggregation whilst biotic factors have a greater role in defining parasite abundance. Together, parasite abundance, aggregation and fecundity can help predict which hosts make the largest contribution to the spread of infectious diseases. PMID- 25444863 TI - Knockout of leucine aminopeptidase in Toxoplasma gondii using CRISPR/Cas9. AB - Leucine aminopeptidases of the M17 peptidase family represent ideal drug targets for therapies directed against the pathogens Plasmodium, Babesia and Trypanosoma. Previously, we characterised Toxoplasma gondii leucine aminopeptidase and demonstrated its role in regulating the levels of free amino acids. In this study, we evaluated the potential of T. gondii leucine aminopeptidase as a drug target in T. gondii by a knockout method. Existing knockout methods for T. gondii have many drawbacks; therefore, we developed a new technique that takes advantage of the CRISPR/Cas9 system. We first chose a Cas9 target site in the gene encoding T. gondii leucine aminopeptidase and then constructed a knockout vector containing Cas9 and the single guide RNA. After transfection, single tachyzoites were cloned in 96-well plates by limiting dilution. Two transfected strains derived from a single clone were cultured in Vero cells, and then subjected to expression analysis by western blotting. The phenotypic analysis revealed that knockout of T. gondii leucine aminopeptidase resulted in inhibition of attachment/invasion and replication; both the growth and attachment/invasion capacity of knockout parasites were restored by complementation with a synonymously substituted allele of T. gondii leucine aminopeptidase. Mouse experiments demonstrated that T. gondii leucine aminopeptidase knockout somewhat reduced the pathogenicity of T. gondii. An enzymatic activity assay showed that T. gondii leucine aminopeptidase knockout reduced the processing of a leucine aminopeptidase-specific substrate in T. gondii. The absence of leucine aminopeptidase activity could be slightly compensated for in T. gondii. Overall, T. gondii leucine aminopeptidase knockout influenced the growth of T. gondii, but did not completely block parasite development, virulence or enzymatic activity. Therefore, we conclude that leucine aminopeptidase would be useful only as an adjunctive drug target in T. gondii. PMID- 25444864 TI - Effect of insulin deficiency on the rewarding properties of methamphetamine in streptozotocin-induced diabetic rats. AB - The reward is a positive behavioural response to the pleasant stimuli that can be induced by drugs, such as psychostimulants. Furthermore, diabetes mellitus is a chronic disease that many people throughout the world suffer from. Methamphetamine (METH), as a psychostimulant, engages the dopaminergic system in the reward circuitry and the synapses of dopaminergic terminals can be modified by insulin. In this study, in order to assess the effect of insulin deficiency on reward, streptozotocin (STZ)-induced diabetic animals were used as an appropriate model. One hundred and thirty-two adult male rats were divided into nine groups (three non-diabetic and six diabetic groups) to determine the most effective dose of METH (0.25, 0.5, 1 and 2mg/kg ip), and insulin replacement (10U/kg; ip) during the acquisition period in a conditioned place preference (CPP) paradigm. The diabetes model was induced by a single injection of STZ (60mg/kg; ip). The conditioning score was considered to be the difference in time spent in drug- and saline-paired compartments. The results demonstrated that the most effective doses of METH were 1 and 2mg/kg in non-diabetic animals. Although the place preference was not shown in non-diabetic animals at the dose of 0.5mg/kg, this dose significantly induced place preference to METH in STZ-diabetic rats. Additionally, insulin replacement could reverse the METH-induced CPP in diabetic animals. Our findings suggest that the positive effect of insulin deficiency on METH rewarding properties is dependent on insulin level in part, and the replacement of the insulin in diabetic rats as a treatment can improve the rewarding properties of METH. PMID- 25444865 TI - Tenuifolin, a secondary saponin from hydrolysates of polygalasaponins, counteracts the neurotoxicity induced by Abeta25-35 peptides in vitro and in vivo. AB - Alzheimer's disease (AD) is associated with damage to hippocampal neurons and declines in cognitive functions. The accumulation of amyloid peptides is regarded as a crucial event in the initiation of AD. The neurotoxicity induced by Abeta25 35 peptides was used to screen for cytoprotective factors in vitro, and the cognitive deficits induced by the injection of Abeta25-35 into the hippocampus were used to evaluate effect on learning and memory. Our previous study revealed that hydrolysate of polygalasaponins (HPS) clearly improve the cognitive deficits induced by the injection of Abeta25-35 in mice, but the potential active constituent of HPS remains unclear. The purposes of this study were to separate and purify the secondary saponins of HPS, screen for neuroprotective effects of the constituents in vitro, and to evaluate the effect of cognition in vivo. Various chromatographic methods were used to separate and purify the HPS. The neuroprotective effects were examined in Abeta25-35-damage-induced PC12 cells. The protective effect of tenuifolin on the cognitive impairments induced by Abeta25-35 injection was assessed using the Morris water maze and step-through passive avoidance tests. Tenuifolin and fallaxsaponin A were isolated from the HPS. Tenuifolin possessed neuroprotective effects against Abeta25-35-induced apoptosis in PC12 cells and significantly improved the cognitive deficits induced by the intrahippocampal injection of Abeta25-35 in mice. Thus, tenuifolin is one of the active constituents of HPS against the neurotoxicity induced by Abeta25-35 peptides in vitro and in vivo. PMID- 25444867 TI - Repeated forced swimming impairs prepulse inhibition and alters brain-derived neurotrophic factor and astroglial parameters in rats. AB - Glutamate perturbations and altered neurotrophin levels have been strongly associated with the neurobiology of neuropsychiatric disorders. Environmental stress is a risk factor for mood disorders, disrupting glutamatergic activity in astrocytes in addition to cognitive behaviours. Despite the negative impact of stress-induced neuropsychiatric disorders on public health, the molecular mechanisms underlying the response of the brain to stress has yet to be fully elucidated. Exposure to repeated swimming has proven useful for evaluating the loss of cognitive function after pharmacological and behavioural interventions, but its effect on glutamate function has yet to be fully explored. In the present study, rats previously exposed to repeated forced swimming were evaluated using the novel object recognition test, object location test and prepulse inhibition (PPI) test. In addition, quantification of brain-derived neurotrophic factor (BDNF) mRNA expression and protein levels, glutamate uptake, glutathione, S100B, GluN1 subunit of N-methyl-D-aspartate receptor and calmodulin were evaluated in the frontal cortex and hippocampus after various swimming time points. We found that swimming stress selectively impaired PPI but did not affect memory recognition. Swimming stress altered the frontal cortical and hippocampal BDNF expression and the activity of hippocampal astrocytes by reducing hippocampal glutamate uptake and enhancing glutathione content in a time-dependent manner. In conclusion, these data support the assumption that astrocytes may regulate the activity of brain structures related to cognition in a manner that alters complex behaviours. Moreover, they provide new insight regarding the dynamics immediately after an aversive experience, such as after behavioural despair induction, and suggest that forced swimming can be employed to study altered glutamatergic activity and PPI disruption in rodents. PMID- 25444868 TI - The disruptive effects of methamphetamine on delayed-matching-to-sample performance reflect proactive interference and are reduced by SCH23390. AB - Different drugs produce different patterns of impairment on delayed matching-to sample tasks. For example, (+/-)3,4-methylenedioxymethamphetamine (MDMA) produces an increase in proactive interference. That is, subjects are less accurate when they are required to make a response different to the one they made on the immediately previous trial. The current study assessed whether methamphetamine also produces this particular pattern of disruption in delayed matching-to-sample performance in rats. Methamphetamine primarily reduced accuracy on trials where the correct response differed from the one made on the previous trial. Thus methamphetamine, like MDMA and other stimulant-based drugs of abuse, increased proactive interference. This impairment was reduced by prior administration of the dopamine D1 antagonist SCH23390. These results further extend a general conclusion that a range of stimulant-based drugs may disrupt working memory function indirectly via a tendency to repeat previously made responses and that this disruption is related to D1 receptor activity. PMID- 25444866 TI - The dopamine D1-D2 receptor heteromer exerts a tonic inhibitory effect on the expression of amphetamine-induced locomotor sensitization. AB - A role for the dopamine D1-D2 receptor heteromer in the regulation of reward and addiction-related processes has been previously implicated. In the present study, we examined the effects of D1-D2 heteromer stimulation by the agonist SKF 83959 and its disruption by a selective TAT-D1 peptide on amphetamine-induced locomotor sensitization, a behavioral model widely used to study the neuroadaptations associated with psychostimulant addiction. D1-D2 heteromer activation by SKF 83959 did not alter the acute locomotor effects of amphetamine but significantly inhibited amphetamine-induced locomotor responding across the 5day treatment regimen. In addition, a single injection of SKF 83959 was sufficient to abolish the expression of locomotor sensitization induced by a priming injection of amphetamine after a 72-hour withdrawal. Conversely, inhibition of D1-D2 heteromer activity by the TAT-D1 peptide enhanced subchronic amphetamine-induced locomotion and the expression of amphetamine locomotor sensitization. Treatment solely with the TAT-D1 disrupting peptide during the initial 5day treatment phase was sufficient to induce a sensitized locomotor phenotype in response to the priming injection of amphetamine. Together these findings demonstrate that the dopamine D1-D2 receptor heteromer exerts a tonic inhibitory control on neurobiological processes involved in sensitization to amphetamine, indicating that the dopamine D1-D2 receptor heteromer may be a novel molecular substrate in addiction processes involving psychostimulants. PMID- 25444869 TI - Design and construction of small perturbation mutagenesis libraries for antibody affinity maturation using massive microchip-synthesized oligonucleotides. AB - We report a rational strategy to design and construct multiple small perturbation mutagenesis (SPM) libraries using massively parallel synthesis of oligonucleotides on a microchip for affinity maturation of an engineered anti ErbB2 antibody chA21. On the basis of a comprehensive analysis of the sequence and structural relationships of six complementary determination regions (CDRs) in the Kabatman database, a computational algorithm was developed to introduce single-site and double-site mutations into variable CDR positions using ambiguous nucleotides. The six SPM libraries were composed of 419 degenerate oligonucleotides that can be expanded into 161,832 unique CDR sequences with a high coverage ratio of 95% natural amino acid diversity. We used Illumina next generation sequencing to demonstrate that the synthetic CDR library sequences, as well as relative quantities per sequence, can be controlled precisely by adjusting reaction chamber assignment and input nucleoside composition. The microchip-synthesized oligonucleotides were used for construction of single-chain antibody fragment (scFv) phage libraries through one-step mutagenic PCR of double stranded plasmids with >10(6)E. coli transformants. A variant with combinatorial mutations from four individual CDRs achieved more than 19-fold affinity increase. The strategy described herein should be broadly applicable to affinity and selectivity studies of antibodies and other proteins. PMID- 25444870 TI - Reprint of Design of synthetic microbial communities for biotechnological production processes. AB - In their natural habitats microorganisms live in multi-species communities, in which the community members exhibit complex metabolic interactions. In contrast, biotechnological production processes catalyzed by microorganisms are usually carried out with single strains in pure cultures. A number of production processes, however, may be more efficiently catalyzed by the concerted action of microbial communities. This review will give an overview of organismic interactions between microbial cells and of biotechnological applications of microbial communities. It focuses on synthetic microbial communities that consist of microorganisms that have been genetically engineered. Design principles for such synthetic communities will be exemplified based on plausible scenarios for biotechnological production processes. These design principles comprise interspecific metabolic interactions via cross-feeding, regulation by interspecific signaling processes via metabolites and autoinducing signal molecules, and spatial structuring of synthetic microbial communities. In particular, the implementation of metabolic interdependencies, of positive feedback regulation and of inducible cell aggregation and biofilm formation will be outlined. Synthetic microbial communities constitute a viable extension of the biotechnological application of metabolically engineered single strains and enlarge the scope of microbial production processes. PMID- 25444871 TI - Complete genome sequence of the novel Porphyromonadaceae bacterium strain ING2 E5B isolated from a mesophilic lab-scale biogas reactor. AB - In this study, the whole genome sequence of the mesophilic, anaerobic Porphyromonadaceae bacterium strain ING2-E5B (LMG 28429, DSM 28696) is reported. The new isolate belongs to the phylum Bacteroidetes and was obtained from a biogas-producing lab-scale completely stirred tank reactor (CSTR) optimized for anaerobic digestion of maize silage in co-fermentation with pig and cattle manure. The genome of strain ING2-E5B contains numerous genes encoding proteins and enzymes involved in the degradation of complex carbohydrates and proteinaceous compounds. Moreover, it possesses genes catalyzing the production of volatile fatty acids. Hence, this bacterium was predicted to be involved in hydrolysis and acidogenesis during anaerobic digestion and biomethanation. PMID- 25444873 TI - Overexpression of Serpinb1 in Chinese hamster ovary cells increases recombinant IgG productivity. AB - We report the discovery and validation of a novel CHO cell engineering target for improving IgG expression, serpin peptidase inhibitor, clade B, member 1 (Serpinb1). Transcriptomic studies using microarrays revealed that Serpinb1 was up-regulated in cultures with IgG heavy and light chain transcription transiently repressed compared with cultures treated with non-targeting siRNA. As proof of concept, a lentiviral vector was employed to overexpress the Chinese Hamster Serpinb1 in a CHOZN((r)) Glutamine Synthetase (-/-) recombinant IgG producing CHO line. The lentiviral stable pool demonstrated 4.2-fold SERPINB1 overexpression compared with the non-transduced control. The peak viable cell density (VCD) and peak IgG volumetric productivity of the lentiviral stable pool increased 1.3 and 2.0 fold, respectively, compared with the non-transduced control. For host cell engineering, a plasmid encoding SERPINB1 was transfected into the CHOZN((r)) GS ( /-) host cell line to create several stable pools. Single-cell clones isolated from the pools were characterized for their SERPINB1 expression levels and growth. The clone (SERPINB1_OE_27) with the highest SERPINB1 expression had decreased peak viable cell density and exponential phase growth rate. Selected SERPINB1 OE clones were subsequently evaluated for their IgG expression capabilities using GS selection. Clone SERPINB1_OE_42 with moderate SERPINB1 overexpression demonstrated increased IgG productivity in "bulk" selection. We conclude that manipulating Serpinb1 expression can lead to increased recombinant IgG productivity, but the effect in host cell lines may vary by clone and by overexpression level. This work represents the ongoing effort in applying " omics" findings to novel CHO host cell line engineering. PMID- 25444872 TI - siRNAs encapsulated in recombinant capsid protein derived from Dengue serotype 2 virus inhibits the four serotypes of the virus and proliferation of cancer cells. AB - siRNA delivery potential of the Dengue virus capsid protein in cultured cells was recently reported, but target knockdown potential in the context of specific diseases has not been explored. In this study we have evaluated the utility of the protein as an siRNA carrier for anti Dengue viral and anti cancer applications using cell culture systems. We show that target specific siRNAs delivered using the capsid protein inhibit infection by the four serotypes of Dengue virus and proliferation of two cancer cell lines. Our data confirm the potential of the capsid for anti Dengue viral and anti cancer RNAi applications. In addition, we have optimized a fermentation strategy to improve the yield of Escherichia coli expressed D2C protein since the reported yields of E. coli expressed flaviviral capsid proteins are low. PMID- 25444874 TI - Genome sequence of Serratia nematodiphila DSM 21420T, a symbiotic bacterium from entomopathogenic nematode. AB - Serratia nematodiphila DSM 21420(T) (=CGMCC 1.6853(T), DZ0503SBS1(T)), isolated from the intestine of Heterorhabditidoides chongmingensis, has been known to have symbiotic-pathogenic life cycle, on the multilateral relationships with entomopathogenic nematode and insect pest. In order to better understanding of this rare feature in Serratia species, we present here the genome sequence of S. nematodiphila DSM 21420(T) with the significance of first genome sequence in this species. PMID- 25444875 TI - Biocompatibility, uptake and endocytosis pathways of polystyrene nanoparticles in primary human renal epithelial cells. AB - Recent years have witnessed an unprecedented growth in the number of applications such as drug delivery, nutraceuticals and production of improved biocompatible materials-in the areas of nanoscience and nanotechnology. Engineered nanoparticles (NPs) are an important tool for the development of quite a few of these applications. Despite intense research activity, mechanisms regulating the uptake of NPs into cells are not completely defined, being the phenomenon dramatically influenced by physico-chemical properties of NPs and cell-specific differences. Since the cellular uptake of NPs is a prerequisite for their use in nanomedicine, the definition of their internalization pathway is crucial. For this reason, we used 44 nm polystyrene NPs as a model to analyze the uptake and endocytosis pathways in primary human renal cortical epithelial (HRCE) cells, which play a key role in the clearance of drugs. NPs were found not to affect the viability and cell cycle progression of HRCE cells. Distinct internalization pathways were analyzed by the use of drugs known to inhibit specific endocytosis routes. Analyses, performed by confocal microscopy in combination with quantitative spectrofluorimetric assays, indicated that NPs enter HRCE cells through multiple mechanisms, either energy-dependent (endocytosis) or energy independent. PMID- 25444876 TI - Extreme furfural tolerance of a soil bacterium Enterobacter cloacae GGT036. AB - Detoxification process of cellular inhibitors including furfural is essential for production of bio-based chemicals from lignocellulosic biomass. Here we isolated an extreme furfural-tolerant bacterium Enterobacter cloacae GGT036 from soil sample collected in Mt. Gwanak, Republic of Korea. Among isolated bacteria, only E. cloacae GGT036 showed cell growth with 35 mM furfural under aerobic culture. Compared to the maximal half inhibitory concentration (IC50) of well-known industrial strains Escherichia coli (24.9 mM furfural) and Corynebacterium glutamicum (10 mM furfural) based on the cell density, IC50 of E. cloacae GGT036 (47.7 mM) was significantly higher after 24 h, compared to E. coli and C. glutamicum. Since bacterial cell growth was exponentially inhibited depending on linearly increased furfural concentrations in the medium, we concluded that E. cloacae GGT036 is an extreme furfural-tolerant bacterium. Recently, the complete genome sequence of E. cloacae GGT036 was announced and this could provide an insight for engineering of E. cloacae GGT036 itself or other industrially relevant bacteria. PMID- 25444878 TI - Blockage of the pyrimidine biosynthetic pathway affects riboflavin production in Ashbya gossypii. AB - The Ashbya gossypii riboflavin biosynthetic pathway and its connection with the purine pathway have been well studied. However, the outcome of genetic alterations in the pyrimidine pathway on riboflavin production by A. gossypii had not yet been assessed. Here, we report that the blockage of the de novo pyrimidine biosynthetic pathway in the recently generated A. gossypii Agura3 uridine/uracil auxotrophic strain led to improved riboflavin production on standard agar-solidified complex medium. When extra uridine/uracil was supplied, the production of riboflavin by this auxotroph was repressed. High concentrations of uracil hampered this (and the parent) strain growth, whereas excess uridine favored the A. gossypii Agura3 growth. Considering that the riboflavin and the pyrimidine pathways share the same precursors and that riboflavin overproduction may be triggered by nutritional stress, we suggest that overproduction of riboflavin by the A. gossypii Agura3 may occur as an outcome of a nutritional stress response and/or of an increased availability in precursors for riboflavin biosynthesis, due to their reduced consumption by the pyrimidine pathway. PMID- 25444877 TI - Complete genome sequence of Thermococcus eurythermalis A501, a conditional piezophilic hyperthermophilic archaeon with a wide temperature range, isolated from an oil-immersed deep-sea hydrothermal chimney on Guaymas Basin. AB - Thermococcus eurythermalis A501 is a conditional piezophilic hyperthermophilic archaeon, isolated from an oil-immersed hydrothermal chimney located on Guaymas Basin. This isolate is an anaerobic chemoorgano-heterotroph and can grow over wide temperature, pressure and pH ranges. The genome consists of one circular chromosome (2,122,535 bp) and one plasmid (3629 bp) as the extra-chromosome DNA. The genomic information will contribute to studying extreme adaptation in hydrothermal vent and also the development of industrial enzymes with high stability under extreme condition. PMID- 25444879 TI - Complete genome sequence of probiotic Lactobacillus plantarum P-8 with antibacterial activity. AB - Lactobacillus plantarum P-8 is a probiotic bacterium, which shows high antibacterial activity. The genome consists of a circular 3,033,693-bp chromosome and six plasmids. Bioinformatics inspection of the genome revealed a gene cluster relating to bacteriocin production. Genome information has provided the basis for understanding the potential molecular mechanism behind the bacteriocin production. PMID- 25444880 TI - Complete genome sequence of Enterobacter cloacae GGT036: a furfural tolerant soil bacterium. AB - Enterobacter cloacae is a facultative anaerobic bacterium to be an important cause of nosocomial infection. However, the isolated E. cloacae GGT036 showed higher furfural-tolerant cellular growth, compared to industrial relevant strains such as Escherichia coli and Corynebacterium glutamicum. Here, we report the complete genome sequence of E. cloacae GGT036 isolated from Mt. Gwanak, Seoul, Republic of Korea. The genomic DNA sequence of E. cloacae GGT036 will provide valuable genetic resources for engineering of industrially relevant strains being tolerant to cellular inhibitors present in lignocellulosic hydrolysates. PMID- 25444881 TI - An innovative wood-chip-framework soil infiltrator for treating anaerobic digested swine wastewater and analysis of the microbial community. AB - Combined anaerobic-aerobic processes are efficacious and economic approaches in treating swine wastewater. Nitrogen removal efficiency of these processes, however, is usually limited due to the low carbon/nitrogen (C/N) ratio of the wastewater. An innovative wood-chip-framework soil infiltrator (WFSI) was developed and its performance in treating anaerobic digested swine wastewater was investigated. The WFSI showed comparable removal of chemical oxygen demand (COD) and amongst the highest efficiency of nitrogen removal in treating low C/N wastewater. At a COD volume loading rate of 98.6 g/m3 d the WFSI could remove up to 47.7 g/m3 d of COD. Removal rates of NH4+-N and total nitrogen, also reached 69.1 and 30.4 g/m3 d, respectively, when NH4+-N loading rate was 88.4 g/m3 d. Biological analysis indicated that aerobic, anoxic and anaerobic microbiota occurred throughout the WFSI. Abundant cellulose and lignin decomposing bacteria could degrade the wood chips and provided extra carbon source to enhance denitrification. PMID- 25444882 TI - Bioelectrochemical removal of carbon dioxide (CO2): an innovative method for biogas upgrading. AB - Innovative methods for biogas upgrading based on biological/in-situ concepts have started to arouse considerable interest. Bioelectrochemical removal of CO2 for biogas upgrading was proposed here and demonstrated in both batch and continuous experiments. The in-situ biogas upgrading system seemed to perform better than the ex-situ one, but CO2 content was kept below 10% in both systems. The in-situ system's performance was further enhanced under continuous operation. Hydrogenotrophic methanogenesis and alkali production with CO2 absorption could be major contributors to biogas upgrading. Molecular studies showed that all the biocathodes associated with biogas upgrading were dominated by sequences most similar to the same hydrogenotrophic methanogen species, Methanobacterium petrolearium (97-99% sequence identity). Conclusively, bioelectrochemical removal of CO2 showed great potential for biogas upgrading. PMID- 25444883 TI - Effects of metal ions on the hydrolysis of bamboo biomass in 1-butyl-3 methylimidazolium chloride with dilute acid as catalyst. AB - In this study, the effects of six metal ions including Na+, K+, Mg2+, Ca2+, Cu2+ and Fe3+ on hydrolysis of bamboo biomass by diluted hydrochloride acid (HCl) in ionic liquid [C4mim]Cl under mild conditions was investigated. These metal ions as co-catalysts exhibited significant effects on accelerating the hydrolysis process and improving the yield of total reducing sugar compared to single diluted hydrochloride acid hydrolysis in [C4mim]Cl at the same conditions. The most effective ion was Cu2+ and the total reducing sugar yield of 67.1% was achieved at 100 degrees C with CuCl2 as co-catalyst after 4-h reaction. The total reducing sugar yield was increased by about 7% and the reaction time was decreased by 3 h. The kinetic model was also investigated to give an insight into the mechanism of hydrolysis process. PMID- 25444884 TI - Growth and lipid accumulation characteristics of Scenedesmus obliquus in semi continuous cultivation outdoors for biodiesel feedstock production. AB - In an effort to identify suitable microalgal species for biodiesel production, seven species were isolated from various habitats and their growth characteristics were compared. The results demonstrated that a green alga Scenedesmus obliquus could grow more rapidly and synthesize more lipids than other six microalgal strains. S. obliquus grew well both indoors and outdoors, and reached higher MUmax indoors than that outdoors. However, the cells achieved higher dry weight (4.36 g L(-1)), lipid content (49.6%) and productivity (183 mg L(-1) day(-1)) outdoors than in indoor cultures. During the 61 days semi continuous cultivation outdoors, high biomass productivities (450-550 mg L(-1) day(-1)) and MUmax (1.05-1.44 day(-1)) were obtained. The cells could also achieve high lipid productivities (151-193 mg L(-1) day(-1)). These results indicated that S. obliquus was promising for lipids production in semi-continuous cultivation outdoors. PMID- 25444885 TI - Enzymatic and acid hydrolysis of Tetraselmis suecica for polysaccharide characterization. AB - Carbohydrate composition of the marine microalgae, Tetraselmis suecica was characterized following acidic and enzymatic hydrolysis. Monitoring intracellular starch as a function of cultivation time at varying nitrate concentrations showed a maximum cellular starch content of 45% of dry biomass when grown under nitrate depleted conditions. Characterization of the cell wall methanolysates using GC/MS showed that the monosaccharide composition did not change in response to the nitrate concentration and consisted of 54% 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo), 17% 3-deoxy-lyxo-2-heptulosaric acid (Dha), 21% galacturonic acid and 6% galactose. Presence of up to 5% Kdo in the dry weight of T. suecica established in this study demonstrates the potential of the cell wall of this species as a feedstock for Kdo, a sugar that is difficult to obtain by chemical synthesis and that has applications in medicinal chemistry. PMID- 25444886 TI - Optimisation of digester performance with increasing organic loading rate for mono- and co-digestion of grass silage and dairy slurry. AB - This study investigated the feasibility of mono-digesting grass silage, dairy slurry and the co-digestion of the two substrates at a range of concentrations with a specific focus on digester performance while increasing organic loading rate (OLR). The results show that the higher the proportion of grass silage in the substrate mix the higher the specific methane yield (SMY) achieved. Optimum conditions were assessed for 100% grass silage at an OLR of 3.5 kg VS m(-3) d(-1) generating a SMY of 398 L CH4 kg(-1) VS equating to a biomethane efficiency of 1.0. For co-digestion of grass silage with 20% dairy slurry the optimum condition was noted at an OLR of 4.0 kg VS m(-3) d(-1) generating a SMY of 349L CH4 kg(-1) VS and a biomethane efficiency of 1.01. Hydraulic retention times of less than 20 days proved to be a limiting factor in the operation of farm digesters. PMID- 25444887 TI - Logistics cost analysis of rice residues for second generation bioenergy production in Ghana. AB - This study explores the techno-economic potential of rice residues as a bioenergy resource to meet Ghana's energy demands. Major rice growing regions of Ghana have 70-90% of residues available for bioenergy production. To ensure cost-effective biomass logistics, a thorough cost analysis was made for two bioenergy routes. Logistics costs for a 5 MWe straw combustion plant were 39.01, 47.52 and 47.89 USD/t for Northern, Ashanti and Volta regions respectively. Logistics cost for a 0.25 MWe husk gasification plant (with roundtrip distance 10 km) was 2.64 USD/t in all regions. Capital cost (66-72%) contributes significantly to total logistics costs of straw, however for husk logistics, staff (40%) and operation and maintenance costs (46%) dominate. Baling is the major processing logistic cost for straw, contributing to 46-48% of total costs. Scale of straw unit does not have a large impact on logistic costs. Transport distance of husks has considerable impact on logistic costs. PMID- 25444888 TI - Production of 5-hydroxymethylfurfural from corn stalk catalyzed by corn stalk derived carbonaceous solid acid catalyst. AB - A carbonaceous solid acid was prepared by hydrothermal carbonization of corn stalk followed by sulfonation and was characterized by FT-IR, XRD, SEM and elemental analysis techniques. The as-prepared corn stalk-derived carbonaceous solid acid catalyst contained SO3H, COOH, and phenolic OH groups, and was used for the one-step conversion of intact corn stalk to 5-hydroxymethylfurfural (5 HMF) in the ionic liquid 1-butyl-3-methyl imidazolium chloride ([BMIM][Cl]), where a 5-HMF yield of 44.1% was achieved at 150 degrees C in 30 min reaction time. The catalytic system was applicable to initial corn stalk concentration of up to ca. 10 wt.% for the production of 5-HMF. The synthesized catalyst and the developed process of using corn stalk-derived carbon catalyst for corn stalk conversion provide a green and efficient strategy for crude biomass utilization. PMID- 25444889 TI - Use of meconium in perinatal epidemiology: potential benefits and pitfalls. AB - PURPOSE: Meconium is a biomarker matrix that can be used to assess cumulative exposures in epidemiologic studies of prenatal risk factors. Depending on when meconium is collected, different exposure windows during pregnancy can be measured. However, little guidance exists regarding the extent to which timing of meconium collection will influence resulting effect estimates. METHODS: We performed a simulation study of prenatal tobacco smoke exposure (assessed from meconium nicotine) and birth weight. We discuss four typical meconium collection methods capturing different exposure windows and assess the biases induced by these methods. RESULTS: In simulations assuming that exposure to tobacco smoke only during late gestation was of etiologic relevance to birth weight, use of a meconium collection method that captured exposure windows other than late gestation resulted in biased estimates of the true nicotine-birth weight association. CONCLUSIONS: Using meconium collection methods that do not reflect an exposure window of etiologic relevance can lead to biased results and erroneous conclusions regarding the nature of prenatal exposure-outcome associations. Understanding how prenatal exposure patterns vary across the pregnancy and exposure windows of etiologic relevance is essential in determining when and how to collect meconium for use in biomarker studies of prenatal exposure. PMID- 25444891 TI - A high risk of hyperlipidemia in epilepsy patients: a nationwide population-based cohort study. AB - PURPOSE: This study evaluated the effect of epilepsy on the development of hyperlipidemia (HL) in Taiwan. METHODS: We conducted a nationwide population based cohort study based on data obtained from the National Health Insurance Research Database of Taiwan. We identified 990 cases involving patients whose epilepsy was newly diagnosed between 2000 and 2005, and we also selected a comparison cohort comprising 3960 patients without epilepsy. Cox proportional hazards regression models were used to examine the association between epilepsy and HL. RESULTS: The mean follow-up period was 6.63 years for the epilepsy cohort and 7.49 years for the comparison cohort. The incidence rate of HL was 1.28-fold higher in the epilepsy cohort than it was in the comparison cohort (34.14 vs. 26.96 per 1000 person-years), with an adjusted hazard ratio of 1.17 (95% confidence interval, 1.01-1.36) after adjusting the model to account for the effects of sex and comorbidities. The most at-risk patients were those aged 50 to 59 years (hazard ratio, 1.35; 95% confidence interval, 1.04-1.79). For the epilepsy patients, the combined effect of ischemic heart disease, hypertension, and diabetes was associated with a significantly higher risk of developing HL compared with the patients with neither epilepsy nor any comorbidity. CONCLUSIONS: Middle-aged epilepsy patients are at a significantly higher risk of developing HL. The results could assist in explaining the high risk of cerebral and cardiac vascular disease in epilepsy patients. PMID- 25444890 TI - Blood spot-based measures of glucose homeostasis and diabetes prevalence in a nationally representative population of young US adults. AB - PURPOSE: We investigated understudied biomarker-based diabetes among young US adults, traditionally characterized by low cardiovascular disease risk. METHODS: We examined 15,701 participants aged 24 to 32 years at Wave IV of the National Longitudinal Study of Adolescent Health (Add Health, 2008). The study used innovative and relatively noninvasive methods to collect capillary whole blood via finger prick at in-home examinations in all 50 states. RESULTS: Assays of dried blood spots produced reliable and accurate values of HbA1c. Reliability was lower for fasting glucose and lowest for random glucose. Mean (SD) HbA1c was 5.6% (0.8%). More than a quarter (27.4%) had HbA1c-defined prediabetes. HbA1c was highest in the black, non-Hispanic race/ethnic group, inversely associated with education, and more common among the overweight/obese and physically inactive. The prevalence of diabetes defined by previous diagnosis or use of antidiabetic medication was 2.9%. Further incorporating HbA1c and glucose values, the prevalence increased to 6.8%, and among these participants, 38.9% had a previous diagnosis of diabetes (i.e., aware). Among those aware, 37.6% were treated and 64.0% were controlled (i.e., HbA1c < 7%). CONCLUSIONS: A contemporary cohort of young adults faces a historically high risk of diabetes but there is ample opportunity for early detection and intervention. PMID- 25444893 TI - Impact of high-fidelity transvaginal ultrasound simulation for radiology on residents' performance and satisfaction. AB - RATIONALE AND OBJECTIVES: Because of the intimate and uncomfortable nature of transvaginal ultrasound, training residents to perform this type of examination is a difficult task. As a consequence, residents may receive inadequate training that leads to a lack of the skills and confidence needed to perform this examination. The aim of the study was to assess the effectiveness of using simulation sessions to teach residents how to perform transvaginal ultrasound, enabling them to diagnose obstetric and gynecologic emergencies and helping them survive on-calls alone while keeping their patients safe. MATERIALS AND METHODS: We used an experimental study design to compare the confidence levels of 20 senior residents who received clinical training only to those of 25 junior residents who were enrolled in a simulation-based teaching session. We also compared the junior residents' levels of performance and confidence using transvaginal ultrasound before and after the sessions. RESULTS: The performance of transvaginal ultrasound by the junior residents and their confidence levels significantly improved after they attended the simulation sessions. They had higher levels of confidence than the senior residents who did not attend the session. It was also observed that the number of nondiagnostic transvaginal ultrasounds performed by the on-call resident that needed to be repeated the next day had significantly dropped. CONCLUSIONS: Simulation-based teaching sessions are an effective method of education, which improve trainees' skills and confidence levels and improve patient safety. PMID- 25444892 TI - Very low maternal lead level in pregnancy and birth outcomes in an eastern Massachusetts population. AB - PURPOSE: Maternal lead exposure is associated with poor birth outcomes in populations with moderate to high blood levels. However, no studies have looked at exposure levels commonly experienced by US women. METHODS: We evaluated the relationship between maternal red blood cell (RBC) lead levels in midpregnancy and birth outcomes in 949 mother-child pairs in a prebirth cohort. We used multiple linear regression and logistic regression, adjusted for potential confounders including maternal age, race, prepregnancy body mass index, and smoking to relate maternal lead to infant birth size and risk for preterm birth (<37 weeks). RESULTS: Mean RBC lead level was 1.2 MUg/dL (range, 0.0-5.0). Mean (standard deviation) birthweight was 3505 (520) g, birthweight for gestational age z-score 0.22 (0.93), and length of gestation 39.5 (1.7) weeks. Mothers in the highest versus lowest lead quartile did not have higher odds (OR, 1.85; 95% confidence interval [CI], 0.79-4.34) of preterm delivery; after stratifying by child sex, there was an association among males (OR, 5.51; 95% CI, 1.21-25.15) but not females (OR, 0.82; 95% CI, 0.24-2.85). Maternal RBC lead was not associated with any continuous outcomes in combined or sex-stratified analyses. CONCLUSIONS: Maternal lead exposure, even at very low levels, may adversely affect some childbirth outcomes, particularly preterm birth among males. PMID- 25444895 TI - OVA12, a novel tumor antigen, promotes cancer cell growth and inhibits 5 fluorouracil-induced apoptosis. AB - To achieve a better understanding of mechanisms that underlie carcinogenesis and to identify novel target molecules for diagnosis and therapy of carcinoma, we previously identified 24 distinct gene clones by immunoscreening of a cDNA library derived from an ovarian cancer patient through SEREX analysis. Among these genes we focused on a novel gene termed OVA12 and which putatively encodes a 114-amino-acid protein. In the present study, we found that OVA12 was ubiquitously overexpressed in diverse human tumor cell lines. Interestingly, we noticed that overexpression of OVA12 promoted proliferation of cancer cells in vitro and accelerated tumor growth in nude mice as compared to controls. Conversely, specific downregulation of OVA12 inhibited tumor cell proliferation and tumor growth both in vitro and in vivo. Furthermore, OVA12 inhibited 5-FU induced apoptosis through specific upregulation of Mcl-1 and survivin. These results demonstrate that OVA12 is able to promote tumor growth, suggesting that this antigen might be a new potential target for development of cancer therapy. PMID- 25444894 TI - Oncolytic reovirus combined with trastuzumab enhances antitumor efficacy through TRAIL signaling in human HER2-positive gastric cancer cells. AB - The human epidermal growth factor receptor 2 (HER2)-targeting agent, trastuzumab, is effective for HER2-overexpressing gastric cancer therapy. As oncolytic reovirus is currently undergoing clinical trials internationally, we wanted to explore whether combination therapy using trastuzumab and reovirus might provide a novel, more effective therapeutic option for gastric cancer. Cell proliferation and cell apoptosis were examined in vitro, while molecular analysis of pathways responsible for cell damage was examined using polymerase chain reaction array. Activation of the proteins related to apoptosis, cell growth and survival was detected by Western blotting. Mouse tumor xenograft models were used to examine antitumor activity in vivo. Reovirus sensitized HER2-overexpressing gastric cancer cells to undergo apoptosis. Both in vitro and in vivo studies provided evidence that the combination therapy is a more powerful modality against HER2 overexpressing gastric cancer cells than treatment using a single agent. Molecular analysis indicated that combination therapy induced significantly higher levels of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in cancer cells. Antibody against TRAIL strongly inhibited cell toxicity caused by the combined treatment. These data suggest that reovirus may augment trastuzumab-induced cytotoxicity in gastric cancer cells. PMID- 25444896 TI - Oxovanadium-based inhibitors can drive redox-sensitive cytotoxicity in neuroblastoma cells and synergise strongly with buthionine sulfoximine. AB - In a wide range of neuroblastoma-derived lines oxovanadium compounds such as bis(maltolato)oxovanadium(IV) (BMOV) are cytotoxic. This is not explained by oxidative stress or inhibition of ion channels. Genotoxicity is unlikely given that a p53 response is absent and p53-mutant lines are also sensitive. Cytotoxicity is inhibited by N-acetyl cysteine and glutathione ester, indicating that BMOV action is sensitive to cytoplasmic redox and thiol status. Significantly, combining BMOV with glutathione synthesis inhibition greatly enhances BMOV-induced cell death. This combination treatment triggers high AKT pathway activation, highlighting the potential functional importance of PTP inhibition by BMOV. AKT activation itself, however, is not required for cytotoxicity. Oxovanadium compounds may thus represent novel leads as p53 independent therapeutics for neuroblastoma. PMID- 25444897 TI - Heterogeneity in cancer stem cells. AB - Accumulating evidence suggests that cancer stem cells (CSCs) are heterogeneous populations and their phenotypes are unstable. A number of intrinsic and extrinsic mechanisms contribute to CSC phenotypic variation. The existence of various CSC subpopulations which would lead to a rapid relapse after primary treatments might pose a problem for CSC targeted therapeutics. In order to develop more effective approaches to cancer therapeutics, more CSC-related surface markers or targeting molecules, as well as some novel targeting strategies should be explored. This review summarized the origin and performance of heterogeneity in CSCs and discussed their therapeutic implications. PMID- 25444898 TI - DNAJB1 destabilizes PDCD5 to suppress p53-mediated apoptosis. AB - Although PDCD5 promotes p53-mediated apoptosis in various cancers, little is known about PDCD5 regulation. We recently found that DNAJB1 interacts with PDCD5 and induces the ubiquitin-dependent proteasomal degradation of PDCD5, thereby inhibiting p53-mediated apoptosis. To investigate these novel roles for PDCD5 and DNAJB1, we performed DNAJB1 mapping with PDCD5. PDCD5 specifically binds to the DNAJB1-D5 domain (Delta180-210), which was found to be essential for the stabilization of PDCD5. Further study showed that DNAJB1 post-translationally regulates PDCD5 stability. DNAJB1 ubiquitinated PDCD5 via a ubiquitin-mediated pathway. In human lung A549 cancer cells, DNAJB1 promoted the ubiquitination and degradation of PDCD5 and inhibited p53 activation. However, DNAJB1 knockdown in A549 cells increased the etoposide-induced activation of the p53-mediated apoptosis pathway and repressed cancer cell growth. Because this function was p53 dependent, DNAJB1 depletion increased the expression of p53-targeted apoptosis genes. In conclusion, we screened a novel PDCD5-associating protein, DNAJB1, by yeast two-hybrid screening and provided evidences that DNAJB1 targets PDCD5 to suppress p53-dependent apoptosis of cancer cells. Thus, we identified DNAJB1 as a negative regulator of PDCD5-mediated apoptosis and found that the apoptosis network of PDCD5 regulates cancer cell death. PMID- 25444899 TI - Skin cancer and new treatment perspectives: a review. AB - Skin cancers are by far the most common malignancy of humans, particularly in the white population. The growing incidence of cutaneous malignancies has heralded the need for multiple treatment options. Although surgical modalities remain the mainstay of treatment, new research and fresh innovation are still required to reduce morbidity and mortality. Approaches for skin cancer may pass through new technological methods instead of new molecules. The first part of this paper provides a review of the state of the art regarding skin cancer disease as well as epidemiology data. Then, it describes the gold standards of the current recommended therapies worldwide and the actual needs of these patients. This is the first paper that highlights the novel and future therapeutic perspectives for the treatment of skin malignancies, new therapeutic agents and promising technological approaches, from nanotechnology to immunotherapy. PMID- 25444900 TI - MiR-193a-3p promotes the multi-chemoresistance of bladder cancer by targeting the HOXC9 gene. AB - Chemoresistance prevents the curative cancer chemotherapy and presents a formidable challenge for both cancer researchers and clinicians. We have previously shown that miR-193a-3p promotes the multi-chemoresistance of bladder cancer cells via repressing its three target genes: SRSF2, PLAU and HIC2. Here, we showed that as a new direct target, the homeobox C9 (HOXC9) gene also executes the promoting effect of miR-193a-3p on the bladder cancer chemoresistance from a systematic study of multi-chemosensitive (5637) and resistant (H-bc) bladder cancer cell lines in both cell culture and tumor-xenograft/nude mice system. Paralleled with the changes in the drug-triggered cell death, the activities of both DNA damage response and oxidative stress pathways were drastically altered by a forced reversal of miR-193a-3p or HOXC9 levels in bladder cancer cells. In addition to a new mechanistic insight, our results provide a set of the essential genes in the miR-193a-3p/HOXC9/DNA damage response/oxidative stress pathway axis as the diagnostic targets for the guided anti-bladder cancer chemotherapy. PMID- 25444901 TI - A small peptide derived from p53 linker region can resume the apoptotic activity of p53 by sequestering iASPP with p53. AB - One of the most important tumor suppression functions of p53 is its ability to induce apoptosis. iASPP is an inhibitory member of the ASPP protein family. It can specifically inhibit the normal function of p53 as a suppressor. The mechanism of iASPP suppressing the cell apoptotosis is through inhibiting the transactivation function of p53 on the promoters of proapoptotic genes by binding with p53. Therefore, relieving the combination of iASPP with p53 and leaving p53 free may be a useful strategy to activate p53 function. We therefore use A34, a small peptide derived from p53 linker region, to investigate the possibility of resuming the apoptosis activity of p53 by sequestering iASPP with p53 and derepressing p53. The results show that A34 can competitively combine with iASPP and therefore release p53 from iASPP; A34 can enhance the transcriptional activity of p53 on the promoters of Bax and PUMA; A34 can increase cell apoptosis and slow tumor growth in vitro and vivo. This study will open the way for using small molecule peptides that directly disturb the interaction of p53 with iASPP, thereby resume function of p53 as a suppressor. PMID- 25444902 TI - EZH2 is a negative prognostic factor and exhibits pro-oncogenic activity in glioblastoma. AB - The identification of single or less genes based on mRNA expression as clinical diagnostic markers for glioblastoma (GBM) remains a challenge. Recent data have shown the potential oncogenic role and prognostic significance of EZH2 in several human cancers. However, the clinical signature and further mechanisms of EZH2 function in gliomagenesis are still poorly understood. In this study, we found that increased EZH2 expression was associated with tumor grade. High expression of EZH2 in GBM was determined to be a strong and independent predictor of short overall survival. Further, we screened EZH2 targets and associated genes in GBM. Repression of EZH2 induced cell cycle arrest and inhibited tumor growth in vivo. This event represents a positive feedback loop with beta-catenin/TCF4 and STAT3 signaling. Taken together, EZH2 could be an independent prognostic factor and potential therapeutic target for GBM. PMID- 25444903 TI - Expression of Sox2 in breast cancer cells promotes the recruitment of M2 macrophages to tumor microenvironment. AB - Transcriptional factor Sox2 promotes tumor metastasis; however its regulatory effect on tumor-associated macrophages (TAMs, M2 phenotype) has not been defined. This study disclosed concomitant expression of TAMs marker-CD163 with SOX2 in human breast cancer and showed that Sox2 in breast cancer cells promotes recruitment of TAMs with altered expression of multiple chemokines, including MIP 1alpha, ICAM-1 etc. and activation of Stat3 and NF-kappaB signalings. In addition, TAMs rescued the compromised lung metastasis induced by Sox2 silencing in breast cancer cells. Together, this study documented that Sox2 plays an important role in recruiting TAMs and promotes tumor metastasis in a TAMs dependent manner. PMID- 25444904 TI - Targeted anticancer effect through microRNA-181a regulated tumor-specific hTERT replacement. AB - We previously generated a group I intron-based ribozyme that can reprogram human telomerase reverse transcriptase (hTERT) RNA to stimulate transgene activity in cancer cells expressing the target RNA via an accurate and specific trans splicing reaction. One of the major concerns of the hTERT RNA targeting anti cancer approach is the potential side effects to hTERT(+) hematopoietic stem cell derived blood cells. Thus, here we modified the ribozyme by inserting target sites against microRNA-181a, which is a blood cell-specific microRNA, downstream of its 3' exon. The specificity of transgene induction and anticancer activity in hTERT(+) cancer cells improved significantly with the modified ribozyme, resulting in selective targeting of hTERT(+) cancer cells, but not hematopoietic cells even if they are hTERT-positive. Importantly, the trans-splicing reaction of the microRNA-regulated ribozyme worked equally well in a nude mouse model of hepatocarcinoma-derived intrasplenic carcinomatosis, inducing highly specific expression of a therapeutic transgene and efficiently regressing hTERT-positive liver tumors with minimal liver toxicity when systemically delivered with an adenoviral vector encoding the ribozyme. These results suggest that a combined approach of microRNA regulation with targeted RNA replacement is more useful for effective anti-cancer treatment. PMID- 25444905 TI - Long noncoding RNAs: novel insights into gastric cancer. AB - Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides. Recent advances in the non-protein coding part of human genome analysis have discovered extensive transcription of large RNA transcripts that lack coding protein function, termed non-coding RNA (ncRNA). It is becoming evident that lncRNAs may be an important class of pervasive genes involved in carcinogenesis and metastasis. However, the biological and molecular mechanisms of lncRNAs in diverse diseases are not yet fully understood. Thus, it is anticipated that more efforts should be made to clarify the lncRNA world. Moreover, accumulating evidence has demonstrated that many lncRNAs are dysregulated in gastric cancer (GC) and closely related to tumorigenesis, metastasis, and prognosis or diagnosis. In this review, we will briefly outline the regulation and functional role of lncRNAs in GC. Finally, we discussed the potential of lncRNAs as prospective novel targets in GC treatment and biomarkers for GC diagnosis. PMID- 25444908 TI - beta-Arrestin1 promotes the self-renewal of the leukemia-initiating cell-enriched subpopulation in B-lineage acute lymphoblastic leukemia related to DNMT1 activity. AB - The self-renewal ability of the leukemia initiating cell-enriched subpopulation is critical for leukemia initiation and maintenance. However, the regulation of leukemia initiating cells for the leukemia progression is poorly understood. In this study, we observed that beta-Arrestin1, a multiple-function protein, is elevated in leukemia initiating cells-enriched fraction from B-lineage acute lymphoblastic leukemia patients. The loss of beta-Arrestin1 in leukemia initiating cells-enriched fraction attenuates its self-renewal capacity both in vitro and in vivo. Further experiments showed that the mRNA expression level of beta-Arrestin1 is negatively correlated with that of PTEN in leukemia initiating cells-enriched fraction. Moreover, DNA methylation of the PTEN promoter region, the activity and expression of DNMTs were enhanced in the leukemia initiating cells-enriched fraction. The inhibition of DNMT1 activity impaired the self renewal and increased expression of PTEN of leukemia initiating cells-enriched fraction. In addition, depletion of beta-Arrestin1 significantly decreased DNMT1 activity and PTEN methylation, and consistently increased PTEN expression in leukemia initiating cells-enriched fraction. Our study reveals a novel function of beta-Arrestin1 in the regulation of the self-renewal of leukemia initiating cells-enriched fraction from B-lineage acute lymphoblastic leukemia patients related to DNMT1 activity, indicating that beta-Arrestin1 is a potential therapeutic target in B-lineage acute lymphoblastic leukemia. PMID- 25444906 TI - Adeno-associated virus-mediated cancer gene therapy: current status. AB - Gene therapy is one of the frontiers of modern medicine. Adeno-associated virus (AAV)-mediated gene therapy is becoming a promising approach to treat a variety of diseases and cancers. AAV-mediated cancer gene therapies have rapidly advanced due to their superiority to other gene-carrying vectors, such as the lack of pathogenicity, the ability to transfect both dividing and non-dividing cells, low host immune response, and long-term expression. This article reviews and provides up to date knowledge on AAV-mediated cancer gene therapy. PMID- 25444907 TI - Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer. AB - Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5%, 21.7%, 17.4%, 17.4%, 13.0%, and 8.7%, respectively. Other genes with deleterious mutations in >=3 (13.0%) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1. Of 315 mutations detected in the primary tumors, 293 (93%) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies. PMID- 25444909 TI - MiR-1181 inhibits stem cell-like phenotypes and suppresses SOX2 and STAT3 in human pancreatic cancer. AB - Recent studies have shown that cancer stem cells (CSCs) play an important role in the development of pancreatic cancer. Multiple oncogenes and signaling pathways have been confirmed to participate in the stemness maintenance and tumorigenicity of CSCs, including sex-determining region Y-box 2 (SOX2) and signal transduction and activation of transcription 3 (STAT3), which may provide novel therapeutic targets on pancreatic cancer. Here, we reported in pancreatic cancer tissues and cells that miR-1181 expression was markedly downregulated, and the low miR-1181 expression was associated with poorer overall survival and disease-free survival in pancreatic cancer patients. Furthermore, overexpression of miR-1181 inhibited, whereas downregulation of miR-1181 promoted, CSCs-like phenotypes in vitro and tumorigenicity in vivo in pancreatic cancer cells. Moreover, we demonstrated that miR-1181 directly suppressed SOX2 and STAT3 expression, resulting in downregulation of SOX2 and inhibition of the STAT3 pathway. Hence, our results suggest that miR-1181 plays a vital role in inhibiting the CSCs-like phenotypes in pancreatic cancer and might represent a potential target for anti-pancreatic cancer. PMID- 25444911 TI - UNC45A localizes to centrosomes and regulates cancer cell proliferation through ChK1 activation. AB - The UCS family of proteins regulates cellular functions through their interactions with myosin. Here we show that one member of this family, UNC45A, is also a novel centrosomal protein. UNC45A is required for cellular proliferation of cancer cell in vitro and for tumor growth in vivo through its ability to bind and regulate ChK1 nuclear-cytoplasmic localization in an Hsp90-independent manner. Immunocytochemical and biochemical fractionation studies revealed that UNC45A and ChK1 co-localize to the centrosome. Inhibition of UNC45A expression reduced ChK1 activation and its tethering to the centrosome, events required for proper centrosome function. Lack of UNC45A caused the accumulation of multi nucleated cells, consistent with a defect in Chk1 regulation of centrosomes. These findings identify a novel centrosomal function for UNC45A and its role in cell proliferation and tumorigenesis. PMID- 25444912 TI - Liposomal simvastatin inhibits tumor growth via targeting tumor-associated macrophages-mediated oxidative stress. AB - Statins possess antitumor actions at doses 100- to 500-fold higher than those needed to lower cholesterol levels. Thus, the antitumor efficacy of statins could be improved greatly by using tumor-targeted delivery systems. Therefore the present work aims to investigate the antitumor activity of long-circulating liposome-encapsulated simvastatin (LCL-SIM) versus free SIM in B16.F10 murine melanoma-bearing mice. Our results showed that LCL-SIM inhibits strongly the B16.F10 melanoma growth (by 85%) whereas free SIM was ineffective. Moreover, the antitumor activity of LCL-SIM depends on the presence of functional tumor associated macrophages (TAM) in tumor tissue and is mainly based on the reduction of the TAM-mediated oxidative stress as well as of the production of the hypoxia inducible factor 1 alpha (HIF-1 alpha) in tumors. In conclusion, our findings suggest that the antitumor activity of LCL-SIM on B16.F10 melanoma growth is a result of the tumor-targeting property of the liposome formulation and is tightly dependent on the presence of TAM in tumor tissue. PMID- 25444910 TI - Arsenic trioxide amplifies cisplatin toxicity in human tubular cells transformed by HPV-16 E6/E7 for further therapeutic directions in renal cell carcinoma. AB - Human papillomavirus (HPV) DNA integrations may affect therapeutic responses in cancers through ATM network-related DNA damage response (DDR). We studied whether cisplatin-induced DDR was altered in human HK-2 renal tubular cells immortalized by HPV16 E6/E7 genes. Cytotoxicity assays utilized thiazolyl blue dye and DDR was identified by gene expression differences, double-strand DNA breaks, ATM promoter activity, and analysis of cell cycling and side population cells. After cisplatin, HK-2 cells showed greater ATM promoter activity indicating activation of this network, but DDR was muted, since little gammaH2AX was expressed, DNA strand breaks were absent and cells continued cycling. When HK-2 cells were treated with the MDM2 antagonist inducing p53, nutlin-3, or p53 transcriptional activator, tenovin-1, cell growth decreased but cisplatin toxicity was unaffected. By contrast, arsenic trioxide, which by inhibiting wild-type p53 induced phosphatase-1 that serves responses downstream of p53, and by depolymerizing tubulin, synergistically enhanced cisplatin cytotoxicity including loss of SP cells. Our findings demonstrated that HPV16 E6/E7 altered DDR through p53-mediated cell growth controls, which may be overcome by targeting of WIP1 and other processes, and thus should be relevant for treating renal cell carcinoma. PMID- 25444913 TI - miR-145, targeting high-mobility group A2, is a powerful predictor of patient outcome in ovarian carcinoma. AB - MicroRNA-145 (miR-145) expression is downregulated in several human cancers, but its clinical and functional relevance to ovarian carcinoma has not yet been elucidated. This study addressed the hypothesis that miR-145 serves as a prognostic biomarker and a tumor suppressor that regulates the expression of high mobility group A2 (HMGA2) oncoprotein in ovarian cancer. Here, we found that low miR-145 expression and HMGA2 overexpression determined by qRT-PCR and immunohistochemistry significantly correlated with advanced stage, lymph node involvement, and distant metastasis in 74 ovarian carcinomas. Low miR-145 expression significantly correlated with tumor recurrence and worse overall survival (HR=8.62, P = 0.039). Transfection of pre-miR-145 resulted in reduced cell growth and migration, and increased apoptosis of ovarian cancer cells by TUNEL, colony forming, and cell migration assays. MiR-145 was found to directly target HMGA2 by luciferase assay and Western blotting. Our findings suggest that miR-145 functions as a tumor suppressor in ovarian cancer and directly targets HMGA2 oncoprotein. Low miR-145 and high HMGA2 expressions are potential biomarkers of poor prognosis of ovarian carcinoma and miR-145 is the more powerful predictor of patient outcome. PMID- 25444914 TI - Synergistic antitumor activity of withaferin A combined with oxaliplatin triggers reactive oxygen species-mediated inactivation of the PI3K/AKT pathway in human pancreatic cancer cells. AB - Application of oxaliplatin for the treatment of pancreatic cancer (PC) is restricted owing to its toxic side effects and drug resistance. We investigated how withaferin A (WA), a bioactive component isolated from the medicinal plant Withania somnifera, acts synergistically with oxaliplatin on human PC in vitro and in vivo. We found that WA enhanced oxaliplatin-induced growth suppression and apoptosis in PC cells dramatically through a mechanism involving mitochondrial dysfunction and inactivation of the PI3K/AKT pathway. Combination treatment resulted in significant accumulation of intracellular reactive oxygen species (ROS). Pretreatment of cells with the ROS scavenger N-acetylcysteine completely blocked the apoptosis induced by combination treatment, and recovered expression of AKT inactivation, which revealed the important role of ROS in apoptosis and AKT regulation. In vivo, combination therapy showed the strongest anti-tumor effects compared with single agents, without obvious additional toxicity. These results support the notion that combination treatment with oxaliplatin and WA could facilitate development of an effective strategy for PC treatment. PMID- 25444915 TI - The palladacycle, AJ-5, exhibits anti-tumour and anti-cancer stem cell activity in breast cancer cells. AB - Breast cancer is the most common malignancy amongst women worldwide but despite enormous efforts to address this problem, there is still limited success with most of the current therapeutic strategies. The current study describes the anti cancer activity of a binuclear palladacycle complex (AJ-5) in oestrogen receptor positive (MCF7) and oestrogen receptor negative (MDA-MB-231) breast cancer cells as well as human breast cancer stem cells. AJ-5 is shown to induce DNA double strand breaks leading to intrinsic and extrinsic apoptosis and autophagy cell death pathways which are mediated by the p38 MAP kinase. This study provides evidence that AJ-5 is potentially an effective compound in the treatment of breast cancer. PMID- 25444916 TI - Curcumin promotes apoptosis by activating the p53-miR-192-5p/215-XIAP pathway in non-small cell lung cancer. AB - Curcumin has attracted increasing interest as an anti-cancer drug for decades. The mechanisms of action involve multiple cancer-related signaling pathways. Recent studies highlighted curcumin has epigenetic regulatory effects on miRNA in cancers. In the present study, we demonstrated the proapoptotic effects of curcumin in vitro and in vivo. miRNA microarray and qPCR indicated that miR-192 5p and miR-215 were the most responsive miRNAs upon curcumin treatment in H460 and A427 cells. Functional studies showed miR-192-5p/215 were putative tumor suppressors in non-small cell lung cancer. Curcumin also promoted miR-192-5p/215 expressions in A549 cells (p53 wild type) but not in H1299 cells (p53-null). Conditional knockdown of p53 by tetracycline inducible expression system significantly abrogated curcumin-induced miR-192-5p/215 upregulation in the p53 wild-type H460, A427 and A549 cells. Conversely, ectopic expression of exogenous wild-type but not R273H mutant p53 in the p53-null H1299 cells enabled miR-192 5p/215 response to curcumin treatment. The proapoptotic effects of curcumin also depended on miR-192-5p/215 induction, and antagonizing miR-192-5p/215 expression attenuated curcumin-induced apoptosis in H460, A427 and A549 cells, but not in H1299 cells. Finally, X-linked inhibitor of apoptosis (XIAP) is proved to be a novel transcriptional target of miR-192-5p/215. Taken together, this study highlights that the proapoptotic effects of curcumin depend on miR-192-5p/215 induction and the p53-miR-192-5p/215-XIAP pathway is an important therapeutic target for non-small cell lung cancer. PMID- 25444917 TI - CCL5 promotes vascular endothelial growth factor expression and induces angiogenesis by down-regulating miR-199a in human chondrosarcoma cells. AB - Chondrosarcoma is a primary malignant bone cancer, with a potent capacity to invade locally and cause distant metastasis. Angiogenesis is a critical step in tumor growth and metastasis. Chemokine CCL5 (previously called RANTES) has been shown to facilitate tumor progression and metastasis. However, the relationship of CCL5 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma is mostly unknown. In this study, CCL5 increased VEGF expression and also promoted chondrosarcoma medium-mediated angiogenesis in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. MicroRNA analysis was performed in CCL5-treated chondrosarcoma cells versus control cells to investigate the mechanism of CCL5-mediated promotion of chondrosarcoma angiogenesis. Among the miRNAs regulated by CCL5, miR-199a was the most downregulated miRNA after CCL5 treatment. In addition, co-transfection with miR 199a mimic reversed the CCL5-mediated VEGF expression and angiogenesis in vitro and in vivo. Moreover, overexpression of CCL5 increased tumor-associated angiogenesis and tumor growth by downregulating miR-199a in the xenograft tumor angiogenesis model. Taken together, these results demonstrated that CCL5 promotes VEGF-dependent angiogenesis in human chondrosarcoma cells by downregulating miR 199a. PMID- 25444918 TI - Targeting pyruvate kinase M2 contributes to radiosensitivity of non-small cell lung cancer cells in vitro and in vivo. AB - Aerobic glycolysis, a metabolic hallmark of cancer, is associated with radioresistance in non-small cell lung cancer (NSCLC). Pyruvate kinase M2 isoform (PKM2), a key regulator of glycolysis, is expressed exclusively in cancers. However, the impact of PKM2 silencing on the radiosensitivity of NSCLC has not been explored. Here, we show a plasmid of shRNA-PKM2 for expressing a short hairpin RNA targeting PKM2 (pshRNA-PKM2) and demonstrate that treatment with pshRNA-PKM2 effectively inhibits PKM2 expression in NSCLC cell lines and xenografts. Silencing of PKM2 expression enhanced ionizing radiation (IR)-induced apoptosis and autophagy in vitro and in vivo, accompanied by inhibiting AKT and PDK1 phosphorylation, but enhanced ERK and GSK3beta phosphorylation. These results demonstrated that knockdown of PKM2 expression enhances the radiosensitivity of NSCLC cell lines and xenografts as well as may aid in the design of new therapies for the treatment of NSCLC. PMID- 25444919 TI - Piperine inhibits the growth and motility of triple-negative breast cancer cells. AB - Piperine, an alkaloid from black pepper, is reported to have anticancer activities. In this study, we investigated the effect of piperine on the growth and motility of triple-negative breast cancer (TNBC) cells. Piperine inhibited the in vitro growth of TNBC cells, as well as hormone-dependent breast cancer cells, without affecting normal mammary epithelial cell growth. Exposure to piperine decreased the percentage of TNBC cells in the G2 phase of the cell cycle. In addition, G1- and G2-associated protein expression was decreased and p21(Waf1/Cip1) expression was increased in piperine-treated TNBC cells. Piperine also inhibited survival-promoting Akt activation in TNBC cells and caused caspase dependent apoptosis via the mitochondrial pathway. Interestingly, combined treatment with piperine and gamma radiation was more cytotoxic for TNBC cells than gamma radiation alone. The in vitro migration of piperine-treated TNBC cells was impaired and expression of matrix metalloproteinase-2 and -9 mRNA was decreased, suggesting an antimetastatic effect by piperine. Finally, intratumoral administration of piperine inhibited the growth of TNBC xenografts in immune deficient mice. Taken together, these findings suggest that piperine may be useful in the treatment of TNBC. PMID- 25444920 TI - Pre-clinical evaluation of AZD-2014, a novel mTORC1/2 dual inhibitor, against renal cell carcinoma. AB - Here we found that dual mTORC1/2 inhibitor AZD-2014 significantly inhibited RCC cell survival and growth, with higher efficiency than conventional mTORC1 inhibitors rapamycin and RAD001. RCC cell apoptosis was also induced by AZD-2014. AZD-2014 disrupted mTORC1/2 assembly and activation, while downregulating HIF 1alpha/2alpha and cyclin D1 expressions in RCC cells. Meanwhile, AZD-2014 activated autophagy, detected by p62 degradation, Beclin-1/ATG-5 upregulation and light LC3B-I/-II conversion. Autophagy inhibition by pharmacologic or siRNA-based means increased AZD-2014 activity in vitro, causing substantial RCC cell apoptosis. In vivo, AZD-2014 was more efficient than RAD001 in inhibiting 786-0 xenografts and downregulating HIF-1alpha/2alpha or p-AKT (Ser-473). Finally, AZD 2014's activity in vivo was further enhanced by co-administration of the autophagy inhibitor 3-methyaldenine. We provide evidence for clinical trials of using AZD-2014 in RCC treatment. PMID- 25444921 TI - GNAI3 inhibits tumor cell migration and invasion and is post-transcriptionally regulated by miR-222 in hepatocellular carcinoma. AB - Guanine nucleotide binding protein, alpha inhibiting activity polypeptide 3 (GNAI3) is involved in many biological processes. However, its biological function in hepatocellular carcinoma (HCC) remains unclear. An immunohistochemical staining analysis revealed that GNAI3 protein was down regulated in HCC compared to non-cancerous liver. Furthermore, transwell assays indicated that GNAI3 inhibits HCC cell migration and invasion. Using software predictions and experimental screening, we found that miR-222 could directly bind to GNAI3 mRNA and decrease GNAI3 protein expression in HCC cells. Moreover, miR 222 was up-regulated in HCC and negatively correlated with GNAI3 protein expression. These results indicated that down-regulation of GNAI3 might be caused by up-regulation of miR-222 in HCC. In conclusion, GNAI3 was down-regulated by miR-222 in HCC, and this deregulation promoted migration and invasion of HCC. These findings extended our insight into the complex molecular mechanisms underlying the invasion and metastasis of HCC and may provide new therapeutic targets. PMID- 25444922 TI - The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells. AB - Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC), the most frequent form of primary liver tumour. The loss of function of the retinoblastoma (Rb) protein is an important event during liver carcinogenesis, but it is unclear whether the Rb status modulates the response of HCC cells to sorafenib. Here, we examined this question in HCC cells with reduced levels of Rb achieved through stable RNA interference. We show that HCC cells with reduced levels of Rb exhibit a two- to threefold increase in cell death induction upon exposure to sorafenib compared with controls. Sorafenib treatment of Balb/c nude mice that received tumour xenografts derived from HCC cells with reduced Rb levels resulted in complete tumour regression in 50% of the animals treated, compared with tumour stabilization in mice that received control cells. We show that, upon exposure to sorafenib, the Rb-negative status of HCC cells promotes the occurrence of ferroptosis, a form of oxidative necrosis. The findings highlight the role of Rb in the response of HCC cells to sorafenib and the regulation of ferroptosis. PMID- 25444923 TI - Upregulation of the mevalonate pathway by cholesterol depletion abolishes tolerance to N-bisphosphonate induced Vgamma9Vdelta2 T cell cytotoxicity in PC-3 prostate cancer cells. AB - Zoledronate (ZOL) inhibits farnesyl pyrophosphate synthase leading to intracellular accumulation of isopentenyl pyrophosphate/triphosphoric acid 1 adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester (IPP/ApppI). Cytotoxic Vgamma9Vdelta2 T cells have been shown to recognize IPP/ApppI in breast cancer cells. Further, human breast cancer cells have been shown to differ remarkably in their ZOL treatment induced IPP/ApppI production and responses to that. In this communication we analysed the responsiveness of prostate cancer cells PC-3 and DU 145, Caki-2 renal carcinoma cells and U87MG glioblastoma cells to ZOL treatment, and the subsequent activation of Vgamma9Vdelta2 T-cell cytotoxicity. Of the cell lines tested, PC-3 cells were not susceptible to Vgamma9Vdelta2 T-cell cytotoxicity due to low activity of the mevalonate pathway and low amount of IPP formed. However, the resistance of PC-3 cells to Vgamma9Vdelta2 T-cell cytotoxicity could be abrogated by upregulation of the mevalonate pathway through cholesterol depletion. PMID- 25444924 TI - Plumbagin induces apoptosis in lymphoma cells via oxidative stress mediated glutathionylation and inhibition of mitogen-activated protein kinase phosphatases (MKP1/2). AB - Maintaining cellular redox homeostasis is imperative for the survival and normal functioning of cells. This study describes the role and regulation of MAPKinases in oxidative stress mediated apoptosis. Plumbagin, a vitamin K3 analog and a pro oxidant, was employed and it induced apoptosis in both mouse and human T-cell lymphoma cell lines via increased oxidative stress, caspase activity and loss of mitochondrial membrane potential. The pro-oxidant and cytotoxic effects of plumbagin were sensitive to antioxidants indicating a decisive role of cellular redox balance. Plumbagin induced persistent activation of JNK and pharmacological inhibition as well as shRNA-mediated JNK knock-down rescued cells from plumbagin induced apoptosis. Further, plumbagin induced cytochrome c release, FasL expression and Bax levels via activation of JNK pathway. Exposure of lymphoma cells to plumbagin led to inhibition of total and specific phosphatase activity, increased total protein S-glutathionylation and induced glutathionylation of dual specific phosphatase- 1 and 4 (MKP-1 and MKP-2). The in vivo anti-tumor efficacy of plumbagin was demonstrated using a mouse model. In conclusion, oxidative stress mediated tumor cytotoxicity operates through sustained JNK activation via a novel redox-mediated regulation of MKP-1 and MKP-2. PMID- 25444925 TI - De novo hepatocellular carcinoma of liver allograft: a neglected issue. AB - De novo hepatocellular carcinoma (HCC) is a rare neoplasm, ensuing after liver transplantation. Its definitive identification requires sophisticated molecular analyses. Hence, some cases, particularly those ensuing in patients who have been transplanted with HCC, are probably misclassified as recurrences of the primary tumor. Nevertheless, a tumor recurrence cannot be excluded in patients transplanted without apparent malignancy, because of an occult HCC. The main risk factor for de novo HCC is the recurrence of hepatitis/cirrhosis in the allograft. All the described de novo HCCs occurred at least 2 years after OLT, whereas most recurrent HCCs develop within 2 years from surgery. The treatment of this tumor can follow the recommendations of guidelines for primary HCC and, unlike recurrent HCC, re-transplant can be considered a therapeutic option for these patients. Prevention of this tumor relies on the prevention/cure of recurrent liver disease in the allograft and on judicious post-transplant immunosuppression. The present review analyzes this topic by addressing seven key questions. An algorithm based on clinical factors - regarding primary and secondary tumors - to trigger the suspicion of de novo origin of a post transplant HCC is proposed. PMID- 25444926 TI - Ran signaling in melanoma: implications for the development of alternative therapeutic strategies. AB - We performed a comparative study between two human metastatic melanoma cell lines (A375 and 526), and melanocytes (FOM78) by gene expression profiling and pathway analysis, using Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) software. Genes involved in Ran signaling were significantly over represented (p <= 0.001) and up-regulated in melanoma cells. A melanoma associated molecular pathway was identified, where Ran, Aurora Kinase A (AurkA) and TERT were up-regulated, while c-myc and PTEN were down-regulated. A consistent high Ran and AurkA gene expression was detected in about 48% and 53%, respectively, of 113 tissue samples from metastatic melanoma patients. AurkA down regulation was observed in melanoma cells, by Ran knockdown, suggesting AurkA protein is a Ran downstream target. Furthermore, AurkA inhibition, by exposure of melanoma cells to MLN8054, a specific AurKA inhibitor, induced apoptosis in both melanoma cell lines and molecular alterations in the IPA-identified molecular pathway. These alterations differed between cell lines, with an up-regulation of c-myc protein level observed in 526 cells and a slight reduction seen in A375 cells. Moreover, Ran silencing did not affect the A375 invasive capability, while it was enhanced in 526 cells, suggesting that Ran knockdown, by AurkA down regulation, resulted in a Ran-independent enhanced melanoma cell invasion. Finally, AurK A inhibition induced a PTEN up-regulation and its action was independent of B-RAF mutational status. These findings provide insights relevant for the development of novel therapeutic strategies as well as for a better understanding of mechanisms underlying therapy resistance in melanoma. PMID- 25444928 TI - Metastasis-associated in colon cancer-1 upregulates vascular endothelial growth factor-C/D to promote lymphangiogenesis in human gastric cancer. AB - Lymphangiogenesis is actively contributed to lymphatic metastasis in gastric cancer (GC), and vascular endothelial growth factor (VEGF)-C and VEGF-D are key regulators for lymphangiogenesis. Metastasis-associated in colon cancer-1 (MACC1) was reported to be associated with lymph node metastasis in a few clinical studies, while little is known about the role of MACC1 in lymphangiogenesis. Hence, in the present study, we explored the potential role of MACC1 in lymphangiogenesis as well as the underlying mechanisms. By clinical observation, we found a positive relationship between MACC1 and lymphangiogenesis. Besides, similar results were also obtained from in vivo and in vitro studies. With an indirect co-culture system, we got that supernatant from MACC1 overexpressed GC cells accelerated human lymphatic endothelial cells' (HLECs') capacity of tube like formation through enhancing cell proliferation and migration. Moreover, MACC1 overexpressed xenografts also presented more lymphatic vessels. Furthermore, MACC1 significantly increased the expression of VEGF-C/VEGF-D in GC cells and transplanted tumors, which was subsequently suppressed by c-Met inhibitor. All these data suggested a critical role for MACC1 in lymphatic dissemination of GC, providing evidence that MACC1 upregulated VEGF-C/VEGF-D secretion to promote lymphangiogenesis via c-Met signaling. PMID- 25444927 TI - The HIF-1alpha/CXCR4 pathway supports hypoxia-induced metastasis of human osteosarcoma cells. AB - HIF-1alpha mediates hypoxia-induced expression of the chemokine receptor CXCR4 and contributes to metastasis in many different cancers. We have previously shown that hypoxia promotes migration of human osteosarcoma cells by activating the HIF 1alpha/CXCR4 pathway. Here, immunohistochemical analysis showed that unlike control osteochondroma samples, osteosarcoma specimens were characterized by elevated expression levels of HIF-1alpha and CXCR4. Moreover, we found that hypoxia-induced invasiveness was more pronounced in high metastatic potential F5M2 osteosarcoma cells than in low metastatic potential F4 cells, and that this induction was sensitive to treatment with the CXCR4 antagonist AMD3100 and the HIF-1alpha inhibitor KC7F2. Interestingly, hypoxia-induced CXCR4 expression persisted after cultured osteosarcoma cells were returned to normoxic conditions. These observations were confirmed by experiments in a mouse model of osteosarcoma lung metastasis showing that hypoxia stimulation of pulmonary metastasis was greater in F5M2 than in F4 cells, and was sensitive to treatment with AMD3100. Our study provides further evidence of the contributions of hypoxia and the HIF 1alpha/CXCR4 pathway to the progression of osteosarcoma, and suggests that this axis might be efficiently leveraged in the development of novel osteosarcoma therapeutics. PMID- 25444929 TI - Tyrosine phosphorylation of HSC70 and its interaction with RFC mediates methotrexate resistance in murine L1210 leukemia cells. AB - We previously identified and characterized a 66-68 kDa membrane-associated, tyrosine phosphorylated protein in murine leukemia L1210 cells as HSC70 which is a methotrexate (MTX)-binding protein. In order to further characterize the functional role of HSC70 in regulating MTX resistance in L1210 cells, we first showed that HSC70 colocalizes and interacts with reduced folate carrier (RFC) in L1210 cells by confocal laser scanning microscopy and Duolink in situ proximity ligation assay. The tyrosine phosphorylation status of HSC70 found in the membrane fraction was different from the parental L1210/0 and cisplatin (CDDP) MTX cross resistant L1210/DDP cells. In MTX-binding assays, HSC70 from L1210/DDP cells showed less affinity for MTX-agarose beads than that of L1210/0 cells. In addition, genistein (a tyrosine phosphorylation inhibitor) significantly enhanced the resistance of L1210/0 cells to MTX. Moreover, site-directed mutation studies indicated the importance of tyrosine phosphorylation of HSC70 in regulating its binding to MTX. These findings suggest that tyrosine phosphorylation of HSC70 regulates the transportation of MTX into the cells via the HSC70-RFC system and contributes to MTX resistance in L1210 cells. PMID- 25444931 TI - Hypoxia-activated pro-drug TH-302 exhibits potent tumor suppressive activity and cooperates with chemotherapy against osteosarcoma. AB - Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, tumor hypoxia also offers treatment opportunities, exemplified by the development compounds that target hypoxic regions within tumors. TH-302 is a pro-drug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide (Br-IPM). When TH-302 is delivered to regions of hypoxia, Br-IPM, the DNA cross linking toxin, is released. In this study we assessed the cytotoxic activity of TH-302 against osteosarcoma cells in vitro and evaluated its anticancer efficacy as a single agent, and in combination with doxorubicin, in an orthotopic mouse model of human osteosarcoma (OS). In vitro, TH-302 was potently cytotoxic to osteosarcoma cells selectively under hypoxic conditions, whereas primary normal human osteoblasts were protected. Animals transplanted with OS cells directly into their tibiae and left untreated developed mixed osteolytic/osteosclerotic bone lesions and subsequently developed lung metastases. TH-302 reduced tumor burden in bone and cooperated with doxorubicin to protect bone from osteosarcoma induced bone destruction, while it also reduced lung metastases. TH-302 may therefore be an attractive therapeutic agent with strong activity as a single agent and in combination with chemotherapy against OS. PMID- 25444930 TI - Lobatin B inhibits NPM/ALK and NF-kappaB attenuating anaplastic-large-cell lymphomagenesis and lymphendothelial tumour intravasation. AB - An apolar extract of the traditional medicinal plant Neurolaena lobata inhibited the expression of the NPM/ALK chimera, which is causal for the majority of anaplastic large cell lymphomas (ALCLs). Therefore, an active principle of the extract, the furanoheliangolide sesquiterpene lactone lobatin B, was isolated and tested regarding the inhibition of ALCL expansion and tumour cell intravasation through the lymphendothelium. ALCL cell lines, HL-60 cells and PBMCs were treated with plant compounds and the ALK inhibitor TAE-684 to measure mitochondrial activity, proliferation and cell cycle progression and to correlate the results with protein- and mRNA-expression of selected gene products. Several endpoints indicative for cell death were analysed after lobatin B treatment. Tumour cell intravasation through lymphendothelial monolayers was measured and potential causal mechanisms were investigated analysing NF-kappaB- and cytochrome P450 activity, and 12(S)-HETE production. Lobatin B inhibited the expression of NPM/ALK, JunB and PDGF-Rbeta, and attenuated proliferation of ALCL cells by arresting them in late M phase. Mitochondrial activity remained largely unaffected upon lobatin B treatment. Nevertheless, caspase 3 became activated in ALCL cells. Also HL-60 cell proliferation was attenuated whereas PBMCs of healthy donors were not affected by lobatin B. Additionally, tumour cell intravasation, which partly depends on NF-kappaB, was significantly suppressed by lobatin B most likely due to its NF-kappaB-inhibitory property. Lobatin B, which was isolated from a plant used in ethnomedicine, targets malignant cells by at least two properties: I) inhibition of NPM/ALK, thereby providing high specificity in combating this most prevalent fusion protein occurring in ALCL; II) inhibition of NF-kappaB, thereby not affecting normal cells with low constitutive NF-kappaB activity. This property also inhibits tumour cell intravasation into the lymphatic system and may provide an option to manage this early step of metastatic progression. PMID- 25444932 TI - Detection and characterisation of biopsy tissue using quantitative optical coherence elastography (OCE) in men with suspected prostate cancer. AB - We present first quantitative three-dimensional (3D) data sets recorded using optical coherence elastography (OCE) for the diagnosis and detection of prostate cancer (PCa). 120 transrectal ultrasound guided prostate biopsy specimens from 10 men suspected with prostate cancer were imaged using OCE. 3D quantitative mechanical assessment of biopsy specimens obtained in kilopascals (kPa) at an interval of 40 um was compared with histopathology. Sensitivity, specificity, and positive and negative predictive values were calculated for OCE in comparison to histopathology. The results show OCE imaging could reliably differentiate between benign prostate tissue, acinar atypical hyperplasia, prostatic intraepithelial neoplasia and malignant PCa. The sensitivity and specificity of OCE for the detection of prostate cancer was 0.98 and 0.91 with AUC > 0.99. Quantitative 3D OCE based on the assessment of mechanical properties of tissues can reliably differentiate prostate tissue specimen in an ex-vivo setting. This is a promising imaging modality for characterising different grades of cancers. PMID- 25444934 TI - SALL4: an emerging cancer biomarker and target. AB - SALL4 is a transcription factor that plays essential roles in maintaining self renewal and pluripotency of embryonic stem cells (ESCs). In fully differentiated cells, SALL4 expression is down-regulated or silenced. Accumulating evidence suggest that SALL4 expression is reactivated in cancer. Constitutive expression of SALL4 transgene readily induces acute myeloid leukemia (AML) development in mice. Gain- and loss-of-function studies reveal that SALL4 regulates proliferation, apoptosis, invasive migration, chemoresistance, and the maintenance of cancer stem cells (CSCs). SALL4 controls the expression of its downstream genes through both genetic and epigenetic mechanisms. High level of SALL4 expression is detected in cancer patients, which predicts adverse progression and poor outcome. Moreover, targeted inhibition of SALL4 has shown efficient therapeutic effects on cancer. We have summarized the recent advances in the biology of SALL4 with a focus on its role in cancer. Further study of the oncogenic functions of SALL4 and the underlying molecular mechanisms will shed light on cancer biology and provide new implications for cancer diagnostics and therapy. PMID- 25444933 TI - Dual functions of gold nanorods as photothermal agent and autofluorescence enhancer to track cell death during plasmonic photothermal therapy. AB - Gold nanorods have the potential to localize the treatment procedure by hyperthermia and influence the fluorescence. The longitudinal plasmon peak contributes to the photothermal effect by converting light to heat. When these nanorods are PEGylated, it not only makes it biocompatible but also acts as a spacer layer during fluorescence enhancement. When the PEGylated nanorods are internalized inside the cells through endocytosis, the transverse plasmonic peak combined with the enhanced absorption and scattering properties of the nanorods can enhance the autofluorescence emission intensity from the cell. The autofluorescence from the mitochondria inside cells which reflects the respiratory status of the cell was enhanced two times by the presence of nanorods within the cell. At four minutes, the nanorods incubated cells reached the hyperthermic temperature when illuminated continuously with near infrared laser. The cell viability test and autofluorescence intensity curve showed a similar trend indicating the progress of cell death over time. This is the first report to the best of our knowledge to suggest the potential of exploiting the dual capabilities of gold nanorods as photothermal agents and autofluorescence enhancer to track cell death. PMID- 25444935 TI - Sequence and secondary structure of the mitochondrial 16S ribosomal RNA gene of Ixodes scapularis. AB - The complete DNA sequences and secondary structure of the mitochondrial (mt) 16S ribosomal (r) RNA gene were determined for six Ixodes scapularis adults. There were 44 variable nucleotide positions in the 1252 bp sequence alignment. Most (95%) nucleotide alterations did not affect the integrity of the secondary structure of the gene because they either occurred at unpaired positions or represented compensatory changes that maintained the base pairing in helices. A large proportion (75%) of the intraspecific variation in DNA sequence occurred within Domains I, II and VI of the 16S gene. Therefore, several regions within this gene may be highly informative for studies of the population genetics and phylogeography of I. scapularis, a major vector of pathogens of humans and domestic animals in North America. PMID- 25444936 TI - Species-specific PCR for the identification of goat cashmere and sheep wool. AB - In order to establish rapid and species-specific method of goat cashmere and sheep wool identification, a polymerase chain reaction using specific primer pairs targeting mitochondrial D-loop was developed. The goat specific primers yielded a 294 bp PCR fragment and the sheep specific primers yielded three PCR fragments of which only the 404 bp fragment was found highly diagnostic. The specificity and reliability of the developed species-specific PCR assay was validated by considering as many as 500 cashmere and wool samples. The developed species-specific PCR was found effective in detecting mixed samples of cashmere and wool precisely with the relative content over 9.09%. The species-specific PCR method proved to be low cost, fast, easy and reliable alternative to determine the addition of sheep wool in goat cashmere. PMID- 25444937 TI - Prion and prion-like diseases in animals. AB - Transmissible spongiform encephalopaties (TSEs) are fatal neurodegenerative diseases characterized by the aggregation and accumulation of the misfolded prion protein in the brain. Other proteins such as beta-amyloid, tau or Serum Amyloid-A (SAA) seem to share with prions some aspects of their pathogenic mechanism; causing a variety of so called prion-like diseases in humans and/or animals such as Alzheimer's, Parkinson's, Huntington's, Type II diabetes mellitus or amyloidosis. The question remains whether these misfolding proteins have the ability to self-propagate and transmit in a similar manner to prions. In this review, we describe the prion and prion-like diseases affecting animals as well as the recent findings suggesting the prion-like transmissibility of certain non prion proteins. PMID- 25444938 TI - Effects of long-term football training on the expression profile of genes involved in muscle oxidative metabolism. AB - We investigated whether long-term recreational football training affects the expression of health-related biochemical and molecular markers in healthy untrained subjects. Five untrained healthy men trained for 1 h 2.4 times/week for 12 weeks and 1.3 times/week for another 52 weeks. Blood samples and a muscle biopsy from the vastus lateralis were collected at T0 (pre intervention) and at T1 (post intervention). Gene expression was measured by RTqPCR on RNA extracted from muscle biopsies. The expression levels of the genes principally involved in energy metabolism (PPARgamma, adiponectin, AMPKalpha1/alpha2, TFAM, NAMPT, PGC1alpha and SIRT1) were measured at T0 and T1. Up-regulation of PPARgamma (p < 0.0005), AMPKalpha1 (p < 0.01), AMPKalpha2 (p < 0.0005) and adiponectin was observed at T1 vs T0. Increases were also found in the expression of TFAM (p < 0.001), NAMPT (p < 0.01), PGC1alpha (p < 0.01) and SIRT1 (p < 0.01), which are directly or indirectly involved in the glucose and lipid oxidative metabolism. Multiple linear regression analysis revealed that fat percentage was independently associated with NAMPT, PPARgamma and adiponectin expression. In conclusion, long-term recreational football training could be a useful tool to improve the expression of muscle molecular biomarkers that are correlated to oxidative metabolism in healthy males. PMID- 25444939 TI - Rapid and sensitive detection of porcine epidemic diarrhea virus by reverse transcription loop-mediated isothermal amplification combined with a vertical flow visualization strip. AB - Porcine epidemic diarrhea virus (PEDV) is an important pathogen that causes vomiting, diarrhea, and dehydration, leading to serious damage to the swine industry worldwide. The establishment of effective diagnostic methods is imperative. However, traditional methods are often unsuitable. In this study, reverse transcription loop-mediated isothermal amplification (RT-LAMP) was combined with a vertical flow (VF) nucleic acid detection strip to detect PEDV. Parameters that affect the RT-LAMP reaction were optimized. The RT-LAMP-VF assay that we established was performed at 62 degrees C for 40 min, and then directly evaluated on the VF visualization strip cassette. The method demonstrated high specificity for PEDV. The detection limit was 10 pg of ribonucleic acid, consistent with RT-PCR, RT-LAMP detected products on agarose gels and by direct calcein fluorescence. Application of this method to clinical samples yielded a positivity rate that was comparable to that obtained for RT-PCR. This technique saves time and is efficient, and is thus expected to be useful for the diagnosis of PEDV infection in the field. PMID- 25444940 TI - Evaluation of carbapenem-resistant Enterobacteriaceae in an Italian setting: report from the trench. AB - The spread of carbapenem resistant Enterobacteriaceae (CRE) has recently become a matter of concern in public health, mainly due to the wide distribution of carbapenemase genes. Italy is a country considered endemic for the spread of blaKPC Klebsiella pneumoniae (KP). The aim of this study was to depict the epidemiological trend of CRE in one Italian hospital over a long period (3 years surveillance, from May 2011 to April 2014). Based on defined MIC cut-off for specific carbapenems, 164 strains isolated from 146 different patients were analyzed both phenotypically and genotypically to establish the resistance genes. Molecular typing was performed using the RAPD technique. 77 strains were demonstrated to harbor the blaKPC gene (73 KP, 4 Escherichia coli - EC), 51 strains the blaVIM gene (44 KP, 3 EC, 2 Enterobacter cloacae and 2 Klebsiella oxytoca), 8 the blaNDM gene (3 KP, 4 EC and one Providencia stuartii), 3 the blaOXA-48 gene (2 KP, 1 EC), whereas 25 out of the 164 isolates (of different genera and species) had a negative multiplex-PCR amplification for all the targets tested. 39 out of the 164 strains analyzed (23.8%) revealed discrepancies between the MICs obtained with automated instrument and gradient MICs of more than two logs of difference; the broth microdilution provided a better agreement with the results obtained with the gradient MIC. The use of RAPD allowed to distinguish different clusters, closely related, both for blaKPC and for blaVIM KP. PMID- 25444942 TI - Toward transparency of financial disclosure. PMID- 25444941 TI - Molecular diversity of Chickpea chlorotic dwarf virus in Sudan: high rates of intra-species recombination - a driving force in the emergence of new strains. AB - In Sudan Chickpea chlorotic dwarf virus (CpCDV, genus Mastrevirus, family Geminiviridae) is an important pathogen of pulses that are grown both for local consumption, and for export. Although a few studies have characterised CpCDV genomes from countries in the Middle East, Africa and the Indian subcontinent, little is known about CpCDV diversity in any of the major chickpea production areas in these regions. Here we analyse the diversity of 146 CpCDV isolates characterised from pulses collected across the chickpea growing regions of Sudan. Although we find that seven of the twelve known CpCDV strains are present within the country, strain CpCDV-H alone accounted for ~73% of the infections analysed. Additionally we identified four new strains (CpCDV-M, -N, -O and -P) and show that recombination has played a significant role in the diversification of CpCDV, at least in this region. Accounting for observed recombination events, we use the large amounts of data generated here to compare patterns of natural selection within protein coding regions of CpCDV and other dicot-infecting mastrevirus species. PMID- 25444943 TI - Imaging the optic nerve and posterior pole in glaucoma. PMID- 25444944 TI - Re: Coster et al.: A comparison of lamellar and penetrating keratoplasty outcomes (Ophthalmology 2014;121:979-87). PMID- 25444945 TI - Author reply: To PMID 24491643. PMID- 25444946 TI - Author reply: To PMID 24268855. PMID- 25444948 TI - Author reply: To PMID 24326107. PMID- 25444947 TI - Re: Garcia-Martin et al.: Retinal layer segmentation in patients with multiple sclerosis using spectral domain optical coherence tomography (Ophthalmology 2014;121:573-9). PMID- 25444949 TI - Re: Rudnisky et al.: Antibiotic choice for the prophylaxis of post-cataract extraction endophthalmitis (Ophthalmology 2014;121:835-41). PMID- 25444950 TI - Is impaired knee confidence related to worse kinesiophobia, symptoms, and physical function in people with knee osteoarthritis after anterior cruciate ligament reconstruction? AB - OBJECTIVES: To compare knee confidence and kinesiophobia (fear of re-injury) in those with and without knee osteoarthritis following anterior cruciate ligament reconstruction, and determine whether poorer knee confidence is associated with greater kinesiophobia, worse knee-related symptoms, and functional impairments in those with knee osteoarthritis. DESIGN: Cross-sectional. METHODS: Sixty-six individuals, 5-12 years following anterior cruciate ligament reconstruction, with (n=30) and without (n=36) knee osteoarthritis were included. Knee injury and Osteoarthritis Outcome Score quality-of-life question (Q3), assessed knee confidence and Tampa Scale of Kinesiophobia assessed kinesiophobia. In the osteoarthritis group, knee-related symptoms (International Knee Documentation Committee and Anterior Knee Pain Scale), self-reported function (Knee injury and Osteoarthritis Outcome Score activities daily living), sport/recreation (Knee injury and Osteoarthritis Outcome Score-sport and recreation), and performance based function (hopping, one leg rise tasks) were assessed. Between-group differences in knee confidence and kinesiophobia were evaluated with the Chi square test and analysis of variance, respectively. In the osteoarthritis group, between-group differences (none, mild/moderate and severe/extreme problems with knee confidence) in kinesiophobia, symptoms and function were determined with analysis of variances: p<0.05. RESULTS: Following anterior cruciate ligament reconstruction, participants with knee osteoarthritis had significantly worse knee confidence (p=0.010) and greater kinesiophobia (p=0.006) than those without osteoarthritis. In those with knee osteoarthritis, poorer knee confidence was significantly associated with worse symptoms (Anterior Knee Pain Scale, p=0.001; International Knee Documentation Committee, p<0.001), kinesiophobia (p=0.030), Knee injury and Osteoarthritis Outcome Score-activities of daily living (p=0.005), Knee injury and Osteoarthritis Outcome Score-sport and recreation (p=0.001), single-leg hop (p=0.011), side-to-side hop (p=0.013) and one leg rise (p=0.001). CONCLUSIONS: Psychological impairments are evident in people with knee osteoarthritis following anterior cruciate ligament reconstruction, compared to those without. Future studies should further investigate the psychological impairments associated with knee osteoarthritis after anterior cruciate ligament reconstruction. PMID- 25444951 TI - Evaluation of three rapid assays for Mycobacterium tuberculosis complex detection in a comprehensive hospital from West China. AB - OBJECTIVES: To assess the capacity of rapid and accurate confirmation of the Mycobacterium tuberculosis complex (MTBC) in a Chinese clinical laboratory. DESIGN AND METHODS: This prospective study investigated three rapid assays, the Amplified Mycobacterium Tuberculosis Direct (MTD) test, real-time PCR, and acid fast bacilli (AFB) smear, for direct detection of MTBC in a large consecutive series of different clinical specimens. Performance parameters were estimated and compared overall and for separate specimen categories using a combined reference gold standard. RESULTS: The overall sensitivities were similar for MTD and real time PCR (62.26% vs. 58.49%), significantly higher than those of AFB smear (31.13%). Among three assays, MTD had a satisfactory sensitivity in respiratory specimen (73.33%) and a nearly perfect detection for smear-positive samples (96.97%). Real-time PCR showed a high positive rate (58.97%) in regard to nonrespiratory specimen. A combination of molecular assays with conventional methods reached marked additive diagnostic values (sensitivity up to 76.42%), higher than each method individually. All detection systems showed excellent specificities (>96.00%). CONCLUSIONS: The present study indicated that our lab had a moderate diagnostic performance for tuberculosis. Quality guarantee for specimen pretreatment, as well as combination analysis, will enable these assays to better incorporate into the routine laboratory workflow in China. PMID- 25444952 TI - Systematic biopsy, targeted biopsy or a combination--how should we detect prostate cancer in the future? PMID- 25444953 TI - Is top-down vs bottom-up radiological evaluation after febrile urinary tract infection really less stressful for the child and family? Challenging the dogma. AB - PURPOSE: We evaluated whether stress levels in children and parents during radiological evaluation after febrile urinary tract infection are really lower using the top-down approach, where (99m)technetium dimercaptosuccinic acid renal scintigraphy is used initially, than the bottom-up approach, where voiding cystourethrography is initially performed and repeated examinations are easier for all. MATERIALS AND METHODS: We prospectively evaluated 120 children 3 to 8 years old. Pain ratings were obtained using the Faces Pain Scale-Revised, and conversation during the procedure was evaluated using the Child-Adult Medical Procedure Interaction Scale-Revised by 2 independent observers. To evaluate parental anxiety, the State-Trait Anxiety Inventory form was also completed. Following a documented febrile urinary tract infection children were randomized to the top-down or bottom-up group. A third group of 44 children undergoing repeat voiding cystourethrography and their parents were also evaluated. RESULTS: Child ratings of pain using the Faces Pain Scale-Revised were not significantly different between the top-down group following (99m)technetium dimercaptosuccinic acid renal scintigraphy (2.99 on a scale of 10) and the bottom-up group following voiding cystourethrography (3.21). Also the Faces Pain Scale-Revised was not significantly different in the repeat voiding cystourethrography group (3.35). On the Child-Adult Medical Procedure Interaction Scale-Revised there was negative correlation between child coping and child distress, as well as rate of child distress and adult coping promoting behavior. Parental state anxiety scores were significantly less in the top-down and repeat voiding cystourethrography groups than in the bottom-up group. CONCLUSIONS: Although the top-down approach and repeat voiding cystourethrography cause less anxiety for caregivers, these values do not correlate to pain scale in children. This finding might be due to lack of appropriate evaluation tools of pediatric pain and anxiety. However, the theory that the top-down approach is less invasive, and thus less stressful, requires further research. The Child-Adult Medical Procedure Interaction Scale-Revised data indicate that influences in adult-child interaction are bidirectional. PMID- 25444954 TI - Protective effect of 2-APB on testicular ischemia-reperfusion injury in rats. AB - PURPOSE: We performed biochemical and histopathological evaluations to assess the effects of 2-APB on ischemia-reperfusion induced testicular damage. MATERIALS AND METHODS: A total of 28 rats were randomly divided into 4 groups, including sham treated, ischemia-reperfusion, ischemia-reperfusion plus 2 mg/kg 2-APB and ischemia-reperfusion plus 4 mg/kg 2-APB. Testicular tissue superoxide dismutase, glutathione, malondialdehyde, total antioxidant capacity and DNA fragmentation levels were determined. Testicular tissue samples were examined by histopathology and TUNEL staining. RESULTS: Mean superoxide dismutase, total antioxidant capacity and glutathione were significantly higher in the sham treated group than in the ischemia-perfusion group (p <0.05). Mean malondialdehyde and DNA fragmentation levels were significantly lower in the sham treated group than in the ischemia-reperfusion group (p <0.05). After 2-APB treatment superoxide dismutase, total antioxidant capacity and glutathione were significantly increased but malondialdehyde and DNA fragmentation levels were significantly decreased compared to the ischemia-reperfusion group (p <0.05). The number of TUNEL positive cells was significantly lower in the 2-APB treatment groups than in the ischemia-reperfusion group (p <0.05). CONCLUSIONS: In rats 2-APB reduced the oxidative stress and apoptosis caused by testicular ischemia-reperfusion injury. The testicular protective effect of 2-APB appears to be mediated through its antiapoptotic and antioxidative effects. PMID- 25444955 TI - Autologous transobturator urethral sling placement for female stress urinary incontinence. AB - PURPOSE: We describe and evaluate a transobturator approach to urethral sling placement using autologous rectus fascia for the management of female stress urinary incontinence. MATERIALS AND METHODS: We performed a feasibility study of 10 cases of autologous transobturator mid urethral sling placement for stress urinary incontinence. The procedure includes an anterior vaginal dissection performed in the standard fashion for a mid urethral sling and harvest of a strip of rectus fascia. A trocar is passed through each obturator foramen and the fascial stay sutures are retracted through the skin incisions. The sling is appropriately tensioned and the stay sutures are tied. Patient outcomes were measured by a 24-hour pad weight test and ICIQ-FLUTS score. RESULTS: Median patient age was 57 years (IQR 48, 69.5) and median body mass index was 30.3 kg/m(2) (IQR 25.2, 32.4). Median followup was 4 months (range 3 to 5). All patients demonstrated a reduction in leakage with 80% being completely dry (0 gm on 24-hour pad test and not wearing pads). Overall there was significant improvement in postoperative vs preoperative 24-hour pad weight (p=0.02). Likewise, all subscores of the ICIQ-FLUTS were significantly improved after surgery, including frequency (p=0.006), voiding (p=0.04) and incontinence (p=0.002). Of the 9 eligible cases 6 (67%) were performed on an outpatient basis. One patient performed intermittent self-catheterization for 24 hours after sling placement. No patients experienced severe (Clavien III-V) postoperative complications or required urethrolysis. CONCLUSIONS: Autologous transobturator urethral sling placement appears to be technically feasible with excellent short term outcomes. Longer followup and larger series are needed for validation. PMID- 25444956 TI - HIF1alpha expression under normoxia in prostate cancer--which pathways to target? AB - PURPOSE: HIF1alpha over expression correlates with poor prognosis in a number of cancers. Although it is widely accepted that hypoxia induces HIF1alpha expression up-regulation by a reduction in oxygen dependent degradation, HIF1alpha up regulation under normoxic conditions is noted with increasing frequency in many cancers. We reviewed the current knowledge of mechanisms of normoxic and hypoxic HIF1alpha up-regulation, and its therapeutic implications with a particular focus on its role as a potential biomarker in prostate cancer. MATERIALS AND METHODS: Although the literature on the role of HIFs in cancer development and progression has been reviewed extensively, few publications have specifically considered the role of HIFs in prostate cancer. Therefore, we searched PubMed(r) and Google(r) with the key words prostate cancer, castration resistance, metastasis, hypoxia, HIF1alpha, HIF2alpha and regulation. Relevant articles, including original research studies and reviews, were selected based on contents and a synopsis was generated. RESULTS: Normoxic expression of HIF1alpha has an important role in the development of prostate cancer chemoresistance, radioresistance and castrate resistance. Thus, HIF1alpha could serve as a potential biomarker. Furthermore, agents that target HIF1alpha could be used as adjuvant therapy to decrease resistance to conventional treatment modalities. HIF1alpha over expression in prostate cancer can be regulated at 3 levels, including transcription, translation and protein stability, by a number of mechanisms such as gene amplification, single nucleotide polymorphism, increased transcription of HIF1alpha mRNA, expression of truncated isoforms of HIF1alpha and stabilization of HIF1alpha. However, there is no definitive consensus and the intriguing question of how HIF1alpha is up-regulated in prostate cancer is still unanswered. CONCLUSIONS: HIF1alpha over expression under normoxia could serve as a biomarker for chemoresistance, radioresistance and castrate resistance in prostate cancer. There is an urgent need to identify the cause of HIF1alpha over expression in castrate resistant prostate cancer cells and tumors to guide the choice of HIF inhibitors (transcription or translation based) that are best suited for treating castrate resistant prostate cancer. PMID- 25444957 TI - Impact of an adjuvant chemotherapeutic regimen on the clinical outcome in high risk patients with upper tract urothelial carcinoma: a Japanese multi-institution experience. AB - PURPOSE: Current guidelines do not yet provide any recommendations for adjuvant chemotherapy in patients with upper tract urothelial carcinoma managed with radical nephroureterectomy. We evaluated whether an adjuvant chemotherapeutic regimen would affect the clinical outcome in patients with high risk upper tract urothelial carcinoma. MATERIALS AND METHODS: We identified 873 patients who had undergone radical nephrouretectomy for localized upper tract urothelial carcinoma at 14 Japanese institutions between 1993 and 2011. We assessed whether the type of regimen, such as methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and cisplatin, in an adjuvant setting, could affect the subsequent clinical outcome of patients with upper tract urothelial carcinoma. RESULTS: On multivariate analysis pathological T stage, tumor grade, lymphovascular invasion and lymph node involvement were prognostic factors for recurrence-free survival and cancer specific survival. We defined 229 patients with 3 or more of these factors as the high risk group. In an analysis according to adjuvant regimen, Kaplan-Meier curves showed that the 1 and 2-year recurrence-free survival rates in the methotrexate, vinblastine, doxorubicin and cisplatin treated group were 71.4% and 47.9%, which were significantly higher than in the gemcitabine and cisplatin treated group (48.2% and not reached, p=0.022) or those not treated with adjuvant chemotherapy (53.4% and 39.6%, p=0.039). Similar results were observed in terms of cancer specific survival. CONCLUSIONS: Our study showed that pT3-4, tumor grade 3, positive lymphovascular invasion and lymph node involvement were independent risk factors for disease mortality in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. In the high risk group methotrexate, vinblastine, doxorubicin and cisplatin adjuvant chemotherapy contributed to improve subsequent mortality compared to gemcitabine and cisplatin or no adjuvant chemotherapy. PMID- 25444959 TI - Cystic nephroma of the kidney. PMID- 25444958 TI - Neuromuscular nicotinic receptors mediate bladder contractions following bladder reinnervation with somatic to autonomic nerve transfer after decentralization by spinal root transection. AB - PURPOSE: We investigated whether the reinnervated neuronal pathway mediates contraction via the same neurotransmitter and receptor mechanisms as the original pathway. MATERIALS AND METHODS: After decentralizing the bladder by transecting the sacral roots in dogs we performed peripheral nerve transfer, including bilateral genitofemoral to pelvic nerve transfer and unilateral left femoral nerve to bilateral pelvic nerve transfer. Reinnervation was assessed 7.5 months postoperatively by monitoring bladder pressure during electrical stimulation of the transferred nerves, spinal ventral roots and spinal cord. RESULTS: Of the 17 dogs with genitofemoral to pelvic nerve transfer 14 (82%) demonstrated functional bladder reinnervation as evidenced by increased bladder pressure during stimulation of the transferred genitofemoral nerve, or L3 or L4 spinal ventral roots. Lumbar spinal cord stimulation caused increased bladder pressure in 9 of 10 dogs (90%) with unilateral left femoral nerve to bilateral pelvic nerve transfer. Succinylcholine virtually eliminated the bladder pressure increases induced by electrical stimulation of the transferred somatic nerves or of the lumbar spinal segments that contribute axons to these donor nerves. In unoperated or sham operated controls succinylcholine had no effect on nerve evoked bladder pressure increases but it substantially decreased the urethral and anal sphincter pressure induced by stimulating the lumbosacral spinal cord or the S2-S3 spinal ventral roots. The reinnervated detrusor muscles of dogs with genitofemoral to pelvic nerve transfer and unilateral left femoral nerve to bilateral pelvic nerve transfer also showed increased alpha1 nicotinic receptor subunit immunoreactivity in punctate dots on detrusor muscle fascicles and in neuronal cell bodies. This staining was not observed in controls. CONCLUSIONS: Succinylcholine sensitive nicotinic receptors, which normally mediate only skeletal muscle neuromuscular junction neurotransmission, appeared in the new neuronal pathway after genitofemoral to pelvic and unilateral femoral nerve to bilateral pelvic nerve transfer. This suggests end organ neuroplasticity after reinnervation by somatic motor axons. PMID- 25444960 TI - Etiology of azoospermia in a military population. AB - PURPOSE: Male infertility is commonly seen at urology clinics and 10% to 20% of infertile males are found to be azoospermic. Azoospermia is classically categorized as nonobstructive or obstructive. This classification tailors the evaluation, diagnosis and proper treatment. We performed a retrospective study to provide an updated etiology of azoospermia in patients in the United States in a universal health care model. MATERIALS AND METHODS: We retrospectively reviewed the records of men with azoospermia who presented to our institution between 2004 and 2012. Laboratory data were analyzed, included semen analysis, follicle stimulating hormone, luteinizing hormone, testosterone, semen fructose and genetic studies. Patients underwent scrotal exploration as indicated for testis biopsy and sperm extraction. RESULTS: We reviewed 139 outpatient records. Nonobstructive azoospermia was diagnosed in 99 men (71%), including 33 (34%) identified with Sertoli-cell only syndrome. Other etiologies included an idiopathic cause in 25 cases (26%), Klinefelter syndrome in 9 (9%), maturation arrest in 9 (9%), Y chromosome microdeletion in 5 (5%), cryptorchidism in 4 (4%), trauma in 4 (4%), exogenous testosterone supplementation in 4 (4%) and other genetic disorders in 6 (6%). Obstructive azoospermia was identified in 40 men (29%), of whom 16 (40%) had congenital bilateral absence of the vas deferens. Other etiologies included an idiopathic cause in 11 cases (28%), an iatrogenic condition due to a surgical cause in 5 (13%), ejaculatory duct obstruction in 3 (8%), trauma in 1 (3%), retrograde ejaculation in 1 (3%), vas deferens occlusion in 2 (5%) and unilateral absence of the vas deferens in 1 (3%). CONCLUSIONS: This study delineates the etiology of azoospermia in men with universal access to care. PMID- 25444961 TI - A pilot randomized controlled trial evaluating the effectiveness of group vs individual urotherapy in decreasing symptoms associated with bladder-bowel dysfunction. AB - PURPOSE: We determined the feasibility of a definitive trial comparing the effectiveness of group vs individual urotherapy for children with bladder-bowel dysfunction. MATERIALS AND METHODS: Children 6 to 10 years old with bladder-bowel dysfunction were recruited during the course of 1 year. Feasibility data on screening, eligibility, recruitment and protocol compliance rates were collected. Patients with high grade hydronephrosis, vesicoureteral reflux or learning disabilities and those who had previously undergone urotherapy were excluded. Patients were randomized to 1-hour group urotherapy or 15-minute individual urotherapy. Symptoms and quality of life were measured using the Vancouver Nonneurogenic Lower Urinary Tract Dysfunction/Dysfunctional Elimination Syndrome Questionnaire and the Pediatric Incontinence Questionnaire at baseline and at 3 to 6 months of followup. Within/between group comparisons were conducted using t tests. RESULTS: Of 455 screened children 79 were eligible and 60 were recruited to participate. A total of 24 patients randomized to group urotherapy and 25 randomized to individual urotherapy completed the pilot trial (6 undergoing group and 5 undergoing individual urotherapy withdrew from the study). Symptomology scores between group and individual urotherapy were not different at followup (mean +/- SD 14.7 +/- 7.9 vs 13.4 +/- 6.3, p = 0.54, 95% CI -5.4-2.8). Quality of life scores between patients undergoing group and individual urotherapy at baseline differed (mean +/- SD 21.1 +/- 10.8 vs 31.0 +/- 14.3, p < 0.01, 95% CI 2.7-7.3) but became similar at followup (21.0 +/- 14.2 vs 20.1 +/- 15.3, p = 0.84, 95% CI -9.4-7.6). Within group analyses demonstrated improvement in symptomology from baseline to followup in patients undergoing group (mean +/- SD 3.6 +/- 7.6, p = 0.03, 95% CI 0.4-6.8) and individual urotherapy (6.0 +/- 5.4, p < 0.01, 95% CI 3.8-8.3). Within group quality of life analyses revealed improvement in Pediatric Incontinence Questionnaire scores from baseline to followup in patients undergoing individual urotherapy (p < 0.01, 95% CI 5.0-16.9) only. CONCLUSIONS: Urotherapy, regardless of modality, effectively improved bladder-bowel dysfunction symptoms. A definitive randomized controlled trial is feasible, considering that a high recruitment rate (76%) for this population has been established. PMID- 25444962 TI - The male bulbospongiosus muscle and its relation to the external anal sphincter. AB - PURPOSE: The bulbospongiosus muscle is part of the superficial muscular layer of the perineum and pelvic floor. Its morphology remains controversial in the literature. Therefore, we reinvestigated the fascial arrangement and fiber courses of the bulbospongiosus muscle and its topographical relation to the external anal sphincter. MATERIALS AND METHODS: The perineum was dissected in 9 male cadavers (mean +/- SD age 78.3 +/- 10.7 years). Select samples were obtained for histology and immunohistochemistry. In 43 patients (mean age 60.7 +/- 12 years) the topographical relation between the bulbospongiosus muscle and the external anal sphincter was determined by magnetic resonance imaging. RESULTS: The perineum contains several fascial layers consisting of elastic and collagen fibers as well as bundles of smooth muscle cells. The bulbospongiosus muscle was subdivided into a ventral and dorsal portion, which developed in 4 variants. The ventral insertion formed a morphological unity with the ischiocavernous muscle while the dorsal origin had a variable relation to the external anal sphincter (5 variants). A muscle-like or connective tissue-like connection was frequently present between the muscles. However, in some cases the muscles were completely separated. CONCLUSIONS: We suggest a concept of variations of bulbospongiosus muscle morphology that unifies the conflicting literature. Its ventral fiber group and the ischiocavernosus muscle form a functional and morphological unity. While the bulbospongiosus muscle and the external anal sphincter remain independent muscles, their frequent connection might have clinical implications for perineal surgery and anogenital disorders. PMID- 25444963 TI - Primary testicular lymphoma. PMID- 25444968 TI - Targeted therapies for metastatic bladder cancer. PMID- 25444964 TI - Treatment of exophytic renal cancer smaller than 3 cm: surgery versus active surveillance. PMID- 25444970 TI - Current role of biofeedback for pediatric lower urinary tract symptoms. PMID- 25444969 TI - Role of 11C-choline positron emission tomography in prostate cancer recurrence- potential for delayed cure or just resetting the clock of the disease? PMID- 25444971 TI - Patterns of repeat prostate biopsy in contemporary clinical practice. AB - PURPOSE: The objectives of this study were to 1) describe the patterns of repeat prostate biopsy in men with a previous negative biopsy and 2) identify predictors of prostate cancer diagnosis on repeat biopsy in these men. MATERIALS AND METHODS: From a university faculty group practice we identified 1,837 men who underwent prostate biopsy between January 1, 1995 and January 1, 2010. Characteristics of repeat biopsy were examined, including the indication for biopsy, the number of repeat biopsies performed, the number of cores obtained and total prostate specific antigen before biopsy. Features of prostate cancer diagnosed on repeat biopsy were examined, including Gleason score, number of positive cores, percent of tumor and treatment choice. Multivariable logistic regression was done to identify prostate cancer predictors. RESULTS: Initial biopsy was negative in 1,213 men. In 255 men a total of 798 repeat biopsies were performed. Of the 63 men diagnosed with prostate cancer Gleason score was 6 or less in 33 (52%), 7 in 22 (35%) and 8-9 in 8 (13%). When categorized by Epstein criteria, the rate of clinically insignificant cancer diagnosis decreased substantially by the third and fourth repeat biopsies. Repeat biopsy in men older than 70 years, biopsies including more than 20 cores and the fourth repeat biopsy were associated with an increased likelihood of prostate cancer diagnosis. CONCLUSIONS: In men selected for multiple repeat biopsies clinically significant cancer is found at each sampling round. Given the continued likelihood of cancer detection even by the fifth biopsy, early consideration of saturation or image guided biopsy may be warranted in the repeat biopsy population. PMID- 25444972 TI - Neurological, visual, and MRI brain scan findings in 87 South African patients with HIV-associated cryptococcal meningoencephalitis. AB - BACKGROUND: HIV-associated cryptococcal meningoencephalitis (CM) is a leading cause of adult meningitis in sub-Saharan Africa. Neuroradiological data is however limited to case reports and small case series from developed countries and/or immunocompetent patients. METHODS: Eighty seven patients aged >=18 hospitalized with a first episode of CM had magnetic resonance (MRI) imaging during the first two weeks of admission. A subset of eleven patients had follow up scans approximately one month from their initial MRI scan. All had prospectively-recorded detailed neurological and visual examinations. RESULTS: An abnormal finding on neurological examination was detected in 33 (39%) patients. 38 (48%) patients experienced some visual loss. Neuroradiological lesions presumed to be cryptococcosis-related, as defined by the presence of dilated Virchow Robin spaces, pseudocysts or cryptococcomas, enhancing nodules, hydrocephalus, meningitis, focal perilesional oedema and infarcts, were detected in 55 (63%) patients. MRI findings suggestive of a second diagnosis were found in 18 (21%) patients. Visual loss was associated with the presence of cryptococcal related lesions (p = 0.02). Blindness was associated with raised intracranial pressure (ICP) (p = 0.02). Of eleven patients with paired scans, brain swelling was identified on the initial scan in only one patient. CONCLUSION: The majority of patients had MRI brain scan abnormalities presumed secondary to CM. Dilated Virchow Robin spaces were the commonest neuroradiological lesion. Visual loss was associated with the degree of cerebral involvement as reflected by the presence of MRI abnormalities. Blindness was associated with the presence of raised ICP. Initial generalised brain swelling does not appear to be common, but further studies with paired scans are needed. PMID- 25444973 TI - IL-4 specific-response in whole blood associates with human Cystic Echinococcosis and cyst activity. AB - OBJECTIVES: Human Cystic Echinococcosis (CE) is estimated in 2-3 million global cases. CE diagnosis and clinical management are based on imaging and serology, which lacks sensitivity and does not provide cyst stage information. This study aimed to evaluate tools for improving diagnosis by analysing the Interleukin (IL) 4-response to Antigen B (AgB) of Echinococcus granulosus. METHODS: Whole blood (WB) and peripheral blood mononuclear cells were stimulated with AgB. IL-4 levels were measured by enzyme-linked immunosorbent assay. RESULTS: WB 1-day stimulation resulted the best experimental condition for evaluating AgB IL-4-response. IL-4 levels were significantly higher in CE patients than healthy donors (p <= 0.0001). A ROC analysis showed significant area under the curve (AUC) results (AUC, 0.85; p = 0.0001) identifying an IL-4 level cut-off point >=0.39 pg/mL which predicted CE with 71.4% sensitivity and 93.3% specificity. Moreover, we found that IL-4 levels were significantly increased in patients with active cysts compared to those with inactive cysts (p <= 0.0001). ROC analysis showed significant AUC results (0.94; p = 0.0001) with a cut-off point of 4.6 pg/mL which predicted active cysts with 84.6% sensitivity and 92% specificity. CONCLUSIONS: We found immunological correlates associated with CE and biological cyst activity. PMID- 25444974 TI - The association between infections and chemotherapy interruptions among cancer patients: prospective cohort study. AB - OBJECTIVES: Adherence to scheduled chemotherapy is important for optimal outcomes of cancer patients. We examined causes for delay or cancellation of planned chemotherapy, focusing on mild respiratory infections during the winter. METHODS: Prospective cohort study. We included all adults with solid or hematologic cancer receiving active chemotherapy treatment during the winter of 2010-2011 in a cancer center. We compared baseline characteristics and outcomes between patients with and without chemotherapy delays, cancellations, or dose-reductions ("chemotherapy delay"). RESULTS: We included 547 patients receiving chemotherapy during the winter of 2011. Of these, 213 (38.9%) patients experienced 306 episodes of chemotherapy delays. The main documented reasons for the chemotherapy delay were neutropenia (84/306, 27.4%), fever or infection (73/306, 23.9%) and thrombocytopenia (26/306, 8.5%). Independent risk factors for chemotherapy delays were upper respiratory infections (OR 1.87, 95% CI 1.27-2.76), lymphopenia, prior hospitalization, peripheral vascular disease and colon cancer relative to hematologic cancer. In the adjusted analysis focusing on chemotherapy delays due to infection alone, upper respiratory infections (OR 5.25, 95% I 2.81-9.84) and age were significant independent risk factors. DISCUSSION: Mild respiratory infections were associated with chemotherapy delays. Our results should encourage modalities to prevent influenza and other upper respiratory infections among cancer patients. PMID- 25444975 TI - Carbohydrate mediated drug delivery: synthesis and characterization of new lipid conjugates. AB - A new synthetic methodology for cationic glycolipids using p-aminophenyl-alpha-D mannopyranoside (PAPM) and p-aminophenyl-alpha-D-galactopyranoside (PAPG) with spacer in between the quaternary nitrogen atom and the sugar unit is developed. In addition, a new class of neutral glycolipid conjugates, such as PAPM-lipids or PAPG-lipids conjugates was also synthesized for targeting drugs to receptors. The precipitation-inhibition assay showed that conjugate of PAPM inhibited the concanavalin A and invertase aggregation. This binding inhibition study of a synthesized compound suggests that conjugates of PAPM can be potentially used to target mannose receptors. In addition, a higher transfection was obtained by mixing PAPM with pSV-beta-gal reporter gene and incubating with mannose binding protein/receptor expressing A549 cells. The coexistence of both mannose group and a net positive charge may result in improved transfection efficiency in cells expressing mannose binding proteins/receptors. PMID- 25444976 TI - Cholesterol, sphingolipids, and glycolipids: what do we know about their role in raft-like membranes? AB - Lipids rafts are considered to be functional nanoscale membrane domains enriched in cholesterol and sphingolipids, characteristic in particular of the external leaflet of cell membranes. Lipids, together with membrane-associated proteins, are therefore considered to form nanoscale units with potential specific functions. Although the understanding of the structure of rafts in living cells is quite limited, the possible functions of rafts are widely discussed in the literature, highlighting their importance in cellular functions. In this review, we discuss the understanding of rafts that has emerged based on recent atomistic and coarse-grained molecular dynamics simulation studies on the key lipid raft components, which include cholesterol, sphingolipids, glycolipids, and the proteins interacting with these classes of lipids. The simulation results are compared to experiments when possible. PMID- 25444977 TI - Reference ranges for serum and salivary testosterone in young men of Mediterranean region. AB - BACKGROUND AND AIMS: The interassay variability found in the measurement of testosterone (T) levels warrants the need for laboratories to validate their methods to establish trustworthy cut-off points for diagnosis of male hypogonadism. The aims of this study were to validate measurement of total T (TT) at our laboratory in order to obtain reference ranges for TT, calculated free T (CFT), calculated bioavailable T (CBT), and salivary T (ST) in healthy young men from the Mediterranean region, and to evaluate the potential clinical value of ST by establishing its correlation with serum T. METHODS: An observational, cross sectional study with sequential sampling. INCLUSION CRITERIA: men aged 18-30 years with body mass index (BMI)<30. EXCLUSION CRITERIA: chronic diseases, hepatic insufficiency or use of drugs altering circulating T levels. Main outcome measures TT (chemiluminescent immunoassay UniCell DXI 800 [Access T Beckman Coulter]), CFT and CBT (Vermeulen's formula), and ST (radioimmunoassay for serum TT modified for saliva [Coat-A-Count, Siemens]). Descriptive statistical analyses and correlation by Spearman's rho (SPSS 19.0 Inc., Chicago) were used. RESULTS: One hundred and twenty-one subjects aged 24+/-3.6 years with BMI 24+/-2.5 kg/m(2) were enrolled. Hormone study: TT, 19+/-5.5 nmol/L (reference range [rr.] 9.7 33.3); CFT, 0.38 nmol/L (rr. 0.22-0.79); CBT, 9.7 nmol/L (rr. 4.9-19.2); and ST, 0.35 nmol/L (rr. 0.19-0.68). Correlation between ST and CFT was 0.46. CONCLUSIONS: In men from the Mediterranean region, values of TT>9.7 nmol/L, CFT>0.22 nmol/L, and/or CBT>4.9 nmol/L make the presence of biochemical hypogonadism unlikely. According to the correlation between serum and ST, the clinical value of ST remains to be established. PMID- 25444978 TI - Insulin resistance, beta-cell dysfunction and differences in curves of plasma glucose and insulin in the intermediate points of the standard glucose tolerance test in adults with cystic fibrosis. AB - BACKGROUND: diabetes has become a co-morbidity with a negative impact on nutritional status, lung function and survival in cystic fibrosis. OBJECTIVE: To identify any changes in intermediate points after a 2-hour oral glucose tolerance test (OGTT), pancreatic beta-cell dysfunction, and insulin resistance in cystic fibrosis-related diabetes. METHODS: It was carried out a retrospective analysis in a cohort of 64 patients affected of cystic fibrosis, older than 14 years, using the first pathological OGTT. Peripheral insulin resistance was measured using the homeostasis model assessment for insulin resistance (HOMA- IR), and pancreatic beta-cell function was calculated according to Wareham. Time to maximum plasma insulin and glucose levels and area under the curve (AUC0-120) were also measured. RESULTS: Twenty-eight women and 36 men with a mean age of 26.8 years were enrolled, of whom 26.7% had normal glucose tolerance (NGT), 18.3% cystic fibrosis-related diabetes without fasting hyperglycemia (CFRD w/o FPG), 10% indeterminate (INDET), and 45% impaired glucose tolerance (IGT). HOMA-IR values were not significantly different between the diagnostic categories. Patients with any pathological change had worse beta cell function, with a significant delay in insulin secretion, although there were no differences in total insulin production (AUC0-120). Time to maximum glucose levels was significantly shorter in NGT patients as compared to other categories, with glucose AUC0-120 being higher in the different diagnostic categories as compared to NGT. CONCLUSIONS: In over half the cases, peak blood glucose levels during a standard OGTT are reached in the intermediate time points, rather than at the usual time of 120minutes. Patients with cystic fibrosis and impaired glucose metabolism have a delayed insulin secretion during the standard OGTT due to loss of first-phase insulin secretion, with no differences in total insulin production. Absence of significant changes in HOMA-IR suggests that beta-cell dysfunction is the main pathogenetic mechanism. PMID- 25444979 TI - Reply to: diagnostic and functional structure of a high-resolution thyroid nodule clinic: an efficiency model. PMID- 25444980 TI - Ultrasensitive prostate specific antigen and its role after radical prostatectomy: a systematic review. AB - PURPOSE: Prostate specific antigen is an important tool to monitor patients with prostate cancer after radical prostatectomy. Ultrasensitive prostate specific antigen assays are increasingly used with a lower limit of detection as low as 0.001 ng/ml. We systematically reviewed currently available ultrasensitive prostate specific antigen technologies and the role of this method in monitoring patients after radical prostatectomy. MATERIALS AND METHODS: We searched the relevant literature using the MEDLINE(r) database. For various study objectives the series eligible for review provided serial ultrasensitive prostate specific antigen (lower detection limit less than 0.1 ng/ml) data on men after radical prostatectomy as well as comparative data on standard prostate specific antigen (lower detection limit 0.1 ng/ml or greater). RESULTS: Ultrasensitive prostate specific antigen could potentially detect prostate cancer recurrence years earlier than standard prostate specific antigen assays. The specificity of detectable ultrasensitive prostate specific antigen is low. Ultrasensitive prostate specific antigen kinetics may improve the positive predictive value for detecting cancer recurrence. However, the usefulness of prostate specific antigen doubling time at the ultrasensitive level remains controversial. Undetectable nadir ultrasensitive prostate specific antigen after radical prostatectomy confers a low risk of disease recurrence while a detectable nadir above 0.01 ng/ml requires additional measurement and consideration of other risk factors to determine management and avoid overtreatment. This monitoring method may spare patients with high risk disease adjuvant radiation therapy and enable more selective early salvage radiation. Currently no data demonstrate improved survival after early salvage therapy prompted by ultrasensitive prostate specific antigen surveillance. CONCLUSIONS: Ultrasensitive prostate specific antigen is useful in the early diagnosis of cancer recurrence after radical prostatectomy but specificity is poor. To date there is a lack of evidence that earlier detection of recurrence translates into prolonged time to metastasis. Integrating ultrasensitive prostate specific antigen with other clinicopathological factors can help determine optimal adjuvant and salvage therapy. PMID- 25444981 TI - DeltaNp63 expression is a protective factor of progression in clinical high grade T1 bladder cancer. AB - PURPOSE: Several risk factors have been claimed to predict the progression of clinically high grade T1 bladder tumors. However, these factors are not specific enough to define which patients should be treated immediately with radical cystectomy. Therefore, it is critical to identify molecular markers that can help provide individualized, risk stratified decision making. Our main goal was to evaluate the role of total p63, p53 and DeltaNp63 expression in cases of clinically high grade T1 bladder cancer progression. MATERIALS AND METHODS: Total p63, p53 and DeltaNp63 expression was analyzed by immunohistochemistry in 134 clinically high grade T1 tumors. We assessed clinical progression to muscle invasive disease or radical cystectomy as a patient outcome end point. Survival analysis was done for recurrence-free, progression-free, disease specific and overall survival. RESULTS: A total of 132 patients (98.5%) underwent repeat transurethral resection. Cases of early progression (less than 3 months) were excluded from study to avoid under staging. Of the tumors 90 (67.2%) showed DeltaNp63 expression loss. During a median followup of 62.1 months 19 patients (14.2%) progressed to muscle invasive disease. The progression rate was 21.1% in patients with tumors characterized by DeltaNp63 loss but no progression was observed in those with tumors with DeltaNp63 expression (p <0.001). There was no difference in the number of patients who underwent repeat transurethral resection, had associated carcinoma in situ, showed lymphovascular invasion or received followup intravesical bacillus Calmette-Guerin courses. CONCLUSIONS: DeltaNp63 expression is a favorable prognostic factor in clinically high grade T1 bladder cancer. This marker identifies patients at low risk for progression who could benefit from conservative therapy with transurethral bladder tumor resection and bacillus Calmette-Guerin, avoiding over treatment with immediate radical cystectomy. PMID- 25444982 TI - Restoration of erectile function by suppression of corporal apoptosis, fibrosis and corporal veno-occlusive dysfunction with rho-kinase inhibitors in a rat model of cavernous nerve injury. AB - PURPOSE: We determined whether Rho-kinase inhibition would improve corporal veno occlusive dysfunction by suppressing apoptosis and fibrosis via normalization of the Rho-kinase driven pathways related to the 2 structural alterations in a rat model of cavernous nerve crush injury. MATERIALS AND METHODS: A total of 30 male 10-week-old male Sprague Dawley(r) rats were equally divided into 3 groups, including sham surgery, cavernous nerve crush injury and cavernous nerve crush injury treated with fasudil. The treated group received fasudil (30 mg/kg) daily for 4 weeks starting day 1 postoperatively. Electrostimulation and dynamic infusion cavernosometry were performed 4 weeks postoperatively. Penile tissue was processed for imm unohistochemistry, double immunofluorescent and Masson trichrome staining, TUNEL, caspase-3 activity assay and Western blot. RESULTS: The cavernous nerve crush injury group showed significantly lower intracavernous pressure/mean arterial pressure, and higher maintenance and drop rates than the sham surgery group. Rho-kinase inhibition in the injury plus fasudil group restored erectile responses and dynamic infusion cavernosometry parameters. Increased apoptosis, decreased immunohistochemical staining of alpha-SMA and increased caspase-3 activity were noted in the injury group. In that group densitometry revealed increased ROCK1 expression, increased MYPT1 phosphorylation, decreased Akt phosphorylation, decreased Bad phosphorylation and a decreased Bcl2-to-Bax ratio. A significantly decreased smooth muscle-to collagen ratio and increased fibroblast pCofilin were also observed in the injury group, as was increased phosphorylation of cofilin, a downstream effector of LIMK2. Rho-kinase inhibition in the injury plus fasudil group alleviated the histological and molecular dysregulation. CONCLUSIONS: Our data suggest that early inhibition of Rho-kinase after cavernous nerve crush injury may prevent corporal apoptosis and fibrosis by suppressing the Akt/Bad/Bax/caspase-3 and LIMK2/cofilin pathways, preventing corporal veno-occlusive dysfunction and erectile dysfunction. PMID- 25444983 TI - Equivocal ureteropelvic junction obstruction on diuretic renogram--should minimally invasive pyeloplasty be offered to symptomatic patients? AB - PURPOSE: Equivocal ureteropelvic junction obstruction refers to clinical symptoms and/or other radiological suggestions of possible ureteropelvic junction obstruction but with inconclusive results of obstruction on diuretic renogram. We evaluated long-term outcomes in patients with equivocal ureteropelvic junction obstruction treated with minimally invasive pyeloplasty. MATERIALS AND METHODS: We retrospectively analyzed the records of 125 consecutive patients who underwent minimally invasive pyeloplasty as performed by a single surgeon from May 2004 to July 2013. Of 98 patients with followup those with more than 6-month followup were included in analysis. Equivocal ureteropelvic junction obstruction, defined as half-life less than 20 minutes on diuretic renogram, was identified in 23 patients. All patients underwent transperitoneal minimally invasive pyeloplasty. We evaluated patient demographics, preoperative and postoperative symptoms and renal function. RESULTS: The 16 female and 7 male patients with equivocal ureteropelvic junction obstruction had flank pain and associated hydronephrosis on imaging. At a median followup of 20.2 months (range 7 to 75) 95.7% of patients with equivocal obstruction achieved complete symptom resolution. Mean +/- SD preoperative and postoperative half-life was 14.1 +/- 3.7 and 7.4 +/- 4.2 minutes, respectively, for an improvement of 6.7 minutes (p < 0.001). In 1 patient (4.3%) with equivocal obstruction of a complicated iatrogenic etiology treatment ultimately failed postoperatively and endopyelotomy was required. There was no statistically significant difference in clinical or radiological success between the equivocal obstruction group and the 75 patients treated with minimally invasive pyeloplasty for definitive ureteropelvic junction obstruction (p = 0.44 and 0.07, respectively). CONCLUSIONS: In patients with radiographic equivocal ureteropelvic junction obstruction and flank pain minimally invasive pyeloplasty efficaciously provides symptomatic relief and functional preservation. Results are comparable to those in patients with high grade obstruction. PMID- 25444984 TI - 5alpha-Reductase inhibition coupled with short off cycles increases survival in the LNCaP xenograft prostate tumor model on intermittent androgen deprivation therapy. AB - PURPOSE: Intermittent androgen deprivation therapy in patients with prostate specific antigen progression after localized prostate cancer treatment is an alternative to standard continuous androgen deprivation therapy. Intermittent androgen deprivation therapy allows for testosterone recovery during off cycles. This stimulates regrowth and differentiation of the regressed prostate tumor, lessens the side effects of continuous androgen deprivation therapy and potentially prolongs survival. Previously intermittent androgen deprivation therapy coupled with finasteride was shown to prolong survival in animals bearing androgen sensitive prostate tumors when the off cycle duration was not prolonged but rather fixed at 10 to 14 days. Regressed prostate tumor xenografts with testosterone replacement were initially responsive to 5alpha-reductase inhibition but growth resumed after several days. In shorter off cycles of testosterone recovery 5alpha-reductase inhibition might maximize tumor growth inhibition during intermittent androgen deprivation therapy and perhaps increase survival. MATERIALS AND METHODS: We used the LNCaP xenograft tumor model to evaluate the effectiveness of short off cycles of 4 days coupled with 5alpha-reductase inhibition on survival and tumor regrowth while on intermittent androgen deprivation therapy. RESULTS: Dutasteride inhibited initial testosterone induced tumor regrowth off cycles 1 and 2, and significantly increased survival. CONCLUSIONS: These results further support the potential for intermittent androgen deprivation therapy combined with 5alpha-reductase inhibition to improve survival in patients with prostate cancer when off cycle duration is short or very short. PMID- 25444986 TI - Risk of end stage kidney disease after radical cystectomy according to urinary diversion type. AB - PURPOSE: The risk of renal insufficiency has historically been viewed as a long term consequence of urinary diversion after radical cystectomy. However, there are little data on the long-term rate of end stage kidney disease after urinary diversion and few studies have compared end stage kidney disease rates by diversion type. In a large, population based cohort we evaluated the risk of end stage kidney disease in patients who received an ileal conduit vs continent urinary diversion after cystectomy for bladder cancer. MATERIALS AND METHODS: Using the SEER-Medicare 1992 to 2010 data set we identified 4,015 patients treated with radical cystectomy for bladder cancer, excluding those with preexisting renal disease or clinically significant preoperative hydronephrosis. The outcome of interest was end stage kidney disease stratified by diversion type. We used a Cox proportional hazard model for multivariate analysis controlling for demographic, tumor and comorbidity characteristics. RESULTS: End stage kidney disease developed in 7.2% of patients, including 84% with an ileal conduit and 16% with continent urinary diversion. Median followup was 34 months (IQR 12-73). On multivariate analysis no increased risk of end stage kidney disease was associated with continent diversion (HR 1.06, 95% CI 0.78-1.44, p = 0.71). Overall the estimated risk at 5, 10 and 15 years was 8.3% (95% CI 7.1 9.5), 16.9% (95% 14.6-19.2) and 24.4% (95% CI 20.3-28.5), respectively. CONCLUSIONS: No significant difference in the rate of end stage kidney disease was identified when comparing ileal conduits to continent urinary diversion. A significant risk of end stage kidney disease in the long term was identified in patients with post-cystectomy survival beyond 5 years. PMID- 25444985 TI - MUSIC: patterns of care in the radiographic staging of men with newly diagnosed low risk prostate cancer. AB - PURPOSE: MUSIC is a statewide consortium of 42 urology practices that aims to improve the quality of prostate cancer care in Michigan. As an initial priority, we examined patterns of care in the radiographic staging of men with newly diagnosed prostate cancer. We determined whether collaborative-wide data review and performance feedback would decrease the imaging rate in men with low risk prostate cancer. MATERIALS AND METHODS: Practices submitted standardized data, including the use and results of staging computerized tomography and bone scan, to a web based clinical registry of all men with newly diagnosed prostate cancer. We identified all patients with low risk prostate cancer and compared imaging use patterns before and after practice level performance feedback and guideline review, which were provided at collaborative-wide meetings. RESULTS: In MUSIC 813 patients were newly diagnosed with low risk prostate cancer during the 19-month study period. Of 410 patients diagnosed in the prefeedback period (phase I) 15 (3.7%) and 21 (5.2%) underwent bone scan and computerized tomography, respectively. Of 403 patients diagnosed after feedback (phase II) radiographic staging was done in 5 men (1.3%) with bone scan and in 13 (3.2%) with computerized tomography (p = 0.03 and 0.17, respectively). CONCLUSIONS: The overall rate of radiographic staging in men with newly diagnosed low risk prostate cancer was appropriately low. The imaging rate decreased even further after collaborative education and performance feedback. MUSIC appears to be a successful tool for quality improvement, affecting practice patterns and increasing efficiency of care. PMID- 25444987 TI - Prognostic impact of synchronous second primary malignancies on the overall survival of patients with metastatic prostate cancer. AB - PURPOSE: We determined the prognostic impact of a synchronous second primary malignancy on overall survival in patients with metastatic prostate cancer. Identifying features that stratify the risk of overall survival is critical for judiciously applying definitive therapy. MATERIALS AND METHODS: We retrospectively analyzed the records of 582 consecutive patients with prostate cancer diagnosed with metastasis between May 7, 1998 and August 27, 2011. Patient age, body mass index, ECOG performance status, Charlson comorbidity index, prostate specific antigen, T and N stages, Gleason and ASA(r) scores, progression to castration resistant prostate cancer, prior local treatments and synchronous second primary malignancies at metastasis were assessed. A synchronous second primary malignancy was defined as a cytologically or histologically proven solid malignancy. Cox proportional hazards regression analysis was done to estimate overall survival by second primary type and evaluate predictive variables. RESULTS: A total of 164 patients (28.1%) had a synchronous second primary malignancy, of which colorectal (9.1%), stomach (7.3%) and lung (7.1%) cancers were the most prevalent types. During a median followup of 34.1 months patients without a synchronous second primary malignancy had a significantly higher overall survival rate than those with lung or stomach cancer. However, men without a second malignancy had outcomes comparable to those in men with colorectal cancer. Clinical stage T4 or greater, ASA score 1 or greater and lung or stomach cancer were independent predictors of overall mortality. CONCLUSIONS: A substantial proportion of patients with metastatic prostate cancer present with a synchronous second primary malignancy. Definitive therapy targeting prostate cancer may confer a limited survival benefit in patients with synchronous lung or stomach cancer. PMID- 25444988 TI - Hounsfield density of renal papillae in stone formers: analysis based on stone composition. AB - PURPOSE: We examined renal papillary Hounsfield density in stone formers with all common stone subtypes to further understand the pathophysiology of stone formation. MATERIALS AND METHODS: Using computerized tomography we measured the Hounsfield density of a 0.2 cm(2) renal papillary area in patients with a single renal calyceal stone. Results were compared with those in patients without a nephrolithiasis history who served as controls. Stone composition was determined by stone passage or extraction during endoscopic procedures using infrared spectroscopy and polarized microscopy. We measured the Hounsfield density of the stone bearing calyx and of a single calyx from the upper, middle and lower poles of each kidney. RESULTS: Mean +/- SD renal papillary Hounsfield density in controls was 36.2 +/- 4.0 HU. In patients with stones Hounsfield density was significantly greater than in controls in stone bearing calyces, nonstone bearing calyces in the affected kidney and calyces in the contralateral nonstone bearing kidney for all stone composition subtypes (range 48.4 to 61.3 HU, each p <0.001). CONCLUSIONS: Patients with kidney stones regardless of composition showed the unique radiographic characteristic of increased renal papillary Hounsfield density. This was true for all calyces and for each kidney in all stone formers with a single renal calyceal stone. This radiographic evidence supports the role of renal papillary deposits or plaques in the pathophysiology of stone formation. PMID- 25444989 TI - Congenital penile pathology is associated with abnormal development of the dartos muscle: a prospective study of primary penile surgery at a tertiary referral center. AB - PURPOSE: Pathophysiological mechanisms leading to chordee in patients with hypospadias and to the hidden state of buried penis in the prepubic fat remain unclear. Resection of dartos tissue usually makes the penis straight in patients with hypospadias and corrects it in those with buried penis, suggesting a common pathophysiology related to dartos tissue. MATERIALS AND METHODS: Tissue samples from 113 children undergoing primary penile surgery for hypospadias (94 patients), epispadias (1) or buried penis (18) were collected between November 2011 and September 2013. Tissue samples from 79 children undergoing circumcision for nonmedical reasons served as controls. All samples were stained with smooth muscle actin and analyzed by the same pathologist, who was blinded to indication for surgery. Chi-square and Fisher exact tests were applied. RESULTS: Three different dartos tissue patterns were observed. Pattern I (normal) consisted of smooth muscle fibers of dartos tissue organized in a parallel configuration in the subcutaneous tissue. Pattern II was characterized by poorly developed and hypotrophic smooth muscle fibers. Pattern III was determined by randomly distributed smooth muscle fibers in the subcutaneous tissue, without parallel configuration. Pattern I was observed in 45 circumcision specimens (64%). Of buried penis cases 78% were considered abnormal (pattern II in 4 cases and III in 10, p = 0.001). Of hypospadias cases 70% were considered abnormal (pattern II in 31 cases, III in 32, and mixed II and III in 3, p < 0.001). The only epispadias case was designated pattern II. CONCLUSIONS: Congenital penile pathology (hypospadias, buried penis) is associated with structural anomalies in dartos tissue. Further research is needed to unveil the pathophysiology of the condition. PMID- 25444990 TI - The effect of the modified Z trendelenburg position on intraocular pressure during robotic assisted laparoscopic radical prostatectomy: a randomized, controlled study. AB - PURPOSE: The Trendelenburg position has a dramatic effect on circulation, consequently increasing cerebral and intraocular pressure. We evaluated whether modifying the Trendelenburg position would minimize the increase in intraocular pressure. MATERIALS AND METHODS: In this prospective, randomized, controlled study we compared intraocular pressure in patients undergoing robot-assisted laparoscopic radical prostatectomy while in the Trendelenburg position or the modified Z Trendelenburg position. In group 1 intraocular pressure, blood pressure and endotracheal CO2 were measured in the patient at anesthesia induction (time 1), before positioning (time 2), and while in the Trendelenburg position (time 3) and in the modified Z Trendelenburg position (time 4). They were also measured after pneumoperitoneum (time 5), every 30 minutes (times 6 to 16), while supine at the end of pneumoperitoneum (time 17) and before awakening (time 18). We modified the Trendelenburg position by placing the head and shoulders horizontally. RESULTS: Group 1 included 29 patients in the modified Z Trendelenburg position. Group 2 included 21 patients in the Trendelenburg position. No difference was found in patient demographics or surgical outcomes. Median intraocular pressure was in the low normal range at times 1 and 2, and increased in time 3 in each group. From time 4 intraocular pressure decreased and at all time points it was significantly lower in group 1 by a mean of 4.61 mm Hg (95% CI -6.90-2.30, p <0.001). At time 17 mean intraocular pressure decreased to normal (19.6 mm Hg) in group 1 but remained in the hypertensive range (24.9 mm Hg) in group 2. At time 18 mean intraocular pressure was 17 mm Hg in each group. Blood pressure was significantly lower in group 1 with a mean reduction in systolic and diastolic pressure of 6.3 and 4.3 mm Hg, respectively. CONCLUSIONS: Our results suggest that modifying the Trendelenburg position during robot assisted laparoscopic radical prostatectomy has a significant positive effect on patient neuro-ocular safety by lowering intraocular pressure and accelerating its recovery to the normal range without affecting the operation. PMID- 25444991 TI - Temporal trends and factors associated with systemic therapy after cytoreductive nephrectomy: an analysis of the National Cancer Database. AB - PURPOSE: We evaluated temporal trends in systemic therapy use in patients undergoing cytoreductive nephrectomy for metastatic renal cell carcinoma. We used data from a large national cancer registry and assessed characteristics associated with the receipt of systemic treatment. MATERIALS AND METHODS: We reviewed the NCDB to identify patients with stage IV renal cell carcinoma who underwent cytoreductive nephrectomy between 1998 and 2010. Systemic therapy was defined as immunotherapy and/or chemotherapy, including targeted agents. We evaluated associations between clinicopathological features and receipt of systemic therapy using multivariable logistic regression with generalized estimating equations. RESULTS: Of 22,409 patients with metastatic renal cell carcinoma treated with cytoreductive nephrectomy 8,830 (39%) received systemic therapy. Use of systemic therapy increased from 32% of cases in 1998 to 49% in 2010 (p < 0.001). After adjustment older patient age (71 years or greater OR 0.36, CI 0.31-0.43), increasing comorbidity count (Charlson comorbidity index 2 or greater OR 0.79, 95% CI 0.68-0.92), papillary histology (OR 0.81, 95% CI 0.71 0.93), sarcomatoid histology (OR 0.88, 95% CI 0.80-0.98), Medicaid (OR 0.61, 95% CI 0.5-0.74), Medicare (OR 0.70, 95% CI 0.62-0.79) and no insurance (OR 0.75, 95% CI 0.63-0.91) were associated with significantly decreased systemic therapy use. Male gender (OR 1.05, 95% CI 1.02-1.08) predicted an increased likelihood of systemic therapy. CONCLUSIONS: Systemic therapy in patients undergoing cytoreductive nephrectomy has increased with time, coinciding with the introduction of targeted therapies. Nevertheless, still less than half of such patients receive systemic treatment. While the etiology of the lack of treatment is likely multifactorial, the potential health policy implications of disparities in care warrant further investigation. PMID- 25444994 TI - A cost comparative study of Gamma Knife radiosurgery versus open surgery for intracranial pathology. AB - Resection is the traditional treatment for common intracranial pathologies including brain metastases, arteriovenous malformations (AVM), and acoustic neuromas. However, more recently Gamma Knife radiosurgery (GKRS; Elekta AB, Stockholm, Sweden) has emerged as an effective, alternative treatment modality. There are limited data investigating the cost effectiveness of these two treatment modalities. In this study, we compare the costs of GKRS and open surgical excision. This was a retrospective study including all patients at a single-institution across a 3 year period with at least 12 months of post resection follow-up for brain metastases, acoustic neuromas, or AVM. The costs of care were then totaled and compared to known average costs for GKRS at the same institution. The average 12 month costs of treating patients with brain metastases, acoustic neuromas, and AVM using open surgery were USD$55,938, $67,538, and $78,332, respectively. The average 12 month costs of treating brain metastases, acoustic neuromas, and AVM with GKRS were USD$23,069, $37,840, and $46,293, respectively. This shows that GKRS was on average 58.8%, 44.0%, and 40.9% of the cost of open surgery for brain metastases, acoustic neuromas, and AVM, respectively. GKRS is a cost effective, first-line, alternative to open surgery for treatment of brain metastatic lesions, acoustic neuromas, and AVM in selected patients. This result conforms to previous studies, which also demonstrate that radiosurgery is the more cost-effective treatment for brain metastases and acoustic neuromas when patients are well suited for either approach. Further prospective studies are needed to show that this result is valid at other institutions. PMID- 25444993 TI - Repair mechanisms help glioblastoma resist treatment. AB - Glioblastoma multiforme (GBM) is a malignant and incurable glial brain tumour. The current best treatment for GBM includes maximal safe surgical resection followed by concomitant radiotherapy and adjuvant temozolomide. Despite this, median survival is still only 14-16 months. Mechanisms that lead to chemo- and radio-resistance underpin treatment failure. Insights into the DNA repair mechanisms that permit resistance to chemoradiotherapy in GBM may help improve patient responses to currently available therapies. PMID- 25444995 TI - Ischemic complications after tailored carotid artery stenting in different subpopulations with high-grade stenosis: feared but rare. AB - Although the procedural and postoperative safety profile of carotid artery stenting (CAS) has been steadily improving, many centers still recommend carotid endarectomy (CEA) over CAS. We assessed outcomes (procedural and postoperative stroke) following tailored CAS in a cohort of patients managed at a single academic medical center. Outcomes for patients with carotid artery stenosis treated from 2005-2013 with CAS were retrospectively reviewed. Stenosis was assessed with Doppler ultrasonography and/or CT angiogram, and angiography. Symptomatic and asymptomatic patients were dichotomized (based on the North American Symptomatic Carotid Endarterectomy Trial [NASCET] and the Asymptomatic Carotid Atherosclerosis Study [ACAS]). CAS technique was chosen based on angiographic and clinical characteristics; procedures were performed with/without pre-angioplasty, cerebral protection, and post-dilation. Endpoints were cumulative incidence of ipsilateral stroke, myocardial infarction, and death within 30 days (primary) or 12 months (secondary). Overall 249 patients (151 men/98 women; mean age 69.9 years) with 254 carotid stenoses were included; 148 lesions (58%) were asymptomatic, and 106 (42%) were symptomatic. CAS was successfully performed in all lesions. At 30 days, ipsilateral transient ischemic attack (TIA)/minor stroke was seen in 6/104 (5.8%) symptomatic patients and no asymptomatic patients; there was no myocardial infarction or ipsilateral major stroke. At 12 months, there was ipsilateral TIA/minor stroke in an additional 3/98 (3.1%) symptomatic and 1/127 (0.8%) asymptomatic patients, and major stroke in 1/98 (1%). The incidence of stroke after CAS compares favorably with rates reported after CEA. The majority of peri-procedural ischemic events following CAS are TIA/minor strokes causing only transient or minor functional impact; major disabling stroke is rare with current techniques. PMID- 25444996 TI - A subchronic toxicity study, preceded by an in utero exposure phase, with refined arachidonic acid-rich oil (RAO) derived from Mortierella alpina XM027 in rats. AB - To evaluate the potential toxicity of refined arachidonic acid-rich oil (RAO) derived from Mortierella alpina (M. alpina) XM027, we performed a 90-day subchronic study in F1 Sprague Dawley (SD) rats. This study was preceded by a 4 week pretreatment period of parental (F0) rats and exposure of the F0 dams throughout mating, gestation, and lactation. The results indicated that RAO, at dose levels of 0.5%, 1.5%, and 5%, did not affect either reproductive performance of the parental rats, or any characteristics of the pups. In the subchronic study with the offspring (F1) rats, no treatment related abnormalities were observed. In summary, no observable adverse effect level (NOAEL) in this study was placed at 5% RAO, the highest level tested. This level corresponds to approximately 3750mg/kg in F0 females, 2850mg/kg in F0 males, 4850mg/kg in F1 females, and 4480mg/kg in F1 males. PMID- 25444997 TI - Comparison of select analytes in aerosol from e-cigarettes with smoke from conventional cigarettes and with ambient air. AB - Leading commercial electronic cigarettes were tested to determine bulk composition. The e-cigarettes and conventional cigarettes were evaluated using machine-puffing to compare nicotine delivery and relative yields of chemical constituents. The e-liquids tested were found to contain humectants, glycerin and/or propylene glycol, (?75% content); water (<20%); nicotine (approximately 2%); and flavor (<10%). The aerosol collected mass (ACM) of the e-cigarette samples was similar in composition to the e-liquids. Aerosol nicotine for the e cigarette samples was 85% lower than nicotine yield for the conventional cigarettes. Analysis of the smoke from conventional cigarettes showed that the mainstream cigarette smoke delivered approximately 1500times more harmful and potentially harmful constituents (HPHCs) tested when compared to e-cigarette aerosol or to puffing room air. The deliveries of HPHCs tested for these e cigarette products were similar to the study air blanks rather than to deliveries from conventional cigarettes; no significant contribution of cigarette smoke HPHCs from any of the compound classes tested was found for the e-cigarettes. Thus, the results of this study support previous researchers' discussion of e cigarette products' potential for reduced exposure compared to cigarette smoke. PMID- 25444992 TI - Relationship between chronic nonurological associated somatic syndromes and symptom severity in urological chronic pelvic pain syndromes: baseline evaluation of the MAPP study. AB - PURPOSE: We used MAPP data to identify participants with urological chronic pelvic pain syndromes only or a chronic functional nonurological associated somatic syndrome in addition to urological chronic pelvic pain syndromes. We characterized these 2 subgroups and explored them using 3 criteria, including 1) MAPP eligibility criteria, 2) self-reported medical history or 3) RICE criteria. MATERIALS AND METHODS: Self-reported cross-sectional data were collected on men and women with urological chronic pelvic pain syndromes, including predominant symptoms, symptom duration and severity, nonurological associated somatic syndrome symptoms and psychosocial factors. RESULTS: Of 424 participants with urological chronic pelvic pain syndromes 162 (38%) had a nonurological associated somatic syndrome, including irritable bowel syndrome in 93 (22%), fibromyalgia in 15 (4%), chronic fatigue syndrome in 13 (3%) and multiple syndromes in 41 (10%). Of 233 females 103 (44%) had a nonurological associated somatic syndrome compared to 59 of 191 males (31%) (p = 0.006). Participants with a nonurological associated somatic syndrome had more severe urological symptoms and more frequent depression and anxiety. Of 424 participants 228 (54%) met RICE criteria. Of 228 RICE positive participants 108 (47%) had a nonurological associated somatic syndrome compared to 54 of 203 RICE negative patients (28%) with a nonurological associated somatic syndrome (p < 0.001). CONCLUSIONS: Nonurological associated somatic syndromes represent important clinical characteristics of urological chronic pelvic pain syndromes. Participants with a nonurological associated somatic syndrome have more severe symptoms, longer duration and higher rates of depression and anxiety. RICE positive patients are more likely to have a nonurological associated somatic syndrome and more severe symptoms. Because nonurological associated somatic syndromes are more common in women, future studies must account for this potential confounding factor in urological chronic pelvic pain syndromes. PMID- 25444998 TI - Development of a category approach to predict the testicular toxicity of chemical substances structurally related to ethylene glycol methyl ether. AB - We propose a category approach to assessing the testicular toxicity of chemicals with a similar structure to ethylene glycol methyl ether (EGME). Based on toxicity information for EGME and related chemicals and accompanied by adverse outcome pathway information on the testicular toxicity of EGME, this category was defined as chemicals that are metabolized to methoxy- or ethoxyacetic acid, a substance responsible for testicular toxicity. A Japanese chemical inventory was screened using the Hazard Evaluation Support System, which we have developed to support a category approach for predicting the repeated-dose toxicity of chemical substances. Quantitative metabolic information on the related chemicals was then considered, and seventeen chemicals were finally obtained from the inventory as a shortlist for the category. Available data in the literature shows that chemicals for which information is available on the metabolic formation of EGME, ethylene glycol ethyl ether, methoxy- or ethoxyacetic acid do in fact possess testicular toxicity, suggesting that testicular toxicity is a concern, due to metabolic activation, for the remaining chemicals. Our results clearly demonstrate practical utility of AOP-based category approach for predicting repeated-dose toxicity of chemicals. PMID- 25444999 TI - Safety evaluation of Se-methylselenocysteine as nutritional selenium supplement: acute toxicity, genotoxicity and subchronic toxicity. AB - The significant toxicity of selenium emphasizes the need to assess the health risk of various selenocompounds as nutritional supplements. Se methylselenocysteine (SeMC) was recently reported to be more bioactive but the toxicological effects have not been sufficiently characterized. This study aimed to evaluate the safety of SeMC and provide the Acceptable Daily Intake (ADI) for its use in human diet. Our results demonstrated that SeMC, with the Median Lethal Dose (LD50) of 12.6 and 9.26mg/kg BW in female and male mice, was of high potent of health hazard under acute oral exposure, but a battery of tests including Ames test, micronucleus assay and mouse sperm malformation assay suggested that SeMC was not genotoxic. The repeated dose study indicated little systemic toxicity of SeMC at supernutritional levels (0.5, 0.7, 0.9mg/kg BW/day) after 90-day oral exposure. Importantly, the 95% lower confidence value of Benchmark Dose (BMDL) was estimated as 0.34mg/kg BW/day according to the elevated relative liver weight. The ADI for human was established at 3.4MUg/kg BW/day. The results suggested greater safety of SeMC as a nutritional selenium supplement, but health risk needs to be further evaluated when SeMC is applied beyond this level to achieve cancer chemoprevention. PMID- 25445001 TI - Evaluation of vinyl laurate in a battery of in vitro and in vivo tests for genotoxicity. AB - Vinyl laurate is a potential residual monomer in chewing gum base formulated with polyvinyl acetate vinyl laurate copolymer (PVAcVL). The genotoxic potential of vinyl laurate was examined in a battery of in vitro and in vivo genotoxicity tests. Vinyl laurate was not mutagenic in Ames tests. In addition, it was not mutagenic in the HPRT mutation assay in L5178Y cells. An in vitro mammalian chromosome aberration assay performed in CHO cells was equivocal. Vinyl laurate and/or its metabolites were not clastogenic in the mouse bone marrow micronucleus test. Kinetic data indicate that VL is metabolised to acetaldehyde and lauric acid. Both metabolites are well known and have been studied previously. Model calculations show, that any exposure to acetaldehyde from the consumption of PVAcVL containing chewing gum will remain far below levels of acetaldehyde exposure from food in which acetaldehyde occurs naturally. Direct exposure to VL will primarily be at the site of entry. The lack of toxicity in a 90-day repeated dose toxicity test, performed with VL doses up to approximately 3000 times higher than the maximal VL intake from the consumption of a typical piece of chewing gum, demonstrates a high safety margin. PMID- 25445000 TI - An analysis of legal warnings after drug approval in Thailand. AB - Drug risk management has many tools for minimizing risk and black-boxed warnings (BBWs) are one of those tools. Some serious adverse drug reactions (ADRs) emerge only after a drug is marketed and used in a larger population. In Thailand, additional legal warnings after drug approval, in the form of black-boxed warnings, may be applied. Review of their characteristics can assist in the development of effective risk mitigation. This study was a cross sectional review of all legal warnings imposed in Thailand after drug approval (2003-2012). Any boxed warnings for biological products and revised warnings which were not related to safety were excluded. Nine legal warnings were evaluated. Seven related to drugs classes and two to individual drugs. The warnings involved four main types of predictable ADRs: drug-disease interactions, side effects, overdose and drug-drug interactions. The average time from first ADRs reported to legal warnings implementation was 12 years. The triggers were from both safety signals in Thailand and regulatory measures in other countries outside Thailand. PMID- 25445002 TI - Regulatory acceptance and use of the Extended One Generation Reproductive Toxicity Study within Europe. AB - The two-generation study (OECD TG 416) is the standard requirement within REACH to test reproductive toxicity effects of chemicals with production volumes >100 tonnes. This test is criticized in terms of scientific relevance and animal welfare. The Extended One Generation Reproductive Toxicity Study (EOGRTS), incorporated into the OECD test guidelines in 2011 (OECD TG 443) has the potential to replace TG 416, while using only one generation of rats and being more informative. However, its regulatory acceptance proved challenging. This article reconstructs the process of regulatory acceptance and use of the EOGRTS and describes drivers and barriers influencing the process. The findings derive from literature research and expert interviews. A distinction is made between three sub-stages; The stage of Formal Incorporation of the EOGRTS into OECD test guidelines was stimulated by retrospective analyses on the value of the second generation (F2), strong EOGRTS advocates, animal welfare concern and changing US and EU chemicals legislation; the stage of Actual Regulatory Acceptance within REACH was challenged by legal factors and ongoing scientific disputes, while the stage of Use by Industry is influenced by uncertainty of registrants about regulatory acceptance, high costs, the risk of false positives and the manageability of the EOGRTS. PMID- 25445004 TI - Pulmonary histopathologic abnormalities and predictor variables in autopsies of burned pediatric patients. AB - Pulmonary abnormalities occur in 30-80% of fatalities after burn. The objective of our study is to investigate lung pathology in autopsy tissues of pediatric burn patients. METHODS: Three scientists with pathology training in pediatric burn care reviewed masked autopsy slides of burned children who died after admission to a burn center from 2002 to 2012 (n=43). Autopsy lung tissue was assigned scores for histologic abnormalities in 9 categories, including alveolar and interstitial fibrosis, hyaline membranes, and type II epithelial cell proliferation. Scores were then tested for correlation with age, TBSA burn, number of days between burn and death, time between burn and admission, and the presence of inhalation injury using analyses with linear models. RESULTS: Type II epithelial cell proliferation was significantly more common in cases with a longer time between burn and admission (p<0.02). Interstitial fibrosis was significantly more severe in cases with longer survival after burn (p<0.01). The scores for protein were significantly higher in cases with longer survival after burn (p<0.03). Enlarged air spaces were significantly more prominent in cases with longer survival after burn (p<0.01), and in cases with the presence of inhalation injury (p<0.01). CONCLUSIONS: Histological findings associated with diffuse alveolar damage (DAD), which is the pathological correlate of the acute respiratory distress syndrome (ARDS), were seen in approximately 42% of autopsies studied. Protein-rich alveolar edema, which is the abnormality that leads to ARDS, may occur from multiple causes, including inhalation injury. PMID- 25445005 TI - Brooke formula revisited. PMID- 25445003 TI - International observational study of nutritional support in mechanically ventilated patients following burn injury. AB - INTRODUCTION: It has been proposed that nutritional therapy in critically ill patients after major burn reduces mortality. However, the actual practice of nutrient delivery, and the effect on outcome, has not been described. STUDY OBJECTIVES: To evaluate international practices related to nutritional support and outcomes in mechanically ventilated patients with burn injury. METHODS: Data from the International Nutrition Surveys (2007-2011) for patients with a primary diagnosis of burn were extracted and analysed. RESULTS: Eighty-eight of 90 patients (aged 16-84 years) received enteral nutrition. The median time for initiation of enteral feeding was 17 h [range 0-65]. Fifty patients (57%) had interruptions to nutrient delivery, most often these interruptions were fasting for operative procedures. There were substantive energy and protein deficits [943 (654) kcal/day and 49 (41) g/day, respectively; mean (SD)]. Nineteen (21%) patients died within 60 days of admission, and the energy and protein deficits were greater in those that died compared with survivors [died vs. survived, energy: 1251 (742) vs. 861 (607) kcal/d; p=0.02; and protein 67(42) vs. 44(39) g/d; p=0.03]. Energy and protein deficits were associated with increased mortality with the greater the deficit, the stronger the association with death (odds ratio for death: energy deficit/100 kcal 1.10 (1.01, 1.19); p=0.028 and protein/10 g 1.16 (1.01, 1.33); p=0.037). Results were similar and remained significant after adjusting for severity of illness. CONCLUSIONS: Mechanically ventilated patients following burn develop substantial energy and protein deficits, with lesser deficits observed in survivors. PMID- 25445006 TI - DNA methylation modifies urine biomarker levels in 1,6-hexamethylene diisocyanate exposed workers: a pilot study. AB - DNA methylation may mediate inter-individual responses to chemical exposure and, thus, modify biomarker levels of exposure and effects. We analyzed inter individual differences in inhalation and skin exposure to 1,6-hexamethylene diisocyanate (HDI) and urine biomarker 1,6-hexamethylene diamine (HDA) levels in 20 automotive spray-painters. Genome-wide 5-methyl cytosine (CpG) DNA methylation was assessed in each individual's peripheral blood mononuclear cells (PBMC) DNA using the Illumina 450K CpG array. Mediation analysis using linear regression models adjusted for age, ethnicity, and smoking was conducted to identify and assess the association between HDI exposure, CpG methylation, and urine HDA biomarker levels. We did not identify any CpGs common to HDI exposure and biomarker level suggesting that CpG methylation is a mediator that only partially explains the phenotype. Functional significance of genic- and intergenic-CpG methylation status was tested using protein-protein or protein-DNA interactions and gene-ontology enrichment to infer networks. Combined, the results suggest that methylation has the potential to affect HDI mass transport, permeation, and HDI metabolism. We demonstrate the potential use of PBMC methylation along with quantitative exposure and biomarker data to guide further investigation into the mediators of occupational exposure and biomarkers and its role in risk assessment. PMID- 25445007 TI - Biomarkers of polycyclic aromatic hydrocarbon exposure in European coke oven workers. AB - Biomonitoring is an excellent method for capturing the results of all exposures, regardless of route. Coke oven workers include certain groups that have the potential for high exposure to polycyclic aromatic hydrocarbons (PAH) and other materials. Biomarkers of exposure to these agents include PAH metabolites as markers of internal dose and carcinogen-DNA adducts as measure of effective dose. The purpose of this study was to determine the levels of these biomarkers in persons with different job duties in a modern coke oven plant. We report that the mean levels of 1-hydroxypyrene (1HP) and carcinogen DNA adducts in the exfoliated urothelial cells of coke oven workers are increased the closer a group of workers is to the ovens and highest in the top oven workers with average 1HP level of 11.6 MUg/l and 22 adducts per 10(9) unadducted nucleotides. Both 1HP and carcinogen DNA adduct levels increased in supervisors, area workers, side oven workers, top and side oven workers, and top oven workers, respectively. These data are the first to demonstrate an increase in target organ genotoxicity in coke oven workers and a relationship with other biomarkers. Future studies will determine the identity of the DNA adducts, their correlation with 1HP levels and the relationship between levels in individual workers. PMID- 25445008 TI - Contribution of human esterases to the metabolism of selected drugs of abuse. AB - Human esterases such as the human carboxylesterases (hCES) are important for the catalytic ester hydrolysis of xenobiotics and they play an important role in the detoxification of drugs (e.g., cocaine) but also in the activation of prodrugs (e.g., ramipril). Therefore, the aim of the presented study was to characterize the enzyme-catalyzed ester hydrolysis of ten drugs (cocaine, dimethocaine, ethylphenidate, 4-fluoro-3alpha-tropacocaine, 4-fluoro-3beta-tropacocaine, heroin, methylphenidate, mitragynine, ramipril, and thebacon) by different esterase-containing systems (recombinant hCES1b, hCES1c, and hCES2, pooled human liver microsomes, pooled human liver S9 fraction, and pooled human plasma). Michaelis-Menten kinetic studies were done using in vitro incubations with the aforementioned enzyme-containing systems and LC coupled to ion trap MS for analysis. Ramipril and heroin were used as known model substrates to ensure reliable incubation conditions. The hydrolysis reactions followed classic Michaelis-Menten kinetics with exception of cocaine and 4-fluoro-3alpha tropacocaine, for which hydrolysis rate was too low for reliable modeling. The substrates were mainly metabolized by the following enzymes systems: cocaine, hCES1c; dimethocaine, human plasma esterases; ethylphenidate, hCES1c; 4-fluoro 3beta-tropacocaine, human plasma esterases; heroin, hCES2; methylphenidate, hCES1c; mitragynine, hCES1c; ramipril, hCES1b; thebacon, hCES2. Compounds bearing a small alcohol part and a larger acyl part showed higher affinity to hCES1 while those with a large alcohol part showed higher affinity to hCES2. The collected data are important for prediction of drug-drug or drug-food interactions as well as for individual variations in metabolism of drugs of abuse due to enzyme polymorphisms. PMID- 25445009 TI - Comparative metabolism and pharmacokinetics of diisobutyl ketone and diisobutyl carbinol in male SD rats. AB - Diisobutyl ketone (DIBK) and diisobutyl carbinol (DIBC) are important organic solvents widely used as industrial intermediates. It was hypothesized that DIBC and DIBK have common metabolic pathways and metabolites, and as such, toxicological data on DIBK could be used to characterize the hazards of DIBC. To confirm or refute this hypothesis a comparative metabolism and pharmacokinetics assessment of DIBK and DIBC was conducted. Dosing was via single oral gavage dosing in male SD rats, followed by blood collection, metabolite identification, major biomarker quantitation, and pharmacokinetics analysis. Overall, the major metabolites of both DIBC and DIBK in blood were their corresponding monohydroxylated metabolites (DIBC alcohol and DIBK alcohol) with the site of hydroxylation at the sigma and sigma-1 positions, respectively. Quantitative analysis of DIBC, DIBK, DIBC-alcohol, and DIBK-alcohol in blood samples collected from 5min to 120h after single dosing indicated the following: (1) DIBC and DIBK are both well absorbed following oral gavage with substantial evidence of enterohepatic recirculation of DIBK, DIBC, DIBK-alcohol, and DIBC-alcohol; (2) DIBK and DIBC are interconverted metabolically in rats; (3) DIBC and DIBK have similar bioavailability after oral administration; (4) higher systemic exposure was found for DIBK-alcohol than DIBC-alcohol, implying that DIBC-alcohol may be more easily conjugated and eliminated in bile. In summary, the metabolic similarities and the difference in systemic exposure to metabolites between these substances observed in the current study support the hypothesis that DIBC might have a lower potential toxicity than that of DIBK. The current study results support that toxicological data on DIBK could be used to characterize the hazards of DIBC. PMID- 25445010 TI - Pathway analysis for a genome-wide association study of pneumoconiosis. AB - OBJECTIVE: The aim of this investigation was to identify pathways involved in pneumoconiosis susceptibility, clarify their potential mechanisms, and generate SNP-to-gene to pathway hypotheses using an analytical pathway-based approach. METHODS: The identify candidate causal SNPs and pathways (ICSNPathway) was used to perform pathway analysis of a GWAS dataset for pneumoconiosis, which, after quality control filtering, harbored genotypes of 710,999 SNPs in 202 pneumoconiosis cases and 198 exposed controls. The first stage involved the pre selection of candidate SNPs by linkage disequilibrium analysis and functional annotation of the most significant SNPs; the second stage involved annotation of biological mechanisms for the selected candidate SNPs using improved-gene set enrichment analysis. RESULTS: ICSNPathway analysis identified 18 candidate SNPs, involving 13 genes and 30 candidate pathways and revealed 13 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was that rs8120 and rs2292151 alters the role of TICAM1, a gene involved in various pathways and processes, including positive regulation of tumor necrosis factor (TNF) production, innate immune response-activating signal transduction, positive regulation of the innate immune response, and the biosynthesis of type I interferon (0.00140% compared with 2 (18%) wealthier families (P = .02). In univariate analyses, 11 (61%) low-income children experienced graft-versus host disease (GVHD) of any grade in the first 180 days after HSCT compared with 2 (7%) wealthier children (P = .004). We conclude that low income and, in particular, material hardship, are prevalent in a New England pediatric HSCT population and represent targets for improvement in quality of life. The role of poverty in mediating GVHD deserves further investigation in larger studies that can control for known risk factors and may provide a targetable source of transplantation-associated morbidity. PMID- 25445022 TI - The impact of amino acid variability on alloreactivity defines a functional distance predictive of permissive HLA-DPB1 mismatches in hematopoietic stem cell transplantation. AB - A major challenge in unrelated hematopoietic stem cell transplantation (HSCT) is the prediction of permissive HLA mismatches, ie, those associated with lower clinical risks compared to their nonpermissive counterparts. For HLA-DPB1, a clinically prognostic model has been shown to be matching for T cell epitope (TCE) groups assigned by cross reactivity of T cells alloreactive to HLA DPB1*09:01; however, the molecular basis of this observation is not fully understood. Here, we have mutated amino acids (aa) in 10 positions of HLA DPB1*09:01 to other naturally occurring variants, expressed them by lentiviral vectors in B cell lines, and quantitatively measured allorecognition by 17 CD4(+) T cell effectors from 6 unrelated individuals. A significant impact on the median alloresponse was observed for peptide contact positions 9, 11, 35, 55, 69, 76, and 84, but not for positions 8, 56, and 57 pointing away from the groove. A score for the "functional distance" (FD) from HLA-DPB1*09:01 was defined as the sum of the median impact of polymorphic aa in a given HLA-DPB1 allele on T cell alloreactivity. Established TCE group assignment of 23 alleles correlated with FD scores of <=0.5, 0.6 to 1.9 and >=2 for TCE groups 1, 2, and 3, respectively. Based on this, prediction of TCE group assignment will be possible for any given HLA-DPB1 allele, including currently 367 alleles encoding distinct proteins for which T cell cross reactivity patterns are unknown. Experimental confirmation of the in silico TCE group classification was successfully performed for 7 of 7 of these alleles. Our findings have practical implications for the applicability of TCE group matching in unrelated HSCT and provide new insights into the molecular mechanisms underlying this model. The innovative concept of FD opens new potential avenues for risk prediction in unrelated HSCT. PMID- 25445024 TI - Improved outcomes after autologous bone marrow transplantation for children with relapsed or refractory Hodgkin lymphoma: twenty years experience at a single institution. AB - The purpose of this study is to evaluate the survival of pediatric patients undergoing autologous bone marrow transplantation (auBMT) for relapsed or refractory Hodgkin lymphoma (rrHL) and to identify factors that might contribute to their outcome. We reviewed the records and clinical course of 89 consecutive rrHL patients <= 21 years old who underwent auBMT at Stanford Hospitals and Clinics and the Lucile Packard Children's Hospital, Stanford between 1989 and 2012. We investigated, by multiple analyses, patient, disease, and treatment characteristics associated with outcome. Endpoints were 5-year overall and event free survival. Our findings include that cyclophosphamide, carmustine, and etoposide (CBV) as a conditioning regimen for auBMT is effective for most patients <= 21 years old with rrHL (5-year overall survival, 71%). Transplantation after the year 2001 was associated with significantly improved overall survival compared with our earlier experience (80% compared with 65%). Patients with multiply relapsed disease or with disease not responsive to initial therapy fared less well compared with those with response to initial therapy or after first relapse. Administration of post-auBMT consolidative radiotherapy (cRT) also appears to contribute to improved survival. We are able to conclude that high-dose chemotherapy with CBV followed by auBMT is effective for the treatment of rrHL in children and adolescents. Survival for patients who undergo auBMT for rrHL has improved significantly. This improvement may be because of patient selection and improvements in utilization of radiotherapy rather than improvements in chemotherapy. Further investigation is needed to describe the role of auBMT across the entire spectrum of patients with rrHL and to identify the most appropriate preparative regimen with or without cRT therapy in the treatment of rrHL in young patients. PMID- 25445026 TI - Choreito formula for BK virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. AB - Therapy for BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC) is limited after hematopoietic stem cell transplantation (HSCT). We examined whether choreito, a formula from Japanese traditional Kampo medicine, is effective for treating BKV-HC. Among children who underwent allogeneic HSCT between October 2006 and March 2014, 14 were diagnosed with BKV-HC (median, 36 days; range, 14 to 330 days) after HSCT, and 6 consecutive children received pharmaceutical-grade choreito extract granules. The hematuria grade before treatment was significantly higher in the choreito group than in the nonchoreito group (P = .018). The duration from therapy to complete resolution was significantly shorter in the choreito group (median, 9 days; range, 4 to 17 days) than in the nonchoreito group (median, 17 days; range, 15 to 66 days; P = .037). In 11 children with macroscopic hematuria, the duration from treatment to resolution of macroscopic hematuria was significantly shorter in the choreito group than in the nonchoreito group (median, 2 days versus 11 days; P = .0043). The BKV load in urine was significantly decreased 1 month after choreito administration. No adverse effects related to choreito administration were observed. Choreito may be a safe and considerably promising therapy for the hemostasis of BKV-HC after HSCT. PMID- 25445023 TI - Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research. AB - Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P < .0001), and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, nonrelapse mortality has decreased over time, but at 5 years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research. PMID- 25445027 TI - Musculoskeletal, Neurologic, and Cardiopulmonary Aspects of Physical Rehabilitation in Patients with Chronic Graft-versus-Host Disease. AB - Chronic graft-versus-host disease (cGVHD) has the potential to cause significant morbidity and mortality in people who undergo allogeneic hematopoietic stem cell transplantation. Management of complications due to cGVHD can be challenging because of multiorgan involvement and variable presentation of the disease. This paper outlines the diagnosis and management of musculoskeletal, neurologic, and cardiopulmonary manifestations of cGVHD that have the potential to cause profound functional impairment and that may significantly impact quality of life and lifespan. Expert evaluation by a physical medicine and rehabilitation physician and multidisciplinary team may be beneficial in the treatment of the disease sequelae, and examples of specific rehabilitation interventions are described. PMID- 25445025 TI - Long-term outcomes of patients with persistent indolent B cell malignancies undergoing nonmyeloablative allogeneic transplantation. AB - Relapse is least common in patients with indolent B cell (iB) malignancies (ie, iB non-Hodgkin lymphoma [NHL]) who undergo nonmyeloablative allogeneic transplantation (NMAT) in complete remission (CR). However, for the many patients unable to achieve this state, outcomes are poorly described and methods to improve results are unknown. We sought to describe the long-term follow-up and predictive factors for these poor-risk patients unable to achieve CR before NMAT. We identified and evaluated patients with iB-NHL including chronic lymphocytic leukemia treated with fludarabine/total body irradiation-based NMAT that had evidence of persistent disease before NMAT. From December 1998 to April 2009, 89 patients were identified, most commonly with small/chronic lymphocytic lymphoma (n = 62) and follicular lymphoma (n = 24). Pretransplant anti-CD20 radioimmunotherapy (RIT) using standard yttrium-90-ibritumomab tiuxetan was administered to 18 patients (20%) who more frequently had chemoresistant disease (81% versus 39%, P = .003), disease bulk > 5 cm (61% versus 15%, P < .001), thrombocytopenia < 25k/MUL (33% versus 7%, P = .002), and Hematopoietic Cell Transplant Comorbidity Index scores >= 3 (72% versus 37%, P = .006). After adjusting for these imbalances, RIT-treated patients had improved rates of progression-free survival (PFS) (hazard ratio [HR] = .4; 95% confidence interval [CI], .2 to .9, P = .02) and overall survival (OS) (HR = .3; 95% CI, .1 to .8, P = .008) compared with the non-RIT group. The 3-year adjusted estimates of PFS and OS for the RIT and non-RIT groups were 71% and 87% versus 44% and 59%, respectively. The use of RIT was the only factor independently associated with improved PFS and OS. Rates of nonrelapse mortality and graft-versus-host disease (GVHD) were similar between the 2 groups, although over 70% of patients developed clinically significant acute or chronic GVHD. In conclusion, despite relatively high rates of GVHD, patients with persistent iB-NHL can derive durable benefit from NMAT. PMID- 25445028 TI - Impact of pretransplant therapy and depth of disease response before autologous transplantation for multiple myeloma. AB - Patients with multiple myeloma (MM) who are eligible for autologous stem cell transplantation (ASCT) typically receive a finite period of initial therapy before ASCT. It is not clear if patients with suboptimal (less than a partial) response to initial therapy benefit from additional alternative therapy with intent to maximize pretransplant response. We identified 539 patients with MM who had an ASCT after having achieved less than a partial response (PR) to first-line induction chemotherapy between 1995 and 2010. These patients were then divided into 2 groups: those who received additional salvage chemotherapy before ASCT (n = 324) and those who had no additional salvage chemotherapy immediately before ASCT (n = 215). Additional pretransplant chemotherapy resulted in deepening responses in 68% (complete response in 8% and PR in 60%). On multivariate analysis there was no impact of pretransplant salvage chemotherapy on treatment related mortality, risk for relapse, progression-free survival, or overall survival. In conclusion, for patients achieving less than a PR to initial induction therapy, including with novel agent combinations, additional pre-ASCT salvage chemotherapy improved the depth of response and pre-ASCT disease status but was not associated with survival benefit. PMID- 25445029 TI - An optimal initial tension for rat basilar artery in wire myography. AB - AIMS: The aim of the present study was to determine the optimal initial tension for the rat basilar artery when using wire myography. METHODS: Rat basilar arteries were mounted in myograph baths. A normalization procedure was performed. K(+)-rich (60mM) buffer solution-induced tension was measured in different initial tensions. RESULTS: The initial tension of the basilar artery increased from 0.47 to 2.68mN/mm. Contractile tension was also elevated along with the initial tension. When the initial tension reached 1.63mN/mm, K(+)-induced contractile tension of basilar artery achieved its maximum. Thereafter, contractile tension declined as initial tension increased. The duration of equilibration time did not affect K(+)-induced contractile tension. CONCLUSION: The optimal initial tension is 1.63+/-0.01mN/mm in rat basilar arteries when using wire myography. PMID- 25445031 TI - Apolipoprotein A-I enhances proliferation of human endothelial progenitor cells and promotes angiogenesis through the cell surface ATP synthase. AB - BACKGROUND: Human endothelial progenitor cells (hEPC) correspond to a subtype of stem cells which, in the presence of angiogenic stimuli, can be mobilized from bone marrow to circulation and then recruited to the damaged endothelium, where they differentiate into mature endothelial cells. High-density lipoproteins (HDL) increase the level and functionality (proliferation, migration, differentiation, angiogenesis capacity) of circulating hEPC; however, the contribution of receptors for HDL and/or apolipoprotein A-I (apoA-I), the main HDL apolipoprotein, in these effects is still unclear. On mature endothelial cells, the cell surface F1-ATP synthase has been previously characterized as a high affinity receptor of apoA-I, whereas the scavenger receptor SR-BI mainly binds with fully lipidated HDL and displays a poor affinity for lipid-free apoA-I. Furthermore, it was shown that apoA-I binding to surface ATP synthase on mature endothelial cells promotes cell proliferation, whereas inhibits apoptosis. In this work, we aimed to determine the effect of apoA-I in the proliferation and the angiogenic capacity of early hEPC, and the contribution of the cell surface ATP synthase in these events. RESULTS: We first evidenced that early hEPC express the ATP synthase at the surface of nonpermeabilized cells, where it is not colocalized with MitoTracker, a mitochondria marker. ApoA-I (50 MUg/mL) increases hEPC proliferation (+14.5%, p<0.001) and potentiates the effect of hEPC on a cellular model of angiogenesis, with an increase of +31% (p<0.01) in branch point counting and in tubule length. These effects of apoA-I were totally reversed in the presence of ATP synthase inhibitors, such as IF1 or oligomycin, whereas the inhibition of the HDL receptor, SR-BI, partially inhibits these events. CONCLUSIONS: These results provide the first evidence that surface ATP synthase is expressed on early hEPC, where it mediates apoA-I effects in hEPC proliferation and in angiogenesis. This knowledge could be helpful for future investigations focused on the regulation of the number and functionality of these cells and in the development of new therapies for the treatment of diseases, such as cardiovascular disease. PMID- 25445032 TI - Knowledge and management of endotracheal tube cuffs. PMID- 25445030 TI - Arginase inhibition enhances angiogenesis in endothelial cells exposed to hypoxia. AB - Hypoxia-induced arginase elevation plays an essential role in several vascular diseases but influence of arginase on hypoxia-mediated angiogenesis is completely unknown. In this study, in vitro network formation in bovine aortic endothelial cells (BAEC) was examined after exposure to hypoxia for 24h with or without arginase inhibition. Arginase activity, protein levels of the two arginase isoforms, eNOS, and VEGF as well as production of NO and ROS were examined to determine the involvement of arginase in hypoxia-mediated angiogenesis. Hypoxia elevated arginase activity and arginase 2 expression but reduced active p eNOS(Ser1177) and NO levels in BAEC. In addition, both VEGF protein levels and endothelial elongation and network formation were reduced with continued hypoxia, whereas ROS levels increased and NO levels decreased. Arginase inhibition limited ROS, restored NO formation and VEGF expression, and prevented the reduction of angiogenesis. These results suggest a fundamental role of arginase activity in regulating angiogenic function. PMID- 25445033 TI - Chinese oncology nurses' experience on caring for dying patients who are on their final days: a qualitative study. AB - BACKGROUND: Caring for dying patients is stressful but an unavoidable responsibility of nurses. However, little is known about Chinese oncology nurses' experience of caring for dying cancer patients who are in their final days. PURPOSE: To elucidate Chinese oncology nurses' experience of caring for dying cancer patients. METHODS: This is a qualitative descriptive study, semi structured interviews was utilized to explore views of purposive sample of 28 nurses who have been taking care of terminally ill patients in a cancer hospital in Tianjin, mainland China. Transcripts were entered into NVivo. Qualitative thematic analysis was used to analyze the data for significant statements and phrases that in turn were organized into themes and sub-themes. RESULTS: Five themes were identified in the data: end-of-life care for dying cancer patients, end-of-life care for family members, cultural sensitivity and communication, moral distress and self-limitations, self-reflection and benefit-finding. Death is a taboo in traditional Chinese culture. This increases the difficulty of effective communication between nurses, patients and families. Although nurses suffered emotional distress when caring for dying cancer patients, these experiences helped them to reflect on the meaning of death and life, and positively influenced their daily lives, attitudes and behaviors toward caring for the dying. Chinese nurses had strong willingness to offer quality end-of-life care to patients and families, however, they suffered moral distress because of self-limitation, lack of knowledge and confidence and inexperience in psychological care. CONCLUSIONS: End-of-life care in China reflects and has been influenced by the traditional Chinese culture. Chinese nurses reported suffering but also benefiting from their experiences. End-of-life cancer care training is needed by Chinese oncology nurses, especially for those who are younger and less experienced. PMID- 25445034 TI - A biochemical and 2, 3, 5-triphenyl tetrazolium chloride staining study on the preventive effects of zingerone (vanillyl acetone) in experimentally induced myocardial infarcted rats. AB - Myocardial infarction continues to be a major public health problem, not only in western countries but also increasingly in developing countries and makes significant contribution to the mortality statistics. Reduction in mortality rate and prevention of myocardial infarction are of utmost importance. Tachycardia, left ventricular hypertrophy (LVH), altered adenosine triphosphatases (ATPases), and shifts in electrolyte balance play a vital role in the pathogenesis of myocardial infarction. This study was designed to evaluate the preventive effects of zingerone (vanillyl acetone) on tachycardia, LVH, altered electrocardiogram (ECG), altered activities of membrane bound ATPases, electrolyte imbalance and myocardial infarct size in isoproterenol induced myocardial infarcted rats. Rats were pretreated with zingerone (vanillyl acetone) 6 mg/kg body weight daily for a period of 14 days and were then induced myocardial infarction with isoproterenol (100 mg/kg body weight) on 15th and 16th day. Isoproterenol induced myocardial infarcted rats showed tachycardia, LVH, altered ECG, serum cardiac troponin-T, plasma myoglobin, heart ATPases, heart sodium ion, calcium ion, potassium ion, and increased myocardial infarct size. Pretreatment with zingerone (vanillyl acetone) revealed preventive effects on tachycardia, LVH, ECG, and all the above mentioned biochemical parameters evaluated in isoproterenol induced myocardial infarcted rats. The 2, 3, 5-triphenyl tetrazolium chloride staining on myocardial infarct size confirmed the prevention of myocardial infarction. Further, the in vitro study revealed a very convincing free radical scavenging of zingerone (vanillyl acetone). Thus, the observed effects of zingerone (vanillyl acetone) are due to its antioxidant and free radical scavenging activities in isoproterenol induced myocardial infarcted rats. PMID- 25445035 TI - The somatostatin receptor 4 agonist J-2156 reduces mechanosensitivity of peripheral nerve afferents and spinal neurons in an inflammatory pain model. AB - Somatostatin (SST) is a peptide hormone that regulates the endocrine system and affects neurotransmission via interaction with G protein-coupled SST receptors and inhibition of the release of different hormones. The aim of this study was to investigate whether the analgesic properties of the selective SSTR4 agonist J 2156 are mediated via peripheral and/or spinal receptors. Effect on mechanical hyperalgesia in the Complete Freund's Adjuvant (CFA) model was measured after intraperitoneal application of J-2156. Electrophysiological neuronal recordings were conducted 24 h after injection of CFA or vehicle into the paw of Wistar rats. Mechanosensitivity of peripheral afferents of the saphenous nerve as well as of spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were measured after systemic or spinal application of J-2156. In CFA animals J-2156 dose dependently reduced hyperalgesia in behavioral studies. The minimal effective dose was 0.1 mg/kg. Mechanosensitivity of peripheral afferents and spinal neurons was significantly reduced by J-2156. NS neurons were dose dependently inhibited by J-2156 while in WDR neurons only the highest concentration of 100 uM had an effect. In sham controls, J-2156 had no effect on neuronal activity. We demonstrated that J-2156 dose-dependently reduces peripheral and spinal neuronal excitability in the CFA rat model without affecting physiological pain transmission. Given the high concentration of the compound required to inhibit spinal neurons, it is unlikely that the behavioral effect seen in CFA model is mediated centrally. Overall these data demonstrated that the analgesic effect of J-2156 is mediated mainly via peripheral SST4 receptors. PMID- 25445036 TI - Effects of antihistamines on the function of human alpha7-nicotinic acetylcholine receptors. AB - Effects of the histamine H1 receptor (H1R) antagonists (antihistamines), promethazine (PMZ), orphenadrine (ORP), chlorpheniramine (CLP), pyrilamine (PYR), diphenhydramine (DPH), citerizine (CTZ), and triprolidine (TRP) on the functional properties of the cloned alpha7 subunit of the human nicotinic acetylcholine receptor expressed in Xenopus oocytes were investigated. Antihistamines inhibited the alpha7-nicotinic acetylcholine receptor in the order PYR>CLP>TRP>PMZ>ORP>=DPH>=CTZ. Among the antihistamines, PYR showed the highest reversible inhibition of acetylcholine (100 uM)-induced responses with IC50 of 6.2 uM. PYR-induced inhibition was independent of the membrane potential and could not be reversed by increasing the concentration of acetylcholine. Specific binding of [125I] alpha-bungarotoxin, a selective antagonist for alpha7-nicotinic acetylcholine receptor, was not changed in the presence of PYR suggesting a non competitive inhibition of nicotinic receptors. In line with functional experiments, docking studies indicated that PYR can potentially bind allosterically with the alpha7 transmembrane domain. Our results indicate that the H2-H4 receptor antagonists tested in this study (10 uM) showed negligible inhibition of alpha7-nicotinic acetylcholine receptors. On the other hand, H1 receptor antagonists inhibited the function of human alpha7-nicotinic acetylcholine receptor, with varying potencies. These results emphasize the importance of alpha7-nicotinic acetylcholine receptor for future pharmacological/toxicological profiling. PMID- 25445037 TI - Cytotoxic and multidrug resistance reversal activities of novel 1,4 dihydropyridines against human cancer cells. AB - Multidrug resistance (MDR) caused by P-glycoprotein (P-gp, ABCB1, MDR-1) transporter over-expression in cancer cells substantially limits the effectiveness of chemotherapy. 1,4-Dihydropyridines (DHPs) derivatives possess several pharmacological activities. In this study, 18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moieties at C3 and C5 positions, respectively, as well as nitrophenyl or hetero aromatic rings at C4 were synthesized and tested for MDR reversal with the aim of establishing a structure-activity relationship (SAR) for these agents. Effect of these compounds on P-gp mediated MDR was assessed in P-gp over-expressing MES-SA/DX5 doxorubicin resistant cells by flow cytometric detection of rhodamine 123 efflux. MDR reversal was further examined as the alteration of doxorubicin's IC50 in MES SA/DX5 cells in the presence of DHPs by MTT assay and was compared to nonresistant MES-SA cells. Direct anticancer effect was examined against 4 human cancer cells including HL-60, K562, MCF-7 and LS180. Calcium channel blocking (CCB) activity was also measured as a potential side effect. Most DHPs, particularly compounds bearing 3-nitrophenyl (A2B2 and A3B2) and 4-nitrophenyl (A3B1 and A4B1) moieties at C4 significantly inhibited rhodamine 123 efflux at 5 25 uM, showing that the mechanism of MDR reversal by these agents is P-gp transporter modulation. Same derivatives were also able to selectively lower the resistance of MES-SA/DX5 to doxorubicin. A2B2 bearing ethyl carboxylate at C5 had also high direct antitumoral effect (IC50 range: 3.77-15.60 MUM). Our findings suggest that SAR studies of DHPs may lead to the discovery of novel MDR reversal agents. PMID- 25445038 TI - Gallic acid attenuates high-fat diet fed-streptozotocin-induced insulin resistance via partial agonism of PPARgamma in experimental type 2 diabetic rats and enhances glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway. AB - In this study, the therapeutic efficacy of gallic acid from Cyamopsis tetragonoloba (L.) Taub. (Fabaceae) beans was examined against high-fat diet fed streptozotocin-induced experimental type 2 diabetic rats. Molecular-dockings were done to determine the putative binding modes of gallic acid into the active sites of key insulin-signaling markers. Gallic acid (20 mg/kg) given to high-fat diet fed-streptozotocin-induced rats lowered body weight gain, fasting blood glucose and plasma insulin in diabetic rats. It further restored the alterations of biochemical parameters to near normal levels in diabetic treated rats along with cytoprotective action on pancreatic beta-cell. Histology of liver and adipose tissues supported the biochemical findings. Gallic acid significantly enhanced the level of peroxisome proliferator-activated receptor gamma (PPARgamma) expression in the adipose tissue of treated rat compared to untreated diabetic rat; it also slightly activated PPARgamma expressions in the liver and skeletal muscle. Consequently, it improved insulin-dependent glucose transport in adipose tissue through translocation and activation of glucose transporter protein 4 (GLUT4) in phosphatidylinositol 3-kinase (PI3K)/phosphorylated protein kinase B (p-Akt) dependent pathway. Gallic acid docked with PPARgamma; it exhibited promising interactions with the GLUT4, glucose transporter protein 1 (GLUT1), PI3K and p-Akt. These findings provided evidence to show that gallic acid could improve adipose tissue insulin sensitivity, modulate adipogenesis, increase adipose glucose uptake and protect beta-cells from impairment. Hence it can be used in the management of obesity-associated type 2 diabetes mellitus. PMID- 25445039 TI - Effect of AS2521780, a novel PKCtheta selective inhibitor, on T cell-mediated immunity. AB - T cell-mediated immunity is central to the pathogenesis of autoimmune diseases, and is a target in the development of alternative therapeutic strategies with reduced adverse effects on other cell types and organs. Protein kinase C (PKC) is a family of serine/threonine kinases, with knockout of the PKCtheta isoform in mice resulting in defective T cell activation. However, the effects of selective inhibition of PKCtheta by small-molecule compounds on T cell signaling are still unknown. Here, we evaluated the effect of the novel PKCtheta inhibitor AS2521780 on T cell activation and joint inflammation in a rat model of arthritis. AS2521780 exerted potent inhibition of recombinant human PKCtheta enzyme activity (IC50=0.48 nM), which was more than 30-fold higher than that of other PKC isoforms. Further, AS2521780 exerted little or no inhibition on other protein kinases. AS2521780 suppressed CD3/CD28-induced Interleukin-2 (IL-2) gene transcription in Jurkat T cells and proliferation of human primary T cells. AS2521780 also suppressed concanavalin A-induced cytokine production by rat splenocytes and monkey peripheral blood mononuclear cells with similar potency. Moreover, AS2521780 significantly reduced paw swelling in a dose-dependent manner in a rat model of adjuvant-induced arthritis. These results indicate that PKCtheta is an attractive drug target and AS2521780 is a potential immunosuppressant for T cell-mediated autoimmune diseases. PMID- 25445040 TI - Involvement of endogenous transforming growth factor-alpha in signal transduction pathway for interleukin-1beta-induced hepatocyte proliferation. AB - We studied the effects of interleukin (IL)-1beta on DNA synthesis and cell proliferation in primary cultures of adult rat hepatocytes in order to elucidate the mechanisms of its action. Hepatocyte parenchymal cells maintained in a serum free, defined medium synthesized DNA and proliferated in the presence of IL-1beta (3-30 ng/ml), but not IL-1alpha (0.1-30 ng/ml) in a time- and dose-dependent manner. Specific inhibitors of growth-related signal transducers, such as AG1478, LY294002, PD98059, and rapamycin, completely abolished IL-1beta-stimulated hepatocyte DNA synthesis and proliferation. Western blot analysis showed that IL 1beta significantly stimulated mitogen-activated protein (MAP) kinase activation within 10 min. Addition of a monoclonal antibody against transforming growth factor (TGF)-alpha, but not a monoclonal antibody against insulin-like growth factor-I, to the culture dose-dependently inhibited IL-1beta-induced hepatocyte mitogenesis. Culture medium TGF-alpha levels increased significantly within 3 min in response to IL-1beta from baseline levels. Peak TGF-alpha levels (33 pg/ml) were reached at 10 min after IL-1beta stimulation. These results indicate that the proliferative mechanism of action of IL-1beta is mediated through an increase in autocrine secretion of TGF-alpha from primary cultured hepatocytes. Secreted TGF-alpha, in turn, acts as a complete mitogen to induce hepatocyte mitogenesis through the receptor tyrosine kinase/phosphatidylinositol 3-kinase/MAP kinase/mammalian target of rapamycin pathway. PMID- 25445041 TI - Epigenetic upregulation of alpha-synuclein in the rats exposed to methamphetamine. AB - Abuse of methamphetamine (METH) increases the risk of occurrence of Parkinson's disease (PD) in the individuals. Increased expression of synaptic protein alpha synuclein (encoded by gene Snca) is remarkably associated with the neuronal loss and motor dysfunction in the patients with PD. The present study aimed to explore the epigenetic mechanism underlying the altered expression of alpha-synuclein in substantia nigra in the rats previously exposed to METH. Exposure to METH induced significant behavioral impairments in the rotarod test and open field test, as well as the upregulation of cytokine synthesis in the substantia nigra. Significantly increased expression of alpha-synuclein was also observed in the substantia nigra in the rats exposed to METH. Further chromatin immunoprecipitation and bisulfite sequencing studies revealed a significantly decreased cytosine methylation in the Snca promoter region in the rats exposed to METH. It was found that the occupancy of methyl CpG binding protein 2 and DNA methyltransferase 1 in Snca promoter region was also significantly decreased in the substantia nigra in the modeled rats. These results advanced our understanding on the mechanism of the increased incidence of PD in the individuals with history use of METH, and shed novel lights on the development of therapeutic approaches for the patients conflicted with this neurological disorder. PMID- 25445042 TI - Modulation of high affinity ATP-dependent cyclic nucleotide transporters by specific and non-specific cyclic nucleotide phosphodiesterase inhibitors. AB - Intracellular cyclic nucleotides are eliminated by phosphodiesterases (PDEs) and by ATP Binding cassette transporters such as ABCC4 and ABCC5. PDE5 and ABCC5 have similar affinity for cGMP whereas ABCC5 has much higher affinity for cGMP compared with cAMP. Since the substrate (cGMP) is identical for these two eliminatory processes it is conceivable that various PDE inhibitors also modulate ABCC5-transport. Cyclic GMP is also transported by ABBC4 but the affinity is much lower with a Km 50-100 times higher than for that of ABBCC5. The present study aimed to determine Ki-values for specific or relative specific PDE5 inhibitors (vardenafil, tadalafil, zaprinast and dipyridamole) and the non-specific PDE inhibitors (IBMX, caffeine and theophylline) for ABCC5 and ABCC4 transport. The transport of [(3)H]-cGMP (2 uM) was concentration-dependently inhibited with the following Ki-values: vardenafil (0.62 uM), tadalafil (14.1 uM), zaprinast (0.68 uM) and dipyridamole (1.2 uM), IBMX (10 uM), caffeine (48 uM) and theophylline (69 uM). The Ki-values for the inhibition of the [(3)H]-cAMP (2 uM) transport were: vardenafil (3.4 uM), tadalafil (194 uM), zaprinast (2.8 uM), dipyridamole (5.5 uM), IBMX (16 uM), caffeine (41 uM) and theophylline (85 uM). The specificity for ABCC5 we defined as ratio between Ki-values for inhibition of [(3)H]-cGMP and [(3)H]-cAMP transport. Tadalafil showed the highest specificity (Ki-ratio: 0.073) and caffeine the lowest (Ki-ratio: 1.2). PMID- 25445043 TI - Enhanced self-administration of alcohol in muscarinic acetylcholine M4 receptor knockout mice. AB - Modulation of cholinergic neurotransmission via nicotinic acetylcholine receptors is known to alter alcohol-drinking behavior. It is not known if muscarinic acetylcholine receptor subtypes have similar effects. The muscarinic M4 receptor is highly expressed in the brain reinforcement system and involved in regulation of cholinergic and dopaminergic transmission. Here we investigate, for the first time, the role of the M4 receptor in alcohol consumption using M4 knockout (M4(-/ )) and wild-type (M4(+/+)) mice. Experimentally naive M4(-/-) and M4(+/+) mice were trained to orally self-administer 5%, 8% and 10% alcohol in 60min sessions, 6 days/week, after having undergone a standard sucrose fading training procedure on a fixed ratio schedule. The mice were further subjected to an extinction period followed by a 1 day reinstatement trial. M4(-/-) mice consumed more alcohol at 5% and 8% compared to their M4(+/+) littermates. The highest alcohol concentration used (10%) did not immediately result in divergent drinking patterns, but after 4 weeks of 10% alcohol self-administration, baseline levels as well as a pattern of M4(-/-) mice consuming more alcohol than their M4(+/+) controls were re-established. Moreover, the M4(-/-) mice displayed a reduced capacity to extinguish their alcohol-seeking behavior. Taken together, alcohol consumption is elevated in M4(-/-) mice, indicating that the M4 receptor is involved in mediating the reinforcing effects of alcohol. The M4 receptor should be further explored as a potential target for pharmacological (positive allosteric modulators or future agonists) treatment of alcohol use disorders. PMID- 25445044 TI - Dual ACE-inhibition and angiotensin II AT1 receptor antagonism with curcumin attenuate maladaptive cardiac repair and improve ventricular systolic function after myocardial infarctionin rat heart. AB - Curcumin has been shown to improve cardiac function by reducing degradation of extracellular matrix and inhibiting synthesis of collagen after ischemia. This study tested the hypothesis that attenuation of maladaptive cardiac repair with curcumin is associated with a dual ACE-inhibition and angiotensin II AT1 receptor antagonism after myocardial infarction. Sprague-Dawley rats were subjected to 45min ischemia followed by 7 and 42 days of reperfusion, respectively. Curcumin was fed orally at a dose of 150mg/kg/day only during reperfusion. Relative to the control animals, dietary treatment with curcumin significantly reduced levels of ACE and AT1 receptor protein as determined by Western blot assay, coincident with less locally-expressed ACE and AT1 receptor in myocardium and coronary vessels as identified by immunohistochemistry. Along with this inhibition, curcumin significantly increased protein level of AT2 receptor and its expression compared with the control. As evidenced by less collagen deposition in fibrotic myocardium, curcumin also reduced the extent of collagen-rich scar and increased mass of viable myocardium detected by Masson's trichrome staining. Echocardiography showed that the wall thickness of the infarcted anterior septum in the curcumin group was significantly greater than that in the control group. Cardiac contractile function was improved in the curcumin treated animals as measured by fraction shortening and ejection fraction. In cultured cardiac muscle cells, curcumin inhibited oxidant-induced AT1 receptor expression and promoted cell survival. These results suggest that curcumin attenuates maladaptive cardiac repair and enhances cardiac function, primarily mediated by a dual ACE-inhibition and AT1 receptor antagonism after myocardial infarction. PMID- 25445045 TI - Gram-negative endotoxin lipopolysaccharide induces cardiac hypertrophy: detrimental role of Na(+)-Ca(2+) exchanger. AB - Several molecular pathways involved in the development of cardiac hypertrophy are triggered by perturbation of intracellular Ca(2+) homeostasis. Within the heart, Na(+)/Ca(2+) exchanger 1 (NCX1) is one of the main determinant in controlling Ca(2+) homeostasis. In cardiac hypertrophy and heart failure NCX1 expression and activity have been reported to be altered. It has been shown that chronic bacterial infections (sepsis, endocarditis, and myocarditis) can promote cardiac hypertrophy. Bacterial stressors, such as the Gram-negative endotoxin lipopolysaccharide (LPS), can directly or indirectly affect intracellular Ca(2+) homeostasis in the heart and induce the development of cardiac hypertrophy. The present study aimed at evaluating the potential link between the signal pathways activated in LPS-exposed myocytes and NCX1. In the whole rat heart, LPS perfusion induced an early hypertrophy response during which NCX1 expression significantly increased. Notably, all these changes were completely prevented by the NCX inhibitor SN-6. We further dissect the role of NCX1 in the LPS-induced hypertrophic response in an in vitro cardiac model based on two H9c2 cardiomyoblast clones, namely H9c2-WT (lacking endogenous NCX1 expression) and H9c2-NCX1 (stably transfected with a functional NCX1). H9c2-NCX1 were more susceptible than H9c2-WT to develop a hypertrophic phenotype, and they displayed a significant increase in NCX1 expression and function after LPS treatment. SN-6 completely counteracted both hypertrophic response and exchanger alterations induced by LPS in H9c2-NCX1 cells, but it had no effects on H9c2-WT. Collectively, our results suggest that NCX1 plays a critical role in promoting myocardial hypertrophy triggered by LPS. PMID- 25445046 TI - A dopamine-alpha-lipoic acid hybridization compound and its acetylated form inhibit LPS-mediated inflammation. AB - In the present study, we synthesized and evaluated the anti-inflammatory effects of dopamine and alpha-lipoic acid (ALA) hybrid compounds, ALA-dopamine (HBU-199) and its acetylated derivative, ALA-acetyl dopamine (HBU-200), in BV2 microglia and RAW264.7 macrophage cells. HBU-199 and HBU-200 both significantly and dose dependently inhibited LPS-induced nitric oxide (NO) productions, NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 and interleukin-1beta mRNA expressions and iNOS and COX-2 protein expressions. Furthermore, HBU-199 and HBU 200 protected RAW264.7 cells from activation-induced cell death. However, at same concentrations, dopamine or ALA did not inhibit LPS-mediated production of inflammatory molecules and activation-induced cell death. HBU-199 and HBU-200 inhibited LPS-induced inhibition of inhibitory kappa-B-alpha (IkappaB-alpha) phosphorylation and nuclear factor-kappa B (NF-kappaB) activation. Furthermore, LPS-mediated DNA binding of p65 and p50 to the NF-kappaB binding site of the iNOS promoter was inhibited by HBU-199 and HBU-200, whereas dopamine and ALA did not inhibit LPS-induced NF-kappaB activation and IkappaB-alpha phosphorylation. Moreover, HBU-199 and HBU-200 suppressed LPS-stimulated phosphorylation of Akt, but not glycogen synthase kinase 3 beta. Overall, our data suggest that the ALA dopamine hybrid compounds down-regulate inflammatory responses via inhibition of NF-kappaB and NF-kappaB-dependent gene expression, suggesting that it is a promising therapeutic agent for both systemic inflammatory diseases and inflammatory diseases of central nervous system. PMID- 25445047 TI - Pharmacological characterization of the selective 11beta-hydroxysteroid dehydrogenase 1 inhibitor, BI 135585, a clinical candidate for the treatment of type 2 diabetes. AB - To combat the increased morbidity and mortality associated with the developing diabetes epidemic new therapeutic interventions are desirable. Inhibition of intracellular cortisol generation from cortisone by blocking 11beta hydroxysteroid dehydrogenase 1 (11beta-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. A challenge in developing 11beta-HSD1 inhibitors has been the species selectivity of small molecules, as many compounds are primate specific. Here we describe our strategy to identify potent selective 11beta-HSD1 inhibitors while ensuring target engagement in key metabolic tissues, liver and fat. This strategy enabled the identification of the clinical candidate, BI 135585. PMID- 25445048 TI - Curcumin regulates peroxisome proliferator-activated receptor-gamma coactivator 1alpha expression by AMPK pathway in hepatic stellate cells in vitro. AB - Curcumin exerts an inhibitory effect on hepatic stellate cell (HSC) activation, a key step for liver fibrogenesis, and on liver fibrosis by up-regulation of peroxisome proliferator-activated receptor-gamma (PPARgamma) expression. PPARgamma plays a crucial role in suppression of HSC activation. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) functions as a co-activator for PPARgamma. Therefore, researches on the effect of curcumin on PGC-1alpha might contribute to understanding of the mechanisms underlying curcumin inhibition of HSC activation and liver fibrosis through PPARgamma. The present study aimed to investigate the effect of curcumin on PGC-1alpha expression in HSCs in vitro and examine the underlying molecular mechanisms by western blot, reat-time PCR, and transfection. Our results showed that curcumin stimulation increased PGC-1alpha expression and the effects of curcumin on PGC 1alpha expression were correlated with the activation of adenosine monophosphate activated protein kinase (AMPK). Curcumin increased superoxide dimutase-2 (SOD2) transcription and activity by AMPK/PGC-1alpha axis. Moreover, PGC-1alpha was demonstrated to inhibit alpha1(I) collagen (a marker for liver fibrosis) transcription in cultured HSCs. These results demonstrated the promotion effect of curcumin on PGC-1alpha expression through AMPK pathway, which led to the increases in PPARgamma activity and in SOD-2 transcription and activity. These data might suggest a possible new explanation for the inhibitory effect of curcumin on HSC activation and on liver fibrogenesis. PMID- 25445049 TI - Antiplatelet activity of loureirin A by attenuating Akt phosphorylation: In vitro studies. AB - Loureirin A is a flavonoid extracted from Dragon's Blood that has been used to promote blood circulation and remove stasis in Chinese traditional medicine. However, the mechanisms of these effects are not fully understood. We explored the anti-platelet activity and underlying mechanism of loureirin A in vitro. Our results indicated that loureirin A negatively affected agonist-induced platelet aggregation such as collagen, collagen-related peptide (CRP), ADP and thrombin. Loureirin A inhibited collagen-induced platelet ATP secretion and thrombin stimulated P-selectin expression in a dose-dependent manner. Platelet spreading on immobilized fibrinogen was significantly impaired in the presence of loureirin A. Immunoblotting analysis indicated that 100MUM of loureirin A almost completely eliminated collagen-induced Akt phosphorylation at Ser473. Interestingly, a submaximal dose (50MUM) of loureirin A had an additive inhibitory effect with the phosphoinositide 3-kinase (PI3K) inhibitor Ly294002 on collage-induced Akt phosphorylation in platelets. Taken together, loureirin A had an inhibitory effect on platelet activation, perhaps through an impairment of PI3K/Akt signaling. PMID- 25445051 TI - Bumetanide is not capable of terminating status epilepticus but enhances phenobarbital efficacy in different rat models. AB - In about 20-40% of patients, status epilepticus (SE) is refractory to standard treatment with benzodiazepines, necessitating second- and third-line treatments that are not always successful, resulting in increased mortality. Rat models of refractory SE are instrumental in studying the changes underlying refractoriness and to develop more effective treatments for this severe medical emergency. Failure of GABAergic inhibition is a likely cause of the development of benzodiazepine resistance during SE. In addition to changes in GABAA receptor expression, trafficking, and function, alterations in Cl(-) homeostasis with increased intraneuronal Cl(-) levels may be involved. Bumetanide, which reduces intraneuronal Cl(-) by inhibiting the Cl(-) intruding Na(+), K(+), Cl(-) cotransporter NKCC1, has been reported to interrupt SE induced by kainate in urethane-anesthetized rats, indicating that this diuretic drug may be an interesting candidate for treatment of refractory SE. In this study, we evaluated the effects of bumetanide in the kainate and lithium-pilocarpine models of SE as well as a model in which SE is induced by sustained electrical stimulation of the basolateral amygdala. Unexpectedly, bumetanide alone was ineffective to terminate SE in both conscious and anesthetized adult rats. However, it potentiated the anticonvulsant effect of low doses of phenobarbital, although this was only seen in part of the animals; higher doses of phenobarbital, particularly in combination with diazepam, were more effective to terminate SE than bumetanide/phenobarbital combinations. These data do not suggest that bumetanide, alone or in combination with phenobarbital, is a valuable option in the treatment of refractory SE in adult patients. PMID- 25445052 TI - beta2-Adrenoceptor agonists as potential therapeutic drugs in diabetic peripheral neuropathy. AB - OBJECTIVES: the aim of the current study was to assess the effect of a beta2 adrenoceptor agonist; namely salbutamol, on hyperalgesic as well as nerve dysfunction components of diabetic peripheral neuropathy. MATERIAL AND METHODS: the present study was conducted on 60 male Wistar albino rats divided into six groups. Groups I and II were normal control rats injected by a single i.p. injection of normal saline and received 2% gum acacia (Group I) or salbutamol (Group II) for six weeks, starting one week following saline injection. Groups III-VI: rats that were rendered diabetic by a single i.p. injection of STZ and received either 2% gum acacia, salbutamol, salbutamol and propranolol or salbutamol and atenolol, respectively daily orally for six weeks, starting one week following STZ injection. RESULTS: vehicle-treated diabetic rats exhibited: significant sciatic nerve dysfunction in the form of significantly prolonged distal latency and significantly decreased maximum peak and peak to peak amplitude of compound muscular action potential, significant thermal and mechanical hyperalgesia evidenced by significant decrease in hot plate latency, tail-flick latency and vocalization threshold, respectively. Salbutamol administration improved nerve dysfunction as well as thermal and mechanical hyperalgesia. These effects of salbutamol are most likely mediated by beta2 adrenoceptors evidenced by significant abolishment of salbutamol effects after administration of the non-selective rather than the selective beta blockers; propranolol and atenolol, respectively. CONCLUSIONS: chronic administration of salbutamol could ameliorate DPN, an effect which is most likely mediated by beta2 adrenoceptors. PMID- 25445050 TI - Free fatty acid induced impairment of insulin signaling is prevented by the diastereomeric mixture of calophyllic acid and isocalophyllic acid in skeletal muscle cells. AB - Elevated fatty acid levels play a pathogenic role in the development of insulin resistance, associated with type 2 diabetes. Interventions with ability to ameliorate fatty acid-induced insulin resistance might be useful for the management of diabetes. Here, we explored the effect of the diastereomeric mixture of calophyllic acid and isocalophyllic acid (F015) on palmitate-induced insulin resistance in skeletal muscle cells. An incubation of L6 myotubes with palmitate inhibited insulin-stimulated glucose uptake and translocation of GLUT4 to cell surface. Addition of F015 strongly prevented these inhibitions. Furthermore, F015 effectively inhibited the ability of palmitate to reduce insulin-stimulated phosphorylation of IRS-1, AKT and GSK-3beta in L6 myotubes. F015 presented a strong inhibition on palmitate-induced production of reactive oxygen species and associated inflammation, as the activation JNK, ERK1/2 and p38 MAPK were greatly reduced. F015 also inhibited inflammation-stimulated IRS-1 serine phosphorylation and restored insulin-stimulated IRS-1 tyrosine phosphorylation in presence of palmitate, resulted in enhanced insulin sensitivity. Results suggest that F015 inhibits palmitate-induced, reactive oxygen species-associated MAPK kinase activation and restored insulin sensitivity through regulating IRS-1 function. All these indicate F015 to be a potentially therapeutic candidate for insulin resistance and type 2 diabetes. PMID- 25445053 TI - Antitumor and antimetastatic actions of dihydroxycoumarins (esculetin or fraxetin) through the inhibition of M2 macrophage differentiation in tumor associated macrophages and/or G1 arrest in tumor cells. AB - Tumor growth and metastasis are closely associated with the M2 macrophage activation of tumor-associated macrophages (TAMs) in the tumor microenvironment as well as the development of tumor cells. In this study, we examined the antiproliferative, antitumor, and antimetastatic effects of three dihydroxycoumarins (esculetin, fraxetin, and daphnetin) against osteosarcoma LM8 cells (in vitro) and a highly metastatic model in LM8-bearing mice (in vivo). Esculetin (20-100MUM) inhibited the proliferation of LM8 cells, whereas fraxetin and daphnetin had no effect. Esculetin inhibited the expressions of cyclin D1, cyclin-dependent kinase (CDK) 4 and matrix metalloproteinase (MMP)-2, and production of both transforming growth factor (TGF)-beta1 and vascular endothelial growth factor (VEGF) in LM8 cells. Esculetin (3 or 10mg/kg) and fraxetin (10mg/kg) inhibited tumor growth and metastasis to the lung or liver, whereas daphnetin did not. These results suggested that the antitumor and antimetastatic actions of esculetin may be partly attributed to G1 arrest by the inhibition of cyclin D1 and CDK4 expression, while its antiangiogenic action may have been due to the inhibition of MMP-2 expression and TGF-beta1 and VEGF productions at tumor sites. Esculetin (10-100MUM) and fraxetin (50-100MUM) inhibited the production of interleukin (IL)-10, monocyte chemoattractant protein (MCP)-1, and TGF-beta1 during the differentiation of M2 macrophages by reducing the phosphorylation of Stat 3 without affecting its expression. These results also suggested that the antitumor and antimetastatic actions of esculetin or fraxetin may be due to the regulated activation of TAM by M2 macrophage differentiation in the tumor microenvironment. PMID- 25445054 TI - Perindopril increases the swallowing reflex by inhibiting substance P degradation and tyrosine hydroxylase activation in a rat model of dysphagia. AB - Patients with hypertension have a high risk of ischemic stroke and subsequent stroke-associated pneumonia. Stroke-associated pneumonia is most likely to develop in patients with dysphagia. The present study was designed to compare the ameliorative effects of different treatments in rat model of dysphagia. Spontaneously hypertensive rats were treated with bilateral common carotid artery occlusion (BCAO) to induce chronic cerebral hypoperfusion causing disorders of the swallowing reflex. Angiotensin-converting enzyme (ACE) inhibitors (perindopril, imidapril and enalapril), an angiotensin II type 1-receptor blocker (losartan), a vasodilator (hydralazine) and an indirect dopamine agonist (amantadine) were dissolved in drinking water and administered to the rats for six weeks. The blood pressure, the swallowing reflex under anesthesia, the substance P content in the striatum and the tyrosine hydroxylase (TH) expression in the substantial nigra were measured. Compared to the vehicle control, the decrease in the swallowing reflex induced by BCAO was attenuated significantly by enalapril, imidapril and perindopril, but only slightly by losartan. Hydralazine had no effect on the swallowing reflex. Amantadine significantly attenuated the decreased swallowing reflex but increased the blood pressure. Cerebral hypoperfusion for six weeks decreased the TH expression and substance P level. Perindopril improved both the TH expressions and substance P level, but imidapril, enalapril and amantadine only improved the substance P level. The present findings indicate that perindopril could be useful for preventing dysphagia in the chronic stage of stroke by attenuating the decrease in TH expression and the decrease in the substance P level. PMID- 25445055 TI - The absence of task-related increases in BOLD signal does not equate to absence of task-related brain activation. AB - Most fMRI studies employ general-linear-model-based analyses (GLM-BA) of BOLD signal changes to identify regions that are active (or not) during specific cognitive processes. However, alternate analytic approaches (like independent component analysis) may identify more complex patterns of activation, including in regions not implicated in GLM-BA of the same data. In our opinion, fMRI findings revealed by a GLM-BA cannot exclude any brain regions from contributing to specific cognitive processes. PMID- 25445056 TI - C57BL/6-specific conditions for efficient in utero electroporation of the central nervous system. AB - BACKGROUND: In utero electroporation is a fast an efficient tool to specifically address gene expression in the murine central nervous system. This technique was originally established in ICR/CD-1 outbred mice. Neuroanatomical differences between the different mouse strains and variations in gestation length require the optimization of the conditions for each strain to avoid severe complications. Furthermore the relevant position information is currently only scarcely standardized and not always easy to transfer to C57BL/6 mice. NEW METHOD: In this study we present an improved method for in utero electroporation of C57BL/6 including a detailed atlas that allows for specific and efficient in vivo transfection. Further we introduce histogram analysis as a tool for neural migration assays. RESULTS: We report individually adapted conditions for in utero electroporation in C57BL/6 mice that differ from the previously published data for ICR/CD-1 mice. Furthermore, this article outlines a detailed angle-map that allows for the specific and efficient in vivo transfection of different regions of the C57BL/6 mouse central nervous system. We also show that histogram analysis is a valuable tool for objectifying and accelerating postmitotic neural migration assays. COMPARISON WITH EXISTING METHODS: Until now, conditions for in utero electroporation of C57BL/6 mice are sparsely defined. Further, compared with time consuming cell body counting histogram analysis allows objectified and accelerated postmitotic neural migration assays. CONCLUSION: Together, our results provide a manual for the in utero electroporation of specific regions of the central nervous systems C57BL/6 mice and objectified data analysis. PMID- 25445058 TI - Anatomical landmarks for registration of experimental image data to volumetric rodent brain atlasing templates. AB - BACKGROUND: Assignment of anatomical reference is a key step in integration of the rapidly expanding collection of rodent brain data. Landmark-based registration facilitates spatial anchoring of diverse types of data not suitable for automated methods operating on voxel-based image information. NEW TOOL: Here we propose a standardized set of anatomical landmarks for registration of whole brain imaging datasets from the mouse and rat brain, and in particular for integration of experimental image data in Waxholm Space (WHS). RESULTS: Sixteen internal landmarks of the C57BL/6J mouse brain have been reliably identified: by different individuals, independent of their experience in anatomy; across different MRI contrasts (T1, T2, T2(*)) and other modalities (Nissl histology and block-face anatomy); in different specimens; in different slice acquisition angles; and in different image resolutions. We present a registration example between T1-weighted MRI and the mouse WHS template using these landmarks and reaching fairly high accuracy. Landmark positions identified in the mouse WHS template are shared through the Scalable Brain Atlas, accompanied by graphical and textual guidelines for locating each landmark. We identified 14 of the 16 landmarks in the WHS template for the Sprague Dawley rat. COMPARISON WITH EXISTING METHODS: This landmark set can withstand substantial differences in acquisition angle, imaging modality, and is less vulnerable to subjectivity. CONCLUSIONS: This facilitates registration of multimodal 3D brain data to standard coordinate spaces for mouse and rat brain taking a step toward the creation of a common rodent reference system; raising data sharing to a qualitatively higher level. PMID- 25445057 TI - Longitudinal assessment of infarct progression, brain metabolism and behavior following anterior cerebral artery occlusion in rats. AB - BACKGROUND: Stroke patients suffering from occlusion of the anterior cerebral artery (ACAo) develop cognitive and executive deficits. Experimental models to investigate such functional impairments and recovery are rare and not satisfyingly validated. NEW METHOD: We stereotactically injected the vasoconstrictor endothelin-1 (ET-1) close to the ACA of rats and assessed magnitude and course of CBF reduction using [(14)C]iodoantipyrine autoradiography and [(15)O]H2O-PET. [(18)F]FDG-PET and T2-weighted MRI determined regional metabolic and structural alterations. To test cognitive and executive functions, we analyzed decision-making in a food-carrying task, spatial working memory in a spontaneous alternation task and anxiety in an elevated plus maze test before and 1 month after ACAo. RESULTS: CBF decreased immediately after ET-1 injection, started to recover 1-2h and returned to control 4h thereafter. Metabolic and structural lesions developed permanently in the ACA territory. Hypometabolism occurring bilaterally in the piriform region may reflect diaschisis. Behavioral testing after ACAo revealed context-dependent changes in decision making, exploratory activity and walking speed, as well as decreased anxiety and spatial working memory. COMPARISON WITH EXISTING METHOD(S): Aside from modeling a known entity of stroke patients, ACAo in rats allows to longitudinally study deterioration of cognitive and executive function without major interference by disturbed primary motor function. It complements therefore stroke research since common models using middle cerebral artery occlusion (MCAo) all affect motor function severely. CONCLUSION: The established ACAo model in rats effectively reflects deficits characteristic for ACA stroke in humans. It is furthermore highly suitable for longitudinal assessment of cognitive and executive functions. PMID- 25445059 TI - Data-analytical stability of cluster-wise and peak-wise inference in fMRI data analysis. AB - BACKGROUND: Carp (2012) demonstrated the large variability that is present in the method sections of fMRI studies. This methodological variability between studies limits reproducible research. NEW METHOD: Evaluation protocols for methods used in fMRI should include data-analytical stability measures quantifying the variability in results following choices in the methods. Data-analytical stability can be seen as a proxy for reproducibility. To illustrate how one can perform such evaluations, we study two competing approaches for topological feature based inference (random field theory and permutation based testing) and two competing methods for smoothing (Gaussian smoothing and adaptive smoothing). We compare these approaches from the perspective of data-analytical stability in real data, and additionally consider validity and reliability in simulations. RESULTS: There is clear evidence that choices in the methods impact the validity, reliability and stability of the results. For the particular comparison studied, we find that permutation based methods render the most valid results. For stability and reliability, the performance of different smoothing and inference types depends on the setting. However, while being more reliable, adaptive smoothing can evoke less stable results when using larger kernel width, especially with cluster size based permutation inference. COMPARISON WITH EXISTING METHODS: While existing evaluation methods focus on validity and reliability, we show that data-analytical stability enables to further distinguish between performance of different methods. CONCLUSION: Data-analytical stability is an important additional criterion that can easily be incorporated in evaluation protocols. PMID- 25445060 TI - Comparison of different quantification methods to determine hippocampal damage after cerebral ischemia. AB - BACKGROUND: Experimental stroke studies use multiple techniques to evaluate histopathological damage. Unfortunately, sensitivity and reproducibility of these techniques are poorly characterized despite pivotal influence on results. METHOD: The present study compared several quantification methods to differentiate between two severities of global cerebral ischemia and reperfusion. Male Sprague Dawley rats were randomized to moderate (10min) or severe (14min) ischemia by bilateral carotid occlusion (BCAO) with hemorrhagic hypotension. Neuronal cell count was determined in hippocampus at bregma -3.14mm and -3.8mm on day 3 and 28 post insult by counting neurons in the whole CA1 or in one to three defined regions of interest (ROI) placed in NeuN and Fluoro-Jade B stained sections. RESULTS: In healthy rats hippocampal neurons were arranged uniformly, while distribution became inhomogeneous after ischemia. The number of NeuN and Fluoro Jade B positive cells was dependent on localization. Differences between ischemia severities became more prominent at 28 days compared to 3 days. Fluoro-Jade B positive cell count increased at 28 days, staining rather injured not dying neurons. COMPARISON WITH EXISTING METHODS: Placement of counting windows has a major influence on extent of differences between degree of neuronal injury and variations within groups. CONCLUSIONS: The investigated quantification methods result in inconsistent information on the degree of damage. To obtain consistent and reliable results observation period should be extended beyond 3 days. Due to inhomogeneous distribution of viable neurons in CA1 after ischemia neuronal counting should not be performed in a single ROI window, but should be performed in multiple ROIs or the whole CA1 band. PMID- 25445061 TI - Babies in waiting: why increasing the IVF age cut-off might lead to fewer wanted pregnancies in the presence of procrastination. AB - Despite the best of intentions, we often act at the last minute when we are faced with a deadline. A recent recommendation by the English National Institute for Health and Clinical Excellence (NICE) to make In Vitro Fertilisation (IVF) available to women up to 42 years of age instead of 39 intends to offer more women the chance of pregnancy. Given what we know about behavioural responses to what is, in essence, a deadline, the policy could lead to procrastination and fewer wanted pregnancies. We examine how many women it would take to delay trying for a baby for this policy to result in fewer pregnancies. We take a cohort of 1000 women from age 34. If no women delay trying, the increased age on access to IVF results in 31 more pregnancies. Because of declining fertility with age, it would take only about a third of these women to delay trying for a baby until age 35 for there to be zero net benefits of increased IVF availability. If all women delayed by a year, the new policy will lead to 59 fewer pregnancies. We also estimate the implications for IVF treatment numbers as this has psychological and personal consequences. Our findings highlight how no policy sits in a behavioural vacuum and all policy decisions should consider the likely behavioural responses and incorporate them into their design and evaluation. PMID- 25445062 TI - Unmet healthcare needs depending on employment status. AB - OBJECTIVES: The purpose of study is to find relevance between unmet healthcare needs and employment status and if factors have relevance to unmet healthcare needs due to "economic burden" and "no time to spare". METHODS: The study conducted a survey of 9163 respondents who said they needed a medical treatment or checkup were asked why the need for care was unmet. RESULTS: 22.9% of the respondents said they did not receive a medical treatment or checkup they needed at least once. The rate of unmet healthcare needs caused by "economic burden" was higher among temporary workers (ORs=2.13), day workers (ORs=1.92). However, the rate of unmet needs due to "no time to spare" was lower for temporary workers (ORs=.58) than for regular workers, studies (ORs=.33), housework (ORs=.26), early retirement (ORs=.19) and disease or injury (ORs=.07). CONCLUSION: Non-regular waged workers were more likely to have an unmet need for healthcare due to "economic burden" than regular waged workers. On the other hand, regular waged workers were less likely to receive necessary healthcare services due to "no time to spare" than non-regular waged workers and economically inactive people. PMID- 25445064 TI - Synaptosome-related (SNARE) genes and their interactions contribute to the susceptibility and working memory of attention-deficit/hyperactivity disorder in males. AB - BACKGROUNDS: N-ethylmaleimide-sensitive attachment protein receptor (SNARE) complex involved in neurotransmission via exocytosis was implicated in attention deficit/hyperactivity disorder (ADHD). The present study investigated the influence of SNARE related genes and their interaction on ADHD susceptibility and their cognitive functions. METHODS: We genotyped eight single nucleotide polymorphisms (SNP) of Syntaxin 1A (STX1A), vesicle-associated membrane protein 2 (VAMP2) and synaptosomal-associated protein 25 kDa (SNAP25) and conducted case control studies in 1404 male ADHD and 617 male controls. Quantitative analyses were performed for genotypes and performance on the Rey-Osterrieth complex figure test (RCFT), digit span test and Stroop test in 383 ADHD males. In addition, we explored gene-gene interactions by generalized multifactor dimensionality reduction (GMDR) followed with logistic regression and analyses of covariance for verifying. RESULTS: Genotypic distribution of rs875342 of STX1A was significantly different between ADHD and controls. The SNPs, rs363039 of SNAP25 and rs1150 of VAMP2, were significantly associated with RCFT scores, while rs875342 of STX1A with digit span. We found genetic interaction models between these three genes and ADHD susceptibility as well as working memory function evaluated by RCFT. CONCLUSION: SNARE complex genes and their interactions may play a significant role in susceptibility and working memory of ADHD. PMID- 25445066 TI - Attention deficit/hyperactivity disorder and medication with stimulants in young children: a DTI study. AB - The relationship between attention deficit/hyperactivity disorder (ADHD) and white matter connectivity has not been well established yet, specially for children under 10 years of age. In addition, the effects of treatment on brain structure have not been sufficiently explored from a Diffusion Tensor Imaging (DTI) perspective. In this study, the influence of treatment with methylphenidate in the white matter of children with ADHD was investigated using two different and complementary DTI analysis methods: Tract-Based Spatial Statistics (TBSS) and a robust tractography selection method. No significant differences were found in Fractional Anisotropy (FA) between medicated, drug-naive patients and healthy controls, but a reduced Mean Diffusivity (MD) was found in ADHD patients under treatment with respect to both healthy controls and drug-naive ADHD patients. Also, correlations were found between MD increases and performance indicators of ADHD. These findings may help elucidate the nature of white matter alterations in ADHD, their relationship with symptoms and the effects of treatment with psychostimulants. PMID- 25445067 TI - [Sclerostin and body fat]. PMID- 25445068 TI - [Bilateral pneumonia and cutaneous tumours]. PMID- 25445063 TI - Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics. AB - Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system - particularly the modulation of P1 and P2 receptor subtypes - plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects. PMID- 25445065 TI - Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: implications for neurodevelopmental psychiatric disorders. AB - Research suggests that maternal immune activation (MIA) during pregnancy increases the risk of neurodevelopmental disorders including schizophrenia and autism in the offspring. Current theories suggest that inflammatory mediators including cytokines and chemokines may underlie the increased risk of these disorders in humans. For example, elevated maternal interleukin-8 (IL-8) during pregnancy is associated with increased risk of schizophrenia in the offspring. Given this association, the present experiments examined ELR-CXC chemokines CXCL1 and CXCL2, rodent homologues of human IL-8, and activation of their receptors (CXCR1 and CXCR2) in an established rodent model of MIA. Pregnant Long Evans rats were treated with the viral mimetic polyinosinic-polycytidylic acid (polyI:C; 4 mg/kg, i.v.) on gestational day 15. Protein analysis using multiplex assays and ELISA showed that polyI:C significantly increased maternal serum concentrations of interleukin-1beta, tumor necrosis factor, and CXCL1 3h after administration. Subsequent experiments tested the role of elevated maternal CXCL1 on behavior of the offspring by administering a CXCR1/CXCR2 antagonist (G31P; 500 MUg/kg, i.p.; 1h before, 48 and 96 h after polyI:C treatment). The male offspring of dams treated with polyI:C demonstrated subtle impairments in prepulse inhibition (PPI), impaired associative and crossmodal recognition memory, and altered behavioral flexibility in an operant test battery. While G31P did not completely reverse the behavioral impairments caused by polyI:C, it enhanced PPI during adolescence and strategy set-shifting and reversal learning during young adulthood. These results suggest that while polyI:C treatment significantly increases maternal CXCL1, elevations of this chemokine are not solely responsible for the effects of polyI:C on the behavior of the offspring. PMID- 25445069 TI - Unilateral musical hallucination after a hybrid cochlear implantation. AB - OBJECTIVE: To provide a description of musical hallucination associated with hybrid cochlear implantation. METHOD: Case report. RESULTS: We report a case of musical hallucination secondary to hybrid cochlear implantation. Activation of electrical stimulation was closely related to onset of musical hallucination and deactivation was associated with attenuation of hallucination. Persistent musical hallucination severely impaired speech discrimination in spite of 2 years of listening rehabilitation. CONCLUSIONS: The hybrid cochlear implant is a relatively new surgical method, and its side effects have not been well documented. This is the first report of musical hallucination after a hybrid cochlear implantation. Also we provide evidence of the peripheral origin of musical hallucination by reporting lateralization and intensity change of hallucination by activation status of cochlear implant. PMID- 25445070 TI - A case of Alzheimer's disease following mild traumatic brain injury. AB - OBJECTIVE: To report a case of Alzheimer's disease (AD) following mild traumatic brain injury (TBI). METHOD: Case report. RESULTS: We report the time course of AD following mild TBI with evidence of AD pathology. A patient complained of minor memory disturbance 6 months after TBI and was diagnosed with mild cognitive impairment 1.5 years after TBI, and she was finally diagnosed as probable AD 4 years after TBI. Amyloid PET revealed brain accumulation of beta-amyloid at a pathological AD level. CONCLUSION: Our case well illustrated how TBI can accelerate the AD process. Clinicians should carefully follow up patients with persistent cognitive impairment after TBI. PMID- 25445071 TI - Disulfiram-induced neuropathy: a case report. AB - Disulfiram is widely used for aversive treatment of alcoholism. Neuropathy is one of the most severe side effects of disulfiram therapy. We report the case of a young man who developed a neuropathy following disulfiram administration, with a virtually complete recovery within 2 months. PMID- 25445072 TI - Evaluation of the dimensions of anger reactions-5 (DAR-5) scale in combat veterans with posttraumatic stress disorder. AB - After a traumatic event many people experience problems with anger which not only results in significant distress, but can also impede recovery. As such, there is value to include the assessment of anger in routine post-trauma screening procedures. The Dimensions of Anger Reactions-5 (DAR-5), as a concise measure of anger, was designed to meet such a need, its brevity minimizing the burden on client and practitioner. This study examined the psychometric properties of the DAR-5 with a sample of 163 male veterans diagnosed with Posttraumatic Stress Disorder. The DAR-5 demonstrated internal reliability (alpha=.86), along with convergent, concurrent and discriminant validity against a variety of established measures (e.g., HADS, PCL, STAXI). Support for the clinical cut-point score of 12 suggested by Forbes et al. (2014, Utility of the dimensions of anger reactions-5 (DAR-5) scale as a brief anger measure. Depression and Anxiety, 31, 166-173) was observed. The results support considering the DAR-5 as a preferred screening and assessment measure of problematic anger. PMID- 25445073 TI - The role of safety behaviors in exposure-based treatment for panic disorder and agoraphobia: associations to symptom severity, treatment course, and outcome. AB - The potentially detrimental effects of safety behaviors during exposure therapy are still subject to debate. Empirical findings are inconsistent, and few studies have investigated effects of idiosyncratic safety behavior manifestations during exposure or in everyday life. These limitations might be due to a lack of appropriate measures that address individual safety behaviors. We examined psychometric properties and predictive value of the Texas Safety Maneuver Scale (TSMS), a questionnaire specifically targeting safety behaviors in panic disorder and agoraphobia. Effects of safety behavior use, both during everyday life and during therapy, were examined using data from a multicenter RCT of N=268 patients that aimed at evaluating efficacy and mechanisms of action of two variants of an exposure-based therapy. The TSMS total score demonstrated good internal consistency (alpha=0.89), and it showed significant correlations with selected measures of baseline anxiety and impairment. The proposed factor structure could not be replicated. Frequent safety behavior use at baseline was associated with actual safety behavior during exposure exercises. Pronounced in-situ safety behavior, but not baseline safety behavior was associated to detrimental treatment outcome. The results underline the relevance of a rigorous safety behavior assessment in therapy. The actual relationship between safety behavior use and treatment outcome is yet to determine. PMID- 25445074 TI - Predictors of CBT outcome in older adults with GAD. AB - The current study is a secondary analysis of data from a randomized controlled trial of CBT for late-life GAD (Stanley et al., 2014) which provided an opportunity to examine predictors of outcome among those who received CBT. Participants were 150 older adults who were randomized to receive 10 sessions of CBT. Completer analyses found that homework completion, number of sessions attended, lower worry severity, lower depression severity, and recruitment site predicted 6-month worry outcome on the PSWQ-A, whereas homework completion, credibility of the therapy, lower anxiety severity, and site predicted 6-month anxiety outcome on the STAI-T. In intent-to-treat multivariate analyses, however, only initial worry and anxiety severity, site, and number of sessions completed predicted treatment outcome. These results are largely consistent with predictors of outcome in younger adults and suggest that lower initial symptom severity and variables consistent with greater engagement in treatment predict outcome. PMID- 25445076 TI - Is there a common pathway to developing ASD and PTSD symptoms? AB - Numerous studies have identified risk factors for acute and long-term posttraumatic stress symptoms following traumatic exposure. However, little is known about whether there are common pathways to the development of acute stress disorder (ASD) and posttraumatic stress disorder (PTSD). Research suggests that a common path to ASD and PTSD may lie in peritraumatic responses and cognitions. The results of structural equation modeling in a national sample of Danish bank robbery victims (N=450) show that peritraumatic panic, anxiety sensitivity, and negative cognitions about self were significant common risk factors for both ASD severity and PTSD severity when controlled for the effect of the other risk factors. The strongest common risk factor was negative cognitions about self. Future research should focus on replicating these results as they point to possible areas of preventive and treatment actions against the development of traumatic stress symptoms. PMID- 25445075 TI - Interpretation bias modification for youth and their parents: a novel treatment for early adolescent social anxiety. AB - Social anxiety is the most prevalent anxiety disorder of late adolescence, yet current treatments reach only a minority of youth with the disorder. Effective and easy-to-disseminate treatments are needed. This study pilot tested the efficacy of a novel, online cognitive bias modification for interpretation (CBM I) intervention for socially anxious youth and their parents. The CBM-I intervention targeted cognitive biases associated with early adolescents' maladaptive beliefs regarding social situations, and with parents' intrusive behavior, both of which have been theoretically linked with the maintenance of social anxiety in youth. To investigate the efficacy of intervening with parents and/or children, clinically diagnosed early adolescents (ages 10-15; N=18) and their mothers were randomly assigned to one of three conditions: the first targeted early adolescents' cognitive biases related to social anxiety (Child only condition); the second targeted parents' biases associated with intrusive behavior (Parent-only condition); and the third targeted both youth and parents' biases in tandem (Combo condition). The use of a multiple baseline design allowed for the efficient assessment of causal links between the intervention and reduction in social anxiety symptoms in youth. Results provided converging evidence indicating modest support for the efficacy of CBM-I, with no reliable differences across conditions. Taken together, results suggest that online CBM-I with anxious youth and/or their parents holds promise as an effective and easily administered component of treatment for child social anxiety that deserves further evaluation in a larger trial. PMID- 25445077 TI - Progress towards understanding the genetics of posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) is a complex syndrome that occurs following exposure to a potentially life threatening traumatic event. This review summarises the literature on the genetics of PTSD including gene-environment interactions (GxE), epigenetics and genetics of treatment response. Numerous genes have been shown to be associated with PTSD using candidate gene approaches. Genome-wide association studies have been limited due to the large sample size required to reach statistical power. Studies have shown that GxE interactions are important for PTSD susceptibility. Epigenetics plays an important role in PTSD susceptibility and some of the most promising studies show stress and child abuse trigger epigenetic changes. Much of the molecular genetics of PTSD remains to be elucidated. However, it is clear that identifying genetic markers and environmental triggers has the potential to advance early PTSD diagnosis and therapeutic interventions and ultimately ease the personal and financial burden of this debilitating disorder. PMID- 25445078 TI - Therapist-assisted Internet-delivered cognitive behavior therapy for depression and anxiety: translating evidence into clinical practice. AB - This dissemination study examined the effectiveness of therapist-assisted Internet-delivered Cognitive Behavior Therapy (ICBT) when offered in clinical practice. A centralized unit screened and coordinated ICBT delivered by newly trained therapists working in six geographically dispersed clinical settings. Using an open trial design, 221 patients were offered 12 modules of ICBT for symptoms of generalized anxiety (n=112), depression (n=83), or panic (n=26). At baseline, midpoint and post-treatment, patients completed self-report measures. On average, patients completed 8 of 12 modules. Latent growth curve modeling identified significant reductions in depression, anxiety, stress and impairment (d=.65-.78), and improvements in quality of life (d=.48-.66). Improvements in primary symptoms were large (d=.91-1.25). Overall, therapist-assisted ICBT was effective when coordinated across settings in clinical practice, but further attention should be given to strategies to improve completion of treatment modules. PMID- 25445079 TI - Posttraumatic stress disorder and alcohol dependence: does order of onset make a difference? AB - Posttraumatic stress disorder (PTSD) and alcohol dependence (AD) are frequently comorbid and the order in which they develop may affect the clinical presentation and response to treatment. This study compared 73 treatment-seeking participants who developed PTSD prior to developing AD ("PTSD-first") with 64 participants who developed AD prior to developing PTSD ("AD-first") on demographics, clinical presentation, and response to treatment for PTSD and AD. All participants received BRENDA, a medication management and motivational enhancement intervention and were randomly assigned to either prolonged exposure (PE) for PTSD plus BRENDA or BRENDA alone and to either naltrexone (NAL) for AD or placebo (PBO). Results showed that participants with AD-first were more likely to report low income, meet criteria for antisocial or borderline personality disorder, report an index trauma of physical assault, compared to those with PTSD-first. Conversely, participants with PTSD-first were more likely to report an index trauma of sexual assault or a combat experience. Notably, no group differences were observed in treatment outcome despite some differences in clinical presentation. PMID- 25445080 TI - Variation in SLC1A1 is related to combat-related posttraumatic stress disorder. AB - Candidate gene studies have yet to investigate the glutamate system, the primary excitatory neurotransmitter of the HPA-axis related to PTSD risk. We investigated 13 SNPs in the glutamate transporter gene (SLC1A1) in relation to PTSD among combat-exposed veterans. Participants (n=418) completed a diagnostic interview and provided a blood sample for DNA isolation and genotyping. A subset of participants (n=391) had severity and combat exposure data available. In the primary logistic regression gender and rs10739062 were significant predictors of PTSD diagnosis (OR=0.50; OR=1.43). In the linear regression analysis, combat exposure was the only significant predictor (beta=0.16) of severity. A computed genetic risk sum score was significant in relation to PTSD diagnosis (OR=1.15) and severity scores (beta=0.14) above and beyond the effects of combat exposure. This study provides preliminary support for the relationship of glutamate transporter polymorphisms to PTSD risk and the need for further genetic studies within this system. PMID- 25445082 TI - Mediators of transdiagnostic group cognitive behavior therapy. AB - The efficacy of cognitive-behavioral therapy (CBT) for anxiety is well established. Investigations into the mechanisms of change in CBT report changes in cognitive vulnerabilities mediating improvements over the course of treatment. As anxiety disorders share certain risk factors, there is a trend toward CBT emphasizing these vulnerabilities, including negative affectivity (NA) and also more specific constructs such as anxiety sensitivity (AS) and intolerance of uncertainty (IU). The purpose of this investigation was to analyze potential mediators of anxiety reduction over the course of transdiagnostic group CBT. NA, AS, and IU all decreased over the course of treatment. Among the potential mediators, change in NA had a significant relationship with change in anxiety but change in AS and change in IU did not. Neither the main effect of primary diagnosis nor the interactions between potential mediators and primary diagnoses were significant, indicating that there were no differential changes in anxiety or the potential mediators across primary diagnoses. Results strongly point toward NA as an overarching mediator of anxiety reduction during transdiagnostic group CBT. PMID- 25445081 TI - The impact of social skills training for social anxiety disorder: a randomized controlled trial. AB - OBJECTIVE: Social anxiety disorder (SAD) impacts social, occupational and academic functioning. Although many interventions report change in social distress, improvement in social behavior remains under-addressed. This investigation examined the additive impact of social skills training (SST) for the treatment of SAD. METHOD: Using a sample of 106 adults who endorsed SAD across numerous social settings, participants were randomized to exposure therapy (imaginal and in vivo) alone, a combination of SST and exposure therapy known as Social Effectiveness Therapy (SET), or a wait list control. The assessment strategy included self-report measures, blinded clinical ratings and blinded assessment of social behavior. RESULTS: Both interventions significantly reduced distress in comparison to the wait list control and at post-treatment, 67% of patients treated with SET and 54% of patients treated with exposure therapy alone no longer met diagnostic criteria for SAD, a difference that was not statistically significant. When compared to exposure therapy alone, SET produced superior outcomes (p<.05) on measures of social skill and general clinical status. In addition to statistical significance, participants treated with SET or exposure reported clinically significant decreases on two measures of self reported social anxiety and several measures of observed social behavior (all ps<.05). CONCLUSIONS: Both interventions produced efficacious treatment outcome, although SET may provide additional benefit on measures of social distress and social behavior. PMID- 25445083 TI - Experience sampling and ecological momentary assessment for studying the daily lives of patients with anxiety disorders: a systematic review. AB - Anxiety disorders are highly prevalent. Symptoms may occur unpredictably (e.g., panic attacks) or predictably in specific situations (e.g., social phobia). Consequently, it may be difficult to assess anxiety and related constructs realistically in the laboratory or by traditional retrospective questionnaires. Experience sampling methods (ESM) and ecological momentary assessment (EMA) can deepen the understanding of the course of anxiety disorders by frequently assessing symptoms and other variables in the natural environment. We review 34 ESM/EMA studies on adult panic disorder, generalized anxiety disorder, social phobia, post-traumatic stress disorder, and obsessive-compulsive disorder, as well as anxiety disorders in youth. Benefits of ESM/EMA for the study of anxiety disorders include generating insight into the temporal variability of symptoms and into the associations among daily affect, behaviors, and situational cues. Further, ESM/EMA has been successfully combined with ambulatory assessment of physiological variables and with treatment evaluations. We provide suggestions for future research, as well as for clinical applications. PMID- 25445084 TI - Development of exposure to combat severity scale of the combat experiences questionnaire (CEQ). AB - Combat exposure is detrimental to physical and mental health, and is an important risk factor for Post-traumatic Stress Disorder (PTSD). The current study aimed to develop the first section of a self-report measure (Combat Experiences Questionnaire - CEQ), and to explore its psychometric properties on Portuguese Overseas War Veterans. The Exposure to Combat Severity Scale (CEQ A), assesses the exposure severity to objective scenarios related to military combat, common to contemporary and older theaters of operations. Studies included structural analysis through Rash Model, internal consistency, convergent validity (n=708), temporal reliability (n=112) and sensibility to differentiate war Veterans with and without war-related PTSD (N=40 and N=47, respectively). The scale's structure presented adequate fit to the data, adequate psychometric properties, and discriminant validity. Thus, the CEQ A is a valid and reliable tool presenting diverse combat scenarios to assess severity of combat exposure in war Veterans. PMID- 25445085 TI - Psychometric properties of the child and parent versions of Spence children's anxiety scale in a Danish community and clinical sample. AB - This study examined the psychometric properties and norms of the Spence Children's Anxiety Scale (SCAS) and the associated parent version (SCAS-P) in a Danish community and a clinical sample. The total sample consisted of 1240 children (972 from community sample), age 7-17 years, and 805 parents (537 from community sample). Results indicated that SCAS and SCAS-P had good internal consistency on the total scale and all subscales, with exception of the subscale for fear of physical injury. Both scales showed satisfactory 2-week and 3-month retest stability. All subscales and total scales of the SCAS and SCAS-P discriminated between the clinical and community sample. A comparison with the Beck Youth Inventories and the Strength and Difficulty Questionnaire in the clinical sample supported the scales' convergent and divergent validity. Results of confirmatory factor analyses for SCAS and SCAS-P were in favor of the original model with six correlated factors. PMID- 25445086 TI - The short form of the fear survey schedule for children-revised (FSSC-R-SF): an efficient, reliable, and valid scale for measuring fear in children and adolescents. AB - The present study examined the psychometric properties of the Short Form of the Fear Survey Schedule for Children-Revised (FSSC-R-SF) in non-clinical and clinically referred children and adolescents from the Netherlands and the United States. Exploratory as well as confirmatory factor analyses of the FSSC-R-SF yielded support for the hypothesized five-factor structure representing fears in the domains of (1) failure and criticism, (2) the unknown, (3) animals, (4) danger and death, and (5) medical affairs. The FSSC-R-SF showed satisfactory reliability and was capable of assessing gender and age differences in youths' fears and fearfulness that have been documented in previous research. Further, the convergent validity of the scale was good as shown by substantial and meaningful correlations with the full-length FSSC-R and alternative childhood anxiety measures. Finally, support was found for the discriminant validity of the scale. That is, clinically referred children and adolescents exhibited higher scores on the FSSC-R-SF total scale and most subscales as compared to their non clinical counterparts. Moreover, within the clinical sample, children and adolescents with a major anxiety disorder generally displayed higher FSSC-R-SF scores than youths without such a diagnosis. Altogether, these findings indicate that the FSSC-R-SF is a brief, reliable, and valid scale for assessing fear sensitivities in children and adolescents. PMID- 25445087 TI - Screen for child anxiety related emotional disorders: are subscale scores reliable? A bifactor model analysis. AB - The aim of this study was to investigate the utility of creating and scoring subscales for the self-report version of the Screen for Child Anxiety Related Emotional Disorders (SCARED) by examining whether subscale scores provide reliable information after accounting for a general anxiety factor in a bifactor model analysis. A total of 2420 children aged 9-18 answered the SCARED in their schools. Results suggested adequate fit of the bifactor model. The SCARED score variance was hardly influenced by the specific domains after controlling for the common variance in the general factor. The explained common variance (ECV) for the general factor was large (63.96%). After accounting for the general total score (omegah=.83), subscale scores provided very little reliable information (omegah ranged from .005 to .04). Practitioners that use the SCARED should be careful when scoring and interpreting the instrument subscales since there is more common variance to them than specific variance. PMID- 25445088 TI - The impact of disaster work on community volunteers: The role of peri-traumatic distress, level of personal affectedness, sleep quality and resource loss, on post-traumatic stress disorder symptoms and subjective health. AB - Disaster work has shown to cause PTSD symptoms and subjective health complaints in professional emergency personnel. However, very little is known about how disaster work affects community volunteers. This first time longitudinal study examined factors contributing to post-traumatic stress disorder symptoms (PTSD) and subjective health complaints in volunteers working in an earthquake setting. At six and eighteen months post disaster, a sample of 506 Indonesian Red Cross volunteers were assessed using the Impact of Event Scale-Revised and the Subjective Health Complaints Inventory. Factors analyzed in relation to the outcomes included: peri-traumatic distress, level of personal affectedness by the disaster, sleep quality and loss of resources as a consequence of the disaster. At 18 months post-disaster the findings showed high levels of PTSD symptoms and subjective health complaints. Quality of sleep was related to both outcomes but resource loss only to PTSD symptoms. Neither peri-traumatic distress nor level of affectedness by the disaster (external versus directly affected volunteers), were predictive of symptoms. This study indicates that characteristics of disaster work e.g. low quality of sleep, may be an important contributor to PTSD symptoms and subjective health complaints in volunteers. PMID- 25445089 TI - Treatment of vitiligo using targeted UVB-Intense Pulsed Light (IPL)- phototherapy: evaluation of variables affecting therapeutic success. AB - BACKGROUND: Targeted UVB intense pulsed light (IPL)-phototherapy has gained interest for repigmentation of vitiligo as it allows selective treatment, sparing the surrounding skin. However, optimal treatment frequency and duration are not known. OBJECTIVES: We compared the efficacy and safety of two treatment protocols, weekly and every two weeks, for a maximum of 12 months. Variables affecting treatment response were evaluated. PATIENTS & METHODS: 22 patients (16 female, 6 male; aged 15 - 67 years) with generalised vitiligo were evaluated retrospectively. UVB-IPL had been administered weekly (13 patients, group A), or every second week (9 patients, group B). In cases of no response, treatment stopped after 6 months. Regimentation was evaluated qualitatively and quantitatively. RESULTS: After 6 months, 12/13 patients (A), 3/9 patients (B) showed repigmentation. Due to lack of success, treatment was stopped after 6 months in 1 group A patient and 6/9 group B patients. After 12 months, lesions on the face and trunk in group A showed a mean of 70 +/- 27% and 60 +/- 29% repigmentation, respectively. Moderate to good repigmentation was seen in 78% of group A patients on the ulnar region on the forearms and the shins. Side effects were minimal. Treatment success depended on treatment frequency, number of treatments and the anatomical site of lesions. CONCLUSIONS: UVB-IPL phototherapy seems to be effective and well-tolerated in non-segmental vitiligo. A treatment frequency of weekly intervals rather than every two weeks appears preferable. Our observations will help in designing a sufficiently powered prospective clinical trial to test this hypothesis. PMID- 25445090 TI - Lymphocyte inhibition is compromised in mesenchymal stem cells from psoriatic skin. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disorder associated with a host of immune abnormalities. Mesenchymal stem cells (MSCs) have immunosuppressive properties and, in earlier studies, we found that the bone marrow MSCs of patients with psoriasis exhibit abnormal cytokine secretion. Since MSCs can be isolated from skin, we hypothesized that the biological characteristics of MSCs in psoriatic skin lesions might reflect the pathogenesis of psoriasis. OBJECTIVE: To investigate the effects of MSCs from psoriatic skin lesions on T-cell proliferation. MATERIALS AND METHODS: MSCs obtained from psoriatic skin lesions and healthy human skin were examined by flow cytometry and cell differentiation assays. MSCs were co-cultured with normal peripheral blood T cells to assess changes in T-cell proliferation. Concentrations of interleukin (IL)-6, IL-11, hepatocyte growth factor (HGF), and transforming growth factor (TGF)-beta1 in the MSC culture supernatants were measured by enzyme-linked immunosorbent assays. RESULTS: Surface markers and differentiation capacity were similar in MSCs from both sources. MSCs in psoriatic skin lesions were weaker inhibitors of T-cell proliferation (p<0.05) and exhibited increased secretion of IL-11 and reduced secretion of IL-6 and HGF (p<0.05). Secretion of TGF-beta1 was unchanged (p > 0.05). CONCLUSION: This study demonstrated abnormalities in MSCs derived from psoriatic skin lesions. We suggest that the attenuated inhibitory effect on T-cell proliferation might be one of the pathogenic mechanisms of psoriasis. PMID- 25445091 TI - Why care about linear hair growth rates (LHGR)? a study using in vivo imaging and computer assisted image analysis after manual processing (CAIAMP) in unaffected male controls and men with male pattern hair loss (MPHL). AB - BACKGROUND: The words "hair growth" frequently encompass many aspects other than just growth. OBJECTIVES: Report on a validation method for precise non-invasive measurement of thickness together with linear hair growth rates of individual hair fibres. To verify the possible correlation between thickness and linear growth rate of scalp hair in male pattern hair loss as compared with healthy male controls. MATERIALS AND METHODS: To document the process of validation of hair growth measurement from in vivo image capturing and manual processing, followed by computer assisted image analysis. We analysed 179 paired images obtained with the contrast-enhanced-phototrichogram method with exogen collection (CE-PTG-EC) in 13 healthy male controls and in 87 men with male pattern hair loss (MPHL). RESULTS: There was a global positive correlation between thickness and growth rate (ANOVA; p<0.0001) and a statistically significantly (ANOVA; p<0.0005) slower growth rate in MPHL as compared with equally thick hairs from controls. Finally, the growth rate recorded in the more severe patterns was significantly (ANOVA; P <= 0.001) reduced compared with equally thick hair from less severely affected MPHL or controls subjects. CONCLUSION: Reduced growth rate, together with thinning and shortening of the anagen phase duration in MPHL might contribute together to the global impression of decreased hair volume on the top of the head. Amongst other structural and functional parameters characterizing hair follicle regression, linear hair growth rate warrants further investigation, as it may be relevant in terms of self-perception of hair coverage, quantitative diagnosis and prognostic factor of the therapeutic response. PMID- 25445093 TI - Autoimmune thyroid disease in Italian patients with non-segmental vitiligo. PMID- 25445092 TI - Good efficacy and tolerability of ustekinumab in a patient with severe psoriasis under haemodialysis. PMID- 25445094 TI - Diagnostic value of nail examination in Hailey-Hailey disease. PMID- 25445099 TI - Diethylene glycol poisoning from transcutaneous absorption. AB - A case of transcutaneous diethylene glycol poisoning with severe acute kidney injury, but a positive outcome, is described. A man without significant medical history was admitted to our hospital due to anuria, gastrointestinal symptoms, and hypertension. Ultrasonography excluded vascular damage and postrenal obstruction. Laboratory tests showed acute kidney injury and metabolic acidosis with increased anion gap; hemodialysis therapy was started. The brother of the patient reported that the patient had been smearing his skin with brake fluid containing diethylene glycol to treat a "dermatitis." Only supportive therapy was given due to the lack of a specific antidote. Continuous venovenous hemofiltration was performed. The kidney biopsy showed acute toxic proximal tubulonecrosis, without deposition of oxalate crystals. His neurologic condition worsened dramatically; supportive care was continued. Over time, acute kidney injury and neurologic damage gradually improved; 33 days after admission, he went to a rehabilitation unit for 5 months, with complete clinical recovery. Historically, diethylene glycol has been the cause of large-scale poisonings from ingestion of contaminated drugs. The clinical evolution is unpredictable. Treatment is not well defined; early hemodialysis treatment reduces levels of toxic metabolites, and fomepizole could be useful in cases with an early diagnosis. A comparison of the characteristics of diethylene glycol versus ethylene glycol poisoning is given. PMID- 25445100 TI - Retroperitoneal fibrosis and asbestosis--a plausible association? PMID- 25445101 TI - Acute kidney injury and prognosis after cardiopulmonary bypass: a meta-analysis of cohort studies. AB - BACKGROUND: Robust estimates and sources of variation in risks of clinical outcomes for cardiopulmonary bypass (CPB)-associated acute kidney injury (AKI) are needed to inform clinical practice and policy. We aimed to assess whether the methods for defining acute kidney disease modify the estimated association of AKI with CPB. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Adults undergoing CPB. SELECTION CRITERIA FOR STUDIES: Cohort studies reporting adjusted associations between CPB-associated AKI and early mortality, later mortality, stroke, myocardial infarction, congestive heart failure, all cause hospitalization, chronic kidney disease, end-stage kidney disease, bleeding complications, or perioperative infection. PREDICTORS: CPB-associated AKI and renal replacement therapy. OUTCOMES: The primary outcome was early mortality (in hospital or within 90 days of surgery) in studies reporting adjusted associations and secondary outcomes including total and cardiovascular mortality, major adverse cardiovascular events, rehospitalization, end-stage kidney disease, bleeding, and perioperative infection. RESULTS: 46 studies with 47 unique cohorts comprising 242,388 participants were included. The pooled rate of CPB-associated AKI was 18.2%, and of renal replacement therapy, 2.1%. CPB-associated AKI was associated with early mortality (risk ratio [RR], 4.0; 95% CI, 3.1-5.2; crude mortality with CPB-associated AKI, 4.6%; without CPB-AKI, 1.5%) with considerable heterogeneity between studies (I(2)=87%). The AKI definition did not modify prognostic estimates (P for subgroup analysis = 0.9). When heterogeneity was fully accounted for using credibility ceilings, risks of early mortality were attenuated (RR, 2.2; 95% CI, 1.8-2.8) but remained high. Renal replacement therapy also was associated with early mortality (RR, 5.3; 95% CI, 3.4-8.1). CPB associated AKI also was associated with long-term mortality (RR, 2.0; 95% CI, 1.7 2.3) and stroke (RR, 2.2; 95% CI, 1.1-4.5). No other outcomes were reported in more than 3 studies. LIMITATIONS: Unclear attrition from follow-up in most studies and variable adjustment for confounders across studies. CONCLUSIONS: CPB associated AKI is associated with a more than 2-fold increase in early mortality regardless of AKI definition. PMID- 25445102 TI - Prevalence of X-aneuploidies, X-structural abnormalities and 46,XY sex reversal in Turkish women with primary amenorrhea or premature ovarian insufficiency. AB - Our objective was to identify the distribution of cytogenetic abnormalities of 175 Turkish women with primary amenorrhea (PA) or premature ovarian insufficiency (POI). A retrospective study was performed using medical records of 94 patients with PA and 81 patients with POI at the Genetics Department, Zeynep Kamil Women's and Children's Research and Training Hospital, Istanbul, Turkey. G-banded metaphase karyotype analysis were prepared and analyzed. Chromosomal abnormalities were present in 44 of 175 cases (25%). 15 were full blown or mosaic numerical X chromosome abnormalities (8.5%), 10 were full blown or mosaic X chromosome structural anomalies (5.7%), one was X-autosome translocation (0.5%), 3 were autosomal anomalies (1.7%), 12 were XY karyotype (6.8%), one was 45,X/46,XY mosaic and 2 were full blown or mosaic structural anomalies of Y chromosome (1.7%). The prevalence of chromosomal abnormalities was 25% in this large series of Turkish women with primary amenorrhea or premature ovarian insufficiency, most cases involving X-aneuploidy or X-structural abnormalities or 46,XY karyotype. High prevalence of chromosomal abnormalities is associated with POI starting at an early age (average age: 26 years). PMID- 25445103 TI - Lidocaine-prilocaine cream as analgesia for hysterosalpingography: a randomized, double blinded, controlled study. AB - OBJECTIVE: The efficacy of lidocaine-prilocaine cream (EMLA((r))) analgesia in the practice of hysterosalpingography is controversial. This study provides new drill results and a new method of application in terms of mode, time and place. The aim of the paper is to investigate the efficacy of 5% lidocaine 25 mg prilocaine 25 mg/g cream applied to the uterine cervix for reducing pain during hysterosalpingography. STUDY DESIGN: A randomized, double blinded, controlled study set in the general gynaecology clinic of a university teaching hospital between September 2012 and June 2013. One hundred successive patients programmed to undergo hysterosalpingography were randomized to either 3 ml of EMLA (50) cream or 3 ml of placebo (50), placed endocervically and exocervically, 10 min before hysterosalpingography. Patients' intensity of pain was assessed in four steps: at baseline (speculum application), after application of Pozzi tenaculum and cannula on the uterine cervix, during cervical traction and after contrast medium injection, using a 10-cm Visual Analogue Scale (VAS) immediately after the procedure. The most painful step was also identified. VAS was administered again at one-month follow-up visit. TRIAL REGISTRATION: NCT01303614. RESULTS: The contrast medium injection was the most painful step of hysterosalpingography in both groups (EMLA 3.96, placebo 4.54, 95%CI: -0.481 to 1.641). No differences were found between the two groups (P=0.281) during this step. When comparing the VAS scale after the application of Pozzi tenaculum and cannula (EMLA 1.06, placebo 3.34, 95%CI: 1.495-3.065) and after cervical traction (EMLA 2.54, placebo 3.46, 95%CI: 0.034-1.806), significantly less pain was experienced by the EMLA group than the placebo group: P=0.000 and P=0.042, respectively. CONCLUSION: Endocervical and exocervical topical application of EMLA 10 min before performing hysterosalpingography significantly reduced pain during cervical manipulation with tenaculum and cannula and during cervical traction, but did not reduce pain during injection of contrast that was the most painful step. PMID- 25445105 TI - Gene variation and premature ovarian failure: a meta-analysis. AB - OBJECTIVE: Premature ovarian failure (POF) is a complex, heterogeneous disorder that is influenced by multiple genetic components. This meta-analysis aimed to investigate the association between gene variants and susceptibility to POF. STUDY DESIGN: MEDLINE and CNKI were searched for studies published from inception (1950) to June 2014. Meta-analysis was performed when three or more studies reported genetic data on the same polymorphism or mutation. Additive and dominant models were analyzed using RevMan Version 5.1. RESULTS: The literature search yielded 575 articles, of which 59 studies on the association between POF and gene variants were identified for meta-analysis. Five genes were selected for analysis, including 10 common gene polymorphisms [BMP15 (-9C>G, 788insTCT and 852C>T), ESR1 (-351A>G and -397C>T), FMR1 CGG repeat, FSHR (919A>G and 2039A>G), INHA (-16C>T and -124A>G)] and two mutations (BMP15 538G>A and INHA 769G>A). BMP15 538G>A was found to be significantly more common in patients with POF compared with controls. No significant associations were found between the other variants of BMP15 and POF. With respect to ESR1, the accumulative results were not significant, although the findings of the individual studies were controversial. The incidence of FMR1 premutation was significantly higher in patients with POF compared with controls [odds ratio (OR) 9.2, 95% confidence interval (CI) 5.42-15.61; p<0.001] in the overall population, as well as in both Caucasian and Asian subgroups. Stratified analysis was applied for INHA 769G>A by ethnicity; a significant association with POF was only found in the Asian subgroup (allelic frequency: OR 8.89, 95% CI 2.1-5.52; p=0.004). No significant associations were found between the other variants of INHA and POF. CONCLUSIONS: BMP15 538A, FMR1 premutation and INHA 769A (in Asians alone) may indicate susceptibility to POF. Further well-designed studies and larger samples are required to confirm the association between gene variants and POF. PMID- 25445106 TI - The challenge of prenatal identification of congenital diaphragmatic hernia in the context of hydrops. PMID- 25445104 TI - Use of medical, surgical and complementary treatments among women with fibroids. AB - OBJECTIVE: To examine the use of medical management, uterus-preserving surgery (UPS), and complementary treatments among women with uterine fibroids. STUDY DESIGN: Prospective cohort study of 933 premenopausal women ages 31-54 years with symptomatic fibroids who participated in the Study of Pelvic Problems, Hysterectomy, and Intervention Alternatives (SOPHIA) for an average of 4.3 years (SD 2.5 years). Incident use of fibroid treatments was determined through annual interviews. Linear regression models were used to compare changes in fibroid related symptoms among women who underwent UPS versus those who did not undergo surgery. RESULTS: Participants were racially and ethnically diverse, with a mean age of 43 years. During study follow-up, 531 participants (57%) did not undergo UPS or hysterectomy, 250 (27%) had at least one UPS, and 152 (16%) underwent hysterectomy. Complementary and alternative treatments were commonly used, including exercise (45%), diet (34%), herbs (37%), and acupuncture (16%): participants reported significant symptom improvement and few side effects with these interventions. In multivariable linear regression models, women who did not undergo surgery during the study reported improvement in dyspareunia (p<.001), pelvic pain (p<.001), and menstrual cramps (p<.001). However, women who underwent UPS reported greater overall resolution of "pelvic problems" compared with women who did not have surgical treatment (difference in change score 1.18 on a four point Likert scale, p<.001). CONCLUSION: UPS are effective treatments for women with fibroids, but many women use hormonal or complementary treatments and report significant symptom improvement without surgical intervention. PMID- 25445107 TI - Safety and five-year re-intervention following magnetic resonance-guided focused ultrasound (MRgFUS) for uterine fibroids. AB - OBJECTIVE: To examine the safety and re-intervention rates following magnetic resonance-guided focused ultrasound (MRgFUS) for uterine fibroids at 5 years. To assess how the non-perfused volume (NPV), fibroid signal intensity and use of gonadotrophin-releasing hormone analogues (GnRHa) affect the re-intervention rates. STUDY DESIGN: Cohort study of women undergoing MRgFUS for treatment of their uterine fibroids between 2003 and 2010. RESULTS: Of 280 women undergoing MRgFUS the rate of minor complications was 3.9% and there were 3 serious complications (1.1%) including one skin burn, a fibroid expulsion and one case of persistent neuropathy. The NPVs achieved following MRgFUS have increased as the experience with this treatment has grown. In a 5-year follow-up study of 162 women, the overall re-intervention rate was 58.64%, but in those treatments with greater than 50% NPV the re-intervention rate was 50%. CONCLUSION: MRgFUS treatment of uterine fibroids is a safe treatment for uterine fibroids. The re intervention rate at 5 years is high, but the improvements in NPVs achieved may further improve the long term results. PMID- 25445108 TI - Preimplantation genetic diagnosis of human leukocyte antigen for X-linked immunoproliferative syndrome caused by SAP mutation. PMID- 25445109 TI - Labetalol for hypertension during pregnancy and nipple pain. PMID- 25445110 TI - Working towards integrated community care for older people: empowering organisational features from a professional perspective. AB - Although multi-disciplinary cooperation between professionals is a prerequisite to provide integrated care in the community, this seems hard to realise in practice. Yet, little is known about the experiences of professionals who implement it nor about the organisational features professionals identify as empowering during this cooperation process. Therefore, a case study of a multi disciplinary geriatric team was performed. The data-collection included observations of meetings, in-depth interviews and focus groups with professionals (N = 12). Data were analysed inductively and related to the three organisational levels within the model of organisational empowerment of Peterson and Zimmerman. Signs of empowering organisational features on the intraorganisational level were mutual trust and clear working routines. On the interorganisational level important features included improved linkages between participating organisations and increased insight into each other's tasks. Tensions occurred relating to the inter- and the extraorganisational level. Professionals felt that the commitment of the management of involved organisations should be improved just as the capacity of the team to influence (local) policy. It is recommended that policymakers should not determine the nature of professional cooperation in advance, but to leave that to the local context as well as to the judgement of involved professionals. PMID- 25445111 TI - Healthcare financing reform in Latvia: switching from social health insurance to NHS and back? AB - In the 1990s, Latvia aimed at introducing Social Health Insurance (SHI) but later changed to a National Health Service (NHS) type system. The NHS is financed from general taxation, provides coverage to the entire population, and pays for a basic service package purchased from independent public and private providers. In November 2013, the Cabinet of Ministers passed a draft Healthcare Financing Law, aiming at increasing public expenditures on health by introducing Compulsory Health Insurance (CHI) and linking entitlement to health services to the payment of income tax. Opponents of the reform argue that linking entitlement to health services to the payment of income tax does not have the potential to increase public expenditures on health but that it can contribute to compromising universal coverage and access to health services of certain population groups. In view of strong opposition, it is unlikely that the law will be adopted before parliamentary elections in October 2014. Nevertheless, the discussion around the law is interesting because of three main reasons: (1) it can illustrate why the concept of SHI remains attractive - not only for Latvia but also for other countries, (2) it shows that a change from NHS to SHI does not imply major institutional reforms, and (3) it demonstrates the potential problems of introducing SHI, i.e. of linking entitlement to health services to the payment of contributions. PMID- 25445112 TI - Implementation of the 2011 Therapeutic Activity Act: will commercialization improve the financial performance of Polish hospitals? AB - The Therapeutic Activity Act that came into force on 1 July 2011 was aimed at achieving a large-scale transformation of public hospitals into Commercial Code companies. The change of the legal form, from a public entity to a for-profit company, was expected to improve the poor economic efficiency of the public hospital sector. However, the mere change of the legal form does not guarantee a better financial performance of hospitals and thus the success of the Act. In many cases, deep internal changes are needed to achieve improvements in the financial performance of particular hospitals. In addition, a set of other measures at the national and regional levels, such as the mapping of health needs of the population, have to accompany the legal transformations in order to improve the efficiency of the hospital sector. The recent slowdown in the rate of the transformations is another factor that renders the success of the Act uncertain. PMID- 25445113 TI - The paradox of public participation in the healthcare in Poland--what citizens want, and what they think. AB - OBJECTIVE: To assess the concept of public involvement in the decision-making process in the healthcare sector in Poland. METHODS: A poll was conducted in 2011 on a representative random sample of residents of Poland. Respondents were asked about their preferences concerning the selection of the groups most appropriately representing public interests in the process of decision-making in the healthcare: Patients' Advocacy Groups (PAGs), Carers' Advocacy Groups (CAGs) and Citizens' Councils (CCs). A systematic literature review was performed to study real life examples of patients' involvement in the decision making processes in the Polish healthcare sector as well. RESULTS: In total, 83% of respondents would wish the participation of PAGs in decision-making concerning healthcare resources. The attitude to the engagement of CAGs and CCs was still positive but significantly lower, by 6 and 7 percentage points respectively. Some socio demographic differences were observed. In the literature review, five examples of the Polish patients' empowerment and three cases of PAGs' engagement in decision making process were identified. CONCLUSIONS: Although its importance was met with a universal approval by the majority of responders, real life examples of public engagement in decision making process indicate there is still room for improvement in the Polish healthcare. PMID- 25445114 TI - Overexpression of activated Cdc42-associated kinase1 (Ack1) predicts tumor recurrence and poor survival in human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers in China. Recent research suggested that activated Cdc42-associated kinase 1 (Ack1) played an important role in facilitating tumorigenesis, tumor invasion and metastasis. However, the role of Ack1 in HCC is not clear. Herein, the expression level of Ack1 mRNA in 30 fresh HCC specimens (carcinoma, peri-carcinoma and distal carcinoma tissues) was detected by reverse transcription-polymerase chain reaction (RT-PCR), while the expression of Ack1 protein in 18 fresh HCC specimens (carcinoma, peri-carcinoma and distal-carcinoma tissues) was analyzed by Western blotting. Immunohistochemical (IHC) staining was also employed to assess both the expression level and distribution of Ack1 protein in HCC tissues collected from 173 lesions, so as to study the correlations between Ack1 protein expression and other HCC-related clinicopathologic parameters. The results showed that both Ack1 mRNA and protein were significantly over-expressed in HCC tissues than that of either peri-carcinoma or distal-carcinoma tissues (P < 0.001, P = 0.012, respectively), while there was no significant difference between peri-carcinoma and distal-carcinoma tissues. Furthermore, the results of IHC indicated that the rates of Ack1 expressions in the patients with capsular invasion, hepatic vessel involvement and recurrence were higher than without above three conditions (P = 0.037, P = 0.036, P = 0.019, respectively), whereas the patients with overexpression of Ack1 protein had low survival rate (P = 0.007). Ack1 expression, tumor size and recurrence were independently related to survival (P = 0.014, P = 0.018, P < 0.001, respectively). Thus, the level of Ack1 is associated with tumor invasion potential, and the expression of Ack1 plays an important role as predictor of recurrence and poor outcome in HCC patients. PMID- 25445115 TI - Analysis of a cytoskeleton-associated kinase PEAK1 and E-cadherin in gastric cancer. AB - The expression of pseudopodium-enriched atypical kinase 1(PEAK1) has been studied in human cancers. However, their roles in gastric cancer are still unknown. In this study, gastric cancer tissue microarrays were constructed with 159 gastric cancer tissue samples, 150 non-neoplastic gastric epithelium specimens and 152 lymph node samples. Immunohistochemical staining for PEAK1 and E-cadherin was performed. Our study found negative expression of PEAK1 in 113 of 159 (71.1%) gastric cancers, in 46 of 150 (30.7%) non-neoplastic gastric epithelium tissues and in 69 of 94 (73.4%) metastatic lymph nodes. Negative expression of PEAK1 and E-cadherin associated with tumor grading, depth of invasion, lymph node metastases, pTNM stage and macroscopic type. Patients with either positive PEAK1 or E-cadherin expression had a significantly higher survival than those with negative expression. When combined, PEAK1(-)/E-cadherin(-) had a significantly poor prognosis than the rest of the patients. The expression of PEAK1 protein was positively correlated with E-cadherin in cancer tissues. Cox regression analyses showed that PEAK1, E-cadherin and PEAK1(-)/E-cadherin(-) were independent predictors of overall survival. In conclusion, our findings suggest that loss of PEAK1 may play an important role in carcinogenesis and development of gastric cancer through activating epithelial to mesenchymal transition. PMID- 25445116 TI - Clinical significance of the reduction of UT-B expression in urothelial carcinoma of the bladder. AB - Urea transporter B (UT-B) is a membrane protein and plays an important role in regulating urea concentration in bladder urothelial cells. It has been reported that UT-B gene mutations were related to bladder carcinogenesis, and UT-B deletion could induce DNA damage and apoptosis in bladder urothelium. However, the functions and clinical significance of UT-B in human bladder cancer remain unknown. The most common type of bladder cancer is urothelial carcinoma (UC). We hypothesized that UT-B expression was related to bladder UC progress. In this study, UT-B was detected using immunohistochemistry in 52 paraffin-embedded specimens of bladder UC and 10 normal urothelium specimens. The results showed that UT-B protein expression in UC tumor cells was significantly lower as compared with normal urothelial cells (P = 0.021). UT-B protein expression was significantly reduced with increasing histological grade (P = 0.010). UT-B protein expression in muscle-invasive stage was significantly lower than in non muscle-invasive stage (P = 0.014). Taken together, our data suggest that the reduction or loss of UT-B expression may be related to the incidence, progression and invasiveness of bladder UC. UT-B may be a novel diagnostic or prognostic biomarker, as well as a potential therapeutic target in UC of the bladder. PMID- 25445117 TI - Emergence of serogroup 15 Streptococcus pneumoniae of diverse genetic backgrounds following the introduction of pneumococcal conjugate vaccines in Hong Kong. AB - Serogroup 15 pneumococcal isolates from nasopharyngeal carriage of hospitalized children admitted to a teaching hospital in Hong Kong from April 2009 to September 2013 were characterized by pulse-field gel electrophoresis (PFGE), multilocus sequence typing, and antimicrobial non-susceptibility testing. The overall proportion of serogroup 15 isolates in the pre-PCV7 and post-PCV13 periods rose from 5.7% to 20.0%. The increase in trend for serotype 15B/C was statistically significant among children presented with pneumonia; bronchiolitis; upper respiratory tract infection; and febrile, non-respiratory diseases and for serotype 15A/F, among children with bronchiolitis and febrile, non-respiratory diseases. The predominant PFGE cluster of serotype 15B/C belonged to sequence type (ST) 199. Replacement of this more susceptible cluster (Ery and Tet non susceptibilities of 32.2% and 25.4%) with the non-susceptible cluster, ST8859 (Ery and Tet non-susceptibilities of 91.7% and 87.5%) was noted. ST63 was the predominant serotype 15A cluster (Ery and Tet non-susceptibilities of 97.4% and 92.3%). Serogroup 15 subtypes have emerged in the post-PCV13 era, and these non susceptible clusters warrant closer monitoring as candidates for incorporation to future pneumococcal vaccines. PMID- 25445118 TI - Identification and characterization of genetic structures coding for carbapenemases in Enterobacteria from Central Greece. AB - The dissemination of carbapenemases among different species of Enterobacteriaceae was investigated in the University Hospital of Larissa, Central Greece. The presence of the isoform (Tn4401a) of the transponson carrying blaKPC-2 and 5 divergent blaVIM-carrying class I integrons, including a novel structure, suggests interspecies transfer of these mobile elements and underscores their ongoing evolution. PMID- 25445119 TI - Evaluation of Vitek MS for rapid classification of clinical isolates belonging to Mycobacterium avium complex. AB - We evaluated the ability of the Vitek MS system to classify clinical pulmonary Mycobacterium avium complex isolates compared to multilocus sequence analysis. Vitek MS accurately identified 55% of the isolates as M. avium and 18% as M. intracellulare, but misidentified 24 (27%) Mycobacterium chimaera isolates as Mycobacterium intracellulare. PMID- 25445120 TI - Real-world performance of a microarray-based rapid diagnostic for Gram-positive bloodstream infections and potential utility for antimicrobial stewardship. AB - The Verigene Gram-positive blood culture assay (BC-GP) is a microarray-based rapid diagnostic test, which includes targets for 12 bacterial species and 3 resistance determinants. We prospectively compared the diagnostic accuracy of the BC-GP to routine microbiologic methods and evaluated the potential of the BC-GP for antimicrobial stewardship programs. A total of 143 consecutive patients with Gram-positive bacteremia were included in the analysis. BC-GP correctly identified 127/128 (99.2%) of organisms from monomicrobial blood cultures and 9/14 (64.3%) from polymicrobial, including all methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Stewardship interventions were possible in 51.0% of patients, most commonly stopping or preventing unnecessary vancomycin or starting a targeted therapy. In Monte Carlo simulations, unnecessary antibiotics could be stopped at least 24 hours earlier in 65.6% of cases, and targeted therapy could be started at least 24 hours earlier in 81.2%. BC-GP is a potentially useful test for antibiotic stewardship in patients with Gram-positive bacteremia. PMID- 25445122 TI - Location of the popliteal artery and its relationship with the vascular risk in the suture of the posterior horn of the lateral meniscus. AB - INTRODUCTION: The proximity of the posterior horn of the lateral meniscus to the popliteal artery determines a risk of vascular injury in its suture. The aim of this study is to determine the location of the popliteal artery, and to establish the minimal distance from the posterior wall of the lateral meniscus to the artery, the common peroneal nerve (CPN), and its correlation to other variables. MATERIAL AND METHODS: A total of 102 magnetic resonance studies were retrospectively reviewed from patients undergoing surgery at our institution. The axial section where the lateral meniscus could be clearly defined was selected, and the measurements were performed. RESULTS: The artery lay laterally to the midline in 94% of the cases. The minimal mean distance from the posterior wall of the lateral meniscus to the popliteal artery was 1.01cm. (0.32-1.74, SD: 0.304). The minimal mean distance to the CPN was 1.74cm. (0.75-2.87, SD: 0.374). No association was found between the minimal mean distance from the posterior wall to the popliteal artery with the height, weight, BMI, the lateral meniscus diameter, or the tibial plateau diameter. An association was found between the distance from the posterior wall to the CPN with the weight and the BMI. CONCLUSIONS: The proximity of the posterior horn to the popliteal artery should be considered when performing sutures. This distance is within the recommended depth for all-inside meniscus repair devices. This distance is not related to height, weight, BMI, lateral meniscus nor tibial plateau diameters. PMID- 25445123 TI - [Acute disseminated encephalomyelitis after rabies vaccination: a case report]. AB - Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system. It is a disease whose incidence is not precisely known. The presumed mechanism is demyelination of the immune-mediated central nervous system. There is no pathognomonic clinical presentation in ADEM. The combination of multifocal neurological disorders arising in the aftermath of an infection or vaccination should alert the clinician. We report a case of ADEM in an 8-year-old child occurring after antirabies vaccination. The diagnosis was made by nuclear magnetic resonance imaging (bilateral and multifocal lesions in the subcortical occipitoparietal and frontal left anterior white matter with involvement of U fibers) and a history of antirabies vaccination. The clinical course was marked by the appearance of motor and visual effects. PMID- 25445124 TI - [Clowns in pediatrics]. PMID- 25445121 TI - Monitoring of polyomavirus BK replication and impact of preemptive immunosuppression reduction in renal-transplant recipients in China: a 5-year single-center analysis. AB - This provides the long-term patient/graft survival and outcome of BK viremia and BK virus allograft nephropathy (BKVAN) in renal transplant recipients in the setting of intensive monitoring and preemptive of reduction of immunosuppression. Quantitative BKV DNA PCR and urinary cytology surveillance were performed regularly after transplantation in 229 kidney recipients. Patients with BK viremia and BKVAN were treated with 30-50% reduction in doses of tacrolimus and/or mycophenolate mofetil and were monitored for BKV every 3-6 months. All the patients were followed for 5 years. Overall 5-year patient and graft survival were 95.6% and 92.1%, respectively, and independent of presence of decoy cells, BK viruria, viremia, or BKVAN. After reduction of immunosuppression, BK viremia (n = 38) resolved in 100% of patients, without increased acute rejection. Recurrent BK viremia was not observed in viremic patients without BKVAN (n = 30). All BKVAN patients (n = 7, 3.1%) cleared viremia with a mean time of 5.9 months (range 1-15 months) and manifested no decline in estimated glomerular filtration rate from 1 month to 5 years after transplantation. Viral monitoring and preemptive reduction of immunosuppression resulted in the successful resolution of BK viremia and BKVAN with excellent graft survival and renal function at 5 years. PMID- 25445126 TI - [Purulent pericarditis and colonic infiltrating to Salmonella enteritidis complicated by acute intussusception in a case of IL-12Rbeta1 deficiency]. AB - IL-12 receptor beta1 deficiency (IL-12Rbeta1) predisposes patients to mycobacteria and Salmonella infections. We report a case of IL-12Rbeta1 deficiency with a fatal multi-resistant Salmonella enteritidis infection. This boy was born after from a consanguineous marriage, and diagnosed as having a IL 12Rbeta1 deficiency since the age of 3 months. He presented with recurrent Salmonella enteritidis essentially digestive localization, complicated by purulent pericarditis at the same germ at the age of two and a half years. At the age of 3, a colonic infiltration due to a Salmonella enteritidis resistant to antibiotics, was complicated by acute intussusception, and the child died. The IL 12Rbeta1 deficiency is considered as having a good prognosis, in contrast to what happened in our patient. We review therapeutic issues in these patients. PMID- 25445125 TI - [Verapamil intoxication: beware of the delayed effect]. AB - Intoxication with calcium channel inhibitory drugs is rare but mortality rates reach 10 %. We report the case of a 5-year-old girl who had ingested five 240-mg tablets of extended-release verapamil (VLP) and a tablet of bromazepam. Thirty hours after the ingestion she had a vasoplegic shock, heart conduction disorders, and metabolic complications. She was treated in pediatric intensive care with continuous epinephrine and insulin and recovered completely 60h after the ingestion. This case underlines the danger of calcium channel blocker overdose, increased by the extended-release mechanism: the drug effect is to slow down gastric motility - which explains the latency of the symptoms - but this also increases the drug absorption, inducing a vicious circle. These mechanisms in calcium blocker intoxication need to be kept in mind in order to decrease the mortality of such accidents. PMID- 25445127 TI - [Uncommon neonatal case of hypoglycemia: ACTH resistance syndrome]. AB - Monitoring of blood glucose is usually reported to reduce the risk of hypoglycemia in term newborns with high risk factors and for prematurity in neonatal intensive care unit patients. Differential diagnosis has rarely been discussed. In the eutrophic term newborn, hypoglycemia remains rare and an etiological diagnosis must be made. Intensive management of neonatal hypoglycemia is required to prevent neurodevelopmental defects. Without evident cause or if hypoglycemia persists, a systematic review of possible causes should be made. We report isolated glucocorticoid deficiency diagnosed in an infant at 10 months of age. This boy had neonatal hypoglycemia and mild jaundice that had not been investigated. During his first 9 months of life, he presented frequent infections. At 10 months of age, febrile seizures occurred associated with shock, hypoglycemia, hyponatremia, mild hyperpigmentation, and coma. He was diagnosed with hypocortisolemia and elevated ACTH levels. Brain injury was revealed by MRI after resuscitation, with hypoxic-ischemic and hypoglycemic encephalopathy. The molecular studies demonstrated the presence of p.Asp107Asn and previously unreported frameshift p.Pro281GlnfsX9 MC2R gene mutations. A substitutive hormone therapy was provided and during a follow-up of 12 months no adrenal crisis was noted. We report an unusual case of familial glucocorticoid deficiency with severe neurological injury. This case demonstrates the importance of an appropriate etiological diagnosis in neonatal hypoglycemia. PMID- 25445128 TI - [VRS bronchiolitis with severe hyponatremia leading to acute seizures: a report of three cases]. AB - Acute bronchiolitis due to respiratory syncytial virus (RSV) can present with extrapulmonary manifestations, notably severe hyponatremia. Hyponatremia is caused by excess secretion of antidiuretic hormone and can be exacerbated by intravenous infusion of hypotonic solutions. We report three cases of infants admitted for acute bronchiolitis and hyponatremia leading to acute seizures. We describe how hyponatremia was corrected and analyze the management aspects that might have worsened the magnitude of hyponatremia. We underline the basic principles of water and electrolyte management of bronchiolitis. PMID- 25445130 TI - [Cerebral venous thrombosis and immune thrombocytopenia in a 7-year-old girl: a fortuitous association?]. AB - Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by autoantibody-mediated peripheral platelet destruction. It is rarely accompanied by thrombosis. Here, we describe a wide cerebral venous thrombosis that occurred at the onset of a primary ITP in a 7-year-old girl. ITP was confirmed by the presence of anti-platelet antibodies. Whether ITP is a risk factor for venous thrombosis is a matter of debate. The platelet microparticles released during the platelet destruction and the interaction between the autoantibodies and the platelet glycoproteins may contribute to platelet activation. Increased risk of thromboembolic events should be considered in all patients with ITP, including children. PMID- 25445129 TI - [Systemic lupus erythematosus in a boy with chronic granulomatous disease: case report and review of the literature]. AB - The association of chronic granulomatosis disease (CGD) with autoimmune diseases such as lupus has been described but remains rare. K... is a boy born of a consanguineous marriage. In the family history, two brothers had died at a young age. He had been followed up since the age of 6 months for CGD. At 11 years of age, he developed malar rash, cheilitis, oral ulceration, and photosensitivity. Systemic lupus erythematosus (SLE) was confirmed by the presence of high levels of antinuclear antibodies. This observation demonstrates that with the clinical association of recurrent infections and skin lesions the diagnosis of CGD with SLE must be considered. PMID- 25445131 TI - [Recurrent distal ileal obstruction by a trichobezoar in a 5-year-old child]. AB - The diagnosis of trichobezoar can be difficult, due to its low prevalence in the pediatric population, limited knowledge of behavioral disorders in children and their prevention, and the difficulty of the clinical diagnosis. We report a case of intestinal occlusion in a 5-year-old child, whose diagnosis was delayed and the trichobezoar, revealed intraoperatively, confined 15cm from the ileocecal valve. Diverging management strategies are proposed in the literature concerning the indication of CT for diagnostic and prognostic purposes, and fibroscopy, still considered as the diagnostic reference. Surgical exploration can lead to the final diagnosis. Bowel obstruction requires emergency surgery to avoid intestinal complications and must be followed by psychological therapy to limit recurrence. PMID- 25445132 TI - Balancing ischaemia and bleeding risks with novel oral anticoagulants. PMID- 25445133 TI - Coronary heart disease: NPC1L1 mutations lower CHD risk. PMID- 25445134 TI - Antiplatelet therapy: risks and benefits of extended DAPT after stenting. PMID- 25445135 TI - Heart failure: another new PARADIGM in treatment for heart failure? PMID- 25445136 TI - Atherosclerosis: cholesterol efflux capacity-a new biomarker for cardiovascular risk? PMID- 25445138 TI - Coronary artery disease: durable-polymer drug-eluting stents might not lead to very late stent thrombosis. PMID- 25445139 TI - Atrial fibrillation: AF management-SAFETY first? PMID- 25445140 TI - Epidemiology: infective endocarditis rises as prophylactic antibiotic use falls. PMID- 25445143 TI - Atherosclerosis: low-dose aspirin failed to improve cardiovascular outcomes. PMID- 25445144 TI - Evidence of brain atrophy detected on magnetic resonance imaging is associated with failure of acquisition of the ability for insulin self-injection. AB - Type 2 diabetes is known to be associated with cognitive dysfunction and an increased risk of dementia in the elderly. Although it is one of the most efficacious therapies in diabetic patients, insulin therapy requires that patients learn to inject themselves with insulin. We studied the association between brain atrophy detected on magnetic resonance imaging (MRI) of the head and the ability of type 2 diabetic patients to learn self-injection. MRI of the head was performed in 41 type 2 diabetic patients aged 60-80 years old. The area of the cerebrum relative to the intracranial area (the brain parenchymal fraction: BPF) was calculated with the WinROOF software program. Learning ability was assessed by counting the number of training sessions needed to acquire the ability to self-inject. Patients were divided into a failure group and success group. The average age was significantly higher (P < 0.001) and the BPF was significantly lower (P < 0.001) in the failure group (patients requiring 14 or more training sessions) than the success group (the remaining patients). A binary logistic regression analysis revealed that both age and BPF were independent predictors of success/failure in acquiring self-injection ability (P = 0.005 and P = 0.031, respectively). We conclude that brain atrophy on MRI is an important determinant of the ability of patients to learn insulin self-injection. PMID- 25445145 TI - Plasma kisspeptin levels in male cases with hypogonadism. AB - The hypothalamic hormone kisspeptin (metastin) regulates human reproduction by modulating gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin is detected in peripheral blood, although GnRH is not. In this study, we measured plasma kisspeptin levels in four male cases with hypogonadism and seven normal male controls using enzyme immunoassay (EIA) to elucidate the clinical implications of kisspeptin levels in male hypogonadism. The results showed a variety of plasma kisspeptin levels: 6.0 fmol/mL in a male with isolated hypogonadotropic hypogonadism (IHH), 43.2 fmol/mL in a male with Kallmann's syndrome, 40.7 fmol/mL in a male with azoospermia, 323.2 fmol/mL in a male with hypergonadotropic hypogonadism, and 12.3 +/- 2.5 fmol/mL (mean +/- SD) in seven normal controls. Except for the case with IHH, the plasma kisspetin levels were elevated in the three cases with Kallmann's syndrome, azoospermia, and hypergonadotropic hypogonadism. The reason why the three cases had high values was their lesions were downstream of the kisspeptin neuron in the hypothalamic pituitary-gonadal axis, suggesting that elevated kisspeptin levels were implicated in hypothalamic kisspeptin secretion under decreased negative feedback of gonadal steroids. The result that the plasma kisspeptin levels were decreased by gonadotropin therapy in the case with Kallmann's syndrome supported this hypothesis. In conclusion, to measure plasma kisspeptin levels could be useful for better understanding of male hypogonadism. PMID- 25445148 TI - Safety of next-day discharge following laparoscopic sleeve gastrectomy. AB - BACKGROUND: The safety of next-day discharge after laparoscopic sleeve gastrectomy (SG) for the treatment of morbid obesity has not been well studied. The objective of this study was to determine if next-day discharge after laparoscopic SG was comparable to standard discharge (i.e., postoperative day [POD] 2) with respect to the rate of 30-day adverse events. METHODS: A retrospective cohort analysis was performed. Patients were selected if they underwent a laparoscopic SG for morbid obesity between 2010 and 2012 and discharged on either POD 1 or 2. The primary outcome was the 30-day adverse event rate, which was a composite endpoint of complications, mortality, or reoperations. A multivariable logistic regression was performed to determine an adjusted odds ratio (OR) of 30-adverse events for next-day discharge. RESULTS: There were 2982 (37.4%) and 4985 (62.6%) patients discharged on POD 1 and 2, respectively. Both groups were comparable with respect to clinical characteristics. The adjusted OR for 30-day adverse events with next-day discharge was .75 (P = .08, 95% CI [.55-1.04]). Preoperative hypertension and dyspnea were significant predictors of adverse events for next-day discharge. CONCLUSION: Based on data from the ACS-NSQIP registry, laparoscopic SG patients discharged on POD 1 did not have a worse rate of 30-day adverse events compared to the POD 2 group. Appropriate perioperative evaluation may help surgeons implement next-day discharge for select patients after uncomplicated laparoscopic SG. PMID- 25445149 TI - Revisional metabolic/bariatric surgery: a moral obligation. PMID- 25445147 TI - Activation of NLRP3 inflammasome by crystalline structures via cell surface contact. AB - Crystalline structures activate the NLRP3 inflammasome, leading to the production of IL-1beta, however, the molecular interactions responsible for NLRP3 activation are not fully understood. Cathepsin B release from the ruptured phagolysosome and potassium ion efflux have been suggested to be critical for this activation. Here, we report that Cathepsin B redistribution was not a crucial event in crystal-induced IL-1beta production. Silica and monosodium urate crystal-treated macrophages with undisturbed lysosomes demonstrated strong co-localization of ASC and Caspase-1, indicative of NLRP3 inflammasome activation. Importantly, we provided evidence to suggest that macrophage cell membrane binding to immobilized crystals was sufficient to induce IL-1beta release, and this activation of the NLRP3 inflammasome was inhibited by blocking potassium efflux. Therefore, this work reveals additional complexity in crystalline structure-mediated NLRP3 inflammasome regulations. PMID- 25445151 TI - One-step synthesis of patterned polymer brushes by photocatalytic microcontact printing. AB - A novel method to prepare microstructured polymer brushes using TiO2 nanoparticles and photocatalytic microcontact printing is described. It is shown that ethanol amine can be polymerized to linear polyethyleneimine (PEI) driven by the photocatalytic action of TiO2. Upon UV irradiation during microcontact printing of ethanol amine with a stamp coated with TiO2 nanoparticles, patterned polymer brushes with a length of around 50 nm are obtained. PMID- 25445150 TI - Outcomes in glycemic control in the intermediate follow-up of Roux-en-Y gastric bypass: a Brazilian cohort study. AB - BACKGROUND: It is not widely known whether glycemic control (GC) is sustained after Roux-en-Y gastric bypass (RYGB). The objective of this study was to investigate incidence and remission of type 2 diabetes mellitus (T2DM) among 284 individuals with body mass index (BMI)>=35 kg/m(2) at operation (1998-2011) through 2013. METHODS: Baseline GC was based on fasting glycemia (FG), hemoglobin A1c (HbA1c), and medication. Incident T2DM, complete (normal GC/HbA1c) and partial (abnormal FG/A1c) remission at the last follow-up visit, and relapse were the outcomes of interest. Kaplan-Meier curves and log-rank tests were used to compare time to improvement according to insulin use and HbA1c levels at baseline. Pre- and postoperative determinants of T2DM improvement were investigated by logistic regression. RESULTS: Participants were predominantly female (220; 77.2%) with mean age of 39.6 (10.5) years and median BMI of 51.9 (46.1-57.5) kg/m(2) at operation. The mean follow-up time was 5.1 (3.2) years with 67.5% (55.0-78.4) of excess BMI loss (EBL) at the 5(th) year. Normal GC, abnormal FG, and T2DM were observed in 169 (59.5%), 32 (11.2%), and 83 (29.3%) participants at baseline, respectively. The 7 (4.1%) patients with incident T2DM had lower BMI at baseline than those who remained with normal GC (43.6 kg/m(2) [42.0-50.8] versus 52.1 kg/m(2) [46.7-57.7]; P = .01). Complete and partial T2DM remission occurred in 61 (61.3%) and 5 (6.7%) participants, respectively. Baseline HbA1c was associated with a significant difference in the proportion of cases with remission at the 5(th) year of follow-up (P = .016). Age (OR .83; 95% CI .72-.95) and % EBL at the 2(nd) year of follow-up (OR 1.05; 95% CI 1.01-1.09) were independent determinants of T2DM improvement. Relapse occurred in 14 (14.3%) cases. CONCLUSION: We observed a low incidence and impressive improvement rates of T2DM after intermediate follow-up of RYGB. PMID- 25445152 TI - Efficient preparation of shuffled DNA libraries through recombination (Gateway) cloning. AB - Efficient and robust subcloning is essential for the construction of high diversity DNA libraries in the field of directed evolution. We have developed a more efficient method for the subcloning of DNA-shuffled libraries by employing recombination cloning (Gateway). The Gateway cloning procedure was performed directly after the gene reassembly reaction, without additional purification and amplification steps, thus simplifying the conventional DNA shuffling protocols. Recombination-based cloning, directly from the heterologous reassembly reaction, conserved the high quality of the library and reduced the time required for the library construction. The described method is generally compatible for the construction of DNA-shuffled gene libraries. PMID- 25445153 TI - Heart transplants: Identity disruption, bodily integrity and interconnectedness. AB - Of heart transplant recipients, 30 per cent report ongoing or episodic emotional issues post-transplant, which are not attributable to medications or pathophysiological changes. To this end, our team theorized that cardiac transplantation introduces pressing new questions about how patients incorporate a transplanted heart into their sense of self and how this impacts their identity. The work of Merleau-Ponty provided the theoretical underpinning for this project as it rationalizes how corporeal changes affect one's self and offer an innovative framework to access these complex aspects of living with a transplanted heart. We used visual methodology and recorded 25 semi-structured interviews videographically. Both visual and verbal data were analyzed at the same time in an iterative process. The most common theme was that participants expressed a disruption to their own identity and bodily integrity. Additionally, participants reported interconnectedness with the donor, even when the transplanted heart was perceived as an intruder or stranger. Finally, transplant recipients were very vivid in their descriptions and speculation of how they imagined the donor. Receiving an anonymous donor organ from a stranger often leaves the recipient with questions about who they themselves are now. Our study provides a nuanced understanding of heart transplant recipients' embodied experiences of self and identity. Insights gained are valuable to educate transplant professionals to develop new supportive interventions both pre- and post-transplant, and to improve the process of informed consent. Ultimately, such insights could be used to enable heart transplant recipients to incorporate the graft optimally over time, easing distress and improving recovery. PMID- 25445155 TI - Integrin-based meningioma cell migration is promoted by photon but not by carbon ion irradiation. AB - PURPOSE: Sublethal doses of photon irradiation (IR) are suspected to increase tumor cell migration and support locoregional recurrence of disease, which has already been shown in other cell lines. This manuscript describes the effect of photon and carbon-ion IR on WHO class I meningioma cell migration and provides an approach to the underlying cellular mechanisms. MATERIALS AND METHODS: Meningioma cells were gained operatively at the university hospital in Homburg/Saar, Germany. For migration, membranes (8-um pore sizes) were coated with collagen I, with collagen IV, and with fibronectin. Cells were analyzed in migration experiments with or without serum stimulation, with or without photon and carbon IR 24 h prior to experiments, and with or without integrin antibodies. Fluorescence-activated cell sorting (FACS) analyses of the integrins alphanubeta1, alphanubeta3, and alphanubeta5 were performed without IR and 6, 12 and 24 h after IR. Enzyme-linked immunosorbent assay (ELISA) analyses of matrix metalloproteinases (MMP)-2 and MMP-9 were realized with and without IR after cells were cultured on collagen I, collagen IV, or fibronectin for 24 h. Cells and supernatants for FACS and ELISA were stored at - 18 degrees C. The significance level was set at 5 % using both Student's t test and two-way ANOVA. RESULTS: Migration of meningioma cells was serum-inducible (p < 0.001). It could be increased by photon IR (p < 0.02). The integrins alphanubeta1 and alphanubeta5 showed a 21 and 11 % higher expression after serum stimulation (not significant), respectively, and alphanubeta1 expression was raised by 14 % (p = 0.0057) after photon IR. Antibody blockage of the integrins alphanubeta1 and alphanubeta5 inhibited serum- and photon-induced migration. Expression of MMP-2 and MMP-9 remained unchanged after both IR and fetal bovine serum (FBS). Carbon-ion IR left both integrin expression and meningioma cell migration unaffected. CONCLUSION: Photon but not carbon-ion IR promotes serum-based meningioma cell migration. Fibronectin receptor integrin alphanubeta1 signaling can be identified as an important mechanism for serum- and photon-induced migration of WHO class I meningioma cells. PMID- 25445157 TI - Erratum to: Identifying decreased peristalsis of abnormal small bowel segments in Crohn's disease using cine MR enterography: the frozen bowel sign. AB - PURPOSE: The purpose of this study was to evaluate whether affected bowel in Crohn's disease patients can be identified by observing decreased peristalsis (frozen bowel sign) using cine balanced steady-state free precession (cine BSSFP) images. MATERIALS AND METHODS: 5 radiologists independently reviewed cine BSSFP sequences from randomized MR Enterography (MRE) exams for 30 normal and 30 Crohn's disease patients, graded overall small bowel peristalsis from slowest to fastest, and graded peristalsis for the most abnormal small bowel segment. Sensitivity and specificity of the frozen bowel sign for diagnosing Crohn's disease were calculated. T tests of the peristalsis difference between abnormal segments and overall small bowel were conducted. RESULTS: For 5 readers, the sensitivity and specificity of cine BSSFP of the frozen bowel sign for diagnosing Crohn's disease ranged from 70% to 100% and 87% to 100%, respectively. There were significant differences in peristalsis between abnormal small bowel segments and the overall small bowel for Crohn's patients, but not in the overall small bowel between normal-MRE patients and Crohn's disease patients. CONCLUSION: Abnormal Crohn's small bowel segments have significantly decreased peristalsis compared to normal small bowel, which can be identified using cine BSSFP sequences as the frozen bowel sign. PMID- 25445156 TI - Dose-dependent changes in renal (1)H-/(23)Na MRI after adjuvant radiochemotherapy for gastric cancer. AB - PURPOSE: Combined radiochemotherapy (RCT) for gastric cancer with three dimensional conformal radiotherapy (3D-CRT) results in ablative doses to the upper left kidney, while image-guided intensity-modulated radiotherapy (IG-IMRT) allows kidney sparing despite improved target coverage. Renal function in long term gastric cancer survivors was evaluated with 3T functional magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI) and (23)Na imaging. PATIENTS AND METHODS: Five healthy volunteers and 13 patients after radiotherapy were included: 11*IG-IMRT; 1*3D-CRT; 1* "positive control" with stereotactic body radiotherapy (SBRT) of a metastasis between the spleen/left kidney. Radiation doses were documented for the upper/middle/lower kidney subvolumes. Late toxicity was evaluated based on CTC criteria, questionnaire, and creatinine values. Morphological sequences, DWI images, and (23)Na images were acquired using a (1)H/(23)Na-tuned body-coil before/after intravenous water load (WL). Statistics for [(23)Na] (concentration) and apparent diffusion coefficient (ADC) values were calculated for upper/middle/lower renal subvolumes. Corticomedullary [(23)Na] gradients and [(23)Na] differences after WL were determined. RESULTS: No major morphological alteration was detected in any patient. Minor scars were observed in the cranial subvolume of the left kidney of the 3D-CRT and the whole kidney of the control SBRT patient. All participants presented a corticomedullary [(23)Na] gradient. After WL, a significant physiological [(23)Na] gradient decrease (p < 0.001) was observed in all HV and IG-IMRT patients. In the cranial left kidney of the 3D-CRT patient and the positive control SBRT patient, the decrease was nonsignificant (p = 0.01, p = 0.02). ADC values were altered nonsignificantly in all renal subvolumes (all participants). Renal subvolumes with doses >= 35 Gy showed a reduced change of the [(23)Na] gradient after WL (p = 0.043). No participants showed clinical renal impairment. CONCLUSIONS: Functional parameters of renal (23)Na MRI after gastric IG-IMRT are identical to those of healthy volunteers, in contrast to renal subvolumes after ablative doses in the control and 3D-CRT patient. While kidney doses to the cortex below 20-25 Gy in fractional doses of ~ 1 Gy in IG-IMRT (combined with intensified chemotherapy) do not seem to cause significant MRI morphological or functional alterations, doses of > 35 Gy in 1.5-2 Gy fractions clearly result in impairment. PMID- 25445158 TI - Magnetic resonance elastography can discriminate normal vs. abnormal liver biopsy in candidates for live liver donation. AB - PURPOSE: The aim of this study was to define liver shear stiffness by magnetic resonance elastography (MRE) that distinguishes normal from abnormal liver biopsy, especially when steatosis >=20%, among potential live liver donors. METHODS: Baseline clinical, laboratory, imaging, MRE, and liver biopsy results were recorded. Using MRE, hepatic shear stiffness in kilopascals (kPa) was measured and compared to liver biopsy. Comparison between groups was done using chi(2) or Fisher's exact test for categorical variables and Wilcoxon test for continuous variables. Receiver operating characteristic (ROC) curve was calculated to assess diagnostic accuracy. Statistical significance was set at p < 0.05. RESULTS: 38 healthy adults were included. Liver biopsy was normal in 27 and abnormal in 11. ROC curve for MRE defined optimal cutoff at 2.6 kPa (sensitivity 0.72, specificity 0.85, AUC 0.81) to distinguish these 2 groups. Hepatic steatosis >=20% on biopsy is a contraindication for liver donation in our center. We evaluated the ability of MRE to distinguish this degree of steatosis: 8 persons had steatosis >=20% and were excluded from donation. ROC curve for MRE defined optimal cutoff at 2.82 kPa (sensitivity 0.88, specificity 1, AUC 0.98) to identify this group. CONCLUSIONS: Liver stiffness measured by MRE, even in the absence of liver fibrosis, can be useful in differentiating normal from abnormal liver histology, and most importantly in patients under evaluation for live liver donation, can very accurately distinguish those with complicated hepatic steatosis >=20%, our cutoff for donation. In the future, MRE might provide supplementary information to make liver biopsy unnecessary in the donor evaluation process. PMID- 25445159 TI - Digital subtraction angiography during transjugular intrahepatic portosystemic shunt creation or revision: data on radiation exposure and image quality obtained using a standard and a low-dose acquisition protocol in a flat-panel detector based system. AB - PURPOSE: To determine whether the use of a low-dose acquisition protocol (LDP) in digital subtraction angiography during transjugular intrahepatic portosystemic shunt (TIPS) creation/revision results in significant reduction of patient radiation exposure and adequate image quality, as compared to a default reference standard-dose acquisition protocol (SDP). METHODS: Two angiographic runs were performed during TIPS creation/revision: the first following catheterization of the portal venous system and the second after stent deployment/angioplasty. Constant field of view, object to image-detector distance, and source to image receptor distance were maintained in each patient during the two angiographic runs. 17 consecutive adult patients who underwent TIPS creation (n = 11) or TIPS revision (n = 6) from December 2013 to March 2014 were considered eligible for this single centre prospective study. In each patient, the LDP and the SDP were used in a random order for the two runs, with each patient serving as his/her own control. The dose-area product (DAP) was calculated for each image and compared. Image quality was graded by two interventional radiologists other than the operator. RESULTS: In all runs acquired with the LDP, image quality was considered adequate for a successful procedural outcome. The DAP per image of the LDP was numerically inferior as compared to the DAP per image of the SDP in all patients. The mean reduction in DAP per image was 75.24% +/- 5.7% (p < 0. 001). CONCLUSION: Radiation exposure during TIPS creation/revision was significantly reduced by selecting a LDP in our flat-panel detector-based system, while maintaining adequate image quality. PMID- 25445160 TI - Predictors of early stages of histological progression of branch duct IPMN. AB - BACKGROUND: An appropriate timing for surgical resection of branch duct-type intraductal papillary mucinous neoplasm (BD-IPMN) to achieve sufficient postoperative survival is still unknown. METHODS: Of 80 patients with histologically proven IPMNs, 61 patients who had BD-IPMN without pancreatic cancer concomitant with IPMN were enrolled in this study. We divided BD-IPMN into four groups according to disease progression: low to intermediate grade of dysplasia (LGD/IGD-IPMN), high grade of dysplasia (HGD-IPMN), minimally invasive IPMN (MI-IPMN: T1a), and invasive IPMN (IN-IPMN: >=T1b). Indicators of surgical resection were investigated on the basis of pathological findings and postoperative prognosis. RESULTS: Postoperative survival was distinctly worse for patients with IN-IPMN than for patients with MI-IPMN, HGD-IPMN, and LGD/IGD-IPMN. Postoperative disease-specific 5-year survival rate was 100 % in patients with IN IPMN, HGD-IPMN, and LGD/IGD-IPMN, by contrast, 40 % in patients with IN-IPMN. The presence of two of the three factors (pancreatitis, serum carbohydrate antigen [CA] 19-9 levels >13 U/mL, and mural nodules) could distinguish HGD-IPMN from LGD/IGD-IPMN with a sensitivity of 92.9 %, specificity of 90.2 %, positive predictive value of 76.5 %, negative predictive value of 97.4 %, and accuracy of 90.9 %. CONCLUSIONS: To manage patients with BD-IPMN and achieve a good postoperative prognosis, surgical resection should be performed before progression to IN-IPMN. PMID- 25445162 TI - Bowel preparation: is endoscopic administration worth the extra risk? PMID- 25445165 TI - Cardiovascular health in low- and middle-income countries. Foreword. PMID- 25445164 TI - Different clinicopathological features between patients who developed early and late recurrence following surgery for renal cell carcinoma. AB - BACKGROUND: To evaluate the clinicopathological features and identify predictive factors in patients with early and late recurrence following initial surgery for localized renal cell carcinoma. METHODS: From April 1988 to January 2013, 486 patients without metastases at the initial diagnosis underwent either radical nephrectomy or partial nephrectomy and were followed up thereafter. Patients were divided into 3 groups; no recurrence, early recurrence (recurrence within 5 years), and late recurrence (recurrence after 5 years). Cancer-specific survival after recurrence was analyzed by using the Kaplan-Meier method. Multivariate logistic regression analysis was applied to define clinical and pathological factors correlated to early and late recurrence following surgery. RESULTS: Seventy-seven (15.8 %) and 18 (3.7 %) patients developed early and late recurrence, respectively. In multivariate logistic regression analysis, positive symptoms at diagnosis, >=pT2, positive lymphovascular invasion, and grade 3 were independent predictive factors for early recurrence. Age at surgery and >=pT2 were significantly correlated to late recurrence. The 5-year cancer-specific survival rate after recurrence was 72.4 and 52.9 % in the late and the early recurrence groups, respectively (P = 0.044). CONCLUSIONS: The risk factors for clinical recurrence differed according to the time that had elapsed between initial surgery and the first metastasis in patients with localized renal cell carcinoma. Our study showed age at initial surgery and the pT stage were independent predictive factors for late recurrence. Further investigation of a larger number of patients is required to predict which patients may develop recurrence in the future and to choose appropriate treatment. PMID- 25445163 TI - Accuracy of Rapid Fecal Calprotectin Test in Monitoring Inflammatory Bowel Diseases Under Treatment with TNFalpha Antagonists. AB - BACKGROUND: Anti-TNFalpha antibodies are effective in treating inflammatory bowel diseases (IBDs) unresponsive to the standard treatments. Information about the role of rapid fecal calprotectin (FC) in monitoring ambulatory IBD patients under treatment with anti-TNFalpha is lacking. Our aim was to assess the accuracy of rapid FC in monitoring those patients. METHODS: Seventy-two patients (38 males, 34 females, mean age 42.5 years, range 23-57 years), affected by ulcerative colitis (UC) (20 patients) or by Crohn's disease (CD) (52 patients) were treated with anti-TNFalpha antibodies. FC was assessed by a rapid semiquantitative test. RESULTS: With respect to the absence of clinical remission, FC test showed sensitivity of 71.8 %, specificity of 65.2 %, PPV of 41.8 %, and NPV of 86.9 %. In UC patients, FC test showed a sensitivity of 66.7 %, a specificity of 56.1 %, a PPV of 18.2 %, and a NPV of 92.0 %. In CD patients, FC test showed sensitivity of 70.6 %, specificity of 65.2 %, PPV of 50.0 %, and NPV of 81.8 %. With respect to the presence of endoscopic lesions, FC test showed sensitivity of 73.5 %, specificity of 96.0 %, PPV of 96.2 %, and NPV of 72.7 %. In UC patients, FC test showed sensitivity of 47.2 %, specificity of 84.6 %, PPV of 89.5 %, and NPV of 36.7 %. In CD patients, FC test showed sensitivity of 90.1 %, specificity of 79.7 %, PPV of 71.9 %, and NPV of 93.3 %. CONCLUSIONS: Diagnostic accuracy of rapid FC seems better in predicting persistence of endoscopic lesions than clinical remission in IBD patients under treatment with anti-TNFalpha. PMID- 25445161 TI - Bone Marrow Stromal Cells Inhibit the Activation of Liver Cirrhotic Fat-Storing Cells via Adrenomedullin Secretion. AB - BACKGROUND: Cirrhosis, or liver fibrosis, which is mainly triggered by cirrhosis fat-storing cells (CFSCs) activation, has traditionally been considered an irreversible disease. However, recent observations indicate that even advanced fibrosis is still reversible by removing the causative agents. Anti-fibrotic effects of bone marrow-derived stromal cells (BMSCs) have been demonstrated by inhibiting CFSCs via cytokines secretion; however, the mechanisms are still unclear. AIMS: The purpose of this study was to explore the underlying mechanisms by which BMSCs modulate the function of activated CFSCs. METHODS: After the co culture of CFSCs with BMSCs supernatants with or without the addition of recombinant rat adrenomedullin (AM)/AM-specific siRNA, western blot analysis was mainly used to detect the differences of relative protein expression on CFSCs. RESULTS: BMSC-secreted adrenomedullin (AM) effectively inhibited the proliferation and activation of CFSCs by suppressing the expression of Ang II and its binding receptor, AT1, which resulted in a reduction of p47-phox formation. CONCLUSIONS: Our data suggested that BMSCs inhibited CFSC activation in vitro via the AM-Ang II-p47-phox signaling pathway, and since CFSC activation is an essential part of hepatic fibrosis process, this inhibition by BMSCs implies us new insights into the potential treatment of hepatic fibrosis via BMSCs. PMID- 25445166 TI - Cardiovascular health in low- and middle-income countries. AB - The American Heart Association has defined cardiovascular health (CVH) through 7 metrics, including 3 health behaviors (tobacco use, diet, and physical activity) and 4 health factors (body weight, blood pressure, blood cholesterol, and blood glucose). Although the American Heart Association has championed the measurement, monitoring, and messaging of CVH through its goal to improve the CVH of all Americans by 20% by 2020, the current state of CVH in low- and middle-income countries (LMICs) has not been well documented. In this review, the author discuss (1) definition of CVH, (2) methods of measuring and monitoring CVH in LMICs, (3) recent trends in CVH metrics in LMICs, and (4) strategies to improve CVH in LMICs. PMID- 25445167 TI - Effect of lamellarity and size on calorimetric phase transitions in single component phosphatidylcholine vesicles. AB - Nano-differential scanning calorimetry (nano-DSC) is a powerful tool in the investigation of unilamellar (small unilamellar, SUVs, or large unilamellar, LUVs) vesicles, as well as lipids on supported bilayers, since it measures the main gel-to-liquid phase transition temperature (Tm), enthalpies and entropies. In order to assign these transitions in single component systems, where Tm often occurred as a doublet, nano-DSC, dynamic light scattering and cryo-transmission electron microscopy (cryo-TEM) data were compared. The two Tms were not attributable to decoupled phase transitions between the two leaflets of the bilayer, i.e. nano-DSC measurements were not able to distinguish between the outer and inner leaflets of the vesicle bilayers. Instead, the two Tms were attributed to mixtures of oligolamellar and unilamellar vesicles, as confirmed by cryo-TEM images. Tm for the oligolamellar vesicles was assigned to the peak closest to that of the parent multilamellar vesicle (MLV) peak. The other transition was higher than that of the parent MLVs for 1,2-dimyristoyl-sn-glycero 3-phosphocholine (DMPC), and increased in temperature as the vesicle size decreased, while it was lower in temperature than that of the parent MLVs for 1,2 dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and decreased as the vesicle size decreased. These subtle shifts arose due to small differences in the values of DeltaH and DeltaS, since Tm is determined by their ratio (DeltaH/DeltaS). It was not possible to completely eliminate oligolamellar structures for MLVs extruded with the 200 nm pore size filter, even after 120 passes, while these structures were eliminated for MLVs extruded through the 50 nm pore size filter. PMID- 25445168 TI - Constitutive L-Sox5 overexpression delays differentiation of ATDC5 cells into chondrocytes and correlates with reduced expression of differentiation markers. AB - L-Sox5 is a member of sex-determining region Y-type high mobility group box (SOX) family of transcription factors. We assessed the effects of retroviral overexpression of L-Sox5 on chondrocyte differentiation using the clonal murine cell line ATDC5. We observed a temporal-restricted expression pattern of L-Sox5 in insulin-induced ATDC5 cells differentiating toward chondrocyte lineage. The protein expression levels of L-Sox5 showed a drastic decrease in contrast to unaltered mRNA levels during differentiation. L-Sox5 delayed the differentiation of ATDC5 cells as evidenced by Alcian blue staining for proteoglycan synthesis. The mRNA levels of chondrocyte and hypertrophic/osteoarthritic markers were markedly decreased or delayed in L-Sox5 overexpressing cells. L-Sox5 abrogated the promoter activity of Runx2. These results suggest that L-Sox5 protein expression may diminish along with the progress of chondrogenic differentiation. L-Sox5 may act as a negative regulator if expressed aberrantly at least in part by regulating the critical fate of chondrogenesis. PMID- 25445169 TI - Sphingosine-1-phosphate inhibits differentiation of C3H10T1/2 cells into adipocyte. AB - Mesenchymal stem cells (MSCs) can differentiate into a number of cell types, including adipocytes and osteoblasts. MSC differentiation into adipocytes inhibits osteogenic differentiation and vice versa. Therefore, understanding the mechanisms of MSC differentiation at the signaling level can lead to the development of novel therapeutic strategies toward tissue regeneration. Sphingosine-1-phosphate (S1P) is a signaling molecule that regulates many cellular responses, including cellular differentiation. However, the effects of S1P on MSC differentiation are largely unknown. The purpose of study was to investigate whether S1P drives MSCs toward either adipogenic or osteogenic differentiation, and if so, to clarify the underlying signaling mechanisms for such differentiation. We found that S1P inhibited adipogenic differentiation of C3H10T1/2 multipotent stem cells, while promoting their osteogenic differentiation. During adipogenic differentiation, S1P suppressed the cAMP accumulation in a Gi-protein-dependent manner. The Gi-dependent S1P signaling suppressed C/EBPbeta expression, which is essential for adipogenic differentiation. Furthermore, S1P did not affect cAMP-independent adipogenic differentiation. These findings suggest that S1P suppresses cAMP accumulation, leading to inhibition of C/EBPbeta expression, thereby resulting in decreased adipogenic differentiation of C3H10T1/2 cells. Thus, our findings provide novel molecular mechanisms as regards how S1P inhibits adipogenic differentiation of C3H10T1/2 cells, indicating a potential beneficial role for regeneration and repair of tissues. PMID- 25445170 TI - The mechanism of UVB irradiation induced-apoptosis in cataract. AB - Cataract is the most common eye disease that causes blindness in patients. Ultraviolet B (UVB) irradiation is considered an important factor leading to cataract by inducing apoptosis in human lens epithelial cells (HLECs), but the mechanism is currently unclear. In this study, we investigated HLECs under different intensities of UVB irradiation and different exposure time. The annexin V-FITC/propidium iodide staining results showed that UVB irradiation could efficiently lead to HLECs apoptosis in time- and dose-dependent manner. The expression of pro-apoptotic Bax gene was promoted by UVB irradiation, while anti apoptotic Bcl-2 gene expression was inhibited at both transcript and protein levels. Notably, the ratio of Bax/Bcl-2 displayed a high and positive correlation to the proportion of apoptotic HLECs. Mitochondrial dysfunction was also observed with rapid loss of potential (?Psi m), as well as changes of the levels of reactive oxygen species, malondialdehyde, total antioxidative capabilities, and superoxide dismutase. In caspase pathway, the level of caspase-3 protein increased after UVB irradiation. All these discovered changes may play important roles in UVB-induced HLECs apoptosis, and would be helpful in understanding the mechanism of UVB-induced cataract and providing potential prevention and treatment strategies. PMID- 25445172 TI - Aneurysmal dilatation of the aortic sinuses of Valsalva -- beyond Marfan syndrome: a single centre experience and review of the literature. AB - Aneurysmal dilatation of the aortic sinuses of Valsalva has been most extensively documented in the setting of aortopathies, particularly Marfan syndrome. On the other hand, there is limited data in the literature about congenital sinus of Valsalva aneurysms outside this context. For the purpose of this review, we carried out a literature search on aneurysmal dilatation of the sinuses of Valsalva in Marfan syndrome, and compared this with congenital sinus of Valsalva aneurysms, also including data from a case series from our institution. In conclusion, there are differences in management of aortic dilatation in Marfan syndrome and congenital sinus of Valsalva aneurysms. Though less well-recognised, congenital aneurysms are often associated with significant morbidity and mortality and timely intervention is necessary. PMID- 25445171 TI - Circulating microRNAs in cardiovascular diseases: from biomarkers to therapeutic targets. AB - microRNAs (miRNAs) are a class of conserved, short, non-coding RNAs that have important and potent capacities to regulate gene expression at the posttranscriptional level. In the past several years, the aberrant expressions of miRNAs in the cardiovascular system have been widely reported, and the crucial roles of some special miRNAs in heart development and pathophysiology of various cardiovascular diseases have been gradually recognized. Recently, it was discovered that miRNAs are presented in peripheral circulation abundantly and stably. This has raised the possibility of using circulating miRNAs as biomarkers for diseases. Furthermore, some studies demonstrated that circulating miRNAs may serve as novel extracellular communicators of cell-cell communication. These discoveries not only reveal the functions of circulating miRNAs in cardiovascular system but also inform the development of miRNAs therapeutic strategies. In this review, we discuss the potential roles of circulating miRNAs in a variety of cardiovascular diseases from biomarkers to therapeutic targets to clearly understand the roles of circulating miRNAs in cardiovascular system. PMID- 25445173 TI - The evolution of surgical and medical treatment of aortic root aneurysm. AB - Since first report of aortic root replacement in 1968, the surgical risk and long term outcome of patients with aortic root aneurysm have been continuously improving. In the last 30 years, the surgical approach is also evolving towards more valve conservation with prophylactical intervention at an earlier clinical stage. Translational research has also led to emerging surgical innovation and new drug therapy. Their efficacies are currently under vigorous clinical trials and evaluations. PMID- 25445174 TI - Preventive treatments for breast cancer: recent developments. AB - Breast cancer is a burden for western societies, and an increasing one in emerging economies, because of its high incidence and enormous psychological, social, sanitary and economic costs. However, breast cancer is a preventable disease in a significant proportion. Recent developments in the armamentarium of effective drugs for breast cancer prevention (namely exemestane and anastrozole), the new recommendation from the National Institute for Health and Care Excellence to use preventative drugs in women at high risk as well as updated Guidelines from the US Preventive Services Task Force and the American Society of Clinical Oncology should give renewed momentum to the pharmacological prevention of breast cancer. In this article we review recent major developments in the field and examine their ongoing repercussion for breast cancer prevention. As a practical example, the potential impact of preventive measures in Spain is evaluated and a course of practical actions is delineated. PMID- 25445177 TI - Probing small-molecule microarrays with tagged proteins in cell lysates. AB - The technique of small-molecule microarray (SMM) screening is based on the ability of small molecules to bind to various soluble proteins. This type of interaction is easily detected by the presence of a fluorescence signal produced by labeled antibodies that specifically recognize a unique sequence (tag) present on the target protein. The fluorescent signal intensity values are determined based on signal-to-noise ratios (SNRs). SMM screening is a high-throughput, unbiased method that can rapidly identify novel direct ligands for various protein targets. This binding-based assay format is generally applicable to most proteins, but it is especially useful for protein targets that do not possess an enzymatic activity. SMMs enable screening a protein in a purified form or in the context of a cellular lysate, likely providing a more physiologically relevant screening environment. PMID- 25445175 TI - The NanoString-based multigene assay as a novel platform to screen EGFR, HER2, and MET in patients with advanced gastric cancer. AB - INTRODUCTION: Molecular targets are emerging rapidly and the development of clinical tests that simultaneously screen for multiple targets has become especially important. We assessed the gene expression levels of three known targets in advanced gastric cancer, epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), and N-methyl-N-nitrosoguanidine human osteosarcoma transforming gene (MET), using the nCounter(r) assay (NanoString Technologies, Seattle, WA, USA) and compared these results with protein overexpression, detected by immunohistochemistry, to evaluate the performance of this new technology. METHODS: We investigated 42 formalin-fixed, paraffin embedded tumor samples from patients with gastric cancer. A NanoString-based assay containing a 522 kinase gene panel was investigated. We analyzed the correlations between immunohistochemical findings and kinase gene expression levels of EGFR, HER2 and MET to validate this assay. RESULTS: EGFR, HER2, and MET overexpression were observed in 7 (16.6 %), 5 (11.9 %), and 3 (7.1 %) cases, respectively. For EGFR, HER2, and MET, the concordance rates between the NanoString-based assay results and the immunohistochemistry methods were 83.3, 97.6, and 100 %, respectively. Relative to immunohistochemistry findings, the NanoString-based assay sensitivities and specificities were 85.7 and 82.8 % for EGFR, 100 and 97.2 % for HER2, and 100 and 100 % for MET, respectively. CONCLUSIONS: We found a high concordance between immunohistochemistry- and nCounter-based assessments of EGFR, HER2, and MET in advanced gastric cancer. Judged against immunohistochemistry results, the NanoString assay had high sensitivities and high specificities. These results suggest that the nCounter assay provides a reliable, high-throughput assay to simultaneously screen for the overexpression of several target proteins. PMID- 25445178 TI - Real-time chemiluminescence imaging using nano-lantern probes. AB - Chemiluminescence imaging can be performed without excitation light sources at various spatial levels ranging from a single cell to the whole body. Thus far, chemiluminescence imaging has been primarily performed with long exposure times because of weak signals, resulting in low temporal resolution. Recently, the brightest-known chemiluminescent proteins--Nano-lantern and Nano-lantern-based functional indicators--have been developed. Nano-lantern probes break the limitation of temporal resolution and enable chemiluminescence imaging of living samples such as cells, plants, and small animals at video rates. This unit describes one protocol for observation of a freely moving unshaved mouse transplanted with Nano-lantern-expressing tumor cells, and another for compatible use of optogenetic tools and a Nano-lantern calcium indicator. Both protocols utilize the synchronization of illumination and camera acquisition sessions, thereby enabling real-time chemiluminescence imaging. PMID- 25445176 TI - Harnessing the PD-1 pathway in renal cell carcinoma: current evidence and future directions. AB - Programmed cell death-1 (PD-1) is a recognized immune checkpoint. It is frequently upregulated on the T cells that infiltrate tumors, providing an inhibitory signal, which may facilitate immune escape. Blocking antibodies have been developed to interrupt the interaction of PD-1 with its ligands PD-L1/PD-L2, with the goal of increasing the host antitumor immune response. Initial results have been encouraging, with durable responses in both treatment-naive and pretreated patients, along with an acceptable toxicity profile. This tolerability makes PD-1 blockade an excellent potential partner for combination strategies with the approved targeted agents, such as tyrosine kinase inhibitors (TKIs) and anti-vascular endothelial growth factor (anti-VEGF) antibodies, as well as other investigational immune checkpoint inhibitors or agonist antibodies that may costimulate an immune response. PD-L1 expression on tumor cells and tumor infiltrating immune cells is also being evaluated as a predictive biomarker of response to treatment. This review summarizes the biological basis, preclinical studies, ongoing trials, and future challenges associated with targeting the PD-1 pathway in renal cell carcinoma. PMID- 25445179 TI - Determination of the cytostatic and cytocidal activities of antimalarial compounds and their combination interactions. AB - Determining the antiplasmodial activity of candidate antimalarial drugs in vitro identifies new therapies for drug-resistant malaria. Importantly though, activity can be either growth-inhibitory (cytostatic) or parasite-kill (cytocidal), or both. The simple methods described here can allow for distinction between these activities, as well as definition of drug interactions between two or more compounds. The latter is important in the definition of novel drug combination therapy for malaria. These methods involve live malarial parasite red blood cell culture, routine pharmacology, high-throughput detection of parasite DNA with fluorescent reporters, and routine mathematical analysis of dose-response curves. The techniques and approaches are accessible to most laboratories and require minimal special equipment beyond a fluorescent plate reader and tissue culture facilities. PMID- 25445181 TI - Sexual selection and the evolution of behavior, morphology, neuroanatomy and genes in humans and other primates. AB - Explaining human evolution means developing hypotheses about the occurrence of sex differences in the brain. Neuroanatomy is significantly influenced by sexual selection, involving the cognitive domain through competition for mates and mate choice. Male neuroanatomy emphasizes subcortical brain areas and visual-spatial skills whereas that of females emphasizes the neocortex and social cognitive areas. In primate species with high degrees of male competition, areas of the brain dealing with aggression are emphasized. Females have higher mirror neuron activity scores than males. Hundreds of genes differ in expression profiles between males and females. Sexually selected differences in gene expression can produce neuroanatomical sex differences. A feedback system links genes, gene expression, hormones, morphology, social structure and behavior. Sex differences, often through female choice, can be rapidly modulated by socialization. Human evolution is a dramatic case of how a trend toward pair bonding and monogamy lowered male competition and increased female choice as a necessary step in releasing the cognitive potential of our species. PMID- 25445182 TI - Cellular and molecular neuropathology of the cuprizone mouse model: clinical relevance for multiple sclerosis. AB - The cuprizone mouse model allows the investigation of the complex molecular mechanisms behind nonautoimmune-mediated demyelination and spontaneous remyelination. While it is generally accepted that oligodendrocytes are specifically vulnerable to cuprizone intoxication due to their high metabolic demands, a comprehensive overview of the etiology of cuprizone-induced pathology is still missing to date. In this review we extensively describe the physico chemical mode of action of cuprizone and discuss the molecular and enzymatic mechanisms by which cuprizone induces metabolic stress, oligodendrocyte apoptosis, myelin degeneration and eventually axonal and neuronal pathology. In addition, we describe the dual effector function of the immune system which tightly controls demyelination by effective induction of oligodendrocyte apoptosis, but in contrast also paves the way for fast and efficient remyelination by the secretion of neurotrophic factors and the clearance of cellular and myelinic debris. Finally, we discuss the many clinical symptoms that can be observed following cuprizone treatment, and how these strengthened the cuprizone model as a useful tool to study human multiple sclerosis, schizophrenia and epilepsy. PMID- 25445183 TI - What is the role for EEG after sleep deprivation in the diagnosis of epilepsy? Issues, controversies, and future directions. AB - In patients with a first seizure, the identification of early sensitive and specific biomarkers for formulating a diagnosis of epilepsy is fundamental. Sleep deprivation (SD) has long been used as a means of enhancing EEG sensitivity in the diagnostic process. However, huge methodological differences among the studies addressing this topic have led to highly variable results and often confusing assumptions. Here, we provide a detailed description of the correlations between SD and epilepsy, along with their putative mechanistic explanations derived from experimental studies in animals and humans. We also outline the clinical studies evaluating the role of SD EEG and discuss them critically in terms of: (a) study design and SD EEG methodology; (b) EEG sensitivity and specificity; (c) the role of drug-induced sleep EEG and EEG during spontaneously occurring sleep; and (d) the relevance of patient features, syndromes, and subsyndromes, as well as their correlations with neuroimaging details. Finally, we propose specific studies that might increase the role of SD EEG in the diagnosis and prognosis of epilepsy. PMID- 25445184 TI - Understanding bimanual coordination across small time scales from an electrophysiological perspective. AB - Bimanual movement involves a variety of coordinated functions, ranging from elementary patterns that are performed automatically to complex patterns that require practice to be performed skillfully. The neural dynamics accompanying these coordination patterns are complex and rapid. By means of electro- and magneto-encephalographic approaches, it has been possible to examine these dynamics during bimanual coordination with excellent temporal resolution, which complements other neuroimaging modalities with superb spatial resolution. This review focuses on EEG/MEG studies that unravel the processes involved in movement planning and execution, motor learning, and executive functions involved in task switching and dual tasking. Evidence is presented for a spatio-temporal reorganization of the neural networks within and between hemispheres to meet increased task difficulty demands, induced or spontaneous switches in coordination mode, or training-induced neuroplastic modulation in coordination dynamics. Future theoretical developments will benefit from the integration of research techniques unraveling neural activity at different time scales. Ultimately this work will contribute to a better understanding of how the human brain orchestrates complex behavior via the implementation of inter- and intra hemispheric coordination networks. PMID- 25445180 TI - Social visual engagement in infants and toddlers with autism: early developmental transitions and a model of pathogenesis. AB - Efforts to determine and understand the causes of autism are currently hampered by a large disconnect between recent molecular genetics findings that are associated with the condition and the core behavioral symptoms that define the condition. In this perspective piece, we propose a systems biology framework to bridge that gap between genes and symptoms. The framework focuses on basic mechanisms of socialization that are highly-conserved in evolution and are early emerging in development. By conceiving of these basic mechanisms of socialization as quantitative endophenotypes, we hope to connect genes and behavior in autism through integrative studies of neurodevelopmental, behavioral, and epigenetic changes. These changes both lead to and are led by the accomplishment of specific social adaptive tasks in a typical infant's life. However, based on recent research that indicates that infants later diagnosed with autism fail to accomplish at least some of these tasks, we suggest that a narrow developmental period, spanning critical transitions from reflexive, subcortically-controlled visual behavior to interactional, cortically-controlled and social visual behavior be prioritized for future study. Mapping epigenetic, neural, and behavioral changes that both drive and are driven by these early transitions may shed a bright light on the pathogenesis of autism. PMID- 25445186 TI - Seasonal forcing in a host-macroparasite system. AB - Seasonal forcing represents a pervasive source of environmental variability in natural systems. Whilst it is reasonably well understood in interacting populations and host-microparasite systems, it has not been studied in detail for host-macroparasite systems. In this paper we analyse the effect of seasonal forcing in a general host-macroparasite system with explicit inclusion of the parasite larval stage and seasonal forcing applied to the birth rate of the host. We emphasise the importance of the period of the limit cycles in the unforced system on the resulting dynamics in the forced system. In particular, when subject to seasonal forcing host-macroparasite systems are capable of multi-year cycles, multiple solution behaviour, quasi-periodicity and chaos. The host macroparasite systems show a larger potential for multiple solution behaviour and a wider range of periodic solutions compared to similar interacting population and microparasite systems. By examining the system for parameters that represent red grouse and the macroparasite nematode Trichostrongylus tenuis we highlight how seasonality could be an important factor in explaining the wide range of seemingly uncorrelated cycle periods observed in grouse abundance in England and Scotland. PMID- 25445185 TI - The idiotypic network in the regulation of autoimmunity: Theoretical and experimental studies. AB - The regulation of autoimmunity is a key issue in fundamental immunology. Despite outstanding achievements on this front, we currently have more questions than answers. The idea of an immune network as a regulatory mechanism is quite attractive, since it enables us to explain the selectivity (specificity), and moreover the clonality, of the regulation. Nevertheless it remains unclear how this mysterious network of immune cells is organized, how it operates, and how it exerts control over autoimmunity. This article presents an attempt to understand how the immune network functions and how it controls autoreactivity. We present a mathematical model of the immune network that is based on principles of immune network organization and function that we arrived at from a survey of the available literature. To test the principles on which the mathematical model is based, we studied the model and compared the different responses to antigen that it generated with the results obtained from experimental studies of immune response. The modeled kinetics of idiotype and anti-idiotype in response to the administration of antigen are in good agreement with the experimental kinetics of idiotypic and anti-idiotypic antibodies. To obtain evidence of the existence of idiotypic mechanisms for regulating autoimmunity, we studied a mathematical model containing autoclones and compared the model results with data from experimental studies in a model of autoimmune hemolytic anemia in mice. Because the results from the theoretical and the experimental studies coincide, there is justification to conclude that autoreactive lymphocytes are normal components of the immune network within which they are regulated. We discuss a possible molecular/cellular mechanism for negative control of autoreactive cells as affected by anti-idiotypic antibodies. PMID- 25445188 TI - Neighborhood functions alter unbalanced facilitation on a stress gradient. AB - The stress-gradient hypothesis states that individual and species competitive and facilitative effects change in relative importance or intensity along environmental gradients of stress. The importance of the number of facilitators in the neighborhood of a potential beneficiary has not been explored. Evenly distributed and stress-correlated facilitation and the increase in the intensity of facilitation with neighbors as linear, logarithmic, and unimodal functions is simulated for two hypothetical species, both of which improve the local environment. The mutualism is unbalanced in that the establishment of one species is enhanced by neighbors more than the other. Compared to no facilitation or evenly distributed facilitation, the stress gradient produces more edges in the spatially advancing population, more overall intensity of facilitation, and more individuals further advanced into the area of higher stress; the more enhanced species has increased population relative to the other - to the point where they are equal. Among three neighborhood functions, little difference exists in outcomes between the linear and logarithmic functions, but the unimodal function, which shifts peak facilitation intensity to fewer neighbors, increases the above state variables more than the differences between the even and stress gradient facilitation scenarios; the population of the beneficiary species exceeds that of the other. Different neighborhood functions change the effects of spatial pattern on the biological outcome. The unbalanced mutualism may be important where additional species alter the basic interaction in the high stress area of the environmental gradient, such as ecotones where the spatial pattern becomes central to facilitation. PMID- 25445187 TI - Modelling production per unit of food consumed in fish populations. AB - The ratio of production-to-consumption (rho) reflects how efficiently a population can transform ingested food into biomass. Usually this ratio is estimated by separately integrating cohort per-recruit production and consumption per unit of biomass. Estimates of rho from cohort analysis differ from those that consider the whole population, because fish populations are usually composed of cohorts that differ in their relative abundance. Cohort models for rho also assume a stable age-structure and a constant population size (stationary condition). This may preclude their application to harvested populations, in which variations in fishing mortality and recruitment will affect age-structure. In this paper, we propose a different framework for estimating (rho) in which production and consumption are modelled simultaneously to produce a population estimator of rho. Food consumption is inferred from the physiological concepts underpinning the generalised von Bertalanffy growth function (VBGF). This general framework allows the effects of different age-structures to be explored, with a stationary population as a special case. Three models with different complexities, depending mostly on what assumptions are made about age-structure, are explored. The full data model requires knowledge about food assimilation efficiency, parameters of the VBGF and the relative proportion of individuals at age a at time y (Py(a)). A simpler model, which requires less data, is based on the stationary assumption. Model results are compared with estimates from cohort models for rho using simulated fish populations of different lifespans. The models proposed here were also applied to three fish populations that are targets of commercial fisheries in the south-east Pacific. Uncertainty in the estimation of rho was evaluated using a resampling approach. Simulation showed that cohort and population models produce different estimates for rho and those differences depend on lifespan, fishing mortality and recruitment variations. Results from the three case studies show that the population model gives similar estimates to those reported by empirical models in other fish species. This modelling framework allows rho to be related directly to population length- or age structure and thus has the potential to improve the biological realism of both population and ecosystem models. PMID- 25445189 TI - Epidemic control analysis: designing targeted intervention strategies against epidemics propagated on contact networks. AB - In cases where there are limited resources for the eradication of an epidemic, or where we seek to minimise possible adverse impacts of interventions, it is essential to optimise the efficacy of control measures. We introduce a new approach, Epidemic Control Analysis (ECA), to design effective targeted intervention strategies to mitigate and control the propagation of infections across heterogeneous contact networks. We exemplify this methodology in the context of a newly developed individual-level deterministic Susceptible Infectious-Susceptible (SIS) epidemiological model (we also briefly consider applications to Susceptible-Infectious-Removed (SIR) dynamics). This provides a flexible way to systematically determine the impact of interventions on endemic infections in the population. Individuals are ranked based on their influence on the level of infectivity. The highest-ranked individuals are prioritised for targeted intervention. Many previous intervention strategies have determined prioritisation based mainly on the position of individuals in the network, described by various local and global network centrality measures, and their chance of being infectious. Comparisons of the predictions of the proposed strategy with those of widely used targeted intervention programmes on various model and real-world networks reveal its efficiency and accuracy. It is demonstrated that targeting central individuals or individuals that have high infection probability is not always the best strategy. The importance of individuals is not determined by network structure alone, but can be highly dependent on the infection dynamics. This interplay between network structure and infection dynamics is effectively captured by ECA. PMID- 25445190 TI - Convergence analysis of a finite element skull model of Herpestes javanicus (Carnivora, Mammalia): implications for robust comparative inferences of biomechanical function. AB - Predictions of skull biomechanical capability based on virtual models constitute a valuable data source for testing hypotheses about craniodental form and feeding behavior. Such comparative analyses also inform dietary reconstruction in extinct species. 3D modeling using Finite Element (FE) methods is a common technique applied to the comparative analysis of craniodental function in extinct and extant vertebrates. However, taxonomically diverse skull models in the literature often are not directly comparable to each other, in part because of distinctions in how boundary conditions are defined, but also because of substantial differences in the number of FEs composing the models. In this study, we test whether a conventional convergence test is adequate in identifying the minimum number of FEs needed to achieve internally stable results for a single species. We constructed a series of skull models of Herpestes javanicus, and simulated unilateral biting across the dentition; the models differed in the number of FEs, degrees of freedom at the joint and bite point constraints, and type of tetrahedral FEs used. We found that convergence patterns differed across constraint types, FE quantities, and bite position simulated. Four-noded tetrahedral (tet-4) FE models with relaxed constraints produced the most stable measurements compared to over-constrained tet-4 models and to relaxed tet-10 models. In absence of an optimal FE quantity from convergence testing, we propose a broadly applicable sub-sampling protocol, whereby average measurement values across multiple models per specimen are used for among-species comparisons. A regime of sampling three low FE quantity models produced the closest estimates of mean measurement values relative to larger model sets, being within the 95% bootstrap estimated confidence intervals. Future studies should focus on identifying sources of variation associated with other FE modeling protocols, so that they can be accounted for before biomechanical attributes from these simulations are used to infer form-function linkage. PMID- 25445191 TI - Variability in action: Contributions of a songbird cortical-basal ganglia circuit to vocal motor learning and control. AB - Many motor behaviors, from walking to speaking, are acquired through experience, in particular, through trial-and-error learning. The acquisition and maintenance of such motor behaviors in a wide range of species, including humans, appear to depend on cortical-basal ganglia circuits. In this review, we discuss recent studies in songbirds that have been pivotal in informing our current understanding of motor learning and cortical-basal ganglia function. Songbirds are important ethological model systems for the study of motor learning because young songbirds naturally develop and refine their songs through trial-and-error learning. In addition, reinforcement mechanisms are hypothesized to be important for the maintenance and plasticity of structured adult song. Computational and experimental studies highlight the importance of vocal motor variability as the substrate upon which reinforcement mechanisms could operate to shape developing song and to maintain adult song. Recent studies in songbirds indicate that this vocal motor variability is actively generated and modulated by a highly specialized cortical-basal ganglia circuit evolved for a single behavior, song. We argue that these and other recent findings illustrate how the tight association between a specialized neural circuit and a natural behavior make songbirds a unique and powerful model in which to investigate the neural substrates of motor learning and plasticity. PMID- 25445192 TI - What studies of macaque monkeys have told us about human color vision. AB - Animal models are a necessary component of systems neuroscience research. Determining which animal model to use for a given study involves a complicated calculus. Some experimental manipulations are easily made in some animal models but impossible in others. Some animal models are similar to humans with respect to particular scientific questions, and others are less so. In this review, I discuss work done in my laboratory to investigate the neural mechanisms of color vision in the rhesus macaque. The emphasis is on the strengths of the macaque model, but shortcomings are also discussed. PMID- 25445193 TI - Social defeat promotes a reactive endothelium in a brain region-dependent manner with increased expression of key adhesion molecules, selectins and chemokines associated with the recruitment of myeloid cells to the brain. AB - Repeated social defeat (RSD) in mice causes myeloid cell trafficking to the brain that contributes to the development of prolonged anxiety-like behavior. Myeloid cell recruitment following RSD occurs in regions where neuronal and microglia activation is observed. Thus, we hypothesized that crosstalk between neurons, microglia, and endothelial cells contributes to brain myeloid cell trafficking via chemokine signaling and vascular adhesion molecules. Here we show that social defeat caused an exposure- and brain region-dependent increase in several key adhesion molecules and chemokines involved in the recruitment of myeloid cells. For example, RSD induced distinct patterns of adhesion molecule expression that may explain brain region-dependent myeloid cell trafficking. VCAM-1 and ICAM-1 mRNA expression were increased in an exposure-dependent manner. Furthermore, RSD induced VCAM-1 and ICAM-1 protein expression were localized to the vasculature of brain regions implicated in fear and anxiety responses, which spatially corresponded to previously reported patterns of myeloid cell trafficking. Next, mRNA expression of additional adhesion molecules (E- and P-selectin, PECAM-1) and chemokines (CXCL1, CXCL2, CXCL12, CCL2) were determined in the brain. Social defeat induced an exposure-dependent increase in mRNA levels of E-selectin, CXCL1, and CXCL2 that increased with additional days of social defeat. While CXCL12 was unaffected by RSD, CCL2 expression was increased by six days of social defeat. Last, comparison between enriched CD11b(+) cells (microglia/macrophages) and enriched GLAST-1(+)/CD11b(-) cells (astrocytes) revealed RSD increased mRNA expression of IL-1beta, CCL2, and CXCL2 in microglia/macrophages but not in astrocytes. Collectively, these data indicate that key mediators of leukocyte recruitment were increased in the brain vasculature following RSD in an exposure- and brain region-dependent manner. PMID- 25445194 TI - The place of dopamine in the cortico-basal ganglia circuit. AB - The midbrain dopamine (DA) neurons play a central role in developing appropriate goal-directed behaviors, including the motivation and cognition to develop appropriate actions to obtain a specific outcome. Indeed, subpopulations of DA neurons have been associated with these different functions: the mesolimbic, mesocortical, and nigrostriatal pathways. The mesolimbic and nigrostriatal pathways are an integral part of the basal ganglia through its reciprocal connections to the ventral and dorsal striatum respectively. This chapter reviews the connections of the midbrain DA cells and their role in integrating information across limbic, cognitive and motor functions. Emphasis is placed on the interface between these functional domains within the striatum through corticostriatal connections, through the striato-nigro-striatal connection, and through the lateral habenula projection to the midbrain. PMID- 25445195 TI - Brain-derived neurotrophic factor heterozygous mutant rats show selective cognitive changes and vulnerability to chronic corticosterone treatment. AB - Brain-derived neurotrophic factor (BDNF) is a widely expressed neurotrophin involved in neurodevelopment, neuroprotection and synaptic plasticity. It is also implicated in a range of psychiatric disorders such as schizophrenia, depression and post-traumatic stress disorder. Stress during adolescence/young adulthood can have long-term psychiatric and cognitive consequences, however it is unknown how altered BDNF signaling is involved in such effects. Here we investigated whether a congenital deficit in BDNF availability in rats increases vulnerability to the long-term effects of the stress hormone, corticosterone (CORT). Compared to wildtype (WT) littermates, BDNF heterozygous (HET) rats showed higher body weights and minor developmental changes, such as reduced relative brain and pituitary weight. These animals furthermore showed deficits in short-term spatial memory in the Y-maze and in prepulse inhibition and startle, but not in object recognition memory. CORT treatment induced impairments in novel-object recognition memory in both genotypes but disrupted fear conditioning extinction learning in BDNF HET rats only. These results show selective behavioral changes in BDNF HET rats, at baseline or after chronic CORT treatment and add to our understanding of the role of BDNF and its interaction with stress. Importantly, this study demonstrates the utility of the BDNF HET rat in investigations into the pathophysiology of various psychiatric disorders. PMID- 25445196 TI - Extracellular matrix molecules exhibit unique expression pattern in the climbing fiber-generating precerebellar nucleus, the inferior olive. AB - Extracellular matrix (ECM) accumulates around different neuronal compartments of the central nervous system (CNS) or appears in diffuse reticular form throughout the neuropil. In the adult CNS, the perineuronal net (PNN) surrounds the perikarya and dendrites of various neuron types, whereas the axonal coats are aggregations of ECM around the individual synapses, and the nodal ECM is localized at the nodes of Ranvier. Previous studies in our laboratory demonstrated on rats that the heterogeneous distribution and molecular composition of ECM is associated with the variable cytoarchitecture and hodological organization of the vestibular nuclei and may also be related to their specific functions in gaze and posture control as well as in the compensatory mechanisms following vestibular lesion. Here, we investigated the ECM expression pattern in the climbing fiber-generating inferior olive (IO), which is functionally related to the vestibular nuclei. By using histochemical and immunohistochemical methods, the most characteristic finding was the lack of PNNs, presumably due to the absence of synapses on the perikarya and proximal dendrites of IO neurons. On the other hand, the darkly stained dots or ring-like structures in the neuropil might represent the periaxonal coats around the axon terminals of olivary synaptic glomeruli. We have observed positive ECM reaction for the hyaluronan, tenascin-R, hyaluronan and proteoglycan link protein 1 (HAPLN1) and various chondroitin sulfate proteoglycans. The staining intensity and distribution of ECM molecules revealed a number of differences between the functionally different subnuclei of IO. We hypothesized that the different molecular composition and intensity differences of ECM reaction is associated with different control mechanisms of gaze and posture control executed by the visuomotor-vestibular, somatosensory and integrative subnuclei of the IO. PMID- 25445197 TI - Pelvic organ cross-sensitization to enhance bladder and urethral pain behaviors in rats with experimental colitis. AB - Neural cross-sensitization has been postulated as a mechanism underlying overlaps of chronic pelvic pain disorders such as bladder pain syndrome/interstitial cystitis (BPS/IC) and irritable bowel syndrome (IBS). Animals with experimental colitis have been used to study the underlying mechanisms for overlapped pelvic pain symptoms, and shown to exhibit bladder overactivity evidenced by frequent voiding; however, it has not directly been evaluated whether pain sensation derived from the lower urinary tract is enhanced in colitis models. Also, the cross-sensitization between the colon and urethra has not been studied previously. In the present study, we therefore investigated pain behaviors induced by nociceptive stimuli in the lower urinary tract and the involvement of C-fiber afferent pathways using rats with colitis induced by intracolonic application of 2,4,6-trinitrobenzenesulfonic acid (TNBS). In TNBS-induced colitis rats at 10 days, intravesical application of resiniferatoxin (RTx) induced a significantly greater number of episodes of both licking and freezing behaviors, which were reduced by capsaicin-sensitive C-fiber afferent desensitization. Histochemical studies using fluorescent dye tracers injected into the colon, bladder or urethra showed that dichotomized afferent neurons comprised 6.9-14.5% of L1, L6 and S1 dorsal root ganglion (DRG) neurons innervating the colon or the lower urinary tract. Transient receptor potential vanilloid 1 (TRPV1) mRNA expression was significantly increased in, the bladder, urethra and S1 DRG in colitis rats. An increase in myeloperoxidase (MPO) activity was found in the colon, but not in the bladder or urethra after intracolonic TNBS treatment. These results indicate that TNBS-induced colitis increased pain sensitivity in the bladder and urethra via activation of C-fiber afferent pathways due to colon-to bladder and colon-to-urethral cross-sensitization, suggesting the contribution of pelvic organ cross-sensitization mechanisms to overlapped pain symptoms in BPS/IC and IBS. PMID- 25445198 TI - Improving meal context in nursing homes. Impact of four strategies on food intake and meal pleasure. AB - In France, in most nursing homes, the composition of menus, the time and the place at which meals are served, the choice of one's place at the table are imposed on residents. Yet, the act of eating cannot be restricted to nutritional and sensory aspects alone. It also includes a psycho-affective dimension, which relates to the context in which the meal is served. We tested the impact of four contextual factors, considered individually, on food intake and meal pleasure in elderly people living in nursing homes: the way the main course was named on the menu, the size and the variety of portions of vegetables served to residents, the presence or not of condiments in the middle of the table and the presence or not of elements to modify the surroundings such as a decorative object on the table or background music. Twelve experimental meals were served to 42 nursing home residents. For each factor, we compared a control condition with two experimental conditions. Our study showed that changing a single contextual element of the meal in nursing homes could be sufficient to improve residents' satisfaction with their meals and increase the quantities of meat or vegetables consumed, as long as this factor had a direct impact on what was going to be consumed (increased variety on the plate, condiments on the table). Factors affecting the context of the meal (names of dishes, decor) proved to be ineffective. Given the budgetary constraints faced by nursing homes, this study proposes interesting and inexpensive ideas to increase satisfaction with meals and food intake in elderly people who are dependent on others for their meals. PMID- 25445200 TI - Head to head comparison of the formulation and stability of concentrated solutions of HESylated versus PEGylated anakinra. AB - Although PEGylation of biologics is currently the gold standard for half-life extension, the technology has a number of limitations, most importantly the non biodegradability of PEG and the extremely high viscosity at high concentrations. HESylation is a promising alternative based on coupling to the biodegradable polymer hydroxyethyl starch (HES). In this study, we are comparing HESylation with PEGylation regarding the effect on the protein's physicochemical properties, as well as on formulation at high concentrations, where protein stability and viscosity can be compromised. For this purpose, the model protein anakinra is coupled to HES or PEG by reductive amination. Results show that coupling of HES or PEG had practically no effect on the protein's secondary structure, and that it reduced protein affinity by one order of magnitude, with HESylated anakinra more affine than the PEGylated protein. The viscosity of HESylated anakinra at protein concentrations up to 75 mg/mL was approximately 40% lower than that of PEG-anakinra. Both conjugates increased the apparent melting temperature of anakinra in concentrated solutions. Finally, HESylated anakinra was superior to PEG-anakinra regarding monomer recovery after 8 weeks of storage at 40 degrees C. These results show that HESylating anakinra offers formulation advantages compared with PEGylation, especially for concentrated protein solutions. PMID- 25445201 TI - Development of antimicrobial resistance in the normal anaerobic microbiota during one year after administration of clindamycin or ciprofloxacin. AB - Thirty healthy subjects (15 males and 15 females) were randomly assigned in three groups and clindamycin (150 mg qid) or ciprofloxacin (500 mg bid) or placebo was given for a 10-day period. Skin, nasal, saliva, faeces samples were collected at day - 1, day 11, 1 month, 2 months, 4 months and 12 months post administration for microbiological analysis. Ciprofloxacin or clindamycin had no impact on the anaerobic skin microbiota and the proportions of antibiotic resistant anaerobic bacteria were similar as in the placebo group. Ciprofloxacin had impact on the Propionibacterium acnes in the nasal microbiota that normalized after 1 month, however, ciprofloxacin-resistant P. acnes strains increased at month 2 and month 12. Clindamycin had no impact on the nasal microbiota. In the oropharyngeal microbiota, a higher proportion of ciprofloxacin resistant Veillonella was found, it lasting up to 12 months post dosing. In the clindamycin group, clindamycin resistant Prevotella spp. were found in increased proportions compared to placebo at various time points except month 4 in the saliva samples. The relative proportion of ciprofloxacin-resistant Bifidobacteria increased in the faecal samples on day 11, 1 month, 4 months and 12 months post dosing compared to placebo. The proportion of clindamycin-resistant Bacteroides spp. increased at 1, 2, 4 and 12 months post dosing compared to placebo in the faecal samples. No Clostridium difficile was recovered from any of the samples from any of the volunteers at any visit. The concentrations of ciprofloxacin or clindamycin in the faeces were higher than the MICs for most of the organisms present in the normal microbiota. No obvious correlation between the groups in resistant patterns for anaerobic bacteria was observed. In conclusion, based on the microbiological data of the microbiota as well as the results of the bioassays for ciprofloxacin and clindamycin concentrations in the faecal samples, oral administration of ciprofloxacin and clindamycin has an impact on the anaerobic microbiota and may have a long-term effect on the development and persistence of antibiotic-resistant anaerobes in the normal microbiota. PMID- 25445202 TI - The effect of moonlighting proteins on the adhesion and aggregation ability of Lactobacillus helveticus. AB - The goal of this study was to identify moonlighting proteins in Lactobacillus helveticus that play an important role in adhesion and aggregation. The label free method was used for identification and analysis of expression of cellular proteins. The analysis revealed the presence of eight moonlighting proteins in the cell envelope of Lb. helveticus. The tested strains mainly differed with respect to the presence of S-layer proteins and the level of expression of moonlighting proteins in Lb. helveticus strain T159. These surface proteins give the cell a hydrophobic character and play a role in specific interactions with intestinal epithelium cells and with other bacteria. In Lb. helveticus T159, the S-layer associated with moonlighting proteins could act as adherence factors, which was evidenced by the high capability of adhesion, auto- and coaggregation. The hydrophobicity, adhesion and aggregation abilities provide biological activities in food products and they are regarded as an important criterion for probiotic selection. PMID- 25445203 TI - Extraction of thymol from different varieties of thyme plants using green solvents. AB - BACKGROUND: Thymol (2-isopropyl-5-methylphenol) is the main monoterpene phenol found in thyme essential oil. This compound has revealed several biological properties, including antibacterial, anti-inflammatory and antioxidant activities. In this work, a comparison was made between the performance of different green solvents (ethanol, limonene and ethyl lactate), by pressurized liquid extraction (PLE) and supercritical fluid extraction (SFE) at different conditions, to extract thymol from three different varieties of thyme (Thymus vulgaris, Thymus zygis and Thymus citriodorus). Additionally, new solubility data of thymol in limonene and ethanol at ambient pressure and temperatures in the range 30-43 degrees C are reported. RESULTS: The highest thymol recoveries were attained with T. vulgaris (7-11 mg g(-1)). No thymol could be quantified in the PLE samples of T. citriodorus. The highest concentrations of thymol in the extracts were obtained with limonene. Thymol is very soluble in both solvents, particularly in ethanol (~900 mg g(-1) at ~40 degrees C), and is the main compound (in terms of peak area) present in the essential oil extracts obtained. CONCLUSION: The three solvents show good capacity to extract thymol from T. vulgaris and T. zygis by PLE. Although PLE proved to be a suitable technology to extract thymol from thyme plants, the highest concentrations of thymol were obtained by SFE with supercritical CO2 . PMID- 25445199 TI - A new look at the science of weight control: how acceptance and commitment strategies can address the challenge of self-regulation. AB - The current manuscript proposes an acceptance-based, self-regulation framework for understanding the challenge of weight maintenance and describes how this framework can be integrated into the behavioral treatment of obesity. According to this framework, intrinsic drives to consume palatable, high-calorie food interact with a modern environment in which high calorie foods are easily accessible. This combination produces a chronic desire to eat unhealthy foods that exists in opposition to individuals' weight control goals. Similarly, low energy expenditure requirements reduce physical activity. We suggest that individuals vary in their responsivity to cues that motivate overeating and sedentary behavior, and that those higher in responsivity need specialized self regulatory skills to maintain healthy eating and exercise behaviors. These skills include an ability to tolerate uncomfortable internal reactions to triggers and a reduction of pleasure, behavioral commitment to clearly-defined values, and metacognitive awareness of decision-making processes. So-called "acceptance based" interventions based on these skills have so far proven efficacious for weight control, especially for those who are the most susceptible to eating in response to internal and external cues (as predicted by the model). Despite the current empirical support for the postulated model, much remains to be learned including whether acceptance-based interventions will prove efficacious in the longer-term. PMID- 25445204 TI - Epigenomics in translational research. PMID- 25445205 TI - Breast tissue-based microRNA panel highlights microRNA-23a and selected target genes as putative biomarkers for breast cancer. AB - We explored the differential expression of breast tissue-based panel of microRNAs (miRNAs) and their potential application as prognostic markers of breast cancer (BC). This study was divided into the following phases: (1) A panel of 6 BC characteristic miRNAs, which were retrieved based on the microarray signature profiling (released by miRWalk), was explored using SYBR Green-based polymerase chain reaction (PCR) array in 16 cancerous and 16 noncancerous breast tissue; (2) pathway enrichment analysis of the key miRNA target genes; (3) marker choice and validation by real-time PCR in a larger set of 76 patients with BC, 36 benign breast conditions, and 36 healthy volunteers; (4) validation of miRNA (miR)-23a target genes (forkhead box m [FOXM1] and histidine-rich glycoprotein [HRG]) by conventional reverse transcriptase (RT)-PCR; and (5) the prognostic significance of the investigated parameters in the BC validation group was explored. In PCR array-based miRNA expression analysis, 4 miRNAs were found to be altered more than twice (miR-96, miR-29c, miR-221, and miR-23a). Bioinformatic analysis of the target genes revealed enrichment for special biological process categories, that is, cell cycle, angiogenesis, apoptosis, cell proliferation, and cell adhesion. miR-23a, HRG messenger RNA, and FOX messenger RNA were positive in BC by 82.9%, 72.4%, and 71.1%, respectively. The overall concordance rates between miR-23a with HRG and FOXM1 tissue RNAs were 91% and 79%, respectively. The median follow up period was 49 months. mi-23a and HRG RNA were significant independent prognostic markers in relapse-free survival. miR-23a may have an oncogenic function and enhance BC progression by directly activating FOXM1 and HRG at RNA level. PMID- 25445207 TI - Soluble urokinase plasminogen activator receptor levels are associated with severity of fibrosis in nonalcoholic fatty liver disease. AB - The identification of individuals with severe liver fibrosis among patients with chronic liver disease is of major importance when evaluating prognosis, potential risk for complications, and when deciding treatment strategies. Although percutaneous liver biopsy is still considered a "gold standard" for staging of liver fibrosis, attempts to find reliable noninvasive markers of liver fibrosis are frequent. Inflammation is essential for the progression of fibrosis. The urokinase plasminogen activator and its receptor have been associated with hepatic inflammation and fibrosis in mice. High serum concentrations of soluble urokinase plasminogen activator receptor (suPAR) are suggested to be involved in inflammation, tissue remodeling, and cancer metastasis. Here, we evaluated serum suPAR as a noninvasive test to detect liver fibrosis in 82 well-characterized patients with nonalcoholic fatty liver disease (NAFLD), and in 38 untreated patients with chronic hepatitis C virus (HCV) infection at the time of their first liver biopsy. suPAR levels were increased in chronic liver disease compared with blood donors (P < 0.001). Patients with HCV had higher suPAR concentrations than patients with NAFLD (P < 0.002). suPAR levels were associated with the severity of fibrosis, particularly in NAFLD, but did not correlate with inflammation. Regarding the performance in predicting severity of fibrosis, suPAR was essentially as good as other commonly used noninvasive fibrosis scoring systems. The results in HCV confirm previous observations. However, this is the first study to investigate suPAR as a biomarker in NAFLD, and the results indicate that suPAR may constitute a severity marker related to fibrosis and prognosis rather than reflecting inflammation. PMID- 25445209 TI - Ubiquitin-specific peptidase 22 overexpression may promote cancer progression and poor prognosis in human gastric carcinoma. AB - Ubiquitin-specific peptidase 22 (USP22) was recently identified as a new tumor cell marker, and previous studies demonstrated its expression in a variety of tumors and its correlation with tumor progression. Because tumor progression plays an important role in cancer, researchers are paying more attention to the correlation between USP22 expression and metastatic potential, resistance to chemotherapy, and patient prognosis. This study showed that USP22 is highly expressed in gastric cancer tissues, and significant differences in USP22 expression (P < 0.01) were identified between different types of gastric cancer (the highest expression was found in poorly differentiated adenocarcinomas). In addition USP22 expression was found to be correlated with the promotion of cancer evolution, tumor invasion, and lymph node metastasis. The C-myc protein was also shown to have synergistic effects with USP22 in gastric cancer tissue. On the basis of the results, USP22 expression may play an important role in gastric carcinoma tissue, particularly in precancerous lesions during the gastric cancer evolution process. PMID- 25445206 TI - Interferon regulatory factors: critical mediators of human lupus. AB - The pathogenesis of systemic lupus erythematosus (SLE) is multifactorial, and the interferon regulatory factors (IRFs) play an important role. Autoantibodies formed in SLE target nuclear antigens, and immune complexes formed by these antibodies contain nucleic acid. These immune complexes can activate antiviral pattern recognition receptors (PRRs), resulting in the downstream activation of IRFs, which can induce type I interferon (IFN-I) and other inflammatory mediators. Genetic variations in IRFs have been associated with susceptibility to SLE, and current evidence supports the idea that these polymorphisms are gain of function in humans. Recent studies suggest that these genetic variations contribute to the break in humoral tolerance that allows for nucleic acid binding autoantibodies, and that the same polymorphisms also augment IFN-I production in the presence of these autoantibody immune complexes, forming a feed-forward loop. In this review, we will outline major features of the PRR/IRF systems and describe the role of the IRFs in human SLE pathogenesis. PMID- 25445208 TI - Applicability of estimating glomerular filtration rate equations in pediatric patients: comparison with a measured glomerular filtration rate by iohexol clearance. AB - Estimating glomerular filtration rate (eGFR) has become popular in clinical medicine as an alternative to measured GFR (mGFR), but there are few studies comparing them in clinical practice. We determined mGFR by iohexol clearance in 81 consecutive children in routine practice and calculated eGFR from 14 standard equations using serum creatinine, cystatin C, and urea nitrogen that were collected at the time of the mGFR procedure. Nonparametric Wilcoxon test, Spearman correlation, Bland-Altman analysis, bias (median difference), and accuracy (P15, P30) were used to compare mGFR with eGFR. For the entire study group, the mGFR was 77.9 +/- 38.8 mL/min/1.73 m(2). Eight of the 14 estimating equations demonstrated values without a significant difference from the mGFR value and demonstrated a lower bias in Bland-Altman analysis. Three of these 8 equations based on a combination of creatinine and cystatin C (Schwartz et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009;20:629 37; Schwartz et al. Improved equations estimating GFR in children with chronic kidney disease using an immunonephelometric determination of cystatin C. Kidney Int 2012;82:445-53; Chehade et al. New combined serum creatinine and cystatin C quadratic formula for GFR assessment in children. Clin J Am Soc Nephrol 2014;9:54 63) had the highest accuracy with approximately 60% of P15 and 80% of P30. In 10 patients with a single kidney, 7 with kidney transplant, and 11 additional children with short stature, values of the 3 equations had low bias and no significant difference when compared with mGFR. In conclusion, the 3 equations that used cystatin C, creatinine, and growth parameters performed in a superior manner over univariate equations based on either creatinine or cystatin C and also had good applicability in specific pediatric patients with single kidneys, those with a kidney transplant, and short stature. Thus, we suggest that eGFR calculations in pediatric clinical practice use only a multivariate equation. PMID- 25445210 TI - Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice. AB - We investigated whether melatonin ameliorates fibrosis and limits the expression of fibrogenic genes in mice treated with carbon tetrachloride (CCl4). Mice in treatment groups received CCl4 5 MUL/g body weight intraperitoneally twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg/kg/d intraperitoneally, beginning 2 weeks after the start of CCl4 administration. Treatment with CCl4 resulted in fibrosis evidenced by the staining of Van Gieson and alpha-smooth muscle actin (alpha-SMA) positive cells in the liver. At both 4 and 6 weeks, CCl4 induced an increase in the messenger RNA levels of collagens I and III, transforming growth factor (TGF)-beta, platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), amphiregulin, matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1. Protein concentrations of CTGF, amphiregulin, MMP-9, TIMP-1, and phospho-Smad3 were also significantly augmented in fibrotic mice. Melatonin successfully attenuated liver injury, as shown by histopathology and decreased levels of serum transaminases. Immunohistochemical staining of alpha-SMA indicated an abrogation of hepatic stellate cell activation by the indol. Furthermore, melatonin treatment resulted in significant inhibition of the expression of collagens I and III, TGF-beta, PDGF, CTGF, amphiregulin, and phospho-Smad3. The MMP-9 activity decreased and the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) increased in mice receiving melatonin. Data obtained suggest that attenuation of multiple profibrogenic gene pathways contributes to the beneficial effects of melatonin in mice with CCl4-induced liver fibrosis. PMID- 25445211 TI - Development of a high-resolution melting curve analysis screening test for SRSF2 splicing factor gene mutations in myelodysplastic syndromes. AB - Somatic mutations of the spliceosome machinery have been recently identified by whole genome analysis in hematologic diseases, such as myelodysplastic syndrome, chronic lymphocytic leukemia, myeloproliferative neoplasms, acute myeloid leukemia, and advanced forms of mastocytosis, and also in nonhematologic conditions. SRSF2 is a member of the serine/arginine-rich family pre-mRNA splicing factors that plays a role in mRNA export from the nucleus and translation. We describe a high-resolution melting (HRM) curve analysis to screen for SRSF2 hotspot mutations in a fast, sensitive, and reliable way. Fifty bone marrow samples from patients with myelodysplastic syndrome were analyzed by the HRM assay and by direct sequencing. HRM screening identified four melting patterns corresponding to a negative (wild-type) group and three different mutated groups. Each mutated group was identified according to the positive control used: P95H, P95L, and P95R, respectively. An HRM mutated pattern was identified in seven patients. Positive and negative results from HRM were compared with direct sequencing results with a sensitivity and specificity of 100% (95% CI, 0.56-1, and 95% CI, 0.89-1, respectively). Analytical sensitivity analysis revealed a detection threshold of up to 1:9 (mutated/wild type) dilution. This rapid screening method may provide useful information for clinical decision making and be helpful to optimize laboratory resources and reduce turnaround time. PMID- 25445212 TI - Diagnostic application of an extensive gene panel for Leber congenital amaurosis with severe genetic heterogeneity. AB - Leber congenital amaurosis (LCA) is a genetically heterogeneous disorder and the most severe form of inherited retinal dystrophy. We report results of a diagnostic application of an extensive gene panel composed of 204 retinal dystrophy-related genes and discuss its feasibility as a diagnostic tool. Nineteen unrelated LCA patients were included in the study: two patients for validation purposes of our gene panel, 15 previously analyzed patients with no identified mutations, and two previously unanalyzed patients. Genetic diagnosis for each patient was conducted according to whether the variants were consistent with the known inheritance pattern of each gene. We identified two heterozygous or homozygous pathogenic variants in seven of 19 patients. On the basis of mutation information, clinical features were re-reviewed, and clinical diagnoses for two patients were revised from LCA to LCA-related disorders. In addition, a coverage simulation was performed to determine the optimal depth of coverage of the gene panel. Using our gene panel, we diagnosed LCA and LCA-related disorders in 36.8% of patients and one or more deleterious variants or variants of unknown significance in 89.5% of patients. Molecular diagnosis using this extensive gene panel is expected to facilitate diagnosis of retinal dystrophy and help provide proper treatment to patients, although further analyses is needed for a complete clinical validation. PMID- 25445213 TI - Assessment of HaloPlex amplification for sequence capture and massively parallel sequencing of arrhythmogenic right ventricular cardiomyopathy-associated genes. AB - The genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is complex. Mutations in genes encoding components of the cardiac desmosomes have been implicated as being causally related to ARVC. Next-generation sequencing allows parallel sequencing and duplication/deletion analysis of many genes simultaneously, which is appropriate for screening of mutations in disorders with heterogeneous genetic backgrounds. We designed and validated a next-generation sequencing test panel for ARVC using HaloPlex. We used SureDesign to prepare a HaloPlex enrichment system for sequencing of DES, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TGFB3, TMEM43, and TTN from patients with ARVC using a MiSeq instrument. Performance characteristics were determined by comparison with Sanger, as the gold standard, and TruSeq Custom Amplicon sequencing of DSC2, DSG2, DSP, JUP, and PKP2. All the samples were successfully sequenced after HaloPlex capture, with >99% of targeted nucleotides covered by >20*. The sequences were of high quality, although one problematic area due to a presumptive context-specific sequencing error-causing motif located in exon 1 of the DSP gene was detected. The mutations found by Sanger sequencing were also found using the HaloPlex technique. Depending on the bioinformatics pipeline, sensitivity varied from 99.3% to 100%, and specificity varied from 99.9% to 100%. Three variant positions found by Sanger and HaloPlex sequencing were missed by TruSeq Custom Amplicon owing to loss of coverage. PMID- 25445214 TI - Whole-genome sequencing identifies patient-specific DNA minimal residual disease markers in neuroblastoma. AB - PCR-based detection of minimal residual disease (MRD) in neuroblastoma is currently based on RNA markers; however, expression of these targets can vary, and only paired-like homeobox 2b has no background expression. We investigated whether chromosomal breakpoints, identified by whole-genome sequencing (WGS), can be used as patient-specific DNA MRD markers. WGS data were used to develop large numbers of real-time PCRs specific for tumors of eight patients. These PCRs were used to quantify chromosomal breakpoints in primary tumor and bone marrow samples. Finally, the DNA breakpoints with the highest abundance were compared with a panel of RNA markers. By WGS we identified 42 chromosomal breakpoints in tumor samples from eight patients and developed specific quantitative real-time PCRs for each breakpoint. The tumor-specific breakpoints were all present in bone marrow at diagnosis. For one patient slight clonal selection was observed in response to treatment. Positivity of DNA MRD markers preceded disease progression in four of five patients; in one patient the RNA markers remained negative. For 16 of 22 samples MRD levels determined by RNA and DNA were comparable and in 6 of 22 samples higher MRD levels were detected by DNA markers. DNA breakpoints used as MRD targets in neuroblastoma are reliable and stable markers. In addition, this technique might be applicable for detecting tumor cells in other types of cancer. PMID- 25445215 TI - Simultaneous detection of clinically relevant mutations and amplifications for routine cancer pathology. AB - In routine cancer molecular pathology, various independent experiments are required to determine mutation and amplification status of clinically relevant genes. Most of these tests are designed to identify a limited number of genetic aberrations, most likely in a given tumor type. We present a modified version of a multiplexed PCR and IonTorrent-based sequencing approach that can replace a large number of existing assays. The test allows for the simultaneous detection of point mutations and gene amplifications in 40 genes, including known hotspot regions in oncogenes (KRAS, BRAF), inactivating mutations in tumor suppressors (TP53, PTEN), and oncogene amplifications (ERBB2, EGFR). All point mutations were confirmed using certified diagnostic assays, and a sensitivity and specificity of 100% (95% CI, 0.875-1.0) and 99% (95% CI, 0.960-0.999), respectively, were determined for amplifications in FFPE material. Implementation of a single assay to effectively detect mutations and amplifications in clinically relevant genes not only improves the efficiency of the workflow within diagnostic laboratories but also increases the chance of detecting (rare) actionable variants for a given tumor type that are typically missed in routine pathology. The ability to obtain comprehensive and rapid mutational overviews is key for improving the efficiency of cancer patient care through tailoring treatments based on the genetic characteristics of individual tumors. PMID- 25445216 TI - Enhancing maternal sensitivity and infant attachment security with video feedback: an exploratory study in Italy. AB - This study aims to explore whether a short-term and attachment-based video feedback intervention, the Video-Feedback Intervention to Promote Positive Parenting With Discussions on the Representational Level (VIPP-R; F. Juffer, M.J. Bakermans-Kranenburg, & M.H. van IJzendoorn, 2008), might be effective in enhancing maternal sensitivity and in promoting infants' attachment security in an Italian sample of dyads with primiparous mothers. Moreover, we explore whether the effectiveness of VIPP-R might be different for parents with insecure attachment representations who might be most in need of preventive intervention, as compared to parents who already have a more balanced and secure state of mind. Thirty-two infants (40% female) and their mothers participated in the study. The sample was divided into an intervention group (n = 16) and a comparison group (n = 16). At 6 and 13 months of age, the Adult Attachment Interview (AAI; M. Main, N. Kaplan, & J. Cassidy, 1985) was administered. Moreover, a 30-min mother-infant play situation was videotaped and coded for maternal sensitivity with the Emotional Availability Scales (Z. Biringen, J. Robinson, & R.N. Emde, 2000). At 13 months of age, the Strange Situation Procedure (M.D.S. Ainsworth, M.D. Blehar, E. Waters, & S. Wall, 1978) was used to assess the security of mother-infant attachment. Results revealed a significant interaction effect between intervention and AAI security for infant attachment security; moreover, main effects of AAI security and intervention for maternal sensitivity were found. The VIPP-R appears effective in enhancing maternal sensitivity and infant attachment security, although only mothers with an insecure attachment representation may benefit from the intervention. PMID- 25445217 TI - Prophylactic effects of elastin peptide derived from the bulbus arteriosus of fish on vascular dysfunction in spontaneously hypertensive rats. AB - AIMS: To determine the prophylactic effects of an elastin peptide derived from the bulbus arteriosus of bonitos and prolylglycine (PG), a degradation product of elastin peptide, on vascular dysfunction in spontaneously hypertensive rats (SHRs). MAIN METHODS: Male 15-week-old SHR/Izm rats were fed without (control group) or with elastin peptide (1 g/kg body weight) for 5 weeks (EP group), or were infused via an osmotic mini-pump for 4 weeks with PG (PG group) or saline (control group). Using thoracic aortas, we assessed endothelial changes by scanning electron microscopy. Vascular reactivity (contraction and relaxation) and pressure-induced distension was compared. mRNA production levels of endothelial nitric oxide synthase (eNOS) and intercellular adhesion molecule-1 (ICAM-1) were investigated by real-time-polymerase chain reaction. KEY FINDINGS: Aortas of the EP group displayed limited endothelial damage compared with that in the control group. Under treatment of SHRs with elastin peptide, the effect of phenylephrine returned closer to the normal level observed in normotensive Wistar Kyoto (WKY/Izm) rats. mRNA production of eNOS (but not ICAM-1) was greater in the EP group than in the control group. Endothelial damage was suppressed and pressure-induced vascular distension was greater in the PG group than in the corresponding control group. SIGNIFICANCE: These results suggest that elastin peptide from bonitos elicits prophylactic affects hypertension-associated vascular dysfunction by targeting the eNOS signaling pathway. PG may be a key mediator of the beneficial effects of elastin peptide. PMID- 25445219 TI - Critical-size bone defect repair using amniotic fluid stem cell/collagen constructs: effect of oral ferutinin treatment in rats. AB - AIMS: This study aims to evaluate the bone regeneration in a rat calvarias critical size bone defect treated with a construct consisting of collagen type I and human amniotic fluid stem cells (AFSCs) after oral administration of phytoestrogen ferutinin. MAIN METHODS: In 12 week old male rats (n=10), we performed two symmetric full-thickness cranial defects on each parietal region, and a scaffold was implanted into each cranial defect. The rats were divided into four groups: 1) collagen scaffold, 2) collagen scaffold+ferutinin at a dose of 2mg/kg/5 mL, 3) collagen scaffold + AFSCs, and 4) collagen scaffold + AFSCs + ferutinin. The rats were sacrificed after 4 weeks, and the calvariae were removed, fixed, embedded in paraffin and cut into 7 MUm thick sections. Histomorphometric measures, immunohistochemical and immunofluorescence analyses were performed on the paraffin sections. KEY FINDINGS: The histomorphometric analysis on H&E stained sections showed a significant increase in the regenerated area of the 4th group compared with the other groups. Immunohistochemistry performed with a human anti-mitochondrial antibody showed the presence of AFSCs 4 weeks after the transplant. Immunofluorescence analysis revealed the presence of osteocalcin and estrogen receptors (ERalpha and GPR30) in all groups, with a greater expression of all markers in samples where the scaffold was treated with AFSCs and the rats were orally administered ferutinin. SIGNIFICANCE: Our results demonstrated that the oral administration of ferutinin is able to improve the bone regeneration of critical-size bone defects in vivo that is obtained with collagen-AFSCs constructs. PMID- 25445218 TI - The urinary bladder of spontaneously hypertensive rat demonstrates bladder hypertrophy, inflammation, and fibrosis but not hyperplasia. AB - AIMS: The present study aims to systemically characterize the factors that are associated with urinary bladder organ enlargement in spontaneously hypertensive rats (SHR). MAIN METHODS: We compared the SHR to age-matched normotensive Wistar Kyoto (WKY) control rats in the levels of bladder pro-inflammatory factors, collagen expression (type I), and detrusor smooth muscle growth. KEY FINDINGS: Our results showed that enhanced inflammatory responses and fibrosis were key factors that were closely associated with bladder wall thickening in SHR. Specifically the mRNA levels of inflammatory factors interleukin (IL)-1alpha, IL 6 and TNFalpha were significantly higher in SHR than those in WKY rats. The SHR also had a higher number of mast cells in the suburothelium space. Type I collagen production was also significantly higher in SHR when compared to that in control rats. However, the smooth muscle content stayed the same in SHR and WKY rats. This was shown by the results that the ratio of alpha-smooth muscle actin (SMA) to the nuclear protein histone H3 had no difference between these two rat strains. The mRNA and protein levels of proliferating cell nuclear antigen (PCNA) also showed no change in the urinary bladder of SHR and WKY rats. Further study showed that the phosphorylation level of Akt in the urinary bladder was not changed in SHR when compared to WKY rats. In contrast, the phosphorylation level of ERK1/2 was significantly higher in SHR bladder when compared to that of WKY rats. SIGNIFICANCE: These results suggest that inflammation and fibrosis are primary factors that may lead to urinary bladder hypertrophy in SHR. PMID- 25445220 TI - Prenatal zinc reduces stress response in adult rat offspring exposed to lipopolysaccharide during gestation. AB - AIMS: Previous investigations by our group have shown that prenatal treatment with lipopolysaccharide (LPS; 100 MUg/kg, intraperitoneally) on gestation day (GD) 9.5 in rats, which mimics infections by Gram-negative bacteria, induces short- and long-term behavioral and neuroimmune changes in the offspring. Because LPS induces hypozincemia, dams were treated with zinc after LPS in an attempt to prevent or ameliorate the impairments induced by prenatal LPS exposure. LPS can also interfere with hypothalamic-pituitary-adrenal (HPA) axis development; thus, behavioral and neuroendocrine parameters linked to HPA axis were evaluated in adult offspring after a restraint stress session. MAIN METHODS: We prenatally exposed Wistar rats to LPS (100 MUg/kg, intraperitoneally, on GD 9.5). One hour later they received zinc (ZnSO4, 2 mg/kg, subcutaneously). Adult female offspring that were in metestrus/diestrus were submitted to a 2 h restraint stress session. Immediately after the stressor, 22 kHz ultrasonic vocalizations, open field behavior, serum corticosterone and brain-derived neurotrophic factor (BDNF) levels, and striatal and hypothalamic neurotransmitter and metabolite levels were assessed. KEY FINDINGS: Offspring that received prenatal zinc after LPS presented longer periods in silence, increased locomotion, and reduced serum corticosterone and striatal norepinephrine turnover compared with rats treated with LPS and saline. Prenatal zinc reduced acute restraint stress response in adult rats prenatally exposed to LPS. SIGNIFICANCE: Our findings suggest a potential beneficial effect of prenatal zinc, in which the stress response was reduced in offspring that were stricken with infectious/inflammatory processes during gestation. PMID- 25445221 TI - Global histone H3 lysine 27 triple methylation levels are reduced in vessels with advanced atherosclerotic plaques. AB - AIMS: Alterations in epigenetic processes are frequently noted in human disease. These epigenetic processes involve methylation of DNA and post-translational modifications of histones. It is well established that in particular histone methylation plays a key role in gene transcription. In this study, we have investigated the relationship between triple methylation of lysine 27 in histone H3 (H3K27Me3) modifications and atherosclerotic plaque stage. MATERIALS AND METHODS: 28 peri-renal aortic tissue patches covering the entire spectrum of atherosclerotic plaque development were evaluated by immunohistochemistry for the levels of H3K27Me3, EZH2, JMJD3 and BMI1. KEY FINDINGS: The results of our studies are in support of a reduction in global levels of the H3K27Me3 modification in vessels with advanced atherosclerotic plaques. This reduction in H3K27Me3 levels is not accompanied by alterations in global levels of the corresponding histone methyltransferase EZH2, the catalytic subunit of the polycomb repressive complex 2 (PRC2). Likewise no alterations in global levels of BMI1, a component of the PRC1 complex, which binds to H3K27Me3-modified histones or the global expression levels of the histone demethylase JMJD3, which removes the methyl marks on H3K27, were observed. SIGNIFICANCE: Together, our data show that in atherosclerosis development alterations in global levels of H3K27Me3 occur. The reduction in the number of nuclei in the tunica media that display the repressive H3K27Me3 mark in vessels with advanced atherosclerosis plaques therefore could be a reflection of the dynamic pattern of smooth muscle cell differentiation and proliferation associated with atherosclerotic disease. PMID- 25445222 TI - Additional noradrenergic depletion aggravates forelimb akinesia and abnormal subthalamic nucleus activity in a rat model of Parkinson's disease. AB - AIMS: This study aims to identify the contribution of additional noradrenergic depletion to forelimb akinesia and abnormal subthalamic nucleus (STN) firing activity in Parkinson's disease (PD). MAIN METHODS: Forelimb akinesia behaviors were tested in awake rats with noradrenergic N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP-4) lesions, unilateral 6-hydroxydopamine (6-OHDA) lesions in the substantia nigra pars compacta (SNc) and with combined 6-OHDA and DSP-4 lesions. STN extracellular single-unit and local field potential (LFP) activities were examined in the animals that were anesthetized with urethane. KEY FINDINGS: The adjusting steps and the contralateral touches of rats in the forelimb akinesia behavior tests were markedly inhibited by a further noradrenergic lesion with DSP-4 in 6-OHDA+DSP-4-lesioned group when compared with those of 6-OHDA lesioned animals (P<0.05 for all comparisons). Meanwhile, the neuronal firing pattern of STN also changed significantly towards more bursty in 6-OHDA + DSP-4 lesioned group (P <0 .05). Compared with 6-OHDA-lesioned animals, an additional noradrenergic lesion increased the 0.3-2.5 Hz oscillatory activity and the spike power of STN neurons (P < 0.01 for both comparisons), and strengthened the synchronized oscillation between subthalamic neuronal firing and LFP activity in 6-OHDA + DSP-4-lesioned group (P < 0.01). SIGNIFICANCE: The results provide evidence to support the correlation between noradrenergic depletion and the further exaggerated dysfunction of STN electrical activity in PD and suggest that an aberrant noradrenergic system might play a specific role in the motor deficits of PD. PMID- 25445223 TI - EGFR inhibitor-driven endoplasmic reticulum stress-mediated injury on intestinal epithelial cells. AB - AIMS: The aim of this study is to understand the underlying mechanisms regulating the adverse effect of diarrhea caused by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). MAIN METHODS: We comparatively examined the effects of two EGFR-TKIs, gefitinib and icotinib, on intestinal epithelial cells (IEC-6). Cell proliferation was measured using MTT analysis. Expression of multiple cytokines was assayed by real-time PCR. Cell cycle and apoptosis of IEC were evaluated using flow cytometry. Protein levels were determined by Western blot. KEY FINDINGS: These two EGFR-TKIs exerted cytotoxicity to inhibit proliferation and induce apoptosis in IEC-6 cells. These effects are due to the ability of these EGFR-TKIs to cause cell cycle arrest at G0/G1 by regulating the expression of cyclin D1 and p27. In addition, gefitinib and icotinib significantly suppressed the levels of cell adhesion molecules while increasing the expression of the proinflammatory cytokines interleukin (IL)-6 and IL-25. Finally, these EGFR-TKIs triggered an endoplasmic reticulum (ER) stress response, characterized by the activation of the RNA dependent protein kinase-like ER kinase (PERK) pathway and the transcriptional induction of XBP-1 signaling, resulting in ER-mediated cell death. Moreover, gefitinib exerted more cytotoxicity than icotinib on IEC-6 cells. SIGNIFICANCE: Because diarrhea is a common adverse event occurring in patients receiving small-molecular EGFR-TKI chemotherapy, the results of this study are clinically significant. The finding that icotinib exerts less cytotoxic activity than gefitinib on IEC-6 cells indicates its usefulness as a less toxic treatment option for non-small-cell lung cancer. PMID- 25445224 TI - Competitive regulation of human intestinal beta-carotene 15,15'-monooxygenase 1 (BCMO1) gene expression by hepatocyte nuclear factor (HNF)-1alpha and HNF-4alpha. AB - AIM: Among the pro-vitamin A carotenoids, beta-carotene is an excellent source of vitamin A. beta-Carotene 15,15'-monooxygenase 1 (BCMO1) is a critical enzyme involved in the conversion of beta-carotene into vitamin A (retinal) in the small intestine of many vertebrates. In the present study, we investigated the regulation of human BCMO1 gene expression using human intestinal Caco-2 BBe cells. MAIN METHODS: We performed electrophoretic mobility shift assays and chromatin immunoprecipitation assays to investigate the binding properties of hepatocyte nuclear factor (HNF)-1alpha and HNF-4alpha to the proximal promoter of the human BCMO1 gene. Caco-2 BBe cells were also transfected with HNF-1alpha and HNF-4alpha siRNAs, and BCMO1 gene expression levels and promoter activity were analyzed by real-time reverse transcription-polymerase chain reaction and luciferase reporter assays, respectively. KEY FINDINGS: We identified overlapping binding sites for HNF-1alpha and HNF-4alpha in the human BCMO1 gene proximal promoter. Endogenous nuclear HNF-1alpha and HNF-4alpha proteins competitively bound these sites in Caco-2 BBe cells. BCMO1 gene expression levels and promoter activity were significantly decreased in HNF-1alpha siRNA-transfected Caco-2 BBe cells. In contrast, HNF-4alpha siRNA-transfected cells exhibited a significant increase in BCMO1 gene expression and promoter activity. Mutation of these overlapping binding sites dramatically decreased BCMO1 promoter activity. SIGNIFICANCE: Our study indicates that the competitive actions of HNF-1alpha and HNF-4alpha on their overlapping binding sites in the human BCMO1 gene promoter oppositely regulate BCMO1 gene expression in the human small intestine. PMID- 25445225 TI - Multi-drug resistance protein (Mrp) 3 may be involved in resveratrol protection against methotrexate-induced testicular damage. AB - AIMS: To investigate the effect of resveratrol (RES) on methotrexate (MTX) induced testicular damage. MAIN METHODS: RES (10mg/kg/day) was given for 8 days orally and MTX (20mg/kg i.p.) was given at day 4 of the experiment, with or without RES in rat. KEY FINDINGS: MTX decreased serum testosterone, induced histopathological testicular damage, and increased testicular tumor necrosis factor-alpha level and expression of nuclear factor-kappaB and cyclooxygenase-2. In MTX/RES group, significant reversal of these parameters was noticed, compared to MTX group. Testicular expression of multidrug resistance protein (Mrp) 3 was three- and five-folds higher in RES- and MTX/RES-treated groups, respectively. In vitro, using prostate cancer cells, each of MTX and RES alone induced cytotoxicity with IC50 0.18 +/- 0.08 and 20.5 +/- 3.6 MUM, respectively. RES also significantly enhanced cytotoxicity of MTX. SIGNIFICANCE: Thus, RES has dual beneficial effects, as it promotes MTX tumor cytotoxicity, while protecting the testes, probably via up-regulation of testicular Mrp3 as a novel mechanism. PMID- 25445226 TI - Corn silk maysin induces apoptotic cell death in PC-3 prostate cancer cells via mitochondria-dependent pathway. AB - AIMS: Despite recent advances in prostate cancer diagnostics and therapeutics, the overall survival rate still remains low. This study was aimed to assess potential anti-cancer activity of maysin, a major flavonoid of corn silk (CS, Zea mays L.), in androgen-independent human prostate cancer cells (PC-3). MAIN METHODS: Maysin was isolated from CS of Kwangpyeongok, a Korean hybrid corn, via methanol extraction and preparative C18 reverse phase column chromatography. Maysin cytotoxicity was determined by either monitoring cell viability in various cancer cell lines by MTT assay or morphological changes. Apoptotic cell death was assessed by annexin V-FITC/PI double staining, depolarization of mitochondrial membrane potential (MMP), expression levels of Bcl-2 and pro-caspase-3 and by terminal transferase mediated dUTP-fluorescein nick end labeling (TUNEL) staining. Underlying mechanism in maysin-induced apoptosis of PC-3 cells was explored by evaluating its effects on Akt and ERK pathway. KEY FINDINGS: Maysin dose-dependently reduced the PC-3 cell viability, with an 87% reduction at 200 MUg/ml. Maysin treatment significantly induced apoptotic cell death, DNA fragmentation, depolarization of MMP, and reduction in Bcl-2 and pro-caspase-3 expression levels. Maysin also significantly attenuated phosphorylation of Akt and ERK. A combined treatment with maysin and other known anti-cancer agents, including 5-FU, etoposide, cisplatin, or camptothecin, synergistically enhanced PC-3 cell death. SIGNIFICANCE: These results suggested for the first time that maysin inhibits the PC-3 cancer cell growth via stimulation of mitochondria dependent apoptotic cell death and may have a strong therapeutic potential for the treatment of either chemo-resistant or androgen-independent human prostate cancer. PMID- 25445227 TI - Docosahexaenoic acid induces M2 macrophage polarization through peroxisome proliferator-activated receptor gamma activation. AB - AIMS: Impaired resolution of acute inflammation results in development of chronic inflammatory disorders such as atherosclerosis, asthma and arthritis. Clearance of apoptotic neutrophils by M2 macrophages, the process termed efferocytosis, is critical for complete resolution of inflammation as it prevents secondary necrosis caused by disgorgement of toxic contents from apoptotic cells in the inflamed site. In the present study, we investigated the effect of docosahexaenoic acid (DHA) on efferocytosis. MAIN METHODS: To determine the effect of DHA on efferocytosis, murine macrophage-like RAW264.7 cells were co incubated with apoptotic Jurkat T cells, and efferocytosis was assessed by flow cytometry. The expression and production of M1 and M2 markers were determined by RT-PCR, ELISA and flow cytometry. To demonstrate the involvement of peroxisome proliferator-activated receptor gamma (PPARgamma) in DHA-mediated effects, siRNA against PPARgamma was utilized. The expression of PPARgamma was examined by semiquantitative reverse-transcription polymerase chain reaction (RT-PCR), Western blot analysis and immunocytochemistry. The PPARgamma activation was measured by the electrophilic gel shift assay. KEY FINDINGS: DHA enhanced the efferocytic ability of RAW264.7 cells, and induced their M2 polarization. Notably, knockdown of PPARgamma abolished the stimulatory effect of DHA on M2 polarization as well as efferocytosis. Furthermore, lipopolysaccharide-induced production of pro-inflammatory cytokines was significantly inhibited by DHA, suggesting that DHA alters the macrophage phenotype in favor of M2 while it suppresses M1 polarization. SIGNIFICANCE: These findings indicate that DHA can promote resolution of inflammation by facilitating efferocytosis through M2 macrophage polarization. Therefore, DHA may have a therapeutic potential in the management of inflammatory diseases which are related to impaired resolution of inflammation. PMID- 25445229 TI - Aldosterone determination: comparison of a RIA assay and a CLIA assay. AB - OBJECTIVE: To extend knowledge about the clinical performances of a new chemiluminescent immunoassay (CLIA) for aldosterone set up in available analysers. DESIGN AND PATIENTS: We compared the results of a RIA assay to those of a CLIA assay in 198 serum and 80 urine samples from patients in endocrine and hypertension departments. Furthermore, for serum samples the concordance of results for postural tests was analysed. RESULTS: RIA and CLIA aldosterone serum concentration was linearly correlated with a slope of 0.988 and an intercept of 70.4pmol/L. The variations of aldosterone serum concentration obtained with the two assays during postural tests were very consistent. There was no significant difference of aldosterone concentrations after thawing with the CLIA assay. RIA and CLIA aldosterone urine concentrations were linearly correlated with a slope of 0.787 and an intercept of -2.64nmol/L. Omitting the preservative boric acid from urine samples did not modify aldosterone concentration at least up to 48h after collection. CONCLUSION: The RIA and CLIA assays were well correlated for the most useful serum samples. It is well suited to circumvent isotopic assays with the throughput of available analysers. PMID- 25445228 TI - The diagnostic value of cerebrospinal fluids procalcitonin and lactate for the differential diagnosis of post-neurosurgical bacterial meningitis and aseptic meningitis. AB - OBJECTIVES: Distinguishing between post-neurosurgical bacterial meningitis (PNBM) and aseptic meningitis is difficult. This study aims to evaluate the combined diagnostic value of CSF procalcitonin and lactate as novel PNBM markers in hospitalized post-neurosurgery patients. DESIGN AND METHODS: This study was performed using CSF samples, collected by lumbar puncture, from 178 PNBM suspected patients enrolled in a retrospective clinical study. The levels of CSF procalcitonin and lactate were appropriately assayed and the combined diagnostic value of these markers was assessed using receiver operating characteristic (ROC) curves, a two by two table, and non-parametric tests. RESULTS: Fifty of the 178 patients were diagnosed with PNBM, based on the clinical symptoms and laboratory results. These PNBM patients showed significantly elevated levels of CSF procalcitonin and CSF lactate compared with the non-PNBM group (p<0.001 for both). It was revealed that the cut-off values for the diagnosis of PNBM were: 0.075ng/mL (sensitivity, 68%; specificity, 73%) for procalcitonin and 3.45mmol/L (sensitivity, 90%; specificity, 85%) for lactate. A serial test combining the levels of these two markers showed decreased sensitivity (64%) and increased specificity (91%), compared with either marker alone. In contrast, a parallel test combining the levels of these both markers showed increased sensitivity (96%) and decreased specificity (65%), compared with either marker alone. CONCLUSION: Our study shows that the combined use of CSF procalcitonin and lactate can reliably distinguish between PNBM and non-PNBM and can be included in the design of diagnostic approaches to circumvent the shortcomings of conventional methods. PMID- 25445230 TI - Association of serum adiponectin with diabetic microvascular complications among south Indian type 2 diabetic subjects - (CURES-133). AB - OBJECTIVES: To assess the association of serum adiponectin and microvascular complications of diabetes in an urban south Indian type 2 diabetic population. DESIGN AND METHODS: Diabetic subjects [n=487] were included from Chennai Urban Rural Epidemiology Study (CURES). Four-field stereo retinal color photography was done and diabetic retinopathy (DR) was classified as non-proliferative DR (NPDR) or proliferative DR (PDR) according to the Early Treatment Diabetic Retinopathy Study grading system. Sight threatening DR (STDR) was defined as the presence of NPDR with diabetic macular edema, and/or PDR. Neuropathy was diagnosed if vibratory perception threshold of the great toe using biothesiometry exceeded >=20V. Nephropathy was diagnosed if urinary albumin excretion (UAE) was >=30MUg/mg creatinine. Serum total adiponectin levels were measured by radioimmunoassay. RESULTS: Subjects with any microvascular complications had significantly higher levels of adiponectin levels compared to those without the complications (geometric mean: 6.1 vs. 5.3MUg/mL, p=0.004). The adiponectin level was significantly higher in subjects with DR (6.8 vs. 5.5MUg/mL, p=0.004) and neuropathy (5.6 vs. 6.5MUg/mL, p=0.024) compared to those without. Adiponectin levels were not significantly different in subjects with and without nephropathy. Serum adiponectin levels increased with the severity of DR [No DR - 5.5MUg/mL; NPDR without DME - 6.5MUg/mL; STDR - 8.3MUg/mL, p=0.001]. Regression analysis revealed adiponectin to be associated with microvascular disease (presence of neuropathy and/or retinopathy and/or nephropathy) (OR: 1.44, 95% CI: 1.01-2.06, p=0.049) even after adjusting for age, gender, BMI, HbA1c, diabetes of duration, serum cholesterol and triglycerides, hypertension and medication status. CONCLUSION: In Asian Indians with type 2 diabetes, serum adiponectin levels are associated with microvascular complications and also with the severity of retinopathy. PMID- 25445231 TI - Evidence against implant-derived cobalt toxicity: case report and retrospective study of serum cobalt concentrations in an orthopedic implant population. AB - OBJECTIVES: Cobalt (Co) exposure has been documented to result in increased erythropoiesis. To evaluate the potential for implant-derived Co toxicity, we examined the relationship between serum Co (sCo) and erythrocyte counts (ERY) in a metal-containing total-hip arthroplasty implant population. METHODS: Retrospective review of sCo concentrations identified 77 patients with concomitant ERY. Statistical analysis was performed to determine if there was a significant difference in ERY for patients divided into clinically relevant sCo ranges. A single detailed case review of a patient with a loose mal-positioned acetabular component and significantly elevated sCo was also performed for symptoms thought to arise from Co toxicity. RESULTS: Statistical difference in ERY was not observed between patients with significantly elevated (>10 ng/mL), elevated (4-10 ng/mL), modestly elevated (1.0-3.9 ng/mL), or normal (<1.0 ng/mL) sCo. While the detailed case report was unremarkable for any of the clinical symptoms previously reported to be associated with Co toxicity and no increase in ERY was observed, this patient's sCo was 84 ng/mL. CONCLUSIONS: Increased erythropoiesis was not observed in patients with implant-derived increased sCo. Even with a sCo 100 * the upper-limit of normal, the patient presented did not have increased ERY nor exhibit any symptoms ascribed with Co toxicity. PMID- 25445232 TI - Fasting serum dipeptidyl peptidase-4 activity is independently associated with alanine aminotransferase in type 1 diabetic patients. AB - OBJECTIVES: Dipeptidyl peptidase-4 (DPP4) was recently proposed as a novel adipokine linked to insulin resistance (IR). As IR represents a cluster of disorders in hepatic and muscle cell insulin signalisation, we aimed to assess the possible correlation between fasting serum DPP4 activity, IR and liver enzymes in order to elucidate the question of hepatic contribution to serum DPP4 activity. DESIGN AND METHODS: This cross-sectional study comprised 44 T1DM patients aged 18 to 65years. IR was estimated using the equation derived from euglycemic-hyperinsulinemic clamp studies-estimated glucose disposal rate (eGDR). DPP4 serum activity was determined spectrophotometrically as a rate of cleavage of 7-amino-4-methyl coumarin (AMC) from H-Gly-Pro-AMC. The patients were divided into two groups according to the mean value of fasting serum DPP4 activity (31.42U/L). RESULTS: The group with lower fasting serum DPP4 activity had lower mean rate of liver biomarkers alanine aminotransferase (ALT) (p=0.001) and aspartate aminotransferase (AST) (p=0.002) while higher eGDR (p=0.003) compared to group with higher DPP4 activity. DPP4 activity showed positive correlation with AST (r=0.358, p=0.017) and ALT (r=0.364, p=0.015) while negative correlation with eGDR (r=-0.612, p<0.001). ALT remained positively associated with fasting serum DPP4 activity after controlling for age, gender, diabetes duration, the use of statins and antihypertensives (p=0.025). CONCLUSIONS: Fasting serum DPP4 activity might be associated with hepatic IR in T1DM patients and a part of soluble DPP4 activity might be of a hepatic origin. Further study investigation is warranted to elucidate this topic. PMID- 25445233 TI - Clinical decision limits for interpretation of direct bilirubin--a CALIPER study of healthy multiethnic children and case report reviews. AB - OBJECTIVE: Measurement of total and direct bilirubin is routinely performed for the differential diagnosis of hyperbilirubinemias. The diagnostic efficiency of a test is dependent on the chosen clinical decision limit. This study is designed to address the clinical decision limits for direct bilirubin. DESIGN AND METHODS: Routine laboratory method was used to measure total and direct bilirubin in children up to the age of 18years. Case study data and serum from a group of healthy children were analyzed and statistical exercise was performed to establish decision limits. RESULTS: The reference interval for total bilirubin was 1-12MUmol/L and for direct bilirubin 1-9MUmol/L with the median direct bilirubin of 3MUmol/L. In 17% of children with non-pathological jaundice, median total bilirubin was 173MUmol/L, median direct bilirubin was 8MUmol/L and median direct bilirubin percent was 49%. From birth direct bilirubin percentage decreased until total bilirubin was 41MUmol/L, then it remained at <=10%. Albumin increased with age, and was on average 2.4g/L higher when measured using bromocresol-green compared with bromocresol-purple. An increased amount of direct bilirubin was observed when albumin (detected using the bromocresol-purple method) was >35g/L. CONCLUSIONS: Direct bilirubin concentration of >=10MUmol/L should be used to consider the presence of conjugated hyperbilirubinemia provided that total bilirubin is also above the reference interval. A high direct bilirubin percentage is unlikely to offer any clinical value when total bilirubin is not increased. It is, however, a useful diagnostic tool when there is a persistence of hyperbilirubinemia or when total bilirubin increases during times of stress with direct bilirubin >10%. PMID- 25445235 TI - Serum nitrate and nitrite levels in patients with hypertension and ischemic stroke depend on diet: a multicenter study. AB - OBJECTIVES: Nitric oxide, NO, is the key vasorelaxing agent produced by vascular endothelium. Stable end products of NO oxidation, nitrate and nitrite (NOx), are considered as markers of endothelial dysfunction associated with hypertension. Our goal was to compare NOx levels in patients with hypertension on controlled low nitrate diet with NOx levels in general population without dietary restrictions. PATIENTS AND METHODS: The study included 1005 participants split into 8 groups: healthy subjects (n=28) and patients with moderate (n=37) and malignant hypertension (n=24) on low nitrate diet; healthy subjects (n=9) and patients with stroke (n=44) on low nitrate diet; normotensive subjects (n=354) and patients with elevated blood pressure (n=430) and severe hypertension (n=79) without dietary restrictions. RESULTS: In groups with controlled low NOx diet, patients with moderate and malignant hypertension had significantly (p<0.01) higher serum NOx versus healthy subject (66.9+/-18.8MUM and 75.3+/-22.7MUM versus 52.8+/-28.8MUM, respectively). Patients with stroke had significantly (p=0.02) higher serum NOx levels versus corresponding group of healthy subjects (106.3+/ 58.4MUM versus 71.2+/-18.1MUM, respectively). In the absence of dietary control, differences in serum NOx levels between normotensive subjects and patients with elevated blood pressure and severe hypertension were not significant (p>0.1). CONCLUSION: Differences in serum NOx concentrations are associated with severity of hypertension only in patients on low nitrate diet. The highest concentrations of NOx were observed in patients with stroke. In the absence of dietary control, NOx levels were not associated with presence or severity of hypertension. PMID- 25445236 TI - Decreasing troponin turnaround time in the emergency department using the central laboratory: A process improvement study. AB - OBJECTIVES: To implement collaborative process improvement measures to reduce emergency department (ED) troponin turnaround time (TAT) to less than 60min using central laboratory. DESIGN AND METHODS: This was an observational, retrospective data study. A multidisciplinary team from the ED and laboratory identified opportunities and developed a new workflow model. Process changes were implemented in ED patient triage, staffing, lab collection and processing. Data collected included TAT of door-to-order, order-to-collect, collect-to-received, received-to-result, door-to-result, ED length of stay, and hemolysis rate before (January-August, 2011) and after (September 2011-June 2013) process improvement. RESULTS: After process improvement and implementation of the new workflow model, decreased median TAT (in min) was seen in door-to-order (54 [IQR43] vs. 11 [IQR20]), order-to-collect (15 [IQR 23] vs. 10 [IQR12]), collect-to-received (6 [IQR8] vs. 5 [IQR5]), received-to-result (30 [IQR12] vs. 24 [IQR11]), and overall door-to-result (117 [IQR60] vs. 60 [IQR40]). A troponin TAT of <60min was realized beginning in May 2012 (59 [IQR39]). Hemolysis rates decreased (14.63+/ 0.74 vs. 3.36+/-1.99, p<0.0001), as did ED length of stay (5.87+/-2.73h vs. 5.15+/-2.34h, p<0.0001). Conclusion Troponin TAT of <60min using a central laboratory was achieved with collaboration between the ED and the laboratory; additional findings include a decreased ED length of stay. PMID- 25445234 TI - Use of biomarkers for the assessment of chemotherapy-induced cardiac toxicity. AB - OBJECTIVES: To review the evidence for the use of various biomarkers in the detection of chemotherapy associated cardiac damage. DESIGN AND METHODS: Pubmed.gov was queried using the search words chemotherapy and cardiac biomarkers with the filters of past 10years, humans, and English language. An emphasis was placed on obtaining primary research articles looking at the utility of biomarkers for the detection of chemotherapy-mediated cardiac injury. RESULTS: Biomarkers may help identify patients undergoing treatment who are at high risk for cardiotoxicity and may assist in identification of a low risk cohort that does not necessitate continued intensive screening. cTn assays are the best studied biomarkers in this context and may represent a promising and potentially valuable modality for detecting cardiac toxicity in patients undergoing chemotherapy. Monitoring cTnI levels may provide information regarding the development of cardiac toxicity before left ventricular dysfunction becomes apparent on echocardiography or via clinical symptoms. A host of other biomarkers have been evaluated for their utility in the field of chemotherapy related cardiac toxicity with intermittent success; further trials are necessary to determine what role they may end up playing for prediction and prognostication in this setting. CONCLUSIONS: Biomarkers represent an exciting potential complement or replacement for echocardiographic monitoring of chemotherapy related cardiac toxicity which may allow for earlier realization of the degree of cardiac damage occurring during treatment, creating the opportunity for more timely modulation of therapy. PMID- 25445237 TI - Role of TGF-beta signaling pathway on Tenascin C protein upregulation in a pilocarpine seizure model. AB - Seizures have been shown to upregulate the expression of numerous extracellular matrix molecules. Tenascin C (TNC) is an extracellular matrix protein involved in several physiological roles and in pathological conditions. Though TNC upregulation has been described after excitotoxins injection, to date there is no research work on the signal transduction pathway(s) participating in TNC protein overproduction. The aim of this study was to evaluate the role of TGF-beta signaling pathway on TNC upregulation. In this study, we used male rats, which were injected with saline or pilocarpine to induce status epilepticus (SE) and killed 24h, 3 and 7 days after pilocarpine administration. For evaluating biochemical changes, we measured protein content of TNC, TGF-beta1 and phospho Smad2/3 for localization of TNC in coronal brain hippocampus at 24h, 3 and 7 days after pilocarpine-caused SE. We found a significant increase of TNC protein content in hippocampal homogenates after 1, 3, and 7 days of pilocarpine-caused SE, together with an enhancement of TNC immunoreactivity in several hippocampal layers and the dentate gyrus field where more dramatic changes occurred. We also observed a significant enhancement of protein content of both the TGF-beta1 and the critical downstream transduction effector phospho-Smad2/3 throughout the chronic exposure. Interestingly, animals injected with SB-431542, a TGF-beta-type I receptor inhibitor, decreased TNC content in cytosolic fraction and diminished phospho-Smad2/3 content in both cytoplasmic and nuclear fraction compared with pilocarpine vehicle-injected. These findings suggest the participation of TGF beta signaling pathway on upregulation of TNC which in turn support the idea that misregulation of this signaling pathway produces changes that may contribute to disease. PMID- 25445238 TI - Differences in graph theory functional connectivity in left and right temporal lobe epilepsy. AB - PURPOSE: To investigate lateralized differences in limbic system functional connectivity between left and right temporal lobe epilepsy (TLE) using graph theory. METHODS: Interictal resting state fMRI was performed in 14 left TLE patients, 11 right TLE patients, and 12 controls. Graph theory analysis of 10 bilateral limbic regions of interest was conducted. Changes in edgewise functional connectivity, network topology, and regional topology were quantified, and then left and right TLE were compared. RESULTS: Limbic edgewise functional connectivity was predominantly reduced in both left and right TLE. More regional connections were reduced in right TLE, most prominently involving reduced interhemispheric connectivity between the bilateral insula and bilateral hippocampi. A smaller number of limbic connections were increased in TLE, more so in left than in right TLE. Topologically, the most pronounced change was a reduction in average network betweenness centrality and concurrent increase in left hippocampal betweenness centrality in right TLE. In contrast, left TLE exhibited a weak trend toward increased right hippocampal betweenness centrality, with no change in average network betweenness centrality. CONCLUSION: Limbic functional connectivity is predominantly reduced in both left and right TLE, with more pronounced reductions in right TLE. In contrast, left TLE exhibits both edgewise and topological changes that suggest a tendency toward reorganization. Network changes in TLE and lateralized differences thereof may have important diagnostic and prognostic implications. PMID- 25445240 TI - Brief asymmetric tonic posturing with diffuse low-voltage fast activity in seizures arising from the mesial parietal region. AB - AIM: Seizures originating from the parietal lobe can demonstrate variable semiology. Our aim was to describe the electroclinical features of seizures originating from the mesial parietal lobe. METHOD: We identified four patients through the Comprehensive Epilepsy Program at our institution, who had strong evidence of a mesial parietal source for their epilepsy, including a mesial parietal structural lesion. RESULTS: Patients had very frequent brief seizures despite anticonvulsants, each lasting 10-30s, with rapid return of awareness post event. Clinically attacks were bland, or showed asymmetric tonic posturing, often with partially preserved awareness. Ictal EEG showed diffuse low voltage fast activity. CONCLUSION: Seizures arising from the precuneus, in the mesial parietal lobe, appear to have a recognizable electroclinical phenotype. Although the clinical and EEG features might have been considered 'non-localizing', there is a striking similarity across patients. The precuneus is a key component of the default mode network (DMN), important for internal reflective thinking. Deactivation of this region has been found to be a prominent feature of generalized spike and wave epileptiform activity. The seizure semiology of these patients presumably reflects activation of this region, and ictal propagation along intrinsically connected components of the DMN. PMID- 25445239 TI - Passive fMRI mapping of language function for pediatric epilepsy surgical planning: validation using Wada, ECS, and FMAER. AB - In this study we validate passive language fMRI protocols designed for clinical application in pediatric epilepsy surgical planning as they do not require overt participation from patients. We introduced a set of quality checks that assess reliability of noninvasive fMRI mappings utilized for clinical purposes. We initially compared two fMRI language mapping paradigms, one active in nature (requiring participation from the patient) and the other passive in nature (requiring no participation from the patient). Group-level analysis in a healthy control cohort demonstrated similar activation of the putative language centers of the brain in the inferior frontal (IFG) and temporoparietal (TPG) regions. Additionally, we showed that passive language fMRI produced more left-lateralized activation in TPG (LI=+0.45) compared to the active task; with similarly robust left-lateralized IFG (LI=+0.24) activations using the passive task. We validated our recommended fMRI mapping protocols in a cohort of 15 pediatric epilepsy patients by direct comparison against the invasive clinical gold-standards. We found that language-specific TPG activation by fMRI agreed to within 9.2mm to subdural localizations by invasive functional mapping in the same patients, and language dominance by fMRI agreed with Wada test results at 80% congruency in TPG and 73% congruency in IFG. Lastly, we tested the recommended passive language fMRI protocols in a cohort of very young patients and confirmed reliable language specific activation patterns in that challenging cohort. We concluded that language activation maps can be reliably achieved using the passive language fMRI protocols we proposed even in very young (average 7.5 years old) or sedated pediatric epilepsy patients. PMID- 25445242 TI - Vitamin D status in anorexia nervosa: A meta-analysis. AB - OBJECTIVE: In anorexia nervosa (AN), osteoporosis and osteopenia are common, which have been associated with low circulating levels of vitamin D (VitD) in other settings. We aimed to meta-analyze cross-sectional studies reporting on VitD parameters in patients with AN and healthy controls (HCs). METHOD: Electronic PubMed search from database inception until December 31, 2013 and meta analysis of cross-sectional studies comparing serum levels of 25-hydroxyvitamin D (25OH-D), 1,25-dihydroxyvitamin D (1,25OH-D) and dietary VitD between patients with AN and HCs, before or after VitD supplementation. We calculated random effects standardized mean differences (SMDs) +/-95% confidence intervals (CIs) as effect size measures. RESULTS: Out of 1,739 initial hits, 15 studies with a total of 927 participants (AN = 408 and HCs = 519) were meta-analyzed. In the unsupplemented state, both serum 25OH-D (studies = 4; n = 168; SMD = -0.43; 95%CI: -0.83 to -0.03; p = .03) and 1,25OH-D levels (studies = 4; n = 113; SMD = 1.06; 95%CI: -1.47 to -0.66; p < .00001) were significantly lower in AN than HCs. In AN patients treated with cholecalciferol supplementation, serum 25OH-D levels were significantly higher than in HCs (studies = 5; n = 449; SMD = 0.66; 95%CI: 0.01-1.31; p = .05). Paradoxically, despite lower 25OH-D and 1,25OH-D levels, AN patients reported similar intake of VitD compared to HCs (studies = 6; n = 314; SMD = 0.33; 95%CI: -0.16, 0.81; p = .19). DISCUSSION: Although AN patients reported similar dietary VitD intake compared to HCs, AN patients had significantly lower 25OH-D and 1,25OH-D levels without supplementation. Conversely, supplementation with cholecalciferol fully normalized VitD serum levels. Future studies are needed to clarify the role of VitD supplementation in AN for improving bone health. PMID- 25445241 TI - Comparison of results obtained with standard and inside out vein graft techniques and their implication on neurotrophin expression in repair of nerve defect: an experimental study. AB - Standard vein graft (SVG) and inside out vein graft (IOVG) techniques to promote peripheral nerve regeneration have been widely studied since last two decades. In this experimental study, we attempted to compare these two techniques and analyze the differences in the expression of the neurotrophins during peripheral nerve regeneration. Thirty-six male Wistar rats were used in this sciatic nerve transection model and were divided into two experimental groups (SVG and IOVG) and one sham operated control group. An overall defect of 10 mm was made in the sciatic nerve of the animals in the experimental groups. Each group consisted of two time intervals of 6 and 12 weeks (n = 6). After each experimental interval, sciatic functional index (SFI) along with area and diameter of the axons and fibers of each group were calculated. Muscle mass measurements were also evaluated to see any functional recovery in the groups. Expression of neurotrophins in the graft and distal stump were analyzed with the help of RT PCR. SFI obtained from walking track analysis showed poor motor recovery in the experimental groups during both time intervals. No significant differences in the histological, morphometric (P > 0.05), and muscle mass measurements (P > 0.05) between the two experimental groups were observed. Analysis of RT-PCR data exhibited an increase in the expression of NT-3 with time in both the grafts (6 weeks 0.428 +/- 0.392, 12 weeks 1.089 +/- 0.455, P < 0.05) and distal stump (6 weeks 0.411 +/- 0.306, 12 weeks 0.807 +/- 0.303, P < 0.05) of the SVG group. The study concludes that there is no substantial difference in the nerve regeneration ability between both the techniques. Also, the difference in the level of NT-3 between SVG and IOVG suggests a distinct regulation of NT-3 in peripheral nerve regeneration. PMID- 25445243 TI - Decoding auditory EEG responses in healthy and clinical populations: A comparative study. AB - BACKGROUND: Analyses of brain responses to external stimuli are typically based on the means computed across conditions. However in many cognitive and clinical applications, taking into account their variability across trials has turned out to be statistically more sensitive than comparing their means. NEW METHOD: In this study we present a novel implementation of a single-trial topographic analysis (STTA) for discriminating auditory evoked potentials at predefined time windows. This analysis has been previously introduced for extracting spatio temporal features at the level of the whole neural response. Adapting the STTA on specific time windows is an essential step for comparing its performance to other time-window based algorithms. RESULTS: We analyzed responses to standard vs. deviant sounds and showed that the new implementation of the STTA gives above chance decoding results in all subjects (in comparison to 7 out of 11 with the original method). In comatose patients, the improvement of the decoding performance was even more pronounced than in healthy controls and doubled the number of significant results. COMPARISON WITH EXISTING METHOD(S): We compared the results obtained with the new STTA to those based on a logistic regression in healthy controls and patients. We showed that the first of these two comparisons provided a better performance of the logistic regression; however only the new STTA provided significant results in comatose patients at group level. CONCLUSIONS: Our results provide quantitative evidence that a systematic investigation of the accuracy of established methods in normal and clinical population is an essential step for optimizing decoding performance. PMID- 25445244 TI - Comprehensive analysis suggests simple processes underlying EEG/ERP - demonstration with the go/no-go paradigm in ADHD. AB - BACKGROUND: Current basic or more advanced methods for analysis of averaged EEG/ERP are based on assumptions on the underlying processes, which are not necessarily precise. NEW METHOD: In this work we present the findings of a method which obviates such assumptions and aims at a comprehensive analysis of the averaged EEG/ERP signal. RESULTS: For the sake of demonstration we chose the established go/no-go paradigm in the context of ADHD. Our analysis method characterized two spatiotemporally distinct neurophysiologic processes which underlie the sampled signal: one which may be related to attention and the other which may be more related to perception. COMPARISON WITH EXISTING METHOD(S): We show how these processes accord with and provide insight on the waveforms reported in the literature. CONCLUSIONS: Finally we suggest that application of our method on averaged EEG/ERP data sampled from other paradigms may point at a similarly parsimonious set of underlying neurophysiologic processes which underlie the signal. PMID- 25445245 TI - Automated tracking and analysis of behavior in restrained insects. AB - BACKGROUND: Insect behavior is often monitored by human observers and measured in the form of binary responses. This procedure is time costly and does not allow a fine graded measurement of behavioral performance in individual animals. To overcome this limitation, we have developed a computer vision system which allows the automated tracking of body parts of restrained insects. NEW METHOD: Our system crops a continuous video into separate shots with a static background. It then segments out the insect's head and preprocesses the detected moving objects to exclude detection errors. A Bayesian-based algorithm is proposed to identify the trajectory of each body part. RESULTS: We demonstrate the application of this novel tracking algorithm by monitoring movements of the mouthparts and antennae of honey bees and ants, and demonstrate its suitability for analyzing the behavioral performance of individual bees using a common associative learning paradigm. COMPARISON WITH EXISTING METHODS: Our tracking system differs from existing systems in that it does not require each video to be labeled manually and is capable of tracking insects' body parts even when working with low frame rate videos. Our system can be generalized for other insect tracking applications. CONCLUSIONS: Our system paves the ground for fully automated monitoring of the behavior of restrained insects and accounts for individual variations in graded behavior. PMID- 25445246 TI - The combination of limb-bud removal and in ovo electroporation techniques: a new powerful method to study gene function in motoneurons undergoing lesion-induced cell death. AB - BACKGROUND: The chicken embryo is an important model organism for developmental biology studies. At present, many techniques on this model have been set up, from surgical procedures to molecular biology methods, to answer capital questions of cell biology. The study of the genes involved in motoneurons (MNs) survival and cell death is critical for a better understanding of the molecular mechanisms leading to MNs degenerative diseases, such as amyothophic lateral sclerosis (ALS) and motor peripheral neuropathies. NEW METHOD: Here, we describe the combination of a well known surgical procedure able to induce MNs cell death, the limb-bud removal (LBR), with a very popular method used in molecular biology to test gene function in living organisms, the in ovo electroporation (IOE). The aim of this work is to provide an effective method for the investigation of genes involved in MNs survival and cell death under lesion conditions. RESULTS: Our method allows the successful electroporation of the 40-50% of MNs on the side of LBR with a high survival rate early and late after procedure. COMPARISON WITH OTHER METHODS: This modified LBR technique combined with IOE allows a higher MN expression efficiency compared to an already published method. CONCLUSIONS: Our work opens the possibility of screening a multitude of genes involved in MNs survival or cell death in vivo with high reproducibility and efficiency on a flexible and inexpensive animal model. The LBR/IOE technique opens a new way for the optimization of subsequent studies on mammalian models of diseases affecting MNs survival. PMID- 25445247 TI - An empirical solution for over-pruning with a novel ensemble-learning method for fMRI decoding. AB - BACKGROUND: Recent functional magnetic resonance imaging (fMRI) decoding techniques allow us to predict the contents of sensory and motor events or participants' mental states from multi-voxel patterns of fMRI signals. Sparse logistic regression (SLR) is a useful pattern classification algorithm that has the advantage of being able to automatically select voxels to avoid over-fitting. However, SLR suffers from over-pruning, in which many voxels that are potentially useful for prediction are discarded. NEW METHOD: We propose an ensemble solution for over-pruning, called "Iterative Recycling" (iRec), in which sparse classifiers are trained iteratively by recycling over-pruned voxels. RESULTS: Our simulation demonstrates that iRec can effectively rectify over-pruning in SLR and improve its classification accuracy. We also conduct an fMRI experiment in which eight healthy volunteers perform a finger-tapping task with their index or middle fingers. The results indicate that SLR with iRec (iSLR) can predict the finger used more accurately than SLR. Further, iSLR is able to identify a voxel cluster representing the finger movements in the biologically plausible contralateral primary sensory-motor cortices in each participant. We also successfully dissociated the regularly arranged representation for each finger in the cluster. CONCLUSION AND COMPARISON WITH OTHER METHODS: To the best of our knowledge, ours is the first study to propose a solution for over-pruning with ensemble-learning that is applicable to any sparse algorithm. In addition, from the viewpoint of machine learning, we provide the novel idea of using the sparse classification algorithm to generate accurate divergent base classifiers. PMID- 25445248 TI - A novel unbiased counting method for the quantification of synapses in the mouse brain. AB - BACKGROUND: The numerical density of synapses and their ultrastructural features are best assessed with electron microscopy. Counting is done within counting frames placed on a pair of sections (disector technique). But this requires that the thin sections are taken from comparable brain regions and the disectors are placed in a uniform random fashion. Small brain areas like the polymorph layer of the mouse dentate gyrus are difficult to encounter, and manually moving the microscope stage for placing the micrographs seems arbitrary. NEW METHOD: Here the polymorph layer was approximated with 20MUm thin, Nissl-stained vibratome sections. The subsequent vibratome section was processed for electron microscopy and serially thin sectioned. The microscope stage was moved using a random number generator, placing at least 20 disectors onto a pair of sections. The numerical synapse density, the numerical density of dense-core vesicles, and other ultrastructural features were compared between mice that had been kept in an enriched environment and mice kept under standard housing conditions. RESULTS: Environmental enrichment significantly decreased the numerical density of dense core vesicles and synaptic cleft widths within the polymorph layer, associated with behavioral improvement in the Morris water maze, a hippocampus-dependent task of spatial learning and memory. COMPARISON WITH EXISTING METHODS: This procedure was easy to handle and enabled us to produce thin sections in small, defined brain areas. Furthermore, placing the disectors with random numbers excluded observer bias. CONCLUSIONS: Our procedure provides an uncomplicated way of assessing numerical densities in small brain areas in an unbiased manner. PMID- 25445249 TI - Selective intra-arterial drug administration in a model of large vessel ischemia. AB - With continuing disconnect between laboratory stroke treatment models and clinical stroke therapy, we propose a novel experimental model to study stroke and vessel recanalization that mirrors acute management of large vessel stroke, with concomitant directed pharmacotherapy. Using the tandem transient ipsilateral common carotid/middle cerebral artery occlusion (MCAO) model to induce stroke in mice we then added selective intra-arterial (IA) drug administration for directed pharmacotherapy. The IA model uses micro-angio tubing placed at the bifurcation of the CCA to selectively administer the drug to the internal carotid distribution. We have shown that delivery of pharmacotherapy agents selectively through an IA injection is feasible in a mouse model, which will permit studies involving pharmacotherapy, transgenic modification, and/or a combination. Our IA model has similarities to previously published models of IA injection but differs in that we do not leave an indwelling micro-port or catheter in our animals, which is not clinically relevant as it does not reflect the human condition or current clinical management. Furthermore, we optimized our model to selectively direct therapy to the ipsilateral, stroke affected hemisphere. By developing an IA drug delivery model that mirrors clinical conditions, we are bridging the gap between basic stroke research and what is standard practice in acute ischemic stroke intervention. The IA model of drug delivery can target agents directly to the site of injury while blunting systemic effects, dose penetration issues, and administration delay that have plagued the intraperitoneal and oral drug administration models. PMID- 25445252 TI - WITHDRAWN: Alternative functional criteria to assess airflow-limitation reversibility in asthma. AB - This article has been withdrawn for editorial reasons because the journal will be published only in English. In order to avoid duplicated records, this article can be found at http://dx.doi.org/10.1016/j.rppnen.2014.08.002. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25445251 TI - High purity of human oligodendrocyte progenitor cells obtained from neural stem cells: suitable for clinical application. AB - BACKGROUND: Recent studies have suggested that the transplantation of oligodendrocyte progenitor cells (OPCs) may be a promising potential therapeutic strategy for a broad range of diseases affecting myelin, such as multiple sclerosis, periventricular leukomalacia, and spinal cord injury. Clinical interest arose from the potential of human stem cells to be directed to OPCs for the clinical application of treating these diseases since large quantities of high quality OPCs are needed. However, to date, there have been precious few studies about OPC induction from human neural stem cells (NSCs). NEW METHOD: Here we successfully directed human fetal NSCs into highly pure OPCs using a cocktail of basic fibroblast growth factor, platelet-derived growth factor, and neurotrophic factor-3. RESULTS: These cells had typical morphology of OPCs, and 80-90% of them expressed specific OPC markers such as A2B5, O4, Sox10 and PDGF alphaR. When exposed to differentiation medium, 90% of the cells differentiated into oligodendrocytes. The OPCs could be amplified in our culture medium and passaged at least 10 times. COMPARISON WITH A EXISTING METHOD: Compared to a recent published method, this protocol had much higher stability and repeatability, and OPCs could be obtained from NSCs from passage 5 to 38. It also obtained more highly pure OPCs (80-90%) via simpler and more convenient manipulation. CONCLUSIONS: This study provided an easy and efficient method to obtain large quantities of high-quality human OPCs to meet clinical demand. PMID- 25445250 TI - Towards real-time detection of seizures in awake rats with GPU-accelerated diffuse optical tomography. AB - BACKGROUND: Advancement in clinically relevant studies like seizure interruption using functional neuro imaging tools has shown that specific changes in hemodynamics precede and accompany seizure onset and propagation. However, preclinical seizure experiments need to be conducted in awake animals with images reconstructed and displayed in real-time. METHODS: This article describes an approach that can be utilized to tackle these challenges. A subject specific head interface and restraining method was designed to allow for DOT to imaging of hemodynamic changes in unanesthetized rats during evoked acute seizures. Using CUDA programming model, the finite-element based nonlinear iterative algorithm for image reconstruction was parallelized. RESULTS: Early hemodynamic changes were monitored in real time and observed tens of seconds prior to seizure onset. Utilizing the massive parallelization offered by graphic processing units (GPU), DOT was extended to online image reconstruction within 1s. COMPARISON WITH EXISTING METHODS: Pre-seizure state related hemodynamic changes were detected in awake rats. 3D monitoring of hemodynamic changes was performed in real time with our parallelized image reconstruction procedure. CONCLUSION: Diffuse optical tomography (DOT) is a promising neuroimaging tool for the investigation of seizures in awake animals. PMID- 25445253 TI - WITHDRAWN: Solitary endobronchial papilloma: A case report. AB - This article has been withdrawn for editorial reasons because the journal will be published only in English. In order to avoid duplicated records, this article can be found at http://dx.doi.org/10.1016/j.rppnen.2014.08.001. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25445254 TI - WITHDRAWN: Respiratory functional evaluation and pulmonary hyperinflation in asymptomatic smokers: Preliminary study. AB - This article has been withdrawn for editorial reasons because the journal will be published only in English. In order to avoid duplicated records, this article can be found at http://dx.doi.org/10.1016/j.rppnen.2014.07.007. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25445256 TI - Mesoporous MnCo2O4 with a flake-like structure as advanced electrode materials for lithium-ion batteries and supercapacitors. AB - A mesoporous flake-like manganese-cobalt composite oxide (MnCo2O4) is synthesized successfully through the hydrothermal method. The crystalline phase and morphology of the materials are characterized by X-ray diffraction, field emission scanning electron microscopy, transmission electron microscopy, and Brunauer-Emmett-Teller methods. The flake-like MnCo2O4 is evaluated as the anode material for lithium-ion batteries. Owing to its mesoporous nature, it exhibits a high reversible capacity of 1066 mA h g(-1), good rate capability, and superior cycling stability. As an electrode material for supercapacitors, the flake-like MnCo2O4 also demonstrates a high supercapacitance of 1487 F g(-1) at a current density of 1 A g(-1), and an exceptional cycling performance over 2000 charge/discharge cycles. PMID- 25445255 TI - Microsurgical anatomy of the posterior median septum of the human spinal cord. AB - The aim of this study was to analyze the topographical anatomy of the dorsal spinal cord (SC) in relation to the posterior median septum (PMS). This included the course and variations in the PMS, and its relationship to and distance from other dorsal spinal landmarks. Microsurgical anatomy of the PMS was examined in 12 formalin-fixed adult cadaveric SCs. Surface landmarks such as the dorsal root entry zone (DREZ), the denticulate ligament, the architecture of the leptomeninges and pial vascular distribution were noted. The PMS was examined histologically in all spinal segments. The PMS extended most deeply at spinal segments C7 and S4. This was statistically significant for all spinal segments except C5. The PMS was shallowest at segments T4 and T6, where it was statistically significantly thinner than at any other segment. In 80% of the SCs, small blood vessels were identified that traveled in a rostrocaudal direction in the PMS. The longest distance between the PMS and the DREZ was at the C1-C4 vertebral levels and the shortest distance was at the S5 level. Prevention of deficits following a dorsal midline neurosurgical approach to deep-seated SC lesions requires careful identification of the midline of the cord. The PMS and septum define the midline on the dorsum of the SC and their accurate identification is essential for a safe midline surgical approach. In this anatomical study, we describe the surface anatomy of the dorsal SC and its relationship with the PMS, which can be used to determine a safe entry zone into the SC. PMID- 25445257 TI - Selective omission of level V nodal coverage for patients with oropharyngeal cancer: Clinical validation of intensity-modulated radiotherapy experience and dosimetric significance. AB - BACKGROUND: We sought to validate the consensus recommendation and assess dosimetric significance of selective omission of nodal level V from intensity modulated radiotherapy (IMRT) clinical target volume (CTV) for oropharyngeal cancer. METHODS: IMRT plans and clinical outcomes for 112 patients with oropharyngeal cancer (nodal classification N0-N2b) were analyzed for coverage of ipsilateral and contralateral nodal level V. Additionally, new IMRT plans were generated in 6 randomly selected patients to assess its dosimetric impact. RESULTS: With median follow-up of 3.4 years, there were no failures identified in nodal level V with or without nodal level V omission. Upon dosimetric evaluation, significant reduction in integral dose, V10 Gy , V20 Gy , V30 Gy , V40 Gy , and V50 Gy was observed by excluding unilateral and bilateral level V from the CTV. CONCLUSION: We clinically validate the consensus recommendation for selective omission of level V nodal coverage in IMRT planning of patients with oropharyngeal cancer and demonstrate significant dosimetric advantages. PMID- 25445258 TI - The Role of Therapist Attachment in Alliance and Outcome: A Systematic Literature Review. AB - OBJECTIVES: This review examined the impact of therapist attachment style on therapeutic alliance and outcomes. METHODS: Systematic search procedures yielded 11 studies for inclusion that measured associations between therapist attachment style and alliance and/or outcome. RESULTS: There is some preliminary evidence that therapist attachment style and interactions between therapist and client attachment style contribute to alliance and therapy outcomes. However, methodological weaknesses and heterogeneity across studies highlight the need for more rigorously designed research in this area. CONCLUSIONS: There is sufficient evidence to suggest that therapists need to pay attention to the influence of their own attachment style in therapeutic processes and that there is merit in pursing this area of research further. The review is important in highlighting key design issues to consider in future studies. Copyright (c) 2014 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Therapist attachment style has the potential to influence therapeutic alliance and client outcome. Improvements in therapeutic practice might be achieved if therapists have greater knowledge of their own attachment styles and how these interact with their clients' attachment styles to influence the psychotherapy relationship and outcomes. From the outset of their careers, therapists should receive training and supervision to enhance the awareness of their individual attachment experiences and how these play out during the therapeutic process. PMID- 25445259 TI - Preliminary observation on the effect of baking soda volume on controlling odour from discarded organic waste. AB - Food wastes with high moisture and organic matter content are likely to emit odours as a result of the decomposition process. The management of odour from decomposing wastes is needed to sustain the interest of residents and local councils in the source separation of kitchen wastes. This study investigated the potential of baking soda (at 50 g, 75 g and 100g per kg food waste) to control odour from seven days stored food waste. It was found that 50 g of baking soda, spread at the bottom of 8l food wastes bin, can reduce the odour by about 70%. A higher amount (above 100g) is not advised as a pH higher than 9.0 may be induced leading to the volatilization of odorous ammonia. This research finding is expected to benefit the waste management sector, food processing industries as well as the local authorities where malodour from waste storage is a pressing issue. PMID- 25445260 TI - Understanding the perceptions, roles and interactions of stakeholder networks managing health-care waste: A case study of the Gaza Strip. AB - The sustainable management of waste requires a holistic approach involving a range of stakeholders. What can often be difficult is to understand the manner in which different types of stakeholder networks are composed and work, and how best to enhance their effectiveness. Using social network analysis and stakeholder analysis of healthcare waste management stakeholders in the case study region of the Gaza Strip, this study aimed to understand and examine the manner in which the networks functioned. The Ministry of Health was found to be the most important stakeholder, followed by municipalities and solid waste management councils. Some international agencies were also mentioned, with specific roles, while other local institutions had a limited influence. Finally while health-care facilities had a strong interest in waste management, they were generally poorly informed and had limited links to each other. The manner in which the networks operated was complicated and influenced by differences in perception, sharing of information, access to finance and levels of awareness. The lack of a clear legal framework generated various mistakes about roles and responsibilities in the system, and evidently regulation was not an effective driver for improvement. Finally stakeholders had different priorities according to the waste management issues they were involved with, however segregation at the source was identified as a key requirement by most. Areas for improving the effectiveness of the networks are suggested. The analysis utilized an innovative methodology, which involved a large number of stakeholders. Such an approach served to raise interest and awareness at different levels (public authorities, health providers, supporting actors, others), stimulate the discussion about the adoption of specific policies, and identify the effective way forward. PMID- 25445261 TI - Household-level dynamics of food waste production and related beliefs, attitudes, and behaviours in Guelph, Ontario. AB - It has been estimated that Canadians waste $27 billion of food annually, and that half of that waste occurs at the household level (Gooch et al., 2010). There are social, environmental, and economic implications for this scale of food waste, and source separation of organic waste is an increasingly common municipal intervention. There is relatively little research that assesses the dynamics of household food waste (particularly in Canada). The purpose of this study is to combine observations of organic, recyclable, and garbage waste production rates to survey results of food waste-related beliefs, attitudes, and behaviours at the household level in the mid-sized municipality of Guelph, Ontario. Waste weights and surveys were obtained from 68 households in the summer of 2013. The results of this study indicate multiple relationships between food waste production and household shopping practices, food preparation behaviours, household waste management practices, and food-related attitudes, beliefs, and lifestyles. Notably, we observed that food awareness, waste awareness, family lifestyles, and convenience lifestyles were related to food waste production. We conclude that it is important to understand the diversity of factors that can influence food wasting behaviours at the household level in order to design waste management systems and policies to reduce food waste. PMID- 25445262 TI - Characterisation of metals in the electronic waste of complex mixtures of end-of life ICT products for development of cleaner recovery technology. AB - Recycling of valuable metals from electronic waste, especially complex mixtures of end-of-life information and communication technology (ICT) products, is of great difficulty due to their complexity and heterogeneity. One of the important reasons is the lack of comprehensive characterisation on such materials, i.e. accurate compositions, physical/chemical properties. In the present research, we focus on developing methodologies for the characterisation of metals in an industrially processed ICT waste. The morphology, particle size distribution, compositional distribution, occurrence, liberation as well as the thermo-chemical properties of the ICT waste were investigated with various characterisation techniques, including X-ray Fluorescence Spectrometry (XRF), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) with energy dispersed spectroscopy (EDS). Due to the high heterogeneity of the material, special sample preparation procedures were introduced to minimise the discrepancies during compositional analyses. As a result, a clearer overview of the ICT waste has been reached. This research provides better understanding of the extractability of each metal and improves the awareness of potential obstacles for extraction. It will lead to smarter decisions during further development of a clean and effective recovery process. PMID- 25445263 TI - Toward environmentally-benign utilization of nonmetallic fraction of waste printed circuit boards as modifier and precursor. AB - Electronic waste, including printed circuit boards, is growing at an alarming rate due to the accelerated technological progress and the shorter lifespan of the electronic equipment. In the past decades, due to the lack of proper economic and environmentally-benign recycling technologies, a major fraction of e-waste generated was either destined to landfills or incinerated with the sole intention of its disposal disregarding the toxic nature of this waste. Recently, with the increasing public awareness over their environment and health issues and with the enaction of more stringent regulations, environmentally-benign recycling has been driven to be an alternative option partially replacing the traditional eco unfriendly disposal methods. One of the most favorable green technologies has been the mechanical separation of the metallic and nonmetallic fraction of the waste printed circuit boards. Although metallic fraction, as the most profitable component, is used to generate the revenue of the separation process, the nonmetallic fraction (NMF) has been left isolated. Herein, the recent developments in the application of NMF have been comprehensively reviewed and an eco-friendly emerging usage of NMF as a value-added material for sustainable remediation has been introduced. PMID- 25445264 TI - Expression of zma-miR169 miRNAs and their target ZmNF-YA genes in response to abiotic stress in maize leaves. AB - The miR169 miRNA family is highly conserved in plants. Its members regulate the expression of genes encoding the universal transcription factor subunit NUCLEAR FACTOR-Y subunit A (NF-YA) via transcript cleavage. NF-YA regulates gene expression by binding the CCAAT box sequence in target promoters. The miR169/NF YA module plays a critical role during plant development and in plant responses to abiotic stress. We characterized the secondary structures of maize pre-miR169 miRNAs and predicted their potential gene targets. Coexpression of zma-miR169 and ZmNF-YA in Nicotiana benthamiana demonstrated that mutations in or deletion of target sites abolished regulation by zma-miR169. Maize seedlings were subjected to short-term (0-48h) and long-term (15days) drought, abscisic acid (ABA), or salt stress. Long-term exposure to PEG (drought stress) or NaCl (salt stress) repressed seedling growth. We investigated the expression patterns of zma-miR169s and their target ZmNF-YA genes in maize leaves and found diverse changes in expression in response to the three stress treatments. The expression of most zma miR169 genes was downregulated by PEG and upregulated by ABA. In response to salt stress, zma-miR169 genes were upregulated initially and subsequently downregulated. Most ZmNF-YA genes were upregulated during the short term and downregulated by 15days in response to the three stress treatments. PMID- 25445266 TI - Molecular cloning and sequence analysis of heat shock proteins 70 (HSP70) and 90 (HSP90) and their expression analysis when exposed to benzo(a)pyrene in the clam Ruditapes philippinarum. AB - HSP70 and HSP90 are the most important heat shock proteins (HSPs), which play the key roles in the cell as molecular chaperones and may involve in metabolic detoxification. The present research has obtained full-length cDNAs of genes HSP70 and HSP90 from the clam Ruditapes philippinarum and studied the transcriptional responses of the two genes when exposed to benzo(a)pyrene (BaP). The full-length RpHSP70 cDNA was 2336bp containing a 5' untranslated region (UTR) of 51bp, a 3' UTR of 335bp and an open reading frame (ORF) of 1950bp encoding 650 amino acid residues. The full-length RpHSP90 cDNA was 2839bp containing a 107-bp 5' UTR, a 554-bp 3' UTR and a 2178-bp ORF encoding 726 amino acid residues. The deduced amino acid sequences of RpHSP70 and RpHSP90 shared the highest identity with the sequences of Paphia undulata, and the phylogenetic trees showed that the evolutions of RpHSP70 and RpHSP90 were almost in accord with the evolution of species. The RpHSP70 and RpHSP90 mRNA expressions were detected in all tested tissues in the adult clams (digestive gland, gill, adductor muscle and mantle) and the highest mRNA expression level was observed in the digestive gland compared to other tissues. Quantitative real-time RT-PCR analysis revealed that mRNA expression levels of the clam RpHSP70, RpHSP90 and other xenobiotic metabolizing enzymes (XMEs) (AhR, DD, GST, GPx) in the digestive gland of R. philippinarum were induced by benzo(a)pyrene (BaP) and the absolute expression levels of these genes showed a temporal and dose-dependent response. The results suggested that RpHSP70 and RpHSP90 were involved in the metabolic detoxification of BaP in the clam R. philippinarum. PMID- 25445265 TI - miR408 overexpression causes increased drought tolerance in chickpea. AB - Drought stress limits yield severely in most of the crops. Plants utilize complex gene regulation mechanisms to tolerate water deficiency as well as other abiotic stresses. MicroRNAs (miRNAs) are a class of small non-coding RNAs that are progressively recognized as important regulators of gene expression acting at post-transcriptional level. miR408, conserved in terrestrial plants, targets copper related genes. Although, expression level of miR408 is influenced by various environmental factors including drought stress, the biological action of miR408 is still unclear. To examine the miR408 function upon drought stress in chickpea, transgenic lines overexpressing the miR408 were generated. Induced tolerance was observed in the plants with enhanced miR408 expression upon 17-day water deficiency. Expression levels of miR408 target gene together with seven drought responsive genes were measured using qRT-PCR. Here, the involvement of miR408 in drought stress response has been reported. The overexpression leading plantacyanin transcript repression caused regulation of DREB and other drought responsive genes. PMID- 25445267 TI - Dinitrophenol modulates gene expression levels of angiogenic, cell survival and cardiomyogenic factors in bone marrow derived mesenchymal stem cells. AB - Various preconditioning strategies influence regeneration properties of stem cells. Preconditioned stem cells generally show better cell survival, increased differentiation, enhanced paracrine effects, and improved homing to the injury site by regulating the expression of tissue-protective cytokines and growth factors. In this study, we analyzed gene expression pattern of growth factors through RT-PCR after treatment of mesenchymal stem cells (MSCs) with a metabolic inhibitor, 2,4 dinitrophenol (DNP) and subsequent re-oxygenation for periods of 2, 6, 12 and 24h. These growth factors play important roles in cardiomyogenesis, angiogenesis and cell survival. Mixed pattern of gene expression was observed depending on the period of re-oxygenation. Of the 13 genes analyzed, ankyrin repeat domain 1 (Ankrd1) and GATA6 were downregulated after DNP treatment and subsequent re-oxygenations. Ankrd1 expression was, however, increased after 24h of re-oxygenation. Placental growth factor (Pgf), endoglin (Eng), neuropilin (Nrp1) and jagged 1 (Jag1) were up-regulated after DNP treatment. Gradual increase was observed as re-oxygenation advances and by the end of the re oxygenation period the expression started to decrease and ultimately regained normal values. Epiregulin (Ereg) was not expressed in normal MSCs but its expression increased gradually from 2 to 24h after re-oxygenation. No change was observed in the expression level of connective tissue growth factor (Ctgf) at any time period after re-oxygenation. Kindlin3, kinase insert domain receptor (Kdr), myogenin (Myog), Tbx20 and endothelial tyrosine kinase (Tek) were not expressed either in normal cells or cells treated with DNP. It can be concluded from the present study that MSCs adjust their gene expression levels under the influence of DNP induced metabolic stress. Their levels of expression vary with varying re oxygenation periods. Preconditioning of MSCs with DNP can be used for enhancing the potential of these cells for better regeneration. PMID- 25445268 TI - De novo characterization of the Lycium chinense Mill. leaf transcriptome and analysis of candidate genes involved in carotenoid biosynthesis. AB - Lycium chinense Mill. (Chinese wolfberry), enriching in carotenoids, is an important Chinese herbal medicine. However, studies on the functional genomics research, especially the carotenoid biosynthesis and accumulation, are limited because of insufficiently available datasets. RNA-Seq was performed by the Illumina sequencing platform. Approximately 26 million clean reads were generated after filtering. Clean reads were assembled by SOAPdenovo and subsequently annotated. Among all 61,595 unigenes, 37,816 (61.39%), 25,266 (41.02%), and 17,598 (28.57%) unigenes were annotated in NCBI non-redundant protein, Swiss Prot, and Kyoto Encyclopedia of Genes and Genomes (KEGG) database, respectively. A total of 16,073 and 11,394 unigenes were assigned to Gene Ontology and Cluster of Orthologous Group, respectively. Furthermore, the majority of genes encoding the enzymes in the carotenoid biosynthesis pathway were identified in the unigene datasets. We first found several genes related to L. chinense carotenoid biosynthesis. The expression levels and the biological functions of these genes involved in carotenoid biosynthesis in the leaf and the green ripening fruit were further confirmed by qPCR and high performance liquid chromatography (HPLC). In the present study, we first characterized the transcriptome of L. chinense leaf, which may provide useful data for functional genomics investigations in L. chinense in the future. And essential genes involved in the carotenoid biosynthesis pathway may contribute to elucidate the expression patterns in different stages of development and fruit ripening and the specific mechanisms of carotenoid biosynthesis/accumulation in L. chinense. PMID- 25445269 TI - The genetic and molecular origin of natural variation for the fragrance trait in an elite Malaysian aromatic rice through quantitative trait loci mapping using SSR and gene-based markers. AB - MRQ74, a popular aromatic Malaysian landrace, allows for charging considerably higher prices than non-aromatic landraces. Thus, breeding this profitable trait has become a priority for Malaysian rice breeding. Despite many studies on aroma genetics, ambiguities considering its genetic basis remain. It has been observed that identifying quantitative trait loci (QTLs) based on anchor markers, particularly candidate genes controlling a trait of interest, can increase the power of QTL detection. Hence, this study aimed to locate QTLs that influence natural variations in rice scent using microsatellites and candidate gene-based sequence polymorphisms. For this purpose, an F2 mapping population including 189 individual plants was developed by MRQ74 crosses with 'MR84', a non-scented Malaysian accession. Additionally, qualitative and quantitative approaches were applied to obtain a phenotype data framework. Consequently, we identified two QTLs on chromosomes 4 and 8. These QTLs explained from 3.2% to 39.3% of the total fragrance phenotypic variance. In addition, we could resolve linkage group 8 by adding six gene-based primers in the interval harboring the most robust QTL. Hence, we could locate a putative fgr allele in the QTL found on chromosome 8 in the interval RM223-SCU015RM (1.63cM). The identified QTLs represent an important step toward recognition of the rice flavor genetic control mechanism. In addition, this identification will likely accelerate the progress of the use of molecular markers for gene isolation, gene-based cloning, and marker-assisted selection breeding programs aimed at improving rice cultivars. PMID- 25445270 TI - Synergistic regulatory networks mediated by microRNAs and transcription factors under drought, heat and salt stresses in Oryza Sativa spp. AB - BACKGROUND: Transcription factors (TFs) and microRNAs (miRNAs) are primary gene regulators within the cell. Regulatory mechanisms of these two main regulators are of great interest to biologists and may provide insights into the abiotic and biotic stresses. However, the interaction between miRNAs and TFs in a gene regulatory network (GRN) still remains uncovered. Previous research has been mostly directed at inferring either miRNA or TF regulatory networks from data. However, networks involving a single type of regulator may not fully reveal the complex gene regulatory mechanisms, therefore study of interplay among these two regulators in gene regulation is important towards explaining the mechanism of different abiotic stresses. RESULT: Oligonucleotide microarrays containing 51,279 transcripts were used to identify total 133 salt responsive target genes regulated by 11 TFs that are also differentially regulated by miRNA under salinity, heat and drought stresses in Oryza sativa. TF's-target interactions which are most enriched in their downstream regulation were also identified. Many genes whose encoded proteins are implicated in response to light and radiation stimulus, hormone stimuli, oxidative stress, copper ion binding and electron transport were found to be enriched. However the majority were novel for the combined abiotic stress, which indicates that there are a great number of genes induced after the exposure these abiotic stresses and regulated by miRNA. CONCLUSION: Analysis of the expression profile data of Oryza provides clues regarding some putative cellular and molecular processes that are undertaken in response to these stresses. The study also identified a large number of candidate functional genes that appear to be constitutively involved in salt, drought and heat stresses tolerance. Further examination of these genes may enable the molecular basis of abiotic stress tolerance in Oryza, to be elucidated. PMID- 25445271 TI - PAX5 is the transcriptional activator of mucolipin-2 (MCOLN2) gene. AB - Transient receptor potential mucolipin (TRPML) proteins belong to the TRP superfamily of non-selective cation channels. The TRPML1, -2, and -3 proteins are encoded by Mucolipin (MCOLN)-1, -2 and -3 genes, respectively. TRPML1 has been associated with mucolipidosis type IV (MLIV), while no disease phenotype has been linked with TRPML2 or -3 protein. The TRPML proteins share high sequence similarities, form hetero-tetramers, and serve in membrane trafficking, autophagy, and metal homeostasis. Previous studies suggest that TRPML2 serves a role in the immune system; however, the evidence is mostly indirect. We hypothesize that if TRPML2 is involved in immune function its expression would be likely regulated by an immune-associated transcription factor protein. Thus, we set out to identify the core promoter region and the transcription factor responsible for MCOLN2 gene expression. Using dual-luciferase assay and over expression analyses, we reveal for the first time that B-cell lineage specific activator protein (BSAP), also known as paired box 5 (PAX5), controls MCOLN2 expression. Specifically, heterologous expression of PAX5 in HEK-293 cells significantly increased endogenous MCOLN2 transcript and TRPML2 protein levels, while RNA interference targeting endogenous PAX5 reduced its effect. Site directed mutagenesis studies showed that the core promoter and PAX5 binding region to be between -79 and -60 base pairs upstream of the transcriptional start site. Thus, our findings add to a growing list of evidence for TRPML2's possible involvement in the immune system. The knowledge gained from this study could be used to further characterize the role of TRPML2 in B-cell development and function. PMID- 25445272 TI - Application of the rank-based method to DNA methylation for cancer diagnosis. AB - Detecting aberrant DNA methylation as diagnostic or prognostic biomarkers for cancer has been a topic of considerable interest recently. However, current classifiers based on absolute methylation values detected from a cohort of samples are typically difficult to be transferable to other cohorts of samples. Here, focusing on relative methylation levels, we employed a modified rank-based method to extract reversal pairs of CpG sites whose relative methylation level orderings differ between disease samples and normal controls for cancer diagnosis. The reversal pairs identified for five cancer types respectively show excellent prediction performance with the accuracy above 95%. Furthermore, when evaluating the reversal pairs identified for one cancer type in an independent cohorts of samples, we found that they could distinguish different subtypes of this cancer or different malignant stages including early stage of this cancer from normal controls. The identified reversal pairs also appear to be specific to cancer type. In conclusion, the reversal pairs detected by the rank-based method could be used for accurate cancer diagnosis, which are transferable to independent cohorts of samples. PMID- 25445274 TI - Molecular cloning, characterization, and expression of sheep FGF5 gene. AB - The fibroblast growth factor 5 gene (FGF5) is a member of the FGF gene family, and represents a candidate gene for hair length because of its role in the regulation of the hair follicle growth cycle. In our current study, we cloned, sequenced, and characterized the full-length FGF5 cDNA of Chinese Merino sheep. We obtained the complete genomic sequence of the FGF5 gene from sheep blood samples, and compared it to other FGF5 sequences in GenBank. We found that the FGF5 gene spanned 21,743bp of genomic DNA, and consisted of 3 exons and 2 introns, both of which differed from those of a previously annotated FGF5 genomic sequence from sheep. We also identified a previously undescribed FGF5 mRNA splicing variant, FGF5S, and the western blot analysis showed that the molecular weights of the FGF5 (34kDa) and FGF5s (17kDa) proteins were consistent with the estimates based on the genomic and cDNA sequence data. We examined the expression of both FGF5 mRNAs in various tissues of sheep, and found that the expression of the FGF5S mRNA was restricted to the brain, spleen, and skin tissue. The single nucleotide polymorphism analysis of the genomic sequence revealed 72 genetic variants of the FGF5 gene. Our findings provide insight into the functions of the FGF5 gene in Chinese Merino. PMID- 25445273 TI - Functional divergence of eukaryotic RNA polymerases: unique properties of RNA polymerase I suit its cellular role. AB - Eukaryotic cells express at least three unique nuclear RNA polymerases. The selective advantage provided by this enhanced complexity is a topic of fundamental interest in cell biology. It has long been known that the gene targets and transcription initiation pathways for RNA polymerases (Pols) I, II and III are distinct; however, recent genetic, biochemical and structural data suggest that even the core enzymes have evolved unique properties. Among the three eukaryotic RNA polymerases, Pol I is considered the most divergent. Transcription of the ribosomal DNA by Pol I is unmatched in its high rate of initiation, complex organization within the nucleolus and functional connection to ribosome assembly. Furthermore, ribosome synthesis is intimately linked to cell growth and proliferation. Thus, there is intense selective pressure on Pol I. This review describes key features of Pol I transcription, discusses catalytic activities of the enzyme and focuses on recent advances in understanding its unique role among eukaryotic RNA polymerases. PMID- 25445275 TI - The homologous genes Vangl1 and Vangl2 are required for embryo implantation in the uterus of mice during early pregnancy. AB - Vangl1 and Vangl2 are homologous genes belonging to the group of highly conserved planar cell polarity proteins. It has been shown that Vangl1 and Vangl2 are essential for embryonic development, cell adhesion, migration and polarity. We examined the expression of Vangl1 and Vangl2 in the uterus of mice during early pregnancy. They are upregulated in the endometrium of peri-implantation and reached the peak on D5. Vangl1 mRNA is widely distributed in the luminal epithelium, glandular epithelium and stromal cells in the endometrium, while its protein only appeared in the stromal cells. The localization of Vangl2 protein overlapped with its mRNA. In addition, expression of Vangl1 in the endometrium of pseudopregnant mice was lower than that of pregnant mice, whereas the level of Vangl2 was not significantly different, suggesting that expression of Vangl1 is induced by embryo. Further study showed that implantation would be suppressed after silencing expressions of Vangl1 and Vangl2 by uterine injection with antisense oligonucleotides. These findings suggest that Vangl1 and Vangl2 may play a key role in the embryo implantation of mice. PMID- 25445276 TI - Effects of ADAM10 deletion on Notch-1 signaling pathway and neuronal maintenance in adult mouse brain. AB - A disintegrin and metalloproteinase 10 (ADAM10) has been demonstrated to regulate embryonic brain development by initiating Notch signaling. However, it is still unclear whether ADAM10 is required to activate the Notch signaling pathway in adult brain. To investigate the physiological role of ADAM10, we generated conditional knockout (cKO) mice lacking the Adam10 gene primarily in the cortex and hippocampus. We found that conditional disruption of ADAM10 resulted in a prominent decrease in the number of proliferating neuronal progenitor cells in the subgranular zone (SGZ), and a significant increase in the number of adult generated postmitotic neurons in the hippocampal dentate gyrus (DG) due to premature neuronal differentiation. Moreover, the mutant mice also displayed an age-dependent reduction in the number of granule neurons in the hippocampal DG. It was further showed that the activation of Notch-1 and its downstream target genes Hes1, Hes5, Hey1, and Hey2 was impaired in ADAM10-deficient hippocampal tissues. Finally, Adam10 cKO mice had impaired learning and memory in the Morris water-maze. Thus, we provided experimental evidence to demonstrate that ADAM10 plays an essential role in the activation of Notch-1 signaling and has a remarkable effect on neuronal maintenance in adult mouse brain. PMID- 25445277 TI - A 5'-3' terminal stem in small non-coding RNAs extends their lifetime. AB - 4.5SI and 4.5SH are two non-coding RNAs about 100nt long, synthesized by RNA polymerase III in cells of various rodents including mice, rats, and hamsters. The first RNA is long-lived whereas the half-life of the second is only 20min. We previously found that the 16bp double-stranded structure (stem), formed by 4.5SI RNA termini, contributes essentially to the long lifetime of this RNA (Koval et al., 2012). The rapid decay of 4.5SH RNA seems to be related to the lack of a similar structure in this RNA. The aim of this work was to verify whether the lifetime of any other short-lived non-coding RNA can be prolonged following creation of the double-stranded structure with its terminal regions. Here RNAs transcribed by RNA polymerase III from short interspersed elements (SINEs) B2 and Rhin-1 from the genomes of mouse and horseshoe bat, respectively, were used. Replacement of 16nt at the 3'-terminal region by the sequence complementary to the 5' end region of B2 and Rhin-1 RNA increased their half-life more than 4 fold. In addition, we demonstrated that shortening of the terminal stem from 16 to 8bp decreased only slightly the 4.5SI RNA lifetime. Finally, we showed that the disruption of an internal (non-terminal) stem in 4.5SI RNA did not accelerate its decay in cells. Possible mechanisms of the small non-coding RNA lifetime extension are discussed. PMID- 25445278 TI - Stress responses to trichlorophenol in Arabidopsis and integrative analysis of alteration in transcriptional profiling from microarray. AB - Trichlorophenols, also known as TCPs, are one of the most persistent environmental pollutants. It is a matter of concern as they are toxic and cumulative in soil and water bodies which could lead to serious consequences to the biosphere. How plants respond to this compound has rarely been examined previously. In our study, detailed morphological and physiological responses of Arabidopsis to 2,4,6-trichlorophenol, a representative TCP, were investigated. Seed germination and seedling growth were markedly inhibited by 2,4,6-TCP. Furthermore, we performed gene expression profiling analysis upon 2,4,6-TCP treatment in Arabidopsis and identified 34 transcripts induced and 212 repressed more than four folds. Gene Ontology (GO) analysis showed that these TCP responsive genes are involved in various biological processes, such as secondary metabolism, biological regulation, response to stimulus and other processes related to growth and development. The activities of two reactive oxygen species related enzymes (peroxidase and superoxide dismutase) and the content of malondialdehyde were increased significantly after 2,4,6-TCP treatment. Our findings have the potential to provide valuable gene resources and theoretical information for more in-depth analyses of TCPs' response in Arabidopsis thaliana and even other organic pollutants. PMID- 25445279 TI - Grape seed extract has superior beneficial effects than vitamin E on oxidative stress and apoptosis in the hippocampus of streptozotocin induced diabetic rats. AB - We aimed to investigate the effects of grape seed extract (GSE) and vitamin E (Vit E) on oxidative stress and apoptosis in the hippocampus of streptozotocin induced diabetic rats. In Control, Diabetic, and Diabetic treated with GSE (Diabetic+GSE) and vitamin E (Diabetic+Vit E) groups, oxidative stress index (OSI), TUNEL staining and Bcl-2, Bcl-XL, Bax, caspase-3, -9, and -8, Cyt-c, TNF alpha, and NF-kappaB gene expressions were evaluated. OSI was significantly increased in the plasma and hippocampus of the Diabetic compared to Control group and decreased in Diabetic+GSE and Diabetic+Vit E groups compared to Diabetic. TUNEL positive neurons significantly increased in the hippocampus of the Diabetic group compared to Control and decreased in Diabetic+GSE (more prominently) and Diabetic+Vit E groups compared to Diabetic. In the hippocampus of the Diabetic group, Bcl-2 and Bcl-XL gene expressions were significantly decreased; Bax, caspase-3, -9, and -8, Cyt-c, TNF-alpha, and NF-kappaB gene expressions were significantly increased compared to Control. In Diabetic+GSE and Diabetic+Vit E groups, Bcl-2 gene expressions were significantly increased; Bcl-XL gene expressions did not differ compared to the Diabetic group. The expression of Bax, caspase-3, -9, and -8, Cyt-c, TNF-alpha, and NF-kappaB genes in the Diabetic+GSE group and the expression of caspase-3 and -9, TNF-alpha, and NF-kappaB genes in the Diabetic+Vit E group were significantly decreased compared to Diabetic. In conclusion, GSE (more prominently) and vitamin E decreased oxidative stress and neuronal apoptosis occurring in the hippocampus of diabetic rats. PMID- 25445280 TI - Meeting report for "OddPols" 2014: the odds invite an even. AB - The Ninth International Biennial Conference on RNA Polymerases I and III (the "OddPols") was held on June 19-21, 2014 at the University of Michigan, Ann Arbor, USA. Sponsored by New England Biolabs, the Cayman Chemical Company, the Rackham Graduate School and the University of Michigan Health System, and organized by David Engelke, Craig Pikaard, Lawrence Rothblum, Andrzej Wierzbicki and Astrid Engel. This year at the conference, the "odds" were increased by expanding the usual topics on the advances in RNA polymerases I and III research to include presentations on RNA polymerase IV and V. The keynote speaker, Craig Pikaard, opened the meeting with his presentation entitled "Five nuclear multisubunit RNA polymerases". The meeting drew attendees from fourteen countries that shared their research discoveries through oral and poster presentations. The talks were organized into 11 sessions covering seven distinct topics. Here we present some of the highlights from the meeting using summaries provided by the participants. PMID- 25445281 TI - Complete mitochondrial genome of Cuora trifasciata (Chinese three-striped box turtle), and a comparative analysis with other box turtles. AB - Cuora trifasciata has become one of the most critically endangered species in the world. The complete mitochondrial genome of C. trifasciata (Chinese three-striped box turtle) was determined in this study. Its mitochondrial genome is a 16,575-bp long circular molecule that consists of 37 genes that are typically found in other vertebrates. And the basic characteristics of the C. trifasciata mitochondrial genome were also determined. Moreover, a comparison of C. trifasciata with Cuora cyclornata, Cuora pani and Cuora aurocapitata indicated that the four mitogenomics differed in length, codons, overlaps, 13 protein coding genes (PCGs), ND3, rRNA genes, control region, and other aspects. Phylogenetic analysis with Bayesian inference and maximum likelihood based on 12 protein-coding genes of the genus Cuora indicated the phylogenetic position of C. trifasciata within Cuora. The phylogenetic analysis also showed that C. trifasciata from Vietnam and China formed separate monophyletic clades with different Cuora species. The results of nucleotide base compositions, protein coding genes and phylogenetic analysis showed that C. trifasciata from these two countries may represent different Cuora species. PMID- 25445282 TI - Functional linc-POU3F3 is overexpressed and contributes to tumorigenesis in glioma. AB - Growing number of long intergenic noncoding RNAs (lincRNAs) have recently been identified in mammals as new modulators in cancer origination and progression involved in a broad range of biological processes. Long intergenic noncoding RNA POU3F3 (linc-POU3F3) has been characterized as a highly conserved functional transcription regulator in esophageal squamous cell carcinoma. The contributions of this lincRNA to glioblastoma remain unknown. In this present study, we investigated the expression pattern and functional role of linc-POU3F3 in glioma by using real-time PCR and gain-/loss-of-function studies. The results revealed that linc-POU3F3 levels were extraordinarily associated with the tumor WHO grade. In related biochemical assays, overexpression of linc-POU3F3 promotes cell viability and proliferation in glioma cells, whereas knockdown of linc-POU3F3 showed the opposite effect. As expected, we also found that linc-POU3F3 expression was negatively correlated with the mRNA level of POU3F3 (the evolutionarily conserved neighbor gene of linc-POU3F3). Our results indicate that linc-POU3F3 might affect glioma development via altering expression level of POU3F3, and lead us to believe that linc-POU3F3 may also have a crucial regulatory role in glioma progression. PMID- 25445283 TI - Lipidomics in the study of lipid metabolism: Current perspectives in the omic sciences. AB - The advances in systems biology and in the development of new technological tools in analysis, as well as in the omic sciences, among which, metabolomics, and more specifically, lipidomics, have made it possible to investigate the structural and functional complexity of lipids in biological systems. Liquid chromatography and mass spectrometry are the analytical approaches most used in lipid research. Biomedical research, with the development of specific markers for lipids, together with new software development, have both enabled the early diagnosis of several illnesses, besides the evaluation of drug activity and treatment efficacy. PMID- 25445284 TI - L-Carnitine intake prevents irregular feeding-induced obesity and lipid metabolism disorder. AB - L-Carnitine supplementation has been used to reduce obesity caused by high-fat diet, which is beneficial for lowering blood and hepatic lipid levels, and for ameliorating fatty liver. However, whether l-carnitine may affect irregular feeding-induced obesity and lipid metabolism disorder is still largely unknown. In the present study, we developed a time-delayed pattern of eating, and investigated the effects of l-carnitine on the irregular eating induced adiposity in mice. After an experimental period of 8 weeks with l-carnitine supplementation, l-carnitine significantly inhibited body weight increase and epididymal fat weight gain induced by the time-delayed feeding. In addition, l carnitine administration decreased levels of serum alanine aminotransferase (GPT), glutamic oxalacetic transaminase (GOT) and triglyceride (TG), which were significantly elevated by the irregular feeding. Moreover, mice supplemented with l-carnitine did not display glucose intolerance-associated hallmarks, which were found in the irregular feeding-induced obesity. Furthermore, quantitative real time polymerase chain reaction (qRT-PCR) analysis indicated that l-carnitine counteracted the negative alterations of lipid metabolic gene expression (fatty acid synthase, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, cholesterol 7alpha-hydroxylase, carnitine/acylcarnitine translocase) in the liver and fat of mice caused by the irregular feeding. Therefore, our results suggest that the time-delayed pattern of eating can induce adiposity and lipid metabolic disorders, while l-carnitine supplementation might prevent these negative symptoms. PMID- 25445285 TI - The association between XRCC1 genetic polymorphisms and the risk of endometrial carcinoma in Chinese. AB - Accumulated evidences report that X-ray repair cross-complementing group 1 gene (XRCC1) genetic polymorphisms play an important role in the development of endometrial carcinoma (EC). This study aims to evaluate the association of XRCC1 c.1161G>A and c.1804C>A genetic polymorphisms with the risk of EC. A total of 218 EC patients and 243 cancer-free controls were included in this study. The genotypes of XRCC1 genetic polymorphisms were determined by the created restriction site-polymerase chain reaction (CRS-PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods. We found that these two genetic polymorphisms were statistically associated with the risk of EC. As for c.1161G>A, in comparison with GG wild genotype, the AA genotype was significantly associated with the increased risk of EC (OR=2.36, 95% CI 1.28-4.37, chi(2)=7.71, P=0.005). As for c.1804C>A, the CC genotype significantly increased the risk of EC in comparison with CC wild genotype (OR=2.77, 95% CI 1.38-5.58, chi(2)=8.54, P=0.003). Our data indicate that the A allele of c.1161G>A and c.1804C>A genetic polymorphisms could contribute to increase the risk of EC (for c.1161G>A: A versus (vs.) G, OR=1.34, 95% CI 1.02-1.76, chi(2)=4.56, P=0.033; for c.1804C>A: A vs. C, OR=1.34, 95% CI 1.01-1.77, chi(2)=4.03, P=0.045). Our results indicate that the XRCC1 c.1161G>A and c.1804C>A genetic polymorphisms significantly influenced the risk of EC in Chinese populations, and might be used as molecular markers for evaluating EC risk. PMID- 25445286 TI - The RNA binding protein MEX-3 retains asymmetric activity in the early Caenorhabditis elegans embryo in the absence of asymmetric protein localization. AB - The RNA binding protein MEX-3 is required to restrict translation of pal-1, the Caenorhabditis elegans caudal homolog, to the posterior of the early embryo. MEX 3 is present uniformly throughout the newly fertilized embryo, but becomes depleted in the posterior by the 4-cell stage. This MEX-3 patterning requires the CCCH zinc-finger protein MEX-5, the RNA Recognition Motif protein SPN-4, and the kinase PAR-4. Genetic and biochemical evidence suggests that MEX-5 binds to MEX-3 in the anterior of the embryo, protecting MEX-3 from degradation and allowing it to bind the pal-1 3'UTR and repress translation. MEX-3 that is not bound to MEX-5 becomes inactivated by par-4, then targeted for spn-4 dependent degradation. After the 4-cell stage, residual MEX-3 is degraded in somatic cells, and only persists in the germline precursors. To better understand regulation of mex-3, GFP was fused to MEX-3 or regions of MEX-3 and expressed in developing oocytes. GFP::MEX-3 expressed in this manner can replace endogenous MEX-3, but surprisingly is not asymmetrically localized at the 4-cell stage. These results indicate that GFP::MEX-3 retains asymmetric activity even in the absence of asymmetric protein localization. Neither the mex-3 3'UTR nor protein degradation at the 4-cell stage is strictly required. A region of MEX-3 containing a glutamine-rich region and potential ubiquitination and phosphorylation sites is sufficient for soma-germline asymmetry. Results from mex-5/6 and spn-4(RNAi) suggest two pathways for MEX-3 degradation, an early spn-4 dependent pathway and a later spn-4 independent pathway. These results indicate that mex-3 activity is regulated at multiple levels, leading to rapid and robust regulation in the quickly developing early embryo. PMID- 25445287 TI - Human L-DOPA decarboxylase mRNA is a target of miR-145: A prediction to validation workflow. AB - l-DOPA decarboxylase (DDC) is a multiply-regulated gene which encodes the enzyme that catalyzes the biosynthesis of dopamine in humans. MicroRNAs comprise a novel class of endogenously transcribed small RNAs that can post-transcriptionally regulate the expression of various genes. Given that the mechanism of microRNA target recognition remains elusive, several genes, including DDC, have not yet been identified as microRNA targets. Nevertheless, a number of specifically designed bioinformatic algorithms provide candidate miRNAs for almost every gene, but still their results exhibit moderate accuracy and should be experimentally validated. Motivated by the above, we herein sought to discover a microRNA that regulates DDC expression. By using the current algorithms according to bibliographic recommendations we found that miR-145 could be predicted with high specificity as a candidate regulatory microRNA for DDC expression. Thus, a validation experiment followed by firstly transfecting an appropriate cell culture system with a synthetic miR-145 sequence and sequentially assessing the mRNA and protein levels of DDC via real-time PCR and Western blotting, respectively. Our analysis revealed that miR-145 had no significant impact on protein levels of DDC but managed to dramatically downregulate its mRNA expression. Overall, the experimental and bioinformatic analysis conducted herein indicate that miR-145 has the ability to regulate DDC mRNA expression and potentially this occurs by recognizing its mRNA as a target. PMID- 25445288 TI - Identification of conserved and novel microRNAs in Catharanthus roseus by deep sequencing and computational prediction of their potential targets. AB - MicroRNAs are small endogenous non-coding RNAs of ~19-24 nucleotides and perform regulatory roles in many plant processes. To identify miRNAs involved in regulatory networks controlling diverse biological processes including secondary metabolism in Catharanthus roseus, an important medicinal plant, we employed deep sequencing of small RNA from leaf tissue. A total of 88 potential miRNAs comprising of 81 conserved miRNAs belonging to 35 families and seven novel miRNAs were identified. Precursors for 16 conserved and seven novel cro-miRNAs were identified, and their stem-loop hairpin structures were predicted. Selected cro miRNAs were analyzed by stem-loop qRT-PCR and differential expression patterns were observed in different vegetative tissues of C. roseus. Targets were predicted for conserved and novel cro-miRNAs, which were found to be involved in diverse biological role(s) including secondary metabolism. Our study enriches available resources and information regarding miRNAs and their potential targets for better understanding of miRNA-mediated gene regulation in plants. PMID- 25445289 TI - BMP and RA signaling cooperate to regulate Apolipoprotein C1 expression during embryonic development. AB - Apolipoproteins, the major components of lipoproteins, play physiological roles in lipoprotein metabolism. Contrary to the well-documented effects on plasma lipid, little is known about the function and regulation of Apolipoproteins during embryonic development. Here we have shown that apolipoprotein C1 (apoc1) gene is highly expressed in the yolk syncytial layer, a structure implicated in embryonic and larval nutrition. The apoc1 transcripts are also observed in the deep cell layer at the ventral and lateral region during gastrulation, and in the tail paraxial mesoderm during somitogenesis. By whole-mount in situ hybridization and quantified RT-RCR, we further demonstrate that apoc1 expression is induced by bone morphogenetic proteins (BMPs) signaling, while retinoic acid (RA) signaling suppresses the expression of BMP ligands and inhibits the BMP effect in this process. PMID- 25445290 TI - Validation of reference genes for accurate normalization of gene expression for real time-quantitative PCR in strawberry fruits using different cultivars and osmotic stresses. AB - The increasing demand of strawberry (Fragaria*ananassa Duch) fruits is associated mainly with their sensorial characteristics and the content of antioxidant compounds. Nevertheless, the strawberry production has been hampered due to its sensitivity to abiotic stresses. Therefore, to understand the molecular mechanisms highlighting stress response is of great importance to enable genetic engineering approaches aiming to improve strawberry tolerance. However, the study of expression of genes in strawberry requires the use of suitable reference genes. In the present study, seven traditional and novel candidate reference genes were evaluated for transcript normalization in fruits of ten strawberry cultivars and two abiotic stresses, using RefFinder, which integrates the four major currently available software programs: geNorm, NormFinder, BestKeeper and the comparative delta-Ct method. The results indicate that the expression stability is dependent on the experimental conditions. The candidate reference gene DBP (DNA binding protein) was considered the most suitable to normalize expression data in samples of strawberry cultivars and under drought stress condition, and the candidate reference gene HISTH4 (histone H4) was the most stable under osmotic stresses and salt stress. The traditional genes GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and 18S (18S ribosomal RNA) were considered the most unstable genes in all conditions. The expression of phenylalanine ammonia lyase (PAL) and 9-cis epoxycarotenoid dioxygenase (NCED1) genes were used to further confirm the validated candidate reference genes, showing that the use of an inappropriate reference gene may induce erroneous results. This study is the first survey on the stability of reference genes in strawberry cultivars and osmotic stresses and provides guidelines to obtain more accurate RT-qPCR results for future breeding efforts. PMID- 25445291 TI - Identification and expression analysis of cold and freezing stress responsive genes of Brassica oleracea. AB - Cold and freezing stress is a major environmental constraint to the production of Brassica crops. Enhancement of tolerance by exploiting cold and freezing tolerance related genes offers the most efficient approach to address this problem. Cold-induced transcriptional profiling is a promising approach to the identification of potential genes related to cold and freezing stress tolerance. In this study, 99 highly expressed genes were identified from a whole genome microarray dataset of Brassica rapa. Blast search analysis of the Brassica oleracea database revealed the corresponding homologous genes. To validate their expression, pre-selected cold tolerant and susceptible cabbage lines were analyzed. Out of 99 BoCRGs, 43 were differentially expressed in response to varying degrees of cold and freezing stress in the contrasting cabbage lines. Among the differentially expressed genes, 18 were highly up-regulated in the tolerant lines, which is consistent with their microarray expression. Additionally, 12 BoCRGs were expressed differentially after cold stress treatment in two contrasting cabbage lines, and BoCRG54, 56, 59, 62, 70, 72 and 99 were predicted to be involved in cold regulatory pathways. Taken together, the cold responsive genes identified in this study provide additional direction for elucidating the regulatory network of low temperature stress tolerance and developing cold and freezing stress resistant Brassica crops. PMID- 25445292 TI - Evaluation of genetic variability, rust resistance and marker-detection in cultivated Artemisia dracunculus from Iran. AB - Artemisia dracunculus L. (tarragon), a small shrubby perennial herb, is cultivated for the use of its aromatic leaves in seasoning, salads, etc., and in the preparation of tarragon vinegar. In the present work, genetic analysis of 29 cultivated individuals of this species was carried out employing 12 ISSR and 11 SRAP markers. A total of 59 (71.64%) and 79 (83.14%) polymorphic bands were detected by 12 ISSR primers and 11 SRAP primer pairs, respectively. High similarity for patterns of genetic diversity and clustering of individuals was observed using two ISSR and SRAP marker systems and combined data. Range of genetic similarity by ISSR markers was 0.14 to 0.95, by SRAP markers was 0.14 to 0.90, while this range varied from 0.18 to 0.91 by ISSR+SRAP. In the UPGMA cluster analysis (ISSR, SRAP and ISSR+SRAP), we always found two clusters, the first cluster included 22 individuals and the second contained seven individuals. The results demonstrated that both ISSR and SRAP methods were suitable for discriminating among the studied individuals and the SRAP markers were more efficient and preferable. The results of multiple regression analysis revealed statistically significant association between rust resistance and some molecular markers that they can provide clues for identification of the individuals with higher rust resistance. The molecular marker-based study of genetic diversity suggests that the germplasm studied representing the kind of variability would be a valuable genetic resource for future breeding. In addition, in situ conservation measures are recommended to preserve the valuable A. dracunculus genetic resources as the most effective and economical approach. PMID- 25445293 TI - Prediction of protein structural classes for low-similarity sequences using reduced PSSM and position-based secondary structural features. AB - Many efficient methods have been proposed to advance protein structural class prediction, but there are still some challenges where additional insight or technology is needed for low-similarity sequences. In this work, we schemed out a new prediction method for low-similarity datasets using reduced PSSM and position based secondary structural features. We evaluated the proposed method with four experiments and compared it with the available competing prediction methods. The results indicate that the proposed method achieved the best performance among the evaluated methods, with overall accuracy 3-5% higher than the existing best performing method. This paper also found that the reduced alphabets with size 13 simplify PSSM structures efficiently while reserving its maximal information. This understanding can be used to design more powerful prediction methods for protein structural class. PMID- 25445294 TI - Structural characterization of Fis - A transcriptional regulator from pathogenic Pasteurella multocida essential for expression of virulence factors. AB - Pasteurella multocida is responsible behind a variety of diseases in animals. The disease causing substance of this bacterium is a capsular polysaccharide. The expression of the gene that codes for the bacterial capsule is regulated by the protein Fis. Fis also regulates the expression of various different genes in P. multocida. So far there have been no previous reports that depict the characterization of Fis from P. multocida from a structural point of view. In the present work, an attempt has been made to characterize Fis by in silico methods. The structure of Fis was built by comparative modeling technique. The model of Fis was then docked onto the corresponding promoter regions of the gene encoding the capsular polysaccharide. The docked complexes of promoter DNA with Fis protein were subjected to molecular dynamics simulations to identify the mode of DNA-protein interactions. The DNA binding amino acid residues from the Fis protein were identified. And a mechanistic detail of the DNA binding interactions was predicted. So far, this is the first report that depicts the mechanistic details of Fis-DNA interactions involved in the regulation of gene expression by Fis protein. This work may therefore be useful to illuminate the still obscure molecular mechanism behind the disease propagation by P. multocida. PMID- 25445295 TI - Use of dose-dependent absorption into target tissues to more accurately predict cancer risk at low oral doses of hexavalent chromium. AB - The mouse dose at the lowest water concentration used in the National Toxicology Program hexavalent chromium (CrVI) drinking water study (NTP, 2008) is about 74,500 times higher than the approximate human dose corresponding to the 35-city geometric mean reported in EWG (2010) and over 1000 times higher than that based on the highest reported tap water concentration. With experimental and environmental doses differing greatly, it is a regulatory challenge to extrapolate high-dose results to environmental doses orders of magnitude lower in a meaningful and toxicologically predictive manner. This seems particularly true for the low-dose extrapolation of results for oral CrVI-induced carcinogenesis since dose-dependent differences in the dose fraction absorbed by mouse target tissues are apparent (Kirman et al., 2012). These data can be used for a straightforward adjustment of the USEPA (2010) draft oral slope factor (SFo) to be more predictive of risk at environmentally-relevant doses. More specifically, the evaluation of observed and modeled differences in the fraction of dose absorbed by target tissues at the point-of-departure for the draft SFo calculation versus lower doses suggests that the draft SFo be divided by a dose specific adjustment factor of at least an order of magnitude to be less over predictive of risk at more environmentally-relevant doses. PMID- 25445296 TI - 13-week oral toxicity study of vinyl laurate in rats. AB - Vinyl laurate (VL) is used as a monomer in the production of polyvinyl acetate vinyl laurate copolymer, a component of chewing gum base. The safety of VL was examined in a 13-week oral toxicity study in Wistar rats. VL was administered in corn coil by daily gavage (5 ml/kg bw/d) to four main groups (10 rats/sex) at doses of 0 (vehicle only), 50, 250 and 1000 mg/kg bw/d, respectively. The control and high-dose group comprised an additional 5 rats/sex which were kept untreated for a further 4 weeks until sacrifice (recovery groups). In addition to standard parameters, male and female fertility parameters were determined as well. There were no mortalities and treatment-related clinical signs. Neurobehavioral observations and motor activity assessment, ophthalmoscopic examinations, body weights, feed and water intakes, blood cell counts, coagulation time, standard clinical chemical parameters and urinalyses, absolute and relative organ weights at the end of the treatment as well as macroscopic examination at necropsy and microscopic examination of standard organs and tissues did not show any treatment related changes. Female and male fertility parameters (estrus cyclicity, testicular and epididymal sperm counts, sperm motility and morphology) were not affected by the treatment. Accordingly, the no-observed-adverse-effect level (NOAEL) for VL was determined to be 1000 mg/kg bw/d, i.e. the highest dose level tested. PMID- 25445297 TI - Airborne asbestos exposures associated with gasket and packing replacement: a simulation study of flange and valve repair work and an assessment of exposure variables. AB - A simulation study was conducted to evaluate worker and area exposure to airborne asbestos associated with the replacement of asbestos-containing gaskets and packing materials from flanges and valves and assess the influence of several variables previously not investigated. Additionally, potential of take home exposures from clothing worn during the study was characterized. Our data showed that product type, ventilation type, gasket location, flange or bonnet size, number of flanges involved, surface characteristics, gasket surface adherence, and even activity type did not have a significant effect on worker exposures. Average worker asbestos exposures during flange gasket work (PCME=0.166 f/cc, 12 59 min) were similar to average worker asbestos exposures during valve overhaul work (PCME=0.165 f/cc, 7-76 min). Average 8-h TWA asbestos exposures were estimated to range from 0.010 to 0.062 f/cc. Handling clothes worn during gasket and packing replacement activities demonstrated exposures that were 0.71% (0.0009 f/cc 40-h TWA) of the airborne asbestos concentration experienced during the 5 days of the study. Despite the many variables considered in this study, exposures during gasket and packing replacement occur within a relatively narrow range, are below current and historical occupational exposure limits for asbestos, and are consistent with previously published data. PMID- 25445298 TI - Safety assessment of essential oil from Minthostachys verticillata (Griseb.) Epling (peperina): 90-days oral subchronic toxicity study in rats. AB - Minthostachys verticillata (Lamiaceae), popularly known as peperina is largely used in popular medicine for its digestive, carminative, antispasmodic and antirheumatic properties. There are no reports of repeated exposure toxicity to guarantee their safety. The present study investigated the chemical composition, analyzed by GC-FID, and the 90-day toxicity and genotoxicity effect of M. verticillata essential oil (Mv-EO), using Wistar rats as test animals. The rats were divided into four groups (5 rats/sex/group) and Mv-EO was administered on diet at doses of 0, 1, 4 and 7 g/kg feed. The main components of Mv-EO were pulegone (64.65%) and menthone (23.92%). There was no mortality, adverse effects on general conditions or changes in body weight, food consumption and feed conversion efficiency throughout the study in male and female rats. Subchronic administration of Mv-EO did not alter the weights, morphological and histopathological analyses of liver, kidney and intestine. Genotoxicity was tested by micronucleus and comet assays. Mv-EO up to a concentration of 7 g/kg feed for 90 days did not exert a cyto-genotoxic effect on the bone marrow and cells blood of Wistar rats. These results suggest that Mv-EO appears to be safe and could be devoid of any toxic risk. PMID- 25445299 TI - A 28-day oral toxicity evaluation of small interfering RNAs and a long double stranded RNA targeting vacuolar ATPase in mice. AB - New biotechnology-derived crop traits have been developed utilizing the natural process of RNA interference (RNAi). However, plant-produced double stranded RNAs (dsRNAs) are not known to present a hazard to mammals because numerous biological barriers limit uptake and potential for activity. To evaluate this experimentally, dsRNA sequences matching the mouse vATPase gene (an established target for control of corn rootworms) were evaluated in a 28-day toxicity study with mice. Test groups were orally gavaged with escalating doses of either a pool of four 21-mer vATPase small interfering RNAs (siRNAs) or a 218-base pair vATPase dsRNA. There were no treatment-related effects on body weight, food consumption, clinical observations, clinical chemistry, hematology, gross pathology, or histopathology endpoints. The highest dose levels tested were considered to be the no observed adverse effect levels (NOAELs) for the 21-mer siRNAs (48 mg/kg/day) and the 218 bp dsRNA (64 mg/kg/day). As an additional exploratory endpoint, vATPase gene expression, was evaluated in selected gastrointestinal tract and systemic tissues. The results of this assay did not indicate treatment related suppression of vATPase. The results of this study indicate that orally ingested dsRNAs, even those targeting a gene in the test species, do not produce adverse health effects in mammals. PMID- 25445300 TI - Left ventricular mechanical function: clinical correlates, heritability, and association with parental heart failure. AB - AIMS: Non-invasive measures of cardiac mechanical function may have the potential to serve as markers of risk for heart failure; however, limited data exist regarding clinical correlates and heritability of these measures in the community. METHODS AND RESULTS: We used speckle-tracking echocardiography to assess LV strain and synchrony in the Framingham Offspring Study (n = 2816; mean age 67 years, 54% women). In multivariable regression analyses, male gender (vs. female, P < 0.001), higher heart rate (P < 0.0001), and presence of cardiovascular disease (P < 0.001) were associated with worse global peak strains across all planes analysed (longitudinal, transverse, circumferential, and radial). Higher diastolic blood pressure and diabetes were associated with worse longitudinal strain (P < 0.01), and greater body mass index was associated with worse radial strain (P = 0.0004). Overall, however, clinical correlates accounted for only 4-19% of the variation in measures of LV mechanical function. Select measures of LV strain were heritable: longitudinal strain (h(2) = 16%, P = 0.002), transverse strain (h(2) = 15%, P = 0.006), and circumferential strain (h(2) = 30%, P < 0.0001). Furthermore, in a subset of 1437 participants with parental data available, parental heart failure was associated with worse circumferential strain in the offspring free of heart failure (P = 0.01). CONCLUSIONS: Our investigation in a large community-based sample identified heritablity and clinical correlates of LV mechanical function, and highlighted an association of parental heart failure with worse global circumferential strain in offspring. PMID- 25445302 TI - A novel oxido-viscosifying Hyaluronic Acid-antioxidant conjugate for osteoarthritis therapy: biocompatibility assessments. AB - To overcome the problem of fast degradation of Hyaluronic Acid (HA) in the treatment of osteoarthritis (OA), HA was protected against the oxidative stress generated by the pathology. Antioxidant conjugated HAs were synthesized and tested in vitro for their resistance in an oxidative environment mimicking OA. HA 4-aminoresorcinol (HA-4AR) displayed the interesting property of increasing in viscosity under oxidative conditions because of crosslinking induced by electron transfer. The novel HA polymer conjugate was shown to be biocompatible in vitro on fibroblast-like synoviocytes extracted from an arthritic patient. This HA conjugate was also assessed in vivo by intra-articular injection in healthy rabbits and was found to be comparable to the native polymer in terms of biocompatibility. This study suggests that HA-4AR is a promising candidate for a next generation viscosupplementation formulation. PMID- 25445301 TI - Influence of trehalose 6,6'-diester (TDX) chain length on the physicochemical and immunopotentiating properties of DDA/TDX liposomes. AB - Linking physicochemical characterization to functional properties is crucial for defining critical quality attributes during development of subunit vaccines toward optimal safety and efficacy profiles. We investigated how the trehalose 6,6'-diester (TDX) chain length influenced the physicochemical and immunopotentiating properties of the clinically tested liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and analogues of trehalose 6,6'-dibehenate (TDB). TDB analogues with symmetrically shortened acyl chains [denoted X: arachidate (A), stearate (S), palmitate (P), myristate (Myr) and laurate (L)] were incorporated into DDA liposomes and characterized with respect to size, polydispersity index, charge, thermotropic phase behavior and lipid lipid interactions. Incorporation of 11 mol% TDX into DDA liposomes significantly decreased the polydispersity index when TDA, TDS, TDP and TDMyr were incorporated, whereas both the initial size and the charge of the liposomes were unaffected. The long-term colloidal stability was only decreased when including TDL in DDA liposomes. The fatty acid length of TDX affected the phase transition of the liposomes, and for the DDA/TDP and DDA/TDS liposomes a homogeneous distribution of the lipids in the bilayer was indicated. The membrane packing was studied further by using the Langmuir monolayer technique. Incorporation of TDS improved the packing of the lipid monolayer, as compared to the other analogues, suggesting the most favorable stability. Finally, immunization of mice with the recombinant tuberculosis fusion antigen Ag85B-ESAT-6-Rv2660c (H56) and the physicochemically most optimal formulations (DDA/TDB, DDA/TDS and DDA/TDP) induced comparable T-cell responses. In conclusion, of the investigated TDB analogues, incorporation of 11 mol% TDS or TDP into DDA liposomes resulted in an adjuvant system with the most favorable physicochemical properties and an immunological profile comparable to that of DDA/TDB. PMID- 25445303 TI - Impact of structural differences in hyperbranched polyglycerol-polyethylene glycol nanoparticles on dermal drug delivery and biocompatibility. AB - Polyglycerol scaffolds and nanoparticles emerged as prominent material for various biomedical applications including topical drug delivery. The impact of slight structural modifications on the nanoparticles' properties, drug delivery potential, and biocompatibility, however, is still not fully understood.Hence, we explored the influence of structural modifications of five structurally related polyglycerol-based nanoparticles (PG-PEG, SK1-SK5) on dermal drug delivery efficiency and biocompatibility. The PG-PEG particles were synthesized via randomly and controlled alkylated chemo-enzymatic approaches resulting in significantly varying particle sizes and interactions with guest molecules. Furthermore, weobserved considerably improved dermal drug delivery with the smallest particles SK4 and SK5 (11 nm and 14 nm) which also correlated with well defined surface properties achieved by the controlled alkylated synthesis approach. The consistently good biocompatibility for all PG-PEG particles was mainly attributed to the neutral surface charge. No irritation potential, major cytotoxicity or genotoxicity was observed. Nevertheless, slightly better biocompatibility was again seen for the particles characterized by alkyl chain substitution in the core and not on the particle surface.Despite the high structural similarity of the PG-PEG particles, the synthesis and the functionalization significantly influenced particle properties, biocompatibility, and most significantly the drug delivery efficiency. PMID- 25445304 TI - Positive-charged solid lipid nanoparticles as paclitaxel drug delivery system in glioblastoma treatment. AB - Paclitaxel loaded solid lipid nanoparticles (SLN) of behenic acid were prepared with the coacervation technique. Generally, spherical shaped SLN with mean diameters in the range 300-600 nm were obtained. The introduction of charged molecules, such as stearylamine and glycol chitosan into the formulation allowed to obtain positive SLN with Zeta potential in the 8-20 mV range and encapsulation efficiency in the 25-90% range.Blood-brain barrier (BBB) permeability, tested in vitro through hCMEC/D3 cells monolayer, showed a significantly increase in the permeation of Coumarin-6, used as model drug, when vehicled in SLN. Positive charged SLN do not seem to enhance permeation although stearylamine-positive SLN resulted the best permeable formulation after 24 h.Cytotoxicity studies on NO3 glioblastoma cell line demonstrated the maintenance of cytotoxic activity of all paclitaxel-loaded SLN that was always unmodified or greater compared with free drug. No difference in cytotoxicity was noted between neutral and charged SLN.Co culture experiments with hCMEC/D3 and different glioblastoma cells evidenced that, when delivered in SLN, paclitaxel increased its cytotoxicity towards glioblastoma cells. PMID- 25445305 TI - Investigation of coco-glucoside as a novel intestinal permeation enhancer in rat models. AB - Due to instability in the GI tract and low intestinal permeability, peptides invariably have oral bioavailabilities below 1% and this has prevented the development of oral formulations. A mild plant-derived naturalalkyl polyglycoside (APG), coco-glucoside (CG), was studied for its capacity to enable rat intestinal permeation of the paracellular sugar marker, fluorescein isothiocyanate-dextran 4000 (FD4), across isolated rat jejunal and colonic mucosae mounted in Ussing chambers, as well as the polypeptide, salmon calcitonin (sCT) following intra intestinal instillations in rats. 0.1% (w/v) CG enabled a 2.9-fold increase in the apparent permeability coefficient (Papp) of FD4 over the basal Papp across colonic mucosae, but it was without effect in jejunal mucosae. In situ intestinal instillations revealed that although sCT was absorbed across rat colonic loops to a greater extent than jejunal, CG still improved sCT absolute bioavailability(F) from both segments. Histopathology of rat intestinal mucosae following exposure to CG indicated only minor perturbation with adequate maintenance of secretory function. High content analysis(HCA) on Caco-2 showed that acute and chronic exposure to a range of concentrations of CG did not cause sub-lethal damage at concentrations at which it was effective as an enhancer. Overall, CG increased bioavailability of sCT across rat jejunal and colonic loops without indication of tissue damage. Thus, CG has potential as a safe and effective intestinal enhancer for oral delivery of proteins and peptides. PMID- 25445306 TI - Crystal coating via spray drying to improve powder tabletability. AB - A continuous crystal coating method was developed to improve both flowability and tabletability of powders. The method includes the introduction of solid, dry particles into an atomized spray during spray drying in order to coat and agglomerate individual particles. Paracetamol was used as a model drug as it exhibits poor flowability and high capping tendency upon compaction. The particle size enlargement and flowability were evaluated by the mean median particle size and flow index of the resulting powders. The crystal coating coprocessing method was successful for the production of powders containing 75% paracetamol with excellent tableting properties. However, the extent of agglomeration achieved during coprocessing was limited. Tablets compressed on a rotary tablet press in manual mode showed excellent compression properties without capping tendency. A formulation with 75% paracetamol, 5% PVP and 20% amorphous lactose yielded a tensile strength of 1.9 MPa at a compression pressure of 288 MPa. The friability of tablets compressed at 188 MPa was only 0.6%. The excellent tabletability of this formulation was attributed to the coating of paracetamol crystals with amorphous lactose and PVP through coprocessing and the presence of brittle and plastic components in the formulation. The coprocessing method was also successfully applied for the production of directly compressible lactose showing improved tensile strength and friability in comparison to a spray dried direct compression lactose grade. PMID- 25445307 TI - Biosynthesis of non-melanin pigment by a divergent polyketide synthase in Metarhizium robertsii. AB - Fungal polyketide synthases (PKSs) and their related gene clusters are highly diversified at both inter- and intra-specific levels. The most well characterized PKS enzymes include those responsible for the biosynthesis of polyketide pigments such as melanins. The genome of the insect pathogenic fungus Metarhizium robertsii contains 20 type I PKSs but none has been functionally characterized. In this study, two PKS genes (designated as MrPks1 and MrPKs2) showing homologies to those counterparts for the biosynthesis of heptaketide pigments and dihydroxynaphthalene (DHN)-melanins, respectively, were deleted in two different strains of M. robertsii. The results indicated that disruption of MrPks1 but not MrPks2 impaired fungal culture pigmentation and cell wall structure. In addition to the negative effect of the DHN-melanin pathway inhibitor, it was postulated that DHN-melanin would not be produced by M. robertsii. Various assays revealed that the stress resistance abilities against ultraviolet radiation, heat shock and oxidants, as well as virulence against insects were not impaired in DeltaMrPks1 and DeltaMrPks2 isolates when compared with the wild-type strain. Thus, the non-melanin pigment(s) produced by the fungus do not contribute to cell damage protection and pathogenicity in M. robertsii. Physiological differences were evident in the two examined wild-type strains. The results from this study advance the understanding of functional divergence of fungal PKSs. PMID- 25445308 TI - Molecules at the interface of Cryptococcus and the host that determine disease susceptibility. AB - Cryptococcus neoformans and Cryptococcus gattii, the predominant etiological agents of cryptococcosis, are fungal pathogens that cause disease ranging from a mild pneumonia to life-threatening infections of the central nervous system (CNS). Resolution or exacerbation of Cryptococcus infection is determined following complex interactions of several host and pathogen derived factors. Alternatively, interactions between the host and pathogen may end in an impasse resulting in the establishment of a sub-clinical Cryptococcus infection. The current review addresses the delicate interaction between the host and Cryptococcus-derived molecules that determine resistance or susceptibility to infection. An emphasis will be placed on data highlighted at the recent 9th International Conference on Cryptococcus and Cryptococcosis (ICCC). PMID- 25445309 TI - Epidemiology of Cryptococcus and cryptococcosis in China. AB - Cryptococcosis is a significant invasive fungal infection with noteworthy morbidity and mortality, primarily caused by Cryptococcus neoformans and Cryptococcus gattii. In China, C. neoformans var. grubii (especially molecular type VNI) is the most common variety in the environment and responsible for the majority of cryptococcal infections. C. gattii infections are quite rare in China and the primary molecular type is VGI, which is closely related to C. gattii isolates in Australia. Interestingly, the majority of cryptococcosis in China were reported in the HIV-uninfected patients (especially immunocompetent hosts). This unique phenomenon may be attributed to multiple polymorphisms in the genes encoding mannose-binding lectin (MBL) and Fc-gamma receptor 2B (FCGR2B) in the Han population, the major ethnic group in China. Compared to immunocompromised patients, immunocompetent patients with cryptococcal meningitis often presented with more intense inflammatory responses and more severe neurological complications, but less fungal burdens and disseminated infection. The overall prognosis, which is independently associated with amphotericin B-based initial therapy, is similar between immunocompetent and immunocompromised patients. In addition, intrathecal administration of amphotericin B has been proved to be an effective adjunctive treatment for cryptococcosis in China. PMID- 25445310 TI - Discordant phylogenies suggest repeated host shifts in the Fusarium-Euwallacea ambrosia beetle mutualism. AB - The mutualism between xyleborine beetles in the genus Euwallacea (Coleoptera: Curculionidae: Scolytinae) and members of the Ambrosia Fusarium Clade (AFC) represents one of 11 known evolutionary origins of fungiculture by ambrosia beetles. Female Euwallacea beetles transport fusarial symbionts in paired mandibular mycangia from their natal gallery to woody hosts where they are cultivated in galleries as a source of food. Native to Asia, several exotic Euwallacea species were introduced into the United States and Israel within the past two decades and they now threaten urban landscapes, forests and avocado production. To assess species limits and to date the evolutionary diversification of the mutualists, we reconstructed the evolutionary histories of key representatives of the Fusarium and Euwallacea clades using maximum parsimony and maximum likelihood methods. Twelve species-level lineages, termed AF 1-12, were identified within the monophyletic AFC and seven among the Fusarium-farming Euwallacea. Bayesian diversification-time estimates placed the origin of the Euwallacea-Fusarium mutualism near the Oligocene-Miocene boundary ~19-24 Mya. Most Euwallacea spp. appear to be associated with one species of Fusarium, but two species farmed two closely related fusaria. Euwallacea sp. #2 in Miami-Dade County, Florida cultivated Fusarium spp. AF-6 and AF-8 on avocado, and Euwallacea sp. #4 farmed Fusarium ambrosium AF-1 and Fusarium sp. AF-11 on Chinese tea in Sri Lanka. Cophylogenetic analyses indicated that the Euwallacea and Fusarium phylogenies were largely incongruent, apparently due to the beetles switching fusarial symbionts (i.e., host shifts) at least five times during the evolution of this mutualism. Three cospeciation events between Euwallacea and their AFC symbionts were detected, but randomization tests failed to reject the null hypothesis that the putative parallel cladogenesis is a stochastic pattern. Lastly, two collections of Euwallacea sp. #2 from Miami-Dade County, Florida shared an identical cytochrome oxidase subunit 1 (CO1) allele with Euwallacea validus, suggesting introgressive hybridization between these species and/or pseudogenous nature of this marker. Results of the present study highlight the importance of understanding the potential for and frequency of host-switching between Euwallacea and members of the AFC, and that these shifts may bring together more aggressive and virulent combinations of these invasive mutualists. PMID- 25445312 TI - Genetic interactions among homologous recombination mutants in Candida albicans. AB - rad52-DeltaDelta and, to a lesser extent, rad51-DeltaDelta deletants of Candidaalbicans displayed slow growth and aberrant filamentous morphology whereas rad59-DeltaDelta mutants, both by growth rate and morphology resembled wild type. In this study, we have constructed pair-wise double deletants to analyze genetic interactions among these homologous recombination (HR) proteins that affect growth and morphology traits. When grown in liquid YPD medium, double mutant rad51-DeltaDelta rad59-DeltaDelta exhibited growth rates, cell and colony morphologies, and plating efficiencies that were not significantly different from those observed for rad51-DeltaDelta. The same was true for rad52-DeltaDelta rad59 DeltaDelta compared to rad52-DeltaDelta. Slow growth and decreased plating efficiency were caused, at least in part, by a decreased viability, as deduced from FUN1 staining. Flow cytometry and microscopic studies of filamentous mutant populations revealed major changes in cell ploidy, size and morphology, whereas DAPI staining identified complex nuclear rearrangements in yeast and filamentous cells. These phenotypes were not observed in the rad59-DeltaDelta mutant populations. Our results show that abolishing Rad51 functions induces the appearance of a subpopulation of aberrant yeast and filamentous forms with increased cell size and ploidy. The size of this complex subpopulation was exacerbated in rad52-DeltaDelta mutants. The combination of filamentous cell morphology and viability phenotypes was reflected on the colony morphology of the respective mutants. We conclude that the rad52 mutation is epistatic to rad51 for all the morphological traits analyzed. We discuss these results in the light of the several functions of these recombination genes. PMID- 25445311 TI - Cryptococcus neoformans Yap1 is required for normal fluconazole and oxidative stress resistance. AB - Cryptococcus neoformans is a pathogen that is the most common cause of fungal meningitis. As with most fungal pathogens, the most prevalent clinical antifungal used to treat Cryptococcosis is orally administered fluconazole. Resistance to this antifungal is an increasing concern in treatment of fungal disease in general. Our knowledge of the specific determinants involved in fluconazole resistance in Cryptococcus is limited. Here we report the identification of an important genetic determinant of fluconazole resistance in C. neoformans that encodes a basic region-leucine zipper transcription factor homologous to Saccharomyces cerevisiae Yap1. Expression of a codon-optimized form of the Cn YAP1 cDNA in S. cerevisiae complemented defects caused by loss of the endogenous S. cerevisiae YAP1 gene and activated transcription from a reporter gene construct. Mutant strains of C. neoformans lacking YAP1 were hypersensitive to a range of oxidative stress agents but importantly also to fluconazole. Loss of Yap1 homologues from other fungal pathogens like Candida albicans or Aspergillus fumigatus was previously found to cause oxidant hypersensitivity but had no detectable effect on fluconazole resistance. Our data provide evidence for a unique biological role of Yap1 in wild-type fluconazole resistance in C. neoformans. PMID- 25445313 TI - PREBIOUS trial: a multicenter randomized controlled trial of PREventive midline laparotomy closure with a BIOabsorbable mesh for the prevention of incisional hernia: rationale and design. AB - BACKGROUND: Development of an incisional hernia is one of the most frequent complications of midline laparotomies requiring reoperation. This paper presents the rationale, design, and study protocol for a randomized controlled trial, the aim of which is to evaluate the efficacy and safety of prophylactically placing a bioabsorbable synthetic mesh for reinforcement of a midline fascial closure. METHODS: The PREBIOUS trial (PREventive midline laparotomy closure with a BIOabsorbable mesh) is a multicenter randomized controlled trial in which adult patients undergoing elective or urgent open abdominal operations through a midline laparotomy incision are assigned to one of two groups based on the laparotomy closure procedure: an intervention group in which a continuous polydioxanone (PDS) suture is reinforced with a commercially available GORE(r) BIO-A(r) Tissue Reinforcement prosthesis (W.L. Gore & Associates, Flagstaff, AZ, USA), or a control group with continuous PDS suture only. Both groups are followed over 6 months. OUTCOMES: The primary outcome is the appearance of incisional hernias assessed by physical examination at clinical visits and radiologically (CT scan) performed at the end of follow-up. Secondary outcomes are the rate of complications, mainly infection, hematoma, burst abdomen, pain, and reoperation. The PREBIOUS trial has the potential to demonstrate that suture plus prosthetic mesh insertion for routine midline laparotomy closure is effective in preventing incisional hernias after open abdominal surgery, to avoid the effects on those affected, such as poor cosmesis, social embarrassment, or impaired quality of life, and to save costs potentially associated with incisional hernia surgical repair. PMID- 25445314 TI - Discharge information and support for veterans Receiving Outpatient Care in the Emergency Department: study design and methods. AB - BACKGROUND: An explicit goal of Patient Aligned Care Teams (PACTs) within the Veterans Health Administration is to promote continuity of care in primary care clinics and thereby reduce Emergency Department (ED) utilization; however, there has been little research to guide PACTs on how to accomplish this. OBJECTIVES: The overall goal of this study is to examine the impact of a primary care-based nurse telephone support program [DISPO ED] on Veterans treated and released from the ED who are at high risk for repeat visits. METHODS: This study is a two group randomized, controlled trial to evaluate DISPO ED for Veterans treated and released from the ED who are at high risk for repeat visits. We define high risk as those who have had an ED visit or hospitalization during the 6 month period before the index ED visit and have >=2 chronic conditions. Veterans are randomized to nurse telephone support or usual care. The primary outcome is repeat ED use within 30 days; secondary outcomes are patient satisfaction with care and total costs. DISCUSSION: The results of this randomized, controlled trial with an Effectiveness-Implementation Type I Hybrid design will be directly relevant to the care of more than 500,000 high risk patients seen in Veterans' Affairs Medical Center (VAMC) EDs annually. Results will also be informative to health systems outside VA aiming to reduce ED use through accountable care organizations. PMID- 25445315 TI - Optical identification of the long-wavelength (700-1700 nm) electronic excitations of the native reaction centre, Mn4CaO5 cluster and cytochromes of photosystem II in plants and cyanobacteria. AB - Visible/UV absorption in PS II core complexes is dominated by the chl-a absorptions, which extend to ~700 nm. A broad 700-730 nm PS II core complex absorption in spinach has been assigned to a charge transfer excitation between ChlD1 and ChlD2. Emission from this state, which peaks at 780 nm, has been seen for both plant and cyanobacterial samples. We show that Thermosynechococcus vulcanus PS II core complexes have parallel absorbance in the 700-730 nm region and similar photochemical behaviour to that seen in spinach. This establishes the low energy charge transfer state as intrinsic to the native PS II reaction centre. High-sensitivity MCD measurements made in the 700-1700 nm region reveal additional electronic excitations at ~770 nm and ~1550 nm. The temperature and field dependence of MCD spectra establish that the system peaking near 1550 nm is a heme-to-Fe(III) charge transfer excitation. These transitions have not previously been observed for cyt b559 or cyt c550. The distinctive characteristics of the MCD signals seen at 770 nm allow us to assign absorption in this region to a dz(2)->d(x2-y2) transition of Mn(III) in the Ca-Mn4O5 cluster of the oxygen evolving centre. Current measurements were performed in the S1 state. Detailed analyses of this spectral region, especially in higher S states, promise to provide a new window on models of water oxidation. PMID- 25445316 TI - Protein chaperones mediating copper insertion into the CuA site of the aa3-type cytochrome c oxidase of Paracoccus denitrificans. AB - The biogenesis of the mitochondrial cytochrome c oxidase is a complex process involving the stepwise assembly of its multiple subunits encoded by two genetic systems. Moreover, several chaperones are required to recruit and insert the redox-active metal centers into subunits I and II, two a-type hemes and a total of three copper ions, two of which form the CuA center located in a hydrophilic domain of subunit II. The copper-binding Sco protein(s) have been implicated with the metallation of this site in various model organisms. Here we analyze the role of the two Sco homologues termed ScoA and ScoB, along with two other copper chaperones, on the biogenesis of the cytochrome c oxidase in the bacterium Paracoccus denitrificans by deleting each of the four genes individually or pairwise, followed by assessing the functionality of the assembled oxidase both in intact membranes and in the purified enzyme complex. Copper starvation leads to a drastic decrease of oxidase activity in membranes from strains involving the scoB deletion. This loss is shown to be of dual origin, (i) a severe drop in steady-state oxidase levels in membranes, and (ii) a diminished enzymatic activity of the remaining oxidase complex, traced back to a lower copper content, specifically in the CuA site of the enzyme. Neither of the other proteins addressed here, ScoA or the two PCu proteins, exhibit a direct effect on the metallation of the CuA site in P. denitrificans, but are discussed as potential interaction partners of ScoB. PMID- 25445317 TI - The rate of second electron transfer to QB(-) in bacterial reaction center of impaired proton delivery shows hydrogen-isotope effect. AB - The 2nd electron transfer in reaction center of photosynthetic bacterium Rhodobacter sphaeroides is a two step process in which protonation of QB(-) precedes interquinone electron transfer. The thermal activation and pH dependence of the overall rate constants of different RC variants were measured and compared in solvents of water (H2O) and heavy water (D2O). The electron transfer variants where the electron transfer is rate limiting (wild type and M17DN, L210DN and H173EQ mutants) do not show solvent isotope effect and the significant decrease of the rate constant of the second electron transfer in these mutants is due to lowering the operational pKa of QB(-)/QBH: 4.5 (native), 3.9 (L210DN), 3.7 (M17DN) and 3.1 (H173EQ) at pH7. On the other hand, the proton transfer variants where the proton transfer is rate limiting demonstrate solvent isotope effect of pH-independent moderate magnitude (2.11+/-0.26 (WT+Ni(2+)), 2.16+/-0.35 (WT+Cd(2+)) and 2.34+/-0.44 (L210DN/M17DN)) or pH-dependent large magnitude (5.7 at pH4 (L213DN)). Upon deuteration, the free energy and the enthalpy of activation increase in all proton transfer variants by about 1 kcal/mol and the entropy of activation becomes negligible in L210DN/M17DN mutant. The results are interpreted as manifestation of equilibrium and kinetic solvent isotope effects and the structural, energetic and kinetic possibility of alternate proton delivery pathways are discussed. PMID- 25445318 TI - Mapping energy transfer channels in fucoxanthin-chlorophyll protein complex. AB - Fucoxanthin-chlorophyll protein (FCP) is the key molecular complex performing the light-harvesting function in diatoms, which, being a major group of algae, are responsible for up to one quarter of the total primary production on Earth. These photosynthetic organisms contain an unusually large amount of the carotenoid fucoxanthin, which absorbs the light in the blue-green spectral region and transfers the captured excitation energy to the FCP-bound chlorophylls. Due to the large number of fucoxanthins, the excitation energy transfer cascades in these complexes are particularly tangled. In this work we present the two-color two-dimensional electronic spectroscopy experiments on FCP. Analysis of the data using the modified decay associated spectra permits a detailed mapping of the excitation frequency dependent energy transfer flow with a femtosecond time resolution. PMID- 25445320 TI - Dynamics of Virus Shedding and In Situ Confirmation of Chelonid Herpesvirus 5 in Hawaiian Green Turtles With Fibropapillomatosis. AB - Cancers in humans and animals can be caused by viruses, but virus-induced tumors are considered to be poor sites for replication of intact virions (lytic replication). Fibropapillomatosis (FP) is a neoplastic disease associated with a herpesvirus, chelonid herpesvirus 5 (ChHV5), that affects green turtles globally. ChHV5 probably replicates in epidermal cells of tumors, because epidermal intranuclear inclusions (EIIs) contain herpesvirus-like particles. However, although EIIs are a sign of herpesvirus replication, they have not yet been firmly linked to ChHV5. Moreover, the dynamics of viral shedding in turtles are unknown, and there are no serological reagents to confirm actual presence of the specific ChHV5 virus in tissues. The investigators analyzed 381 FP tumors for the presence of EIIs and found that overall, about 35% of green turtles had lytic replication in skin tumors with 7% of tumors showing lytic replication. A few (11%) turtles accounted for more than 30% cases having lytic viral replication, and lytic replication was more likely in smaller tumors. To confirm that turtles were actively replicating ChHV5, a prerequisite for shedding, the investigators used antiserum raised against F-VP26, a predicted capsid protein of ChHV5 that localizes to the host cell nucleus during viral replication. This antiserum revealed F-VP26 in EIIs of tumors, thus confirming the presence of replicating ChHV5. In this light, it is proposed that unlike other virus-induced neoplastic diseases, FP is a disease that may depend on superspreaders, a few highly infectious individuals growing numerous small tumors permissive to viral production, for transmission of ChHV5. PMID- 25445319 TI - Enhancing the role of nutrition professionals in weight management: A cross sectional survey. AB - OBJECTIVE: (1) To determine the nonphysician health profession perceived as best qualified to provide weight management. (2) To examine nutrition professionals' current practice characteristics and perceived challenges and solutions for obesity care. (3) To examine the association between nutrition professionals' quality of training and self-efficacy in weight management. METHODS: A 2014 national cross-sectional online survey of 500 U.S. nonphysician health professionals (100 from each: nutrition, nursing, behavioral/mental health, exercise, pharmacy) was analyzed. RESULTS: Nutrition professionals most commonly self-identified as the most qualified group to help patients lose weight (92%), sentiments supported by other health professionals (57%). The most often cited challenge was lack of patient adherence (87%). Among nutrition professionals, 77% reported receiving high-quality training in weight loss counseling. Nutrition professionals who reported high-quality training were significantly more likely to report confidence (95% vs. 48%) and success (74 vs. 50%) in helping obese patients lose weight (P<0.05) than those reporting lower-quality training. CONCLUSIONS: Across all nonphysician health professionals, nutrition professionals were identified as best suited to provide routine weight management counseling to obese patients. Yet nutrition professionals' receipt of high quality weight management training appears critical to their success in helping patients lose weight. PMID- 25445321 TI - Mutations in and Expression of the Tumor Suppressor Gene p53 in Egg-Type Chickens Infected With Subgroup J Avian Leukosis Virus. AB - To investigate the molecular mechanisms of the oncogenic effects of avian leukosis virus subgroup J (ALV-J), we examined mutations in and the expression of p53 in the myelocytomas distributed in the liver, spleen, trachea, and bone marrow, as well as in fibrosarcomas in the abdominal cavity and hemangiomas in skin from chickens that were naturally or experimentally infected with ALV-J. Two types of mutations in the p53 gene were detected in myelocytomas of both the experimentally infected and the naturally infected chickens and included point mutations and deletions. Two of the point mutations have not been reported previously. Partial complementary DNA clones with a 122-bp deletion in the p53 gene ORF and a 15-bp deletion in the C-terminus were identified in the myelocytomas. In addition, moderate expression of the mutant p53 protein was detected in the myelocytomas that were distributed in the liver, trachea, spleen, and bone marrow. Mutant p53 protein was not detected in the subcutaneous hemangiomas or in the abdominal fibrosarcomas associated with natural and experimental ALV-J infection, respectively. These results identify mutations associated with abnormal expression of p53 in ALV-J-associated myelocytomas, suggesting a role in tumorigenesis. PMID- 25445322 TI - Aleutian Disease: An Emerging Disease in Free-Ranging Striped Skunks (Mephitis mephitis) From California. AB - Aleutian disease virus (ADV, Amdovirus, Parvoviridae) primarily infects farmed mustelids (mink and ferrets) but also other fur-bearing animals and humans. Three Aleutian disease (AD) cases have been described in captive striped skunks; however, little is known about the relevance of AD in free-ranging carnivores. This work describes the pathological findings and temporospatial distribution in 7 cases of AD in free-ranging striped skunks. All cases showed neurologic disease and were found in a 46-month period (2010-2013) within a localized geographical region in California. Lesions included multisystemic plasmacytic and lymphocytic inflammation (ie, interstitial nephritis, myocarditis, hepatitis, meningoencephalitis, pneumonia, and splenitis), glomerulonephritis, arteritis with or without fibrinoid necrosis in several organs (ie, kidney, heart, brain, and spleen), splenomegaly, ascites/hydrothorax, and/or encephalomalacia with cerebral microangiopathy. ADV infection was confirmed in all cases by specific polymerase chain reaction and/or in situ hybridization. The results suggest that AD is an emerging disease in free-ranging striped skunks in California. PMID- 25445323 TI - Spinal Cord Ependymal Responses to Naturally Occurring Traumatic Spinal Cord Injury in Dogs. AB - The spinal cord ependymal layer (SEL) is a recent focus in spinal cord injury (SCI) research because of its potential to serve as a source of endogenous neural stem cells. Dogs are an important spontaneous model of SCI; however, there is a paucity of information available in the literature regarding the canine SEL. Here we describe the histologic appearance and immunohistochemical staining patterns of the SEL in normal dogs (n = 4) and dogs with acute SCI caused by intervertebral disk extrusion (n = 7). Immunohistochemical staining for PCNA, Ki 67, caspase 3, E-cadherin, GFAP, and vimentin was employed in both groups. Staining for Ki-67 was absent in the SEL of normal and SCI-affected dogs, indicating possible restricted proliferative capacity of the canine SEL acutely after SCI. GFAP-positive cells were increased after SCI at both at the lesion epicenter and at proximal spinal cord sites (P = .001 and P = .006, respectively), supporting the possibility of astrocytic differentiation within the SEL after SCI. Total E-cadherin staining did not differ between normal and SCI-affected dogs (P = .42 for lesion epicenter, P = .09 at proximal sites) and was restricted to the apical cell surface in normal dogs. After SCI, E-cadherin staining was membrane-circumferential and cytosolic in nature, indicating possible loss of cellular polarity after injury that could drive cell migration from the SEL to injury sites. Enhanced GFAP expression and changes in E-cadherin expression patterns support additional studies to evaluate the canine SEL as a source of endogenous neural precursors that may be modulated for future clinical interventions after SCI. PMID- 25445325 TI - Development and characterization of a pre-treatment procedure to eliminate human monoclonal antibody therapeutic drug and matrix interference in cell-based functional neutralizing antibody assays. AB - Biological therapeutics can induce an undesirable immune response resulting in the formation of anti-drug antibodies (ADA), including neutralizing antibodies (NAbs). Functional (usually cell-based) NAb assays are preferred to determine NAb presence in patient serum, but are often subject to interferences from numerous serum factors, such as growth factors and disease-related cytokines. Many functional cell-based NAb assays are essentially drug concentration assays that imply the presence of NAbs by the detection of small changes in functional drug concentration. Any drug contained in the test sample will increase the total amount of drug in the assay, thus reducing the sensitivity of NAb detection. Biotin-drug Extraction with Acid Dissociation (BEAD) has been successfully applied to extract ADA, thereby removing drug and other interfering factors from human serum samples. However, to date there has been no report to estimate the residual drug level after BEAD treatment when the drug itself is a human monoclonal antibody; mainly due to the limitation of traditional ligand-binding assays. Here we describe a universal BEAD optimization procedure for human monoclonal antibody (mAb) drugs by using a LC-MS/MS method to simultaneously measure drug (a mutant human IgG4), NAb positive control (a mouse IgG), and endogenous human IgGs as an indicator of nonspecific carry-over in the BEAD eluate. This is the first report demonstrating that residual human mAb drug level in clinical sample can be measured after BEAD pre-treatment, which is critical for further BEAD procedure optimization and downstream immunogenicity testing. PMID- 25445324 TI - Integrative analysis of T cell motility from multi-channel microscopy data using TIAM. AB - Integrative analytical approaches are needed to study and understand T cell motility as it is a highly coordinated and complex process. Several computational algorithms and tools are available to track motile cells in time-lapse microscopy images. In contrast, there has only been limited effort towards the development of tools that take advantage of multi-channel microscopy data and facilitate integrative analysis of cell-motility. We have implemented algorithms for detecting, tracking, and analyzing cell motility from multi-channel time-lapse microscopy data. We have integrated these into a MATLAB-based toolset we call TIAM (Tool for Integrative Analysis of Motility). The cells are detected by a hybrid approach involving edge detection and Hough transforms from transmitted light images. Cells are tracked using a modified nearest-neighbor association followed by an optimization routine to join shorter segments. Cell positions are used to perform local segmentation for extracting features from transmitted light, reflection and fluorescence channels and associating them with cells and cell-tracks to facilitate integrative analysis. We found that TIAM accurately captures the motility behavior of T cells and performed better than DYNAMIK, Icy, Imaris, and Volocity in detecting and tracking motile T cells. Extraction of cell associated features from reflection and fluorescence channels was also accurate with less than 10% median error in measurements. Finally, we obtained novel insights into T cell motility that were critically dependent on the unique capabilities of TIAM. We found that 1) the CD45RO subset of human CD8 T cells moved faster and exhibited an increased propensity to attach to the substratum during CCL21-driven chemokinesis when compared to the CD45RA subset; and 2) attachment area and arrest coefficient during antigen-induced motility of the CD45A subset is correlated with surface density of integrin LFA1 at the contact. PMID- 25445327 TI - Surface profiles of live colorectal cancer cells and tumor infiltrating lymphocytes from surgical samples correspond to prognostic categories. AB - Extensive surface profiles of colorectal cancer (CRC) cells and tumor infiltrating lymphocytes (TIL) have been obtained from 45 surgical resection samples. Live cells were captured on an antibody microarray and stained with fluorescently-labeled antibodies. Minimal panels of 11 CRC antigens (CD13, CD24, CD26, CD49d, CD138, CD166, CA-125, CA19-9, EGFR, Galectin-4 and HLA-DR) and 11 T cell antigens (CD10, CD11b, CD11c, CD25, CD31, CD95, CD151, CD181, Galectin-4, CA19-9, TSP-1) provide signatures for relapse and survival. Hierarchical clustering of profiles from CRC cells and TIL identified groups of patients for survival, systemic relapse and death. The groups from CRC and TIL profiles for systemic relapse showed 79.2% concordance, enabling prediction of relapse after surgery. The results demonstrate communication between CRC cells and TIL. PMID- 25445328 TI - Efficient conditional gene expression following transplantation of retrovirally transduced bone marrow stem cells. AB - Retroviral gene therapy combined with bone marrow stem cell transplantation can be used to generate mice with ectopic gene expression in the bone marrow compartment in a quick and cost effective manner when compared to generating and maintaining transgenic mouse lines. However a limitation of this procedure is the lack of cell specificity in gene expression that is associated with the use of endogenous retroviral promoters. Restricting gene expression to specific cell subsets utilising tissue-specific promoter driven retroviral vectors is a challenge. Here we describe the generation of conditional expression of retrovirally encoded genes in specific bone marrow derived cell lineages utilising a Cre-dependent retroviral vector. By utilising Lck and CD19 restricted Cre transgenic bone marrow stem cells, we generate chimeric animals with T or B lymphocyte restricted gene expression respectively. The design of the Cre dependent retroviral vector enables expression of encoded MOG and GFP genes only in association with Cre mediated DNA inversion. Importantly this strategy does not significantly increase the size of the retroviral vector; as such we are able to generate bone marrow chimeric animals with significantly higher chimerism levels than previous studies utilising Cre-dependent retroviral vectors and Cre transgenic bone marrow stem cells. This demonstrates that the use of Cre dependent retroviral vectors is able to yield high chimerism levels for experimental use and represent a viable alternative to generating transgenic animals. PMID- 25445326 TI - Vaccine-induced plasmablast responses in rhesus macaques: phenotypic characterization and a source for generating antigen-specific monoclonal antibodies. AB - Over 100 broadly neutralizing antibodies have been isolated from a minority of HIV infected patients, but the steps leading to the selection of plasma cells producing such antibodies remain incompletely understood, hampering the development of vaccines able to elicit them. Rhesus macaques have become a preferred animal model system used to study SIV/HIV, for the characterization and development of novel therapeutics and vaccines as well as to understand pathogenesis. However, most of our knowledge about the dynamics of antibody responses is limited to the analysis of serum antibodies or monoclonal antibodies generated from memory B cells. In a vaccine setting, relatively little is known about the early cellular responses that elicit long-lived plasma cells and memory B cells and the tools to dissect plasmablast responses are not available in macaques. In the current study, we show that the majority (>80%) of the vaccine induced plasmablast response are antigen-specific by functional ELISPOT assays. While plasmablasts are easily defined and isolated in humans, those same phenotypic markers have not been useful for identifying macaque plasmablasts. Here we describe an approach that allows for the isolation and single cell sorting of vaccine-induced plasmablasts. Finally, we show that isolated plasmablasts can be used to efficiently recover antigen-specific monoclonal antibodies through single cell expression cloning. This will allow detailed studies of the early plasmablast responses in rhesus macaques, enabling the characterization of both their repertoire breadth as well as the epitope specificity and functional qualities of the antibodies they produce, not only in the context of SIV/HIV vaccines but for many other pathogens/vaccines as well. PMID- 25445329 TI - Quantification of the epitope diversity of HIV-1-specific binding antibodies by peptide microarrays for global HIV-1 vaccine development. AB - An effective vaccine against human immunodeficiency virus type 1 (HIV-1) will have to provide protection against a vast array of different HIV-1 strains. Current methods to measure HIV-1-specific binding antibodies following immunization typically focus on determining the magnitude of antibody responses, but the epitope diversity of antibody responses has remained largely unexplored. Here we describe the development of a global HIV-1 peptide microarray that contains 6564 peptides from across the HIV-1 proteome and covers the majority of HIV-1 sequences in the Los Alamos National Laboratory global HIV-1 sequence database. Using this microarray, we quantified the magnitude, breadth, and depth of IgG binding to linear HIV-1 sequences in HIV-1-infected humans and HIV-1 vaccinated humans, rhesus monkeys and guinea pigs. The microarray measured potentially important differences in antibody epitope diversity, particularly regarding the depth of epitope variants recognized at each binding site. Our data suggest that the global HIV-1 peptide microarray may be a useful tool for both preclinical and clinical HIV-1 research. PMID- 25445330 TI - Physical activity patterns and metabolic syndrome in Costa Rica. AB - OBJECTIVE: To examine whether total physical activity or activity patterns are associated with metabolic syndrome and its components. METHODS: Participants include 1994 controls from a case-control study of non-fatal myocardial infarction in Costa Rica (1994-2004). Physical activity was assessed via self administered questionnaire and patterns were identified using principal components analysis. Metabolic syndrome was assessed via blood samples and anthropometry measurements from in-home study visits. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated using log binomial regression. Adjusted least squares means of metabolic syndrome components were calculated by quintile of total activity and pattern scores. RESULTS: Four activity patterns were identified: rest/sleep, agricultural, light indoor activity, and manual labor. Total activity was not associated with metabolic syndrome. Metabolic syndrome prevalence was 20% lower in participants with the highest scores on the agricultural job pattern compared to those with the lowest (PR: 0.80, 95% CI: 0.68-0.94). Higher total activity was associated with lower triglycerides and lower HDL cholesterol. Higher scores on each pattern were inversely associated with metabolic syndrome components, particularly waist circumference and fasting blood glucose. CONCLUSIONS: Patterns or types of physical activity may be more strongly associated with metabolic syndrome and its components than total activity levels. PMID- 25445331 TI - Effectiveness of psychological and/or educational interventions to prevent the onset of episodes of depression: A systematic review of systematic reviews and meta-analyses. AB - OBJECTIVE: To determine the effectiveness of psychological and/or educational interventions to prevent the onset of episodes of depression. METHODS: Systematic review of systematic reviews and meta-analyses (SR/MA). We searched PubMed, PsycINFO, Cochrane Database of Systematic Reviews, OpenGrey, and PROSPERO from their inception until February 2014. Two reviewers independently evaluated the eligibility criteria of all SR/MA, abstracted data, and determined bias risk (AMSTAR). RESULTS: Twelve SR/MA (156 non-repeated trials and 56,158 participants) were included. Of these, 142 (91%) were randomized-controlled, 13 (8.3%) controlled trials, and 1 (0.6%) had no control group. Five SR/MA focused on children and adolescents, four on specific populations (women after childbirth, of low socioeconomic status, or unfavorable circumstances; patients with severe traumatic physical injuries or stroke) and three addressed the general population. Nine (75%) SR/MA concluded that interventions to prevent depression were effective. Of the 156 trials, 137 (87.8%) reported some kind of effect size calculation. Effect sizes were small in 45 (32.8%), medium in 26 (19.1%), and large in 25 (18.2%) trials; 41 (29.9%) trials were not effective. Of the 141 trials for which follow-up periods were available, only 34 (24.1%) exceeded 12 months. CONCLUSION: Psychological and/or educational interventions to prevent onset of episodes of depression were effective, although most had small or medium effect sizes. PMID- 25445332 TI - Step based physical activity guidelines for preschool-aged children. AB - OBJECTIVE: Public health organizations recommend that preschool-aged children accumulate at least 3h of physical activity (PA) daily. Objective monitoring using pedometers offers an opportunity to measure preschooler's PA and assess compliance with this recommendation. The purpose of this study was to derive step based recommendations consistent with the 3h PA recommendation for preschool-aged children. METHOD: The study sample comprised 916 preschool-aged children, aged 3 to 6years (mean age=5.0+/-0.8years). Children were recruited from kindergartens located in Portugal, between 2009 and 2013. Children wore an ActiGraph GT1M accelerometer that measured PA intensity and steps per day simultaneously over a 7-day monitoring period. Receiver operating characteristic (ROC) curve analysis was used to identify the daily step count threshold associated with meeting the daily 3hour PA recommendation. RESULTS: A significant correlation was observed between minutes of total PA and steps per day (r=0.76, p<0.001). The optimal step count for >=3h of total PA was 9099 steps per day (sensitivity (90%) and specificity (66%)) with area under the ROC curve=0.86 (95% CI: 0.84 to 0.88). CONCLUSION: Preschool-aged children who accumulate less than 9000 steps per day may be considered Insufficiently Active. PMID- 25445333 TI - Implications of lower risk thresholds for statin treatment in primary prevention: analysis of CPRD and simulation modelling of annual cholesterol monitoring. AB - OBJECTIVE: To estimate numbers affected by a recent change in UK guidelines for statin use in primary prevention of cardiovascular disease. METHOD: We modelled cholesterol ratio over time using a sample of 45,151 men (>=40years) and 36,168 women (>=55years) in 2006, without statin treatment or previous cardiovascular disease, from the Clinical Practice Research Datalink. Using simulation methods, we estimated numbers indicated for new statin treatment, if cholesterol was measured annually and used in the QRISK2 CVD risk calculator, using the previous 20% and newly recommended 10% thresholds. RESULTS: We estimate that 58% of men and 55% of women would be indicated for treatment by five years and 71% of men and 73% of women by ten years using the 20% threshold. Using the proposed threshold of 10%, 84% of men and 90% of women would be indicated for treatment by 5years and 92% of men and 98% of women by ten years. CONCLUSION: The proposed change of risk threshold from 20% to 10% would result in the substantial majority of those recommended for cholesterol testing being indicated for statin treatment. Implications depend on the value of statins in those at low to medium risk, and whether there are harms. PMID- 25445334 TI - Association of cardiovascular health screening with mortality, clinical outcomes, and health care cost: a nationwide cohort study. AB - OBJECTIVE: To determine whether a cardiovascular disease (CVD) health screening program is associated with CVD-related health conditions, incidence of cardiovascular events, mortality, healthcare utilization, and costs. METHODS: Cohort study of a 3% random sample of all Korea National Health Insurance members 40years of age or older and free of CVD or CVD-related health conditions was conducted. A total 443,337 study participants were followed-up from January 1, 2005 through December 31, 2010. RESULTS: In primary analysis, the hazard ratios for CVD mortality, all-cause mortality, incident composite CVD events, myocardial infarction, cerebral infarction, and cerebral hemorrhage comparing participants who attended a screening exam during 2003-2004 compared to those who did not were 0.58 (95% CI: 0.53-0.63), 0.62 (95% CI: 0.60-0.64), 0.82 (95% CI: 0.78-0.85), 0.84 (95% CI: 0.75-0.93), 0.84 (95% CI: 0.79-0.89), and 0.73 (95% CI: 0.67-0.80), respectively. Screening attenders had higher rates of newly diagnosed hypertension, diabetes mellitus, and dyslipidemia, lower inpatient days of stay and cost, and lower outpatient cost compared to non-attenders. CONCLUSIONS: Participation in CVD health screening was associated with lower rates of CVD, all cause mortality, and CVD events, higher detection of CVD-related health conditions, and lower healthcare utilization and costs. PMID- 25445335 TI - Evaluation of a brief counseling for tobacco cessation in dental clinics among Swedish smokers and snus users. A cluster randomized controlled trial (the FRITT study). AB - OBJECTIVE: The aim of this study is to assess the effectiveness of a very brief structured counseling for tobacco cessation in dentistry clinics. METHOD: A cluster randomized trial was conducted in Sweden in 2012-2013. Twenty-seven dentistry clinics in two Swedish counties were randomized to provide either a structured brief advice based on the 5 A's model or usual care. Participants were 467 patients currently using tobacco daily (225 in the intervention group and 242 in usual care), of which 97% were retained at follow-up, six months after enrolment. Study outcomes were: 7-day abstinence (primary outcome); 3-month sustained abstinence; 50% reduction of the amount tobacco used; quit attempts lasting at least 24h. RESULTS: Compared to usual care, brief counseling was not associated to statistically significant increase in the proportion abstinent from tobacco use after 6months. However, there was a statistically significant association with reduction of tobacco consumption (OR=2.07 95% CI 1.28-3.35). Changes in the expected direction for all outcomes were more frequent in the intervention than in the usual care group, and larger among exclusive snus users than among smokers. CONCLUSIONS: Very brief and structured counseling in dentistry may achieve positive behavioral modifications among tobacco users, with significant reduction of tobacco consumption, particularly among smokeless tobacco users. PMID- 25445337 TI - Multiple functions of capsid proteins in (+) stranded RNA viruses during plant virus interactions. AB - In addition to providing a protective shell for genomic RNA(s), the coat (capsid) proteins (CPs) of plus-stranded RNA viruses play a variety of other functions that condition the plant-virus relationship. In this review we outline the extensive research progress that has been made within the last decade on those CP characteristics that relate to virus infectivity, pathogenicity, symptom expression, interactions with host factors, virus movement, vector transmission, host range, as well as those used to study virus evolution. By discussing the examples among a variety of plant RNA viruses we show that in addition to general features and pathways, the involvement of CPs may assume very distinct tasks that depend on the particular virus life style. Research perspectives and potential applications are discussed at the end. PMID- 25445338 TI - Measles virus genetic evolution throughout an imported epidemic outbreak in a highly vaccinated population. AB - Measles virus circulates endemically in African and Asian large urban populations, causing outbreaks worldwide in populations with up-to-95% immune protection. We studied the natural genetic variability of genotype B3.1 in a population with 95% vaccine coverage throughout an imported six month measles outbreak. From first pass viral isolates of 47 patients we performed direct sequencing of genomic cDNA. Whilst no variation from index case sequence occurred in the Nucleocapsid gene hyper-variable carboxy end, in the Hemagglutinin gene, main target for neutralizing antibodies, we observed gradual nucleotide divergence from index case along the outbreak (0% to 0.380%, average 0.138%) with the emergence of transient and persistent non-synonymous and synonymous mutations. Little or no variation was observed between the index and last outbreak cases in Phosphoprotein, Nucleocapsid, Matrix and Fusion genes. Most of the H non-synonymous mutations were mapped on the protein surface near antigenic and receptors binding sites. We estimated a MV-Hemagglutinin nucleotide substitution rate of 7.28 * 10-6 substitutions/site/day by a Bayesian phylogenetic analysis. The dN/dS analysis did not suggest significant immune or other selective pressures on the H gene during the outbreak. These results emphasize the usefulness of MV-H sequence analysis in measles epidemiological surveillance and elimination programs, and in detection of potentially emergence of measles virus neutralization-resistant mutants. PMID- 25445336 TI - Receptor-binding domain-based subunit vaccines against MERS-CoV. AB - Development of effective vaccines, in particular, subunit-based vaccines, against emerging Middle East respiratory syndrome (MERS) caused by the MERS coronavirus (MERS-CoV) will provide the safest means of preventing the continuous spread of MERS in humans and camels. This review briefly describes the structure of the MERS-CoV spike (S) protein and its receptor-binding domain (RBD), discusses the current status of MERS vaccine development and illustrates the strategies used to develop RBD-based subunit vaccines against MERS. It also summarizes currently available animal models for MERS-CoV and proposes a future direction for MERS vaccines. Taken together, this review will assist researchers working to develop effective and safe subunit vaccines against MERS-CoV and any other emerging coronaviruses that might cause future pandemics. PMID- 25445339 TI - Changes in the mycovirus (LeV) titer and viral effect on the vegetative growth of the edible mushroom Lentinula edodes. AB - This study attempted to cure the edible mushroom Lentinula edodes strain FMRI0339 of the L. edodes mycovirus (LeV) in order to obtain an isogenic virus-free fungal strain as well as a virus-infected strain for comparison. Mycelial fragmentation, followed by being spread on a plate with serial dilutions resulted in a virus free colony. Viral absence was confirmed with gel electrophoresis after dsRNA specific virus purification, Northern blot analysis, and PCR using reverse transcriptase (RT-PCR). Once cured, all of fungal cultures remained virus-free over the next two years. Interestingly, the viral titer of LeV varied depending on the culture condition. The titer from the plate culture showed at least a 20 fold higher concentration than that grown in the liquid culture. However, the reduced virus titer in the liquid culture was recovered by transferring the mycelia to a plate containing the same medium. In addition, oxygen-depleted culture conditions resulted in a significant decrease of viral concentration, but not to the extent seen in the submerged liquid culture. Although no discernable phenotypic changes in colony morphology were observed, virus-cured strains showed significantly higher growth rates and mycelial mass than virus-infected strains. These results indicate that LeV infection has a deleterious effect on mycelial growth. PMID- 25445341 TI - Protein misfolding cyclic amplification (PMCA): Current status and future directions. AB - Transmissible spongiform encephalopathies (TSEs) most commonly known as prion diseases are invariably fatal neurological disorders that affect humans and animals. These disorders differ from other neurodegenerative conformational diseases caused by the accumulation in the brain of misfolded proteins, sometimes with amyloid properties, in their ability to infect susceptible species by various routes. While the infectious properties of amyloidogenic proteins, other than misfolded prion protein (PrP(TSE)), are currently under scrutiny, their potential to transmit from cell to cell, one of the intrinsic properties of the prion, has been recently shown in vitro and in vivo. Over the decades, various cell culture and laboratory animal models have been developed to study TSEs. These assays have been widely used in a variety of applications but showed to be time consuming and entailed elevated costs. Novel economic and fast alternatives became available with the development of in vitro assays that are based on the property of conformationally abnormal PrP(TSE) to recruit normal cellular PrP(C) to misfold. These include the cell-free conversion assay, protein misfolding cyclic amplification (PMCA) and quaking induced conversion assay (QuIC), of which the PMCA has been the only technology shown to generate infectious prions. Moreover, it allows indefinite amplification of PrP(TSE) with strain-specific biochemical and biological properties of the original molecules and under certain conditions may give rise to new spontaneously generated prions. The method also allows addressing the species barrier phenomena and assessing possible risks of animal-to-animal and animal-to-human transmission. Additionally, its unprecedented sensitivity has made possible the detection of as little as one infectious dose of PrP(TSE) and the biochemical identification of this protein in different tissues and biological fluids, including blood, cerebral spinal fluid (CSF), semen, milk, urine and saliva during the pre-clinical and clinical phases of the disease. The mechanistic similarities between TSEs and other conformational disorders have resulted in the adaptation of the PMCA to the amplification and detection of various amyloidogenic proteins. Here we provide a compelling discussion of the different applications of this technology to the study of TSEs and other neurodegenerative diseases. PMID- 25445342 TI - Amino acids substitutions in sigma1 and MU1 outer capsid proteins of a Vero cell adapted mammalian orthoreovirus are required for optimal virus binding and disassembly. AB - In a recent study, the serotype 3 Dearing strain of mammalian orthoreovirus was adapted to Vero cells; cells that exhibit a limited ability to support the early steps of reovirus uncoating and are unable to produce interferon as an antiviral response upon infection. The Vero cell-adapted virus (VeroAV) exhibits amino acids substitutions in both the sigma1 and MU1 outer capsid proteins but no changes in the sigma3 protein. Accordingly, the virus was shown not to behave as a classical uncoating mutant. In the present study, an increased ability of the virus to bind at the Vero cell surface was observed and is likely associated with an increased ability to bind onto cell-surface sialic acid residues. In addition, the kinetics of MU1 disassembly from the virions appears to be altered. The plasmid-based reverse genetics approach confirmed the importance of sigma1 amino acids substitutions in VeroAV's ability to efficiently infect Vero cells, although MU1 co-adaptation appears necessary to optimize viral infection. This approach of combining in vitro selection of reoviruses with reverse genetics to identify pertinent amino acids substitutions appears promising in the context of eventual reovirus modification to increase its potential as an oncolytic virus. PMID- 25445343 TI - Influence of amino acid variations in the NS3, NS4A and NS4B of HCV genotypes 1a, 1b, 3a, 3b and 6f on the response to pegylated interferon and ribavirin combination therapy. AB - BACKGROUND: It has been suggested that HCV proteins, core, NS3/4A, NS4B, and NS5A, contribute to the resistance of HCV to IFN and ribavirin (RBV) treatments. AIM: To assess the effects of HCV amino acid variations in NS3, NS4A and NS4B of HCV subtypes 1a, 1b, 3a, 3b and 6f on the response to pegylated interferon (Peg IFN) and RBV therapy. METHODS: One hundred and thirty four HCV isolates of genotypes 1a, 1b, 3a, 3b and 6f obtained from HCV patients both before and at week 4 of treatments were evaluated. Amino acid sequences of NS3, NS4A and NS4B were analyzed and in compared to reference sequences of corresponding genotypes. RESULTS: The data revealed that amino acid variations within the full-length NS3, protease and helicase domains of NS3 of HCV 1a from responders were significantly higher than those from treatment failure groups as compared to reference sequences of each corresponding genotype. Similar results were observed in the full-length and helicase domain but not in the protease domain of HCV 1b. However, the number of amino acid variations in NS3 of HCV 3a, 3b and 6f as well as in NS4A and NS4B showed no difference between the viruses from responders and treatment failure group. Analysis of amino acid variations both before and at week 4 of treatment revealed that the mean number of amino acid variation in the full-length NS3 of HCV 3a and 3b from responders were also significantly higher than those from the treatment failure group. CONCLUSION: Our study suggests that the increase of amino acid variations within the NS3 protein of HCV 1a, 1b, 3a and 3b were associated with the response to Peg-IFN and RBV treatment in Thai patients. PMID- 25445340 TI - Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis. AB - Coronaviruses are a large group of enveloped, single-stranded positive-sense RNA viruses that infect a wide range of avian and mammalian species, including humans. The emergence of deadly human coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) have bolstered research in these viral and often zoonotic pathogens. While coronavirus cell and tissue tropism, host range, and pathogenesis are initially controlled by interactions between the spike envelope glycoprotein and host cell receptor, it is becoming increasingly apparent that proteolytic activation of spike by host cell proteases also plays a critical role. Coronavirus spike proteins are the main determinant of entry as they possess both receptor binding and fusion functions. Whereas binding to the host cell receptor is an essential first step in establishing infection, the proteolytic activation step is often critical for the fusion function of spike, as it allows for controlled release of the fusion peptide into target cellular membranes. Coronaviruses have evolved multiple strategies for proteolytic activation of spike, and a large number of host proteases have been shown to proteolytically process the spike protein. These include, but are not limited to, endosomal cathepsins, cell surface transmembrane protease/serine (TMPRSS) proteases, furin, and trypsin. This review focuses on the diversity of strategies coronaviruses have evolved to proteolytically activate their fusion protein during spike protein biosynthesis and the critical entry step of their life cycle, and highlights important findings on how proteolytic activation of coronavirus spike influences tissue and cell tropism, host range and pathogenicity. PMID- 25445344 TI - Form follows function in geminiviral minichromosome architecture. AB - A comprehensive survey on the viral minichromosomes of the begomoviruses Abutilon mosaic virus, tomato yellow leaf curl Sardinia virus, African cassava mosaic virus, Indian cassava mosaic virus (family Geminiviridae) during the course of infections in Nicotiana benthamiana is summarized. Using optimized one dimensional and two-dimensional gel systems combined with blot hybridization and a standardized evaluation, discrete and heterogeneous virus-specific signals with different DNA forms were compared to trace functions of viral multiplication with inactive/active replication and/or transcription. A quantitative approach to compare the distantly related viruses during the course of infection with the aim to generalize the conclusions for geminiviruses has been developed. Focussing on the distribution of topoisomers of viral supercoiled DNA, which reflect minichromosomal stages, predominant minichromosomes with 12 nucleosomes, less with 13 nucleosomes and no with 11 nucleosomes were found. These results indicate that chromatin with only one open gap to bind transcription factors is the favourite form. The dynamics during infections in dependence on the experimental conditions is discussed with reference to the design of experiments for resistance breeding and molecular analyses. PMID- 25445345 TI - Intranasal immunization of recombinant Lactococcus lactis induces protection against H5N1 virus in ferrets. AB - The increasing outbreaks of highly pathogenic avian influenza A (HPAI) H5N1 viruses in birds and human bring out an urgent need to develop a safe and effective vaccine to control and prevent H5N1 infection. Lactococcus lactis (L. lactis) based vaccine platform is a promising approach for mucosal H5N1 vaccine development. Intranasal immunization is the potential to induce mucosal immune response which is associated with protective immunity. To develop a safe and effective mucosal vaccine against HAPI H5N1, we extended our previous study by evaluating the immunogenicity of L. lactis-psA-HA1 in the absence of adjuvant via intranasal route in the ferret model. Ferrets administered intranasally with L. lactis-pgsA-HA1 could elicit robust humoral and mucosal immune responses, as well as significant HI titers. Importantly, ferrets were completely protected from H5N1 virus challenge. These findings suggest that L. lactis-pgsA-HA1 can be considered an alternative mucosal vaccine during A/H5N1 pandemic. PMID- 25445346 TI - Transcription analysis on response of porcine alveolar macrophages to co infection of the highly pathogenic porcine reproductive and respiratory syndrome virus and Mycoplasma hyopneumoniae. AB - Porcine respiratory disease complex (PRDC) is of great concern economically, for swine producers worldwide. Co-infections with porcine reproductive and respiratory syndrome virus (PRRSV) and Mycoplasma hyopneumoniae (Mhp) are considered the major causative agents of PRDC, and responsible for mass mortality in pigs. Nevertheless, the molecular mechanisms underlying the host factors involved in pathogenesis and persistent infection have not been clearly established because of a lack of information regarding host responses following co-infection. In the current study, high throughput cDNA microarray assays were employed to evaluate host responses of porcine alveolar macrophages (PAM) to co infection with highly pathogenic PRRSV (HP-PRRSV) and Mhp. A total of 2152 and 1760 genes were identified as being differentially expressed between the control group and PRRSV+Mhp co-infected group at 6 and 15 h post infection, respectively. The DE genes were involved in many vital functional classes, including inflammatory response, immune response, apoptosis, defense response, signal transduction. The pathway analysis demonstrated that the most significant pathways were associated with chemokine signaling pathway, cytokine, TLR, RLR and NLR signaling pathways and Jak-STAT signaling pathway. STRING analysis demonstrated that IL-1beta is an integral gene in co-infections with PRRSV and Mhp. The present study is the first to document the response of PAMs to co infection with HP-PRRSV and Mhp. The observed gene expression profile could help with the screening of potential host agents for reducing the prevalence of co infections, and to further develop our understanding of the molecular pathogenesis associated with PRRSV and Mhp co-infection in pigs. PMID- 25445347 TI - A naturally occurring substitution in the E2 protein of Salmonid alphavirus subtype 3 changes viral fitness. AB - Phylogenetic analyses of the Salmonid alphavirus subtype 3 (SAV3) epizootic have suggested that a substitution from proline to serine in the receptor binding protein E2 position 206 has occurred after the introduction of virus from a wild reservoir to farmed salmonid fish in Norway. We modelled the 3D structure of P62, the uncleaved E3-E2 precursor, of SAVH20/03 based on its sequence homology to the Chikungunya virus (CHIKV), and studied in vitro and in vivo effects of the mutation using reverse genetics. E2(206) is located on the surface of the B domain of E2, which is associated with receptor attachment in alphaviruses. Recombinant virus expressing the E2(206S) codon replicated slower and produced significantly less genomic copies than virus expressing the ancestral E2(206P) codon in vitro in Bluegill Fry (BF2) cells. The E2(206S) mutant was out-competed by the E2(206P) mutant after 5 passages in an in vitro competition assay, confirming that the substitution negatively affects the efficacy of virus multiplication in cell culture. Both mutants were highly infectious to Atlantic salmon (Salmo salar), produced similar viral RNA loads in gills, heart, kidney and brain, and induced similar histopathologic changes in these organs. The E2(206S) mutant produced a less persistent infection in salmon and was shed more rapidly to water than the E2(206P) mutant. Reduced generation time through more rapid shedding could therefore explain why a serine in this position became dominant in the viral population after SAV3 was introduced to farmed salmon from the wild reservoir. PMID- 25445348 TI - Genome-wide analysis of codon usage bias in Ebolavirus. AB - Ebola virus (EBOV) is a member of the family Filoviridae and its genome consists of a 19-kb, single-stranded, negative sense RNA. EBOV is subdivided into five distinct species with different pathogenicities, being Zaire ebolavirus (ZEBOV) the most lethal species. The interplay of codon usage among viruses and their hosts is expected to affect overall viral survival, fitness, evasion from host's immune system and evolution. In the present study, we performed comprehensive analyses of codon usage and composition of ZEBOV. Effective number of codons (ENC) indicates that the overall codon usage among ZEBOV strains is slightly biased. Different codon preferences in ZEBOV genes in relation to codon usage of human genes were found. Highly preferred codons are all A-ending triplets, which strongly suggests that mutational bias is a main force shaping codon usage in ZEBOV. Dinucleotide composition also plays a role in the overall pattern of ZEBOV codon usage. ZEBOV does not seem to use the most abundant tRNAs present in the human cells for most of their preferred codons. PMID- 25445349 TI - On the interaction and localization of the beet necrotic yellow vein virus replicase. AB - Beet necrotic yellow vein virus (BNYVV) is a multipartite positive-strand RNA virus. BNYVV RNA-1 encodes a non-structural p237 polyprotein processed in two proteins (p150 and p66) by a cis-acting protease activity. BNYVV non-structural proteins are closely related to replication proteins of positive strand RNA viruses such as hepeviruses rather to other plant virus replicases. The p237 and dsRNA have been localized by TEM in ER structures of infected leaf cells whereas dsRNA was immunolabeled in infected protoplasts. The p150 contains domains with methyltransferase, protease, helicase and two domains of unknown function whereas p66 encompasses the RNA-dependent RNA-polymerase signature. We report the existing interactions between functional domains of the p150 and p66 proteins and the addressing of the benyvirus replicase to the endoplasmic reticulum. Yeast two hybrid approach, colocalization with FRET-FLIM analyses and co immunoprecipitation highlighted existing interactions that suggest the presence of a multimeric complex at the vicinity of the cellular membranous web. PMID- 25445351 TI - Infectious pancreatic necrosis virus proteins VP2, VP3, VP4 and VP5 antagonize IFNa1 promoter activation while VP1 induces IFNa1. AB - Infectious pancreatic necrosis virus (IPNV) is one of the major viral pathogens causing disease in farmed Atlantic salmon worldwide. In the present work we show that several of the IPN proteins have powerful antagonistic properties against type I IFN induction in Atlantic salmon. Each of the five IPNV genes cloned into an expression vector were tested for the ability to influence activation of the Atlantic salmon IFNa1 promoter by the interferon promoter inducing protein one (IPS-1) or interferon regulatory factors (IRF). This showed that preVP2, VP3 and VP5 inhibited activation of both promoters, while VP4 only antagonized activation of the IFNa1 promoter. The viral protease VP4 was the most potent inhibitor of IFN induction, apparently targeting the IRF1 and IRF3 branch of the signaling cascade. VP4 antagonism is independent of its protease activity since the catalytically dead mutant VP4K674A inhibited activation of the IFNa1 promoter to a similar extent as wild type VP4. In contrast to the other IPNV proteins, the RNA-dependent RNA polymerase VP1 activated the IFNa1 promoter. The ability to activate the IFN response was disrupted in the mutant VP1S163A, which has lost the ability to produce dsRNA. VP1 also exhibited synergistic effects with IRF1 and IRF3 in inducing an IFNa1-dependent antiviral state in cells. Taken together these results suggest that IPNV has developed multiple IFN antagonistic properties to prevent IFN-induction by VP1 and its dsRNA genome. PMID- 25445350 TI - Let-7c overexpression inhibits dengue virus replication in human hepatoma Huh-7 cells. AB - MicroRNAs (miRNAs) constitute an important class of non-coding RNA implicated in gene expression regulation. More than 1900 miRNA molecules have been identified in humans and their modulation during viral infection and it is recognized to play a role in latency regulation or in establishing an antiviral state. The liver cells are targets during DENV infection, and alteration of liver functions contributes to severe disease. In this work the miRNAs expression profile of the human hepatoma cell line, Huh-7, infected with DENV-2 was determined using microarray and real-time PCR. Let-7c is one of the miRNAs up-regulated during DENV infection in the hepatic Huh-7 as well as in the macrophage-monocytic cell line U937-DC-SIGN. Let-7c overexpression down-regulates both DENV-2 and DENV-4 infection. Additionally, we found that the transcription factor BACH1, a let-7c target, is also down-regulated during DENV infection. In accordance with this finding, HO-1, the main responsive factor of BACH1 was found up-regulated. The up regulation of HO-1 may contribute to the stress oxidative response in infected cells. PMID- 25445352 TI - Vitamin E isomer delta-tocopherol enhances the efficiency of neural stem cell differentiation via L-type calcium channel. AB - The effects of the vitamin E isomer delta-tocopherol on neural stem cell (NSC) differentiation have not been investigated until now. Here we investigated the effects of delta-tocopherol on NSC neural differentiation, maturation and its possible mechanisms. Neonatal rat NSCs were grown in suspended neurosphere cultures, and were identified by their expression of nestin protein and their capacity for self-renewal. Treatment with a low concentration of delta-tocopherol induced a significant increase in the percentage of beta-III-tubulin-positive cells. delta-Tocopherol also stimulated morphological maturation of neurons in culture. We further observed that delta-tocopherol stimulation increased the expression of voltage-dependent Ca(2+) channels. Moreover, a L-type specific Ca(2+) channel blocker verapamil reduced the percentage of differentiated neurons after delta-tocopherol treatment, and blocked the effects of delta-tocopherol on NSC differentiation into neurons. Together, our study demonstrates that delta tocopherol may act through elevation of L-type calcium channel activity to increase neuronal differentiation. PMID- 25445354 TI - Dendritic spine dysgenesis in neuropathic pain. AB - Neuropathic pain is a significant unmet medical need in patients with variety of injury or disease insults to the nervous system. Neuropathic pain often presents as a painful sensation described as electrical, burning, or tingling. Currently available treatments have limited effectiveness and narrow therapeutic windows for safety. More powerful analgesics, e.g., opioids, carry a high risk for chemical dependence. Thus, a major challenge for pain research is the elucidation of the mechanisms that underlie neuropathic pain and developing targeted strategies to alleviate pathological pain. The mechanistic link between dendritic spine structure and circuit function could explain why neuropathic pain is difficult to treat, since nociceptive processing pathways are adversely "hard wired" through the reorganization of dendritic spines. Several studies in animal models of neuropathic pain have begun to reveal the functional contribution of dendritic spine dysgenesis in neuropathic pain. Previous reports have demonstrated three primary changes in dendritic spine structure on nociceptive dorsal horn neurons following injury or disease, which accompany chronic intractable pain: (I) increased density of dendritic spines, particularly mature mushroom-spine spines, (II) redistribution of spines toward dendritic branch locations close to the cell body, and (III) enlargement of the spine head diameter, which generally presents as a mushroom-shaped spine. Given the important functional implications of spine distribution, density, and shape for synaptic and neuronal function, the study of dendritic spine abnormality may provide a new perspective for investigating pain, and the identification of specific molecular players that regulate spine morphology may guide the development of more effective and long-lasting therapies. PMID- 25445353 TI - Influence of worry on sustained attention to emotional stimuli: evidence from the late positive potential. AB - There is preliminary evidence to suggest that worry is associated with dysregulated emotion processing resulting from sustained attention to emotional versus neutral stimuli; however, this hypothesis has not been directly tested in prior research. Therefore, the current study used the event-related late positive potential (LPP) to directly examine if high levels of trait worry moderate sustained attention to emotional versus neutral stimuli. Electroencephalogram data was recorded while twenty-two women passively viewed neutral, positive, dysphoric, and threatening emotional images. Consistent with our hypotheses, higher levels of worry were associated with larger LPP amplitudes for emotional images but not neutral images. Importantly, the positive correlations between trait worry and LPP responses to threatening and positive images were maintained even when controlling for the influence of current anxiety symptoms, suggesting that worry may influence emotion processing whether or not the person is currently anxious. This sustained attention to emotional information may be one mechanism underlying how trait worry increases risk for anxiety disorders. PMID- 25445355 TI - Association of paraoxonase (PON)1 activity, glutathione S-transferase GST T1/M1 and STin.2 polymorphisms with comorbidity of tobacco use disorder and mood disorders. AB - There is evidence that genetic factors influence the probability of comorbidity of tobacco use disorder (TUD) with mood disorders. This study was carried out to examine whether both TUD and mood disorders are associated with genetic biomarkers particularly paraoxonase 1 (PON1) status, polymorphisms of glutathione S-transferases (GSTs), such as GSTM1 and GSTT1, and the STIn 2 polymorphism of the serotonin transporter. PON1 status (Q192R polymorphism and PON1 plasmatic activity), GSTM1, GSTT1, and STin.2 genotypes and alleles were assayed in 4 mutually exclusive study groups, i.e., comorbid mood disorder and TUD (n=95); TUD without mood disorders (n=90); mood disorders but no TUD (n=62); and controls (never-smokers without mood disorders; n=113). Logistic regression analyses showed that comorbid mood disorders and TUD were associated with significantly lower PON1 activity, the STin2.10/10 genotype (protective) or the Stin2.12 allele (risk factor) and the GSTM1 and GSTT1 null genotypes (protective). These results show that comorbid mood disorders and TUD are associated with specific biomarkers related to oxidative stress and serotonin pathways. PMID- 25445357 TI - Diabetes and the plasticity of sensory neurons. AB - Diabetes mellitus targets sensory neurons during the development of peripheral neuropathy. While polyneuropathy is often routinely considered as another 'microvascular' complication of diabetes mellitus, this concept may no longer address the complexities and unique qualities of direct neuronal involvement. The list of altered molecules and pathways in diabetic neurons continues to grow and includes those related to structure, neuronal 'stress', and protection. A role for abnormal direct neuronal insulin signaling has emerged as an important contributing factor in neurodegeneration. Finally, important molecular players that influence neuronal and axon growth, such as PTEN (phosphatase and tensin homolog deleted on chromosome 10) are considered. A better mechanistic understanding of the pathogenesis of diabetic polyneuropathy may foster targeted therapies that reverse a long history of therapeutic failures. PMID- 25445356 TI - Direction of magnetoencephalography sources associated with feedback and feedforward contributions in a visual object recognition task. AB - Identifying inter-area communication in terms of the hierarchical organization of functional brain areas is of considerable interest in human neuroimaging. Previous studies have suggested that the direction of magneto- and electroencephalography (MEG, EEG) source currents depend on the layer-specific input patterns into a cortical area. We examined the direction in MEG source currents in a visual object recognition experiment in which there were specific expectations of activation in the fusiform region being driven by either feedforward or feedback inputs. The source for the early non-specific visual evoked response, presumably corresponding to feedforward driven activity, pointed outward, i.e., away from the white matter. In contrast, the source for the later, object-recognition related signals, expected to be driven by feedback inputs, pointed inward, toward the white matter. Associating specific features of the MEG/EEG source waveforms to feedforward and feedback inputs could provide unique information about the activation patterns within hierarchically organized cortical areas. PMID- 25445358 TI - Cortical spreading depression decreases Fos expression in rat periaqueductal gray matter. AB - The migraine headache involves activation and central sensitization of the trigeminovascular pain pathway. The migraine aura is likely due to cortical spreading depression (CSD), a propagating wave of brief neuronal depolarization followed by prolonged inhibition. The precise link between CSD and headache remains controversial. Our objectives were to study the effect of CSD on neuronal activation in the periaqueductal grey matter (PAG), an area known to control pain and autonomic functions, and to be involved in migraine pathogenesis. Fos immunoreactive nuclei were counted in rostral PAG and Edinger-Westphal nuclei (PAG-EWn bregma -6.5 mm), and caudal PAG (bregma -8 mm) of 17 adult male Sprague Dawley rats after KCl-induced CSD under chloral hydrate anesthesia. Being part of a pharmacological study, six animals had received, for the preceding 4 weeks daily, intraperitoneal injections of lamotrigine (15 mg/kg), six others had been treated with saline, while five sham-operated animals served as controls. We found that the number of Fos-immunoreactive nuclei in the PAG decreased after CSD provocation. There was no difference between lamotrigine- and saline-treated animals. The number of CSDs correlated negatively with Fos-immunoreactive counts. CSD-linked inhibition of neuronal activity in the PAG might play a role in central sensitization during migraine attacks and contribute to a better understanding of the link between the aura and the headache. PMID- 25445359 TI - Systemic or intra-amygdala infusion of an endocannabinoid CB1 receptor antagonist AM251 blocked propofol-induced anterograde amnesia. AB - Propofol is well-known for its anterograde amnesic actions. However, a recent experiment showed that propofol can also produce retrograde memory enhancement effects via an interaction with the endocannabinoid CB1 system. Therefore, the authors hypothesized that the regulating effect of propofol on the endocannabinoid CB1 system might also decrease the anterograde amnesic effect of propofol under some conditions, which might be a risk factor for intraoperative awareness. Since, the basolateral amygdala (BLA) has been confirmed to mediate propofol-induced anterograde amnesia and the BLA contains a high concentration of CB1 receptors, the authors investigated whether and how the endocannabinoid system, particularly the CB1 receptor within BLA, influences propofol-induced anterograde amnesia. Male Sprague-Dawley rats trained with inhibitory avoidance (IA) were systematically pre-trained using a memory-impairing dose of propofol (25 mg/kg). Before propofol administration, rats received an intraperitoneal injection of a CB1 receptor antagonist AM251 (1 mg/kg or 2 mg/kg) or a bilateral intra-BLA injection of AM251 (0.6 ng or 6 ng per 0.5 MUl). Twenty-four hours after IA training, the IA retention latency was tested. It was found that systemic or intra-BLA injection of a non-regulating dose of AM251 (2 mg/kg or 6 ng per 0.5 MUl, respectively) blocked the memory-impairing effect of propofol. These results indicate that the anterograde amnesic effect of propofol is mediated, in part, by activation of the CB1 cannabinoid receptors in the BLA. PMID- 25445361 TI - Arithmetic memory networks established in childhood are changed by experience in adulthood. AB - Adult bilinguals show stronger access to multiplication tables when using the language in which they learned arithmetic during childhood (LA+) than the other language (LA-), implying language-specific encoding of math facts. However, most bilinguals use LA+ throughout their life, confounding the impact of encoding and use. We tested if using arithmetic facts in LA- could reduce this LA- disadvantage. We measured event related brain potentials while bilingual teachers judged the correctness of multiplication problems in each of their languages. Critically, each teacher taught arithmetic in either LA+ or LA-. Earlier N400 peak latency was observed in both groups for the teaching than non-teaching language, showing more efficient access to these facts with use. LA+ teachers maintained an LA+ advantage, while LA- teachers showed equivalent N400 congruency effects (for incorrect versus correct solutions) in both languages. LA- teachers also showed a late positive component that may reflect conflict monitoring between their LA+ and a strong LA-. Thus, the LA- disadvantage for exact arithmetic established in early bilingual education can be mitigated by later use of LA-. PMID- 25445360 TI - Rosuvastatin attenuated the existing morphine tolerance in rats with L5 spinal nerve transection through inhibiting activation of astrocytes and phosphorylation of ERK42/44. AB - Recent studies suggested that statins have anti-inflammatory effects beyond their lipid-lowering properties. In the present study, we sought to investigate whether rosuvastatin could alleviate morphine tolerance by attenuating the glia mediated neuroinflammation in the spinal cord. Using a rat model of L5 spinal nerve transection, on day 8 after surgery morphine (10 mg/kg) was injected subcutaneously twice daily for consecutive 10 days. On day 13, with the establishment of morphine tolerance, rosuvastatin (10 mg/kg) was given o.p. for 5 days. On day 18, lumbar spinal cord was collected immediately after last behavioral testing. The analgesic effect of morphine was determined as the percentage of maximal possible effect (%MPE) after a single morphine (4 mg/kg) injection via tail vein on day 8, 13, and 18. The MPE decreased significantly after administration of morphine to rats with neuropathy for 5 days. Rosuvastatin administration for 5 days could restore morphine antinociceptive effect significantly. Additionally, the activation of astrocytes, the phosphorylation of extracellular signal-regulated kinase 42/44 (ERK(42/44)) and the expressions of TNFalpha and IL-1beta were inhibited significantly by rosuvastatin. Our data suggested that rosuvastatin was a promising choice to treat neuropathic pain in combination with morphine. PMID- 25445362 TI - L1 modulates PKD1 phosphorylation in cerebellar granule neurons. AB - The neural cell adhesion molecule L1 (L1CAM) is crucial for the development of the nervous system, with an essential role in regulating multiple cellular activities. Protein kinase D1 (PKD1) serves as a key kinase given its diverse array of functions within the cell. Here, we investigated various aspects of the functional relationship between L1 and phosphorylated PKD1 (pPKD1) in cerebellar granule neurons. To study the relationship between L1 and PKD1 phosphorylation, human cerebellar tissue microarrays were subject to immunofluorescence staining. We observed a positive correlation between L1 protein levels and PKD1 phosphorylation. In addition, L1 also co-localized with pPKD1. To analyze the regulatory role of L1 on PKD1 phosphorylation, primary mouse cerebellar granule neurons were treated with various concentrations of rL1 for 48 h. Using Western blot, we revealed that L1 significantly increased PKD1 phosphorylation compared with vehicle control, with the maximal effect observed at 5 nM. ERK1/2 phosphorylation was significantly increased by 2.5 nM and 10nM L1, with no apparent change in SRC phosphorylation. However, SRC expression was markedly reduced by 10nM rL1. AKT1 expression and phosphorylation levels were significantly increased by rL1, with the maximal effect observed at 2.5 and 5 nM, respectively. Our combined data revealed a positive relationship between L1 and pPKD1 in both cultured cerebellar neurons and human cerebellar tissue, suggesting that L1 functions in the modulation of PKD1 phosphorylation. PMID- 25445363 TI - Role of Drosophila calcium channel cacophony in dopaminergic neurodegeneration and neuroprotection. AB - One of the most important questions in Parkinson's disease (PD) regards the selective vulnerability of a specific population of dopaminergic (DA) neurons. Recent reports identify Ca(2+) channel as a potential source of this vulnerability. This work uses a Drosophila primary neuronal cell culture system as an in vitro PD model to explore the role of Ca(2+) homeostasis in DA neurodegeneration and protection. Our data showed that the Ca(2+) chelator EGTA is neuroprotective against a PD toxin MPP(+) (40 MUM). We also use the genetic tools available in Drosophila to manipulate Ca(2+) channel activity. DA neurons lacking functional Ca(2+) channels (i.e., cacophony mutant) are inherently protected against MPP(+) toxicity. Furthermore, overexpression of wild type Ca(2+) channels in DA neurons blocks the rescue effect of a D2 agonist quinpirole on DA neurodegeneration. Our findings support the idea that Ca(2+) is a source of vulnerability for DA neurons and that the modulation of Ca(2+) levels in DA neurons could be a potential neuroprotective treatment. PMID- 25445364 TI - Gintonin, a novel ginseng-derived lysophosphatidic acid receptor ligand, stimulates neurotransmitter release. AB - Gintonin is a novel ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand. Gintonin elicits an intracellular calcium concentration [Ca(2+)]i transient via activation of LPA receptors and regulates calcium dependent ion channels and receptors. [Ca(2+)]i elevation by neurotransmitters or depolarization is usually coupled to neurotransmitter release in neuronal cells. Little is known about whether gintonin-mediated [Ca(2+)]i transients are also coupled to neurotransmitter release. The PC12 cell line is derived from a pheochromocytoma of the rat adrenal medulla and is widely used as a model for catecholamine release. In the present study, we examined the effects of gintonin on dopamine release in PC12 cells. Application of gintonin to PC12 cells induced [Ca(2+)]i transients in concentration-dependent and reversible manners. However, ginsenoside Rg3, another active ingredient of ginseng, induced a lagged and irreversible [Ca(2+)]i increase. The induction of gintonin-mediated [Ca(2+)]i transients was attenuated or blocked by the LPA1/3 receptor antagonist Ki16425, a phospholipase C inhibitor, an inositol 1,4,5-triphosphate receptor antagonist, and an intracellular Ca(2+) chelator. Repeated treatment with gintonin induced homologous desensitization of [Ca(2+)]i transients. Gintonin treatment in PC12 cells increased the release of dopamine in a concentration-dependent manner. Intraperitoneal administration of gintonin to mice also increased serum dopamine concentrations. The present study shows that gintonin-mediated [Ca(2+)]i transients are coupled to dopamine release via LPA receptor activation. Finally, gintonin-mediated [Ca(2+)]i transients and dopamine release via LPA receptor activation might explain one mechanism of gintonin-mediated inter-neuronal modulation in the nervous system. PMID- 25445365 TI - Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation. AB - In addition to the hallmark accumulation of amyloid and hyper-phosphorylation of tau, brain changes in Alzheimer's disease are multifactorial including inflammation, oxidative stress, and metal dysregulation. Metal chelators have been explored as a less well known approach to treatment. One chelator currently being developed is deferoxamine (DFO), administered via the intranasal (IN) route. In the current study, APP/PS1 amyloid mice were treated with a chronic, low dose of IN DFO, subjected to a rigorous battery of behavior tests, and the mechanism of action was examined. Mice were treated 3x/week with 0.24 C IN DFO for 18 weeks from 36 to 54 weeks of age, 4 weeks of behavior tests were performed that included both working and reference memory, anxiolytic and motor behaviors, and finally brain tissues were analyzed for amyloid, protein oxidation, and other proteins affected by DFO. We found that IN DFO treatment significantly decreased loss of both reference and working memory in the Morris and radial arm water mazes (p < 0.05), and also decreased soluble Abeta40 and Abeta42 in cortex and hippocampus (p < 0.05). Further, IN DFO decreased activity of GSK3beta, and led to decreases in oxidative stress (p < 0.05). These data demonstrate that low doses of IN DFO can modify several targets along the multiple pathways implicated in the neuropathology of Alzheimer's, making it an attractive candidate for the treatment of this heterogeneous disease. PMID- 25445366 TI - Infusions of muscimol into the lateral septum do not reduce rats' defensive behaviors toward a cat odor stimulus. AB - The lateral septum (LS) is implicated in behavioral defense. We tested whether bilateral infusions of the GABAA receptor agonist muscimol into the LS suppress rats' defensive responses to cat odor. Rats received intra-LS infusions of either saline or muscimol (40 ng/rat) and were exposed to either a piece of a cat collar that had been previously worn by a cat or to a control (cat odor free) collar. Rats exposed to the cat odor collar displayed more head-out postures, while intra LS application of muscimol reduced the number of head-out postures. However, this reduction was also present in rats exposed to a control (cat odor free) collar. This latter finding suggests that despite its involvement in other defensive behaviors (e.g., open arm avoidance in the elevated plus maze), the LS does not selectively regulate rats' receptor defensive responding to the olfactory cues present in our cat odor stimulus. PMID- 25445367 TI - The coexistence of VGluT2 and neurotensin or leu-enkephalin in the medullary dorsal horn: a confocal and electron microscopic immunohistochemical study in the rat. AB - Neuropeptides such as neurotensin (NT), and enkephalin (ENK) in the medullary dorsal horn (MDH) are involved in excitatory synaptic transmission to modulate nociceptive information. However, morphological evidence indicating that NT or ENK coexists with glutamate in the MDH is still meager. Using fluorescent immunohistochemistry, the results showed that double labeling of NT or ENK terminals with VGluT2 is mainly concentrated in the lamina II of the MDH, and many axon terminals exhibiting NT or ENK immunoreactivity in the superficial layers of the MDH showed VGluT2 immunoreactivity. Electron microscopy confirmed the coexpression of NT or ENK and VGluT2 in axon terminals within the laminae I and II of the MDH. These axon terminals make asymmetrical synapses with immunonegative neuronal cell bodies and dendrites. The findings suggest that glutamate is coreleased with NT or ENK from axon terminals of interneurons in the superficial layers of the MDH. PMID- 25445368 TI - Presynaptic Ca2+-permeable AMPA-receptors modulate paired-pulse depression in nociceptive sensory synapses. AB - The role of Ca(2+)-permeable AMPA-receptors (CP-AMPARs) in the induction of paired-pulse depression (PPD) at glutamatergic nociceptive sensory synapses was examined in co-culture of rat's dorsal root ganglion and dorsal horn neurons. CP AMPARs make a considerable contribution to excitatory postsynaptic currents recorded in DH neurons following action potential generation in nociceptive DRG neurons. Activation of CP-AMPARs during fast synaptic transmission induces strong PPD (with a 200 ms inter-pulse interval). Blockage of CP-AMPARs with Naspm (100 MUM) results in most cases in a significant reduction of the PPD magnitude, also reversing to paired-pulse facilitation in some cases. However, loading of postsynaptic DH neurons with BAPTA (10 mM) did not alter the effect of Naspm (100 MUM) on the paired-pulse ratio. Our data provide evidence that presynaptic CP AMPARs in nociceptive sensory synapses regulate the magnitude of PPD and that postsynaptic Ca(2+)-permeable glutamatergic receptors are not required for PPD induction. PMID- 25445370 TI - Chronic resistance training enhances the spinal excitability of the biceps brachii in the non-dominant arm at moderate contraction intensities. AB - The purpose of the study was to assess corticospinal excitability of the biceps brachii in the non-dominant arm of chronic resistance-trained (RT) and non-RT individuals. Seven chronic-RT and six non-RT male participants performed 4 sets of 5s pseudo-randomized contractions of the non-dominant elbow flexors at 25, 50, 75, 90, and 100% of maximum voluntary contraction (MVC). During each contraction, transcranial magnetic stimulation, transmastoid electrical stimulation, and Erb's point electrical stimulation were administered to assess the amplitudes of motor evoked potentials (MEPs), cervicomedullary evoked potentials (CMEPs), and maximal muscle compound potentials (Mmax), respectively, in the biceps brachii. MEP and CMEP amplitudes were normalized to Mmax. Training did not affect (p>0.14) MEP amplitudes across any contraction intensity. CMEP amplitudes were significantly (p<0.05) higher in the chronic-RT group at 50% and 75% of MVC by 38% and 27%, respectively, and there was a trend for higher amplitudes at 25%, 90%, and 100% MVC by 25% (p=0.055), 36% (p=0.077), and 35% (p=0.078), respectively, compared to the non-RT group. Corticospinal excitability of the non-dominant biceps brachii was increased in chronic-RT individuals mainly due to changes in spinal excitability. PMID- 25445369 TI - The involvement of norepinephrine in pain modulation in the nucleus accumbens of morphine-dependent rats. AB - Opioids are effective analgesics used clinically for both acute and chronic pain management. However, repeated opioid treatment can induce serious side effects such as nausea, vomiting, drowsiness, respiratory depression, euphoria, dependence, hyperalgesia, and tolerance. The mechanism of noxious information transmission in the central nervous system following dependence is still not clear. Norepinephrine (NE), an important neurotransmitter, participates both in the process of opioid dependence and also pain modulation in the central nervous system. In this study, we examined the role of NE on the evoked discharges of pain-excitation neurons (PENs) and pain-inhibition neurons (PINs) in the nucleus accumbens (NAc) of rats, following the development of morphine dependence. Our results revealed that NE inhibited the evoked discharges of PENs and attenuated the inhibition of PINs, while phentolamine enhanced the evoked discharges of PENs and facilitated the inhibition of PINs. These results indicate that the inhibitory action of NE on pain modulation acts via alpha adrenoceptors in the NAc of morphine-dependent rats. PMID- 25445371 TI - The intrathecal administration of losartan, an AT1 receptor antagonist, produces an antinociceptive effect through the inhibiton of p38 MAPK phosphorylation in the mouse formalin test. AB - We have recently reported that an intrathecal (i.t.) administration of angiotensin II (Ang II) into mice induces a nociceptive behavior accompanied by the activation of p38 MAPK signaling via AT1 receptors (Nemoto et al., 2013, Mol. Pain 9, 38). These results suggested that Ang II participates in the facilitation of nociceptive transmission in the spinal cord. In the present study, we used formalin test to examine the effect of i.t.-administered losartan, an AT1 receptor antagonist, and determine whether Ang II acts as a neurotransmitter and/or neuromodulator in the spinal transmission of nociceptive information. When administered i.t. 5 min before the injection of a 2% formalin solution into the plantar surface of the hindpaw, losartan (30-100 nmol) produced a dose-dependent and significant antinociceptive effect during both the first and second phases of the test. In the superficial dorsal horn of the spinal cord (laminae I and II), the fluorescence intensities for Ang II and phospho-p38 MAPK were both significantly increased on the ipsilateral side 3 min after the injection of formalin compared to saline-treated controls. Moreover, the increase of phospho p38 MAPK fluorescence intensity was significantly inhibited by the i.t. administration of losartan (54.8 nmol) 5 min prior to formalin. These results indicate that losartan produces an antinociceptive effect through the inhibition of p38 MAPK phosphorylation in the mouse formalin test and that Ang II may act as a neurotransmitter and/or neuromodulator in the spinal transmission of nociceptive information. PMID- 25445372 TI - Ameliorative effect of rosmarinic acid on scopolamine-induced memory impairment in rats. AB - Rosmarinic acid (RA) is a natural phenol that exerts different biological activities, such as antioxidant activity and neuroprotective effects. In this study, we hypothesized that administration of RA (8, 16, and 32 mg/kg, p.o.) for 7 days would effect on scopolamine-induced cognitive dysfunction as an extensively used model of cognitive impairment. The rats were divided into 10 groups. The acquisition trial was done 1h after the last administration of RA. Animals were divided into control, RA (8, 16, and 32 mg/kg) and donepezil (2 mg/kg) treated controls, scopolamine, RA (8, 16, and 32 mg/kg), and donepezil (2 mg/kg) treated scopolamine groups. Memory impairment was induced by scopolamine treatment (1 mg/kg, i.p.) 30 min after the administration of RA, donepezil, or saline. Scopolamine administration caused cognition deficits in the PAL and memory paradigm. While orally RA administration (16 and 32 mg/kg) improved learning and memory in control rats, it reversed learning and memory deficits of scopolamine received groups. Administration of RA at the dose of 8 mg/kg did not alter cognitive function in control and scopolamine treated groups. The combination of anticholinesterase, neuroprotective, and antioxidant properties of RA may all be responsible for the observed effects. These results indicate the beneficial effects of subchronic RA administration in passive avoidance learning and memory in control rats as well as in a pharmacological model of cholinergic deficit which continue to expand the knowledge base in creating new treatment strategies for cognition deficits and dementia. Of course, further studies are warranted for clinical use of RA in the management of demented subjects. PMID- 25445373 TI - Toll-like receptor 4 and tumor necrosis factor-alpha as diagnostic biomarkers for diabetic peripheral neuropathy. AB - Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes, but currently no protein biomarkers have been introduced into clinical diagnosis, especially among early-stage diabetic patients. Our previous study in animal model showed Toll-like receptor (TLR) 4 and its downstream signaling molecules were associated with DPN. To assess the diagnostic values of TLR4, TNF alpha, and IL-6 as biomarkers, here we detected their expressions in peripheral blood from normal controls, type 2 diabetic and DPN subjects. Both TLR4 mRNA and protein expressions increased significantly in DPN compare with both diabetic and control subjects. The protein levels of TNF-alpha and IL-6 were also raised significantly and correlated with TLR4 expression. Receiver operating characteristics (ROC) analysis suggested TLR4 and TNF-alpha had great potential advantages to predict the progression of neuropathy, the risks of DPN were increased in subjects with higher TLR4 (odds ratio: 5.27; 95% CI: 1.02-26.40) and TNF-alpha (odds ratio: 12.67; 95% CI: 2.35-68.22). These findings demonstrated TLR4 and TNF-alpha could be potential sensitive diagnostic biomarkers for DPN in both general population and type 2 diabetic subjects. PMID- 25445375 TI - Acute toxicity and anticonvulsant activity of liposomes containing nimodipine on pilocarpine-induced seizures in mice. AB - Nimodipine has been shown to have an inhibitory action on seizures and brain damage in rodents. However, the pharmaceutical applicability of this drug is limited by its low solubility in gastrointestinal fluids and high first-pass effect in the liver, which leads to low bioavailability. These difficulties can be overcome through the use of liposomes. The aim of the present study is to evaluate the toxicity and anticonvulsant activity of liposomes containing nimodipine (NMD-Lipo) on pilocarpine-induced seizures. NMD-Lipo was prepared using the lipid-film hydration method. Central nervous system toxicity of NMD Lipo was assessed by Hippocratic screening. Systemic toxicity was evaluated by analyses of biochemical and hematological parameters and by observing possible signs of toxicity. The possible anticonvulsant activity was tested by the pilocarpine model. The administration of the NMD-Lipo at doses of 0.1, 1, and 10 mg/kg caused no toxicity in animals. Furthermore, NMD-Lipo prevented the installation of 100% of the pilocarpine-induced seizures and prevented the death of 100% of the mice treated with pilocarpine. These data shown that NMD-Lipo has an anticonvulsant activity significantly superior to free NMD, suggesting that the liposomes promoted a drug controlled release by improving its bioavailability and consequently increasing its pharmacological activity. PMID- 25445374 TI - Chronic levodopa treatment alters expression and function of dopamine D3 receptor in the MPTP/p mouse model of Parkinson's disease. AB - Chronic treatment with levodopa or antipsychotics results in manifestation of side-effects such as dyskinesia which correlates with changes in expression and function of receptors and signaling proteins. Previous studies have suggested a role for the dopamine D3 receptor in Parkinson's disease (PD) and tardive dyskinesia. Yet the expression and signaling function of D3 receptor in these disorders is not well understood. Here we tested the hypothesis that chronic levodopa treatment alters both expression and function of D3 receptors in the 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid (MPTP/p) mouse model of PD. drd3-EGFP reporter mice were injected biweekly with saline or MPTP and probenecid for a 5-week period. During the last two weeks of the 5-week period, the mice were administered saline or levodopa twice daily. Locomotor activity was measured during the treatment period. D3 receptor expression was determined by western blot analysis. D3 receptor signaling function was determined at tissue and single cell level by measuring the activation of D3 receptor-mitogen activated protein kinase (MAPK) pathway. The drd3-EGFP mice administered MPTP/p exhibited akinesia/bradykinesia. Expression of D3 receptor protein in the dorsal striatum specifically increased in the MPTP/p-treated mice administered levodopa. In the dorsal striatum of levodopa and MPTP/p-treated drd3-EGFP mice, administration of a D3 receptor-selective dose of agonist, PD128907, failed to activate D3 receptor-MAPK signaling. These results suggest that MPTP-induced lesion and chronic levodopa treatment alters D3 receptor expression and function in the dorsal striatum which could contribute to the development of dyskinesias and other motor side-effects. PMID- 25445376 TI - Emotional content of stimuli improves visuospatial working memory. AB - Processing and storage in visuospatial working memory (VSWM) seem to depend on attention-based mechanisms. In order to explore the effect of attention attractive stimuli, such as emotional faces on VSWM performance, ERPs were obtained from 20 young adults while reproducing spatial sequences of six facial (happy and neutral) and non-facial control stimuli in inverse order. Behavioral performances revealed that trials with happy facial expressions resulted in a significantly higher amount of correct responses. For positive emotional facial stimuli, N170 amplitude was higher over right temporo-parietal regions, while P2 amplitude was higher over frontal and lower over parietal regions. In addition, LPP amplitude was also significantly higher for this type of stimuli. Both behavioral and electrophysiological results support the notion of the domain general attention-based mechanism of VSWM maintenance, in which spatial to-be remembered locations might be influenced by the emotional content of the stimuli. PMID- 25445377 TI - Neural processing of speech in children is influenced by extent of bilingual experience. AB - Language experience fine-tunes how the auditory system processes sound. Bilinguals, relative to monolinguals, have more robust evoked responses to speech that manifest as stronger neural encoding of the fundamental frequency (F0) and greater across-trial consistency. However, it is unknown whether such enhancements increase with increasing second language experience. We predict that F0 amplitude and neural consistency scale with dual-language experience during childhood, such that more years of bilingual experience leads to more robust F0 encoding and greater neural consistency. To test this hypothesis, we recorded auditory brainstem responses to the synthesized syllables 'ba' and 'ga' in two groups of bilingual children who were matched for age at test (8.4 +/- 0.67 years) but differed in their age of second language acquisition. One group learned English and Spanish simultaneously from birth (n=13), while the second group learned the two languages sequentially (n=15), spending on average their first four years as monolingual Spanish speakers. We find that simultaneous bilinguals have a larger F0 response to 'ba' and 'ga' and a more consistent response to 'ba' compared to sequential bilinguals and we demonstrate that these neural enhancements track with years of bilingual experience. These findings support the notion that bilingualism enhances subcortical auditory processing. PMID- 25445378 TI - 3,4,5-Trimethoxycinnamin acid ameliorates restraint stress-induced anxiety and depression. AB - The present study investigated whether 3,4,5-trimethoxycinnamic acid (TMCA) treatment ameliorated restraint stress-provoked anxiety- and depression-like behaviors in mice. Fourteen consecutive days of restraint stress produced anxiety and depression-like behaviors, including reduced time and frequency in the open arms of the elevated plus maze (EPM), as well as enhanced immobility times in the forced swim test (FST). However, TMCA (50 mg/kg) treatment ameliorated this effect; mice showed increased time and frequency of visits in the open arms of the EPM and showed reduced immobility in the FST. In parallel with the behavioral data, long-lasting stimulation of DeltaFosB in the nucleus accumbens shell subregion was exhibited in response to TMCA. Furthermore, a reduction in expression of SC1, a target of DeltaFosB, in the nucleus accumbens of mice subjected to restraint stress was significantly reversed by TMCA (50 mg/kg) treatment. Collectively, these results suggest that TMCA treatment might provide a therapeutic strategy for treatment of anxiety and depression. PMID- 25445379 TI - X-ray irradiation accelerates senescence in hippocampal neural stem/progenitor cells via caspase-1 activation. AB - Despite the effectiveness in controlling the progression of brain tumors, cranial irradiation often causes neuropsychological deficits in cancer survivors. Inflammation is considered a major cause of tissue injury from irradiation. The caspase-1 activation complexes (inflammasomes) can facilitate caspase-1 and IL 1beta processing, which amplifies the inflammatory response. In the present study we examined whether caspase-1 activation contributes to irradiation-induced damage to neural stem and progenitor cells (NSPCs). We found that X-ray irradiation induced activation of caspase-1 in NSPCs in vitro and in vivo. Next, using a caspase-1 inhibitor (Ac-YVAD-CMK) to block caspase-1 activation in vitro and in vivo, we further demonstrated that X-ray irradiation may inhibit proliferation, induce senescence of NSPCs through caspase-1 activation. Together, our results suggest that caspase-1 activation is involved in irradiation-induced damage to NSPCs. PMID- 25445380 TI - Effect of task-specific execution on accuracy of imagined aiming movements. AB - Ideomotor theory states that the neural codes that represent action and the perceptual consequences of those actions are tightly bound in a common code. For action imagination, bound action, and perceptual codes are thought to be internally activated at a sub-threshold level through action simulation. In support of this hypothesis, previous research revealed that imagined movement times (MTs) for reciprocal aiming movements were closer to actual execution MTs after the participants gained experience executing the task. The current study examined the task-specific nature of the effects of experience on imagination by determining if improvements in accuracy in the imagination of reciprocal aiming movements occur only with experience of the reciprocal aiming task or with any aiming task. To this end, one group of participants executed a reciprocal pointing task, whereas a second group executed a discrete aiming task with comparable accuracy requirements before and after imagining reciprocal aiming movements. Influence of task specificity on imagination was assessed by evaluating the changes in imagined MTs before and after execution. Consistent with previous findings, there was a reduction in imagined MTs following task execution. Critically, there was a significant time by group interaction revealing a significant pre/post reduction in imagined MTs for the group that executed the reciprocal aiming movements, but not for the group that executed the discrete aiming movements. These data support ideomotor accounts of action imagination because it appears that the imagination of a movement is affected by task-specific experience with that movement. PMID- 25445381 TI - Aging of corticospinal tract fibers according to the cerebral origin in the human brain: a diffusion tensor imaging study. AB - The corticospinal tract (CST) is known to originate from multiple cerebral areas, including the primary motor cortex (M1). In this study, using diffusion tensor imaging (DTI), we attempted to investigate the differences of aging of CST fibers according to the cerebral origin in the human brain. Sixty healthy subjects aged from the 20s to the 70s were recruited, and 10 subjects were assigned to each age group. CST fibers were reconstructed from the M1 (Broadmann's area [BA] 4), the secondary motor area (M2, BA 6), and the primary somatosensory cortex (S1, BA 1 3), respectively. Values of fractional anisotropy (FA), mean diffusivity (MD), and tract volume (TV) of CST fibers from each cerebral area were measured. Significant differences in the TV values of CST fibers from the M2 were observed between the 70s age group and the other age groups, except the 60s age group (p<0.05). However, no significant difference in the values of FA and MD of CST fibers from the M2 were observed between age group (p>0.05). No significant differences in the values of FA, MD, and TV of CST fibers from the S1 and M1 were observed between age groups (p>0.05). We found that the fiber number of CST fibers from the M2 was decreased in the 70s age group compared with the 20s-50s age groups. Because the main function of the M2 is motor planning and coordination, our results would be helpful in development of strategies for coping with aging of the CST. PMID- 25445382 TI - The synergistic effect between beta-amyloid(1-42) and alpha-synuclein on the synapses dysfunction in hippocampal neurons. AB - OBJECTIVE: This study was to explore the molecular mechanisms underpinning the synergetic effect between beta-amyloid (Abeta) and alpha-synuclein (alpha-syn) on synapses dysfunction during the development of neurodegenerative disorders including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Alzheimer disease (AD). METHODS: The primary cultured hippocampal neurons prepared from the fetal tissue of mice were divided into six groups and treated with DMSO, Abeta(42 1), alpha-syn, Abeta(1-42), alpha-syn plus Abeta(42-1) and alpha-syn plus Abeta(1 42), respectively. After incubation for 24 h, the synapsin I content was calculated by immunofluorescence and the synaptic vesicle recycling was monitored by FM1-43 staining. Furthermore, the expression of cysteine string protein-alpha (CSPalpha) detected by western blot was also conducted. RESULTS: Either Abeta(1 42) or alpha-syn alone could induce a significant synapses dysfunction through reducing the content of synapsin I, inhibiting the synaptic vesicle recycling as well as down-regulating the expression of CSPalpha compared with the controls (P<0.05). However, simultaneous intervention with both alpha-syn and Abeta(1-42) aggravated these effects in cultured hippocampal neurons compared with the treatment with alpha-syn (synapsin I content: P<0.001; synaptic vesicle recycling: P=0.007; CSPalpha expression: P<0.001) or Abeta(1-42) (synapsin I number: P<0.001; synaptic vesicle recycling: P=0.007 CSPalpha expression: P<0.001) alone. CONCLUSION: There was synergistic effect between Abeta and alpha syn on synapses dysfunction through reducing the synapsin I content, inhibiting the synaptic vesicle recycling and down-regulating the expression of CSPalpha in several neurodegenerative diseases. PMID- 25445383 TI - Identification of cell-free microRNAs in the urine of patients with prostate cancer. AB - OBJECTIVES: Current methods for the early detection of prostate cancer (PCa), in particular prostate-specific antigen screening, are likely to benefit from complementary molecular analyses to enhance specificity. MicroRNAs (miRNA) are small endogenously expressed noncoding RNAs that negatively regulate the expression of protein-coding genes at the transcriptional or translational level. Accumulating evidence suggests that miRNAs play an important role in tumorigenesis, are differentially expressed in different cancer types, and can be found in all bodily fluids so-far tested, including urine. METHODS AND MATERIALS: This study was undertaken to determine if miRNA could be isolated from the cell free fraction of freely voided urine of PCa patients and if a miRNA signature could be found that would identify patients with cancer. RESULTS: In a first set of proof-of-concept experiments, we isolated RNA from the supernatant of cultured PCa cells, as well as cellular RNA, and compared the expression of cell-free miRNAs vs. cellular miRNAs. We identified miRNA-483-5p, miRNA-1275, and miRNA 1290 among the most abundant cell-free miRNAs. We then tested the expression of these miRNAs in patient urine samples. A total of 18 patients without detectable PCa by transperineal template-saturation biopsy and 71 patients with diagnosed biopsy-proven PCa were retrospectively analyzed. We could confirm that cell-free miRNAs found in cultures of PCa cells can in fact be isolated from freely voided patients' urine. Furthermore, we found that patients with PCa express miR-483-5p in the cell-free urine fraction at a higher level than control patients do. CONCLUSIONS: The present study is among the first to show that miRNAs can be detected in the cell-free, non-exosome-enriched fraction of urine collected from patients with PCa. As the method used here does not require isolation of exosomes, it could potentially simplify the future use of miRNAs as urine-based biomarkers. PMID- 25445384 TI - Radical cystectomy vs. chemoradiation in T2-4aN0M0 bladder cancer: a case-control study. AB - BACKGROUND: Muscle-invasive bladder cancer is most commonly treated by radical cystectomy. Patients who are too sick to go through this surgery or who are unwilling to accept the mutilation associated with it are referred to chemoradiation. We compared the results of these 2 modalities using age-matched populations. PARTICIPANTS AND METHODS: Between 1998 and 2008, 33 patients were treated with chemoradiation for biopsy-proven T2-4aN0M0 urothelial bladder cancer. For every patient treated with chemoradiation, an age-matched patient who underwent radical cystectomy on the same year was selected for comparison. Mean radiotherapy dose was 62 Gy (standard deviation = 8.4) and median follow-up of both groups was approximately 36 months. RESULTS: The groups were similar in age, proportion of men, and length of follow-up. However, the Charlson comorbidity index was significantly lower for operated patients (3.45 vs. 4.36, P = 0.01). Furthermore, 2 patients (6%) in the chemoradiation group had salvage cystectomy (one for disease recurrence and another for bladder shrinkage). The 2- and 5-year overall survival rates after surgery were 74.4% and 54.8%, respectively, and after chemoradiation were 70.2% and 56.6% (P = 0.8), respectively. The 2- and 5 year disease-free survival rates after surgery were 67.8% and 63.2%, respectively, and after chemoradiation were 63% and 54.3% (P = 0.89), respectively. Side effects were mild in both groups, with grade 3+toxicity seen in only 2 operated and 4 irradiated patients. CONCLUSIONS: Despite having a significantly higher comorbidity index, patients treated with chemoradiation had similar overall and disease-free survival rates with low toxicity. Treatment with chemoradiation should be considered in patients with T2-4aN0M0 bladder cancer. PMID- 25445385 TI - Capnocytophaga canimorsus bacteremia presenting with acute cholecystitis after a dog bite. AB - Capnocytophaga canimorsus is part of normal gingival flora of dogs and cats. The organism can cause septicemia, meningitis, and endocarditis in humans after contact with dogs or cats. In spite of the frequency of gastrointestinal symptoms in C. canimorsus infection patients, specific gastrointestinal disease or clinical images have not been reported. We report a case of C. canimorsus bacteremia presenting with acute cholecystitis in elderly woman. She suffered from general fatigue and right upper abdominal pain. She had leukocytosis and abnormal liver function tests. She showed abnormal findings of the gallbladder by abdominal computed tomography and ultrasonography. She was diagnosed with acute cholecystitis without gallstones and was administered with antibiotics. C. canimorsus was isolated from blood cultures. A history of an insignificant wound secondary to a dog bite was elicited. She recovered completely with antibiotic treatment. This case revealed that C. canimorsus bacteremia can be presented with acute cholecystitis, suggesting that C. canimorsus could cause cholecystitis. And this cholecystitis can be treated with antibiotics without operation. Physicians seeing patients with acute cholecysitis should ask questions regarding animal contact. PMID- 25445386 TI - Use of aesthetic rhinoplasty procedures in reconstructive nasal surgery. AB - Resection of cancer often involves the excision of underlying hard tissue, and some procedures in aesthetic rhinoplasty can be used in reconstructive nasal surgery to increase the margin of safety while still achieving an acceptable aesthetic and functional outcome. We have used techniques from aesthetic rhinoplasty to shape the nasal framework. Osteotomy and formation of the tip were used in 17 patients with defects (ranging from 1 to 3.5 cm in size) from the nasal root to the tip of the nose. After the underlying bony or cartilaginous framework, or both, had been removed, the resulting open roof deformity had to be corrected by osteotomy of the bony nasal wall and the tip shaped by excision and suturing, including insertion of the tip graft and columellar strut graft. After this, and narrowing of the nose, the defect was smaller and could be closed with local tissue without tension. There were no deformities in the contour, and patency of the airway was maintained. Patients were satisfied with both the aesthetic and functional results. Although the margin of safety was increased, shaping the nasal framework reduced the size of the defect, which allowed tension free closure with a local flap. The operation requires a thorough knowledge of procedures used in aesthetic rhinoplasty. PMID- 25445388 TI - Treatment of a unilateral Tessier number 4 facial cleft in an adult: role of nasolabial V-Y advancement flap. PMID- 25445387 TI - Brachytherapy for recurrent malignant tumours of the parotid gland. AB - To find out if brachytherapy with radioactive seeds was effective in patients with recurrent malignant tumours of the parotid gland we retrospectively studied 64 such patients, 24 of whom were treated with implantation of radioactive seeds alone, and 40 of whom had their recurrent tumours resected followed by implantation of radioactive seeds. Patients were followed up for a mean of 50 months (range 4 months to 12 years). The local control rate was 76.6%, and overall survival 79.7%. Of the 24 patients treated with brachytherapy alone, 22 achieved a complete response (91.7%). At 1, 3, and 5 years the local control rates were 81.5%, 67.2%, and 53.8%, respectively, and the overall survival 82.7%, 70%, and 61.2%, respectively. In the 40 patients whose tumours were resected before brachytherapy, the local control rates at 1, 3, and 5 years were 87.5%, 82.4%, and 78.6%, respectively, and the overall survival was 97.5%, 86.5%, and 86.5%, respectively. Sex, age, histopathological grade, size of tumour, history of radiotherapy, time of recurrence and method of treatment were not shown to have a significant effect on local control, but method of treatment had a significant impact on overall survival (p=0.008). We conclude that treatment of recurrent malignant tumours of the parotid efficacy can be successfully treated with brachytherapy with radioactive seeds, either alone or combined with resection. PMID- 25445389 TI - Innovative use of anterior subapical setback combined with bilateral sagittal split osteotomy in patients with obstructive sleep apnoea. AB - We describe the use of anterior mandibular subapical setback osteotomy combined with bilateral sagittal split osteotomy in the treatment of selected patients with obstructive sleep apnoea (OSA). The technique enables maximal mandibular advancement, it alleviates pharyngeal narrowing, and minimises the alteration to the mid facial profile that is associated with traditional maxillomandibular advancement. PMID- 25445390 TI - Incidence of different causes of benign obstruction of the salivary glands: retrospective analysis of 493 cases using fluoroscopy and digital subtraction sialography. AB - To identify the incidence of different causes of benign obstruction of the salivary glands, we retrospectively analysed 788 anonymised sialography reports of 719 patients referred to the department of dental and maxillofacial radiology between 2006 and 2012. Reports that showed evidence of benign obstruction were included (n=493). Salivary stones were identified in 151 (31%), ductal strictures in 115 (23%), and mucus plugs in 295 (60%). In 67 cases (14%) there was evidence of 2 or 3 causes of obstruction. As previously reported, mucous plugs were the most common finding, possibly because of the use of fluoroscopy or digital subtraction sialography, or both. These methods enable images to be captured during the initial filling of the main duct and are likely to prevent mucus plugs from being obscured by the contrast medium, which is the case in conventional sialography when a single image is produced after the contrast has been injected. PMID- 25445391 TI - Genetic variants in ABCA1 promoter affect transcription activity and plasma HDL level in pigs. AB - Excess accumulation of cholesterol in plasma may result in coronary artery disease. Numerous studies have demonstrated that ATP-binding cassette protein A1 (ABCA1) mediates the efflux of cholesterol and phospholipids to apolipoproteins, a process necessary for plasma high density lipoprotein (HDL) formation. Higher plasma levels of HDL are associated with lower risk for cardiovascular disease. Studies of human disease and animal models had shown that an increased hepatic ABCA1 activity relates to an enhanced plasma HDL level. In this study, we hypothesized that functional mutations in the ABCA1 promoter in pigs may affect gene transcription activity, and consequently the HDL level in plasma. The promoter region of ABCA1 was comparatively scanned by direct sequencing with pool DNA of high- and low-HDL groups (n=30 for each group). Two polymorphisms, c. - 608A>G and c. - 418T>A, were revealed with reverse allele distribution in the two groups. The two polymorphisms were completely linked and formed only G-A or A-T haplotypes when genotyped in a larger population (n=526). Furthermore, we found that the G-A/G-A genotype was associated with higher HDL and ABCA1 mRNA level than A-T/A-T genotype. Luciferase assay also revealed that G-A haplotype promoter had higher activity than A-T haplotype. Single-nucleotide mutant assay showed that c.-418T>A was the causal mutation for ABCA1 transcription activity alteration. Conclusively, we identified two completely linked SNPs in porcine ABCA1 promoter region which have influence on the plasma HDL level by altering ABCA1 gene transcriptional activity. PMID- 25445392 TI - Genome-wide identification and expression analysis of the polyamine oxidase gene family in sweet orange (Citrus sinensis). AB - Polyamine oxidases (PAOs) are FAD-dependent enzymes associated with polyamine catabolism. In plants, increasing evidences support that PAO genes play essential roles in abiotic and biotic stresses response. In this study, six putative PAO genes (CsPAO1-CsPAO6) were unraveled in sweet orange (Citrus sinensis) using the released citrus genome sequences. A total of 203 putative cis-regulatory elements involved in hormone and stress response were predicted in 1.5-kb promoter regions at the upstream of CsPAOs. The CsPAOs can be divided into four major groups, with similar organizations with their counterparts of Arabidopsis thaliana. Transcripts of CsPAOs were detected in leaf, stem, cotyledon, and root, with the highest levels detected in the roots. The CsPAOs displayed various responses to exogenous treatments with polyamines and ABA and were differentially altered by abiotic stresses, including cold, salt, and mannitol. Overexpression of CsPAO3 in tobacco demonstrated that spermidine and spermine were decreased in the transgenic line, while putrescine was significantly enhanced, implying a potential role of this gene in polyamine back conversion. These data provide valuable knowledge for understanding the roles of the PAO genes in the future. PMID- 25445393 TI - BRCA mutations cause reduction in miR-200c expression in triple negative breast cancer. AB - Triple negative breast cancer (TNBC) is the most aggressive and poorly understood subclass of breast cancer (BC). Over the recent years, miRNA expression studies have been providing certain detailed overview that aberrant expression of miRNAs is associated with TNBC. Although TNBC tumors are strongly connected with loss of function of BRCA genes, there is no knowledge about the effect of BRCA mutation status on miRNA expressions in TNBC cases. The aims of this study were to evaluate the expression profile of miRNAs that plays role in TNBC progression and the role of BRCA mutations in their regulation. The expression level of BC associated 13 miRNAs was analyzed in 7 BRCA mutations positive, 6 BRCA mutations negative TNBC cases and 20 non-tumoral tissues using RT-PCR. According to RT2 Profiler PCR Array Data Analysis, let-7a expression was 4.67 fold reduced in TNBCs as compared to normal tissues (P=0.031). In addition, miR-200c expression was 5.75 fold reduced in BRCA mutation positive TNBC tumors (P=0.005). Analysis revealed a negative correlation between miR-200c and VEGFA expressions (r=-468). Thus, miR-200c may be involved in invasion and metastasis in TNBC cases with BRCA mutation. In this study we provide the knowledge on the first report of association between microRNA-200c and BRCA mutations in TNBC. Further studies and evaluations are required, but this miRNA may provide novel therapeutic molecular targets for TNBC treatment and new directions for the development of anticancer drugs. PMID- 25445394 TI - MicroRNA expression profiling and bioinformatics analysis of dysregulated microRNAs in vinorelbine-resistant breast cancer cells. AB - Vinorelbine (NVB) is one of the most active cytotoxic agents in breast cancer, especially metastatic breast cancer. However, breast cancer patients who are treated with the drug often develop resistance to it and some other drugs. Recently studies have shown that microRNAs (miRNAs) play an important role in drug resistance. In present study, miRNA expression profiles of breast cancer cells MDA-MB-231/S and its NVB-resistant variant MDA-MB-231/NVB cells were analyzed using microarray and the results were confirmed by real-time quantitative polymerase chain reaction. Bioinformatic analyses were carried out to predict gene targets of the dysregulated miRNAs and to analyze their potential roles in the development of drug resistance. Here, 123 differentially expressed miRNAs were identified in the resistant subline compared to MDA-MB-231/S. Networks of KEGG pathways, Gene Ontology (GO) terms, and protein-protein interaction (PPI) of 17 specific selected dysregulated miRNAs were constructed. The results showed that MAPK, mTOR, Wnt, and TGF-beta signaling pathways and several target genes such as CCND1, GRB2 and NT5E may associate with drug resistance of breast cancer cells to NVB. In summary, this study demonstrates that altered miRNA expression pattern is involved in acquiring resistance to NVB in breast cancer MDA-MB-231 cells. All these analysis results provided us a comprehensive view of the function of differential expression miRNAs related to drug resistance of breast cancer and may be helpful for the further study. PMID- 25445396 TI - Intracellular accumulation of subviral HBsAg particles and diminished Nrf2 activation in HBV genotype G expressing cells lead to an increased ROI level. AB - BACKGROUND & AIMS: Hepatitis B virus genotype G (HBV/G) is characterized by a lack of HBeAg secretion and very low HBsAg secretion. This study aimed at (1) comparing HBV genotype G and A2 with respect to morphogenesis and release of HBV derived particles, (2) characterizing factors contributing to HBV/G-associated pathogenesis. METHODS: HBV/G- and HBV/A-expressing hepatoma cells and infected HepaRG cells were analyzed by confocal laser scanning microscopy, Western blot, real-time PCR, density gradient centrifugation, and electron microscopy. Modulation of the transcription factors Nrf2 and AP-1 was analyzed. RESULTS: While the release of viral particles is not affected in HBV/G replicating cells, the secretion of subviral particles is impaired, although they are produced in high amounts. These subviral particles, which display an increased density and a predominantly filamentous morphology, accumulate at the endoplasmic reticulum. The PreS1PreS2 domain of genotype G, which forms aggregates, causes the block of HBsAg-secretion at the ER and leads to decreased transcriptional activator function of LHBs. Intracellular accumulation of HBsAg and impaired induction of the cytoprotective transcription factor Nrf2 lead to an elevated level of ROIs. This results in activation of JNK and as a consequence in Ser-phosphorylation of IRS-1, which is known to impair insulin signaling, a key factor for liver regeneration. CONCLUSIONS: Although competent for release of viral particles, secretion of subviral particles is impaired in HBV/G expressing cells leading to ER-stress. In parallel, HBV-induced Nrf2 activation diminishes, which causes a decrease of the capacity to inactivate ROIs. This might be related to genotype specific pathogenesis. PMID- 25445395 TI - Epicardial fat, cardiac geometry and cardiac function in patients with non alcoholic fatty liver disease: association with the severity of liver disease. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has been associated with increased cardiovascular risk, including coronary artery disease and cardiac dysfunction. In addition, recent evidence highlighted the possible role of epicardial fat as a new cardiometabolic risk factor. We tested the correlation between epicardial fat, alterations in cardiac geometry and function, and severity of liver damage, in patients with biopsy-proven NAFLD. METHODS: The anthropometric, biochemical and metabolic features were recorded in 147 consecutive biopsy-proven NAFLD cases (Kleiner score). Epicardial fat thickness was measured by echocardiography. RESULTS: Epicardial fat was higher in patients with severe vs. milder fibrosis (8.5 +/- 3.0 vs. 7.2 +/- 2.3 mm; p=0.006); this association was maintained at multivariate logistic regression analysis (OR 1.22, 95%C.I. 1.01-1.47; p=0.04) after correction for gender, age >50 years, visceral obesity, IFG/diabetes, non-alcoholic steatohepatitis and severe steatosis. Of note, 37.1% of patients with epicardial fat >7 mm (median value) had severe liver fibrosis, compared to 18.3% of the cases with lower epicardial fat (p=0.01). As for echocardiographic indices, after adjusting for cardiometabolic confounders, diastolic posterior-wall thickness (p=0.01), left ventricular mass (p=0.03), relative wall thickness (p=0.02), and left atrial volume (0.04), as well as ejection fraction (p=0.004), lower lateral TDI e' (p=0.009), E/A ratio (0.04) (cardiac geometry alterations and diastolic dysfunction) were linked to severe liver fibrosis. CONCLUSIONS: In patients with NAFLD, a higher epicardial fat thickness is associated with the severity of liver fibrosis, in keeping with a possible pathogenic role of ectopic fat depots in whole body organ damage. In addition, morphological and functional cardiac alterations are more pronounced according to the severity of fibrosis. Further studies are needed to validate our results. PMID- 25445397 TI - Biallelic inactivation of protoporphyrinogen oxidase and hydroxymethylbilane synthase is associated with liver cancer in acute porphyrias. AB - Variegate porphyria (VP) and acute intermittent porphyria (AIP), the two most common types of acute porphyrias (AHPs), result from a partial deficiency of protoporphyrinogen oxidase (PPOX) and hydroxymethylbilane synthase (HMBS), respectively. A rare but serious complication in the AHPs is hepatocellular carcinoma (HCC). However, the underlying pathomechanisms are yet unknown. We performed DNA sequence analysis in cancerous and non-cancerous liver tissue of a VP and an AIP patient, both with HCC. In samples of both cancerous and non cancerous liver tissues from the patients, we identified the underlying PPOX and HMBS germline mutations, c.1082dupC and p.G111R, respectively. Additionally, we detected a second somatic mutation, only in the cancer tissue i.e., p.L416X in the PPOX gene of the VP patient and p.L220X in the HMBS gene of the AIP patient, both located in trans to the respective germline mutations. Both somatic mutations were not detected in 10 non-porphyria-associated HCCs. Our data demonstrate that in the hepatic cancer tissue of AHP patients, somatic second-hit mutations result in nearly complete inactivation of the enzymes catalyzing major steps in the heme biosynthetic pathway. Both PPOX and HMBS, which might act as tumor suppressors, play a crucial role in the development of HCC in these individuals. PMID- 25445399 TI - Incidence of hepatocellular carcinoma after HBsAg seroclearance in chronic hepatitis B patients: a need for surveillance. AB - BACKGROUND & AIMS: Little is known about whether surveillance for hepatocellular carcinoma (HCC) is worthwhile in chronic hepatitis B virus (HBV)-infected patients who have achieved HBsAg seroclearance. METHODS: A retrospective analysis of 829 patients (mean age: 52.3 years; 575 males; 98 with cirrhosis) achieving HBsAg seroclearance was performed at a tertiary hospital in Korea between 1997 and 2012. We evaluated incidence rates of HCC, and validated CU-HCC score based on data at the time of HBsAg seroclearance. RESULTS: During a follow-up of 3464 patient-years, 19 patients developed HCC (annual rate: 0.55%). Liver cirrhosis (hazard ratio [HR]: 10.80; 95% confidence interval [CI]: 4.25-27.43), male gender (HR: 8.96; 95% CI: 1.17-68.80), and age ?50 years at the time of HBsAg seroclearance (HR: 12.14; 95% CI: 1.61-91.68) were independently associated with HCC. The estimated annual incidence of HCC was 2.85% and 0.29% in patients with and without cirrhosis, respectively. Among the non-cirrhotic patients, the annual rate of HCC was higher in the male patients than in the females (0.40% vs. 0%, respectively), and all the HCCs developed after age 50. The time-dependent area under the receiver operating characteristic curves for the CU-HCC score for 5 year and 10 year HCC prediction were 0.85 and 0.74, respectively. CONCLUSIONS: HCC surveillance should be considered for cirrhotic patients and non-cirrhotic male patients over age 50, even after HBsAg seroclearance, especially those infected with HBV genotype C. HBsAg seroclearance at age ?50years was also an independent predictor for HCC. PMID- 25445398 TI - TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess. AB - BACKGROUND & AIMS: Low-grade chronic inflammation is a cardinal feature of the metabolic syndrome, yet its pathogenesis is not well defined. The purpose of this study was to examine the role of TRAIL receptor (TR) signaling in the pathogenesis of obesity-associated inflammation using mice with the genetic deletion of TR. METHODS: TR knockout (TR(-/-)) mice and their littermate wild type (WT) mice were fed a diet high in saturated fat, cholesterol and fructose (FFC) or chow. Metabolic phenotyping, liver injury, and liver and adipose tissue inflammation were assessed. Chemotaxis and activation of mouse bone marrow derived macrophages (BMDMphi) was measured. RESULTS: Genetic deletion of TR completely repressed weight gain, adiposity and insulin resistance in FFC-fed mice. Moreover, TR(-/-) mice suppressed steatohepatitis, with essentially normal serum ALT, hepatocyte apoptosis and liver triglyceride accumulation. Gene array data implicated inhibition of macrophage-associated hepatic inflammation in the absence of the TR. In keeping with this, there was diminished accumulation and activation of inflammatory macrophages in liver and adipose tissue. TR(-/-) BMDMphi manifest reduced chemotaxis and diminished activation of nuclear factor kappa B signaling upon activation by palmitate and lipopolysaccharide. CONCLUSIONS: These data advance the concept that macrophage-associated hepatic and adipose tissue inflammation of nutrient excess requires TR signaling. PMID- 25445400 TI - Virology analyses of HCV isolates from genotype 1-infected patients treated with simeprevir plus peginterferon/ribavirin in Phase IIb/III studies. AB - BACKGROUND & AIMS: Simeprevir is an oral hepatitis C virus (HCV) NS3/4A protease inhibitor approved for treatment of chronic HCV infection. Baseline NS3 polymorphisms in all patients and emerging mutations in patients who failed to achieve sustained virologic response (SVR) with simeprevir plus peginterferon/ribavirin (PR) in Phase IIb/III studies are described. METHODS: Baseline sequencing data were available for 2007 genotype 1 (GT1)-infected patients. Post-baseline data were available for 197/245 simeprevir-treated patients who did not achieve SVR. In vitro simeprevir susceptibility was assessed in a transient replicon assay as site-directed mutants or in chimeric replicons with patient-derived NS3 protease sequences. RESULTS: Baseline NS3 polymorphisms at positions associated with reduced in vitro susceptibility to simeprevir (43, 80, 122, 155, 156, and/or 168; EC50 fold change >2.0) were uncommon (1.3% [26/2007]), with the exception of Q80K, which confers ~10-fold reduction in simeprevir activity in vitro (13.7% [274/2007]; GT1a 29.5% [269/911], GT1b 0.5% [5/1096]). Baseline Q80K had minor effect on initial response to simeprevir/PR, but resulted in lower SVR rates. Overall, 91.4% of simeprevir-treated patients [180/197] without SVR had emerging mutations at NS3 positions 80, 122, 155, and/or 168 at failure (mainly R155K in GT1a with and without Q80K, and D168V in GT1b), conferring high-level resistance in vitro (EC50 fold change >50). Emerging mutations were no longer detectable by population sequencing at study end in 50% [90/180] of patients (median follow-up 28.4weeks). CONCLUSIONS: Simeprevir treatment failure was usually associated with emerging high-level resistance mutations, which became undetectable over time in half of the patients. PMID- 25445403 TI - T cell responses in psoriasis and psoriatic arthritis. AB - According to the current view the histological features of psoriasis arise as a consequence of the interplay between T cells, dendritic cells and keratinocytes giving rise to a self-perpetuating loop that amplifies and sustains inflammation in lesional skin. In particular, myeloid dendritic cell secretion of IL-23 and IL 12 activates IL-17-producing T cells, Th22 and Th1 cells, leading to the production of inflammatory cytokines such as IL-17, IFN-gamma, TNF and IL-22. These cytokines mediate effects on keratinocytes thus establishing the inflammatory loop. Unlike psoriasis the immunopathogenic features of psoriatic arthritis are poorly characterized and there is a gap in the knowledge of the pathogenic link between inflammatory T cell responses arising in the skin and the development of joint inflammation. Here we review the knowledge accumulated over the years from the early evidence of autoreactive CD8 T cells that was studied mainly in the years 1990s and 2000s to the recent findings of the role of Th17, Tc17 cells and gammadelta T cells in psoriatic disease pathogenesis. The review will also focus on common and distinguishing features of T cell responses in psoriatic plaques and in synovial fluid of patients with psoriatic arthritis. The integration of this information could help to distinguish the role played by T cells in the initiation phase of the disease from the role of T cells as downstream effectors sustaining inflammation in psoriatic plaques and potentially leading to disease manifestation in distant joints. PMID- 25445402 TI - Reduction of selenium-binding protein 1 sensitizes cancer cells to selenite via elevating extracellular glutathione: a novel mechanism of cancer-specific cytotoxicity of selenite. AB - Selenium is an essential trace element and has been extensively studied for preventive effects on cancers. Recent emerging evidence has also shown that selenium at supranutritional dosage has a preferential cytotoxicity in cancer cells and chemotherapeutic drug-resistant cells, but the underlying mechanisms remain largely unknown. This study was to investigate the roles of two distinct representatives of selenium-containing proteins, selenium-binding protein 1 (SBP1) and glutathione peroxidase 1 (GPX1), in selenite-mediated cancer-specific cytotoxicity. We found that there was a significantly inverse correlation between SBP1 and GPX1 protein level in human breast cancers and adjacent matched nontumor tissues (Pearson r=-0.4347, P=0.0338). Ectopic expression of GPX1 enhanced selenite cytotoxicity through down-regulation of SBP1, and SBP1 was likely to be a crucial determinant for selenite-mediated cytotoxicity. Reduction of SBP1 in cancer cells and epirubicin-resistant cells on selenite exposure resulted in a dramatic increase in the generation of hydrogen peroxide and superoxide anion, which in turn caused oxidative stress and triggered apoptosis. Furthermore, knockdown SBP1 by small interfering RNA increased selenite sensitivity by elevating extracellular glutathione (GSH), which spontaneously reacted with selenite and led to the rapid depletion of selenium (IV) in growth medium and the high-affinity uptake of selenite. In conclusion, these findings would improve our understanding of the roles of selenium-containing proteins in selenite-mediated cytotoxicity, and revealed a potent mechanism of the selective cytotoxicity of selenite in cancer cells and drug-resistant cells, in which SBP1 was likely to play an important role in modulating the extracellular microenvironment by regulating the levels of extracellular GSH. PMID- 25445401 TI - Increased mitochondrial prooxidant activity mediates up-regulation of Complex I S glutathionylation via protein thiyl radical in the murine heart of eNOS(-/-). AB - In response to oxidative stress, mitochondrial Complex I is reversibly S glutathionylated. We hypothesized that protein S-glutathionylation (PrSSG) of Complex I is mediated by a kinetic mechanism involving reactive protein thiyl radical (PrS(*)) and GSH in vivo. Previous studies have shown that in vitro S glutathionylation of isolated Complex I at the 51 and 75-kDa subunits was detected under the conditions of (*)O2(-) production, and mass spectrometry confirmed that formation of Complex I PrS(*) mediates PrSSG. Exposure of myocytes to menadione resulted in enhanced Complex I PrSSG and PrS(*) (Kang et al., Free Radical Biol. Med.52:962-973; 2012). In this investigation, we tested our hypothesis in the murine heart of eNOS(-/-). The eNOS(-/-) mouse is known to be hypertensive and develops the pathological phenotype of progressive cardiac hypertrophy. The mitochondria isolated from the eNOS(-/-) myocardium exhibited a marked dysfunction with impaired state 3 respiration, a declining respiratory control index, and decreasing enzymatic activities of ETC components. Further biochemical analysis and EPR measurement indicated defective aconitase activity, a marked increase in (*)O2(-) generation activity, and a more oxidized physiological setting. These results suggest increasing prooxidant activity and subsequent oxidative stress in the mitochondria of the eNOS(-/-) murine heart. When Complex I from the mitochondria of the eNOS(-/-) murine heart was analyzed by immunospin trapping and probed with anti-GSH antibody, both PrS(*) and PrSSG of Complex I were significantly enhanced. Overexpression of SOD2 in the murine heart dramatically diminished the detected PrS(*), supporting the conclusion that mediation of Complex I PrSSG by oxidative stress-induced PrS(*) is a unique pathway for the redox regulation of mitochondrial function in vivo. PMID- 25445404 TI - The diagnosis of inflammatory bowel disease is often unsupported in clinical practice. AB - BACKGROUND: The diagnosis of inflammatory bowel disease can be challenging and requires the efforts of a multidisciplinary team. We performed a retrospective analysis with the aim of evaluating the adequacy of the prerequisites for arriving at an accurate histological diagnosis. METHODS: The following parameters were considered as prerequisites for a diagnosis of inflammatory bowel disease: clinical and endoscopic data; proper sampling and handling of biopsies; and elementary microscopic lesions. We collected 345 cases from 13 centres. RESULTS: The date of onset and treatment were available for 13% and 16% of the cases, respectively. Endoscopy information was accessible for 77% of the cases. Endoscopic mapping was completed in 13% of the cases. In no cases were the biopsies oriented on acetate strips. The diagnosis was conclusive in 47% of the cases. Activity, epithelial disruption and crypt distortion were described in 35% of the reports with a conclusive diagnosis. CONCLUSION: Our study showed that the diagnostic prerequisites were widely unfulfilled, although approximately half of the diagnoses were conclusive for inflammatory bowel disease. Thus, in our assessment of clinical practice: (1) clinicians seldom provide suitable clinical and/or endoscopic information for a histological diagnosis and (2) histopathological diagnoses of inflammatory bowel disease are often not supported by morphology. PMID- 25445405 TI - Tripterygium wilfordii Hook. f. versus azathioprine for prevention of postoperative recurrence in patients with Crohn's disease: a randomized clinical trial. AB - BACKGROUND: Tripterygium wilfordii Hook. f. (TwHF) has been used for many years to induce the remission of Crohn's disease in China. AIMS: To compare TwHF versus azathioprine for the prevention of postoperative recurrence in Crohn's disease. METHODS: 90 Crohn's disease patients who had undergone resection were treated with TwHF 1.5mg/kg/day or azathioprine 2.0 mg/kg/day. The primary endpoint was clinical recurrence, and the secondary endpoint was endoscopic recurrence. RESULTS: 47 patients completed the trial. Clinical recurrence was observed in 6/45 patients in the TwHF group and 4/45 patients in the azathioprine group at week 26 (P=0.74). At week 52, 8/45 azathioprine patients and 12/45 TwHF patients had clinical recurrence (P = 0.45). During the first 26 weeks, 56.8% of the patients in the TwHF group versus 47.7% in the azathioprine group experienced endoscopic recurrence (P = 0.52). However, at week 52, 74.4% of patients in the TwHF group and 50% in the azathioprine group had endoscopic recurrence (P = 0.03). CONCLUSIONS: TwHF was less effective in maintaining endoscopic remission at week 52, even though TwHF was comparable to azathioprine for preventing postoperative clinical recurrence. PMID- 25445406 TI - Transjugular intrahepatic portosystemic shunt placement increases feasibility of colorectal surgery in cirrhotic patients with severe portal hypertension. AB - BACKGROUND: Colorectal resection in cirrhotic patients is associated with high mortality and morbidity related to portal hypertension and liver insufficiency. METHODS: This retrospective study evaluated the clinical outcomes of cirrhotic patients who underwent transjugular intrahepatic porto-systemic shunt (TIPS) placement before colorectal resection for cancer. Main outcomes measures were postoperative morbidity and mortality rates. RESULTS: TIPS placement was successful in all eight patients and significantly decreased the mean hepatic venous pressure gradient from 15.5 +/- 2.9 to 7.5 +/- 1.9 mmHg (p = 0.02). Surgical procedures included right colectomy (n = 3), left colectomy (n = 2), and proctectomy with total mesorectal excision (n=3). Post-operatively, two patients (25%) died of multiple organ failure. The overall postoperative morbidity rate was 75%, and major complications were seen in 25%. CONCLUSION: Portal decompression via TIPS placement may enable selected cirrhotic patients with severe portal hypertension to undergo colorectal resection for cancer. PMID- 25445407 TI - GATA6 expression in Barrett's oesophagus and oesophageal adenocarcinoma. AB - BACKGROUND: Barrett's oesophagus can progress towards oesophageal adenocarcinoma through a metaplasia-dysplasia-carcinoma sequence, but the underlying mechanisms are poorly understood. The transcription factor GATA6 is known to be involved in columnar differentiation and proliferation, and GATA6 gene amplification was recently linked with poor survival in oesophageal adenocarcinoma. AIM: To study the expression of GATA6 during Barrett's oesophagus development and malignant transformation. To determine the prognostic value of GATA6 in oesophageal adenocarcinoma. METHODS: Two retrospective cohorts were derived from the pathological archive of the University Medical Center Groningen. The first cohort contained 130 tissue samples of normal squamous epithelium, metaplasia, dysplasia and oesophageal adenocarcinoma. The second cohort consisted of a tissue microarray containing tissue from 92 oesophageal adenocarcinoma patients. Immunohistochemistry was used to examine GATA6 protein expression and to correlate GATA6 expression in oesophageal adenocarcinoma with overall and disease free survival. RESULTS: The percentage of GATA6-positive cells was low in squamous epithelium (10%) but increased progressively in Barrett's oesophagus (30%, P < 0.001) and high-grade dysplasia (82%, P = 0.005). GATA6 expression was not associated with overall or disease-free survival in oesophageal adenocarcinoma patients (P = 0.599 and P = 0.700 respectively). CONCLUSION: GATA6 expression is progressively increased during Barrett's oesophagus development and its malignant transformation. However, no prognostic value of GATA6 expression could be found in oesophageal adenocarcinoma. PMID- 25445408 TI - Sessile serrated adenoma: from identification to resection. AB - Until the past two decades, almost all colorectal polyps were divided into two main groups: hyperplastic polyps and adenomas. Sessile serrated adenomas presented endoscopic, pathological and molecular profiles distinct from others polyps. Previously under-diagnosed, physicians now identified sessile serrated adenomas. The serrated neoplastic pathway is accounting for up to one-third of all sporadic colorectal cancers and sessile serrated adenomas have been identified as the main precursor lesions in serrated carcinogenesis. By analogy with the adenoma-adenocarcinoma sequence, the sessile serrated adenomas adenocarcinoma sequence, has been identified. The development of endoscopic resection techniques permits the consideration of a non-surgical approach as the first option regardless of the size of the lesion. Sessile serrated adenoma warrants the watchfulness of physicians and requires an optimal quality of the colonoscopy procedure, a thorough evaluation of the lesion, an adequate endoscopic resection and follow-up colonoscopies in accordance with sessile serrated adenomas guidelines. We herein present a review on sessile serrated adenomas focusing on their pathological specificities, epidemiology, treatment modalities and follow-up. PMID- 25445409 TI - Anti-nuclear antibody detection in cryoprecipitates: distinctive patterns in hepatitis C virus-infected patients. AB - BACKGROUND: Anti-nuclear antibodies are immunoglobulins directed against nuclear antigens. They are associated with many autoimmune disorders, but are frequently found in patients infected with hepatitis C virus, possibly indicating an underlying common origin. Likewise, mixed cryoglobulinemia often accompanies autoimmune diseases and hepatitis C infection. AIM: To compare anti-nuclear antibodies and immunoglobulin content of cryoprecipitates from hepatitis C virus positive patients in order to assess their predictive value in the onset of hepatitis C virus-driven extrahepatic disorders. METHODS: Serum from 40 hepatitis C virus-positive patients and 50 controls with rheumatoid arthritis was processed for cryoglobulin detection: all subjects presented with Type III mixed cryoglobulinemia. Immunoglobulin content and immunoglobulin subclasses of cryoprecipitates were assessed by immunofixation and tested by ELISA for rheumatoid factor. Cryoprecipitates were also analysed for anti-nuclear antibodies by indirect immuno-fluorescence to identify specific patterns typical of each condition. RESULTS: Anti-nuclear antibody patterns differed significantly; 26 infected subjects (65%) were IgG3 positive: of these, 25 were also anti-nuclear antibody-positive (96.1%). CONCLUSIONS: IgG3 are autoreactive clones unrelated to viral recognition and possibly involved in autoimmune disorders. Altogether, these results may represent useful diagnostic device for early detection of hepatitis C virus-induced autoimmune diseases. PMID- 25445410 TI - Treating children with HBeAg-positive chronic hepatitis B: no small accomplishment. PMID- 25445411 TI - Biomarkers of activation of renin-angiotensin-aldosterone system in heart failure: how useful, how feasible? AB - Renin-angiotensin-aldosterone system (RAAS), participated by kidney, liver, vascular endothelium, and adrenal cortex, and counter-regulated by cardiac endocrine function, is a complex endocrine system regulating systemic functions, such as body salt and water homeostasis and vasomotion, in order to allow the accomplishment of physiological tasks, such as orthostasis, physical and emotional stimuli, and to react towards the hemorrhagic insult, in tight conjunction with other neurohormonal axes, namely the sympathetic nervous system, the endothelin and vasopressin systems. The systemic as well as the tissue RAAS are also dedicated to promote tissue remodeling, particularly relevant after damage, when chronic activation may configure as a maladaptive response, leading to fibrosis, hypertrophy and apoptosis, and organ dysfunction. RAAS activation is a fingerprint of systemic arterial hypertension, kidney dysfunction, vascular atherosclerotic disease, and is definitely an hallmark of heart failure, which rapidly shifts from organ disease to a disorder of neurohormonal regulatory systems. Chronic RAAS activation is an indirect or direct target of most effective pharmacological treatments in heart failure, such as beta-blockers, inhibitors of angiotensin converting enzyme, angiotensin receptor blockers, direct renin inhibitors, and mineralocorticoid receptor blockers. Biomarkers of RAAS activation are available, with different feasibility and accuracy, such as plasma renin activity, renin, angiotensin II, and aldosterone, which all accompany the increasing clinical severity of heart failure disease, and are well recognized prognostic factors, even in patients with optimal therapy. Polymorphisms influencing the expression and activity of RAAS pathways have been recognized as clinically relevant biomarkers, likely influencing either the individual clinical phenotype, or the response to drugs. This solid, growing evidence strongly suggests the rationale for the use of biomarkers of the RAAS activation, as a guide to tailor individual therapy in the current practice, and their implementation as a rule-in marker for future trials on novel drugs in the heart failure setting. PMID- 25445412 TI - NMR-based urinalysis for rapid diagnosis of beta-ureidopropionase deficiency in a patient with Dravet syndrome. AB - BACKGROUND: Beta-ureidopropionase deficiency is a rare inborn error of metabolism (IEM) affecting pyrimidine metabolism. To-date, about 30 genetically confirmed cases had been reported. The clinical phenotypes of this condition are variable; some patients were asymptomatic while some may present with developmental delay or autistic features. In severe cases, patients may present with profound neurological deficit including hypotonia, seizures and mental retardation. Using NMR-based urinalysis, this condition can be rapidly diagnosed within 15 min. CASE: An 11-month-old Chinese boy had dual molecular diagnoses, beta ureidopropionase deficiency and Dravet syndrome. He presented with intractable and recurrent convulsions, global developmental delay and microcephaly. Urine organic acid analysis using GC-MS and NMR-based urinalysis showed excessive amount of beta-ureidopropionic acid and beta-ureidoisobutyric acid, the two disease-specific markers for beta-ureidopropionase deficiency. Genetic analysis confirmed homozygous known disease-causing mutation UPB1 NM_016327.2: c.977G>A; NP_057411.1:p.R326Q. In addition, genetic analysis for Dravet syndrome showed the presence of heterozygous disease-causing mutation SCN1A NM_001165963.1:c.4494delC; NP_001159435.1:p.F1499Lfs*2. CONCLUSIONS: The differentiation between Dravet syndrome and beta-ureidopropionase deficiency is clinically challenging since both conditions share overlapping clinical features. The detection of urine beta-ureidoisobutyric and beta-ureidopropionic acids using NMR or GC-MS is helpful in laboratory diagnosis of beta-ureidopropionase deficiency. The disease-causing mutation, c.977G>A of beta-ureidopropionase deficiency, is highly prevalent in Chinese population (allele frequency=1.7%); beta-ureidopropionase deficiency screening test should be performed for any patients with unexplained neurological deficit, developmental delay or autism. PMID- 25445414 TI - Combined detection of sialic acid and hydroxyproline in diagnosis of ovarian cancer and its comparison with human epididymis protein 4 and carbohydrate antigen 125. AB - BACKGROUND: Elevated serum sialic acid (SA) and hydroxyproline (Hyp) concentrations have been found in a variety of malignant cancers. We simultaneously detect serum concentrations of SA and Hyp (SA&Hyp) in ovarian cancer, and compare its diagnostic value with classic tumor markers-human epididymis protein 4 (HE4) and carbohydrate antigen 125 (CA125). METHODS: Serum concentrations of SA&Hyp, HE4 and CA125A were detected in a total of 767 serum samples collected from 484 patients with gynecologic diseases, 180 healthy individuals, 45 pregnant women and 58 patients with renal failure using chemical colorimetry and electrochemiluminescence immunoassay (ECLIA), respectively. Risk of ovarian malignancy algorithm (ROMA) was calculated based on HE4 and CA125 values. RESULTS: Serum SA&Hyp concentrations were influenced significantly by renal failure and pregnancy but not age and menopausal status. The median concentrations of SA&Hyp, HE4 and CA125 in patients with ovarian cancer were 119.0 U/ml, 190.2 pmol/l and 366.0 pmol/l, which were significantly higher than concentrations in patients with benign gynecologic diseases (P<0.001). SA&Hyp showed a significantly higher AUC than HE4 and CA125 in the diagnosis of gynecologic malignancies (P<0.001), while no significance was found when compared with ROMA. Specially, SA&Hyp in 48.3% subjects (29/60) diagnosed as positive before primary surgery showed negative after surgery. CONCLUSIONS: Renal failure and pregnancy are the main source for increased false positive of SA and Hyp. Compared with HE4 and CA125, SA&Hyp shows a better diagnosis value and can be used in the diagnosis and dynamic monitoring of gynecologic pelvic malignancies, while no statistical significance was found compared with ROMA. PMID- 25445415 TI - Validation and evaluation of eight commercially available point of care CRP methods. AB - BACKGROUND: There are several situations compelling to measure CRP with a point of care (POC) method. Assay performance of various available POC CRP methods were evaluated as analytical quality is important and should be known before clinical use. METHODS: We compared 2 semi-quantitative strips; Actim and Cleartest and 6 quantitative CRP tests; Afinion, QuikRead go, Smart, iChroma, Microsemi and AQT90 Flex to the Synchron CRP method, using the CLSI EP9 protocol. The coefficient of variance (CV) was determined. Various aspects of pre-analytical and analytical steps were evaluated. RESULTS: CRP strips showed 50-60% concordance with the Synchron CRP. The linear regression lines (95% CI) of the quantitative POC CRP methods compared to the Synchron CRP method were: y=[0.96-1.04]x+[-4.7 to -2.04] (Smart); y=[1.00-1.06]x+[1.05-4.99] (AQT90 Flex), y=[0.84-0.91]x+[-1.13 to 3.95] (Afinion); y=[0.83-0.87]x+[0.25-1.5] (QuikRead go); y=[0.76-0.82]x+[-0.18 to 1.35] (iChroma) and y=[1.14-1.18]x+[-3.17 to -1.83] (Microsemi). CONCLUSIONS: At best, the semi-quantitative CRP strips could be used to discriminate between normal and increased levels of CRP. Of the quantitative methods, when combining analytical with practical evaluation, the Smart and Afinion would be the preferred analyzers for POCT. PMID- 25445416 TI - Fortuitous detection of a case of unknown haemoglobin Athens-Georgia from atypical HbA1c electropherogram. PMID- 25445413 TI - Pathophysiology and the cardiorenal connection in heart failure. Circulating hormones: biomarkers or mediators. AB - Heart failure (HF) is a syndrome characterized by a complex pathophysiology which involves multiple organ systems, with the kidney playing a major role. HF can present with reduced ejection fraction (EF), HFrEF, or with preserved EF (HFpEF). The interplay between diverse organ systems contributing to HF is mediated by the activation of counteracting neurohormonal pathways focused to re-establishing hemodynamic homeostasis. During early stages of HF, these biochemical signals, consisting mostly of hormones and neurotransmitters secreted by a variety of cell types, are compensatory and the patient is asymptomatic. However, with disease progression, the attempt to reverse or delay cardiac dysfunction is deleterious, leading to multi-organ congestion, fibrosis and decompensation and finally symptomatic HF. In conclusion, these neurohormonal pathways mediate the evolution of HF and have become a way to monitor HF. Specifically, these mediators have become important in the diagnosis and prognosis of this highly fatal cardiovascular disease. Finally, while these multiple neurohumoral factors serve as important HF biomarkers, they can also be targeted for more effective and curative HF treatments. PMID- 25445417 TI - The role of circulating lipoprotein lipase and adiponectin on the particle size of remnant lipoproteins in patients with diabetes mellitus and metabolic syndrome. AB - BACKGROUND: The factors regulating particle size of remnant lipoproteins (RLPs) in type 2 diabetes (T2DM) and metabolic syndrome (MetS) cases have not been well elucidated. METHODS: T2DM, MetS and healthy controls with and without a fatty liver were studied. Remnant lipoprotein (RLP)-cholesterol (RLP-C) and RLP triglyceride (RLP-TG), small dense LDL-cholesterol (sdLDL-C), lipoprotein lipase (LPL), hepatic triglyceride lipase (HTGL) and adiponectin concentrations were measured in the fasting pre-heparin plasma. The RLP particle size was estimated by the RLP-TG/RLP-C ratio. RESULTS: The serum TG, RLP-C, RLP-TG, RLP-TG/RLP-C ratio and sdLDL-C were significantly greater in T2DM and MetS than in controls. Fatty liver and high serum TG were significantly associated with an increased RLP TG/RLP-C ratio which was used to estimate the particle size of RLP in controls, T2DM and MetS. LPL and adiponectin in the pre-heparin plasma were inversely correlated with RLP-TG/RLP-C ratio in normal, T2DM and MetS. LPL was also positively correlated with adiponectin in all three cases. CONCLUSIONS: RLP particle size in T2DM and MetS was significantly larger than in controls and was regulated by circulating LPL and adiponectin, but not HTGL. Fatty liver and high TG were significantly associated with the prevalence of the large RLP particle size. PMID- 25445418 TI - Effects of second and subsequent lines of chemotherapy for metastatic breast cancer. AB - BACKGROUND: We assessed the effect of chemotherapy regimens beyond first-line agents on the clinical outcomes in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). PATIENTS AND METHODS: We included 240 patients who were prospectively enrolled into various clinical trials and were receiving cytotoxic chemotherapy for HER2-negative MBC at the National Cancer Center, Korea, from October 2002 to September 2012. Clinicopathologic data were collected for the analysis. RESULTS: A total of 240, 209, and 166 patients received first-, second-, and third-line chemotherapy, respectively. The median age was 49 years (range, 28-77 years), and most had hormone receptor-positive cancer (n = 177; 73.8%). The median progression-free survival (PFS) was 7.6 months for first-line (PFS1) versus 5.1 months for second line (PFS2) versus 3.6 months for third-line (PFS3) chemotherapy. The PFS from previous chemotherapy significantly affected subsequent PFS: PFS1 for PFS2, PFS1 >= 7.6 months, hazard ratio (HR) 0.647; 95% confidence interval (CI), 0.0.484 0.864 (P = .003); PFS2 for PFS3, PFS2 >= 5.1 months, HR 0.676; 95% CI, 0.0.484 0.944; P = .022). The median overall survival was 31.2 months (95% CI, 26.4-36.0 months). Hormone receptor positivity (HR 0.548; 95% CI, 0.261-0.499; P < .001) and PFS1 >= 7.6 months (HR 0.361; 95% CI, 0.393-0.765; P < .001) were significant factors for survival on multivariate analysis. CONCLUSION: The efficacy of previous treatment significantly affected the outcomes of subsequent treatment. We have confirmed that the succession of chemotherapy is justified in patients with MBC who benefited from previous chemotherapy. PMID- 25445419 TI - BRCAness predicts resistance to taxane-containing regimens in triple negative breast cancer during neoadjuvant chemotherapy. AB - BACKGROUND: To provide optimal treatment of heterogeneous triple negative breast cancer (TNBC), we need biomarkers that can predict the chemotherapy response. PATIENTS AND METHODS: We retrospectively investigated BRCAness in 73 patients with breast cancer who had been treated with taxane- and/or anthracycline-based neoadjuvant chemotherapy (NAC). Using multiplex, ligation-dependent probe amplification on formalin-fixed core needle biopsy (CNB) specimens before NAC and surgical specimens after NAC. BRCAness status was assessed with the assessor unaware of the clinical information. RESULTS: We obtained 45 CNB and 60 surgical specimens from the 73 patients. Of the 45 CNB specimens, 17 had BRCAness (38.6% of all subtypes). Of the 23 TNBC CNB specimens, 14 had BRCAness (61% of TNBC cases). The clinical response rates were significantly lower for BRCAness than for non-BRCAness tumors, both for all tumors (58.8% vs. 89.3%, P = .03) and for TNBC (50% vs. 100%, P = .02). All tumors that progressed with taxane therapy had BRCAness. Of the patients with TNBC, those with non-BRCAness cancer had pathologic complete responses significantly more often than did those with BRCAness tumors (77.8% vs. 14.3%, P = .007). After NAC, the clinical response rates were significant lower for BRCAness than for non-BRCAness tumors in all subtypes (P = .002) and in TNBC cases (P = .008). After a median follow-up of 26.4 months, 6 patients-all with BRCAness-had developed recurrence. Patients with BRCAness had shorter progression-free survival than did those with non- BRCAness (P = .049). CONCLUSION: Identifying BRCAness can help predict the response to taxane, and changing regimens for BRCAness TNBC might improve patient survival. A larger prospective study is needed to further clarify this issue. PMID- 25445420 TI - Comparison of toxicity experienced by older versus younger patients enrolled in breast cancer clinical trials. AB - BACKGROUND: Elderly patients form a large proportion of patients with breast cancer but are underrepresented in clinical trials. We examined whether elderly patients experience more toxicity than younger patients within breast cancer clinical trials. MATERIALS AND METHODS: All breast cancer trials open from 1999 to 2012 at BCCA, Vancouver Center, were reviewed. The primary endpoint was meaningful toxicity (MTOX), defined as any grade 3 or 4 adverse event (AE), any AE leading to dose delay or reduction, or premature discontinuation of therapy. RESULTS: In the 46 trials enrolling 799 patients, the therapy given was chemotherapy to 18% of the patients, hormonal therapy to 40%, skeletal therapy to 14%, and targeted therapy and a combination of chemotherapy and targeted therapy to 14%. Elderly patients were more likely to enroll in hormonal and skeletal therapy trials, and younger patients were evenly distributed among the therapy types. Toxicity data were available for 778 patients (97%). Elderly patients and younger patients experienced a similar number and frequency of MTOX. The therapy type was the strongest predictor of toxicity on multivariate analysis. In non chemotherapy-containing trials, elderly and younger patients had a similar frequency and number of toxicities. Few elderly patients were enrolled in cytotoxic chemotherapy trials, but they experienced no more toxicity than did the younger patients. CONCLUSION: The appropriate selection of elderly patients using eligibility criteria, self selection, and/or clinician assessment will allow safe participation of elderly patients in breast cancer trials. PMID- 25445421 TI - Papulopustular acneiform eruptions resulting from trastuzumab, a HER2 inhibitor. PMID- 25445422 TI - Variability in measuring the Ki-67 labeling index in patients with breast cancer. AB - BACKGROUND: Luminal-type breast cancer is divided into types A and B, depending on the Ki-67 labeling index (LI). However, the area at which Ki-67 is measured and the choice of specimen greatly affects the results. The aim of the present study was to evaluate the Ki-67 LI variability using different measurement methods and specimens. We also evaluated how the chemotherapy indication changed for luminal-type breast cancer using the different measurements. MATERIALS AND METHODS: The Ki-67 levels in 87 patients with breast cancer were assessed, and the Ki-67 LI was calculated. Five measurement sites were randomly selected, including the most densely labeled areas (hot spots) in both core needle biopsy (CNB) and surgical specimens. RESULTS: The intraclass correlation coefficient of the CNB and surgical specimens was 0.91 and 0.95, respectively. If the hot spot was used, the correlation coefficient (CC) between the CNB and surgical specimens was 0.635. If the average score was used, the CC was 0.730. If the average score was used, the CNB specimens indicated that 49 patients had a high Ki-67 LI, and 48 patients had a high Ki-67 LI using surgical specimens. If the hot spot was used, 60 patients using the CNB specimens and 58 patients using the surgical specimens had a high Ki-67 LI. If the average score was used, 17 patients were identified as being in different groups, and if the hot spot was used, 16 patients were identified as being in different groups, depending on the specimens that were used. CONCLUSION: The results differed according to the method and specimen type that was used. PMID- 25445423 TI - Breast cancer in male-to-female transgender patients: a case for caution. PMID- 25445424 TI - Breast cancer in a RAD51D mutation carrier: case report and review of the literature. PMID- 25445425 TI - Triple negative breast cancer in BRCA1 mutation carriers with a complete radiologic response to neoadjuvant paclitaxel: a case report. PMID- 25445426 TI - Yes, Virginia, Chemo Brain is Real. PMID- 25445427 TI - Left ventricular diastolic function assessment using time differences between mitral annular velocities and transmitral inflow velocities in patients with heart failure. AB - BACKGROUND: Evaluation of left ventricular (LV) diastolic function is important in clinical echocardiography. The relationship between mitral annular velocities and transmitral inflow velocities provide additional information about LV filling and diastolic function. This study evaluates the relationships of time intervals between peaks E of mitral inflow velocities and E' of mitral annular velocities, and peaks A and A' in patients with heart failure (HF). METHODS: Eighty patients with HF and 50 age- and gender-matched normal healthy subjects were prospectively recruited and underwent full echocardiograms. The following time intervals were measured: (1) from the onset of R-wave on the ECG to the peak of E-wave on the transmitral flow (TMF) (R-pE); (2) from R to peak of E'-wave on the LV lateral wall of tissue Doppler imaging (TDI) (R-pE'); (3) from onset of P-wave to peak of A-wave on the TMF (P-pA); and (4) from onset of P-wave to peak of A'-wave (P-pA') of TDI. Early-diastolic temporal discordance (EDTD) and late-diastolic temporal discordance (LDTD) were calculated as the difference between the time intervals (R-E) and (R-E'), (P-pA) and (P-p A'). RESULTS: EDTD significantly decreased in patients with HF compared with normal subjects (18.0+/-54.1ms vs. 28.0+/-33.5ms, P<0.05). There was also a significant decrease in LDTD in HF patients compared with normal subjects (19.6+/-23.5ms vs. 34.8+/-20.6; P<0.05). CONCLUSIONS: EDTD and LDTD decreased in patients with heart failure, and they may be useful tools in identifying abnormal LV relaxation and left atrial contraction for LV diastolic function. PMID- 25445428 TI - Systematic detection of familial hypercholesterolaemia in primary health care: a community based prospective study of three methods. AB - BACKGROUND: Familial hypercholesterolaemia (FH), a co-dominantly inherited disease of cholesterol that markedly increases risk of premature coronary artery disease (CAD), is significantly under-diagnosed. Primary health care is increasingly seen as a setting in which to increase the detection rate of index cases. We report a prospective study of three methods of case detection using pre existing primary health care services in one community. METHODS: Three methods of case detection were tested: pathology laboratory database search, workplace health checks and general practice database search. People identified at risk by each of the three screening methods were offered detailed assessment for FH using the Dutch Lipid Clinic Network Criteria score (DLCNCS). RESULTS: 1316 participants underwent detailed assessment for FH. The proportion of at risk people identified for further assessment was in decreasing order: GP (659 of 2494, 26.4%), workplace assessment (60 of 268, 22.4%) and pathology database (597 of 4517, 13.2%) p<0.001. Eight-six (6.5%) were identified as clinical FH (DLCNCS>5) of which 59 had genetic testing and 11 of 59, 18.6%, were confirmed to have a mutation causing FH. Pathology database detected the greatest number of clinical FH (51 of 86, 59.3%) and mutation positive participants (8 of 11, 72.7%). CONCLUSION: Screening within primary health care was successful in detecting participants with FH. An integrated case detection model combining screening of pathology and GP databases is proposed. PMID- 25445429 TI - Endovascular treatment in a patient with left main coronary and pulmonary arterial stenoses as an initial manifestation of Takayasu's arteritis. AB - Takayasu's arteritis is a chronic inflammatory disorder that mainly involves medium to large sized arteries. Although it affects coronary and pulmonary arteries occasionally, physicians should consider the possibility of involvement of coronary or pulmonary arteries in patients with Takayasu's arteritis with chest pain or exertional dyspnoea. We report a case of Takayasu's arteritis who presented with exertional dyspnoea and generalised oedema due to severe bilateral pulmonary and left main coronary arterial stenoses. The patient was successfully treated by a one-stage percutaneous transluminal balloon angioplasty and stent implantation of the involved left main coronary and pulmonary arteries. The endovascular treatment may be one of the treatment options for the stenotic vascular lesions in patients with Takayasu's arteritis. PMID- 25445430 TI - Takotsubo syndrome is a systemic, rather than merely a cardiac, disease: possible effects on the systemic and pulmonary vasculature. PMID- 25445431 TI - An unusual case of syncope in a young female with incidental long QTc interval. AB - Syncope is a common presentation to emergency departments. Arrhythmias account for 14% of those presentations [1], which requires careful assessment due to the potential for sudden cardiac death (SCD). QTc prolongation either due to congenital channelopathy or acquired aetiology can lead to polymorphic ventricular tachycardia and SCD, and should be excluded on electrocardiography. On the other hand, detailed history and thorough clinical examination are the most important tools in reaching the diagnosis, even in the presence of QTC prolongation. PMID- 25445432 TI - Effective pre-hospital care for out-of-hospital cardiac arrest caused by respiratory disease. AB - BACKGROUND: The relationship between pre-hospital care and the prognosis of out of-hospital cardiac arrest (OHCA) caused by respiratory disease is unclear. This study aimed to assess the impact of pre-hospital care on the prognosis of OHCA caused by respiratory disease. METHODS: In a nationwide, population-based, observational study, we enrolled 121,081 adults aged >=18 years who experienced OHCA from January 1, 2010, to December 31, 2010. The primary endpoint was favourable neurological outcomes. RESULTS: Of the 120,256 eligible adult OHCA patients, 7,071 (5.9%) experienced OHCA caused by respiratory disease. Of these 7,071 patients, 3,911 (55.3%) received no cardiopulmonary resuscitation (CPR), 2,403 (34.0%) received chest-compression-only CPR, and 757 (10.7%) received conventional CPR by a bystander. There was no significant difference between the three types of bystander CPR with regard to the neurological outcome (no CPR: OR 0.68, 95%CI 0.39-1.24, p=0.1951; chest-compression-only CPR: OR 0.68, 95%CI 0.37 1.29, p=0.2295; and conventional CPR: as a reference). Pre-hospital administration of epinephrine (OR 0.37, 95%CI 0.13-0.85, p=0.0170) and the implementation of advanced airway management (OR 0.32, 95%CI 0.19-0.52, p<0.0001) were associated with poor neurological outcomes. CONCLUSIONS: Even in OHCA caused by respiratory disease, not only pre-hospital epinephrine administration but also pre-hospital advanced airway management and rescue breathing in bystander CPR may not be critical. PMID- 25445433 TI - Regulation of inflammation and proliferation of human bladder carcinoma cells by type-1 and type-2 cannabinoid receptors. AB - AIMS: Pro-inflammatory cytokines, growth and angiogenic factors released by leukocytes are involved in carcinogenesis and cancer progression, but they are also crucial for fighting tumour growth and spreading. We have previously demonstrated that endocannabinoids modulate cell-to-cell crosstalk during inflammation. Here, we investigated the inflammatory and tumourigenic properties of endocannabinoids in a human urinary bladder carcinoma cell line. MAIN METHODS: Endocannabinoid-treated ECV304 cells were checked for tumour necrosis factor (TNF)-alpha secretion (by ELISA assay) and surface exposure of selectins (by in situ ELISA and FACS analysis). ECV304/Jurkat T cell interaction was assessed by adhesion and live imaging experiments. Proliferation rate, cell death and cell cycle were determined by FACS analysis. KEY FINDINGS: By binding to type-1 (CB1) and type-2 (CB2) cannabinoid receptors, the endocannabinoid 2 arachidonoylglycerol (2-AG) exacerbates the pro-inflammatory status surrounding bladder carcinoma ECV304 cells, by: (i) enhancing TNF-alpha release, (ii) increasing surface exposure of P- and E-selectins, and (iii) allowing Jurkat T lymphocytes to adhere to treated cancer cells. We also found that the CB1 inverse agonist AM281, unlike 2-AG, decreases cancer proliferation by delaying cell cycle progression. SIGNIFICANCE: Our data suggest that 2-AG modulates the inflammatory milieu of cancer cells in vitro, while AM281 plays a more specific role in proliferation. Collectively, these findings suggest that CB receptors may play distinct roles in cancer biology, depending on the specific ligand employed. CONCLUSIONS: The in vivo assessment of the role of CB receptors in inflammation and cancer might be instrumental in broadening the understanding about bladder cancer biology. PMID- 25445434 TI - A painful link between the TRPV1 channel and lysophosphatidic acid. AB - The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed mainly by sensory neurons that detect noxious stimuli from the environment such as high temperatures and pungent compounds (such as allicin and capsaicin) and has been extensively linked to painful and inflammatory processes. This extraordinary protein also responds to endogenous stimuli among which we find molecules of a lipidic nature. We recently described that lysophosphatidic acid (LPA), a bioactive lysophospholipid linked to the generation and maintenance of pain, can directly activate TRPV1 and produce pain by binding to the channels' C terminal region, specifically to residue K710. In an effort to further understand how activation of TRPV1 is achieved by this negatively-charged lipid, we used several synthetic and naturally-occurring lipids to determine the structural requirements that need to be met by these charged lipids in order to produce the activation of TRPV1. In this review, we detail the findings obtained by other research groups and our own on the field of TRPV1-regulation by negatively charged lipids and discuss the possible therapeutic relevance of these findings on the basis of the role of TRPV1 in pathophysiological processes. PMID- 25445435 TI - Azure B and a synthetic structural analogue of methylene blue, ethylthioninium chloride, present with antidepressant-like properties. AB - AIMS: The phenothiazinium compound, methylene blue (MB), possesses diverse pharmacological actions and is attracting attention for the treatment of bipolar disorder and Alzheimer's disease. MB acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and possesses antidepressant activity in rodents. The goal of this study was to synthesise a structural analogue of MB, ethylthioninium chloride (ETC), and to evaluate the effects of the structural changes on the MAO inhibitory and antidepressant properties of MB. This study also investigated the antidepressant properties of azure B, the major metabolite of MB, versus MB and imipramine as active comparators. MAIN METHODS: ETC and azure B were firstly evaluated as inhibitors of human MAO, and secondly for antidepressant-like activity in the acute forced swim test (FST) in rats, and compared to saline, imipramine and MB. KEY FINDINGS: The results document that ETC is a reversible inhibitor of MAO-A and MAO-B with IC50 values of 0.510 MUM and 0.592 MUM, respectively, and that it is a weaker MAO-A inhibitor than MB and azure B. ETC and azure B were more effective than imipramine and MB in reversing immobility in the FST without inducing locomotor effects, with evidence supporting a serotonergic action. Of interest is the finding that ETC is more toxic for cultured cells than MB. CONCLUSION: Azure B may therefore be a contributor to the antidepressant effect of MB. Small structural changes made to MB retain its antidepressant effect, even though the resulting phenothiazinium compound possesses reduced MAO-A inhibitory potency. PMID- 25445436 TI - Beneficial effects of phosphatidylcholine on high-fat diet-induced obesity, hyperlipidemia and fatty liver in mice. AB - AIMS: Soybean-derived PC is an essential cell membrane phospholipid that is composed of unsaturated fatty acids, including oleic acid. The present study aimed to evaluate the potential alleviation effects of soybean PC on high fat diet (HFD)-induced obesity and its related complications. MAIN METHODS: We fed C57BL/6 mice a HFD for 12 weeks and administered PC orally for 8 or 12 weeks at different doses. At the end of the experiment, blood was prepared for biochemical analysis and leptin ELISA. Aorta, epididymal and mesenteric fat and liver were removed surgically, weighed and observed for histological or immunohistochemical changes. KEY FINDINGS: PC significantly prevented body weight gain and lipid accumulation and alleviated hyperlipidemia by decreasing triglyceride (TG) and total cholesterol (TC) levels and the atherogenic index in serum or by increasing the HDL/TC ratio. Aortic apoE expression and serum leptin levels were suppressed by PC treatment in the HFD-induced obese mouse model. Elevated serum aspartate aminotransferase and alanine aminotransferase levels in HFD-fed mice were decreased in the PC groups. PC treatment significantly decreased HFD-induced liver weight and hepatic lipid accumulation. SIGNIFICANCE: PC treatment alleviated HFD-induced obese status and obesity-related complications such as hyperlipidemic changes that induce cardiovascular disease and NAFLD. PMID- 25445437 TI - Aminoguanidine inhibits ventricular fibrosis and remodeling process in isoproterenol-induced hypertrophied rat hearts by suppressing ROS and MMPs. AB - AIM: Aminoguanidine (AG), a well known inhibitor of advanced glycation end products, has been reported to attenuate cardiac hypertrophy and fibrosis. However, the underlying mechanism by which AG exerts its anti-fibrotic activity is not well understood. Reactive oxygen species (ROS) and matrix metalloproteinases (MMPs) are implicated as playing a major role in the development of cardiac fibrosis. Hence, the present study was designed to investigate the effect of AG on ROS generation and MMPs during the progress of hypertrophic growth. MAIN METHODS: Isoproterenol (ISO) (7 mg/kg/day, s.c., for 15 days) was used to induce cardiac hypertrophy in experimental adult Wistar rats. ISO-treated rats were co-treated with AG (50 mg/kg/day, i.p., for 15 days). Ventricular collagen deposition, gelatinase activity of MMP-2 and MMP-9, and the level of tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were investigated. In addition, in silico docking of MMP-2 and MMP-9 proteins, ROS generation, and nuclear translocation of NF-kappaB-p65 were also studied. KEY FINDINGS: AG co-treatment markedly attenuated the ISO-induced hypertrophic growth and fibrosis. Heart-weight-to-body weight ratio and ventricular collagen levels were normalized upon AG co-treatment. A significantly decreased level of ventricular ROS generation (p < 0.001) and NF-kappaB-p65 nuclear translocation was observed in the rat hearts co-treated with AG. Furthermore, in silico docking analysis revealed that AG interacts at the active site of MMP-2 and MMP-9. SIGNIFICANCE: Anti-fibrotic and anti-hypertrophic activities of AG were mainly attributed to its ROS quenching efficacy and its direct interaction with MMP-2 and MMP-9. PMID- 25445438 TI - Adipose tissue regulates hepatic cholesterol metabolism via adiponectin. AB - AIMS: Lipid metabolic disorder involves multiple tissues and organs. Hepatic cholesterol metabolism is an important physiological process, which is tightly related to obesity and lipid metabolic disorders. In this study, we examined the direct effects of adipocytes on hepatic cholesterol metabolic factors and investigated the role of potential adipocytokines in it. MAIN METHODS: Male SD rats were induced by a high-fat diet (HFD) and hepatic cholesterol metabolic factors, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) and ATP-binding cassette transporter A1 (ABCA1) were measured by immunoblotting. Then the effects of adipocytes on the expressions of hepatic cholesterol metabolism proteins were examined in the co-culture system. Finally, the concentrations of several adipocytokines were detected by ELISA and the effect of adiponectin (APN) on hepatic cholesterol metabolism was confirmed by short interference RNA (siRNA) in vitro. KEY FINDINGS: Our results showed that adipocytes significantly increased ABCA1 and decreased HMGR in hepatocytes after co-culture. Lipopolysaccharide (LPS) treatment in this co-culture system reversed cholesterol metabolism compared with the untreated group. APN, which also decreased in obese rats, had a significant positive correlation with ABCA1 and inversed correlation with HMGR in vitro. Co-culturing with APN-silenced adipocytes partially restored ABCA1 and HMGR levels. SIGNIFICANCE: The present study demonstrates that adipocytes regulate hepatic cholesterol metabolism partly via APN. PMID- 25445439 TI - Engineered heart tissue transplantation alters electrical-conduction function in rats with myocardial infarction. AB - AIMS: To investigate how affects electrical-conduction function following myocardial infarction (MI) in rats. MAIN METHODS: Thirty SD rats of either sex (220-250 g) were anesthetized using chlorine hydrate and were randomly divided into three groups: control group, MI group and transplantation group. The field potential (FP) morphology and activation-conduction duration were recorded with microeletrode array techniques. KEY FINDINGS: The MEA recorded clear FP morphology. Activation-conduction duration was (6.5 +/- 2.12) ms in the control group, (17.5 +/- 3.54) ms in the MI group, and (9.13 +/- 1.31) ms in the transplantation group. SIGNIFICANCE: EHT transplantation can improve electrical conduction and function of MI rats. PMID- 25445440 TI - Postconditioning with a CpG containing oligodeoxynucleotide ameliorates myocardial infarction in a murine closed-chest model. AB - AIMS: Toll-like receptor (TLR)9 ligand CpG-oligodeoxynucleotide (CpG-ODN) exerts preconditioning in myocardial ischemia/reperfusion. We hypothesized a postconditioning effect of CpG-ODN in a murine closed-chest model of myocardial infarction. MATERIALS AND METHODS: C57BL/6 (12 weeks, male, WT) mice were instrumented at the left anterior descending artery, then allowed 5d of recovery before 30 min ischemia. Treatments comprised: 1) PBS: 250 MUl phosphate buffer solution intraperitoneally 5 min before reperfusion and 2) IPC (ischemic postconditioning): 3 twenty-second reperfusion and occlusion episodes at the end of ischemia 3) CpG-ODN: 1668 thioate 0.2 MUmol/kg BW intraperitoneally 5 min before reperfusion. Infarct size was assessed via triphenyltetrazolium chloride (TTC) staining after 2 and 24h reperfusion. Myocardial mRNA-expression of cytokines was measured using real-time PCR after 2h reperfusion. Phosphatidylinositol-3 kinase (PI3K)-inhibitor wortmannin was injected intraperitoneally in WT 15 min before postconditioning and PBS in each group. Cardiac function in WT was assessed with a left-ventricular pressure-volume catheter at 24h reperfusion. KEY FINDINGS: Following 30 min ischemia and 2h reperfusion, infarct size was diminished by 90% in WT postconditioned with CpG ODN (2.4 +/- 1.55 IS/AAR%) and IPC (1.98 +/- 1.03 IS/AAR%) compared to PBS mice (23.2 +/- 3.97 IS/AAR%). Infarct size increased following 24h reperfusion but the differences remained robust. Expression of TNF-alpha and IL-10 was increased in CpG-ODN. Wortmannin abolished the postconditioning effect of CpG-ODN and IPC. Ejection fraction and preload-recruitable stroke work were significantly greater in CpG-ODN mice. SIGNIFICANCE: CpG-ODN confers postconditioning via activation of TLR9. Cardiac function is preserved following CpG-ODN postconditioning. The PI3K inhibitor wortmannin attenuates CpG-ODN postconditioning. PMID- 25445441 TI - Geniposide inhibited lipopolysaccharide-induced apoptosis by modulating TLR4 and apoptosis-related factors in mouse mammary glands. AB - AIMS: Geniposide, a major iridoid glycoside found in gardenia fruit, is widely used in Asian countries for its anti-inflammatory, anti-tumor and anti-apoptotic activities. Although the anti-inflammatory effect of geniposide has been widely reported, its anti-apoptotic role in mastitis remains unclear. In the present study, we investigated whether geniposide exerts anti-apoptotic activity in lipopolysaccharide (LPS)-induced mouse mammary glands. MAIN METHODS: We established a LPS-induced mouse mastitis model and LPS-stimulated primary mouse mammary epithelial cells (mMECs) model to investigate the anti-apoptotic effect of geniposide and the underlying mechanism of action. In the in vivo studies, apoptosis in mammary glands was detected by TUNEL. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to analyze the expression of Bax, Bcl-2, Caspase-3 and p53. In the in vitro study, the apoptosis in mammary epithelial cells was measured by Live-Dead staining. Western blot and qRT-PCR analysis were used to analyze the expression of Bax, Bcl-2, Caspase-3, p53 and TLR4. KEY FINDINGS: Geniposide alleviated mammary gland apoptosis, down regulated Bax expression, inhibited Caspase-3 cleavage and p53 phosphorylation and up-regulated Bcl-2 expression in vivo. In vitro, geniposide decreased the ratio of dead cells in a dose-dependent manner. Geniposide inhibited Bax expression and Caspase-3 cleavage, and up-regulated the expression of Bcl-2. Moreover, geniposide down-regulated the expression of TLR4 and repressed the phosphorylation of p53. SIGNIFICANCE: These results demonstrate that the anti apoptotic property of geniposide is due to its modulation of TLR4 and apoptosis related factors (p53, Bax, Bcl-2 and Caspase-3) in LPS-induced mouse mastitis. PMID- 25445442 TI - Fundamental for life: mTOR orchestrates developing biological systems. AB - Mechanistic target of rapamycin (mTOR) (historically known as mammalian target of rapamycin) functions as a master regulator of cell growth control. Although the regulation of protein translation is probably the best understood function of mTOR, it is clear that mTOR governs many additional processes within the cell that together orchestrates organism growth and development. Our 'growing' knowledge of the regulation of mTOR and signalling pathways has broadened significantly over the last few decades. Together, the eight reviews described in this special series on mTOR covers fundamental and up-to-date facets of mTOR function and signalling. The review topics herein underpin the importance of mTOR for developing and maintaining biological systems through the regulation of cellular growth and homeostatic pathways, which is fundamental for life and well being. PMID- 25445443 TI - Autophagy protects endplate chondrocytes from intermittent cyclic mechanical tension induced calcification. PMID- 25445444 TI - Does autophagy activation really inhibit calcification of endplate chondrocytes under intermittent cyclic mechanical tension? PMID- 25445445 TI - Characterization of bone marrow-derived mesenchymal stem cells in aging. AB - Adult mesenchymal stem cells are a resource for autologous and allogeneic cell therapies for immune-modulation and regenerative medicine. However, patients most in need of such therapies are often of advanced age. Therefore, the effects of the aged milieu on these cells and their intrinsic aging in vivo are important considerations. Furthermore, these cells may require expansion in vitro before use as well as for future research. Their aging in vitro is thus also an important consideration. Here, we focus on bone marrow mesenchymal stem cells (BMSCs), which are unique compared to other stem cells due to their support of hematopoietic cells in addition to contributing to bone formation. BMSCs may be sensitive to age-related diseases and could perpetuate degenerative diseases in which bone remodeling is a contributory factor. Here, we review (1) the characterization of BMSCs, (2) the characterization of in vivo-aged BMSCs, (3) the characterization of in vitro-aged BMSCs, and (4) potential approaches to optimize the performance of aged BMSCs. This article is part of a Special Issue entitled "Stem Cells and Bone". PMID- 25445446 TI - Duration-dependent effects of clinically relevant oral alendronate doses on cortical bone toughness in beagle dogs. AB - Bisphosphonates (BPs) have been shown to significantly reduce bone toughness in vertebrae within one year when given at clinical doses to dogs. Although BPs also reduce toughness in the cortical bone when given at high doses, their effect on cortical bone material properties when given at clinical doses is less clear. In part, this may be due to the use of small sample sizes that were powered to demonstrate differences in bone mineral density rather than the bone's material properties. Our lab has conducted several studies in which dogs were treated with alendronate at a clinically relevant dose. The goal of this study was to examine these published and unpublished data collectively to determine whether there is a significant time-dependent effect of alendronate on toughness of the cortical bone. This analysis seemed particularly relevant given the recent occurrence of atypical femoral fractures in humans. Differences in the toughness of ribs taken from dogs derived from five separate experiments were measured. The dogs were orally administered saline (CON, 1ml/kg/day) or alendronate (ALN) at a clinical dose (0.2mg/kg/day). Treatment duration ranged from 3months to 3years. Groups were compared using ANOVA, and time trends analyzed with linear regression analysis. Linear regressions of the percent difference in toughness between CON and ALN at each time point revealed a significant reduction in toughness with longer exposure to ALN. The downward trend was primarily driven by a downward trend in post-yield toughness, whereas toughness in the pre-yield region was not changed relative to CON. These data suggest that a longer duration of treatment with clinical doses of ALN results in deterioration of cortical bone toughness in a time-dependent manner. As the duration of treatment is lengthened, the cortical bone exhibits increasingly brittle behavior. This may be important in assessing the role that long-term BP treatments play in the risk of atypical fractures of the femoral cortical bone in humans. PMID- 25445447 TI - Periostin expression contributes to cortical bone loss during unloading. AB - Periostin (a product of Postn gene) is a matricellular protein which is increased in periosteal osteoblasts and osteocytes upon mechanical stimulation. We previously reported that periostin-deficient mice (Postn(-/-)) have low bone mass and a diminished response to physical activity due to a lack of sclerostin (a product of Sost gene) inhibition by mechanical loading. Here we hypothesized that periostin could play a central role in the control of bone loss during unloading induced by hindlimb suspension (HU). In Postn(+/+) mice (wildtype littermate), HU significantly decreased femur BMD, as well as trabecular BV/TV and thickness (Tb.Th). Cortical bone volume and thickness at the femoral midshaft, also significantly decreased. These changes were explained by an inhibition of endocortical and periosteal bone formation activity and correlated with a decrease of Postn expression and a consecutive increase in Sost early after HU. Whereas trabecular bone loss in Postn(-/-) mice was comparable to Postn(+/+) mice, HU did not significantly alter cortical bone microstructure and strength in Postn(-/-) mice. Bone formation remained unchanged in these mice, as Sost did not increase in the absence of periostin. In contrast, changes in Dkk1, Rankl and Opg expression in response to HU were similar to Postn(+/+) mice, indicating that changes in periostin expression were quite specifically related to changes in Sost. In conclusion, HU inhibits periostin expression, which in turn plays an important role in cortical bone loss through an increase in Sost. These results further indicate that periostin is an essential mediator of cortical bone response to mechanical forces (loading and unloading). PMID- 25445448 TI - The effects of thyrotropin-suppressing therapy on bone metabolism in patients with well-differentiated thyroid carcinoma. AB - Studies on the effects of levothyroxine (LT4) therapy on bone and bone metabolism have yielded conflicting results. This 1-year prospective study examined whether LT4 in patients with well-differentiated thyroid carcinoma (DTC) is a risk factor for bone mass loss and the subsequent development of osteoporosis. We examined 93 patients with DTC over 12months after initiating LT4 therapy (early postoperative period). We examined another 33 patients on long-term LT4 therapy for DTC (late postoperative period). Dual energy X-ray absorptiometry was performed at baseline and after 1year. The mean bone losses during the early postoperative period in the lumbar spine, femoral neck, and total hip, calculated as the percentage change between levels at baseline and 12months, were -0.88, -1.3 and -0.81%, respectively. Bone loss was more evident in postmenopausal women (lumbar spine 2.1%, femoral neck -2.2%, and hip -2.1%; all P<0.05). We compared the changes in annual bone mineral density (BMD) in postmenopausal women according to calcium/vitamin D supplementation. Bone loss tended to be higher in the postmenopausal women receiving no supplementation. There was no decrease in BMD among patients during the late postoperative period. The mean bone loss was generally greater in the early than in the late postoperative group, and this was significant at the lumbar spine (P=0.041) and femoral neck (P=0.010). TSH suppressive levothyroxine therapy accelerates bone loss, predominantly in postmenopausal women and exclusively during the early post-thyroidectomy period. PMID- 25445450 TI - Rapidly growing Brtl/+ mouse model of osteogenesis imperfecta improves bone mass and strength with sclerostin antibody treatment. AB - Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk that presents most severely in children. Anti-resorptive bisphosphonates are frequently used to treat pediatric OI and controlled clinical trials have shown that bisphosphonate therapy improves vertebral outcomes but has little benefit on long bone fracture rate. New treatments which increase bone mass throughout the pediatric OI skeleton would be beneficial. Sclerostin antibody (Scl-Ab) is a potential candidate anabolic therapy for pediatric OI and functions by stimulating osteoblastic bone formation via the canonical Wnt signaling pathway. To explore the effect of Scl-Ab on the rapidly growing OI skeleton, we treated rapidly growing 3week old Brtl/+ mice, harboring a typical heterozygous OI-causing Gly >Cys substitution on col1a1, for 5weeks with Scl-Ab. Scl-Ab had anabolic effects in Brtl/+ and led to new cortical bone formation and increased cortical bone mass. This anabolic action resulted in improved mechanical strength to WT Veh levels without altering the underlying brittle nature of the material. While Scl Ab was anabolic in trabecular bone of the distal femur in both genotypes, the effect was less strong in these rapidly growing Brtl/+ mice compared to WT. In conclusion, Scl-Ab was able to stimulate bone formation in a rapidly growing Brtl/+ murine model of OI, and represents a potential new therapy to improve bone mass and reduce fracture risk in pediatric OI. PMID- 25445451 TI - FGF23 gene variation and its association with phosphate homeostasis and bone mineral density in Finnish children and adolescents. AB - Fibroblast growth factor 23 (FGF23), a bone-derived hormone, participates in the hormonal bone-parathyroid-kidney axis, which is modulated by PTH, 1,25 dihydroxyvitamin D, plasma phosphate (Pi), and diet. Inappropriately high serum FGF23, seen in certain genetic and acquired disorders, results in urinary phosphate wasting and impaired bone mineralization. This study investigated the impact of FGF23 gene variation on phosphate homeostasis and bone health. The study included 183 children and adolescents (110 girls) aged 7-19 years (median 13.2years). Urine and blood parameters of calcium and phosphate homeostasis were analyzed. Bone characteristics were quantified by DXA and peripheral quantitative computed tomography (pQCT). Genetic FGF23 variation was assessed by direct sequencing of coding exons and flanking intronic regions. Nine FGF23 polymorphisms were detected; three of them were common: rs3832879 (c.212-37insC), rs7955866 (c.716C>T, p.T239M) and rs11063112 (c.2185A>T). Four different haplotypes and six different diplotypes were observed among these three polymorphisms. The variations in FGF23 significantly associated with plasma PTH and urinary Pi excretion, even after adjusting for relevant covariates. FGF23 variations independently associated with total hip BMD Z-score, but not with other bone outcomes. In instrument analysis, genetic variance in FGF23 was considered a weak instrument as it only induced small variations in circulating FGF23, PTH and Pi concentrations (F statistic less than 10). The observed associations between FGF23 variations and circulating PTH, and Pi excretion and total hip BMD Z-scores suggest that FGF23 polymorphisms may play a role in mineral homeostasis and bone metabolism. PMID- 25445449 TI - Biomechanical properties of bone in a mouse model of Rett syndrome. AB - Rett syndrome (RTT) is an X-linked genetic disorder and a major cause of intellectual disability in girls. Mutations in the methyl-CpG binding protein 2 (MECP2) gene are the primary cause of the disorder. Despite the dominant neurological phenotypes, MECP2 is expressed ubiquitously throughout the body and a number of peripheral phenotypes such as scoliosis, reduced bone mineral density and skeletal fractures are also common and important clinical features of the disorder. In order to explore whether MeCP2 protein deficiency results in altered structural and functional properties of bone and to test the potential reversibility of any defects, we have conducted a series of histological, imaging and biomechanical tests of bone in a functional knockout mouse model of RTT. Both hemizygous Mecp2(stop/y) male mice in which Mecp2 is silenced in all cells and female Mecp2(stop/+) mice in which Mecp2 is silenced in ~50% of cells as a consequence of random X-chromosome inactivation, revealed significant reductions in cortical bone stiffness, microhardness and tensile modulus. Microstructural analysis also revealed alterations in both cortical and cancellous femoral bone between wild-type and MeCP2-deficient mice. Furthermore, unsilencing of Mecp2 in adult mice cre-mediated stop cassette deletion resulted in a restoration of biomechanical properties (stiffness, microhardness) towards wild-type levels. These results show that MeCP2-deficiency results in overt, but potentially reversible, alterations in the biomechanical integrity of bone and highlights the importance of targeting skeletal phenotypes in considering the development of pharmacological and gene-based therapies. PMID- 25445452 TI - STAT-6 mediates TRAIL induced RANK ligand expression in stromal/preosteoblast cells. AB - Receptor activator of nuclear factor kappa-B ligand (RANKL) is a critical osteoclastogenic factor expressed in bone marrow stromal/osteoblast lineage cells. Tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) levels are elevated in pathologic conditions such as multiple myeloma and inflammatory arthritis, and have been positively correlated with osteolytic markers. Osteoprotegerin (OPG) which inhibits osteoclastogenesis is a decoy receptor for RANKL and also known to interact with TRAIL. Herein, we show that TRAIL increases DR5 and DcR1 receptors but no change in the levels of DR4 and DcR2 expression in human bone marrow derived stromal/preosteoblast (SAKA-T) cell line. We further demonstrated that TRAIL treatment significantly decreased OPG mRNA expression. Interestingly, TRAIL treatment induced RANKL mRNA expression in these cells. In addition, TRAIL significantly increased NF-kB and c-Jun N terminal kinase (JNK) activity. Human transcription factor array screening by real-time RT-PCR identified TRAIL up-regulation of the signal transducers and activators of the transcription (STAT)-6 expression in SAKA-T cells. TRAIL stimulation induced p-STAT-6 expression in human bone marrow derived primary stromal/preosteoblast cells. Confocal microscopy analysis further revealed p-STAT 6 nuclear localization in SAKA-T cells. Chromatin immunoprecipitation (ChIP) assay confirmed p-STAT-6 binding to the hRANKL gene distal promoter region. In addition, siRNA suppression of STAT-6 expression inhibits TRAIL increased hRANKL gene promoter activity. Thus, our results suggest that TRAIL induces RANKL expression through a STAT-6 dependent transcriptional regulatory mechanism in bone marrow stromal/preosteoblast cells. PMID- 25445453 TI - Endochondral fracture healing with external fixation in the Sost knockout mouse results in earlier fibrocartilage callus removal and increased bone volume fraction and strength. AB - Sclerostin deficiency, via genetic knockout or anti-Sclerostin antibody treatment, has been shown to cause increased bone volume, density and strength of calluses following endochondral bone healing. However, there is limited data on the effect of Sclerostin deficiency on the formative early stage of fibrocartilage (non-bony tissue) formation and removal. In this study we extensively investigate the early fibrocartilage callus. Closed tibial fractures were performed on Sost(-/-) mice and age-matched wild type (C57Bl/6J) controls and assessed at multiple early time points (7, 10 and 14days), as well as at 28days post-fracture after bony union. External fixation was utilized, avoiding internal pinning and minimizing differences in stability stiffness, a variable that has confounded previous research in this area. Normal endochondral ossification progressed in wild type and Sost(-/-) mice with equivalent volumes of fibrocartilage formed at early day 7 and day 10 time points, and bony union in both genotypes by day 28. There were no significant differences in rate of bony union; however there were significant increases in fibrocartilage removal from the Sost(-/-) fracture calluses at day 14 suggesting earlier progression of endochondral healing. Earlier bone formation was seen in Sost(-/-) calluses over wild type with greater bone volume at day 10 (221%, p<0.01). The resultant Sost( /-) united bony calluses at day 28 had increased bone volume fraction compared to wild type calluses (24%, p<0.05), and the strength of the fractured Sost(-/-) tibiae was greater than that that of wild type fractured tibiae. In summary, bony union was not altered by Sclerostin deficiency in externally-fixed closed tibial fractures, but fibrocartilage removal was enhanced and the resultant united bony calluses had increased bone fraction and increased strength. PMID- 25445454 TI - Prospective heterotopic ossification progenitors in adult human skeletal muscle. AB - Skeletal muscle has strong regenerative capabilities. However, failed regeneration can lead to complications where aberrant tissue forms as is the case with heterotopic ossification (HO), in which chondrocytes, osteoblasts and white and brown adipocytes can arise following severe trauma. In humans, the various HO cell types likely originate from multipotent mesenchymal stromal cells (MSCs) in skeletal muscle, which have not been identified in humans until now. In the present study, adherent cells from freshly digested skeletal muscle tissue were expanded in defined culture medium and were FACS-enriched for the CD73(+)CD105(+)CD90(-) population, which displayed robust multilineage potential. Clonal differentiation assays confirmed that all three lineages originated from a single multipotent progenitor. In addition to differentiating into typical HO lineages, human muscle resident MSCs (hmrMSCs) also differentiated into brown adipocytes expressing uncoupling protein 1 (UCP1). Characterizing this novel multipotent hmrMSC population with a brown adipocyte differentiation capacity has enhanced our understanding of the contribution of non-myogenic progenitor cells to regeneration and aberrant tissue formation in human skeletal muscle. PMID- 25445457 TI - The 3D structure of the collagen fibril network in human trabecular bone: relation to trabecular organization. AB - Trabecular bone is morphologically and functionally different from compact bone at the tissue level, but both are composed of lamellae at the micrometer-scale level. We present a three-dimensional study of the collagenous network of human trabecular lamellar bone from the proximal femur using the FIB-SEM serial surface view method. The results are compared to human compact lamellar bone of the femoral shaft, studied by the same method. Both demineralized trabecular and compact lamellar bone display the same overall structural organization, namely the presence of ordered and disordered materials and the confinement of the canalicular network to the disordered material. However, in trabecular bone lamellae a significant proportion of the ordered collagen fibril arrays is aligned with the long axis of the trabecula and, unlike in compact bone, is not related to the anatomical axis of the whole femur. The remaining ordered collagen fibrils are offset from the axis of a trabecula either by about 30 degrees or 70 degrees . Interestingly, at the tissue scale of millimeters, the most abundant angles between any two connected trabeculae - the inter-trabecular angles - center around 30 degrees and 70 degrees . This implies that within a framework of interconnected trabeculae the same lamellar structure will always have a significant component of the fibrils aligned with the long axes of connected trabeculae. This structural complementarity at different hierarchical levels presumably reflects an adaptation of trabecular bone to function. PMID- 25445455 TI - Individuals with high bone mass have an increased prevalence of radiographic knee osteoarthritis. AB - We previously reported an association between high bone mass (HBM) and a bone forming phenotype of radiographic hip osteoarthritis (OA). As knee and hip OA have distinct risk factors, in this study we aimed to determine (i) whether HBM is also associated with knee OA, and (ii) whether the HBM knee OA phenotype demonstrates a similar pattern of radiographic features to that observed at the hip. HBM cases (defined by DXA BMD Z-scores) from the UK-based HBM study were compared with unaffected family controls and general population controls from the Chingford and Hertfordshire cohort studies. A single blinded observer graded AP weight-bearing knee radiographs for features of OA (Kellgren-Lawrence score, osteophytes, joint space narrowing (JSN), sclerosis) using an atlas. Analyses used logistic regression, adjusting a priori for age and gender, and additionally for BMI as a potential mediator of the HBM-OA association, using Stata v12. 609 HBM knees in 311 cases (mean age 60.8years, 74% female) and 1937 control knees in 991 controls (63.4years, 81% female) were analysed. The prevalence of radiographic knee OA, defined as Kellgren-Lawrence grade>=2, was increased in cases (31.5% vs. 20.9%), with age and gender adjusted OR [95% CI] 2.38 [1.81, 3.14], p<0.001. The association between HBM and osteophytosis was stronger than that for JSN, both before and after adjustment for BMI which attenuated the ORs for knee OA and osteophytes in cases vs. controls by approximately 50%. Our findings support a positive association between HBM and knee OA. This association was strongest for osteophytes, suggesting HBM confers a general predisposition to a subtype of OA characterised by increased bone formation. PMID- 25445456 TI - Novel immunostimulatory effects of osteoclasts and macrophages on human gammadelta T cells. AB - It has been widely reported that T cells are capable of influencing osteoclast formation and bone remodelling, yet relatively little is known of the reciprocal effects of osteoclasts for affecting T cell function and/or activity. In this study we investigated the effects of human osteoclasts on the function of gammadelta T cells, a subset of non-CD4(+) T cells implicated in a variety of inflammatory disease states. gammadelta T cells and CD4(+) T cells were isolated from peripheral blood of healthy volunteers and were co-cultured with autologous mature osteoclasts (generated by treatment with M-CSF and RANKL) before phenotypical and functional changes in the T cell populations were assessed. Macrophages, osteoclasts, and conditioned medium derived from macrophages or osteoclasts induced activation of gammadelta T cells, as determined by the expression of the early activation marker CD69. TNFalpha was a major mediator of this stimulatory effect on gammadelta T cells. Consistent with this stimulatory effect, osteoclasts augmented proliferation of IL-2-stimulated gammadelta T cells and also supported the survival of unstimulated gammadelta and CD4(+) T cells, although these effects required co-culture with osteoclasts. Co-culture with osteoclasts also increased the proportion of gammadelta T cells producing IFNgamma, but did not modulate IFNgamma or IL-17 production by CD4(+) T cells. We provide new insights into the in vitro interactions between human gammadelta T cells and osteoclasts/macrophages, and demonstrate that osteoclasts or their precursors are capable of influencing gammadelta T function both via the release of soluble factors and also through direct cell-cell interactions. PMID- 25445459 TI - Measurement of the biophysical properties of porcine adipose-derived stem cells by a microperfusion system. AB - Adipose-derived stem cells (ADSCs), which are an accessible source of adult stem cells with capacities for self-renewal and differentiation into various cell types, have a promising potential in tissue engineering and regenerative medicine strategies. To meet the clinical demand for ADSCs, cryopreservation has been applied for long-term ADSC preservation. To optimize the addition, removal, freezing, and thawing of cryoprotective agents (CPAs) applied to ADSCs, we measured the transport properties of porcine ADSCs (pADSCs). The cell responses of pADSCs to hypertonic phosphate-buffered saline and common CPAs, dimethyl sulfoxide, ethylene glycol, and glycerol were measured by a microperfusion system at temperatures of 28, 18, 8, and -2 degrees C. We determined the osmotically inactive cell volume (Vb), hydraulic conductivity (Lp), and CPA permeability (Ps) at various temperatures in a two-parameter model. Then, we quantitatively analyzed the effect of temperature on the transport properties of the pADSC membrane. Biophysical parameters were used to optimize CPA addition, removal, and freezing processes to minimize excessive shrinkage of pADSCs during cryopreservation. The biophysical properties of pADSCs have a great potential for effective optimization of cryopreservation procedures. PMID- 25445458 TI - Bone marrow transplantation improves autoinflammation and inflammatory bone loss in SH3BP2 knock-in cherubism mice. AB - Cherubism (OMIM#118400) is a genetic disorder in children characterized by excessive jawbone destruction with proliferation of fibro-osseous lesions containing a large number of osteoclasts. Mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for cherubism. Analysis of the knock-in (KI) mouse model of cherubism showed that homozygous cherubism mice (Sh3bp2(KI/KI)) spontaneously develop systemic autoinflammation and inflammatory bone loss and that cherubism is a TNF-alpha-dependent hematopoietic disorder. In this study, we investigated whether bone marrow transplantation (BMT) is effective for the treatment of inflammation and bone loss in Sh3bp2(KI/KI) mice. Bone marrow (BM) cells from wild-type (Sh3bp2(+/+)) mice were transplanted to 6-week-old Sh3bp2(KI/KI) mice with developing inflammation and to 10-week-old Sh3bp2(KI/KI) mice with established inflammation. Six-week-old Sh3bp2(KI/KI) mice transplanted with Sh3bp2(+/+) BM cells exhibited improved body weight loss, facial swelling, and survival rate. Inflammatory lesions in the liver and lung as well as bone loss in calvaria and mandibula were ameliorated at 10weeks after BMT compared to Sh3bp2(KI/KI) mice transplanted with Sh3bp2(KI/KI) BM cells. Elevation of serum TNF-alpha levels was not detected after BMT. BMT was effective for up to 20weeks in 6-week-old Sh3bp2(KI/KI) mice transplanted with Sh3bp2(+/+) BM cells. BMT also ameliorated the inflammation and bone loss in 10-week-old Sh3bp2(KI/KI) mice. Thus our study demonstrates that BMT improves the inflammation and bone loss in cherubism mice. BMT may be effective for the treatment of cherubism patients. PMID- 25445460 TI - Hatching, survival and deformities of piracanjuba (Brycon orbignyanus) embryos subjected to different cooling protocols. AB - Groups of one hundred Brycon orbignyanus embryos at the stage of blastopore closure were subjected to different cooling protocols. Different combinations and concentrations of cryoprotectants were tested: sucrose, methanol, ethylene glycol and dimethyl sulfoxide (Me2SO); at different temperatures (0.0+/-2.0 degrees C and 8.0+/-2.0 degrees C) and refrigeration times (6, 10, 24, 72 and 168 h), with the exception of the positive control (incubation without previous cooling). At the end of each refrigeration time, the embryos were acclimatized, rehydrated and incubated to determine hatching, survival and deformity rates. Morphological analysis of embryos was also carried out. The results showed that temperature and refrigeration time are critical factors for embryo survival. No embryos survived after 24, 72 and 168 h of refrigeration. Furthermore, when the refrigeration time increased from 6 to 10h and the temperature decreased from 8.0+/-2.0 degrees C to 0.0+/-2.0 degrees C, mortality rates increased significantly. It was also found that in all protocols dead eggs and/or larvae with some degree of deformity were present. The main larval deformities observed were the malformation of the head, tail, yolk sac, vertebral column and eyes. PMID- 25445461 TI - Cryoprotective therapy for huge hepatocellular carcinoma: a study of 14 patients with a single lesion. AB - Percutaneous cryoablation is a potential cure for hepatocellular carcinoma (HCC). This study reviewed retrospectively clinical data from 14 patients who underwent cryoablation of huge HCC (long diameter >7 cm). The side effects of cryosurgeries and liver function reverse were recorded and compared everyday. All the patients survived cryosurgery and none died before leaving hospital 2 weeks later. Despite liver-protective treatment before cryosurgery, alanine transaminase (ALT) and aspartate transaminase (AST) levels were increased significantly, but returned to preoperative levels 2 weeks post-cryosurgery. Before cryosurgery, mean total bilirubin (T.BIL) and direct bilirubin (D.BIL) levels were normal; 8-10 days after cryosurgery, they increased more than two-fold, but returned to the preoperative level 2 weeks post-cryosurgery. Serum transaminase and bilirubin levels were compared between hepatitis B positive and negative patients. The hepatitis B negative group's AST level increased significantly 1 day post cryosurgery (mean, 186 U/L) and decreased to the preoperative level at day 14. In the hepatitis B positive group, means transaminase and bilirubin reached peak values at different days post-cryosurgery. Overall, ALT and AST are valuable indicators of liver function impairment following cryosurgery. In patients with hepatitis B virus, close attention to the serum bilirubin level should be paid 8 10 days after cryosurgery. Liver-protective treatment may alleviate liver function impairment caused by cryosurgery of huge HCC. PMID- 25445462 TI - Cryopreservation of rainbow trout Oncorhynchus mykiss spermatozoa: effects of extender supplemented with different antioxidants on sperm motility, velocity and fertility. AB - In present study, it was examined whether addition of different antioxidants to the cryopreservation extenders had an effect on semen post-thaw fertility and motility in rainbow trout (Oncorhynchus mykiss) and also it was investigated the sperm characteristics post-thaw sperm characteristics and fertility. The collected semen was pooled to minimize individual variation. Each pooled ejaculate was split into 12 equal aliquots and diluted with base extenders supplemented with the antioxidants, and a base extender with no additives (control). The pooled semen samples diluted at the ratio of 1:10 by the extenders were subjected to cryopreservation. Antioxidants were separately added to the extenders (one per experimental group): catalase (250 U/l), superoxide dismutase (250 U/l), peroxidase (250 U/l), oxidized glutathione (1.5 mmol/l), reduced glutathione (1.5 mmol/l), L-methionine (1.5 mmol/l), uric acid (0.25 mmol/l), L ascorbic acid (0.5 mmol/l), alpha-tocopherol (2.0 mmol/l), beta-carotene (0.5 mmol/l) and carnitine (0.5 mmol/l). After dilution the semen was aspirated into 0.25 ml straws, the straws were placed on the tray, frozen for 10 min, and plunged into liquid nitrogen. Our results indicated that the post-thaw motility rate increased in extenders supplemented with uric acid, L-methionine, SOD, L carnitine, alpha-tocopherol and L-reduced glutathione (p<0.05). The motility duration of frozen thawed semen increased in extenders supplemented with uric acid, L-methionine, SOD, alpha-tocopherol and L-reduced glutathione (p<0.05). Fertilization rate and hatching rate of frozen-thawed semen was not affected by the tested antioxidants. Consequently, the tested antioxidants affected the motility parameters and cryopreservation extenders could be supplement with antioxidants. This study suggested usage of antioxidants in the cryopreservation of rainbow trout. PMID- 25445463 TI - Cryoprotective effect of phosphorous-containing phenolic anti-oxidant for the cryopreservation of beluga sperm. AB - A cryoprotective effect of an addition of a new synthetic antioxidant - a representative of phosphorus-containing sterically hindered phenols is presented. The efficiency of the compound was shown to exceed the effect of lipid-soluble antioxidants butylated hydroxytoluene (BHT) and trolox in the conditions of cryopreservation of beluga sperm in the presence of the modified Stein's medium. It was shown that the level of carbonyl oxidation by-products, which can react with thiobarbituric acid (TBARS), in beluga sperm was inversely proportional to the motility time of sperm cells. The fertility of beluga sperm increased 2 times upon the addition of phosphorus-containing phenol to a modified Stein's medium. The prospects of the new antioxidant application to improve cryoresistance of beluga sperm in the conditions of cryopreservation for its efficient protection from the peroxidation processes are discussed. PMID- 25445465 TI - Motility and fertility of cryopreserved semen in Persian sturgeon, Acipenser persicus, stored for 30-60 min after thawing. AB - We investigated the effect of storage times of frozen-thawed Persian sturgeon (Acipenser persicus) semen on the duration of sperm motility, percentage of motile sperm, and fertilization and hatching rates of fresh sperm and sperm stored for 0, 30, and 60 min at 4 degrees C post-thawing. Frozen thawed semen analyzed immediately after thawing had similar quality characteristics as fresh semen. For cryopreserved semen stored for 30 min after thawing the characteristics did not differ to fresh semen and cryopreserved semen. For cryopreserved semen stored for 60 min a significant decline in the parameters was observed. Fertilization and hatching rates were not affected by storage times of maximally 30 min of storage. PMID- 25445464 TI - Use of hypometabolic TRIS extenders and high cooling rate refrigeration for cryopreservation of stallion sperm: presence and sensitivity of 5' AMP-activated protein kinase (AMPK). AB - This study evaluated the effect of the use of hypometabolic TRIS extenders in the presence or the absence of AMPK activators as well as the utilization of high cooling rates in the refrigeration step on the freezability of stallion sperm. Twelve ejaculates were cryopreserved using Botucrio(r) as a control extender and a basic TRIS extender (HM-0) separately supplemented with 10 mM metformin, 2mM 5 aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), 2 mM Adenosine monophosphate (AMP), 40 MUM compound C AMPK inhibitor or 2 mM AMP+40 MUM compound C. Our results showed that the utilization of a hypometabolic TRIS extender supplemented or not with AMP or metformin significantly improves stallion sperm freezability when compared with a commercial extender. Additionally, high cooling rates do not affect stallion sperm quality after cooling and post-thawing. Finally, stallion spermatozoa present several putative AMPK sperm isoforms that do not seem to respond to classical activators, but do respond to the Compound C inhibitor. PMID- 25445466 TI - Novel agents in the treatment of chronic lymphocytic leukemia: a review about the future. AB - Half of a century ago, physicians managing chronic lymphocytic leukemia (CLL) recognized some of its presenting features such as lymphocytosis, lymphadenopathy, and splenomegaly. Subsequently, an enhanced understanding of the disease mechanisms involved in CLL led to new, more targeted treatments. There is now a plethora of treatments available for CLL. In this review article we discuss in detail several of the novel agents that are being studied or approved for the treatment of CLL including: phosphatidylinositol 3-kinase inhibitors (idelalisib and IPI-145), Bruton tyrosine kinase inhibitors (ibrutinib), B cell lymphoma 2 inhibitors (ABT-263 and ABT-199), new anti-CD20 monoclonal antibodies (obinutuzumab), cyclin-dependent kinase inhibitors (flavopiridol and dinaciclib), immunomodulators (lenalidomide) and chimeric antigen receptor T-cell therapy. PMID- 25445467 TI - Randomized controlled trials in relapsed/refractory chronic lymphocytic leukemia: a systematic review and meta-analysis. AB - This systematic literature review with meta-analysis was conducted on the clinical efficacy and safety of interventions used in the treatment of chronic lymphocytic leukemia (CLL). We systematically searched databases (PubMed, Cochrane Library, and Embase; 1997 to August 2, 2012), conference abstracts, bibliographic reference lists, recent reviews, and Clinicaltrials.gov. Primary efficacy outcomes were objective response rate, progression-free survival, and overall survival. Safety end points were Grade 3/4 toxicities, serious adverse events, withdrawals because of toxicity, and deaths due to toxicity. Studies were selected if they were randomized controlled trials (RCTs) reporting on the efficacy or safety of relapsed or refractory CLL and if outcomes for CLL were reported separately from trials that included other lymphoid neoplasms. We used the Bucher method for conducting adjusted indirect comparisons within a meta analysis. We identified 6 RCTs of pharmacologic treatment for relapsed/refractory CLL. The most common drugs investigated (alone or in combination) were fludarabine and cyclophosphamide. When reported, median overall survival ranged from 27.3 to 52.9 months, and overall response rate from 58% to 82%. Although meta-analysis of efficacy results was considered, details are not presented because only 3 studies qualified and the common comparator treatment was not clinically relevant. The relatively small number of RCTs, few overlapping treatment arms, and variability in end points studied make it difficult to formally compare therapies for relapsed/refractory CLL. Significant variability in RCT features presents a further challenge to meaningful comparisons. Additional well-designed RCTs are needed to fully understand the relative efficacy and safety of older and more recently developed therapies. PMID- 25445469 TI - Characteristics of patients with development of large granular lymphocyte expansion among dasatinib-treated patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia after allogeneic stem cell transplantation. AB - INTRODUCTION: Widespread use of tyrosine kinase inhibitors (TKIs) in combination with chemotherapy and allogeneic hematopoietic stem cell transplantation (allo SCT) has totally changed the existing treatment strategies for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL). However, the prognosis after relapse after allo-SCT is still dismal. PATIENTS AND METHODS: We analyzed the clinical outcome of therapy using dasatinib, a second-generation TKI, in 9 patients with relapsed Ph(+)ALL after allo-SCT. Dasatinib was initiated at a median time of 168 days after allo-SCT at dosages ranging from 20 mg to 100 mg daily. RESULTS: Six of 9 patients manifested a marked increase in large granular lymphocytes (LGLs), but all 6 patients discontinued dasatinib because of adverse events (AEs) such as pleural effusion. Four of 6 patients resumed dasatinib, and 3 of them have been alive with molecular complete remission and a persistent increase of LGLs. CONCLUSION: Our results demonstrated that dasatinib therapy can induce LGL expansion accompanied by AEs, but this phenomenon can be associated with long-term survival benefit in a proportion of relapsed Ph(+)ALL patients after allo-SCT. PMID- 25445468 TI - Pegylated liposomal doxorubicin replacing conventional doxorubicin in standard R CHOP chemotherapy for elderly patients with diffuse large B-cell lymphoma: an open label, single arm, phase II trial. AB - BACKGROUND: The present multicenter phase II trial evaluated the safety and efficacy of pegylated liposomal doxorubicin (PLD) instead of conventional doxorubicin in standard R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone) therapy for elderly patients with diffuse large B-cell lymphoma. MATERIALS AND METHODS: Patients aged > 60 years who had stage II to IV disease were included. Treatment consisted of rituximab 375 mg/m(2) intravenously (I.V.); cyclophosphamide 750 mg/m(2) IV; PLD 40 mg/m(2) (maximum, 90 mg) I.V. over 1 hour; and vincristine 2.0 mg I.V., all on day 1. Additionally prednisone, 40 mg/m(2), was given orally on days 1 to 1 to 5 (DRCOP [rituximab, cyclophosphamide, PLD, vincristine, and prednisone]). The cycles were repeated every 3 weeks for 6 to 8 cycles. RESULTS: Eighty patients were enrolled and were evaluable for toxicity. The median age was 69 years. All except 1 had additional cardiac risk factors for anthracycline-induced cardiac toxicity beyond advanced age. From the intent-to-treat analysis of 79 eligible patients, the overall response rate was 86%, and the complete response rate was 78%. Cardiac events greater than grade 3 were identified in 3 patients (4%); grade 1 to 2 events, mostly asymptomatic declines in ejection fraction, were noted in another 16 patients. One death was attributed to cardiac failure. The estimated 5-year event-free and overall survival rate was 52% and 70%, respectively. CONCLUSION: DRCOP represents an effective strategy for potentially mitigating cardiotoxicity in elderly patients with aggressive B-cell lymphoma. Future studies incorporating baseline cardiac risk assessments, long-term follow-up data, and biospecimen collection for correlative science should be undertaken. PMID- 25445470 TI - Do biologic parameters affect the time to first treatment of clinical monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia Rai stage 0? Results of a prospective analysis. AB - BACKGROUND: We investigated the clinical relevance of classic and new prognostic markers, immunoglobulin heavy-chain variable (IGHV) gene mutational status, and chromosomal abnormalities in clinical monoclonal B lymphocytosis (cMBL) compared with chronic lymphocytic leukemia (CLL) Rai stage 0. PATIENTS AND METHODS: We analyzed the clinical outcomes in terms of the time to the first treatment (TTFT) of a prospective cohort, including 125 patients with cMBL and 197 patients with CLL Rai stage 0. RESULTS: In the overall patient population, prognostic parameters such as IGHV gene mutational status (P < .0001), CD38 expression (P < .0001), 70-kDa zeta-associated protein (ZAP-70) expression (P < .0001), and cytogenetic abnormalities (P = .01) predicted for TTFT on univariate analysis. IGHV gene identity was significant on multivariate analysis (P < .0001), regardless of the B-cell cutoff (5.0 or 10 * 10(9) B cells/L). A prognostic stratification using the combination of IGHV mutational status and absolute B cell lymphocytosis identified 3 different groups that were significantly different with respect to the TTFT (P < .0001). CONCLUSION: In the present series of patients with cMBL and CLL Rai stage 0, we have confirmed that IGHV mutation status appeared to be the best predictor of TTFT. In addition, when associated with the B-cell count, IGHV mutational status might help to better stratify patients into more precise subgroups. PMID- 25445471 TI - Determining the clinical significance of monoclonal gammopathy of undetermined significance: a SEER-Medicare population analysis. AB - BACKGROUND: Clinical guidelines have recommended annual follow-up examinations of most patients with monoclonal gammopathy of undetermined significance (MGUS); however, evidence supporting this practice is lacking. We performed a population based study to examine the patterns of disease presentation and outcomes of patients with multiple myeloma, Waldenstrom macroglobulinemia, and lymphoplasmacytic lymphoma (monoclonal gammopathy-associated malignancies) comparing those with or without a previous MGUS follow-up examination. MATERIALS AND METHODS: Patients with monoclonal gammopathy-associated malignancy from 1994 through 2007 were identified using the Surveillance, Epidemiology, and End Results-Medicare linked database and divided into 2 cohorts: those with follow-up (MGUS follow-up examination preceding the diagnosis) and those with no follow-up (no such follow-up examination). We compared the outcomes, including the rates of major complications at cancer diagnosis (acute kidney injury, cord compression, dialysis use, fracture, and hypercalcemia) and survival using propensity score adjustment and Cox proportional hazard models. All statistical tests were 2 sided. RESULTS: Of the 17,457 study patients, 6% had undergone MGUS follow-up. After multivariable modeling, the follow-up group had significantly fewer major complications at diagnosis (odds ratio 0.68; 95% confidence interval [CI], 0.57 0.80) and better disease-specific (median, 38 vs. 29 months, P < .001; hazard ratio [HR] 0.85; 95% CI, 0.76-0.94) and overall (median, 23 vs. 19 months, P < .001; HR 0.87; 95% CI, 0.80-0.95) survival. CONCLUSION: Patients with MGUS follow up preceding the diagnosis of a monoclonal gammopathy-associated malignancy can experience fewer major complications and have longer survival than those without such follow-up examinations. Future studies replicating our findings in the non Medicare population and determining the optimal schedule and cost-effectiveness of MGUS follow-up are warranted. PMID- 25445472 TI - Relationship of P-selectin glycoprotein ligand-1 to prognosis in patients with multiple myeloma. AB - BACKGROUND: Changes occur in adhesion molecules in the disease course of multiple myeloma. P-selectin glycoprotein ligand-1 (PSGL-1, CD162) works as the ligand of selectin-neutrophil adhesion molecules. The aim of the present study was to investigate the relationship between PSGL-1 expression in the bone marrow and the known prognostic factors for multiple myeloma disease, disease stage, and survival. MATERIALS AND METHODS: This research included 63 patients with multiple myeloma (26 women [41.3%]; 37 men [58.7%]). The bone marrow biopsy samples obtained at disease diagnosis for each patient were stained immunohistochemically in terms of CD162 expression using standard diagnostic immunohistochemical staining methods. The laboratory results, CD162 expression, overall survival, demographic characteristics of the disease, and the relationship between CD162 expression and the disease stage were evaluated. RESULTS: Among the 63 patients included in the present study, the survival rate was 82.3% for 1 year, 73.2% for 2 years, 63.4% for 3 years, 51.7% for 4 years, 40.3% for 5 years, and 33.6% for 6 and 7 years. A statistically significant difference was not detected between the CD162 staining ratio and disease survival (P = .232). A statistically significant difference was not detected between the CD162 staining degree and survival rate (P = .184). However, the overall survival of the patients with no CD162 expression in the bone marrow was lower than that for the patients whose CD162 was stained 1, 2, and 3 degrees (12.33 +/- 11.49, 28.65 +/- 31.44, 37.25 +/- 29.32, and 47.92 +/- 45.29 months, respectively; P < .001). CONCLUSION: In the present study, CD162 staining and the staining degree, with the other standard immunohistochemical stains, were shown to be beneficial in the diagnosis of multiple myeloma disease. However, the results did not provide information about the disease course. Studies of a larger number of patients to examine P-selectin and interleukin-6 levels are needed to investigate the disease course. PMID- 25445473 TI - Quantitative measures of physical functioning after autologous hematopoietic stem cell transplantation in multiple myeloma: a feasibility study. AB - BACKGROUND: The safety and feasibility of the symptom-limited cardiopulmonary exercise test (CPET) and the 6-minute walk test (6MWT) has not been rigorously tested in patients with multiple myeloma (MM) after high-dose chemotherapy with autologous stem cell transplantation (ASCT), nor have correlations with patient reported outcomes (PROs) been explored. PATIENTS AND METHODS: We undertook CPET, 6MWT, and PRO assessments using standardized measurements and questionnaires in patients with MM in remission after ASCT. RESULTS: A total of 22 patients who were a median of 17 months after ASCT underwent assessment. No severe adverse events were observed. Exercise capacity, measured during CPET as the peak oxygen consumption, was 17.5 +/- 5.9 mL/kg/min, the equivalent of 38% +/- 18% less than that for age- and sex-predicted sedentary normative values. During the 6MWT, the mean 6-minute walk distance was 500 m, or 25% +/- 13% less than the predicted values. Additional analysis using Pearson's correlation revealed no significant univariate associations between exercise or functional capacity and any PROs. CONCLUSION: Patients with MM have marked and significant reductions in quantitative measures of physical function for years after the initial therapy, although that did not correlate with PROs in the present pilot study. Larger prospective studies are required to determine the clinical ramifications of these findings and to mechanistically dissect them, as well to test interventions aimed at mitigating them. PMID- 25445474 TI - Infralimbic cortex Rho-kinase inhibition causes antidepressant-like activity in rats. AB - Depression is one of the most common psychiatric disorders in the world; however, its mechanisms remain unclear. Recently, a new signal-transduction pathway, namely Rho/Rho-kinase signalling, has been suggested to be involved in diverse cellular events in the central nervous system; such as epilepsy, anxiety-related behaviors, regulation of dendritic and axonal morphology, antinociception, subarachnoid haemorrhage, spinal cord injury and amyotrophic lateral sclerosis. However there is no evidence showing the involvement of Rho-kinase pathway in depression. In addition, the infralimbic cortex, rodent equivalent to subgenual cingulate cortex has been shown to be responsible for emotional responses. Thus, in the present study, intracranial guide cannulae were stereotaxically implanted bilaterally into the infralimbic cortex, and the effects of repeated microinjections of a Rho-kinase (ROCK) inhibitor Y-27632 (10 nmol) were investigated in rats. Y-27632 significantly decreased immobility time and increased swimming and climbing behaviors when compared to fluoxetine (10 MUg) and saline groups in the forced swim test. In addition, Y-27632 treatment did not affect spontaneous locomotor activity and forelimb use in the open-field and cylinder tests respectively; but it enhanced limb placing accuracy in the ladder rung walking test. Our results suggest that Y-27632 could be a potentially active antidepressant agent. PMID- 25445475 TI - Decreased functional connectivity in an executive control network is related to impaired executive function in Internet gaming disorder. AB - BACKGROUND: Resting brain spontaneous neural activities across cortical regions have been correlated with specific functional properties in psychiatric groups. Individuals with Internet gaming disorder (IGD) demonstrate impaired executive control. Thus, it is important to examine executive control networks (ECNs) during resting states and their relationships to executive control during task performance. METHODS: Thirty-five IGD and 36 healthy control participants underwent a resting-state fMRI scan and performed a Stroop task inside and outside of the MRI scanner. Correlations between Stroop effect and functional connectivity among ECN regions of interest (ROIs) were calculated within and between groups. RESULTS: IGD subjects show lower functional connectivity in ECNs than do HC participants during resting state; functional-connectivity measures in ECNs were negatively correlated with Stroop effect and positively correlated with brain activations in executive-control regions across groups. Within groups, negative trends were found between Stroop effect and functional connectivity in ECNs in IGD and HC groups, separately; positive trends were found between functional connectivity in ECNs and brain activations in Stroop task in IGD and HC groups, separately. CONCLUSIONS: Higher functional connectivity in ECNs may underlie better executive control and may provide resilience with respect to IGD. Lower functional connectivity in ECNs may represent an important feature in understanding and treating IGD. PMID- 25445477 TI - Blockade of spinal glutamate recycling produces paradoxical antinociception in rats with orofacial inflammatory pain. AB - In our current study, we investigated the role of spinal glutamate recycling in the development of orofacial inflammatory pain. DL-threo-beta-benzyloxyaspartate (TBOA) or methionine sulfoximine (MSO) was administered intracisternally to block spinal glutamate transporter and glutamine synthetase activity in astroglia. Intracisternal administration of high dose TBOA (10 MUg) produced thermal hyperalgesia in naive rats but significantly attenuated the thermal hyperalgesia in rats that had been pretreated with interleukin (IL)-1beta or Complete Freund's Adjuvant (CFA). In contrast, intracisternal injection of MSO produced anti hyperalgesic effects against thermal stimuli in CFA-treated rats only. To confirm the paradoxical antinociceptive effects of TBOA and MSO, we examined changes in c Fos expression in the medullary dorsal horn produced by thermal stimulation in naive, IL-1beta-, or CFA-treated rats, after intracisternal injections of TBOA and MSO. Intracisternal administration of TBOA significantly increased c-Fos immunoreactivity in naive rats. In contrast, intracisternal administration of TBOA significantly decreased the up-regulation of c-Fos immunoreactivity in the medullary dorsal horn of IL-1beta- and CFA-treated rats. However, intracisternal injection of MSO blocked the up-regulation of c-Fos immunoreactivity in CFA treated rats only. We also investigated the effects of botulinum toxin type A (BoNT-A) on TBOA-induced paradoxical antinociception in CFA-treated rats, as BoNT A inhibits the release of neurotransmitters, including glutamate. BoNT-A treatment reversed behavioral responses produced by intracisternal administration of TBOA in CFA-treated rats. These results suggest that the paradoxical responses produced by blocking glutamate transporters under inflammatory pain conditions are mediated by the modulation of glutamate release from presynaptic terminals. Moreover, blockade of glutamate reuptake could represent a new therapeutic target for the treatment of chronic inflammatory pain conditions. PMID- 25445476 TI - Maternal thyroid autoantibody and elevated risk of autism in a national birth cohort. AB - OBJECTIVE: Autoimmune disruption may contribute to risk for autism; however, since previous studies relied upon clinical diagnoses, exposure misclassification and recall bias are limitations. Thyroid peroxidase antibody (TPO-Ab) is an autoantibody involved in autoimmune thyroiditis. We aimed to test the a priori hypothesis that positivity to maternal serum TPO-Ab (TPO-Ab+) (defined as >156 IU/ml) during pregnancy is related to childhood autism. METHOD: The study was based on a nested case-control design of the Finnish Prenatal Study of Autism (FiPS-A), a national birth cohort that includes prospectively drawn archived maternal serum specimens from virtually the entire pregnant population of Finland beginning in 1983. Cases of childhood autism (ICD-10F84.0) born from 1987 to 2005 were ascertained by performing linkages between national birth and inpatient/outpatient registries. All diagnosed cases in Finland over the birth years, and comparison subjects without ASD or severe/profound intellectual disability were matched 1:1 on date of birth, sex, birthplace, and residence in Finland. Maternal serum specimens were assayed in 967 matched case-control pairs for TPO-Ab by a chemiluminescent microparticle immunoassay blind to case/control status. Data were analyzed by conditional logistic regression for matched sets. RESULTS: The prevalence of maternal TPO-Ab+ was significantly increased in pregnancies giving rise to autism cases (6.15%) compared to controls (3.54%). The odds of autism were increased by nearly 80% among offspring of mothers who were TPO-Ab+ during pregnancy (OR=1.78, 95% CI=1.16-2.75, p=0.009), compared to mothers negative for this autoantibody. There was also a significant relationship between maternal TPO-Ab defined as a continuous variable and odds of autism (OR=1.09, 95% CI=1.01, 1.17, p=0.02). Measures of maternal thyroid hormones did not differ between groups. CONCLUSIONS: These findings provide the first biomarker-based evidence that a class of known maternal autoimmune disorders is related to autism in offspring. PMID- 25445478 TI - Acute anticonvulsant effects of capric acid in seizure tests in mice. AB - Capric acid (CA10) is a 10-carbon medium-chain fatty acid abundant in the medium chain triglyceride ketogenic diet (MCT KD). The purpose of this study was to characterize acute anticonvulsant effects of CA10 across several seizure tests in mice. Anticonvulsant effects of orally (p.o.) administered CA10 were assessed in the maximal electroshock seizure threshold (MEST), 6-Hz seizure threshold, and intravenous pentylenetetrazole (i.v. PTZ) seizure tests in mice. Acute effects of CA10 on motor coordination were assessed in the grip and chimney tests. Plasma and brain concentrations of CA10 were measured. Co-administration studies with CA10 and another abundant medium-chain fatty acid, caprylic acid (CA8) were performed. CA10 showed significant and dose-dependent anticonvulsant properties by increasing seizure thresholds in the 6-Hz and MEST seizure tests; it was ineffective in the i.v. PTZ seizure test. At higher doses than those effective in the 6-Hz and MEST seizure tests, CA10 impaired motor performance in the grip and chimney tests. An enhanced anticonvulsant response in the 6-Hz seizure test was produced when CA8 and CA10 were co-administered. An acute p.o. administration of CA10 resulted in dose-proportional increases in its plasma and brain concentrations. CA10 exerted acute anticonvulsant effects at doses that produce plasma exposures comparable to those reported in epileptic patients on the MCT KD. An enhanced anticonvulsant effect is observed when CA10 and the other main constituent of the MCT KD, CA8, were co-administered. Thus, acute anticonvulsant properties of CA10 and CA8 may influence the overall clinical efficacy of the MCT KD. PMID- 25445479 TI - Withdrawal from repeated administration of a low dose of reserpine induced opposing adaptive changes in the noradrenaline and serotonin system function: a behavioral and neurochemical ex vivo and in vivo studies in the rat. AB - Reserpine is an inhibitor of the vesicular monoamine transporter 2 (VMAT2) and monoamine releaser, so it can be used as a pharmacological model of depression. In the present paper, we investigated the behavioral and neurochemical effects of withdrawal from acute and repeated administration of a low dose of reserpine (0.2 mg/kg) in Wistar Han rats. We demonstrated the behavioral and receptor oversensitivity (postsynaptic dopamine D1) during withdrawal from chronic reserpine. It was accompanied by a significant increase in motility in the locomotor activity test and climbing behavior in the forced swim test (FST). Neurochemical studies revealed that repeated but not acute administration the a low dose of reserpine triggered opposing adaptive changes in the noradrenergic and serotonin system function analyzed during reserpine withdrawal, i.e. 48 h after the last injection. The tissue concentration of noradrenaline was significantly decreased in the hypothalamus and nucleus accumbens only after repeated drug administration (by about 20% and 35% vs. control; p<0.05, respectively). On the other hand, the concentration of its extraneuronal metabolite, normetanephrine (NM) increased significantly in the VTA during withdrawal both from acute and chronic reserpine. The serotonin concentration was significantly reduced in the VTA after chronic reserpine (by about 40% vs. the control group, p<0.05) as well as its main metabolite, 5-HIAA (by about 30% vs. control; p<0.05) in the VTA and hypothalamus. Dopamine and its metabolites were not changed after acute or chronic reserpine administration. In vivo microdialysis studies clearly evidenced the lack of the effect of a single dose of reserpine, and its distinct effects after chronic treatment on the release of noradrenaline and serotonin in the rat striatum. In fact, the withdrawal from repeated administration of reserpine significantly increased an extraneuronal concentration of noradrenaline in the rat striatum but at the same time produced a distinct fall in the extraneuronal serotonin in this brain structure. On the basis of the presented behavioral and neurochemical experiments, we suggest that chronic administration of reserpine even in such low dose which not yet acted on the release of monoamines but produced an inhibition of VMAT2 caused a long lasting disadvantageous effect of plasticity in the brain resembling depressive disorders. PMID- 25445480 TI - CD123 and its potential clinical application in leukemias. AB - The alpha chain of interleukin 3 receptor (IL-3Ralpha or CD123), together with the common beta (betac) subunit, forms a high-affinity IL-3R with biological function. In recent years, emerging research has found that CD123 is highly expressed on the surface of various cells (e.g., leukemia stem cells, LSCs), and it is associated with the initiation and development of many diseases, such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). As a novel biological marker, it has an attractive prospect in the diagnosis, targeted therapy, and evaluation of prognosis of many diseases. For these reasons, much attention has been attracted to the studies of the biological functions and potential value in the clinical application of CD123. In this review, the clinical prospects of CD123 will be discussed on the basis of information available. PMID- 25445482 TI - Quantifying the determinants of outbreak detection performance through simulation and machine learning. AB - OBJECTIVE: To develop a probabilistic model for discovering and quantifying determinants of outbreak detection and to use the model to predict detection performance for new outbreaks. MATERIALS AND METHODS: We used an existing software platform to simulate waterborne disease outbreaks of varying duration and magnitude. The simulated data were overlaid on real data from visits to emergency department in Montreal for gastroenteritis. We analyzed the combined data using biosurveillance algorithms, varying their parameters over a wide range. We then applied structure and parameter learning algorithms to the resulting data set to build a Bayesian network model for predicting detection performance as a function of outbreak characteristics and surveillance system parameters. We evaluated the predictions of this model through 5-fold cross validation. RESULTS: The model predicted performance metrics of commonly used outbreak detection methods with an accuracy greater than 0.80. The model also quantified the influence of different outbreak characteristics and parameters of biosurveillance algorithms on detection performance in practically relevant surveillance scenarios. In addition to identifying characteristics expected a priori to have a strong influence on detection performance, such as the alerting threshold and the peak size of the outbreak, the model suggested an important role for other algorithm features, such as adjustment for weekly patterns. CONCLUSION: We developed a model that accurately predicts how characteristics of disease outbreaks and detection methods will influence on detection. This model can be used to compare the performance of detection methods under different surveillance scenarios, to gain insight into which characteristics of outbreaks and biosurveillance algorithms drive detection performance, and to guide the configuration of surveillance systems. PMID- 25445481 TI - The effects of organizational contextual factors on physicians' attitude toward adoption of Electronic Medical Records. AB - INTRODUCTION: Physicians' adoption seems to be a significant issue when comprehensive implementation of Electronic Medical Records (EMR) is considered. This study was conducted to determine the organizational contextual factors affecting physicians' adoption of EMR. METHODS: This was a descriptive-analytical study in which a sample of 330 physicians working in hospitals affiliated to Tehran University of Medical Sciences was selected. Physicians' attitudes toward EMRs' adoption have been assessed by a conceptual path model of Technology Acceptance model (TAM) and organizational context variables. Collected data were analyzed by SPSS16 using regression analysis. The final model was tested by structural equation modeling (SEM) and represented by SPSS-AMOS, structural equation modeling software. RESULTS: The results suggest that modified proposed conceptual path model explains about 56% of the variance of EMRs' adoption. The findings also evidenced that perceived usefulness (PU), perceived ease of use (PEOU), management support; physicians' involvement, physicians' autonomy, and the doctor-patient relationship have direct and significant effect on physicians' attitudes toward EMRs' adoption. However, training showed to have no significant effect on PU and PEOU. CONCLUSION: The present study acknowledged that considerable part of physicians' attitude toward EMRs' adoption is controlled by organizational contextual factors. These factors should be subsequently the major concern of health organizations and health policy makers. PMID- 25445483 TI - Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. AB - Increasing evidence underlines that prototypical inflammatory cytokines (IL 1beta, TNF-alpha and IL-6) either synthesized in the central (CNS) or peripheral nervous system (PNS) by resident cells, or imported by immune blood cells, are involved in several pathophysiological functions, including an unexpected impact on synaptic transmission and neuronal excitability. This review describes these unconventional neuromodulatory properties of cytokines, that are distinct from their classical action as effector molecules of the immune system. In addition to the role of cytokines in brain physiology, we report evidence that dysregulation of their biosynthesis and cellular release, or alterations in receptor-mediated intracellular pathways in target cells, leads to neuronal cell dysfunction and modifications in neuronal network excitability. As a consequence, targeting of these cytokines, and related signalling molecules, is considered a novel option for the development of therapies in various CNS or PNS disorders associated with an inflammatory component. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. PMID- 25445484 TI - Synaptic rearrangement following axonal injury: Old and new players. AB - Following axotomy, the contact between motoneurons and muscle fibers is disrupted, triggering a retrograde reaction at the neuron cell body within the spinal cord. Together with chromatolysis, a hallmark of such response to injury is the elimination of presynaptic terminals apposing to the soma and proximal dendrites of the injured neuron. Excitatory inputs are preferentially eliminated, leaving the cells under an inhibitory influence during the repair process. This is particularly important to avoid glutamate excitotoxicity. Such shift from transmission to a regeneration state is also reflected by deep metabolic changes, seen by the regulation of several genes related to cell survival and axonal growth. It is unclear, however, how exactly synaptic stripping occurs, but there is substantial evidence that glial cells play an active role in this process. In one hand, immune molecules, such as the major histocompatibility complex (MHC) class I, members of the complement family and Toll-like receptors are actively involved in the elimination/reapposition of presynaptic boutons. On the other hand, plastic changes that involve sprouting might be negatively regulated by extracellular matrix proteins such as Nogo-A, MAG and scar-related chondroitin sulfate proteoglycans. Also, neurotrophins, stem cells, physical exercise and several drugs seem to improve synaptic stability, leading to functional recovery after lesion. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. PMID- 25445488 TI - Functional reconstitution of glycinergic synapses incorporating defined glycine receptor subunit combinations. AB - Glycine receptor (GlyR) chloride channels mediate fast inhibitory neurotransmission in the spinal cord and brainstem. Four GlyR subunits (alpha1-3, beta) have been identified in humans, and their differential anatomical distributions underlie a diversity of synaptic isoforms with unique physiological and pharmacological properties. To improve our understanding of these properties, we induced the formation of recombinant synapses between cultured spinal neurons and HEK293 cells expressing GlyR subunits of interest plus the synapse-promoting molecule, neuroligin-2A. In the heterosynapses thus formed, recombinant alpha1beta and alpha3beta GlyRs mediated fast decaying inhibitory postsynaptic currents (IPSCs) whereas alpha2beta GlyRs mediated slow decaying IPSCs. These results are consistent with the fragmentary information available from native synapses and single channel kinetic studies. As beta subunit incorporation is considered essential for localizing GlyRs at the synapse, we were surprised that alpha1-3 homomers supported robust IPSCs with beta subunit incorporation accelerating IPSC rise and decay times in alpha2beta and alpha3beta heteromers only. Finally, heterosynapses incorporating alpha1(D80A)beta and alpha1(A52S)beta GlyRs exhibited accelerated IPSC decay rates closely resembling those recorded in native synapses from mutant mice homozygous for these mutations, providing an additional validation of our technique. Glycinergic heterosynapses should prove useful for evaluating the effects of drugs, hereditary disease mutations or other interventions on defined GlyR subunit combinations under realistic synaptic activation conditions. PMID- 25445485 TI - Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease. AB - Glia of the central nervous system (CNS) help to maintain homeostasis in the brain and support efficient neuronal function. Microglia are innate immune cells of the brain that mediate responses to pathogens and injury. They have key roles in phagocytic clearing, surveying the local microenvironment and propagating inflammatory signals. An interruption in homeostasis induces a cascade of conserved adaptive responses in glia. This response involves biochemical, physiological and morphological changes and is associated with the production of cytokines and secondary mediators that influence synaptic plasticity, cognition and behavior. This reorganization of host priorities represents a beneficial response that is normally adaptive but may become maladaptive when the profile of microglia is compromised. For instance, microglia can develop a primed or pro inflammatory mRNA, protein and morphological profile with aging, traumatic brain injury and neurodegenerative disease. As a result, primed microglia exhibit an exaggerated inflammatory response to secondary and sub-threshold challenges. Consequences of exaggerated inflammatory responses by microglia include the development of cognitive deficits, impaired synaptic plasticity and accelerated neurodegeneration. Moreover, impairments in regulatory systems in these circumstances may make microglia more resistant to negative feedback and important functions of glia can become compromised and dysfunctional. Overall, the purpose of this review is to discuss key concepts of microglial priming and immune-reactivity in the context of aging, traumatic CNS injury and neurodegenerative disease. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. PMID- 25445487 TI - Inhibitory learning is modulated by nicotinic acetylcholine receptors. AB - Prior research has established that stimulating nicotinic acetylcholine receptors can facilitate learning and memory. However, most studies have focused on learning to emit a particular behavior, while little is known about the effects of nicotine on learning to withhold a behavioral response. The present study consisted of a dose response analysis of the effects of nicotine on negative occasion setting, a form of learned inhibition. In this paradigm, rats received one type of training trial in which presentation of a tone by itself was followed immediately by food reward. During the other type of trials, the tone was preceded by presentation of a light and no food was delivered after the tone. Rats gradually learned to approach the cup in anticipation of receiving food reward during presentations of the tone alone, but withheld that behavior when the tone was preceded by the light. Nicotine (0.35 mg/kg) facilitated negative occasion setting by reducing the number of sessions needed to learn the discrimination between trial types and by reducing the rate of responding on non reinforced trials. Nicotine also increased the orienting response to the light, suggesting that nicotine may have affected the ability to withhold food cup behavior on non-reinforced trials by increasing attention to the light. In contrast to the effects of nicotine, rats treated with mecamylamine (0.125, 0.5, or 2 mg/kg) needed more training sessions to discriminate between reinforced and non-reinforced trials compared to saline-treated rats. The findings indicate that nicotinic acetylcholine receptors may be active during negative occasion setting and that nicotine can potentiate learned inhibition. PMID- 25445489 TI - HINT1 protein: a new therapeutic target to enhance opioid antinociception and block mechanical allodynia. AB - In the nervous system, the glutamate N-methyl-D-aspartate receptor (NMDAR) restricts the activity of the mu-opioid receptor (MOR). Both receptors are present in midbrain periaqueductal grey (PAG) neurons, an area that plays a central role in the supraspinal antinociceptive effects of opioids. The cross talk that occurs between these receptors is sustained by the MOR-associated histidine triad nucleotide binding protein 1 (HINT1), which displays nucleoside phosphoramidase and acyl-AMP hydrolase activity. Here we report that the inhibitor of HINT1 enzymatic activity guanosine-5'-tryptamine carbamate (TpGc) significantly enhanced morphine antinociception while preventing the development of tolerance. At the molecular level, TpGc reduced the capacity of MORs to recruit NMDAR activity to negatively regulate opioid signaling. In mice suffering from chronic constriction injury concurrent with increased NMDAR activity, a single intracerebroventricular administration of TpGc attenuated NMDAR function and alleviated mechanical allodynia for several days. These data suggest a potential therapeutic role for HINT1 inhibitors in the clinical management of acute and neuropathic pain. PMID- 25445491 TI - Dietary long chain n-3 polyunsaturated fatty acids prevent impaired social behaviour and normalize brain dopamine levels in food allergic mice. AB - Allergy is suggested to exacerbate impaired behaviour in children with neurodevelopmental disorders. We have previously shown that food allergy impaired social behaviour in mice. Dietary fatty acid composition may affect both the immune and nervous system. The aim of this study was to assess the effect of n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) on food allergy-induced impaired social behaviour and associated deficits in prefrontal dopamine (DA) in mice. Mice were fed either control or n-3 LCPUFA-enriched diet before and during sensitization with whey. Social behaviour, acute allergic skin response and serum immunoglobulins were assessed. Monoamine levels were measured in brain and intestine and fatty acid content in brain. N-3 LCPUFA prevented impaired social behaviour of allergic mice. Moreover, n-3 LCPUFA supplementation increased docosahexaenoic acid (DHA) incorporation into the brain and restored reduced levels of prefrontal DA and its metabolites 3,4-dihydroxyphenylacetic acid, 3 methoxytyramine and homovanillic acid in allergic mice. In addition to these brain effects, n-3 LCPUFA supplementation reduced the allergic skin response and restored decreased intestinal levels of serotonin metabolite 5 hydroxyindoleacetic acid in allergic mice. N-3 LCPUFA may have beneficial effects on food allergy-induced deficits in social behaviour, either indirectly by reducing the allergic response and restoring intestinal 5-HT signalling, or directly by DHA incorporation into neuronal membranes, affecting the DA system. Therefore, it is of interest to further investigate the relevance of food allergy enhanced impairments in social behaviour in humans and the potential benefits of dietary n-3 LCPUFA supplementation. PMID- 25445490 TI - Acute dietary tryptophan manipulation differentially alters social behavior, brain serotonin and plasma corticosterone in three inbred mouse strains. AB - Clinical evidence indicates brain serotonin (5-HT) stores and neurotransmission may be inadequate in subpopulations of individuals with autism, and this may contribute to characteristically impaired social behaviors. Findings that depletion of the 5-HT precursor tryptophan (TRP) worsens autism symptoms support this hypothesis. Yet dietetic studies show and parents report that many children with autism consume less TRP than peers. To measure the impact of dietary TRP content on social behavior, we administered either diets devoid of TRP, with standard TRP (0.2 g%), or with 1% added TRP (1.2 g%) overnight to three mouse strains. Of these, BTBRT(+)Itpr3(tf)/J and 129S1/SvImJ consistently exhibit low preference for social interaction relative to C57BL/6. We found that TRP depletion reduced C57BL/6 and 129S social interaction preference, while TRP enhancement improved BTBR sociability (p < 0.05; N = 8-10). Subsequent marble burying did not differ among diets or strains. After behavior tests, brain TRP levels and plasma corticosterone were higher in TRP enhanced C57BL/6 and BTBR, while 5-HT levels were reduced in all strains by TRP depletion (p < 0.05; N = 4 10). Relative hyperactivity of BTBR and hypoactivity of 129S, evident in self grooming and chamber entries during sociability tests, were uninfluenced by dietary TRP. Our findings demonstrate mouse sociability and brain 5-HT turnover are reduced by acute TRP depletion, and can be enhanced by TRP supplementation. This outcome warrants further basic and clinical studies employing biomarker combinations such as TRP metabolism and 5-HT regulated hormones to characterize conditions wherein TRP supplementation may best ameliorate sociability deficits. PMID- 25445493 TI - How does the humoral response to HIV-2 infection differ from HIV-1 and can this explain the distinct natural history of infection with these two human retroviruses? AB - A substantial proportion of people infected with HIV-2, the second causative agent of acquired immune deficiency syndrome (AIDS), behave as long-term non progressors (LTNP) and are able to control the infection more effectively than most HIV-1-infected patients. A better understanding of the differences in the natural history of HIV-1 and HIV-2 infection, and how these relate to the relative immunogenicity and evolution of the two virus strains, could provide important insights into the mechanisms of protective immunity in HIV infection. One of the most striking differences is that most people infected with HIV-2 generate high titers of broadly neutralizing antibodies, whereas this is relatively uncommon in HIV-1 infection. In this review we compare the underlying structural differences of the envelope (Env) between HIV-1 and HIV-2, and examine how these might affect the antibody responses as well as their impact on Env evolution and control of viral replication. PMID- 25445494 TI - B cell epitope spreading: mechanisms and contribution to autoimmune diseases. AB - While a variety of factors act to trigger or initiate autoimmune diseases, the process of epitope spreading is an important contributor in their development. Epitope spreading is a diversification of the epitopes recognized by the immune system. This process happens to both T and B cells, with this review focusing on B cells. Such spreading can progress among multiple epitopes on a single antigen, or from one antigenic molecule to another. Systemic lupus erythematosus, multiple sclerosis, pemphigus, bullous pemphigoid and other autoimmune diseases, are all influenced by intermolecular and intramolecular B cell epitope spreading. Endocytic processing, antigen presentation, and somatic hypermutation act as molecular mechanisms that assist in driving epitope spreading and broadening the immune response in autoimmune diseases. The purpose of this review is to summarize our current understanding of B cell epitope spreading with regard to autoimmunity, how it contributes during the progression of various autoimmune diseases, and treatment options available. PMID- 25445495 TI - Insights into peptidyl-prolyl cis-trans isomerase structure and function in immunocytes. AB - Peptidyl-prolyl isomerase (PPIase) catalyzes the interconversion of a specific Pro-imide bond between the cis and trans conformations. Two families of PPIases, cyclophilins and FKBPs, have been extensively studied because of their high affinity for immunosuppressive drugs in particular cyclosporine A and FK506. Despite apparent differences, these protein families share conserved amino acid sequences in their catalytic domains and impose similar enzymatic functions to their substrates. PPIases have been implicated in multiple aspects of cell cycle regulation and cellular processes related to a number of human pathologies, including cancer. More recent studies provide evidence for participation of PPIases in regulation of immune cell functions. In this review, we focus on the role of cyclophilins and FKBPs in the regulation of innate and adaptive immunity functions. PPIase-mediated isomerization of proteins represents a unique signaling mechanism that regulates normal immune functions and contributes to the development of immunopathologies. PPIases may therefore serve as useful diagnostic tools and potential therapeutic targets. PMID- 25445486 TI - IL-6 regulation of synaptic function in the CNS. AB - A growing body of evidence supports a role for glial-produced neuroimmune factors, including the cytokine IL-6, in CNS physiology and pathology. CNS expression of IL-6 has been documented in the normal CNS at low levels and at elevated levels in several neurodegenerative or psychiatric disease states as well as in CNS infection and injury. The altered CNS function associated with these conditions raises the possibility that IL-6 has neuronal or synaptic actions. Studies in in vitro and in vivo models confirmed this possibility and showed that IL-6 can regulate a number of important neuronal and synaptic functions including synaptic transmission and synaptic plasticity, an important cellular mechanism of memory and learning. Behavioral studies in animal models provided further evidence of an important role for IL-6 as a regulator of CNS pathways that are critical to cognitive function. This review summarizes studies that have lead to our current state of knowledge. In spite of the progress that has been made, there is a need for a greater understanding of the physiological and pathophysiological actions of IL-6 in the CNS, the mechanisms underlying these actions, conditions that induce production of IL-6 in the CNS and therapeutic strategies that could ameliorate or promote IL-6 actions. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. PMID- 25445492 TI - Dopamine and norepinephrine receptors participate in methylphenidate enhancement of in vivo hippocampal synaptic plasticity. AB - Attention-deficit hyperactive disorder (ADHD) is the most commonly studied and diagnosed psychiatric disorder in children. Methylphenidate (MPH, e.g., Ritalin) has been used to treat ADHD for over 50 years. It is the most commonly prescribed treatment for ADHD, and in the past decade it was the drug most commonly prescribed to teenagers. In addition, MPH has become one of the most widely abused drugs on college campuses. In this study, we examined the effects of MPH on hippocampal synaptic plasticity, which serves as a measurable quantification of memory mechanisms. Field potentials were recorded with permanently implanted electrodes in freely-moving mice to quantify MPH modulation of perforant path synaptic transmission onto granule cells of the dentate gyrus. Our hypothesis was that MPH affects hippocampal synaptic plasticity underlying learning because MPH boosts catecholamine signaling by blocking the dopamine and norepinephrine transporters (DAT and NET respectively). In vitro hippocampal slice experiments indicated MPH enhances perforant path plasticity, and this MPH enhancement arose from action via D1-type dopamine receptors and beta-type adrenergic receptors. Similarly, MPH boosted in vivo initiation of long-term potentiation (LTP). While there was an effect via both dopamine and adrenergic receptors in vivo, LTP induction was more dependent on the MPH-induced action via D1-type dopamine receptors. Under biologically reasonable experimental conditions, MPH enhances hippocampal synaptic plasticity via catecholamine receptors. PMID- 25445496 TI - Potential limitations of IL-2 administration for the treatment of experimental acute graft-versus-host disease. AB - Low-dose IL-2 administration can control autoimmunity by specifically activating CD4(+) Foxp3(+) regulatory T cells (Tregs). Here, we studied IL-2-based immunotherapy in experimental graft-versus-host disease (GVHD). IL-2 administration to donor mice induced a dose-dependent expansion of Tregs in the graft but was insufficient to control GVHD. IL-2 administration to allogeneic grafted recipient mice activated T-conventional cells (Tcons) and did not prevent GVHD. This loss of IL-2 selectivity toward Tregs was explained by an IL-2-induced increase in the IL-2 receptor alpha-chain expression on Tcons. Finally, in xeno GVHD generated by human PBMCs transplanted into immunodeficient mice, low-dose IL 2 increased Treg frequencies but did neither control pro-inflammatory cytokine production by pathogenic Tcons, nor prevented GVHD. Furthermore, combination of low-dose IL-2 with rapamycin was ineffective in this model. Our results indicate that limitations on the use of IL-2 during acute GVHD are likely due to the massive activation of the allogeneic T cells unique to this setting. PMID- 25445497 TI - Tissue-specific selection of optimal reference genes for expression analysis of anti-cancer drug-related genes in tumor samples using quantitative real-time RT PCR. AB - Gene transcription analysis in clinical tumor samples can help with diagnosis, prognosis, and treatment of cancers. We aimed to identify the optimal reference genes for reliable expression analysis in various tumor samples by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Using a one step TaqMan-based qRT-PCR, 5 commonly used reference genes (ACTB, GAPDH, RPLPO, GUSB, and TFRC) and 10 anticancer drug-related genes (TYMS, RRM1, TUBB3, STMN1, TOP2A, EGFR, VEGFR2, HER2, ERCC1, and BRCA1) were analyzed in 327 tissue samples from lung, rectal, colon, gastric, esophageal, and breast tumors. According to the expression stability assessments obtained by using three programs (geNorm, NormFinder, and BestKeeper) and a comprehensive ranking method, the optimal reference genes for lung, gastric, esophageal, and breast tumors were RPLPO, GAPDH, ACTB, and ACTB, respectively. For rectal tumors, a combination of the 3 most stable genes (GUSB, ACTB, and RPLPO) was suitable for qRT-PCR, whereas for colon tumors, a combination of the 4 most stable genes (GAPDH, ACTB, GUSB, and RPLPO) was optimal for qRT-PCR. Based on the expression data of target genes normalized against selected reference genes, the principal component analysis revealed 4 expression patterns in 6 different tissues. One pattern was observed in gastric, rectal, and colon tumor tissues, which are gastrointestinal tumors. Expressions in the breast, lung, and esophageal tissues were separately represented as one pattern. Our results could facilitate the practice of personalized cancer medicine based on the gene expression profile of the patients. PMID- 25445498 TI - A common polymorphism in pre-miR-146a underlies Hirschsprung disease risk in Han Chinese. AB - BACKGROUND: Hirschsprung disease (HSCR) is a rare multigenic congenital disorder characterized by the absence of the enteric ganglia. To date, single nucleotide polymorphisms (SNPs) in pre-miRNAs have been confirmed related with some diseases. Thus, we hypothesized that pre-miRNA polymorphisms might contribute to HSCR susceptibility. We investigated whether rs2910164 and rs11614913 of pre-miR 146a and pre-miR-196a2, are associated with HSCR. METHODS: Polymorphisms were genotyped using the Taqman method. Real-time PCR was used for detecting the expression level of miR-146a and its target gene ROBO1 in CC and GG genotypes. RESULTS: Significant differences were found in the genotype distribution of rs2910164 and rs11614913 polymorphism between HSCR cases and controls (p = 0.023 and 0.041, respectively). Furthermore, G allele of rs2910164 might increase the risk of HSCR (OR, 1.54; 95% CI, 1.06-2.23). Moreover, the expression level of miR 146a for homozygote GG was also higher than homozygote CC (p = 0.0193). In contrast, the expression level of its target gene ROBO1 predicted in bioinformatics for homozygote GG was much lower than homozygote CC (p = 0.0096). CONCLUSIONS: Our results showed that the polymorphism rs2910164 in pre-miR-146a might alter the production of mature miR-146a and then down-regulate the target gene ROBO1, which plays an important role in pathogenesis of HSCR. PMID- 25445499 TI - Microarray gene expression profiling and bioinformatics analysis of premature ovarian failure in a rat model. AB - Premature ovarian failure (POF) remains one of the major gynecological problems worldwide which affected 1% of women. Even though tremendous achievements had been acquired as opposed to years past, molecular pathogenesis associated with POF is still unclear and needs to be well-defined. The aim of this study was to analyze the gene expression profiles in the POF rat model. To predict potential regulating factors, we firstly treated female Sprague Dawley (SD) rat with 4 vinylcyclohexene diepoxide (VCD). Total RNA from ovarian tissue was converted to cDNA and hybridized to mRNA Chip array. The differentially expressed genes (DEGs) were identified by two-sample t test and assessed using hierarchical clustering and Principal Component Analysis methods. Potential regulatory targets associated with these DEGs were constructed using BisoGenet in Cytoscape. Gene Ontology (GO) and functional enrichment analysis were performed using BiNGO and DAVID, respectively. As the results, 25 DEGs were found to be closely associated with POF initiation. Hierarchical clustering and Principal Component Analysis on the transcriptional profiles revealed an excellent separation of the vehicle and POF compartments. Pathway enrichment analysis based on the disease-gene interaction network analysis led to the identification of two core signaling pathways that were strongly affected during POF initiation and progression: immune response and cardiovascular disorders. In conclusion, we constructed a gene regulatory network associated with POF using the microarray gene expression profiling, and screened out some genes or transcription factors that may be used as potential molecular therapeutic targets for POF. PMID- 25445500 TI - Ski diminishes TGF-beta1-induced myofibroblast phenotype via up-regulating Meox2 expression. AB - OBJECTIVE: The aim of the present work was to investigate the mechanism of transforming growth factor (TGF)-beta1 and Sloan-Kettering Institute (Ski) in the pathogenesis of hypertrophic scars (HS). BACKGROUND: Wound healing is an inherent process, but the aberrant wound healing of skin injury may lead to HS. There has been growing evidence suggesting a role for TGF-beta1 and Ski in the pathogenesis of fibrosis. MATERIAL AND METHODS: The MTT assay was used to detect the cell proliferation induced by TGF-beta1. The Ski gene was transduced into cells with an adenovirus, and then the function of Ski in cell proliferation and differentiation was observed. Ski mRNA levels were measured by RT-PCR. Western blotting was used to detect the protein expression of alpha-SMA, E-cadherin, Meox1, Meox2, Zeb1 and Zeb2. RESULTS: TGF-beta1 can promote human skin fibroblast (HSF) cell proliferation in a time-dependent manner, but the promoting effect could be suppressed by Ski. TGF-beta1 also induces the formation of the myofibroblast phenotype and the effect of TGF-beta1 could be diminished by Ski. Also, Ski modulates the cardiac myofibroblast phenotype and function through suppression of Zeb2 by up-regulating the expression of Meox2. CONCLUSIONS: Ski diminishes the myofibroblast phenotype induced by TGF-beta1 through the suppression of Zeb2 by up-regulating the expression of Meox2. PMID- 25445501 TI - Long noncoding RNA PCA3 gene promoter region is related to the risk of prostate cancer on Chinese males. AB - INTRODUCTION: Long noncoding RNA prostate cancer gene antigen 3 (PCA3) is one of the most prostate cancer-specific genes at present. Consequently, the prostate specific expression and the sharp up-regulation of PCA3 RNA in prostate cancer suggest a unique transcriptional regulation, which possibly can be attributed to promoter polymorphism. In this study, we investigated a short tandem repeat (STR) polymorphism of TAAA in the promoter region of PCA3 gene found in our previous study in prostate cancer (PCa) patients and benign prostatic hypertrophy (BPH) patients, aiming to evaluate the association between the STR and increased risk for PCa. MATERIAL AND METHODS: 120 PCa cases and 120 benign prostatic hypertrophy (BPH) cases were identified among participants. The region encompassing the TAAA repeat was amplified with a specific primer set we designed and screened by PCR based cloning and sequencing in paired peripheral blood leukocytes and prostate tissues. Genotype-specific risks were estimated as odds ratios (ORs) associated with 95% confidence intervals (CIs) and adjusted for age by means of unconditional logistic regression. RESULTS: 5 PCA3 TAAA STR polymorphisms and 8 genotypes were found in both peripheral blood leukocytes and prostate tissues, the carriers with more TAAA repeats were associated with increased risk for PCa than individuals having less TAAA repeats. Interestingly, 18 (15.0%) of 120 PCa patients had more (TAAA)n repeats in prostate tissues than that in peripheral blood leukocytes, and 3 (2.5%) of 120 had less (TAAA)n repeats in prostate tissues. CONCLUSIONS: The results of this study suggest that short tandem repeat polymorphism of TAAA in the promoter region of PCA3 gene is a risk-increasing factor for prostate cancer in the Chinese population. In addition to the hereditary factor, the insertion mutation of (TAAA)n in a local tissue maybe another mechanism of the onset of PCa. PMID- 25445502 TI - Raman microspectroscopy for the early detection of pre-malignant changes in cervical tissue. AB - Cervical cancer is the third most common cancer affecting women worldwide. The mortality associated with cervical cancer can, however, be significantly reduced if the disease is detected at the pre-malignant stage. The aim of this study was to evaluate the potential of Raman microspectroscopy for elucidation of the biochemical changes associated with the pre-malignant stages of cervical cancer. Formalin fixed paraffin preserved tissue sections from cervical biopsies classified as negative for intraepithelial lesion and malignancy (NILM), low grade squamous intraepithelial lesion (LSIL) or high grade squamous intraepithelial lesion (HSIL) were analysed by Raman spectral mapping. Raman mapping, with K-means cluster analysis (KMCA), was able to differentiate the NILM cervical tissue into three layers including stroma, basal/para-basal and superficial layers, characterised by spectral features of collagen, DNA bases and glycogen respectively. In the LSIL and HSIL samples, KMCA clustered regions of the superficial layer with the basal layer. Using principal components analysis (PCA), biochemical changes associated with disease were also observed in normal areas of the abnormal samples, where morphological changes were not apparent. This study has shown that Raman microspectroscopy could be useful for the early detection of pre-malignant changes in cervical tissue. PMID- 25445503 TI - Overexpression of MAGE-A9 predicts unfavorable outcome in breast cancer. AB - Melanoma-associated antigens (MAGEs) are a group of well-characterized members of the cancer/testis antigen (CTA) family, which is one of the largest groups of human tumor-associated antigens. MAGE-A9 is a particular member in the context of the MAGE-A gene family and was defined as presenting prognostic relevance in certain type of human cancer. However, the expression of MAGE-A9 in invasive ductal breast cancer (IDC) and the relationship with the clinical attributes of IDC, especially prognostic characteristic, remain poorly understood. In this present study, one-step quantitative reverse transcription polymerase chain reaction (18 fresh-frozen IDC tissues and corresponding non-cancerous tissues) and immunohistochemistry by tissue microarrays (82 IDC tissue samples and 70 matched tumor-adjacent non-cancerous tissue samples) were performed to characterize expression of the MAGE-A9 gene in IDC. Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognosis of IDC. The results of qPCR and IHC analysis showed that the expression of MAGE-A9 in IDC was significantly higher than that in corresponding non-cancerous tissue. Moreover, the expression level of MAGE-A9 protein in IDC was significantly related to histological grade (p = 0.011) and distant metastasis (p = 0.019). Multivariate analysis with the Cox regression model showed that MAGE-A9 protein expression (p = 0.009), histological grade (p = 0.014), lymph node metastasis (p = 0.012) and distant metastasis (p = 0.011) were independent prognostic factors for overall survival of IDC patients. The data suggest that MAGE-A9 expression is correlated with malignant attributes of IDC and it may serve as a novel prognostic factor and an ideal candidate for targeted therapy in IDC treatment. PMID- 25445504 TI - Ezrin protein overexpression predicts the poor prognosis of pancreatic ductal adenocarcinomas. AB - Ezrin, a member of the ezrin/radixin/moesin (ERM) protein family, plays an important role in tumor metastasis. Accumulating studies demonstrated that a high expression level of human ezrin has been correlated with numerous human malignancies. This study was aimed to explore the clinicopathological significance of ezrin protein expression in pancreatic ductal adenocarcinomas (PDAC), and to further identify its role as a potential biomarker and therapeutic target of PDAC. Immunohistochemical (IHC) staining of ezrin protein was performed on 106 PDAC tissue samples and 37 adjacent and 21 normal pancreatic tissue samples. Additionally, localization of ezrin protein in Panc-1 PDAC cell line was observed using immunofluorescence (IF) staining. The correlation between ezrin overexpression and the clinicopathological features of PDAC was evaluated using Chi-square test, and differences in survival curves were analyzed using log-rank tests. In results, ezrin protein is widely distributed in the cytoplasm and membrane of PDAC cells by IHC and IF staining, but some cases showed a cell membrane staining pattern. The positive rate of ezrin protein expression was 82.1% (87/106) in PDAC, which was significantly higher than it in either adjacent pancreatic tissues (37.8%, 14/37) or normal pancreatic tissues (19.0%, 4/21). Overexpression of ezrin was closely related with larger tumor size, positive lymph node metastasis and advanced clinical stage. However, it was not correlated with patient age, gender, differentiation, Ki-67 expression index, and pancreas calcification point. Survival analysis showed that patients with ezrin high expression level had significantly lower overall survival rate than that with ezrin low expression level. Importantly, further analysis using a Cox proportional hazard regression model revealed that high ezrin expression emerged as a significant independent hazard factor for overall survival rates of patients with PDAC along with lymph node metastasis and TNM stage. In conclusion, ezrin protein played an important role in the progression of PDAC, and the overexpression of ezrin protein might be a useful prognostic marker of PDAC. PMID- 25445506 TI - Promoting quality of program delivery via an internet message delivery system. AB - This article presents results from a study that evaluated an online message system designed to improve the delivery of prevention programs. We conducted a quasi-experimental study with 32 agencies and schools that implemented substance use prevention programs and examined differences between the comparison and intervention groups. We also examined the impact of dosage of the message system by comparing results among three groups of teachers: non-users, low users, and high users. Results for norm setting were marginally significant, such that teachers within the agencies assigned to the intervention condition scored higher on their understanding of norm setting at posttest compared to teachers within comparison agencies, after controlling for pretest knowledge scores and demographic items. In the model examining impact of dosage, high users of the intervention scored significantly higher on self-reported understanding of their program, quality of delivery, and program effectiveness compared to non-users. Low users of the intervention reported significantly higher quality of delivery compared to non-users. PMID- 25445505 TI - Methamphetamine use among rural White and Native American adolescents: an application of the stress process model. AB - Methamphetamine use has been identified as having significant adverse health consequences, yet we know little about the correlates of its use. Additionally, research has found that Native Americans are at the highest risk for methamphetamine use. Our exploratory study, informed by the stress process model, examines stress and stress buffering factors associated with methamphetamine use among a cross-sectional sample of rural White and Native American adolescents (n = 573). Results of logistic regression analyses revealed mixed support for the stress process model; while stress exposure and family methamphetamine use predicted past year methamphetamine use, the inclusion of these variables failed to attenuate the association between race and past year use. PMID- 25445507 TI - The impact of science education games on prescription drug abuse attitudes among teens: a case study. AB - Two online science education games, in which players learn about the risks of prescription drug abuse in the context of investigating crimes, were evaluated to determine shifts of prescription drug abuse attitudes attributable to game exposure. High school students from grades 11 and 12 (n = 179) were assigned to one of the games and participated in a pretest, two game-play sessions, and a delayed posttest. Students in both groups demonstrated more negative attitudes toward prescription drug abuse after playing the game, driven by changes of students' normative beliefs and their ability to make the connection between prescription drug abuse and illicit drugs. A secondary aim was to assess gains in science knowledge; however, due to low internal consistency reliabilities of content measures, students' knowledge acquisition could not be determined. PMID- 25445508 TI - Randomized controlled evaluation of the Too Good for Drugs prevention program: impact on adolescents at different risk levels for drug use. AB - Sixth graders participating in the Too Good for Drugs (TGFD) prevention program in comparison to 6th graders not participating show different results by student risk level. Sixth graders from 20 middle schools were randomly assigned to receive the intervention and those from 20 paired middle schools assigned to serve as controls (N = 10,762). Participants were identified as low, moderate, or high risk for drug usage based on their rates of behaviors reported prior to the start of the study. Student behavior outcomes (smoking, alcohol consumption, binge drinking, and marijuana usage) as well as risk and protective (R&P) outcomes were surveyed at three points in time (before, after, and 6 months following treatment). Results show the TGFD to have a suppressive effect on reported drug use behavior and a strengthening effect on R&P outcomes among high risk students following treatment and 6 months later. Some effects were also found for low and moderate risk students. A favorable treatment effect was found on mathematics achievement. PMID- 25445509 TI - A subchronic oral toxicity study on pyrroloquinoline quinone (PQQ) disodium salt in rats. AB - A subchronic oral toxicity study on pyrroloquinoline quinone (PQQ) disodium salt was performed in rats. Sprague-Dawley rats were randomly divided into four groups (10 rats/sex/group) and administered with PQQ disodium salt at doses of 0 (control), 100, 200 and 400 mg/kg bw/day by gavage for 13 weeks. Daily clinical observations and weekly measurement of body weights and food consumption were conducted. Blood samples were obtained on day 46 and day 91 for measurement of hematology and serum biochemical parameters. Animals were euthanized for necropsy, selected organs were weighted and recorded. Histological examination was performed on all tissues from animals in the control and PQQ disodium salt treatment groups. No mortality or toxicologically significant changes in clinical signs, body weight, food consumption, necropsy findings or organ weights was observed. Differences between treated and control groups in some hematological and serum biochemical examinations and histopathological examination were not considered treatment-related. The no-observed-adverse-effect-level (NOAEL) of PQQ disodium salt in rats was considered to be 400 mg/kg bw/day for both sexes, the highest dose tested. PMID- 25445510 TI - Estimation of dietary exposure to acrylamide of Polish teenagers from an urban environment. AB - The aim of this study was to evaluate the dietary exposure to acrylamide (AA) in a group of teenagers (n = 261) from an urban environment. The intake of AA from food was estimated based on a 7-day food record diary (consecutive days). The food rations obtained (n = 1827) were used to calculate the amounts of the consumed food products, which were the main sources of AA. In the case of girls, the estimated dietary intake of AA per kg body weight (BW) amounted to 0.09 ug/kg BW/day (50th percentile), 0.32 ug/kg BW/day (75th percentile) and 1.04 ug/kg BW/day (95th percentile), and among boys it was 0.13, 0.41, and 1.18 ug/kg BW/day, respectively. The main sources of AA exposure were French fries, potato crisps, corn flakes, bread and salty sticks. The lowest values for margin of exposure (MOE) were calculated for the P95th percentiles of exposure, and ranged from 152 to 173. PMID- 25445513 TI - The use of plant-derived bioactive compounds to target cancer stem cells and modulate tumor microenvironment. AB - In the last decades cancer has been considered as an epigenetic dysfunction, given the profound role of diet and lifestyle in cancer prevention and the determination of cancer risk. A plethora of recent publications have addressed the specific role of several environmental factors, such as nutritional habits, behavior, stress and toxins in the regulation of the physiological and cancer epigenome. In particular, plant-derived bioactive nutrients have been seen to positively affect normal cell growth, proliferation and differentiation and also to revert cancer related epigenetic dysfunctions, reducing tumorigenesis, preventing metastasis and/or increasing chemo and radiotherapy efficacy. Moreover, virtually all cancer types are characterized by the presence of cancer stem cell (CSC) subpopulations, residing in specific hypoxic and acidic microenvironments, or niches, and these cells are currently considered responsible for tumor resistance to therapy and tumor relapse. Modern anti-cancer strategies should be designed to selectively target CSCs and modulate the hypoxic and acidic tumor microenvironment, and, to this end, natural bioactive components seem to play a role. This review aims to discuss the effects elicited by plant derived bioactive nutrients in the regulation of CSC self-renewal, cancer metabolism and tumor microenvironment. PMID- 25445511 TI - 1-deoxynojirimycin isolated from Bacillus subtilis improves hepatic lipid metabolism and mitochondrial function in high-fat-fed mice. AB - The aim of this study was to determine whether 1-deoxynojirimycin (DNJ) isolated from Bacillus subtilis MORI beneficially influences lipid metabolism and mitochondrial function in the liver of mice fed a high-fat diet in addition to the anti-obesity properties of DNJ. Male C57BL/6 mice (n = 29; 5 weeks old) were randomly assigned to three groups: normal control diet (CTL, n = 10), high-fat diet (HF, n = 10), and high-fat diet supplemented with DNJ (DNJ, n = 9). After 12 weeks, the HF group exhibited higher overall weight gain, of the liver, and of various fat pads than the CTL and DNJ groups did. The HF group also showed greater expression of C/EBPalpha and CD36 mRNA in the liver than that in the CTL and/or DNJ groups. In addition, mRNA expressions of AAC and FAS were lower, while mRNA expression of PGC-1beta was higher in the liver of the DNJ group than that of the HF group. The hepatic expression of p-AMPK/AMPK was higher in the DNJ group than in the HF group. This study provides novel insight into the protective effect of DNJ supplementation against obesity-induced hepatic lipid abnormalities and mitochondrial dysfunction. PMID- 25445512 TI - Safety assessment of dietary bamboo charcoal powder: a 90-day subchronic oral toxicity and mutagenicity studies. AB - Vegetable carbon has been used as food additive in EU (E153) and China for many years; however, no experimental data have been available on its dietary safety. This study was designed to evaluate the subchronic toxicity and genotoxicity of bamboo charcoal powder (BCP). In the study of subchronic oral toxicity, BCP was administered orally at doses of 2.81, 5.62, and 11.24 g/kg BW for 90 days to SD rats. Additional satellite groups from the control group and high dose group were observed for a 28-day recovery period. At the end of the treatment and recovery periods, animals were sacrificed, and their organs were weighed and blood samples were collected. The toxicological endpoints observed included clinical signs, food consumption, body and organ weights, hematological and biochemical parameters, macroscopic and microscopic examinations. The results showed no significant differences between the BCP treated groups and control group. The genotoxicity of BCP was assessed with the Salmonella typhimurium mutagenicity assay (Ames test) and a combination of comet assay and mammalian erythrocyte micronucleus protocol. The results did not reveal any genotoxicity of BCP. Based on our study, the no-observed-adverse-effect level (NOAEL) for BCP is 11.24 g/kg BW/day. PMID- 25445514 TI - Risk assessment derived from migrants identified in several adhesives commonly used in food contact materials. AB - Adhesives are used to manufacture multilayer materials, where their components pass through the layers and migrate to the food. Nine different adhesives (acrylic, vinyl and hotmelt) and their migration in 21 laminates for future use as market samples have been evaluated and risk assessment has been carried out. A total of 75 volatiles and non volatile compounds were identified by gas chromatography-mass spectrometry and ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Most of the compounds migrated below their specific migration limit (SML), lowest observed adverse effect level (LOAEL), no observed adverse effect level (NOAEL) and values recommended by Cramer. Six compounds classified as high toxicity class III according to Cramer classification, migrated over their SML and exposure values recommended by Cramer, when they were applied in the full area of the packaging. Nevertheless, these adhesives fulfill the threshold in the real application as they are applied in a small area of the packaging. PMID- 25445515 TI - Monoclonal antibody-targeted PEGylated liposome-ICG encapsulating doxorubicin as a potential theranostic agent. AB - Indocyanine green (ICG) is an FDA-approved, strongly photo-absorbent/fluorescent probe that has been incorporated into a clinically-relevant PEGylated liposome as a flexible optoacoustic contrast agent platform. This study describes the engineering of targeted PEGylated liposome-ICG using the anti-MUC-1 "humanized" monoclonal antibody (MoAb) hCTM01 as a tumour-specific theranostic system. We aimed to visualise non-invasively the tumour accumulation of these MoAb-targeted liposomes over time in tumour-bearing mice using multispectral optoacoustic tomography (MSOT). Preferential accumulation of targeted PEGylated liposome-ICG was studied after intravenous administration in comparison to non-targeted PEGylated liposome-ICG using both fast growing (4T1) and slow growing (HT-29) MUC 1 positive tumour models. Monitoring liposomal ICG in the tumour showed that both targeted and non-targeted liposome-ICG formulations preferentially accumulated into the tumour models studied. Rapid accumulation was observed for targeted liposomes at early time points mainly in the periphery of the tumour volume suggesting binding to available MUC-1 receptors. In contrast, non-targeted PEGylated liposomes showed accumulation at the centre of the tumour at later time points. In an attempt to take this a step further, we successfully encapsulated the anticancer drug, doxorubicin (DOX) into both targeted and non-targeted PEGylated liposome-ICG. The engineering of DOX-loaded targeted ICG liposome systems present a novel platform for combined tumour-specific therapy and diagnosis. This can open new possibilities in the design of advanced image-guided cancer therapeutics. PMID- 25445516 TI - Results from a preliminary review of scientific evidence for appropriateness of preparations, dosage forms and other product design elements for older adult patients. AB - The aging population and the growing multimorbidity of the major patient population as well as the advanced (pharmaco)therapeutic treatment options are increasing the complexity of independent drug therapy management and administration. The increased complexity may have an impact on drug adherence (including any need for patients initiated coping strategies), and consequently on the safety and efficacy of the medicine. To overcome adherence issues caused by the design of the medicine, it is crucial that developers consider the age appropriateness of the medicine (route of administration, dosage form, excipients in the composition, frequency of dosing) in meeting patients' needs to manage their therapy without the support of a care giver. In order to understand the scientific evidence on such age appropriately designed medicines for use by older adults, a literature search was performed in the Medline database (all languages included). The search produced 34 publications that met the inclusion and exclusion criteria for the patient population of 65 years an older. An in-depth analysis of the included publications with respect to the methodological quality (study design, data collection, endpoints chosen) and results showed that none of these publications had adequately investigated the age appropriateness of the medicine for use by older adults. The authors consider that the knowledge gap in this area requires attention of all stakeholders in the healthcare community. PMID- 25445517 TI - Release characteristics of polyurethane tablets containing dicarboxylic acids as release modifiers - a case study with diprophylline. AB - The influence of several dicarboxylic acids on the release characteristics of polyurethane tablets with a high drug load was investigated. Mixtures of diprophylline (Dyph) and thermoplastic polyurethane (TPUR) (ratio: 50/50, 65/35 and 75/25 wt.%) were hot-melt extruded and injection molded with the addition of 1, 2.5, 5 and 10% wt.% dicarboxylic acid as release modifier. Incorporating malonic, succinic, maleic and glutaric acid in the TPUR matrices enhanced drug release, proportional to the dicarboxylic acid concentration in the formulation. No correlation was found between the water solubility, melting point, logP and pKa of the acids and their drug release modifying capacity. Succinic and maleic acid had the highest drug release modifying capacity which was linked to more intense molecular interactions with Dyph. A structural fit between the primary and secondary alcohol of Dyph and both carboxylic groups of the acids was at the origin of this enhanced interaction. PMID- 25445518 TI - Effects of stabilizing agents on the development of myricetin nanosuspension and its characterization: an in vitro and in vivo evaluation. AB - Although myricetin has various pharmacological applications, it shows low oral bioavailability (<10%) in rats due to its poor aqueous solubility. To overcome this issue, myricetin nanosuspensions were developed and the effects of stabilizers were investigated. Based on the particle size and zeta potential, stabilizers soya lecithin, TPGS, HP-beta-CD, and/or a combination thereof were used. The prepared nanosuspensions were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRD). The resulting myricetin nanosuspensions contained particles in the size range of 300-500 nm and were physically stable. Myricetin was partially transformed from crystalline to amorphous forms in the presence of different excipients after the nanosizing process. The solubility and in vitro dissolution of all myricetin nanosuspensions were greatly increased compared with those of the myricetin powder. Consequently, the relative bioavailability in rats were 2.44, 3.57, 1.61, and 2.96 for nanosuspensions stabilized with TPGS, soya lecithin, soya lecithin+TPGS, and HP-beta-CD+TPGS, respectively, relative to that of the coarse myricetin. This research demonstrated that nanosuspension is a promising strategy for delivering poor water-soluble drugs such as myricetin and that stabilizers played a critical role in the formulation design of myricetin nanosuspensions. PMID- 25445519 TI - Protein release from electrospun nonwovens: improving the release characteristics through rational combination of polyester blend matrices with polidocanol. AB - Nonwoven scaffolds consisting of poly-epsilon-caprolactone (PCL), poly(lactic-co glycolic acid) (PLGA) and polidocanol (PD), and loaded with lysozyme crystals were prepared by electrospinning. The composition of the matrix was varied and the effect of PD content in binary mixtures, and of PD and PLGA content in ternary mixtures regarding processability, fiber morphology, water sorption, swelling and drug release was investigated. Binary PCL/PD blend nonwovens showed a PD-dependent increase in swelling of up to 30% and of lysozyme burst release of up to 45% associated with changes of the fiber morphology. Furthermore, addition of free PD to the release medium resulted in a significant increase of lysozyme burst release from pure PCL nonwovens from approximately 2-35%. Using ternary PCL/PD/PLGA blends, matrix degradation could be significantly improved over PCL/PD blends, resulting in a biphasic release of lysozyme with constant release over 9 weeks, followed by constant release with a reduced rate over additional 4 weeks. Based on these results, protein release from PCL scaffolds is improved by blending with PD due to improved lysozyme desorption from the polymer surface and PD-dependent matrix swelling. PMID- 25445520 TI - Micro and nano polycaprolactone particles preparation by pulsed back-and-forward cross-flow batch membrane emulsification for parenteral administration. AB - In the pharmaceutical field, manufacturing processes which are able to make products with tailored size at suitable shear stress conditions and high productivity are important requirements for their industrial application. Cross flow and premix membrane emulsification are the membrane-based processes generally used for particles preparation at large scale, however some disadvantages still limit their applicability for the production of fragile products. In this work, we investigated, for the first time, the preparation of micro and nano polymeric particles in a size range between 2.35 (+/-0.14)MUm and 210 (+/-10)nm by using pulsed back-and-forward membrane emulsification for the application in pharmaceutical field. The suitability of the method to produce tailored particles by applying mild shear conditions has been demonstrated. The optimized fluid-dynamic conditions studied allowed the production of particles with target size by selecting the appropriate pore size of the membrane (1 MUm and 0.1 MUm). The uniformity of the particles could be obtained with an axial velocity of 0.5 ms(-1) (corresponding to a shear stress of 4.1 Pa) that is 9 times lower than the maximum cross flow velocity reported in literature (4.5 ms( 1)). PMID- 25445522 TI - Preparation and optimization of ophiopogon polysaccharide liposome and its activity on Kupffer cells. AB - The purpose of this study was to prepare and optimize ophiopogon polysaccharide liposome (OPL), and to improve the immune-enhancing activity of ophiopogon polysaccharide (OP). OPL was prepared and optimized using the methods of reverse phase evaporation and response surface methodology. The property was evaluated with particle size, zeta potential, and morphology. The results showed that the optimum preparation conditions were: soybean phosphatide to OP ratio of 9.5:1, soybean phospholipid to cholesterol ratio of 8:1, and chloroform to phosphate buffered saline ratio of 3:1. Subsequently, the immune-enhancing activity of OPL on Kupffer cells (KCs) was performed. The results showed that OPL could significantly promote the phagocytosis of KCs, induce the secretion of nitric oxide, induced nitric oxide synthase, IL-6 and IL-12, and improve the expression of CD80 and CD86 compared with OP at 125-7.813 MUg mL(-1). These results indicated that the immune-enhancing activity of OP was significantly improved after encapsulated with liposome. Therefore, liposome would be expected to exploit into a new-type preparation of OP. PMID- 25445521 TI - Soluplus((r)) based 9-nitrocamptothecin solid dispersion for peroral administration: preparation, characterization, in vitro and in vivo evaluation. AB - Our study aimed to develop an amorphous 9-nitrocamptothecin solid dispersion (9 NC-SD) using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus((r))) for improving its oral bioavailability and antitumor efficacy in vivo. Freeze-dried 9-NC-SD with an optimized drug/polymer ratio at 1:15 (w/w) was characterized by powder X-ray diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy. The amorphous form of 9 NC was obtained by freeze-drying and the aqueous solubility of 9-NC was increased to 1.42 mg/mL. Upon dilution, 9-NC-SD was proven to form micellar structures with an average size distribution around 58 nm +/- 5 nm (PDI=0.107 +/- 0.016). Moreover, 9-NC-SD showed significantly increased intracellular uptake efficiency in Caco-2 cells compared to free 9-NC. Furthermore, the AUC0-8h of 9-NC-SD following oral administration showed a 2.68-fold increase in the lactone form of 9-NC compared to that of free 9-NC in Sprague-Dawley rats. The 9-NC-SD did not show obvious inflammatory responses and gastrointestinal toxicity following oral administration as demonstrated by the histological analysis of the rat intestinal sections. Thus, 9-NC-SD represents a promising approach for improving the solubility and oral bioavailability of drugs with poor solubility. PMID- 25445523 TI - Quality by Design approach to understand the physicochemical phenomena involved in controlled release of captopril SR matrix tablets. AB - The aim of this study is to obtain swelling controlled release matrix tablets of captopril using the Quality by Design methodology (ICH Q8) and to know the transport mechanisms involved in captopril release. To obtain the area of knowledge, the design of experiments studying the effect of two components (HPMC K15M and ethylcellulose) at different levels has been applied, with the captopril dissolution profile as the product's most important critical quality attribute (CQA). Different dissolution profiles have been obtained with the design of experiments performed, which is a key factor in the development of controlled release matrix tablets. Kinetic analysis according to the equations of Higuchi and Korsmeyer-Peppas demonstrates that the release mechanism is a mechanism of erosion when the whole percentage of the polymer is ethylcellulose, and a diffusion mechanism when the whole percentage of the polymer is HPMC K15M. The physico-chemical characteristics of the gel layer determine the release rate of captopril. The thickness of the gel layer, the porosity which is formed in the matrix upon contact with water, pore size, the swelling rate, the erosion rate of the matrix, and the physico-chemical characteristics of captopril, are factors related to the kinetic equations described and that allow us to predict the release mechanism of captopril. A new relationship of the kinetic equations governing the in vitro behavior with the physical characteristics of the gel layer of the different formulations has been established. This study shows that the size of water-filled pores and the degree of crosslinking between the chains of HPMC K15M of the matrix are related to the exponent n of the Korsmeyer-Peppas equation and the type of transport of the captopril from within the matrix to the dissolution medium, that is, if the transport is only through water-filled pores, or if a combination of diffusion occurs through water-filled pores with a transport through continuous polymeric networks. PMID- 25445524 TI - Synthesis, biological activity, and biopharmaceutical characterization of tacrine dimers as acetylcholinesterase inhibitors. AB - Tacrine (THA), as the first approved acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD), has been extensively investigated in last seven decades. After dimerization of THA via a 7-carbon alkyl spacer, bis(7) tacrine (B7T) showed much potent anti-AChE activity than THA. We here report synthesis, biological evaluation and biopharmaceutical characterization of six THA dimers referable to B7T. According to IC50 values, the in vitro anti-AChE activities of THA dimers were up to 300-fold more potent and 200-fold more selective than that of THA. In addition, the anti-AChE activities of THA dimers were found to be associated with the type and length of the linkage. All studied THA dimers showed much lower cytotoxicity than B7T, but like B7T, they demonstrated much lower absorptive permeabilities than that of THA on Caco-2 monolayer model. In addition, all THA dimers demonstrated significant efflux transport (efflux ratio >4), indicating that the limited permeability could be associated with the efflux transport during absorption process. Moreover, the dimer with higher Log P value was accompanied with higher permeability but lower aqueous solubility. A balanced consideration of activity, solubility, cytotoxicity and permeability should be conducted in selection of the potential candidates for further in vivo investigation. PMID- 25445525 TI - Sterically stabilized polymeric nanoparticles with a combinatorial approach for multi drug resistant cancer: in vitro and in vivo investigations. AB - The present work describes the preparation of sterically stabilize polymeric nanoparticles of mitoxantrone dihydrochloride (MTO) along with an efflux transporter (Pgp/BCRP) inhibitor that enhance the circulation time of nanoparticles and simultaneously surmount the problem of multidrug resistance (MDR). Mitoxantrone dihydrochloride being hydrophilic in nature had very low entrapment efficiency (%E.E.), thus in order to further enhance the lipophilicity and the %E.E., it was complexed with sodium deoxycholate (SDC) and this MTO-SDC complex was used to formulate nanoparticles with/without Pgp/BCRP inhibitor by nanoprecipitation technique and was characterized for various in vitro and in vivo attributes. In vitro cell line studies were conducted on MCF7, A2780(p) and A2780(adr) cells. Furthermore, the targeting potential of hyaluronic acid (HA) coated nanoparticles for CD44 receptors was investigated using the MCF7 cell line. A reduction in the IC50 value observed with the inhibitor loaded nanoparticles in different cell lines indicated the BCRP/Pgp inhibiting ability of the formulated nanoparticles. The reduced macrophage uptake and the increased residence time in blood demonstrated the long circulating behaviour of the nanoparticles. The enhanced cellular uptake of HA coated nanoparticles in MCF7 cells revealed their targeting potential. The HA coated nanoparticles along with efflux transporter inhibitor exhibits a great potential for targeted chemotherapy in CD44 overexpressing MDR breast cancer. PMID- 25445526 TI - High-throughput in vitro drug release and pharmacokinetic simulation as a tool for drug delivery system development: application to intravitreal ocular administration. AB - In vitro estimation of release kinetics from drug delivery systems is needed in formulation development. Cost-effective methods of assessment for delivery systems are needed particularly in the case of biologicals and drug administration routes that are difficult to screen in vivo (e.g. intraocular drug delivery). As a proof-of-concept, we demonstrate here a practical high-throughput methodology to investigate in vitro drug release and predict resulting drug concentrations in the eye after intravitreal administration. 96-well plate based assay aided with robotic sampling was used to study release of eight model drugs of varying physicochemical properties (dexamethasone, vancomycin, alpha lactalbumin, lysozyme, myoglobin, albumin, lactoferrin, human IgG) from twelve alginate microsphere formulations. The amount of drug released over a period of time was assessed by photometric and fluorescence methods. In vitro drug release rates obtained were used in pharmacokinetic simulations using one-compartment model of the vitreal cavity with anatomical volume of distribution and clearance estimates based on the literature precedence. An integrated approach of drug release screening and pharmacokinetic simulations can prove to be a useful methodology in guiding formulation development for ocular delivery in animal models. In general, the methodology has the potential to be a cost-effective tool for early stage drug delivery system discovery and development. PMID- 25445527 TI - Development of a new test for the easy characterization of the adhesion at the interface of bilayer tablets: proof-of-concept study by experimental design. AB - Although, adhesion at the interface of bilayer tablets is critical for their design it is difficult to characterize this adhesion between layers. In view of this, a new test with an easy implementation was proposed for the characterization of the interface of bilayer tablets. This work is presented as a proof-of-concept study to investigate the reliability of this new test with regard to the effects of some critical process parameters (e.g., compaction pressure applied on each layer) and material attributes (e.g., elasticity of the layered materials) on the interfacial adhesion of bilayer tablets. This was investigated using a design of experiment approach and the results obtained were in good accordance with those obtained with other tests and thus, confirms the potential of such a method for the measurement of the interfacial adhesion of bilayer tablets. PMID- 25445528 TI - Sodium colistimethate loaded lipid nanocarriers for the treatment of Pseudomonas aeruginosa infections associated with cystic fibrosis. AB - Lung impairment is the most life-threatening factor for cystic fibrosis patients. Indeed, Pseudomonas aeruginosa is the main pathogen in the pulmonary infection of these patients. In this work, we developed sodium colistimethate loaded lipid nanoparticles, namely, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), as a strategy to enhance the antimicrobial therapy against P. aeruginosa in cystic fibrosis patients. The nanoparticles obtained displayed a 200-400 nm size, high drug entrapment (79-94%) and a sustained drug release profile. Moreover, both SLN and NLC presented antimicrobial activity against clinically isolated P. aeruginosa. The integrity of the nanoparticles was not affected by nebulization through a mesh vibrating nebulizer. Moreover, lipid nanoparticles appeared to be less toxic than free sodium colistimethate in cell culture. Finally, an in vivo distribution experiment showed that nanoparticles spread homogenously through the lung and there was no migration of lipid nanoparticles to other organs, such as liver, spleen or kidneys. PMID- 25445529 TI - Bioadhesive emulsions for control release of progesterone resistant to vaginal fluids clearance. AB - The aim of this study is to propose that mucoadhesive vaginal emulsions can be able to resist the clearance effect of vaginal fluid and to have an effective control release of progesterone. With this goal, silicon derivative, cyclomethicone pentamer, was selected as the bioadhesive and water resistant material. In order to obtain a system which is insensitive to the dilution of aqueous fluids, water in silicone (W/S) emulsions were prepared and different proportions of cyclomethicone as well as 8% or 15% w/w of progesterone were employed. The rheological, mechanical and mucoadhesive properties of emulsions were characterized and the drug release was measured for each formulation. Mucoadhesive behavior was determined and the influence of simulated vaginal fluid (SVF) at bioadhesion was assessed using three commercial mucoadhesive vaginal gels (Crinone((r)), K-Y jelly((r)) and Zidoval((r))) as the bioadhesive references. All assayed emulsions have good rheological and mechanical properties and their consistence and viscosity increase when the proportion of the internal phase increases. Related to mucoadhesion, in the absence of SVF, W/S emulsions showed similar bioadhesive levels like the commercial formulations. However, in the presence of SVF, W/S emulsions are able to keep their mucoadhesive properties while the marketed references drastically lose their consistency and adherence to the vaginal mucosa. Drug release profiles from W/S emulsion show that progesterone is released with pseudo-order zero kinetics and a constant release rate is maintained for at least two weeks. The results of the in vivo studies developed in rats show that after a single vaginal administration, bioadhesive W/S emulsions increase the uterine tissue progesterone levels in young and postmenopausal rats. Moreover in postmenopausal rats, they provide high uterine levels of progesterone compared to the bioadhesive-marketed gel used as a reference. Therefore, W/S emulsions have an interesting potential as bioadhesive vaginal delivery systems for drug administration. PMID- 25445530 TI - Novel semisolid SNEDDS based on PEG-30-dipolyhydroxystearate: development and characterization. AB - The aim of the current study is to explore the potential of PEG-30 dipolyhydroxystearate (Cithrol((r)) DPHS) and Soluplus((r)) as ingredients in novel semisolid self-nanoemulsifying drug delivery systems (SNEDDS). Semisolid SNEDDS consisting of Cithrol((r)) DPHS, Capmul((r)) MCM and Kolliphor((r)) HS 15 were successfully prepared. The formulations were comprehensively characterized by photon correlation spectroscopy (PCS), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), electron spin resonance (ESR) and proton nuclear magnetic resonance ((1)H NMR). All formulations were semisolid at room temperature and melted at body temperature. The hydrodynamic diameter of the dispersions was less than 25 nm. The ratio Cithrol((r)) DPHS:Capmul((r)) MCM was found to be critical for the dispersibility and the stability of the formed nanoemulsion. PMID- 25445531 TI - Chemical imaging and solid state analysis at compact surfaces using UV imaging. AB - Fast non-destructive multi-wavelength UV imaging together with multivariate image analysis was utilized to visualize distribution of chemical components and their solid state form at compact surfaces. Amorphous and crystalline solid forms of the antidiabetic compound glibenclamide, and microcrystalline cellulose together with magnesium stearate as excipients were used as model materials in the compacts. The UV imaging based drug and excipient distribution was in good agreement with hyperspectral NIR imaging. The UV wavelength region can be utilized in distinguishing between glibenclamide and excipients in a non-invasive way, as well as mapping the glibenclamide solid state form. An exploratory data analysis supported the critical evaluation of the mapping results and the selection of model parameters for the chemical mapping. The present study demonstrated that the multi-wavelength UV imaging is a fast process analytical technique with the potential for real-time monitoring of critical quality attributes. PMID- 25445532 TI - Nanocarrier improves the bioavailability, stability and antitumor activity of camptothecin. AB - Camptothecin (CPT) nanosuspension was prepared by anti-solvent precipitation with TPGS as stabilizer to improve the solubility, stability and antitumor activity of CPT. And an increased solubility, stability and dissolution rate was achieved after nanosuspension being prepared. While, enhanced intracellular accumulation and cellular cytotoxicity was also observed for CPT nanosuspension than that of CPT solution.In addition, nanosuspension could increase bioavailability and intratumor accumulation of CPT in vivo after intravenous administration, and then produced a much higher antitumor effect and biocompatibility than that of CPT solution. Meanwhile, an enhanced cellular CPT uptake in hypoxic or acid conditions could also be observed for nanosuspension. As a result, nanosuspension represents a potentially feasible formation for insoluble drug in antitumor research. PMID- 25445533 TI - Administration strategies for proteins and peptides. AB - Proteins are a vital constituent of the body as they perform many of its major physiological and biological processes. Recently, proteins and peptides have attracted much attention as potential treatments for various dangerous and traditionally incurable diseases such as cancer, AIDS, dwarfism and autoimmune disorders. Furthermore, proteins could be used for diagnostics. At present, most therapeutic proteins are administered via parenteral routes that have many drawbacks, for example, they are painful, expensive and may cause toxicity. Finding more effective, easier and safer alternative routes for administering proteins and peptides is the key to therapeutic and commercial success. In this context, much research has been focused on non-invasive routes such as nasal, pulmonary, oral, ocular, and rectal for administering proteins and peptides. Unfortunately, the widespread use of proteins and peptides as drugs is still faced by many obstacles such as low bioavailability, short half-life in the blood stream, in vivo instability and numerous other problems. In order to overcome these hurdled and improve protein/peptide drug efficacy, various strategies have been developed such as permeability enhancement, enzyme inhibition, protein structure modification and protection by encapsulation. This review provides a detailed description of all the previous points in order to highlight the importance and potential of proteins and peptides as drugs. PMID- 25445534 TI - PEGylated mesoporous silica as a redox-responsive drug delivery system for loading thiol-containing drugs. AB - In this paper, we describe the development of a redox-responsive delivery system based on 6-mercaptopurine (6-MP)-conjugated colloidal mesoporous silica (CMS) via disulfide bonds. mPEG was modified on the surface of silica to improve the dispersibility and biocompatiblity of CMS by reducing hemolysis and protein adsorption. The CMS carriers with different amounts of thiol groups were prepared to evaluate the impact of modified thiol on the drug loading efficiency. In vitro release studies demonstrated that the CMS nanoparticles exhibited highly redox responsive drug release. The cumulative release of 6-MP was less than 3% in absence of GSH, and reached more than 70% within 2h in the presence of 3mM GSH. In addition, by comparing the cumulative release profiles of CMS-SS-MP@mPEG with their counterparts without the grafting of hydrophilic PEG, it was found that mPEG chains did not hinder the drug release due to the cleavable disulfide bonds and the improved dispersibility. Overall, this work provides a new strategy to connect thiol-containing/thiolated drugs and hydrophilic polymers to the interior and exterior of silica via disulfide bonds to obtain redox-responsive release and improve the dispersibility and biocompatibility of silica. PMID- 25445535 TI - Transbuccal delivery of doxepin: studies on permeation and histological investigation. AB - According to previous studies reporting the anesthetic/analgesic action of oral topical doxepin administration, this study evaluated a model of buccal permeation to determine the depth of delivery of doxepin into excised porcine buccal mucosa following topical application of a saturated aqueous doxepin solution. Buccal mucosa permeation studies were performed using Franz diffusion cells. Cumulative amounts of doxepin permeated were plotted as a function of time. Kinetic permeation parameters as flux (Js), lag time (Tl) and permeability coefficient (Kp) were calculated. Theoretical human plasmatic steady-state doxepin concentration and drug retained in the tissue were also determined in order to evaluate its potential therapeutic use, central or peripheral. Finally, a histological evaluation of the buccal mucosa was performed to test potential damage due to the permeation phenomenon. Obtained results showed a poor aqueous doxepin permeation through buccal mucosa membrane (median parameters Js=34.79 MUg/h, Kp=0.49*10(-3)cm/h and Tl=2.8h). Predicted doxepin plasma concentrations would reach 46 ng/mL, far from the required to have central nervous system activity as tricyclic agent. However, median doxepin amount remaining in the mucosa membrane was 0.24 MUg/cm(2)/MUg tissue, which evidenced a reservoir function of the buccal mucosa. Histologically, no structural damage was observed in the tissues. This study lays the foundation for further research within this area with a view to potentially adopting alternative strategies for enhanced buccal absorption of doxepin in clinical practice. PMID- 25445536 TI - Electrospun polyurethane/Eudragit (r) L100-55 composite mats for the pH dependent release of paclitaxel on duodenal stent cover application. AB - A nanofiber composite mat of PU and Eudragit((r)) L100-55 was created using electrospinning process. The pH dependent release of paclitaxel was successfully done with the use of PU/EL100-55 nanocomposite mats as the controlling platform. The morphology of the nanofiber composites was surveyed using FESEM and ratios of the polymers affects the diameter of the nanofiber. Characterization of the nanofiber composite mat was done using FTIR, DSC-TGA method. The release rate of paclitaxel was determined and analyzed by in vitro drug release method. In order to mimic the condition of a human duodenum, the fibers were submersed on PBS of different pH levels (4.0, 6.0,) respectively, and then analyzed using high performance liquid chromatography (HPLC). Composite mats submersed in PBS with pH 4.0 showed lesser release profile compared to mats submersed in PBS with pH of 6.0. The composite mat has adequate mechanical properties and in vitro cell biocompatibility indicating that the material can be used for drug eluting stent cover application. PMID- 25445537 TI - The enhancement of gene silencing efficiency with chitosan-coated liposome formulations of siRNAs targeting HIF-1alpha and VEGF. AB - RNA interference (RNAi) holds considerable promise as a novel therapeutic strategy in the silencing of disease-causing genes. The development of effective delivery systems is important for the use of small interfering RNA (siRNA) as therapy. In the present study, we investigated the effect on breast cancer cell lines and the co-delivery of liposomes containing siHIF1-alpha and siVEGF. In order to achieve the co-delivery of siHIF1-alpha and siVEGF and to obtain lower cytotoxicity, higher transfection and silencing efficiency, in this study, we used chitosan-coated liposomal formulation as the siRNA delivery system. The obtained particle size and zeta potential values show that the chitosan coating process is an effective parameter for particle size and the zeta potential of liposomes. The liposome formulations loaded with siHIF1-alpha and siVEGF showed good stability and protected siRNA from serum degradation after 24-h of incubation. The expression level of VEGF mRNA was markedly suppressed in MCF-7 and MDA-MB435 cells transfected with chitosan-coated liposomes containing HIF1 alpha and VEGF siRNA, respectively (95% and 94%). In vitro co-delivery of siVEGF and siHIF1-alpha using chitosan-coated liposome significantly inhibited VEGF (89%) and the HIF1-alpha (62%) protein expression when compared to other liposome formulations in the MDA-MB435 cell. The co-delivery of siVEGF and siHIF1-alpha was greatly enhanced in the vitro gene silencing efficiency. In addition, chitosan-coated liposomes showed 96% cell viability. Considering the role of VEGF and HIF1-alpha in breast cancer, siRNA-based therapies with chitosan coated liposomes may have some promises in cancer therapy. PMID- 25445538 TI - Resveratrol and diabetes: from animal to human studies. AB - Diabetes mellitus is a serious disease affecting about 5% of people worldwide. Diabetes is characterized by hyperglycemia and impairment in insulin secretion and/or action. Moreover, diabetes is associated with metabolic abnormalities and serious complications. Resveratrol is a natural, biologically active polyphenol present in different plant species and known to have numerous health-promoting effects in both animals and humans. Anti-diabetic action of resveratrol has been extensively studied in animal models and in diabetic humans. In animals with experimental diabetes, resveratrol has been demonstrated to induce beneficial effects that ameliorate diabetes. Resveratrol, among others, improves glucose homeostasis, decreases insulin resistance, protects pancreatic beta-cells, improves insulin secretion and ameliorates metabolic disorders. Effects induced by resveratrol are strongly related to the capability of this compound to increase expression/activity of AMPK and SIRT1 in various tissues of diabetic subjects. Moreover, anti-oxidant and anti-inflammatory effects of resveratrol were shown to be also involved in its action in diabetic animals. Preliminary clinical trials show that resveratrol is also effective in type 2 diabetic patients. Resveratrol may, among others, improve glycemic control and decrease insulin resistance. These results show that resveratrol holds great potential to treat diabetes and would be useful to support conventional therapy. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre clincial findigns to improved patient outcomes. PMID- 25445539 TI - Zinc-induced structural changes of the disordered tppp/p25 inhibits its degradation by the proteasome. AB - Tubulin Polymerization Promoting Protein/p25 (TPPP/p25), a neomorphic moonlighting protein displaying both physiological and pathological functions, plays a crucial role in the differentiation of the zinc-rich oligodendrocytes, the major constituent of myelin sheath; and it is enriched and co-localizes with alpha-synuclein in brain inclusions hallmarking Parkinson's disease and other synucleinopathies. In this work we showed that the binding of Zn(2+) to TPPP/p25 promotes its dimerization resulting in increased tubulin polymerization promoting activity. We also demonstrated that the Zn(2+) increases the intracellular TPPP/p25 level resulting in a more decorated microtubule network in CHO10 and CG 4 cells expressing TPPP/p25 ectopically and endogenously, respectively. This stabilization effect is crucial for the differentiation and aggresome formation under physiological and pathological conditions, respectively. The Zn(2+) mediated effect was similar to that produced by treatment of the cells with MG132, a proteasome inhibitor or Zn(2+) plus MG132 as quantified by cellular ELISA. The enhancing effect of zinc ion on the level of TPPP/p25 was independent of the expression level of the protein produced by doxycycline induction at different levels or inhibition of the protein synthesis by cycloheximide. Thus, we suggest that the zinc as a specific divalent cation could be involved in the fine-tuning of the physiological TPPP/p25 level counteracting both the enrichment and the lack of this protein leading to distinct central nervous system diseases. PMID- 25445541 TI - Nucleotide receptors control IL-8/CXCL8 and MCP-1/CCL2 secretions as well as proliferation in human glioma cells. AB - Glioma cells release cytokines to stimulate inflammation that facilitates cell proliferation. Here, we show that Lipopolysaccharide (LPS) treatment could induce glioma cells to proliferate and this process was dependent on nucleotide receptor activation as well as interleukin-8 (IL-8/CXCL8) secretion. We observed that extracellular nucleotides controlled IL-8/CXCL8 and monocyte chemoattractant protein 1 (MCP-1/CCL2) release by U251MG and U87MG human glioma cell lines via P2X7 and P2Y6 receptor activation. The LPS-induced release of these cytokines was also modulated by purinergic receptor activation since IL-8 and MCP-1 release was decreased by the nucleotide scavenger apyrase as well as by the pharmacological P2Y6 receptor antagonists suramin and MRS2578. In agreement with these observations, the knockdown of P2Y6 expression decreased LPS-induced IL-8 release as well as the spontaneous release of IL-8 and MCP-1, suggesting an endogenous basal release of nucleotides. Moreover, high millimolar concentrations of ATP increased IL-8 and MCP-1 release by the glioma cells stimulated with suboptimal LPS concentration which were blocked by P2X7 and P2Y6 antagonists. Altogether, these data suggest that extracellular nucleotides control glioma growth via P2 receptor-dependent IL-8 and MCP-1 secretions. PMID- 25445540 TI - Role of microtubules in attenuation of PepG-induced vascular endothelial dysfunction by atrial natriuretic peptide. AB - Apart from control of circulating fluid, atrial natriuretic peptide (ANP) exhibits anti-inflammatory effects in the lung. However, molecular mechanisms of ANP anti-inflammatory effects are not well-understood. Peripheral microtubule (MT) dynamics is essential for agonist-induced regulation of vascular endothelial permeability. Here we studied the role of MT-dependent signaling in ANP protective effects against endothelial cell (EC) barrier dysfunction and acute lung injury induced by Staphylococcus aureus-derived peptidoglican-G (PepG). PepG induced vascular endothelial dysfunction was accompanied by MT destabilization and disruption of MT network. ANP attenuated PepG-induced MT disassembly, NFkappaB signaling and activity of MT-associated Rho activator GEF-H1 leading to attenuation of EC inflammatory activation reflected by expression of adhesion molecules ICAM1 and VCAM1. ANP-induced EC barrier preservation and MT stabilization were linked to phosphorylation and inactivation of MT depolymerizing protein stathmin. Expression of stathmin phosphorylation-deficient mutant abolished ANP protective effects against PepG-induced inflammation and EC permeability. In contrast, siRNA-mediated stathmin knockdown prevented PepG induced peripheral MT disassembly and endothelial barrier dysfunction. ANP protective effects in a murine model of PepG-induced lung injury were associated with increased phosphorylation of stathmin, while exacerbated lung injury in the ANP knockout mice was accompanied by decreased pool of stable MT. Stathmin knockdown in vivo reversed exacerbation of lung injury in the ANP knockout mice. These results show a novel MT-mediated mechanism of endothelial barrier protection by ANP in pulmonary EC and animal model of PepG-induced lung injury via stathmin-dependent control of MT assembly. PMID- 25445542 TI - Bone marrow-derived c-jun N-terminal kinase-1 (JNK1) mediates liver regeneration. AB - Liver regeneration is controlled by a complex network of signaling molecules, and a prominent role for c-jun N-terminal kinase has been suggested during this process. In the present study, we aimed to characterize and define the cell-type specific contribution of JNK1 activation during liver regeneration. We used hepatocyte-specific JNK1 knockout mice (JNK1(Deltahepa)) using the cre/lox-P system. We performed partial hepatectomy (PH) in WT, JNK1(Deltahepa) and JNK1(-/ ) animals and investigated time-points up to 72 h after PH. Additionally, bone marrow transplantation experiments were conducted in order to identify the contribution of hematopoietic cell-derived JNK1 activation for liver regeneration. Our results show that liver regeneration was significantly impaired in JNK1(-/-) compared to JNK1(Deltahepa) and WT animals. These data were evidenced by lower BrdU incorporation and decreased cell cycle markers such as Cyclin A, Cyclin D, E2F1 and PCNA 48 h after PH in JNK1(-/-) compared with JNK1(Deltahepa) and WT livers. In JNK1(-/-) mice, our findings were associated with a reduced acute phase response as evidenced by a lower activation of the IL 6/STAT3/SAA-1 cascade. Additionally, CD11b(+)Ly6G(+)-cells were decreased in JNK1(-/-) compared with JNK1(Deltahepa) and WT animals after PH. The transplantation of bone marrow-derived JNK1(-/-) into WT recipients caused significant reduction in liver regeneration. Interestingly, the transplantation of JNK1(-/-) into mice lacking JNK1 in hepatocytes only partially delayed liver regeneration. In summary, we provide evidence that (1) JNK1 in hematopoietic cells is crucial for liver regeneration, and (2) a synergistic function between JNK1 in hepatocytes and hematopoietic-derived cells is involved in the hepatic regenerative response. PMID- 25445543 TI - Metabolic engineering for the production of hydrocarbon fuels. AB - Biofuels have been attracting increasing attention to provide a solution to the problems of climate change and our dependence on limited fossil oil. During the last decade, metabolic engineering has been performed to develop superior microorganisms for the production of so called advanced biofuels. Among the advanced biofuels, hydrocarbons possess high-energy content and superior fuel properties to other biofuels, and thus have recently been attracting much research interest. Here we review the recent advances in the microbial production of hydrocarbon fuels together with the metabolic engineering strategies employed to develop their production strains. Strategies employed for the production of long-chain and short-chain hydrocarbons derived from fatty acid metabolism along with the isoprenoid-derived hydrocarbons are reviewed. Also, the current limitations and future prospects in hydrocarbon-based biofuel production are discussed. PMID- 25445544 TI - Biogenic nanomaterials from photosynthetic microorganisms. AB - The use of algal cell cultures represents a sustainable and environmentally friendly platform for the biogenic production of nanobiomaterials and biocatalysts. For example, advances in the production of biogeneic nanomaterials from algal cell cultures, such as crystalline beta-chitin nanofibrils and gold and silver nanoparticles, could enable the 'green' production of biomaterials such as tissue-engineering scaffolds or drug carriers, supercapacitors and optoelectric materials. The in vivo functionalization, as well as newly demonstrated methods of production and modification, of biogenic diatom biosilica have led to the development of organic-inorganic hybrid catalytic systems as well as new biomaterials for drug delivery, biosensors and heavy-metal adsorbents. PMID- 25445545 TI - Progress and challenges in the engineering of non-cellulolytic microorganisms for consolidated bioprocessing. AB - Lignocellulosic biomass is an abundant, renewable feedstock for the production of fuels and chemicals, if an efficient and affordable conversion technology can be established to overcome its recalcitrance. Consolidated bioprocessing (CBP) featuring enzyme production, substrate hydrolysis and fermentation in a single step is a biologically mediated conversion approach with outstanding potential if a fit-for-purpose microorganism(s) can be developed. Progress in developing CBP enabling microorganisms is ongoing by engineering (i) naturally cellulolytic microorganisms for improved product-related properties or (ii) non-cellulolytic organisms exhibiting high product yields to heterologously produce different combinations of cellulase enzymes. We discuss progress on developing yeast and bacteria for the latter strategy and consider further challenges that require attention to bring this technology to market. PMID- 25445546 TI - Recent advances in the microbial production and recovery of apolar molecules. AB - Several apolar molecules of interest for the production of fuels and chemicals can nowadays be produced by fermentation. Those secreted from the microbial cell are of particular interest for large scale bioprocessing, since they allow for cell reuse, in situ product recovery and competitive production levels. So far, however, bioprocess strategies for fermentation and product recovery have been developed for addressing needs at the laboratory scale, rather than the process scale. Most commonly used strategies include extractive fermentations, product stripping in the gas phase, and off-line de-emulsification followed by intensive centrifugation. At the same time, current techno-economic studies at process scale have demonstrated the absolute need for significant improvements in both microorganism and process technology, for these processes to become competitive. PMID- 25445547 TI - Ecology-based selective environments as solution to contamination in microalgal cultivation. AB - Large-scale production of energetic storage compounds by microalgae is hampered by competition and evolution. Both phenomena result in contamination and arise due to a mismatch between the desired productive microalgal strain and the constructed environment. The prevailing approach to solve this issue involves increasing the survival potential of the desired strain, for example by working in closed systems or at extreme conditions. We advocate adjusting the environment in such a way that lipid production, or any other desired characteristic, gives a competitive advantage. Competition and evolution become a value rather than a threat to processes in which the desired characteristic is ensured by a selective environment. Research and cultivation efforts will benefit from this approach as it harnesses the microalgal diversity in nature. PMID- 25445548 TI - Metabolic pathway balancing and its role in the production of biofuels and chemicals. AB - In the last decade, metabolic engineering benefited greatly from systems and synthetic biology due to substantial advancements in those fields. As a result, technologies and methods evolved to be more complex and controllable than ever. In this review, we highlight up-to-date case studies using these techniques, examine their potential, and stress their importance for production of compounds such as fatty acids, alcohols, and high value chemicals. Beginning with basic rational control techniques and continuing with advanced level modern approaches, we review the vast number of possibilities for controlling metabolic fluxes. Our aim is to give a brief and informative insight about commonly used tools and universalized methodologies for metabolic pathway balancing and optimization. PMID- 25445549 TI - Unreduced gametes: meiotic mishap or evolutionary mechanism? AB - Unreduced gametes (gametes with the somatic chromosome number) are known to facilitate polyploid formation. Unreduced gametes result from a plethora of different mechanisms across different taxa, suggesting that the ability to produce unreduced gametes has evolutionary utility. Heritable genetic variation for unreduced gamete production has been observed, thereby providing an evolutionary substrate. Unreduced gametes are also frequently involved in interspecific hybridisation events as well as being produced by interspecific hybrids, facilitating allopolyploidisation. Environmental stress often triggers unreduced gamete production, suggesting that unreduced gametes may facilitate polyploid speciation in response to changing environments. Thus, although unreduced gamete formation may be a meiotic mishap, we suggest that unreduced gametes can be more explicitly considered as a mechanism for evolutionary speciation that should be measured and tested across and within lineages for exaptive evolution (a feature with evolutionary utility that has not arisen under conventional selective pressure) and evolvability (the capacity to generate adaptive genetic variation). PMID- 25445551 TI - The IMPORT HIGH image-guided radiotherapy study: a model for assessing image guided radiotherapy. PMID- 25445550 TI - Defining bowel dose volume constraints for bladder radiotherapy treatment planning. AB - AIMS: Increases to radiotherapy dose are constrained by normal tissue effects. The relationship between bowel dose volume data and late bowel toxicity in patients with muscle-invasive bladder cancer treated with radical radiotherapy was assessed. MATERIALS AND METHODS: The bowel was contoured retrospectively on radiotherapy plans of 47 patients recruited to the BC2001 trial (CRUK/01/004). The relationship between bowel volume at various dose levels and prospectively collected late bowel toxicity was explored. RESULTS: Fifteen per cent and 6% of patients experienced grade 1 and grade 2 or more late bowel toxicity, respectively. The mean bowel volume was significantly less at doses >=50 Gy in those treated with reduced high dose volume radiotherapy compared with standard radiotherapy. The probability of late bowel toxicity increased as bowel volume increased (P <= 0.05 for dose levels 30-50 Gy). No grade 2 or more late bowel toxicity was observed in patients with bowel volumes under the thresholds given in the model that predict for 25% probability of late bowel toxicity. CONCLUSIONS: There is a dose volume effect for late bowel toxicity in radical bladder radiotherapy. We have modelled the probability of late bowel toxicity from absolute bowel volumes to guide clinicians in assessing radical bladder radiotherapy plans. Thresholds predicting for a 25% probability of late bowel toxicity are proposed as dose volume constraints. PMID- 25445552 TI - The LORIS Trial: Addressing overtreatment of ductal carcinoma in situ. PMID- 25445553 TI - Meta-analysis of epidermal growth factor receptor and KRAS gene status between primary and corresponding metastatic tumours of non-small cell lung cancer. AB - The epidermal growth factor receptor (EGFR) and KRAS gene status in paired primary non-small cell lung cancer (NSCLC) and metastatic tumours has been investigated by many studies, but remains controversial. We systematically reviewed studies in English of EGFR and KRAS gene status in primary and corresponding metastatic NSCLC up to 15 January 2014. Studies were selected rigorously from PubMed, EMBASE, as well as Cochrane Library databases. We carried out a meta-analysis to clarify EGFR mutations, EGFR amplification, positive rate of EGFR protein expression and KRAS mutations in primary and corresponding metastatic NSCLC. Our data suggested that the overall EGFR mutation rate, gene copy number, protein expression were not different between primary tumours and corresponding metastases, with the pooled odd ratios and 95% confidence interval 1.043 (0.686-1.586, P = 0.844), 0.604 (0.355-1.027, P = 0.063) and 1.447 (0.948 2.208, P = 0.087), respectively. The overall KRAS mutation rate of primary tumours was not different from that of matched metastases, with the odds ratio and 95% confidence interval being 1.224 (0.808-1.856, P = 0.340). The discordant rates of EGFR and KRAS mutations in paired primary and metastatic NSCLC were 14.5 and 16.7%, respectively. Among the discordant gene mutations in primary and metastatic lesions, the frequency of occurrence of mutation was not different from the frequency of loss of mutation for EGFR (P = 0.093) and KRAS gene (P = 0.227). These results indicate that EGFR and KRAS mutations are present frequently in metastases and occur before metastasis. Therefore, routine analysis of EGFR or KRAS gene status both in primary and metastatic tumours is not recommended. PMID- 25445554 TI - Efficacy of high-dose palliative radiotherapy for localised, castration-resistant prostate cancer. AB - AIMS: There are limited outcome data after radiotherapy treatment for clinically localised, castration-resistant prostate cancer. We report our single institution experience on patient outcomes in this group using high-dose palliative radiotherapy (HDPRT). MATERIALS AND METHODS: A retrospective review of patient hospital records was conducted in prostate cancer patients treated with palliative intent radiotherapy and restricted to those who had castration resistant disease, no evidence of regional or distant disease and who received a local radiotherapy dose equivalent to 40 Gy or greater. RESULTS: Fifty-one patients met the study criteria, 88% of these had high-risk disease at initial diagnosis. The median time to delivery of HDPRT was 66 months and the median follow-up from HDPRT was 54 months. Grade 3 or worse toxicity was experienced in 8%. The estimated freedom from local failure, cause-specific survival and overall survival at 5 years were 81, 65 and 35%, respectively. Local procedures were a significant contributor to local morbidity, with the most common procedure a transurethral resection of the prostate (27% patients). Only two patients died from complications of local failure. CONCLUSION: HDPRT was well tolerated and provided a high rate of local control in a clinically localised castration resistant prostate cancer population. Although prostate cancer remained the most frequent cause of death, some patients had extended survival without evidence of disease progression. PMID- 25445555 TI - Six degrees-of-freedom prostate and lung tumor motion measurements using kilovoltage intrafraction monitoring. AB - PURPOSE: Tumor positional uncertainty has been identified as a major issue that deteriorates the efficacy of radiation therapy. Tumor rotational movement, which is not well understood, can result in significant geometric and dosimetric inaccuracies. The objective of this study was to measure 6 degrees-of-freedom (6 DoF) prostate and lung tumor motion, focusing on the more novel rotation, using kilovoltage intrafraction monitoring (KIM). METHODS AND MATERIALS: Continuous kilovoltage (kV) projections of tumors with gold fiducial markers were acquired during radiation therapy for 267 fractions from 10 prostate cancer patients and immediately before or after radiation therapy for 50 fractions from 3 lung cancer patients. The 6 DoF motion measurements were determined from the individual 3 dimensional (3D) marker positions, after using methods to reject spurious and smooth noisy data, using an iterative closest point algorithm. RESULTS: There were large variations in the magnitude of the tumor rotation among different fractions and patients. Various rotational patterns were observed. The average prostate rotation angles around the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) axes were 1.0 +/- 5.0 degrees , 0.6 +/- 3.3 degrees , and 0.3 +/- 2.0 degrees , respectively. For 35% of the time, the prostate rotated more than 5 degrees about the LR axis, indicating the need for intrafractional adaptation during radiation delivery. For lung patients, the average LR, SI, and AP rotation angles were 0.8 +/- 4.2 degrees , -0.8 +/- 4.5 degrees , and 1.7 +/- 3.1 degrees , respectively. For about 30% of the time, the lung tumors rotated more than 5 degrees around the SI axis. Respiration-induced rotation was detected in 2 of the 3 lung patients. CONCLUSIONS: The prostate and lung tumors were found to undergo rotations of more than 5 degrees for about a third of the time. The lung tumor data represent the first 6 DoF tumor motion measured by kV images. The 6 DoF KIM method can enable rotational and translational adaptive radiation therapy and potentially reduce treatment margins. PMID- 25445557 TI - Investigation of Functional Genes at Homologous Loci Identified Based on Genome wide Association Studies of Blood Lipids via High-fat Diet Intervention in Rats using an in vivo Approach. AB - AIM: It is challenging to identify causal (or target) genes at individual loci detected using genome-wide association studies (GWAS). In order to follow up GWAS loci, we investigated functional genes at homologous loci identified using human lipid GWAS that responded to a high-fat, high-cholesterol diet (HFD) intervention in an animal model. METHODS: The HFD intervention was carried out for four weeks in male rats of the spontaneously hypertensive rat strain. The liver and adipose tissues were subsequently excised for analyses of changes in the gene expression as compared to that observed in rats fed normal rat chow (n=8 per group). From 98 lipid-associated loci reported in previous GWAS, 280 genes with rat orthologs were initially selected as targets for the two-staged analysis involving screening with DNA microarray and validation with quantitative PCR (qPCR). Consequently, genes showing a differential expression due to HFD were examined for changes in the expression induced by atorvastatin, which was independently administered to the rats. RESULTS: Using the HFD intervention in the rats, seven known (Abca1, Abcg5, Abcg8, Lpl, Nr1h3, Pcsk9 and Pltp) and three novel (Madd, Stac3 and Timd4) genes were identified as potential significant targets, with an additional list of 23 suggestive genes. Among these 33 genes, Stac3, Fads1 and six known genes exhibited nominally significant expression changes following treatment with atorvastatin. Six (of 33) genes overlapped with those previously detected in the expression QTL studies. CONCLUSIONS: Our experimental in vivo approach increases the ability to identify target gene(s), when combined with other functional studies, thus improving understanding of the mechanisms by which GWAS variants act. PMID- 25445556 TI - Prostate-specific antigen persistence after radical prostatectomy as a predictive factor of clinical relapse-free survival and overall survival: 10-year data of the ARO 96-02 trial. AB - OBJECTIVE: The ARO 96-02 trial primarily compared wait-and-see (WS, arm A) with adjuvant radiation therapy (ART, arm B) in prostate cancer patients who achieved an undetectable prostate-specific antigen (PSA) after radical prostatectomy (RP). Here, we report the outcome with up to 12 years of follow-up of patients who retained a post-RP detectable PSA and received salvage radiation therapy (SRT, arm C). METHODS AND MATERIALS: For the study, 388 patients with pT3-4pN0 prostate cancer with positive or negative surgical margins were recruited. After RP, 307 men achieved an undetectable PSA (arms A + B). In 78 patients the PSA remained above thresholds (median 0.6, range 0.05-5.6 ng/mL). Of the latter, 74 consented to receive 66 Gy to the prostate bed, and SRT was applied at a median of 86 days after RP. Clinical relapse-free survival, metastasis-free survival, and overall survival were determined by the Kaplan-Meier method. RESULTS: Patients with persisting PSA after RP had higher preoperative PSA values, higher tumor stages, higher Gleason scores, and more positive surgical margins than did patients in arms A + B. For the 74 patients, the 10-year clinical relapse-free survival rate was 63%. Forty-three men had hormone therapy; 12 experienced distant metastases; 23 patients died. Compared with men who did achieve an undetectable PSA, the arm C patients fared significantly worse, with a 10-year metastasis-free survival of 67% versus 83% and overall survival of 68% versus 84%, respectively. In Cox regression analysis, Gleason score >=8 (hazard ratio [HR] 2.8), pT >= 3c (HR 2.4), and extraprostatic extension >=2 mm (HR 3.6) were unfavorable risk factors of progression. CONCLUSIONS: A persisting PSA after prostatectomy seems to be an important prognosticator of clinical progression for pT3 tumors. It correlates with a higher rate of distant metastases and with worse overall survival. A larger prospective study is required to determine which patient subgroups will benefit most from which treatment option. PMID- 25445558 TI - Lung cancer. How much platinum-based chemotherapy is enough in NSCLC? AB - With no large randomized phase III trials to provide definitive answers, the ideal number of platinum-based chemotherapy cycles in patients with advanced non small-cell lung cancer has long been unclear. Most guidelines recommend a maximum of 4-6 cycles. Rossi and colleagues now suggest that four chemotherapy cycles is the optimal regimen. PMID- 25445559 TI - Chemotherapy. After 25 years, therapy for poor-prognosis GCTs advances. PMID- 25445560 TI - Breast cancer. Risedronate reduces bone loss. PMID- 25445563 TI - Cerebro-renal interactions and cognitive function: the important role of sleep. PMID- 25445561 TI - Interventional oncology in multidisciplinary cancer treatment in the 21(st) century. AB - Interventional oncology is an evolving branch of interventional radiology, which relies on rapidly evolving, highly sophisticated treatment tools and precise imaging guidance to target and destroy malignant tumours. The development of this field has important potential benefits for patients and the health-care system, but as a new discipline, interventional oncology has not yet fully established its place in the wider field of oncology; its application does not have a comprehensive evidence base, or a clinical or quality-assurance framework within which to operate. In this regard, radiation oncology, a cornerstone of modern cancer care, has a lot of important information to offer to interventional oncologists. A strong collaboration between radiation oncology and interventional oncology, both of which aim to cure or control tumours or to relieve symptoms with as little collateral damage to normal tissue as possible, will have substantial advantages for both disciplines. A close relationship with radiation oncology will help facilitate the development of a robust quality-assurance framework and accumulation of evidence to support the integration of interventional oncology into multidisciplinary care. Furthermore, collaboration between interventional oncology and radiation oncology fields will have great benefits to practitioners, people affected by cancer, and to the wider field of oncology. PMID- 25445562 TI - RILP interacts with HOPS complex via VPS41 subunit to regulate endocytic trafficking. AB - The HOPS complex serves as a tethering complex with GEF activity for Ypt7p in yeast to regulate late endosomal membrane maturation. While the role of HOPS complex is well established in yeast cells, its functional and mechanistic aspects in mammalian cells are less well defined. In this study, we report that RILP, a downstream effector of Rab7, interacts with HOPS complex and recruits HOPS subunits to the late endosomal compartment. Structurally, the amino-terminal portion of RILP interacts with HOPS complex. Unexpectedly, this interaction is independent of Rab7. VPS41 subunit of HOPS complex was defined to be the major partner for interacting with RILP. The carboxyl-terminal region of VPS41 was mapped to be responsible for the interaction. Functionally, either depletion of VPS41 by shRNA or overexpression of VPS41 C-terminal half retarded EGF-induced degradation of EGFR. These results suggest that interaction of RILP with HOPS complex via VPS41 plays a role in endocytic trafficking of EGFR. PMID- 25445564 TI - Protective effect of apple (Ralls) polyphenol extract against aluminum-induced cognitive impairment and oxidative damage in rat. AB - Aluminum (Al) has long been implicated in the pathogenesis of Alzheimer's disease (AD). Dietary polyphenols have been strongly associated with reduced risk of AD and the other nervous diseases. We aimed to evaluate the preventive effect of the apple polyphenol extract (APE) on Al-induced biotoxicity, in order to provide a new focus on the design of strategies to prevent AD and the other human diseases related to Al overload. Control, Al-treated (171.8 mg Al kg(-1)day(-1) 10 weeks), APE+Al (Al-treatment as previously plus 200 mg kg(-1)day(-1) 10 weeks), and group of APE per se were used. Al intake caused memory impairment, significant decrease of acetylcholinesterase, CK, SOD, CAT activity and the rate of ATP synthesis, increase the Al content, the level of malondialdehyde and beta-amyloid 42. Administration of APE significantly improved memory retention, attenuated oxidative damage, acetylcholinesterase activity and Al level in Al treated rats. Furthermore, chlorogenic acid (ChA) was used for analyzing stability of polyphenols-Al(3+) complex. Log K1 was 10.51, and the mole ratio of Al(3+) to ligand was 1:1. We further found that the amounts of Al increased significantly in feces of the rats gavaged with AlCl3 plus ChA compared with AlCl3. Our finding has shown APE has neuroprotective effects against Al-induced biotoxicity. Chelating with Al and disturbing its absorption could account for the neuroprotective roles of dietary polyphenols against Al toxicity. PMID- 25445565 TI - Potential of protease inhibitor in 3-nitropropionic acid induced Huntington's disease like symptoms: mitochondrial dysfunction and neurodegeneration. AB - Huntington's disease (HD) is a genetic, neurodegenerative disorder mainly characterized by motor dysfunction, cognitive decline and psychiatric disturbances. 3-Nitropropionic acid (3-NP) is an inhibitor of succinate dehydrogenase (Complex II) of the mitochondrial respiratory chain, which thereby reduces production of ATP. It induces neurotoxicity by causing striatal degeneration, energy deficit and oxidative stress. Angiotensin converting enzyme (ACE) is an important protease in the renin angiotensin system (RAS) responsible for the conversion of Angiotensin I to Angiotensin II. Angiotensin-II stimulates mitochondrial oxidant release leading to depression of energy metabolism. ACE inhibitors have shown promise in disorders like stress, anxiety, and depression in addition to showing beneficial effects in cognitive disorders like Alzheimer's. Angiotensin-II inhibition enhances energy production by lowering mitochondrial oxidant production, and hence protects mitochondrial structure. Trandolapril is a centrally active ACE inhibitor. 3-NP administered systematically (20mg/kg, i.p) for 4 days consecutively induced HD like symptoms - loss of body weight, neurobehavioral alterations like memory dysfunction (elevated plus maze, Morris water maze performance), Hind-limb impairment (Narrow beam test), motor incoordination (locomotor activity). Biochemical studies on brain tissue showed increased lipid peroxidation, nitrite levels and acetylcholinesterase activity along with decreased levels of reduced glutathione, catalase activity. Mitochondrial enzyme complex activities (I, II, IV and MTT assay) were found to be significantly lowered in brain mitochondria. Administration of Trandolapril (4 and 6 mg/kg, p.o) daily for 12 days showed significant improvement in body weight, neurobehavioral parameters, oxidative stress and mitochondrial enzyme activities in rat brain. These findings were further confirmed by histopathological studies which showed improvement in 3-NP induced brain lesions. This study indicates that Trandolapril could be an effective treatment option for the management of HD. PMID- 25445567 TI - Genomic analyses of Clostridium perfringens isolates from five toxinotypes. AB - Clostridium perfringens can be isolated from a range of environments, including soil, marine and fresh water sediments, and the gastrointestinal tracts of animals and humans. Some C. perfringens strains have attractive industrial applications, e.g., in the degradation of waste products or the production of useful chemicals. However, C. perfringens has been most studied as the causative agent of a range of enteric and soft tissue infections of varying severities in humans and animals. Host preference and disease type in C. perfringens are intimately linked to the production of key extracellular toxins and on this basis toxigenic C. perfringens strains have been classified into five toxinotypes (A E). To date, twelve genome sequences have been generated for a diverse collection of C. perfringens isolates, including strains associated with human and animal infections, a human commensal strain, and a strain with potential industrial utility. Most of the sequenced strains are classified as toxinotype A. However, genome sequences of representative strains from each of the other four toxinotypes have also been determined. Analysis of this collection of sequences has highlighted a lack of features differentiating toxinotype A strains from the other isolates, indicating that the primary defining characteristic of toxinotype A strains is their lack of key plasmid-encoded extracellular toxin genes associated with toxinotype B to E strains. The representative B-E strains sequenced to date each harbour many unique genes. Additional genome sequences are needed to determine if these genes are characteristic of their respective toxinotypes. PMID- 25445568 TI - Fungal jarosite biomineralization in Rio Tinto. AB - Rio Tinto is an extreme environment located at the core of the Iberian Pyrite Belt (IPB). It is an unusual ecosystem due to its size, constant acidic pH, high concentration of heavy metals and a high level of microbial diversity, mainly eukaryotic. Recently it was described the biomineralization of jarosite by Purpureocillium lilacinum, an acidic filamentous fungi isolated from the banks of the Tinto basin. In this study we further investigate the specificity of jarosite biomineralization by this fungi and its importance in the generation of jarosite in the Rio Tinto basin. Our results clearly show that the ratio of the redox pairs and the Fe(3+) concentration is important to achieve a specific biomineralization of jarosite. The amount of nucleation sites also seems to be critical, although the presence of nucleation sites by itself is not sufficient to precipitate jarosite. There is a good correlation between the sampling sites along the river in which hydronium-jarosite has been identified and the presence of P. lilacinum. PMID- 25445569 TI - Pesticides used in cotton production affect reproductive development, endocrine regulation, liver status and offspring fitness in African catfish Clarias gariepinus (Burchell, 1822). AB - We exposed African catfish Clarias gariepinus from embryo-larvae stage to adult stage (13 months old, BW) to chronic doses of Tihan 175 O-TEQ and endosulfan (Thionex) and assessed the impact of this exposure on endocrine regulation, liver status and offspring fitness. Endosulfan exposure caused a significant increase in plasma estradiol-17beta (E2) and decreased plasma testosterone (T) but not 11 ketotestosterone (11-KT). Tihan decreased significantly plasma E2 and 11-KT, but not T. Endosulfan doses altered gonad histology and induced high proportions (18 30% of males) of ovotestis in males and follicular atretic oocytes in females, indicating occurrence of feminization in fish. Tihan also altered gonad histology but only one case of ovotestis was observed at the highest dose. Presence of foam cells in lobular lumen, fibrosis, necrosis, and immature cells released in lobular lumen were found in male gonads and melano-macrophage centers (MMCs), necrosis, fibrosis and vacuolation were observed in female gonads. Fish livers also suffered injuries such as MMCs, necrosis, fibrosis, vacuolation, dilatation of sinusoids, and nuclear pleomorphism. Chronic Tihan and Thionex exposures decreased fertilization rate, hatching rate, ova and larval weight, as well as larval resistance to osmotic choc. They also delayed hatching and increased abnormalities in the F1 generation, all these indicators suggesting transgenerational effects of these compounds. PMID- 25445566 TI - Integration of metabolism and virulence in Clostridium difficile. AB - Synthesis of the major toxin proteins of the diarrheal pathogen, Clostridium difficile, is dependent on the activity of TcdR, an initiation (sigma) factor of RNA polymerase. The synthesis of TcdR and the activation of toxin gene expression are responsive to multiple components in the bacterium's nutritional environment, such as the presence of certain sugars, amino acids, and fatty acids. This review summarizes current knowledge about the mechanisms responsible for repression of toxin synthesis when glucose or branched-chain amino acids or proline are in excess and the pathways that lead to synthesis of butyrate, an activator of toxin synthesis. The regulatory proteins implicated in these mechanisms also play key roles in modulating bacterial metabolic pathways, suggesting that C. difficile pathogenesis is intimately connected to the bacterium's metabolic state. PMID- 25445570 TI - Morphology, cell viability, karyotype, expression of surface markers and plasticity of three human primary cell line cultures before and after the cryostorage in LN2 and GN2. AB - Primary cell line cultures from human skin biopsies, adipose tissue and tumor tissue are valuable samples for research and therapy. In this regard, their derivation, culture, storage, transport and thawing are important steps to be studied. Towards this end, we wanted to establish the derivation, and identify the culture characteristics and the loss of viability of three human primary cell line cultures (human adult dermal fibroblasts (hADFs), human adult mesenchymal stem cells (hMSCs), and primary culture of tumor cells from lung adenocarcinoma (PCTCLA)). Compared to fresh hADFs, hMSCs and PCTCLA, thawed cells stored in a cryogenic Dewar tanks with liquid nitrogen (LN2), displayed 98.20% +/- 0.99, 95.40% +/- 1.41 and 93.31% +/- 3.83 of cell viability, respectively. Thawed cells stored in a Dry Vapor Shipper container with gas phase (GN2), for 20 days, in addition displayed 4.61% +/- 2.78, 3.70% +/- 4.09 and 9.13% +/- 3.51 of average loss of cells viability, respectively, showing strong correlation between the loss of viability in hADFs and the number of post-freezing days in the Dry Vapor Shipper. No significant changes in morphological characteristics or in the expression of surface markers (being hADFs, hMSCs and PCTCLA characterized by positive markers CD73+; CD90+; CD105+; and negative markers CD14-; CD20-; CD34-; and CD45-; n=2) were found. Chromosome abnormalities in the karyotype were not found. In addition, under the right conditions hMSCs were differentiated into adipogenic, osteogenic and chondrogenic lineages in vitro. In this paper, we have shown the characteristics of three human primary cell line cultures when they are stored in LN2 and GN2. PMID- 25445571 TI - Negative inotropic effects of epinephrine in the presence of increased beta adrenoceptor sensitivity during hypothermia in a rat model. AB - BACKGROUND: Animal studies show reduced inotropic effects of cardiac beta adrenoceptor agonists like epinephrine (Epi) during hypothermia and rewarming, while drugs targeting other pharmacological mechanisms have positive effects. This study therefore aimed to determine beta-adrenoceptor sensitivity in isolated cardiomyocytes and investigate hemodynamic effects of Epi and its ability to stimulate cardiac beta-adrenoceptors at different temperatures in vivo. METHODS: Isolated rat myocardial cells were incubated with the radioactive beta adrenoceptor ligand [(3)H]-CGP12177 and propranolol, used as a displacer. Cells were subjected to normothermia (37 degrees C) or hypothermia (15 degrees C). After incubation, radioactivity was measured to estimate beta-adrenoceptor affinity for propranolol (IC50), as a measure of beta-adrenoceptor sensitivity. In separate in vivo experiments, Epi (1.25 MUg/min) was administered the last 5min of experiments in normothermic (37 degrees C, 5h), hypothermic (4h at 15 degrees C) and rewarmed rats (4h at 15 degrees C, and subsequently rewarmed to 37 degrees C). Hemodynamic parameters were monitored during infusion. Hearts were thereafter freeze-clamped and tissue cAMP was measured. RESULTS: In vitro measurements of IC50 for propranolol showed a hypothermia-induced increase in beta-adrenoceptor sensitivity at 15 degrees C. Corresponding in vivo experiments at 15 degrees C showed decreased cardiac output and stroke volume, whereas total peripheral resistance (TPR) increased during Epi infusion, simultaneous with a 4 fold cAMP increase. CONCLUSIONS: This experiment shows a hypothermia-induced in vivo and in vitro increase of cardiac beta-adrenoceptor sensitivity, and simultaneous lack of inotropic effects of Epi in the presence of increased TPR. Our findings therefore indicate that hypothermia-induced reduction in inotropic effects of Epi is due to substantial elevation of TPR, rather than beta adrenoceptor dysfunction. PMID- 25445572 TI - Antioxidant effects of clove bud (Syzygium aromaticum) extract used with different extenders on ram spermatozoa during cryopreservation. AB - Clove bud (Syzygium aromaticum) extract was added at concentrations of 0, 35, 75, and 115 MUg/ml to ovine semen extenders in order to investigate the antioxidant activities of clove bud extract and its effects on semen quality parameters after cryopreservation of ram spermatozoa. The basic extender was composed of Tris, egg yolk, and glycerol. Two other extenders were prepared by substitution of egg yolk with either LDL or egg yolk+SDS. The DPPH inhibition test was employed to assess the antioxidant activity of clove bud extract. Results showed that, compared to vitamin E, clove bud extract had a higher antioxidant activity. Better sperm motility and movement characteristics (P<0.05) were observed in the semen diluted with medium containing egg yolk+SDS than in that containing egg yolk and LDL. Progressive motility and movement characteristics of the sperm were significantly improved (P<0.05) by adding 35 and/or 75 MUg/ml of clove bud extract to semen extenders. Sperm viability and plasma membrane integrity were also higher (P<0.05) in the semen exposed to medium containing egg yolk+SDS and 75 MUg of clove buds extract after cryopreservation processes. Higher levels of clove bud extract, however, had adverse effects on all the sperm quality parameters and significantly reduced (P<0.05) the motility, movement parameters, viability, and plasma membrane integrity of ovine sperm. It was concluded that the clove bud extract had an antioxidant potential that makes it useful for addition to semen extenders and that the best results are obtained with a maximum clove bud extract of 75 MUg/ml. Moreover, the combination of egg yolk and a detergent was found to improve sperm quality after the cooling and freeze-thawing processes. PMID- 25445573 TI - Determination of heat transfer coefficients in plastic French straws plunged in liquid nitrogen. AB - The knowledge of the thermodynamic process during the cooling of reproductive biological systems is important to assess and optimize the cryopreservation procedures. The time-temperature curve of a sample immersed in liquid nitrogen enables the calculation of cooling rates and helps to determine whether it is vitrified or undergoes phase change transition. When dealing with cryogenic liquids, the temperature difference between the solid and the sample is high enough to cause boiling of the liquid, and the sample can undergo different regimes such as film and/or nucleate pool boiling. In the present work, the surface heat transfer coefficients (h) for plastic French straws plunged in liquid nitrogen were determined using the measurement of time-temperature curves. When straws filled with ice were used the cooling curve showed an abrupt slope change which was attributed to the transition of film into nucleate pool boiling regime. The h value that fitted each stage of the cooling process was calculated using a numerical finite element program that solves the heat transfer partial differential equation under transient conditions. In the cooling process corresponding to film boiling regime, the h that best fitted experimental results was h=148.12+/-5.4 W/m(2) K and for nucleate-boiling h=1355+/-51 W/m(2) K. These values were further validated by predicting the time-temperature curve for French straws filled with a biological fluid system (bovine semen-extender) which undergoes freezing. Good agreement was obtained between the experimental and predicted temperature profiles, further confirming the accuracy of the h values previously determined for the ice-filled straw. These coefficients were corroborated using literature correlations. The determination of the boiling regimes that govern the cooling process when plunging straws in liquid nitrogen constitutes an important issue when trying to optimize cryopreservation procedures. Furthermore, this information can lead to improvements in the design of cooling devices in the cryobiology field. PMID- 25445575 TI - Stochastic modeling in biological populations with sexual reproduction through branching models: application to Coho salmon populations. AB - The motivation behind this research is to develop appropriate mathematical models to describe the demographic dynamics of animal populations with sexual reproduction. We introduce a new class of two-sex branching models where several mating strategies between females and males and a variety of possibilities for the process of reproduction are taken into account. Unlike other classes of two sex models which assume that mating and reproduction are influenced by the number of couples in the population, we now consider the most realistic case where both biological processes are affected by the numbers of females and males in the population, which may differ. Under a general parametric setting, we deal with inferential questions about the main parameters affecting the reproduction process. By considering the observation over time of the numbers of females and males up to when a certain pre-set generation is reached, we derive Bayes estimators for such parameters. With the purpose of determining highest posterior density credibility sets, we also propose a computational algorithm. As illustration, we include an application to Coho salmon populations. PMID- 25445574 TI - Circadian characteristics of permissive and suppressive effects of cortisol and their role in homeostasis and the acute inflammatory response. AB - In this work we explore a semi-mechanistic model that considers cortisol's permissive and suppressive effects through the regulation of cytokine receptors and cytokines respectively. Our model reveals the proactive role of cortisol during the resting period and its reactive character during the body's activity phase. Administration of an acute LPS dose during the night, when cortisol's permissive effects are higher than suppressive, leads to increased cytokine levels compared to LPS administration at morning when cortisol's suppressive effects are higher. Interestingly, our model presents a hysteretic behavior where the relative predominance of permissive or suppressive effects results not only from cortisol levels but also from the previous states of the model. Therefore, for the same cortisol levels, administration of an inflammatory stimulus at cortisol's ascending phase, that follows a time period where cytokine receptor expression is elevated ultimately sensitizing the body for the impending stimulus, leads to higher cytokine expression compared to administration of the same stimulus at cortisol's descending phase. PMID- 25445576 TI - A model for spatio-temporal dynamics in a regulatory network for cell polarity. AB - Cell polarity in Myxococcus xanthus is crucial for the directed motility of individual cells. The polarity system is characterised by a dynamic spatio temporal localisation of the regulatory proteins MglA and MglB at opposite cell poles. In response to signalling by the Frz chemosensory system, MglA and MglB are released from the poles and then rebind at the opposite poles. Thus, over time MglA and MglB oscillate irregularly between the poles in synchrony but out of phase. A minimal macroscopic model of the Mgl/Frz regulatory system based on a reaction-diffusion PDE system is presented. Mathematical analysis of the steady states derives conditions on the reaction terms for formation of dynamic localisation patterns of the regulatory proteins under different biologically relevant regimes, i.e. with and without Frz signalling. Numerical simulations of the model system produce either a stationary pattern in time (fixed polarity), periodic solutions in time (oscillating polarity), or excitable behaviour (irregular switching of polarity). PMID- 25445577 TI - Re: Partial nephrectomy in the setting of metastatic renal cell carcinoma: K. N. Babaian, M. M. Merrill, S. Matin, P. Tamboli, N. M. Tannir, E. Jonasch, C. G. Wood and J. A. Karam J Urol 2014; 192: 36-42. PMID- 25445578 TI - Re: Overactive bladder changes with time: a 5-year longitudinal followup of changes in overactive bladder symptoms, urodynamic studies and urinary nerve growth factor levels: F.-C. Chuang, H.-T. Liu, L.-Y. Wang and H.-C. Kuo J Urol 2014; 192: 458-463. PMID- 25445580 TI - Re: Multiparametric magnetic resonance imaging guided diagnostic biopsy detects significant prostate cancer and could reduce unnecessary biopsies and over detection: a prospective study: J. E. Thompson, D. Moses, R. Shnier, P. Brenner, W. Delprado, L. Ponsky, M. Pulbrook, M. Bohm, A.-M. Haynes, A. Hayen and P. D. Stricker J Urol 2014;192:67-74. PMID- 25445579 TI - Re: Inhibition of peripheral FAAH depresses activities of bladder mechanosensitive nerve fibers of the rat: N. Aizawa, P. Hedlund, C. Fullhase, H. Ito, Y. Homma and Y. Igawa J Urol 2014; 192: 956-963. PMID- 25445581 TI - Re: Editorial comment on Role of marker lesion when applying intravesical instillations of IL-2 for non-muscle-invasive bladder cancer comparison of the therapeutic effects in two pilot studies: D. P. Wood J Urol 2014; 191: 348. PMID- 25445583 TI - MicroRNA-21, up-regulated by arsenite, directs the epithelial-mesenchymal transition and enhances the invasive potential of transformed human bronchial epithelial cells by targeting PDCD4. AB - Arsenic is well established as a human carcinogen, but the molecular mechanisms leading to arsenic-induced carcinogenesis are complex and elusive. It is not been determined if the epithelial-mesenchymal transition (EMT) contributes to carcinogen-induced malignant transformation and subsequent tumor formation. We have found that, during the neoplastic transformation induced in human bronchial epithelial (HBE) cells by a low concentration (1.0MUM) of arsenite, the cells undergo an EMT and show enhanced invasion and migration. With longer times for transformation of HBE cells, there was increased miR-21 expression. Further, during the transformation of HBE cells, inhibition of miR-21 with an miR-21 inhibitor increased levels of PDCD4, an inhibitor of neoplastic transformation; reduced Twist1, a transcription factor involved in cell differentiation; and inhibited cell invasion and migration. In addition, PDCD4 interacted with Twist1 and inhibited its expression function, which is involved in arsenite-induced EMT. Thus, miR-21, acting on PDCD4, which interacts with Twist1 and represses the expression of Twist1, contributes to the EMT induced by arsenite. These observations add to an understanding of the processes involved in arsenite induced carcinogenesis. PMID- 25445582 TI - Oral administration of aflatoxin G1 induces chronic alveolar inflammation associated with lung tumorigenesis. AB - Our previous studies showed oral gavage of aflatoxin G1 (AFG1) induced lung adenocarcinoma in NIH mice. We recently found that a single intratracheal administration of AFG1 caused chronic inflammatory changes in rat alveolar septum. Here, we examine whether oral gavage of AFG1 induces chronic lung inflammation and how it contributes to carcinogenesis. We evaluated chronic lung inflammatory responses in Balb/c mice after oral gavage of AFG1 for 1, 3 and 6 months. Inflammatory responses were heightened in the lung alveolar septum, 3 and 6 months after AFG1 treatment, evidenced by increased macrophages and lymphocytes infiltration, up-regulation of NF-kappaB and p-STAT3, and cytokines production. High expression levels of superoxide dismutase (SOD-2) and hemoxygenase-1 (HO-1), two established markers of oxidative stress, were detected in alveolar epithelium of AFG1-treated mice. Promoted alveolar type II cell (AT-II) proliferation in alveolar epithelium and angiogenesis, as well as increased COX-2 expression were also observed in lung tissues of AFG1-treated mice. Furthermore, we prolonged survival of the mice in the above model for another 6 months to examine the contribution of AFG1-induced chronic inflammation to lung tumorigenesis. Twelve months later, we observed that AFG1 induced alveolar epithelial hyperplasia and adenocarcinoma in Balb/c mice. Up-regulation of NF-kappaB, p-STAT3, and COX-2 was also induced in lung adenocarcinoma, thus establishing a link between AFG1 induced chronic inflammation and lung tumorigenesis. This is the first study to show that oral administration of AFG1 could induce chronic lung inflammation, which may provide a pro-tumor microenvironment to contribute to lung tumorigenesis. PMID- 25445584 TI - Comparative proteomic analysis of outer membrane vesicles from Shigella flexneri under different culture conditions. AB - The production of outer membrane vesicles (OMVs) is a common and regulated process of gram-negative bacteria. Nonetheless, the processes of Shigella flexneri OMV production still remain unclear. S. flexneri is the causative agent of endemic shigellosis in developing countries. The Congo red binding of strains is associated with increased infectivity of S. flexneri. Therefore, understanding the modulation pattern of OMV protein expression induced by Congo red will help to elucidate the bacterial pathogenesis. In the present study, we investigated the proteomic composition of OMVs and the change in OMV protein expression induced by Congo red using mTRAQ-based quantitative comparative proteomics. mTRAQ labelling increased the confidence in protein identification, and 148 total proteins were identified in S. flexneri-derived OMVs. These include a variety of important virulence factors, including Ipa proteins, TolC family, murein hydrolases, and members of the serine protease autotransporters of Enterobacteriaceae (SPATEs) family. Among the identified proteins, 28 and five proteins are significantly up- and down-regulated in the Congo red-induced OMV, respectively. Additionally, by comprehensive comparison with previous studies focused on DH5a-derived OMV, we identified some key node proteins in the protein protein interaction network that may be involved in OMV biogenesis and are common to all gram-negative bacteria. PMID- 25445586 TI - Molecular cloning and characterization of a tyrosine phosphatase from Monosiga brevicollis. AB - Protein tyrosine phosphorylation is thought to be a unique feature of multicellular animals. Interestingly, the genome of the unicellular protist Monosiga brevicollis reveals a surprisingly high number and diversity of protein tyrosine kinases, protein tyrosine phosphatases (PTPs), and phosphotyrosine binding domains. Our study focuses on a hypothetical SH2 domain-containing PTP (SHP), which interestingly has a predicted structure that is distinct from SHPs found in animals. In this study, we isolated cDNA of the enzyme and discovered that its actual sequence was different from the predicted sequence as a result of non-consensus RNA splicing. Contrary to the predicted structure with one SH2 domain and a disrupted phosphatase domain, Monosiga brevicollis SHP (MbSHP) contains two SH2 domains and an intact PTP domain, closely resembling SHP enzymes found in animals. We further expressed the full-length and SH2 domain-truncated forms of the enzyme in Escherichiacoli cells and characterized their enzymatic activities. The double-SH2 domain-truncated form of the enzyme effectively dephosphorylated a common PTP substrate with a specific activity among the highest in characterized PTPs, while the full-length and the N-terminal SH2 domain-truncated forms of the enzyme showed much lower activity with altered pH dependency and responses to ionic strength and common PTP inhibitors. This indicates that SH2 domains suppress the catalytic activity. SHP represents a highly conserved ancient PTP, and studying MbSHP should provide a better understanding about the evolution of tyrosine phosphorylation. PMID- 25445587 TI - An in vitro hepatic zonation model with a continuous oxygen gradient in a microdevice. AB - In a hepatic lobule, different sets of metabolic enzymes are expressed in the periportal (PP) and pericentral (PC) regions, forming a functional zonation, and the oxygen gradient is considered a determinant of zone formation. It is desirable to reproduce lobular microenvironment in vitro, but incubation of primary hepatocytes in conventional culture dishes has been limited at fixed oxygen concentrations due to technical difficulties. We designed a cell culture microdevice with an oxygen gradient to reproduce the hepatic microenvironment in vitro. The oxygen gradient during cell culture was monitored using a laser assisted phosphorescence quenching method, and the cellular oxygen consumption rate could be estimated from changes in the gradient. Culture medium was continuously exchanged through microchannels installed in the device to maintain the oxygen gradient for a long term without transient hyper-oxygenation. The oxygen consumption rates of hepatocytes at 70.0mmHg and 31.4mmHg of partial oxygen pressure, which correspond to PP and PC regions in the microdevice, were 3.67*10(-10) and 3.15*10(-10)mol/s/10(6) cells, respectively. Antimycin A changed the oxygen gradient profile, indicating that cellular respiration can be estimated during cell culture. RT-PCR analysis of hepatocytes cultured under the oxygen gradient showed that mRNA expression of PEPCK and GK significantly increased in culture areas corresponding to PP and PC regions, respectively. These results indicate that the developed microdevice can reproduce the hepatic lobular microenvironment. The oxygen gradient in the microdevice can be closely controlled by changing the sizes of gas channels and the ambient oxygen concentration around the device; therefore, it could be expected to mimic the oxygen gradient of various organs, and it may be applicable to other pathological models. PMID- 25445585 TI - Cdk1, PKCdelta and calcineurin-mediated Drp1 pathway contributes to mitochondrial fission-induced cardiomyocyte death. AB - Myocardial ischemia-reperfusion (I/R) injury is one of the leading causes of death and disability worldwide. Mitochondrial fission has been shown to be involved in cardiomyocyte death. However, molecular machinery involved in mitochondrial fission during I/R injury has not yet been completely understood. In this study we aimed to investigate molecular mechanisms of controlling activation of dynamin-related protein 1 (Drp1, a key protein in mitochondrial fission) during anoxia-reoxygenation (A/R) injury of HL1 cardiomyocytes. A/R injury induced cardiomyocyte death accompanied by the increases of mitochondrial fission, reactive oxygen species (ROS) production and activated Drp1 (pSer616 Drp1), and decrease of inactivated Drp1 (pSer637 Drp1) while mitochondrial fusion protein levels were not significantly changed. Blocking Drp1 activity with mitochondrial division inhibitor mdivi1 attenuated cell death, mitochondrial fission, and Drp1 activation after A/R. Trolox, a ROS scavenger, decreased pSer616 Drp1 level and mitochondrial fission after A/R. Immunoprecipitation assay further indicates that cyclin dependent kinase 1 (Cdk1) and protein kinase C isoform delta (PKCdelta) bind Drp1, thus increasing mitochondrial fission. Inhibiting Cdk1 and PKCdelta attenuated the increases in pSer616 Drp1, mitochondrial fission, and cardiomyocyte death. FK506, a calcineurin inhibitor, blocked the decrease in expression of inactivated pSer637 Drp1 and mitochondrial fission. Our findings reveal the following novel molecular mechanisms controlling mitochondrial fission during A/R injury of cardiomyocytes: (1) ROS are upstream initiators of mitochondrial fission; and (2) the increased mitochondrial fission is resulted from both increased activation and decreased inactivation of Drp1 through Cdk1, PKCdelta, and calcineurin-mediated pathways, respectively. PMID- 25445588 TI - Lack of REDD1 reduces whole body glucose and insulin tolerance, and impairs skeletal muscle insulin signaling. AB - A lack of the REDD1 promotes dysregulated growth signaling, though little has been established with respect to the metabolic role of REDD1. Therefore, the goal of this study was to determine the role of REDD1 on glucose and insulin tolerance, as well as insulin stimulated growth signaling pathway activation in skeletal muscle. First, intraperitoneal (IP) injection of glucose or insulin were administered to REDD1 wildtype (WT) versus knockout (KO) mice to examine changes in blood glucose over time. Next, alterations in skeletal muscle insulin (IRS-1, Akt, ERK 1/2) and growth (4E-BP1, S6K1, REDD1) signaling intermediates were determined before and after IP insulin treatment (10min). REDD1 KO mice were both glucose and insulin intolerant when compared to WT mice, evident by higher circulating blood glucose concentrations and a greater area under the curve following IP injections of glucose or insulin. While the REDD1 KO exhibited significant though blunted insulin-stimulated increases (p<0.05) in Akt S473 and T308 phosphorylation versus the WT mice, acute insulin treatment has no effect (p<0.05) on REDD1 KO skeletal muscle 4E-BP1 T37/46, S6K1 T389, IRS-1 Y1222, and ERK 1/2 T202/Y204 phosphorylation versus the WT mice. Collectively, these novel data suggest that REDD1 has a more distinct role in whole body and skeletal muscle metabolism and insulin action than previously thought. PMID- 25445589 TI - Development of a bioautographic method for the detection of lipase inhibitors. AB - An autobiographic method based on the thin layer chromatogram was developed by using the chemical system that comprises p-Nitrophenyl butyrate and bromothymol blue for detecting the lipase inhibitor. Lipase inhibitory zones were visualized as blue spots against the greenish yellow background. This method could able to detect the well known lipase inhibitor, orlistat up to the concentration of 1ng which is better than the earlier method. This method could also able to detect the lipase inhibition activities from the un-explored species of Streptomyces. The developed method can be used not only for the screening of unknown samples for the lipase inhibitors but also for the purification of the lipase inhibitors from the unknown samples. PMID- 25445590 TI - Aculeatin, a coumarin derived from Toddalia asiatica (L.) Lam., enhances differentiation and lipolysis of 3T3-L1 adipocytes. AB - Toddalia asiatica (L.) Lam. (T. asiatica) has been utilized traditionally for medicinal purposes such as the treatment of diabetes. Currently, the extract is considered to be a good source of anti-diabetic agents, but the active compounds have yet to be identified. In this study, we investigated the effects of fractionated T. asiatica extracts on the differentiation of 3T3-L1 preadipocytes and identified aculeatin as a potential active agent. When 3T3-L1 preadipocytes were treated with aculeatin isolated from T. asiatica in the presence of insulin, aculeatin increased cellular triglyceride levels and glycerol-3-phosphate dehydrogenase activity. This indicated that aculeatin could enhance the differentiation of preadipocytes into adipocytes. Further analyses using a DNA microarray and real-time quantitative reverse-transcription PCR showed an increase in the expression of peroxisome proliferator-activated receptor-gamma target genes (Pparg, Ap2, Cd36, Glut4 and Adipoq) by aculeatin, suggesting that aculeatin enhances the differentiation of 3T3-L1 cells by modulating the expression of genes critical for adipogenesis. Interestingly, after treatment of differentiated adipocytes with aculeatin, glucose uptake and lipolysis were enhanced. Overall, our results suggested that aculeatin is an active compound in T. asiatica for enhancing both differentiation and lipolysis of adipocytes, which are useful for the treatment of lipid abnormalities as well as diabetes. PMID- 25445591 TI - Protein kinase C regulates vascular calcification via cytoskeleton reorganization and osteogenic signaling. AB - Vascular calcification is an active cell-mediated process that reduces elasticity of blood vessels and increases blood pressure. Until now, the molecular basis of vascular calcification has not been fully understood. We previously reported that microtubule disturbances mediate vascular calcification. Here, we found that protein kinase C (PKC) signaling acted as a novel coordinator between cytoskeletal changes and hyperphosphatemia-induced vascular calcification. Phosphorylation and expression of both PKCalpha and PKCdelta decreased during inorganic phosphate (Pi)-induced vascular smooth muscle cell (VSMC) calcification. Knockdown of PKC isoforms by short interfering RNA as well as PKC inactivation by Go6976 or rottlerin treatment revealed that specific inhibition of PKCalpha and PKCdelta accelerated Pi-induced calcification both in VSMCs and ex vivo aorta culture through upregulation of osteogenic signaling. Additionally, inhibition of PKCalpha and PKCdelta induced disassembly of microtubule and actin, respectively. In summary, our results indicate that cytoskeleton perturbation via PKCalpha and PKCdelta inactivation potentiates vascular calcification through osteogenic signal induction. PMID- 25445592 TI - A chimeric antigen receptor for TRAIL-receptor 1 induces apoptosis in various types of tumor cells. AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its associated receptors (TRAIL-R/TR) are attractive targets for cancer therapy because TRAIL induces apoptosis in tumor cells through TR while having little cytotoxicity on normal cells. Therefore, many agonistic monoclonal antibodies (mAbs) specific for TR have been produced, and these induce apoptosis in multiple tumor cell types. However, some TR-expressing tumor cells are resistant to TR specific mAb-induced apoptosis. In this study, we constructed a chimeric antigen receptor (CAR) of a TRAIL-receptor 1 (TR1)-specific single chain variable fragment (scFv) antibody (TR1-scFv-CAR) and expressed it on a Jurkat T cell line, the KHYG-1 NK cell line, and human peripheral blood lymphocytes (PBLs). We found that the TR1-scFv-CAR-expressing Jurkat cells killed target cells via TR1 mediated apoptosis, whereas TR1-scFv-CAR-expressing KHYG-1 cells and PBLs killed target cells not only via TR1-mediated apoptosis but also via CAR signal-induced cytolysis, resulting in cytotoxicity on a broader range if target cells than with TR1-scFv-CAR-expressing Jurkat cells. The results suggest that TR1-scFv-CAR could be a new candidate for cancer gene therapy. PMID- 25445593 TI - Epithelial-mesenchymal transition of A549 cells is enhanced by co-cultured with THP-1 macrophages under hypoxic conditions. AB - Epithelial-mesenchymal transition (EMT) is associated with pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF). In this study, we investigated EMT of human pulmonary epithelial-derived cells (A549). A549 cells was either cultured by itself or co-cultured with THP-1 macrophages under normoxic (21% O2) and hypoxic (2% O2) conditions. We evaluated the presence of EMT by determining the expression of EMT markers, E-cadherin, vimentin, and fibronectin. To determine the role of TGF-beta1 and IL-1beta in EMT of the A549 cells, we analyzed the effects of blocking their activity with TGF-beta1 inhibitor or IL 1beta neutralizing antibody respectively. The A549 cells presented EMT when they were co-cultured with THP-1 macrophages. The EMT of the A549 cells co-cultured with THP-1 macrophages was exacerbated under hypoxia. In addition, the EMT were prevented by the addition of TGF-beta1 type I receptor kinase inhibitor. The hypoxic condition increased the mRNA levels of TGF-beta1 in A549 cells and THP-1 macrophages and that of IL-1beta in THP-1 macrophages when each cells were co cultured. Anti-IL-1beta neutralizing antibody attenuated TGF-beta1 secretion in co-culture media under hypoxic conditions. Thus, the IL-1beta from THP-1 macrophages up-regulated the TGF-beta1 from A549 cells and THP-1 macrophages, and then the TGF-beta1 from both cells induced and promoted the EMT of A549 cells when they were co-cultured under hypoxia. Together, these results demonstrate that the interaction between type II pneumocytes and macrophages under hypoxia is necessary for the development of pulmonary fibrosis. PMID- 25445594 TI - Histone deacetylase1 promotes TGF-beta1-mediated early chondrogenesis through down-regulating canonical Wnt signaling. AB - Cartilage formation during both embryonic development and bone repairing processes involves mesenchymal stem cells (MSCs) differentiation. Wnt/beta catenin signaling pathway inhibits early chondrogenesis and is down-regulated during Transforming growth factor-beta1 (TGF-beta1)-induced chondrogenesis. However, the regulatory molecules that participate in the process is unknown. This study was designed to investigate the underlying mechanisms that down regulate Wnt/beta-catenin pathway during chondrogenesis. TGF-beta1-induced micromass cultures of C3H10T1/2 were used as chondrocyte differentiation model. Gene expression profile was detected by realtime-PCR. Regulatory role of HDAC1 on beta-catenin was investigated by luciferase assay, chromatin immunoprecipitation (ChIP) assay, co-immunoprecipitation (Co-IP) assay and in vitro ubiquitination assay. In this study, we showed that HDAC1 was induced and suppressed beta catenin gene expression through direct binding to its promoter. Besides, HDAC1 could also interact with deacetylate beta-catenin protein through its deacetylase domain, which causes degradation of beta-catenin. Our results indicate that HDAC1 plays an important role in chondrogenesis and may represent a therapeutic target for modulation of cartilage development. PMID- 25445595 TI - Nanog positively regulates Zfp57 expression in mouse embryonic stem cells. AB - To maintain the self-renewal of embryonic stem (ES) cells, several core transcription factors, including Oct3/4, STAT3, and Nanog, regulate the expression of their target genes. Zinc finger protein 57 (Zfp57) is specifically expressed in self-renewing ES cells and its expression level is reduced upon ES cell differentiation, suggesting that expression of this transcription factor is regulated by core transcription factors. In the present study, we investigated whether Zfp57 expression is regulated by Nanog. Nanog overexpression resulted in the upregulation of Zfp57. On the other hand, knockdown of Nanog reduced the expression level of Zfp57. In addition, we identified the Nanog-responsive region in the promoter of the Zfp57 gene. These results suggest that Nanog is an upstream regulator of Zfp57. Moreover, Nanog overexpression promoted the growth of ES cells in soft agar and this was suppressed by Zfp57 knockdown, suggesting that the Nanog/Zfp57 pathway plays a central role in anchorage-independent growth of ES cells. Interestingly, NANOG overexpression also led to the upregulation of ZFP57 in two human tumor cell lines. Taken together, our results suggest that Nanog positively regulates Zfp57 expression in multiple types of cells. PMID- 25445596 TI - Activation of AMPK participates hydrogen sulfide-induced cyto-protective effect against dexamethasone in osteoblastic MC3T3-E1 cells. AB - Long-time glucocorticoids (GCs) usage causes osteoporosis. In the present study, we explored the potential role of hydrogen sulfide (H2S) against dexamethasone (Dex)-induced osteoblast cell damage, and focused on the underlying mechanisms. We showed that two H2S-producing enzymes, cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), were significantly downregulated in human osteonecrosis tissues as well as in Dex-treated osteoblastic MC3T3-E1 cells. H2S donor NaHS as well as the CBS activator S-adenosyl-l-methionine (SAM) inhibited Dex-induced viability reduction, death and apoptosis in MC3T3-E1 cells. NaHS activated adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling, which participated its cyto-protective activity. AMPK inhibition by its inhibitor (compound C) or reduction by targeted-shRNA suppressed its pro survival activity against Dex in MC3T3-E1 cells. Further, we found that NaHS inhibited Dex-mediated reactive oxygen species (ROS) production and ATP depletion. Such effects by NaHS were again inhibited by compound C and AMPKalpha1 shRNA. In summary, we show that H2S inhibits Dex-induced osteoblast damage through activation of AMPK signaling. H2S signaling might be further investigated as a novel target for anti-osteoporosis treatment. PMID- 25445597 TI - Isolation and characterization of an antifungal protein from Bacillus licheniformis HS10. AB - Bacillus licheniformis HS10 is a good biocontrol agent against Pseudoperonospora cubensis which caused cucumber downy disease. To identify and characterize the antifungal proteins produced by B.licheniformis HS10, the proteins from HS10 were isolated by using 30-60% ammonium sulfate precipitation, and purified with column chromatography on DEAE Sepharose Fast Flow, RESOURCE Q and Sephadex G-75. And the SDS-PAGE and MALDI-TOF/TOF-MS analysis results demonstrated that the antifungal protein was a monomer with molecular weight of about 55 kDa, identified as carboxypeptidase. Our experiments also showed that the antifungal protein from B. licheniformis HS10 had significantly inhibition on eight different kinds of plant pathogenic fungi, and it was stable with good biological activity at as high as 100 degrees C for 30 min and in pH value ranged from 6 to 10. The biological activity was negatively affected by protease K and 10mM metal cations except Ca(2+). PMID- 25445598 TI - Oral supplementation with a combination of L-citrulline and L-arginine rapidly increases plasma L-arginine concentration and enhances NO bioavailability. AB - BACKGROUND: Chronic supplementation with L-citrulline plus L-arginine has been shown to exhibit anti-atherosclerotic effects. However, the short-term action of this combination on the nitric oxide (NO)-cGMP pathway remains to be elucidated. The objective of the present study was to investigate the acute effects of a combination of oral L-citrulline and L-arginine on plasma L-arginine and NO levels, as well as on blood circulation. METHODS: Rats or New Zealand white rabbits were treated orally with L-citrulline, or L-arginine, or a combination of each at half dosage. Following supplementation, plasma levels of L-arginine, NOx, cGMP and changes in blood circulation were determined sequentially. RESULTS: L Citrulline plus L-arginine supplementation caused a more rapid increase in plasma L-arginine levels and marked enhancement of NO bioavailability, including plasma cGMP concentrations, than with dosage with the single amino acids. Blood flow in the central ear artery in rabbits was also significantly increased by L citrulline plus L-arginine administration as compared with the control. CONCLUSION: Our data show for the first time that a combination of oral L citrulline and L-arginine effectively and rapidly augments NO-dependent responses at the acute stage. This approach may have clinical utility for the regulation of cardiovascular function in humans. PMID- 25445599 TI - ATF3 represses PPARgamma expression and inhibits adipocyte differentiation. AB - Activating transcription factor 3 (ATF3) is a stress-adaptive transcription factor that mediates cellular stress response signaling. We previously reported that ATF3 represses CCAAT/enhancer binding protein alpha (C/EBPalpha) expression and inhibits 3T3-L1 adipocyte differentiation. In this study, we explored potential role of ATF3 in negatively regulating peroxisome proliferator activated receptor-gamma (PPARgamma). ATF3 decreased the expression of PPARgamma and its target gene in 3T3-L1 adipocytes. ATF3 also repressed the activity of -2.6Kb promoter of mouse PPARgamma2. Overexpression of PPARgamma significantly prevented the ATF3-mediated inhibition of 3T3-L1 differentiation. Transfection studies with 5' deleted-reporters showed that ATF3 repressed the activity of -2037bp promoter, whereas it did not affect the activity of -1458bp promoter, suggesting that ATF3 responsive element is located between the -2037 and -1458. An electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that ATF3 binds to ATF/CRE site (5'-TGACGTTT-3') between -1537 and -1530. Mutation of the ATF/CRE site abrogated ATF3-mediated transrepression of the PPARgamma2 promoter. Treatment with thapsigargin, endoplasmic reticulum (ER) stress inducer, increased ATF3 expression, whereas it decreased PPARgamma expression. ATF3 knockdown significantly blocked the thapsigargin-mediated downregulation of PPARgamma expression. Furthermore, overexpression of PPARgamma prevented inhibition of 3T3-L1 differentiation by thapsigargin. Collectively, these results suggest that ATF3-mediated inhibition of PPARgamma expression may contribute to inhibition of adipocyte differentiation during cellular stress including ER stress. PMID- 25445600 TI - Perillaldehyde attenuates cerebral ischemia-reperfusion injury-triggered overexpression of inflammatory cytokines via modulating Akt/JNK pathway in the rat brain cortex. AB - Perillaldehyde (PAH), one of the major oil components in Perilla frutescens, has anti-inflammatory effects. Few studies have examined the neuroprotective effect of PAH on stroke. So the aim of our study is to investigate the effect of PAH on ischemia-reperfusion-induced injury in the rat brain cortex. Middle cerebral artery occlusion (MCAO) model was selected to make cerebral ischemia-reperfusion injury. Rats were assigned randomly to groups of sham, MCAO, and two treatment groups by PAH at 36.0, 72.0mg/kg. Disease model was set up after intragastrically (i.g.) administering for 7 consecutive days. The neurological deficit, the cerebral infarct size, biochemical parameters and the relative mRNA and protein levels were examined. The results showed that the NO level, the iNOS activity, the neurological deficit scores, the cerebral infarct size and the expression of inflammatory cytokines including interleukin (IL)-1beta, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha were significantly decreased by PAH treatment. PAH also increased the Phospho-Akt level and decrease the Phospho-JNK level by Western blot analysis. Meanwhile, the PAH groups exhibited a dramatically decrease of apoptosis-related mRNA expression such as Bax and caspase-3. Our findings shown that PAH attenuates cerebral ischemia/reperfusion injury in the rat brain cortex, and suggest its neuroprotective effect is relate to regulating the inflammatory response through Akt /JNK pathway. The activation of this signalling pathway eventually inhibits apoptotic cell death induced by cerebral ischemia-reperfusion. PMID- 25445602 TI - Comparative analysis of CRISPR loci in different Listeria monocytogenes lineages. AB - Listeria monocytogenes, an important food-borne pathogen, causes high mortality rate of listeriosis. Pan-genomic comparisons revealed the species genome of L. monocytogenes is highly stable but not completely clonal. The population structure of this species displays at least four evolutionary lineages (I-IV). Isolates of different lineages displayed distinct genetic, phenotypic and ecologic characteristics, which appear to affect their ability to be transmitted through foods and to cause human disease, as well as their ability to thrive in markedly phage-rich environments. CRISPR (clustered regularly interspaced short palindrome repeats), a recently described adaptive immunity system, not only confers defense against invading elements derived from bacteriophages or plasmids in many bacteria and archaeal, but also displays strains-level variations in almost any given endowed species. This work was aimed to investigate CRISPR diversity in L. monocytogenes strains of different lineages and estimated the potential practicability of the CRISPR-based approach to resolve this species' biodiversity. Only a third of strains contained all three CRISPR loci (here defined as LMa, LMb and LMc) at same time. Combined the strain-level variations in presence/absence of each CRISPR locus and its relative size and spacer arrangements, a total of 29 CRISPR genotypes and 11 groups were defined within a collection of 128 strains covering all serotypes. The CRISPR-based approach showed powerful ability to subtype the more commonly food-borne isolates of serotype 1/2a (lineage II) and serotypes 1/2b (lineage I), but limited by the absence of typical CRISPR structure in many lineage I isolates. Strikingly, we found a long associated cas1 gene as well as two self-targeting LMb spacers accidently homologous with endogenous genes in a fraction of serotype 1/2a isolations, demonstrated that CRISPR I B system might involve in bacterial physiology besides antiviral immunity. PMID- 25445601 TI - RBP-J-interacting and tubulin-associated protein induces apoptosis and cell cycle arrest in human hepatocellular carcinoma by activating the p53-Fbxw7 pathway. AB - Aberrant Notch signaling is observed in human hepatocellular carcinoma (HCC) and has been associated with the modulation of cell growth. However, the role of Notch signaling in HCC and its underlying mechanism remain elusive. RBP-J interacting and tubulin-associated (RITA) mediates the nuclear export of RBP-J to tubulin fibers and downregulates Notch-mediated transcription. In this study, we found that RITA overexpression increased protein expression of p53 and Fbxw7 and downregulated the expression of cyclin D1, cyclin E, CDK2, Hes-1 and NF-kappaB p65. These changes led to growth inhibition and induced G0/G1 cell cycle arrest and apoptosis in SMMC7721 and HepG2 cells. Our findings indicate that RITA exerts tumor-suppressive effects in hepatocarcinogenesis through induction of G0/G1 cell cycle arrest and apoptosis and suggest a therapeutic application of RITA in HCC. PMID- 25445603 TI - High abundant protein removal from rodent blood for biomarker discovery. AB - In order to realize the goal of stratified and/or personalized medicine in the clinic, significant advances in the field of biomarker discovery are necessary. Adding to the abundance of nucleic acid biomarkers being characterized, additional protein biomarkers will be needed to satisfy diverse clinical needs. An appropriate source for finding these biomarkers is within blood, as it contains tissue leakage factors as well as additional proteins that reside in blood that can be linked to the presence of disease. Unfortunately, high abundant proteins and complexity of the blood proteome present significant challenges for the discovery of protein biomarkers from blood. Animal models often enable the discovery of biomarkers that can later be translated to humans. Therefore, determining appropriate sample preparation of proteomic samples in rodent models is an important research goal. Here, we examined both mouse and rat blood samples (including both serum and plasma), for appropriate high abundant protein removal techniques for subsequent gel-based proteomic experiments. We assessed four methods of albumin removal: antibody-based affinity chromatography (MARS), Cibacron(r) Blue-based affinity depletion (SwellGel(r) Blue Albumin Removal Kit), protein-based affinity depletion (ProteaPrep Albumin Depletion Kit) and TCA/acetone precipitation. Albumin removal was quantified for each method and SDS PAGE and 2-DE gels were used to quantify the number of protein spots obtained following albumin removal. Our results suggest that while all four approaches can effectively remove high abundant proteins, antibody-based affinity chromatography is superior to the other three methods. PMID- 25445604 TI - Preparation and anti-osteoporotic activities in vivo of phosphorylated peptides from Antarctic krill (Euphausia superba). AB - Antarctic krill (Euphausia superba) protein serves as a novel sustainable protein source for human. Krill protein isolate was phosphorylated by the dry-heating method with sodium pyrophosphate. Phosphorylated peptides from Antarctic krill (PP-AKP) were obtained from phosphorylated protein through tryptic hydrolysis. Two types of phosphate bonds were introduced by phosphorylation, i.e. PO and PO bonds. The anti-osteoporotic activities of PP-AKP at two doses (400 and 800mg/kg body weight) were investigated with an osteoporotic rat model, which was established with bilateral ovariectomy surgery. Different doses of PP-AKP were given intraperitoneal injections to rats once a day with alendronate as a positive control. Phosphorylated peptides from Antarctic krill dose-dependently preserved bone mineral density in osteoporotic rats by increasing the degree of bone mineralization. Both trabecular and cortical bone strength in osteoporotic rats was significantly improved with PP-AKP treatment. The mechanism by which PP AKP augmented bone mineral density and bone strength was relation to the reduction in osteoclast-mediated bone remodeling, as was supported by the decrease in bone resorption markers. Phosphorylated peptides from Antarctic krill could be developed as functional food or nutritional supplements. PMID- 25445605 TI - Haloganan: a novel antimicrobial peptide for treatmentof wound infections. AB - HG1 is a Leu-rich antimicrobial peptide (AMP). Previously, the peptide was shown to lose its activity in human serum although it possessed potent and broad spectrum antimicrobial activity against a wide range of pathogenic microbes. In an attempt to design an HG1 isomer that can overcome the problem of HG1, a structure-activity relationship study was conducted by substitution of each of five Leu residues with a Gln residue. Each substitute was tested for its antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) or Candida strains. In addition, the antimicrobial activity of HG1 isomers was examined in the presence of glycosaminoglycans or lipid components occurring in the extracellular matrix, human serum and wound fluid. As a result, it was determined that the third residue (Leu) in the sequence of HG1 was mainly responsible for abrogation of its antimicrobial activity in human serum or wound fluid. An HG1 isomer (L3Q) with a Gln-3 substitution exhibited a potent antibacterial activity in 50% human serum. While the anti-MRSA activity of L3Q was equivalent to that of HG1, its anti-Candida activity was found to be substantially reduced. In order to improve anti-Candida activity of L3Q, its cationicity was enhanced by replacement of the C-terminal Ala-19 with a Lys residue. Overall, an HG1 isomer with two substitutions of Gln-3 and Lys-19, named haloganan, was verified to have an advantage over HG1 in that it exerted its potent antimicrobial activity under conditions containing human serum and/or wound fluid. PMID- 25445606 TI - The predictive value of the first-trimester maternal serum chemerin level for pre eclampsia. AB - Chemerin is a novel adipokine linked to inflammation. The cross-sectional studies have reported that maternal chemerin serum concentrations are significantly increased in pre-eclampsia. However, limited data are available regarding the cause-effect relationship between chemerin and pre-eclampsia. The aim of this prospective observational study was to evaluate predictive significance of the first-trimester maternal serum chemerin levels for pre-eclampsia and to further confirm the hypothesis that chemerin is an important causative factor in the pathogenesis of pre-eclampsia. 518 pregnancy women were recruited. The first trimester maternal serum chemerin levels were determined using enzyme-linked immunosorbent assay. The first-trimester maternal serum chemerin levels were statistically significantly elevated in women with pre-eclampsia compared with those without pre-eclampsia and in severe pre-eclampsia women compared with mild pre-eclampsia women. Serum chemerin levels remained positively associated with plasma C-reactive protein levels using a linear regression model. A logistic regression analysis demonstrated that body mass index and serum chemerin levels appeared to be the independent predictors of pre-eclampsia. A receiver-operating characteristic curve analysis identified that serum chemerin levels predicted pre eclampsia with high predictive value. The predictive value of the chemerin concentrations was similar to that of body mass index. Chemerin improved the predictive value of body mass index statistically significantly. Thus, our results suggest that high serum chemerin levels are associated with inflammation and pre-eclampsia independently, as well as chemerin may play a role as predictive biomarker for pre-eclampsia and be an important causative factor in the pathogenesis of pre-eclampsia. PMID- 25445607 TI - The role of apelin-13 in novel object recognition memory. AB - Apelin and its receptor APJ (apelin receptor) are prominently expressed in brain regions involved in learning and memory. However, the role of apelin in cognition was largely unclear. Here, the role of apelin-13 in memory processes was investigated in mice novel object recognition task. Post-training injection of apelin-13 (0.3 and 1 nmol) dose-dependently impaired short-term memory (STM), however, pre-training infusion of apelin-13 (1 nmol) did not affect STM, suggesting apelin-13 blocks formation but not acquisition of STM. Apelin-13 (1 nmol) administered immediately, 30, 60 or 120 min post-training impaired long term memory (LTM) in a time-dependent manner (30 min), however, both pre-training and pre-test infusion of apelin-13 (1 nmol) did not affect LTM, suggesting apelin 13 impaired consolidation but not acquisition and recall of LTM. Taken together, for the first time, our results indicate that apelin-13 blocks STM formation and LTM consolidation in novel object recognition task. PMID- 25445608 TI - Effect of endogenous galanin on glucose transporter 4 expression in cardiac muscle of type 2 diabetic rats. AB - Although galanin has been shown to increase glucose transporter 4 (GLUT4) expression in skeletal muscle and adipocytes of rats, there is no literature available about the effect of galanin on GLUT4 expression in cardiac muscle of type 2 diabetic rats. In this study, we investigated the relationship between intracerebroventricular administration of M35, a galanin receptor antagonist, and GLUT4 expression in cardiac muscle of type 2 diabetic rats. The rats tested were divided into four groups: rats from healthy and type 2 diabetic drug groups were injected with 2 MUM M35 for three weeks, while both control groups with 2 MUl vehicle control. The euglycemic-hyperinsulinemic clamp test was conducted for an index of glucose infusion rates. The cardiac muscle was processed for determination of GLUT4 expression levels. The present study showed that the plasma insulin and retinol binding protein 4 (RBP4) levels were higher in both drug groups than controls respectively. Moreover, the results showed the inhibitive effect of central M35 treatment on glucose infusion rates in the euglycemic-hyperinsulinemic clamp test and GLUT4 expression levels in the cardiac muscle. These results demonstrate that endogenous galanin, acting through its central receptor, has an important attribute to increase GLUT4 expression, leading to enhance insulin sensitivity and glucose uptake in cardiac muscle of type 2 diabetic rats. Galanin and its fragment can play a significant role in regulation of glucose metabolic homeostasis in cardiac muscle and galanin is an important hormone relative to diabetic heart. PMID- 25445609 TI - A study of effects of peptide fragments of bovine and human lactoferrins on activities of three key HIV-1 enzymes. AB - The intent of this study was to examine human and bovine lactoferrin fragments including lactoferrin (1-11), lactoferricin and lactoferrampin, all of which did not demonstrate hemolytic activity toward rabbit erythrocytes at 1 mM concentration, for possible inhibitory effects on the activities of HIV-1 reverse transcriptase, protease and integrase. The data showed that human lactoferricin was the most potent in inhibiting HIV-1 reverse transcriptase (IC50 =2 MUM). Bovine lactoferricin (IC50 = 10 MUM) and bovine lactoferrampin (IC50 = 150 MUM) were less potent. Human lactoferrampin and human and bovine lactoferrin (1-11) at 1 mM concentration did not exhibit any inhibitory effect on HIV-1 reverse transcriptase. All peptides showed only a slight inhibitory effect (from slightly below 2% to 6% inhibition) on HIV-1 protease. Human lactoferrampin and bovine lactoferrampin showed obvious inhibitory effect on HIV-1 integrase at 37 MUM and 18.5 MUM, respectively. The HIV-1 integrase inhibitory activity of human lactoferrampin and bovine lactoferrampin was dose-dependent. The other peptides were devoid of HIV-1 integrase inhibitory activity. Thus, it is concluded that some lactoferrin fragments exert an inhibitory action on HIV-1 reverse transcriptase and HIV-1 integrase. PMID- 25445610 TI - Trefoil factors (TFFs) are increased in bronchioalveolar lavage fluid from patients with chronic obstructive lung disease (COPD). AB - Trefoil factors (TFFs) 1, 2 and 3 are small polypeptides that are co-secreted with mucin throughout the body. They are up-regulated in cancer and inflammatory processes in the gastrointestinal system, where they are proposed to be involved in tissue regeneration, proliferation and protection. Our aim was to explore their presence in pulmonary secretions and to investigate whether they are up regulated in pulmonary diseases characterized by mucin hypersecretion. Bronchioalveolar lavage fluid was obtained from 92 individuals referred to bronchoscopy. The patients were grouped according to diagnosis and pulmonary function. The concentrations of TFF1, TFF2 and TFF3 were measured by ELISA. All three peptides were detected in bronchioalveolar lavage fluid. Patients with chronic obstructive pulmonary disease had concentrations two to three times above the levels in the healthy reference group, and patients with pulmonary malignancies had concentrations of TFF1 and TFF2 three times that of the reference group. The results suggest that TFFs are involved in tissue regeneration, proliferation and protection in lung diseases. PMID- 25445611 TI - The effects of D-allose on transient ischemic neuronal death and analysis of its mechanism. AB - The present study investigates the neuroprotective effects of d-allose, a rare sugar, against ischemia/reperfusion injury in a gerbil model. Transient forebrain ischemia was induced by occlusion of the bilateral common carotid arteries for 5 min. D-Allose was intravenously injected before and after ischemia (200 mg/kg). Extracellular glutamate and lactate release from the gerbil brain, and PO2 profiles were monitored during ischemia and reperfusion. We also examined neuronal death and oxidative damage in the hippocampus one week after ischemia reperfusion, and investigated functional outcome. D-Allose administration suppressed glutamate and lactate release compared to vehicle controls. Brain damage, 8-OHdG levels (a marker of oxidative stress) and locomotor activities were significantly decreased by D-allose treatment. The present results suggest that d-allose reduces delayed neuronal death and behavioral deficits after transient ischemia by changing cerebral metabolism and inhibiting oxidative stress. PMID- 25445612 TI - Acetylcholine, GABA and neuronal networks: a working hypothesis for compensations in the dystrophic brain. AB - Duchenne muscular dystrophy (DMD), a genetic disease arising from a mutation in the dystrophin gene, is characterized by muscle failure and is often associated with cognitive deficits. Studies of the dystrophic brain on the murine mdx model of DMD provide evidence of morphological and functional alterations in the central nervous system (CNS) possibly compatible with the cognitive impairment seen in DMD. However, while some of the alterations reported are a direct consequence of the absence of dystrophin, others seem to be associated only indirectly. In this review we reevaluate the literature in order to formulate a possible explanation for the cognitive impairments associated with DMD. We present a working hypothesis, demonstrated as an integrated neuronal network model, according to which within the cascade of events leading to cognitive impairments there are compensatory mechanisms aimed to maintain functional stability via perpetual adjustments of excitatory and inhibitory components. Such ongoing compensatory response creates continuous perturbations that disrupt neuronal functionality in terms of network efficiency. We have theorized that in this process acetylcholine and network oscillations play a central role. A better understating of these mechanisms could provide a useful diagnostic index of the disease's progression and, perhaps, the correct counterbalance of this process might help to prevent deterioration of the CNS in DMD. Furthermore, the involvement of compensatory mechanisms in the CNS could be extended beyond DMD and possibly help to clarify other physio-pathological processes of the CNS. PMID- 25445614 TI - A lack of confirmation with alternative assays questions the validity of IL-17A expression in human neutrophils using immunohistochemistry. AB - We identified IL-17A-positive neutrophils in Wolbachia-positive Onchocerca volvulus nodules using an antibody that has previously reported IL-17A-positive neutrophils in several inflammatory conditions. However, we could not detect IL 17A using a range of alternative assays. Our data question the IL-17A antibody specificity and the ability of human neutrophils to express IL-17A. PMID- 25445615 TI - Thymus-deriving natural regulatory T cell generation in vitro: role of the source of activation signals. AB - In this research we have examined different sources of activation signals in order to optimize culture conditions for in vitro generation of thymus-deriving natural regulatory T cells (nTregs). We have established a novel model using JAWS II dendritic cell line of immature phenotype and compared it to commonly used methods for the generation of Tregs from peripheral lymphoid organs or blood T cells. In our model the first activation signal is provided by anti-CD3 monoclonal antibodies while the second is delivered by costimulatory molecules expressed on JAWS II cells. The presence of JAWS II cells co-cultured in vitro with unsorted thymocytes directly isolated from the thymus gland creates environment favoring SP CD4+ differentiation, provides the apoptotic cells clearance, maintains the survival of thymocytes and facilitate nTreg generation. Moreover the usage of immature dendritic cells stimuli enables to conduct research on agents affecting nTreg survival, proliferation and development in conditions of cell-to-cell contact of undifferentiated thymocytes with dendritic cells. PMID- 25445613 TI - The bacterial lysate Lantigen B reduces the number of acute episodes in patients with recurrent infections of the respiratory tract: the results of a double blind, placebo controlled, multicenter clinical trial. AB - Studies in the 1970s and 1980s reported that bacterial lysates (BL) had a prophylactic effect on recurrent respiratory tract infections (RRTI). However, controlled clinical study procedures have evolved substantially since then. We performed a trial using updated methods to evaluate the efficacy of Lantigen B(r), a chemical BL. This double blind, placebo controlled, multi-center clinical trial had the primary objective of assessing the capacity of Lantigen B to significantly reduce the total number of infectious episodes in patients with RRTI. Secondary aims were the RRTI duration, the frequency and the severity of the acute episodes, the use of drugs and the number of missed workdays. In the subgroup of allergic patients with RRTI, the number of allergic episodes (AE) and the use of anti-allergic drugs were also evaluated. One hundred and sixty patients, 79 allocated to the treated group (TG) and 81 to the placebo group (PG), were enrolled; 30 were lost during the study and 120 (79 females and 38 males) were evaluated. The PG had 1.43 episodes in the 8-months of follow-up while the TG had 0.86 episodes (p=0.036). A similar result was observed in the allergic patients (1.80 and 0.86 episodes for the PG and the TG, respectively, p=0.047). The use of antibiotics was reduced (mean 1.24 and 2.83 days of treatment for the TG and the PG). Logistic regression analysis indicated that the estimated risk of needing antibiotics and NSAIDs was reduced by 52.1 and 30.6%, respectively. With regard to the number of AE, no significant difference was observed between the two groups, but bronchodilators, antihistamines and local corticosteroids were reduced by 25.7%, 56.2% and 41.6%, respectively, in the TG. Lantigen B significantly reduced the number of infectious episodes in patients with RRTI. This finding suggests a first line use of this drug for the prophylaxis of infectious episodes in these patients. PMID- 25445616 TI - GITR promoter polymorphism contributes to risk of coal workers' pneumoconiosis: a case-control study from China. AB - BACKGROUND: Glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein (GITR) mainly affects the functions of effector T cells and regulatory T cells thus it may influence various diseases. Coal workers' pneumoconiosis (CWP) is a serious occupational disease worldwide. In the present study, we examined the association between the functional polymorphisms in GITR and risk of CWP in a Chinese population. METHODS: An association study analyzing three polymorphisms (rs3753348, rs2298213, and rs11466668) in GITR were performed in a case-control study including 693 patients with CWP and 690 controls. Genotyping was carried out by Taqman method. RESULTS: The GITR rs3753348 GG/GC genotypes significantly enhanced the risk of CWP (adjusted OR=1.32, 95%CI=1.02-1.71), compared with the CC genotype, particularly among subgroups of long exposure years (adjusted OR=1.47, 95%CI=1.06-2.04) and non-smokers (adjusted OR=1.45, 95%CI=1.01-2.09). Moreover, the polymorphism was significantly associated with risk for CWP cases with stage II. CONCLUSIONS: This is the first report revealing an association between the GITR rs3753348 polymorphism and CWP, and our results suggest that the GITR rs3753348 polymorphism may be involved in the development and susceptibility of CWP. PMID- 25445617 TI - Favorable immune phenotype predicts successful implantation and pregnancy. AB - Immune markers that may predict IVF failure and successful implantation and pregnancy were studied. Favorable immune parameters were selected based on 90% of data of women who got pregnant and had uneventful pregnancy course and outcome in present IVF cycle. Immune phenotype and NK cell activity of peripheral blood of 123 women with multiple IVF failure were studied by flow cytometry. Some parameters that were out of favorable borders (elevated expression of CD56, CD158a in T lymphocytes, decreased levels of CD4 T lymphocytes, up-regulated expression of HLA DR in CD8+ T cells and NK cells, elevated number of NK cells and increased NK cytotoxicity, increased and decreased expression of CD158a and CD8 in NK cells) were considered to be immune deviations (ID) potentially predictive for IVF failure. In women with 0-1 ID implantation rate (IR) was 50.9% (27/53), with two ID - 42.8% (12/28), with three and more ID - 21.4% (9/42). IR in group with three ID was lower than in group with 0-1 ID (p<0.01, OR=3.8, CI: 1.52-9.48) and in group with two ID (p<0.05). Live birth rate (LBR) in women with 0-1 ID was 33.9%, with two ID - 28.5%, with three and more ID - 9.5%. LBR in group with three ID was lower than in group with 0-1 ID (p<0.01, OR=4.8, CI: 1.52 15.8) and in group with two ID (p<0.05). The absence or single ID seems to be more favorable for successful IVF program. Combination of ID may predict implantation failure to a greater degree than isolated ID. Multiple immune deviations form unfavorable "immune phenotype" for implantation and pregnancy development. PMID- 25445618 TI - Mesenchymal stem cells ameliorate experimental autoimmune hepatitis by activation of the programmed death 1 pathway. AB - Previous studies have shown beneficial effects of mesenchymal stem cells (MSCs) transplantation in many autoimmune diseases. However, few studies have focused on the effects of MSCs on autoimmune hepatitis. In our study, we investigated the therapeutic effects of BMSCs (bone mesenchymal stem cells) transplantation in mouse experimental autoimmune hepatitis (EAH) and explored the potential mechanism. BMSCs were injected intravenously into EAH mice. Then, serum levels of ALT and AST, and pathologic alteration of liver tissue were measured to evaluate the liver function and inflammation degree. The expressions of programmed death ligand 1, IL-17 and IL-23 were detected by enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR), and western blotting. Upon serum biochemical levels and pathological examination, the BMSCs treated mice especially with multiple dosing administration showed significantly reduction of liver damage. Moreover, the expression of IL-17 was down-regulated by BMSCs intervention as compared to the model group, whereas the PD-L1 and IL-23 were up-regulated following the administration of MSCs. In conclusion, the results of this study suggest that BMSCs transplantation, especially on multiple dosing, may exert immunosuppression effect to ameliorate EAH through the inhibition of IL-17 and up-regulation of PD-L1. PMID- 25445619 TI - A novel 96-well multielectrode array based impedimetric monitoring platform for comparative drug efficacy analysis on 2D and 3D brain tumor cultures. AB - Aggressive cancer entities like neuroblastoma and glioblastoma multiforme are still difficult to treat and have discouraging prognosis in malignant stage. Since each tumor has its own characteristics concerning the sensitivity towards different chemotherapeutics and moreover, can obtain resistance, the development of novel chemotherapeutics with a broad activity spectrum, high efficacy and minimum side effects is a continuous process. Sophisticated in vitro assays for comprehensive prediction of in vivo drug efficacy and side effects represent an actual bottleneck in the drug development process. In this context, we developed a novel in vitro 2D and 3D multiwell-multielectrode device for drug efficacy monitoring based on direct real-time impedance spectroscopy measurement in combination with our unique 96-well multielectrode arrays and microcavity arrays. For demonstration, we used three neuro- and glioblastoma cell lines that were cultured as monolayer and multicellular tumor spheroids for recapitulating in vivo conditions. Using our novel 96-well multielectrode array based system it was possible to detect time and concentration dependent responses concerning treatment with doxorubicin, etoposide and vincristine. While all tested chemotherapeutics revealed high potency for apoptosis induction in neuroblastoma cells, etoposide was ineffective for glioblastoma cell lines. Determination of IC50 values allowed us to compare drug efficacy in 2D and 3D culture models and moreover, revealed chemotherapeutic and tumor cell line specific activity patterns. These pharmacokinetic patterns are of great interest in the context of preclinical drug development. Thus, impedance spectroscopy based monitoring systems could be used for the fast in vitro based in vivo prediction of novel anti-tumor drugs. PMID- 25445620 TI - Chemiluminescent imaging of transpired ethanol from the palm for evaluation of alcohol metabolism. AB - A 2-dimensional imaging system was constructed and applied in measurements of gaseous ethanol emissions from the human palm. This imaging system measures gaseous ethanol concentrations as intensities of chemiluminescence by luminol reaction induced by alcohol oxidase and luminol-hydrogen peroxide-horseradish peroxidase system. Conversions of ethanol distributions and concentrations to 2 dimensional chemiluminescence were conducted on an enzyme-immobilized mesh substrate in a dark box, which contained a luminol solution. In order to visualize ethanol emissions from human palm skin, we developed highly sensitive and selective imaging system for transpired gaseous ethanol at sub ppm-levels. Thus, a mixture of a high-purity luminol solution of luminol sodium salt HG solution instead of standard luminol solution and an enhancer of eosin Y solution was adapted to refine the chemiluminescent intensity of the imaging system, and improved the detection limit to 3 ppm gaseous ethanol. The highly sensitive imaging allows us to successfully visualize the emissions dynamics of transdermal gaseous ethanol. The intensity of each site on the palm shows the reflection of ethanol concentrations distributions corresponding to the amount of alcohol metabolized upon consumption. This imaging system is significant and useful for the assessment of ethanol measurement of the palmar skin. PMID- 25445622 TI - The risks of major osteoporotic fractures in patients with schizophrenia: a population-based 10-year follow-up study. AB - OBJECTIVE: The aim of the study is to explore the incidence and the risks associated with major osteoporotic fractures, all-cause mortality with osteoporotic fractures and the effect of the psychiatric drug exposure in patients with schizophrenia during a 10-year follow-up period. METHODS: Two nationwide cohorts were selected from the Taiwan National Health Insurance Research Database (NHIRD) consisting of 30,335 patients with schizophrenia (age >= 40 years) and 121,340 age- and sex-matched control participants without schizophrenia. The psychiatric proportion of days covered (PDC) is an indicator of the intensity of drug exposure in patients with schizophrenia. The incidence and risk factors of major osteoporotic fractures were calculated for both cohorts. Additionally, the patient survival rate after major osteoporotic fractures was also calculated. RESULTS: During a 10-year follow-up period, 1677 (5.53%) schizophrenia and 4257 (3.51%) control subjects had major osteoporotic fractures (P < 0.001). The schizophrenia patients with a PDC > 0.1 showed a significantly higher incidence of major osteoporotic fractures than did the non schizophrenia controls; however, those with a psychiatric PDC <= 0.1 did not. After adjustment, the psychiatric PDC was significantly and independently associated with the risk of major osteoporotic fractures except some medical morbidities but the schizophrenia diagnosis was not. In addition, among all 5934 patients with major osteoporotic fracture, the adjusted mortality hazard ratio for psychiatric PDC was 1.92 (95% CI = 1.63-2.26). CONCLUSIONS: Patients with schizophrenia are at a higher risk for major osteoporotic fractures than the general population and also have a higher mortality rate due to major osteoporotic fractures. These findings may be caused by psychiatric drug use rather than schizophrenia, which suggests that directions can be taken in future studies. PMID- 25445621 TI - White matter microstructure in schizophrenia: associations to neurocognition and clinical symptomatology. AB - BACKGROUND: Diffusion tensor imaging (DTI) studies in schizophrenia report widespread aberrations in brain white matter (WM). These appear related to poorer neurocognitive performance and higher levels of negative and positive symptomatology. However, identification of the most salient WM aberrations to neurocognition and clinical symptoms is limited by relatively small samples with divergent results. METHODS: We examined 53 well-characterized patients with schizophrenia and 62 healthy controls. All participants were administered a computerized neurocognitive battery, which evaluated performance in several domains. Patients were assessed for negative and positive symptoms. Fractional anisotropy (FA) of WM cortical regions and WM fiber tracts were compared across the groups. FA values were also used to predict neurocognitive performance and symptoms. RESULTS: We confirm widespread aberrant WM microstructure in a relatively large sample of well-characterized patients with schizophrenia in comparison to healthy participants. Moreover, we illustrate the utility of FA measures in predicting global neurocognitive performance in healthy participants and schizophrenia patients, especially for reaction time. FA was less predictive of clinical symptomatology. CONCLUSIONS: Using a standardized computerized neurocognitive battery and diffusion tensor imaging we show that behavioral performance is moderated by a particular constellation of WM microstructure in healthy individuals that differs in schizophrenia. PMID- 25445623 TI - Disruptive changes of cerebellar functional connectivity with the default mode network in schizophrenia. AB - The default mode network (DMN) plays an important role in the physiopathology of schizophrenia. Previous studies have suggested that the cerebellum participates in higher-order cognitive networks such as the DMN. However, the specific contribution of the cerebellum to the DMN abnormalities in schizophrenia has yet to be established. In this study, we investigated cerebellar functional connectivity differences between 60 patients with schizophrenia and 60 healthy controls from a public resting-state fMRI database. Seed-based correlation analysis was performed by using seeds from the left Crus I, right Crus I and Lobule IX, which have previously been identified as being involved in the DMN. Our results revealed that, compared with the healthy controls, the patients showed significantly reduced cerebellar functional connectivity with the thalamus and several frontal regions including the middle frontal gyrus, anterior cingulate cortex, and supplementary motor area. Moreover, the positive correlations between the strength of frontocerebellar and thalamocerebellar functional connectivity observed in the healthy subjects were diminished in the patients. Our findings implicate disruptive changes of the fronto-thalamo cerebellar circuit in schizophrenia, which may provide further evidence for the "cognitive dysmetria" concept of schizophrenia. PMID- 25445625 TI - Family-based association study of common variants, rare mutation study and epistatic interaction detection in HDAC genes in schizophrenia. AB - BACKGROUND: Histone deacetylases (HDACs) are key enzymes of histone acetylation, and abnormalities in histone modifications and in the level of HDAC proteins have been reported in schizophrenia. The objective of the present study was to systematically test the HDAC genes for its association with schizophrenia. METHODS: A family-based genetic association study (951 Caucasian subjects in 313 nuclear families) using 601 tag-single nucleotide polymorphisms in HDAC genes was conducted followed by a replication study of top-ranked markers in a sample of 1427 Caucasian subjects from 241 multiplex families and 176 trios. Epistasis interaction was tested by using the pedigree-based generalized multifactor dimensionality reduction (GMDR). Furthermore, we analyzed exome sequencing data of 1134 subjects for detection of rare mutations in HDAC genomic regions. RESULTS: In the exploratory study, ten markers were in significant association with schizophrenia (P<0.01). One maker rs14251 (HDAC3) was replicated (P=0.04) and remained significant in the whole sample (P=0.004). GMDR identified that a significant three-locus interaction model was detected involving rs17265596 (HDAC9), rs7290710 (HDAC10) and rs7634112 (HDAC11) with a good testing accuracy (0.58). No rare mutations were found associated with schizophrenia. CONCLUSION: This first exploratory systematic study of the HDAC genes provides consistent support for the involvement of the HDAC3 gene in the etiology of schizophrenia. A statistical epistatic interaction between HDAC9, HDAC10, and HDAC11 was detected and seems biologically plausible. PMID- 25445624 TI - Promoter variant rs2301228 on the neural cell adhesion molecule 1 gene confers risk of schizophrenia in Han Chinese. AB - BACKGROUND: Schizophrenia is recognized as a disorder of the brain and neuronal connectivity. The neural cell adhesion molecule 1 (NCAM1) gene plays a crucial role in regulating neuronal connectivity. METHODS: We conducted a two-stage association analysis on 17 NCAM1 SNPs in two independent Han Chinese schizophrenia case-control cohorts (discovery sample from Hunan Province: 986 patients and 1040 normal controls; replication sample from Yunnan Province: 564 cases and 547 healthy controls). Allele, genotype and haplotype frequencies were compared between case and control samples. Transcription factor binding site prediction and luciferase reporter assays were employed to assess the potential function of promoter SNPs. We detected developmental changes at the transcriptional level of NCAM1 during neuron differentiation in Macaca mulatta neural progenitor cells (NPC). Serum levels of NCAM1 were measured in 72 cases and 88 controls. RESULTS: A promoter variant, rs2301228, was found to be associated with schizophrenia at the allelic level and was validated in a replication cohort. Luciferase reporter assays demonstrated that risk allele rs2301228-A significantly down-regulated NCAM1 gene transcription compared to the G-allele. Concordantly, schizophrenia patients had a significantly lower level of serum NCAM1 compared to healthy donors. During the NPC neuronal differentiation, NCAM1 mRNA was significantly increased, suggesting a critical role of this gene in neural development. CONCLUSIONS: Our results provide direct evidence for NCAM1 as a susceptibility gene for schizophrenia, which offers support to a neurodevelopmental model and neuronal connectivity hypothesis in the onset of schizophrenia. PMID- 25445626 TI - Effects of paternal age and offspring cognitive ability in early adulthood on the risk of schizophrenia and related disorders. AB - Advanced paternal age (APA) and intelligence quotient (IQ) are both associated with the risk of schizophrenia spectrum disorder (SSD) in young adult offspring. We hypothesized that the offspring SSD risk gradient associated with paternal age is mediated by offspring IQ. We investigated joint and separate associations of paternal age and offspring IQ with the risk of SSD. We used IQ routinely measured at conscription in Danish males (n=138,966) from cohorts born in 1955-84 and in 1976-1993 and followed them from a year after the conscription through 2010. We used Cox regression to estimate the incidence rate ratio (IRR) of SSD. During the follow-up, 528 men developed SSD (incidence rate [IR] 5.2 and 8.6 per 10,000 person-years in the first and second cohorts, respectively). APA was associated with higher risk of SSD (IRR, 1.32; 95% CI, 1.10-1.60 per a ten-year increase in paternal age). A higher IQ was associated with lower SSD risk (IRR, 0.68; 95% confidence interval [CI], 0.63-0.74 per one SD increase). The IR of SSD was higher among persons who were draft-exempt for health reasons (<20% of the men). Overall, there was little evidence of lower premorbid IQ in APA-related SSD (individuals who developed SSD and were also offspring of older fathers). Our results do not support the notion that risk gradient for offspring SSD associated with paternal age is mediated by offspring IQ. PMID- 25445627 TI - Multiple-interactions among EMILIN1 and EMILIN2 N- and C-terminal domains. AB - EMILIN1 and EMILIN2 belong to a family of extracellular matrix glycoproteins characterized by the N-terminal cysteine-rich EMI domain, a long segment with high probabilty for coiled-coil structure formation and a C-terminal gC1q domain. To study EMILIN1 and EMILIN2 interaction and assembly we have applied qualitative and quantitative two hybrid systems using constructs corresponding to the gC1q and EMI domains. The identified interactions were further confirmed in yeast extracts of co-transfected cells followed by co-immunoprecipitation. The data indicated that gC1q domains are able to self-interact as well as to interact one each other and with the EMI domains, but no self interactions were detected between the EMI domains. Furthermore EMILINs interactions were studied in 293 EBNA cells co-transfected with full lenght EMILIN1 and EMILIN2 constructs. Specific antibodies were able to co-immunoprecipitate EMILINs, indicating that also full-lenght proteins can give rise to non-covalent homo- and hetero multimers even if reduced and alkylated before mixing. Immunofluorescence analysis on mouse cell cultures and tissues sections with specific antibodies showed co-distribution of EMILIN1 and EMILIN2. Thus, we can hypothesize that EMILINs multimers are formed by head-to-tail interaction between C-terminal and N terminal domains of EMILIN1 and/or EMILIN2 but also by tail-to-tail interaction between gC1q domains. These multiple interactions may regulate homo-typic and/or hetero-typic linear and eventually lateral branching assemblies of EMILIN1 and EMILIN2 in tissues. PMID- 25445628 TI - [Higher nitric oxide levels are associated with disease activity in Egyptian rheumatoid arthritis patients]. AB - BACKGROUND: Oxidative stress generated within inflammatory joints can produce autoimmune phenomena and joint destruction. Radical species with oxidative activity, including reactive nitrogen species, represent mediators of inflammation and cartilage damage. OBJECTIVES: To assess serum nitric oxide as a marker of oxidative stress in Egyptian patients with rheumatoid arthritis and its relation to disease activity. METHODS: 80 patients with rheumatoid arthritis were divided into 2 groups, according to the DAS-28 score: Group I: 42 patients with disease activity, and Group II: 38 patients with no disease activity. Forty age- and sex-matched individuals were included as control group (Group III). Routine laboratory investigations were done, and nitric oxide was measured using Elisa. Hand plain radiographies were done for radiological status scoring using the Sharp method. RESULTS: A comparison between nitric oxide in all three groups showed a highly significant difference (p < 0.001), significantly higher levels were obtained among rheumatoid arthritis patients in comparison to controls, and higher levels were obtained in patients with active disease (mean+/-SD 82.38+/ 20.46) in comparison to patients without active disease (35.53+/-7.15). Nitric oxide in Group I showed a significant positive correlation with morning stiffness (r=0.45), arthritis (r=0.43), platelet count (r=0.46), erythrocyte sedimentation rate (r=0.83), C-reactive protein (r=0.76) and Disease Activity Score (r=0.85). Nitric oxide showed a significant positive correlation (r=0.43) with hand radiographies (Sharp score) in Group I. CONCLUSION: There are increased levels of nitric oxide in the serum of patients with rheumatoid arthritis. Nitric oxide correlates significantly with disease activity, inflammatory markers and radiological joint status. PMID- 25445629 TI - [Polyunsaturated omega-3 fatty acids and systemic lupus erythematosus: what do we know?]. AB - Various studies have demonstrated the impact of omega-3 fatty acids on the concentration of C reactive protein (CRP), pro-inflammatory eicosanoids, cytokines, chemokines and other inflammatory mediators. Therefore, the supplementation of these types of lipids may represent additional option treatment for chronic systemic diseases, such as Systemic Lupus Erythematous and other rheumatic diseases. The role of these lipids has not been well established, yet. However, it seems there is a direct relationship between its intake and the decrease of the disease clinical manifestations as well as of the inflammatory status of the patients. Thus, the aim of this manuscript is to present a thorough review on the effects of omega-3 fatty acids in patients with SLE. Bibliographic data set as the Medical Literature Analysis and Retrieval System Online (MEDLINE) and Literatura Latino-Americana e do Caribe em Ciencias da Saude (LILACS) were searched using as key words: systemic lupus erythematous (SLE), polyunsaturated fatty acids omega-3, eicosapentanoic acid (EPA), docosahexanoic acid (DHA), antioxidants and diet. Manuscripts published up to September 2013 were included. There were 43 articles related to the topic, however only 15 pertained human studies, with three review articles and 12 clinical studies. PMID- 25445630 TI - [Differences of spectral Doppler in psoriatic arthritis and onychomycosis]. AB - OBJECTIVE: To evaluate the use of the spectral Doppler (SDoppler) to quantify inflammatory activity and to detect nail echotextural differences in patients with psoriatic arthritis and onychomycosis. METHODS: Two patients, one with psoriatic arthritis but with no joint pain nor nail clinical change and the other with onychomycosis and rheumatoid arthritis were included. The gray scale ultrasound study, showed changes in the regular presence of echotexture at the nail insertion, thickening of the nail bed and loss of trilaminar nail pattern. The spectral Dopplerresistance index (RI), detects the inflammatory process in nail entheses. RESULTS: Seven distal interphalangeal (DIP) joints in both patients were evaluated in two planes, getting nine RI. In the patient with psoriatic arthritis the author found: loss of normal trilaminar nail plate aspect, and nail beds and DIP joint capsules preserved. The spectral Doppler showed RI<1, with mean+/-SD=0.50+/-0.75 in the microcirculation at nail entheses, with characterization of a bone erosion in the third left DIP joint, with RI=0.38 and 0.63 in transverse and longitudinal planes, respectively. The patient with onychomycosis showed the following changes: hypoechogenicity at nail insertion; loss of nail shape, and spectral Doppler in nail entheses with RI>1, with mean+/ SD=1.71+/-0.98. CONCLUSION: The use of ultrasound can detect changes in the nail beds in these diseases. Future studies will further characterize these changes. PMID- 25445631 TI - [The dermatoscopy in the skin pathergy testing: case series in patients with suspected Behcet's Disease]. AB - Behcet's disease is a multisystemic disease consisting of a varying combination of ocular, mucocutaneous, neurologic, cardiovascular, gastrointestinal and other manifestations. Its diagnosis is based on clinical criteria, in which a positive pathergy test scores 1. A case series with 26 suspected patients is presented, and the skin pathergy test was performed in 23. The results were read in 48hours, and they were considered negative when without papule, and positive with a papule or pustule. Positive results were divided by papule size, and dermatoscopy was done to measure and observe its clinical aspects. After the readings, a biopsy was performed, with annotation of histopathological aspects. The test was negative in 2 (8.7%) and positive in 21 (91.3%) patients. The results and the literature review are presented. PMID- 25445632 TI - Effects of acute supplementation of L-arginine and nitrate on endurance and sprint performance in elite athletes. AB - This study examined the effects of acute supplementation with L-arginine and nitrate on running economy, endurance and sprint performance in endurance-trained athletes. In a randomised cross-over, double-blinded design we compared the effects of combined supplementation with 6 g L-arginine and 614 mg nitrate against 614 mg nitrate alone and placebo in nine male elite cross-country skiers (age 18 +/- 0 years, VO2max 69.3 +/- 5.8 ml ? min(-1) ? kg(-1)). After a 48-hour standardisation of nutrition and exercise the athletes were tested for plasma nitrate and nitrite concentrations, blood pressure, submaximal running economy at 10 km ? h(-1) and 14 km ? h(-1) at 1% incline and 180 m as well as 5-km time trial running performances. Plasma nitrite concentration following L-arginine + nitrate supplementation (319 +/- 54 nmol ? L(-1)) did not differ from nitrate alone (328 +/- 107 nmol ? L(-1)), and both were higher than placebo (149 +/- 64 nmol ? L(-1), p < 0.01). There were no differences in physiological responses during submaximal running or in 5-km performance between treatments. The plasma nitrite concentrations indicate greater nitric oxide availability both following acute supplementation of L-arginine + nitrate and with nitrate alone compared to placebo, but no additional effect was revealed when L-arginine was added to nitrate. Still, there were no effects of supplementation on exercise economy or endurance running performance in endurance-trained cross-country skiers. PMID- 25445633 TI - Validation of a method to directly and specifically measure nitrite in biological matrices. AB - The bioactivity of nitric oxide (NO) is influenced by chemical species generated through reactions with proteins, lipids, metals, and its conversion to nitrite and nitrate. A better understanding of the functions played by each of these species could be achieved by developing selective assays able of distinguishing nitrite from other NO species. Nagababu and Rifkind developed a method using acetic and ascorbic acids to measure nitrite-derived NO in plasma. Here, we adapted, optimized, and validated this method to assay nitrite in tissues. The method yielded linear measurements over 1-300 pmol of nitrite and was validated for tissue preserved in a nitrite stabilization solution composed of potassium ferricyanide, N-ethylmaleimide and NP-40. When samples were processed with chloroform, but not with methanol, ethanol, acetic acid or acetonitrile, reliable and reproducible nitrite measurements in up to 20 sample replicates were obtained. The method's accuracy in tissue was ~ 90% and in plasma 99.9%. In mice, during basal conditions, brain, heart, lung, liver, spleen and kidney cortex had similar nitrite levels. In addition, nitrite tissue levels were similar regardless of when organs were processed: immediately upon collection, kept in stabilization solution for later analysis or frozen and later processed. After ip nitrite injections, rapidly changing nitrite concentrations in tissue and plasma could be measured and were shown to change in significantly distinct patterns. This validated method could be valuable for investigations of nitrite biology in conditions such as sickle cell disease, cardiovascular disease, and diabetes, where nitrite is thought to play a role. PMID- 25445635 TI - Current trends in clinical studies of allogeneic hematopoietic stem cell transplantation. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) is a specialized intervention performed at select centers worldwide. The extent to which specific aspects of care in allogeneic HSCT have been studied and the types of studies performed for different aspects of care remains incompletely documented. Studies in allogeneic HSCT were systematically identified from selected high-profile transplant journals between July 2010 and June 2011 and previously reported in a study addressing the definition of clinical outcomes in HSCT. All articles were retrieved and assessed for study characteristics and categorized by specific aspects of care related to allogeneic HSCT. One hundred sixteen articles were retrieved and reviewed in detail by 2 investigators. The most studied aspect of care was conditioning regimens. Transfusion practices were the most understudied aspect of care. Interestingly, most studies included both adult and pediatric patients. Studies involving all hematological malignancies were encountered more often than disease-specific studies. Geographically, most patients described in the published reports were treated only in North America or only in Europe. Most studies were retrospective (78), and 25 reported on multicenter registry data. Of the 38 prospective studies, 8 were randomized controlled trials (RCTs) and predominantly focused on prevention and treatment of graft-versus-host disease (GVHD) and infections. Median follow-up was longer in retrospective registry studies (54 months) and shortest in RCTs (32 months). The proportion of positive outcomes in retrospective and prospective studies was remarkably high (>80% for all categories) and not significantly different across all aspects of care (P > .05). When comparing RCTs and registry data studies, this proportion was similar and high (95% and 100%, respectively, P > .05). Our study highlights the established and important role of retrospective registry studies for many aspects of care and suggests RCTs may be most relevant for studies on infectious complications and GVHD. PMID- 25445634 TI - Dietary nitrate supplementation improves exercise performance and decreases blood pressure in COPD patients. AB - Dietary nitrate (NO3(-)) supplementation via beetroot juice has been shown to increase the exercise capacity of younger and older adults. The purpose of this study was to investigate the effects of acute NO3(-) ingestion on the submaximal constant work rate exercise capacity of COPD patients. Fifteen patients were assigned in a randomized, single-blind, crossover design to receive one of two treatments (beetroot juice then placebo or placebo then beetroot juice). Submaximal constant work rate exercise time at 75% of the patient's maximal work capacity was the primary outcome. Secondary outcomes included plasma NO3(-) and nitrite (NO2(-)) levels, blood pressure, heart rate, oxygen consumption (VO2), dynamic hyperinflation, dyspnea and leg discomfort. Relative to placebo, beetroot ingestion increased plasma NO3(-) by 938% and NO2(-) by 379%. Median (+interquartile range) exercise time was significantly longer (p = 0.031) following the ingestion of beetroot versus placebo (375.0 + 257.0 vs. 346.2 + 148.0 s, respectively). Compared with placebo, beetroot ingestion significantly reduced iso-time (p = 0.001) and end exercise (p = 0.008) diastolic blood pressures by 6.4 and 5.6 mmHg, respectively. Resting systolic blood pressure was significantly reduced (p = 0.019) by 8.2 mmHg for the beetroot versus the placebo trial. No other variables were significantly different between the beetroot and placebo trials. These results indicate that acute dietary NO3(-) supplementation can elevate plasma NO3(-) and NO2(-) concentrations, improve exercise performance, and reduce blood pressure in COPD patients. PMID- 25445637 TI - Incidence, risk factors, and outcome of cytomegalovirus viremia and gastroenteritis in patients with gastrointestinal graft-versus-host disease. AB - Gastrointestinal (GI) graft-versus-host disease (GVHD) is one of the most common causes of morbidity and mortality after allogeneic stem cell transplantation. In addition, cytomegalovirus (CMV) infection of the gastrointestinal tract can complicate the post-transplantation course of these patients and it can be difficult to differentiate the 2 diagnoses given that they can present with similar symptoms. We retrospectively analyzed 252 patients who were diagnosed with GI GVHD to evaluate the incidence, risk factors, and outcomes of CMV viremia and CMV gastroenteritis in these patients. The median age at the time of transplantation was 51 years, 35% were related donor transplantations, and 65% were unrelated donor transplantations. A total of 114 (45%) patients developed CMV viremia at a median of 34 days (range, 14 to 236 days) after transplantation. Only recipient CMV IgG serostatus was significantly associated with development of CMV viremia (P < .001). The incidence of CMV viremia with relation to donor (D) and recipient (R) CMV serostatus subgroups was as follows: D+/R+, 73%; D-/R+, 67%; D+/R-, 19%; and D-/R-, 0. A total of 31 patients were diagnosed with a biopsy-proven CMV gastroenteritis; 2 patients had evidence of CMV gastroenteritis and GVHD on the first biopsy and 29 on the second biopsy. Median time to development of CMV gastroenteritis was 52 days (range, 19 to 236 days) after transplantation. Using death as a competing risk, the cumulative incidence of CMV gastroenteritis at 1 year was 16.4%. The incidence of CMV gastroenteritis in relation to the donor/recipient serostatus was as follows: D+/R+, 22%; D-/R+, 31%; D+/R-, 12%; and D-/R-, 0. Median follow-up time for the 252 patients was 35.4 (95% CI 23.8 to 44.8) months. The estimated overall survival rate at 1 and 2 years was .45 (95% confidence interval [CI], .39 to .52) and .39 (95% CI, .33 to .46), respectively. Of the examined variables, those related to the overall survival were maximal clinical GVHD grade (P < .001) and development of CMV gastroenteritis (P = .008). Development of CMV viremia was not associated with increased mortality. In conclusion, CMV gastroenteritis is common complication in patients with GI GVHD and can adversely affect the prognosis. PMID- 25445639 TI - High fever occurring 4 to 5 days post-transplant of haploidentical bone marrow or peripheral blood stem cells after reduced-intensity conditioning associated with the use of post-transplant cyclophosphamide as prophylaxis for graft-versus-host disease. PMID- 25445636 TI - Blood and marrow transplant clinical trials network state of the Science Symposium 2014. PMID- 25445638 TI - Significant improvement in survival after unrelated donor hematopoietic cell transplantation in the recent era. AB - Patients and physicians may defer unrelated donor hematopoietic cell transplantation (HCT) as curative therapy because of the mortality risk associated with the procedure. Therefore, it is important for physicians to know the current outcomes data when counseling potential candidates. To provide this information, we evaluated 15,059 unrelated donor hematopoietic cell transplant recipients between 2000 and 2009. We compared outcomes before and after 2005 for 4 cohorts: age <18 years with malignant diseases (n = 1920), ages 18 to 59 years with malignant diseases (n = 9575), ages >= 60 years with malignant diseases (n = 2194), and nonmalignant diseases (n = 1370). Three-year overall survival in 2005 to 2009 was significantly better in all 4 cohorts (<18 years: 55% versus 45%, 18 to 59 years: 42% versus 35%, >= 60 years: 35% versus 25%, nonmalignant diseases: 69% versus 60%; P < .001 for all comparisons). Multivariate analyses in leukemia patients receiving HLA 7/8 to 8/8-matched transplants showed significant reduction in overall and nonrelapse mortality in the first year after HCT among patients who underwent transplantation in 2005 to 2009; however, risks for relapse did not change over time. Significant survival improvements after unrelated donor HCT have occurred over the recent decade and can be partly explained by better patient selection (eg, HCT earlier in the disease course and lower disease risk), improved donor selection (eg, more precise allele-level matched unrelated donors) and changes in transplantation practices. PMID- 25445643 TI - Natural transformation and genome evolution in Streptococcus pneumoniae. AB - Streptococcus pneumoniae is a frequent colonizer of the human nasopharynx that has the potential to cause severe infections such as pneumonia, bacteremia and meningitis. Despite considerable efforts to reduce the burden of pneumococcal disease, it continues to be a major public health problem. After the Second World War, antimicrobial therapy was introduced to fight pneumococcal infections, followed by the first effective vaccines more than half a century later. These clinical interventions generated a selection pressure that drove the evolution of vaccine-escape mutants and strains that were highly resistant against antibiotics. The remarkable ability of S. pneumoniae to acquire drug resistance and evade vaccine pressure is due to its recombination-mediated genetic plasticity. S. pneumoniae is competent for natural genetic transformation, a property that enables the pneumococcus to acquire new traits by taking up naked DNA from the environment and incorporating it into its genome through homologous recombination. In the present paper, we review current knowledge on pneumococcal transformation, and discuss how the pneumococcus uses this mechanism to adapt and survive under adverse and fluctuating conditions. PMID- 25445640 TI - Gamma delta T cell reconstitution is associated with fewer infections and improved event-free survival after hematopoietic stem cell transplantation for pediatric leukemia. AB - After hematopoietic stem cell transplantation (HSCT), successful engraftment and immune recovery is necessary to protect the patient from relapse and infection. Many studies highlight the importance of conventional alphabeta T cell recovery after HSCT, but the impact of gammadelta T cell recovery has not been well described. Here, we investigate the recovery of gammadelta T cells in 102 pediatric patients with acute leukemia in first clinical remission who underwent allogeneic HSCT at St. Jude Children's Research Hospital from 1996 to 2011. Mean patient age was 10.5 +/- 5.9 years (range, .6 to 25.2), and mean survivor follow up was 2.7 +/- 1.8 years (range, .12 to 6.0). Diagnoses included 59% patients with acute lymphoblastic leukemia and 41% patients with acute myelogenous leukemia. Multivariate analysis demonstrated significant impact of the maximum number of CD3(+), CD4(+), and CD8(+) T cells and donor source on the gammadelta T cell recovery (P < .0001, P < .0001, P < .0001, and P < .004, respectively). Univariate and multivariate models found the number of gammadelta T cells after HSCT to be associated with infections (P = .026 and P = .02, respectively). We found the probability of infections for patients with an elevated number of gammadelta T cells was significantly lower compared with patients with low or normal gammadelta T cells after HSCT (18% versus 54%; P = .025). Bacterial infections were not observed in patients with elevated gammadelta T cells. Finally, event-free survival was significantly higher in patients with enhanced gammadelta T cell reconstitution compared with patients with low/normal gammadelta T cell reconstitution after HSCT (91% versus 55%; P = .04). Thus, gammadelta T cells may play an important role in immune reconstitution after HSCT. PMID- 25445642 TI - Preventive azithromycin treatment reduces noninfectious lung injury and acute graft-versus-host disease in a murine model of allogeneic hematopoietic cell transplantation. AB - Noninfectious lung injury and acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) are associated with significant morbidity and mortality. Azithromycin is widely used in allogeneic HCT recipients for pulmonary chronic GVHD, although current data appear controversial. We induced GVHD and noninfectious lung injury in lethally irradiated B6D2F1 mice by transplanting bone marrow and splenic T cells from allogeneic C57BL/6 mice. Experimental groups were treated with oral azithromycin starting on day 14 until the end of week 6 or week 14 after transplantation. Azithromycin treatment resulted in improved survival and decreased lung injury; the latter characterized by improved pulmonary function, reduced peribronchial and perivascular inflammatory cell infiltrates along with diminished collagen deposition, and a decrease in lung cytokine and chemokine expression. Azithromycin also improved intestinal GVHD but did not affect liver GVHD at week 6 early after transplantation. At week 14, azithromycin decreased liver GVHD but had no effect on intestinal GVHD. In vitro, allogeneic antigen-presenting cell (APC)- dependent T cell proliferation and cytokine production were suppressed by azithromycin and inversely correlated with relative regulatory T cell (Treg) expansion, whereas no effect was seen when T cell proliferation occurred APC independently through CD3/CD28-stimulation. Further, azithromycin reduced alloreactive T cell expansion but increased Treg expansion in vivo with corresponding downregulation of MHC II on CD11c(+) dendritic cells. These results demonstrate that preventive administration of azithromycin can reduce the severity of acute GVHD and noninfectious lung injury after allo-HCT, supporting further investigation in clinical trials. PMID- 25445641 TI - Nonmyeloablative allogeneic hematopoietic stem cell transplant for the treatment of patients with hematologic malignancies using busulfan, fludarabine, and total body irradiation conditioning is effective in an elderly and infirm population. AB - The BuFluTBI conditioning regimen was designed with the primary goal of reducing non-relapse mortality (NRM) while maximizing primary disease control in patients ineligible for myeloablative conditioning. Patients with hematologic malignancies for whom limited long-term survival was expected with standard therapy were administered an outpatient conditioning regimen of busulfan 3.2 mg/kg IV on day 5, fludarabine 30 mg/m(2) IV on days -4, -3, -2, and 200 cGy of total body irradiation (TBI) followed by stem cell infusion from related or unrelated donors. GVHD prophylaxis included cyclosporine and mycophenolate mofetil. 147 patients were enrolled from 2005-2011; 59% with myeloid disease and 41% with lymphoid disease. The median age was 64, and the median comorbidity index (HCT CI) score was 3. Overall survival (OS), with 3.2 years median follow-up, was 60% at 1 year and 48% at 2 years, with projected OS 37% at 5 years. Relapse rates were 29% at 1 year and 33% at 2 years, with relapse mortality of 13% at 1 year, and 20% at 2 years. Nonrelapse mortality (NRM) at 1 year was 27% and 33% at 2 years. 54% of patients developed grade II-IV aGVHD and 67% of patients developed cGVHD within 2 years. On multivariate analysis, HCT-CI score 4 or greater, pre transplant KPS less than 90, delayed platelet engraftment of more than 15 days, and grade II-IV aGVHD were found to be independent predictors of poor survival. There was no difference in OS or PFS between lymphoid and myeloid malignancies. BuFluTBI is an efficacious NMA regimen, active in both myeloid and lymphoid disease, and is ideally suited for use in patients age 65 and older or with an HCT-CI of 4 or greater. PMID- 25445644 TI - Identification of new sub-genotypes of virulent Newcastle disease virus with potential panzootic features. AB - Virulent Newcastle disease virus (NDV) isolates from new sub-genotypes within genotype VII are rapidly spreading through Asia and the Middle East causing outbreaks of Newcastle disease (ND) characterized by significant illness and mortality in poultry, suggesting the existence of a fifth panzootic. These viruses, which belong to the new sub-genotypes VIIh and VIIi, have epizootic characteristics and do not appear to have originated directly from other genotype VII NDV isolates that are currently circulating elsewhere, but are related to the present and past Indonesian NDV viruses isolated from wild birds since the 80s. Viruses from sub-genotype VIIh were isolated in Indonesia (2009-2010), Malaysia (2011), China (2011), and Cambodia (2011-2012) and are closely related to the Indonesian NDV isolated in 2007, APMV1/Chicken/Karangasem, Indonesia (Bali 01)/2007. Since 2011 and during 2012 highly related NDV isolates from sub genotype VIIi have been isolated from poultry production facilities and occasionally from pet birds, throughout Indonesia, Pakistan and Israel. In Pakistan, the viruses of sub-genotype VIIi have replaced NDV isolates of genotype XIII, which were commonly isolated in 2009-2011, and they have become the predominant sub-genotype causing ND outbreaks since 2012. In a similar fashion, the numbers of viruses of sub-genotype VIIi isolated in Israel increased in 2012, and isolates from this sub-genotype are now found more frequently than viruses from the previously predominant sub-genotypes VIId and VIIb, from 2009 to 2012. All NDV isolates of sub-genotype VIIi are approximately 99% identical to each other and are more closely related to Indonesian viruses isolated from 1983 through 1990 than to those of genotype VII, still circulating in the region. Similarly, in addition to the Pakistani NDV isolates of the original genotype XIII (now called sub-genotype XIIIa), there is an additional sub-genotype (XIIIb) that was initially detected in India and Iran. This sub-genotype also appears to have as an ancestor a NDV strain from an Indian cockatoo isolated in 1982. These data suggest the existence of a new panzootic composed of viruses of subgenotype VIIi and support our previous findings of co-evolution of multiple virulent NDV genotypes in unknown reservoirs, e.g. as recorded with the virulent NDV identified in Dominican Republic in 2008. The co-evolution of at least three different sub-genotypes reported here and the apparent close relationship of some of those genotypes from ND viruses isolated from wild birds, suggests that identifying wild life reservoirs may help predict new panzootics. PMID- 25445645 TI - Penicillin-resistant, ampicillin-susceptible Enterococcus faecalis of hospital origin: pbp4 gene polymorphism and genetic diversity. AB - Despite the spread of penicillin-resistant, ampicillin-susceptible Enterococcus faecalis (PRASEF) isolates in diverse countries, the mechanisms leading to this unusual resistance phenotype have not yet been investigated. The aim of this study was to evaluate whether polymorphism in the pbp4 gene is associated with penicillin resistance in PRASEF isolates and to determine their genetic diversity. E. faecalis isolates were recovered from different clinical specimens of hospitalized patients from February 2006 to June 2010. The beta-lactam minimal inhibitory concentrations (MICs) were determined by E-test(r). The PCR-amplified pbp4 gene was sequenced with an automated sequencer. The genetic diversities of the isolates were established by PFGE (pulsed-field gel electrophoresis) and MLST (multilocus sequencing typing). Seventeen non-producing beta-lactamase PRASEF and 10 penicillin-susceptible, ampicillin-susceptible E. faecalis (PSASEF) strains were analyzed. A single-amino-acid substitution (Asp-573->Glu) in the penicillin binding domain was significantly found in all PRASEF isolates by sequencing of the pbp4 gene but not in the penicillin-susceptible isolates. In contrast to the PSASEF isolates, a majority of the PRASEFs had similar PFGE profiles. Six representative PRASEF isolates were resolved by MLST into ST9 and ST524 and belong to the globally dispersed clonal complex 9 (CC9). In conclusion, it appears quite likely that the amino acid alteration (Asp-573->Glu) found in the PBP4 of the Brazilian PRASEF isolates may account for their reduced susceptibility to penicillin, although other resistance mechanisms remain to be investigated. PMID- 25445647 TI - Dissemination of OXA-carbapenemase-producing Acinetobacter baumannii ST195 and ST642 in a Mongolian hospital. PMID- 25445648 TI - Phylogenetic analyses of Norovirus strains detected in Uruguay reveal the circulation of the novel GII.P7/GII.6 recombinant variant. AB - Noroviruses (NoV) are one of the major etiological agent of acute gastroenteritis (AGE) outbreaks worldwide. Distinct NoV genotypes have been associated with different transmission patterns and disease severity in humans. Therefore, it is important to identify genetically different NoV genotypes circulating in a particular region. However, genotyping has become a challenge due to recombination events occurring mainly nearby ORF1/ORF2 junction of NoV genome, leading to distinct genotypes with polymerase and capsid regions derived from parenteral strains. Taking this into account, ORF1/ORF2 sequences were obtained from NoV strains collected from patients with AGE in Uruguay. This study reveals in silico evidences of recombination events taking place in four out of six strains analyzed for which its polymerase gene and its capsid region correspond to GII.P7 and to GII.6 genotype, respectively. These results also reveal the circulation of a GII.P7/GII.6 recombinant variant in the natural populations of NoV strains in the northwestern region of Uruguay. As far as we know this is the first report about the circulation of a NoV GII.P7/GII.6 recombinant variant in the Americas. PMID- 25445649 TI - Genome characterization of a novel chicken picornavirus distantly related to the members of genus Avihepatovirus with a single 2A protein and a megrivirus-like 3' UTR. AB - The members of the genus Avihepatovirus and related picornaviruses ("Aalivius") of ducks, turkey and chickens possess identical 2A peptide composition including three functionally unrelated 2A peptides which is a characteristic genome feature of these monophyletic avian picornaviruses. The complete genome of a novel picornavirus provisionally named Orivirus A1 (KM203656) from a cloacal sample of a 4-week-old diarrheic chicken (Gallus gallus domesticus) distantly related to members of genus Avihepatovirus was characterized. The study strain contains a type-II-like IRES, a single 2A protein of unknown function unrelated to the 2A proteins of avihepatoviruses and a long 3' untranslated region (UTR) with multiple repeated sequence motifs followed by an AUG-rich region. The repeated sequences of the 3' UTR show significant identity to the "Unit A" sequences of the phylogenetically distant megriviruses. The presence of a novel single 2A and the megrivirus-like "Unit A" motifs suggest multiple recombination events in the evolution of this novel picornavirus. PMID- 25445650 TI - Molecular systematics applied to Phlebotomine sandflies: review and perspectives. AB - A review of the literature related to the molecular systematics of the Phlebotomine sandflies (Diptera, Psychodidae) is proposed. It shows that molecular systematics is more frequently used to perform evolutionary systematics than to help in the field of alpha taxonomy. On more than 900 living species and subspecies described, 180 (about 20%) have been processed for molecular systematics. The countries of origin where the sandflies processed come from are endemic for leishmaniases and the ratio of species sampled for molecular systematics studies is high for vector groups and low for species not involved in the transmission of leishmaniasis. The main studies focused on intraspecific topics, others on closely related species, and a few compared genera of sandflies. Mitochondrial markers (more than 50% of the markers studied) are preferred to non mitochondrial markers. The use of mtDNA markers alone to explore phylogenetic relationships is considered as dangerous, especially concerning closely related species. PMID- 25445646 TI - Co-circulation of soricid- and talpid-borne hantaviruses in Poland. AB - Previously, we reported the discovery of a genetically distinct hantavirus, designated Boginia virus (BOGV), in the Eurasian water shrew (Neomys fodiens), as well as the detection of Seewis virus (SWSV) in the Eurasian common shrew (Sorex araneus), in central Poland. In this expanded study of 133 shrews and 69 moles captured during 2010-2013 in central and southeastern Poland, we demonstrate the co-circulation of BOGV in the Eurasian water shrew and SWSV in the Eurasian common shrew, Eurasian pygmy shrew (Sorex minutus) and Mediterranean water shrew (Neomys anomalus). In addition, we found high prevalence of Nova virus (NVAV) infection in the European mole (Talpa europaea), with evidence of NVAV RNA in heart, lung, liver, kidney, spleen and intestine. The nucleotide and amino acid sequence variation of the L segment among the SWSV strains was 0-18.8% and 0 5.4%, respectively. And for the 38 NVAV strains from European moles captured in Huta Dlutowska, the L-segment genetic similarity ranged from 94.1%-100% at the nucleotide level and 96.3%-100% at the amino acid level. Phylogenetic analyses showed geographic-specific lineages of SWSV and NVAV in Poland, not unlike that of rodent-borne hantaviruses, suggesting long-standing host-specific adaptation. The co-circulation and distribution of BOGV, SWSV and NVAV in Poland parallels findings of multiple hantavirus species co-existing in their respective rodent reservoir species elsewhere in Europe. Also, the detection of SWSV in three syntopic shrew species resembles spill over events observed among some rodent borne hantaviruses. PMID- 25445651 TI - Isolation and characterization of a novel H10N2 avian influenza virus from a domestic duck in Eastern China. AB - During the surveillance for avian influenza viruses (AIVs) in live poultry markets (LPMs) in Eastern China, in 2013, an H10N2 AIV was isolated from a domestic duck. Phylogenetic analysis showed that this strain received its genes from H10, H1 and H7 AIVs of wild birds in China. The virulence of this strain was examined in chickens and mice, and was found to be low pathogenic in chickens but demonstrated moderate pathogenicity in mice. These results suggest that active surveillance of AIVs in LPMs should be used in an early warning system for avian influenza outbreaks. PMID- 25445653 TI - Establishment of six homozygous MHC-B haplotype populations associated with susceptibility to Marek's disease in Chinese specific pathogen-free BWEL chickens. AB - The highly polymorphic chicken major histocompatibility complex (MHC) is associated with different levels of immunologic responses to certain avian pathogens. MHC-B haplotype chickens are an important genetic resource for studying the genetic determination of pathogen resistance and susceptibility. The BWEL chicken population is the only specific pathogen-free (SPF) chickens bred and developed by the State Center of Poultry Genetic Resources of Laboratory Animals in China. In this study, we successfully established six homozygous MHC-B haplotype populations from the BWEL chickens using microsatellite marker technology, named as BW/G(1, 2, 3, 5, 6, 7) lines, and their molecular genotypes were matched to six serologically defined MHC-B haplotypes, B13, B15, B2, B5, B21 and B19, respectively. The sequences of BF genes exons 2 and 3 from four successive generations (F1-F4) of the BW/G(n) lines were completely consistent with those of serologically defined MHC-B haplotypes. Subsequently, six BW/G(n) line specific allo-antisera were prepared by immunization with red blood cells (RBCs) and hemagglutination tests results showed the BW/G(n) SPF chickens could be serologically differentiated. Additionally, susceptibility to Marek's disease (MD) in the BW/G3 (B2 haplotype) and BW/G7 (B19 haplotype) lines were determined by comparing mortality, macroscopic and histopathological lesions, and viral loads in feather pulp. The BW/G7 line showed greater genetic susceptibility to the very virulent MD virus (MDV) strain than the BW/G3 line. The establishment of MHC-B haplotype chicken populations associated with susceptibility to MD will be helpful for studying host immune responses and further developing the more effective vaccines in the context of MHC specificities, and they are also very useful for an understanding of MHC genes architecture and function. PMID- 25445652 TI - Interferon-gamma (IFNG) microsatellite repeat and single nucleotide polymorphism haplotypes of IFN-alpha receptor (IFNAR1) associated with enhanced malaria susceptibility in Indian populations. AB - Pro-inflammatory cytokines IFNgamma and IFNalpha function through their cellular receptors IFNgammaR1 and IFNalphaR1, respectively to mediate immune processes during malaria infection. A total of 21 SNPs, 2 ins/del polymorphisms and a microsatellite repeat, selected on the basis of their reported association with infectious diseases including malaria in world populations, were analysed for association with Plasmodium falciparum malaria susceptibility in a case-control study with adult patients and ethnically-matched controls drawn from a disease meso- to hyperendemic and a nonendemic region of India. Among the five IFNG SNPs tested, an intron 3 and a 3'UTR SNP associated with disease in the endemic region. In addition, large (CA)n repeats of IFNG intron 1 associated with protection from severe malaria in the endemic region (severe vs. control, odds ratio=0.21, 95% CI=0.08-0.52, P=1.3 * 10(-4)). The TA11CAG haplotype (rs2069705 T/C, rs2430561 A/T, rs3138557 (CA)n, rs2069718 T/C, rs2069727 A/G, rs2069728 G/A) carrying a short CA11 repeat also exhibited very strong association with severe malaria, particularly in the endemic region (severe vs. control, OR=14.56, 95% CI=3.39-85.81, P=3 * 10(-5)). One SNP each from the IFNA8 and IFNA17 of IFNA gene cluster had a protective effect in the non-endemic region but not in the endemic region. A promoter and an intron 2 SNP of IFNAR1 were risk factors for disease and the IFNAR1 haplotype GCCAGG (rs2843710 C/G, rs2850015 C/T, +6993 C/T, rs2243594 A/G, rs1012335 G/C, rs2257167 G/C) carrying both the risk alleles strikingly associated with disease manifestation in the endemic region (severe vs. control, OR=27.14, 95% CI=3.12-1254, P=2 * 10(-5); non-severe vs. control, OR=61.87, 95% CI=10.08-2521, P=1 * 10(-8)). The data indicates dissimilar contribution of cytokine and cytokine receptor variants to disease in populations residing in areas of differential malaria endemicity. PMID- 25445654 TI - The hidden face of academic researches on classified highly pathogenic microorganisms. AB - Highly pathogenic microorganisms and toxins are manipulated in academic laboratories for fundamental research purposes, diagnostics, drugs and vaccines development. Obviously, these infectious pathogens represent a potential risk for human and/or animal health and their accidental or intentional release (biosafety and biosecurity, respectively) is a major concern of governments. In the past decade, several incidents have occurred in laboratories and reported by media causing fear and raising a sense of suspicion against biologists. Some scientists have been ordered by US government to leave their laboratory for long periods of time following the occurrence of an incident involving infectious pathogens; in other cases laboratories have been shut down and universities have been forced to pay fines and incur a long-term ban on funding after gross negligence of biosafety/biosecurity procedures. Measures of criminal sanctions have also been taken to minimize the risk that such incidents can reoccur. As United States and many other countries, France has recently strengthened its legal measures for laboratories' protection. During the past two decades, France has adopted a series of specific restriction measures to better protect scientific discoveries with a potential economic/social impact and prevent their misuse by ill intentioned people without affecting the progress of science through fundamental research. French legal regulations concerning scientific discoveries have progressively strengthened since 2001, until the publication in November 2011 of a decree concerning the "PPST" (for "Protection du Potentiel Scientifique et Technique de la nation", the protection of sensitive scientific data). Following the same logic of protection of sensitive scientific researches, regulations were also adopted in an order published in April 2012 concerning the biology and health field. The aim was to define the legal framework that precise the conditions for authorizing microorganisms and toxins experimentation in France; these regulations apply for any operation of production, manufacturing, transportation, import, export, possession, supply, transfer, acquisition and use of highly pathogenic microorganisms and toxins, referred to as "MOT" (for "MicroOrganismes et Toxines hautement pathogenes") by the French law. Finally, laboratories conducting researches on such infectious pathogens are henceforth classified restricted area or ZRR (for "Zone a Regime Restrictif"), according an order of July 2012. In terms of economic protection, biosafety and biosecurity, these regulations represent an undeniable progress as compared to the previous condition. However, the competitiveness of research laboratories handling MOTs is likely to suffer the side effects of these severe constraints. For example research teams working on MOTs can be drastically affected both by (i) the indirect costs generated by the security measure to be applied; (ii) the working time devoted to samples recording; (iii) the establishment of traceability and reporting to national security agency ANSM, (iv) the latency period required for staff members being officially authorized to conduct experiments on MOTs; (v) the consequent reduced attractiveness for recruiting new trainees whose work would be significantly hampered by theses administrative constraints; and (vi) the limitations in the exchange of material with external laboratories and collaborators. Importantly, there is a risk that French academic researchers gradually abandon research on MOTs in favor of other projects that are less subject to legal restrictions. This would reduce the acquisition of knowledge in the field of MOTs which, in the long term, could be highly detrimental to the country by increasing its vulnerability to natural epidemics due to pathogenic microorganisms that are classified as MOTs and, by reducing its preparedness against possible bioterrorist attacks that would use such microorganisms. PMID- 25445655 TI - Sequence types diversity of Legionella pneumophila isolates from environmental water sources in Guangzhou and Jiangmen, China. AB - In this study, 159 Legionella pneumophila strains isolated from various natural and artificial water sources in Guangzhou and Jiangmen, China, were subjected to genotyping by the sequence-based typing (SBT) scheme. These isolates were assigned into 53 sequence types (STs) (50 STs with seven loci data and three unidentified STs with incomplete loci profiles) with ST1 as the dominant one (14.5%), and the index of diversity (IOD) was 0.950. Eight new alleles and 34 new STs were reported here. Notably, most of the newly identified STs with seven loci data (24/34) contained no new allele, implying frequent recombination events in L. pneumophila. Five intragenic recombination events were identified in the concatenated sequences of seven loci. The diversity of STs in natural environmental isolates (41 STs, IOD=0.956) is higher than that of artificial environmental ones (17 STs, IOD=0.824). The ST patterns varied in isolates from these two sources: the most common STs from artificial water sources, ST1 and ST752 (39.2% and 13.7%), were only occasionally isolated from natural water sources (2.9% and 3.8%, respectively); while the predominant STs from natural water sources, ST1048, ST739 and ST1267 (15.2%, 6.7% and 6.7%), were less frequently seen in artificial environments (2.0%, 0% and 0%, respectively). We also found out that Legionnaires' disease associated STs might be more frequently isolated in artificial environments than in natural ones. Our data revealed remarkable genetic diversity of L. pneumophila isolates from environmental water systems of Guangzhou and Jiangmen, and the different ST distribution patterns between natural water and artificial water sources as well. PMID- 25445656 TI - A novel transducible chimeric phage from Escherichia coli O157:H7 Sakai strain encoding Stx1 production. AB - Shiga toxin-producing Escherichia coli (STEC), and especially enterohaemorrhagic E. coli (EHEC) are important, highly virulent zoonotic and food-borne pathogens. The genes encoding their key virulence factors, the Shiga toxins, are distributed by converting bacteriophages, the Stx phages. In this study we isolated a new type of inducible Stx phage carrying the stx1 gene cluster from the prototypic EHEC O157:H7 Sakai strain. The phage showed Podoviridae morphology, and was capable of converting the E. coli K-12 MG1655 strain to Shiga toxin-producing phenotype. The majority of the phage genes originate from the stx2-encoding Sakai prophage Sp5, with major rearrangements in its genome. Beside certain minor recombinations, the genomic region originally containing the stx2 genes in Sp5 was replaced by a region containing six open reading frames from prophage Sp15 including stx1 genes. The rearranged genome, together with the carriage of stx1 genes, the morphology and the capability of lysogenic conversion represent a new type of recombinant Stx1 converting phage from the Sakai strain. PMID- 25445657 TI - The clinical characteristics and genotype distribution of Chlamydia trachomatis infection in infants less than six months of age hospitalized with pneumonia. AB - BACKGROUND: Chlamydia trachomatis is a common sexually-transmitted bacterial pathogen. As no routine screening is performed during pregnancy, neonates and infants are at high risk for C. trachomatis infection. The objective of this study was to investigate the morbidity, clinical characteristics and genotype distribution of C. trachomatis pneumonia in infants less than six months of age. METHODS: Clinical manifestations and laboratory results were recorded. Respiratory sputum specimens were tested using RT-PCR targeting C. trachomatis cryptic plasmid. Simultaneously, respiratory virus antigens were detected by direct immunofluorescence and bacterial pathogens were examined by culture in all sputum samples. Positive C. trachomatis samples were further genotyped using a multiplex PCR reverse line blot assay. The relationship between genotype and pneumonia severity was explored. RESULTS: Of 1408 infants, 101 (7.2%) were infected with C. trachomatis. Sixteen of 101 (15.8%) were assessed as severe pneumonia. These severe cases had a higher proportion of viral co-infection (37.5%) compared to mild pneumonia cases (9.4%, P<0.05).Infants with tachypnea (OR 9.2) and wheezing (OR 3.5) were more likely to be classified as severe pneumonia (P<0.05). Amongst 66 C. trachomatis specimens for which a genotyping result was available, seven genotypes were detected, and 39.4% of these specimens contained two or three genotypes. Overall, genotype E (48.5%) was the most frequent, followed by genotype F (42.4%), J (31.8%), D (12.1%), K (10.6%), G (4.5%) and H (3.0%). There were no significant correlations of particular genotypes with severity of disease, although there was a weak indication that more severe pneumonia might be associated with having certain mixed genotypes of C. trachomatis. CONCLUSIONS: The prevalence of C. trachomatis in the population of young hospitalized infants with pneumonia in Shenzhen was very high. The relationship between genotype distribution and severity of pneumonia was not clear based on this study due to small sample size. Further in-depth investigation correlating genotype and disease severity based on a larger population is needed. PMID- 25445658 TI - Trypanosoma cruzi diversity in the Gran Chaco: mixed infections and differential host distribution of TcV and TcVI. AB - The transmission cycles of Trypanosoma cruzi in the Gran Chaco are complex networks involving domestic and wild components, whose interrelationships are not well understood. Knowing the circuit of transmission of the different Discrete Typing Units (DTUs) of T. cruzi in the complex environment of the Chaco region is relevant to understanding how the different components (reservoirs, vectors, ecotopes) interact. In the present study we identified the DTUs infecting humans and dogs in two rural areas of the Gran Chaco in Argentina, using molecular methods which avoid parasite culture. Blood samples of humans and dogs were typified by PCR-DNA blotting and hybridization assays with five specific DNA probes (TcI, TcII, TcIII, TcV and TcVI). PCR analyses were performed on seropositive human and dog samples and showed the presence of T. cruzi DNA in 41.7% (98/235) and 53% (35/66) samples, respectively. The identification of infective DTUs was determined in 83.6% (82/98) and 91.4% (32/35) in human and dog samples, respectively. Single infections (36.7% - 36/98) and a previously not detected high proportion of mixed infections (47.9% - 47/98) were found. In a 15.3% (15/98) of samples the infecting DTU was not identified. Among the single infections TcV was the most prevalent DTU (30.6% - 30/98) in human samples; while TcVI (42.8% - 15/35) showed the highest prevalence in dog samples. TcV/TcVI was the most prevalent mixed infection in humans (32.6% - 32/98); and TcI/TcVI (14.3% - 5/35) in dogs. Significant associations between TcV with humans and TcVI with dogs were detected. For the first time, the presence of TcIII was detected in humans from this region. The occurrence of one human infected whit TcIII (a principally wild DTU) could be suggested the emergence of this, in domestic cycles in the Gran Chaco. PMID- 25445659 TI - AIDS-related Pneumocystis jirovecii genotypes in French Guiana. AB - The study described Pneumocystis jirovecii (P. jirovecii) multilocus typing in seven AIDS patients living in French Guiana (Cayenne Hospital) and seven immunosuppressed patients living in Brest, metropolitan France (Brest Hospital). Archival P. jirovecii specimens were examined at the dihydropteroate synthase (DHPS) locus using a PCR-RFLP technique, the internal transcribed spacer (ITS) 1 and ITS 2 and the mitochondrial large subunit rRNA (mtLSUrRNA) gene using PCR and sequencing. Analysis of typing results were combined with an analysis of the literature on P. jirovecii mtLSUrRNA types and ITS haplotypes. A wild DHPS type was identified in six Guianese patients and in seven patients from metropolitan France whereas a DHPS mutant was infected in the remaining Guianese patient. Typing of the two other loci pointed out a high diversity of ITS haplotypes and an average diversity of mtLSUrRNA types in French Guiana with a partial commonality of these haplotypes and types described in metropolitan France and around the world. Combining DHPS, ITS and mtLSU types, 12 different multilocus genotypes (MLGs) were identified, 4 MLGs in Guianese patients and 8 MLGs in Brest patients. MLG analysis allows to discriminate patients in 2 groups according to their geographical origin. Indeed, none of the MLGs identified in the Guianese patients were found in the Brest patients and none of the MLGs identified in the Brest patients were found in the Guianese patients. These results show that in French Guiana (i) PCP involving DHPS mutants occur, (ii) there is a diversity of ITS and mtLSUrRNA types and (iii) although partial type commonality in this territory and metropolitan France can be observed, MLG analysis suggests that P. jirovecii organisms from French Guiana may present specific characteristics. PMID- 25445660 TI - Analysis of the genotypic diversity of strains of Helicobacter pylori isolated from pediatric patients in Mexico. AB - Genotypic differences in Helicobacter pylori play an important role in infection. We characterized the diversity of the cagA, cagE, babA2, and vacA genes in H. pylori strains isolated from pediatric patients and the relationship between these genes and clinical disease. Additionally, we employed the Neighbor-net algorithm to predict the behavior of the genotypes of the strains isolated from patients. Of 93 patients analyzed, 32 were positive for infection. A total of 160 H. pylori strains (five isolates per positive patient) were analyzed. A total of 91% and 83% of strains possessed the cagA and cagE genes, respectively. For the vacA gene, 84% of strains possessed the s1 allele, 15% the s2 allele, 81% the m1 allele and 13.8% the m2 allele. The babA2 gene was present in 79% of strains. Infection with H. pylori strains with the vacA (s1m1) genotype was associated with risk of esophagitis and gastritis (p=0.0001). The combination of cagA and vacA (s1m1) was significantly associated with abdominal pain (p=0.002); however, EPIYA type was not significantly associated with abdominal pain. A total of 16 different genotypes were identified; the most common genotype was vacAs1m1cagA+cagE+babA2+ (47.5%). A total of 84% of pediatric patients were infected by at least two and up to five different genotypes. The network recovered two genotype groups (A: strains with vacAs1 and B: strains with vacAs2). The presence of multiple paths in the network suggests that reticulate events, such as recombination or reinfection, have contributed to the observed genotypic diversity. PMID- 25445661 TI - Molecular and phylogenetic characterization of multidrug resistant extended spectrum beta-lactamase producing Escherichia coli isolated from poultry and cattle in Odisha, India. AB - The present study was undertaken to determine the occurrence and characterization of extended spectrum beta-lactamase (ESBL) producing Escherichia coli isolated from cattle and poultry in Odisha, India. Of 316 E. coli isolated from 305 samples (170 fecal samples from poultry and 135 milk samples from cattle), a total of 18 E. coli isolates were confirmed as ESBL producers by combination disc method and ESBL E-test. The isolates were resistant to oxyimino cephalosporins and monobactam as revealed by disc diffusion assay and determination of minimum inhibitory concentration. Resistance against other antibiotics was frequently noted as well. Further, beta-lactamase genes viz., blaSHV, blaCTXM, blaTEM and blaampC were detected in 17, 13, 9 and 2 isolates, respectively in PCR. Of the 18 ESBL strains, 16 were positive for class I integron (int1), nine of them carried sulphonamide resistance gene (sul1) and one harbored quinolone resistance gene (qnrB). Virulence markers for extraintestinal pathogenic E. coli like astA, tsh and iucD were also present in 4, 3 and 3 isolates, respectively. All the PCR amplified products were cloned and subjected to sequencing for homology analysis and data were submitted to gene bank. Sequence analysis of the amplified variable regions of class 1 integron of four representative isolates revealed the presence of aadA2 and dfrA12 gene cassettes conferring resistance to aminoglycosides and trimethoprim, respectively. Most of the ESBL producing strains emerged as single lineage through phylogenetic analysis by RAPD and ERIC PCR. This is the first ever systemic study on multidrug resistant ESBL producing E. coli in food producing animals from India. PMID- 25445662 TI - Cloning and characterization of a basic cysteine-like protease (cathepsin L1) expressed in the gut of larval Diaprepes abbreviatus L. (Coleoptera: Curculionidae). AB - Diaprepes abbreviatus is an important pest that causes extensive damage to citrus in the USA. Analysis of an expressed sequence tag (EST) library from the digestive tract of larvae and adult D. abbreviatus identified cathepsins as major putative digestive enzymes. One class, sharing amino acid sequence identity with cathepsin L's, was the most abundant in the EST dataset representing 14.4% and 3.6% of the total sequences in feeding larvae and adults, respectively. The predominant cathepsin (Da-CTSL1) among this class was further studied. Three dimensional modeling of the protein sequence showed that the mature Da-CTSL1 protein folds into an expected cathepsin L structure producing a substrate binding pocket with appropriate positioning of conserved amino acid residues. A full-length cDNA was obtained and the proCTSL1 encoding sequence was expressed in RosettaTM Escherichia coli cells engineered to express tRNAs specific for eukaryotic codon usage. The Da-CTSL1 was expressed as a fusion protein with GST and His6 tags and purified in the presence of 1% Triton X-100 by Ni-NTA affinity and size exclusion chromatography. Recombinant mature Da-CTSL1 (23 KDa) exhibits optimal activity at pH 8, rather than at acidic pH that was shown of all previously characterized cathepsins L. Substrate specificity supports the hypothesis that Da-CTSL1 is a unique basic cathepsin L and protease inhibitor studies also suggest unique activity, unlike other characterized acidic cathepsin Ls. This paper describes for the first time a prokaryotic expression system for the production of a functional eukaryotic cathepsin L1 from larval gut of D. abbreviatus. PMID- 25445665 TI - Pretty in pink? Firearm hazards for domestic violence victims. PMID- 25445664 TI - Coordinated changes in JH biosynthesis and JH hemolymph titers in Aedes aegypti mosquitoes. AB - Juvenile hormone III (JH) is synthesized by the corpora allata (CA) and plays a key role in mosquito development and reproduction. A decrease in JH titer during the last instar larvae allows pupation and metamorphosis to proceed. As the anti metamorphic role of JH comes to an end, the CA of the late pupa once again synthesizes JH, which plays an essential role in orchestrating reproductive maturation. In spite of the importance of Aedes aegypti as a vector, a detailed study of the changes of JH hemolymph titers during the gonotrophic cycle has never been performed. In the present studies, using a high performance liquid chromatography coupled to a fluorescent detector (HPLC-FD) method, we measured changes in JH levels in the hemolymph of female mosquitoes during the pupal and adult stages. Our results revealed tightly concomitant changes in JH biosynthesis and JH hemolymph titers during the gonotrophic cycle of female mosquito. Feeding high sugar diets resulted in an increase of JH titers, and mating also modified JH titers in hemolymph. In addition these studies confirmed that JH titer in mosquitoes is fundamentally determined by the rate of biosynthesis in the CA. PMID- 25445663 TI - Effects of atrazine exposure on male reproductive performance in Drosophila melanogaster. AB - Atrazine is a commonly utilized herbicide to control broadleaf weeds in the agricultural setting. It can, however, have negative effects on male reproductive performance in a variety of vertebrate species. Much less is known, however, about the effects of atrazine on invertebrates. In this study, we investigated the effects of several different concentrations of larval atrazine exposure on measures of reproductive performance in adult male Drosophila melanogaster. Atrazine exposure had significant effects on a male's mating ability and the number of eggs his partner laid when he was successful at mating. Exposed males also sired a smaller proportion of the offspring under competitive conditions when they were the first male to mate to a doubly mated female. Atrazine exposure had no measurable effect on a male's ability to prevent a mated female from mating to another male or on the proportion of offspring sired when the exposed males were the second male to mate. Exposure upregulated expression of one male reproductive gene, ovulin, but had no effect on expression of another, sex peptide. Exposed males produced and transferred more sex peptide protein to the female during mating but ovulin protein levels were not affected. In general, we observed non-monotonic responses such that the intermediate exposure levels showed the largest reduction in male reproductive performance. This study suggests that atrazine exposure affects male reproductive performance in insects and future studies should aim to understand the molecular mechanisms underlying the fitness effects of exposure. PMID- 25445666 TI - Same-day intrauterine device placement is rarely complicated by pelvic infection. AB - PURPOSE: To compare rates of pelvic inflammatory disease (PID) among women who did and did not receive an intrauterine device (IUD) the day they sought emergency contraception (EC) or pregnancy testing. METHODS: Women, 15 to 45 years of age, who sought EC or pregnancy testing from an urban family planning clinic completed surveys at the time of their clinic visit (August 22, 2011, to May 30, 2013) and 3 months after their clinic visit. The surveys assessed contraceptive use and symptoms, testing, and treatment for sexually transmitted infections (STI) and PID. We reviewed the medical records of participants who reported IUD placement within 3 months of enrollment and abstracted de-identified electronic medical record (EMR) data on all women who sought EC or pregnancy testing from the study clinic during the study period. FINDINGS: During the study period, 1,060 women visited the study clinic; 272 completed both enrollment and follow-up surveys. Among survey completers with same-day IUD placement, PID in the 3 months after enrollment was not more common (1/28 [3.6%]; 95% CI, 0%-10.4%) than among women who did not have a same-day IUD placed (11/225 [4.9%]; 95% CI, 2.7%-8.6%; p = .71). Chart review and EMR data similarly showed that rates of PID within 3 months of seeking EC or pregnancy testing were low whether women opted for same day or delayed IUD placement. CONCLUSIONS: Same-day IUD placement was not associated with higher rates of PID. Concern for asymptomatic STI should not delay IUD placement, and efforts to increase the uptake of this highly effective reversible contraception should not be limited to populations at low risk of STI. PMID- 25445667 TI - Ion channels and transporters in metastasis. AB - An elaborate interplay between ion channels and transporters, components of the cytoskeleton, adhesion molecules, and signaling cascades provides the basis for each major step of the metastatic cascade. Ion channels and transporters contribute to cell motility by letting through or transporting ions essential for local Ca2+, pH and--in cooperation with water permeable aquaporins--volume homeostasis. Moreover, in addition to the actual ion transport they, or their auxiliary subunits, can display non-conducting activities. They can exert kinase activity in order to phosphorylate cytoskeletal constituents or their associates. They can become part of signaling processes by permeating Ca2+, by generating local pH-nanodomains or by being final downstream effectors. A number of channels and transporters are found at focal adhesions, interacting directly or indirectly with proteins of the extracellular matrix, with integrins or with components of the cytoskeleton. We also include the role of aquaporins in cell motility. They drive the outgrowth of lamellipodia/invadopodia or control the number of beta1 integrins in the plasma membrane. The multitude of interacting ion channels and transporters (called transportome) including the associated signaling events holds great potential as therapeutic target(s) for anticancer agents that are aimed at preventing metastasis. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25445668 TI - Differential repositioning of the second transmembrane helices from E. coli Tar and EnvZ upon moving the flanking aromatic residues. AB - Aromatic tuning, i.e. repositioning aromatic residues found at the cytoplasmic end of transmembrane (TM) domains within bacterial receptors, has been previously shown to modulate signal output from the aspartate chemoreceptor (Tar) and the major osmosensor EnvZ of Escherichia coli. In the case of Tar, changes in signal output consistent with the vertical position of the native Trp-Tyr aromatic tandem within TM2 were observed. In contrast, within EnvZ, where a Trp-Leu-Phe aromatic triplet was repositioned, the surface that the triplet resided upon was the major determinant governing signal output. However, these studies failed to determine whether moving the aromatic residues was sufficient to physically reposition the TM helix within a membrane. Recent coarse-grained molecular dynamics (CG-MD) simulations predicted displacement of Tar TM2 upon moving the aromatic residues at the cytoplasmic end of the helix. Here, we demonstrate that repositioning the Trp-Tyr tandem within Tar TM2 displaces the C-terminal boundary of the helix relative to the membrane. In a similar analysis of EnvZ, an abrupt initial displacement of TM2 was observed but no subsequent movement was seen, suggesting that the vertical position of TM2 is not governed by the location of the Trp-Leu-Phe triplet. Our results also provide another set of experimental data, i.e. the resistance of EnvZ TM2 to being displaced upon aromatic tuning, which could be useful for subsequent refinement of the initial CG-MD simulations. Finally, we discuss the limitations of these methodologies, how moving flanking aromatic residues might impact steady-state signal output and the potential to employ aromatic tuning in other bacterial membrane-spanning receptors. PMID- 25445669 TI - The role of tryptophans on the cellular uptake and membrane interaction of arginine-rich cell penetrating peptides. AB - Cell-penetrating peptides (CPP) are able to efficiently transport cargos across cell membranes without being cytotoxic to cells, thus present a great potential in drug delivery and diagnosis. While the role of cationic residues in CPPs has been well studied, that of Trp is still not clear. Herein 7 peptide analogs of RW9 (RRWWRRWRR, an efficient CPP) were synthesized in which Trp were systematically replaced by Phe residues. Quantification of cellular uptake reveals that substitution of Trp by Phe strongly reduces the internalization of all peptides despite the fact that they strongly accumulate in the cell membrane. Cellular internalization and biophysical studies show that not only the number of Trp residues but also their positioning in the helix and the size of the hydrophobic face they form are important for their internalization efficacy, the highest uptake occurring for the analog with 3 Trp residues. Using CD and ATR FTIR spectroscopy we observe that all peptides became structured in contact with lipids, mainly in alpha-helix. Intrinsic tryptophan fluorescence studies indicate that all peptides partition in the membrane in about the same manner (Kp~10(5)) and that they are located just below the lipid headgroups (~10 A) with slightly different insertion depths for the different analogs. Plasmon Waveguide Resonance studies reveal a direct correlation between the number of Trp residues and the reversibility of the interaction following membrane washing. Thus a more interfacial location of the CPP renders the interaction with the membrane more adjustable and transitory enhancing its internalization ability. PMID- 25445670 TI - Conserved disulfide bond is not essential for the adenosine A2A receptor: Extracellular cysteines influence receptor distribution within the cell and ligand-binding recognition. AB - G protein-coupled receptors (GPCRs) are integral membrane proteins involved in cellular signaling and constitute major drug targets. Despite their importance, the relationship between structure and function of these receptors is not well understood. In this study, the role of extracellular disulfide bonds on the trafficking and ligand-binding activity of the human A2A adenosine receptor was examined. To this end, cysteine-to-alanine mutations were conducted to replace individual and both cysteines in three disulfide bonds present in the first two extracellular loops. Although none of the disulfide bonds were essential for the formation of plasma membrane-localized active GPCR, loss of the disulfide bonds led to changes in the distribution of the receptor within the cell and changes in the ligand-binding affinity. These results indicate that in contrast to many class A GPCRs, the extracellular disulfide bonds of the A2A receptor are not essential, but can modulate the ligand-binding activity, by either changing the conformation of the extracellular loops or perturbing the interactions of the transmembrane domains. PMID- 25445672 TI - Molecular dynamics methods to predict peptide locations in membranes: LAH4 as a stringent test case. AB - Determining the structure of membrane-active peptides inside lipid bilayers is essential to understand their mechanism of action. Molecular dynamics simulations can easily provide atomistic details, but need experimental validation. We assessed the reliability of self-assembling (or "minimum-bias") and potential of mean force (PMF) approaches, using all-atom (AA) and coarse-grained (CG) force fields. The LAH4 peptide was selected as a stringent test case, since it is known to attain different orientations depending on the protonation state of its four histidine residues. In all simulations the histidine side-chains inserted in the membrane when neutral, while they interacted with phospholipid headgroups in their charged state. This led to transmembrane orientations for neutral-His LAH4 in all minimum-bias AA simulations and in most CG trajectories. By contrast, the charged-His peptide stabilized membrane defects in AA simulations, whereas it was located at the membrane surface in some CG trajectories, and interacted with both lipid leaflets in others. This behavior is consistent with the higher antimicrobial activity and membrane-permeabilizing behavior of the charged-His LAH4. In addition, good agreement with solid-state NMR orientational data was observed in AA simulations. PMF calculations correctly predicted a higher membrane affinity for the neutral-His peptide. Interestingly, the structures and relative populations of PMF local free-energy minima corresponded to those determined in the less computationally demanding minimum-bias simulations. These data provide an indication about the possible membrane-perturbation mechanism of the charged-His LAH4 peptide: by interacting with lipid headgroups of both leaflets through its cationic side-chains, it could favor membrane defects and facilitate translocation across the bilayer. PMID- 25445671 TI - The YhhN protein of Legionella pneumophila is a Lysoplasmalogenase. AB - Lysoplasmalogenase catalyzes hydrolytic cleavage of the vinyl-ether bond of lysoplasmalogen to yield fatty aldehyde and glycerophospho-ethanolamine or glycerophospho-choline. We recently purified lysoplasmalogenase from rat liver microsomes and identified the protein as TMEM86B, an integral membrane protein that is a member of the YhhN family found in numerous species of eukaryotes and bacteria. To test the hypothesis that bacterial YhhN proteins also function as lysoplasmalogenase enzymes, we cloned the Lpg1991 gene of Legionella pneumophila, which encodes a 216 amino acid YhhN protein (LpYhhN), and expressed it in Escherichia coli as a C-terminal-GFP-His8-fusion. Membranes were solubilized and the fusion protein was purified by nickel-affinity chromatography, cleaved with Tobacco Etch Virus protease, and subjected to a reverse nickel column to purify the un-tagged LpYhhN. Both the fusion protein and un-tagged LpYhhN exhibit robust lysoplasmalogenase activity, cleaving the vinyl-ether bond of lysoplasmalogen with a Vmax of 12 umol/min/mg protein and a Km of 45 MUM. LpYhhN has no activity on diradyl plasmalogen, 1-alkenyl-glycerol, and monoacylglycerophospho ethanolamine or monoacylglycerophospho-choline; the pH optimum is 6.5-7.0. These properties are very similar to mammalian TMEM86B. Sequence analysis suggests that YhhN proteins contain eight transmembrane helices, an N-in/C-in topology, and about 5 highly conserved amino acid residues that may form an active site. This work is the first to demonstrate a function for a bacterial YhhN protein, as a vinyl ether bond hydrolase specific for lysoplasmalogen. Since L. pneumophila does not contain endogenous plasmalogens, we hypothesize that LpYhhN may serve to protect the bacterium from lysis by lysoplasmalogen derived from plasmalogens of the host. PMID- 25445673 TI - Role of ion channels in ionizing radiation-induced cell death. AB - Neoadjuvant, adjuvant or definitive fractionated radiation therapy are implemented in first line anti-cancer treatment regimens of many tumor entities. Ionizing radiation kills the tumor cells mainly by causing double strand breaks of their DNA through formation of intermediate radicals. Survival of the tumor cells depends on both, their capacity of oxidative defense and their efficacy of DNA repair. By damaging the targeted cells, ionizing radiation triggers a plethora of stress responses. Among those is the modulation of ion channels such as Ca2+-activated K+ channels or Ca2+-permeable nonselective cation channels belonging to the super-family of transient receptor potential channels. Radiogenic activation of these channels may contribute to radiogenic cell death as well as to DNA repair, glucose fueling, radiogenic hypermigration or lowering of the oxidative stress burden. The present review article introduces these channels and summarizes our current knowledge on the mechanisms underlying radiogenic ion channel modulation. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25445675 TI - Effect of glycyrrhetinic acid on lipid raft model at the air/water interface. AB - To investigate an interfacial behavior of the aglycon of glycyrrhizin (GC), glycyrrhetinic acid (GA), with a lipid raft model consisting of equimolar ternary mixtures of N-palmitoyl sphingomyelin (PSM), dioleoylphosphatidylcholine (DOPC), and cholesterol (CHOL), Langmuir monolayer techniques were systematically conducted. Surface pressure (pi)-molecular area (A) and surface potential (DeltaV)-A isotherms showed that the adsorbed GA at the air/water interface was desorbed into the bulk upon compression of the lipid monolayer. In situ morphological analysis by Brewster angle microscopy and fluorescence microscopy revealed that the raft domains became smaller as the concentrations of GA in the subphase (CGA) increased, suggesting that GA promotes the formation of fluid networks related to various cellular processes via lipid rafts. In addition, ex situ morphological analysis by atomic force microscopy revealed that GA interacts with lipid raft by lying down at the surface. Interestingly, the distinctive striped regions were formed at CGA=5.0 MUM. This phenomenon was observed to be induced by the interaction of CHOL with adsorbed GA and is involved in the membrane-disrupting activity of saponin and its aglycon. A quantitative comparison of GA with GC (Sakamoto et al., 2013) revealed that GA interacts more strongly with the raft model than GC in the monolayer state. Various biological activities of GA are known to be stronger than those of GC. This fact allows us to hypothesize that differences in the interactions of GA/GC with the model monolayer correlate to their degree of exertion for numerous activities. PMID- 25445674 TI - Fungicidal effect of isoquercitrin via inducing membrane disturbance. AB - Isoquercitrin is a flavonoid isolated from Aster yomena, which has been used as a traditional medicinal herb. In the present study, we investigated the antifungal activity and the underlying mechanism of isoquercitrin. Isoquercitrin had a potent effect in the susceptibility test against pathogenic fungi and almost no hemolysis. Propidium iodide and potassium release assays were conducted in Candida albicans, and these studies confirmed that isoquercitrin induced membrane damage, thereby, increasing permeability. Membrane potential was analyzed using 3,3'-dipropylthiacarbocyanine iodide [DiSC3(5)], and the transition of membrane potential was indicated by an increased fluorescence intensity. To further analyze these results using model membranes, giant unilamellar vesicles and large unilamellar vesicles that encapsulated calcein were prepared and the detection of calcein leakage from liposomes indicated that membrane was disturbed. We further verified membrane disturbance by observing the disordered status of the lipid bilayer with 1,6-diphenyl-1,3,5-hexatriene fluorescence. Moreover, changes in size and granularity of the cell were revealed in flow cytometric analysis. All these results suggested the membrane disturbance and the degree of disturbance was estimated to be within a range of 2.3 nm to 3.3 nm by fluorescein isothiocyanate-dextran analysis. Taken together, isoquercitrin exerts its fungicidal effect by disturbing the membrane of cells. PMID- 25445677 TI - Novel endosomolytic peptides for enhancing gene delivery in nanoparticles. AB - Trapping in the endosomes is currently believed to represent the main barrier for transfection. Peptides, which allow endosomal escape have been demonstrated to overcome this barrier, similarly to the entry of viruses. However, the design principles of such endosomolytic peptides remain unclear. We characterized three analogs derived from membrane disrupting antimicrobial peptides (AMP), viz. LL 37, melittin, and bombolitin V, with glutamic acid substituting for all basic residues. These analogs are pH-sensitive and cause negligible membrane permeabilization and insignificant cytotoxicity at pH7.4. However, at pH5.0, prevailing in endosomes, membrane binding and hemolysis of human erythrocytes become evident. We first condensed the emerald green fluorescent protein (emGFP) containing plasmid by protamine, yielding 115 nm diameter soluble nanoplexes. For coating of the nanoplex surface with a lipid bilayer we introduced a hydrophobic tether, stearyl-octa-arginine (SR8). The indicated peptides were dissolved in methanol and combined with lipid mixtures in chloroform, followed by drying at RT under a nitrogen flow. The dry residues were hydrated with nanoplexes in Hepes, pH7.4 yielding after a 30 min incubation at RT,rather monodisperse nanoparticles having an average diameter of 150-300 nm, measured by DLS and cryo-TEM. Studies with cell cultures showed the above peptides to yield expression levels comparable to those obtained using Lipofectamine 2000. However, unlike the polydisperse aggregates formed upon mixing Lipofectamine 2000 and plasmid, the procedure described yields soluble, and reasonably monodisperse nanoparticles, which can be expected to be suitable for gene delivery in vivo, using intravenous injection. PMID- 25445676 TI - Mutations of the central tyrosines of putative cholesterol recognition amino acid consensus (CRAC) sequences modify folding, activity, and sterol-sensing of the human ABCG2 multidrug transporter. AB - Human ABCG2 is a plasma membrane glycoprotein causing multidrug resistance in cancer. Membrane cholesterol and bile acids are efficient regulators of ABCG2 function, while the molecular nature of the sterol-sensing sites has not been elucidated. The cholesterol recognition amino acid consensus (CRAC, L/V-(X)(1-5) Y-(X)(1-5)-R/K) sequence is one of the conserved motifs involved in cholesterol binding in several proteins. We have identified five potential CRAC motifs in the transmembrane domain of the human ABCG2 protein. In order to define their roles in sterol-sensing, the central tyrosines of these CRACs (Y413, 459, 469, 570 and 645) were mutated to S or F and the mutants were expressed both in insect and mammalian cells. We found that mutation in Y459 prevented protein expression; the Y469S and Y645S mutants lost their activity; while the Y570S, Y469F, and Y645F mutants retained function as well as cholesterol and bile acid sensitivity. We found that in the case of the Y413S mutant, drug transport was efficient, while modulation of the ATPase activity by cholesterol and bile acids was significantly altered. We suggest that the Y413 residue within a putative CRAC motif has a role in sterol-sensing and the ATPase/drug transport coupling in the ABCG2 multidrug transporter. PMID- 25445679 TI - Process variables influence on microwave assisted extraction of pectin from waste Carcia papaya L. peel. AB - The objectives of the present study were to evaluate and optimize the influence of process variables such as microwave power, pH, time and solid-liquid ratio on the extraction of pectin from waste Carcia papaya L peel. The experiments were carried out based on a four factors three level Box-Behnken response surface design. A quadratic model was developed from the experimental data in order to predict the pectin yield. The optimal condition was found to be: microwave power of 512 w, pH of 1.8, time of 140 s and solid-liquid ratio of 1:15 g/ml with maximum pectin yield (25.41%). PMID- 25445680 TI - Tough and elastic hydrogel of hyaluronic acid and chondroitin sulfate as potential cell scaffold materials. AB - Natural polysaccharides are extensively investigated as cell scaffold materials for cellular adhesion, proliferation, and differentiation due to their excellent biocompatibility, biodegradability, and biofunctions. However, their application is often severely limited by their mechanical behavior. In this study, a tough and elastic hydrogel scaffold was prepared with hyaluronic acid (HA) and chondroitin sulfate (CS). HA and CS were conjugated with tyramine (TA) and the degree of substitution (DS) was 10.7% and 11.3%, respectively, as calculated by (1)H NMR spectra. The hydrogel was prepared by mixing HA-TA and CS-TA in presence of H2O2 and HRP. The sectional morphology of hydrogels was observed by SEM, static and dynamic mechanical properties were analyzed by Shimadzu electromechanical testing machine and dynamic mechanical thermal analyzer Q800. All samples showed good ability to recover their appearances after deformation, the storage modulus (E') of hydrogels became higher as the testing frequency went up. Hydrogels also showed fatigue resistance to cyclic compression. Mesenchymal stem cells encapsulated in hydrogels showed good cell viability as detected by CLSM. This study suggests that the hydrogels have both good mechanical properties and biocompatibility, and may serve as model systems to explore mechanisms of deformation and energy dissipation or find some applications in tissue engineering. PMID- 25445678 TI - Monitoring antibacterial permeabilization in real time using time-resolved flow cytometry. AB - Despite the intensive study of antibiotic-induced bacterial permeabilization, its kinetics and molecular mechanism remain largely elusive. A new methodology that extends the concept of the live-dead assay in flow cytometry to real time resolved detection was used to overcome these limitations. The antimicrobial activity of pepR was monitored in time-resolved flow cytometry for three bacterial strains: Escherichia coli (ATCC 25922), E. coli K-12 (CGSC Strain 4401) and E. coli JW3596-1 (CGSC Strain 11805). The latter strain has truncated lipopolysaccharides (LPS) in the outer membrane. This new methodology provided information on the efficacy of the antibiotics and sheds light on their mode of action at membrane-level. Kinetic data regarding antibiotic binding and lytic action were retrieved. Membrane interaction and permeabilization events differ significantly among strains. The truncation of LPS moieties does not hamper AMP binding but compromises membrane disruption and bacterial killing. We demonstrated the usefulness of time-resolved flow cytometry to study antimicrobial-induced permeabilization by collecting kinetic data that contribute to characterize the action of antibiotics directly on bacteria. PMID- 25445681 TI - Kinetic release studies of nitrogen-containing bisphosphonate from gum acacia crosslinked hydrogels. AB - Natural polymer hydrogels are useful for controlling release of drugs. In this study, hydrogels containing gum acacia were synthesized by free-radical polymerization of acrylamide with gum acacia. The effect of gum acacia in the hydrogels on the release mechanism of nitrogen-containing bisphosphonate (BP) was studied at pH 1.2 and 7.4. The hydrogels exhibited high swelling ratios at pH 7.4 and low swelling ratios at pH 1.2. The release study was performed using UV Visible spectroscopy via complex formation with Fe(III) ions. At pH 1.2, the release profile was found to be anomalous while at pH 7.4, the release kinetic of BP was a perfect zero-order release mechanism. The hydrogels were found to be pH sensitive and the release profiles of the BP were found to be influenced by the degree of crosslinking of the hydrogel network with gum acacia. The preliminary results suggest that these hydrogels are promising devices for controlled delivery of bisphosphonate to the gastrointestinal region. PMID- 25445683 TI - Heat-induced formation of myosin oligomer-soluble filament complex in high-salt solution. AB - Heat-induced aggregation of myosin into an elastic gel plays an important role in the water-holding capacity and texture of meat products. Here, we investigated thermal aggregation of porcine myosin in high-salt solution over a wide temperature range by dynamic light scattering experiments. The myosin samples were readily dissolved in 1.0 M NaCl at 25 degrees C followed by dilution into various salt concentrations. The diluted solutions consistently contained both myosin monomers and soluble filaments. The filament size decreased with increasing salt concentration and temperature. High temperatures above Tm led to at least partial dissociation of soluble filaments and thermal unfolding, resulting in the formation of soluble oligomers and binding to the persistently present soluble filaments. Such a complex formation between the oligomers and filaments has never been observed. Our results provide new insight into the heat induced myosin gelation in high-salt solution. PMID- 25445682 TI - Hierarchically organization of biomineralized alginate beads for dual stimuli responsive drug delivery. AB - Compartmentalized biomineralized alginate beads ranging from the micro to the visible scales with thermal- and pH-responsive drug delivery properties have been prepared via a one-step method in the present paper. Hollow multilayer microcapsules made of aliphatic poly(urethane-amine) (PUA) and sodium poly(styrenesulfonate) (PSS) serve as drug container to slow down the drug release. The results indicate that internal hollow multilayer microcapsules could hinder the permeation of the encapsulated Vitamin B2 (VB2) and retard the initial burst release of VB2. In addition, the drug release of compartmentalized biomineralized alginate beads exhibit distinguished pH- and thermal-dependent property due to pH-responsive alginate and the thermal-responsive aliphatic PUA. The drug release decreases when decreasing the pH value because the compact construction of alginate and biomineralized layer could prevent VB2 release from the beads. Moreover, the drug release is higher at 55 degrees C than that at 37 degrees C for the sake of the shrinkage of aliphatic PUA above its lower critical solution temperature (LCST). The results demonstrate that the compartmentalized biomineralized alginate beads show great potential as smart materials for controllable drug delivery. PMID- 25445684 TI - Heparin-like native protein aggregate dissociation by 1-alkyl-3-methyl imidazolium chloride ionic liquids. AB - At room temperature, ionic liquids (ILs) 1-alkyl-3-methyl imidazolium chloride (alkyl: ethyl, butyl, hexyl and octyl) are observed to exhibit aggregate dissociation behavior of native proteins. This is similar to the well known protein aggregation inhibitor and aggregate dissociation molecule heparin. Dynamic light scattering (DLS) experiments performed on three model proteins bovine serum albumin (BSA), beta-lactoglobulin (beta-Lg) and immunoglobulin (IgG) revealed that on addition of ILs the fractal aggregates of proteins (apparent maximum hydrodynamic radius Rmax and fractal dimension df=1.5+/-0.2) dissociated into oligomers (hydrodynamic radius Rh) following an exponential decay profile with time, Rh=Rmaxexp(-kat) The dissociation constant ka has been correlated to hydrophobicity index (H-index) of the protein concerned. Thus, if the combined contributions of dissociation constant and hydration effect on secondary structure are taken into account together, [C8mim][Cl] with BSA, [C2mim][Cl] with beta-Lg and IgG, rank as the best aggregation reversal agent (ARA) amongst all other ionic liquid samples examined. The additional advantage of the used ILs over heparin is the release of mobile Cl(-) ions to the solution. This lead to the increased solution entropy, thereby, providing stability to the final dispersions. PMID- 25445685 TI - In situ generation of silver nanoparticles within crosslinked 3D guar gum networks for catalytic reduction. AB - The direct use of guar gum (GG) as a green reducing agent for the facile production of highly stable silver nanoparticles (Ag NPs) within this biopolymer and subsequent crosslinking with borax to form crosslinked Ag@GG beads with a 3D structured network are presented here. These crosslinked Ag@GG beads were characterized using UV-vis absorption spectroscopy, X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM) and Fourier transform infrared (FTIR) spectroscopy, and then tested as a solid-phase heterogenerous catalyst for the reduction of 4 nitrophenol (4-NP) to 4-aminophenol (4-AP) in the presence of excess borohydride. The results indicate that these crosslinked Ag@GG beads show excellent catalytic performance for the reduction of 4-NP within 20 min and can be readily used for 10 successive cycles. PMID- 25445686 TI - Pasting investigation, SEM observation and the possible interaction study on rice starch-pullulan combination. AB - The pasting properties of rice starch (RS) with high concentration (10%, w/w) were investigated in the presence or absence of pullulan (PUL) using a rapid visco-analyzer (RVA). Addition of pullulan resulted in the reduction of peak viscosity, trough viscosity, final viscosity, and setback value of RS. Furthermore, an interesting phenomenon, i.e. a small viscosity peak appeared in the RVA curves of RS-PUL mixtures, was observed. It indicated that addition of pullulan might suppress the gelatinization of starch granules by maintaining the integration of some granules. The scanning electron microscope (SEM) observation of samples suggested that starch granules could be wrapped by a thin membrane composed of pullulan and/or pullulan-amylose associations. The coating ability of pullulan and/or the possible molecular interactions between pullulan and amylose could be responsible for these results. PMID- 25445687 TI - Phycoerythrins in phycobilisomes from the marine red alga Polysiphonia urceolata. AB - Phycoerythrins (PE) in phycobilisomes from Polysiphonia urceolata were studied in this research. Dissociative products of phycobilisomes were analyzed by sucrose density gradient centrifugation and native-PAGE. At least three types of PEs were found in the dissociative products of phycobilisomes. According to their molecular weights, absorption spectra and subunit components, they should be PE hexamer containing gamma1 subunit, PE hexamer containing gamma2 subunit and PE monomer containing no gamma subunit. PEs bigger than hexmer were also found in the dissociative products of phycobilisomes in 200mM phosphate buffer when dissociated phycobilisomes were analyzed by sucrose density gradient centrifugation. PE trimers containing no gamma subunits were also found in products of dissociated phycobilisomes in deionized water when dissociated phycobilisomes were analyzed by native-PAGE. This is the first time that pure PE hexamers containing gamma2 subunits were isolated from P. urceolata. The PE monomers containing no gamma subunits should come from PE trimers or hexamers containing no gamma subunits in the "rod" of phycobilisomes. It can be concluded that there are three types of PEs in "rod" of phycobilisomes from P. urceolata: PE containing gamma1 subunit, PE containing gamma2 subunit and PE containing no gamma subunit. PMID- 25445689 TI - Magnetic nanoparticles-serum proteins bioconjugates for binding of irinotecan. AB - The binding of irinotecan to serum proteins (hemoglobin, globulin and human serum albumin) was studied on the surface of epoxide modified superparamagnetic iron oxide nanoparticles (GPTS-SPIONs), which were synthesized by the coprecipitation of ferrous and ferric salts with NH4OH and then modified with [3-(2,3 epoxypropoxy)propyl] trimethoxy silane (GPTS) to obtain functional epoxide groups on the SPIONs' surface. Results were compared to find an alternative as drug carries system. Data showed that binding amount of human serum albumin (HSA), globulin (Glb) and hemoglobin (Hb) found to be as 44, 21.2 and 32.6 MUg per 20 mg of GPTS modified SPIONs, respectively. The thermal behavior of the serum protein Ir interaction on GPTS-SPIONs was also studied by using thermo gravimetric analysis (TGA) technique and then the kinetic parameters for the thermal decomposition were determined using Horowitz-Metzger method. PMID- 25445688 TI - Fucoidan delays apoptosis and induces pro-inflammatory cytokine production in human neutrophils. AB - Although some immune modulatory effects of fucoidan have been elucidated, the effects of fucoidan on the apoptosis and activation of human neutrophils have not been investigated. In this study, we demonstrated that fucoidan purified from the brown seaweed Undaria pinnatifilda delays spontaneous apoptosis of human neutrophils and induces their activation. Fucoidan treatment inhibited apoptotic nuclei changes and phosphatidyl serine (PS) exposure on neutrophils cultured in vitro for 24h. The delay in neutrophil apoptosis mediated by fucoidan was associated with increased levels of the anti-apoptotic protein Mcl-1 and decreased levels of activated caspase-3. Screening of the signaling pathways by specific inhibitors indicated that fucoidan-induced delay in neutrophil apoptosis was dependent on the activation of PI3K/AKT signaling pathway, whereas MAPK signaling pathway was not critical. In addition, fucoidan enhanced the production of IL-6, IL-8 and TNF-alpha from neutrophils in an AKT-dependent manner. Taken together, these results demonstrated that fucoidan delays human neutrophil apoptosis and induces their production of pro-inflammatory cytokines. This knowledge could facilitate the development of novel therapeutic strategies for infectious diseases and neutropenia by controlling neutrophil homeostasis and function with fucoidan. PMID- 25445690 TI - Quantification of anti-aggregation activity of UV-irradiated alpha-crystallin. AB - Ultraviolet radiation is a risk factor for cataractogenesis. It is believed that enhanced rates of lens opacification and cataract formation are the results of gradual loss of chaperone-like efficiency of alpha-crystallin upon exposure to UV light. To characterize chaperone-like activity of alpha-crystallin damaged by UV irradiation, a test system based on dithiothreitol-induced aggregation of holo alpha-lactalbumin from bovine milk was used. The adsorption capacity of alpha crystallin (AC0) with respect to the target protein (alpha-lactalbumin) was used as a measure of anti-aggregation activity of alpha-crystallin. The data on SDS PAGE testify that UV irradiation of alpha-crystallin results in covalent cross linking of subunits in alpha-crystallin oligomers. The dependence of AC0 value on the irradiation dose was compared with the UV-induced diminution of the portion of native alpha-crystallin estimated from the data on differential scanning calorimetry. On the basis of such comparison a conclusion has been made that the loss in chaperone-like activity is mainly due to UV-induced denaturation of alpha crystallin subunits. Cross-linking of remaining native subunits leads to an additional decrease in anti-aggregation activity. PMID- 25445691 TI - The effects of physical and chemical treatments on Na2S produced feather keratin films. AB - The industrial utilisation of feather keratin as a biopolymer has proven difficult due to the lack of a viable extraction technique and the poor mechanical properties of the regenerated products. Here, pure keratin films were produced from chicken feathers using sodium sulphide as sole extraction reagent in a scheme that allows films to be formed without residual chemicals. In a comparison to other films, those produced using Na2S extraction were found to be superior to other regenerated protein films and were similar to un-oriented commercial polymers. However, there was considerable variation in tensile properties between twenty repetitions of extracting and casting films which was attributed to variations in chain entanglement caused by the drying conditions. Chemical and physical treatments including crosslinking, dehydration and addition of nano-particles were investigated as means to enhance these properties. Significant increases were achieved by soaking films in isopropyl alcohol or weak acid (13 to 50% increases) or by formaldehyde or glutaraldehyde crosslinking (24 to 40% increases). The wide range of values across the pure keratin films indicates that the best route to further strength improvement may be from optimising self-assembly via controlling drying conditions, rather than from chemical treatment. PMID- 25445692 TI - Simultaneous delivery of therapeutic antagomirs with paclitaxel for the management of metastatic tumors by a pH-responsive anti-microbial peptide mediated liposomal delivery system. AB - The roles of microRNAs (miRNAs) in the regulation of metastasis have been widely recognized in the recent years. Mir-10b antagomir (antagomir-10b) was shown to impede metastasis through the down-regulation of mir-10b; however, it could not stunt the growth of primary tumors. In this study we showed that the co-delivery of antagomir-10b with paclitaxel (PTX) by a novel liposomal delivery system modified with an anti-microbial peptide [D]-H6L9 (D-Lip) could significantly both hinder the migration of 4T1 cells and induce evident cellular apoptosis and cell death in the meantime. The histidines in the sequence of [D]-H6L9 allowed the peptide to get protonated under pH5.0 (mimicking the lysosome/endosome environment), and strong membrane lytic effect could thus be activated, leading to the escape of liposomes from the lysosomes and the decrease of of mir-10b expression. The in vivo and ex vivo fluorescence imaging showed that D-Lip could reach 4T1 tumors efficaciously. Incorporation of PTX did not influence the antagomir-10b delivery effect of D-Lip; for the in vivo tumor inhibition assay, compared with all the other groups, the combination of antagomir-10b and PTX delivered by D-Lip could prominently delay the growth of 4T1 tumors and reduce the lung metastases at the same time, and the expression of Hoxd10 in tumors was also significantly up-regulated. Taken together, these results demonstrated that D-Lip could act as a sufficient tool in co-delivering antagomir-10b and PTX. PMID- 25445693 TI - Charge-conversional and reduction-sensitive poly(vinyl alcohol) nanogels for enhanced cell uptake and efficient intracellular doxorubicin release. AB - Charge-conversional and reduction-sensitive polyvinyl alcohol (PVA) nanogels were developed for efficient cancer treatment by enhanced cell uptake and intracellular triggered doxorubicin (DOX) release. These PVA nanogels were prepared in a straightforward manner by inverse nanoprecipitation via "click" reaction with an average diameter of 118nm. The introduction of COOH into the PVA nanogels efficiently improved the DOX encapsulation due to the electrostatic interaction. The in vitro release result showed that the decrease of electrostatic interaction between COOH and DOX under a mimicking endosomal pH, in combination with the cleavage of the intervening disulfide bonds in response to a high glutathione (GSH) concentration led to a fast and complete release of DOX. Furthermore, confocal laser scanning microscopy (CLSM) revealed that the ultra pH sensitive terminal groups allowed nanogels to reverse their surface charge from negative to positive under a tumor extracellular pH (6.5-6.8) which facilitated cell internalization. MTT assays and real time cell analysis (RTCA) showed that these DOX-loaded charge-conversional and reducible PVA nanogels had much better cell toxicity than DOX-loaded non-charge-conversional or reduction-insensitive PVA nanogels following 48h of incubation. These novel charge-conversional and stimuli-responsive PVA nanogels are highly promising for targeted intracellular anticancer drug release. PMID- 25445695 TI - Brain delivery of insulin boosted by intranasal coadministration with cell penetrating peptides. AB - Intranasal administration is considered as an alternative route to enable effective drug delivery to the central nervous system (CNS) by bypassing the blood-brain barrier. Several reports have proved that macromolecules can be transferred directly from the nasal cavity to the brain. However, strategies to enhance the delivery of macromolecules from the nasal cavity to CNS are needed because of their low delivery efficiencies via this route in general. We hypothesized that the delivery of biopharmaceuticals to the brain parenchyma can be facilitated by increasing the uptake of drugs by the nasal epithelium including supporting and neuronal cells to maximize the potentiality of the intranasal pathway. To test this hypothesis, the CNS-related model peptide insulin was intranasally coadministered with the cell-penetrating peptide (CPP) penetratin to mice. As a result, insulin coadministered with l- or d-penetratin reached the distal regions of the brain from the nasal cavity, including the cerebral cortex, cerebellum, and brain stem. In particular, d-penetratin could intranasally deliver insulin to the brain with a reduced risk of systemic insulin exposure. Thus, the results obtained in this study suggested that CPPs are potential tools for the brain delivery of peptide- and protein-based pharmaceuticals via intranasal administration. PMID- 25445694 TI - Combination therapy with epigenetic-targeted and chemotherapeutic drugs delivered by nanoparticles to enhance the chemotherapy response and overcome resistance by breast cancer stem cells. AB - Aberrant DNA hypermethylation is critical in the regulation of renewal and maintenance of cancer stem cells (CSCs), which represent targets for carcinogenic initiation by chemical and environmental agents. The administration of decitabine (DAC), which is a DNA hypermethylation inhibitor, is an attractive approach to enhancing the chemotherapeutic response and overcoming drug resistance by CSCs. In this study, we investigated whether low-dose DAC encapsulated in nanoparticles could be used to sensitize bulk breast cancer cells and CSCs to chemotherapy. In vitro studies revealed that treatment with nanoparticles loaded with low-dose DAC (NPDAC) combined with nanoparticles loaded with doxorubicin (NPDOX) better reduced the proportion of CSCs with high aldehyde dehydrogenase activity (ALDH(hi)) in the mammospheres of MDA-MB-231 cells, and better overcame the drug resistance by ALDH(hi) cells. Subsequently, systemic delivery of NPDAC significantly down-regulated the expression of DNMT1 and DNMT3b in a MB-MDA-231 xenograft murine model and induced increased caspase-9 expression, which contributed to the increased sensitivity of the bulk cancer cells and CSCs to NPDOX treatment. Importantly, the combined treatment of NPDAC and NPDOX resulted in the lowest proportion of ALDH(hi) CSCs and the highest proportion of apoptotic tumor cells, and the best tumor suppressive effects in inhibiting breast cancer growth. PMID- 25445696 TI - In vivo efficacy of microbiota-sensitive coatings for colon targeting: a promising tool for IBD therapy. AB - The first proof of concept in vivo for a new type of microbiota-sensitive film coatings allowing for colon targeting is presented. The efficacy of these polysaccharide barriers to optimize drug release for the treatment of inflammation is demonstrated in an experimental colitis model with Wister rats. 5 Aminosalicylic acid (5-ASA) pellets were prepared by extrusion-spheronization and coated with Nutriose:ethylcellulose (EC) 1:4 or peas starch:ethylcellulose 1:2 blends. The pellets were mixed with standard chow, and the daily drug dose was 150mg/kg. For reasons of comparison, also commercially available Pentasa pellets and placebo pellets were studied. At day 3 after the beginning of the treatment, colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS). Animals were sacrificed on day 6. Macroscopic and histological evaluations of colitis were performed blindly. In addition, inflammatory markers were evaluated using ELISA and real-time PCR. Rats receiving TNBS and placebo pellets developed a severe colitis in the distal half of the colon. 5-ASA administered in the form of Pentasa pellets reduced macroscopic inflammation by only 5%. In contrast, the colon lesions were much less severe upon treatment with Nutriose:EC- and peas starch:EC-coated pellets: The macroscopic score was reduced by 25 and 24%, respectively. Decreases of 37 and 38% of the histological lesions confirmed the efficacy of these new colon targeting systems. Also, inflammatory markers (MPO, IL-1beta mRNA, TNF mRNA) were significantly decreased in rats receiving Nutriose:EC- and peas starch:EC-coated pellets compared to Pentasa pellets. Furthermore, real-time PCR analysis indicated increased activation of the target receptor PPAR-gamma and the HMGCS2 gene in rats upon administration of 5-ASA loaded Nutriose:EC- and peas starch:EC pellets compared to the commercial product. Also, HPLC-MS/MS analysis of plasma samples demonstrated that the level of the main metabolite of the drug (N-acetyl-5-ASA) was much lower upon administration of Nutriose:EC or peas starch:EC coated pellets compared to Pentasa pellets, indicating that undesired premature drug release in the upper gastrointestinal tract was more effectively hindered. In addition to the rat study, in vivo imaging of transgenic mice expressing the luciferase gene evidenced much more pronounced PPAR-gamma activation upon 5-ASA administration in the form of Nutriose:EC-coated pellets versus Pentasa pellets. All these results clearly demonstrate the superiority of these microbiota-sensitive polysaccharide based film coatings for colon targeting in vivo. PMID- 25445697 TI - Magnetic heating properties and neutron activation of tungsten-oxide coated biocompatible FePt core-shell nanoparticles. AB - Magnetic nanoparticles are highly desirable for biomedical research and treatment of cancer especially when combined with hyperthermia. The efficacy of nanoparticle-based therapies could be improved by generating radioactive nanoparticles with a convenient decay time and which simultaneously have the capability to be used for locally confined heating. The core-shell morphology of such novel nanoparticles presented in this work involves a polysilico-tungstate molecule of the polyoxometalate family as a precursor coating material, which transforms into an amorphous tungsten oxide coating upon annealing of the FePt core-shell nanoparticles. The content of tungsten atoms in the nanoparticle shell is neutron activated using cold neutrons at the Heinz Maier-Leibnitz (FRMII) neutron facility and thereby transformed into the radioisotope W-187. The sizeable natural abundance of 28% for the W-186 precursor isotope, a radiopharmaceutically advantageous gamma-beta ratio of gammabeta~30% and a range of approximately 1mm in biological tissue for the 1.3MeV beta-radiation are promising features of the nanoparticles' potential for cancer therapy. Moreover, a high temperature annealing treatment enhances the magnetic moment of nanoparticles in such a way that a magnetic heating effect of several degrees Celsius in liquid suspension - a prerequisite for hyperthermia treatment of cancer - was observed. A rise in temperature of approximately 3 degrees C in aqueous suspension is shown for a moderate nanoparticle concentration of 0.5mg/ml after 15min in an 831kHz high-frequency alternating magnetic field of 250Gauss field strength (25mT). The biocompatibility based on a low cytotoxicity in the non-neutron-activated state in combination with the hydrophilic nature of the tungsten oxide shell makes the coated magnetic FePt nanoparticles ideal candidates for advanced radiopharmaceutical applications. PMID- 25445698 TI - Release and bioactivity of bone morphogenetic protein-2 are affected by scaffold binding techniques in vitro and in vivo. AB - A low dose of 1MUg rhBMP-2 was immobilised by four different functionalising techniques on recently developed poly(l-lactide)-co-(epsilon-caprolactone) [(poly(LLA-co-CL)] scaffolds. It was either (i) physisorbed on unmodified scaffolds [PHY], (ii) physisorbed onto scaffolds modified with nanodiamond particles [nDP-PHY], (iii) covalently linked onto nDPs that were used to modify the scaffolds [nDP-COV] or (iv) encapsulated in microspheres distributed on the scaffolds [MICS]. Release kinetics of BMP-2 from the different scaffolds was quantified using targeted mass spectrometry for up to 70days. PHY scaffolds had an initial burst of release while MICS showed a gradual and sustained increase in release. In contrast, NDP-PHY and nDP-COV scaffolds showed no significant release, although nDP-PHY scaffolds maintained bioactivity of BMP-2. Human mesenchymal stem cells cultured in vitro showed upregulated BMP-2 and osteocalcin gene expression at both week 1 and week 3 in the MICS and nDP-PHY scaffold groups. These groups also demonstrated the highest BMP-2 extracellular protein levels as assessed by ELISA, and mineralization confirmed by Alizarin red. Cells grown on the PHY scaffolds in vitro expressed collagen type 1 alpha 2 early but the scaffold could not sustain rhBMP-2 release to express mineralization. After 4weeks post-implantation using a rat mandible critical-sized defect model, micro CT and Masson trichrome results showed accelerated bone regeneration in the PHY, nDP-PHY and MICS groups. The results demonstrate that PHY scaffolds may not be desirable for clinical use, since similar osteogenic potential was not seen under both in vitro and in vivo conditions, in contrast to nDP-PHY and MICS groups, where continuous low doses of BMP-2 induced satisfactory bone regeneration in both conditions. The nDP-PHY scaffolds used here in critical-sized bone defects for the first time appear to have promise compared to growth factors adsorbed onto a polymer alone and the short distance effect prevents adverse systemic side effects. PMID- 25445699 TI - Exploring the possible relationship between the drug release of Compritol(r) containing tablets and its polymorph forms using micro X-ray diffraction. AB - Lipid excipients are more and more commonly used in the pharmaceutical industry as sustained drug delivery agents. However, their development may still be hindered by the well-known polymorphism of lipids which is perceived as a disadvantage with possible impact on drug release upon storage. In order to explore the eventual link between drug release modification and lipid polymorphism, we used a synchrotron radiation-based micro X-ray diffraction that allows probing the crystalline structures of the lipid matrix-forming excipient at a local scale and scanning it across the whole tablet. This technique demonstrated that only one polymorph of Compritol(r) 888 ATO is present in each tablet. This polymorph is identical whatever the compression force applied during the manufacturing is, and stays the same after storage at 40 degrees C for 45days, even if these tablets exhibit different drug release profiles. Hence modification of drug release observed after storage is not due to lipid polymorphism. Implementation of post-compression thermal treatments generates another lipid polymorph. Again drug release is not linked with polymorphism because two different polymorphs of Compritol(r) 888 ATO lead to exactly the same dissolution profile. Variation of drug release observed during storage in accelerated conditions could be attributed to an altered distribution of the lipid component within the matrix structure. The lipid may flow within the matrix structure and increase the hydrophobicity of tablets. PMID- 25445700 TI - Nanotoxicity of poly(n-butylcyano-acrylate) nanoparticles at the blood-brain barrier, in human whole blood and in vivo. AB - Therapy of diseases of the central nervous system is a major challenge since drugs have to overcome the blood-brain barrier (BBB). A powerful strategy to enhance cerebral drug concentration is administration of drug-loaded poly(n butylcyano-acrylate) (PBCA) nanoparticles coated with polysorbate 80 (PS80). This study evaluates the toxicity of PBCA-nanoparticles at the BBB, representing the target organ, the inflammatory response in human whole blood, as the site of administration and in a rat model in vivo. PBCA-nanoparticles were prepared by a mini-emulsion method and characterized concerning size, surface charge, shape and PS80-adsorption. The influence on metabolic activity, cell viability and integrity of the BBB was analyzed in an in vitro model of the BBB. In ex vivo experiments in human whole blood the release of 12 inflammatory cytokines was investigated. In addition, the inflammatory response was studied in vivo in rats and complemented with the analysis of different organ toxicity parameters. PBCA nanoparticles showed time- and concentration-dependent effects on metabolic activity, cell viability and BBB integrity. No cell death or loss of metabolic activity was observed for nanoparticle-concentrations <=500MUg/ml up to 3h of treatment. Within 12 tested inflammatory cytokines, only interleukin-8 displayed a significant release after nanoparticle exposure in human blood. No severe inflammatory processes or organ damages were identified in rats in vivo. Thus, PBCA-nanoparticles are a promising drug delivery system to overcome the BBB since they showed hardly any cytotoxic or inflammatory effect at therapeutic concentrations and incubation times. PMID- 25445701 TI - Functionalized heparin-protamine based self-assembled nanocomplex for efficient anti-angiogenic therapy. AB - Angiogenesis is a key feature of cancer development, thus it is a good target for cancer therapy. However, drugs that have been designed to block angiogenesis mainly capture growth factors in circulation, resulting not only in the transient inhibition of tumor progression but also in producing undesirable side effects. Nanoparticular drug delivery systems, on the other hand, may help overcome such drawbacks and improve the efficacy of anti-angiogenic therapies by altering the biodistribution and pharmacokinetics, improving tumor targeting ability, and reducing side effects. In this light, we propose a new approach of anti angiogenic therapy that combines strategies of long circulating, passive tumor targeting, and anti-angiogenesis efficacy using a new polyelectrolyte complex system that combines LHT7, a previously developed heparin-based angiogenesis inhibitor, with a protamine to form a self-assembling nanocomplex with a mean diameter of 200nm, which is effective for anti-angiogenesis therapy. At first, LHT7 was modified with polyethylene glycol (PEG). We observed that PEG LHT7/protamine nanocomplex was stable in buffer and slowly dissociated in plasma (9% dissociation for 24h). Compared to the free form of PEG-LHT7, the mean residence time of PEG-LHT7/protamine nanocomplex was found higher (15.9h) with its increased accumulation in tumor. Most importantly, PEG-LHT7/protamine nanocomplex was diffused and extravasated through the dense collagen matrix of the tumor. Thus, the study describes a successful application of functionalized PEG-LHT/protamine nanocomplex that can inhibit angiogenesis with long circulating, passive targeting, and tumor extravasating ability. PMID- 25445702 TI - Nanobody conjugated PLGA nanoparticles for active targeting of African Trypanosomiasis. AB - Targeted delivery of therapeutics is an alternative approach for the selective treatment of infectious diseases. The surface of African trypanosomes, the causative agents of African trypanosomiasis, is covered by a surface coat consisting of a single variant surface glycoprotein, termed VSG. This coat is recycled by endocytosis at a very high speed, making the trypanosome surface an excellent target for the delivery of trypanocidal drugs. Here, we report the design of a drug nanocarrier based on poly ethylen glycol (PEG) covalently attached (PEGylated) to poly(D,L-lactide-co-glycolide acid) (PLGA) to generate PEGylated PLGA nanoparticles. This nanocarrier was coupled to a single domain heavy chain antibody fragment (nanobody) that specifically recognizes the surface of the protozoan pathogen Trypanosoma brucei. Nanoparticles were loaded with pentamidine, the first-line drug for T. b. gambiense acute infection. An in vitro effectiveness assay showed a 7-fold decrease in the half-inhibitory concentration (IC50) of the formulation relative to free drug. Furthermore, in vivo therapy using a murine model of African trypanosomiasis demonstrated that the formulation cured all infected mice at a 10-fold lower dose than the minimal full curative dose of free pentamidine and 60% of mice at a 100-fold lower dose. This nanocarrier has been designed with components approved for use in humans and loaded with a drug that is currently in use to treat the disease. Moreover, this flexible nanobody-based system can be adapted to load any compound, opening a range of new potential therapies with application to other diseases. PMID- 25445703 TI - Inhalable self-assembled albumin nanoparticles for treating drug-resistant lung cancer. AB - Direct pulmonary delivery of anti-cancer agents is viewed as an effective way of treating lung cancer. Here, we fabricated inhalable nanoparticles made of human serum albumin (HSA) conjugated with doxorubicin and octyl aldehyde and adsorbed with apoptotic TRAIL protein (TRAIL/Dox HSA-NP). The octyl aldehyde and doxorubicin endowed HSA with significant hydrophobicity that facilitated self assembly. TRAIL/Dox HSA-NP was found to have excellent particle size (~340nm), morphology, dispersability, and aerosolization properties. TRAIL/Dox HSA-NP displayed synergistic cytotoxicity and apoptotic activity in H226 lung cancer cells vs. HSA-NP containing TRAIL or Dox alone. TRAIL/Dox HSA-NP was well deposited in the mouse lungs using an aerosolizer, and TRAIL and Dox-HSA were found to be gradually released over 3days. The anti-tumor efficacy of pulmonary administered TRAIL/Dox HSA-NP was evaluated in BALB/c nu/nu mice bearing H226 cell-induced metastatic tumors. It was found that the tumors of H226-implanted mice treated with TRAIL/Dox HSA-NP were remarkably smaller and lighter than those of mice treated with TRAIL or Dox HSA-NP alone (337.5+/-7.5; 678.2+/-51.5; and 598.9+/-24.8mg, respectively). Importantly, this improved anti-tumor efficacy was found to be due to the synergistic apoptotic effects of Dox and TRAIL. In the authors' opinion, TRAIL/Dox HSA-NP offers a potential inhalable anti-lung cancer drug delivery system. Furthermore, the synergism displayed by combined use of Dox and TRAIL could be used to markedly reduce doxorubicin doses and minimize its side effects. PMID- 25445704 TI - Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity-implications for therapeutic targeting of Nrf2. AB - The transcription factor Nrf2 regulates the basal and inducible expression of a battery of cytoprotective genes. Whereas numerous Nrf2-inducing small molecules have been reported, very few chemical inhibitors of Nrf2 have been identified to date. The quassinoid brusatol has recently been shown to inhibit Nrf2 and ameliorate chemoresistance in vitro and in vivo. Here, we show that brusatol provokes a rapid and transient depletion of Nrf2 protein, through a posttranscriptional mechanism, in mouse Hepa-1c1c7 hepatoma cells. Importantly, brusatol also inhibits Nrf2 in freshly isolated primary human hepatocytes. In keeping with its ability to inhibit Nrf2 signaling, brusatol sensitizes Hepa 1c1c7 cells to chemical stress provoked by 2,4-dinitrochlorobenzene, iodoacetamide, and N-acetyl-p-benzoquinone imine, the hepatotoxic metabolite of acetaminophen. The inhibitory effect of brusatol toward Nrf2 is shown to be independent of its repressor Keap1, the proteasomal and autophagic protein degradation systems, and protein kinase signaling pathways that are known to modulate Nrf2 activity, implying the involvement of a novel means of Nrf2 regulation. These findings substantiate brusatol as a useful experimental tool for the inhibition of Nrf2 signaling and highlight the potential for therapeutic inhibition of Nrf2 to alter the risk of adverse events by reducing the capacity of nontarget cells to buffer against chemical and oxidative insults. These data will inform a rational assessment of the risk:benefit ratio of inhibiting Nrf2 in relevant therapeutic contexts, which is essential if compounds such as brusatol are to be developed into efficacious and safe drugs. PMID- 25445705 TI - Extracellular cyclophilins in health and disease. AB - BACKGROUND: Extracellular cyclophilins (eCyPs) are pro-inflammatory factors implicated in pathogenesis of a number of inflammatory diseases. Most pathogenic activities of eCyPs are related to their chemotactic action towards leukocytes, which is mediated by eCyP receptor on target cells, CD147, and involves peptidyl prolyl cis-trans isomerase activity of cyclophilins. This activity is inhibited by cyclosporine A (CsA) and non-immunosuppressive derivatives of this drug. Accumulating evidence for the role of eCyPs in disease pathogenesis stimulated research on the mechanisms of eCyP-initiated events, resulting in identification of multiple signaling pathways, characterization of a variety of effector molecules released from eCyP-treated cells, and synthesis of CsA derivatives specifically blocking eCyPs. However, a number of important questions related to the mode of action of eCyPs remain unanswered. SCOPE OF REVIEW: In this article, we integrate available information on release and function of extracellular cyclophilins into a unified model, focusing on outstanding issues that need to be clarified. MAJOR CONCLUSIONS: Extracellular cyclophilins are critical players in pathogenesis of a number of inflammatory diseases. Their mechanism of action involves interaction with the receptor, CD147, and initiation of a poorly characterized signal transduction process culminating in chemotaxis and production of pro-inflammatory factors. GENERAL SIGNIFICANCE: Extracellular cyclophilins present an attractive target for therapeutic interventions that can be used to alleviate symptoms and consequences of acute and chronic inflammation. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. PMID- 25445709 TI - Multidomain Peptidyl Prolyl cis/trans Isomerases. AB - BACKGROUND: Peptidyl prolyl cis/trans isomerases (PPIases) assist the folding and restructuring of client proteins by catalysis of the slow rotational motion of peptide bonds preceding a proline residue. Catalysis is performed by relatively small, distinct protein domains of 10 to 18kDa for all PPIase families. PPIases are involved in a wide variety of physiological and pathophysiological processes like signal transduction, cell differentiation, apoptosis as well as viral, bacterial and parasitic infection. SCOPE OF REVIEW: There are multidomain PPIases consisting of one to up to four catalytic domains of the respective PPIase family supplemented by N- or C-terminal extensions. This review examines the biochemical and functional properties of the members of the PPIase class of enzymes which contain additional protein domains with defined biochemical functions. MAJOR CONCLUSIONS: The versatile domain architecture of multidomain PPIases is important for the control of enzyme specificity and organelle-specific targeting, the establishment of molecular connections and hence the coordination of PPIase functions across the cellular network. GENERAL SIGNIFICANCE: Accessory domains covalently linked to a PPIase domain supply an additional layer of control to the catalysis of prolyl isomerization in specific client proteins. Understanding these control mechanisms will provide new insights into the physiological mode of action of the multidomain PPIases and their ability to form therapeutic targets. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. PMID- 25445707 TI - Structural mechanisms of cyclophilin D-dependent control of the mitochondrial permeability transition pore. AB - BACKGROUND: Opening of the mitochondrial permeability transition pore is the underlying cause of cellular dysfunction during diverse pathological situations. Although this bioenergetic entity has been studied extensively, its molecular componentry is constantly debated. Cyclophilin D is the only universally accepted modulator of this channel and its selective ligands have been proposed as therapeutic agents with the potential to regulate pore opening during disease. SCOPE OF REVIEW: This review aims to recapitulate known molecular determinants necessary for Cyclophilin D activity regulation and binding to proposed pore constituents thereby regulating the mitochondrial permeability transition pore. MAJOR CONCLUSIONS: While the main target of Cyclophilin D is still a matter of further research, permeability transition is finely regulated by post translational modifications of this isomerase and its catalytic activity facilitates pore opening. GENERAL SIGNIFICANCE: Complete elucidation of the molecular determinants required for Cyclophilin D-mediated control of the mitochondrial permeability transition pore will allow the rational design of therapies aiming to control disease phenotypes associated with the occurrence of this unselective channel. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. PMID- 25445708 TI - The role of immunophilins in viral infection. AB - BACKGROUND: Tremendous progress has been made in the past 20 years in understanding the roles played by immunophilins, and in particular the cyclophilins, in supporting the replication cycles of human viruses. A growing body of genetic and biochemical evidence and data from clinical trials confirm that cyclophilins are essential cofactors that contribute to establishing a permissive environment within the host cell that supports the replication of HIV 1 and HCV. Cyclophilin A regulates HIV-1 replication kinetics and infectivity, modulates sensitivity to host restriction factors, and cooperates in the transit of the pre-integration complex into the nucleus of infected cells. Cyclophilin A is an essential cofactor whose expression supports HCV-specific RNA replication in human hepatocytes. GENERAL SIGNIFICANCE: Peptidyl-prolyl isomerase inhibitors have been used in clinical trials to validate cyclophilins as antiviral targets for the treatment of HIV-1 and Chronic Hepatitis C virus infection and as molecular probes to identify the roles played by immunophilins in supporting the replication cycles of human viruses. SCOPE OF REVIEW: This review summarizes emerging research that defines the functions of immunophilins in supporting the replication cycles of HIV-1, HCV, HBV, coronaviruses, and other viral pathogens and describes new information that suggests a role for immunophilins in regulating innate immune responses against chronic viral infection. MAJOR CONCLUSIONS: The dependence on cyclophilins by evolutionarily distinct viruses for accomplishing various steps in replication such as viral entry, initiation of genomic nucleic acid replication, viral genome uncoating, nuclear import and nuclear entry, emphasizes the potential of cyclophilin inhibitors as therapeutic agents. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. PMID- 25445710 TI - Effect of the urease-derived peptide Jaburetox on the central nervous system of Triatoma infestans (Insecta: Heteroptera). AB - BACKGROUND: Triatoma infestans is the main vector of Chagas'disease in Southern Cone countries. In triatomines, symptoms suggesting neurotoxicity were observed after treatment with Jaburetox (Jbtx), the entomotoxic peptide obtained from jackbean urease. Here, we study its effect in the central nervous system (CNS) of this species. METHODS: Immunohistochemistry, Western blots, immunoprecipitation, two-dimensional electrophoresis, tandem mass spectrometry and enzymatic assays were performed. RESULTS: Anti-Jbtx antibody labeled somata of the antennal lobe only in Jbtx-treated insects. Western blot assays of nervous tissue using the same antibody reacted with a 61kDa protein band only in peptide-injected insects. Combination of immunoprecipitation, two-dimensional electrophoresis and tandem mass spectrometry identified UDP-N-acetylglucosamine pyrophosphorylase (UDP GlcNAcP) as a molecular target for Jbtx. The activity of UDP-GlcNAcP increased significantly in the CNS of Jbtx-treated insects. The effect of Jbtx on the activity of nitric oxide synthase (NOS) and NO production was investigated as NO is a recognized messenger molecule in the CNS of T. infestans. NOS activity and NO levels decreased significantly in CNS homogenates of Jbtx-treated insects. CONCLUSIONS: UDP-GlcNAcP is a molecular target of Jbtx. Jbtx impaired the activity of T. infestans nitrergic system, which may be related with early behavioral effects. GENERAL SIGNIFICANCE: We report that the CNS of Triatoma infestans is a target for the entomotoxic peptide and propose that a specific area of the brain is involved. Besides potentially providing tools for control strategies of Chagas' disease vectors our data may be relevant in various fields of research as insect physiology, neurobiology and protein function. PMID- 25445711 TI - Neuroprotection by Kukoamine A against oxidative stress may involve N-methyl-D aspartate receptors. AB - BACKGROUND: Accumulative evidences have indicated that oxidative-stress and over activation of N-methyl-d-aspartate receptors (NMDARs) are important mechanisms of brain injury. This study investigated the neuroprotection of Kukoamine A (KuA) and its potential mechanisms. METHODS: Molecular docking was used to discover KuA that might have the ability of blocking NMDARs. Furthermore, the MTT assay, the measurement of LDH, SOD and MDA, the flow cytometry for ROS, MMP and Annexin V-PI double staining, the laser confocal microscopy for intracellular Ca2+ and western blot analysis were employed to evaluate the neuroprotection of KuA. RESULTS: KuA attenuated H2O2-induced cell apoptosis, LDH release, ROS production, MDA level, MMP loss, and intracellular Ca2+ overload (both induced by H2O2 and NMDA), as well as increased the SOD activity. In addition, it could modulate the apoptosis related proteins (Bax, Bcl-2, p53, procaspase-3 and procaspase-9), the SAPKs (ERK, p38), AKT, CREB, NR2A and NR2B expression. CONCLUSIONS: All the results indicated that KuA has the ability of anti-oxidative stress and this effect may partly via blocking NMDARs in SH-SY5Y cells. GENERAL SIGNIFICANCE: KuA might have the potential therapeutic interventions for brain injury. PMID- 25445706 TI - Oxidative stress, redox regulation and diseases of cellular differentiation. AB - BACKGROUND: Within cells, there is a narrow concentration threshold that governs whether reactive oxygen species (ROS) induce toxicity or act as second messengers. SCOPE OF REVIEW: We discuss current understanding of how ROS arise, facilitate cell signaling, cause toxicities and disease related to abnormal cell differentiation and those (primarily) sulfur based pathways that provide nucleophilicity to offset these effects. PRIMARY CONCLUSIONS: Cellular redox homeostasis mediates a plethora of cellular pathways that determine life and death events. For example, ROS intersect with GSH based enzyme pathways to influence cell differentiation, a process integral to normal hematopoiesis, but also affecting a number of diverse cell differentiation related human diseases. Recent attempts to manage such pathologies have focused on intervening in some of these pathways, with the consequence that differentiation therapy targeting redox homeostasis has provided a platform for drug discovery and development. GENERAL SIGNIFICANCE: The balance between electrophilic oxidative stress and protective biomolecular nucleophiles predisposes the evolution of modern life forms. Imbalances of the two can produce aberrant redox homeostasis with resultant pathologies. Understanding the pathways involved provides opportunities to consider interventional strategies. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. PMID- 25445712 TI - Pancreatic polypeptide regulates glucagon release through PPYR1 receptors expressed in mouse and human alpha-cells. AB - BACKGROUND: Plasma levels of pancreatic polypeptide (PP) rise upon food intake. Although other pancreatic islet hormones, such as insulin and glucagon, have been extensively investigated, PP secretion and actions are still poorly understood. METHODS: The release of PP upon glucose stimulation and the effects of PP on glucagon and insulin secretion were analyzed in isolated pancreatic islets. Expression of PP receptor (PPYR1) was investigated by immunoblotting, quantitative RT-PCR on sorted pancreatic islet cells, and immunohistochemistry. RESULTS: In isolated mouse pancreatic islets, glucose stimulation increased PP release, while insulin secretion was up and glucagon release was down. Direct exposure of islets to PP inhibited glucagon release. In mouse islets, PPYR1 protein was observed by immunoblotting and quantitative RT-PCR revealed PPYR1 expression in the FACS-enriched glucagon alpha-cell fraction. Immunohistochemistry on pancreatic sections showed the presence of PPYR1 in alpha cells of both mouse and human islets, while the receptor was absent in other islet cell types and exocrine pancreas. CONCLUSIONS: Glucose stimulates PP secretion and PP inhibits glucagon release in mouse pancreatic islets. PP receptors are present in alpha-cells of mouse and human pancreatic islets. GENERAL SIGNIFICANCE: These data demonstrate glucose-regulated secretion of PP and its effects on glucagon release through PPYR1 receptors expressed by alpha cells. PMID- 25445713 TI - Chemical and thermal influence of the [4Fe-4S]2+ cluster of A/G-specific adenine glycosylase from Corynebacterium pseudotuberculosis. AB - The gram-positive bacteria Corynebacterium pseudotuberculosis, the causative agent of caseous lymphadenitis in livestock significantly reduces productivity and often causes death. The adenine/guanine-specific DNA glycosylase (MutY) prevents mutations in the DNA of the pathogen and a unique feature of the MutY protein family is the [4Fe-4S]2+ cluster that interlinks two protein subdomains. MutY from C. pseudotuberculosis was expressed in E. coli and purified, the CD experiments indicate a high content of alpha-helices and random coiled secondary structure and a typical near-UV CD fingerprint for the [4Fe-4S]2+ cluster. EDTA and copper sulfate possess a strong destabilizing effect on the [4Fe-4S]2+ cluster. UV-vis and fluorescence spectroscopy results demonstrate that between pH3.0 and 4.0 the integrity of the [4Fe-4S]2+ cluster is destroyed. To investigate the thermal stability of the protein differential scanning calorimetry and fluorescence spectroscopy were used and the Tm was determined to be 45 degrees C. The analysis presented provides information concerning the protein stability under different physio-chemical conditions. PMID- 25445714 TI - Psammaplin A induces Sirtuin 1-dependent autophagic cell death in doxorubicin resistant MCF-7/adr human breast cancer cells and xenografts. AB - BACKGROUND: Psammaplin A (PsA) is a natural product isolated from marine sponges, which has been demonstrated to have anticancer activity against several human cancer cell lines via the induction of cell cycle arrest and apoptosis. New drugs that are less toxic and more effective against multidrug-resistant cancers are urgently needed. METHODS: We tested cell proliferation, cell cycle progression and autophagic cell death pathway in doxorubicin-resistant MCF-7 (MCF-7/adr) human breast cancer cells. The potency of PsA was further determined using an in vivo xenograft model. RESULTS AND CONCLUSION: PsA significantly inhibited MCF 7/adr cells proliferation in a concentration-dependent manner, with accumulation of cells in G2/M phase of the cell cycle. PsA significantly decreased SIRT1 enzyme activity and reduced expression of SIRT1 protein in the cultured cells with greater potency than sirtinol or salermide. Acetylation of p53, a putative target of SIRT1, increased significantly following PsA treatment. In addition, PsA markedly increased the expression levels of autophagy-related proteins. In support of this, it was found that PsA significantly increased the expression of damage-regulated autophagy modulator (DRAM), a p53-induced protein. GENERAL SIGNIFICANCE: The results of this study suggest that PsA is sufficient to overcome multidrug-resistant cancer via SIRT1-mediated autophagy in MCF-7/adr breast cancer cells, indicating that PsA has therapeutic potential for clinical use. PMID- 25445715 TI - Solid state, thermal synthesis of site-specific protein-boron cluster conjugates and their physicochemical and biochemical properties. AB - BACKGROUND: Boron clusters represent a vast family of boron-rich compounds with extraordinary properties that provide the opportunity of exploitation in different areas of chemistry and biology. In addition, boron clusters are clinically used in boron neutron capture therapy (BNCT) of tumors. In this paper, a novel, in solid state (solvent free), thermal method for protein modification with boron clusters has been proposed. METHODS: The method is based on a cyclic ether ring opening in oxonium adduct of cyclic ether and a boron cluster with nucleophilic centers of the protein. Lysozyme was used as the model protein, and the physicochemical and biological properties of the obtained conjugates were characterized. RESULTS: The main residues of modification were identified as arginine-128 and threonine-51. No significant changes in the secondary or tertiary structures of the protein after tethering of the boron cluster were found using mass spectrometry and circular dichroism measurements. However, some changes in the intermolecular interactions and hydrodynamic and catalytic properties were observed. CONCLUSIONS: To the best of our knowledge, we have described the first example of an application of cyclic ether ring opening in the oxonium adducts of a boron cluster for protein modification. In addition, a distinctive feature of the proposed approach is performing the reaction in solid state and at elevated temperature. GENERAL SIGNIFICANCE: The proposed methodology provides a new route to protein modification with boron clusters and extends the range of innovative molecules available for biological and medical testing. PMID- 25445716 TI - Sono-synthesis of biodiesel from soybean oil by KF/gamma-Al2O3 as a nano-solid base catalyst. AB - In this work, biodiesel has successfully prepared via ultrasonic method in a short time and low temperature by nano-solid-base catalyst (KF/gamma-Al2O3). The catalyst was obtained by calcination of a mixture of KF and gamma-Al2O3 m(KF)/m(gamma-Al2O3) at 500 degrees C for 3 h. Nano-solid-base catalyst was characterized with scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD), Fourier transform infrared (FT-IR), thermal gravimetry (TG) and the Hammett indicator methods. The TEM image depicted nanoparticles and uniform dispersion of active phase over alumina. The XRD analysis confirmed the formation of potassium aluminum fluoride (K3AlF6) and potassium oxide, active catalyst for transesterification. The transesterification of soybean oil with methanol was performed by using both low frequency ultrasonic reactor (20 kHz) and mechanical stirring in the presence of KF/gamma-Al2O3. The influence of various parameters such as ultrasonic power, oil/methanol molar ratio, catalyst concentration, time, and temperature were studied on the biodiesel formation. The maximum yield (95%) was achieved by applying 45 W acoustic power, molar ratio of alcohol to oil at 12:1, catalyst concentration of 2.0 wt%, 40 min sonication, and temperature of 50 degrees C. The transesterification was performed in 360 min using mechanical stirring with 76% yield. The results confirm that ultrasound significantly accelerates the transesterification reaction in comparison with the mechanical stirring. PMID- 25445720 TI - One-month persistence of inflammation and alteration of fibrotic marker and cytoskeletal proteins in rat kidney after Cd-doped silica nanoparticle instillation. AB - In vivo effects of model cadmium-containing silica nanoparticles (SiNPs-Cd, 1 mg/rat) were investigated by i.t. instillation in rats to evaluate potential effects on secondary target organ, e.g., kidney. Specific endpoints and pathological outcomes were focused to assess inflammation and fibrosis in renal tissue, 7 and 30 days after exposure to SiNPs-Cd, as well as to equivalent amount of CdCl2 or SiNPs. Immunohistochemistry was employed to investigate the presence/distribution of selected markers, i.e., (i) TGF-beta1, (ii) IL-6 (iii) collagen (type I), (iv) fibronectin, and (v) vimentin. An ongoing inflammatory process was demonstrated, together with a general overexpression of extracellular matrix components and alteration of cytoskeletal proteins, mainly in cortex and medulla, 7 days after SiNPs-Cd, lasting until 30th day. Less pronounced effects were observed after CdCl2, while SiNPs did not cause any insult except for IL-6 expression increase. Briefly, engineered SiNPs-Cd cause long-lasting injury in rat kidney, following a single pulmonary exposure. Renal response may be due to (i) translocation, i.e., nanoparticles migration from lung to systemic circulation, or (ii) secondary organ changes, caused by circulating inflammatory factors (e.g., IL-6, TGF-beta1) released from lung following local insult, or (iii) direct renal action of cadmium ions released from the absorbed SiNPs-Cd. PMID- 25445718 TI - The double-edged sword: Neurotoxicity of chemotherapy. AB - The number of available therapies for hematologic malignancies continues to grow at a rapid pace. Unfortunately, many of these treatments carry both central and peripheral nervous system toxicities, potentially limiting a patient's ability to tolerate a full course of treatment. Neurotoxicity with chemotherapy is common and second only to myelosuppression as a reason to limit dosing. This review addresses the neurotoxicity of newly available therapeutic agents including brentuximab vedotin and blinatumomab as well as classic ones such as methotrexate, vinca alkaloids and platinums. Although peripheral neuropathy is common with many drugs, other complications such as seizures and encephalopathy may require more immediate attention. Rapid recognition of adverse neurologic effects may lead to earlier treatment and appropriate adjustment of dosing regimens. In addition, knowledge of common toxicities may help differentiate chemotherapy-related symptoms from actual progression of cancer into the CNS. PMID- 25445721 TI - Toxicokinetics of perfluorooctane sulfonate in birds under environmentally realistic exposure conditions and development of a kinetic predictive model. AB - This article describes the toxicokinetics of perfluorooctane sulfonate (PFOS) in birds under low repeated dosing, equivalent to 0.085 MUg/kg per day, representing environmentally realistic exposure conditions. The best fitting was provided by a simple pseudo monocompartmental first-order kinetics model, regulated by two rates, with a pseudo first-order dissipation half-life of 230 days, accounting for real elimination as well as binding of PFOS to non-exchangeable structures. The calculated assimilation efficiency was 0.66 with confidence intervals of 0.64 and 0.68. The model calculations confirmed that the measured maximum concentrations were still far from the steady state situation, which for this dose regime, was estimated at a value of about 65 MUg PFOS/L serum achieved after a theoretical 210 weeks continuous exposure. The results confirm a very different kinetics than that observed in single-dose experiments confirming clear dose related differences in apparent elimination rates in birds, as described for humans and monkeys; suggesting that a capacity-limited saturable process should also be considered in the kinetic behavior of PFOS in birds. Pseudo first-order kinetic models are highly convenient and frequently used for predicting bioaccumulation of chemicals in livestock and wildlife; the study suggests that previous bioaccumulation models using half-lives obtained at high doses are expected to underestimate the biomagnification potential of PFOS. The toxicokinetic parameters presented here can be used for higher-tier bioaccumulation estimations of PFOS in chickens and as surrogate values for modeling PFOS kinetics in wild bird species. PMID- 25445717 TI - Global characteristics of childhood acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) comprises approximately 5-10% of childhood acute myeloid leukemia (AML) cases in the US. While variation in this percentage among other populations was noted previously, global patterns of childhood APL have not been thoroughly characterized. In this comprehensive review of childhood APL, we examined its geographic pattern and the potential contribution of environmental factors to observed variation. In 142 studies (spanning >60 countries) identified, variation was apparent-de novo APL represented from 2% (Switzerland) to >50% (Nicaragua) of childhood AML in different geographic regions. Because a limited number of previous studies addressed specific environmental exposures that potentially underlie childhood APL development, we gathered 28 childhood cases of therapy-related APL, which exemplified associations between prior exposures to chemotherapeutic drugs/radiation and APL diagnosis. Future population-based studies examining childhood APL patterns and the potential association with specific environmental exposures and other risk factors are needed. PMID- 25445724 TI - Aryl hydrocarbon receptor SNP -130 C/T associates with dioxins susceptibility through regulating its receptor activity and downstream effectors including interleukin 24. AB - Dioxins are persistent environmental pollutants that cause multiple adverse health effects in humans, mainly through binding to the ligand-activated transcription factor, aryl hydrocarbon receptor (AhR). Genetic variation in AhR may modulate the susceptibility to dioxins. In this study, we aimed to evaluate the effects of the single nucleotide polymorphism (SNP) -130 C/T in the AhR promoter on dioxin-inducible gene transcription, and to investigate interleukin 24 (IL-24) and interleukin-1beta (IL-1beta) as proxies for 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) exposure. Using primary human chorionic stromal cells, we found that cells with the TT genotype showed higher AhR mRNA and protein levels than did those of the CC genotype. Microarray was carried out to analyze the gene expression profiles of cells (CC and TT genotype) after exposing the cells to TCDD. Several genes associated with human disorders were more highly up-regulated in cells of the TT genotype. Higher up-regulation of IL 24 and IL-1beta mRNA in cells with the TT genotype was observed. Furthermore, blood samples from 64 Yusho patients who were accidentally exposed to high concentrations of dioxins were analyzed for the genotype, dioxins concentrations and serum levels of IL-24 and IL-1beta. We observed higher serum IL-24 levels and lower serum IL-1beta levels in Yusho patients with the TT genotype than in those with the CC genotype. AhR SNP -130 C/T affects serum IL-24 and IL-1beta levels, independently of serum dioxins concentrations in Yusho patients. Our observations demonstrate that SNP -130 C/T modulates AhR expression and expression levels of IL-24 and IL-1beta, and suggest an association of AhR SNP -130 C/T with the susceptibility to dioxins. PMID- 25445723 TI - Inutero exposure to diisononyl phthalate caused testicular dysgenesis of rat fetal testis. AB - Diisononyl phthalate (DINP) is a synthetic material that has been widely used as a substitute for other plasticizers prohibited due to reproductive toxicity in consumer products. Some phthalates have been associated with testicular dysgenesis syndrome in male fetus when female pregnant dams were exposed to them. The present study investigated effects of DINP on fetal Leydig cell function and testis development. Female pregnant Sprague Dawley rats received control vehicle (corn oil) or DINP (10, 100, 500, and 1000 mg/kg) by oral gavage from gestational day (GD) 12 to 21. At GD 21.5, testicular testosterone production, fetal Leydig cell numbers and distribution, testicular gene and protein expression levels were examined. DINP showed dose-dependent increase of fetal Leydig cell aggregation with the low observed adverse-effect level (LOAEL) of 10 mg/kg and multinucleated gonocyte with LOAEL of 100 mg/kg. At 10 mg/kg, DINP also significantly increased fetal Leydig cell size, but inhibited insulin-like 3 and 3beta-hydroxysteroid dehydrogenase gene expression and protein levels. DINP inhibited testicular testosterone levels at 1000 mg/kg. The results indicate that in utero exposure to DINP affects the expression levels of some fetal Leydig cell steroidogenic genes, gonocyte multinucleation and Leydig cell aggregation. PMID- 25445722 TI - Dissolution of lipids from mucus: a possible mechanism for prompt disruption of gut barrier function by alcohol. AB - Acute and/or chronic alcohol ingestion has been shown to exacerbate the morbidity and mortality rate associated with acute mechanical and/or thermal trauma. While alcohol ingestion can affect many organs and systems, clinical and preclinical studies indicate that alcohol ingestion can cause a 'leaky gut' syndrome which in turn contributes to infection and systemic organ dysfunction. This study investigated the acute effect of alcohol on gut barrier function. Using an in vivo isolated gut sac model of naive male rats, each individual gut sac was injected with different concentrations (0, 5, 10, 20, and 40%, v/v) of alcohol. After different times of alcohol exposure, each isolated gut segment was harvested and intestinal permeability and mucosal surface hydrophobicity (a physiologic marker of mucus barrier function) were measured as well as luminal DNA, mucus, protein and free fatty acids. The results showed that alcohol caused dose-dependent and time-dependent increases in gut permeability and decreases in mucosal surface hydrophobicity, with significant changes to be observed 5 min after treatment with 10% alcohol. In addition, it is further found that these changes in permeability and hydrophobicity are more closely associated with increased intestinal luminal free fatty acids levels but not protein or DNA levels. These results suggest that alcohol may cause loss of gut barrier function by extracting and dissolving lipids from the mucus with a resultant decrease in mucosal surface hydrophobicity, which is a critical component of gut barrier function. PMID- 25445725 TI - Leishmanial lipid affords protection against oxidative stress induced hepatic injury by regulating inflammatory mediators and confining apoptosis progress. AB - Persistence of liver injury alters the internal milieu, promotes deregulation of inflammatory factors, and leads to dysplastic lesions like fibrosis, cirrhosis to hepatocellular carcinoma. Our previous study revealed that leishmanial lipid (pLLD) exerts potential anti-inflammatory activity in sepsis associated hepatic injury. We now show that pLLD gives protection against chemical induced hepatotoxicity in murine system. The beneficial effect of treatment with pLLD on such hepatic injury in mice was analyzed using different assays including ELISA, FACS, western blot and immunohistochemical analysis. pLLD significantly suppressed serum enzymes and rectified the histopathological alteration to induce the antioxidant level in CCl4 intoxicated liver. Levels of several growth factors including TGF-beta, HGF, and EGF were significantly improved in serum and hepatic tissue with consequent reduction of caspase activities and expressions of Bad, Bax, p53, and NF-kappaBp65. Moreover, pLLD modulated inflammatory responses by decreasing the production of several cytokines and chemokines, thus preventing the infiltration of immune cells to the damaged area. It accelerated the repair process in liver damage with modulation of signalling cascade via alteration of apoptotic factors. Our experimental approaches suggest that pLLD effectively prevents liver injury mainly through down regulation of oxidative stress and inflammatory response towards anti-apoptotic changes. PMID- 25445726 TI - Very urgent carotid endarterectomy does not increase the procedural risk. AB - OBJECTIVES: The timing of CEA for symptomatic internal carotid artery (ICA) stenosis remains a matter of controversy. Recent registry data showed a significantly increased risk, especially in the very early days after the onset of symptoms. In this study the outcome of CEA in the hyperacute phase has been investigated. METHODS: The outcome of CEA for symptomatic ICA stenosis between January 2004 and December 2013 has been retrospectively analyzed. Patients were divided into four timing groups: surgery within 0 and 2 days, between 3 and 7 days, 8 and 14 days, and thereafter. The post-operative 30 day stroke and death rates were assessed. RESULTS: A total of 761 symptomatic patients (40.1% with transient ischemic attack [TIA], 21.3% with amaurosis fugax, and 38.6% with ischemic stroke) were included, with an overall peri-operative stroke and death rate of 3.3%. A stroke and death rate of 4.4% (9/206) for surgery within 0 and 2 days, 1.8% (4/219) between 3 and 7 days, 4.4% (6/136) between 8 and 14 days, and 2.5% (5/200) in the period thereafter (p = .25 for the difference between the groups) was observed. The timing of surgery did not influence the peri-operative outcome in a multivariate regression analysis (OR 0.93 [0.63-1.36], p = .71). CONCLUSIONS: These data show that very urgent surgery in symptomatic patients can be performed without increased procedural risk. Given the fact that ruptured plaques with neurological symptoms carry the highest risk of a recurrent ischemic event in the first 2 days, treating patients as soon as possible to offer the highest benefit in stroke prevention is recommended. PMID- 25445727 TI - Screening for abdominal aortic aneurysm in a modern context and issues for the future. PMID- 25445728 TI - Effects of toluene, acrolein and vinyl chloride on motor activity of Drosophila melanogaster. AB - The data generated by current high-throughput assays for chemical toxicity require information to link effects at molecular targets to adverse outcomes in whole animals. In addition, more efficient methods for testing volatile chemicals are needed. Here we begin to address these issues by determining the utility of measuring behavioral responses of Drosophila melanogaster to airborne volatile organic compounds (VOCs) as a potential model system for discovering adverse outcome pathways and as a method to test for toxicity. In these experiments, we measured motor activity in male and female flies to determine concentration effect functions for three VOCs that differ in their mode of action: toluene, a narcotic; acrolein, an irritant; and vinyl chloride, a hepatocarcinogen. These experiments were conducted in Flyland, an outbred population of flies derived from 40 lines of the Drosophila Genetics Reference Panel (DGRP) (Mackay et al., 2012), in preparation for subsequent experiments with individual lines of the DGRP. Systematic, concentration-related changes in activity were observed with toluene, but not with acrolein; high concentrations of vinyl chloride reduced activity by a small amount. Despite higher activity levels in males than in females under control conditions, the sexes were equally sensitive to toluene. Transient increases in activity at the onset and offset of exposure to toluene and vinyl chloride suggested that the flies detected changes in air quality at concentrations that did not persistently suppress activity. The effects and potency of toluene are consistent with those observed in rodents. The lack of clear concentration-related changes in response to acrolein and vinyl chloride shows limitations of this method is for screening toxicity attributed to VOCs. This abstract does not reflect U.S. EPA policy. PMID- 25445719 TI - Spatial regulation of controlled bioactive factor delivery for bone tissue engineering. AB - Limitations of current treatment options for critical size bone defects create a significant clinical need for tissue engineered bone strategies. This review describes how control over the spatiotemporal delivery of growth factors, nucleic acids, and drugs and small molecules may aid in recapitulating signals present in bone development and healing, regenerating interfaces of bone with other connective tissues, and enhancing vascularization of tissue engineered bone. State-of-the-art technologies used to create spatially controlled patterns of bioactive factors on the surfaces of materials, to build up 3D materials with patterns of signal presentation within their bulk, and to pattern bioactive factor delivery after scaffold fabrication are presented, highlighting their applications in bone tissue engineering. As these techniques improve in areas such as spatial resolution and speed of patterning, they will continue to grow in value as model systems for understanding cell responses to spatially regulated bioactive factor signal presentation in vitro, and as strategies to investigate the capacity of the defined spatial arrangement of these signals to drive bone regeneration in vivo. PMID- 25445729 TI - Work of breathing in children with diffuse parenchymal lung disease. AB - Respiratory mechanics have been poorly studied in children with chronic diffuse parenchymal lung disease (DPLD). The aim of the study was to assess the usefulness of respiratory mechanics to monitor lung function alteration in children with DPLD. Respiratory mechanics, total (WOBt), elastic (WOBe) and resistive (WOBr) work of breathing, gas exchange, lung function and respiratory muscle strength were measured in 10 children, aged 1.8-18.4 years old, who were followed in our national reference centre. Mean tidal volume (Vt) was normal (11+/-4mL/kg) but respiratory rate (fr, 32+/-19breaths/min), fr/Vt (118+/ 75breaths/min/L) and total lung resistance (10.2+/-4.8cmH2OL(-1)s) were increased. Mean WOBt was increased mainly due to WOBe. Dynamic lung compliance (Cldyn) was severely reduced (26+/-24mL/cmH2O). Cldyn and the oesophageal pressure-time product strongly correlated with vital capacity and functional residual capacity. Respiratory muscle strength was within the normal range. In conclusion, lung mechanics may be considered as useful complementary or alternative markers of functional abnormalities in children with DPLD. PMID- 25445730 TI - Screening for adenylosuccinate lyase deficiency using tandem mass spectrometry analysis of succinylpurines in neonatal dried blood spots. AB - OBJECTIVES: Stable isotope dilution coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the sensitive method for screening for various inherited metabolic disorders using dried blood spots (DBSs). We present a method for LC-MS/MS determination of succinyladenosine (SAdo) and succinylaminoimidazole carboxamide riboside (SAICAr), biomarkers for adenylosuccinate lyase deficiency (dADSL), in DBS. DESIGN AND METHODS: SAICAr and SAdo were separated on a Symmetry C18 column and detected using positive electrospray ionisation in selected reaction monitoring mode. The quantification was performed using the isotopically labelled internal standards SAdo-(13)C4 and SAICAr-(13)C4, which were prepared via ADSL-catalysed reactions of fumarate-(13)C4 with adenosine monophosphate and aminoimidazole carboxamide ribotide, respectively, and subsequent alkaline phosphatase-catalysed dephosphorylation of the resulting products. RESULTS: The detection of SAICAr and SAdo in DBS was linear over the range of 0-25MUmol/L. The respective intra-assay and inter-assay imprecision values were less than 10.7% and 15.2% for SAICAr and 4.7% and 5.7% for SAdo. The recoveries from DBS spiked with different concentrations of SAICAr and SAdo were between 94% and 117%. The concentrations of SAICAr and SAdo were higher in the archived DBS from dADSL patients (SAICAr, 0.03-4.7MUmol/L; SAdo, 1.5-21.3MUmol/L; n=5) compared to those of the control subjects (SAICAr, 0-0.026MUmol/L; SAdo, 0.06-0.14MUmol/L; n=31), even after DBSs from dADSL patients were stored for 2-23years. CONCLUSIONS: We developed and validated a method of succinylpurine analysis in DBS that improves selective screening for dADSL in the paediatric population and may be used for retrospective diagnosis to aid the genetic counselling of affected families. PMID- 25445731 TI - Influence of a prolonged fasting and mild activity on routine laboratory tests. AB - OBJECTIVES: Despite the standardization of the phlebotomy procedure, blood analysis is occasionally requested after recommended hours with the excuse that the patient is still fasting. We aimed to examine the influence of prolonged fasting and mild physical activity on routine laboratory tests. DESIGN AND METHODS: The study was conducted on 30 volunteers (27 female) median age 40y (20 59). Blood samples were taken in the morning (7:00-8:00a.m.) and early afternoon (1:00-2:00p.m.) after prolonged fasting and usual daily activities. Serum glucose (GLU), urea, creatinine, triglyceride, uric acid (UA), iron and electrolytes were analyzed on Roche cobas 6000 c501 and complete blood count on Siemens ADVIA 2120i. Statistical significance between the two measurements was tested using paired t-test or Wilcoxon test according to data distribution. Clinical significance was judged against calculated reference change values (RCV). RESULTS: A statistically significant decrease was found for red blood cell count, hemoglobin, hematocrit, mean corpuscular volume (MCV), GLU, urea, creatinine, triglycerides and electrolytes, whereas white blood cell count and iron were significantly increased. Judging against desirable bias derived from biological variation, a significant change was found for all the analytes except MCV, platelet count, UA and triglycerides. A clinically significant change was not found for any of the tested analytes when compared to RCV. CONCLUSIONS: Prolonged fasting and mild activity will not influence the medical decision for healthy subjects with normal results. Despite the present statistically significant change, the clinically significant change was not shown. However, the study did not include pathological results which have to be interpreted more carefully. PMID- 25445733 TI - India's latest sterilisation camp massacre. PMID- 25445732 TI - Feasibility of psychoeducational interventions in managing chemotherapy associated nausea and vomiting (CANV) in pediatric oncology patients. AB - PURPOSE: Childhood cancer patients often suffer from Chemotheraphy-Associated Nausea and Vomiting (CANV). To alleviate CANV, relaxation techniques and patient education were combined to develop a multidimensional psychoeducational intervention package. The aim of this pilot study was to assess the feasibility of the two major components, namely, (1) relaxation, and (2) patient education, of a psychoeducational intervention, prior to the commencement of the main study. METHODS: A pre-test-post-test control group design was adopted. Twenty patients were allocated equally to the relaxation group (10 participants) and to the educational group (10 participants). Twenty historical matched control cases were identified to form the control groups. Besides, a process evaluation was adopted to assess the feasibility of the study. RESULTS: In relation to episodes of vomiting on day 3, a significant difference was detected from the results (X(2) = 8.54, p = 0.036), in that fewer patients in the relaxation group experienced vomiting. A significant difference was not found in both the use of antiemetics and body weight between the groups. All subjects in the intervention groups adhered to the intervention and completed the questionnaire without difficulty. Patients and parents perceived the intervention as being moderately useful. CONCLUSIONS: Although the beneficial effect of relaxation and education in alleviating CANV was not well-supported statistically, the findings from descriptive data suggest that these interventions promoted the intake of antiemetics as a preventive method. Both interventions and instruments were well received by the patients and also by their parents. PMID- 25445734 TI - The inverse problem in mathematical biology. AB - Biological systems present particular challengers to model for the purposes of formulating predictions of generating biological insight. These systems are typically multi-scale, complex, and empirical observations are often sparse and subject to variability and uncertainty. This manuscript will review some of these specific challenges and introduce current methods used by modelers to construct meaningful solutions, in the context of preserving biological relevance. Opportunities to expand these methods are also discussed. PMID- 25445735 TI - Special issue on Mathematical Models of Inflammation. PMID- 25445736 TI - A new general analytical approach for modeling patterns of genetic differentiation and effective size of subdivided populations over time. AB - The main purpose of this paper is to develop a theoretical framework for assessing effective population size and genetic divergence in situations with structured populations that consist of various numbers of more or less interconnected subpopulations. We introduce a general infinite allele model for a diploid, monoecious and subdivided population, with subpopulation sizes varying over time, including local subpopulation extinction and recolonization, bottlenecks, cyclic census size changes or exponential growth. Exact matrix analytic formulas are derived for recursions of predicted (expected) gene identities and gene diversities, identity by descent and coalescence probabilities, and standardized variances of allele frequency change. This enables us to compute and put into a general framework a number of different types of genetically effective population sizes (Ne) including variance, inbreeding, nucleotide diversity, and eigenvalue effective size. General expressions for predictions (gST) of the coefficient of gene differentiation GST are also derived. We suggest that in order to adequately describe important properties of a subdivided population with respect to allele frequency change and maintenance of genetic variation over time, single values of gST and Ne are not enough. Rather, the temporal dynamic patterns of these properties are important to consider. We introduce several schemes for weighting subpopulations that enable effective size and expected genetic divergence to be calculated and described as functions of time, globally for the whole population and locally for any group of subpopulations. The traditional concept of effective size is generalized to situations where genetic drift is confounded by external sources, such as immigration and mutation. Finally, we introduce a general methodology for state space reduction, which greatly decreases the computational complexity of the matrix analytic formulas. PMID- 25445739 TI - Global stability and exact solution of an arbitrary-solute nonlinear cellular mass transport system. AB - The prediction of the cellular state as a function of extracellular concentrations and temperatures has been of interest to physiologists for nearly a century. One of the most widely used models in the field is one where mass flux is linearly proportional to the concentration difference across the membrane. These fluxes define a nonlinear differential equation system for the intracellular state, which when coupled with appropriate initial conditions, define the intracellular state as a function of the extracellular concentrations of both permeating and nonpermeating solutes. Here we take advantage of a reparametrization scheme to extend existing stability results to a more general setting and to a develop analytical solutions to this model for an arbitrary number of extracellular solutes. PMID- 25445737 TI - Complex Daphnia interactions with parasites and competitors. AB - Species interactions can strongly influence the size and dynamics of epidemics in populations of focal hosts. The "dilution effect" provides a particularly interesting type of interaction from a biological standpoint. Diluters - other host species which resist infection but remove environmentally-distributed propagules of parasites (spores) - should reduce disease prevalence in focal hosts. However, diluters and focal hosts may compete for shared resources. This combination of positive (dilution) and negative (competition) effects could greatly complicate, even undermine, the benefits of dilution and diluter species from the perspective of the focal host. Motivated by an example from the plankton (i.e., zooplankton hosts, a fungal parasite, and algal resources), we study a model of dilution and competition. Our model reveals a suite of five results: * A diluter that is a superior competitor wipes out the host, regardless of parasitism. Although expected, this outcome is an ever-present danger in strategies that might use diluters to control disease. * If the diluter is an inferior competitor, it can reduce disease prevalence, despite the competition, as parameterized in our model. However, competition may also reduce density of susceptible hosts to levels below that seen in focal host-parasite systems alone. * As they decrease disease prevalence, diluters destabilize dynamics of the focal host and their resources. Thus, diluters undermine the stabilizing effects of disease. * The four species combination can generate very complex dynamics, including period-doubling bifurcations and torus (Neimark-Sacker) bifurcations. * At lower resource carrying capacity, the diluter's dilution of spores is 'helpful' to the focal host, i.e., dilution can elevate host density by reducing disease. But, as the resource carrying capacity increases further, the equilibrium density of the diluter increases while the density of the focal host decreases, despite competition. Namely, the negative effects of competition start to outweigh the positive effects of dilution from the perspective of equilibrium density of the focal host. PMID- 25445740 TI - Efficient electrochemiluminescence of a boron-dipyrromethene (BODIPY) dye. AB - Electrochemiluminescence (ECL) of a boron-dipyrromethene dye (BDY) in the presence of tri-n-propylamine as a co-reactant was found to be efficient. The ECL of BDY showed a unique peak wavelength of 707 nm, indicative of the intermolecular electronic transition mechanism. PMID- 25445738 TI - A kinetic model for the frequency dependence of cholinergic modulation at hippocampal GABAergic synapses. AB - In this paper we use a simple model of presynaptic neuromodulation of GABA signaling to decipher paired whole-cell recordings of frequency dependent cholinergic neuromodulation at CA1 parvalbumin-containing basket cell (PV BC) pyramidal cell synapses. Variance-mean analysis is employed to normalize the data, which is then used to estimate parameters in the mathematical model. Various parameterizations and hidden parameter dependencies are investigated using Markov Chain Monte Carlo (MCMC) parameter estimation techniques. This analysis reveals that frequency dependence of cholinergic modulation requires both calcium-dependent recovery from depression and mAChR-induced inhibition of presynaptic calcium entry. A reduction in calcium entry into the presynaptic terminal in the kinetic model accounted for the frequency-dependent effects of mAChR activation. PMID- 25445741 TI - Differences in the use of contraception between Roma and non-Roma women in Serbia. AB - BACKGROUND: Unwanted pregnancies are still common in Central and Eastern European countries, including Serbia. Little is known about the use of contraception in different ethnic groups. This research was undertaken to investigate the use of contraception between Roma and non-Roma women in Serbia and factors associated with it. METHODS: Data from the 2010 Multiple Indicator Cluster Survey (MICS4) conducted in Serbia were used. This research included 1082 Roma and 2145 non-Roma women aged 15-49. Univariate and multivariate logistic regression analyses were used to analyze socio-demographic factors associated with the use of contraception in both population groups. RESULTS: Roma women use any type of contraception more often than non-Roma women. However, Roma women rely more on traditional and unsafe methods such as withdrawal and lactational amenorrhea method, but significantly less on modern methods such as pill, condom and intrauterine device. Place of living (region) is also associated with contraceptive usage. CONCLUSIONS: Inequalities in the use of contraception between Roma and non-Roma women exist. Promoting modern methods of contraception and education about the importance of the use of contraception should be in the focus of national health policies and strategies related to reproductive health to reduce these inequalities. PMID- 25445743 TI - Differential susceptibility to chronic social defeat stress relates to the number of Dnmt3a-immunoreactive neurons in the hippocampal dentate gyrus. AB - The enzyme DNA methyltransferase 3a (Dnmt3a) is crucially involved in DNA methylation and recent studies have demonstrated that Dnmt3a is functionally involved in mediating and moderating the impact of environmental exposures on gene expression and behavior. Findings in rodents have suggested that DNA methylation is involved in regulating neuronal proliferation and differentiation. So far, it has been shown that chronic social defeat might influence neurogenesis, while susceptibility to social defeat stress is dependent on gene expression changes in the nucleus accumbens and the mesolimbic dopaminergic system. However, the role of Dnmt3a herein has not been fully characterized. Our earlier immunohistochemical work has revealed the existence of two types of Dnmt3a-immunoreactive cells in the mouse hippocampus, of which one represents a distinct type with intense Dnmt3a-immunoreactivity (Dnmt3a type II cells) co localizing with a marker of recent proliferation. Based on this, we hypothesize that behavioral susceptibility to chronic social defeat stress is linked to (i) Dnmt3a protein levels in the nucleus accumbens and hippocampus, and (ii) to the density of Dnmt3a type II cells in the hippocampal dentate gyrus. While no differences were found in global levels of Dnmt3a protein expression in the nucleus accumbens and hippocampus, our stereological quantifications indicated a significantly increased density of Dnmt3a type II cells in the dentate gyrus of animals resilient to social defeat stress compared to susceptible and control animals. Further characterization of the Dnmt3a type II cells revealed that these cells were mostly doublecortin (25%) or NeuN (60%) immunopositive, thus defining them as immature and mature neurons. Moreover, negative associations between the density of Dnmt3a type II cells and indices of depressive-like behavior in the sucrose intake and forced swim test were found. These correlational data suggest that DNA methylation via Dnmt3a in the hippocampus co-regulates adaptivity of the behavioral response to chronic social defeat stress, and set the stage for further experimental studies testing a mediating role of Dnmt3a in experience dependent plasticity, neurogenesis and (mal) adaptation to severe stressors. PMID- 25445744 TI - Ticks infesting wild and domestic animals and humans of Sri Lanka with new host records. AB - An island-wide collection of tick species infesting humans, domesticated and wild animals and questing ticks in domestic and peridomestic environments was carried out during 2009-2011. A total of 30,461 ticks were collected from 30 different hosts and free living stages from the ground. The collection consisted of 22 tick species from 30 different hosts recording 12 tick species from humans, 19 from domesticated animals and 21 from wild animals, with a total of 97 new host records. The most common tick species on humans were Dermacentor auratus and Amblyomma testudinairum, while Haemaphysalis intermedia, Rhipicephalus microplus and Rhipicephalus sanguineus were common in domesticated and wild animals sharing 20 host species. Among the questing ticks, immature D. auratus was the most abundant. Humans and domesticated animals were mostly infested by the nymphal stages while adult ticks were found on wild animals. High number of new host records could be due to domestic animals picking tick species from wildlife and vise versa at the human/animal interface. Habitat destruction due to forest fragmentation has lead to wild animals roaming in urban and semi-urban neighbourhoods increasing the interactions of wild animals with domesticated animals. Wild animals play a significant role as a reservoir of many tick borne infections which can easily be spread to domesticated animals and then to humans via tick infestations. Data in this paper are useful for those interested in tick infesting wild and domestic animals and humans in describing the zoonotic potential of tick borne infections. PMID- 25445745 TI - The effects of Sarconesiopsis magellanica larvae (Diptera: Calliphoridae) excretions and secretions on fibroblasts. AB - Sarconesiopsis magellanica is a necrophagous blowfly which is relevant in both forensic and medical sciences. Previous studies regarding this species have led to understanding life-cycle, population and reproduction parameters, as well as identifying and characterising proteolytic enzymes derived from larval excretions and secretions (ES). As other studies have shown that ES proteolytic activity plays a significant role in wound healing and fibroblasts play a relevant role in granulation tissue formation during such healing, the present study was aimed at analysing the biological effect of S. magellanica larval ES on fibroblasts. ES were obtained from third-instar larvae and added to fibroblast cells at three concentrations (10, 5 and 1 MUg/mL) to evaluate their behaviour. MTT assays were used for analysing cell proliferation and viability, whilst cell adhesion was measured by optical density with 10% SDS. Fibroblast migration and morphology was recorded by microscopic observation. ES did not affect fibroblast viability and induced an increase in cell proliferation; cell adhesion became reduced, whilst cell migration through extracellular matrix increased. ES also induced a decreased cell surface and morphological alterations. Changes in all the above mentioned parameters were reduced when ES were incubated at 60 degrees C, probably due to protease denaturation. These results suggested that the proteases contained in S. magellanica larval ES contributed towards granulation tissue formation, increased cell migration and promoted cell proliferation. All these data support carrying out further experiments aimed at validating S. magellanica usefulness in larval therapy. PMID- 25445746 TI - Tackling infection owing to brain-eating amoeba. AB - In view of the devastating nature of primary amoebic meningoencephalitis caused by Naegleria fowleri and the problems associated with diagnostic delays and chemotherapeutic failures, here we propose a noninvasive diagnostic method using the 'reverse transcribrial route device', a novel strategy in the management of this life-threatening infection with a case fatality rate of more than 90%. The proposed rationale should stimulate interest in this emerging infection that almost always proves fatal. PMID- 25445747 TI - Study of mosquito fauna in rice ecosystems around Hanoi, northern Vietnam. AB - Species of the Culex vishnui subgroup, Cx. fuscocephala and Cx. gelidus, which are known Japanese encephalitis (JE) vectors, are distributed in rice agroecosystems in Asian countries. Hence, although ecological studies of rice agroecosystems in northern Vietnam are necessary, very few integrated studies of breeding habitats of mosquitoes, including JE vectors, have been conducted. We carried out a field study and investigated the mosquito fauna in six rice production areas in northern Vietnam during the rainy and dry seasons of 2009. Mosquitoes and potential mosquito predators were collected from aquatic habitats by using larval dippers. We collected 1780 Culex individuals (including 254 Cx. tritaeniorhynchus; 113 Cx. vishnui, 58 Cx. vishnui complex, consisting of Cx. vishnui and Cx. pseudovishnui; 12 Cx. gelidus; 1 Cx. bitaeniorhynchus; and 1 Cx. fuscocephala), 148 Anopheles individuals (including 5 An. vagus), 1 Mansonia annulifera, and 1 Mimomyia chamberlaini during the rainy season. During the dry season, we collected 176 Culex individuals (including 33 Cx. vishnui, 24 Cx. tritaeniorhynchus, 8 Cx. vishnui complex, and 1 Cx. gelidus) and 186 Anopheles individuals (including 9 An. tessellatus, 2 An. kochi, and 2 An. barbumbrosus). We found mosquitoes in all aquatic habitats, namely, rice fields, ditches, ponds, wetlands, irrigation canals, and rice nurseries, and Cx. tritaeniorhynchus and Cx. vishnui complex were found in all the above six areas. Heteroptera such as Micronecta, Veliidae, and Pleidae were abundant and widely distributed in both the seasons. The abundance of mosquito larvae was higher in the rice fields, ditches, and ponds during the rainy season than during the dry season. Cx. tritaeniorhynchus, Cx. vishnui complex, Cx. fuscocephala, and Cx. gelidus were abundant in rice agroecosystems (rice fields, ditches, ponds, and wetlands) in northern Vietnam, and their abundance was high during the rainy season. These findings deepen our understanding of mosquito ecology and strengthen mosquito control strategies to be applied in rice ecosystems Vietnam in the future. PMID- 25445748 TI - Superconductivity in Sm-doped [n]phenacenes (n = 3, 4, 5). AB - We report here the discovery of a new aromatic hydrocarbon superconductor, Sm doped chrysene, with Tc ~ 5 K, and compare its behavior with those measured in the full series of Sm-doped [n]phenacene superconductors, with n = 3, 4, 5, thus determining the trend of Tc as a function of the number of fused benzene rings and for an odd or even number of units. PMID- 25445749 TI - Methylation of promoter and expression silencing of GPX3 gene in hepatocellular carcinoma tissue. AB - BACKGROUND/AIMS: Accumulating evidence has identified transcriptional silencing by aberrant methylation of CpG islands as a potential mechanism for the inactivation of tumor suppressor genes. The role of aberrant methylation of the GPX3 promoter in hepatocellular carcinoma (HCC) is not yet clear. We investigated the association of the status of GPX3 promoter methylation and GPX3 protein expression with the clinicopathological progression of HCC. METHODOLOGY: Sixty HCC tumor and matched non-cancerous tissues were included in this study, and methylation was examined using MSP. GPX3 mRNA and protein levels were evaluated using RT-PCR and western blot analysis, respectively. Clinicopathological data were compiled for correlation analyses. RESULTS: Among the 60 HCC cases, 76.7% (46/60) showed at elevated DNA methylation and displayed significantly lower levels of GPX3 mRNA and protein expression. Low or undetectable GPX3 protein expression was observed in 10 of 60 tumors. GPX3 promoter methylation was detected in 46 of 60 (76.7%) tumors, while no GPX3 gene promoter methylation was observed in the matched non-cancerous specimens. There was a negative correlation between promoter methylation and GPX3 mRNA levels (P<0.05). Analysis of clinicopathological data revealed that both mRNA and protein were significantly associated with portal tumor thrombosis, metastasis and differentiation. In additional, GPX3 methylation showed a relationship with portal tumor thrombosis, metastasis and differentiation. CONCLUSIONS: Our results suggest that promoter methylation may be a mechanism for inactivation of GPX3, possibly leading to subsequent carcinogenesis and progression of HCC. PMID- 25445750 TI - Interleukin-12B+1188A/C polymorphism contributes to increased hepatocellular carcinoma susceptibility: evidence from a meta-analysis. AB - BACKGROUND: Interleukin-12 (IL-12) is a multifunctional cytokine that induces interferon (IFN)-gamma secretion and plays an important role in antitumor immunity. The IL-12B +1188A/C polymorphism was found to correlate with a decreased cytokine production and/or activity, which may lead to increased susceptibility to cancers including hepatocellular carcinoma (HCC). Previous epidemiological studies investigating the association between IL-12B +1188A/C polymorphism and HCC risk reported inconsistent results. We performed a meta analysis to derive a precise estimation of the association. METHODS: All studies published up to July 2014 on the association between IL-12B +1188A/C polymorphism and HCC risk were identified by searching electronic databases including PubMed, Embase, Cochrane library, and Chinese Biomedical Literature database (CBM). Data were extracted by two independent authors and the odds ratios (ORs) together with corresponding 95% confidence intervals (CIs) were used to assess the association between IL-12B +1188A/C polymorphism and HCC risk. RESULTS: Five studies with 1864 cases and 2077 controls were included in the meta-analysis. We observed that the IL-12B +1188A/C polymorphism was significantly correlated with increased HCC risk when all studies were pooled into the meta-analysis (CC vs. AA: OR=1.306, 95% CI 1.063-1.606, P=0.011; AC vs. AA: OR=1.193, 95% CI 1.014-1.405, P=0.034; CC+AC vs. AA: OR=1.260, 95% CI 1.098-1.445, P=0.001). In subgroup analyses by ethnicity, source of control, and study quality, significant increased HCC risk was found in Asians, hospital-based studies, and high quality studies. CONCLUSIONS: The present meta-analysis suggests that the IL-12B+1188A/C polymorphism is a low-penetrant risk factor for HCC development, especially among Asians. Further large and well-designed studies are needed to confirm this association. PMID- 25445751 TI - Baroreceptor stimulation for resistant hypertension: first implantation in France and literature review. AB - Despite a wide choice of effective antihypertensive treatments, blood pressure (BP) in roughly half of hypertensive subjects is not controlled. Resistant hypertension is defined as an uncontrolled BP despite optimal doses of three antihypertensive treatments, including a diuretic. After confirmation of resistant BP using home BP measurement or 24-hour ambulatory BP monitoring (ABPM), patients usually go through a work-up to rule out secondary hypertension. If secondary hypertension is ruled out, the recent European guidelines on hypertension consider baroreceptor stimulation or renal denervation to be possible options. The prevalence of resistant primary hypertension may reach up to 10% in specialized centres. The two proposed non-pharmacological therapeutic strategies have been developed recently to inhibit sympathetic overactivity in resistant hypertension. Among them, baroreceptor activation therapy (BAT) is an innovative approach that interferes with baroreflex function. The first generation BAT device (Rheos((r)); CVRx, Inc., Minneapolis, MN, USA) demonstrated good efficacy in lowering office BP and ABPM, but had an insufficient safety profile due to complex surgery. The second-generation BAT device (Barostim neoTM system; CVRx, Inc.) seems to share the same BP-lowering efficacy but has a better safety profile. We report the first French case of baroreceptor stimulation for hypertension using the Barostim neoTM system. We also discuss the pathophysiological features of and current levels of evidence for this technique. PMID- 25445752 TI - Incidence and predictors of Melody(r) valve endocarditis: a prospective study. AB - BACKGROUND: Percutaneous pulmonary valve replacement (PPVR) has achieved standard of care for the management of dysfunctional right ventricular outflow tract. AIM: Because of increasing reports of Melody((r)) valve (Medtronic, Inc., Minneapolis, MN, USA) infective endocarditis (IE), we aimed to evaluate its incidence and predictors of occurrence. METHODS: We collected data on all patients who received a Melody valve in the pulmonary position from 2009 to 2012. RESULTS: A total of 86 consecutive patients underwent PPVR from 2009 to 2012; of these, five developed IE (5.8%). Freedom from IE was 91% at 50 months. Baseline demographics, type of conduit, PPVR procedural success, residual gradients and in situ duration of Melody valve were similar in IE and non-IE patients. A significant number of IE patients had additional unprotected invasive procedures during follow-up and abruptly discontinued antiplatelet therapy (P=0.0139 and P=0.002, respectively). The cumulative probability of survival without cardiovascular events for IE patients was 20% at 20 months, compared with 98.1% for non-IE patients (P<0.0001). Death was statistically associated with IE. CONCLUSION: Early- and late-onset IE of the Melody valve is emerging as a catastrophic complication of PPVR. Abrupt aspirin discontinuation and additional unprotected invasive procedures during follow-up are significant predictors of Melody valve IE. Owing to its rapidly progressive nature, aggressive invasive management should not be delayed. PMID- 25445753 TI - Percutaneous pulmonary valve endocarditis: incidence, prevention and management. AB - The epidemiology of infective endocarditis is changing rapidly due to the emergence of resistant microorganisms, the indiscriminate use of antibiotics, and an increase in the implantation of cardiovascular devices including percutaneous valves. Percutaneous pulmonary valve implantation has achieved standard of care for the management of certain patients with right ventricular outflow tract dysfunction. With its expanding use, several cases of early and delayed infective endocarditis with higher morbidity and mortality rates have been reported. This review summarizes the trends in percutaneous pulmonary valve infective endocarditis, postulates proposed mechanisms, and elaborates on the prevention and management of this unique and potentially fatal complication. PMID- 25445754 TI - Computational tool for usual intake modelling workable at the European level. AB - In this paper two models present in the computational tool Monte Carlo Risk Assessment (MCRA) were compared for assessing the usual intake of lead in five countries. For this, we used national food consumption data organised according to the format of the European Food Safety Authority (EFSA) Comprehensive database and a single lead concentration database in which analysed commodities were organised according to EFSA's Standard Sampling Description (SSD) system. This meant that both input data were coded according to the hierarchical FoodEx1 classification system. We demonstrate that the naive Observed Individual Means model resulted in more conservative estimates of the exposure in the right tail of the exposure distribution compared to a refined usual intake model, the LogisticNormal-Normal model. With MCRA, the usual intake could be estimated with both models using food consumption and concentration data that were coded according to the hierarchical FoodEx1 classification system demonstrating that this tool can be used in EFSA's data environment. Additionally, the computational tool has functionalities 1) to check the input data quality by presenting detailed information about these data around a specified percentile of exposure and 2) to decide whether the use of a more refined usual intake model is appropriate. PMID- 25445755 TI - Hepatotoxic effects of mycotoxin combinations in mice. AB - This study was performed to assess the individual and combined toxic effects of aflatoxin B1 (AFB1), zearalenone (ZEA) and deoxynivalenol (DON) within the liver of mice. A total of 56 4-week-old weanling female mice were divided into seven groups (n = 8). For 2 weeks, each group received an oral administration of either solvent (control), AFB1, ZEA, DON, AFB1 + ZEA, AFB1 + DON or ZEA + DON per day. The results showed that AFB1, ZEA and DON induced liver injury, indicated by elevated relative liver weight, activities of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), as well as decreased albumin (ALB) and/or total protein (TP) concentration in the serum. These mycotoxins also decreased hepatic total antioxidant capacity (T-AOC), and/or increased the concentration of malondialdehyde (MDA). Moreover, AFB1 + DON displayed synergistic effects, while AFB1 + ZEA displayed antagonistic effects on those parameters previously described. Furthermore, the apoptotic potential was demonstrated associated with an upregulation of the apoptotic genes Caspase-3 and Bax, along with a downregulation of the antiapoptotic gene Bcl-2 in liver. In conclusion, this study provides a better understanding of the toxic effects of AFB1, ZEA, DON, alone or in combinations on the liver of mice, which could contribute to the risk assessment of these mycotoxins in food and feed. PMID- 25445757 TI - Antitumor activity of glycyrol via induction of cell cycle arrest, apoptosis and defective autophagy. AB - Glycyrol is a coumestan isolated from Glycyrrhiza uralensis and synthesized to use. In this study, the antitumor activity and the underlying mechanism of glycyrol were evaluated in vitro and in vivo. It was shown that glycyrol induced cell death associated with apoptosis and autophagy as evidenced by morphological changes in AGS and HCT 116 cells. The apoptosis-inducing effect was characterized by increase in ratio of sub-G1 phase, poly (ADP-ribose) polymerase-1 (PARP-1) cleavage and caspase-3 activation. Mechanistic studies showed that glycyrol induced G0/G1 phase cell cycle arrest as indicated by increase in p21. Furthermore, c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinases (MAPKs) activation induced caspase-dependent apoptosis accompanied by adenosine monophosphate-activated protein kinase (AMPK) activation. Defective autophagy was triggered, which stopped the autophagic flux by the slowing of lysosomal degradation. In addition, glycyrol suppressed tumor growth in a nude mouse tumor xenograft model bearing HCT 116 cells. Taken together, glycyrol is demonstrated to have antitumor activity, and might potentially serve as potential candidate for cancer therapy. PMID- 25445756 TI - Anaphylaxis to Spirulina confirmed by skin prick test with ingredients of Spirulina tablets. AB - Spirulina (Arthrospira platensis), blue-green microalgae, has high content in proteins, gamma-linoleic acid and vitamins and therefore gained popularity as food supplement. According to the Food and Agriculture Organization of the United Nations Spirulina is also an interesting alternative and sustainable protein source with the growing world population. We present a case of a 17-year-old male, who developed anaphylaxis the first time he ingested a Spirulina tablet. Skin prick test with diluted Spirulina tablet was positive. Further skin prick testing with separated ingredients (Spirulina platensis algae, silicon dioxide, inulin and magnesium stearate) was only positive for Spirulina platensis algae and negative in controls, confirming the allergy was caused by Spirulina and not by one of the additives. This case report shows that diagnosis of Spirulina allergy can safely be made by skin prick test with dilutions of the A. platensis or even more simple by skin prick test with the diluted tablet. Since Spirulina has gained popularity as food and nutritional supplement, it is important to realize the potential risk of this dietary supplement. Before Spirulina is produced and consumed on a wider scale, allergenicity risk assessment should be performed, including investigation of potential crossreactivity with well-known inhalant allergens and foods. PMID- 25445758 TI - Acute and subacute (28 days) oral toxicity assessment of the oil extracted from Acrocomia aculeata pulp in rats. AB - Acrocomia aculeata, popularly known as "bocaiuva", is a species used for nutritional purposes and for the treatment of various diseases, as it has, among other things, high levels of antioxidant compounds. This study aimed to assess the toxicological profile of A. aculeata, through acute and subacute toxicity tests. Male and female rats (Wistar) received by gavage 2000 mg/kg of oil extracted from the pulp of A. aculeata (OPAC) for the acute toxicity test and 125, 250, 500 or 1000 mg/kg of OPAC for subacute toxicity test. In the acute toxicity study no mortality or behavioral changes were observed in rats treated with 2000 mg/kg, indicating that the LD50 is higher than this dose. In the subacute toxicity test, the tested doses produced no significant changes in hematological, biochemical or histopathological parameters in the animals exposed. These results demonstrate the absence of acute and subacute toxicity after oral exposure to A. aculeata oil in rats. However, further studies in animals and in humans are needed in order to have sufficient safety evidence for its use in humans. PMID- 25445759 TI - Cumulative health risk assessment of co-occurring mycotoxins of deoxynivalenol and its acetyl derivatives in wheat and maize: case study, Shanghai, China. AB - Humans are naturally and frequently exposed to a multitude of mycotoxins, but health risk assessments are usually performed on individual mycotoxins, which may underestimate the total risks. In this study, we assessed for the first time the cumulative health risks of concomitant exposure via dietary intake (DI) to multiple mycotoxins, namely deoxynivalenol (DON) and its acetyl derivatives of 3 acetyldeoxynivalenol (3-ADON) and 15-acetyldeoxynivalenol (15-ADON), based on the concentration addition (CA) concept. A cross-sectional study was conducted in seven districts in Shanghai, China with 1269 participants and 330 wheat and maize samples analyzed. After probabilistic analysis using Monte Carlo simulation, the results showed no health risks to the population in Shanghai considering individual mycotoxins. However, if the cumulative health risks were calculated based on the combined consideration of DON with either 3-ADON or 15-ADON or both, the DI values in 95th percentile were up to 1087 ng/kg body weight/day, exceeding the Provisional Maximum Tolerable Daily Intake (PMTDI) of 1000 ng/kg body weight/day and hence representing potential health risks to the population in Shanghai. The integrated study proposed here could be a model strategy for cumulative health risk assessment on the co-occurring hazards in the fields of food safety combined with environmental contaminants. PMID- 25445760 TI - A 3-week pre-clinical study of 2'-fucosyllactose in farm piglets. AB - One of the most abundant oligosaccharides found in human milk is 2' fucosyllactose, a trisaccharide composed of fucose and lactose, and multiple studies have demonstrated a health benefit to this compound. Recent advances have allowed for the large-scale production of oligosaccharides via fermentation, including 2'-fucosyllactose. A neonatal piglet model was used to evaluate the tolerability of 2'-fucosyllactose, produced through this process, in order to demonstrate the suitability of this compound for human infants under 12 weeks of age. Crossbred farm piglets, at lactation day 2, were assigned to one of four treatment groups receiving a liquid diet containing 0, 200, 500 or 2000 mg/L of 2'-fucosyllactose. The calculated consumption of 2'-fucosyllactose corresponded to dose levels of 29.37, 72.22 and 291.74 mg/kg/day, respectively, in males and 29.30, 74.31, and 298.99 mg/kg/day, respectively in females. Piglets were administered diet for 3 weeks; and there were no test article-related effects on growth and development (clinical observations, body weight and food consumption), clinical pathology parameters (hematology, clinical chemistry, coagulation and urinalysis), or any histopathologic changes. Therefore, dietary exposure to 2' fucosyllactose at concentrations up to 2000 mg/L was well tolerated by neonatal farm piglets and did not result in adverse health effects or impact piglet growth. PMID- 25445761 TI - In vitro evaluation of inorganic mercury and methylmercury effects on the intestinal epithelium permeability. AB - The mercurial forms [inorganic divalent mercury, Hg(II) and methylmercury, CH3Hg] produce neurological and immune effects as well as hematological and renal alterations. The main route of exposure is through the diet. Consequently, the gastrointestinal mucosa is exposed to these mercurial forms, though the potential toxic effects upon the mucosa are not clear. The present study evaluates the toxicity of Hg(II) and CH3Hg (0.1-2 mg/L) in an intestinal epithelium model using the differentiated and undifferentiated human Caco-2 cell line.The experiments made show the mercurial forms generate reactive oxygen and/or nitrogen species and a significant decrease in glutathione contents. This redox imbalance could be the cause of the lipid peroxidation observed after short exposure times. Such conditions of stress lead to a modulation of stress proteins, intercellular junction proteins and tumor necrosis factor-alpha expression and to a redistribution of F-actin and ZO1 protein in the intestinal monolayer. The abovementioned effects may be the cause of the increase in permeability in the differentiated cells observed at concentrations similar to those found in food products (0.5-1 mg/L). The increase in permeability could produce an impairment of the barrier function of the intestinal epithelium. PMID- 25445762 TI - A framework to determine the effectiveness of dietary exposure mitigation to chemical contaminants. AB - In order to ensure the food safety, risk managers may implement measures to reduce human exposure to contaminants via food consumption. The evaluation of the effect of a measure is often an overlooked step in risk analysis process. The aim of this study was to develop a systematic approach for determining the effectiveness of mitigation measures to reduce dietary exposure to chemical contaminants. Based on expert opinion, a general framework for evaluation of the effectiveness of measures to reduce human exposure to food contaminants was developed. The general outline was refined by application to three different cases: 1) methyl mercury in fish and fish products, 2) deoxynivalenol in cereal grains, and 3) furan in heated products. It was found that many uncertainties and natural variations exist, which make it difficult to assess the impact of the mitigation measure. Whenever possible, quantitative methods should be used to describe the current variation and uncertainty. Additional data should be collected to cover natural variability and reduce uncertainty. For the time being, it is always better for the risk manager to have access to all available information, including an assessment of uncertainty; however, the proposed methodology provides a conceptual framework for addressing these systematically. PMID- 25445763 TI - Impact of maximum levels in European legislation on exposure of mycotoxins in dried products: case of aflatoxin B1 and ochratoxin A in nuts and dried fruits. AB - In this study the impact of setting European criteria on exposure to aflatoxin B1 via nuts and figs and ochratoxin A via dried fruits is evaluated for the Belgian population, as an example of the European population. Two different scenarios were evaluated. In scenario 1 all collected literature data are considered, assuming that there is no border control nor legal limits in Europe. In the second scenario, contamination levels above the maximum limits are excluded. The results from scenario 1 demonstrated that if no regulation is in place, AFB1 and OTA concentrations reported in the analysed food can have potential health risk to the population. The estimated exposure of OTA for scenario 2 is below the TDI of 5 ng/kg BW?day, indicating that OTA concentrations accepted by EU legislation pose a low risk to the Belgian population. For AFB1, the MOE values of scenario 2 are above 10,000 and can be considered to be of low health concern, based on BDML10 for humans, except for figs (MOE = 5782). This means that for all matrices, with exception of figs, the maximum values of AFB1 in the European legislation are sufficient to be of a low health concern for consumers. PMID- 25445764 TI - On the behavior of the leading eigenvalue of Eigen's evolutionary matrices. AB - We study general properties of the leading eigenvalue w-(q) of Eigen's evolutionary matrices depending on the replication fidelity q. This is a linear algebra problem that has various applications in theoretical biology, including such diverse fields as the origin of life, evolution of cancer progression, and virus evolution. We present the exact expressions for w-(q),w-(')(q),w-('')(q) for q = 0, 0.5, 1 and prove that the absolute minimum of w-(q), which always exists, belongs to the interval (0, 0.5]. For the specific case of a single peaked landscape we also find lower and upper bounds on w-(q), which are used to estimate the critical mutation rate, after which the distribution of the types of individuals in the population becomes almost uniform. This estimate is used as a starting point to conjecture another estimate, valid for any fitness landscape, and which is checked by numerical calculations. The last estimate stresses the fact that the inverse dependence of the critical mutation rate on the sequence length is not a generally valid fact. PMID- 25445765 TI - Categorization of patients with reflux symptoms referred for pH and impedance testing while off therapy. AB - BACKGROUND & AIMS: Patients with suspected gastroesophageal reflux disease (GERD) often are treated empirically with proton pump inhibitors (PPIs). Patients whose symptoms are not reduced during the PPI trial are referred for further tests. We investigated whether patients referred for the evaluation of reflux symptoms had GERD. We also aimed to categorize patients with a poor response to PPIs into groups with hypersensitive esophagus or functional heartburn. METHODS: We performed a retrospective study, searching a clinical database of patients referred for GERD testing from 2006 through 2011. We collected data on all patients who underwent upper endoscopy, esophageal manometry, and 24-hour pH impedance monitoring, and were off PPIs for at least 1 week. Evidence of GERD was determined by an abnormal upper endoscopy or 24-hour pH-impedance monitoring. Further categorization was determined by impedance results and the symptom association probability index. RESULTS: We identified 221 patients (mean age, 47.6 +/- 13.3 y; 56% male; 61% Caucasians); 97% previously had been prescribed PPIs, before they were tested. The patients had erosive esophagitis (n = 21; 10%), nonerosive reflux disease with increased pH (n = 61; 27%), nonerosive reflux disease with abnormal impedance (n = 18; 8%), hypersensitive esophagus (n = 30; 14%), functional heartburn (n = 18; 8%), functional disorders other than heartburn (n = 30; 14%), and undetermined disorders (n = 43; 19%). CONCLUSIONS: In a retrospective analysis of 221 patients, roughly half of the patients referred for testing did not have evidence of GERD. Further categorization of patients can help guide diagnosis and management. PMID- 25445766 TI - Gallbladder halo sign: emphysematous cholecystitis caused by cystic duct obstruction. PMID- 25445768 TI - Effects of metabolic syndrome and findings from baseline colonoscopies on occurrence of colorectal neoplasms. AB - BACKGROUND & AIMS: Metabolic syndrome is associated with increased risk of colorectal neoplasm, but little is known about its effects on the occurrence of neoplasm after colonoscopy. We investigated the effects of metabolic syndrome on the risk of advanced neoplasm after colonoscopy. METHODS: We performed a prospective study of 4483 subjects age 50 years and older who underwent screening and surveillance colonoscopies as part of an annual health check-up at National Taiwan University Hospital. Baseline demographic data and colonoscopic findings were recorded. Subjects with either advanced adenoma or 3 or more adenomas detected at baseline were classified as high risk; those with fewer than 3 nonadvanced adenomas were classified as low risk; and those without any neoplastic lesions were classified as normal. The cumulative risk of detecting an advanced neoplasm during surveillance colonoscopies (3 and 5 years later) was correlated with risk group and metabolic syndrome. Hazard ratios (HRs) were calculated for occurrence of neoplasm according to baseline colonoscopic findings and clinical risk factors, including metabolic syndrome. RESULTS: Advanced neoplasms were detected during the surveillance colonoscopies in 1.3% of subjects in the normal group and in 2.4% of those in the low-risk group at 5 years, and in 8.5% of subjects in the high-risk group at 3 years. Subjects with metabolic syndrome had a significantly higher risk for subsequent advanced neoplasms (P < .0001). After stratification based on findings from baseline colonoscopies, the risk for neoplasm was significant in the normal (P < .001) and low-risk groups (P = .04), but not in the high-risk group (P = .48). In Cox regression analysis, metabolic syndrome had significant effects on the risk for advanced neoplasms in the normal (HR, 2.07; 95% confidence interval, 1.13-3.81) and low-risk groups (HR, 2.34; 95% confidence interval, 1.01-5.41), but not in the high-risk group. CONCLUSIONS: Metabolic syndrome is a significant risk factor for occurrence of an advanced adenoma after a negative or low-risk finding from a baseline colonoscopy. Metabolic syndrome should be considered in risk stratification for surveillance intervals. PMID- 25445769 TI - An unusual case of obscure gastrointestinal bleeding in a patient with neurofibromatosis type 1. PMID- 25445770 TI - How does a gastroenterologist show value? PMID- 25445767 TI - Adjusting for patient demographics has minimal effects on rates of adenoma detection in a large, community-based setting. AB - BACKGROUND & AIMS: Reliable estimates of adenoma detection rates (ADRs) are needed to inform colonoscopy quality standards, yet little is known about the contributions of patient demographics to variation in ADRs. We evaluated the effects of adjusting for patient age, race/ethnicity, and family history of colorectal cancer on variations in ADRs and the relative rank order of physicians. METHODS: In a retrospective cohort study, we collected data from Kaiser Permanente Northern California members who were >= 50 years old who received colonoscopies from 2006 through 2008. We evaluated ADRs (before and after adjustment for age, sex, race/ethnicity, and family history of colorectal cancer) for 102 endoscopists who performed 108,662 total colonoscopies and 20,792 screening colonoscopies. Adenomas were identified from the pathology database, and cancers were detected by using the Kaiser Permanente Northern California cancer registry. RESULTS: About two-thirds of examiners had unadjusted ADRs for screening exams that met gastroenterology society guidelines (>25% for men and >15% for women), although rates of detection varied widely (7.7%-61.5% for male patients and 1.7%-45.6% for female patients). Adjusting for case mix reduced the variation in detection rates (from 8-fold to 3-fold for male patients and from 27 fold to 5-fold for female patients), but the median change in physician order by detection rate was just 2 ranks, and few physicians changed quartiles of detection. For example, only 3 of 102 endoscopists moved into and 3 out of the lowest quartile of ADR. CONCLUSIONS: In a community-based setting, most endoscopists met the ADR standards, although there was wide variation in ADRs, which was similar to that reported from academic and referral settings. Case-mix adjustment reduced variability but had only small effects on differences in ADRs between physicians, and only a small percentage of physicians changed quartiles of detection. Adjustments to ADRs are therefore likely only needed in settings in which physicians have very different patient demographics, such as in sex or age. Moderate differences in patient demographics between physicians are unlikely to substantially change rates of adenoma detection. PMID- 25445771 TI - Reply: To PMID 24534548. PMID- 25445773 TI - Adverse effects of vitamin D deficiency on outcomes of patients with chronic hepatitis B. AB - BACKGROUND & AIMS: Vitamin D is an immunomodulator that might be involved in the pathogenesis of viral hepatitis. We investigated the effects of vitamin D deficiency on long-term outcomes of patients with chronic hepatitis B (CHB). METHODS: We performed a prospective cohort study of 426 patients with CHB (65% male; mean age, 41 +/- 13 years), who were enrolled from 1997 through 2000. Serum levels of 25-hydroxycholecalciferol (25(OH)D3) were measured on study enrollment (baseline). Patients were followed for 159 +/- 46 months until last clinic visit or death; approximately 33% received antiviral therapy during the follow-up period. The primary outcome was a clinical event (hepatocellular carcinoma, complications of cirrhosis, or death). RESULTS: At baseline, the patients' mean serum level of hepatitis B virus DNA was 5.0 +/- 2.1 log10 IU/mL; their mean level of 25(OH)D3 was 24.3 +/- 9.4 ng/mL, and 348 patients (82%) had vitamin D deficiency (<32 ng/mL). Serum levels of 25(OH)D3 did not correlate with cirrhosis or viral load. Ninety-seven patients (22.8%) developed clinical events by a mean time of 118 +/- 60 months after study enrollment. Patients who developed clinical events had lower baseline serum levels of 25(OH)D3 (23.2 +/- 10.4 ng/mL) than patients who did not (28.2 +/- 9.3 ng/mL, P < .001). Low baseline serum 25(OH)D3 was an independent factor associated with clinical events after adjustment for sex, age, and cirrhosis. The adjusted hazard ratio of vitamin D deficiency for clinical events was 1.90 (95% confidence interval [CI], 1.06-2.43; P = .04). The 15-year cumulative incidence rate of clinical events among patients with vitamin D deficiency was 25.5% (95% CI, 23.1%-27.9%), compared with 11.1% (95% CI, 7.4% 14.8%) in patients with normal serum levels of 25(OH)D3. CONCLUSIONS: Vitamin D deficiency is common among patients with CHB and is associated with adverse clinical outcomes. PMID- 25445772 TI - Cognitive reserve is a determinant of health-related quality of life in patients with cirrhosis, independent of covert hepatic encephalopathy and model for end stage liver disease score. AB - BACKGROUND & AIMS: Covert hepatic encephalopathy (CHE) is associated with cognitive dysfunction, which affects daily function and health-related quality of life (HRQOL) in patients with cirrhosis. The effects of CHE and liver disease are determined by cognitive reserve-the ability of the brain to cope with increasing damage while continuing to function-and are assessed by composite intelligence quotient (IQ) scores. We examined cognitive reserve as a determinant of HRQOL in patients with cirrhosis. METHODS: We performed a prospective study of 118 outpatients with cirrhosis without overt HE (age, 56 y). We studied cognition using the standard paper-pencil battery; patients with below-normal results for more than 2 tests were considered to have CHE. We also assessed HRQOL (using the sickness impact profile [SIP]), psychosocial and physical scores (a high score indicates reduced HRQOL), model for end-stage liver disease (MELD) scores, and cognitive reserve (using the Barona Index, a validated IQ analysis, based on age, race, education, residence area, and occupation). Cognitive reserve was divided into average and high groups (<109 or >109), and MELD and SIP scores were compared. We performed regression analyses, using total SIP score and psychosocial and physical dimensions as outcomes, with cognitive reserve, CHE, and MELD score as predictors. RESULTS: Study participants had average MELD scores of 9, and 14 years of education; 81% were white, 63% were urban residents, their mean IQ was 108 +/- 8, and 54% had average cognitive reserve (the remaining 46% had high reserves). CHE was diagnosed in 49% of patients. Cognitive reserve was lower in patients with CHE (109) than without (105; P = .02). Cognitive reserve correlated with total SIP and psychosocial score (both r = -0.4; P < .001) and physical score (r = -0.3; P = .01), but not MELD score (P = .8). Patients with high cognitive reserve had a better HRQOL, despite similar MELD scores. In regression analyses, cognitive reserve was a significant predictor of total SIP (P < .001), psychosocial (P < .001), and physical scores (P < .03), independent of CHE, MELD, or psychiatric disorders. CONCLUSIONS: A higher cognitive reserve is associated with a better HRQOL in patients with cirrhosis, despite similar disease severity and prevalence. This indicates that patients with good cognitive reserve are better able to withstand the demands of cirrhosis progression and CHE, leading to a better HRQOL. Patients with lower cognitive reserve may need more dedicated and earlier measures to improve HRQOL. Cognitive reserve should be considered when interpreting HRQOL and cognitive tests to evaluate patients with cirrhosis. PMID- 25445774 TI - Clinical events after cessation of lamivudine therapy in patients recovered from hepatitis B flare with hepatic decompensation. AB - BACKGROUND & AIMS: Before guidelines were issued, many patients with hepatitis B flare and hepatic decompensation had discontinued lamivudine therapy instead of indefinite therapy. We investigated their outcomes. METHODS: We performed a retrospective cohort study of 263 consecutive patients with chronic hepatitis B (94 with cirrhosis) who recovered from a flare of hepatitis with hepatic decompensation and were followed after cessation of lamivudine therapy. Clinical events that occurred during the follow-up period were assessed by chart review and analysis of results from retrospective assays. RESULTS: The mean duration of lamivudine therapy was 12.1 +/- 8.6 months; data were collected from patients for 89.1 +/- 38.7 months after therapy ended. In the first year off therapy, 29.9% of patients had clinical relapse, 16.2% had hepatitis flares, and 8.2% had hepatic decompensation. There was no significant difference in the incidence of hepatic decompensation between patients with and without cirrhosis. Hepatocellular carcinoma developed in 14 patients 20-109 months after cessation of therapy, with 5-year cumulative incidence of 5.2% in patients with cirrhosis. Three patients with cirrhosis died of hepatic decompensation 38-76 months after cessation of therapy (5-year cumulative mortality, 2.9%). Multivariate analyses showed that men were more likely than women to have recurrence of hepatic decompensation (hazard ratio [HR], 4.339; P = .014). Liver cirrhosis (HR, 2.766; P = .041) and age (HR, 1.054; P = .023) increased risk for hepatocellular carcinoma. CONCLUSIONS: Cessation of lamivudine therapy after recovery from hepatitis B flare with decompensation was safe for most patients. However, 8.2% develop decompensation within 1 year and can be rescued by timely retreatment. With close monitoring, the stopping strategy could be a feasible alternative to indefinite therapy, especially in low resource settings. PMID- 25445776 TI - Subliminal galvanic-vestibular stimulation influences ego- and object-centred components of visual neglect. AB - Neglect patients show contralesional deficits in egocentric and object-centred visuospatial tasks. The extent to which these different phenomena are modulated by sensory stimulation remains to be clarified. Subliminal galvanic vestibular stimulation (GVS) induces imperceptible, polarity-specific changes in the cortical vestibular systems without the unpleasant side effects (nystagmus, vertigo) induced by caloric vestibular stimulation. While previous studies showed vestibular stimulation effects on egocentric spatial neglect phenomena, such effects were rarely demonstrated in object-centred neglect. Here, we applied bipolar subsensory GVS over the mastoids (mean intensity: 0.7mA) to investigate its influence on egocentric (digit cancellation, text copying), object-centred (copy of symmetrical figures), or both (line bisection) components of visual neglect in 24 patients with unilateral right hemisphere stroke. Patients were assigned to two patient groups (impaired vs. normal in the respective task) on the basis of cut-off scores derived from the literature or from normal controls. Both groups performed all tasks under three experimental conditions carried out on three separate days: (a) sham/baseline GVS where no electric current was applied, (b) left cathodal/right anodal (CL/AR) GVS and (c) left anodal/right cathodal (AL/CR) GVS, for a period of 20min per session. CL/AR GVS significantly improved line bisection and text copying whereas AL/CR GVS significantly ameliorated figure copying and digit cancellation. These GVS effects were selectively observed in the impaired- but not in the unimpaired patient group. In conclusion, subliminal GVS modulates ego- and object-centred components of visual neglect rapidly. Implications for neurorehabilitation are discussed. PMID- 25445777 TI - Role of the anterior temporal lobes in semantic representations: Paradoxical results of a cTBS study. AB - According to the 'Semantic Hub' model, which was developed from data gathered in the moderate to advanced stages of semantic dementia (SD), a unitary amodal mechanism, located in the anterior parts of both temporal lobes (ATLs), should support the interactive activation of semantic representations in all modalities and for all semantic categories. This model has been challenged by clinical findings, which show that in the early stages of SD, when important asymmetries can be observed at the level of the right and left ATLs, the semantic impairment can be modality-specific, mainly affecting lexical-semantic knowledge when the left temporal lobe is more atrophic and pictorial representations when atrophy prevails on the right side. On the other hand, findings of experiments conducted in normal subjects with repetitive transcranial magnetic stimulations (rTMS), support the unitary model. In the most compelling of these studies, rTMS was used to investigate the role of right and left ATLs directly, by comparing semantic processing of the same concepts, presented as written words or pictures. The efficiency of semantic processing for words and pictures was reduced to the same degree by rTMS applied to the left and right ATLs. However, to consider more in depth some methodological inconsistencies of these studies and with the aim of discussing the effects of rTMS on high-level cognitive functions, we decided to repeat that experimental paradigm, using the continuous theta burst stimulation (cTBS) protocol over the right ATL, left ATL and vertex (as control site). A significant interaction was found between side of cTBS application and type of stimulus, but, contrary to our predictions, we observed significantly faster (rather than slower) responses to pictures after application of cTBS to the right ATL and no difference between responses to written words after application of cTBS to the left ATL in comparison with the vertex. These unexpected results are discussed with respect to the nature of the semantic representations supported by the right and left ATLs and to re-appraisal of the 'virtual lesion' account to explain results obtained with rTMS experiments on high-level cognitive functions. PMID- 25445775 TI - Object identification leads to a conceptual broadening of object representations in lateral prefrontal cortex. AB - Recent experience identifying objects leads to later improvements in both speed and accuracy ("repetition priming"), along with simultaneous reductions of neural activity ("repetition suppression"). A popular interpretation of these joint behavioral and neural phenomena is that object representations become perceptually "sharper" with stimulus repetition, eliminating cells that are poorly stimulus-selective and responsive and reducing support for competing representations downstream. Here, we test this hypothesis in an fMRI-adaptation experiment using pictures of objects. Prior to fMRI, participants repeatedly named a set of object pictures. During fMRI, participants viewed adaptation sequences composed of rapidly repeated objects (3-6 repetitions over several seconds) that were either named previously or that were new for the fMRI session, followed by single "deviant" object pictures used to measure recovery from adaptation and that shared a relationship to the adapted picture (a different exemplar of the same object, a conceptual associate, or an unrelated picture). Effects of adaptation and recovery were found throughout visually responsive brain regions. Occipitotemporal cortical regions displayed repetition suppression to previously named relative to new adapters but failed to exhibit pronounced changes in neural tuning. In contrast, changes in the slope of the recovery curves were found in the left lateral prefrontal cortex: Greater residual adaptation was observed to exemplar stimuli and conceptual associates following previously named adapting stimuli, consistent with greater rather than reduced neural overlap among representations of conceptually related objects. Furthermore, this change in neural tuning was directly related to the proportion of conceptual errors made by participants in the naming sessions pre- and post fMRI, establishing that the experience-dependent conceptual broadening of object representations seen in fMRI is also manifest in behavior. In a follow-up behavioral experiment, we further show that recent naming experience leads to greater semantic priming when using the previously named pictures as briefly presented primes. Taken together, our results fail to support perceptual sharpening as the primary mediator between repetition suppression and behavioral priming at durations typically used to study priming and instead highlight an experience-dependent broadening of conceptual representations. We suggest that alternative mechanisms, such as increases in neural synchronization, are more promising in explaining priming in the face of repetition suppression. PMID- 25445778 TI - Short-term retention of visual information: Evidence in support of feature-based attention as an underlying mechanism. AB - Retention of features in visual short-term memory (VSTM) involves maintenance of sensory traces in early visual cortex. However, the mechanism through which this is accomplished is not known. Here, we formulate specific hypotheses derived from studies on feature-based attention to test the prediction that visual cortex is recruited by attentional mechanisms during VSTM of low-level features. Functional magnetic resonance imaging (fMRI) of human visual areas revealed that neural populations coding for task-irrelevant feature information are suppressed during maintenance of detailed spatial frequency memory representations. The narrow spectral extent of this suppression agrees well with known effects of feature based attention. Additionally, analyses of effective connectivity during maintenance between retinotopic areas in visual cortex show that the observed highlighting of task-relevant parts of the feature spectrum originates in V4, a visual area strongly connected with higher-level control regions and known to convey top-down influence to earlier visual areas during attentional tasks. In line with this property of V4 during attentional operations, we demonstrate that modulations of earlier visual areas during memory maintenance have behavioral consequences, and that these modulations are a result of influences from V4. PMID- 25445779 TI - Relationships between acute imaging biomarkers and theory of mind impairment in post-acute pediatric traumatic brain injury: A prospective analysis using susceptibility weighted imaging (SWI). AB - Theory of Mind (ToM) forms an integral component of socially skilled behavior, and is critical for attaining developmentally appropriate goals. The protracted development of ToM is mediated by increasing connectivity between regions of the anatomically distributed 'mentalizing network', and may be vulnerable to disruption from pediatric traumatic brain injury (TBI). The present study aimed to evaluate the post-acute effects of TBI on first-order ToM, and examine relations between ToM and both local and global indices of macrostructural damage detected using susceptibility-weighted imaging (SWI). 104 children and adolescents with TBI and 43 age-matched typically developing (TD) controls underwent magnetic resonance imaging including a susceptibility-weighted imaging (SWI) sequence 2-8 weeks post-injury and were assessed on cognitive ToM tasks at 6-months after injury. Compared to TD controls and children with mild-moderate injuries, children with severe TBI showed significantly poorer ToM. Moreover, impairments in ToM were related to diffuse neuropathology, and parietal lobe lesions. Our findings support the vulnerability of the immature social brain network to disruption from TBI, and suggest that global macrostructural damage commonly associated with traumatic axonal injury (TAI) may contribute to structural disconnection of anatomically distributed regions that underlie ToM. This study suggests that SWI may be a valuable imaging biomarker to predict outcome and recovery of social cognition after pediatric TBI. PMID- 25445781 TI - A music perception disorder (congenital amusia) influences speech comprehension. AB - This study investigated the underlying link between speech and music by examining whether and to what extent congenital amusia, a musical disorder characterized by degraded pitch processing, would impact spoken sentence comprehension for speakers of Mandarin, a tone language. Sixteen Mandarin-speaking amusics and 16 matched controls were tested on the intelligibility of news-like Mandarin sentences with natural and flat fundamental frequency (F0) contours (created via speech resynthesis) under four signal-to-noise (SNR) conditions (no noise, +5, 0, and -5dB SNR). While speech intelligibility in quiet and extremely noisy conditions (SNR=-5dB) was not significantly compromised by flattened F0, both amusic and control groups achieved better performance with natural-F0 sentences than flat-F0 sentences under moderately noisy conditions (SNR=+5 and 0dB). Relative to normal listeners, amusics demonstrated reduced speech intelligibility in both quiet and noise, regardless of whether the F0 contours of the sentences were natural or flattened. This deficit in speech intelligibility was not associated with impaired pitch perception in amusia. These findings provide evidence for impaired speech comprehension in congenital amusia, suggesting that the deficit of amusics extends beyond pitch processing and includes segmental processing. PMID- 25445780 TI - The neural mechanism underlying the effects of preceding contexts on current categorization decisions. AB - Preceding contexts strongly influence current decision-making. To elucidate the neural mechanism that underlies this phenomenon, magnetoencephalographic signals were recorded while participants performed a binary categorization task on a sequence of facial expressions. The behavioral data indicated that the categorization of current facial expressions differed between the contexts shaped by the immediately preceding expression. We found that the effects of the preceding context were linked to prestimulus power activities in the low frequency band. However, these context-dependent neural markers did not reflect behavioral decisions. Rather, the beta power observed primarily after stimulus onset and located at distinct sensors was predictive of the trial-by-trial decisions. Despite these results, the coupling strength between context-dependent and decision-related power differed between preceding contexts, suggesting that the context-dependent power interacted with decision-related power in a systemic manner and in turn biased behavioral decisions. Taken together, these findings suggest that categorization decisions are mediated by a series of power activities that coordinate the influence of preceding contexts on current categorization. PMID- 25445782 TI - Affect differentially modulates brain activation in uni- and multisensory body voice perception. AB - Emotion perception naturally entails multisensory integration. It is also assumed that multisensory emotion perception is characterized by enhanced activation of brain areas implied in multisensory integration, such as the superior temporal gyrus and sulcus (STG/STS). However, most previous studies have employed designs and stimuli that preclude other forms of multisensory interaction, such as crossmodal prediction, leaving open the question whether classical integration is the only relevant process in multisensory emotion perception. Here, we used video clips containing emotional and neutral body and vocal expressions to investigate the role of crossmodal prediction in multisensory emotion perception. While emotional multisensory expressions increased activation in the bilateral fusiform gyrus (FFG), neutral expressions compared to emotional ones enhanced activation in the bilateral middle temporal gyrus (MTG) and posterior STS. Hence, while neutral stimuli activate classical multisensory areas, emotional stimuli invoke areas linked to unisensory visual processing. Emotional stimuli may therefore trigger a prediction of upcoming auditory information based on prior visual information. Such prediction may be stronger for highly salient emotional compared to less salient neutral information. Therefore, we suggest that multisensory emotion perception involves at least two distinct mechanisms; classical multisensory integration, as shown for neutral expressions, and crossmodal prediction, as evident for emotional expressions. PMID- 25445784 TI - Novel methods of applying direct chemical and mechanical stimulation to the oral mucosa for traditional behavioral pain assays in conscious rats. AB - BACKGROUND: Stomatitis induces severe and painful hypersensitivity to pungency and physical contact during meals. Many studies have used anesthetized animals to examine evoked nociception in the oral mucosa, but no reports have used traditional behavioral assays to evaluate nociception in conscious animals. NEW METHODS: We developed two new methods of applying chemical or mechanical stimulation directly to the oral mucosa of the mandibular vestibule of conscious rats. Nociceptive evaluations were performed by measuring facial grooming time and the head withdrawal threshold to von Frey stimulations. (1) For the intraoral dropping method, rat mucosa was transiently exposed by hand, and a drop of a pungent solution was applied. (2) For the stable intraoral opening method, rat mucosa was long-term exposed following piercing surgery of the mental skin after habitual training for 2-3 weeks. RESULTS: In the intraoral dropping method, the application of 100 MUM capsaicin or 100 mM allyl isothiocyanate prolonged mouth rubbing time. Capsaicin-induced mouth-rubbing time was further enhanced following the development of an acetic acid-induced ulcer. The stable intraoral opening method enabled stable measurements of the mechanical withdrawal threshold in the oral mucosa of conscious rats. Ulcer development decreased the mechanical threshold, whereas topical lidocaine treatment increased the threshold. COMPARISON WITH EXISTING METHODS: These new methods enable the evaluations of motivational nocifensive behaviors in response to intraoral stimulations without any anesthetic effects. CONCLUSIONS: The intraoral dropping and stable intraoral opening methods can be used in combination with traditional behavioral assays to evaluate nociception in the oral mucosa of conscious rats. PMID- 25445785 TI - Optimized protocol for high resolution functional magnetic resonance imaging at 3T using single-shot echo planar imaging. AB - BACKGROUND: To translate highly accelerated EPI-fMRI protocols as commonly used at ultra-high field strengths to clinical 3T settings. NEW METHOD: EPI protocols with increasing matrix sizes and parallel imaging (PI) factors were tested in two separate fMRI studies, a simple motor-task and a complex motivation-task experiment with focus on the sensorimotor cortex (SMC) and the nucleus accumbens (NAcc), respectively. RESULTS: By increasing the matrix size and the PI-factor simultaneously, BOLD-sensitivity in terms of maximal t-values and numbers of activated clusters was uncompromised in single individuals in both fMRI experiments. In the SMC, the multi-subject analysis revealed an increase of 66% of the maximal t-value whereby the number of activated clusters was increased by a factor of 3.3 when the matrix size (PI-factor) was increased from 96*96 (R=2) to 192*192 (R=4). In the NAcc, the number of activated clusters increased from 5 to 7 whereby the maximal t-value remained unaffected when the matrix size (PI factor) was increased from 96*96 (R=2) to 160*160 (R=3). COMPARISON WITH EXISTING METHOD: Using the proposed high-resolution EPI protocol, spatial blurring was clearly reduced. Further, BOLD sensitivity was clearly improved in multi-subject analyses and remained unaffected in single individuals compared to using the standard protocols. CONCLUSIONS: Conventionally used matrix sizes (PI-factors) might be non-optimal for some applications sacrificing BOLD spatial specificity. We recommend using the proposed high-resolution protocols applicable in detecting robust BOLD activation in fMRI. PMID- 25445783 TI - Brain network activity in monolingual and bilingual older adults. AB - Bilingual older adults typically have better performance on tasks of executive control (EC) than do their monolingual peers, but differences in brain activity due to language experience are not well understood. Based on studies showing a relation between the dynamic range of brain network activity and performance on EC tasks, we hypothesized that life-long bilingual older adults would show increased functional connectivity relative to monolinguals in networks related to EC. We assessed intrinsic functional connectivity and modulation of activity in task vs. fixation periods in two brain networks that are active when EC is engaged, the frontoparietal control network (FPC) and the salience network (SLN). We also examined the default mode network (DMN), which influences behavior through reduced activity during tasks. We found stronger intrinsic functional connectivity in the FPC and DMN in bilinguals than in monolinguals. Although there were no group differences in the modulation of activity across tasks and fixation, bilinguals showed stronger correlations than monolinguals between intrinsic connectivity in the FPC and task-related increases of activity in prefrontal and parietal regions. This bilingual difference in network connectivity suggests that language experience begun in childhood and continued throughout adulthood influences brain networks in ways that may provide benefits in later life. PMID- 25445786 TI - Sirtuin 7 promotes cellular survival following genomic stress by attenuation of DNA damage, SAPK activation and p53 response. AB - Maintaining the genomic integrity is a constant challenge in proliferating cells. Amongst various proteins involved in this process, Sirtuins play a key role in DNA damage repair mechanisms in yeast as well as mammals. In the present work we report the role of one of the least explored Sirtuin viz., SIRT7, under conditions of genomic stress when treated with doxorubicin. Knockdown of SIRT7 sensitized osteosarcoma (U2OS) cells to DNA damage induced cell death by doxorubicin. SIRT7 overexpression in NIH3T3 delayed cell cycle progression by causing delay in G1 to S transition. SIRT7 overexpressing cells when treated with low dose of doxorubicin (0.25 uM) showed delayed onset of senescence, lesser accumulation of DNA damage marker gammaH2AX and lowered levels of growth arrest markers viz., p53 and p21 when compared to doxorubicin treated control GFP expressing cells. Resistance to DNA damage following SIRT7 overexpression was also evident by EdU incorporation studies where cellular growth arrest was significantly delayed. When treated with higher dose of doxorubicin (>1 uM), SIRT7 conferred resistance to apoptosis by attenuating stress activated kinases (SAPK viz., p38 and JNK) and p53 response thereby shifting the cellular fate towards senescence. Interestingly, relocalization of SIRT7 from nucleolus to nucleoplasm together with its co-localization with SAPK was an important feature associated with DNA damage. SIRT7 mediated resistance to doxorubicin induced apoptosis and senescence was lost when p53 level was restored by nutlin treatment. Overall, we propose SIRT7 attenuates DNA damage, SAPK activation and p53 response thereby promoting cellular survival under conditions of genomic stress. PMID- 25445787 TI - Role for chondroitin sulfate glycosaminoglycan in NEDD9-mediated breast cancer cell growth. AB - There are lines of evidence demonstrating that NEDD9 (Cas-L, HEF-1) plays a key role in the development, progression, and metastasis of breast cancer cells. We previously reported that NEDD9 plays a critical role for promoting migration and growth of MDA-MB-231. In order to further characterize the mechanisms of NEDD9 mediated cancer migration and growth, stable cells overexpressing NEDD9 were generated using HCC38 as a parental cell line which expresses low level of endogenous NEDD9. Microarray studies demonstrated that core proteins of CD44 and Serglycin were markedly upregulated in HCC38(NEDD9) cells compared to HCC38(Vector) cells, while those of Syndecan-1, Syndecan-2, and Versican were downregulated in HCC38(NEDD9). Importantly, enzymes generating chondroitin sulfate glycosaminoglycans (CS) such as CHST11, CHST15, and CSGALNACT1 were upregulated in HCC38(NEDD9) compared to HCC38(Vector). Immunofluorescence studies using specific antibody, GD3G7, confirmed the enhanced expression of CS-E subunit in HCC38(NEDD9). Immunoprecipitation and western blotting analysis demonstrated that CS-E was attached to CD44 core protein. We demonstrated that removing CS by chondroitinase ABC significantly inhibited anchorage-independent colony formation of HCC38(NEDD9) in methylcellulose. Importantly, the fact that GD3G7 significantly inhibited colony formation of HCC38(NEDD9) cells suggests that CS-E subunit plays a key role in this process. Furthermore, treatment of HCC38(NEDD9) cells with chondroitinase ABC or GD3G7 significantly inhibited mammosphere formation. Exogenous addition of CS-E enhanced colony formation and mammosphere formation of HCC38 parental and HCC38(Vector) cells. These results suggest that NEDD9 regulates the synthesis and expression of tumor associated glycocalyx structures including CS-E, which plays a key role in promoting and regulating breast cancer progression and metastasis and possibly stem cell phenotypes. PMID- 25445788 TI - Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process. AB - In this study, we determined the effects of transforming growth factor-beta (TGF beta) and Wnt/beta-catenin signaling on myofibroblast differentiation of NIH/3T3 fibroblasts in vitro and evaluated the therapeutic efficacy of NSC668036 in bleomycin-induced pulmonary fibrosis murine model. In vitro study, NSC668036, a small organic inhibitor of the PDZ domain in Dvl, suppressed beta-catenin-driven gene transcription and abolished TGF-beta1-induced migration, expression of collagen I and alpha-smooth muscle actin (alpha-SMA) in fibroblasts. In vivo study, we found that NSC668036 significantly suppressed accumulation of collagen I, alpha-SMA, and TGF-beta1 but increased the expression of CK19, Occludin and E cadherin that can inhibit pulmonary fibrogenesis. Because fibrotic lung exhibit aberrant activation of Wnt/beta-catenin signaling, these data collectively suggest that inhibition of Wnt/beta-catenin signaling at the Dvl level may be an effective approach to the treatment of fibrotic lung diseases. PMID- 25445790 TI - Phosphorylation of filamin A by Cdk1 regulates filamin A localization and daughter cell separation. AB - In cell culture, many adherent mammalian cells undergo substantial actin cytoskeleton rearrangement prior to mitosis as they detach from the extracellular matrix and become spherical. At the end of mitosis, the actin cytoskeleton is required for cytokinesis and the reassembly of interphase structures as cells spread and reattach to substrate. To understand the processes regulating mitotic cytoskeletal remodeling, we studied how mitotic phosphorylation regulates filamin A (FLNa). FLNa is an actin-crosslinking protein that was previously identified as a cyclin-dependent kinase 1 (Cdk1) binding partner and substrate in vitro. Using quantitative label-based mass spectrometry, we find that FLNa serines 1084, 1459 and 1533 are phosphorylated in mitotic HeLa cells and all three sites match the phosphorylation consensus sequence of Cdk1. To investigate the functional role of mitotic FLNa phosphorylation, we mutated serines 1084, 1459 and 1533 to nonphosphorylatable alanine residues and expressed GFP-tagged FLNa(S1084A,S1459A,S1533A) (FLNa-AAA GFP) in a FLNa-deficient human melanoma cell line called M2. M2 cells expressing FLNa-AAA GFP have enhanced FLNa-AAA GFP and actin localization at sites of contact between daughter cells, impaired post mitotic daughter cell separation and defects in cell migration. Therefore, mitotic phosphorylation of FLNa is important for successful cell division and interphase cell behavior. PMID- 25445791 TI - Development and evaluation of an N9-specific enzyme-linked immunosorbent assay to detect antibodies in duck and chicken sera. AB - A serological test for detecting N9-specific antibodies may be useful as a DIVA strategy to differentiate vaccinated from infected animals or simply for direct serological detection of infection with N9-subtype virus. The method currently recommended for the detection of antibodies against neuraminidase is neuraminidase inhibition (NI), which is a laborious method using toxic chemicals and has low sensitivity. The present study describes the development and validation of an N9-specific ELISA. Data obtained with this N9 ELISA were compared to those obtained with nucleoprotein-based ELISA, haemagglutination inhibition test using homologous antigen and NI assay. 785 sera from ducks and chickens were used, from flocks previously determined to be AI negative or from experimentally infected or immunized flocks. Sensitivity and specificity were evaluated, and a ROC curve and kappa values, which provide a comparison between methods, were calculated. The results obtained in this study indicate that the N9 based-ELISA is effective in detecting N9-specific antibodies with high specificity and with better sensitivity than the recommended NI method; using data from 177 common sera tested with N9 ELISA and NI assay both compared to NP based ELISA, their specificity were evaluated at 93.6% and 91.5% respectively, and sensitivity at 90.8% and 39.2% respectively. PMID- 25445792 TI - Evaluation of GS Junior and MiSeq next-generation sequencing technologies as an alternative to Trugene population sequencing in the clinical HIV laboratory. AB - Population HIV-1 sequencing is currently the method of choice for the identification and follow-up of HIV-1 antiretroviral drug resistance. It has limited sensitivity and results in a consensus sequence showing the most prevalent nucleotide per position. Moreover concomitant sequencing and interpretation of the results for several samples together is laborious and time consuming. In this study, the practical use of GS Junior and MiSeq bench-top next generation sequencing (NGS) platforms as an alternative to Trugene Sanger-based population sequencing in the clinical HIV laboratory was assessed. DeepChek((r)) HIV TherapyEdge software was used for processing all the protease and reverse transcriptase sequences and for resistance interpretation. Plasma samples from nine HIV-1 carriers, representing the major HIV-1 subtypes in Israel, were compared. The total number of amino acid substitutions identified in the nine samples by GS Junior (232 substitutions) and MiSeq (243 substitutions) was similar and higher than Trugene (181 substitutions), emphasizing the advantage of deep sequencing on population sequencing. More than 80% of the identified substitutions were identical between the GS Junior and MiSeq platforms, most of which (184 of 199) at similar frequency. Low abundance substitutions accounted for 20.9% of the MiSeq and 21.9% of the GS Junior output, the majority of which were not detected by Trugene. More drug resistance mutations were identified by both the NGS platforms, primarily, but not only, at low abundance. In conclusion, in combination with DeepChek, both GS Junior and MiSeq were found to be more sensitive than Trugene and adequate for HIV-1 resistance analysis in the clinical HIV laboratory. PMID- 25445789 TI - Planar cell polarity of the kidney. AB - Planar cell polarity (PCP) or tissue polarity refers to the polarization of tissues perpendicular to the apical-basal axis. Most epithelia, including the vertebrate kidney, show signs of planar polarity. In the kidney, defects in planar polarity are attributed to several disease states including multiple forms of cystic kidney disease. Indeed, planar cell polarity has been shown to be essential for several cellular processes that appear to be necessary for establishing and maintaining tubule diameter. However, uncovering the genetic mechanisms underlying PCP in the kidney has been complicated as the roles of many of the main players are not conserved in flies and vice versa. Here, we review a number of cellular and molecular processes that can affect PCP of the kidney with a particular emphasis on the mechanisms that do not appear to be conserved in flies or that are not part of canonical determinants. PMID- 25445794 TI - Development of a reverse transcription loop-mediated isothermal amplification (RT LAMP) assay for the detection of Sugarcane mosaic virus and Sorghum mosaic virus in sugarcane. AB - A reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay was developed for detecting Sugarcane mosaic virus (SCMV) and Sorghum mosaic virus (SrMV) in sugarcane. Six sets of four primers corresponding to the conserved coat protein gene were designed and tested for each virus. Three primer sets designed for detecting SCMV and four for detecting SrMV were successful in the RT-LAMP assay. The effective primer sets were not only specific for their target virus, but also able to detect multiple virus strains. The magnesium sulfate concentration of the reaction solution was optimized, with both viruses requiring a minimum of 5mM for detection. The sensitivity of this RT-LAMP assay was less than that of conventional and real-time RT-PCR. PMID- 25445793 TI - Expression of E2 gene of bovine viral diarrhea virus in Pichia pastoris: a candidate antigen for indirect Dot ELISA. AB - The E2 gene containing the EcoR I and Not I sites of bovine viral diarrhea virus (BVDV) was amplified from the plasmid pMD-18T-E2 of the HB-bd isolated, and inserted into Pichia pastoris (P. pastoris) expression vector pPIC9K, and transfected into Escherichia coli DH5alpha. The recombinant plasmid pPIC9K-E2 was digested by the SalI restriction enzyme and transformed into the P. pastoris strain GS115 by electroporation. High copy integrative transformants were obtained by G418 screening and induced for expression with methanol. The expressed products in the culture medium were identified by the sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), the Western blotting and the antibody test for immunity. An indirect Dot-ELISA for the detection of antibody against BVDV was established by the recombinant E2 protein as the coating antigen. The reaction conditions of the indirect Dot-ELISA were optimized. The coating concentration of the E2 recombinant protein antigen, the dilution of serum sample, the optimal concentration of HRP labeled antibody, the optimal blocking reagent and blocking time were studied. 100 sera samples from cows in the field were tested for the antibody against BVDV by the Dot-ELISA and the IDEXX HerdChek BVDV antibody ELISA kit simultaneously to compare the specificity, sensitivity and accuracy. The results showed that the expressed products in the culture medium resulted in single band of 44kDa by SDS-PAGE and Western blotting. The results of the immunogenicity assay indicated that the protein E2 expressed in P. pastoris could induce the experimental animals of the rabbit to produce BVDV specific antibodies. The results of the indirect Dot-ELISA showed that the optimal coating concentration of the E2 recombinant protein was 2.0MUg/mL, the bovine serum dilution was 1:100, the optimal concentration of HRP labeled rabbit anti-bovine antibody IgG was 1:500, and the optimal blocking reagent was 3% glutin-TBS and blocking for 45min. The indirect Dot-ELISA showed 96.7%, 92.5% and 95% in the terms of specificity, sensitivity and accuracy compared to the IDEXX ELISA test kit. The indirect Dot-ELISA using the E2 recombinant protein can be used for the detection of antibody against the BVDV and could be considered in the surveillance programs. PMID- 25445795 TI - Establishment and evaluation of a loop-mediated isothermal amplification (LAMP) assay for the semi-quantitative detection of HIV-1 group M virus. AB - The past decade has witnessed a dramatic increase of anti-retroviral treatment of human immunodeficiency virus (HIV) infected patients in many African countries. Due to costs and lack of currently available commercial viral load assays, insufficient attention has been paid to therapy monitoring through measurement of plasma viral load. This challenge of patient monitoring by tests as viral load, CD4 cell count, and finally HIV drug resistance could reverse achievements already made against HIV/AIDS infection. Loop-mediated isothermal amplification (LAMP) has been shown to be simple, rapid and cost-effective, characteristics which make this assay suitable for viral load monitoring in resource limited settings. This paper describes a revised LAMP assay using primers in the HIV-1 integrase region. The assay can be used for semi-quantitative measurement of HIV 1 group M viral load. The lower limit of detection (LLOD) was determined as 1200copies/mL and lower limit of quantitation (LLOQ) at 9800copies/mL. Sensitivities of 82 and 86% (in 135 and 99 plasma samples respectively from Kenya) and 93% (in 112 plasma samples from Germany) and specificities of 99 and 100% were realized. HIV-1 group O and HIV-2 virus samples were not detected. This LAMP assay has the potential for semi-quantitation of HIV-1 group M viral load in resource limited countries. There is still a need for further improvement by refinement of primers in respect to detection of HIV-1 group M non-B virus. PMID- 25445796 TI - Analytical and clinical performance of a new molecular assay for Epstein-Barr virus DNA quantitation. AB - Quantitation of EBV DNA has been shown to be a useful tool to identify and monitor patients with immunosuppression and high risk for EBV-associated disease. In this study, the analytical and clinical performance of the new Realquality RS EBV Kit (AB Analitica, Padova, Italy) was investigated. The clinical performance was compared to that of the EBV R-gene (bioMerieux, Varilhes, France) assay. When the accuracy of the new assay was tested, all results except of one were found to be within +/-0.5log10 unit of the expected panel results. Determination of linearity showed a quasilinear curve, the between day imprecision ranged from 18% to 88% and the within run imprecision from 16% to 53%. When 96 clinical EDTA whole blood samples were tested, 77 concordant and 19 discordant results were obtained. When the results for the 69 samples quantifiable with both assays were compared, the new assay revealed a mean 0.31log10 unit higher measurement. The new assay proved to be suitable for the detection and quantitation of EBV DNA in EDTA whole blood in the routine diagnostic laboratory. The variation between quantitative results obtained by the assays used in this study reinforces the use of calibrators traceable to the existing international WHO standard making different assays better comparable. PMID- 25445797 TI - Comparison of three methods for extraction of HCV RNA in sera collected from individuals with hyperlipidemia, hyperbilirubinemia and hyperglobulinemia. AB - Efficient detection of HCV RNA in serum is critical for the diagnosis of hepatitis C virus (HCV) infection. Various nucleic acid extraction methods have been used to extract viral RNA for real-time reverse transcription PCR (RT-PCR). However, the efficiencies of extraction methods for HCV RNA in sera collected from individuals with hyperlipidemia, hyperbilirubinemia and hyperglobulinemia have not been investigated. In the present study, the efficiencies of three extraction methods, i.e., Trizol, guanidine isothiocyanate and silica nanoparticles, were evaluated and compared. All serum samples were collected from HCV-infected patients. For serum samples in which bilirubin, lipids and globulins were all within the normal range, the medians of HCV RNA concentration with Trizol, guanidine isothiocyanate and silica method were 2.25*10(4), 2.80*10(4) and 3.26*10(5)IU/ml HCV RNA respectively (n=180). For hyperlipidemia serum samples, the medians were 6.70*10(3), 8.79*10(3) and 1.10*10(6) respectively (n=158). For hyperbilirubinemia serum samples, the medians were 5.71*10(4), 1.59*10(5) and 1.09*10(6) respectively (n=107). For hyperglobulinemia serum samples, the medians were 3.44*10(4), 3.10*10(4) and 3.06*10(5) respectively (n=71). The medians were highest with silica method from all these types of serum samples. The silica method is, therefore, efficient for HCV RNA extraction even for sera from hyperlipidemia, hyperbilirubinemia and hyperglobulinemia patients. PMID- 25445798 TI - An improved validated SYBR green-based real-time quantitative PCR assay for the detection of the Penaeus stylirostris densovirus in penaeid shrimp. AB - The Penaeus stylirostris densovirus (PstDV) (also known as infectious hypodermal and hematopoietic necrosis virus, IHHNV), one of the major shrimp pathogens, has a worldwide distribution in farmed and wild shrimp populations. Outbreaks of IHHNV have been associated with substantial economic losses which are accompanied by a negative social impact. Current diagnostic PCR tests may result in false positive results as several parts of PstDV genome may be endogenized in the nuclear genome of the shrimp P. stylirostris. A one-step qPCR SYBR-Green based quantitative real-time polymerase chain reaction (qPCR) assay to detect different isolates of the IHHNV in shrimp samples was developed. The detection limit of the assay was 81 viral copies of targeted DNA per reaction. The specificity of the assay was evaluated by melting curve analysis, which showed that the IHHNV product generated a single melt peak at 81.4+/-0.044 degrees C. The assay was more sensitive than conventional PCR. The standardized PCR was shown to be highly sensible, specific, robust, and reproducible, which makes it an economical and powerful tool for both diagnostic applications and general research of IHHNV. PMID- 25445799 TI - Development of one-tube real-time qRT-PCR and evaluation of RNA extraction methods for the detection of Eggplant mottled dwarf virus in different species. AB - A one-tube real-time qRT-PCR assay was developed, for the detection and quantification of Eggplant mottled dwarf virus (EMDV), a pathogen affecting cultivated and ornamental plants. The amplification efficiency of the assay was 98% and the linear range of quantification was from 20 to 2*10(8) RNA transcripts. Total RNA extraction methods (three developed methods and one commercially available RNA extraction kit) were evaluated using tissues from seven different plant species and synthetic EMDV RNA transcripts of known concentration. The recovery rates of RNA and the effect of co-extracted inhibitors revealed that methods involving PVPP and phenol-chloroform extraction were the most efficient. These modifications were necessary for processing samples containing high phenolic and polysaccharide compounds such as woody plants. The developed EMDV detection protocol was successfully applied in forty naturally infected woody and herbaceous plants belonging to six different species. The protocol comprises a useful method for low-cost detection of ssRNA viruses in diverse plant tissues. PMID- 25445800 TI - Disparate detection outcomes for anti-HCV IgG and HCV RNA in dried blood spots. AB - Dried blood spots (DBS) expedite the collection, storage and shipping of blood samples, thereby facilitating large-scale serologic studies. We evaluated the sensitivity of anti-HCV IgG testing and HCV-RNA quantitation using freshly prepared and stored DBS derived from HCV-infected patients. Protocols for elution were optimized using DBS prepared from plasma of 52 HCV-infected persons and 51 uninfected persons (control DBS), then applied to DBS from 33 chronic hepatitis C patients that had been stored at -20 degrees C for 5 years (stored DBS). Control and stored DBS, and their corresponding plasma, were processed for anti-HCV IgG testing using the VITROS chemiluminescence assay (CIA) and the HCV 3.0 enzyme immunoassay (EIA) (Ortho-Clinical Diagnostics), and for HCV RNA quantitation by quantitative (q) RT-PCR. HCV genotyping was conducted by nucleotide sequencing. The sensitivity of CIA and EIA in control DBS was 92% and 90%, respectively, compared to 100% and 97%, respectively, in stored DBS. The sensitivity of HCV RNA detection was 88% in control DBS, compared to 36% in stored DBS. Specificity was 100% for all the assays in both control and stored DBS. Genotypes 1, 2 and 3 were detected in 16 (62%), 6 (23.1%), and 4 (15.3%) samples, respectively. Sequences generated from DBS and their corresponding plasma samples were identical. Whereas the sensitivity of anti-HCV IgG detection in stored DBS was equivalent to that in recently prepared DBS, the sensitivity of HCV RNA detection was markedly lower in stored DBS compared to recently prepared DBS. Stored DBS may be reliably used for anti-HCV detection but for HCV-RNA-based testing freshly prepared DBS is preferable to stored DBS. PMID- 25445801 TI - Precision-cut intestinal slices as a culture system to analyze the infection of differentiated intestinal epithelial cells by avian influenza viruses. AB - Many viruses infect and replicate in their host via the intestinal tract, e.g. many picornaviruses, several coronaviruses and avian influenza viruses of waterfowl. To analyze infection of enterocytes is a challenging task as culture systems for differentiated intestinal epithelial cells are not readily available and often have a life span that is too short for infection studies. Precision-cut intestinal slices (PCIS) from chicken embryos were prepared and shown that the epithelial cells lining the lumen of the intestine are viable for up to 4 days. Using lectin staining, it was demonstrated that alpha2,3-linked sialic acids, the preferred receptor determinants of avian influenza viruses, are present on the apical side of the epithelial cells. Furthermore, the epithelial cells (at the tips) of the villi were shown to be susceptible to infection by an avian influenza virus of the H9N2 subtype. This culture system will be useful to analyze virus infection of intestinal epithelial cells and it should be applicable also to the intestine of other species. PMID- 25445802 TI - Cardiovascular magnetic resonance-based evaluation of myocardial rotational mechanics. PMID- 25445803 TI - Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts alpha-linolenate, tryptophan, tyrosine and other major metabolic pathways. AB - Overexposure to the commonly used herbicide atrazine (ATR) affects several organ systems, including the brain. Previously, we demonstrated that short-term oral ATR exposure causes behavioral deficits and dopaminergic and serotonergic dysfunction in the brains of mice. Using adult male C57BL/6 mice, the present study aimed to investigate effects of a 10-day oral ATR exposure (0, 5, 25, 125, or 250mg/kg) on the mouse plasma metabolome and to determine metabolic pathways affected by ATR that may be reflective of ATR's effects on the brain and useful to identify peripheral biomarkers of neurotoxicity. Four hours after the last dosing on day 10, plasma was collected and analyzed with high-performance, dual chromatography-Fourier-transform mass spectrometry that was followed by biostatistical and bioinformatic analyses. ATR exposure (>=5mg/kg) significantly altered plasma metabolite profile and resulted in a dose-dependent increase in the number of metabolites with ion intensities significantly different from the control group. Pathway analyses revealed that ATR exposure strongly correlated with and disrupted multiple metabolic pathways. Tyrosine, tryptophan, linoleic acid and alpha-linolenic acid metabolic pathways were among the affected pathways, with alpha-linolenic acid metabolism being affected to the greatest extent. Observed effects of ATR on plasma tyrosine and tryptophan metabolism may be reflective of the previously reported perturbations of brain dopamine and serotonin homeostasis, respectively. ATR-caused alterations in the plasma profile of alpha-linolenic acid metabolism are a potential novel and sensitive plasma biomarker of ATR effect and plasma metabolomics could be used to better assess the risks, including to the brain, associated with ATR overexposure. PMID- 25445804 TI - Regorafenib impairs mitochondrial functions, activates AMP-activated protein kinase, induces autophagy, and causes rat hepatocyte necrosis. AB - The tyrosine kinase inhibitor regorafenib was approved by regulatory agencies for cancer treatment, albeit with strong warnings of severe hepatotoxicity included in the product label. The basis of this toxicity is unknown; one possible mechanism, that of mitochondrial damage, was tested. In isolated rat liver mitochondria, regorafenib directly uncoupled oxidative phosphorylation (OXPHOS) and promoted calcium overload-induced swelling, which were respectively prevented by the recoupler 6-ketocholestanol (KC) and the mitochondrial permeability transition (MPT) pore blocker cyclosporine A (CsA). In primary hepatocytes, regorafenib uncoupled OXPHOS, disrupted mitochondrial inner membrane potential (MMP), and decreased cellular ATP at 1h, and triggered MPT at 3h, which was followed by necrosis but not apoptosis at 7h and 24h, all of which were abrogated by KC. The combination of the glycolysis enhancer fructose plus the mitochondrial ATPase synthase inhibitor oligomycin A abolished regorafenib induced necrosis at 7h. This effect was not seen at 24h nor with the fructose or oligomycin A separately. CsA in combination with trifluoperazine, both MPT blockers, showed similar effects. Two compensatory mechanisms, activation of AMP-activated protein kinase (AMPK) to ameliorate ATP shortage and induction of autophagy to remove dysfunctional mitochondria, were found to be mobilized. Hepatocyte necrosis was enhanced either by the AMPK inhibitor Compound C or the autophagy inhibitor chloroquine, while autophagy inducer rapamycin was strongly cytoprotective. Remarkably, all toxic effects were observed at clinically-relevant concentrations of 2.5-15MUM. These data suggest that uncoupling of OXPHOS and the resulting ATP shortage and MPT induction are the key mechanisms for regorafenib induced hepatocyte injury, and AMPK activation and autophagy induction serve as pro survival pathways against such toxicity. PMID- 25445805 TI - An overview of current techniques for ocular toxicity testing. AB - Given the hazardous nature of many materials and substances, ocular toxicity testing is required to evaluate the dangers associated with these substances after their exposure to the eye. Historically, animal tests such as the Draize test were exclusively used to determine the level of ocular toxicity by applying a test substance to a live rabbit's eye and evaluating the biological response. In recent years, legislation in many developed countries has been introduced to try to reduce animal testing and promote alternative techniques. These techniques include ex vivo tests on deceased animal tissue, computational models that use algorithms to apply existing data to new chemicals and in vitro assays based on two dimensional (2D) and three dimensional (3D) cell culture models. Here we provide a comprehensive overview of the latest advances in ocular toxicity testing techniques, and discuss the regulatory framework used to evaluate their suitability. PMID- 25445806 TI - Perceptions and practices of student binge drinking: an observational study of residential college students. AB - Professionals have debated the use of the term binge drinking over the past couple of decades, yet little attention has been paid to college student perceptions. We explored how students at one university qualitatively defined binge drinking; whether their own definitions coincided with those adopted by researchers; and whether students' own definitions varied according to their behavior. The most common definition provided by students included a description of the consumption of a large, non-specific, amount of alcohol. Only half of the students who, by standard definition, participated in binge drinking in the previous 30 days actually identified their behavior as such. Finally, binge drinkers were more likely to define binge drinking in an extreme manner such that it results in vomiting or blacking out. PMID- 25445807 TI - Smoking status and intention to quit: the role of affective associations and expectancies. AB - The purpose of this research was to examine how affective associations with smoking and outcome expectancies regarding smoking are related to smoking status and intention to quit among smokers. Researchers and practitioners can draw on findings regarding affective associations and outcome expectancies to provide a further basis for smoking prevention and intervention efforts. Four-hundred and one participants, half of whom were current smokers, from the United States and Australia completed measures of affective associations with smoking and outcome expectancies relating to smoking. Current smokers also indicated their readiness to quit. Participants with more positive affective associations were more likely to be smokers. Current smokers with more positive affective associations expressed less readiness to quit smoking. Outcome expectancies regarding reinforcement stemming from smoking and consequences stemming from smoking were related to smoking status and intention to quit. Outcome expectancies related to smoking significantly mediated the relationship between affective associations and smoking status. Among smokers, outcome expectancies related to smoking significantly mediated the relationship between affective associations and readiness to quit. Implications for prevention and intervention programs are discussed. PMID- 25445808 TI - Public commitment, resistance to advertising, and leisure promotion in a school based drug abuse prevention program: a component dismantling study. AB - The objective of the present study was to examine the contribution of three intervention components (public commitment, resistance to advertising, and leisure promotion) on alcohol and protective variables in a school-based substance use prevention program. Participants included 480 Spanish students aged from 14 to 16 who received the Saluda prevention program in one of the following five experimental conditions: complete program, program minus public commitment, program minus resistance to advertising, program minus leisure promotion, and a waiting-list control. The students completed self-report surveys at pretest, posttest, and 6-month follow-up assessments. When excluding the healthy leisure promotion component, the Saluda program showed no loss of efficacy neither on alcohol use nor on other substance-related variables, while public commitment and resistance to advertising improved the aforementioned program's efficacy. PMID- 25445809 TI - Reasons for synthetic THC use among college students. AB - Synthetic THC, also known as fake marijuana, is used by college students in the United States. The present study examined reasons for recent synthetic THC use among college students (N = 339). Students completed a 3-page survey during regularly scheduled class times. Results indicated students reported using synthetic THC for curiosity, to get high, and the fun of feeling high. No significant differences in reasons for use were found based on sex and grade. College students reported most often obtaining synthetic THC from head shops. Study findings may be beneficial to college health professionals and others working with college students. High rates of lifetime use may suggest that educational and intervention programs are needed. PMID- 25445810 TI - Alcohol consumption and negative sex-related consequences among college women: the moderating role of alcohol protective behavioral strategies. AB - Alcohol protective behavioral strategies (PBS) limit overall negative consequences; however, less is known about the relationship between PBS and negative sex-related consequences. The purpose of the current study was to examine the moderating effects of 2 distinct types of PBS-controlled consumption strategies and serious harm reduction strategies-on the relationship between alcohol consumption and alcohol-related risky sexual behavior and sexual victimization. Participants were 459 undergraduate women (ages 18-25) who had consumed alcohol within the past 30 days. Both types of PBS significantly qualified the alcohol-sexual victimization link, but neither type of PBS qualified the alcohol-risky sexual behavior link. PMID- 25445811 TI - Youth acquisition of alcohol and drinking contexts: an in-depth look. AB - Despite efforts to limit underage access to alcohol, alcohol availability remains a challenge for youth drinking prevention. This article fills a gap in our understanding of alcohol consumption among youths by systematically investigating how and under what circumstances they obtain alcohol and the context within which they consume it. Qualitative interviews (n = 47) were conducted with teens to collect information about where and how they obtain alcohol and the contexts within which they drink. Respondents were knowledgeable about commercial and social sources and used this knowledge in their decision making regarding where to obtain alcohol. Teens used their social relationships to circumvent existing policies designed to limit underage access to alcohol. Findings indicate that the majority of teens' drinking occasions occur in their own or someone else's home. PMID- 25445813 TI - [Negative behavioral changes in children and adolescents after anesthesia : Development of a German language version of the Post Hospitalization Behavior Questionnaire]. AB - BACKGROUND: Negative behavioral changes after anesthesia in children are common. The Post Hospitalization Behavior Questionnaire (PHBQ) was particularly developed and has been widely used in English-speaking countries to investigate such behavioral changes. The PHBQ consists of 27 questions related to behavioral features observed by parents after anesthesia or hospitalization, each involving comparison with their baseline status. AIM: A comparable diagnostic tool in German should be established. MATERIAL AND METHODS: The PHBQ was translated into German using a well defined back-translation method. A 3-point Likert scale was used to categorize behavioral features as less than, equal to or more than baseline. Overall 600 questionnaires were given out at children's hospital discharge, following surgical or medical procedures or examinations with or without concurrent anesthesia or deep sedation. After questionnaires were returned, factor and item analysis was conducted. Cronbach's alpha was calculated to determine internal consistency as a measure of reliability. RESULTS: In total, 155 returned and completed questionnaires were assessed, with patients' age ranging from 1.1 to 15.9 (median 5.7) years and length of hospitalization between 1 to 15 (median 2.5) days. The German translation of the PHBQ has a factorial structure that is similar to the English version, and its psychometric properties are also similar. After analysis of the main components and consideration of the Scree plot, either 6 or 7 factors were indicated. Analogously to the original version, we chose 6 factors, which explain 58% of variance. Items were not identically assigned to factors as with the original version, and terms used to describe the factors were slightly adapted. Reliability was adequate, with Cronbach's alpha for the 6 factors being between 0.6 and 0.82 (for total scale: Cronbach's alpha = 0.89, compared to 0.82 for the original version). Children younger than 5 years showed more negative behavioral changes than older children. There were no gender differences. CONCLUSION: With the German translation of the PHBQ presented here an instrument is available to detect negative behavioral changes after anesthesia in children among German speaking populations. The translation is comparable to the English version with minor differences concerning its factorial structure, which may be due to the predominant role of anxiety in all items. Like the original, this questionnaire does not per se discriminate between anesthesia and hospitalization induced behavioral changes. However, the German translation of the PHBQ is a questionnaire that is feasible for clinical routine and scientific settings and can be easily and quickly completed by caregivers. PMID- 25445815 TI - Association of high CD4-positive T cell infiltration with mutations in HLA class II-regulatory genes in microsatellite-unstable colorectal cancer. AB - Besides being expressed on professional antigen-presenting cells, HLA class II antigens are expressed on various tumors of non-lymphoid origin, including a subset of colorectal cancers (CRC). Information about the regulation of HLA class II antigen expression is important for a better understanding of their role in the interactions between tumor and immune cells. Whether lack of HLA class II antigen expression in tumors reflects the selective immune destruction of HLA class II antigen-expressing tumor cells is unknown. To address this question, we tested whether lack of HLA class II antigen expression in CRC was associated with immune cell infiltration. We selected microsatellite-unstable (MSI-H) CRC, because they show pronounced tumor antigen-specific immune responses and, in a subset of tumors, lack of HLA class II antigen expression due to mutations inactivating HLA class II-regulatory genes. We examined HLA class II antigen expression, mutations in regulatory genes, and CD4-positive T cell infiltration in 69 MSI-H CRC lesions. Mutations in RFX5, CIITA, and RFXAP were found in 13 (28.9%), 3 (6.7%), and 1 (2.2%) out of 45 HLA class II antigen-negative tumors. CD4-positive tumor-infiltrating lymphocyte counts were significantly higher in HLA class II antigen-negative tumors harboring mutations in HLA class II regulatory genes (107.4 T cells per 0.25 mm(2)) compared to tumors without mutations (55.5 T cells per 0.25 mm(2), p = 0.008). Our results suggest that the outgrowth of tumor cells lacking HLA class II antigen expression due to mutations of regulatory genes is favored in an environment of dense CD4-positive T cell infiltration. PMID- 25445814 TI - Fever and the use of paracetamol during IL-2-based immunotherapy in metastatic melanoma. AB - Fever is frequently observed in conjunction with interleukin-2 (IL-2)-based immunotherapy. Traditionally, fever has been regarded as an undesirable side effect and treated with fever-lowering drugs. However, new insights in tumor immunology suggest that elevated temperature may facilitate a more effective antitumor immune response. The purpose of this retrospective study was to examine the potential role of the IL-2-induced fever in melanoma patients treated with or without paracetamol in two consecutive cohorts. One hundred and seventy-nine patients with metastatic melanoma treated with a modified decrescendo regimen of IL-2 and Interferon (IFN) between 2004 and 2010 were retrospectively studied. 87 patients treated before 2007 received paracetamol as part of the treatment schedule, and 92 patients treated after 2007 did not receive paracetamol routinely. Body temperature was analyzed as dichotomized and continuous variables and correlated to objective tumor response and overall survival using logistic regression and Cox proportional hazard analysis. Patients experiencing peak temperature of >= 39.5 degrees C had a median OS of 15.2 months compared to 8.7 months among patients with lower temperatures (P = 0.01). In the multivariate analysis, peak temperature of >= 39.5 degrees C (HR 0.53; P = 0.026) and high mean temperature (HR 0.56; P = 0.004) were independent prognostic factors for improved survival. We suggest high fever as a biomarker for improved survival in melanoma patients treated with IL-2/IFN. The routine use of fever-reducing drugs during immunotherapy can therefore be questioned. More studies are needed to evaluate the role of fever and the use of antipyretics during cytokine-based immunotherapy. PMID- 25445816 TI - Gradual adaptation to auditory frequency mismatch. AB - What is the best way to help humans adapt to a distorted sensory input? Interest in this question is more than academic. The answer may help facilitate auditory learning by people who became deaf after learning language and later received a cochlear implant (a neural prosthesis that restores hearing through direct electrical stimulation of the auditory nerve). There is evidence that some cochlear implants (which provide information that is spectrally degraded to begin with) stimulate neurons with higher characteristic frequency than the acoustic frequency of the original stimulus. In other words, the stimulus is shifted in frequency with respect to what the listener expects to hear. This frequency misalignment may have a negative influence on speech perception by CI users. However, a perfect frequency-place alignment may result in the loss of important low frequency speech information. A trade-off may involve a gradual approach: start with correct frequency-place alignment to allow listeners to adapt to the spectrally degraded signal first, and then gradually increase the frequency shift to allow them to adapt to it over time. We used an acoustic model of a cochlear implant to measure adaptation to a frequency-shifted signal, using either the gradual approach or the "standard" approach (sudden imposition of the frequency shift). Listeners in both groups showed substantial auditory learning, as measured by increases in speech perception scores over the course of fifteen one hour training sessions. However, the learning process was faster for listeners who were exposed to the gradual approach. These results suggest that gradual rather than sudden exposure may facilitate perceptual learning in the face of a spectrally degraded, frequency-shifted input. This article is part of a Special Issue entitled . PMID- 25445818 TI - Biological correlates of tinnitus-related distress: an exploratory study. AB - During the process of tinnitus diagnostics, various psychometric instruments are used to measure tinnitus-related distress. The aim of present work was to explore whether candidates for biological correlates of the tinnitus-related distress could be found in peripheral blood of patients and if so, whether there was association between them and psychometric scores that reflect tinnitus-related distress. The concentrations of interleukin-1beta (IL1beta), interleukin-6 (IL6), tumor necrosis factor-alpha (TNFalpha) and a brain-derived neutrotrophic factor (BDNF) were measured in serum of 30 patients diagnosed with chronic tinnitus and tested for correlation with psychometric scores collected on the same day. Spearman's correlation analyses detected significant positive association between the concentrations of tumor necrosis factor alpha and tinnitus loudness, total perceived stress, tension and depression and a negative association between tumor necrosis factor alpha and a psychometric score "joy". Concentrations of interleukin-1beta correlated with the awareness grade of tinnitus. The correlation between visual analogue scale (VAS) "loudness" and tumor necrosis factor alpha as well as between "joy" and tumor necrosis factor alpha retained their significance (p < 0.00167) after the application of Bonferroni correction for multiple testing. Partial correlations removing the effects of age, hearing loss and the duration of tinnitus verified the results obtained using Spearman correlation. We conclude that measuring the concentrations of selected circulating cytokines could possibly become an additional objective element of tinnitus diagnostics in the future. PMID- 25445819 TI - Attentional modulation of medial olivocochlear inhibition: evidence for immaturity in children. AB - Efferent feedback shapes afferent auditory processing. Auditory attention has been shown to modulate medial olivocochlear (MOC) efferent activity in human adults. Since auditory attention continues to develop throughout childhood, the present study explored whether attentional control of medial-efferent inhibition in 5-10 year-old children is adult-like. MOC inhibition was measured in adults (n = 14) and children (n = 12) during no-task (contralateral broadband noise), passive (contralateral noise with tone-pips) and active listening conditions (attended tone-pips embedded in contralateral broadband noise). A stronger MOC inhibition was observed when measured during the active listening condition for adults which is consistent with past work. However, the effect of auditory attention on MOC inhibition in children was not robust and was significantly lower compared to that observed for adults. These findings suggest the potential immaturity of the attentional mediation of MOC inhibition in tested children. PMID- 25445817 TI - Assessment of responses to cochlear implant stimulation at different levels of the auditory pathway. AB - This paper reviews characteristics of both the electrically evoked compound action potential (ECAP) and analogous measures of cortically evoked responses (CAEP) to electrical stimulation in cochlear implant users. Specific comparisons are made between the two levels of processing for measures of threshold, growth of responses with increasing stimulus level, changes in stimulation electrode and, finally, in temporal response properties. The results are interpreted in a context that ECAPs primarily reflect the characteristics of the electrode-neural interface for an individual ear. CAEPs clearly are dependent on those peripheral responses but also reflect differences in central processing among individual implant users. The potential applicability of combined measures in clinical situations is discussed. This article is part of a Special Issue entitled . PMID- 25445820 TI - Turtle utricle dynamic behavior using a combined anatomically accurate model and experimentally measured hair bundle stiffness. AB - Anatomically correct turtle utricle geometry was incorporated into two finite element models. The geometrically accurate model included appropriately shaped macular surface and otoconial layer, compact gel and column filament (or shear) layer thicknesses and thickness distributions. The first model included a shear layer where the effects of hair bundle stiffness was included as part of the shear layer modulus. This solid model's undamped natural frequency was matched to an experimentally measured value. This frequency match established a realistic value of the effective shear layer Young's modulus of 16 Pa. We feel this is the most accurate prediction of this shear layer modulus and fits with other estimates (Kondrachuk, 2001b). The second model incorporated only beam elements in the shear layer to represent hair cell bundle stiffness. The beam element stiffness's were further distributed to represent their location on the neuroepithelial surface. Experimentally measured striola hair cell bundles mean stiffness values were used in the striolar region and the mean extrastriola hair cell bundles stiffness values were used in this region. The results from this second model indicated that hair cell bundle stiffness contributes approximately 40% to the overall stiffness of the shear layer-hair cell bundle complex. This analysis shows that high mass saccules, in general, achieve high gain at the sacrifice of frequency bandwidth. We propose the mechanism by which this can be achieved is through increase the otoconial layer mass. The theoretical difference in gain (deflection per acceleration) is shown for saccules with large otoconial layer mass relative to saccules and utricles with small otoconial layer mass. Also discussed is the necessity of these high mass saccules to increase their overall system shear layer stiffness. Undamped natural frequencies and mode shapes for these sensors are shown. PMID- 25445821 TI - Metagenomic heterogeneity explains dual immune effects of endotoxins. PMID- 25445822 TI - beta2-Agonist therapy may contribute to the air pollution and IL-6-associated risk of developing severe asthma with dual-positive TH2/TH17 cells. PMID- 25445823 TI - Reply: To PMID 25042748. PMID- 25445824 TI - Perception versus reality: the saga of inhaled asthma controller medication and fetal risk. PMID- 25445826 TI - RhoA signaling through platelet P2Y1 receptor controls leukocyte recruitment in allergic mice. AB - BACKGROUND: Clinical studies reveal platelet activation in patients with asthma, allergic rhinitis, and eczema. This is distinct from platelet aggregation, which is critical for the maintenance of hemostasis and in which a role for platelet purinergic receptors is well documented. However, purines are also essential for inflammatory cell trafficking in animal models of allergic lung inflammation, which are known to be platelet dependent, yet the role of purines in the platelet activation accompanying inflammation is unknown. OBJECTIVES: We investigated whether the involvement of purine activation of platelets during allergic inflammation is distinct from purine involvement in platelet aggregation. METHODS: BALB/c mice were sensitized to ovalbumin and subsequent airway ovalbumin challenge. Bronchoalveolar lavage fluid was analyzed for inflammatory cells, and blood samples were assessed for platelet activation. The role of platelet purinergic receptors and associated signaling mechanisms (RhoA) were assessed. RESULTS: P2Y1, but not P2Y12 or P2X1, antagonism inhibited pulmonary leukocyte recruitment. The formation of platelet-leukocyte complexes in vivo and platelet/P selectin-dependent polymorphonuclear cell migration in vitro were exclusively platelet P2Y1 receptor dependent. Furthermore, platelet P2Y1 activation resulted in RhoA activity in vivo after allergen challenge, and RhoA signaling in platelets through P2Y1 stimulation was required for platelet-dependent leukocyte chemotaxis in vitro. Leukocyte recruitment in thrombocytopenic mice remained suppressed after reinfusion of platelets pretreated with a P2Y1 antagonist or a Rho-associated kinase 1 inhibitor, confirming the crucial role of platelet P2Y1 receptor and subsequent activation of RhoA. CONCLUSION: RhoA signaling downstream of platelet P2Y1, but not P2Y12, represents a clear dichotomy in platelet activation during allergic inflammation versus hemostasis. PMID- 25445825 TI - Prenatal exposure to bisphenol A and phthalates and childhood respiratory tract infections and allergy. AB - BACKGROUND: There is growing concern that prenatal exposure to bisphenol A (BPA) and phthalates, which are widely used in consumer products, might affect susceptibility to infections and the development of allergy and asthma in children, but there are currently very few prospective studies. OBJECTIVE: We sought to evaluate whether prenatal exposure to BPA and phthalates increases the risk of respiratory and allergic outcomes in children at various ages from birth to 7 years. METHODS: We measured BPA and metabolites of high-molecular-weight phthalates, 4 di-(2-ethylhexyl) phthalate (DEHP) metabolites (Sigma4DEHP) and mono-benzyl phthalate (MBzP), and 3 low-molecular-weight phthalate (LMWP) metabolites (Sigma3LMWP) in urine samples collected during the first and third trimesters in pregnant women participating in the Infancia y Medio Ambiente Sabadell birth cohort study. The occurrence of chest infections, bronchitis, wheeze, and eczema in children was assessed at ages 6 and 14 months and 4 and 7 years through questionnaires given to the mothers. Atopy (specific IgE measurement) and asthma (questionnaire) were assessed at ages 4 and 7 years, respectively. RESULTS: The relative risks (RRs) of wheeze (RR, 1.20; 95% CI, 1.03 1.40; P = .02), chest infections (RR, 1.15; 95% CI, 1.00-1.32; P = .05), and bronchitis (RR, 1.18; 95% CI, 1.01-1.37; P = .04) at any age increased for each doubling in concentration of maternal urinary BPA. Sigma4DEHP metabolites were associated with the same outcomes (wheeze: RR, 1.25; 95% CI, 1.04-1.50, P = .02; chest infections: RR, 1.15; 95% CI, 0.97-1.35; P = .11; bronchitis: RR, 1.20; 95% CI, 1.01-1.43; P = .04). MBzP was associated with higher risk of wheeze (RR, 1.15; 95% CI, 1.00-1.33; P = .05). The risk of asthma at age 7 years was also increased with increasing prenatal BPA, Sigma4DEHP, and MBzP exposure. There were no other exposure-outcome associations. CONCLUSIONS: Prenatal exposure to BPA and high-molecular-weight phthalates might increase the risk of asthma symptoms and respiratory tract infections throughout childhood. PMID- 25445828 TI - High blood eosinophil counts predict sputum eosinophilia in patients with severe asthma. PMID- 25445827 TI - A cluster-randomized trial shows telephone peer coaching for parents reduces children's asthma morbidity. AB - BACKGROUND: Childhood asthma morbidity remains significant, especially in low income children. Most often, asthma management is provided by the child's primary care provider. OBJECTIVE: We sought to evaluate whether enhancing primary care management for persistent asthma with telephone-based peer coaching for parents reduced asthma impairment and risk in children 3 to 12 years old. METHODS: Over 12 months, peer trainers provided parents with asthma management training by telephone (median, 18 calls) and encouraged physician partnership. The intervention was evaluated in a cluster-randomized trial of 11 intervention and 11 usual care pediatric practices (462 and 486 families, respectively). Patient outcomes were assessed by means of telephone interviews at 12 and 24 months conducted by observers blinded to intervention assignment and compared by using mixed-effects models, controlling for baseline values and clustering within practices. In a planned subgroup analysis we examined the heterogeneity of the intervention effect by insurance type (Medicaid vs other). RESULTS: After 12 months, intervention participation resulted in 20.9 (95% CI, 9.1-32.7) more symptom-free days per child than in the control group, and there was no difference in emergency department (ED) visits. After 24 months, ED visits were reduced (difference in mean visits/child, -0.28; 95% CI, -0.5 to -0.02), indicating a delayed intervention effect. In the Medicaid subgroup, after 12 months, intervention participation resulted in 42% fewer ED visits (difference in mean visits/child, -0.50; 95% CI, -0.81 to -0.18) and 62% fewer hospitalizations (difference in mean hospitalizations/child, -0.16; 95% CI, -0.30 to -0.014). Reductions in health care use endured through 24 months. CONCLUSIONS: This pragmatic telephone-based peer-training intervention reduced asthma impairment. Asthma risk was reduced in children with Medicaid insurance. PMID- 25445829 TI - Loss of sirtuin 1 (SIRT1) disrupts skin barrier integrity and sensitizes mice to epicutaneous allergen challenge. AB - BACKGROUND: Skin barrier integrity requires a highly coordinated molecular system involving the structural protein filaggrin (FLG). Mutational loss of the skin barrier protein FLG predisposes subjects to the development of atopic dermatitis (AD). OBJECTIVE: We sought to determine the role of sirtuin 1 (SIRT1) in skin barrier function, FLG expression, and development of AD. METHODS: Skin histology of mice with skin-specific SIRT1 deletion and wild-type control animals was examined by using hematoxylin and eosin staining. Protein and mRNA abundance was analyzed by means of immunoblotting, immunohistochemistry, immunofluorescence, and RT-PCR. Serum antibody levels were assessed by means of ELISA. RESULTS: Here we show that FLG is regulated by the protein deacetylase SIRT1 and that SIRT1 is critical for skin barrier integrity. Epidermis-specific SIRT1 ablation causes AD like skin lesions in mice, and mice with epidermal SIRT1 deletion are sensitive to percutaneous challenge by the protein allergen ovalbumin. In normal human keratinocytes and mouse skin SIRT1 knockdown or genetic deletion downregulates FLG, and regulation of FLG expression by SIRT1 requires the deacetylase activity of SIRT1. SIRT1 also promotes activation of the aryl hydrocarbon receptor, and the aryl hydrocarbon receptor ligand restores FLG expression in SIRT1-inhibited cells. Compared with normal human skin, SIRT1 is downregulated in both AD and non AD lesions. CONCLUSION: Our findings demonstrate a critical role of SIRT1 in skin barrier maintenance, open up new opportunities to use SIRT1 as a pharmacologic target, and might facilitate the development of mechanism-based agents for AD prevention and therapy. PMID- 25445830 TI - The draft genome, transcriptome, and microbiome of Dermatophagoides farinae reveal a broad spectrum of dust mite allergens. AB - BACKGROUND: A sequenced house dust mite (HDM) genome would advance our understanding of HDM allergens, a common cause of human allergies. OBJECTIVE: We sought to produce an annotated Dermatophagoides farinae draft genome and develop a combined genomic-transcriptomic-proteomic approach for elucidation of HDM allergens. METHODS: A D farinae draft genome and transcriptome were assembled with high-throughput sequencing, accommodating microbiome sequences. The allergen gene structures were validated by means of Sanger sequencing. The mite's microbiome composition was determined, and the predominant genus was validated immunohistochemically. The allergenicity of a ubiquinol-cytochrome c reductase binding protein homologue was evaluated with immunoblotting, immunosorbent assays, and skin prick tests. RESULTS: The full gene structures of 20 canonical allergens and 7 noncanonical allergen homologues were produced. A novel major allergen, ubiquinol-cytochrome c reductase binding protein-like protein, was found and designated Der f 24. All 40 sera samples from patients with mite allergy had IgE antibodies against rDer f 24. Of 10 patients tested, 5 had positive skin reactions. The predominant bacterial genus among 100 identified species was Enterobacter (63.4%). An intron was found in the 13.8-kDa D farinae bacteriolytic enzyme gene, indicating that it is of HDM origin. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed a phototransduction pathway in D farinae, as well as thiamine and amino acid synthesis pathways, which is suggestive of an endosymbiotic relationship between D farinae and its microbiome. CONCLUSION: An HDM genome draft produced from genomic, transcriptomic, and proteomic experiments revealed allergen genes and a diverse endosymbiotic microbiome, providing a tool for further identification and characterization of HDM allergens and development of diagnostics and immunotherapeutic vaccines. PMID- 25445831 TI - Growth and nutrition in children with food allergy requiring amino acid-based nutritional formulas. PMID- 25445832 TI - Thiolated poly(aspartic acid) as potential in situ gelling, ocular mucoadhesive drug delivery system. AB - The ophthalmic formulations on the market suffer from poor bioavailability, and it would therefore be useful to design a new formulation which is able to prolong the residence time and reduce the administration frequency. Polymer matrices which exhibit strong mucoadhesion are promising platforms in ocular drug delivery from the aspect of improved bioavailability. In the present study, an in situ gelling, mucoadhesive drug delivery system was fabricated from thiolated poly(aspartic acid) (ThioPASP). The thiol groups of ThioPASP are able to form disulphide linkages with the mucin glycoproteins and prolong the residence time on the eye. The effects of the thiol groups on the structure, swelling behaviour and mucoadhesive character of the gel and on the drug release profile were determined. The gel structure was characterized by means of rheology. The ThioPASP gel was demonstrated by rheology, tensile test and 'wash away' measurements to display strong mucoadhesion. The drug release from the ThioPASP gel was studied on a vertical Franz diffusion cell: a burst release of sodium diclofenac occurred in the first hour, followed by sustained release of the encapsulated drug for up to 24h. The results proved the importance of the presence of the thiol groups and suggested that a ThioPASP formulation can be useful as an in situ gelling, ocular dosage form. PMID- 25445833 TI - Analyzing the impact of different excipients on drug release behavior in hot-melt extrusion formulations using FTIR spectroscopic imaging. AB - The drug release performance of hot-melt extrudate formulations is mainly affected by its composition and interactions between excipients, drug and the dissolution media. For targeted formulation development, it is crucial to understand the role of these interactions on the drug release performance of extrudate formulations. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopic imaging was used with an in-situ flow-cell device to analyze the impact of different excipients on drug release from extrudates. The compositions differed in the type of polymer (copovidone and Soluplus(r)), the salt or acid form of ibuprofen and the addition of sodium carbonate. For comparison, conventional USP (United States Pharmacopeia) Apparatus 2 dissolution studies were performed. FTIR imaging revealed that differences in the drug release rate were mainly due to drug-polymer interactions. Ibuprofen acid showed interactions with the matrix polymer and exhibited a slower drug release compared to non-interacting ibuprofen salt. Addition of sodium carbonate to the ibuprofen acid containing formulations enhanced the drug release rate of these systems by interfering with the drug-polymer interactions. In addition, drug release rates also depended on the polymer type, showing faster drug release rates for extrudate formulations containing copovidone compared to Soluplus(r). FTIR imaging revealed that the stronger the drug-polymer interaction in the formulations, the slower the drug release. The addition of sodium carbonate improved release as it reduces drug-polymer interactions and allows for the formation of the more water-soluble ibuprofen salt. PMID- 25445834 TI - D-optimal experimental approach for designing topical microemulsion of itraconazole: Characterization and evaluation of antifungal efficacy against a standardized Tinea pedis infection model in Wistar rats. AB - The study aims to statistically develop a microemulsion system of an antifungal agent, itraconazole for overcoming the shortcomings and adverse effects of currently used therapies. Following preformulation studies like solubility determination, component selection and pseudoternary phase diagram construction, a 3-factor D-optimal mixture design was used for optimizing a microemulsion having desirable formulation characteristics. The factors studied for sixteen experimental trials were percent contents (w/w) of water, oil and surfactant, whereas the responses investigated were globule size, transmittance, drug skin retention and drug skin permeation in 6h. Optimized microemulsion (OPT-ME) was incorporated in Carbopol based hydrogel to improve topical applicability. Physical characterization of the formulations was performed using particle size analysis, transmission electron microscopy, texture analysis and rheology behavior. Ex vivo studies carried out in Wistar rat skin depicted that the optimized formulation enhanced drug skin retention and permeation in 6h in comparison to conventional cream and Capmul 908P oil solution of itraconazole. The in vivo evaluation of optimized formulation was performed using a standardized Tinea pedis model in Wistar rats and the results of the pharmacodynamic study, obtained in terms of physical manifestations, fungal burden score, histopathological profiles and oxidative stress. Rapid remission of Tinea pedis from rats treated with OPT-ME formulation was observed in comparison to commercially available therapies (ketoconazole cream and oral itraconazole solution), thereby indicating the superiority of microemulsion hydrogel formulation over conventional approaches for treating superficial fungal infections. The formulation was stable for a period of twelve months under refrigeration and ambient temperature conditions. All results, therefore, suggest that the OPT-ME can prove to be a promising and rapid alternative to conventional antifungal therapies against superficial fungal infections. PMID- 25445835 TI - Is the lateralization distance important in terms in patients undergoing the modified Limberg flap procedure for treatment of pilonidal sinus? AB - BACKGROUND: The aim of this study was to determine whether the lateralization distance causes differences in the flattening ratio of the natal cleft, early complications, or recurrence rates in patients with sacrococcygeal pilonidal sinus disease undergoing the modified Limberg flap. METHODS: This clinical study was conducted from March 2012 to April 2013. Forty patients with sacrococcygeal pilonidal sinus disease were divided into two groups of 20 patients, each according to the lateralization distance of the lower part of the Limberg flap incision (Group I, 1 cm lateralized; Group II, 2 cm lateralized). Early wound complications, recurrence rates, and the flattening ratio of the natal cleft were evaluated. RESULTS: No statistically significant differences in operating time (mean 42.2 +/- 5.7 and 42.3 +/- 6.4 min, respectively; p = 0.855), drain removal time [median 3 (range 2-10) and 4 (range 2-14) days, respectively; p = 0.1], or length of hospitalization [median 1 (range 1-3) and 1 (range 1-4) days, respectively; p = 0.775] were found between the groups. The mean follow-up period was 12.8 +/- 3.7 months. Recurrence was observed in only one patient of Group II. There were no statistically significant differences in the flattening ratio of the natal cleft, overall wound complications, or recurrence between the two groups. CONCLUSIONS: No statistically significant differences in early complications or recurrence rates were found between the two different lateralization distances in the modified Limberg flap procedure. Therefore, we conclude that 1-cm lateralization of the lower part of the incision is sufficient. PMID- 25445836 TI - White matter changes in breast cancer brain metastases patients who undergo radiosurgery alone compared to whole brain radiation therapy plus radiosurgery. AB - Delayed toxicity after whole brain radiation therapy (WBRT) is of increasing concern in patients who survive more than one year with brain metastases from breast cancer. Radiation-related white matter toxicity is detected by magnetic resonance imaging (MRI) and has been correlated with neurocognitive dysfunction. This study assessed the risk of developing white matter changes (WMC) in breast cancer patients who underwent either WBRT plus stereotactic radiosurgery (SRS) or SRS alone. We retrospectively compared 35 patients with breast cancer brain metastases who received WBRT and SRS to 30 patients who only received SRS. All patients had evaluable imaging at a median of one year after their initial management. The development of white matter T2 prolongation as detected by T2 or FLAIR imaging was graded: grade 1 = little or no white matter T2 hyperintensity; grade 2 = limited periventricular hyperintensity; and grade 3 = diffuse white matter hyperintensity. After WBRT plus SRS, patients demonstrated a significantly higher incidence of WMC (p < 0.0001). After one year, 71.5 % of patients whose treatment included WBRT demonstrated WMC (42.9 % grade 2; 28.6 % grade 3). Only one patient receiving only SRS developed WMC. In long-term survivors of breast cancer, the risk of WMC was significantly reduced when SRS alone was used for management. Further prospective studies are necessary to determine how these findings correlate with neurocognitive toxicity. WBRT usage as initial management of limited brain disease should be replaced by SRS alone to reduce the risk of delayed white matter toxicity. PMID- 25445837 TI - Excessive Skin and Sexual Function: Relationship with Psychological Variables and Weight Regain in Women After Bariatric Surgery. AB - BACKGROUND: After bariatric surgery, the majority of patients develop a problem with excessive hanging skin. This can negatively influence the psychological benefits associated with bariatric surgery. The present study aims to explore the relationship between overall impairment related to the presence of excessive skin, body image, depressive symptomatology, sexual functioning, and weight regain in a sample of women after bariatric surgery. METHODS: Sixty-one women (body mass index (BMI) = 30.45 +/- 5.35 kg/m(2)) with excessive skin who had undergone bariatric surgery 19.02 +/- 9.98 months before were evaluated as part of a cross-sectional study using a semi-structured clinical interview and completed a set of self-report measures. A path analysis, an extension of multiple regression analysis, using IBM(r) SPSS(r) AmosTM was conducted to explore simultaneously the associations between the variables under study. RESULTS: The model tested with path analysis showed a good fit to the data (chi (2) = 1.241, df = 4, p = 0.871; Comparative Fit Index (CFI) = 1.000, Tucker-Lewis Index (TLI) = 1.138, Incremental Fit Index (IFI) = 1.049, Root-Mean-Square of Approximation (RMSEA) = 0.000) and suggests that sexual functioning and overall impairment caused by excessive skin were associated with concerns regarding body image and depressive symptomatology, which in turn relate to a greater percentage of total weight regain. CONCLUSIONS: These data stress the importance of considering sexual intimacy and body image in order to optimize psychological and weight outcomes after bariatric surgery. PMID- 25445839 TI - Predictive coding for motion stimuli in human early visual cortex. AB - The current study investigates if early visual cortical areas, V1, V2 and V3, use predictive coding to process motion information. Previous studies have reported biased visual motion responses at locations where novel visual information was presented (i.e., the motion trailing edge), which is plausibly linked to the predictability of visual input. Using high-field functional magnetic resonance imaging (fMRI), we measured brain activation during predictable versus unpreceded motion-induced contrast changes during several motion stimuli. We found that unpreceded moving dots appearing at the trailing edge gave rise to enhanced BOLD responses, whereas predictable moving dots at the leading edge resulted in suppressed BOLD responses. Furthermore, we excluded biases in directional sensitivity, shifts in cortical stimulus representation, visuo-spatial attention and classical receptive field effects as viable alternative explanations. The results clearly indicate the presence of predictive coding mechanisms in early visual cortex for visual motion processing, underlying the construction of stable percepts out of highly dynamic visual input. PMID- 25445838 TI - Technical feasibility and safety profile of laparoscopic diverted sleeve gastrectomy with ileal transposition (DSIT). AB - BACKGROUND: In this study, we specifically aimed to analyze the technical and safety aspects of laparoscopic diverted sleeve gastrectomy with ileal transposition (DSIT) in patients with type 2 diabetes (T2DM). METHODS: A total of 360 patients with type 2 diabetes who underwent a DSIT procedure within the past 2-year period (2011-2013) were analyzed. Operation time, length of hospital stay, perioperative and postoperative complications, and mortality were recorded and analyzed. RESULTS: The participants consisted of 229 males (63.6 %) and 131 females (36.4 %). Mean duration of follow-up was 12.4 months (range, 6-31). One early and two late mortalities occurred. Early mortality was due to an anastomotic leak, and late mortalities were related to myocardial infarction and a traffic accident. Leakage and bleeding were the most common surgical complications. The total number of surgical complications was 22 (6.1 %). Of those, 19 occurred within the first month (early) and 3 occurred after the first month (late). Among early complications, seven (1.94 %) required re-operation, two patients (0.55 %) required endoscopic treatment, and the remaining ten were managed conservatively. Late surgical complications (sleeve angulation) were noted in three patients (0.83) and were treated by endoscopic stents. Surgery related non-surgical complications occurred in 19 cases (5.2 %), and neurological complications were noted in 11 patients (3.05 %). Additional surgical intervention was required in 26 patients (7.22 %). Of those, 15 (4.16 %) required cholecystectomy. CONCLUSIONS: Our data demonstrate that DSIT is a technically feasible operation and can be safely performed in type 2 diabetic patients with acceptable complication and mortality rates. PMID- 25445840 TI - Altered functional connectivity networks in acallosal and socially impaired BTBR mice. AB - Agenesis of the corpus callosum (AgCC) is a congenital condition associated with wide-ranging emotional and social impairments often overlapping with the diagnostic criteria for autism. Mapping functional connectivity in the acallosal brain can help identify neural correlates of the deficits associated with this condition, and elucidate how congenital white matter alterations shape the topology of large-scale functional networks. By using resting-state BOLD functional magnetic resonance imaging (rsfMRI), here we show that acallosal BTBR T+tpr3tf/J (BTBR) mice, an idiopathic model of autism, exhibit impaired intra hemispheric connectivity in fronto-cortical, but not in posterior sensory cortical areas. We also document profoundly altered subcortical and intra hemispheric connectivity networks, with evidence of marked fronto-thalamic and striatal disconnectivity, along with aberrant spatial extension and strength of ipsilateral and local connectivity. Importantly, inter-hemispheric tracing of monosynaptic connections in the primary visual cortex using recombinant rabies virus confirmed the absence of direct homotopic pathways between posterior cortical areas of BTBR mice, suggesting a polysynaptic origin for the synchronous rsfMRI signal observed in these regions. Collectively, the observed long-range connectivity impairments recapitulate hallmark neuroimaging findings in autism, and are consistent with the behavioral phenotype of BTBR mice. In contrast to recent rsfMRI studies in high functioning AgCC individuals, the profound fronto cortical and subcortical disconnectivity mapped suggest that compensatory mechanism may not necessarily restore the full connectional topology of the brain, resulting in residual connectivity alterations that serve as plausible substrates for the cognitive and emotional deficits often associated with AgCC. PMID- 25445841 TI - Separate effects of sex hormones and sex chromosomes on brain structure and function revealed by high-resolution magnetic resonance imaging and spatial navigation assessment of the Four Core Genotype mouse model. AB - Males and females exhibit several differences in brain structure and function. To examine the basis for these sex differences, we investigated the influences of sex hormones and sex chromosomes on brain structure and function in mice. We used the Four Core Genotype (4CG) mice, which can generate both male and female mice with XX or XY sex chromosome complement, allowing the decoupling of sex chromosomes from hormonal milieu. To examine whole brain structure, high resolution ex vivo MRI was performed, and to assess differences in cognitive function, mice were trained on a radial arm maze. Voxel-wise and volumetric analyses of MRI data uncovered a striking independence of hormonal versus chromosomal influences in 30 sexually dimorphic brain regions. For example, the bed nucleus of the stria terminalis and the parieto-temporal lobe of the cerebral cortex displayed steroid-dependence while the cerebellar cortex, corpus callosum, and olfactory bulbs were influenced by sex chromosomes. Spatial learning and memory demonstrated strict hormone-dependency with no apparent influence of sex chromosomes. Understanding the influences of chromosomes and hormones on brain structure and function is important for understanding sex differences in brain structure and function, an endeavor that has eventual implications for understanding sex biases observed in the prevalence of psychiatric disorders. PMID- 25445842 TI - Disruption of structural covariance networks for language in autism is modulated by verbal ability. AB - The presence of widespread speech and language deficits is a core feature of autism spectrum disorders (ASD). These impairments have often been attributed to altered connections between brain regions. Recent developments in anatomical correlation-based approaches to map structural covariance offer an effective way of studying such connections in vivo. In this study, we employed such a structural covariance network (SCN)-based approach to investigate the integrity of anatomical networks in fronto-temporal brain regions of twenty children with ASD compared to an age and gender-matched control group of twenty-two children. Our findings reflected large-scale disruption of inter and intrahemispheric covariance in left frontal SCNs in the ASD group compared to controls, but no differences in right fronto-temporal SCNs. Interhemispheric covariance in left seeded networks was further found to be modulated by verbal ability of the participants irrespective of autism diagnosis, suggesting that language function might be related to the strength of interhemispheric structural covariance between frontal regions. Additionally, regional cortical thickening was observed in right frontal and left posterior regions, which was predicted by decreasing symptom severity and increasing verbal ability in ASD. These findings unify reports of regional differences in cortical morphology in ASD. They also suggest that reduced left hemisphere asymmetry and increased frontal growth may not only reflect neurodevelopmental aberrations but also compensatory mechanisms. PMID- 25445844 TI - Evaluating plasma pharmacokinetics of intravenous iron formulations: judging books by their covers? PMID- 25445843 TI - Role of zona pellucida glycoproteins during fertilization in humans. AB - In the last decade, scientific investigations pertaining to the role of zona pellucida (ZP) glycoproteins during fertilization in humans have led to new insights. This has been achieved using purified native/recombinant human zona proteins and transgenic mice expressing human ZP glycoproteins. The proposed model in mice of ZP glycoprotein-3 (ZP3) acting as primary sperm receptor and ZP glycoprotein-2 (ZP2) as secondary sperm receptor has been modified for sperm-egg binding in humans. ZP glycoprotein-1 (ZP1), ZP3, and ZP glycoprotein-4 (ZP4) have been shown to bind to the capacitated human sperm. ZP2 binds to the acrosome reacted human spermatozoa. Further, the eggs obtained from transgenic mice expressing human ZP2 alone or in conjunction with other human instead of mouse zona proteins showed binding of human sperm, suggesting that ZP2 might also play a role in sperm-egg binding. This function has been mapped to a domain corresponding to amino acid residues 51-144 of ZP2. In contrast to mice, where ZP3 is the primary agonist for inducing the acrosome reaction, in humans, the acrosome reaction can be mediated by ZP1, ZP3, and ZP4. The effect of mutations in the genes encoding zona proteins on the ZP morphology and infertility has not been established. Further, the role of autoantibodies against ZP in women with 'unexplained infertility' leading to poor outcome of in vitro fertilization is currently controversial and needs further investigations. Understanding the role of ZP glycoproteins during human fertilization facilitates the development of new contraceptives and strategies to overcome the problem of infertility. PMID- 25445845 TI - Quantitative prediction of human pharmacokinetics for mAbs exhibiting target mediated disposition. AB - Prediction of human pharmacokinetics (PK) can be challenging for monoclonal antibodies (mAbs) exhibiting target-mediated drug disposition (TMDD). In this study, we performed a quantitative analysis of a diverse set of six mAbs exhibiting TMDD to explore translational rules that can be utilized to predict human PK. A TMDD model with rapid-binding approximation was utilized to fit PK and PD (i.e., free and/or total target levels) data, and average absolute fold error (AAFE) was calculated for each model parameter. Based on the comparative analysis, translational rules were developed and applied to a test antibody not included in the original analysis. AAFE of less than two-fold was observed between monkey and human for baseline target levels (R 0), body-weight (BW) normalized central elimination rate (K el/BW(-0.25)) and central volume (V c/BW(1.0)). AAFE of less than three-fold was estimated for the binding affinity constant (K D). The other four parameters, i.e., complex turnover rate (K int), target turnover rate (K deg), central to peripheral distribution rate constant (K pt) and peripheral to central rate constant (K tp) were poorly correlated between monkey and human. The projected human PK of test antibody based on the translation rules was in good agreement with the observed nonlinear PK. In conclusion, we recommend a TMDD model-based prediction approach that integrates in vitro human biomeasures and in vivo preclinical data using translation rules developed in this study. PMID- 25445846 TI - Diabetes: Acinar-cell reprogramming generates functional beta cells that persist for a long time. PMID- 25445847 TI - Thyroid function: Inactivation of T3 in muscle stem cells. PMID- 25445850 TI - Metabolism: Nutrient-sensing and autophagic genes in fed and fasted states. PMID- 25445851 TI - Results of Early Versus Intermediate or Delayed Voice Therapy in Patients With Unilateral Vocal Fold Paralysis: Our Experience in 171 Patients. AB - OBJECTIVES: Vocal fold paralysis can have an important impact on a patient's quality of life. The goal of this study was to compare, in terms of vocal improvement and motility recovery, the post-vocal treatment results of our patients with unilateral vocal fold paralysis (UVFP) when treatment was started early (within 4 weeks from injury) versus intermediate (from 4 to 8 weeks) or delayed (at least 8 weeks after injury) treatment. STUDY DESIGN: An 11-year retrospective study of patients with UVFP who underwent multidimensional diagnostic-therapeutic assessment. METHODS: In total, 171 patients with UVFP were included in our study, divided into three groups who underwent early (first group), intermediate (second group), or delayed (third group) voice treatment. All patients underwent voice therapy based on forcible exercises supplemented by manipulations and maneuvers. RESULTS: Of the 171 patients with UVFP, 106 (62%) recovered vocal fold motility. Of these 106 patients, 51/78 (65%) were in the first group, 30/49 (61%) in the second group, and 25/44 (56%) in the third group. A significant (P < 0.0001) reduction in fundamental frequency (Fo) was present in the first group with a manifest improvement in the mean values of Jitter (Jitt%; P = 0.001), Shimmer (Shim%; P < 0.0001), and noise-to-harmonic ratio (NHR; P < 0.0001). A significant (P < 0.0001) reduction in Fo was found in the second group with a manifest improvement in Jitt% (P < 0.001), Shim% (P < 0.0001), and NHR (P < 0.0001). For the third group, no values were statistically significant apart from the improvement in NHR (P < 0.001). CONCLUSIONS: This study confirms the importance of early rehabilitation underlining the non-functional vocal recovery in patients who started treatment later than 8 weeks after injury. PMID- 25445848 TI - Diabetes mellitus and severe mental illness: mechanisms and clinical implications. AB - The prevalence of diabetes mellitus is twofold to threefold higher in people with severe mental illness (SMI) than in the general population, with diabetes mellitus affecting ~12% of people receiving antipsychotics. The consequences of diabetes mellitus are more severe and frequent in people with SMI than in those without these conditions, with increased rates of microvascular and macrovascular complications, acute metabolic dysregulation and deaths related to diabetes mellitus. Multiple complex mechanisms underlie the association between diabetes mellitus and SMI; these mechanisms include genetic, environmental and disease specific factors, and treatment-specific factors. Although antipsychotics are the mainstay of treatment in SMI, a causative link, albeit of uncertain magnitude, seems to exist between antipsychotics and diabetes mellitus. The principles of managing diabetes mellitus in people with SMI are similar to those for the general population and should follow currently established treatment algorithms. Lifestyle interventions are needed to reduce incident diabetes mellitus. In addition, improved uptake of opportunities to screen for this disease will reduce the high prevalence of undiagnosed diabetes mellitus. Currently, people with SMI receive poorer treatment for diabetes mellitus than the general population. Thus, health-care professionals in primary care, diabetes mellitus services and mental health teams have a responsibility to ensure that patients with SMI are not disadvantaged. PMID- 25445852 TI - Ten-year results comparing posterior cruciate-retaining versus posterior cruciate substituting total knee arthroplasty. AB - We compared the 10-year survival rates and clinical outcomes of posterior cruciate-retaining (CR) versus posterior cruciate-substituting (CS) total knee arthroplasty (TKA), using the Genesis II knee system (Smith and Nephew, Memphis, TN). Our institutional database identified patients undergoing a primary knee with the Genesis II system between 1995 and 2000. These patients were followed for an average of 12.3years (range 10.2-14.4years). There were 143 (34.5%) CR and 271 (65.5%) CS implants. No significant difference in 10-year survivorship was noted between the two cohorts. The postoperative clinical scores (KSCRS, WOMAC, SF-12) and knee ROM were significantly better for the CS cohort. In this large, long-term, single-implant prospective study, CS performed better than CR in terms of clinical scores and range of motion. PMID- 25445853 TI - Treatment of severe bone defects during revision total knee arthroplasty with structural allografts and porous metal cones-a systematic review. AB - Aseptic loosening and focal osteolysis are the most common reasons for knee arthroplasty failure. The best treatment remains unclear. We reviewed the literature on the treatment of revision knee arthroplasty using bony structural allografts (476 cases) and porous metal cones (223 cases) to determine if a difference in the revision failure rates was discernable. The failure rates were compared using a logistic regression model with adjustment for discrepancies in FU time and number of grafts used (femoral, tibial, or both). In this analysis, the porous implant shows a significantly decreased loosening rate in AORI 2 and 3 defects. The overall failure rate was also substantially lower in the porous metal group than the structural allograft group; little difference in the infection rates was noted. PMID- 25445854 TI - Safety and efficacy of continuous femoral nerve catheter with single shot sciatic nerve block vs epidural catheter anesthesia for same-day bilateral total knee arthroplasty. AB - In a retrospective analysis, we evaluated the safety and efficacy of peripheral nerve blocks (PNB) compared to epidural anesthesia in 221 consecutive patients undergoing same-day bilateral total knee arthroplasty (TKA). Primary outcome measures included: hypotension requiring physician intervention, number of blood transfusions, perioperative hespan and crystalloid consumption, incidences of respiratory desaturation, pruritis, urinary retention, and nausea/vomiting. The incidences of hypotension, urinary retention, and pruritis were all higher in the epidural group, compared to PNB. Epidural patients also required more blood transfusions and greater volumes of hespan and crystalloid. PNB are safe and efficacious modality of analgesia for same day bilateral TKA and provide adequate pain relief with a significant decrease in postoperative complications compared to epidural anesthesia. PMID- 25445849 TI - Insulin and IGF receptor signalling in neural-stem-cell homeostasis. AB - Neural stem cells (NSCs) are found in two regions in the adult brain: the subgranular zone (SGZ) in the hippocampal dentate gyrus and the subventricular zone (SVZ) adjacent to the lateral ventricles. Similarly to other somatic stem cells, adult NSCs are found within specialized niches that are organized to facilitate NSC self-renewal. Alterations in stem-cell homeostasis can contribute to the consequences of neurodegenerative diseases, healthy ageing and tissue repair after damage. Insulin and the insulin-like growth factors (IGFs) function in stem-cell homeostasis across species. Studies in the mammalian central nervous system support essential roles for IGF and/or insulin signalling in NSC self renewal, neurogenesis, cognition and sensory function through distinct ligand receptor interactions. IGF-II is of particular interest as a result of its production by the choroid plexus and presence in cerebrospinal fluid (CSF). CSF regulates and supports the development, division and migration of cells in the adult brain and is required for NSC maintenance. In this Review, we discuss emerging data on the functions of IGF-II and IGF and/or insulin receptor signalling in the context of NSC regulation in the SVZ and SGZ. We also propose a model for IGF-II in which the choroid plexus is a major component of the NSC niche. PMID- 25445855 TI - ED compliance with influenza antiviral recommendations. PMID- 25445856 TI - The critical care literature 2013. PMID- 25445857 TI - "Hard" and "soft" patient cues that influence ED prescribing for potential opioid misusers. PMID- 25445858 TI - Comparison of exercise electrocardiogram and exercise echocardiography in intermediate-risk chest pain patients. AB - BACKGROUND: The novel exercise computer-assisted high-frequency QRS analysis (HF/QRS) has demonstrated improved sensitivity and specificity over the conventional ST/electrocardiogram-segment analysis (ST/ECG) in the detection of myocardial ischemia. The aim of the present study was to compare the diagnostic value of the validated exercise echocardiography (ex-Echo) with the novel exercise ECG (ex-ECG) including HF/QRS and ST/ECG analysis. METHODS: A prospective cohort study was conducted in the emergency department of a tertiary care teaching Hospital. Patients with chest pain (CP), normal resting ECGs, troponins, and echocardiography, labeled as "intermediate-risk" for adverse coronary events, underwent the novel ex-ECG and ex-Echo. An ST-segment depression of at least 2 mV or at least 1 mV when associated with CP was considered as an index of ischemia, as well as a decrease of at least 50% in HF/QRS intensity, or new wall motion abnormalities on ex-Echo. Exclusion criteria were QRS duration of at least 120 milliseconds, poor echo-acoustic window, and inability to exercise. Patients were followed up to 3 months. The end point was the composite of coronary stenoses of 50% or greater at angiography or acute coronary syndrome, revascularization, and cardiovascular death on the 3-month follow-up. RESULTS: Of 188 patients enrolled, 18 achieved the end point. The novel ex-ECG and ex-Echo showed comparable negative predictive value (97% vs 96%; P = .930); however, sensitivity was 83% vs 61%, respectively (P = .612), and specificity was 64% vs 92%, respectively,(P = .026). The areas on receiver operating characteristic analysis were comparable (ex-ECG: 0.734 [95% confidence interval, or CI, 0.62 0.85] vs ex-Echo: 0.767 [CI, 0.63-0.91]; C statistic, P = .167). On multivariate analysis, both ex-ECG (hazard ratio, 5; CI, 1-20; P = .017) and ex-Echo (HR, 12; CI, 4-40; P < .001) were predictors of the end point. CONCLUSIONS: In intermediate-risk CP patients, the novel ex-ECG including HF/QRS added to ST/ECG analysis was a valuable diagnostic tool and might be proposed to avoid additional imaging. However, the novel test needs additional study before it can be recommended as a replacement for current techniques. PMID- 25445861 TI - A novel simulation-based program for ultrasound-guided fracture reductions: program evaluation. PMID- 25445859 TI - A randomized trial of benralizumab, an antiinterleukin 5 receptor alpha monoclonal antibody, after acute asthma. AB - BACKGROUND: Patients with frequent asthma exacerbations resulting in emergency department (ED) visits are at increased risk for future exacerbations. We examined the ability of 1 dose of benralizumab, an investigational antiinterleukin 5 receptor alpha monoclonal antibody, to reduce recurrence after acute asthma exacerbations. METHODS: In this randomized, double-blind, placebo controlled study, eligible subjects presented to the ED with an asthma exacerbation, had partial response to treatment, and greater than or equal to 1 additional exacerbation within the previous year. Subjects received 1 intravenous infusion of placebo (n = 38) or benralizumab (0.3 mg/kg, n = 36 or 1.0 mg/kg, n = 36) added to outpatient management. The primary outcome was the proportion of subjects with greater than or equal to 1 exacerbation at 12 weeks in placebo vs the combined benralizumab groups. Other outcomes included the time-weighted rate of exacerbations at week 12, adverse events, blood eosinophil counts, asthma symptom changes, and health care resource utilization. RESULTS: The proportion of subjects with greater than or equal to 1 asthma exacerbation at 12 weeks was not different between placebo and the combined benralizumab groups (38.9% vs 33.3%; P = .67). However, compared with placebo, benralizumab reduced asthma exacerbation rates by 49% (3.59 vs 1.82; P = .01) and exacerbations resulting in hospitalization by 60% (1.62 vs 0.65; P = .02) in the combined groups. Benralizumab reduced blood eosinophil counts but did not affect other outcomes, while demonstrating an acceptable safety profile. CONCLUSIONS: When added to usual care, 1 dose of benralizumab reduced the rate and severity of exacerbations experienced over 12 weeks by subjects who presented to the ED with acute asthma. PMID- 25445860 TI - Pediatric overtriage as a consequence of the tachycardia responses of children upon ED admission. AB - BACKGROUND: Overtriage has been observed among pediatric patients in emergency departments (EDs) under 5-level acuity pediatric triage systems. This study aimed to investigate the causes of overtriage and to provide suggestions for future amendments to such systems. METHODS: This study has a retrospective follow-up design in which 42000 pediatric patients who were admitted to the ED of the largest medical center in Taiwan between January and December of 2010 were recruited. The study variables included patient demographics, chief concerns, individual vital signs (ie, blood pressure, heart rate, body temperature, respiratory rate, and O2 saturation), triage level, ED final disposition, ED expenses, and total medical expenses. A logistic regression model was applied to explore the causes of overtriage and the effectiveness of a modified acuity system. RESULTS: Approximately 13.6% of the pediatric ED visits were upgraded to acuity level 1 based on vital signs that included heart rate (97.3%). The strength of the trend association (odds ratio) between decreasing acuity urgency (from levels 1 to 5) and hospitalization increased from 0.73 (95% confidence interval, 0.72-0.75) with the Pediatric Triage and Acuity System (Ped-TTAS) to 0.57 (95% confidence interval, 0.55-0.59) with the modified Ped-TTAS, which downgraded acuity levels by excluding the weighting of vital signs. Further validation was accomplished by comparing the trend association between decreasing acuity urgency and total medical expenses (Ped-TTAS: beta = -0.13; modified Ped TTAS: beta = -0.18). CONCLUSIONS: Heart rate is prone to be affected by emotional responses among pediatric patients in certain specific age groups. Appropriate revisions of the pediatric triage system are suggested. PMID- 25445862 TI - Emergence dual-energy imaging and clinical decision making in urolithiasis. PMID- 25445863 TI - Acute urinary retention as a manifestation of emphysematous cystitis. PMID- 25445864 TI - Extensive subarachnoid and epidural hematoma after lumbar puncture. PMID- 25445865 TI - Lidocaine-induced delirium: a case report. PMID- 25445866 TI - State-to-state variability likely affects admission rates. PMID- 25445867 TI - Various admission glucose cut-offs for prognostication and for therapeutic threshold in acute myocardial infarction. PMID- 25445868 TI - The diagnostic role of signal peptide-C1r/C1s, Uegf, and Bmp1-epidermal growth factor domain-containing protein 1 in non-ST-elevation acute coronary syndrome. AB - OBJECTIVE: Chest pain and/or electrocardiogram changes in non-ST elevation or suspicious chest pain and cardiac marker elevations are defined as non-ST elevation acute coronary syndrome (NSTE-ACS). Serial electrocardiogram and marker follow-up are needed to make a diagnosis of NSTE-ACS and to eliminate noncoronary chest pain (NCCP). Signal peptide-C1r/C1s, Uegf, and Bmp1-epidermal growth factor domain-containing protein 1 (SCUBE1) is stored within the alpha granules of inactive platelets and secreted at a high rate during thrombosis. We believe that SCUBE1 may be a sensitive early diagnostic indicator in distinguishing coronary induced chest pain from noncoronary-induced chest pain. MATERIALS AND METHODS: The study included 190 patients with an initial diagnosis of acute coronary syndrome in the emergency department. Based on a definitive diagnosis, these patients were classified into 3 groups: ST-elevation myocardial infarction (STEMI), NSTE-ACS, and NCCP. RESULTS: Plasma SCUBE1 levels were significantly higher in the STEMI group when compared with those of the other groups (P < .05). They were also significantly higher in the NSTE-ACS group when compared with those of the NCCP group (P < .01). Troponin I, creatinine kinase, and creatinine kinase MB levels were significantly different in the NSTE-ACS group when compared with those of the NCCP group (P < .05). CONCLUSION: High rates of SCUBE1 were found both in the STEMI and NSTE-ACS patients. Furthermore, in the study group, SCUBE1 was an adequate marker for distinguishing NSTE-ACS from NCCP. PMID- 25445869 TI - Risk factors for QT prolongation associated with acute psychotropic drug overdose. AB - BACKGROUND: Antipsychotic/Antidepressant use is a risk factor for QT interval (QT) prolongation and sudden cardiac death. However, it is unclear which drugs are risk factors for QT prolongation and torsades de pointes in cases of psychotropic drug overdose. METHODS: After correction of QT data by Bazett formula (QTc), QTc was classified into 3 categories (QTc<440 milliseconds, 440 milliseconds<=QTc<500 milliseconds, and QTc>=500 milliseconds), and the blood concentration of each drug was classified as not detected, therapeutic range, or toxic range. The association of the blood concentration of each drug with QTc was analyzed using the ordinal logistic regression model. Drugs that induced QT-heart rate pairs higher than the at-risk line of Isbister's QT-heart rate nomogram (QT nomogram) were further analyzed using the binomial logistic regression model. RESULTS: A total of 649 patients were enrolled in the study. The independent risk factors for QTc prolongation were therapeutic and toxic range of phenotiazine antipsychotic drug (therapeutic range: odds ratio [OR], 1.56 [P=.039]; toxic range: OR, 3.85 [P<.001]), and toxic range of cyclic antidepressants (OR, 2.39; P=.018). In addition, toxic range of phenotiazine antipsychotic drug (OR, 3.87; P=.012) and tricyclic antidepressants (OR, 4.94; P<.001) were risk factors for QT higher than the at-risk line of the QT nomogram. CONCLUSIONS: The possibility of QT prolongation and torsades de pointes due to overdose of phenotiazine antipsychotic drug or tricyclic antidepressants requires particular consideration. PMID- 25445870 TI - The effects of an electronic order set on vancomycin dosing in the ED. AB - OBJECTIVE: The objective of the study was to assess the impact of a computer physician order entry (CPOE) electronic order set on appropriate vancomycin dosing in the emergency department (ED). METHODS: We conducted a retrospective study examining ED dosing of vancomycin before and after the implementation of an electronic weight-based vancomycin order set. Preimplementation and postimplementation patient records were analyzed between the dates of June 1st and August 31st 2010 for the pre-CPOE group and January 1st to March 31st 2013 for the post-CPOE group. STATISTICAL ANALYSIS: chi(2) analysis, Fisher exact test, and t tests were performed with a 2-sided P value <.05 denoting statistical significance, where appropriate. RESULTS: A total of 597 patients were included in the study, with 220 in the pre-CPOE group and 377 in the post-CPOE group. The use of the electronic order set resulted in a 21.9% increase (P < .05) in appropriate dosing with 67.4% (254/377) of post-CPOE vancomycin doses considered appropriate vs 45.5% (100/220) in the pre-CPOE group. In critically ill patients, there was a 16.3% increase in appropriate dosing with 44.7% (38/85) in the post CPOE group compared with 28.4% (19/67) in the pre-CPOE group. CONCLUSION: The implementation of an electronic order set increased the percentage of ED patients receiving appropriate initial vancomycin doses. The impact of increasing compliance to vancomycin guidelines is in accordance with stewardship principles that promote optimization of antimicrobial dosing based on individual patient characteristics. More studies are needed to assess the relationship between appropriate vancomycin loading doses in the ED and therapeutic outcomes. PMID- 25445872 TI - ED operational factors associated with patient satisfaction. PMID- 25445873 TI - Osmolal gap, the clue of diagnosis and role of sodium bicarbonate and hemodialysis in methanol intoxication. PMID- 25445871 TI - A randomized controlled trial of capnography during sedation in a pediatric emergency setting. AB - OBJECTIVE: Data suggest that capnography is a more sensitive measure of ventilation than standard modalities and detects respiratory depression before hypoxemia occurs. We sought to determine if adding capnography to standard monitoring during sedation of children increased the frequency of interventions for hypoventilation, and whether these interventions would decrease the frequency of oxygen desaturations. METHODS: We enrolled 154 children receiving procedural sedation in a pediatric emergency department. All subjects received standard monitoring and capnography, but were randomized to whether staff could view the capnography monitor (intervention) or were blinded to it (controls). Primary outcome were the rate of interventions provided by staff for hypoventilation and the rate of oxygen desaturation less than 95%. RESULTS: Seventy-seven children were randomized to each group. Forty-five percent had at least 1 episode of hypoventilation. The rate of hypoventilation per minute was significantly higher among controls (7.1% vs 1.0%, P = .008). There were significantly fewer interventions in the intervention group than in the control group (odds ratio, 0.25; 95% confidence interval [CI], 0.13-0.50). Interventions were more likely to occur contemporaneously with hypoventilation in the intervention group (2.26; 95% CI, 1.34-3.81). Interventions not in time with hypoventilation were associated with higher odds of oxygen desaturation less than 95% (odds ratio, 5.31; 95% CI, 2.76-10.22). CONCLUSION: Hypoventilation is common during sedation of pediatric emergency department patients. This can be difficult to detect by current monitoring methods other than capnography. Providers with access to capnography provided fewer but more timely interventions for hypoventilation. This led to fewer episodes of hypoventilation and of oxygen desaturation. PMID- 25445874 TI - Bimodality of plant height: fact or artifact? A response to Scheffer et al. PMID- 25445875 TI - The road to confusion is paved with novel ecosystem labels: a reply to Hobbs et al. PMID- 25445876 TI - Even more functions of sperm RNA: a response to Hosken and Hodgson. PMID- 25445877 TI - Ultimate and proximate functions of sperm RNA: a reply to Holman and Price. PMID- 25445878 TI - Secondary extinctions of biodiversity. AB - Extinctions beget further extinctions when species lose obligate mutualists, predators, prey, or hosts. Here, we develop a conceptual model of species and community attributes affecting secondary extinction likelihood, incorporating mechanisms that buffer organisms against partner loss. Specialized interactors, including 'cryptic specialists' with diverse but nonredundant partner assemblages, incur elevated risk. Risk is also higher for species that cannot either evolve new traits following partner loss or obtain novel partners in communities reorganizing under changing environmental conditions. Partner loss occurs alongside other anthropogenic impacts; multiple stressors can circumvent ecological buffers, enhancing secondary extinction risk. Stressors can also offset each other, reducing secondary extinction risk, a hitherto unappreciated phenomenon. This synthesis suggests improved conservation planning tactics and critical directions for research on secondary extinctions. PMID- 25445879 TI - Did I miss that: subtle and commonly missed findings on chest radiographs. AB - This article reviews examples of easily missed, subtle, or ambiguous lesions on chest radiography. Anecdotally, reliance on cross-sectional imaging has diminished radiologists' comfort level with chest radiograph interpretation. However, plain film chest radiography remains a valuable tool in diagnostic imaging. It is noninvasive, inexpensive, easily obtained, and diagnostic for many common conditions with the benefit of a very low radiation dose. It is one of the most commonly ordered radiographic examinations; therefore, proficiency in chest radiograph interpretation remains an essential tool in our diagnostic armamentarium. Certain anatomical regions on chest radiographs are particularly prone to perceptual errors. These are often referred to as "blind spots" and have been emphasized as we demonstrate methods that can be applied to search patterns to improve detection of abnormalities. PMID- 25445880 TI - Identification of microRNAs 758 and 33b as potential modulators of ABCA1 expression in human atherosclerotic plaques. AB - BACKGROUND AND AIM: Adenosine triphosphate (ATP)-binding cassette (ABC) transporters A1 and G1 are the main transporters involved in macrophage cholesterol efflux. The understanding of the molecular mechanism(s) of their regulation in atherosclerosis is crucial for potential therapeutic approaches. Preclinical studies support a role for microRNAs in the posttranscriptional regulation of these transporters; however, no evidence is still available on human atherosclerosis. Thus, the aim of this study was to investigate the modulation of the ABCA1 and ABCG1 pathway in human atherosclerotic plaques and microRNA involvement in its modulation. METHODS AND RESULTS: Thirty-one human atherosclerotic plaques were obtained from patients undergoing carotid endarterectomy for high-grade (>70%) vessel stenosis, and divided into normocholesterolemic (n = 15) and hypercholesterolemic groups (n = 16) according to the presence/absence of hypercholesterolemia. Both ABCA1 and ABCG1 messenger RNAs (mRNAs) were significantly upregulated in carotid plaques from hypercholesterolemic patients as assessed by real-time polymerase chain reaction (RT-PCR). Despite this result, no difference was found at the protein levels analyzed by Western blot, thus suggesting a strong posttranscriptional modulation. MicroRNA microarray and subsequent validation by RT-PCR showed a significant upregulation of ABCA1-linked miR-758 and miR-33b in plaques from hypercholesterolemic patients. CONCLUSION: We provide evidence of a strong posttranscriptional regulation of ABCA1 and ABCG1 expression in human atherosclerotic plaques from hypercholesterolemic patients. This effect is potentially due to the concomitant increase of miR-33b and miR-758, two well established regulators of ABCA1 and ABCG1 expression. The identification of miR 33b and miR-758 as putative key regulators of ABCA1 protein expression within human atherosclerotic plaques provides further data for the realization of new anti-atherosclerotic drugs with specific targets based on anti-miRNA technologies. PMID- 25445881 TI - Serum fructosamine and risk of cardiovascular and all-cause mortality: a 24-year prospective population-based study. AB - BACKGROUND AND AIMS: The association between fructosamine and cardiovascular complications is not well established. We sought to evaluate whether serum fructosamine may be a risk factor for cardiovascular and all-cause mortality in nondiabetic subjects. METHODS AND RESULTS: Fructosamine and other cardiovascular risk factors were measured in a sample of 1909 nondiabetic middle-aged men without a known history of coronary heart disease (CHD) at baseline. Associations between baseline fructosamine levels and fatal CHD and cardiovascular disease (CVD) events, and all-cause mortality were estimated using a Cox regression analysis, progressively adjusted for potential confounders. Mean baseline age was 52 years and 30% were smokers. During a median follow-up of 24 years (interquartile range: 18-26 years), 177 (9%) fatal CHD, 289 (15%) fatal CVD, and 728 (38%) all-cause mortality events occurred. In analyses adjusted for several conventional risk factors (i.e., age, systolic blood pressure, smoking, LDL- and HDL-cholesterol), the hazard ratios (HRs) comparing top vs bottom quartile of serum fructosamine levels resulted: 1.33 (95% CI: 0.97, 1.82; p = 0.078) for CHD death and 0.93 (0.72, 1.19; p = 0.567) for CVD death, and 1.04 (0.89, 1.22; p = 0.617) for all-cause mortality. In similar comparisons, further adjustments for body mass index, alcohol consumption, C-reactive protein, and fasting plasma glucose did not materially change these estimates. The exclusion of participants with prevalent CVD at baseline yielded similar results. CONCLUSION: In our cohort of nondiabetic men without known CHD, baseline fructosamine levels were not independently associated with cardiovascular and all-cause mortality. Further studies are warranted to confirm these results in other populations. PMID- 25445882 TI - Exploring the path of Mediterranean diet on 10-year incidence of cardiovascular disease: the ATTICA study (2002-2012). AB - BACKGROUND AND AIMS: A Mediterranean diet has been associated with lower all cause and cardiovascular disease (CVD) morbidity and mortality, but the clinical and behavioral pathway has not been well understood and appreciated. The aim of this work was to explore the path between adherence to a Mediterranean-type diet, lifestyle behaviors, clinical status, and a 10-year incidence of CVD. METHODS AND RESULTS: The ATTICA study was carried out in the Athens area during 2001-2002 and included 3042 participants free of CVD at baseline (49.8% men, aged 18-89). Adherence to a Mediterranean diet was assessed using the MedDietScore (range 0 55). During 2011-2012, 2583 out of the 3042 participants were found during the 10 year follow-up (15% lost to follow-up). Adherence to a Mediterranean diet decreased CVD risk (relative Risk (RR) per 1/55 unit = 0.96, 95% confidence interval (CI): 0.93, 1.00), independently of various sociodemographic, lifestyle, and clinical factors. Subgroup analyses revealed that participants with an unhealthy lifestyle (i.e., smokers, and obese and sedentary persons) remained protected from CVD through a greater adherence to a Mediterranean diet (RR for smokers = 0.92, 95%CI: 0.88, 0.97; RR for obese participants = 0.90, 95%CI: 0.82, 0.979; and RR for sedentary participants = 0.95, 95%CI: 0.90, 0.99). Path analysis revealed that adherence to a Mediterranean diet not only decreases the levels of C-reactive protein and interleukin-6 but also has an independent protective role against CVD risk per se (total effect of the MedDietScore on CVD = -0.003, 95%CI: -0.005 to 0.000). CONCLUSION: Adherence to a Mediterranean diet confers a considerable reduction on CVD risk, independent of various factors. Therefore, even subjects with unhealthy lifestyle behaviors may benefit from adherence to this diet, suggesting another dimension to prevention strategies. PMID- 25445883 TI - Eliciting specific humoral immunity from a plasmid DNA encoding infectious bursal disease virus polyprotein gene fused with avian influenza virus hemagglutinin gene. AB - DNA vaccine coding for infectious bursal disease virus (IBDV) polyprotein gene and that for avian influenza virus (AIV) hemagglutinin (HA) gene have been shown to induce immunity and provide protection against the respective disease. The present study was carried out to determine whether an IBDV polyprotein gene-based DNA fused with AIV HA gene could trigger immune response to both IBDV and AIV. After transfection, VP2 and HA were detected in the cytoplasm and at cell membrane, respectively, by immunofluorescent antibody double staining method, suggesting the fusion strategy did not affect the location of protein expression. VP4 cleavage between VP2 and HA was confirmed by Western blot, indicating the fusion strategy did not affect VP4 function in transfected cells. After vaccination in chickens, the DNA construct VP24-HA/pcDNA induced ELISA and virus neutralizing antibodies against VP2 and hemagglutination inhibition antibody against the HA subtype. The results indicated that a single plasmid construct carrying IBDV VP243 gene-based DNA fused with AIV HA gene can elicit specific antibody responses to both IBDV and AIV by DNA vaccination. PMID- 25445885 TI - Shared microbiome in gums and the lung in an outpatient population. AB - OBJECTIVES: Whether periopathogenic bacteria occur in the lung and gums simultaneously and what impact periodontitis has is unknown. METHODS: In consecutive outpatients scheduled for bronchoscopies we performed a periodontal screening index. PCR to determine four periopathogens and seven less pathogenic species in both the periodontal pocket and bronchial protected specimen brush was used. Activated MMP8 in saliva and bronchial fluid was measured. RESULTS: Periopathogens were detectable in gums and in the bronchial protected specimen brush in 75 (80%) and 27 (30%) of the cases, respectively. The concentration of activated MMP 8 was above 40 ng/ml in the saliva and in the bronchial fluid sample in six and 31 subjects, respectively. Significant agreement between the periodontal and bronchial compartment was found in three out of the four periopathogens. Patients with periopathogens in the lung suffered from periodontitis more frequently (p = 0.01). In patients with periopathogens detectable in the lung the concentration of aMMP8 tends to be more frequently above 40 ng/ml in the bronchial fluid (p = 0.09). CONCLUSIONS: Agreement between periodontal and bronchial microbiome is more distinct for periopathogens than for less pathogenic species. Periodontitis itself represents a risk factor for pulmonary colonization with certain periopathogens. Pulmonary colonization with periopathogens seems to be associated with increased local inflammation. PMID- 25445884 TI - A plasmid-based reporter system for live cell imaging of dengue virus infected cells. AB - Cell culture models are used widely to study the effects of dengue virus (DENV) on host cell function. Current methods of identification of cells infected with an unmodified DENV requires fixation and permeablization of cells to allow DENV specific antibody staining. This method does not permit imaging of viable cells over time. In this report, a plasmid-based reporter was developed to allow non destructive identification of DENV-infected cells. The plasmid-based reporter was demonstrated to be broadly applicable to the four DENV serotypes, including low passaged strains, and was specifically cleaved by the viral protease with minimal interference on viral production. This study reveals the potential for this novel reporter system to advance the studies of virus-host interactions during DENV infection. PMID- 25445886 TI - Debridement, antibiotics and implant retention in early postoperative infection with Pseudomonas aeruginosa. PMID- 25445887 TI - Resistance patterns and outcomes in intensive care unit (ICU)-acquired pneumonia. Validation of European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC) classification of multidrug resistant organisms. AB - INTRODUCTION: Bacterial resistance has become a major public health problem. OBJECTIVE: To validate the definition of multidrug-resistant organisms (MDRO) based on the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC) classification. MATERIAL: Prospective, observational study in six medical and surgical Intensive-Care-Units (ICU) of a University hospital. RESULTS: Three-hundred-and-forty-three patients with ICU-acquired pneumonia (ICUAP) were prospectively enrolled, 140 patients had no microbiological confirmation (41%), 82 patients (24%) developed ICUAP for non MDRO, whereas 121 (35%) were MDROs. Non-MDRO, MDRO and no microbiological confirmation patients did not present either a significant different previous antibiotic use (p 0.18) or previous hospital admission (p 0.17). Appropriate antibiotic therapy was associated with better ICU survival (105 [92.9%] vs. 74 [82.2%]; p = 0.03). An adjusted multivariate regression logistic analysis identified that only MDRO had a higher ICU-mortality than non-MDRO and no microbiological confirmation patients (OR 2.89; p < 0.05; 95% CI for Exp [beta]. 1.02-8.21); Patients with MDRO ICUAP remained in ICU for a longer period than MDRO and no microbiological confirmation respectively (p < 0.01) however no microbiological confirmation patients had more often antibiotic consumption than culture positive ones. CONCLUSIONS: Patients who developed ICUAP due to MDRO showed a higher ICU-mortality than non-MDRO ones and use of ICU resources. No microbiological confirmation patients had more often antibiotic consumption than culture positive patients. Risk factors for MDRO may be important for the selection of initial antimicrobial therapy, in addition to local epidemiology. PMID- 25445889 TI - Lysophosphatidylserine has Bilateral Effects on Macrophages in the Pathogenesis of Atherosclerosis. AB - AIM: Lysophospholipids, particularly sphingosine 1-phosphate and lysophosphatidic acid, are known to be involved in the pathogenesis of atherosclerosis; however, the role of lysophosphatidylserine (LysoPS) in the onset of atherosclerotic diseases remains uncertain. METHODS: We investigated the effects of LysoPS on the uptake of oxidized low-density lipoprotein (oxLDL) and the modulation of inflammatory mediators and ER stress utilizing RAW264.7 cells and mouse peritoneal macrophages (MPMs). RESULTS: We found that LysoPS augmented cholesterol accumulation in both models. Consistent with these findings, LysoPS increased the expression of scavenger receptors (CD36, MSR1, LOX1 and TLR4). Regarding the involvement of these lipids in inflammation, LysoPS significantly decreased the expression of inflammatory mediators in lipopolysaccharide (LPS) treated RAW264.7 cells and MPMs. LysoPS also attenuated ER stress in LPS untreated RAW264.7 cells. The expression patterns of LysoPS receptors differed considerably among the LPS-untreated RAW264.7 cells, LPS-treated RAW264.7 cells and MPMs. CONCLUSIONS: LysoPS may have proatherosclerotic properties in the setting of foam cell formation as well as antiatherosclerotic effects on inflammation in macrophages. PMID- 25445888 TI - Associations between Inflammatory Markers and Subclinical Atherosclerosis in Middle-aged White, Japanese-American and Japanese Men: The ERA-JUMP Study. AB - AIM: To examine whether the inflammatory markers C-reactive protein (CRP) and fibrinogen are associated with biomarkers of atherosclerosis [carotid intima media thickness (IMT) and coronary artery calcification (CAC)] in the general male population, including Asians. METHODS: Population-based samples of 310 Japanese, 293 Japanese-American and 297 white men 40-49 years of age without clinical cardiovascular disease underwent measurement of IMT, CAC and the CRP and fibrinogen levels as well as other conventional risk factors using standardized methods. Statistical associations between the variables were evaluated using multiple linear or logistic regression models. RESULTS: The Japanese group had significantly lower levels of inflammatory markers and subclinical atherosclerosis than the Japanese-American and white groups (P-values all <0.001). The mean level of CRP was 0.66 vs. 1.11 and 1.47 mg/L, while that of fibrinogen was 255.0 vs. 313.0 and 291.5 mg/dl, respectively. In addition, the mean carotid IMT was 0.61 vs. 0.73 and 0.68 mm, while the mean prevalence of CAC was 11.6% vs. 32.1% and 26.3%, respectively. Body mass index (BMI) showed significant positive associations with both the CRP and fibrinogen levels. Although CRP showed a significant positive association with IMT in the Japanese men, this association became non-significant following adjustment for traditional risk factors or BMI. In all three populations, CRP was not found to be significantly associated with the prevalence of CAC. Similarly, fibrinogen did not exhibit a significant association with either IMT or the prevalence of CAC. CONCLUSIONS: The associations between inflammatory markers and subclinical atherosclerosis may merely reflect the strong associations between BMI and the levels of inflammatory markers and incidence of subclinical atherosclerosis in both Eastern and Western populations. PMID- 25445890 TI - Beta-blocker Treatment Does Not Worsen Critical Limb Ischemia in Patients Receiving Endovascular Therapy. AB - AIM: It has been reported that beta-blockers (BB) reduce cardiovascular events in patients with atherosclerotic disease. However, little is known about the efficacy of these drugs in patients with critical limb ischemia (CLI). We investigated whether beta-blocker therapy affects the clinical outcomes of CLI patients. METHODS: Between March 2004 and December 2011, 1,873 consecutive CLI patients who received endovascular therapy (EVT) (394 BB-treated patients and 1,479 non-BB-treated patients) for de novo infrainguinal lesions were identified retrospectively. A propensity score analysis was used for risk adjustment in a multivariable analysis and one-to-one matching (BB: 305, non-BB 305). The primary endpoint was amputation-free survival (AFS), and the secondary endpoints were overall survival and the rates of limb salvage and freedom from major adverse limb events (MALE; including repeat reintervention, surgical conversion and major amputation). The mean follow-up period was 22 +/- 15 months. RESULTS: In the propensity score-matched pair analysis, there were no significant differences in AFS between the patients treated with and without beta-blockers (58.8% vs. 58.5% at three years, log-rank p = 0.76). There were also no significant differences in the limb salvage rate (88.3% vs. 88.8 at three years, log-rank P = 0.41), overall survival (63.0% vs. 62.4% at three years, log-rank P = 0.70) and freedom from MALE (43.6% vs. 44.9% at three years, log-rank P = 0.58) between the patients treated with and without beta-blockers. CONCLUSIONS: The present results suggest that beta-blocker therapy does not worsen the clinical outcomes after EVT in CLI patients. PMID- 25445891 TI - Involvement of MicroRNA-133a in the Development of Arteriosclerosis Obliterans of the Lower Extremities via RhoA Targeting. AB - AIM: RhoA is a critical factor in regulating the proliferation and migration of arterial smooth muscle cells (ASMCs) in patients with arteriosclerosis obliterans (ASO). RhoA is modulated by microRNA-133a (miR-133a) in cardiac myocytes and bronchial smooth muscle cells. However, the relationship between miR-133a and RhoA with respect to the onset of ASO in the lower extremities is uncertain. METHODS: We employed in situ hybridization (ISH) and immunohistochemistry (IHC) to detect the location of miR-133a and RhoA in ASO clinical samples, respectively. 5-ethynyl-2'-deoxyuridine (EdU), cell counting kit-8 (CCK-8), Transwell and wound closure assays were utilized to determine the features of human ASMC (HASMC) proliferation and migration. The expression of miR-133a in the HASMCs was assessed using quantitative real-time PCR (qRT-PCR), while that of RhoA was examined via qRT-PCR and Western blotting. RESULTS: We found miR-133a and RhoA to be primarily located in the ASMCs of ASO. miR-133a was significantly downregulated in the ASO tissues and proliferating HASMCs. In contrast, RhoA was upregulated in the ASO samples. The proliferation and migration of HASMCs was markedly promoted by the downregulation of miR-133a and inhibited by the upregulation of miR-133a. The Luciferase assay confirmed that RhoA was a direct target of miR-133a. The upregulation of miR-133a in the HASMCs decreased the RhoA expression at the protein level. Inversely, the downregulation of miR-133a increased the RhoA protein expression. Of note, the overexpression of RhoA in the HASMCs attenuated the anti-proliferative and anti-migratory effects of miR-133a. CONCLUSIONS: Our data indicate that miR-133a regulates the functions of HASMCs by targeting RhoA and may be involved in the pathogenesis of ASO. These findings may lead to the development of potential therapeutic targets for ASO of the lower extremities. PMID- 25445892 TI - Elevated Lipoprotein(a) has Incremental Prognostic Value in Type 2 Diabetic Patients with Symptomatic Coronary Artery Disease. AB - AIM: In addition to type 2 diabetes, an elevated Lp(a) level is known to be a surrogate biomarker of cardiovascular disease. However, recent studies have demonstrated that the Lp(a) levels are lower in type 2 diabetic patients than in non-diabetic subjects. Therefore, we sought to evaluate the prognostic value of elevated lipoprotein(a) [Lp(a)] in type 2 diabetic patients with symptomatic coronary artery disease (CAD). METHODS: A total of 1494 diabetic patients with CAD (62.3% men, mean age: 63.5 +/- 10.3 years) were enrolled. CAD was diagnosed using invasive coronary angiography, and laboratory values for lipid parameters, including Lp(a), were obtained on the day of coronary angiography. The patients were divided into tertile groups according to the individual Lp(a) level. The baseline characteristics, coronary angiographic findings, duration of follow-up and major adverse cardiovascular events (MACEs) were recorded. RESULTS: Over a mean follow-up period of 4.4 +/- 2.6 years, there were 59 MACEs (35 cardiac deaths and 24 cases of non-fatal myocardial infarction), for an event rate of 3.9%. A survival probability plot according to the Lp(a) tertile revealed that an elevated Lp(a) level was associated with a worse prognosis (p = 0.008), after adjusting for age, gender, hypertension, hyperlipidemia, smoking and the extent of CAD. Furthermore, the addition of an elevated Lp(a) level to the reference model improved the integrated discrimination improvement (0.0216, p < 0.001), continuous net reclassification improvement (NRI) (0.5721, p = 0.012) and NRI (0.1549, p = 0.004) values. CONCLUSIONS: In terms of the prognosis, elevated Lp(a) is associated with worse outcomes in type 2 diabetic patients with symptomatic CAD. Furthermore, an elevated Lp(a) level has incremental prognostic value in type 2 diabetic patients with symptomatic CAD. PMID- 25445893 TI - Added value of lung perfused blood volume images using dual-energy CT for assessment of acute pulmonary embolism. AB - PURPOSE: To investigate the added value of lung perfused blood volume (LPBV) using dual-energy CT for the evaluation of intrapulmonary clot (IPC) in patients suspected of having acute pulmonary embolism (PE). MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective study. Eighty-three patients suspected of having PE who underwent CT pulmonary angiography (CTPA) using a dual-energy technique were enrolled in this study. Two radiologists who were blinded retrospectively and independently reviewed CTPA images alone and the combined images with color-coded LPBV over a 4-week interval, and two separate sessions were performed with a one-month interval. Inter- and intraobserver variability and diagnostic accuracy were evaluated for each reviewer with receiver operating characteristic (ROC) curve analysis. RESULTS: Values for inter- and intraobserver agreement, respectively, were better for CTPA combined with LPBV (ICC=0.847 and 0.937) than CTPA alone (ICC=0.748 and 0.861). For both readers, diagnostic accuracy (area under the ROC curve [Az]) were also superior, when CTPA alone (Az=0.888 [reader 1] and 0.912 [reader 2]) was compared with that after the combination with LPBV images (Az=0.966 [reader 1] and 0.959 [reader 2]) (p<0.001). However, Az values of both images might not have significant difference in statistics, because Az value of CTPA alone was high and 95% confidence intervals overlapped in both images. CONCLUSION: Addition of dual-energy perfusion CT to CTPA improves detection of peripheral IPCs with better interobserver agreement. PMID- 25445894 TI - Tibial cortical lesions: a multimodality pictorial review. AB - Shin pain is a common complaint, particularly in young and active patients, with a wide range of potential diagnoses and resulting implications. We review the natural history and multimodality imaging findings of the more common causes of cortically-based tibial lesions, as well as the rarer pathologies less frequently encountered in a general radiology department. PMID- 25445895 TI - Correlation between enhancement characteristics of MR mammography and capillary density of breast lesions. AB - OBJECTIVE: To correlate capillary density of breast lesions using the markers D2 40, CD31, and CD34 with early and late enhancement of magnetic resonance mammography (MRM). MATERIALS AND METHODS: The local ethics committee approved this study, and informed consent was avail-able from all patients. The study included 64 women with 66 histologically proven breast lesions (41 malignant, 25 benign). MR-enhancement 1 min after contrast medium administration was determined in the tumor (It1/It0 ratio) and in comparison to the surrounding tissue (It1/It1 fat ratio). Capillary density was quantified based on immunohistological staining with D2-40, CD31, and CD34 in breast tumors and surrounding breast tissue. Mean capillary densities were correlated with contrast enhancement in the tumor and surrounding breast tissue. The Kruskal-Wallis test was used to test whether lesions with different MR enhancement patterns differed in terms of capillary density. RESULTS: For CD34, there was statistically significant correlation between capillary density and tumor enhancement (r = 0.329, p = 0.012), however not for the malignant or benign groups separately. Mean vessel number identified by staining with D2-40 and CD31 did not correlate significantly with tumor enhancement (D2-40: r = -0.188, p = 0.130; CD31: r = 0.095, p = 0.448). There were no statistically significant differences in capillary density between breast lesions with delayed enhancement or a plateau and lesions showing washout (Kruskal-Wallis test. D2-40: p = 0.173; CD31: p = 0.647; CD34: p = 0.515). CONCLUSION: Of the three markers tested, CD34 showed best correlation between early contrast enhancement on MRM and capillary density. Further studies are necessary to clearly demonstrate an association between capillary density and contrast enhancement in breast tumors and surrounding tissue. PMID- 25445896 TI - Impact of fibroglandular tissue and background parenchymal enhancement on diffusion weighted imaging of breast lesions. AB - PURPOSE: To evaluate the influence of the amount of fibroglandular breast tissue (FGT) and background-parenchymal enhancement (BPE) on lesion detection, quantitative analysis of normal breast tissue and of breast lesions on DWI. MATERIALS AND METHODS: IRB approved this retrospective study on focal findings at contrast-enhanced (CE)breast MR and DWI performed during July-December 2011. Patients with cysts, previous irradiation,silicone implants and current chemotherapy were excluded. DWI with fat suppression was acquired before dynamic acquisition (b factors: 0.1000 s/mm2) using 1.5 and 3 T scanners. Using correlation with dynamic and T2 images, ROIs were drawn free-hand within the borders of any visible lesion and incontralateral normal breast. Fisher's exact test to evaluate visibility and Wilcoxon-rank-sum test for comparison of ADC values were used. The amount of FGT and BPE was visually assessed by concurrent MRI. Analysis was stratified by menopausal status. RESULTS: 25/127 (20%) lesions were excluded for technical reasons. 65/102 (64%) lesions were visible on DWI (median diameter: 1.85 cm). Mass lesions (M) were more visible (43/60 = 72%) than non-mass enhancement (NME) (22/42 = 52%) and malignant lesions were more visible (55/72 = 76%) than benign(10/30 = 33%). BPE and FGT did not influence visibility of M (p = 0.35 and p = 0.57 respectively) as well as of NME (p = 0.54 and p = 0.10). BPE and FGT did not influence visibility of malignant (p = 0.96 and p = 1.0)and benign lesions (p = 1.0 and p = 0.10). Results were confirmed adjusting for menopausal status. The ADC value of normal breast tissue was not influenced by BPE, while it was lower in predominantly fatty breasts compared to dense ones (p = 0.002). CONCLUSIONS: FGT affects the quantitative evaluation of ADC in normal breast tissue whereas BPE does not.Furthermore, both BPE and FGT do not influence visibility of benign or malignant findings, including both mass lesions and non-mass enhancement, on DWI. PMID- 25445897 TI - Direct lymphangiography as treatment option of lymphatic leakage: indications, outcomes and role in patient's management. AB - BACKGROUND: To evaluate the effectiveness of lymphography as a minimally invasive treatment option of lymphatic leakage in terms of local control and to investigate which parameters influence the success rate. METHOD: This retrospective study protocol was approved by the ethic committee. Patient history, imaging data, therapeutic options and follow-up were recorded and retrospectively analyzed. Between June 1998 and February 2013, 71 patients (m:w = 42:29, mean age, 52.4; range 42-75 years) with lymphatic leakage in form of lymphatic fistulas (n = 37), lymphocele (n = 11), chylothorax (n = 13) and chylous ascites (n = 10)underwent lymphography. Sixty-four patients (90.1%) underwent successful lymphography while lymphography failed in 7 cases. Therapeutic success was evaluated and correlated to the volume of lymphatic leakage and to the volume of the applied iodized oil. RESULT: Signs of leakage or contrast extravasation were directly detected in 64 patients. Of 64 patients, 45 patients (70.3%) were treated and cured after lymphography. Based on the lymphography findings, 19 patients (29.7%) underwent surgical intervention with a completely occlusion of lymphatic leakage. The lymphatic leak could be completely occluded in 96.8% of patients when the lymphatic drainage volume was less than 200 mL/day (n = 33). Even when lymphatic drainage was higher than 200 mL/day (n = 31),therapeutic lymphography was still successful in 58.1% of the patients. CONCLUSION: Lymphography is an effective, minimally invasive method in the detection and treatment of lymphatic leakage. The volume of lymphatic drainage per day is a significant predictor of the therapeutic success rate. PMID- 25445898 TI - Diagnosis of vertebral fractures on lateral chest X-ray: intraobserver agreement of semi-quantitative vertebral fracture assessment. AB - BACKGROUND: In clinical practice lateral images of the chest are performed for various reasons. As these lateral chest X rays show the vertebrae of the thoracic and thoraco-lumbar region, we wondered if these X-rays can be used for evaluation of vertebral fractures instead of separate thoracic spine X-rays. METHODS: To evaluate the agreement and intraobserver reliability of the semi-quantitative method for vertebral fractures on the lateral chest X-ray (X-chest) in comparison to the lateral thoracic spine X-ray (X-Tspine), two observers scored vertebral fractures on X-Tspine and twice on X-chest, separately,blinded and in different time periods. Agreement and Cohens' kappa were calculated for a diagnosis of any fracture on patient level and on vertebral body level. The study was done in patients visiting an outpatient geriatric day clinic, with a high prevalence of vertebral fractures. RESULTS: 109 patients were included. The intraobserver agreement for X-chest versus X-Tspine was 95-98%for the two levels of fracturing, with a Cohen's kappa of 0.88-0.91. The intraobserver agreement and reliability of the re-test on the X-chest showed an agreement between 91 and 98% with a Cohen's kappa of 0.81-0.93. More vertebrae were visible on the X-chest, mean 10.2, SD 0.66 versus mean 9.8, SD 0.73 on the X-Tspine (p < 0.001). CONCLUSION: The results show good agreement and intraobserver reliability on the X-chest compared to the X-Tspine for visualizing vertebral fractures. The results of this study emphasizes that the routinely performed X-chest is reliable in order to diagnose vertebral fractures. PMID- 25445899 TI - Emphysema quantification on low-dose CT using percentage of low-attenuation volume and size distribution of low-attenuation lung regions: effects of adaptive iterative dose reduction using 3D processing. AB - PURPOSE: To evaluate the effects of adaptive iterative dose reduction using 3D processing (AIDR 3D) for quantification of two measures of emphysema: percentage of low-attenuation volume (LAV%) and size distribution of low-attenuation lung regions. METHOD AND MATERIALS: Fifty-two patients who underwent standard-dose (SDCT) and low-dose CT (LDCT)were included. SDCT without AIDR 3D, LDCT without AIDR 3D, and LDCT with AIDR 3D were used for emphysema quantification. First, LAV% was computed at 10 thresholds from -990 to -900 HU. Next, at the same thresholds, linear regression on a log-log plot was used to compute the power law exponent (D)for the cumulative frequency-size distribution of low-attenuation lung regions. Bland-Altman analysis was used to assess whether AIDR 3D improved agreement between LDCT and SDCT for emphysema quantification of LAV% and D. RESULTS: The mean relative differences in LAV% between LDCT without AIDR 3D and SDCT were 3.73%-88.18% and between LDCT with AIDR 3D and SDCT were -6.61% to 0.406%. The mean relative differences in D between LDCT without AIDR 3D and SDCT were 8.22%-19.11% and between LDCT with AIDR3D and SDCT were 1.82%-4.79%. AIDR 3D improved agreement between LDCT and SDCT at thresholds from -930 to -990 HU for LAV% and at all thresholds for D. CONCLUSION: AIDR 3D improved the consistency between LDCT and SDCT for emphysema quantification of LAV% and D. PMID- 25445900 TI - First molecular cloning and gene expression analysis of teleost CD42 (glycoprotein Ib beta chain) GPIb-IX-V subunit from rock bream, Oplegnathus fasciatus. AB - CD42 is a platelet membrane glycoprotein Ib that plays a key role in haemostasis and thrombin-induced platelet activation. Here, we report the molecular cloning and sequence analysis of the CD42c gene from rock bream (Oplegnathus fasciatus). Rock bream CD42 (RbCD42c) gene expression profiles were determined after infection with Streptococcus iniae, Edwardsiella tarda and red seabream iridovirus (RSIV). The full-length RbCD42c cDNA contained an open reading frame of 624 bp encoding 207 amino acids. The deduced amino acid sequences of the leucine-rich repeat (LRR)-N terminal and LRR-C terminal were conserved between fish and mammals. RbCD42c was highly expressed in red blood cells, spleen, gill, liver and kidney of healthy rock bream. The RbCD42c gene was not significantly up or downregulated after E. tarda exposure. However, RbCD42c gene expression was upregulated in kidney, spleen and gill after S. iniae infection. RbCD42c was upregulated in spleen, liver and gill, but downregulated in kidney 24 and 48 h after RSIV infection. These results suggest that RbCD42c has different expression patterns after infection with bacterial or viral pathogens. This gene may be directly involved in haemostasis. PMID- 25445901 TI - Antimicrobial peptides in echinoderm host defense. AB - Antimicrobial peptides (AMPs) are important effector molecules in innate immunity. Here we briefly summarize characteristic traits of AMPs and their mechanisms of antimicrobial activity. Echinoderms live in a microbe-rich marine environment and are known to express a wide range of AMPs. We address two novel AMP families from coelomocytes of sea urchins: cysteine-rich AMPs (strongylocins) and heterodimeric AMPs (centrocins). These peptide families have conserved preprosequences, are present in both adults and pluteus stage larvae, have potent antimicrobial properties, and therefore appear to be important innate immune effectors. Strongylocins have a unique cysteine pattern compared to other cysteine-rich peptides, which suggests a novel AMP folding pattern. Centrocins and SdStrongylocin 2 contain brominated tryptophan residues in their native form. This review also includes AMPs isolated from other echinoderms, such as holothuroidins, fragments of beta-thymosin, and fragments of lectin (CEL-III). Echinoderm AMPs are crucial molecules for the understanding of echinoderm immunity, and their potent antimicrobial activity makes them potential precursors of novel drug leads. PMID- 25445903 TI - Identification of candidate antimicrobial peptides derived from abalone hemocyanin. AB - Hemocyanins present in invertebrate hemolymph are multifunctional proteins, responsible for oxygen transport and contributing to innate immunity through phenoloxidase-like activity. In arthropods, hemocyanin has been identified as a source of broad-spectrum antimicrobial peptides during infection. Conversely, no hemocyanin-derived antimicrobial peptides have been reported for molluscs. The present study describes a putative antimicrobial region, termed haliotisin, located within the linking sequence between the alpha-helical domain and beta sheet domain of abalone (Haliotis tuberculata) hemocyanin functional unit E. A series of synthetic peptides based on overlapping fragments of the haliotisin region were tested for their bactericidal potential. Incubating Gram-positive and Gram-negative bacteria in the presence of certain haliotisin peptides, notably peptides 3-4-5 (DTFDYKKFGYRYDSLELEGRSISRIDELIQQRQEKDRTFAGFLLKGFGTSAS) led to reductions in microbial growth. Furthermore, transmission electron micrographs of haliotisin-treated bacteria revealed damages to the microbial cell wall. Data discussed here provides the first evidence to suggest that molluscan hemocyanin may act as a source of anti-infective peptides. PMID- 25445902 TI - MicroRNA-regulation of Anopheles gambiae immunity to Plasmodium falciparum infection and midgut microbiota. AB - Invasion of the malaria vector Anopheles gambiae midgut by Plasmodium parasites triggers transcriptional changes of immune genes that mediate the antiparasitic defense. This response is largely regulated by the Toll and Immune deficiency (IMD) pathways. To determine whether A. gambiae microRNAs (miRNAs) are involved in regulating the anti-Plasmodium defense, we showed that suppression of miRNA biogenesis results in increased resistance to Plasmodium falciparum infection. In silico analysis of A. gambiae immune effector genes identified multiple transcripts with miRNA binding sites. A comparative miRNA microarray abundance analysis of P. falciparum infected and naive mosquito midgut tissues showed elevated abundance of miRNAs aga-miR-989 and aga-miR-305 in infected midguts. Antagomir inhibition of aga-miR-305 increased resistance to P. falciparum infection and suppressed the midgut microbiota. Conversely, treatment of mosquitoes with an artificial aga-miR-305 mimic increased susceptibility to P. falciparum infection and resulted in expansion of midgut microbiota, suggesting that aga-miR-305 acts as a P. falciparum and gut microbiota agonist by negatively regulating the mosquito immune response. In silico prediction of aga-miR-305 target genes identified several anti-Plasmodium effectors. Our study shows that A. gambiae aga-miR-305 regulates the anti-Plasmodium response and midgut microbiota, likely through post-transcriptional modification of immune effector genes. PMID- 25445904 TI - Chemokine receptors in Atlantic salmon. AB - Teleost sequence data have revealed that many immune genes have evolved differently when compared to other vertebrates. Thus, each gene family needs functional studies to define the biological role of individual members within major species groups. Chemokine receptors, being excellent markers for various leukocyte subpopulations, are one such example where studies are needed to decipher individual gene function. The unique salmonid whole genome duplication that occurred approximately 95 million years ago has provided salmonids with many additional duplicates further adding to the complexity and diversity. Here we have performed a systematic study of these receptors in Atlantic salmon with particular focus on potential inflammatory receptors. Using the preliminary salmon genome data we identified 48 chemokine or chemokine-like receptors including orthologues to the ten receptors previously published in trout. We found expressed support for 40 of the bona fide salmon receptors. Eighteen of the chemokine receptors are duplicated, and when tested against a diploid sister group the majority were shown to be remnants of the 4R whole genome duplication with subsequent high sequence identity. The salmon chemokine receptor repertoire of 40 expressed bona fide genes is comparably larger than that found in humans with 23 receptors. Diversification has been a major driving force for these duplicate genes with the main variability residing in ligand binding and signalling domains. PMID- 25445905 TI - Molecular characterization and functional analysis of duck TRAF6. AB - Tumor necrosis factor receptor-associated factor 6 (TRAF6) plays a pivotal role in activating various signaling cascades as an intracellular signal transducer. Although significant progress has been made clarifying TRAF6 function in mammals, the role of TRAF6 in ducks (duTRAF6) remains poorly understood. In the present study, we cloned the full-length duTRAF6 cDNA from duck embryo fibroblasts (DEFs) for the first time. Real-time quantitative reverse transcription-polymerase chain reaction assays showed that duTRAF6 was widely expressed in different tissues. Overexpression of duTRAF6 activated nuclear factor kappa B (NF-kappaB) and induced interferon-beta expression. Furthermore, a deletion mutant analysis revealed that the duTRAF6 region between aa 115 and 375 was essential for activating NF-kappaB. In addition, duTRAF6 knockdown by RNA interference significantly reduced poly(I:C)- and Sendai virus-induced NF-kappaB activation in DEFs. Taken together, our results demonstrate that duTRAF6 plays a crucial immunoregulatory role in the duck innate immune response. PMID- 25445906 TI - The promoter of the white spot syndrome virus immediate-early gene WSSV108 is activated by the cellular KLF transcription factor. AB - A series of deletion and mutation assays of the white spot syndrome virus (WSSV) immediate-early gene WSSV108 promoter showed that a Kruppel-like factor (KLF) binding site located from -504 to -495 (relative to the transcription start site) is important for the overall level of WSSV108 promoter activity. Electrophoretic mobility shift assays further showed that overexpressed recombinant Penaeus monodon KLF (rPmKLF) formed a specific protein-DNA complex with the (32)P-labeled KLF binding site of the WSSV108 promoter, and that higher levels of Litopenaeus vannamei KLF (LvKLF) were expressed in WSSV-infected shrimp. A transactivation assay indicated that the WSSV108 promoter was strongly activated by rPmKLF in a dose-dependent manner. Lastly, we found that specific silencing of LvKLF expression in vivo by dsRNA injection dramatically reduced both WSSV108 expression and WSSV replication. We conclude that shrimp KLF is important for WSSV genome replication and gene expression, and that it binds to the WSSV108 promoter to enhance the expression of this immediate-early gene. PMID- 25445907 TI - MAVS splicing variants contribute to the induction of interferon and interferon stimulated genes mediated by RIG-I-like receptors. AB - The mitochondrial antiviral signaling protein (MAVS) plays a key role in the signal transduction of RIG-I-like receptors (RLRs)-mediated antiviral response. In the present study, zebrafish MAVS transcript variants, namely MAVS_tv1 and MAVS_tv2, were cloned from zebrafish embryos. The putative MAVS_tv1 protein (full length form) contains an N-terminal CARD domain, a central proline region, and a C-terminal transmembrane domain (TM). MAVS_tv2 is generated by a 190 bp intron fragment insertion. The putative MAVS_tv2 protein lacked TM domain due to a frame shift, with the N-terminal 303 aa residues identical to MAVS_tv1, and no sequence homology for the C-terminal 41 aa residues. Real-time PCR showed that the expression of MAVS_tv1 in ZF4 cells was higher than that of MAVS_tv2, and MAVS variants were induced by Edwardsiella tarda and SVCV infection during the early time points of infection, whereas MAVS_tv1 unchanged or MAVS_tv2 decreased at a later time point after the infection, respectively. Overexpression of MAVS_tv1 and MAVS_tv2 in fish cells conferred antiviral resistance, and activated zebrafish IFN1 and IFN3 promoters. MAVS_tv1 overexpression induced a slow (48 hpf) increased expression of IFN1, mxa, mxb, mxe and RSAD2. In contrast, MAVS_tv2 overexpression increased rapidly and transiently the expression of IFN1, IFN2, IFN3, mxc and rsad2 at 6 or 24 hpf. The simultaneous overexpression of MAVS variants and RIG-I in zebrafish embryos led to an accumulative induction of IFNs and IFN-stimulated genes including IFN1, IFN4, mxc, mxe and rsad. Furthermore, MAVS_tv1 cooperated with RIG-I in the accumulation of RIG-I transcript in a positive feedback loop; MAVS_tv2 synergized with MDA5 in the accumulation of MAVS_tv2 transcript. Collectively, these data suggest the molecular mechanisms of fish MAVS variants in antiviral immunity. PMID- 25445908 TI - Reduction of rainbow trout spleen size by splenectomy does not alter resistance against bacterial cold water disease. AB - In lower vertebrates, the contribution of the spleen to anti-bacterial immunity is poorly understood. We have previously reported a phenotypic and genetic correlation between resistance to Flavobacterium psychrophilum, the causative agent of bacterial cold water disease (BCWD) and spleen somatic index (spleen weight normalized to body weight, SI). Fish families with larger pre-challenge SI values were found to have greater BCWD survival (resistance) following intraperitoneal injection of a lethal dose of F. psychrophilum. Since the mammalian spleen is known to be crucial for capture and destruction of encapsulated bacteria, we tested the hypothesis that reduction of spleen size, by surgical splenectomy, should reduce the survival advantage of the larger-spleen, disease-resistant fish. Experiments were performed using two separate lines of fish that had previously been selected either based on BCWD survival (resistant and susceptible), or selected based on spleen size (high and low SI). Following 65 to 81 days post-surgical recovery, fish were challenged with F. psychrophilum and mortality monitored for a minimum of 21 days. No significant difference in the relative survival was detected between splenectomized or sham-operated groups, while SI of splenectomized fish was reduced to an average of 8-12% of control animals. A positive correlation was observed between the SI, measured at the time of splenectomy, and time-to-death post-challenge. In summary, these experiments argue that larger spleen size alone is not sufficient for greater BCWD resistance, but rather it is an indirect indicator of immunological status. PMID- 25445910 TI - Cxcl8-l1 and Cxcl8-l2 are required in the zebrafish defense against Salmonella Typhimurium. AB - In recent years zebrafish has emerged as an excellent model for studying the Cxcl8 signaling pathway in inflammation elicited upon tissue damage or infection. Zebrafish has two true homologs of mammalian CXCL8, named Cxcl8-l1 and Cxcl8-l2. Previously, we have shown that in wound-associated inflammation, these chemokines are up-regulated and are relevant for neutrophil recruitment. In infections, no such knowledge is available as most studies performed on this subject in zebrafish have mainly focused on Cxcl8-l1 even though Cxcl8-l2 shares higher homology with human CXCL8. In this study, we aimed to address the biological function of both zfCxcl8s in infection to improve our understanding of their respective roles under different inflammatory conditions. Gene expression analysis first confirmed that both Cxcl8-l1 and l2 are induced upon infection or in PAMP-elicited inflammatory processes. In addition, we also found that cxcl8 deficient larvae show higher susceptibility to Salmonella enterica serovar Typhimurium (S. Typhimurium) infection, reduced neutrophil recruitment to the infection site assayed in the line Tg(mpx:gfp), and decreased bacterial clearance. These data indicate that both zebrafish Cxcl8s play important roles in neutrophil recruitment and in the inflammatory response elicited upon infection or tissue damage, suggesting that even though the divergence of lower vertebrates and humans from a common ancestor occurred about 450 millions years ago, the basic principles of neutrophil recruitment are apparently conserved in all vertebrates. PMID- 25445909 TI - Characterization of surface phenotypic molecules of teleost dendritic cells. AB - Dendritic cells (DCs) are among the most important professional antigen presenting cells (APCs) that participate in various biological activities in mammals. However, evidence of the existence of DCs in teleost fish and other lower vertebrates remains limited. In this study, phenotypic and functional characteristics of teleost DCs were described in a zebrafish model. An improved method to efficiently enrich DCs was established. Immunofluorescence staining revealed that the surface phenotypic hallmarks of mammalian DCs, including MHC II, CD80/86, CD83, and CD209, were distributed on the surfaces of zebrafish DCs (DrDCs). Functional analysis results showed that DrDCs could initiate antigen specific CD4(+) T cell activation, in which MHC-II, CD80/86, CD83, and CD209 are implicated. Hence, teleost DCs exhibit conserved immunophenotypes and functions similar to those of their mammalian counterparts. Our findings contributed to the current understanding of the evolutionary history of DCs and the DC-regulatory mechanisms of adaptive immunity. PMID- 25445912 TI - The genome of the Pacific oyster Crassostrea gigas brings new insights on the massive expansion of the C1q gene family in Bivalvia. AB - C1q domain-containing (C1qDC) proteins are regarded as important players in the innate immunity of bivalve mollusks and other invertebrates and their highly adaptive binding properties indicate them as efficient pathogen recognition molecules. Although experimental studies support this view, the molecular data available at the present time are not sufficient to fully explain the great molecular diversification of this family, present in bivalves with hundreds of C1q coding genes. Taking advantage of the fully sequenced genome of the Pacific oyster Crassostrea gigas and more than 100 transcriptomic datasets, we: (i) re annotated the oyster C1qDC loci, thus identifying the correct genomic organization of 337 C1qDC genes, (ii) explored the expression pattern of oyster C1qDC genes in diverse developmental stages and adult tissues of unchallenged and experimentally treated animals; (iii) investigated the expansion of the C1qDC gene family in all major bivalve subclasses. Overall, we provide a broad description of the functionally relevant features of oyster C1qDC genes, their comparative expression levels and new evidence confirming that a gene family expansion event has occurred during the course of Bivalve evolution, leading to the diversification of hundreds of different C1qDC genes in both the Pteriomorphia and Heterodonta subclasses. PMID- 25445913 TI - Identification of novel chicken CD4+ CD3- blood population with NK cell like features. AB - Chicken NK cells have been defined in embryonic spleen and intestinal epithelium as CD8(+) lymphoid cells that lack BCR and TCR, whereas blood NK cells have not been phenotypically defined. Here we employed the mab, 8D12 directed against CHIR AB1, a chicken Fc receptor, to define a previously uncharacterized lymphoid cell population in the blood. Although CHIR-AB1 expression was found on several cell populations, cells with extraordinary high CHIR-AB1 levels ranged between 0.4 and 2.8% in five different chicken lines. The widespread applicability of the CHIR AB1 mab was unexpected, since CHIR-AB1-like genes form a polygenic and polymorphic subfamily. Surprisingly the CHIR-AB1 high cells coexpressed low MHCII, low CD4 and CD5, while other T cell markers CD3 and CD8, the B cell marker Bu1, the macrophage marker KUL01 were absent. Moreover, they stained with the mab 28-4, 20E5 and 1G7, which define chicken NK cells and they also expressed CD25, CD57, CD244 and the vitronectin receptor (alphaVbeta3 integrin). In functional assays, PMA stimulation led to high levels of IFNgamma release, while spontaneous cytotoxicity was not detectable. The expression of typical NK cell markers in the absence of characteristic B- or T-cell markers, and their IFNgamma release is suggestive of a yet unidentified NK like population. PMID- 25445911 TI - In contrast to other species, alpha-Galactosylceramide (alpha-GalCer) is not an immunostimulatory NKT cell agonist in horses. AB - alpha-GalCer is a potent immunomodulatory molecule that is presented to NKT cells via the CD1 antigen-presenting system. We hypothesized that when used as an adjuvant alpha-GalCer would induce protective immune responses against Rhodococcus equi, an important pathogen of young horses. Here we demonstrate that the equine CD1d molecule shares most features found in CD1d from other species and has a suitable lipid-binding groove for presenting glycolipids to NKT cells. However, equine CTL stimulated with alpha-GalCer failed to kill cells infected with R. equi, and alpha-GalCer did not increase killing by CTL co-stimulated with R. equi antigen. Likewise, alpha-GalCer did not induce the lymphoproliferation of equine PBMC or increase the proliferation of R. equi-stimulated cells. Intradermal injection of alpha-GalCer in horses did not increase the recruitment of lymphocytes or cytokine production. Furthermore, alpha-GalCer-loaded CD1d tetramers, which have been shown to be broadly cross-reactive, did not bind equine lymphocytes. Altogether, our results demonstrate that in contrast to previously described species, horses are unable to respond to alpha-GalCer. This raises questions about the capabilities and function of NKT cells and other lipid specific T lymphocytes in horses. PMID- 25445914 TI - Origin of the response to adrenal and sex steroids: Roles of promiscuity and co evolution of enzymes and steroid receptors. AB - Many responses to adrenal and sex steroids are mediated by receptors that belong to the nuclear receptor family of transcription factors. We investigated the co evolution of these vertebrate steroid receptors and the enzymes that synthesize adrenal and sex steroids through data mining of genomes from cephalochordates [amphioxus], cyclostomes [lampreys, hagfish], chondrichthyes [sharks, rays, skates], actinopterygii [ray-finned fish], sarcopterygii [coelacanths, lungfishes and terrestrial vertebrates]. An ancestor of the estrogen receptor and 3 ketosteroid receptors evolved in amphioxus. A corticoid receptor and a progesterone receptor evolved in cyclostomes, and an androgen receptor evolved in gnathostomes. Amphioxus contains CYP11, CYP17, CYP19, 3beta/Delta5-4-HSD and 17beta-HSD14, which suffice for the synthesis of estradiol and Delta5 androstenediol. Amphioxus also contains CYP27, which catalyzes the synthesis of 27-hydroxy-cholesterol, another estrogen. Lamprey contains, in addition, CYP21, which catalyzes the synthesis of 11-deoxycortisol. Chondrichthyes contain, in addition, CYP11A, CYP11C, CYP17A1, CYP17A2. Coelacanth also contains CYP11C1, the current descendent from a common ancestor with modern land vertebrate CYP11B genes, which catalyze the synthesis of cortisol, corticosterone and aldosterone. Interestingly, CYP11B2, aldosterone synthase, evolved from separate gene duplications in at least old world monkeys and two suborders of rodents. Sciurognathi (including mice and rats) and Hystricomorpha (including guinea pigs). Thus, steroid receptors and steroidogenic enzymes co-evolved at key transitions in the evolution of vertebrates. Together, this suite of receptors and enzymes through their roles in transcriptional regulation of reproduction, development, homeostasis and the response to stress contributed to the evolutionary diversification of vertebrates. This article is part of a Special Issue entitled 'Steroid/Sterol signaling'. PMID- 25445915 TI - Non-linear increase of vitamin D content in eggs from chicks treated with increasing exposure times of ultraviolet light. AB - Vitamin D fortified food can help to reduce the prevalence for vitamin D deficiency. Previous data provided evidence that eggs from hens exposed to ultraviolet (UV) light contain large quantities of vitamin D. In the current study, we assessed the efficacy of vitamin D enrichment in eggs upon increasing daily UVB exposure times. We further addressed the question whether extended UVB irradiation affects the skin content of 7-dehydrocholesterol. To this end, 35 hens were assigned to 7 groups of 5 animals each and were exposed to UVB light (76MUW/cm(2)) for 0, 15, 30, 60, 120, 180 and 300min per day, respectively. Eggs from the treatment groups were collected at baseline and after 2, 3 and 4 weeks of treatment, respectively. Skin samples were gained at the end of 4 weeks. Vitamin D metabolites were quantified by liquid chromatography-tandem mass spectrometry. The contents of vitamin D3 and 25(OH)D3 in egg yolk raised non linear in response to increasing daily UVB exposure times. The vitamin D3 content did not reach a clear-cut plateau within the chosen UVB treatment times. A daily UVB exposure time of 300min resulted in vitamin D3 contents of 28.6MUg/100g egg yolk dry matter. In contrast to vitamin D3, the 25(OH)D3 content in the egg yolk achieved a maximum upon an UVB irradiation time of 60min/d. The cutaneous 7 dehydrocholesterol contents were not altered in response to the chosen UVB irradiation times. In conclusion, the data show a distinct non-linear dose response relationship of UVB exposure times on the total vitamin D content in eggs. This article is part of a special issue entitled '17th Vitamin D Workshop'. PMID- 25445917 TI - Novel mechanisms for the vitamin D receptor (VDR) in the skin and in skin cancer. AB - The VDR acting with or without its principal ligand 1,25(OH)2D regulates two central processes in the skin, interfollicular epidermal (IFE) differentiation and hair follicle cycling (HFC). Calcium is an important co-regulator with 1,25(OH)2D at least of epidermal differentiation. Knockout of the calcium sensing receptor (CaSR) in addition to VDR accelerates the development of skin cancer in mice on a low calcium diet. Coactivators such as mediator 1 (aka DRIP205) and steroid receptor coactivator 3 (SRC3) regulate VDR function at different stages of the differentiation process, with Med 1 essential for hair follicle differentiation and early stages of epidermal differentiation and proliferation and SRC3 essential for the latter stages of differentiation including formation of the permeability barrier and innate immunity. The corepressor of VDR, hairless (HR), is essential for hair follicle cycling, although its effect on epidermal differentiation in vivo is minimal. In its regulation of HFC and IFE VDR controls two pathways-wnt/beta-catenin and sonic hedgehog (SHH). In the absence of VDR these pathways are overexpressed leading to tumor formation. Whereas, VDR binding to beta-catenin may block its activation of TCF/LEF1 sites, beta-catenin binding to VDR may enhance its activation of VDREs. 1,25(OH)2D promotes but may not be required for these interactions. Suppression of SHH expression by VDR, on the other hand, requires 1,25(OH)2D. The major point of emphasis is that the role of VDR in the skin involves a number of novel mechanisms, both 1,25(OH)2D dependent and independent, that when disrupted interfere with IFE differentiation and HFC, predisposing to cancer formation. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25445916 TI - Targeted delivery of 1,25-dihydroxyvitamin D3 to colon tissue and identification of a major 1,25-dihydroxyvitamin D3 glycoside from Solanumglaucophyllum plant leaves. AB - Leaves of the Solanum glaucophyllum (Sg) plant, indigenous to South America, have long been known for their calcinogenic toxicity in ruminant animals. It was determined the leaves contained glycosidic derivatives of 1,25-dihydroxyvitamin D3 (1,25D3) and liberation of the free hormone by rumen bacterial populations elicited a hypercalcemic response. Our interest in the leaves is predicated on the concept that the glycoside forms of 1,25D3 would target release of the active hormone in the lower gut of non-ruminant mammals. This would provide a means of delivering 1,25D3 directly to the colon, where the hormone has been shown to have beneficial effects in models of inflammatory bowel disease (IBD) and colon cancer. We fed mice for 10 days with variable amounts of Sg leaf. Feeding 7 333MUg leaf/day produced no changes in plasma Ca(2+) and 1,25D3 concentrations, and only at >=1000MUg leaf/day did these values become significantly elevated compared to controls. Gene expression studies from colon tissue indicated a linear relationship between the amount of leaf consumed and expression of the Cyp24a1 gene. In contrast, Cyp24a1 gene expression in the duodenums and ileums of these mice was unchanged compared to controls. One of the major 1,25D3-glycosides was isolated from leaves following extraction and purification by Sep-Pak cartridges and HPLC fractionation. Ultraviolet absorbance was consistent with modification of the 1-hydroxyl group, and positive ion ESI mass spectrometry indicated a diglycoside of 1,25D3. 2-Dimensional NMR analyses were carried out and established the C1 proton of the A-ring was interacting with a C1' sugar proton, while the C3 proton of the A-ring was linked with a second C1' sugar proton. The structure of the isolated compound is therefore consistent with a beta-linked 1,3-diglycoside of 1,25D3. Thus, Sg leaf administered to mice at up to 333 ug/day can elicit colon-specific enhancement of Cyp24a1 gene expression without inducing hypercalcemia, and the 1,3-diglycoside is one of the major forms of 1,25D3 found in the leaf. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25445918 TI - Stimulation of in-vitro angiogenesis by low concentrations of risedronate is mitigated by 1,25-dihydroxyvitamin D3 or 24,25-dihydroxyvitamin D3. AB - The nitrogen-containing or nitrogenous bisphosphonates (N-BF) are currently the main class of drugs used for the treatment of diseases characterized by an increased bone resorption. Preliminary data suggest that N-BF have also direct or indirect anti-tumoral effects, and recent evidence suggests that part of the anti tumoral activity of N-BF may be attributed to their anti-angiogenic capacity when they are used at high concentrations. On the other hand, an optimal vitamin-D status seems to be necessary to maximize the bone response to N-BF. Our aim has been to evaluate the effect of risedronate, alone or in combination with either 1,25(OH)2D3 or 24,25(OH)2D3 (two main vitamin-D metabolites) on parameters related to the angiogenic capacity of human umbilical-vein endothelial cells (HUVEC). The studies of tube formation through in-vitro angiogenesis assays with Matrigel, chemotaxis and migration in a scratch assay showed that low concentrations of risedronate (0.01 to 1MUM) stimulated angiogenesis and cellular migration in vitro. The presence of 1,25(OH)2D3 in the medium inhibited tubular structure formation and cellular migration. In addition, the presence of 1,25 or 24,25(OH)2D3 in the culture medium also decreased the pro-angiogenic effects of low-concentrations of risedronate. These data show the differential effects of different concentrations of vitamin-D metabolites and risedronate on angiogenesis, thus stressing the importance of an adequate vitamin D status during medical treatment with risedronate. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25445919 TI - Vitamin D compounds reduce mammosphere formation and decrease expression of putative stem cell markers in breast cancer. AB - Breast cancer stem cells (BCSCs) are a subset of tumor cells that are believed to be the cells responsible for the establishment and maintenance of tumors. Moreover, BCSCs are suggested to be the main cause of progression to metastasis and recurrence of cancer because of their tumor-initiating abilities and resistance to conventional therapies. Ductal carcinoma in situ (DCIS) is an early precursor in breast carcinogenesis which progresses to invasive ductal carcinoma (IDC). We have previously reported that a vitamin D compound, BXL0124, inhibits the progression of DCIS to IDC. In the present study we sought to determine whether this effect was mediated through an influence on BCSCs. In MCF10DCIS cells treated with vitamin D compounds (1alpha25(OH)2D3 or BXL0124), the breast cancer stem cell-like population, identified by the CD44(+)/CD24(-/low) and CD49f(+)/CD24(-/low) subpopulations, was reduced. To determine the effects of vitamin D compounds on cancer stem cell activity, the MCF10DCIS mammosphere cell culture system, which enriches for mammary progenitor cells and putative BCSCs, was utilized. Untreated MCF10DCIS mammospheres showed a disorganized and irregular shape. When MCF10DCIS cells were treated with 1alpha25(OH)2D3 or BXL0124, the mammospheres that formed exhibited a more organized, symmetrical and circular shape, similar to the appearance of spheres formed by the non-malignant, normal mammary epithelial cell line, MCF10A. The mammosphere forming efficiency (MFE) was significantly decreased upon treatment with 1alpha25(OH)2D3 or BXL0124, indicating that these compounds have an inhibitory effect on mammosphere development. Treatment with 1alpha25(OH)2D3 or BXL0124 repressed markers associated with the stem cell-like phenotype, such as CD44, CD49f, c-Notch1, and pNFkappaB. Furthermore, 1alpha25(OH)2D3 and BXL0124 reduced the expression of pluripotency markers, OCT4 and KLF-4 in mammospheres. This study suggests that vitamin D compounds repress the breast cancer stem cell-like population, potentially contributing to their inhibition of breast cancer. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25445920 TI - Combining automatic table classification and relationship extraction in extracting anticancer drug-side effect pairs from full-text articles. AB - Anticancer drug-associated side effect knowledge often exists in multiple heterogeneous and complementary data sources. A comprehensive anticancer drug side effect (drug-SE) relationship knowledge base is important for computation based drug target discovery, drug toxicity predication and drug repositioning. In this study, we present a two-step approach by combining table classification and relationship extraction to extract drug-SE pairs from a large number of high profile oncological full-text articles. The data consists of 31,255 tables downloaded from the Journal of Oncology (JCO). We first trained a statistical classifier to classify tables into SE-related and -unrelated categories. We then extracted drug-SE pairs from SE-related tables. We compared drug side effect knowledge extracted from JCO tables to that derived from FDA drug labels. Finally, we systematically analyzed relationships between anti-cancer drug associated side effects and drug-associated gene targets, metabolism genes, and disease indications. The statistical table classifier is effective in classifying tables into SE-related and -unrelated (precision: 0.711; recall: 0.941; F1: 0.810). We extracted a total of 26,918 drug-SE pairs from SE-related tables with a precision of 0.605, a recall of 0.460, and a F1 of 0.520. Drug-SE pairs extracted from JCO tables is largely complementary to those derived from FDA drug labels; as many as 84.7% of the pairs extracted from JCO tables have not been included a side effect database constructed from FDA drug labels. Side effects associated with anticancer drugs positively correlate with drug target genes, drug metabolism genes, and disease indications. PMID- 25445921 TI - The clinician in the driver's seat: part 2 - intelligent uses of space in a drag/drop user-composable electronic health record. AB - User-composable approaches provide clinicians with the control to design and assemble information elements on screen via drag/drop. They hold considerable promise for enhancing the electronic-health-records (EHRs) user experience. We previously described this novel approach to EHR design and our illustrative system, MedWISE. The purpose of this paper is to describe clinician users' intelligent uses of space during completion of real patient case studies in a laboratory setting using MedWISE. Thirteen clinicians at a quaternary academic medical center used the system to review four real patient cases. We analyzed clinician utterances, behaviors, screen layouts (i.e., interface designs), and their perceptions associated with completing patient case studies. Clinicians effectively used the system to review all cases. Two coding schemata pertaining to human-computer interaction and diagnostic reasoning were used to analyze the data. Users adopted three main interaction strategies: rapidly gathering items on screen and reviewing ('opportunistic selection' approach); creating highly structured screens ('structured' approach); and interacting with small groups of items in sequence as their case review progressed ('dynamic stage' approach). They also used spatial arrangement in ways predicted by theory and research on workplace spatial arrangement. This includes assignment of screen regions for particular purposes (24% of spatial codes), juxtaposition to facilitate calculation or other cognitive tasks ('epistemic action'), and grouping elements with common meanings or relevance to the diagnostic facets of the case (20.3%). A left-to-right progression of orienting materials, data, and action items or reflection space was a commonly observed pattern. Widget selection was based on user assessment of what information was useful or relevant. We developed and tested an illustrative system that gives clinicians greater control of the EHR, and demonstrated its feasibility for case review by typical clinicians. Producing the simplifying inventions, such as user-composable platforms that shift control to the user, may serve to promote productive EHR use and enhance its value as an instrument of patient care. PMID- 25445923 TI - Feature-expression heat maps--a new visual method to explore complex associations between two variable sets. AB - INTRODUCTION: Existing methods such as correlation plots and cluster heat maps are insufficient in the visual exploration of multiple associations between genetics and phenotype, which is of importance to achieve a better understanding of the pathophysiology of psychiatric and other illnesses. The implementation of a combined presentation of effect size and statistical significance in a graphical method, added to the ordering of the variables based on the effect ordered data display principle was deemed useful by the authors to facilitate in the process of recognizing meaningful patterns in these associations. MATERIALS AND METHODS: The requirements, analyses and graphical presentation of the feature expression heat map are described. The graphs display associations of two sets of ordered variables where a one-way direction is assumed. The associations are depicted as circles representing a combination of effect size (color) and statistical significance (radius). RESULTS: An example dataset is presented and relation to other methods, limitations, areas of application and possible future enhancements are discussed. CONCLUSION: The feature-expression heat map is a useful graphical instrument to explore associations in complex biological systems where one-way direction is assumed, such as genotype-phenotype pathophysiological models. PMID- 25445924 TI - Towards actionable risk stratification: a bilinear approach. AB - Risk stratification is instrumental to modern clinical decision support systems. Comprehensive risk stratification should be able to provide the clinicians with not only the accurate assessment of a patient's risk but also the clinical context to be acted upon. However, existing risk stratification techniques mainly focus on predicting the risk score for individual patients; at the cohort level, they offer little insight beyond a flat score-based segmentation. This essentially reduces a patient to a score and thus removes him/her from his/her clinical context. To address this limitation, in this paper we propose a bilinear model for risk stratification that simultaneously captures the three key aspects of risk stratification: (1) it predicts the risk of each individual patient; (2) it stratifies the patient cohort based on not only the risk score but also the clinical characteristics; and (3) it embeds all patients into clinical contexts with clear interpretation. We apply our model to a cohort of 4977 patients, 1127 among which were diagnosed with Congestive Heart Failure (CHF). We demonstrate that our model cannot only accurately predict the onset risk of CHF but also provide rich and actionable clinical insights into the patient cohort. PMID- 25445922 TI - Modeling workflow to design machine translation applications for public health practice. AB - OBJECTIVE: Provide a detailed understanding of the information workflow processes related to translating health promotion materials for limited English proficiency individuals in order to inform the design of context-driven machine translation (MT) tools for public health (PH). MATERIALS AND METHODS: We applied a cognitive work analysis framework to investigate the translation information workflow processes of two large health departments in Washington State. Researchers conducted interviews, performed a task analysis, and validated results with PH professionals to model translation workflow and identify functional requirements for a translation system for PH. RESULTS: The study resulted in a detailed description of work related to translation of PH materials, an information workflow diagram, and a description of attitudes towards MT technology. We identified a number of themes that hold design implications for incorporating MT in PH translation practice. A PH translation tool prototype was designed based on these findings. DISCUSSION: This study underscores the importance of understanding the work context and information workflow for which systems will be designed. Based on themes and translation information workflow processes, we identified key design guidelines for incorporating MT into PH translation work. Primary amongst these is that MT should be followed by human review for translations to be of high quality and for the technology to be adopted into practice. CONCLUSION: The time and costs of creating multilingual health promotion materials are barriers to translation. PH personnel were interested in MT's potential to improve access to low-cost translated PH materials, but expressed concerns about ensuring quality. We outline design considerations and a potential machine translation tool to best fit MT systems into PH practice. PMID- 25445925 TI - alpha-Melanocyte stimulating hormone (MSH) and prostaglandin E2 (PGE2) drive melanosome transfer by promoting filopodia delivery and shedding spheroid granules: Evidences from atomic force microscopy observation. AB - BACKGROUND: Skin pigmentation is accomplished by production of melanin in melanosome and by transfer of these organelles from melanocytes (MCs) to surrounding keratinocytes (KCs). However, the detailed mechanism is still unknown. OBJECTIVE: We aimed to investigate the morphological structure changes on human epidermal MCs and KCs, which were either mono-cultured or co-cultured, with or without the treatment of both alpha-Melanocyte-stimulating hormone (alpha MSH) and prostaglandin E2 (PGE2), by atomic force microscopy (AFM) and to provide more direct proofs for process of melanosome transfer. METHODS: Human epidermal MCs and KCs were isolated and co-cultured with 1:10 ratio in a defined Keratinocyte-serum free medium (K-SFM). After exposure with 100 nM alpha-MSH or 20 MUM PGE2 for 3 days, cells were fixed with 0.5% glutaraldehyde and AFM images of scanning observation were captured by contacting and tapping model under normal atmospheric pressure and temperature. RESULTS: It showed that human epidermal MCs in culture had secondary or tertiary branches. Except for globular granules structure on the surface of dendrites, some filopodia were protruded on the tips and lateral sides of the dendrites. The administration of alpha-MSH and PGE2 made not only the dendrites thinner and longer, but also the globular granules more intensive and denser. Many spheroid granules were shed from branches of dendrite and most of them adhered with dense filopodia. Compared with untreated group, the number of filopodia per cell, diameter of filopodia, and shedding spheroid granules per field all increased following alpha-MSH and PGE2 exposure (P<0.05, n=3). However, many crest-like protrusions, which were distributed homogenously on the surface of mono-cultured KCs, were less changed after alpha-MSH and PGE2 exposure. In co-culture model, alpha-MSH and PGE2 increased the number of transferred melanosomes in KCs under laser confocal microscopic examination. Filopodia were observed only on the adhesion area of KCs and MCs in a coiled style by AFM examination. In addition, the number of filopodia per field, diameter of filopodia and shedding spheroid granules per field all increased after the administration of alpha-MSH and PGE2 (P<0.05, n=3). CONCLUSIONS: Our data suggest that shedding spheroid granules, filopodia delivery and KC phagocytosis are major mode of melanosome transfer between MCs and KCs. PGE2, as well as alpha-MSH, drives melanosome transfer by promoting filopodia delivery and numbers of shedding spheroid granules in MCs, but no direct morphological effects on KCs. These findings open a new path in our understanding of MCs-KCs communication regulating pigmentation. PMID- 25445926 TI - Efficient fabrication of epidermal cell sheets using gamma-secretase inhibitor. AB - BACKGROUND: Epidermal cell sheets have been utilized for regeneration of skin when skin defects occur and prevention of esophageal stricture after endoscopic submucosal dissection. To reduce the cost of cultivation, a novel culture method to shorten a culture process needs to be developed. OBJECTIVES: To shorten a culture process of epidermal cell sheets, we developed a novel culture method to accelerate the fabrication of epidermal cell sheets using gamma-secretase inhibitor. METHODS: Normal human epidermal keratinocytes (NHEKs) were cultured using gamma-secretase inhibitor, DAPT, during expansion of the cells to confluence and culture without DAPT during stratification. The cell growth, quantitative gene expression of stem/progenitor or differentiation markers, and protein expression of these markers were analyzed to verify the effectiveness of the novel method. RESULTS: The proliferation of NHEKs on cell-culture inserts was promoted using DAPT. However, NHEKs were not stratified completely in the presence of DAPT. In contrast, NHEKs cultured using DAPT were stratified and differentiated by eliminating the inhibitor after the cells reached confluence. Real-time PCR analyses showed that the gene expressions of putative epithelial stem/progenitor cell markers and epidermis differentiation markers in the cell sheets fabricated using this novel method were significantly higher than those in the cell sheets fabricated without DAPT. Histological and immunofluorescence analyses revealed that it was possible to fabricate well-differentiated epidermal cell sheets efficiently by the novel culture method. The culture period was shortened to 67% of the time required for the control group. In feeder-free conditions, stratified epidermal cell sheets were also fabricated using DAPT. CONCLUSIONS: The novel culture method using gamma-secretase inhibitor, DAPT, was found to be effective for fabricating epidermal cell sheets. PMID- 25445928 TI - Differences in the efficacy and safety among inhaled corticosteroids (ICS)/long acting beta2-agonists (LABA) combinations in the treatment of chronic obstructive pulmonary disease (COPD): Role of ICS. AB - Inhaled corticosteroids (ICS) are frequently recommended for the treatment of asthma and COPD, often in combination with long-acting beta2-agonists (LABA), depending on the severity of the disease and/or on the specific phenotype. Several ICS/LABA combinations are currently available that differ in their pharmacokinetic characteristics and dose of both components. Thus, this review assesses differences in the efficacy and the safety profiles of the ICS components in the two more frequently used ICS/LABA combinations (budesonide/formoterol and fluticasone/salmeterol) for the management of COPD. Whereas the basic mechanism of action is similar for all ICS (binding with the intracellular glucocorticoid receptor, which mediates both genomic and non genomic effects), the pharmacokinetic and characteristics of ICS are quite different in terms of receptor affinity, bioavailability, lipophilicity and drug persistence in the airways. Fluticasone persists longer in airway mucus and requires more time to dissolve in the lining fluid and then enter the airway wall, whereas budesonide is cleared more quickly from the airways. Comparative efficacy of the two major ICS/LABA combinations recommended for the treatment of COPD show similar efficacy in terms of reduction of exacerbations, improvement in forced expiratory volume in the first second (FEV1) and quality of life. One retrospective cohort study suggested a greater efficacy for the budesonide/formoterol combination on hospital or emergency department admissions, oral corticosteroid courses, and addition of tiotropium, and an observational real-life study reported a greater reduction of COPD exacerbations with budesonide/formoterol than with fluticasom/salmeterol combination. Among the potential side effects of chronic ICS treatment in patients with COPD, recently the use of fluticasone or fluticasone/salmeterol combination has been associated with a higher prevalence of pneumonia in the major long-term studies. On the other hand, no similar increased risk of pneumonia has been reported in patients with COPD treated with the budesonide/formoterol combination. A recent population based cohort study from the Quebec database showed that the adjusted odds ratio for having severe pneumonia was higher for fluticasone (2.1) than for budesonide (1.17) or other ICS (1.41). Of the ICS studied, only fluticasone demonstrated a dose-related increase in risk of pneumonia in patients with COPD. This difference between fluticasone and budesonide may be explained by the longer retention of fluticasone in the airways, with potentially greater inhibition of type-1 innate immunity. Therefore, the risk:benefit ratio should be evaluated thoroughly when choosing an ICS/LABA combination for patients with COPD. PMID- 25445927 TI - A novel mechanism of protein thermostability: a unique N-terminal domain confers heat resistance to Fe/Mn-SODs. AB - Superoxide dismutases (SODs), especially thermostable SODs, are widely applied in medical treatments, cosmetics, food, agriculture, and other industries given their excellent antioxidant properties. A novel thermostable cambialistic SOD from Geobacillus thermodenitrificans NG80-2 exhibits maximum activity at 70 degrees C and high thermostability over a broad range of temperatures (20-80 degrees C). Unlike other reported SODs, this enzyme contains an extra repeat containing N-terminal domain (NTD) of 244 residues adjacent to the conserved functional SODA domain. Deletion of the NTD dramatically decreased its optimum active temperature (OAT) to 30 degrees C and also impaired its thermostability. Conversely, appending the NTD to a mesophilic counterpart from Bacillus subtilis led to a moderately thermophilic enzyme (OAT changed from 30 to 55 degrees C) with improved heat resistance. Temperature-dependant circular dichroism analysis revealed the enhanced conformational stability of SODs fused with this NTD. Furthermore, the NTD also contributes to the stress resistance of host proteins without altering their metal ion specificity or oligomerisation form except for a slight effect on their pH profile. We therefore demonstrate that the NTD confers outstanding thermostability to the host protein. To our knowledge, this is the first discovery of a peptide capable of remarkably improving protein thermostability and provides a novel strategy for bioengineering thermostable SODs. PMID- 25445929 TI - Indacaterol and tiotropium combination therapy in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Combination therapy with a long-acting antimuscarinic agent and a long-acting beta2-agonist are recommended in chronic obstructive pulmonary disease (COPD) if control is not adequate with one long-acting bronchodilator alone. We evaluated the effects of indacaterol and tiotropium combination therapy, including the effects of adding indacaterol to tiotropium (indacaterol add-on group) and adding tiotropium to indacaterol (tiotropium add-on group). METHODS: We recruited 79 patients with COPD already treated with tiotropium or indacaterol. We undertook pulmonary function tests, the COPD assessment test (CAT), and the multi-frequency forced oscillation technique (to measure respiratory resistance and reactance) before and after 8 weeks of indacaterol and tiotropium combination therapy. RESULTS: The median age was 72.1 years and the mean forced expiratory volume in 1 s (FEV1) as a proportion of predicted was 57.2 +/- 18.3%. After 8 weeks of combination therapy, FEV1 and %predicted FEV1 had increased significantly. There was no change in CAT score. For respiratory impedance, combination therapy improved resistance at 5 Hz (R5) and resistance at 20 Hz (R20) in the whole-breath, inspiratory and expiratory phases, and resonant frequency (Fres) in the inspiratory phase. The indacaterol add-on group (43 patients) and tiotropium add-on group (36 patients) showed improvements in FEV1 and %predicted FEV1 over monotherapy, although the CAT score fell significantly in the indacaterol add-on group (p = 0.005). CONCLUSIONS: Indacaterol and tiotropium combination therapy improved airflow limitation and respiratory resistances. Adding indacaterol to tiotropium, or tiotropium to indacaterol, had similar effects on airflow limitation. PMID- 25445930 TI - Roflumilast added to triple therapy in patients with severe COPD: a real life study. AB - BACKGROUND: Roflumilast is used in severe chronic obstructive pulmonary disease (COPD) patients with frequent exacerbations. However, limited information is available on its impact in a "real-life" population that may be receiving triple therapy. OBJECTIVE: This study aimed to evaluate the effectiveness and safety of roflumilast in COPD patients already receiving triple therapy (long-acting beta agonist/inhaled corticosteroids and long-acting muscarinic antagonist). METHODS: Prospective registry that included COPD patients who were prescribed roflumilast added to triple therapy. The yearly rate of all COPD exacerbations before and after roflumilast and side effects related to the drug were registered. RESULTS: Among 55 patients prescribed 500 mg of roflumilast. Only 50.9% (n = 28) completed 1 year of therapy (roflumilast group). A reduction of all exacerbations with roflumilast was observed (2.75 +/- 0.29 vs. 3.57 +/- 0.26; P = 0.022), with a particular benefit in patients with >=4 exacerbations prior to initiating therapy (3.55 +/- 0.51 vs. 5.00 +/- 0.30; P = 0.034). Side effects (mainly gastrointestinal) and treatment discontinuation occurred in 69.1% and 49.1% of the overall population, respectively. CONCLUSIONS: Roflumilast, when added to triple therapy, reduces exacerbations in a "real-life" population of severe COPD patients with frequent exacerbations. However, side effects are more common and lead more frequently to discontinuation of therapy than has been reported in trials. PMID- 25445932 TI - Utility of animal and in vivo experimental infection of humans with rhinoviruses in the development of therapeutic agents for viral exacerbations of asthma and chronic obstructive pulmonary disease. AB - There is an association with acute viral infection of the respiratory tract and exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Although these exacerbations are associated with several types of viruses, human rhinoviruses (HRVs) are associated with the vast majority of disease exacerbations. Due to the lack of an animal species that is naturally permissive for HRVs to use as a facile model system, and the limitations associated with animal models of asthma and COPD, studies of controlled experimental infection of humans with HRVs have been used and conducted safely for decades. This review discusses how these experimental infection studies with HRVs have provided a means of understanding the pathophysiology underlying virus-induced exacerbations of asthma and COPD with the goal of developing agents for their prevention and treatment. PMID- 25445931 TI - Plp1 gene duplication inhibits airway responsiveness and induces lung inflammation. AB - Mice with Plp1 gene duplication model the most common form of Pelizaeus Merzbacher disease (PMD), a CNS disease in which patients may suffer respiratory complications. We hypothesized that affected mice would lack airway responsiveness compared to wild-type and carrier mice during methacholine challenge. Wild-type (n = 10), carrier female (n = 6) and affected male (n = 8) mice were anesthetized-paralyzed, tracheostomized and ventilated. Respiratory mechanics were recorded at baseline and during escalating doses of nebulized methacholine followed by albuterol. Lung resistance (RL) was the primary endpoint. Lung tissues were assayed for inflammatory and histological differences. At baseline, phase angles were higher in carrier and affected mice than wild-type. Dose-response RL curves in affected and carrier mice indicated a lack of methacholine response. Albuterol reduced RL in wild-type and carrier, but not affected mice. Affected mice exhibited lower interleukin (IL)-6 tissue levels and alveolar inflammatory infiltrates. Affected and carrier mice, compared to wild-type, lacked airway reactivity during methacholine challenge, but only affected mice exhibited decreased lung tissue levels of IL-6 and inflammation. PMID- 25445935 TI - International migration of health professionals and the marketization and privatization of health education in India: from push-pull to global political economy. AB - Health worker migration theories have tended to focus on labour market conditions as principal push or pull factors. The role of education systems in producing internationally oriented health workers has been less explored. In place of the traditional conceptual approaches to understanding health worker, especially nurse, migration, I advocate global political economy (GPE) as a perspective that can highlight how educational investment and global migration tendencies are increasing interlinked. The Indian case illustrates the globally oriented nature of health care training, and informs a broader understanding of both the process of health worker migration, and how it reflects wider marketization tendencies evident in India's education and health systems. The Indian case also demonstrates how the global orientation of education systems in source regions is increasingly central to comprehending the place of health workers in the global and Asian rise in migration. The paper concludes that Indian corporate health care training systems are increasingly aligned with the production of professionals orientated to globally integrated health human resource labour markets, and our conceptual analysis of such processes must effectively reflect these tendencies. PMID- 25445936 TI - The continuum from extreme conditions to the intensive care unit. PMID- 25445937 TI - Asthma: still a promising future? PMID- 25445938 TI - New horizons in pulmonary arterial hypertension management. PMID- 25445939 TI - Healthy behaviours and COPD. PMID- 25445940 TI - Lung injury related to extreme environments. PMID- 25445942 TI - A review of the Hispanic paradox: time to spill the beans? AB - Past epidemiological observations and recent molecular studies suggest that chronic obstructive pulmonary disease (COPD) and lung cancer are closely related diseases, resulting from overlapping genetic susceptibility and exposure to aero pollutants, primarily cigarette smoke. Statistics from the American Lung Association and American Cancer Society reveal that mortality from COPD and lung cancer are lowest in Hispanic subjects and generally highest in African American subjects, with mortality in non-Hispanic white subjects and Asian subjects in between. This observation, described as the "Hispanic paradox", persists after adjusting for confounding variables, notably smoking exposure and sociodemographic factors. While differences in genetic predisposition might underlie this observation, differences in diet remain a possible explanation. Such a hypothesis is supported by the observation that a diet high in fruit and vegetables has been shown to confer a protective effect on both COPD and lung cancer. In this article, we hypothesise that a diet rich in legumes may explain, in part, the Hispanic paradox, given the traditionally high consumption of legumes (beans and lentils) by Hispanic subjects. Legumes are very high in fibre and have recently been shown to attenuate systemic inflammation significantly, which has previously been linked to susceptibility to COPD and lung cancer in large prospective studies. A similar protective effect could be attributed to the consumption of soy products (from soybeans) in Asian subjects, for whom a lower incidence of COPD and lung cancer has also been reported. This hypothesis requires confirmation in cohort studies and randomised control trials, where the effects of diet on outcomes can be carefully examined in a prospective study design. PMID- 25445941 TI - Noninvasive mechanical ventilation in high-risk pulmonary infections: a clinical review. AB - The aim of this article was to review the role of noninvasive ventilation (NIV) in acute pulmonary infectious diseases, such as severe acute respiratory syndrome (SARS), H1N1 and tuberculosis, and to assess the risk of disease transmission with the use of NIV from patients to healthcare workers. We performed a clinical review by searching Medline and EMBASE. These databases were searched for articles on "clinical trials" and "randomised controlled trials". The keywords selected were non-invasive ventilation pulmonary infections, influenza-A (H1N1), SARS and tuberculosis. These terms were cross-referenced with the following keywords: health care workers, airborne infections, complications, intensive care unit and pandemic. The members of the International NIV Network examined the major results regarding NIV applications and SARS, H1N1 and tuberculosis. Cross referencing mechanical ventilation with SARS yielded 76 studies, of which 10 studies involved the use of NIV and five were ultimately selected for inclusion in this review. Cross-referencing with H1N1 yielded 275 studies, of which 27 involved NIV. Of these, 22 were selected for review. Cross-referencing with tuberculosis yielded 285 studies, of which 15 involved NIV and from these seven were selected. In total 34 studies were selected for this review. NIV, when applied early in selected patients with SARS, H1N1 and acute pulmonary tuberculosis infections, can reverse respiratory failure. There are only a few reports of infectious disease transmission among healthcare workers. PMID- 25445943 TI - The changing landscape of pulmonary arterial hypertension and implications for patient care. AB - Registries have provided a wealth of information on the clinical and disease characteristics of patients living with pulmonary arterial hypertension (PAH) since the 1980s. Certain PAH demographics, such as the prevalence of various PAH subgroups and preponderance of female patients, appear to have remained stable over time. Contemporary registry data indicate that the average age of patients diagnosed with PAH has increased, at least in the Western world. Older patients with PAH are more likely to be diagnosed with a more advanced stage of the disease, have lower exercise capacity and present with multiple comorbidities. They also have worse survival compared with younger patients. Within the PAH population, there is also a subset of patients with a lower diffusing capacity of the lung for carbon monoxide who are generally older and display more severe disease characteristics. This review discusses the implications that the increased age of the PAH population at diagnosis has on the treatment and management of the disease, as well as the need for earlier and improved diagnosis in these patients. PMID- 25445944 TI - Physicians' and patients' expectations of therapies for pulmonary arterial hypertension: where do they meet? AB - In recent years, many new, effective therapies for pulmonary arterial hypertension (PAH) have become available and are widely used, yet the long-term prognosis for patients with PAH remains poor. In the absence of a cure, physicians' expectations of PAH-specific therapies are to: 1) improve patients' symptoms and functional capacity; 2) slow disease progression; and 3) improve survival. However, patients with PAH may prioritise other more tangible needs, such as improvements in their ability to carry out their daily tasks and increase their quality of life. Patients with PAH have also called out for social and emotional support from their physicians, caregivers, families and patient associations. Therefore, it is necessary that clinical trials of PAH-specific treatments include end-points that are meaningful to both patients and physicians, and that a multidisciplinary approach to the management of patients with PAH takes into consideration the broader aspects of patients' and caregivers' needs and wishes beyond simple physiological measurements. PMID- 25445945 TI - The role of combination therapy in managing pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a complex, progressive disease with several pathobiological mechanisms, including the endothelin, nitric oxide and prostacyclin pathways. Current treatments for PAH target one of these pathways and, in more severe cases or instances of disease worsening, may be combined with a view to target multiple pathways in parallel. Treatment combination is performed sequentially (as an intensification from initial monotherapy) or upfront (use of two or more therapies in treatment-naive patients). Whilst combination therapy has been historically considered to be an option for the treatment of PAH, supporting evidence was typically limited to expert opinion, clinical experience and registry data. Data from randomised controlled trials on sequential combination therapy in particular has grown in recent years, resulting in a change in the level of recommendations in the latest update to the PAH treatment algorithm. However, short-term trials have shown inconsistent results, and have not been powered to assess morbidity/mortality outcomes. More recent data from long-term trials suggest a potential clinical benefit associated with sequential combination therapy. In this review we will introduce the concept of combination therapy, consider the latest evidence for both sequential and upfront combination therapy, and discuss additional considerations when initiating combination therapy in clinical practice. PMID- 25445946 TI - The right ventricle in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a right heart failure syndrome. In early stage PAH, the right ventricle tends to remain adapted to afterload with increased contractility and little or no increase in right heart chamber dimensions. However, less than optimal right ventricular (RV)-arterial coupling may already cause a decreased aerobic exercise capacity by limiting maximum cardiac output. In more advanced stages, RV systolic function cannot remain matched to afterload and dilatation of the right heart chamber progressively develops. In addition, diastolic dysfunction occurs due to myocardial fibrosis and sarcomeric stiffening. All these changes lead to limitation of RV flow output, increased right-sided filling pressures and under-filling of the left ventricle, with eventual decrease in systemic blood pressure and altered systolic ventricular interaction. These pathophysiological changes account for exertional dyspnoea and systemic venous congestion typical of PAH. Complete evaluation of RV failure requires echocardiographic or magnetic resonance imaging, and right heart catheterisation measurements. Treatment of RV failure in PAH relies on: decreasing afterload with drugs targeting pulmonary circulation; fluid management to optimise ventricular diastolic interactions; and inotropic interventions to reverse cardiogenic shock. To date, there has been no report of the efficacy of drug treatments that specifically target the right ventricle. PMID- 25445948 TI - The challenges in paediatric pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a rare, progressive disease affecting both adults and children. While overall survival has improved in recent years, the need for improved therapeutic approaches remains. Treatments for paediatric PAH have not yet been sufficiently examined, particularly regarding potential toxicities and optimal dosing, and there is a lack of appropriate clinical trial end-points and validated treatment goals that might enable a goal-oriented therapeutic approach. Adult randomised controlled trials in PAH are demonstrating a shift towards more long-term designs, focusing on mortality and morbidity end points rather than changes in 6-min walking distance. However, such trial designs may not be feasible within the paediatric setting due to challenges such as sufficient recruitment and retention of paediatric patients. Consideration should, therefore, be given towards identifying optimal end-points for the paediatric population, allowing sufficient duration to evaluate efficacy and safety of potential treatments. Herein we consider some of the complexities involved in the management of paediatric PAH, specifically presenting diagnostic challenges as well as reflecting on the lack of evidence currently available to support various therapeutic approaches within the paediatric population. PMID- 25445947 TI - Severe pulmonary arterial hypertension: treatment options and the bridge to transplantation. AB - Pulmonary arterial hypertension (PAH) is a rare disease leading to right heart failure and death. Prognosis remains poor, particularly for patients with severe disease, i.e. World Health Organization functional class IV. There have been significant improvements in treatment options. Several agents are available that target the three main established PAH disease pathways, and can be combined sequentially or upfront. Strong scientific evidence supports the use of intravenous epoprostenol in severe PAH; however, despite recommendations, many patients do not receive parenteral prostanoids and there is a lack of evidence from randomised clinical trials supporting the value of other PAH medications alone in severe PAH. Lung transplantation is an important option in patients with severe PAH who have not responded sufficiently to therapy, or who have worsened despite maximal treatment. Bridging techniques are available for patients who worsen while awaiting transplantation. The type of bridging technique used depends on various factors including patient illness severity, physician experience and the anticipated waiting time for transplantation. With the aim to facilitate the treatment decision-making process, herein we review the medical treatment options available for patients with severe PAH, and the bridging techniques that may be used to sustain patients awaiting transplantation. PMID- 25445949 TI - Connective tissue disease associated with pulmonary arterial hypertension: management of a patient with severe haemodynamic impairment. PMID- 25445950 TI - Bronchial thermoplasty: a new therapeutic option for the treatment of severe, uncontrolled asthma in adults. AB - Bronchial thermoplasty is a young yet promising treatment for severe asthma whose benefit for long-term asthma control outweighs the short-term risk of deterioration and hospitalisation in the days following the treatment. It is an innovative treatment whose clinical efficacy and safety are beginning to be better understood. Since this is a device-based therapy, the overall evaluation of risk-benefit is unlike that of pharmaceutical products; safety aspects, regulatory requirements, study design and effect size assessment may be unfamiliar. The mechanisms of action and optimal patient selection need to be addressed in further rigorous clinical and scientific studies. Bronchial thermoplasty fits in perfectly with the movement to expand personalised medicine in the field of chronic airway disorders. This is a device-based complimentary asthma treatment that must be supported and developed in order to meet the unmet needs of modern severe asthma management. The mechanisms of action and the type of patients that benefit from bronchial thermoplasty are the most important challenges for bronchial thermoplasty in the future. PMID- 25445951 TI - Overview of current lung imaging in acute respiratory distress syndrome. AB - Imaging plays a key role in the diagnosis and follow-up of acute respiratory distress syndrome (ARDS). Chest radiography, bedside lung ultrasonography and computed tomography scans can provide useful information for the management of patients and detection of prognostic factors. However, imaging findings are not specific and several possible differential diagnoses should be taken into account. Herein we will review the role of radiological techniques in ARDS, highlight the plain radiological and computed tomography findings according to the pathological stage of the disease (exudative, inflammatory and fibroproliferative), and summarise the main points for the differential diagnosis with cardiogenic oedema, which is still challenging in the acute stage. PMID- 25445952 TI - Hypoxaemia during pregnancy: pulmonary arteriovenous dilatation as a likely cause. PMID- 25445953 TI - Pulmonary hypertension associated with Whipple disease. PMID- 25445955 TI - Fibroblasts feeder niche and Flt3 Ligand as a novel inducer of plasmacytoid dendritic cells development in vitro. AB - Plasmacytoid dendritic cell (pDC), plays central role in antiviral immunity. The aim of this study was to assess the effect of Flt3 ligand (FL) alone or with L929 fibroblast feeder or L929 conditioned media on differentiation of mouse bone marrow (BM) cells into pDC in vitro. Murine BM cells were cultured with FL or with L929 or conditioned media for 9days. The differentiated cells were analyzed using flow cytometry for PDCA-1, B220 and CXCR4. The relative expression of Stat3, CXCR4, CXCR7, IFN-beta, TGF-beta and Runx2 in differentiated cells determined by real time PCR. The development of pDC showed up to 19% increase after co-culture of BM cells with fibroblast feeder. Upregulation of Stat3, Runx2 and CXCR4 due to the presence of fibroblast feeder with FL in culture results in improved pDC development. Furthermore, 30% L929 supernatant along with Flt3 ligand was able to derive pDC up to 8.9% in comparison with FL alone, which was 6.6% in vitro. Thus, for the first time we introduced L929 fibroblast feeder as a niche producer of M-CSF and probably other growth factors and chemokines, which promotes the development of pDC in vitro along with FL, similar to in vivo niche. PMID- 25445956 TI - Oral immunization with recombinant hepatitis E virus antigen displayed on the Lactococcus lactis surface enhances ORF2-specific mucosal and systemic immune responses in mice. AB - Hepatitis E virus (HEV) as a recognized zoonotic pathogen has posed global burden on public health, which is exacerbated by lack of efficient vaccine. In this study, we constructed a recombinant (inaQ-ORF2 gene fusion) Lactococcus lactis (L. lactis) strain NZ3900 that expresses and displays the hepatitis E virus antigen ORF2 utilizing an ice uncleation protein-based anchor system. After oral vaccination of BALB/c mice, significantly higher levels of ORF2-specific mucosal IgA and serum IgG were detected and cellular immunity was also induced. These findings further support that L. lactis-based HEV antigen vaccines could be used for human and animal protection against infection. PMID- 25445957 TI - The effects of a humanized recombinant anti-cocaine monoclonal antibody on the disposition of cocaethylene in mice. AB - The chimeric human/mouse anti-cocaine monoclonal antibody (mAb) 2E2 and its further humanized variant h2E2 have been reported to sequester a significant portion of cocaine in plasma and decrease cocaine concentrations in the brain in mice and rats. However, many cocaine users co-abuse alcohol, leading to the formation of the centrally active metabolite cocaethylene. This potentially compromises the efficacy of a cocaine-specific immunotherapy. Because h2E2 has high affinity for cocaethylene as well as cocaine, the ability of h2E2 to prevent cocaethylene entry into the brain was investigated. Mice were infused with h2E2 (1.6 MUmol/kg i.v.) or vehicle and after one hour were injected with cocaethylene fumarate (1.2 MUmol/kg i.v.). At times from 45 s to 60 min, brain and plasma were collected and cocaethylene concentrations were measured using GC/MS. In control mice, a two-compartment pharmacokinetic model generated values for cocaethylene distribution and terminal elimination half-lives of 0.5 and 8.1 min respectively. Initial plasma cocaethylene concentrations increased 13-fold from controls in the presence of h2E2. In brain, h2E2 produced a 92% decrease in the area under the time-concentration curve for cocaethylene. The pharmacokinetics of h2E2 was also characterized in detail. A three-compartment model resolved an initial distribution half-life of 4.4 min and a second distribution half-life of 4.2 h, and a terminal elimination half-life of 7.8 days. The ability of h2E2 to protect the brain from both cocaine and cocaethylene predicts that the clinical efficacy of h2E2 will be retained in cocaine users who co-abuse alcohol. PMID- 25445958 TI - Staphylococcus aureus enterotoxins A and B inhibit human and mice eosinophil chemotaxis and adhesion in vitro. AB - Staphylococcus aureus aggravates the allergic eosinophilic inflammation. We hypothesized that Staphylococcus aureus-derived enterotoxins directly affect eosinophil functions. Therefore, this study investigated the effects of Staphylococcal enterotoxins A and B (SEA and SEB) on human and mice eosinophil chemotaxis and adhesion in vitro, focusing on p38 MAPK phosphorylation and intracellular Ca(2+) mobilization. Eosinophil chemotaxis was evaluated using a microchemotaxis chamber, whereas adhesion was performed in VCAM-1 and ICAM-1 coated plates. Measurement of p38 MAPK phosphorylation and intracellular Ca(2+) levels were monitored by flow cytometry and fluorogenic calcium-binding dye, respectively. Prior incubation (30 to 240 min) of human blood eosinophils with SEA (0.5 to 3 ng/ml) significantly reduced eotaxin-, PAF- and RANTES-induced chemotaxis (P<0.05). Likewise, SEB (1 ng/ml, 30 min) significantly reduced eotaxin-induced human eosinophil chemotaxis (P<0.05). The reduction of eotaxin induced human eosinophil chemotaxis by SEA and SEB was prevented by anti-MHC monoclonal antibody (1 MUg/ml). In addition, SEA and SEB nearly suppressed the eotaxin-induced human eosinophil adhesion in ICAM-1- and VCAM-1-coated plates. SEA and SEB prevented the increases of p38 MAPK phosphorylation and Ca(2+) levels in eotaxin-activated human eosinophils. In separate protocols, we evaluated the effects of SEA on chemotaxis and adhesion of eosinophils obtained from mice bone marrow. SEA (10 ng/ml) significantly reduced the eotaxin-induced chemotaxis along with cell adhesion to both ICAM-1 and VCAM-1-coated plates (P<0.05). In conclusion, the inhibition by SEA and SEB of eosinophil functions (chemotaxis and adhesion) are associated with reductions of p38 MAPK phosphorylation and intracellular Ca(2+) mobilization. PMID- 25445959 TI - NF-kappaB activation and proinflammatory cytokines mediated protective effect of Indigofera caerulea Roxb. on CCl4 induced liver damage in rats. AB - Indigofera caerulea Roxb. is a well known shrub among native medical practitioners in folk medicine used for the treatment of jaundice, epilepsy, night blindness and snake bites. It is also reported to have antioxidant and antimicrobial properties. However its actual efficacy and hepatoprotective mechanism in particular is uncertain. Thus the present study investigates the hepatoprotective effect of the methanolic extract of I. caerulea Roxb. leaves (MIL) and elucidation of its mode of action against carbon tetrachloride (CCl4) induced liver injury in rats. HPLC analysis of MIL when carried out showed peaks close to standard ferulic acid and quercetin. Intragastric administration of MIL up to 2000 mg/kg bw, didn't show any toxicity and mortality in acute toxicity studies. During "in-vivo" study, hepatic injury was established by intraperitoneal administration of CCl4 3 ml/kg bw (30% CCl4 in olive oil; v/v) twice a week for 4 weeks in Sprague-Dawley rats. Further, hepatoprotective activity of MIL assessed using two different doses (100 and 200mg/kg bw) showed that intra-gastric administration of MIL (200mg/kg bw) significantly attenuates liver injury. Investigation of the underlying mechanism revealed that MIL treatment was capable of reducing inflammation by an antioxidant defense mechanism that blocks the activation of NF-kappaB as well as inhibits the release of proinflammatory cytokine TNF-alpha and IL-1beta. The results suggest that MIL has a significant hepatoprotective activity which might be due to the presence of phytochemicals namely analogues of ferulic acid and other phytochemicals which together may suppress the inflammatory signaling pathways and promote hepatoprotective activity against CCl4 intoxicated liver damage. PMID- 25445960 TI - Higenamine promotes M2 macrophage activation and reduces Hmgb1 production through HO-1 induction in a murine model of spinal cord injury. AB - Spinal cord injury (SCI) is considered to be primarily associated with loss of motor function and leads to the activation of diverse cellular mechanisms in the central nervous system to attempt to repair the damaged spinal cord tissue. Higenamine (HG) (1-[(4-hydroxyphenyl) methyl]-1,2,3,4-tetrahydroisoquinoline-6,7 diol), an active ingredient of Aconiti Lateralis Radix Praeparata, has been traditionally used as a heart stimulant and anti-inflammatory agent in oriental countries. However, the function and related mechanism of HG on SCI have never been investigated. In our current study, HG treatment displayed increased myelin sparring and enhanced spinal cord repair process. The numbers of CD4(+) T cells, CD8(+) T cells, Ly6G(+) neutrophils and CD11b(+) macrophages were all significantly lower in the HG-treated group than that in the control group after SCI. HG administration increased the expression of IL-4 and IL-10 and promoted M2 macrophage activation. Significantly reduced Hmgb1 expression was also observed in HG-treated mice with SCI. Furthermore, HG treatment promoted HO-1 production. The increased number of M2 macrophages, decreased expression of Hmgb1 and promoted locomotor recovery induced by HG were all reversed with additional HO-1 inhibitor treatment. In conclusion, HG promotes M2 macrophage activation and reduces Hmgb1 expression dependent on HO-1 induction and then promotes locomotor function after SCI. PMID- 25445961 TI - Iminosugar derivative WGN-26 suppresses acute allograft rejection via inhibiting the IFN-gamma/p-STAT1/T-bet signaling pathway. AB - This study aimed to investigate the effect of the iminosugar derivative WGN-26 on suppressing acute allograft rejection and to explore the underlying mechanisms. The results demonstrated that WGN-26 (12, 6 and 3mg/kg) significantly prolonged the skin allograft survival time in a dose-dependent manner and minimized the pathological changes. The minimum lethal dose was 320 mg/kg. By exploring the potential cellular and molecular mechanisms, we found that WGN-26 dose dependently inhibited T lymphocyte proliferation, as determined through the single mixed lymphocyte reaction (sMLR) or the ConA-induced T cell proliferation assay in allograft recipients. The FCM results indicated that WGN-26 particularly reduced the percentage of CD3(+)CD4(+) T cells in allograft recipients. After treatment with WGN-26, the secretion of IFN-gamma in allograft recipients was lowered, whereas the IL-4 and IL-17 levels remained stable. Furthermore, we found that WGN-26 inhibited the phosphorylation of STAT1 and accelerated the degradation of T-bet protein in allograft recipients. This study provides the first report that the iminosugar derivative WGN-26 dose-dependently prolongs skin allograft survival and that the possible mechanism is mediated by inhibiting CD4(+) T cell proliferation and suppressing the IFN-gamma/p-STAT1/T-bet signaling pathway. PMID- 25445962 TI - Blockade of p38 mitogen-activated protein kinase pathway ameliorates delayed gastric emptying in streptozotocin-induced diabetic rats. AB - BACKGROUND AND AIM: Gastrointestinal dysfunction is one of the major complications of diabetes. The roles of inflammation in diabetes and its associated complications are increasingly recognized. p38 mitogen-activated protein kinase (MAPK) has been shown to be involved in the production of pro inflammatory mediators. The aims of this study were to investigate the effects of SB203580, a specific p38 MAPK inhibitor, on delayed gastric emptying in diabetic rats and to elucidate its possible mechanism. METHODS: SB203580 was administered in diabetic rats induced by intraperitoneal injection of streptozotocin. The gastric emptying rate of rats was measured by using phenol red solution, and blood glucose levels and body weights were observed. p38 MAPK activity and iNOS expression were assessed by Western blot analysis. The expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta were determined by enzyme linked immunosorbent assay. RESULTS: Gastric emptying was delayed significantly in diabetic rats and improved significantly with SB203580; high glucose significantly activated p38 MAPK and increased the expression of iNOS, TNF-alpha and IL-1beta. The administration of SB203580 led to a significant decrease in the activation of p38 MAPK and the expression of iNOS, TNF-alpha and IL-1beta. CONCLUSIONS: Inflammation was associated with the development of delayed gastric emptying, and blockade of p38 MAPK pathway with SB203580 ameliorates delayed gastric emptying in diabetic rats, at least in part, by inhibiting the expression of iNOS, TNF-a and IL-1beta. Therefore, p38MAPK may serve as a novel target for the therapy of diabetes-related gastrointestinal dysmotility. PMID- 25445963 TI - Rosiglitazone impedes Porphyromonas gingivalis-accelerated atherosclerosis by downregulating the TLR/NF-kappaB signaling pathway in atherosclerotic mice. AB - Porphyromonas gingivalis,a predominant periodontal pathogen, is known to accelerate atherosclerosis in hyperlipidemic animals via aberrant inflammatory responses. Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have been reported to exert anti-inflammatory effects in vitro. The purpose of the present study was to investigate the potential protective role of the PPARgamma agonist rosiglitazone in pathogen accelerated atherosclerosis in an apolipoprotein E-deficient (ApoE-/-) mouse model. ApoE-/- mice were inoculated intravenously with live P. gingivalis (strain 33277) or the buffer vehicle and treated with rosiglitazone or saline over a 10-week period. Their atherosclerotic status in aortic artery was assessed through histomorphometric analysis, inflammatory agent and lipid profiles in blood was determined by ELISA, and levels of relevant cytokines and Toll-like receptors (TLRs) in aortic tissues were evaluated using immunohistochemistry and quantitative PCR. P. gingivalis inoculation was associated with increased atherosclerotic plaque formation in the aorta and higher levels of serum pro-inflammatory cytokines (tumor necrosis factor-alpha, monocyte chemotactic protein-1 and interleukin-1beta), but the serum lipid profile was not affected by P. gingivalis infection. Levels of tumor necrosis factor-alpha, monocyte chemotactic protein-1 intercellular cell adhesion molecule-1 and TLRs were higher in the aortic tissues of mice exposed to P. gingivalis, and activation of nuclear factor-kappaB was also observed. In both P. gingivalis-treated and -untreated ApoE-/- mice, rosiglitazone treatment was associated with less atherosclerotic plaque formation; lower serum inflammatory cytokines, total cholesterol, and low density lipoprotein cholesterol; higher levels of PPARgamma, lower amounts of TLR2/4 and downregulated nuclear factor kappaB activity in aortic tissues. These findings suggest that rosiglitazone mitigates or prevents P. gingivalis-accelerated atherosclerosis by inhibiting the inflammatory response via downregulation of the TLR/ nuclear factor-kappaB signaling pathway. PMID- 25445964 TI - Adjunctive dexamethasone therapy improves lung injury by inhibiting inflammation and reducing RIP3 expression during Staphylococcus aureus pneumonia in mice. AB - Antibiotic-induced immunopathology associated with the release of bacterial cell wall components has been suggested to contribute to poor outcomes in bacterial pneumonia. Adjunctive systemic glucocorticoid steroid (GC) therapy for pneumonia has been a controversial issue. In the present study, we first found that dexamethasone (2.5 mg/kg/day) in combination with oxacillin was beneficial for improving lung injury in mice inoculated intratracheally with live Staphylococcus aureus, and did not interfere with bacterial clearance. Alleviation of lung injury was evidenced by attenuated lung pathology, reduced total protein levels, soluble receptor for advanced glycation end-products (sRAGE), tumor necrosis factor alpha (TNF-alpha), and keratinocyte chemoattractant (KC) and interleukin (IL)-6 in bronchoalveolar lavage fluid (BALF). It was further confirmed by inhibition of receptor interacting protein-3 (RIP3) expression in pulmonary tissues. As in the live S. aureus experiments, dexamethasone (2.5 mg/kg/day) improved lung injury in mice challenged with heat-killed S. aureus (HKSA). In conclusion, our results demonstrated that an appropriate dose of adjunctive dexamethasone (2.5 mg/kg/day) with oxacillin alleviated experimental S. aureus induced lung injury via its inhibition of inflammatory cytokine release and RIP3 expression. PMID- 25445965 TI - 5-Hydroxymethylfurfural, an antioxidant agent from Alpinia oxyphylla Miq. improves cognitive impairment in Abeta 1-42 mouse model of Alzheimer's disease. AB - 5-Hydroxymethylfurfural (5-HMF) is a main effective compound of Alpinia oxyphylla Miq. ethanol extract, which showed memory improvement activity against Alzheimer's disease in previous study. In order to identify a potential therapeutic agent, the neuroprotective effects of 5-HMF on impairment of cognition and memory function induced by intracerebroventricular (ICV) injection of Abeta 1-42 were investigated in vivo. The mice were treated with 5-HMF at dose of 15 MUg/kg and 150 MUg/kg (ICV) for five consecutive days after ICV-Abeta 1-42. The results showed that 5-HMF significantly ameliorated learning and memory impairment evaluated by the locomotor activity, Y-maze test, and Morris water maze test. Furthermore, 5-HMF significantly inhibited the beta-secretase activity, decreased the content of Abeta 1-42 and malondialdehyde (MDA), and increased the antioxidative enzyme activities including superoxide dismutase (SOD) and glutathione peroxidase (GPx). Results of hippocampus slices showed that neuronal were integrated and regularly arranged in the groups which were administered along with 5-HMF, indicating that 5-HMF could mitigate the degree of neuronal damage. The present study indicated that 5-HMF may serve as a potential therapeutic agent for the treatment of Alzheimer's disease. PMID- 25445966 TI - New compound, 5-O-isoferuloyl-2-deoxy-D-ribono-gamma-lacton from Clematis mandshurica: Anti-inflammatory effects in lipopolysaccharide-stimulated BV2 microglial cells. AB - Microglia are main immune cells to exacerbate neural disorders in persistent overactivating. Therefore, it is a good strategy to regulate microglia for the treatment of neural disorders. In the present study, we isolated and characterized a novel compound, 5-O-isoferuloyl-2-deoxy-D-ribono-gamma-lacton (5 DRL) from Clematis mandshurica, and evaluated its anti-inflammatory effect in lipopolysaccharide (LPS)-treated BV2 microglial cells. 5-DRL inhibited the expression of LPS-stimulated proinflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2), as well as their regulatory genes inducible NO syntheses (iNOS) and cyclooxygenase-2 (COX-2). 5-DRL also downregulated the LPS induced DNA-binding activity of nuclear factor-kappaB (NF-kappaB) through suppression of the nuclear translocation of the NF-kappaB subunits, p65 and p50. Consistent with the inhibition of iNOS and COX-2 via NF-kappaB activity with 5 DRL, an inhibitor of NF-kappaB, pyrrolidine dithiocarbamate (PDTC), also led to the suppression of LPS-induced iNOS and COX-2 expression. Additionally, 5-DRL corresponding with antioxidants, N-acetylcysteine (NAC) and glutathione (GSH), remarkably inhibited reactive oxygen species (ROS) generation. Both NAC and GSH, thus attenuated the expression of iNOS and COX-2 by suppressing NF-kappaB activation, indicating that 5-DRL suppresses LPS-induced iNOS and COX-2 expression through downregulation of the ROS-dependent NF-kappaB signaling pathway. The present study also indicated that 5-DRL suppresses NO and PGE2 production by inducing heme oxygenase-1 (HO-1) via nuclear factor erythroid 2 related factor 2 (Nrf2). Taken together, the present data indicate that 5-DRL attenuates the production of proinflammatory mediators such as NO and PGE2 as well as their regulatory genes in LPS-stimulated BV2 microglial cells by inhibiting ROS-dependent NF-kappaB activation and stimulating the Nrf2/HO-1 signal pathway. These data may be implicated in the application of 5-DRL in LPS stimulated inflammatory disease. PMID- 25445967 TI - Suppressive effects of 1-[4-fluoro-2-(2-nitrovinyl)phenyl]pyrrolidine on the Toll like receptor signaling pathways. AB - When various pathogens invade a host, toll-like receptors (TLRs) play a significant role in recognizing the pathogen-associated molecular patterns carried by the pathogens to induce innate immune reaction, followed by acquired immunity reaction. TLRs have two downstream signaling pathways, the myeloid differential factor 88 (MyD88)-dependent and toll-interleukin-1 receptor domain containing adapter inducing interferon-beta (TRIF)-dependent pathways. To evaluate the therapeutic potential of 1-[4-fluoro-2-(2 nitrovinyl)phenyl]pyrrolidine (FPP), previously synthesized in our laboratory, its effect on signal transduction via the TLR signaling pathways was examined. FPP inhibited the activation of nuclear factor-kappaB (NF-kappaB) and interferon regulatory factor 3 (IRF3) induced by TLR agonists, as well as inhibited the expression of cyclooxygenase-2, inducible nitric oxide synthase, and interferon inducible protein-10. FPP also inhibited the activation of NF-kappaB and IRF3 when induced by the overexpression of downstream signaling components of the TLRs. As a result, FPP has potential to become a new therapeutic drug for many inflammatory diseases. PMID- 25445968 TI - CapsMorph(r) technology for oral delivery--theory, preparation and characterization. AB - The CapsMorph((r)) technology prepares amorphous drugs for oral delivery by encapsulating them into porous materials. Hesperidin as model compound was loaded onto AEROPERL((r)) 300 Pharma using the wetness impregnation method. Hesperidin was dissolved in dimethyl sulfoxide (DMSO) and alternatively in DMSO with addition of Tween 80. The drug solutions were added dropwise to the porous material and subsequently DMSO was evaporated. The AEROPERL((r)) 300 Pharma could be loaded with about 30% hesperidin in the amorphous form. Amorphous state was verified by X-ray diffraction and differential scanning calorimetry. The CapsMorph((r)) formulation was compared regarding properties determining oral bioavailability, i.e., kinetic saturation solubility and dissolution rate to raw drug powder and hesperidin nanocrystals. The saturation solubility of CapsMorph((r)) without Tween 80 was 654 MUg/ml, which is 36-fold higher than the raw drug powder (18 MUg/ml) and about 20 times higher than nanocrystals (30 MUg/ml). In vitro release was faster (100% in 10 min at pH 6.8) compared to dissolution of nanocrystals with about 15%. Addition of Tween 80 to CapsMorph((r)) lowered the solubility (168 MUg/ml) and slowed down the release, but provided longer times of supersaturation without precipitation of drug. Based on these data, it appears that drug loaded porous materials provide better formulations compared to nanocrystals for poorly soluble drugs. PMID- 25445969 TI - Authors' response to the letter from Kalleian Eserian et al. AB - This letter is a response to the comments of Kalleian Eserian et al. on our study relating to the accuracy, precision and sustainability of six tablet splitters and a kitchen knife as an alternative to breaking paracetamol 500mg tablets by hand. We would like to inform the readers of International Journal of Pharmaceutics that our study focused on splitting tablets with a mechanical tool rather than breaking tablets by hand. Although publications on hand breaking tablets were not cited for this reason, we are familiar with the conclusions of these publications. This is especially true for the publications that were written by direct colleagues from the department of the corresponding author e.g., Van Santen et al. and Van der Steen et al. PMID- 25445970 TI - A new topical formulation for psoriasis: development of methotrexate-loaded nanostructured lipid carriers. AB - The aim of the present work was to develop and assess the potential of nanostructured lipid carriers (NLCs) loaded with methotrexate as a new approach for topical therapy of psoriasis. Methotrexate-loaded NLCs were prepared via a modified hot homogenization combined with ultrasonication techniques using either polysorbate 60 (P60) or 80 (P80) as surfactants. The produced NLCs were within the nanosized range (274-298 nm) with relatively low polydispersity index (<0.25) and zeta potential values around -40 mV. NLCs demonstrated storage stability at 25 degrees C up to 28 days. The entrapment efficiency of methotrexate in NLC-P60 and -P80 was ~65%. Cryo-SEM images showed the spherical shape of the empty and methotrexate-loaded NLCs. FT-IR confirmed methotrexate presence within the NLCs. The in vitro release of methotrexate from the NLCs followed a fast release pattern reaching ~70% in 2h. In vitro skin penetration study demonstrated that methotrexate-loaded NLCs-P60 had higher skin penetration when compared to free methotrexate, suggesting a significant role of drug-nanocarriers on topical administration. Methotrexate-loaded NLC-P60 provided drug fluxes of 0.88 MUg/cm(2)/h, higher (P<0.001) than with the free drug (control, 0.59 MUg/cm(2)/h). The results indicate the potential of NLCs for the delivery of methotrexate to topical therapy of psoriasis. PMID- 25445971 TI - Nanonization of curcumin by antisolvent precipitation: process development, characterization, freeze drying and stability performance. AB - The present work aims to investigate applicability of antisolvent precipitation method for preparation of nanosized curcumin and to control their characteristics by determining the influence of process and solvents on solid-state properties of curcumin nanoparticles. Effects of different experimental parameters on particle size were investigated using dynamic light scattering. Particle morphology was studied using SEM. Drug content in stabilized nanoparticles was determined using HPLC. Residual moisture content after lyophilisation was determined using Karl Fischer method and solid state properties were investigated using DSC, TGA, FTIR and powder-XRD. The resulting product showed a high drug load and contained the drug in amorphous form. The particle diameters of prepared curcumin nanoparticles were found in the range of 100-200 nm. In vitro drug release studies indicated a sustained release profile of curcumin from the nanoparticles. Antisolvent precipitation produced amorphous curcumin nanoparticles whose size and morphology could be controlled using gelatine as stabilizer. Lyophilized curcumin nanoparticles with d-sorbitol as lyoprotectant possessed good redispersibility and showed up to 4 times faster in vitro curcumin release rate than that of unprocessed curcumin. Stability tests (at 2-8 degrees C and ambient conditions) indicated that the product was stable for up to 6 months of storage. PMID- 25445972 TI - Lipid based nanocarrier system for the potential oral delivery of decitabine: formulation design, characterization, ex vivo, and in vivo assessment. AB - The aim of this study was to design and fabricate nanostructured lipid carrier (NLC) for the potential oral delivery of decitabine (DCB). NLC was prepared by cold homogenization technique and optimized by the Box-Behnken experimental design. It was further characterized by particle size, zeta potential, transmission electron microscopy (TEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), in vitro release study, and stability study. Moreover, ex vivo and in vivo efficacy of the NLC was assessed by gut permeation study, gamma scintigraphy imaging, and MTT assay. NLC was found to have particle size (116.64 +/- 6.67 nm), zeta potential ( 31.8 +/- 0.96 mV) and sustained drug release (80.23 +/- 4.67%) up to 24h. TEM and AFM proved that the particles were spherical in shape and smooth surface. DSC and XRD studies had demonstrated the reduced crystallinity and stability enhancing effect of the NLC. Stability studies revealed the changes in the observed parameters up to 45 days were not significantly differences (p>0.05). Ex vivo gut permeation study showed 4-folds increment in the permeation of drug compared with the plain drug solution. gamma Scintigraphy imaging and MTT assay results inferred that DCB loaded NLC possesses excellent cytotoxic activity against cancer cells. Thus, NLC holds high potential for the oral delivery of DCB to treat cancer cells and future prospects for the industrial purpose. PMID- 25445973 TI - Defining cisplatin incorporation properties in thermosensitive injectable biodegradable hydrogel for sustained delivery and enhanced cytotoxicity. AB - Injectable thermoreversible chitosan (CS)/beta-glycerophosphate (beta-GP) hydrogels were developed for prolonged localized delivery of cisplatin (Cis). The effects of formulation variables on the thermoreversible hydrogels preparation as well as the impact of drug incorporation method on Cis release were studied. Antitumor activity of Cis CS/beta-GP thermoreversible hydrogels were evaluated against HCT-116 human colorectal cancer cells and MCF-7 human breast cancer cells. Incorporation of Cis to CS solution adjusted at pH 6.2 prior to hydrogel preparation deemed necessary to achieve a sustained release up to 4 days. Cis loaded CS/beta-GP thermoreversible hydrogels showed enhanced antitumor activity with about 1.2 fold and 2.05 fold that of Cis solution against HCT-116 cancer cells and MCF-7 cancer cells respectively. The obtained enhanced antitumor activity elected this delivery system for further in vivo and toxicological investigations. PMID- 25445974 TI - Novel in situ gelling ocular films for the opioid growth factor-receptor antagonist-naltrexone hydrochloride: fabrication, mechanical properties, mucoadhesion, tolerability and stability studies. AB - Naltrexone hydrochloride (NTX) is an innovative drug used in ophthalmology for treatment of ocular surface diseases such as impaired corneal wound healing and severe dry eye. Poor chemical stability has been a major limitation for development of NTX in solution form. The aim of this study was to develop and characterise NTX in situ ocular films for enhanced chemical stability and improved ocular tolerability. The films were prepared from different amorphous polymers and characterised for physicochemical compatibility, moisture-sorption, surface pH, mechanical properties, sterilisability, surface morphology, mucoadhesion, in vitro release, conjunctival irritation and accelerated stability at 40 degrees C/75% relative humidity for 3 months. Glycerin (GLY)-plasticised films exhibited significantly better mechanical properties, compared with polyethylene glycol (PEG) 400 and triethylcitrate (TEC)-plasticised formulations. Superior mucoadhesion was recorded for F7 and F9 plasticised with GLY and PEG 400, respectively. The stability of NTX was significantly enhanced more than 18 times, compared with the solution form. Combination of carboxymethylcellulose sodium (CMC) and sodium alginate (ALG) in a film formulation demonstrated minimal % moisture sorption, good mechanical properties, in vitro release, excellent chemical stability and minimal conjunctival irritation lending them as promising ocular formulations. PMID- 25445975 TI - Development of multicore hybrid particles for drug delivery through the precipitation of CO2 saturated emulsions. AB - Hybrid lipid-polymer particles are gaining increasing interest to be applied as drug delivery systems due to their greater stability in biological fluids and enhanced cellular uptake of drugs. However, a major drawback is the fact that these particles are usually produced through techniques that use organic solvents. This work studies the possibility of producing for the first time hybrid particles composed by lipid multicores enveloped in a polymeric layer through Particles from Gas Saturated Solutions (PGSS((r))), without using organic solvents. An oil-in-water emulsion, composed by Gelucire 43/01TM (GEL) as the discontinuous phase and by an aqueous polyethylene glycol 4000 (PEG) solution as the continuous phase, was successfully precipitated by PGSS((r)). Operating conditions that ensured the stability of the CO2 saturated emulsion were previously evaluated. The resulting PEG-GEL particles present a spherical-like morphology constituted by several lipid cores encapsulated into a polymeric shell. The applicability of these structured particles to be used as drug delivery system (DDS) was studied by using ketoprofen, a nonsteroidal anti inflammatory drug (NSAID), as model drug. The particles provided an initial burst release of the drug due to the progressive dissolution of the external layer of PEG, followed by a controlled release of the NSAID from the GEL cores. PMID- 25445976 TI - How to easily provide zero order release of freely soluble drugs from coated pellets. AB - Coated pellets offer a great potential as controlled drug delivery systems. However, constant drug release rates are difficult to achieve with this type of dosage forms if the drug is freely water-soluble. This is because diffusional mass transport generally plays a major role and with time the drug concentration within the system decreases, resulting in decreased concentration gradients, which are the driving forces for drug release. Thus, generally "curve-shaped" release profiles with monotonically decreasing slopes are observed. This type of release kinetics might be inappropriate for an efficient and safe drug treatment. Despite the great practical importance of this potentially crucial formulation challenge, surprisingly little is yet known on how to effectively address it. In this study, a novel approach is presented based on sequential layers of drug and polymer (initially free of drug) to provide a non-homogeneous initial drug distribution, combined with lag-time effects, and partial initial drug diffusion towards the pellet's core. Sugar and microcrystalline cellulose beads were used as starter cores, metoprolol succinate as freely soluble drug, ethylcellulose, and poly(vinyl acetate) as release rate controlling polymers. The type, number, thickness, and sequence of the drug and polymer layers were varied. Interestingly, a rather simple four layer system (two drug and two polymer layers) allowed providing about constant drug release during 8h. Compared to previously proposed coated pellets aiming at constant release of freely water soluble drugs based on non-homogeneous initial drug distribution, the total coating level in this study was very much reduced: to only about 20%. Hence, the suggested formulation approach is relatively simple and can help overcoming a potentially major hurdle in practice. Its applicability has also been demonstrated for another type of drug: propranolol hydrochloride. PMID- 25445977 TI - Topical formulation and dermal delivery of active phenolic compounds in the Thai medicinal plant--Clerodendrum petasites S. Moore. AB - PURPOSE: To develop topical formulations of Clerodendrum petasites S. Moore (CP), and to optimize the skin permeability and topical bioavailability of the active phenolic compounds therein. METHODS: The skin uptake and delivery of active compounds from two formulations, an oil-in-water cream and a lotion (both containing 10% w/w CP extracts), were examined (a) invitro using pig skin, and (b) invivo in human volunteers. Stratum corneum (SC) was collected by tape stripping and the compounds were detected and quantified by high performance liquid chromatography coupled with either mass spectrometry (HPLC-MS) or ultraviolet and photodiode array (HPLC-UV-PDA) detection. RESULTS: From the invitro results, vanillic acid, verbascoside, nepetin and hispidulin, were chosen as potential phenolic actives for topical delivery optimization from the formulations. Invivo, vanillic acid, nepetin and hispidulin were appreciably taken up into the SC within 6h, while verbascoside did not penetrate beyond the most superficial layers. No significant differences in delivery were observed between the two formulations, both of which were well tolerated. CONCLUSIONS: The detected topical absorption of hispidulin, nepetin, and vanillic acid, from the cream and lotion vehicles investigated, suggest that these compounds are potentially active compounds in Thai traditional medicine for the treatment of a wide range of skin diseases. PMID- 25445978 TI - Counter-intuitive effect of non-crystallizing sugars on the crystallization of gemcitabine HCl in frozen solutions. AB - In this study, the effect of four non-crystallizing sugars, namely fructose, trehalose, sucrose and raffinose, was assessed on the crystallization of gemcitabine hydrochloride (GHCl) in frozen solutions. Aqueous solutions containing GHCl (50 mg/mL) and a sugar at varying concentrations (10-60 mg/mL) were frozen in situ in DSC and analyzed in the subsequent heating run. Crystallization propensity of GHCl was quantified in terms of reduced crystallization temperature (RCT) as a function of sugar type and concentration. Multivariate analysis option in JMP((r)) software was employed for calculating correlation between the variables. All sugars inhibited GHCl crystallization in a concentration dependent manner. At equal concentration, fructose (with the lowest Tg') exerted the strongest inhibitory effect, whereas raffinose (with the highest Tg') exerted the weakest inhibitory effect. Additionally, RCT showed a poor correlation with Tg' (r=0.2327). Thus, the inhibitory effect of sugars could not be described by their anti-plasticization effect. This counter-intuitive behavior was explained by the inhibitory effect of sugars on ice crystallization, which increased the unfrozen water content (UWC) in the freeze concentrate, thereby lowering the supersaturation of GHCl. This was established by observing a good correlation (r=0.9666) between RCT and ln(1/UWC). Additionally, reduced diffusion kinetics of GHCl in presence of sugar molecules was also postulated. This study highlights the importance of unfrozen water towards governing the crystallization behavior of solutes in multi-component frozen systems. PMID- 25445979 TI - Attitudes About and Practices of Health Promotion and Prevention Among Primary Care Providers. AB - The Patient Protection and Affordable Care Act's emphasis on health promotion and prevention activities required an examination of the current practices of primary care providers in these areas. A total of 196 primary care providers completed a survey to assess current health promotion and prevention attitudes, practices, and barriers. Results of this study showed that family physicians in Pennsylvania recognize the importance of and their role in providing health promotion and prevention and offer advice in key behavioral and disease prevention areas. Results from the study suggest that their ability to provide these services is hindered by a lack of time and the heavy workload. Although most family physicians provided advice to patients in several health promotion and prevention areas, few participants reported that they referred patients to other health professionals. Finally, when it comes to preventive services, participants ranked blood pressure screening, tobacco use screening, and tobacco use cessation interventions as the most important services. Effective implementation of the Patient Protection and Affordable Care Act will require necessary resources and support of primary care providers to help patients achieve healthier lives. PMID- 25445980 TI - School-Based Educational Intervention to Improve Children's Oral Health-Related Knowledge. AB - OBJECTIVE: To evaluate a brief oral health promotion intervention delivered in schools by a primary care dental practice, aimed at changing oral health care knowledge and oral health-related behaviors in children. DESIGN: Cohort study with pretest-posttest design. SETTING: Three primary schools. PARTICIPANTS: One hundred and fifty children (aged 9-12 years). INTERVENTION: Children received a 60-minute theory-driven classroom-based interactive educational session delivered by a dental care professional and received take-home literature on oral health. MAIN OUTCOME MEASURES: All children completed a questionnaire on oral health related knowledge and self-reported oral health-related behaviors before, immediately after, and 6 weeks following the intervention. RESULTS: Children's dental knowledge significantly improved following the intervention, with improvement evident at immediate follow-up and maintained 6 weeks later. Significantly more children reported using dental floss 6 weeks after the intervention compared with baseline. No significant differences were detected in toothbrushing or dietary behaviors. CONCLUSIONS: School-based preventative oral health education delivered by primary care dental practices can generate short term improvements in children's knowledge of oral health and some aspects of oral hygiene behavior. Future research should engage parents/carers and include objective clinical and behavioral outcomes in controlled study designs. PMID- 25445981 TI - Comparing two observational measures to evaluate compliance with tobacco-free campus policy. AB - Despite potential benefits of tobacco-free campus policies, compliance remains a challenge. Observational measures hold the most promise in determining compliance with these policies. There is need for further study to determine validity of observational measures of compliance with tobacco-free campus policies. The purpose of this study was to determine the validity of two observational measures of compliance with a tobacco-free campus policy: direct observation of violators and cigarette butts. Data collection took place over a 1-year time period. Direct observation was operationally defined as the number of observed violators in hot spots. A cigarette butt protocol previously found to be reliable was used to count the number of butts in campus hot spots. Results indicated a positive relationship between number of violators observed per visit and number of cigarette butts collected. Although most of the hot spots exhibited two or fewer violators per visit and 100 butts or fewer per collection, the data points outside this range supported a positive association between observed violators per visit and cigarette butts. The findings support that direct observation of violators is a valid measure of compliance compared to cigarette butts. Given available resources, using one or the other as evaluation measures is warranted. PMID- 25445982 TI - Addressing language barriers in client-centered health promotion: lessons learned and promising practices from Texas WIC. AB - The growing population of nonnative English speakers in the United States challenges program planners to offer services that will effectively reach limited English proficiency (LEP) audiences. This article presents findings from evaluation research conducted with the Special Supplemental Program for Women, Infants, and Children (WIC) to identify best practices and areas of concern for working with LEP clients. Data were collected through online surveys of 338 WIC teaching staff in 2010 and 65 WIC local agency directors in 2011 as part of an implementation evaluation of client-centered nutrition education. Data identified current practices, facilitating factors, and challenges in working with LEP clients. Facilitating factors included cultural competency, material and translation resources, linguistic competency, professional development opportunities, and rapport with clients. Challenges cited included linguistic challenges, lack of cultural competencies, issues related to the client-staff interaction, and insufficient time, materials, and staffing. Best practices inferred from the data relate to developing linguistic standards for bilingual staff, considerations for translating written materials, interpretation services, cultural competency, and staff training. Findings may help inform the development of this and other linguistically and culturally appropriate health promotion programs. PMID- 25445984 TI - Development of a shear measurement sensor for measuring forces at human-machine interfaces. AB - Measuring shear force is crucial for investigating the pathology and treatment of pressure ulcers. In this study, we introduced a bi-axial shear transducer based on strain gauges as a new shear sensor. The sensor consisted of aluminum and polyvinyl chloride plates placed between quadrangular aluminum plates. On the middle plate, two strain gauges were placed orthogonal to one another. The shear sensor (54 mm * 54 mm * 4.1 mm), which was validated by using standard weights, displayed high accuracy and precision (measurement range, -50 to 50 N; sensitivity, 0.3N; linear relationship, R(2)=0.9625; crosstalk error, 0.635% +/- 0.031%; equipment variation, 4.183). The shear force on the interface between the human body and a stand-up wheelchair was measured during sitting or standing movements, using two mats (44.8 cm * 44.8 cm per mat) that consisted of 24 shear sensors. Shear forces on the sacrum and ischium were almost five times higher (15.5 N at last posture) than those on other sites (3.5 N on average) during experiments periods. In conclusion, the proposed shear sensor may be reliable and useful for measuring the shear force on human-machine interfaces. PMID- 25445983 TI - Research challenges and lessons learned from conducting community-based research with the Hmong community. AB - BACKGROUND: Conducting research with underserved communities with little exposure to research presents a number of challenges and opportunities. Our study used a community-based approach to better understand factors that influence breast and cervical cancer screening among Hmong women. OBJECTIVE: This article shares lessons learned during the process of developing and conducting qualitative research with a Hmong community with limited experience with research. METHOD: We conducted 17 key informant and 84 in-depth interviews with Hmong women and men. Research team discussions, insights from Hmong research team members, input from our Community Advisory Committee, and project documents were sources of information about the process of conducting research in this community. RESULTS: Lessons learned concern including a cultural insider as an investigator; building community partnerships and support; establishing and working with a community advisory committee; hiring and training bilingual, bicultural staff; and using culturally appropriate materials and methods in a small, kinship-based community. We used multiple strategies to ensure that this study was conducted in a culturally appropriate manner. CONCLUSION: The lessons learned from our experiences can provide guidance to researchers on methodological and practical issues in conducting research with the Hmong and can inform future research with the Hmong and other similar underserved populations. PMID- 25445985 TI - Ischemia/reperfusion-induced upregulation of TIGAR in brain is mediated by SP1 and modulated by ROS and hormones involved in glucose metabolism. AB - We previously found that TIGAR (TP53-induced glycolysis and apoptosis regulator) was upregulated in response to ischemia/reperfusion insult in a TP53-independent manner. The present study sought to investigate the regulatory mechanisms of TIGAR upregulation in animal and cellular models of stroke. The animal and cellular models of ischemia/reperfusion were produced by transient middle cerebral artery occlusion and reperfusion (tMCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R), respectively. The expression of TIGAR protein in cortical tissues and hippocampal neuronal cell line HT22 cells or primary neurons was determined. Glucose, hormones and hydrogen peroxide (H2O2) were administered to mice via injection into the tail vein or lateral ventricle or directly added into cell culture medium. In mice subjected to tMCAO/R, the blood glucose level rapidly increased, peaking at 0.5 h and then declined. TIGAR protein was also significantly increased and then declined with a delayed time course. The increase in TIGAR protein was blunted when blood glucose levels were controlled with insulin. However, administering glucose solution to mice or adding glucose to cell culture medium had no effect on TIGAR protein levels. In contrast adrenaline, hydrocortisone, glucagon and H2O2 significantly increased TIGAR protein expression, whereas insulin inhibited TIGAR expression. The transcription factor SP1 was induced by ischemia/reperfusion ahead of TIGAR upregulation. Inhibiting SP1 with mithramycin A or silencing SP1 with siRNA blocked the ischemia-induced TIGAR upregulation. These results suggest that ROS and hormones regulating blood glucose metabolism play a role in ischemia/reperfusion-induced TIGAR upregulation. PMID- 25445986 TI - Vitis labrusca extract effects on cellular dynamics and redox modulations in a SH SY5Y neuronal cell model: a similar role to lithium. AB - Oxidative stress and calcium imbalance are consistently reported in bipolar disorder (BD). Polymorphism of voltage-dependent calcium channel, L type, alpha 1C subunit (CACNA1c), which is responsible for the regulation of calcium influx, was also shown to have a strong association with BD. These alterations can lead to a number of different consequences in the cell including production of reactive species causing oxidative damage to proteins, lipids and DNA. Lithium is the most frequent medication used for the treatment of BD. Despite lithium's effects, long-term use can result in many negative side effects. Therefore, there is an urgent need for the development of drugs that may have similar biological effects as lithium without the negative consequences. Moreover, polyphenols are secondary metabolites of plants that present multi-faceted molecular abilities, such as regulation of cellular responses. Vitis labrusca extract (VLE), a complex mixture of polyphenols obtained from seeds of winery wastes of V. labrusca, was previously characterized by our group. This extract presented powerful antioxidant and neuroprotective properties. Therefore, the ability of VLE to ameliorate the consequences of hydrogen peroxide (H2O2)-induced redox alterations to cell viability, intracellular calcium levels and the relative levels of the calcium channel CACNA1c in comparison to lithium's effects were evaluated using a neuroblastoma cell model. H2O2 treatment increased cell mortality through apoptotic and necrotic pathways leading to an increase in intracellular calcium levels and alterations to relative CACNA1c levels. VLE and lithium were found to similarly ameliorate cell mortality through regulation of the apoptotic/necrotic pathways, decreasing intracellular calcium levels and preventing alterations to the relative levels of CACNA1c. The findings of this study suggest that VLE exhibits protective properties against oxidative stress-induced alterations similar to that of lithium. These findings suggest that VLE may be an attractive potential candidate as a novel therapeutic agent for BD. PMID- 25445987 TI - Oxidative stress reduces levels of dysbindin-1A via its PEST domain. AB - Oxidative stress resulting from the generation of reactive oxygen species has been proposed as an etiological factor in schizophrenia. The present study tests the hypothesis that oxidative stress can affect levels of dysbindin-1A, encoded by Dtnbp1, a genetic risk factor for schizophrenia, via its PEST domain. In vitro studies on SH-SY5Y cells indicate that oxidative stress triggers proteasomal degradation of dysbindin-1A, and that this requires interactions with its PEST domain, which may be a TRIM32 target. We specifically found (a) that oxidative stress induced in SH-SY5Y cells by 500 uM hydrogen peroxide reduced levels of full-length dysbindin-1, but did not reduce levels of that protein lacking its PEST domain and (b) that levels of full-length dysbindin-1, but not dysbindin-1 lacking its PEST domain, were higher in cells treated with the proteasome inhibitor MG132. Oxidative stress thus emerges as the first known cellular factor regulating dysbindin-1 isoforms with PEST domains. These findings are consistent with the previously noted fact that phosphorylation of PEST domains often marks proteins for proteasomal degradation, and raises the possibility that treatments reducing oxidative stress in the brain, especially during development, may lower schizophrenia risk. PMID- 25445988 TI - A pilot study comparing opaque, weighted bottles with conventional, clear bottles for infant feeding. AB - It is hypothesized that the visual and weight cues afforded by bottle-feeding may lead mothers to overfeed in response to the amount of liquid in the bottle. The aim of the present pilot study was to test this hypothesis by comparing mothers' sensitivity and responsiveness to infant cues and infants' intakes when mothers use opaque, weighted bottles (that remove visual and weight cues) compared to conventional, clear bottles to feed their infants. We also tested the hypothesis that mothers' pressuring feeding style would moderate the effect of bottle type. Formula-feeding dyads (N = 25) visited our laboratory on two separate days. Mothers fed their infants from a clear bottle one day and an opaque, weighted bottle on the other; bottle-order was counterbalanced across the two days. Infant intake was assessed by weighing each bottle before and after the feeding. Maternal sensitivity and responsiveness to infant cues was objectively assessed using the Nursing Child Assessment Feeding Scale. Mothers were significantly more responsive to infant cues when they used opaque compared to clear bottles (p = .04). There was also a trend for infants to consume significantly less formula when fed from opaque compared to clear bottles (p = .08). Mothers' pressuring feeding style moderated the effect of bottle type on maternal responsiveness to infant cues (p = .02) and infant intake (p = .03). Specifically, mothers who reported higher levels of pressuring feeding were significantly more responsive to their infants' cues (p = .02) and fed their infants significantly less formula when using opaque versus clear bottles (p = .01); no differences were seen for mothers who reported lower levels of pressuring feeding. This study highlights a simple, yet effective intervention for improving the bottle-feeding practices of mothers who have pressuring feeding styles. PMID- 25445989 TI - Dosimetric evaluation of simultaneous integrated boost during stereotactic body radiation therapy for pancreatic cancer. AB - Stereotactic body radiation therapy (SBRT) provides a promising way to treat locally advanced pancreatic cancer and borderline resectable pancreatic cancer. A simultaneous integrated boost (SIB) to the region of vessel abutment or encasement during SBRT has the potential to downstage otherwise likely positive surgical margins. Despite the potential benefit of using SIB-SBRT, the ability to boost is limited by the local geometry of the organs at risk (OARs), such as stomach, duodenum, and bowel (SDB), relative to tumor. In this study, we have retrospectively replanned 20 patients with 25Gy prescribed to the planning target volume (PTV) and 33~80Gy to the boost target volume (BTV) using an SIB technique for all patients. The number of plans and patients able to satisfy a set of clinically established constraints is analyzed. The ability to boost vessels (within the gross target volume [GTV]) is shown to correlate with the overlap volume (OLV), defined to be the overlap between the GTV + a 1(OLV1)- or 2(OLV2) cm margin with the union of SDB. Integral dose, boost dose contrast (BDC), biologically effective BDC, tumor control probability for BTV, and normal tissue complication probabilities are used to analyze the dosimetric results. More than 65% of the cases can deliver a boost to 40Gy while satisfying all OAR constraints. An OLV2 of 100cm(3) is identified as the cutoff volume: for cases with OLV2 larger than 100cm(3), it is very unlikely the case could achieve 25Gy to the PTV while successfully meeting all the OAR constraints. PMID- 25445990 TI - Preactivated hyaluronic acid: A potential mucoadhesive polymer for vaginal delivery. AB - The objective of this study was to develop mucoadhesive polymeric excipients for vaginal drug delivery systems. Hyaluronic acid was thiolated and subsequently preactivated with 6-mercaptonicotinamide (HA-CYS-MNA) to enhance stability and mucoadhesive properties on vaginal mucosa. After determination of the thiol group content, disintegration studies and in vitro mucoadhesion studies (rotating cylinder and tensile) were performed. Furthermore, swelling behavior and cytotoxicity studies were performed in comparison with corresponding polymers. Both, disintegration and in vitro mucoadhesive studies revealed that modifying HA CYS with MNA resulted in higher stability (3.6-fold prolonged disintegration time compared to unmodified hyaluronic acid) and prolonged mucoadhesion time. MTT assay and LDH revealed no toxicity for the polymeric excipients and safe for their use. Disintegration and swelling results conducted more pronounced stability of the preactivated thiomers compared to corresponding unmodified ones. According to these results preactivated hyaluronic acid might be a useful tool for vaginal delivery systems. PMID- 25445991 TI - Improved insulin loading in poly(lactic-co-glycolic) acid (PLGA) nanoparticles upon self-assembly with lipids. AB - Polymeric nanoparticles are widely investigated as drug delivery systems for oral administration. However, the hydrophobic nature of many polymers hampers effective loading of the particles with hydrophilic macromolecules such as insulin. Thus, the aim of this work was to improve the loading of insulin into poly(lactic-co-glycolic) acid (PLGA) nanoparticles by pre-assembly with amphiphilic lipids. Insulin was complexed with soybean phosphatidylcholine or sodium caprate by self-assembly and subsequently loaded into PLGA nanoparticles by using the double emulsion-solvent evaporation technique. The nanoparticles were characterized in terms of size, zeta potential, insulin encapsulation efficiency and loading capacity. Upon pre-assembly with lipids, there was an increased distribution of insulin into the organic phase of the emulsion, eventually resulting in significantly enhanced encapsulation efficiencies (90% as compared to 24% in the absence of lipids). Importantly, the insulin loading capacity was increased up to 20% by using the lipid-insulin complexes. The results further showed that a main fraction of the lipid was incorporated into the nanoparticles and remained associated to the polymer during release studies in buffers, whereas insulin was released in a non-complexed form as a burst of approximately 80% of the loaded insulin. In conclusion, the protein load in PLGA nanoparticles can be significantly increased by employing self-assembled protein lipid complexes. PMID- 25445993 TI - Matrix based system of isotretinoin as nail lacquer to enhance transungal delivery across human nail plate. AB - The project was aimed at development of isotretinoin nail lacquer and assessment of its penetration efficiency across human nail plate. Preliminary studies (hydration enhancement factor and SEM) aided the selection of thioglycolic acid as permeation and eugenol was selected as local anesthetic in the formulation. The nail lacquer was optimized by 3(2) factorial design and a total of nine formulations were prepared and screened. In vitro adhesion and ex vivo permeation (cumulative drug permeation per unit area (CDP/A) = 6.61 +/- 0.57 mg/cm(2)) across bovine hoof guided the selection of F3 as optimized formulation that was improvised. Viscosity adjustments to improve handling characteristics were affected by incorporation of ethyl cellulose (6%; F3M1) that scaled the viscosity to 312.681 cp and insignificantly (p > 0.05) affected CDP/A (6.32 +/- 0.45 mg/cm(2)). In comparison to marketed preparation (Retino-A cream) F3M1 afforded two fold increase in CDP/A. The permeation characteristics were defined by Higuchi model (r(2) = 0.964) and flux value of 176 MUg/cm(2)/h. Confocal laser scanning microscopy, after 72 h of nail lacquer application, revealed extensive distribution of the fluorescent tracer across the human nail plate in comparison to control that was confined to the top layer. Conclusively, an efficacious and stable nail lacquer of isotretinoin was developed for potential clinical topical use to target the drug to nail bed in treatment of nail psoriasis. PMID- 25445992 TI - Resveratrol-loaded polymeric nanoparticles suppress glucose metabolism and tumor growth in vitro and in vivo. AB - Resveratrol (RSV) is a natural phenol with promising anti-tumor activities, but its use for in vivo cancer treatment is limited by low aqueous solubility and poor stability. In this study, we prepared RSV-loaded polyethylene glycol polylactic acid (PEG-PLA; M.W. 5000-5000) polymer nanoparticles (NPs) for improved stability and controlled delivery, and investigated its metabolic and anti-tumor effect in vitro and in vivo. CT26 colon cancer cells displayed significantly reduced cell number to 5.6% and colony forming capacity to 6.3% of controls by 72 h treatment with 40 and 20 MUM of RSV-NP, respectively. Flow cytometry and western blots demonstrated increased apoptotic cell death, and (18)F FDG uptake and reactive oxygen species was significantly reduced by RSV-NP. All of these effects were comparable to or greater in potency compared to free RSV. When RSV-NP was intravenously administered to CT26 tumor bearing mice, there was a reduction of (18)F FDG uptake on PET/CT by day 4. Longer treatment led to retardation of tumor growth accompanied by an improvement in survival compared to empty NP-injected controls. These results demonstrate that the in vitro and in vivo metabolic and anti-tumor effects of RSV is preserved by PEG-PLA NP loading, and provide an encouraging outlook on the potential of polymeric NPs as an effective method to deliver RSV for cancer therapy. PMID- 25445994 TI - Design of salmon calcitonin particles for nasal delivery using spray-drying and novel supercritical fluid-assisted spray-drying processes. AB - The overall aim of this study was to prepare a nasal powder formulation of salmon calcitonin (sCT) using an absorption enhancer to improve its bioavailability. In this work, powder formulations for nasal delivery of sCT were studied using various absorption enhancers and stabilizers. Powders were prepared by two different methods: conventional spray-drying (SD) and novel supercritical fluid assisted spray-drying (SASD) to investigate the role of CO2 in the particle formation process. The prepared sCT powder formulations were characterized by several analyses; powder X-ray diffractometry (PXRD), scanning electron microscopy (SEM), and the Fourier transform infrared (FT-IR) spectroscopy method. The particle size distribution was also evaluated. In vivo absorption tests were carried out in Sprague-Dawley rat using the prepared powder formulations, and the results were compared to those of raw sCT. Quantitative analysis by high performance liquid chromatography (HPLC) indicated that sCT was chemically stable after both the SD and SASD processes. Results of PXRD, SEM, and FT-IR did not indicate a strong interaction or defragmentation of sCT. The in vivo absorption test showed that SD- and SASD-processed sCT powders increased the bioavailability of the drug when compared to the nasal administration of raw sCT. In addition, SASD-processed sCT exhibited higher nasal absorption when compared with SD processed sCT in all formulations due to a reduction of particle size. The results from this study illustrate that the preparation of nasal powders using the SASD process could be a promising approach to improve nasal absorption of sCT. PMID- 25445995 TI - Toward an immune-mediated subtype of autism spectrum disorder. AB - A role for immunological involvement in autism spectrum disorder (ASD) has long been hypothesized. This review includes four sections describing (1) evidence for a relationship between familial autoimmune disorders and ASD; (2) results from post-mortem and neuroimaging studies that investigated aspects of neuroinflammation in ASD; (3) findings from animal model work in ASD involving inflammatory processes; and (4) outcomes from trials of anti-inflammatory/immune modulating drugs in ASD that have appeared in the literature. Following each section, ideas are provided for future research, suggesting paths forward in the continuing effort to define the role of immune factors and inflammation in the pathophysiology of a subtype of ASD. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease. PMID- 25445996 TI - The effect of simvastatin treatment on proliferation and differentiation of neural stem cells after traumatic brain injury. AB - OBJECTIVE: To study the effect of simvastatin on neurological functional recovery after traumatic brain injuries (TBI) and the possible molecular mechanisms, we evaluated simvastatin-induced proliferation and differentiation of neural stem cells (NSCs) in vitro and in vivo and possible involvement of Notch-1 signaling in this process. METHODS: Adult Wistar rats were randomly divided into three groups (n=28 for each): sham group, saline-treated group and simvastatin-treated group. Simvastatin was given orally at a dose of 1mg/kg/day starting at day 1 after TBI. At 1, 3, 7, 14, 21, 28, and 35 days after simvastatin treatment, functional outcome was measured using modified neurological severity scores (mNSS). Immunofluorescence of nestin was used to identify neurogenesis of NSCs in injured area of TBI rats. Western blot was applied to detect the expression level of Notch-1 protein in TBI rats with simvastatin. RESULTS: Immunostaining showed a significant increase in the number of nestin-positive cells in injured area of the simvastatin-treated group compared to that of the saline-treated group (p<0.05). In in vitro experiment, simvastatin induced enhanced proliferation and neurogenesis of cultured NSCs and elevated Notch-1 protein expression. Co incubation of gamma-secretase inhibitor, an inhibitor of Notch-1 pathway, with simvastatin abolished its neurorestoration effect. Most importantly, the simvastatin-treated group had significantly decreased mNSS at day 35 after TBI compared with the saline-treated group (p<0.05). CONCLUSION: Simvastatin treatment enhanced neurological functional recovery after TBI possibly via activation of Notch signaling and increasing neurogenesis in the injured area. PMID- 25445997 TI - Long term creatine monohydrate supplementation, following neonatal hypoxic ischemic insult, improves neuromuscular coordination and spatial learning in male albino mouse. AB - Creatine is known to rescue animals following brain damage. Present study was designed to demonstrate the effect of long term (15 week) supplementation of 2% creatine monohydrate (Cr), following neonatal hypoxic ischemic insult, on learning and memory formation in male albino mouse. Albino mice pups were subjected to right common carotid artery ligation followed by 8% hypoxia for 25 minutes. Following weaning, animals were separated and grouped on the basis of dietry supplementation for 15 weeks followed by a battery of neurological tests including Morris water maze, open field and rota rod. It was observed that HI mice fed on 2% Cr for 15 weeks performed better than their littermates mice on normal rodent diet during water maze (learning and memory) and rotating rod (neuro-muscular coordination and balance) test while the results of open field test remained unaffected. It was also observed that Cr treated animals had a reduced brain infarct volume than untreated but this difference did not reached statistical significance. We have also observed an overall increase in body weight in Cr treated mice during the study. Over all our results are indicating that long term Cr supplementation is beneficial for male albino following hypoxic ischemic insult. PMID- 25445998 TI - Brain source localization of MMN, P300 and N400: aging and gender differences. AB - The localization of neuronal generators during an ERP study, using a high-density electroencephalogram (HD-EEG) equipment was made on three Evoked Related Potential (ERP) components, i.e., the Mismatch Negativity (MMN), the P300 and the N400. Furthermore, the ERP characteristics, their field distribution and the area of their maximum field intensity were extracted and compared between young and elderly, as well as between females and males. A two tone oddball experiment was conducted, involving 27 young adults and 18 elderly, healthy and right handed, and HD-EEG data were acquired. These data were then subjected to auditory ERPs extraction and thorough statistical analysis. The derived experimental results revealed significant age-related differences to both the latencies and the amplitudes of the MMN and the P300 and the topographic distribution of the HD-EEG amplitudes. Additionally, a shift in the maximum intensities from frontal to temporal lobe with aging appeared in the case of the P300, whereas no effect was observed for the MMN component. No statistical significant differences (p>0.05) due to age was found in N400 characteristics. Finally, gender-related differences were significant in the response time of the subjects, finding males response faster. The level and the location of the maximum intensity of sources also differed between genders, especially in young subjects. These findings justify the enhanced potential of HD-EEG data to accurately reflect the age and gender dependencies at the three components of simple auditory ERPs and pave the way for the investigation of neurodegenerative pathologies, such as the Alzheimer's disease. PMID- 25445999 TI - Does visual working memory represent the predicted locations of future target objects? An event-related brain potential study. AB - During the maintenance of task-relevant objects in visual working memory, the contralateral delay activity (CDA) is elicited over the hemisphere opposite to the visual field where these objects are presented. The presence of this lateralised CDA component demonstrates the existence of position-dependent object representations in working memory. We employed a change detection task to investigate whether the represented object locations in visual working memory are shifted in preparation for the known location of upcoming comparison stimuli. On each trial, bilateral memory displays were followed after a delay period by bilateral test displays. Participants had to encode and maintain three visual objects on one side of the memory display, and to judge whether they were identical or different to three objects in the test display. Task-relevant memory and test stimuli were located in the same visual hemifield in the no-shift task, and on opposite sides in the horizontal shift task. CDA components of similar size were triggered contralateral to the memorized objects in both tasks. The absence of a polarity reversal of the CDA in the horizontal shift task demonstrated that there was no preparatory shift of memorized object location towards the side of the upcoming comparison stimuli. These results suggest that visual working memory represents the locations of visual objects during encoding, and that the matching of memorized and test objects at different locations is based on a comparison process that can bridge spatial translations between these objects. This article is part of a Special Issue entitled SI: Prediction and Attention. PMID- 25446000 TI - Cognitive impairment induced by permanent bilateral common carotid occlusion exacerbates depression-related behavioral, biochemical, immunological and neuronal markers. AB - There is a strong link between cognitive impairment and depression, but up to date it is not clear whether cognitive impairment is 'cause' or 'consequence' of depression. Therefore, we here examined the effect of cognitive impairment induced by permanent occlusion of common carotid arteries, a model known as two vessel occlusion (2VO), on chronic unpredictable stress (CUS)-induced depression related markers in rats. Male Sprague-Dawley rats underwent 2VO or sham surgery. Sixty days after the surgery, the cognitive function of the rats was tested using the radial arm maze task measuring working and reference memory. Subsequently, the animals were randomly assigned to undergo 21 days of CUS or to stay non stressed. One week after the last stressor, psychomotor retardation, a feature of depression-like behavior, was assessed using the forced swim test (FST) by measuring time spent on immobility. Plasma amino acid (glutamine, glutamate and glycine) and serum pro-inflammatory cytokine (interleukin 6) levels, and hippocampus CA1 neuronal damage were measured 24h after FST exposure. Results show that 2VO increased immobility in the FST only when rats had been exposed to CUS. In addition, 2VO surgery intensified the effect of CUS on IL-6, glutamate and glycine levels and increased CA1 hippocampal damage. In conclusion, our findings show that cognitive impairment may predispose to depression by intensifying the effect of stress on depression-related behavioral, biochemical, immunological and neuronal markers. PMID- 25446002 TI - alpha-Synuclein amino terminus regulates mitochondrial membrane permeability. AB - Parkinson's disease (PD) is a common neurodegenerative movement disorder affecting an increasing number of elderly. Various studies have shown that mitochondrial dysfunction and abnormal protein aggregation are two major contributors to the progression of PD. The N terminus of alpha-synuclein (alpha Syn/N), which adopts an alpha-helical conformation upon lipid binding, is essential for membrane interaction; yet its role in mitochondria remains poorly defined. A functional characterization of the alpha-Syn N-terminal domain and investigation of its effect on mitochondrial membrane permeability were undertaken in this study. alpha-Syn/N and alpha-Syn/delN (amino acids 1-65 and 61 140, respectively) constructs were overexpressed in dopaminergic MN9D cells and primary cortical neurons. A decrease in cell viability was observed in cells transfected with alpha-Syn/N but not alpha-Syn/delN. In addition, an alpha-Syn/N induced increase in the level of intracellular reactive oxygen species, alteration in mitochondrial morphology, and decrease in mitochondrial membrane potential were accompanied by the activation of mitochondrial permeability transition pores (mPTP). These changes were also associated with a decline in mitochondrial cardiolipin content and interaction with the voltage-dependent anion channel and adenine nucleotide translocator in the mitochondrial membrane. The activation of mPTPs and reduction in cell viability were partially reversed by bongkrekic acid, an inhibitor of adenine nucleotide translocator (ANT), suggesting that the interaction between alpha-Syn and ANT promoted mPTP activation and was toxic to cells. BKA treatment reduced interaction of alpha Syn/N with ANT and VDAC. These results suggest that the N terminus of alpha-Syn is essential for the regulation of mitochondrial membrane permeability and is a likely factor in the neurodegeneration associated with PD. PMID- 25446001 TI - Ligustilide prevents cognitive impairment and attenuates neurotoxicity in D galactose induced aging mice brain. AB - Ligustilide (LIG) is a principal active ingredient of traditional Chinese medicine, Radix Angelica sinensis, which has versatile pharmacological activities including neuroprotection. Previous studies have demonstrated that LIG has beneficial effects on cognition deficits associated with cerebral damage or neurodegenerative disorders. In present study, we investigated the neuroprotective effect of LIG on cognitive impairment and neurotoxicity in the brain of aging mouse induced by d-galactose (d-gal). The aging model mice were induced by subcutaneous (S.C.) injection of d-gal once daily for 8 weeks and LIG (80 mg/kg) was simultaneously administered orally. The Morris water maze (MWM) test was used to assess the spatial learning and memory abilities. The activity of Na(+)-K(+)-ATPase and the content of lipid peroxidation product malondialdehyde (MDA) in brain were examined. The levels of glial fibrillary acidic protein (GFAP), growth-associated protein GAP-43, and cleaved caspase-3 in brain were also determined by immunohistochemistry. The MWM test showed that LIG administration markedly improved behavioral performance of d-gal treated mice. This action could be partly explained by the results that LIG reduced the level of MDA as well as increased the activity of Na(+)-K(+)-ATPase in the brain of d gal induced aging mice. Moreover, LIG significantly raised the expression of GAP 43 and reduced cleaved caspase-3 and GFAP levels in the brain of d-gal treated mice. These results demonstrated that LIG improves d-gal-induced cognitive dysfunction and brain toxicity, which suggests that LIG may be developed as a new medicine for the treatment of aged-related conditions. PMID- 25446003 TI - How do conceptual representations interact with processing demands: An fMRI study on action- and abstract-related words. AB - This fMRI study investigated the functional mechanisms related to mental simulation of abstract- and action-related words and measured the effect of the type of stimulus (Abstract vs. action verbs) and the type of task (imagery vs. control task) to explore how conceptual representations interact with processing demands. A significant task by stimuli interaction showed that action-related words activated the left sensorimotor cortex during explicit imagery (as compared to the control task), whereas abstract-related verbs did not automatically activate this area. Rather, as we made sure that Abstract verbs were not associated with motor states (as tested in a rating study of our stimulus list), imagery elicited by abstract verb processing (as compared to Action verbs, and controlled for letter detection) differentially activated a right hemisphere neural network including the right supramarginal (SMG) gyrus and the precuneus which might be related to mental imagery of emotion-related scenes and not to the semantics of the stimuli per se. Our results confirmed the view that the activation of the sensorimotor cortex during language processing of abstract- and action-related words is strategy-dependent. PMID- 25446005 TI - Saturation of auditory short-term memory causes a plateau in the sustained anterior negativity event-related potential. AB - The maintenance of information in auditory short-term memory (ASTM) is accompanied by a sustained anterior negativity (SAN) in the event-related potential measured during the retention interval of simple auditory memory tasks. Previous work on ASTM showed that the amplitude of the SAN increased in negativity as the number of maintained items increases. The aim of the current study was to measure the SAN and observe its behavior beyond the point of saturation of auditory short-term memory. We used atonal pure tones in sequences of 2, 4, 6, or 8t. Our results showed that the amplitude of SAN increased in negativity from 2 to 4 items and then levelled off from 4 to 8 items. Behavioral results suggested that the average span in the task was slightly below 3, which was consistent with the observed plateau in the electrophysiological results. Furthermore, the amplitude of the SAN predicted individual differences in auditory memory capacity. The results support the hypothesis that the SAN is an electrophysiological index of brain activity specifically related to the maintenance of auditory information in ASTM. PMID- 25446006 TI - Resveratrol prevents akinesia and restores neuronal tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta of diabetic rats. AB - This study evaluated the effects of resveratrol on locomotor behaviors, neuronal and glial densities, and tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta of rats with streptozotocin-induced diabetes. Animals were divided into four groups: non-diabetic rats treated with saline (SAL), non diabetic rats treated with resveratrol (RSV), diabetic rats treated with saline (DM) and diabetic rats treated with resveratrol (DM+RSV). The animals received oral gavage with resveratrol (20 mg/kg) for 35 days. The open field test and the bar test were performed to evaluate bradykinesia and akinesia, respectively. The Nissl-stained neuronal and glial densities and the dopaminergic neuronal density were estimated using planar morphometry. Tyrosine hydroxylase immunoreactivity was evaluated using regional and cellular optical densitometry. In relation to the locomotor behaviors, it was observed that the DM group developed akinesia, which was attenuated by resveratrol in the DM+RSV group, while the DM and DM+RSV groups showed bradykinesia. Our main morpho-physiological results demonstrated: a decrease in the cellular tyrosine hydroxylase immunoreactivity in the DM group, which was attenuated by resveratrol in the DM+RSV group; a higher neuronal density in the RSV group, when compared to the DM and DM+RSV groups; an increase in the glial density in the DM group, which was also reversed by resveratrol in the DM+RSV group. Resveratrol treatment prevents akinesia development and restores neuronal tyrosine hydroxylase immunoreactivity and glial density in the substantia nigra pars compacta of diabetic rats, suggesting that this polyphenol could be a potential therapeutic option against diabetes-induced nigrostriatal dysfunctions. PMID- 25446004 TI - Neurogranin binds alpha-synuclein in the human superior temporal cortex and interaction is decreased in Parkinson's disease. AB - Neurogranin is a calmodulin binding protein that has been implicated in learning and memory, long-term potentiation and synaptic plasticity. Neurons expressing neurogranin in the cortex degenerate in late stages of Parkinson's disease with widespread alpha-synuclein pathology. While analyzing neurogranin gene expression levels through rtPCR in brains of mouse models overexpressing human alpha synuclein, we found levels were elevated 2.5 times when compared to nontransgenic animals. Immunohistochemistry in the cortex revealed colocalization between alpha synuclein and neurogranin in mouse transgenics when compared to control mice. Coimmunoprecipitation studies in the superior temporal cortex in humans confirmed interaction between alpha-synuclein and neurogranin, and decreased interaction between alpha-synuclein and neurogranin was noticed in patients diagnosed with Parkinson's disease when compared to normal control brains. Additionally, phosphorylated neurogranin levels were also decreased in the human superior temporal cortex in patients diagnosed with Parkinson's disease and patients diagnosed with dementia with Lewy bodies. Here, we show for the first time that neurogranin binds to alpha-synuclein in the human cortex, and this interaction decreases in Parkinson's disease along with the phosphorylation of neurogranin, a molecular process thought to be involved in learning and memory. PMID- 25446007 TI - The effects of electroacupuncture treatment on the postoperative cognitive function in aged rats with acute myocardial ischemia-reperfusion. AB - Many literatures have proven that postoperative cognitive dysfunction (POCD) was very common in old patients after the injury of acute myocardial ischemia reperfusion (AMIR) clinically such as the off-pump coronary artery bypass surgery (OPCAB) without definite mechanism; however, reports on the animal experiments were rarely seen. We hypothesized that AMIR could contribute to cognitive dysfunction, and this severe injury might be impeded by EA via hindering neuroinflammation and oxidative stress response as well as modulating the balance of the autonomic nervous system. The aged male Sprague Dawley rats were randomly assigned into three experimental groups: sham (sham operation), AMIR, and EA (electroacupunture treatment, acupoints GV20 and ST36+AMIR) groups. The survival rate, heart rate variability analysis, examination of pathology within the hippocampal CA1, oxidative stress, systemic inflammation and the behavior testing were evaluated by their corresponding methods. The results showed that the rats subjected to AMIR had lower survival rates, higher malondialdehyde (MDA), decreased superoxide dismutase (SOD) activity, more microglial activation, and presented evidence of severe brain injury and cognitive dysfunction on the 1st, 3rd, 7th days after reperfusion compared to sham-operated controls. Most important of all, the above damages induced by the AMIR were significantly improved by the EA treatment. Our findings indicated that EA treatment could be a neuroprotective therapy for the cognitive dysfunction induced by the AMIR event, which might be attributablefor balancing the autonomic nervous system, inhibiting the neuronic apoptosis, hindering microglial activation, attenuating oxidative stress and restraining the central and peripheral inflammation reactions. PMID- 25446008 TI - A change in hippocampal protocadherin gamma expression in a learned helpless rat. AB - Depression is a disease with a complex etiology, that is only beginning to be studied from a genetic perspective. A selectively bred line of rats susceptible to learned helplessness, a model of depression, presents an opportunity to search for genes affecting the depressive symptoms found in the helpless model which may provide clues toward understanding the human disease. A microarray study revealed a small set of genes with altered expression in the hippocampus of the congenitally helpless rats. We selected one of these genes, a member of the gamma protocadherins for further study to determine the basis for the change in expression. Helpless animals demonstrated an increased expression primarily in CA1 neurons. Protocadherins have been implicated in synapse development and these results suggest they may play a role related to the reduced neuroplasticity observed in depression. Additionally, a number of genes linked to pathways known or suspected to be involved in depression were also detected, these will require further verification and study. PMID- 25446009 TI - Evaluation of gold nanoparticles toxicity towards human endothelial cells under static and flow conditions. AB - A new in vitro model system, adding advection and shear stress associated with a flowing medium, is proposed for the investigation of nanoparticles uptake and toxicity towards endothelial cells, since these processes are normally present when nanoparticles formulations are intravenously administered. In this model system, mechanical forces normally present in vivo, such as advection and shear stress were applied and carefully controlled by growing human umbilical vein endothelial cells inside a microfluidic device and continuously infusing gold nanoparticle (Au NPs) solution in the device. The tests performed in the microfluidic device were also run in multiwells, where no flow is present, so as to compare the two model systems and evaluate if gold nanoparticles toxicity differs under static and flow culture conditions. Full characterization of Au NPs in water and in culture medium was accomplished by standard methods. Two-photon fluorescence correlation spectroscopy was also employed to map the flow speed of Au NPs in the microfluidic device and characterize Au NPs before and after interactions with the cells. Au NPs uptake in both in vitro systems was investigated through electron and fluorescence microscopy and ICP-AES, and NPs toxicity measured through standard bio-analytical tests. Comparison between experiments run in multiwells and in microfluidic device plays a pivotal role for the investigation of nanoparticle-cell interaction and toxicity assessment: our work showed that administration of equal concentrations of Au NPs under flow conditions resulted in a reduced sedimentation of nanoparticle aggregates onto the cells and lower cytotoxicity with respect to experiments run in ordinary static conditions (multiwells). PMID- 25446010 TI - Anti inflammatory and anti angiogenic effect of black raspberry extract on human esophageal and intestinal microvascular endothelial cells. AB - Polyphenolic compounds (anthocyanins, flavonoid glycosides) in berries prevent the initiation, promotion, and progression of carcinogenesis in rat's digestive tract and esophagus, in part, via anti-inflammatory pathways. Angiogenesis has been implicated in the pathogenesis of chronic inflammation and tumorigenesis. In this study, we investigated the anti-inflammatory and anti-angiogenic effects of black raspberry extract (BRE) on two organ specific primary human intestinal microvascular endothelial cells, (HIMEC) and human esophageal microvascular endothelial cells (HEMEC), isolated from surgically resected human intestinal and donor discarded esophagus, respectively. HEMEC and HIMEC were stimulated with TNF alpha/IL-1beta with or without BRE. The anti-inflammatory effects of BRE were assessed based upon COX-2, ICAM-1 and VCAM-1 gene and protein expression, PGE2 production, NFkappaB p65 subunit nuclear translocation as well as endothelial cell-leukocyte adhesion. The anti-angiogenic effects of BRE were assessed on cell migration, proliferation and tube formation following VEGF stimulation as well as on activation of Akt, MAPK and JNK signaling pathways. BRE inhibited TNF-alpha/IL 1beta-induced NFkappaB p65 nuclear translocation, PGE2 production, up-regulation of COX-2, ICAM-1 and VCAM-1 gene and protein expression and leukocyte binding in HEMEC but not in HIMEC. BRE attenuated VEGF-induced cell migration, proliferation and tube formation in both HEMEC and HIMEC. The anti-angiogenic effect of BRE is mediated by inhibition of Akt, MAPK and JNK phosphorylations. BRE exerted differential anti-inflammatory effects between HEMEC and HIMEC following TNF alpha/IL-1beta activation whereas demonstrated similar anti-angiogenic effects following VEGF stimulation in both cell lines. These findings may provide more insight into the anti-tumorigenic capacities of BRE in human disease and cancer. PMID- 25446012 TI - Association of lifetime exposure to fluoride and cognitive functions in Chinese children: a pilot study. AB - BACKGROUND: A systematic review and meta-analysis of published studies on developmental fluoride neurotoxicity support the hypothesis that exposure to elevated concentrations of fluoride in water is neurotoxic during development. METHODS: We carried out a pilot study of 51 first-grade children in southern Sichuan, China, using the fluoride concentration in morning urine after an exposure-free night; fluoride in well-water source; and dental fluorosis status as indices of past fluoride exposure. We administered a battery of age appropriate, relatively culture-independent tests that reflect different functional domains: the Wide Range Assessment of Memory and Learning (WRAML), Wechsler Intelligence Scale for Children-Revised (WISC-IV) digit span and block design; finger tapping and grooved pegboard. Confounder-adjusted associations between exposure indicators and test scores were assessed using multiple regression models. RESULTS: Dental fluorosis score was the exposure indicator that had the strongest association with the outcome deficits, and the WISC-IV digit span subtest appeared to be the most sensitive outcome, where moderate and severe fluorosis was associated with a digit span total score difference of -4.28 (95% CI -8.22, -0.33) and backward score with -2.13 (95% CI -4.24, -0.02). CONCLUSIONS: This pilot study in a community with stable lifetime fluoride exposures supports the notion that fluoride in drinking water may produce developmental neurotoxicity, and that the dose-dependence underlying this relationship needs to be characterized in detail. PMID- 25446011 TI - Deletion of prolyl hydroxylase domain proteins (PHD1, PHD3) stabilizes hypoxia inducible factor-1 alpha, promotes neovascularization, and improves perfusion in a murine model of hind-limb ischemia. AB - BACKGROUND: There is an emerging focus on investigating innovative therapeutic molecules that can potentially augment neovascularization in order to treat peripheral arterial disease (PAD). Although prolyl hydroxylase domain proteins 1 and 3 (PHD1 and PHD3) may modulate angiogenesis via regulation of hypoxia inducible factor-1alpha (HIF-1alpha), there has been no study directly addressing their roles in ischemia-induced vascular growth. We hypothesize that PHD1(-/-) or PHD3(-/-) deficiency might promote angiogenesis in the murine hind-limb ischemia (HLI) model. STUDY DESIGN: Wild type (WT), PHD1(-/-) and PHD3(-/-) male mice aged 8-12weeks underwent right femoral artery ligation. Post-procedurally, motor function assessment and laser Doppler imaging were periodically performed. The mice were euthanized after 28days and muscles were harvested. Immunohistochemical analysis was performed to determine the extent of angiogenesis by measuring capillary and arteriolar density. VEGF expression was quantified by enzyme-linked immunosorbent assay (ELISA). Bcl-2 and HIF-1alpha were analyzed by immunofluorescence. Fibrosis was measured by picrosirius red staining. RESULTS: PHD1(-/-) and PHD3(-/-) mice showed significantly improved recovery of perfusion and motor function score when compared to WT after femoral artery ligation. These mice also exhibited increased capillary and arteriolar density, capillary/myocyte ratio along with decreased fibrosis compared to WT. VEGF, Bcl-2 and HIF-1alpha expression increased in PHD1(-/-) and PHD3(-/-) mice compared to WT. CONCLUSIONS: Taken together these results suggest that PHD1 and PHD3 deletions promote angiogenesis in ischemia-injured tissue, and may present a promising therapeutic strategy in treating PAD. PMID- 25446014 TI - Prenatal marijuana exposure predicts marijuana use in young adulthood. AB - BACKGROUND: Studies have reported effects of prenatal marijuana exposure (PME) on cognitive and behavioral outcomes. An earlier publication from this study found that PME predicted early onset of marijuana use and frequency of marijuana use at age 14. No study has reported the effects of PME on marijuana use in young adulthood. This is a developmental period when substance use peaks, and by which, initiation of substance use has largely occurred. METHODS: Subjects were from a longitudinal cohort. Women were interviewed initially in their fourth prenatal month and women and their offspring were followed through 22 years. Significant covariates of offspring marijuana use at 22 years were identified and controlled for using ordinal logistic regression. RESULTS: PME predicted marijuana use in the offspring at 22 years after controlling for significant covariates. Prenatal alcohol exposure, offspring race, gender, and age were also significant predictors, but family history of substance abuse or disorder, and sociodemographic and psychological characteristics of the mother and offspring were not. This association was not moderated by gender or race. CONCLUSIONS: PME is associated with subsequent marijuana use in young adulthood after considering the effects of other significant factors. These findings have important implications for public health given the recent trend toward legitimization of marijuana use. PMID- 25446013 TI - Effects of prenatal cocaine exposure on pubertal development. AB - The purpose of the current study was to examine the relationship between prenatal cocaine exposure (PCE) and pubertal development. Children (n=192; 41% with PCE) completed the Pubertal Development Scale (Petersen et al. 1988) and provided salivary dehydroepiandrosterone (DHEA) samples at 6month intervals from 11 to 13years. PCE was examined as a predictor of pubertal status, pubertal tempo, and DHEA levels in mixed models analyses controlling for age, sex, environmental risk, neonatal medical problems, other prenatal exposures, and BMI. PCE interacted with age such that PCE predicted slower pubertal tempo during early adolescence. PCE also interacted with age to predict slower increases in DHEA levels during early adolescence. These findings suggest that PCE may affect pubertal development and, if slower pubertal tempo continues, could lead to delayed pubertal status in mid-adolescence. PMID- 25446015 TI - Angiotensin AT2 receptor stimulation inhibits activation of NADPH oxidase and ameliorates oxidative stress in rotenone model of Parkinson's disease in CATH.a cells. AB - Oxidative stress has long been considered as a major contributing factor in the pathogenesis of Parkinson's disease (PD). The brain has an independent local renin-angiotensin system (RAS). Angiotensin II (Ang II) activates NADPH-dependent oxidases, which are a major source of superoxide and are upregulated in major aging-related diseases such as hypertension and neurodegenerative disease. In this study, we firstly examined whether CGP42112, an AT2 receptor (AT2R) agonist, may exert direct protective effects on the rotenone-induced CATH.a cell injury in vitro. We used CATH.a cell line to evaluate changes in cultured dopaminergic neuron levels of superoxide dismutase (SOD), glutathione (GSH) and reactive oxygen species (ROS). We also evaluated expression of NADPH oxidase, AT1 and AT2 receptors in treated with phosphate buffer saline (PBS), rotenone, Ang II, AT2R agonist CGP42112, or AT2R antagonist PD123319, alone and combined (n=6, each group). Quantitative reverse transcriptase PCR (qRT-PCR) and western blot were used to determine messenger RNA (mRNA) and protein levels of the AT1, AT2 receptors and NADPH oxidase. ROS generation was determined by the dichlorodihydrofluorescein diacetate fluorescent probe assay. The levels of SOD and GSH were measured by using available kits. In our study, CGP42112 (100nM) significantly reduced rotenone-induced oxidative stress and elevated the total SOD activity and GSH level. In addition, CGP42112 significantly increased AT2R expression and attenuated Ang II-induced NADPH oxidase activation, and these effects were completely abolished by the AT2R antagonist, PD123319 (1MUM). Our results suggest that CGP42112 attenuates rotenone-induced oxidative stress in CATH.a neuron via activating AT2R and suppressing NADPH oxidase expression. PMID- 25446016 TI - Behavioral assessment of NIH Swiss mice acutely intoxicated with tetramethylenedisulfotetramine. AB - Tetramethylenedisulfotetramine (TETS) is a potent convulsant poison that is thought to trigger seizures by inhibiting the function of the type A gamma aminobutyric acid receptor (GABAAR). Acute intoxication with TETS can cause vomiting, convulsions, status epilepticus (SE) and even death. Clinical case reports indicate that individuals who survive poisoning may exhibit long-term neuropsychological issues and cognitive deficits. Therefore, the objective of this research was to determine whether a recently described mouse model of acute TETS intoxication exhibits persistent behavioral deficits. Young adult male NIH Swiss mice received a seizure-inducing dose of TETS (0.15mg/kg, ip) and then were rescued from lethality by administration of diazepam (5mg/kg, ip) approximately 20min post-TETS-exposure. TETS-intoxicated mice typically exhibited 2 clonic seizures prior to administration of diazepam with no subsequent seizures post diazepam injection as assessed using behavioral criteria. Seizures lasted an average of 72s. Locomotor activity, anxiety-like and depression-relevant behaviors and cognition were assessed at 1week, 1month and 2months post-TETS exposure using open field, elevated-plus maze, light<->dark transitions, tail suspension, forced swim and novel object recognition tasks. Interestingly, preliminary validation tests indicated that NIH Swiss mice do not respond to the shock in fear conditioning tasks. Subsequent evaluation of hot plate and tail flick nociception tasks revealed that this strain exhibits significantly decreased pain sensitivity relative to age- and sex-matched C57BL/6J mice, which displayed normal contextual fear conditioning. NIH Swiss mice acutely intoxicated with TETS exhibited no significant anxiety-related, depression-relevant, learning or memory deficits relative to vehicle controls at any of the time points assessed with the exception of significantly increased locomotor activity at 2months post-TETS intoxication. The general absence of long-term behavioral deficits in TETS-intoxicated mice on these six assays suggests that the neurobehavioral consequences of TETS exposure described in human survivors of acute TETS intoxication are likely due to sustained seizure activity, rather than a direct effect of the chemical itself. Future research efforts are directed toward developing an animal model that better recapitulates the SE and seizure duration reported in humans acutely intoxicated with TETS. PMID- 25446017 TI - Low-dose paroxetine exposure causes lifetime declines in male mouse body weight, reproduction and competitive ability as measured by the novel organismal performance assay. AB - Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that is currently available on the market and is suspected of causing congenital malformations in babies born to mothers who take the drug during the first trimester of pregnancy. We utilized organismal performance assays (OPAs), a novel toxicity assessment method, to assess the safety of paroxetine during pregnancy in a rodent model. OPAs utilize genetically diverse wild mice (Mus musculus) to evaluate competitive performance between experimental and control animals as they compete among each other for limited resources in semi-natural enclosures. Performance measures included reproductive success, male competitive ability and survivorship. Paroxetine-exposed males weighed 13% less, had 44% fewer offspring, dominated 53% fewer territories and experienced a 2.5-fold increased trend in mortality, when compared with controls. Paroxetine-exposed females had 65% fewer offspring early in the study, but rebounded at later time points, presumably, because they were no longer exposed to paroxetine. In cages, paroxetine-exposed breeders took 2.3 times longer to produce their first litter and pups of both sexes experienced reduced weight when compared with controls. Low-dose paroxetine-induced health declines detected in this study that were undetected in preclinical trials with doses 2.5-8 times higher than human therapeutic doses. These data indicate that OPAs detect phenotypic adversity and provide unique information that could be useful towards safety testing during pharmaceutical development. PMID- 25446018 TI - Hospital-acquired acute kidney injury and hospital readmission: a cohort study. AB - BACKGROUND: Hospital-acquired acute kidney injury (AKI) is associated with increased mortality and resource consumption. Little is known about the association of AKI with short-term hospital readmissions. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: We investigated whether adult survivors of hospital-acquired AKI were at increased odds for early hospital readmission. PREDICTOR: The peak-to-nadir serum creatinine difference during the index hospitalization was used to define AKI according to the KDIGO (Kidney Disease: Improving Global Outcomes) classification and staging system. MEASUREMENTS: Multivariable logistic regression analyses examined the association of AKI with 30-, 60-, and 90-day hospital readmission, adjusting for age, sex, race, Charlson-Deyo comorbidity index score, acute hospital-related factors, common causes of hospitalization, and baseline estimated glomerular filtration rate. RESULTS: 3,345 (15%) of 22,001 included patients experienced AKI during the index hospitalization. Compared to the non-AKI group, the AKI group had a significantly higher 30-day hospital readmission rate (11% vs 15%; P<0.001), which persisted at 60 and 90 days. The AKI group also was more likely to be readmitted to the hospital within 30 days for cardiovascular-related conditions, mainly heart failure (P<0.001) and acute myocardial infarction (P=0.01). AKI associated independently with higher odds of 30-day hospital readmission (OR, 1.21; 95% CI, 1.08-1.36), which persisted at 60 (OR, 1.15; 95% CI, 1.03-1.27) and 90 days (adjusted OR, 1.13; 95% CI, 1.02-1.25). Results were attenuated in a propensity score-matched cohort of 5,912 patients. LIMITATIONS: Single-center study of mild forms of AKI; ascertainment bias and outcome misclassification due to the use of administrative codes. CONCLUSIONS: Our results suggest that survivors of hospital-acquired AKI experience higher odds of early hospital readmission. Transitions of care services may be warranted for such patients to prevent readmissions and reduce health care costs. PMID- 25446019 TI - Kidney function and influence of sunlight exposure in patients with impaired 24 hydroxylation of vitamin D due to CYP24A1 mutations. AB - Loss-of-function mutations of CYP24A1, the enzyme that converts the major circulating and active forms of vitamin D to inactive metabolites, recently have been implicated in idiopathic infantile hypercalcemia. Patients with biallelic mutations in CYP24A1 present with severe hypercalcemia and nephrocalcinosis in infancy or hypercalciuria, kidney stones, and nephrocalcinosis in adulthood. We describe a cohort of 7 patients (2 adults, 5 children) presenting with severe hypercalcemia who had homozygous or compound heterozygous mutations in CYP24A1. Acute episodes of hypercalcemia in infancy were the first symptom in 6 of 7 patients; in all patients, symptoms included nephrocalcinosis, hypercalciuria, low parathyroid hormone (PTH) levels, and higher than expected 1,25 dihydroxyvitamin D levels. Longitudinal data suggested that in most patients, periods of increased sunlight exposure tended to correlate with decreases in PTH levels and increases in calcemia and calciuria. Follow-up of the 2 adult patients showed reduced glomerular filtration rate and extrarenal manifestations, including calcic corneal deposits and osteoporosis. Cases of severe PTH independent hypercalcemia associated with hypercalciuria in infants should prompt genetic analysis of CYP24A1. These patients should be monitored carefully throughout life because they may be at increased risk for developing chronic kidney disease. PMID- 25446020 TI - Thrombotic microangiopathy in systemic lupus erythematosus: efficacy of eculizumab. AB - Thrombotic microangiopathy (TMA) is a severe disorder with poor outcomes. The cause is unknown for many patients, although TMA is associated with connective tissue disorders, including systemic lupus erythematosus (SLE). While uncommon, TMA is one of the most serious complications of SLE and in many cases may be resistant to therapy. We report a patient with SLE complicated by TMA that was refractory to standard therapy but responded well to eculizumab, with continued remission after 1 year of follow-up. Eculizumab might be useful in the management of resistant cases of TMA caused by SLE. PMID- 25446021 TI - Monoclonal IgG1kappa anti-glomerular basement membrane disease: a case report. AB - We report a case of anti-glomerular basement membrane (anti-GBM) nephritis with indolent course, monoclonal IgG1kappa (immunoglobulin G, subclass 1, kappa light chain) linear staining of the GBM, and multifocal GBM breaks but without crescents or detectable serum anti-GBM antibody in a patient followed over 9 years. Atypically, anti-GBM nephritis follows an indolent course. A very small fraction of patients with anti-GBM nephritis lack detectable circulating anti-GBM antibodies, and rare reports of monoclonal anti-GBM nephritis exist. We report what is to our knowledge the first case manifesting all 3 of these rare variations. Our patient initially presented with asymptomatic decreased kidney function following an upper respiratory tract infection. He was found to have microhematuria and subnephrotic proteinuria with mild diffuse endocapillary proliferative and exudative glomerulonephritis with linear IgG1kappa staining of the GBM. He was treated with an induction regimen of intravenous cyclophosphamide and corticosteroids followed by maintenance monotherapy with mycophenolic acid. Nine years later, repeat kidney biopsy for worsening kidney function after an upper respiratory tract infection showed persistent monoclonal staining of the GBM and acute glomerulonephritis with increased chronicity, including a single fibrocellular crescent. Despite extensive clinical investigations spanning nearly a decade, no circulating anti-GBM antibody or monoclonal protein has been detected. In this case report, we explore the unique features of this monoclonal IgG1kappa-associated anti-GBM nephritis. PMID- 25446022 TI - Peritoneal dialysis in China: meeting the challenge of chronic kidney failure. AB - Due to limited medical and economic resources, particularly in the countryside and remote areas, the proportion of individuals with end-stage kidney disease who are treated with dialysis in China is only about 20%. For the rest, renal replacement therapy currently is not available. Peritoneal dialysis (PD) has been developed and used for more than 30 years in China to treat patients with end stage kidney disease. Several national PD centers of first-rate scale and quality have sprung up, but the development of PD varies widely among geographic regions across China. The Chinese government has dedicated itself to continually increasing the coverage and level of medical service for patients with end-stage kidney disease. Under the guidance of the government and because of promotion by kidney care professionals, presently there are more than 40,000 prevalent PD patients in China, representing approximately 20% of the total dialysis population. Recently, a National Dialysis Unit Training Program for countywide hospitals has been initiated. Through the efforts of programs like this, we believe that awareness of PD and advances in the underlying technology will benefit more patients with end-stage kidney disease in China. PMID- 25446024 TI - Tonsillectomy for IgA nephropathy: a meta-analysis. AB - BACKGROUND: The efficacy of tonsillectomy in immunoglobulin A nephropathy (IgAN) remains controversial. Our meta-analysis was intended to investigate its efficacy as an adjunct or independent treatment. STUDY DESIGN: Meta-analysis of prospective and retrospective studies using PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. SETTING & POPULATION: Patients with IgAN treated with or without tonsillectomy. SELECTION CRITERIA FOR STUDIES: Studies that compared clinical remission or end-stage renal disease (ESRD) in patients with IgAN with or without tonsillectomy. INTERVENTION: Tonsillectomy. OUTCOMES: Clinical remission and ESRD. RESULTS: 14 studies (1,794 patients) were included and a random-effects model was applied. There were significantly greater odds of clinical remission with tonsillectomy (10 studies, 1,431 patients; pooled OR, 3.40; 95% CI, 2.58-4.48; P<0.001). Sensitivity analysis to exclude the effects of renin-angiotensin system inhibitors yielded consistent results (6 studies, 671 patients; pooled OR for remission, 2.80; 95% CI, 1.91-4.09; P<0.001). In subgroup analysis of the remission outcome, tonsillectomy plus steroid pulse therapy was superior to steroid pulse therapy alone (7 studies, 783 patients; pooled OR, 3.15; 95% CI, 1.99-5.01; P<0.001), and tonsillectomy plus conventional steroid therapy was superior to conventional steroid therapy alone (2 studies, 159 patients; pooled OR, 4.13; 95% CI, 1.23-13.94; P=0.02). Tonsillectomy was superior to general treatment (3 studies, 187 patients; pooled OR for remission, 2.21; 95% CI, 1.20-4.05; P=0.01). In addition, tonsillectomy was associated with decreased odds of ESRD (9 studies, 873 patients; pooled OR, 0.25; 95% CI, 0.12 0.52; P<0.001). 2 sensitivity analyses, one excluding studies with less than 5 years' follow-up and another excluding the confounding effect of renin angiotensin system inhibitors, yielded nearly the same reduction in ESRD risk (6 studies, 691 patients; pooled OR, 0.20; 95% CI, 0.11-0.36; P<0.001; and 6 studies, 547 patients; pooled OR, 0.24; 95% CI, 0.14-0.44; P<0.001). LIMITATIONS: Most included studies were retrospective cohort studies; we were unable to adjust uniformly for potential confounding variables. CONCLUSIONS: As adjunct or independent therapy, tonsillectomy may induce clinical remission and reduce the rates of ESRD in patients with IgAN. PMID- 25446023 TI - Association of high-sensitivity cardiac troponin T and natriuretic peptide with incident ESRD: the Atherosclerosis Risk in Communities (ARIC) study. AB - BACKGROUND: Epidemiologic data for cardiac abnormality predating decreased kidney function are sparse. We investigated the associations of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) with end-stage renal disease (ESRD) risk in a community-based cohort. STUDY DESIGN: A prospective cohort study. SETTING & PARTICIPANTS: 10,749 white and black participants at the fourth visit (1996-1998) of the Atherosclerosis Risk in Communities (ARIC) Study with follow-up through 2010. PREDICTOR: hs-cTnT (3, 6, 9, and 14ng/L) and NT-proBNP (41.6, 81.0, 142.5, and 272.5pg/mL) levels were divided into 5 categories at the same percentiles (32th, 57th, 77th, and 91th; corresponding to ordinary thresholds of hs-cTnT), with the lowest category as a reference. OUTCOMES: Incident ESRD defined as initiation of dialysis therapy, transplantation, or death due to kidney disease. MEASUREMENTS: Relative risk and risk prediction of ESRD according to hs-cTnT and NT-proBNP levels based on Cox proportional hazards models. RESULTS: During a median follow-up of 13.1 years, 235 participants developed ESRD (1.8 cases/1,000 person-years). hs-cTnT and NT proBNP levels were associated with ESRD risk independently of each other and of potential confounders, including kidney function and albuminuria (adjusted HRs for highest category, 4.43 [95% CI, 2.43-8.09] and 2.28 [95% CI, 1.44-3.60], respectively). For hs-cTnT level, the association was significant even at the third category (HR for 6-8ng/L of hs-cTnT, 2.74 [95% CI, 1.54-4.88]). Their associations were largely consistent even among persons without decreased kidney function or history of cardiovascular disease. hs-cTnT and NT-proBNP levels both significantly improved ESRD prediction (C statistic differences of 0.0084 [95% CI, 0.0005-0.0164] and 0.0045 [95% CI, 0.0004-0.0087], respectively, from 0.884 with conventional risk factors). LIMITATIONS: Relatively small number of ESRD cases and single measurement of hs-cTnT and NT-proBNP. CONCLUSIONS: hs-cTnT and NT-proBNP levels independently predicted ESRD risk in the general population, with more evident results for hs-cTnT. These results suggest the involvement of cardiac abnormality, particularly cardiac injury, in the progression of reduced kidney function and/or may reflect the useful property of hs-cTnT as an end-organ damage marker. PMID- 25446026 TI - GFR decline as an end point in trials of CKD: a viewpoint from the FDA. PMID- 25446025 TI - beta-Trace protein: a marker of GFR and other biological pathways. AB - beta-Trace protein (BTP), also known as lipocalin prostaglandin D2 synthase (L PGDS; encoded by the PTGDS gene), is a low-molecular-weight glycoprotein and an emerging novel marker of glomerular filtration rate. BTP is an important constituent of cerebral spinal fluid and is found in much lower concentrations in blood. Its serum origin and renal handling remain poorly understood. Unlike serum creatinine, BTP is not physiologically inert. It possesses both ligand-binding and enzymatic properties. BTP catalyzes the conversion of prostaglandin H2 (PGH2) to PGD2. PGD2 is an eicosanoid involved in a variety of important physiologic processes, including platelet aggregation, vasodilation, inflammation, adipogenesis, and bone remodeling. Several studies now have documented BTP's strong association with glomerular filtration rate, end-stage renal disease, cardiovascular disease, and death in a variety of different patient populations. This review provides an overview of the biochemistry, physiology and metabolism, biological functions, and measurement of BTP; summarizes the evidence for BTP as a marker of both kidney function and cardiovascular disease; and then considers the interplay between its biological properties, serum concentration, and patient outcomes. PMID- 25446027 TI - Synthesis, anticonvulsant activity and metabolism of 4-chlor-3 methylphenoxyethylamine derivatives of trans-2-aminocyclohexan-1-ol. AB - In this study, we report the synthesis, spectral characterization, antiepileptic activity and biotransformation of three new, chiral, N-aminoalkyl derivatives of trans - 2 aminocyclohexan-1-ol: (R enantiomer), (S enantiomer) and (racemate). Antiepileptic activity of the titled compounds was studied using MES and scMet. Moreover, in this study, the biotransformation of , and in microbial model (Cunninghamella), liver microsomal assay as well as in silico studies (MetaSite) was evaluated. Studies have indicated that , and have good antiepileptic activity in vivo, comparable to valproate. Biotransformation assays showed that the most probable metabolite (indicated in every tested assays) was . The microbial model as well as in silico study showed no difference in biotransformation between tested enantiomers. However, in a rat liver microsomal study compound and (R and S enantiomer) had different main metabolite - for and for . MS/MS fragmentation allowed us to predict the structures of obtained metabolites, which were in agreement with 1 degrees alcohol () and carboxylic acid (). Our research has shown that microbial model, microsomal assay, and computational methods can be included as useful and reliable tools in early ADME-Tox assays in the process of developing new drug candidates. PMID- 25446028 TI - Xenopus laevis FGF receptor substrate 3 (XFrs3) is important for eye development and mediates Pax6 expression in lens placode through its Shp2-binding sites. AB - Members of the fibroblast growth factor (FGF) family play important roles during various developmental processes including eye development. FRS (FGF receptor substrate) proteins bind to FGFR and serve as adapters for coordinated assembly of multi-protein complexes involved in Ras/MAPK and PI3 kinase/Akt pathways. Here, we identified Xenopus laevis Frs3 (XFrs3), a homolog of vertebrate Frs3, and investigated its roles during embryogenesis. XFrs3 is expressed maternally and zygotically with specific expression patterns throughout the early development. Knockdown of XFrs3 using a specific antisense morpholino oligonucleotide (MO) caused reduction of Pax6 expression in the lens placode, and defects in the eye ranging from microphthalmia to anophthalmia. XFrs3 MO-induced defects were alleviated by wild type XFrs3 or a mutant XFrs3 (XFrs3-4YF), in which the putative tyrosine phosphorylation sites served as Grb2-binding sites are mutated. However, another XFrs3 mutant (XFrs3-2YF), in which the putative Shp2-binding sites are mutated, could not rescue the defects of XFrs3 morphants. In addition, we found that XFrs3 is important for FGF or IGF-induced ERK activation in ectodermal tissue. Taken together, our results suggest that signaling through Shp2-binding sites of XFrs3 is necessary for the eye development in Xenopus laevis. PMID- 25446029 TI - Non-muscle myosin IIA and IIB differentially regulate cell shape changes during zebrafish brain morphogenesis. AB - During brain morphogenesis, the neuroepithelium must fold in specific regions to delineate functional units, and give rise to conserved embryonic brain shape. Individual cell shape changes are the basis for the morphogenetic events that occur during whole tissue shaping. We used the zebrafish to study the molecular mechanisms that regulate the first fold in the vertebrate brain, the highly conserved midbrain-hindbrain boundary (MHB). Since the contractile state of the neuroepithelium is tightly regulated by non-muscle myosin II (NMII) activity, we tested the role of NMIIA and NMIIB in regulating cell shape changes that occur during MHB morphogenesis. Using morpholino knockdown, we show that NMIIA and NMIIB are both required for normal MHB tissue angle. Quantification of cell shapes revealed that NMIIA is required for the shortening of cells specifically at the MHB constriction (MHBC), while NMIIB is required for the proper width of cells throughout the MHB region. NMIIA and NMIIB knockdown also correlated with abnormal distribution of actin within the cells of the MHBC. Thus, NMIIA and NMIIB perform distinct functions in regulating cell shape during MHB morphogenesis. PMID- 25446030 TI - Pax8 and Pax2 are specifically required at different steps of Xenopus pronephros development. AB - The respective role of Pax2 and Pax8 in early kidney development in vertebrates is poorly understood. In this report, we have studied the roles of Pax8 and Pax2 in Xenopus pronephros development using a loss-of-function approach. Our results highlight a differential requirement of these two transcription factors for proper pronephros formation. Pax8 is necessary for the earliest steps of pronephric development and its depletion leads to a complete absence of pronephric tubule. Pax2 is required after the establishment of the tubule pronephric anlage, for the expression of several terminal differentiation markers of the pronephric tubule. Neither Pax2 nor Pax8 is essential to glomus development. We further show that Pax8 controls hnf1b, but not lhx1 and Osr2, expression in the kidney field as soon as the mid-neurula stage. Pax8 is also required for cell proliferation of pronephric precursors in the kidney field. It may exert its action through the wnt/beta-catenin pathway since activation of this pathway can rescue MoPax8 induced proliferation defect and Pax8 regulates expression of the wnt pathway components, dvl1 and sfrp3. Finally, we observed that loss of pronephros in Pax8 morphants correlates with an expanded vascular/blood gene expression domain indicating that Pax8 function is important to delimit the blood/endothelial genes expression domain in the anterior part of the dorso-lateral plate. PMID- 25446032 TI - Embryonic development of the nervous system in the planarian Schmidtea polychroa. AB - The development of a nervous system is a key innovation in the evolution of metazoans, which is illustrated by the presence of a common developmental toolkit for the formation of this organ system. Neurogenesis in the Spiralia, in particular the Platyhelminthes, is, however, poorly understood when compared with other animal groups. Here, we characterize embryonic neurogenesis in the freshwater flatworm Schmidtea polychroa and analyze the expression of soxB and a set of proneural bHLH genes, which are gene families with a well-established role in metazoan early neural development. We show that the nervous system is fully de novo assembled after the early embryo ingests the maternal nutrients. At early stages of neurogenesis, soxB1 genes are expressed in putative neural progenitor cells, whereas soxB2 and neural bHLH genes (achaete-scute, neuroD and beta3) are associated with late neurogenesis and the specification of neural subpopulations of the central and peripheral nervous system. Our findings are consistent with the role of proneural genes in other bilaterians, suggesting that the ancestral neural-specific gene regulatory network is conserved in triclads, despite exhibiting a divergent mode of development. PMID- 25446033 TI - The transcription factor hairy/E(spl)-related 2 induces proliferation of neural progenitors and regulates neurogenesis and gliogenesis. AB - The study of molecular regulation in neural development provides information to understand how diverse neural cells are generated. It also helps to establish therapeutic strategies for the treatment of neural degenerative disorders and brain tumors. The Hairy/E(spl) family members are potential targets of Notch signaling, which is fundamental to neural cell maintenance, cell fate decisions, and compartment boundary formation. In this study, we isolated a zebrafish homolog of Hairy/E(spl), her2, and showed that this gene is expressed in neural progenitor cells and in the developing nervous system. The expression of her2 required Notch activation, as revealed by a Notch-defective mutant and a chemical inhibitor, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). The endogenous expression of Her2 was altered by both overexpression and morpholino-knockdown approaches, and the results demonstrated that Her2 was both necessary and sufficient to promote the proliferation of neural progenitors by inhibiting the transcription of the cell cycle inhibitors cdkn1a, cdkn1ba, and cdkn1bb. Her2 knockdown caused premature neuronal differentiation, which indicates that Her2 is essential for inhibiting neuronal differentiation. At a later stage of neural development, Her2 could induce glial differentiation. The overexpression of Her2 constructs lacking the bHLH or WRPW domain phenocopied the effect of the morpholino knockdown, demonstrating the essential function of these two domains and further confirming the knockdown specificity. In conclusion, our data reveal that Her2 promotes progenitor proliferation and maintains progenitor characteristics by inhibiting neuronal differentiation. Together, these two mechanisms ensure the proper development of the neural progenitor cell pool. PMID- 25446031 TI - Retinoic acid regulates Kit translation during spermatogonial differentiation in the mouse. AB - In the testis, a subset of spermatogonia retains stem cell potential, while others differentiate to eventually become spermatozoa. This delicate balance must be maintained, as defects can result in testicular cancer or infertility. Currently, little is known about the gene products and signaling pathways directing these critical cell fate decisions. Retinoic acid (RA) is a requisite driver of spermatogonial differentiation and entry into meiosis, yet the mechanisms activated downstream are undefined. Here, we determined a requirement for RA in the expression of KIT, a receptor tyrosine kinase essential for spermatogonial differentiation. We found that RA signaling utilized the PI3K/AKT/mTOR signaling pathway to induce the efficient translation of mRNAs for Kit, which are present but not translated in undifferentiated spermatogonia. Our findings provide an important molecular link between a morphogen (RA) and the expression of KIT protein, which together direct the differentiation of spermatogonia throughout the male reproductive lifespan. PMID- 25446035 TI - A health status survey of clams, Mya arenaria and Ensis siliqua, in the Irish Sea. AB - The soft shell clam, Mya arenaria, and the razor clam, Ensis siliqua, are widely distributed in Irish waters. Though the reproductive biology and other aspects of the physiology of these species has been previously investigated, little or no data are currently available on their health status. As this knowledge is essential for correct management of a species, M. arenaria and E. siliqua were examined to assess their current health status using histological and molecular methods, over a period of sixteen months. No pathogens or disease were observed in M. arenaria, and low incidences of Prokaryote inclusions, trematode parasites, Nematopsis spp. and eosinophilic bodies were recorded in razor clams for the first time in Northern European waters. PMID- 25446034 TI - Quantitative real-time PCR (qPCR)--based tool for detection and quantification of Cordyceps militaris in soil. AB - A quantitative real-time PCR using a primer pair CM2946F/CM3160R was developed for specific detection and quantification of Cordyceps militaris from soil. Standard curves were obtained for genomic DNA and DNA extracts from autoclaved soil with a certain dose of C. militaris suspension. C. militaris was detected from two forest soil samples out of ten that were collected when fruit bodies of C. militaris were found. This method seemed effective in detection of C. militaris in the soil and useful for rapid and reliable quantification of C. militaris in different ecosystems. PMID- 25446036 TI - Aspergillus flavus impairs antioxidative enzymes of Sternochetus mangiferae during mycosis. AB - Insects depend upon cuticular, humoral and cellular defenses to resist mycosis. However, entomopathogenic fungi through co-evolution have developed mechanisms to counter such defenses. Although a plethora of mechanisms of mycosis by entomopathogenic fungi are well-established, studies on the impairment of insects' antioxidative enzymes during mycosis remain elusive. Here, we used the interaction of Sternochetus mangiferae and its associated entomopathogenic fungus, Aspergillus flavus, as a model to validate our hypothesis. Uninfected insects were exposed to fungal spores for infection to occur. We observed symptoms of mycosis within 48 h of incubation period. Biochemical studies on antioxidative enzymes namely catalase, peroxidase and phenoloxidase, in infected and uninfected insects revealed decreased activity of these enzymes. It appears that A. flavus disables the host's antioxidative enzyme system that plays a crucial role in elimination of oxidative toxins produced during mycosis. PMID- 25446037 TI - Mortality risk from entomopathogenic fungi affects oviposition behavior in the parasitoid wasp Trybliographa rapae. AB - Biological control of pests in agroecosystems could be enhanced by combining multiple natural enemies. However, this approach might also compromise the control efficacy through intraguild predation (IGP) among the natural enemies. Parasitoids may be able to avoid the risk of unidirectional IGP posed by entomopathogenic fungi through selective oviposition behavior during host foraging. Trybliographa rapae is a larval parasitoid of the cabbage root fly, Delia radicum. Here we evaluated the susceptibility of D. radicum and T. rapae to two species of generalist entomopathogenic fungi, Metarhizium brunneum isolate KVL 04-57 and Beauveria bassiana isolate KVL 03-90. Furthermore, T. rapae oviposition behavior was assessed in the presence of these entomopathogenic fungi either as infected hosts or as infective propagules in the environment. Both fungi were pathogenic to D. radicum larvae and T. rapae adults, but with variable virulence. When host patches were inoculated with M. brunneum conidia in a no choice situation, more eggs were laid by T. rapae in hosts of those patches compared to control and B. bassiana treated patches. Females that later succumbed to mycosis from either fungus laid significantly more eggs than non-mycosed females, indicating that resources were allocated to increased oviposition due to perceived decreased life expectancy. When presented with a choice between healthy and fungal infected hosts, T. rapae females laid more eggs in healthy larvae than in M. brunneum infected larvae. This was less pronounced for B. bassiana. Based on our results we propose that T. rapae can perceive and react towards IGP risk posed by M. brunneum but not B. bassiana to the foraging female herself and her offspring. Thus, M. brunneum has the potential to be used for biological control against D. radicum with a limited risk to T. rapae populations. PMID- 25446038 TI - Bacillus licheniformis as a cause of a deep skin abscess in a 5-year-old girl: An exceptional case following a plant thorn injury. PMID- 25446041 TI - New advances in understanding stem cell fate and function. PMID- 25446039 TI - Management and outcome of adults with skin and soft tissue infection caused by methicillin-resistant Staphylococcus aureus in a tertiary hospital in central Taiwan. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) has been increasingly causing skin and soft tissue infections (SSTIs). Only limited studies have made comparisons between incision and drainage (I&D) alone and I&D with adjunctive antibiotic therapy for treatment effects, and most of the studies were conducted before the emergence of MRSA. This study was to evaluate whether antibiotics provide added benefit to I&D alone for purulent MRSA SSTIs. METHODS: This retrospective study collected data on SSTI patients, including patient demographics, treatment strategies, antibiotic susceptibilities of the infecting MRSA isolates, and clinical outcomes over the course of 24 months. RESULTS: Antimicrobial drug susceptibility rate were 100% for vancomycin, teicoplanin, and linezolid. Among the 211 patients, 7.6% were treated solely with I&D (Group A), 62.6% were treated via I&D with adjunctive antibiotic (Group B), and 29.8% patients received only antibiotics (Group C). The cure rate was highest in Group A (93.8%), followed by Group B (90.9%) and Group C (77.8%). Combining Group B and Group C, patients who were treated appropriately demonstrated a higher cute rate (91.3% vs. 75.4%, p = 0.005). Multivariate analysis showed that Group B was more likely to be successfully treated compared to Group C (odds ratio = 2.51, 95% confidence interval = 1.01-6.25, p = 0.047), whereas no difference between Group A and Group B was found (odds ratio = 2.09, 95% confidence interval = 0.20-22.34, p = 0.542, data not shown). CONCLUSION: Surgical intervention is the definitive therapy for purulent SSTIs. Adjunctive antibiotic therapy increased the cure rate and appropriateness of prescription is influential. PMID- 25446040 TI - Hydrogeochemistry of the drinking water sources of Derebogazi Village (Kahramanmaras) and their effects on human health. AB - The aim of this study was to investigate the sources of drinking water for Derebogazi Village, Kahramanmaras Province, Turkey, in terms of hydrogeochemistry, isotope geochemistry, and medical geology. Water samples were obtained from seven different water sources in the area, all of which are located within quartzite units of Paleozoic age, and isotopic analyses of (18)O and (2)H (deuterium) were conducted on the samples. Samples were collected from the region for 1 year. Water quality of the samples was assessed in terms of various water quality parameters, such as temperature, pH, conductivity, alkalinity, trace element concentrations, anion-cation measurements, and metal concentrations, using ion chromatography, inductively coupled plasma (ICP) mass spectrometry, ICP optical emission spectrometry techniques. Regional health surveys had revealed that the heights of local people are significantly below the average for the country. In terms of medical geology, the sampled drinking water from the seven sources was deficient in calcium and magnesium ions, which promote bone development. Bone mineral density screening tests were conducted on ten females using dual energy X-ray absorptiometry to investigate possible developmental disorder(s) and potential for mineral loss in the region. Of these ten women, three had T-scores close to the osteoporosis range (T-score < -2.5). PMID- 25446042 TI - Resistance to sunitinib in renal cell carcinoma: From molecular mechanisms to predictive markers and future perspectives. AB - The introduction of agents that inhibit tumor angiogenesis by targeting vascular endothelial growth factor (VEGF) signaling has made a significant impact on the survival of patients with metastasized renal cell carcinoma (RCC). Sunitinib, a tyrosine kinase inhibitor of the VEGF receptor, has become the mainstay of treatment for these patients. Although treatment with sunitinib substantially improved patient outcome, the initial success is overshadowed by the occurrence of resistance. The mechanisms of resistance are poorly understood. Insight into the molecular mechanisms of resistance will help to better understand the biology of RCC and can ultimately aid the development of more effective therapies for patients with this infaust disease. In this review we comprehensively discuss molecular mechanisms of resistance to sunitinib and the involved biological processes, summarize potential biomarkers that predict response and resistance to treatment with sunitinib, and elaborate on future perspectives in the treatment of metastasized RCC. PMID- 25446043 TI - Enhanced dissolution rate and oral bioavailability of Ginkgo biloba extract by preparing solid dispersion via hot-melt extrusion. AB - The aim of this study was to improve the dissolution rate and oral bioavailability of Ginkgo biloba extract (GBE) through the preparation of G. biloba extract solid dispersions (GBE-SD) via hot-melt extrusion (HME). First, we prepared the GBE-SD based on a Kollidon(r) VA64/Kolliphor(r) RH40 (85:15) spray dried powder. Then physicochemical properties were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR). The results indicated that GBE dispersed well in a carrier matrix. Subsequently, we studied the dissolution profile of total flavonoids (TFs) by HPLC-UV and total terpene lactones (TTLs) by HPLC-ELSD. The dissolution percentage of TFs and TTLs was improved within 120min. Finally, we studied the pharmacokinetic characteristics and bioavailability in rats by UPLC MS/MS. The results showed that the Cmax and AUC0-t of bilobalide (BB), ginkgolide A (GA), ginkgolide B (GB), ginkgolide C (GC), quercetin (QCT), kaempferol (KMF) and isorhamnetin (ISR) in rats were significantly increased after the oral administration of GBE-SD compared with results after the oral administration of GBE. These results suggest that the solid dispersion preparation by HME could serve as a promising formulation approach to enhancing the dissolution rate and oral bioavailability of GBE. PMID- 25446044 TI - Cytotoxic prenylated bibenzyls and flavonoids from Macaranga kurzii. AB - One unique prenylated bibenzyl, kurzphenol A (1), two new prenylated flavonoids, kurzphenols B and C (2 and 3), as well as fourteen known compounds (4-17) were isolated from the twigs of Macaranga kurzii. Compound 1 was the first example of prenylated bibenzyl which possesses a benzofuran ring. All the known compounds were isolated from M. kurzii for the first time. Their structures were elucidated on the basis of extensive spectroscopic interpretation. Compounds 1-17 were tested for their cytotoxicity against A-549 and Hep G2 cancer cell lines and showed IC50 values in the range of 9.76-30.14 MUg/mL. PMID- 25446045 TI - The 20 advances that have defined contemporary hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) emerged as a distinct disease entity in about 1960. Over the subsequent 55-year time span, HCM has undergone vast changes in its perception by the cardiovascular community, often fraught with controversy and misunderstanding, but ultimately benefiting from innovations in therapy and diagnosis, such as echocardiography and cardiovascular magnetic resonance imaging, implantable defibrillators, surgical myectomy and alcohol ablation, and heart transplantation. Once considered an oddity and exotic disease, HCM can now take its place as a contemporary and treatable disease with relatively low mortality risks. Here we have listed and discussed what we believe to be the 20 most important advances in the evolution of HCM based on more than 50 years of our combined experience with this complex genetic disease. PMID- 25446046 TI - Cellular and ionic basis of J-wave syndromes. AB - J-wave syndromes are disorders of ventricular repolarization characterized by prominent J waves on the ECG and have the potential to predispose affected individuals to lethal ventricular arrhythmias. These disorders share a common cellular mechanism with prominent Ito in ventricular epicardium. This current causes transmural dispersion of repolarization and the generation of phase 2 reentry, leading to short-coupled extrasystoles and VF. Several autonomic, chemical, and hormonal factors modulate Ito and are therefore vital in attenuating or increasing the arrhythmic potential of these syndromes. Future research should focus on evaluating the arrhythmogenic potential of patients with pathogenic genotypes and/or J waves and no history of VF. PMID- 25446048 TI - Early repolarization and arrhythmic death: six more years? PMID- 25446047 TI - What if the FDA had launched its action plan to close the health disparities gap for women two decades earlier? PMID- 25446049 TI - Impact of obesity on cardiac metabolism, fibrosis, and function. AB - Obesity is a global pandemic with a huge burden on the healthcare system. Obesity is not only linked to the development of risk factors for atherosclerotic vascular disease but also has a strong association with ventricular hypertrophy, heart failure, atrial fibrillation, and stroke. Recent experimental and clinical studies have demonstrated that obesity is associated with cardiac dysfunction, adipokine dysregulation, and activation of the pro-fibrotic signaling pathways leading to cardiac fibrosis, which is a key structural change responsible for atrial fibrillation. Importantly, these also have been shown to be reversible with weight reduction strategies. This review discusses the alterations in cardiac metabolism and function due to obesity. In addition, it addresses the complex and not yet fully understood mechanisms underlying cardiac fibrosis, with a focus on atrial substrate predisposing to atrial fibrillation in obesity. PMID- 25446050 TI - Mouse models of cardiac conduction system markers: revealing the past, present, and future of pacemaking and conduction. PMID- 25446051 TI - Oxaliplatin-related acute disseminated intravascular coagulation syndrome in a patient with metastatic colon cancer. PMID- 25446052 TI - Case report of rhabdoid colon cancer and review of literature. PMID- 25446053 TI - Incidence of chemotherapy- and chemoradiotherapy-induced amenorrhea in premenopausal women with stage II/III colorectal cancer. AB - BACKGROUND: The incidence rates of colorectal cancer (CRC) in young individuals are increasing. There has been a significant improvement in overall survival in CRC because of advances in adjuvant chemotherapy and chemoradiotherapy over the past decades. However, these procedures may compromise the function of the reproductive system, and ovarian failure and premature menopause may occur. The objective of this analysis was to determine the incidence of long-term amenorrhea (>= 12 months) in women with CRC aged 40 years and younger after adjuvant treatment. PATIENTS AND METHODS: The authors identified 162 premenopausal women with CRC aged 40 years or younger who were treated with adjuvant chemotherapy and chemoradiotherapy at Fudan University Shanghai Cancer Center from January 2008 to December 2012. One hundred twenty-three patients met all eligibility criteria and had sufficient follow-up for evaluation. The median age at diagnosis in patients with colon and rectal cancers was, respectively, 36 and 35 years (range, 17-40 and 24-40 years). RESULTS: All patients had regular menses before treatment; 3 patients with colon cancer (4.2%) experienced long-term amenorrhea, and 48 patients with rectal cancer (94.1%) experienced long-term amenorrhea. The incidence of amenorrhea was significantly lower in patients with colon cancer (4.2%; 3 of 72) than in patients with rectal cancer (94.1%; 48 of 51) (P < .01). CONCLUSION: In this retrospective series, the incidence of amenorrhea in patients with colon and rectal cancers was 4.2% and 94.1%, respectively. We believe our data support the fact that young female patients with CRC, especially those with rectal cancer who are scheduled to undergo pelvic irradiation, should be counseled regarding fertility preservation options, including ovarian transposition and cryopreservation of ovarian tissue, embryo, or oocyte. PMID- 25446054 TI - A guide to research partnerships for pragmatic clinical trials. PMID- 25446056 TI - Fontan circulation: the search for targeted therapy. PMID- 25446058 TI - Coronary computed tomographic angiography: its role in emergency department triage. PMID- 25446055 TI - Isoprenoid precursor biosynthesis is the essential metabolic role of the apicoplast during gametocytogenesis in Plasmodium falciparum. AB - The malaria parasite harbors a relict plastid called the apicoplast and its discovery opened a new avenue for drug discovery and development due to its unusual, nonmammalian metabolism. The apicoplast is essential during the asexual intraerythrocytic and hepatic stages of the parasite, and there is strong evidence supporting its essential metabolic role during the mosquito stages of the parasite. Supply of the isoprenoid building blocks isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) is the essential metabolic function of the apicoplast during the asexual intraerythrocytic stages. However, the metabolic role of the apicoplast during gametocyte development, the malaria stages transmitted to the mosquito, remains unknown. In this study, we showed that production of IPP for isoprenoid biosynthesis is the essential metabolic function of the apicoplast during gametocytogenesis, by obtaining normal gametocytes lacking the apicoplast when supplemented with IPP. When IPP supplementation was removed early in gametocytogenesis, developmental defects were observed, supporting the essential role of isoprenoids for normal gametocytogenesis. Furthermore, mosquitoes infected with gametocytes lacking the apicoplast developed fewer and smaller oocysts that failed to produce sporozoites. This finding further supports the essential role of the apicoplast in establishing a successful infection in the mosquito vector. Our study supports isoprenoid biosynthesis as a valid drug target for development of malaria transmission-blocking inhibitors. PMID- 25446060 TI - ECG response: December 2, 2014. PMID- 25446059 TI - Explaining unexplained dyspnea: the ever "holesome" heart. PMID- 25446057 TI - Bosentan improves exercise capacity in adolescents and adults after Fontan operation: the TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study. AB - BACKGROUND: The Fontan procedure has improved survival in children with functionally univentricular hearts. With time, however, complications such as reduced exercise capacity are seen more frequently. Exercise intolerance is multifactorial, but pulmonary vascular resistance probably plays a crucial role. Elevated pulmonary vascular resistance has been associated with raised levels of endothelin-1, which are common both before and after Fontan operations. Treatment with endothelin-1 receptor antagonists could theoretically improve cardiopulmonary hemodynamics and exercise capacity. The aim of this study was therefore to examine the efficacy and safety of bosentan in Fontan patients. METHODS AND RESULTS: Seventy-five adolescents and adults were randomized 1:1 to 14 weeks of treatment with bosentan or placebo. Cardiopulmonary exercise test, functional class, blood samples, and quality-of-life questionnaires were evaluated at baseline and at the end of treatment. Sixty-nine patients (92%) completed the study. Peak oxygen consumption increased 2.0 mL.kg(-1).min(-1) (from 28.7 to 30.7 mL.kg(-1).min(-1)) in the bosentan group compared with 0.6 mL.kg(-1).min(-1) (from 28.4 to 29.0 mL.kg(-1).min(-1)) in the placebo group (P=0.02). Cardiopulmonary exercise test time increased by 0.48 minute (from 6.79 to 7.27 minutes) versus 0.08 minute (from 6.94 to 7.02 minutes; P=0.04). Nine bosentan-treated patients improved 1 functional class, whereas none improved in the placebo group (P=0.0085). Side effects were mild and occurred equally in both groups. No serious adverse effects were seen, and no patients had liver enzyme levels above the 3-fold upper limit. CONCLUSIONS: Bosentan improves exercise capacity, exercise time, and functional class in Fontan patients without serious adverse events or hepatotoxicity. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01292551. PMID- 25446061 TI - Cannabis-associated angiopathy: an uncommon cause of crescendo transient ischemic attacks. PMID- 25446063 TI - Marked septal dyskinesis from Wolff-Parkinson-White syndrome. PMID- 25446064 TI - Letter from Cohen and Alderman regarding article, "lower levels of sodium intake and reduced cardiovascular risk". PMID- 25446065 TI - Response to letter regarding article, "lower levels of sodium intake and reduced cardiovascular risk". PMID- 25446069 TI - Zinc-alpha2 -glycoprotein is associated with insulin resistance in children. PMID- 25446068 TI - Comparison of microsuspension laryngoscopy positions: a randomized, prospective study. AB - OBJECTIVES/HYPOTHESIS: To evaluate muscle fatigue and participant pain in the upper back, cervical, and arm muscles associated with microlaryngeal surgery (MLS) in standardized favorable and unfavorable ergonomic positions. STUDY DESIGN: Individual randomized counterbalanced design. METHODS: Electromyographic sensors were placed on targeted muscles involved with performing MLS on 18 otolaryngology residents/fellows. Subjects were randomly counterbalanced in both favorable and unfavorable positions while completing simulated laryngeal microsurgical tasks. Participants reported their extent of muscle discomfort in targeted muscle regions on a standardized survey. RESULTS: Muscle fatigue and self-reported pain were reduced, and productivity was improved in the favorable position. In the lower trapezius, significantly less muscle activation (P = 0.025) and less pain (P < 0.05) were found while in the favorable position compared to the unfavorable position. CONCLUSION: This is the first study to demonstrate electromyographic evidence of decreased muscle activation and fatigue, in addition to self-reported pain with a more favorable microsurgical ergonomic position, which may help surgeons avoid musculoskeletal injuries. PMID- 25446070 TI - Sensate superficial inferior epigastric artery flap innervated by the iliohypogastric nerve for reconstruction of a finger soft tissue defect. AB - In the era of perforator flaps, lower-abdominal/inguinal perforator flaps such as superficial circumflex iliac artery perforator (SCIP) flap and superficial inferior epigastric artery (SIEA) perforator flap are becoming popular with its longer vascular pedicle and usefulness in various reconstructions. SIEA flap's region is innervated by the T12 nerve and the iliohypogastric nerve (IHN), but no sensate SIEA flap has been reported so far. In this report, we present a case in which a sensate SIEA flap innervated by the IHN was used for reconstruction of a finger soft tissue defect. A 55-year-old male suffering from the volar skin necrosis of the right ring finger underwent the volar soft tissue reconstruction using a free sensate SIEA flap because of hypoplastic SCIA. The SIEA flap included the IHN anterior branch, and neuroraphy was performed between the IHN and the third common digital nerve in an end-to-side manner after vascular anastomoses. The reconstructed volar skin could sensate 14 weeks after the surgery. At postoperative 6 months, Semmes-Weinstein test and moving 2-point discrimination revealed 3.64 and 8 mm in the proximal portion of the SIEA flap where the IHN was supposed to innervate. The IHN may be included in a SIEA flap, and a sensate SIEA flap may be a useful option when a SCIP flap is not available. Further anatomical and clinical studies are required to clarify anatomy and clinical usefulness of the IHN. PMID- 25446071 TI - Impact of cadmium, cobalt and nickel on sequence-specific DNA binding of p63 and p73 in vitro and in cells. AB - Site-specific DNA recognition and binding activity belong to common attributes of all three members of tumor suppressor p53 family proteins: p53, p63 and p73. It was previously shown that heavy metals can affect p53 conformation, sequence specific binding and suppress p53 response to DNA damage. Here we report for the first time that cadmium, nickel and cobalt, which have already been shown to disturb various DNA repair mechanisms, can also influence p63 and p73 sequence specific DNA binding activity and transactivation of p53 family target genes. Based on results of electrophoretic mobility shift assay and luciferase reporter assay, we conclude that cadmium inhibits sequence-specific binding of all three core domains to p53 consensus sequences and abolishes transactivation of several promoters (e.g. BAX and MDM2) by 50MUM concentrations. In the presence of specific DNA, all p53 family core domains were partially protected against loss of DNA binding activity due to cadmium treatment. Effective cadmium concentration to abolish DNA-protein interactions was about two times higher for p63 and p73 proteins than for p53. Furthermore, we detected partial reversibility of cadmium inhibition for all p53 family members by EDTA. DTT was able to reverse cadmium inhibition only for p53 and p73. Nickel and cobalt abolished DNA-p53 interaction at sub-millimolar concentrations while inhibition of p63 and p73 DNA binding was observed at millimolar concentrations. In summary, cadmium strongly inhibits p53, p63 and p73 DNA binding in vitro and in cells in comparison to nickel and cobalt. The role of cadmium inhibition of p53 tumor suppressor family in carcinogenesis is discussed. PMID- 25446072 TI - DNAJC6 promotes hepatocellular carcinoma progression through induction of epithelial-mesenchymal transition. AB - Epithelial-mesenchymal transition (EMT) is a developmental program, which is associated with hepatocellular carcinoma (HCC) development and progression. DNAJC6 (DNA/HSP40 homolog subfamily C member 6) encodes auxilin, which is responsible for juvenile Parkinsonism with phenotypic variability. However, the role of DNAJC6 in HCC development and progression is limited. Here, we report that DNAJC6 is up-regulated in HCC tissues and up-regulation of DNAJC6 expression predicts poor outcome in patients with HCC. Furthermore, overexpression of DNAJC6 enhances the ability for acquisition of mesenchymal traits, enhanced cell proliferation and invasion. DNAJC6 positively regulated expression of EMT-related transcription factor, also activating transforming growth factor beta (TGF-beta) pathway to contribute to EMT. Our findings demonstrated an important function of DNAJC6 in the progression of HCC by induction of EMT, and they implicate DNAJC6 as a marker of poor outcome in HCC. PMID- 25446073 TI - Inhibiting epigenetic enzymes to improve atherogenic macrophage functions. AB - Macrophages determine the outcome of atherosclerosis by propagating inflammatory responses, foam cell formation and eventually necrotic core development. Yet, the pathways that regulate their atherogenic functions remain ill-defined. It is now apparent that chromatin remodeling chromatin modifying enzymes (CME) governs immune responses but it remains unclear to what extent they control atherogenic macrophage functions. We hypothesized that epigenetic mechanisms regulate atherogenic macrophage functions, thereby determining the outcome of atherosclerosis. Therefore, we designed a quantitative semi-high-throughput screening platform and studied whether the inhibition of CME can be applied to improve atherogenic macrophage activities. We found that broad spectrum inhibition of histone deacetylases (HDACs) and histone methyltransferases (HMT) has both pro- and anti-inflammatory effects. The inhibition of HDACs increased histone acetylation and gene expression of the cholesterol efflux regulators ATP binding cassette transporters ABCA1 and ABCG1, but left foam cell formation unaffected. HDAC inhibition altered macrophage metabolism towards enhanced glycolysis and oxidative phosphorylation and resulted in protection against apoptosis. Finally, we applied inhibitors against specific HDACs and found that HDAC3 inhibition phenocopies the atheroprotective effects of pan-HDAC inhibitors. Based on our data, we propose the inhibition of HDACs, and in particular HDAC3, in macrophages as a novel potential target to treat atherosclerosis. PMID- 25446074 TI - The basic helix-loop-helix (bHLH) transcription factor DEC2 negatively regulates Twist1 through an E-box element. AB - Differentiated embryo chondrocyte 2 (DEC2/Sharp-1/Bhlhe41), a basic helix-loop helix (bHLH) transcription factor, has been shown to regulate the transcription of target genes by binding to their E-box elements. We identified a possible DEC2 response element (consensus E-box: CACGTG) in the promoter region of Twist1. Forced expression of DEC2 significantly repressed Twist1 promoter activity under normoxia and under hypoxia as assessed by a luciferase reporter assay. In addition, over-expression of DEC2 repressed Twist1 mRNA expression assessed by quantitative real-time PCR. Site-directed mutagenesis studies showed that mutagenesis of the consensus E-box sequence eliminated the ability of DEC2 to reduce the Twist1 promoter activity. Chromatin immunoprecipitation (ChIP) assays confirmed that the DEC2-mediated repression is primarily achieved by binding to the E-box in the Twist1 promoter. Knockdown of DEC2 by siRNA significantly attenuated the repression of Twist1 expression. DEC2 and Twist1 exhibit inversed protein expression patterns during development of mouse tongue embryo tissue. Given the fact that DEC2 protein is emerging as an important regulator in a vast array of cellular events, including cell differentiation, maturation of lymphocytes and the molecular clock, our study elucidates an important mechanism by which DEC2 regulates cellular function by modulating the expression of Twist1. PMID- 25446075 TI - Improvement of insulin signaling in myoblast cells by an addition of SKIP-binding peptide within Pak1 kinase domain. AB - Abnormalities in insulin-induced glucose incorporation in skeletal muscle were observed in Type 2 diabetes. Our previous studies revealed that the binding between skeletal muscle and kidney-enriched inositol polyphosphate phosphatase (SKIP) and p21-activated protein kinase (Pak1) at the plasma membrane is induced insulin-dependently and that this binding mediated a rapid and efficient termination of insulin signaling and a subsequent glucose uptake into skeletal muscle cells. Here, we identified 11-amino-acids peptide within kinase domain of Pak1, necessary and sufficient for SKIP binding. Expression of this region in C2C12 cells resulted in an increase in insulin signaling. Supplementation of a synthetic peptide of this sequence increased insulin signaling and insulin induced glucose uptake into skeletal muscle cell lines. These findings suggest the physiological role of Pak1-SKIP binding in the regulation of insulin signaling in skeletal muscle. PMID- 25446076 TI - Five eIF4E isoforms from Arabidopsis thaliana are characterized by distinct features of cap analogs binding. AB - The assembly of the ribosome on majority of eukaryotic mRNAs is initiated by the recruitment of eIF4E protein to the mRNA 5' end cap structure. Flowering plants use two eIF4E isoforms, named eIF4E and eIF(iso)4E, as canonical translation initiation factors and possess a homolog of mammalian 4EHP (or eIF4E-2) termed nCBP. Plants from Brassicaceae family additionally conserve a close paralog of eIF4E which in Arabidopsis thaliana has two copies named eIF4E1b and eIF4E1c. In order to assess the efficiency of plant non-canonical (eIF4E1b/1c and nCBP) and canonical (eIF4E and eIF(iso)4E) eIF4E proteins to bind mRNAs we utilized fluorescence titrations to determine accurate binding affinities of five A.thaliana eIF4E isoforms for a series of cap analogs. We found that eIF4E binds cap analogs from 4-fold to 10-fold stronger than eIF(iso)4E, while binding affinities of nCBP and eIF(iso)4E are comparable. Furthermore, eIF4E1c interacts similarly strongly with the cap as eIF4E, but eIF4E1b binds cap analogs ca. 2 fold weaker than eIF4E1c, regardless of the 95% sequence identity between these two proteins. The use of differentially chemically modified cap analogs in binding studies and a detailed analysis of the obtained homology models gave us insight into the molecular characteristic of varying cap-binding abilities of Arabidopsis eIF4E isoforms. PMID- 25446077 TI - HL-217, a new topical anti-angiogenic agent, inhibits retinal vascular leakage and pathogenic subretinal neovascularization in Vldlr-/- mice. AB - HL-217 is a new synthetic angiogenesis inhibitor. Platelet derived growth factor (PDGF) is a vasoactive factor and has been implicated in proliferative retinopathies. In this study, we examined the mechanism of action and efficacy of topical application of HL-217 on subretinal neovascularization in very low density lipoprotein receptor knockout (Vldlr(-/-)) mice. In three-week-old male Vldlr(-/-) mice, HL-217 (1.5 or 3mg/ml) was administered twice per day for 4 weeks by topical eye drop instillation. Neovascular areas were then measured. We used a protein array to evaluate the expression levels of angiogenic factors. The inhibitory effect of HL-217 on the PDGF-BB/PDGFRbeta interaction was evaluated in vitro. The neovascular area in the Vldlr(-/-) mice was significantly reduced by HL-217. Additionally, HL-217 decreased the expression levels of PDGF-BB protein and VEGF mRNA. Moreover, HL-217 dose-dependently inhibited the PDGF-BB/PDGFRbeta interaction (IC50=38.9 +/- 0.7 MUM). These results suggest that HL-217 is a potent inhibitor of PDGF-BB. HL-217, when applied topically, is an effective inhibitor of subretinal neovascularization due to its ability to inhibit the pro angiogenic effects of PDGF-BB. PMID- 25446078 TI - Endogenous S-sulfhydration of PTEN helps protect against modification by nitric oxide. AB - Hydrogen sulfide (H2S) is a gaseous regulatory factor produced by several enzymes, and plays a pivotal role in processes such as proliferation or vasodilation. Recent reports demonstrated the physiological and pathophysiological functions of H2S in neurons. PTEN is a target of nitric oxide (NO) or hydrogen peroxide, and the oxidative modification of cysteine (Cys) residue(s) attenuates its enzymatic activity. In the present study, we assessed the effect of H2S on the direct modification of PTEN and the resulting downstream signaling. A modified biotin switch assay in SH-SY5Y human neuroblastoma cells revealed that PTEN is S-sulfhydrated endogenously. Subsequently, site-directed mutagenesis demonstrated that both Cys71 and Cys124 in PTEN are targets for S sulfhydration. Further, the knockdown of cystathionine beta-synthetase (CBS) using siRNA decreased this modification in a manner that was correlated to amount of H2S. PTEN was more sensitive to NO under these conditions. These results suggest that the endogenous S-sulfhydration of PTEN via CBS/H2S plays a role in preventing the S-nitrosylation that would inhibition its enzymatic activity under physiological conditions. PMID- 25446079 TI - An alpha-adrenergic agonist protects hearts by inducing Akt1-mediated autophagy. AB - Alpha-adrenergic agonists is known to be protective in cardiac myocytes from apoptosis induced by beta-adrenergic stimulation. Although there has been a recent focus on the role of cardiac autophagy in heart failure, its role in heart failure with adrenergic overload has not yet been elucidated. In the present study, we investigated the contribution of autophagy to cardiac failure during adrenergic overload both in vitro and in vivo. Neonatal rat cardiac myocytes overexpressing GFP-tagged LC3 were prepared and stimulated with the alpha1 adrenergic agonist, phenylephrine (PE), the beta-adrenergic agonist, isoproterenol (ISO), or norepinephrine (NE) in order to track changes in the formation of autophagosomes in vitro. All adrenergic stimulators increased cardiac autophagy by stimulating autophagic flux. Blocking autophagy by the knockdown of autophagy-related 5 (ATG5) exacerbated ISO-induced apoptosis and negated the anti-apoptotic effects of PE, which indicated the cardioprotective role of autophagy during adrenergic overload. PE-induced cardiac autophagy was mediated by the PI3-kinase/Akt pathway, but not by MEK/ERK, whereas both pathways mediated the anti-apoptotic effects of PE. Knock down of Akt1 was the most essential among the three Akt family members examined for the induction of cardiac autophagy. The four-week administration of PE kept the high level of cardiac autophagy without heart failure in vivo, whereas autophagy levels in a myocardium impaired by four-week persistent administration of ISO or NE were the same with the control state. These present study indicated that cardiac autophagy played a protective role during adrenergic overload and also that the Akt pathway could mediate cardiac autophagy for the anti-apoptotic effects of the alpha adrenergic pathway. PMID- 25446080 TI - Tissue-specific splice variants of HARE/Stabilin-2 are expressed in bone marrow, lymph node, and spleen. AB - The hyaluronan receptor for endocytosis (HARE), or Stabilin-2, is the mammalian endocytic clearance receptor for HA, heparin, advanced glycation end-products, acetylated and oxidized low-density lipoproteins and collagen N-terminal propeptides. This large 2551 amino acid receptor is encoded by a gene that covers over 180 kbp on human chromosome 12 and is predicted to be composed of 69 exons. Due to the expression profile of this gene and the number of exons it contains, we hypothesized that splice variants of stab2 are encoded in these tissues. In addition, a correlation between alternative splice variants and cancer progression has been shown in other HA receptors such as RHAMM and CD42. In this study, two methods were utilized in identifying and/or isolating the HARE splice variants. The first method used primer sets to amplify the 190-HARE encoding region that could contain splice junctions; therefore, they were purified from agarose gels and sequenced. Five splice variants were detected in that manner. In the second approach, the entire open reading frame of HARE was amplified. This allowed four splice variants with extensive exon splicing to be isolated. After the splice variants were sequenced, three were cloned into a mammalian expression vector. Next, stable cell lines expressing the variants were created in order to determine stable protein expression. In this study, the splice variants were found to be tissue specific in most cases. This suggests that tissue specific regulatory splicing mechanisms may lead to differences in functionality between the splice variants. PMID- 25446081 TI - Silibinin attenuates ionizing radiation-induced pro-angiogenic response and EMT in prostate cancer cells. AB - Radiotherapy of is well established and frequently utilized in prostate cancer (PCa) patients. However, recurrence following therapy and distant metastases are commonly encountered problems. Previous studies underline that, in addition to its therapeutic effects, ionizing radiation (IR) increases the vascularity and invasiveness of surviving radioresistant cancer cells. This invasive phenotype of radioresistant cells is an upshot of IR-induced pro-survival and mitogenic signaling in cancer as well as endothelial cells. Here, we demonstrate that a plant flavonoid, silibinin can radiosensitize endothelial cells by inhibiting expression of pro-angiogenic factors. Combining silibinin with IR not only strongly down-regulated endothelial cell proliferation, clonogenicity and tube formation ability rather it strongly (p<0.001) reduced migratory and invasive properties of PCa cells which were otherwise marginally affected by IR treatment alone. Most of the pro-angiogenic (VEGF, iNOS), migratory (MMP-2) and EMT promoting proteins (uPA, vimentin, N-cadherin) were up-regulated by IR in PCa cells. Interestingly, all of these invasive and EMT promoting actions of IR were markedly decreased by silibinin. Further, we found that potentiated effect was an end result of attenuation of IR-activated mitogenic and pro-survival signaling, including Akt, Erk1/2 and STAT-3, by silibinin. PMID- 25446082 TI - Proteasome inhibitors induce auditory hair cell death through peroxisome dysfunction. AB - Even though bortezomib, a proteasome inhibitor, is a powerful chemotherapeutic agent used to treat multiple myeloma (MM) and other lymphoma cells, recent clinical reports suggest that the proteasome inhibitor therapy may be associated with severe bilateral hearing loss. We herein investigated the adverse effect of proteasome inhibitor on auditory hair cells. Treatment of a proteasome inhibitor destroys stereocilia bundles of hair cells resulting in the disarray of stereocilia in the organ of Corti explants. Since proteasome activity may be potentially important for biogenesis and function of the peroxisome, we tested whether proteasome activity is necessary for maintaining functional peroxisomes. Our results showed that treatment of a proteasome inhibitor significantly decreases both the number of peroxisomes and expression of peroxisomal proteins such as PMP70 and Catalase. In addition, we also found that proteasome inhibitor impairs the import pathway of PTS1-peroxisome matrix proteins. Taken together, our findings support recent clinical reports of hearing loss associated with proteasome inhibition. Mechanistically, peroxisome dysfunction may contribute to hair cell damage and hearing loss in response to the treatment of a proteasome inhibitor. PMID- 25446084 TI - Direct comparison of different coating matrix on the hepatic differentiation from adipose-derived stem cells. AB - Various extracellular matrix components were employed as coating materials to promote hepatic differentiation from ADSCs. However, no consensus was achieved about the optimal coating matrix due to the lack of direct comparison among different coating matrix. In this study, several coating extracellular matrixs were used for hepatic differentiation of ADSCs and direct comparison between them was performed. We demonstrated that liver DCM as coating matrix could significantly enhance the hepatic differentiation from ADSCs compared with collagen, fibronectin and Matrigel both in the presence and absence of GFs, including enhanced hepatocyte-specific genes expression, hepatocyte related protein secretion with improved liver functions. And the differentiated cells also exhibited the characteristics of mature hepatocytes. In conclusion, the study proved an effective hepatic-inducing method and indicated that DCM could promote the differentiation of ADSCs into hepatocyte-like cells, which demonstrates feasibility of liver DCM as a bio-scaffold for liver regenerative medicine and tissue engineering. PMID- 25446085 TI - A mutation in the mitochondrial protein UQCRB promotes angiogenesis through the generation of mitochondrial reactive oxygen species. AB - Ubiquinol-cytochrome c reductase binding protein (UQCRB) is one of the subunits of mitochondrial complex III and is a target protein of the natural anti angiogenic small molecule terpestacin. Previously, the biological role of UQCRB was thought to be limited to the maintenance of complex III. However, the identification and validation of UQCRB as a target protein of terpestacin enabled the role of UQCRB in oxygen sensing and angiogenesis to be elucidated. To explore the biological role of this protein further, UQCRB mutant stable cell lines were generated on the basis of a human case report. We demonstrated that these cell lines exhibited glycolytic and pro-angiogenic activities via mitochondrial reactive oxygen species (mROS)-mediated HIF1 signal transduction. Furthermore, a morphological abnormality in mitochondria was detected in UQCRB mutant stable cell lines. In addition, the proliferative effect of the UQCRB mutants was significantly regulated by the UQCRB inhibitors terpestacin and A1938. Collectively, these results provide a molecular basis for UQCRB-related biological processes and reveal potential key roles of UQCRB in angiogenesis and mitochondria-mediated metabolic disorders. PMID- 25446083 TI - Synergistic cytotoxicity of afatinib and cetuximab against EGFR T790M involves Rab11-dependent EGFR recycling. AB - EGFR is an important therapeutic target for non-small cell lung cancers (NSCLCs). Tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, are effective in cases with EGFR-activating mutations. However, most such cases become resistant through a secondary EGFR mutation, T790M. While the second-generation TKI afatinib has a higher affinity for double-mutant EGFRs, better efficacy is needed. Combining afatinib with the anti-EGFR monoclonal antibody cetuximab improves clinical outcomes, but the mechanism is unclear. Here we examined this effect using erythroleukemic K562 cells. The activating EGFR mutation L858R is sensitive to first-generation TKIs, and adding T790M confers resistance to these drugs. This double-mutant EGFR was moderately sensitive to afatinib, but responded weakly to cetuximab. Combined afatinib and cetuximab synergistically increased their cytotoxicity for K562 cells expressing the double-mutant EGFR. Apoptosis in these cells followed induction of the pro-apoptotic protein BIM. Unexpectedly, afatinib caused redistribution of EGFR to the cell surface through Rab11a-dependent recycling. Cetuximab reduced cell-surface EGFR, and total EGFR decreased synergistically when cetuximab was combined with afatinib. Our results suggest that the synergistic effect exerted by afatinib and cetuximab on NSCLCs is associated with BIM induction and alterations in EGFR status. PMID- 25446086 TI - The antitumor effects of methyl-beta-cyclodextrin against primary effusion lymphoma via the depletion of cholesterol from lipid rafts. AB - Primary effusion lymphoma (PEL) is a subtype of aggressive and chemotherapy resistant non-Hodgkin lymphoma that occurs predominantly in patients with advanced AIDS. In this study, we examined the antitumor activity of methyl-beta cyclodextrin (M-beta-CyD) in vitro and in vivo. M-beta-CyD quickly induced caspase-dependent apoptosis in PEL cells via cholesterol depletion from the plasma membrane. In a PEL xenograft mouse model, M-beta-CyD significantly inhibited the growth and invasion of PEL cells without apparent adverse effects. These results strongly suggest that M-beta-CyD has the potential to be an effective antitumor agent against PEL. PMID- 25446087 TI - TLE1 promotes EMT in A549 lung cancer cells through suppression of E-cadherin. AB - The Groucho transcriptional corepressor TLE1 protein has recently been shown to be a putative lung specific oncogene, but its underlying oncogenic activity in lung cancer has not been fully elucidated. In this report, we investigated whether TLE1 regulates lung cancer aggressiveness using the human lung adenocarcinoma cell line A549 as a model system. Through a combination of genetic approaches, we found that TLE1 potentiates epithelial-to-mesenchymal transition (EMT) in A549 cells in part through suppression of the tumor suppressor gene E cadherin. Exogenous expression of TLE1 in A549 cells resulted in heightened EMT phenotypes (enhanced fibroblastoid morphology and increased cell migratory potential) and in molecular alterations characteristic of EMT (downregulation of the epithelial marker E-cadherin and upregulation of the mesenchymal marker Vimentin). Conversely, downregulation of endogenous TLE1 expression in these cells resulted in reversal of basal EMT characterized by a cuboidal-like epithelial cell phenotype, reduced cell motility, and upregulated E-cadherin expression. Mechanistic studies showed that TLE1 suppresses E-cadherin expression at the transcriptional level in part by recruiting histone deacetylase (HDAC) activity to the E-cadherin promoter. Consistently, the HDAC inhibitor TSA partially reversed the TLE1-induced E-cadherin downregulation and cell migration, suggesting a role for HDACs in TLE1-mediated transcriptional repression of E cadherin and EMT function. These findings uncover a novel role of TLE1 in regulating EMT in A549 cells through its repressive effect on E-cadherin and provide a mechanism for TLE1 oncogenic activity in lung cancer. PMID- 25446088 TI - Establishment of a novel model of chondrogenesis using murine embryonic stem cells carrying fibrodysplasia ossificans progressiva-associated mutant ALK2. AB - Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder characterized by heterotopic endochondral ossification in soft tissue. A mutation in the bone morphogenetic protein (BMP) receptor ALK2, R206H, has been identified in patients with typical FOP. In the present study, we established murine embryonic stem (ES) cells that express wild-type human ALK2 or typical mutant human ALK2 [ALK2(R206H)] under the control of the Tet-Off system. Although wild-type ALK2 and mutant ALK2(R206H) were expressed in response to a withdrawal of doxycycline (Dox), BMP signaling was activated only in the mutant ALK2(R206H)-expressing cells without the addition of exogenous BMPs. The Dox-dependent induction of BMP signaling was blocked by a specific kinase inhibitor of the BMP receptor. The mutant ALK2(R206H)-carrying cells showed Dox-regulated chondrogenesis in vitro, which occurred in co-operation with transforming growth factor-beta1 (TGF-beta1). Overall, our ES cells are useful for studying the molecular mechanisms of heterotopic ossification in FOP in vitro and for developing novel inhibitors of chondrogenesis induced by mutant ALK2(R206H) associated with FOP. PMID- 25446089 TI - Structural and biochemical characterizations of an intramolecular tandem coiled coil protein. AB - Coiled coil has served as an excellent model system for studying protein folding and developing protein-based biomaterials. Most designed coiled coils function as oligomers, namely intermolecular coiled coils. However, less is known about structural and biochemical behavior of intramolecular coiled coils where coiled coil domains are covalently linked in one polypeptide. Here we prepare a protein which harbors three coiled coil domains with two short linkers, termed intramolecular tandem coiled coil (ITCC) and characterize its structural and biochemical behavior in solution. ITCC consists of three coiled coil domains whose sequences are derived from Coil-Ser and its domain swapped dimer. Modifications include positioning E (Glu) residue at "e" and K (Lys) at "g" positions throughout heptad repeats to enhance ionic interaction among its constituent coiled coil domains. Molecular modeling of ITCC suggests a compact triple helical bundle structure with the second and the third coiled coil domains forming a canonical coiled coil. ITCC exists as a mixture of monomeric and dimeric species in solution. Small-angle X-ray scattering reveals ellipsoidal molecular envelopes for both dimeric and monomeric ITCC in solution. The theoretically modeled structures of ITCC dock well into the envelopes of both species. Higher ionic strength shifts the equilibrium into monomer with apparently more compact structure while secondary structure remains unchanged. Taken together, our results suggest that our designed ITCC is predominantly monomeric structure through the enhanced ionic interactions, and its conformation is affected by the concentration of ionic species in the buffer. PMID- 25446090 TI - Treatment with insulin-like growth factor 1 receptor inhibitor reverses hypoxia induced epithelial-mesenchymal transition in non-small cell lung cancer. AB - Insulin-like growth factor 1 receptor (IGF1R) is expressed in many types of solid tumors including non-small cell lung cancer (NSCLC), and enhanced activation of IGF1R is thought to reflect cancer progression. Epithelial-mesenchymal transition (EMT) has been established as one of the mechanisms responsible for cancer progression and metastasis, and microenvironment conditions, such as hypoxia, have been shown to induce EMT. The purposes of this study were to address the role of IGF1R activation in hypoxia-induced EMT in NSCLC and to determine whether inhibition of IGF1R might reverse hypoxia-induced EMT. Human NSCLC cell lines A549 and HCC2935 were exposed to hypoxia to investigate the expression of EMT related genes and phenotypes. Gene expression analysis was performed by quantitative real-time PCR and cell phenotypes were studied by morphology assessment, scratch wound assay, and immunofluorescence. Hypoxia-exposed cells exhibited a spindle-shaped morphology with increased cell motility reminiscent of EMT, and demonstrated the loss of E-cadherin and increased expression of fibronectin and vimentin. Hypoxia also led to increased expression of IGF1, IGF binding protein-3 (IGFBP3), and IGF1R, but not transforming growth factor beta1 (TGFbeta1). Inhibition of hypoxia-inducible factor 1alpha (HIF1alpha) with YC-1 abrogated activation of IGF1R, and reduced IGF1 and IGFBP3 expression in hypoxic cells. Furthermore, inhibition of IGF1R using AEW541 in hypoxic condition restored E-cadherin expression, and reduced expression of fibronectin and vimentin. Finally, IGF1 stimulation of normoxic cells induced EMT. Our findings indicated that hypoxia induced EMT in NSCLC cells through activation of IGF1R, and that IGF1R inhibition reversed these phenomena. These results suggest a potential role for targeting IGF1R in the prevention of hypoxia-induced cancer progression and metastasis mediated by EMT. PMID- 25446091 TI - Arsenite inhibits mRNA deadenylation through proteolytic degradation of Tob and Pan3. AB - The poly(A) tail of mRNAs plays pivotal roles in the posttranscriptional control of gene expression at both translation and mRNA stability. Recent findings demonstrate that the poly(A) tail is globally stabilized by some stresses. However, the mechanism underlying this phenomenon has not been elucidated. Here, we show that arsenite-induced oxidative stress inhibits deadenylation of mRNA primarily through downregulation of Tob and Pan3, both of which mediate the recruitment of deadenylases to mRNA. Arsenite selectively induces the proteolytic degradation of Tob and Pan3, and siRNA-mediated knockdown of Tob and Pan3 recapitulates stabilization of the mRNA poly(A) tail observed during arsenite stress. Although arsenite also inhibits translation by activating the eIF2alpha kinase HRI, arsenite-induced mRNA stabilization can be observed under HRI depleted conditions. These results highlight the essential role of Tob and Pan3 in the stress-induced global stabilization of mRNA. PMID- 25446092 TI - Bifendate-chalcone hybrids: a new class of potential dual inhibitors of P glycoprotein and breast cancer resistance protein. AB - We previously described bifendate-chalcone hybrids as potent P-glycoprotein inhibitors. In the present work, we determine whether these compounds could reverse breast cancer resistance protein (BCRP, ABCG2)-mediated multidrug resistance using HEK293/BCRP cells which was BCRP-transfected stable HEK293 cells. Results indicated that compounds 8d, 8f, 8g and 8h could significantly enhance mitoxantrone accumulation in HEK293/BCRP cells via inhibiting BCRP drug efflux function. The most active compound 8g exhibited little intrinsic cytotoxicity (IC50>100 MUM), and could reverse BCRP-mediated drug resistance independent of decreasing BCRP expression level. Notably, 8g had little inhibitory effect on multidrug resistance-associated protein 1 (MRP1, ABCC1), another drug efflux transporter. The present findings, together with the previous results, suggest that 8g might be act as dual inhibitors of P-gp and BCRP. PMID- 25446093 TI - Splicing factor SR34b mutation reduces cadmium tolerance in Arabidopsis by regulating iron-regulated transporter 1 gene. AB - Serine/arginine-rich (SR) proteins are important splicing factors. However, the biological functions of plant SR proteins remain unclear especially in abiotic stresses. Cadmium (Cd) is a non-essential element that negatively affects plant growth and development. In this study, we provided clear evidence for SR gene involved in Cd tolerance in planta. Systemic expression analysis of 17 Arabidopsis SR genes revealed that SR34b is the only SR gene upregulated by Cd, suggesting its potential roles in Arabidopsis Cd tolerance. Consistent with this, a SR34b T-DNA insertion mutant (sr34b) was moderately sensitive to Cd, which had higher Cd(2+) uptake rate and accumulated Cd in greater amounts than wild-type. This was due to the altered expression of iron-regulated transporter 1 (IRT1) gene in sr34b mutant. Under normal growth conditions, IRT1 mRNAs highly accumulated in sr34b mutant, which was a result of increased stability of IRT1 mRNA. Under Cd stress, however, sr34b mutant plants had a splicing defect in IRT1 gene, thus reducing the IRT1 mRNA accumulation. Despite of this, sr34b mutant plants still constitutively expressed IRT1 proteins under Cd stress, thereby resulting in Cd stress-sensitive phenotype. We therefore propose the essential roles of SR34b in posttranscriptional regulation of IRT1 expression and identify it as a regulator of Arabidopsis Cd tolerance. PMID- 25446094 TI - Herbimycin A inhibits cell growth with reversal of epithelial-mesenchymal transition in anaplastic thyroid carcinoma cells. AB - We aimed to elucidate the effect of herbimycin A (HMA), a heat shock protein 90 inhibitor, on cell growth and epithelial-mesenchymal transition (EMT) in anaplastic thyroid carcinoma (ATC) cells. HMA inhibited cell growth and migration concomitantly with increase of E-cadherin as well as decrease of N-cadherin and vimentin. Moreover, HMA upregulated p21 and p27, while it downregulated p53 and Akt. In HMA-treated condition, knockdown of E-cadherin and overexpression of p53 increased N-cadherin and vimentin, and mitigated the inhibitory effects of HMA on cell growth and migration. Furthermore, knockdown of p21 and p27 ameliorated inhibition of cell growth and reversal of EMT. In addition, the activation of Akt attenuated growth inhibition, cell death and EMT reversal. Therefore, we propose that HMA suppresses cell growth, and reverses EMT in conjunction with the activation of E-cadherin, p21 and p27 and the inactivation of p53 and PI3K/Akt signaling in ATC cells. PMID- 25446096 TI - RASAL2 promotes lung cancer metastasis through epithelial-mesenchymal transition. AB - It was reported that genetically-engineered RASAL2 knockout mice are prone to development of several sporadic tumor, including lung adenocarcinoma. However, a causative relationship between RASAL2 deficiency and lung adenocarcinoma development still remains unknown. In the present study, RASAL2 level was determined in patients with lung adenocarcinoma and control subjects in an attempt to explore its potential clinical diagnostic and prognostic value. Low RASAL2 expression levels were found in 71% (37 of 52) of lung adenocarcinoma, which were correlated with lymph node metastasis in lung adenocarcinoma. Moreover, Low RASAL2 expression levels were correlated with reduced overall survival (OS) in lung adenocarcinoma. We find that inactivation of RASAL2 promotes lung cancer cell migration through the induction of epithelial mesenchymal transition (EMT) and promoted lung metastasis in nude mice. Our results suggest that the down-regulation of RASAL2 promotes metastatic progression of lung adenocarcinoma, hence it could serve as a potential target for the development of lung cancer therapies. PMID- 25446097 TI - Expression and functions of ASIC1 in the zebrafish retina. AB - It has been demonstrated that acid sensing ionic channels (ASICs) are present in the central and peripheral nervous system of mammals, including the retina. However, it remains unclear whether the zebrafish retina also expresses ASICs. In the present study, the expression and distribution of zasic1 were examined in the retina of zebrafish. Both zasic1 mRNA and protein expressions were detected in the adult zebrafish retina. A wide distribution of ASIC1 in zebrafish retina was confirmed using whole mount in situ hybridization and immunohistochemistry study. Acidosis-induced currents in the isolated retinal ganglion cells (RGCs) were also recorded using whole cell patch clamping. Moreover, blockade of ASICs channel significantly reduced the locomotion of larval zebrafish in response to light exposure. In sum, our data demonstrate the presence of ASIC1 and its possible functional relevance in the retina of zebrafish. PMID- 25446095 TI - Longitudinal monitoring adipose-derived stem cell survival by PET imaging hexadecyl-4-124I-iodobenzoate in rat myocardial infarction model. AB - This study aims to monitor how the change of cell survival of transplanted adipose-derived stem cells (ADSCs) responds to myocardial infarction (MI) via the hexadecyl-4-(124)I-iodobenzoate ((124)I-HIB) mediated direct labeling method in vivo. Stem cells have shown the potential to improve cardiac function after MI. However, monitoring of the fate of transplanted stem cells at target sites is still unclear. Rat ADSCs were labeled with (124)I-HIB, and radiolabeled ADSCs were transplanted into the myocardium of normal and MI model. In the group of (124)I-HIB-labeled ADSC transplantation, in vivo imaging was performed using small-animal positron emission tomography (PET)/computed tomography (CT) for 9 days. Twenty-one days post-transplantation, histopathological analysis and apoptosis assay were performed. ADSC viability and differentiation were not affected by (124)I-HIB labeling. In vivo tracking of the (124)I-HIB-labeled ADSCs was possible for 9 and 3 days in normal and MI model, respectively. Apoptosis of transplanted cells increased in the MI model compared than that in normal model. We developed a direct labeling agent, (124)I-HIB, and first tried to longitudinally monitor transplanted stem cell to MI. This approach may provide new insights on the roles of stem cell monitoring in living bodies for stem cell therapy from pre-clinical studies to clinical trials. PMID- 25446099 TI - Chaperone protein HYPK interacts with the first 17 amino acid region of Huntingtin and modulates mutant HTT-mediated aggregation and cytotoxicity. AB - Huntington's disease is a polyglutamine expansion disorder, characterized by mutant HTT-mediated aggregate formation and cytotoxicity. Many reports suggests roles of N-terminal 17 amino acid domain of HTT (HTT-N17) towards subcellular localization, aggregate formation and subsequent pathogenicity induced by N terminal HTT harboring polyQ stretch in pathogenic range. HYPK is a HTT interacting chaperone which can reduce N-terminal mutant HTT-mediated aggregate formation and cytotoxicity in neuronal cell lines. However, how HYPK interacts with N-terminal fragment of HTT remained unknown. Here we report that specific interaction of HYPK with HTT-N17 is crucial for the chaperone activity of HYPK. Deletion of HTT-N17 leads to formation of tinier, SDS-soluble nuclear aggregates formed by N-terminal mutant HTT. The increased cytotoxicity imparted by these tiny aggregates might be contributed due to loss of interaction with HYPK. PMID- 25446098 TI - The macrophage-TCRalphabeta is a cholesterol-responsive combinatorial immune receptor and implicated in atherosclerosis. AB - Recent evidence indicates constitutive expression of a recombinatorial TCRalphabeta immune receptor in mammalian monocytes and macrophages. Here, we demonstrate in vitro that macrophage-TCRbeta repertoires are modulated by atherogenic low density cholesterol (LDL) and high-density cholesterol (HDL). In vivo, analysis of freshly obtained artery specimens from patients with severe carotid atherosclerosis reveals massive abundance of TCRalphabeta(+) macrophages within the atherosclerotic lesions. Experimental atherosclerosis in mouse carotids induces accumulation of TCR bearing macrophages in the vascular wall and TCR deficient rag(-/-) mice have an altered macrophage-dependent inflammatory response. We find that the majority of TCRalphabeta bearing macrophages are localized in the hot spot regions of the atherosclerotic lesions. Advanced carotid artery lesions express highly restricted TCRalphabeta repertoires that are characterized by a striking usage of the Vbeta22 and Vbeta16 chains. This together with a significant degree of interindividual lesion repertoire sharing suggests the existence of atherosclerosis-associated TCRalphabeta signatures. Our results implicate the macrophage-TCRalphabeta combinatorial immunoreceptor in atherosclerosis and thus identify an as yet unknown adaptive component in the innate response-to-injury process that underlies this macrophage-driven disease. PMID- 25446100 TI - QCM-4, a 5-HT3 receptor antagonist ameliorates plasma HPA axis hyperactivity, leptin resistance and brain oxidative stress in depression and anxiety-like behavior in obese mice. AB - Several preclinical studies have revealed antidepressant and anxiolytic-like effect of 5-HT3 receptor antagonists. In our earlier study, we have reported the antidepressive-like effect of 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) in obese mice subjected to chronic stress. The present study deals with the biochemical mechanisms associated with depression co-morbid with obesity. Mice were fed with high fat diet (HFD) for 14 weeks, further subjected for treatment with QCM-4 (1 and 2mg/kg p.o.) and standard antidepressant escitalopram (ESC) (10mg/kg p.o.) for 28 days. Behavioral assays for depression such as sucrose preference test (SPT), forced swim test (FST) and for anxiety such as light and dark test (LDT) and hole board test (HBT) were performed in obese mice. Biochemical assessments including plasma leptin and corticosterone concentration followed by brain oxidative stress parameters malonaldehyde (MDA) and reduced glutathione (GSH) were performed. Results confirmed that QCM-4 exhibits antidepressive effect by increasing the sucrose consumption in SPT, reducing immobility time in FST and anxiolytic effect by increasing transitions and time in light chamber in LDT, increasing head dip and crossing score in HBT. Furthermore, QCM-4 attenuated the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity by reducing the plasma corticosterone, reversing altered plasma leptin, restoring the imbalance of brain MDA and GSH concentration. In conclusion, QCM-4 showed antidepressive and anxiolytic effect by reversing the behavioral alterations that were supported by biochemical estimations in obese mice. PMID- 25446101 TI - ATF3 inhibits PPARgamma-stimulated transactivation in adipocyte cells. AB - Previously, we reported that activating transcription factor 3 (ATF3) downregulates peroxisome proliferator activated receptor (PPARgamma) gene expression and inhibits adipocyte differentiation in 3T3-L1 cells. Here, we investigated another role of ATF3 on the regulation of PPARgamma activity. ATF3 inhibited PPARgamma-stimulated transactivation of PPARgamma responsive element (PPRE)-containing reporter or GAL4/PPARgamma chimeric reporter. Thus, ATF3 effectively repressed rosiglitazone-stimulated expression of adipocyte fatty acid binding protein (aP2), PPARgamma target gene, in 3T3-L1 cells. Coimmunoprecipitation and GST pulldown assay demonstrated that ATF3 interacted with PPARgamma. Accordingly, ATF3 prevented PPARgamma from binding to PPRE on the aP2 promoter. Furthermore, ATF3 suppressed p300-mediated transcriptional coactivation of PPRE-containing reporter. Chromatin immunoprecipitation assay showed that overexpression of ATF3 blocked both binding of PPARgamma and recruitment of p300 to PPRE on aP2 promoter induced by rosiglitazone treatment in 3T3-L1 cells. Taken together, these results suggest that ATF3 interacts with PPARgamma and represses PPARgamma-mediated transactivation through suppression of p300-stimulated coactivation in 3T3-L1 cells, which may play a role in inhibition of adipocyte differentiation. PMID- 25446103 TI - miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1. AB - miR-320 expression level is found to be down-regulated in human colon cancer. To date, however, its underlying mechanisms in the chemo-resistance remain largely unknown. In this study, we demonstrated that ectopic expression of miR-320 led to inhibit HCT-116 cell proliferation, invasion and hypersensitivity to 5-Fu and Oxaliplatin. Also, knockdown of miR-320 reversed these effects in HT-29 cells. Furthermore, we identified an oncogene, FOXM1, as a direct target of miR-320. In addition, miR-320 could inactive the activity of Wnt/beta-catenin pathway. Finally, we found that miR-320 and FOXM1 protein had a negative correlation in colon cancer tissues and adjacent normal tissues. These findings implied that miR 320-FOXM1 axis may overcome chemo-resistance of colon cancer cells and provide a new therapeutic target for the treatment of colon cancer. PMID- 25446102 TI - Inhibition of MEK/ERK activation attenuates autophagy and potentiates pemetrexed induced activity against HepG2 hepatocellular carcinoma cells. AB - Identification of efficient chemo-therapeutic/chemo-preventive agents for treatment of hepatocellular carcinoma (HCC) is important. In this study, we examined the activity of pemetrexed, an anti-folate chemotherapy drug, against HepG2 human HCC cells. Pemetrexed treatment in vitro exerted weak but significant cytotoxic activity against HepG2 cells. When analyzing the possible pemetrexed resistance factors, we indentified that pemetrexed treatment in HepG2 cells induced cyto-protective autophagy activation, evidenced by GFP-light chain 3B (LC3B) puncta formation, p62 downregulation and Beclin-1/LC3B-II upregulation. Correspondingly, autophagy inhibitors, including bafliomycin A1, 3-methyladenine and chloroquine, enhanced pemetrexed-induced cytotoxicity against HepG2 cells. Further, RNAi-mediated knockdown of Beclin-1 in HepG2 cells also increased pemetrexed sensitivity. Pemetrexed activated MEK (mitogen-activated protein kinase/ERK kinase)/ERK (extracellular-signal-regulated kinase) signaling in HepG2 cells, which was required for autophagy induction. Pharmacological inhibition of MEK/ERK activation attenuated pemetrexed-induced autophagy, enhanced HepG2 cell death and apoptosis. In summary, pemetrexed activates MEK/ERK-dependent cyto protective autophagy, and inhibition of this pathway potentiates pemetrexed's activity in HepG2 cells. PMID- 25446104 TI - Secondhand smoke exposure-induced nucleocytoplasmic shuttling of HMGB1 in a rat premature skin aging model. AB - Secondhand cigarette smoke exposure (SSE) has been linked to carcinogenic, oxidative, and inflammatory reactions. Herein, we investigated whether premature skin aging could be induced by SSE in a rat model, and assessed the cytoplasmic translocation of high mobility group box 1 (HMGB1) protein and collagen loss in skin tissues. Animals were divided into two groups: SSE and controls. Whole body SSE was carried out for 12 weeks. Dorsal skin tissue specimens were harvested for HMGB1 and Mallory's azan staining. Correlations between serum HMGB1 and collagen levels were determined. Rat skin exposed to secondhand smoke lost collagen bundles in the papillary dermis and collagen decreased significantly (p<0.05) compared with control rats. In epidermal keratinocytes, cytoplasmic HMGB1 staining was more diffuse and there were more HMGB1-positive cells after four weeks in SSE compared to control rats. A negative correlation between HMGB1 serum and collagen levels (r=-0.631, p=0.28) was also observed. Therefore, cytoplasmic HMGB1 expression in skin tissues might be associated with skin collagen loss upon the initiation of SSE. Additionally, long-term SSE might affect the appearance of the skin, or could accelerate the skin aging process. PMID- 25446105 TI - C-terminal domain of CagX is responsible for its interaction with CagT protein of Helicobacter pylori type IV secretion system. AB - Helicobacter pylori are the well known human pathogen associated with gastric cancer and peptic ulcer. Pathogenesis is mainly due to the presence of 40 kb cagPAI (cag Pathogenicity Island) region that encodes the type IV secretion system (TFSS) consisting of a cytoplasmic part, a middle part/core complex (spans from inner membrane to outer membrane), and an outer membrane associated part. CagX and CagT are two important proteins of TFSS that have homology with virB9 and virB7 of Agrobacterium tumefaciens TFSS. In this study, we have shown that the CagX and CagT interact directly by using co-immunoprecipitation of endogenous CagX and CagT and MBP pull down assay. We further authenticate this observation using yeast two-hybrid assay and co-expression of both the protein coding gene in Escherichia coli. We also observed that the C-terminal region of CagX is important for CagT interaction. We reconfirm that CagT depends on CagX for its stabilization. These observations could contribute in overall visualization of assembly and architecture of TFSS because protein-protein interactions among Cag proteins are likely to have an important role in assembly. Thorough understanding about architecture and mechanism of action of cag-TFSS may lead to design controlled drug delivery system. PMID- 25446106 TI - Peptide inhibitors of human HMG-CoA reductase as potential hypocholesterolemia agents. AB - Hypercholesterolemia may lead to obesity and cardiovascular diseases. To prevent hypercholesterolemia, many drugs have been developed while searching for better drugs to treat hypercholesterolemia has never been ended. Other than small molecule drugs, peptide drugs are gaining more visibilities in many therapeutic areas. In the present study, we employed phage-display techniques to screen peptide inhibitors against human HMG-CoA reductase. The results indicate that the tetrapeptide PMAS inhibits hHMGR effectively (IC50=68 MUM), could be a lead compound to develop hypocholesterolemic agents. PMID- 25446107 TI - RNA polymerase III control elements are required for trans-activation by the murine retroviral long terminal repeat sequences. AB - RNA leukemia viruses induce T-cell lymphoblastic lymphomas or myeloid leukemias. Infection of cells with Moloney murine leukemia virus (M-MuLV) up-regulates the expression of a number of cellular genes, including those involved in T lymphocyte activation. Previously, we demonstrated that this up-regulation occurs via the trans-activation activity of the M-MuLV long terminal repeat (LTR) sequences which produce an LTR-encoded transcript. Sequence analysis of the LTR revealed a potential transcription unit for RNA polymerase III (Pol III) within the U3 region that is actively occupied by Pol II factors. Here, we provide the direct evidence of involvement of Pol III in the trans-activation process and demonstrate the precise localization of the intragenic control elements for accurate and active Pol III transcription. Deletions of a copy of the directed repeats and further immediate upstream sequences significantly abrogated the generation of LTR-encoded transcript and abolished the trans-activational activity, whereas the deletion of a copy of directed repeats alone proportionally reduced the transcript size, but still retained moderately high trans activational activity. In electrophoretic mobility shift assay, the fraction containing a multiple transcription factor TFIIIC complex strongly bound to the LTR-U3 probe containing the essential control elements. The specificity of the DNA-TFIIIC interaction was confirmed by conducting competition assays with DNA fragments containing a genuine Pol III-transcribed gene, VA1, and by vaccinia virus infection which stimulates the expression of Pol III factors. However, a deletion mutant lacking an essential control element bound to the TFIIIC complex poorly, consequently resulting in weak Pol III transcription as assessed by an IRES-GFP reporter system. This correlation strongly supports the possibility that the generation of LTR-encoded transcript is directed by Pol III. Therefore, this finding suggests the involvement of Pol III transcription in the retrovirus induced activation of cellular genes, potentially contributing to leukemogenesis. PMID- 25446108 TI - Co-expression of human agouti-related protein enhances expression and stability of human melanocortin-4 receptor. AB - G protein-coupled receptors (GPCRs) represent the largest family of transmembrane signaling proteins, and they are considered major targets of approximately half of all therapeutic agents. Human melanocortin-4 receptor (hMC4R) plays an important role in the control of energy homeostasis, and its mutants are directly related to severe human obesity. Here, we describe optimized protocols for the high-yield expression and purification of hMC4R that will accelerate structural study. Truncations of the N- and C-termini of hMC4R with T4 lysozyme (T4L) insertion increase the solubility as well as stability of the protein. Strikingly, co-expression of human mini-agouti-related protein (mini-AgRP) in Spodoptera frugiperda (Sf9) cells enables excellent stability of hMC4R. The protein yield in the human mini-AgRP co-expression system is increased by about 3 4 times compared to that of hMC4R alone. Data from analytical size exclusion chromatography (aSEC) and thermostability assay show that hMC4R becomes homogeneous and stable with a melting temperature of 58 degrees C in the presence of human mini-AgRP. PMID- 25446109 TI - Crosstalk between JNK and NF-kappaB signaling pathways via HSP27 phosphorylation in HepG2 cells. AB - The crosstalk of intracellular signaling pathways is extremely complex. Previous studies have shown that there is a potential crosstalk between MAPKs and NF kappaB signaling pathways. It has been reported that JNK regulates cell survival under some conditions. But the molecular mechanism through which JNK regulates cell survival is still unclear. In the present study, we hypothesized that there was a crosstalk between JNK and NF-kappaB signaling pathway regulating cell survival and HSP27 phosphorylation mediates such a crosstalk. Our data showed that in HepG2 cells, suppression of JNK activation by a specific inhibitor or overexpression of JNK inactive mutant enhanced TNF-alpha-induced apoptosis. In addition, reduction of JNK activation attenuated HSP27 phosphorylation envoked by TNF-alpha, especially the phosphorylation of HSP27 at serine 78 residue. Our results also showed that suppression of JNK activation reduced the degradation of IkappaB-alpha, but did not affect IKK phosphorylation upon TNF-alpha stimulation. Co-immunoprecipitation experiments demonstrated that JNK regulated the degradation of IkappaB-alpha through promoting the formation of HSP27/IKK/IkappaB alpha ternary complex in response to TNF-alpha. Suppression of JNK activation hindered HSP27 phosphorylation at Ser78 residue and subsequently reduced the interaction between IKK and IkappaB-alpha. Taken together, our study suggests that through modulation the phosphorylation of HSP27, JNK plays an important roles in cell survival via regulating NF-kappaB signaling pathway. PMID- 25446111 TI - Opposite effects of GPR120 and GPR40 on cell motile activity induced by ethionine in liver epithelial cells. AB - Free fatty acids (FFAs) are dietary nutrients which act as ligands for FFAs receptors. G-protein-coupled receptor 120 (GPR120) and GPR40 are activated by long and medium chain FFAs. In the present study, we investigated the role of the GPR120 and GPR40 in cell motile activity stimulated by ethionine in rat liver epithelial WB-F344 cells. Cells were treated with ethionine at a concentration of 10MUM every 24h for 2days. The expression levels of the Gpr120 and Gpr40 genes in WB-F344 cells treated ethionine were significantly higher than those in untreated cells. In cell motility assay, the cell motile activity of WB-F344 cells was markedly elevated by ethionine, compared with untreated cells. To evaluate the effects of GPR120 on the cell motile activity by ethionine, we established GPR120 knockdown cells from WB-F344 cells. The cell motile activity stimulated by ethionine was significantly suppressed by GPR120 knockdown. In addition, a potent GPR40 antagonist GW1100 enhanced the cell motile activity by ethionine. These results suggest that opposite effects of GPR120 and GPR40 may be involved in the cell motile activity stimulated by ethionine in WB-F344 cells. PMID- 25446110 TI - ABCD2 identifies a subclass of peroxisomes in mouse adipose tissue. AB - ATP-binding cassette transporter D2 (D2) is an ABC half transporter that is thought to promote the transport of very long-chain fatty acyl-CoAs into peroxisomes. Both D2 and peroxisomes increase during adipogenesis. Although peroxisomes are essential to both catabolic and anabolic lipid metabolism, their function, and that of D2, in adipose tissues remain largely unknown. Here, we investigated the D2 localization and the proteome of D2-containing organelles, in adipose tissue. Centrifugation of mouse adipose homogenates generated a fraction enriched with D2, but deficient in peroxisome markers including catalase, PEX19, and ABCD3 (D3). Electron microscopic imaging of this fraction confirmed the presence of D2 protein on an organelle with a dense matrix and a diameter of ~ 200 nm, the typical structure and size of a microperoxisome. D2 and PEX19 antibodies recognized distinct structures in mouse adipose. Immunoisolation of the D2-containing compartment confirmed the scarcity of PEX19 and proteomic profiling revealed the presence of proteins associated with peroxisome, endoplasmic reticulum (ER), and mitochondria. D2 is localized to a distinct class of peroxisomes that lack many peroxisome proteins, and may associate physically with mitochondria and the ER. PMID- 25446112 TI - DPP IV inhibitor suppresses STZ-induced islets injury dependent on activation of the IGFR/Akt/mTOR signaling pathways by GLP-1 in monkeys. AB - BACKGROUND: To evaluate the protective effect of the DPP IV inhibitor in STZ induced islet injury and to identify the molecular events that protect islet against apoptosis. METHODS: 4 diabetic monkeys were treated with streptozotocin (70 mg/kg) in the presence or absence of the DPP IV inhibitor (Sitagliptin), continuing administered for 4 weeks after STZ. The monkeys were evaluated by plasma DPP IV activity, serum active GLP-1 response, blood glucose, insulin and C P levels, the insulin resistance index (HOMA-IR), and the expression of insulin, caspase-3, IGF receptor (IGFR), p-Akt and p-mTOR in pancreas islets tissues. To test that DPP IV inhibitors might against islets apoptosis via IGFR/Akt/mTOR signaling pathways, the isolated islets from the normal monkeys were pre-treated with or without 10mM STZ for 1h, followed by GLP-1 (10 MUM) in the presence or absence of NVP-AEW541 or Wortmannin for 24h, to determined islets function and islet apoptosis. RESULTS: DPP IV inhibitors treatment showed depressing the degradation of GLP-1 and significantly increased serum GLP-1 levels in DM monkeys. Moreover, treatment of diabetic monkeys with the DPP IV inhibitor or treatment of isolated islets with GLP-1 can decrease islet apoptosis, and enhanced islet function and survival, and the expression of IGF receptor, p-Akt and p-mTOR in islets. When the IGFR/Akt/mTOR signaling pathways was blocked by NVP-AEW541 or Wortmannin, the protective effects of GLP1 on STZ-induced islets injury were inhibited in vitro. CONCLUSIONS: Our data provides evidence that DPP IV inhibitors confer resistance to STZ-induced islet injury. The protective effects of DPP IV inhibitor on STZ-induced islets injury were dependent on activation of the IGFR/Akt/mTOR signaling pathways by GLP-1 in islets of monkeys. PMID- 25446113 TI - Inhibition of protein kinase C affects on mode of synaptic vesicle exocytosis due to cholesterol depletion. AB - Previous studies demonstrated that depletion of membrane cholesterol by 10mM methyl-beta-cyclodextrin (MCD) results in increased spontaneous exocytosis at both peripheral and central synapses. Here, we investigated the role of protein kinase C in the enhancement of spontaneous exocytosis at frog motor nerve terminals after cholesterol depletion using electrophysiological and optical methods. Inhibition of the protein kinase C by myristoylated peptide and chelerythrine chloride prevented MCD-induced increases in FM1-43 unloading, whereas the frequency of spontaneous postsynaptic events remained enhanced. The increase in FM1-43 unloading still could be observed if sulforhodamine 101 (the water soluble FM1-43 quencher that can pass through the fusion pore) was added to the extracellular solution. This suggests a possibility that exocytosis of synaptic vesicles under these conditions could occur through the kiss-and-run mechanism with the formation of a transient fusion pore. Inhibition of phospholipase C did not lead to similar change in MCD-induced exocytosis. PMID- 25446114 TI - The myosin super-relaxed state is disrupted by estradiol deficiency. AB - We have used quantitative epifluorescence microscopy of fluorescent ATP to measure single-nucleotide turnover in skinned skeletal muscle fibers from mouse models of female aging and hormone treatment. Aging causes declines in muscle strength, often leading to frailty, disability, and loss of independence for the elderly. Female muscle is additionally affected by age due to reduction of ovarian hormone production with menopause. Estradiol (E2) is the key hormonal signal to skeletal muscle in females, and strength loss is attenuated by E2 treatment. To investigate E2 mechanisms on skeletal muscle, single fibers were isolated from sham-operated or ovariectomized (OVX) mice, with or without E2 treatment, and were incubated with 2'-(or-3')-O-(N-methylanthraniloyl) adenosine 5'-triphosphate (mantATP). We measured decay of mantATP fluorescence in an ATP chase experiment, as pioneered by Cooke and coworkers, who unveiled a novel regulated state of muscle myosin characterized by slow nucleotide turnover on the order of minutes, termed the super-relaxed state (SRX). We detected a slow phase of nucleotide turnover in a portion of the myosin heads from sham fibers, consistent with SRX. Turnover was substantially faster in OVX fibers, with a turnover time constant for the slow phase of 65 +/- 8s as compared to 102 +/- 7s for sham fibers. 60-days E2 treatment in OVX mice substantially reversed this effect on SRX, while acute exposure of isolated muscles from OVX mice to E2 had no effect. We conclude that E2-mediated signaling reversibly regulates slow ATP turnover by myosin. Age- and hormone-related muscle functional losses may be targetable at the level of myosin structure/function for strategies to offset weakness and metabolic changes that occur with age. PMID- 25446115 TI - A thiazepino[4,5-a]benzimidazole derivative hampers the RNA replication of Eurasian serotypes of foot-and-mouth disease virus. AB - The stamping-out policy for the control of foot-and-mouth disease virus (FMDV) in countries that are free from FMD without vaccination has a dramatic socio economic impact, huge animal welfare issues and may result in the loss of farm animal genetic resources. As an alternative to pre-emptive culling or emergency vaccination we further explore the possibility to use antiviral drugs in the event of an FMD outbreak. In the present study, we tested the in vitro cytotoxicity and anti-FMDV activity of 1,2,4,5-tetrahydro-[1,4]thiazepino[4,5 a]benzimidazole. The molecule was shown to inhibit the replication of reference strains of the Eurasian FMDV serotypes O, A, C and Asia but not the FMDV serotypes from the South African Territories (SAT) neither a related picornavirus, i.e. swine vesicular disease virus. The molecule can be added until 2h post inoculation in a 'single replication cycle experiment' without losing its antiviral activity. The genetic characterization of progressively selected resistant FMD viruses shows that the molecule presumably interacts with the non structural 2C protein of FMDV. Further studies are required on the use of this molecule in vivo. PMID- 25446116 TI - Discovering novel direct acting antiviral agents for HBV using in silico screening. AB - The treatments for chronic hepatitis B (CHB) are interferon and nucleoside analogues reverse transcriptase (RT) inhibitors. Because both treatments are less than ideal, we conducted to identify novel anti-viral agents for HBV-reverse transcriptase (HBV-RT). We determined the ligand-binding site of the HBV-RT by conducting a homological search of the amino acid sequence and then we also determined not only structural arrangement of the target protein but the target protein-binding site of the ligand using known protein-ligand complexes in registered in the protein data bank (PDB). Finally we simulated binding between the ligand candidates and the HBV-RT and evaluated the degree of binding (in silico screening). PXB cells derived from human-mouse chimeric mouse liver, infected with HBV were administrated with the candidates, and HBVDNA in the culture medium was monitored by realtime qPCR. Among compounds from the AKosSamples database, twelve candidates that can inhibit RT were also identified, two of which seem to have the potential to control HBV replication in vitro. PMID- 25446118 TI - A new type of protein lysine methyltransferase trimethylates Lys-79 of elongation factor 1A. AB - The elongation factors of Saccharomyces cerevisiae are extensively methylated, containing a total of ten methyllysine residues. Elongation factor methyltransferases (Efm1, Efm2, Efm3, and Efm4) catalyze at least four of these modifications. Here we report the identification of a new type of protein lysine methyltransferase, Efm5 (Ygr001c), which was initially classified as N6-adenine DNA methyltransferase-like. Efm5 is required for trimethylation of Lys-79 on EF1A. We directly show the loss of this modification in efm5Delta strains by both mass spectrometry and amino acid analysis. Close homologs of Efm5 are found in vertebrates, invertebrates, and plants, although some fungal species apparently lack this enzyme. This suggests possible unique functions of this modification in S. cerevisiae and higher eukaryotes. The misannotation of Efm5 was due to the presence of a DPPF sequence in post-Motif II, typically associated with DNA methylation. Further analysis of this motif and others like it demonstrates a potential consensus sequence for N-methyltransferases. PMID- 25446117 TI - COMP-angiopoietin 1 increases proliferation, differentiation, and migration of stem-like cells through Tie-2-mediated activation of p38 MAPK and PI3K/Akt signal transduction pathways. AB - Recombinant COMP-Ang1, a chimera of angiopoietin-1 (Ang1) and a short coiled-coil domain of cartilage oligomeric matrix protein (COMP), is under consideration as a therapeutic agent capable of inducing the homing of cells with increased angiogenesis. However, the potentials of COMP-Ang1 to stimulate migration of mesenchymal stem cells (MSCs) and the associated mechanisms are not completely understood. We examined the potential of COMP-Ang1 on bone marrow (BM)-MSCs, human periodontal ligament stem cells (PDLSCs), and calvarial osteoblasts. COMP Ang1 augmented Tie-2 induction at protein and mRNA levels and increased proliferation and expression of runt-related transcription factor 2 (Runx2), osterix, and CXCR4 in BMMSCs, but not in osteoblasts. The COMP-Ang1-mediated increases were inhibited by Tie-2 knockdown and by treating inhibitors of phosphoinositide 3-kinase (PI3K), LY294002, or p38 mitogen-activated protein kinase (MAPK), SB203580. Phosphorylation of p38 MAPK and Akt was prevented by siRNA-mediated silencing of Tie-2. COMP-Ang1 also induced in vitro migration of BMMSCs and PDLSCs. The induced migration was suppressed by Tie-2 knockdown and by CXCR4-specific peptide antagonist or LY294002, but not by SB203580. Furthermore, COMP-Ang1 stimulated the migration of PDLSCs into calvarial defect site of rats. Collectively, our results demonstrate that COMP-Ang1-stimulated proliferation, differentiation, and migration of progenitor cells may involve the Tie-2-mediated activation of p38 MAPK and PI3K/Akt pathways. PMID- 25446119 TI - PXD101 significantly improves nuclear reprogramming and the in vitro developmental competence of porcine SCNT embryos. AB - In this study, we investigated the effects of the histone deacetylase inhibitor PXD101 (belinostat) on the preimplantation development of porcine somatic cell nuclear transfer (SCNT) embryos and their expression of the epigenetic markers histone H3 acetylated at lysine 9 (AcH3K9). We compared the in vitro developmental competence of SCNT embryos treated with various concentrations of PXD101 for 24h. Treatment with 0.5 MUM PXD101 significantly increased the proportion of SCNT embryos that reached the blastocyst stage, in comparison to the control group (23.3% vs. 11.5%, P<0.05). We tested the in vitro developmental competence of SCNT embryos treated with 0.5 MUM PXD101 for various amounts of times following activation. Treatment for 24h significantly improved the development of porcine SCNT embryos, with a significantly higher proportion of embryos reaching the blastocyst stage in comparison to the control group (25.7% vs. 10.6%, P<0.05). PXD101-treated SCNT embryos were transferred into two surrogate sows, one of whom became pregnant and four fetuses developed. PXD101 treatment significantly increased the fluorescence intensity of immunostaining for AcH3K9 in embryos at the pseudo-pronuclear and 2-cell stages. At these stages, the fluorescence intensities of immunostaining for AcH3K9 were significantly higher in PXD101-treated embryos than in control untreated embryos. In conclusion, this study demonstrates that PXD101 can significantly improve the in vitro and in vivo developmental competence of porcine SCNT embryos and can enhance their nuclear reprogramming. PMID- 25446120 TI - HAP1 gene expression is associated with radiosensitivity in breast cancer cells. AB - OBJECTIVES: The purpose of this study was to investigate the relationship between huntingtin-associated protein1 (HAP1) gene and radiation therapy of breast cancer cells. METHODS: HAP1 gene was transfected into breast cancer MCF-7 cells, which was confirmed by quantitative reverse transcription-polymerase chain reaction analysis (qRT-PCR) and Western blot in vitro. The changes of cell radiosensitivity were assessed by colony formation assay. Apoptosis were examined by flow cytometry. The expressions of two radiation-induced genes were evaluated by Western blot. Tumor growth was investigated in nude mice xenograft models in vivo. RESULTS: Our data showed that HAP1 gene expression was significantly increased in HAP1-transfected MCF-7 cells in comparison with the parental cells or negative control cells. The survival rate in MCF-7/HAP1 cells was significantly decreased after irradiation (0, 2, 4, 6, 8Gy), compared to cells in MCF-7 and MCF-7/Pb groups in vitro. HAP1 gene increased apoptosis in MCF-7 cells after irradiation. Additionally, the tumor volume and weight in MCF-7/HAP1+RT group were observably lower than in MCF-7/HAP1 group and MCF-7/Pb+RT group. CONCLUSION: The present study indicated that HAP1 gene expression was related to the radiosensitivity of breast cancer cells and may play an important role in the regulation of cellular radiosensitivity. PMID- 25446121 TI - Prostaglandin potentiates 5-HT responses in stomach and ileum innervating visceral afferent sensory neurons. AB - Gastrointestinal disorder is a common symptom induced by diverse pathophysiological conditions that include food tolerance, chemotherapy, and irradiation for therapy. Prostaglandin E2 (PGE2) level increase was often reported during gastrointestinal disorder and prostaglandin synthetase inhibitors has been used for ameliorate the symptoms. Exogenous administration of PGE2 induces gastrointestinal disorder, however, the mechanism of action is not known. Therefore, we tested PGE2 effect on visceral afferent sensory neurons of the rat. Interestingly, PGE2 itself did not evoked any response but enhanced serotonin (5 HT)-evoked currents up to 167% of the control level. The augmented 5-HT responses were completely inhibited by a 5-HT type 3 receptor antagonist, ondansetron. The PGE2-induced potentiation were blocked by a selective E-prostanoid type 4 (EP4) receptors antagonist, L-161,982, but type 1 and 2 receptor antagonist AH6809 has no effect. A membrane permeable protein kinase A (PKA) inhibitor, KT5720 also inhibited PGE2 effects. PGE2 induced 5-HT current augmentation was observed on 15% and 21% of the stomach and ileum projecting neurons, respectively. Current results suggest a synergistic signaling in visceral afferent neurons underlying gastrointestinal disorder involving PGE2 potentiation of 5-HT currents. Our findings may open a possibility for screen a new type drugs with lower side effects than currently using steroidal prostaglandin synthetase inhibitors by selectively targeting EP4 receptor/PKA pathway without interrupt prostaglandin synthesis. PMID- 25446123 TI - Structural insight into the assembly of human anti-HIV dynamin-like protein MxB/Mx2. AB - Interferon (IFN) is a key component of the innate immune response to exogenous pathogens. Interferon increases the mRNA levels of interferon-stimulated genes (ISGs) in vivo, which is thought to account for its antiviral activity. Recent studies have indicated that human myxovirus resistance protein 2 (Mx2 or MxB), one of these ISGs, contributes to the inhibition of HIV-1 replication by interferon. MxB may bind to HIV-1 relatively late in the post-entry phase, and it leads to a reduced level of integrated viral DNA, thereby restricting HIV-1 infection. The N-terminal 91-aa domain of MxB and the assembly of MxB mediated by the Stalk domain have also been shown to be indispensible for MxB's anti-viral functions, but the mechanism involved has remained elusive. Here, we report the crystal structure (2.9A) of the human MxB Stalk domain. MxB Stalk shows one dimer in the asymmetric unit. Each monomer contains a four-helix bundle. Interestingly, analyses of MxB dimer interfaces show that the majority of residues involved in the interface are not conserved between MxB and MxA, contributing to the building of a more stable MxB dimer. MxA and MxB Stalk domains share 46.7% sequence identity, and the structure of the MxA Stalk domain and the overall structure of MxB Stalk have a similar conformation. Our results indicate that although human Mx proteins share common structural characteristics, their dimerization strategies are unique, contributing to their unique contributions to viral restriction. PMID- 25446122 TI - Protein tyrosine kinase 6 mediates TNFalpha-induced endothelial barrier dysfunction. AB - A key event in the progression of systemic inflammation resulting from severe trauma or shock involves microvascular hyperpermeability, which leads to excessive plasma fluid and proteins accumulating in extravascular space resulting in tissue edema. The precise molecular mechanism of the hyperpermeability response is not completely understood. Protein tyrosine kinase 6 (PTK6, also known as breast tumor kinase BRK) is a non-receptor tyrosine kinase related to Src-family proteins. Although it has also been shown that PTK6 participates in regulating epithelial barrier function, the role of PTK6 in endothelial barrier function has not been reported. In this study, we hypothesized that PTK6 is (1) expressed in vascular endothelial cells, and (2) contributes to vascular endothelial hyperpermeability in response to TNFalpha. Results showed that PTK6 was detected in mouse endothelial cells at the level of protein and mRNA. In addition, PTK6 knockdown attenuated TNFalpha induced decrease in endothelial barrier function as measured by electric cell-substrate impedance sensing (ECIS) and in vitro transwell albumin-flux assays. Furthermore, we showed that TNFalpha treatment of endothelial cells increased active PTK6 association with p120 catenin at endothelial cell-cell junctions. Further analysis using immunocytochemistry and immunoprecipitation demonstrated that PTK6 knockdown attenuated TNFalpha induced VE-cadherin internalization as well as promoting its association with p120-catenin. Our study demonstrates a novel role of PTK6 in mediating endothelial barrier dysfunction. PMID- 25446124 TI - Proteomics-based identification of immunodominant proteins of Brucellae using sera from infected hosts points towards enhanced pathogen survival during the infection. AB - Brucella (B.) species lack classical virulence factors, but escape effectively the immune response of the host. The species Brucella abortus and Brucella melitensis infect predominantly cattle and small ruminants such as sheep or goats, respectively, but account also for most human cases. These two species share remarkably similar genomes but different proteomes have been demonstrated. This might be one of the reasons for their host specificity. A comprehensive identification of immunodominant proteins of these two species using antibodies present in the serum of naturally infected ruminants might provide insight on the mechanism of their infection in different hosts. In the present study, whole-cell protein extracts of B. abortus and B. melitensis were separated using SDS-PAGE and western blotting was performed using field sera from cows, buffaloes, sheep and goats. Protein bands that matched with western blot signals were excised, digested with trypsin and subjected to protein identification using MALDI-TOF MS. Identified proteins included heat shock proteins, enzymes, binding proteins and hypothetical proteins. Antibodies against the same set of antigen were found for all species investigated, except for superoxide dismutase of B. melitensis for which antibodies were demonstrated only in sheep serum. Brucellae appear to express these proteins mainly for their survival in the host system during infection. PMID- 25446125 TI - The pH-sensitive structure of the C-terminal domain of voltage-gated proton channel and the thermodynamic characteristics of Zn2+ binding to this domain. AB - The voltage-gated proton channel Hv1 is strongly sensitive to Zn(2+). The H(+) conduction is decreased at a high concentration of Zn(2+) and Hv1 channel closing is slowed by the internal application of Zn(2+). Although the recent studies demonstrated that Zn(2+) interacts with the intracellular C-terminal domain, the binding sites and details of the interaction remain unknown. Here, we studied the pH-dependent structural stability of the intracellular C-terminal domain of human Hv1 and showed that Zn(2+) binds to His(244) and His(266) residues. The thermodynamics signature of Zn(2+) binding to the two sites was investigated by isothermal titration calorimetry. The binding of Zn(2+) to His(244) (mutant H266A) and His(266) (mutant H244A) were an endothermic heat reaction and an exothermic heat reaction, respectively. PMID- 25446127 TI - Fibroblast growth factor 10 protects neuron against oxygen-glucose deprivation injury through inducing heme oxygenase-1. AB - Fibroblast growth factors (FGFs) are a family of structurally related heparin binding proteins with diverse biological functions. FGFs participate in mitogenesis, angiogenesis, cell proliferation, development, differentiation and cell migration. Here, we investigated the potential effect of FGF10, a member of FGFs, on neuron survival in oxygen-glucose deprivation (OGD) model. In primary cultured mouse cortical neurons upon OGD, FGF10 treatment (100 and 1000 ng/ml) attenuated the decrease of cell viability and rescued the LDH release. Tuj-1 immunocytochemistry assay showed that FGF10 promoted neuronal survival. Apoptosis assay with Annexin V+PI by flow cytometry demonstrated that FGF10 treatment reduced apoptotic cell proportion. Moreover, immunoblotting showed that FGF10 alleviated the cleaved caspase-3 upregulation caused by OGD. FGF10 treatment also depressed the OGD-induced increase of caspase-3, -8 and -9 activities. At last, we found FGF10 triggered heme oxygenase-1 (HO-1) protein expression rather than hypoxia-inducible factor-1 (HIF-1), AMP-activated protein kinase (AMPK) signaling and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling. Knockdown of HO-1 by siRNA partly abolished the neuroprotection of FGF10 in OGD model. In summary, our observations provide the first evidence for the neuroprotective function of FGF10 against ischemic neuronal injury and suggest that FGF10 may be a promising agent for treatment of ischemic stroke. PMID- 25446126 TI - Characterization of the minimal length of functional SecA in Escherichia coli. AB - Previous studies showed that certain regions of E. coli SecA can be deleted from its N- and/or C-termini to complement a SecA amber ts mutant. In this study, we determined and characterized the dispensability of both ends of SecA molecules. With N-terminal intact or 9-aa deleted, 826aa (SecA1-826 and SecA10-826, respectively) is the minimum for complementation activity, while with N-terminus deleted by 2-21aa, SecA22-829 is the minimum. Further deletion at the C-terminus of SecA1-826/SecA10-826/SecA22-829 abolished the complementation activity in the cells. A hydrophobic amino acid is required for the 826th residue in the minimal length SecAs. Chemical crosslinking and gel filtration result showed that both purified SecA22-828 and SecA22-829 could form a dimer. Moreover, the in vitro ATPase and protein translocation activities of SecA22-828 and SecA22-829 were similar, though lower than wild-type SecA. The active mutants had more truncated SecA in soluble than membrane-bound form, but was more stably embedded in membranes. In contrast, the inactive mutants tended to have truncated SecA more membrane-bound than soluble form, and were more loosely bound and easily chased out. Thus, the loss of complementation appears to be related to their altered subcellular localization and stability in the membranes. This study defines the substantial regions of N- and C-termini of SecA that may be deleted without losing complementation activity. PMID- 25446128 TI - Global epigenomic analysis indicates protocadherin-7 activates osteoclastogenesis by promoting cell-cell fusion. AB - Gene expression is dependent not only on genomic sequences, but also epigenetic control, in which the regulation of chromatin by histone modification plays a crucial role. Histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 27 trimethylation (H3K27me3) are related to transcriptionally activated and silenced sequences, respectively. Osteoclasts, the multinucleated cells that resorb bone, are generated by the fusion of precursor cells of monocyte/macrophage lineage. To elucidate the molecular and epigenetic regulation of osteoclast differentiation, we performed a chromatin immunoprecipitation sequencing (ChIP-seq) analysis for H3K4me3 and H3K27me3 in combination with RNA sequencing. We focused on the histone modification change from H3K4me3(+)H3K27me3(+) to H3K4me3(+)H3K27me3(-) and identified the protocadherin-7 gene (Pcdh7) to be among the genes epigenetically regulated during osteoclastogenesis. Pcdh7 was induced by RANKL stimulation in an NFAT-dependent manner. The knockdown of Pcdh7 inhibited RANKL-induced osteoclast differentiation due to the impairment of cell-cell fusion, accompanied by a decreased expression of the fusion-related genes Dcstamp, Ocstamp and Atp6v0d2. This study demonstrates that Pcdh7 plays a key role in osteoclastogenesis by promoting cell cell fusion. PMID- 25446130 TI - Crystal structure of 5-formyl-3-hydroxy-2-methylpyridine 4-carboxylic acid 5 dehydrogenase, an NAD+-dependent dismutase from Mesorhizobium loti. AB - 5-Formyl-3-hydroxy-2-methylpyridine 4-carboxylic acid 5-dehydrogenase (FHMPCDH) from Mesorhizobium loti is the fifth enzyme in degradation pathway I for pyridoxine. The enzyme catalyzes a dismutation reaction: the oxidation of 5 formyl-3-hydroxy-2-methylpyridine 4-carboxylic acid (FHMPC) to 3-hydroxy-2 methylpyridine 4,5-dicarboxylic acid with NAD(+) and reduction of FHMPC to 4 pyridoxic acid with NADH. FHMPCDH belongs to the l-3-hydroxyacyl-CoA dehydrogenase (HAD) family. The crystal structure was determined by molecular replacement and refined to a resolution of 1.55A (R-factor of 16.4%, Rfree=19.4%). There were two monomers in the asymmetric unit. The overall structure of the monomer consisted of N- and C-terminal domains connected by a short linker loop. The monomer was similar to members of the HAD family (RMSD=1.9A). The active site was located between the domains and highly conserved to that of human heart l-3-hydroxyacyl-CoA dehydrogenase (HhHAD). His-Glu catalytic dyad, a serine and two asparagine residues of HhHAD were conserved. Ser116, His137 and Glu149 in FHMPCDH are connected by a hydrogen bonding network forming a catalytic triad. The functions of the active site residues in the reaction mechanism are discussed. PMID- 25446131 TI - Engineering of tumor microenvironments. PMID- 25446129 TI - Mitochondrial division inhibitor 1 (mdivi-1) enhances death receptor-mediated apoptosis in human ovarian cancer cells. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) based strategy is a promising targeted therapeutic approach for the treatment of a variety of cancers including ovarian cancer. However, the inherent or acquired resistance of tumor cells to TRAIL limits the potential application of TRAIL-mediated therapy. In this study, we identified that mitochondrial division inhibitor-1 (mdivi-1) is able to enhance the sensitivity of human ovarian cancer cells to death receptor ligands including TRAIL, FAS ligands, and TNF-alpha. Importantly, the combination of TRAIL and mdivi-1 has no apparent cytotoxic effect on non-transformed human cells, indicating a significant therapeutic window. We identified that caspase-8 and not the modulation of TRAIL receptors is required for the combination effect of TRAIL and mdivi-1. We further demonstrated that the enhanced efficacy of combination of mdivi-1 and death ligands is not dependent on the originally reported target of mdivi-1, Drp1, and is also not dependent on the two important pro-apoptotic Bcl-2 family proteins Bax and Bak. Thus, our study presents a novel strategy in enhancing the apoptotic effect of death receptor ligands and provides a new effective TRAIL-based combination approach for treating human ovarian cancer. PMID- 25446132 TI - Meeting the challenges of advanced drug delivery in critical illness. PMID- 25446133 TI - Peripheral nerve regeneration: experimental strategies and future perspectives. AB - Peripheral nerve injuries represent a substantial clinical problem with insufficient or unsatisfactory treatment options. This review summarises all the events occurring after nerve damage at the level of the cell body, the site of injury and the target organ. Various experimental strategies to improve neuronal survival, axonal regeneration and target reinnervation are described including pharmacological approaches and cell-based therapies. Given the complexity of nerve regeneration, further studies are needed to address the biology of nerve injury, to improve the interaction with implantable scaffolds, and to implement cell-based therapies in nerve tissue engineering. PMID- 25446134 TI - The ethics of stem cells revisited. AB - Stem cells constitute one of the most promising tools for regenerative medicine. Thus, it seems morally compelling to explore all the sources that might provide us with them. However, some of these sources, such as somatic cell nuclear transfer, embryo destruction, or even induced pluripotency obtained by reprogramming have raised deep ethical issues. The aim of this paper is to reflect on the stem cell ethical debate at the current moment through an analysis of the academic literature. It will also provide an analysis of the ethical implications of the most relevant scientific advances that have happened in recent months or those which seem about to merge. PMID- 25446136 TI - Bladder tissue engineering: a literature review. AB - PURPOSE OF REVIEW: In bladder cancer and neuro-bladder, reconstruction of the bladder requires bowel segment grafting for augmentation cystoplasty or neo bladder creation. However, even if currently considered as the gold standard, it is associated with potentially severe short- and long-term adverse effects. Thus, bladder tissue engineering is a promising approach to bladder reconstruction. RECENT FINDINGS: In the last few years, progress has been made with the development of new biomaterials for bladder tissue replacement and in deciphering the role of stem cells as well as their contribution to bladder scaffold integration and tissue regeneration. SUMMARY: This review of recently published articles allows us to forecast the characteristics of efficient and safe bladder biomaterials. However, several factors, such as native bladder traits, the specific involvement of urine, and bladder tissue replacement indications, have to be assessed with caution before including bladder tissue engineering in clinical trials. Many authors agree that these challenging techniques could deliver significant benefits with clinical application, reducing morbidity and global long-term costs. PMID- 25446137 TI - Biomarkers of spinal cord injury and ensuing bladder dysfunction. AB - During the acute phase of SCI, the extension and residual neurological deficits that will persist after the waning of the spinal shock period are difficult to estimate on clinical grounds. Therefore, objective biomarkers able to estimate the extension of the lesion and the degree of neurological recovery are of great importance. Research has been focused on the detection of structural neuronal and glial proteins that leak from damaged cells, inflammatory proteins recruited to remove necrotic debris and more accurate neuroimaging methods that are able to discriminate the extension and functional consequences of the SCI. Urinary biomarkers are also being investigated to estimate functional changes that typically affect bladder function following SCI which can endanger patient's life in the long run. Future studies are needed to precisely characterize the composition and function of the glial scar that appears in the area of SCI and repeals axonal growth, therefore preventing axonal rewiring. PMID- 25446138 TI - Growth factor and small molecule influence on urological tissue regeneration utilizing cell seeded scaffolds. AB - Regenerative medicine strategies combine various attributes from multiple disciplines including stem cell biology, chemistry, materials science and medicine. The junction at which these disciplines intersect provides a means to address unmet medical needs in an assortment of pathologies with the goal of creating sustainable, functional replacement tissues. Tissue damage caused by trauma for example, requires rapid responses in order to mitigate further tissue deterioration. Cell/scaffold composites have been utilized to initiate and stabilize regenerative responses in vivo with the hope that functional tissue can be attained. Along with the gross reconfiguration of regenerating tissues, small molecules and growth factors also play a pivotal role in tissue regeneration. Several regenerative studies targeting a variety of urological tissues demonstrate the utility of these small molecules or growth factors in an in vivo setting. PMID- 25446139 TI - Regulatory challenges for autologous tissue engineered products on their way from bench to bedside in Europe. AB - Since the late eighties of last century the high potential of tissue engineered products (TEP)s has been shown for the treatment of various diseases and many scientific publications appeared in this field. However, only few products reached the market since. Development of TEPs is a promising but owing to its novelty a very challenging task that requires experts in this still developing field as well as ample financial resources. This paper summarises relevant regulatory challenges during quality, preclinical and clinical development of autologous TEPs in Europe. Selected strategies on how to manage major issues are presented, together with some examples from the development of an autologous TEP for urethroplasty. Considering these aspects may help other investigators with potential strategies during the development of novel TEPs. PMID- 25446135 TI - Biologics for tendon repair. AB - Tendon injuries are common and present a clinical challenge to orthopedic surgery mainly because these injuries often respond poorly to treatment and require prolonged rehabilitation. Therapeutic options used to repair ruptured tendons have consisted of suture, autografts, allografts, and synthetic prostheses. To date, none of these alternatives has provided a successful long-term solution, and often the restored tendons do not recover their complete strength and functionality. Unfortunately, our understanding of tendon biology lags far behind that of other musculoskeletal tissues, thus impeding the development of new treatment options for tendon conditions. Hence, in this review, after introducing the clinical significance of tendon diseases and the present understanding of tendon biology, we describe and critically assess the current strategies for enhancing tendon repair by biological means. These consist mainly of applying growth factors, stem cells, natural biomaterials and genes, alone or in combination, to the site of tendon damage. A deeper understanding of how tendon tissue and cells operate, combined with practical applications of modern molecular and cellular tools could provide the long awaited breakthrough in designing effective tendon-specific therapeutics and overall improvement of tendon disease management. PMID- 25446142 TI - Stem cell treatment of erectile dysfunction. AB - Erectile Dysfunction (ED) is a common disease that typically affects older men. While oral type-5 phosphodieserase inhibitors (PDE5Is) represent a successful first-line therapy, many patients do not respond to this treatment leading researchers to look for alternative treatment modalities. Stem cell (SC) therapy is a promising new frontier for the treatment of those patients and many studies demonstrated its therapeutic effects. In this article, using a Medline database search of all relevant articles, we present a summary of the scientific principles behind SCs and their use for treatment of ED. We discuss specifically the different types of SCs used in ED, the methods of delivery tested, and the methods attempted to enhance SC therapy effect. In addition, we review the current preclinical literature on SC therapy for ED and present a summary of its findings in addition to the single clinical trial published. PMID- 25446143 TI - Emergence of multidrug-resistant bacteria: important role of macromolecules and drug delivery systems. PMID- 25446144 TI - The magnitude of the naturally occurring isotopic enrichment of 13C in exhaled CO2 is directly proportional to exercise intensity in humans. AB - Due to various biochemical fractionation processes during lipid synthesis, the lipid molecules in the body contain substantially lower concentrations of 13C than the nonlipid molecules. Because of the isotopic differences between these two endogenous nutrient pools, any shift toward nonlipid fuel oxidation would be expected to increase in the delta13C of the exhaled breath. Interestingly, the possibility of whether or not an exercise-induced change actually occurs has been debated in literature for over two decades and researchers have still not reached a consensus. We measured ventilatory and metabolic variables before, during, and after exercise in forty-eight adults (n = 25 females, n = 23 males; 20.1 +/- 1.9 years) assigned to either a resting treatment or one of three exercising treatments where they maintained a heart rate of 130, 150, or 170 bpm for 56 min. We found that the mean metabolic rates of the exercising groups increased 4.4 fold, 6.1-fold, and 7.7-fold above resting values, respectively. Exercise caused small increases in respiratory exchange ratios (e.g., from 0.83 +/- 0.08 to 0.86 +/- 0.10) indicative of increased carbohydrate oxidation, but these changes were too variable to be reliably correlated with exercise intensity. In contrast, the delta13C of the exhaled breath increased by 0.62 +/- 0.190/00, 1.14 +/- 0.290/00, and 1.79 +/- 0.500/00, respectively, for the three groups and was significantly correlated with the intensity of exercise. We also show that the isotopic difference of the lipid and nonlipids of the body is similar (~ 2.70/00) even when consuming bulk diets that are isotopically distinct (> 80/00). If not corrected for, these exercise-induced changes in delta13C of the breath would be sufficiently large to skew the results of studies investigating the oxidative fates of exogenous nutritional supplements. PMID- 25446141 TI - Role of microRNAs in maintaining cancer stem cells. AB - Increasing evidence sustains that the establishment and maintenance of many, if not all, human cancers are due to cancer stem cells (CSCs), tumor cells with stem cell properties, such as the capacity to self-renew or generate progenitor and differentiated cells. CSCs seem to play a major role in tumor metastasis and drug resistance, but albeit the potential clinical importance, their regulation at the molecular level is not clear. Recent studies have highlighted several miRNAs to be differentially expressed in normal and cancer stem cells and established their role in targeting genes and pathways supporting cancer stemness properties. This review focuses on the last advances on the role of microRNAs in the regulation of stem cell properties and cancer stem cells in different tumors. PMID- 25446145 TI - Immune response, oxidative stress and dietary antioxidants in great tit nestlings. AB - The activation of immune defences counteracts pathogens, but mounting an immune response is costly and can negatively impact life-history traits. Immune activation releases highly reactive species that kill pathogens but can also cause oxidative damage to host tissues, and these negative effects may therefore constrain further investment in immune responses. To offset these toxic effects, animals rely on a complex system of antioxidants. Here, we tested if vitamin E, a dietary antioxidant, can reduce oxidative damage induced by an immune challenge and thus enhance the immune response. In a 2 * 2 experimental design, we supplemented great tit nestlings with either vitamin E or a placebo, and then injected them with either a bacterial lipopolysaccharide (LPS), or a buffer solution (PBS) as a control. LPS-treated nestlings mounted an inflammatory response and increased antioxidant capacity, without any change in ROM (reactive oxygen metabolites), an index of early oxidative damage. These results suggest that the likely transient increase in reactive species of the LPS injection was counteracted by a rise in endogenous antioxidant defences that was independent of supplementary dietary antioxidants. Indeed, vitamin E supplementation neither affected oxidative status nor enhanced the immune response, suggesting that in our experimental condition great tit nestlings were not limited in vitamin E and in antioxidants in general. Overall, our results show that birds can mount an effective antioxidant response to face an immune challenge, and can therefore avoid stress caused by a transient increase in reactive species generated by immune activation. PMID- 25446146 TI - Methane emission by adult ostriches (Struthio camelus). AB - Ostriches (Struthio camelus) are herbivorous birds with a digestive physiology that shares several similarities with that of herbivorous mammals. Previous reports, however, claimed a very low methane emission from ostriches, which would be clearly different from mammals. If this could be confirmed, ostrich meat would represent a very attractive alternative to ruminant-and generally mammalian-meat by representing a particularly low-emission agricultural form of production. We individually measured, by chamber respirometry, the amount of oxygen consumed as well as carbon dioxide and methane emitted from six adult ostriches (body mass 108.3+/-8.3 kg) during a 24-hour period when fed a pelleted lucerne diet. While oxygen consumption was in the range of values previously reported for ostriches, supporting the validity of our experimental setup, methane production was, at 17.5+/-3.2 L d(-1), much higher than previously reported for this species, and was of the magnitude expected for similar-sized, nonruminant mammalian herbivores. These results suggest that methane emission is similar between ostriches and nonruminant mammalian herbivores and that the environmental burden of these animals is comparable. The findings furthermore indicate that it appears justified to use currently available scaling equations for methane production of nonruminant mammals in paleo-reconstructions of methane production of herbivorous dinosaurs. PMID- 25446147 TI - Exogenous recombinant bovine growth hormone stimulates growth and hepatic IGF expression in shovelnose sturgeon Scaphirhynchus platorhynchus. AB - Sturgeon are a unique fish for physiological research as they are long-lived, slow-growing, and late-maturing. Furthermore, sturgeon growth hormones appear to share greater structural and molecular similarity with mammalian somatotropins than teleostean somatotropins. In this study, changes in insulin-like growth factor (IGF)-I and IGF-II mRNA expression and corresponding whole-body growth and composition following 6 weeks of bi-weekly recombinant bovine growth hormone (rbGH) administration in shovelnose sturgeon Scaphirhynchus platorhynchus were evaluated. Fish were injected intraperitoneally with 240 MUg rbGH/g body weight or a sesame oil sham. Hepatic IGF-I and IGF-II mRNA abundance was significantly higher (P<=0.02) in rbGH-treated fish, as were length (P<0.001) and weight gain (P<0.001). In addition, proximate whole-body analysis demonstrated a significant (P<0.05) increase in protein composition of rbGH-treated fish versus sham-treated fish. There were no significant differences in whole-body moisture, lipid, or ash between the two treatments. These results demonstrate functional roles for GH and IGFs in the promotion of lean growth within this ancient fish species and support the view that the functional effects of GH on hepatic IGF-I expression and somatic growth are conserved from chondostrean to teleostean fishes. PMID- 25446148 TI - Mechanisms of Cl(-) uptake in rainbow trout: cloning and expression of slc26a6, a prospective Cl(-)/HCO3(-) exchanger. AB - In fresh waters, fishes continuously acquire ions to offset diffusive losses to a more dilute ambient environment and to maintain acid-base status. The objectives of the present study were to clone slc26a6, a prospective Cl(-)/HCO3(-) exchanger from rainbow trout, investigate its expression patterns in various tissues, at different developmental stages and after differential salinity exposure, and probe the mechanisms of Cl(-) uptake in rainbow trout embryos during development using a pharmacological inhibitor approach combined with (36)Cl(-) unidirectional fluxes. Results showed that the cloned gene encoded a 783 amino acid protein with conserved domains characteristic of the SLC26a family of anion exchange proteins. Phylogenetic analysis of this sequence against all subfamilies of the SLC26a family demonstrated that this translated protein shared a common ancestor with other actinopterygii and mammalian SLC26a6 isoforms and thus confirmed the identity of the cloned gene. Expression of slc26a6 was detected in all tissues and developmental stages assayed but was highest in the gill of juvenile trout. In trout embryos, Cl(-) uptake increased significantly post-hatch and was demonstrated to be mediated via an anion exchanger specific (DIDS sensitive) pathway that was also sensitive to hypercapnia. This parallels well with the predicted function of slc26a6, and the detection of the transcript in embryos and tissues of trout. In conclusion, this study is the first report of slc26a6 in rainbow trout and functional and expression analyses indicate its likely involvement in Cl(-)/HCO3(-) exchange in two life stages of rainbow trout. PMID- 25446149 TI - Selection for high activity-related aerobic metabolism does not alter the capacity of non-shivering thermogenesis in bank voles. AB - An intriguing question is how the capacity of non-shivering thermogenesis (NST)-a special mechanism supporting endothermic thermoregulation in mammals-is affected by selection for high exercise metabolism. It has been proposed that high NST could be a mechanism to compensate for a low basal production of heat. On the other hand, high basal or activity metabolism is associated with physiological characteristics such as high performance of the circulatory system, which are also required for achieving a high NST. Here we tested whether selection for high aerobic exercise performance, which correlates with an increased basal metabolic rate, led to a correlated evolution of maximum and facultative NST. Therefore, we measured the NST of bank voles, Myodes (= Clethrionomys) glareolus, from lines selected for 13-14 generations (n=46) for high aerobic metabolism achieved during swimming and from unselected, control lines (n=46). Open-flow respirometry was used to measure the rate of oxygen consumption (V(.)O2) in anesthetized bank voles injected with noradrenaline (NA). After adjusting for body mass, maximum NST (maximum V(.)O2 recorded after injection of NA) did not differ between the selected (2.38+/-0.08 mLO2min(-1)) and control lines (2.36+/-0.08 mLO2min(-1); P=0.891). Facultative NST (= maximum NST minus resting metabolic rate of anesthetized animals) did not differ between the selected (1.49+/-0.07 mLO2min( 1)) and control lines (1.50+/-0.07 mLO2min(-1); P=0.985), either. Therefore, our results suggest that NST capacity is not strongly linked to maximum activity related aerobic metabolic rate. PMID- 25446140 TI - Inhaled anti-infective chemotherapy for respiratory tract infections: successes, challenges and the road ahead. AB - One of the most common causes of illnesses in humans is from respiratory tract infections caused by bacterial, viral or fungal pathogens. Inhaled anti-infective drugs are crucial for the prophylaxis and treatment of respiratory tract infections. The benefit of anti-infective drug delivery via inhalation is that it affords delivery of sufficient therapeutic dosages directly to the primary site of infection, while minimizing the risks of systemic toxicity or avoiding potential suboptimal pharmacokinetics/pharmacodynamics associated with systemic drug exposure. This review provides an up-to-date treatise of approved and novel developmental inhaled anti-infective agents, with particular attention to effective strategies for their use, pulmonary pharmacokinetic properties and safety. PMID- 25446150 TI - Oxidative radical 1,2-alkylarylation of alkenes with alpha-C(sp(3))-H bonds of acetonitriles involving 1,2-aryl migration. AB - A novel metal-free oxidative 1,2-alkylarylation of unactivated alkenes with the alpha-C(sp(3))-H bonds of acetonitriles for the synthesis of 5-oxo pentanenitriles is presented. In the presence of TBPB (tert-butyl peroxybenzoate), a variety of alpha-aryl allylic alcohols underwent the 1,2 alkylarylation reaction with acetonitriles, giving 5-oxo-pentanenitriles in good to excellent yields. This method proceeds via the C(sp(3))-H oxidative coupling with the C-C double bond and 1,2-aryl-migration, and represents a new access to acyclic molecules through metal-free oxidative alkene 1,2-alkylarylation. PMID- 25446151 TI - Sex-dependent pathophysiological mechanisms in hypertrophic cardiomyopathy: implications for rhythm disorders. AB - Differences in cardiac physiology are seen between men and women in terms of health and disease. Sex differences start to develop at puberty and are maintained during aging. The prevalence of almost all cardiovascular diseases is found to be higher in men than in women, and disease progression tends to be more rapid in male than in female patients. In cohorts of patients with hypertrophic cardiomyopathy (HCM), the most common autosomal inherited cardiac disease, men are overrepresented, suggesting increased penetrance of HCM-causing mutations in male patients. Cardiac remodeling in patients with HCM is higher in men than in women, the same is seen in HCM animal models. Patients with HCM are at increased risk of sudden cardiac death (SCD) and developing rhythm disorders. There seems to be no sex effect on the risk of SCD or arrhythmias in patients with HCM; however, animal studies suggest that certain mutations predispose men to SCD. PMID- 25446152 TI - The simultaneous presence of sustained atrial fibrillation and atrioventricular nodal reentrant tachycardia. PMID- 25446154 TI - The sodium channel complex at the intercalated disc: Outside the domains of SAP97? PMID- 25446155 TI - Electrocardiographic and electrophysiological predictors of atrioventricular block after transcatheter aortic valve replacement. AB - BACKGROUND: Electrophysiological predictors of atrioventricular (AV) block after transcatheter aortic valve replacement (TAVR) are unknown. OBJECTIVE: We sought to assess the value of electrophysiology study before and after TAVR. METHODS: Seventy-five consecutive pacemaker-free patients undergoing TAVR at the Montreal Heart Institute were prospectively studied. RESULTS: Eleven patients (14.7%) developed AV block during the index hospitalization and 3 (4.0%) after hospital discharge over a median follow-up of 1.4 years (interquartile range 0.6-2.1 years). AV block developed in 5 of 6 patients with preprocedural right bundle branch block (83.3%), 8 of 30 patients with new-onset left bundle branch block (LBBB; 26.7%), and 1 of 7 patients with preexisting LBBB (14.3%). In multivariate analysis that considered all patients, the delta-HV interval (HV interval after TAVR minus HV interval before TAVR) was the only factor independently associated with AV block. In the subgroup of patients with new-onset LBBB, the postprocedural HV interval was strongly associated with AV block. By receiver operating characteristic analysis, a delta-HV interval of >=13 ms predicted AV block with 100.0% sensitivity and 84.4% specificity and an HV interval of >=65 ms predicted AV block with 83.3% sensitivity and 81.6% specificity. In multivariate analysis, the HV interval after TAVR (hazard ratio 1.073 per ms; 95% confidence interval 1.029-1.119; P = .001) was also independently associated with all-cause mortality. CONCLUSION: A prolonged delta-HV interval (>=13 ms) is strongly associated with AV block after TAVR. In patients with new-onset LBBB after TAVR, a postprocedural HV interval of >=65 ms is likewise predictive of AV block. PMID- 25446153 TI - Clinical and serum-based markers are associated with death within 1 year of de novo implant in primary prevention ICD recipients. AB - BACKGROUND: Implantable cardioverter-defibrillator (ICD) implantation is contraindicated in those with <1-year life expectancy. OBJECTIVES: The aim of this study was to develop a risk prediction score for 1-year mortality in patients with primary prevention ICDs and to determine the incremental improvement in discrimination when serum-based biomarkers are added to traditional clinical variables. METHODS: We analyzed data from the Prospective Observational Study of Implantable Cardioverter-Defibrillators, a large prospective observational study of patients undergoing primary prevention ICD implantation who were extensively phenotyped for clinical and serum-based biomarkers. We identified variables predicting 1-year mortality and synthesized them into a comprehensive risk scoring construct using backward selection. RESULTS: Of 1189 patients deemed by their treating physicians as having a reasonable 1-year life expectancy, 62 (5.2%) patients died within 1 year of ICD implantation. The risk score, composed of 6 clinical factors (age >=75 years, New York Heart Association class III/IV, atrial fibrillation, estimated glomerular filtration rate <30 mL/min/1.73 m(2), diabetes, and use of diuretics), had good discrimination (area under the curve 0.77) for 1-year mortality. Addition of 3 biomarkers (tumor necrosis factor alpha receptor II, pro-brain natriuretic peptide, and cardiac troponin T) further improved model discrimination to 0.82. Patients with 0-1, 2-3, 4-6, or 7-9 risk factors had 1-year mortality rates of 0.8%, 2.7%, 16.1%, and 46.2%, respectively. CONCLUSION: Individuals with more comorbidities and elevation of specific serum biomarkers were at increased risk of all-cause mortality despite being deemed as having a reasonable 1-year life expectancy. A simple risk score composed of readily available clinical data and serum biomarkers may better identify patients at high risk of early mortality and improve patient selection and counseling for primary prevention ICD therapy. PMID- 25446156 TI - Moving beyond the reductionist approach-Time to put the pieces back together in a broken (infarcted) heart. PMID- 25446157 TI - Location of epicardial adipose tissue affects the efficacy of a combined dominant frequency and complex fractionated atrial electrogram ablation of atrial fibrillation. AB - BACKGROUND: Epicardial adipose tissue (EAT) is located adjacent to high dominant frequency (DF) sites. OBJECTIVE: This study aimed to clarify the relationship between the EAT location and efficacy of a combined high DF site and continuous complex fractionated activation electrogram (CFAE) site ablation. METHODS: Fifty five patients with nonparoxysmal atrial fibrillation (AF) (26 (47%) persistent and 29 (53%) long-standing persistent) underwent pulmonary vein isolation followed by high DF site and continuous CFAE site ablation. High DF sites (DF >=8 Hz) and continuous CFAE sites (fractionated intervals <=50 ms) were targeted. The patients were divided into an AF-free group and an AF-recurrent group. RESULTS: The AF freedom rate on antiarrhythmic drugs in patients with persistent and long standing persistent AF was 88.5% and 75.9% over a 12-month follow-up period, respectively. The total EAT, left atrial (LA)-EAT, and right atrial (RA)-EAT volumes did not indicate significant differences between the AF-free and AF recurrent groups. In the LA, the overlap between high DF sites and EAT was larger in the AF-free group than in the AF-recurrent group (57.0% +/- 33.3% vs 22.6% +/- 23.3%; P < .01). However, this overlap did not differ between the AF-free and AF recurrent groups in the RA (20.4% +/- 28.2% vs 19.0% +/- 24.4%; P = .91). The overlap between continuous CFAE sites and EAT did not differ between the 2 groups in both the LA and the RA. CONCLUSION: High DF sites that overlap with EAT may be important sources of AF. However, the contribution of EAT to the AF substrate may differ between the LA and the RA. PMID- 25446158 TI - Permanent His-bundle pacing is feasible, safe, and superior to right ventricular pacing in routine clinical practice. AB - BACKGROUND: Right ventricular pacing (RVP) has been associated with heart failure and increased mortality. His-bundle pacing (HBP) is more physiological but requires a mapping catheter or a backup right ventricular lead and is technically challenging. OBJECTIVE: We sought to assess the feasibility, safety, and clinical outcomes of permanent HBP in an unselected population as compared to RVP. METHODS: All patients requiring pacemaker implantation routinely underwent attempt at permanent HBP using the Select Secure (model 3830) pacing lead in the year 2011 delivered through a fixed-shaped catheter (C315 HIS) at one hospital and RVP at the second hospital. Patients were followed from implantation, 2 weeks, 2 months, 1 year, and 2 years. Fluoroscopy time (FT), pacing threshold (PTh), complications, heart failure hospitalization, and mortality were compared. RESULTS: HBP was attempted in 94 consecutive patients, while 98 patients underwent RVP. HBP was successful in 75 patients (80%). FT was similar (12.7 +/- 8 minutes vs 10 +/- 14 minutes; median 9.1 vs 6.4 minutes; P = .14) and PTh was higher in the HBP group than in the RVP group (1.35 +/- 0.9 V vs 0.6 +/- 0.5 V at 0.5 ms; P < .001) and remained stable over a 2-year follow-up period. In patients with >40% ventricular pacing (>60% of patients), heart failure hospitalization was significantly reduced in the HBP group than in the RVP group (2% vs 15%; P = .02). There was no difference in mortality between the 2 groups (13% in the HBP group vs 18% in the RVP group; P = .45). CONCLUSION: Permanent HBP without a mapping catheter or a backup right ventricular lead was successfully achieved in 80% of patients. PTh was higher and FT was comparable to those of the RVP group. Clinical outcomes were better in the HBP group than in the RVP group. PMID- 25446159 TI - Reduced incidence of esophageal lesions by luminal esophageal temperature-guided second-generation cryoballoon ablation. AB - BACKGROUND: An increased incidence of esophageal lesions (EL) after pulmonary vein isolation (PVI) using the second-generation cryoballoon (CB2) has been described. We hypothesized that luminal esophageal temperature (LET)-guided PVI reduces the incidence of EL. OBJECTIVE: The aim of this study was to investigate the incidence of EL after LET-guided PVI using the CB2. METHODS: Ninety-four consecutive patients underwent CB2-PVI for paroxysmal or persistent atrial fibrillation. Target freezing time was 2 * 240 seconds. LET was continuously measured by a probe with 3 thermocouples. Early freezing interruption was performed when LET reached a prespecified cutoff temperature. A group of 32 patients who underwent CB2-PVI with observational LET measurement served as the control group. Postprocedural esophagoscopy was performed in all patients. RESULTS: Compared with observational LET measurement, a strategy of LET-guided CB PVI significantly reduced the incidence of EL from 18.8% to 3.2% (P = .008). A progressive decline in the incidence of EL was observed with an increasing LET cutoff: 7.1% (2/28 patients, 12 degrees C cutoff) and 1.5% (1/66 patients, 15 degrees C cutoff, P = .005 vs control). Despite early freezing interruption at a single pulmonary vein in 27% (25/94) of patients, complete PVI was achieved in all patients using the 28 mm balloon. Repeat esophagoscopy confirmed healing of EL after 1 week. After a mean of 268 +/- 119 days, 87% (76/87) of patients were free of recurrent atrial fibrillation or atrial tachycardia following a 90-days blanking period. CONCLUSION: LET-guided CB2-PVI significantly reduced the incidence of thermal EL. Interrupting cryoablation at 15 degrees C LET was associated with the lowest incidence of esophageal injury. PMID- 25446160 TI - Neonatal sex and weight influence CD34(+) cell concentration in umbilical cord blood but not stromal cell-derived factor 1-3'A polymorphism. AB - BACKGROUND: Umbilical cord blood (UCB) has been used as an alternative source of donor hematopoietic stem cells for hematologic transplant setting over the past decade. This study attempted to evaluate potential predictors of cord blood quality. METHODS: A total of 750 UCB samples were studied (male, n = 365; female, n = 385). The impact of neonatal sex, weight and stromal cell-derived factor 1alpha polymorphism on the quality of these UCB samples was investigated. RESULTS: Male neonatal UCB was significantly richer in CD34(+) cells than was female UCB (P < 0.001), whereas female UCB was richer in total nucleated cells (P = 0.01). There was a slight correlation between CD34(+) cells concentration and UCB sample weight (P < 0.01) that could be attributed to the higher weight of male neonates. The use of tetra-polymerase chain reaction to detect stromal cell derived factor-1alpha polymorphisms in 180 neonates revealed no differences between A/A, G/G and A/G allelic combinations. CONCLUSIONS: These data emphasize the lack of predictive factors for CD34(+) cells and total nucleated cell concentrations in UCB samples before processing. PMID- 25446161 TI - Differential mechanisms for insulin-induced relaxations in mouse posterior tibial arteries and main mesenteric arteries. AB - The characteristics of endothelium-dependent relaxations in response to insulin and acetylcholine (ACh) in the mouse posterior tibial artery (PTA) were studied on wire myograph, and compared to those in the mouse main mesenteric artery (MMA). Insulin-induced relaxation in PTA was reversed by PI3K and Akt inhibitors, LY294002 and triciribine, but not by nitric oxide synthase inhibitor, N(G)-nitro L-arginine methyl ester (L-NAME) or guanylate cyclase inhibitor, ODQ. The relaxation in PTA was also inhibited by apamin (small-conductance Ca(2+) activated K(+) channel blocker) plus charybdotoxin (intermediate-conductance Ca(2+)-activated K(+) channel blocker), elevated KCl or ouabain (Na(+)-K(+) ATPase inhibitor) plus BaCl(2) [inwardly rectifying K(+) (K(IR)) channel inhibitor]; whereas L-NAME but not triciribine inhibited ACh-induced relaxation in PTA. On the other hand, nitric oxide and endothelium-derived hyperpolarizing factor albeit to a less extent mediated both insulin- and ACh-induced relaxations in MMA. The present study is for the first time dissecting out the components of endothelium-dependent relaxation in mouse PTA and suggesting differential responses to different agonists in distinctive blood vessels. PMID- 25446162 TI - Organic nitrates: update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction. AB - Given acutely, organic nitrates, such as nitroglycerin (GTN), isosorbide mono- and dinitrates (ISMN, ISDN), and pentaerythrityl tetranitrate (PETN), have potent vasodilator and anti-ischemic effects in patients with acute coronary syndromes, acute and chronic congestive heart failure and arterial hypertension. During long term treatment, however, side effects such as nitrate tolerance and endothelial dysfunction occur, and therapeutic efficacy of these drugs rapidly vanishes. Recent experimental and clinical studies have revealed that organic nitrates per se are not just nitric oxide (NO) donors, but rather a quite heterogeneous group of drugs considerably differing for mechanisms underlying vasodilation and the development of endothelial dysfunction and tolerance. Based on this, we propose that the term nitrate tolerance should be avoided and more specifically the terms of GTN, ISMN and ISDN tolerance should be used. The present review summarizes preclinical and clinical data concerning organic nitrates. Here we also emphasize the consequences of chronic nitrate therapy on the supersensitivity of the vasculature to vasoconstriction and on the increased autocrine expression of endothelin. We believe that these so far rather neglected and underestimated side effects of chronic therapy with at least GTN and ISMN are clinically important. PMID- 25446163 TI - Vascular effects of the Mediterranean diet-part II: role of omega-3 fatty acids and olive oil polyphenols. AB - The lower occurrence of cardiovascular disease and cancer in populations around the Mediterranean basin as detected in the 1950s was correctly attributed to the peculiar dietary habits of those populations. Essentially, until the mid-20th century, typical Mediterranean diets were rich in fruits, vegetables, legumes, whole-wheat bread, nuts, fish, and, as a common culinary trait, the routine use of extra-virgin olive oil. Nowadays, the regular adoption of such dietary patterns is still thought to result in healthful benefits. Such patterns ensure the assumption of molecules with antioxidant and anti-inflammatory actions, among which omega-3 polyunsaturated fatty acids (PUFAs), omega-9 monounsaturated fatty acids (oleic acid), and phenolic compounds. The aim of this review is to provide an update of the vasculo-protective pathways mediated by omega-3 PUFAs and polyphenols in the context of the modern Mediterranean dietary habits, including the possible cross-talk and synergy between these typical components. This review complements a parallel one focusing on the role of dietary nitrates and alimentary fats. PMID- 25446164 TI - Reduced levels of S-nitrosothiols in plasma of patients with systemic sclerosis and Raynaud's phenomenon. AB - OBJECTIVE: S-Nitrosothiols (RSNOs) are bioactive forms of nitric oxide which are involved in cell signalling and redox regulation of vascular function. Circulating S-nitrosothiols are predominantly in the form of S-nitrosoalbumin. In this study plasma concentrations of S-nitrosothiols were measured in patients with systemic sclerosis (SSc) where NO metabolism is known to be abnormal. PATIENTS AND METHODS: Venous blood was collected from 16 patients with Raynaud's phenomenon (RP), 45 with systemic sclerosis (SSc) (34 patients had limited SSc (IcSSc) and 11 diffuse cutaneous disease (dcSSc)). Twenty six healthy subjects were used as controls. Plasma S-nitrosothiol concentrations were measured by chemiluminescence. The measurements were related to the extent of biological age, capillary/skin scores and disease duration. RESULTS: Plasma RSNO levels in patients with Raynaud's phenomenon (RP) and in those with SSc was significantly lower compared to the concentrations in control subjects. In SSc, plasma S nitrosothiols were often below the level of detection (1nM). CONCLUSIONS: Low S nitrosothiol concentrations were observed in the blood of patients with SSc and patients with RP indicating a profound disturbance of nitric oxide metabolism. PMID- 25446165 TI - Vascular effects of the Mediterranean diet part I: anti-hypertensive and anti thrombotic effects. AB - This review summarizes available evidence on the beneficial effects of inorganic nitrates and the monounsaturated fatty acid (MUFA) oleic acid, largely contained in Mediterranean diet, on blood pressure and coagulation activity. Inorganic nitrate. Normal vascular function requires NO production from the 1-arginine-NO synthase (NOS) pathway. This process is defective in conditions of local hypoxia, and here nitrite can substitute for 1-arginine-NOS derived NO. In this context, NO generation from the nitrate-nitrite-NO pathway mostly derived from green leafy vegetables appears to be an alternative source for NOS-dependent NO production, ensuring NO bioavailability also in situations when the endogenous 1-arginine/NO synthase pathway is dysfunctional or physiologically reduced in local hypoxic conditions. Olive oil and oleic acid. In addition to effects on lipoprotein metabolism and oxidation, the beneficial effects of oleic acid occur also on coagulation activity, namely on coagulation factor VII (FVII). Normally, a substantial increase of FVII coagulant activity (FVIIc) occurs within 2-3h after a fatty meal and persists for several hours thereafter. When a background diet high in MUFA is consumed, a lower post-prandial increase of FVIIc takes place. PMID- 25446166 TI - The role of the osteoprotegerin/tumor necrosis factor related apoptosis-inducing ligand axis in the pathogenesis of pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a fatal condition driven by a progressive remodelling of the small pulmonary arteries through sustained vasoconstriction, and vascular cell proliferation. This process causes a substantial reduction in luminal area increasing pulmonary vascular resistance and blood pressure leading to right heart failure. Current medical therapies can alleviate some symptoms and reduce the vasoconstrictive aspects of disease but new treatments are required that target the vascular cell proliferation if we are to develop new therapies. Expression of the tumour necrosis factor related apoptosis-inducing ligand (TRAIL) and osteoprotegerin (OPG) proteins are increased in IPAH. Specifically OPG is increased within the serum of patients with idiopathic pulmonary arterial hypertension (IPAH) and has prognostic utility, and both OPG and TRAIL are increased within pulmonary vascular lesions of patients with IPAH, and are mitogens for pulmonary artery smooth muscle cells in vitro. We have demonstrated that genetic deletion, or antibody blockade of TRAIL prevents, and critically reverses the development of PAH in multiple rodent models. The role OPG plays in this process both through interacting with TRAIL, and indirectly through other mechanisms is currently unclear these but data highlight the critical importance of this pathway in PAH pathogenesis, and its potential for future therapies. PMID- 25446167 TI - Gallic acid inhibits vascular calcification through the blockade of BMP2 Smad1/5/8 signaling pathway. AB - Vascular calcification is associated with increased risk of morbidity and mortality in patients with cardiovascular diseases, chronic kidney diseases, and diabetes. Gallic acid, a natural compound found in gallnut and green tea, is known to be antifungal, antioxidant, and anticancer. Here we investigated the effect of gallic acid on vascular smooth muscle cell (VSMC) calcification and the underlying mechanism. Gallic acid inhibited inorganic phosphate-induced osteoblast differentiation markers as well as calcification phenotypes (as determined by calcium deposition, Alizarin Red, and Von Kossa staining). Knockdown of BMP2 or Noggin blocked phosphate-induced calcification. Gallic acid suppressed phosphorylation of Smad1/5/8 protein induced by inorganic phosphate. Taken together, we suggest that gallic acid acts as a novel therapeutic agent of vascular calcification by mediating BMP2-Smad1/5/8 signaling pathway. PMID- 25446169 TI - Reprint of "An overview of freshwater snails in Asia with main focus on Vietnam". AB - Freshwater snails have received much attention for their role as intermediate hosts for trematodes causing disease in people and animals such as schistosomiasis and various food-borne trematodes. While effective medical treatment exists for some of these diseases there is need for preventive measures to reduce transmission, e.g. control of intermediate hosts because transmission patterns are often complicated due to presence of reservoir final hosts. In order to implement control measures against the intermediate host snails with minimal impact on the freshwater ecosystems and their biodiversity, a profound knowledge on transmission patterns of the trematodes is required and this is partly related to distribution, habitat preferences, and seasonal variation in density of the intermediate host species. Identification of snail species can be problematic on the basis of morphological and anatomical characters alone as some species show morphological plasticity and similarly morphological differentiation of cercariae found in snails may be difficult and this could lead to biased perceptions of intermediate host spectra and transmission patterns. In this paper, we give an overview of the snail families and their medical and veterinary importance in Asia but with main focus on Vietnam. PMID- 25446168 TI - Statin therapy in lower limb peripheral arterial disease: Systematic review and meta-analysis. AB - OBJECTIVE: To investigate and analyse the existing evidence supporting statin therapy in patients with lower limb atherosclerotic arterial disease. METHODS: A systematic search of electronic information sources was undertaken to identify studies comparing cardiovascular outcomes in patients with lower limb peripheral arterial disease treated with a statin and those not receiving a statin. Estimates were combined applying fixed- or random-effects models. RESULTS: Twelve observational cohort studies and two randomised trials reporting 19,368 patients were selected. Statin therapy was associated with reduced all-cause mortality (odds ratio 0.60, 95% confidence interval 0.46-0.78) and incidence of stroke (odds ratio 0.77, 95% confidence interval 0.67-0.89). A trend towards improved cardiovascular mortality (odds ratio 0.62, 95% confidence interval 0.35-1.11), myocardial infarction (odds ratio 0.62, 95% confidence interval 0.38-1.01), and the composite of death/myocardial infarction/stroke (odds ratio 0.91, 95% confidence interval 0.81-1.03), was identified. Meta-analyses of studies performing adjustments showed decreased all-cause mortality in statin users (hazard ratio 0.77, 95% confidence interval 0.68-0.86). CONCLUSIONS: Evidence supporting statins' protective role in patients with lower limb peripheral arterial disease is insufficient. Statin therapy seems to be effective in reducing all-cause mortality and the incidence cerebrovascular events in patients diagnosed with peripheral arterial disease. PMID- 25446170 TI - Progress in research, control and elimination of helminth infections in Asia. AB - Global health has substantially improved over the past 20 years. In low- and middle-income countries, in particular, great strives have been made in the control of communicable diseases, including helminth infections. Nevertheless, the most marginalised communities still suffer from infectious diseases that are intimately connected with poverty and lack of access to essential commodities and services, such as clean water, improved sanitation and sufficient food. A two pronged approach is thus necessary: (i) intensifying control in remaining high endemicity areas and pockets of high transmission; and (ii) moving from morbidity control to interruption of disease transmission in low-endemicity areas with the goal of local elimination. The latter will require new tools and strategies, going hand-in-hand with strong partnerships and new strategic alliances. In this special issue of Acta Tropica, 35 articles are featured that, together, provide an up-to-date overview of the latest progress made in research, control and elimination of helminth infections in East and Southeast Asia. The first 12 articles expound tools and approaches for improved detection, surveillance and monitoring of helminth infections. Control and elimination approaches for the most important helminth infections are revisited in the next 20 articles. The three remaining articles are cross-cutting pieces examining the interface of agriculture, environment and helminth infections and providing a rationale for integrated, multi-sectorial control approaches that are necessary for sustaining helminthiasis control and progressively moving towards elimination. An interesting aspect revealed through an in-depth analysis of the provenance of the 35 contributions is that the People's Republic of China emerges as a key player in global health, which is documented through its prominent role in research and control of helminth infection and networking throughout Asia. Policy implications are discussed and will hopefully shape the future agenda for the control and elimination of helminth infections the world over. PMID- 25446171 TI - Barcoding Turkish Culex mosquitoes to facilitate arbovirus vector incrimination studies reveals hidden diversity and new potential vectors. AB - As a precursor to planned arboviral vector incrimination studies, an integrated systematics approach was adopted using morphology and DNA barcoding to examine the Culex fauna present in Turkey. The mitochondrial COI gene (658bp) were sequenced from 185 specimens collected across 11 Turkish provinces, as well as from colony material. Although by morphology only 9 species were recognised, DNA barcoding recovered 13 distinct species including: Cx. (Barraudius) modestus, Cx. (Culex) laticinctus, Cx. (Cux.) mimeticus, Cx. (Cux.) perexiguus, Cx. (Cux.) pipiens, Cx. (Cux.) pipiens form molestus, Cx. (Cux.) quinquefasciatus, Cx. (Cux.) theileri, Cx. (Cux.) torrentium, Cx. (Cux.) tritaeniorhynchus and Cx. (Maillotia) hortensis. The taxon formerly identified as Cx. (Neoculex) territans was shown to comprise two distinct species, neither of which correspond to Cx. territans s.s. These include Cx. (Neo.) impudicus and another uncertain species, which may be Cx. (Neo.) europaeus or Cx. (Neo.) martinii (herein=Cx. (Neo.) sp. 1). Detailed examination of the Pipiens Group revealed Cx. pipiens, Cx. pipiens f. molestus and the widespread presence of the highly efficient West Nile virus vector Cx. quinquefasciatus for the first time. Four new country records are reported, increasing the Culex of Turkey to 15 recognised species and Cx. pipiens f. molestus. A new taxonomic checklist is provided, annotated with respective vector competencies for transmission of arboviruses. PMID- 25446172 TI - Distribution of rickettsioses in Oceania: past patterns and implications for the future. AB - Rickettsioses present a threat to human health worldwide, but relatively little is known on their epidemiology and ecology in Oceania. These bacteria are the cause of potentially fatal febrile illnesses in humans (categorized into scrub typhus, typhus group and spotted fever group rickettsioses). They are transmitted by arthropod vectors such as ticks, mites, fleas and lice, which are associated with vertebrate host animals including rodents and companion animals. We conducted a search in the scientific and grey literature of Rickettsia spp. and Orientia tsutsugamushi within the Oceania region. Human case reports, human serosurveys and PCR-based testing of vectors and host animals reviewed here highlight the widespread distribution of these pathogens in the region, with the majority of human serological and vector surveys reporting positive results. These findings suggest that rickettsioses may have a significantly higher burden of disease in Oceania than is currently appreciated due to diagnostic challenges. Furthermore, consideration of the ecology and risk factors for rickettsioses reported for Oceania suggests that their importance as a cause of undifferentiated acute febrile illness may grow in the future: environmental and social changes driven by predicted climate change and population growth have the potential to lead to the emergence of rickettsioses as a significant public health problem in Oceania. PMID- 25446173 TI - Reprint of "Experimental infection of Opisthorchis viverrini cercariae to the cyprinid fish, Barbonymus gonionotus". AB - Opisthorchis viverrini is an important public health problem, a major cause of cholangiocarcinoma in the Greater Mekong subregion including Lao PDR, Cambodia, Vietnam and Thailand. Humans acquire the infection by consumption of raw, fermented or partially cooked freshwater cyprinid fish containing infective metacercariae. This study examined the effect of cercarial infection dosage (25 200 cercariae), age (1-60 day) and size (1-24 mm) of Barbonymus gonionotus fish on infection success of O. viverrini cercariae. Additionally, the site of cyst formation of O. viverrini cercariae and subsequent development to the metacercariae was examined. The result showed that cercarial infection dose (F4,95=8.52, P<0.001) age (P<0.001, lambdaLR(2)=954.72) and size (P<0.001, lambdaLR(2)=1204.84) were significantly associated with number of O. viverrini metacercariae recovery with in every additional fish age, the O. viverrini metacercarial recovery rate increased by 5.4% (P<0.001). Most metacercariae were found in the body of the fish (81.4%). We concluded that O. viverrini cercarial infection dosage, and age and size of fish were important determinants for a successful infection to fish. PMID- 25446175 TI - Identification and biochemical characterization of macrophage migration inhibitory factor-2 (MIF-2) homologue of human lymphatic filarial parasite, Wuchereria bancrofti. AB - Homologues of human macrophage migration inhibitory factor (hMIF) have been reported from vertebrates, invertebrates and prokaryotes, as well as plants. Filarial parasites produce two homologues of hMIF viz., MIF-1 and MIF-2, which play important role in the host immune modulation. Earlier, we have characterized MIF-1 (Wba-mif-1) from Wuchereria bancrofti, the major causal organism of human lymphatic filariasis. Here, we are reporting the molecular and biochemical characterization of MIF-2 from this parasite (Wba-mif-2). The complete Wba-mif-2 gene and its cDNA were amplified, cloned and sequenced. The size of Wba-mif-2 gene and cDNA were found to be 4.275 kb and 363 bp, respectively. The gene annotation revealed the presence of a large intron of 3.912 kb interspersed with two exons of 183 bp and 180 bp. The alignment of derived amino acid sequences of Wba-MIF-2 with Wba-MIF-1 showed 44% homology. The conserved CXXC oxido-reductase catalytic site present in Wba-mif-1 was found absent in Wba-mif-2 coding sequence. The amplified Wba-mif-2 cDNA was cloned into an expression vector pRSET B and transformed into salt inducible Escherichia coli strain GJ1158. The expressed recombinant Wba-MIF-2 protein showed tautomerase activity against L dopachrome methyl ester and the specific activity was determined to be 18.57+/ 0.77 MUmol/mg/min. Three known inhibitors of hMIF tautomerase activity significantly inhibited the tautomerase activity of recombinant Wba-MIF-2. Although the conserved CXXC oxido-reductase motif is absent in Wba-mif-2, the recombinant protein showed significant oxido-reductase activity in the insulin reduction assay, possibly because of the presence of vicinal cysteine residues. PMID- 25446174 TI - Effect of transmission intensity and age on subclass antibody responses to Plasmodium falciparum pre-erythrocytic and blood-stage antigens. AB - Cytophilic immunoglobulin (IgG) subclass responses (IgG1 and IgG3) to Plasmodium falciparum antigens have been associated with protection from malaria, yet the relative importance of transmission intensity and age in generation of subclass responses to pre-erythrocytic and blood-stage antigens have not been clearly defined. We analyzed IgG subclass responses to the pre-erythrocytic antigens CSP, LSA-1, and TRAP and the blood-stage antigens AMA-1, EBA-175, and MSP-1 in asymptomatic residents age 2 years or older in stable (n=116) and unstable (n=96) transmission areas in Western Kenya. In the area of stable malaria transmission, a high prevalence of cytophilic (IgG1 and IgG3) antibodies to each antigen was seen in all age groups. Prevalence and levels of cytophilic antibodies to pre erythrocytic and blood-stage P. falciparum antigens increased with age in the unstable transmission area, yet IgG1 and IgG3 responses to most antigens for all ages in the unstable transmission area were less prevalent and lower in magnitude than even the youngest age group from the stable transmission area. The dominance of cytophilic responses over non-cytophilic (IgG2 and IgG4) was more pronounced in the stable transmission area, and the ratio of IgG3 over IgG1 generally increased with age. In the unstable transmission area, the ratio of cytophilic to non-cytophilic antibodies did not increase with age, and tended to be IgG3-biased for pre-erythrocytic antigens yet IgG1-biased for blood-stage antigens. The differences between areas could not be attributed to active parasitemia status, as there were minimal differences in antibody responses between those positive and negative for Plasmodium infection by microscopy in the stable transmission area. Individuals in areas of unstable transmission have low cytophilic to non cytophilic IgG subclass ratios and low IgG3:IgG1 ratios to P. falciparum antigens. These imbalances could contribute to the persistent risk of clinical malaria in these areas and serve as population-level, age-specific biomarkers of transmission. PMID- 25446176 TI - Reversible transformation between cubane and stairstep Cu4I4 clusters using heat or solvent vapor. AB - The controlled self-assembly of CuI and an asymmetric ligand with mixed N/S donors, 2-(tert-butylthio)-N-(pyridin-3-yl)acetamide (L), afforded three Cu(I) coordination polymers (CPs), [Cu4I4L2(MeCN)2]n (1), [Cu4I4L2]n (2), and {[Cu4I4L2]?MeOH}n (3). X-ray analyses showed that CPs 1-3 are supramolecular isomers with 1, 2, and 3D structures, respectively. CP 1 adopts a stairstep Cu4I4 cluster, whereas CPs 2 and 3 are composed of cubane-like Cu4I4 clusters. Crystal to-crystal transformations of 1 to 2 and 3 showed reversible transformations between different Cu4I4 clusters using heat or solvent (acetonitrile or methanol) vapor. CP 2 was reversibly transformed to 3 by the addition of methanol and heat. Therefore, the transformations between supramolecular isomers 1, 2, and 3 are completely reversible. PMID- 25446177 TI - Magnetic resonance imaging characteristics of hepatocyte apoptosis (induced by right portal vein ligation) and necrosis (induced by combined right portal vein and right hepatic artery ligation) in rats. AB - OBJECTIVE: Using magnetic resonance imaging (MRI), this study aimed to demonstrate the appearance of hepatocytes following ligation of the right portal vein or combined ligation of the right portal vein and right hepatic artery, in a rat model. METHODS: Ninety adult Sprague-Dawley rats (body weight 250-300 g) were divided into three groups (n = 30 per group): ligation of the right portal vein (Group A); combined ligation of the right portal vein and right hepatic artery (Group B); no intervention to obstruct blood supply (control group). Rats were then randomly subdivided into five groups that underwent examination at 3 h and 1, 3, 7 and 14 days postprocedure (n = 6 per group). Livers were examined by routine MRI, diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy (MRS). After examination, each group of rats was sacrificed. Right hepatic lobes were removed and examined by pathology in six rats per timepoint; transmission electron microscopy (TEM) was undertaken in up to three rats per timepoint. RESULTS: Hepatocyte apoptosis and necrosis, by right portal vein ligation and combined right portal vein and right hepatic artery ligation respectively, were confirmed by pathology and TEM. In Group A, there were slight increases in intensity of T1- and T2-weighted images and in the apparent diffusion coefficient (ADC). In addition there were larger areas under the lactic acid and lipid peaks on MRS. In Group B, there were increased T1 and T2 signals, a decrease in the ADC and an increase of the area under the lactic acid peaks on MRS. CONCLUSIONS: Hepatocyte apoptosis and necrosis induced by ligation procedures exhibited specific changes that were evident on MRI, DWI and MRS, and could be detected in vivo by MRI, in a rat model. PMID- 25446178 TI - Endothelial MRTF-A mediates angiotensin II induced cardiac hypertrophy. AB - Angiotensin II (Ang II) stimulates endothelin (ET-1) transcription, which contributes to cardiac hypertrophy and fibrosis. We have previously reported that myocardin related transcription factor A (MRTF-A) is indispensable for ET-1 transcription in vascular endothelial cells under hypoxic conditions, indicating that MRTF-A might mediate Ang II-induced pathological hypertrophy. Here we report that Ang II augmented the expression of MRTF-A in cultured endothelial cells and in the lungs of mice with cardiac hypertrophy. Over-expression of MRTF-A enhanced, whereas depletion of MRTF-A attenuated, transcriptional activation of ET-1 gene by Ang II. MRTF-A deficiency ameliorated Ang II induced cardiac hypertrophy and fibrosis in mice paralleling diminished synthesis and release of ET-1. Mechanistically, MRTF-A was recruited to the ET-1 promoter by c-Jun/c-Fos (AP-1) in response to Ang II treatment. Once bound, MRTF-A altered the chromatin structure by modulating histone acetylation and H3K4 methylation on the ET-1 promoter. More importantly, mice with endothelial-specific MRTF-A silencing by lentiviral particles phenocopied mice with systemic MRTF-A deletion in terms of Ang II-induced pathological hypertrophy. In conclusion, we data have unveiled a MRTF-A-containing complex that links ET-1 transactivation in endothelial cells to cardiac hypertrophy and fibrosis by Ang II. PMID- 25446179 TI - Mitochondrial DNA damage and repair during ischemia-reperfusion injury of the heart. AB - Ischemia-reperfusion (IR) injury of the heart generates reactive oxygen species that oxidize macromolecules including mitochondrial DNA (mtDNA). The 8-oxoguanine DNA glycosylase (OGG1) works synergistically with MutY DNA glycosylase (MYH) to maintain mtDNA integrity. Our objective was to study the functional outcome of lacking the repair enzymes OGG1 and MYH after myocardial IR and we hypothesized that OGG1 and MYH are important enzymes to preserve mtDNA and heart function after IR. Ex vivo global ischemia for 30min followed by 10min of reperfusion induced mtDNA damage that was removed within 60min of reperfusion in wild-type mice. After 60min of reperfusion the ogg1(-/-) mice demonstrated increased mtDNA copy number and decreased mtDNA damage removal suggesting that OGG1 is responsible for removal of IR-induced mtDNA damage and copy number regulation. mtDNA damage was not detected in the ogg1(-/-)/myh(-/-), inferring that adenine opposite 8-oxoguanine is an abundant mtDNA lesion upon IR. The level and integrity of mtDNA were restored in all genotypes after 35min of regional ischemia and six week reperfusion with no change in cardiac function. No consistent upregulation of other mitochondrial base excision repair enzymes in any of our knockout models was found. Thus repair of mtDNA oxidative base lesions may not be important for maintenance of cardiac function during IR injury in vivo. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease." PMID- 25446181 TI - Combined action potential- and dynamic-clamp for accurate computational modelling of the cardiac IKr current. AB - In the present work Action-Potential clamp (APC) and Dynamic clamp (DC) were used in combination in order to optimize the Luo-Rudy (LRd) mathematical formulation of the guinea-pig rapid delayed rectifier K(+) current (IKr), and to validate the optimized model. To this end, IKr model parameters were adjusted to fit the experimental E4031-sensitive current (IE4031) recorded under APC in guinea-pig myocytes. Currents generated by LRd model (ILRd) and the optimized one (IOpt) were then compared by testing their suitability to replace IE4031 under DC. Under APC, ILRd was significantly larger than IE4031 (mean current densities 0.51+/ 0.01 vs 0.21+/-0.05pA/pF; p<0.001), mainly because of different rectification. IOpt mean density (0.17+/-0.01pA/pF) was similar to the IE4031 one (NS); moreover, IOpt accurately reproduced IE4031 distribution along the different AP phases. Models were then compared under DC by blocking native IKr (5MUM E4031) and replacing it with ILRd or IOpt. Whereas injection of ILRd overshortened AP duration (APD90) (by 25% of its pre-block value), IOpt injection restored AP morphology and duration to overlap pre-block values. This study highlights the power of APC and DC for the identification of reliable formulations of ionic current models. An optimized model of IKr has been obtained which fully reversed E4031 effects on the AP. The model strongly diverged from the widely used Luo Rudy formulation; this can be particularly relevant to the in silico analysis of AP prolongation caused by IKr blocking or alterations. PMID- 25446180 TI - cAMP-induced actin cytoskeleton remodelling inhibits MKL1-dependent expression of the chemotactic and pro-proliferative factor, CCN1. AB - Elevation of intracellular cAMP concentration has numerous vascular protective effects that are in part mediated via actin cytoskeleton-remodelling and subsequent regulation of gene expression. However, the mechanisms are incompletely understood. Here we investigated whether cAMP-induced actin cytoskeleton remodelling modulates VSMC behaviour by inhibiting expression of CCN1. In cultured rat VSMC, CCN1-silencing significantly inhibited BrdU incorporation and migration in a wound healing assay. Recombinant CCN1 enhanced chemotaxis in a Boyden chamber. Adding db-cAMP, or elevating cAMP using forskolin, significantly inhibited CCN1 mRNA and protein expression in vitro; transcriptional regulation was demonstrated by measuring pre-spliced CCN1 mRNA and CCN1-promoter activity. Forskolin also inhibited CCN1 expression in balloon injured rat carotid arteries in vivo. Inhibiting RhoA activity, which regulates actin-polymerisation, by cAMP-elevation or pharmacologically with C3-transferase, or inhibiting its downstream kinase, ROCK, with Y27632, significantly inhibited CCN1 expression. Conversely, expression of constitutively active RhoA reversed the inhibitory effects of forskolin on CCN1 mRNA. Furthermore, CCN1 mRNA levels were significantly decreased by inhibiting actin-polymerisation with latrunculin B or increased by stimulating actin-polymerisation with Jasplakinolide. We next tested the role of the actin-dependent SRF co-factor, MKL1, in CCN1 expression. Forskolin inhibited nuclear translocation of MKL1 and binding of MKL1 to the CCN1 promoter. Constitutively-active MKL1 enhanced basal promoter activity of wild type but not SRE-mutated CCN1; and prevented forskolin inhibition. Furthermore, pharmacological MKL-inhibition with CCG-1423 significantly inhibited CCN1 promoter activity as well as mRNA and protein expression. Our data demonstrates that cAMP-induced actin-cytoskeleton remodelling regulates expression of CCN1 through MKL1: it highlights a novel cAMP-dependent mechanism controlling VSMC behaviour. PMID- 25446182 TI - The mitochondrial permeability transition pore and its role in myocardial ischemia reperfusion injury. AB - Ischemic heart disease (IHD) remains the leading cause of death and disability worldwide. For patients presenting with an acute myocardial infarction, the most effective treatment for limiting myocardial infarct (MI) size is timely reperfusion. However, in addition to the injury incurred during acute myocardial ischemia, the process of reperfusion can itself induce myocardial injury and cardiomyocyte death, termed 'myocardial reperfusion injury', the combination of which can be referred to as acute ischemia-reperfusion injury (IRI). Crucially, there is currently no effective therapy for preventing this form of injury, and novel cardioprotective therapies are therefore required to protect the heart against acute IRI in order to limit MI size and preserve cardiac function. The opening of the mitochondrial permeability transition pore (MPTP) in the first few minutes of reperfusion is known to be a critical determinant of IRI, contributing up to 50% of the final MI size. Importantly, preventing its opening at this time using MPTP inhibitors, such as cyclosporin-A, has been reported in experimental and clinical studies to reduce MI size and preserve cardiac function. However, more specific and novel MPTP inhibitors are required to translate MPTP inhibition as a cardioprotective strategy into clinical practice. In this article, we review the role of the MPTP as a mediator of acute myocardial IRI and as a therapeutic target for cardioprotection. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease". PMID- 25446183 TI - Mechanisms of epigenetic and cell-type specific regulation of Hey target genes in ES cells and cardiomyocytes. AB - Hey bHLH transcription factors are critical effectors of Notch signaling. During mammalian heart development they are expressed in atrial and ventricular cardiomyocytes and in the developing endocardium. Hey knockout mice suffer from lethal cardiac defects, such as ventricular septum defects, valve defects and cardiomyopathy. Despite this functional relevance, little is known about the regulation of downstream targets in relevant cell types. The objective of this study was to elucidate the regulatory mechanisms by which Hey proteins affect gene expression in a cell type specific manner. We used an in vitro cardiomyocyte differentiation system with inducible Hey1 or Hey2 expression to study target gene regulation in cardiomyocytes (CM) generated from murine embryonic stem cells (ESC). The effects of Hey1 and Hey2 are largely redundant, but cell type specific. The number of regulated genes is comparable between ESC and CM, but the total number of binding sites is much higher, especially in ESC, targeting mainly genes involved in transcriptional regulation and developmental processes. Repression by Hey proteins generally correlates with the extent of Hey-binding to target promoters, Hdac recruitment and lower histone acetylation. Functionally, treatment with the Hdac inhibitor TSA abolished Hey target gene regulation. However, in CM the repressive effect of Hey-binding is lost for a subset of genes. These also lack Hey-dependent histone deacetylation in CM and are enriched for binding sites of cardiac specific activators like Srf, Nkx2-5, and Gata4. Ectopic Nkx2-5 overexpression in ESC blocks Hey-mediated repression of these genes. Thus, Hey proteins mechanistically repress target genes via Hdac recruitment and histone deacetylation. In CM Hey-repression is counteracted by cardiac activators, which recruit histone acetylases and prevent Hey mediated deacetylation and subsequent repression for a subset of genes. PMID- 25446184 TI - alpha-Enolase plays a catalytically independent role in doxorubicin-induced cardiomyocyte apoptosis and mitochondrial dysfunction. AB - BACKGROUND: alpha-Enolase is a glycolytic enzyme with "second jobs" beyond its catalytic activity. However, its possible contribution to cardiac dysfunction remains to be determined. The present study aimed to investigate the role of alpha-enolase in doxorubicin (Dox)-induced cardiomyopathy as well as the underlying mechanisms. EXPERIMENTAL APPROACHES: The expression of alpha-enolase was detected in rat hearts and primary cultured rat cardiomyocytes with or without Dox administration. An adenovirus carrying short-hairpin interfering RNA targeting alpha-enolase was constructed and transduced specifically into the heart by intramyocardial injection. Heart function, cell apoptosis and mitochondrial function were measured following Dox administration. In addition, by using gain- and loss-of-function approaches to regulate alpha-enolase expression in primary cultured rat cardiomyocytes, we investigated the role of endogenous, wide type and catalytically inactive mutant alpha-enolase in cardiomyocyte apoptosis and ATP generation. Furthermore, the involvement of alpha enolase in AMPK phosphorylation was also studied. KEY RESULTS: The mRNA and protein expression of cardiac alpha-enolase was significantly upregulated by Dox. Genetic silencing of alpha-enolase in rat hearts and cultured cardiomyocytes attenuated Dox-induced apoptosis and mitochondrial dysfunction. In contrast, overexpression of wide-type or catalytically inactive alpha-enolase in cardiomyocytes mimicked the detrimental role of Dox in inducing apoptosis and ATP reduction. AMPK dephosphorylation was further demonstrated to be involved in the proapoptotic and ATP-depriving effects of alpha-enolase. CONCLUSION: Our findings provided the evidence that alpha-enolase has a catalytically independent role in inducing cardiomyocyte apoptosis and mitochondrial dysfunction, which could be at least partially contributed to the inhibition of AMPK phosphorylation. PMID- 25446185 TI - Induction of SENP1 in myocardium contributes to abnormities of mitochondria and cardiomyopathy. AB - Defect in mitochondrial biogenesis and cardiac energy metabolism is a critical contributing factor to cardiac hypertrophy and heart failure. Sentrin/SUMO specific protease 1 (SENP1) mediated regulation of PGC-1alpha transcriptional activity plays an essential role in mitochondrial biogenesis and mitochondrial function. However, whether SENP1 plays a role in cardiac hypertrophy and failure is unknown. We investigated whether alteration in SENP1 expression affects cardiomyopathy and the underlying mechanism. In our present study, we found that the expression of SENP1 was induced in mouse and human failing hearts associated with induced expression of mitochondrial genes. SENP1 expression in cardiomyocytes was induced by hypertrophic stimuli through calcium/calcineurin NFAT3. SENP1 regulated mitochondrial gene expression by de-SUMOylation of MEF-2C, which enhanced MEF-2C-mediated PGC-1alpha transcription. Genetic induction of SENP1 led to mitochondrial dysregulation and cardiac dysfunction in vivo. Our data showed that pathogenesis of cardiomyopathy is attributed by SENP1 mediated regulation of mitochondrial abnormities. SENP1 up-regulation in diseased heart is mediated via calcineurin-NFAT/MEF2C-PGC-1alpha pathway. PMID- 25446187 TI - Pellino1-mediated TGF-beta1 synthesis contributes to mechanical stress induced cardiac fibroblast activation. AB - Activation of cardiac fibroblasts is a key event in the progression of cardiac fibrosis that leads to heart failure. However, the molecular mechanisms underlying mechanical stress-induced cardiac fibroblast activation are complex and poorly understood. This study demonstrates that Pellino1, an E3 ubiquitin ligase, was activated in vivo in pressure overloaded rat hearts and in cultured neonatal rat cardiac fibroblasts (NRCFs) exposed to mechanical stretch in vitro. Suppression of the expression and activity of Pellino1 by adenovirus-mediated delivery of shPellino1 (adv-shpeli1) attenuated pressure overload-induced cardiac dysfunction and cardiac hypertrophy and decreased cardiac fibrosis in rat hearts. Transfection of adv-shpeli1 also significantly attenuated mechanical stress induced proliferation, differentiation and collagen synthesis in NRCFs. Pellino1 silencing also abrogated mechanical stretch-induced polyubiquitination of tumor necrosis factor-alpha receptor association factor-6 (TRAF6) and receptor interacting protein 1 (RIP1) and consequently decreased the DNA binding activity of nuclear factor-kappa B (NF-kappaB) in NRCFs. In addition, Pellino1 silencing prevented stretch-induced activation of p38 and activator protein 1 (AP-1) binding activity in NRCFs. Chromatin Immunoprecipitation (ChIP) and luciferase reporter assays showed that Pellino1 silencing prevented the binding of NF-kappaB and AP-1 to the promoter region of transforming growth factor-beta1 (TGF-beta1) thus dampening TGF-beta1 transactivation. Our data reveal a previously unrecognized role of Pellino1 in extracellular matrix deposition and cardiac fibroblast activation in response to mechanical stress and provides a novel target for treatment of cardiac fibrosis and heart failure. PMID- 25446186 TI - Cyclic stretch of embryonic cardiomyocytes increases proliferation, growth, and expression while repressing Tgf-beta signaling. AB - Perturbed biomechanical stimuli are thought to be critical for the pathogenesis of a number of congenital heart defects, including Hypoplastic Left Heart Syndrome (HLHS). While embryonic cardiomyocytes experience biomechanical stretch every heart beat, their molecular responses to biomechanical stimuli during heart development are poorly understood. We hypothesized that biomechanical stimuli activate specific signaling pathways that impact proliferation, gene expression and myocyte contraction. The objective of this study was to expose embryonic mouse cardiomyocytes (EMCM) to cyclic stretch and examine key molecular and phenotypic responses. Analysis of RNA-Sequencing data demonstrated that gene ontology groups associated with myofibril and cardiac development were significantly modulated. Stretch increased EMCM proliferation, size, cardiac gene expression, and myofibril protein levels. Stretch also repressed several components belonging to the Transforming Growth Factor-beta (Tgf-beta) signaling pathway. EMCMs undergoing cyclic stretch had decreased Tgf-beta expression, protein levels, and signaling. Furthermore, treatment of EMCMs with a Tgf-beta inhibitor resulted in increased EMCM size. Functionally, Tgf-beta signaling repressed EMCM proliferation and contractile function, as assayed via dynamic monolayer force microscopy (DMFM). Taken together, these data support the hypothesis that biomechanical stimuli play a vital role in normal cardiac development and for cardiac pathology, including HLHS. PMID- 25446188 TI - Particle shape effects on subvisible particle sizing measurements. AB - Particle analysis tools for the subvisible (<100 MUm) size range, such as light obscuration, flow imaging (FI), and electrical sensing zone (ESZ), often produce results that do not agree with one another, despite their general agreement when characterizing polystyrene latex spheres of different sizes. To include the effect of shape in comparison studies, we have used the methods of photolithography to create rods and disks. Although the rods are highly monodisperse, the instruments produce broadened peaks and report mean size parameters that are different for different instruments. We have fabricated a microfluidic device that simultaneously performs ESZ and FI measurements on each particle to elucidate the causes of discrepancies and broadening. Alignment of the rods with flow causes an oversizing by FI and undersizing by ESZ. FI also oversizes rods because of the incorrect edge definition that results from diffraction and imperfect focus. We present an improved correction algorithm for this effect that reduces discrepancies for rod-shaped particles. Tumbling of particles is observed in the microfluidic ESZ/FI and results in particle oversizing and breadth of size distribution for the monodisperse rods. PMID- 25446189 TI - Comparing methods to collect saliva from children to analyze cytokines related to allergic inflammation. PMID- 25446190 TI - Allergy and immunology interfaces with ophthalmology and optometry. PMID- 25446192 TI - Prurigo nodularis and Hashimoto thyroiditis. PMID- 25446191 TI - Effect of photoaging on skin test response to histamine independent of chronologic age. AB - BACKGROUND: Skin prick-puncture test responses to histamine on the upper back and forearms in older individuals are frequently small or absent but are often present or larger when repeated on the lower back. OBJECTIVE: To determine whether photoaging or natural aging causes a smaller response to a prick-puncture skin test. METHODS: Prick-puncture skin tests to histamine were performed on sun exposed and sun-protected areas in younger (n = 61, aged 20-50 years) and older (n = 63, aged 60-87 years) adult volunteers. The skin was scored for photoaging by physical examination, and coloration was measured by a colorimeter. RESULTS: Large variation of photoaging occurred within age groups. Histamine wheals and flare were not different between the 2 age groups, but those adults with the greatest photoaging had smaller histamine wheals and flare on the upper back, with a trend for smaller flares on the volar aspect of the forearms and lower back. There was marked variability in response to histamine within individual adults, depending on the locale of the tests. CONCLUSION: Photoaging, but not age alone, is associated with a smaller response to histamine in sun-exposed areas. Before prick-puncture skin tests are performed, the skin should be examined for sun damage, and a sun-protected area should be selected; in vitro allergy testing may be substituted if there is no sun-protected skin area. PMID- 25446193 TI - Epidural anesthesia for cesarean section in a primigravida woman with Ebstein's anomaly with recurrent supraventricular tachycardia. AB - Ebstein's anomaly is an uncommon congenital heart defect with an extremely variable natural history due to a wide spectrum of pathological features. We report on the anesthetic management of a 24-year-old primigravida woman with Ebstein's anomaly with recurrent supraventricular tachycardia for emergency cesarean section. PMID- 25446194 TI - An analysis of surgical outcomes in patients aged 80 years and older. AB - OBJECTIVES: Elderly patients (aged >= 80 years) undergo an increasing number of operations. Elderly patients undergoing operations usually develop more postoperative complications and have poorer outcomes. The aim of this study is to identify the relative importance between preoperative and intraoperative variables to predict adverse postoperative outcomes in these patients. METHODS: We retrospectively analyzed the records of 404 patients (aged >= 80 years and underwent a noncardiac surgery) collected from the quality assurance database in our department. We reviewed the patients' preoperative and intraoperative variables as well as postoperative complications and outcomes. Odds ratios of risk factors were then calculated by univariate and multivariate analyses. In addition, hazard ratios of incidence of discharge and mortality rates were analyzed. RESULTS: Overall, 26.4% of patients developed one or more postoperative complications, and the in-hospital mortality rate was 6.7%. The majority of these patients had pre-existing cardiovascular disorders such as hypertension (47.5%). Respiratory complication was the most common postoperative complication (12.9%). Multivariate analysis showed male sex, anesthesia method, and colloid infusion were risk factors for increased respiratory complication. Our results showed that patients who developed different kinds of postoperative complications had a different level of risks associated with prolonged hospital stay and mortality. CONCLUSION: Patients over the age of 80 years, of male sex, under general anesthesia, and receiving colloid infusion were at a higher risk of developing respiratory complications. Postoperative respiratory complications occurred in most of the geriatric surgical patients. Efforts to improve the surgical outcomes must include measures to minimize in-hospital complications. Detailed evaluation and better communicating the aforementioned risk factors to these patients are suggested for improving anesthesia quality and surgical outcomes. PMID- 25446195 TI - Cesarean under general or epidural anesthesia: does it differ in terms of regional cerebral oxygenation? AB - OBJECTIVE: It is aimed to evaluate whether there is a difference in regional cerebral saturation of newborns measured by near infrared spectroscopy born either by general anesthesia or combined spinal epidural anesthesia during elective cesarean deliveries. METHODS: After approval from the ethics committee of our hospital, and informed consents of the parturients were taken, 68 patients were included in the study. The regional cerebral oxygen saturations (RcSO2) of newborns were measured by near infrared spectroscopy (NIRS) measurements at 1st, 5th min after birth. In group I (n=32), general anesthesia was performed for the cesarean operation and in group II (n=36), combined spinal epidural anesthesia (CSEA) was the anesthetic management. The age of the mother, gestation, the problems related to the pregnancy, heart rate, blood pressure, oxygen saturation (SpO2) of the mother had been recorded. The measurements of the newborn were; SpO2 of right hand, RcSO2 measured by NIRS, the delivery time (from incision to the cessation of circulation in the placental cord), Apgar score. Data were analyzed using GraphPad Prism 5.0 (GraphPad Software, La Jolla, California) and presented as mean +/- SD. Results obtained in different groups were compared using upaired t-test. Differences were statistically significant at p < 0.05. RESULTS: There were no significant differences between the groups related to the mother's age, gestation week and baseline blood pressure. Both the systolic and diastolic blood pressures measured at 1st and 5th min after induction or start of the spinal block were significantly lower in the mothers who had undergone combined spinal epidural anesthesia. The heart rates of the mothers who had been under CSEA were significantly higher than the general anesthesia group. The Apgar at the 1st min were observed significantly higher in Group II. Oxygen saturation of the newborns were significantly higher in Group II. Regional cerebral oxygenation measured by NIRS were significantly higher in CSEA group. CONCLUSION: Combined spinal epidural anesthesia, besides other known advantages, had been shown to be superior to general anesthesia as a means of regional cerebral oxygenation of the newborns. PMID- 25446197 TI - Nasal temperatures in dairy cows are influenced by positive emotional state. AB - Understanding how animals express positive emotions is an important area of focus for animal welfare science, yet it is widely neglected. Emotions can be either positive or negative in valence, depending on the rewarding or punishing nature of the stimulus, and they can vary in the degree of arousal or excitement. Previous literature has shown a strong connection between peripheral temperatures and high arousal, negative experiences. Stress, fear and frustration have all been found to cause a drop in peripheral temperature. Little is known however, about whether the experience of positive emotions affects peripheral temperatures. In this study we sought to identify whether the nasal temperature of cows was affected by emotions, and if nasal temperature could be reliably used as a measure of emotional state in cows. We induced a positive, low arousal emotional state by stroking cows in preferred regions, in a similar manner to allogrooming. We performed 350 full focal observations, each comprising three conditions; pre-stroking, stroking, and post-stroking. During each 15minute focal observation we remotely took the focal cow's nasal temperature six times, twice during each condition. We analysed the data using the one-way ANOVA repeated measures test and found a significant difference overall (F (2, 1.935)=9.372, p<0.01). Post-hoc pairwise comparisons indicated that the total mean nasal temperature decreased significantly during the stroking condition (25.91 degrees C, SD=1.21), compared with both the pre-stroking (26.27 degrees C, SD=1.01, p<0.01) and post-stroking conditions (26.44 degrees C, SD=1.12, p<0.01). There was no significant difference between the pre-stroking and post-stroking conditions (p=0.14). We suggest that the cows were in a low state of arousal during the entire focal observation, as no other changes to the cows' environment had been made, and the cows were habituated to both the procedure and the researchers. Furthermore, the stroking stimulus is known to induce a state of relaxation and lower the heart rate of cows. This leads us to conclude that the drop in nasal temperature was indicative of the change in valence, rather than a change in arousal. These findings show that positive emotional state may have the same effect on the peripheral temperatures of mammals as a negative state does. This raises questions regarding the triggers for emotional fever, which is often considered to be associated only with negative states and high arousal. Our results indicate that nasal temperature in cows may prove to be a useful measure of a change in emotional state, but further research is required to validate these findings and to explore the effect of arousal on peripheral temperatures. PMID- 25446196 TI - Impact of social isolation and enriched environment during adolescence on voluntary ethanol intake and anxiety in C57BL/6J mice. AB - This study was designed to determine the impact of an enriched environment in a previously established stress model of isolation during early development that induces high alcohol (ethanol) self-administration. The study was conducted with male and female C57BL/6J mice housed in isolation or in groups that were either provided or withheld enrichment during adolescence. The impact of these housing conditions was assessed during adulthood by measuring weight gain, quantifying voluntary ethanol intake, measuring plasma corticosterone levels, and assessing anxiety-like behavior. Results showed that, regardless of sex, mice that were single-housed during adolescence showed a significant increase in voluntary ethanol intake, which was not observed in isolated mice that were provided with nesting material during adolescence (compared to group-housed non-enriched control group). Basal corticosterone was not affected by housing, enrichment conditions, or sex. Corticosterone levels did not relate to levels of voluntary ethanol intake. However, corticosterone levels were higher after three weeks of ethanol intake. Surprisingly, mice that were group-housed during adolescence showed higher levels of anxiety-like behavior in the light/dark test. Overall, these results indicate that housing conditions during a critical developmental period can significantly modulate voluntary ethanol intake later in life. PMID- 25446198 TI - Relearning a context-shock association after forgetting is an NMDAr-independent process. AB - Infantile amnesia (i.e., the rapid rate of forgetting in young animals) is at least partially due to a memory retrieval, rather than a storage, failure as studies have shown that these engrams can continue to influence later behavior. For example, prior conditioning affects the neural mechanisms underlying future learning. In adult animals, the initial learning of a context-shock association depends upon N-Methyl-D-Aspartate (NMDA) receptors, but this conditioning renders subsequent learning to a similar context NMDAr-independent. In the present study, we examined whether this transition from NMDAr-dependent to NMDAr-independent context conditioning occurs even after infantile amnesia. Experiment 1 demonstrated that infant (i.e., postnatal day 17) rats acquire a context-shock association when trained with multiple shocks, as assessed by context freezing one day later. However, they exhibit significant forgetting of this association 10days later. Experiments 2 and 3 showed that even when animals had forgotten the initial learning experience, future conditioning to the same context was NMDAr independent. There was evidence of a transition to NMDAr-independent context fear learning in animals exposed only to the foot shock in infancy (Experiment 3) or only to the context in infancy (Experiment 3 but not Experiment 2). These latter results suggest that animals do not have to be exposed to the entire conditioning procedure at postnatal day 17 to show a transition to NMDAr-independent context learning. These experiments add to a growing body of evidence that forgotten infant memories can continue to affect later behavior by demonstrating that prior experience alters the mechanisms of future learning. PMID- 25446199 TI - A mouse model for binge-like sucrose overconsumption: Contribution of enhanced motivation for sweetener consumption. AB - Behavioral and neural features of binge-like sugar overconsumption have been studied using rat models. However, few mouse models are available to examine the interaction between neural and genetic underpinnings of bingeing. In the present study, we first aim to establish a simple mouse model of binge-like sucrose overconsumption using daytime limited access training in food-restricted male mice. Trained mice received 4-h limited access to both 0.5M sucrose solution and chow for 10 days. Three control groups received (1) 4-h sucrose and 20-h chow access, (2) 20-h sucrose and 4-h, or (3) 20-h chow access, respectively. Only the trained group showed progressively increased sucrose consumption during brief periods of time and developed binge-like excessive behavior. Next, we examined whether the present mouse model mimicked a human feature of binge eating known as "eating when not physically hungry." Trained mice consumed significantly more sucrose or non-caloric sweetener (saccharin) during post-training days even after they nocturnally consumed substantial chow prior to daytime sweetener access. In other trained groups, both a systemic administration of glucose and substantial chow consumption prior to the daytime limited sucrose access failed to reduce binge-like sucrose overconsumption. Our results suggest that even when caloric consumption is not necessarily required, limited access training shapes and triggers binge-like overconsumption of sweetened solution in trained mice. The binge-like behavior in trained mice may be mainly due to enhanced hedonic motivation for the sweetener's taste. The present study suggests that our mouse model for binge-like sugar overconsumption may mimic some human features of binge eating and can be used to investigate the roles of neural and genetic mechanisms in binge-like overconsumption of sweetened substances in the absence of physical hunger. PMID- 25446200 TI - The roles of AMY1 copies and protein expression in human salivary alpha-amylase activity. AB - Salivary alpha-amylase (sAA) activity has been extensively investigated in nutrition and psychology. But few studies were performed to assess the role played by sAA gene (AMY1) copies and protein expression in basal and stimulus induced sAA activity. The sAA activity, amount and AMY1 copy number were determined from 184 saliva samples pre- and post-citric acid stimulation. Our findings showed that citric acid could induce significant increase in sAA activity, total sAA amount, and glycosylated sAA amount, among which the glycosylated sAA amount had the largest response. The correlation analysis showed that AMY1 copy number, total sAA amount and AMY1 copy number*total sAA amount had significantly positive and successively increasing correlations with sAA activity in unstimulated and stimulated saliva, respectively, and furthermore, we observed higher correlations in unstimulated saliva when compared with the corresponding correlations in stimulated saliva. We also observed significant correlations between glycosylated sAA amount and sAA activity in unstimulated and stimulated saliva, respectively. Interestingly, the correlations were higher in stimulated saliva than in unstimulated saliva, and the correlations between glycosylated sAA amount and sAA activity were higher than that of between total sAA amount and sAA activity in stimulated saliva. Moreover, total sAA amount ratio and glycosylated sAA amount ratio showed significantly positive correlation with sAA activity ratio. AMY1 copy number had no correlation with sAA activity ratio. These findings suggested that AMY1 copy number and sAA amount played crucial roles in sAA activity; however, the roles were attenuated after stimulation due to fortified release of glycosylated sAA. PMID- 25446201 TI - Gastrointestinal microbiota in children with autism in Slovakia. AB - Development of Autism Spectrum Disorders (ASD), including autism, is based on a combination of genetic predisposition and environmental factors. Recent data propose the etiopathogenetic role of intestinal microflora in autism. The aim of this study was to elucidate changes in fecal microbiota in children with autism and determine its role in the development of often present gastrointestinal (GI) disorders and possibly other manifestations of autism in Slovakia. The fecal microflora of 10 children with autism, 9 siblings and 10 healthy children was investigated by real-time PCR. The fecal microbiota of autistic children showed a significant decrease of the Bacteroidetes/Firmicutes ratio and elevation of the amount of Lactobacillus spp. Our results also showed a trend in the incidence of elevated Desulfovibrio spp. in children with autism reaffirmed by a very strong association of the amount of Desulfovibrio spp. with the severity of autism in the Autism Diagnostic Interview (ADI) restricted/repetitive behavior subscale score. The participants in our study demonstrated strong positive correlation of autism severity with the severity of GI dysfunction. Probiotic diet supplementation normalized the Bacteroidetes/Firmicutes ratio, Desulfovibrio spp. and the amount of Bifidobacterium spp. in feces of autistic children. We did not find any correlation between plasma levels of oxytocin, testosterone, DHEA-S and fecal microbiota, which would suggest their combined influence on autism development. This pilot study suggests the role of gut microbiota in autism as a part of the "gut-brain" axis and it is a basis for further investigation of the combined effect of microbial, genetic, and hormonal changes for development and clinical manifestation of autism. PMID- 25446202 TI - Correlation of prolactin levels and PRL-receptor expression with Stat and Mapk cell signaling in the prostate of long-term sexually active rats. AB - Prolactin (PRL) is a key hormone for prostate function, with a basal level in serum and associated with two characteristic circadian peaks. In the male rat, the execution of one bout of sexual behavior with consecutive ejaculations produces a significant transient increase in PRL. However, the impact of a constant sexual life on both PRL levels and prostate function is unknown. Thus, by using constantly copulating males we analyzed the levels of serum PRL, the effect on prostate PRL receptors, and activation of pStat3, pStat5 and Mapk signaling pathways. Sexually experienced Wistar male rats were used, which underwent periodic sessions of sexual behavior tests. Males were subjected to a session of sexual behavior to achieve at least one and up to four ejaculations. Of these, a blood sample was collected from randomly selected males and the ventral prostate was removed for analysis. Serum PRL was quantified, the mRNA for PRL receptors was determined, and signaling pathways were analyzed. Data show that a constant sexual life produced a constant elevation of PRL in serum during four consecutive ejaculations. The ventral prostate showed a different mRNA expression profile for the long and short isoform of the PRL receptor, and both mRNA levels increased. Although the gland did not show modification of the activation of the pStat5 signaling pathway, the levels of pStat3 increased, and the Mapk pathway showed one significant elevation after the third ejaculation. Thus, we showed that an active and constant sexual life produces a sustained increase in serum PRL, its receptors, and the pStat3 signaling pathway. These responses seem to underlie the required physiological need to produce the quantity and quality of prostatic semen to ensure the appropriate environment for sperm to reach and fertilize the ovum. PMID- 25446203 TI - Hypothalamus-pituitary-adrenal axis daily fluctuation, anxiety and age interact to predict cortisol concentrations in boys with an autism spectrum disorder. AB - There is considerable evidence of a confound between symptoms of generalised anxiety disorder (GAD) and autism spectrum disorder (ASD) in children who have an ASD. Although there have been several attempts to describe how these two disorders overlap and interact to influence the assessment and diagnosis of children with an ASD, principally by reference to cortisol assayed from these children's saliva, the overall evidence is inconsistent. Because previous models of these relationships have focused upon cortisol and GAD to the exclusion of age, diurnal fluctuation in the HPA axis and the source of GAD data, these variables were examined in a sample of 150 young males with an ASD. Results indicated that there was a significant interaction between these variables, with the association between GAD and cortisol demonstrated for children but not for adolescents, with an interaction between the source of GAD information (self- vs parent-ratings) and whether the child's cortisol concentrations followed the expected diurnal reduction during the day. These data suggest that the validity of cortisol as a biomarker of GAD in children and adolescents with an ASD may be established for only selected subgroups of this population. PMID- 25446205 TI - The impact of individual variations in taste sensitivity on coffee perceptions and preferences. AB - Despite a few relationships between fungiform papillae (FP) density and 6-n propylthiouracil (PROP) taster status have been reported for sensory qualities within foods, the impact on preferences remains relatively unclear. The present study investigated responses of FP number and PROP taster groups to different bitter compounds and how these affect coffee perception, consumption and liking. Subjects (Ss) with higher FP numbers (HFP) gave higher liking ratings to coffee samples than those with lower FP numbers (LFP), but only for sweetened coffee. Moreover, HFP Ss added more sugar to the samples than LFP Ss. Significant differences between FP groups were also found for the sourness of the coffee samples, but not for bitterness and astringency. However, HFP Ss rated bitter taste stimuli as stronger than did LFP Ss. While coffee liking was unrelated to PROP status, PROP non-tasters (NTs) added more sugar to the coffee samples than did super-tasters (STs). In addition, STs rated sourness, bitterness and astringency as stronger than NTs, both in coffee and standard solutions. These results confirm that FP density and PROP status play a significant role in taste sensitivity for bitter compounds in general and also demonstrate that sugar use is partly a function of fundamental individual differences in physiology. PMID- 25446206 TI - The opioid system contributes to the acquisition of reinforcement for dietary fat but is not required for its maintenance. AB - The opioid system plays an important role in ingestive behavior, especially with regard to palatable high-fat or sweetened foods. In the present study, we investigated the role of the opioid system in the regulation of ingestive behavior in mice with regard to dietary fat intake, reinforcement, and particularly the processes involved in development of these behavior types. Subcutaneous administration of the non-selective opioid receptor antagonist naltrexone (0.5 or 2.0mg/kg body weight [BW]) reduced the spontaneous intake of fat emulsion (Intralipid). We investigated the effect of naltrexone on reinforcement by using an operant behavioral paradigm under a progressive ratio schedule in which the number of lever presses required to obtain a test sample increased progressively. Mice showed stronger reinforcement by Intralipid as a function of concentration. However, naltrexone (0.5 or 2.0mg/kg BW) did not affect reinforcement at any concentration of Intralipid in mice that had repeatedly ingested Intralipid before testing was carried out. Intralipid ingestion also induced conditioned place preference (CPP), which is another evaluation index of reinforcement. High-dose naltrexone (2.0mg/kg BW) administration during CPP conditioning suppressed the reinforcement induced by Intralipid ingestion, although the drug administration (0.5 or 2.0mg/kg BW) during CPP testing did not affect reinforced behavior. These results suggest that the amount of fat ingestion and reinforcement for fat ingestion are separately regulated by the opioid system. Furthermore, our results indicate that the opioid system plays an important role in acquiring reinforcement for fat but is not required for maintenance of learned reinforcement. PMID- 25446204 TI - Hexosamine biosynthetic pathway activity in leptin resistant sucrose-drinking rats. AB - Rats offered 30% sucrose solution in addition to chow and water become leptin resistant therefore we investigated the effect of sucrose solution consumption on leptin signaling. In Experiment 1 rats were resistant to 3rd ventricle injections of1.5 MUg leptin after 36 days of sucrose and western blot indicated that resistance was associated with increased basal levels of signal transducer and activator of transcription 3 phosphorylation (pSTAT3). In Experiment 2 rats were resistant to a peripheral injection of 2mg leptin/kg after 26 days of sucrose. Immunohistochemistry indicated that increased basal pSTAT3 was limited to the medial and lateral arcuate nucleus of the hypothalamus. Increased availability of glucose and fructose can stimulate the hexosamine biosynthetic pathway (HBP) which O-GlcNAc-modifies proteins. This has the potential to change protein bioactivity. We tested whether this pathway could account for the leptin resistance. There was no increase in the expression of HBP enzymes in tissues from sucrose rats in Experiment 1, however, direct activation of the HBP with a 3h intravenous infusion of 30 MUmol/kg/min glucosamine significantly increased hypothalamic pSTAT3. Although sucrose consumption and activation of the HBP both increase hypothalamic pSTAT3 experiments described here did not provide evidence of a direct link between sucrose consumption, HBP activity and leptin resistance. Unexpectedly, we found that the HBP enzyme glutamine fructose-6-phosphate amidotransferase (GFAT) in liver and O-GlcNAcase in hypothalamus were increased 30min after leptin injection in leptin responsive animals, implying a complex interaction between activity of the HBP and leptin responsiveness. PMID- 25446207 TI - Surprisingly low risk of overheating during digging in two subterranean rodents. AB - Capacities for and constraints of heat dissipation are considered to be important factors governing maximum intensity and duration of physical activity. Subterranean mammals are endurance diggers, but because of lack of air currents in their burrows, high relative humidity and other physical constraints, the capacity of common mammalian cooling mechanisms underground is very limited. We analyzed surface and body core temperature changes after digging in soft and hard substrates in two species of African mole-rats (Bathyergidae, Rodentia); the social giant mole-rat Fukomys mechowii and the solitary silvery mole-rat Heliophobius argenteocinereus. As expected, we observed an increase of body core temperature in both species after digging in both substrates. Surprisingly, and contrary to our expectations, we observed remarkable decrease of mole-rats' surface temperature immediately after the end of the digging trials. This decrease was greater in soft and moister soil than that in hard and drier soil. Our results suggest that mole-rats may effectively avoid overheating in burrows by effective cooling while digging, especially in wet soil. This indicates that burrowing in soils moistened by rains could be easier than previously thought contributing thus to mole-rats success in challenging environment of subterranean burrows. PMID- 25446209 TI - Physical activity and nicotine dependence among a national sample of young U.S. adults who smoke daily: evaluation of cross-sectional and longitudinal associations to determine which behavior drives this relationship. AB - The association between nicotine dependence and physical activity (PA) is relatively unknown. No study has concurrently examined the cross-sectional and longitudinal associations between PA and nicotine dependence, which was the primary purpose of this study. A secondary purpose was to examine how well nicotine dependence and PA behavior track over a two-year period. Data from the 2003-2005 National Youth Smoking Cessation Survey (NYSCS) were used, with young adults (18-24 yrs; n=1168) being followed over a two-year period. Physical activity was assessed using a questionnaire and nicotine dependence was assessed using the modified Fagerstrom Test for Nicotine Dependence scale. This study identified three notable findings: 1) baseline PA and nicotine dependence demonstrated a bidirectional, cross-sectional association (e.g., beta=-0.23; 95% CI: -0.44 to -0.02; p=0.02); 2) when examined longitudinally, nicotine dependence influenced PA (OR=0.90; 95% CI: 0.82-0.99; p=0.04), but there was no evidence of the reverse pathway (i.e., PA influencing 2-year follow-up smoking status [OR=0.95; 95% CI: 0.66-1.39; p=0.82) or nicotine dependence (beta=0.05; 95% CI: 0.14 to 0.24, p=0.61]); and 3) both PA (OR=3.52, 95% CI: 2.68-4.69; p<0.001) and nicotine dependence (beta=0.52; 95% CI: 0.46-0.58, p<0.001) tracked relatively well over a two-year period during early adulthood. These findings suggest that both behaviors (physical activity and nicotine dependence) track over time, but nicotine dependence appears to be driving the cross-sectional relationship between nicotine dependence and physical activity, as opposed to the reverse pathway. PMID- 25446208 TI - Comparison of Polar(r) RS800CX heart rate monitor and electrocardiogram for measuring inter-beat intervals in healthy dogs. AB - The aim of the present study was to assess the criterion validity, relative reliability and level of agreement of Polar(r) RS800CX heart rate monitor measuring inter-beat intervals (IBIs), compared to simultaneously recorded electrocardiogram (ECG) in dogs. METHODS: Five continuous minutes of simultaneously recorded IBIs from Polar(r) RS800CX and Cardiostore ECG in 11 adult healthy dogs maintaining standing position were analyzed. Polar(r) data was statistically compared to ECG data to assess for systematic differences between the methods. Three different methods for handling missing IBI data were used. Criterion validities were calculated by intraclass correlation coefficients (ICCs) and corresponding 95% confidence intervals (CIs). Relative reliabilities and levels of agreement were calculated by ICCs and the Bland and Altman analysis for repeated measurements per subject. RESULTS: Correlation coefficients between IBI data from ECG and Polar(r) RS800CX varied between 0.73 and 0.84 depending on how missing values were handled. Polar(r) was over- and underestimating IBI data compared to ECG. The mean difference in log transformed (base10) IBI data was 0.8%, and 93.2% of the values were within the limits of agreement. Internally excluding three subjects presenting IBI series containing more than 5% erroneous IBIs resulted in ICCs between 0.97 and 0.99. Bland and Altman analysis (n=8) showed mean difference was 1.8ms, and 98.5% of the IBI values were plotted inside limits of agreement. CONCLUSION: This study showed that Polar(r) systematically biased recorded IBI series and that it was fundamental to detect measurement errors. For Polar(r) RS800CX heart rate monitor to be used interchangeably to ECG, by showing excellent criterion validity and reliable IBI measures in group and individual samples, only less than 5% of artifacts could be accepted. PMID- 25446210 TI - Protective effect of n-butanol extract from Alpinia oxyphylla on learning and memory impairments. AB - Alzheimer's disease (AD) is one of the major neurological diseases of the elderly. How to safely and effectively remove the toxic Abeta42 peptide through blood-brain barrier (BBB) is considered to be an effective method for the prevention and treatment of AD. The compounds whose molecule weight is less than 400 Da and the number of hydrogen bonding is less than 10 are more likely to permeate BBB. In our previous study, we have several small molecule compounds which are isolated from n-butanol (NB) extract of Alpinia oxyphylla that are similar with this kind of compounds This study explored the neuroprotective effects of the NB significantly protected against learning and memory impairments induced by Abeta(1-42) in Y-maze test, active avoidance test and Morris water maze test. Besides, NB (180 mg/kg, 360 mg/kg) was able to attenuate the neuronal damage and apoptosis in the frontal cortex and hippocampus in mice. In addition, the inhibition of beta-secretase and the level of Abeta(1-42) are also involved in the action mechanisms of NB in this experimental model. This study provided an experimental basis for clinical application of A. oxyphylla Miq. in AD therapy. PMID- 25446211 TI - Palmar grasp behavior in full-term newborns in the first 72 hours of life. AB - BACKGROUND: The palmar grasp behavior is one of the items of an infant's routine neurological tests. Its exacerbated presence after the fifth month of age or absence in the first day after birth is an important sign of neuro-sensorimotor disorders. This study aimed to describe the palmar grasp behavior of full-term newborns in the first 72 h of life. METHODS: This nonrandomized cross-sectional developmental study included 219 typical newborns aged 12-2 4h, 25-48 h and 49-72 h. Three measurements were performed with newborns in the supine position, recording the palmar grasp time and strength. Statistical analysis was applied with significant level of p<0.05. RESULTS: Higher palmar grasp strength was observed in newborns aged 49-72 h compared to newborns aged 12-24 h and 25-48 h (F=7.42, p=0.01). There was significant difference in palmar grasp strength between hands (F=6.55, p=0.01), only in 12-24h, with greater strength in the left hand (t=-2.43, p=0.01), and difference in palmar grasp between strength (F=18.7, p=0.01) with greater strength in females (t=-5.40, p=0.01) only at the age 48-72 h. CONCLUSIONS: It was concluded that the palmar grasp behavior modifies in the first 72 h of life. PMID- 25446212 TI - Effects of treadmill running exercise during the adolescent period of life on behavioral deficits in juvenile rats induced by prenatal morphine exposure. AB - Prenatal exposure to morphine throughout pregnancy results in an array of prolonged or permanent neurochemical and behavioral deficits, including deficits in learning and memory in children of addicted mothers. This study investigated the effects of forced exercise on behavioral deficits of pups born to mothers addicted to morphine in rats. After mating and ensuring of pregnancy of female Wistar rats, they were divided into morphine or saline groups and in the second half of pregnancy (on days 11-18 of gestation) were injected subcutaneously with morphine or saline, respectively. Pups were weaned at postnatal day (PND) 21 and trained at mild intensity on a treadmill 20 days. On PND 41-47, the behavioral responses were studied. Light/dark (L/D) box and elevated plus maze (EPM) apparatus were used for investigation of anxiety, shuttle box and forced swimming tests were used to assess passive avoidance learning and memory and depression behavior, respectively. The results showed that prenatal morphine exposure caused reductions in time spent in light compartment of L/D box and EPM open arm, while postnatal exercise reversed these effects. We also found that prenatal morphine exposure caused a reduction in step through latency in passive avoidance memory test and exercise counteracted with this effect. Performance in the forced swimming test did not affected by prenatal morphine exposure or postnatal exercise. Exercise seems to be one of the strategies in reduction of behavioral deficits of children born to addicted mothers to morphine. PMID- 25446213 TI - Environmental enrichment and cafeteria diet attenuate the response to chronic variable stress in rats. AB - Exposure to an enriched environment (EE) or the intake of a highly palatable diet may reduce the response to chronic stress in rodents. To further explore the relationships between EE, dietary intake and stress, male Sprague-Dawley rats were fed one of two diets for 5 weeks: high carbohydrate (HC) or "cafeteria" (CAF) (Standard HC plus a choice of highly palatable cafeteria foods: chocolate, biscuits, and peanut butter). In addition, they were either housed in empty cages or cages with EE. After the first two weeks, half of the animals from each group were stressed daily using a chronic variable stress (CVS) paradigm, while the other half were kept undisturbed. Rats were sacrificed at the end of the 5-week period. The effects of stress, enrichment and dietary intake on animal adiposity, serum lipids, and stress hormones were analyzed. Results showed an increase in intra-abdominal fat associated with the CAF diet and an increase in body weight gain associated with both the CAF diet and EE. Furthermore, the increase in ACTH associated with CVS was attenuated in the presence of EE and the CAF diet independently while the stress-induced increase in corticosterone was reduced by the combination of EE and CAF feeding. The present study provides evidence that the availability of a positive environment combined to a highly palatable diet increases resilience to the effects of CVS in rats. These results highlight the important place of palatable food and supportive environments in reducing central stress responses. PMID- 25446215 TI - Increased ultrasonic vocalizations and risk-taking in rat pups of sleep-deprived dams. AB - Ultrasonic vocalizations (USVs) in rodent pups are analogous to cries in human babies. There is reduction in USVs in pups after experimental deprivation of rapid eye movement sleep of dams during pregnancy. However, the effects of total sleep deprivation on the USVs of newborns and their emotional development are not documented. Male pups born to the rats that underwent total sleep deprivation for 5h during the third trimester made higher vocalizations, when tested on early postnatal days (pnds) in an isolation-paradigm. Their anxiety-related behaviors during pnds 25-28, were tested using elevated plus maze (EPM). In comparison to the control pups, weanlings of sleep-deprived dams made increased entries into the open arms and higher mobility in the EPM. Enhanced distress calls during early pnds and reduction in risk assessment in weanlings indicate a link between the two behaviors. The USVs during ontogeny may provide early signals about altered emotional development. PMID- 25446214 TI - Ethanol-induced tolerance and sex-dependent sensitization in preweanling rats. AB - According to genetic studies, the acute stimulating effect of ethanol seems to be associated with an increased predisposition to consume large quantities of ethanol. Ethanol-induced stimulation has been rarely reported in adult rats. However, infant rats, particularly during the second postnatal week of life, are highly sensitive to ethanol-induced behavioral activation. They also consume more ethanol than in later ontogenetic stages. In adult mice repeated ethanol experience usually results in sensitization to the stimulating effect of ethanol, while tolerance is the predominant result in rats. The present study was designed to explore in rats whether repeated exposure to ethanol during infancy modifies subjects' sensitivity to the stimulating effect of the drug, either increasing or decreasing its magnitude (i.e. sensitization or tolerance, respectively). Furthermore, we also explored the possible context-modulation of these effects. In two experiments, subjects were trained with water or ethanol (2.5 g/kg) between postnatal days (PDs) 8 and 12 (Experiment 1) or between PDs 14 and 18 (Experiment 2), and tested in response to water or ethanol two days later. In these experiments we identified three variables that critically modulate the effect of the repeated ethanol exposure: sex, context and age. Ethanol exclusively and consistently induced locomotor sensitization in males trained outside of the testing context (Experiments 1a and 1b), while tolerance to the stimulating effect of ethanol was observed in males and females trained in the testing context (Experiment 1a). In Experiment 2 tolerance was detected in females trained outside of the testing context. Finally, experience with the testing context during training strongly attenuated the stimulating effect of ethanol in the older subjects (Experiment 2). These results show that the same ethanol treatment can produce opposite effects (tolerance or sensitization) and demonstrate the involvement of Pavlovian conditioning in the development of tolerance. Furthermore, sex was revealed as an important factor to take into consideration in the analysis of chronic experience with ethanol during infancy. We can conclude that specific ontogenetic stages can be used to study the biological determinants underlying both ethanol-induced tolerance and sensitization, and the environmental modulators of these effects. PMID- 25446216 TI - Changes in social functioning and circulating oxytocin and vasopressin following the migration to a new country. AB - Prior studies have reported associations between plasma oxytocin and vasopressin and markers of social functioning. However, because most human studies have used cross-sectional designs, it is unclear whether plasma oxytocin and vasopressin influences social functioning or whether social functioning modulates the production and peripheral release of these peptides. In order to address this question, we followed individuals who experienced major changes in social functioning subsequent to the migration to a new country. In this study, 59 new international students were recruited shortly after arrival in the host country and reassessed 2 and 5 months later. At each assessment participants provided information on their current social functioning and blood samples for oxytocin and vasopressin analysis. Results indicated that changes in social functioning were not related to changes in plasma oxytocin. Instead, baseline oxytocin predicted changes in social relationship satisfaction, social support, and loneliness over time. In contrast, plasma vasopressin changed as a function of social integration. Baseline vasopressin was not related to changes in social functioning over time. These results emphasize the different roles of plasma oxytocin and vasopressin in responses to changes in social functioning in humans. PMID- 25446217 TI - Metabolic responses to dietary fatty acids in obese women. AB - BACKGROUND: The composition of fatty acids in a diet may differentially affect metabolism, thus playing a role in the development of obesity. Our purpose was to study the effects of three high-fat (HF) meals with different dietary fatty acid compositions on the thermic effect of meal (TEM) and substrate oxidation in obese premenopausal women. METHODS: 16 healthy obese women, aged 18-39 years, participated in a single-blinded randomized cross-over study, in which they consumed isocaloric HF meals (70% of energy from fat) rich in either saturated fat (SFA), monounsaturated fat (MUFA) or polyunsaturated fat (PUFA). Indirect calorimetry was used to measure respiratory gases for a 5-hour postprandial period. Data collected was used to determine respiratory exchange ratio (RER) for assessing substrate oxidation, and energy expenditure for the determination of TEM. RESULTS: There was a significant time effect on both substrate oxidation and TEM (p<0.05). With and without using RMR as a covariate, there were no significant differences in TEM between test meals (TEM of 10.8+/-0.8 vs 11.0+/ 1.0 kcal * 5 h for high-MUFA vs. high-SFA meals, respectively, p=0.06). No treatment difference was found for postprandial substrate utilization (4.9+/-0.4, 4.9+/-0.3 and 4.6+/-0.4 g of fat oxidation following SFA, MUFA, and PUFA-rich HF meals, respectively; 13.2+/-0.9, 13.3+/-0.5 and 13.9+/-0.6 g of carbohydrate oxidation following SFA, MUFA, and PUFA-rich HF meals, respectively). CONCLUSIONS: In premenopausal obese women, HF meals rich in either MUFAs, PUFAs, or SFAs did not differentially affect TEM or postprandial substrate oxidation. PMID- 25446219 TI - Postpartum repeated separation from pups affects the behavior and neuroendocrine parameters of mandarin vole fathers. AB - Repeated separation from pups results in anxiety and depression-like behaviors in mothers. This level of attachment has also been established between fathers and pups in monogamous rodents. We hypothesized that brief and lengthy separation from their pups would affect emotion, social behavior and neuroendocrine parameters in socially monogamous male mandarin voles (Microtus mandarinus). The results indicate that brief pup separation (BPS) of 15 min/day significantly reduced the percentage of time spent in the central area, total distance and total transition in open field tests. BPS resulted in increased sniffing and self grooming in fathers, but reduced attacking and climbing. Long pup separation (LPS) of 3h/day suppressed attacking, sniffing, no-social investigating and digging in fathers, but increased time in immobile in social interaction and forced swimming tests. LPS upregulated levels of central oxytocin (OT) and vasopressin (AVP), serum corticosterone (CORT); BPS increased central OT and serum corticosterone only. These findings show that BPS and LPS are critical stressors for fathers and alter anxiety and depression-like and social behaviors in monogamous mandarin voles. These changes in behaviors may be associated with alteration in OT, AVP and CORT. PMID- 25446218 TI - Effects of long-term cycling between palatable cafeteria diet and regular chow on intake, eating patterns, and response to saccharin and sucrose. AB - When exposed to a diet containing foods that are rich in fat and sugar, rats eat to excess and gain weight. We examined the effects of alternating this diet with laboratory chow on intake of each type of diet, the eating elicited by a palatable food (biscuits), and the drinking elicited by sweet solutions that did (sucrose) or did not (saccharin) contain calories. Each week for 13 weeks, cycled rats were provided with the cafeteria diet for three successive days/nights and the chow diet for the remaining four days/nights, whereas other rats received continuous access to either the cafeteria or the chow diets. On each of the 13 weeks, cycled rats ate more across the first 24 hour exposure to the cafeteria diet than rats continuously fed this diet. In contrast, cycled rats ate less across the first 24 hour exposure to the chow diet than rats continuously fed this diet and ate less when presented a novel palatable biscuit than chow-fed rats. The three groups exhibited similar licks per cluster to saccharin, but cafeteria-fed and cycled rats showed fewer clusters than chow-fed rats. In contrast, chow-fed rats and cycled rats exhibited more licks per cluster to sucrose than cafeteria-fed rats, but all three groups had a similar number of clusters. The results were discussed in relation to the effects of diet cycling on eating patterns, body weight, and 'wanting' and 'liking'. These findings with rats may have important implications for yo-yo dieting in people. PMID- 25446220 TI - Communal nesting exerts epigenetic influences on affective and social behaviors in rats selectively bred for an infantile trait. AB - Communal nesting (CN) is a mouse model of early social enrichment during pregnancy and lactation. In this study, a rat model of CN was developed to determine if CN exerts an epigenetic effect in rats selectively bred for an infantile affective trait (high and low rates of ultrasonic distress calls). High and Low offspring from CN groups were compared to standard reared (SN) offspring on five measures of social and affective behavior at three critical ages. A differential effect of the CN paradigm on High and Low lines was seen in measures of anxiety and arousal, but not in measures of depression or social behavior. Neonatal CN subjects emitted fewer distress calls than SN subjects when separated from their dams, and the High line subjects were more affected by the CN procedure. As juveniles, CN subjects showed increased social behaviors in tests of juvenile parenting and play compared to SN subjects. In adulthood, CN differentially increased the activity of Low line subjects. All CN subjects displayed less anxiety behavior in an open field compared to SN subjects; High line subjects were more anxious than Lows. CN reduced immobility and increased attempts to escape on the Porsolt forced swim task relative to SN subjects. These results extend the usefulness of this early enrichment paradigm from mice to rats, and found some rodent species differences in outcomes dependent on the behavioral test. They also emphasize the importance of social contact during pregnancy and lactation on offspring's optimal development across behaviors and ages. PMID- 25446221 TI - Breakfast glycaemic index and exercise: combined effects on adolescents' cognition. AB - The aim of the present study was to examine the combined effects of breakfast glycaemic index (GI) and a mid-morning bout of exercise on adolescents' cognitive function. Participants were randomly allocated to a high or low GI breakfast group in a mixed research design, where each participant completed two experimental trials (exercise and resting). Forty-two adolescents (12.4+/-0.5 years old), undertook a bout of exercise (ten repeats of level one of the multi stage fitness test; exercise trial) or continued to rest (resting trial) following consumption of either a high or low GI breakfast. A battery of cognitive function tests (visual search test, Stroop test and Sternberg paradigm) was completed 30 min before and 45 min following the exercise. Average heart rate during exercise was 170+/-15 beats.min(-1). On the complex level of the Stroop test, response times improved across the morning following the low GI breakfast on both the exercise and resting trials, though the improvement was greatest on the exercise trial. However, response times only improved on the resting trial following the high GI breakfast (p=0.012). On the 5 letter level of the Sternberg paradigm, response times improved across the morning following the low GI breakfast (regardless of exercise) and only on the exercise trial following the high GI breakfast (p=0.019). The findings of the present study suggest that the combined effects of breakfast GI and exercise in adolescents depend upon the component of cognitive function examined. A low GI breakfast and mid-morning bout of exercise were individually beneficial for response times on the Sternberg paradigm, whereas they conferred additional benefits for response times on the Stroop test. PMID- 25446222 TI - Nucleus incertus inactivation impairs spatial learning and memory in rats. AB - Nucleus incertus (NI) is a pontine nucleus which releases mainly GABA and relaxin 3 in rats. Its suggested functions include response to stress, arousal, and modulation of hippocampal theta rhythm. Since the role of NI in learning and memory has not been well characterized, therefore the involvement of this nucleus in spatial learning and memory and the aftermath hippocampal levels of c-fos and pCREB were evaluated. NI was targeted by implanting cannula in male rats. For reference memory, NI was inactivated by lidocaine (0.4 MUl, 4%) at three stages of acquisition, consolidation and retrieval in Morris water maze paradigm. For working memory, NI was inactivated in acquisition and retrieval phases. Injection of lidocaine prior to the first training session of reference memory significantly increased the distance moved, suggesting that inactivation of NI delays acquisition in this spatial task. Inactivation also interfered with the retrieval phase of spatial reference memory, as the time in target quadrant for lidocaine group was less, and the escape latency was higher compared to the control group. However, no difference was observed in the consolidation phase. In the working memory task, with inter-trial intervals of 75 min, the escape latency was higher when NI was inactivated in the retrieval phase. In addition, c-fos and pCREB/CREB levels decreased in NI-inhibited rats. This study suggests that nucleus incertus might participate in acquisition of spatial reference, and retrieval of both spatial reference and working memory. Further studies should investigate possible roles of NI in the hippocampal plasticity. PMID- 25446224 TI - Effects of lighting condition on circadian behavior in 5-HT1A receptor knockout mice. AB - Serotonin (5-HT) is an important regulator of the mammalian circadian system, and has been implicated in modulating entrained and free-running rhythms, as well as photic and non-photic phase shifting. In general, 5-HT appears to oppose the actions of light on the circadian system of nocturnal rodents. As well, 5-HT mediates, at least in part, some non-photic responses. The 5-HT1A, 1B and 7 receptors regulate these acute responses to zeitgebers. 5-HT also regulates some entrained and free-running properties of the circadian clock. The receptors that contribute to these phenomena have not been fully examined. Here, we use 5-HT1A receptor knockout (KO) mice to examine the response of the mouse circadian system to a variety of lighting conditions, including a normal light-dark cycle (LD), T cycles, phase advanced LD cycles, constant darkness (DD), constant light (LL) and a 6 hour dark pulse starting at CT5. Relative to wildtype mice, the 5-HT1A receptor KO mice have lower levels of activity during the first 8h of the night/subjective night in LD and LL, later activity onsets on transient days during re-entrainment, shorter free-running periods in LL when housed with wheels, and smaller phase shifts to dark pulses. No differences were noted in activity levels during DD, alpha under any light condition, free-running period in DD, or phase angle of entrainment in LD. While the 5-HT1A receptor plays an important role in regulating photic and non-photic phase shifting, its contribution to entrained and free-running properties of the circadian clock is relatively minor. PMID- 25446223 TI - Individual differences in gene expression of vasopressin, D2 receptor, POMC and orexin: vulnerability to relapse to heroin-seeking in rats. AB - Individual vulnerability to stress-induced relapse during abstinence from chronic heroin exposure is a key feature of opiate addiction, with limited studies on this topic. Arginine vasopressin (AVP) and its V1b receptor, components of the brain stress responsive systems, play a role in heroin-seeking behavior triggered by foot shock (FS) stress in rats. In this study, we tested whether individual differences in the FS-induced heroin-seeking were associated with alterations of AVP and V1b, as well as other stress responsive systems, including pro opiomelanocortin (POMC), orexin, plasma ACTH and corticosterone, as well as dopamine D2 receptor (D2) and plasma prolactin. Sprague-Dawley rats were subjected to 3-hour intravenous heroin self-administration (SA) and then tested in extinction, and FS-induced and heroin priming-induced reinstatements. The rats that self-administered heroin were divided into high and low reinstatement responders induced by FS (H-RI; L-RI). Over SA sessions, both the H-RI and L-RI displayed similar active lever responding, heroin infusion and total heroin intake. Compared to the L-RI, however, the H-RI showed greater active lever responses during stress-induced reinstatement, with higher AVP mRNA levels in medial/basolateral amygdala and lower D2 mRNA levels in caudate putamen. However, heroin priming resulted in similar reinstatement in both groups and produced similarly low POMC and high orexin mRNA levels in hypothalamus. Our results indicate that: 1) enhanced amygdalar AVP and reduced striatal D2 expression may be related to individual vulnerability to stress-induced reinstatement of heroin- seeking; and 2) heroin abstinence-associated alterations of hypothalamic orexin and POMC expression may be involved in drug priming-induced heroin-seeking. PMID- 25446225 TI - Behavioral and physiological antipredator responses of the San Marcos salamander, Eurycea nana. AB - Exposure to predatory stimuli typically results in the elevation of circulating glucocorticoid levels and a behavioral response of freezing or escape behavior in many prey species. Corticosterone (CORT) is the main glucocorticoid in amphibians and is known to be important in modulating many behaviors and developmental functions. The federally threatened San Marcos salamander, Eurycea nana, decreases activity in response to both native and introduced predatory fish, however, experience may further influence these interactions. To better understand the indirect effects of fish predators on this salamander, we examined both the antipredator behavior and water-borne CORT release rates in response to chemical cues (kairomones) from two fish species that varied in temporal risk of predation: (1) a low encounter frequency predator (largemouth bass, Micropterus salmoides), (2) a high encounter frequency predator (redbreast sunfish, Lepomis auritus), and (3) a blank water control. Salamanders reduced activity (antipredator response) after exposure to both predator treatments, but not to the blank water control, and the response to M. salmoides was significantly stronger than that to L. auritus. The CORT response (post-stimulus/pre-stimulus release rates) did not differ between the blank water control and L. auritus treatments, and both were significantly less than the CORT response to M. salmoides. Overall, E. nana showed a decreased antipredator response and no CORT response towards the high encounter frequency L. auritus as compared to the low encounter frequency M. salmoides. Eurycea nana may mute antipredator and CORT responses to high temporal frequency predators. There was, however, no correlation between CORT release rates and antipredator behavior, which suggests that the presence of predators may be affecting CORT response and behavior independently. PMID- 25446226 TI - Immune challenge but not dietary restriction affects spatial learning in the wild subterranean rodent Ctenomys talarum. AB - Several lines of evidence suggest that learning and triggering an immune response are both metabolically expensive and thus likely to be subject to nutritional trade-offs between them and other competing demands. Therefore, we evaluated if an immune challenge with a novel antigen affects spatial learning in the subterranean rodent Ctenomys talarum under two different dietary conditions. The results showed that immune-challenged animals were affected in their spatial learning capabilities, increasing the number of errors and marginally the time required to reach the goal of a complex labyrinth. No effect of the dietary restriction nor interaction between factors were observed. This work provides support for the existence of a trade-off between the costs of the immune defense and learning abilities, indicating that when investment is required to fight infection, fewer resources are available for learning. The absence of effect of nutritional condition on this trade-off suggests that other physiological processes, besides cognition, may be limited by the energetic resources necessary to the more immediately critical immune response. PMID- 25446227 TI - Chronic exposure to low dose bacterial lipopolysaccharide inhibits leptin signaling in vagal afferent neurons. AB - Bacterially derived factors are implicated in the causation and persistence of obesity. Ingestion of a high fat diet in rodents and obesity in human subjects is associated with chronic elevation of low plasma levels of lipopolysaccharide (LPS), a breakdown product of Gram-negative bacteria. The terminals of vagal afferent neurons are positioned within the gut mucosa to convey information from the gut to the brain to regulate food intake and are responsive to LPS. We hypothesized that chronic elevation of LPS could alter vagal afferent signaling. We surgically implanted osmotic mini-pumps that delivered a constant, low-dose of LPS into the intraperitoneal cavity of rats (12.5 MUg/kg/hr for 6 weeks). LPS treated rats developed hyperphagia and showed marked changes in vagal afferent neuron function. Chronic LPS treatment reduced vagal afferent leptin signaling, characterized by a decrease in leptin-induced STAT3 phosphorylation. In addition, LPS treatment decreased cholecystokinin-induced satiety. There was no alteration in leptin signaling in the hypothalamus. These findings offer a mechanism by which a change in gut microflora can promote hyperphagia, possibly leading to obesity. PMID- 25446229 TI - Temporal behaviour profiles of Mus musculus in nature are affected by population activity. AB - Animals have circadian clocks that govern their activity pattern, resulting in 24h rhythms in physiology and behaviour. Under laboratory conditions, light is the major external signal that affects temporal patterns in behaviour, and Mus musculus is strictly nocturnal in its behaviour. In the present study we questioned whether under natural conditions, environmental factors other than light affect the temporal profile of mice. In order to test this, we investigated the activity patterns of free-ranging M. musculus in a natural habitat, using sensors and a camera integrated into a recording unit that the mice could freely enter and leave. Our data show that mice have seasonal fluctuations in activity duration (6.7+/-0.82 h in summer, 11.3+/-1.80 h in winter). Furthermore, although primarily nocturnal, wild mice also exhibit daytime activity from spring until late autumn. A multivariate analysis revealed that the major factor correlating with increased daytime activity was population activity, defined as the number of visits to the recording site. Day length had a small but significant effect. Further analysis revealed that the relative population activity (compared to the past couple of days) is a better predictor of daytime activity than absolute population activity. Light intensity and temperature did not have a significant effect on daytime activity. The amount of variance explained by external factors is 51.9%, leaving surprisingly little unexplained variance that might be attributed to the internal clock. Our data further indicate that mice determine population activity by comparing a given night with the preceding 2-7 nights, a time frame suggesting a role for olfactory cues. We conclude that relative population activity is a major factor controlling the temporal activity patterns of M. musculus in an unrestricted natural population. PMID- 25446228 TI - Oxytocin and vasopressin modulate risk-taking. AB - The modulation of risk-taking is critical for adaptive and optimal behavior. This study examined how oxytocin (OT) and arginine vasopressin (AVP) influence risk taking in function of three parameters: sex, risk-valence, and social context. Twenty-nine healthy adults (14 males) completed a risk-taking task, the Stunt task, both in a social-stress (evaluation by unfamiliar peers) and non-social context, in three separate drug treatment sessions. During each session, one of three drugs, OT, AVP, or placebo (PLC), was administered intra-nasally. OT and AVP relative to PLC reduced betting-rate (risk-averse effect). This risk-averse effect was further qualified: AVP reduced risk-taking in the positive risk valence (high win-probability), and regardless of social context or sex. In contrast, OT reduced risk-taking in the negative risk-valence (low win probability), and only in the social-stress context and men. The reduction in risk-taking might serve a role in defensive behavior. These findings extend the role of these neuromodulators to behaviors beyond the social realm. How the behavioral modulation of risk-taking maps onto the function of the neural targets of OT and AVP may be the next step in this line of research. PMID- 25446230 TI - Validity of physiological biomarkers for maternal behavior in cows--a comparison of beef and dairy cattle. AB - The objectives of the present study were to evaluate the suitability of potential biomarkers for maternal ability in cattle, and in addition to test the hypothesis that dairy cows have a less pronounced motherliness than beef cows. Therefore, maternal behavior of 20 Simmental beef-type (S) and 20 German Black Pied (dairy type) Cattle (BP) was assessed on the 2nd and again on the 3rd day of the calf's life. Measurements included the frequency of interactions between cow and calf, the cow's willingness to defend her calf, the overall maternal behavior, saliva cortisol, saliva oxytocin, heart rate, and thermal images of the eye (ET). Mixed model analysis revealed that BP had significantly (P<0.05) higher oxytocin (88.6+/-9.2 vs. 62.8+/-9.2 pg/ml saliva) and cortisol (1.3+/-0.1 vs. 1.0+/-0.1 ng/ml saliva) levels, but lower heart rates (80.0+/-2.0 vs. 95.8+/-2.0bpm) than S cows. Simmental (beef) cows showed more defensive behavior (3.5+/-0.2 vs. 2.7+/ 0.2 scores), but fewer total interactions between cow and calf (8.1+/-1.4 vs. 13.8+/-1.4), compared to BP (dairy). However, with the exception of heart rate and overall maternal behavior, breed differences tended to diminish from the 2nd to the 3rd day of the calf's life. Repeatabilities ranged from 9+/-23% (ET) to 77+/-7% (maternal behavior measured on a visual analogue scale), and correlations between physiological parameters and behavior differed between breeds and were generally at a low level. In conclusion, beef cows do not seem to be per se more maternal compared to dairy cows, and the assessed parameters are of limited use as biomarkers for maternal behavior. PMID- 25446232 TI - Reactive oxygen species in cell wall metabolism and development in plants. AB - Although reactive oxygen species (ROS) are highly toxic substances that are produced during aerobic respiration and photosynthesis, many studies have demonstrated that ROS, such as superoxide anion radical (O2(.-)) and hydrogen peroxide (H2O2), are produced in the plant cell wall in a highly regulated manner. These molecules are important signalling messengers playing key roles in controlling a broad range of physiological processes, such as cellular growth and development, as well as adaptation to environmental changes. Given the toxicity of ROS, especially of hydroxyl radical (.OH), the enzymatic ROS production needs to be tightly regulated both spatially and temporally. Respiratory burst oxidase homologues (Rboh) have been identified as ROS-producing NADPH oxidases, which act as key signalling nodes integrating multiple signal transduction pathways in plants. Also other enzyme systems, such as class III peroxidases, amine oxidases, quinone reductases and oxalate oxidases contribute to apoplastic ROS production, some especially in certain plant taxa. Here we discuss the interrelationship among different enzymes producing ROS in the plant cell wall, as well as the physiological roles of the ROS produced. PMID- 25446231 TI - Identification of the pI 4.6 extensin peroxidase from Lycopersicon esculentum using proteomics and reverse-genomics. AB - The regulation of plant cell growth and early defense response involves the insolubilization of hydroxyproline-rich glycoproteins (HRGPs), such as extensin, in the primary cell wall. In tomato (Lycopersicon esculentum), insolubilization occurs by the formation of tyrosyl-crosslinks catalyzed specifically by the pI 4.6 extensin peroxidase (EP). To date, neither the gene encoding EP nor the protein itself has been identified. Here, we have identified tomato EP candidates using both proteomic and bioinformatic approaches. Bioinformatic screening of the tomato genome yielded eight EP candidates, which contained a putative signal sequence and a predicted pI near 4.6. Biochemical fractionation of tomato culture media followed by proteomic detection further refined our list of EP candidates to three, with the lead candidate designated (CG5). To test for EP crosslinking activity, we cloned into a bacterial expression vector the CG5 open-reading frame from tomato cDNA. The CG5 was expressed in Escherichia coli, fractionated from inclusion bodies, and folded in vitro. The peroxidase activity of CG5 was assayed and quantified by ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)) assay. Subsequent extensin crosslinking assays showed that CG5 can covalently crosslink authentic tomato P1 extensin and P3-type extensin analogs in vitro supporting our hypothesis that CG5 encodes a tomato EP. PMID- 25446233 TI - The plant cell wall integrity maintenance mechanism--a case study of a cell wall plasma membrane signaling network. AB - Some of the most important functions of plant cell walls are protection against biotic/abiotic stress and structural support during growth and development. A prerequisite for plant cell walls to perform these functions is the ability to perceive different types of stimuli in both qualitative and quantitative manners and initiate appropriate responses. The responses in turn involve adaptive changes in cellular and cell wall metabolism leading to modifications in the structures originally required for perception. While our knowledge about the underlying plant mechanisms is limited, results from Saccharomyces cerevisiae suggest the cell wall integrity maintenance mechanism represents an excellent example to illustrate how the molecular mechanisms responsible for stimulus perception, signal transduction and integration can function. Here I will review the available knowledge about the yeast cell wall integrity maintenance system for illustration purposes, summarize the limited knowledge available about the corresponding plant mechanism and discuss the relevance of the plant cell wall integrity maintenance mechanism in biotic stress responses. PMID- 25446235 TI - The fungal leaf endophyte Paraconiothyrium variabile specifically metabolizes the host-plant metabolome for its own benefit. AB - Fungal endophytes live inside plant tissues and some have been found to provide benefits to their host. Nevertheless, their ecological impact is not adequately understood. Considering the fact that endophytes are continuously interacting with their hosts, it is conceivable that both partners have substantial influence on each other's metabolic processes. In this context, we have investigated the action of the endophytic fungus Paraconiothyrium variabile, isolated from the leaves of Cephalotaxus harringtonia, on the secondary metabolome of the host plant. The alteration of the leaf compounds by the fungus was monitored through metabolomic approaches followed by structural characterization of the altered products. Out of more than a thousand molecules present in the crude extract of the plant leaf, we have observed a specific biotransformation of glycosylated flavonoids by the endophyte. In all cases it led to the production of the corresponding aglycone via deglycosylation. The deglycosylated flavonoids turned out to display significant beneficial effects on the hyphal growth of germinated spores. Our finding, along with the known allelopathic role of flavonoids, illustrates the chemical cooperation underlying the mutualistic relationship between the plant and the endophyte. PMID- 25446234 TI - Distinct catalytic capacities of two aluminium-repressed Arabidopsis thaliana xyloglucan endotransglucosylase/hydrolases, XTH15 and XTH31, heterologously produced in Pichia. AB - Xyloglucan plays an important structural role in primary cell walls, possibly tethering adjacent microfibrils and restraining cell expansion. There is therefore considerable interest in understanding the role of xyloglucan endotransglucosylase/hydrolases (XTHs), which are encoded in Arabidopsis by a 33 member gene family. We compared the key catalytic properties of two very different Arabidopsis XTHs (heterologously produced in Pichia), both of which are aluminium-repressed. Reductively tritiated oligosaccharides of xyloglucan were used as model acceptor substrates. Untransformed Pichia produced no xyloglucan acting enzymes; therefore purification of the XTHs was unnecessary. XTH15, a classical group-I/II XTH, had high XET and undetectable XEH activity in vitro; its XET Km values were 31 MUM XXXGol (acceptor substrate) and 2.9 mg/ml xyloglucan (donor substrate). In contrast, XTH31, a group-III-A XTH, showed predominant XEH activity and only slight XET activity in vitro; its XET Km was 86MUM XXXGol (acceptor), indicating a low affinity of this predominantly hydrolytic protein for a transglycosylation acceptor substrate. The Km of XTH31's XEH activity was 1.6 mg/ml xyloglucan. For both proteins, the preferred XET acceptor substrate, among five cellotetraitol-based oligosaccharides tested, was XXXGol. XTH31's XET activity was strongly compromised when the second Xyl residue was galactosylated. XTH15's XET activity, in contrast, tolerated substitution at the second Xyl residue. The two enzymes also showed different pH preferences, XTH31 exhibiting an unusually low pH optimum and XTH15 an unusually broad optimum. XTH31's hydrolase activity increased almost linearly with decreasing pH in the apoplastic range, 6.2-4.5, consistent with a possible role in 'acid growth'. In conclusion, these two Al(3+)-repressed XTHs differ, in several important enzymic features, from other members of the Arabidopsis XTH family. PMID- 25446236 TI - Heliolactone, a non-sesquiterpene lactone germination stimulant for root parasitic weeds from sunflower. AB - Root exudates of sunflower (Helianthus annuus L.) line 2607A induced germination of seeds of root parasitic weeds Striga hermonthica, Orobanche cumana, Orobanche minor, Orobanche crenata, and Phelipanche aegyptiaca. Bioassay-guided purification led to the isolation of a germination stimulant designated as heliolactone. FT-MS analysis indicated a molecular formula of C20H24O6. Detailed NMR spectroscopic studies established a methylfuranone group, a common structural component of strigolactones connected to a methyl ester of a C14 carboxylic acid via an enol ether bridge. The cyclohexenone ring is identical to that of 3-oxo alpha-ionol and the other part of the molecule corresponds to an oxidized carlactone at C-19. It is a carlactone-type molecule and functions as a germination stimulant for seeds of root parasitic weeds. Heliolactone induced seed germination of the above mentioned root parasitic weeds, while dehydrocostus lactone and costunolide, sesquiterpene lactones isolated from sunflower root exudates, were effective only on O. cumana and O. minor. Heliolactone production in aquacultures increased when sunflower seedlings were grown hydroponically in tap water and decreased on supplementation of the culture with either phosphorus or nitrogen. Costunolide, on the other hand, was detected at a higher concentration in well-nourished medium as opposed to nutrient-deficient media, thus suggesting a contrasting contribution of heliolactone and the sesquiterpene lactone to the germination of O. cumana under different soil fertility levels. PMID- 25446237 TI - Triterpene glycosides and other polar constituents of shea (Vitellaria paradoxa) kernels and their bioactivities. AB - The MeOH extract of defatted shea (Vitellaria paradoxa; Sapotaceae) kernels was investigated for its constituents, and fifteen oleanane-type triterpene acids and glycosides, two steroid glucosides, two pentane-2,4-diol glucosides, seven phenolic compounds, and three sugars, were isolated. The structures of five triterpene glycosides were elucidated on the basis of spectroscopic and chemical methods. Upon evaluation of the bioactivity of the isolated compounds, it was found that some or most of the compounds have potent or moderate inhibitory activities against the following: melanogenesis in B16 melanoma cells induced by alpha-melanocyte-stimulating hormone (alpha-MSH); generation of 1,1-diphenyl-2 picrylhydrazyl (DPPH) radicals, against Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-teradecanoylphorbol 13-acetate (TPA) in Raji cells; t TPA-induced inflammation in mice, and proliferation of one or more of HL-60, A549, AZ521, and SK-BR-3 human cancer cell lines, respectively. Western blot analysis established that paradoxoside E inhibits melanogenesis by regulation of expression of microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein-1 (TRP-1) and TRP-2. In addition, tieghemelin A was demonstrated to exhibit cytotoxic activity against A549 cells (IC50 13.5 MUM) mainly due to induction of apoptosis by flow cytometry. The extract of defatted shea kernels and its constituents may be, therefore, valuable as potential antioxidant, anti-inflammatory, skin-whitening, chemopreventive, and anticancer agents. PMID- 25446238 TI - Terpenoids with alpha-glucosidase inhibitory activity from the submerged culture of Inonotus obliquus. AB - Lanostane-type triterpenoids, inotolactones A and B, a drimane-type sesquiterpenoid, inotolactone C, and five known terpenoids 6beta-hydroxy-trans dihydroconfertifolin, inotodiol, 3beta,22-dihydroxyanosta-7,9(11),24-triene, 3beta-hydroxycinnamolide, and 17-hydroxy-ent-atisan-19-oic acid, were isolated from the submerged culture of chaga mushroom, Inonotus obliquus. Their structures were characterized by spectroscopic methods, including MS and NMR (1D and 2D) spectroscopic techniques. Inotolactones A and B, examples of lanostane-type triterpenoids bearing alpha,beta-dimethyl, alpha,beta-unsaturated delta-lactone side chains, exhibited more potent alpha-glucosidase inhibitory activities than the positive control acarbose. This finding might be related to the anti hyperglycemic properties of the fungus and to its popular role as a diabetes treatment. In addition, a drimane-type sesquiterpenoid and an atisane-type diterpenoid were isolated from I. obliquus. PMID- 25446239 TI - Occlusal wear and occlusal condition in a convenience sample of young adults. AB - OBJECTIVE: To study progression of tooth wear quantitatively in a convenient sample of young adults and to assess possible correlations with occlusal conditions. METHODS: Twenty-eight dental students participated in a three-year follow up study on tooth wear. Visible wear facets on full arch gypsum casts were assessed using a flatbed scanner and measuring software. Regression analyses were used to assess possible associations between the registered occlusal conditions 'occlusal guidance scheme', 'vertical overbite', 'horizontal overbite', 'depth of sagittal curve', 'canine Angle class relation', 'history of orthodontic treatment', and 'self-reported grinding/clenching' (independent variables) and increase of wear facets (dependent variable). RESULTS: Mean increase in facet surface areas ranged from 1.2 mm2 (premolars, incisors) to 3.4 mm2 (molars); the relative increase ranged from 15% to 23%. Backward regression analysis showed no significant relation for 'group function', 'vertical overbite', 'depth of sagittal curve', 'history of orthodontic treatment' nor 'self-reported clenching. The final multiple linear regression model showed significant associations amongst 'anterior protected articulation' and 'horizontal overbite' and increase of facet surface areas. For all teeth combined, only 'anterior protected articulation' had a significant effect. 'Self reported grinding' did not have a significant effect (p>0.07). CONCLUSIONS: In this study 'anterior protected articulation' and 'horizontal overbite', were significantly associated with the progression of tooth wear. Self reported grinding was not significantly associated with progression of tooth wear. CLINICAL SIGNIFICANCE: Occlusal conditions such as anterior protected articulation and horizontal overbite seem to have an effect on the progression of occlusal tooth wear in this convenient sample of young adults. PMID- 25446240 TI - Prospective evaluation of zirconia based tooth- and implant-supported fixed dental prostheses: 3-year results. AB - OBJECTIVES: This prospective clinical study compared the performance of implant retained (study group) and tooth-retained (control) zirconia based fixed dental prostheses (FDPs) with at least 4 units. The null-hypothesis stated that complication rates in both groups are equally distributed. METHODS: The study included patients in need of one 4- to 6-unit implant- or tooth-retained FDP each. All patients were examined 2 weeks after insertion (baseline) and then at 6 month intervals up to 3 years. At follow-up all restorations were examined for framework fracture, chipping, marginal integrity, surface roughness and biological complications. Kaplan-Meier estimation was used for data analysis. RESULTS: 20 patients received tooth-retained and 7 patients implant-retained FDPs. The study was halted early when differences in chipping rates reached a statistically significant level. One FDP in the study group was lost due to implant abutment failure. FDP related chipping rates were 71% in the study group (mean observation time 32 months) and 15% in the control (mean observation time 34 months). Unit (abutment crown/pontic) related chipping rates were 32% in the study group and 6% in the control. Chipping rates differed statistically significant (log-rank test, p<.05). However, all ceramic defects could be corrected by grinding and polishing. No framework fracture was detected. CONCLUSIONS: Within the study limitations, survival rates seem satisfactorily in both implant- and tooth retained long-span zirconia based FDPs. However, implant supported FDPs seem more susceptible to veneering ceramic chippings. CLINICAL SIGNIFICANCE: The high chipping rates found in this study discourage the use of long-span implant-retained FDPs with zirconia frameworks. The study was registered in ClinicalTrials.gov with the ID Number NCT02220764. PMID- 25446241 TI - Relative fluoride response of caries lesions created in fluorotic and sound teeth studied under remineralizing conditions. AB - OBJECTIVES: The present in vitro pH cycling study investigated potential differences between caries lesions created in fluorosed and sound enamel with regards to their responsiveness to fluoride under remineralizing conditions. METHODS: 360 human first molars (sound and fluorosed) were divided into four groups based on their Thylstrup-Fejerskov score (TF0-3). Each group was further divided into two treatment groups (n=45): deionized water or 383 ppm fluoride. Artificial enamel caries lesions were created and pH cycled for 20 d using an established net remineralization model. Quantitative light-induced fluorescence was used throughout the study to investigate lesion severity and changes thereof. Data were analyzed using two-way ANOVA. RESULTS: There were no differences in lesion severity between all groups after lesion creation (plesion=0.1934). The TF score vs. treatment interaction was significant at all other time points (p10 d=0.0280; p20 d<=0.0001; psecdemin=0.0411). Relative differences in responsiveness to fluoride vs. deionized water increased with increasing TF scores. In comparison to lesions created in sound enamel, lesions created in enamel with moderate fluorosis (TF 2/3) were more prone to remineralization in the presence than in the absence of fluoride. Furthermore, lesions created in enamel with moderate fluorosis exhibited more remineralization in the presence of fluoride than lesions created in sound teeth, whereas the opposite was true for deionized water. CONCLUSION: Bearing in mind the limitations of laboratory research, the extent of enamel fluorosis severity may directly impact subsequent lesion re- and progression as well as the lesion's responsiveness to fluoride. CLINICAL RELEVANCE: Caries lesions in fluorotic teeth are more vulnerable to progression but respond more strongly to fluoride than those in non-impacted teeth. PMID- 25446243 TI - Estimated prevalence of erosive tooth wear in permanent teeth of children and adolescents: an epidemiological systematic review and meta-regression analysis. AB - OBJECTIVES: The main purpose of this systematic review was to estimate the prevalence of dental erosion in permanent teeth of children and adolescents. METHODS: An electronic search was performed up to and including March 2014. Eligibility criteria included population-based studies in permanent teeth of children and adolescents aged 8-19-year-old reporting the prevalence or data that allowed the calculation of prevalence rates of tooth erosion. Data collection assessed information regarding geographic location, type of index used for clinical examination, sample size, year of publication, age, examined teeth and tissue exposure. The estimated prevalence of erosive wear was determined, followed by a meta-regression analysis. RESULTS: Twenty-two papers were included in the systematic review. The overall estimated prevalence of tooth erosion was 30.4% (95%IC 23.8-37.0). In the multivariate meta-regression model use of the Tooth Wear Index for clinical examination, studies with sample smaller than 1000 subjects and those conducted in the Middle East and Africa remained associated with higher dental erosion prevalence rates. CONCLUSIONS: Our results demonstrated that the estimated prevalence of erosive wear in permanent teeth of children and adolescents is 30.4% with high heterogeneity between studies. Additionally, the correct choice of a clinical index for dental erosion detection and the geographic location play an important role for the large variability of erosive tooth wear in permanent teeth of children and adolescents. CLINICAL SIGNIFICANCE: The prevalence of tooth erosion observed in permanent teeth of children and adolescents was considerable high. Our results demonstrated that prevalence rate of erosive wear was influenced by methodological and diagnosis factors. When tooth erosion is assessed, the clinical index should be considered. PMID- 25446242 TI - Impact of procedures during prosthodontic treatment on patients' perceived burdens. AB - OBJECTIVES: To assess patient-perceived process-related quality of care in patients undergoing different prosthodontic treatments, and to investigate whether perceived burdens are related to specific procedures during prosthodontic treatments, i.e., to specific treatment components. METHODS: In this non randomised prospective intervention study, 104 dental patients (mean age: 52.2+/ 13.9 years, 50% female) were included. Burdens during treatments with fixed dental prostheses (FDP, n=90), removable dental prostheses (RDP, n=10), and complete dentures (CD; n=4) were assessed with the Burdens in Prosthetic Dentistry Questionnaire (BiPD-Q). The BiPD-Q total score was calculated as mean of all 25 items, and subscale scores were derived from items corresponding to six specific treatment components (anesthesia, preparation, impression, provisional care/try-in, fixation, global perception), with values ranging from 0 (best) to 100 (worst). Subscale scores were compared by using repeated-measures ANOVA, paired t-tests, and effect sizes, to identify treatment components with highest burdens. RESULTS: Mean BiPD-Q total score was 22.1, ranging from 8.6 for patients with CD to 24.0 for FDP patients. Perceived burdens differed significantly between treatment components, with highest burdens for anesthesia (score: 34.0), followed by preparation (score: 26.8) and impression (score: 24.7). When subscale score for anesthesia was compared to scores for other treatment components, effect sizes were medium to large. CONCLUSION: While prosthodontic treatment is overall perceived as only moderately burdening, specific treatment components differ significantly in perceived burdens. CLINICAL SIGNIFICANCE: Anesthesia, preparation, and impression are treatment components with most unpleasant perceptions, offering the highest potential for improvements for patient perceived process-related quality of care in prosthetic dentistry. PMID- 25446244 TI - Further tests of the local nonlinear interaction-based mechanism for simultaneous suppression of tone burst-evoked otoacoustic emissions. AB - Tone burst-evoked otoacoustic emission (TBOAE) components measured in response to a 1 kHz tone burst (TB1) are suppressed by the simultaneous presence of an additional tone burst (TB2). This "simultaneous suppression of TBOAEs" has been explained in terms of a mechanism based on local nonlinear interactions between the basilar membrane (BM) travelling waves caused by TB1 and TB2. A test of this local nonlinear interaction (LNI)-based mechanism, as a function of the frequency separation (Deltaf, expressed in kHz) between TB1 and TB2, has previously been reported by Killan et al. (2012) using a simple mathematical model [Killan et al., Hear. Res. 285, 58-64 (2012)]. The two experiments described in this paper add additional data on the extent to which the LNI-based mechanism can account for simultaneous suppression, by testing two further hypotheses derived from the model predictions. Experiment I tested the hypothesis that TBOAE suppression is directly linked to TBOAE amplitude nonlinearity where ears that exhibit a higher degree of amplitude nonlinearity yield greater suppression than more linear ears, and this relationship varies systematically as a function of Deltaf. In order to test this hypothesis simultaneous suppression at a range of values of Deltaf at 60 dB peak-equivalent sound pressure level (p.e. SPL) and TBOAE amplitude nonlinearity from normal human ears was measured. In Experiment II the hypothesis that suppression will also increase progressively as a function of increasing tone burst level was tested by measuring suppression for a range of Deltaf and tone burst levels at 40, 50, 60 and 70 dB p.e. SPL. The majority of the findings from both experiments provide support for the LNI-based mechanism being primarily responsible for simultaneous suppression. However, some data were inconsistent with this view. Specifically, a breakdown in the relationship between suppression and TBOAE amplitude nonlinearity at Deltaf = 1 (i.e. when TB2 was reasonably well separated from, and had a higher frequency than TB1) and unexpected level dependence, most notably at Deltaf = 1, but also where Deltaf = -0.5, was observed. Either the LNI model is too simple or an alternative explanation, involving response components generated at basal regions of the basilar membrane, is required to account for these findings. PMID- 25446245 TI - Neural correlates of perceptual grouping effects in the processing of sound omission by musicians and nonmusicians. AB - Perceptual grouping is the process of organizing sounds into perceptually meaningful elements. Psychological studies have found that tones presented as a regular frequency or temporal pattern are grouped according to gestalt principles, such as similarity, proximity, and good continuity. Predictive coding theory suggests that this process helps create an internal model for the prediction of sounds in a tone sequence and that an omission-related brain response reflects the violation of this prediction. However, it remains unclear which brain areas are related to this process, especially in paying attention to the stimuli. To clarify this uncertainty, the present study investigated the neural correlates of perceptual grouping effects. Using magnetoencephalography (MEG), we recorded the evoked response fields (ERFs) of amateur musicians and nonmusicians to sound omissions in tone sequences with a regular or random pattern of three different frequencies during an omission detection task. Omissions in the regular sequences were detected faster and evoked greater activity in the left Heschl's gyrus (HG), right postcentral gyrus, and bilateral superior temporal gyrus (STG) than did omissions in the irregular sequences. Additionally, an interaction between musical experience and regularity was found in the left HG/STG. Tone-evoked responses did not show this difference, indicating that the expertise effect did not reflect the superior tone processing acquired by amateur musicians due to musical training. These results suggest that perceptual grouping based on repetition of a pattern of frequencies affects the processing of omissions in tone sequences and induces more activation of the bilateral auditory cortex by violating internal models. The interaction in the left HG/STG may suggest different styles of processing for musicians and nonmusicians, although this difference was not reflected at the behavioral level. PMID- 25446246 TI - Prognostic and diagnostic implications of MMP-2, MMP-9, and VEGF-alpha expressions in colorectal cancer. AB - PURPOSE: Angiogenesis and tumor invasion are complex processes that are mediated by various proteins, such as vascular endothelial growth factor (VEGF-alpha) and the matrix-degrading enzymes metalloproteinase-2 and -9 (MMP-2, MMP-9). The aim of this study was to determine what roles MMP-2, MMP-9, and VEGF-alpha play in colorectal cancer (CRC) by correlating their expression levels with the cancer TNM stage, modified Dukes criteria, degree of cell differentiation, and long-term patient survival. METHODS: The present series consisted of tissue samples obtained from 180 patients who had undergone large bowel resection during 1995 and 2005 at the Luis Antonio Hospital. Archival paraffin-embedded CRC tissue samples were used to generate tissue microarray blocks, which were immunohistochemically stained for MMP-2, MMP-9, and VEGF-alpha. Three different grading systems were applied to evaluate staining intensity. Chi-squared Person test and Kaplan-Meier survival curves were used, and values of p<0.05 were considered statistically significant. RESULTS: MMP-2 expression showed a significant association with more invasive cancer stages (p<0.001) and death (p<0.041). VEGF-alpha expression correlated with a high TNM stage (p<0.009), the degree of cell differentiation (p<0.025) and patient death as a result of disease (p<0.035). The Kaplan-Meier survival estimated that patients with strong staining for MMP-2 (log-rank x(2)=34.09; p<0.0001), MMP-9 (log-rank x(2)=12.83; p<0.0003) and VEGF (log-rank x(2)=33.9; p<0.0001) showed a greater tendency towards death during 60 months of follow up. CONCLUSIONS: The quantification of VEGF-alpha, MMP 2 and MMP-9 expression in colorectal cancer may be related to survival. These data add to the growing epidemiological and experimental evidence that VEGF alpha, MMP-2 and MMP-9 may play a role in colorectal tumorigenesis. PMID- 25446249 TI - Paradoxical increase of plasma vitamin B12 and folates with disease severity in anorexia nervosa. AB - OBJECTIVE: Anorexia nervosa (AN) is a complex disorder involving severe psychological manifestations and multiple organ damage, including liver dysfunction. The primary aim of this study consisted in assessing plasma levels of vitamin B12 and folates with respect to liver function enzymes considering the liver-storage properties of this vitamin. METHOD: We recruited 70 restrictive type AN adolescents and the severity of psychopathological traits was assessed using EDI-3 scale. Plasma levels of vitamin B12 , folates, transaminases (AST, ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP) and cholinesterase (CHE) were determined. RESULTS: About 38.5% of patients displayed vitamin B12 values (H-B12) above the upper range of normal reference; 4.3% of patients had increased values of folates; 20 and 11.4% of patients displayed ALT and AST values above reference limits; none had GGT values above normal range. Albeit low CHE and ALP values were found in 55 and 20% of patients, respectively, a linear correlation with both transaminases was present only for vitamin B12 and folates; furthermore, H-B12 patients had both higher AST and ALT values. EDI- 3 subscores significantly correlated with vitamin B12 and folates plasma values and H-B12 patients displayed EDI-3 higher values. DISCUSSION: These data suggest that plasma levels of vitamin B12 might be an early marker of liver dysfunction, possibly also related to more severe psychopathological aspects. The identification of patients with higher fasting plasma vitamin B12 levels could therefore lead to earlier and more careful refeeding interventions. Further studies will clarify the potential role of this vitamin in AN clinical practice. PMID- 25446248 TI - Relationship between oxidative stress and pathological findings in abomasum of infected lambs by Haemonchus contortus. AB - The aim of this study was to evaluate the nitric oxide (NO) levels, and oxidative and antioxidant markers of lambs experimentally and naturally infected by Haemonchus contortus, and its relation to lesions in the abomasum. For experimental study, a total of 14 healthy lambs were divided into two groups with seven animals each. Group A represented the uninfected animals (control), and Group B was formed by infected animals with 15,000 larvae of H. contortus. Blood was collected on days 15, 45, and 75 post-infection (PI) to obtain serum for biochemical analysis: lactate dehydrogenase (LDH), nitrite/nitrate (NOx), advanced oxidation protein products (AOPP), and ferric reducing ability of plasma (FRAP). Parasitological stool examination (eggs per gram of feces--EPG) was performed on days 15, 45, and 75 PI to verify the evolution of the infection. On day 15 PI EPG was negative, but on days 45 and 75 PI the EPG was positive for animals from Group B. In the three periods evaluated it was observed an increase of LDH levels in serum of lambs infected with gastrointestinal nematodes, but on the other hand NOx levels were reduced on the same periods in infected animals. The AOPP and FRAP levels did not differ between groups on days 15 and 45 PI, but increased significantly on day 75 PI in infected lambs. The same variables were studied in 10 lambs naturally infected with helminths, where more than 97% corresponded to H. contortus (hematocrit and EPG values were 18.8 +/- 2.5% and 7120 +/- 2940, respectively). Similar to the experimental study, the levels of NOx reduced, and the levels of LDH, FRAP, and AOPP increased in serum of this animal associated inflammatory infiltrate in the mucosa of the abomasum. Therefore, during the infection by H. contortus it was observed alterations in oxidative markers, indicators of cell lesion confirmed by histological examination of the abomasum, and consequently there were changes in antioxidant levels, with the purpose of cell protection. We also conclude that helminth infection interferes with the nitric oxide metabolism. PMID- 25446247 TI - Fluorescence in situ analysis of soft tissue tumor associated genetic alterations in formalin-fixed paraffin-embedded tissue. AB - No prospective studies are available to date evaluating the combined analysis of chromosomal alterations via interphase FISH in different soft tissue sarcoma (STS) subtypes. We tested 64 consecutive sarcoma specimens with FISH probes to detect aberrations specific for a given STS subtype. We first determined the translocation frequency in the specific STS subtypes in 48 tumors, with the primary pathological diagnosis as the gold standard. Subsequently, to evaluate sensitivity and specificity, all FISH probes were hybridized to 16 STS of hitherto unknown diagnosis. DDIT3 translocations occurred in 8/10 (80%) of myxoid liposarcomas. FOXO1 translocations were noted in 4/4 (100%) of alveolar but in none of 7 embryonal rhabdomyosarcomas. All 15 (100%) Ewing sarcomas/PNET and 4 clear cell sarcomas (4/4) harbored EWSR1 translocations. SS18 rearrangements were demonstrated in 8/9 (89%) synovial sarcomas. MDM2 amplification was noted in 7/8 (88%) atypical lipomatous tumors/well-differentiated and 3/3 (100%) dedifferentiated liposarcomas, respectively, but not in four pleomorphic liposarcomas. Sensitivities and specificities ranged from 80% to 100% and from 93% to 100%, respectively, with the highest values observed for FOXO1 (100% each). We conclude, therefore, that is possible to accurately predict the STS subtype using a panel of different subtype-specific FISH probes, thereby greatly facilitating the differential diagnosis of these tumors. PMID- 25446250 TI - Hydrogen sulfide protects testicular germ cells against heat-induced injury. AB - OBJECTIVE: The present study was designed to investigate whether H2S can protect testicular germ cells against heat exposure induced injury and the underlying mechanisms. RESULTS: It was found that all three H2S generating enzymes, cystathionine beta-synthase (CBS), cystathionine gamma-lysase (CSE), and 3 mercaptopyruvate sulfurtransferase (3 MST), were expressed in mouse testicular tissue. Three episodes of heat exposure (42 degrees C, 30 min/day, 3 days) significantly decreased endogenous H2S production and down-regulated the expression of CBS and CSE in testes. In primary cultured testicular germ cells, exogenous application of NaHS (an H2S donor) attenuated heat stress (42 degrees C, 30 min) induced cell death and apoptosis. This was mediated by the inhibitory effects of H2S on cytochrome C release and the ratio of the Bax/Bcl-2. NaHS also improved mitochondrial function by decreasing oxygen consumption and increasing ATP production. NaHS treatment also stimulated SOD activity and reduced ROS production. CONCLUSIONS: Our results revealed both physiological and pharmacological roles of H2S in testicular germ cells. Exogenous application of H2S may protect germ cells by preservation of mitochondrial function and stimulation of anti-oxidant activity. PMID- 25446251 TI - Hydrogen sulphide and the kidney: important roles in renal physiology and pathogenesis and treatment of kidney injury and disease. AB - The kidney is an essential mammalian organ that serves to filter toxins and metabolic by-products out of the blood, which are then excreted through urine. Hydrogen sulphide (H2S) is a recently characterized, endogenous gaseous molecule with important physiological roles. Many interesting roles continue to be identified for H2S related specifically to the kidney. The current review discusses how production and action of H2S influences normal physiology of the kidney. We investigate as well the many roles H2S plays in the pathogenesis and treatment of kidney injury and disease, such as chronic kidney disease (CKD), ureteral obstruction (UO), hyperhomocysteinaemia (HHcy), drug-induced nephrotoxicity (DIN) and renal ischaemia reperfusion injury (IRI). We suggest that H2S plays a complex and essential role in the normal function of the kidney and dysregulation of H2S production can directly or indirectly contribute to the pathogenesis of renal disease and injury. Also, H2S could be a promising potential therapeutic treatment to decrease the severity of several renal diseases. Further research will identify increasingly important and complex roles for H2S in renal physiology and how H2S can be effectively utilized to improve clinical outcomes of renal disease. PMID- 25446252 TI - Pitfalls in measuring NO bioavailability using NOx. PMID- 25446253 TI - HSP90 inhibitor NVP-AUY922 enhances TRAIL-induced apoptosis by suppressing the JAK2-STAT3-Mcl-1 signal transduction pathway in colorectal cancer cells. AB - TRAIL has been shown to induce apoptosis in cancer cells, but in some cases, certain cancer cells are resistant to this ligand. In this study, we explored the ability of representative HSP90 (heat shock protein 90) inhibitor NVP-AUY922 to overcome TRAIL resistance by increasing apoptosis in colorectal cancer (CRC) cells. The combination of TRAIL and NVP-AUY922 induced synergistic cytotoxicity and apoptosis, which was mediated through an increase in caspase activation. The treatment of NVP-AUY922 dephosphorylated JAK2 and STAT3 and decreased Mcl-1, which resulted in facilitating cytochrome c release. NVP-AUY922-mediated inhibition of JAK2/STAT3 signaling and down-regulation of their target gene, Mcl 1, occurred in a dose and time-dependent manner. Knock down of Mcl-1, STAT3 inhibitor or JAK2 inhibitor synergistically enhanced TRAIL-induced apoptosis. Taken together, our results suggest the involvement of the JAK2-STAT3-Mcl-1 signal transduction pathway in response to NVP-AUY922 treatment, which may play a key role in NVP-AUY922-mediated sensitization to TRAIL. By contrast, the effect of the combination treatments in non-transformed colon cells was minimal. We provide a clinical rationale that combining HSP90 inhibitor with TRAIL enhances therapeutic efficacy without increasing normal tissue toxicity in CRC patients. PMID- 25446255 TI - VIP induces NF-kappaB1-nuclear localisation through different signalling pathways in human tumour and non-tumour prostate cells. AB - The nuclear factor kappaB (NF-kappaB) is a powerful activator of angiogenesis, invasion and metastasis. Transactivation and nuclear localisation of NF-kappaB is an index of recurrence in prostate cancer. Vasoactive intestinal peptide (VIP) exerts similar effects in prostate cancer models involving increased expression of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) which are related to NF-kappaB transactivation. Here we studied differential mechanisms of VIP-induced NF-kappaB transactivation in non-tumour RWPE-1 and tumour LNCaP and PC3 human prostate epithelial cells. Immunofluorescence studies showed that VIP increases translocation of the p50 subunit of NF-kappaB1 to the nucleus, an effect that was inhibited by curcumin. The signalling transduction pathways involved are different depending on cell transformation degree. In control cells (RWPE1), the effect is mediated by protein kinase A (PKA) activation and does not implicate extracellular signal-regulated kinase (ERK) or phosphoinositide 3 kinase (PI3-K) pathways whereas the opposite is true in tumour LNCaP and PC3 cells. Exchange protein directly activated by cAMP (EPAC) pathway is involved in transformed cells but not in control cells. Curcumin blocks the activating effect of VIP on COX-2 promoter/prostaglandin E2 (PGE2) production and VEGF expression and secretion. The study incorporates direct observation on COX-2 promoter and suggests that VIP effect on VEGF may be indirectly mediated by PGE2 after being synthesised by COX-2, thus amplifying the initial signal. We show that the signalling involved in VIP effects on VEGF is cAMP/PKA in non-tumour cells and cAMP/EPAC/ERK/PI3K in tumour cells which coincides with pathways mediating p50 nuclear translocation. Thus, VIP appears to use different pathways for NF-kappaB1 (p50) transactivation in prostate epithelial cells depending on whether they are transformed or not. Transformed cells depend on pro-survival and pro proliferative signalling pathways involving ERK, PI3-K and cAMP/EPAC which supports the potential therapeutic value of these targets in prostate cancer. PMID- 25446254 TI - TRAIL activates JNK and NF-kappaB through RIP1-dependent and -independent pathways. AB - The death receptor (DR) ligand TRAIL is being evaluated in clinical trials as an anti-cancer agent; however, many studies have found that TRAIL also enhances tumor progression by activating the NF-kappaB pathway in apoptosis-resistant cells. Although RIP1, cFLIP and caspase-8 have been implicated in TRAIL-induced JNK and NF-kappaB activation, underlying mechanisms are unclear. By examining the kinetics of pathway activation in TRAIL-sensitive lymphoma cells wild-type or deficient for RIP1, TRAF2, cIAP1/2 or HOIP, we report here that TRAIL induces two phases of JNK and NF-kappaB activation. The early phase is activated by TRAF2- and cIAP1-mediated ubiquitination of RIP1, whereas the delayed phase is induced by caspase-dependent activation of MEKK1 independent of RIP1 and TRAF2 expression. cFLIP overexpression promotes the early phase but completely suppresses the delayed phase of pathway activation in lymphoma cells, whereas Bcl 2 overexpression promotes both the early and delayed phases of the pathways. In addition, stable overexpression of cFLIP in RIP1- or TRAF2-deficient cells confers resistance to apoptosis, but fails to mediate NF-kappaB activation. HOIP is not essential for, but contributes to, TRAIL-induced NF-kappaB activation in cFLIP-overexpressing cells. These findings not only elucidate details of the mechanisms underlying TRAIL-induced JNK and NF-kappaB activation, but also clarify conflicting reports in the field. PMID- 25446256 TI - Cannabinoid receptor interacting protein (CRIP1a) attenuates CB1R signaling in neuronal cells. AB - CB1 cannabinoid receptors (CB1R) are one of the most abundantly expressed G protein coupled receptors (GPCR) in the CNS and regulate diverse neuronal functions. The identification of GPCR interacting proteins has provided additional insight into the fine-tuning and regulation of numerous GPCRs. The cannabinoid receptor interacting protein 1a (CRIP1a) binds to the distal carboxy terminus of CB1R, and has been shown to alter CB1R-mediated neuronal function [1]. The mechanisms by which CRIP1a regulates CB1R activity have not yet been identified; therefore the focus of this investigation is to examine the cellular effects of CRIP1a on CB1R signaling using neuronal N18TG2 cells stably transfected with CRIP1a over-expressing and CRIP1a knockdown constructs. Modulation of endogenous CRIP1a expression did not alter total levels of CB1R, ERK, or forskolin-activated adenylyl cyclase activity. When compared to WT cells, CRIP1a over-expression reduced basal phosphoERK levels, whereas depletion of CRIP1a augmented basal phosphoERK levels. Stimulation of phosphoERK by the CB1R agonists WIN55212-2, CP55940 or methanandamide was unaltered in CRIP1a over expressing clones compared with WT. However, CRIP1a knockdown clones exhibited enhanced ERK phosphorylation efficacy in response to CP55940. In addition, CRIP1a knockdown clones displayed a leftward shift in CP55940-mediated inhibition of forskolin-stimulated cAMP accumulation. CB1R-mediated Gi3 and Go activation by CP99540 was attenuated by CRIP1a over-expression, but robustly enhanced in cells depleted of CRIP1a. Conversely, CP55940-mediated Gi1 and Gi2 activation was significant enhanced in cells over-expressing CRIP1a, but not in cells deficient of CRIP1a. These studies suggest a mechanism by which endogenous levels of CRIP1a modulate CB1R-mediated signal transduction by facilitating a Gi/o protein subtype preference for Gi1 and Gi2, accompanied by an overall suppression of G-protein mediated signaling in neuronal cells. PMID- 25446257 TI - A novel crosstalk between calcium/calmodulin kinases II and IV regulates cell proliferation in myeloid leukemia cells. AB - CaMKs link transient increases in intracellular Ca(2+) with biological processes. In myeloid leukemia cells, CaMKII, activated by the bcr-abl oncogene, promotes cell proliferation. Inhibition of CaMKII activity restricts cell proliferation, and correlates with growth arrest and differentiation. The mechanism by which the inhibition of CaMKII results in growth arrest and differentiation in myeloid leukemia cells is still unknown. We report that inhibition of CaMKII activity results in an upregulation of CaMKIV mRNA and protein in leukemia cell lines. Conversely, expression of CaMKIV inhibits autophosphorylation and activation of CaMKII, and elicits G0/G1cell cycle arrest,impairing cell proliferation. Furthermore, U937 cells expressing CaMKIV show elevated levels of Cdk inhibitors p27(kip1) and p16(ink4a) and reduced levels of cyclins A, B1 and D1. These findings were also confirmed in the K562 leukemic cell line. The relationship between CaMKII and CaMKIV is also observed in primary acute myeloid leukemia (AML) cells, and it correlates with their immunophenotypic profile. Indeed, immature MO/M1 AML showed increased CaMKIV expression and decreased pCaMKII, whereas highly differentiated M4/M5 AML showed decreased CaMKIV expression and increased pCaMKII levels. Our data reveal a novel cross-talk between CaMKII and CaMKIV and suggest that CaMKII suppresses the expression of CaMKIV to promote leukemia cell proliferation. PMID- 25446258 TI - ECM1 promotes the Warburg effect through EGF-mediated activation of PKM2. AB - The Warburg effect is an oncogenic metabolic switch that allows cancer cells to take up more glucose than normal cells and favors anaerobic glycolysis. Extracellular matrix protein 1 (ECM1) is a secreted glycoprotein that is overexpressed in various types of carcinoma. Using two-dimensional digest-liquid chromatography-mass spectrometry (LC-MS)/MS, we showed that the expression of proteins associated with the Warburg effect was upregulated in trastuzumab resistant BT-474 cells that overexpressed ECM1 compared to control cells. We further demonstrated that ECM1 induced the expression of genes that promote the Warburg effect, such as glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and hypoxia-inducible factor 1 alpha (HIF-1alpha). The phosphorylation status of pyruvate kinase M2 (PKM-2) at Ser37, which is responsible for the expression of genes that promote the Warburg effect, was affected by the modulation of ECM1 expression. Moreover, EGF-dependent ERK activation that was regulated by ECM1 induced not only PKM2 phosphorylation but also gene expression of GLUT1 and LDHA. These findings provide evidence that ECM1 plays an important role in promoting the Warburg effect mediated by PKM2. PMID- 25446260 TI - RTK SLAP down: the emerging role of Src-like adaptor protein as a key player in receptor tyrosine kinase signaling. AB - SLAP (Src like adaptor protein) contains adjacent Src homology 3 (SH3) and Src homology 2 (SH2) domains closely related in sequence to that of cytoplasmic Src family tyrosine kinases. Expressed most abundantly in the immune system, SLAP function has been predominantly studied in the context of lymphocyte signaling, where it functions in the Cbl dependent downregulation of antigen receptor signaling. However, accumulating evidence suggests that SLAP plays a role in the regulation of a broad range of membrane receptors including members of the receptor tyrosine kinase (RTK) family. In this review we highlight the role of SLAP in the ubiquitin dependent regulation of type III RTKs PDGFR, CSF-1R, KIT and Flt3, as well as Eph family RTKs. SLAP appears to bind activated type III and Eph RTKs via a conserved autophosphorylated juxtamembrane tyrosine motif in an SH2-dependent manner, suggesting that SLAP is important in regulating RTK signaling. PMID- 25446261 TI - Long non-coding RNA CASC2 suppresses malignancy in human gliomas by miR-21. AB - Long non-coding RNAs (lncRNAs) are aberrantly expressed in many diseases including cancer. LncRNA CASC2 (cancer susceptibility candidate 2) has been characterized as a tumor suppressor in endometrial cancer and colorectal cancer. However, the role and function of CASC2 in human gliomas remain unknown. In this study, we confirmed that CASC2 was lowly expressed in glioma tissues as well as in U251 and U87 glioma cell lines. Overexpression of CASC2 inhibited the malignancy of glioma cells, including proliferation, migration, and invasion, and promoted cell apoptosis. MicroRNA-21 (miR-21) has been reported to be overexpressed in human glioma tissues and cell lines, which is responsible for the malignant progression of glioma. We found that up-regulated CASC2 decreased the expression of miR-21 significantly and there is a reciprocal repression between CASC2 and miR-21 in an Argonaute2-dependent manner. Furthermore, bioinformatics, luciferase reporter assays and pull-down assay confirmed that miR 21 binds to CASC2 in a sequence-specific manner. Introduction of miR-21 largely abrogated CASC2-mediated inhibition of glioma cell proliferation, migration, and invasion, and promotion of cell apoptosis. This study demonstrated that CASC2 plays a tumor suppressive role in glioma via negative regulation of miR-21, which may be a novel therapeutic target for treating gliomas. PMID- 25446262 TI - High glucose activates Raw264.7 macrophages through RhoA kinase-mediated signaling pathway. AB - Hyperglycemia has been shown to accelerate atherogenesis, an inflammation process resulting from macrophage activation. Although high glucose (HG) was previously demonstrated to accentuate ROCK activity in macrophages and enhance their activation in vitro, the role of ROCK signaling in HG-mediated macrophage activation remains unclear. This study aimed to elucidate potential signal transduction pathways of HG-mediated ROCK upregulation and macrophage activation, including c-Jun or NF-kappaB pathways. A macrophage cell line, RAW264.7, was used to investigate the atherogenic effects of HG on RhoA/ROCK activity and macrophage functions. Exposure to HG significantly induced RhoA membrane translocation, RhoA kinase activity, and phosphorylation of myosin-binding subunit, a RhoA-kinase substrate. Macrophage behaviors, including cell proliferation, adhesion, migration, and TNF-alpha de novo synthesis, were also increased by HG exposure. However, pharmacological ROCK inhibition by hydroxyfasudil attenuated the HG enhanced adhesion and TNF-alpha production. Nuclear translocation of c-Jun and transcription factor NF-kappaB was simultaneously noted after HG stimulation. Pharmacological ROCK inhibition by hydroxyfasudil and siRNA-mediated ROCK1 or ROCK2 gene silencing confirmed the ROCK-dependent JNK and ERK phosphorylation, but not NF-kappaB activation in macrophages. In addition, both interventions effectively ameliorated the HG-mediated macrophage activation under the conditions mimicking diabetes. These findings suggest that hyperglycemia activates macrophages mainly through ROCK/JNK and ROCK/ERK pathways, which results in a more pro-inflammatory phenotype and eventually contributes to atherogenesis. In conclusion, ROCK inhibition might become a novel therapeutic strategy in atherosclerosis treatment and prevention in diabetic patients. PMID- 25446263 TI - NKD1 marks intestinal and liver tumors linked to aberrant Wnt signaling. AB - The activity of the Wnt pathway undergoes complex regulation to ensure proper functioning of this principal signaling mechanism during development of adult tissues. The regulation may occur at several levels and includes both positive and negative feedback loops. In the present study we employed one of such negative feedback regulators, naked cuticle homolog 1 (Nkd1), to follow the Wnt pathway activity in the intestine and liver and in neoplasia originated in these organs. Using lineage tracing in transgenic mice we localized Nkd1 mRNA to the bottom parts of the small intestinal crypts and hepatocytes surrounding the central vein of the hepatic lobule. Furthermore, in two mouse models of intestinal tumorigenesis, Nkd1 expression levels were elevated in tumors when compared to healthy tissue. We utilized a collection of human intestinal polyps and carcinomas to confirm that NKD1 represents a robust marker of neoplastic growth. In addition, expression analysis of NKD1 in liver cancer showed that high expression levels of the gene distinguish a subclass of hepatocellular carcinomas related to aberrant Wnt signaling. Finally, our results were confirmed by bioinformatic analysis of large publicly available datasets that included gene expression profiling and high-throughput sequencing data of human colon and liver cancer specimens. PMID- 25446259 TI - The interplay of NR4A receptors and the oncogene-tumor suppressor networks in cancer. AB - Nuclear receptor (NR) subfamily 4 group A (NR4A) is a family of three highly homologous orphan nuclear receptors that have multiple physiological and pathological roles, including some in cancer. These NRs are reportedly dysregulated in multiple cancer types, with many studies demonstrating pro oncogenic roles for NR4A1 (Nur77) and NR4A2 (Nurr1). Additionally, NR4A1 and NR4A3 (Nor-1) are described as tumor suppressors in leukemia. The dysregulation and functions of the NR4A members are due to many factors, including transcriptional regulation, protein-protein interactions, and post-translational modifications. These various levels of intracellular regulation result from the signaling cross-talk of the NR4A members with various signaling pathways, many of which are relevant to cancer and likely explain the family members' functions in oncogenesis and tumor suppression. In this review, we discuss the multiple functions of the NR4A receptors in cancer and summarize a growing body of scientific literature that describes the interconnectedness of the NR4A receptors with various oncogene and tumor suppressor pathways. PMID- 25446265 TI - Impact of oxidative stress on cellular biomechanics and rho signaling in C2C12 myoblasts. AB - Although cells often can tolerate oxidative environments, abnormal oxidative stress has been identified in inflammation, cardiovascular and neurodegenerative diseases, and aging. The impact of oxidative stress on the cellular biomechanics is poorly understood, however. In this study, we used C2C12 myoblasts to investigate the effect of oxidative stress, mimicked by hydrogen peroxide (H2O2), on the cell elasticity (i.e., Young's modulus), viability, and production of intracellular reactive oxygen species (ROS). To better understand the mechanisms underlying the impact of H2O2, we examined various effectors of the Rho signaling pathway, which has been shown to play a key role in the control of cell mechanics. H2O2 decreased the cell stiffness in a dose-dependent manner, caused cell death, and reduced the RhoA expression that was accompanied by down regulation of alpha-actin, cytoskeleton-membrane linker proteins (ezrin-radixin moesion proteins), and focal adhesion. Modulating the Rho signaling by using a Rho activator partially restored the cell stiffness, enhanced the cell viability, and decreased the intracellular ROS level, suggesting a potential intervention strategy to maintain the cellular biomechanical homeostasis and rescue cell damage in the threat of oxidative stresses. PMID- 25446264 TI - The effect of inlet waveforms on computational hemodynamics of patient-specific intracranial aneurysms. AB - Due to the lack of patient-specific inlet flow waveform measurements, most computational fluid dynamics (CFD) simulations of intracranial aneurysms usually employ waveforms that are not patient-specific as inlet boundary conditions for the computational model. The current study examined how this assumption affects the predicted hemodynamics in patient-specific aneurysm geometries. We examined wall shear stress (WSS) and oscillatory shear index (OSI), the two most widely studied hemodynamic quantities that have been shown to predict aneurysm rupture, as well as maximal WSS (MWSS), energy loss (EL) and pressure loss coefficient (PLc). Sixteen pulsatile CFD simulations were carried out on four typical saccular aneurysms using 4 different waveforms and an identical inflow rate as inlet boundary conditions. Our results demonstrated that under the same mean inflow rate, different waveforms produced almost identical WSS distributions and WSS magnitudes, similar OSI distributions but drastically different OSI magnitudes. The OSI magnitude is correlated with the pulsatility index of the waveform. Furthermore, there is a linear relationship between aneurysm-averaged OSI values calculated from one waveform and those calculated from another waveform. In addition, different waveforms produced similar MWSS, EL and PLc in each aneurysm. In conclusion, inlet waveform has minimal effects on WSS, OSI distribution, MWSS, EL and PLc and a strong effect on OSI magnitude, but aneurysm averaged OSI from different waveforms has a strong linear correlation with each other across different aneurysms, indicating that for the same aneurysm cohort, different waveforms can consistently stratify (rank) OSI of aneurysms. PMID- 25446266 TI - Characterization and assessment of hyperelastic and elastic properties of decellularized human adipose tissues. AB - Decellularized adipose tissue (DAT) has shown potential as a regenerative scaffold for plastic and reconstructive surgery to augment or replace damaged or missing adipose tissue (e.g. following lumpectomy or mastectomy). The mechanical properties of soft tissue substitutes are of paramount importance in restoring the natural shape and appearance of the affected tissues, and mechanical mismatching can lead to unpredictable scar tissue formation and poor implant integration. The goal of this work was to assess the linear elastic and hyperelastic properties of decellularized human adipose tissue and compare them to those of normal breast adipose tissue. To assess the influence of the adipose depot source on the mechanical properties of the resultant decellularized scaffolds, we performed indentation tests on DAT samples sourced from adipose tissue isolated from the breast, subcutaneous abdominal region, omentum, pericardial depot and thymic remnant, and their corresponding force-displacement data were acquired. Elastic and hyperelastic parameters were estimated using inverse finite element algorithms. Subsequently, a simulation was conducted in which the estimated hyperelastic parameters were tested in a real human breast model under gravity loading in order to assess the suitability of the scaffolds for implantation. Results of these tests showed that in the human breast, the DAT would show similar deformability to that of native normal tissue. Using the measured hyperelastic parameters, we were able to assess whether DAT derived from different depots exhibited different intrinsic nonlinearities. Results showed that DAT sourced from varying regions of the body exhibited little intrinsic nonlinearity, with no statistically significant differences between the groups. PMID- 25446267 TI - On the kinematics and efficiency of advective mixing during gastric digestion - A numerical analysis. AB - The mixing performance of gastric contents during digestion is expected to have a major role on the rate and final bioavailability of nutrients within the body. The aim of this study was to characterize the ability of the human stomach to advect gastric contents with different rheological properties. The flow behavior of two Newtonian fluids (10(-3)Pas, 1Pas) and a pseudoplastic solution (K=0.223Pas(0.59)) during gastric digestion were numerically characterized within a simplified 3D model of the stomach geometry and motility during the process (ANSYS-FLUENT). The advective performances of each of these gastric flows were determined by analyzing the spatial distribution and temporal history of their stretching abilities (Lagrangian analysis). Results illustrate the limited influence that large retropulsive and vortex structures have on the overall dynamics of gastric flows. Even within the distal region, more than 50% of the flow experienced velocity and shear values lower than 10% of their respective maximums. While chaotic, gastric advection was always relatively poor (with Lyapunov exponents an order of magnitude lower than those of a laminar stirred tank). Contrary to expectations, gastric rheology had only a minor role on the advective properties of the flow (particularly within the distal region). As viscosity increased above 1St, the role of fluid viscosity became largely negligible. By characterizing the fluid dynamic and mixing conditions that develop during digestion, this work will inform the design of novel in vitro systems of enhanced biomechanical performance and facilitate a more accurate diagnosis of gastric digestion processes. PMID- 25446268 TI - A resistance band increased internal hip abduction moments and gluteus medius activation during pre-landing and early-landing. AB - An increased knee abduction angle during jump-landing has been identified as a risk factor for anterior cruciate ligament injuries. Activation of the hip abductors may decrease the knee abduction angle during jump-landing. The purpose of this study was to examine the effects of a resistance band on the internal hip abduction moment and gluteus medius activation during the pre-landing (100ms before initial contact) and early-landing (100ms after initial contact) phases of a jump-landing-jump task. Thirteen male and 15 female recreational athletes (age: 21.1+/-2.4yr; mass: 73.8+/-14.6kg; height: 1.76+/-0.1m) participated in the study. Subjects performed jump-landing-jump tasks with or without a resistance band applied to their lower shanks. During the with-band condition, subjects were instructed to maintain their movement patterns as performing the jump-landing task without a resistance band. Lower extremity kinematics, kinetics, and gluteus medius electromyography (EMG) were collected. Applying the band increased the average hip abduction moment during pre-landing (p<0.001, Cohen's d (d)=2.8) and early-landing (p<0.001, d=1.5), and the average gluteus medius EMG during pre landing (p<0.001, d=1.0) and early-landing (p=0.003, d=0.55). Applying the band decreased the initial hip flexion angle (p=0.028, d=0.25), initial hip abduction angle (p<0.001, d=0.91), maximum knee flexion angle (p=0.046, d=0.17), and jump height (p=0.004, d=0.16). Applying a resistance band provides a potential strategy to train the strength and muscle activation for the gluteus medius during jump-landing. Additional instructions and feedback regarding hip abduction, hip flexion, and knee flexion may be required to minimize negative changes to other kinematic variables. PMID- 25446269 TI - Realistic non-Newtonian viscosity modelling highlights hemodynamic differences between intracranial aneurysms with and without surface blebs. AB - Most computational fluid dynamic (CFD) simulations of aneurysm hemodynamics assume constant (Newtonian) viscosity, even though blood demonstrates shear thinning (non-Newtonian) behavior. We sought to evaluate the effect of this simplifying assumption on hemodynamic forces within cerebral aneurysms, especially in regions of low wall shear stress, which are associated with rupture. CFD analysis was performed for both viscosity models using 3D rotational angiography volumes obtained for 26 sidewall aneurysms (12 with blebs, 12 ruptured), and parametric models incorporating blebs at different locations (inflow/outflow zone). Mean and lowest 5% values of time averaged wall shear stress (TAWSS) computed over the dome were compared using Wilcoxon rank-sum test. Newtonian modeling not only resulted in higher aneurysmal TAWSS, specifically in areas of low flow and blebs, but also showed no difference between aneurysms with or without blebs. In contrast, for non-Newtonian analysis, bleb-bearing aneurysms showed significantly lower 5% TAWSS compared to those without (p=0.005), despite no significant difference in mean dome TAWSS (p=0.32). Non-Newtonian modeling also accentuated the differences in dome TAWSS between ruptured and unruptured aneurysms (p<0.001). Parametric models further confirmed that realistic non Newtonian viscosity resulted in lower bleb TAWSS and higher focal viscosity, especially when located in the outflow zone. The results show that adopting shear thinning non-Newtonian blood viscosity in CFD simulations of intracranial aneurysms uncovered hemodynamic differences induced by bleb presence on aneurysmal surfaces, and significantly improved discriminant statistics used in risk stratification. These findings underline the possible implications of using a realistic model of blood viscosity in predictive computational hemodynamics. PMID- 25446270 TI - Quantitative analysis of brain microstructure following mild blunt and blast trauma. AB - We induced mild blunt and blast injuries in rats using a custom-built device and utilized in-house diffusion tensor imaging (DTI) software to reconstruct 3-D fiber tracts in brains before and after injury (1, 4, and 7 days). DTI measures such as fiber count, fiber length, and fractional anisotropy (FA) were selected to characterize axonal integrity. In-house image analysis software also showed changes in parameters including the area fraction (AF) and nearest neighbor distance (NND), which corresponded to variations in the microstructure of Hematoxylin and Eosin (H&E) brain sections. Both blunt and blast injuries produced lower fiber counts, but neither injury case significantly changed the fiber length. Compared to controls, blunt injury produced a lower FA, which may correspond to an early onset of diffuse axonal injury (DAI). However, blast injury generated a higher FA compared to controls. This increase in FA has been linked previously to various phenomena including edema, neuroplasticity, and even recovery. Subsequent image analysis revealed that both blunt and blast injuries produced a significantly higher AF and significantly lower NND, which correlated to voids formed by the reduced fluid retention within injured axons. In conclusion, DTI can detect subtle pathophysiological changes in axonal fiber structure after mild blunt and blast trauma. Our injury model and DTI method provide a practical basis for studying mild traumatic brain injury (mTBI) in a controllable manner and for tracking injury progression. Knowledge gained from our approach could lead to enhanced mTBI diagnoses, biofidelic constitutive brain models, and specialized pharmaceutical treatments. PMID- 25446271 TI - Fitted hyperelastic parameters for Human brain tissue from reported tension, compression, and shear tests. AB - The mechanical properties of human brain tissue are the subject of interest because of their use in understanding brain trauma and in developing therapeutic treatments and procedures. To represent the behavior of the tissue, we have developed hyperelastic mechanical models whose parameters are fitted in accordance with experimental test results. However, most studies available in the literature have fitted parameters with data of a single type of loading, such as tension, compression, or shear. Recently, Jin et al. (Journal of Biomechanics 46:2795-2801, 2013) reported data from ex vivo tests of human brain tissue under tension, compression, and shear loading using four strain rates and four different brain regions. However, they do not report parameters of energy functions that can be readily used in finite element simulations. To represent the tissue behavior for the quasi-static loading conditions, we aimed to determine the best fit of the hyperelastic parameters of the hyperfoam, Ogden, and polynomial strain energy functions available in ABAQUS for the low strain rate data, while simultaneously considering all three loading modes. We used an optimization process conducted in MATLAB, calling iteratively three finite element models developed in ABAQUS that represent the three loadings. Results showed a relatively good fit to experimental data in all loading modes using two terms in the energy functions. Values for the shear modulus obtained in this analysis (897-1653Pa) are in the range of those presented in other studies. These energy-function parameters can be used in brain tissue simulations using finite element models. PMID- 25446272 TI - Temperature as a predictive tool for plantar triaxial loading. AB - Diabetic foot ulcers are caused by moderate repetitive plantar stresses in the presence of peripheral neuropathy. In severe cases, the development of these foot ulcers can lead to lower extremity amputations. Plantar pressure measurements have been considered a capable predictor of ulceration sites in the past, but some investigations have pointed out inconsistencies when solely relying on this method. The other component of ground reaction forces/stresses, shear, has been understudied due to a lack of adequate equipment. Recent articles reported the potential clinical significance of shear in diabetic ulcer etiology. With the lack of adequate tools, plantar temperature has been used as an alternative method for determining plantar triaxial loading and/or shear. However, this method has not been previously validated. The purpose of this study was to analyze the potential association between exercise-induced plantar temperature increase and plantar stresses. Thirteen healthy individuals walked on a treadmill for 10 minutes at 3.2km/h. Pre and post-exercise temperature profiles were obtained with a thermal camera. Plantar triaxial stresses were quantified with a custom-built stress plate. A statistically significant correlation was observed between peak shear stress (PSS) and temperature increase (r=0.78), but not between peak resultant stress (PRS) and temperature increase (r=0.46). Plantar temperature increase could predict the location of PSS and PRS in 23% and 39% of the subjects, respectively. Only a moderate linear relationship was established between triaxial plantar stresses and walking-induced temperature increase. Future research will investigate the value of nonlinear models in predicting plantar loading through foot temperature. PMID- 25446274 TI - Abnormal development of placenta in HtrA1-deficient mice. AB - Abnormal levels of High temperature requirement A1 (HtrA1) protein have been repeatedly observed in sera and placentas of preeclampsia patients. To understand the functions of HtrA1 in placentation and in the etiology of preeclampsia, we established HtrA1(-/-) mice. HtrA1(-/-) mice show intrauterine growth retardation, and their placentas are small due to a reduced size of the junctional zone and aberrant vascularization in the labyrinth at the mid gestation stage. HtrA1 is expressed by Tpbpa-positive trophoblast precursors in the outer ectoplacental cone and junctional zone from embryonic day 7.5 to 10.5. In the HtrA1(-/-) placenta, Tpbpa-positive cell precursors are decreased in the early stage. Spongiotrophoblasts and glycogen trophoblast cells, both of which differentiate from Tpbpa-positive precursors, are consequently decreased in the junctional zone. Fewer spiral artery-associated trophoblast giant cells, another cell type derived from Tpbpa-positive precursors, invade the decidua and associate with maternal arteries in the HtrA1(-/-) placenta than in the wild type placenta. Maternal arteries in the HtrA1(-/-) decidua have narrower lumens, thicker arterial walls, and more vascular smooth muscle cells remaining in the walls than those in the wild type decidua, indicating impaired remodeling of maternal arteries. These results indicate that HtrA1 plays important roles in the differentiation of trophoblasts from Tpbpa-positive precursors in the ectoplacental cone. Insufficient levels of HtrA1 cause poor placental development and intrauterine growth retardation, due to aberrant trophoblast differentiation and consequent defects in maternal artery remodeling, and may contribute to the onset of preeclampsia. PMID- 25446273 TI - Comprehensive single cell-resolution analysis of the role of chromatin regulators in early C. elegans embryogenesis. AB - Chromatin regulators are widely expressed proteins with diverse roles in gene expression, nuclear organization, cell cycle regulation, pluripotency, physiology and development, and are frequently mutated in human diseases such as cancer. Their inhibition often results in pleiotropic effects that are difficult to study using conventional approaches. We have developed a semi-automated nuclear tracking algorithm to quantify the divisions, movements and positions of all nuclei during the early development of Caenorhabditis elegans and have used it to systematically study the effects of inhibiting chromatin regulators. The resulting high dimensional datasets revealed that inhibition of multiple regulators, including F55A3.3 (encoding FACT subunit SUPT16H), lin-53 (RBBP4/7), rba-1 (RBBP4/7), set-16 (MLL2/3), hda-1 (HDAC1/2), swsn-7 (ARID2), and let-526 (ARID1A/1B) affected cell cycle progression and caused chromosome segregation defects. In contrast, inhibition of cir-1 (CIR1) accelerated cell division timing in specific cells of the AB lineage. The inhibition of RNA polymerase II also accelerated these division timings, suggesting that normal gene expression is required to delay cell cycle progression in multiple lineages in the early embryo. Quantitative analyses of the dataset suggested the existence of at least two functionally distinct SWI/SNF chromatin remodeling complex activities in the early embryo, and identified a redundant requirement for the egl-27 and lin-40 MTA orthologs in the development of endoderm and mesoderm lineages. Moreover, our dataset also revealed a characteristic rearrangement of chromatin to the nuclear periphery upon the inhibition of multiple general regulators of gene expression. Our systematic, comprehensive and quantitative datasets illustrate the power of single cell-resolution quantitative tracking and high dimensional phenotyping to investigate gene function. Furthermore, the results provide an overview of the functions of essential chromatin regulators during the early development of an animal. PMID- 25446275 TI - A gene expression map of the larval Xenopus laevis head reveals developmental changes underlying the evolution of new skeletal elements. AB - The morphology of the vertebrate head skeleton is highly plastic, with the number, size, shape, and position of its components varying dramatically between groups. While this evolutionary flexibility has been key to vertebrate success, its developmental and genetic bases are poorly understood. The larval head skeleton of the frog Xenopus laevis possesses a unique combination of ancestral tetrapod features and anuran-specific novelties. We built a detailed gene expression map of the head mesenchyme in X. laevis during early larval development, focusing on transcription factor families with known functions in vertebrate head skeleton development. This map was then compared to homologous gene expression in zebrafish, mouse, and shark embryos to identify conserved and evolutionarily flexible aspects of vertebrate head skeleton development. While we observed broad conservation of gene expression between X. laevis and other gnathostomes, we also identified several divergent features that correlate to lineage-specific novelties. We noted a conspicuous change in dlx1/2 and emx2 expression in the second pharyngeal arch, presaging the differentiation of the reduced dorsal hyoid arch skeletal element typical of modern anamniote tetrapods. In the first pharyngeal arch we observed a shift in the expression of the joint inhibitor barx1, and new expression of the joint marker gdf5, shortly before skeletal differentiation. This suggests that the anuran-specific infrarostral cartilage evolved by partitioning of Meckel's cartilage with a new paired joint. Taken together, these comparisons support a model in which early patterning mechanisms divide the vertebrate head mesenchyme into a highly conserved set of skeletal precursor populations. While subtle changes in this early patterning system can affect skeletal element size, they do not appear to underlie the evolution of new joints or cartilages. In contrast, later expression of the genes that regulate skeletal element differentiation can be clearly linked to the evolution of novel skeletal elements. We posit that changes in the expression of downstream regulators of skeletal differentiation, like barx1 and gdf5, is one mechanism by which head skeletal element number and articulation are altered during evolution. PMID- 25446278 TI - Pox neuro control of cell lineages that give rise to larval poly-innervated external sensory organs in Drosophila. AB - The Pox neuro (Poxn) gene of Drosophila plays a crucial role in the development of poly-innervated external sensory (p-es) organs. However, how Poxn exerts this role has remained elusive. In this study, we have analyzed the cell lineages of all larval p-es organs, namely of the kolbchen, papilla 6, and hair 3. Surprisingly, these lineages are distinct from any previously reported cell lineages of sensory organs. Unlike the well-established lineage of mono innervated external sensory (m-es) organs and a previously proposed model of the p-es lineage, we demonstrate that all wild-type p-es lineages exhibit the following features: the secondary precursor, pIIa, gives rise to all three support cells-socket, shaft, and sheath, whereas the other secondary precursor, pIIb, is neuronal and gives rise to all neurons. We further show that in one of the p-es lineages, that of papilla 6, one cell undergoes apoptosis. By contrast in Poxn null mutants, all p-es lineages have a reduced number of cells and their pattern of cell divisions is changed to that of an m-es organ, with the exception of a lineage in a minority of mutant kolbchen that retains a second bipolar neuron. Indeed, the role of Poxn in p-es lineages is consistent with the specification of the developmental potential of secondary precursors and the regulation of cell division but not apoptosis. PMID- 25446279 TI - CD41 marks the initial myelo-erythroid lineage specification in adult mouse hematopoiesis: redefinition of murine common myeloid progenitor. AB - Previous studies have predicted that reciprocal activation of GATA-1 and PU.1 regulates myelo-erythroid versus myelo-lymphoid lineage commitment in early hematopoiesis. Such PU.1-activating myelo-lymphoid progenitors exist within the lymphoid-primed multipotent progenitor (LMPP) population at the primitive Lineage(-) Sca-1(+) c-Kit(+) (LSK) stage. We here show that the counterpart of GATA-1-activating myelo-erythroid progenitor resides also at the LSK stage, expressing CD41 at a high level. Purified CD41(hi) LSK cells showed exceedingly strong and prolonged myelo-erythroid-restricted reconstitution, and primed myelo erythroid gene expression with a more primitive molecular signature as compared to the original common myeloid progenitor (CMP). The CD41(hi) LSK cells more strongly contributed to emergent and malignant myelopoiesis than LMPPs, and produced the original CMP by downregulating Sca-1 and CD41, suggesting that they are the earliest CMPs. Thus, the hematopoietic developmental map should be revised by integrating the primary branchpoint comprised of the new, isolatable CD41(hi) CMP and the LMPP populations. PMID- 25446277 TI - Epigenetic regulation in neural crest development. AB - The neural crest is a migratory and multipotent cell population that plays a crucial role in many aspects of embryonic development. In all vertebrate embryos, these cells emerge from the dorsal neural tube then migrate long distances to different regions of the body, where they contribute to formation of many cell types and structures. These include much of the peripheral nervous system, craniofacial skeleton, smooth muscle, and pigmentation of the skin. The best studied regulatory events guiding neural crest development are mediated by transcription factors and signaling molecules. In recent years, however, growing evidence supports an important role for epigenetic regulation as an additional mechanism for controlling the timing and level of gene expression at different stages of neural crest development. Here, we summarize the process of neural crest formation, with focus on the role of epigenetic regulation in neural crest specification, migration, and differentiation as well as in neural crest related birth defects and diseases. PMID- 25446276 TI - From classical to current: analyzing peripheral nervous system and spinal cord lineage and fate. AB - During vertebrate development, the central (CNS) and peripheral nervous systems (PNS) arise from the neural plate. Cells at the margin of the neural plate give rise to neural crest cells, which migrate extensively throughout the embryo, contributing to the majority of neurons and all of the glia of the PNS. The rest of the neural plate invaginates to form the neural tube, which expands to form the brain and spinal cord. The emergence of molecular cloning techniques and identification of fluorophores like Green Fluorescent Protein (GFP), together with transgenic and electroporation technologies, have made it possible to easily visualize the cellular and molecular events in play during nervous system formation. These lineage-tracing techniques have precisely demonstrated the migratory pathways followed by neural crest cells and increased knowledge about their differentiation into PNS derivatives. Similarly, in the spinal cord, lineage-tracing techniques have led to a greater understanding of the regional organization of multiple classes of neural progenitor and post-mitotic neurons along the different axes of the spinal cord and how these distinct classes of neurons assemble into the specific neural circuits required to realize their various functions. Here, we review how both classical and modern lineage and marker analyses have expanded our knowledge of early peripheral nervous system and spinal cord development. PMID- 25446280 TI - Phase II study of cixutumumab in combination with temsirolimus in pediatric patients and young adults with recurrent or refractory sarcoma: a report from the Children's Oncology Group. AB - BACKGROUND: The combined inhibition of insulin-growth factor type 1 receptor (IGF 1R) and the mammalian target of rapamycin (mTOR) has shown activity in preclinical models of pediatric sarcoma and in adult sarcoma patients. We evaluated the activity of the anti-IGF-1R antibody cixutumumab with the mTOR inhibitor temsirolimus in patients with relapsed or refractory Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, and other soft tissue sarcoma, using the recommended dosages from a pediatric phase I trial. METHODS: Cixutumumab 6 mg/kg and temsirolimus 8 mg/m(2) were administered intravenously once weekly in 4-week cycles to patients <30 years. Temsirolimus was escalated to 10 mg/m(2) for subsequent cycles in patients who did not experience unacceptable first-cycle toxicity. A two-stage design was used to identify a response rate <10 or >35% for each tumor-specific cohort. Tumor tissue was analyzed by immunohistochemistry for potential biomarkers of response. RESULTS: Forty-three evaluable patients received a median of 2 cycles (range 1-7). No objective responses were observed, and 16% of patients were progression-free at 12 weeks. Dose-limiting toxicity was observed in 15 (16%) of 92 cycles. The most common toxicities were mucositis, electrolyte disturbances, and myelosuppression. The majority of patients receiving a second cycle were not eligible for temsirolimus escalation due to first-cycle toxicity. The lack of objective responses precluded correlation with tissue biomarkers. CONCLUSIONS: Despite encouraging preclinical data, the combination of cixutumumab and temsirolimus did not result in objective responses in this phase II trial of pediatric and young adults with recurrent or refractory sarcoma. PMID- 25446281 TI - "Post-it" type connected DNA created with a reversible covalent cross-link. AB - We report the development of a new heterobase that is held together through reversible bonding. The so-formed cross-link adds strong stabilization to the DNA duplex. Despite this, the cross-link opens and closes through reversible imine bonding. Moreover, even enzymatic incorporation of the cross-link is possible. The new principle can be used to stabilize DNA duplexes and nanostructures that otherwise require high salt concentrations, which may hinder biological applications. PMID- 25446282 TI - Effectiveness of surgical banding for high flow in brachial artery-based hemodialysis vascular access. AB - OBJECTIVE: Autogenous arteriovenous hemodialysis (HD) access may develop high flow (>2 L/min) over time. Reducing flow volume of a high-flow access (HFA) using a surgical banding technique has been reported to be successful in the short term. The aim of this study was to evaluate the efficacy of banding in HFAs in terms of freedom from recurrence of high flow during a 1-year follow-up. METHODS: All HD patients undergoing surgical banding of an HFA during an 8-year period in three hospitals were retrospectively studied. Access flow data, freedom of recurrent high flow, and complications were analyzed during a 12-month postoperative observation period. RESULTS: A total of 50 patients (30 males; age, 51 +/- 2 years) were available for analysis. Banding was performed 30 +/- 6 months after arteriovenous access construction. Most of the HFA patients (56%) required medication for hypertension, but diabetes mellitus and peripheral arterial obstructive disease were seldom observed (6% and 12%, respectively). Most HFAs (96%) were brachial artery-based fistulas (brachiocephalic: 56%, basilic vein transposition: 40%, radiocephalic: 4%). Banding initially reduced access flow by >50% (3070 +/- 95 vs 1490 +/- 105 mL/min, P < .001). Recurrent high flow (>2 L/min) developed in 52% of the patients during the observation period. Young age (45 +/- 3 vs 57 +/- 3 years; P = .02) and an access flow >1 L/min immediately after banding (P = .03) were risk factors for recurrent high flow. CONCLUSIONS: An immediate postbanding access flow >1 L/min and young age are risk factors for recurrent high flow in a banded brachial artery-based HD access during a 1-year follow-up. PMID- 25446283 TI - Ephrin type-B receptor 4 activation reduces neointimal hyperplasia in human saphenous vein in vitro. AB - BACKGROUND: Vein bypass is an essential therapy for patients with advanced peripheral and coronary artery disease despite development of neointimal hyperplasia. We have shown that stimulation of the receptor tyrosine kinase ephrin type-B receptor 4 (Eph-B4) with its ligand ephrin-B2 prevents neointimal hyperplasia in murine vein grafts. This study determines whether Eph-B4 in adult human veins is capable of phosphorylation and activation of downstream signaling pathways, as well as functional to release nitric oxide (NO) and prevent neointimal hyperplasia in vitro. METHODS: Discarded human saphenous veins were taken from the operating room and placed in organ culture without or with ephrin B2/Fc (2 MUg/mL) for 14 days, and the neointima/media ratio was measured in matched veins. Primary human umbilical vein endothelial cells were treated with ephrin-B2/Fc (2 MUg/mL) and examined with quantitative polymerase chain reaction, Western blot, immunoassays, and for release of NO. Ephrin-B2/Fc (2 MUg/mL) was placed on the adventitia of saphenous veins treated with arterial shear stress for 24 hours in a bioreactor and activated Eph-B4 examined with immunofluorescence. RESULTS: The baseline intima/media ratio in saphenous vein rings was 0.456 +/- 0.097, which increased to 0.726 +/- 0.142 in untreated veins after 14 days in organ culture but only to 0.630 +/- 0.132 in veins treated with ephrin-B2/Fc (n = 19, P = .017). Ephrin-B2/Fc stimulated Akt, endothelial NO synthase and caveolin-1 phosphorylation, and NO release (P = .007) from human umbilical vein endothelial cells (n = 6). Ephrin-B2/Fc delivered to the adventitia stimulated endothelial Eph-B4 phosphorylation after 24 hours of arterial stress in a bioreactor (n = 3). CONCLUSIONS: Eph-B4 is present and functional in adult human saphenous veins, with intact downstream signaling pathways capable of NO release and prevention of neointimal hyperplasia in vitro. Adventitial delivery of ephrin-B2/Fc activates endothelial Eph-B4 in saphenous veins treated with arterial shear stress in vitro. These results suggest that stimulation of Eph-B4 function may be a candidate strategy for translation to human clinical trials designed to inhibit venous neointimal hyperplasia. PMID- 25446286 TI - Numerical simulation of red blood cell distributions in three-dimensional microvascular bifurcations. AB - We constructed three-dimensional microvascular bifurcation models using a parent vessel of diameter 10MUm and investigated the flow behavior of the red blood cells (RBCs) through bifurcations. We considered symmetric and asymmetric model types. Two cases of equal daughter vessel diameter were employed for the asymmetric models, where the first was 10MUm, which is the same as the parent vessel and the second was 7.94MUm, which satisfies Murray's law. Simulated blood flow was computed using the lattice Boltzmann method in conjunction with the immersed boundary method for incorporating fluid-membrane interactions between the flow field and deformable RBCs. First, we investigated the flow behavior of a single RBC through microvascular bifurcations. In the case of the symmetric bifurcation, the turning point of the fractional plasma flow wherein the RBC flow changed from one daughter vessel to the other was 0.50. This turning point was however different for asymmetric bifurcations. Additionally, we varied the initial offset of RBCs from the centerline of the parent vessel. The simulation results indicated that the RBCs preferentially flow through the branch of a larger flow ratio. Next, we investigated the distribution characteristics of multiple RBCs. Simulations indicated that the results of the symmetric model were similar to those predicted by a previously published empirical model. On the other hand, results of asymmetric models deviated from those of the symmetric and empirical models. These results suggest that the distribution of RBCs varies according to the bifurcation angle and daughter vessel diameter in a microvascular bifurcation of the size considered. PMID- 25446285 TI - Inflammation and L-carnitine therapy in hemodialysis patients: a review. AB - Inflammation is a common complication in hemodialysis (HD) patients with no valid treatment strategy. In addition, carnitine deficiency occurs frequently in HD patients because of intradialytic loss of carnitine, impaired de novo carnitine renal synthesis, and reduced dietary intake. It appears that carnitine deficiency is related to inflammation in HD patients. A few clinical trials have investigated the effect of L-carnitine supplement on inflammatory markers in HD patients. All studies in this field, except one, showed that L-carnitine could significantly reduce C-reactive protein and serum amyloid A, as two systemic inflammation markers, in HD patients. Therefore, considering high prevalence of inflammation and carnitine deficiency in HD patients, L-carnitine therapy is a reasonable approach for reducing systemic inflammation and its complications in these patients. PMID- 25446284 TI - A successful experimental model for intimal hyperplasia prevention using a resveratrol-delivering balloon. AB - OBJECTIVE: Restenosis due to intimal hyperplasia is a major clinical problem that compromises the success of angioplasty and endovascular surgery. Resveratrol (RSV) has demonstrated a beneficial effect on restenosis from angioplasty. Unfortunately, the physicochemical characteristics of RSV reduce the practicality of its immediate clinical application. This work proposes an experimental model aiming to setup an intravessel, elutable, RSV-containing compound. METHODS: A 140 MUg/mL RSV sterile injectable solution with a suitable viscosity for intravascular administration by drug-delivery catheter (RSV-c) was prepared. This solution was locally administered in the common iliac artery of adult male New Zealand White rabbits using a dedicated device (Genie; Acrostak, Geneva, Switzerland) after the induction of intimal hyperplasia by traumatic angioplasty. The RSV concentrations in the wall artery were determined, and the thickness of the harvested iliac arteries was measured over a 1-month period. RESULTS: The Genie catheter was applied in rabbit vessels, and the local delivery resulted in an effective reduction in restenosis after plain angioplasty. Notably, RSV-c forced into the artery wall by balloon expansion might accumulate in the interstitial areas or within cells, avoiding the washout of solutions. Magnification micrographs showed intimal proliferation was significantly inhibited when RSV-c was applied. Moreover, no adverse events were documented in in vitro or in vivo studies. CONCLUSIONS: RSV can be advantageously administered in the arterial walls by a drug-delivery catheter to reduce the risk of restenosis. PMID- 25446287 TI - Editor's statement. PMID- 25446288 TI - Modeling human liver cancer heterogeneity: virally induced transgenic models and mouse genetic models of chronic liver inflammation. AB - In addition to being the most common primary liver cancer, hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in humans. Treatment options are limited for this chemoresistant cancer, with liver transplantation and surgical intervention in early stages being the most successful treatments. Drug development over the past 15 years has focused on generating mouse models that mimic the human pathology for HCC. This has enabled the laboratory testing of potentially new human therapeutics. Described in this unit are the classification of HCC and an overview of hepatitis virus-related transgenic and genetically engineered mouse models (GEMMs) that are employed for elucidating the mechanism(s) responsible for the development of HCC, with particular emphasis on genetic, dietary, and environmental factors. PMID- 25446291 TI - Guinea pig models of asthma. AB - Described in this unit are methods for establishing guinea pig models of asthma. Sufficient detail is provided to enable investigators to study bronchoconstriction, cough, airway hyperresponsiveness, inflammation, and remodeling. PMID- 25446292 TI - Appreciation and new beginnings. PMID- 25446289 TI - Overview of different mechanisms of arrestin-mediated signaling. AB - Arrestins are characterized by their ability to selectively bind active, phosphorylated GPCRs and suppress (arrest) receptor coupling to G proteins. Nonvisual arrestins are also signaling proteins in their own right, activating a variety of cellular pathways. Arrestins are highly flexible proteins that can assume many distinct conformations. In their receptor-bound conformation, arrestins have higher affinity for a subset of partners. This explains how receptor activation regulates certain branches of arrestin-dependent signaling via arrestin recruitment to GPCRs. However, free arrestins are also active molecular entities that act in other pathways and localize signaling proteins to particular subcellular compartments, such as cytoskeleton. These functions are regulated by the enhancement or reduction of arrestin affinity for target proteins by other binding partners and by proteolytic cleavage. Recent findings suggest that the two visual arrestins, arrestin-1 and arrestin-4, which are expressed in photoreceptor cells, do not regulate signaling solely via binding to photopigments but also interact with a variety of nonreceptor partners, critically affecting the health and survival of photoreceptor cells. Detailed in this overview are GPCR-dependent and independent modes of arrestin-mediated regulation of cellular signaling pathways. PMID- 25446290 TI - Arrestin expression in E. coli and purification. AB - Purified arrestin proteins are necessary for biochemical, biophysical, and crystallographic studies of these versatile regulators of cell signaling. Described herein is a basic protocol for arrestin expression in E. coli and purification of the tag-free wild-type and mutant arrestins. The method includes ammonium sulfate precipitation of arrestins from cell lysates, followed by heparin-Sepharose chromatography. Depending on the arrestin type and/or mutations, the next step is Q-Sepharose or SP-Sepharose chromatography. In many cases the nonbinding column is used as a filter to bind contaminants without retaining arrestin. In some cases both chromatographic steps must be performed sequentially to achieve high purity. Purified arrestins can be concentrated up to 10 mg/ml, remain fully functional, and withstand several cycles of freezing and thawing, provided that overall salt concentration is maintained at or above physiological levels. PMID- 25446293 TI - Teaching metacognitive skills: helping your physician trainees in the quest to 'know what they don't know'. PMID- 25446294 TI - Two-hour algorithm for triage toward rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T. AB - BACKGROUND: High-sensitivity cardiac troponin (hs-cTn) may allow an earlier diagnosis of acute myocardial infarction (AMI). METHODS: We prospectively enrolled 1148 (derivation cohort) and 517 (external validation cohort) unselected patients presenting with suspected AMI to the emergency department. Final diagnosis was adjudicated by 2 independent cardiologists. Hs-cTnT was measured at presentation and after 2 hours. A diagnostic algorithm incorporating hs-cTnT values at presentation and absolute changes within the first 2 hours was derived. RESULTS: AMI was the final diagnosis in 16% of patients in the derivation and 9.1% in the validation cohort. The 2-hour algorithm developed in the derivation cohort classified 60% of patients as "rule-out," 16% as "rule-in," and 24% in the "observational-zone." Resulting sensitivity and negative predictive value (NPV) were 99.5% and 99.9%, respectively, for rule-out, and specificity and positive predictive value (PPV) were 96% and 78%, respectively, for rule-in. Applying the 2-hour triage algorithm in the external validation cohort, 78% of patients could be classified as "rule-out," 8% as "rule-in," and 14% in the "observational zone." Resulting sensitivity and NPV were 96% and 99.5%, respectively, for rule out, and specificity and PPV were 99% and 85%, respectively, for rule-in. Cumulative 30-day survival rates were 100%, 98.9%, and 95.2% (P < .001), and 100%, 100%, and 95% (P < .001) in patients classified as "rule-out," "observational-zone," and "rule-in" in the 2 cohorts, respectively. CONCLUSIONS: A simple algorithm incorporating hs-cTnT baseline values and absolute changes over 2 hours allowed a triage toward safe rule-out, or accurate rule-in, of AMI in the vast majority of patients, with only 20% requiring more prolonged monitoring and serial blood sampling. PMID- 25446295 TI - Steroid exposure, acute coronary syndrome, and inflammatory bowel disease: insights into the inflammatory milieu. AB - BACKGROUND: Steroids are anti-inflammatory agents commonly used to treat inflammatory bowel disease. Inflammation plays a critical role in the pathophysiology of both inflammatory bowel disease and acute coronary syndrome. We examined the relationship between steroid use in patients with inflammatory bowel disease and acute coronary syndrome. METHODS: In 177 patients with inflammatory bowel disease (mean age 67 years, 75% male, 44% Crohn's disease, 56% ulcerative colitis), we performed a 1:2 case-control study matched for age, sex, and inflammatory bowel disease type, and compared 59 patients with inflammatory bowel disease with acute coronary syndrome to 118 patients with inflammatory bowel disease without acute coronary syndrome. Steroid use was defined as current or prior exposure. Acute coronary syndrome was defined as myocardial infarction or unstable angina, confirmed by cardiac biomarkers and coronary angiography. RESULTS: In patients with inflammatory bowel disease, 34% with acute coronary syndrome had exposure to steroids, vs 58% without acute coronary syndrome (P < .01). Steroid exposure reduced the adjusted odds of acute coronary syndrome by 82% (odds ratio [OR] 0.39; 95% confidence interval [CI], 0.20-0.74; adjusted OR 0.18; 95% CI, 0.06-0.51) in patients with inflammatory bowel disease, 77% in Crohn's disease (OR 0.36; 95% CI, 0.14-0.92; adjusted OR 0.23; 95% CI, 0.06 0.98), and 78% in ulcerative colitis (OR 0.41; 95% CI, 0.16-1.04; adjusted OR 0.22; 95% CI, 0.06-0.90). There was no association between other inflammatory bowel disease medications and acute coronary syndrome. CONCLUSIONS: In patients with inflammatory bowel disease, steroid use significantly reduces the odds of acute coronary syndrome. These findings provide further mechanistic insight into the inflammatory processes involved in inflammatory bowel disease and acute coronary syndrome. PMID- 25446296 TI - Effectiveness of inferior vena cava filters on mortality as an adjuvant to antithrombotic therapy. AB - BACKGROUND: Despite growing evidence of complications, inferior vena cava filters are being used increasingly in patients with venous thromboembolism based on limited efficacy data. In such a controversial situation, the effectiveness of filter use on mortality as an adjuvant to antithrombotic therapy for pulmonary embolism remains uncertain. METHODS: Using the Diagnosis Procedure Combination database in Japan, we identified patients hospitalized with pulmonary embolism who received anticoagulation or thrombolytic therapy from the day of admission. We compared the in-hospital mortality between patients who received a filter and patients who did not, using propensity score and instrumental variable methods. RESULTS: Of 13,125 eligible patients, 3948 received a filter, and 9177 did not receive a filter. The propensity score-matched analysis showed that filter use was significantly associated with lower in-hospital mortality than nonuse (2.6% vs 4.7%, P < .001; risk ratio 0.55; 95% confidence interval [CI], 0.43-0.71; risk difference -2.1%; 95% CI, -3.0% to -1.2%; number needed to treat, 48; 95% CI, 34 82). We obtained similar results in the inverse probability of treatment weighting analysis. The instrumental variable analysis confirmed that filter use was associated with a decreased risk of in-hospital mortality with adjustment for all measured variables (risk difference -2.5%, 95% CI, -4.6% to -0.4%). CONCLUSIONS: This study suggested that filter use was potentially effective for reducing in-hospital mortality in patients with pulmonary embolism. Prospective studies are needed to confirm the effectiveness observed in our results and to define which subpopulations of patients would benefit most from filters. PMID- 25446297 TI - Novel markers and therapies for patients with acute heart failure and renal dysfunction. AB - BACKGROUND: Acute kidney injury complicates decompensated heart failure in ~33% of cases and is associated with morbidity and mortality; thus, we sought to systematically review this topic in order to summarize novel diagnostic and therapeutic approaches. METHODS: Structured PubMed searches on these topics were conducted in February 2014 and relevant literature was identified. The PubMed search identified a total of 192 articles that were individually screened for inclusion in this analysis, and 58 were included. RESULTS: Acute kidney injury, defined by substantial increases in serum creatinine, is associated consistently with prolonged length of stay, rehospitalization, and mortality. Biomarker studies suggested that natriuretic peptides are prognostic for shorter- and longer-term mortality. Novel proteins indicating kidney damage and albumin in the urine are associated with acute kidney injury. The most promising acute pharmacologic treatment appears to be serelaxin, which has been shown to improve acute heart failure symptoms, hemodynamic parameters, and renal function. CONCLUSIONS: The presence of acute kidney injury results in worse clinical outcomes for patients with acute heart failure. Novel biomarkers and therapies hold the promise of improving both cardiac and renal outcomes in these patients. PMID- 25446298 TI - Screening for abdominal aortic aneurysms in outpatient primary care clinics. AB - BACKGROUND: The US Preventive Services Task Force (USPSTF) guidelines recommend one-time abdominal aortic aneurysm ultrasound screening for men aged 65 to 75 years who ever smoked. Reported screening rates have been 13% to 26% but did not include computed tomography, magnetic resonance imaging, and nonaortic abdominal ultrasound, which provide adequate visualization of the aorta. The objective of this study was to evaluate rates of screening performed intentionally with ultrasound and incidentally with other abdominal imaging, determine rates of redundant screening, and evaluate patient and physician characteristics associated with screening. METHODS: Cross-sectional study of patient encounters in 2007 and 2012 to determine abdominal aortic aneurysm screening trends in primary care practices. Participants included all patients who were seen in a primary care office and were eligible for screening by USPSTF guidelines. The primary outcome was percentage of eligible patients screened for abdominal aortic aneurysm by ultrasound or other abdominal imaging. RESULTS: There were 15,120 patients eligible for screening in 2007, and 22,355 in 2012. Screening with ultrasounds increased from 3.6% in 2007 to 9.2% in 2012. Screening with any imaging that included the aorta increased from 31% in 2007 to 41% in 2012. Of 2595 screening ultrasounds performed in either cohort, 800 (31%) were performed on patients who had already undergone another imaging modality. Of 153 physicians who had >50 eligible patients, rates of abdominal aortic aneurysm screening ranged from 7.5% to 79% (median 39%, interquartile range 31%-47%), and rates of ultrasound screening ranged from 0% to 47% (median 6.3%, interquartile range 3.6% 11.4%). Physician characteristics positively associated with screened patients included female sex (odds ratio [OR] 1.32; 95% confidence interval [CI], 1.12 1.54), specialty (Internal Medicine vs Family Medicine: OR 1.32; 95% CI, 1.14 1.54), and location (academic medical center vs family health center: OR 1.30; 95% CI, 1.04-1.62). CONCLUSIONS: Abdominal aortic aneurysm screening rates remain below 50%, but are improving over time. Screening by individual physicians varied widely, indicating substantial opportunity for educational interventions. Most abdominal aortic aneurysm screening is completed incidentally, and some patients later undergo unnecessary ultrasound screening. Before ordering screening, physicians and electronic health record-based reminder tools should ensure that the aorta has not been previously visualized. PMID- 25446300 TI - Death by caring: Ebola and Alcott's Little Women. PMID- 25446301 TI - Role of delta-aminolevulinic acid in the symptoms of acute porphyria. AB - BACKGROUND: Attacks of neuropathic pain, usually abdominal, are characteristic of the acute porphyrias and accompanied by overproduction of heme-precursor molecules, specifically delta-aminolevulinic acid and porphobilinogen. The basis for the acute symptoms in these diseases has been speculative. METHODS: We review genetic acute porphyria, hereditary tyrosinemia, and an acquired condition, lead poisoning. All perturb heme synthesis and present with a similar pain syndrome. RESULTS: Although each of these conditions has characteristic urine biochemistry, all exhibit excess delta-aminolevulinic acid. Moreover, in all, treatment with hemin reduces delta-aminolevulinic acid and relieves symptoms. In contrast, use of recombinant porphobilinogen deaminase to knock down porphobilinogen in acute porphyria was ineffective. CONCLUSIONS: There is now convincing evidence that delta-aminolevulinic acid is the cause of pain in the acute porphyrias. The efficacy of hemin infusion is due mainly, if not entirely, to its inhibition of hepatic delta-aminolevulinic acid synthase-1, the enzyme that catalyzes delta aminolevulinic acid formation. Delta-aminolevulinic acid synthase-1 is a rational target for additional therapies to control symptoms in acute porphyria. PMID- 25446302 TI - The role of thromboprophylaxis in patients with permanent immobility. PMID- 25446299 TI - Decade-long trends in atrial fibrillation incidence and survival: a community study. AB - BACKGROUND: Contemporary data on temporal trends in incidence and survival after atrial fibrillation are scarce. METHODS: Residents of Olmsted County, Minn., with a first-ever atrial fibrillation or atrial flutter event between 2000 and 2010 were identified. Age- and sex-adjusted incidence rates were standardized to the 2010 US population, and the relative risk of atrial fibrillation in 2010 versus 2000 was calculated using Poisson regression. Standardized mortality ratios of observed versus expected survival were calculated, and time trends in survival were examined using Cox regression. RESULTS: We identified 3344 patients with incident atrial fibrillation/atrial flutter events (52% were male, mean age 72.6 years, 95.7% were white). Incidence did not change over time (age- and sex adjusted rate ratio, 1.01; 95% confidence interval [CI], 0.91-1.13 for 2010 vs 2000). Within the first 90 days, the risk of all-cause mortality was greatly elevated compared with individuals of a similar age and sex distribution in the general population (standardized mortality ratios 19.4 [95% CI, 17.3-21.7] and 4.2 [95% CI, 3.5-5.0] for the first 30 days and 31 to 90 days after diagnosis, respectively). Survival within the first 90 days did not improve over the study period (adjusted hazard ratio, 0.96; 95% CI, 0.71-1.32 for 2010 vs 2000); likewise, no difference in mortality between 2010 and 2000 was observed among 90 day survivors (hazard ratio, 1.05; 95% CI, 0.85-1.31). CONCLUSIONS: In the community, atrial fibrillation incidence and survival have remained constant over the last decade. A dramatic and persistent excess risk of death was observed in the 90 days after atrial fibrillation diagnosis, underscoring the importance of early risk stratification. PMID- 25446303 TI - Afebrile endocarditis presenting as purpura and acute renal failure. PMID- 25446305 TI - Paradoxical hypokalemia: where has all the potassium gone? PMID- 25446304 TI - Myocardial infarction associated with Kawasaki disease in adult man: case report and review of literature. PMID- 25446306 TI - A new comparison of nested case-control and case-cohort designs and methods. AB - Existing literature comparing statistical properties of nested case-control and case-cohort methods have become insufficient for present day epidemiologists. The literature has not reconciled conflicting conclusions about the standard methods. Moreover, a comparison including newly developed methods, such as inverse probability weighting methods, is needed. Two analytical methods for nested case control studies and six methods for case-cohort studies using proportional hazards regression model were summarized and their statistical properties were compared. The answer to which design and method is more powerful was more nuanced than what was previously reported. For both nested case-control and case-cohort designs, inverse probability weighting methods were more powerful than the standard methods. However, the difference became negligible when the proportion of failure events was very low (<1%) in the full cohort. The comparison between two designs depended on the censoring types and incidence proportion: with random censoring, nested case-control designs coupled with the inverse probability weighting method yielded the highest statistical power among all methods for both designs. With fixed censoring times, there was little difference in efficiency between two designs when inverse probability weighting methods were used; however, the standard case-cohort methods were more powerful than the conditional logistic method for nested case-control designs. As the proportion of failure events in the full cohort became smaller (<10%), nested case-control methods outperformed all case-cohort methods and the choice of analytic methods within each design became less important. When the predictor of interest was binary, the standard case-cohort methods were often more powerful than the conditional logistic method for nested case-control designs. PMID- 25446308 TI - [The new Patients' Rights Act: changes in the issue of physician liability?]. AB - The present article provides an overview of the (legal) sphere of influence of the new German Patients' Rights Act, the extent to which the provisions of the treatment contract directly affect the everyday professional conduct of physicians, and the changes that are coming about as a result of the law. Furthermore, it cannot be ignored that the new legal situation risks not only putting a strain on the trust between doctor and patient, but also hindering the physician when carrying out his or her key medical tasks. The following presentation addresses these aspects and the key issues. It is essentially an overview of the current legal position and a guideline for use in the day-to-day work of the health care sector. PMID- 25446309 TI - [Current methods in genetic analysis : an approach for genetics-based preventive medicine]. AB - Modern genetic analysis methods such as DNA arrays (gene chips) or high throughput DNA sequencing of the next generation (Next Generation Sequencing, NGS) have once again accelerated the pace of innovation that has been powered by genome research over the past 10 years of the "post-genomic era". The present paper introduces array and NGS methods as two important innovation driving methods and provides examples for their application in large-scale scientific projects. However, a broad application of these very powerful technologies for genetic screening for the purpose of disease prevention is currently not yet in sight. The complexity of the interaction of genes, gene products and the environment has so far exceeded all expectations, suggesting that reliable statements about the medical relevance of common genetic variants can presently only be made in a few areas such as pharmacogenetics and oncology. We also discuss ethical issues raised by genetic population screening. The aim of this paper is to provide a brief outline of the development of methods in molecular genetics to the now dominant modern technologies and present their applications in research, in the diagnosis of rare diseases, and in terms of screening approaches. PMID- 25446307 TI - Serum osteoprotegerin and future risk of cancer and cancer-related mortality in the general population: the Tromso study. AB - The purpose was to investigate the association between serum osteoprotegerin (OPG) and risk of incident cancer and cancer mortality in a general population. OPG was measured in serum collected from 6,279 subjects without prior cancer recruited from a general population. Incident cancer and cancer-related mortality were registered from inclusion in 1994-95 until end of follow-up December 31, 2008. Cox regression models were used to estimate crude and adjusted (for age, sex and other confounders) hazard ratios and 95% confidence intervals (HR 95% CI). There were 948 incident cancers and 387 deaths in the cohort during 71,902 person-years of follow up (median 13.5 years). Subjects with serum OPG in the upper tertile had 79% higher risk of incident gastrointestinal cancer than those in the lowest tertile (HR 1.79, 95% CI 1.19-2.67). In women <60 years, serum OPG (per SD 0.81 ng/ml) was associated with reduced risk of incident cancer (all cancers merged; 0.73; 0.57-0.94) and breast cancer (0.51; 0.31-0.83) after adjustment. Subjects in the upper tertile of OPG had higher risk of cancer related mortality (1.63; 1.16-2.28), particularly mortality from cancer in the gastrointestinal system (2.28; 1.21-4.28) compared to those in the lowest OPG tertile. No significant association was detected between OPG and risk of death from cancer in the respiratory system or death from prostatic cancer. Our findings from a large population based cohort study suggest that serum OPG was associated with increased risk of incident gastrointestinal cancer, inversely associated with breast cancer, and predicts cancer-related mortality. PMID- 25446310 TI - [Biomaterial banks are crucial to developing genetically-based prevention concepts]. AB - Collections of human biological samples and their link to additional information is not a new concept. However, the demands on the quantity, quality, and the information content of biological samples have increased considerably in recent years. The legal and ethical frameworks have changed accordingly, as well as the degree of (IT) networking and communication between biomaterial banks. Due to this development, biobanks contribute significantly to the generation of genetically-based prevention concepts and to new therapeutic approaches. PMID- 25446311 TI - [Genetics and prevention of genetic aortic syndromes (GAS) and of the Marfan syndrome]. AB - BACKGROUND: Genetic aortic syndromes are autosomal-dominantly heritable aneurysms of the thoracic aorta, which carry a high risk of aortic rupture or acute thoracic aortic dissection at young age. OBJECTIVES: We introduce the reader to the principles of genetic diagnostics and the medical and surgical prevention of thoracic aortic dissection in patients with genetic aortic syndromes. METHODS: A cardiologist, a health economist, a patient representative, a heart surgeon, and a molecular geneticist teamed up to elucidate their perspective on major aspects of genetics and prevention of genetic aortic syndromes. RESULTS: Genetic aortic syndromes reflect a broad spectrum of diverse disease entities comprising the Marfan syndrome, the Loeys-Dietz syndrome or the vascular Ehlers-Danlos syndrome. The diagnosis of each respective disease entity requires combined assessment of phenotype and genotype information. A medical prevention of aortic complications such as dissection is mandatory although a curative therapy currently appears unlikely in humans. The single most important measure against acute aortic dissection is the preventive replacement of the aortic root, where valve preserving techniques appear preferable. Comprehensive prophylaxis including molecular diagnostics seem reasonable also from an economic point of view. DISCUSSION: Optimal prevention requires individualization of concepts, which entail a detailed diagnostic characterization of each specific genetic aortic syndrome including characterization of the genotype. PMID- 25446312 TI - [Genetic and epigenetic mechanisms in obesity]. AB - Obesity is a relevant medical problem. Around 60 % of German adults are overweight, 20 % are obese. The hereditary contribution to the variance of body weight is high. Nevertheless, molecular genetic studies have as yet explained only a small part of the inter-individual variability in the body mass index (BMI). Monogenic forms of obesity, in which loss of a single gene product leads to extreme obesity, are very infrequent. Variance of body weight is commonly explained by a complex interplay of many genetic variants (polygenic obesity). Each variant contributes only a small amount to the body weight. Currently, the largest published analysis of individuals of European origin identified 32 genetic variations (single nucleotide polymorphisms, SNPs) associated with BMI (obesity). Overall, these polygenic obesity variants only explain about 5 % of the variance of the BMI. In addition to the DNA variants epigenetic factors seem to also play a role in body weight regulation. These epigenetic marks can change in the course of life. They might provide an interface between genetic and environmental influences. It is conceivable that in future it will be possible to use epigenetic and genetic markers to detect a predisposition for obesity and to improve prevention and therapy. PMID- 25446313 TI - [Influenza, tetanus, and pertussis vaccination coverage among adults in Germany]. AB - In order to be adequately protected throughout life and to protect specific risk groups from particular diseases, regular booster or specific indicator vaccinations are also recommended during adulthood. Adults should be vaccinated against seasonal influenza (annually, e.g., persons with underlying chronic diseases and persons aged >= 60 years), tetanus (every 10 years), and pertussis (as a one-time vaccination with the next due tetanus vaccine and, e.g., when people have close contact to newborn babies). The aim of this study was to provide an overview of the current status of vaccination uptake among adults living in Germany, focusing on these three vaccines. In line with nationwide continuous health monitoring, the Robert Koch Institute conducted the representative study "German Health Update" (GEDA 2012) between 2012 and 2013. The survey is conducted regularly and adults are asked questions relating to their vaccination status through computer-assisted telephone interviews. Overall, 19,294 interviews were held. In 2010/2011 and 2011/2012, seasonal influenza uptake among persons aged >= 60 years was 54.3 and 52.6 % and among individuals with underlying chronic diseases 46.2 and 42.9 %. 7.6 and 75.6 % of participants reported up-to-date pertussis and tetanus vaccination, respectively. 22 % of people living with a baby in one household were vaccinated against pertussis. In general, vaccination rates against seasonal influenza, pertussis, and tetanus among adults are still low, but differ depending on the specific vaccination. The required aim of the European Commission to reach influenza vaccination coverage by the 2014/2015 winter season of 75 % of higher age groups has not yet been reached. The low pertussis vaccination coverage among persons in close household contact to infants poses a big challenge to the implementation of the cocooning strategy to protect the very vulnerable newborns. To emphasize the importance of a complete vaccination schedule and to increase vaccination uptake, tailored interventions should be provided for both physicians and adults. PMID- 25446314 TI - Genomics: The best-laid plans of mice and men. PMID- 25446317 TI - Molecular evolution: Decoupled transcription factor output? PMID- 25446315 TI - Spatially resolved transcriptomics and beyond. AB - Considerable progress in sequencing technologies makes it now possible to study the genomic and transcriptomic landscape of single cells. However, to better understand the complexity of multicellular organisms, we must devise ways to perform high-throughput measurements while preserving spatial information about the tissue context or subcellular localization of analysed nucleic acids. In this Innovation article, we summarize pioneering technologies that enable spatially resolved transcriptomics and discuss how these methods have the potential to extend beyond transcriptomics to encompass spatially resolved genomics, proteomics and possibly other omic disciplines. PMID- 25446318 TI - The pathophysiology of Fuchs' endothelial dystrophy--a review of molecular and cellular insights. AB - Fuchs' endothelial corneal dystrophy (FECD) is the most common corneal endothelial dystrophy and commonly results in loss of vision. This review highlights the advances in our understanding of the pathophysiology of FECD through in vivo confocal microscopy (IVCM) and in vitro studies. All layers of the cornea may be affected by FECD, either primarily or secondary to corneal oedema. The primary changes include reduction of endothelial cell density and changes to endothelial morphology. Thickening of Descemet's membrane occurs, with addition of collagenous layers and formation of guttae. Changes secondary to corneal oedema include formation of epithelial bullae and sub-epithelial fibroblast and collagen infiltration, reduction of sub-basal corneal nerve density, and reduced anterior keratocyte density and fibroblastic transformation of stressed keratocytes in the stroma. Many of the microstructural changes occurring in FECD may be observed with IVCM, and these observations correlate well with histological studies. IVCM studies of early and mid-stage FECD are likely to provide further insight into the sequence of pathological processes that occur in this disease. PMID- 25446316 TI - Single-cell and multivariate approaches in genetic perturbation screens. AB - Large-scale genetic perturbation screens are a classical approach in biology and have been crucial for many discoveries. New technologies can now provide unbiased quantification of multiple molecular and phenotypic changes across tens of thousands of individual cells from large numbers of perturbed cell populations simultaneously. In this Review, we describe how these developments have enabled the discovery of new principles of intracellular and intercellular organization, novel interpretations of genetic perturbation effects and the inference of novel functional genetic interactions. These advances now allow more accurate and comprehensive analyses of gene function in cells using genetic perturbation screens. PMID- 25446319 TI - Normalization of wound healing and stem cell marker patterns in organ-cultured human diabetic corneas by gene therapy of limbal cells. AB - Overexpression of c-met and suppression of matrix metalloproteinase-10 (MMP-10) and cathepsin F genes was previously shown to normalize wound healing, epithelial and stem cell marker patterns in organ-cultured human diabetic corneas. We now examined if gene therapy of limbal cells only would produce similar effects. Eight pairs of organ-cultured autopsy human diabetic corneas were used. One cornea of each pair was treated for 48 h with adenoviruses (Ad) harboring full length c-met mRNA or a mixture (combo) of Ad with c-met and shRNA to MMP-10 and cathepsin F genes. Medium was kept at the limbal level to avoid transduction of central corneal epithelium. Fellow corneas received control Ad with EGFP gene. After additional 5 (c-met) or 10 days (combo) incubation, central corneal epithelial debridement with n-heptanol was performed, and wound healing times were determined microscopically. Corneal cryostat sections were immunostained for diabetic and putative limbal stem cell markers, alpha3beta1 integrin, nidogen-1, fibronectin, laminin gamma3 chain, DeltaNp63alpha, keratins 14, 15, and 17, as well as for activated signaling intermediates, phosphorylated EGFR, Akt, and p38. Limbal c-met overexpression significantly accelerated healing of 8.5-mm epithelial wounds over EGFP controls (6.3 days vs. 9.5 days, p < 0.02). Combo treatment produced a similar result (6.75 days vs. 13.5 days, p < 0.03). Increased immunostaining vs. EGFP controls for most markers and signaling intermediates accompanied c-met gene or combo transduction. Gene therapy of limbal epithelial stem cell compartment has a beneficial effect on the diabetic corneal wound healing and on diabetic and stem cell marker expression, and shows potential for alleviating symptoms of diabetic keratopathy. PMID- 25446320 TI - Intravitreal controlled release of dexamethasone from engineered microparticles of porous silicon dioxide. AB - Dexamethasone is a glucocorticoid that is widely used in the ophthalmic arena. The recent FDA approved dexamethasone implant can provide a three month efficacy but with high rate of drug related cataract and high intraocular pressure (IOP). It seems that higher steroid in aqueous humor and around lens may be associated with these complications based on clinical fact that higher IOP was observed with intravitreal triamcinolone acetonide (TA) than with subtenon TA. We hypothesize that placing a sustained dexamethasone release system near back of the eye through a fine needle can maximize efficacy while mitigate higher rate of IOP rise and cataract. To develop a sustained intravitreal dexamethasone delivery system, porous silicon dioxide (pSiO2) microparticles were fabricated and functionalized with amines as well as carboxyl groups. Dexamethasone was conjugated to pSiO2 through the Steglich Esterification Reaction between hydroxyl of dexamethasone and carboxyl groups on the pSiO2. The drug loading was confirmed by Fourier transform infrared spectroscopy (FTIR) and loading efficiency was quantitated using thermogravimetric analysis (TGA). In vitro release was conducted for three months and dexamethasone was confirmed in the released samples using liquid chromatography-tandem mass spectrometry (LC/MS/MS). A pilot ocular safety and determination of vitreous drug level was performed in rabbit eyes. The drug loading study demonstrated that loading efficiency was from 5.96% to 10.77% depending on the loading reaction time, being higher with longer loading reaction time before reaching saturation around 7 days. In vitro drug release study revealed that dexamethasone release from pSiO2 particles was sustainable for over 90 days and was 80 days longer than free dexamethasone or infiltration-loaded pSiO2 particle formulation in the same setting. Pilot in vivo study demonstrated no sign of ocular adverse reaction in rabbit eyes following a single 3 mg intravitreal injection and free drug level at 2-week was 107.23 +/- 10.54 ng/mL that is well above the therapeutic level but only around 20% level of dexamethasone released from OZURDEX((r)) (dexamethasone intravitreal implant) in a rabbit eye model. In conclusion, dexamethasone is able to covalently load to the pSiO2 particles and provide sustained drug release for at least 3 months in vitro. Intravitreal injection of these particles were well tolerated in rabbit eyes and free drug level in vitreous at 2-week was well above the therapeutic level. PMID- 25446322 TI - Therapeutic efficacy of a novel non-peptide alphavbeta3 integrin antagonist for pathological retinal angiogenesis in mice. AB - alphavbeta3 integrin has been reported as a promising therapeutic target for angiogenesis. In the present study, we tested the antiangiogenic activity of 3-[3 (6-guanidino-1-oxoisoindolin-2-yl) propanamido]-3-(pyridin-3-yl) propanoic acid dihydrochloride (GOPPP), a novel non-peptide alphavbeta3 antagonist. Both human umbilical vein endothelial cells (HUVECs) and a mouse model of oxygen-induced retinopathy (OIR) were investigated separately. HUVEC adhesion, proliferation, migration, ERK1/2 and Akt phosphorylation were assessed. C57BL/6 mice were used for the studies in the OIR model. After exposure to 75% oxygen from postnatal day (PD) 7 to PD12, the mice were returned to room air, and GOPPP was intravitreally administered on PD12. Retinal neovascularization was evaluated on PD17. Hypoxia inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) protein levels and ERK1/2 phosphorylation were determined by Western blot analysis of retina proteins. GOPPP significantly inhibited the pro-angiogenic effects of vitronectin on HUVECs, including adhesion, proliferation, and migration, and inhibited ERK1/2 and Akt phosphorylation. Retinal neovascularization in the OIR model was significantly suppressed by intravitreal administration of 50 ng GOPPP. The pro-angiogenic factors HIF-1alpha and VEGF induced by hypoxia were significantly inhibited by GOPPP in OIR mice. GOPPP administration also inhibited ERK1/2 phosphorylation in the OIR model. These results indicate that GOPPP, a novel alphavbeta3 integrin antagonist, may have potential for the treatment of pathological retinal angiogenesis. PMID- 25446321 TI - Transcriptomic analysis across nasal, temporal, and macular regions of human neural retina and RPE/choroid by RNA-Seq. AB - Proper spatial differentiation of retinal cell types is necessary for normal human vision. Many retinal diseases, such as Best disease and male germ cell associated kinase (MAK)-associated retinitis pigmentosa, preferentially affect distinct topographic regions of the retina. While much is known about the distribution of cell types in the retina, the distribution of molecular components across the posterior pole of the eye has not been well-studied. To investigate regional difference in molecular composition of ocular tissues, we assessed differential gene expression across the temporal, macular, and nasal retina and retinal pigment epithelium (RPE)/choroid of human eyes using RNA-Seq. RNA from temporal, macular, and nasal retina and RPE/choroid from four human donor eyes was extracted, poly-A selected, fragmented, and sequenced as 100 bp read pairs. Digital read files were mapped to the human genome and analyzed for differential expression using the Tuxedo software suite. Retina and RPE/choroid samples were clearly distinguishable at the transcriptome level. Numerous transcription factors were differentially expressed between regions of the retina and RPE/choroid. Photoreceptor-specific genes were enriched in the peripheral samples, while ganglion cell and amacrine cell genes were enriched in the macula. Within the RPE/choroid, RPE-specific genes were upregulated at the periphery while endothelium associated genes were upregulated in the macula. Consistent with previous studies, BEST1 expression was lower in macular than extramacular regions. The MAK gene was expressed at lower levels in macula than in extramacular regions, but did not exhibit a significant difference between nasal and temporal retina. The regional molecular distinction is greatest between macula and periphery and decreases between different peripheral regions within a tissue. Datasets such as these can be used to prioritize candidate genes for possible involvement in retinal diseases with regional phenotypes. PMID- 25446324 TI - Fill and aspirate foam sclerotherapy (FAFS): a new approach for sclerotherapy of large superficial varicosities concomitant to endovenous laser ablation of truncal vein. AB - AIM: To define and assess the short-term clinical feasibility of fill and aspirate foam sclerotherapy (FAFS) for treating large superficial varicose veins concomitant to endovenous laser ablation (EVLA). MATERIALS AND METHODS: Twenty seven patients who refused to have phlebectomies with great saphenous vein reflux and large superficial varicosities were included in the study. Both EVLA and FAFS were performed concomitantly. FAFS is a technique in which all or most of the bubbles and blood-foam mixture are removed from the targeted large varicose veins immediately after the foam has caused sufficient damage to the endothelial cells. Patients were reviewed 1 month and 6 months after the treatment. Improvement in the clinical, aetiological, anatomical, and pathological classification (CEAP), and clinical severity was graded using the revised venous clinical severity score (rVCSS) and cosmetic results were investigated at the 6 month visit. RESULTS: Ablation of GSV was performed in 27 limbs in 27 patients (19 males, 70.3%; mean age 44 years; range 21-69 years). All patients had a technically successful FAFS treatment. The CEAP classification score, the rVCSS values, and the cosmetic results showed prominent improvement 6 months after the treatment. There were no significant complications, such as stroke, skin burns, necrosis, paresthesia, deep-vein thrombosis, or allergic reaction. None of the patients experienced neurological events. CONCLUSION: FAFS is a promising safe and effective technique for treating large superficial varicosities concomitant to EVLA of the truncal veins with excellent clinical results. Randomized prospective studies with larger series are required to compare the FAFS with ambulatory phlebectomy and standard foam sclerotherapy. PMID- 25446323 TI - Effects of mTOR inhibition on normal retinal vascular development in the mouse. AB - We aimed to determine the role of age-related changes in the mammalian target of rapamycin (mTOR) activity in endothelial cell growth during retinal vascular development in mice. Mice were administered the mTOR inhibitor rapamycin as follows: (i) for 6 days from postnatal day 0 (P0) to P5, (ii) for 2 days on P6 and P7, and (iii) for 2 days on P12 and P13. For comparison, we examined the effects of KRN633, an inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinase, on retinal vascular development. The retinal vasculature and phosphorylated ribosomal protein S6 (pS6), a downstream indicator of mTOR activity, were evaluated using immunohistochemistry. Vascularization was delayed and capillary density was reduced in mice administered rapamycin from P0 to P5 compared to the vehicle-treated mice. Rapamycin administration on P6 and P7 decreased the vascular density but did not significantly delay the radial vascular growth. Rapamycin administration on P12 and P13 did not significantly affect the retinal superficial blood vessels. Immunoreactivity for pS6 was detected in both endothelial cells in the vascular front and non-vascular cells in the retinal parenchyma, and rapamycin markedly diminished the pS6 immunoreactivity. KRN633 administration on P0 and P1 completely inhibited retinal vascularization. The effects of KRN633 on retinal blood vessels decreased in magnitude in an age-dependent manner. These results suggest that the mTOR pathway in endothelial cells activated by VEGF contributes to physiologic vascular development, and that the mTOR pathway in endothelial cells is modulated in a postnatal age-dependent manner. PMID- 25446325 TI - Osteoradionecrosis of the mandible: through a radiologist's eyes. AB - Head and neck malignancies constitute a major cause of morbidity and mortality all over the world. Radiotherapy plays a pivotal role in the management of these tumours; however, it has associated complications, with mandibular osteoradionecrosis (ORN) being one of the gravest orofacial complications. Early diagnosis, extent evaluation, and detection of complications of ORN are imperative for instituting an appropriate management protocol. ORN can closely mimic tumour recurrence, the differentiation of which has obvious clinical implications. The purpose of the present review is to acquaint the radiologist with the imaging features of mandibular ORN and the ways to differentiate ORN from tumour recurrence. PMID- 25446326 TI - Optimizing CT angiography in patients with Fontan physiology: single-center experience of dual-site power injection. AB - AIM: To identify adult patients with single-ventricle congenital heart disease and Fontan procedure palliation who have been misdiagnosed with or incompletely evaluated for pulmonary embolism. Additionally, this study was designed to demonstrate that simultaneous, dual-injection of contrast medium into an upper and lower extremity vein is superior to single-injection protocols for CT angiography (CTA) of the chest in this population. MATERIALS AND METHODS: Patients included in the study were retrospectively selected from the Adult Congenital Heart Disease (ACHD) database. Search criteria included history of Fontan palliation and available chest CT examination. Patients were evaluated for (1) type of congenital heart disease and prior operations;(2) indication for initial CT evaluation;(3) route of contrast medium administration for the initial CT examination and resulting diagnosis;(4) whether or not anticoagulation therapy was initiated; and (5) final diagnosis and treatment plan.Results: The query of the ACHD database resulted in 28 individuals or patients with Fontan palliation (superior and inferior venae cavae anastomosed to the pulmonary arteries). Of these, 19 patients with Fontan physiology underwent CTA of the pulmonary circulation, and 17 had suboptimal imaging studies. Unfortunately, seven of these 17 patients (41%) were started on anticoagulation therapy due to a diagnosis of pulmonary embolism that was later excluded. CONCLUSION: Patients with single ventricle/Fontan physiology are at risk of thromboembolic disease. Therefore, studies evaluating their complex anatomy must be performed with the optimal imaging protocol to ensure diagnostic accuracy, which is best achieved with dual injection of an upper and lower extremity central vein. PMID- 25446327 TI - Graphene quantum dots induce apoptosis, autophagy, and inflammatory response via p38 mitogen-activated protein kinase and nuclear factor-kappaB mediated signaling pathways in activated THP-1 macrophages. AB - The biomedical application of graphene quantum dots (GQDs) is a new emerging area. However, their safety data are still in scarcity to date. Particularly, the effect of GQDs on the immune system remains unknown. This study aimed to elucidate the interaction of GQDs with macrophages and the underlying mechanisms. Our results showed that GQDs slightly affected the cell viability and membrane integrity of macrophages, whereas GQDs significantly increased reactive oxygen species (ROS) generation and apoptotic and autophagic cell death with an increase in the expression level of Bax, Bad, caspase 3, caspase 9, beclin 1, and LC3-I/II and a decrease in that of Bcl-2. Furthermore, low concentrations of GQDs significantly increased the expression of tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta), IL-8, whereas high concentrations of GQDs elicited opposite effects on the cytokines production. SB202190, a selective inhibitor of p38 mitogen-activated protein kinase (MAPK), abolished the cytokine inducing effect of GQDs in macrophages. Moreover, GQDs significantly increased the phosphorylation of p38 MAPK and p65, and promoted the nuclear translocation of nuclear factor-kappaB (NF-kappaB). Taken together, these results show that GQDs induce ROS generation, apoptosis, autophagy, and inflammatory response via p38MAPK and NF-kappaB mediated signaling pathways in THP-1 activated macrophages. PMID- 25446328 TI - Cross matching observations on toxicological and clinical data for the assessment of tolerability and safety of Ginkgo biloba leaf extract. AB - Ginkgo biloba is one of the most widely used herbal remedies in Europe and the US. It may be purchased in different types of formulations, but most of the clinical studies have been performed with the controlled G. biloba extract EGb761((r)). Indications include Alzheimers disease, cardiovascular disease, dementia, memory loss, and cerebral ischemia. The pharmacological modes of action cover antioxidant effects, radical scavenging, inhibition of platelet activating factor, alterations in membrane fluidity (signal transduction), and inhibition of glucocorticoid synthesis. Due to the widespread and long-term use of G. biloba - about a million doses of EGb761((r)) are sold per day - tolerability and safety are a crucial issue. Based on broad and long-term clinical use of G. biloba extracts, it is regarded as well tolerated in man. Cross matching, a tool we introduced, combines different fields of knowledge and types of data to a consolidated result. In this article, we combine toxicological and clinical data and utilize other sources of information to assess tolerability and safety of G. biloba. It is well known that because of biological differences between animals and man or even between animal species, animal experiments do not necessarily mimic the effects in humans. Therefore, for adequate risk assessment, the relevance of non-clinical toxicological findings should be correlated with human data. The cross matching of toxicological data and results from clinical studies is possible because many toxicological and clinical studies are available on G. biloba. We give an in depth analysis of the modes of action in animals and describe toxicological studies with regard to metabolism, pharmacokinetics, genotoxicity, as well as carcinogenicity (e.g., the Technical Report TR 578 of the US National Toxicology Program). In addition, 75 clinical trials with high methodological quality are summarized. They included a total of 7115 patients treated with G. biloba. Based on this extensive amount of information, the broad variety of investigations, and their accordance we conclude that G. biloba extract is well tolerated and safe for humans. PMID- 25446329 TI - Acute cadmium administration to rats exerts both immunosuppressive and proinflammatory effects in spleen. AB - Conflicting data (both suppression and augmentation as well as lack of the effect) exist in respect to cadmium (Cd) and splenic T cell-based immune cell activity. Spleen is also the site of innate immune responses but impact of Cd on this type of immunity has been less explored. In the present study the effects of acute Cd administration on basic aspects of both T cell-based and innate immune spleen cell activity were examined in rats. Intraperitoneal injection of 1mg of Cd/kg resulted in decrease in concanavalin A (ConA) induced proliferation which seems to be more related to altered spleen cells responsiveness to IL-2 than to apoptosis. Differential effects on proinflammatory T cell derived cytokines were observed (decreases of IFN-gamma gene expression and ConA-stimulated production, but increases in IL-17 mRNA levels with no effect on concentrations of protein product). Reduction of IFN-gamma production seemed not to rely on IL-4 and IL-10, but at least partly on nitric oxide (NO). Increased activity relevant for innate immunity (granulocyte and CD11b(+) cell accumulation in the spleen, inducible nitric oxide synthase/iNOS expression and NO production by spleen cells) was observed, but there was a decrease in respiratory burst (dihydrorhodamine/DHR oxidation and nitroblue tetrazolium/NBT reduction). Increases of TNF-alpha and IL 1beta gene expression and IL-1beta protein product were noted as well. Administration of 0.5mg Cd/kg resulted in less pronounced (ConA-induced proliferation) or lack of the effect (IFN-gamma production) on spleen T cell activities and on innate activities (granulocyte accumulation, NO production) as well. However, increases of spleen cell respiratory burst activity and IL-1beta production were observed. Effects of lower cadmium doses (5ppm and 50ppm) on several aspects of spleen cell immune activity were observed in intermediate period of exposure (30 days, oral intake) as well. Differential effects of Cd on immune activities of spleen cells might contribute to our understanding of the complexity of immunomodulatory effects of this metal. PMID- 25446330 TI - Maternal rat serum concentrations of dimethadione do not explain intra-litter differences in the incidence of dimethadione-induced birth defects, including novel findings in foetal lung. AB - To investigate mechanisms of chemical-induced congenital heart defects (CHD) we have developed a rat model using dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant, trimethadione (TMD). Dosing pregnant rats with 300mg/kg DMO every 12h from the evening of gestational day (GD) 8 until the morning of GD 11 (six total doses) produces a mean 74% incidence of CHD with inter litter variability ranging from 40 to 100%. The goal of this study was to determine if the variability in maternal serum concentrations of DMO on GD 14, a surrogate marker for total exposure, was related to the inter-litter differences in teratogenic outcomes. To test this hypothesis, pregnant rats were dosed as described above and serum levels of DMO assessed on GD 14. On GD 21, foetuses were collected by caesarean section, assessed for a number endpoints and the outcomes were correlated with the GD 14 serum concentrations of DMO. DMO exposure was associated with decreased foetal body weight, increased incidence of sternal defects and CHD, but these endpoints were not meaningfully correlated with maternal concentrations of DMO. Novel findings were decreased viability as measured one-hour following caesarean section, and delayed alveolar maturation. The major conclusions from these studies were first, that serum DMO concentrations on GD 14 did not predict teratogenicity, and second, delayed lung development may contribute to the decreased survival of foetuses at the time of caesarean section. PMID- 25446331 TI - Time-dependence in mixture toxicity prediction. AB - The value of time-dependent toxicity (TDT) data in predicting mixture toxicity was examined. Single chemical (A and B) and mixture (A+B) toxicity tests using Microtox((r)) were conducted with inhibition of bioluminescence (Vibrio fischeri) being quantified after 15, 30 and 45-min of exposure. Single chemical and mixture tests for 25 sham (A1:A2) and 125 true (A:B) combinations had a minimum of seven duplicated concentrations with a duplicated control treatment for each test. Concentration/response (x/y) data were fitted to sigmoid curves using the five parameter logistic minus one parameter (5PL-1P) function, from which slope, EC25, EC50, EC75, asymmetry, maximum effect, and r(2) values were obtained for each chemical and mixture at each exposure duration. Toxicity data were used to calculate percentage-based TDT values for each individual chemical and mixture of each combination. Predicted TDT values for each mixture were calculated by averaging the TDT values of the individual components and regressed against the observed TDT values obtained in testing, resulting in strong correlations for both sham (r(2)=0.989, n=25) and true mixtures (r(2)=0.944, n=125). Additionally, regression analyses confirmed that observed mixture TDT values calculated for the 50% effect level were somewhat better correlated with predicted mixture TDT values than at the 25 and 75% effect levels. Single chemical and mixture TDT values were classified into five levels in order to discern trends. The results suggested that the ability to predict mixture TDT by averaging the TDT of the single agents was modestly reduced when one agent of the combination had a positive TDT value and the other had a minimal or negative TDT value. PMID- 25446332 TI - Release of titanium ions from an implant surface and their effect on cytokine production related to alveolar bone resorption. AB - Although interest in peri-implant mucositis and peri-implantitis has recently been increasing, the mechanisms driving these diseases remain unknown. Here, the effects of titanium ions on the inflammation and bone resorption around an implant were investigated. First, the accumulated amount of Ti ions released into gingival and bone tissues from an implant exposed to sodium fluoride solution was measured using inductively coupled plasma mass spectrometry. Next, the cellular responses in gingival and bone tissues to Ti ions and/or Porphyromonas gingivalis lipopolysaccharide (P. gingivalis-LPS) were assessed using a rat model. More Ti ions were detected in the gingival tissues around an implant after treatment with sodium fluoride (pH 4.2) than in its absence, which suggests that the fluoride corroded the implant surface under salivary buffering capacity. The injection of Ti ions (9ppm) significantly increased the mRNA expression and protein accumulation of chemokine (C-C motif) ligand 2, as well as the ratio of receptor activator of nuclear factor-kappaB ligand to osteoprotegerin, in rat gingival tissues exposed to P. gingivalis-LPS in a synergistic manner. In addition, the enhanced localization of toll-like receptor 4, which is an LPS receptor, was observed in gingival epithelium loaded with Ti ions (9ppm). These data suggest that Ti ions may be partly responsible for the infiltration of monocytes and osteoclast differentiation by increasing the sensitivity of gingival epithelial cells to microorganisms in the oral cavity. Therefore, Ti ions may be involved in the deteriorating effects of peri-implant mucositis, which can develop into peri implantitis accompanied by alveolar bone resorption. PMID- 25446333 TI - Inhibitory effects of Pycnogenol(r) on hepatitis C virus replication. AB - Chronic hepatitis C virus (HCV) infection increases the risk of liver cirrhosis and hepatocellular carcinoma. In the last decade, the current standard HCV treatment, pegylated interferon and ribavirin, have limited efficacy and significant side effects. Novel direct acting antivirals show promise, but escape mutants are expected, along with potential side effects. Pycnogenol(r), a French maritime pine extract, has been reported to have antioxidant and antiviral effects. Here, we evaluated the effect of Pycnogenol(r) on HCV replication. Wild type and protease inhibitor (VX-950; telaprevir)-resistant HCV replicon cells were treated with Pycnogenol(r), Pycnogenol(r) and interferon-alpha, and ribavirin and telaprevir. Pycnogenol(r) effects on replication were also evaluated in HCV-infected chimeric mice. Pycnogenol(r) treatment showed antiviral effects without cytotoxicity at doses up to 50 MUg/mL. Pycnogenol(r) in combination with interferon-alpha or ribavirin showed synergistic effects. Moreover, Pycnogenol(r) inhibited HCV replication in telaprevir-resistant replicon cells; telaprevir and Pycnogenol(r) acted additively to reduce HCV RNA levels in wild-type HCV replicon cells without significantly increasing cytotoxicity. Pycnogenol(r) antiviral activity was higher than its components procyanidin and taxifolin. Further, treatment of infected chimeric mice with Pycnogenol(r) suppressed HCV replication and showed a synergistic effect with interferon-alpha. In addition, Pycnogenol(r) treatment resulted in dose-dependent reduction of reactive oxygen species in HCV replicon cell lines. Pycnogenol(r) is a natural product that may be used to improve the efficacy of the current standard antiviral agents and even to eliminate resistant HCV mutants. PMID- 25446334 TI - The green tea catechin, epigallocatechin gallate inhibits chikungunya virus infection. AB - Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes chikungunya fever and has infected millions of people mainly in developing countries. The associated disease is characterized by rash, high fever and severe arthritis that can persist for years. CHIKV has adapted to Aedes albopictus, which also inhabits temperate regions, including Europe and the United States of America and might cause new, large outbreaks there. No treatment or licensed CHIKV vaccine exists. Epigallocatechin-3-gallate (EGCG), the major component of green tea, has, among other beneficial properties, antiviral activities. Therefore, we examined if EGCG has antiviral activity against CHIKV. EGCG inhibited CHIKV infection in vitro, blocked entry of CHIKV Env-pseudotyped lentiviral vectors and inhibited CHIKV attachment to target cells. Thus EGCG might be used as a lead structure to develop more effective antiviral drugs. PMID- 25446335 TI - Synthesis and antiviral activity of PB1 component of the influenza A RNA polymerase peptide fragments. AB - This study is devoted to the antiviral activity of peptide fragments from the PB1 protein - a component of the influenza A RNA polymerase. The antiviral activity of the peptides synthesized was studied in MDCK cell cultures against the pandemic influenza strain A/California/07/2009 (H1N1) pdm09. We found that peptide fragments 6-13, 6-14, 26-30, 395-400, and 531-540 of the PB1 protein were capable of suppressing viral replication in cell culture. Terminal modifications i.e. N-acetylation and C-amidation increased the antiviral properties of the peptides significantly. Peptide PB1 (6-14) with both termini modified showed maximum antiviral activity, its inhibitory activity manifesting itself during the early stages of viral replication. It was also shown that the fluorescent-labeled analog of this peptide was able to penetrate into the cell. The broad range of virus-inhibiting activity of PB1 (6-14) peptide was confirmed using a panel of influenza A viruses of H1, H3 and H5 subtypes including those resistant to oseltamivir, the leading drug in anti-influenza therapy. Thus, short peptide fragments of the PB1 protein could serve as leads for future development of influenza prevention and/or treatment agents. PMID- 25446336 TI - Antiviral effect of cidofovir on parvovirus B19 replication. AB - Parvovirus B19 (B19V) is a human ssDNA virus responsible for a wide range of clinical manifestations, still lacking for a specific antiviral therapy. The identification of compounds active against B19V may add therapeutic options to the treatment of B19V infections, that now entirely relies on symptomatic treatments. In the search for compounds possibly inhibiting B19V replication, a particular focus was raised to cidofovir, an acyclic nucleoside phosphonate broadly active against dsDNA viruses. The present study was aimed at evaluating the effect of cidofovir against B19V in two model systems, the UT7/EpoS1 cell line and erythroid progenitor cells (EPC), generated from peripheral blood mononuclear cells. Experiments were carried out at different multiplicity of infections and cidofovir concentrations (0-500 MUM) during a course of infection. The effects of cidofovir on B19V replication were assessed by qPCR assays while influence of cidofovir on host cells was measured by cell proliferation and viability assays. Our findings demonstrated that cidofovir has a relevant inhibiting activity on B19V replication within infected UT7/EpoS1, and that the effect on B19V DNA amounts is dose-dependent allowing for the determination of EC50 and EC90 values (7.45-41.27 MUM, and 84.73-360.7 MUM, respectively). In EPCs, that constitute a cellular population close to the natural target cells in bone marrow, the inhibitory effect was demonstrated to a lesser extent, however provoking a significant reduction on B19V DNA amounts at 500 MUM (68.2-92.8%). To test infectivity of virus released from EPCs cultured in the presence of cidofovir, cell culture supernatants were used as inoculum for a further course of infection in UT7/EpoS1 cells, indicating a significant reduction in viral infectivity at 500 MUM cidofovir. Since the drug did not interfere with the overall cellular DNA synthesis and metabolic activity, the observed effect of cidofovir could be likely related to a specific inhibition of B19V replication. PMID- 25446337 TI - Everolimus-based immunosuppressive regimens in lung transplant recipients: impact on CMV infection. AB - Cytomegalovirus (CMV) is one of the most important viral pathogen in solid organ transplant (SOT) recipients, with heart and lung transplant patients being at considerably high risk for CMV direct and indirect effects. Prevention strategies have resulted in significant reduction in disease and CMV related morbidity and mortality. Few studies reported a lower incidence of CMV infections in solid organ transplant recipients treated with immunosuppressive protocols including the mTOR inhibitor everolimus (EVR). PURPOSE: The aim of the current study was to evaluate the impact of EVR-based immunosuppressive regimens on the occurrence and kinetics of CMV infection in a population of lung transplant recipients, at both systemic and pulmonary level. Thirty-two lung transplants (LT) were investigated; eighteen were on EVR-based immunosuppressive regimens. CMV events occurring in the first two years post-transplantation at both systemic and pulmonary levels were reported. PRINCIPAL RESULTS: No differences were reported in CMV viraemia occurrence at both one- and two-year follow up between patients undergoing EVR based and EVR-free immunosuppressive regimens. Considering CMV episodes at pulmonary levels, as determined by routinely performed broncho-alveolar lavages (BALs), during EVR-administration the patients experienced significantly fewer episodes of high-load CMV (as defined by viral loads?10(5) copies/mL) than during EVR-free immunosuppressive regimens. MAJOR CONCLUSION: EVR-based immunosuppressive regimens in lung transplantation settings appear to be associated to lower incidence of clinically relevant CMV episodes at pulmonary levels, striking the possibility of extending the use of EVR to such a group of transplant recipients. PMID- 25446338 TI - Interferon lambda-3 is not associated with clinical outcome in patients with HCV induced compensated cirrhosis: a long-term cohort study. AB - BACKGROUND: Interferon Lambda-3 (IFN-lambda3) gene polymorphism is associated with spontaneous clearance of hepatitis C virus (HCV) and response to IFN-based therapy (IFN). However, very few data are available about its value in predicting sustained virologic response (SVR) in patients with cirrhosis, and whether IFN lambda3 genotype influences liver disease progression remains unclear. METHODS: We determined IFN-lambda3 genotype by PCR in a cohort of patients with compensated HCV-related cirrhosis, enrolled between 1989 and 1992. Person-years follow-up was calculated for each individual from the date of enrolment to the development of first episode of decompensation, HCC, liver transplant, death or end of follow-up. The follow-up of patients who achieved SVR was censored at the time of IFN initiation. Kaplan-Meier curves and Cox regression analyses were used to assess the association between IFN-lambda3 genotype and clinical outcome. RESULTS: IFN-lambda3 was determined in 264 patients (52% males, mean age 57+/-8 years, 67% HCV genotype (G)1, while CC, CT and TT genotypes were 36%, 50% and 14%, respectively. During a median follow-up of 14.8 years, 149 (56%) patients received IFN. Overall, SVR was achieved in 31 (21%) patients, 40% among those with CC genotype (22% in G1 and 61% in G2, respectively) compared to 10% and 13% among patients with CT and TT genotypes (p<0.0001). Univariate and multivariate analyses found no association between IFN-lambda3 (CC vs. non-CC genotype) and disease progression. CONCLUSION: IFN-lambda3 determination is fundamental for allocating cirrhotic patients to be treated with IFN, while it has no value in predicting the outcome of the disease. PMID- 25446339 TI - Nanotech-derived topical microbicides for HIV prevention: the road to clinical development. AB - More than three decades since its discovery, HIV infection remains one of the most aggressive epidemics worldwide, with more than 35 million people infected. In sub-Saharan Africa, heterosexual transmissions represent nearly 80% of new infections, with 50% of these occurring in women. In an effort to stop the dramatic spread of the HIV epidemic, new preventive treatments, such as microbicides, have been developed. Nanotechnology has revolutionized this field by designing and engineering novel highly effective nano-sized materials as microbicide candidates. This review illustrates the most recent advances in nanotech-derived HIV prevention strategies, as well as the main steps required to translate promising in vitro results into clinical trials. PMID- 25446340 TI - Baicalin inhibits autophagy induced by influenza A virus H3N2. AB - Baicalin, a natural product isolated from Scutellariaradix, has been reported to have significant in vivo and in vitro anti-influenza virus activity, but the underlying mechanism remains poorly understood. In this study, we found that baicalin inhibited autophagy induced by influenza virus A3/Beijing/30/95 (H3N2) in both A549 and Ana-1 cells. The results showed that H3N2 induced autophagy by suppressing mTOR signaling pathway, which however could be significantly inhibited by baicalin. Baicalin could suppress the expression of Atg5-Atg12 complex and LC3-II, and attenuate autophagy induced by starvation. Thus, the inhibition of autophagy induced by virus may account for the antiviral activities of baicalin against H3N2. Autophagy may be a potential marker in developing novel anti-influenza drugs. PMID- 25446341 TI - Freezing of gait subtypes have different cognitive correlates in Parkinson's disease. AB - BACKGROUND: Freezing of gait (FOG) is a major concern for Parkinson's disease (PD) patients because it is a leading cause of falls and is associated with poor quality of life. The pathophysiology is unknown but it is hypothesized that it relates to cognitive abnormalities; particularly executive and visuospatial dysfunction. However, prior results have been discrepant. Pharmacologic subtypes of FOG include those that are responsive and unresponsive to levodopa. OBJECTIVE: To determine whether executive and visuospatial dysfunction are associated specifically with the levodopa unresponsive subtype of FOG. METHODS: 135 PD subjects completed a single assessment included FOG questionnaire, UPDRS motor scale, comprehensive cognitive battery and measure of hallucinations. Analyses compared unresponsive (n = 16), responsive (n = 20) and no FOG (n = 99) subtypes. RESULTS: The unresponsive subtype had a significantly older age of onset of PD than the responsive group (p = .03) and had worse motor scores (p = .003) than the no FOG group. Longer disease duration was associated with the responsive group compared to the no FOG group (p = .002). The unresponsive FOG group had significantly poorer visuospatial ability (p = .001) and executive functioning (p = .02) than both the no and responsive FOG subgroups. These latter groups were not significantly different. The responsive FOG group was associated with the presence of hallucinations. CONCLUSION: Aside from pharmacological differences, unresponsive FOG is associated with executive and visuospatial dysfunction implicating frontostriatal pathways while responsive FOG is associated with hallucinations suggesting involvement of posterior cortical regions. Further study and treatment of FOG should include appropriate subtype classification. PMID- 25446342 TI - Comparison of sleep and other non-motor symptoms between SWEDDs patients and de novo Parkinson's disease patients. AB - BACKGROUND: SWEDDs (Scans Without Evidence of Dopaminergic Deficits) was defined from a series of pharmaceutical trials on Parkinson's disease (PD). Non-motor features including sleep-related problems are common even in early-stage PD patients; however, little is known about the burden of the non-motor symptoms in SWEDDs patients. METHODS: The Non-motor Symptoms Assessment Scale (NMSS), revised version of the Parkinson's Disease Sleep Scale (PDSS-2), Epworth Sleepiness Scale (ESS), and EuroQol 5-Dimension (EQ-5D) were applied to evaluate 17 SWEDDs patients and 28 de novo PD patients. The presence of clinically probable rapid eye movement sleep behavior disorder (cpRBD) was assessed using the International Classification of Sleep Disorders-Revised (ICSD-R) criteria. RESULTS: The total NMSS score for the SWEDDs group was significantly lower than for the de novo PD group (p = 0.032). The most distinct difference was in taste or smell change (p < 0.000). Prevalence of cpRBD was higher in de novo PD patients than in SWEDDs patients (p = 0.030), though no significant differences in the PDSS-2 total score (p = 0.496) or the ESS score (p = 0.517) were found. The SWEDDs patients did not significantly differ from the de novo PD patients with regard to quality of life, as measured by the EQ-5D index score (p = 0.177). CONCLUSIONS: The patients with SWEDDs have less non-motor problems than newly diagnosed untreated PD patients. Given the difficulty distinguishing between SWEDDs and early PD, identifying some of non-motor symptoms, such as RBD or olfactory impairment, could aid clinicians in their work. PMID- 25446344 TI - Cardiovascular and behavioral effects produced by administration of liposome entrapped GABA into the rat central nervous system. AB - Liposomes are nanosystems that allow a sustained release of entrapped substances. Gamma-aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter of the central nervous system (CNS). We developed a liposomal formulation of GABA for application in long-term CNS functional studies. Two days after liposome entrapped GABA was injected intracerebroventricularly (ICV), Wistar rats were submitted to the following evaluations: (1) changes in mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) to ICV injection of bicuculline methiodide (BMI) in anesthetized rats; (2) changes in cardiovascular reactivity to air jet stress in conscious rats; and (3) anxiety like behavior in conscious rats. GABA and saline-containing pegylated liposomes were prepared with a mean diameter of 200 nm. Rats with implanted cannulas targeted to lateral cerebral ventricle (n = 5-8/group) received either GABA solution (GS), empty liposomes (EL) or GABA-containing liposomes (GL). Following (48 h) central microinjection (2 MUL, 0.09 M and 99 g/L) of liposomes, animals were submitted to the different protocols. Animals that received GL demonstrated attenuated response of RSNA to BMI microinjection (GS 48 +/- 9, EL 43 +/- 9, GL 11 +/- 8%; P < 0.05), blunted tachycardia in the stress trial (DeltaHR: GS 115 +/ 14, EL 117 +/- 10, GL 74 +/- 9 bpm; P<0.05) and spent more time in the open arms of elevated plus maze (EL 6 +/- 2 vs. GL 18 +/- 5%; P = 0.028) compared with GS and EL groups. These results indicate that liposome-entrapped GABA can be a potential tool for exploring the chronic effects of GABA in specific regions and pathways of the central nervous system. PMID- 25446343 TI - Spinal astrocyte gap junction and glutamate transporter expression contributes to a rat model of bortezomib-induced peripheral neuropathy. AB - There is increasing evidence implicating astrocytes in multiple forms of chronic pain, as well as in the specific context of chemotherapy-induced peripheral neuropathy (CIPN). However, it is still unclear what the exact role of astrocytes may be in the context of CIPN. Findings in oxaliplatin and paclitaxel models have displayed altered expression of astrocytic gap junctions and glutamate transporters as means by which astrocytes may contribute to observed behavioral changes. The current study investigated whether these changes were also generalizable to the bortezomib CIPN. Changes in mechanical sensitivity were verified in bortezomib-treated animals, and these changes were prevented by co treatment with a glial activation inhibitor (minocycline), a gap junction decoupler (carbenoxolone), and by a glutamate transporter upregulator (ceftriaxone). Immunohistochemistry data at day 30 in bortezomib-treated animals showed increases in expression of glial fibrillary acidic protein (GFAP) and connexin 43 but a decrease in GLAST expression. These changes were prevented by co-treatment with minocycline. Follow-up Western blotting data showed a shift in connexin 43 from a non-phosphorylated state to a phosphorylated state, indicating increased trafficking of expressed connexin 43 to the cell membrane. These data suggest that increases in behavioral sensitivity to cutaneous stimuli may be tied to persistent synaptic glutamate resulting from increased calcium flow between spinal astrocytes. PMID- 25446345 TI - Effects of thyroxine treatment on histology and behavior using the methimazole model of congenital hypothyroidism in the rat. AB - The timing of thyroxine (T4) replacement treatment in congenital hypothyroidism (CH) has been suggested to be important for optimizing cognitive recovery in humans; however this has not been fully established using modern animal models of CH. Consequently, the current studies investigated the ameliorating effects of postnatal T4 treatment on neuropathology and behavior in CH rats. Rat dams were administered methimazole to produce CH offspring, then brain tissue from male CH pups was analyzed to determine the effects of postnatal (P3, P7, P14 and P21) T4 treatment on hippocampal dendritic branching and the expression of nerve growth factor (NGF). Two operant behavioral procedures were employed to confirm and extend previous findings obtained using this model, and to investigate timelines for instigating T4 treatment on improved behavioral outcomes. T4 treatment initiated at P14 was protective of a reduction in dendritic branching in the hippocampus, and initiated at P7 was protective of a reduction of NGF expression in the fimbria of the hippocampus. Induction of CH did not affect the acquisition of simple operant response rules but had a significant effect on the acquisition of complex operant rules subsequently imposed. Furthermore, T4 treatment initiated at P3 protected learning deficits seen following the imposition of complex operant response rules. These findings indicate T4 treatment initiated at P7 is sufficient for the protection of hippocampal NGF expression and dendritic branching but for the protection of complex behavioral abilities T4 treatment is necessary prior to or approximating P3. PMID- 25446346 TI - Prenatal protein malnutrition decreases KCNJ3 and 2DG activity in rat prefrontal cortex. AB - Prenatal protein malnutrition (PPM) in rats causes enduring changes in brain and behavior including increased cognitive rigidity and decreased inhibitory control. A preliminary gene microarray screen of PPM rat prefrontal cortex (PFC) identified alterations in KCNJ3 (GIRK1/Kir3.1), a gene important for regulating neuronal excitability. Follow-up with polymerase chain reaction and Western blot showed decreased KCNJ3 expression in the PFC, but not hippocampus or brainstem. To verify localization of the effect to the PFC, baseline regional brain activity was assessed with (14)C-2-deoxyglucose. Results showed decreased activation in the PFC but not hippocampus. Together these findings point to the unique vulnerability of the PFC to the nutritional insult during early brain development, with enduring effects in adulthood on KCNJ3 expression and baseline metabolic activity. PMID- 25446347 TI - Cannabinoid receptor agonists reduce the short-term mitochondrial dysfunction and oxidative stress linked to excitotoxicity in the rat brain. AB - The endocannabinoid system (ECS) is involved in a considerable number of physiological processes in the Central Nervous System. Recently, a modulatory role of cannabinoid receptors (CBr) and CBr agonists on the reduction of the N methyl-d-aspartate receptor (NMDAr) activation has been demonstrated. Quinolinic acid (QUIN), an endogenous analog of glutamate and excitotoxic metabolite produced in the kynurenine pathway (KP), selectively activates NMDAr and has been shown to participate in different neurodegenerative disorders. Since the early pattern of toxicity exerted by this metabolite is relevant to explain the extent of damage that it can produce in the brain, in this work we investigated the effects of the synthetic CBr agonist WIN 55,212-2 (WIN) and other agonists (anandamide or AEA, and CP 55,940 or CP) on early markers of QUIN-induced toxicity in rat striatal cultured cells and rat brain synaptosomes. WIN, AEA and CP exerted protective effects on the QUIN-induced loss of cell viability. WIN also preserved the immunofluorescent signals for neurons and CBr labeling that were decreased by QUIN. The QUIN-induced early mitochondrial dysfunction, lipid peroxidation and reactive oxygen species (ROS) formation were also partially or completely prevented by WIN pretreatment, but not when this CBr agonist was added simultaneously with QUIN to brain synaptosomes. These findings support a neuroprotective and modulatory role of cannabinoids in the early toxic events elicited by agents inducing excitotoxic processes. PMID- 25446348 TI - The volatile anesthetic methoxyflurane protects motoneurons against excitotoxicity in an in vitro model of rat spinal cord injury. AB - Neuroprotection of the spinal cord during the early phase of injury is an important goal to determine a favorable outcome by prevention of delayed pathological events, including excitotoxicity, which otherwise extend the primary damage and amplify the often irreversible loss of motor function. While intensive care and neurosurgical intervention are important treatments, effective neuroprotection requires further experimental studies focused to target vulnerable neurons, particularly motoneurons. The present investigation examined whether the volatile general anesthetic methoxyflurane might protect spinal locomotor networks from kainate-evoked excitotoxicity using an in vitro rat spinal cord preparation as a model. The protocols involved 1h excitotoxic stimulation on day 1 followed by electrophysiological and immunohistochemical testing on day 2. A single administration of methoxyflurane applied together with kainate (1h), or 30 or even 60 min later prevented any depression of spinal reflexes, loss of motoneuron excitability, and histological damage. Methoxyflurane per se temporarily decreased synaptic transmission and motoneuron excitability, effects readily reversible on washout. Spinal locomotor activity recorded as alternating electrical discharges from lumbar motor pools was fully preserved on the second day after application of methoxyflurane together with (or after) kainate. These data suggest that a volatile general anesthetic could provide strong electrophysiological and histological neuroprotection that enabled expression of locomotor network activity 1 day after the excitotoxic challenge. It is hypothesized that the benefits of early neurosurgery for acute spinal cord injury (SCI) might be enhanced if, in addition to injury decompression and stabilization, the protective role of general anesthesia is exploited. PMID- 25446349 TI - Performance monitoring and behavioral adaptation during task switching: an fMRI study. AB - Despite significant advances, the neural correlates and neurochemical mechanisms involved in performance monitoring and behavioral adaptation are still a matter for debate. Here, we used a modified Eriksen-Flanker task in a magnetic resonance imaging (MRI) study that required the participants to derive the correct stimulus response association based on a feedback given after each flanker stimulus. Participants had to continuously monitor and adapt their performance as the stimulus-response association switched after a jittered time interval without notice. After every switch an increase of reaction times was observed. At the neural level, the feedback indicating the need to switch was associated with activation of the precuneus, the cingulate cortex, the insula and a brainstem region tentatively identified as the locus coeruleus. This brainstem system appears to interact with this cortical network and seems to be essential for performance monitoring and behavioral adaptation. In contrast, the cerebellum crus and prefrontal areas are activated during error feedback processing. Furthermore we found activations of the hippocampus and parahippocampal gyrus bilaterally after a correct feedback in learnable stimulus-response associations. These results highlight the contribution of brainstem nuclei to performance adaptation. PMID- 25446351 TI - Otx1 promotes basal dendritic growth and regulates intrinsic electrophysiological and synaptic properties of layer V pyramidal neurons in mouse motor cortex. AB - The transcription factor Otx1 is specifically expressed in layer V pyramidal cells (L5PCs) in the cerebral cortex. Otx1 null mutant mice have a defect in the developmental axon pruning of L5PCs and show epileptic seizures. However, the role of Otx1 in electrophysiology, morphology and synaptology of the cortical neurons has not been fully investigated. This study examines the influences of Otx1 on neuronal properties of L5PCs by loss- and gain-of-function approaches. Mice with an Otx1-null mutation had decreased structural measurements of basal dendrites in L5PCs. In contrast, the size of basal dendrites was increased in the Otx1-over-expressed pyramidal cells (PCs) in L2/3 where the gene normally does not express. PCs showed burst and non-burst firing patterns of action potentials. The proportion of burst firing neurons was reduced in the Otx1 mutant but increased in the neurons over-expressing Otx1. Although the burst firing population decreased, the proportion of those bursting neurons with a low threshold increased in the Otx1 mutant mice. Moreover, excitatory facilitating synaptic connections formed between L5PCs were predominant in the Otx1 mutant mice, which greatly contrasted with the predominant depressing synaptic connections in the controls. Taken together, it suggests an enhanced activity of neuronal network in the cortex of Otx1 mutant mice. These data indicate that the Otx1 expression is essential for the normal development of dendritic morphology, intrinsic electrophysiology and synaptic dynamics of L5PCs. This study provides new insights into molecular mechanisms underlying the spatial and temporal regulation of neuronal and synaptic properties of L5PCs, and improves our understanding on the generation of epileptic seizures. PMID- 25446350 TI - Regulation of c-fos expression by the dopamine D1-D2 receptor heteromer. AB - The dopamine D1 and D2 receptors form the D1-D2 receptor heteromer in a subset of neurons and couple to the Gq protein to regulate intracellular calcium signaling. In the present study the effect of D1-D2 heteromer activation and disruption on neuronal activation in the rat brain was mapped. This was accomplished using the dopamine agonist SKF 83959 to activate the D1-D2 heteromer in combination with a TAT-D1 disrupting peptide we developed, and which has been shown to disrupt the D1/D2 receptor interaction and antagonize D1-D2 heteromer-induced cell signaling and behavior. Acute SKF 83959 administration to rats induced significant c-fos expression in the nucleus accumbens that was significantly inhibited by TAT-D1 pretreatment. No effects of SKF 83959 were seen in caudate putamen. D1-D2 heteromer disruption by TAT-D1 did not have any effects in any striatal subregions, but induced significant c-fos immunoreactivity in a number of cortical regions including the orbitofrontal cortex, prelimbic and infralimbic cortices and piriform cortex. The induction of c-fos by TAT-D1 was also evident in the anterior olfactory nucleus, as well as the lateral habenula and thalamic nuclei. These findings show for the first time that the D1-D2 heteromer can differentially regulate c-fos expression in a region-dependent manner either through its activation or through tonic inhibition of neuronal activity. PMID- 25446352 TI - The role of ventral midline thalamus in cholinergic-based recovery in the amnestic rat. AB - The thalamus is a critical node for several pathways involved in learning and memory. Damage to the thalamus by trauma, disease or malnourishment can impact the effectiveness of the prefrontal cortex (PFC) and hippocampus (HPC) and lead to a profound amnesia state. Using the pyrithiamine-induced thiamine deficiency (PTD) rat model of human Wernicke-Korsakoff syndrome, we tested the hypothesis that co-infusion of the acetylcholinesterase inhibitor physostigmine across the PFC and HPC would recover spatial alternation performance in PTD rats. When cholinergic tone was increased by dual injections across the PFC-HPC, spontaneous alternation performance in PTD rats was recovered. In addition, we tested a second hypothesis that two ventral midline thalamic nuclei, the rhomboid nucleus and nucleus reuniens (Rh-Re), form a critical node needed for the recovery of function observed when cholinergic tone was increased across the PFC and HPC. By using the GABAA agonist muscimol to temporarily deactivate the Rh-Re the recovery of alternation behavior obtained in the PTD model by cholinergic stimulation across the PFC-HPC was blocked. In control pair-fed (PF) rats, inactivation of the Rh-Re impaired spontaneous alternation. However, when inactivation of the Rh Re co-occurred with physostigmine infusions across the PFC-HPC, PF rats had normal performance. These results further demonstrate that the Rh-Re is critical in facilitating interactions between the HPC and PFC, but other redundant pathways also exist. PMID- 25446353 TI - Muscle hyperalgesia induced by peripheral P2X3 receptors is modulated by inflammatory mediators. AB - ATP, via activation of P2X3 receptors, has been highlighted as a key target in inflammatory hyperalgesia. Therefore, the aim of this study was to confirm whether the activation of P2X3 receptors in the gastrocnemius muscle of rats induces mechanical muscle hyperalgesia and, if so, to analyze the involvement of the classical inflammatory mediators (bradykinin, prostaglandins, sympathetic amines, pro-inflammatory cytokines and neutrophil migration) in this response. Intramuscular administration of the non-selective P2X3 receptor agonist alpha,beta-meATP in the gastrocnemius muscle of rats induced mechanical muscle hyperalgesia, which, in turn, was prevented by the selective P2X3 and P2X2/3 receptors antagonist A-317491, the selective bradykinin B1-receptor antagonist Des-Arg9-[Leu8]-BK (DALBK), the cyclooxygenase inhibitor indomethacin, the beta1- or beta2-adrenoceptor antagonist atenolol and ICI 118,551, respectively. Also, the nonspecific selectin inhibitor fucoidan. alpha,beta-meATP induced increases in the local concentration of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta), which were reduced by bradykinin antagonist. Finally, alpha,beta-meATP also induced neutrophil migration. Together, these findings suggest that alpha,beta-meATP induced mechanical hyperalgesia in the gastrocnemius muscle of rats via activation of peripheral P2X3 receptors, which involves bradykinin, prostaglandins, sympathetic amines, pro-inflammatory cytokines release and neutrophil migration. It is also indicated that bradykinin is the key modulator of the mechanical muscle hyperalgesia induced by P2X3 receptors. Therefore, we suggest that P2X3 receptors are important targets to control muscle inflammatory pain. PMID- 25446354 TI - The effect of CA1 dopaminergic system in harmaline-induced amnesia. AB - In the present study, the effects of bilateral injections of dopaminergic drugs into the hippocampal CA1 regions (intra-CA1) on harmaline-induced amnesia were examined in male mice. A one-trial step-down passive avoidance task was used for the assessment of memory retention in adult male mice. Pre-training intra peritoneal (i.p.) administration of harmaline (1 mg/kg) induced impairment of memory retention. Moreover, intra-CA1 administration of dopamine D1 receptor antagonist, SCH23390 (0.02 MUg/mouse), dopamine D1 receptor agonist, SKF38393 (0.5 MUg/mouse), dopamine D2 receptor antagonist, sulpiride (1 MUg/mouse) and dopamine D2 receptor agonist, quinpirole (0.25 and 0.5 MUg/mouse) suppressed the learning of a single-trial passive avoidance task. Also, pre-training intra-CA1 injection of subthreshold doses of SCH23390 (0.001 MUg/mouse) or sulpiride (0.25 MUg/mouse) with the administration of harmaline (1 mg/kg, i.p.) reversed impairment of memory formation. However, pre-training intra-CA1 injection of SKF38393 (0.1 MUg/mouse) or quinpirole (0.1 MUg/mouse) increased pre-training harmaline (0.25 and 0.5 mg/kg, i.p.)-induced retrieval impairment. Moreover, SKF Ca blocker (SKF) (0.01 MUg/mouse) decrease the amnesia induced by harmaline (1 mg/kg), while co-administration of SKF (0.01 MUg/mouse)/sulpiride (0.25 MUg/mouse) or SCH23390 (0.001 MUg/mouse)/sulpiride (0.25 MUg/mouse) potentiate amnesia caused by harmaline. These findings implicate the involvement of CA1 dopaminergic mechanism in harmaline-induced impairment of memory acquisition. PMID- 25446356 TI - Calorie restriction increases lipopolysaccharide-induced neuropeptide Y immunolabeling and reduces microglial cell area in the arcuate hypothalamic nucleus. AB - Calorie restriction (CR) increases longevity and elicits many health promoting benefits including delaying immunosenescence and reducing the incidence of age related diseases. Although the mechanisms underlying the health-enhancing effects of CR are not known, a likely contributing factor is alterations in immune system functioning. CR suppresses lipopolysaccharide (LPS)-induced release of pro inflammatory cytokines, blocks LPS-induced fever, and shifts hypothalamic signaling pathways to an anti-inflammatory bias. Furthermore, we have recently shown that CR attenuates LPS-stimulated microglial activation in the hypothalamic arcuate nucleus (ARC), a brain region containing neurons that synthesize neuropeptide Y (NPY), an orexigenic neuropeptide that is upregulated by a CR diet and has anti-inflammatory properties. To determine if increased NPY expression in the ARC following CR was associated with changes in microglial activation, a set of brain sections from mice that were exposed to 50% CR or ad libitum feeding for 28 days before being injected with LPS were immunostained for NPY. The density of NPY-immunolabeling was assessed across the rostrocaudal extent of the ARC and hypothalamic paraventricular nucleus (PVN). An adjacent set of sections were immunostained for ionized calcium-binding adapter molecule-1 (Iba1) and immunostained microglia in the ARC were digitally reconstructed to investigate the effects of CR on microglial morphology. We demonstrated that exposure to CR increased NPY expression in the ARC, but not the PVN. Digital reconstruction of microglia revealed that LPS increased Iba1 intensity in ad libitum fed mice but had no effect on Iba1 intensity in CR mice. CR also decreased the size of ARC microglial cells following LPS. Correlational analyses revealed strong associations between NPY and body temperature, and body temperature and microglia area. Together these results suggest that CR-induced changes in NPY are not directly involved in the suppression of LPS-induced microglial activation, however, NPY may indirectly affect microglial morphology through changes in body temperature. PMID- 25446355 TI - Self administration of oxycodone alters synaptic plasticity gene expression in the hippocampus differentially in male adolescent and adult mice. AB - Abuse and addiction to prescription opioids such as oxycodone (a short-acting Mu opioid receptor (MOP-r) agonist) in adolescence is a pressing public health issue. We have previously shown differences in oxycodone self-administration behaviors between adolescent and adult C57BL/6J mice and expression of striatal neurotransmitter receptor genes, in areas involved in reward. In this study, we aimed to determine whether oxycodone self-administration differentially affects genes regulating synaptic plasticity in the hippocampus of adolescent compared to adult mice, since the hippocampus may be involved in learning aspects associated with chronic drug self administration. Hippocampus was isolated for mRNA analysis from mice that had self administered oxycodone (0.25 mg/kg/infusion) 2h/day for 14 consecutive days or from yoked saline controls. Gene expression was analyzed with real-time polymerase chain reaction (PCR) using a commercially available "synaptic plasticity" PCR array containing 84 genes. We found that adolescent and adult control mice significantly differed in the expression of several genes in the absence of oxycodone exposure, including those coding for mitogen-activated protein kinase, calcium/calmodulin-dependent protein kinase II gamma subunit, glutamate receptor, ionotropic AMPA2 and metabotropic 5. Chronic oxycodone self administration increased proviral integration site 1 (Pim1) and thymoma viral proto-oncogene 1 mRNA levels compared to controls in both age groups. Both Pim1 and cadherin 2 mRNAs showed a significant combined effect of Drug Condition and Age * Drug Condition. Furthermore, the mRNA levels of both cadherin 2 and cAMP response element modulators showed an experiment-wise significant difference between oxycodone and saline control in adult but not in adolescent mice. Overall, this study demonstrates for the first time that chronic oxycodone self administration differentially alters synaptic plasticity gene expression in the hippocampus of adolescent and adult mice. PMID- 25446357 TI - Dynamic characteristics of otolith ocular response during counter rotation about dual yaw axes in mice. AB - The central vestibular system plays an important role in higher neural functions such as self-motion perception and spatial orientation. Its ability to store head angular velocity is called velocity storage mechanism (VSM), which has been thoroughly investigated across a wide range of species. However, little is known about the mouse VSM, because the mouse lacks typical ocular responses such as optokinetic after nystagmus or a dominant time constant of vestibulo-ocular reflex for which the VSM is critical. Experiments were conducted to examine the otolith-driven eye movements related to the VSM and verify its characteristics in mice. We used a novel approach to generate a similar rotating vector as a traditional off-vertical axis rotation (OVAR) but with a larger resultant gravito inertial force (>1g) by using counter rotation centrifugation. Similar to results previously described in other animals during OVAR, two components of eye movements were induced, i.e. a sinusoidal modulatory eye movement (modulation component) on which a unidirectional nystagmus (bias component) was superimposed. Each response is considered to derive from different mechanisms; modulations arise predominantly through linear vestibulo-ocular reflex, whereas for the bias, the VSM is responsible. Data indicate that the mouse also has a well-developed vestibular system through otoliths inputs, showing its highly conserved nature across mammalian species. On the other hand, to reach a plateau state of bias, a higher frequency rotation or a larger gravito-inertial force was considered to be necessary than other larger animals. Compared with modulation, the bias had a more variable profile, suggesting an inherent complexity of higher-order neural processes in the brain. Our data provide the basis for further study of the central vestibular system in mice, however, the underlying individual variability should be taken into consideration. PMID- 25446358 TI - Paeoniflorin inhibition of 6-hydroxydopamine-induced apoptosis in PC12 cells via suppressing reactive oxygen species-mediated PKCdelta/NF-kappaB pathway. AB - Parkinson's disease (PD) is second only to Alzheimer's disease as the most common devastating human neurodegenerative disorder. Despite intense investigation, no curative therapy is available for PD. Paeoniflorin, a monoterpene glucoside isolated from the Paeonia lactiflora Pall., possesses wide pharmacological effects in the nervous system. This study aims at evaluating the effect of paeoniflorin on 6-hydroxydopamine (6-OHDA)-induced apoptosis and to characterize involved signal transduction pathways in PC12 cells. Our results showed that paeoniflorin suppresses mitochondria-mediated apoptosis of PC12 cells induced by 6-OHDA, and anti-apoptotic effects of paeoniflorin on PC12 cells might mainly result from its antioxidant capability by increasing glutathione (GSH). Moreover, we also found that paeoniflorin can dramatically attenuate the 6-OHDA-induced nuclear factor kappaB (NF-kappaB) translocation without affecting phosphorylation of Akt, JNK, p38, and ERK1/2. 6-OHDA-induced protein kinase Cdelta (PKCdelta) upregulation was blocked by paeoniflorin treatment in PC12 cells. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenyleneiodonium or NF-kappaB inhibitor BAY 11-7082 could partially attenuate 6-OHDA-induced cell death. Together, our results indicate that the inhibition of PC12 cell apoptosis by paeoniflorin might be mediated, at least in part, by inhibiting reactive oxygen species (ROS)/PKCdelta/NF-kappaB signaling pathway. This evidence supports the pharmacological potential of paeoniflorin in the management of neurodegenerative disorders associated with oxidative stress, including PD. PMID- 25446360 TI - Energy status determines hindbrain signal transduction pathway transcriptional reactivity to AMPK in the estradiol-treated ovariectomized female rat. AB - Dorsal vagal complex (DVC) AMPK regulation of food intake in the estradiol treated ovariectomized (OVX) female rat is energy state-dependent. Here, RT-PCR array technology was used to identify estradiol-sensitive AMPK-regulated DVC signal transduction pathways that exhibit differential reactivity to sensor activation during energy balance versus imbalance. The AMP mimetic AICAR correspondingly reduced or stimulated cDVC phosphoAMPK (pAMPK) and estrogen receptor-beta (ERbeta) proteins in full-fed (F) versus 12-h food-deprived (D) estradiol-treated ovariectomized (OVX) rats, but elevated ER-alpha (ERalpha) in F only. Estradiol suppressed DVC ERbeta protein and hypoxia, NFkappaB, STAT3, STAT6, and Hedgehog signaling pathway marker genes against oil-implanted OVX controls. F+(A)ICAR and D+(S)aline groups each exhibited further inhibition of NFkappaB, STAT3, and Hedgehog pathway genes, and diminished PPAR, Notch, and STAT5 transcripts versus F+S. Conversely, genes in these six pathways were up regulated by AICAR treatment of D. Results show that in this animal model, acute AMP augmentation or feeding cessation each inhibit both pAMPK and ERbeta expression, but in combination increase these protein profiles. pAMPK protein and DVC TNF (NFkappaB), SOCS3 (JAK/STAT), WNT6 (Hedgehog), and FABP1 (PPAR) mRNAs were down- or upregulated in parallel by AICAR in F versus D states, respectively. Further research is needed to determine the impact of ERbeta on opposing directionality of these responses, and to characterize the role of the aforementioned signaling pathways in hyperphagic responses in the female to AICAR induced DVC AMPK activation during acute interruption of feeding. PMID- 25446361 TI - Rotenone impairs autophagic flux and lysosomal functions in Parkinson's disease. AB - BACKGROUND: Rotenone is an environmental neurotoxin that induces accumulation of alpha-synuclein and degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc), but the molecular mechanisms are not fully understood. We investigated whether rotenone induced impairment of autophagic flux and lysosomal functions. METHODS: Autophagy flux, accumulation of alpha-synuclein, lysosomal membrane integrity and neurodegeneration were assessed in the rotenone-treated rat model and PC12 cells, and the effects of the autophagy inducer trehalose on rotenone's cytotoxicity were also studied. RESULTS: Rotenone administration significantly reduced motor activity and caused a loss of tyrosine hydroxylase in SNpc of Lewis rats. The degeneration of nigral dopaminergic neurons was accompanied by the deposition of alpha-synuclein aggregates, autophagosomes and redistribution of cathepsin D from lysosomes to the cytosol. In cultured PC12 cells, rotenone also induced increases in protein levels of alpha-synuclein, microtubule-associated protein 1 light chain 3-II, Beclin 1, and p62. Rotenone increased lysosomal membrane permeability as evidenced by leakage of N-acetyl beta-d-glucosaminidase and cathepsin D, the effects were blocked by reactive oxygen species scavenger tiron. Autophagy inducer trehalose enhanced the nuclear translocation of transcription factor EB, accelerated the clearance of autophagosomes and alpha-synuclein and attenuated rotenone-induced cell death of PC12 cells. Meanwhile, administration of trehalose to rats in drinking water (2%) decreased rotenone-induced dopaminergic neurons loss in SNpc. CONCLUSIONS: These studies indicate that the lysosomal dysfunction contributes to rotenone's neurotoxicity and restoration of lysosomal function could be a new therapeutic strategy for Parkinson's disease. PMID- 25446359 TI - The injury resistant ability of melanopsin-expressing intrinsically photosensitive retinal ganglion cells. AB - Neurons in the mammalian retina expressing the photopigment melanopsin have been identified as a class of intrinsically photosensitive retinal ganglion cells (ipRGCs). This discovery more than a decade ago has opened up an exciting new field of retinal research, and following the initial identification of photosensitive ganglion cells, several subtypes have been described. A number of studies have shown that ipRGCs subserve photoentrainment of circadian rhythms. They also influence other non-image forming functions of the visual system, such as the pupillary light reflex, sleep, cognition, mood, light aversion and development of the retina. These novel photosensitive neurons also influence form vision by contributing to contrast detection. Furthermore, studies have shown that ipRGCs are more injury-resistant following optic nerve injury, in animal models of glaucoma, and in patients with mitochondrial optic neuropathies, i.e., Leber's hereditary optic neuropathy and dominant optic atrophy. There is also an indication that these cells may be resistant to glutamate-induced excitotoxicity. Herein we provide an overview of ipRGCs and discuss the injury-resistant character of these neurons under certain pathological and experimental conditions. PMID- 25446362 TI - Pharmacological induction of the 70-kDa heat shock protein protects against brain injury. AB - The 70-kDa heat shock protein (HSP70) is known to protect the brain from injury through multiple mechanisms. We investigated the effect of pharmacological HSP70 induction in experimental traumatic brain injury (TBI). 3-month-old male C57/B6 mice were given 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) intraperitoneally (IP, 2 mg/kg) or intracerebroventricularly (ICV, 1 MUg/kg) to determine whether HSP70 could be induced in the brain. Mice were subjected to TBI via cortical controlled impact, and were treated with 17-AAG (or vehicle) IP according to one of two treatment regimens: (1) 2 mg/kg at the time of injury, (2) a total of three doses (4 mg/kg) at 2 and 1d prior to TBI and again at the time of injury. Brains were assessed for HSP70 induction, hemorrhage volume at 3 d, and lesion size at 14 d post-injury. Immunohistochemistry showed that both IP and ICV administration of 17-AAG increased HSP70 expression primarily in microglia and in a few neurons by 24 h but not in astrocytes. 17-AAG induced HSP70 in injured brain tissue as early as 6 h, peaking at 48 h and largely subsiding by 72 h after IP injection. Both treatment groups showed decreased hemorrhage volume relative to untreated mice as well as improved neurobehavioral outcomes. These observations indicate that pharmacologic HSP70 induction may prove to be a promising treatment for TBI. PMID- 25446364 TI - Species differences in androgen receptor expression in the medial preoptic and anterior hypothalamic areas of adult male and female rodents. AB - The medial preoptic and anterior hypothalamic areas (MPO/AH) are important androgen targets regulating homeostasis, neuroendocrinology and circadian rhythm as well as instinctive and sociosexual behaviors. Although species differences between rats and mice have been pointed out in terms of morphology and physiology, detailed distributions of androgen receptor (AR) have never been compared between the two rodents. In the present study, AR distribution was examined immunohistochemically in serial sections of the MPO/AH and compared for adult rats and mice. Western blotting and immunohistochemistry clearly demonstrated that AR expression in the brain was stronger in mice than in rats and was stronger in males than in females. In addition, we found (1) an "obliquely elongated calbindin-ir cell island" in mice medial preoptic nucleus (MPN) expressed AR intensely, as well as the sexually dimorphic nucleus in the MPN (SDN-MPN) in rats, strongly supporting a "putative SDN-MPN" previously proposed in mice; (2) AR expression in the suprachiasmatic nucleus (SCN) was much more prominent in mice than in rats and differed in localization between the two species; (3) a mouse-specific AR-ir cell cluster was newly identified as the "tear drop nucleus (TDN)", with male-dominant sexual dimorphism; and (4) two rat specific AR-ir cell clusters were also newly identified as the "rostral and caudal nebular islands", with male-dominant sexual dimorphism. The present results may provide basic morphological evidence underlying species differences in androgen-modified psychological, physiological and endocrinergic responses. Above all, the findings of the mouse-specific TDN and differing AR expression in the SCN might explain not only species difference in gonadal modification of circadian rhythm, but also distinct structural bases in the context of transduction of SCN oscillation. The current study could also serve as a caution that data on androgen-sensitive functions obtained from one species should not always be directly applied to others among rodents. PMID- 25446363 TI - Specific contributions of N-methyl-D-aspartate receptors in the dorsal striatum to cognitive flexibility. AB - Behavioral flexibility is known to be mediated by corticostriatal systems and to involve several major neurotransmitter signaling pathways. The current study investigated the effects of inactivation of glutamatergic N-methyl-D-aspartate (NMDA) receptor signaling in the dorsal striatum on behavioral flexibility in mice. NMDA-receptor inactivation was achieved by virus-mediated inactivation of the Grin1 gene, which encodes the essential NR1 subunit of NMDA receptors. To assess behavioral flexibility, we used a water U-maze paradigm in which mice had to shift from an initially acquired rule to a new rule (strategy shifting) or had to reverse an initially learned rule (reversal learning). Inactivation of NMDA receptors in all neurons of the dorsal striatum did not affect learning of the initial rule or reversal learning, but impaired shifting from one strategy to another. Strategy shifting was also compromised when NMDA-receptors were inactivated only in dynorphin-expressing neurons in the dorsal striatum, which represent the direct pathway. These data suggest that NMDA-receptor-mediated synaptic plasticity in the dorsal striatum contributes to strategy shifting and that striatal projection neurons of the direct pathway are particularly relevant for this process. PMID- 25446366 TI - Reduced systemic microvascular density and reactivity in individuals with early onset coronary artery disease. AB - OBJECTIVE: This study sought to test whether patients with early-onset coronary artery disease (EOCAD, n=30) showed systemic microvascular rarefaction and endothelial dysfunction in comparison to age- and sex-matched healthy controls (CTL, n=30), as evaluated by skin video-capillaroscopy. METHODS: Functional capillary density (FCD) was defined as the number of spontaneously perfused capillaries per square millimeter of skin area and assessed by high-resolution intra-vital color microscopy in the dorsum of the middle phalanx. Capillary recruitment (capillary reserve) was evaluated using post-occlusive reactive hyperemia (PORH) after arm ischemia for 3min. RESULTS: The mean capillary density at rest was significantly reduced in patients with EOCAD compared to controls (CTL 95+/-20 and EOCAD 80+/-18capillaries/mm(2), P=0.0040). During PORH, capillary density was also markedly reduced in EOCAD patients (CTL 96+/-18 and EOCAD 71+/-20capillaries/mm(2), P<0.0001). Moreover, the capillary density in EOCAD patients was significantly reduced during PORH (EOCAD at rest 80+/-19 and EOCAD during PORH 71+/-20capillaries/mm(2), P=0.0073). CONCLUSIONS: Patients with EOCAD presented systemic capillary rarefaction and impaired microvascular endothelial function. Thus, the early detection of these microvascular alterations in young adults at an increased risk of coronary artery disease could be useful as a surrogate marker of subclinical atherosclerosis. PMID- 25446365 TI - Alterations in brain connectivity in three sub-regions of the anterior cingulate cortex in heroin-dependent individuals: Evidence from resting state fMRI. AB - Previous studies that utilized task-based approaches have demonstrated that the chronic use of heroin is associated with altered activity of the anterior cingulate cortex (ACC). However, few studies have focused on examining the variation in resting-state functional connectivity in heroin-dependent individuals, which might help further understanding the mechanisms underlying heroin addiction. Due to the structural and functional heterogeneity of the ACC, we systematically mapped the resting-state functional connectivity patterns of three sub-regions of the ACC in heroin-dependent individuals, wondered whether the partition of three sub-regions of the ACC is feasible in heroin-dependent individuals, and identified how heroin affected the correlated activities among three sub-regions of the ACC using resting-state functional magnetic resonance imaging (fMRI). In the present study, fMRI data were acquired from 21 heroin dependent individuals (Her group) and 15 non-addicted controls (CN group). Compared to controls, there were reduced functional connectivities in the dorsal ACC (dACC) and rostral ACC (rACC) networks with different areas of the dorsal striatum (the caudate and the putamen) in the Her group. Meanwhile, there exhibited an inverted alteration of pattern for orbital frontal cortex (OFC) and superior frontal gyrus (SFG) in the functional connectivity network with the dACC and subcallosal ACC (sACC), and a different alteration of the cerebellum and the amygdala in the functional connectivity network with the rACC and the sACC. In addition, we also found reduced connectivities between dACC and rACC, as well as reduced connectivities between sACC and dACC. Our findings of variations of functional connectivities in three sub-regions of ACC in Her group implied that these sub-regions of the ACC together with other key brain areas (such as dorsal striatum, OFC, SFG, cerebellum, amygdale, etc.) might potentially play independent and/or overlapping roles in heroin addiction, which might indicate the potential direction of future research. PMID- 25446367 TI - Wavelet-analysis of skin temperature oscillations during local heating for revealing endothelial dysfunction. AB - Skin microvessels have proven to be a model to investigate the mechanisms of vascular disease; in particular, endothelial dysfunction. To analyze skin blood flow, high-resolution thermometry can be used because low-amplitude skin temperature oscillations are caused by changes in the tone of skin vessels. The aim of our study was to test the possibilities of wavelet analysis of skin temperature (WAST) for the diagnosis of impaired regulation of microvascular tone in patients with type 2 diabetes. A local heating functional test was used for the assessment of microvascular tone regulation. A control group consisted of healthy male and female volunteers (n=5 each), aged 39.1+/-5.3years. A group of patients with type 2 diabetes comprised thirteen people, seven men and six women, aged 36 to 51years old (43.2+/-3.4years). The diagnosis of diabetes was made according to the criteria of the World Health Organization (WHO). The mean disease duration was 7.36+/-0.88years. Skin temperature oscillations, reflecting intrinsic myogenic activity (0.05-0.14Hz), neurogenic factors (0.02-0.05Hz) and endothelial activity (0.0095-0.02Hz) increase greatly during local heating for healthy subjects. In the group of patients with type 2 diabetes, no statistically significant differences in the amplitudes in the endothelial range were observed. Relative changes in the oscillation amplitudes in patients with type 2 diabetes were markedly lower compared to the control group. The latter indicates that the WAST method enables assessment of the state of vascular tone and the effects of mechanisms responsible for regulation of blood flow in the microvasculature. PMID- 25446368 TI - The use of hydrogen gas clearance for blood flow measurements in single endogenous and transplanted pancreatic islets. AB - The blood perfusion of pancreatic islets is regulated independently from that of the exocrine pancreas, and is of importance for multiple aspects of normal islet function, and probably also during impaired glucose tolerance. Single islet blood flow has been difficult to evaluate due to technical limitations. We therefore adapted a hydrogen gas washout technique using microelectrodes to allow such measurements. Platinum micro-electrodes monitored hydrogen gas clearance from individual endogenous and transplanted islets in the pancreas of male Lewis rats and in human and mouse islets implanted under the renal capsule of male athymic mice. Both in the rat endogenous pancreatic islets as well as in the intra pancreatically transplanted islets, the vascular conductance and blood flow values displayed a highly heterogeneous distribution, varying by factors 6-10 within the same pancreas. The blood flow of human and mouse islet grafts transplanted in athymic mice was approximately 30% lower than that in the surrounding renal parenchyma. The present technique provides unique opportunities to study the islet vascular dysfunction seen after transplantation, but also allows for investigating the effects of genetic and environmental perturbations on islet blood flow at the single islet level in vivo. PMID- 25446369 TI - Trypanosoma cruzi antigens induce inflammatory angiogenesis in a mouse subcutaneous sponge model. AB - Acute inflammation and angiogenesis are persistent features of several pathological conditions induced by biological agents leading to the resolution of local and systemic events. Glycoproteins derived from the protozoan Trypanosoma cruzi are suggested to mediate angiogenesis induced by inflammatory cells with still undescribed mechanisms. In this study, we investigated the effects of total antigen from trypomastigote forms of T. cruzi (Y strain), inoculated in sponges 24h after implantation in mice, on angiogenesis, inflammatory cell pattern and endogenous production of inflammatory and angiogenic mediators on days 1, 4, 7 and 14 post-implant. There was an increase in hemoglobin content and in the number of blood vessels associated with T. cruzi antigen stimuli on the 14th day, assessed by the hemoglobin of the implants and by morphometric analysis. However, these antigens were not able to increase type I collagen content on the 14th day. Parasite antigens also induced high production of vascular endothelial growth factor (VEGF) and inflammatory mediators TNF-alpha, CCL2 and CCL5 on the 7th day in sponges when compared to the unstimulated group. Neutrophils and macrophages were determined by measuring myeloperoxidase (MPO) and N-acetyl-beta-d glucosaminidase (NAG) enzyme activities, respectively. Only NAG was increased after stimulation with antigens, starting from day 4 and peaking at day 7. Together, these data showed that antigens from the Y strain of T. cruzi are able to promote inflammatory neovascularization probably induced by macrophage-induced angiogenic mediators in T. cruzi antigen-stimulated sponges in Swiss mice. PMID- 25446370 TI - Laser speckle contrast imaging for measurement of hepatic microcirculation during the sepsis: a novel tool for early detection of microcirculation dysfunction. AB - BACKGROUND: Sepsis is a fatal systemic inflammatory response syndrome caused by severe infection. The aim of this study was to measure hepatic microcirculation during the sepsis with laser speckle contrast imaging (LSCI), as well as investigating the underlying mechanisms. METHODS: Sepsis was induced by cecal ligation and puncture. Rats were divided into the sham group and sepsis group. The hepatic microcirculation was monitored with LSCI. In addition, hepatic endothelial function (expression of cell adhesion molecules, coagulation and vascular permeability) and neutrophils accumulation in the liver were compared between the two groups. RESULTS: During the sepsis, hepatic microcirculation decreased dramatically (290.3+/-70.1 LSPU (laser speckle perfusion units) at baseline vs. 230.4+/-60.7 LSPU at 12h vs. 125.2+/-25.4 LSPU at 48h, P<0.001). The rats developed hyperbilirubinemia since 6h. In the early phase of sepsis, the accumulation of neutrophils and formation of microthrombus increased rapidly. In the late phase, hepatic neutrophils accumulation was already at its maximum level. Meanwhile, the endothelial coagulation status shifted from procoagulation to anticoagulation. The vascular leakage was involved in the microcirculation dysfunction since 12h after sepsis. CONCLUSIONS: Hepatic microcirculation dysfunction occurs early during the sepsis and is associated with liver injury. This microcirculation dysfunction is due to neutrophil-endothelium interactions, microthrombus formation and vascular leakage. PMID- 25446371 TI - Comparison between endothelial progenitor cells and human umbilical vein endothelial cells on neovascularization in an adipogenesis mouse model. AB - Volume stability and growth of tissue engineered adipose tissue equivalents using adipose-derived stem cells (ASCs) rely strongly on angiogenesis and neovascularization to support the maintenance of cells. An attractive cellular approach is based on coimplantation of endothelial cells to create a vascular network. Endothelial progenitor cells (EPCs) are a promising cell population, since they can be easily isolated from autologous human peripheral blood and thus represent a clinically feasible option. We have previously shown in in vitro and semi-in vivo studies that ASCs exert beneficial effects on EPCs in terms of enhanced tube formation and formation of blood vessels, respectively. In this study, we investigated the in vivo effects of coimplantation on endothelial cell mediated neovascularization and ASC-mediated adipose tissue formation. For this purpose, human ASCs and human EPCs (or HUVECs as direct comparison to EPCs) were suspended alone or in coculture in fibrin and subcutaneously injected into the back of athymic nude mice and explanted after 1, 3 or 6months. Our results show that monocultures of EPCs or HUVECs were not able to perform vasculogenesis and constructs exhibited complete resorption already after 1month. However, a remarkable difference between EPCs and HUVECs was detected when coimplanted with ASCs. While coimplanted HUVECs gave rise to a stable neovasculature which was characterized by perfusion with erythrocytes, coimplanted EPCs showed no ability to form vascular structures. In the case of HUVEC-derived neovasculature, coimplanted ASCs displayed perivascular properties by stabilizing these neovessels. However, formation of human adipose tissue was independent of coimplanted endothelial cells. Our results indicate that HUVECs are superior to EPCs in terms of promoting in vivo neovascularization and recruiting perivascular cells for vessel stabilization when coimplanted with ASCs. PMID- 25446373 TI - Enabling electrochemical reduction of nitrogen to ammonia at ambient conditions through rational catalyst design. AB - Commercial design of a sustainable route for on-site production of ammonia represents a potential economic and environmental breakthrough. In an analogous process to the naturally occurring enzymatic mechanism, synthesis of ammonia could be achieved in an electrochemical cell, in which electricity would be used to reduce atmospheric nitrogen and water into ammonia at ambient conditions. To date, such a process has not been realized due to slow kinetics and low faradaic efficiencies. Although progress has been made in this regard, at present there exists no device that can produce ammonia efficiently from air and water at room temperature and ambient pressure. In this work, a scheme is presented in which electronic structure calculations are used to screen for catalysts that are stable, active and selective towards N2 electro-reduction to ammonia, while at the same time suppressing the competing H2 evolution reaction. The scheme is applied to transition metal nitride catalysts. The most promising candidates are the (100) facets of the rocksalt structures of VN and ZrN, which show promise of producing ammonia in high yield at low onset potentials. PMID- 25446372 TI - Pain measurement in mechanically ventilated critically ill patients: Behavioral Pain Scale versus Critical-Care Pain Observation Tool. AB - PURPOSE: The Behavioral Pain Scale (BPS) and Critical-Care Pain Observation Tool (CPOT) are behavioral pain assessment tools for uncommunicative and sedated intensive care unit (ICU) patients. This study compares the discriminant validation and reliability of the CPOT and the BPS, simultaneously, in mechanically ventilated patients on a mixed-adult ICU. MATERIALS AND METHODS: This is a prospective observational cohort study in 68 mechanically ventilated medical ICU patients who were unable to report pain. RESULTS: The BPS and CPOT scores showed a significant increase of 2 points between rest and the painful procedure (turning). The median BPS scores between rest and the nonpainful procedure (oral care) showed a significant increase of 1 point, whereas the median CPOT score remained unchanged. The interrater reliability of the BPS and CPOT scores showed a fair to good agreement (0.74 and 0.75, respectively). CONCLUSIONS: This study showed that the BPS and the CPOT are reliable and valid for use in a daily clinical setting. Although both scores increased with a presumed painful stimulus, the discriminant validation of the BPS use was less supported because it increased during a nonpainful stimulus. The CPOT appears preferable in this particular group of patients, especially with regard to its discriminant validation. PMID- 25446374 TI - Aristolochic acid nephropathy: epidemiology, clinical presentation, and treatment. AB - Aristolochic acid (AA) is a compound extracted from the Aristolochia species of herbs. It has been used for centuries as a remedy for various illnesses and diseases. However, in the early 1990s in the setting of a weight loss herbal remedy, AA exposure was associated with a syndrome of kidney injury, termed aristolochic acid nephropathy (AAN). This entity is marked by elevated serum creatinine, significant anemia, and histopathologic changes demonstrating a hypocellular interstitial infiltrate with severe fibrosis. Progression towards end-stage renal disease (ESRD) is rapid, with most patients having chronic kidney disease for less than 2 years. In addition, AAN is associated with a 40-45 % prevalence of urothelial carcinomas. Treatment of AAN is limited to glucocorticoids that have been shown to delay progression in non-randomized trials. As most patients progress to ESRD, need for renal replacement therapy, as either dialysis or kidney transplant, usually ensues. However, given the high malignant potential, care must be taken to minimize future development of upper urinary tract cancers by performing prophylactic bilateral nephroureterectomies and aggressive cancer surveillance. PMID- 25446375 TI - An exploratory analysis of the factors leading to delays in cancer drug reimbursement in the European Union: the trastuzumab case. AB - BACKGROUND: The European Union (EU) has adopted a common procedure for granting marketing authorisation for cancer drugs. Nevertheless, pricing and reimbursement decisions are a competency of EU national governments, and their policies are diverse. We aimed to evaluate the time for trastuzumab reimbursement approval and its association to health expenditure, to health policy performance, to the availability of cost-effectiveness studies and to breast cancer outcome. METHODS: Breast cancer outcome was estimated by the mortality/incidence (M/I) ratio. Trastuzumab reimbursement approval dates were provided by Roche. Spearman's rank correlation and Wilcoxon rank-sum test were used to evaluate associations and/or differences between the variables studied. Additional analyses were made by grouping countries according to compliance to the 180 day timeframe stipulated in the EU 89/105/EEC Directive for drug pricing and reimbursement. RESULTS: A statistically significant inverse and strong correlation between breast cancer M/I ratio and health expenditure (r(s)=-0.730, p<0.001) and health policy performance (r(s)=-0.711, p<0.001) was found, meaning the better the score and the higher the expenditure, the fewer patients died after a breast cancer diagnosis. Factors associated with trastuzumab faster reimbursement and compliance to the 89/105/EEC Directive were better health policy score, higher health expenditure and availability of cost-effectiveness studies. CONCLUSION: Higher health policy scores and health expenditure are associated with faster reimbursement of trastuzumab and better breast cancer outcome. Although the study design does not allow inference of causal associations, a marked difference is observed between Eastern and Western Europe, with long delays and increased breast cancer mortality identified in Eastern European countries. PMID- 25446377 TI - Synergism of arsenic trioxide and MG132 in Raji cells attained by targeting BNIP3, autophagy, and mitochondria with low doses of valproic acid and vincristine. AB - We previously demonstrated that arsenic trioxide (ATO) and proteasome inhibitor MG132 synergistically induced cell death in promonocytic leukaemia cell line U937 but were antagonistic in Burkitt's lymphoma cell line Raji. Here we explore the role of autophagy, expression of BNIP3, and mitochondrial mass, in determining whether ATO and MG132 interaction can be shifted from antagonism to synergism in Raji cells. Treatment with ATO+MG132 increased the percentage of cells with collapsed mitochondrial membrane potential (MMP) in U937 cells, but had no effect in Raji cells. Mitochondria were found in cytoplasmic marginal location in U937 cells but at perinuclear location in Raji cells. ATO+MG132 increased mitochondrial mass in U937 cells but decreased it in Raji cells, while autophagy was increased in both cell lines. BNIP3 was expressed in U937 cells at cytoplasmic marginal locations and was hardly detected in Raji cells. Histone deacetylase (HDAC) inhibitor valproic acid (VPA) increased expression of BNIP3 in Raji cells at perinuclear locations. However antagonism between ATO and MG132 was increased in the presence of low doses of VPA. Addition of vincristine (VCR) blocked autophagy, while VPA+VCR treatment of Raji cells at sub-cytotoxic doses caused BNIP3 and mitochondria to redistribute to cytoplasmic peripheral location and increased mitochondrial mass. ATO+MG132 in the presence of subcytotoxic doses of VPA+VCR caused collapse of MMP in Raji cells, while interaction between ATO and MG132 shifted from antagonism to synergism. We conclude that synergism between ATO and MG132 was attained in Raji cells by disruption of the perinuclear mitochondrial cluster, blockage of selective autophagy of mitochondria (mitophagy) by VCR, increased mitochondrial mass, and upregulation of BNIP3 by VPA. PMID- 25446376 TI - Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme. AB - BACKGROUND: Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study. PATIENTS AND METHODS: 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0-2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks+1-week rest followed by once 3 weeks+1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell derived factor 1 (SDF1)alpha by enzyme-linked immunosorbent assay (ELISA). RESULTS: Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P=0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P=0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P=0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR 2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1alpha were associated with lymph node metastases and T stage. Absence of PDGFRbeta expression correlated with longer PFS. CONCLUSION: The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment. PMID- 25446378 TI - Unravelling crucial biomechanical resilience of myelinated peripheral nerve fibres provided by the Schwann cell basal lamina and PMP22. AB - There is an urgent need for the research of the close and enigmatic relationship between nerve biomechanics and the development of neuropathies. Here we present a research strategy based on the application atomic force and confocal microscopy for simultaneous nerve biomechanics and integrity investigations. Using wild-type and hereditary neuropathy mouse models, we reveal surprising mechanical protection of peripheral nerves. Myelinated peripheral wild-type fibres promptly and fully recover from acute enormous local mechanical compression while maintaining functional and structural integrity. The basal lamina which enwraps each myelinated fibre separately is identified as the major contributor to the striking fibre's resilience and integrity. In contrast, neuropathic fibres lacking the peripheral myelin protein 22 (PMP22), which is closely connected with several hereditary human neuropathies, fail to recover from light compression. Interestingly, the structural arrangement of the basal lamina of Pmp22(-/-) fibres is significantly altered compared to wild-type fibres. In conclusion, the basal lamina and PMP22 act in concert to contribute to a resilience and integrity of peripheral nerves at the single fibre level. Our findings and the presented technology set the stage for a comprehensive research of the links between nerve biomechanics and neuropathies. PMID- 25446380 TI - Transoral vs. endoscopic endonasal approach for clival/upper cervical chordoma. AB - The surgical results of 18 cases of clival/upper cervical chordoma treated in the last decade via the endoscopic endonasal approach (EEA, 9 cases) and the transoral-transpalatal approach (TO-TPA, 9 cases) were compared. Each group showed the same incidence of subdural invasion, with 5 cases each. The superior (frontal base) and lateral surgical fields were wider by EEA, but the inferior view lower than the cranio-vertebral junction (CVJ) was wider by TO-TPA. Gross total removal was achieved in 3 cases in the EEA group, but in only 1 case in the TO-TPA group. Differences in radicality might be due to the extent of the lateral and subdural overview. However for large tumors extending below the CVJ, TO-TPA was the only viable approach for surgical removal. Surgical complications were higher in the EEA (4 cases) than the TO-TPA group (1 case), and were mainly caused by aggressive management of subdural invasion in the EEA group. Post operative oral intake was earlier and the operative time was shorter in the EEA group. The surgical results were more radical and less invasive in the EEA group than the TO-TPA group. However in tumors extending below the CVJ, the surgical field in EEA was limited, indicating the need to use the transoral route or a combination of routes. A higher complication rate following subdural management was a negative factor that requires improvement in the EEA group and two-staged EEA followed by a transcranial approach may be considered for the cases with subdural invasion. PMID- 25446379 TI - Endoscopic endonasal skull base surgery: advantages, limitations, and our techniques to overcome cerebrospinal fluid leakage: technical note. AB - In recent years, resections of midline skull base tumors have been conducted using endoscopic endonasal skull base (EESB) approaches. Nevertheless, many surgeons reported that cerebrospinal fluid (CSF) leakage is still a major complication of these approaches. Here, we report the results of our 42 EESB surgeries and discuss the advantages and limits of this approach for resecting various types of tumors, and also report our technique to overcome CSF leakage. All 42 cases involved midline skull base tumors resected using the EESB technique. Dural incisions were closed using nasoseptal flaps and fascia patch inlay sutures. Total removal of the tumor was accomplished in seven pituitary adenomas (33.3%), five craniopharyngiomas (62.5%), five tuberculum sellae meningiomas (83.3%), three clival chordomas (100%), and one suprasellar ependymoma. Residual regions included the cavernous sinus, the outside of the intracranial part of the internal carotid artery, the lower lateral part of the posterior clivus, and the posterior pituitary stalk. Overall incidence of CSF leakage was 7.1%. Even though the versatility of the approach is limited, EESB surgery has many advantages compared to the transcranial approach for managing mid-line skull base lesions. To avoid CSF leakage, surgeons should have skills and techniques for complete closure, including use of the nasoseptal flap and fascia patch inlay techniques. PMID- 25446381 TI - Indocyanine green fluorescence endoscopy at endonasal transsphenoidal surgery for an intracavernous sinus dermoid cyst: case report. AB - The complete resection of intracavernous sinus dermoid cysts is very difficult due to tumor tissue adherence to important anatomical structures such as the internal carotid artery (ICA), cavernous sinus, and cranial nerves. As residual dermoid cyst tissue sometimes induces symptoms and repeat surgery may be required after cyst recurrence, minimal invasiveness is an important consideration when selecting the surgical approach to the lesion. We addressed a recurrent intracavernous sinus dermoid cyst by the endoscopic endonasal transsphenoidal approach assisted by neuronavigation and indocyanine green (ICG) endoscopy to confirm the ICA and patency of the cavernous sinus. The ICG endoscope detected the fluorescence signal from the ICA and cavernous sinus; its intensity changed with the passage of time. The ICG endoscope was very useful for real-time imaging, and its high spatial resolution facilitated the detection of the ICA and the patent cavernous sinus. We found it to be of great value for successful endonasal transsphenoidal surgery. PMID- 25446382 TI - Treatment of pituitary carcinomas and atypical pituitary adenomas: a review. AB - Atypical pituitary adenomas (APAs) are aggressive tumors, harboring a Ki-67 (MIB 1) staining index of 3% or more, and positive immunohistochemical staining for p53 protein, according to the World Health Organization (WHO) classification in 2004. Pituitary carcinomas (PC) usually develop from progressive APAs and predominantly consist of hormone-generating tumors, defined by the presence of disseminations in the cerebrospinal system or systemic metastases. Most of the cases with these malignant pituitary adenomas underwent surgeries, irradiations and adjuvant medical treatments, nevertheless, the therapies are mainly palliative. Recently, the efficacy of temozolomide (TMZ), an orally administered alkylating agent, has been reported as an alternative medical treatment. However, some recent studies have demonstrated a significant recurrence rate after effective response to TMZ. Further clinical and pathological researches of malignant pituitary adenomas will be required to improve the outcome of patients with these tumors. PMID- 25446383 TI - Third Ventriculostomy in Late-onset Idiopathic Aqueductal Stenosis Treatment: A Focus on Clinical Presentation and Radiological Diagnosis. AB - Endoscopic third ventriculostomy (ETV) is considered the gold standard treatment for obstructive hydrocephalus due to partial or complete obstruction of cerebrospinal fluid (CSF) ventricular pathways caused by mass lesions. However long-term efficacy of this procedure remains controversial as treatment of chronic adult hydrocephalus due to stenosis of Sylvian acqueduct [late-onset idiopathic aqueductal stenosis (LIAS)]. The authors describe clinical presentation, diagnostic investigations in patients affected by LIAS, and define their clinical and radiological outcome after ETV. From January 2003 to December 2008, 13 consecutive LIAS patients treated by ETV were retrospectively reviewed. Pre- and post-operative clinical and radiological findings, including conventional and phase-contrast (PC) cine magnetic resonance imaging (MRI) were investigated. ETV was successfully performed in all patients. Patient's neurological condition improved. No one required a second ETV procedure or shunt implantation. Clinical and radiological results reveal a satisfactory outcome of LIAS patients treated by ETV. At follow-up a clinical improvement could be demonstrated in all cases. Selection criteria of LIAS patients seem to be crucial to obtain satisfactory and long-lasting results. Even in elderly patients with chronic hydrocephalus, ETV can be considered the treatment of choice. PMID- 25446384 TI - Indication and limitations of endoscopic extended transsphenoidal surgery for craniopharyngioma. AB - The transsphenoidal approach has been utilized in intrasellar craniopharyngioma surgeries. However, the advent of endoscopic extended transsphenoidal approach (EETSA) has expanded its indication to suprasellar craniopharyngiomas. We compared the indication and limitations of EETSA to those of unilateral basal interhemispheric approach (UBIHA), which presents similar indications for surgery. We analyzed 30 patients with tumors located below the foramen of Monro and the lateral boundary extending slightly beyond the internal carotid artery (UBIHA: N = 18; EETSA: N = 12). Postoperative magnetic resonance imaging (MRI) revealed gross total resection in 10 patients in the EETSA group (83.3%) and 12 in the UBIHA group (66.7%). Postoperative MRI in the EETSA group revealed residual tumor at the cavernous sinus in one patient, at the prepontine in one; in the UBIHA group, residual tumors were located in the retrochiasmatic area in two patients, infundibulum-hypothalamus in one, on the stalk in one, and in the intrasellar region in two. No intergroup differences were observed in the preservation of pituitary function and postoperative improvement of visual function. The extent of resection was better with EETSA than with UBIHA. EETSA is considered the first-line therapy because the distance between the optic chiasm and the superior border of the pituitary is large; the lateral extension does not go beyond the internal carotid artery; and the tumor does not extend inferiorly beyond the posterior clinoid process. However, in patients showing poorly developed sphenoid sinuses or pituitary stalks anterior to the tumor, surgery is difficult regardless of the selection criteria. PMID- 25446385 TI - Endoscopic endonasal approach to the middle cranial fossa through the cavernous sinus triangles: anatomical considerations. AB - The lateral limit of endoscopic endonasal surgery has yet to be defined. The aim of this study was to investigate the lateral limit of endoscopic endonasal surgery at the level of the sphenoid sinus. Access from the sphenoid sinus to the middle cranial fossa through the cavernous sinus triangles was evaluated by cadaver dissection. Anatomical analysis demonstrated that the medial temporal dura mater was exposed through the anterior area of the clinoidal triangle, anteromedial triangle, and superior area of the anterolateral triangle, indicating potential corridors to the middle cranial fossa. This study suggests that the cavernous sinus triangles are applicable in selected cases to manage middle cranial fossa lesions by endoscopic endonasal surgery. PMID- 25446386 TI - Analysis of the bacterial flora in the nasal cavity and the sphenoid sinus mucosa in patients operated on with an endoscopic endonasal transsphenoidal approach. AB - The aim of this study was to analyze the bacterial flora in the nasal cavity and sphenoid sinus and evaluate the sensitivity of these bacteria to antibiotics that can be used to prevent postoperative meningitis. Bacteria of the preoperative nasal cavity and intraoperative sphenoid sinus mucosa were cultured and analyzed in 40 patients (20 men and 20 women; mean age, 52.2 years) who underwent endoscopic transsphenoidal surgery. The sensitivity of these bacteria to cephalosporin, a representative prophylactic antibiotic, was examined. Staphylococcus epidermidis was the most frequently detected species in both spaces; 24 (38.7%) of 62 isolates in the nasal cavity and 26 (37.1%) of 70 isolates in the sphenoid sinus. In contrast, Corynebacterium species were found mainly in the nasal cavity, and anaerobic bacteria were found only in the sphenoid sinus. Bacteria that were resistant to cephalosporin were found in the nasal cavity in 3.2% of patients and in the sphenoid sinus in 20% of patients. In conclusion, the composition of bacterial flora, including bacteria that are resistant to prophylactic antibiotics, differs between the nasal cavity and the sphenoid sinus. PMID- 25446389 TI - The association between diabetes and liver disease: the need for a consensus. PMID- 25446388 TI - Medical management of functioning pituitary adenoma: an update. AB - The treatment of functioning pituitary adenoma (FPA) must achieve endocrinological remission as well as tumor size reduction. The first-line treatment of FPA except prolactinoma is transsphenoidal surgery (TSS). Medical treatments and/or radiation will be applied as adjuvant therapies succeeding to TSS. In patients with prolactinoma, dopamine agonists, especially cabergoline, are quite efficient. Dopamine agonists decrease plasma prolactin levels and induce shrinkage in most patients and can be ceased in some of them. In patients with acromegaly, dopamine agonists, somatostatin analogues, and growth hormone receptor antagonist have been used as a monotherapy or the combination, and the high remission rate can be achieved. Pasireotide having high affinity to type 5 somatostatin receptors will be available for the patients presenting resistance against type 2 receptor agonists, such as octreotide and lanreotide. The preceding treatment with somatostatin analogues is beneficial for improving the success rate of TSS. The chimera compounds of somatostatin analogues and dopamine agonists have been investigated. The medical treatments of Cushing's disease are challenging, if TSS is not successful. To suppress ACTH secretion, dopamine agonists and somatostatin analogues have been examined, but neither came to show a sufficient effect. Pasireotide reduces urinary cortisol excretion with a high remission rate. Adrenal enzyme inhibitors (AEIs), such as metyrapone, can inhibit cortisol synthesis form adrenal glands promptly and sufficiently in most of patients. LCI699, a newly developed AEI, is more potent than metyrapone and will be available. We should use available medical treatments for improving the prognosis and quality of life. PMID- 25446391 TI - Involvement of FTZ-F1 in the regulation of pupation in Leptinotarsa decemlineata (Say). AB - During the final instar larvae of holometabolous insects, a pulse of 20 hydroxyecdysone (20E) and a drop in juvenile hormone (JH) trigger larval-pupal metamorphosis. In this study, two LdFTZ-F1 cDNAs (LdFTZ-F1-1 and LdFTZ-F1-2) were cloned in Leptinotarsa decemlineata. Both LdFTZ-F1-1 and LdFTZ-F1-2 were highly expressed just before or right after each molt, similar to the expression pattern of an ecdysteroidogenesis gene LdSHD. Ingestion of an ecdysteroid agonist halofenozide (Hal) enhanced LdFTZ-F1-1 and LdFTZ-F1-2 expression in the final larval instar. Conversely, a decrease in 20E by feeding a double-stranded RNA (dsRNA) against LdSHD repressed the expression. Moreover, Hal rescued the expression levels in LdSHD-silenced larvae. Thus, 20E peaks seem to induce the transcription of LdFTZ-F1s. Furthermore, ingesting dsLdFTZ-F1 from a common fragment of LdFTZ-F1-1 and LdFTZ-F1-2 successfully knocked down both LdFTZ-F1s, and impaired pupation. Finally, knocking down LdFTZ-F1s significantly repressed the transcription of three ecdysteroidogenesis genes, lowered 20E titer, and reduced the expression of two 20E receptor genes. Silencing LdFTZ-F1s also induced the expression of a JH biosynthesis gene, increased JH titer, but decreased the mRNA level of a JH early-inducible gene. Thus, LdFTZ-F1s are involved in the regulation of pupation by modulating 20E and JH titers and mediating their signaling pathways. PMID- 25446390 TI - Identification of differentially expressed microRNAs in Culex pipiens and their potential roles in pyrethroid resistance. AB - Pyrethroids are the major class of insecticides used for mosquito control. Excessive and improper use of insecticides, however, has resulted in pyrethroid resistance, which has become a major obstacle for mosquito control. The development of pyrethroid resistance is a complex process involving many genes, and information on post-transcription regulation of pyrethroid resistance is lacking. In this study, we extracted RNA from mosquitoes in various life stages (fourth-instar larvae, pupae, male and female adult mosquitoes) from deltamethrin sensitive (DS) and resistant (DR) strains. Using illumina sequencing, we obtained 13760296 and 12355472 reads for DS-strains and DR-strains, respectively. We identified 100 conserved miRNAs and 42 novel miRNAs derived from 21 miRNA precursors in Culex pipiens. After normalization, we identified 28 differentially expressed miRNAs between the two strains. Additionally, we found that cpp-miR-71 was significant down regulated in female adults from the DR-strain. Based on microinjection and CDC Bottle Bioassay data, we found that cpp-miR-71 may play a contributing role in deltamethrin resistance. The present study provides the firstly large-scale characterization of miRNAs in Cu. pipiens and provides evidence of post-transcription regulation. The differentially expressed miRNAs between the two strains are expected to contribute to the development of pyrethroid resistance. PMID- 25446393 TI - Clinical application of whole exome sequencing reveals a novel compound heterozygous TK2-mutation in two brothers with rapidly progressive combined muscle-brain atrophy, axonal neuropathy, and status epilepticus. AB - Mutations in several genes cause mtDNA depletion associated with encephalomyopathy. Due to phenotypic overlap, it is difficult to conclude from clinical phenotype to genetic defect. Here we report on two brothers who presented with rapid fatty muscle degeneration, axonal neuropathy, rapid loss of supratentorial white and gray matter, and status epilepticus. Whole exome sequencing coupled with 'identity-by-state' (IBS) analysis revealed a compound heterozygous missense mutation (p.M117V, p.A139V) in the thymidine kinase 2 (TK2) gene that segregated with the phenotype. Both mutations were located in the thymidine binding pouch of the enzyme. Residual mtDNA copy numbers in muscle were 8.5%, but normal in blood and fibroblasts. Our results broaden the clinical phenotype spectrum of TK2 mutations and promote WES as a useful method in the clinical setting for mutation detection, even in untypical cases. If two or more affected siblings from a non-consanguineous family can be investigated, IBS analysis provides a powerful tool to narrow the number of disease candidates, similarly to autozygosity mapping in consanguineous families. PMID- 25446392 TI - Syntaxin 1A modulates the sexual maturity rate and progeny egg size related to phase changes in locusts. AB - The migratory locust (Locusta migratoria) exhibits clear phenotypic plasticity depending on its population density. Previous studies have explored the molecular mechanisms of body colour, behavior, immunity, and metabolism between high population density gregarious (G) and low population density solitarious (S) locusts. However, the molecular mechanisms underlying differences in reproductive traits remain unknown. G locusts reach sexual maturation much faster and lay larger eggs compared with S locusts. The traits of G locusts decreased significantly with isolation, whereas those of S locusts increased with crowding. Analysis of gene expression in female adults indicated that syntaxin 1A (Syx1A) was expressed significantly higher in G locusts than in S locusts. After silencing Syx1A expression in G locusts by RNA interference (RNAi), their sexual maturity rate and progeny egg size changed towards those of S locusts. Similarly, increment in the traits of S locusts with crowding was blocked by Syx1A interference. Changes in the traits were also confirmed by decrease in the level of vitellogenin, which is regulated by Syx1A. In conclusion, plasticity of the sexual maturity rate and progeny egg size of G and S locusts, which is beneficial for locusts to adapt to environmental changes, is regulated by Syx1A. PMID- 25446394 TI - Mitochondria in health and disease - 3rd annual conference of society for mitochondrial research and medicine - 19-20 December 2013 - Bengaluru, India. AB - The primary role of mitochondria was long considered to be production of cellular energy. However, as the understanding of mitochondria in disease is ever expanding, so is their additional function for a healthy organism. Mitochondrial dysfunction is linked to a range of pathologies, including cancer, neurodegenerative disorders, premature aging, diabetes and muscular diseases. Mitochondrial diseases can be hard to diagnose and treat and, therefore, interdisciplinary research and communication are important. The Third Annual Conference of Society for Mitochondrial Research and Medicine - India (SMRM) was titled "Mitochondria in Health and Disease". The conference was organized by Gayathri N, K Thangaraj, and KK Singh and was held at the National Institute of Mental Health & Neuro Sciences (NIMHANS) in Bangalore, India, from the 19th to 20th of December 2013. The meeting featured internationally renowned speakers within the field of mitochondrial research and medicine with the goal of bridging the gap between basic and clinical researchers. This review summarizes key outcomes of the conference. PMID- 25446387 TI - The role of genetic and epigenetic changes in pituitary tumorigenesis. AB - Pituitary adenomas are one of the most common intracranial tumors. Despite their benign nature, dysregulation of hormone secretion causes systemic metabolic deterioration, resulting in high mortality and an impaired quality of life. Tumorigenic pathogenesis of pituitary adenomas is mainly investigated by performing genetic analyses of somatic mutations in the tumor or germline mutations in patients. Genetically modified mouse models, which develop pituitary adenomas, are also used. Genetic analysis in rare familial pituitary adenomas, including multiple endocrine neoplasia type 1 and type 4, Carney complex, familial isolated pituitary adenomas, and succinate dehydrogenases (SDHs) mediated paraganglioma syndrome, revealed several causal germline mutations and sporadic somatic mutations in these genes. The analysis of genetically modified mouse models exhibiting pituitary adenomas has revealed the underlying mechanisms, where cell cycle regulatory molecules, tumor suppressors, and growth factor signaling are involved in pituitary tumorigenesis. Furthermore, accumulating evidence suggests that epigenetic changes, including deoxyribonucleic acid (DNA) methylation, histone modification, micro ribonucleic acids (RNAs), and long noncoding RNAs play a pivotal role. The elucidation of precise mechanisms of pituitary tumorigenesis can contribute to the development of novel targeted therapy for pituitary adenomas. PMID- 25446395 TI - Tissue-specific mtDNA abundance from exome data and its correlation with mitochondrial transcription, mass and respiratory activity. AB - Eukaryotic cells contain a population of mitochondria, variable in number and shape, which in turn contain multiple copies of a tiny compact genome (mtDNA) whose expression and function is strictly coordinated with the nuclear one. mtDNA copy number varies between different cell or tissues types, both in response to overall metabolic and bioenergetics demands and as a consequence or cause of specific pathological conditions. Here we present a novel and reliable methodology to assess the effective mtDNA copy number per diploid genome by investigating off-target reads obtained by whole-exome sequencing (WES) experiments. We also investigate whether and how mtDNA copy number correlates with mitochondrial mass, respiratory activity and expression levels. Analyzing six different tissues from three age- and sex-matched human individuals, we found a highly significant linear correlation between mtDNA copy number estimated by qPCR and the frequency of mtDNA off target WES reads. Furthermore, mtDNA copy number showed highly significant correlation with mitochondrial gene expression levels as measured by RNA-Seq as well as with mitochondrial mass and respiratory activity. Our methodology makes thus feasible, at a large scale, the investigation of mtDNA copy number in diverse cell-types, tissues and pathological conditions or in response to specific treatments. PMID- 25446397 TI - GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases. AB - Pyruvate therapy is a promising approach for the treatment of mitochondrial diseases. To identify novel biomarkers for diagnosis and to evaluate therapeutic efficacy, we performed microarray analysis of 2SD cybrid cells harboring a MELAS causing mutation and control cells treated with either lactate or pyruvate. We found that expression and secretion of growth differentiation factor 15 (GDF15) were increased in 2SD cells treated with lactate and that serum GDF15 levels were significantly higher in patients with mitochondrial diseases than in those with other diseases, suggesting that GDF15 could be a useful marker for diagnosis and evaluating the therapeutic efficacy of pyruvate. PMID- 25446396 TI - Physical exercise prior and during treatment reduces sub-chronic doxorubicin induced mitochondrial toxicity and oxidative stress. AB - Doxorubicin (DOX) is an anti-cancer agent whose clinical usage results in a cumulative and dose-dependent cardiotoxicity. We have previously shown that exercise performed prior to DOX treatment reduces the resulting cardiac(mito) toxicity. We sought to determine the effects on cardiac mitochondrial toxicity of two distinct chronic exercise models (endurance treadmill training-TM and voluntary free-wheel activity-FW) when used prior and during DOX treatment. Male young Sprague-Dawley rats were divided into six groups (n=6 per group): SAL+SED (saline sedentary), SAL+TM (12-weeks TM), SAL+FW (12-weeks FW), DOX+SED (7-weeks of chronic DOX treatment 2mg/kg per week), DOX+TM and DOX+FW. DOX administration started 5weeks after the beginning of the exercise protocol. Heart mitochondrial ultrastructural alterations, mitochondrial function (oxygen consumption and membrane potential), semi-quantification of oxidative phosphorylation (OXPHOS) proteins and their in-gel activity, as well as proteins involved in mitochondrial oxidative stress (SIRT3, p66shc and UCP2), biogenesis (PGC1alpha and TFAM), acetylation and markers for oxidative damage (carbonyl groups, MDA,SH, aconitase, Mn-SOD activity) were evaluated. DOX treatment resulted in ultrastructural and functional alterations and decreased OXPHOS. Moreover, DOX decreased complex I activity and content, mitochondrial biogenesis (TFAM), increased acetylation and oxidative stress. TM and FW prevented DOX-induced alteration in OXPHOS, the increase in oxidative stress, the decrease in complex V activity and in complex I activity and content. DOX-induced decreases in TFAM and SIRT3 content were prevented by TM only. Both chronic models of physical exercise performed before and during the course of sub-chronic DOX treatment translated into an improved mitochondrial bioenergetic fitness, which may result in part from the prevention of mitochondrial oxidative stress and damage. PMID- 25446398 TI - Polymorphisms in oxidative stress-related genes are associated with nasopharyngeal carcinoma susceptibility. AB - Nasopharyngeal carcinoma (NPC) is a complex multifactorial disorder involving both genetic and environmental factors. Polymorphisms of genes encoding nitric oxide synthase (NOS) and antioxidant glutathione-S transferases (GSTs) have been associated with various tumors. We examined the combined role of NOS3, NOS2 and GST polymorphisms in NPC risk in Tunisians. We found that NOS3-786C allele and 786 CC genotype, NOS3+894T allele and +894 GT+TT genotypes, NOS2-277 G allele and -277 GG genotype, and GSTT1 del/del genotype, are more prevalent in NPC patients as compared to healthy controls. Our results suggest that genetically driven dysfunction in red-ox stress pathway could augment the risk in NPC-susceptible individuals. PMID- 25446399 TI - Synergistic effect of muramyl dipeptide with heat shock protein 70 from Mycobacterium tuberculosis on immune activation. AB - Heat shock protein 70 from Mycobacterium tuberculosis (Mtb Hsp70) has been known to modulate immune response including dendritic cell activation. Muramyl dipeptide (MDP) is an immunoreactive derivative of peptidoglycan from all Gram negative and Gram-positive bacteria and recognized to be responsible for function of Freund's complete adjuvant. In this study, we evaluated effect of MDP on in vitro activation of bone marrow derived dendritic cells (BMDCs) and in vivo production of cytokines and chemokines induced by Mtb Hsp70. MDP treatment with Mtb Hsp70 dramatically increased production of IL-6, IL-12p40 and TNF-alpha in BMDCs compared with Mtb Hsp70 alone whereas these effects were abolished in Nod2 deficient BMDCs. Phosphorylation of IkappaB-alpha and ERK and impairment of phagocytosis, which is an indicator of DC maturation were enhanced by MDP co treatment with Mtb hsp70 in BMDCs. In addition, ability of Mtb Hsp70-stimulated BMDCs to induce IFN-gamma productions of T cells was increased by MDP co treatment. Finally, intraperitoneal injection of MDP with Mtb Hsp70 dramatically increased production of IL-6, CXCL-1 and CCL2 in serum compared with Mtb hsp70 injection. Our study showed the synergistic effects of MDP with Mtb Hsp70 on DCs and in vivo immune activation. The use of MDP with Mtb Hsp70 to induce immune activation may provide an effective strategy for vaccination to treat cancer and protect against pathogens. PMID- 25446400 TI - Polymorphisms in RNA sensing toll like receptor genes and its association with clinical outcomes of dengue virus infection. AB - Functional polymorphisms in RNA recognizing toll like receptors (TLR) 3, 7, 8 and toll-interleukin-1 receptor domain containing adapter protein adapter (TIRAP) coding genes were investigated in 120 dengue cases [87 dengue fever (DF) cases and 33 dengue hemorrhagic fever (DHF) cases] and 109 healthy controls (HC) to identify their association with clinical outcomes of dengue virus infection. Results revealed significantly lower frequency of TLR3 rs3775291 T allele [DHF vs. DF P = 0.015 odds ratio (OR) with 95% confidence interval (CI) 0.390 (0.160 0.880); DHF vs. HC P = 0.018 OR with 95% CI 0.410 (0.170-0.900)] and 'T' allele carriers [DHF vs. DF P = 0.008 OR with 95% CI 0.288 (0.115-0.722); DHF vs. HC P = 0.040 OR with 95% CI 0.393 (0.162-0.956)] and higher frequency of TIRAP rs8177374 'C/T' genotype [DHF vs. HC P = 0.020 OR with 95% CI 2.643 (1.167-5.986)] in DHF. Higher frequency of TLR8 rs3764879-rs3764880 haplotype C-A was observed in male DF cases compared to male HC [P = 0.025 OR with 95% CI 2.185 (1.101-4.336)]. The results suggest that TLR3 and TIRAP gene variants influence the risk for DHF. PMID- 25446401 TI - Anti-pneumococcal deficits of monocyte-derived macrophages from the advanced-age, frail elderly and related impairments in PI3K-AKT signaling. AB - The advanced-age, frail elderly are especially vulnerable to developing pneumococcal infection and disease. Macrophages are critical mediators in the defence against Streptococcus pneumoniae at the upper respiratory tract, however, little is known of their anti-pneumococcal capacity in the elderly. Herein we demonstrate that monocyte-derived macrophages (MDMs) from the advanced-age, frail elderly produce less TNF, IL-6, IL-1beta and IL-8 in response to heat-killed S. pneumoniae, which does not appear to be related to mRNA stability or decay. Furthermore, despite maintaining the ability to bind and phagocytose bacteria, MDMs from these individuals have a reduced capacity to kill S. pneumoniae. These defects parallel reduced PI3K-AKT signaling, which can significantly abrogate bacterial killing, but does not affect cytokine responses. Since macrophages are critical in the defence against S. pneumoniae, this study adds valuable insight into the susceptibility of the elderly to pneumococcal disease and highlights the PI3K-AKT signaling pathway as a potential therapeutic target. PMID- 25446402 TI - B7-H4 overexpression impairs the immune response of T cells in human cervical carcinomas. AB - OBJECTIVE: To investigate B7-H4 expression and its correlation with the number of infiltrating T lymphocytes and cytokine production by those lymphocytes in human cervical cancer and to determine the effect of recombinant B7-H4 on the active peripheral blood T cells of the patients in vitro. METHODS: B7-H4 expression was detected in 67 cases of cervical cancer using immunohistochemical staining. Tumor infiltrating CD8(+)T, CD4(+)T, and FOXP3(+) (Forkhead Box P3) T lymphocytes and their levels of IFN-gamma and TGF-beta1 production were determined by immunofluorescent double-staining. After the peripheral blood T lymphocytes of patients were co-cultured with B7-H4, proliferation, apoptosis, and cell subtypes were analyzed using flow cytometry. Cytokines in the supernatant were detected by ELISA. RESULTS: B7-H4 was expressed in 46% (31/67) of the cases of cervical cancer. The number of infiltrating CD8(+)T lymphocytes and their IFN-gamma production in positive B7-H4 expression cervical cancers was significantly lower than in negative B7-H4 cases (P<0.01, P<0.05), but there was no significant difference between cases positive and negative for B7-H4 with respect to infiltrating FOXP3(+)T and CD4(+)T cells or TGF-beta1 production. After co culture with B7-H4 for 48 h, the patients' activated T lymphocytes were arrested at G1/G2 phase. The Ki67 positive rates of CD4(+)T and CD8(+)T cells were 2.13 +/ 0.13% and 1.03 +/- 1.33%, and they were lower than in the blank group. The proportion of CD4(+)T and CD8(+)T cells decreased, but CD4(+)T/CD8(+)T and the proportion of CD4(+)CD25(+)Foxp3(+)T cells increased. In addition, concentrations of IL-10 and TGF-beta1 in the supernatant of co-cultured T cells increased significantly (P<0.05, P<0.05), but that of IFN-gamma decreased. B7-H4 had no significant effect on apoptosis of the T cells. CONCLUSION: B7-H4 is overexpressed in human cervical cancers, and it is associated with lower numbers of tumor-infiltrating CD8(+)T lymphocytes and therefore less IFN-gamma production. In vitro, B7-H4 inhibits the proliferation of CD4(+)T and CD8(+)T but promotes the proliferation of Tregs and the secretion of IL-10 and TGF-beta1. B7 H4 plays an important role in depressing the anti-tumor immunity of CD8(+)T cell in microenvironments of cervical cancer. PMID- 25446403 TI - Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia. AB - Acyclic nucleoside phosphonates (ANPs) are well-known for their antiviral properties, three of them being approved for the treatment of human immunodeficiency virus infection (tenofovir), chronic hepatitis B (tenofovir and adefovir) or human cytomegalovirus retinitis (cidofovir). In addition, cidofovir is mostly used off-label for the treatment of infections caused by several DNA viruses other than cytomegalovirus, including papilloma- and polyomaviruses, which do not encode their own DNA polymerases. There is considerable interest in understanding why cidofovir is effective against these small DNA tumor viruses. Considering that papilloma- and polyomaviruses cause diseases associated either with productive infection (characterized by high production of infectious virus) or transformation (where only a limited number of viral proteins are expressed without synthesis of viral particles), it can be envisaged that cidofovir may act as antiviral and/or antiproliferative agent. The aim of this review is to discuss the advances in recent years in understanding the mode of action of ANPs as antiproliferative agents, given the fact that current data suggest that their use can be extended to the treatment of non-viral related malignancies. PMID- 25446404 TI - Global geno-proteomic analysis reveals cross-continental sequence conservation and druggable sites among influenza virus polymerases. AB - Influenza virus is one of the major causes of mortality and morbidity associated with respiratory diseases. The high rate of mutation in the viral proteome provides it with the ability to survive in a variety of host species. This property helps it in maintaining and developing its pathogenicity, transmission and drug resistance. Alternate drug targets, particularly the internal proteins, can potentially be exploited for addressing the resistance issues. In the current analysis, the degree of conservation of influenza virus polymerases has been studied as one of the essential elements for establishing its candidature as a potential target of antiviral therapy. We analyzed more than 130,000 nucleotide and amino acid sequences by classifying them on the basis of continental presence of host organisms. Computational analyses including genetic polymorphism study, mutation pattern determination, molecular evolution and geophylogenetic analysis were performed to establish the high degree of conservation among the sequences. These studies lead to establishing the polymerases, in particular PB1, as highly conserved proteins. Moreover, we mapped the conservation percentage on the tertiary structures of proteins to identify the conserved, druggable sites. The research study, hence, revealed that the influenza virus polymerases are highly conserved (95-99%) proteins with a very slow mutation rate. Potential drug binding sites on various polymerases have also been reported. A scheme for drug target candidate development that can be employed to rapidly mutating proteins has been presented. Moreover, the research output can help in designing new therapeutic molecules against the identified targets. PMID- 25446407 TI - Erratum to: Determinants of exclusive breastfeeding cessation: identifying an "at risk population" for special support. PMID- 25446405 TI - Development of a high-content screen for the identification of inhibitors directed against the early steps of the cytomegalovirus infectious cycle. AB - Human cytomegalovirus (CMV) is a latent and persistent virus whose proliferation increases morbidity and mortality of immune-compromised individuals. The current anti-CMV therapeutics targeting the viral DNA polymerase or the major immediate early (MIE) gene locus are somewhat effective at limiting CMV-associated disease. However, due to low bioavailability, severe toxicity, and the development of drug resistant CMV strains following prolonged treatment, current anti-CMV therapeutics are insufficient. To help address this shortfall, we established a high-content assay to identify inhibitors targeting CMV entry and the early steps of infection. The infection of primary human fibroblasts with a variant of the CMV laboratory strain AD169 expressing a chimeric IE2-yellow fluorescence protein (YFP) (AD169IE2-YFP) provided the basis for the high-content assay. The localization of IE2-YFP to the nucleus shortly following an AD169IE2-YFP infection induced a robust fluorescent signal that was quantified using confocal microscopy. The assay was optimized to achieve outstanding assay fitness and high Z' scores. We then screened a bioactive chemical library consisting of 2080 compounds and identified hit compounds based on the decrease of fluorescence signal from IE2-YFP nuclear expression. The hit compounds likely target various cellular processes involved in the early steps of infection including capsid transport, chromatin remodeling, and viral gene expression. Extensive secondary assays confirmed the ability of a hit compound, convallatoxin, to inhibit infection of both laboratory and clinical CMV strains and limit virus proliferation. Collectively, the data demonstrate that we have established a robust high-content screen to identify compounds that limit the early steps of the CMV life cycle, and that novel inhibitors of early infection events may serve as viable CMV therapeutics. PMID- 25446406 TI - MED20 mutation associated with infantile basal ganglia degeneration and brain atrophy. AB - Infantile movement disorders are rare and genetically heterogeneous. We set out to identify the disease-causing mutation in siblings with a novel recessive neurodegenerative movement disorder. Genetic linkage analysis and whole-exome sequencing were performed in the original family. A cohort of six unrelated patients were sequenced for further mutations in the identified candidate gene. Pathogenicity of the mutation was evaluated by in silico analyses and by structural modeling. We identified the first and homozygous mutation (p.Gly114Ala) in the Mediator subunit 20 gene (MED20) in siblings presenting with infantile-onset spasticity and childhood-onset dystonia, progressive basal ganglia degeneration, and brain atrophy. Mediator refers to an evolutionarily conserved multi-subunit RNA polymerase II co-regulatory complex. Pathogenicity of the identified missense mutation is suggested by in silico analyses, by structural modeling, and by previous reporting of mutations in four distinct Mediator subunits causing neurodegenerative phenotypes. No further MED20 mutations were detected in this study. CONCLUSION: We delineate a novel infantile onset neurodegenerative movement disorder and emphasize the Mediator complex as critical for normal neuronal function. Definitive proof of pathogenicity of the identified MED20 mutation will require confirmation in unrelated patients. PMID- 25446408 TI - Adolescent displaced midshaft clavicle fracture. PMID- 25446409 TI - A randomized comparison of volar plate and external fixation for intra-articular distal radius fractures. AB - PURPOSE: To compare surgical outcomes of volar locking plates (VP) and external fixation (EF) (with or without intra-focal fixation) for AO-type C2 and C3 fractures of the distal radius. METHODS: From an initial group of 92 patients with AO-type C2 and C3 distal radius fractures who were enrolled in a prospective, randomized study comparing volar plate fixation with external fixation (with or without intra-focal fixation), 74 patients were studied. The researchers evaluated functional assessments (wrist range of motion, grip strength, and Michigan Hand Questionnaire) at each patient visit and measured radiographic assessment (radial inclination, volar tilt, ulnar variance, and articular congruity) at 12 months. RESULTS: The grip strength of the VP group was significantly greater than that of the EF group at 3 and 6 months. The range of motion was significantly greater in the VP group than in the EF group at 3 months. There were no significant differences in the range of motion and grip strength between the 2 groups at 12 months. The Michigan Hand Questionnaire score was higher in the VP group than in the EF group at 3 months but was same at 12 months. There was no significant difference between groups with respect to volar tilt or radial inclination. The VP group showed superior radiologic outcomes in terms of the ulnar variance. One patient in the VP group and 3 in the EF group had an intra-articular stepoff deformity greater than 2 mm. This difference did not reach statistical significance. CONCLUSIONS: These results for functional recovery after distal radius surgery offer insight into treatment decisions and interpretations of treatment outcomes for patients with comminuted intra articular distal radius fractures. PMID- 25446410 TI - Guyon canal: the evolution of clinical anatomy. AB - Guyon canal refers to the ulnar tunnel at the wrist named for the French surgeon Jean Casimir Felix Guyon, who described this space in 1861. After Guyon's description, clinicians have focused their interest on symptoms caused by compression of structures occupying this canal (later named ulnar tunnel syndrome or Guyon syndrome). However, disagreement and confusion persisted over the correct anatomical boundaries and terminology used to describe the ulnar tunnel. Through anatomical investigation and evolving clinical case studies, the current understanding of the anatomy of the ulnar tunnel was established. This article examines the evolution of the anatomical description of the ulnar tunnel and its relevant clinical associations and casts light on the life and contributions of Guyon. PMID- 25446411 TI - Options for digital nerve gap. PMID- 25446412 TI - Longitudinal split tear of the extensor pollicis brevis tendon: report of 2 cases. AB - Two patients presented with radial-sided wrist pain and longitudinal split tears of the extensor pollicis brevis tendon. Surgical debridement and repair was performed on the first patient with good results. Early diagnosis in the second patient led to successful treatment with immobilization alone. If diagnostic maneuvers for de Quervain tenosynovitis produce pain in a location other than the radial styloid, advanced imaging should be considered to identify other anatomic causes for the pain. PMID- 25446413 TI - Ultrasound guidance of steroid injections. PMID- 25446421 TI - Percutaneous radiofrequency ablation of sporadic Bosniak III or IV lesions: treatment techniques and short-term outcomes. AB - PURPOSE: To evaluate retrospectively the techniques and outcomes of percutaneous radiofrequency (RF) ablation for treatment of Bosniak III or IV lesions. MATERIALS AND METHODS: Between August 2006 and August 2013, 30 patients (25 men and 5 women; mean age, 57 y; range, 22-77 y) with 35 nonhereditary Bosniak III (n = 15) or IV (n = 20) lesions underwent computed tomography-guided RF ablation. The mean size of the lesions was 2.8 cm +/- 0.9 (range, 1.1-4.3 cm). The mean follow-up period was 24 months +/- 16 (range, 6-70 mo). Duration of ablation, number of sessions and electrode repositions, primary and secondary effectiveness rates, major complication rate, reduction rate of lesion size, estimated glomerular filtration rate (GFR), and local tumor progression were recorded. Wilcoxon signed rank test was used for statistical analysis. RESULTS: Mean duration of ablation was 18 minutes +/- 14 (range, 2-65 min), and median number of sessions was one. Median number of electrode repositions was 1.0 +/- 1.6 (range, 0-6). Primary and secondary effectiveness rates were 97.1% (34 of 35) and 100% (1 of 1), respectively. Mean reduction rate of lesion size was significantly greater from before RF ablation to 1 month after RF ablation (7.1 mm/mo +/- 4.5) compared with from 1 month after RF ablation to the last month of follow-up (0.2 mm/mo +/- 0.2; P < .0001). Mean GFR after RF ablation (65.4 mL/min/1.73 m(2) +/- 26.1) was minimally reduced but significantly different from mean GFR before RF ablation (76.0 mL/min/1.73 m(2) +/- 28.4; P < .0001). Major complications occurred in 2 of 35 RF ablation sessions for a rate of 5.7%, resulting from pneumothorax. Of 30 patients, 29 (96.7%) did not have local tumor progression or metastasis for 2 years. CONCLUSIONS: Percutaneous RF ablation is technically feasible and yields excellent short-term outcomes in treating sporadic Bosniak III or IV lesions. PMID- 25446422 TI - Radiofrequency ablation is a thyroid function-preserving treatment for patients with bilateral benign thyroid nodules. AB - PURPOSE: To evaluate the efficacy and safety of radiofrequency (RF) ablation for treatment of bilateral thyroid nodules as well as preservation of thyroid function. MATERIALS AND METHODS: Between January 2007 and October 2012, 18 patients (16 women and 2 men; mean age, 49.9 y; median age, 44 y; age range, 27 81 y) with bilateral thyroid nodules treated by RF ablation were included in this study. The inclusion criteria included bilateral thyroid nodules, pressure symptoms or cosmetic problems, cytologic confirmation of benignancy without atypical cells, and patient refusal of surgery. We used an RF generator (Cool-tip RF system [Covidien, Boulder, Colorado] or SSP-2000, Taewoong Medical Co, Ltd [Gyeonggi-do, Republic of Korea]) and an 18-gauge internally cooled electrode with 1-cm active tips (Cool-tip [Covidien] or Well-Point RF electrode [Taewoong Medical Co, Ltd]). RF ablation was conducted using the moving shot technique and a trans-isthmic approach. RF ablation was performed in separate sessions for nodules in each lobe. Follow-up ultrasound examinations were performed at 1-6 months, 6-12 months, and during the last month of follow-up. The diameter and volume of the nodule and clinical problems including cosmetic and symptom scores were evaluated before and after the procedure. RESULTS: The mean initial nodule size was 4.1 cm +/- 1.9, although there was a significant decrease by the time of the last follow-up examination (range, 1-48 mo; mean, 18.1 mo +/- 12.8; P < .001, 2.5 cm +/- 1.4). The initial nodule volume was 24.4 mL +/- 32.2 and was decreased at the last follow-up (6.3 mL +/- 19.0, P < .001), with a mean volume reduction of 75.9% +/- 19.0. The symptom (P < .001) and cosmetic (P < .001) scores were decreased. Serum hormone levels did not differ significantly before treatment and at the last follow-up (P > .05). CONCLUSIONS: RF ablation improves cosmetic problems and symptoms and preserves thyroid function in patients with bilateral thyroid nodules. PMID- 25446423 TI - Optimal imaging surveillance schedules after liver-directed therapy for hepatocellular carcinoma. AB - PURPOSE: To optimize surveillance schedules for the detection of recurrent hepatocellular carcinoma (HCC) after liver-directed therapy. MATERIALS AND METHODS: New methods have emerged that allow quantitative analysis and optimization of surveillance schedules for diseases with substantial rates of recurrence such as HCC. These methods were applied to 1,766 consecutive chemoembolization, radioembolization, and radiofrequency ablation procedures performed on 910 patients between 2006 and 2011. Computed tomography or magnetic resonance imaging performed just before repeat therapy was set as the time of "recurrence," which included residual and locally recurrent tumor as well as new liver tumors. Time-to-recurrence distribution was estimated by Kaplan-Meier method. Average diagnostic delay (time between recurrence and detection) was calculated for each proposed surveillance schedule using the time-to-recurrence distribution. An optimized surveillance schedule could then be derived to minimize the average diagnostic delay. RESULTS: Recurrence is 6.5 times more likely in the first year after treatment than in the second. Therefore, screening should be much more frequent in the first year. For eight time points in the first 2 years of follow-up, the optimal schedule is 2, 4, 6, 8, 11, 14, 18, and 24 months. This schedule reduces diagnostic delay compared with published schedules and is cost-effective. CONCLUSIONS: The calculated optimal surveillance schedules include shorter-interval follow-up when there is a higher probability of recurrence and longer-interval follow-up when there is a lower probability. Cost can be optimized for a specified acceptable diagnostic delay or diagnostic delay can be optimized within a specified acceptable cost. PMID- 25446424 TI - Strut penetration: local complications, breakthrough pulmonary embolism, and retrieval failure in patients with Celect vena cava filters. AB - PURPOSE: To investigate strut penetration in patients with Celect filters, specifically local complications and association with breakthrough pulmonary embolism (PE) or retrieval failure. MATERIALS AND METHODS: A retrospective single center study was conducted to evaluate patients who received Celect filters between January 2007 and May 2013. A total of 595 filters were placed during the study period. Primary indications included thromboembolic disease (93%) and primary surgical prophylaxis (7%). Complications and retrieval data were assessed by computed tomography (CT) and electronic medical records. RESULTS: A total of 193 patients underwent follow-up abdominal CT at a mean follow-up interval of 176.2 days (range, 0-1,739 d). The rate of strut penetration more than 3 mm outside the caval wall was 28.5% (n = 55). One patient had CT evidence of clinically major strut penetration (1.8%) with strut compression of the right ureter causing hydronephrosis. Indwelling filter time longer than 100 days was associated with strut penetration (P < .001). Age, sex, and history of thromboembolic disease were not associated with strut penetration (P = .51, P = .81, and P = .89). Sixty-three patients presented for follow-up CT pulmonary angiography at a mean of 128.1 days (range, 1-895 d). The rate of breakthrough PE was 12.7%. The overall retrieval success rate was 96.7% (n = 150). Strut penetration was not associated with breakthrough PE or retrieval failure (P = .49 and P = .22). CONCLUSIONS: Although strut penetration is a common complication with Celect filters, there is no association with breakthrough PE or retrieval failure. CT evidence of local complications associated with strut penetration is rare. PMID- 25446425 TI - Percutaneous microwave ablation of hepatocellular carcinoma with a gas-cooled system: initial clinical results with 107 tumors. AB - PURPOSE: To retrospectively review the results of hepatocellular carcinoma (HCC) treatment with a high-power, gas-cooled, multiantenna-capable microwave device. MATERIALS AND METHODS: A total of 107 HCCs in 75 patients (65 men) with a mean age of 61 years (range, 44-82 y) were treated via percutaneous approach. Combination microwave ablation and transarterial chemoembolization was performed for 22 tumors in 19 patients with tumors larger than 4 cm (n = 10), tumors larger than 3 cm with ill-defined margins (n = 7), or lesions not identified with ultrasonography (n = 5). Mean tumor size was 2.1 cm (range, 0.5-4.2 cm), with median follow-up of 14 months, for ablation alone; compared with 3.7 cm (range, 1.0-7.0 cm) and 12 months, respectively, for combination therapy. All procedures were performed with a single microwave system (Certus 140) with one to three 17 gauge antennas. RESULTS: Mean ablation time was 5.3 minutes (range, 1-11.5 min). All treatments were considered technically successful in a single session. Primary technique effectiveness rates were 91.6% (98 of 107) overall, 93.7% (89 of 95) for tumors 4 cm or smaller, and 75.0% (nine of 12) for tumors larger than 4 cm; and 91.8% (78 of 85) for ablation alone and 90.9% (20 of 22) for combination therapy. There was no major complication or procedure-related mortality. The overall survival rate was 76.0% at a median 14-month clinical follow-up, with most deaths related to end-stage liver disease (n = 11) or multifocal HCC (n = 5). CONCLUSIONS: Treating HCC with a gas-cooled, multiantenna capable microwave ablation device is safe, with promising treatment effectiveness. PMID- 25446426 TI - Caramiphen-induced block of sodium currents and spinal anesthesia. AB - The underlying mechanisms for the action of caramiphen used in local anesthesia are not well understood. The purpose of this study was to evaluate the block of caramiphen on voltage-gated Na+ channels and in spinal anesthesia. We investigated the effect of caramiphen on voltage-gated sodium channels in differentiated neuronal NG108-15 cells as well as on rat motor function, proprioception, and pain behavior (when administered intrathecally). In in vitro experiments, lidocaine produced concentration- and state-dependent effects on tonic block of voltage-gated Na+ currents (IC50 of 66.2 and 212.9 uM at holding potentials of -70 and -100 mV, respectively). Caramiphen exhibited a milder state dependence of block (IC50 of 52.1 and 99.5 uM at holding potentials of -70 and 100 mV, respectively). Lidocaine showed a much stronger frequency-dependence of block than caramiphen: with high frequency stimulation (3.33 Hz), 50 uM caramiphen elicited an additional 20% blockade, whereas the same concentration of lidocaine produced 50% more block. In in vivo experiments, caramiphen with a more sensory-selective action over motor blockade was more potent than lidocaine (P<0.05) in spinal anesthesia. On an equipotent basis (25% effective dose (ED25), ED50, and ED75), the duration of caramiphen at producing spinal anesthesia was longer than that of lidocaine (P<0.01). Our data revealed that caramiphen had a more potent, prolonged spinal blockade with a more sensory/nociceptive-selective action over motor blockade in comparison with lidocaine. Spinal anesthesia with caramiphen could be through the suppression of voltage-gated Na+ currents. PMID- 25446427 TI - Subcellular distribution and early signalling events of P2X7 receptors from mouse cerebellar granule neurons. AB - The subcellular distribution and early signalling events of P2X7 receptors were studied in mouse cerebellar granule neurons. Whole-cell patch-clamp recordings evidenced inwardly directed non-desensitizing currents following adenosine 5' triphosphate (ATP; 600 uM) or 2'-3'-o-(4-benzoylbenzoyl)-adenosine 5' triphosphate (BzATP; 100 uM) administration to cells bathed in a medium with no added divalent cations (Ca(2+) and Mg(2+)). Nucleotide-activated currents were inhibited by superfusion of 2.5 mM Ca(2+), 1.2 mM Mg(2+) or 100 nM Brilliant Blue G (BBG), hence indicating the expression of ionotropic P2X7 receptors. Fura-2 calcium imaging showed [Ca(2+)]i elevations in response to ATP or BzATP at the somas and at a small number of axodendritic regions of granule neurons. Differential sensitivity of these [Ca(2+)]i increases to three different P2X7 receptor antagonists (100 nM BBG, 10 MUM 4-[(2S)-2-[(5 isoquinolinylsulfonyl)methylamino]-3-oxo-3-(4-phenyl-1-piperazinyl)propyl] phenyl isoquinolinesulfonic acid ester, KN-62, and 1 MUM 3-(5-(2,3-dichlorophenyl)-1H tetrazol-1-yl)methyl pyridine hydrochloride hydrate, A-438079) revealed that P2X7 receptors are co-expressed with different P2Y receptors along the plasmalemma of granule neurons. Finally, experiments with the fluorescent dye YO-PRO-1 indicated that prolonged stimulation of P2X7 receptors does not lead to the opening of a membrane pore permeable to large cations. Altogether, our results emphasise the expression of functional P2X7 receptors at both the axodendritic and somatic levels in mouse cerebellar granule neurons, and favour the notion that P2X7 receptors might function in a subcellular localisation-specific manner: presynaptically, by controlling glutamate release, and on the cell somas, by supporting granule neuron survival against glutamate excytotoxicity. PMID- 25446428 TI - Derivation of ligands for the complement C3a receptor from the C-terminus of C5a. AB - The complement cascade is a highly sophisticated network of proteins that are well regulated and directed in response to invading pathogens or tissue injury. Complement C3a and C5a are key mediators produced by this cascade, and their dysregulation has been linked to a plethora of inflammatory and autoimmune diseases. Consequently, this has stimulated interest in the development of ligands for the receptors for these complement peptides, C3a receptor, and C5a1 (C5aR/CD88). In this study we used computational methods to design novel C5a1 receptor ligands. However, functional screening in human monocyte-derived macrophages using the xCELLigence label-free platform demonstrated altered specificity of our ligands. No agonist/antagonist activity was observed at C5a1, but we instead saw that the ligands were able to partially agonize the closely related complement receptor C3a receptor. This was verified in the presence of C3a receptor antagonist SB 290157 and in a stable cell line expressing either C5a1 or C3a receptor alone. C3a agonism has been suggested to be a potential treatment of acute neutrophil-driven traumatic pathologies, and may have great potential as a therapeutic avenue in this arena. PMID- 25446429 TI - Antinociceptive effect of botulinum toxin type A on experimental abdominal pain. AB - Visceral pain, especially in the abdominal region, represents one of the most common types of pain. Its chronic form is usually very hard to treat by conventional analgesic agents and adjuvants. We investigated the antinociceptive effect of botulinum toxin type A (BTX-A) in male Wistar rats in two models of visceral pain: peritonitis induced by intraperitoneal injection of 1% acetic acid and colitis induced by intracolonic instillation of 0.1% capsaicin. Pain was measured as the number of abdominal writhes. Additionally, referred mechanical sensitivity in the ventral abdominal area was evaluated by von Frey test and the extent of spinal c-Fos expression was immunohistochemically examined. BTX-A significantly reduced the number of abdominal writhes in both models of visceral pain after intrathecal application in a dose of 2 U/kg. In the experimental colitis model, BTX-A (2 U/kg) reduced both referred mechanical allodynia and c Fos expression in the dorsal horn of the spinal cord (S2/S3 segments). In contrast to intrathecal administration, BTX-A (2 U/kg) administered into the cisterna magna had no effect on pain suggesting that the primary site of its action is a spinal cord. PMID- 25446430 TI - Role of hippocampal CA1 area gap junction channels on morphine state-dependent learning. AB - Morphine produces a state dependent learning. The hippocampus is involved in this kind of learning. Gap junctions (GJs) are involved in some of the effects of morphine and exist in different areas of the hippocampus. We investigated the effects of blocking GJ channels of the hippocampal CA1 area, by means of pre-test bilateral injection of carbenoxolone (CBX), on morphine state dependent learning, using a passive avoidance task. Post-training subcutaneous administrations of morphine (0.5, 2.5, 5 and 7.5 mg/kg) dose-dependently impaired memory retrieval. Pre-test administration of morphine (0.5, 2.5, 5 and 7.5 mg/kg) induced a state dependent retrieval of the memory acquired under post-training morphine influence. Pre-test injections of CBX (25, 75 and 150 nM) dose dependently prevented memory retrieval by post-training (7.5 mg/kg) and pre-test (0.5, 2.5, 5, 7.5 mg/kg) injections of morphine. The results suggest that intercellular coupling via GJ channels of the hippocampal CA1 area modulates morphine state dependent learning. PMID- 25446431 TI - Characterization of the triazine, T4, a representative from a novel series of CaV2 inhibitors with strong state-dependence, poor use-dependence, and distinctively fast kinetics. AB - There is strong pharmacological, biological, and genetic evidence supporting the role of N-type calcium channels (CaV2.2) in nociception. There is also human validation data from ziconotide, the CaV2.2-selective peptidyl inhibitor used clinically to treat refractory pain. Unfortunately, ziconotide utility is limited by its narrow therapeutic window and required intrathecal route of administration. A major focus has been placed on identifying state-dependent CaV2.2 inhibitors to improve safety margins. Much less attention, however, has been given to characterizing the kinetics of CaV2.2 inhibitors as a means to further differentiate compounds and maximize therapeutic potential. Here we provide a detailed characterization of the CaV2.2 inhibitor T4 in terms of its state-dependence, use-dependence, kinetics, and mechanism of inhibition. Compound T4 displayed a >20-fold difference in potency when measured under inactivating conditions (IC50=1.1 MUM) as compared to closed-state conditions (IC50=25 MUM). At 3 MUM, T4 produced a 15-fold hyperpolarizing shift in the inactivation curve for CaV2.2 while having no effect on channel activation. To assess the kinetic properties of T4 in a more physiological manner, its inhibition kinetics were assessed at 32 degrees C using 2 mM Ca(2+) as the charge carrier. Surprisingly, the repriming rate for CaV2.2 channels at hyperpolarized potentials was similar in both the presence and absence of T4. This was in contrast to other compounds which markedly delayed repriming. Furthermore, T4 inhibited CaV2.2 channels more potently when channel inactivation was driven through a tonic sub-threshold depolarization rather than through a use-dependent protocol, despite similar levels of inactivation. PMID- 25446434 TI - Brain activity and learning of mathematical rules--effects on the frequencies of EEG. AB - We investigated the change of evoked EEG frequencies induced by learning to solve mathematical tasks by applying divisibility rules. The performance on easy (divisibility by 2, 3, or 5) and hard tasks (divisibility by 9 or by 11) was compared. In a behavioral experiment on 52 adults we found a significant increase in performance from 67% to 90% correct responses induced by rule learning. Subsequently, the EEG data recorded from 30 additional volunteers were analyzed. EEG recordings were performed in two parts: First, subjects had to solve 200 tasks without knowing the divisibility rules. Then the rules were explained, followed by another set of 200 tasks. EEG was measured simultaneously in 30 channels, artifacts were removed offline, and the data before and after rule learning were compared. A wavelet transformation with the Morlet-5 wavelet was computed, and the scalp topography of the maximal frequency and its occurrence time was compared. Largest effects were observed with frequencies between about 6 and 18 Hz. In the frequency band between 12 and 30 Hz maximal frequencies were significantly different after successful learning over frontal and centro parietal scalp areas of the right hemisphere. These changes were paralleled by decreased response times. In summary, our data illustrate a significant relation between successful learning divisibility rules and changes in the frequency content of the task-related EEG. Significant effects were observed after a very short training period of less than 10 min. PMID- 25446432 TI - Angiotensin II limits NO production by upregulating arginase through a p38 MAPK ATF-2 pathway. AB - Enhanced vascular arginase activity can impair endothelium-dependent vasorelaxation by decreasing l-arginine availability to endothelial nitric oxide (NO) synthase, thereby reducing NO production and uncoupling NOS function. Elevated angiotensin II (Ang II) is a key component of endothelial dysfunction in many cardiovascular diseases and has been linked to elevated arginase activity. In this study we explored the signaling pathway leading to increased arginase expression/activity in response to Ang II in bovine aortic endothelial cells (BAEC). Our previous studies indicate involvement of p38 mitogen activated protein kinase (MAPK) in Ang II-induced arginase upregulation and reduced NO production. In this study, we further investigated the Ang II-transcriptional regulation of arginase 1 in endothelial cells. Our results indicate the involvement of ATF-2 transcription factor of the AP1 family in arginase 1 upregulation and in limiting NO production. Using small interfering RNA (siRNA) targeting ATF-2, we showed that this transcription factor is required for Ang II induced arginase 1 gene upregulation and increased arginase 1 expression and activity, leading to reduced NO production. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay further confirmed the involvement of ATF 2. Moreover, our data indicate that p38 MAPK phosphorylates ATF-2 in response to Ang II. Collectively, our results indicate that Ang II increases endothelial arginase activity/expression through a p38 MAPK/ATF-2 pathway leading to reduced endothelial NO production. These signaling steps might be therapeutic targets for preventing vascular endothelial dysfunction associated with elevated arginase activity/expression. PMID- 25446435 TI - Associated occurrence of p75 neurotrophin receptor expressing aldynoglia and microglia/macrophages in long term organotypic murine brain slice cultures. AB - Growth-promoting aldynoglia, characterized by the expression of the prototype immature Schwann cell marker p75 neurotrophin receptor (NTR) have been shown to occur in some demyelinating diseases. However, the mechanisms determining the emergence and fate of such cells are largely unknown. This study aimed at the identification of such cells and potential triggering factors using an in vitro slice culture approach. Organotypic cerebrum and brain stem slices of adult mice were cultivated for up to 18 days in vitro. Immunohistochemistry for the detection of p75(NTR), CD107b, periaxin, growth associated protein (GAP)-43, and glial fibrillary acidic protein (GFAP) was performed. The results for p75(NTR) were substantiated by the use of in situ hybridization. Cultivation was associated with a progressively increasing spontaneous occurrence of bi- to multipolar p75(NTR)-positive, but periaxin-negative glia, indicative of aldynoglial Schwann cell like cells. Similar cells stained intensely positive for GAP-43, a marker for non-myelinating Schwann cells. The number of p75(NTR) positive glia did not correlate with GFAP expression, but showed a strong correlation with a remarkable spontaneous response of CD107b positive phagocytic microglia/macrophages. Moreover, aldynoglial p75(NTR) immunoreactivity negatively correlated to neuronal p75(NTR) expression, which was lost during culturing. The present results demonstrate that the cultivation of organotypic murine brain slices is accompanied by a spontaneous response of both microglia/macrophages and p75(NTR) positive cells, suggestive of Schwann cell like aldynoglia. The findings highlights the role of microglia/macrophages, which seem to be an important triggering factor, facilitating the occurrence of this unique type of macroglia. PMID- 25446436 TI - From brain synapses to systems for learning and memory: Object recognition, spatial navigation, timed conditioning, and movement control. AB - This article provides an overview of neural models of synaptic learning and memory whose expression in adaptive behavior depends critically on the circuits and systems in which the synapses are embedded. It reviews Adaptive Resonance Theory, or ART, models that use excitatory matching and match-based learning to achieve fast category learning and whose learned memories are dynamically stabilized by top-down expectations, attentional focusing, and memory search. ART clarifies mechanistic relationships between consciousness, learning, expectation, attention, resonance, and synchrony. ART models are embedded in ARTSCAN architectures that unify processes of invariant object category learning, recognition, spatial and object attention, predictive remapping, and eye movement search, and that clarify how conscious object vision and recognition may fail during perceptual crowding and parietal neglect. The generality of learned categories depends upon a vigilance process that is regulated by acetylcholine via the nucleus basalis. Vigilance can get stuck at too high or too low values, thereby causing learning problems in autism and medial temporal amnesia. Similar synaptic learning laws support qualitatively different behaviors: Invariant object category learning in the inferotemporal cortex; learning of grid cells and place cells in the entorhinal and hippocampal cortices during spatial navigation; and learning of time cells in the entorhinal-hippocampal system during adaptively timed conditioning, including trace conditioning. Spatial and temporal processes through the medial and lateral entorhinal-hippocampal system seem to be carried out with homologous circuit designs. Variations of a shared laminar neocortical circuit design have modeled 3D vision, speech perception, and cognitive working memory and learning. A complementary kind of inhibitory matching and mismatch learning controls movement. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25446433 TI - Effects of rolipram and roflumilast, phosphodiesterase-4 inhibitors, on hypertension-induced defects in memory function in rats. AB - Hypertension (HT) is a prevailing risk factor for cognitive impairment, the most common cause of vascular dementia; yet, no possible mechanism underlying the cognitive impairment induced by hypertension has been identified so far. Inhibition of PDE-4 has been shown to increase phosphorylation of cAMP-response element binding protein in the hippocampus and enhance the memory performance. Here, we examined the effects of PDE-4 inhibitors, rolipram and roflumilast, on the impairment of learning and memory observed in hypertensive rats. We used 2k 1c hypertensive model to induce learning and memory defects. In addition, mRNA expression of PDE-4 sub-types A-D was also assessed in the hippocampus tissue. Systolic blood pressure (SBP) was measured by tail-cuff method was significantly increased in 2k-1c rats when compared to sham operated rats; this effect was reversed by clonidine, whereas, PDE-4 inhibitors did not. PDE-4 inhibitors significantly reversed time induced memory deficit in novel object recognition task (NORT). Further, the retention latency on the second day in the elevated plus maze model was significantly shortened after repeated administration of rolipram and roflumilast. Plasma and brain concentrations of rolipram, roflumilast and roflumilast N-oxide were also measured after the NORT and showed linear increase in plasma and brain concentrations. The PDE4B and PDE4D gene expression was significantly enhanced in hypertensive rats compared with sham operated however PDE4A and PDE4C remained unaltered. Repeated treatment with PDE 4 inhibitors caused down regulation of PDE4B and PDE4D in hypertensive rats. These results suggest that inhibition of PDE-4 ameliorates HT-induced impairment of learning and memory functions. PMID- 25446437 TI - Association of IL-1, IL-18, and IL-33 gene polymorphisms with late-onset Alzheimer's disease in a Hunan Han Chinese population. AB - Interleukin (IL)-1 plays an important role in Alzheimer's disease (AD), and single nucleotide polymorphisms (SNPs) in the IL-1 gene have been shown to be associated with AD susceptibility. IL-18 and IL-33 are proinflammatory cytokines of the IL-1 family, and increasing evidence has accumulated to support their crucial role in AD pathogenesis. To examine whether SNPs in IL-1alpha (rs1800587), IL-1beta (rs1143627), IL-18 (rs187238), and IL-33 (rs11792633) are associated with late-onset Alzheimer's disease (LOAD) in a Hunan Han Chinese population, we carried out a case-control study involving 201 LOAD patients and 257 healthy controls. No significant differences were found in genotype frequencies of rs1800587 between LOAD patients and controls (P=0.079), but the T allele of rs1800587 was associated with a significantly increased risk of LOAD (P=0.032, odds ratio (OR)=1.592). Significant differences in genotype (P=0.004) and allele (P=0.001) frequencies of rs11792633 were found between LOAD patients and controls, but not for rs1143627 (P=0.535, 0.262, respectively) or rs187238 (P=0.257, 0.139, respectively). The T allele of rs11792633 was found to be a protective factor for LOAD (OR=0.648). These findings suggest that the IL-1alpha SNP rs1800587 and IL-33 SNP rs11792633, but not the IL-1beta SNP rs1143627 or the IL-18 SNP rs187238, contribute to LOAD susceptibility in the Hunan Han Chinese population. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25446438 TI - Restoration of vision in blind individuals using bionic devices: a review with a focus on cortical visual prostheses. AB - The field of neurobionics offers hope to patients with sensory and motor impairment. Blindness is a common cause of major sensory loss, with an estimated 39 million people worldwide suffering from total blindness in 2010. Potential treatment options include bionic devices employing electrical stimulation of the visual pathways. Retinal stimulation can restore limited visual perception to patients with retinitis pigmentosa, however loss of retinal ganglion cells precludes this approach. The optic nerve, lateral geniculate nucleus and visual cortex provide alternative stimulation targets, with several research groups actively pursuing a cortically-based device capable of driving several hundred stimulating electrodes. While great progress has been made since the earliest works of Brindley and Dobelle in the 1960s and 1970s, significant clinical, surgical, psychophysical, neurophysiological, and engineering challenges remain to be overcome before a commercially-available cortical implant will be realized. Selection of candidate implant recipients will require assessment of their general, psychological and mental health, and likely responses to visual cortex stimulation. Implant functionality, longevity and safety may be enhanced by careful electrode insertion, optimization of electrical stimulation parameters and modification of immune responses to minimize or prevent the host response to the implanted electrodes. Psychophysical assessment will include mapping the positions of potentially several hundred phosphenes, which may require repetition if electrode performance deteriorates over time. Therefore, techniques for rapid psychophysical assessment are required, as are methods for objectively assessing the quality of life improvements obtained from the implant. These measures must take into account individual differences in image processing, phosphene distribution and rehabilitation programs that may be required to optimize implant functionality. In this review, we detail these and other challenges facing developers of cortical visual prostheses in addition to briefly outlining the epidemiology of blindness, and the history of cortical electrical stimulation in the context of visual prosthetics. PMID- 25446439 TI - Sleep deprivation during late pregnancy produces hyperactivity and increased risk taking behavior in offspring. AB - Sleep deprivation in women resulting from their modern lifestyle, especially during pregnancy, is a serious concern as it can affect the health of the newborn. Anxiety disorders and cognitive deficits in the offspring are also on the rise. However, experimental studies on the effects of sleep loss during pregnancy, on emotional development and cognitive function of the newborn, are scanty in literature. In the current study, female rats were sleep-deprived for 5h by gentle handling, during the 6 days of the third trimester (days 14-19 of pregnancy). The effects of this sleep deprivation on anxiety-related behaviors of pups during their peri-adolescence age were studied using elevated plus maze (EPM). In addition to body weights of dams and offspring, the maternal behavior was also monitored. The weanlings of sleep-deprived dams showed heightened risk taking behavior as they made increased explorations into the open arms of EPM. They also showed higher mobility in comparison to the control group. Though the body weights of sleep-deprived dams were comparable to those of the control group, their newborns had lower birth weight. Nevertheless, these pups gained weight and reached the control group values during the initial post-natal week. But after weaning, their rate of growth was lower than that of the control group. This is the first report providing evidences for the role of sleep during late pregnancy in shaping the neuropsychological development in offspring. PMID- 25446440 TI - Effects of simulated weightlessness on intramuscular hypertonic saline induced muscle nociception and spinal Fos expression in rats. AB - We assessed the effects of simulated weightlessness, hindlimb unloading (HU) by 7 days of tail suspension, on noxious mechanically and heat evoked spinal withdrawal reflexes and spinal Fos expression during muscle nociception elicited by intramuscular (i.m.) injection of hypertonic (HT; 5.8%) saline into gastrocnemius muscle in rats. In HU rats, i.m. HT saline-induced secondary mechanical hyperalgesia was enhanced, and secondary heat hypoalgesia was significantly delayed. After 7 days of HU, basal Fos expression in spinal L4-6 segments was bilaterally enhanced only in superficial (I-II) but not middle and deep laminae (III-VI) of the spinal dorsal horn, which finding was not influenced by tail denervation. Unilateral i.m. HT saline injection increased spinal Fos expression bilaterally in both the control rats and 7 days of HU rats. The HT saline-induced bilateral increase of spinal Fos occurred within 0.5h and reached its peak within 1h, after which it gradually returned to the control levels within 8h. Spatial patterns of spinal Fos expression differed between the control group and 7 days of HU group. In superficial laminae, the HT saline-induced increases in Fos expression were higher and in the middle and deep laminae V-VI lower in the 7 days of HU than control rats. It is suggested that supraspinal mechanisms presumably underlie the effects of HU on spinally-organized nociception. Simulated weightlessness may enhance descending facilitation and weaken descending inhibition of nociception. PMID- 25446442 TI - Angiotensin-(1-7) in the basolateral amygdala attenuates the cardiovascular response evoked by acute emotional stress. AB - The basolateral amygdala (BLA) plays a critical role in mediating physiological responses to emotional stress. Recent data suggest that angiotensin-(1-7) [Ang-(1 7)] can act centrally attenuating the cardiovascular response to acute stress. We investigated whether Ang-(1-7) in the BLA plays a role in the cardiovascular response to emotional stress. Under anesthesia, guide cannulas were implanted into the BLA of Wistar rats. Five days later, the femoral artery was cannulated for mean arterial pressure (MAP) and heart rate (HR) recordings. Microinjections of Ang-(1-7) (5 or 50 pmol), the Mas receptor antagonist A-779 (100 pmol), Ang-(1 7)+A-779 (50 + 100 pmol, respectively), or vehicle (NaCl 0.9%, control) were performed after 24h and rats were then submitted to stress trials. Injection of Ang-(1-7) into the BLA blocked the tachycardia (DeltaHR: vehicle 135 +/- 23 vs. Ang-(1-7) 9 +/- 12 bpm; P<0.05) and the pressor response (DeltaMAP: vehicle 28 +/ 3 mmHg vs. Ang-(1-7) 6 +/- 2 mmHg; P<0.05) produced by air jet stress. These effects were completely reversed by A-779 (DeltaHR: 109 +/- 11 bpm; DeltaMAP: 18 +/- 2 mmHg). Ang-(1-7) into the BLA also attenuated the pressor response evoked by cage-switch stress paradigm. These findings indicate that Ang-(1-7) can act in the BLA through the Mas receptors modulating the cardiovascular response evoked by emotional stress. PMID- 25446441 TI - Dopamine receptor signaling in the medial orbital frontal cortex and the acquisition and expression of fructose-conditioned flavor preferences in rats. AB - Systemic dopamine (DA) D1 (SCH23390: SCH) and D2 (raclopride: RAC) antagonists blocked fructose-conditioned flavor preference (CFP) acquisition and expression. Fructose-CFP acquisition was eliminated by medial prefrontal cortex (mPFC) SCH and mPFC or amygdala (AMY) RAC. Fructose-CFP expression was reduced following SCH or RAC in AMY or nucleus accumbens (NAc). The present study examined fructose-CFP acquisition and expression following SCH and RAC in the medial orbital frontal cortex (MOFC), another ventral tegmental area DA target. For fructose-CFP acquisition, five groups of rats received vehicle, SCH (24 or 48 nmol) or RAC (24 or 48 nmol) in the MOFC 0.5h prior to 8 training sessions with one flavor (CS+/Fs) mixed in 8% fructose and 0.2% saccharin, and another flavor (CS-/s) mixed in 0.2% saccharin. In six 2-bottle choice tests in 0.2% saccharin, similar fructose-CFP preferences occurred in groups trained with vehicle (76-77%), SCH24 (69-78%), SCH48 (70-74%) and RAC48 (85-92%). RAC24-trained rats displayed significant CS+ preferences during the first (79%) and third (71%), but not second (58%) test pair. For fructose-CFP expression, rats similarly trained with CS+/Fs and CS- solutions received 2-bottle choice tests following MOFC injections of SCH or RAC (12-48 nmol). CS+ preference expression was significantly reduced by RAC (48 nmol: 58%), but not SCH relative to vehicle (78%). A control group receiving RAC in the dorsolateral prefrontal cortex displayed fructose-CFP expression similar to vehicle. These data demonstrate differential frontal cortical DA mediation of fructose-CFP with mPFC D1 and D2 signaling exclusively mediating acquisition, and MOFC D2 signaling primarily mediating expression. PMID- 25446443 TI - Module number of default mode network: inter-subject variability and effects of sleep deprivation. AB - Sleep deprivation have shown its great influence on the default mode network (DMN). The DMN is a core system in resting state brain activity. Recent studies have focused on its subsystems and multiple functions. However, the individual specific organization of the DMN is rarely investigated. As the effects of sleep deprivation (SD) on mood are well documented, a more interesting question is whether changes in the processing of emotional information due to sleep deprivation are related to any specific topological properties of the DMN. In this study, we proposed an index, module number of DMN (mnDMN), to measure the specific modular structure of the DMN for each individual. Our results showed that the DMN was generally split into two modules after SD, and the decreased functional connectivity between the two modules was related to a worsening of the participants' self-reported emotional state. Furthermore, the mnDMN was correlated with participants' rating scores of high valence pictures in the SD session, indicating that the mnDMN might reflect mood valuation in the human brain. Overall, our research reveals the diversity of the DMN, and may contribute towards a better understanding of the properties and functions of the DMN. PMID- 25446444 TI - Neuromodulation and metamodulation by adenosine: Impact and subtleties upon synaptic plasticity regulation. AB - Synaptic plasticity mechanisms, i.e. the sequence of events that underlies persistent changes in synaptic strength as a consequence of transient alteration in neuronal firing, are greatly influenced by the 'chemical atmosphere' of the synapses, that is to say by the presence of molecules at the synaptic cleft able to fine-tune the activity of other molecules more directly related to plasticity. One of those fine tuners is adenosine, known for a long time as an ubiquitous neuromodulator and metamodulator and recognized early as influencing synaptic plasticity. In this review we will refer to the mechanisms that adenosine can use to affect plasticity, emphasizing aspects of the neurobiology of adenosine relevant to its ability to control synaptic functioning. This article is part of a Special Issue entitled Brain and Memory. PMID- 25446445 TI - Plasticity of alpha2-adrenergic spinal antinociception following nerve injury: selective, bidirectional interaction with the delta opioid receptor. AB - Interactions of opioid receptors with other receptor families can be made use of to improve analgesia and reduce adverse effects of opioid analgesics. We investigated interactions of the alpha2-adrenergic receptor (alpha2AR) with opioid receptors of the mu (MOR) and delta (DOR) types in the spinal dorsal horn in an animal model of neuropathic pain induced by spinal nerve ligation. Nine days after nerve injury, immunoreactivity for the alpha2AR subtype A (alpha2AAR) was increased both in tissue homogenates and at pre- and post-synaptic sites in transverse sections. The efficacy of spinally administered alpha2AAR agonist guanfacine at reducing C-fiber-evoked field potentials was increased in nerve ligated rats. This reducing effect was impaired by simultaneous administration of DOR antagonist naltrindole, but not MOR antagonist CTOP, suggesting that concurrent DOR activation was required for alpha2AAR-mediated inhibition. While DOR agonist deltorphin II and MOR agonist DAMGO both effectively depressed C fiber-evoked spinal field potentials, DOR- but not MOR-mediated depression was enhanced by subclinical guanfacine. In conscious, nerve-ligated rats, chronically administered deltorphin II produced stable thermal and mechanical antinociception over the 9 following days after nerve injury without apparent signs of habituation. Such an effect was dramatically enhanced by co-administration of a low dose of guanfacine, which reversed thermal and mechanical thresholds to levels near those prior to injury. The results suggest that spinal, alpha2AAR mediated antinociception is increased after nerve injury and based on DOR co activation. We demonstrate in vivo that alpha2AAR/DOR interaction can be exploited to provide effective behavioral antinociception during neuropathic pain. PMID- 25446447 TI - Cytidine 5'-diphosphocholine (CDP-choline) adversely effects on pilocarpine seizure-induced hippocampal neuronal death. AB - Citicoline (CDP-choline; cytidine 5'-diphosphocholine) is an important intermediate in the biosynthesis of cell membrane phospholipids. Citicoline serves as a choline donor in the biosynthetic pathways of acetylcholine and neuronal membrane phospholipids, mainly phosphatidylcholine. The ability of citicoline to reverse neuronal injury has been tested in animal models of cerebral ischemia and clinical trials have been performed in stroke patients. However, no studies have examined the effect of citicoline on seizure-induced neuronal death. To clarify the potential therapeutic effects of citicoline on seizure-induced neuronal death, we used an animal model of pilocarpine-induced epilepsy. Temporal lobe epilepsy (TLE) was induced by intraperitoneal injection of pilocarpine (25mg/kg) in adult male rats. Citicoline (100 or 300 mg/kg) was injected into the intraperitoneal space two hours after seizure onset and a second injection was performed 24h after the seizure. Citicoline was injected once per day for one week after pilocarpine- or kainate-induced seizure. Neuronal injury and microglial activation were evaluated at 1 week post-seizure. Surprisingly, rather than offering protection, citicoline treatment actually enhanced seizure-induced neuronal death and microglial activation in the hippocampus compared to vehicle treated controls. Citicoline administration after seizure-induction increased immunoglobulin leakage via BBB disruption in the hippocampus compared with the vehicle-only group. To clarify if this adverse effect of citicoline is generalizable across alternative seizure models, we induced seizure by kainate injection (10mg/kg, i.p.) and then injected citicoline as in pilocarpine-induced seizure. We found that citicoline did not modulate kainate seizure-induced neuronal death, BBB disruption or microglial activation. These results suggest that citicoline may not have neuroprotective effects after seizure and that clinical application of citicoline after seizure needs careful consideration. PMID- 25446449 TI - Mitochondrial complex I defects increase ubiquitin in substantia nigra. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder in the developed world, and is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN) of midbrain. Mitochondrial complex I dysfunction has been implicated in PD pathophysiology, yet the molecular mechanism by which complex I defects may cause DA neurodegeneration remain unclear. Using Ndufs4 mouse model of mitochondrial complex I deficiency, we observed a remarkable ubiquitin protein increase in SN of Ndufs4-/- (KO) mice. By contrast, neurofilaments were significantly decreased in SN of KO mice. Furthermore, mass spectrometry and co-immunoprecipitation (Co-IP) analysis indicated an increase in ubiquitinated neurofilaments in midbrain of KO mice, whereas 20S proteasome activities were decreased, which could potentially explain the buildup of ubiquitin protein. Collectively, these data suggest that mitochondrial complex I defects cause proteasome inhibition, a consequent increase in ubiquitinated neurofilaments and other proteins, and decrease the expression of neurofilaments that could be relevant to the mechanism of DA neuronal death in PD. PMID- 25446446 TI - NMDA receptors control vagal afferent excitability in the nucleus of the solitary tract. AB - Previous behavioral studies have demonstrated that presynaptic N-methyl-d aspartate (NMDA) receptors expressed on vagal afferent terminals are involved in food intake and satiety. Therefore, using in vitro live cell calcium imaging of prelabeled rat hindbrain slices, we characterized which NMDA receptor GluN2 subunits may regulate vagal afferent activity. The nonselective NMDA receptor antagonist d,l-2-amino-5-phosphonopentanoic acid (d,l-AP5) significantly inhibited vagal terminal calcium influx, while the excitatory amino acid reuptake inhibitor d,l-threo-beta-benzyloxyaspartic acid (TBOA), significantly increased terminal calcium levels following pharmacological stimulation with ATP. Subunit specific NMDA receptor antagonists and potentiators were used to identify which GluN2 subunits mediate the NMDA receptor response on the vagal afferent terminals. The GluN2B-selective antagonist, ifenprodil, selectively reduced vagal calcium influx with stimulation compared to the time control. The GluN2A selective antagonist, 3-chloro-4-fluoro-N-[4-[[2 (phenylcarbonyl)hydrazino]carbonyl] benzyl]benzenesulfonamide (TCN 201) produced smaller but not statistically significant effects. Furthermore, the GluN2A/B selective potentiator (pregnenolone sulfate) and the GluN2C/D-selective potentiator [(3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4 dihydroisoquinolin-2(1H)-yl)methanone; (CIQ)] enhanced vagal afferent calcium influx during stimulation. These data suggest that presynaptic NMDA receptors with GluN2B, GluN2C, and GluN2D subunits may predominantly control vagal afferent excitability in the nucleus of the solitary tract. PMID- 25446448 TI - Involvement of diacylglycerol kinase beta in the spine formation at distal dendrites of striatal medium spiny neurons. AB - Spine formation, a salient feature underlying neuronal plasticity to adapt to a changing environment, is regulated by complex machinery involving membrane signal transduction. The diacylglycerol kinase (DGK) family, which is involved in membrane lipid metabolism, catalyzes the phosphorylation of a lipid second messenger, diacylglycerol (DG). Of the DGKs, DGKbeta is characterized by predominant expression in a specific brain region: the striatum. We previously demonstrated that DGKbeta is expressed selectively in medium spiny neurons (MSNs) and that it is highly enriched in the perisynaptic membrane on dendritic spines contacted with excitatory terminals. Moreover, DGKbeta regulates spinogenesis through actin-based remodeling in an activity-dependent manner. However, the detailed mechanisms of spinogenesis regulation and its functional significance remain unclear. To address these issues, we performed Golgi-Cox staining to examine morphological aspects of MSNs in the striatum of DGKbeta-knockout (KO) mice. Results show that striatal MSNs of DGKbeta-KO mice exhibited lower dendritic spine density at distal dendrites than wild-type mice did. We also sought protein targets that interact with DGKbeta and identified the GluA2 AMPA receptor subunit as a novel DGKbeta binding partner. In addition, DGKbeta deficient brain exhibits significant reduction of TARP gamma-8, which represents a transmembrane AMPA receptor regulatory protein. These findings suggest that DGKbeta regulates the spine formation at distal dendrites in MSNs. PMID- 25446450 TI - Enhanced post-ischemic angiogenesis in mice lacking RNF213; a susceptibility gene for moyamoya disease. AB - Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease with unknown etiology that is characterized by the development of abnormal vascular networks at the base of the brain. Recent genome-wide studies identified RNF213 as an important MMD susceptibility gene. However, the exact mechanism by which the RNF213 abnormality leads to MMD remains unknown. Thus, we sought to clarify the role of RNF213 in angiogenesis under ischemic conditions using conventional RNF213 knockout mice. We assessed the infarction volume, cerebral edema, and vascular density in the ischemic brain after transient middle cerebral artery occlusion (tMCAO). To further evaluate systemic angiogenesis following chronic ischemia, we investigated blood flow recovery using laser speckle flowmetry, the severity of ambulatory impairments, and vascular density in the hind-limb after permanent femoral artery ligation. Results were compared between homozygous RNF213 knockout mice (RNF213 -/-) and wild-type littermates (Wt). No significant differences were observed in infarction volume or the formation of edema following tMCAO, or in vascular density 28 days after tMCAO between RNF213 -/- and Wt. Blood flow recovery was significantly improved in RNF213 -/- from 3 to 28 days after femoral artery ligation, and angiogenesis as shown by vascular density in the hind-limb was significantly enhanced in RNF213 -/- at 28 days. The amelioration of ambulatory impairments was also evident in RNF213 -/-. Angiogenesis was enhanced in mice lacking RNF213 after chronic hind-limb ischemia, which suggested the potential role of the RNF213 abnormality in the development of pathological vascular networks in chronic ischemia. PMID- 25446451 TI - Expression of fragile X mental retardation protein in neurons and glia of the developing and adult mouse brain. AB - Fragile X syndrome is the most common inherited form of mental retardation and autism. It is caused by a reduction or elimination of the expression of fragile X mental retardation protein (FMRP). Because fragile X syndrome is a neurodevelopmental disorder, it is important to fully document the cell type expression in the developing CNS to provide a better understanding of the molecular function of FMRP, and the pathogenesis of the syndrome. We investigated FMRP expression in the brain using double-labeling immunocytochemistry and cell type markers for neurons (NeuN), astrocytes (S100beta), microglia (Iba-1), and oligodendrocyte precursor cells (NG2). The hippocampus, striatum, cingulate cortex, retrosplenial cortex, corpus callosum and cerebellum were assessed in wild-type C57/BL6 mice at postnatal days 0, 10, 20, and adult. Our results demonstrate that FMRP is ubiquitously expressed in neurons at all times and brain regions studied, except for corpus callosum where FMRP was predominantly present in astrocytes at all ages. FMRP expression in Iba-1 and NG2-positive cells was detected at postnatal day 0 and 10 and gradually decreased to very low or undetectable levels in postnatal day 20 and adult mice. Our results reveal that in addition to continuous and extensive expression in neurons in the immature and mature brain, FMRP is also present in astrocytes, oligodendrocyte precursor cells, and microglia during the early and mid-postnatal developmental stages of brain maturation. Prominent expression of FMRP in glia during these crucial stages of brain development suggests an important contribution to normal brain function, and in its absence, to the fragile X phenotype. PMID- 25446453 TI - Illusion-related brain activations: a new virtual reality mirror box system for use during functional magnetic resonance imaging. AB - Extended viewing of movements of one's intact limb in a mirror as well as motor imagery have been shown to decrease pain in persons with phantom limb pain or complex regional pain syndrome and to increase the movement ability in hemiparesis following stroke. In addition, mirrored movements differentially activate sensorimotor cortex in amputees with and without phantom limb pain. However, using a so-called mirror box has technical limitations, some of which can be overcome by virtual reality applications. We developed a virtual reality mirror box application and evaluated its comparability to a classical mirror box setup. We applied both paradigms to 20 healthy controls and analyzed vividness and authenticity of the illusion as well as brain activation patterns. In both conditions, subjects reported similar intensities for the sensation that movements of the virtual left hand felt as if they were executed by their own left hand. We found activation in the primary sensorimotor cortex contralateral to the actual movement, with stronger activation for the virtual reality 'mirror box' compared to the classical mirror box condition, as well as activation in the primary sensorimotor cortex contralateral to the mirrored/virtual movement. We conclude that a virtual reality application of the mirror box is viable and that it might be useful for future research. PMID- 25446452 TI - The effect of ASK1 on vascular permeability and edema formation in cerebral ischemia. AB - Apoptosis signal-regulating kinase-1 (ASK1) is the mitogen-activated protein kinase kinase kinase (MAPKKK) and participates in the various central nervous system (CNS) signaling pathways. In cerebral ischemia, vascular permeability in the brain is an important issue because regulation failure of it results in edema formation and blood-brain barrier (BBB) disruption. To determine the role of ASK1 on vascular permeability and edema formation following cerebral ischemia, we first investigated ASK1-related gene expression using microarray analyses of ischemic brain tissue. We then measured protein levels of ASK1 and vascular endothelial growth factor (VEGF) in brain endothelial cells after hypoxia injury. We also examined protein expression of ASK1 and VEGF, edema formation, and morphological alteration through cresyl violet staining in ischemic brain tissue using ASK1-small interference RNA (ASK1-siRNA). Finally, immunohistochemistry was performed to examine VEGF and aquaporin-1 (AQP-1) expression in ischemic brain injury. Based on our findings, we propose that ASK1 is a regulating factor of vascular permeability and edema formation in cerebral ischemia. PMID- 25446454 TI - Changes and overlapping distribution in the expression of CB1/OX1-GPCRs in rat hippocampus by kainic acid-induced status epilepticus. AB - Status epilepticus (SE) is a life-threatening neurological disorder. It is important to discover new drugs to control SE without the development of pharmacoresistance. Focus on the cannabinoid receptor and cannabinoid-related compounds might be a good option. Cannabinoid receptor 1 (CB1) and orexin receptor 1 (OX1) both belong to the GPCR superfamily and display "cross-talk" interactions, however, there has been no study of the effect of OX1/CB1 in epilepsy. Therefore, we investigated the potential long-term effects of SE on CB1 and OX1 expression in rat hippocampus, aiming to elucidate whether they are involved in the causative mechanism of epilepsy and whether they might form a heterodimer. In this study, SE was induced with kainic acid, and results of immunohistochemistry and RT-PCR both showed that the expression of CB1 in the hippocampus increased after SE and was significantly higher compared to controls especially 1 week post-SE. However we did not find any significant difference in the expression of OX1 between the SE group and the controls at any time. Under immunofluorescence staining, we observed an overlapping distribution of CB1 and OX1 in the hippocampus. The increased expression of CB1 in the hippocampus indicates that CB1 may play an important role in the underlying mechanism of SE, but the effect of OX1 was not obvious. The overlapping distribution of CB1 and OX1 in the hippocampus indicates that they may form a heterodimer to exert their effect in epilepsy. PMID- 25446455 TI - Activation of spinal locomotor circuits in the decerebrated cat by spinal epidural and/or intraspinal electrical stimulation. AB - The present study was designed to further compare the stepping-like movements generated via epidural (ES) and/or intraspinal (IS) stimulation. We examined the ability to generate stepping-like movements in response to ES and/or IS of spinal lumbar segments L1-L7 in decerebrate cats. ES (5-10 Hz) of the dorsal surface of the spinal cord at L3-L7 induced hindlimb stepping-like movements on a moving treadmill belt, but with no rhythmic activity in the forelimbs. IS (60 Hz) of the dorsolateral funiculus at L1-L3 (depth of 0.5-1.0mm from the dorsal surface of the spinal cord) induced quadrupedal stepping-like movements. Forelimb movements appeared first, followed by stepping-like movements in the hindlimbs. ES and IS simultaneously enhanced the rhythmic performance of the hindlimbs more robustly than ES or IS alone. The differences in the stimulation parameters, site of stimulation, and motor outputs observed during ES vs. IS suggest that different neural mechanisms were activated to induce stepping-like movements. The effects of ES may be mediated more via dorsal structures in the lumbosacral region of the spinal cord, whereas the effects of IS may be mediated via more ventral propriospinal networks and/or brainstem locomotor areas. Furthermore, the more effective facilitation of the motor output during simultaneous ES and IS may reflect some convergence of pathways on the same interneuronal populations involved in the regulation of locomotion. PMID- 25446456 TI - Progesterone-associated increase in ERP amplitude correlates with an improvement in performance in a spatial attention paradigm. AB - Ovarian sex hormones modulate neuronal circuits not directly involved in reproductive functions. In the present study, we investigated whether endogenous fluctuations of estradiol and progesterone during the menstrual cycle are associated with early cortical processing stages in a cued spatial attention paradigm. EEG was monitored while young women responded to acoustically cued visual stimuli. Women with large mean amplitude of the event-related potential (ERP) (80-120 ms following visual stimuli) responded faster to visual stimuli. In luteal women, mean amplitude of the ERP as well as alpha amplitude, an indicator of attentional modulation, correlated positively with progesterone. Further, cerebral asymmetry in ERP amplitude in the alpha frequency band following target presentation was restricted to luteal women. Critically, early follicular women responded slower to right hemifield compared to left hemifield targets. In late follicular or luteal women, we did not detect a right hemifield disadvantage. Progesterone correlated negatively with RTs in luteal women. Therefore, whereas our behavioral data indicate a functional cerebral asymmetry in early follicular women, EEG recording reveal a physiological cerebral hemisphere asymmetry in the alpha frequency band in luteal women. We assume that a progesterone-associated enhancement in synchronization of synaptic activity in the alpha frequency band in luteal women improves early categorization of visual targets in a cued spatial attention paradigm. PMID- 25446458 TI - Differential effects of androgenic and anti-androgenic progestins on fusiform and frontal gray matter volume and face recognition performance. AB - Effects of oral hormonal contraceptives (OC) on human brain structure and behavior have only recently become a focus of research. Two explorative reports observed larger regional gray matter (GM) volumes in OC users within the prefrontal cortex, ACC and fusiform gyri, as well as parahippocampal gyri, hippocampus and cerebellum. These studies did however not control for the androgenicity of the progestin compound of OC, did not take into consideration how long OC users had been on their OC, and did not control for age differences between the OC group and the naturally cycling group. We compared 20 naturally cycling women during their early follicular cycle phase to 18 users of OC containing androgenic progestins and 22 users of OC containing anti-androgenic progestins. When controlling for age, we found that in users of anti-androgenic progestins relative GM volumes within the bilateral fusiform gyri, fusiform face area (FFA), parahippocampal place area (PPA) and cerebellum, were significantly larger than in naturally cycling women, while in users of androgenic progestins, relative as well as absolute volumes within the bilateral middle and superior frontal gyri were significantly smaller compared to naturally cycling women. These morphological changes were related to performance in a face recognition task. Face recognition performance was significantly better in users of anti androgenic progestins compared to the other groups and significantly related to absolute as well as relative GM volumes in the FFA and PPA. Total GM volume, as well as absolute GM volumes within the bilateral fusiform gyri, FFA, hippocampus, parahippocampus, PPA, middle frontal gyri and ACC were significantly larger, the longer the duration of OC use, particularly in users of androgenic progestins. Morphological differences between active and inactive pill phase were observed in users of androgenic progestins. These findings suggest differential effects of androgenic and anti-androgenic progestins on human brain structure. PMID- 25446459 TI - Role of the lateral hypothalamus in submandibular salivary secretion during feeding in rats. AB - To evaluate the role of the lateral hypothalamic area (LH) in the masticatory salivary reflex, we investigated submandibular salivary secretion and the electromyographic (EMG) activity of the jaw-closer masseter muscle in sham operated rats and rats with unilateral LH lesions. One week prior to surgery and recording, the rats were given daily experience of eating pellets; powder; or hard, medium or soft mash, all of which were composed of laboratory chow. Salivary secretion was induced during eating and grooming behavior. During eating, the powdered food induced the highest salivary flow rate, and the soft (wet) mash induced the lowest salivary flow rate. Conversely, the amount of food consumed (dry weight) was greatest when soft mash was provided and lowest when the powder or pellets (a dry diet) were provided. The EMG activity of the masseter muscle during eating was greatest during consumption of the pellets and weakest during consumption of the powder. LH lesions that were ipsilateral to the examined submandibular gland reduced salivary secretion to about 20-30% of the control value, whereas contralateral LH lesions reduced it to about 40-50% of the control value. Neither masseter muscle EMG activity nor food consumption was markedly affected by the presence of an LH lesion. These results suggest that the texture of food, especially its water content, affects the flow rate of saliva and that the LH is heavily involved in the masticatory-salivary reflex. PMID- 25446460 TI - Creatine monohydrate supplementation for 10 weeks mediates neuroprotection and improves learning/memory following neonatal hypoxia ischemia encephalopathy in female albino mice. AB - Currently there are no uniform standard treatments for newborn suffering from cerebral hypoxia-ischemia (HI) and to find new and effective strategies for treating the HI injury remains a key direction for future research. Present study was designed to demonstrate that optimal dose (1 or 3%) of creatine monohydrate (Cr) for the treatment of neonatal HI in female albino mice. On postnatal day 10, animals were subjected to left carotid artery ligation followed by 8% hypoxia for 25 minutes. Following weaning on postnatal day 20, mice were divided into three treatments on the basis of diet supplementation (Normal rodent diet, 1% and 3% creatine supplemented diet) for 10 week. A battery of neurological tests (Rota rod, open field and Morris water maze) was used to demonstrate effect of Cr supplementation on neurofunction and infarct size following HI. Open field test results indicated that Cr supplementation had significantly improved locomotory and exploratory behavior in subjects. It was observed that Cr treated mice showed better neuromuscular coordination (rota rod) and improved spatial memory (Morris Water Maze test). A significant affect of creatine supplementation in reducing infarct size was also observed. Post hoc analysis of post hoc multiple comparisons revealed that mice supplemented with 3% Cr for 10 weeks performed better during Morris water maze test while 1% Cr supplementation improved the exploratory behavior and gain in body weight than control group indicating that Cr supplementation has the potential to improve the neurofunction following neonatal brain damage. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25446461 TI - Increase of circulating BDNF levels and its relation to improvement of physical fitness following 12 weeks of combined exercise in chronic patients with schizophrenia: a pilot study. AB - Brain-derived neurotrophic factor (BDNF), the most abundant of neurotrophins in the brain, is known to be responsible for maintenance of neurons has been implicated in the pathology of schizophrenia. In the present pilot study, we investigated the effect of a combined exercise program on circulating BDNF expression and the relationship between BDNF and improvements in physical fitness. Twenty-four patients with schizophrenia participated in the exercise intervention, three nonconsecutive days per week for 12 weeks. The resistance exercise program used the elastic band for eight different exercises for 25 min, and the aerobic exercise consisted of moderate walking for 25 min. After the training program, there were positive improvements in body composition and blood pressure. Also, there was significant improvement in leg strength, cardiovascular fitness, balance, and jump. Serum BDNF values had significantly increased following the combined exercise program. The elevation in serum BDNF concentrations correlated significantly with improvements in cardiovascular fitness and leg strength. These results suggest that exercise induced modulation of BDNF may play an important role in developing non-pharmacological treatment for chronic schizophrenic patients. In addition, these preliminary results serve to generate further hypothesis and facilitate the planning the exercise training program and management of participants. PMID- 25446462 TI - Ethnic differences in prevalence and correlates of self-harm behaviors in a treatment-seeking sample of emerging adults. AB - The present study examined differences between White and ethnic minority emerging adults in the prevalence of self-harm behaviors - i.e., non-suicidal self-injury (NSSI) and suicide attempts (SA) - and in well-documented risk (i.e., depressive symptoms, generalized anxiety symptoms, social anxiety symptoms, suicidal ideation (SI), substance use, abuse history) and protective factors (i.e., religiosity/spirituality, family support, friend support) associated with NSSI and SAs. Emerging adults (N=1156; 56% ethnic minority), ages 17-29 (M=22.3, S.D.=3.0), who were presented at a counseling center at a public university in the Northeastern U.S., completed a clinical interview and self-report symptom measures. Univariate and multivariate logistic regression models were used to examine the association between risk and protective factors in predicting history of NSSI-only, any SA, and no self-harm separately among White and ethnic minority individuals. Ethnic differences emerged in the prevalence and correlates of NSSI and SAs. Social anxiety was associated with SAs among White individuals but with NSSI among ethnic minority individuals. Substance use was a more relevant risk factor for White individuals, and friend support was a more relevant protective factor for ethnic minority individuals. These findings suggest differing vulnerabilities to NSSI and SAs between White and ethnic minority emerging adults. PMID- 25446463 TI - Is research on borderline personality disorder underfunded by the National Institute of Health? AB - The relationship between bipolar disorder and borderline personality disorder has generated intense interest. Similar to patients with bipolar disorder, patients with borderline personality disorder are frequently hospitalized, are chronically unemployed, abuse substances, attempt and commit suicide. However, one significant difference between the two disorders is that patients with borderline personality disorder are often viewed negatively by mental health professionals. In the present paper we examined whether this negative bias against borderline personality disorder might be reflected in the level of research funding on the disorder. We searched the National Institute of Health (NIH) Research Portfolio Online Portfolio Reporting Tool (RePORT) for the past 25 years and compared the number of grants funded and the total amount of funding for borderline personality disorder and bipolar disorder. The yearly mean number of grants receiving funding was significantly higher for bipolar disorder than for borderline personality disorder. Results were the same when focusing on newly funded grants. For every year since 1990 more grants were funded for bipolar disorder than borderline personality disorder. Summed across all 25 years, the level of funding for bipolar disorder was more than 10 times greater than the level of funding for borderline personality disorder ($622 million vs. $55 million). These findings suggest that the level of NIH research funding for borderline personality disorder is not commensurate with the level of psychosocial morbidity, mortality, and health expenditures associated with the disorder. PMID- 25446464 TI - Self-injury in autism spectrum disorder: an effect of serotonin transporter gene promoter variants. AB - Self-injurious behavior in autism spectrum disorder (ASD) has been associated with lower whole blood serotonin levels and the role of serotonin transporter gene promoter region (5HTTLPR) polymorphisms is of interest because of their effects on transporter functioning. This study examined the association between self-injurious behavior in ASD and allelic frequencies of 5HTTLPR. Sixty-four children and adolescents with ASD who were not taking serotonergic medication at the time of the assessment were included in the analysis. Self-injury was assessed using the Autism Diagnostic Interview-Revised (ADI-R) and whole blood serotonin levels were measured using high-pressure liquid chromatography (HPLC) with fluorometic detection. DNA was extracted from saliva and PCR amplified with fluorescent primers. Self-injury significantly increased with the number of La alleles of the 5HTTLPR and decreased with the number of Lg alleles. Self-injury in ASD may be associated with a specific genotype of the serotonin transporter gene promoter region. Future studies should continue to explore subgroups to clarify the underlying clinical and genetic heterogeneity in ASD. PMID- 25446457 TI - Using c-fos to study neuronal ensembles in corticostriatal circuitry of addiction. AB - Learned associations between drugs and environment play an important role in addiction and are thought to be encoded within specific patterns of sparsely distributed neurons called neuronal ensembles. This hypothesis is supported by correlational data from in vivo electrophysiology and cellular imaging studies in relapse models in rodents. In particular, cellular imaging with the immediate early gene c-fos and its protein product Fos has been used to identify sparsely distributed neurons that were strongly activated during conditioned drug behaviors such as drug self-administration and context- and cue-induced reinstatement of drug seeking. Here we review how Fos and the c-fos promoter have been employed to demonstrate causal roles for Fos-expressing neuronal ensembles in prefrontal cortex and nucleus accumbens in conditioned drug behaviors. This work has allowed identification of unique molecular and electrophysiological alterations within Fos-expressing neuronal ensembles that may contribute to the development and expression of learned associations in addiction. PMID- 25446465 TI - Role of insular cortex in visceral hypersensitivity model in rats subjected to chronic stress. AB - Abnormal processing of visceral sensation at the level of the central nervous system has been proven to be important in the pathophysiologic mechanisms of stress related functional gastrointestinal disorders. However, the specific mechanism is still not clear. The insular cortex (IC) was considered as one important visceral sensory area. Moreover, the IC has been shown to be involved in various neuropsychiatric diseases such as panic disorders and post-traumatic stress disorder. However, whether the IC is important in psychological stress related visceral hypersensitivity has not been studied yet. In our study, through destruction of the bilateral IC, we explored whether the IC played a critical role in the formation of visceral hypersensitivity induced by chronic stress on rats. Chronic partial restraint stress was used to establish viscerally hypersensitive rat model. Bilateral IC lesions were generated by N-methyl-D-day (door) aspartate. After a recovery period of 7 days, 14-day consecutive restraint stress was performed. The visceromotor response to colorectal distension was monitored by recording electromyogram to measure rats' visceral sensitivity. We found that bilateral insular cortex lesion could markedly inhibit the formation of visceral hypersensitivity induced by chronic stress. The insular cortex plays a critical role in the pathophysiology of stress-related visceral hypersensitivity. PMID- 25446468 TI - Smoking and plastic surgery a Montreal perspective. PMID- 25446467 TI - Myrtus communis L. as source of a bioactive and safe essential oil. AB - In Algeria, Myrtus communis L. is distributed throughout the Tell Atlas and the coastal regions of Algiers and Constantine. The leaves are used in respiratory disorders, diarrhea and hemorrhoids. The aims of this work were to evaluate the antifungal and anti-inflammatory potential of well characterized essential oils (EO). Since EO can be applied by inhalation, dermal application and oral administration, we used several mammalian cell lines to assess safe bioactive doses. The chemical composition of two samples was investigated by GC-FID, GC-MS and (13)C NMR spectroscopy. Monoterpene derivatives are the main compounds: alpha pinene (50.8 and 33.6%), 1,8-cineole (21.9 and 13.3%), linalool (2.7 and 14.8%), and linalyl acetate (0.5 and 9.5%). The antifungal evaluation revealed that the oils were more active against Cryptococcus neoformans (yeast) and Epidermophyton floccosum, Microsporum canis, Trichophyton rubrum (dermatophytes). The anti inflammatory potential was evaluated using an in vitro model of lipopolysaccharide (LPS)-stimulated macrophages. Assessment of cell viability was made through the MTT assay. Both oils were able to significantly inhibit NO production, without affecting cell viability, in concentrations up to 0.64 mg/mL. These promising results, disclose bioactive concentrations of Myrtle essential oils with a safety profile suggesting a potential oral and topical application or use by inhalation. PMID- 25446469 TI - [Adipose-derived stromal cells: history, isolation, immunomodulatory properties and clinical perspectives]. AB - Over the last decade, the clinical use of adipose-derived stromal/stem cells (ASC) in regenerative medicine is rapidly increasing. ASC belong to the mesenchymal stromal cells initially obtained from the bone marrow. Their limited differentiation capacity in vivo into functional mature cells has led to a reassessment of their mechanisms of action. One of the major clinical interests appears related to paracrine effects through a temporary production of trophic and immunomodulatory factors. Our purpose is to provide a review on the latest knowledge in the field of ASC, mechanisms of action, mainly immunomodulatory/immunosuppressive properties, methods of obtention, with a focus on clinical perspectives particularly in the field of cellular therapy and fat grafting technique in plastic surgery. PMID- 25446466 TI - Sensitivity to hepatotoxicity due to epigallocatechin gallate is affected by genetic background in diversity outbred mice. AB - Consumer use of herbal and dietary supplements has recently grown in the United States and, with increased use, reports of rare adverse reactions have emerged. One such supplement is green tea extract, containing the polyphenol epigallocatechin gallate (EGCG), which has been shown to be hepatotoxic at high doses in animal models. The Drug-Induced Liver Injury Network has identified multiple patients who have experienced liver injury ascribed to green tea extract consumption and the relationship to dose has not been straightforward, indicating that differences in sensitivity may contribute to the adverse response in susceptible people. The Diversity Outbred (DO), a genetically heterogeneous mouse population, provides a potential platform for study of interindividual toxicity responses to green tea extract. Within the DO population, an equal exposure to EGCG (50 mg/kg; daily for three days) was found to be tolerated in the majority of mice; however, a small fraction of the animals (16%; 43/272) exhibited severe hepatotoxicity (10-86.8% liver necrosis) that is analogous to the clinical cases. The data indicate that the DO mice may provide a platform for informing risk of rare, adverse reactions that may occur in consumer populations upon ingestion of concentrated herbal products. PMID- 25446470 TI - [Breast lesions of a metastatic melanoma on a radiotherapy territory: Treatment by vemurafenib and carcinologic surgery]. AB - INTRODUCTION: This article describes the unique case of a female patient who presented distant melanoma metastasis on the breast while having irradiation therapy for breast cancer. This happened eight months after the initial treatment for a melanoma of the back (under the right scapula). Furthermore, this case report demonstrates the efficiency of Vemurafenib(r) as a treatment for late stage melanomas. CASE REPORT: The patient was a 47-year-old female that had a superficial spreading melanoma under the right scapula (Breslow 1.02mm) that was treated with 2cm skin excision and sentinel lymph node sampling that was negative. The melanoma was positive for the BRAF600E mutation. One month after this incident, the patient developed breast cancer that was treated with conservative surgery and radiotherapy. Three months after the end of the irradiation treatment, she developed multiple melanoma metastasis on the skin of the breast. Our multidisciplinary team decided to initiate a treatment with vemurafenib. The patient showed an excellent response, so the surgical team completed the treatment with a radical mastectomy and immediate reconstruction with a pedicled latissimus dorsi flap. The histologic report of the mastectomy specimen showed no sign of melanocytic proliferation, that demonstrates the efficacy of vemurafenib. The patient showed no relapse after two years of follow up. DISCUSSION: The speed of development and location of cutaneous metastases in this case brought us to think about the effects of radiation therapy on the skin. Radiation therapy causes acute complications (radiodermatitis) by cellular and molecular mechanisms. Moreover, depressed immunity is found after irradiation. Association of these mecanisms could explain the appearance of these metastases in irradiation field. The efficiency of vemurafenib found in our case is consistent with what is described in literature, especially with the improvement in median overall survival. CONCLUSION: This case demonstrates a unique case of distant melanoma metastasis on the irradiation field of a breast cancer. It also demonstrates the efficacy of vemurafenib as well as the efficacy of a radical complementary surgical treatment in these patients. PMID- 25446471 TI - The underestimated risk of cancer in patients with multinodular goiters after a benign fine needle aspiration. AB - IMPORTANCE: Ultrasound-guided fine needle aspiration (FNA) is an excellent tool for evaluating patients with solitary thyroid nodules, with a false-negative malignancy rate of <3%. The utility of FNA in patients with a cervical multinodular goiter (MNG) is unknown, because biopsy and surveillance of thyroids with numerous nodules may be impractical. OBJECTIVE: To evaluate the incidence and risk factors for unsuspected thyroid cancer on final pathology in patients with a non-functional, cervical MNG who had a benign preoperative FNA and underwent thyroidectomy. DESIGN, SETTING AND PARTICIPANTS: Retrospective review of patients with non-functional, cervical MNG at a high-volume tertiary referral center between 2005 and 2012. MAIN OUTCOME MEASURE(S): Incidence of thyroid cancer on surgical pathology. RESULTS: Of the 134 patients included in the study, 31 (23.1%) were found to have thyroid cancer on final pathology. Twenty-one (15.7%) patients had a microscopic papillary cancer (<1 cm) and 10 (7.5%) patients had other forms of thyroid cancer [five follicular, four papillary (>1 cm), and one patient with a papillary and follicular cancer]. On univariate analysis, male gender had a near-significant association with non-micropapillary thyroid cancer (p = 0.06). On multivariate analysis, male gender (OR = 10.2, 95% CI 1.35-76.8) and FNA cytology not reviewed at our institution (OR = 6.0, 95% CI 1.2-30) were independently associated with non-micropapillary thyroid cancer. CONCLUSIONS AND RELEVANCE: The incidence of thyroid cancer in patients with MNG and benign FNA is significant. Men and patients in whom the FNA cytology is not reviewed by an experienced cytopathologist may be at an increased risk for an undetected thyroid cancer. PMID- 25446472 TI - Operative procedures in the elderly in low-resource settings: a review of Medecins Sans Frontieres facilities. AB - BACKGROUND: As the demographic transition occurs across developing countries, an increasing number of elderly individuals are affected by disasters and conflicts. This study aimed to evaluate the elderly population that underwent an operative procedure at MSF facilities. METHODS: A retrospective review of prospectively collected operative cases performed at MSF-Operational Centre Brussels (MSF-OCB) facilities between June 2008 and December 2012 was completed. Baseline demographic data, American Society of Anesthesiologists (ASA) physical status and surgical indications were collected for each patient. For each procedure, the degree of urgency, anesthesia type, and intra-operative mortality were noted. All patients aged 50 and over at the time of the procedure were considered elderly, as proposed by the World Health Organization (WHO). Comparisons were made with the 18-49 age group in order to elucidate differences between older and younger individuals. RESULTS: We reviewed a total of 93,385 procedures performed on 83,911 patients in 21 different countries. Patients aged 50 and over comprised 11.5% (9,628/83,911) of all patients. While most procedures (57.6%) in the comparison group were urgent, this proportion decreased substantially in the elderly. Intra-operative mortality was considerably lower in the 50-59 group (0.12%) but increased with each age stratum. The most commonly performed surgical procedures in the elderly included herniorrhaphies, simple and extensive wound debridements, abscess incision and drainages, minor tumorectomies, and urological procedures. CONCLUSIONS: In light of the increasing elderly population in developing countries, efforts should be made to better quantify and address their surgical needs. PMID- 25446473 TI - Recognizing pitfalls in breast cancer follow-up: a necessity--reply. PMID- 25446474 TI - Current concepts in penetrating and blast injury to the central nervous system. AB - AIM: To review the current management, prognostic factors and outcomes of penetrating and blast injuries to the central nervous system and highlight the differences between gunshot wound, blast injury and stabbing. METHODS: A review of the current literature was performed. RESULTS: Of patients with craniocerebral GSW, 66-90% die before reaching hospital. Of those who are admitted to hospital, up to 51% survive. The patient age, GCS, pupil size and reaction, ballistics and CT features are important factors in the decision to operate and in prognostication. Blast injury to the brain is a component of multisystem polytrauma and has become a common injury encountered in war zones and following urban terrorist events. GSW to the spine account for 13-17% of all gunshot injuries. CONCLUSIONS: Urgent resuscitation, correction of coagulopathy and early surgery with wide cranial decompression may improve the outcome in selected patients with severe craniocerebral GSW. More limited surgery is undertaken for focal brain injury due to GSW. A non-operative approach may be taken if the clinical status is very poor (GCS 3, fixed dilated pupils) or GCS 4-5 with adverse CT findings or where there is a high likelihood of death or poor outcome. Civilian spinal GSWs are usually stable neurologically and biomechanically and do not require exploration. The indications for exploration are as follows: (1) compressive lesions with partial spinal cord or cauda equina injury, (2) mechanical instability and (3) complications. The principles of management of blast injury to the head and spine are the same as for GSW. Multidisciplinary specialist management is required for these complex injuries. PMID- 25446475 TI - How's the weather? Relationship between weather and trauma admissions at a Level I Trauma Center. AB - BACKGROUND: It is believed commonly that the rate of trauma admissions is affected by weather, particularly temperature. OBJECTIVE: We hypothesized that there are significant relationships between temperature and trauma admission rates. MATERIALS AND METHODS: Trauma admission data (moderate-to-severe injuries as reported to the NY State Department of Health) from a Level I Trauma Center in Queens, NY were linked with archived hourly weather service data for John F. Kennedy International Airport (4.8 miles distant) from the National Oceanic and Atmospheric Administration for the period January 2000-December 2009. The incidence rate ratio (IRR) of trauma admissions was analyzed by Poisson regression as a function of temperature (per 10 degrees F as well as other weather parameters); night shift, day of week, and month were added to the model as control variables. RESULTS: There were 9,490 reportable admissions over 87,144 h, (average 0.109 admissions/h). By mechanism, 7,157 (75.4%) were blunt and 1,967 (20.7%) were penetrating; the remainder were burns, ingestions, or unknown. By Poisson regression analysis, temperature was significantly associated with trauma admissions [IRR 1.19, 95% confidence interval (CI) 1.16-1.22], and had a stronger association with penetrating trauma (IRR 1.24, 95% CI 1.17-1.31). Precipitation, overcast sky, and snow depth were negatively associated with trauma admissions overall, but these did not reach significance for the penetrating subgroup. CONCLUSIONS: Trauma admission rate is significantly associated with temperature. Taking weather forecasts into account may be important for planning of care provision, staffing, and resource allocation in trauma units and emergency departments. PMID- 25446476 TI - Emphysematous gastritis and gastric emphysema: similar radiographic findings, distinct clinical entities. AB - INTRODUCTION: Despite similar appearances on imaging studies, emphysematous gastritis (EG) and gastric emphysema (GE) are rare clinical entities encountered in surgical practices. The purpose of this review is to clarify the presentation, natural history, and optimal treatment strategies for these two disorders. METHODS: We conducted a comprehensive literature review for reported adult cases of EG and GE in MEDLINE. Two cases from our institution were also included. Patient with demographics, diagnostic and therapeutic data, and outcomes were compared between patients with EG and GE. RESULTS: A total of 75 cases were included for our review. The finding of intramural air in the stomach was often associated with portal vein gas, pneumatosis intestinalis, or pneumoperitoneum in both groups. Surgical removal of the stomach was performed in 23.1% of EG patients, but only one patient in the GE group. In the EG group, overall mortality (55%) appeared to be driven by sepsis and its complications, whereas in the GE group, mortality (29%) was attributable to comorbid conditions and the underlying illness. CONCLUSIONS: Prompt surgical intervention is more commonly indicated for severe EG and is directed at removal of the septic organ, while the primary indication for surgical intervention in GE is the uncertainty of the diagnosis. PMID- 25446478 TI - The impact of anastomotic leak and its treatment on cancer recurrence and survival following elective colorectal cancer resection. AB - AIM: Anastomotic leakage is a serious complication in restorative colorectal surgery. Anastomotic leakage and its subsequent management may have long-term impact on survival. This study aims to assess the impact of colorectal anastomotic leak (AL) on overall survival (OS) and disease-free survival (DFS). METHODS: A prospective database of 1,048 patients undergoing restorative colorectal cancer resections at St Mark's hospital between October 2004 and October 2013 was examined. RESULTS: The overall leak rate was 99/1,048 (9.4%). 43 ALs were managed conservatively with antibiotics or radiological drainage and 56 with reoperations. OS was significantly reduced in the AL group treated with a reoperation (HR 2.74, 95% CI 1.67-4.52, p < 0.001). AL was not significantly associated with worse DFS [conservatively managed AL's vs. no AL-HR 2.07 (95% CI 1.05-4.10); reoperated AL's vs. no AL-HR 1.56 (95% CI 0.81-2.99), overall p value = 0.058]. CONCLUSION: Patients who suffer anastomotic leaks requiring reoperations have worse OS compared to patients who do not leak, but there were no significant differences in DFS between patients who leaked and those who did not. PMID- 25446477 TI - Systematic review and meta-analysis of the open abdomen and temporary abdominal closure techniques in non-trauma patients. AB - BACKGROUND: Several challenging clinical situations in patients with peritonitis can result in an open abdomen (OA) and subsequent temporary abdominal closure (TAC). Indications and treatment choices differ among surgeons. The risk of fistula development and the possibility to achieve delayed fascial closure differ between techniques. The aim of this study was to review the literature on the OA and TAC in peritonitis patients, to analyze indications and to assess delayed fascial closure, enteroatmospheric fistula and mortality rate, overall and per TAC technique. METHODS: Electronic databases were searched for studies describing the OA in patients of whom 50% or more had peritonitis of a non-traumatic origin. RESULTS: The search identified 74 studies describing 78 patient series, comprising 4,358 patients of which 3,461 (79%) had peritonitis. The overall quality of the included studies was low and the indications for open abdominal management differed considerably. Negative pressure wound therapy (NPWT) was the most frequent described TAC technique (38 of 78 series). The highest weighted fascial closure rate was found in series describing NPWT with continuous mesh or suture mediated fascial traction (6 series, 463 patients: 73.1%, 95% confidence interval 63.3-81.0%) and dynamic retention sutures (5 series, 77 patients: 73.6%, 51.1-88.1%). Weighted rates of fistula varied from 5.7% after NPWT with fascial traction (2.2-14.1%), 14.6% (12.1-17.6%) for NPWT only, and 17.2% after mesh inlay (17.2-29.5%). CONCLUSION: Although the best results in terms of achieving delayed fascial closure and risk of enteroatmospheric fistula were shown for NPWT with continuous fascial traction, the overall quality of the available evidence was poor, and uniform recommendations cannot be made. PMID- 25446479 TI - Laparoscopic anterior versus posterior fundoplication for gastro-esophageal reflux disease: a meta-analysis and systematic review. AB - OBJECTIVES: Although laparoscopic posterior fundoplication (LPF) i.e., Nissen or Toupet have the proven efficacy for controlling gastro-esophageal reflux surgically, there remain problems with postoperative dysphagia and gas bloat syndrome. To decrease some of these postoperative complications, laparoscopic anterior fundoplication (LAF) was introduced. The aim of this study was to conduct a meta-analysis and systematic review of randomized controlled trials (RCTs) to investigate the merits and drawbacks of LPF versus LAF for the treatment of gastro-esophageal reflux disease (GERD). DATA SOURCES, STUDY SELECTION, AND REVIEW METHODS: A search of Medline, Embase, Science Citation Index, Current Contents, PubMed, ISI Web of Science, and the Cochrane Database identified all RCTs comparing different types of LPF and LAF published in the English Language between 1990 and 2013. The meta-analysis was prepared in accordance with the Preferred Reporting Items for Systematic reviews and Meta analyses (PRISMA) statement. Data was extracted and analyzed on ten variables which include dysphagia score, heartburn rate, redo operative rate, operative time, overall complications, rate of conversion to open, Visick grading of satisfaction, overall satisfaction, length of hospital stay, and postoperative 24 h pH scores. DATA SYNTHESIS: Nine trials totaling 840 patients (anterior = 425, posterior = 415) were analyzed. There was a significant reduction in the odds ratio for dysphagia in the LAF group compared to the LPF group. Conversely, significant reduction in the odds ratio for heartburn was observed for LPF compared to LAF. Comparable effects were noted for both groups for other variables which include redo surgery, operating time, overall complications, conversion rate, Visick's grading, patients' satisfaction, length of hospital stay, and postoperative 24-h pH scores. CONCLUSIONS: Based on this meta-analysis, LPF compared to LAF is associated with significant reduction in heartburn at the expense of higher dysphagia rate on a short- and medium-term basis. We therefore conclude that LPF is a better alternative to LAF for controlling GERD symptoms. PMID- 25446480 TI - "Is general surgery still relevant to the subspecialised trainee?" A 10 year comparison of general versus specialty surgical practice. AB - BACKGROUND: The splintering of general surgery into subspecialties in the past decade has brought into question the relevance of a continued emphasis on traditional general surgical training. With the majority of trainees now expressing a preference to subspecialise early, this study sought to identify if the requirement for proficiency in managing general surgical conditions has reduced over the past decade through comparison of general and specialty surgical admissions at a tertiary referral center. METHODS: A cross-sectional review of all surgical admissions at Cork University Hospital was performed at three individual time points: 2002, 2007 & 2012. Basic demographic details of both elective & emergency admissions were tabulated & analysed. Categorisation of admissions into specialty relevant or general surgery was made using International guidelines. RESULTS: 11,288 surgical admissions were recorded (2002:2773, 2007:3498 & 2012:5017), showing an increase of 81 % over the 10-year period. While growth in overall service provision was seen, the practice of general versus specialty relevant emergency surgery showed no statistically significant change in practice from 2002 to 2012 (p = 0.87). General surgery was mostly practiced in the emergency setting (84 % of all emergency admissions in 2012) with only 28 % elective admissions for general surgery. A reduction in length of stay was seen in both elective (3.62-2.58 bed days, p = 0.342) & emergency admissions (7.36-5.65, p = 0.026). CONCLUSIONS: General surgical emergency work continues to constitute a major part of the specialists practice. These results emphasize the importance of general surgical training even for those trainees committed to sub-specialisation. PMID- 25446483 TI - Postoperative vocal cord dysfunction despite normal intraoperative neuromonitoring: an unexpected complication with the risk of bilateral palsy. PMID- 25446482 TI - Positron emission tomography-computed tomography in oesophageal cancer staging: a tailored approach. AB - BACKGROUND: Positron emission tomography-computed tomography (PET-CT) scanning is used routinely in the staging of oesophageal cancer to identify occult metastases not apparent on CT and changes the management in typically 3-18% patients. The authors aim to re-evaluate its role in the management of oesophageal cancer, investigating whether it is possible to identify a group of patients that will not benefit and can safely be spared from this investigation. METHODS: Consecutive patients with oesophageal cancer undergoing PET-CT staging between 2010 and 2013 were identified from a specialist modern multidisciplinary team database. Without knowledge of the PET-CT result, patients were stratified into low-risk or high-risk groups according to the likelihood of identifying metastatic disease on PET-CT based on specified criteria routinely available from endoscopy and CT reports. Clinical outcomes in the two groups were investigated. RESULTS: In 383 undergoing PET-CT, metastatic disease was identified in 52 (13.6%) patients. Eighty-three patients were stratified as low risk and 300 as high risk. None of the low-risk patients went on to have metastatic disease identified on PET-CT. Of the high-risk patients, 17% had metastatic disease identified on PET-CT. CONCLUSIONS: In one of the largest studies to date investigating the influence of staging PET-CT on management of patients with oesophageal cancer, the authors report a classification based on endoscopy/CT criteria is able to accurately stratify patients according to the risk of having metastatic disease. This could be used to avoid unnecessary PET-CT 22% of patients, saving cost, inconvenience and reducing potential delay to definitive treatment in this group. PMID- 25446481 TI - Blood transfusion is associated with recurrence of hepatocellular carcinoma after hepatectomy in Child-Pugh class A patients. AB - INTRODUCTION: Previous reports have indicated an association between blood transfusion and prognosis of hepatocellular carcinoma (HCC) after hepatectomy. However, clinicopathological biases were not adjusted in these studies. We aimed to clarify the effect of blood transfusions in patients with HCC and Child-Pugh class A after hepatectomy by using inverse probability of treatment weighting (IPTW) analysis for selection bias control. MATERIALS AND METHODS: We enrolled 479 patients with primary HCC and Child-Pugh class A retrospectively (91 transfused and 388 nontransfused patients) who underwent curative hepatectomy. After adjusting for different covariate distributions for both groups by IPTW, we analyzed the prognostic outcomes. RESULTS: In the unweighted analyses, overall survival (OS) rate of transfused patients was significantly lower than in nontransfused patients (P < 0.0001). Recurrence-free survival (RFS) rate of transfused patients was significantly lower than that of nontransfused patients (P = 0.0024). Multivariate analysis showed that blood transfusion was an independent prognostic factor of OS and RFS. The different distributive covariates between the two groups were age, presence of liver cirrhosis, serum level of alpha-fetoprotein, maximum tumor diameter, and amount of intraoperative blood loss. After IPTW by these covariates, OS rate of transfused patients was not significantly lower than those of nontransfused patients, whereas RFS rate of transfused patients remained significantly lower than those of nontransfused patients (P = 0.038, adjusted HR 1.45; 95% CI 1.0-2.1). CONCLUSIONS: These results suggest that blood transfusion was associated with recurrence of HCC after hepatectomy in patients with HCC and Child-Pugh class A. PMID- 25446484 TI - Ventral segment-preserving right hepatectomy in patients with hepatocellular carcinoma. AB - BACKGROUND: Transection along the anterior fissure was proposed as a mechanism by which to open the third door of the liver. In this study, we investigated surgical outcomes of a ventral segment-preserving right hepatectomy (VSPRH) compared with those of conventional right hepatectomy in patients with hepatocellular carcinoma (HCC). METHODS: Between January 2007 and December 2010, 595 primary HCC patients underwent liver resection at the authors' institution. Among them, the 123 HCC patients who underwent a right hepatectomy were retrospectively analyzed. The patients were classified into two groups according to the type of resection: those who underwent a VSPRH (Group A; 27 cases) and those who underwent a conventional right hepatectomy (Group B; 96 cases). RESULTS: In Group A, expected remnant liver volume after a right hepatectomy was calculated to be 32.1 +/- 7.2% of functional total liver volume (FTLV); remnant liver volume increased up to 54.7 +/- 7.2% of FTLV after a VSPRH. Clinicopathologic characteristics and intraoperative data did not differ between the two groups. The liver-related complication rate was higher in Group B (P = 0.02). Overall survival and disease-free survival rates were similar (3-year disease-free survival (Group A: 67.8%; Group B: 71.7%; P = 0.65); 3-year overall survival (Group A: 91.7%; Group B: 87.4%; P = 0.26). In regard to long-term synthetic function, the 1-year postoperative serum albumin level was higher in Group A. CONCLUSIONS: A VSPRH yielded fewer liver-related complications and similar long-term oncologic outcomes, compared with conventional right hepatectomy in cirrhotic patients with a small left lobe volume. Therefore, VSPRH can be considered to be an alternative procedure for a right hepatectomy. PMID- 25446485 TI - Major neonatal surgery under local anesthesia: a cohort study from Bangladesh. AB - BACKGROUND: Surgeons and anesthetists must respond to the perioperative mortality associated with general anesthesia in developing countries. The safety of performing major neonatal surgery under local anesthesia is one pragmatic response. This study describes and evaluates such practice in a tertiary pediatric surgery center in Bangladesh. METHODS: Seven hundred and twenty neonates were admitted for major surgery during a 3.5-year study period. Hundred and fifty two neonates died pre-operatively, and 568 underwent major neonatal surgery. 352 (62.0%) neonates were operated under general anesthesia, while the 216 most fragile neonates (38.0%) were operated with local infiltrative anesthesia alone. Medical files were reviewed; data were collected prospectively; mortality risk factors were assessed by univariate and multivariate analysis. RESULTS: Two hundred and sixteen procedures were performed under local anesthesia: sigmoid colostomies (37.5%), laparotomies with anastomosis (21.3%), anoplasties (18.1%), laparotomies with enterostomy (8.3%), closures of abdominal wall defects (6.9%), fixations of silastic bags (3.7%), peritoneal tube drainage (2.3%), and gastrostomies (1.9%). Median weight was 2,400 g (2,200-2,460), median gestational age was 37.0 weeks (36.0-38.0), and median age at surgery was 5.0 days (3.0-14.7). In-hospital postoperative mortality was 10.6% among those selected for local anesthesia, and 11.4% among neonates operated under general anesthesia. Low birth weight was an independent risk factor for mortality on multivariate analysis (OR 1.002 g(-1), 95% CI [1.000-1.004], p = 0.029). CONCLUSIONS: Local anesthesia is an established option for the most fragile neonates with major surgical disease. Safe anesthesia ought to be accessible to all children of the world. The global pandemic of perioperative mortality needs to be addressed. PMID- 25446487 TI - The impact of feedback of surgical outcome data on surgical performance: a systematic review. AB - BACKGROUND: Increasing patient demands, costs and emphasis on safety have led to performance tracking of individual surgeons. Several methods of using these data, including feedback have been proposed. Our aim was to systematically review the impact of feedback of outcome data to surgeons on their performance. STUDY DESIGN: MEDLINE, Embase, PsycINFO, AMED and the Cochrane Database of Systematic Reviews (from their inception to February 2013) were searched. Two reviewers independently reviewed citations using predetermined inclusion and exclusion criteria. Forty two data-points per study were extracted. RESULTS: The search strategy yielded 1,531 citations. Seven studies were eligible comprising 18,632 cases or procedures by 52 surgeons. Overall, feedback was found to be a powerful method for improving surgical outcomes or indicators of surgical performance, including reductions in hospital mortality after CABG of 24% (P = 0.001), decreases of stroke and mortality following carotid endarterectomy from 5.2 to 2.3%, improved ovarian cancer resection from 77 to 85% (P = 0.157) and reductions in wound infection rates from 14 to 10.3%. Improvements in performance occurred in concert with reduced costs: for hepaticojejunostomy, implementation of feedback was associated with a decrease in overall hospital costs from $24,446 to $20,240 (P < 0.01). Similarly, total cost of carotid endarterectomy and following management decreased from $13,344 to $9548. CONCLUSIONS: The available literature suggests that feedback can improve surgical performance and outcomes; however, given the heterogeneity and limited number of studies, in addition to their non randomised nature, it is difficult to draw clear conclusions from the literature with regard to the efficacy of feedback and the specific nuances required to optimise the impact of feedback. There is a clear need for more rigorous studies to determine how feedback of outcome data may impact performance, and whether this low-cost intervention has potential to benefit surgical practice. PMID- 25446486 TI - Radiofrequency ablation of benign symptomatic thyroid nodules: prospective safety and efficacy study. AB - BACKGROUND: Radiofrequency ablation (RFA) is a relatively novel procedure in the management of benign nodular goiter. This study was conducted to evaluate the safety and efficacy of ultrasound (US)-guided percutaneous RFA for benign symptomatic thyroid nodules as an alternative to surgery. METHODS: The study involved patients for whom a fine needle aspiration biopsy had proved a diagnosis of benign nodular goiter and had nodule-related symptoms such as dysphagia, cosmetic problems, sensation of foreign body in the neck, hyperthyroidism due to autonomous nodules or fear of malignancy. Percutaneous RFA was performed as an outpatient procedure under local anesthesia. The primary outcome was an evaluation of the changes in symptom scores (0-10) for pain, dysphagia and foreign body sensation at the 1st, 3rd, and 6th months after the RFA procedure. Secondary outcomes were assessing volume changes in nodules, complication rates, and changes in thyroid function status. RESULTS: A total of 33 patients (24% female, 76% male) and a total of 65 nodules were included into the study. More than one nodule was treated in 63.6% of the patients. We found a statistically significant improvement from baseline to values at the 1st, 3rd, and 6th months, respectively, as follows: pain scores (2.9 +/- 2.7, 2.3 +/- 2.01, 1.8 +/- 1.7, and 1.5 +/- 1.2, p 0.005), dysphagia scores (3.9 +/- 2.7, 2.6 +/- 1.9; 1.7 +/- 1.6, and 1.1 +/- 0.3, p 0.032), and foreign body sensation scores 3.6 +/- 3, 2.5 +/- 2.2; 1.6 +/- 1.5, and 1.1 +/- 0.4, p 0.002).The mean pre-treatment nodule volume was 7.3 +/- 8.3 mL. There was a statistically significant size reduction in the nodules at the 1st, 3rd, and 6th months after RFA (3.5 +/- 3.8, 2.7 +/- 3.4, and 1.2 +/- 1.7 mL, p 0.002). The volume reduction was found to be 74% at 6th months following the RFA (p 0.005). 8 patients had autonomously functioning nodules in the pre-treatment period, 50% (n: 4) became euthyroid at the 6th month after RFA. There were no complaints other than pain (12%). CONCLUSION: RFA can be an alternative treatment modality in the management of benign symptomatic thyroid nodules. The results showed that it is a safe and effective procedure. PMID- 25446488 TI - A comparison of video-assisted thoracoscopic surgery with open thoracotomy for the management of chest trauma: a systematic review and meta-analysis. AB - BACKGROUND: This study aimed to systematically review and compare the perioperative outcomes of video-assisted thoracoscopy (VATS) with open thoracotomy for chest trauma patients. METHODS: We conducted a systematic review and meta-analysis of randomized control trials and cohort studies comparing the perioperative outcomes of VATS with open thoracotomy for chest trauma patients. Clinical endpoints included postoperative complications, perioperative mortality rate, chest tube drainage volume, duration of tube drainage, duration of hospitalization, operation time, and amount of bleeding and transfusion volume in operation. A subgroup analysis was performed to explore the potential source of heterogeneity. RESULTS: Twenty-six studies were included. Pooled analyses showed significant reductions in the incidence of postoperative complications (risk ratio [RR] [95% confidence interval (CI)], 0.47 [0.35, 0.64]), chest tube drainage volume (mean difference [MD] [95% CI], -146.88 ml [-196.04, -97.72]), duration of tube drainage (MD, -1.71 days; 95% CI -2.16 to -1.26), duration of hospitalization (MD, -4.67 days; 95% CI -5.19 to-4.14), operation time (MD, 41.18 min; 95% CI -52.85 to -29.51), and amount of bleeding (MD, -119.10 ml; 95% CI -147.28 to -90.92) and transfusion volume (MD, -379.51 ml; 95% CI -521.24 to 237.77) in chest trauma patients treated with VATS compared with open thoracotomy. The perioperative mortality rate was not significantly different between patients received VATS and open thoracotomy (RR, 0.52; 95% CI 0.22-1.21). CONCLUSIONS: Compared to open thoracotomy, VATS is an effective and even better treatment for improving perioperative outcomes of hemodynamically stable patients with chest trauma and reduce the complications. However, caution should also be exercised in certain clinical scenarios. PMID- 25446489 TI - What's in a name?: Providing clarity in the definition of minimally invasive parathyroidectomy. AB - BACKGROUND: In recent years minimally invasive parathyroidectomy has become the procedure of choice for many surgeons, but the meaning of the term is unclear. This is confusing for both the medical community and patients. We hypothesize that because the definition of minimally invasive parathyriodectomy in the literature is so variable this term has little meaning. METHODS: We performed a Pubmed search using the terms: parathyroidectomy, minimally invasive, localized, focused, unilateral, radio-guided, video-assisted, and endoscopic. Data were collected for: author, journal title, year published, and all described aspects of parathyroidectomy. RESULTS: We analyzed 443 (44%) articles after applying the exclusion criteria. Eighteen words were used in 75 different combinations to describe minimally invasive parathyroidectomy. We established four categories that encompassed all 75 definitions: 1. operative approach (incision size, describing as open; endoscopic; robotic; or video-assisted), 2. number of glands explored, 3. operative adjuncts, and 4. anesthesia type. Operative approach was the most commonly described attribute and was mentioned in 47% (n = 207) of the articles (mean incision size was found to be 2.2 cm), followed by number of glands explored, operative adjuncts, and anesthesia type. CONCLUSIONS: The finding that there are 75 different definitions for minimally invasive parathyroidectomy confirms that this term is too generic to be useful. We propose a new taxonomic format to describe minimally invasive parathyroidectomy based on the four descriptive categories identified: (operative approach), (# of glands explored), parathyroidectomy using (operative adjuncts) under (anesthesia type). For example, "2 cm, single gland parathyroidectomy using intraoperative parathyroid hormone measurement, under general anesthesia". PMID- 25446491 TI - Laparoscopy in penetrating abdominal trauma. AB - If morbidity and mortality are to be reduced in patients with penetrating abdominal trauma, first priority goes to prompt and accurate determination of peritoneal penetration and identification of the need for surgery. In this setting, laparoscopy may have an important impact on the rate of negative or non therapeutic laparotomies. We analyzed indications and patient selection criteria for laparoscopy in penetrating trauma along with outcomes. The analysis focused on identification of peritoneal penetration and injuries to the diaphragm, small intestine, and mesentery. Results from the early phase of laparoscopy were compared with those from recent decades with more advanced laparoscopic equipment and instruments and more experienced surgeons. A systematic review of the role of laparoscopy in penetrating abdominal trauma shows a sensitivity ranging from 66.7 to 100%, specificity from 33.3 to 100% and accuracy from 50 to 100%. Publications from the 1990s found trauma laparoscopy to be inadequate for detecting intestinal injuries and so to lead to missed injuries. Twenty-three of the 50 studies including the most recent ones report sensitivity, specificity, and accuracy of 100%. Laparoscopy is more cost effective than negative laparotomy. Laparoscopy can be performed safely and effectively on stable patients with penetrating abdominal trauma. The most important advantages are reduction of morbidity, accuracy in detecting diaphragmatic and intestinal injuries, and elimination of prolonged hospitalization for observation, so reducing the length of stay and increasing cost effectiveness. PMID- 25446490 TI - A randomized controlled trial comparing post-operative pain in single-incision laparoscopic cholecystectomy versus conventional laparoscopic cholecystectomy. AB - INTRODUCTION: An increasing body of evidence is being published about single incision laparoscopic cholecystectomy (SILC), but there are no well-powered trials with an adequate evaluation of post-operative pain. This randomized trial compares SILC against four-port laparoscopic cholecystectomy (LC) with post operative pain as the primary endpoint. METHODS: Hundred patients were randomized to either SILC (n = 50) or LC (n = 50). Exclusion criteria were (1) Acute cholecystitis; (2) ASA 3 or above; (3) Bleeding disorders; and (4) Previous open upper abdominal surgery. Patients and post-operative assessors were blinded to the procedure performed. The site and severity of pain were compared at 4 h, 24 h, 14 days and 6 months post-procedure using the visual analog scale; non inferiority was assumed when the lower boundary of the 95% confidence interval of the difference was above -1 and superiority when p <= 0.05. RESULTS: The study arms were demographically similar. At 24 h post-procedure, SILC was associated with less pain at extra-umbilical sites (rest: p = 0.004; movement: p = 0.008). Pain data were inconclusive at 24 h at the umbilical site on movement; SILC was otherwise non-inferior for pain at all other points. Operating duration was longer in SILC (79.46 vs 58.88 min, p = 0.003). 8% of patients in each arm suffered complications (p = 1.000). Re-intervention rates, analgesic use, return to function, and patient satisfaction did not differ significantly. CONCLUSIONS: SILC has improved short-term pain outcomes compared to LC and is not inferior in both short-term and long-term pain outcomes. The operating time is longer, but remains feasible in routine surgical practice. PMID- 25446492 TI - Surgical Care in Liberia and Implications for Capacity Building. AB - BACKGROUND: Situational needs of health care facilities inform the optimal allocation of resources and quality improvement efforts. This study examines surgical care delivery metrics at a tertiary care institution in Liberia. METHODS: We retrospectively reviewed operative and ward logbooks from January 1 to December 31, 2012. Data parameters included patients' age, diagnosis, procedure, mortality, and perioperative provider information. RESULTS: In 2012, 1,036 operations were performed. The breakdown of adult surgical cases reveals 452 (45.1%) general surgery operations, 192 (18.5%) orthopedic operations, and 180 (17.4%) ophthalmic operations. Other significant case volume included urologic 53 (5.1%), ENT 36 (3.5%), neurosurgical 31 (3.0%), vascular 24 (2.3%), and plastic 14 (1.4%) operations. Pediatric patients accounted for 24.5% (243) of surgical cases, and 9% of pediatric surgical cases were for hydrocephalus. General, spinal, and total intravenous anesthesia was provided by non-physician personnel, except when surgeons provided their own anesthesia. Ward logs documented 7.4% mortality among all patients admitted to the surgical ward, most of which occurred after exploratory laparotomy (44%), in burn (14%) patients, and in patients with head/neck emergencies (12%). CONCLUSIONS: This operative log review can be used to identify surgical practice patterns, needs, and deficits in order to inform the growth of surgical capacity at Liberia's only tertiary medical institution. Using this data to identify critical areas of high-yield operations (e.g., for pediatric hydrocephalus), or excessively high mortality rates (e.g., in burn care), can focus the direction of limited resources toward areas of need. While the heavy reliance on non-consultant surgeons reflects human capacity shortages and a pressing need for postgraduate training programs, identifying the breadth of surgical expertise demonstrated in these operative logs reveals the proficiencies required of surgeons to provide comprehensive surgical care in this setting. PMID- 25446493 TI - Papillary thyroid carcinoma with exclusive involvement of a functioning recurrent laryngeal nerve may be treated with shaving technique. AB - OBJECTIVES: We sought to validate the feasibility of preserving a functioning recurrent laryngeal nerve (RLN) invaded by papillary thyroid carcinoma (PTC) using a shaving technique followed by high-dose radioactive iodine (RAI) therapy. METHODS: A retrospective review of 34 patients with locally invasive PTC who had exclusive tumor involvement of a functioning RLN was performed. All patients underwent total thyroidectomy and high-dose RAI therapy. A shaving technique was conducted with the goal of leaving the smallest amount of residual tumor as possible while attempting to preserve nerve function. Clinicopathologic factors and oncologic outcomes of the patients with resected RLN (group A, n = 14) and preserved RLN (group B, n = 20) were compared. RESULTS: The two groups showed no differences in clinicopathologic factors or follow-up period. Mean dose of radioiodine therapy was 245.0 +/- 140.3 mCi (range 100-540 mCi). Permanent postoperative vocal cord paralysis after RLN shaving occurred in two patients of group B (10%). Only one patient (5%) in group B had local recurrence at the thyroid bed where the residual tumor was located. The overall recurrence rate was 35.7% (5/14) and 20.0% (4/20) in groups A and B, respectively showing no significant difference (p = 0.525). There were no cases of death due to PTC during the median follow-up of 75 months (range 36-159 months). CONCLUSIONS: Patients with locally invasive PTC with exclusive involvement of a functioning RLN may be treated by nerve shaving followed by treatment of the macroscopic residual tumor with high-dose RAI therapy. PMID- 25446494 TI - Nutritional B vitamin deficiency alters the expression of key proteins associated with vascular smooth muscle cell proliferation and migration in the aorta of atherosclerotic apolipoprotein E null mice. AB - Low B vitamin status is linked with human vascular disease. We employed a proteomic and biochemical approach to determine whether nutritional folate deficiency and/or hyperhomocysteinemia altered metabolic processes linked with atherosclerosis in ApoE null mice. Animals were fed either a control fat (C; 4 % w/w lard) or a high-fat [HF; 21 % w/w lard and cholesterol (0/15 % w/w)] diet with different B vitamin compositions for 16 weeks. Aorta tissue was prepared and global protein expression, B vitamin, homocysteine and lipoprotein status measured. Changes in the expression of aorta proteins were detected in response to multiple B vitamin deficiency combined with a high-fat diet (P < 0.05) and were strongly linked with lipoprotein concentrations measured directly in the aorta adventitia (P < 0.001). Pathway analysis revealed treatment effects in the aorta-related primarily to cytoskeletal organisation, smooth muscle cell adhesion and invasiveness (e.g., fibrinogen, moesin, transgelin, vimentin). Combined B vitamin deficiency induced striking quantitative changes in the expression of aorta proteins in atherosclerotic ApoE null mice. Deregulated expression of these proteins is associated with human atherosclerosis. Cellular pathways altered by B vitamin status included cytoskeletal organisation, cell differentiation and migration, oxidative stress and chronic inflammation. These findings provide new insight into the molecular mechanisms through which B vitamin deficiency may accelerate atherosclerosis. PMID- 25446495 TI - A combined molecular docking and charge density analysis is a new approach for medicinal research to understand drug-receptor interaction: curcumin-AChE model. AB - In the present study, a molecular docking analysis has been performed on diketone form of curcumin molecule with acetylcholinesterase (AChE). The calculated lowest docked energy of curcumin molecule in the active site of AChE is -11.21 kcal/mol; this high negative value indicates that the molecule exhibits large binding affinity towards AChE. When the curcumin molecule present in the active site of AChE, subsequently, its conformation has altered significantly and the molecule adopts a U-shape geometry as it is linear in gas phase (before entering into the active site). This conformational transition facilitates curcumin to form strong interaction with Phe330 of acyl-binding pocket and the choline binding site with indole ring of Trp84 and Asp72. The gas phase and the active site analysis of curcumin allows to understand the conformational geometry, nature of molecular flexibility, charge density redistribution and the variation of electrostatic properties of curcumin in the active site. To obtain the gas phase structure, the curcumin molecule was optimized using Hartree-Fock and density functional methods (B3LYP) with the basis set 6-311G(**). A charge density analysis on both gas phase as well as the molecule lifted from the active site was carried out using Bader's theory of atoms in molecules (AIM). The difference in molecular electrostatic potential between the two forms of curcumin displays the difference in charge distribution. The large dipole moment of curcumin (7.54 D) in the active site reflects the charge redistribution as it is much less in the gas phase (4.34 D). PMID- 25446497 TI - Isolation and prevention of calcium oxalate-induced apoptotic death and oxidative stress in MDCK cells by diosgenin. AB - Calcium oxalate monohydrate (COM) has been shown to be the most frequent constituent of kidney stones. The interactions of cells with COM crystals produce a variety of physiological and pathological changes including the development of oxidative stress, cellular injury and apoptosis. On the other hand, diosgenin, a steroidal sapogenin, is well known for its antioxidant activity. Therefore, the aim of this study was to evaluate whether diosgenin protects MDCK renal epithelial cells from COM-induced apoptotic death. Diosgenin was isolated from fruits of Solanum xanthocarpum by silica gel column chromatography. It was obtained in high yields (1.23%) and the purity was ascertained by HPTLC analysis. Characterization of diosgenin was done by mp, UV-visible spectrophotometry, elemental analysis, FT-IR, (1)H NMR and (13)C NMR analysis. Cells were co incubated with COM (80MUg/cm(2)) and diosgenin (2.5, 5, 7.5 and 10MUg/mL) for 24h. It was found that diosgenin attenuated the apoptotic death induced by COM as measured in terms of cell viability, caspase -9/3 activities and DNA fragmentation percent. The inhibitory role of diosgenin on caspase -9/3 activities was also analyzed using molecular docking experiments, which showed interactions to their active sites by H-bonds. Diosgenin also attenuated the increase in lipid peroxidation and glutathione depletion induced by COM crystals. In conclusion, the preventive effect of diosgenin is associated to the inhibition of oxidative stress and caspases. PMID- 25446498 TI - Synthesis and characterisation of morin reduced gold nanoparticles and its cytotoxicity in MCF-7 cells. AB - There is significant interest in investigating the therapeutic potential of phytochemical reduced and bound gold nanoparticles (AuNPs) as it bridges the gap between nanotechnology and therapy. In the present study, AuNPs prepared using the flavonoid morin (mAuNPs) are characterised and have been studied for their anti-cancer effects. The -OH groups of morin reduce Au(3+) and stabilize Au(0) to form spherical and crystalline mAuNPs. These mAuNPs are biocompatible towards normal human blood cells and breast epithelial cells. Through TEM analysis, we report that they are readily taken up by breast cancer cells (MCF-7) to induce cell death. Apoptosis has also been assessed by other morphological observations and cell viability studies. Flow cytometric studies reveal that the cells undergo a transient phase of apoptosis progressing towards secondary necrosis as the dose and time of mAuNPs treatment increases. The ability of mAuNPs to induce cell death in MCF-7 cells indicates its potential as an anti-cancer agent. PMID- 25446496 TI - 4-Amino-2-chlorophenol: Comparative in vitro nephrotoxicity and mechanisms of bioactivation. AB - Chlorinated anilines are nephrotoxicants both in vivo and in vitro. The mechanism of chloroaniline nephrotoxicity may occur via more than one mechanism, but aminochlorophenol metabolites appear to contribute to the adverse in vivo effects. The purpose of this study was to compare the nephrotoxic potential of 4 aminophenol (4-AP), 4-amino-2-chlorophenol (4-A2CP), 4-amino-3-chlorophenol (4 A3CP) and 4-amino-2,6-dichlorophenol (4-A2,6DCP) using isolated renal cortical cells (IRCC) from male Fischer 344 rats as the model and to explore renal bioactivation mechanisms for 4-A2CP. For these studies, IRCC (~4*10(6)cells/ml) were incubated with an aminophenol (0.5 or 1.0mM) or vehicle for 60min at 37 degrees C with shaking. In some experiments, cells were pretreated with an antioxidant or cytochrome P450 (CYP), flavin-containing monooxygenase (FMO), peroxidase or cyclooxygenase inhibitor prior to 4-A2CP (1.0mM). Lactate dehydrogenase (LDH) release served as a measure of cytotoxicity. The order of decreasing nephrotoxic potential in IRCC was 4-A2,6-DCP>4-A2CP>4-AP>4-A3CP. The cytotoxicity induced by 4-A2CP was reduced by pretreatment with the peroxidase inhibitor mercaptosuccinic acid, and some antioxidants (ascorbate, glutathione, N acetyl-l-cysteine) but not by others (alpha-tocopherol, DPPD). In addition, pretreatment with the iron chelator deferoxamine, several CYP inhibitors (except for the general CYP inhibitor piperonyl butoxide), FMO inhibitors or indomethacin (a cyclooxygenase inhibitor) failed to attenuate 4-A2CP cytotoxicity. These results demonstrate that the number and ring position of chloro groups can influence the nephrotoxic potential of 4-aminochlorophenols. In addition, 4-A2CP may be bioactivated by cyclooxygenase and peroxidases, and free radicals appear to play a role in 4-A2CP cytotoxicity. PMID- 25446499 TI - 4'-Demethyl-deoxypodophyllotoxin glucoside isolated from Podophyllum hexandrum exhibits potential anticancer activities by altering Chk-2 signaling pathway in MCF-7 breast cancer cells. AB - We investigated the root of Podophyllum hexandrum as a potential source of lead bioactive metabolites with anticancer activity. The present study led to the isolation of six known aryltetralin-type lignans designated as 4'-demethyl deoxypodophyllotoxin (1), podophyllotoxin (2), 4'-demethyl-podophyllotoxin (3), podophyllotoxin-4-O-beta-d-glucopyranoside (4), 4'-demethyl-deoxypodophyllotoxin 4-O-beta-d-glucopyranoside (5), 4'-demethyl-podophyllotoxin-4-O-beta-d glucopyranoside (6), along with three known flavones Kaempferol (7), Quercetin (8), Astragalin (9) from the root of P. hexandrum. Compounds (1-9) exhibited the remarkable cytotoxic potential in diverse cancer cell lines. 5 therapeutic potential was extensively studied first time which exhibiting antiproliferative and ROS generating activity than its non-glycoside analogue 1. Furthermore, 5 augmented the apoptotic cascades in MCF-7 breast cancer cells, viz. nuclear condensation, membrane blebbing, probably by destabilizing the micro-tubular protein tubulin. Strikingly, our docking study and in vitro assays demonstrate that 5 binds to and modulate checkpoint kinase-2, a key cell cycle regulatory protein in normal and cancer cells. PMID- 25446500 TI - Study of the association of total and differential white blood cell counts with geriatric conditions, cardio-vascular diseases, seric IL-6 levels and telomere length. AB - BACKGROUND/OBJECTIVES: Geriatric patients are highly susceptible to infections. While reduced lymphocyte count has been associated with age, other studies found no change in WBC counts with age. Increased circulating white blood cell (WBC) count has been associated with cardiovascular (CV) diseases and frailty but there are discrepancies. Frailty, geriatric conditions, cardiovascular diseases and WBC count have also been associated with low grade inflammation. Association between geriatric conditions and WBC has been scarcely studied. The aim of the study is to assess the association between WBC and geriatric conditions, CV diseases, and seric IL-6 levels. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: We recruited 100 subjects in the general population and hospitalized for chronic medical conditions (age, 23-96years). We collected information on clinical status (medical history, comorbidities, treatments and geriatric syndromes), biological parameters (hematological tests, cytomegalovirus serology) and cytokine production (basal IL-6). Using stepwise backward multivariate analyses, we defined which set of clinical and biological variables could be predictive of increased total and differential WBC counts. RESULTS: We found that low-grade inflammation is independently associated with total WBC, monocyte and neutrophil counts, but not geriatric conditions. CV diseases were the only significant associated factor for high monocyte count. CONCLUSION: In this study, we observed that differential and total WBC counts do not seem to be associated with geriatric conditions but with CV diseases, low-grade inflammation and telomere length. PMID- 25446501 TI - Losing grip: Senescent decline in physical strength in a small-bodied primate in captivity and in the wild. AB - Muscle strength reflects physical functioning, declines at old age and predicts health and survival in humans and laboratory animals. Age-associated muscle deterioration causes loss of strength and may impair fitness of wild animals. However, the effects of age and life-history characteristics on muscle strength in wild animals are unknown. We investigated environment- and sex-specific patterns of physical functioning by measuring grip strength in wild and captive gray mouse lemurs. We expected more pronounced strength senescence in captivity due to condition-dependent, extrinsic mortality found in nature. Males were predicted to be stronger but potentially experience more severe senescence than females as predicted by life history theory. We found similar senescent declines in captive males and females as well as wild females, whereas wild males showed little decline, presumably due to their early mortality. Captive animals were generally weaker and showed earlier declines than wild animals. Unexpectedly, females tended to be stronger than males, especially in the reproductive season. Universal intrinsic mechanisms (e.g. sarcopenia) likely cause the similar patterns of strength loss across settings. The female advantage in muscle strength merits further study; it may follow higher reproductive investment by males, or be an adaptation associated with female social dominance. PMID- 25446502 TI - MutSalpha and MutLalpha immunoexpression analysis in diagnostic grading of oral epithelial dysplasia and squamous cell carcinoma. AB - OBJECTIVES: This study explored the expression of DNA mismatch repair (MMR) proteins in a range of oral biopsies. We further evaluated the significance of MMR protein expression combined with basic demographic data in differentiating grades of oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC). STUDY DESIGN: Immunohistochemical expression of MutSalpha (hMLH1 and hPMS2) and MutLalpha (hMSH2 and hMSH6) were compared in 98 formalin-fixed paraffin embedded oral biopsies: 21 normal, 24 mild-dysplasia (MD), 8 moderate-to severe-dysplasia (SD), and 45 OSCC. RESULTS: Expression of hMLH1, hPMS2, and hMSH2 was reduced in MD, SD, and OSCC compared with the normal. Reduced hMSH2 immunoreactivity discriminated poorly differentiated OSCC from well differentiated OSCC. The diagnostic model correctly classified 71.4% of cases and revealed that hPMS2-negative biopsies were more likely to be cancerous (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.000-0.813; P = .040). CONCLUSION: The results suggested a diagnostic role for MMR proteins in OED and OSCC. PMID- 25446503 TI - The usefulness of cephalometric measurement as a diagnostic tool for obstructive sleep apnea syndrome: a retrospective study. AB - OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) is a disorder characterized by apnea and hypopnea maintained for over 10 seconds and occurring at least 5 times per hour, with at least 30 episodes during 7 hours of nocturnal sleep. The most important pathophysiology in OSAS is the obstruction of the upper airway during sleep. The aim of this study was to identify the correlations between lateral cephalometric parameters, which seemed to be related to OSAS severities, and polysomnography (PSG) indices and to thus determine the cephalometric parameters reflecting OSAS severity. PATIENTS AND METHODS: A total of 140 participants (122 males, 18 females) were evaluated by lateral cephalography and PSG. A total of 29 measurements (24 distances and 5 angles) were made on lateral cephalography. Cephalometric and PSG parameters were evaluated statistically to select and validate the cephalometric parameters reflecting OSAS severity. RESULT: OSAS has a significant relationship with the anatomic deformities of craniofacial and soft tissues. Lateral cephalometry revealed that patients with OSAS have a significant vertical airway length, a regrognathic mandible, a thick uvula, a large tongue, and a long mid-face length. The position of the hyoid bone had a tendency to displace inferiorly and/or posteriorly. Using the discriminant variable combination, including tongue base-posterior nasal spine (T1-PNS), sella-nasion-B point angle (SNB), maximum uvula thickness (Max U), tongue base-tongue tip (T1 TT), and nasion-anterior nasal spine (N-ANS), 102 of 140 (72.9%) patients were correctly assigned to the normal-to-mild and moderate-to-severe apnea-hypopnea index (AHI) groups. CONCLUSIONS: Lateral cephalometric radiography may be an accessible and suitable tool for evaluation of craniofacial and soft tissue deformities in their correlations with OSAS severity. Further research on the cephalometric parameters reflecting OSAS severity is needed. PMID- 25446504 TI - Initial outcomes of an integrated outpatient-based screening program for oral cancers. AB - OBJECTIVE: To evaluate the feasibility of an integrated outpatient-based screening program for oral cancer. STUDY DESIGN: An automated system was used to refer high-risk patients presenting to the outpatient clinic for oral cavity examination. The outcomes between the screened and concurrently symptomatic cohorts were compared to assess the program's effectiveness at identifying oral cancers. RESULTS: Among the 38,693 candidates flagged as high-risk patients by our automated referral system, a total of 8037 participants were recruited to our screened cohort; 1664 patients were identified with positive lesions, and 302 patients underwent a biopsy. Five patients were diagnosed with oral cancer and 121 with dysplastic precancers. The symptomatic cohort comprised 157 patients with oral cancers and 61 with precancers. The screening program identified earlier stages of oral cancers than in the symptomatic cohort. CONCLUSION: Automated outpatient-based oral cancer screening programs may be a practicable strategy to identify precancerous lesions or early-stage cancers in high-risk adults. PMID- 25446505 TI - Central xanthoma of the jaws: a clinicopathologic entity? AB - OBJECTIVE: To investigate central lesions of the jaws dominated by foamy macrophages (foam cells), which are interpreted to be "central xanthomas of the jaws" and to differentiate this condition from reported cases of jaw nonossifying fibroma/fibrous cortical defect and benign fibrous histiocytoma of bone. STUDY DESIGN: The study is a literature review and a retrospective analysis of clinical, radiographic, microscopic, and immunohistochemical features of five new cases of this condition. RESULTS: The lesion has a predilection for the mandible in adults of variable ages, with the potential to become very large and destructive; however, it has a very low recurrence rate, if any, following surgical curettage. CONCLUSION: We suggest that the "central xanthoma of the jaws" be considered a unique, although rare, clinicopathologic entity. It is unclear whether this lesion is a benign neoplastic process or a persistent reactive process. PMID- 25446506 TI - Intraosseous pneumatocysts of the cervical spine: a report of four cases and review of literature. AB - Pneumatocysts are benign, gas-containing lesions, most commonly observed affecting the vertebrae, sacrum, and ileum. Most often, these lesions are asymptomatic and are detected incidentally during imaging examinations. Although once believed to be a rare lesion, recent studies suggest that it is more common than previously thought. We present four cases of pneumatocysts affecting the cervical vertebrae detected as incidental findings on cone beam computed tomography (CBCT). Given the increased use of CBCT in dentistry to evaluate the maxillofacial structures, it is likely that dentists will encounter this lesion on CBCT scans that encompass the superior cervical spine. Recognition of the pathognomonic features of this benign, innocuous lesion is important to avoid unnecessary investigations and causing alarm to the patient. We also present a comprehensive review of the literature on the demographic characteristics and clinical presentation of this relatively unknown lesion. PMID- 25446507 TI - RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance. AB - OBJECTIVES: To determine the distribution patterns of bone resorption regulators, receptor activator of nuclear factor kappa-B (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) in recurrent ameloblastoma (RAs) and to clarify their impact on the biologic behavior of these neoplasms. MATERIALS AND METHODS: Fifteen paraffin-embedded RA cases were subjected to immunohistochemistry for expression of RANK, RANKL, and OPG. RESULTS: The RANK-RANKL-OPG triad was heterogeneously detected in RA samples. RANK, essential for osteoclast differentiation, was strongly expressed in tumoral epithelium. Conversely, RANKL, an osteoclast activator, was markedly underexpressed, and protein localization was predominantly stromal. OPG, an osteoclastogenesis inhibitory factor, was detected in neoplastic epithelium more than in stroma, suggesting functional inactivation of RANKL. Most RA (n = 12/15; 80%) exhibited a bimolecular spatial expression pattern, the most common being RANK-positive/OPG-positive (n = 8/15; 53.3%). All three proteins showed no significant correlation with the clinical/histopathologic parameters in RA patients (P > .05). CONCLUSIONS: The RANK(+)/RANKL(low/-)/OPG(+) phenotype observed in RA suggests an altered local bone metabolism characterized by low bone resorptive activity in these recurrent tumors. PMID- 25446508 TI - Endogenous ergothioneine is required for wild type levels of conidiogenesis and conidial survival but does not protect against 254 nm UV-induced mutagenesis or kill. AB - Ergothioneine, a histidine derivative, is concentrated in conidia of ascomycetous fungi. To investigate the function of ergothioneine, we crossed the wild type Neurospora crassa (Egt(+)) and an ergothioneine non-producer (Egt(-), Deltaegt-1, a knockout in NCU04343.5) and used the Egt(+) and Egt(-) progeny strains for phenotypic analyses. Compared to the Egt(+) strains, Egt(-) strains had a 59% reduction in the number of conidia produced on Vogel's agar. After storage of Egt(+) and Egt(-) conidia at 97% and 52% relative humidity (RH) for a time course to either 17 or 98 days, respectively, Egt(-) strains had a 23% and a 18% reduction in life expectancy at 97% and 52% RH, respectively, compared to the Egt(+) strains. Based on a Cu(II) reduction assay with the chelator bathocuproinedisulfonic acid disodium salt, ergothioneine accounts for 38% and 33% of water-soluble antioxidant capacity in N. crassa conidia from seven and 20 day-old cultures, respectively. In contrast, ergothioneine did not account for significant (alpha=0.05) anti-oxidant capacity in mycelia, which have lower concentrations of ergothioneine than conidia. The data are consistent with the hypothesis that ergothioneine has an antioxidant function in vivo. In contrast, experiments on the spontaneous mutation rate in Egt(+) and Egt(-) strains and on the effects of 254 nm UV light on mutation rate and conidial viability do not support the hypothesis that ergothioneine protects DNA in vivo. PMID- 25446510 TI - Development and characterization of a cationic lipid nanocarrier as non-viral vector for gene therapy. AB - The aim of the present work was to produce a cationic solid lipid nanoparticle (SLN) as non-viral vector for protein delivery. Cationic SLN were produced by double emulsion method, composed of softisan((r)) 100, cetyltrimethylammonium bromide (CTAB), Tween((r)) 80, Span((r)) 80, glycerol and lipoid((r)) S75 loading insulin as model protein. The formulation was characterized in terms of mean hydrodynamic diameter (z-ave), polydispersity index (PI), zeta potential (ZP), stability during storage time, stability after lyophilization, effect of toxicity and transfection ability in HeLa cells, in vitro release profile and morphology. SLN were stable for 30days and showed minimal changes in their physicochemical properties after lyophilization. The particles exhibited a relatively slow release, spherical morphology and were able to transfect HeLa cells, but toxicity remained an obstacle. Results suggest that SLN are nevertheless promising for delivery of proteins or nucleic acids for gene therapy. PMID- 25446511 TI - Preparation and evaluation of a novel liposomal formulation of cisplatin. AB - A novel liposomal formulation of cisplatin (L-CDDP) was synthesized and characterized. The L-CDDP was formed by conjugating CDDP to the carboxyl of oleic acid incorporated into empty liposomes. Particle size (155.4+/-16.1nm) and zeta potential (-50.92+/-1.19mV) of the L-CDDP were determined. In addition, pharmacokinetic properties and antitumor activity in vitro and in vivo were evaluated. Pharmacokinetic study demonstrated that L-CDDP had markedly prolonged circulation time relative to the free drug. Furthermore, L-CDDP showed significantly enhanced in vitro cytotoxicity in comparison to free CDDP. A549 engrafted mice treated with L-CDDP had a higher survival rate compared to those treated with free CDDP. Finally, A549-engrafted mice treated with L-CDDP showed no significant loss of body weight, whereas free CDDP treatment at the same dose caused significant loss of body weight. These results suggest further evaluation of the in vivo antitumor efficacy of the novel L-CDDP formulation is warranted. PMID- 25446512 TI - Nanomicelles based on X-shaped four-armed peglyated distearylglycerol as long circulating system for doxorubicin delivery. AB - A novel X-shaped four-armed gemini-like peglyated distearylglycerol (Gemini-PEG2K GCDS), with two hydrophilic PEG heads and two hydrophobic stearic acid tails, was successfully synthesized and used as a nanomicellar carrier for delivery of doxorubicin. The critical micelle concentration of the amphiphilic copolymer was higher than 10(-6). Mean particle size and zeta potential of DOX-encapsulated Gemini-PEG2K-GCDS nanomicelles (DOX-GNMs) was 20.4nm and+3.91mv, respectively. Encapsulation efficiency of DOX-GNMs was as high as 94.6 and DOX release was pH dependent from DOX-GNMs, ensuring the stability of nanomicelles in blood circulation and rapid release of DOX in tumor cells. Pharmacokinetic studies in rats following i.v. administration, DOX-GNMs demonstrated longer retention in blood and larger AUC (19.1-fold of t1/2 and 12.9-fold of AUC) compared with DOX solutions (DOX-Sol). Tissue distribution studies indicate that DOX-GNMs had higher tumor accumulation (4.6-fold) and lower heart toxicity in H22 tumor bearing mice (17.4-fold) at 48h after administration in comparison with DOX-Sol. Moreover, IC50 of DOX-GNMs increased by 3.3-fold, 2.0-fold and 2.3-fold compared with DOX-Sol in P-gp over-expressing MCF-7/Adr cells after 24h, 48h and 72h, internalized via macropinocytosis-mediated and clathrin-mediated endocytosis. This study suggests that Gemini-PEG2K-GCDS nanomicelle is a promising long circulating delivery system for anti-tumor drugs via extended blood circulation and improved tumor distribution. PMID- 25446514 TI - Antiviral effects of polyphenols: development of bio-based cleaning wipes and filters. AB - Polyphenol molecules play multiple essential roles in plant physiology such as defences against plant-pathogens and micro-organisms. The present study reports a chemical modification of the surface of non-woven cellulosic fibre filters (Kimwipes((r))) by fixing polyphenol in order to confer them antiviral properties. The grafting of the non-woven fibres by the antiviral entity was performed using laccase. T4D bacteriophage virus of Escherichia coli B was used as virus model. Catechin polyphenol was tested as antiviral entity. Proteomic experiments were performed to quantify the potential protein target of catechin on viruses. When the modified filter was in contact with the viral suspension a large improvement in the reduction of the viral concentration was observed (5-log after 1h). Thus, we propose that this material could be used as virucidal wipes for the virus elimination from contaminated surfaces. Virus filtration experiments were performed by spraying an aerial suspension of T4D bacteriophage virus through the designed filter. The best virus capture factor f (ratio of upstream to downstream virus contents) was obtained when using 2 functionalized filters (f=2.9*10(3)). When these 2 layers were placed inside a commercial medical mask in place of its cellulose layer (Kolmi M24001 mask) (f=3.5*10(4)), the f ratio then reached 2.6*10(5) for 2h of filtration. Based on these results, this novel bio-based antiviral mask represents a significant improvement over conventional medical masks. PMID- 25446513 TI - Investigation on fabrication process of dissolving microneedle arrays to improve effective needle drug distribution. AB - The dissolving microneedle array (DMNA) offers a novel potential approach for transdermal delivery of biological macromolecular drugs and vaccines, because it can be as efficient as hypodermic injection and as safe and patient compliant as conventional transdermal delivery. However, effective needle drug distribution is the main challenge for clinical application of DMNA. This study focused on the mechanism and control of drug diffusion inside DMNA during the fabrication process in order to improve the drug delivery efficiency. The needle drug loading proportion (NDP) in DMNAs was measured to determine the influences of drug concentration gradient, needle drying step, excipients, and solvent of the base solution on drug diffusion and distribution. The results showed that the evaporation of base solvent was the key factor determining NDP. Slow evaporation of water from the base led to gradual increase of viscosity, and an approximate drug concentration equilibrium was built between the needle and base portions, resulting in NDP as low as about 6%. When highly volatile ethanol was used as the base solvent, the viscosity in the base rose quickly, resulting in NDP more than 90%. Ethanol as base solvent did not impact the insertion capability of DMNAs, but greatly increased the in vitro drug release and transdermal delivery from DMNAs. Furthermore, the drug diffusion process during DMNA fabrication was thoroughly investigated for the first time, and the outcomes can be applied to most two-step molding processes and optimization of the DMNA fabrication. PMID- 25446515 TI - Rapid identification of HPV 16 and 18 by multiplex nested PCR immunochromatographic test. AB - Human papillomavirus (HPV) types 16 and 18 are known to be high-risk viruses that cause cervical cancer. An HPV rapid testing kit that could help physicians to make early and more informed decisions regarding patient care is needed urgently but not yet available. This study aimed to develop a multiplex nested polymerase chain reaction-immunochromatographic test (PCR-ICT) for the rapid identification of HPV 16 and 18. A multiplex nested PCR was constructed to amplify the HPV 16 and 18 genotype-specific L1 gene fragments and followed by ICT which coated with antibodies to identify rapidly the different PCR products. The type-specific gene regions of high-risk HPV 16 and 18 could be amplified successfully by multiplex nested PCR at molecular sizes of approximately 99 and 101bp, respectively. The capture antibodies raised specifically against the moleculars labeled on the PCR products could be detected simultaneously both HPV 16 and 18 in one strip. Under optimal conditions, this PCR-ICT assay had the capability to detect HPV in a sample with as low as 100 copies of HPV viral DNA. The PCR-ICT system has the advantage of direct and simultaneous detection of two high-risk HPV 16 and 18 DNA targets in one sample, which suggested a significant potential of this assay for clinical application. PMID- 25446516 TI - IFT27 links the BBSome to IFT for maintenance of the ciliary signaling compartment. AB - Vertebrate hedgehog signaling is coordinated by the differential localization of the receptors patched-1 and Smoothened in the primary cilium. Cilia assembly is mediated by intraflagellar transport (IFT), and cilia defects disrupt hedgehog signaling, causing many structural birth defects. We generated Ift25 and Ift27 knockout mice and show that they have structural birth defects indicative of hedgehog signaling dysfunction. Surprisingly, ciliary assembly is not affected, but abnormal hedgehog signaling is observed in conjunction with ciliary accumulation of patched-1 and Smoothened. Similarly, Smoothened accumulates in cilia on cells mutated for BBSome components or the BBS binding protein/regulator Lztfl1. Interestingly, the BBSome and Lztfl1 accumulate to high levels in Ift27 mutant cilia. Because Lztfl1 mutant cells accumulate BBSome but not IFT27, it is likely that Lztfl1 functions downstream of IFT27 to couple the BBSome to the IFT particle for coordinated removal of patched-1 and Smoothened from cilia during hedgehog signaling. PMID- 25446518 TI - The benefit of early rehabilitation following tendon repair of the hand: A population-based claims database analysis. AB - STUDY DESIGN: A retrospective cohort. INTRODUCTION: The benefits of early rehabilitation after hand tendon repair have not been analyzed using population based datasets. PURPOSE OF THE STUDY: to analyze whether early rehabilitation reduces the resurgery risk and the use of rehabilitation resources. METHODS: Patients (n = 1219) who underwent hand tendon repairs followed by rehabilitation were identified from a nationwide claims database and divided into 3 groups: early (<1 wk after tendon repair), intermediate (1-6 wk), or late (>6 wk) rehabilitation. The resurgery rate and the use of rehabilitation resources after tendon repair were calculated. Cox proportional hazards models were used to evaluate the relevant predictors of resurgery. RESULTS: The early rehabilitation group exhibited the lowest resurgery rate and used the fewest rehabilitation resources. Compared with late rehabilitation, early or intermediate rehabilitation conferred protective effects against resurgery in patients without a concomitant upper-limb fracture. CONCLUSION: Our findings suggest the benefit of early rehabilitation after hand tendon repair. LEVEL OF EVIDENCE: 4. PMID- 25446519 TI - The effects of orthotic intervention on nerve conduction and functional outcome in carpal tunnel syndrome: A prospective follow-up study. AB - AIM: To evaluate the effects of using night orthosis for 6 weeks in patients with mild to moderate carpal tunnel syndrome (CTS), including a follow up after 3 months using electrophysiological and functional outcome measurements. STUDY DESIGN: 12 week follow-up prospective study. METHODS: Twenty-two patients with a total of 36 hands diagnosed as CTS were included. Subjects were informed about using a night orthosis for 6 weeks and were evaluated at the baseline, 6th and 12th week. RESULTS: Median motor distal latency was significantly decreased and median motor compound muscle action potential was significantly increased at the 6th week. Median sensory velocity was significantly increased at the 12th week. No significant difference was found in terms of functional outcome measurements. CONCLUSION: Electrophysiological follow-up findings support the positive effects of using a wrist orthosis on median nerve conduction for CTS patients. PMID- 25446520 TI - Brazilian version of the Patient Rated Wrist Evaluation (PRWE-BR): Cross-cultural adaptation, internal consistency, test-retest reliability and construct validity. AB - STUDY DESIGN: Clinical measurements. PURPOSE: Perform the translation and cross cultural adaptation of the Patient Rated Wrist Evaluation (PRWE) into a Brazilian version (PRWE-BR), and assess its internal consistency, test-retest reliability and construct validity. METHODS: PRWE-BR was developed using standardized guidelines. Sixty-one patients with different wrist injuries were recruited. They were submitted to two assessments, 2-7 days apart. Reliability was measured by internal consistency (Cronbach's alpha) and test-retest reliability (Intraclass Correlation Coefficient). Construct validity was determined via hypothesis testing (Spearman's correlation) of correlations with subscales of SF-36 and DASH. RESULTS: PRWE-BR and its subscales achieved high internal consistency (Cronbach's alpha >= 0.85) and excellent test-retest reliability (ICC >= 0.90). Construct validity was established by confirmation of 85.7% of our previously formulated hypotheses. CONCLUSIONS: PRWE-BR is a valid and reliable tool for the assessment of pain and dysfunction in Brazilian patients with injuries involving the wrist joint. LEVEL OF EVIDENCE: N/A. PMID- 25446521 TI - Effects of taping the hand in children with cerebral palsy. AB - BACKGROUND: Thumb in palm deformity restricts hand function by preventing somatosensory input in children with cerebral palsy who have spasticity in their hands. OBJECTIVES: To investigate the effects of thenar palmar tape application with and without pressure on upper extremity function in children with cerebral palsy. METHOD: 45 children were randomly assigned to one of the thenar taping groups either with or without pressure or to the control group. Nine hole peg test and nine parts puzzle test were used to measure upper extremity function. The two study groups were evaluated initially, with taping 20 min later and 20 min after taping was removed. The control group was evaluated initially, 20 min later and again after 20 min. RESULTS: Intragroup analyses showed that initially there was a difference in favor of the control group: number of pegs placed in the hole in 25 s (p = 0.032); number of puzzle parts placed in the hole in 25 s (p = 0.028). Following 20 min of application, there was no longer any difference between the groups (p = 0.458, p = 0.286 respectively). This was accepted as a manifestation of the effectiveness of taping. Intergroup analyses also showed a carry over effect 20 min after removing the tape only in the palmar pressure group (p = 0.004 and p = 0.014). CONCLUSION: It was concluded that taping can be an effective option for repositioning the thumb and improves upper extremity function by controlling the thumb in palm mechanically and enabling sensorial input by maintaining the correct hand position. PMID- 25446517 TI - The chromosome axis controls meiotic events through a hierarchical assembly of HORMA domain proteins. AB - Proteins of the HORMA domain family play central, but poorly understood, roles in chromosome organization and dynamics during meiosis. In Caenorhabditis elegans, four such proteins (HIM-3, HTP-1, HTP-2, and HTP-3) have distinct but overlapping functions. Through combined biochemical, structural, and in vivo analysis, we find that these proteins form hierarchical complexes through binding of their HORMA domains to cognate peptides within their partners' C-terminal tails, analogous to the "safety belt" binding mechanism of Mad2. These interactions are critical for recruitment of HIM-3, HTP-1, and HTP-2 to chromosome axes. HTP-3, in addition to recruiting the other HORMA domain proteins to the axis, plays an independent role in sister chromatid cohesion and double-strand break formation. Finally, we find that mammalian HORMAD1 binds a motif found both at its own C terminus and at that of HORMAD2, indicating that this mode of intermolecular association is a conserved feature of meiotic chromosome structure in eukaryotes. PMID- 25446522 TI - Self-management strategies used by patients who are hypersensitive to cold following a hand injury. A prospective study with two years follow-up. AB - STUDY DESIGN: Prospective cohort study. INTRODUCTION: Knowledge of the strategies used by patients with injuries of the hand to manage cold hypersensitivity should guide information given by health-care workers. PURPOSE: To explore the use of cold-associated self-management strategies in patients with severe hand injuries. METHODS: Seventy patients being cold hypersensitive following a hand injury, reported use of strategies to limit cold-induced symptoms in the injured hand(s) and the severity of cold-associated activity limitations one and two years after surgery. RESULTS: The patients used several strategies, including clothing (100%), use of own body (movement/use of muscles to produce heat or massage of the fingers) (94%), and heating aids (48%), but were still limited in valued cold associated activities two years after surgery. The number of patients staying indoors, using heating aids and hand wear indoors and during summer-time increased with severity of cold hypersensitivity. Patients both implemented and discontinued different strategies after the first year, but for most strategies, the proportions of users were quite stable. CONCLUSION: The most common strategies used to limit cold-induced symptoms in the injured hand(s) were clothing and use of own body. Many patients also seemed to benefit from using heating aids. After one year, a number of patients still experimented in finding the best strategies and were still limited in valued cold-associated activities. LEVEL OF EVIDENCE: 2b. PMID- 25446523 TI - Conservative Surgery for Right Colon Perforation Leads to Better Long-Term Outcomes in Children: A 21-year Experience. AB - OBJECTIVE: There is no consensus on standard treatment for right colon perforation in pediatric patients. We reviewed our cases over the past 21 years, comparing the effects of different operations to the long-term growth of patients. METHODS: From February 1990 to October 2011, 29 patients of right colon perforation were enrolled in our analysis after excluding tumors, diverticulum, volvulus, and tuberculosis. Clinical information was collected from medical records, and analysis was done over 26 cases younger than 10 years at the time of the treatment. Surgical options included primary repair (D group, 12 cases), segmental resection (S group, 5 cases) and right hemicolectomy (H group, 9 cases). The length of postoperative stay, complications, and body weight growth in body weight percentile curve chart at last follow-up visit in each group were compared by analysis of variance. RESULTS: Of the 26 patients who underwent the right colon perforation treatment, cecum perforation was found in 16 (62%), ascending colon perforation in six (23%), transverse colon perforation in three (12%), and combined ascending and transverse colon in one (4%). No mortality or anastomotic leakage occurred. The mean length of postoperative stay was shorter in the D group than in the S and H groups but without statistical significance (mean 10.9 days vs. 11.6 days and 17.9 days, respectively). Long-term body weight growth was significantly better in the D group (+26.3 +/- 22.2 percentile) than the H group (-4.8 +/- 8.0 percentile; p = 0.02). CONCLUSION: For right colon perforation in children, simple closure following debridement has long-term benefits over more extensive resections. PMID- 25446524 TI - Life-threatening Dilated Cardiomyopathy Induced by Late-onset Neonatal Hypocalcemia. AB - Neonatal seizures caused by hypocalcemia may be associated with cardiopulmonary dysfunction and may require specific management other than calcium supplementation. Severe dilated cardiomyopathy is an extremely rare complication in neonatal hypocalcemia and often results in high morbidity and mortality. We report here a 14-day-old neonate presenting with a gradually increasing frequency of tonic seizures. After admission, arterial desaturation was found despite supplying oxygen (4 L/min) through nasal prongs and the patient developed life threatening respiratory distress and heart failure secondary to dilated cardiomyopathy. His critical cardiopulmonary derangements rapidly improved after respiratory support, the administration of diuretic and inotropic drugs, and the correction of his hypocalcemia and hypomagnesemia. The patient responded to treatment and was well during the 1-year follow-up period. We present this unique case history of seizure, respiratory distress, and heart failure induced by transient hypocalcemia to remind clinicians about the importance of this rare, life-threatening, but reversible, disorder. PMID- 25446525 TI - Surface-modified silicone T-tubes for prevention of tracheal stenosis in a rabbit model. AB - OBJECTIVES/HYPOTHESIS: This study was conducted to determine whether a surface modified tracheal T-tube can prevent tracheal stenosis in a rabbit model. STUDY DESIGN: Animal model study. METHODS: We designed surface-modified tracheal T tubes in which silicone rubber was modified by coating it with hyaluronic acid (HA) or polyethylene glycol (PEG). Sixteen rabbits were divided into four insertion groups: normal, silicone tube, silicone tube coated with HA, and silicone tube coated with PEG. Surface-modified tubes were inserted into the tracheal lumen after a scraping injury on the inner tracheal mucosa around the preformed tracheostoma. Laryngoscopy was performed to evaluate formation of stenosis in the trachea. Histological examinations were performed to evaluate epithelial thickness, inflammatory response, and fibrosis. RESULTS: Endoscopic finding showed that the HA- and PEG-coated tube groups had less granulation tissue in the trachea than the noncoated tube group. Greater epithelialization was observed in the noncoated tube group than in the normal group. HA- and PEG coated tube groups showed a tendency to decreasing epithelialization compared with the noncoated tube group. More inflammatory cells were observed in the noncoated tube group than in the normal group, and fewer inflammatory cells were observed in the HA- and PEG-coated tube groups than in the noncoated tube group. The noncoated tube group showed a greater area of fibrosis than the HA- and PEG coated tube groups. CONCLUSIONS: A surface-modified tracheal T-tube may have a favorable effect on reducing tracheal stenosis in a rabbit model. We suggest that local application of HA and PEG should be further researched for prevention of tracheal stenosis. Our rabbit model could be helpful in providing an additional scenario for evaluating new strategies to prevent tracheal stenosis. LEVEL OF EVIDENCE: NA PMID- 25446526 TI - Androgen receptor DNA methylation regulates the timing and androgen sensitivity of mouse prostate ductal development. AB - Androgen receptor (AR) signaling initiates mouse prostate development by stimulating prostate ductal bud formation and specifying bud patterns. Curiously, however, prostatic bud initiation lags behind the onset of gonadal testosterone synthesis by about three days. This study's objective was to test the hypothesis that DNA methylation controls the timing and scope of prostate ductal development by regulating Ar expression in the urogenital sinus (UGS) from which the prostate derives. We determined that Ar DNA methylation decreases in UGS mesenchyme during prostate bud formation in vivo and that this change correlates with decreased DNA methyltransferase expression in the same cell population during the same time period. To examine the role of DNA methylation in prostate development, fetal UGSs were grown in serum-free medium and 5 alpha dihydrotestosterone (DHT) and the DNA methylation inhibitor 5'-aza-2'-deoxycytidine (5AzadC) were introduced into the medium at specific times. As a measure of prostate development, in situ hybridization was used to visualize and count Nkx3-1 mRNA positive prostatic buds. We determined that inhibiting DNA methylation when prostatic buds are being specified, accelerates the onset of prostatic bud development, increases bud number, and sensitizes the budding response to androgens. Inhibition of DNA methylation also reduces Ar DNA methylation in UGS explants and increases Ar mRNA and protein in UGS mesenchyme and epithelium. Together, these results support a novel mechanism whereby Ar DNA methylation regulates UGS androgen sensitivity to control the rate and number of prostatic buds formed, thereby establishing a developmental checkpoint. PMID- 25446527 TI - The thyroxine inactivating gene, type III deiodinase, suppresses multiple signaling centers in Dictyostelium discoideum. AB - Thyroxine deiodinases, the enzymes that regulate thyroxine metabolism, are essential for vertebrate growth and development. In the genome of Dictyostelium discoideum, a single intronless gene (dio3) encoding type III thyroxine 5' deiodinase is present. The amino acid sequence of D. discoideum Dio3 shares 37% identity with human T4 deiodinase and is a member of the thioredoxin reductase superfamily. dio3 is expressed throughout growth and development and by generating a knockout of dio3, we have examined the role of thyroxine 5' deiodinase in D. discoideum. dio3(-) had multiple defects that affected growth, timing of development, aggregate size, cell streaming, and cell-type differentiation. A prominent phenotype of dio3(-) was the breaking of late aggregates into small signaling centers, each forming a fruiting body of its own. cAMP levels, its relay, photo- and chemo-taxis were also defective in dio3(-). Quantitative RT-PCR analyses suggested that expression levels of genes encoding adenylyl cyclase A (acaA), cAMP-receptor A (carA) and cAMP-phosphodiesterases were reduced. There was a significant reduction in the expression of CadA and CsaA, which are involved in cell-cell adhesion. The dio3(-) slugs had prestalk identity, with pronounced prestalk marker ecmA expression. Thus, Dio3 seems to have roles in mediating cAMP synthesis/relay, cell-cell adhesion and slug patterning. The phenotype of dio3(-) suggests that Dio3 may prevent the formation of multiple signaling centers during D. discoideum development. This is the first report of a gene involved in thyroxine metabolism that is also involved in growth and development in a lower eukaryote. PMID- 25446528 TI - CbGRiTS: cerebellar gene regulation in time and space. AB - The mammalian CNS is one of the most complex biological systems to understand at the molecular level. The temporal information from time series transcriptome analysis can serve as a potent source of associative information between developmental processes and regulatory genes. Here, we introduce a new transcriptome database called, Cerebellar Gene Regulation in Time and Space (CbGRiTS). This dataset is populated with transcriptome data across embryonic and postnatal development from two standard mouse strains, C57BL/6J and DBA/2J, several recombinant inbred lines and cerebellar mutant strains. Users can evaluate expression profiles across cerebellar development in a deep time series with graphical interfaces for data exploration and link-out to anatomical expression databases. We present three analytical approaches that take advantage of specific aspects of the time series for transcriptome analysis. We demonstrate the use of CbGRiTS dataset as a community resource to explore patterns of gene expression and develop hypotheses concerning gene regulatory networks in brain development. PMID- 25446530 TI - Hepatic Notch2 deficiency leads to bile duct agenesis perinatally and secondary bile duct formation after weaning. AB - Notch signaling plays an acknowledged role in bile-duct development, but its involvement in cholangiocyte-fate determination remains incompletely understood. We investigated the effects of early Notch2 deletion in Notch2(fl/fl)/Alfp Cre(tg/-) ("Notch2-cKO") and Notch2(fl/fl)/Alfp-Cre(-/-) ("control") mice. Fetal and neonatal Notch2-cKO livers were devoid of cytokeratin19 (CK19)-, Dolichos biflorus agglutinin (DBA)-, and SOX9-positive ductal structures, demonstrating absence of prenatal cholangiocyte differentiation. Despite extensive cholestatic hepatocyte necrosis and growth retardation, mortality was only ~15%. Unexpectedly, a slow process of secondary cholangiocyte differentiation and bile duct formation was initiated around weaning that histologically resembled the ductular reaction. Newly formed ducts varied from rare and non-connected, to multiple, disorganized tubular structures that connected to the extrahepatic bile ducts. Jaundice had disappeared in ~30% of Notch2-cKO mice by 6 months. The absence of NOTCH2 protein in postnatally differentiating cholangiocyte nuclei of Notch2-cKO mice showed that these cells had not originated from non-recombined precursor cells. Notch2 and Hnf6 mRNA levels were permanently decreased in Notch2 cKO livers. Perinatally, Foxa1, Foxa2, Hhex, Hnf1beta, Cebpalpha and Sox9 mRNA levels were all significantly lower in Notch2-cKO than control mice, but all except Foxa2 returned to normal or increased levels after weaning, coincident with the observed secondary bile-duct formation. Interestingly, Hhex and Sox9 mRNA levels remained elevated in icteric 6 months old Notch2-cKOs, but decreased to control levels in non-icteric Notch2-cKOs, implying a key role in secondary bile-duct formation. CONCLUSION: Cholangiocyte differentiation becomes progressively less dependent on NOTCH2 signaling with age, suggesting that ductal plate formation is dependent on NOTCH2, but subsequent cholangiocyte differentiation is not. PMID- 25446529 TI - Zebrafish pronephros tubulogenesis and epithelial identity maintenance are reliant on the polarity proteins Prkc iota and zeta. AB - The zebrafish pronephros provides an excellent in vivo system to study the mechanisms of vertebrate nephron development. When and how renal progenitors in the zebrafish embryo undergo tubulogenesis to form nephrons is poorly understood, but is known to involve a mesenchymal to epithelial transition (MET) and the acquisition of polarity. Here, we determined the precise timing of these events in pronephros tubulogenesis. As the ternary polarity complex is an essential regulator of epithelial cell polarity across tissues, we performed gene knockdown studies to assess the roles of the related factors atypical protein kinase C iota and zeta (prkciota, prkczeta). We found that prkciota and prkczeta serve partially redundant functions to establish pronephros tubule epithelium polarity. Further, the loss of prkciota or the combined knockdown of prkciota/zeta disrupted proximal tubule morphogenesis and podocyte migration due to cardiac defects that prevented normal fluid flow to the kidney. Surprisingly, tubule cells in prkciota/zeta morphants displayed ectopic expression of the transcription factor pax2a and the podocyte-associated genes wt1a, wt1b, and podxl, suggesting that prkciota/zeta are needed to maintain renal epithelial identity. Knockdown of genes essential for cardiac contractility and vascular flow to the kidney, such as tnnt2a, or elimination of pronephros fluid output through knockdown of the intraflagellar transport gene ift88, was not associated with ectopic pronephros gene expression, thus suggesting a unique role for prkciota/zeta in maintaining tubule epithelial identity separate from the consequence of disruptions to renal fluid flow. Interestingly, knockdown of pax2a, but not wt1a, was sufficient to rescue ectopic tubule gene expression in prkciota/zeta morphants. These data suggest a model in which the redundant activities of prkciota and prkczeta are essential to establish tubule epithelial polarity and also serve to maintain proper epithelial cell type identity in the tubule by inhibiting pax2a expression. These studies provide a valuable foundation for further analysis of MET during nephrogenesis, and have implications for understanding the pathways that affect nephron epithelial cells during kidney disease and regeneration. PMID- 25446531 TI - Gro/TLE enables embryonic stem cell differentiation by repressing pluripotent gene expression. AB - Gro/TLE proteins (TLE1-4) are a family of transcriptional corepressors acting downstream of multiple signalling pathways. Several TLEs are expressed in a dynamic manner throughout embryonic development and at high levels in embryonic stem cells (ESCs). Here we find that Gro/TLE is not required in ESC for sustaining pluripotency and suppressing differentiation genes, but rather is important for the shutting down of the pluripotency network in differentiation. Consistent with this view, we found that one of the Gro/TLE family, TLE4 is expressed heterogeneously in ESCs in a population that corresponds to a Nanog low subset of ESC culture. TLE4 expression is also increased in response to LIF withdrawal and Fgf/Mek/Erk stimulation. To explore the role of Gro/TLE in more detail we generated an allelic series of knockout ESCs of two TLE genes expressed most dynamically in early differentiation, TLE3 and TLE4. Genetic reduction in TLE dose resulted in an increase in the expression of pluripotency markers and inhibition of ESC differentiation towards both epiblast and endoderm lineages. Overexpression of a drug inducible TLE4 could both rescue TLE3/TLE4 compound phenotypes and induce early expression of endoderm (Hhex-Venus) and neural (Sox1 GFP) reporter genes. Taken together, our results suggest that TLE activity is essential for early differentiation where it acts to suppress the pluripotency network, allowing for the initiation of lineage specific gene expression programs. PMID- 25446532 TI - Epiblast morphogenesis before gastrulation. AB - The epiblast is a single cell-layered epithelium which generates through gastrulation all tissues in an amniote embryo proper. Specification of the epiblast as a cell lineage in early development is coupled with that of the trophoblast and hypoblast, two lineages dedicated to forming extramebryonic tissues. The complex relationship between molecular specification and morphogenetic segregation of these three lineages is not well understood. In this review I will compare the ontogeny of epithelial epiblast in different amniote groups and emphasize the diversity in cell biological mechanisms employed by each group to reach this conserved epithelial structure as the pre-requisite for gastrulation. The limitations of associating cell fate with cell shape and position will also be discussed. In most amniote groups, bi-potential precursors for the epiblast and hypoblast, similar to the inner cell mass in the eutherian mammals, are not associated with an apolar, inside location in the blastocyst. Conversely, a blastocyst cell with epithelial morphology and superficial location is not indicative of its trophoblast fate. The polar trophoblast is absent in all amniotes except for the eutherian mammals. In the avian, reptilian and eutherian groups, epithelialization of the epiblast occurs after its fate specification and involves a mesenchymal-to-epithelial transition (MET) process, whereas in the monotremes and marsupials, pre-epiblast cells adopt an epithelial morphology prior to their commitment to the epiblast fate. The conservation of an epithelialized epiblast is viewed as an adaptation to evolutionary constraints placed on pre-gastrulation ectoderm in the ancestral amniote. The relationship between epiblast MET and epiblast pluripontency will also be discussed. Whether such an MET/epithelialization process is advantageous for the self-renewal and/or differentiation of human epiblast stem cells in vitro is unclear. PMID- 25446533 TI - Zn2+-stimulation of sperm capacitation and of the acrosome reaction is mediated by EGFR activation. AB - Extracellular zinc regulates cell proliferation via the MAP1 kinase pathway in several cell types, and has been shown to act as a signaling molecule. The testis contains a relatively high concentration of Zn(2+), required in both the early and late stages of spermatogenesis. Despite the clinical significance of this ion, its role in mature sperm cells is poorly understood. In this study, we characterized the role of Zn(2+) in sperm capacitation and in the acrosome reaction. Western blot analysis revealed the presence of ZnR of the GPR39 type in sperm cells. We previously demonstrated the presence of active epidermal growth factor receptor (EGFR) in sperm, its possible transactivation by direct activation of G-protein coupled receptor (GPCR), and its involvement in sperm capacitation and in the acrosome reaction (AR). We show here that Zn(2+) activates the EGFR during sperm capacitation, which is mediated by activation of trans-membrane adenylyl cyclase (tmAC), protein kinase A (PKA), and the tyrosine kinase, Src. Moreover, the addition of Zn(2+) to capacitated sperm caused further stimulation of EGFR and phosphatydil-inositol-3-kinase (PI3K) phosphorylation, leading to the AR. The stimulation of the AR by Zn(2+) also occurred in the absence of Ca(2+) in the incubation medium, and required the tmAC, indicating that Zn(2+) activates a GPCR. The AR stimulated by Zn(2+) is mediated by GPR39 receptor, PKA, Src and the EGFR, as well as the EGFR down-stream effectors PI3K, phospholipase C (PLC) and protein kinase C (PKC). These data support a role for extracellular zinc, acting through the ZnR, in regulating multiple signaling pathways in sperm capacitation and the acrosome reaction. PMID- 25446534 TI - Drosophila C-terminal Src kinase regulates growth via the Hippo signaling pathway. AB - The Hippo signaling pathway is involved in regulating tissue size by inhibiting cell proliferation and promoting apoptosis. Aberrant Hippo pathway function is often detected in human cancers and correlates with poor prognosis. The Drosophila C-terminal Src kinase (d-Csk) is a genetic modifier of warts (wts), a tumor-suppressor gene in the Hippo pathway, and interacts with the Src oncogene. Reduction in d-Csk expression and the consequent activation of Src are frequently seen in several cancers including hepatocellular and colorectal tumors. Previous studies show that d-Csk regulates cell proliferation and tissue size during development. Given the similarity in the loss-of-function phenotypes of d-Csk and wts, we have investigated the interactions of d-Csk with the Hippo pathway. Here we present multiple lines of evidence suggesting that d-Csk regulates growth via the Hippo signaling pathway. We show that loss of dCsk caused increased Yki activity, and our genetic epistasis places dCsk downstream of Dachs. Furthermore, dCsk requires Yki for its growth regulatory functions, suggesting that dCsk is another upstream member of the network of genes that interact to regulate Wts and its effector Yki in the Hippo signaling pathway. PMID- 25446535 TI - Elf5 and Ets2 maintain the mouse extraembryonic ectoderm in a dosage dependent synergistic manner. AB - The ETS superfamily transcription factors Elf5 and Ets2 have both been implicated in the maintenance of the extraembryonic ectoderm (ExE) of the mouse embryo. While homozygous mutants of either gene result in various degrees of ExE tissue loss, heterozygotes are without phenotype. We show here that compound heterozygous mutants exhibit a phenotype intermediate to that of the more severe Elf5-/- and the milder Ets2-/- mutants. Functional redundancy is shown via commonalities in expression patterns, in target gene expression, and by partial rescue of Elf5-/- mutants through overexpressing Ets2 in an Elf5-like fashion. A model is presented suggesting the functional division of the ExE region into a proximal and distal domain based on gene expression patterns and the proximal to distal increasing sensitivity to threshold levels of combined Elf5 and Ets2 activity. PMID- 25446536 TI - Interactions between FGF18 and retinoic acid regulate differentiation of chick embryo limb myoblasts. AB - During limb development Pax3 positive myoblasts delaminate from the hypaxial dermomyotome of limb level somites and migrate into the limb bud where they form the dorsal and ventral muscle masses. Only then do they begin to differentiate and express markers of myogenic commitment and determination such as Myf5 and MyoD. However the signals regulating this process remain poorly characterised. We show that FGF18, which is expressed in the distal mesenchyme of the limb bud, induces premature expression of both Myf5 and MyoD and that blocking FGF signalling also inhibits endogenous MyoD expression. This expression is mediated by ERK MAP kinase but not PI3K signalling. We also show that retinoic acid (RA) can inhibit the myogenic activity of FGF18 and that blocking RA signalling allows premature induction of MyoD by FGF18 at HH19. We propose a model where interactions between FGF18 in the distal limb and retinoic acid in the proximal limb regulate the timing of myogenic gene expression during limb bud development. PMID- 25446537 TI - Aggrecan is required for growth plate cytoarchitecture and differentiation. AB - The proteoglycan aggrecan is a prominent component of the extracellular matrix in growth plate cartilage. A naturally occurring, recessive, perinatally lethal mutation in the aggrecan core protein gene, cmd(bc) (Acan(cmd-Bc)), that deletes the entire protein-coding sequence provided a model in which to characterize the phenotypic and morphologic effects of aggrecan deletion on skeletal development. We also generated a novel transgenic mouse, Tg(COL2A1-ACAN), that has the chick ACAN coding sequence driven by the mouse COL2A1 promoter to enable the production of cmd(bc)/cmd(bc); Tg(COL2A1-ACAN) rescue embryos. These were used to assess the impact of aggrecan on growth plate organization, chondrocyte survival and proliferation, and the expression of mRNAs encoding chondrocyte differentiation markers and growth factors. Homozygous mutant (cmd(bc)/cmd(bc)) embryos exhibited severe defects in all skeletal elements with deformed and shortened (50%) limb elements. Expression of aggrecan in rescue embryos reversed the skeletal defects to varying degrees with a 20% increase in limb element length and near-full reversal (80%) of size and diameter of the ribcage and vertebrae. Aggrecan-null growth plates were devoid of matrix and lacked chondrocyte organization and differentiation, while those of the rescue embryos exhibited matrix production concomitant with partial zonation of chondrocytes having proliferative and hypertrophic morphologies. Deformation of the trachea, likely the cause of the mutation's lethality, was reduced in the rescue embryos. Aggrecan-null embryos also had abnormal patterns of COL10A1, SOX9, IHH, PTCH1, and FGFR3 mRNA expression in the growth plate. Expression of chick aggrecan in the rescue embryos notably increased COLX expression, accompanied by the reappearance of a hypertrophic zone and IHH expression. Significantly, in transgenic rescue embryos, the cell death and decreased proliferation phenotypes exhibited by the mutants were reversed; both were restored to wild-type levels. These findings suggest that aggrecan has a major role in regulating the expression of key growth factors and signaling molecules during development of cartilaginous tissue and is essential for proper chondrocyte organization, morphology, and survival during embryonic limb development. PMID- 25446539 TI - The BED finger domain protein MIG-39 halts migration of distal tip cells in Caenorhabditis elegans. AB - Organs are often formed by the extension and branching of epithelial tubes. An appropriate termination of epithelial tube extension is important for generating organs of the proper size and morphology. However, the mechanism by which epithelial tubes terminate their extension is mostly unknown. Here we show that the BED-finger domain protein MIG-39 acts to stop epithelial tube extension in Caenorhabditis elegans. The gonadal leader cells, called distal tip cells (DTCs), migrate in a U-shaped pattern during larval development and stop migrating at the young adult stage, generating a gonad with anterior and posterior U-shaped arms. In mig-39 mutants, however, DTCs overshot their normal stopping position. MIG-39 promoted the deceleration of DTCs, leading to the proper timing and positioning of the cessation of DTC migration. Among three Rac GTPase genes, mutations in ced 10 and rac-2 enhanced the overshoot of anterior DTCs, while they suppressed that of posterior DTCs of mig-39 mutants. On the other hand, the mutation in mig-2 suppressed both the anterior and posterior DTC defects of mig-39. Genetic analyses suggested that MIG-39 acts in parallel with Rac GTPases in stopping DTC migration. We propose a model in which the anterior and posterior DTCs respond in an opposite manner to the levels of Rac activities in the cessation of DTC migration. PMID- 25446538 TI - BMP signaling is required for cell cleavage in preimplantation-mouse embryos. AB - The mechanisms regulating cell division during development of the mouse pre implantation embryo are poorly understood. We have investigated whether bone morphogenetic protein (BMP) signaling is involved in controlling cell cycle during mouse pre-implantation development. We mapped and quantitated the dynamic activities of BMP signaling through high-resolution immunofluorescence imaging combined with a 3D segmentation method. Immunostaining for phosphorylated Smad1/5/8 shows that BMP signaling is activated in mouse embryos as early as the 4-cell stage, and becomes spatially restricted by late blastocyst stage. Perturbation of BMP signaling in preimplantation mouse embryos, whether by treatment with a small molecule inhibitor, with Noggin protein, or by overexpression of a dominant-negative BMP receptor, indicates that BMPs regulate cell cleavage up to the morula stage. These results indicate that BMP signaling is active during mouse pre-implantation development and is required for cell cleavage in preimplantation mouse embryos. PMID- 25446540 TI - Overcrowding in emergency department: an international issue. AB - Overcrowding in the emergency department (ED) has become an increasingly significant worldwide public health problem in the last decade. It is a consequence of simultaneous increasing demand for health care and a deficit in available hospital beds and ED beds, as for example it occurs in mass casualty incidents, but also in other conditions causing a shortage of hospital beds. In Italy in the last 12-15 years, there has been a huge increase in the activity of the ED, and several possible interventions, with specific organizational procedures, have been proposed. In 2004 in the United Kingdom, the rule that 98 % of ED patients should be seen and then admitted or discharged within 4 h of presentation to the ED ('4 h rule') was introduced, and it has been shown to be very effective in decreasing ED crowding, and has led to the development of further acute care clinical indicators. This manuscript represents a synopsis of the lectures on overcrowding problems in the ED of the Third Italian GREAT Network Congress, held in Rome, 15-19 October 2012, and hopefully, they may provide valuable contributions in the understanding of ED crowding solutions. PMID- 25446542 TI - Increased serum cancer antigen-125 is a marker for severity of deep endometriosis. AB - STUDY OBJECTIVE: To determine whether cancer antigen-125 (CA-125) levels are increased in women with endometriosis, especially in those with endometriomas (OMAs), deep infiltrating lesions (DIE), and superficial endometriosis (SUP) compared with controls without endometriosis in a large cohort of operated women. DESIGN: Cross-sectional study (Canadian Task Force classification II-2). SETTING: Tertiary-care university hospital. PATIENTS: Four hundred six women with histologically proven endometriosis and 279 women without endometriosis. INTERVENTIONS: Surgical examination of the abdomino-pelvic cavity. MEASUREMENTS AND MAIN RESULTS: Preoperative serum CA-125 antigen levels were evaluated by electrochemoluminescence immunoassay in women with endometriosis and controls. Correlations between serum CA-125 levels and clinical and anatomical characteristics of disease severity were examined. Women with endometriosis displayed higher mean serum CA-125 levels compared with disease-free controls (50.1 +/- 62.4 U/mL vs 22.5 +/- 25.2 U/mL; p <= .001). CA-125 levels were significantly increased in women with OMA (60.8 +/- 63.5 U/mL) and DIE (55.2 +/- 68.7 U/mL) compared with women with SUP (23.2 +/- 24.5 U/mL) and controls (22.5 +/- 25.2 U/mL). There was no difference in CA-125 levels between patients with SUP and controls and between patients with OMA and DIE. CA-125 serum levels were correlated with DIE severity: the mean number of DIE lesions and worst DIE lesion. CONCLUSION: Serum CA-125 levels were significantly increased in women with severe forms of endometriosis, OMA, and DIE lesions. In addition, elevated serum Ca-125 levels were associated with more severe and extended DIE lesions. In women with superficial peritoneal lesions, CA-125 levels were not different from women without endometriosis. PMID- 25446541 TI - Plasmids in the driving seat: The regulatory RNA Rcd gives plasmid ColE1 control over division and growth of its E. coli host. AB - Regulation by non-coding RNAs was found to be widespread among plasmids and other mobile elements of bacteria well before its ubiquity in the eukaryotic world was suspected. As an increasing number of examples was characterised, a common mechanism began to emerge. Non-coding RNAs, such as CopA and Sok from plasmid R1, or RNAI from ColE1, exerted regulation by refolding the secondary structures of their target RNAs or modifying their translation. One regulatory RNA that seemed to swim against the tide was Rcd, encoded within the multimer resolution site of ColE1. Required for high fidelity maintenance of the plasmid in recombination proficient hosts, Rcd was found to have a protein target, elevating indole production by stimulating tryptophanase. Rcd production is up-regulated in dimer containing cells and the consequent increase in indole is part of the response to the rapid accumulation of dimers by over-replication (known as the dimer catastrophe). It is proposed that indole simultaneously inhibits cell division and plasmid replication, stopping the catastrophe and allowing time for the resolution of dimers to monomers. The idea of a plasmid-mediated cell division checkpoint, proposed but then discarded in the 1980s, appears to be enjoying a revival. PMID- 25446543 TI - Single site laparoscopy for fertility preservation: a cohort study. AB - STUDY OBJECTIVE: To compare operative and postoperative results of ovarian cortex retrieval by conventional laparoscopy (1cm umbilical site and 3 accessory 5-mm reusable working ports) (HASS) versus single site laparoscopy (SSL). DESIGN: Prospective cohort study. SETTING: Fertility Preservation Programme at La Fe University Hospital-University of Valencia, Valencia, Spain, 2011 to 2012. Fertility Preservation Programme at La Fe University Hospital of Valencia, Valencia, Spain. PATIENTS: Twenty-one patients with cancer (breast cancer: n = 17; Hodgkin's lymphoma: n = 3; and non-Hodgkin's lymphoma: n = 1). INTERVENTION: Ovarian cortex retrieval either by conventional laparoscopy using an umbilical Hasson port and 3 accessory ports (HASS group: n = 11) or by SSL (SSL group: n = 10). MEASUREMENTS AND MAIN RESULTS: Operative length, blood loss, postoperative pain (visual analog scale for pain at 6, 24, and 48 hours), need of additional analgesia, quality of life (European Quality of Life-5 Dimensions), cosmesis of the scar, and patient's self-perception were assessed at 24 and 48 hours and 3 months after surgery. Baseline characteristics were similar between groups. Estimated blood loss, operative length, and postoperative pain did not differ between groups. The start of chemotherapy was not delayed in either group, and cosmesis and image self-perception were also similar. CONCLUSION: The SSL approach can be considered a safe option compared with the classic multisite approach. PMID- 25446544 TI - Reply to letter to the editor re.: Perforated intraperitoneal intrauterine contraceptive devices: diagnosis, management and clinical outcomes. PMID- 25446545 TI - Rare case of cystadenoma from an ectopic ovary presenting with acute abdominal pain. PMID- 25446546 TI - Radiofrequency electrical energy guidelines for authors: what's in a name? PMID- 25446548 TI - Current role of second-look laparoscopy for benign gynecologic conditions. PMID- 25446547 TI - Twelve-month outcomes for patients undergoing hysteroscopic morcellation of uterine polyps and myomas in an office or ambulatory surgical center. AB - STUDY OBJECTIVE: To examine efficacy of hysteroscopic removal of polyps and myomas on health-related quality of life and symptom severity at 1-year postprocedure. DESIGN: Randomized, prospective, comparative setting clinical trial (Canadian Task Force classification II-2). SETTING: Nine outpatient obstetrics and gynecology practices and hospitals in the United States. PATIENTS: Women 18 to 55 years of age with polyps and/or type 0 or I myomas >=1.5 and <=3.0 cm. INTERVENTIONS: Treatment of polyps and fibroids with the MyoSure device. MEASUREMENTS AND MAIN RESULTS: A total of 118 lesions (76 polyps, 42 myomas) were removed. Among the 118 pathologies removed, 53 were removed in an office setting (28 myomas, 25 polyps), and 55 were removed in an ambulatory surgical center (ASC) setting (14 myomas, 41 polyps). The mean percentage of pathology removed was 95.9 +/- 6.8% for fibroids and 99.9 +/- 0.7% for polyps. Symptom severity as measured by the Uterine Fibroid Symptom-Quality of Life (UFS-QOL) scale improved significantly (p < .01) between baseline (mean score of 67.5 +/- 15.4) and 12 months postprocedure (mean score of 22.3 +/- 22.6). The Health-Related Quality of Life (HRQOL) scale also improved significantly (p < .01) between baseline (mean score 38.7 +/- 23.3) and 12 months postprocedure (mean score of 83.9 +/- 24.4). Both the office and ASC groups demonstrated a statistically significant (p < .01) improvement in UFS-QOL and HRQOL. CONCLUSION: For women with intrauterine polyps and/or myomas who experienced abnormal uterine bleeding, hysteroscopic morcellation with the MyoSure device provided significant, durable health related, quality-of-life improvements up to 12 months postprocedure. These findings were the same for patients treated in both an office-based setting and ASCs. PMID- 25446549 TI - Late-onset endometrial ablation failure--etiology, treatment, and prevention. AB - This review summarizes the history and demographics of nonresectoscopic endometrial ablation and global endometrial ablation procedures as well as the presentation, etiology, risk factors, treatment options, and prevention of late onset endometrial ablation failures. PMID- 25446550 TI - Quantification of perfusion in murine myocardium: A retrospectively triggered T1 based ASL method using model-based reconstruction. AB - PURPOSE: A method for the quantification of perfusion in murine myocardium is demonstrated. The method allows for the reconstruction of perfusion maps on arbitrary time points in the heart cycle while addressing problems that arise due to the irregular heart beat of mice. METHODS: A flow-sensitive alternating inversion recovery arterial spin labeling method using an untriggered FLASH-read out with random sampling is used. Look-Locker conditions are strictly maintained. No dummy pulses or mechanism to reduce deviation from Look-Locker conditions are needed. Electrocardiogram and respiratory data are recorded for retrospective gating and triggering. A model-based technique is used to reconstruct missing k space data to cope with the undersampling inherent in retrospectively gated methods. Acquisition and reconstruction were validated numerically and in phantom measurements before in vivo experimentation. RESULTS: Quantitative perfusion maps were acquired within a single slice measurement time of 11 min. Perfusion values are in good accordance to literature values. Myocardial infarction could be clearly visualized and results were confirmed with histological results. CONCLUSION: The proposed method is capable of producing quantitative perfusion maps on arbitrary positions in the heart cycle within a short measurement time. The method is robust against irregular breathing patterns and heart rate changes and can be implemented on all scanners. PMID- 25446552 TI - A message from modern-day healthcare to physical activity and fitness: welcome home! PMID- 25446551 TI - Osteopontin binding to the alpha 4 integrin requires highest affinity integrin conformation, but is independent of post-translational modifications of osteopontin. AB - Osteopontin (OPN) is a ligand for the alpha4beta1 integrin, but the physiological importance of this binding is not well understood. Here, we have assessed the effect of post-translational modifications on OPN binding to the alpha4 integrin on cultured human leukocyte cell lines and compared OPN interaction with alpha4 integrin to that of VCAM and fibronectin. Jurkat cells, whose alpha4 integrins are inherently activated, adhered to different preparations of OPN in the presence of Mn(2+): the EC50 of adhesion was not affected by phosphorylation or glycosylation status. Thrombin cleavage of OPN at the C-terminus of the alpha4 integrin-binding site also did not affect binding affinity. THP-1 cells express a low-affinity conformation of the integrin and adhered to OPN only in the presence of Mn(2+) plus PMA or an activating antibody. This was in contrast to VCAM and fibronectin: THP-1 cells adhered to these ligands without integrin activation. Studies with ligand-induced binding site antibodies demonstrated that the SVVYGLR peptide of OPN bound to the alpha4 integrin with a similar affinity as the LDV peptide of fibronectin, suggesting that a high off-rate is responsible for the reduced binding of OPN to the low-affinity forms of this integrin. Together, the results suggest OPN has very low affinity for the alpha4 integrin on human leukocytes under physiological conditions. PMID- 25446553 TI - Impact of pharmacologic interventions--treating endothelial dysfunction and group 2 pulmonary hypertension. AB - Pulmonary hypertension (PH) secondary to left heart disease (LHD) is a largely underappreciated therapeutic target. Except for a specific focus on PH consequences in patients with advanced heart failure (HF) receiving a left ventricular assist device or candidates for heart transplant, prevention and treatment of initial subclinical forms of PH are not considered a priority in the management of this chronic disease population. Nonetheless, there is recent growing evidence supporting a clinical and prognostic role of PH in the elderly populations and in HF with preserved ejection fraction (pEF). Although the prevalence of PH in these populations still remains largely unknown, there is a large potential for effective pharmacological approaches that might impact the natural history of HFpEF by targeting earlier stages. However, pharmacological studies performed to date with traditional pulmonary vasodilators (i.e. prostanoids and endothelin receptor blockers) in cohorts with HF and left-sided PH have not been positive, primarily because of concomitant systemic hypotension and hepatic toxicity. The encouraging preliminary data with more selective well tolerated pulmonary vasodilators, such as phosphodiesterase type 5 inhibitors and guanylate cyclase stimulators/activators, however, suggest the need for new targets of pulmonary microvascular dysfunction and for treating PH-LHD at both early and later stages of the disease process. PMID- 25446554 TI - Benefits of exercise training on coronary blood flow in coronary artery disease patients. AB - Every 34 seconds an American experiences a myocardial infarction or cardiac death. Approximately 80% of these coronary artery disease (CAD)-related deaths are attributable to modifiable behaviors, such as a lack of physical exercise training (ET). Regular ET decreases CAD morbidity and mortality through systemic and cardiac-specific adaptations. ET increases myocardial oxygen demand acting as a stimulus to increase coronary blood flow and thus myocardial oxygen supply, which reduces myocardial infarction and angina. ET augments coronary blood flow through direct actions on the vasculature that improve endothelial and coronary smooth muscle function, enhancing coronary vasodilation. Additionally, ET promotes collateralization, thereby, increasing blood flow to ischemic myocardium and also treats macrovascular CAD by attenuating the progression of coronary atherosclerosis and restenosis, potentially through stabilization of atherosclerotic lesions. In summary, ET can be used as a relatively safe and inexpensive way to prevent and treat CAD. PMID- 25446556 TI - Endothelial dysfunction and lung capillary injury in cardiovascular diseases. AB - Cardiac dysfunction of both systolic and diastolic origins leads to increased left atrial pressure, lung capillary injury and increased resistance to gas transfer. Acutely, pressure-induced trauma disrupts the endothelial and alveolar anatomical configuration and definitively causes an impairment of cellular pathways involved in fluid-flux regulation and gas exchange efficiency, a process well identified as stress failure of the alveolar-capillary membrane. In chronic heart failure (HF), additional stimuli other than pressure may trigger the true remodeling process of capillaries and small arteries characterized by endothelial dysfunction, proliferation of myofibroblasts, fibrosis and extracellular matrix deposition. In parallel there is a loss of alveolar gas diffusion properties due to the increased path from air to blood (thickening of extracellular matrix) and loss of fine molecular mechanism involved in fluid reabsorption and clearance. Deleterious changes in gas transfer not only reflect the underlying lung tissue damage but also portend independent prognostic information and may play a role in the pathogenesis of exercise limitation and ventilatory abnormalities observed in these patients. Few currently approved treatments for chronic HF have the potential to positively affect structural remodeling of the lung capillary network; angiotensin-converting enzyme inhibitors are one of the few currently established options. Recently, more attention has been paid to novel therapies specifically targeting the nitric oxide pathway as a suitable target to improve endothelial function and permeability as well as alveolar gas exchange properties. PMID- 25446555 TI - The current state of physical activity assessment tools. AB - Physical activity (PA) is a behavior that involves bodily movements resulting in energy expenditure. When assessing PA, the goal is to identify the frequency, duration, intensity, and types of behaviors performed during a period of time. Self-report measures of PA include administration of questionnaires and completion of detailed diaries and/or brief logs. Direct measures include motion sensors such as accelerometers, pedometers, heart-rate monitors, and multiple sensor devices. The PA assessment period can range from a few hours to a lifetime depending on the tools used. Considerations when selecting a PA tool should include the literacy requirements of a tool, the purpose for assessing PA, the recall or time period to measure, the validity evidence of an assessment tool for the populations measured, and the generalizability of the results to diverse populations. PMID- 25446557 TI - Competitive adsorption of monoclonal antibodies and nonionic surfactants at solid hydrophobic surfaces. AB - Two monoclonal antibodies from the IgG subclasses one and two were compared in their adsorption behavior with hydrophobic surfaces upon dilution to 10 mg/mL with 0.9% NaCl. These conditions simulate handling of the compounds at hospital pharmacies and surfaces encountered after preparation, such as infusion bags and i.v. lines. Total internal reflection fluorescence and quartz crystal microbalance with dissipation monitoring were used to follow and quantify this. Furthermore, the influence of the nonionic surfactant polysorbate 80 (PS80) on the adsorption process of these two antibodies was investigated. Despite belonging to two different IgG subclasses, both antibodies displayed comparable adsorption behavior. Both antibodies readily adsorbed in the absence of PS80, whereas adsorption was reduced in the presence of 30 mg/L surfactant. The sequence of exposure of the surfactant and protein to the surface was found to have a major influence on the extent of protein adsorption. Although only a fraction of adsorbed protein could be removed by rinsing with 30 mg/L surfactant solution, adsorption was entirely prevented when surfaces were pre-exposed to PS80. PMID- 25446558 TI - The olfactory bulbectomy model in mice and rat: one story or two tails? AB - Olfactory bulbectomy (OBX), the surgical removal of the olfactory bulbs, lead, both in mice and rats, to a specific set of behavioral changes in social behavior, cognitive function and activity. The latter is often used as a readout measure to predict antidepressant effects of new compounds. More recently, the model is used to study neurodegeneration and the associated cognitive decline. Although most of the OBX-induced behavioral and neurochemical changes seen in mice and rats are very similar, there are also some remarkable differences. For instance, OBX has different effects on BDNF and the 5-HT2c receptor of these two species. These species differ also in how they respond to certain treatments after OBX. In this review we describe these species-specific differences and discuss what they may mean in terms of translational value. PMID- 25446559 TI - Mirtazapine as positive control drug in studies examining the effects of antidepressants on driving ability. AB - The development of effective and safe antidepressant medications is ongoing, and driving studies are critical to assess a drug's safety. The current review summarizes the effects of a sedating effective antidepressant, mirtazapine, on driving ability, and its potential to serve as positive control drug in future driving studies. Three on-road driving studies and four driving simulator studies of mirtazapine were identified. The studies, conducted in healthy volunteers, showed a significant dose-dependent driving impairment, the first day following bedtime administration of mirtazapine. The magnitude of impairment after a single dose of 15 mg or 30 mg mirtazapine was comparable to that observed with a blood alcohol concentration of 0.05%, the legal limit for driving in many countries. After 1 or 2 weeks of daily treatment with mirtazapine, partial tolerance developed to mirtazapine's effects on driving. Driving studies conducted in patients were less informative, as the effect on driving caused by mirtazapine was obscured by a drug-disease interaction and increased variability in patient groups. In conclusion, mirtazapine is useful as positive control drug to assess the potential effects of new antidepressant drugs on driving. Studies in normal healthy volunteers are more sensitive to drug effects than studies in patient populations. PMID- 25446560 TI - Serotonin: a never-ending story. AB - The neurotransmitter serotonin is an evolutionary ancient molecule that has remarkable modulatory effects in almost all central nervous system integrative functions, such as mood, anxiety, stress, aggression, feeding, cognition and sexual behavior. After giving a short outline of the serotonergic system (anatomy, receptors, transporter) the author's contributions over the last 40 years in the role of serotonin in depression, aggression, anxiety, stress and sexual behavior is outlined. Each area delineates the work performed on animal model development, drug discovery and development. Most of the research work described has started from an industrial perspective, aimed at developing animals models for psychiatric diseases and leading to putative new innovative psychotropic drugs, like in the cases of the SSRI fluvoxamine, the serenic eltoprazine and the anxiolytic flesinoxan. Later this research work mainly focused on developing translational animal models for psychiatric diseases and implicating them in the search for mechanisms involved in normal and diseased brains and finding new concepts for appropriate drugs. PMID- 25446561 TI - Reactive oxygen species contribute to TRAIL receptors upregulation; the mechanism for PH II-7 augmenting TRAIL induced apoptosis in leukemia cells. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in cancer cells and is verified to be effective in various cancers. However, a variety of cancer cells are found to be resistant to TRAIL and the mechanisms are largely unknown. Moreover, multidrug resistance to traditional chemotherapeutic agents still remains a tough problem in clinical practice. Fortunately, our previous work proved the ability of PH II-7 in overcoming MDR phenotype through reactive oxygen species production in K562 and its MDR counterpart K562/A02 cells. Additionally, we further explored its potential in augmenting TRAIL induced apoptosis in cancer cells with various tissue origins. Our results showed PH II-7 up-regulated DR4/DR5 expression and augment TRAIL cytotoxicity through reactive oxygen species production, which provide a solid foundation for TRAIL in combination with PH II-7 in future clinical application. PMID- 25446562 TI - ?FosB: a transcriptional regulator of stress and antidepressant responses. AB - DeltaFosB is a member of the Fos family of transcription factors. While other family members are induced rapidly but transiently in response to a host of acute stimuli, DeltaFosB is unique in that it accumulates in response to repeated stimulation due to its unusual protein stability. Such prolonged induction of DeltaFosB, within nucleus accumbens (NAc), a key brain reward region, has been most studied in animal models of drug addiction, with considerable evidence indicating that DeltaFosB promotes reward and motivation and serves as a mechanism of drug sensitization and increased drug self-administration. In more recent years, prolonged induction of ?FosB has also been observed within NAc in response to chronic administration of certain forms of stress. Increasing evidence indicates that this induction represents a positive, homeostatic adaptation to chronic stress, since overexpression of ?FosB in this brain region promotes resilience to stress, whereas blockade of its activity promotes stress susceptibility. Chronic administration of several antidepressant medications also induces ?FosB in the NAc, and this induction is required for the therapeutic-like actions of these drugs in mouse models. Validation of these rodent findings is the demonstration that depressed humans, examined at autopsy, display reduced levels of ?FosB within the NAc. As a transcription factor, DeltaFosB produces this behavioral phenotype by regulating the expression of specific target genes, which are under current investigation. These studies of DeltaFosB are providing new insight into the molecular basis of depression and antidepressant action, which is defining a host of new targets for possible therapeutic development. PMID- 25446563 TI - Anesthetic agent propofol inhibits myeloid differentiation factor 88-dependent and independent signaling and mitigates lipopolysaccharide-mediated reactive oxygen species production in human neutrophils in vitro. AB - Engagement of toll-like receptor 4 (TLR4) can activate the myeloid differentiation factor 88 (MyD88)/toll-interleukin-1-resistance domain-containing adapter-inducing interferon-beta (TRIF) dependent pathways, inducing production of reactive oxygen species (ROS) in neutrophils. Propofol (PPF) has both anti oxidant and anti-inflammatory properties. However, the molecular mechanism by which PPF influences human neutrophil function is yet to be elucidated. This study aimed to investigate the influence of PPF on lipopolysaccharide (LPS) induced reactive oxygen species production in human neutrophils. We isolated neutrophils from the peripheral blood of 10 healthy male donors. Neither 1 ug/ml LPS nor 10-150 MUmol/L PPF influenced the rate of neutrophil apoptosis, but PPF significantly inhibited LPS-mediated reactive oxygen species production in a dose dependent manner. PPF inhibited LPS-induced expression of MyD88, tumor necrosis factor receptor-associated factor 6, and TRIF, but not the expression of interferon regulatory factor 3 or phosphorylation of p47(phox), p38-mitogen activated protein kinase, and nuclear factor (NF)-kappaB, particularly in the neutrophils in which MyD88 or TRIF had been silenced by siRNA. The inhibitory effect of PPF on LPS-induced activation of p47(phox), p38-mitogen-activated protein kinase, and NF-kappaB was partially antagonized by over-expression of MyD88 or TRIF in neutrophils. These observations provide insights into the mechanisms responsible for the anti-inflammatory properties of PPF. PPF reduces LPS-induced production of reactive oxygen species in neutrophils via inhibiting expression of MyD88 and TRIF signaling. PMID- 25446564 TI - Effects of desipramine on prazosin potency at alpha1A- and alpha1D-adrenoceptors in rat vas deferens: implications for the alpha1L-adrenoceptor subclassification. AB - This study investigates the interaction between cocaine, desipramine and prazosin at alpha1-adrenoceptor subtypes mediating contractions to noradrenaline in epididymal portions of rat vas deferens. Noradrenaline potency was not significantly affected by desipramine (0.1-1.0 MUM) and reduced by desipramine (10 MUM), but was increased by the presence of cocaine (3.0-30 MUM), particularly in terms of phasic contractions to low concentrations of noradrenaline. In vehicle experiments, prazosin exhibited relatively low potency as an antagonist against the predominantly alpha1A-adrenoceptor mediated response (pKB 8.50). In the presence of cocaine, prazosin exhibited higher potency against the revealed alpha1D-adrenoceptor mediated component (e.g. pKB 9.12). In the presence of desipramine, the potency of prazosin was either unchanged or indeed decreased. Cocaine (0.3-30 MUM) significantly increased the single pulse nerve-stimulation evoked contraction, with a maximum increase to 156+/-12% of control (n=9). In contrast, desipramine in low concentrations (0.1-0.3 MUM) produced a small but significant increase to 126.6+/-5.5% (n=11), but higher concentrations failed to increase the response. In conclusion, desipramine fails to produce sufficient noradrenaline transporter block in low concentrations (0.1 MUM) and produces alpha1-adrenoceptor antagonism in slightly higher concentrations (0.3-1 MUM), and so is unsuitable for use in alpha1-adrenoceptor subclassification studies. Contractions of rat vas deferens are mediated by alpha1A- and alpha1D adrenoceptors, and prazosin has selectivity for alpha1D- over alpha1A adrenoceptors. The alpha1L-adrenoceptor previously identified in rat vas deferens is the native alpha1A-adrenoceptor. The range of prazosin potencies and receptor subtypes previously reported in rat vas deferens may be explained by the choice of cocaine or desipramine as noradrenaline transporter blocker. PMID- 25446565 TI - Tadalafil enhances working memory, and reduces hippocampal oxidative stress in both young and aged mice. AB - Tadalafil, a type-5 phosphodiesterase enzyme inhibitor with long half-life used to treat erectile dysfunction. Recently it has been reported that tadalafil improves cognitive function. Here, we aimed to investigate the age dependent effects of tadalafil on memory, locomotor, behavior, and oxidative stress in the hippocampus. Tadalafil was orally administered everyday (5 mg/kg) to young (2 months) and old (16 months) healthy mice for 4 weeks. Control mice from each group received equal volume of 0.9% normal saline for the same duration. Memory and locomotor activity were tested using radial arm maze and open field test respectively. The level of malondialdehyde (MDA), nitric oxide (NO), and advanced protein oxidation product (APOP) was analyzed and catalase activity was determined from the isolated hippocampus. Treatment with tadalafil in aged mice improves working memory than the corresponding tadalafil treated young mice in radial arm maze test. Tadalafil treated mice traveled less distance in the center and the mean speed of tadalafil treated aged mice was significantly lower than the tadalafil treated young mice in open field test. Tadalafil treatment elicited a decrease of MDA level in the hippocampus of aged mice than that of young mice. APOP level was decreased only in aged mice treated with tadalafil. Treatment with tadalafil decreased NO and increased catalase activity in both young and aged mice. On the basis of previous and our findings, we conclude that tadalafil treatment reduces oxidative stress while increased cGMP level in the hippocampus might be responsible for memory enhancement. PMID- 25446566 TI - Pharmacological characterization of the interaction between aclidinium bromide and formoterol fumarate on human isolated bronchi. AB - Long-acting muscarinic receptor antagonists (LAMAs) and long-acting beta2 adrenoceptor agonists (LABAs) cause airway smooth muscle (ASM) relaxation via different signal transduction pathways, but there are limited data concerning the interaction between these two drug classes on human bronchi. The aim of this study was to investigate the potential synergistic interaction between aclidinium bromide and formoterol fumarate on the relaxation of human ASM. We evaluated the influence of aclidinium bromide and formoterol fumarate on the contractile response induced by acetylcholine or electrical field stimulation (EFS) on human isolated airways (segmental bronchi and bronchioles). We analyzed the potential synergistic interaction between the compounds when administered in combination by using Bliss independence (BI) theory. Both aclidinium bromide and formoterol fumarate completely relaxed segmental bronchi pre-contracted with acetylcholine (Emax: 97.5+/-2.6% and 96.4+/-1.1%; pEC50 8.5+/-0.1 and 8.8+/-0.1; respectively). Formoterol fumarate, but not aclidinium bromide, abolished the contraction induced by acetylcholine in bronchioles (Emax: 68.1+/-4.5% and 99.0+/-5.6%; pEC50 7.9+/-0.3 and 8.4+/-0.3; respectively). The BI analysis indicated synergistic interaction at low concentrations in segmental bronchi (+18.4+/-2.7%; P<0.05 versus expected effect) and from low to high concentrations in bronchioles (+19.7+/-0.9%; P<0.05 versus expected effect). Low concentrations of both drugs produced a synergistic relaxant interaction on isolated bronchi stimulated with EFS that was sustained for 6h post-treatment (+55.1+/-9.4%; P<0.05 versus expected effect). These results suggest that combining aclidinium bromide plus formoterol fumarate provides synergistic benefit on ASM relaxation of both medium and small human airways, which may have major implications for the use of this combination in the clinic. PMID- 25446567 TI - Mechanisms of Nattokinase in protection of cerebral ischemia. AB - In vivo, the level of cyclic Adenosine Monophosphate (cAMP) and the pathway of the Janus Kinase1/Signal Transducers and Activators of Transcription1 (JAK1/STAT1) were studied. In vitro, the Ca(2+) mobilization in human platelet stimulated by thrombin was observed. In addition, vasomotion of vascular smooth muscle was measured by adding KCl or norepinephrine(NE) under the Ca(2+) contained bath solutions. The effect induced by NE in the presence of N-nitro-L arginine methyl ester (L-NAME) or indometacin (Indo) was also detected. At last, the levels of tissue plasminogen activator (t-PA) and Plasminogen activator inhibitor-1 (PAI-1) in cultured supernatans in Human umbilical vein endothelial cells (Huvecs) were measured by means of ELISA kit. Results showed that Nattokinase (NK) significantly increased the cAMP level, activated the signal passage of JAK1/STAT1 in injured part and inhibited remarkably the rise of platelet intracellular Ca(2+) ([Ca(2+)]i) in human platelet. Furthermore, NK relaxed rat thoracic aortic artery in the dose-dependent manner and in the endothelium dependent manner and its effect could be attenuated by L-NAME. Also, the secretion of t-PA and PAI-1 were reduced stimulated by Adr on Huvecs. These data indicated that the neuroprotective effect of NK was associated with its antiplatelet activity by elevating cAMP level and attenuating the calcium release from calcium stores; with its anti-apoptotic effect through the activation of JAK1/STAT1 pathway; with its relaxing vascular smooth muscle by promoting synthesis and release of NO, reducing ROC calcium ion influx and with its protection on endothelial cells through increasing fibrinolytic activity and facilitating spontaneous thrombolysis. PMID- 25446569 TI - Naringenin reduces cholesterol-induced hepatic inflammation in rats by modulating matrix metalloproteinases-2, 9 via inhibition of nuclear factor kappaB pathway. AB - Nonalcoholic fatty liver disease (NAFLD) is a spectrum of hepatic abnormalities that extends from isolated steatosis to non-alcoholic steatohepatitis (NASH) and steatofibrosis. NASH is the progressive form of the disease that can lead to fibrosis, cirrhosis and hepatocellular carcinoma. Naringenin (NGEN), a healthful food, increases resistance to oxidative stress, inflammation and protects against multiple organ injury in various animal models. However, specific mechanisms responsible for such effects are poorly understood. Thus, this study investigates the effect of treatment with NGEN (50mg/kg) on oxidative events and the molecular mechanisms underlying inflammatory changes triggered in the rat liver by a high cholesterol diet for 90 days. NGEN significantly decreased the plasma fatty acid composition, the hepatic pro-inflammatory mediators and the expression of relevant genes including tumor necrosis factor-alpha, interlukin-6, interleukin 1beta, inducible nitric oxide synthase and matrix metalloproteinases (MMP-2, 9), EGF-like module-containing mucin-like hormone receptor-like 1 (macrophage F4/80 specific gene); which suggests a reduced macrophage infiltration, and inhibited oxidative stress related biomarker levels at the end point of the experiment. Mechanistically, studies showed that NGEN markedly reduced lipid and protein oxidations, recruited the anti-oxidative defense system and promoted extracellular matrix degradation by modulating the levels of necrotic inflammation. PMID- 25446568 TI - Effects of the NOP agonist SCH221510 on producing and attenuating reinforcing effects as measured by drug self-administration in rats. AB - Nociceptin/orphanin FQ peptide (NOP) receptor agonists attenuate morphine-induced conditioned place preference in rodents. However, it is not known whether NOP agonists have reinforcing properties or can inhibit mu opioid receptor (MOP) mediated reinforcement as measured by drug self-administration in rodents. Further understanding the behavioral effects of NOP agonists could suggest them as having potential in attenuating reinforcing effects of opioids. In the first part of the study, reinforcing properties of selective NOP agonist SCH221510 were determined and compared with the full MOP agonist remifentanil under fixed-ratio 5 (FR5) and progressive-ratio (PR) schedules of drug self-administration. In the second part, effects of systemic and intracisternal pretreatment of SCH221510 were determined and compared with MOP antagonist naltrexone in attenuating reinforcing effects of remifentanil and a non-drug reinforcer (sucrose pellets). Remifentanil self-administration (0.3-10 ug/kg/infusion) generated a biphasic dose-response curve, characteristic of drugs with reinforcing properties. SCH221510 (3-300 ug/kg/infusion) self-administration resulted in flat dose response curves and early break-points under the PR, indicative of drugs lacking reinforcing value. Intracisternally, but not systemically, administered SCH221510 (0.3-3 ug) attenuated remifentanil self-administration, comparable with systemic naltrexone (0.03-0.3 mg/kg). SCH221510 (1-3 ug), unlike naltrexone (0.03-1 mg/kg), attenuated responding for sucrose pellets. Both effects of SCH221510 were reversed by the NOP antagonist J-113397 (0.3-3 ug). These results suggest that SCH221510 does not function as a reinforcer in rats, and that it can attenuate the reinforcing value of MOP agonists; therefore, the potential utility of NOP agonists for the treatment of drug addiction warrants further evaluation. PMID- 25446570 TI - The nicotinic cholinergic system function in the human brain. AB - Research on the nicotinic cholinergic system function in the brain was previously mainly derived from animal studies, yet, research in humans is growing. Up to date, findings allow significant advances on the understanding of nicotinic cholinergic effects on human cognition, emotion and behavior using a range of functional brain imaging approaches such as pharmacological functional magnetic resonance imaging or positron emission tomography. Studies provided insights across various mechanistic psychological domains using different tasks as well as at rest in both healthy individuals and patient populations, with so far partly mixed results reporting both enhancements and decrements of neural activity related to the nicotinic cholinergic system. Moreover, studies on the relation between brain structure and the nicotinic cholinergic system add important information in this context. The present review summarizes the current status of human brain imaging studies and presents the findings within a theoretical and clinical perspective as they may be useful not only for an advancement of the understanding of basic nicotinic cholinergic-related mechanisms, but also for the development and integration of psychological and pharmacological treatment approaches. Patterns of functional neuroanatomy and neural circuitry across various cognitive and emotional domains may be used as neuropsychological markers of mental disorders such as addiction, Alzheimer's disease, Parkinson disease or schizophrenia, where nicotinic cholinergic system changes are characteristic. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID- 25446572 TI - Serotonin2C receptor stimulation inhibits cocaine-induced Fos expression and DARPP-32 phosphorylation in the rat striatum independently of dopamine outflow. AB - The serotonin(2C) receptor (5-HT(2C)R) is known to control dopamine (DA) neuron function by modulating DA neuronal firing and DA exocytosis at terminals. Recent studies assessing the influence of 5-HT(2C)Rs on cocaine-induced neurochemical and behavioral responses have shown that 5-HT2CRs can also modulate mesoaccumbens DA pathway activity at post-synaptic level, by controlling DA transmission in the nucleus accumbens (NAc), independently of DA release itself. A similar mechanism has been proposed to occur at the level of the nigrostriatal DA system. Here, using in vivo microdialysis in freely moving rats and molecular approaches, we assessed this hypothesis by studying the influence of the 5-HT(2C)R agonist Ro 60 0175 on cocaine-induced responses in the striatum. The intraperitoneal (i.p.) administration of 1 mg/kg Ro 60-0175 had no effect on the increase in striatal DA outflow induced by cocaine (15 mg/kg, i.p.). Conversely, Ro 60-0175 inhibited cocaine-induced Fos immunoreactivity and phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine 75 residue in the striatum. Finally, the suppressant effect of Ro 60-0175 on cocaine-induced DARPP 32 phosphorylation was reversed by the selective 5-HT(2C)R antagonist SB 242084 (0.5 mg/kg, i.p.). In keeping with the key role of DARPP-32 in DA neurotransmission, our results demonstrate that 5-HT(2C)Rs are capable of modulating nigrostriatal DA pathway activity at post-synaptic level, by specifically controlling DA signaling in the striatum. PMID- 25446573 TI - Involvement of 5-HT7 receptors in vortioxetine's modulation of circadian rhythms and episodic memory in rodents. AB - Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders, antidepressants that target key 5-HT (serotonin) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility. Vortioxetine is a multimodal antidepressant that inhibits 5 HT1D, 5-HT3, 5-HT7 receptor activity, 5-HT reuptake, and enhances the activity of 5-HT1A and 5-HT1B receptors. In this study, we investigated the effects of vortioxetine on the period length of PER2::LUC expression, circadian behavior, and episodic memory, using tissue explants from genetically modified PER2::LUC mice, locomotor activity rhythm monitoring, and the object recognition test, respectively. Incubation of tissue explants from the suprachiasmatic nucleus of PER2::LUC mice with 0.1 MUM vortioxetine increased the period length of PER2 bioluminescence. Monitoring of daily wheel-running activity of Sprague-Dawley rats treated with vortioxetine (10 mg/kg, s.c.), alone or in combination with the 5-HT1A receptor agonist flesinoxan (2.5 mg/kg, s.c.) or the 5-HT7 receptor antagonist SB269970 (30 mg/kg, s.c.), just prior to activity onset revealed significant delays in wheel-running behavior. The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the 5-HT7 receptor partial agonist AS19. Finally, in the object recognition test, vortioxetine (10 mg/kg, i.p.) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 (5 mg/kg, i.p.). In conclusion, the present study shows that vortioxetine, partly via its 5-HT7 receptor antagonism, induced a significant effect on circadian rhythm and presented promnesic properties in rodents. PMID- 25446574 TI - Impairment of acquisition of intravenous cocaine self-administration by RNA interference of dopamine D1-receptors in the nucleus accumbens shell. AB - Microdialysis during i.v. drug self-administration (SA) have implicated nucleus accumbens (NAc) shell DA in cocaine and heroin reinforcement. However, this correlative evidence has not been yet substantiated by experimental evidence obtained by studying the effect of selective manipulation of NAc shell DA transmission on cocaine and heroin SA. In order to investigate this issue, DA D1a receptor (D1aR) expression was impaired in the NAc shell and core by locally infusing lentiviral vectors (LV) expressing specific D1aR-siRNAs (LV-siRNAs). Control rats were infused in the same areas with LV expressing GFP. Fifteen days later, rats were trained to acquire i.v. cocaine or heroin self-administration (SA). At the end of behavioral experiments, in order to evaluate the effect of LV siRNA on D1aR expression, rats were challenged with amphetamine and the brains were processed for immunohistochemical detection of c-Fos and D1aR. Control rats acquired i.v. cocaine and heroin SA. Infusion of LV-siRNAs in the medial NAc shell reduced D1aR density and the number of c-Fos positive nuclei in the NAc shell, while sparing the core, and prevented the acquisition of cocaine, but not heroin SA. In turn, LV-siRNAs infusion in the core reduced D1aR density and the number of c-Fos positive nuclei in the same area, while sparing the shell, and failed to affect acquisition of cocaine. The differential effect of LV impairment of NAc shell D1aR on cocaine and heroin SA indicates that NAc shell DA acting on D1aR specifically mediates cocaine reinforcement. PMID- 25446575 TI - 17alpha-estradiol is generated locally in the male rat brain and can regulate GAD65 expression and anxiety. AB - Increasing evidence suggests that 17beta-estradiol, a sex hormone, is synthesized by neurons. In addition, 17alpha-estradiol, the stereoisomer of 17beta-estradiol, is reported to be the dominant form in the male mouse brain. However, probably because the method to detect these isomers requires unusual and precise experimental design, the presence of this endogenous 17alpha-estradiol has not been reported subsequently and the actual role is therefore not well elucidated. We first quantified the estradiol level in hippocampal extracts using gas chromatography/mass spectrometry. As a result, 17alpha-estradiol was found in all of the male rats tested, while that of 17beta-estradiol was detected only in a certain subset. The estrogen-biosynthesis inhibitor letrozole decreased the expression of the major presynaptic GABA synthesizing enzyme GAD65 in cultured neurons and the effect was abrogated by exogenously supplied 17alpha-estradiol. Next, injection of the inhibitor into the brain reduced the 17alpha-estradiol level, indicating its biogenesis in the brain. Under the same conditions, immuno staining of GAD65 was also decreased. Furthermore, the inhibitor treatment increased anxiety index of rats in the open field and this was ameliorated by the addition of 17alpha-estradiol. We showed that 17alpha-estradiol was generated in the brain and acted as a regulator of inhibitory neurotransmission as well as behavior. These results may have implications for a variety of diseases, such as the menopausal depression and Alzheimer's disease that have been reported to be related to estrogen levels. PMID- 25446571 TI - The therapeutic potential of interleukin-10 in neuroimmune diseases. AB - Neuroimmune diseases have diverse symptoms and etiologies but all involve pathological inflammation that affects normal central nervous system signaling. Critically, many neuroimmune diseases also involve insufficient signaling/bioavailability of interleukin-10 (IL-10). IL-10 is a potent anti inflammatory cytokine released by immune cells and glia, which drives the regulation of a variety of anti-inflammatory processes. This review will focus on the signaling pathways and function of IL-10, the current evidence for insufficiencies in IL-10 signaling/bioavailability in neuroimmune diseases, as well as the implications for IL-10-based therapies to treating such problems. We will review in detail four pathologies as examples of the common etiologies of such disease states, namely neuropathic pain (nerve trauma), osteoarthritis (peripheral inflammation), Parkinson's disease (neurodegeneration), and multiple sclerosis (autoimmune). A number of methods to increase IL-10 have been developed (e.g. protein administration, viral vectors, naked plasmid DNA, plasmid DNA packaged in polymers to enhance their uptake into target cells, and adenosine 2A agonists), which will also be discussed. In general, IL-10-based therapies have been effective at treating both the symptoms and pathology associated with various neuroimmune diseases, with more sophisticated gene therapy-based methods producing sustained therapeutic effects lasting for several months following a single injection. These exciting results have resulted in IL-10-targeted therapeutics being positioned for upcoming clinical trials for treating neuroimmune diseases, including neuropathic pain. Although further research is necessary to determine the full range of effects associated with IL-10-based therapy, evidence suggests IL-10 may be an invaluable target for the treatment of neuroimmune disease. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. PMID- 25446577 TI - Meta-analysis of absolute mean differences from randomised trials with treatment related clustering associated with care providers. AB - Nesting of patients within care providers in trials of physical and talking therapies creates an additional level within the design. The statistical implications of this are analogous to those of cluster randomised trials, except that the clustering effect may interact with treatment and can be restricted to one or more of the arms. The statistical model that is recommended at the trial level includes a random effect for the care provider but allows the provider and patient level variances to differ across arms. Evidence suggests that, while potentially important, such within-trial clustering effects have rarely been taken into account in trials and do not appear to have been considered in meta analyses of these trials. This paper describes summary measures and individual patient-data methods for meta-analysing absolute mean differences from randomised trials with two-level nested clustering effects, contrasting fixed and random effects meta-analysis models. It extends methods for incorporating trials with unequal variances and homogeneous clustering to allow for between-arm and between trial heterogeneity in intra-class correlation coefficient estimates. The work is motivated by a meta-analysis of trials of counselling in primary care, where the control is no counselling and the outcome is the Beck Depression Inventory. Assuming equal counsellor intra-class correlation coefficients across trials, the recommended random-effects heteroscedastic model gave a pooled absolute mean difference of -2.53 (95% CI -5.33 to 0.27) using summary measures and -2.51 (95% CI -5.35 to 0.33) with the individual-patient-data. Pooled estimates were consistently below a minimally important clinical difference of four to five points on the Beck Depression Inventory. PMID- 25446578 TI - Dysregulation of adaptive immune responses in complement C3-deficient patients. AB - In addition to its effector functions, complement is an important regulator of adaptive immune responses. Murine studies suggest that complement modulates helper T-cell differentiation, and Th1 responses in particular are impaired in the absence of functional complement. Here, we have studied humoral responses to toxoid vaccines in eight patients with C3 deficiency, representing more than 25% of all the known patients worldwide. Serum cytokine levels were also studied. The patients developed normal Ig responses to tetanus and diphtheria toxoids, but IgE levels were low. The pattern of antigen-specific IgG subclasses was abnormal, with increased Th1-related IgG3 responses, low IgG2, and almost completely undetectable IgG4. The patients also had increased amounts of Th1-related cytokines IL-12p70 and IL-21, and these showed a positive correlation with IgG3 levels. Our results confirm that complement modulates Th differentiation, but reveal a more nuanced outcome than previously reported. Since IgG4 has been linked to tolerogenic responses, the data also suggest that in the absence of functional complement at least some aspects of systemic tolerance are impaired. PMID- 25446579 TI - In the shadow of a pepper-centric historiography: Understanding the global diffusion of capsicums in the sixteenth and seventeenth centuries. AB - Historians of the Eurasian spice trade focus on the fortunes of black pepper (Piper Nigrum L.), largely because the trading companies of the Dutch and English which they study also did. Capsicum peppers are, however, the world's most consumed spice, and their story needs to be told in parallel. The five species of capsicum peppers spread across the world in less than two hundred years following their discovery by Europeans in South and Central America and proved both hardier than Piper nigrum and able to reproduce spontaneously. While the taste was similar but more pungent than black pepper, capsicums provided an important vitamin C and bioflavanoid supplement to poorer people in southern and eastern Europe far from the precepts of good taste as dictated from Paris, and rapidly became a mainstay of tropical cuisine across the world. This contribution seeks both to trace and to understand that diffusion and its principal vectors from historical research amongst a plethora of primary source materials in European and Asian languages. Medical and dietetic reaction is presented from a wide range of contemporary texts. The work proceeds according to deductive reasoning and in comparison to the diffusion of black pepper consumption. It reveals the very different strategies of import substitution and commercial embargo undertaken by Portuguese and Spanish authorities, a somewhat later date of arrival in China than previously thought, and three different, competing lines of entry into an important area of later cultivation, namely Central Europe. PMID- 25446576 TI - Elevated levels of kynurenic acid during gestation produce neurochemical, morphological, and cognitive deficits in adulthood: implications for schizophrenia. AB - The levels of kynurenic acid (KYNA), an endogenous negative modulator of alpha7 nicotinic acetylcholine receptors (alpha7nAChRs), are elevated in the brains of patients with schizophrenia (SZ). We reported that increases of brain KYNA in rats, through dietary exposure to its precursor kynurenine from embryonic day (ED)15 to postnatal day (PD) 21, result in neurochemical and cognitive deficits in adulthood. The present experiments focused on the effects of prenatal exposure to elevated kynurenine on measures of prefrontal excitability known to be impaired in SZ. Pregnant dams were fed a mash containing kynurenine (100 mg/day; progeny = EKYNs) from ED15 until ED22. Controls were fed an unadulterated mash (progeny = ECONs). The dietary loading procedure elevated maternal and fetal plasma kynurenine (2223% and 693% above controls, respectively) and increased fetal KYNA (forebrain; 500% above controls) on ED21. Elevations in forebrain KYNA disappeared after termination of the loading (PD2), but KYNA levels in the prefrontal cortex (PFC) were unexpectedly increased again when measured in adults (PD56-80; 75% above controls). We also observed changes in several markers of prefrontal excitability, including expression of the alpha7nAChR (22% and 17% reductions at PD2 and PD56-80), expression of mGluR2 (31% and 24% reductions at ED21 and PD56-80), dendritic spine density (11-14% decrease at PD56-80), subsensitive mesolimbic stimulation of glutamate release in PFC, and reversal/extra-dimensional shift deficits in the prefrontally-mediated set shifting task. These results highlight the deleterious impact of elevated KYNA levels during sensitive periods of early development, which model the pathophysiological and cognitive deficits seen in SZ. PMID- 25446580 TI - Oligosaccharidic fractions derived from Triticum vulgare extract accelerate tissutal repairing processes in in vitro and in vivo models of skin lesions. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Triticum vulgare has been extensively used in traditional medicine thanks to its properties of accelerating tissue repair. The aqueous extract of Triticum vulgare (TVE) is currently an active component used by Farmaceutici Damor in the manufacture of certain pharmaceutical products already marketed in Italy and abroad under the brand name Fitostimoline((r)), in the formulation of cream and medicated gauze and is commonly used for the treatment of decubitus ulcers, sores, burns, scarring delays, dystrophic diseases, and, more broadly, in the presence of problems relating to re epithelialization or tissue regeneration. The active components of Fitostimoline((r))-based products determine a marked acceleration of tissutal repairing processes, stimulate chemotaxis and the fibroblastic maturation, and significantly increase the fibroblastic index, which are crucial points in the repairing processes. The aim of the present paper was to identify and characterize the active fractions of TVE responsible for the pharmacological effect in tissutal repairing processes. MATERIALS AND METHODS: Several fractions obtained from TVE by ultrafiltration procedures and HPAE chromatography were tested to measure their growth-enhancing activity on NIH-3T3 fibroblasts. The healing action of the same fractions, prepared as cream formulation, was assessed in rat subjected to two different models of skin lesion, skin scarification and excision. RESULTS: Our results showed a pro-proliferative effect of the fractions ST-98 and K>1000 in NIH-3T3 fibroblasts. Moreover these fractions formulated as cream preparations were effective also in in vivo models of skin lesion. CONCLUSIONS: The results of the present study showed that these active fractions of TVE are responsible for its pro-proliferative effect. PMID- 25446581 TI - Inhibitory effects of teuclatriol, a sesquiterpene from salvia mirzayanii, on nuclear factor-kappaB activation and expression of inflammatory mediators. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Salvia mirzayanii Rech. f. & Esfand. is an endemic plant, which is only distributed in the south of Iran. In traditional Iranian medicine, the aerial parts of Salvia mirzayanii have been used for infections, inflammatory diseases, and as a tonic. From this plant, the sesquiterpene teuclatriol was isolated by bioactivity-guided fractionation due to its anti-proliferative actions on human lymphocytes. The guaiane sesquiterpene is lacking the methylene-gamma-lactone function that is typically involved in the inhibiting properties of sesquiterpenes on NF-kappaB, a pivotal transcription factor in inflammatory processes. We here investigated anti-inflammatory effects of teuclatriol on human macrophage-like and endothelial cells. MATERIALS AND METHODS: Non-toxic doses of teuclatriol were determined for both cell types by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)-assay. The effect of teuclatriol on the activity of NF-kappaB in LPS-stimulated human monocytic THP-1 cells was studied using infrared electrophoretic mobility shift assay (IR-EMSA) using curcumin as positive control (32uM). THP-1 were differentiated into macrophage-like cells and evaluated for TNF-alpha secretion by L929 bioassay following stimulation with LPS and treatment with teuclatriol. Inflammatory gene expression in human umbilical vein endothelial cells (HUVEC), modeling target cells for TNF-alpha-induced inflammatory gene activation, was investigated by real-time RT-PCR. RESULTS: The LPS-induced DNA binding activity of NF-kappaB in THP-1 was significantly decreased by non-toxic doses of teuclatriol (312 and 390uM). Teuclatriol reduced the production of TNF-alpha in a dose-dependent manner. mRNA levels of both monocyte chemoattractant protein (MCP) 1 and toll-like receptor (TLR)2 were decreased in TNF-alpha-activated HUVEC. CONCLUSION: These data show an inhibitory effect of teuclatriol on NF-kappaB signaling at doses of 312uM and higher, validating the traditional use of Salvia mirzayanii in the treatment of inflammatory diseases. Future work on the mode of action of teuclatriol may provide new lead structures with NF-kappaB inhibiting properties, lacking possible side effects mediated via alkylating centers of sesquiterpene lactones. PMID- 25446582 TI - Anti-inflammatory effect of a standardized triterpenoid-rich fraction isolated from Rubus coreanus on dextran sodium sulfate-induced acute colitis in mice and LPS-induced macrophages. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rubus coreanus Miquel (Rosaceae), the Korean black raspberry, has traditionally been used to treat inflammatory diseases including diarrhea, asthma, stomach ailment, and cancer. Although previous studies showed that the 19alpha-hydroxyursane-type triterpenoids isolated from Rubus coreanus exerted anti-inflammatory activities, their effects on ulcerative colitis and mode of action have not been explored. This study was designed to assess the anti-inflammatory effects and the molecular mechanisms involving19alpha-hydroxyursane-type triterpenoid-rich fraction from Rubus coreanus (TFRC) on a mice model of colitis and lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. MATERIALS AND METHODS: Experimental colitis was induced by DSS for 7 days in ICR mice. Disease activity indices (DAI) took into account body weight, stool consistency, and gross bleeding. Histological changes and macrophage accumulation were observed by immunohistochemical analysis. Pro inflammatory markers were determined using immunoassays, RT-PCR, and real time PCR. Signaling pathway involving nuclear factor-kappaB (NF-kappaB) and mitogen activated protein kinases (MAPKs) activation was determined by luciferase assay and Western blotting. RESULTS: In DSS-induced colitis mice, TFRC improved DAIs and pathological characteristics including colon shortening and colonic epithelium injury. TFRC suppressed tissue levels of pro-inflammatory cytokines and reduced macrophage infiltration into colonic tissues. In LPS-induced RAW 264.7 macrophages, TFRC inhibited the production of NO, PGE2, and pro inflammatory cytokines by down-regulating the activation of NF-kappaB and p38 MAPK signaling. CONCLUSION: The study demonstrates that TFRC has potent anti inflammatory effects on DSS-induced colonic injury and LPS-induced macrophage activation, and supports its possible therapeutic and preventive roles in colitis. PMID- 25446583 TI - Casticin inhibits COX-2 and iNOS expression via suppression of NF-kappaB and MAPK signaling in lipopolysaccharide-stimulated mouse macrophages. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The fruits of Vitex rotundifolia L. are widely used to treat inflammation of the airway in Traditional Chinese medicine. Previous studies found that casticin, isolated from Vitex rotundifolia, could induce apoptosis of tumor cells. In this study, we evaluated the anti inflammatory effects of casticin and its underlying molecular mechanism in lipopolysaccharide (LPS)-stimulated macrophages. MATERIALS AND METHODS: RAW264.7 cells were pretreated with various concentrations of casticin (0.3-10MUM), and then treated with LPS to induce inflammation. We assayed the levels of proinflammatory cytokines and prostaglandin E2 (PGE2) using ELISA, and examined the protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and heme oxygenase (HO)-1 by Western blot. We also investigated the anti inflammatory molecular mechanism by analyzing inflammatory-associated signaling pathways, including the nuclear transcription factor kappa-B (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathways. RESULTS: We found casticin inhibited the levels of nitric oxide and PGE2, and decreased the production of proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha). In addition, iNOS and COX-2 expression levels were suppressed and casticin increased HO-1 and Nrf2 production in a concentration-dependent manner. Furthermore, casticin significantly inhibited NF kappaB subunit p65 proteins in the nucleus and decreased Akt and MAPK activation. CONCLUSION: These results suggest that the anti-inflammatory effect of casticin is due to inhibition of proinflammatory cytokines and mediators by blocking the NF-kappaB, Akt, and MAPK signaling pathways. PMID- 25446584 TI - Evaluation of the indicative roles of seven potential biomarkers on hepato nephrotoxicity induced by Genkwa Flos. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Genkwa Flos, a classical traditional Chinese medicine, is used for the definite antitumor activity and tends to be taken overdose or long term in these years. While the excessive application can result in damage to liver and kidney. In this study, the indicative roles of seven potential biomarkers were evaluated to investigate hepato-nephrotoxicity in the early stages after oral administration of Genkwa Flos for 14 days. MATERIALS AND METHODS: Histopathology, serum biochemistry and seven potential biomarkers in serum or urine from male Sprague-Dawley rats were monitored. Hepatic and renal tissues were histopathologically examined to identify specific changes occurring. Routine serum biochemical parameters were tested by using standard clinical laboratory methods. Seven biomarkers including cholic acid, taurine, 5 oxoproline, hippuric acid, uric acid, 3-indoxyl sulfate and kynurenic acid were detected by a developed LC-MS method. RESULTS: The histopathological alterations and the increased levels of serum biochemistry were detected on the 8th day after Genkwa Flos treated. The seven analytes were also found significantly changed in Genkwa Flos treated group, especially cholic acid, taurine, 5-oxoproline and hippuric acid which were changed on the 2nd or 4th day. CONCLUSIONS: Although serum biochemistry and histopathology suggested that Genkwa Flos was responsible for the hepato-nephrotoxicity that occurred following the ingestion of this medicinal herb, evaluation of these biomarkers might be more beneficial for the early detection of liver and kidney injuries. This study could be further used in hepatic and renal failures caused by other reasons in the following research works. PMID- 25446586 TI - Effects of broad-spectrum antibiotics on the metabolism and pharmacokinetics of ginsenoside Rb1: a study on rats' gut microflora influenced by lincomycin. AB - Ginsenoside Rb1 is a biologically active compound that is abundant in ginseng (Panax ginseng). It has been reported that ginsenosides could be metabolized by enzymes and bacteria in the large intestine. In this study, the effects of intestinal bacteria on the metabolism and pharmacokinetics of ginsenoside Rb1 were investigated using lincomycin-treated rat models (4.8g/kg and 0.12g/kg). Specifically, ginsenoside Rb1 was incubated anaerobically with rat fecal suspensions obtained from the control and two model groups at 0, 6, 12, 24, and 48h. Ginsenoside Rb1 and its metabolites were determined by HPLC analysis. Compared with the normal rats case where Rd and compound K were detected in the incubation mixture, ginsenoside Rd and F2 were found in the 0.12g/kg group, but only Rd was found in the 4.8g/kg group. Moreover, fecal beta-glucosidase activity was significantly lower in lincomycin-treated (0.12g/kg and 4.8g/kg) model rats. After administration of Rb1 to rats, ginsenoside Rb1 and its metabolites Rd, Rg3, and Rh2 were detectable in normal rat urine, whereas none was detected in the two model groups. The plasma concentration-time Rb1 were compared between model groups and normal rats. The systemic exposure as evidenced by the AUC and T1/2 values was significantly higher in model groups than in normal rats. Our findings demonstrated that consumption of lincomycin could lead to the formation of specific metabolites and pharmacokinetic changes of ginsenoside Rb1 in the gut, attributed to alterations in metabolic activities of intestinal bacteria. Our results also suggested that patients who want to use intestinal bacteria metabolized drugs such as ginseng (Panax ginseng) should pay attention to the profile of intestinal bacteria or potential drug interactions to ensure therapeutic efficacy. PMID- 25446585 TI - Evaluation of antioxidant-associated efficacy of flavonoid extracts from a traditional Chinese medicine Hua Ju Hong (peels of Citrus grandis (L.) Osbeck). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hua Ju Hong (HJH, peels of Citrus grandis (L.) Osbeck) is a popularly used traditional Chinese medicine recorded by "Compendium of Materia Medica" (Ben Cao Gang Mu) in Ming Dynasty of China (1578 A.D.). With flavonoid components, HJH possesses hypolipidemic effect associated with antioxidation action. However, no report was found regarding the flavonoid profile and antioxidant activity of HJH. MATERIALS AND METHODS: Five purified flavonoid extracts (TFCA, TFCB, TFCC, TFCD and TFCE.) were obtained from HJH using Ca(OH)2 and HPD-300 macroporous resins, and their total flavonoids and representative flavonoid components were analyzed. In vitro tests of DPPH free radical scavenging activity, reducing power, and total antioxidant activity of each extract were evaluated. The most effective extract was selected for in vivo antioxidative evaluation using a rat hyperlipemia model. RESULTS: The total flavonoid content was varying among each HJH extract and decreased in an order of TFCB>TFCD>TFCC>TFCE>TFCA. TFCB, TFCD, and TFCC contained more than 50% of total flavonoids, the highest content of which was found in TFCB (80.7%). HPLC analysis showed that the contents of three flavonoid components, narirutin, naringin and neohesperidin, displayed a similar trend as that of total flavonoids. In vitro antioxidative tests determined that TFCB at 0.24 to 1.2mg/ml possessed the most significant antioxidant effects among other extracts and was also superior to BHT. In vivo experiment also revealed the significant antioxidant and antihyperlipidemic activities of TFCB started from 50 to 200mg/kg after oral administration to hyperlipemia rats. These results indicate that TFCB with the highest flavonoid contents has the strongest antioxidant-associated activities. CONCLUSION: This is the first report regarding antioxidant-associated activities and relevant flavonoid components of HJH extracts, providing a promising candidate of traditional Chinese medicine for antioxidative treatment. PMID- 25446587 TI - Antiulcer activities of the hydroethanolic extract of Sedum dendroideum Moc et Sesse ex DC. (balsam). AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Sedum dendroideum, commonly known as balsam, have long been employed for the treatment of gastric ulcers. The aim of study was to evaluate the antiulcer activity and toxicological properties of Sedum dendroideum using induced gastric ulcer models in Wistar rats. MATERIALS AND METHODS: The hydroethanolic extract of Sedum dendroideum (ESD) was analyzed using an acute ulcer model using ethanol and indomethacin and a chronic ulcer model using acetic acid. The toxicity was evaluated with acute and subacute toxicity tests. The gastric secretion was assessed by the performance of pyloric ligation and the gastric volume, pH, and hydrogen ion concentration. The mechanism of the gastroprotective activity of ESD through the involvement of nitric oxide and sulfhydryl compounds was assessed. Moreover, a phytochemical screening and antioxidant assays were performed. RESULTS: No signs of toxicity were observed. In the ethanol-induced ulceration model, ESD doses of 25, 50, and 100mg/kg significantly reduced the gastric lesions by 66.03%, 71.11%, and 70.82%, respectively. In the indomethacin-induced ulceration model, ESD doses of 25, 50, and 100mg/kg significantly reduced the gastric lesions by 89.88%, 94.36%, and 90.64%, respectively. Treatment with ESD at 50mg/kg and cimetidine at 200mg/kg significantly reduced acetic acid-induced ulcerations and resulted in 92.99% and 77.16% cure, respectively. ESD doses of 25, 50, and 100mg/kg inhibited oxidation by 79.7%, 82.4%, and 82.3%, respectively. The antiulcer activity of ESD may involve sulfhydryl compounds, considering that this activity was inhibited in the animals treated with sulfhydryl compound blockers. Furthermore, ESD increased mucus secretion and reduced gastric acidity and volume. CONCLUSIONS: The leaf extract of Sedum dendroideum exhibited gastroprotective activity, potentially due to sulfhydryl compounds and antioxidant activity. Therefore, other studies are warranted to elucidate the antiulcer properties of these compounds. PMID- 25446588 TI - Tabebuia aurea decreases inflammatory, myotoxic and hemorrhagic activities induced by the venom of Bothrops neuwiedi. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ethnobotanical studies show that Tabebuia aurea has been used as anti-inflammatory and for snake bite. Evaluate the effect of treatment with the hydroethanolic extract of Tabebuia aurea (HETa) on inflammatory, hemorrhagic and myotoxic activities induced by Bothrops neuwiedi (BnV) in mice. MATERIALS AND METHODS: The anti-inflammatory, antihemorragic and antimyotoxic properties of the HETa 100, 200 and 400mg/kg or BnV neutralized with HETa (1:50) were evaluated using the following animal models: BnV-induced paw edema, BnV-induced recruitment of polymorphonuclear cells into the peritoneal cavity, hemorrhagic activity, myotoxic activity and hydrogen peroxide production by peritoneal macrophages in vitro. RESULTS: HETa inhibited the paw edema and polymorphonuclear cell recruitment into the peritoneal cavity. BnV neutralized with HETa reduced the hemorrhagic activity and histopathological analysis of skeletal muscle tissue showed that the hemorrhagic area was smaller and multifocal. The leukocyte infiltrate was less intense and muscle necrosis discrete. BnV induced hydrogen peroxide production and BnV neutralized reduced this production. In addition, the HETa was nontoxic to macrophages. CONCLUSIONS: The activities of the HETa presented herein justify the popular use of Tabebuia aurea in inflammatory situations from snake bite. PMID- 25446589 TI - The protective activity of Conyza blinii saponin against acute gastric ulcer induced by ethanol. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Conyza blinii H.Lev., is a type of natural plant. Its dried overground section is used to treat infections and inflammations in traditional Chinese medicine. Triterpenoidal saponins have a wide range of bioactivities, for instance, anti-cancer, anti-virus and anti-anaphylaxis. Conyza blinii saponin (CBS), mainly composed of triterpenoidal saponins, is the total saponin of Conyza blinii H.Lev. It has been reported that CBS also has gastric mucous membrane protection activity. This study aims to test CBS's protective activity of gastric's mucous membrane against ethanol. This investigation may lead to the development of novel drug from natural products as anti-ulcer agent, or as gastric mucous protective against chemical damage. MATERIALS AND METHODS: CBS (Conyza blinii saponin) is the total saponin of Conyza blinii H.Lev., which was obtained as described previously. We tested the protective activity of CBS against ethanol-induced ulcer. Thirty six rats were grouped randomly as 'NORMAL', 'CONTROL', 'MODEL', 'LOW DOSE', 'MEDIUM DOSE' and 'HIGH DOSE'. The 'NORMAL' group were rats with no pathological model established within it. The 'CONTROL' group was administrated with colloidal bismuth subcitrate, while 'MODEL' group was not given any active agents apart from absolute ethanol in order to obtain gastric ulcer model. The three 'DOSE' groups were treated with different concentrations of CBS (5, 10, 20mg/mL) before administration followed by absolute ethanol. All rats were sacrificed after the experiment to acquire the gastric tissue. The ulcer index (UI), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured to monitor the activity of CBS. Besides, the rat gastric tissue was made to paraffin section and stained using the Hematoxylin-Eosin (HE) method. The histopathology examination was carried out to examine CBS efficacy in terms of gastric mucous protection. RESULTS: We found that CBS had a profound protection activity against acute gastric ulcer induced by ethanol and this activity displayed a concentration-dependent manner. The efficacy of 10 and 20mg/mL CBS was comparable with colloidal bismuth subcitrate (P<0.05). All three level of CBS tested were able to significantly reduce UI, MDA and enhance SOD level (P<0.05). CONCLUSIONS: It was deduced that the mechanism for such activity would be anti lipid peroxidation, facilitating free radicals clearance. In addition , histopathology examination of the gastric mucous membrane supported the same conclusion, that CBS can efficiently suppress the inflammatory reactions, bleeding and protect the gastric mucosa. PMID- 25446590 TI - Traditional uses, phytochemistry, pharmacology, toxicology and quality control of Alisma orientale (Sam.) Juzep: a review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rhizoma alismatis (simplified as RA, "Zexie" in Chinese, ) is a well-known natural medicine with long history in Chinese medicine. As a traditional medicine in China, RA is an important part of many prescriptions and has been commonly used for treating a wide range of ailments related to dysuria, edema, nephropathy, hyperlipidaemia, diabetes, inflammation as well as tumor in clinical applications. Based on scientific literatures, the present paper aims to provide comprehensive and up-to date information about the traditional uses, phytochemistry, pharmacology, toxicology and quality control of RA as well as critical analysis of the research. The review will provide a new foundation and direction for the further studies of RA. MATERIALS AND METHODS: All available information about RA was supplied by library database and electronic search (ScienceDirect, Web of Science, Pubmed, Google Scholar, etc.). The different types of useful information were collected and arranged in corresponding part of the paper. RESULTS: Phytochemical studies showed that the main chemical composition of RA was the terpenoid including sesquiterpene, diterpene and triterpene. The crude extracts and isolated compounds from RA showed diverse pharmacological activities including diuretic, nephroprotective, anti-hyperlipidemic, anti-atherosclerotic, anti-cancer, anti-inflammatory and anti-oxidative activities. However, high-dose or long-term use of RA can lead to water-electrolyte imbalance, bloody urine, acidosis and even hepatotoxicity or nephrotoxicity, which have been proven by several studies. CONCLUSIONS: Pharmacological researches show RA possessing various bioactivities including diuresis, nephroprotective effect, anti-hyperlipidemia, etc. However, more bioactive components especially diuretic and nephroprotective compounds need to be isolated and identified, and more rigorous researches on action mechanisms are required. More experiments in vitro or in vivo and clinical studies are encouraged to clarify correlation between traditional uses and modern applications, and the toxicity need to be further and precisely explored. In addition, a standardized fingerprint for RA is indispensable and emergent. These achievements will further expand to therapeutic potential and usage of RA and provide a powerful support for clinical use. PMID- 25446591 TI - Salvia miltiorrhiza (Danshen) inhibits L-type calcium current and attenuates calcium transient and contractility in rat ventricular myocytes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza (SM, Danshen), a traditional Chinese herbal drug, has been widely used for hundreds of years to treat coronary artery disease. MATERIALS AND METHODS: We studied the effects of SM on the L-type Ca(2+) current (ICa-L) with whole-cell patch-clamp technique in rat ventricular myocytes, and its influence on Ca(2+) transient and contractility using video based edge detection and dual excitation fluorescence photomultiplier systems as well. RESULTS: Exposure to SM solution caused a concentration- and voltage dependent blockade of ICa-L, and the dose of SM solution (10g/l) decreased the maximal inhibitory effect of 35.2+/-1.2%. However, SM solution did not significantly change the current-voltage relationship or reversal potential of ICa-L, nor did it altered the activation and inactivation gating properties of cardiac Ca(2+) channels. Meanwhile, SM decreased the amplitude of myocyte shortening and the peak value of Ca(2+) transient with a significant decrease in the time to 90% of the baseline (Tr), but the time to 10% of the peak (Tp) was not dramatically prolonged. CONCLUSIONS: The results indicated that SM significantly inhibited L-type Ca(2+) channels, decreased [Ca(2+)]i and contractility in adult rat cardiac myocytes. These findings may be relevant to the cardioprotective efficacy of SM. PMID- 25446592 TI - Modulation of thioacetamide-induced hepatic inflammations, angiogenesis and fibrosis by andrographolide in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Liver fibrosis is a complex disease in which several pathological processes, such as inflammation and angiogenesis, are closely integrated. MATERIALS AND METHODS: We hypothesised that treatment with the pharmacological agent, andrographolide (AP), which has multiple mechanisms of action, will provide a greater understanding of the role of AP during the multiple pathological processes that occur in advanced liver disease. RESULTS: Liver fibrogenesis was induced in mice using thioacetamide (TAA), which was administrated for 6 weeks. Andrographolide (5, 20 or 100mg/kg) was then given once daily following TAA injection. Liver collagen was examined using hydroxyproline and alpha-SMA, while the inflammatory response was quantified by Western blot and RT-PCR assays. Liver angiogenesis, neutrophil infiltration and hypoxia were assessed using CD11b+, vWF and HIF-1alpha immunostaining. Mice with liver injuries that were treated with andrographolide showed improved inflammatory response and diminished angiogenesis and hepatic fibrosis. Andrographolide treatment inhibited liver neutrophil infiltration, while a decreased in TNF-alpha and COX-2 signalling indicated macrophage activation. Andrographolide decreased overall liver hypoxia, as shown by the downregulation of hypoxia-inducible cascade genes, such as VEGF. Andrographolide treatment resulted in a significant decrease in hepatic fibrogenesis, alpha-SMA abundance, and TGF-betaR1 expression. CONCLUSIONS: The present results suggest that multi targeted therapies directed against angiogenesis, inflammation, and fibrosis should be considered for the treatment of advanced liver injury. They further suggest that andrographolide treatment may be a novel therapeutic agent for the treatment of liver disease. PMID- 25446593 TI - Inhibitory effects of flavonoids from stem bark of Derris indica on the formation of advanced glycation end products. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Derris indica (Lamk.) Bennet has been used in traditional medicine in many countries for the treatment of bronchitis, whooping cough, rheumatic joints and dipsia in diabetes. In addition, several studies have revealed that this plant displayed various pharmacological activities including anti-diabetic. The present study was designed to isolate the active compounds from its stem bark and evaluate their inhibitory activity on the formation of advanced glycation end products. MATERIAL AND METHODS: The EtOAc extract of the stem bark of Derris indica was isolated by column chromatographic techniques. The structures of isolated compounds were established on the basis of extensive spectroscopic methods. All compounds were assayed for their inhibitory effects on advanced glycation end products formation using BSA-methylglyoxal assay. RESULTS: Chromatographic fractionation of the EtOAc extract of Derris indica stem bark led to the isolation of two new pyranoflavonoids, derrisins A and B (1-2), along with 11 known flavonoids (3-13). The inhibitory activities of the compounds on the formation of advanced glycation end products were evaluated. Derrisin B (2) was the most active compound with IC50 value of 18.0uM, and displayed stronger inhibitory activity compared with positive control aminoguanidine. CONCLUSIONS: This study provided the possibility that a pyranoflavonoid (2) found in Derris indica might have therapeutic potential as an inhibitor against the formation of advanced glycation end products. PMID- 25446594 TI - Hepatoprotective activity of ginsenosides from Panax ginseng adventitious roots against carbon tetrachloride treated hepatic injury in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng (Panax ginseng C. A. Meyer) has a beneficial role in the treatment of various diseases including liver disorders like acute/chronic hepatotoxicity, hepatitis, hepatic fibrosis/cirrhosis and hepatocellular carcinoma. MATERIALS AND METHODS: Tissue culture raised mountain ginseng adventitious root (TCMGARs) extract with ginsenosides in abundance was used as an experimental material. 'Sprague-Dawley' male rats were used as experimental systems and were fed with TCMGARs extracts at doses of 30, 100, 300mg/kg body weight for two weeks to test the effect on carbon tetrachloride (CCl4) induced acute liver damage. Field cultivated Korean ginseng root extract fed rats (100mg/kg) were used as positive control. Plasma enzyme levels, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were assessed. Glutathione (GSH) and malondialdehyde (MDA) concentrations were also evaluated. RESULTS: TCMGARs extracts remarkably prevented the elevation of ALT, AST, ALP and liver peroxides in CCl4-treated rats. Hepatic glutathione levels were significantly increased by the treatment with the extracts in experimental groups. CONCLUSION: The TCMGARs rich in varied ginsenosides can afford protection against CCl4-induced hepatocellular injury. PMID- 25446595 TI - Emoghrelin, a unique emodin derivative in Heshouwu, stimulates growth hormone secretion via activation of the ghrelin receptor. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Heshouwu, the root of Polygonum multiflorum, is an anti-aging Chinese traditional medicine. Fresh (raw) Heshouwu is commonly converted to processed Heshouwu by specialized heating to alleviate its side effects of diarrhea presumably caused by anthraquinones. However, raw Heshouwu has been noted to be better than processed Heshouwu regarding anti-aging effects. The therapeutic effects of raw Heshouwu on aging-related diseases were somehow similar to the anti-aging effects of growth hormone release induced by ghrelin MATERIALS AND METHODS: Major ingredients in the methanol extract from raw Heshouwu were separated and identified. Emodin-8-O-(6'-O-malonyl)-glucoside, a unique anthraquinone glycoside known to be completely eliminated in the conversion process of Heshouwu was isolated. This emodin derivative, tentatively named emoghrelin, was examined for its cytotoxicity and capability of stimulating growth hormone release of rat primary anterior pituitary cells via activation of the ghrelin receptor. Moreover, molecular modeling of emoghrelin docking to the ghrelin receptor was exhibited to explore the possible interaction within the binding pocket. RESULTS: No apparent cytotoxicity was observed for emoghrelin of 10(-7)-10(-4)M. Similar to growth hormone-releasing hormone-6 (GHRP-6), a synthetic analog of ghrelin, emoghrelin was demonstrated to stimulate growth hormone secretion of rat primary anterior pituitary cells in a dose dependent manner, and the stimulation was inhibited by [d-Arg(1), d-Phe(5), d-Trp(7,9), Leu(11)]-substance P, an antagonist of the ghrelin receptor. Molecular modeling and docking showed that emoghrelin as well as GHRP-6 could fit in and adequately interact with the binding pocket of the ghrelin receptor. CONCLUSION: The results suggest that emoghrelin is a key ingredient accounting for the anti-aging effects of Heshouwu, and possesses great potential to be a promising non-peptidyl analog of ghrelin. PMID- 25446597 TI - Atractylodes macrocephala Koidz stimulates intestinal epithelial cell migration through a polyamine dependent mechanism. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Atractylodes macrocephala Koidz (AMK), a valuable traditional Chinese herbal medicine, has been widely used in clinical practice for treating patients with disorders of the digestive system. AMK has shown noteworthy promoting effect on improving gastrointestinal function and immunity, which might represent a promising candidate for the treatment of intestinal mucosa injury. The aim of this study was to investigate the efficacy of AMK on intestinal mucosal restitution and the underlying mechanisms via intestinal epithelial (IEC-6) cell migration model. MATERIALS AND METHODS: A cell migration model of IEC-6 cells was induced by a single-edge razor blade along the diameter of the cell layers in six-well polystyrene plates. After wounding, the cells were grown in control cultures and in cultures containing spermidine (5MUM, SPD, reference drug), alpha-difluoromethylornithine (2.5mM, DFMO, polyamine inhibitor), AMK (50, 100, and 200mg/L), DFMO plus SPD and DFMO plus AMK for 12h. The polyamines content was detected by high-performance liquid chromatography (HPLC) with pre-column derivatization. The Rho mRNAs expression levels were assessed by Q-RT-PCR. The Rho and non-muscle myosin II proteins expression levels were analyzed by Western blot. The formation and distribution of non-muscle myosin II stress fibers were monitored with immunostaining techniques using specific antibodies and observed by confocal microscopy. Cell migration assay was carried out using inverted microscope and the Image-Pro Plus software. All of these indexes were used to evaluate the effectiveness of AMK. RESULTS: (1) Treatment with AMK caused significant increases in cellular polyamines content and Rho mRNAs and proteins expression levels, as compared to control group. Furthermore, AMK exposure increased non-muscle myosin II protein expression levels and formation of non-muscle myosin II stress fibers, and resulted in an acceleration of cell migration in IEC-6 cells. (2) Depletion of cellular polyamines by DFMO resulted in a decrease of cellular polyamines levels, Rho mRNAs and proteins expression, non-muscle myosin II protein formation and distribution, thereby inhibiting IEC-6 cell migration. AMK not only reversed the inhibitory effects of DFMO on the polyamines content, Rho mRNAs and proteins expression, non-muscle myosin II protein formation and distribution, but also restored cell migration to control levels. CONCLUSIONS: The results obtained from this study revealed that AMK significantly stimulates the migration of IEC-6 cells through a polyamine dependent mechanism, which could accelerate the healing of intestinal injury. These findings suggest the potential value of AMK in curing intestinal diseases characterized by injury and ineffective repair of the intestinal mucosa in clinical practice. PMID- 25446596 TI - In vivo and in vitro anti-inflammatory activities of Persicaria chinensis methanolic extract targeting Src/Syk/NF-kappaB. AB - ETHNOPHARMACOLOGIC RELEVANCE: Persicaria chinensis L. (Polygonaceae) [also synonym as Polygonum chimnense L.] has been used as Chinese traditional medicine to treat ulcer, eczema, stomach ache, and various inflammatory skin diseases. Due to no molecular pharmacological evidence of this anti-inflammatory herbal plant, we investigated the inhibitory mechanisms and target proteins contributing to the anti-inflammatory responses of the plant by using its methanolic extract (Pc-ME). MATERIALS AND METHODS: We used lipopolysaccharide (LPS)-treated macrophages and a murine HCl/EtOH-induced gastritis model to evaluate the anti-inflammatory activity of Pc-ME. HPLC analysis was employed to identify potential active components of this extract. Molecular approaches including kinase assays, reporter gene assays, immunoprecipitation analysis, and overexpression of target enzymes were used to confirm target enzymes. RESULTS: Pc-ME inhibited LPS-induced nitric oxide and prostaglandin E2 release by RAW264.7 macrophages and ameliorated HCl/EtOH-induced gastric ulcers in mice. The nuclear translocation of NF-kappaB (p65 and p50) was suppressed by Pc-ME. Phosphorylation of Src and Syk, their kinase activities, and formation of the signaling complex of these proteins were repressed by Pc-ME. Phosphorylation of p85 and Akt induced by Src or Syk overexpression was blocked by Pc-ME. In the mouse gastritis model, orally administered Pc-ME suppressed the increased phosphorylation of IkappaBalpha, Alphakt, Src, and Syk. Caffeic acid, kaempferol, and quercetin, identified as major anti-inflammatory components of Pc-ME by HPLC, displayed strong nitric oxide inhibitory activity in LPS-treated macrophages. CONCLUSION: Pc-ME might play a pivotal ethnopharmacologic role as an anti-inflammatory herbal medicine by targeting Syk and Src kinases and their downstream transcription factor NF kappaB. PMID- 25446598 TI - Can organoleptic properties explain the differential use of medicinal plants? Evidence from Northeastern Brazil. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This study examined how people classify plants in terms of their taste and smell, and how those organoleptic properties influence the differential use of medicinal plants for treating different diseases. METHODS: We conducted an ethnobotanical survey of household heads in the community of Sucruiu, located in Barreiras, Bahia, Brazil. The head of each family was questioned concerning their knowledge and use of medicinal plants, as well as the therapeutic indications (TIs), taste, and smell of each plant. We then tested for associations between the therapeutic indications and taste attributes of various plants using the Chi-squared test on a contingency table with Monte Carlo simulations. The same analysis was performed for associations between TIs and smell. RESULTS: The study participants provided more details when classifying tastes than when classifying smells. We considered only the most cited TIs and attributes, and found significant associations between both taste and therapeutic indications (p<0.001) and smell and therapeutic indications (p<0.0001). CONCLUSIONS: Our results showed that the taste and smell of a plant can influence its differential medicinal use, since plants with certain tastes and smells prevailed in the treatment of distinct diseases. However, our results are valid only for the most popular TIs and organoleptic attributes. PMID- 25446599 TI - Kelussia odoratissima Mozzaf - a promising medicinal herb to prevent pulmonary hypertension in broiler chickens reared at high altitude. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Kelussia odoratissima Mozzaf, formerly Apium odoratissima, is a plant locally called "Karafs", found in central Zagros region of Iran. Leaves and stems of the plant are traditionally used in the treatment of hypertension and inflammation. Lowering blood pressure effects of Kelussia odoratissima Mozzaf (wild celery) was evaluated in preventing pulmonary hypertension syndrome (PHS) in broiler chickens reared at high altitude (2,100 m). MATERIALS AND METHODS: A total number of 208 day-old male broilers (Ross 308) were randomly assigned to four treatments including different levels of Kelussia odoratissima Mozzaf (0%, 0.25%, 0.5%, and 0.75%) in a 42-day trial. RESULTS: Body weight gain and feed:gain responses significantly (P<0.05) improved when Kelussia odoratissima Mozzaf was included in broiler diets at 0.75% in the growing stage and throughout the trial. Over-expression of inducible nitric oxide (NO) synthase in the heart was observed in chickens fed Kelussia odoratissima Mozzaf. Birds received Kelussia odoratissima Mozzaf at 0.5% and 0.75% had significantly (P<0.05) higher circulatory concentrations of NO though significantly (P<0.05) lower serum malondialdehyde concentration, hematocrit and heterophil to lymphocyte ratio when compared to the birds fed the control diet. Feeding Kelussia odoratissima Mozzaf at 0.5% and 0.75% prevented from right ventricular hypertrophy and led to a significant decline in mortality from PHS. CONCLUSION: It can be concluded that Kelussia odoratissima Mozzaf is a promising medicinal herb to prevent PHS in broiler chickens by improving blood pressure and antioxidant responses. PMID- 25446600 TI - Ethanol extraction preparation of American ginseng (Panax quinquefolius L) and Korean red ginseng (Panax ginseng C.A. Meyer): differential effects on postprandial insulinemia in healthy individuals. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ginsenosides are the proposed bioactive constituent of ginseng, especially for the attenuation of postprandial glycemia (PPG). The efficacious proportion of total and specific ginsenosides, remains unknown. Alcohol extraction of whole ginseng root can be used to selectively manipulate the ginsenoside profile with increasing alcohol concentrations producing high yields of total ginsenosides and varying their individual proportions. AIM OF THE STUDY: We aimed to compare the acute efficacy of different ethanol-extraction preparations of American ginseng (AG) and Korean red ginseng (KRG), with their whole-root origins, on PPG and insulin parameters in healthy adults. MATERIALS AND METHODS: Following an overnight fast, 13 healthy individuals (Gender: 5M:8F, with mean +/- SD, age: 28.9 +/- 9.2 years, BMI: 26.3 +/- 2.7 kg/m(2) and fasting plasma glucose: 4.21 +/- 0.04 mmol/L) randomly received 3g of each of the following 10 different ginseng treatments on separate visits: whole root KRG and AG; 30%, 50% or 70% ethanol extracts of KRG and AG and 2 cornstarch placebos. Treatments were consumed 40 min prior to a 50 g oral glucose challenge test with capillary blood samples collected at baseline, 15, 30, 45, 60, 90 and 120 min. Insulin samples were collected at 0, 30, 60 and 120 min. RESULTS: There was no difference in attenuation of PPG among the tested ginseng preparations. Measures of Insulin Sensitivity Index (ISI) showed increased insulin sensitivity (IS) with KRG-30% and AG-50% extracts compared to placebo (p<0.05). CONCLUSIONS: The insulin sensitizing effects of KRG-30% and AG 50% extracts suggest that other root parts, including other ginsenosides not typically measured, may influence PPG and insulin parameters. There is potential for AG and KRG extracts to modulate IS, an independent predictor of type 2 diabetes. PMID- 25446601 TI - Neuroprotective effect of water extract of Panax ginseng on corticosterone induced apoptosis in PC12 cells and its underlying molecule mechanisms. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The root of Panax ginseng C.A. Meyer (Family Araliaceae) is an important medicinal plant which has been employed as a panacea for more than 2,000 years in China. It has the actions of invigorating primordial qi, recovering pulse and desertion, engendering liquid, and calming spirit. The water extract of Panax ginseng (WEG) has been used to treat kinds of central nervous system disorders, such as depression, insomnia, Alzheimer's disease and Parkinson's disease. Our previous work has demonstrated that WEG possessed antidepressant-like activities in both acute and chronic stress models of depression. Nevertheless, there are no studies on the cytoprotection and potential mechanisms of WEG on corticosterone-induced apoptosis. The present study focuses on cytoprotection against corticosterone-induced neurotoxicity in PC12 cells and its underlying molecule mechanisms of the antidepressant-like effect of WEG. MATERIALS AND METHODS: The PC12 cells were treated with 250 MUmol/L corticosterone in the absence or presence of WEG for 24h, then 3-(4,5 dimethy thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) detection, Hoechst33342 staining and TUNEL staining were investigated to confirm the neuroprotection of WEG. Then, mitochondrial permeability transition pore (mPTP), mitochondrial membrane potential (MMP), intracellular Ca(2+) ([Ca(2+)]i), reactive oxygen species (ROS) concentration, and the expression level of glucocorticoid receptor (GR), heat shock protein 90 (Hsp90), histone deactylase 6 (HDAC6), glucose-regulated protein 78 (GRP78), growth arrest and DNA damage inducible protein 153 (GADD153), X-box DNA-binding protein-1 (XBP-1), caspase-12, cytochrome C, inhibitor of caspase-activated deoxyribonuclease (ICAD), caspase-3 and caspase-9 were assessed by Western Blot analysis to understand the molecule mechanisms of neuroprotection of WEG. RESULTS: WEG partly reversed corticosterone-induced damage in PC12 cells, which increased cell viability, decreased LDH release, and attenuated corticosterone induced apoptosis as compared with the corticosterone-treated group. Mechanistically, compared with the corticosterone-treated group, WEG strongly attenuated [Ca(2+)]i overload and ROS level, and restored mitochondrial function, including mPTP and MMP. Furthermore, WEG strongly up-regulated the expression of GR and HDAC6, and down-regulated the expression of Hsp90, cytochrome C, ICAD, caspase-3, caspase-9 as well as endoplasmic reticulum (ER) stress-related proteins, such as GADD153, GRP78, XBP-1, and caspase-12. CONCLUSION: WEG possessed neuroprotection against corticosterone-induced damage in PC12 cells, and the underlying molecule mechanisms was depended on the intervening of HDAC6 and HSP90 of the GR-related function proteins, and subsequent restoration of ER and mitochondria functions. PMID- 25446602 TI - Protective effects of glycycoumarin and procyanidin B1, active components of traditional Japanese medicine yokukansan, on amyloid beta oligomer-induced neuronal death. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Yokukansan, a traditional Japanese (Kampo) medicine, is composed of seven medicinal herbs, and has been traditionally used to treat neurosis, insomnia, and night crying and irritability in children. Yokukansan and its constituent herbs, Glycyrrhiza and Uncaria Hook, have recently been shown to have protective effects against amyloid beta (Abeta) oligomer induced apoptosis by suppressing the activation of caspase-3 in primary cultured neurons. The aim of the present study was to identify the effective components of Glycyrrhiza and Uncaria Hook against Abeta oligomer-induced neurotoxicity. We also attempted to clarify the mechanisms by which yokukansan and these herbs, as well as their components, suppressed the activation of caspase-3 in Abeta oligomer-treated neurons. MATERIALS AND METHODS: Rat primary cultured cortical neurons were treated with Abeta oligomer (3 MUM). The protective effects of 16 components derived from Glycyrrhiza or Uncaria Hook against Abeta oligomer induced neurotoxicity were determined using the MTT reduction assay 48 h after the treatment. The suppressive effects of the test substances, i.e., yokukansan, Glycyrrhiza, Uncaria Hook, and screened components, on the Abeta oligomer-induced activation of caspase-3(/7) were evaluated using the caspase-Glo assay 48 h after the Abeta oligomer treatment. The suppressive effects of the test substances on the activation of caspase-8 and -9, both of which are located upstream of caspase 3, were also examined 24h after the Abeta oligomer treatment. RESULTS: Two of the 16 components tested, glycycoumarin derived from Glycyrrhiza and procyanidin B1 derived from Uncaria Hook, significantly inhibited Abeta oligomer-induced neuronal death in a dose-dependent manner. Glycyrrhiza, Uncaria Hook, and yokukansan significantly suppressed the Abeta oligomer-induced activation of caspase-3 as well as caspase-8 and -9. Glycycoumarin also suppressed the activation of caspase-3, but not caspase-8 and -9. Procyanidin B1 suppressed the activation of caspase-3, -8, and -9. CONCLUSIONS: Our results demonstrated that glycycoumarin and procyanidin B1 had ameliorative effects on Abeta oligomer induced neurotoxicity. The neuroprotective effects of glycycoumarin are thought to be due to the attenuated activation of caspase-3, but not caspase-8 or -9. Procyanidin B1, as well as yokukansan, Glycyrrhiza, and Uncaria Hook, may attenuate the activation of caspase-3 by inhibiting that of caspase-8 and -9. PMID- 25446603 TI - Differential cytotoxic properties of Helleborus niger L. on tumour and immunocompetent cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Romanian folk medicine, Helleborus niger L. is used for the treatment of rheumatoid arthritis or viral infections and in complementary therapy, especially in anthroposophic medicine (AM), where the plant is administered as an adjuvant to treat malignant diseases. In the present study, we investigated the differential cytotoxic effects of H. niger on human tumour and healthy cells of the human immune system in vitro. MATERIAL AND METHODS: Protoanemonin and saponins, as significant constituents of H. niger extracts, were quantified in five individual batches using validated HPLC methods. Further, the impact of H. niger on proliferation capacity (MTT assay) as well as on apoptosis and necrosis induction in a panel of tumour cell lines and human lymphocytes (combined annexin V and propidium iodide staining) was monitored. In addition, NK cell function (degranulation-CD107a assay and IFN gamma secretion) was also investigated since these immunocompetent cells are important for the control of malignancies within the human body. RESULTS: Extracts of H. niger induced proliferation inhibition not only of lymphoblastic leukaemia cells (MOLT4; IC50: 171 ug/mL) but also of myosarcoma (SK-UT-1b; IC50: 304 ug/mL) and melanoma cells (HT-144; IC50: 569 ug/mL) due to the induction of apoptosis. Purified T cells or NK cells were significantly affected through the presence of high H. niger concentrations while bulk lymphocytes were not affected. NK cells' anti-tumour functions expressed by degranulation capacity as well as IFN-y production were unaffected by the presence of the H. niger extract. Since protoanemonin and saponins have been reported in the literature to exert cytotoxic effects, their content was also determined. CONCLUSIONS: H. niger extracts exhibit differential cytotoxicity towards tumour cell lines and healthy human T- and NK-cells. PMID- 25446604 TI - Medicinal plants from the genus Acalypha (Euphorbiaceae)--a review of their ethnopharmacology and phytochemistry. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acalypha is the fourth largest genus of the Euphorbiaceae family with approximately 450-570 species. Several Acalypha species are used as medicinal plants in Africa and in the Mascarene Islands. Almost every part of the plant including the leaves, stem and roots are used as traditional remedies to treat and manage a panoply of ailments. However, there is no updated compilation of traditionally important medicinal plants from the Acalypha genus. The present review therefore, endeavors to provide for the first time an updated compilation of documented ethnopharmacological information in relation to the ethnomedicinal, ethnoveterinary, zoopharmacognosy, phytochemistry and biological activities of medicinal plants from the Acalypha genus which can subsequently open new perspectives for further pharmacological research. MATERIALS AND METHODS: A literature search was performed on Acalypha species using ethnobotanical text books and scientific databases such as Pubmed, Scopus, EBSCO, Google Scholar and other web sources such as records from PROTA, PROSEA, and Botanical Dermatology Database. The Plant List, International Plant Name index and Kew Botanical Garden Plant name databases were used to validate scientific names. RESULTS AND DISCUSSION: Plants from Acalypha genus are traditionally used in the treatment and/or management of diverse ailments such as diabetes, jaundice, hypertension, fever, liver inflammation, schistosomiasis, dysentery, respiratory problems including bronchitis, asthma and pheumonia as well as skin conditions such as scabies, eczema and mycoses. Approximately 124 species were listed in ethnobotanical studies with some botanical description and others mentioned from different web sources. However, only 40 species have been included in the present review due to the unavailability of ethnopharmacological data on the remaining species. Among the 40 cited species, 30 were traditionally used for the treatment and/or management of approximately 70 human diseases or health conditions. Two species, Acalypha alnifolia and Acalypha fruticosa are used as insecticides and sand fly repellent respectively. Only 2 species (Acalypha fruticosa and Acalypha indica) are used in ethnoveterinary practice and have similar human and veterinary applications. In zoopharmacognosy, only Acalypha ornata has been mentioned. Natives from Africa, Central America, North America, Southern China, India, Bangladesh, Papua New Guinea and Mascarenes islands utilize Acalypha species as ethnomedicine. Traditionally used Acalypha species have been reported to possess at least one of the following biological activities: antimicrobial, anti-diabetic, antioxidant, anti-inflammatory, larvidal, pupicidal, hepatoprotective, anticancer, leishmanicidal, antihyperglycemic, antihypertensive, anti-venom, analgesic, anthelmintic, antiemetic, laxative, expectorant, diuretic, post-coital antifertility effects and wound healing. A total of 167 compounds have been identified from 19 species, with 16 from eight species were reported to be bioactive. CONCLUSION: The present review represents 32.3% of species from the Acalypha genus and can be considered as the first compilation of ethnopharmacologically useful plants from this genus. There is a great potential to discover new biologically active phytochemicals from the Acalypha genus because only few species have been studied comprehensively. Therefore, the clinical evaluation of species from this genus is warranted in future studies to confirm the ethnomedicinal claims and for the safety approval of therapeutic applications. PMID- 25446605 TI - Starving/re-feeding processes induce metabolic modifications in thick-lipped grey mullet (Chelon labrosus, Risso 1827). AB - The effects of starvation and re-feeding on metabolites and tissue composition, GH/IGF-I axis, and digestive enzyme activities in juvenile thick-lipped grey mullet (Chelon labrosus) were evaluated. Fish were divided into three feeding groups (n=72, 82.00+/-4.09 g initial body mass). The control group was fed 1% of their body mass once a day throughout the experiment with commercial pellets. The other two groups were deprived of feed for 21 days (starved), or re-fed for 7 days after 14 days of food deprivation (re-fed). Full-length cDNAs from pituitary GH and hepatic IGF-I were cloned by screening a cDNA library or by PCR techniques. Furthermore, changes in their mRNA expressions were assessed by real time PCR in specimens maintained under the different feeding patterns. Results showed a negative growth in starved and re-feeding groups. Starvation induced a significant increase in plasma triglycerides as well as a decrease in liver glucose and glycogen. Re-feeding increased plasma glucose, lactate and protein, as well as liver glucose and glycogen. In addition, starvation significantly increased pituitary GH expression, while re-feeding down-regulated it. No significant changes were observed in hepatic IGF-I expression in any dietary treatment. Digestive enzyme activities were not significantly affected either by starvation or by re-feeding. The results of the present work suggest that juveniles of the thick-lipped grey mullet may easily adjust their metabolism under situations characterized by a short-term starvation and re-feeding. PMID- 25446606 TI - Automated voxel-based analysis of volumetric dynamic contrast-enhanced CT data improves measurement of serial changes in tumor vascular biomarkers. AB - OBJECTIVES: Development of perfusion imaging as a biomarker requires more robust methodologies for quantification of tumor physiology that allow assessment of volumetric tumor heterogeneity over time. This study proposes a parametric method for automatically analyzing perfused tissue from volumetric dynamic contrast enhanced (DCE) computed tomography (CT) scans and assesses whether this 4 dimensional (4D) DCE approach is more robust and accurate than conventional, region-of-interest (ROI)-based CT methods in quantifying tumor perfusion with preliminary evaluation in metastatic brain cancer. METHODS AND MATERIALS: Functional parameter reproducibility and analysis of sensitivity to imaging resolution and arterial input function were evaluated in image sets acquired from a 320-slice CT with a controlled flow phantom and patients with brain metastases, whose treatments were planned for stereotactic radiation surgery and who consented to a research ethics board-approved prospective imaging biomarker study. A voxel-based temporal dynamic analysis (TDA) methodology was used at baseline, at day 7, and at day 20 after treatment. The ability to detect changes in kinetic parameter maps in clinical data sets was investigated for both 4D TDA and conventional 2D ROI-based analysis methods. RESULTS: A total of 7 brain metastases in 3 patients were evaluated over the 3 time points. The 4D TDA method showed improved spatial efficacy and accuracy of perfusion parameters compared to ROI-based DCE analysis (P<.005), with a reproducibility error of less than 2% when tested with DCE phantom data. Clinically, changes in transfer constant from the blood plasma into the extracellular extravascular space (Ktrans) were seen when using TDA, with substantially smaller errors than the 2D method on both day 7 post radiation surgery (+/-13%; P<.05) and by day 20 (+/-12%; P<.04). Standard methods showed a decrease in Ktrans but with large uncertainty (111.6 +/- 150.5) %. CONCLUSIONS: Parametric voxel-based analysis of 4D DCE CT data resulted in greater accuracy and reliability in measuring changes in perfusion CT-based kinetic metrics, which have the potential to be used as biomarkers in patients with metastatic brain cancer. PMID- 25446607 TI - Nomogram for predicting the risk of locoregional recurrence in patients treated with accelerated partial-breast irradiation. AB - PURPOSE: To develop a nomogram taking into account clinicopathologic features to predict locoregional recurrence (LRR) in patients treated with accelerated partial-breast irradiation (APBI) for early-stage breast cancer. METHODS AND MATERIALS: A total of 2000 breasts (1990 women) were treated with APBI at William Beaumont Hospital (n=551) or on the American Society of Breast Surgeons MammoSite Registry Trial (n=1449). Techniques included multiplanar interstitial catheters (n=98), balloon-based brachytherapy (n=1689), and 3-dimensional conformal radiation therapy (n=213). Clinicopathologic variables were gathered prospectively. A nomogram was formulated utilizing the Cox proportional hazards regression model to predict for LRR. This was validated by generating a bias corrected index and cross-validated with a concordance index. RESULTS: Median follow-up was 5.5 years (range, 0.9-18.3 years). Of the 2000 cases, 435 were excluded because of missing data. Univariate analysis found that age <50 years, pre-/perimenopausal status, close/positive margins, estrogen receptor negativity, and high grade were associated with a higher frequency of LRR. These 5 independent covariates were used to create adjusted estimates, weighting each on a scale of 0-100. The total score is identified on a points scale to obtain the probability of an LRR over the study period. The model demonstrated good concordance for predicting LRR, with a concordance index of 0.641. CONCLUSIONS: The formulation of a practical, easy-to-use nomogram for calculating the risk of LRR in patients undergoing APBI will help guide the appropriate selection of patients for off-protocol utilization of APBI. PMID- 25446608 TI - High-dose-rate brachytherapy boost effect on local tumor control in young women with breast cancer. AB - PURPOSE: To evaluate the local control rate and complications of a single fraction of high-dose-rate brachytherapy (HDR BT) boost in women aged 45 yeas and younger after breast-conserving therapy. METHODS AND MATERIALS: Between 1999 and 2007, 167 patients between the ages of 26 and 45 years old (72 were 40 years old or younger), with stages T1 to T2 invasive breast cancer with disease-free margin status of at least 5 mm after breast-conserving surgery received 46 to 50 Gy whole-breast irradiation plus a 7-Gy HDR-BT boost ("fast boost"). An axillary dissection was performed in 72.5% of the patients and sentinel lymph node biopsy in 27.5%. A supraclavicular area was irradiated in 19% of the patients. Chemotherapy was used in 86% of the patients and hormone treatment in 77%. Clinical nodes were present in 18% and pathological nodes in 29%. The pathological stage was pT0: 5%, pTis: 3%, pT1: 69% and pT2: 23%. Intraductal component was present in 40% and 28% were G3. RESULTS: At a median follow-up of 92 months, 9 patients relapsed on the margin of the implant, and 1 patient in another quadrant, resulting in a 10-year local relapse rate of 4.3% and a breast relapse rate of 4.9%, with breast preservation in 93.4%; no case of mastectomy due to poor cosmesis arose. Actuarial 5- and 10-year disease-free, cause specific, and overall survival rates were 87.9% and 85.8%, and 92.1% and 88.4%, and 92.1% and 87.3%, respectively. In a univariate analysis, triple-negative cases and negative hormone receptors did worse, but in a multivariate analysis, only the last factor was significant for local and breast control. Asymptomatic fibrosis G2 was recorded in 3 cases, and there were no other late complications. Cosmetic results were good to excellent in 97% of cases. CONCLUSIONS: A single dose of 7 Gy using the fast-boost technique is well tolerated, with a low rate of late complications and improved local tumor control in women aged 45 and younger, compared to published data. This approach is recommended in breast-preserving treatment. PMID- 25446609 TI - Relationship between low hemoglobin levels and outcomes after treatment with radiation or chemoradiation in patients with cervical cancer: has the impact of anemia been overstated? AB - PURPOSE: Previous reports have suggested that anemia increases rates of recurrence after radiation therapy for cervical cancer. However, these studies may not have fully corrected for confounding risk factors. Using a well characterized cohort of cervical cancer patients, we examined the association between anemia and outcomes before and after the introduction of chemoradiation as standard of care. METHODS AND MATERIALS: We reviewed the records of 2454 patients who underwent definitive radiation therapy from 1980 through 2011. Minimum hemoglobin level (Hgbmin) was recorded for 2359 patients (96%). Endpoints included freedom from central recurrence (FFCR), freedom from distant metastasis (FFDM), and disease-specific survival (DSS). RESULTS: For the entire cohort, hemoglobin concentrations of 9, 10, and 12 g/dL before and during radiation were all significantly associated with FFCR, FFDM, and DSS (all P<.001) on univariate analysis. However, on multivariate analysis, only Hgbmin less than 10 g/dL during RT (RT-Hgb<10) remained significant, and it was correlated with lower DSS (P=.02, hazard ratio [HR] = 1.28) and FFDM (P=.03, HR = 1.33) but not with FFCR. In a subset analysis of patients receiving chemoradiation (n=678), RT-Hgb<10 was associated only with DSS (P=.008, HR = 1.49), not with FFCR or FFDM. In this subgroup, despite an association between RT-Hgb<10 and DSS, the use of transfusion was not correlated with benefit. CONCLUSIONS: No evidence was found supporting anemia as an independent predictor of central recurrence in patients treated with definitive radiation therapy with or without chemotherapy. Less emphasis on correcting anemia in cervical cancer patients may be warranted. PMID- 25446610 TI - Efficacy endpoints of radiation therapy group protocol 0247: a randomized, phase 2 study of neoadjuvant radiation therapy plus concurrent capecitabine and irinotecan or capecitabine and oxaliplatin for patients with locally advanced rectal cancer. AB - PURPOSE: To report secondary efficacy endpoints of Radiation Therapy Oncology Group protocol 0247, primary endpoint analysis of which demonstrated that preoperative radiation therapy (RT) with capecitabine plus oxaliplatin achieved a pathologic complete remission prespecified threshold (21%) to merit further study, whereas RT with capecitabine plus irinotecan did not (10%). METHODS AND MATERIALS: A randomized, phase 2 trial evaluated preoperative RT (50.4 Gy in 1.8 Gy fractions) with 2 concurrent chemotherapy regimens: (1) capecitabine (1200 mg/m(2)/d Monday-Friday) plus irinotecan (50 mg/m(2)/wk * 4); and (2) capecitabine (1650 mg/m(2)/d Monday-Friday) plus oxaliplatin (50 mg/m(2)/wk * 5) for clinical T3 or T4 rectal cancer. Surgery was performed 4 to 8 weeks after chemoradiation, then 4 to 6 weeks later, adjuvant chemotherapy (oxaliplatin 85 mg/m(2); leucovorin 400 mg/m(2); 5-fluorouracil 400 mg/m(2); 5-fluorouracil 2400 mg/m(2)) every 2 weeks * 9. Disease-free survival (DFS) and overall survival (OS) were estimated univariately by the Kaplan-Meier method. Local-regional failure (LRF), distant failure (DF), and second primary failure (SP) were estimated by the cumulative incidence method. No statistical comparisons were made between arms because each was evaluated individually. RESULTS: A total of 104 patients (median age, 57 years) were treated; characteristics were similar for both arms. Median follow-up for RT with capecitabine/irinotecan arm was 3.77 years and for RT with capecitabine/oxaliplatin arm was 3.97 years. Four-year DFS, OS, LRF, DF, and SP estimates for capecitabine/irinotecan arm were 68%, 85%, 16%, 24%, and 2%, respectively. The 4-year DFS, OS, LRF, DF, and SP failure estimates for capecitabine/oxaliplatin arm were 62%, 75%, 18%, 30%, and 6%, respectively. CONCLUSIONS: Efficacy results for both arms are similar to other reported studies but suggest that pathologic complete remission is an unsuitable surrogate for traditional survival metrics of clinical outcome. Although it remains uncertain whether the addition of a second cytotoxic agent enhances the effectiveness of fluorouracil plus RT, these results suggest that further study of irinotecan may be warranted. PMID- 25446611 TI - New FeFe-hydrogenase genes identified in a metagenomic fosmid library from a municipal wastewater treatment plant as revealed by high-throughput sequencing. AB - A fosmid metagenomic library was constructed with total community DNA obtained from a municipal wastewater treatment plant (MWWTP), with the aim of identifying new FeFe-hydrogenase genes encoding the enzymes most important for hydrogen metabolism. The dataset generated by pyrosequencing of a fosmid library was mined to identify environmental gene tags (EGTs) assigned to FeFe-hydrogenase. The majority of EGTs representing FeFe-hydrogenase genes were affiliated with the class Clostridia, suggesting that this group is the main hydrogen producer in the MWWTP analyzed. Based on assembled sequences, three FeFe-hydrogenase genes were predicted based on detection of the L2 motif (MPCxxKxxE) in the encoded gene product, confirming true FeFe-hydrogenase sequences. These sequences were used to design specific primers to detect fosmids encoding FeFe-hydrogenase genes predicted from the dataset. Three identified fosmids were completely sequenced. The cloned genomic fragments within these fosmids are closely related to members of the Spirochaetaceae, Bacteroidales and Firmicutes, and their FeFe-hydrogenase sequences are characterized by the structure type M3, which is common to clostridial enzymes. FeFe-hydrogenase sequences found in this study represent hitherto undetected sequences, indicating the high genetic diversity regarding these enzymes in MWWTP. Results suggest that MWWTP have to be considered as reservoirs for new FeFe-hydrogenase genes. PMID- 25446612 TI - Role of 1-acyl-sn-glycerol-3-phosphate acyltransferase in psychrotrophy and stress tolerance of Serratia plymuthica RVH1. AB - A mutant with a transposon insertion just upstream of the lysophosphatidic acid acyltansferase gene plsC was isolated in a screen for mutants affected in growth at low temperature of the psychrotroph Serratia plymuthica RVH1. This mutant had lost its ability to grow at 4 degrees C and was severely affected in growth at 10 degrees C, but showed only slightly reduced growth at 30 degrees C. Fatty acid analysis of membrane extracts showed that the ratio of C16:1/C18:1 fatty acids was six-to sevenfold reduced in the mutant, although the ratio of unsaturated to saturated fatty acids was unaffected. The homeoviscous adaptation ability of the mutant was also unaffected. Growth and fatty acid composition were mostly restored by overexpressing plsC on a plasmid. Supplementation of C16:1 (palmitoleic acid) into the growth medium partially rescued low temperature growth, indicating that a balanced ratio of the two main unsaturated fatty acids is required for psychrotrophy. The mutant was significantly more strongly inactivated by high pressure treatment at 250 MPa, but not at higher pressures. It also showed reduced growth at low pH, but not at increased NaCl concentrations. This work provides novel information on the role of membrane fatty acid composition in stress tolerance. PMID- 25446613 TI - Diagnosis accuracy of serum glypican-3 in patients with hepatocellular carcinoma: a systematic review with meta-analysis. AB - BACKGROUND AND AIMS: The diagnostic value of serum GPC3 in patients with hepatocellular carcinoma (HCC) remains controversial. Thus, we performed a systematic review and meta-analysis to assess the diagnostic accuracy of serum GPC3 for HCC. METHODS: A systematic search was performed for the related studies. Sensitivity, specificity and other measures regarding the accuracy of serum GPC3 and alpha-fetoprotein (AFP) in the diagnosis of HCC were pooled using random effects models. Summary receiver operating characteristic curve (sROC) analysis was used to summarize the overall test performance. RESULTS: Nineteen studies were included in this meta-analysis. Pooled sensitivity, specificity and 95% confidence interval (CI) of serum GPC3 for the diagnosis of HCC were 55.2% (52.9 57.4%) and 84.2% (82.2-86.0%), respectively. When combining GPC3 with AFP, pooled sensitivity, specificity, and 95% CI were 75.7% (71.8-79.4%) and 83.3% (79.6 86.6%), respectively. The area under sROC (AUC) and 95% CI for AFP combined with GPC3 were 0.762 (0.649-0.875). For diagnosis of early HCC, pooled sensitivity and specificity of serum GPC3 were 55.1% (47.9-66.2%) and 97.0% (95.2-98.2%), respectively. The AUC of GPC3 for early HCC was 0.793 (0.668-0.917). CONCLUSIONS: This meta-analysis indicates that serum GPC3 has a comparable accuracy to AFP for the diagnosis of HCC, and there is an elevation in the sensitivity of diagnosis when GPC3 was combined with AFP. Diagnostic accuracy of serum GPC3 for early HCC is still unsatisfactory. PMID- 25446614 TI - Compounds blocking methylglyoxal-induced protein modification and brain endothelial injury. AB - BACKGROUND AND AIMS: Elevated levels of reactive carbonyl species such as methylglyoxal triggers carbonyl stress and activates a series of inflammatory responses leading to accelerated vascular damage. Carbonyl stress is implicated in conditions and diseases like aging, diabetes mellitus, Alzheimer's disease and cardiovascular diseases. Our aim was to examine the effects of methylglyoxal on human hCMEC/D3 brain endothelial cells and search for protective molecules to prevent endothelial damage. METHODS: Methylglyoxal-induced modification of albumin was tested in a cell-free assay. Endothelial cell viability was monitored by impedance measurement in real-time. The following compounds were tested in cell-free and viability assays: beta-alanine, all-trans-retinoic acid, aminoguanidine, ascorbic acid, L-carnosine, GW-3333, indapamide, piracetam, gamma tocopherol, U0126, verapamil. Barrier function of brain endothelial monolayers was characterized by permeability measurements and visualized by immunohistochemistry for beta-catenin. mRNA expression level of 60 selected blood brain barrier-related genes in hCMEC/D3 cells was investigated by a custom Taqman gene array. RESULTS: Methylglyoxal treatment significantly elevated protein modification, exerted toxicity, reduced barrier integrity, increased permeability for markers FITC-dextran and albumin and caused higher production of reactive oxygen species in hCMEC/D3 endothelial cells. Changes in the mRNA expression of 30 genes coding tight junction proteins, transporters and enzymes were observed in methylglyoxal-treated hCMEC/D3 cells. From the tested 11 compounds only all trans-retinoic acid, an antioxidant and antiglycation agent, U0126, a MAP/ERK kinase inhibitor and aminoguanidine attenuated methylglyoxal-induced damage in hCMEC/D3 cells. CONCLUSIONS: All-trans-retinoic acid and inhibition of the MAP/ERK signaling pathway may be protective in carbonyl stress induced brain endothelial damage. PMID- 25446615 TI - The blood-brain barrier as a target in traumatic brain injury treatment. AB - Traumatic brain injury (TBI) is one of the most frequent causes of death in the young population. Several clinical trials have unsuccessfully focused on direct neuroprotective therapies. Recently immunotherapeutic strategies shifted into focus of translational research in acute CNS diseases. Cross-talk between activated microglia and blood-brain barrier (BBB) could initiate opening of the BBB and subsequent recruitment of systemic immune cells and mediators into the brain. Stabilization of the BBB after TBI could be a promising strategy to limit neuronal inflammation, secondary brain damage and acute neurodegeneration. This review provides an overview on the pathophysiology of TBI and brain edema formation including definitions and classification of TBI, current clinical treatment strategies, as well as current understanding on the underlying cellular processes. A summary of in vivo and in vitro models to study different aspects of TBI is presented. Three mechanisms proposed for stabilization of the BBB, myosin light chain kinases, glucocorticoid receptors and peroxisome proliferator activated receptors are reviewed for their influence on barrier-integrity and outcome after TBI. In conclusion, the BBB is recommended as a promising target for the treatment of traumatic brain injury, and it is suggested that a combination of BBB stabilization and neuroprotectants may improve therapeutic success. PMID- 25446616 TI - WITHDRAWN: Intense Seasonal A/H1N1 Influenza in Mexico, Winter 2013-2014. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.arcmed.2014.11.005. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25446617 TI - Transcriptional profile of HIV-induced nuclear translocation of amyloid beta in brain endothelial cells. AB - BACKGROUND AND AIMS: Increased amyloid deposition in HIV-infected brains may contribute to the pathogenesis of neurocognitive dysfunction in infected patients. We have previously shown that exposure to HIV results in enhanced amyloid beta (Abeta) levels in human brain microvascular endothelial cells, suggesting that brain endothelial cells contribute to accumulation of Abeta in HIV-infected brains. Importantly, Abeta not only accumulates in the cytoplasm of HIV-exposed cells but also enters the nuclei of brain endothelial cells. METHODS: cDNA microarray analysis was performed in order to examine changes in the transcriptional profile associated with Abeta nuclear entry in the presence of HIV-1. RESULTS: Gene network analysis indicated that inhibition of nuclear entry of Abeta resulted in enrichment in gene sets involved in apoptosis and survival, endoplasmic reticulum stress response, immune response, cell cycle, DNA damage, oxidative stress, cytoskeleton remodeling and transforming growth factor beta (TGFbeta) receptor signaling. CONCLUSIONS: The obtained data indicate that HIV induced Abeta nuclear uptake affects several cellular stress-related pathways relevant for HIV-induced Abeta pathology. PMID- 25446619 TI - Blood-brain barrier proteomics: towards the understanding of neurodegenerative diseases. AB - The blood-brain barrier (BBB) regulates the passage of endogenous and exogenous compounds and thus contributes to the brain homeostasis with the help of well known proteins such as tight junction proteins, plasma membrane transporters and metabolic barrier proteins. In the last decade, proteomics have emerged as supplementary tools for BBB research. The development of proteomic technologies has provided several means to extend knowledge on the BBB and to investigate additional routes for the bypass of this barrier. Proteomics approaches have been used in vivo and also using in vitro BBB models to decipher the physiological characteristics and, under stress conditions, to understand the molecular mechanisms of brain diseases. This work has demonstrated that both quantitative global and targeted proteomics approaches are powerful and provide significant information on the brain microvessel endothelium. However, current knowledge is only partial and it is necessary to increase the studies using proteomics tools that will provide additional information concerning brain pathologies or BBB metabolism. Highly sensitive, accurate and specific protein quantification by quantitative targeted proteomics appears as an essential methodology for human BBB studies. PMID- 25446618 TI - Intense seasonal A/H1N1 influenza in Mexico, winter 2013-2014. AB - BACKGROUND AND AIMS: A recrudescent wave of pandemic influenza A/H1N1 affected Mexico during the winter of 2013-2014 following a mild 2012-2013 A/H3N2 influenza season. METHODS: We compared the demographic and geographic characteristics of hospitalizations and inpatient deaths for severe acute respiratory infection (SARI) and laboratory-confirmed influenza during the 2013-2014 influenza season compared to previous influenza seasons, based on a large prospective surveillance system maintained by the Mexican Social Security health care system. RESULTS: A total of 14,236 SARI hospitalizations and 1,163 inpatient deaths (8.2%) were reported between October 1, 2013 and March 31, 2014. Rates of laboratory confirmed A/H1N1 hospitalizations and deaths were significantly higher among individuals aged 30-59 years and lower among younger age groups for the 2013-2014 A/H1N1 season compared to the previous A/H1N1 season in 2011-2012 (chi(2) test, p <0.001). The reproduction number for the winter 2013-2014 influenza season in central Mexico was estimated at 1.3-1.4, in line with that reported for the 2011 2012 A/H1N1 season but lower than during the initial waves of pandemic A/H1N1 activity in 2009. CONCLUSIONS: We documented a substantial increase in the number of A/H1N1-related hospitalizations and deaths during the period from October 2013 March 2014 in Mexico and a proportionate shift of severe disease to middle-aged adults, relative to the preceding A/H1N1 2011-2012 season. In the absence of clear antigenic drift in globally circulating A/H1N1 viruses in the post-2009 pandemic period, the gradual change in the age distribution of A/H1N1 infections observed in Mexico suggests a slow build-up of immunity among younger populations, reminiscent of the age profile of past pandemics. PMID- 25446620 TI - Role of histaminergic system in blood-brain barrier dysfunction associated with neurological disorders. AB - Blood-brain barrier (BBB) disruption has been associated with several acute and chronic brain disorders such as Alzheimer's disease, Parkinson's disease and epilepsy. This represents a critical situation because damaged integrity of the BBB is related to the influx of immune mediators, plasma proteins and other outside elements from blood to the central nervous system (CNS) that may trigger a cascade of events that leads to neuroinflammation. In this review, evidence that mast cells and the release of factors such as histamine play an important role in the neuroinflammatory process associated with brain disorders such as Alzheimer's disease, Parkinson's disease and epilepsy is presented. PMID- 25446621 TI - Relationship of glycated hemoglobin A1c, coronary artery calcification and insulin resistance in males without diabetes. AB - BACKGROUND AND AIMS: We undertook this study to compare the prevalence of coronary artery calcification (CAC) across glycated hemoglobin A1c (HbA1c) in nondiabetic males and to evaluate the impact of insulin resistance on CAC in relation to HbA1c levels. METHODS: A cross-sectional study was performed in 18,504 adult males without diabetes mellitus and cardiovascular disease (CVD). CAC scores were measured by multidetector computed tomography; CAC was defined as a CAC score >0. Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR). Subjects were grouped by HbA1c quartile (<=5.4%, 5.4-5.6%, 5.7%, 5.8-6.4%). RESULTS: Thirteen percent of subjects (n = 2,406) had a CAC score >0. The prevalence of CAC increased with increasing HbA1c quartile (9.4%, 11.1%, 14.1%, 17.3%). Crude odds ratios (ORs) for CAC were 1.2, 1.58 and 2.01 for the HbA1c quartiles 2, 3, and 4 when compared with the first quartile. Mean HOMA-IR levels were different among HbA1C categories and CAC status. HOMA-IR levels were higher in subjects with CAC than in those without, except in the third HbA1c quartile. Stratification by HbA1c showed a significant association between CAC and insulin resistance only in the first (OR 1.67) and fourth (OR 1.33) HbA1c quartile. After adjustment for CV risk factors, insulin resistance remained an independent predictor of CAC only in the first HbA1c quartile. CONCLUSIONS: Our study demonstrated that not only glucose status represented by HbA1c but also insulin resistance might be associated with CAC in non-diabetic Korean men. The magnitude of association of CAC with insulin resistance was greater in the lowest HbA1c quartile group. PMID- 25446622 TI - Cerebral ABC transporter-common mechanisms may modulate neurodegenerative diseases and depression in elderly subjects. AB - In elderly subjects, depression and dementia often coincide but the actual reason is currently unknown. Does a causal link exist or is it just a reactive effect of the knowledge to suffer from dementia? The ABC transporter superfamily may represent a causal link between these mental disorders. Since the transporters ABCB1 and ABCC1 have been discovered as major beta-amyloid-exporting molecules at the blood-brain barrier and ABCC1 was found to be directly activated by St. John's wort (SJW), depression and dementia certainly share an important pathophysiologic link. It was recognized that herbal anti-depressant formulations made from SJW are at least as effective for the treatment of unipolar depression in old age as classical pharmacotherapy, while having fewer side effects (Cochrane reports, 2008). SJW is known to activate various metabolizing and transport systems in the body, with cytochrome P450 enzymes and ABC transporters being most important. Does the treatment of depression in elderly subjects using pharmacological compounds or phytomedical extracts target a mechanism that also accounts for peptide storage in Alzheimer's disease and perhaps other proteopathies of the brain? In this review we summarize recent data that point to a common mechanism and present the first promising causal treatment results of demented elderly subjects with distinct SJW extracts. Insufficient trans-barrier clearance may indeed present a common problem in all the proteopathies of the brain where toxic peptides are deposited in a location-specific manner. Thus, activation of efflux molecules holds promise for future treatment of this large group of devastating disorders. PMID- 25446623 TI - Glutamate efflux at the blood-brain barrier: cellular mechanisms and potential clinical relevance. AB - L-Glutamate is considered the most important excitatory amino acid in the mammalian brain. Strict control of its concentration in the brain interstitial fluid is important to maintain neurotransmission and avoid excitotoxicity. The role of astrocytes in handling L-glutamate transport and metabolism is well known, however endothelial cells may also play an important role through mediating brain-to-blood L-glutamate efflux. Expression of excitatory amino acid transporters has been demonstrated in brain endothelial cells of bovine, human, murine, rat and porcine origin. These can account for high affinity concentrative uptake of L-glutamate from the brain interstitial fluid into the capillary endothelial cells. The mechanisms in between L-glutamate uptake in the endothelial cells and L-glutamate appearing in the blood are still unclear and may involve a luminal transporter for L-glutamate, metabolism of L-glutamate and transport of metabolites or a combination of the two. However, both in vitro and in vivo studies demonstrated blood-to-brain transport of L-glutamate, at least during pathological events. This review summarizes the current knowledge on the brain-to-blood L-glutamate efflux hypothesis including possible mechanisms to account for the transport, in vivo studies on blood glutamate scavenging and potential clinical relevance of the phenomenon. PMID- 25446624 TI - Revisiting the concept of behavior patterns in animal behavior with an example from food-caching sequences in wolves (Canis lupus), coyotes (Canis latrans), and red foxes (Vulpes vulpes). AB - We discuss the history, conceptualization, and relevance of behavior patterns in modern ethology by explaining the evolution of the concepts of fixed action patterns and modal action patterns. We present the movement toward a more flexible concept of natural action sequences with significant degrees of (production and expressive) freedom. An example is presented with the food caching behavior of three Canidae species: red fox (Vulpes vulpes), coyote (Canis latrans) and gray wolf (Canis lupus). Evolutionary, ecological, and neuroecological/neuroethological arguments are presented to explain the difference in levels of complexity and stereotypy between Canis and Vulpes. This article is part of a Special Issue entitled: Canine Behavior. PMID- 25446625 TI - Sexual bias in probe tool manufacture and use by wild bearded capuchin monkeys. AB - Here we examine data from a two-year research on the use of sticks as probes by two groups of wild capuchin monkeys (Sapajus libidinosus) in Serra da Capivara National Park (PI), Brazil. The use of sticks as probes is not usually observed among wild tufted capuchin (Sapajus spp.) populations, having been reported as a customary behavior only in SCNP groups. Probe tools are used to access small prey (insects or lizards) in rock cracks or tree trunks, or honey from wasps' nests, and also to poke toads and poisonous snakes. Probe use is, so far, the only known case in which wild capuchins modify objects used as tools: branches are trimmed off, and tips, thinned. Tool preparation episodes involved up to four modification steps. Contrary to the stone tools used to crack hard nuts, probe tools don't present any weight constraint for use by females, but there is nevertheless a strong male bias (97%) in the occurrence of probe tool use. There are also no diet biases that could explain this difference. Although males hunt more often than females, the latter main prey items are lizards, which are also the main targets of probe tool use. One possibility is that females may have fewer social opportunities to learn about probe tools. PMID- 25446626 TI - Multimodal sensory reliance in the nocturnal homing of the amblypygid Phrynus pseudoparvulus (Class Arachnida, Order Amblypygi)? AB - Like many other nocturnal arthropods, the amblypygid Phrynus pseudoparvulus is capable of homing. The environment through which these predators navigate is a dense and heterogeneous tropical forest understory and the mechanism(s) underlying their putatively complex navigational abilities are presently unknown. This study explores the sensory inputs that might facilitate nocturnal navigation in the amblypygid P. pseudoparvulus. Specifically, we use sensory system manipulations in conjunction with field displacements to examine the potential involvement of multimodal - olfactory and visual - stimuli in P. pseudoparvulus' homing behavior. In a first experiment, we deprived individuals of their olfactory capacity and displaced them to the opposite side of their home trees (<5m). We found that olfaction-intact individuals were more likely to be re sighted in their home refuges than olfaction-deprived individuals. In a second experiment, we independently manipulated both olfactory and visual sensory capacities in conjunction with longer-distance displacements (8m) from home trees. We found that sensory-intact individuals tended to be re-sighted on their home tree more often than sensory-deprived individuals, with a stronger effect of olfactory deprivation than visual deprivation. Comparing across sensory modality manipulations, olfaction-manipulated individuals took longer to return to their home trees than vision-manipulated individuals. Together, our results indicate that olfaction is important in the nocturnal navigation of P. pseudoparvulus and suggest that vision may also play a more minor role. PMID- 25446628 TI - Core outcomes and definitions for pediatric fever and neutropenia research: a consensus statement from an international panel. AB - BACKGROUND: There are no specific recommendations for the design and reporting of studies of children with fever and neutropenia (FN). As a result, there is marked heterogeneity in the variables and outcomes that are reported and new definitions continue to emerge. These inconsistencies hinder the ability of researchers and clinicians to compare, contrast and combine results. The objective was to achieve expert consensus on a core set of variables and outcomes that should be measured and reported, as a minimum, in pediatric FN studies. PROCEDURE: The Delphi method was used to achieve consensus among an international group of clinicians, pharmacists, researchers, and patient representatives. Four surveys focusing on (i) the identification of a core set of variables and outcomes; and (ii) definitions of these variables and outcomes, were administered electronically. Consensus was predefined as more than 80% agreement on any statement. RESULTS: There were forty-five survey participants and the response rate ranged between 84 and 96%. There was consensus on eight core variables and 10 core outcomes that should be collected and reported in all studies of children with FN. Consensus definitions were identified for all of the core outcomes. CONCLUSION: Using the Delphi method, expert consensus on a set of core variables and outcomes, and their corresponding definitions, was achieved. These core sets represent the minimum that should be collected and reported in all studies of children with FN. This will promote collaboration and ensure consistency and comparability between studies. PMID- 25446627 TI - TWIST1 silencing enhances in vitro and in vivo osteogenic differentiation of human adipose-derived stem cells by triggering activation of BMP-ERK/FGF signaling and TAZ upregulation. AB - Mesenchymal stem cells (MSCs) show promise for cellular therapy and regenerative medicine. Human adipose tissue-derived stem cells (hASCs) represent an attractive source of seed cells in bone regeneration. How to effectively improve osteogenic differentiation of hASCs in the bone tissue engineering has become a very important question with profound translational implications. Numerous regulatory pathways dominate osteogenic differentiation of hASCs involving transcriptional factors and signaling molecules. However, how these factors combine with each other to regulate hASCs osteogenic differentiation still remains to be illustrated. The highly conserved developmental proteins TWIST play key roles for transcriptional regulation in mesenchymal cell lineages. This study investigates TWIST1 function in hASCs osteogenesis. Our results show that TWIST1 shRNA silencing increased the osteogenic potential of hASCs in vitro and their skeletal regenerative ability when applied in vivo. We demonstrate that the increased osteogenic capacity observed with TWIST1 knockdown in hASCs is mediated through endogenous activation of BMP and ERK/FGF signaling leading, in turn, to upregulation of TAZ, a transcriptional modulator of MSCs differentiation along the osteoblast lineage. Inhibition either of BMP or ERK/FGF signaling suppressed TAZ upregulation and the enhanced osteogenesis in shTWIST1 hASCs. Cosilencing of both TWIST1 and TAZ abrogated the effect elicited by TWIST1 knockdown thus, identifying TAZ as a downstream mediator through which TWIST1 knockdown enhanced osteogenic differentiation in hASCs. Our functional study contributes to a better knowledge of molecular mechanisms governing the osteogenic ability of hASCs, and highlights TWIST1 as a potential target to facilitate in vivo bone healing. PMID- 25446629 TI - The isothiocyanato moiety: an ideal protecting group for the stereoselective synthesis of sialic acid glycosides and subsequent diversification. AB - The preparation of a crystalline, peracetyl adamantanyl thiosialoside donor protected by an isothiocyanate group is described. On activation at -78 degrees C in the presence of typical carbohydrate acceptors, this donor gives high yields of the corresponding sialosides with exquisite alpha-selectivity. The high selectivity extends to the 4-O-benzyl-protected 3-OH acceptors, which are typically less reactive and selective than galactose 3,4-diols. Treatment of the alpha-sialosides with tris(trimethylsilyl)silane or allyltris(trimethylsilyl)silane results in replacement of the C5-N5 bond by a C-H or a C-C bond. The reaction of the isothiocyanate-protected sialosides with thioacids generates amides, while reaction with an amine gives a thiourea, which can be converted into a guanidine. The very high alpha-selectivities observed with the new donor and the rich chemistry of the isothiocyante function considerably extend the scope for optimization at the sialoside 5-position. PMID- 25446631 TI - How to come to evidence-based herbal medicines, what are the rules? PMID- 25446630 TI - Investigation of anti-inflammatory, antinociceptive and antipyretic activities of Stahlianthus involucratus rhizome ethanol extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Stahlianthus involucratus (Zingiberaceae) has long been used in traditional medicine to treat inflammation, pain, and fever. However, no pharmacological study of this plant has been reported to confirm these activities. The aim of this study was to investigate the anti-inflammatory, antinociceptive and antipyretic activities of Stahlianthus involucratus rhizome ethanol extract (SiE) in animal models. MATERIALS AND METHODS: Anti-inflammatory activity of SiE was investigated in rats using ethyl phenylpropiolate (EPP) induced ear edema, carrageenan- and arachidonic acid (AA)-induced hind paw edema, and cotton pellet-induced granuloma formation models. Acetic acid-induced writhing response in mice and tail-flick test in rats as well as yeast-induced hyperthermia in rats were used to investigate the antinociceptive and antipyretic activities, respectively. RESULTS: SiE significantly inhibited EPP-induced ear edema, carrageenan- and AA-induced hind paw edema. Its inhibitory effect in carrageenan-induced hind paw edema seemed to be in a dose-dependent manner. In cotton pellet-induced granuloma formation, SiE showed suppressive effects on granuloma formation but not on body weight gain and dry thymus weight. It could normalize serum alkaline phosphatase activity to nearly normal level. SiE also possessed a significant inhibitory effect, which seemed to be dose-dependent, on acetic acid-induced writhing response, whereas only at the highest dose of SiE could significantly increase test reaction time at all time-points in tail-flick test. However, no antipyretic activity was observed. CONCLUSIONS: These results suggest that SiE possesses anti-inflammatory and antinociceptive, but not antipyretic, activities. This study therefore rationalizes the traditional use of SiE for the treatment of inflammation and pain. PMID- 25446632 TI - Regulation of herbal medicines. PMID- 25446634 TI - Forming, transfer and globalization of medical-pharmaceutical knowledge in South East Asian missions (17th to 18th c.) - historical dimensions and modern perspectives. AB - From the 17th to the 18th centuries, missionaries in Southeast Asia dedicated themselves to providing and establishing a professional medical-pharmaceutical supply for the local population and therefore explored the genuine Materia medica for easily available and affordable remedies, especially medicinal plants. In characteristic medical-pharmaceutical compendia, which can be classified as missionary pharmacopoeias, they laid down their knowledge to advise others and to guarantee a professional health care. As their knowledge often resulted from an exchange with indigenous communities, these compendia provide essential information about traditional plant uses of Southeast Asian people. Individual missionaries such as the Jesuit Georg Joseph Kamel (1661-1706) not only strove to explore medicinal plants but performed botanical studies and even composed comprehensive herbals. The Jesuit missionaries in particular played roles in both the order's own global network of transfer of medicinal drugs and knowledge about the application, and within the contemporary local and European scientific networks which included, for example, the famous Royal Society of London. The results of their studies were distributed all over the world, were introduced into the practical Materia medica of other regions, and contributed significantly to the academization of knowledge. In our article we will explain the different intentions and methods of exploring, the resulting works and the consequences for the forming of the pharmaceutical and scientific knowledge. Finally, we will show the options which the works of the missionaries can offer for the saving of traditional ethnopharmacological knowledge and for the development of modern phytotherapeutics and pharmaceutical supply. The publication is based on a comprehensive study on the phenomenon of missionary pharmacy which has been published as a book in 2011 (Anagnostou, 2011a) and shows now the potential of historical medical-pharmaceutical works written in the Asian missions of the 17th to 18th century and influenced by ethnopharmaceutical knowledge and the relevance of historical studies for modern investigation in phytotherapy. PMID- 25446633 TI - Effect of alcohol extract of Acanthus ilicifolius L. on anti-duck hepatitis B virus and protection of liver. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acanthus ilicifolius L. is an important medicinal mangrove plant. It is popularly used for its anti-inflammatory, antioxidant activity and hepatoprotective effects. The present study was conducted to evaluate the effect of treatment with alcohol extract of Acanthus ilicifolius L. on duck hepatitis B. MATERIALS AND METHODS: One-day-old Guangxi shelducks injected intraperitoneally with strong positive duck hepatitis B virus (DHBV) serum were used to establish a duck hepatitis B animal model in the study. The ducks were respectively administered in different groups with low-, middle- and high-dose alcohol extracts of Acanthus ilicifolius L., the positive control drug acyclovir (ACV) and double-distilled water. The levels of serum DHBV DNA were detected by fluorescence quantitative PCR (FQ-PCR). Duck hepatitis B surface antigen (DHBsAg) and duck hepatitis B e antigen (DHBeAg) OD values in the serum were measured by ELISA. The activity of Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) in the serum was measured, and the livers were taken for histopathological examination. RESULTS: The levels of serum DHBV DNA and the values of DHBsAg and DHBeAg OD were not significant in any of the dose extract groups. However, the ALT activity was obviously lower in the middle- and high-dose extract groups. It was also found that a high dose of alcohol extract could reduce the activity of AST significantly and significantly improve hepatic pathological effects. CONCLUSIONS: High-dose alcohol extract of Acanthus ilicifolius L. has an obvious protective effect on the liver function and liver tissue. However, the present study finds that Acanthus ilicifolius L. cannot inhibit the replication of duck hepatitis B virus. PMID- 25446635 TI - Food and medicines in the Mediterranean tradition. A systematic analysis of the earliest extant body of textual evidence. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The relationship between food and medicines has long been investigated and is of crucial importance for the understanding of the development of ethnopharmacological knowledge through time. Hippocrates, considered the Father of Medicine, is credited with an aphorism equating food and medicine. No inquiry has been performed, however, into the collection of texts attributed to Hippocrates and, going beyond, into this statement, which is generally accepted without further examination. A clarification is much needed as the question of the relationship between food and medicines as potent substances are crucial to ethnopharmacology. MATERIALS AND METHODS: To verify the validity (if not the authenticity) of the theory on the identity of food and medicine attributed to Hippocrates, we digitized the whole collection of texts ascribed to Hippocrates in the original Greek language (the so-called Hippocratic Collection), which date back from the age of Hippocrates (late 5th century and 4th century BCE) to a more recent time (2nd century CE). On this basis, we extracted and databased all the information related to remedial therapy, that is, their materia medica (vegetable, animal and mineral) and their use(s). We identified both the plant species according to modern up-to-date taxonomy and the medical conditions as precisely as possible. We then screened these plants to discover what their uses were and, going backward in time, we examined (when possible) their native distribution, domestication, possible introduction (in the case of non-native species) and cultivation to determine whether these species had been known for a long time and might have been the object of long-term observation as both foodstuffs and medicines. RESULTS: Tabulated data from the Hippocratic Collection revealed that 40% of the remedies in the Collection are made out of only 44 plants. Of this group, 33 species (=75% of the group) were also used for nutritional purposes in Antiquity. Domestication history of these species indicates that humans have long been in contact with them, something that the medical uses of these species confirm, as they are multiple and finely distinguished. A pilot analysis of archeological remains of medicines confirms that textual evidence corresponds to physical evidence, that is, to the practice of medicine. As a consequence, textual information can be accepted as reflecting actual practice. CONCLUSIONS: Although the pseudo-aphorism according to which food are medicines and medicines are food does not appear as such in the Hippocratic Collection, it aptly expresses a fundamental element of the Hippocratic approach to therapeutics, without being, however, a creation of neither Hippocrates nor his followers and the physicians who practiced a form of medicine in the way of Hippocrates. A vast majority of the core group of plant species used for the preparation of medicines were also consumed as foodstuff. Knowledge and use of these plants probably resulted from a long co-existence in the same environment and also from multiple experiences of trial and error over millennia, whose results accumulated over time and contributed to the formation of the Mediterranean medical tradition. PMID- 25446636 TI - From medical tradition to traditional medicine: A Tibetan formula in the European framework. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The increasing prevalence of complex multi factorial chronic diseases and multimorbidity reveals the need for an enlargement of the therapeutic options. Potent multicompound herbal formulations from traditional medicine systems such as Tibetan Medicine might meet the requirements. With its practice over the centuries Tibetan Medicine is one of the important medical heritages of the world. In the 20th century Tibetan formulas came to Switzerland, where the formula Gabur-25 was then registered as medicine in 1977 (Padma 28, Swissmedic No 35872). The new European directive 2004/24/EC opened the avenue for traditional herbal medicinal products and registrations followed in Austria (HERB-00037) and the UK (39568/0001). The aim of this review was to analyse not only the critical points and hazards but also chances that occur in the endeavour of bringing a ethnopharmacological based preparation to the market within a modern Western medical and regulatory framework and to discuss the necessary transformation steps from a traditional herbal formula towards a modern pharmaceutical product with the example of the Tibetan formula Gabur-25. METHODS: The historic transformation process from the 19th to the 21st century is analysed, using the registration documents and other material from the library of Padma AG, Hinwil, Switzerland. RESULTS: The transformation of a traditional formula into a modern traditional herbal medicinal product according to the present EU regulations is a multi faceted process. The modern indication represents only a small part of the possible traditional indications. Quality and product labelling has to be adopted to modern standards. The formula, once registered, is a fixed combination of herbal and mineral ingredients. Contrary to this the concept of Asian medical tradition allows a certain flexibility in the composition of an herbal formula. The ingredients are constantly adapted to local conditions, availability of raw material and therapeutic situation. CONCLUSIONS: The example shows that in principle complex herbal formulas from Asian medicine can meet the requirements of the European regime of traditional herbal medicinal products. A structured process of transformation from a traditional herbal formula to a modern medicinal product has to include selection of a suitable formula, development of an analytic concept and selection of a suitable indication with regard to the empirical set of possible indications. To extend the range of high quality medicinal products from other medical traditions within the European context the European legislators have to re-evaluate the imposed restrictions given in directive 2004/24/EC. Without amendment of the prerequisite of 15 years documented use in the EU and the limitation of indications for traditional herbal medicinal products, European citizens will be excluded from access to high quality medical traditions with their accumulated empirical knowledge. PMID- 25446637 TI - The search for plants with anticancer activity: pitfalls at the early stages. AB - Inhibition assays on tumour cells in vitro are commonly used to confirm the activity of extracts, fractions and compounds from plants reported to be antitumoural. The majority of assays report the IC50 (50% inhibitory concentration), whereas others distinguish between inhibition of cell proliferation (cytostasis) and cell death (cytotoxicity). Here, we offer some suggestions as to the different types of assay, the cell lines that may be used, control cells and drugs, as well as the interpretation of the results. Using both theoretical considerations and experimental data, we specifically question the frequent overinterpretation of reported results regarding the selectivity for cancer cells of the plant extract or compound under study, concluding that this "selectivity" is due to a quantitative difference in cell proliferation rates, rather than a qualitative difference between normal and tumour cells. Inhibition assays will always represent one of the first steps in the discovery of clinically valuable new drugs, but these assays do not allow us to conclude that we have found the "magic bullet". PMID- 25446638 TI - An ethnopharmacological survey and in vitro confirmation of the ethnopharmacological use of medicinal plants as anthelmintic remedies in the Ashanti region, in the central part of Ghana. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Infections with helminths are still a big problem in many parts of the world. The majority of the people in West Africa treat such infections with medicinal plants related to the local traditional medicine. The present study aims at identifying medicinal plants traditionally used for worm infections in the Ashanti region, Ghana. In vitro screening of selected extracts from plants on which scientific knowledge is limited was to be performed. MATERIALS AND METHODS: Validated questionnaires were administered to 50 traditional healers in the Ashanti region, Ghana. Interviews and structured conversations were used to obtain relevant information. Quantitative and qualitative evaluation was performed additionally to structured cross-referencing of the data using SciFinder((r)) data base. Selected plant species were used for in vitro testing on anthelmintic activity against the free-living model nematode Caenorhabditis elegans. RESULTS: 35 plant species were recorded for the use in humans and 6 for the use in animals. Plant material most frequently used were the seeds from Carica papaya, mentioned by nearly all healers. The plausibility of most plants used for treatment of infections with helminths was given in most cases by documentation of potential anthelmintic activity in recent scientific literature. 9 species from plants not or scarcely described in literature for this indication were investigated on in vitro activity. A hydroethanolic (1:1) extract of Combretum mucronatum was most active with a survival rate of nematodes of 89% at 0.1mg/mL and 58% at 1mg/mL respectively (levamisole 16%). Extracts of Paullinia pinnata and Phyllanthus urinaria were also assessed to exhibit a minor (85% and 89% respectively at 1mg/mL), but still significant activity. CONCLUSION: Traditional use of anthelmintic plants from Ghana can be well rationalized by cross-referencing with published literature and phytochemical/pharmacological plausibility.The in vitro investigations of extracts from Combretum mucronatum, Paullinia pinnata and Phyllanthus urinaria exhibited significant effects against nematodes. The anthelmintic activity of these plants should be investigated in detail for pinpointing the respective lead structures responsible for the activity. PMID- 25446639 TI - Evaluation of antinociceptive and anti-inflammatory activities of standardised rootbark extract of Xeromphis nilotica. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Xeromphis nilotica (Stapf) Keay (Rubiaceae), popularly known as 'barbaji' (in Nigeria), is a lowland shrub that grows wild in tropical areas of Africa and Asia. The plant's extract is used for the treatment of various diseases in folk medicine including pain related ailments. Important bioactive constituents have been isolated from the plant among them are coumarin, alkaloids, flavonoids, saponins, and terpenes. This study is aimed to evaluate the analgesic and anti-inflammatory efficacy of standardised aqueous extract of the plant using in vivo models of pain and inflammation in mice and rats. MATERIALS AND METHODS: Aqueous extract of Xeromphis nilotica root bark was prepared and standardised using HPLC technique. Three dose levels (25, 100 and 400mg/kg) of the extract were used, administered orally to laboratory mice and rats. Acetylsalicylic acid (100mg/kg, p.o.) was used as the positive control. Nociception was induced in laboratory rodents: chemically using acetic acid and formalin, and mechanically using analgesy meter; while inflammation was induced using fresh raw egg albumin. RESULTS: The extract showed 11 constituents peak profiles in the HPLC analysis. The extract alleviates mice response to acetic acid-induced writhing, analgesy-meter and formalin tests. It significantly decreased the oedema induced by egg albumin induced inflammation, but failed to show significant effect beyond 80min of the test. CONCLUSION: The extract has antinociceptive effect and short acting anti-inflammatory activities. The results justify its usage in the treatment of pain and inflammatory conditions, and also provided evidence of its potential as source of new pain relief drug prototype. PMID- 25446640 TI - Evaluation of the impact of Polygonum capitatum, a traditional Chinese herbal medicine, on rat hepatic cytochrome P450 enzymes by using a cocktail of probe drugs. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum capitatum is a well-known Miao medicinal plant that has been used for many years for its unique therapeutic effects on various urological disorders, including urinary calculus and urinary tract infections. To investigate the effect of Polygonum capitatum on cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4) in vivo using a "cocktail" approach by administering five probe drugs to rats. This study assessed the potential of Polygonum capitatum to interact with co-administered drugs. MATERIALS AND METHODS: An aqueous extract of dried whole Polygonum capitatum was prepared and administered orally to rats at a dose of 0.58g/kg or 1.74g/kg twice daily for 7 or 14 consecutive days. A cocktail of caffeine (1.0mg/kg), tolbutamide (1.0mg/kg), omeprazole (2.0mg/kg), chlorzoxazone (4.0mg/kg) and midazolam (4.0mg/kg) was then administered on the eighth or fifteenth day to evaluate the effects of Polygonum capitatum on CYP1A2, 2C9, 2C19, 2E1, and 3A4, respectively. Blood samples were collected at a range of time points and the plasma concentrations of the probe drugs were simultaneously quantified using ultra high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated to evaluate the effects of Polygonum capitatum on the activities of these CYP enzymes in rats. RESULTS: Polygonum capitatum pre-treatment had no significant effect on the pharmacokinetic parameters of caffeine, omeprazole or chlorzoxazone. However, the pharmacokinetics of tolbutamide and midazolam were affected significantly (P<0.05) by Polygonum capitatum, which induced more rapid metabolism of these probe compounds. CONCLUSIONS: These results suggested that Polygonum capitatum could induce CYP2C9 and CYP3A4, and did not influence CYP1A2, CYP2C19 or CYP2E1. Therefore, the clinical dose of drugs metabolized by human CYP2C9 or CYP3A4 may need to be adjusted in patients taking Polygonum capitatum, as this herbal medication may result in reduced effective concentrations of these drugs. PMID- 25446641 TI - Protective effects of the active fraction from the tuber of Scirpus yagara in mouse endotoxin shock model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Scirpus yagara Ohwi is a perennial, aquatic plant, whose dry tubers have long been used as Traditional Chinese Medicine (TCM) "Sanleng" for the treatment of postpartum abdominal pain, hyperemesis gravidarum, amenorrhea, dyspepsia and several inflammatory related diseases. Although it is known to have anti-inflammatory activities, its mechanism of action on lipopolysaccharide (LPS)-induced inflammation has not yet been identified in detail.This study was designed to investigate the anti-inflammatory activity of the active fraction (AF) from the tuber of Scirpusyagara both in vitro and in vivo. MATERIALS AND METHODS: RAW264.7 macrophage was incubated for 16h with 1ug/ml of LPS in absence or presence of AF (0, 10, 50 and 100ug/ml) and the secretions of tumor necrosis-alpha (TNF-alpha) and interleukin-6 (IL-6) in the medium were determined by using an enzyme-linked immunosorbent assay (ELISA). In the in vivo study, mice were orally administrated with AF (50 and 300mg/kg) for three days consecutively. 1h after the last AF administration, the mice were intraperitoneally injected with LPS (15mg/kg), and the life span of LPS challenged mice were determined. Furthermore, the levels of pro-inflammatory cytokines TNF-alpha and IL-6 in the serum, lung and liver were measured using ELISA kit, and histological change in lungs was examined by light microscopy. Additionally, the components of AF were analyzed by high performance liquid chromatography (HPLC) using a C18 column. RESULTS: AF significantly decreased TNF alpha and IL-6 production induced by LPS in RAW264.7 macrophage. In LPS-induced mouse endotoxin shock model, AF pre-treatment significantly improved the survival rate of mice. And LPS-induced increases of pro-inflammatory cytokines TNF-alpha and IL-6 in the serum, lung and liver were markedly suppressed by AF. Moreover, the histopathological examination indicated that AF could significantly attenuate lung tissues injury in endotoxemic mice. In addition, eight compounds (protocatechuic acid, vanillic acid, p-coumaric acid, ferulic acid, methyl-3,6 dihydroxy-2-[2-(2-hydroxyphenyl)-ethynyl] benzoate, sciryagarol I, sparstolonin B, SanLeng diphenyllactone) of AF were quantified by HPLC analysis. CONCLUSIONS: These results suggested that AF protected mice against LPS-induced lethality by inhibiting the production of multiple cytokines and organ dysfunction. Thus AF may prove beneficial in the prevention and treatment of endotoxin shock. PMID- 25446642 TI - Effect of repeated alcohol exposure during the third trimester-equivalent on messenger RNA levels for interleukin-1beta, chemokine (C-C motif) ligand 2, and interleukin 10 in the developing rat brain after injection of lipopolysaccharide. AB - Microglia undergo maturation during the third trimester of human development (equivalent to the first 1-2 weeks of postnatal life in rodents), during which these cells may be particularly sensitive to insult. Alcohol exposure during this period can activate the neuroimmune system, an effect that may contribute to the pathophysiology of fetal alcohol spectrum disorders. Here, we investigated whether repeated alcohol exposure during the third trimester-equivalent in rats has a priming effect on the neuroimmune response to injection of bacterial lipopolysaccharide (LPS). Pups were exposed to alcohol in vapor chambers for 4 h daily from postnatal day (PD)2 to PD16 (peak blood alcohol concentrations ~150 mg/dL). On PD17, rats were injected with either saline or LPS (50 MUg/kg) and the frontal cortex, cerebellar vermis, and dentate gyrus were collected 2 h later. Messenger RNA (mRNA) levels for the pro-inflammatory agents interleukin 1beta (IL 1beta) and chemokine (C-C) motif ligand 2 (CCL2), as well as levels of the anti inflammatory cytokine interleukin 10 (IL-10), were measured using reverse transcriptase polymerase chain reaction. LPS consistently increased IL-1beta and CCL2 mRNA levels in the dentate gyrus, frontal cortex, and cerebellum of both male and female rats. Furthermore, the LPS-induced increase of IL-1beta mRNA levels was significantly blunted in the frontal cortex of alcohol-exposed female rats. Conversely, LPS only minimally affected IL-10 mRNA expression and there were no significant differences between air- and alcohol-exposed rats. Taken together with the literature regarding the effect of third-trimester alcohol exposure on the neuroimmune system, our findings suggest that chronic exposure to lower levels is less disruptive to the neuroimmune system than binge-like exposure to high doses of alcohol. PMID- 25446643 TI - Restraint stress exacerbates alcohol-induced reproductive toxicity in male rats. AB - Cumulative exposure to multiple stresses may lead to aggravating the toxicity of each stress, qualitatively or quantitatively altering biological responses because of toxicological interaction. In this study, we intended to determine the possible effects of restraint stress on reproductive toxicity due to ethanol usage in male rats. Early pubertal male Wistar rats were subjected to either restraint stress (5 h/day) or alcohol intoxication (2 mg/kg body weight) or both for 60 days. Body weights of control and experimental rats were similar during the 60 days of this study. Testes were harvested, weighed, and prepared for enzyme assays, and cauda epididymides were isolated for the determination of density, motility, and viability of stored spermatozoa. Restraint stress or alcohol treatment significantly reduced testis weight and caused significant reductions in steroidogenesis and spermatogenesis. Mean density, motility, and viability of stored spermatozoa were reduced in experimental rats. Plasma testosterone concentrations in rats subjected to restraint stress or alcohol were decreased compared with those of controls, concomitant with increased concentrations of LH and FSH in experimental rats. These data suggest that sub chronic exposure to restraint stress or alcohol contribute to reduce testicular and epididymal function in exposed rats. The study also suggests that restraint stress exacerbates alcohol-induced reproductive toxicity in rats. PMID- 25446648 TI - Higher circulating leukocytes in women with PCOS is reversed by aerobic exercise. AB - Polycystic ovary syndrome (PCOS) is characterized by insulin resistance, elevated circulating leukocytes, and hypothesized to have higher adipose tissue inflammation. Aerobic exercise reduces circulating leukocytes and improves insulin sensitivity in obese individuals, but the effect of exercise on inflammation in PCOS is not known. We investigated circulating leukocytes, insulin sensitivity by euglycemic-hyperinsulinemic clamp, serum pro- and anti inflammatory markers (hsCRP, TNF-alpha, total and high molecular weight adiponectin), and abdominal subcutaneous adipose tissue (SAT) gene expression of proinflammatory markers in 8 PCOS women and 8 obese control females matched for BMI. Additionally, in a prospective study, the 8 women with PCOS underwent a 16 week aerobic exercise regimen with the same measures performed post-intervention. Compared to controls, white blood cell counts (WBC) were 30% higher (p = 0.04) and circulating total adiponectin levels were 150% lower (p = 0.03) in women with PCOS at baseline/pre-exercise conditions. SAT gene expression of macrophage migration inhibitory factor (MIF, p < 0.01) and interleukin-6 (IL-6, p < 0.05) were also lower in women with PCOS. In response to 16 weeks of aerobic exercise, insulin sensitivity improved (p < 0.01) and WBC counts decreased (p = 0.02). The exercise-induced change in WBC and circulating neutrophils correlated inversely with changes in glucose disposal rate (r = -0.73, p = 0.03; and r = -0.82, p = 0.01, respectively). Aerobic exercise reduced serum leptin (p < 0.05) after 4 weeks, trended to reduce the ratio of leptin-to-high molecular weight adiponectin (p < 0.1) by the 8th week, and significantly increased serum dehydroepiandrosterone sulfate (DHEA-S, p < 0.001) after 16 weeks. In conclusion, women with PCOS have higher circulating leukocytes compared to controls, which can be reversed by aerobic exercise and is associated with improvements in insulin sensitivity. PMID- 25446651 TI - Replication and re-replication: Different implications of the same mechanism. AB - Replication is a process which provides two copies of genetic material to a mother cell that are essential for passing complete genetic information to daughter cells. Despite the extremely precise control of this process, regulation of replication can be impaired. This may trigger e.g. re-replication which leads to an increase in the total DNA content in a cell and, depending on the intensity, may result in gene amplification, genomic instability or apoptosis. Both replication and re-replication require pre-replication complex assembly, licensing, firing and initiation of DNA synthesis. Implications of each process in a cell are very different and all such possibilities are under intensive research because in both processes the same protein apparatus is used to carry out DNA synthesis. Therefore this article is meant to show the consequences of the same mechanism underlying two different processes. PMID- 25446650 TI - Regulation of the human Suv3 helicase on DNA by inorganic cofactors. AB - Mitochondria are essential organelles and consequently proper expression and maintenance of the mitochondrial genome are indispensable for proper cell function. The mitochondrial Suv3 (SUPV3L1) helicase is known to have a central role in mitochondrial RNA metabolism and to be essential for maintenance of mitochondrial DNA stability. Here we have performed biochemical investigations to determine the potential regulation of the human Suv3 (hSuv3) helicase function by inorganic cofactors. We find that hSuv3 helicase and ATPase activity in vitro is strictly dependent on the presence of specific divalent cations. Interestingly, we show that divalent cations and nucleotide concentration have a direct effect on helicase substrate stability. Also, hSuv3 helicase is able to utilize several different nucleotide cofactors including both NTPs and dNTPs. Intriguingly, the potency of the individual nucleotide as energy source for hSuv3 unwinding differed depending on the included divalent cation and nucleotide concentration. At low concentrations, all four NTPs could support helicase activity with varying effectiveness depending on the included divalent cation. However, at higher nucleotide concentrations, only ATP was able to elicit the helicase activity of hSuv3. Consequently, we speculate that the capacity of hSuv3 DNA unwinding activity might be sensitive to the local availability of specific inorganic cofactors. PMID- 25446652 TI - H2 and H3 relaxin inhibit high glucose-induced apoptosis in neonatal rat ventricular myocytes. AB - High concentrations of glucose induce cardiomyocyte apoptosis, and contribute to diabetic cardiomyopathy. Relaxin-2 and relaxin-3 are two members of the relaxin peptide family that are cardioprotective. However, it remains unknown whether relaxin-2 or relaxin-3 can regulate apoptosis in high glucose treated-neonatal rat ventricular myocytes (NRVMs). In cultured NRVMs, 33 mmol/l high glucose (HG) increased apoptosis in a time-dependent manner. HG-increased the protein expression of cleaved caspase-8 and -9, two initiators of the extrinsic and intrinsic pathways of apoptosis, Caspase-3 was attenuated by human recombinant relaxin-2 (H2 relaxin) or relaxin-3 (H3 relaxin), indicating that H2 and H3 relaxin inhibited HG-induced apoptosis. Furthermore, endoplasmic reticulum stress (ERS) markers CHOP and caspase-12 were markedly increased in HG-treated NRVMs, leading to apoptosis; this effect was also effectively attenuated by H2 relaxin or H3 relaxin. Treatment of NRVMs with HG reduced autophagy which cannot be adjusted by H2 relaxin or H3 relaxin. In conclusion, HG-induced apoptosis in NRVMs was mediated, in part, by the activation of the extrinsic and intrinsic pathways of apoptosis and ERS, all inhibited by H2 relaxin or H3 relaxin. PMID- 25446653 TI - Quaternary structure of human small heat shock protein HSPB6 (Hsp20) in crowded media modeled by trimethylamine N-oxide (TMAO): Effect of protein phosphorylation. AB - Effect of trimethylamine N-oxide (TMAO), well-known osmolyte, widely used to imitate crowded intracellular conditions, on the quaternary structure of recombinant human small heat shock protein HspB6 (Hsp20) was analyzed by means of size-exclusion chromatography, chemical crosslinking and analytical ultracentrifugation. Consistent with previous reports, in the absence of TMAO unphosphorylated, pseudophosphorylated (S16D mutant) and phosphorylated HspB6 form only small oligomers (presumably dimers). Addition of TMAO to unphosphorylated HspB6 leads to formation of different large oligomers being in equilibrium with dimers. Pseudophosphorylation (S16D mutation) or phosphorylation partially or completely prevent TMAO-induced oligomerization of HspB6. Pseudophosphorylation affects bis-ANS binding suggesting decreased hydrophobicity of HspB6. According to size-exclusion chromatography, TMAO-induced changes of HspB6 oligomerization result in its altered interaction with HspB1 and this effect can be reversed by HspB6 phosphorylation. It is concluded that under conditions of molecular crowding, characteristic for intracellular environment, HspB6 undergoes reversible changes of its oligomeric state which can affect its physiologically important properties and can be delicately regulated by phosphorylation. PMID- 25446649 TI - NMD: At the crossroads between translation termination and ribosome recycling. AB - Nonsense-mediated mRNA decay (NMD) is one of three regulatory mechanisms that monitor the cytoplasm for aberrant mRNAs. NMD is usually triggered by premature translation termination codons that arise from mutations, transcription errors, or inefficient splicing, but which also occur in transcripts with alternately spliced isoforms or upstream open reading frames, or in the context of long 3' UTRs. This surveillance pathway requires detection of the nonsense codon by the eukaryotic release factors (eRF1 and eRF3) and the activities of the Upf proteins, but the exact mechanism by which a nonsense codon is recognized as premature, and the individual roles of the Upf proteins, are poorly understood. In this review, we highlight important differences between premature and normal termination. Based on our current understanding of normal termination and ribosome recycling, we propose a similar mechanism for premature termination events that includes a role for the Upf proteins. In this model, the Upf proteins not only target the mRNA and nascent peptide for degradation, but also assume the role of recycling factors and rescue a ribosome stalled at a premature nonsense codon. The ATPase and helicase activities of Upf1, with the help of Upf2 and Upf3, are thus thought to be the catalytic force in ribosome subunit dissociation and ribosome recycling at an otherwise poorly dissociable termination event. While this model is somewhat speculative, it provides a unified vision for current data and a direction for future research. PMID- 25446654 TI - Identification and optimization of a novel thermo- and solvent stable ketol-acid reductoisomerase for cell free isobutanol biosynthesis. AB - Due to its enhanced energy content and hydrophobicity, isobutanol is flagged as a next generation biofuel and chemical building block. For cellular and cell-free isobutanol production, NADH dependent (over NADPH dependent) enzyme systems are desired. To improve cell-free isobutanol processes, we characterized and catalytically optimized a NADH dependent, thermo- and solvent stable ketol-acid reductoisomerase (KARI) derived from the bacterium Meiothermus ruber (Mr). The wild type Mr-KARI has the most temperature tolerant KARI specific activity reported to date. The KARI screening procedure developed in this study allows accelerated molecular optimization. Thus, a KARI variant with a 350% improved activity and enhanced NADH cofactor specificity was identified. Other KARI variants gave insights into Mr-KARI structure-function relationships. PMID- 25446656 TI - Fsn0503h antibody-mediated blockade of cathepsin S as a potential therapeutic strategy for the treatment of solid tumors. AB - Degradation of extracellular matrix components is a key step in tumor progression, facilitating invasion, angiogenesis, and metastasis. The lysosomal cysteine protease cathepsin S (Cat-S) is a prominent player in this process. We evaluated the antitumor activity of Fsn0503h, the first Cat-S-antagonistic humanized monoclonal antibody, in a panel of cancer cell lines and in human colon carcinoma xenografts. Cat-S was expressed in 11 out of 36 solid tumor-derived cell lines. Fsn0503h significantly reduced the invasive capacity of all Cat-S expressing cell lines in vitro. This was confirmed by the Cat-S small-molecule inhibitor Z-FL-COCHO, validating the importance of this protease in tumor cell invasiveness. Interestingly, Fsn0503h displayed antiproliferative effects in Cat S positive and some Cat-S-negative cell lines. We provide the first demonstration of in vivo activity of Fsn0503h against a colorectal tumor xenograft model, with a 10 mg/kg three times a week intravenous schedule being optimal. In conclusion, Fsn0503h not only inhibited the invasiveness of cancer cells in vitro, but also exerted antitumor effects both in vitro and in vivo. These findings validate Cat S as a therapeutic target, and support the development of Fsn0503h for the therapy of solid tumors. PMID- 25446655 TI - Bisbenzimidazole derivatives as potent inhibitors of the trypsin-like sites of the immunoproteasome core particle. AB - In this study, a monomeric (MB) and a dimeric (DB) bisbenzimidazoles were identified as novel proteasome inhibitors of the trypsin-like activity located on beta2c sites of the constitutive 20S proteasome (IC50 values at 2-4 MUM range). Remarkably, they were further shown to be 100- and 200-fold more potent inhibitors of the immunoproteasome trypsin-like activity (beta2i sites, IC50=24 nM) than of the homologous constitutive activity. Molecular models of inhibitor/enzyme complexes in the two types of trypsin-like sites and corresponding computed binding energy values corroborated kinetic data. Different binding modes were suggested for MB and DB to the beta2c and beta2i trypsic sites. Each pointed to better contacts of the ligand inside the beta2i active site than for beta2c site. MB and DB represent the first selective inhibitors of the immunoproteasome trypsin-like activity described to date and can be considered as prototypes for inhibiting this activity. PMID- 25446657 TI - Economic hardship and suicide mortality in Finland, 1875-2010. AB - We investigate the determinants of suicide in Finland using annual data for consumption and suicides from 1860 to 2010. Instead of using some ad hoc measures of cyclical movements of the economy, we build our analysis on a more solid economic theory. A key feature is the habit persistence in preferences, which provides a way to measure individual well-being and predict suicide. We estimate time series of habit levels and develop an indicator (the hardship index) to describe the economic hardship of consumers. The higher the level of the index, the worse off consumers are. As a rational response to such a bad situation, some consumers might commit suicide. We employ the autoregressive distributed lags cointegration method and find that our index works well in explaining the long term behavior of people committing suicide in Finland. PMID- 25446658 TI - Ultrasound predictors of placental invasion: the Placenta Accreta Index. AB - OBJECTIVE: We sought to apply a standardized evaluation of ultrasound parameters for the prediction of placental invasion in a high-risk population. STUDY DESIGN: This was a retrospective review of gravidas with >=1 prior cesarean delivery who received an ultrasound diagnosis of placenta previa or low-lying placenta in the third trimester at our institution from 1997 through 2011. Sonographic images were reviewed by an investigator blinded to pregnancy outcome and sonography reports. Parameters assessed included loss of retroplacental clear zone, irregularity and width of uterine-bladder interface, smallest myometrial thickness, presence of lacunar spaces, and bridging vessels. Diagnosis of placental invasion was based on histologic confirmation. Statistical analyses were performed using linear logistic regression and multiparametric analyses to generate a predictive equation evaluated using a receiver operating characteristic curve. RESULTS: Of 184 gravidas who met inclusion criteria, 54 (29%) had invasion confirmed on hysterectomy specimen. All sonographic parameters were associated with placental invasion (P < .001). Constructing a receiver operating characteristic curve, the combination of smallest sagittal myometrial thickness, lacunae, and bridging vessels, in addition to number of cesarean deliveries and placental location, yielded an area under the curve of 0.87 (95% confidence interval, 0.80-0.95). Using logistic regression, a predictive equation was generated, termed the "Placenta Accreta Index." Each parameter was weighted to create a 9-point scale in which a score of 0-9 provided a probability of invasion that ranged from 2-96%, respectively. CONCLUSION: Assignment of the Placenta Accreta Index may be helpful in predicting individual patient risk for morbidly adherent placenta. PMID- 25446659 TI - Management of fetal malposition in the second stage of labor: a propensity score analysis. AB - OBJECTIVE: We sought to determine the factors associated with selection of rotational instrumental vs cesarean delivery to manage persistent fetal malposition, and to assess differences in adverse neonatal and maternal outcomes following delivery by rotational instruments vs cesarean delivery. STUDY DESIGN: We conducted a retrospective cohort study over a 5-year period in a tertiary United Kingdom obstetrics center. In all, 868 women with vertex-presenting, single, liveborn infants at term with persistent malposition in the second stage of labor were included. Propensity score stratification was used to control for selection bias: the possibility that obstetricians may systematically select more difficult cases for cesarean delivery. Linear and logistic regression models were used to compare maternal and neonatal outcomes for delivery by rotational forceps or ventouse vs cesarean delivery, adjusting for propensity scores. RESULTS: Increased likelihood of rotational instrumental delivery was associated with lower maternal age (odds ratio [OR], 0.95; P < .01), lower body mass index (OR, 0.94; P < .001), lower birthweight (OR, 0.95; P < .01), no evidence of fetal compromise at the time of delivery (OR, 0.31; P < .001), delivery during the daytime (OR, 1.45; P < .05), and delivery by a more experienced obstetrician (OR, 7.21; P < .001). Following propensity score stratification, there was no difference by delivery method in the rates of delayed neonatal respiration, reported critical incidents, or low fetal arterial pH. Maternal blood loss was higher in the cesarean group (295.8 +/- 48 mL, P < .001). CONCLUSION: Rotational instrumental delivery is often regarded as unsafe. However, we find that neonatal outcomes are no worse once selection bias is accounted for, and that the likelihood of severe obstetric hemorrhage is reduced. More widespread training of obstetricians in rotational instrumental delivery should be considered, particularly in light of rising cesarean delivery rates. PMID- 25446660 TI - Perinatal outcomes among women with bipolar disorder: a population-based cohort study. AB - OBJECTIVE: To evaluate the risk of adverse perinatal outcomes among pregnant women previously hospitalized for bipolar disorder. STUDY DESIGN: We completed a population-based cohort study of women with a singleton delivery in Ontario, Canada (2003 to 2011). Women previously hospitalized for bipolar disorder (n = 1859) or major depressive disorder (n = 3724) were each compared to women without a documented mental illness (n = 432,358). Main study outcomes were preterm birth, severe small for gestational age <3rd percentile birthweight, and severe large for gestational age >97th percentile birthweight. Secondary outcomes included stillbirth, congenital malformations, neonatal morbidity and readmission to hospital <28 days. Odds ratios (ORs) were adjusted for maternal age, parity, prepregnancy obesity, substance use, and diabetes mellitus or hypertension before or during pregnancy. RESULTS: Bipolar disorder (adjusted OR [AOR], 1.95; 95% confidence interval [CI], 1.68-2.26) and major depressive disorder (AOR, 1.91; 95% CI, 1.72-2.13) were each associated with preterm birth. Bipolar disorder was associated with severe large for gestational age (AOR, 1.31; 95% CI, 1.03-1.67). Major depressive disorder was associated with severe small for gestational age (AOR, 1.22; 95% CI, 1.05-1.42). Both mood disorder groups had significantly higher risk of congenital malformations, neonatal morbidity, and neonatal hospital readmission. Although study covariates explained some of the increased risk, we could not address all potential explanatory factors. CONCLUSION: Women previously hospitalized for bipolar disorder are at increased risk of adverse perinatal outcomes compared with the general population. Their level of risk is comparable to women previously hospitalized for major depressive disorder. These risks must be considered in the management of pregnant women with a history of major mood disorders. Attention to potentially modifiable risk factors such as obesity, diabetes, and hypertension before and during pregnancy could reduce the risk for adverse perinatal outcomes. PMID- 25446661 TI - Perinatal risks of planned home births in the United States. AB - OBJECTIVE: We analyzed the perinatal risks of midwife-attended planned home births in the United States from 2010 through 2012 and compared them with recommendations from the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) for planned home births. STUDY DESIGN: Data from the US Centers for Disease Control and Prevention's National Center for Health Statistics birth certificate data files from 2010 through 2012 were utilized to analyze the frequency of certain perinatal risk factors that were associated with planned midwife-attended home births in the United States and compare them with deliveries performed in the hospital by certified nurse midwives. Home birth deliveries attended by others were excluded; only planned home births attended by midwives were included. Hospital deliveries attended by certified nurse midwives served as the reference. Perinatal risk factors were those established by ACOG and AAP. RESULTS: Midwife-attended planned home births in the United States had the following risk factors: breech presentation, 0.74% (odds ratio [OR], 3.19; 95% confidence interval [CI], 2.87 3.56); prior cesarean delivery, 4.4% (OR, 2.08; 95% CI, 2.0-2.17); twins, 0.64% (OR, 2.06; 95% CI, 1.84-2.31); and gestational age 41 weeks or longer, 28.19% (OR, 1.71; 95% CI, 1.68-1.74). All 4 perinatal risk factors were significantly higher among midwife-attended planned home births when compared with certified nurse midwives-attended hospital births, and 3 of 4 perinatal risk factors were significantly higher in planned home births attended by non-American Midwifery Certification Board (AMCB)-certified midwives (other midwives) when compared with home births attended by certified nurse midwives. Among midwife-attended planned home births, 65.7% of midwives did not meet the ACOG and AAP recommendations for certification by the American Midwifery Certification Board. CONCLUSION: At least 30% of midwife-attended planned home births are not low risk and not within clinical criteria set by ACOG and AAP, and 65.7% of planned home births in the United States are attended by non-AMCB certified midwives, even though both AAP and ACOG state that only AMCB-certified midwives should attend home births. PMID- 25446662 TI - Mode of delivery preferences in a diverse population of pregnant women. AB - OBJECTIVE: The objective of the study was to assess women's preferences for vaginal vs cesarean delivery in 4 contexts: prior cesarean delivery, twins, breech presentation, and absent indication for cesarean. STUDY DESIGN: This was a cross-sectional study of pregnant women at 24-40 weeks' gestation. After assessing stated preferences for vaginal or cesarean delivery, we used the standard gamble metric to measure the strength of these preferences and the time tradeoff metric to determine how women value the potential processes and outcomes associated with these 2 delivery approaches. RESULTS: Among the 240 participants, 90.8% had a stated preference for vaginal delivery. Across the 4 contexts, these women indicated that, on average, they would accept a 59-75% chance of an attempted vaginal birth ending in a cesarean delivery before choosing a planned cesarean delivery, indicating strong preferences for spontaneous, uncomplicated vaginal delivery. Variations in preferences for labor processes emerged. Although uncomplicated labor ending in vaginal birth was assigned mean utilities of 0.993 or higher (on a 0-1 scale, with higher scores indicating more preferred outcomes), the need for oxytocin, antibiotics, or operative vaginal delivery resulted in lower mean scores, comparable with those assigned to uncomplicated cesarean delivery. Substantially lower scores (ranging from 0.432 to 0.598) were obtained for scenarios ending in severe maternal or neonatal morbidity. CONCLUSION: Although most women expressed strong preferences for vaginal delivery, their preferences regarding interventions frequently used to achieve that goal varied. These data underscore the importance of educating patients about the process of labor and delivery to facilitate incorporation of informed patient preferences in shared decision making regarding delivery approach. PMID- 25446663 TI - Trends in management of pelvic organ prolapse among female Medicare beneficiaries. AB - OBJECTIVE: In the last decade, many new surgical treatments have been developed to achieve less-invasive approaches to prolapse management. However, limited data exist on how the patterns of care for women with pelvic organ prolapse (POP) may have changed over the last decade, and whether mesh implantation techniques have influenced the type of specific compartment repair performed. We used a national data set to analyze the temporal trends in patterns of care for women with POP. STUDY DESIGN: Data were obtained from Public Use Files from the Centers for Medicare and Medicaid Services for a 5% random sample of national beneficiaries with an International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis of POP from 1999 through 2009. Current Procedural Terminology, 4th Edition and International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes were used to evaluate nonsurgical and surgical management trends for this cohort. Types of surgery were categorized by prolapse compartment and combinations of repairs. After 2005, when applicable codes became available, mesh or graft repairs were also analyzed. RESULTS: Over the study time period, the number of women with a diagnosis of POP in any 1 year in our 5% sample of Medicare beneficiaries remained relatively stable (range, 21,245-23,268 per year). Rates of pessary insertion were also consistent at 11 13% over the study period. Of the women with a prolapse diagnosis, 14-15% underwent surgical repair, and there was little change over time in surgical management patterns based on compartment. Most commonly, multiple compartments were repaired simultaneously. There was a rapid increase in mesh use such that in 2009, 41% of all women who underwent surgery (5.8% of the total cohort) had mesh or graft inserted in their repair. Hysterectomy rates for prolapse decreased over time. Rates of vault suspension at the time of hysterectomy for prolapse were low; however, they showed a relative increase over time (22% in 1999 to 26% in 2009). CONCLUSION: Patterns and rates of prolapse repairs remained relatively unchanged from 1999 through 2009, with an exception of a rapid rise in mesh use. These data suggest that the majority of mesh techniques were used for augmentation purposes only, but did not result in an increase in apical repairs performed in the United States. There remains a disappointingly low rate of vault suspension repairs concomitantly at time of hysterectomy for POP. PMID- 25446665 TI - Provision of specific preconception care messages and associated maternal health behaviors before and during pregnancy. AB - OBJECTIVE: The purpose of this study was to examine the associations between receipt of specific preconception care messages before pregnancy and maternal behaviors before and during pregnancy. STUDY DESIGN: Data were from the Pregnancy Risk Assessment Monitoring System 2009-2010. Only women who reported receiving general preconception care were asked questions about specific health messages that they received before pregnancy (32.2% of the total sample; N = 10,267). Preconception care messages that were received and corresponding behaviors that were examined included taking vitamins with folic acid before pregnancy, dieting to lose weight or exercising before pregnancy (for women who were overweight or obese before pregnancy), and smoking and drinking alcohol during pregnancy (for women who reported smoking or alcohol use in the past 2 years). Separate weighted multivariable logistic regression models were used to assess the association between receipt of specific preconception care messages and maternal behaviors before and during pregnancy. RESULTS: Women who reported receiving the message about taking vitamins with folic acid before pregnancy reported taking vitamins more often in the month before pregnancy compared with women who did not receive the message (77% vs 40%; P < .01; adjusted odds ratio [aOR], 2.99; 95% confidence interval [CI], 2.24-4.00). Among overweight and obese women, there was no difference in dieting or exercising between those who received the message about maintaining a healthy weight before pregnancy and those who did not (dieting: 41% vs 39% [P = .58; aOR, 1.06; 95% CI, 0.77-1.47]; exercising: 43% vs 40% [P = .42; aOR, 1.10; 95% CI, 0.81-1.51]). Among smokers, women who received the message regarding smoking during pregnancy smoked more often during the last 3 months of pregnancy than women who did not receive the message (47% vs 27%; P < .01; aOR, 2.22; 95% CI, 1.21-4.09). Among drinkers, the same percentage of women who did and did not receive the message about alcohol use during pregnancy drank in the last 3 months of pregnancy (13% vs 13%; P = .86; aOR, 0.95; 95% CI, 0.65-1.38). CONCLUSION: Our study found that counseling on folic acid was associated with greater vitamin use, although counseling on dieting, exercising, drinking, and smoking among women who were at high risk was not associated with behaviors before or during pregnancy. PMID- 25446666 TI - Home birth study fails to identify credentials of midwives conducting home birth. PMID- 25446664 TI - Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models. AB - OBJECTIVE: There is increasing preclinical evidence indicating that metformin, a medication commonly used for type 2 diabetes mellitus, may protect against cancer. Motivated by this emerging evidence we asked 2 questions: (1) can metformin prevent ovarian cancer growth by altering metabolism and (2) will metformin increase sensitivity to chemotherapy. STUDY DESIGN: The effect of metformin in ovarian cancer was tested in vitro and with 2 different mouse models. In vitro, cell lines (n = 6) were treated with metformin (10-40 mmol/L) or phosphate-buffered saline solution and cellular proliferation and metabolic alterations (adenosine monophosphate-activated protein kinase activity, glycolysis, and lipid synthesis) were compared between the 2 groups. In mouse models, a prevention study was performed by treating mice with metformin (250 mg/kg/d intraperitoneally) or placebo for 2 weeks followed by intraperitoneal injection of the SKOV3ip1 human ovarian cancer cell line, and the mean number of tumor implants in each treatment group was compared. In a treatment study, the LSL-K-ras(G12D/+)/PTEN(floxP/floxP) genetic mouse model of ovarian cancer was used. Mice were treated with placebo, paclitaxel (3 mg/kg/wk intraperitoneally for 7 weeks), metformin (100 mg/kg/d in water for 7 weeks), or paclitaxel plus metformin, and tumor volume was compared among treatment groups. RESULTS: In vitro, metformin decreased proliferation of ovarian cancer cell lines and induced cell cycle arrest, but not apoptosis. Further analysis showed that metformin altered several aspects of metabolism including adenosine monophosphate-activated protein kinase activity, glycolysis, and lipid synthesis. In the prevention mouse model, mice that were pretreated with metformin had 60% fewer tumor implants compared with controls (P < .005). In the treatment study, mice that were treated with paclitaxel plus metformin had a 60% reduction in tumor weight compared with controls (P = .02), which is a level of tumor reduction greater than that resulting from either paclitaxel or metformin alone. CONCLUSION: Based on these results, we conclude that metformin alters metabolism in ovarian cancer cells, prevents tumor growth, and increases sensitivity to chemotherapy in vitro and in mouse models. These preclinical findings suggest that metformin warrants further investigation for use as an ovarian cancer therapeutic. PMID- 25446667 TI - Is fetal cerebroplacental ratio an independent predictor of intrapartum fetal compromise and neonatal unit admission? AB - OBJECTIVE: We sought to evaluate the association between fetal cerebroplacental ratio (CPR) and intrapartum fetal compromise and admission to the neonatal unit (NNU) in term pregnancies. STUDY DESIGN: This was a retrospective cohort study in a single tertiary referral center over a 14-year period from 2000 through 2013. The umbilical artery pulsatility index, middle cerebral artery pulsatility index, and CPR were recorded within 2 weeks of delivery. The birthweight (BW) values were converted into centiles and Doppler parameters converted into multiples of median (MoM), adjusting for gestational age using reference ranges. Logistic regression analysis was performed to identify, and adjust for, potential confounders. RESULTS: The study cohort included 9772 singleton pregnancies. The rates of operative delivery for presumed fetal compromise and neonatal admission were 17.2% and 3.9%, respectively. Doppler CPR MoM was significantly lower in pregnancies requiring operative delivery or admission to NNU for presumed fetal compromise (P < .01). On multivariate logistic regression, both CPR MoM and BW centile were independently associated with the risk of operative delivery for presumed fetal compromise (adjusted odds ratio [OR], 0.67; 95% confidence interval [CI], 0.52-0.87; P = .003 and adjusted OR, 0.994; 95% CI, 0.992-0.997; P < .001, respectively). The latter associations persisted even after exclusion of small-for-gestational-age cases from the cohort. Multivariate logistic regression also demonstrated that CPR MoM was an independent predictor for NNU admission at term (adjusted OR, 0.55; 95% CI, 0.33-0.92; P = .021), while BW centile was not (adjusted OR, 1.00; 95% CI, 0.99-1.00; P = .794). The rates of operative delivery for presumed fetal compromise were significantly higher for appropriate-for gestational-age fetuses with low CPR MoM (22.3%) compared to small-for gestational-age fetuses with normal CPR MoM (17.3%). CONCLUSION: Lower fetal CPR, regardless of the fetal size, was independently associated with the need for operative delivery for presumed fetal compromise and with NNU admission at term. The extent to which fetal hemodynamic status could be used to predict perinatal morbidity and optimize the mode of delivery merits further investigation. PMID- 25446668 TI - Asymmetric anti-selective Michael reaction of imidazole-modified ketones with trans-beta-nitroalkenes. AB - The successful application of imidazole-modified ketones in asymmetric anti selective Michael reactions with trans-beta-nitroalkenes is presented by employing a newly developed 3-bromothiophene-modified chiral diamine ligand. The corresponding conjugate adduct was submitted to further transformations with Grignard reagents to solve the problem of alpha-site selectivity of simple linear ketones. Additionally, the syn-selective product was obtained by treating the anti-selective adduct with a simple base. In this way, the site-specific products for both diastereomers in the asymmetric conjugate addition of simple ketones to nitroalkenes can be obtained. PMID- 25446669 TI - Expression of cloned alpha6* nicotinic acetylcholine receptors. AB - Nicotinic acetylcholine receptors (AChRs) are ACh-gated ion channels formed from five homologous subunits in subtypes defined by their subunit composition and stoichiometry. Some subtypes readily produce functional AChRs in Xenopus oocytes and transfected cell lines. alpha6beta2beta3* AChRs (subtypes formed from these subunits and perhaps others) are not easily expressed. This may be because the types of neurons in which they are expressed (typically dopaminergic neurons) have unique chaperones for assembling alpha6beta2beta3* AChRs, especially in the presence of the other AChR subtypes. Because these relatively minor brain AChR subtypes are of major importance in addiction to nicotine, it is important for drug development as well as investigation of their functional properties to be able to efficiently express human alpha6beta2beta3* AChRs. We review the issues and progress in expressing alpha6* AChRs. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID- 25446671 TI - Ambient GABA modulates septo-hippocampal inhibitory terminals via presynaptic GABAb receptors. AB - The septo-hippocampal GABAergic pathway connects inhibitory neurons in the medial septum with hippocampal interneurons. Phasic release of GABA from septo hippocampal terminals is thought to play an important role in shaping hippocampal network activity during behavior. Here, we found that GABA release from septo hippocampal terminals is under negative feedback from the hippocampal local inhibitory network. We found that the strength of septo-hippocampal GABAergic inhibition is constrained by presynaptic GABAb receptors that are activated by ambient GABA during states of increased hippocampal network activity. PMID- 25446672 TI - How to reduce the accumulation of autophagic vacuoles in NPC1-deficient neurons: a comparison of two pharmacological strategies. AB - A disturbed autophagic pathway leads to chronically increased levels of autophagic vacuoles in Niemann Pick Type-C 1 (NPC1) deficient neurons. Since these accumulations potentially contribute to neuronal cell death associated with the disease, we investigated two pharmacological strategies which potentially reduce the number of autophagic structures under following aspects: efficiency, sustainability and effect on neuronal cell viability. The strategies comprised (i) an interruption of the autophagic flux by the class III PI3K inhibitor 3 methyladenine (3-MA) and (ii) an acceleration of the autophagic execution by 2 hydroxypropyl-beta-cyclodextrin (pCD). Our data show that the inhibition of autophagy with 3-MA only initially reduced the number of autophagic vacuoles in cultured neurons. Prolonged treatments with the PI3K-inhibitor reversed this lowering effect. The re-increase in the number of autophagic vacuoles was combined with a defect in the integrity of lysosomes which endangered further survival of cells. The treatment with pCD evoked a slow but sustained reduction of autophagic structures and had no negative effects on neuronal survival. PMID- 25446670 TI - Agonist activation of a nicotinic acetylcholine receptor. AB - How does an agonist activate a receptor? In this article I consider the activation process in muscle nicotinic acetylcholine receptors (AChRs), a prototype for understanding the energetics of binding and gating in other ligand gated ion channels. Just as movements that generate gating currents activate voltage-gated ion channels, movements at binding sites that generate an increase in affinity for the agonist activate ligand-gated ion channels. The main topics are: i) the schemes and intermediate states of AChR activation, ii) the energy changes of each of the steps, iii) the sources of the energies, iv) the three kinds of AChR agonist binding site and v) the correlations between binding and gating energies. The binding process is summarized as sketches of different conformations of an agonist site. The results suggest that agonists lower the free energy of the active conformation of the protein in stages by establishing favorable, local interactions at each binding site, independently. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID- 25446673 TI - Low dosage of rimonabant leads to anxiolytic-like behavior via inhibiting expression levels and G-protein activity of kappa opioid receptors in a cannabinoid receptor independent manner. AB - WHAT IS KNOWN: There is an increasing number of studies demonstrating the direct effect of the cannabinoid receptor 1 (CB1) antagonist/inverse agonist rimonabant on the opioid system. The kappa opioid receptors (KORs) are well known to mediate depression- and anxiety-like behavior. Clinical studies on chronic rimonabant administration have revealed that rimonabant leads to a very similar pathophysiology, suggesting a potential impact of rimonabant on KORs. OBJECTIVES: Our objectives were to examine the putative effects of rimonabant on KOR ligand binding, G-protein activity, protein expression and how all these contribute to the development of depression- and anxiety-like behavior. RESULTS: In Chinese hamster ovary (CHO) cell membranes transfected with rat KOR (CHO-rKOR) rimonabant inhibited KOR agonist [3H]U69593 binding in the micromolar range in competition binding experiments and specifically reduced KOR basal activity at lower micromolar concentrations in [35S]GTPgammaS binding assays. Rimonabant significantly inhibited dynorphin (1-11)-induced [35S]GTPgammaS binding in micromolar range in CHO-rKOR cells, CB1 knockout (CB1 K.O.) and CB1/CB2 double knockout mouse forebrain membranes. A single dose of i.p. 0.1 mg/kg rimonabant significantly reduced dynorphin (1-11)-induced KOR G-protein activity and KOR protein expression levels 24 h following the administration in both wild type and CB1 K.O. mice forebrain. Furthermore, in elevated plus maze mice showed an anxiolytic-like effect upon rimonabant injection that could be reversed by 1 mg/kg KOR antagonist norbinaltorphimine. The anxiolytic-like effects were further confirmed with the light-dark box test. CONCLUSION: Rimonabant reduced KOR ligand binding, receptor mediated G-protein activity and protein expression level, which overall leads to altered anxiety-like behavior. PMID- 25446674 TI - Saxagliptin: a novel antiparkinsonian approach. AB - The emergence of glucagon-like peptide-1 as a crucial contender in modifying neurodegenerative diseases in the preclinical studies has instigated interest in investigating the antiparkinsonian effect of dipeptidyl peptidase (DPP)-4 inhibition. Notably, saxagliptin (SAX), the DPP-4 inhibitor, recently showed efficacy in ameliorating streptozotocin-induced Alzheimer's disease; however, its effect on Parkinson's disease (PD) has not yet been elucidated. In a rat rotenone (ROT) model, SAX prominently improved motor performance as well as muscle coordination and corrected akinesia. Moreover, SAX preserved substantia nigra pars compacta tyrosine hydroxylase (TH) immunoreactivity while halting the reduction in the striatal TH, dopamine (DA) and complex I. Meanwhile, SAX prevented the ROT-induced increment of striatal DPP-4 and the decline in cAMP, ATP/ADP and brain-derived neurotropic factor levels. Improvement in striatal energy level was associated with partial hindrance of ROT-induced body weight reduction. In addition, through its anti-inflammatory potential, SAX decreased the ROT-induced nuclear factor-kappaBeta, inducible nitric oxide synthase, tumor necrosis factor-alpha, intracellular adhesion molecule-1 and myeloperoxidase. The antiapoptotic marker B-cell lymphoma-2 was enhanced by SAX, versus reduction in caspase-3 and its intrinsic apoptotic activator cytochrome C. Furthermore, SAX amended alterations induced by ROT in the thiobarbituric acid reactive substances and the transcriptional factor Nrf-2 level. In conclusion, SAX can be introduced as a novel approach for the management of PD based on the remarkable improvement in motor functions denoting antiparkinsonian efficacy via antioxidant, anti inflammatory, antiapoptotic, neuroprotective and neurorestorative mechanisms. These effects were linked to DPP-4 inhibition, reduced neurodegeneration and enhanced DA synthesis. PMID- 25446675 TI - Insulin-like growth factor 2 mitigates depressive behavior in a rat model of chronic stress. AB - Depression is a common psychiatric disorder associated with chronic stress. Insulin-like growth factor 2 (IGF2) is a growth factor that serves important roles in the brain during development and at adulthood. Here, the role of IGF2 expression in the hippocampus was investigated in a rat model of depression. A chronic restraint stress (CRS) model of depression was established in rats, exhibiting depression-like behavior as assessed with the sucrose preference test (SPT) and forced swimming test (FST), and with evaluation of the corticosterone levels. Hippocampal IGF2 levels were significantly lower in rats suffering CRS than in controls, as were levels of pERK1/2 and GluR1. Lentivirus-mediated hippocampal IGF2 overexpression alleviated depressive behavior in restrained rats, elevated the levels of pERK1/2 and GluR1 proteins, but it did not affect the expression of pGSK3beta, GluR2, NMDAR1, and NMDAR2A. These results suggest the chronic restraint stress induces depressive behavior, which may be mediated by ERK-dependent IGF2 signaling, pointing to an antidepressant role for this molecular pathway. PMID- 25446676 TI - Knockdown of ventral tegmental area mu-opioid receptors in rats prevents effects of social defeat stress: implications for amphetamine cross-sensitization, social avoidance, weight regulation and expression of brain-derived neurotrophic factor. AB - Social defeat stress causes social avoidance and long-lasting cross-sensitization to psychostimulants, both of which are associated with increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA). Moreover, social stress upregulates VTA mu-opioid receptor (MOR) mRNA. In the VTA, MOR activation inhibits GABA neurons to disinhibit VTA dopamine neurons, thus providing a role for VTA MORs in the regulation of psychostimulant sensitization. The present study determined the effect of lentivirus-mediated MOR knockdown in the VTA on the consequences of intermittent social defeat stress, a salient and profound stressor in humans and rodents. Social stress exposure induced social avoidance and attenuated weight gain in animals with non manipulated VTA MORs, but both these effects were prevented by VTA MOR knockdown. Rats with non-manipulated VTA MOR expression exhibited cross-sensitization to amphetamine challenge (1.0 mg/kg, i.p.), evidenced by a significant augmentation of locomotion. By contrast, knockdown of VTA MORs prevented stress-induced cross sensitization without blunting the locomotor-activating effects of amphetamine. At the time point corresponding to amphetamine challenge, immunohistochemical analysis was performed to examine the effect of stress on VTA BDNF expression. Prior stress exposure increased VTA BDNF expression in rats with non-manipulated VTA MOR expression, while VTA MOR knockdown prevented stress-induced expression of VTA BDNF. Taken together, these results suggest that upregulation of VTA MOR is necessary for the behavioral and biochemical changes induced by social defeat stress. Elucidating VTA MOR regulation of stress effects on the mesolimbic system may provide new therapeutic targets for treating stress-induced vulnerability to substance abuse. PMID- 25446677 TI - Protein kinase C beta regulates the D2-like dopamine autoreceptor. AB - The focus of this study was the regulation of the D2-like dopamine autoreceptor (D2 autoreceptor) by protein kinase Cbeta, a member of the protein kinase C (PKC) family. Together with the dopamine transporter, the D2 autoreceptor regulates the level of extracellular dopamine and thus dopaminergic signaling. PKC regulates neuronal signaling via several mechanisms, including desensitizing autoreceptors to increase the release of several different neurotransmitters. Here, using both PKCbeta(-/-) mice and specific PKCbeta inhibitors, we demonstrated that a lack of PKCbeta activity enhanced the D2 autoreceptor-stimulated decrease in dopamine release following both chemical and electrical stimulations. Inhibition of PKCbeta increased surface localization of D2R in mouse striatal synaptosomes, which could underlie the greater sensitivity to quinpirole following inhibition of PKCbeta. PKCbeta(-/-) mice displayed greater sensitivity to the quinpirole induced suppression of locomotor activity, demonstrating that the regulation of the D2 autoreceptor by PKCbeta is physiologically significant. Overall, we have found that PKCbeta downregulates the D2 autoreceptor, providing an additional layer of regulation for dopaminergic signaling. We propose that in the absence of PKCbeta activity, surface D2 autoreceptor localization and thus D2 autoreceptor signaling is increased, leading to less dopamine in the extracellular space and attenuated dopaminergic signaling. PMID- 25446679 TI - ["Smarter medicine" - already another new trend?]. PMID- 25446678 TI - Potentiation of 5-methoxy-N,N-dimethyltryptamine-induced hyperthermia by harmaline and the involvement of activation of 5-HT1A and 5-HT2A receptors. AB - 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are serotonin (5-HT) analogs often abused together, which alters thermoregulation that may indicate the severity of serotonin toxicity. Our recent studies have revealed that co administration of monoamine oxidase inhibitor harmaline leads to greater and prolonged exposure to 5-HT agonist 5-MeO-DMT that might be influenced by cytochrome P450 2D6 (CYP2D6) status. This study was to define the effects of harmaline and 5-MeO-DMT on thermoregulation in wild-type and CYP2D6-humanized (Tg CYP2D6) mice, as well as the involvement of 5-HT receptors. Animal core body temperatures were monitored noninvasively in the home cages after implantation of telemetry transmitters and administration of drugs. Harmaline (5 and 15 mg/kg, i.p.) alone was shown to induce hypothermia that was significantly affected by CYP2D6 status. In contrast, higher doses of 5-MeO-DMT (10 and 20 mg/kg) alone caused hyperthermia. Co-administration of harmaline (2, 5 or 15 mg/kg) remarkably potentiated the hyperthermia elicited by 5-MeO-DMT (2 or 10 mg/kg), which might be influenced by CYP2D6 status at certain dose combination. Interestingly, harmaline-induced hypothermia was only attenuated by 5-HT1A receptor antagonist WAY-100635, whereas 5-MeO-DMT- and harmaline-5-MeO-DMT-induced hyperthermia could be suppressed by either WAY-100635 or 5-HT2A receptor antagonists (MDL-100907 and ketanserin). Moreover, stress-induced hyperthermia under home cage conditions was not affected by WAY-100635 but surprisingly attenuated by MDL-100907 and ketanserin. Our results indicate that co-administration of monoamine oxidase inhibitor largely potentiates 5-MeO-DMT-induced hyperthermia that involves the activation of both 5-HT1A and 5-HT2A receptors. These findings shall provide insights into development of anxiolytic drugs and new strategies to relieve the lethal hyperthermia in serotonin toxicity. PMID- 25446680 TI - [Lofgren syndrome - the acute form of sarcoidosis]. PMID- 25446682 TI - [Nerve sonography of intraneural ganglia as cause painful peroneal palsies: a case series]. AB - In selected cases acquired peroneal palsy is caused by intraneural ganglia. In contrast to the much more frequent "loco typico" lesion which is caused by external pressure, intraneural ganglia can be treated by microscopic nerve surgery as part of primary treatment strategy. A careful clinical history as well as a profound clinical and electrophysiological examination is required to disclose unusual findings. These are common in non-typical peroneal palsy. In this situation high resolution nerve sonography is a fast and sensitive method to detect intraneural ganglia. We report a case series of three patients with peroneal palsy caused by intraneural ganglia and give a review of the literature. PMID- 25446683 TI - [Total hip replacement: between normal rehabilitation and complication]. AB - Total hip replacement is a common and succesful treatment of the osteoarthritis of the hip. According to the demographical trends in Switzerland in the coming decades, there will be a significant increase in the demand for total hip replacement surgery. The 20-year survival of a total hip prosthesis is approximately 85%. New prosthesis designs aim to improve the hip biomechanics, sacrifice less bone stock and facilitate "minimal-invasive"' approaches to the hip joint. Severe complications in total hip replacement comprise dislocation, aseptic loosening, infection, periprosthetic fracture and limping. The painful total hip replacement requires thourough and systematic work up of extrinsic and intrinsic causes. A referral to the orthopaedic specialist should be considered early. PMID- 25446684 TI - [Treatments strategies for intracranial cavernomas]. AB - Cerebral cavernomatous malformations (CCM) are a subgroup of low-pressure cerebral vascular malformation. They have an estimated prevalence of 0,1-4% of the population and account for 8-15% of all cerebral vascular malformations. Depending on their size and localization (supratentorial or infratentorial, brain stem), CCM may present with focal bleedings with or without neurological deficits, as epileptic seizures, or are diagnosed incidentally by MRI performed for unspecific symptoms (e.g. headache, vertigo), especially in younger patients (mostly in 2nd or 3rd decade). The decision-making in patients with CCM can be classified into four categories: surgical or conservative treatment of symptomatic or incidental lesions. The decision regarding the optimal therapy in the individual patient must be made in the knowledge of the natural history (risk for bleeding or epilepsy) on the one hand, and the surgical possibilities (accessibility of the lesion) including their estimated outcome on the other hand. Therefore, careful patient selection and appropriate experience of the centre is warranted in the management of CCM. PMID- 25446685 TI - [My hands hurt so much!]. AB - We present the case of a 48-year-old man complaining of pain in his hands. In a first step, a two-sided carpal tunnel syndrome was found, and in the further course of the disease an acromegaly. The combinations of carpal tunnel syndrome, impaired glucose tolerance and radiological findings in the area of the sella turcica were the clues for the diagnosis of acromegaly. PMID- 25446687 TI - [Arterial hypertension: blood pressure self-monitoring and self-titration of medications improves blood pressure readings]. PMID- 25446688 TI - [Brain injury in isolated head hematoma?]. PMID- 25446693 TI - [Drug-induced interstitial lung diseases: often forgotten]. AB - Drug-induced interstitial lung diseases (DILD) are probably more common than diagnosed. Due to their potential reversibility, increased vigilance towards DILD is appropriate also from the radiologist's point of view, particularly as these diseases regularly exhibit radiological correlates in high-resolution computed tomography (HRCT) of the lungs.Based on personal experience typical relatively common manifestations of DILD are diffuse alveolar damage (DAD), eosinophilic pneumonia (EP), hypersensitivity pneumonitis (HP), organizing pneumonia (OP), non specific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). These patterns are presented based on case studies, whereby emphasis is placed on the clinical context. This is to highlight the relevance of interdisciplinary communication and discussion in the diagnostic field of DILD as it is a diagnosis of exclusion or of probability in most cases.Helpful differential diagnostic indications for the presence of DILD, such as an accompanying eosinophilia or increased attenuation of pulmonary consolidations in amiodarone-induced pneumopathy are mentioned and the freely available online database http://www.pneumotox.com is presented. PMID- 25446695 TI - Candy twists as an alternative to the glucola beverage in gestational diabetes mellitus screening. AB - OBJECTIVE: Screening for gestational diabetes mellitus commonly uses an oral glucose challenge test with a 50-g glucola beverage and subsequent venous puncture. However, up to 30% of pregnant women report significant side-effects, and the beverage is costly. We hypothesized that equivalent glucose loads could be achieved from a popular candy twist (Twizzlers; The Hershey Company, Hershey, PA) and tested it as cost-effective, tolerable alternative with a test of equivalency. STUDY DESIGN: The glucose equivalent of the 50-g glucola was calculated as 10 candy twists. We initially used a triple crossover design in nonpregnant patients whereby each subject served as her own control; this ensured the safety and equivalency of this load before using it among pregnant subjects. We then recruited pregnant women with an abnormal screening at 1 hour (glucose challenge test) in a double crossover design study. Subjects consumed 10 candy twists with a 1-hour venous blood glucose assessment. All subjects subsequently completed the confirmatory 3-hour glucose tolerance test. Sensitivity, specificity, positive predictive values, negative predictive values, false referral rates, and detection rates were calculated. RESULTS: At >=130 mg/dL, the sensitivity (100%) was the same for candy twists and glucola. However, the false referral rate (82% vs 90%), positive predictive value (18% vs 10%), and detection rate (18% vs 10%) were improved for candy twists when compared with the 50-g glucola beverage. CONCLUSION: Our results indicate that strawberry-flavored candy twists are potentially an equally effective screening test, compared with the gold standard glucola beverage but lead to fewer false-positive screens and therefore could be a cost-effective alternative. PMID- 25446696 TI - Associations of trimester-specific gestational weight gain with maternal adiposity and systolic blood pressure at 3 and 7 years postpartum. AB - OBJECTIVE: Our objective was to examine the associations of total and trimester specific gestational weight gain (GWG) rate with postpartum maternal weight and cardiometabolic risk. We hypothesized that first-trimester GWG would be most strongly associated with long-term maternal health. STUDY DESIGN: We studied 801 women enrolled during the first trimester of pregnancy in the Boston-area Project Viva cohort 1999 through 2002. At 3 years postpartum we measured maternal weight, waist circumference (WC), and systolic blood pressure (SBP) and collected fasting blood from a subset. At 7 years postpartum we again measured weight and WC. We used multivariable linear regression to evaluate relations of total and trimester specific GWG rate with weight change (vs self-reported prepregnancy weight) and WC at each time point, stratified by prepregnancy weight, as well as associations with SBP and insulin resistance at 3 years. RESULTS: Median age at enrollment was 34.0 years (range, 16.4-44.9); 65% were white. Mean (SD) total GWG rate was 0.38 (0.14) kg/wk. Women gained weight faster during the second (0.47 [0.19] kg/wk) and third (0.44 [0.22] kg/wk) trimesters than the first (0.22 [0.22] kg/wk). Total and first-trimester GWG rate were most strongly associated with postpartum weight change. Among normal-weight women, each 1-SD increase in total and first trimester GWG rate corresponded with 0.85 (95% confidence interval [CI], 0.07 1.63) kg and 2.08 (1.32-2.84) kg greater weight change at 3 and 7 years postpartum, respectively, but there was not strong evidence of association for either second- (-0.30 kg; 95% CI, -1.08 to 0.48) or third- (-0.26 kg; 95% CI, 1.08 to 0.55) trimester GWG. First-trimester GWG rate also related to 3-year postpartum weight change in overweight (2.28 kg; 95% CI, 0.95-3.61) and obese (2.47 kg; 95% CI, 0.98-3.97) women. Greater total and first-trimester GWG rate were associated with larger WC and higher SBP but not insulin resistance. CONCLUSION: In this observational cohort, first-trimester weight gain was more strongly associated with maternal weight retention as well as higher WC and blood pressure than second- or third-trimester gain. Interventions targeting GWG beginning very early in pregnancy may benefit long-term maternal health. PMID- 25446694 TI - Vitamin D status in early pregnancy and risk of preeclampsia. AB - OBJECTIVE: We sought to examine the association between maternal serum 25 hydroxyvitamin D (25[OH]D) concentration in early pregnancy and the subsequent diagnosis of preeclampsia (PE). STUDY DESIGN: This was a nested case-control study from 2 prospective Canadian cohorts conducted in Quebec City, Quebec, and Halifax, Nova Scotia, from 2002 through 2010. Participants were pregnant women (n = 169 cases with PE and 1975 controls). Maternal serum was drawn <20 weeks of gestation, and 25(OH)D measurement was performed. Cases were ascertained from medical records. Logistic regression analysis was used to estimate adjusted odds ratios with 95% confidence intervals. RESULTS: Women who developed PE had a significantly lower 25(OH)D concentration at a mean gestational age of 14 weeks compared with women in the control group (mean +/- SD 25[OH]D 47.2 +/- 17.7 vs 52.3 +/- 17.2 nmol/L, P < .0001). Women with 25(OH)D <30 nmol/L compared to those with at least 50 nmol/L had a greater risk of developing PE (adjusted odds ratio, 2.23; 95% confidence interval, 1.29-3.83) after adjustment for prepregnancy body mass index, maternal age, smoking, parity, season and year of blood collection, gestational week at blood collection, and cohort site. Exploratory analysis with cubic splines demonstrated a dose-response relationship between maternal 25(OH)D and risk of PE, up to levels around 50 nmol/L, where the association appeared to plateau. CONCLUSION: Maternal vitamin D deficiency early in pregnancy defined as 25(OH)D <30 nmol/L may be an independent risk factor for PE. The relevance of vitamin D supplementation for women of childbearing age should be explored as a strategy for reducing PE and for promoting a healthier pregnancy. PMID- 25446698 TI - An incidental finding of endometrial osseous metaplasia during office hysteroscopy. PMID- 25446697 TI - Two practice models in one labor and delivery unit: association with cesarean delivery rates. AB - OBJECTIVE: The objective of the study was to examine the association between labor and delivery practice model and cesarean delivery rates at a community hospital. STUDY DESGIN: This was a retrospective cohort study of 9381 singleton live births at 1 community hospital, at which women were provided labor and delivery care under 1 of 2 distinct practice models: a traditional private practice model and a midwife-physician laborist practice model. Cesarean rates were compared by practice model, adjusting for potential sociodemographic and clinical confounders. Statistical comparisons were performed using the chi(2) test and multivariable logistical regression. RESULTS: Compared with women managed under the midwife/laborist model, women in the private model were significantly more likely to have a cesarean delivery (31.6% vs 17.3%; P < .001; adjusted odds ratio [aOR], 2.11; 95% confidence interval [CI], 1.73-2.58). Women with nulliparous, term, singleton, vertex gestations also were more likely to have a cesarean delivery if they were cared for in the private model (29.8% vs 15.9%; P < .001; aOR, 1.86; 95% CI, 1.33-2.58) as were women who had a prior cesarean delivery (71.3% vs 41.4%; P < .001; aOR, 3.19; 95% CI, 1.74-5.88). CONCLUSION: In this community hospital setting, a midwife-physician laborist practice model was associated with lower cesarean rates than a private practice model. PMID- 25446699 TI - Reply: To PMID 24315859. PMID- 25446700 TI - Host reaction to vaginally inserted collagen containing polypropylene implants in sheep. AB - OBJECTIVE: We aimed to characterize the effect of vaginal or abdominal mesh insertion and of different collagen augmentation of polypropylene mesh in a sheep model. Outcome measures were passive and active biomechanical properties and semiquantitative morphometry. STUDY DESIGN: Forty-two Texel sheep were used: 6 were nonimplanted controls (n = 6), the rest were implanted with polypropylene mesh (n = 12; Avaulta Solo; Bard Medical, Covington, GA) or collagen-coated meshes: Avaulta Plus (n = 12; Bard Medical) and Ugytex (n = 12; Sofradim International, Trevoux, France). Through a single incision, the rectovaginal septum was dissected and a 35 * 35-mm mesh was sutured to the underlying tissues. Abdominally, a 50 * 50-mm mesh was laid over a primarily sutured full thickness 40-mm longitudinal incisional defect. Animals were explanted after 60 or 180 days (n = 6 per group). Outcome measures were passive biomechanics by biaxial tensiometry, active contractility of vaginal explants, and histologic evidence. RESULTS: Vaginal explants were 2.4 times stiffer compared with native vaginal tissue (P < .001), but without differences in comfort zone stiffness or slope of the load-elongation in the physiologic range between the products that were tested. Collagen coating was associated with a 16-fold reduction in contractile force at 180 days, compared with native vaginal tissue, both for Avaulta Plus (P = .032) and Ugytex (P = .015). Abdominal explants were 1.3-times stiffer compared with native abdominal wall tissue (P < .001) and were 1.9-times stiffer compared with vaginal explants. CONCLUSION: Vaginal mesh implantation yields less stiff explants compared with abdominal explants. Vaginal mesh implantation also alters the passive and active biomechanical properties compared with native vaginal tissues. Collagen matrices did not reduce the number of graft-related complications. PMID- 25446701 TI - Cerebral autoregulation in different hypertensive disorders of pregnancy. AB - OBJECTIVE: Cerebrovascular complications that are associated with hypertensive disorders of pregnancy (preeclampsia, chronic hypertension [CHTN], and gestational hypertension [GHTN]) are believed to be associated with impaired cerebral autoregulation, which is a physiologic process that maintains blood flow at an appropriate level despite changes in blood pressure. The nature of autoregulation dysfunction in these conditions is unclear. We therefore evaluated autoregulation in 30 patients with preeclampsia, 30 patients with CHTN, and 20 patients with GHTN and compared them with a control group of 30 normal pregnant women. STUDY DESIGN: The autoregulatory index (ARI) was calculated with the use of simultaneously recorded cerebral blood flow velocity in the middle cerebral artery (transcranial Doppler ultrasound), blood pressure (noninvasive arterial volume clamping), and end-tidal carbon dioxide during a 7-minute period of rest. ARI values of 0 and 9 indicate absent and perfect autoregulation, respectively. We use analysis of variance with Bonferroni test vs a control group. Data are presented as mean +/- standard deviation. RESULTS: ARI was significantly reduced in preeclampsia (ARI, 5.5 +/- 1.6; P = .002) and CHTN (ARI, 5.6 +/- 1.7; P = .004), but not in GHTN (ARI, 6.7 +/- 0.8; P = 1.0) when compared with control subjects (ARI, 6.7 +/- 0.8). ARI was more decreased in patients with CHTN who subsequently experienced preeclampsia than in those who did not (ARI, 3.9 +/- 1.9 vs 6.1 +/- 1.2; P = .001). This was not true for women with GHTN or control subjects who later experienced preeclampsia. CONCLUSION: Pregnant women with CHTN or preeclampsia (even after exclusion of superimposed preeclampsia) have impaired autoregulation when compared with women with GHTN or normal pregnancy. Whether the decreased ARI in patients with CHTN who later experience preeclampsia is due to preexistent differences or early affected cerebral circulation remains to be determined. PMID- 25446702 TI - Maternal oxygen use during labor. PMID- 25446703 TI - Maternal oxygen administration for intrauterine resuscitation. PMID- 25446704 TI - Reply: To PMID 24412117. PMID- 25446705 TI - Modified obstetric early warning scoring systems (MOEWS): validating the diagnostic performance for severe sepsis in women with chorioamnionitis. AB - OBJECTIVE: We sought to compare the predictive power of published modified obstetric early warning scoring systems (MOEWS) for the development of severe sepsis in women with chorioamnionitis. STUDY DESIGN: This was a retrospective cohort study using prospectively collected clinical observations at a single tertiary unit (Chicago, IL). Hospital databases and patient records were searched to identify and verify cases with clinically diagnosed chorioamnionitis during the study period (June 2006 through November 2007). Vital sign data (heart rate, respiratory rate, blood pressure, temperature, mental state) for these cases were extracted from an electronic database and the single worst composite recording was identified for analysis. Global literature databases were searched (2014) to identify examples of MOEWS. Scores for each identified MOEWS were derived from each set of vital sign recordings during the presentation with chorioamnionitis. The performance of these MOEWS (the primary outcome) was then analyzed and compared using their sensitivity, specificity, positive and negative predictive values, and receiver-operating characteristic curve for severe sepsis. RESULTS: Six MOEWS were identified. There was wide variation in design and pathophysiological thresholds used for clinical alerts. In all, 913 women with chorioamnionitis were identified from the clinical database. In all, 364 cases with complete data for all physiological indicators were included in analysis. Five women developed severe sepsis, including 1 woman who died. The sensitivities of the MOEWS in predicting the severe deterioration ranged from 40-100% and the specificities varied even more ranging from 4-97%. The positive predictive values were low for all MOEWS ranging from <2-15%. The MOEWS with simpler designs tended to be more sensitive, whereas the more complex MOEWS were more specific, but failed to identify some of the women who developed severe sepsis. CONCLUSION: Currently used MOEWS vary widely in terms of alert thresholds, format, and accuracy. Most MOEWS have not been validated. The MOEWS generally performed poorly in predicting severe sepsis in obstetric patients; in general severe sepsis was overdetected. Simple MOEWS with high sensitivity followed with more specific secondary testing is likely to be the best way forward. Further research is required to develop early warning systems for use in this setting. PMID- 25446706 TI - Intrapartum antibiotic prophylaxis for Group B Streptococcus and risks of unnecessary antibiotics. PMID- 25446707 TI - Optimal T cell cross-reactivity and the role of regulatory T cells. AB - The T lymphocytes of the adaptive immune system constitute a highly diverse repertoire of clones expressing a unique T cell receptor (TCR). It has been argued that TCRs are cross-reactive, meaning that one receptor can recognize a multitude of epitopes. Cross-reactivity between self and foreign epitopes can potentially lead to autoimmune responses. Regulatory T cells (Tregs) down regulate immune reactions, and play an important role in the avoidance of autoimmunity. We use a probabilistic modeling approach to investigate how suppression of antigen-presenting dendritic cells (DCs) by Tregs influences the probability of mounting a successful immune response against a pathogen while remaining self-tolerant. For T cell cross-reactivity values close to experimental estimates, we find that the presence of Tregs increases this success probability somewhat. However, the probability of a successful immune response remains relatively low for these cross-reactivity values, and the probability of success is optimized when T cells are more specific and no Tregs are formed. We conclude that DC suppression on its own is insufficient to provide an evolutionary benefit of regulatory T cells. Rejecting one intuitively likely hypothesis for the function of Tregs thus narrows down the search for the mechanisms by which they are suppressing inappropriate immune responses. PMID- 25446708 TI - Modeling the effects of systemic mediators on the inflammatory phase of wound healing. AB - The normal wound healing response is characterized by a progression from clot formation, to an inflammatory phase, to a repair phase, and finally, to remodeling. In many chronic wounds there is an extended inflammatory phase that stops this progression. In order to understand the inflammatory phase in more detail, we developed an ordinary differential equation model that accounts for two systemic mediators that are known to modulate this phase, estrogen (a protective hormone during wound healing) and cortisol (a hormone elevated after trauma that slows healing). This model describes the interactions in the wound between wound debris, pathogens, neutrophils and macrophages and the modulation of these interactions by estrogen and cortisol. A collection of parameter sets, which qualitatively match published data on the dynamics of wound healing, was chosen using Latin Hypercube Sampling. This collection of parameter sets represents normal healing in the population as a whole better than one single parameter set. Including the effects of estrogen and cortisol is a necessary step to creating a patient specific model that accounts for gender and trauma. Utilization of math modeling techniques to better understand the wound healing inflammatory phase could lead to new therapeutic strategies for the treatment of chronic wounds. This inflammatory phase model will later become the inflammatory subsystem of our full wound healing model, which includes fibroblast activity, collagen accumulation and remodeling. PMID- 25446709 TI - Fast maximum likelihood estimation of mutation rates using a birth-death process. AB - Since fluctuation analysis was first introduced by Luria and Delbruck in 1943, it has been widely used to make inference about spontaneous mutation rates in cultured cells. Under certain model assumptions, the probability distribution of the number of mutants that appear in a fluctuation experiment can be derived explicitly, which provides the basis of mutation rate estimation. It has been shown that, among various existing estimators, the maximum likelihood estimator usually demonstrates some desirable properties such as consistency and lower mean squared error. However, its application in real experimental data is often hindered by slow computation of likelihood due to the recursive form of the mutant-count distribution. We propose a fast maximum likelihood estimator of mutation rates, MLE-BD, based on a birth-death process model with non differential growth assumption. Simulation studies demonstrate that, compared with the conventional maximum likelihood estimator derived from the Luria Delbruck distribution, MLE-BD achieves substantial improvement on computational speed and is applicable to arbitrarily large number of mutants. In addition, it still retains good accuracy on point estimation. PMID- 25446710 TI - On the interplay of speciation and dispersal: an evolutionary food web model in space. AB - We introduce an evolutionary metacommunity of multitrophic food webs on several habitats coupled by migration. In contrast to previous studies that focus either on evolutionary or on spatial aspects, we include both and investigate the interplay between them. Locally, the species emerge, interact and go extinct according to the rules of the well-known evolutionary food web model proposed by Loeuille and Loreau (2005). Additionally, species are able to migrate between the habitats. With random migration, we are able to reproduce common trends in diversity-dispersal relationships: Regional diversity decreases with increasing migration rates, whereas local diversity can increase in case of a low level of dispersal. Moreover, we find that the total biomasses in the different patches become similar even when species composition remains different. With adaptive migration, we observe species compositions that differ considerably between patches and contain species that are descendant from ancestors on both patches. This result indicates that the combination of spatial aspects and evolutionary processes affects the structure of food webs in different ways than each of them alone. PMID- 25446711 TI - Modelling of Arabidopsis LAX3 expression suggests auxin homeostasis. AB - Emergence of new lateral roots from within the primary root in Arabidopsis has been shown to be regulated by the phytohormone auxin, via the expression of the auxin influx carrier LAX3, mediated by the ARF7/19 IAA14 signalling module (Swarup et al., 2008). A single cell model of the LAX3 and IAA14 auxin response was formulated and used to demonstrate that hysteresis and bistability may explain the experimentally observed 'all-or-nothing' LAX3 spatial expression pattern in cortical cells containing a gradient of auxin concentrations. The model was tested further by using a parameter fitting algorithm to match model output with qRT-PCR mRNA expression data following exogenous auxin treatment. It was found that the model is able to show good agreement with the data, but only when the exogenous auxin signal is degraded over time, at a rate higher than that measured in the experimental medium, suggesting the triggering of an endogenous auxin homeostasis mechanism. Testing the model over a more physiologically relevant range of extracellular auxin shows bistability and hysteresis still occur when using the optimised parameters, providing the rate of LAX3 active auxin transport is sufficiently high relative to passive diffusion. PMID- 25446712 TI - A new technique for generating pathogenic barcodes in breast cancer susceptibility analysis. AB - Complex diseases usually involve complex interactions between multiple loci. The artificial intelligent algorithm is a plausible strategy to evade combinatorial explosion. However, the randomness of solution of this algorithm loses decreases the confidence of biological researchers on this algorithm. Meanwhile, the lack of an efficient and effective measure to profile the distribution of cases and controls impedes the discovery of pathogenic epistasis. Here we present an efficient method called maximum dissimilarity-minimum entropy (MDME) to analyze breast cancer single-nucleotide polymorphism (SNP) data. The method searches risky barcodes, which to increase the odds ratio and relative risk of the breast cancer. This method based on the hypothesis that if a specific barcode is associated with a disease, then the barcode permits distinction of cases from controls and more importantly it shows a relative consistent pattern in cases. An analysis based on simulated dataset explains the necessity of minimum entropy. Experimental results show that our method can find the most risky barcode that contributes to breast cancer susceptibility. Our method may also mine several pathogenic barcodes that condition the different subtypes of cancer. PMID- 25446713 TI - Strategy of tuning gene expression ratio in prokaryotic cell from perspective of noise and correlation. AB - Genes are organized into operons in procaryote, and these genes in one operon generally have related functions. However, genes in the same operon are usually not equally expressed, and the ratio needs to be fine-tuned for specific functions. We examine the difference of gene expression noise and correlation when tuning the expression level at the transcriptional or translational level in a bicistronic operon driven by a constitutive or a two-state promoter. We get analytic results for the noise and correlation of gene expression levels, which is confirmed by our stochastic simulations. Both the noise and the correlation of gene expressions in an operon with a two-state promoter are higher than in an operon with a constitutive promoter. Premature termination of mRNA induced by transcription terminator in the intergenic region or changing translation rates can tune the protein ratio at the transcriptional level or at the translational level. We find that gene expression correlation between promoter-proximal and promoter-distal genes at the protein level decreases as termination increases. In contrast, changing translation rates in the normal range almost does not alter the correlation. This explains why the translation rate is a key factor of modulating gene expressions in an operon. Our results can be useful to understand the relationship between the operon structure and the biological function of a gene network, and also may help in synthetic biology design. PMID- 25446714 TI - Modelling the dynamics of CaMKII-NMDAR complex related to memory formation in synapses: the possible roles of threonine 286 autophosphorylation of CaMKII in long term potentiation. AB - A synaptic protein, Ca(2+)/Calmodulin dependent protein kinase II (CaMKII), has complex state transitions and facilitates the emergence of long term potentiation (LTP), which is highly correlated to memory formation. Two of the state transitions are critical for LTP: (1) threonine 286 autophosphorylation of CaMKII; and (2) binding to N-methyl-d-aspartate receptor (NMDAR) in the postsynaptic density (PSD) to form CaMKII-NMDAR complex. Both of these state transitions retain the activity of CaMKII when the induction signal disappears which is very important for the long-lasting characteristics of LTP. However, the possible relationships between the state transitions in the emergence of LTP are not well understood. We develop a mathematical model of the formation of CaMKII NMDAR complex with the full state transitions of CaMKII, including the autophosphorylation, based on ordinary differential equations. In addition, we formulate a probabilistic framework for the binding between CaMKII and NMDAR. The model gives accurate predictions of the behaviours of CaMKII in comparisons to the experimental observations. Using the model, we show that: (1) the formation of CaMKII-NMDAR complex is dependent not only on the binding affinity between CaMKII and NMDAR, but also on the translocation of CaMKII into PSD; and (2) the autophosphorylation is not a requirement for the formation of CaMKII-NMDAR complex, but is important for the rapid formation of CaMKII-NMDAR complex during LTP. PMID- 25446715 TI - Quantification of 3-n-butylphthalide in beagle plasma samples by supercritical fluid chromatography with triple quadruple mass spectrometry and its application to an oral bioavailability study. AB - A high-throughput, rapid, sensitive, environmentally friendly, and economical supercritical fluid chromatography with triple quadruple mass spectrometry method was established and validated for the first time to determine a cerebral stroke treatment drug named 3-n-butylphthalide in dog plasma. Plasma samples were prepared by protein precipitation with methanol and the analytes were eluted on an ACQUITY UPC(2TM) HSS-C(18) SB column (3 * 100 mm, 1.8 MUm) maintained at 50 degrees C. The mobile phase comprised supercritical carbon dioxide/methanol (90:10, v/v) at a flow rate of 1.5 mL/min, the compensation solvent was methanol at a flow rate of 0.2 mL/min and the total run time was 1.5 min per sample. The detection was carried out on a tandem mass spectrometer with an electrospray ionization source. Calibration curves were linear over the concentration range of 1.02-1021.00 ng/mL (r(2) >= 0.993) with the lower limit of quantification of 1.02 ng/mL. The intra- and inter-day precision values were below 15% and the accuracy was from 97.90 to 103.70% at all quality control levels. The method was suitable for a pharmacokinetic study of 3-n-butylphthalide in beagle dogs. PMID- 25446716 TI - Dissipation behavior of hexaconazole and kresoxim-methyl residues in ginseng and soil under field conditions. AB - The dissipation and terminal residues of a fungicide suspension (5% hexaconazole, 25% kresoxim-methyl) in ginseng and soil were investigated by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). At fortified levels of 0.01, 0.02, and 0.20 mg kg(-1), the recoveries of hexaconazole and kresoxim-methyl were in the range of 80.6~94.8% and 82.4~98.8% with relative standard deviation of 3.42-9.12% and 3.19-8.58%, respectively. The half-lives were 7.09-10.73 days in root, 6.80-7.95 days in stem, 5.31-8.49 days in leaf, and 6.30-7.97 days in soil. The terminal residues were all below the maximum residue limits (MRLs) of EU and South Korea. Risk assessment results indicated that the risk of hexaconazole and kresoxim-methyl use in ginseng at dosage of 60-90 g a.i. ha(-1) was negligible to humans. This work would help the government to establish the MRL and provide guidance on the proper and safe use of hexaconazole and kresoxim-methyl in ginseng. PMID- 25446718 TI - Potentially toxic elements in lignite and its combustion residues from a power plant. AB - The presence of potentially toxic elements in lignite and coal is a matter of global concern during energy extraction from them. Accordingly, Barsingsar lignite from Rajasthan (India), a newly identified and currently exploited commercial source of energy, was evaluated for the presence of these elements and their fate during its combustion. Mobility of these elements in Barsingsar lignite and its ashes from a power plant (Bikaner-Nagaur region of Thar Desert, India) is presented in this paper. Kaolinite, quartz, and gypsum are the main minerals in lignite. Both the fly ash and bottom ash of lignite belong to class-F with SiO2 > Al2O3 > CaO > MgO. Both the ashes contain quartz, mullite, anhydrite, and albite. As, In, and Sr have higher concentration in the feed than the ashes. Compared to the feed lignite, Ba, Co, U, Cu, Cd, and Ni are enriched (10-5 times) in fly ash and Co, Pb, Li, Ga, Cd, and U in bottom ash (9-5 times). Earth crust normalization pattern showed enrichment of Ga, U, B, Ag, Cd, and Se in the lignite; Li, Ba, Ga, B, Cu, Ag, Cd, Hg, Pb, and Se, in fly ash; and Li, Sr, Ga, U, B, Cu, Ag, Cd, Pb, and Se in bottom ash. Hg, Ag, Zn, Ni, Ba, and Se are possibly associated with pyrite. Leaching test by toxicity characteristic leaching procedure (TCLP) showed that except B all the elements are within the safe limits prescribed by Indian Standards. PMID- 25446717 TI - Elevated titanium levels in Iraqi children with neurodevelopmental disorders echo findings in occupation soldiers. AB - Anthropogenic release of pollutants into the environment is especially harmful to growing fetuses and young children. These populations are at an increased risk of damage because exposure to pollutants during critical periods of development can cause many impairments. Children's exposure to mixtures of metals could be responsible for the rising numbers of neurological disorders surfacing in Iraqi children. Titanium (Ti) and magnesium (Mg) are heavily used in war industries. Exposure to Ti and Mg has been linked to the dust in occupation soldiers' lungs. Hair samples of children in Hawija, Iraq (n = 13) contained significantly higher levels of Ti compared to Iranian children (n = 13) living near the Iraqi border (2080 +/- 940 vs 707 +/- 421 MUg/kg, p < 0.0001). Magnesium was 1.7 times higher in Hawija children compared to Iranian children (115,763 +/- 118,155 vs 67,650 +/ 46,729 MUg/kg). In samples from Hawija, Ti was 1.3 times higher in children with neurodevelopmental disorders (2198 +/- 1108 vs 1942 +/- 779 MUg/kg), and Mg was 1.9 times higher in children without neurodevelopmental disorders (155,618 +/- 140,791 vs 81,602 +/- 91,940 MUg/kg). Lead, arsenic, and cadmium in Hawija children with neurodevelopmental disorders (n = 6) were 2.5, 2.2, and 1.37 times higher compared to non-disabled children (n = 7). To get a clear understanding of the current status of neurodevelopmental disorders in Iraqi children and to determine the magnitude of this suspected global health issue, registries should be set up to compile and aggregate data from hospitals, clinics, and health centers across the country. Functional registries can develop collaborations with researchers toward finding causes of these disorders in Iraqi children and toward preventing them. PMID- 25446719 TI - Rapid field estimation of biochemical oxygen demand in a subtropical eutrophic urban lake with chlorophyll a fluorescence. AB - Development of a technique for rapid field estimation of biochemical oxygen demand (BOD) is necessary for cost-effective monitoring and management of urban lakes. While several studies reported the usefulness of laboratory tryptophan like fluorescence technique in predicting 5-day BOD (BOD5) of wastewater and leachates, little is known about the predictability of field chlorophyll fluorescence measurements for BOD of urban lake waters that are constantly exposed to the mixture of chemical compounds. This study was conducted to develop a numeric relationship between chlorophyll a fluorescence and BOD for a eutrophic urban lake that is widely representative of lake water conditions in the subtropical southern USA. From October 2012 to September 2013, in situ measurements at the studied lake were made every 2 weeks on chlorophyll a fluorescence and other water quality parameters including water temperature, pH, dissolved oxygen, and specific conductivity. Water samples were taken for 5-day BOD and 10-day BOD (BOD10) analysis with and without incubation. The results showed a clear seasonal trend of both BOD measurements being high during the summer and low during the winter. There was a linear, positive relationship between chlorophyll a fluorescence and BOD, and the relationship appeared to be stronger with the 10-day BOD (r(2) = 0.83) than with the 5-day BOD (r(2) = 0.76). BOD dropped each day with declining chlorophyll a fluorescence, suggesting that die-off of phytoplankton has been the main consumption of oxygen in the studied lake. Ambient conditions such as rainfall and water temperature may have partially affected BOD variation. PMID- 25446720 TI - Reduced expression of regeneration associated genes in chronically axotomized facial motoneurons. AB - Chronically axotomized motoneurons progressively fail to regenerate their axons. Since axonal regeneration is associated with the increased expression of tubulin, actin and GAP-43, we examined whether the regenerative failure is due to failure of chronically axotomized motoneurons to express and sustain the expression of these regeneration associated genes (RAGs). Chronically axotomized facial motoneurons were subjected to a second axotomy to mimic the clinical surgical procedure of refreshing the proximal nerve stump prior to nerve repair. Expression of alpha1-tubulin, actin and GAP-43 was analyzed in axotomized motoneurons using in situ hybridization followed by autoradiography and silver grain quantification. The expression of these RAGs by acutely axotomized motoneurons declined over several months. The chronically injured motoneurons responded to a refreshment axotomy with a re-increase in RAG expression. However, this response to a refreshment axotomy of chronically injured facial motoneurons was less than that seen in acutely axotomized facial motoneurons. These data demonstrate that the neuronal RAG expression can be induced by injury-related signals and does not require acute deprivation of target derived factors. The transient expression is consistent with a transient inflammatory response to the injury. We conclude that transient RAG expression in chronically axotomized motoneurons and the weak response of the chronically axotomized motoneurons to a refreshment axotomy provides a plausible explanation for the progressive decline in regenerative capacity of chronically axotomized motoneurons. PMID- 25446721 TI - Novel connection between newborn granule neurons and the hippocampal CA2 field. AB - Newborn neurons are continuously added to the hippocampal dentate gyrus (DG) throughout life. Mature and immature granule neurons are believed to send their axonal projections exclusively to the hippocampal CA3 field. However, recent data point to an alternative trisynaptic circuit, involving a direct axonal projection from mature granule neurons to the CA2 field. Whether this circuit takes place only in mature granule neurons or, on the contrary, whether immature granule neurons also contribute to this novel connection is unknown. We used various retroviral vectors to show that immature granule neurons send axonal processes to and establish synaptic contacts with CA2 pyramidal neurons and that axonal growth follows a similar time course to that described for CA3 innervation. In addition, we provide experimental evidence demonstrating that the pathway connecting newborn granule neurons and the CA2 field can be modulated by physiological and deleterious stimuli. PMID- 25446722 TI - SOCS3: a common target for neuronal protection and axon regeneration after spinal cord injury. PMID- 25446723 TI - Transforming growth factor beta-induced expression of chondroitin sulfate proteoglycans is mediated through non-Smad signaling pathways. AB - The expression of chondroitin sulfate proteoglycans (CSPGs) by reactive astrocytes is a major factor contributing to glial scarring and regenerative failure after spinal cord injury, but the molecular mechanisms underlying CSPG expression remain largely undefined. One contributing factor is transforming growth factor beta (TGFbeta), which is upregulated after injury and has been shown to induce expression of CSPGs in vitro. TGFbeta typically mediates its effects through the Smad2/3 signaling pathway, and it has been suggested that this pathway is responsible for CSPG expression. However, there is evidence that TGFbeta can also activate non-Smad signaling pathways. In this study, we report that TGFbeta-induced expression of three different CSPGs--neurocan, brevican, and aggrecan--is mediated through non-Smad signaling pathways. We observed significant increases in TGFbeta-induced expression of neurocan, brevican, and aggrecan following siRNA knockdown of Smad2 or Smad4, which indicates that Smad signaling is not required for the expression of these CSPGs. In addition, we show that neurocan, aggrecan, and brevican levels are significantly reduced when TGFbeta is administered in the presence of either the PI3K inhibitor LY294002 or the mTOR inhibitor rapamycin, but not the MEK1/2 inhibitor U0126. This suggests that TGFbeta mediates this effect through non-Smad-dependent activation of the PI3K-Akt-mTOR signaling pathway, and targeting this pathway may therefore be an effective means of reducing CSPG expression in the injured CNS. PMID- 25446724 TI - The Yoruba version of the Beck Hopelessness Scale: psychometric characteristics and correlates of hopelessness in a sample of Nigerian psychiatric outpatients. AB - BACKGROUND: Previous studies from the developed western countries have repeatedly demonstrated that hopelessness positively correlates with an increased risk of suicide in the context of chronic mental disorders such as schizophrenia and affective disorders. Despite this persistently strong association, the construct of hopelessness in terms of its factorial structure and correlates has not been explored among Nigerian psychiatric outpatients. OBJECTIVE: The aim of this present study is to examine the psychometric characteristics of the Yoruba language culturally adapted version of the Beck Hopelessness Scale in a cross sectional sample of psychiatric outpatients in South-western Nigeria. METHOD: The participants were 327 Nigerian adult outpatients receiving treatment for schizophrenia, bipolar and depressive disorders, consecutively recruited from the outpatient psychiatric clinics of a university teaching hospital in South-western Nigeria. The outpatients were recruited over a one year period. They completed the Yoruba translated version of the Beck Hopelessness Scale (BHS-Y), a sociodemographic and illness-related questionnaire, the Beck Depression Inventory II (BDI-II). Their level of functioning was assessed with the Global Assessment of Functioning Scale (GAF), psychopathology was evaluated with the Positive and Negative Syndrome Scale (PANSS) and the level of disability measured with the World Health Organization Disability Assessment Schedule (WHODAS-II). Suicidality and confirmation of the diagnoses of schizophrenia, bipolar and depressive disorders were evaluated with the Mini International Neuropsychiatric Interview (MINI). The construct of hopelessness in terms of factorial structure, reliability, validity and correlates was explored. Exploratory Factor Analysis using Principal Component Analysis with Varimax rotation was used to examine the factorial structure of the BHS-Y. Internal consistency was examined with Cronbach's alpha, and the construct validity of the scale was assessed using correlational analyses with the MINI suicidality module, BDI-II, GAF and WHODAS II domain scores. We also tested the hypothesis that a shortened version of the BHS-Y will possess psychometric properties similar to the 20 item version. RESULTS: Exploratory Factor Analysis using Principal Component Analysis with Varimax rotation showed that the construct of hopelessness among our outpatients was best explained by a 3 factor model. Reliability of the translated version of the scale was adequate as indicated by a Cronbach's alpha of 0.92. Construct validity was also satisfactory as reflected by the strong correlations with MINI suicidality, Beck Depression Inventory-II and Global Assessment of Functioning scores. The shortened 4 item single factor BHS-Y composed of items 8, 9, 13 and 15 demonstrated psychometric properties similar to those of the full item version. CONCLUSION: The Beck Hopelessness Scale (Yoruba Version) demonstrated satisfactory reliability and validity and therefore may be useful in measuring the construct of hopelessness and in clinical suicide risk assessments among Nigerian psychiatric outpatients. There is the need for more studies to further explore the psychometric features and correlates of this scale among other Nigerian ethnic groups in addition to other medical patients' populations. PMID- 25446725 TI - The relationship between childhood history of ADHD symptoms and DSM-IV borderline personality disorder features among personality disordered outpatients: the moderating role of gender and the mediating roles of emotion dysregulation and impulsivity. AB - A number of studies have reported data suggestive of a significant association between attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD). However, the nature of this relation is not fully understood. This study aimed to evaluate if the relation between retrospectively assessed ADHD symptoms and adult BPD features is moderated by participants' gender and mediated by emotion dysregulation and impulsivity. Two hundred seventeen outpatients meeting DSM-IV criteria for at least one personality disorder (PD) consecutively admitted to the Clinical Psychology and Psychotherapy Unit of the Scientific Institute H San Raffaele of Milan, Italy, were administered Italian versions of the following instruments: Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II), Wender Utah Rating Scale (WURS), Difficulties in Emotion Regulation Scale (DERS), and the Barratt Impulsiveness Scale-11 (BIS-11). Moderation analyses revealed a significant association between ADHD and BPD symptoms among only female (vs. male) outpatients. Furthermore, in the female subsample, mediation analyses revealed that both impulsivity and emotion dysregulation fully mediated the relationship between retrospectively assessed ADHD symptoms and current BPD features. PMID- 25446726 TI - Oesophageal cancer in 2014: Advances in curatively intended treatment. PMID- 25446729 TI - Hepatitis: new drug regimen for HCV infection. PMID- 25446730 TI - IBD: cathelicidin can reverse intestinal fibrosis in models of colitis. PMID- 25446727 TI - Epidemiology, risk factors and management of cardiovascular diseases in IBD. AB - IBD is an established risk factor for venous thromboembolism. In the past few years, studies have suggested that patients with IBD might also be at an increased risk of coronary heart disease and stroke. The increased risk is thought to be similar to the level of risk seen in patients with other chronic systemic inflammatory diseases such as rheumatoid arthritis. The risk of developing these conditions is particularly increased in young adults with IBD, and more so in women than in men. Conventional cardiovascular risk factors are not over-represented in patients with IBD, so the increased risk could be attributable to inflammation-mediated atherosclerosis. Patients with IBD often have premature atherosclerosis and have biochemical and genetic markers similar to those seen in patients with atherosclerotic cardiovascular disease. The role of chronic inflammation in IBD-associated cardiovascular disease merits further evaluation. Particular attention should be given to the increased risk observed during periods of increased disease activity and potential modification of the risk by immunosuppressive and biologic therapies for IBD that can modify the disease activity. In addition, preclinical studies suggest that cardiovascular medications such as statins and angiotensin-converting enzyme inhibitors might also favourably modify IBD disease activity, which warrants further evaluation. PMID- 25446731 TI - IBD pathogenesis in 2014: Molecular pathways controlling barrier function in IBD. PMID- 25446732 TI - IBS: biomarkers for IBS: ready for prime time? AB - Evidence is mounting that molecular mechanisms underlie gut dysfunction and symptom generation in IBS. Although it is still an uphill struggle, this mounting evidence is a good starting point for the discovery of one or more IBS biomarkers. PMID- 25446733 TI - Hepatitis: treating HCV after liver transplant. PMID- 25446734 TI - Treatment of caries in relation to lesion severity: implications for minimum intervention dentistry. AB - OBJECTIVES: To date there is little evidence of minimum intervention in relation to treatment patterns, particularly for initial carious lesions. The objective of this study was to investigate treatment provided to patients with a main diagnosis of coronal caries in relation to the severity of the caries lesion. METHODS: A random sample of Australian dentists was surveyed by mailed questionnaires in 2009-2010 (response rate 67%). Data on services, patient characteristics and main diagnosis were collected from a service log. RESULTS: Models of service rates adjusted for age, sex, insurance status and reason for visit showed that compared to the reference category of gross caries lesions, there were higher rates [rate ratio, 95% CI] of restorative services for initial [1.63, 1.31-2.03] and cavitated [1.69, 1.39-2.05] lesions, higher rates of prophylaxis for initial [3.77, 2.09-6.79] and cavitated [3.88, 2.29-6.58] lesions, lower rates of endodontic services for initial [0.07, 0.02-0.30] and cavitated [0.11, 0.04-0.30] lesions, and lower rates of extraction for initial [0.15, 0.06-0.34] and cavitated [0.15, 0.07-0.31] lesions. CONCLUSIONS: Treatment of coronal caries was characterized by high rates of restorative services, but gross lesions had lower restorative rates and higher rates of endodontic and extraction services. There was little differentiation in treatment of coronal caries between initial and cavitated lesions, suggesting scope for increased management of initial carious lesions by the adoption of more minimum intervention approaches. PMID- 25446735 TI - Effect of autogenous and fresh-frozen bone grafts on osteoblast differentiation. AB - OBJECTIVE: Fresh-frozen bone allograft (FFBA) is an alternative to autogenous bone (AB) for reconstructing maxillary bone. Despite the promising clinical results, cell responses to FFBA and AB were not evaluated. Thus, our aim was to compare cells harvested from maxillary reconstructed sites with either AB or FFBA in terms of osteoblast differentiation and to evaluate the effect of culturing cells in contact with FFBA. METHODS: Cells harvested from three patients submitted to bilateral maxillary reconstruction with AB and FFBA were cultured to evaluate: proliferation, alkaline phosphatase activity, extracellular matrix mineralization and gene expression of osteoblastic markers. The effect of FFBA on osteoblast differentiation was studied by culturing cells harvested from AB in contact with FFBA and evaluating the same parameters. Data were compared using either two-way ANOVA followed by Tukey-b test or Student's t test (p<=0.05). RESULTS: Cell proliferation was higher in cultures from AB grafted sites and extracellular matrix mineralization was higher in cultures derived from FFBA grafted sites. The gene expression of alkaline phosphatase, RUNX2, bone sialoprotein and osteocalcin was higher in cells derived from FFBA compared with cells from AB grafted sites. However, the exposure of cells derived from AB to FFBA particles did not have any remarkable effect on osteoblast differentiation. CONCLUSIONS: These results indicate the higher osteogenic activity of cells derived from FFBA compared with AB reconstructed sites, offering an explanation at cellular level of why FFBA could be a suitable alternative to AB for reconstructing maxillary bone defects. PMID- 25446736 TI - Digital evaluation of the accuracy of impression techniques and materials in angulated implants. AB - OBJECTIVES: The aim of this study was to investigate the accuracy of 2 different impression techniques and 3 different impression materials in models simulating parallel and angulated implants. METHODS: Three master models simulating partial edentulous mandible with 2 implants at the sites of second premolars (parallel) and second molars with different angulations (parallel, 10 degrees or 20 degrees angulated) were fabricated. Two different impression techniques [splinted direct (D), indirect (I)] and 3 different monophase impression materials [polyether (PE), vinyl polysiloxane (VPS), vinyl polyether silicone (VPES)] were used for each master model and a total of 180 impressions were made (n=10). Master model and casts were scanned by a modified laser scanner and data were transferred to VRMesh software. Master model and duplicate cast scans were digitally aligned observing the superposition of anatomic markers. Angular and coronal deviations between master and duplicated copings were calculated and data were statistically analyzed. RESULTS: Mean angular and coronal deviations were in a range of 0.205 0.359 degrees and 22.56-33.33MUm, respectively. Statistical analysis revealed that the angulation of implant affected both coronal and angular deviations of the impression copings (P<0.05). According to statistical analyses, for parallel implants, the accuracy of impression materials and techniques were ranging as VPS D=PE-D>VPS-I=PE-I>VPES-D>VPES-I from most accurate to the least. For 10 degrees and 20 degrees angulated implants the most accurate material and technique was VPS-D whereas the least accurate combination was VPES-I (P<0.05). CONCLUSION: Angulation, impression technique and material were found to be effective on the accuracy of implant impressions. CLINICAL SIGNIFICANCE: Clinicians may prefer VPS impression material and splinted direct technique for impressions of both parallel and up to 20 degrees angulated implants. PMID- 25446728 TI - Crosstalk at the mucosal border: importance of the gut microenvironment in IBS. AB - The aetiology and pathology of IBS, a functional bowel disorder thought to lack an organic cause, is largely unknown. However, studies suggest that various features, such as altered composition of the gut microbiota, together with increased intestinal permeability, a changed balance in the enteroendocrine system and a dysregulated immune system in the gut, most likely have an important role in IBS. Exactly how these entities act together and give rise to symptoms is still unknown, but an altered gut microbiota composition could lead to dysregulation of the intestinal barrier as well as the enteroendocrine and the immune systems, which (through interactions with the nervous system) might generate symptoms. This Review highlights the crosstalk between the gut microbiota, the enteroendocrine system, the immune system and the role of intestinal permeability in patients with IBS. PMID- 25446737 TI - Preparation and characterisation of poly p-phenylene-2,6-benzobisoxazole fibre reinforced resin matrix composite for endodontic post material: a preliminary study. AB - OBJECTIVES: Currently used fibre-reinforced composite (FRC) intracanal posts possess low flexural strength which usually causes post fracture when restoring teeth with extensive loss. To improve the flexural strength of FRC, we aimed to apply a high-performance fibre, poly p-phenylene-2, 6-benzobisoxazole (PBO), to FRCs to develop a new intracanal post material. METHODS: To improve the interfacial adhesion strength, the PBO fibre was treated with coupling agent (Z 6040), argon plasma, or a combination of above two methods. The effects of the surface modifications on PBO fibre were characterised by determining the single fibre tensile strength and interfacial shear strength (IFSS). The mechanical properties of PBO FRCs were characterised by flexural strength and flexural modulus. The cytotoxicity of PBO FRC was evaluated by the MTT assay. RESULTS: Fibres treated with a combination of Z-6040 and argon plasma possessed a significantly higher IFSS than untreated fibres. Fibre treated with the combination of Z-6040-argon-plasma FRC had the best flexural strength (531.51 +/- 26.43MPa) among all treated fibre FRCs and had sufficient flexural strength and appropriate flexural moduli to be used as intracanal post material. Furthermore, an in vitro cytotoxicity assay confirmed that PBO FRCs possessed an acceptable level of cytotoxicity. CONCLUSIONS: In summary, our study verified the feasibility of using PBO FRC composites as new intracanal post material. Although the mechanical property of PBO FRC still has room for improvement, our study provides a new avenue for intracanal post material development in the future. CLINICAL SIGNIFICANCE: To our knowledge, this is the first study to verify the feasibility of using PBO FRC composites as new intracanal post material. Our study provided a new option for intracanal post material development. PMID- 25446738 TI - Medical genetics-based drug repurposing for Alzheimer's disease. AB - Alzheimer's disease (AD) is a disease that threatens the elderly. No efficient therapeutic method is currently available to combat AD. Drug repurposing has provided a new route for AD drug discovery, and medical genetics has shown potential in target-based drug repurposing. We compared AD-associated genes with approved drug targets and found that three are targeted by 23 approved drugs. Thus, these drugs may be used to treat AD according to the medical genetic information of the targets. In vitro and in vivo experiments revealed that four drugs, all of which are angiotensin-converting enzyme (ACE) inhibitors, had potential to treat AD. PMID- 25446739 TI - Different action of a specific NR2B/NMDA antagonist Ro 25-6981 on cortical evoked potentials and epileptic afterdischarges in immature rats. AB - Ro 25-6981 maleate is a highly selective and activity-dependent antagonist of NMDA ionotropic glutamate receptors containing NR2B subunit (NR2B/NMDARs). The aim of our study was to investigate the influence of Ro 25-6981 administration in developing rats on physiological (single and paired pulse cortical interhemispheric evoked potentials) and epileptic brain activity (cortical afterdischarges (ADs)). Electrophysiological experiments were performed in animals with epidurally implanted electrodes at postnatal days (P) P12, P18, and P25. The drug was injected intraperitoneally at a dose of 1 or 3mg/kg. Control animals were injected with saline (1ml/kg). Single interhemispheric responses were evoked with 0.5-ms biphasic pulses with intensities increasing from 0.4 to 5mA, paired-pulse responses were elicited by twofold threshold intensity. The ADs were elicited by series of 15-s of 1-ms pulses at 8-Hz frequency. Firstly, six stimulations with stable suprathreshold intensity repeated at 30-min intervals were used to determine the time course of Ro 25-6981 effects against ADs in P12 animals. Secondly, similar experiment was performed in all age groups of animals but with 20-min intervals as well as a further experiment using stimulations with stepwise intensities increasing at 10-min intervals from 0.2 to 15 mA. Pretreatment with the 3-mg/kg (but not the lower) dose of Ro 25-9681 decreased significantly the amplitude of single responses evoked with higher stimulation intensities in P12 and P18 animals. Both doses affected responses in P25 animals, only the 1-mg/kg dose was more efficacious than the 3-mg/kg one. Paired pulse responses were not affected by either dose of Ro 25-6981 in any age group. Ro 25 9681 clearly influenced the duration of ADs only in P12 animals. The 1-mg/kg dose did not change the duration of ADs whereas the 3-mg/kg dose suppressed progressive prolongation of ADs with repeated stimulations. This effect was seen even 110-min after the drug injection. The modification of ADs, i.e. stimulations with stepwise increasing intensities (10 min intervals) was used to demonstrate possible dependence on activity. The Ro 25-6981 was administered immediately after the 4-mA stimulation (i.e. when rats experienced six ADs on the average). The 3-mg/kg dose resulted in shorter ADs after high stimulation intensities in P12. There were no significant effects in older animals, only a tendency to ADs shortening was observed in P25 rats. In conclusion, our results indicate that Ro 25-6981 as a selective antagonist of NR2B/NMDARs exhibit age- and activation dependent anticonvulsant action at early postnatal development. In contrast, the influence of Ro 25-6981 on physiological excitability induced by single pulse stimulation of sensorimotor cortex does not depend on age. This compound may thus represent a useful antiepileptic agent in immature brain since its action against ADs prolongation can be observed even 110 min after the single administration of the drug. PMID- 25446740 TI - Bred to breed?! Implications of continuous mating on the emotional status of mouse offspring. AB - Working with mice represents a smart method to study pathophysiological mechanisms in vivo. However, using animals as model organisms also bears immense caveats. While many aspects in animal research are meanwhile standardized (e.g. nutrition, housing, health) the breeding environment remains unaddressed. Moreover, since the "production" of mice is mostly performed pragmatically, continuous mating (CM) represents a common method to boost the amount of offspring. This condition implies simultaneous pregnancy and lactation in presence of the male, which is associated with increased costs for the breeding dam. Facing the widely-accepted impact of perinatal conditions, our aim was to elucidate how CM affects emotional behaviour of mouse offspring. We therefore compared pregnant mice in CM with mice raising their pups without potentially disturbing influences. According to our hypothesis CM-deriving offspring should demonstrate increased anxiety and depression-like behaviour shaped by pre- and postnatal stress of the mother. Maternal care, i.e. nest building and pup retrieval, was analysed around delivery. To assess the emotional state of the offspring, males and females of either condition were exposed to a behavioural test battery for exploration, anxiety and fear, social and despair behaviour. In addition we analysed corticosterone as stressphysiological correlate. Our study demonstrates that CM affects the emotional phenotype regarding nearly all parameters addressed. These findings emphasize (i) the impact of the perinatal environment on stress-associated behaviour such as depression, and (ii) the need to imply perinatal conditions in the experimental design to decrease the risk of artefacts and increase the overall validity of animal studies. PMID- 25446741 TI - Cognitive and emotional alterations in young Alzheimer's disease (3xTgAD) mice: effects of neonatal handling stimulation and sexual dimorphism. AB - Alzheimer disease is the most common neurodegenerative disorder and cause of senile dementia. It is characterized by an accelerated memory loss, and alterations of mood, reason, judgment and language. The main neuropathological hallmarks of the disorder are beta-amyloid (betaA) plaques and neurofibrillary Tau tangles. The triple transgenic 3xTgAD mouse model develops betaA and Tau pathologies in a progressive manner which mimicks the pattern that takes place in the human brain with AD, and showing cognitive alterations characteristic of the disease. The present study intended to examine whether 3xTgAD mice of both sexes present cognitive, emotional and other behavioral alterations at the early age of 4 months, an age in which only some intraneuronal amyloid accumulation is found. Neonatal handling (H) is an early-life treatment known to produce profound and long-lasting behavioral and neurobiological effects in rodents, as well as improvements in cognitive functions. Therefore, we also aimed at evaluating the effects of H on the behavioral/cognitive profile of 4-month-old male and female 3xTgAD mice. The results indicate that, (1) 3xTgAD mice present spatial learning/memory deficits and emotional alterations already at the early age of 4 months, (2) there exists sexual dimorphism effects on several behavioral variables at this age, (3) neonatal handling exerts a preventive effect on some cognitive (spatial learning) and emotional alterations appearing in 3xTgAD mice already at early ages, and 4) H treatment appears to produce stronger positive effects in females than in males in several spatial learning measures and in the open field test. PMID- 25446742 TI - Noradrenergic and serotonergic neurochemistry arising from intranasal inoculation with alpha-synuclein aggregates which incite parkinsonian-like symptoms. AB - Alpha-synuclein (alpha-syn) toxic aggregates delivered by the nasal vector have been shown to modify the neurochemistry of dopamine (DA) which is associated with parkinsonian-like motor symptoms. The aim was therefore to study the intranasal effects of alpha-syn oligomers, fibrils or their combination on the motor behavior of aged mice in relation to possible noradrenergic and serotonergic correlates. In vitro generated alpha-syn oligomers and fibrils were verified using atomic force microscopy and the thioflavin T binding assay. Levels of noradrenaline (NA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were detected using HPLC with electrochemical detection in the substantia nigra (SN) and striatum. The oligomers or fibrils administered alone or in a 50:50 combination (total dose of 0.48 mg/kg) were given intranasally for 14 days and "open-field" behaviour was tested on days 0, 15 and 28 of the protocol, at which time brain structures were sampled. Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i.e. 14 days after treatment completion) induced hypokinesia and immobility whilst the aggregate combination additionally produced rigidity. The alpha-Syn oligomer/fibril mixture also instigated PD-like motor symptoms which correlated heterochronically with elevated NA levels in the striatum but then later in the SN while intranasal fibrils alone augmented 5-HT and 5-HIAA nigral concentrations throughout the protocol. In contrast, alpha-syn oligomers displayed a delayed serotonin upsurge in the SN. Neurodegenerative and/or actions on neurotransmitter transporters (such as NET, SERT and VMAT2) are discussed as being implicated in these alpha-syn amyloid induced neurochemical and motoric disturbances. PMID- 25446743 TI - An associative analysis of object memory. AB - Different aspects of recognition memory in rodents are commonly assessed using variants of the spontaneous object recognition procedure in which animals explore objects that differ in terms of their novelty, recency, or where they have previously been presented. The present article describes three standard variants of this procedure, and outlines a theory of associative learning, SOP which can offer an explanation of performance on all three types of task. The implications of this for theoretical interpretations of recognition memory and the procedures used to explore it are discussed. PMID- 25446744 TI - Putting memory in context: dissociating memories by distinguishing the nature of context. AB - In recent years, spontaneous recognition tasks have become commonplace methods of assessing memory in animals. Adaptations of these tasks allow us to look at the role of objects, contexts and spatial locations in memory. Recent findings have highlighted that not all types of contexts in these tasks rely on the same neural systems. Similarly, asking different questions about the same types of context can allow the dissociation of neural systems underlying these memories. Here we review the current position in how context is used in such tasks, and we consider the fundamental importance of clearly defining both the nature of the context being used, and the questions asked of it in order to fully appreciate the neural and cognitive mechanisms being studied in such tasks. PMID- 25446745 TI - Irrational beliefs, biases and gambling: exploring the role of animal models in elucidating vulnerabilities for the development of pathological gambling. AB - Gambling is a heterogeneous and complex disorder. Multiple factors may lead to problem gambling, yet one of the most important appears to be the increased presence of cognitive biases or distortions. These biases are thought to precipitate gambling as they can lead to dysfunctional decision making under risk or ambiguity. Modelling these cognitive perturbations in animals can improve our understanding of their neurobiological bases, and potentially stimulate novel treatment options. The first aim of this review is to give a broad overview of some of the cognitive biases that are most commonly associated with gambling. Secondly, we will discuss several animal models that we have developed in which rodent decision-making appears hallmarked by the same cognitive inconsistencies as human choice. In particular, we will discuss two tasks that capture elements of risk and loss averse decision making, and another in which rats appear susceptible to the 'near-miss' effect. To date, findings from both human and non human studies suggest that these different biases are neuropharmacologically and neurostructurally dissociable, and that dopamine plays a key role in their expression. Lastly, we will briefly discuss areas in both human and animal research where limitations within the field may be hampering a more complete understanding of pathological gambling as a disorder. PMID- 25446746 TI - The object pattern separation (OPS) task: a behavioral paradigm derived from the object recognition task. AB - The object recognition task (ORT) is widely used to measure object memory processes in rodents. Recently, the memory process known as pattern separation has received increasing attention, as impaired pattern separation can be one of the cognitive symptoms of multiple neurological and psychiatric disorders. Pattern separation is the formation of distinct representations out of similar inputs. In the search for an easily implemented task for rodents that can be used to measure pattern separation, we developed a task derived from the ORT and the object location task (OLT), which we called the object pattern separation (OPS) task. This task aims to measure spatial pattern separation per se, which utilizes memory processes centered in the DG and CA3 region of the hippocampus. Adult male C57BL/6 mice and adult male Wistar rats were used to validate different object locations which can be used to measure spatial pattern separation. Furthermore, different inter-trial time intervals were tested with the most optimal object location, to further evaluate pattern separation-related memory in mice. We found that specific object locations show gradual effects, which is indicative of pattern separation, and that the OPS task allows the detection of spatial pattern separation bi-directionally at intermediate spatial separations. Thus, object locations and time intervals can be specifically adjusted as needed, in order to investigate an expected improvement or impairment. We conclude that the current spatial OPS task can be best described as a specific version of the ORT, which can be used to investigate pattern separation processes. PMID- 25446747 TI - Strain and sex differences in brain and behaviour of adult rats: Learning and memory, anxiety and volumetric estimates. AB - Alterations in behaviour can arise through a number of factors, including strain and sex. Here, we explored strain and sex differences between Long-Evans (LER) and Wistar (WR) male and female rats that had been trained in a myriad of behavioural tasks. Tests included those assessing motor learning (skilled reaching task), spatial learning and memory (Morris water task), contextual learning (discriminative fear-conditioning to context) and anxiety behaviour (elevated plus maze). Following behavioural assessment, associated brain areas were examined for volumetric differences, including the hippocampus and its subregions, prefrontal cortex areas and the amygdala. LER and WR differed in their rates of performance in the skilled reaching task throughout the training period. Overall, LER outperformed WR in tasks related to contextual and spatial learning, although this was not accompanied by larger volumes of associated brain areas. Males outperformed females in spatial learning, and females outperformed males in the contextual fear-conditioning task and had an associated larger amygdalar volume, although these sexual dimorphisms were only observed within the LER strain. Overall, this study highlights differences between these two rat strains as well as highlights that larger volumetric estimates of brain areas do not always confer improved function of associated behaviours. PMID- 25446748 TI - Serotonin and conditioning: focus on Pavlovian psychostimulant drug conditioning. AB - Serotonin containing neurons are located in nuclei deep in the brainstem and send axons throughout the central nervous system from the spinal cord to the cerebral cortex. The vast scope of these connections and interactions enable serotonin and serotonin analogs to have profound effects upon sensory/motor processes. In that conditioning represents a neuroplastic process that leads to new sensory/motor connections, it is apparent that the serotonin system has the potential for a critical role in conditioning. In this article we review the basics of conditioning as well as the serotonergic system and point up the number of non associative ways in which manipulations of serotonin neurotransmission have an impact upon conditioning. We focus upon psychostimulant drug conditioning and review the contribution of drug stimuli in the use of serotonin drugs to investigate drug conditioning and the important impact drug stimuli can have on conditioning by introducing new sensory stimuli that can create or mask a CS. We also review the ways in which experimental manipulations of serotonin can disrupt conditioned behavioral effects but not the associative processes in conditioning. In addition, we propose the use of the recently developed memory re-consolidation model of conditioning as an approach to assess the possible role of serotonin in associative processes without the complexities of performance effects related to serotonin treatment induced alterations in sensory/motor systems. PMID- 25446750 TI - The postnatal origin of adult neural stem cells and the effects of glucocorticoids on their genesis. AB - The relevance of adult neurogenesis in hippocampal function is well documented, as is the potential impact stress has on the adult neurogenic niche. Adult born neurons are generated from neural precursors in the dentate gyrus (DG), although the point in postnatal development that these cell precursors originate is not known. This is particularly relevant if we consider the effects stress may have on the development of neural precursors, and whether such effects on adult neurogenesis and behavior may persist in the long-term. We have analyzed the proportion of neural precursors in the adult murine hippocampus born on specific days during postnatal development using a dual birth-dating analysis, and we assessed their sensitivity to dexamethasone (DEX) on the peak day of cell generation. We also studied the consequences of postnatal DEX administration on adult hippocampal-dependent behavior. Postnatal day 6 (P6) is a preferred period for proliferating neural stem cells (NSCs) to become the precursors that remain in a proliferative state throughout adulthood. This window is independent of gender, the cell's location in the DG granule cell layer or their rostro-caudal position. DEX administration at P6 reduces the size of the adult NSC pool in the DG, which is correlated with poor learning/memory capacity and increased anxiety like behavior. These results indicate that aNSCs are generated non-uniformly during postnatal development, with peak generation on day P6, and that stress receptor activation during the key period of postnatal NSC generation has a profound impact on both adult hippocampal neurogenesis and behavior. PMID- 25446749 TI - Extinction retention and fear renewal in a lifetime obsessive-compulsive disorder sample. AB - Obsessive-compulsive disorder (OCD), like other illnesses with prominent anxiety, may involve abnormal fear regulation and consolidation of safety memories. Impaired fear extinction memory (extinction recall, ER) has been shown in individuals with current symptoms of OCD [1]. However, contrary to expectations, the only previous study investigating this phenomenon showed a positive correlation between extinction recall abilities and OCD symptomology (i.e., as OCD symptoms worsened, extinction memory improved). The purpose of the current study was to determine if patients with a lifetime diagnosis of OCD (not necessarily currently symptomatic) also demonstrate impairments in extinction memory, and the relationship between OCD symptomology and extinction memory in this type of sample. In addition, we also examined fear renewal, which has never been investigated in an OCD sample. We enrolled 37 patients with OCD, the majority of whom were on serotonin reuptake inhibitors, and 18 healthy control participants in a 2-day paradigm assessing fear conditioning and extinction (Day 1) and extinction retention and renewal (Day 2). Skin conductance responses (SCRs) were the dependent measure. Results, as in the prior study, indicated that the only between-group difference was impaired ER in OCD patients relative to controls. Contrary to our prediction, OCD symptom severity was not correlated with the magnitude of extinction recall. There were no differences in fear renewal between OCD patients and controls. PMID- 25446751 TI - B2 receptor blockage prevents Abeta-induced cognitive impairment by neuroinflammation inhibition. AB - BACKGROUND AND PURPOSE: Abeta-induced neuronal toxicity and memory loss is thought to be dependent on neuroinflammation, an important event in Alzheimer's disease (AD). Previously, we demonstrated that the blockage of the kinin B2 receptor (B2R) protects against the memory deficits induced by amyloid beta (Abeta) peptide in mice. In this study, we aimed to investigate the role of B2R on Abeta-induced neuroinflammation in mice and the beneficial effects of B2R blockage in synapses alterations. EXPERIMENTAL APPROACH: The selective kinin B2R antagonist HOE 140 (50 pmol/site) was given by intracerebroventricular (i.c.v.) route to male Swiss mice 2 h prior the i.c.v. injection of Abeta(1-40) (400 pmol/site) peptide. Animals were sacrificed, at specific time points after Abeta(1-40) injection (6 h, 1 day or 8 days), and the brain was collected in order to perform immunohistochemical analysis. Different groups of animals were submitted to behavioral cognition tests on day 14 after Abeta(1-40) administration. KEY RESULTS: In this study, we report that the pre-treatment with the selective kinin B2R antagonist HOE 140 significantly inhibited Abeta-induced neuroinflammation in mice. B2R antagonism reduced microglial activation and the levels of pro-inflammatory proteins, including COX-2, iNOS and nNOS. Notably, these phenomena were accompanied by an inhibition of MAPKs (JNK and p38) and transcription factors (c-Jun and p65/NF-kappaB) activation. Finally, the anti inflammatory effects of B2R antagonism provided significant protection against Abeta(1-40)-induced synaptic loss and cognitive impairment in mice. CONCLUSIONS AND IMPLICATIONS: Collectively, these results suggest that B2R activation may play a critical role in Abeta-induced neuroinflammation, one of the most important contributors to AD progression, and its blockage can provide synapses protection. PMID- 25446752 TI - Neural network activity and neurological soft signs in healthy adults. AB - Previous neuroimaging studies in schizophrenia have shown that neurological soft signs (NSS) are associated with abnormal brain structure and function, but it remains unclear whether these findings truly reflect pathological processes or if they may be confounded by antipsychotics. To address these issues, structural neuroimaging studies conducted in healthy populations have shown an association between NSS and cortical regions but to date, studies of brain function in healthy participants are scarce. In this study, using functional magnetic resonance imaging we investigated 37 healthy adults under "resting-state" conditions. Functional connectivity of motor cortical and subcortical neural networks was assessed using a group spatial independent component analysis (ICA). NSS were measured using the "Heidelberg Scale". The relationship between functional connectivity at rest and NSS was analyzed using a regression model where age, gender and movement parameters were included as nuisance variables. We identified 35 stable components, from which five networks of interest were chosen for further analyses. Within three motor cortical networks, negative correlations were found between NSS levels and functional connectivity of the right precuneus, right superior frontal areas, supplementary motor area, and left paracentral gyrus. There were no significant associations between NSS scores and striatal or thalamic connectivity. In conclusion, the data indicate that in healthy young adults NSS are associated with regionally confined levels of cortical activity and not with striatal or thalamic function. The neural mechanisms underlying NSS in healthy individuals appear to rely on cortically mediated motor control and planning to a higher degree than on functions subserved by subcortical structures. PMID- 25446753 TI - Involvement of the dopaminergic system in the consolidation of fear conditioning in hippocampal CA3 subregion. AB - The hippocampus, the primary brain structure related to learning and memory, receives sparse but comprehensive dopamine innervations and contains dopamine D1 and D2 receptors. Systematic hippocampal dopaminergic dysfunction can cause deficits in spatial working memory and impair consolidation of contextual fear memories. CA3 is involved in the rapid acquisition of new memories and has extensive nerve fibre connections with other brain structures such as CA1, the amygdala, and the medial prefrontal cortex (mPFC). A bidirectional fibrous connection between CA3 and the amygdala reflects the importance of CA3 in fear conditioning. The present study evaluated the effects of a 6-OHDA lesion in CA3 on the acquisition and expression of conditioned fear. The results showed CA3 involvement in the expression but not the acquisition of conditioned fear. Injection of SCH23390 and quinpirole into the bilateral CA3 attenuated a conditioned fear-related freezing response, whereas SKF38393 and sulpiride were not associated with this effect. The present study found that a 6-OHDA lesion in CA3 up-regulated the expression of GluR1 in BLA and down-regulated NR2B in CA1 and the basolateral amygdala (BLA). Our data suggest that dopamine depletion in hippocampal subdivision CA3 may not be necessary for the acquisition of conditioned fear, but the expression of conditioned fear is likely dependent on the integrity of mesohippocampal dopaminergic connections. It is probable that both D1 and D2 dopaminergic receptors modulate the expression of conditioned fear. Changes in the expression of NR2B and GluR1 indicate that CA3 may modulate the activities of other brain structures. PMID- 25446754 TI - Intracerebroventricular injection of propionic acid, an enteric metabolite implicated in autism, induces social abnormalities that do not differ between seizure-prone (FAST) and seizure-resistant (SLOW) rats. AB - Autism is a complex neurodevelopmental disorder that is characterized by social abnormalities. Genetic, dietary and gut-related factors are implicated in autism, however the causal properties of these factors and how they may interact are unclear. Propionic acid (PPA) is a product of gut microbiota and a food preservative. PPA has been linked to autism, and PPA administration to rats is an animal model of the condition. Seizure-prone (FAST) and seizure-resistant (SLOW) rats were initially developed to investigate differential vulnerability to developing epilepsy. However, FAST rats also display autistic-like features, and have been proposed as a genetic model of autism. Here we examined the effects of PPA on social behavior in FAST and SLOW rats. A single intracerebroventricular injection of PPA, or phosphate-buffered saline (PBS), was administered to young adult male FAST and SLOW rats. Immediately after treatment, rats were placed in same-treatment and same-strain pairs, and underwent social behavior testing. PPA induced social abnormalities in both FAST and SLOW rat strains. While there was no evidence of social impairment in FAST rats that were not treated with PPA, these rats were hyperactive relative to SLOW rats. Post-mortem immunofluorescence analysis of brain tissue indicated that PPA treatment resulted in increased astrogliosis in the corpus callosum and cortex compared to PBS treatment. FAST rats had increased astrogliosis in the cortex compared to SLOW rats. Together these findings support the use of PPA as a rat model of autism, but indicate there are no interactive effects between the PPA and FAST models. PMID- 25446755 TI - Sub-processes of motor learning revealed by a robotic manipulandum for rodents. AB - Rodent models are widely used to investigate neural changes in response to motor learning. Usually, the behavioral readout of motor learning tasks used for this purpose is restricted to a binary measure of performance (i.e. "successful" movement vs. "failure"). Thus, the assignability of research in rodents to concepts gained in human research - implying diverse internal models that constitute motor learning - is still limited. To solve this problem, we recently introduced a three-degree-of-freedom robotic platform designed for rats (the ETH Pattus) that combines an accurate behavioral readout (in the form of kinematics) with the possibility to invasively assess learning related changes within the brain (e.g. by performing immunohistochemistry or electrophysiology in acute slice preparations). Here, we validate this platform as a tool to study motor learning by establishing two forelimb-reaching paradigms that differ in degree of skill. Both conditions can be precisely differentiated in terms of their temporal pattern and performance levels. Based on behavioral data, we hypothesize the presence of several sub-processes contributing to motor learning. These share close similarities with concepts gained in humans or primates. PMID- 25446757 TI - The antidepressant effects of ventromedial prefrontal cortex stimulation is associated with neural activation in the medial part of the subthalamic nucleus. AB - The nucleus accumbens (NAc), ventromedial prefrontal cortex (vmPFC), and cingulate gyrus (Cg) are key regions in the control of mood-related behaviors. Electrical stimulation of these areas induces antidepressant-like effects in both patients and animal models. Another structure whose limbic connections are receiving more interest in the context of mood-related behaviors is the medial part of the subthalamic nucleus (STN). Here, we tested the hypothesis that the mood-related effects of NAc, vmPFC, and Cg are accompanied by changes in the neural activity of the STN. We performed high-frequency stimulation (HFS) of the NAc, vmPFC, and Cg. Animals were behaviorally tested for hedonia and forced swim immobility; and the cellular activities in the different parts of the STN were assessed by means of c-Fos immunoreactivity (c-Fos-ir). Our results showed that HFS of the NAc and vmPFC, but not Cg reduced anhedonic-like and forced swim immobility behaviors. Interestingly, there was a significant increase of c-Fos-ir in the medial STN with HFS of the vmPFC, but not the NAc and Cg as compared to the sham. Correlation analysis showed that the medial STN is associated with the antidepressant-like behaviors in vmPFC HFS animals. No behavioral correlation was found with respect to behavioral outcome and activity in the lateral STN. In conclusion, HFS of the vmPFC induced profound antidepressant-like effects with enhanced neural activity in the medial part of the STN. PMID- 25446759 TI - Repeated threat (without harm) in a living environment potentiates defensive behavior. AB - Children exposed to neighborhood violence have higher rates of aggression, but it is unclear whether aggression is associated with threat, harm or the combination of factors. All animals, including humans, experience threat as they leave the safety of home and risk harm to gather resources (foraging). To better understand how selective environmental variables drive behavioral tendencies, we developed a semi-naturalistic living environment that includes the need to navigate across space to obtain resources. Rats were housed for three weeks in two tub cages, one with food and the other with water, both consistently available, but separated by a 91 cm long tunnel. After habituating for three days, half the rats (threat stress condition) received unpredictable threats (simultaneous puff of air with ferret dander, abrupt flash of light, and an abrupt sound) when crossing the central position of the tunnel (random order with p=0.25) for 21 days. During the manipulation, the threat stress rats crossed the tunnel less and exhibited risk assessment behaviors. After cessation of the treatment conditions, the threat stress group spent more time burying a rag with ferret dander odor and was more likely to bury, and spent more time burying a highly novel stimulus. There were no group differences in symptoms of depression, avoidance, or exploration. The results suggest that repeated threats without harm increase pre-emptive defense behaviors, a form of active coping, without affecting passive forms of coping. PMID- 25446756 TI - Differential effects of CB1 receptor agonism in behavioural tests of unconditioned and conditioned fear in adult male rats. AB - We investigated the effects of the highly selective CB1 receptor agonist ACEA and the CB1 receptor antagonist/inverse agonist AM251 on two behavioural tests of unconditioned fear, the elevated plus maze (EPM) and open field test (OFT), as well as on the recall and extinction of a conditioned auditory fear. Both ACEA and AM251 increased anxiety-like behaviour in the EPM and OFT. There was no effect of either drug on recall of the conditioned fear, and ACEA enhanced and AM251 impaired fear extinction. Further, though both the low (0.1 mg/kg) and high (0.5 mg/kg) dose of ACEA facilitated fear extinction, the low dose attenuated, and the high dose potentiated, fear induced corticosterone release suggesting independent effects of the drug on fear and stress responses. Although the extent to which cannabinoids are anxiogenic or anxiolytic has been proposed to be dose dependent, these results indicate that the same dose has differential effects across tasks, likely based in differences in sensitivities of CB1 receptors to the agonist in the neural regions subserving unconditioned and conditioned fear. PMID- 25446760 TI - The CRF1 receptor antagonist SSR125543 prevents stress-induced long-lasting sleep disturbances in a mouse model of PTSD: comparison with paroxetine and d cycloserine. AB - The selective CRF1 (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term behavioral and electrophysiological effects produced by traumatic stress exposure in mice. Sleep disturbances are one of the most commonly reported symptoms by people with post traumatic stress disorder (PTSD). The present study aims at investigating whether SSR125543 (10 mg/kg/day/i.p. for 2 weeks) is able to attenuate sleep/wakefulness impairment induced by traumatic stress exposure in a model of PTSD in mice using electroencephalographic (EEG) analysis. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day/i.p.), and the partial N-methyl-d-aspartate (NMDA) receptor agonist, d-cycloserine (10 mg/kg/day/i.p.), two compounds which have demonstrated clinical efficacy against PTSD. Baseline EEG recording was performed in the home cage for 6h prior to the application of two electric foot-shocks of 1.5 mA. Drugs were administered from day 1 post-stress to the day preceding the second EEG recording session, performed 14 days later. Results showed that at day 14 post-stress, shocked mice displayed sleep fragmentation as shown by an increase in the occurrence of both non-rapid eye movement (NREM) sleep and wakefulness bouts. The duration of wakefulness, NREM and REM sleep were not significantly affected. The stress induced effects were prevented by repeated administration of SSR125543, paroxetine and D-cycloserine. These findings confirm further that the CRF1 receptor antagonist SSR125543 is able to attenuate the deleterious effects of traumatic stress exposure. PMID- 25446758 TI - Traumatic brain injury induces neuroinflammation and neuronal degeneration that is associated with escalated alcohol self-administration in rats. AB - BACKGROUND: Traumatic brain injury (TBI) affects millions of people each year and is characterized by direct tissue injury followed by a neuroinflammatory response. The post-TBI recovery period can be associated with a negative emotional state characterized by alterations in affective behaviors implicated in the development of Alcohol Use Disorder in humans. The aim of this study was to test the hypothesis that post-TBI neuroinflammation is associated with behavioral dysfunction, including escalated alcohol intake. METHODS: Adult male Wistar rats were trained to self-administer alcohol prior to counterbalanced assignment into naive, craniotomy, and TBI groups by baseline drinking. TBI was produced by lateral fluid percussion (LFP; >2 ATM; 25ms). Alcohol drinking and neurobehavioral function were measured at baseline and following TBI in all experimental groups. Markers of neuroinflammation (GFAP and ED1) and neurodegeneration (FJC) were determined by fluorescence histochemistry in brains excised at sacrifice 19 days post-TBI. RESULTS: The cumulative increase in alcohol intake over the 15 days post-TBI was greater in TBI animals compared to naive controls. A higher rate of pre-injury alcohol intake was associated with a greater increase in post-injury alcohol intake in both TBI and craniotomy animals. Immediately following TBI, both TBI and craniotomy animals exhibited greater neurobehavioral dysfunction compared to naive animals. GFAP, IBA-1, ED1, and FJC immunoreactivity at 19 days post-TBI was significantly higher in brains from TBI animals compared to both craniotomy and naive animals. CONCLUSIONS: These results show an association between post-TBI escalation of alcohol drinking and marked localized neuroinflammation at the site of injury. Moreover, these results highlight the relevance of baseline alcohol preference in determining post-TBI alcohol drinking. Further investigation to determine the contribution of neuroinflammation to increased alcohol drinking post-TBI is warranted. PMID- 25446761 TI - Resurgence of sucrose and cocaine seeking in free-feeding rats. AB - Resurgence is relapse of an extinguished operant response following the removal of alternative reinforcement. In animal models of resurgence to date, rats have been food deprived and food is used as the source of alternative reinforcement. Thus, when the alternative reinforcer is removed, the only remaining source of food during experimental sessions is no longer available. Acute food deprivation is known to produce reinstatement of drug seeking, thus such deprivation has been suggested a potential mechanism of resurgence. The present experiments examined whether resurgence of sucrose and cocaine seeking could be obtained with rats that were not food deprived. Free-feeding rats were trained to press a lever for either sucrose (Experiment 1) or cocaine infusions (Experiment 2). Next, lever pressing was extinguished and an alternative response (nose poking) was reinforced with sucrose. When nose poking was also placed on extinction, resurgence of both sucrose and cocaine seeking was observed. Thus, resurgence of both sucrose and cocaine seeking can be obtained in rats that are not food restricted and it appears unlikely that an acute hunger state is responsible for resurgence. In addition, the present procedures for studying resurgence in the absence of interpretive complexities introduced by the use of food-deprivation may prove useful for further investigations of the neurobiological mechanisms of resurgence. PMID- 25446762 TI - The rotenone-induced rat model of Parkinson's disease: behavioral and electrophysiological findings. AB - Exposure to rotenone leads to parkinsonian features, such as loss of dopaminergic neurons in the substantia nigra and motor impairment, however, the validity of this model has recently been questioned. In rodent and monkey models of Parkinson's disease (PD) abnormal neuronal activity in the basal ganglia motor loop has been described, with hyperactivity of the subthalamic nucleus (STN) similar to that found in PD. The present study aims at providing new and more specific evidence for the validity of the rotenone rat model of PD by examining whether neuronal activity in the STN is altered. Male Sprague Dawley rats were treated with rotenone injections (2.5mg/kg bodyweight intraperitoneally) for 60 days. Behavioral analysis showed an impairment in the rotarod and hanging wire test in the rotenone group (p<0.05), accompanied by a decline in tyrosine hydroxylase immunoreactive neurons in the nigro-striatal region (p<0.001). Thereafter, single unit (SU) activities and local field potentials were recorded in the STN in urethane anesthetized rats. The SU analysis revealed a higher neuronal discharge rate (p<0.001), more bursts per minute (p=0.006) and a higher oscillatory activity (p=0.008) in the STN of rotenone treated rats. Spectral analysis showed an increase of relative beta power in the STN as well as in the motor cortex. We found electrophysiological key features of PD pathology and pathophysiology in the STN of rotenone treated rats. Therefore, the rotenone induced rat model of PD deserves further attention since it covers more aspects than dopamine depletion and implies the reproducibility of PD specific features. PMID- 25446763 TI - White matter integrity and cognitive performance in children with prenatal methamphetamine exposure. AB - There is emerging evidence on the harmful effects of prenatal methamphetamine (MA) exposure on the structure and function of the developing brain. However, few studies have assessed white matter structural integrity in the presence of prenatal MA exposure, and results are inconsistent. This investigation thus used diffusion tensor imaging (DTI) to investigate white matter microstructure and cognitive performance in a group of prenatal MA exposed (or MA) children and controls of similar age. Seventeen MA children and 15 healthy controls (aged 6-7 years) underwent DTI and assessment of motor function and general cognitive ability. Whole brain analyses of white matter structure were performed using FSL's tract-based spatial statistics comparing fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD). Mean diffusion values were extracted from white matter regions shown to differ across groups to determine whether variations in FA predicted cognitive performance. Analyses were controlled for maternal nicotine use. MA children showed significantly lower FA as well as higher MD, RD and AD in tracts that traverse striatal, limbic and frontal regions. Abnormal FA levels in MA children were significantly associated with poorer motor coordination and general cognitive ability sub-items that relate to aspects of executive function. Our findings suggest that, consistent with previous studies in older children, there are disruptions of white matter microstructural integrity in striatal, limbic and frontal regions of young MA exposed children, with prominent cognitive implications. Future longitudinal studies may clarify how prenatal MA exposure affects white matter structural connectivity at different stages of brain maturation. PMID- 25446765 TI - Focal cerebral ischemia impairs motivation in a progressive FR schedule of reinforcement in mice. AB - Characterization of functional outcome in animal stroke models is essential to improve preclinical drug screenings. Operant procedures showed promising results for the identification of long-lasting functional deficits. In particular, a suppression of lever-pressing in high ratio schedules has been consistently found in rodent models of ischemic stroke. In the present work, we attempted to replicate these isolated observations, by submitting C57Bl/6J mice to a progressive fixed-ratio schedule of reinforcement three weeks after MCAO or sham surgery. Results showed a significant lever-pressing impairment in the MCAO group. Motivational factors (longer post-reinforcement pause, lesser appeal for food rewards) seemed accountable for the deficit, while motor abilities appeared preserved. These findings resemble fatigue-like states experienced by stroke survivors and may be used as long-term measures of behavioral outcome following experimental stroke. PMID- 25446764 TI - Transcranial direct current stimulation over the supplementary motor area modulates the preparatory activation level in the human motor system. AB - Transcranial direct current stimulation (tDCS) is a non-invasive stimulation method that can induce transient polarity-specific neuroplastic changes in cortical excitability lasting up to 1h post-stimulation. While excitability changes with stimulation over the primary motor cortex have been well documented, the functional effects of stimulation over premotor regions are less well understood. In the present experiment, we tested how cathodal and anodal tDCS applied over the region of the supplementary motor area (SMA) affected preparation and initiation of a voluntary movement. Participants performed a simple reaction time (RT) task requiring a targeted wrist-extension in response to a go-signal. In 20% of RT trials a startling acoustic stimulus (SAS) was presented 500 ms prior to the "go" signal in order to probe the state of motor preparation. Following the application of cathodal, anodal, or sham tDCS (separate days) over SMA for 10 min, participants performed blocks of RT trials at 10 min intervals. While sham stimulation did not affect RT or incidence of early release by the SAS, cathodal tDCS led to a significant slowing of RT that peaked 10 min after the end of stimulation and was associated with a marked decrease in the incidence of movement release by the SAS. In contrast, anodal tDCS resulted in faster RTs, but the incidence of release was unchanged. These results are consistent with the SMA playing a role in the pre-planning of movements and that modulating its activity with tDCS can lead to polarity specific changes in motor behavior. PMID- 25446766 TI - Role of intra-hippocampal orexin 1 and orexin 2 receptors in conditioned place preference induced by chemical stimulation of the lateral hypothalamus. AB - Evidence from animal models suggests a role for orexinergic system in reward processing and drug addiction. The lateral hypothalamus (LH) orexin neurons send projections to the dorsal hippocampus (CA1 region) which plays a pivotal role in reward processes. Moreover, it has been shown that orexin containing terminals and orexin receptors are distributed in the hippocampal formation. In this study, we assessed the role of orexin 1 (OX1r) and orexin2 (OX2r) receptors in the CA1 on the development of LH stimulation-induced conditioned place preference (CPP). Animals weighing 230-280 g were unilaterally implanted by two separate cannulae into the LH and CA1. The CPP paradigm was done; SB334867 and TCSOX229, as selective OX1r and OX2r antagonists (1, 3, 10 and 30 nM/0.5 MUl DMSO) administrated into the CA1 prior to intra-LH carbachol microinjection (250 nM; the most effective dose) during the 3-days conditioning phase, respectively. Conditioning scores and locomotor activities were recorded by Ethovision software on the test day. The results showed that the administration of OX1r and OX2r antagonists into the CA1 attenuated the development of CPP induced by chemical stimulation of the LH. However, this decrease in OX1r antagonist treated groups was more significant than that in OX2r antagonist treated animals. Our findings suggest that OX1 and OX2 receptors in the CA1 region of the hippocampus were involved in the development of CPP induced by chemical stimulation of the LH and the efficiency of OX1 receptors in this phenomenon was more considerable than OX2 receptors in rats. PMID- 25446767 TI - Omega-3 fatty acids improve behavioral coping to stress in multiparous rats. AB - Behavioral coping refers to the ability to modify behavior to escape from stress, and is protective against the development of depressive disorders. Omega-3 fatty acid (n-3 FA) intake is inversely correlated with anxiety and depression in humans. The objective of this study was to determine if consumption of n-3 FAs promotes adaptive coping behaviors in a multiparous rat model. Twenty female rats were randomly assigned to diets with or without n-3 FA containing menhaden oil or sunflower oil as the fat source, respectively. Rats experienced two cycles of gestation and lactation. Behavioral testing began on the second day after the last parturition. Rats consuming n-3 FAs displayed improved escape learning in the shuttle box test. Specifically, rats consuming n-3 FAs escaped footshock more quickly and had a greater number of successful escapes in the shuttle box than rats not consuming n-3 FAs. Diet did not affect general activity in the open field, but rats consuming n-3 FAs showed less reactivity and habituation to novelty in the open field than rats not consuming n-3 FAs. Immobility and swimming in the forced swim test, risk-taking assessed by the light/dark test, sucrose drinking, and motor coordination were not significantly affected by diet. A diet enriched with n-3 FAs promoted behavioral escape changes consistent with increased adaptive coping to stressful events, suggesting that n-3 FAs may help prevent the development of stress-related depressive disorders. PMID- 25446770 TI - Profiling the role of deacylation-reacylation in the lymphatic transport of a triglyceride-mimetic prodrug. AB - PURPOSE: Recent studies have demonstrated the potential for a triglyceride (TG) mimetic prodrug to promote the delivery of mycophenolic acid (MPA) to the lymphatic system. Here, the metabolic pathways that facilitate the lymphatic transport of the TG prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) were examined to better inform the design of next generation prodrugs. METHODS: In vitro hydrolysis experiments in simulated intestinal conditions and in vivo rat lymphatic transport experiments were conducted in the presence and absence of orlistat and A922500 (inhibitors of lipolysis and TG re-esterification, respectively), to evaluate the importance of 2-MPA-TG digestion and re esterification of 2-MPA-MG (the 2-monoglyceride derivative) in promoting lymphatic transport. RESULTS: 2-MPA-TG was rapidly hydrolysed to 2-MPA-MG on incubation with fresh bile and pancreatic fluid (BPF), but not in simulated gastric fluid, heat-inactivated BPF or BPF + orlistat. Orlistat markedly decreased lymphatic transport and systemic exposure of 2-MPA-TG derivatives suggesting that inhibition of pancreatic lipase hindered luminal digestion and absorption of the prodrug. A922500 also significantly decreased lymphatic transport of 2-MPA-TG but redirected MPA to the portal blood, suggesting that hindered re-acylation of 2-MPA-MG resulted in intracellular degradation. CONCLUSION: Incorporation into TG deacylation-reacylation pathways is a critical determinant of the utility of lymph directed TG-mimetic prodrugs. PMID- 25446768 TI - A thickened amino-acid formula in infants with cow's milk allergy failing to respond to protein hydrolysate formulas: a randomized double-blind trial. AB - INTRODUCTION: Amino-acid-based formulas (AAFs) are recommended for children with cow's milk protein allergy (CMPA) failing to respond to extensively hydrolyzed formulas (eHFs). OBJECTIVE: This study aimed to assess the tolerance/hypoallergenicity and efficacy of a thickened AAF (TAAF) in these infants. METHODS: This multicenter, double-blind, randomized controlled trial (NCT01940068) compared 3-month feeding with a pectin-based TAAF (Novalac((r)), United Pharmaceuticals, Paris, France) and a commercially available "reference" AAF (RAAF; Neocate((r)), Nutricia, Germany) in infants aged <18 months with CMPA and persistent allergy symptoms with eHF feeding. Reported here are the results of an interim analysis after 1 month of feeding. RESULTS: Of the 86 infants randomized, CMPA with eHF intolerance was confirmed in 75 infants; all of them tolerated the allocated AAFs. The major allergic symptom disappeared within 1 month in 61.9 and 51.5 % and regurgitations disappeared in 66.7 and 42.3 % of infants who received TAAF and RAAF, respectively. Infants had significantly more normal stools (soft or formed consistency) with the TAAF (90.5 vs. 66.7 %; p = 0.011). From baseline, daily family life significantly improved with both AAFs: crying time decreased by 97.3 (p < 0.001) and 28.6 min (p = 0.014) and sleeping time increased by 64.6 (p = 0.009) and 29.0 min with TAAF and RAAF, respectively. At day 30, weight and body mass index z-score gains were 0.1 and 0.2 with TAAF and 0.2 and 0.0 with RAAF. CONCLUSION: Both AAFs were well tolerated by infants with CMPA and eHF intolerance and ensured appropriate growth, with the TAAF providing additional comfort. PMID- 25446771 TI - Development and Application of a Mechanistic Pharmacokinetic Model for Simvastatin and its Active Metabolite Simvastatin Acid Using an Integrated Population PBPK Approach. AB - PURPOSE: To develop a population physiologically-based pharmacokinetic (PBPK) model for simvastatin (SV) and its active metabolite, simvastatin acid (SVA), that allows extrapolation and prediction of their concentration profiles in liver (efficacy) and muscle (toxicity). METHODS: SV/SVA plasma concentrations (34 healthy volunteers) were simultaneously analysed with NONMEM 7.2. The implemented mechanistic model has a complex compartmental structure allowing inter-conversion between SV and SVA in different tissues. Prior information for model parameters was extracted from different sources to construct appropriate prior distributions that support parameter estimation. The model was employed to provide predictions regarding the effects of a range of clinically important conditions on the SV and SVA disposition. RESULTS: The developed model offered a very good description of the available plasma SV/SVA data. It was also able to describe previously observed effects of an OATP1B1 polymorphism (c.521 T > C) and a range of drug drug interactions (CYP inhibition) on SV/SVA plasma concentrations. The predicted SV/SVA liver and muscle tissue concentrations were in agreement with the clinically observed efficacy and toxicity outcomes of the investigated conditions. CONCLUSIONS: A mechanistically sound SV/SVA population model with clinical applications (e.g., assessment of drug-drug interaction and myopathy risk) was developed, illustrating the advantages of an integrated population PBPK approach. PMID- 25446772 TI - Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for THIOMABTM Drug Conjugates. AB - PURPOSE: THIOMABTM drug conjugates (TDCs) with engineered cysteine residues allow site-specific drug conjugation and defined Drug-to-Antibody Ratios (DAR). In order to help elucidate the impact of drug-loading, conjugation site, and subsequent deconjugation on pharmacokinetics and efficacy, we have developed an integrated mathematical model to mechanistically characterize pharmacokinetic behavior and preclinical efficacy of MMAE conjugated TDCs with different DARs. General applicability of the model structure was evaluated with two different TDCs. METHOD: Pharmacokinetics studies were conducted for unconjugated antibody and purified TDCs with DAR-1, 2 and 4 for trastuzumab TDC and Anti-STEAP1 TDC in mice. Total antibody concentrations and individual DAR fractions were measured. Efficacy studies were performed in tumor-bearing mice. RESULTS: An integrated model consisting of distinct DAR species (DAR0-4), each described by a two compartment model was able to capture the experimental data well. Time series measurements of each Individual DAR species allowed for the incorporation of site specific drug loss through deconjugation and the results suggest a higher deconjugation rate from heavy chain site HC-A114C than the light chain site LC V205C. Total antibody concentrations showed multi-exponential decline, with a higher clearance associated with higher DAR species. The experimentally observed effects of TDC on tumor growth kinetics were successfully described by linking pharmacokinetic profiles to DAR-dependent killing of tumor cells. CONCLUSION: Results from the integrated model evaluated with two different TDCs highlight the impact of DAR and site of conjugation on pharmacokinetics and efficacy. The model can be used to guide future drug optimization and in-vivo studies. PMID- 25446769 TI - Nanoparticles and the blood-brain barrier: advancing from in-vitro models towards therapeutic significance. AB - The blood-brain barrier is a unique cell-based restrictive barrier that prevents the entry of many substances, including most therapeutics, into the central nervous system. A wide range of nanoparticulate delivery systems have been investigated with the aim of targeting therapeutics (drugs, nucleic acids, proteins) to the brain following administration by various routes. This review provides a comprehensive description of the design and formulation of these nanoparticles including the rationale behind individual approaches. In addition, the ability of currently available in-vitro BBB models to accurately predict the in-vivo performance of targeted nanoparticles is critically assessed. PMID- 25446773 TI - Preclinical Pharmacokinetic Considerations for the Development of Antibody Drug Conjugates. AB - Antibody drug conjugates (ADCs) are an emerging new class of targeted therapeutics for cancer that use antibodies to deliver cytotoxic drugs to cancer cells. There are two FDA approved ADCs on the market and over 30 ADCs in the clinical pipeline against a number of different cancer types. The structure of an ADC is very complex with multiple components and considerable efforts are ongoing to determine the attributes necessary for clinical success. Understanding the pharmacokinetics of an ADC and how it impacts efficacy and toxicity is a critical part of optimizing ADC design and delivery i.e., dose and schedule. This review discusses the pharmacokinetic considerations for an ADC and tools and strategies that can be used to evaluate molecules at the preclinical stage. PMID- 25446775 TI - Erratum to: Fluorescent Dye Labeled Iron Oxide/Silica Core/Shell Nanoparticle as a Multimodal Imaging Probe. PMID- 25446776 TI - One-health approach as counter-measure against "autoimmune" responses in biosecurity. AB - This Swine flu pandemic of 2009 and the potential Avian flu threat of 2011-2012 have revived a most challenging debate on protection against infectious diseases. The response to the Swine flu pandemic has been ambivalent, both on the societal (political) and the scientific level. While some scientists warned against potential massive loss of human lives and urged for immediate and large-scale vaccination, others accused them of unnecessary scaremongering, arguing that the pandemic would not be that severe. The lab-created virulent Avian flu virus - which has been created in order to 'fight' a potential Avian flu pandemic - sparked a fierce debate on the dual-use risks of such a pre-emptive strategy. This article involves an analysis of the medical-political response to these recent viral threats using Peter Sloterdijk's immunological framework as diagnostic tool. In his trilogy Spheres Sloterdijk uses immunological concepts to analyse and assess the contemporary biopolitical situation. It shows how drawing a parallel between the functioning of the biological immune system and "immune responses" on socio-political level enables to assess and reconceptualise biosecurity. It demonstrates that ideas such as "nature is the biggest terrorist" - as advanced by many virologists - sometimes result in exaggerated "immunisation responses". This strong defensive attitude sometimes brings about collateral damage. In other words, fierce biosecurity measures sometimes risk developing into "autoimmune" responses that actually destruct the body politic they are meant to protect. By drawing on recent insights in the functioning of the biological immune system it is shown how a One-Health approach that incorporates a broader and nuanced "immunological" repertoire could act as counter-measure against "autoimmune" responses in biosecurity. PMID- 25446777 TI - Developing and validating a measure of community capacity: Why volunteers make the best neighbours. AB - Social support and community connectedness are key determinants of both mental and physical wellbeing. While social capital has been used to indicate the instrumental value of these social relationships, its broad and often competing definitions have hindered practical applications of the concept. Within the health promotion field, the related concept of community capacity, the ability of a group to identify and act on problems, has gained prominence (Labonte and Laverack, 2001). The goal of this study was to develop and validate a scale measuring community capacity including exploring its associations with socio demographic and civic behaviour variables among the residents of four small (populations 1500-2000) high-deprivation towns in southern New Zealand. The full (41-item) scale was found to have strong internal consistency (Cronbach's alpha = 0.89) but a process of reducing the scale resulted in a shorter 26-item instrument with similar internal consistency (alpha 0.88). Subscales of the reduced instrument displayed at least marginally acceptable levels of internal consistency (0.62-0.77). Using linear regression models, differences in community capacity scores were found for selected criterion, namely time spent living in the location, local voting, and volunteering behaviour, although the first of these was no longer statistically significant in an adjusted model with potential confounders including age, sex, ethnicity, education, marital status, employment, household income, and religious beliefs. This provides support for the scale's concurrent validity. Differences were present between the four towns in unadjusted models and remained statistically significant in adjusted models (including variables mentioned above) suggesting, crucially, that even when such factors are accounted for, perceptions of one's community may still depend on place. PMID- 25446774 TI - Pharmacokinetic/Pharmacodynamic Modeling of Renin-Angiotensin Aldosterone Biomarkers Following Angiotensin-Converting Enzyme (ACE) Inhibition Therapy with Benazepril in Dogs. AB - PURPOSE: The objective of this research was to provide a comprehensive description of the effect of benazepril on the dynamics of the renin-angiotensin aldosterone system (RAAS) in dogs. METHODS: Blood specimens for renin activity (RA), angiotensin II (AII), and aldosterone (ALD) quantitation in plasma were drawn from 12 healthy adult beagle dogs randomly allocated to 2 treatment groups: (i) benazepril 5 mg PO, q24 h (n: 6) and (ii) placebo (n: 6), in a cross-over design. A mechanism-based pharmacokinetic/pharmacodynamic model, which includes the periodic nature of RA, AII, and ALD during placebo treatment and the subsequent changes in dynamics following repeated dosing with benazepril, was developed. RESULTS: The disposition kinetics of benazepril active metabolite, benazeprilat, was characterized using a saturable binding model to the angiotensin converting enzyme. The modulatory effect of benazeprilat on the RAAS was described using a combination of immediate response models. Our data show that benazepril noticeably influences the dynamics of the renin cascade, resulting in a substantial decrease in AII and ALD, while increasing RA throughout the observation span. CONCLUSIONS: The model provides a quantitative framework for better understanding the effect of ACE inhibition on the dynamics of the systemic RAAS in dogs. PMID- 25446778 TI - Public or private? The role of the state and civil society in health and health inequalities across nations. AB - Social scientists have long recognized that macro-level factors have the potential to shape the health of populations and individuals. Along these lines, they have theorized about the role of the welfare state in creating more equal opportunities and outcomes and how this intervention may benefit health. More recently, scholars and policymakers alike have pointed out how the involvement of civil society actors may replace or complement any state effort. Using data from the World Values Surveys and the European Values Study, combined with national level indicators for welfare state and civil society involvement, we test the impact of each sector on health and health inequalities in 25 countries around the world. We find that both have a statistically significant effect on overall health, but the civil society sector may have a greater independent influence in societies with weaker welfare states. The health inequalities results are less conclusive, but suggest a strong civil society may be particularly beneficial to vulnerable populations, such as the low income and unemployed. Our paper represents an early step in providing empirical evidence for the impact of the welfare state and civil society on health and health inequalities. PMID- 25446779 TI - Cytokines and chemokines as biomarkers of ethanol-induced neuroinflammation and anxiety-related behavior: role of TLR4 and TLR2. AB - Recent evidence supports the influence of neuroimmune system activation on behavior. We have demonstrated that ethanol activates the innate immune system by stimulating toll-like receptor 4 (TLR4) signaling in glial cells, which triggers the release of inflammatory mediators and causes neuroinflammation. The present study aimed to evaluate whether the ethanol-induced up-regulation of cytokines and chemokines is associated with anxiety-related behavior, 24 h after ethanol removal, and if TLR4 or TLR2 is involved in these effects. We used WT, TLR4-KO and TLR2-KO mice treated with alcohol for 5 months to show that chronic ethanol consumption increases the levels of cytokines (IL-1beta, IL-17, TNF-alpha) and chemokines (MCP-1, MIP-1alpha, CX3CL1) in the striatum and serum (MCP-1, MIP 1alpha, CX3CL1) of WT mice. Alcohol deprivation for 24 h induces IFN-gamma levels in the striatum and maintains high levels of some cytokines (IL-1beta, IL-17) and chemokines (MIP-1alpha, CX3CL1) in this brain region. The latter events were associated with an increase in anxiogenic-related behavior, as evaluated by the dark and light box and the elevated plus maze tests. Notably, mice lacking TLR4 or TLR2 receptors are largely protected against ethanol-induced cytokine and chemokine release, and behavioral associated effects during alcohol abstinence. These data support the role of TLR4 and TLR2 responses in neuroinflammation and in anxiogenic-related behavior effects during ethanol deprivation, and also provide evidence that chemokines and cytokines can be biomarkers of ethanol induced neuroimmune response. PMID- 25446780 TI - An in silico screen links gene expression signatures to drug response in glioblastoma stem cells. AB - Cancer stem cells (CSCs) are thought to promote resistance to chemotherapeutic drugs in glioblastoma, the most common and aggressive primary brain tumor. However, the use of high-throughput drug screens to discover novel small-molecule inhibitors for CSC has been hampered by their instability in long-term cell culture. We asked whether predictive models of drug response could be developed from gene expression signatures of established cell lines and applied to predict drug response in glioblastoma stem cells. Predictions for active compounds were confirmed both for 185 compounds in seven established glioma cell lines and 21 compounds in three glioblastoma stem cells. The use of established cell lines as a surrogate for drug response in CSC lines may enable the large-scale virtual screening of drug candidates that would otherwise be difficult or impossible to test directly in CSCs. PMID- 25446782 TI - Lutein production from biomass: marigold flowers versus microalgae. AB - Microalgae have faster growth rates and more free lutein than marigold flowers, the current source of lutein. However, no commercial lutein production uses microalgae. This review compares lutein content, cultivation, harvesting, cell disruption, and extraction stages of lutein production using marigold flowers and those using microalgae as feedstock. The lutein production rate of microalgae is 3-6 times higher than that of marigold flowers. To produce 1 kg of pure lutein, marigolds need more land and water, but require less nutrients (N, P, K) and less energy than microalgae. Since lutein is tightly bound in microalgae and microalgae are small, cell disruption and subsequent extraction stages consume a considerable amount of energy. Research and development of affordable lutein production from microalgae are discussed. PMID- 25446783 TI - Anaerobic digestion of lignocellulosic biomass: challenges and opportunities. AB - Anaerobic digestion (AD) of lignocellulosic biomass provides an excellent opportunity to convert abundant bioresources into renewable energy. Rumen microorganisms, in contrast to conventional microorganisms, are an effective inoculum for digesting lignocellulosic biomass due to their intrinsic ability to degrade substrate rich in cellulosic fiber. However, there are still several challenges that must be overcome for the efficient digestion of lignocellulosic biomass. Anaerobic biorefinery is an emerging concept that not only generates bioenergy, but also high-value biochemical/products from the same feedstock. This review paper highlights the current status of lignocellulosic biomass digestion and discusses its challenges. The paper also discusses the future research needs of lignocellulosic biomass digestion. PMID- 25446781 TI - Association study of UGT1A9 promoter polymorphisms with DILI based on systematically regional variation screen in Chinese population. AB - Drug-induced liver injury (DILI) is caused by unpredictable adverse drug reaction due mainly to the accumulation of hepatotoxic compounds in the liver resulting in significant damage. Drug-metabolizing enzymes have been prime targets for molecular studies relevant to DILI. The gene UGT1A9 mainly expresses in the liver and has an important role in drug metabolism. The Han Chinese has a very long and complex demographic history, and the population stratification arising from the interplay of different geographic areas may influence the polymorphism pattern. We selected 260 healthy subjects in three different geographic areas (including Xian, Shanghai and Liuzhou) for systemic screening and analysis of single nucleotide polymorphisms (SNPs) in the promoter region of UGT1A9. Eight SNPs were identified and no regional disparity exists among the three populations. Based on these results, 213 DILI patients from all over the Chinese mainland were further recruited to investigate possible association between UGT1A9 and DILI. We observed statistically significant associations between SNP rs2741045 and DILI at both allele and genotype levels (allele: P=0.032; genotype: P=0.029; after Bonferroni correction). Also, multivariate interaction analysis discovered the interaction between rs2741045 and age associated with DILI significantly. This is the first such screening study to investigate the association between UGT1A9 promoter polymorphisms and DILI in the Chinese population and it could provide the basis for further study of DILI mechanisms. PMID- 25446784 TI - Upscaling of an electronic nose for completely stirred tank reactor stability monitoring from pilot-scale to real-scale agricultural co-digestion biogas plant. AB - This study investigated the use of an electronic nose for on-line anaerobic reactor state monitoring at the pilot-scale level and then upscaling to the full scale level. E-nose indicator was compared to classical state indicators such as pH, alkalinity, volatile fatty acids concentration and to other gas phase compounds. Multivariate statistical process control method, based on principal component analysis and the Hotelling's T(2) statistics was used to derive an indicator representative of the reactor state. At the pilot-scale level, the e nose indicator was relevant and could distinguish 3 process states: steady-state, transient and collapsing process. At the full-scale level, the e-nose indicator could provide the warning of the major disturbance whereas two slight disturbances were not detected and it gave one major false alarm. This work showed that gas phase relation with anaerobic process should be deeper investigated, as an e-nose could indicate the reactor state, focusing on the gas phase. PMID- 25446785 TI - Foam formation in biogas plants caused by anaerobic digestion of sugar beet. AB - The use of sugar beet in anaerobic digestion (AD) during biogas production can lead to process upsets such as excessive foaming in fermenters. In the present study, foam formation in sugar beet-fed digestates was studied in foaming tests. The increasing disintegration grade of sugar beet was observed to have a promoting effect on foaming in the digestate but did not affect the biogas yield. Chemical analysis of foam and digestate from sugar beet silage AD showed high concentrations of pectin, other carbohydrates and N-containing substances in the foam. Both pectin and sucrose showed little foaming in AD. Nevertheless, sucrose and calcium chloride had a promoting effect on foaming for pectin AD. Salts of divalent ions also enhanced the foam intensity in the case of sugar beet silage AD, whereas ammonium chloride and urea had a lessening effect on sugar beet-based foaming. PMID- 25446786 TI - Determination of methane emission rates on a biogas plant using data from laser absorption spectrometry. AB - The aim of the work was to establish a method for emission control of biogas plants especially the observation of fugitive methane emissions. The used method is in a developmental stage but the topic is crucial to environmental and economic issues. A remote sensing measurement method was adopted to determine methane emission rates of a biogas plant in Rhineland-Palatinate, Germany. An inverse dispersion model was used to deduce emission rates. This technique required one concentration measurement with an open path tunable diode laser absorption spectrometer (TDLAS) downwind and upwind the source and basic wind information, like wind speed and direction. Different operating conditions of the biogas plant occurring on the measuring day (December 2013) could be represented roughly in the results. During undisturbed operational modes the methane emission rate averaged 2.8 g/s, which corresponds to 4% of the methane gas production rate of the biogas plant. PMID- 25446787 TI - Retrofitting hetrotrophically cultivated algae biomass as pyrolytic feedstock for biogas, bio-char and bio-oil production encompassing biorefinery. AB - Algal biomass grown hetrotrophically in domestic wastewater was evaluated as pyrolytic feedstock for harnessing biogas, bio-oil and bio-char. Freshly harvested microalgae (MA) and lipid extracted microalgae (LEMA) were pyrolysed in packed bed reactor in the presence and absence of sand as additive. MA (without sand additive) depicted higher biogas (420 ml/g; 800 degrees C; 3 h) and bio-oil (0.70 ml/g; 500 degrees C; 3 h). Sand addition enhanced biogas production (210 ml/g; 600 degrees C; 2 h) in LEMA operation. The composition of bio-gas and bio oil was found to depend on the nature of feedstock as well as the process conditions viz., pyrolytic-temperature, retention time and presence of additive. Sand additive improved the H2 composition while pyrolytic temperature increment caused a decline in CO2 fraction. Bio-char productivity increased with increasing temperature specifically with LEMA. Integration of thermo-chemical process with microalgae cultivation showed to yield multiple resources and accounts for environmental sustainability in the bio-refinery framework. PMID- 25446788 TI - Granulation and ferric oxides loading enable biochar derived from cotton stalk to remove phosphate from water. AB - Granulation of biochar powder followed by immobilization of ferric oxides on the macroporous granular biochar (Bg-FO-1) substantially enhanced phosphate removal from water. BET analysis confirmed that both granulation and ferric oxides loading can increase the surface areas and pore volumes effectively. Bg-FO-1 was proven to be a favorable adsorbent for phosphate. The phosphate adsorption capacity was substantially increased from 0 mg/g of raw biochar powder to 0.963 mg/g (Bg-FO-1). When the ferric oxides loading was prior to granulation, the adsorption capacity was decreased by 59-0.399 mg/g, possibly due to the decrease of micropore and mesopore area as well as the overlaying of binders to the activated sites produced by ferric oxides. PMID- 25446789 TI - Air gasification of rice husk in bubbling fluidized bed reactor with bed heating by conventional charcoal. AB - An experimental study of air gasification of rice husk was conducted in a bench scale fluidized bed gasifier (FBG) having 210 mm diameter and 1600 mm height. Heating of sand bed material was performed using conventional charcoal fuel. Different operating conditions like bed temperature, feeding rate and equivalence ratio (ER) varied in the range of 750-850 degrees C, 25-31.3 kg/h, and 0.3-0.38, respectively. Flow rate of air was kept constant (37 m(3)/h) during FBG experiments. The carbon conversion efficiencies (CCE), cold gas efficiency, and thermal efficiency were evaluated, where maximum CCE was found as 91%. By increasing ER, the carbon conversion efficiency was decreased. Drastic reduction in electric consumption for initial heating of gasifier bed with charcoal compared to ceramic heater was ~45%. Hence rice husk is found as a potential candidate to use directly (without any processing) in FBG as an alternative renewable energy source from agricultural field. PMID- 25446790 TI - [Non-Hodgkin lymphoma: Excellent results at the expense of the high toxicity of the treatment]. AB - INTRODUCTION: Lymphomas are the third malignancy in children, and within them non Hodgkin lymphoma (NHL) accounts for just 7% of cancers in children under 15 years old. Chemotherapy is currently the treatment of choice. The objective of this study is to analyze the toxicity caused by the treatment in pediatric patients diagnosed with NHL. MATERIAL AND METHODS: A retrospective study was conducted on patients diagnosed with mature B-cell NHL, treated according to the LMB protocol 2001, from January 2007 to February 2014. Data concerning the diagnosis, treatment and toxicities that developed in the patients during the same period were collected. RESULTS: A total of 20 mature B-cell NHL cases were diagnosed: 16 Burkitt lymphomas, 2 diffuse large cell lymphomas and 2 mature leukemias. Almost two-thirds (65%) of patients were classified in a high grade stage (iii-iv) at diagnosis. Serious infectious processes, severe myelosuppression, liver abnormalities, and mucositis were the most frequent toxicities. Overall survival was 95% (19/20). One patient died of causes unrelated to the illness. CONCLUSION: Despite the excellent survival rate, most patients diagnosed with NHL mature B cells experience grade iii and iv toxicities during treatment. PMID- 25446791 TI - [Focal delayed post-chickenpox myelitis. Case report. A review and update]. PMID- 25446792 TI - [Testicular microlithiasis and the importance of follow-up]. PMID- 25446793 TI - [Hiccups and horizontal stomach: signs of gastric volvulus]. PMID- 25446795 TI - [Terrestrial rabies alert in Spain in 2013. Paediatric update]. PMID- 25446794 TI - [Recurrent meningitis due to anatomical defects: The bacteria indicates its origin]. AB - INTRODUCTION: Recurrent meningitis is a rare disease. Anatomical abnormalities and immunodeficiency states are predisposing factors. Four cases, in which immunodeficiency was excluded, are presented. The causal microorganism led to the detection of the anatomical defect responsible for the recurrences. PATIENTS AND METHODS: Retrospective review of 4 cases with clinical diagnosis of recurrent bacterial meningitis. RESULTS: Case 1: a thirty month-old boy with unilateral hearing loss, diagnosed with Mondini abnormality by magnetic resonance imaging (MRI) after 2 episodes of Haemophilus influenzae meningitis. Surgical repair after third recurrence. Case 2: fourteen year-old girl diagnosed by MRI with cribriform plate defect after 3 episodes of meningitis due to Streptococcus pneumoniae. Ventriculoperitoneal shunt was placed. Case 3: girl with meningitis due to Staphylococcus aureus at 2 and 7 months. MRI shows occipital dermal sinus requiring excision. Complication with cerebellar abscesses because of a coexisting dermoid cyst. Case 4: child with meningitis due to Streptococcus bovis at 9 days and Enterococcus faecium, Klebsiella pneumoniae and Escherichia coli at 7 months, with positive cultures to Citrobacter freundii and E. faecium later on. Spinal MRI led to the diagnosis of Currarino syndrome with CSF fistula, which was surgically repaired. The 4 patients had undergone image studies reported as normal during the first episodes. CONCLUSIONS: In patients with recurrent meningitis the possibility of an anatomical defect should be considered. The isolated microorganism should help to locate it. It is essential to know the normal flora of the different anatomical sites. The definitive treatment is usually surgical. PMID- 25446796 TI - [Ischaemic stroke secondary to unilateral focal cerebral arteriopathy]. PMID- 25446797 TI - [Vaginal reflux: A forgotten cause of diurnal incontinence in prepubertal girls]. PMID- 25446798 TI - Sexual orientation and risk factors for suicidal ideation and suicide attempts: a multi-centre cross-sectional study in three Asian cities. AB - PURPOSE: Despite robust empirical and theoretical evidence for higher rates of suicide among lesbian, gay, and bisexual (LGB) youths, little is known about the relationship between suicide and sexual orientation among Asian youths. This study examined differences in prevalence of suicidal ideation and suicide attempts between LGB and heterosexual youths in the cities of Hanoi, Shanghai, and Taipei, China. METHODS: The data are from a community-based multi-centre cross-sectional study conducted from 2006 to 2007, with a sample of 17 016 youths aged 15-24 years from Hanoi, Shanghai, and Taipei. Chi-square test and logistic regression were used to evaluate correlates of suicidal ideation and suicide attempts. RESULTS: The overall prevalence of suicidal ideation and suicide attempts in the preceding 12 months in LGB youths were both higher than in heterosexual youth (12.8% vs. 8.1% and 4.0% vs. 2.4%, respectively). Stratified by city, the prevalence of suicidal ideation was lowest in Hanoi (2.2%), followed by Shanghai (8.0%) and Taipei (17.0%). Similar trends were observed in the prevalence of suicide attempts, which was lowest in Hanoi (0.3%), followed by Shanghai (1.2%) and Taipei (2.5%). Of note, however, multivariate logistic regression results revealed that LGB youth were at a higher risk for suicidal ideation than heterosexual youth only in Taipei (odds ratio 1.65). CONCLUSIONS: Suicidality is common among Asian youth, with higher prevalence observed in urbanized cities. LGB youths are at greater risk of suicidal ideation than their heterosexual counterparts in Taipei than in the other two examined cities. PMID- 25446799 TI - The effects of taurine on vigabatrin, high light intensity and mydriasis induced retinal toxicity in the pigmented rat. AB - The overall purpose of this study was to establish a model that may be used for examining the effect of Vigabatrin-induced retinal toxicity in pigmented rats, and subsequently examine the possible effects of taurine on the retinal toxicity. In the first part of the study, pigmented Long Evans rats were subjected to combinations of induced mydriasis, low/high light intensities (40/2000 lx) and oral administration of near-MTD (Maximum Tolerated Dose) doses (200 mg/kg/day) of Vigabatrin for up to 6 weeks. The combination of mydriasis and high light intensity applied to Long Evans rats resulted in retinal damage that was increased by the administration of Vigabatrin. In the second part of the study Long Evans rats were subjected to combinations of induced mydriasis and high/low light intensity (40/2000 lx) while being orally administered low (30 mg/kg/day) or high (200 mg/kg/day) doses of Vigabatrin for up to 6 weeks. In addition, selected groups of animals were administered taurine via the drinking water (20 mg/ml), resulting in systemic taurine concentrations of approximately threefold the endogenous concentration. The combined results of the studies demonstrate that retinal damage can be induced in pigmented animals when combining mydriasis and high light intensity. Retinal damage was functionally evaluated by electroretinography (ERG), then confirmed by histopathology. While depending on mydriasis and high light intensity, administration of Vigabatrin increased the retinal toxicity and resulted in the formation of rosette-like structures in the retina in a dose-related manner. Administration of taurine did not alleviate the Vigabatrin-induced retinal toxicity, as demonstrated either functionally by ERG or morphologically, although systemic concentrations of 3-fold the endogenous levels were reached, and it was thus not possible to demonstrate a protective effect of taurine in these pigmented animals. PMID- 25446800 TI - Evaluation of hepatotoxic and genotoxic potential of silver nanoparticles in albino rats. AB - Silver nanoparticles (AgNPs) have wide medical applications regarding their antimicrobial effects. They are applied also in appliances such as refrigerators and washing machines. For assessment of toxicological potential of silver nanoparticles 20 mature female albino rats were divided into four groups (five rats per each). Animals were injected i/p by different doses of approximately 8.7 nm silver nanoparticles (1, 2 and 4 mg/kg b.w) daily for 28 days in addition to control group which were injected by deionized water only. Indicators of oxidative stress in liver tissue, determination of silver nanoparticles tissue concentration, description of hepatic histopathological alterations and detection of possible chromosomal aberrations in bone marrow were carried out. Results revealed various hepatic histopathological lesions that were dose dependent. The effect of Ag-NPs on hepatic malondialdhyde (MDA) and glutathione (GSH) levels were variable in different treated groups compared with the control. The tissue residues of silver nanoparticles were found in hepatic tissue and related to original treated dose. Finally, silver nanoparticles induced variable chromosomal aberrations that were dose dependent. CONCLUSION: Silver nanoparticles had the ability for inducing various hepatic histopathological alterations indicating hepatocytotoxicity presumably by oxidative stress, in addition to the induction of chromosomal aberrations in bone marrow cells denoting the genotoxicity of nanosilver particles. PMID- 25446802 TI - Histopathological characterization of renal tubular and interstitial changes in 5/6 nephrectomized marmoset monkeys (Callithrix jacchus). AB - Common marmosets (Callithrix jacchus) have become a useful animal model, particularly for development of biopharmaceuticals. While various renal failure models have been established in rodents, there is currently no acceptable model in marmosets. We analyzed the damaged renal tubules and tubulointerstitial changes (inflammation and fibrosis) of 5/6 nephrectomized (Nx) common marmosets by histopathological/immunohistochemical methods, and compared these findings to those in 5/6 Nx SD rats. In Nx marmosets and rats sacrificed at 5 and 13 weeks after Nx, variously dilated and atrophied renal tubules were seen in the cortex in common; however, the epithelial proliferating activity was much less in Nx marmosets. Furthermore, the degrees of inflammation and fibrosis seen in the affected cortex were more severe and massive in Nx marmosets with time-dependent increase. Interestingly, inflammation in Nx marmosets, of which degree was less in Nx rats, consisted of a large number of CD3-positive T cells and CD20-positive B cells (occasionally forming follicles), and a few CD68-positive macrophages. Based on these findings, lymphocytes might contribute to the progressive renal lesions in Nx marmosets. Fibrotic areas in Nx marmosets comprised myofibroblasts expressing vimentin and alpha-smooth muscle actin (alpha-SMA), whereas along with vimentin and alpha-SMA expressions, desmin was expressed in myofibroblasts in Nx rats. This study shows that there are some differences in renal lesions induced by Nx between marmosets and rats, which would provide useful, base-line information for pharmacology and toxicology studies using Nx marmosets. PMID- 25446801 TI - A medium-term gpt delta rat model as an in vivo system for analysis of renal carcinogenesis and the underlying mode of action. AB - The kidney is a major target site of chemical carcinogenesis. However, a reliable in vivo assay for rapid identification of renal carcinogens has not been established. The purpose of this study was to develop a new medium-term gpt delta rat model (the GNP model) to facilitate identification of renal carcinogens. In this model, we carried out an in vivo mutation assay using unilaterally nephrectomized kidney tissue and a tumor-promoting assay using residual kidney tissue, with diethylnitrosamine (DEN) as the renal tumor initiator. To clarify the optimal time of DEN injection after nephrectomy, time-dependent changes in bromodeoxyuridine-labeling indices in the tubular epithelium of nephrectomized rats were examined. The optimal dose of DEN injection and sufficient duration of subsequent nitrilotriacetic acid treatment were determined for detection of renal preneoplastic lesions. The standard protocol for the GNP model was determined as follows. Six-week-old female gpt delta rats were treated with test chemicals for 4 weeks, followed by a 2-week washout period, and 40 mg/kg DEN was administered intraperitoneally to initiate renal carcinogenesis. Unilateral nephrectomy was performed 48 h before DEN injection, followed by gpt assays using excised kidney tissues. One week after DEN injection, rats were further exposed to test chemicals for 12 weeks, and histopathological analysis of renal preneoplastic lesions was performed as an indicator of tumor-promoting activity in residual kidney tissue. Validation studies using aristolochic acid, potassium dibasic phosphate, phenylbutazone, and d-limonene indicated the reliability of the GNP model for predicting renal carcinogens and the underlying mode of action. PMID- 25446803 TI - Immunohistochemical characterization of glial fibrillary acidic protein (GFAP) expressing cells in a rat liver cirrhosis model induced by repeated injections of thioacetamide (TAA). AB - Hepatic stellate cells, the principal fibrogenic cell type in the liver, are known to express the astrocyte marker glial fibrillary acidic protein (GFAP). However, the exact role of GFAP-expressing cells in liver fibrosis remains to be elucidated. In this study, cellular properties of GFAP-expressing cells were investigated in a rat model of liver cirrhosis. Six-week-old male F344 rats were injected intraperitoneally with thioacetamide (100 mg/kg BW, twice a week) and examined at post first injection weeks 5, 10, 15, 20 and 25. Appearance of GFAP expressing myofibroblasts peaked at week 15, associated with fibrosis progression. The majority of GFAP-expressing myofibroblasts co-expressed vimentin, desmin and alpha-smooth muscle actin. Some GFAP-positive myofibroblasts co-expressed nestin (neural stem cell marker), while a few co-expressed A3 (mesenchymal stem cell marker) and Thy-1 (immature mesenchymal cell marker). A few GFAP expressing cells underwent both mitosis and apoptosis. These results indicate that there is a dynamic participation of GFAP-expressing myofibroblasts in rat liver cirrhosis, and that they are mainly derived from hepatic stellate cells, and partly from cells in the stem cell lineage. These findings, which were shown for the first time in detail, would be useful to understand the role of GFAP-expressing myofibroblasts in the pathogenesis of chemically induced liver cirrhosis. PMID- 25446805 TI - Genetic factors associated with longevity: a review of recent findings. AB - Given the rising rate of survival into advanced old age in the United States, achieving longevity and healthy aging is becoming increasingly important. Besides maintaining healthy lifestyle behaviors, positive aging outcomes may also be heritable, with estimates ranging from 20% to 35%. In this qualitative review, we summarize recent findings on genetic factors linked to longevity across different populations and study designs. Recent studies not only confirm the association of APOE with longevity in different populations, but also implicate several other pathways that may influence longevity including nitric oxide production, inflammation, immunity, and DNA damage response and repair. Recent evidence also suggests that mitochondrial DNA may play an important role in attaining longevity. Despite these implicated pathways, longevity may be a polygenic trait influenced by a complex interplay of multiple genes. Future genetic studies on aging would benefit from larger samples of long-lived individuals, birth-cohort matched controls, inclusion of different aging phenotypes (e.g., aging free of morbidities), and analysis of gender differences. PMID- 25446806 TI - Stem cells and aberrant signaling of molecular systems in skin aging. AB - The skin is the body's largest organ and it is able to self-repair throughout an individual's life. With advanced age, skin is prone to degenerate in response to damage. Although cosmetic surgery has been widely adopted to rejuvinate skin, we are far from a clear understanding of the mechanisms responsible for skin aging. Recently, adult skin-resident stem/progenitor cells, growth arrest, senescence or apoptotic death and dysfunction caused by alterations in key signaling genes, such as Ras/Raf/MEK/ERK, PI3K/Akt-kinases, Wnt, p21 and p53, have been shown to play a vital role in skin regeneration. Simultaneously, enhanced telomere attrition, hormone exhaustion, oxidative stress, genetic events and ultraviolet radiation exposure that result in severe DNA damage, genomic instability and epigenetic mutations also contribute to skin aging. Therefore, cell replacement and targeting of the molecular systems found in skin hold great promise for controlling or even curing skin aging. PMID- 25446807 TI - Atypical Spitz tumors in patients younger than 18 years. AB - BACKGROUND: Diagnosis and proper management of atypical Spitz tumors in pediatric age are still controversial. OBJECTIVE: We sought to investigate the clinicopathological and molecular features of atypical Spitz tumors in patients aged 18 years or younger. METHODS: We performed a retrospective clinicopathological and fluorescence in situ hybridization study on 50 pediatric atypical Spitz tumors. RESULTS: Parameters that were significantly correlated with a diagnosis of atypical Spitz tumors over Spitz nevus included asymmetry, level IV/V, lack of maturation, solid growth, nuclear pleomorphism, high nuclear cytoplasmic ratio, atypical and deep mitoses, and more than 6 mitoses/mm(2). In the atypical Spitz tumors group, a significantly higher mitotic rate was observed in prepuberal age (P = .04). The 4-probe fluorescence in situ hybridization melanoma assay did not discriminate atypical Spitz tumors from Spitz nevi. Heterozygous 9p21 loss was found in 3 of 37 cases and homozygous 9p21 loss in 2 of 37 cases. Only 1 child experienced a fatal outcome, showing genetic abnormalities by melanoma fluorescence in situ hybridization probe and a heterozygous 9p21 deletion. LIMITATIONS: The limited number of adverse outcomes did not allow the prognostic analysis of single morphologic features. CONCLUSION: Pediatric atypical Spitz tumors are associated with minimal lethal potential. Atypical Spitz tumors require complete excision and careful follow-up while our data do not support any clinical benefit for the sentinel lymph node biopsy procedure and completion lymphadenectomy. PMID- 25446808 TI - Soluble CD30 does not predict late acute rejection or safe tapering of immunosuppression in renal transplantation. AB - BACKGROUND: Previous reports revealed the potential value of the soluble CD30 level (sCD30) as biomarker for the risk of acute rejection and graft failure after renal transplantation, here we examined its use for the prediction of safe tapering of calcineurin inhibitors as well as late acute rejection. METHODS: In a cohort of renal transplant patients receiving triple immunosuppressive therapy we examined whether sCD30 can be used as a marker for safe (rejection-free) discontinuation of tacrolimus at six months after transplantation (TDS cohort: 24 rejectors and 44 non-rejecting controls). Also, in a second cohort of patients (n=22, rejectors n=11 and non-rejectors n=11), participating in a clinical trial of rituximab as induction therapy after renal transplantation (RITS cohort), we examined whether sCD30 could predict the occurrence of late (>3months post transplant) acute rejection episodes. sCD30 was measured by ELISA in serum taken before and at several time points after transplantation. RESULTS: Overall, in the TDS cohort sCD30 decreased after transplantation. No difference in sCD30 was observed between rejectors and non-rejecting controls at any of the time points measured. In addition, in the RITS cohort, sCD30 measured at three months after transplantation were not indicative for the occurrence of late acute rejection. CONCLUSION: In two prospectively followed cohorts of renal transplant patients we found no association between sCD30 and the occurrence of either late acute rejection or acute rejection after reduction of immunosuppression. PMID- 25446809 TI - Impaired CD8(+) T cell immunity after allogeneic bone marrow transplantation leads to persistent and severe respiratory viral infection. AB - RATIONALE: Bone marrow transplant (BMT) recipients experience frequent and severe respiratory viral infections (RVIs). However, the immunological mechanisms predisposing to RVIs are uncertain. Therefore, we hypothesized that antiviral T cell immunity is impaired as a consequence of allogeneic BMT, independent of pharmacologic immunosuppression, and is responsible for increased susceptibility to RVI. METHODS: Bone marrow and splenocytes from C57BL/6(H2(b)) mice were transplanted into B10.BR(H2(k)) (Allo) or C57BL/6(H2(b)) (Syn) recipients. Five weeks after transplantation, recipient mice were inoculated intranasally with mouse parainfluenza virus type 1 (mPIV-1), commonly known as Sendai virus (SeV), and monitored for relevant immunological and disease endpoints. MAIN RESULTS: Severe and persistent airway inflammation, epithelial injury, and enhanced mortality are found after viral infection in Allo mice but not in control Syn and non-transplanted mice. In addition, viral clearance is delayed in Allo mice as evidenced by prolonged detection of viral transcripts at Day 15 post-inoculation (p.i.) but not in control mice. In concert with these events, we also detected decreased levels of total and virus-specific CD8(+) T cells, as well as increased T cellexpression of inhibitory receptor programmed death-1 (PD-1), in the lungs of Allo mice at Day 8 p.i. Adoptive transfer of CD8(+) T cells from non transplanted mice recovered from SeV infection into Allo mice at Day 8 p.i. restored normal levels of viral clearance, epithelial repair, and lung inflammation. CONCLUSIONS: Taken together these results indicate that allogeneic BMT results in more severe RVI based on the failure to develop an appropriate pulmonary CD8(+) T cell response, providing an important potential mechanism to target in improving outcomes of RVI after BMT. PMID- 25446810 TI - The effects of Ginkgo biloba extract on cognitive functions in aged female rats: the role of oxidative stress and brain-derived neurotrophic factor. AB - The aim of this study was to investigate the effects of Ginkgo biloba extract (GBE) on cognitive functions as well as oxidative stress and brain-derived neurotrophic factor (BDNF) levels in aged female rats. Rats were divided into 4 groups according to age (young vs. aged) and treatment (GBE vs. vehicle). GBE or vehicle was given for 30 d, and a series of behavioral tests were performed. Following behavioral testing, blood samples and brain tissues were obtained for analysis of BDNF, malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and glutathione levels, and superoxide dismutase activity. Locomotor activity and anxiety levels were lower in the aged rats. Based on Morris water maze probe trial findings, GBE supplementation increased the number of platform crossings in the aged rats. MDA and 8-OHdG levels were lower in the brain tissue, and BDNF levels were higher in plasma in the rates treated with GBE. Based on these findings, we concluded that GBE supplementation improved cognitive functions by decreasing oxidative damage and increasing the BDNF level in aged female rats. PMID- 25446811 TI - Individual variation in the propensity to attribute incentive salience to a food cue: influence of sex. AB - There is considerable individual variation in the propensity of animals to attribute incentive salience to discrete reward cues, but to date most of this research has been conducted in male rats. The purpose of this study was to determine whether sex influences the propensity to attribute incentive salience to a food cue, using rats from two different outbred strains (Sprague-Dawley [SD] and Heterogeneous Stock [HS]). The motivational value of a food cue was assessed in two ways: (i) by the ability of the cue to elicit approach toward it and (ii) by its ability to act as a conditioned reinforcer. We found that female SD rats acquired Pavlovian conditioned approach behavior slightly faster than males, but no sex difference was detected in HS rats, and neither strain showed a sex difference in asymptotic performance of approach behavior. Moreover, female approach behavior did not differ across estrous cycle. Compared to males, females made more active responses during the test for conditioned reinforcement, although they made more inactive responses as well. We conclude that although there are small sex differences in performance on these tasks, these are probably not due to a notable sex difference in the propensity to attribute incentive salience to a food cue. PMID- 25446804 TI - DAMPs, ageing, and cancer: The 'DAMP Hypothesis'. AB - Ageing is a complex and multifactorial process characterized by the accumulation of many forms of damage at the molecular, cellular, and tissue level with advancing age. Ageing increases the risk of the onset of chronic inflammation associated diseases such as cancer, diabetes, stroke, and neurodegenerative disease. In particular, ageing and cancer share some common origins and hallmarks such as genomic instability, epigenetic alteration, aberrant telomeres, inflammation and immune injury, reprogrammed metabolism, and degradation system impairment (including within the ubiquitin-proteasome system and the autophagic machinery). Recent advances indicate that damage-associated molecular pattern molecules (DAMPs) such as high mobility group box 1, histones, S100, and heat shock proteins play location-dependent roles inside and outside the cell. These provide interaction platforms at molecular levels linked to common hallmarks of ageing and cancer. They can act as inducers, sensors, and mediators of stress through individual plasma membrane receptors, intracellular recognition receptors (e.g., advanced glycosylation end product-specific receptors, AIM2-like receptors, RIG-I-like receptors, and NOD1-like receptors, and toll-like receptors), or following endocytic uptake. Thus, the DAMP Hypothesis is novel and complements other theories that explain the features of ageing. DAMPs represent ideal biomarkers of ageing and provide an attractive target for interventions in ageing and age-associated diseases. PMID- 25446812 TI - Reference and working memory deficits in the 3xTg-AD mouse between 2 and 15 months of age: a cross-sectional study. AB - Impairments in working memory (WM) can predict the shift from mild cognitive impairment (MCI) to Alzheimer's disease (AD) and the rate at which AD progresses with age. The 3xTg-AD mouse model develops both Abeta plaques and neurofibrillary tangles, the neuro-pathological hallmarks of AD, by 6 months of age, but no research has investigated the age-related changes in WM in these mice. Using a cross-sectional design, we tested male and female 3xTg-AD and wildtype control (B6129SF2/J) mice between 2 and 15 months of age for reference and working memory errors in the 8-arm radial maze. The 3xTg-AD mice had deficits in both working and reference memory across the ages tested, rather than showing the predicted age-related memory deficits. Male 3xTg-AD mice showed more working and reference memory errors than females, but there were no sex differences in wildtype control mice. These results indicate that the 3xTg-AD mouse replicates the impairments in WM found in patients with AD. However, these mice show memory deficits as early as two months of age, suggesting that the genes underlying reference and working memory in these mice cause deficits from an early age. The finding that males were affected more than females suggests that more attention should be paid to sex differences in transgenic AD mice. PMID- 25446814 TI - Deep brain stimulation of the inferior colliculus: a possible animal model to study paradoxical kinesia observed in some parkinsonian patients? AB - The inferior colliculus (IC) plays an important role in the normal processing of the acoustic message and is also involved in the filtering of acoustic stimuli of aversive nature. The neural substrate of the IC can also influence haloperidol induced catalepsy. Considering that (i) paradoxical kinesia, observed in some parkinsonian patients, seems to be dependent of their emotional state and (ii) deep brain stimulation (DBS) represents an alternative therapeutic route for the relief of parkinsonian symptoms, the present study investigated the consequence of DBS at the IC on the catalepsy induced by haloperidol in rats. Additionally, we investigated if DBS of the IC can elicit motor responses in anesthetized rats and whether DBS elicits distinct neural firing patterns of activity at the dorsal cortex (DCIC) or central nucleus (CNIC) of the IC. A significant reduction of the catalepsy response was seen in rats previously given haloperidol and receiving DBS at the IC. In addition, electrical stimulation to the ventral part of the CNIC induced immediate motor responses in anesthetized rats. The neuronal spontaneous activity was higher at the ventral part of the CNIC than the dorsal part. DBS to the ventral part but not to the dorsal part of the CNIC increased the spike rate at neurons a few hundred microns away from the stimulation site. It is possible that the IC plays a role in the sensorimotor gating activated by emotional stimuli, and that DBS at the IC can be a promising new animal model to study paradoxical kinesia in rats. PMID- 25446813 TI - Roles of human hippocampal subfields in retrieval of spatial and temporal context. AB - While numerous studies indicate the involvement of the hippocampus in encoding and retrieval of spatial and temporal context, the neural basis of spatial and temporal processing within the hippocampal circuit remains unclear. We employed a novel paradigm in which participants encoded stores within a spatial layout by visiting them in a specific temporal order. Participants then underwent high resolution functional magnetic resonance imaging (fMRI) targeting the hippocampus while retrieving details of the spatial or temporal context in alternating blocks. During retrieval, participants made judgments about either near or far intervals within the spatial layout or temporal sequence. Across both near and far intervals, we found that retrieving spatial layout and temporal order information resulted in comparable levels of activation in the hippocampus that was not preferentially localized to a specific subfield. Furthermore, using a multivariate approach called multivariate pattern similarity analysis (MPSA), we found that correct near judgments vs. correct far judgments differed in their patterns of activity for spatial vs. temporal order judgments. Despite these differences in MPSA patterns, we did not find any specific subfields differentially recruited for spatial vs. temporal order retrieval. We discuss our results in terms of their relation to computational models of hippocampal subfield function and suggest mechanisms by which the hippocampus could process space and temporal order without the need for specific contributions from hippocampal subfields. PMID- 25446815 TI - Monocarboxylate transporter 4 predicts poor prognosis in hepatocellular carcinoma and is associated with cell proliferation and migration. AB - PURPOSE: Monocarboxylate transporter 4 (MCT4) is a critical component in the glycolytic metabolism of cancer cells, and is also important for malignant behavior. We investigated the expression profile of MCT4, its prognostic value in hepatocellular carcinoma (HCC) patients, its role in HCC cell proliferation and metastasis, and associated initial molecular mechanism. METHODS: MCT4 expression was examined through immunohistochemical staining of pathological specimens from 318 HCC patients who had undergone hepatectomy. The HCC cell lines were used to validate the relationship between MCT4 expression and cell proliferation, migration, and invasion. RESULTS: The results show that high MCT4 expression is indicative of elevated alpha fetoprotein levels and larger tumor size, which leads to poorer disease-free survival (DFS) and overall survival (OS). Multivariate regression analysis shows that MCT4 expression is an independent prognostic factor for DFS and OS in HCC patients. In 91 recurrent HCC patients who underwent transarterial chemoembolization (TACE) treatment, low MCT4 expression predicted an effective treatment response and improved OS. Furthermore, in cell line experiments with MCT4 siRNA, cancer cell proliferation, migration, and invasion were closely correlated with the MCT4 expression. Knockdown of MCT4 was associated with down-regulation of phosphorylated AKT and HIF-1alpha. CONCLUSIONS: MCT4 expression can predict survival and TACE treatment response for HCC patients. Furthermore, MCT4 plays an important role in HCC cell proliferation, migration, and invasion. The inhibition of MCT4 can induce inactivation of HIF-1alpha and inhibit phosphorylation of AKT. MCT4 may be a potential therapeutic target for the treatment of HCC. PMID- 25446817 TI - [Jose Joaquin Palma (Bayamo, Cuba, 1844 - Guatemala, Guatemala, 1911)]. PMID- 25446816 TI - Presence of podoplanin-positive cancer-associated fibroblasts in surgically resected primary lung adenocarcinoma predicts a shorter progression-free survival period in patients with recurrences who received platinum-based chemotherapy. AB - PURPOSE: The influence of microenvironmental factors on the effectiveness of chemotherapy is being increasingly recognized. The purpose of this study was to investigate the relationships between cancer cell and stromal cell phenotypes in primary tumors and the progression-free survival (PFS) of recurrent lung cancer patients who received platinum-based chemotherapy. METHODS: We retrospectively analyzed 87 postoperative recurrent lung adenocarcinoma patients treated with platinum-based chemotherapy. The expressions of drug resistance-related proteins including BCRP, ezrin, and ALDH1 in cancer cells, the number of CD204-positive tumor-associated macrophages (TAMs), and the presence of podoplanin-positive cancer-associated fibroblasts (CAFs) in the primary tumor were examined. The relationships between the immunohistochemical staining results of primary tumors and the PFS after receiving chemotherapy were also analyzed. RESULTS: Among the clinicopathological factors of primary tumors, only an advanced pathological stage was significantly associated with a shorter PFS. As for immunohistochemical staining, no significant relationships were found between the PFS and the expression of BCRP, ezrin, or ALDH1. Although the number of CD204-positive TAMs was not associated with the PFS, the presence of podoplanin-positive CAFs was significantly associated with a shorter PFS (median PFS: 5.1 vs. 7.8 months, P = 0.028). A multivariate analysis revealed a tendency of podoplanin-positive CAFs to be correlated with a shorter PFS (P = 0.087). CONCLUSIONS: The presence of podoplanin-positive CAFs in the primary tumor could be a predictor of a shorter PFS in recurrent lung adenocarcinoma patients who received chemotherapy. These findings suggest that stromal-cell-derived factors should be incorporated into predictions of the effectiveness of chemotherapy. PMID- 25446818 TI - Measles-mumps-rubella vaccination and respiratory syncytial virus-associated hospital contact. AB - BACKGROUND: The live measles vaccine has been associated with lower non-measles mortality and admissions in low-income countries. The live measles-mumps-rubella vaccine has also been associated with lower rate of admissions with any type of infection in Danish children; the association was strongest for admissions with lower respiratory infections. OBJECTIVE: To examine whether measles, mumps, and rubella (MMR) vaccination was associated with reduced rate of hospital contact related to respiratory syncytial virus (RSV) in a high-income country. METHODS: Nationwide cohort study of laboratory-confirmed RSV hospital contacts at age 14 23 months in all children born in Denmark 1997-2002 who had already received the vaccine against diphtheria, tetanus, pertussis (acellular), polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) at the recommended ages of 3, 5, and 12 months. RESULTS: The study included 888 RSV hospital contacts in 128,588 person years of follow up (rate 6.8/1000 person years). Having MMR as the most recent vaccine was associated with a reduced rate of RSV hospital contacts compared with having DTaP-IPV-Hib as the most recent vaccine (Incidence rate ratio (IRR), 0.75; 95% confidence interval (CI), 0.63-0.89). After adjustment for potential confounders including exact age in days the IRR was 0.78 (95% CI, 0.66 0.93). The adjusted IRR was 0.74 (95% CI, 0.60-0.92) in males and 0.84 (95% CI, 0.66-1.06) in females (P Interaction, 0.42). There was no association in the first month after MMR vaccination (adjusted IRR, 0.97; 95% CI, 0.76-1.24) but the adjusted IRR was 0.70 (95% CI, 0.58-0.85) from one month after MMR vaccination. CONCLUSIONS: MMR vaccination was associated with reduced rate of hospital contacts related to laboratory-confirmed RSV infection. Further research on the association between MMR vaccination and other unrelated pathogens are warranted. PMID- 25446820 TI - The history of the United States Advisory Committee on Immunization Practices (ACIP). AB - The United States Advisory Committee on Immunization Practices (ACIP) is a federal advisory committee that develops written recommendations for use of vaccines licensed by the Food and Drug Administration (FDA) for the U.S. civilian population. Vaccine development and disease outbreaks contributed to the need for a systematized, science-based, formal mechanism for establishing national immunization policy in this country. Formed in 1964, the ACIP was charged with this role. The committee has undergone significant changes in structure and operational activities during its 50-year history. The ACIP works closely with many liaison organizations to develop its immunization recommendations, which are harmonized among key professional medical societies. ACIP vaccine recommendations form two immunization schedules, which are updated annually: (1) the childhood and adolescent immunization schedule and (2) the adult immunization schedule. Today, once ACIP recommendations are adopted by the Director of the Centers for Disease Control and Prevention and the Secretary of the Department of Health and Human Services, these recommendations are published in Morbidity and Mortality Weekly Report (MMWR), become official policy, and are incorporated into the appropriate immunization schedule. PMID- 25446821 TI - Transcriptional profiles reveal a stepwise developmental program of memory CD8(+) T cell differentiation. AB - The generation of CD8(+) T-cell memory is a major aim of vaccination. While distinct subsets of CD8(+) T-cells are generated following immunization that differ in their ability to confer long-term immunity against infection, the transcriptional profiles of these subsets within endogenous vaccine-induced CD8(+) T cell responses have not been resolved. Here, we measure global transcriptional profiles of endogenous effector (TEFF), effector memory (TEM) and central memory (TCM) CD8(+) T-cells arising from immunization with three distinct prime-boost vaccine regimens. While a proportion of transcripts were uniquely regulated within distinct CD8(+) T cell populations, we observed progressive up- or down-regulation in the expression of a majority of differentially expressed transcripts when subsets were compared in the order TN>TCM>TEM>TEFF. Strikingly, when we compared global differences in gene expression between TN, TCM, TEM and TEFF cells with known transcriptional changes that result when CD8(+) T cells repetitively encounter antigen, our analysis overwhelmingly favored a model whereby cumulative antigen stimulation drives differentiation specifically from TN>TCM>TEM>TEFF and this was common to all vaccines tested. These findings provide insight into the molecular basis of immunological memory and identify potential biomarkers for characterization of vaccine-induced responses and prediction of vaccine efficacy. PMID- 25446822 TI - International meeting on influenza vaccine effectiveness, 3-4 December 2012, Geneva, Switzerland. AB - On December 3-4 2012, the World Health Organization convened a meeting of influenza vaccine effectiveness (VE) experts from over 25 countries in Geneva, Switzerland, to review recent developments in the global influenza vaccine landscape and evaluate approaches to determining the effectiveness of influenza vaccine products among target populations. Vaccine manufacturers from Thailand, Vietnam, India, and Brazil shared recent advances illustrating the expansion of influenza vaccine production worldwide. Randomized controlled trials are underway in several low and middle-income countries including India, Thailand, Bangladesh, and South Africa, to fill knowledge gaps in target populations such as children and pregnant women. National and international networks in the United States, Canada, Europe, Latin America and Australia are conducting multi-site observational studies with shared methodologies to generate national influenza VE estimates and pool data for regional estimates. Standardized VE estimation methods are key to generating point estimates that are comparable internationally and across different settings. PMID- 25446819 TI - Live virus vaccines based on a yellow fever vaccine backbone: standardized template with key considerations for a risk/benefit assessment. AB - The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety of live, recombinant viral vaccines incorporating genes from heterologous viruses inserted into the backbone of another virus (so called "chimeric virus vaccines"). Many viral vector vaccines are in advanced clinical trials. The first such vaccine to be approved for marketing (to date in Australia, Thailand, Malaysia, and the Philippines) is a vaccine against the flavivirus, Japanese encephalitis (JE), which employs a licensed vaccine (yellow fever 17D) as a vector. In this vaccine, two envelope proteins (prM-E) of YF 17D virus were exchanged for the corresponding genes of JE virus, with additional attenuating mutations incorporated into the JE gene inserts. Similar vaccines have been constructed by inserting prM-E genes of dengue and West Nile into YF 17D virus and are in late stage clinical studies. The dengue vaccine is, however, more complex in that it requires a mixture of four live vectors each expressing one of the four dengue serotypes. This vaccine has been evaluated in multiple clinical trials. No significant safety concerns have been found. The Phase 3 trials met their endpoints in terms of overall reduction of confirmed dengue fever, and, most importantly a significant reduction in severe dengue and hospitalization due to dengue. However, based on results that have been published so far, efficacy in preventing serotype 2 infection is less than that for the other three serotypes. In the development of these chimeric vaccines, an important series of comparative studies of safety and efficacy were made using the parental YF 17D vaccine virus as a benchmark. In this paper, we use a standardized template describing the key characteristics of the novel flavivirus vaccine vectors, in comparison to the parental YF 17D vaccine. The template facilitates scientific discourse among key stakeholders by increasing the transparency and comparability of information. The Brighton Collaboration V3SWG template may also be useful as a guide to the evaluation of other recombinant viral vector vaccines. PMID- 25446823 TI - Glycoprotein E2 of classical swine fever virus expressed by baculovirus induces the protective immune responses in rabbits. AB - Classical swine fever (CSF) caused by CSF virus (CSFV) is a highly contagious and devastating disease that affects the pig industry worldwide. The glycoprotein E2 of CSFV is the principal immunogenic protein that induces neutralizing antibodies and protective immunity. Several CSFV genotypes, including 1.1, 2.1, 2.2, and 2.3, have been identified in Mainland China. The glycoprotein E2 of genotypes 1.1 and 2.1 was expressed by using a baculovirus system and tested for its protective immunity in rabbits to develop novel CSF vaccines that elicit a broad immune response. Twenty CSFV seronegative rabbits were randomly divided into five groups. Each rabbit was intramuscularly immunized with E2 of genotypes 1.1 (CSFV 1.1E2), 2.1 (CSFV-2.1E2), or their combination (CSFV-1.1 + 2.1E2). A commercial CSF vaccine (C-strain) and phosphate-buffered saline (PBS) were used as positive or negative controls, respectively. All animals were challenged with CSFV C strain at 4 weeks and then boosted with the same dose. All rabbits inoculated with CSFV-1.1E2, CSFV-2.1E2, and CSFV-1.1 + 2.1E2 elicited high levels of ELISA antibody, neutralizing antibody, and lymphocyte proliferative responses to CSFV. The rabbits inoculated with CSFV-1.1E2 and CSFV-1.1 + 2.1E2 received complete protection against CSFV C-strain. Two of the four rabbits vaccinated with CSFV 2.1E2 were completely protected. These results demonstrate that CSFV-1.1E2 and CSFV-1.1 + 2.1E2 not only elicit humoral and cell-mediated immune responses but also confer complete protection against CSFV C-strain in rabbits. Therefore, CSFV 1.1E2 and CSFV-1.1 + 2.1E2 are promising candidate subunit vaccines against CSF. PMID- 25446824 TI - Adverse events and association with age, sex and immunological parameters of Q fever vaccination in patients at risk for chronic Q fever in the Netherlands 2011. AB - BACKGROUND: Following a large Q fever outbreak in the Netherlands, patients at risk for chronic Q fever received a whole-cell Q fever vaccine. Sensitized people were excluded based on pre-vaccination screening with skin test (ST) and serology. An investigational IFN-gamma-production assay was added. No previous experience existed for Q fever vaccination in this patient risk-group with predefined cardiac valvular anomalies or aortic aneurysm/prosthesis and many co morbidities. We studied the adverse events (AE) and their association with patient characteristics and immunological parameters. METHODS: AE registration covered the week after skin test and 90 days following vaccination, with the use of diaries, interviews and spontaneous reports. Serious (S)AE were assessed immediately to ensure safety. We coded AE according to reported severity. Univariate and multivariate analysis addressed associations. RESULTS: Pre vaccination screening led to exclusion of 182 patients with positive serology and 207 patients with positive skin test-reading. The skin test did not lead to any causally related SAE. Subsequent vaccination of 1370 patients did not reveal unexpected AE; however, 80% of vaccinees reported local AE (in 26% of these pronounced or extensive). The two causally related SAE (0.1%) both concerned a persistent subcutaneous injection site mass. AE were more frequent in women, younger patients, and those without immunosuppressive co-morbidity/medication. The occurrence of local AE after skin test was associated with pre-vaccination positive serology and high IFN-gamma production. This was also true for local AE following vaccination, with a strong association with local AE after skin test as well. The proportion of vaccinees with positive serology and positive IFN-gamma values 6 months after vaccination was higher in those with local AE after skin test or after vaccination (non-significant, probably due to small numbers). CONCLUSION: Q fever vaccination was safe but reactogenic in this high-risk patient-group. Rates of local AE were higher in women, younger age groups and in those with positive immunological parameters. Vaccinees with local AE after skin test or after vaccination appear to have more pronounced post-vaccination immune responses. PMID- 25446825 TI - Human papillomavirus vaccine uptake among males 11-26 years in United States: findings from the National Health and Nutrition Examination Survey, 2011-2012. AB - Anogenital human papillomavirus (HPV) infection is the leading sexually transmitted infection in the United States. In October 2011, the quadrivalent HPV vaccine (HPV4) was recommended for males in the U.S. We analyzed a subsample of 11-26 year old (N = 1012) males, from the National Health and Nutritional Examination Survey 2011-2012 dataset, to examine HPV vaccine uptake. The initiation rates in the 11-17 years and the 18-26 years age-groups were 10.7% (95% confidence interval (CI): 8.09-16.6%) and 5.5% (95%CI: 3.1-9.5%) respectively. The corresponding HPV vaccine completion rates were 39.3% (16.7 67.7%) for the 11-17 year old males and 59.1% (37.2-77.6) for the 18-26-year-old males. Despite a slight increase, HPV vaccine uptake remained low among males. These findings can help in HPV vaccination policy in the United States, with a focus on informational messages directed toward young males and their parents in order to increase uptake of HPV vaccine. PMID- 25446826 TI - Integration of vaccine supply chains with other health commodity supply chains: a framework for decision making. AB - One of the primary objectives of National Immunization Programs is to strengthen and optimize immunization supply chains so that vaccines are delivered to the end recipients effectively, efficiently and sustainably. As a result of larger investments in global health and a wider portfolio of vaccines, global agencies are recognizing the need for vaccine supply chains to operate at their most optimal levels. Integration with other supply chains is often presented as a strategy to improve efficiency. However, it remains unclear if the proposed benefits from integration of vaccine supply chains with other supply chains will outweigh the costs. This paper provides a framework for deciding where such integration offers the most significant benefits. It also cautions about the pitfalls of integration as a one size fits all strategy. It also highlights the need for systematic collection of cost and efficiency data in order to understand the value of integration and other such initiatives. PMID- 25446828 TI - Continued use of IBV 793B vaccine needs reassessment after its withdrawal led to the genotype's disappearance. AB - Over a period of almost two years, broilers chickens on several hundred Italian farms, were monitored for infectious bronchitis virus. Detections were genotyped using a hypervariable region of the gene coding for the S1 segment of the spike protein. A range of genotypes were detected which comprised QX, Q1, Mass, D274 and 793B. Sequences of 793B viruses detected in chickens, vaccinated with either of the two commonly used 793B type vaccines were almost identical to sequences of one or other of these vaccines. This strong indication of vaccine association led to the withdrawal of live 793B vaccine use on all of the farms of the study. Except for one sample collected soon after 793B vaccination ceased, it was no longer possible to detect 793B vaccine on these farms. It appears that field 793B strains have disappeared from the region of Italy tested thus obviating any need for current vaccine protection against 793B. PMID- 25446829 TI - In vivo targeting of porcine reproductive and respiratory syndrome virus antigen through porcine DC-SIGN to dendritic cells elicits antigen-specific CD4T cell immunity in pigs. AB - Immunogenicity of protein subunit vaccines may be dramatically improved by targeting them through antibodies specific to c-type lectin receptors (CLRs) of dendritic cells in mice, cattle, and primates. This novel vaccine development approach has not yet been explored in pigs or other species largely due to the lack of key reagents. In this study, we demonstrate that porcine reproductive and respiratory syndrome virus (PRRSV) antigen was targeted efficiently to dendritic cells through antibodies specific to a porcine CLR molecule DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) in pigs. A recombinant PRRSV antigen (shGP45M) was constructed by fusing secretory-competent subunits of GP4, GP5 and M proteins derived from genetically-shuffled strains of PRRSV. In vaccinated pigs, when the PRRSV shGP45M antigen was delivered through a recombinant mouse-porcine chimeric antibody specific to the porcine DC-SIGN (pDC SIGN) neck domain, porcine dendritic cells rapidly internalized them in vitro and induced higher numbers of antigen-specific interferon-gamma producing CD4T cells compared to the pigs receiving non-targeted PRRSV shGP45M antigen. The pDC-SIGN targeting of recombinant antigen subunits may serve as an alternative or complementary strategy to existing vaccines to improve protective immunity against PRRSV by inducing efficient T cell responses. PMID- 25446830 TI - Safety and immunogenicity of dry powder measles vaccine administered by inhalation: a randomized controlled Phase I clinical trial. AB - BACKGROUND: Measles is a highly infectious respiratory disease which causes 122,000 deaths annually. Although measles vaccine is extremely safe and effective, vaccine coverage could be improved by a vaccine that is more easily administered and transported. We developed an inhalable dry powder measles vaccine (MVDP) and two delivery devices, and demonstrated safety, immunogenicity, and efficacy of the vaccine in preclinical studies. Here we report the first clinical trial of MVDP delivered by inhalation. METHODOLOGY: Sixty adult males aged 18 to 45 years, seropositive for measles antibody, were enrolled in this controlled Phase I clinical study. Subjects were randomly assigned in 1:1:1 ratio to receive either MVDP by Puffhaler((r)) or by SoloventTM devices or the licensed subcutaneous measles vaccine. Adverse events (AEs) were recorded with diary cards until day 28 post-vaccination and subjects were followed for 180 days post vaccination to assess potential serious long term adverse events. Measles antibody was measured 7 days before vaccination and at days 21 and 77 after vaccination by ELISA and a plaque reduction neutralization test. RESULTS: All subjects completed the study according to protocol. Most subjects had high levels of baseline measles antibody. No adverse events were reported. MVDP produced serologic responses similar to subcutaneous vaccination. CONCLUSIONS: MVDP was well tolerated in all subjects. Most subjects had high baseline measles antibody titer which limited ability to measure the serologic responses, and may have limited the adverse events following vaccination. Additional studies in subjects without pre-existing measles antibody are needed to further elucidate the safety and immunogenicity of MVDP. PMID- 25446827 TI - The challenges and opportunities for the development of a T-cell epitope-based herpes simplex vaccine. AB - Herpes simplex virus type 1 and type 2 (HSV-1 & HSV-2) infections have been prevalent since the ancient Greek times. To this day, they still affect a staggering number of over a billion individuals worldwide. HSV-1 infections are predominant than HSV-2 infections and cause potentially blinding ocular herpes, oro-facial herpes and encephalitis. HSV-2 infections cause painful genital herpes, encephalitis, and death in newborns. While prophylactic and therapeutic HSV vaccines remain urgently needed for centuries, their development has been difficult. During the most recent National Institute of Health (NIH) workshop titled "Next Generation Herpes Simplex Virus Vaccines: The Challenges and Opportunities", basic researchers, funding agencies, and pharmaceutical representatives gathered: (i) to assess the status of herpes vaccine research; and (ii) to identify the gaps and propose alternative approaches in developing a safe and efficient herpes vaccine. One "common denominator" among previously failed clinical herpes vaccine trials is that they either used a whole virus or a whole viral protein, which contain both "pathogenic symptomatic" and "protective asymptomatic" antigens and epitopes. In this report, we continue to advocate developing "asymptomatic" epitope-based sub-unit vaccine strategies that selectively incorporate "protective asymptomatic" epitopes which: (i) are exclusively recognized by effector memory CD4(+) and CD8(+) T cells (TEM cells) from "naturally" protected seropositive asymptomatic individuals; and (ii) protect human leukocyte antigen (HLA) transgenic animal models of ocular and genital herpes. We review the role of animal models in herpes vaccine development and discuss their current status, challenges, and prospects. PMID- 25446832 TI - Oral immunization against porcine pleuropneumonia using the cubic phase of monoolein and purified toxins of Actinobacillus pleuropneumoniae. AB - The main goal of this work was to obtain an orally administered immunogen that would protect against infections by Actinobacillus pleuropneumoniae. The Apx I, II and III toxins were obtained from the supernatants of cultures of serotypes 1 and 3 of A. pleuropneumoniae. The capacity of monoolein gel to trap and protect the Apx toxins, and the effect of their incorporation on the stability of the cubic phase were evaluated. The gel was capable of trapping a 400-MUg/ml concentration of the antigen with no effects on its structure. Approximately 60% of the protein molecules were released from the gel within 4h. Four experimental groups were formed, each one with four pigs. All challenges were conducted in a nebulization chamber. Group A: Control (-) not vaccinated and not challenged; Group B: Control (+) not vaccinated but challenged; Group C: vaccinated twice intramuscularly with ToxCom (a commercial toxoid) at an interval of 15 days and then challenged; and Group D: vaccinated orally twice a week for 4 weeks with ToxOral (an oral toxoid) and challenged on day 28 of the experiment with a same dose of 2.0 * 10(4) UFC of A. pleuropneumoniae serotypes 1 and 3. The lesions found in group B covered 27.7-43.1% of the lungs; the pigs in group C had lesions over 12.3-28%; and those in group D over 15.4-32.3%. No lesions were found in the Group A pigs. A. pleuropneumoniae induced macroscopic lesions characteristic of infection by and lesions microscopic detected by histopathology. The etiologic agent was recovered from the infected lungs, tonsils and spleen. The serotypes identified were 1 and 3. An indirect ELISA test identified the antibodies against the Apx toxins in the serum of the animals immunized orally. PMID- 25446831 TI - Live attenuated H7N7 influenza vaccine primes for a vigorous antibody response to inactivated H7N7 influenza vaccine. AB - BACKGROUND: H7 influenza viruses have emerged as potential pandemic threat. We evaluated the safety and immunogenicity of two candidate H7 pandemic live attenuated influenza vaccines (pLAIV) and their ability to prime for responses to an unadjuvanted H7 pandemic inactivated influenza vaccine (pIIV). METHODS: Healthy seronegative adults received two doses of A/Netherlands/219/03 (H7N7) or one dose of A/chicken/British Columbia/CN-6/04 (H7N3) pLAIV all given as 10(7.5) 50% tissue culture infective doses (TCID50) intranasally. A subset of subjects received one 45 MUg dose of H7N7 pIIV containing the A/Mallard/Netherlands/12/2000 HA intramuscularly 18-24 months after pLAIV. Viral shedding was assessed by culture and real-time polymerase chain reaction (rRT PCR), B cell responses following pLAIV were evaluated by ELISPOT and flow cytometry. Serum antibody was assessed by hemagglutination-inhibition (HAI), microneutralization (MN) and ELISA assays after each vaccine. RESULTS: Serum HAI or MN responses were not detected in any subject following one or two doses of either H7 pLAIV, although some subjects had detectable H7 specific B cells after vaccination. However, 10/13 subjects primed with two doses of H7N7 pLAIV responded to a subsequent dose of the homologous H7N7 pIIV with high titer HAI and MN antibody that cross-reacted with both North American and Eurasian lineage H7 viruses, including H7N9. In contrast, naive subjects and recipients of a single dose of the mismatched H7N3 pLAIV did not develop HAI or MN antibody after pIIV. CONCLUSIONS: While pLAIVs did not elicit detectable serum MN or HAI antibody, strain-specific pLAIV priming established long term immune memory that was cross-reactive with other H7 influenza strains. Understanding the mechanisms underlying priming by pLAIV may aid in pandemic vaccine development. PMID- 25446833 TI - A recombinant truncated surface immunogenic protein (tSip) plus adjuvant FIA confers active protection against Group B streptococcus infection in tilapia. AB - PURPOSE: Tilapia is an important agricultural fish that has been plagued by Group B streptococcus (GBS) infections in recent years, some of them severe. It is well known that surface immunogenicity protein (Sip) is an effective vaccine against GBS. EXPERIMENTAL DESIGN: Since Sip was not expressed in either E. coli BL21 or E. coli Rosetta, we removed the N-terminal signal peptide and LysM of the virus to produce purified truncated Sip (tSip(1)), which multiplied easily in an E. coli host. The antibody's ability to recognize and combine with GBS was determined by Western-blot and specific staining in vitro. The relative percentage of survival (RPS), antibody titers, bacterial recovery, and pathologic morphology were monitored in vivo to evaluate the immune effects. Freund's incomplete adjuvant (FIA) plus tSip and aluminum hydroxide gel (AH) plus tSip were also evaluated. RESULTS: It revealed that tSip mixed with FIA was an effective vaccine against GBS in tilapia, while AH is toxic to tilapia. PMID- 25446835 TI - Biologically inspired, sophisticated motions from helically assembled, conducting fibers. AB - A hierarchically helical organization of carbon nanotubes into macroscopic fibers enables sophistication while controlling three-dimensional electromechanical actuations, e.g., an artificial swing and tail. The actuation generates a stress of more than 260 times that of a typical natural skeletal muscle and an accelerated velocity of more than 10 times that of a cheetah at low electric currents with high reversibility, good stability, and availability to various media. PMID- 25446836 TI - Building high-resolution synthetic lethal networks: a 'Google map' of the cancer cell. AB - The most commonly used therapies for cancer involve delivering high doses of radiation or toxic chemicals to the patient that also cause substantial damage to normal tissue. To overcome this, researchers have recently resorted to a basic biological concept called 'synthetic lethality' (SL) that takes advantage of interactions between gene pairs. The identification of SL interactions is of considerable therapeutic interest because if a particular gene is SL with a tumor causing mutation, then the targeting that gene carries therapeutic advantages. Mapping these interactions in the context of human cancer cells could hold the key to effective, targeted cancer treatments. In this review, we cover the recent advances that aim to identify these SL interactions using unbiased genetic screens. PMID- 25446834 TI - Seasonal variation in rates of emergency room visits and acute admissions following recommended infant vaccinations in Ontario, Canada: a self-controlled case series analysis. AB - OBJECTIVES: To determine if birth month has an effect on the incidence of adverse events following the 2- and 12-month recommended vaccinations. STUDY DESIGN: Using health administrative databases, we conducted a population-based retrospective cohort study and employed a self-controlled case series analysis approach. We included children born in Ontario, Canada between April 1st 2002 and March 31st 2010 who received the diphtheria, tetanus, pertussis, inactivated poliovirus and Haemophilus influenzae type b (DTaP-IPV-Hib) vaccine recommended at 2 months and/or the measles, mumps, and rubella vaccine recommended at 12 months. We calculated the relative incidence (RI) of hospitalizations and emergency room visits within a pre-specified risk period compared to a control period following vaccination. We measured the effect of birth month using relative incidence ratios (RIRs) to compare the RI for infants born in each month to that for the month having the lowest RI. RESULTS: For the 2-month vaccination, we observed the lowest and highest RIs for infants born in October and April, respectively. The RIR (95% CI) for April compared to October was 2.06 (1.59-2.67, p<0.0001), consistent with a strong seasonal effect. For the 12-month vaccination, November births had the lowest RI, whereas August births had the highest. The RIR (95% CI) for August compared to November was 1.52 (1.30-1.77, p<0.0001). CONCLUSIONS: Our findings suggest a seasonal effect on susceptibility to adverse events following vaccination exists. Further study will be important to elucidate potential biological and/or behavioral explanations for the seasonal effect we observed. PMID- 25446838 TI - Subjective global assessment remains an important nutrition assessment tool: response to Marcelli, DiBenedetto, Ciotola, Grassmann, and Canaud. PMID- 25446837 TI - Fiber supplementation lowers plasma p-cresol in chronic kidney disease patients. AB - OBJECTIVE: To determine the effects of supplemental fiber on plasma p-cresol, stool frequency, and quality of life (QoL) in chronic kidney disease (CKD) patients. DESIGN AND SETTING: In a 12-week single-blind study, participants were provided with control muffins and supplements (5.5 g sucrose/day) for 2 weeks, muffins containing 10 g/day pea hull fiber and control supplements for 4 weeks, and muffins with 10 g/day pea hull fiber and 15 g/day inulin as a supplement for 6 weeks. SUBJECTS: Individuals with CKD (n = 13; 6 males, 7 females; aged 65 +/- 3 years; estimated glomerular filtration rate <50 mL/minute/1.73(2)) completed the study. MAIN OUTCOME MEASURES: Plasma p-cresol was determined by gas chromatography-mass spectrometry, stool frequency by 5-day journals, and QoL by the KDQOL-36TM. RESULTS: Plasma p-cresol decreased from 7.25 +/- 1.74 mg/L during week 1 to 5.82 +/- 1.72 mg/L during week 12 (P < .05), and in participants with high compliance (>70% inulin intake), from 6.71 +/- 1.98 mg/L to 4.22 +/- 1.16 mg/L (P < .05). Total fiber intake increased from 16.6 +/- 1.7 g/day during control to 26.5 +/- 2.4 g/day (P < .0001) with the added pea hull and to 34.5 +/- 2.2 g/day with pea hull and inulin (P < .0001). Stool frequency increased from 1.4 +/- 0.2 stools/day during control to 1.9 +/- 0.3 stools/day during both fiber periods (P < .05). No change in overall QoL was observed. CONCLUSIONS: Supplementing the diet of CKD patients with fiber may be a dietary therapy to reduce p-cresol and improve stool frequency. PMID- 25446839 TI - Is routine multivitamin supplementation necessary in US chronic adult hemodialysis patients? A systematic review. AB - Because of concern that United States (US) chronic hemodialysis patients are at high risk for the development of vitamin deficiencies, the great majority of such patients are routinely supplemented with a multivitamin. This policy is supported by major US dialysis providers and nonprofit organizations. Yet routine multivitamin supplementation expands hemodialysis patients' already large pill burden, probably accounts for many millions of dollars in annual costs, and in light of previous reports may even carry with it the possibility of increased risk of adverse outcomes. An analysis of the benefits of routine multivitamin supplementation in US patients is therefore in order. We performed a systematic review of the medical literature between 1970 and 2014 using the Ovid MEDLINE database to address this question. We conclude that there is insufficient evidence to support routine multivitamin use and recommend that the decision to supplement be made on an individual basis. PMID- 25446842 TI - Single tube genotyping of CYP2A6 gene deletion based on copy number determination by quantitative real-time PCR. AB - The CYP2A6*4 allele, characterized as the whole deletion of this gene, is closely associated with nicotine dependence, cancer susceptibility, and drug responsiveness. It has long been a significant challenge for pharmacogenetics scientists to develop a reliable method to detect this molecular variant due to its high homology with its homologous genes CYP2A6 and CYP2A3 in the clinical setting. Here, we introduce a quantitative real-time PCR assay that specifically amplifies CYP2A6 by designing a specific set of primers and the probe, which effectively prevent the amplification of the CYP2A7 and CYP2A13 alleles. CYP2A6 gene copy numbers were normalized to albumin (ALB) which was co-amplified simultaneously in a single-tube duplex reaction and at a setting as the internal reference gene. The established assay was validated with a selection of previously genotyped DNA samples, which harbored none, one or two CYP2A6 gene copies. The results were in complete concordance with previously published data and no overlap between the three groups was observed. Further analysis of a cohort of 120 samples revealed high specificity and sensitivity of this assay as demonstrated by the agreement of determined gene copy numbers in all of the cases. In conclusion, this novel assay allows reliable and sensitive detection of the CYP2A6 gene deletion, which will be useful for pharmacogenetics studies and routine clinical settings. PMID- 25446840 TI - Periostin in intrahepatic cholangiocarcinoma: pathobiological insights and clinical implications. AB - Periostin is a modular glycoprotein frequently observed to be a major constituent of the extracellular milieu of mass-forming intrahepatic cholangiocarcinoma and other desmoplastic malignant tumors. In intrahepatic cholangiocarcinoma, as well as in desmoplastic pancreatic ductal adenocarcinoma, periostin is overexpressed and hypersecreted in large part, if not exclusively, by cancer-associated fibroblasts within the tumor stroma. Through its interaction with specific components of the extracellular tumor matrix, particularly collagen type I and tenascin-C, and with cell surface receptors, notably integrins leading to activation of the Akt and FAK signaling pathways, this TGF-beta family-inducible matricellular protein appears to be functioning as a key extracellular matrix molecule regulating such critically important and diverse malignant tumor behaviors as tumor fibrogenesis and desmoplasia, invasive malignant cell growth, chemoresistance, and metastatic colonization. This review will discuss current evidence and basic molecular mechanisms implicating periostin as a mediator of intrahepatic cholangiocarcinoma invasive growth. In addition, its significance as a potential prognostic biomarker for intrahepatic cholangiocarcinoma patients, as well as future possibilities and challenges as a molecular target for cholangiocarcinoma therapy and/or prevention, will be critically evaluated. PMID- 25446843 TI - Melatonin modifies cellular stress in the liver of septic mice by reducing reactive oxygen species and increasing the unfolded protein response. AB - BACKGROUND & AIMS: Melatonin's hepatoprotective actions have numerously been demonstrated in the past but the underlying molecular mechanisms are widely unknown. For a better understanding of melatonin's effects on hepatic stress response this study aimed to elucidate alterations in oxidative stress, unfolded protein response and acute phase response in septic mice. METHODS: Male C3H/HeN mice underwent sham operation or cecal ligation and incision and remained anesthetized for 5h. Production of reactive oxygen species was determined by electron spin resonance spectroscopy. Protein and mRNA expression levels were determined by western blot analysis and quantitative real-time PCR, respectively. RESULTS: Production of reactive oxygen species was strongly increased in the aorta and liver after 5h of polymicrobial sepsis which was entirely inhibited by treatment with melatonin. SOD-1 levels did not differ between the groups. Sepsis also induced the upregulation of VCAM-1 and ICAM-1 independent of melatonin treatment but probably regulated via ERK1/2 signaling. Melatonin triggered the transcriptional upregulation of PERK in septic animals which seems to be independent on ERK1/2 signaling and NR4A1 activation. Melatonin therapy also engendered an increased expression of CHOP, but apoptosis was not initiated. Furthermore, sepsis reduced the expression of the transcription factor CREBH which was entirely suppressed by melatonin. CONCLUSIONS: This study gives new insight into the mechanisms by which melatonin might confer its hepatoprotective actions during polymicrobial sepsis. The results clearly show the melatonin mediated amelioration of oxidative stress as well as alterations in the cellular stress mechanisms via the unfolded protein response and the acute phase response. PMID- 25446841 TI - Crisp1 and alopecia areata in C3H/HeJ mice. AB - Alopecia areata (AA), a cell mediated autoimmune disease, is the second most common form of hair loss in humans. While the autoimmune disease is responsible for the underlying pathogenesis, the alopecia phenotype is ultimately due to hair shaft fragility and breakage associated with structural deficits. Quantitative trait genetic analyses using the C3H/HeJ mouse AA model identified cysteine-rich secretory protein 1 (Crisp1), a hair shaft structural protein, as a candidate gene within the major AA locus. Crisp1 transcripts in the skin at various times during disease development were barely detectable. In situ hybridization identified Crisp1 expression within the medulla of hair shafts from clinically normal strains of mice but not C3H/HeJ mice with AA. Follow-up work with 5-day old C3H/HeJ mice with normal hair also had essentially no expression of Crisp1. Other non-inflammatory based follicular dystrophy mouse models with similar hair shaft abnormalities also have little or no Crisp1 expression. Shotgun proteomics, used to determine strain difference in hair proteins, confirmed that there was very little CRISP1 within normal C3H/HeJ mouse hair in comparison to 11 other strains. However, mutant mice with hair medulla defects also had undetectable levels of CRISP1 in their hair. Crisp1 null mice had normal skin, hair follicles, and hair shafts indicating that the lack of the CRISP1 protein does not translate directly into defects in the hair shaft or hair follicle. These results suggest that CRISP1 may be an important structural component of mouse hair and that its strain-specific dysregulation may indicate a predisposition to hair shaft disease such as AA. PMID- 25446844 TI - Next-generation sequencing of salivary high-grade neuroendocrine carcinomas identifies alterations in RB1 and the mTOR pathway. AB - Salivary gland high-grade neuroendocrine carcinomas are rare, aggressive tumors that are morphologically and immunohistochemically similar to cutaneous high grade neuroendocrine (Merkel cell) carcinomas. The majority of Merkel cell carcinomas harbor Merkel cell polyomavirus, while the virus is rare or absent in salivary high-grade neuroendocrine carcinomas. Inactivation of retinoblastoma 1 (RB1) has been implicated in the pathogenesis of both virus-positive and negative Merkel cell carcinomas but by different mechanisms. In virus-positive tumors, a portion of the viral genome, the large T antigen, may inactivate RB1, and in virus-negative Merkel cell carcinomas truncating mutations in the RB1 gene have been identified. The molecular genetics of salivary high-grade neuroendocrine carcinomas are not well understood. Here, we performed targeted next-generation sequencing of 151 cancer-related genes on 4 four Merkel cell polyomavirus-negative primary salivary gland high-grade neuroendocrine carcinoma cases. Somatic mutations were predominantly found within tumor suppressor genes [TP53 (3 cases), PTEN (2 cases), RB1 (1 case)]. Truncating RB1 mutations, as seen in virus-negative Merkel cell carcinomas, were not identified. However, 3 of 4 cases had RB1 deletions by copy number variation analysis. The 4th case had loss of heterozygosity for RB1. Fluorescence in situ hybridization confirmed RB1 deletions in 2 of 3 cases, and the absence of RB1 deletion in the 4th case that had loss of heterozygosity. All 4 cases showed loss of RB1 protein expression by immunohistochemistry, indicating that RB1 inactivation is important. However, the mechanism of RB1 inactivation appears different than that seen in Merkel cell carcinomas. In addition, copy number variation consistent with activation of the PI3KCA/AKT/mTOR pathway was also observed in all 4 cases. The mTOR pathway may be a potential therapeutic target in these tumors as mTOR inhibitors are currently used to treat other tumor types. PMID- 25446845 TI - IL-10 negatively regulates oxLDL-P38 pathway inhibited macrophage emigration. AB - The effect of IL-10 on macrophage migration was investigated, including the analysis of protein expression, cytokine secretion and activation of the MAPKs and NF-kB pathway. The expression of endogenic IL-10 was down-regulated in macrophage stimulated with oxLDL for indicated time. Exogenous IL-10 reversed oxLDL-inhibited chemotactic macrophage numbers by 48.18 +/- 4.93% (3h), 64.8 +/- 5.61% (6h) and 63.66 +/- 3.05% (12h), and pretreated with SB203580 (P38 signaling inhibitor) in macrophage, oxLDL could not inhibit macrophage emigration. IL-10 significantly decreased oxLDL-mediated increase of SR-A expression, and pretreatment with beta-arrestin2 RNAi in macrophage could not change oxLDL induced SR-A expression. IL-10 also significantly decreased oxLDL-mediated increase of beta-arrestin2 expression, and pre-treated with SR-A RNAi in macrophage, oxLDL could not induce the increase of beta-arrestin2 expression. However, IL-10 significantly reversed oxLDL-mediated inhibition of CCR7 expression about 95.7 8 +/- 0.99% (mRNA) and 80.06 +/- 19.46% (protein), and pretreated with P38 inhibitor SB203580 in macrophage, oxLDL could not decrease CCR7 expression. IL-10 inhibited oxLDL-mediated inhibition of MMP9 secretion about 74.02 +/- 22.35%, and pretreated with P38 inhibitor SB203580 in macrophage, oxLDL could not decrease MMP9 secretion. Treatment with oxLDL increased P38 phosphorylation by 31.88 +/- 2.79%, 40.24 +/- 5.69% and 30.93 +/- 4.66% at 15, 30 and 60 min, respectively, whereas the effect of IL-10 on the expression of phosphorylated P38 was reversed by 49.49 +/- 12.12%, 70.93 +/- 16.14% and 47.62 +/- 6.00% in up-indicated time-points, respectively. From these data, we speculated oxLDL-SR-A-beta-arrestin2-P38-MMP9/CCR7 could play a critical role in the macrophages migration, which was blocked by IL-10 through inhibiting oxLDL uptake. PMID- 25446846 TI - Identification of a single nucleotide promoter polymorphism regulating the transcription of ubiquitin specific protease 18 gene related to the resistance to porcine reproductive and respiratory syndrome virus infection. AB - Porcine reproductive and respiratory syndrome (PRRS), characterized by reproductive failure in sows and respiratory disease and mortality in piglets, is a major infectious disease that causes great economic loss throughout the world. Previous studies revealed that the overexpression of porcine ubiquitin specific protease 18 (USP18) gene inhibits PRRSV replication in vitro. The objective of this study is to compare the promoter activity of USP18 in Chinese indigenous Dapulian (DPL) pigs and Duroc*Landrace*Yorkshire (DLY) commercial pigs and screen single nucleotide polymorphism (SNP) affecting porcine USP18 transcription. We found that the promoter activity was significantly higher in DPL pigs than DLY commercial pigs (p<0.05), deletion of the promoter from -1790 to -1314bp decreased the transcriptional activity by roughly 60% (p<0.05) and a SNP G-1533A in this region increased the mRNA expression both prior to and post PRRSV infection in MARC-145 cells. Population genetics analysis showed that allele A was only detected in Chinese pig breeds which are generally resistant to PRRSV. These results suggest that the SNP G-1533A polymorphism in the promoter region of porcine USP18 gene is a potential DNA marker for the resistance to PRRSV. PMID- 25446847 TI - Identification of alternatively spliced isoforms of interleukin-2/15 receptor beta chain in ducks. AB - Interleukin (IL)-2 and IL-15 receptor beta (IL-2/15Rbeta, CD122) play important roles in signal transduction for biological functions of IL-2 and IL-15. We found that ducks possess three different IL-2/15Rbeta transcripts, a conventional form (duIL-2/15Rbeta) and two variants. Comparisons between the cDNA and genomic sequences revealed that the two variants, duIL-2/15Rbeta-d7 and duIL-2/15Rbeta d9, were novel spliced transcripts resulting from skipping exons 7 and 9, respectively. Expression profiles of duIL-2/15Rbeta and its isoforms were examined in healthy tissues, concanavalin A (ConA)-stimulated splenic lymphocytes and in livers and spleens of Riemerella anatipestifer-infected ducks using quantitative real-time PCR (qRT-PCR). Generally, duIL-2/15Rbeta-d9 expression was undetectable in healthy tissues, ConA-activated samples, and R. anatipestifer infected ducks. Expression levels of duIL-2/15Rbeta transcript were relatively high to moderate in all healthy tissues tested, while duIL-2/15Rbeta-d7 expression was low. Compared to untreated controls, expression levels of duIL 2/15Rbeta were elevated in ConA-activated splenic lymphocytes and in livers on day 7 in R. anatipestifer-infected ducks, while duIL-2/15Rbeta-d7 expression was unchanged. Additionally, COS-7 cells transfected with duIL-2/15Rbeta, duIL 2/15Rbeta-d7, or duIL-2/15Rbeta-d9 constructs generated 73 kilodalton (kDa), 31kDa, and 40kDa proteins, respectively. This study identified three different IL 2/15Rbeta transcripts, including two isoforms generated by alternative splicing and their gene expression patterns in stimulated conditions. PMID- 25446848 TI - Sub-isotypic differences in the immunoglobulin G response to Lawsonia intracellularis in vaccinated, seropositive, and equine proliferative enteropathy affected horses. AB - In the horse, Lawsonia intracellularis infection results in equine proliferative enteropathy (EPE). While upwards of 100% of weanlings on an endemic farm may seroconvert, only a small percentage (approximately 5%) will develop clinical disease. Cell-mediated immune mechanisms likely play a role in resistance to L. intracellularis and the absence of a L. intracellularis-specific IFN-gamma response has been associated with the development of EPE. The goal of this study was to determine whether protection from clinical EPE is associated with the induction of a systemic IgG sub-isotypic response consistent with a Th1-type cytokine response. To describe their L. intracellularis/EPE status, horses enrolled in this study were placed into one of three categories: seropositive only, vaccinated, and presumptive clinical EPE. An existing ELISA method was modified to detect L. intracellularis-specific IgG(a), IgG(b), and IgG(t) antibodies using the mouse anti-equine hybridomas CVS-48, CVS-39, and CVS-40, respectively. Additionally, the existing ELISA method was used to quantify total IgG antibodies specific for L. intracellularis for comparison between the groups. Total L. intracellularis-specific IgG was found to be significantly higher (p<0.05) in presumptive clinical EPE cases (n=21) when compared with seropositive (exposed but unaffected) (n=36) and vaccinated horses (n=27). Further, a similar pattern for IgG(a) was seen in that the presumptive clinical EPE horses had significantly more L. intracellularis-specific IgG(a) (p<0.05) than the seropositive or vaccinated horses. With IgG(b), however, the vaccinated horses had significantly more IgG(b) (p<0.05) than the presumptive clinical or seropositive horses. No L. intracellularis-specific IgG(t) was detected in samples from any of the groups. While the results presented here with respect to IgG(a) response in the presumptive clinical EPE group were expected, a higher concentration of IgG(a) was anticipated in the seropositive horses that failed to develop clinical disease as well as in the vaccinated horses. Future work utilizing newer reagents against a broader range of equine IgG sub-isotypes may provide additional information once these become commercially available. PMID- 25446849 TI - Spectroscopic studies on the in vitro antioxidant capacity of isopentyl ferulate. AB - Essential oils have played a prominent role in research on natural products, due to the high level of bioactive constituents, which include those derived from phenylpropanoids or terpenoids. This study aimed to evaluate the antioxidant capacity of isopentyl ferulate (IF) employing in vitro experimental models for elimination of the 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis-3 ethylbenzothiazoline-6-sulfonic acid (ABTS+), hydroxyl (OH) and nitric oxide (NO), as well as its capacity to electron transfer by reducing potential and inhibition of lipid peroxidation by TBARS (thiobarbituric acid reactive substances) method. In all in vitro antioxidants protocols, isopentyl ferulate showed to be potent in a concentration of 54.4 nM, presenting a percentage inhibition of 91.29+/-0.57, 92.63+/-0.28, 83.62+/-0.18, 77.07+/-0.72 and 79.51+/ 0.32% for DPPH, ABTS+, hydroxyl, nitric oxide and TBARS level, respectively. The increase of absorbance at 700 nm in the concentrations of 3.4, 6.8, 13.6, 27.2 and 54.4 nM shows the reducing potential of IF. Similar results were obtained with Trolox (559 nM), a hydrophilic synthetic analogue of alpha-tocopherol, which is widely used as a standard antioxidant. The present study demonstrated that isopentyl ferulate has an antioxidant activity in vitro experimental models, suggesting that this compound could enhance the development of a new product with antioxidant properties. However, further in vivo studies are needed to assign possible implications in the treatment of diseases related with free radicals. PMID- 25446850 TI - Expression of AKR1B1, AKR1C3 and other genes of prostaglandin F2alpha biosynthesis and action in ovarian endometriosis tissue and in model cell lines. AB - Endometriosis is a frequent benign gynecological disease characterized by endometrial tissue outside the uterine cavity. The estimated prevalence in the general population is 6-10%, but this reaches 30-50% in women with infertility and/or pain. As ectopic tissue within the pelvic cavity provokes inflammation, endometriosis is also considered a chronic inflammatory disease, and is characterized by increased peritoneal fluid levels of prostaglandin (PG)E2 and PGF2alpha. The AKR1B1 and AKR1C3 enzymes act as PG synthases and catalyze reduction of PGH2 to PGF2alpha, and PGD2 to 9alpha,11beta-PGF2alpha, respectively. AKR1B1 and AKR1C3 may thus be associated with increased PGF2alpha production in endometriosis patients, as supported by our previous report of increased AKR1C1-AKR1C3 mRNA levels in endometriotic tissue, compared to control endometrium. Here, we initially evaluated PGF2alpha concentrations in peritoneal fluid from endometriosis patients and healthy women. We also examined expression of AKR1B1, AKR1C3 and other genes involved in PGF2alpha biosynthesis, metabolism, and action in ovarian endometriosis tissue versus healthy endometrium, and in peritoneal endometriosis and control endometrium model cell lines. Compared to controls, increased PGF2alpha concentrations in peritoneal fluid of patients were supported by endometriotic tissue showing increased AKR1B1 mRNA and protein levels, but unchanged AKR1C3 protein levels. Among genes involved in PGF2alpha biosynthesis, metabolism and action PLA2G2A, PTGS2/COX-2, ABCC4 and PTGFR were up regulated, mRNA levels of SLCO2A, PTGDS and HPGDS were unchanged, and genes PLA2G4A and HPGD were down-regulated in diseased tissue. All of these PGF2alpha associated genes were also expressed in control endometrial HIEEC epithelial and HIESC stromal cell lines, and in peritoneal endometriosis 12-Z epithelial and 22 B stromal cell lines. Higher expression of PLA2G2A, PTGS2, AKR1B1, AKR1C3 and ABCC4 was seen in 22-B endometriosis cells compared to HIESC control cells. These cell models characterized in this study will enable further investigations into the role of PGF2alpha in the pathophysiology of endometriosis and the involvement of AKR1B1 and AKR1C3. PMID- 25446851 TI - Metabolism of doxorubicin to the cardiotoxic metabolite doxorubicinol is increased in a mouse model of chronic glutathione deficiency: A potential role for carbonyl reductase 3. AB - Doxorubicin is highly effective at inducing DNA double-strand breaks in rapidly dividing cells, which has led to it being a widely used cancer chemotherapeutic. However, clinical administration of doxorubicin is limited by off-target cardiotoxicity, which is thought to be mediated by doxorubicinol, the primary alcohol metabolite of doxorubicin. Carbonyl reductase 1 (CBR1), a well characterized monomeric enzyme present at high basal levels in the liver, is known to exhibit activity toward doxorubicin. Little is known about a closely related enzyme, carbonyl reductase 3 (CBR3), which is present in the liver at low basal levels but is highly inducible by the transcription factor Nrf2. Genetic polymorphisms in CBR3, but not CBR1, are associated with differential cardiac outcomes in doxorubicin treated pediatric patients. Cbr3 mRNA and CBR3 protein are highly expressed in the livers of Gclm-/- mice (a mouse model of glutathione deficiency) relative to wild type mice. In the present study, we first investigated the ability of CBR3 to metabolize doxorubicin. Incubations of doxorubicin and purified recombinant murine CBR3 (mCBR3) were analyzed for doxorubicinol formation using HPLC, revealing for the first time that doxorubicin is a substrate of mCBR3. Moreover, hepatocytes from Gclm-/- mice produced more doxorubicinol than Gclm+/+ hepatocytes. In addition, differentiated rat myoblasts (C2C12 cells) co-cultured with primary Gclm-/- murine hepatocytes were more sensitive to doxorubicin-induced cytostasis/cytotoxicity than incubations with Gclm+/+ hepatocytes. Our results indicate a potentially important role for CBR3 in doxorubicin-induced cardiotoxicity. Because there is likely to be variability in hepatic CBR3 activity in humans (due to either genetic or epigenetic influences on its expression), these data also suggest that inhibition of CBR3 may provide protection from doxorubicinol cardiotoxicity. PMID- 25446853 TI - Hypoglycemic effect of deoxynojirimycin-polysaccharide on high fat diet and streptozotocin-induced diabetic mice via regulation of hepatic glucose metabolism. AB - Type 2 diabetes mellitus (T2DM) is currently considered a worldwide epidemic and finding effective therapeutic strategies against this disease is highly important. A deoxynojirimycin-polysaccharide mixture (DPM) has previously been shown to exert hypoglycemic effects on alloxan- or streptozotocin (STZ)-induced diabetic mice. The purpose of the present study was to evaluate the therapeutic effects and underlying mechanism(s) of DPM on T2DM induced by high fat diet following low-dose STZ treatment in mice. After daily oral treatment of diabetic mice with DPM (150 mg/kg b.w.) for 90 d, significant decline in blood glucose, pyruvate, triglyceride (TG), aspartate transaminase (AST), alanine transaminase (ALT), creatinine (Cr), lipid peroxide (LPO) and malondialdehyde (MDA) levels as well as evident increases in high density lipoprotein (HDL-c) and hepatic glycogen concentrations were observed. In the first stage, in which DPM was administered for 60 d, blood insulin levels did not undergo significant change but a significant decrease in the HOMA-IR index was detected. By contrast, the HOMA-IR index increased significantly in T2MD controls. In the second stage, in which DPM treatment was continued for another 30 d, insulin levels significantly increased in DPM-treated mice in comparison with T2DM controls. These results indicate that insulin resistance in the pre-diabetic period and the dysfunction of pancreatic beta-cells are ameliorated by DPM treatment. DPM also down regulated protein levels of insulin receptor (IR) and gluconeogenic enzymes (pyruvate carboxylase, fructose-1, 6-bisphosphatase, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) in peripheral tissues (liver and/or muscle), but enhanced the expressions of insulin in pancreas, lipoprotein lipase (LPL) and glycolysis enzymes (glucokinase, phosphofructokinase, private kinase and pyruvate decarboxylase E1) in the liver. Furthermore, deoxynojirimycin (DNJ) and polysaccharide (P) were found to increase proliferation of hepatic LO-2 cells and scavenging of radicals in vitro. These results support the results of our biochemical analyses and underscore possible mechanisms underlying the protective effects of DPM on STZ-induced damage to the pancreas and the liver. Taken together, our findings suggest that DPM may be developed as an antihyperglycemic agent for the treatment of diabetes mellitus. PMID- 25446852 TI - 5,3'-Dihydroxy-6,7,4'-trimethoxyflavanone exerts its anticancer and antiangiogenesis effects through regulation of the Akt/mTOR signaling pathway in human lung cancer cells. AB - 5,3'-Dihydroxy-6,7,4'-trimethoxyflavanone (DHTMF) is one of the constituents of Vitex rotundifolia, a medicinal herb that is used for the treatment of various disorders in China and Korea. In this study we evaluated the antitumor and antiangiogeneic activities of DHTMF. DHTMF significantly suppressed growth and induced apoptosis in lung carcinoma cells in a dose-dependent manner, as indicated by a decrease in Bcl-2 levels and increases in Bax and cleaved caspase 3 levels. In addition, DHTMF treatment significantly reduced the phosphorylation of Akt and mammalian target of rapamycin (mTOR), accompanied by reductions in the protein level of hypoxia-inducible factor (HIF-1alpha) and vascular endothelial growth factor (VEGF), which are key angiogenic molecules in H522 lung cancer cells. Furthermore DHTMF inhibited VEGF-induced angiogenesis, as indicated by reduced expression of CD34, tube formation and migration in human umbilical vein endothelial cells (HUVECs), as well as reduced neovascularization in an in vivo mouse Matrigel plug assay. DHTMF also inhibited phosphorylation of Akt, mTOR, and p70S6K in HUVECs and lung cancer cells. Taken together, our finding indicated that DHTMF inhibits Akt/mTOR signaling and reduces the expression of HIF-1 alpha and VEGF in tumor cells, which in turns inhibits endothelial cell-mediated angiogenesis. These results suggest that DHTMF inhibits angiogenesis as well as induces apoptosis via the Akt/mTOR pathway and might elicit pharmacological effects that are useful for treatment of lung cancer. PMID- 25446854 TI - Identification and isolation of a regulator protein for 3,17beta-HSD expressional regulation in Comamonas testosteroni. AB - Comamonas testosteroni (C. testosteroni) is able to catabolize a variety of steroids and polycyclic aromatic hydrocarbons. 3,17beta-Hydroxysteroid dehydrogenase (3,17beta-HSD) from C. testosteroni is a member of the short-chain dehydrogenase/reductase (SDR) superfamily. It is an inducible and key enzyme in steroid degradation. Elucidating the mechanism of 3,17beta-HSD gene (betahsd) regulation may help us to generate prospective C. testosteroni mutants for bioremediation. The genome of C. testosteroni ATCC11996 was sequenced in our previous work. Upon examining the genome with bioinformatics tools, a gene (brp) coding for a regulator protein (BRP) for 3,17beta-HSD expression was found upstream of the betahsd gene. A Blast search revealed high identities to a nucleotide binding protein with unknown function in other bacteria. Two potential promoters and two repeat sequences (RS, 16 bp), spaced to each other by 1661 bp, were also found upstream of the betahsd gene C. testosteroni. The brp gene was cloned into plasmid pK18 and pET-15b, expressed in Escherichia coli, and the recombinant BRP protein was purified on a Ni-column. In addition, a brp gene knock-out mutant of C. testosteroni was prepared. These knock-out mutants showed an enhanced expression of both the betahsd gene and the hsdA gene (the latter coding for 3alpha-HSD/CR) in the presence of testosterone. To characterize the BRP functional DNA domain, different fragments of the betahsd upstream regulatory region were tested in a cotransformation system. Our data reveal that the betahsd gene undergoes complex regulation involving the two promoters, a loop structure via the two repeat sequences, and the steroid testosterone. Furthermore, a proximal repressor gene for betahsd expression, phaR, had been identified in our previous investigations. The exact interplay between all these factors will be determined in future experiments. PMID- 25446855 TI - Ruthenium complexes as inhibitors of the aldo-keto reductases AKR1C1-1C3. AB - The human aldo-keto reductases (AKRs) from the 1C subfamily are important targets for the development of new drugs. In this study, we have investigated the possible interactions between the recombinant AKR1C enzymes AKR1C1-AKR1C3 and ruthenium(II) complexes; in particular, we were interested in the potential inhibitory actions. Five novel ruthenium complexes (1a, 1b, 2a, 2b, 2c), two precursor ruthenium compounds (P1, P2), and three ligands (a, b, c) were prepared and included in this study. Two different types of novel ruthenium(II) complexes were synthesized. First, bearing the sulphur macrocycle [9]aneS3, S-bonded dimethylsulphoxide (dmso-S), and an N,N-donor ligand, with the general formula of [Ru([9]aneS3)(dmso)(N,N-ligand)](PF6)2 (1a, 1b), and second, with the general formula of [(eta(6)-p-cymene)RuCl(N,N-ligand)]Cl (2a, 2b, 2c). All of these synthesized compounds were characterized by high-resolution NMR spectroscopy, X ray crystallography (compounds a, b, c, 1a, 1b) and other standard physicochemical methods. To evaluate the potential inhibitory actions of these compounds on the AKR1C enzymes, we followed enzymatically catalyzed oxidation of the substrate 1-acenaphthenol by NAD(+) in the absence and presence of various micromolar concentrations of the individual compounds. Among 10 compounds, one ruthenium complex (2b) and two precursor ruthenium compounds (P1, P2) inhibited all three AKR1C enzymes, and one ruthenium complex (2a) inhibited only AKR1C3. Ligands a, b and c revealed no inhibition of the AKR1C enzymes. All four of the active compounds showed multiple binding with the AKR1C enzymes that was characterized by an initial instantaneous inhibition followed by a slow quasi irreversible step. To the best of our knowledge, this is the first study that has examined interactions between these AKR1C enzymes and ruthenium(II) complexes. PMID- 25446856 TI - Comparative and evolutionary studies of vertebrate ALDH1A-like genes and proteins. AB - Vertebrate ALDH1A-like genes encode cytosolic enzymes capable of metabolizing all trans-retinaldehyde to retinoic acid which is a molecular 'signal' guiding vertebrate development and adipogenesis. Bioinformatic analyses of vertebrate and invertebrate genomes were undertaken using known ALDH1A1, ALDH1A2 and ALDH1A3 amino acid sequences. Comparative analyses of the corresponding human genes provided evidence for distinct modes of gene regulation and expression with putative transcription factor binding sites (TFBS), CpG islands and micro-RNA binding sites identified for the human genes. ALDH1A-like sequences were identified for all mammalian, bird, lizard and frog genomes examined, whereas fish genomes displayed a more restricted distribution pattern for ALDH1A1 and ALDH1A3 genes. The ALDH1A1 gene was absent in many bony fish genomes examined, with the ALDH1A3 gene also absent in the medaka and tilapia genomes. Multiple ALDH1A1-like genes were identified in mouse, rat and marsupial genomes. Vertebrate ALDH1A1, ALDH1A2 and ALDH1A3 subunit sequences were highly conserved throughout vertebrate evolution. Comparative amino acid substitution rates showed that mammalian ALDH1A2 sequences were more highly conserved than for the ALDH1A1 and ALDH1A3 sequences. Phylogenetic studies supported an hypothesis for ALDH1A2 as a likely primordial gene originating in invertebrate genomes and undergoing sequential gene duplication to generate two additional genes, ALDH1A1 and ALDH1A3, in most vertebrate genomes. PMID- 25446857 TI - Carnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and in vitro model of Parkinson's disease: involvement of antioxidative enzymes induction. AB - The neuroprotective effects of carnosic acid (CA), a phenolic diterpene isolated from rosemary (Rosmarinus officinalis), have been widely investigated in recent years, however, its protection in in vivo still unclear. In this study, we investigated the behavioral activity and neuroprotective effects of CA in a rat model of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA). Rats were treated with 20mg/kg body weight of CA for 3 weeks before 6-OHDA exposure. Results indicated that CA improved the locomotor activity and reduced the apomorphine-caused rotation in 6-OHDA-stimulated rats. Significant protection against lipid peroxidation and GSH reduction was observed in the 6-OHDA rats pretreated with CA. Pretreatment with CA increased the protein expression of gamma-glutamate-cysteine ligase catalytic subunit, gamma-glutamate-cysteine ligase modifier subunit, superoxide dismutase, and glutathione reductase compared with 6-OHDA-stimulated rats and SH-SY5Y cells. Immunoblots showed that the reduction of the Bcl-2/Bax ratio, the induction of caspase 3 cleavage, and the induction of poly(ADP-ribose) polymerase (PARP) cleavage by 6-OHDA was reversed in the presence of SB203580 (a p38 inhibitor) or SP600125 (a JNK inhibitor) in SH SY5Y cells. Rats treated with CA reversed the 6-OHDA-mediated the activation of c Jun NH2-terminal kinase and p38, the down-regulation of the Bcl-2/Bax ratio, the up-regulation of cleaved caspase 3/caspase 3 and cleaved PARP/PARP ratio, and the down-regulation of tyrosine hydroxylase protein. However, BAM7, an activator of Bax, attenuated the effect of CA on apoptosis in SH-SY5Y cells. These results suggest that CA protected against 6-OHDA-induced neurotoxicity is attributable to its anti-apoptotic and anti-oxidative action. The present findings may help to clarify the possible mechanisms of rosemary in the neuroprotection of PD. PMID- 25446858 TI - Protective effects of ferulic acid and related polyphenols against glyoxal- or methylglyoxal-induced cytotoxicity and oxidative stress in isolated rat hepatocytes. AB - Glyoxal (GO) and methylglyoxal (MGO) cause protein and nucleic acid carbonylation and oxidative stress by forming reactive oxygen and carbonyl species which have been associated with toxic effects that may contribute to cardiovascular disease, complications associated with diabetes mellitus, Alzheimer's and Parkinson's disease. GO and MGO can be formed through oxidation of commonly used reducing sugars e.g., fructose under chronic hyperglycemic conditions. GO and MGO form advanced glycation end products which lead to an increased potential for developing inflammatory diseases. In the current study, we have investigated the protective effects of ferulic acid and related polyphenols e.g., caffeic acid, p coumaric acid, methyl ferulate, ethyl ferulate, and ferulaldehyde on GO- or MGO induced cytotoxicity and oxidative stress (ROS formation, protein carbonylation and mitochondrial membrane potential maintenance) in freshly isolated rat hepatocytes. To investigate and compare the protective effects of ferulic acid and related polyphenols against GO- or MGO-induced toxicity, five hepatocyte models were used: (a) control hepatocytes, (b) GSH-depleted hepatocytes, (c) catalase-inhibited hepatocytes, (d) aldehyde dehydrogenase (ALDH2)-inhibited hepatocytes, and (e) hepatocyte inflammation system (a non-toxic H2O2-generating system). All of the polyphenols tested significantly decreased GO- or MGO-induced cytotoxicity, ROS formation and improved mitochondrial membrane potential in these models. The rank order of their effectiveness was caffeic acid~ferulaldehyde>ferulic acid>ethyl ferulate>methyl ferulate>p-coumaric acid. Ferulic acid was found to decrease protein carbonylation in GSH-depleted hepatocytes. This study suggests that ferulic acid and related polyphenols can be used therapeutically to inhibit or decrease GO- or MGO-induced hepatotoxicity. PMID- 25446859 TI - Effects of avermectin on heat shock proteins expression and histopathology in spleen tissues of pigeon. AB - Avermectin (AVM) is the active component of some insecticidal and nematicidal product used in agriculture and veterinary medicine for the prevention of parasitic diseases. Residues of AVM in environment have toxic effects on non target aquatic and terrestrial organisms. Heat shock proteins (Hsps) are commonly used by environmental toxicologists as biochemical markers of exposure to various chemical and other stressors. The objective of this study was to investigate whether sub-chronic AVM exposure would alter the levels of stress proteins, Hsps in the pigeon spleen after 30, 60 and 90days. Our results showed that Hsp60, Hsp70 and Hsp90, and their corresponding messenger RNA (mRNA) transcriptions (as well as Hsp30) significantly elevated, meanwhile, obviously histopathological changes were not observed in pigeons spleens after early AVM exposure. Then the expression of Hsps relatively decreased and obvious histopathological damages occurred in the spleen tissues with continued AVM exposure. So we suggest that the elevations of Hsps can be as a part of protective mechanism to reduce cellular damage, and important markers to help assess the toxicity induced by AVM. The reduction of Hsps in spleen implies that the tissues are damaged by long term and excessive AVM exposure. Thus, the information presented in this study is believed to be helpful in supplementing data for further AVM toxicity study. PMID- 25446860 TI - Arsenic, cadmium, mercury and nickel stimulate cell growth via NADPH oxidase activation. AB - Exposure to metals and metalloids including arsenic, cadmium, mercury, and nickel has been a worldwide health problem for several decades. The aim of this study was to learn how metal-induced oxidative stress triggers cell proliferation, a process of great significance for cancer. NADPH oxidase (NOX) activity and cell proliferation were measured as endpoints in both NOX-deficient and NOX-proficient cells. The X chromosome linked CGD (X-CGD) human promyelocytic leukemia PLB-985 cells lacking gp91phox and the X-CGD cells re-transfected with gp91phox (X-CGD gp91(phox)) were used together with immortalized human keratinocyte cells (HaCaT). The cells were exposed to different concentrations of the metals alone or together with the NOX inhibitor, diphenyleneiodonium (DPI). We found that the studied metals increased NOX activity. They stimulated cell proliferation in HaCaT and X-CGD-gp91(phox) cells at concentrations below 1MUM but not in the X CGD cells that lack functional NOX. Addition of DPI attenuated the metal-induced cell proliferation. At concentrations above 1MUM these metals inhibited cell proliferation. Based on these findings, we propose that many environmental pollutants, including metals and also endogenous NOX-activators such as oxidants and growth factors, interfere with cell growth kinetics by increasing the levels of the diffusible molecule H2O2. Here, we provide evidence that NOXs is central to the mechanism of metal-mediated reactive oxygen species production and stimulation of cell proliferation. PMID- 25446861 TI - Biological effects of conjugated linoleic acid on obesity-related cancers. AB - Considerable evidence suggests that obesity and overweight play an important role in cancers i.e., breast, colon, endometrial, kidney, pancreatic, and liver. In fact, overweight and obesity are now established risk factors for cancer and cancer-related mortality. Conjugated linoleic acid (CLA) consists of a group of positional and geometric fatty acid (FA) isomers that are derived from linoleic acid (LA) [18:2(n-6)], which occurs naturally in food with a high concentration in products from ruminant animals. Studies in both in vitro cell and in vivo animal models have shown that CLA, specifically cis 9-trans 11 and trans 10-cis 12 CLA isomer, inhibits the initiation and promotion stages of carcinogenesis, suggesting that CLA has received considerable attention as a chemopreventive agent. In this review, the biological activities and multiple mechanisms of CLA in obesity-related cancers including cell lines, animal models and clinical observations are explained. PMID- 25446862 TI - Protective effect of Satureja montana extract on cyclophosphamide-induced testicular injury in rats. AB - The present study investigated the protective effect of Satureja montana extract against cyclophosphamide-induced testicular injury in rats. Total phenolic and flavonoid contents of the extract were 1.03% and 0.34%w/w of dry herb expressed as chlorogenic acid and quercetin, respectively. HPLC analysis identified caffeic, syringic and rosmarinic acids as the chief phenolic acids, and rutin as the major flavonoid in the extract. Oral daily administration of S.montana extract (50mg/kg/day) for 7days before and 7days after an intraperitoneal injection of cyclophosphamide (200mg/kg) restored the reduced relative testicular weight, serum testosterone level and testicular alkaline phosphatase activity, raised the lowered testicular sorbitol dehydrogenase and acid phosphatase activities, and decreased the elevated testicular hemoglobin absorbance. It also attenuated lipid peroxidation, restored the lowered glutathione content, glucose 6-phosphate dehydrogenase, glutathione peroxidase and glutathione reductase activities, and improved total antioxidant capacity. Moreover, S.montana extract mitigated testicular DNA fragmentation, decreased the elevated Fas and Bax gene expression, up-regulated the decreased Bcl-2 and peroxisome proliferator activated receptor-gamma (PPAR-gamma) gene expression and normalized Akt1 protein level. Histopathological investigation confirmed the protective effects of the extract. Conclusively, S.montana extract protects the rat testis against cyclophosphamide-induced damage via anti-oxidative and anti-apoptotic mechanisms that seem to be mediated, at least in part, by PPAR-gamma and Akt1 up-regulation. PMID- 25446863 TI - Ribosome rescue systems in bacteria. AB - Ribosomes often stall during protein synthesis in various situations in a cell, either unexpectedly or in a programmed fashion. While some of them remain stalled for gene regulation, many are rescued by some cellular systems. Ribosomes stalled at the 3' end of a truncated mRNA lacking a stop codon (non-stop mRNA) are rescued by trans-translation mediated by tmRNA (transfer-messenger RNA) and a partner protein, SmpB. Through trans-translation, a degradation tag is added to the C-termini of truncated polypeptides from a truncated mRNA to prevent them from accumulation in the cell. Trans-translation has crucial roles in a wide variety of cellular events, especially under stressful conditions. The trans translation system is thought to be universally present in the bacterial domain, although it is not necessarily essential in all bacterial cells. It has recently been revealed that two other systems, one involving a small protein, ArfA, with RF2 and the other involving YaeJ (ArfB), a class I release factor homologue, operate to relieve ribosome stalling in Escherichia coli. Thus, many bacterial species would have multiple systems to cope with various kinds of stalled translation events. PMID- 25446864 TI - Global tuberculosis elimination: the relevance of trend surveillance in Mexico and beyond. PMID- 25446865 TI - Sandblasting in the naval industry: another life-threatening activity related to silicosis. PMID- 25446867 TI - Superior vena cava syndrome caused by an idiopathic localized form of mediastinal fibrosis. PMID- 25446866 TI - Prevalence of Work-Related Asthma and its Impact in Primary Health Care. AB - BACKGROUND AND OBJECTIVE: To determine the prevalence of occupational asthma (OA) and work-exacerbated asthma (WEA) among asthmatic patients diagnosed in Primary Health Care (PHC). To analyze the impact at PHC level caused by under-diagnosis and inappropriate referral of OA. PATIENTS AND METHODS: A descriptive, cross sectional multicenter study in patients aged between 16 and 64years diagnosed with asthma, according to their medical record; all were working or had worked, and were assigned to one of 16 PHC centers in a healthcare district. Based on the responses to the questionnaire completed at the study visit, which included a thorough review of the subject's entire working history, patients were classified into three categories by an expert in occupational asthma: OA, WEA or common asthma (CA). RESULTS: Three hundred and sixty-eight patients completed the questionnaire. The prevalence of OA was 18.2% (25% in men and 14.6% in women, P=.046), and 54 patients (14.7%) were classified as WEA. The proportion of patients with work-related asthma (WRA) was therefore 32.9%. Asthmatic patients with WRA took more sick leave than CA patients (P<.001). CONCLUSIONS: A high prevalence of WRA was found, mostly treated in PHC. Under-diagnosis of WRA is widespread in PHC. PMID- 25446868 TI - Skin fold resembling pneumothorax. PMID- 25446869 TI - Bronchial thermoplasty for severe asthma: Initial experience in Chile. PMID- 25446870 TI - Exogenous Lipoid Pneumonia in Laryngectomy Patients: Radiological Findings. AB - Exogenous lipoid pneumonia (ELP) is a rare (incidence 1.0%-2.5%), often under diagnosed disease, caused by the aspiration and accumulation of exogenous lipids within the pulmonary alveoli. Various cases have been described due to inhalation of lubricants via the nasal passages and oropharynx, aspiration of mineral oils in laxatives in patients with eating disorders, application of lip gloss, occupational exposure to liquid paraffin or mineral oils ("fire-eaters", industrial use in washing of machinery, automobile workshops, plastic paints, etc.) and application of Vaseline during the insertion of nasogastric tubes and in the care of tracheotomy patients. ELP usually presents radiologically as areas of low-attenuation peribronchial consolidation and ground glass opacities, with a predominantly bibasal distribution. We present 5 cases of long-standing laryngectomy patients diagnosed with ELP who admitted using Vaseline in their tracheal stoma care. PMID- 25446871 TI - Multidisciplinary management of Paget-Schroetter syndrome. A case series of eight patients. AB - Paget-Schroetter syndrome (PSS) in the context of upper extremity deep venous thrombosis (DVT) is an uncommon but potentially very serious condition affecting young, healthy adults, in which secondary post-thrombotic syndrome (PTS) can be a complication with major implications. The best treatment option remains controversial, with current guidelines recommending anticoagulation for at least 3 months. However, an incidence of PTS of approximately 50% after 6 months, 30% after 1 year and 25% after 2 years has been found using this therapeutic approach. Consequently, specialized units recommend local thrombolysis and early decompressive surgery. We describe a series of eight cases treated in this way. None of the patients showed signs of complications, and an early return to regular activities with no PTS was observed in 90% of cases. PMID- 25446872 TI - Non-invasive ventilation in amyotrophic lateral sclerosis in outpatients and inpatients. Different perspectives? PMID- 25446874 TI - Alterations of natural killer cells in traumatic brain injury. AB - To investigate the relationship between natural killer (NK) cells and traumatic brain injury (TBI), we tracked an established phenotype of circulating NK cells at several time points in patients with different grades of TBI. In serial peripheral blood samples, NK cells were prospectively measured by flow cytometry of CD3(-) CD56(+) lymphocytes. Compared to healthy controls, TBI patients had reductions in both the percentage and the absolute number of NK cells. Furthermore, the magnitude of NK cell reduction correlated with the degree of TBI severity at several time points. That is, NK cell population size was independently associated with lower Glasgow Coma Scale scores. In addition, at some time points, a positive correlation was found between the NK cell counts and Glasgow Outcome Scale scores. Our results indicate that TBI induces a reduction in the number of NK cells, and the magnitude of the reduction appears to parallel the severity of TBI. PMID- 25446877 TI - Galectin-3 and heart failure: prognosis, prediction & clinical utility. AB - Heart failure (HF) is a leading cause of mortality in the western world. Despite advances in the treatment of HF, like the use of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and implantable cardiac defibrillators, prognosis of HF patients remains poor. For clinicians dealing with HF patients, risk prediction in both acute, chronic, and new onset HF remains a challenge. Biomarkers might help in risk stratification and may guide the proper use of limited resources and therapy. Galectin-3 is an emerging biomarker which has been linked to tissue fibrosis, a hallmark in cardiac remodeling and HF. Galectin-3 can reliably be measured in the circulation, and several recent studies have shown the prognostic value of galectin-3 in acute and chronic HF, and its potential utility in the general population. The purpose of this review was to summarize the literature and explore the potential role of galectin-3 as a biomarker in HF. PMID- 25446876 TI - Acute systemic accumulation of acrolein in mice by inhalation at a concentration similar to that in cigarette smoke. AB - Cigarette smoke is an important environmental factor associated with a wide array of public health concerns. Acrolein, a component of tobacco smoke and a known toxin to various cell types, may be a key pathological factor mediating the adverse effects linked with tobacco smoke. Although acrolein is known to accumulate in the respiratory system after acute nasal exposure, it is not clear if it accumulates systemically, and less is known in the nervous system. The aim of this study was to assess the degree of acrolein accumulation in the circulation and in the spinal cord following acute acrolein inhalation in mice. Using a laboratory-fabricated inhalation chamber, we found elevated urinary 3 HPMA, an acrolein metabolite, and increased acrolein adducts in the spinal cord after weeks of nasal exposure to acrolein at a concentration similar to that in tobacco smoke. The data indicated that acrolein is absorbed into the circulatory system and some enters the nervous system. It is expected that these findings may facilitate further studies to probe the pathological role of acrolein in the nervous system resulting from smoke and other external sources. PMID- 25446875 TI - Toll-like receptor 4-mediated nuclear factor-kappaB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats. AB - Nuclear factor kappa B (NF-kappaB) in the spinal cord is involved in pro inflammatory cytokine-mediated pain facilitation. However, the role of NF-kappaB activation in chronic morphine-induced analgesic tolerance and the underlying mechanisms remain unclear. In the present study, we found that the level of phosphorylated NF-kappaB p65 (p-p65) was increased in the dorsal horn of the lumbar 4-6 segments after intrathecal administration of morphine for 7 consecutive days, and the p-p65 was co-localized with neurons and astrocytes. The expression of TNF-alpha and IL-1beta was also increased in the same area. In addition, pretreatment with pyrrolidinedithiocarbamate (PDTC) or SN50, inhibitors of NF-kappaB, prevented the development of morphine analgesic tolerance and alleviated morphine withdrawal-induced allodynia and hyperalgesia. The increase in TNF-alpha and IL-1beta expression induced by chronic morphine exposure was also partially blocked by PDTC pretreatment. In another experiment, rats receiving PDTC or SN50 beginning on day 7 of morphine injection showed partial recovery of the anti-nociceptive effects of morphine and attenuation of the withdrawal-induced abnormal pain. Meanwhile, intrathecal pretreatment with lipopolysaccharide from Rhodobacter sphaeroides, an antagonist of toll-like receptor 4 (TLR4), blocked the activation of NF-kappaB, and prevented the development of morphine tolerance and withdrawal-induced abnormal pain. These data indicated that TLR4-mediated NF-kappaB activation in the spinal cord is involved in the development and maintenance of morphine analgesic tolerance and withdrawal-induced pain hypersensitivity. PMID- 25446878 TI - Improved sensitivity of circulating tumor DNA measurement using short PCR amplicons. AB - Circulating tumor DNA is being extensively investigated as a clinically relevant cancer marker. KRAS mutations are present in 40% of colorectal tumors and monitoring the mutational status together with the level of mutated DNA is of great interest. The measurement of DNA from plasma or serum, however, presents a number of challenges that require attention. The amount of DNA is low and highly fragmented and analyses need to be optimized accordingly. KRAS ARMS-qPCR assays with amplicon lengths of 120 and 85 base pairs, respectively, were compared using positive control material (PCR fragments) and plasma samples from 46 colorectal cancer patients known to harbor a tumor KRAS mutation. KRAS mutated DNA was detected in significantly more clinical samples using the short amplicon assays compared to the long amplicon assays (74% vs. 61%, p=0.03). The level of mutated DNA in plasma was on average three times higher using short amplicon assays. Our results reflect the importance of minimizing the assay length when analyzing highly fragmented DNA, especially if these analyses are to be used for treatment monitoring and relapse detection. PMID- 25446879 TI - Interaction between carcinogenic and anti-carcinogenic trace elements in the scalp hair samples of different types of Pakistani female cancer patients. AB - BACKGROUND: It was investigated that carcinogenic processes are linked with the imbalances of essential trace and toxic elements in body fluid and tissues of human. In this study, the relationship between carcinogenic elements, arsenic (As), cadmium (Cd), and nickel (Ni), and anti-carcinogenic elements, selenium (Se) and zinc (Zn), in the scalp hair of different female cancer patients (breast, cervix, mouth and ovarian) was studied. METHODS: The scalp hair samples were collected from cancer patients and referent female subjects of the same age group and socioeconomic status. The scalp hair samples were oxidized by 65% nitric acid and 30% hydrogen peroxide by microwave oven and analyzed by atomic absorption spectrometry. The validity and accuracy of the methodology were checked using certified reference material of human hair (BCR 397). RESULTS: The mean concentrations of As, Cd, and Ni were found to be significantly higher in the scalp hair samples of cancerous patients as compared to referents, while reverse results were obtained in the case of Zn and Se (p<0.01). CONCLUSIONS: The study revealed that low level of trace elements (Se, Zn) and high level of heavy elements (As, Cd, and Ni) were associated with increased risk of cancer. PMID- 25446880 TI - Interference of cerebrospinal fluid total protein measurement by povidone-iodine contamination. AB - BACKGROUND: A falsely high cerebrospinal fluid (CSF) total protein (TP) result measured by pyrogallol red (PGR) method was suspected to be caused by preparation of the collection site with povidone-iodine (PVP-iodine) solution. METHODS: CSF TP was evaluated for interference in samples with different final concentrations of PVP-iodine (up to 0.25% PVP and 0.025% iodine) or iodine alone (up to 0.025% iodine) using three methods: PGR, modified biuret and benzethonium chloride (BZTC). Interference exceeding +/-20% of the baseline value is considered clinically significant according to the criterion defined by the College of American Pathologists. RESULTS: There were positive interference with the PGR method and negative inference for the BZTC method in CSF samples spiked with PVP iodine. The PVP-iodine (up to 0.25% PVP and 0.025% iodine) did not cause a clinically significant interference with the modified biuret method. PVP alone without iodine caused a positive interference with the PGR method but did not interfere with the modified biuret or the BZTC method. When the samples were spiked with iodine alone, none of the three methods was affected (change<20%) by iodine concentration up to 0.025%. CONCLUSIONS: Contamination of CSF specimens with PVP-iodine can lead to interference with CSF TP measurements using PGR or BZTC methods. PMID- 25446881 TI - Sphingolipids in pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by alveolar epithelial cell injury, accumulation of fibroblasts/myofibroblasts and deposition of extracellular matrix proteins. Levels of sphingosine-1-phosphate (S1P), a naturally occurring bioactive lipid, are elevated in bronchoalveolar fluids and lung tissues from IPF patients and animal models of pulmonary fibrosis. However, the in vivo contribution of S1P, regulated by its synthesis catalyzed by Sphingosine kinases (SphKs) 1 & 2 and catabolism by S1P phosphatases and S1P lyase (S1PL), in the pathogenesis of pulmonary fibrosis is not well defined. Microarray analysis of blood mononuclear cells from patients with IPF and SphK1-, SphK2- or S1PL-knockout mice and SphK inhibitor were used to assess the role of S1P in fibrogenesis. The expression of SphK1 negatively correlated with lung function and survival of patients with IPF. Further, the expressions of SphK1 and S1PL were increased in lung tissues from patients with IPF and bleomycin-challenged mice. Genetic knockdown of SphK1, but not SphK2, ameliorated bleomycin-induced pulmonary fibrosis in mice while deletion of S1PL (SGPL1(+/-)) in mice potentiated fibrosis post-bleomycin challenge. TGF-beta increased the expression of SphK1 and S1PL in human lung fibroblasts and knockdown of SphK1 or treatment with SphK inhibitor attenuated S1P generation and TGF-beta mediated signal transduction. Over-expression of S1PL attenuated bleomycin-induced TGF beta secretion and S1P mediated differentiation of human lung fibroblasts through regulation of autophagy. Administration of SphK1 inhibitor 8 days post-bleomycin challenge reduced bleomycin-induced mortality and pulmonary fibrosis. Our results suggest that SphK1 and S1PL play critical roles in the pathology of lung fibrosis and may be novel therapeutic targets. PMID- 25446882 TI - PTEN inhibitors: an evaluation of current compounds. AB - Small molecule inhibitors of many classes of enzymes, including phosphatases, have widespread use as experimental tools and as therapeutics. Efforts to develop inhibitors against the lipid phosphatase and tumour suppressor, PTEN, was for some time limited by concerns that their use as therapy could result in increased risk of cancer. However, the accumulation of evidence that short term PTEN inhibition may be valuable in conditions such as nerve injury has raised interest. Here we investigate the inhibition of PTEN by four available PTEN inhibitors, bpV(phen), bpV(pic), VO-OHpic and SF1670 and compared this inhibition with that of only 3 other related enzymes, the tyrosine phosphatase SHP1 and the phosphoinositide phosphatases INPP4A and INPP4B. Even with this very small number of comparators, for all compounds, inhibition of multiple enzymes was observed and with all three vanadate compounds, this was similar or more potent than the inhibition of PTEN. In particular, the bisperoxovanadate compounds were found to inhibit PTEN poorly in the presence of reducing agents including the cellular redox buffer glutathione. PMID- 25446883 TI - Diacylglycerol, phosphatidic acid, and their metabolic enzymes in synaptic vesicle recycling. AB - The synaptic vesicle (SV) cycle includes exocytosis of vesicles loaded with a neurotransmitter such as glutamate, coordinated recovery of SVs by endocytosis, refilling of vesicles, and subsequent release of the refilled vesicles from the presynaptic bouton. SV exocytosis is tightly linked with endocytosis, and variations in the number of vesicles, and/or defects in the refilling of SVs, will affect the amount of neurotransmitter available for release (Sudhof, 2004). There is increasing interest in the roles synaptic vesicle lipids and lipid metabolizing enzymes play in this recycling. Initial emphasis was placed on the role of polyphosphoinositides in SV cycling as outlined in a number of reviews (Lim and Wenk, 2009; Martin, 2012; Puchkov and Haucke, 2013; Rohrbough and Broadie, 2005). Other lipids are now recognized to also play critical roles. For example, PLD1 (Humeau et al., 2001; Rohrbough and Broadie, 2005) and some DGKs (Miller et al., 1999; Nurrish et al., 1999) play roles in neurotransmission which is consistent with the critical roles for phosphatidic acid (PtdOH) and diacylglycerol (DAG) in the regulation of SV exo/endocytosis (Cremona et al., 1999; Exton, 1994; Huttner and Schmidt, 2000; Lim and Wenk, 2009; Puchkov and Haucke, 2013; Rohrbough and Broadie, 2005). PLD generates phosphatidic acid by catalyzing the hydrolysis of phosphatidylcholine (PtdCho) and in some systems this PtdOH is de-phosphorylated to generate DAG. In contrast, DGK catalyzes the phosphorylation of DAG thereby converting it into PtdOH. While both enzymes are poised to regulate the levels of DAG and PtdOH, therefore, they both lead to the generation of PtdOH and could have opposite effects on DAG levels. This is particularly important for SV cycling as PtdOH and DAG are both needed for evoked exocytosis (Lim and Wenk, 2009; Puchkov and Haucke, 2013; Rohrbough and Broadie, 2005). Two lipids and their involved metabolic enzymes, two sphingolipids have also been implicated in exocytosis: sphingosine (Camoletto et al., 2009; Chan et al., 2012; Chan and Sieburth, 2012; Darios et al., 2009; Kanno et al., 2010; Rohrbough et al., 2004) and sphingosine-1-phosphate (Chan, Hu, 2012; Chan and Sieburth, 2012; Kanno et al., 2010). Finally a number of reports have focused on the somewhat less well studies roles of sphingolipids and cholesterol in SV cycling. In this report, we review the recent understanding of the roles PLDs, DGKs, and DAG lipases, as well as sphingolipids and cholesterol play in synaptic vesicle cycling. PMID- 25446884 TI - Genetic analysis of the Warburg effect in yeast. AB - We recently discovered that the Warburg effect, defined by the dramatically enhanced metabolism of glucose to pyruvate, even in well-oxygenated cancer cells, can occur as a consequence of mutations that enhance lipid biosynthesis at the expense of respiratory capacity. Specifically, mutations in the E1 subunit of either of two respiratory enzymes, pyruvate dehydrogenase (PDC) or alpha ketoglutarate dehydrogenase (KGDC), change substrate specificity from the 3 carbon alpha-ketoacid pyruvate, or the 5-carbon alpha-ketoacid alpha ketoglutarate, to the 4-carbon alpha-ketoacid oxaloacetate (OADC). These mutations result in OADC-catalyzed synthesis of malonyl-CoA (MaCoA), the essential precursor of all fatty acids. These mutants arose as spontaneous suppressors of a yeast acc1(cs) cold-sensitive mutation encoding an altered form of AcCoA carboxylase (Acc1) that fails to produce MaCoA at the restrictive temperature (16 degrees C). Notably, these suppressors are respiratory defective as a result of the same nuclear mutations that suppress acc1(cs). These mutants also suppress sensitivity to Soraphen A, a potent inhibitor of Acc1 activity, at normal temperature (30 degrees C). To our knowledge, OADC activity has never been identified in eukaryotic cells. Our results offer a novel perspective on the Warburg effect: the reprogramming of energy metabolism in cancer cells as a consequence of mutational impairment of respiration to meet the fatty acid requirements of rapidly proliferating cells. We suggest OADC activity is a common feature of cancer cells and represents a novel target for the development of chemotherapeutics. PMID- 25446886 TI - Cytochrome b5 modulates multiple reactions in steroidogenesis by diverse mechanisms. AB - Cytochrome b5 (cyt-b5) is a relatively small haemoprotein which plays an important role in the regulation of mammalian steroidogenesis. This unique protein has the ability to modulate the activity of key steroidogenic enzymes via a number of diverse reaction mechanisms. Cyt-b5 can augment the 17,20-lyase activity of CYP17A1 by promoting the interaction of CYP17A1 and POR; enhance the 16-ene-synthase activity of CYP17A1 by acting as an electron donor; and enhance the activity of 3betaHSD by increasing the affinity of 3betaHSD for its cofactor NAD(+). We review the modulation of CYP17A1 and 3betaHSD activity by cyt-b5 and discuss the reaction mechanisms associated with each activity. The physiological importance of cyt-b5 in regulating mammalian steroidogenesis is presented and the impact of inactivating cyt-b5 mutations are reviewed. This article is part of a Special Issue entitled 'Steroid/Sterol signaling'. PMID- 25446885 TI - Alterations in vitamin D metabolite, parathyroid hormone and fibroblast growth factor-23 concentrations in sclerostin-deficient mice permit the maintenance of a high bone mass. AB - Humans with mutations of the sclerostin (SOST) gene, and knockout animals in which the Sost gene has been experimentally deleted, exhibit an increase in bone mass. We review the mechanisms by which Sost knockout mice are able to accrete increased amounts of calcium and phosphorus required for the maintenance of a high bone mass. Recently published information from our laboratory, shows that bone mass is increased in Sost-deficient mice through an increase in osteoblast and a decrease in osteoclast activity, which is mediated by activation of beta catenin and an increase in prostacyclin synthesis in osteocytes and osteoblasts. The increases in calcium and phosphorus retention required for enhanced bone mineral accretion are brought about by changes in the vitamin D endocrine system, parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). Thus, in Sost knockout mice, concentrations of serum 1,25-dihydroxyvitamin D (1,25(OH)2D) are increased and concentrations of FGF-23 are decreased thereby allowing a positive calcium and phosphorus balance. Additionally, in the absence of Sost expression, urinary calcium is decreased, either through a direct effect of sclerostin on renal calcium handling, or through its effect on the synthesis of 1,25(OH)2D. Adaptations in vitamin D, PTH and FGF-23 physiology occur in the absence of sclerostin expression and mediate increased calcium and phosphorus retention required for the increase in bone mineralization. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25446887 TI - Modified-release oral calcifediol corrects vitamin D insufficiency with minimal CYP24A1 upregulation. AB - Vitamin D insufficiency is prevalent in chronic kidney disease (CKD) and associated with secondary hyperparathyroidism (SHPT) and increased risk of bone and vascular disease. Unfortunately, supplementation of stage 3 or 4 CKD patients with currently recommended vitamin D2 or D3 regimens does not reliably restore serum total 25-hydroxyvitamin D to adequacy (>=30ng/mL) or effectively control SHPT. Preclinical and clinical studies were conducted to evaluate whether the effectiveness of vitamin D repletion depends, at least in part, on the rate of repletion. A modified-release (MR) oral formulation of calcifediol (25 hydroxyvitamin D3) was developed which raised serum 25-hydroxyvitamin D3 and calcitriol levels gradually. Single doses of either bolus intravenous (IV) or oral MR calcifediol were administered to vitamin D deficient rats. Bolus IV calcifediol produced rapid increases in serum 25-hydroxyvitamin D3, calcitriol and FGF23, along with significant induction of CYP24A1 in both kidney and parathyroid gland. In contrast, oral MR calcifediol produced gradual increases in serum 25-hydroxyvitamin D3 and calcitriol and achieved similar hormonal exposure, yet neither CYP24A1 nor FGF23 were induced. A 10-fold greater exposure to bolus IV than oral MR calcifediol was required to similarly lower intact parathyroid hormone (iPTH). Single doses of oral MR (450 or 900MUg) or bolus IV (450MUg) calcifediol were administered to patients with stage 3 or 4 CKD, SHPT and vitamin D insufficiency. Changes in serum 25-hydroxyvitamin D3 and calcitriol and in plasma iPTH were determined at multiple time-points over the following 42 days. IV calcifediol produced abrupt and pronounced increases in serum 25 hydroxyvitamin D3 and calcitriol, but little change in plasma iPTH. As in animals, these surges triggered increased vitamin D catabolism, as evidenced by elevated production of 24,25-dihydroxyvitamin D3. In contrast, MR calcifediol raised serum 25-hydroxyvitamin D3 and calcitriol gradually, and meaningfully lowered plasma iPTH levels. Taken together, these studies indicate that rapid increases in 25-hydroxyvitamin D3 trigger CYP24A1 and FGF23 induction, limiting effective exposure to calcitriol and iPTH reduction in SHPT. They also support further investigation of gradual vitamin D repletion for improved clinical effectiveness. This article is part of a Special Issue entitled "17th Vitamin D Workshop". PMID- 25446888 TI - Loss of the PGE2 receptor EP1 enhances bone acquisition, which protects against age and ovariectomy-induced impairments in bone strength. AB - PGE2 exerts anabolic and catabolic effects on bone through the discrete actions of four prostanoid receptors (EP1-4). We have previously demonstrated that loss EP1 accelerates fracture repair by enhancing bone formation. In the present study we defined the role of EP1 in bone maintenance and homeostasis during aging and in response to ovariectomy. The femur and L4 vertebrae of wild type (WT) and EP1( /-) mice were examined at 2-months, 6-months, and 1-year of age, and in WT and EP1(-/-) mice following ovariectomy (OVX) or sham surgery. Bone volume fraction, trabecular architecture and mechanical properties were maintained during aging in EP1(-/-) mice to a greater degree than age-matched WT mice. Moreover, significant increases in bone formation rate (BFR) (+60%) and mineral apposition rate (MAR) (+50%) were observed in EP1(-/-), relative to WT, while no change in osteoclast number and osteoclast surface were observed. Following OVX, loss of EP1 was protective against bone loss in both femur and L4 vertebrae, with increased bone volume/total volume (BV/TV) (+32% in femur) and max load at failure (+10% in femur) relative to WT OVX, likely resulting from the increased bone formation rate that was observed in these mice. Taken together these studies identify inhibition of EP1 as a potential therapeutic approach to suppress bone loss in aged or post-menopausal patients. PMID- 25446889 TI - Comparison of the Vitek MS and Bruker Microflex LT MALDI-TOF MS platforms for routine identification of commonly isolated bacteria and yeast in the clinical microbiology laboratory. AB - This study compared the diagnostic performance of Bruker's Microflex LT and bioMerieux's Vitek MS matrix-assisted laser desorption ionization-time of flight mass spectrometry systems. A total of 477 isolates were tested on both instruments. Discrepant results were resolved by sequencing. Overall, there was no statistically significant difference between the proportion of isolates correctly identified, miscalled or not called by each instrument. Although both systems were good at identifying yeast (66/69 to species level), the confidence level was high only to genus level for 30% of the isolates on the Bruker. Both systems performed with high accuracy when evaluated solely on Food and Drug Administration-approved organisms for each database. A user-based assessment of the 2 instruments revealed an overall preference for the Vitek MS instrument. PMID- 25446890 TI - Catheter-related bacteremia by Cupriavidus metallidurans. AB - Cupriavidus bacteremia is a rare infection and identification of the pathogen is difficult. We present four cases of bacteremia by Cupriavidus metallidurans that were initially identified to the genus level by both Bruker and Vitek matrix assisted laser desorption ionization-time of flight mass spectrometry and later identified to the species level by 16S rRNA gene sequencing. To our knowledge, these are the first cases of C. metallidurans catheter-related infections. Patients were successfully treated with antibiotic therapy and catheter removal. PMID- 25446892 TI - Geographic variation in acoustic communication in anurans and its neuroethological implications. AB - Geographic variation of traits may represent the first step for evolutionary divergence potentially leading to speciation. Signals are behavioral traits of particular interest for the study of variation at a geographic scale. The anuran acoustic communication system represents an excellent model for studies of this kind, because their vocalizations play a main role in reproduction and the extant variation in this system may determine the evolution of this group. This review is committed to studies on geographic variation of acoustic communication systems in anurans, focusing on temporal and spectral characteristics of signals, environmental constraints affecting them and sound producing and receiving organs. In addition to the review of the literature on these topics, I highlight the deficit of investigation in some areas and propose alternative directions to overcome these drawbacks. Further, I propose the four-eyed frog, Pleurodema thaul, as an excellent model system to study geographic variation using a wide spectrum of approaches. PMID- 25446893 TI - Comparative analysis of oxytocin receptor density in the nucleus accumbens: an adaptation for female and male alloparental care? AB - Parental behavior is commonly displayed by progenitors. However, other individuals, genetically related (e.g. siblings, aunts, uncles) or not with the newborns, also display parental behavior (commonly called alloparental, or adoptive behavior). I hypothesize that species that live in family or social groups where other non-reproductive members (males and females) take care of infants, have brain adaptations to promote or facilitate that behavioral response. The present work revises the evidence supporting the hypothesis that high density of oxytocin receptors (OXTR) in the nucleus accumbens (NA) is one of those adaptations. All species known to have high NA OXTR show not only female, but also male alloparental care. Therefore, I predict that high NA OXTR could be present in all species in which juvenile and adult male alloparental behavior have been observed. Strategies to test this and other alternative working hypothesis and its predictions are presented. PMID- 25446894 TI - An adenosine nucleoside analogue NITD008 inhibits EV71 proliferation. AB - Enterovirus 71 (EV71), one of the major causative agents of Hand-Foot-Mouth Disease (HFMD), causes severe pandemics and hundreds of deaths in the Asia Pacific region annually and is an enormous public health threat. However, effective therapeutic antiviral drugs against EV71 are rare. Nucleoside analogues have been successfully used in the clinic for the treatment of various viral infections. We evaluated a total of 27 nucleoside analogues and discovered that an adenosine nucleoside analogue NITD008, which has been reported to be an antiviral reagent that specifically inhibits flaviviruses, effectively suppressed the propagation of different strains of EV71 in RD, 293T and Vero cells with a relatively high selectivity index. Triphosphorylated NITD008 (ppp-NITD008) functions as a chain terminator to directly inhibit the RNA-dependent RNA polymerase activity of EV71, and it does not affect the EV71 VPg uridylylation process. A significant synergistic anti-EV71 effect of NITD008 with rupintrivir (AG7088) (a protease inhibitor) was documented, supporting the potential combination therapy of NITD008 with other inhibitors for the treatment of EV71 infections. PMID- 25446895 TI - Long-term follow-up of patients receiving boceprevir for treatment of chronic hepatitis C. AB - The durability of sustained virologic response (SVR) following boceprevir-based therapy in patients with hepatitis C virus (HCV) infection has not been reported. Furthermore, in patients receiving protease inhibitor-based therapies, development of resistance can contribute to treatment failure. The aim of the present study was to follow the clinical progression of patients treated with boceprevir after treatment in phase 2/3 clinical trials. This was a 3-year, long term follow-up analysis of patients enrolled in boceprevir phase 2/3 studies. No treatment was administered during follow-up. Patients with SVR were assessed for durability of viral eradication. Non-SVR patients with on-treatment resistance associated variants (RAVs) were assessed for longevity of RAVs. A total of 1148 patients (SVR, n=696; virologic failure, n=452) were enrolled in this follow-up analysis. The median duration of follow-up was approximately 3.4 years (range of 0.0-4.1 years). Overall, 3 of 696 patients with SVR had detectable HCV RNA during the follow-up period (relapse rate of 0.4% or 1.3 relapses/1000 person-years). The majority of patients who developed RAVs during the initial treatment study (228/314, 73%) reverted to wild-type (WT) within 3 years (RAVs persisted in 27% of patients). The median time for all RAVs to become undetectable was 1.11 years (95% confidence interval 1.05-1.20 years). V36M, T54A, A156S, I/V170A and V36M+R155K appeared to have a faster rate of return to WT (median times to return to WT of ?0.9 years); whereas, T54S, R155K, V55A and T54S+R155K had a slower rate of return to WT (median times to return to WT of approximately 1.1 years). Return to WT appeared slightly faster in patients with G1b RAVs compared to those with G1a RAVs, and in patients with previous non-response or relapse versus breakthrough or incomplete virologic response. SVR was durable in most patients treated with boceprevir. Furthermore, most RAVs present at the time of virologic failure reverted to WT over time. Time to return to WT was associated with the phenotype of RAV, presumably a reflection of the fitness of the mutant virus, suggesting that HCV RAVs are not permanently archived, but are replaced in the viral population by WT virus. PMID- 25446896 TI - Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. AB - Blockade of colony-stimulating factor-1 (CSF-1) limits macrophage infiltration and improves response of mammary carcinomas to chemotherapy. Herein we identify interleukin (IL)-10 expression by macrophages as the critical mediator of this phenotype. Infiltrating macrophages were the primary source of IL-10 within tumors, and therapeutic blockade of IL-10 receptor (IL-10R) was equivalent to CSF 1 neutralization in enhancing primary tumor response to paclitaxel and carboplatin. Improved response to chemotherapy was CD8(+) T cell-dependent, but IL-10 did not directly suppress CD8(+) T cells or alter macrophage polarization. Instead, IL-10R blockade increased intratumoral dendritic cell expression of IL 12, which was necessary for improved outcomes. In human breast cancer, expression of IL12A and cytotoxic effector molecules were predictive of pathological complete response rates to paclitaxel. PMID- 25446897 TI - Dissecting the tumor myeloid compartment reveals rare activating antigen presenting cells critical for T cell immunity. AB - It is well understood that antigen-presenting cells (APCs) within tumors typically do not maintain cytotoxic T cell (CTL) function, despite engaging them. Across multiple mouse tumor models and human tumor biopsies, we have delineated the intratumoral dendritic cell (DC) populations as distinct from macrophage populations. Within these, CD103(+) DCs are extremely sparse and yet remarkably capable CTL stimulators. These are uniquely dependent on IRF8, Zbtb46, and Batf3 transcription factors and are generated by GM-CSF and FLT3L cytokines. Regressing tumors have higher proportions of these cells, T-cell-dependent immune clearance relies on them, and abundance of their transcripts in human tumors correlates with clinical outcome. This cell type presents opportunities for prognostic and therapeutic approaches across multiple cancer types. PMID- 25446898 TI - Cells of origin in the embryonic nerve roots for NF1-associated plexiform neurofibroma. AB - Neurofibromatosis type 1 is a tumor-predisposing genetic disorder. Plexiform neurofibromas are common NF1 tumors carrying a risk of malignant transformation, which is typically fatal. Little is known about mechanisms mediating initiation and identity of specific cell type that gives rise to neurofibromas. Using cell lineage tracing, we identify a population of GAP43(+) PLP(+) precursors in embryonic nerve roots as the cells of origin for these tumors and report a non germline neurofibroma model for preclinical drug screening to identify effective therapies. The identity of the tumor cell of origin and facility for isolation and expansion provides fertile ground for continued analysis to define factors critical for neurofibromagenesis. It also provides unique approaches to develop therapies to prevent neurofibroma formation in NF1 patients. PMID- 25446901 TI - Protruding fat from the posterior atrioventricular groove: a novel echocardiographic finding useful in distinguishing pericardial effusions from left pleural effusions. PMID- 25446903 TI - Urban living and psychosis--an overview. AB - Since more than half a century, the association of urbanicity with psychosis has been explored. The research interest initially stemmed from the finding of a higher proportion of cases of psychotic disorder coming for treatment from the inner parts of cities. Subsequently, interest in the relationship of urbanicity and schizophrenia expanded and various facets of this association were explored. This narrative review provides an overview of the relationship between urbanicity and psychosis, and evaluates the link from the standpoint of causality. The review further delves into the possible risk factors and mechanisms explaining this association; both biological ones like genetic vulnerability and infections, as well as environmental ones like pollution. Since the literature has primarily emerged from the developed western countries, the review draws attention to the caveats while extrapolating the results to a developing country scenario. PMID- 25446902 TI - Psychometric properties of translated outcome measures of cognitive behavioural therapy for psychosis in the Chinese context. AB - OBJECTIVES: Growing evidence supporting the use of Cognitive Behavioural Therapy (CBT) to improve outcomes in patients with psychosis has largely originated from American and European countries, its applicability and effectiveness in Chinese patients with psychosis is still under-explored. However, the lack of stable and reliable outcome measures to evaluate the effectiveness of CBT for patients with psychosis hinders further development of psychological intervention in patients with psychosis in the Chinese context. The present study therefore aims to translate selected outcomes measures developed in American and European countries to measure the effectiveness of CBT for psychosis into Chinese and evaluate their psychometric properties. METHODS: Thirty-three patients with residual psychotic symptoms were recruited in the Department of Psychiatry, Kowloon Hospital, Hong Kong. Participants were asked to complete a set of self-reported questionnaires twice with an interval of a week, including Beliefs About Voices Questionnaire Revised (BAVQ-R), Beck Cognitive Insight Scale (BCIS) and Southampton Mindfulness Questionnaire (SMQ). RESULTS: The results found that the Chinese versions of BAVQ R, BCIS and SMQ had excellent test-retest reliability with good to acceptable internal reliability. CONCLUSIONS: Generally, all three translated outcome measures were found to be stable and reliable, and were ready for evaluating the effectiveness of cognitive therapy for psychosis in the Chinese population. Further discussions on scoring and interpretations of the Chinese version of SMQ were made. PMID- 25446900 TI - Rab1A is an mTORC1 activator and a colorectal oncogene. AB - Amino acid (AA) is a potent mitogen that controls growth and metabolism. Here we describe the identification of Rab1 as a conserved regulator of AA signaling to mTORC1. AA stimulates Rab1A GTP binding and interaction with mTORC1 and Rheb mTORC1 interaction in the Golgi. Rab1A overexpression promotes mTORC1 signaling and oncogenic growth in an AA- and mTORC1-dependent manner. Conversely, Rab1A knockdown selectively attenuates oncogenic growth of Rab1-overexpressing cancer cells. Moreover, Rab1A is overexpressed in colorectal cancer (CRC), which is correlated with elevated mTORC1 signaling, tumor invasion, progression, and poor prognosis. Our results demonstrate that Rab1 is an mTORC1 activator and an oncogene and that hyperactive AA signaling through Rab1A overexpression drives oncogenesis and renders cancer cells prone to mTORC1-targeted therapy. PMID- 25446904 TI - Factors associated with suicidal ideations and suicidal attempts in patients with obsessive compulsive disorder. AB - Aim of this study was to evaluate the prevalence of suicidal ideations (SI) and to study the risk factors for SI and suicide attempt in patients with OCD. One hundred and thirty patients with OCD were assessed on Yale-Brown Obsessive Compulsive Scale and Symptom Checklist, Beck Depression Inventory, Beck Hopelessness Scale, Beck Anxiety Inventory, State-Trait Anxiety Inventory, Buss Durkee Hostility Inventory, Barratt Impulsiveness Scale, Family Interview for Genetic Studies, Brown Assessment of Beliefs Scale and DSM-IV insight criteria for OCD. Of the 130 patients, 60 (46.1%) had current SI and 81 (62.3%) patients had life time SI. Of the 60 patients with current SI, 30 had current depression as assessed on SCID-CV. More than half (48 out of 81; 59.25%) of the patients with lifetime SI had lifetime comorbid depression. Ten patients had history of lifetime suicide attempts. Current SI in patients without current depression were associated with female gender, presence of comorbid psychiatric illness, contamination obsessions and cleaning/washing compulsions. To conclude this study suggests that SI are highly prevalent in patients with OCD and although depression may be a contributory factor for suicidal ideations in patients with OCD, but it is not the sole risk factor for suicidal ideations. PMID- 25446899 TI - Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. AB - Exosomes are secreted by all cell types and contain proteins and nucleic acids. Here, we report that breast cancer associated exosomes contain microRNAs (miRNAs) associated with the RISC-Loading Complex (RLC) and display cell-independent capacity to process precursor microRNAs (pre-miRNAs) into mature miRNAs. Pre miRNAs, along with Dicer, AGO2, and TRBP, are present in exosomes of cancer cells. CD43 mediates the accumulation of Dicer specifically in cancer exosomes. Cancer exosomes mediate an efficient and rapid silencing of mRNAs to reprogram the target cell transcriptome. Exosomes derived from cells and sera of patients with breast cancer instigate nontumorigenic epithelial cells to form tumors in a Dicer-dependent manner. These findings offer opportunities for the development of exosomes based biomarkers and therapies. PMID- 25446905 TI - Molecular epidemiology of CTX-M-type extended-spectrum beta-lactamase-producing Proteus mirabilis isolates in Taiwan. PMID- 25446906 TI - Complete nucleotide sequence of the IncI1 plasmid pSH4469 encoding CTX-M-15 extended-spectrum beta-lactamase in a clinical isolate of Shigella sonnei from an outbreak in the Republic of Korea. AB - An outbreak of extended-spectrum beta-lactamase (ESBL)-producing Shigella sonnei infections occurred in a school for disabled children in Gyeongbuk Province, Republic of Korea, in 2008. Five students were affected. Pulsed-field gel electrophoresis (PFGE) analysis revealed that all of the ESBL-producing S. sonnei isolates belonged to the same clone, and nucleotide sequence analysis of ESBL genes revealed that they harboured bla(CTX-M-15). This is the first identification of bla(CTX-M-15) in Shigella spp. in South Korea. In this study, a plasmid carrying the bla(CTX-M-15) gene, designated pSH4469, recovered from a S. sonnei isolate responsible for the outbreak was characterised. Replicon typing and plasmid multilocus sequence typing (pMLST) analysis of plasmids in the outbreak strain identified that the bla(CTX-M-15) gene was located on an IncI1 incompatibility group plasmid of sequence type 16 (ST16). The complete nucleotide sequence of pSH4469 revealed that this plasmid is 91109bp and harbours 119 putative genes, including another antibiotic resistance gene (bla(TEM-1b)) that is often associated with the ISEcp1-bla(CTX-M-15)-orf477delta transposable unit. The plasmid consists of a large backbone with considerable homology to the pEK204 plasmid isolated from Escherichia coli in the UK, except for insertion of an IS66 element found in pEK204. These data demonstrate that IncI1 plasmids are used as a successful platform for efficient horizontal gene transfer, thereby resulting in the dissemination of CTX-M-type beta-lactamases among Enterobacteriaceae. PMID- 25446908 TI - Biomineralization-induced self-assembly of porous hollow carbon nanocapsule monoliths and their application in Li-S batteries. AB - A carbon capsule monolith possessing ultrasmall hollow nanocores and ultrathin nanoshells with a high surface area and porosity is synthesized by a facile biomineralization-induced self-assembly approach. As a sulfur host in Li-S batteries, it serves as an excellent solvent-restricted, ionic-electronic conductive 'nanoreactor' for sulfur lithiation, enabling superior performance upon cycling. PMID- 25446907 TI - Characterisation of the first ongoing outbreak due to KPC-3-producing Klebsiella pneumoniae (ST512) in Spain. AB - The aim of this study was to characterise carbapenem-resistant Klebsiella pneumoniae isolates that caused an outbreak in a hospital in the south of Spain, originating from a patient transferred in 2012 from Italy. Forty-four K. pneumoniae isolates, recovered from 28 patients, were screened by PCR for extended-spectrum beta-lactamase (ESBL) and carbapenemase genes and the products were further sequenced. Plasmids were transferred by electroporation and were classified using PCR-based Inc/rep typing and IncF subtyping. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were used to determine the genetic relatedness of the isolates. All isolates yielded positive modified Hodge test results, harboured bla(SHV-11), bla(TEM-1) and bla(KPC-3) genes, showed an identical PFGE pattern, and were assigned to clone sequence type 512 (ST512). The bla(KPC-3) gene was located on a 140-kb K2:A-:B-plasmid. In conclusion, the successful K. pneumoniae ST512 clone caused a major outbreak in Spain from an imported case and is the first description of an outbreak in this country due to the KPC-3-producing K. pneumoniae ST512 clone. PMID- 25446909 TI - Oral mucocele/ranula: Another human immunodeficiency virus-related salivary gland disease? AB - OBJECTIVES/HYPOTHESIS: To describe clinical characteristics of oral mucoceles/ranulas, with a focus on human immunodeficiency virus (HIV)-related salivary gland diseases. STUDY DESIGN: A descriptive and clinical study, with review of patient data. MATERIAL AND METHODS: We reviewed 113 referred cases of oral mucocele. The following anatomical sites were identified: lip, tongue, and floor of the mouth (simple ranulas), as well as plunging ranulas. The age and gender data of the patients with oral mucoceles were recorded. The HIV status of the patients and other information were reviewed. RESULTS: There were 30 (26.5%) males and 83 (73.5%) females. Most patients were below 30 years of age, with the peak frequency in the first and second decade. Ranula (simple and plunging) represented 84.1% of the mucocele locations. Mucocele on the lips represented 10.6%. Seventy-two (63.7%) patients were HIV positive; and 97.2% of them had ranulas. Thirty-eight (33.6%) patients presented with plunging ranulas; and 92.1% of them were HIV positive, compared with two patients presenting with plunging ranulas in the HIV-negative group. These results strongly suggest that an HIV positive patient is statistically (P < 0.001) more at risk of presenting with not only a simple, but also a plunging ranula type. CONCLUSION: This study presents a different clinical picture of oral mucoceles/ranulas, as observed in HIV-positive patients. Additionally, it suggests a possible clinical link between the two pathologies. The authors strongly support the suggestion that oral mucocele/ranula is an HIV-related salivary gland disease. LEVEL OF EVIDENCE: 4. PMID- 25446911 TI - Preclinical experimental stress studies: protocols, assessment and comparison. AB - Stress is a state of threatened homeostasis during which a variety of adaptive processes are activated to produce physiological and behavioral changes. Preclinical models are pivotal for understanding these physiological or pathophysiological changes in the body in response to stress. Furthermore, these models are also important for the development of novel pharmacological agents for stress management. The well described preclinical stress models include immobilization, restraint, electric foot shock and social isolation stress. Stress assessment in animals is done at the behavioral level using open field, social interaction, hole board test; at the biochemical level by measuring plasma corticosterone and ACTH; at the physiological level by measuring food intake, body weight, adrenal gland weight and gastric ulceration. Furthermore the comparison between different stressors including electric foot shock, immobilization and cold stressor is described in terms of intensity, hormonal release, protein changes in brain, adaptation and sleep pattern. This present review describes these preclinical stress protocols, and stress assessment at different levels. PMID- 25446910 TI - Body image in cancer survivors: a systematic review of case-control studies. AB - PURPOSE: There is common consensus that cancer and its treatment can impair the body, but combined evidence of the previous literature in cancer survivors is missing. Therefore, we reviewed body image in cancer survivors and focused on case-control studies, in order to draw conclusions as to whether body image might be altered due to cancer. METHODS: Medline, Cinahl, Embase, and PsycInfo were searched and after duplicate extraction, 1932 hits were retrieved and screened for eligibility. Included studies were rated on selection, measurement, and reporting bias. RESULTS: Twenty-five studies were identified using 19 different scales to measure body image. Ten studies reported a more negative body image in survivors, nine found no differences, three reported mixed findings, and three reported a more positive body image in survivors. Potential bias was common and 16 studies had at least three sources of potential bias. Less-biased studies (i.e., <=2 sources of bias) hinted to weak differences between survivors and controls, favoring healthy controls. A meta-analysis could not be performed. CONCLUSIONS: This review was long overdue and indicates a somewhat more negative body image in cancer survivors than healthy controls. However, numerous problems potentially biasing study results have been detected and firm conclusions cannot be drawn. IMPLICATIONS FOR CANCER SURVIVORS: Future studies should recruit larger samples, match samples, and pay attention to how body image is conceptualized and measured in order to draw reliable conclusions as to whether body image is impaired in cancer survivors. PMID- 25446912 TI - Prostaglandin F2alpha modulates atrial chronotropic hyporesponsiveness to cholinergic stimulation in endotoxemic rats. AB - Endotoxemia induces various physiological adaptive responses such as tachycardia. There is evidence to show that inflammatory tachycardia might be linked to a direct action of prostanoids on the cardiac pacemaker cells. Recent reports have indicated that systemic inflammation may uncouple of cardiac pacemaker from cholinergic neural control in experimental animals; however, the exact mechanism of this phenomenon is uncertain. This study was aimed to explore the hypothesis that prostanoids modulate atrial chronotropic hyporesponsiveness to cholinergic stimulation in endotoxemic rats. Male albino rats were given intraperitoneal injection of either saline or lipopolysaccharide (LPS, 1 mg/kg). 3 h after saline or LPS injection, the atria were isolated and chronotropic responsiveness to cholinergic stimulation was evaluated in an organ bath. The expression of atrial cyclooxygenases (COX)-1, COX-2 and COX-3 mRNA was assessed by quantitative real time RT-PCR and cytosocalcium-dependent phospholipase A2 (cPLA2) activity was measured in the atria. The expression of atrial COX-2 mRNA and cPLA2 activity increased significantly in endotoxemic atria (P<0.05). Incubation with prostaglandin F2alpha (PGF2alpha, 100 pM) could significantly decrease chronotropic response to cholinergic stimulation in vitro. Likewise, LPS injection could induce a significant hyporesponsiveness to cholinergic stimulation, and incubation of isolated atria with either indomethacin (5 uM) or AL-8810 (a PGF2alpha antagonist, 10 uM) could reverse it (P<0.01, P<0.05, respectively), while SQ29548 (a thromboxane A2 antagonist, 10 nM) was failed (P>0.05). Our data showed that PGF2alpha may contribute to the atrial chronotropic hyporesponsiveness to cholinergic stimulation in endotoxemic rats. PMID- 25446913 TI - Neuroprotection by the PARP inhibitor PJ34 modulates cerebral and circulating RAGE levels in rats exposed to focal brain ischemia. AB - The receptor for advanced glycation end products (RAGE) has a potential role as a damage-sensing molecule; however, to date, its involvement in the pathophysiology of stroke and its modulation following neuroprotective treatment are not completely understood. We have previously demonstrated that expression of distinct RAGE isoforms, recognized by different antibodies, is differentially modulated in the brain of rats subjected to focal cerebral ischemia. Here, we focus on the full-length membrane-bound RAGE isoform, showing that its expression is significantly elevated in the striatum, whereas it is reduced in the cortex of rats subjected to transient middle cerebral artery occlusion (MCAo). Notably, the reduction of cortical levels of full-length RAGE detected 24 h after reperfusion is abolished by systemic administration of a neuroprotective dose of the poly(ADP ribose) polymerase (PARP) inhibitor, N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N dimethylacetamide (PJ34). More interestingly, a significant reduction of plasma soluble RAGE (sRAGE) occurs 24 h after reperfusion and this effect is reverted by a neuroprotective dose of PJ34. Soluble forms of RAGE, generated either by alternative splicing or by proteolysis of the full-length form, effectively bind advanced glycation end products, thereby competing with the cell surface full length RAGE, thus providing a 'decoy' function that may counteract the adverse effects of receptor signaling in neurons and may possibly exert cytoprotective effects. Thus, our data confirm the important role of RAGE in ischemic cerebral damage and, more interestingly, suggest the potential use of sRAGE as a blood biomarker of stroke severity and of neuroprotective treatment efficacy. PMID- 25446915 TI - Synthesis and biological evaluation of a novel baicalein glycoside as an anti inflammatory agent. AB - Baicalein-6-alpha-glucoside (BG), a glycosylated derivative of baicalein, was synthesized by using sucrose and the amylosucrase of Deinococcus geothermalis and tested for its solubility, chemical stability, and anti-inflammatory activity. BG was 26.3 times more soluble than baicalein and highly stable in buffered solutions and Dulbecco's modified Eagle medium containing 10% fetal bovine serum. BG treatment decreased the production of nitric oxide in RAW 264.7 cells treated with lipopolysaccharide (LPS). Luciferase reporter assays, western blots, reverse transcription-polymerase chain reaction, and flow cytometric analyses indicated that BG activated nuclear factor erythroid 2-related factor 2 (Nrf2), an antioxidant transcription factor that confers protection from various inflammatory diseases, induced Nrf2-dependent gene expression, and suppressed the production of reactive oxygen species elicited by LPS more effectively than baicalein. Cellular uptake of BG assessed by confocal microscopy and HPLC analysis of the cell-free extracts of RAW 264.7 cells demonstrated that BG was gradually converted to baicalein inside the cells. These results explain that glycosylation increased the bioavailability of baicalein by helping to protect this vital molecule from chemical or enzymatic oxidation. Therefore, BG, a glycosylated derivative of baicalein, can be an alternative to baicalein as a therapeutic drug. PMID- 25446914 TI - Honokiol abrogates lipopolysaccharide-induced depressive like behavior by impeding neuroinflammation and oxido-nitrosative stress in mice. AB - Depression is an inflammatory, commonly occurring and lethal psychiatric disorder having high lifetime prevalence. Preclinical and clinical studies suggest that activation of immuno-inflammatory and oxido-nitrosative stress pathways play major role in the pathophysiology of depression. Honokiol (HNK) is a biphenolic neolignan possessing multiple biological activities including antioxidant, anti inflammatory, anxiolytic, antidepressant and neuroprotective. The present study investigated the effect of HNK (2.5 and 5 mg/kg, i.p.) pretreatment (30 min prior to LPS) on lipopolysaccharide (LPS) (0.83 mg/kg, i.p.) induced depressive like behavior, neuroinflammation, and oxido-nitrosative stress in mice. HNK pretreatment at both the doses significantly attenuated LPS induced depressive like behavior by reducing the immobility time in forced swim and tail suspension test, and by improving the anhedonic behavior observed in sucrose preference test. HNK pretreatment ameliorated LPS induced neuroinflammation by reducing IL 1beta, IL-6 and TNF-alpha level in hippocampus (HC) and prefrontal cortex (PFC). HNK pretreatment prevented LPS evoked oxidative/nitrosative stress via improving reduced glutathione level along with reduction in the lipid peroxidation and nitrite level in HC and PFC. Pretreatment with HNK also prevented the increase in plasma corticosterone (CORT) and decrease in hippocampal BDNF level in LPS challenged mice. In conclusion, current investigation suggested that HNK pretreatment provided protection against LPS-induced depressive like behavior which may be mediated by repression of pro-inflammatory cytokines as well as oxido-nitrosative stress in HC and PFC. Our results strongly speculated that HNK could be a therapeutic approach for the treatment of depression and other pathophysiological conditions which are closely associated with neuroinflammation and oxido-nitrosative stress. PMID- 25446916 TI - Pharmacological evaluation of sedative and hypnotic effects of schizandrin through the modification of pentobarbital-induced sleep behaviors in mice. AB - The fruits of Schisandra chinensis have been recorded as an effective somnificant for the treatment of insomnia in some oriental countries pharmacopoeias. However, the mechanism of sedative and hypnotic effects of this kind of herb is still unclear. In the present study, schizandrin, which is the main component of Schisandra chinensis, was selected as a target compound to investigate possible mechanisms through behavioral pharmacology methods. The results showed that schizandrin possessed dose-dependent (5-45 mg/kg, i.p.) sedative effects on locomotion activity in normal mice, and produced a dose-dependent decrease in sleep latency and an increase in sleep duration in pentobarbital-treated mice; thus, itself did not induce sleep at higher dose which was used in this experiment (45 mg/kg, i.p.). It also can reverse the rodent models of insomnia induced by p-chlorophenylalanine (PCPA) and caffeine, which could exhibit a syne with 5-hydroxytryptophan (5-HTP) as well; therefore, the hypnotic effects of schizandrin were not inhibited by flumazenil (a specific gamma aminobutyric acid (GABA)-A-BZD receptor antagonist). Altogether, these results indicated that schizandrin produces beneficial sedative and hypnotic bioactivity, which might be mediated by the modification of the serotonergic system. PMID- 25446917 TI - Combination therapy with spironolactone and candesartan protects against streptozotocin-induced diabetic nephropathy in rats. AB - Diabetic nephropathy is one of the most common causes of end-stage kidney disease. Aldosterone and angiotensin II appear to play a crucial role in the pathogenesis of this disease. The present study aimed to investigate effects of the combination therapy with spironolactone and candesartan on diabetic nephropathy and elucidate the underlying mechanism(s) involved. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg). The diabetic rats were orally treated with spironolactone (50 mg/kg/day) and/or candesartan (1 mg/kg/day) for 8 weeks. Administration of STZ caused a marked elevation in the serum level of creatinine, urea and urinary albumin creatinine ratio (ACR). This was associated with upregulated renal protein levels of nuclear factor-kappa B (NF-kappaB), transforming growth factor (TGF)-beta, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) alongside increasing the renal superoxide anion (O2(-)) production, malondialdehyde (MDA) level and the systolic blood pressure. There was a marked decrease in nitric oxide (NO) bioavailability and antioxidant enzyme capacity. The combined therapy of spironolactone and candesartan significantly normalized the oxidative stress and fibrotic/inflammatory alterations. Additionally, the elevated blood pressure was attenuated by administration of candesartan alone or in combination. This was associated with improving the renal function parameters. The combined therapy exhibited more profound response compared to the monotherapy. In conclusion, our results demonstrate that the combined therapy of spironolactone and candesartan can confer an additive benefit over the use of either drug alone against STZ induced diabetic nephropathy, presumably via attenuating the inflammatory responses and oxidative status markers. PMID- 25446918 TI - Capsaicin modulates acetylcholine release at the myoneural junction. AB - Transient receptor potential (TRP) proteins are non-selective cation channel proteins that are expressed throughout the body. Previous studies demonstrated the expression of TRP Vanilloid 1 (TRPV1), capsaicin (CAP) receptor, in sensory neurons. Recently, we reported TRPV1 expression in mouse motor nerve terminals [MNTs; (Thyagarajan et al., 2009)], where we observed that CAP protected MNTs from botulinum neurotoxin A (BoNT/A). Phrenic nerve diaphragm nerve muscle preparations (NMP) isolated from isoflurane anesthetized adult mice were analyzed for twitch tension, spontaneous (mEPCs) and nerve stimulus evoked (EPCs) acetylcholine release. When acutely applied to isolated NMP, CAP produced a concentration-dependent decline of twitch tension and produced a significant decline in the amplitude of EPCs and quantal content without any effect on the mEPCs. The suppression of nerve stimulus evoked acetylcholine release by CAP was antagonized by capsazepine (CPZ), a TRPV1 antagonist. CAP did not suppress phrenic nerve stimulus evoked acetylcholine release in TRPV1 knockout mice. Also, CAP treatment, in vitro, interfered with the localization of adapter protein 2 in cholinergic Neuro 2a cells. Wortmannin, (WMN; non-selective phosphoinositol kinase inhibitor), mimicked the effects of CAP by inhibiting the acetylcholine exocytosis. Our data suggest that TRPV1 proteins expressed at the MNT are coupled to the exo-endocytic mechanisms to regulate neuromuscular functions. PMID- 25446919 TI - Erythropoietin protects myocardium against ischemia-reperfusion injury under moderate hyperglycemia. AB - Erythropoietin (EPO), an essential hormone for erythropoiesis, provides protection against myocardial ischemia/reperfusion (I/R) injury. Hyperglycemia during acute myocardial infarction aggravates organ damage and attenuates the efficacies of various protective measures. This study aimed to investigate the protective role of EPO against myocardial I/R injury under a clinically relevant moderate hyperglycemic condition and its associated mechanisms. Eighty-two Sprague-Dawley rats were randomly assigned to six groups: normoglycemia-Sham, normoglycemia-I/R-control-saline (IRC), normoglycemia-I/R-EPO (IRE), hyperglycemia-Sham, hyperglycemia-IRC, and hyperglycemia-IRE. The rats received 1.2 g/kg dextrose or same volume of normal saline depending on the group. I/R was induced by a 30 min period of ischemia followed by reperfusion for 4 h. For 1 h before I/R injury, intravenous 4000 IU/kg of EPO was administered. EPO pretreatment significantly reduced the number of apoptotic cells and the infarct size compared with those of the control groups. EPO increased GATA-4 phosphorylation and acetylation against I/R in hyperglycemic myocardium. It also enhanced ERK induced GATA-4 post-translational modifications such as increased GATA-4 phosphorylation and acetylation, and decreased GATA-4 ubiquitination following hypoxia-reoxygenation in H9c2 cells in hyperglycemic medium. Increased GATA-4 stability by EPO diminished I/R-related down-regulation of Bcl-2 and reduction of caspase-3 activities in hyperglycemic myocardium. In conclusion, EPO pretreatment before I/R injury conveyed significant myocardial protection under moderate hyperglycemic condition through mechanisms involved in reduction of caspase-3 activity and up-regulation of Bcl-2 in association with enhanced ERK induced GATA-4 stability. PMID- 25446920 TI - A novel Pseudolaric acid B derivative, Hexahydropseudolaric acid B, exterts an immunomodulatory effect in vitro/in vivo evaluation. AB - Identification of immunosuppressants from natural sources has a proven track record in immune mediated disorders. Pseudolaric acid B is a diterpenoid isolated from the roots of Pseudolarix amabilis, possessing potent immunomodulatory effect. However, the cytotoxicity limits its future clinical application. The purpose of this study was to investigate the immunosuppressive activity of Hexahydropseudolaric acid B, a Pseudolaric acid B derivative, on T cell-mediated immune response both in vitro and in vivo, and investigated its immunomodulatory effect to develop a more ascendant immunosuppressive agent. The results showed that Hexahydropseudolaric acid B could exert more preferable immunosuppressive activity and lower cytotoxicity than Pseudolaric acid B. Hexahydropseudolaric acid B significantly inhibited T cell proliferation activated by mitogen and alloantigen without obvious cytotoxicity in vitro. Furthermore, Hexahydropseudolaric acid B could ameliorate ear swelling in a mouse model of 2,4 dinitrofluorobenzene-induced delayed-type hypersensitivity in vivo. Mechanistic study revealed that Hexahydropseudolaric acid B could enhance regulatory T cells via promoting Foxp3 expression and TGF-beta level, accompanied by attenuating Akt activation, blocking p38MAPK/MK2-HSP27 signal cascades, and up-regulating PPAR gamma expression. Taken together, these results suggest that Hexahydropseudolaric acid B exerts more preferable immunosuppressive activity than its precursor Pseudolaric acid B by affecting multiple targets, which support the need for continued efforts to characterize the efficacy of HPAB as a promising and safe candidate to treat immune-related diseases. PMID- 25446921 TI - SPA0355 suppresses T-cell responses and reduces airway inflammation in mice. AB - In recent studies, SPA0355, a thiourea analog, has been demonstrated to possess strong anti-inflammatory activity. However, the mechanisms underlying the effects of SPA0355 on immune-mediated diseases have not been fully defined. The present study was designed to investigate the immunological and molecular mechanisms by which SPA0355 modulates cluster of differentiation of (CD4)(+) T-cell-mediated immune responses in allergic airway inflammation. In vitro studies have shown that SPA0355 suppresses CD4(+) T-cell activation, proliferation, and differentiation via modulation of T-cell receptor (TCR) signal transduction and cytokine-induced Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. Next, we investigated the efficacy of SPA0355 in ovalbumin (OVA)-induced allergic airway inflammation. Intraperitoneal administration of SPA0355 inhibited inflammatory cell recruitment into the airways as well as the production of Th2 cytokines in bronchoalveolar fluid and suppressed OVA-induced IgE production in serum. Additionally, SPA0355 suppressed mucin production and smooth muscle hypertrophy and prevented the development of airway hyperresponsiveness. Given that allergic airway inflammation is mainly driven by Th2 cell responses, it is highly possible that the defects in CD4(+) T-cell activation and Th2 cell differentiation in the draining lymph nodes and suppressed NF-kappaB activation in the lungs of SPA0355-treated mice illustrate an immunological mechanism of the preventive effect of SPA0355 on the aforementioned asthmatic characteristics. Collectively, our results suggest that SPA0355 directly modulates Th1 and Th2 responses through the suppression of multiple signaling pathways triggered by TCR or cytokine receptor stimulation, and that SPA0355 has protective effects in a murine model of allergic airway inflammation. PMID- 25446922 TI - Reversal of novelty-induced hippocampal c-Fos expression in GluA1 subunit deficient mice by chronic treatment targeting glutamatergic transmission. AB - Malfunction of glutamate transmission is implicated in several neuropsychiatric disorders. Gria1-/- mouse line with knocked-out GluA1 subunits of ionotropic AMPA glutamate receptor displays several behavioural features of schizoaffective disorder. Typically, these mice show hyperactivity provoked by environmental novelty, which is attenuated after 4-week treatment with the standard mood stabilisers lithium and valproate and the mood-stabilising anticonvulsants topiramate and lamotrigine (Maksimovic, M., Vekovischeva, O.Y., Aitta-Aho, T., Korpi, E.R., 2014. Chronic treatment with mood-stabilizers attenuates abnormal hyperlocomotion of GluA1-subunit deficient mice. PloS One. 9, e100188). Here, we complement our study by treating these mice chronically with perampanel, a novel non-competitive antagonist of AMPA receptors, for 4 weeks at the dose of 60 mg/kg diet, and found reduced locomotor hyperactivity in the Gria1-/- animals, while not affecting the wild-type littermates. To study the cellular mechanism by which chronic treatments with glutamate-modulating mood-stabilizing drugs alleviate this hyperactivity, we used the immediate early gene c-Fos protein expression as a marker of neuronal activity in the brain. Chronic lithium, valproate and topiramate blunted the c-Fos expression especially in the dorsal hippocampus of the Gria1-/- mice, with all of them reducing the number of c-Fos-positive cells in the CA3 region and valproate and topiramate also in the dentate gyrus (DG). Lamotrigine and perampanel treatments had the same effect in the all CA1, CA3 and DG subfields of the dorsal hippocampus of Gria1-/- mice. The results suggest that abnormal (hippocampal) glutamatergic transmission underlies the hyperactive phenotype of the Gria1-/- mice in a novel environment, and based on the efficacies of the present chronic drug treatments, this mouse model may serve as a predictive tool for studying novel mood-stabilisers. PMID- 25446923 TI - Antidepressant-like effect of atorvastatin in the forced swimming test in mice: the role of PPAR-gamma receptor and nitric oxide pathway. AB - Atorvastatin is a synthetic and lipophilic statin which has been reported to have a positive role in reducing depression. The potential antidepressant-like effects of atorvastatin and the possible involvement of peroxisome proliferator-activated receptor gamma (PPAR_gamma) and nitric oxide system were determined using forced swimming test (FST) in mice was studied. Atorvastatin (0.01, 0.1 and 1 mg/kg, p.o.) was administered 1 h before FST. To assess the involvement of PPAR_gamma in the possible antidepressant effect of atorvastatin, pioglitazone, a PPAR_gamma agonist (5 mg/kg), and GW-9662, a specific PPAR_gamma antagonist (2 mg/kg), was co-administered with atorvastatin (0.01 mg/kg, p.o.) and then FST was performed. The possible role of nitric oxide pathway was determined by using co administration of a non-specific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.p.), and a NO precursor, L-arginine (750 mg/kg, i.p.) with sub-effective doses of atorvastatin and pioglitazone. Immobility time was significantly decreased after atorvastatin administration (0.1 and 1 mg/kg, p.o.). Administration of pioglitazone or L-NAME in combination with the sub effective dose of atorvastatin (0.01 mg/kg, p.o.) reduced the immobility time in the FST compared to drugs alone, showing the participation of these pathways; while co-administration of non-effective doses of atorvastatin and pioglitazone with GW9662 or L-arginine reversed antidepressant-like effect of atorvastatin in FST. Data from concurrent use of GW9662 and atorvastatin also demonstrated that the antidepressant effect of atorvastatin was significantly reversed by GW9662. The antidepressant-like effect of atorvastatin on mice in the FST is mediated at least in part through PPAR_gamma receptors and NO pathway. PMID- 25446924 TI - Quercetin, luteolin and epigallocatechin gallate alleviate TXNIP and NLRP3 mediated inflammation and apoptosis with regulation of AMPK in endothelial cells. AB - Endoplasmic reticulum stress (ER stress)-associated thioredoxin-interacting protein (TXNIP) and NOD-like receptor pyrin domain containing-3 (NLRP3) signaling is a key event in the endothelial dysfunction. It induces the IL-1beta production and thus accounts for inflammation and cell death. Quercetin, luteolin and epigallocatechin gallate (EGCG) are flavonoids with beneficial effects on cardiovascular functions, and we wondered whether these flavonoids protect endothelial functions against ER stress-associated impairments. Palmitate stimulation evoked oxidative stress and then induced TXNIP and NLRP3 inflammasome activation in the endothelial cells. Quercetin, luteolin and EGCG reduced reactive oxygen species production and inhibited TXNIP and NLRP3 inflammasome activation, lead to the downregulation of IL-1beta expression. Meanwhile, these agents protected cells from apoptosis by restoration of mitochondrial membrane potential (Deltapsim) and inhibition of caspase-3 activity. PA stimulation induced inflammation accompanied by the loss of NO production in endothelial cells, but these alterations were reversed by treatment with quercetin, luteolin and EGCG. Co-treatment with AMPK inhibitor compound C diminished the beneficial effects of these flavonoids, suggesting the involvement of AMPK. In conclusion, quercetin, luteolin and EGCG inhibited ER stress-associated TXNIP and NLRP3 inflammasome activation, and thereby protected endothelial cells from inflammatory and apoptotic damage. PMID- 25446925 TI - Involvement of central and peripheral cannabinoid receptors on antinociceptive effect of tetrahydrocannabinol in muscle pain. AB - Cannabinoid (CB) receptors have emerged as an attractive therapeutic target for pain management in recent years and the interest in the use of cannabinoids is gradually increasing, particularly in patients where conventional treatments fail. Muscle pain is a major clinical problem and new pharmacological approaches are being studied. Recently, we have demonstrated that cannabinoid synthetic agonists are useful to reduce muscular pain in two animal models, where the local administration is effective. Now, we want to know if tetrahydrocannabinol (THC), a cannabinoid natural derivative with therapeutic use in humans, is also effective in reducing acute muscle pain. The antinociceptive effect of THC by systemic (i.p.) and local (i.m.) administration was tested in two animal models of acute muscle pain, rat masseter and gastrocnemius, induced by hypertonic saline (HS) injection. The drugs used were the non-selective agonist THC and two selective cannabinoid antagonists, AM251 (CB1) and AM630 (CB2). THC, i.p. and i.m. administered, reduced the nociceptive behaviours induced by HS in both muscular pain models. The antinociceptive effect induced by the systemic administration of THC was mediated by CB1 receptors in the masseter muscle whereas in gastrocnemius both CB1 and CB2 receptors participated. When THC was administered locally, only CB2 receptors were involved in the antinociceptive effect in both muscles. This study suggests that THC could be a future pharmacological option in the treatment of muscle pain. The local administration of THC could be an interesting option to treat this type of pain avoiding the central adverse effects. PMID- 25446926 TI - Carnitine congener mildronate protects against stress- and haloperidol-induced impairment in memory and brain protein expression in rats. AB - The present study investigates the efficacy of mildronate, a carnitine congener, to protect stress and haloperidol-induced impairment of memory in rats and the expression of brain protein biomarkers involved in synaptic plasticity, such as brain-derived neurotrophic factor (BDNF), acetylcholine esterase and glutamate decarboxylase 67 (GAD67). Two amnesia models were used: 2h immobilization stress and 3-week haloperidol treatment. Stress caused memory impairment in the passive avoidance test and induced a significant 2-fold BDNF elevation in hippocampal and striatal tissues that was completely inhibited by mildronate. Mildronate decreased the level of GAD67 (but not acetylcholine esterase) expression by stress. Haloperidol decrease by a third hippocampal BDNF and acetylcholine esterase (but not GAD67) expression, which was normalized by mildronate; it also reversed the haloperidol-induced memory impairment in Barnes test. The results suggest the usefulness of mildronate as protector against neuronal disturbances caused by stress or haloperidol. PMID- 25446927 TI - 5-Hydroxytryptamine 1A (5HT1A) receptors mediate increases in plasma glucose independent of corticosterone. AB - Hypothalamic 5HT1A receptors play an important role in the regulation of satiety, glycemia and endocrine status. In the present study, 8-OH-DP administered centrally and peripherally to C57/Bl6 mice and plasma glucose insulin and corticosterone were evaluated. In these studies, dose and time dependent increases in glucose and corticosterone were observed while no alterations in insulin were seen. The increases in plasma corticosterone were prevented by prior central or peripheral administration of LY426965, a specific 5HT1A antagonist. Intracerebroventricular coadministration of a 5HT1A antagonist with 8-OH-DPAT prevented the increase in plasma glucose establishing this response as a centrally mediated response in mice. Given that increases in plasma corticosterone are associated with increases in plasma glucose, we conducted experiments to determine if increased plasma corticosterone was the mechanism by which 8-OH-DPAT increased plasma glucose. Prior administration of the glucocorticoid antagonist mifepristone did not affect the increase in plasma glucose produced by 8-OH-DPAT. Prior administration of the glucocorticoid synthesis inhibitor, metyrapone, reduced basal corticosterone and the concentrations of corticosterone associated with 8-OH-DPAT administration. However, metyrapone administration did not affect the increases in plasma glucose. Therefore, 5HT1A receptors regulate glucose through brain mechanisms, but not through regulation of the hypophyseal-pituitary axis. Antagonism of brain 5HT1A receptors may enable discovery of novel antidiabetic agents. PMID- 25446928 TI - The alpha-tocopherol derivative ESeroS-GS induces cell death and inhibits cell motility of breast cancer cells through the regulation of energy metabolism. AB - Cancer cells are known to exhibit different hallmarks compared with normal cells. Therefore, targeting these features may improve the response to cancer therapy. In this study, we provided direct evidence that the alpha-tocopherol derivative ESeroS-GS inhibited the viability, migration, and invasion of breast cancer cells. ESeroS-GS induced cell death in different cancer cells in a dose-dependent manner but showed no significant effects on MCF-10A mammary epithelial cells. Although the ESeroS-GS-induced cell death in MDA-MB-231 breast cancer cells was accompanied with the generation of reactive oxygen species and the down regulation of mitochondrial membrane potential (MMP), no such effect on reactive oxygen species and MMP was seen in MCF-10A cells. Further studies indicated that ESeroS-GS down-regulated the expression of hexokinase II, SDH B, UQCRC2 and COX II in MDA-MB-231 cells but not in MCF-10A cells. The down-regulation of these enzymes accounts for the decreased oxidative phosphorylation (OXPHOS) and glycolysis in MDA-MB-231 cells upon ESeroS-GS treatment. We also found that sub toxic concentration of ESeroS-GS treatment resulted in the impairment of F-actin cytoskeleton assembly and the consequently decreased migratory and invasive ability of MDA-MB-231 cells, which might be due to the inhibition of cellular energy metabolism. These results indicate that ESeroS-GS shows potential to become a novel anti-cancer agent by targeting the energy metabolism of cancer cells. PMID- 25446929 TI - Protective effects of the melanocortin analog NDP-alpha-MSH in rats undergoing cardiac arrest. AB - We previously reported that melanocortins afford cardioprotection in conditions of experimental myocardial ischemia/reperfusion, with involvement of the janus kinases (JAK), extracellular signal-regulated kinases (ERK) and signal transducers and activators of transcription (STAT) signalings. We investigated the influence of the melanocortin analog [Nle(4), D-Phe(7)]alpha-melanocyte stimulating hormone (NDP-alpha-MSH) on short-term detrimental responses to cardiac arrest (CA) induced in rats by intravenous (i.v.) administration of potassium chloride, followed by cardiopulmonary resuscitation (CPR) plus epinephrine treatment. In CA/CPR rats i.v. treated with epinephrine (0.1 mg/kg) and returned to spontaneous circulation (48%) we recorded low values of mean arterial pressure (MAP) and heart rate (HR), alteration of hemogasanalysis parameters, left ventricle low expression of the cardioprotective transcription factors pJAK2 and pTyr-STAT3 (JAK-dependent), increased oxidative stress, up regulation of the inflammatory mediators tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and down-regulation of the anti-inflammatory cytokine IL-10, as assessed at 1h and 3h after CPR. On the other hand, i.v. treatment during CPR with epinephrine plus NDP-alpha-MSH (340 MUg/kg) almost completely restored the basal conditions of MAP and HR, reversed metabolic acidosis, induced left ventricle up-regulation of pJAK2, pTyr-STAT3 and IL-10, attenuated oxidative stress, down-regulated TNF-alpha and IL-6 levels, and improved survival rate by 81%. CA/CPR plus epinephrine alone or in combination with NDP-alpha-MSH did not affect left ventricle pSer-STAT3 (ERK1/2-dependent) and pERK1/2 levels. These results indicate that melanocortins improve return to spontaneous circulation, reverse metabolic acidosis, and inhibit heart oxidative stress and inflammatory cascade triggered by CA/CPR, likely via activation of the JAK/STAT signaling pathway. PMID- 25446930 TI - The ligand binding ability of dopamine D1 receptors synthesized using a wheat germ cell-free protein synthesis system with liposomes. AB - G-protein coupled receptors (GPCRs) share a common seven-transmembrane topology and mediate cellular responses to a variety of extracellular signals. However, structural and functional approaches to GPCRs have often been limited by the difficulty of producing a sufficient amount of receptor protein using conventional expression systems. We synthesized human dopamine D1 receptors using a wheat cell-free protein synthesis system with liposomes and then analyzed their receptor binding ability. We determined the specific binding of [(3)H]SCH23390 to the synthesized receptors generated from a cell-free protein synthesis system or rat striatal membranes. From Scatchard plot analysis, the dissociation constant (Kd) and the maximum density (Bmax) of the synthesized receptors were 6.61+/-0.06 nM and 1.85+/-0.05 pmol/mg protein, respectively. The same analysis for rat striatal membrane gave a Kd of 2.67+/-0.05 nM and Bmax of 0.70+/-0.10 pmol/mg protein. Using a competition binding assay, Ki values of antagonists, SCH23390, LE300 and SKF83566, for the synthetic receptors were the same as those for rat striatal membranes, but Ki values of agonists, A68930, SKF38393 and dopamine, were 5-17 fold higher than those for rat striatal membranes. These results suggest that the dopamine D1 receptors synthesized in liposomes have a functional binding capacity. The different patterns of binding of antagonists and agonists to the synthetic receptors and rat striatal membranes indicate that G proteins are involved in agonist binding to dopamine D1 receptors. The cell-free protein synthesis method with liposomes will be invaluable for the functional analysis of GPCRs. PMID- 25446931 TI - Procognitive effect of AC-3933 in aged mice, and synergistic effect of combination with donepezil in scopolamine-treated mice. AB - We have previously reported that AC-3933, a newly developed benzodiazepine receptor partial inverse agonist, facilitates acetylcholine release in the hippocampus and ameliorates scopolamine-induced memory deficits in rats. To further confirm the procognitive effect of AC-3933, we assessed in this study the beneficial effects of this compound in aged mice using the Y-maze and object recognition tests. In addition, we investigated the synergistic effect of AC-3933 and donepezil, a cholinesterase inhibitor, on scopolamine-induced memory impairment in mice. In aged mice, oral administration of AC-3933 at doses of 0.05 0.1 mg/kg and 0.05 mg/kg significantly improved spatial working memory and episodic memory, respectively. In scopolamine-treated mice, both AC-3933 and donepezil significantly ameliorated memory deficits in the Y-maze test at doses of 0.3-3 mg/kg and 10-15 mg/kg, respectively. The beneficial effect of AC-3933, but not that of donepezil, on scopolamine-induced memory impairment was antagonized by flumazenil, a benzodiazepine receptor antagonist, indicating that the procognitive action of AC-3933 arises via a mechanism different from that of donepezil. Co-administration of donepezil at the suboptimal dose of 3 mg/kg with AC-3933 at doses of 0.1-1 mg/kg significantly ameliorated scopolamine-induced memory impairment, suggesting that AC-3933 potentiates the effect of donepezil on memory impairment induced by cholinergic hypofunction. These findings indicate that AC-3933 not only has good potential as a cognitive enhancer by itself, but also is useful as a concomitant drug for the treatment of Alzheimer's disease. PMID- 25446932 TI - Involvement of cholinergic nicotinic receptors in the menthol-induced gastric relaxation. AB - We have previously demonstrated that menthol reduces murine gastric tone in part through a neural mechanism, involving adrenergic pathways and reduction of ongoing release of acetylcholine from enteric nerves. In the present study we aimed to verify whether the gastric relaxation to menthol may be triggered by interaction with neural receptors or ionic channels proteins, such as transient receptor potential (TRP)-melastatin8 (TRPM8), TRP-ankyrin 1 (TRPA1), 5 hydroxytriptamine 3 (5-HT3) receptor or cholinergic nicotinic receptors. Spontaneous mechanical activity was detected in vitro as changes in intraluminal pressure from isolated mouse stomach. Menthol (0.3-30 mM) induced gastric relaxation which was not affected by 5-benzyloxytryptamine, a TRPM8 receptor antagonist, HC030031, a TRPA1 channel blocker. In addition, allylisothiocyanate, a TRPA1 agonist, but not (2S,5R)-2-Isopropyl-N-(4-methoxyphenyl)-5 methylcyclohexanecarboximide, a selective TRPM8 agonist, induced gastric relaxation. Genic expression of TRPA1, but not of TRPM8, was revealed in mouse stomach. Indeed, menthol-induced gastric relaxation was significantly reduced by hexamethonium, cholinergic nicotinic receptor antagonist. Menthol, at concentrations that failed to affect gastric tone, reduced the contraction induced by dimethylphenylpiperazinium, nicotinic receptor agonist. The joint application of hexamethonium and atropine, muscarinc receptor antagonist, or hexamethonium and phentholamine, alpha-adrenergic receptor antagonist, did not produce any additive reduction of the relaxant response to menthol. Lastly, ondansetron, a 5-HT3 receptor antagonist, was ineffective. In conclusion, our study suggests that nicotinic receptors, but not TRP and 5-HT3 receptors, are molecular targets for menthol inducing murine gastric relaxation, ultimately due to the reduction of acetylcholine release from enteric nerves. PMID- 25446934 TI - Prospective motion correction of segmented diffusion weighted EPI. AB - PURPOSE: Recently, a new algorithm was introduced to combine segments of under sampled diffusion weighted data using multiplexed sensitivity encoding. While the algorithm provides good results in cooperative volunteers, motion during the data acquisition is not accounted for. In this work, the continuous prospective motion correction of a segmented diffusion weighted acquisition is combined with multiplexed sensitivity encoding. METHODS: Simulations investigate the influence of motion on the reconstruction. Additionally, the change in coil sensitivities due to patient motion is taken into consideration. Finally, in vivo experiments display the effects of motion and its prospective correction on high resolution diffusion weighted imaging. RESULTS: Inconsistencies of the imaging plane lead to artifacts and blurring in the reconstructed dataset. Additionally, motion during the diffusion weighting period can lead to substantial image artifacts and signal dropouts. The change in coil sensitivities shows minor effect for the simulated range of motion (5 degrees ). Prospective motion correction is shown to improve image quality in the case of large motion (5 degrees ) and to reliably correct for small motion (1 degrees ). CONCLUSION: The combination of prospective motion correction and multiplexed sensitivity encoding allows for high resolution diffusion weighted imaging even in the presence of substantial head motion. PMID- 25446933 TI - Carboxyamidotriazole: a novel inhibitor of both cAMP-phosphodiesterases and cGMP phosphodiesterases. AB - Carboxyamidotriazole (CAI) is a non-cytotoxic anti-tumor drug, which also shows considerable anti-inflammatory effects in a variety of animal models of inflammation. The exact target and mechanism of CAI were not clearly understood yet. In the present study, we demonstrate that CAI is a non-selective phosphodiesterase (PDE) inhibitor, which provides comprehensive inhibitions of both adenosine 3',5'-cyclic monophosphate specific PDE (cAMP-PDE) and guanosine 3',5'-cyclic monophosphate specific PDE (cGMP-PDE) isolated from rat brain, mouse pulmonary tissue, primary mouse peritoneal macrophages, RAW264.7 cells, Lewis lung carcinoma (LLC) cells and lymphocytic leukemia cells (L1210) with moderate potencies (IC50~0.5-30MUM). The comprehensive elimination of PDE activities in living LLC cells by CAI results in accumulation of intracellular cAMP and cGMP, which can be visualized by fluorescence resonance energy transfer (FRET)-based cyclic nucleotide sensors. The stimulation by 30MUM CAI yielded ~1.5-fold greater cGMP responses compared with 10MUM sildenafil citrate, whereas the influence of 30MUM CAI on cAMP levels was similar as that of 100MUM 3-isobutyl-1 methylxanthine (IBMX). The non-selective inhibitory effect of CAI on cAMP-PDE and cGMP-PDE increases the likelihood for CAI to affect the balance between the levels of intracellular cyclic nucleotides cAMP and cGMP, then a variety of cellular signaling pathways that regulate cell functions and even related disease processes. When examining the widely proven anti-tumor and anti-inflammatory activities of CAI, it is important to affirm its comprehensive inhibitory effect on PDEs, which makes it superior to some selective PDE inhibitors in a way. PMID- 25446935 TI - Blood oxygen affinity increases during digestion in the South American rattlesnake, Crotalus durissus terrificus. AB - Digesting snakes experience massive increases in metabolism that can last for many days and are accompanied by adjustments in the oxygen transport cascade. Accordingly, we examined the oxygen-binding properties of the blood in the South American rattlesnake (Crotalus durissus terrificus) during fasting and 24 and 48h after the snakes have ingested a rodent meal corresponding to 15% (+/-2%) of its own body mass. In general, oxygen-hemoglobin (Hb-O2) affinity was significantly increased 24h post-feeding, and then returned toward fasting values within 48h post-feeding. Content of organic phosphates ([NTP] and [NTP]/[Hb]), hemoglobin cooperativity (Hill's n), and Bohr Effect (DeltalogP50/DeltapH) were not affected by feeding. The postprandial increase in Hb-O2 affinity in the South American rattlesnake can be almost entirely ascribed by the moderate alkaline tide that follows meal ingestion. In general, digesting snakes were able to regulate blood metabolites at quite constant levels (e.g., plasma osmolality, lactate, glucose, and total protein levels). The level of circulating lipids, however, was considerably increased, which may be related to their mobilization, since lipids are known to be incorporated by the enterocytes after snakes have fed. In conclusion, our results indicate that the exceptional metabolic increment exhibited by C. d. terrificus during meal digestion is entirely supported by the aerobic pathways and that among the attending cardiorespiratory adjustments, pulmonary Hb-O2 loading is likely improved due to the increment in blood O2 affinity. PMID- 25446936 TI - Control of breathing and the circulation in high-altitude mammals and birds. AB - Hypoxia is an unremitting stressor at high altitudes that places a premium on oxygen transport by the respiratory and cardiovascular systems. Phenotypic plasticity and genotypic adaptation at various steps in the O2 cascade could help offset the effects of hypoxia on cellular O2 supply in high-altitude natives. In this review, we will discuss the unique mechanisms by which ventilation, cardiac output, and blood flow are controlled in high-altitude mammals and birds. Acclimatization to high altitudes leads to some changes in respiratory and cardiovascular control that increase O2 transport in hypoxia (e.g., ventilatory acclimatization to hypoxia). However, acclimatization or development in hypoxia can also modify cardiorespiratory control in ways that are maladaptive for O2 transport. Hypoxia responses that arose as short-term solutions to O2 deprivation (e.g., peripheral vasoconstriction) or regional variation in O2 levels in the lungs (i.e., hypoxic pulmonary vasoconstriction) are detrimental at in chronic high-altitude hypoxia. Evolved changes in cardiorespiratory control have arisen in many high-altitude taxa, including increases in effective ventilation, attenuation of hypoxic pulmonary vasoconstriction, and changes in catecholamine sensitivity of the heart and systemic vasculature. Parallel evolution of some of these changes in independent highland lineages supports their adaptive significance. Much less is known about the genomic bases and potential interactive effects of adaptation, acclimatization, developmental plasticity, and trans-generational epigenetic transfer on cardiorespiratory control. Future work to understand these various influences on breathing and circulation in high altitude natives will help elucidate how complex physiological systems can be pushed to their limits to maintain cellular function in hypoxia. PMID- 25446937 TI - Carbon dioxide sensitivity and its role in multifunctional neurons in the mollusk Onchidium. AB - Intrinsically photoresponsive neurons in the abdominal ganglion of the amphibious mollusk Onchidium named Ip-1 and Ip-2 (Ip-1/2) react to several different stimuli. These neurons respond to light with slow hyperpolarization and to CO2 stimulation with slow depolarization. In this study, increasing the concentration of CO2 in the air caused hyperventilation and enlargement of the pneumostome in the intact animal. In a semi-intact preparation, pouring artificial seawater (ASW) with dissolved CO2 onto the central ganglia caused the previously closed pneumostome to open. In an ASW environment, Ip-1/2 neurons depolarized even under conditions of constant pH (alkaline ASW) and after dissolution of CO2. This depolarization prolonged the firing of action potentials in Ip-1/2 neurons. Adding protons (H+) to ASW caused Ip-1/2 depolarization only when the neurons' membranes were depolarized to a potential above the resting potential. Furthermore, in the presence of the carbonic anhydrase inhibitor acetazolamide (AZ), CO2-induced excitation in Ip-1/2 neurons was increased in both normal and alkaline ASW. These results suggest that when dissolved in ASW, CO2 directly induced the depolarizing response in Ip-1/2 neurons. Since Ip-1/2 neurons participate in pneumostome opening, these results suggest that increased CO2 levels in ASW directly stimulate CO2-sensitive central neurons, promoting ventilation. PMID- 25446938 TI - Faecal particle size: digestive physiology meets herbivore diversity. AB - In herbivore ecophysiology, comparative chewing efficiency has only recently received increased attention. This measure is best assessed on un-processed forage-only diets; corresponding comparative datasets are missing. We measured a faecal mean particle size (MPS [mm]) in 14 large herbivore species (body mass (M) range 60-4000 kg; 8 ruminants and 6 hindgut fermenters) fed a consistent grass hay diet, in which intake, digesta mean retention times (MRT [h]) and digestive efficiency (as digestibility of faecal fibre measured by 96 h cumulative in vitro gas production GP96h [ml per 200 mg faecal fibre], and metabolic faecal nitrogen MFN [% organic faecal matter]) had been quantified simultaneously. MPS was generally lower in ruminants than in hindgut fermenters and increased with M in the total dataset, but was nearly constant among closely related taxa (e.g. within ruminants, within equids) irrespective of M. MPS (but not MRT) was significantly correlated to GP96h, whereas MRT (but not MPS) was significantly correlated to MFN, suggesting different effects of these factors on different aspects of digestibility. Combinations of measures including MPS mostly explained digestibility better than other combinations. The phylogenetic signal lambda, which was mostly 1 when linking any single measure to digestibility, was estimated 0 in models that linked digestive efficiency to combinations of measures. These results support the intuitive concept that species diversification in large herbivores is tightly related to digestive physiology, and that chewing efficiency as measured by faecal particle size is an integral aspect of this scenario. PMID- 25446939 TI - GnRH mRNA levels in male three-spined sticklebacks, Gasterosteus aculeatus, under different reproductive conditions. AB - In vertebrates, reproduction is regulated by the brain-pituitary-gonad (BPG) axis, where the gonadotropin-releasing hormone (GnRH) is one of the key components. However, very little is known about the possible role of GnRH in the environmental and feedback control of fish reproduction. To investigate this, full-length gnrh2 (chicken GnRH II) and gnrh3 (salmon GnRH) sequences of male three-spined sticklebacks (Gasterosteus aculeatus), which are clustered with the taxa of the same GnRH type as other Euteleostei, were cloned and annotated. gnrh1 is absent in this species. The mRNA levels of gnrh2 and gnrh3 in the sticklebacks' brain were measured under breeding and post-breeding conditions as well as in castrated and sham-operated breeding fish and castrated/sham-operated fish kept under long-day (LD 16:8) and short-day (LD 8:16) conditions. Fully breeding males had considerably higher mRNA levels of gnrh2 and gnrh3 in the thalamus (Th) and in the telencephalon and preoptic area (T+POA), respectively, than post-breeding males. Sham-operated breeding males have higher gnrh3 mRNA levels than the corresponding castrated males. Moreover, higher gnrh2 mRNA levels in the Th and higher gnrh3 mRNA levels in the T+POA and hypothalamus (HypTh) were also found in long-day sham-operated males than in sham-operated fish kept under an inhibitory short day photoperiod. Nevertheless, gnrh2 and gnrh3 mRNA levels were not up-regulated in castrated males kept under long-day photoperiod, which suggests that positive feedbacks on the brain-pituitary-gonad axis are necessary for this response. PMID- 25446940 TI - Avian influenza A (H7N9) virus infection in humans: epidemiology, evolution, and pathogenesis. AB - New human influenza A virus strains regularly emerge causing seasonal epidemics and occasional pandemics. Lately, several zoonotic avian influenza A strains have been reported to directly infect humans. In early 2013, a novel avian influenza A virus (H7N9) strain was discovered in China to cause severe respiratory disease in humans. Since then, over 450 human cases of H7N9 infection have been discovered and 165 of them have died. Multiple epidemiological, phylogenetic, in vivo, and in vitro studies have been done to determine the origin and pathogenesis of novel H7N9 strain. This article reviews the literature related to the epidemiology, evolution, and pathogenesis of the H7N9 strain since its discovery in February 2013 till August 2014. The data available so far indicate that H7N9 was originated by a two-step reassortment process in birds and transmitted to humans through direct contact with live-bird markets. H7N9 is a low-pathogenic avian virus and contains several molecular signatures for adaptation in mammals. The severity of the respiratory disease caused by novel H7N9 virus in humans can be partly attributed to the age, sex, and underlying medical conditions of the patients. A universal influenza vaccine is not available, though several strain-specific H7N9 candidate vaccine viruses have been developed. Further, novel H7N9 virus is resistant to antiviral drug amantadine and some H7N9 isolates have acquired the resistance to neuraminidase inhibitors. Therefore, constant surveillance and prompt control measures combined with novel research approaches to develop alternative and effective anti influenza strategies are needed to overcome influenza A virus. PMID- 25446941 TI - Major Histocompatibility Complex, demographic, and environmental predictors of antibody presence in a free-ranging mammal. AB - Major Histocompatibility Complex (MHC) variability plays a key role in pathogen resistance, but its relative importance compared to environmental and demographic factors that also influence resistance is unknown. We analyzed the MHC II DRB exon 2 for 165 raccoons (Procyon lotor) in Missouri (USA). For each animal we also determined the presence of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to two highly virulent pathogens, canine distemper virus (CDV) and parvovirus. We investigated the role of MHC polymorphism and other demographic and environmental factors previously associated with predicting seroconversion. In addition, using an experimental approach, we studied the relative importance of resource availability and contact rates. We found important associations between IgG antibody presence and several MHC alleles and supertypes but not between IgM antibody presence and MHC. No effect of individual MHC diversity was found. For CDV, supertype S8, one allele within S8 (Prlo-DRB(*)222), and a second allele (Prlo-DRB(*)204) were positively associated with being IgG+, while supertype S4 and one allele within the supertype (Prlo-DRB(*)210) were negatively associated with being IgG+. Age, year, and increased food availability were also positively associated with being IgG+, but allele Prlo-DRB(*)222 was a stronger predictor. For parvovirus, only one MHC allele was negatively associated with being IgG+ and age and site were stronger predictors of seroconversion. Our results show that negative-frequency dependent selection is likely acting on the raccoon MHC and that while the role of MHC in relation to other factors depends on the pathogen of interest, it may be one of the most important factors predicting successful immune response. PMID- 25446942 TI - Unexpected inverse correlation between Native American ancestry and Asian American variants of HPV16 in admixed Colombian cervical cancer cases. AB - BACKGROUND: European (E) variants of HPV 16 are evenly distributed among world regions, meanwhile Non-European variants such as European-Asian (EAs), Asian American (AA) and African (Af) are mostly confined to Eastern Asia, The Americas and African regions respectively. Several studies have shown that genetic variation of HPV 16 is associated with the risk of cervical cancer, which also seems to be dependent on the population. This relationship between ethnicity and variants have led to the suggestion that there is co-evolution of variants with humankind. Our aim was to evaluate the relationship between the individual ancestry proportion and infection with HPV 16 variants in cervical cancer. METHODS: We examined the association between ancestry and HPV 16 variants in samples of 82 cervical cancer cases from different regions of Colombia. Individual ancestry proportions (European, African and Native American) were estimated by genotyping 106 ancestry informative markers. Variants were identified by PCR amplification of the E6 gene, followed by reverse line blot hybridization (RLB) with variants specific probes. RESULTS: Overall European (E) and Asian American (AA) variants frequency was 66.5% and 33.5% respectively. Similar distribution was observed in cases with higher proportions of European or African ancestry. A higher Native American ancestry was significantly associated with higher frequency of E variants (median ancestry>23.6%, Age and place of birth adjusted OR: 3.55, 95% CI: 1.26-10.03, p=0.01). Even further, an inverse geographic correlation between Native American ancestry and frequency of infections with AA variants was observed (rho=-0.825, p=0.008). Regions with higher proportion of Native American ancestry had a lower frequency of AA variants of HPV 16. CONCLUSIONS: This study suggests replacement of AA variants by E variants of human papillomavirus 16 in cervical cancer cases with high Native American ancestry. PMID- 25446944 TI - Peri-encoding predictors of memory encoding and consolidation. AB - We review reports of brain activations that occur immediately prior to the onset or following the offset of to-be-remembered information and can predict subsequent mnemonic success. Memory-predictive pre-encoding processes, occurring from fractions of a second to minutes prior to event onset, are mainly associated with activations in the medial temporal lobe (MTL), amygdala and midbrain, and with enhanced theta oscillations. These activations may be considered as the neural correlates of one or more cognitive operations, including contextual processing, attention, and the engagement of distinct computational modes associated with prior encoding or retrieval. Post-encoding activations that correlate with subsequent memory performance are mainly observed in the MTL, sensory cortices and frontal regions. These activations may reflect binding of elements of the encoded information and initiation of memory consolidation. In all, the findings reviewed here illustrate the importance of brain states in the immediate peri-encoding time windows in determining encoding success. Understanding these brain states and their specific effects on memory may lead to optimization of the encoding of desired memories and mitigation of undesired ones. PMID- 25446943 TI - Assessing recovery from neurodegeneration in spinocerebellar ataxia 1: Comparison of in vivo magnetic resonance spectroscopy with motor testing, gene expression and histology. AB - Suppression of transgene expression in a conditional transgenic mouse model of spinocerebellar ataxia 1 (SCA1) reverses the Purkinje cell pathology and motor dysfunction that are hallmarks of SCA1. We previously showed that cerebellar neurochemical levels measured by magnetic resonance spectroscopy (MRS) correlate with progression of pathology and clinical status of patients and that abnormal neurochemical levels normalize upon suppression of transgene expression, indicating their potential as robust surrogate markers of treatment effects. Here we investigated the relative sensitivities of MRS, histology, transgene expression and motor behavioral testing to disease reversal in conditional SCA1 mice. Transgene expression was suppressed by doxycycline administration and treated and untreated mice were assessed by MRS at 9.4tesla before and after treatment and with an accelerating Rotarod, histology and quantitative polymerase chain reaction (qPCR) for ataxin-1 transgene expression following doxycycline treatment. The MRS-measured N-acetylaspartate-to-myo-inositol ratio (NAA/Ins) correlated significantly with the molecular layer (ML) thickness and transgene expression. NAA/Ins, ML thickness and transgene expression were highly significantly different between the treated vs. untreated groups (p<0.0001), while the Rotarod assessment showed a trend for treatment effect. MRS, qPCR and histology had high sensitivity/specificity to distinguish treated from untreated mice, all with areas under the curve (AUC)=0.97-0.98 in receiver operating characteristic (ROC) analyses, while Rotarod had significantly lower sensitivity and specificity (AUC=0.72). Therefore, MRS accurately reflects the extent of recovery from neurodegeneration with sensitivity similar to invasive measures, further validating its potential as a surrogate marker in pre-clinical and clinical treatment trials. PMID- 25446945 TI - Functional heterogeneity of the limbic thalamus: From hippocampal to cortical functions. AB - Today, the idea that the integrity of the limbic thalamus is necessary for normal memory functions is well established. However, if the study of thalamic patients emphasized the anterior and the mediodorsal thalamus as the critical thalamic loci supporting cognitive functions, clinical studies have so far failed to attribute a specific role to each of these regions. In view of these difficulties, we review here the experimental data conducted in rodents harboring specific lesions of each thalamic region. These data clearly indicate a major functional dissociation within the limbic thalamus. The anterior thalamus provides critical support for hippocampal functions due to its cardinal location in the Papez circuit, while the mediodorsal thalamus may signal relevant information in a circuit encompassing the basolateral amygdala and the prefrontal cortex. Interestingly, while clinical studies have suggested that diencephalic pathologies may disconnect the medial temporal lobe from the cortex, experimental studies conducted in rodent show how this may differently affect distinct temporo thalamo-cortical circuits, sharing the same general organization but supporting dissociable functions. PMID- 25446946 TI - The role of endogenous opioids in non-suicidal self-injurious behavior: methodological challenges. AB - Relief from emotional pain is a frequently cited reason for engaging in non suicidal self-injury. The exact mechanism by which self-injury brings about this relief is unknown, but the potential role of endogenous opioids in affective regulation has been posited. Few studies have investigated this and there are a number of methodological challenges to measuring endogenous opioid activity in this population. Furthermore as the majority of research to date has focused on inpatients with borderline personality disorder (BPD), it is uncertain if the findings of previous studies would also apply to those who self-injure but who do not have BPD. Whether or not altered endogenous opioid levels are a cause or a consequence of self-injury is unknown and to this end, comparing self-injury ideators with enactors, may offer a window of insight. Another candidate system, the endocannabinoid system, should also be explored in relation to this research question. The current commentary aims to tease apart the methodological issues in this area of research and stimulate further discussion of this topic. PMID- 25446947 TI - A computational theory of hippocampal function, and tests of the theory: new developments. AB - The aims of the paper are to update Rolls' quantitative computational theory of hippocampal function and the predictions it makes about the different subregions (dentate gyrus, CA3 and CA1), and to examine behavioral and electrophysiological data that address the functions of the hippocampus and particularly its subregions. Based on the computational proposal that the dentate gyrus produces sparse representations by competitive learning and via the mossy fiber pathway forces new representations on the CA3 during learning (encoding), it has been shown behaviorally that the dentate gyrus supports spatial pattern separation during learning. Based on the computational proposal that CA3-CA3 autoassociative networks are important for episodic memory, it has been shown behaviorally that the CA3 supports spatial rapid one-trial learning, learning of arbitrary associations where space is a component, pattern completion, spatial short-term memory, and spatial sequence learning by associations formed between successive items. The concept that the CA1 recodes information from CA3 and sets up associatively learned backprojections to neocortex to allow subsequent retrieval of information to neocortex, is consistent with findings on consolidation. Behaviorally, the CA1 is implicated in processing temporal information as shown by investigations requiring temporal order pattern separation and associations across time; and computationally this could involve associations in CA1 between object and timing information that have their origins in the lateral and medial entorhinal cortex respectively. The perforant path input from the entorhinal cortex to DG is implicated in learning, to CA3 in retrieval from CA3, and to CA1 in retrieval after longer time intervals ("intermediate-term memory") and in the temporal sequence memory for objects. PMID- 25446949 TI - Omega-3 fatty acids intake and risks of dementia and Alzheimer's disease: a meta analysis. AB - BACKGROUND: We systematically reviewed the association of omega-3 fatty acids intake with the incidence of dementia and Alzheimer's disease (AD) in this meta analysis of prospective cohort studies, as evidence from previous studies suggests inconsistent results. METHODS: We identified relevant studies by searching PubMed, EmBase, and Web of Science databases up to June 2013. Prospective cohort studies reporting on associations of dietary intake of long chain omega-3 fatty acids or fish with the incidence of dementia and AD were eligible. RESULTS: Comparing the highest to lowest category of long-chain omega-3 fatty acids intake and fish intake, the pooled relative risks (RRs) for dementia were 0.97 (95% CI 0.85-1.10) and 0.84 (95% CI 0.71-1.01), respectively. Evidence synthesis for AD risk did not show a statistically significant association with long-chain omega-3 fatty acids intake (RR=0.89, 95% CI 0.74-1.08). However, a higher intake of fish was associated with a 36% (95% CI 8-56%) lower risk of AD. Dose-response meta-analysis showed that an increment of 100g per week of fish intake was associated with an 11% lower risk of AD (RR=0.89, 95% CI 0.79-0.99). There was limited evidence of heterogeneity across studies or within subgroups. CONCLUSION: A higher intake of fish was associated with a lower risk of AD. However, there was no statistical evidence for similar inverse association between long-chain omega-3 fatty acids intake and risk of dementia or AD, nor was there inverse association between fish intake and risk of dementia. PMID- 25446950 TI - Mitochondrial dysfunction in schizophrenia: pathways, mechanisms and implications. AB - Mitochondria play a critical role in regulating cellular functions including bioenergetics, calcium homeostasis, redox signalling, and apoptotic cell death. Mitochondria are also essential to many aspects of neurodevelopment and neuronal functions. However, mitochondrial impairment may affect bioenergetics in the developing brain and alter critical neuronal processes leading to neurodevelopmental abnormalities. Schizophrenia is a chronic and severe neuropsychiatric disorder of neurodevelopmental origin. Immuno-inflammatory pathway is one of the widely appreciated mechanisms that has consistently been implicated in the neurodevelopmental origin of schizophrenia. However, the source of inflammation and the underlying neurobiological mechanisms leading to schizophrenia are yet to be fully ascertained. Recent understanding reveals that perturbation of mitochondrial network dynamics might lead to various nervous system disorders with inflammatory pathologies. Mitochondrial deficit, altered redox balance and chronic low-grade inflammation are evident in schizophrenia. It is hypothesized that oxidative/nitrosative stress responses due to mitochondrial dysfunctions might activate immuno-inflammatory pathways and subsequently lead to neuroprogressive changes in schizophrenia. Herein, we summarise the current understanding of molecular links between mitochondrial dysfunctions and pathogenesis of schizophrenia based on evidence from genomics, proteomics and imaging studies, which together support a role for mitochondrial impairment in the pathogenetic pathways of schizophrenia. PMID- 25446952 TI - Drawing connections between white matter and numerical and mathematical cognition: a literature review. AB - In this review we examine white matter tracts that may support numerical and mathematical abilities and whether abnormalities in these pathways are associated with deficits in numerical and mathematical abilities. Diffusion tensor imaging (DTI) yields indices of white matter integrity and can provide information about the axonal organization of the brain. A growing body of research is using DTI to investigate how individual differences in brain microstructures relate to different numerical and mathematical abilities. Several tracts have been associated with numerical and mathematical abilities such as the superior longitudinal fasciculus, the posterior segment of the corpus callosum, inferior longitudinal fasciculus, corona radiata, and the corticospinal tract. Impairments in mathematics tend to be associated with atypical white matter structures within similar regions, especially in inferior parietal and temporal tracts. This systematic review summarizes and critically examines the current literature on white matter correlates of numerical and mathematical abilities, and provides directions for future research. PMID- 25446954 TI - New journal on patient involvement will be launched next year. PMID- 25446953 TI - Behavioral neuroscience of psychological pain. AB - Pain is a common word used to refer to a wide range of physical and mental states sharing hedonic aversive value. Three types of pain are distinguished in this article: Physical pain, an aversive state related to actual or potential injury and disease; social pain, an aversive emotion associated to social exclusion; and psychological pain, a negative emotion induced by incentive loss. This review centers on psychological pain as studied in nonhuman animals. After covering issues of terminology, the article briefly discusses the daily-life significance of psychological pain and then centers on a discussion of the results originating from two procedures involving incentive loss: successive negative contrast-the unexpected devaluation of a reward-and appetitive extinction-the unexpected omission of a reward. The evidence reviewed points to substantial commonalities, but also some differences and interactions between physical and psychological pains. This evidence is discussed in relation to behavioral, pharmacological, neurobiological, and genetic factors that contribute to the multidimensional experience of psychological pain. PMID- 25446955 TI - Control of thermal fabrication and size of beta-lactoglobulin-based microgels and their potential applications. AB - HYPOTHESIS: Factors influencing fabrication and size of microgels formed from beta-lactoglobulin with or without pectin can tune selected attributes for material applications. Protein aggregation was expected to be influenced by pH, added anions, and reducing agents, while ionic strength was expected to be more influenced by electrostatically interacting pectin. EXPERIMENTS: Turbidity measurements during thermal aggregation to form microgels were determined for pure beta-lactoglobulin as a function of pH, added ionic strength, anion type (chloride, sulfate, and thiocyanate), and reducing agent concentration. beta lactoglobulin and pectin complexation pH values and thermal aggregation were determined by turbidity measurements with added potassium chloride, sulfate, and thiocyanate. Microgel size and morphology were determined by light scattering and atomic force microscopy, respectively. FINDINGS: Thermal aggregation of pure beta lactoglobulin increased with decreased pH, reducing conditions, and increased ionic strength with no observed anion effect. beta-lactoglobulin microgel radii increased from 86 to 115nm with decreasing pH and increased to 124nm in reducing conditions, while salts promoted agglomeration. Increased ionic strength (0 100mmol/kg) decreased beta-lactoglobulin-pectin complexation pH from 5.40 to 5.00, while first increasing and then decreasing thermal aggregation. Thermal aggregation and microgel size were greatest with potassium thiocyanate, followed by potassium chloride and potassium sulfate. PMID- 25446948 TI - Molecular imaging of neuropsychiatric symptoms in Alzheimer's and Parkinson's disease. AB - Neuropsychiatric symptoms (NPS) are very common in neurodegenerative diseases and are a major contributor to disability and caregiver burden. There is accumulating evidence that NPS may be a prodrome and/or a "risk factor" of neurodegenerative diseases. The medications used to treat these symptoms in younger patients are not very effective in patients with neurodegenerative disease and may have serious side effects. An understanding of the neurobiology of NPS is critical for the development of more effective intervention strategies. Targeting these symptoms may also have implications for prevention of cognitive or motor decline. Molecular brain imaging represents a bridge between basic and clinical observations and provides many opportunities for translation from animal models and human post-mortem studies to in vivo human studies. Molecular brain imaging studies in Alzheimer's disease (AD) and Parkinson's disease (PD) are reviewed with a primary focus on positron emission tomography studies of NPS. Future directions for the field of molecular imaging in AD and PD to understand the neurobiology of NPS will be discussed. PMID- 25446956 TI - Structuring of colloidal particles at interfaces and the relationship to food emulsion and foam stability. AB - We consider the influence of spherical colloidal particles on the structure and stabilization of dispersions, emulsions and foams. Emphasis is placed on developments in the use of the methods of liquid state theory and computer simulation to understand short-range structuring of concentrated colloidal dispersions and ordering of particle layers near surfaces and within liquid films. Experimental information on the structuring of surfactant micelles and caseinate particles in thin liquid films is described, including an assessment of the effect of particle polydispersity on depletion interactions and kinetic structural stabilization. We specifically discuss the relevance of some of these structural concepts to the stability of food colloids. PMID- 25446957 TI - Cationic gemini surfactants with cleavable spacer: chemical hydrolysis, biodegradation, and toxicity. AB - The paper describes synthesis and characterization of a new type of cationic gemini surfactant, which has dodecyl tails and a spacer that contains an ester bond. The nomenclature used to describe the structure is 12Q2OCO1Q12, with Q being a quaternary ammonium group and the numbers indicating the number of methylene or methyl groups. Due to the close proximity to the two quaternary ammonium groups, the ester bond is very stable on the acid side and very labile already at slightly alkaline conditions. The hydrolysis products are two single chain surfactants (i.e. 12Q2OH and 12Q1COOH) which are less surface active than the intact gemini surfactant. 12Q2OCO1Q12 was found to be readily biodegradable, i.e. it gave more than 60% biodegradation after 28 days. This is interesting because similar gemini surfactants but with ester bonds in the tails instead of the spacer, have previously been found not to be readily biodegradable. The gemini surfactant was found to be toxic to aquatic organisms (ErC50 value of 0.27 mg/l), although less toxic than the two hydrolysis products. PMID- 25446958 TI - Quantitative and qualitative MR-imaging assessment of vastus medialis muscle volume loss in asymptomatic patients after anterior cruciate ligament reconstruction. AB - BACKGROUND: To quantitatively and qualitatively assess vastus medialis muscle atrophy in asymptomatic patients with anterior cruciate ligament reconstruction, using the nonoperated leg as control. METHODS: Prospective Institutional Review Board approved study with written informed patient consent. Thirty-three asymptomatic patients (men, 21; women,12) with ACL-reconstruction underwent MR imaging of both legs (axial T1-weighted spin-echo and 3D spoiled dual gradient echo sequences). Muscle volume and average fat-signal fraction (FSF) of the vastus medialis muscles were measured. Additionally, Goutallier classification was used to classify fatty muscle degeneration. Significant side differences were evaluated using the Wilcoxon test and, between volumes and FSF, using student t tests with P-value < 0.05 and < 0.025, respectively. RESULTS: The muscle volume was significantly smaller in the operated (mean +/- SD, 430.6 +/- 119.6 cm(3) ; range, 197.3 to 641.7 cm(3) ) than in the nonoperated leg (479.5 +/- 124.8 cm(3) ; 261.4 to 658.9 cm(3) ) (P < 0.001). Corresponding FSF was 6.3 +/- 1.5% (3.9 to 9.2%) and 5.8 +/- 0.9% (4.0 to 7.4%), respectively, with a nonsignificant (P > 0.025) difference. The relative muscle-volume and FSF differences were -10.1 +/- 8.6% (7.1 to -30.1%) and 10.9 +/- 29.4% (39.7 to 40.1%). The qualitative assessment revealed no significant differences (P > 0.1). CONCLUSION: A significant muscle volume loss of the vastus medialis muscle does exist in asymptomatic patients with ACL-reconstruction, but without fatty degeneration. PMID- 25446951 TI - Three key regions for supervisory attentional control: evidence from neuroimaging meta-analyses. AB - The supervisory attentional system has been proposed to mediate non-routine, goal oriented behaviour by guiding the selection and maintenance of the goal-relevant task schema. Here, we aimed to delineate the brain regions that mediate these high-level control processes via neuroimaging meta-analysis. In particular, we investigated the core neural correlates of a wide range of tasks requiring supervisory control for the suppression of a routine action in favour of another, non-routine one. Our sample comprised n=173 experiments employing go/no-go, stop signal, Stroop or spatial interference tasks. Consistent convergence across all four paradigm classes was restricted to right anterior insula and inferior frontal junction, with anterior midcingulate cortex and pre-supplementary motor area being consistently involved in all but the go/no-go task. Taken together with lesion studies in patients, our findings suggest that the controlled activation and maintenance of adequate task schemata relies, across paradigms, on a right-dominant midcingulo-insular-inferior frontal core network. This also implies that the role of other prefrontal and parietal regions may be less domain general than previously thought. PMID- 25446959 TI - Clines in quantitative traits: the role of migration patterns and selection scenarios. AB - The existence, uniqueness, and shape of clines in a quantitative trait under selection toward a spatially varying optimum is studied. The focus is on deterministic diploid two-locus n-deme models subject to various migration patterns and selection scenarios. Migration patterns may exhibit isolation by distance, as in the stepping-stone model, or random dispersal, as in the island model. The phenotypic optimum may change abruptly in a single environmental step, more gradually, or not at all. Symmetry assumptions are imposed on phenotypic optima and migration rates. We study clines in the mean, variance, and linkage disequilibrium (LD). Clines result from polymorphic equilibria. The possible equilibrium configurations are determined as functions of the migration rate. Whereas for weak migration, many polymorphic equilibria may be simultaneously stable, their number decreases with increasing migration rate. Also for intermediate migration rates polymorphic equilibria are in general not unique, however, for loci of equal effects the corresponding clines in the mean, variance, and LD are unique. For sufficiently strong migration, no polymorphism is maintained. Both migration pattern and selection scenario exert strong influence on the existence and shape of clines. The results for discrete demes are compared with those from models in which space varies continuously and dispersal is modeled by diffusion. Comparisons with previous studies, which investigated clines under neutrality or under linkage equilibrium, are performed. If there is no long-distance migration, the environment does not change abruptly, and linkage is not very tight, populations are almost everywhere close to linkage equilibrium. PMID- 25446960 TI - A general condition for adaptive genetic polymorphism in temporally and spatially heterogeneous environments. AB - Both evolution and ecology have long been concerned with the impact of variable environmental conditions on observed levels of genetic diversity within and between species. We model the evolution of a quantitative trait under selection that fluctuates in space and time, and derive an analytical condition for when these fluctuations promote genetic diversification. As ecological scenario we use a generalized island model with soft selection within patches in which we incorporate generation overlap. We allow for arbitrary fluctuations in the environment including spatio-temporal correlations and any functional form of selection on the trait. Using the concepts of invasion fitness and evolutionary branching, we derive a simple and transparent condition for the adaptive evolution and maintenance of genetic diversity. This condition relates the strength of selection within patches to expectations and variances in the environmental conditions across space and time. Our results unify, clarify, and extend a number of previous results on the evolution and maintenance of genetic variation under fluctuating selection. Individual-based simulations show that our results are independent of the details of the genetic architecture and whether reproduction is clonal or sexual. The onset of increased genetic variance is predicted accurately also in small populations in which alleles can go extinct due to environmental stochasticity. PMID- 25446963 TI - Right hemisphere control of visuospatial attention in near space. AB - Traditionally, the right cerebral hemisphere has been considered to be specialized for spatial attention and orienting. A large body of research has demonstrated dissociable representations of the near space immediately surrounding the body and the more distance far space. In this study, we investigated whether right hemisphere activations commonly reported for tasks involving spatial attention (such as the line bisection and landmark tasks) are specific to stimuli presented in near space. In separate blocks of trials, participants judged either whether a vertical transector was to the left or right of the centre of a line (landmark task) or whether the line was red or blue (colour task). Stimuli were seen from four distances (30, 60, 90, 120 cm). We used EEG to measure an ERP component (the 'line-bisection effect') specific to the direction of spatial attention (i.e., landmark minus colour). Consistent with previous results, spatial attention produced a right-lateralized negativity over occipito-parietal channels. The magnitude of this negativity was inversely related to viewing distance, being largest in near space and reduced in far space. These results suggest that the right occipito-temporal cortex may be specialized not just for the orientation of spatial attention generally, but specifically for orienting attention in the near space immediately surrounding the body. PMID- 25446962 TI - Nanocrystals of zeolite act as enhanced sensing interface for biosensing of leviteracetum. AB - In present work, nanocrystals of zeolites were employed as sensing interface for augmented electrochemical sensing of antiepileptic drug, that is, leviteracetum (LEV). Electrochemical sensing method was developed by depositing nanocrystals of zeolites and horseradish peroxidase (nanocrys zeolites-HRP) onto indium tin oxide (ITO)-coated glass surface for LEV detection. Various stages of biosensor fabrication were characterized by Transmission electron microscopy, X-ray diffraction, scanning electron microscopy, and electrochemical impedance spectroscopy. The fabricated nanocrys zeolites-HRP-modified sensor exhibited wide linear range (10-500 MUM) and a low detection limit of 0.01 MUM. The biosensor also showed a short response time (within 2 s). In addition, the biosensor exhibited high reproducibility, good storage stability, and anti-interference ability. The applicability of the nanocrys zeolites-HRP-modified sensor is to determine LEV level in spiked serum samples. PMID- 25446964 TI - The robot hand illusion: inducing proprioceptive drift through visuo-motor congruency. AB - The representation of one's own body sets the border of the self, but also shapes the space where we interact with external objects. Under particular conditions, such as in the rubber hand illusion external objects can be incorporated in one's own body representation, following congruent visuo-tactile stroking of one's own and a fake hand. This procedure induces an illusory sense of ownership for the fake hand and a shift of proprioceptive localization of the own hand towards the fake hand. Here we investigated whether pure visuo-motor, instead of visuo tactile, congruency between one's own hand and a detached myoelectric-controlled robotic hand can induce similar embodiment effects. We found a shift of proprioceptive hand localization toward the robot hand, only following synchronized real hand/robot hand movements. Notably, no modulation was found of the sense of ownership following either synchronous or asynchronous-movement training. Our findings suggest that visuo-motor synchrony can drive the localization of one's own body parts in space, even when somatosensory input is kept constant and the experience of body ownership is maintained. PMID- 25446961 TI - A hidden Markov model for investigating recent positive selection through haplotype structure. AB - Recent positive selection can increase the frequency of an advantageous mutant rapidly enough that a relatively long ancestral haplotype will be remained intact around it. We present a hidden Markov model (HMM) to identify such haplotype structures. With HMM identified haplotype structures, a population genetic model for the extent of ancestral haplotypes is then adopted for parameter inference of the selection intensity and the allele age. Simulations show that this method can detect selection under a wide range of conditions and has higher power than the existing frequency spectrum-based method. In addition, it provides good estimate of the selection coefficients and allele ages for strong selection. The method analyzes large data sets in a reasonable amount of running time. This method is applied to HapMap III data for a genome scan, and identifies a list of candidate regions putatively under recent positive selection. It is also applied to several genes known to be under recent positive selection, including the LCT, KITLG and TYRP1 genes in Northern Europeans, and OCA2 in East Asians, to estimate their allele ages and selection coefficients. PMID- 25446965 TI - Virtual arm's reach influences perceived distances but only after experience reaching. AB - Considerable empirical evidence has shown influences of the action capabilities of the body on the perception of sizes and distances. Generally, as one's action capabilities increase, the perception of the relevant distance (over which the action is to be performed) decreases and vice versa. As a consequence, it has been proposed that the body's action capabilities act as a perceptual ruler, which is used to measure perceived sizes and distances. In this set of studies, we investigated this hypothesis by assessing the influence of arm's reach on the perception of distance. By providing participant with a self-representing avatar seen in a first-person perspective in virtual reality, we were able to introduce novel and completely unfamiliar alterations in the virtual arm's reach to evaluate their impact on perceived distance. Using both action-based and visual matching measures, we found that virtual arm's reach influenced perceived distance in virtual environments. Due to the participants' inexperience with the reach alterations, we also were able to assess the amount of experience with the new arm's reach required to influence perceived distance. We found that minimal experience reaching with the virtual arm can influence perceived distance. However, some reaching experience is required. Merely having a long or short virtual arm, even one that is synchronized to one's movements, is not enough to influence distance perception if one has no experience reaching. PMID- 25446966 TI - Similarities between explicit and implicit motor imagery in mental rotation of hands: an EEG study. AB - Chronometric and imaging studies have shown that motor imagery is used implicitly during mental rotation tasks in which subjects for example judge the laterality of human hand pictures at various orientations. Since explicit motor imagery is known to activate the sensorimotor areas of the cortex, mental rotation is expected to do similar if it involves a form of motor imagery. So far, functional magnetic resonance imaging and positron emission tomography have been used to study mental rotation and less attention has been paid to electroencephalogram (EEG) which offers a high time-frequency resolution. The time-frequency analysis is an established method for studying explicit motor imagery. Although hand mental rotation is claimed to involve motor imagery, the time-frequency characteristics of mental rotation have never been compared with those of explicit motor imagery. In this study, time-frequency responses of EEG recorded during explicit motor imagery and during a mental rotation task, inducing implicit motor imagery, were compared. Fifteen right-handed healthy volunteers performed motor imagery of hands in one condition and hand laterality judgement tasks in another while EEG of the whole head was recorded. The hand laterality judgement was the mental rotation task used to induce implicit motor imagery. The time-frequency analysis and sLORETA localisation of the EEG showed that the activities in the sensorimotor areas had similar spatial and time-frequency characteristics in explicit motor imagery and implicit motor imagery conditions. Furthermore this sensorimotor activity was different for the left and for the right hand in both explicit and implicit motor imagery. This result supports that motor imagery is used during mental rotation and that it can be detected and studied with EEG technology. This result should encourage the use of mental rotation of body parts in rehabilitation programmes in a similar manner as motor imagery. PMID- 25446967 TI - Social conflicts elicit an N400-like component. AB - When people have different opinions, they often adjust their own attitude to match that of others, known as social conformity. How social conflicts trigger subsequent conformity remains unclear. One possibility is that a conflict with the group opinion is perceived as a violation of social information, analogous to using wrong grammar, and activates conflict monitoring and adjustment mechanisms. Using event related potential (ERP) recording combined with a face attractiveness judgment task, we investigated the neural encoding of social conflicts. We found that social conflicts elicit an N400-like negative deflection, being more negative for conflict with group opinions than no-conflict condition. The social conflict related signals also have a bi-directional profile similar to reward prediction error signals: it was more negative for under-estimation (i.e. one's own ratings were smaller than group ratings) than over-estimation, and the larger the differences between ratings, the larger the N400 amplitude. The N400 effects were significantly diminished in the non-social condition. We conclude that social conflicts are encoded in a bidirectional fashion in the N400-like component, similar to the pattern of reward-based prediction error signals. Our findings also suggest that the N400, a well-established ERP component encoding semantic violation, might be involved in social conflict processing and social learning. PMID- 25446969 TI - Processing of action- but not stimulus-related prediction errors differs between active and observational feedback learning. AB - Learning of stimulus-response-outcome associations is driven by outcome prediction errors (PEs). Previous studies have shown larger PE-dependent activity in the striatum for learning from own as compared to observed actions and the following outcomes despite comparable learning rates. We hypothesised that this finding relates primarily to a stronger integration of action and outcome information in active learners. Using functional magnetic resonance imaging, we investigated brain activations related to action-dependent PEs, reflecting the deviation between action values and obtained outcomes, and action-independent PEs, reflecting the deviation between subjective values of response-preceding cues and obtained outcomes. To this end, 16 active and 15 observational learners engaged in a probabilistic learning card-guessing paradigm. On each trial, active learners saw one out of five cues and pressed either a left or right response button to receive feedback (monetary win or loss). Each observational learner observed exactly those cues, responses and outcomes of one active learner. Learning performance was assessed in active test trials without feedback and did not differ between groups. For both types of PEs, activations were found in the globus pallidus, putamen, cerebellum, and insula in active learners. However, only for action-dependent PEs, activations in these structures and the anterior cingulate were increased in active relative to observational learners. Thus, PE related activity in the reward system is not generally enhanced in active relative to observational learning but only for action-dependent PEs. For the cerebellum, additional activations were found across groups for cue-related uncertainty, thereby emphasising the cerebellum's role in stimulus-outcome learning. PMID- 25446968 TI - Multiple forms of contour grouping deficits in schizophrenia: what is the role of spatial frequency? AB - Schizophrenia patients poorly perceive Kanizsa figures and integrate co-aligned contour elements (Gabors). They also poorly process low spatial frequencies (SFs), which presumably reflects dysfunction along the dorsal pathway. Can contour grouping deficits be explained in terms of the spatial frequency content of the display elements? To address the question, we tested patients and matched controls on three contour grouping paradigms in which the SF composition was modulated. In the Kanizsa task, subjects discriminated quartets of sectored circles ("pac-men") that either formed or did not form Kanizsa shapes (illusory and fragmented conditions, respectively). In contour integration, subjects identified the screen quadrant thought to contain a closed chain of co-circular Gabors. In collinear facilitation, subjects attempted to detect a central low contrast element flanked by collinear or orthogonal high-contrast elements, and facilitation corresponded to the amount by which collinear flankers reduced contrast thresholds. We varied SF by modifying the element features in the Kanizsa task and by scaling the entire stimulus display in the remaining tasks (SFs ranging from 4 to 12 cycles/deg). Irrespective of SF, patients were worse at discriminating illusory, but not fragmented shapes. Contrary to our hypothesis, collinear facilitation and contour integration were abnormal in the clinical group only for the higher SF (>=10 c/deg). Grouping performance correlated with clinical variables, such as conceptual disorganization, general symptoms, and levels of functioning. In schizophrenia, three forms of contour grouping impairments prominently arise and cannot be attributed to poor low SF processing. Neurobiological and clinical implications are discussed. PMID- 25446971 TI - Statistical methods for meta-analyses including information from studies without any events-add nothing to nothing and succeed nevertheless. AB - Meta-analyses with rare events, especially those that include studies with no event in one ('single-zero') or even both ('double-zero') treatment arms, are still a statistical challenge. In the case of double-zero studies, researchers in general delete these studies or use continuity corrections to avoid them. A number of arguments against both options has been given, and statistical methods that use the information from double-zero studies without using continuity corrections have been proposed. In this paper, we collect them and compare them by simulation. This simulation study tries to mirror real-life situations as completely as possible by deriving true underlying parameters from empirical data on actually performed meta-analyses. It is shown that for each of the commonly encountered effect estimators valid statistical methods are available that use the information from double-zero studies without using continuity corrections. Interestingly, all of them are truly random effects models, and so also the current standard method for very sparse data as recommended from the Cochrane collaboration, the Yusuf-Peto odds ratio, can be improved on. For actual analysis, we recommend to use beta-binomial regression methods to arrive at summary estimates for the odds ratio, the relative risk, or the risk difference. Methods that ignore information from double-zero studies or use continuity corrections should no longer be used. We illustrate the situation with an example where the original analysis ignores 35 double-zero studies, and a superior analysis discovers a clinically relevant advantage of off-pump surgery in coronary artery bypass grafting. PMID- 25446970 TI - Language and task switching in the bilingual brain: Bilinguals are staying, not switching, experts. AB - Bilinguals' ability to control which language they speak and to switch between languages may rely on neurocognitive mechanisms shared with non-linguistic task switching. However, recent studies also reveal some limitations on the extent control mechanisms are shared across domains, introducing the possibility that some control mechanisms are unique to language. We investigated this hypothesis by directly comparing the neural correlates of task switching and language switching. Nineteen Spanish-English bilingual university students underwent a functional magnetic resonance imaging (fMRI) study employing a hybrid (event related and blocked) design involving both color-shape switching and language switching paradigms. We compared the two switching tasks using within-subject voxel-wise t-tests for each of three trial types (single trials in single blocks, and stay and switch trials in mixed blocks). Comparing trial types to baseline in each task revealed widespread activation for single, stay, and switch trials in both color-shape and language switching. Direct comparisons of each task for each trial type revealed few differences between tasks on single and switch trials, but large task differences during stay trials, with more widespread activation for the non-linguistic than for the language task. Our results confirm previous suggestions of shared mechanisms of switching across domains, but also reveal bilinguals have greater efficiency for sustaining the inhibition of the non target language than the non-target task when two responses are available. This efficiency of language control might arise from bilinguals' need to control interference from the non-target language specifically when not switching languages, when speaking in single- or mixed-language contexts. PMID- 25446972 TI - Differential expression of the immunosuppressive enzyme IL4I1 in human induced Aiolos+, but not natural Helios+, FOXP3+ Treg cells. AB - IL4I1 encodes an L-phenylalanine oxidase that inhibits T-cell proliferation. It has been recently reported that IL4I1 is expressed in TH17 cells as part of a mechanism that limits their pathogenicity. We have previously identified a population of human FOXP3(+) Treg cells that secrete IL-17 ex vivo; here, we addressed the expression of IL4I1 in that Treg-cell population. We found that in ex vivo isolated circulating Treg cells, IL4I1 expression is induced by activation. Moreover, IL4I1 expression is restricted to cells that do not express Helios, a transcription factor that characterizes natural Treg cells, but that express Aiolos, which is involved in the differentiation of TH17 and induced Treg cells. We also showed that conversion of Treg cells under inflammatory conditions increases IL4I1 expression, likely as part of a regulatory loop that attempts to limit the pathogenicity resulting from their conversion into TH17. The specific expression of IL4I1 in TH17 and iTreg cells may provide insights into approaches that aim at modulating these populations in different pathological conditions involving inflammation-mediated immunosuppression. PMID- 25446973 TI - A cost-effective polyphosphate-based metabolism fuels an all E. coli cell-free expression system. AB - A new cost-effective metabolism providing an ATP-regeneration system for cell free protein synthesis is presented. Hexametaphosphate, a polyphosphate molecule, is used as phosphate donor together with maltodextrin, a polysaccharide used as carbon source to stimulate glycolysis. Remarkably, addition of enzymes is not required for this metabolism, which is carried out by endogenous catalysts present in the Escherichia coli crude extract. This new ATP regeneration system allows efficient recycling of inorganic phosphate, a strong inhibitor of protein synthesis. We show that up to 1.34-1.65mg/mL of active reporter protein is synthesized in batch-mode reaction after 5h of incubation. Unlike typical hybrid in vitro protein synthesis systems based on bacteriophage transcription, expression is carried out through E. coli promoters using only the endogenous transcription-translation molecular machineries provided by the extract. We demonstrate that traditional expensive energy regeneration systems, such as creatine phosphate, phosphoenolpyruvate or phosphoglycerate, can be replaced by a cost-effective metabolic scheme suitable for cell-free protein synthesis applications. Our work also shows that cell-free systems are useful platforms for metabolic engineering. PMID- 25446974 TI - Improved artificial pathway for biosynthesis of poly(3-hydroxybutyrate-co-3 hydroxyhexanoate) with high C6-monomer composition from fructose in Ralstonia eutropha. AB - Poly((R)-3-hydroxybutyrate-co-(R)-3-hydroxyhexanoate) [P(3HB-co-3HHx)], a flexible and practical kind of polyhydroxyalkanoates, is generally produced from plant oils and fatty acids by several wild and recombinant bacteria. This study established an improved artificial pathway for the biosynthesis of P(3HB-co-3HHx) with high 3HHx composition from structurally unrelated fructose in Ralstonia eutropha. Depression of (R)-specific reduction of acetoacetyl-CoA by the deletion of phaB1 was an effective modification for formation of the C6-monomer unit from fructose driven by crotonyl-CoA carboxylase/reductase (Ccr). Co-overexpression of phaJ4a, which encodes medium-chain-length (R)-enoyl-CoA hydratase, with ccr promoted the incorporation of both 3HB and 3HHx units. Further introduction of emdMm, a synthetic gene encoding ethylmalonyl-CoA decarboxylase derived from mouse, was remarkably effective for P(3HB-co-3HHx) biosynthesis, probably by converting ethylmalonyl-CoA generated by the reductive carboxylase activity of Ccr back into butyryl-CoA. A high cellular content of P(3HB-co-3HHx) composed of 22mol% 3HHx could be produced from fructose by the engineered strain of R. eutropha with DeltaphaB1 genotype expressing ccr, phaJ4a, and emd. PMID- 25446975 TI - Efficient diterpene production in yeast by engineering Erg20p into a geranylgeranyl diphosphate synthase. AB - Terpenes have numerous applications, ranging from pharmaceuticals to fragrances and biofuels. With increasing interest in producing terpenes sustainably and economically, there has been significant progress in recent years in developing methods for their production in microorganisms. In Saccharomyces cerevisiae, production of the 20-carbon diterpenes has so far proven to be significantly less efficient than production of their 15-carbon sesquiterpene counterparts. In this report, we identify the modular structure of geranylgeranyl diphosphate synthesis in yeast to be a major limitation in diterpene yields, and we engineer the yeast farnesyl diphosphate synthase Erg20p to produce geranylgeranyl diphosphate. Using a combination of protein and genetic engineering, we achieve significant improvements in the production of sclareol and several other isoprenoids, including cis-abienol, abietadiene and beta-carotene. We also report the development of yeast strains carrying the engineered Erg20p, which support efficient isoprenoid production and can be used as a dedicated chassis for diterpene production or biosynthetic pathway elucidation. The design developed here can be applied to the production of any GGPP-derived isoprenoid and is compatible with other yeast terpene production platforms. PMID- 25446977 TI - Hippocampal volume, early cognitive decline and gait variability: which association? AB - BACKGROUND: In contrast to its prominent function in cognition, the involvement of the hippocampus in gait control is still a matter of debate. The present study aimed to examine the association of the hippocampal volume with mean values and coefficients of variation (CoV) of spatio-temporal gait parameters among cognitively healthy individuals (CHI) and patients with mild cognitive impairment (MCI). METHODS: A total of 90 individuals (47 CHI with a mean age of 69.7+/ 3.6years and 48.9% women, and 43 MCI individuals with a mean age of 70.2+/ 3.7years and 62.8% women) were included in this cross-sectional study. The hippocampal volume was quantified from a three-dimensional T1-weighted MRI using semi-automated software. Mean values and CoV of stride time, swing time and stride width were measured at self-selected pace with a 10m electronic portable walkway (GAITRite(r)). Age, gender, body mass index, number of drugs daily taken, Mini-Mental State Examination (MMSE) score, history of falls, walking speed and white matter signal-intensity abnormality scoring with Manolio scale were used as covariates. RESULTS: Patients with MCI had a lower MMSE score (P<0.001), a higher CoV of stride time (P=0.013) and a lower hippocampal volume (P=0.007) compared with CHI. Multiple linear regression models showed that CoV of stride time was specifically associated with higher hippocampal volume among CHI (P<0.05) but not among patients with MCI (P>0.650). CONCLUSIONS: Our findings revealed a positive association between a greater (i.e., better morphological structure) hippocampal volume and a greater (i.e., worse performance) stride time variability among CHI, but not among MCI individuals. PMID- 25446976 TI - Clinical strategies and animal models for developing senolytic agents. AB - Aging is associated with increasing predisposition to multiple chronic diseases. One fundamental aging process that is often operative at sites of the pathology underlying chronic age-related diseases is cellular senescence. Small molecule senolytic agents are being developed. For successful drug development: 1) appropriate animal models of human age-related diseases need to be devised. 2) Models have to be made in which it can be proven that beneficial phenotypic effects are actually caused through clearing senescent cells by putative senolytic agents, as opposed to "off-target" effects of these agents on non senescent cells. 3) Models are needed to test efficacy of drugs and to uncover potential side effects of senolytic agents. Development of the optimal animal models and clinical trial paradigms for senolytic agents warrants an intensive effort, since senolytic agents, if successful in delaying, preventing, alleviating, or reversing age-related diseases as a group would be transformative. PMID- 25446978 TI - Higher baseline serum uric acid is associated with poorer cognition but not rates of cognitive decline in women. AB - Serum uric acid is a powerful antioxidant that may have neuroprotective properties. While some studies have found that greater serum uric acid is associated with better cognition in older adults, it is also associated with numerous vascular risk factors that increase risk for dementia. Women may also be particularly vulnerable to the vascular effects of elevated uric acid. We previously found that mildly elevated serum uric acid is a biomarker of cognitive dysfunction in older adults, and that this likely is mediated by cerebral ischemic burden. Here we examine both cross-sectional and longitudinal associations between serum uric acid and declines in cognition and functioning in 423 cognitively healthy community-dwelling older women in the Women's Health and Aging Study (WHAS II). We hypothesized that higher serum uric acid would be associated with poorer concurrent functioning and greater declines over 9 years. In linear regression analyses, higher baseline serum uric acid was associated with poorer working memory, with a trend toward slower manual speed and dexterity before and after adjusting for baseline serum uric acid, demographic and health/cardiovascular variables. However, there were no associations for global cognitive functioning, learning/memory, sequencing, verbal fluency, or visuoconstruction. Mixed effects models also revealed no association with subsequent cognitive declines. Future research should examine changes in serum uric acid at earlier periods in the lifespan and their relationships with later cognitive declines. PMID- 25446979 TI - Long-term streptozotocin diabetes impairs arachidonic and docosahexaenoic acid metabolism and ?5 desaturation indices in aged rats. AB - We have investigated the long term effects of insulin dependent diabetes mellitus (IDDM) on the fatty acid profile of tissues in aging rats. For this purpose, a rat model for IDDM was established by streptozotocin application. The rats were randomly divided into four groups of 8 animals each: CON 6 (control group sacrificed after 6 months of the experiment), CON 12 (control group sacrificed after 12 months of the experiment), DM 6 (streptozotocin treated and sacrificed after 6 months of diabetes) and DM 12 (streptozotocin treated and sacrificed after 12 months of diabetes). The periods of 6 and 12 months were taken to observe the changes in lipid metabolism for chronic, long-term diabetes. Fatty acid profiles of the liver and skeletal muscle total lipids and phospholipids as well as desaturation indices for ?6 desaturase (D6D), ?5 desaturase (?6D), ?9 desaturase (?9D) and de novo lipogenesis index (DNL) were estimated. Additionally the long-term effects (12 months) were tested in the brain, perirenal fat and bone marrow. The fatty acid composition of lipids was altered in IDDM rats in all tested tissues. The desaturation indices revealed the expected significant decrease in ?9D and ?5D indices in tested tissues, while indices for ?6D were not influenced by diabetes. DNL revealed the strong inhibition of de novo lipogenesis in the liver tissue. Values for arachidonic C20:4n6 (arachidonic acid) significantly decreased in liver total lipids in DM 6 and DM 12 groups and in phospholipids in the DM 12 group. Surprisingly, values for C20:4n6 were also significantly lower in the brain tissue in the DM 12 group. Accumulation of C20:4n6 precursors (C18:2n6 and C20:3n6) was visible in all tissues. Docosahexaenoic acid (C22:6n3) significantly decreased in liver total lipids, liver phospholipids and in the brain phospholipids of the DM 12 group. The present results show that age could exacerbate the expected decrease in the liver synthesis of C20:4n6 in IDDM. Moreover, long-term diabetes could impair C22:6n3 synthesis in the liver and muscle, and incorporation of both important fatty acids into brain phospholipids. In conclusion, numerous changes in fatty acid composition are caused by long-term diabetes in aged rats. These changes could be involved in the pathogenesis of senile and diabetes-induced damage. The results could have clinical significance due to the increasing age of diabetic patients. PMID- 25446980 TI - Melatonin maintains calcium-binding calretinin-positive neurons in the dentate gyrus during aging of Balb/C mice. AB - Melatonin, the main product synthesized by the pineal gland, modulates several brain functions through different mechanisms, some of them involving the activation or participation of calcium binding intracellular proteins, such as the alpha calcium dependent protein kinase C and calmodulin. Another calcium binding protein is calretinin, which exerts an essential role for adult hippocampal neurogenesis. Melatonin favors calretinin-positive neurons in the dentate gyrus (DG) of young mice but hippocampal neurogenesis and plasma levels of melatonin decrease during aging. Thus, in this study, we analyzed the impact of exogenous supplementation with melatonin in calretinin-neurons and their distribution along the dorsal-ventral DG in the hippocampus at three different time points (1, 3, or 6 months) after daily treatment with melatonin (8 mg/kg) in male Balb/C mice. We found an increase in the number of calretinin-positive neurons in the DG after treatment (>66%). Although a significant decline in the number of calretinin-neurons was found in both treated (~60.46-69.56%) and untreated mice (~68.81-70.34%) with respect to the youngest mice analyzed, melatonin still maintained higher number of cells in the DG. Also, the distribution of calretinin-neurons along the dorsal-ventral DG significantly showed more cells in the ventral-DG of mice treated with melatonin. Together, the data suggest that melatonin also acts on calretinin in the DG, supporting it as a molecule connecting calcium signaling and neuronal development. PMID- 25446981 TI - Males do not senesce faster in large herbivores with highly seasonal rut. AB - Patterns of actuarial senescence vary among long-lived species. A proposed explanation of the evolution of species-specific senescence patterns is that increased levels of energy allocation to intra-male competition decrease the amount of energy available for somatic maintenance, leading to earlier or faster actuarial senescence. Previous studies did not provide support for such relationships, but did not focus on the intensity of allocation likely to shape inter-specific variation in actuarial senescence in males. Here, by analyzing data from 56 species of captive large herbivores, we tested whether actuarial senescence is more pronounced in species displaying a well-defined 'rut' period than in species with year-round reproduction. Using an original quantitative metric of the annual duration of reproductive activity, we demonstrated that the length of the mating season has no detectable effect on actuarial senescence. On the other hand, both diet and body mass are important factors shaping actuarial senescence patterns in male captive herbivores. PMID- 25446982 TI - Thermogenesis and longevity in mammals. Thyroxin model of accelerated aging. AB - Development of experimental models of life span regulation is an important goal of modern gerontology. We proposed a thyroxin model of accelerated aging. Male Wistar rats at the age of 17 months received thyroxin in drinking water at a concentration of 6 mg/L for 2 months as a model of induced hyperthyroidism (IH). Administration of thyroxin resulted in a decrease in life span and a 2 degrees C increase in body temperature that was accompanied by a 2 fold increase in thyroxin level and a 40% increase in triiodothyronine in blood serum. Induced hyperthyroidism can be used as a model of accelerated aging. We also found that thyroxin administration acts as uncoupler of oxidative phosphorylation as treatment was accompanied by an increase in the generation of superoxide radicals by 50%. Antioxidant enzyme activity remained unchanged (glutathione peroxidase, glutathione reductase mitochondrial) or was reduced (glutathione-S-transferase by 1.7 times) as compared with the control. The activity of glucose-6-transferase was increased by 2.8 times as compared with control, and malate dehydrogenase activity in liver increased by 6.8 times. Induced hyperthyroidism in rats resulted in distinct epigenotype which was accompanied by a decrease in life span. PMID- 25446983 TI - Effects of age and caloric restriction on the cardiac and coronary response to endothelin-1 in rats. AB - BACKGROUND AND AIMS: Aging is associated with alterations in the cardiovascular system such as increased vasoconstriction and decreased vasodilatation. Some of these changes are partially reversed by caloric restriction. Endothelin-1 is a potent vasoconstrictor which levels increased with age. The aim of this study is to analyze the role of endothelin-1 in the cardiac and coronary changes induced by age and whether these changes may be attenuated by a three-month caloric restriction. METHODS AND RESULTS: Hearts from young (3 months old), aged (24 months old) and aged rats after 3 months of caloric restriction were perfused according to the Langendorff technique. Coronary vasoconstriction to endothelin-1 was reduced in old rats, and endothelin-1 increased myocardial contractility (dP/dt) and heart rate in old but not in young rats. These changes observed in old rats were partly reversed by caloric restriction. Also, in the myocardial tissue of old rats the gene expression of endothelin-1, inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-a) was increased, and the gene expression of endothelin ETB receptors and endothelial nitric oxide syntase (eNOS) was reduced, compared with young rats. Aging induced changes in the expression of ETB receptors and eNOS were reversed by caloric restriction. CONCLUSIONS: These results suggest that aging produces alterations in myocardial and coronary responses to endothelin-1, that may be related to changes in expression of nitric oxide synthases and/or endothelin receptor subtypes, with some of these changes being prevented by caloric restriction. PMID- 25446985 TI - Vector competence of Aedes aegypti mosquitoes for filarial nematodes is affected by age and nutrient limitation. AB - Mosquitoes are one of the most important vectors of human disease. The ability of mosquitoes to transmit disease is dependent on the age structure of the population, as mosquitoes must survive long enough for the parasites to complete their development and infect another human. Age could have additional effects due to mortality rates and vector competence changing as mosquitoes senesce, but these are comparatively poorly understood. We have investigated these factors using the mosquito Aedes aegypti and the filarial nematode Brugia malayi. Rather than observing any effects of immune senescence, we found that older mosquitoes were more resistant, but this only occurred if they had previously been maintained on a nutrient-poor diet of fructose. Constant blood feeding reversed this decline in vector competence, meaning that the number of parasites remained relatively unchanged as mosquitoes aged. Old females that had been maintained on fructose also experienced a sharp spike in mortality after an infected blood meal ("refeeding syndrome") and few survived long enough for the parasite to develop. Again, this effect was prevented by frequent blood meals. Our results indicate that old mosquitoes may be inefficient vectors due to low vector competence and high mortality, but that frequent blood meals can prevent these effects of age. PMID- 25446984 TI - Metals in plasma of nonagenarians and centenarians living in a key area of longevity. AB - The concentration of calcium (Ca), cobalt (Co), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn) and selenium (Se) in plasma of 76 nonagenarians (mean age, 89.0+/-6.3 years), 64 centenarians (mean age, 101+/-1 years) and 24 middle-aged subjects as controls (mean age 61.2+/-1.1 years), was determined by sector field inductively coupled plasma mass spectrometry. All the subjects lived in Sardinia, an Italian island, that has the higher prevalence of centenarians than in other European countries. A comparison among the three classes of age showed a significant depletion of Ca, Co, Fe, Mn and Se (all p<0.001) in nonagenarians and centenarians with respect to controls. In particular, the geometric mean (GM) values of Ca, Co, Fe, Mn and Se were: 94.1 MUg/ml, 0.46 ng/ml, 1314 ng/ml, 2.47 ng/ml and 111 ng/ml in controls; 87.6 MUg/ml, 0.22 ng/ml, 815 ng/ml, 1.07 ng/ml and 88.9 ng/ml in nonagenarians; 87.0 MUg/ml, 0.29 ng/ml, 713 ng/ml, 1.27 ng/ml and 81.9 ng/ml in centenarians. The highest inverse relationship with age was observed for Fe (p<0.001; rho=-0.352) and Se (p<0.001; rho=-0.417). This trend was also observed when data were sorted by gender. On the other hand, Cu and Mg levels in plasma remained substantially unchanged during aging. As regards Cu, it was significantly higher in females than in males in controls (GM, 1294 ng/ml vs. 1077 ng/ml; p=0.012), in nonagenarians (GM, 1216 ng/ml vs. 1081 ng/ml; p=0.011) as well as in centenarians (GM, 1226 ng/ml vs. 1152 ng/ml; p=0.045) and in hypertensive subjects with respect to healthy people (GM, 1215 ng/ml vs. 1129 ng/ml; p=0.021). These data can be used to enhance knowledge and support the research on: i) metals involved in aging in areas with high rates of human longevity; ii) variables (gender, lifestyle habits and health status) as critical determinants in aging; and iii) mineral intake and supplementation at older age affecting the healthy aging. PMID- 25446986 TI - Emerging potential of therapeutic targeting of autophagy and protein quality control in the management of cardiometabolic diseases. PMID- 25446987 TI - MALAT1 promotes colorectal cancer cell proliferation/migration/invasion via PRKA kinase anchor protein 9. AB - Our previous studies have shown that the 3' end of metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is involved in colorectal cancer (CRC) cell proliferation and migration/invasion in vitro. The role and mechanism of MALAT1 in CRC metastasis in vivo, however, remain largely unknown. In the present study, we found that MALAT1 was up-regulated in human primary CRC tissues with lymph node metastasis. Overexpression of MALAT1 via RNA activation promoted CRC cell proliferation, invasion and migration in vitro, and stimulated tumor growth and metastasis in mice in vivo. Conversely, knockdown of MALAT1 inhibited CRC tumor growth and metastasis. MALAT1 regulated at least 243 genes in CRC cells in a genome-wide expression profiling. Among these genes, PRKA kinase anchor protein 9 (AKAP-9) was significantly up-regulated at both mRNA and protein levels. AKAP-9 was highly expressed in CRC cells with metastatic potential and human primary CRC tissues with lymph node metastasis, but not in normal cells or tissues. Importantly, knockdown of AKAP-9 blocked MALAT1-mediated CRC cell proliferation, migration and invasion. These data indicate that MALAT1 may promote CRC tumor development via its target protein AKAP-9. PMID- 25446988 TI - Resveratrol and obesity: Can resveratrol relieve metabolic disturbances? AB - There is an increasing need for novel preventive and therapeutic strategies to combat obesity and related metabolic disorders. In this respect, the natural polyphenol resveratrol has attracted significant interest. Animal studies indicate that resveratrol mimics the effects of calorie restriction via activation of sirtuin 1 (SIRT1). SIRT1 is an important player in the regulation of cellular energy homeostasis and mitochondrial biogenesis. Rodent studies have shown beneficial effects of resveratrol supplementation on mitochondrial function, glucose metabolism, body composition and liver fat accumulation. However, confirmation of these beneficial effects in humans by placebo-controlled clinical trials remains relatively limited. This review will give an overview of pre-clinical and clinical studies examining the effects of resveratrol on obesity induced negative health outcomes. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes. PMID- 25446989 TI - Identification of thyrotropin-releasing hormone as hippocampal glutaminyl cyclase substrate in neurons and reactive astrocytes. AB - Recently, Abeta peptide variants with an N-terminal truncation and pyroglutamate modification were identified and shown to be highly neurotoxic and prone to aggregation. This modification of Abeta is catalyzed by glutaminyl cyclase (QC) and pharmacological inhibition of QC diminishes Abeta deposition and accompanying gliosis and ameliorates memory impairment in transgenic mouse models of Alzheimer's disease (AD). QC expression was initially described in the hypothalamus, where thyrotropin-releasing hormone (TRH) is one of its physiological substrates. In addition to its hormonal role, a novel neuroprotective function of TRH following excitotoxicity and Abeta-mediated neurotoxicity has been reported in the hippocampus. Functionally matching this finding, we recently demonstrated QC expression by hippocampal interneurons in mouse brain. Here, we detected neuronal co-expression of QC and TRH in the hippocampus of young adult wild type mice using double immunofluorescence labeling. This provides evidence for TRH being a physiological QC substrate in hippocampus. Additionally, in neocortex of aged but not of young mice transgenic for amyloid precursor protein an increase of QC mRNA levels was found compared to wild type littermates. This phenomenon was not observed in hippocampus, which is later affected by Abeta pathology. However, in hippocampus of transgenic - but not of wild type mice - a correlation between QC and TRH mRNA levels was revealed. This co-regulation of the enzyme QC and its substrate TRH was reflected by a co-induction of both proteins in reactive astrocytes in proximity of Abeta deposits. Also, in primary mouse astrocytes a co-induction of QC and TRH was demonstrated upon Abeta stimulation. PMID- 25446990 TI - Resveratrol and cancer: Challenges for clinical translation. AB - Significant work has been done towards identifying the health-beneficial effects of the grape antioxidant resveratrol in a variety of bioassay- and disease- models, with much research being focused on its possible application to cancer management. Despite the large number of preclinical studies dealing with different aspects of the biological effects of resveratrol, its translation to clinics is far from reality due to a variety of challenges. In this review, we discuss the issues and questions associated with resveratrol becoming an effective in vivo anticancer drug, from basic metabolic issues to the problems faced by incomplete understanding of the mechanism(s) of action in the body. We also explore efforts taken by researchers, both public and private, to contend with some of these issues. By examining the published data and previous clinical trials, we have attempted to identify the problems and issues that hinder the clinical translation of resveratrol for cancer management. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes. PMID- 25446992 TI - Protein phosphatase-1 is involved in the maintenance of normal homeostasis and in UVA irradiation-induced pathological alterations in HaCaT cells and in mouse skin. AB - The number of ultraviolet (UV) radiation-induced skin diseases such as melanomas is on the rise. The altered behavior of keratinocytes is often coupled with signaling events in which Ser/Thr specific protein kinases and phosphatases regulate various cellular functions. In the present study the role of protein phosphatase-1 (PP1) was investigated in the response of human keratinocyte (HaCaT) cells and mouse skin to UV radiation. PP1 catalytic subunit (PP1c) isoforms, PP1calpha/gamma and PP1cdelta, are all localized to the cytoskeleton and cytosol of keratinocytes, but PP1cdelta was found to be dominant over PP1alpha/gamma in the nucleus. PP1c-silencing in HaCaT cells decreased the phosphatase activity and suppressed the viability of the cells. Exposure to a 10 J/cm(2) UVA dose induced HaCaT cell death and resulted in a 30% decrease of phosphatase activity. PP1c-silencing and UVA irradiation altered the gene expression profile of HaCaT cells and suggested that the expression of 19 genes was regulated by the combined treatments with many of these genes being involved in malignant transformation. Microarray analysis detected altered expression levels of genes coding for melanoma-associated proteins such as keratin 1/10, calcium binding protein S100A8 and histone 1b. Treatment of Balb/c mice with the PP1-specific inhibitor tautomycin (TM) exhibited increased levels of keratin 1/10 and S100A8, and a decreased level of histone 1b proteins following UVA irradiation. Moreover, TM treatment increased pigmentation of the skin which was even more apparent when TM was followed by UVA irradiation. Our data identify PP1 as a regulator of the normal homeostasis of keratinocytes and the UV-response. PMID- 25446991 TI - Threonine 56 phosphorylation of Bcl-2 is required for LRRK2 G2019S-induced mitochondrial depolarization and autophagy. AB - The G2019S leucine-rich repeat kinase 2 (LRRK2) mutation is the most common cause of genetic Parkinson's disease (PD). However, the molecular mechanism underlying LRRK2 G2019S-induced cellular pathology is poorly understood. Here, we demonstrated that LRRK2 G2019S bound to and phosphorylated Bcl-2, a mitochondrial anti-apoptotic protein, at Threonine 56. Either stable expression of Bcl-2 or transient expression of a Bcl-2 phosphor mutant (Bcl-2(T56A)) abolished LRRK2 G2019S-induced mitochondrial depolarization and autophagy. Together, our findings reveal a previously unidentified target of LRRK2 G2019S, showing that Bcl-2 serves as a point of crosstalk between LRRK2 G2019S-mediated mitochondrial disorder and dysregulation of autophagy. PMID- 25446993 TI - Novel curcumin analog C66 prevents diabetic nephropathy via JNK pathway with the involvement of p300/CBP-mediated histone acetylation. AB - Glomerulosclerosis and interstitial fibrosis represent the key events in development of diabetic nephropathy (DN), with connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1) and fibronectin 1 (FN-1) playing important roles in these pathogenic processes. To investigate whether the plant metabolite curcumin, which exerts epigenetic modulatory properties when applied as a pharmacological agent, may prevent DN via inhibition of the JNK pathway and epigenetic histone acetylation, diabetic and age-matched non-diabetic control mice were administered a 3-month course of curcumin analogue (C66), c-Jun N-terminal kinase inhibitor (JNKi, sp600125), or vehicle alone. At treatment end, half of the mice were sacrificed for analysis and the other half were maintained without treatment for an additional 3 months. Renal JNK phosphorylation was found to be significantly increased in the vehicle-treated diabetic mice, but not the C66- and JNKi-treated diabetic mice, at both the 3-month and 6-month time points. C66 and JNKi treatment also significantly prevented diabetes-induced renal fibrosis and dysfunction. Diabetes-related increases in histone acetylation, histone acetyl transferases' (HATs) activity, and the p300/CBP HAT expression were also significantly attenuated by C66 or JNKi treatment. Chromatin immunoprecipitation assays showed that C66 and JNKi treatments decreased H3 lysine9/14-acetylation (H3K9/14Ac) level and p300/CBP occupancy at the CTGF, PAI 1 and FN-1 gene promoters. Thus, C66 may significantly and persistently prevent renal injury and dysfunction in diabetic mice via down-regulation of diabetes related JNK activation and consequent suppression of the diabetes-related increases in HAT activity, p300/CBP expression, and histone acetylation. PMID- 25446996 TI - Curcumin ameliorates testicular damage in diabetic rats by suppressing cellular stress-mediated mitochondria and endoplasmic reticulum-dependent apoptotic death. AB - In the present study, we sought to explore whether curcumin plays any beneficial role against STZ induced testicular abnormalities in diabetic rats, and if so, what possible mechanism it utilizes to provide protection. Exposure to STZ (50mg/kg body weight, i.p., once) reduced testis-to-body weight ratio, enhanced blood glucose level and intracellular ROS, altered testicular markers, diminished serum testosterone and impaired cellular redox balance. Administration of curcumin at a dose of 100mg/kg body weight for 8 weeks effectively normalized all the alterations. Curcumin also showed inhibitory effect on the elevation of pro inflammatory cytokines and translocation of NFkappaB into the nucleus and promoted the activation of the transcription factor Nrf-2 to provide protection against oxidants. To protect cells from STZ-induced stress-mediated damage, curcumin acted on the key mediators of the apoptotic cell death such as JNK and p38. In addition, this active molecule upregulated Bcl-2 expression, blocked the expression of pro-apoptotic proteins (Bax, Bad and Bid), decreased intracellular Ca(2+) level, inhibited active caspase cascade and attenuated PARP cleavage. These results suggest that curcumin provides protection against cellular stress mediated mitochondrial and endoplasmic reticulum-dependent apoptotic death of the testicular cells under diabetic condition and suggests the possibility of using this molecule as a potential therapeutic in the treatment of stress-mediated diabetic testicular dysfunction. PMID- 25446995 TI - Reductive potential - a savior turns stressor in protein aggregation cardiomyopathy. AB - Redox homeostasis is essential for basal signaling of several physiological processes, but a unilateral shift towards an 'oxidative' or 'reductive' trait will alter intracellular redox milieu. Typically, such an event influences the structure and the native function of a cell or an organelle. Numerous experimental research and clinical trials over the last 6 decades have demonstrated that enhanced oxygen-derived free radicals constitute a major stimulus to trigger damage in several human diseases, including cardiovascular complications supporting the theory of oxidative stress (OS). However, until our key discovery, the dynamic interrelationship between "Reductive Stress (RS)" and cardiac health has been obscured by overwhelming OS studies (Rajasekaran et al., 2007). Notably, this seminal finding spurred considerable interest in investigations of other mechanistic insights, and thus far the results indicate a similar or stronger role for RS, as that of OS. In addition, from our own findings we strongly believe that constitutive activation of pathways that enable sustained generation of reducing equivalents of glutathione (GSH), reduced nicotinamide adenine dinucleotide phosphate (NADPH) will cause RS and impair the basal cellular signaling mechanisms operating through harmless pro-oxidative events, in turn, disrupting single and/or a combination of key cellular processes such as growth, maturation, differentiation, survival, death etc., that govern healthy cell physiology. Here, we have discussed the role of RS as a causal or contributing factor in relevant pathophysiology of a major cardiac disease of human origin. PMID- 25446997 TI - Total bile acids in the maternal and fetal compartment in relation to placental ABCG2 expression in preeclamptic pregnancies complicated by HELLP syndrome. AB - OBJECTIVE: To investigate total bile acid (TBA) levels in maternal (MB) and umbilical cord blood (UCB) in normotensive, preeclamptic (PE), and PE pregnancies complicated by hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in the context of ABCG2 placental gene expression levels, a recently reported placental bile acid transporter. METHODS: TBA levels were determined in 83 paired MB and UCB samples of normotensive, PE and PE/HELLP pregnancies and in 22 paired arterial and venous UCB samples from uncomplicated term pregnancies. ABCG2 gene expression was measured in 104 human placentas by reverse transcriptase quantitative polymerase chain reaction. RESULTS: Overall, TBA levels in MB are higher compared to levels in UCB (p<0.0001), but this comparison looses statistical significance for the 11 PE/HELLP cases. TBA levels in maternal blood are increased in PE/HELLP compared to PE pregnancies (p=0.016). TBA levels in arterial and venous UCB from 22 normotensive pregnancies are not statistically different. ABCG2 expression is reduced in pregnancies where preeclampsia is further complicated by HELLP syndrome. ABCG2 expression in human placenta is not correlated with TBA levels in either the maternal or fetal compartment. CONCLUSION: Increased maternal TBA levels in PE/HELLP pregnancies indicate a relation between bile acids in the maternal circulation and HELLP syndrome. As overall TBA levels in maternal blood are increased compared to UCB, we conclude that the placenta partly protects the fetus from increased maternal TBA levels. This consistent difference in TBA levels between the maternal and fetal compartment is unrelated to the placental expression of ABCG2. PMID- 25446994 TI - Sarcomeric protein isoform transitions in cardiac muscle: a journey to heart failure. AB - Sarcomeric protein isoforms are mainly governed by alternative promoter-driven expression, distinct gene expression, gene mutation and alternative mRNA splicing. The transitions of sarcomeric proteins have been implicated to play a role in the onset and development of human heart failure. In this mini-review, we summarized isoform transitions of several most widely examined sarcomeric proteins including myosin, actin, troponin, tropomyosin, titin and myosin binding protein-C, and the consequence of these abnormal isoform transitions. Even though the isoform transitions of sarcomeric proteins have been described in individual sarcomeric protein reviews, no concise summary of these results has been presented previously. This review is intended to fill this gap and discuss possible future perspectives. PMID- 25446999 TI - Biomechanical analysis of flexor tendon repair using knotted Kessler and Bunnell techniques and the knotless Bunnell technique. AB - PURPOSE: To evaluate a knotless Bunnell suture in flexor tendon repair. METHODS: Eighty porcine flexor digitorum tendons were assigned to 4 different suture techniques. Group 1 was repaired using a modified 4-strand knotted Kessler suture and served as a control group. Group 2 was repaired using a 4-strand knotted Bunnell suture. Group 3 used a 4-strand knotless Bunnell suture. Group 4 used a 4 strand knotless Bunnell and knotless peripheral suture. Under static and cyclic testing we studied mode of failure, 2-mm gap formation force, displacement, and maximum load. RESULTS: The 4-strand knotless Bunnell suture did not show a notable difference with regard to 2-mm gap formation force, displacement, or maximum load in comparison to the modified 4-strand knotted Kessler suture. Adding a knotless peripheral suture improved the repair by a significant reduction of gap formation and displacement and an increase in maximum load. The 4-strand knotted Bunnell showed the highest maximum load but also a considerable lower resistance to gap formation and major displacement. CONCLUSIONS: Flexor tendon repair using a 4-strand knotless Bunnell suture showed similar tensile strength to a modified 4-strand knotted Kessler suture. Adding a knotless peripheral suture further improved the repair. CLINICAL RELEVANCE: A complete knotless 4-strand Bunnell suture including a barbed core- and peripheral suture might be an option for flexor tendon reconstruction. PMID- 25446998 TI - Displaced intra-articular fractures involving the volar rim of the distal radius. AB - PURPOSE: To describe the features of displaced intra-articular fractures confined to the volar rim of the distal radius and compare outcomes after their operative fixation to complete intra-articular and extra-articular fractures treated with operative fixation. METHODS: A total of 627 distal radius fractures were treated over a 6-year period. Twenty-eight patients had volar rim fractures (type 23-B3, as classified by the Orthopaedic Trauma Association [OTA]), all treated with operative reduction and fixation using a volar buttress plate. Clinical outcome information including radiographs, Short Form-36 health survey, and Disabilities of the Arm, Shoulder, and Hand questionnaire were collected at regular postoperative intervals. Patients with volar rim fractures were compared with patients who sustained other types of operatively managed distal radius fractures (OTA types 23-A, 23-B1/B2, and 23-C). RESULTS: The most common type of volar rim fracture consisted of a single large fragment (OTA 23-B3.2; 46%), followed by comminuted fractures (OTA 23-B3.3; 36%). Restoration of radiographic parameters was similar between groups except for an increased volar tilt in volar rim fractures compared with group 23-B1/B2. Active wrist and finger motion improved in all groups except for wrist extension, which was less in the 23-B1/B2 groups. The 23-B1/B2 group had the greatest pain and worst Short Form-36 scores. Disabilities of the Arm, Shoulder, and Hand questionnaire scores were similar and without differences between groups. CONCLUSIONS: Our data suggest that patients with volar rim distal radius fractures can expect a rapid return to function with minimal risk for complications and have outcomes similar to other types of operatively treated distal radius fractures. Further investigation of type 23-B fractures (23-B1/B2) is warranted owing to evidence of diminished outcomes. PMID- 25447000 TI - The quality of control groups in nonrandomized studies published in the Journal of Hand Surgery. AB - PURPOSE: To evaluate control group selection in nonrandomized studies published in the Journal of Hand Surgery American (JHS). METHODS: We reviewed all papers published in JHS in 2013 to identify studies that used nonrandomized control groups. Data collected included type of study design and control group characteristics. We then appraised studies to determine whether authors discussed confounding and selection bias and how they controlled for confounding. RESULTS: Thirty-seven nonrandomized studies were published in JHS in 2013. The source of control was either the same institution as the study group, a different institution, a database, or not provided in the manuscript. Twenty-nine (78%) studies statistically compared key characteristics between control and study group. Confounding was controlled with matching, exclusion criteria, or regression analysis. Twenty-two (59%) papers explicitly discussed the threat of confounding and 18 (49%) identified sources of selection bias. CONCLUSIONS: In our review of nonrandomized studies published in JHS, papers had well-defined controls that were similar to the study group, allowing for reasonable comparisons. However, we identified substantial confounding and bias that were not addressed as explicit limitations, which might lead the reader to overestimate the scientific validity of the data. CLINICAL RELEVANCE: Incorporating a brief discussion of control group selection in scientific manuscripts should help readers interpret the study more appropriately. Authors, reviewers, and editors should strive to address this component of clinical importance. PMID- 25447001 TI - The effect of lunate morphology on the 3-dimensional kinematics of the carpus. AB - PURPOSE: To assess carpal kinematics in various ranges of motion in 3 dimensions with respect to lunate morphology. METHODS: Eight cadaveric wrists (4 type I lunates, 4 type II lunates) were mounted into a customized platform that allowed controlled motion with 6 degrees of freedom. The wrists were moved through flexion-extension (15 degrees -15 degrees ) and radioulnar deviation (RUD; 20 degrees -20 degrees ). The relative motion of the radius, carpus, and third metacarpal were recorded using optical motion capture methods. RESULTS: Clear patterns of carpal motion were identified. Significantly greater motion occurred at the radiocarpal joint during flexion-extension of type I wrist than a type II wrist. The relative contributions of the midcarpal and radiocarpal articulations to movement of the wrist differed between the radial, the central, and the ulnar columns. During wrist flexion and extension, these contributions were determined by the lunate morphology, whereas during RUD, they were determined by the direction of wrist motion. The midcarpal articulations were relatively restricted during flexion and extension of a type II wrist. However, during RUD, the midcarpal joint of the central column became the dominant articulation. CONCLUSIONS: This study describes the effect of lunate morphology on 3 dimensional carpal kinematics during wrist flexion and extension. Despite the limited size of the motion arcs tested, the results represent an advance on the current understanding of this topic. CLINICAL RELEVANCE: Differences in carpal kinematics may explain the effect of lunate morphology on pathological changes within the carpus. Differences in carpal kinematics due to lunate morphology may have implications for the management of certain wrist conditions. PMID- 25447002 TI - Risk factors for complications following open reduction internal fixation of distal radius fractures. AB - PURPOSE: A national surgical database was used to determine risk factors for complications in patients undergoing open reduction internal fixation (ORIF) for distal radius fractures. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database for the 2006-2012 years was queried to identify all patients who underwent an ORIF of a distal radius fracture based on Current Procedural Terminology codes 25607, 25608, or 25609. The database is a statistically representative sample of prospectively collected perioperative surgical data from hospitals primarily in the United States. Demographics, comorbidities, preoperative laboratory values, and 30-day complications were compared between the patient groups with and without a postoperative complication. Multivariate analysis was performed to identify patient characteristics and comorbidities that were independently associated with early postoperative complications. RESULTS: This retrospective analysis identified 3,003 patients who underwent an ORIF of the distal radius over 7 years. The number of patients with a complication within 30 days after surgery was 62 (2%), totaling 90 complications. Incidence of return to the operative room for the entire study population was 1.1%. Multivariate analysis, adjusting for confounding variables, showed that patients with a complication were more likely to have hypertension, congestive heart failure, preoperative chemotherapy or radiotherapy, longer operating time, and manifest preoperative impairment in independent living. CONCLUSIONS: Approximately 2% of patients sustained a complication within 30 days following ORIF of a distal radius fracture. Recognition of the risk factors may help avoid complications in the identified high-risk patients. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 25447003 TI - Risk factors for 30-day postoperative complications and mortality following open reduction internal fixation of distal radius fractures. AB - PURPOSE: To identify the incidence and risk factors for 30-day postoperative morbidity and mortality following operative treatment of distal radius fractures in a multicenter cohort. METHODS: We retrospectively queried the American College of Surgeons National Surgical Quality Improvement Program database for the years 2005-2011 for cases of closed distal radius fractures treated operatively with internal fixation. Patient demographics, comorbidities, and operative characteristics were analyzed. Thirty-day postoperative complications were identified and separated into categories of major morbidity or mortality, minor morbidity, and any complication. Risk factors were identified using univariate and multivariate analyses. RESULTS: We identified 1,673 cases of closed distal radius fractures managed with internal fixation. The overall incidence of having any early complication was 3%. Major morbidity was 2.1%, which included 4 patient deaths, and minor morbidity was 1%. The most common major morbidity was a return to the operating room (16 patients). The most common minor morbidity was urinary tract infection (6 patients). The multivariate analysis demonstrated ASA class III or IV, dependent functional status, hypertension, and myocardial infarction/congestive heart failure to be significant risk factors for any early complication. There was a 10.0% complication rate in the inpatient group and a 1.3% complication rate in the outpatient group. CONCLUSIONS: The incidence of early complications following internal fixation for closed distal radius fractures was low, especially in the outpatient group. In the setting of an isolated injury to the distal radius, the data presented here can provide prognostic information for patients during informed consent for what is considered to be an elective procedure. Surgeons should consider risk of morbidity and mortality when considering surgery for patients with noteworthy cardiopulmonary disease, increased ASA class, or poor functional status. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 25447004 TI - Double tension band wiring for treatment of olecranon fractures. AB - PURPOSE: Although tension band wiring (TBW) is generally accepted as standard treatment for olecranon fractures, it has several shortcomings such as loss of reduction, skin irritation, and migration of the K-wires. To overcome these problems and increase fixation stability, we used a rigid fixation technique with double tension band wiring (DTBW). Here, we describe the technique and outcomes of the treatment. METHODS: We retrospectively reviewed 21patients with olecranon fractures who were treated by DTBW. We evaluated clinical and radiological outcomes by checking the range of motion, loss of reduction, functional scoring, skin complications, and pin migration. There were 15 cases of Mayo type IIA fractures (71%) and 6 of type IIB fractures (29%). The mean follow-up period was 37 months (range, 12-58 mo). We also compared the mechanical stability of DTBW and TBW in a sawbone model using a single cycle load to failure protocol. RESULTS: All fractures united without displacement, and no migration of the K wires was observed during the period of follow-up. Mean loss of elbow extension was 2 degrees (range, 0 degrees -15 degrees ) and mean elbow flexion was 134 degrees (range, 125 degrees -140 degrees ). The mean Mayo Elbow Performance Score was 94 (range, 70-100). Biomechanical testing revealed greater mechanical strength in the DTBW technique than in the TBW when measured by mean maximum failure load and mean bending moment at failure. CONCLUSIONS: DTBW produced good clinical and radiological outcomes and could be an effective option for the treatment of olecranon fractures by providing additional stability through a second TBW. Biomechanical comparison with a control group (TBW) supported the mechanical benefits of DTBW. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25447005 TI - Endoscopic release for severe carpal tunnel syndrome in octogenarians. AB - PURPOSE: To investigate the clinical outcomes of endoscopic carpal tunnel release for severe carpal tunnel syndrome in octogenarians compared with a younger cohort. METHODS: Fifty-five hands in 48 patients were enrolled in this study. There were 27 hands in 24 octogenarians and 28 hands in 24 patients in a younger group with average ages of 83 and 60 years, respectively. Postoperative follow ups were 8.5 and 7.2 months, respectively. Clinical evaluation included documentation of subjective symptoms and Semmes-Weinstein testing before surgery, 3 months after surgery, and at final follow-up. Symptom severity and function outcomes scores and compound muscle action potential of abductor pollicis brevis as an electrophysiological assessment were evaluated before surgery and at the final follow-up. RESULTS: Nocturnal pain and paresthesias were improved in all patients. The octogenarians had poorer recovery of Semmes-Weinstein testing score and better improvement of outcomes scores than the younger group. There was no difference of the results in postoperative electrophysiological improvement between the groups. CONCLUSIONS: Endoscopic release for severe carpal tunnel syndrome relieved symptoms and improved activities of daily living in octogenarians. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 25447006 TI - Pronator-sparing technique for volar plating of distal radius fractures. AB - Acute distal radius fractures are commonly treated by volar locking plate fixation and typically involve reflection of the pronator quadratus for adequate exposure of the fracture. Recently, attention has been centered on the role and repair of the pronator quadratus. This article presents an alternative approach to fixation of distal radius fractures with a pronator-sparing technique that offers similar short-term radiographic outcomes to the conventional volar plating approach. PMID- 25447007 TI - Double tightrope for basilar thumb arthritis. AB - Several surgical options exist for the treatment of basilar thumb joint arthritis. Suspending the thumb metacarpal with a suture button device provides a stabilizing force to maintain pinch strength, precludes the necessary healing time associated with ligamentous reconstruction and allows for earlier motion and return to work, and creates a stable construct that may prevent metacarpal subsidence over time. One of the concerns with this technique is over-tightening of the suture device, which results with impingement of the thumb and index metacarpal bases. We present a surgical technique of open trapeziectomy, simultaneous application of 2 Mini TightRope button devices to provide additional stabilization that prevents impingement of the thumb and index finger metacarpal, with imbrication of the flexor carpi radialis and abductor pollicis longus tendons as reinforcement of the construct. PMID- 25447009 TI - Paternal modeling, household availability, and paternal intake as predictors of fruit, vegetable, and sweetened beverage consumption among African American children. AB - The current study examined how African American fathers' dietary practices were associated with their children's dietary consumption. The sample consisted of one hundred and two African American fathers, who had children between the ages of three and thirteen. The fathers provided self-reports of their consumption of fruits, vegetables, and sugar sweetened beverages; modeling of healthy eating; household availability of foods and beverages; and their children's previously mentioned consumption. Sweetened beverages are considered to be any beverage that contains added sweeteners, high-fructose corn syrup, and/or fruit juice concentrates. Paternal modeling and household availability of food and beverages were measured using subscales from the Comprehensive Feeding Practices Questionnaire (CFPQ). Three separate hierarchical regressions were performed to reveal that child fruit and vegetable consumption was only predicted by parental intake. Child sweetened beverage consumption, however, was predicted by paternal intake and household availability. Modeling did not significantly predict children's consumption of fruits, vegetables, or sweetened beverages. The findings suggest that paternal intake of fruits, vegetables, and sweetened beverages predicts child consumption of fruits, vegetables, and sweetened beverages. Family efforts should be made toward increasing father's consumption of healthy foods while decreasing the consumption and availability of sweetened beverages. PMID- 25447008 TI - A qualitative study of parents' perceptions and use of portion size strategies for preschool children's snacks. AB - OBJECTIVE: Increases in childhood obesity correspond with shifts in children's snacking behaviors and food portion sizes. This study examined parents' conceptualizations of portion size and the strategies they use to portion snacks in the context of preschool-aged children's snacking. METHODS: Semi-structured qualitative interviews were conducted with non-Hispanic white (W), African American (AA), and Hispanic (H) low-income parents (n = 60) of preschool-aged children living in Philadelphia and Boston. The interview examined parents' child snacking definitions, purposes, contexts, and frequency. Verbatim transcripts were analyzed using a grounded theory approach. Coding matrices compared responses by race/ethnicity, parent education, and household food security status. RESULTS: Parents' commonly referenced portion sizes when describing children's snacks with phrases like "something small." Snack portion sizes were guided by considerations including healthfulness, location, hunger, and timing. Six strategies for portioning snacks were presented including use of small containers, subdividing large portions, buying prepackaged snacks, use of hand measurement, measuring cups, scales, and letting children determine portion size. Differences in considerations and strategies were seen between race/ethnic groups and by household food security status. CONCLUSIONS: Low-income parents of preschool-aged children described a diverse set of considerations and strategies related to portion sizes of snack foods offered to their children. Future studies should examine how these considerations and strategies influence child dietary quality. PMID- 25447010 TI - Mechanisms of the portion size effect. What is known and where do we go from here? AB - Childhood obesity is a persistent problem worldwide, and of particular concern in the United States. Clarifying the role of the food environment in promoting overeating is an important step toward reducing the prevalence of obesity. One potential contributor to the obesity epidemic is the increased portion sizes of foods commonly served. Portion sizes of foods served both at home and away from home have dramatically increased over the past 40 years. Consistently, short-term studies have demonstrated that increasing portion size leads to increased food intake in adults and children, a phenomenon known as the portion size effect. However, the mechanisms underlying this effect are poorly understood. Understanding these mechanisms could assist in clarifying the relationship between portion size and weight status and help inform the development of effective obesity interventions. First, we review the role of visual cues, such as plate size, unit, and utensil size as a potential moderator of the portion size effect. In addition, we discuss meal microstructure components including bite size, rate, and frequency, as these may be altered in response to different portion sizes. We also review theories that implicate post-ingestive, flavor nutrient learning as a key moderator of the portion size effect. Furthermore, we present preliminary data from an ongoing study that is applying neuroimaging to better understand these mechanisms and identify modifiable child characteristics that could be targeted in obesity interventions. Our tentative findings suggest that individual differences in cognitive (e.g. loss of control eating) and neural responses to food cues may be critical in understanding the mechanisms of the portion size effect. To advance this research area, studies that integrate measures of individual subject-level differences with assessment of food-related characteristics are needed. PMID- 25447011 TI - Approach avoidance training in the eating domain: testing the effectiveness across three single session studies. AB - Dual-process models propose that impulsive behavior plays a key role in the development and maintenance of maladaptive eating patterns. Research outside the eating domain suggests that approach avoidance training, a paradigm which aims to modify automatic behavioral dispositions toward critical stimuli, is an effective tool to weaken unhealthy impulses. The present research tested the effectiveness of approach avoidance training in the eating domain. We conducted three single session studies with varying methodologies in a normal-weight female student population (total N = 258), in which one group was always trained to avoid pictures of unhealthy food and to approach pictures of healthy food or neutral objects. We found no conclusive evidence that approach avoidance training can change participants' implicit and explicit food preferences and eating behavior. We discuss the potential and the limitations of approach avoidance training in the eating domain and provide suggestions for future research avenues. PMID- 25447012 TI - Effects of norm referent salience on young people's dietary orientation. AB - We examined the effects of making salient different norm referents on young people's dietary orientation. Participants were exposed to a referent who was either of similar age to themselves or older before reporting their normative beliefs, attitudes and intentions concerning dietary behavior. As predicted, exposure to the older referent was associated with stronger perceptions that eating five portions of fruit and vegetables each day was normative. Compared to those exposed to the same-age referent, participants exposed to the older referent reported more positive attitudes towards eating "five-a-day" and stronger intentions to do so over the coming week. Referent salience was also associated with a behavioral outcome, with those participants exposed to the older referent more likely to take a piece of fruit upon completion of the study (OR: 4.97, 95% CI: 1.39-17.82). The implications of these findings for norms based interventions for changing dietary behavior are discussed. PMID- 25447013 TI - Blue lighting decreases the amount of food consumed in men, but not in women. AB - Previous research has demonstrated that colors of lighting can modulate participants' motivation to consume the food placed under the lighting. This study was designed to determine whether the colors of lighting can affect the amount of food consumed, in addition to sensory perception of the food. The influence of lighting color was also compared between men and women. One-hundred twelve participants (62 men and 50 women) were asked to consume a breakfast meal (omelets and mini-pancakes) under one of three different lighting colors: white, yellow, and blue. During the test, hedonic impression of the food's appearance, willingness to eat, overall flavor intensity and overall impression of the food, and meal size (i.e., the amount of food consumed) were measured. Blue lighting decreased the hedonic impression of the food's appearance, but not the willingness to eat, compared to yellow and white lighting conditions. The blue lighting significantly decreased the amount consumed in men, but not in women, compared to yellow and white lighting conditions. Overall flavor intensity and overall impression of the food were not significantly different among the three lighting colors. In conclusion, this study provides empirical evidence that the color of lighting can modulate the meal size. In particular, blue lighting can decrease the amount of food eaten in men without reducing their acceptability of the food. PMID- 25447014 TI - Awareness of social influence on food intake. An analysis of two experimental studies. AB - There is consistent evidence that the amount of food we consume can be influenced by the eating behaviour of other people. Some previous experimental studies reported that consumers are unaware of this influence on their behaviour. The present research tested whether people may be more aware of social influence on their eating than previously assumed. In two studies, participants (total n = 160) were exposed to information about the amount of snack food other people had been eating shortly before being served the same snack food and eating as much as they liked. After this, participants responded to questions regarding whether they thought their food intake had been socially influenced, and reported the reasons why they believed they had or had not been influenced. Of the 160 participants, 34% reported that they had been influenced, 10% were unsure and 56% reported they had not been influenced. Crucially, participants' reports of social influence appeared to be accurate; the food intake of participants reporting social influence was significantly affected by the amount of food other people had been eating, whereas the food intake of participants denying social influence was unaffected. Individuals may be more aware of the effect that social influence has on their eating behaviour than previously assumed. Further work is needed to identify the factors which determine whether people are susceptible to social influence on eating behaviour. PMID- 25447015 TI - Caught in a 'spiral'. Barriers to healthy eating and dietary health promotion needs from the perspective of unemployed young people and their service providers. AB - The number of young people in Europe who are not in education, employment or training (NEET) is increasing. Given that young people from disadvantaged backgrounds tend to have diets of poor nutritional quality, this exploratory study sought to understand barriers and facilitators to healthy eating and dietary health promotion needs of unemployed young people aged 16-20 years. Three focus group discussions were held with young people (n = 14). Six individual interviews and one paired interview with service providers (n = 7). Data were recorded, transcribed verbatim and thematically content analysed. Themes were then fitted to social cognitive theory (SCT). Despite understanding of the principles of healthy eating, a 'spiral' of interrelated social, economic and associated psychological problems was perceived to render food and health of little value and low priority for the young people. The story related by the young people and corroborated by the service providers was of a lack of personal and vicarious experience with food. The proliferation and proximity of fast food outlets and the high perceived cost of 'healthy' compared to 'junk' food rendered the young people low in self-efficacy and perceived control to make healthier food choices. Agency was instead expressed through consumption of junk food and drugs. Both the young people and service providers agreed that for dietary health promotion efforts to succeed, social problems needed to be addressed and agency encouraged through (individual and collective) active engagement of the young people themselves. PMID- 25447017 TI - A longitudinal investigation of overweight children's body perception and satisfaction during a weight management program. AB - BACKGROUND: The Children's Body Image Scale (CBIS) is a measure of body perception and satisfaction. Obesity has a negative impact on children's body satisfaction. This study aimed to (1) determine the construct validity of the CBIS in a purely overweight/obese sample, and (2) explore longitudinal changes in body perception and satisfaction in overweight/obese children participating in a six month weight management program delivered to parents. Data were self-reported by overweight/obese 5 to 9 year old children (n = 127) over a 36 month period. FINDINGS: The CBIS demonstrated good construct validity (Rho: range 0.38 to 0.71, p < 0.05). Accuracy in body size perception did not alter significantly over time (Rho: range 0.45 to 0.59, p < 0.001). No consistent differences in body satisfaction by age or sex were observed. Body satisfaction improved after the six month weight management intervention (mean difference = 0.74, 95% CI 0.15 1.26) which was maintained at 36 month follow up. CONCLUSION: The CBIS is a useful measure to monitor overweight/obese children's body satisfaction. In this cohort, it is suggestive that the child weight management program delivered to parents did not impact negatively on children's body satisfaction. PMID- 25447016 TI - Energy intake estimation from counts of chews and swallows. AB - Current, validated methods for dietary assessment rely on self-report, which tends to be inaccurate, time-consuming, and burdensome. The objective of this work was to demonstrate the suitability of estimating energy intake using individually-calibrated models based on Counts of Chews and Swallows (CCS models). In a laboratory setting, subjects consumed three identical meals (training meals) and a fourth meal with different content (validation meal). Energy intake was estimated by four different methods: weighed food records (gold standard), diet diaries, photographic food records, and CCS models. Counts of chews and swallows were measured using wearable sensors and video analysis. Results for the training meals demonstrated that CCS models presented the lowest reporting bias and a lower error as compared to diet diaries. For the validation meal, CCS models showed reporting errors that were not different from the diary or the photographic method. The increase in error for the validation meal may be attributed to differences in the physical properties of foods consumed during training and validation meals. However, this may be potentially compensated for by including correction factors into the models. This study suggests that estimation of energy intake from CCS may offer a promising alternative to overcome limitations of self-report. PMID- 25447018 TI - Eating and inflicting pain out of boredom. AB - In the present study it was investigated whether boredom promotes eating and if so, whether this effect likely reflects an increased drive for rewarding stimulation (positive reinforcement) or more plainly the drive to escape boredom (negative reinforcement). In the latter case, the valence of the stimulation should not matter and people might even be willing to look for negative stimulation, for instance to hurt oneself, just to escape boredom. In two parallel experiments, it was tested whether induced boredom promotes the consumption of chocolate (Experiment 1) and whether participants likewise are more inclined to self-administer electrocutaneous stimuli (Experiment 2). In both experiments, a total of 30 participants attended two separate sessions watching a documentary for 1 h (neutral condition) and a monotonous repetition of a single clip from the same documentary for 1 h (boring condition), in balanced order. During Experiment 1, participants had free access to M&Ms and during Experiment 2 participants could freely self-administer brief electrical shocks. It was found that participants ate more M&Ms when bored but also that they more readily self administered electrical shocks when bored. It is concluded that eating when bored is not driven by an increased desire for satisfying incentive stimulation, but mainly by the drive to escape monotony. PMID- 25447019 TI - It's always snack time: an investigation of event scripts in young children. AB - This study examined whether young children include eating in their cognitive scripts for various events, and whether food-related scripts are associated with body mass index (BMI) percentile. Data were collected in a structured interview format. Participants, recruited from area preschools and day cares, provided a four-activity sequence for each of three events, and responses were recorded verbatim. Forty-four children (45% female) participated, with an average BMI percentile of 73.3% (SD = 25.9). Data were binarily coded to indicate whether each response was food-related. Frequencies were obtained, and responses were correlated with BMI percentile. Over 22% of the activities in the children's scripts involved food. The number of food-related activities reported was positively correlated with children's BMI percentile (r = 0.53, p = 0.03). Results provide preliminary evidence that food features prominently in young children's event scripts and that children with higher BMI percentiles may possess scripts that feature more food-related themes. Future researchers should investigate the causal nature of this relationship. PMID- 25447020 TI - Does salt increase thirst? AB - Our diet is believed to be overly rich in sodium, and it is commonly believed that sodium intake increases drinking. Hence the concern of a possible contribution of dietary sodium to beverage intake which in turn may contribute to obesity and ill health. Here we examine whether voluntary, acute intake of a sodium load, as occurs in routine eating and snacking, increases thirst and drinking. We find that after ingesting 3.5 or 4.4 g NaCl (men) and 1.9 or 3.7 g (women) on nuts during 15 minutes, there is no increase in thirst or drinking of freely available water in the following 2 h compared with eating similar amounts of sugared or unflavored nuts. This suggests that routine ingestion of boluses of salt (~30-40% of daily intake for men, ~ 20-40% for women) does not increase drinking. Methodological concerns such as about nuts as vehicle for sodium suggest further research to establish the generalizability of this unexpected result. PMID- 25447021 TI - Development of the Mealtime Emotions Measure for adolescents (MEM-A): gender differences in emotional responses to family mealtimes and eating psychopathology. AB - This study aimed to examine the factor structure of the Mealtime Emotions Measure for adolescents (MEM-A), a novel measure of emotional responses experienced during family mealtimes. Additionally, it examined gender differences in mealtime emotions and also the relationships between mealtime emotions and levels of eating psychopathology, when controlling for anxiety or depression. Adolescent participants (N = 527; 282 girls, 245 boys) with a mean age of 15.9 years completed the new mealtime measure for adolescents (MEM-A), in addition to questions about family mealtime atmosphere, and measures assessing symptoms of anxiety, depression, and eating psychopathology. Factor analysis produced a three factor solution for the MEM-A with two subscales relating to different types of negative mealtime emotions (Anxiety-related mealtime emotions and Anger-related mealtime emotions) and one subscale relating to Positive mealtime emotions. Generally, girls reported experiencing more Anxiety-related mealtime emotions compared to boys. Having conducted separate analyses controlling for levels of either anxiety or depression, there were several significant associations for both girls and boys between mealtime emotions, particularly Anxiety-related emotions, and eating psychopathology. The findings suggest that some mealtime emotions are associated with increased eating psychopathology. Replication and detailed examination of these emotional responses is required. PMID- 25447022 TI - Associations between commercial complementary food consumption and fruit and vegetable intake in children. Results of the DONALD study. AB - OBJECTIVES: Fruit and vegetable (FV) consumption is influenced by individual taste and food preferences that are developed early in life. Thus, the sensory properties of foods given during complementary feeding may shape later food acceptance and dietary intake. However, those experiences differ with respect to the preparation method of complementary food (CF), that is, homemade and commercial CF. The aim of this study therefore was to examine the association between the infant's consumption of commercial CF and FV intake and variety during infancy, preschool and school age. METHODS: In total, 281 children of the DONALD Study with 3-day weighed dietary records at 0.5 and 0.75 (infancy), 3 and 4 (preschool age), 6 and 7 years of age (school age) were included in this analysis. Percentage of commercial CF (%cCF) was averaged at 0.5 and 0.75 years. Individual FV intake (g/day) and FV variety scores were calculated and averaged separately for all three age groups. Multivariate linear regression was used to analyse associations between %cCF and FV intake and variety. Models were adjusted for early life and socioeconomic factors. RESULTS: For boys, higher %cCF was associated with lower vegetable intake in infancy (p < 0.0001) and preschool age (p = 0.036) as well as lower total FV intake in preschool and school age (p < 0.009). For girls, higher %cCF was associated with lower vegetable intake (p < 0.0001) in infancy. FV variety scores showed no clear associations with %cCF in girls and boys. CONCLUSION: The results of the DONALD Study suggest that the preparation method of CF is associated with FV consumption in infancy and at least for boys also in preschool and school age. PMID- 25447023 TI - Stopping to food can reduce intake. Effects of stimulus-specificity and individual differences in dietary restraint. AB - Overeating in our food-rich environment is a key contributor to obesity. Computerised response-inhibition training could improve self-control in individuals who overeat. Evidence suggests that training people to inhibit motor responses to specific food pictures can reduce the subsequent choice and consumption of those foods. Here we undertook three experiments using the stop signal task to examine the effects of food and non-food related stop-training on immediate snack food consumption. The experiments examined whether training effects were stimulus-specific, whether they were influenced by the comparator (control) group, and whether they were moderated by individual differences in dietary restraint. Experiment 1 revealed lower intake of one food following stop- vs. double- (two key-presses) response training to food pictures. Experiment 2 offered two foods, one of which was not associated with stopping, to enable within- and between-subjects comparisons of intake. A second control condition required participants to ignore signals and respond with one key-press to all pictures. There was no overall effect of training on intake in Experiment 2, but there was a marginally significant moderation by dietary restraint: Restrained eaters ate significantly less signal-food following stop- relative to double response training. Experiment 3 revealed that stop- vs. double-response training to non-food pictures had no effect on food intake. Taken together with previous findings, these results suggest some stimulus-specific effects of stop-training on food intake that may be moderated by individual differences in dietary restraint. PMID- 25447024 TI - Energy compensation in the real world: good compensation for small portions of chocolate and biscuits over short time periods in complicit consumers using commercially available foods. AB - While investigations using covert food manipulations tend to suggest that individuals are poor at adjusting for previous energy intake, in the real world adults rarely consume foods of which they are ill-informed. This study investigated the impact in fully complicit consumers of consuming commercially available dark chocolate, milk chocolate, sweet biscuits and fruit bars on subsequent appetite. Using a repeated measures design, participants received four small portions (4 * 10-11 g) of either dark chocolate, milk chocolate, sweet biscuits, fruit bars or no food throughout five separate study days (counterbalanced in order), and test meal intake, hunger, liking and acceptability were measured. Participants consumed significantly less at lunch following dark chocolate, milk chocolate and sweet biscuits compared to no food (smallest t(19) = 2.47, p = 0.02), demonstrating very good energy compensation (269-334%). No effects were found for fruit bars (t(19) = 1.76, p = 0.09), in evening meal intakes (F(4,72) = 0.62, p = 0.65) or in total intake (lunch + evening meal + food portions) (F(4,72) = 0.40, p = 0.69). No differences between conditions were found in measures of hunger (largest F(4,76) = 1.26, p = 0.29), but fruit bars were significantly less familiar than all other foods (smallest t(19) = 3.14, p = 0.01). These findings demonstrate good compensation over the short term for small portions of familiar foods in complicit consumers. Findings are most plausibly explained as a result of participant awareness and cognitions, although the nature of these cognitions cannot be discerned from this study. These findings however, also suggest that covert manipulations may have limited transfer to real world scenarios. PMID- 25447025 TI - IS elements in Aliivibrio salmonicida LFI1238: occurrence, variability and impact on adaptability. AB - Insertion sequence (IS) elements are short, self-replicating DNA sequences that are capable of efficiently spreading over the host genome. Possessing varied integration specificity IS elements are capable of the irreversible inactivation of genes, which diversifies the pool of intact genetic determinants in host populations. In the current study, we performed a complex analysis of IS elements (Vsa IS) in the previously sequenced genome of Aliivibrio salmonicida LFI1238 and proposed a model of the spread of the Vsa IS elements over the genome of this microorganism. Along with the prediction of the integration sites for Vsa IS elements, the current study provides an overview of the properties of A. salmonicida IS elements, as well as information regarding their occurrence in different bacterial classes. An analysis of individual alleles of the IS elements has allowed us to depict a history of the accumulation of mutations and to describe distinctive microevolution lines for actively transposing Vsa IS elements in the genome of A. salmonicida LFI1238. Our results demonstrate the high importance of the dead end microevolution of actively transposing Vsa IS elements for the inactivation of genes in A. salmonicida LFI1238. PMID- 25447027 TI - Neonate with orbital bleed. PMID- 25447028 TI - Intermolecular dynamic kinetic resolution cooperatively catalyzed by an N heterocyclic carbene and a Lewis acid. AB - The ubiquitous structure of delta-lactones makes the development of new methods for their enantioselective and stereoselective synthesis an important ongoing challenge. The intermolecular dynamic kinetic resolution (DKR) of beta-halo-alpha ketoesters cooperatively catalyzed by an N-heterocyclic carbene and a Lewis acid generates two contiguous stereocenters with remarkable diastereoselectivity through an oxidation/lactonization sequence. PMID- 25447026 TI - Age-specific functional epigenetic changes in p21 and p16 in injury-activated satellite cells. AB - The regenerative capacity of muscle dramatically decreases with age because old muscle stem cells fail to proliferate in response to tissue damage. Here, we uncover key age-specific differences underlying this proliferative decline: namely, the genetic loci of cyclin/cyclin-dependent kinase (CDK) inhibitors (CDKIs) p21 and p16 are more epigenetically silenced in young muscle stem cells, as compared to old, both in quiescent cells and those responding to tissue injury. Interestingly, phosphorylated ERK (pERK) induced in these cells by ectopic FGF2 is found in association with p21 and p16 promoters, and moreover, only in the old cells. Importantly, in the old satellite cells, FGF2/pERK silences p21 epigenetically and transcriptionally, which leads to reduced p21 protein levels and enhanced cell proliferation. In agreement with the epigenetic silencing of the loci, young muscle stem cells do not depend as much as old on ectopic FGF/pERK for their myogenic proliferation. In addition, other CDKIs, such asp15(INK4B) and p27(KIP1) , become elevated in satellite cells with age, confirming and explaining the profound regenerative defect of old muscle. This work enhances our understanding of tissue aging, promoting strategies for combating age-imposed tissue degeneration. PMID- 25447030 TI - Usefulness of intraoperative diagnosis of hepatic tumors located at the liver surface and hepatic segmental visualization using indocyanine green-photodynamic eye imaging. AB - BACKGROUND: To improve the diagnostic accuracy for hepatic tumors on the liver surface, we investigated the usefulness of an indocyanine green-photodynamic eye (ICG-PDE) system by comparison with Sonazoid intraoperative ultrasonography (IOUS) in 117 patients. Hepatic segmentation by ICG-PDE was also evaluated. METHODS: ICG was administered preoperatively for functional testing and images of the tumor were observed during hepatectomy using a PDE camera. ICG was injected into portal veins to determine hepatic segmentation. RESULTS: Accurate diagnosis of liver tumors was achieved with ICG-PDE in 75% of patients, lower than with IOUS (94%). False-positive and false-negative diagnosis rates for ICG-PDE were 24% and 9%, respectively. New small HCCs were detected in 3 patients. The ICG fluorescent pattern in tumors was strong staining in 41%, weak staining in 13%, rim staining in 20% and no staining in 26%. Hepatocellular carcinoma predominantly showed strong staining (61%), while rim staining predominated in cholangiocellular carcinoma (60%) and liver metastasis (55%). Hepatic segmental staining was performed in 28 patients, proving successful in 89%. CONCLUSION: ICG PDE is a useful tool for detecting the precise tumor location at the liver surface, identifying new small tumors, and determining liver segmentation for liver resection. PMID- 25447029 TI - Grand average ERP-image plotting and statistics: A method for comparing variability in event-related single-trial EEG activities across subjects and conditions. AB - BACKGROUD: With the advent of modern computing methods, modeling trial-to-trial variability in biophysical recordings including electroencephalography (EEG) has become of increasingly interest. Yet no widely used method exists for comparing variability in ordered collections of single-trial data epochs across conditions and subjects. NEW METHOD: We have developed a method based on an ERP-image visualization tool in which potential, spectral power, or some other measure at each time point in a set of event-related single-trial data epochs are represented as color coded horizontal lines that are then stacked to form a 2-D colored image. Moving-window smoothing across trial epochs can make otherwise hidden event-related features in the data more perceptible. Stacking trials in different orders, for example ordered by subject reaction time, by context related information such as inter-stimulus interval, or some other characteristic of the data (e.g., latency-window mean power or phase of some EEG source) can reveal aspects of the multifold complexities of trial-to-trial EEG data variability. RESULTS: This study demonstrates new methods for computing and visualizing 'grand' ERP-image plots across subjects and for performing robust statistical testing on the resulting images. These methods have been implemented and made freely available in the EEGLAB signal-processing environment that we maintain and distribute. PMID- 25447031 TI - Gliadin-dependent cytokine production in a bidimensional cellular model of celiac intestinal mucosa. AB - The downstream cascade of the inflammatory response to gliadin in celiac intestinal mucosa encompasses the early activation of the innate immunity that triggers the adaptive response. Therefore, the in vitro study of the pathogenic mechanism of celiac disease (CD) on enterocytes alone or mucosal T lymphocytes alone does not fully consider all the aspects of gliadin-dependent inflammation. Although the in vitro culture of specimens of intestinal mucosa obtained from celiac patients is the gold standard for the study of CD, this technique presents several technical challenges and the bioptic specimens are not easily available. So, in this paper, we described the gliadin-dependent cytokine production in a bidimensional cellular system, which is able to mimic both the innate and the adaptive steps of the mucosal immune response of CD. In the upper compartment, the intestinal epithelial cells are grown on a filter, and in the lower compartment, the mononuclear cells isolated from peripheral blood of celiac patients are cultured. Cells were apically exposed to the toxic gliadin peptide p31-43 for 3 h and then with the immunodominant gliadin fragment palpha-9 for 21 h. The incubation with gliadin peptides resulted in increased levels of IL-15, INF-gamma, IL-6, tumor necrosis factor (TNF)-alpha, IL-1beta, and CCL 2, 3 and 4 in the basal supernatants, with respect to cells exposed to medium alone. The p31 43-driven epithelial priming of mucosal response consists of transglutaminase (TG2)-mediated deamidation of the immunostimulatory gliadin peptides, as demonstrated by the inhibition of palpha-9 activity, when the system is exposed to blocking anti-TG2 antibody. PMID- 25447033 TI - A novel beta-fructofuranosidase in Coleoptera: Characterization of a beta fructofuranosidase from the sugarcane weevil, Sphenophorus levis. AB - beta-fructofuranosidases or invertases (EC 3.2.1.26) catalyze the hydrolysis of sucrose into fructose and glucose. beta-fructofuranosidases have been widely described in microorganisms, but were not known in the animal kingdom until very recently. There are studies reporting lepidopteran beta-fructofuranosidases, but no beta-fructofuranosidase gene sequence or encoding transcript has previously been identified in beetles. Considering the scarcity of functional studies on insect beta-fructofuranosidases and their apparent non-occurrence among coleopterans, the aim of the present study was to investigate the occurrence and characterize a beta-fructofuranosidase transcript identified in a cDNA library from the sugarcane weevil, Sphenophorus levis (Curculionidae). To validate that the beta-fructofuranosidase sequence (herein denominated Sl-beta-fruct) is indeed encoded by the S. levis genome, PCRs were performed using genomic DNA extracted from the larval fat body as well as DNA from the midgut with microbial content. Amplification of Sl-beta-fruct gene using larval fat body DNA indicated its presence in the insect's genomic DNA. The Sl-beta-fruct gene was cloned in Pichia pastoris to produce the recombinant enzyme (rSl-beta-fruct). Molecular weight of the recombinant protein was about 64 kDa, indicating possible glycosylation, since the theoretical weight was 54.8 kDa. The substrate specificity test revealed that rSl-beta-fruct hydrolyzes sucrose and raffinose, but not melibiose or maltose, thereby confirming invertase activity. The pH curve revealed greatest activity at pH 5.0, demonstrating rSl-beta-fruct to be an acidic beta fructofuranosidase. Quantitative PCR (qRT-PCR) analyses indicated that the production of mRNA only occurs in the midgut and reaches the greatest expression level in 30-day-old larvae, which is the expected pattern for digestive enzymes. Chromatography of glycosidases from S. levis midguts showed two enzymes acting as beta-fructofuranosidase, indicating the presence of a Sl-beta-fruct isoform or a beta-fructofuranosidase from insect intestinal microbiota. Moreover, it was found that alpha-glucosidases do not act on sucrose hydrolysis. Phylogenetic analyses indicated this enzyme to be similar to enzymes found in other coleopteran and lepidopteran beta-fructofuranosidases, but also closely similar to bacterial enzymes, suggesting potential horizontal gene transfer. Despite this, the enzyme seems to be restricted to different groups of bacteria, which suggests distinct origin events. The present study expands the concept of the occurrence of beta fructofuranosidase in insects. Despite the few descriptions of this gene in the animal kingdom, it is possible to state that beta-fructofuranosidase is crucial to the establishment of some insects throughout their evolutionary history, especially members of the Lepidoptera and Coleoptera clades. PMID- 25447034 TI - Save-a-life at the ballpark: 10-min spectator training achieves proficiency in cardiac arrest response. AB - OBJECTIVE: To determine immediate recall, feasibility, and efficiency of a brief out-of-hospital cardiac arrest (OHCA) bystander response training session at a large sporting event. We introduce two new measures of efficiency for training: (i) cardiac arrest training yield (CATY), i.e., number trained/number of spectators, and (ii) the training efficiency index for cardiac arrest (TEICA), i.e., persons trained per volunteer hours. METHODS: A convenience sample of baseball fans participated in a 10-min training on OHCA recognition, CPR and automatic external defibrillator (AED) use and completed post-training knowledge surveys. RESULTS: Out of 20,000 spectators, 198 participated for a CATY of 1%. Seventy-five volunteers over 3h of training generated a TEICA of 0.88. 90% of respondents identified the proper rate of chest compressions. 90% of respondents recognized an AED's function; 98% recognized it was easy to use. 83% recognized chest compressions as the next step after calling 911 and 62% included AED as part of the OHCA response. CONCLUSIONS: A 10-min training session is feasible and can achieve good recall in cardiac arrest response. However, participant recruitment dominated most of our volunteer effort. Our results can serve as a framework in the development of future health promotion campaigns. PMID- 25447032 TI - Behcet syndrome: from pathogenesis to novel therapies. AB - Behcet syndrome is a chronic disease hallmarked by inflammation of the blood vessels that is related to an autoimmune reaction caused by inherited susceptibility due to specific genes and environmental factors, probably components of infectious microorganisms, which turn on or get going the disease in genetically susceptible subjects. The more common clinical expression of the disease is represented by a triple-symptom complex of recurrent oral aphthous ulcers, genital ulcers, and uveitis, sometimes associated with inflammatory arthritis, phlebitis, iritis, as well as inflammation of the digestive tract, brain, and spinal cord. The treatment strategies used to manage the manifestations of Behcet syndrome have gradually progressed, and a number of new therapeutic resources have been implemented in recent years, allowing better control of pathogenic mechanisms, reducing symptoms and suffering, and ameliorating patient's outcome. PMID- 25447035 TI - Code status and resuscitation options in the electronic health record. AB - AIM: The advance discussion and documentation of code-status is important in preventing undesired cardiopulmonary resuscitation and related end of life interventions. Code-status documentation remains infrequent and paper-based, which limits its usefulness. This study evaluates a tool to document code-status in the electronic health records at a large teaching hospital, and analyzes the corresponding data. METHODS: Encounter data for patients admitted to the Medical Center were collected over a period of 12 months (01-APR-2012-31-MAR-2013) and the code-status attribute was tracked for individual patients. The code-status data were analyzed separately for adult and pediatric patient populations. We considered 131,399 encounters for 83,248 adult patients and 80,778 encounters for 55,656 pediatric patients in this study. RESULTS: 71% of the adult patients and 30% of the pediatric patients studied had a documented code-status. Age and severity of illness influenced the decision to document code-status. Demographics such as gender, race, ethnicity, and proximity of primary residence were also associated with the documentation of code-status. CONCLUSION: Absence of a recorded code-status may result in unnecessary interventions. Code-status in paper charts may be difficult to access in cardiopulmonary arrest situations and may result in unnecessary and unwanted interventions and procedures. Documentation of code-status in electronic records creates a readily available reference for care providers. PMID- 25447037 TI - Outcomes of asphyxial cardiac arrest patients who were treated with therapeutic hypothermia: a multicentre retrospective cohort study. AB - INTRODUCTION: While therapeutic hypothermia (TH) is in clinical use, its efficacy in certain patient groups is unclear. This study was designed to describe the characteristics and outcomes of patients with out-of-hospital cardiac-arrest (OHCA) caused by asphyxia, who were treated with TH. PATIENTS AND METHODS: A multicentre, retrospective, registry-based study was performed using data from the period 2007-2012. Comatose patients who were treated with TH after asphyxial cardiac arrest were included, while those who with cardiac arrest attributed to hanging, drowning or gas intoxication were excluded. RESULTS: Of a total of 932 OHCA patients in the registry, 111 were enrolled in this study. The mean age was 65.8+/-16.3 years with individuals who were >=65 years of age accounted for 61.3% of the cohort. Foreign-body airway obstruction was the most common cause (70.3%) of the cardiac arrest. Eighty patients (72.1%) presented with an initial non shockable rhythm. In all institutions target TH temperatures were 32-34 degrees C, but TH maintenance times varied. A total of 52 patients (46.8%) survived, of whom six patients (5.4%) showed a good neurologic outcome (cerebral performance category scale 1-2). The pupil light reflex, corneal reflex and time to return of spontaneous circulation (p=0.012, 0.015 and 0.032, respectively) were associated with survival. Witnessed arrest, age, previous lung disease, bystander basic life support and time factors were not associated with survival. CONCLUSION: About half of patients who underwent TH after asphyxial cardiac arrest survived, but a very small number showed a good neurologic outcome. The TH maintenance times were not uniform in these patients. Additional research regarding both the appropriate TH guidelines for patients with asphyxial cardiac arrest and improvement of their neurologic outcome is needed. PMID- 25447038 TI - Simulation exercise to improve retention of cardiopulmonary resuscitation priorities for in-hospital cardiac arrests: A randomized controlled trial. AB - BACKGROUND: Traditional American Heart Association (AHA) cardiopulmonary resuscitation (CPR) curriculum focuses on teams of two performing quality chest compressions with rescuers on their knees but does not include training specific to In-Hospital Cardiac Arrests (IHCA), i.e. patient in hospital bed with large resuscitation teams and sophisticated technology available. DESIGN: A randomized controlled trial was conducted with the primary goal of evaluating the effectiveness and ideal frequency of in-situ training on time elapsed from call for help to; (1) initiation of chest compressions and (2) successful defibrillation in IHCA. METHODS: Non-intensive care unit nurses were randomized into four groups: standard AHA training (C) and three groups that participated in 15 min in-situ IHCA training sessions every two (2M), three (3M) or six months (6M). Curriculum included specific choreography for teams to achieve immediate chest compressions, high chest compression fractions and rapid defibrillation while incorporating use of a backboard, stepstool. RESULTS: More frequent training was associated with decreased median (IQR) seconds to: starting compressions: [C: 33(25-40) vs. 6M: 21(15-26) vs. 3M: 14(10-20) vs. 2M: 13(9-20); p < 0.001]; and defibrillation: [C: 157(140-254) vs. 6M: 138(107-158) vs. 3M: 115(101-119) vs. 2M: 109(98-129); p < 0.001]. A composite outcome of key priorities, compressions within 20s, defibrillation within 180 s and use of a backboard, revealed improvement with more frequent training sessions: [C:5%(1/18) vs. 6M: 23%(4/17) vs. 3M: 56%(9/16) vs. 2M: 73%(11/15); p < 0.001]. CONCLUSION: Results revealed short in-situ training sessions conducted every 3 months are effective in improving timely initiation of chest compressions and defibrillation in IHCA. PMID- 25447036 TI - Bundled postconditioning therapies improve hemodynamics and neurologic recovery after 17 min of untreated cardiac arrest. AB - OBJECTIVE: Ischemic postconditioning (stutter CPR) and sevoflurane have been shown to mitigate the effects of reperfusion injury in cardiac tissue after 15min of ventricular fibrillation (VF) cardiac arrest. Poloxamer 188 (P188) has also proven beneficial to neuronal and cardiac tissue during reperfusion injury in human and animal models. We hypothesized that the use of stutter CPR, sevoflurane, and P188 combined with standard advanced life support would improve post-resuscitation cardiac and neurologic function after prolonged VF arrest. METHODS: Following 17min of untreated VF, 20 pigs were randomized to Control treatment with active compression/decompression (ACD) CPR and impedance threshold device (ITD) (n=8) or Bundle therapy with stutter ACD CPR+ITD+sevoflurane+P188 (n=12). Epinephrine and post-resuscitation hypothermia were given in both groups per standard protocol. Animals that achieved return of spontaneous circulation (ROSC) were evaluated with echocardiography, biomarkers, and a blinded neurologic assessment with a cerebral performance category score. RESULTS: Bundle therapy improved hemodynamics during resuscitation, reduced need for epinephrine and repeated defibrillation, reduced biomarkers of cardiac injury and end-organ dysfunction, and increased left ventricular ejection fraction compared to Controls. Bundle therapy also improved rates of ROSC (100% vs. 50%), freedom from major adverse events (50% vs. 0% at 48h), and neurologic function (42% with mild or no neurologic deficit and 17% achieving normal function at 48h). CONCLUSIONS: Bundle therapy with a combination of stutter ACD CPR, ITD, sevoflurane, and P188 improved cardiac and neurologic function after 17min of untreated cardiac arrest in pigs. All studies were performed with approval from the Institutional Animal Care Committee of the Minneapolis Medical Research Foundation (protocol #12-11). PMID- 25447039 TI - The association between chest compression release velocity and outcomes from out of-hospital cardiac arrest. AB - BACKGROUND: Previous studies have demonstrated significant relationships between cardiopulmonary resuscitation (CPR) quality metrics and survival to hospital discharge from out-of-hospital cardiac arrest (OHCA). Recently, it has been suggested that a new metric, chest compression release velocity (CCRV), may be associated with improved survival from OHCA. METHODS AND RESULTS: We performed a retrospective review of all treated adult OHCA occurring over a two year period beginning January 1, 2012. CPR metrics were abstracted from accelerometer measurements during each resuscitation. Multivariable regression analysis was used to examine the impact of CCRV on survival to hospital discharge. Secondary outcome measures were the impact of CCRV on return of spontaneous circulation (ROSC) and neurologically intact survival (MRS <= 3). Among 1800 treated OHCA, 1137 met inclusion criteria. The median (IQR) age was 71.6 (60.6, 82.3) with 724 (64%) being male. The median (IQR) CCRV (mm/s) amongst 96 survivors was 334.5 (300.0, 383.2) compared to 304.0 (262.6, 354.1) in 1041 non survivors (p < 0.001). When adjusted for Utstein variables, the odds of survival to hospital discharge for each 10 mm/s increase in CCRV was 1.02 (95% CI: 0.98, 1.06). Similarly the odds of ROSC and neurologically intact survival were 1.01 (95% CI: 0.99, 1.03) and 1.02 (95% CI: 0.98, 1.06), respectively. CONCLUSIONS: When adjusted for Utstein variables, CCRV was not significantly associated with outcomes from OHCA. Further research in other EMS systems is required to clarify the potential impact of this variable on OHCA survival. PMID- 25447040 TI - Cost-utility analysis of treating out of hospital cardiac arrests in Jerusalem. AB - BACKGROUND: Out-of-hospital cardiac arrest (OHCA) initiates a chain of responses including emergency medical service mobilization and medical treatment, transfer and admission first to a hospital Emergency Department (ED) and then usually to an intensive care unit and ward. Costly pre- and in-hospital care may be followed by prolonged post discharge expenditure on treatment of patients with severe neurological sequelae. We assessed the cost-effectiveness of treatment of OHCA by calculating the cost per Disability Adjusted Life Year (DALY) averted. METHODS AND RESULTS: We studied 3355 consecutive non-traumatic OHCAs (2005-2010) in Jerusalem, Israel, supplemented by hospital utilization data extracted from patient files (n = 570) and post-discharge follow-up (n = 196). Demographic, utilization and economic data were incorporated into a spreadsheet model to calculate the cost-utility ratio. Advanced life support was administered to 2264 of the 3355 OHCAs (67.5%) and 1048 (45.6%) patients were transferred to the ED. Of 676 (20.1%) patients who survived the ED and were admitted, there were 206 (6.1%) survivors to discharge, among them only 113 (3.4%) neurologically intact. Total cost ($39,100,000) per DALY averted (1353) was $28,864. CONCLUSIONS: The current package of OHCA interventions in Jerusalem appears to be very cost effective as the cost per averted DALY of $28,864 is less than the Gross Domestic Product per capita ($33,261). This paper provides a basis for studying the effects of potential interventions that can be evaluated in terms of their incremental costs per averted DALY for treatment of OHCA. PMID- 25447041 TI - Effect of continuous oxygen insufflation on induced-gastric air volume during cardiopulmonary resuscitation in a cadaveric model. AB - BACKGROUND: The main objective of this study was to compare the volume of gas insufflated in the stomach with continuous external chest compressions plus continuous oxygen insufflation (C-CPR) versus standard-CPR (S-CPR) which alternates external chest compressions and synchronized positive insufflations through a bag-valve-mask with a 30/2 ratio. The secondary objective was to compare upper airway pressures (intratracheal and intramask) generated during continuous oxygen insufflation. MATERIAL AND METHODS: Open, prospective, randomized, cross over, comparative, non-inferiority study. CPR was performed for six minutes periods, on seven fresh human corpses, with C-CPR or S-CPR in a random order. Before each CPR period, the stomach was completely emptied through the gastrostomy tube, and then 200 mL of air was injected in the stomach to be sure it was not collapsed. The gastric volume was measured at the end of each intervention. Intratracheal and intramask pressures were recorded continuously during C-CPR. Results were provided as mean +/- standard deviation. Statistical analyses were done with a paired student t test. RESULTS: Induced-gastric inflation was lower with C-CPR (221 +/- 130 mL) than with S-CPR (5401 +/- 2208 mL, p = 0.001). Throughout C-CPR, no difference was found between the intratracheal and intramask pressures (4.4 +/- 1.2; 4.0 +/- 0.8 cmH2O, respectively, p = 0.45). CONCLUSION: This human cadaver study demonstrates that continuous oxygen insufflation induced less gastric inflation than intermittent insufflation during CPR. PMID- 25447042 TI - Formal [4+2] reaction between 1,3-diynes and pyrroles: gold(I)-catalyzed indole synthesis by double hydroarylation. AB - Indole synthesis by a gold(I)-catalyzed intermolecular formal [4+2] reaction between 1,3-diynes and pyrroles has been developed. This reaction involves the hydroarylation of 1,3-diynes with pyrroles followed by an intramolecular hydroarylation to give the 4,7-disubstituted indoles. This reaction can also be applied to the synthesis of carbazoles when indoles are used as the nucleophiles instead of pyrroles. PMID- 25447043 TI - Assessing neighborhood-level effects on disparities in cardiovascular diseases. PMID- 25447044 TI - Neighborhood-level racial/ethnic residential segregation and incident cardiovascular disease: the multi-ethnic study of atherosclerosis. AB - BACKGROUND: Previous research suggests that neighborhood-level racial/ethnic residential segregation is linked to health, but it has not been studied prospectively in relation to cardiovascular disease (CVD). METHODS AND RESULTS: Participants were 1595 non-Hispanic black, 2345 non-Hispanic white, and 1289 Hispanic adults from the Multi-Ethnic Study of Atherosclerosis free of CVD at baseline (aged 45-84 years). Own-group racial/ethnic residential segregation was assessed by using the Gi* statistic, a measure of how the neighborhood racial/ethnic composition deviates from surrounding counties' racial/ethnic composition. Multivariable Cox proportional hazards modeling was used to estimate hazard ratios for incident CVD (first definite angina, probable angina followed by revascularization, myocardial infarction, resuscitated cardiac arrest, coronary heart disease death, stroke, or stroke death) over 10.2 median years of follow-up. Among blacks, each standard deviation increase in black segregation was associated with a 12% higher hazard of developing CVD after adjusting for demographics (95% confidence interval, 1.02-1.22). This association persisted after adjustment for neighborhood-level characteristics, individual socioeconomic position, and CVD risk factors (hazard ratio, 1.12; 95% confidence interval, 1.02 1.23). For whites, higher white segregation was associated with lower CVD risk after adjusting for demographics (hazard ratio, 0.88; 95% confidence interval, 0.81-0.96), but not after further adjustment for neighborhood characteristics. Segregation was not associated with CVD risk among Hispanics. Similar results were obtained after adjusting for time-varying segregation and covariates. CONCLUSIONS: The association of residential segregation with cardiovascular risk varies according to race/ethnicity. Further work is needed to better characterize the individual- and neighborhood-level pathways linking segregation to CVD risk. PMID- 25447045 TI - A novel role for microphthalmia-associated transcription factor-regulated pigment epithelium-derived factor during melanoma progression. AB - Microphthalmia-associated transcription factor (MITF) acts via pigment epithelium derived factor (PEDF), an antiangiogenic protein, to regulate retinal pigment epithelium migration. PEDF expression and/or regulation during melanoma development have not been investigated previously. Using immunohistochemistry, we determined expression of PEDF in common and dysplastic melanocytic nevi, melanoma in situ, invasive melanoma, and metastatic melanoma (n = 102). PEDF expression was consistently decreased in invasive and metastatic melanoma, compared with nevi and melanoma in situ (P < 0.0001). PEDF was lost in thicker melanomas (P = 0.003), and correlated with depth of invasion (P = 0.003) and distant metastasis (P = 0.0331), but only marginally with mitotic index, AJCC stage, nodal metastasis, or blood vascular density (0.05 < P < 0.10). Quantitative real-time PCR and microarray analyses confirmed PEDF down-regulation at the mRNA level in several melanoma lines, compared with melanocytes. MITF positively correlated with PEDF expression in invasive melanomas (P = 0.0003). Searching for PEDF regulatory mechanisms revealed two occupied conserved E-boxes (DNA recognition elements) in the first intron of the human and mouse PEDF promoter regions, confirmed by binding assays. Dominant-negative and siRNA approaches in vivo demonstrated direct transcriptional influence of MITF on PEDF, establishing the PEDF gene (SERPINF1) as a MITF target in melanocytes and melanoma cells. These findings suggest that loss of PEDF expression promotes early invasive melanoma growth. PMID- 25447046 TI - Activation of the Wnt/planar cell polarity pathway is required for pericyte recruitment during pulmonary angiogenesis. AB - Pericytes are perivascular cells localized to capillaries that promote vessel maturation, and their absence can contribute to vessel loss. Whether impaired endothelial-pericyte interaction contributes to small vessel loss in pulmonary arterial hypertension (PAH) is unclear. Using 3G5-specific, immunoglobulin G coated magnetic beads, we isolated pericytes from the lungs of healthy subjects and PAH patients, followed by lineage validation. PAH pericytes seeded with healthy pulmonary microvascular endothelial cells failed to associate with endothelial tubes, resulting in smaller vascular networks compared to those with healthy pericytes. After the demonstration of abnormal polarization toward endothelium via live-imaging and wound-healing studies, we screened PAH pericytes for abnormalities in the Wnt/planar cell polarity (PCP) pathway, which has been shown to regulate cell motility and polarity in the pulmonary vasculature. PAH pericytes had reduced expression of frizzled 7 (Fzd7) and cdc42, genes crucial for Wnt/PCP activation. With simultaneous knockdown of Fzd7 and cdc42 in healthy pericytes in vitro and in a murine model of angiogenesis, motility and polarization toward pulmonary microvascular endothelial cells were reduced, whereas with restoration of both genes in PAH pericytes, endothelial-pericyte association was improved, with larger vascular networks. These studies suggest that the motility and polarity of pericytes during pulmonary angiogenesis are regulated by Wnt/PCP activation, which can be targeted to prevent vessel loss in PAH. PMID- 25447047 TI - Identification and characterization of mesenchymal-epithelial progenitor-like cells in normal and injured rat liver. AB - In normal rat liver, thymocyte antigen 1 (Thy1) is expressed in fibroblasts/myofibroblasts and in some blood progenitor cells. Thy1-expressing cells also accumulate in the liver during impaired liver regeneration. The origin and nature of these cells are not well understood. By using RT-PCR analysis and immunofluorescence microscopy, we describe the presence of rare Thy1(+) cells in the liver lobule of normal animals, occasionally forming small collections of up to 20 cells. These cells constitute a small portion (1.7% to 1.8%) of nonparenchymal cells and reveal a mixed mesenchymal-epithelial phenotype, expressing E-cadherin, cytokeratin 18, and desmin. The most potent mitogens for mesenchymal-epithelial Thy1(+) cells in vitro are the inflammatory cytokines interferon gamma, IL-1, and platelet-derived growth factor-BB, which are not produced by Thy1(+) cells. Thy1(+) cells express all typical mesenchymal stem cell and hepatic progenitor cell markers and produce growth factor and cytokine mRNA (Hgf, Il6, Tgfa, and Tweak) for proteins that maintain oval cell growth and differentiation. Under appropriate conditions, mesenchymal-epithelial cells differentiate in vitro into hepatocyte-like cells. In this study, we show that the adult rat liver harbors a small pool of endogenous mesenchymal-epithelial cells not recognized previously. In the quiescent state, these cells express both mesenchymal and epithelial cell markers. They behave like hepatic stem cells/progenitors with dual phenotype, exhibiting high plasticity and long lasting proliferative activity. PMID- 25447048 TI - Expression of human complement factor H prevents age-related macular degeneration like retina damage and kidney abnormalities in aged Cfh knockout mice. AB - Complement factor H (CFH) is an important regulatory protein in the alternative pathway of the complement system, and CFH polymorphisms increase the genetic risk of age-related macular degeneration dramatically. These same human CFH variants have also been associated with dense deposit disease. To mechanistically study the function of CFH in the pathogenesis of these diseases, we created transgenic mouse lines using human CFH bacterial artificial chromosomes expressing full length human CFH variants and crossed these to Cfh knockout (Cfh(-/-)) mice. Human CFH protein inhibited cleavage of mouse complement component 3 and factor B in plasma and in retinal pigment epithelium/choroid/sclera, establishing that human CFH regulates activation of the mouse alternative pathway. One of the mouse lines, which express relatively higher levels of CFH, demonstrated functional and structural protection of the retina owing to the Cfh deletion. Impaired visual function, detected as a deficit in the scotopic electroretinographic response, was improved in this transgenic mouse line compared with Cfh(-/-) mice, and transgenics had a thicker outer nuclear layer and less sub-retinal pigment epithelium deposit accumulation. In addition, expression of human CFH also completely protected the mice from developing kidney abnormalities associated with loss of CFH. These humanized CFH mice present a valuable model for study of the molecular mechanisms of age-related macular degeneration and dense deposit disease and for testing therapeutic targets. PMID- 25447050 TI - Aromatase controls Sjogren syndrome-like lesions through monocyte chemotactic protein-1 in target organ and adipose tissue-associated macrophages. AB - Several autoimmune diseases are known to develop in postmenopausal women. However, the mechanism by which estrogen deficiency influences autoimmunity is unknown. Aromatase is an enzyme that converts androgens to estrogens. Herein, we used female aromatase gene knockout (ArKO) mice as a model of estrogen deficiency to investigate the molecular mechanism that underlies the onset and development of autoimmunity. Histological analyses showed that inflammatory lesions in the lacrimal and salivary glands of ArKO mice increased with age. Adoptive transfer of spleen cells or bone marrow cells from ArKO mice into recombination activating gene 2 knockout mice failed to induce the autoimmune lesions. Expression of mRNA encoding proinflammatory cytokines and monocyte chemotactic protein-1 increased in white adipose tissue of ArKO mice and was significantly higher than that in wild-type mice. Moreover, an increased number of inflammatory M1 macrophages was observed in white adipose tissue of ArKO mice. A significantly increased monocyte chemotactic protein-1 mRNA expression of the salivary gland tissue in ArKO was found together with adiposity. Furthermore, the autoimmune lesions in a murine model of Sjogren syndrome were exacerbated by administration of an aromatase inhibitor. These results suggest that aromatase may play a key role in the pathogenesis of Sjogren syndrome-like lesions by controlling the target organ and adipose tissue-associated macrophage. PMID- 25447049 TI - Role of the urokinase-fibrinolytic system in epithelial-mesenchymal transition during lung injury. AB - Alveolar type II epithelial (ATII) cell injury precedes development of pulmonary fibrosis. Mice lacking urokinase-type plasminogen activator (uPA) are highly susceptible, whereas those deficient in plasminogen activator inhibitor (PAI-1) are resistant to lung injury and pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) has been considered, at least in part, as a source of myofibroblast formation during fibrogenesis. However, the contribution of altered expression of major components of the uPA system on ATII cell EMT during lung injury is not well understood. To investigate whether changes in uPA and PAI-1 by ATII cells contribute to EMT, ATII cells from patients with idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, and mice with bleomycin-, transforming growth factor beta-, or passive cigarette smoke-induced lung injury were analyzed for uPA, PAI-1, and EMT markers. We found reduced expression of E cadherin and zona occludens-1, whereas collagen-I and alpha-smooth muscle actin were increased in ATII cells isolated from injured lungs. These changes were associated with a parallel increase in PAI-1 and reduced uPA expression. Further, inhibition of Src kinase activity using caveolin-1 scaffolding domain peptide suppressed bleomycin-, transforming growth factor beta-, or passive cigarette smoke-induced EMT and restored uPA expression while suppressing PAI-1. These studies show that induction of PAI-1 and inhibition of uPA during fibrosing lung injury lead to EMT in ATII cells. PMID- 25447053 TI - Tumor necrosis factor alpha decreases glucagon-like peptide-2 expression by up regulating G-protein-coupled receptor 120 in Crohn disease. AB - Glucagon-like peptide (GLP)-2, secreted by L cells in the small intestine, has anti-inflammatory effects in the gastrointestinal tract. A GLP-2 analogue has been an effective treatment for Crohn disease (CD). G-protein-coupled receptor (GPR) 40 and GPR120 are probably involved in GLP-2 production, the mechanisms of which remain unclear. In our experiments, normal ileal mucosa expressed GPR40, but rarely expressed GPR120. However, both GPRs were overexpressed in the L cells of the inflamed ileal mucosa of CD patients. Mucosal inflammation induced the overexpression of GPR40, GPR120, and several inflammatory cytokines, with correlations between ileal concentrations of tumor necrosis factor (TNF)-alpha and GPR expression levels; however, inflammation did not induce the expression of proglucagon, a precursor of GLP-2 in CD patients. In rat L cells and GLUTag cells, TNF-alpha treatment increased GPR120 mRNA expression without affecting GPR40 mRNA expression. Dual agonists of GPR40 and GPR120, GW9508 and linoleic acid, respectively, increased GLP-2 production from L cells, but these agonists decreased it in the presence of TNF-alpha. The GPR40 antagonist, GW1100, inhibited the GW9508-induced increase in GLP-2 production, and silencing GPR120 resulted in further elevation of GLP-2 production. Thus, GPR120-dependent signaling inhibited the stimulatory effects of GPR40 on GLP-2 expression, and TNF alpha treatment decreased GLP-2 expression by up-regulating GPR120 expression in L cells. PMID- 25447052 TI - Chronic continuous exenatide infusion does not cause pancreatic inflammation and ductal hyperplasia in non-human primates. AB - In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67-positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67-positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67-positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30 positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a beta-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates. PMID- 25447055 TI - In vivo depletion of CD206+ M2 macrophages exaggerates lung injury in endotoxemic mice. AB - Although phenotypically polarized macrophages are now generally classified into two major subtypes termed proinflammatory M1 and anti-inflammatory M2 macrophages, a contributory role of lung M2 macrophages in the pathophysiological features of acute lung injury is not fully understood. Herein, we show in an endotoxemic murine model that M2 macrophages serve as key anti-inflammatory cells that play a regulatory role in the severity of lung injury. To study whether M2 macrophages can modify inflammation, we depleted M2 macrophages from lungs of CD206-diphtheria toxin (DT) receptor transgenic (Tg) mice during challenge with lipopolysaccharide. The i.p. administration of DT depleted CD206-positive cells in bronchoalveolar lavage fluid. The use of M2 macrophage markers Ym1 and arginase-1 identified pulmonary CD206-positive cells as M2 macrophages. A striking increase in neutrophils in bronchoalveolar lavage fluid cell contents was found in DT-treated CD206-DT receptor Tg mice. In CD206-DT receptor Tg mice given DT, endotoxin challenge exaggerated lung inflammation, including up regulation of proinflammatory cytokines and increased histological lung damage, but the endotoxemia-induced increase in NF-kappaB activity was significantly reduced, suggesting that M2 phenotype-dependent counteraction of inflammatory insult cannot be attributed to the inhibition of the NF-kappaB pathway. Our results indicate a critical role of CD206-positive pulmonary macrophages in triggering inflammatory cascade during endotoxemic lung inflammation. PMID- 25447057 TI - Keeping your distance: attentional withdrawal in individuals who show physiological signs of social discomfort. AB - Being in close social proximity to a stranger is generally perceived to be an uncomfortable experience, which most people seek to avoid. In circumstances where crowding is unavoidable, however, people may seek to withdraw their attention from the other person. This study examined whether social discomfort, as indexed by electrodermal activity, is related to a withdrawal of attention in 28 (m=8, f=20) university students. Students performed a radial line bisection task while alone or together with a stranger facing them. Physiological arousal was indexed by a wrist monitor, which recorded electrodermal activity. Correlational analyses showed that individuals who displayed physiological discomfort when together showed a withdrawal of the perceived midpoint of the line towards them (and away from the stranger). Conversely, individuals who showed no discomfort exhibited an expansion of the perceived midpoint away from them. We propose that participants shift their attention away from the stranger to increase interpersonal distance and reduce anxiety/arousal. PMID- 25447051 TI - Transient receptor potential vanilloid 1 gene deficiency ameliorates hepatic injury in a mouse model of chronic binge alcohol-induced alcoholic liver disease. AB - Experimental alcohol-induced liver injury is exacerbated by a high polyunsaturated fat diet rich in linoleic acid. We postulated that bioactive oxidized linoleic acid metabolites (OXLAMs) play a critical role in the development/progression of alcohol-mediated hepatic inflammation and injury. OXLAMs are endogenous ligands for transient receptor potential vanilloid 1 (TRPV1). Herein, we evaluated the role of signaling through TRPV1 in an experimental animal model of alcoholic liver disease (ALD). Chronic binge alcohol administration increased plasma OXLAM levels, specifically 9- and 13-hydroxy octadecadienoic acids. This effect was associated with up-regulation of hepatic TRPV1. Exposure of hepatocytes to these OXLAMs in vitro resulted in activation of TRPV1 signal transduction with increased intracellular Ca(2+) levels. Genetic depletion of TRPV1 did not blunt hepatic steatosis caused by ethanol, but prevented hepatic injury. TRPV1 deficiency protected from hepatocyte death and prevented the increase in proinflammatory cytokine and chemokine expression, including tumor necrosis factor-alpha, IL-6, macrophage inflammatory protein-2, and monocyte chemotactic protein 1. TRPV1 depletion markedly blunted ethanol mediated induction of plasminogen activator inhibitor-1, an important alcohol induced hepatic inflammation mediator, via fibrin accumulation. This study indicates, for the first time, that TRPV1 receptor pathway may be involved in hepatic inflammatory response in an experimental animal model of ALD. TRPV1-OXLAM interactions appear to play a significant role in hepatic inflammation/injury, further supporting an important role for dietary lipids in ALD. PMID- 25447054 TI - Pathogenesis of necrotizing enterocolitis: modeling the innate immune response. AB - Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in premature infants. The pathophysiology is likely secondary to innate immune responses to intestinal microbiota by the premature infant's intestinal tract, leading to inflammation and injury. This review provides an updated summary of the components of the innate immune system involved in NEC pathogenesis. In addition, we evaluate the animal models that have been used to study NEC with regard to the involvement of innate immune factors and histopathological changes as compared to those seen in infants with NEC. Finally, we discuss new approaches to studying NEC, including mathematical models of intestinal injury and the use of humanized mice. PMID- 25447058 TI - Probing ERP correlates of verbal semantic processing in patients with impaired consciousness. AB - Our ability to identify covert cognitive abilities in non-communicating patients is of prime importance to improve diagnosis, to guide therapeutic decisions and to better predict their cognitive outcome. In the present study, we used a basic and rigorous paradigm contrasting pairs of words orthogonally. This paradigm enables the probing of semantic processing by comparing neural activity elicited by similar words delivered in various combinations. We describe the respective timing, topography and estimated cortical sources of two successive event-related potentials (ERP) components (N400 and late positive component (LPC)) using high density EEG in conscious controls (N=20) and in minimally conscious (MCS; N=15) and vegetative states (VS; N=15) patients recorded at bedside. Whereas N400-like ERP components could be observed in the VS, MCS and conscious groups, only MCS and conscious groups showed a LPC response, suggesting that this late effect could be a potential specific marker of conscious semantic processing. This result is coherent with recent findings disentangling early and local non conscious responses (e.g.: MMN in odd-ball paradigms, N400 in semantic violation paradigms) from late, distributed and conscious responses (e.g.: P3b to auditory rule violation) in controls and in patients with disorders of consciousness. However, N400 and LPC responses were not easily observed at the individual level, - even in conscious controls - , with standard ERP analyses, which is a limiting factor for its clinical use. Of potential interest, the only 3 patients presenting both significant N400 and LPC effects were MCS, and 2 of them regained consciousness and functional language abilities. PMID- 25447059 TI - Flexibly weighted integration of tactile reference frames. AB - To estimate the location of a tactile stimulus, the brain seems to integrate different types of spatial information such as skin-based, anatomical coordinates and external, spatiotopic coordinates. The aim of the present study was to test whether the use of these coordinates is fixed, or whether they are weighted according to the task context. Participants made judgments about two tactile stimuli with different vibration characteristics, one applied to each hand. First, they always performed temporal order judgments (TOJ) of the tactile stimuli with respect to the stimulated hands that were either crossed or uncrossed. The resulting crossing effect, that is, impaired performance in crossed compared to uncrossed conditions, was used as a measure of reference frame weighting and was compared across conditions. Second, in dual judgment conditions participants subsequently made judgments about the stimulus vibration characteristics, either with respect to spatial location or with respect to temporal order. Responses in the spatial secondary task either accented anatomical (Experiment 1) or external (Experiment 2) coding. A TOJ crossing effect emerged in all conditions, and secondary tasks did not affect primary task performance in the uncrossed posture. Yet, the spatial secondary task resulted in improved crossed hands performance in the primary task, but only if the secondary judgment stressed the anatomical reference frame (Experiment 1), rather than the external reference frames (Experiment 2). Like the anatomically coded spatial secondary task, the temporal secondary task improved crossed hand performance of the primary task. The differential influence of the varying secondary tasks implies that integration weights assigned to the anatomical and external reference frames are not fixed. Rather, they are flexibly adjusted to the context, presumably through top-down modulation. PMID- 25447060 TI - Neural correlates of spelling difficulties in Alzheimer's disease. AB - Alzheimer's disease (AD) is associated with a general cognitive decline that affects the memory and language domains. Thus, an oral production deficit with a lexical-semantic origin has been widely observed in these patients. Their written production capacities, however, have been much less studied. We assessed the spelling abilities of 22 AD patients and a group of matched healthy controls with a test battery including written picture naming and word and pseudoword dictation tests, as well as text dictation and spontaneous writing tasks. The results of the AD patients in the discriminative tasks were then entered into voxel-based morphometry analyses along with their grey matter volumes. The patient group presented a selective impairment for word dictation, which contrasted with a spared capacity to spell pseudowords, and showed more difficulties for words with arbitrary and rule-based orthography. Moreover, they also produced less complete syntactic units in the spontaneous writing task. These results point out the lexical-semantic, as opposed to sublexical, nature of the spelling deficit associated to AD. In addition, we recognized a mainly left-lateralized cortical network, including areas in the posterior inferior temporal lobe and the superior region of the parietal cortex, which might be responsible for this impairment. Other regions, such as the putamen, were also associated to the deficit. The results of this study, hence, improve our understanding of the neuropsychological and neuroanatomical mechanisms that underlie the cognitive symptoms associated to AD. PMID- 25447062 TI - Both "?" and "?" are yellow: cross-linguistic investigation in search of the determinants of synesthetic color. AB - Individuals with grapheme-color synesthesia experience "colors" when viewing achromatic letters and digits. Despite the large individual difference in synesthetic association between inducing graphemes and induced colors, the search for the determinants of synesthetic experience has begun. So far, however, research has drawn an inconsistent picture; some studies have shown that graphemes of similar visual shape tend to induce similar synesthetic colors, while others suggested sound as an important factor. Moreover, meaning seems to affect synesthetic color. In the present work, we sought to investigate the determinants of synesthetic color by testing four multilingual grapheme-color synesthetes who experience "colors" upon viewing Korean (hangul), Japanese (katakana and hiragana), and English (Latin alphabet) characters on a standardized color-matching procedure. Results showed that pairs of characters of matched sound tended to induce similar synesthetic colors. This was the case not only between two scripts within the same language (Japanese hiragana and katakana) but also between two different languages (Japanese and Korean). In addition, pairs of characters with similar initial phonemes tended to induce similar colors; this was general across multiple languages. Results also showed that pairs of sequential words in Korean, Japanese, English, and Chinese that have the same meaning tended to elicit similar synesthetic colors. When those pairs of words shared not only meaning but also sound, the similarity of the induced synesthetic colors was even greater. Our work is one of the few initial attempts to examine the influence of visual shape, sound, meaning, and their interaction on synesthetic color induced by characters across multiple languages. PMID- 25447063 TI - Hemispheric asymmetry in the formation of musical pitch expectations: a monaural listening and probe tone study. AB - This study investigated hemispheric asymmetry in the formation of musical pitch expectations by combining the monaural listening and probe tone paradigms. On each trial, adult participants heard a short context melody and a single pitch (i.e. a probe tone). Both the context and the probe tone were played in the left or right ear. The context was an ascending major scale or pitches from the major scale in a random order. Following each context, participants rated one of three probe tones for how well it fit with the context they just heard. Probe tones were one of two pitches from the major scale (the tonic or the supertonic) or an out-of-set pitch. Participants provided the highest ratings for the tonic, followed by the supertonic, followed by the out-of-set pitch. Ratings did not differ for the tonic or out-of-set pitch between the two ears, but participants provided lower ratings for the supertonic in the right ear. For the ascending context only, the difference in ratings between the tonic and supertonic was greater in the right ear. These results suggest that the left hemisphere differentiates the stability of pitches in a set by forming temporal expectations for specific, in-set pitches. PMID- 25447061 TI - Oddball distractors demand attention: neural and behavioral responses to predictability in the flanker task. AB - Predictable and unpredictable distractors may differentially affect attention. We adapted the Eriksen flanker task by manipulating the probability with which specific flankers occurred. Subjects reported the orientation of briefly presented targets while attempting to ignore four flanking items. Flankers had either standard (90% of trials) or oddball (10%) orientations. Congruent and incongruent configurations were equiprobable, as were target orientations. Oddball flanker orientations substantially enhanced congruency effects: performance was best when the target was congruent with oddball flankers and worst when it was incongruent. We recorded scalp EEG while subjects performed the task, and later computed ERPs timelocked to stimulus onset. Oddball flanker orientations evoked a visual mismatch negativity (vMMN). Subjects' temperament predicted individual differences in vMMN magnitude. Orientation sensitivity predicted larger vMMNs; attentional selectivity predicted smaller. Behavioral and vMMN results indicate that subjects exploit distractor predictability to support more-effective active inhibition; oddballs disrupt this strategy. Despite subjects' attempts to ignore the flankers, unexpected distractors strongly influence neural responses and behavioral performance. PMID- 25447065 TI - Voluntary action modulates the brain response to rule-violating events indexed by visual mismatch negativity. AB - An event-related brain potential (ERP) component called visual mismatch negativity (MMN) is automatically elicited when sequential rules inherent in a visual stimulus sequence are violated. To elucidate whether the visual MMN generating processes are strictly determined in a bottom-up (i.e., stimulus driven) manner, or can be modulated by top-down control, we investigated whether or not visual MMN is affected by prior information about the occurrence of rule violation derived from the participant's voluntary action. The participants were required to produce a visual stimulus sequence by pressing one button frequently (about 90%) and another button infrequently (10%) in random order; an oddball sequence consisting of repetition-rule-conforming and -violating stimuli in Experiment 1 and a more complex sequence consisting of change-rule-conforming and -violating stimuli in Experiment 2. Frequently-performed button presses triggered rule-conforming stimuli (81%), but occasionally rule-violating stimuli (9%). In contrast, infrequently-performed button presses triggered rule-violating stimuli (9%), but occasionally rule-conforming stimuli (1%). The results showed that visual MMN was elicited by rule-violating stimuli triggered by frequently performed button presses, while it was not elicited by physically the same rule violating stimuli triggered by infrequently-performed button presses. That is, visual MMN was strongly affected by action-based prior information about the occurrence of rule violation. This result suggests that the visual MMN-generating processes can be flexibly controlled in a top-down manner, so that rule violation that can carry significant information is selectively detected. PMID- 25447064 TI - Neural changes associated with the generation of specific past and future events in depression. AB - It is well established that individuals affected by depression experience difficulty in remembering the past and imagining the future. This impairment is evident in increased rumination on non-specific, generic events and in the generation of fewer specific events during tasks tapping past and future thinking. The present fMRI study investigated whether neural changes during the construction of autobiographical events was evident in depression, even when key aspects of performance (event specificity, vividness) were matched. We employed a multivariate technique (Spatiotemporal Partial Least Squares) to examine whether task-related whole brain patterns of activation and functional connectivity of the hippocampus differed between depressed participants and non-depressed controls. Results indicate that although the depression group retained the ability to recruit the default network during the autobiographical tasks, there was reduced activity in regions associated with episodic richness and imagery (e.g., hippocampus, precuneus, cuneus). Moreover, patterns of hippocampal connectivity in the depression group were comparable to those of the control group, but the strength of this connectivity was reduced in depression. These depression-related reductions were accompanied by increased recruitment of lateral and medial frontal regions in the depression group, as well as distinct patterns of right hippocampal connectivity with regions in the default and dorsal attention networks. The recruitment of these additional neural resources may reflect compensatory increases in post-retrieval processing, greater effort and/or greater self-related referential processing in depression that support the generation of specific autobiographical events. PMID- 25447067 TI - Auditory semantic processing in dichotic listening: effects of competing speech, ear of presentation, and sentential bias on N400s to spoken words in context. AB - The effects of ear of presentation and competing speech on N400s to spoken words in context were examined in a dichotic sentence priming paradigm. Auditory sentence contexts with a strong or weak semantic bias were presented in isolation to the right or left ear, or with a competing signal presented in the other ear at a SNR of -12 dB. Target words were congruent or incongruent with the sentence meaning. Competing speech attenuated N400s to both congruent and incongruent targets, suggesting that the demand imposed by a competing signal disrupts the engagement of semantic comprehension processes. Bias strength affected N400 amplitudes differentially depending upon ear of presentation: weak contexts presented to the le/RH produced a more negative N400 response to targets than strong contexts, whereas no significant effect of bias strength was observed for sentences presented to the re/LH. The results are consistent with a model of semantic processing in which the RH relies on integrative processing strategies in the interpretation of sentence-level meaning. PMID- 25447066 TI - Degradation of cognitive timing mechanisms in behavioural variant frontotemporal dementia. AB - The current study examined motor timing in frontotemporal dementia (FTD), which manifests as progressive deterioration in social, behavioural and cognitive functions. Twenty-patients fulfilling consensus clinical criteria for behavioural variant FTD (bvFTD), 11 patients fulfilling consensus clinical criteria for semantic-variant primary progressive aphasia (svPPA), four patients fulfilling criteria for nonfluent/agrammatic primary progressive aphasia (naPPA), eight patients fulfilling criteria for Alzheimer's disease (AD), and 31 controls were assessed on both an externally- and self-paced finger-tapping task requiring maintenance of a regular, 1500 ms beat over 50 taps. Grey and white matter correlates of deficits in motor timing were examined using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). bvFTD patients exhibited significant deficits in aspects of both externally- and self-paced tapping. Increased mean inter-response interval (faster than target tap time) in the self paced task was associated with reduced grey matter volume in the cerebellum bilaterally, right middle temporal gyrus, and with increased axial diffusivity in the right superior longitudinal fasciculus, regions and tracts which have been suggested to be involved in a subcortical-cortical network of structures underlying timing abilities. This suggests that such structures can be affected in bvFTD, and that impaired motor timing may underlie some characteristics of the bvFTD phenotype. PMID- 25447068 TI - Preserved mid-fusiform activation for visual words in a patient with a visual word recognition impairment. AB - Previous functional imaging studies have highlighted the role of left ventral temporal cortex in processing written word forms. We explored activation and anatomical connectivity of this region in HE, a professional writer with alexia as a result of stroke affecting primarily white matter in the left inferior temporal lobe. We used a one-back visual recognition task and functional Magnetic Resonance Imaging to elicit automatic activation to various orthographic and non orthographic stimuli. Surprisingly, HE showed cortical activation in the left mid fusiform area during the presentation of words and word-like stimuli, suggesting that this region's role in processing visual words is intact despite his severely impaired reading. Diffusion Tensor Imaging data further suggest that HE shows an anatomical disconnection between the ventral temporal cortex and posterior middle temporal cortex. Together, these findings suggest that activation of word specific regions of mid-fusiform gyrus is not sufficient to yield the conscious experience of reading in the absence of activity in downstream regions of the classical reading network. PMID- 25447069 TI - The cumulative semantic interference effect in normal and pathological ageing. AB - People affected by mild cognitive impairment (MCI), a precursor of Alzheimer's Disease, present with impairments in picture naming, a lexical/semantic task which rests on the activation of perceptual, semantic, and phonological representations. The poor performance of MCI individuals in picture naming has been accounted for in terms of deficits of either the perceptual, semantic, or phonological stages. To disentangle the source of this deficit we compared the cumulative semantic interference effect (Howard et al., 2006. Cognition. 100, 464 482.) and the repetition priming effect of a group of people with MCI to that of a group of healthy elderly participants and with a group of healthy young participants. The cumulative semantic interference effect defines a linear increase in the picture naming reaction times which is function of the already named pictures belonging to the same semantic category to which the named picture belongs. The repetition priming effect refers to an increase in performance for repeated items compared to unrepeated items. Results showed that whereas the cumulative semantic interference effect was present in the healthy elderly and young samples, it was absent in the MCI sample; instead, all groups showed comparable repetition priming effects. This pattern of results suggests that the impairment in picture naming exhibited by MCI individuals is due to an inefficient semantic access. PMID- 25447071 TI - Effects can precede their cause in the sense of agency. AB - The sense of agency, i.e., the feeling that one's action is the cause of an external sensory event, involves causal inference based on the predicted sensory outcome of a motor act. Here, we investigated whether this inference process faithfully implements the physical principle that a cause (motor act) temporally precedes its effect (external sensory feedback). To this end, we presented participants with visual flashes that were temporally offset from voluntary button presses, including scenarios where the flash occurred shortly before the press. Participants then judged their experience of agency. As expected, cause effect order is an important cue for this task: participants were far more likely to report agency for temporally lagging flashes than for leading flashes, even if very long sensory delays also disrupted the sense of agency (Experiment 1). This suggests that the temporal order between action and sensation is the dominant temporal cue for agency. However, when participants judged whether they had caused a first flash that occurred before the button press or a second flash that occurred afterwards, the temporal threshold for rejecting leading first flashes was relaxed proportionally to the delay of the second flash (Experiment 2). There was competition between different sensorimotor timing cues (temporal order favored the second flash and temporal proximity favored the first flash), and participants' tolerance for cause-effect inversions was modulated by the strength of the later, conflicting cue. We conclude that the perceived order of action and sensation is not used in a winner-take-all fashion in inference of agency. Instead, a probabilistic negotiation of the different timing cues favoring different flash events takes place postdictively, after presentation of the second flash. PMID- 25447070 TI - Working memory and reward association learning impairments in obesity. AB - Obesity has been associated with impaired executive functions including working memory. Less explored is the influence of obesity on learning and memory. In the current study we assessed stimulus reward association learning, explicit learning and memory and working memory in healthy weight, overweight and obese individuals. Explicit learning and memory did not differ as a function of group. In contrast, working memory was significantly and similarly impaired in both overweight and obese individuals compared to the healthy weight group. In the first reward association learning task the obese, but not healthy weight or overweight participants consistently formed paradoxical preferences for a pattern associated with a negative outcome (fewer food rewards). To determine if the deficit was specific to food reward a second experiment was conducted using money. Consistent with Experiment 1, obese individuals selected the pattern associated with a negative outcome (fewer monetary rewards) more frequently than healthy weight individuals and thus failed to develop a significant preference for the most rewarded patterns as was observed in the healthy weight group. Finally, on a probabilistic learning task, obese compared to healthy weight individuals showed deficits in negative, but not positive outcome learning. Taken together, our results demonstrate deficits in working memory and stimulus reward learning in obesity and suggest that obese individuals are impaired in learning to avoid negative outcomes. PMID- 25447072 TI - Prefrontal and parietal activity is modulated by the rule complexity of inductive reasoning and can be predicted by a cognitive model. AB - In neuroimaging studies, increased task complexity can lead to increased activation in task-specific regions or to activation of additional regions. How the brain adapts to increased rule complexity during inductive reasoning remains unclear. In the current study, three types of problems were created: simple rule induction (i.e., SI, with rule complexity of 1), complex rule induction (i.e., CI, with rule complexity of 2), and perceptual control. Our findings revealed that increased activations accompany increased rule complexity in the right dorsal lateral prefrontal cortex (DLPFC) and medial posterior parietal cortex (precuneus). A cognitive model predicted both the behavioral and brain imaging results. The current findings suggest that neural activity in frontal and parietal regions is modulated by rule complexity, which may shed light on the neural mechanisms of inductive reasoning. PMID- 25447073 TI - In situ detection of integrin ligands. AB - Integrins are cell surface receptors for cell adhesion. Integrin-mediated cell adhesion regulates various cellular processes, including cell survival, migration, proliferation, and differentiation. In vivo, ligands for integrins are immobilized within extracellular matrices, insoluble sheet-like or fibrous supramolecular complexes that associate with or surround cells. To better understand the molecular basis of integrin-mediated regulation of cellular behavior in vivo, it is of critical importance to collect information regarding the activities as well as spatial distributions of integrin ligands in situ. This unit describes a protocol for detecting the spatial distribution of the complement of integrin ligands in situ by overlaying soluble recombinant integrins. PMID- 25447074 TI - A High-Content Assay for Biosensor Validation and for Examining Stimuli that Affect Biosensor Activity. AB - Biosensors are valuable tools used to monitor many different protein behaviors in vivo. Demand for new biosensors is high, but their development and characterization can be difficult. During biosensor design, it is necessary to evaluate the effects of different biosensor structures on specificity, brightness, and fluorescence responses. By co-expressing the biosensor with upstream proteins that either stimulate or inhibit the activity reported by the biosensor, one can determine the difference between the biosensor's maximally activated and inactivated state, and examine response to specific proteins. We describe here a method for biosensor validation in a 96-well plate format using an automated microscope. This protocol produces dose-response curves, enables efficient examination of many parameters, and unlike cell suspension assays, allows visual inspection (e.g., for cell health and biosensor or regulator localization). Optimization of single-chain and dual-chain Rho GTPase biosensors is addressed, but the assay is applicable to any biosensor that can be expressed or otherwise loaded in adherent cells. The assay can also be used for purposes other than biosensor validation, using a well-characterized biosensor as a readout for effects of upstream molecules. PMID- 25447075 TI - Standardized isolation and culture of murine liver sinusoidal endothelial cells. AB - Isolation of murine liver sinusoidal endothelial cells (LSECs) is an exacting and finicky procedure. After exhaustive standardization, we were able to devise an easily reproducible protocol which produced consistent results. Moreover, we scripted a protocol which clarifies even the smallest of steps, following which isolation of LSECs is made significantly easier. Using the standardized LSEC isolation protocol herein, we demonstrated that the bacterial toxin pyocyanin (from Pseudomonas aeruginosa) induced a significant dose-dependent reduction in LSEC porosity, this being preventable by the enzyme catalase, but not by the enzyme superoxide dismutase. PMID- 25447076 TI - Analysis of Copy-Number Alterations in Single Cells Using Microarray-Based Comparative Genomic Hybridization (aCGH). AB - In this unit, we describe a workflow that enables array comparative genomic hybridization (aCGH) of single cells. The unit first describes the isolation and preparation of single peripheral mononuclear cells from blood (PBMC) to prepare a suitable reference DNA for aCGH experiments. An alternative procedure is described for the preparation of single cells of GM14667 and GM05423 cell lines to use as reference DNA and for sex-mismatched control experiments. A guide is also provided for micromanipulation of single cells. Next, the unit describes whole-genome amplification using adapter-linker PCR (Ampli1 WGA Kit) and an alternative nonlinear WGA method (PicoPLEX WGA Kit) for single-cell amplification. A protocol is also included for reamplification of Ampli1 WGA products, which can be used for aCGH as well. Finally, the use of 4 * 180k oligonucleotide microarrays to perform aCGH with single-cell WGA products is described. PMID- 25447077 TI - Mapping replication origin sequences in eukaryotic chromosomes. AB - Recent advances in genome-sequencing technology have led to the complete mapping of DNA replication initiation sites in the human genome. This thorough origin mapping facilitates understanding of the relationship between replication initiation events, transcription, and chromatin modifications, and allows the characterization of consensus sequences of potential replication origins. This unit provides a detailed protocol for isolation and sequence analysis of nascent DNA strands. Two variations of the protocol based on non-overlapping assumptions are described below, addressing potential bias issues for whole-genome analyses. PMID- 25447078 TI - Freeze-fracture immunocytochemistry: fracture-label and label-fracture for the localization of membrane proteins. AB - Freeze-fracture is a unique investigative tool for visualization of the en face topography of individual membrane leaflets of cell membranes at high resolution under the electron microscope. The development of a system of freeze-fracture cytochemical and immunocytochemical techniques has further advanced the utility of this methodological approach for high-resolution localization of specific membrane and intracellular macromolecules in tissues and cells. The unit focuses on description, in a step-by-step manner, of the experimental procedures for two specific freeze-fracture labeling techniques, namely fracture-label and label fracture. Users are guided in a stepwise manner, starting from the preparation of tissue or cell samples to the final retrieval and mounting of fracture-label and label-fracture specimens for examination on the electron microscope. PMID- 25447081 TI - Unmasking a naked left atrial appendage closure device: a case of a silent embolic threat. PMID- 25447082 TI - [Editorial]. PMID- 25447079 TI - Increased gluconeogenesis in youth with newly diagnosed type 2 diabetes. AB - AIMS/HYPOTHESIS: The role of increased gluconeogenesis as an important contributor to fasting hyperglycaemia at diabetes onset is not known. We evaluated the contribution of gluconeogenesis and glycogenolysis to fasting hyperglycaemia in newly diagnosed youths with type 2 diabetes following an overnight fast. METHODS: Basal rates (MUmol kg(FFM) (-1) min(-1)) of gluconeogenesis ((2)H2O), glycogenolysis and glycerol production ([(2)H5] glycerol) were measured in 18 adolescents (nine treatment naive diabetic and nine normal-glucose-tolerant obese adolescents). RESULTS: Type 2 diabetes was associated with higher gluconeogenesis (9.2 +/- 0.6 vs 7.0 +/- 0.3 MUmol kg(FFM) (-1) min(-1), p < 0.01), plasma fasting glucose (7.0 +/- 0.6 vs 5.0 +/- 0.2 mmol/l, p = 0.004) and insulin (300 +/- 30 vs 126 +/- 31 pmol/l, p = 0.001). Glucose production and glycogenolysis were similar between the groups (15.4 +/- 0.3 vs 12.4 +/- 1.4 MUmol kg(FFM) (-1) min(-1), p = 0.06; and 6.2 +/- 0.8 vs 5.3 +/- 0.7 MUmol kg(FFM) (-1) min(-1), p = 0.5, respectively). After controlling for differences in adiposity, gluconeogenesis, glycogenolysis and glucose production were higher in diabetic youth (p <= 0.02). Glycerol concentration (84 +/- 6 vs 57 +/- 6 MUmol/l, p = 0.01) and glycerol production (5.0 +/- 0.3 vs 3.6 +/- 0.5 MUmol kg(FFM) (-1) min(-1), p = 0.03) were 40% higher in youth with diabetes. The increased glycerol production could account for only ~1/3 of substrate needed for the increased gluconeogenesis in diabetic youth. CONCLUSION/INTERPRETATIONS: Increased gluconeogenesis was a major contributor to fasting hyperglycaemia and hepatic insulin resistance in newly diagnosed untreated adolescents and was an early pathological feature of type 2 diabetes. Increased glycerol availability may represent a significant source of new carbon substrates for increased gluconeogenesis but would not account for all the carbons required to sustain the increased rates. PMID- 25447080 TI - Cardiac-specific ablation of synapse-associated protein SAP97 in mice decreases potassium currents but not sodium current. AB - BACKGROUND: Membrane-associated guanylate kinase (MAGUK) proteins are important determinants of ion channel organization in the plasma membrane. In the heart, the MAGUK protein SAP97, encoded by the DLG1 gene, interacts with several ion channels via their PDZ domain-binding motif and regulates their function and localization. OBJECTIVE: The purpose of this study was to assess in vivo the role of SAP97 in the heart by generating a genetically modified mouse model in which SAP97 is suppressed exclusively in cardiomyocytes. METHODS: SAP97(fl/fl) mice were generated by inserting loxP sequences flanking exons 1-3 of the SAP97 gene. SAP97(fl/fl) mice were crossed with alphaMHC-Cre mice to generate alphaMHC Cre/SAP97(fl/fl) mice, thus resulting in a cardiomyocyte-specific deletion of SAP97. Quantitative reverse transcriptase-polymerase chain reaction, western blots, and immunostaining were performed to measure mRNA and protein expression levels, and ion channel localization. The patch-clamp technique was used to record ion currents and action potentials. Echocardiography and surface ECGs were performed on anesthetized mice. RESULTS: Action potential duration was greatly prolonged in alphaMHC-Cre/SAP97(fl/fl) cardiomyocytes compared to SAP97(fl/fl) controls, but maximal upstroke velocity was unchanged. This was consistent with the decreases observed in IK1, Ito, and IKur potassium currents and the absence of effect on the sodium current INa. Surface ECG revealed an increased corrected QT interval in alphaMHC-Cre/SAP97(fl/fl) mice. CONCLUSION: These data suggest that ablation of SAP97 in the mouse heart mainly alters potassium channel function. Based on the important role of SAP97 in regulating the QT interval, DLG1 may be a susceptibility gene to be investigated in patients with congenital long QT syndrome. PMID- 25447083 TI - [Necessary or unnecessary? a critical glance on spine surgery]. AB - Patients with complaints and symptoms caused by spinal degenerative diseases demonstrate a high rate of spontaneous improvement. Except of severe neurological symptoms such as high grade motor deficits, medically intractable pain and vegetative symptoms (cauda syndrome) operations require 1) symptoms, 2) a mechanical cause visible on imaging that sufficiently explains the symptoms, 3) a completed conservative treatment protocol performed over a 4) 6-12 week period. According to the evidence found in the literature, patients with lumbar disk herniation significantly benefit from surgery by a faster relieve of pain and return to social and professional activity, however, the results are converging after a period of 1-2 years. Surgery of lumbar spinal stenosis is considered a gold standard and superior to conservative care when symptoms are severe and leg pain is present. Bilateral microsurgical decompression using a bilateral or a unilateral approach with over-the-top decompression of the contralateral nerve root are superior to laminectomy as the decompression procedure. Lumbar fusion is only indicated in patients with spinal stenosis when a major or mobile spondylolisthesis is diagnosed. There is no indication of prophylactic surgery to avoid a "dangerous" deficit that might develop in the future. PMID- 25447084 TI - [The evolving of cardiac interventions]. AB - Treatment modalities for heart diseases have considerable evolved during the last 20 years. Coronary and valvular heart disease are treated increasingly by less invasive percutaneous catheter based procedures instead of open-heart surgery. In addition, new cutting-edge interventions allow to cure heart disease for which until recently only medical treatment options were available. Whilst many patients benefit from these innovative therapies, rapidly developing technologies potentially carry the risk of overtreatment. In order to select patients for the most appropriate treatment, an intensive interdisciplinary teamwork between cardiologists and cardiac surgeons is a mandatory requirement. Additionally, knowledge transfer between cardiologists, their growing subspecialties and practitioners should be encouraged. Finally, timely scientific evaluation of new therapies and subsequent incorporation in guidelines remains crucial. PMID- 25447085 TI - [Unnecessary operations in shoulder surgery: "table of confusion" applied to "field of confusion"]. AB - Attributing a surgical procedure as unnecessary or necessary is a binomial classifier that can be analysed in a so called "table of confusion". Ambroise Parre (1510 - 1590) observed that wound treatment with hot oil was harming instead of healing, and concluded that it should be discarded as "standard of care". Still today, the answer to the same question "What is the standard of care?" is decisive when an operation needs to be classified as "necessary" or "unnecessary". Patients' expectations can also influence the decision making process between surgical and conservative treatment options. Fracture of the humeral head is an example how two different surgical strategies (primary versus secondary joint replacement) can lead to "unnecessary" operation. However, it is only retrospectively that an operation appears unnecessary. Further factors that could be analysed are the delay between decision and operation (so called "test of time") and financial aspects. In conclusion, it is only objective and scientific analysis that can lead to viable standards of care for our practice. This is the only way to protect patients as well as surgeons from unnecessary operations. PMID- 25447086 TI - [Sectio caesarea: actual controversy]. AB - Caesarean section is one of the most frequently performed operations in human medicine. It has become a routine procedure with a very low morbidity and mortality. Over the centuries, it has emerged an essential achievement in obstetric medicine. In the presence of cephalo-pelvic-disproportion, cervical dystocia, malpresentation, preterm birth, macrosomia, placental insufficiency, placenta praevia or fetal distress it is crucial to improve the perinatal morbiditiy and mortality of mother and child. The procedure has become much more frequent over the past 20 years for multiple reasons. There is variety in incidence between countries but also regional differences. It's occurrence is being influenced by level of education and socio-economic status of the pregnant woman. In the meantime, also the longterm consequences of cesarean section are well known. The potential hazards for future pregnancies and deliveries are well described. Actual controversy addresses cesarean section on demand without any medical indication, which in fact is only seldom performed in Switzerland. The ethical justification of this procedure needs to be discussed in view of the current tendency towards autonomy and self-determination of the pregnant woman. PMID- 25447087 TI - [Is hysterectomy nowadays an obsolete procedure?]. AB - After the general morbidity reduction at the beginning of the century and the routine use of prophylactic antibiotics, a hysterectomy was generously, sometimes to generously indicated in the middle of the 20th century. This might be one of the major reasons why the procedure got a bad reputation. Furthermore, in the last decade, several new treatments for benign uterine pathologies have been developed which can be proposed to the patients instead of performing a hysterectomy. Therefore, the question might be asked, if nowadays there are still some indications for a hysterectomy or if the procedure is obsolete. PMID- 25447088 TI - [Changes in indications for surgery in the management of diverticulitis]. AB - Diverticulitis is a common disease in western countries and its incidence is increasing especially among young patients. Colonic diverticulosis, incidentally diagnosed by endoscopy or CT-scanning, has no immediate clinical consequences. Progression to diverticulitis develops in only 4 % of cases. In the last decades management of diverticular disease evolved and expectative treatment and less invasive techniques have gained importance. Elective resection has traditionally been advised after a second episode of diverticulitis or after a first episode if the patient was less than 50 years of age or complicated disease occurred. Recent changes in understanding the natural history of diverticular disease have substantially modified treatment paradigms. Elective resection in case of recurrent diverticular disease should be performed on a individual basis and in cases with complications like intestinal obstruction or fistulas. Primary anastomosis is an option even in emergency surgery due to colonic perforation, while diverting operations are indicated for selected patient groups with a high risk profile. Several prospective studies showed good results for laparoscopic drainage and lavage in the setting of perforated diverticulitis with generalized peritonitis, though this concept needs to be controlled with randomized clinical trials before application into the daily practice. This article should provide a short overview of trends in the surgical treatment of diverticulitis, help to understand the natural history of the disease and thereby explain the currently lower frequency of surgical interventions for diverticulitis. PMID- 25447090 TI - [Incidental appendectomy: standard or unjustified risk?]. AB - Incidental appendectomy is the surgical removal of a macroscopically non-diseased appendix during another primary surgical procedure. The benefits and risks of this surgery give rise to controversy. Incidental appendectomy is contraindicated in patients whose conditions are unstable, with previous diagnosis of Crohn's disease, inaccessible appendix, planned radiation treatment, immunosuppression, vascular grafts or other intraabdominal foreign material. It should be conditional on primary disease, surgical technique (open vs. laparoscopic) and age of the patient. Independently from the surgical technique used, incidental appendectomy should be evaluated in healthy patients younger than 25 years old. In any case, preoperative informed consent is necessary. PMID- 25447089 TI - [Necessary and unnecessary treatment options for hemorrhoids]. AB - Up to one third of the general population suffers from symptoms caused by hemorrhoids. Conservative treatment comes first unless the patient presents with an acute hemorrhoidal prolapse or a thrombosis. A fiber enriched diet is the primary treatment option, recommended in the perioperative period as well as a long-term prophylaxis. A timely limited application of topical ointments or suppositories and/or flavonoids are further treatment options. When symptoms persist interventional procedures for grade I-II hemorrhoids, and surgery for grade III-IV hemorrhoids should be considered. Rubber band ligation is the interventional treatment of choice. A comparable efficacy using sclerosing or infrared therapy has not yet been demonstrated. We therefore do not recommend these treatment options for the cure of hemorrhoids. Self-treatment by anal insertion of bougies is of lowrisk and may be successful, particularly in the setting of an elevated sphincter pressure. Anal dilation, sphincterotomy, cryosurgery, bipolar diathermy, galvanic electrotherapy, and heat therapy should be regarded as obsolete given the poor or missing data reported for these methods. For a long time, the classic excisional hemorrhoidectomy was considered to be the gold standard as far as surgical procedures are concerned. Primary closure (Ferguson) seems to be superior compared to the "open" version (Milligan Morgan) with respect to postoperative pain and wound healing. The more recently proposed stapled hemorrhoidopexy (Longo) is particularly advisable for circular hemorrhoids. Compared to excisional hemorrhoidectomy the Longo-operation is associated with reduced postoperative pain, shorter operation time and hospital stay as well as a faster recovery, with the disadvantage though of a higher recurrence rate. Data from Hemorrhoidal Artery Ligation (HAL)-, if appropriate in combination with a Recto-Anal Repair (HAL/RAR)-, demonstrates a similar trend towards a better tolerance of the procedure at the expense of a higher recurrence rate. These relatively "new" procedures equally qualify for the treatment of grade III and IV hemorrhoids, and, in the case of stapled hemorrhoidopexy, may even be employed in the emergency situation of an acute anal prolapse. While under certain circumstances different treatment options are equivalent, there is a clear specificity with respect to the application of those procedures in other situations. The respective pros and cons need to be discussed separately with every patient. According to their own requirements a treatment strategy has to be defined according to their individual requirements. PMID- 25447091 TI - [The risk-reducing mastectomy: unnecessary hysteria or life-saving prophylaxis?]. AB - The prophylactic (risk-reducing) mastectomy is a world-wide recognized method for specifically treating the increased breast cancer risk in patients showing a BRCA1 and/or BRCA2 mutation as well as other patient groups at increased breast cancer risk. This option should be offered to all patients having the pertinent risk profile. Breast reconstruction is an integral part of the risk-reducing mastectomy procedure and all possible methods of breast reconstruction, especially autologous tissue reconstruction should be offered to all patients having a medical indication and desiring this surgical treatment. These patients are best managed in certified Breast Care Centres where the different medical and surgical specialists can address interdisciplinary all aspects of genetic counselling, preoperative counselling, mastectomy and reconstructive techniques as well as the necessary postoperative surveillance. PMID- 25447092 TI - [Today's cancer medicine: less could often be more]. AB - Modern oncology has much to offer, and the prognosis of cancer patients has undoubtedly improved over the last few decades. Nevertheless, medical and economic toxicities of modern cancer medicine demand that our many tools are viewed with a critical eye. Screening mammography and PSA screening for the detection of early breast, or prostate cancer, resp., are widely used. However, reduction of mortality from these disorders through early detection and treatment is quantitatively modest, whereas overdiagnosis of low-risk cancers and non malignant conditions with these two methods is frequent. Cancer drug therapy increasingly uses predictive bio-markers to select patients (and their tumors) particularly likely to benefit from new drugs. Nevertheless palliative systemic treatment in oncology suffers from over-use of drugs with at times considerable toxicity and cost but little patient gain. It is still common practice to validate new cancer drugs in clinical trials using progression-free survival as a primary endpoint. PFS is easily measurable but often inadequate to discover true clinical benefit (i. e. prolonged overall survival and/or improved lasting quality of life). Licensing agencies such as the FDA or Swissmedic as well as clinical trialists are therefore challenged to review their criteria for the validation of new cancer drugs. Follow-up of cancer patients after treatment is widely practiced, often with "subscription series" for CT- or PET-scans and repetitive lab tests including tumor markers. Early detection of asymptomatic cancer relapse with these methods, however, is only warranted, if early re treatment is proven to prolong survival, as cancer treatment in asymptomatic patients produces toxicity and costs that can only be justified if chances for long-term benefits are bettered. PMID- 25447093 TI - [Who is the decision maker in medicine - the doctor or the patient?]. AB - In earlier times physicians decided on their own which diagnostic tests and treatments the patient should undergo, receive and follow. At least, such physicians' behavior is described in the literature. In recent decades the pendulum moved in the other direction. Nowadays and deservedly so patients have to be actively involved in the process of decision-making. The old fashioned method of decision-making is called the paternalistic model and the modern one the participative model (shared decision making). A prerequisite for being actively involved in the decision process patients have to be informed about their health status and the consequences of different options and potential decisions. There is no plausible reason to question the values of the participative model, but patients also have a right to be not informed about things they do not want to know. Transparency is desirable, but transparency is not 'per se' a good thing only. PMID- 25447094 TI - [Asymptomatic inguinal hernia: is there an indication for surgery]. AB - Until recently, the repair of asymptomatic groin hernia has been advocated as a prophylaxis for incarceration. However, incarcerations of inguinal hernias are rare events and can be treated adequately if the patient presents himself early after onset of symptoms. Randomized controlled trials showed, that watchful waiting is not associated with increased incarcerations and can be offered as a save alternative. However, within seven years after randomization 50 % to 70 % of the patients in the watchful waiting groups required surgery, mainly because of new onset or increasing symptoms. PMID- 25447095 TI - [The general practitioner is amazed, the specialist is astonished - or put differently: unnecessary operations? - a fictive interview with a general practitioner]. AB - From the sight of a General Practitioner time and again certain indications for some interventions on patients in hospitals are questionable. Enough evidence based studies are of great importance, so that the individual evidence of the patient including the view of his General Practitioner can be put in first place when making decisions for interventions. In order to generate as much data with as little time and effort possible, structures for patient-centered care have to be created over the whole therapeutic chain (GPs, specialists, hospitals), where the necessary data can be gathered. In an interview GP Dr. med. H.U. Blunier speaks his mind, about how he is persistently pursuing his goal to develop patient paths across all institutions to finally close the therapy chain in terms of an integrated health care. PMID- 25447099 TI - Epithelial-to-mesenchymal transition in a virally induced cancer. PMID- 25447101 TI - Radical cystectomy: open vs robotic approach. PMID- 25447100 TI - Metastatic renal cell carcinoma presenting as a thyroid mass. PMID- 25447102 TI - Penile cancer: new insights into the "way forward" for this rare disease. PMID- 25447103 TI - Interdisciplinary management of locally advanced and metastatic genitourinary cancers: a team sport. PMID- 25447104 TI - Management of ureterocele? The search for the holy grail. PMID- 25447105 TI - Optimal management of germ cell cancer: more a matter of expertise than of chemotherapy regimen. PMID- 25447106 TI - Autosomal recessive polycystic kidney disease with Caroli syndrome. PMID- 25447107 TI - Overweight and obesity in pediatric secondary pseudotumor cerebri syndrome. AB - PURPOSE: To examine the clinical, demographic, and anthropometric patient characteristics of secondary pseudotumor cerebri syndrome in children and adolescents based on the recently revised diagnostic criteria. DESIGN: Retrospective observational case series. METHODS: Patients seen at a tertiary children's hospital for pseudotumor cerebri syndrome were classified as having either primary idiopathic (n = 59) or secondary pseudotumor cerebri syndrome (n = 16), as rigorously defined by recently revised diagnostic criteria. Outcomes included body mass index Z-scores (BMI-Z), height and weight Z-scores, demographics, and clinical features at presentation, such as headache, sixth nerve palsy, and cerebrospinal fluid (CSF) opening pressure. RESULTS: In this cohort, the associated conditions and exposures seen in definite secondary pseudotumor cerebri syndrome included tetracycline-class antibiotics (n = 11), chronic kidney disease (n = 3), withdrawal from chronic glucocorticoids (n = 1), and lithium (n = 1). Other associations observed in the possible secondary pseudotumor cerebri syndrome group included Down syndrome, vitamin A derivatives, and growth hormone. In comparison with primary pseudotumor cerebri syndrome, definite secondary pseudotumor cerebri syndrome patients were on average older (15.0 vs 11.6 years; P = .003, Mann-Whitney test). According to US Centers for Disease Control (CDC) classifications, 79% of children with secondary pseudotumor cerebri syndrome were either overweight or obese (36% overweight [n = 5] and 43% obese [n = 6]), as compared to 32% nationally. CONCLUSIONS: Even when a potential inciting exposure is identified for pediatric pseudotumor cerebri syndrome, the possible contribution of overweight and obesity should be considered. PMID- 25447108 TI - Circadian macular volume changes in the healthy human choroid. AB - PURPOSE: To investigate a potential circadian fluctuation of the choroidal volume in healthy adults by enhanced depth imaging (EDI) via spectral-domain optical coherence tomography (SD OCT). DESIGN: Prospective observational case series. METHODS: Thirty healthy eyes of 15 healthy subjects with a median age of 26 years (range 22-55) underwent EDI SD OCT scans for macular choroidal volume measurement every 3 hours within a 24-hour period at a single tertiary center. The mean ocular perfusion pressure was calculated for each eye at each of the 8 time points as 2/3(mean arterial pressure-intraocular pressure [IOP]). The circadian fluctuation of the macular choroidal volume as well as the association with axial length, mean ocular perfusion pressure, or IOP was assessed using a linear mixed model. RESULTS: Macular choroidal volume showed a significant circadian fluctuation (P < .05) and was lowest at midday (mean +/- SD, 10.14 +/- 2.62 mm(3)) and highest at 3 AM (mean +/- SD, 10.66 +/- 2.70 mm(3)). Of all factors tested, only mean ocular perfusion pressure showed a significant association with macular choroidal volume fluctuation (P = .016). CONCLUSIONS: Macular choroidal volume shows a significant circadian pattern with higher values at night and lower values during the day in young adults. Besides time, mean ocular perfusion pressure is significantly associated with this fluctuation. PMID- 25447109 TI - Comparison of smartphone ophthalmoscopy with slit-lamp biomicroscopy for grading diabetic retinopathy. AB - PURPOSE: To assess the accuracy and reliability of smartphone ophthalmoscopy, we compared the ability of a smartphone ophthalmoscope with that of a slit-lamp biomicroscope to grade diabetic retinopathy (DR) in patients with diabetes mellitus (DM). DESIGN: Clinical-based, prospective, comparative instrument study. METHODS: This comparative clinical study was performed in 120 outpatients (240 eyes) with type 1 or type 2 DM. After pupil dilation, the patients underwent smartphone ophthalmoscopy with the D-Eye device, followed by dilated retinal slit lamp examination, to grade DR according to a 5-step scale. RESULTS: Overall exact agreement between the 2 methods was observed in 204 of 240 eyes (85%) (simple kappa = 0.78; CI 0.71-0.84) and agreement within 1 step was observed in 232 eyes (96.7%). Compared to biomicroscopy, the sensitivity and specificity of smartphone ophthalmoscopy for the detection of clinically significant macular edema were 81% and 98%, respectively. Smartphone ophthalmoscopy and biomicroscopy could not be used to examine the fundus and grade DR in 9 eyes (3.75%) and 4 eyes (1.7%), respectively, because of cataract and/or small pupil diameter. CONCLUSION: Smartphone ophthalmoscopy showed considerable agreement with dilated retinal biomicroscopy for the grading of DR. The portability, affordability, and connectivity of a smartphone ophthalmoscope make smartphone ophthalmoscopy a promising technique for community screening programs. PMID- 25447110 TI - Iris suture fixation of subluxated intraocular lenses. AB - PURPOSE: To assess the results of iris suture fixation of subluxated intraocular lenses. DESIGN: Retrospective study. METHODS: This was a nonrandomized chart review of eyes with subluxated intraocular lenses that underwent iris suture fixation at an academic institutional care center. Seventy-two eyes of 67 consecutive patients were included. The following cases were excluded: posterior dislocations necessitating pars plana vitrectomy; secondary implantations for aphakia; and iris suture fixation at primary cataract extraction. Main outcome measures included visual acuity improvement, surgically induced astigmatism, and postsurgical complications. RESULTS: The mean follow-up duration was 16.64 +/- 24.37 months (median = 4.03 months). All patients had preoperative monocular diplopia or unstable vision attributable to the subluxated intraocular lenses, and 40.3% of them required aphakic correction. There was an overall improvement in best-corrected visual acuity from a mean preoperative logMAR 0.35 +/- 0.32 (Snellen equivalent~20/45) to logMAR 0.21 +/- 0.25 (20/32, P = .001). There was no significant change in astigmatism secondary to the surgery. The mean difference in preoperative keratometry readings was 1.6 +/- 1.07 diopter (D), whereas the mean postoperative manifest refraction astigmatic error (vertexed to the corneal surface) was 1.29 +/- 0.92 D (P < .02). Re-subluxations occurred in 7 eyes during follow-up; the majority of these eyes underwent repeat fixation. Most (93.55%) intraocular lenses were stable and centered at the final follow-up. Glaucoma developed in 2 eyes postoperatively. CONCLUSIONS: Iris suture fixation of subluxated intraocular lenses was efficacious for the eyes included in this study, and it led to long-term stability of the intraocular lenses in 93.55% of cases. PMID- 25447112 TI - Optical density ratio in the subretinal fluid: differentiating chronic central serous chorioretinopathy and polypodial choroidal vasculopathy. AB - PURPOSE: To investigate the differences in the optical density ratios between chronic central serous chorioretinopathy (CSC) and polypoidal choroidal vasculopathy (PCV) obtained from subretinal fluid (SRF) analyses to identify the diagnostic role of optical density ratios. DESIGN: Retrospective cohort study. METHODS: Patients with acute CSC (n = 36), chronic CSC (n = 38), and PCV (n = 32) were included in the study. Spectral-domain optical coherence tomography (SD OCT) images of SRF were analyzed. The optical density measurements were obtained by using ImageJ. The optical density ratios were calculated from the SRF to the vitreous, retinal pigment epithelium (RPE), and retinal nerve fiber layer (RNFL) reflectivity ratios. RESULTS: Optical density ratios of SRF to the vitreous, RPE, and RNFL were significantly higher in patients with PCV than in those with chronic CSC (P = .002, P = .001, P = .001). There was no significant difference between acute and chronic CSC (P = .358, P = .433, P = .774). RPE reflectivity was significantly different between groups (P = .002) but no significant difference in vitreous and RNFL reflectivity were detected between groups (P = .172, P = .171). CONCLUSIONS: The optical density ratio differs significantly between chronic CSC and PCV, but not between chronic and acute CSC. This suggests the usefulness of this parameter in differentiating between chronic CSC resembling PCV and PCV itself. PMID- 25447111 TI - Advanced imaging for glaucoma study: design, baseline characteristics, and inter site comparison. AB - PURPOSE: To report the baseline characteristics of the participants in the Advanced Imaging for Glaucoma Study. To compare the participating sites for variations among subjects and the performance of imaging instruments. DESIGN: Multicenter longitudinal observational cohort study. METHODS: A total of 788 participants (1329 eyes) were enrolled from 3 academic referral centers. There were 145 participants (289 eyes) in the normal group, 394 participants (663 eyes) in the glaucoma suspect/preperimetric glaucoma group, and 249 participants (377 eyes) in the perimetric glaucoma group. Participants underwent a full clinical examination, standard automated perimetry, and imaging with time-domain and Fourier-domain optical coherence tomography (OCT), scanning laser polarimetry, and confocal scanning laser ophthalmoscopy. The baseline average, population standard deviation, and repeatability of imaging-derived anatomic variables were reported for each technology and center. RESULTS: Compared to the normal participants, glaucoma suspect/preperimetric glaucoma and perimetric glaucoma groups had significantly reduced anatomic measurements. Repeatability of nerve fiber layer thickness was best for Fourier-domain OCT (overall coefficient of variation <2%), followed by time-domain OCT (coefficient of variation 2%-2.9%), scanning laser polarimetry (coefficient of variation 2.6%-4.5%), and confocal scanning laser ophthalmoscopy rim area (coefficient of variation 4.2%-7.6%). A mixed-effects model showed that the differences between sites was less than 25 percent of the variation within groups and less than the differences between the normal and glaucoma suspect/preperimetric glaucoma group. CONCLUSIONS: Site-to site variation was smaller than both the variation within groups and the changes attributable to glaucoma. Therefore pooling of participants between sites is appropriate. PMID- 25447113 TI - Short-term enhancement of visual field sensitivity in glaucomatous eyes following surgical intraocular pressure reduction. AB - PURPOSE: To examine the hypothesis that surgical intraocular pressure (IOP) reduction leads to enhancement of visual field (VF) sensitivity in glaucomatous eyes. DESIGN: Prospective case-control study. METHODS: Patients with uncontrolled IOP requiring trabeculectomy or aqueous drainage device were enrolled. Controls consisted of medically treated glaucoma patients with stable IOP and no change in medical therapy during follow-up. Two baseline preoperative VFs and 3 follow-up VF examinations at 1, 2, and 3 months postoperatively were used for analysis. The same number of VF examinations measured within an 18-month interval was used for control eyes. VF locations with significant change were defined as exceeding 95% test-retest confidence limits based upon the mean sensitivity using the 2 baseline VF exams. The number of significantly changing locations per eye and changes in mean and pattern standard deviation (PSD) from the mean baseline fields were compared between groups using a Poisson generalized estimating equation model. RESULTS: Thirty eyes of 30 surgically treated glaucoma patients and 41 eyes of 28 stable controls were enrolled. Postoperative IOP was decreased at follow-up 3 compared with baseline (P < .001) in the surgical eyes, but was similar in control eyes (P = .92). At follow-up 3, the number of test locations improving in central (P = .014) and peripheral (P = .019) VF locations was significantly greater in the surgical eyes. The number of eyes with improved PSD at follow-up 3 was significantly greater in the surgical eyes compared with controls (P = .02). CONCLUSIONS: Short-term enhancement of central and peripheral VF sensitivity occurs after surgical reduction of IOP in glaucomatous eyes and may represent a potential biomarker for retinal ganglion cell response to therapeutic interventions in glaucoma. PMID- 25447114 TI - Changes in macular thickness after Descemet stripping automated endothelial keratoplasty. AB - PURPOSE: To assess changes in macular thickness after Descemet stripping automated endothelial keratoplasty (DSAEK), using optical coherence tomography. DESIGN: Prospective interventional case series. METHODS: setting: Institutional. patients and intervention: Thirty-three eyes of 31 patients who had Fuchs dystrophy or pseudophakic bullus keratopathy (PBK) and underwent DSAEK or combined DSAEK with cataract surgery. main outcome measure: Changes in macular thickness. RESULTS: There were 7 eyes with Fuchs endothelial dystrophy and 9 eyes with pseudophakic bullous keratopathy (PBK) that underwent DSAEK, and 17 eyes with Fuchs endothelial dystrophy and cataract that underwent combined DSAEK with phacoemulsification cataract surgery. For the whole group there was a significant increase of 19.32 MUm in macular thickness at 1 month after surgery (P = .025). At 3 months the increase of 10.33 MUm was not statistically significant (P = .192). For the Fuchs endothelial dystrophy there was a mean increase of 11.83 MUm and a mean decrease of 9 MUm at 1 and 3 months, respectively. For the PBK group there was an increase of 12.37 MUm and 2.428 MUm at 1 month (P = .603) and at 3 months after surgery (P = .883), respectively. These changes were not significant. For the Fuchs endothelial dystrophy and cataract group there was a significant increase of 26.50 MUm at 1 month (P = .012) and 23.15 MUm at 3 months after surgery (P = .038). CONCLUSIONS: Macular thickness significantly increased after DSAEK combined with cataract surgery but did not change significantly when only DSAEK was performed. PMID- 25447115 TI - Risk factors for geographic atrophy after intravitreal ranibizumab injections for retinal angiomatous proliferation. AB - PURPOSE: To describe the risk factors for the development of geographic atrophy (GA) following intravitreal ranibizumab injection treatment for retinal angiomatous proliferation (RAP). DESIGN: Retrospective interventional series. METHODS: Forty-three eyes (38 South Korean patients) from patients being treated for naive RAP with intravitreal ranibizumab injection were included in this study. All patients were treated with an initial series of 3 monthly loading injections, followed by further injections as required. Baseline ocular characteristics and lesion features assessed using fluorescein angiography (FA), indocyanine angiography (ICGA), and spectral-domain optical coherence tomography (SD OCT) were evaluated as potential risk factors for GA through 2 years of follow-up. RESULTS: At 2 years follow-up, GA had developed in 16 of 43 eyes (37.2%). The mean number of ranibizumab injections was 7.52 +/- 2.11. Using multiple logistic regression, thinning of the subfoveal choroid at baseline (odds ratio [OR], 0.955; 95% confidence interval [CI], 0.929-0.982; P = .002), presence of reticular pseudodrusen (OR, 1.092; 95% CI, 1.017-1.485; P = .039), and presence of GA in the fellow eye at baseline (OR, 1.433; 95% CI, 1.061-1.935; P = .025) were identified as significant risk factors for GA development. CONCLUSIONS: GA developed in 37.2% of eyes with RAP during the 24 months following intravitreal ranibizumab injections. Subfoveal choroidal thinning at baseline, the presence of reticular pseudodrusen, and the presence of GA in the fellow eye at baseline were associated with increased risk of GA development after treatment. PMID- 25447116 TI - Clinical features and incidence rates of ocular complications in patients with ocular syphilis. AB - PURPOSE: To describe the clinical outcomes of ocular syphilis. DESIGN: Retrospective chart review. METHODS: The charts of patients with ocular syphilis (regardless of human immunodeficiency virus [HIV] status) seen in a uveitis referral center between 1984 and 2014 were reviewed. RESULTS: The study included 35 patients (61 eyes). Panuveitis was the most common type of ocular inflammation (28 eyes), independent of HIV status. Thirty-three of 35 patients received systemic antibiotics with 24 patients treated with intravenous (IV) penicillin only. When compared to the HIV-positive patients, HIV-negative patients with ocular syphilis were older (P < .001), were more likely to be female (P = .004), and had poorer visual acuity at presentation (P = .01). During follow-up, the incidence rates of visual impairment were 0.29 per eye-year (EY; 95% confidence interval [CI]: 0.06/EY-0.86/EY) and 0.12/EY (95% CI: 0.01/EY-0.42/EY) among the HIV-negative and the HIV-positive patients, respectively. The incidence of blindness was 0.07/EY (95% CI: 0.009/EY-0.27/EY) and 0.06/EY (95% CI: 0.002/EY 0.35/EY) among the HIV-negative and the HIV-positive patients, respectively. Longer duration of uveitis prior to diagnosis and chorioretinitis in the macula at presentation were associated with >= 2 Snellen lines of visual loss (P < .01) and visual acuity loss to 20/50 or worse (P = .03) in HIV-negative patients, respectively. CONCLUSIONS: Syphilis is an uncommon cause of ocular inflammation in both HIV-negative and HIV-positive patients. Visual loss and ocular complications were common among HIV-negative patients even with systemic antibiotic treatment. Delay of diagnosis and chorioretinitis in the macula were associated with visual loss in these patients. PMID- 25447117 TI - Handheld reflectance confocal microscopy for the diagnosis of conjunctival tumors. AB - PURPOSE: To evaluate whether the handheld in vivo reflectance confocal microscopy that has been recently developed for the study of skin tumors is suitable for the diagnosis of conjunctival tumors. DESIGN: Prospective study, observational case series. METHODS: We prospectively evaluated the reflectance confocal microscopy features of 53 conjunctival lesions clinically suspicious for tumors of 46 patients referred to the University Hospital of Saint-Etienne (France) by using the handheld device. Twenty-three lesions were excised (3 nevi, 10 melanomas, 5 squamous cell carcinoma, 2 lymphomas, and 3 pinguecula/pterygium) while the other 30, presenting no reflectance confocal microscopy malignant features, were under follow-up for at least 1 year. Clinical reflectance confocal microscopy and histologic diagnosis were compared. RESULTS: In vivo reflectance confocal microscopy diagnosis was in agreement with the histologic diagnosis in all cases and none of the lesions that were not excised show any clinical progression under follow-up. CONCLUSION: In vivo reflectance confocal microscopy with a handheld dermatology-dedicated microscope can play a role in the noninvasive diagnosis of conjunctival lesions. Further studies should be performed to better define the diagnostic ability of this technique. PMID- 25447118 TI - Macular ganglion cell imaging study: interocular symmetry of ganglion cell-inner plexiform layer thickness in normal healthy eyes. AB - PURPOSE: To determine cutoffs for interocular differences in ganglion cell-inner plexiform layer thickness in normal healthy eyes and to evaluate the diagnostic performance of these values for differentiating between normal subjects and glaucoma patients. DESIGN: Observational, cross-sectional study. METHODS: Macular and optic disc scanning were performed in 275 normal subjects, 58 glaucoma patients, and 58 normal controls by high-definition optical coherence tomography. The ganglion cell-inner plexiform layer thickness was calculated, and the normal ranges of the interocular differences were determined as 2.5th and 97.5th percentiles. The signed and absolute interocular differences were compared between normal subjects and glaucoma patients. RESULTS: The mean +/- standard deviation interocular difference in the average ganglion cell-inner plexiform layer thickness thickness was 0.10 +/- 2.31 MUm, which was not statistically significant (P = .466). The 2.5th and 97.5th percentiles of the interocular difference were -4.10 MUm and +5.00 MUm, respectively. On multiple regression analysis, the interocular difference in axial length was correlated with the interocular difference in average ganglion cell-inner plexiform layer thickness thickness (beta = 2.044, P = .003). The signed and absolute interocular differences in ganglion cell-inner plexiform layer thickness were higher in glaucoma patients than in normal subjects (all P < .001). Sensitivity and specificity of absolute interocular differences ranged from 25.9% to 51.7% and from 93.1% to 100.0%, respectively. CONCLUSIONS: Ganglion cell-inner plexiform layer thickness shows significant interocular symmetry in normal subjects. An absolute interocular difference exceeding normal limits may be indicative of glaucoma. PMID- 25447119 TI - High prevalence of PRPH2 in autosomal dominant retinitis pigmentosa in france and characterization of biochemical and clinical features. AB - PURPOSE: To assess the prevalence of PRPH2 in autosomal dominant retinitis pigmentosa (adRP), to report 6 novel mutations, to characterize the biochemical features of a recurrent novel mutation, and to study the clinical features of adRP patients. DESIGN: Retrospective clinical and molecular genetic study. METHODS: Clinical investigations included visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging, and electroretinogram (ERG) recording. PRPH2 was screened by Sanger sequencing in a cohort of 310 French families with adRP. Peripherin-2 protein was produced in yeast and analyzed by Western blot. RESULTS: We identified 15 mutations, including 6 novel and 9 previously reported changes in 32 families, accounting for a prevalence of 10.3% in this adRP population. We showed that a new recurrent p.Leu254Gln mutation leads to protein aggregation, suggesting abnormal folding. The clinical severity of the disease in examined patients was moderate with 78% of the eyes having 1-0.5 of visual acuity and 52% of the eyes retaining more than 50% of the visual field. Some patients characteristically showed vitelliform deposits or macular involvement. In some families, pericentral RP or macular dystrophy were found in family members while widespread RP was present in other members of the same families. CONCLUSIONS: The mutations in PRPH2 account for 10.3% of adRP in the French population, which is higher than previously reported (0%-8%) This makes PRPH2 the second most frequent adRP gene after RHO in our series. PRPH2 mutations cause highly variable phenotypes and moderate forms of adRP, including mild cases, which could be underdiagnosed. PMID- 25447120 TI - Distribution and determinants of choroidal thickness and volume using automated segmentation software in a population-based study. AB - PURPOSE: To objectively quantify choroidal thickness and choroidal volume using fully automated choroidal segmentation software applied to images obtained from enhanced depth imaging spectral-domain optical coherence tomography (EDI SD OCT) in a population-based study; and evaluate the ocular and systemic determinants of choroidal thickness and choroidal volume. DESIGN: Prospective cross-sectional study. METHODS: Participants ranging in age from 45 to 85 years were recruited from the Singapore Malay Eye Study-2 (SiMES-2), a follow-up population-based study. All participants (n = 540) underwent a detailed ophthalmic examination, including EDI SD OCT for measurements of thickness and volume of the choroid. RESULTS: The intrasession repeatability of choroidal thickness at 5 measured horizontal locations and macular choroidal volume using automated choroidal segmentation software was excellent (intraclass correlation coefficient, 0.97 0.99). Choroid was significantly thicker under the fovea (242.28 +/- 97.58 MUm), followed by 3 mm temporal (207.65 +/- 80.98 MUm), and was thinnest at 3 mm nasal (142.44 +/- 79.19 MUm) location. The mean choroidal volume at central macular region (within a circle of 1 mm diameter) was 0.185 +/- 0.69 mm(3). Among the range of ocular and systemic factors studied, age, sex, and axial length were the only significant predictors of choroidal thickness and choroidal volume (all P < .05). CONCLUSIONS: Using a new automated choroidal segmentation software, we provide fast, reliable, and objective measurements of choroidal thickness and volume in a population-based sample. Male sex, younger age, and shorter axial length are the factors independently associated with thicker choroid and larger choroidal volume. These factors should be taken into consideration when interpreting EDI SD OCT-based choroidal thickness measurements in clinics. PMID- 25447121 TI - Erythrocyte sedimentation rate as baseline predictor for the development of uveitis in children with juvenile idiopathic arthritis. AB - PURPOSE: To analyze inflammatory parameters as possible predictors for the development of uveitis in juvenile idiopathic arthritis (JIA) patients. Further, to analyze the predictive value of demographic and clinical factors at the onset of arthritis. DESIGN: Retrospective cohort study. METHODS: In 358 children with oligoarthritis and rheumatoid factor-negative polyarthritis, erythrocyte sedimentation rate (ESR), C-reactive protein, leukocyte count, presence of antinuclear antibodies (ANA), presence of human leukocyte antigen (HLA-)B27, age of onset of JIA, and sex were analyzed for their predictive value for the onset of uveitis. RESULTS: One hundred forty-seven patients (41%) were diagnosed with chronic anterior uveitis. Young age of onset, presence of ANA, and elevated ESR appeared to be predictive factors according to univariate analyses (P = .029, P = .007, and P = 5E(-4), respectively). According to multivariate analysis, young age of onset and elevated ESR appeared to be predictive after adjusting for the other relevant factors (P = .004 and P = .001, respectively). A prediction model was developed. CONCLUSIONS: Elevated ESR appears to be a predictor for the occurrence of uveitis in patients with JIA. Since ESR is already routinely tested in patients with recently diagnosed arthritis, its use as a biomarker can easily be implemented in daily practice. PMID- 25447122 TI - Rapid discrimination of slimming capsules based on illegal additives by electronic nose and flash gas chromatography. AB - The discrimination of counterfeit and/or illegally manufactured medicines is an important task in the pharmaceutical industry for pharmaceutical safety. In this study, 22 slimming capsule samples with illegally added sibutramine and phenolphthalein were analyzed by electronic nose and flash gas chromatography. To reveal the difference among the different classes of samples, principal component analysis and linear discriminant analysis were employed to analyze the data acquired from electronic nose and flash gas chromatography, respectively. The samples without illegal additives can be discriminated from the ones with illegal additives by using electronic nose or flash gas chromatography data individually. To improve the performance of classification, a data fusion strategy was applied to integrate the data from electronic nose and flash gas chromatography data into a single model. The results show that the samples with phenolphthalein, sibutramine and both can be classified well by using fused data. PMID- 25447123 TI - Identification and initial characterisation of a Plasmodium falciparum Cox17 copper metallochaperone. AB - Copper is an essential micronutrient for all living organisms as an important catalytic co-factor for key enzymes. In higher eukaryotes intracellular copper is distributed by copper metallochaperones. Copper chelators such as neocuproine and tetrathiomolybdate inhibit Plasmodium falciparum erythrocytic development, indicating a requirement for copper by the parasite. A screen of the P. falciparum genome database identified eight potential copper-requiring protein orthologs, including four candidate copper metallochaperones implicated in the delivery of copper to cytochrome-c oxidase. A P. falciparum Cox17 ortholog (PfCox17) was recombinantly expressed and the purified protein bound reduced copper in vitro. PfCox17 was localised to the parasite cytoplasm. Characterisation of plasmodial proteins involved in copper metabolism will help us understand the role of this essential microelement in plasmodial homeostasis. PMID- 25447124 TI - Target validation of the inosine monophosphate dehydrogenase (IMPDH) gene in Cryptosporidium using Phylomer((r)) peptides. AB - Cryptosporidiosis, a gastroenteric disease characterised mainly by diarrheal illnesses in humans and mammals is caused by infection with the protozoan parasite Cryptosporidium. Treatment options for cryptosporidiosis are limited, with the current therapeutic nitazoxanide, only partly efficacious in immunocompetent individuals. The parasite lacks de novo purine synthesis, and is exclusively dependant on purine salvage from its host. Inhibition of the inosine 5' monophosphate dehydrogenase (IMPDH), a purine salvage enzyme that is essential for DNA synthesis, thereby offers a potential drug target against this parasite. In the present study, a yeast-two-hybrid system was used to identify Phylomer peptides within a library constructed from the genomes of 25 phylogenetically diverse bacteria that targeted the IMPDH of Cryptosporidium parvum (IMPcp) and Cryptosporidium hominis (IMPch). We identified 38 unique interacting Phylomers, of which, 12 were synthesised and screened against C. parvum in vitro. Two Phylomers exhibited significant growth inhibition (81.2-83.8% inhibition; P < 0.05), one of which consistently exhibited positive interactions with IMPcp and IMPch during primary and recapitulation yeast two-hybrid screening and did not interact with either of the human IMPDH proteins. The present study highlightsthe potential of Phylomer peptides as target validation tools for Cryptosporidium and other organisms and diseases because of their ability to bind with high affinity to target proteins and disrupt function. PMID- 25447125 TI - Ox40L-Ox40 pathway plays distinct roles in regulating Th2 responses but does not determine outcome of cutaneous leishmaniasis caused by Leishmania mexicana and Leishmania major. AB - Ox40 ligand (Ox40L)-Ox40 pathway has been shown to enhance Th2 responses and play a role in pathogenesis of cutaneous leishmaniasis (CL) caused by Leishmania major. Using Ox40l(-/-) BALB/c mice we analyzed the role of this pathway in determining the outcome to CL caused by L. mexicana and compared to L. major. Contrary to our expectations, Ox40l(-/-) mice were highly susceptible to both L. major (LV39) and L. mexicana (M379) and developed large non-healing lesions containing parasites comparable to Ox40l(+/+) BALB/c mice. Interestingly, upon in vitro stimulation with Leishmania antigen (LmAg), the lymph node cells from L. major infected Ox40l(-/-) mice produced significantly less IL-4 and IL-10 compared to Ox40l(+/+) mice. L. mexicana infected Ox40l(-/-) and Ox40l(+/+) mice did not show any difference in the production of IL-4 and IL-10. No difference was noted in the amount of Th1 cytokines IFN-? and IL-12 produced by Ox40l(-/-) and Ox40l(+/+) mice infected with either parasite. These results indicate that the Ox40L-Ox40 pathway promotes Th2 bias only in L. major infection but not L. mexicana infection and this pathway is not critical for susceptibility to CL. PMID- 25447126 TI - Understanding of the molecular evolution of deafness-associated pathogenic mutations of connexin 26. AB - Connexins (Cxs) were first identified as subunit proteins of the intercellular membrane channels that cluster in the cell communication structures known as gap junctions. Mutations in the gap junction beta2 (GJB2) gene encoding connexin 26 (Cx26) have been linked to sporadic and hereditary hearing loss. In some cases, the mechanisms through which these mutations lead to hearing loss have been partly elucidated using cell culture systems and animal models. The goal of this study was to re-assess the pathogenic roles of the GJB2 mutations by combining comparative evolutionary studies. We used Bayesian phylogenetic analyses to determine the relationships among 35 orthologs and to calculate the ancestral sequences of these orthologs. By aligning sequences from the 35 orthologs and their ancestors and categorizing amino acid sites by degree of conservation, we used comparative evolutionary methods to determine potential functionally important amino acid sites in Cx26 and to identify missense changes that are likely to affect function. We identified six conserved regions in Cx26, five of which are located in the Connexin_CCC, and another is in the connexin super family domain. Finally, we identified 51 missense changes that are likely to disrupt function, and the probability of these changes occurring at hydrophilic amino acid residues was twice that of occurring at hydrophobic residues in the trans-membrane regions of Cx26. Our findings, which were obtained by combining comparative evolutionary methods to predict Cx26 mutant function, are consistent with the pathogenic characteristics of Cx26 mutants. This study provides a new pathway for studying the role of aberrant Cx26 in hereditary hearing loss. PMID- 25447128 TI - Risk factors: sickle cell trait increases the risk of chronic kidney disease. PMID- 25447129 TI - Glomerular disease: thrombospondin type-1 domain-containing 7A-a new player in membranous nephropathy. PMID- 25447127 TI - Heterochromatin and molecular characterization of DsmarMITE transposable element in the beetle Dichotomius schiffleri (Coleoptera: Scarabaeidae). AB - Cytogenetic studies of the Neotropical beetle genus Dichotomius (Scarabaeinae, Coleoptera) have shown dynamism for centromeric constitutive heterochromatin sequences. In the present work we studied the chromosomes and isolated repetitive sequences of Dichotomius schiffleri aiming to contribute to the understanding of coleopteran genome/chromosomal organization. Dichotomius schiffleri presented a conserved karyotype and heterochromatin distribution in comparison to other species of the genus with 2n = 18, biarmed chromosomes, and pericentromeric C positive blocks. Similarly to heterochromatin distributional patterns, the highly and moderately repetitive DNA fraction (C 0 t-1 DNA) was detected in pericentromeric areas, contrasting with the euchromatic mapping of an isolated TE (named DsmarMITE). After structural analyses, the DsmarMITE was classified as a non-autonomous element of the type miniature inverted-repeat transposable element (MITE) with terminal inverted repeats similar to Mariner elements of insects from different orders. The euchromatic distribution for DsmarMITE indicates that it does not play a part in the dynamics of constitutive heterochromatin sequences. PMID- 25447130 TI - Transplantation: levofloxacin treatment does not prevent BK virus infection. PMID- 25447131 TI - Transplantation: induction of chimerism and immune tolerance using belatacept. PMID- 25447134 TI - Continue to improve women's health: ICPD Beyond 2014. PMID- 25447132 TI - Causes and pathogenesis of focal segmental glomerulosclerosis. AB - Focal segmental glomerulosclerosis (FSGS) describes both a common lesion in progressive kidney disease, and a disease characterized by marked proteinuria and podocyte injury. The initial injuries vary widely. Monogenetic forms of FSGS are largely due to alterations in structural genes of the podocyte, many of which result in early onset of disease. Genetic risk alleles in apolipoprotein L1 are especially prevalent in African Americans, and are linked not only to adult-onset FSGS but also to progression of some other kidney diseases. The recurrence of FSGS in some transplant recipients whose end-stage renal disease was caused by FSGS points to circulating factors in disease pathogenesis, which remain incompletely understood. In addition, infection, drug use, and secondary maladaptive responses after loss of nephrons from any cause may also cause FSGS. Varying phenotypes of the sclerosis are also manifest, with varying prognosis. The so-called tip lesion has the best prognosis, whereas the collapsing type of FSGS has the worst prognosis. New insights into glomerular cell injury response and repair may pave the way for possible therapeutic strategies. PMID- 25447135 TI - Survival and innovation: The role of mutational robustness in evolution. AB - Biological systems are resistant to perturbations caused by the environment and by the intrinsic noise of the system. Robustness to mutations is a particular aspect of robustness in which the phenotype is resistant to genotypic variation. Mutational robustness has been linked to the ability of the system to generate heritable genetic variation (a property known as evolvability). It is known that greater robustness leads to increased evolvability. Therefore, mechanisms that increase mutational robustness fuel evolvability. Two such mechanisms, molecular chaperones and gene duplication, have been credited with enormous importance in generating functional diversity through the increase of system's robustness to mutational insults. However, the way in which such mechanisms regulate robustness remains largely uncharacterized. In this review, I provide evidence in support of the role of molecular chaperones and gene duplication in innovation. Specifically, I present evidence that these mechanisms regulate robustness allowing unstable systems to survive long periods of time, and thus they provide opportunity for other mutations to compensate the destabilizing effects of functionally innovative mutations. The findings reported in this study set new questions with regards to the synergy between robustness mechanisms and how this synergy can alter the adaptive landscape of proteins. The ideas proposed in this article set the ground for future research in the understanding of the role of robustness in evolution. PMID- 25447136 TI - N-Glycosylation of the archaellum filament is not important for archaella assembly and motility, although N-Glycosylation is essential for motility in Sulfolobus acidocaldarius. AB - N-Glycosylation is one of the predominant posttranslational modifications, which is found in all three domains of life. N-Glycosylation has been shown to influence many biological aspects of proteins, like protein folding, stability or activity. In this study we demonstrate that the archaellum filament subunit FlaB of Sulfolobus acidocaldarius is N-glycosylated. Each of the six predicted N Glycosylation sites within FlaB are modified with the attachment of an N-glycan. Although, it has been previously shown that N-Glycosylation is essential for motility in S. acidocaldarius, as defects in the N-Glycosylation process resulted in none or reduced motile cells, strains lacking one to all six N-Glycosylation sites within FlaB still remained motile. Deletion of the first five N Glycosylation sites in FlaB did not significantly affect the motility, whereas removal of all six N-Glycosylation sites reduced motility by about 40%. Transmission electron microscopy analyses of non glycosylated and glycosylated archaellum filament revealed no structural change in length. Therefore N Glycosylation does not appear to be important for the stability and assembly of the archaellum filament itself, but plays a role in other parts of the archaellum assembly. PMID- 25447133 TI - Histopathology of MPGN and C3 glomerulopathies. AB - 'Membranoproliferative' describes glomerular injury characterized by capillary wall thickening and mesangial expansion owing to increased matrix deposition and hypercellularity. The presence of immune deposits is indicative of membranoproliferative glomerulonephritis (MPGN). Historically, MPGN was further classified into three types according to the appearance and site of the electron dense deposits seen by electron microscopy, but it is now recognized that many cases show only deposition of the complement component C3, owing to abnormal control of the alternative pathway of complement activation-these cases are now classified as C3 glomerulopathies. Not all cases of C3 glomerulopathy, however, show an MPGN pattern. C3 glomerulopathies include dense deposit disease, which shows dense osmiophilic deposits, and C3 glomerulonephritis, which shows isolated deposits. In many cases, the genetic mutations or autoantibodies responsible for C3 deposition have been identified. Some patients in whom complement control is abnormal will accumulate small amounts of immunoglobulin in their glomeruli and so, in everyday practice, the morphological diagnosis of 'glomerulonephritis with dominant C3' is useful for identifying patients who require investigation of the complement pathway. The recognition that many cases of MPGN are C3 glomerulopathies and that the underlying cause can often be identified in immunoglobulin-associated cases means that the diagnosis of idiopathic MPGN is now very uncommon. PMID- 25447137 TI - Two fundamental questions about protein evolution. AB - Two basic questions are considered that approach protein evolution from different directions; the problems arising from using Markov models for the deeper divergences, and then the origin of proteins themselves. The real problem for the first question (going backwards in time) is that at deeper phylogenies the Markov models of sequence evolution must lose information exponentially at deeper divergences, and several testable methods are suggested that should help resolve these deeper divergences. For the second question (coming forwards in time) a problem is that most models for the origin of protein synthesis do not give a role for the very earliest stages of the process. From our knowledge of the importance of replication accuracy in limiting the length of a coding molecule, a testable hypothesis is proposed. The length of the code, the code itself, and tRNAs would all have prior roles in increasing the accuracy of RNA replication; thus proteins would have been formed only after the tRNAs and the length of the triplet code are already formed. Both questions lead to testable predictions. PMID- 25447138 TI - Special issue: from membranes to pathologies. PMID- 25447139 TI - The role of membrane curvature elastic stress for function of rhodopsin-like G protein-coupled receptors. AB - The human genome encodes about 800 different G protein-coupled receptors (GPCR). They are key molecules in signal transduction pathways that transmit signals of a variety of ligands such as hormones and neurotransmitters to the cell interior. Upon ligand binding, the receptors undergo structural transitions that either enhance or inhibit transmission of a specific signal to the cell interior. Here we discuss results which indicate that transmission of such signals can be strongly modulated by the composition of the lipid matrix into which GPCR are imbedded. Experimental results have been obtained on rhodopsin, a prototype GPCR whose structure and function is representative for the great majority of GPCR in humans. The data shed light on the importance of curvature elastic stress in the lipid domain for function of GPCR. PMID- 25447140 TI - Mutational analysis of residues in human arsenic (III) methyltransferase (hAS3MT) belonging to 5 A around S-adenosylmethionine (SAM). AB - The functions of residues 57-RY-58, G60, L77, 80-GSGR-83, I101, T104, 134-GY-135, N155, V157 and 160-LV-161 in human arsenic (III) methyltransferase (hAS3MT) 5 A around S-adenosylmethionine (SAM) have not been studied. Herein, sixteen mutants were designed by substituting these residues with Ala. Mutants G60A, G80A, I101A, N155A and L160A were completely inactive. Only MMA was detected when mutants R57A, Y58A, G82A and T104A were used as the enzymes, which suggested that their catalytic activities were seriously impaired compared with that of wild type (WT). The catalytic capacities of other mutants were also lower than that of WT hAS3MT. The KM(SAM) values of mutants were 1.9-8.7 times that of WT, suggesting their affinities to SAM were weakened. As evidenced by the experimental data herein, earlier literature and the model of hAS3MT-SAM, 57-RYYG-60, G78, G80, G82 and 155-NCV-157 interacted with the methionine of SAM, and 101-IDMT-104 and 135 YIE-137 were associated with the nucleotide adenosine of SAM. Since C156 and L160 were the common residues between 5 A around SAM and 5 A around As, and C156S and L160A were inactive, we proposed that C156 and L160 functioned in the methyl transfer process. G78, G80 and G82 belonging to the consensus GxGxG were located in a loop connecting the first beta-strand and alpha-helix in the Rossmann fold core. Y59, N155, C156 and L160 oriented S(+)-CH(3) during its approach to the arsenic lone pair, and further activated methyl transfer. G78, D102, M103, T104, I136 and N155 formed hydrogen bonds with SAM. PMID- 25447141 TI - Hypoxia-inducible factor-1alpha in hepatic fibrosis: A promising therapeutic target. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) is a regulated subunit of the hypoxia-inducible factor 1 (HIF1), which functions as a key transcription factor in response to hypoxic stress by regulating genes involved in maintaining oxygen homeostasis. In recent years, a growing body of studies showed that HIF-1alpha was significantly increased in hepatic fibrotic tissues and activated hepatic stellate cells (HSCs). Furthermore, knockdown of HIF-1alpha expression inhibited the proliferation and activation of HSCs. In addition, HIF-1alpha-dependent genes and the extensive network of signaling cascades focus on HIF-1alpha have been reported to associate with the development of hepatic fibrosis, suggesting that HIF-1alpha might play a crucial role in hepatic fibrosis. However, the mechanisms by which HIF-1alpha regulates hepatic fibrosis are still undefined. In this review, we concentrate on multiple signaling pathways and genes related with HIF 1alpha which may be involved in the development of hepatic fibrosis, further discussing its potential as a novel therapeutic target for hepatic fibrosis. PMID- 25447142 TI - Mutagenic and kinetic support for an allosteric site in arginase from the extreme thermophile Bacillus caldovelox, which allows activation by arginine. AB - To substantiate the functionality of a crystallographically evidenced allosteric site in Bacillus caldovelox arginase (Bewley et al., 1999), we have examined the kinetic consequences of the single mutations of Asp199 and Glu256, which interact with l-arginine in this site. The introduced mutations (Asp199 -> Asn, Asp199 -> Ala, Glu256 -> Gln and Glu256 -> Ala) had no effect on the hexameric structure of the enzyme (mol. wt. 195 +/- 10 kDa). However, in contrast with the Michaelis Menten kinetics exhibited by the wild-type species, the D199A, D199N, E256A and E256Q variants exhibited positive cooperativity with respect to l-arginine. The Glu278 -> Ala mutation, which compromise interactions at the trimer-trimer interface, yielded trimeric species (mol. wt. 100 +/- 5 kDa) exhibiting hyperbolic kinetics that changed to sigmoidal by the additional Glu256 -> Ala mutation. In addition to demonstrating the total functionality of the trimer, our results also suggest that B. caldovelox is kinetically cooperative and that the commonly detected hyperbolic behavior results from binding of l-arginine as a typical allosteric activator. PMID- 25447143 TI - The activity of the wheat MAP kinase phosphatase 1 is regulated by manganese and by calmodulin. AB - MAPK phosphatases (MKPs) are negative regulators of MAPKs in eukaryotes and play key roles in the regulation of different cellular processes. However in plants, little is known about the regulation of these Dual Specific Phosphatases (DSPs) by Ca(2+) and calmodulin (CaM). Here, we showed that the wheat MKP (TMKP1) harboring a calmodulin (CaM) binding domain, binds to CaM in a Ca(2+)-dependent manner. In addition, TMKP1 exhibited a phosphatase activity in vitro that is specifically enhanced by Mn(2+) and to a lesser extent by Mg(2+), but without any synergistic effect between the two bivalent cations. Most interestingly, CaM/Ca(2+) complex inhibits the catalytic activity of TMKP1 in a CaM-dose dependent manner. However, in the presence of Mn(2+) this activity is enhanced by CaM/Ca(2+) complex. These dual regulatory effects seem to be mediated via interaction of CaM/Ca(2+) to the CaM binding domain in the C-terminal part of TMKP1. Such effects were not reported so far, and raise a possible role for CaM and Mn(2+) in the regulation of plant MKPs during cellular response to external signals. PMID- 25447144 TI - NF90 isoforms, a new family of cellular proteins involved in viral replication? AB - The Nuclear Factor 90 (NF90) and its isoforms constitute a family of proteins that can interact with double-stranded (ds) RNA, through its dsRNA binding motifs. Due to various potential translational events such as alternative splicing, the human Interleukin enhancer binding factor 3 (ilf3) gene codes for multifunctional proteins that are NF90 and its isoforms, involved in transcription, translation, mRNA export and microRNA biogenesis. These proteins can act as cellular partners affecting viral replication and they are also implicated in host defense. As a result of these numerous functions, these protein isoforms have been given various names over the years, leading to confusion in determining their specific functions. In this review we focus on the role of the human NF90 protein isoforms in DNA and RNA virus replication. PMID- 25447145 TI - Structural insight into the conformational change of alcohol dehydrogenase from Arabidopsis thaliana L. during coenzyme binding. AB - Alcohol dehydrogenase (ADH, EC 1.1.1.1) plays important roles in the metabolism of alcohols and aldehydes. They are often subjected to conformational changes that are critical for the enzymatic activity and have received intensive investigation for horse liver ADH. However, for the large plant ADH members, little is known regarding both the conformational change and its relationship to catalytic activity as plant ADH structures were rarely available. Here we describe three Arabidopsis ADH conformations obtained from two crystals, the apo crystal that was free of ligand, and the complex crystal that was with NAD. The NAD-complexed crystal yielded two different structural forms for the two subunits, one was occupied by the coenzyme, and the other was free and open. Structural comparisons demonstrate that the occupied subunit is in a closed conformation while the free subunit is fully open, and the apo structure in intermediate. Though all the forms have an overall fold similar to that of horse and human ADHs, the catalytic domain has an over 10 degrees rotation. Additionally, unlike horse liver ADH, the loop (295-302aa) adopts different conformation. It does not rearrange upon the binding of the coenzyme norVal297 side chain experiences a flipping. Instead it always remains in the active site. His48 plays a switching role in the structure. Its imidazole ring has to swim away from the binding site to permit NAD binding. These together with the large differences in the substrate binding pocket, as well as in the proton relay system demonstrate that AtADH adopts a different catalysis mechanism from horse liver ADH. PMID- 25447147 TI - Kinetic characterization, optimum conditions for catalysis and substrate preference of secretory phospholipase A2 from Glycine max in model membrane systems. AB - Two secretory phospholipase A2 (sPLA2s) from Glycine max, GmsPLA2-IXA-1 and GmsPLA2-XIB-2, have been purified as recombinant proteins and the activity was evaluated in order to obtain the optimum conditions for catalysis using mixed micelles and lipid monolayers as substrate. Both sPLA2s showed a maximum enzyme activity at pH 7 and a requirement of Ca(2+) in the micromolar range. These parameters were similar to those found for animal sPLA2s but a surprising optimum temperature for catalysis at 60 degrees C was observed. The effect of negative interfacial charges on the hydrolysis of organized substrates was evaluated through initial rate measurements using short chain phospholipids with different head groups. The enzymes showed subtle differences in the specificity for phospholipids with different head groups (DLPC, DLPG, DLPE, DLPA) in presence or absence of NaCl. Both recombinant enzymes showed lower activity toward anionic phospholipids and a preference for the zwitterionic ones. The values of the apparent kinetic parameters (Vmax and KM) demonstrated that these enzymes have more affinity for phosphatidylcholine compared with phosphatidylglycerol, in contrast with the results observed for pancreatic sPLA2. A hopping mode of catalysis was proposed for the action of these sPLA2 on mixed phospholipid/triton micelles. On the other hand, Langmuir-monolayers assays indicated an optimum lateral surface pressure for activity in between 13 and 16 mN/m for both recombinant enzymes. PMID- 25447146 TI - Comparative biochemical analysis of three members of the Schistosoma mansoni TAL family: Differences in ion and drug binding properties. AB - The tegumental allergen-like (TAL) proteins from Schistosoma mansoni are part of a family of calcium binding proteins found only in parasitic flatworms. These proteins have attracted interest as potential drug or vaccine targets, yet comparatively little is known about their biochemistry. Here, we compared the biochemical properties of three members of this family: SmTAL1 (Sm22.6), SmTAL2 (Sm21.7) and SmTAL3 (Sm20.8). Molecular modelling suggested that, despite similarities in domain organisation, there are differences in the three proteins' structures. SmTAL1 was predicted to have two functional calcium binding sites and SmTAL2 was predicted to have one. Despite the presence of two EF-hand-like structures in SmTAL3, neither was predicted to be functional. These predictions were confirmed by native gel electrophoresis, intrinsic fluorescence and differential scanning fluorimetry: both SmTAL1 and SmTAL2 are able to bind calcium ions reversibly, but SmTAL3 is not. SmTAL1 is also able to interact with manganese, strontium, iron(II) and nickel ions. SmTAL2 has a different ion binding profile interacting with cadmium, manganese, magnesium, strontium and barium ions in addition to calcium. All three proteins form dimers and, in contrast to some Fasciola hepatica proteins from the same family; dimerization is not affected by calcium ions. SmTAL1 interacts with the anti-schistosomal drug praziquantel and the calmodulin antagonists trifluoperazine, chlorpromazine and W7. SmTAL2 interacts only with W7. SmTAL3 interacts with the aforementioned calmodulin antagonists and thiamylal, but not praziquantel. Overall, these data suggest that the proteins have different biochemical properties and thus, most likely, different in vivo functions. PMID- 25447148 TI - Efficacy of bovine viral diarrhea virus vaccination to prevent reproductive disease: a meta-analysis. AB - Bovine viral diarrhea virus (BVDV) is an important reproductive pathogen of cattle worldwide. The reproductive outcome of BVDV infection is largely dependent on the immune status of the dam and the stage of gestation at the time of infection. Potential sequelae include failure of conception, abortion, a variety of congenital malformations, and fetal infection. Vaccination is a possible tool in the control of BVDV, and there has been a recently renewed focus on providing fetal protection through vaccination. Consequently, the aim of this study was to evaluate the efficacy of BVDV vaccination to prevent reproductive disease by performing a quantitative synthesis of previously published studies. Pertinent articles to be included in the analysis were identified by performing a search in four relevant scientific databases (PubMed, CAB abstracts, National Agricultural Library catalog, and Web of Science) and examining the reference lists of 10 germane review articles. Inclusion criteria for the meta-analysis mandated that the studies were controlled, primary studies that included necessary data for use in the meta-analysis (e.g., group size, number of abortions). Forty-six studies in 41 separate articles matched the inclusion criteria. Risk ratio effect sizes were used in random effects, weighted meta-analyses to assess the impact of BVDV vaccination on three outcomes: risk of fetal infection, abortion risk, and pregnancy risk. Within each outcome, subanalyses were performed to evaluate the effect of a variety of interventions, including modified live, inactivated, polyvalent and monovalent vaccination, homologous, heterologous, or field challenge, and studies with only bovine subjects. The analysis revealed a decrease in abortions of nearly 45% and a nearly 85% decrease in fetal infection rate in cattle vaccinated for BVDV compared with unvaccinated cohorts. Additionally, pregnancy risk was increased by approximately 5% in field trials of BVDV vaccinates. This meta-analysis provides quantitative support for the benefit of vaccination in the prevention of BVDV-associated reproductive disease. PMID- 25447150 TI - Identification of side population cells in chicken embryonic gonads. AB - The side population (SP) phenotype, defined by the ability of a cell to efflux fluorescent dyes such as Hoechst, is common to several stem/progenitor cell types. In avian species, SP phenotype has been identified in pubertal and adult testes, but nothing is known about its expression during prenatal development of a male gonad. In this study, we characterized the Hoechst SP phenotype via the cytofluorimetric analysis of disaggregated testes on different days of chicken embryonic development. Male prenatal gonads contained a fraction of SP cells at each stage analyzed. At least two main SP fractions, named P3 and P4, were identified. The percentage of P3 fraction decreased as development proceeds, whereas P4 cell number was not affected by gonad growth. Functional inhibition of BCRP1 channel membrane using Verapamil and/or Ko143 showed that P3, but not P4 phenotype, was dependent on BCRP1 activity. Molecular analysis of both P3- and P4 sorted fractions revealed a differential RNA expression pattern, indicating that P3 cells mainly contained germinal stem cell markers, whereas P4 was preferentially composed of both Sertoli and Leydig cell progenitor markers. Finally, these findings provided evidence that the SP phenotype is a common feature of both germ and somatic cells detected in chicken developing testis. PMID- 25447149 TI - The interval between the emergence of pharmacologically synchronized ovarian follicular waves and ovum pickup does not significantly affect in vitro embryo production in Bos indicus, Bos taurus, and Bubalus bubalis. AB - The aim of the present study was to determine the optimal phase of the follicular wave to perform ovum pickup (OPU) for in vitro embryo production (IVEP) in various genetic groups. For this purpose, 27 heifers-nine Bos taurus (Holstein), nine Bos indicus (Nelore), and nine Bubalus bubalis (Mediterranean)-were maintained under the same nutritional, management, and environmental conditions. Heifers within each genetic group were submitted to six consecutive OPU trials with 14-day intersession intervals, at three different phases of the pharmacologically synchronized follicular wave (Day 1, 3, or 5 after follicular wave emergence), in a 3 * 3 crossover design. When OPU was performed at different phases of the pharmacologically synchronized follicular wave (Day 1, 3, or 5), no differences were found in the percent of oocytes recovered (70.5 +/- 3.1%, 75.0 +/- 3.1%, 76.0 +/- 3.2%, respectively; P = 0.41) or blastocyst production rates (19.4 +/- 2.9%, 16.6 +/- 2.9%, 15.9 +/- 2.6%, respectively; P = 0.36). Comparing genetic groups, B indicus showed a higher blastocyst rate (28.3(a) +/- 2.8%; P < 0.01) than B taurus and B bubalis (14.1(b) +/- 2.9% and 10.2(b) +/- 2.0%, respectively). However, only B indicus heifers showed a variation in the number of visualized follicles and the total and viable oocytes along consecutive OPU sessions. In conclusion, different phases of the pharmacologically synchronized ovarian follicular wave did not affect OPU-IVEP in B indicus, B taurus, and B bubalis heifers. Additionally, B indicus heifers showed greater OPU-IVEP efficiency than did the other genetic groups, under the same management conditions. PMID- 25447151 TI - Maternal and neonatal evaluation of derivated reactive oxygen metabolites (d ROMs) and biological antioxidant potential in the horse. AB - The aim of the present work was to evaluate derivated reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) in mares and foals to study perinatal oxidative status. A total of 60 animals were included in the present study. Maternal and foal venous blood samples were collected immediately after delivery along with a sample drawn from one of the umbilical arteries, and plasma samples were evaluated for lactatemia, d-ROMs, and BAP. The t test for unpaired data was applied between mares versus umbilical artery blood versus foals, both for d-ROMs and BAP. The Pearson test with two-tailed P value and a confidence interval of 95% was performed between d-ROMs and BAP and between d-ROMs and lactatemia, both for mares and foals. Finally, the t test for unpaired data was performed between fillies and colts. The t test showed differences between mares versus their own foals versus umbilical artery blood but not foals versus. umbilical artery blood, both for d-ROMs and BAP. A positive correlation was found both in mares and foals between BAP and d-ROMs and in mares between lactatemia and d-ROM. No differences in gender were found in BAP concentration. Our data are in line to previous studies performed in women and cattle. PMID- 25447152 TI - Evaluation of the simulated physiological oocyte maturation system for improving bovine in vitro embryo production. AB - The aim of this study was to test the simulated physiological oocyte maturation (SPOM)- adapted system during bovine oocyte maturation to improve embryo development. Oocytes were obtained from follicles of 3 to 8 mm in diameter that were aspirated from ovaries obtained from a slaughterhouse. To verify the effect of the maturation system on in vitro embryo production, the cleavage, blastocyst rates on Days 7 and 8, embryo size, and total cell number were evaluated. The resulting data on embryo development were analyzed by the chi-square test, whereas data on embryo size and total cell number were analyzed by the Kruskal Wallis test. First, the SPOM system principle was tested in our IVM system, in which 0.01 IU/mL of purified FSH and 10% of fetal calf serum were used during maturation. However, the cleavage and blastocyst rates on Days 7 and 8 were drastically reduced compared with those of the control group (P < 0.05). Increasing the dose of purified FSH to 0.1 IU/mL in the SPOM-adapted system did not affect (P > 0.05) embryo production, which remained lower than that of the control group. When less competent oocytes obtained from 1 to 3 mm follicles were used, the SPOM-adapted system was also unable to improve embryo production. To make the adapted system as similar as possible to the reported system, recombinant FSH was associated with BSA during maturation and embryo culture was performed under low oxygen tension conditions. Nevertheless, a reduction (P < 0.05) in the blastocyst rates was also observed, whereas the size and total cell number were similar to those of the control group (P > 0.05). It can be concluded that an SPOM-adapted system used under different culture conditions does not improve in vitro embryo development. PMID- 25447154 TI - Multiple pro-apoptotic targets of abietane diterpenoids from Salvia species. AB - The genus Salvia contains a large number of biologically active diterpenoids with various skeletons including abietanes, labdanes, clerodanes, pimaranes and icetexanes. Diterpenes of Salvia species showed various biological activities, particularly cytotoxic and anti-proliferative properties. In recent years many studies have been focused on the molecular mechanisms of these diterpenes in cancer cells. It should be noted, however, that anticancer studies on diterpenoids from Salvia species were dominated by tanshinones (a class of abietanes) over the past decades. A large number of targets of diterpenes have been identified in cancer cells including NF-kappaB, STAT3, Bcl-xL, beta-catenin, cytochrome C and caspases. These studies give us deeper insights into the mechanisms of actions and cell signaling pathways of anticancer diterpenoids from Salvia species. This paper reviews protein targets of diterpenoids from Salvia species and highlights the gaps in our knowledge deserving future research. PMID- 25447155 TI - Antiplatelet aggregation triterpene saponins from the barks of Ilex rotunda. AB - Four new triterpene saponins, rotundinosides A-D (1-4) and seven known triterpene saponins (5-11) were isolated from a methanol extract of the barks of Ilex rotunda Thunb. The new saponins were characterized as 3-O-beta-d-glucopyranosy1 (1->2)-beta-d-xylopyranosyl siaresinolic acid 28-O-beta-d-glucopyranoside (1), 3 O-[beta-d-glucopyranosy1-(1->2)-beta-d-xylopyranosyl]-3beta,19alpha-dihydroxyurs 12-en-28-oic-O-beta-d-glucopranosy1ester (2), 3-O-[alpha-l-rhamnopyranosyl-(1->2) beta-d-glucopyranosy1-(1->2)-alpha-l-arabinopyranosyl]-3beta,19alpha-dihydroxyurs 12-en-28-oic-O-beta-d-glucopyranosy1 ester (3), and 3-O-alpha-l-rhamanopyranosyl (1->2)-beta-d-glucopyranosy1-(1->2)-alpha-l-arabinopyranosyl ilexgenin B 28-O beta-d-glucopyranosy1 ester (4), respectively. Their structures were established by extensive spectroscopic analysis, including HSQC, HMBC, (1)H-(1)H COSY, NOESY and acid hydrolysis, and also by the comparison of their spectroscopic data with those of related compounds. The known compounds 5-11 were all obtained from this species for the first time. The biological activity of compounds 1-11 against ADP induced platelet aggregation in rabbit plasma was determined. Among the tested compounds 1, 3, 5 and 10 exhibited strong inhibition of platelet aggregation in vitro, with IC50 values of 11.4+/-2.2, 10.4+/-1.3, 13.2+/-2.4, and 15.1+/-3.4MUM, respectively. PMID- 25447153 TI - Alpha-momorcharin (alpha-MMC) exerts effective anti-human breast tumor activities but has a narrow therapeutic window in vivo. AB - Alpha-momorcharin (alpha-MMC), a ribosome inactivating protein (RIP) extracted from the seeds of Momordica charantia, exerts anti-tumor, antiviral, and anti fungal activities. However, alpha-MMC has an obvious toxicity that limits its clinical application. We examined the effect of alpha-MMC on the inhibition of human breast cancer and assessed its general toxicity to find the therapeutic window in vivo for its potential clinical use. It was purified using column chromatography, and then injected into the xenograft nude mouse model induced by MDA-MB-231 and MCF-7. The anti-tumor efficacy was evaluated with T/C%. Next, the alpha-MMC was injected at a series of doses to Balb/C mice to assess its general toxicity. The MTT assay, the apoptosis test, and the cell cycle inhibition of alpha-MMC in human breast cancer cells were performed. In the xenografted tumors induced by MDA-MB-231 and MCF-7, alpha-MMC exerted an obvious inhibition effects on tumor growth at the dosage of 1.2mg/kg and 0.8 mg/kg. For in vivo toxicity experiments of alpha-MMC in Balb/C mice, the minimal toxic dose of alpha-MMC was 1.2mg/kg. Alpha-MMC induced apoptosis by increasing caspase3 activities, and the cell cycle was arrested at the G0/G1 or G2/M phases. The measurements of IC50 were 15.07 MUg/mL, 33.66 MUg/mL, 42.94 MUg/mL for MDA-MB-231, MCF-7 and MDA-MB 453 respectively. Alpha-MMC exhibits anti-tumor effects in human breast cancer in vivo and in vitro. It inhibits breast cancer cells through the inhibition of tumor growth and induction of cell apoptosis. However, due to its obvious toxicity, alpha-MMC has a relatively narrow therapeutic window in vivo. PMID- 25447156 TI - Oridonin: a small molecule inhibitor of cystic fibrosis transmembrane conductance regulator (CFTR) isolated from traditional Chinese medicine. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial chloride channel regulating the transepithelial transport of electrolyte and water. In the recent years, CFTR chloride channel becomes the new molecular target of treating secretory diarrhea. The objective of this study is to find out a novel CFTR inhibitor from traditional Chinese medicine (TCM) and study on its pharmacological activity. About 34,000 factions of TCM extracts were screened by high throughput screening (HTS) in this research. We found that Rabdosia rubescens show a potent inhibition on CFTR. Under the bio-active analysis guidance, an ent-kaurane diterpenoid - oridonin (PubChem CID: 34378) was isolated from R. rubescens. A series of intensive studies showed that oridonin remarkably reduced iodide influx in wt-CFTR and DeltaF508-CFTR FRT epithelial cells in a dose-dependent and irreversible way. Oridonin sharply blocked FSK-stimulated short-circuit current in both rats and mice intestine in vitro. In mouse closed loop model, oridonin reduced cholera toxin-induced fluid secretion significantly over 6hours in vivo. Thus we concluded that oridonin is a new inhibitor of CFTR Cl(-) channel. It will be a good leading compound for developing the new drug of cholera toxin-induced secretory diarrhea. PMID- 25447157 TI - Cytotoxic, anti-inflammatory and hemostatic spirostane-steroidal saponins from the ethanol extract of the roots of Bletilla striata. AB - Four new spirostane steroidal saponins, (1alpha,3alpha)-1-O-[(beta-d xylopyranosyl-(1->2)-alpha-l-rhamnopyranosyl)]-3-O-d-glucopyranosyl-5alpha spirostan (1), (1alpha,3alpha)-1-O-[(beta-d-xylopyranosyl-(1->2)-alpha-l rhamnopyranosyl)oxy]-3-O-d-glucopyranosyl-25(27)-ene-5alpha-spirostan (2), (1alpha,3alpha)-1-O-[(beta-d-xylopyranosyl-(1->2)-alpha-l-rhamnopyranosyl)oxy] epiruscogenin (3), and (1alpha,3alpha)-1-O-[(beta-d-xylopyranosyl-(1->2)-alpha-l rhamnopyranosyl)oxy]-epineoruscogenin (4) together with two known compounds, bletilnoside A (5) and 3-O-beta-d-glucopyranosyl-3-epi-neoruscogenin (6), were isolated from the ethanol extract of the roots of Bletilla striata (Thunb.) Reichb. f. The structures of the isolated compounds were established based on 1D and 2D ((1)H-(1)H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated compounds were tested in vitro for cytotoxicities against seven tumor cell lines, anti-inflammatory activities against Cox-1 and Cox-2, and hemostatic activities. As a result, compounds 1-4 and 6 exhibited significant cytotoxicities against all the tested tumor cell lines with IC50 value less than 30MUM and selective inhibition of Cox-2 comparable with the standard drug NS-398 (>90%). Additionally, compounds 1-6 showed potent hemostatic activities. PMID- 25447158 TI - Bis-spirolabdane diterpenoids from Leonurus japonicus and their anti-platelet aggregative activity. AB - Six bis-spirolabdane diterpenoids along with four known analogues were isolated from the aerial parts of Leonurus japonicus. Their structures and absolute configurations were elucidated by spectroscopic analyses, single-crystal X-ray diffraction, and a modified Mosher's method. The inhibitory activity of the compounds against the abnormal increase in platelet aggregation induced by adenosine diphosphate was investigated. Only the (13R)-bis-spirolabdane diterpenoids exhibited a significant effect. PMID- 25447159 TI - Penthorin A and B, two unusual 2,4'-epoxy-8,5'-neolignans from Penthorum chinese. AB - Two new 2,4'-epoxy-8,5'-neolignans (1 and 2), together with five known 7,9';7',9 diepoxylignans (3-7), were isolated from an ethyl acetate soluble portion of a hepatoprotective water decoction of Penthorum chinese. Their structures and absolute configurations were elucidated by extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. This is the second report of 2,4'-epoxy-8,5'-neolignans from plants. Compounds 2, 6, and 7 showed in vitro protective activities against acetaminophen-induced hepatocyte injury at 5 MUM. PMID- 25447160 TI - Five new phenolic compounds from Dendrobium aphyllum. AB - One new phenanthrene, aphyllone A (1) and four new bibenzyl derivatives, aphyllone B (2) and aphyllals C-D (3-5), together with nine known compounds (6 14), were isolated from the stems of Dendrobium aphyllum (Roxb.) C. E. Fischer. The structures of these new compounds were elucidated by means of extensive spectroscopic analyses, and the absolute configuration of compound 1 was determined by single crystal X-ray diffraction and quantum calculations. Compounds 6, 8 and 14 inhibited NO production at the concentration of 25 MUM in LPS-stimulated RAW264.7 cells with the inhibition (%) of 32.48, 35.68, and 38.50. Compound 2 possessed significant DPPH radical scavenging activity with scavenging percentage of 87.97% at the concentration of 100 MUg/mL. PMID- 25447162 TI - Anti-hepatitis B virus active constituents from Swertia chirayita. AB - Four new compounds swertiachiralatone A (1), swertiachoside A (2), swertiachirdiol A (3) and swertiachoside B (4), together with twenty-six known ones were isolated from the ethanol extract of Swertia chirayita. Their structures were elucidated by extensive spectroscopic analyses (1D- and 2D-NMR, HRESIMS, UV, IR and [alpha]D). All compounds were evaluated for anti-hepatitis B virus (anti-HBV) activities on HepG 2.2.15 cells line in vitro, of which compounds 14 and 19 showed inhibitory activity on hepatitis B surface antigen (HBsAg) secretion with IC50 values of 0.31 +/- 0.045 and 1.49 +/- 0.033 mM; compounds 14 and 28 exhibited activity against hepatitis B e antigen (HBeAg) secretion with IC50 values of 0.77 +/- 0.076 and 5.92 +/- 1.02 mM; and eight compounds (8,9,13,14,24-26,29) possessed activity against HBV DNA replication with IC50 values of 0.07-0.33 mM. In particular (+)-cycloolivil-4'-O-beta-d glucopyranoside (14) exhibited inhibition not only on the secretions of HBsAg and HBeAg with IC50 values of 0.31 +/- 0.045 mM (SI=4.29) and 0.77 +/- 0.076 mM (SI=1.75), respectively, but also on HBV DNA replication with an IC50 value of 0.29 +/- 0.034 mM (SI=4.66). PMID- 25447161 TI - Endogenous enzyme-hydrolyzed fruit of Cirsium brachycephalum: optimal source of the antiproliferative lignan trachelogenin regulating the Wnt/beta-catenin signaling pathway in the SW480 colon adenocarcinoma cell line. AB - The molecular constituents of Cirsium brachycephalum fruits were identified, quantified and isolated for the first time. The lignan glycoside tracheloside was the main compound, which was transformed quantitatively into its aglycone trachelogenin by endogenous enzymatic treatment of the fruit. Following this transformation by high performance liquid chromatography (HPLC) hyphenated with UV and mass spectrometry (MS) detections on a quantitative basis, the enzyme hydrolyzed fruit was found to be the richest raw material containing trachelogenin (17.2mg/g) reported to date. Thus, the enzyme-hydrolyzed fruit was used to isolate trachelogenin using preparative HPLC in order to (1) unambiguously confirm its identity by gas chromatography-MS, nuclear magnetic resonance spectroscopy and optical rotation, and (2) investigate its in vitro antiproliferative activities against the SW480 colon adenocarcinoma cell line. Trachelogenin significantly affected the phosphorylation of key proteins such as beta-Catenin, c-Myc and GSK3 in the beta-Catenin signaling pathway in a concentration-dependent manner. These changes account for the antiproliferative effects of trachelogenin. PMID- 25447163 TI - Gelsemium analgesia and the spinal glycine receptor/allopregnanolone pathway. AB - Gelsemium, a small genus of flowering plant from the family Loganiaceae, comprises five species including the popular Gelsemium sempervirens Ait. and Gelsemium elegans Benth., which are indigenous to North America and China/East Asia, respectively. Approximately 120 alkaloids have been isolated and identified from Gelsemium, with the predominant indole alkaloids including gelsemine, koumine, gelsemicine, gelsenicine, gelsedine, sempervirine, koumidine, koumicine and humantenine. Gelsemine is the principal active alkaloid in G. sempervirens Ait., and koumine and gelsemine are the most and second-most dominant alkaloids in G. elegans Benth. Gelsemium extract and its active alkaloids serve a variety of biological functions, including neurobiological, immunosuppressive and antitumor effects, and have traditionally been used to treat pain, neuralgia, anxiety, insomnia, asthma, respiratory ailments and cancers. This review focuses on animal-based studies of Gelsemium as a pain treatment and its mechanism of action. In contrast to morphine, when administered intrathecally and systemically, koumine, gelsemine and gelsenicine have marked antinociception in inflammatory, neuropathic and bone cancer pains without inducing antinociceptive tolerance. Gelsemium and its active alkaloids may produce antinociception by activating the spinal alpha3 glycine/allopregnanolone pathway. The results of this review support the clinical use of Gelsemium and suggest that its active alkaloids may be developed to treat intractable and other types of pain, preferably after chemical modification. However, Gelsemium is a known toxic plant, and its toxicity limits its appropriate dosage and clinical use. To avoid or decrease the side/toxic effects of Gelsemium, an individual monomer of highly potent alkaloids must be selected, or alkaloids that exhibit greater alpha3 glycine receptor selectivity may be discovered or modified. PMID- 25447165 TI - Synthesis and biological evaluation of ambradiolic acid as an inhibitor of glycogen phosphorylase. AB - Ambradiolic acid (3) with oleanane skeleton is a natural pentacyclictriterpene. The first synthesis of 3 starting from 23-hydroxybetulinic acid (2) has been accomplished in 12-steps with a total yield of 18.1% in our study. Compound 3 was further biologically evaluated and found to exhibit significant inhibitory activity against rabbit muscle glycogen phosphorylase (GP) with an IC50 value of 12.4 MUM, suggesting it could be a potential lead compound for the development of hypoglycemic drugs. PMID- 25447164 TI - Five new eudesmane-type sesquiterpenoids from Chinese agarwood induced by artificial holing. AB - Five new eudesmane-type sesquiterpenoids (1-5), along with six known ones (6-11), were isolated from Chinese agarwood induced by artificial holing originating from Aquilaria sinensis (Lour.) Gilg (Thymelaeaceae). The structures of the new sesquiterpenoids were established by spectroscopic methods including UV, IR, MS, 1D, and 2D NMR. Compounds 1, 3, 6 and 7 exhibited antibacterial activities against both Staphylococcus aureus and Ralstonia solanacearum, and compound 5 only showed an inhibitory activity towards S. aureus. Compounds 1, 6, 7 and 10 showed weak acetylcholinesterase inhibitory activity. PMID- 25447166 TI - Investigation of natural gas theft by magnetic remanence mapping. AB - Natural gas theft causes major losses in the energy industry in Hungary. Among the non-technical losses occurring in natural gas networks, fraudulent residential consumption is one of the main factors. Up to 2014, gas meters that are most widely used in residential monitoring are manufactured with ferromagnetic moving components, which makes it possible to alter or disrupt the operation of the meters non-intrusively by placing permanent magnets on the casing of the meters. Magnetic remanence mapping was used to investigate a sample of 80 recalled residential meters and detect potentially fraudulent activity. 10% of the meters were found suspect by magnetic remanence measurement, of which 50% were confirmed to be potentially hijacked by further mechanical investigation. The details of the technique are described in this paper, along with experimental results and the discussion of the analysis of the real-world samples. PMID- 25447167 TI - A retrospective analysis of alcohol in medico-legal autopsied deaths in Pretoria over a 1 year period. AB - The misuse of alcohol has a particularly detrimental effect and is one of the most significant public health problems in South Africa and it also has an impact on the criminal justice system with evidence of association between high levels of alcohol and risk-taking behaviour, committing crimes, or being a victim of crime. A global trend has been set worldwide with alcohol being one of the most common drugs found in post mortem specimens and especially with regard to cases admitted for medico-legal autopsies. The influence of alcohol on the cause of death is either a contributory or an underlying factor in a substantial number of violent deaths. We retrospectively reviewed 1455 cases, in which alcohol was taken, of 2344 medico-legal autopsies done in 2009. We found that 47% of the cases tested positive for alcohol, with the reported blood alcohol concentrations varying from 0.01 to 0.95g per 100ml (mean=0.16+/-0.11g per 100ml) with the highest proportion being in the 0.10-0.19g per 100ml range. A breakdown of the results showed that road traffic accidents, assaults and firearm-related deaths predominated the alcohol-positive cases. The results showed that there was a definite correlation between alcohol consumption and the incidence of other that natural deaths. PMID- 25447168 TI - Review of immunological and virological aspects as contributory factors in Sudden Unexpected Death in Infancy (SUDI). AB - Currently in South Africa research into sudden unexpected death in infancy (SUDI) is limited. The causes of sudden infant death syndrome (SIDS) remain obscure despite full medico-legal investigations inclusive of autopsy, scene visit and ancillary studies. Viral infections play an important role as a multitude of respiratory viruses have been detected in autopsy specimens and are implicated in these deaths. The specific contribution of viruses in the events preceding SIDS still warrants deciphering. Infancy is characterised by marked vulnerability to infections due to immaturities of the immune system that may only resolve by the age of 24 months. Routine viral screening of all SUDI cases at Tygerberg Forensic Pathology Service (FPS) Mortuary in Cape Town focuses on only a portion of respiratory viruses from lung and liver tissue. This review highlights important virological and immunological aspects regarding investigations into the infectious nature of SUDI, including the lack of national standardised guidelines for appropriate specimen collection at autopsy and subsequent laboratory analysis. PMID- 25447169 TI - Detection of single graves by airborne hyperspectral imaging. AB - Airborne hyperspectral imaging (HSI) was assessed as a potential tool to locate single grave sites. While airborne HSI has shown to be useful to locate mass graves, it is expected the location of single graves would be an order of magnitude more difficult due to the smaller size and reduced mass of the targets. Two clearings were evaluated (through a blind test) as potential sites for containing at least one set of buried remains. At no time prior to submitting the locations of the potential burial sites from the HSI were the actual locations of the sites released or shared with anyone from the analysis team. The two HSI sensors onboard the aircraft span the range of 408-2524nm. A range of indicators that exploit the narrow spectral and spatial resolutions of the two complimentary HSI sensors onboard the aircraft were calculated. Based on the co-occurrence of anomalous pixels within the expected range of the indicators three potential areas conforming to our underlying assumptions of the expected spectral responses (and spatial area) were determined. After submission of the predicted burial locations it was revealed that two of the targets were located within GPS error (10m) of the true burial locations. Furthermore, due to the history of the TPOF site for burial work, investigation of the third target is being considered in the near future. The results clearly demonstrate promise for hyperspectral imaging to aid in the detection of buried remains, however further work is required before these results can justifiably be used in routine scenarios. PMID- 25447170 TI - Effects of temperature and tissue type on Chrysomya rufifacies (Diptera: Calliphoridae) (Macquart) development. AB - The hairy maggot blow fly, Chrysomya rufifacies (Diptera: Calliphoridae), is a forensically important fly often encountered on human and other vertebrate remains in temperate and tropic regions throughout the world including Australia, Asia, Central America and North America. C. rufifacies was reared under controlled laboratory conditions on three muscle types (i.e., porcine, equine and canine) at three temperatures (i.e., 20.8, 24.8 and 28.3 degrees C). Rate of larval weight gain across time was statistically significant between muscle types (P<=0.0001) and approaching significance across time between temperatures (P=0.0511). This research represents the first development study for C. rufifacies from central Texas, USA and the first study to examine the impact of tissue type on its development. Furthermore, these data, when compared to those available in the literature, indicate developmental differences that could be due to genetic differences in populations or possibly methods employed during the studies. Caution should be emphasized when applying development data for this species from one region to forensic investigations in other ecoregions as such differences in development based on tissue fed upon by larvae, population genetics, and methodologies used in the studies could represent error in estimating the time of colonization. PMID- 25447171 TI - Post-mortem genetic analysis in juvenile cases of sudden cardiac death. AB - BACKGROUND: The reason behind a sudden death of a young individual remains unknown in up to 50% of postmortem cases. Pathogenic mutations in genes encoding heart proteins are known to cause sudden cardiac death. OBJECTIVE: The aim of our study was to ascertain whether genetic alterations could provide an explanation for sudden cardiac death in a juvenile cohort with no-conclusive cause of death after comprehensive autopsy. METHODS: Twenty-nine cases <15 years showing no conclusive cause of death after a complete autopsy were studied. Genetic analysis of 7 main genes associated with sudden cardiac death was performed using Sanger technology in low quality DNA cases, while in good quality cases the analysis of 55 genes associated with sudden cardiac death was performed using Next Generation Sequencing technology. RESULTS: Thirty-five genetic variants were identified in 12 cases (41.37%). Ten genetic/variants in genes encoding cardiac ion channels were identified in 8 cases (27.58%). We also identified 9 cases (31.03%) carrying 25 genetic variants in genes encoding structural cardiac proteins. Nine cases carried more than one genetic variation, 5 of them combining structural and non structural genes. CONCLUSIONS: Our study supports the inclusion of molecular autopsy in forensic routine protocols when no conclusive cause of death is identified. Around 40% of sudden cardiac death young cases carry a genetic variant that could provide an explanation for the cause of death. Because relatives could be at risk of sudden cardiac death, our data reinforce their need of clinical assessment and, if indicated, of genetic analysis. PMID- 25447172 TI - Studying the variability in the Raman signature of writing pen inks. AB - This manuscript aims to study the inter and intra brand, model and batch variability in the Raman spectral signature among modern pen inks that will help forensic document examiners during the interpretation process. Results showed that most oil-based samples have similar Raman signatures that are characteristic of the Crystal Violet dye, independently of the brand. Exception was the Pilot samples that use Victoria Pure Blue BO instead. This small inter-brand variability makes oil-based pens difficult to discriminate by brand. On the contrary, gel and liquid-based samples use different colorants such as Rhodamine B, Copper Phthalocyanine, Ethyl Violet and Victoria Blue B. No particular pattern was observed regarding the colorants used by each brand, except the Pilot samples that were the only brand using the Victoria Blue B dye, which is a clear distinct feature. Additionally, the intra-brand variability was also large among gel-based Pilot samples. The small spectral differences observed among several batches of Bic Crystal Medium samples demonstrated that changes were introduced in their chemical formula over the years. The intra-batch variability was small and no spectral differences were observed within batches. This manuscript demonstrates the potential of Raman spectroscopy for discriminating pens inks from different brands and models and even, batches. Additionally, the main colorants used in modern pens were also identified. PMID- 25447173 TI - The utilization of stable isotope analysis for the estimation of the geographic origins of unidentified cadavers. AB - The number of unidentified cadavers is increasing worldwide and the effective methods which reveal their geographic origin are not well known. This study reports on the utilization of delta(18)O, delta(13)C, delta(2)H and delta(15)N ratios gained through stable isotope analysis of urine samples collected from eight locations: Chiba, Japan; Fuzhou, China; and Denpasar, Indonesia in our pilot study with data from healthy volunteers from five further locations from healthy volunteers: Melbourne and Perth, Australia; Qingdao, China; Turku, Finland and Oklahoma, USA. This study posits that the utilization of delta(18)O and delta(2)H is more feasible than delta(13)C and delta(15)N stable isotope ratios in differentiating or estimating the origin of human samples. Secondly, this study demonstrated that the delta(18)O and delta(2)H stable isotope ratios of urine samples from eight locations differed significantly. PMID- 25447174 TI - An old dog and new tricks: Genetic analysis of a Tudor dog recovered from the Mary Rose wreck. AB - The Tudor warship the Mary Rose sank in the Solent waters between Portsmouth and the Isle of Wight on the 19th of July 1545, whilst engaging a French invasion fleet. The ship was rediscovered in 1971 and between 1979 and 1982 the entire contents of the ship were excavated resulting in the recovery of over 25,000 objects, including the skeleton of a small to medium sized dog referred to as the Mary Rose Dog (MRD). Here we report the extraction and analysis of both mitochondrial and genomic DNA from a tooth of this animal. Our results show that the MRD was a young male of a terrier type most closely related to modern Jack Russell Terriers with a light to dark brown coat colour. Interestingly, given the antiquity of the sample, the dog was heterozygotic for the SLC2A9 gene variant that leads to hyperuricosuria when found in modern homozygotic animals. These findings help shed light on a notable historical artefact from an important period in the development of modern dog breeds. PMID- 25447175 TI - Verification of AFLP kinship methods of entomological evidence by sequencing. AB - Kinship analysis allows the determination of sibship based on the individuals' genetic profile. In a recent empirical study, amplified fragment length polymorphism (AFLP) analysis was proposed as a test to determine kinship between Phormia regina individuals useful in inferring postmortem transport of a corpse. In order to validate this technique, mitochondrial DNA gene cytochrome oxidase II was sequenced for all individuals used in the previous study. Then, the relatedness coefficient based on AFLP profiles was determined for the pairs of individuals that had different haplotypes, and thus could not be full siblings, to determine a conservative false positive error rate of this proposed test. A majority, 96%, of pair wise comparisons of individuals with different haplotypes had relatedness coefficients <0.41 supporting the conclusion that AFLP analysis for full sibship is a valid and robust technique and thus useful for the detection of postmortem movement of a corpse. PMID- 25447176 TI - A safe, free and efficient way to control Nasonia vitripennis, a common pest in forensic entomology laboratories. AB - Nasonia vitripennis Walker (Hymenoptera: Pteromalidae) is a parasitoid of necrophagous blowflies. Its presence in a forensic entomology laboratory can be extremely damaging to samples and can compromise the PMI estimation. We describe for the first time a simple, safe and efficient trap to control N. vitripennis infestations. Adhesive tape is placed horizontally on windows to create an obstacle. Wasps go underneath until they reach the adhesive side of the tape and become stuck by their wings. This method is highly selective, costless and has been successfully used in our laboratory for years. PMID- 25447177 TI - Hydrocarbon profiles throughout adult Calliphoridae aging: A promising tool for forensic entomology. AB - Blow flies (Diptera: Calliphoridae) are typically the first insects to arrive at human remains and carrion. Predictable succession patterns and known larval development of necrophagous insects on vertebrate remains can assist a forensic entomologist with estimates of a minimum post-mortem interval (PMImin) range. However, adult blow flies are infrequently used to estimate the PMImin, but rather are used for a confirmation of larval species identification. Cuticular hydrocarbons have demonstrated potential for estimating adult blow fly age, as hydrocarbons are present throughout blow fly development, from egg to adult, and are stable structures. The goal of this study was to identify hydrocarbon profiles associated with the adults of a North American native blow fly species, Cochliomyia macellaria (Fabricius) and a North American invasive species, Chrysomya rufifacies (Macquart). Flies were reared at a constant temperature (25 degrees C), a photoperiod of 14:10 (L:D) (h), and were provided water, sugar and powdered milk ad libitum. Ten adult females from each species were collected at day 1, 5, 10, 20, and 30 post-emergence. Hydrocarbon compounds were extracted and then identified using gas chromatography-mass spectrometry (GC-MS) analysis. A total of 37 and 35 compounds were detected from C. macellaria and Ch. rufifacies, respectively. There were 24 and 23 n-alkene and methyl-branched alkane hydrocarbons from C. macellaria and Ch. rufifacies, respectively (10 compounds were shared between species), used for statistical analysis. Non-metric multidimensional scaling analysis and permutational multivariate analysis of variance were used to analyze the hydrocarbon profiles with significant differences (P<0.001) detected among post-emergence age cohorts for each species, and unique hydrocarbon profiles detected as each adult blow fly species aged. This work provides empirical data that serve as a foundation for future research into improving PMImin estimates made by forensic practitioners and potentially increase the use of adult insects during death investigations. PMID- 25447178 TI - Fat from contused adipose tissue may cause yellow discoloration of clothes in blunt trauma victims. AB - In some fatalities from intense blunt trauma, the victims' clothes show strikingly yellow discoloration being in topographic correspondence with lacerated skin and crush damage to the underlying fatty tissue. This phenomenon is especially pronounced in light-colored textiles such as underwear made of cotton and in the absence of concomitant blood-staining. The constellation of findings seems to indicate that the fabric has been soaked with liquid body fat deriving from the contused adipose tissue. To check this hypothesis, textiles suspected to be contaminated with fat were investigated in 6 relevant cases. GC MS-analysis proved the presence of 11 fatty acids. The fatty acid composition was similar to that of human adipose tissue with a high proportion of oleic acid (18:1). In total, the morphological and chemical findings demonstrated that the yellow discoloration of the victims' clothes was caused by fat from traumatized adipose tissue. PMID- 25447179 TI - Computer vision and soft computing for automatic skull-face overlay in craniofacial superimposition. AB - Craniofacial superimposition can provide evidence to support that some human skeletal remains belong or not to a missing person. It involves the process of overlaying a skull with a number of ante mortem images of an individual and the analysis of their morphological correspondence. Within the craniofacial superimposition process, the skull-face overlay stage just focuses on achieving the best possible overlay of the skull and a single ante mortem image of the suspect. Although craniofacial superimposition has been in use for over a century, skull-face overlay is still applied by means of a trial-and-error approach without an automatic method. Practitioners finish the process once they consider that a good enough overlay has been attained. Hence, skull-face overlay is a very challenging, subjective, error prone, and time consuming part of the whole process. Though the numerical assessment of the method quality has not been achieved yet, computer vision and soft computing arise as powerful tools to automate it, dramatically reducing the time taken by the expert and obtaining an unbiased overlay result. In this manuscript, we justify and analyze the use of these techniques to properly model the skull-face overlay problem. We also present the automatic technical procedure we have developed using these computational methods and show the four overlays obtained in two craniofacial superimposition cases. This automatic procedure can be thus considered as a tool to aid forensic anthropologists to develop the skull-face overlay, automating and avoiding subjectivity of the most tedious task within craniofacial superimposition. PMID- 25447180 TI - Postmortem distribution of guaifenesin concentrations reveals a lack of potential for redistribution. AB - Therapeutic (or non-toxic) postmortem guaifenesin blood and liver concentrations have not been previously described. Peripheral blood guaifenesin concentrations were compared to central blood and liver concentrations in eight medical examiner cases. Specimens were initially screened for alcohol and simple volatiles, drugs of abuse, alkaline, and acid/neutral drugs. Guaifenesin, when detected by the acid/neutral drug screen, was subsequently confirmed and quantified by a high performance liquid chromatography procedure. Data suggest that postmortem guaifenesin peripheral blood concentrations may be considered non-toxic to at least 5.4mg/L with liver concentrations to at least 7.0mg/kg. Overall, guaifenesin concentrations ranged from 1.9 to 40mg/L in peripheral blood, 2.2 150mg/L in central blood, and 2.6-36mg/kg in liver. The median guaifenesin central blood to peripheral blood ratio was 1.1 (N=8). Similarly, liver to peripheral blood ratios showed a median value of 0.9L/kg (N=5). Given that a liver to peripheral blood ratio less than 5L/kg is consistent with little to no propensity for postmortem redistribution, these data suggest that guaifenesin is not prone to substantial postmortem redistribution. PMID- 25447181 TI - A review of the changing culture and social context relating to forensic facial depiction of the dead. AB - The recognition of a decedent by a family member is commonplace in forensic investigation and is often employed as identity confirmation. However, it is recognised that misidentification from facial recognition is also common and faces of the dead may be extremely difficult to recognise due to decomposition or external damage, and even immediate post-mortem changes may be significant enough to confuse an observer. The depiction of faces of the dead can be a useful tool for promoting recognition leading to identification and post-mortem facial depiction is described as the interpretation of human remains in order to suggest the living appearance of an individual. This paper provides an historical context relating to the changing view of society to the presentation and publication of post-mortem facial depictions and discusses the current ethical, practical and academic challenges associated with these images. PMID- 25447182 TI - Changes to soil bacterial profiles as a result of Sus scrofa domesticus decomposition. AB - The importance of cadaver decomposition knowledge for clandestine grave location cannot be over emphasised. Notwithstanding this, only a limited understanding is available on the resulting soil microbial community dynamics. To address this paucity, a pig leg (Sus scrofa domesticus; 5kg) was buried in freshly weighed (20kg) sandy loamy soil in a sealed microcosm (40cm height) in parallel with a soil only control. Both microcosms were perforated nine times at equal distances and maintained outside. Soil samples were collected through these perforations from the top (0-10cm), middle (10-20cm) and bottom (20-30cm) segments every three days for the first two weeks, and then weekly up to 14 weeks. PCR-DGGE gels quantified by 1D Phoretix showed increases in the cumulative soil community richness values of 43, 66 and 106 for the top, middle and bottom segments, respectively, in the presence of Sus scrofa domesticus. Shannon-Wiener's (H') and Simpon's (D) indices confirmed corresponding species diversity increases in the middle (H'=1.58-2.33; D=0.79-0.91) and bottom (H'=2.48-3.16; D=0.85-0.95) depths between days 10 and 71 compared with the control. In contrast, similar evenness was recorded for all segments in both the Sus scrofa domesticus and control soils. PMID- 25447183 TI - Experimental validation of a numerical model for predicting the trajectory of blood drops in typical crime scene conditions, including droplet deformation and breakup, with a study of the effect of indoor air currents and wind on typical spatter drop trajectories. AB - Bloodstain Pattern Analysis (BPA) provides information about events during an assault, e.g. location of participants, weapon type and number of blows. To extract the maximum information from spatter stains, the size, velocity and direction of the drop that produces each stain, and forces acting during flight, must be known. A numerical scheme for accurate modeling of blood drop flight, in typical crime scene conditions, including droplet oscillation, deformation and in flight disintegration, was developed and validated against analytical and experimental data including passive blood drop oscillations, deformation at terminal velocity, cast-off and impact drop deformation and breakup features. 4th order Runge-Kutta timestepping was used with the Taylor Analogy Breakup (TAB) model and Pilch and Erdman's (1987) expression for breakup time. Experimental data for terminal velocities, oscillations, and deformation was obtained via digital high-speed imaging. A single model was found to describe drop behavior accurately in passive, cast off and impact scenarios. Terminal velocities of typical passive drops falling up to 8m, distances and times required to reach them were predicted within 5%. Initial oscillations of passive blood drops with diameters of 1mm60 was rare. Concomitant other opioid findings were more frequent in abuser- than in other cases for codeine, oxycodone, and tramadol, whereas alcohol findings were more frequent in buprenorphine, codeine, and fentanyl abuse. Buprenorphine and methadone were most often related to drug abuse. Every other opioid studied involved some abuse, and especially tramadol. Abuse and fatal poisonings were concentrated in men aged 20-49. PMID- 25447185 TI - Fatal intoxication with 3-methyl-N-methylcathinone (3-MMC) and 5-(2 aminopropyl)benzofuran (5-APB). AB - The emergence of a large number of new psychoactive substances (NPSs) in recent years poses a serious problem to clinical and forensic toxicologists. Here we report a patient who administrated ca. 500mg of 3-MMC (3-methyl-N methylcathinone) and 400mg of 5-APB (5-(2-aminopropyl)benzofuran) in combination with 80g of ethyl alcohol. The clinical manifestations included agitation, seizures, hypertension, tachycardia, hyperthermia and bradycardia. The patient did not recover and died around 4h after the use of drugs. The cause of death was acute cardiovascular collapse that occurred following mixed intoxication with NPSs and alcohol. Toxicological analysis of post-mortem blood revealed 3-MMC and 5-APB in concentrations of 1.6MUg/mL and 5.6MUg/mL, respectively. Moreover, the serum alcohol concentration was 1.4g/L in ante-mortem sample collected 1h after admission to the hospital. This is the first report on blood concentration of 3 MMC and 5-APB in fatal intoxication. PMID- 25447186 TI - Cost-consequence analysis of cause of death investigation in Finland and in Denmark. AB - The 1990s 12-16% total autopsy rate in Denmark has until now declined to 4%, while in Finland, it has remained between 25 and 30%. The decision to proceed with a forensic autopsy is based on national legislation, but it can be assumed that the financing of autopsies influences the decision process. Only little is known about the possible differences between health economics of Finnish and Danish cause of death investigation systems. The aims of this article were to analyse costs and consequences of Finnish and Danish cause of death investigations, and to develop an alternative autopsy practice in Denmark with another cost profile. Data on cause of death investigation systems and costs were derived from Departments of Forensic Medicine, Departments of Pathology, and the National Police. Finnish and Danish autopsy rates were calculated in unnatural (accident, suicide, homicide and undetermined intent) and natural (disease) deaths, and used to develop an alternative autopsy practice in Denmark. Consequences for society were analysed. The estimated unit cost (?) for one forensic autopsy is 3.2 times lower in Finland than in Denmark (?1400 versus ?4420), but in Finland the salaries for forensic pathologists working at the National Institute for Health and Welfare are not included in the unit cost. The unit cost for one medical autopsy is also lower in Finland than in Denmark; ?700 versus ?1070. In our alternative practice in Denmark, the forensic autopsy rate was increased from 2.2% to 8.5%, and the medical autopsy rate from 2.4% to 5.8%. Costs per 10,000 deaths were estimated to be 50% (+/-25%) higher than now; i.e. ?3,678,724 (2,759,112-4,598,336), but would result in a lower unit cost for forensic autopsies ?3,094 (2,320-3,868) and for medical autopsies ?749 (562-936). This practice would produce a higher accuracy of national mortality statistics, which, consequently, would entail higher quality in public health, an accurate basis for decision-making in health politics, and better legislative safety in society. The implementation of this alternative practice in Denmark requires that legislation demands that forensic autopsy be performed if causality between unnatural death and cause of death cannot be clarified or if cause of death remains unknown. The Danish Health and Medicines Authority should provide guidelines that request a medical autopsy in natural deaths where more information about disease as a cause of death is needed. Our study results warrant similar health economic analyses of different cause of death investigations in other countries. PMID- 25447187 TI - Beetle succession and diversity between clothed sun-exposed and shaded pig carrion in a tropical dry forest landscape in Southern Mexico. AB - Over a 31-day period, the decomposition process, beetle diversity and succession on clothed pig (Sus scrofa L.) carcasses were studied in open (agricultural land) and shaded habitat (secondary forest) in Southern Mexico. The decomposition process was categorised into five stages: fresh, bloated, active decay, advanced decay and remains. Except for the bloated stage, the elapsed time for each decomposition stage was similar between open and shaded habitats, all carcasses reached an advanced decay stage in seven days, and the fifth stage (remains) was not recorded in any carcass during the time of this study. A total of 6344 beetles, belonging to 130 species and 21 families, were collected during the entire decomposition process, and abundances increased from fresh to advanced decay stages. Staphylinidae, Scarabaeidae and Histeridae were taxonomically and numerically dominant, accounting for 61% of the species richness and 87% of the total abundance. Similar numbers of species (87 and 88 species for open and shaded habitats, respectively), levels of diversity and proportions (open 49%; shaded 48%) of exclusive species were recorded at each habitat. There were significantly distinct beetle communities between habitats and for each stage of decomposition. An indicator species analysis ("IndVal") identified six species associated to open habitats, 10 species to shaded habitats and eight species to advanced decay stages. In addition, 23 beetle species are cited for the first time in the forensic literature. These results showed that open and shaded habitats both provide suitable habitat conditions for the carrion beetle diversity with significant differences in community structure and identity of the species associated to each habitat. This research provides the first empirical evidence of beetle ecological succession and diversity on carrion in Mexican agro pastoral landscapes. PMID- 25447188 TI - Genuine and simulated suicide notes: An analysis of content. AB - The present study examined genuine and simulated suicide notes aiming to identify the measures of content that best differentiate between the two. Thirty-three genuine and thirty-three simulated suicide notes were content-analysed and data subjected to smallest space analysis (SSA), a Multidimensional Scaling Procedure. The core of all suicide notes was discovered to be constructed with the use of three variables: expressions of love, positive construction of partner and apologies. Furthermore, four different genuine suicide note themes ('planned escape', 'negative affect and self-mitigation', 'positive affect and failed relationship', 'lack of self-acceptance') and three simulated suicide note themes ('escape', 'positive affect and self-blame', 'purposeless life') were identified revealing that authentic suicide note themes were more internally consistent and clearer to interpret. PMID- 25447189 TI - A novel approach for latent print identification using accurate overlays to prioritize reference prints. AB - A novel approach to automated fingerprint matching and scoring that produces accurate locally and nonlinearly adjusted overlays of a latent print onto each reference print in a corpus is described. The technology, which addresses challenges inherent to latent prints, provides the latent print examiner with a prioritized ranking of candidate reference prints based on the overlays of the latent onto each candidate print. In addition to supporting current latent print comparison practices, this approach can make it possible to return a greater number of AFIS candidate prints because the ranked overlays provide a substantial starting point for latent-to-reference print comparison. To provide the image information required to create an accurate overlay of a latent print onto a reference print, "Ridge-Specific Markers" (RSMs), which correspond to short continuous segments of a ridge or furrow, are introduced. RSMs are reliably associated with any specific local section of a ridge or a furrow using the geometric information available from the image. Latent prints are commonly fragmentary, with reduced clarity and limited minutiae (i.e., ridge endings and bifurcations). Even in the absence of traditional minutiae, latent prints contain very important information in their ridges that permit automated matching using RSMs. No print orientation or information beyond the RSMs is required to generate the overlays. This automated process is applied to the 88 good quality latent prints in the NIST Special Database (SD) 27. Nonlinear overlays of each latent were produced onto all of the 88 reference prints in the NIST SD27. With fully automated processing, the true mate reference prints were ranked in the first candidate position for 80.7% of the latents tested, and 89.8% of the true mate reference prints ranked in the top ten positions. After manual post-processing of those latents for which the true mate reference print was not ranked first, these frequencies increased to 90.9% (1st rank) and 96.6% (top ten), respectively. Because the computational process is highly parallelizable, it is feasible for this method to work with a reference corpus of several thousand prints. PMID- 25447190 TI - Drugged driving arrests in Norway before and after the implementation of per se law. AB - Norway introduced legislative limits for driving under the influence of drugs (DUID) February 1st, 2012, to harmonize with the legislation on driving under the influence of alcohol. Per se limits corresponding to blood alcohol concentrations (BACs) of 0.02% were established for 20 drugs and concentration limits for graded sanctions corresponding to BACs of 0.05% and 0.12% were established for 13 of these drugs as well. The new system is not applied to individuals with valid prescriptions for medicinal drugs. The aim of this study was to investigate if the implementation of legislative limits for drugs affected the number of blood samples taken from suspected drugged drivers, drug findings and the number of expert witness statement requests. The number of blood samples taken in suspected DUID cases increased by 20% after introduction of legislative limits (3320 cases in 2010 and 3970 in 2013). The number of samples with at least one drug above the per se limit corresponding to BAC of 0.02% increased by 17% (from 2646 in 2010 to 3090 in 2013), whereas the number of expert witness statements was reduced by the half (from 63.4% in 2010 and 28.7% in 2013). PMID- 25447192 TI - Parental bonding in subjects with pathological gambling disorder compared with healthy controls. AB - The new Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM V) includes pathological gambling disorder (PGD) in the subgroup of "Addiction and Related Disorders" due to the similarities between PGD and substance-based addictions in neurobiological, psychological, and social risk factors. Family factors as parental rearing attitudes play a crucial role in the development of substance use disorders and PGD. The aim of the present study was to assess the parental bonding during childhood perceived for adults with PGD compared with healthy controls. Twenty males with PGD and 20 control subjects answered the parental bonding instrument, which measures subjects' recollections of parenting on dimensions of care and protection. Subjects with PGD showed significantly lower maternal and paternal care (p = 0.016 and p = 0.031, respectively) than controls, and higher paternal protection (p = 0.003). The most common parental pattern for PGD subjects was the affectionless control (50% for the father and 60% for the mother). Preliminary results suggest that, as previously reported for substance use disorders, an affectionless control parenting style is associated with PGD. PMID- 25447191 TI - Trends in licit and illicit drug-related deaths in Florida from 2001 to 2012. AB - BACKGROUND: Florida, the epicenter of the recent prescription drug epidemic in the United States, maintains a statewide drug mortality surveillance system. We evaluated yearly profiles, demographic characteristics, and correlation between drug trends to understand the factors influencing drug-induced mortality. METHODS: All drug-related deaths reported to the Florida Medical Examiners Commission during 2001-2012 were included (n=92,596). A death was considered "drug-related" if at least one drug was identified in the decedent. Depending on its contribution to death, a drug could be listed as a causative agent or merely present, but not both. RESULTS: Rate of drug-caused deaths was 8.0 per 100,000 population in 2001, increasing to 17.0 in 2010 and then decreasing to 13.9 in 2012. Benzodiazepines had the highest mortality rate in 2010, although <10% were solely due these drugs. Opioid-caused mortality rate also peaked in 2010 and started to decline (-28%) in 2010-2012. The heroin-caused mortality rates were negatively correlated with opioids and benzodiazepines (rho's >= -0.670; P<=0.034). Ethanol- and cocaine-mortality rates stabilized to 3.0-3.1 and 2.8-3.0 per 100,000 over 2009-2012, respectively. Amphetamines, zolpidem, and inhalants caused deaths were on the rise with rates of <=0.6 per 100,000. CONCLUSIONS: Overall declines in benzodiazepine- and opioid-caused deaths in 2011-2012 may have been related to Florida's attempts to regulate prescription drug abuse. This period, however, was also marked by a rise in heroin-caused mortality, which may reflect growing use of heroin as an alternative. Increases in amphetamines, zolpidem, and inhalants-induced mortality are an additional public health concern. PMID- 25447193 TI - Antimicrobial and immunomodulatory properties of PGLa-AM1, CPF-AM1, and magainin AM1: potent activity against oral pathogens. AB - Cationic amphipathic alpha-helical peptides are intensively studied classes of host defence peptides (HDPs). Three peptides, peptide glycine-leucine-amide (PGLa AM1), caerulein-precursor fragment (CPF-AM1) and magainin-AM1, originally isolated from norepinephrine-stimulated skin secretions of the African volcano frog Xenopus amieti (Pipidae), were studied for their antimicrobial and immunomodulatory activities against oral and respiratory pathogens. Minimal effective concentrations (MECs), determined by radial diffusion assay, were generally lower than minimal inhibitory concentrations (MICs) determined by microbroth dilution. PGLa-AM1 and CPF-AM1 were particularly active against Streptococcus mutans and all three peptides were effective against Fusobacterium nucleatum, whereas Enterococcus faecalis and Candida albicans proved to be relatively resistant micro-organisms. A type strain of Pseudomonas aeruginosa was shown to be more susceptible than the clinical isolate studied. PGLa-AM1 displayed the greatest propensity to bind lipopolysaccharide (LPS) from Escherichia coli, P. aeruginosa and Porphyromonas gingivalis. All three peptides showed less binding to P. gingivalis LPS than to LPS from the other species studied. Oral fibroblast viability was unaffected by 50 MUM peptide treatments. Production of the pro-inflammatory cytokine IL-8 by oral fibroblasts was significantly increased following treatment with 1 or 10 MUM magainin-AM1 but not following treatment with PGLa-AM1 or CPF-AM1. In conclusion, as well as possessing potent antimicrobial actions, the X. amieti peptides bound to LPS from three human pathogens and had no effect on oral fibroblast viability. CPF-AM1 and PGLa-AM1 show promise as templates for the design of novel analogues for the treatment of oral and dental diseases associated with bacteria or fungi. PMID- 25447194 TI - Anti-cancer, immunoregulatory, and antimicrobial activities of the frog skin host defense peptides pseudhymenochirin-1Pb and pseudhymenochirin-2Pa. AB - Pseudhymenochirin-1Pb (Ps-1Pb) and pseudhymenochirin-2Pa (Ps-2Pa) are host defense peptides, first isolated from skin secretions of the frog Pseudhymenochirus merlini (Pipidae). Ps-1Pb and Ps-2Pa are highly cytotoxic (LC50<12 MUM) against non-small cell lung adenocarcinoma A549 cells, breast adenocarcinoma MDA-MB-231 cells, and colorectal adenocarcinoma HT-29 cells but are also hemolytic against human erythrocytes (LC50=28+/-2 MUM for Ps-1Pb and LC50=6+/-1 MUM for Ps-2Pa). Ps-2Pa shows selective cytotoxicity for tumor cells (LC50 against non-neoplastic human umbilical vein (HUVEC) cells=68+/-2 MUM). Ps 1Pb and Ps-2Pa (5 MUg/mL) significantly inhibit production of the anti inflammatory cytokine IL-10 and the multifunctional cytokine IL-6 from lipopolysaccharide (LPS)-stimulated peritoneal macrophages from C57BL/6 mice and enhance the production of the pro-inflammatory cytokine IL-23 from both unstimulated and LPS-stimulated macrophages. Ps-1Pb potently (MIC<=10 MUM) inhibits growth of multidrug-resistant clinical isolates of the Gram-positive bacteria methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, and the Gram-negative bacteria Acinetobacter baumannii and Stenotrophomonas maltophilia. Ps-2Pa shows the same high potency (MIC<=10 MUM) against the Gram-positive bacteria but is 2-4 fold less potent against the Gram negative isolates. Ps-1Pb at 4*MIC kills 99.9% of Escherichia coli within 30 min and 99.9% of S. aureus within 180 min. In conclusion, cytotoxicity against tumor cells, cytokine-mediated immunomodulatory properties, and broad-spectrum antimicrobial activity suggest that the Ps-1Pb and Ps-2Pa represent templates for design of non-hemolytic analogs for tumor therapy and for treatment of infections in cancer patients produced by multidrug-resistant pathogens. PMID- 25447196 TI - Long-term quality of life after posterior chamber phakic intraocular lens implantation and after wavefront-guided laser in situ keratomileusis for myopia. AB - PURPOSE: To compare the vision-related quality of life 5 years after Implantable Collamer Lens phakic intraocular lens (pIOL) implantation and after wavefront guided laser in situ keratomileusis (LASIK) for myopia. SETTING: Department of Ophthalmology, Kitasato University, Kanagawa, Japan. DESIGN: Retrospective case series. METHODS: Quality of life was measured with the National Eye Institute Refractive Error Quality of Life instrument in consecutive patients 5 years after pIOL implantation or wavefront-guided LASIK to correct myopia. RESULTS: Phakic IOL implantation was performed in 48 patients and LASIK in 55 patients. The scores for activity limitations, symptoms, appearance, and satisfaction with correction were significantly higher in the pIOL group than in the LASIK group (P<.05, Mann-Whitney U test). No significant differences in other scores were observed between the 2 groups (P >=.05). The scores for near vision and dependence on correction were significantly higher in the younger subgroup than in the older subgroup with both techniques. CONCLUSIONS: Phakic IOL implantation may offer significant vision-related quality-of-life advantages (eg, fewer activity limitations and symptoms and better appearance and satisfaction with correction) over wavefront-guided LASIK for myopia in the long term. Moreover, refractive surgery may provide a better quality of life in younger patients. PMID- 25447195 TI - Economic features of antibiotic resistance: the case of methicillin-resistant Staphylococcus aureus. AB - This paper analyses and updates the economic information regarding methicillin resistant Staphylococcus aureus (MRSA), including information that has been previously reviewed by other authors, and new information, for the purpose of facilitating health management and clinical decisions. The analysed articles reveal great disparity in the economic burden on MRSA patients; this is mainly due to the diversity of the designs of the studies, as well as the variability of the patients and the differences in health care systems. Regarding prophylactic strategies, the studies do not provide conclusive results that could unambiguously orientate health management. The studies addressing treatments noted that linezolid seems to be a cost-effective treatment for MRSA, mostly because it is associated with a shorter length of stay (LOS) in hospital. However, important variables such as antimicrobial susceptibility, infection type and resistance emergence should be included in these analyses before a conclusion is reached regarding which treatment is the best (most efficient). The reviewed studies found that rapid MRSA detection, using molecular techniques, is an efficient technique to control MRSA. As a general conclusion, the management of MRSA infections implicates important economic costs for hospitals, as they result in higher direct costs and longer LOS than those related to methicillin susceptible S. aureus (MSSA) patients or MRSA-free patients; there is wide variability in those increased costs, depending on different variables. Moreover, the research reveals a lack of studies on other related topics, such as the economic implications of changes in MRSA epidemiology (community patients and lineages associated with farm animals). PMID- 25447197 TI - Incomplete femtosecond laser-assisted capsulotomy and lens fragmentation due to emulsified silicone oil in the anterior chamber. AB - We report 2 cases involving femtosecond laser-assisted cataract surgery following a retinal-detachment repair performed 1 and 2 years earlier using silicone oil endotamponade that was subsequently removed. Preoperative slitlamp examination did not show emulsified silicone oil in the anterior chamber. Intraoperatively, however, emulsified silicone oil was seen on anterior segment optical coherence tomography (AS-OCT) as a distinct hyperreflective retrocorneal line and there was no penetration of the OCT signal or delivery of the femtosecond laser treatment through this area, resulting in incomplete capsulotomy and lens fragmentation in both cases. Because silicone oil has a lower density than aqueous and migrates superiorly, careful preoperative gonioscopic examination to evaluate for emulsified silicone oil in the superior angle is warranted in eyes having femtosecond laser-assisted cataract surgery after a vitrectomy with silicone-oil endotamponade. Review of intraoperative OCT images can detect emulsified silicone oil, which would allow the procedure to be modified appropriately to prevent complications. PMID- 25447198 TI - Surface-attached cells, biofilms and biocide susceptibility: implications for hospital cleaning and disinfection. AB - Microbes tend to attach to available surfaces and readily form biofilms, which is problematic in healthcare settings. Biofilms are traditionally associated with wet or damp surfaces such as indwelling medical devices and tubing on medical equipment. However, microbes can survive for extended periods in a desiccated state on dry hospital surfaces, and biofilms have recently been discovered on dry hospital surfaces. Microbes attached to surfaces and in biofilms are less susceptible to biocides, antibiotics and physical stress. Thus, surface attachment and/or biofilm formation may explain how vegetative bacteria can survive on surfaces for weeks to months (or more), interfere with attempts to recover microbes through environmental sampling, and provide a mixed bacterial population for the horizontal transfer of resistance genes. The capacity of existing detergent formulations and disinfectants to disrupt biofilms may have an important and previously unrecognized role in determining their effectiveness in the field, which should be reflected in testing standards. There is a need for further research to elucidate the nature and physiology of microbes on dry hospital surfaces, specifically the prevalence and composition of biofilms. This will inform new approaches to hospital cleaning and disinfection, including novel surfaces that reduce microbial attachment and improve microbial detachment, and methods to augment the activity of biocides against surface-attached microbes such as bacteriophages and antimicrobial peptides. Future strategies to address environmental contamination on hospital surfaces should consider the presence of microbes attached to surfaces, including biofilms. PMID- 25447199 TI - Nanomedicines for antimicrobial interventions. AB - The development of new antimicrobial therapeutic tools addresses the emergence of multidrug-resistant micro-organisms or clones and the need for more effective antimicrobial strategies. Overcoming the hurdles in providing early diagnosis and intervention on hard-to-reach and/or resting bacteria (i.e. biofilm-embedded cells) represents a challenging task. In this review, we identify a set of organic, inorganic, and hybrid materials that might be used for prevention and control of healthcare-associated infections. We report the current knowledge on nano- and microparticle-based antimicrobial agents and describe the possible mode of their action. PMID- 25447200 TI - Outbreak of Clostridium difficile ribotype 027 in a residential home. AB - This article reports a significant outbreak of Clostridium difficile ribotype 027 infection in a residential care home in the UK. Five of six affected residents died within one month of diagnosis. Investigation of the facility revealed problems with hand hygiene and environmental cleaning. Affected residents had received a mean of 2.7 antibiotic courses in the two months preceding diagnosis. It is important to recognize that C. difficile outbreaks can occur in residential homes. There is a need for health- and social-care systems to work closely together to assure the safety of people in their care. PMID- 25447202 TI - Status and prospects of DNA barcoding in medically important parasites and vectors. AB - For over 10 years, DNA barcoding has been used to identify specimens and discern species. Its potential benefits in parasitology were recognized early, but its utility and uptake remain unclear. Here we review studies using DNA barcoding in parasites and vectors affecting humans and find that the technique is accurate (accords with author identifications based on morphology or other markers) in 94 95% of cases, although aspects of DNA barcoding (vouchering, marker implicated) have often been misunderstood. In a newly compiled checklist of parasites, vectors, and hazards, barcodes are available for 43% of all 1403 species and for more than half of 429 species of greater medical importance. This is encouraging coverage that would improve with an active campaign targeting parasites and vectors. PMID- 25447203 TI - Anti-tumor activity of sorafenib in a model of a pediatric hepatocellular carcinoma. AB - BACKGROUND: Treatment outcome of children with pediatric hepatocellular carcinoma (pHCC) is poor. Therefore, we evaluated the tyrosine kinase inhibitor sorafenib in a model of pHCC. METHODS: Cell viability after treatment with sorafenib was evaluated in HC-AFW1 cells (pHCC) using MTT assay and compared to an adult HCC (aHCC) and two hepatoblastoma (HB) cell lines. ERK, pERK, E-cadherin, and vimentin expression were investigated using Western Blot. Sorafenib (60 mg/kg) was administered orally to NOD.Cg-Prkdcscid-IL2rgtmWjl/Sz mice bearing subcutaneous HC-AFW1-derived tumors. Tumor progression, viability, and vascularization were monitored by tumor volume, AFP levels, and CD31 immunostaining, respectively. Sensitization to sorafenib was evaluated using the beta-catenin inhibitor ICG001. RESULTS: Sorafenib reduced cell viability in HC AFW1 (IC50: 8 uM), comparable to HB cells, however less pronounced in aHCC cells (IC50: 23 uM). Sorafenib inhibited ERK signaling in both, HC-AFW1 cells and xenografts. In vivo, sorafenib treatment only led to a moderate tumor growth inhibition, although significant reduction of vascularization and tumor growth kinetics was observed. Long-term treatment with sorafenib decreased E-cadherin, but showed no induction of vimentin expression. Combining sorafenib with a beta catenin inhibitor led to an additional reduction of cell viability. CONCLUSION: Sorafenib together with inhibitors of the beta-catenin pathway might be an effective tool in the treatment of pediatric HCC. PMID- 25447201 TI - Cross-colonization of infants with probiotic organisms in a neonatal unit. AB - This study aimed to assess probiotic cross-colonization between infants in a neonatal unit where probiotics were being administered to preterm infants during a clinical trial. We tested stool samples from all infants present in the unit at two time points; the first was during the trial and the second was after trial completion. Samples from 43 infants were tested during the trial; all five infants receiving probiotics and three of 38 not receiving probiotics were colonized. Only one of 44 infants tested after the trial was colonized. The rate of cross-colonization was lower than in previous probiotic studies. PMID- 25447204 TI - OSBP-related protein 3 (ORP3) coupling with VAMP-associated protein A regulates R Ras activity. AB - ORP3 is an R-Ras interacting oxysterol-binding protein homolog that regulates cell adhesion and is overexpressed in several cancers. We investigated here a novel function of ORP3 dependent on its targeting to both the endoplasmic reticulum (ER) and the plasma membrane (PM). Using biochemical and cell imaging techniques we demonstrate the mechanistic requirements for the subcellular targeting and function of ORP3 in control of R-Ras activity. We show that hyperphosphorylated ORP3 (ORP3-P) selectively interacts with the ER membrane protein VAPA, and ORP3-VAPA complexes are targeted to PM sites via the ORP3 pleckstrin homology (PH) domain. A novel FFAT (two phenylalanines in an acidic tract)-like motif was identified in ORP3; only disruption of both the FFAT-like and canonical FFAT motif abolished the phorbol-12-myristate-13-acetate (PMA) stimulated interaction of ORP3-P with VAPA. Co-expression of ORP3 and VAPA induced R-Ras activation, dependent on the interactions of ORP3 with VAPA and the PM. Consistently, downstream AktS473 phosphorylation and beta1-integrin activity were enhanced by ORP3-VAPA. To conclude, phosphorylation of ORP3 controls its association with VAPA. Furthermore, we present evidence that ORP3-VAPA complexes stimulate R-Ras signaling. PMID- 25447205 TI - MxA interacts with and is modified by the SUMOylation machinery. AB - Mx proteins are evolutionarily conserved dynamin-like large GTPases involved in viral resistance triggered by types I and III interferons. The human MxA is a cytoplasmic protein that confers resistance to a large number of viruses. The MxA protein is also known to self-assembly into high molecular weight homo-oligomers. Using a yeast two-hybrid screen, we identified 27 MxA binding partners, some of which are related to the SUMOylation machinery. The interaction of MxA with Small Ubiquitin MOdifier 1 (SUMO1) and Ubiquitin conjugating enzyme 9 (Ubc9) was confirmed by co-immunoprecipitation and co-localization by confocal microscopy. We identified one SUMO conjugation site at lysine 48 and two putative SUMO interacting motifs (SIMa and SIMb). We showed that MxA interacts with the EIL loop of SUMO1 in a SIM-independent manner via its CID-GED domain. The yeast two hybrid mapping also revealed that Ubc9 binds to the MxA GTPase domain. Mutation in the putative SIMa and SIMb, which are located in the GTPase binding domain, reduced MxA antiviral activity. In addition, we showed that MxA can be conjugated to SUMO2 or SUMO3 at lysine 48 and that the SUMOylation-deficient mutant of MxA (MxAK48R) retained its capacity to oligomerize and to inhibit Vesicular Stomatitis Virus (VSV) and Influenza A Virus replication, suggesting that MxA SUMOylation is not essential for its antiviral activity. PMID- 25447206 TI - The miR-134 attenuates the expression of transcription factor FOXM1 during pluripotent NT2/D1 embryonal carcinoma cell differentiation. AB - Transcription factor FOXM1 plays a critical role in maintenance of stem cell pluripotency through stimulating the transcription of pluripotency-related genes in mouse pluripotent stem cells. In this study, we have found that the repression of FOXM1 expression is mediated by FOXM1 3'UTR during retinoic acid-induced differentiation of human pluripotent NT2/D1 embryonal carcinoma cells. FOXM1 3'UTR contains a microRNA response element (MRE) for miR-134, which has been shown to attenuate the expression of pluripotency-related genes post transcriptionally during mouse embryonic stem cell differentiation. We have determined that miR-134 is induced during RA-induced differentiation of NT2/D1 cells and the overexpression of miR-134 represses the expression of FOXM1 protein but not FOXM1 mRNA. Furthermore, the expression of OCT4 is diminished by FOXM1 knockdown and the OCT4 promoter is regulated directly by FOXM1, suggesting that FOXM1 is required for maintaining the expression of OCT4 in NT2/D1 cells. Together, our results suggest that FOXM1 is essential for human pluripotent stem cells and miR-134 attenuates its expression during differentiation. PMID- 25447207 TI - Single chain fragment variable antibodies developed by using as target the 3rd fibronectin type III homologous repeat fragment of human neural cell adhesion molecule L1 promote cell migration and neuritogenesis. AB - L1CAM plays important roles during ontogeny, including promotion of neuronal cell migration and neuritogenesis, and stimulation of axonal outgrowth, fasciculation and myelination. These functions are at least partially exerted through a 16-mer amino acid sequence in the third fibronectin type III-like repeat of L1, which associates with several interaction partners, including integrins, other adhesion molecules and growth factor receptors. Here, using the Tomlinson I library for phage display, we obtained two single-chain variable fragment antibodies (scFvs) against this peptide sequence of human L1, hereafter called H3 peptide. Both scFvs recognize the H3 peptide and the extracellular domain of L1, as tested by enzyme-linked immunosorbent assay (ELISA), Western blot analysis and immunofluorescence staining of L1 expresssing cells. Furthermore, both scFvs reduce U-87 MG cell adhesion to fibronectin, while stimulating cell migration. Application of scFvs to human neuroblastoma SK-N-SH cells promote process outgrowth. Similar to triggering of endogenous L1 functions at the cell surface, both scFvs activate the signal transducers Erk and Src in these cells. Our results indicate that scFvs against a functionally pivotal domain in L1 trigger its regeneration-beneficial functions in vitro, encouraging thoughts on therapy of neurodegenerative diseases in the hope to ameliorate human nervous system diseases. PMID- 25447209 TI - Preventive and therapeutic role of traditional Chinese herbal medicine in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. The clinical management of HCC remains a substantial challenge. Although surgical resection of tumor tissues seems promising, a high recurrence and/or metastasis rate accounting for disease-related death has led to an urgent need for improved postsurgical preventive/therapeutic clinical intervention. Developing advanced target-therapy agents such as sorafenib appears to be the only effective clinical intervention for patients with HCC to date, but only limited trials have been conducted in this regard. Because of their enhanced preventive/therapeutic effects, traditional Chinese herbal medicine (CHM)-derived compounds are considered suitable agents for HCC treatment. The CHM-derived compounds also possess multilevel, multitarget, and coordinated intervention effects, making them ideal candidates for inhibition of tumor progression and HCC metastasis. This article reviews the anticancer activity of various CHMs with the hope of providing a better understanding of how to best use CHM for HCC treatment. PMID- 25447208 TI - Toward tract-specific fractional anisotropy (TSFA) at crossing-fiber regions with clinical diffusion MRI. AB - PURPOSE: White matter fractional anisotropy (FA), a measure suggesting microstructure, is significantly underestimated with single diffusion tensor model at crossing-fiber regions (CFR). We propose a tract-specific FA (TSFA), corrected for the effects of crossing-fiber geometry and free water at CFR, and adapted for tract analysis with diffusion MRI (dMRI) in clinical research. METHODS: At CFR voxels, the proposed technique estimates free water fraction (fiso ) as a linear function of mean apparent diffusion coefficient (mADC), fits the dual tensors and estimates TSFA. Digital phantoms were designed for testing the accuracy of fiso and fitted dual-anisotropies at CFR. The technique was applied to clinical dMRI of normal subjects and hereditary spastic paraplegia (HSP) patients to test the effectiveness of TSFA. RESULTS: Phantom simulation showed unbiased estimates of dual-tensor anisotropies at CFR and high accuracy of fiso as a linear function of mADC. TSFA at CFR was highly consistent to the single tensor FA at non-CFR within the same tract with normal human dMRI. Additional HSP imaging biomarkers with significant correlation to clinical motor function scores could be identified with TSFA. CONCLUSION: Results suggest the potential of the proposed technique in estimating unbiased TSFA at CFR and conducting tract analysis in clinical research. PMID- 25447210 TI - Paradoxical brain embolism associated with Kimura disease mimics watershed infarction. AB - Kimura disease (KD) is an uncommon chronic inflammatory disease presenting as subcutaneous lymphadenopathy with eosinophilia. To date, only a single case of brain embolism caused by fibroblastic endocarditis associated with KD has been reported. Watershed infarction was seen in patients with episodes of severe hypotension or cardiac surgery. We here report a young case of KD who developed ischemic stroke and showed multiple small infarcts in the border zones between the territories of major cerebral arteries, mimicking watershed infarction. Transesophageal echocardiography revealed patent foramen ovale and atrial septal aneurysm. Concurrently, deep venous thrombus in the femoral vein was found on duplex ultrasonography. Our case supports the notion that paradoxical brain embolism associated with KD can cause multiple small embolisms and mimic watershed infarction. PMID- 25447212 TI - Free tendon grafts in elder patients, a case report of repair of flexor pollicis longus tendon with a free palmaris longus graft in an 89-year-old woman. AB - Flexor tendon rupture is a potential complication after volar plating of distal radius fracture. Palliative procedures such as tenodesis and arthrodesis are usually employed in elder patients with imperfect results. We report a case of delayed flexor pollicis longus rupture seven years after volar plating of a distal radius fracture occurring in an 89-year-old woman. The repair with a free tendon graft of palmaris longus was successful in terms of strength and range of motion. Free tendon grafts should not be limited to younger patients and could be used in elder patients after careful selection. PMID- 25447213 TI - [Interest of dermal substitute (Matriderm (c)) to cover long fingers after congenital syndactyly: About 20 commissures]. AB - INTRODUCTION: Surgical treatment of congenital syndactylies is based on the creation of a new commissure - with a commissural flap - and on the management of fingers lateral faces - with mirror zigzag incisions. Lateral skin defects are covered by full-thickness skin graft. Since their discover 30 years ago, dermal substitutes applications have been enlarged. We have wandered if these technique could be interesting for the treatment of these lateral skin defects. MATERIALS AND METHOD: We have launched a monocentric and retrospective study with only one surgeon. The assessor and the operator were different. Included patients have a simple or complex congenital syndactyly, complete or not, associated with a syndrome or not. Children with a first web space syndactyly were excluded. Surgical treatment was performed with a dorsal commissural flap, with mirror incisions and with a lateral skin defects coverage by dermal substitute (Matriderm((c))) and split-thickness skin graft taken from the scalp. The initial assessment criterion was the quality of the scare measured by the OSAS score. Web creep (Whitney's scale) and time of surgery were two minor criteria. RESULTS: Twenty commissures (11 children) have been included between 2008 and 2013. Fourteen complex syndactylies were noted. The average aftercare was equal to 2.7 years (0.5-5.5 years). Interventions were performed at the age of 1.8 years (0.5 4 years). Surgical time was equal to 44.6 min (22-95 min). Patients OSAS score was 11.9 (6-18). It was 12.2 (60-20) for complex forms and 11.9 (10-16) for simple forms. Graft weren't hairy. There was no complication on the donor site. Whitney's score was 1.2 (0-3) and three web spaces were reoperated. CONCLUSION: We think that the use of dermal substitute Matriderm((c)) is a new and serious alternative to treat congenital syndactylies. Results have to be confirmed by a new study which would compare this material to full-thickness skin graft, gold standard technique for these skin defects. PMID- 25447211 TI - Subsequent vascular events after ischemic stroke: the Japan Statin Treatment Against Recurrent Stroke-Longitudinal. AB - BACKGROUND: We undertook a multicenter cohort observational study to investigate the frequency and type of subsequent vascular events after an ischemic stroke and to compare the rates of vascular events between patients with and without hyperlipidemia. METHODS: This nationwide study was conducted in 19 hospitals participating in the Japan Standard Stroke Registry Study. We enrolled ischemic stroke patients, including those with a transient ischemic attack, who had not experienced any vascular events before enrollment after their ischemic stroke events. Each subject was observed prospectively from September 1, 2003, to October 1, 2005, or until a primary end point or death. Primary end points included subsequent fatal or nonfatal vascular events: stroke, angina pectoris, acute myocardial infarction, aortic aneurysm, or arteriosclerosis obliterans. RESULTS: A total of 449 patients (mean age, 67.6 years; 64.8% men) were enrolled in this study. Of the 41 vascular events observed during follow-up, 40 were stroke. The median observation period was 568 days. We found that patients with hyperlipidemia had a significantly higher rate of vascular events compared with those without hyperlipidemia according to the Kaplan-Meier method and the log rank test (P = .013). Hyperlipidemia significantly increased the risk of vascular events (hazard ratio, 2.169 [1.125-4.312]; P = .021) according to the Cox proportional hazard model after adjusting for confounding factors (age, sex, days from ischemic stroke until enrollment, smoking habits, and daily drinking habits). CONCLUSIONS: This study demonstrated that stroke was the most common subsequent vascular event after ischemic stroke; the study also indicated that hyperlipidemia could be a risk factor for subsequent vascular events after ischemic stroke. PMID- 25447214 TI - Supermicrosurgery and hyaluronic acid: experimental feasability study of a new method. AB - INTRODUCTION: As a technique of anastomosis for vessels of less than 0.8mm in diameter, supermicrosurgery has aroused renewed interest on account of its potential clinical applications. The technical difficulty of surgery at such a small scale necessitates exploration of new methods likely to render the anastomoses accessible and reliable. The aim of this article is to present the results of an experimental study on the feasibility of anastomoses (arterial diameter <=0.5mm), assisted by the injection of hyaluronic acid (HA). MATERIALS AND METHODS: Ten end-to-end arterial anastomoses of the inferior epigastric artery (diameter <=0.5mm) were performed in 5 rats. An injection of HA had previously been carried out in the vessel lumen and the sutures were made with 12 0 nylon. Immediate and 3-day permeability were controlled and anastomosis times were measured. RESULTS: Average diameter of the arteries was 0.42 mm (range 0.29 0.48 mm). Mean anastomosis duration was 19.5 min (range 15-23 min). The average number of stitches was 6. Immediate patency was 100% with a success rate of 80% at 3 days. CONCLUSIONS: The properties of HA seem to effectively facilitate anastomoses of arteries with a diameter <=0.5mm. HA provides comfort and promotes safety in performance of exceedingly small-scale surgery. While the results appear promising, but further studies are needed in order to determine the potential toxicity of this method on tissues. PMID- 25447215 TI - [Scalp flap pedicled on the posterior auricular artery. Anatomical study and clinical application]. AB - INTRODUCTION: Management of scalps defect is a common subject for reconstructive surgery. The use of local flap is better because of the hairy skin. OBJECTIVE: The auricular posterior artery is often described as an accessory blood supply for the scalp. METHOD: We present an original case of 16*6 cm scalp flap harvested almost in "vascular island" on the right retro-auricular pedicle to cover an occipital wound. RESULTS: We have obtained an effective healing in 20 days. Despite its considerable length, no distal necrosis has occurred. CONCLUSION: Rarely reported in the surgical literature, the posterior auricular vessels are a good blood supply to harvest scalp flap. This procedure adds to overall techniques of reconstructive surgery for scalps defects that plastic surgeons can use. PMID- 25447216 TI - Smoking and plastic surgery, part I. Pathophysiological aspects: update and proposed recommendations. AB - OBJECTIVES: Smoking patients undergoing a plastic surgery intervention are exposed to increased risk of perioperative and postoperative complications. It seemed useful to us to establish an update about the negative impact of smoking, especially on wound healing, and also about the indisputable benefits of quitting. We wish to propose a minimum time lapse of withdrawal in the preoperative and postoperative period in order to reduce the risks and maximize the results of the intervention. METHODS: A literature review of documents from 1972 to 2014 was carried out by searching five different databases (Medline, PubMed Central, Cochrane library, Pascal and Web of Science). RESULTS: Cigarette smoke has a diffuse and multifactorial impact in the body. Hypoxia, tissue ischemia and immune disorders induced by tobacco consumption cause alterations of the healing process. Some of these effects are reversible by quitting. Data from the literature recommend a preoperative smoking cessation period lasting between 3 and 8 weeks and up until 4 weeks postoperatively. Use of nicotine replacement therapies doubles the abstinence rate in the short term. When a patient is heavily dependent, the surgeon should be helped by a tobacco specialist. CONCLUSIONS: Total smoking cessation of 4 weeks preoperatively and lasting until primary healing of the operative site (2 weeks) appears to optimize surgical conditions without heightening anesthetic risk. Tobacco withdrawal assistance, both human and drug-based, is highly recommended. PMID- 25447217 TI - [An atypical lacrymal cyst]. AB - INTRODUCTION: Lacrimal cysts are rarely described and must be differentiated from diseases of the lacrimal gland. We present a rare case of lacrimal cyst developed from an accessory lacrimal gland. CASE REPORT: The management consisted of excision using a tarsoconjonctivale approach. DISCUSSION: Most cysts are diagnosed from the third decade, manifested by progressive exophthalmos. It is a benign disease. However, the differential diagnosis with malignancy is not excluded. Surgical resection is desirable if tumors become symptomatic. PMID- 25447218 TI - Smoking and plastic surgery, part II. Clinical implications: a systematic review with meta-analysis. AB - OBJECTIVES: Tobacco addiction is a risk factor for complication in plastic surgery. The authors have assembled concrete arguments detailing the risks of perioperative and postoperative complication that are incurred by a patient with continued tobacco intoxication who wishes to undergo a surgical intervention. RESEARCH STRATEGY: Through application of the PRISMA criteria, we have carried out a systematic review of the literature, in which we explored five databases while using predefined keywords. We selected randomized, controlled observational studies on the perioperative and postoperative complications related to tobacco use in actively smoking, abstinent and non-smoking patients. DATA COLLECTION AND ANALYSIS: The levels of evidence for each article were evaluated. Risk of bias was assessed using the Newcastle-Ottawa Scale. Incidence parameters including the Odds Ratio and relative risk were calculated for each complication of which the number of occurrences had been indicated. Meta-analysis of the results was carried out. RESULTS: We included 60 observational studies. In the cosmetic surgery group, we calculated a combined Odds Ratio of 2.3 [1.51-3.54] P<0.001 for surgical site infections and 2.5 [1.49-4.08] P<0.001 for delayed wound healing. In the bariatric surgery sequelae group, we found a combined Odds Ratio of 3.3 [1.90-5.64] P<0.001 with regard to delayed wound healing and 3.1 [1.39-7.13] P=0.006 for cutaneous necrosis. No proof was provided as to the possible influence of tobacco on the success rate of free flap microsurgery, but it is difficult to extrapolate results on the latter to digital reimplantation. CONCLUSIONS: The review underlines the fact that patients with smoking habits run a significantly heightened risk of cutaneous necrosis, particularly in the event of major detachment (cervico-facial lift, skin-sparing mastectomy, abdominoplasty), of additionally delayed wound healing and of addition surgical site infections. Rigorous preoperative evaluation of smokers could help to diminish these risks. PMID- 25447219 TI - MALDI-MS and NanoSIMS imaging techniques to study cnidarian-dinoflagellate symbioses. AB - Cnidarian-dinoflagellate photosynthetic symbioses are fundamental to biologically diverse and productive coral reef ecosystems. The hallmark of this symbiotic relationship is the ability of dinoflagellate symbionts to supply their cnidarian host with a wide range of nutrients. Many aspects of this association nevertheless remain poorly characterized, including the exact identity of the transferred metabolic compounds, the mechanisms that control their exchange across the host-symbiont interface, and the precise subcellular fate of the translocated materials in cnidarian tissues. This lack of knowledge is mainly attributed to difficulties in investigating such metabolic interactions both in situ, i.e. on intact symbiotic associations, and at high spatial resolution. To address these issues, we illustrate the application of two in situ and high spatial resolution molecular and ion imaging techniques-matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and the nano-scale secondary-ion mass spectrometry (NanoSIMS) ion microprobe. These imaging techniques provide important new opportunities for the detailed investigation of many aspects of cnidarian-dinoflagellate associations, including the dynamics of cellular interactions. PMID- 25447220 TI - Antagonizing reactive oxygen species during ex vivo lung perfusion. PMID- 25447221 TI - Response to letter by Dr. M. S. A. Mohamed (Antagonizing reactive oxygen species during lung perfusion). PMID- 25447223 TI - Angiopoietin-1 blocks neurotoxic zinc entry into cortical cells via PIP2 hydrolysis-mediated ion channel inhibition. AB - Excessive entry of zinc ions into the soma of neurons and glial cells results in extensive oxidative stress and necrosis of cortical cells, which underlies acute neuronal injury in cerebral ischemia and epileptic seizures. Here, we show that angiopoietin-1 (Ang1), a potent angiogenic ligand for the receptor tyrosine kinase Tie2 and integrins, inhibits the entry of zinc into primary mouse cortical cells and exerts a substantial protective effect against zinc-induced neurotoxicity. The neuroprotective effect of Ang1 was mediated by the integrin/focal adhesion kinase (FAK) signaling axis, as evidenced by the blocking effects of a pan-integrin inhibitory RGD peptide and PF-573228, a specific chemical inhibitor of FAK. Notably, blockade of zinc-permeable ion channels by Ang1 was attributable to phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate. Collectively, these data reveal a novel role of Ang1 in regulating the activity of zinc-permeable ion channels, and thereby protecting cortical cells against zinc-induced neurotoxicity. PMID- 25447222 TI - A novel neuroferritinopathy mouse model (FTL 498InsTC) shows progressive brain iron dysregulation, morphological signs of early neurodegeneration and motor coordination deficits. AB - Neuroferritinopathy is a rare genetic disease with a dominant autosomal transmission caused by mutations of the ferritin light chain gene (FTL). It belongs to Neurodegeneration with Brain Iron Accumulation, a group of disorders where iron dysregulation is tightly associated with neurodegeneration. We studied the 498-499InsTC mutation which causes the substitution of the last 9 amino acids and an elongation of extra 16 amino acids at the C-terminus of L-ferritin peptide. An analysis with cyclic voltammetry on the purified protein showed that this structural modification severely reduces the ability of the protein to store iron. In order to analyze the impact of the mutation in vivo, we generated mouse models for the some pathogenic human FTL gene in FVB and C57BL/6J strains. Transgenic mice in the FVB background showed high accumulation of the mutated ferritin in brain where it correlated with increased iron deposition with age, as scored by magnetic resonance imaging. Notably, the accumulation of iron-ferritin bodies was accompanied by signs of oxidative damage. In the C57BL/6 background, both the expression of the mutant ferritin and the iron levels were lower than in the FVB strain. Nevertheless, also these mice showed oxidative alterations in the brain. Furthermore, post-natal hippocampal neurons obtained from these mice experienced a marked increased cell death in response to chronic iron overload and/or acute oxidative stress, in comparison to wild-type neurons. Ultrastructural analyses revealed an accumulation of lipofuscin granules associated with iron deposits, particularly enriched in the cerebellum and striatum of our transgenic mice. Finally, experimental subjects were tested throughout development and aging at 2-, 8- and 18-months for behavioral phenotype. Rotarod test revealed a progressive impaired motor coordination building up with age, FTL mutant old mice showing a shorter latency to fall from the apparatus, according to higher accumulation of iron aggregates in the striatum. Our data show that our 498-499InsTC mouse models recapitulate early pathological and clinical traits of the human neuroferritinopathy, thus providing a valuable model for the study of the disease. Finally, we propose a mechanistic model of lipofuscine formation that can account for the etiopathogenesis of human neuroferritinopathy. PMID- 25447225 TI - Evidence for orexinergic mechanisms in migraine. AB - OBJECTIVE: To examine the effect of the orexinergic blockade with a dual orexin receptor antagonist (DORA) on experimental models of peripheral and central trigeminal as well as cortical activation relevant to migraine and migraine aura. METHODS: In this study we used a precursor of suvorexant, a dual orexin receptor antagonist #12 (DORA-12) in established experimental in vivo models of dural trigeminovascular nociception in rat. Neurogenic dural vasodilation and electrophysiological recordings of second order trigeminocervical neurons were used to study trigeminal nociceptive mechanisms directly. KCl-evoked cortical spreading depression was also used as a surrogate for migraine aura. RESULTS: Neurogenically-induced vasodilation of the middle meningeal artery, caused by nociceptive activation of peripheral afferent projections of the trigeminal nerve, was attenuated by intravenous DORA-12 (1 mgkg(-1)). Second-order trigeminocervical complex neuronal activity was significantly inhibited by intravenous DORA-12 (1 mgkg(-1)). DORA-12 significantly reduced susceptibility to KCl-evoked cortical spreading depression. CONCLUSION: The study provides the first direct evidence, that simultaneous antagonism on both orexin receptors is able to attenuate trigeminal nociceptive activity as well as to induce an elevation of the threshold for the induction of a cortical spreading depression (CSD). In the clinical context, these data imply that targeting the hypothalamic orexinergic system may offer an entirely novel mechanism for the preventive treatment of migraine with and without aura. PMID- 25447226 TI - Dynamic cortical gray matter volume changes after botulinum toxin in cervical dystonia. AB - Previous electrophysiological and functional imaging studies in focal dystonia have reported on cerebral reorganization after botulinum toxin (BoNT) injections. With the exception of microstructural changes, alterations in gray matter volume after BoNT have not been explored. In this study, we sought to determine whether BoNT influences gray matter volume in a group of cervical dystonia (CD) patients. We analyzed whole brain gray matter volume in a sample of CD patients with VBM analysis. In patients, scans were repeated immediately before and some weeks after BoNT injections; controls were only scanned once. We analyzed 1) BoNT related gray matter volume changes within patients; 2) gray matter volume differences between patients and controls; and 3) correlations between gray matter volume and disease duration and disease severity. The pre- and post-BoNT treatment analysis revealed an increase of gray matter volume within the right precentral sulcus, at the lateral border of the premotor cortex. In comparison to healthy controls, CD patients had reduced gray matter volume in area 45 functionally corresponding to the left ventral premotor cortex. No gray matter volume increase was found for CD patients in comparison to controls. Gray matter volume of the left supramarginal gyrus and left premotor cortex correlated positively with disease duration, and that of the right inferior parietal lobule correlated negatively with disease severity. We have identified structural, yet dynamic gray matter volume changes in CD. There were specific gray matter volume changes related to BoNT injections, illustrating indirect central consequences of modified peripheral sensory input. As differences were exclusively seen in higher order motor areas relevant to motor planning and spatial cognition, these observations support the hypothesis that deficits in these cognitive processes are crucial in the pathophysiology of CD. PMID- 25447228 TI - Post-status epilepticus treatment with the cannabinoid agonist WIN 55,212-2 prevents chronic epileptic hippocampal damage in rats. AB - Repeated seizures are often associated with development of refractory chronic epilepsy, the most common form of which is temporal lobe epilepsy. G-protein coupled cannabinoid receptors (CB1 and CB2 receptors) regulate neuronal excitability and have been shown to mediate acute anticonvulsant effects of cannabinoids in animal models. However, the potential of cannabinoids to prevent chronic neuronal damage and development of epilepsy remains unexplored. We hypothesized that treatment with a CB receptor agonist after an episode of status epilepticus--but before development of spontaneous recurrent seizures--might prevent the development of functional changes that lead to chronic epilepsy. Using the rat pilocarpine model, a therapeutic approach was simulated by administering the CB agonist, WIN 55,212-2 after an episode of status epilepticus. Epileptic behavior was monitored during development of spontaneous recurrent seizures for up to 6 months. Histology, neurochemistry, redox status and NMDA receptor subunit expression were assessed at 6 months after pilocarpine induced seizures. Sub-acute treatment with WIN 55,212-2 (for 15 days starting 24h after PILO injection) dramatically attenuated the severity, duration and frequency of spontaneous recurrent seizures. Further, in contrast to vehicle treated animals, hippocampi from WIN 55,212-2-treated animals showed: normal thiol redox state, normal NR2A and NR2B subunit expression, preservation of GABAergic neurons and prevention of abnormal proliferation of GABAergic progenitors. This study shows for the first time that, after a known inciting event, treatment with a compound targeting CB receptors has the potential to prevent the epileptogenic events that result in chronic epileptic damage. PMID- 25447227 TI - BTBR ob/ob mice as a novel diabetic neuropathy model: Neurological characterization and gene expression analyses. AB - Given the lack of treatments for diabetic neuropathy (DN), a common diabetic complication, accurate disease models are necessary. Characterization of the leptin-deficient BTBR ob/ob mouse, a type 2 diabetes model, demonstrated that the mice develop robust diabetes coincident with severe neuropathic features, including nerve conduction deficits and intraepidermal nerve fiber loss by 9 and 13 weeks of age, respectively, supporting its use as a DN model. To gain insight into DN mechanisms, we performed microarray analysis on sciatic nerve from BTBR ob/ob mice, identifying 1503 and 642 differentially expressed genes associated with diabetes at 5 and 13 weeks, respectively. Further analyses identified overrepresentation of inflammation and immune-related functions in BTBR ob/ob mice, which interestingly were more highly represented at 5 weeks, an observation that may suggest a contributory role in DN onset. To complement the gene expression analysis, we demonstrated that protein levels of select cytokines were significantly upregulated at 13 weeks in BTBR ob/ob mouse sciatic nerve. Furthermore, we compared our array data to that from an established DN model, the C57BKS db/db mouse, which reflected a common dysregulation of inflammatory and immune-related pathways. Together, our data demonstrate that BTBR ob/ob mice develop rapid and robust DN associated with dysregulated inflammation and immune related processes. PMID- 25447229 TI - Glial activation is associated with l-DOPA induced dyskinesia and blocked by a nitric oxide synthase inhibitor in a rat model of Parkinson's disease. AB - l-3, 4-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease but can induce debilitating abnormal involuntary movements (dyskinesia). Here we show that the development of L-DOPA-induced dyskinesia in the rat is accompanied by upregulation of an inflammatory cascade involving nitric oxide. Male Wistar rats sustained unilateral injections of 6 hydroxydopamine (6-OHDA) into the medial forebrain bundle. After three weeks animals started to receive daily treatment with L-DOPA (30 mg/kg plus benserazide 7.5 mg/kg, for 21 days), combined with an inhibitor of neuronal NOS (7 nitroindazole, 7-NI, 30 mg/kg/day) or vehicle (saline-PEG 50%). All animals treated with L-DOPA and vehicle developed abnormal involuntary movements, and this effect was prevented by 7-NI. L-DOPA-treated dyskinetic animals exhibited an increased striatal and pallidal expression of glial fibrillary acidic protein (GFAP) in reactive astrocytes, an increased number of CD11b-positive microglial cells with activated morphology, and the rise of cells positive for inducible nitric oxide-synthase immunoreactivity (iNOS). All these indexes of glial activation were prevented by 7-NI co-administration. These findings provide evidence that the development of L-DOPA-induced dyskinesia in the rat is associated with activation of glial cells that promote inflammatory responses. The dramatic effect of 7-NI in preventing this glial response points to an involvement of nitric oxide. Moreover, the results suggest that the NOS inhibitor prevents dyskinesia at least in part via inhibition of glial cell activation and iNOS expression. Our observations indicate nitric oxide synthase inhibitors as a therapeutic strategy for preventing neuroinflammatory and glial components of dyskinesia pathogenesis in Parkinson's disease. PMID- 25447224 TI - Brain-controlled muscle stimulation for the restoration of motor function. AB - Loss of the ability to move, as a consequence of spinal cord injury or neuromuscular disorder, has devastating consequences for the paralyzed individual, and great economic consequences for society. Functional electrical stimulation (FES) offers one means to restore some mobility to these individuals, improving not only their autonomy, but potentially their general health and well being as well. FES uses electrical stimulation to cause the paralyzed muscles to contract. Existing clinical systems require the stimulation to be preprogrammed, with the patient typically using residual voluntary movement of another body part to trigger and control the patterned stimulation. The rapid development of neural interfacing in the past decade offers the promise of dramatically improved control for these patients, potentially allowing continuous control of FES through signals recorded from motor cortex, as the patient attempts to control the paralyzed body part. While application of these 'brain-machine interfaces' (BMIs) has undergone dramatic development for control of computer cursors and even robotic limbs, their use as an interface for FES has been much more limited. In this review, we consider both FES and BMI technologies and discuss the prospect for combining the two to provide important new options for paralyzed individuals. PMID- 25447231 TI - 18FDG-microPET and MR DTI findings in Tor1a+/- heterozygous knock-out mice. AB - TorsinA is an important protein in brain development, and plays a role in the regulation of neurite outgrowth and synaptic function. Patients with the most common form of genetic dystonia carry a mutation (DYT1) in one copy of the Tor1a gene, a 3-bp deletion, causing removal of a single glutamic acid from torsinA. Previous imaging studies have shown that abnormal cerebellar metabolism and damaged cerebello-thalamo-cortical pathway contribute to the pathophysiology of DYT1 dystonia. However, how a mutation in one copy of the Tor1a gene causes these abnormalities is not known. We studied Tor1a heterozygous knock-out mice in vivo with FDG-PET and ex vivo with diffusion tensor imaging. We found metabolic abnormalities in cerebellum, caudate-putamen, globus pallidus, sensorimotor cortex and subthalamic nucleus. We also found that FA was increased in caudate putamen, sensorimotor cortex and brainstem. We compared our findings with a previous imaging study of the Tor1a knock-in mice. Our study suggested that having only one normal copy of Tor1a gene may be responsible for the metabolic abnormalities observed; having a copy of mutant Tor1a, on the other hand, may be responsible for white matter pathway damages seen in DYT1 dystonia subjects. PMID- 25447230 TI - Characterisation of immune cell function in fragment and full-length Huntington's disease mouse models. AB - Inflammation is a growing area of research in neurodegeneration. In Huntington's disease (HD), a fatal inherited neurodegenerative disease caused by a CAG-repeat expansion in the gene encoding huntingtin, patients have increased plasma levels of inflammatory cytokines and circulating monocytes that are hyper-responsive to immune stimuli. Several mouse models of HD also show elevated plasma levels of inflammatory cytokines. To further determine the degree to which these models recapitulate observations in HD patients, we evaluated various myeloid cell populations from different HD mouse models to determine whether they are similarly hyper-responsive, as well as measuring other aspects of myeloid cell function. Myeloid cells from each of the three mouse models studied, R6/2, HdhQ150 knock-in and YAC128, showed increased cytokine production when stimulated. However, bone marrow CD11b(+) cells did not show the same hyper responsive phenotype as spleen and blood cells. Furthermore, macrophages isolated from R6/2 mice show increased levels of phagocytosis, similar to findings in HD patients. Taken together, these results show significant promise for these mouse models to be used to study targeting innate immune pathways identified in human cells, thereby helping to understand the role the peripheral immune system plays in HD progression. PMID- 25447233 TI - BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation. AB - The pathogenic mechanisms underlying neuropathic pain still remain largely unknown. In this study, we investigated whether spinal BDNF contributes to dorsal horn LTP induction and neuropathic pain development by activation of GluN2B-NMDA receptors via Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) phosphorylation in rats following spinal nerve ligation (SNL). We first demonstrated that spinal BDNF participates in the development of long-lasting hyperexcitability of dorsal horn WDR neurons (i.e. central sensitization) as well as pain allodynia in both intact and SNL rats. Second, we revealed that BDNF induces spinal LTP at C-fiber synapses via functional up-regulation of GluN2B NMDA receptors in the spinal dorsal horn, and this BDNF-mediated LTP-like state is responsible for the occlusion of spinal LTP elicited by subsequent high frequency electrical stimulation (HFS) of the sciatic nerve in SNL rats. Finally, we validated that BDNF-evoked SHP2 phosphorylation is required for subsequent GluN2B-NMDA receptors up-regulation and spinal LTP induction, and also for pain allodynia development. Blockade of SHP2 phosphorylation in the spinal dorsal horn using a potent SHP2 protein tyrosine phosphatase inhibitor NSC-87877, or knockdown of spinal SHP2 by intrathecal delivery of SHP2 siRNA, not only prevents BDNF-mediated GluN2B-NMDA receptors activation as well as spinal LTP induction and pain allodynia elicitation in intact rats, but also reduces the SNL-evoked GluN2B-NMDA receptors up-regulation and spinal LTP occlusion, and ultimately alleviates pain allodynia in neuropathic rats. Taken together, these results suggest that the BDNF/SHP2/GluN2B-NMDA signaling cascade plays a vital role in the development of central sensitization and neuropathic pain after peripheral nerve injury. PMID- 25447234 TI - Comparative pathway and network analysis of brain transcriptome changes during adult aging and in Parkinson's disease. AB - Aging is considered as one of the main factors promoting the risk for Parkinson's disease (PD), and common mechanisms of dopamine neuron degeneration in aging and PD have been proposed in recent years. Here, we use a statistical meta-analysis of human brain transcriptomics data to investigate potential mechanistic relationships between adult brain aging and PD pathogenesis at the pathway and network level. The analyses identify statistically significant shared pathway and network alterations in aging and PD and an enrichment in PD-associated sequence variants from genome-wide association studies among the jointly deregulated genes. We find robust discriminative patterns for groups of functionally related genes with potential applications as combined risk biomarkers to detect aging- and PD-linked oxidative stress, e.g., a consistent over-expression of metallothioneins matching with findings in previous independent studies. Interestingly, analyzing the regulatory network and mouse knockout expression data for NR4A2, a transcription factor previously associated with rare mutations in PD and here found as the most significantly under-expressed gene in PD among the jointly altered genes, suggests that aging-related NR4A2 expression changes may increase PD risk via downstream effects similar to disease-linked mutations and to expression changes in sporadic PD. Overall, the analyses suggest mechanistic explanations for the age-dependence of PD risk and reveal significant and robust shared process alterations with potential applications in biomarker development for pre-symptomatic risk assessment or early stage diagnosis. PMID- 25447232 TI - Altered intrathalamic GABAA neurotransmission in a mouse model of a human genetic absence epilepsy syndrome. AB - We previously demonstrated that heterozygous deletion of Gabra1, the mouse homolog of the human absence epilepsy gene that encodes the GABAA receptor (GABAAR) alpha1 subunit, causes absence seizures. We showed that cortex partially compensates for this deletion by increasing the cell surface expression of residual alpha1 subunit and by increasing alpha3 subunit expression. Absence seizures also involve two thalamic nuclei: the ventrobasal (VB) nucleus, which expresses only the alpha1 and alpha4 subtypes of GABAAR alpha subunits, and the reticular (nRT) nucleus, which expresses only the alpha3 subunit subtype. Here, we found that, unlike cortex, VB exhibited significantly reduced total and synaptic alpha1 subunit expression. In addition, heterozygous alpha1 subunit deletion substantially reduced miniature inhibitory postsynaptic current (mIPSC) peak amplitudes and frequency in VB. However, there was no change in the expression of the extrasynaptic alpha4 or delta subunits in VB and, unlike other models of absence epilepsy, no change in tonic GABAAR currents. Although heterozygous alpha1 subunit knockout increased alpha3 subunit expression in medial thalamic nuclei, it did not alter alpha3 subunit expression in nRT. However, it did enlarge the presynaptic vesicular inhibitory amino acid transporter puncta and lengthen the time constant of mIPSC decay in nRT. We conclude that increased tonic GABAA currents are not necessary for absence seizures. In addition, heterozygous loss of alpha1 subunit disinhibits VB by substantially reducing phasic GABAergic currents and surprisingly, it also increases nRT inhibition by prolonging phasic currents. The increased inhibition in nRT likely represents a partial compensation that helps reduce absence seizures. PMID- 25447238 TI - Generics manufacturer Apotex files lawsuit against Health Canada over import ban. PMID- 25447237 TI - Nuclear import factor transportin and arginine methyltransferase 1 modify FUS neurotoxicity in Drosophila. AB - Inclusions containing Fused in Sarcoma (FUS) are found in familial and sporadic cases of the incurable progressive motor neuron disease amyotrophic lateral sclerosis and in a common form of dementia, frontotemporal dementia. Most disease associated mutations are located in the C-terminal proline-tyrosine nuclear localization sequence (PY-NLS) of FUS and impair its nuclear import. It has been shown in cell culture that the nuclear import of FUS is mediated by transportin, which binds the PY-NLS and the last arginine/glycine/glycine-rich (RGG) domain of FUS. Methylation of this last RGG domain by protein arginine methyltransferases (PRMTs) weakens transportin binding and therefore impairs nuclear translocation of FUS. To investigate the requirements for the nuclear import of FUS in an in vivo model, we generated different transgenic Drosophila lines expressing human FUS wild type (hFUS wt) and two disease-related variants P525L and R495X, in which the NLS is mutated or completely absent, respectively. To rule out effects caused by heterologous hFUS expression, we analysed the corresponding variants for the Drosophila FUS orthologue Cabeza (Caz wt, P398L, Q349X). Expression of these variants in eyes and motor neurons confirmed the PY-NLS-dependent nuclear localization of FUS/Caz and caused neurodegenerative effects. Surprisingly, FUS/Caz toxicity was correlated to the degree of its nuclear localization in this overexpression model. High levels of nuclear FUS/Caz became insoluble and reduced the endogenous Caz levels, confirming FUS autoregulation in Drosophila. RNAi mediated knockdown of the two transportin orthologues interfered with the nuclear import of FUS/Caz and also enhanced the eye phenotype. Finally, we screened the Drosophila PRMT proteins (DART1-9) and found that knockdown of Dart1 led to a reduction in methylation of hFUS P525L and aggravated its phenotype. These findings show that the molecular mechanisms controlling the nuclear import of FUS/Caz and FUS autoregulation are conserved between humans and Drosophila. In addition to the well-known neurodegenerative effects of FUS loss-of function, our data suggest toxic potential of overexpressed FUS in the nucleus and of insoluble FUS. PMID- 25447241 TI - Message from the president. PMID- 25447239 TI - Development of administrative data algorithms to identify patients with critical limb ischemia. AB - Administrative data have been used to identify patients with various diseases, yet no prior study has determined the utility of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)-based codes to identify CLI patients. CLI cases (n=126), adjudicated by a vascular specialist, were carefully defined and enrolled in a hospital registry. Controls were frequency matched to cases on age, sex and admission date in a 2:1 ratio. ICD-9 CM codes for all patients were extracted. Algorithms were developed using frequency distributions of these codes, risk factors and procedures prevalent in CLI. The sensitivity for each algorithm was calculated and applied within the hospital system to identify CLI patients not included in the registry. Sensitivity ranged from 0.29 to 0.92. An algorithm based on diagnosis and procedure codes exhibited the best overall performance (sensitivity of 0.92). Each algorithm had differing CLI identification characteristics based on patient location. Administrative data can be used to identify CLI patients within a health system. The algorithms, developed from these data, can serve as a tool to facilitate clinical care, research, quality improvement, and population surveillance. PMID- 25447236 TI - Increased expression of the dopamine transporter leads to loss of dopamine neurons, oxidative stress and l-DOPA reversible motor deficits. AB - The dopamine transporter is a key protein responsible for regulating dopamine homeostasis. Its function is to transport dopamine from the extracellular space into the presynaptic neuron. Studies have suggested that accumulation of dopamine in the cytosol can trigger oxidative stress and neurotoxicity. Previously, ectopic expression of the dopamine transporter was shown to cause damage in non dopaminergic neurons due to their inability to handle cytosolic dopamine. However, it is unknown whether increasing dopamine transporter activity will be detrimental to dopamine neurons that are inherently capable of storing and degrading dopamine. To address this issue, we characterized transgenic mice that over-express the dopamine transporter selectively in dopamine neurons. We report that dopamine transporter over-expressing (DAT-tg) mice display spontaneous loss of midbrain dopamine neurons that is accompanied by increases in oxidative stress markers, 5-S-cysteinyl-dopamine and 5-S-cysteinyl-DOPAC. In addition, metabolite to-dopamine ratios are increased and VMAT2 protein expression is decreased in the striatum of these animals. Furthermore, DAT-tg mice also show fine motor deficits on challenging beam traversal that are reversed with l-DOPA treatment. Collectively, our findings demonstrate that even in neurons that routinely handle dopamine, increased uptake of this neurotransmitter through the dopamine transporter results in oxidative damage, neuronal loss and l-DOPA reversible motor deficits. In addition, DAT over-expressing animals are highly sensitive to MPTP-induced neurotoxicity. The effects of increased dopamine uptake in these transgenic mice could shed light on the unique vulnerability of dopamine neurons in Parkinson's disease. PMID- 25447235 TI - Neuroinflammation and brain atrophy in former NFL players: An in vivo multimodal imaging pilot study. AB - There are growing concerns about potential delayed, neuropsychiatric consequences (e.g, cognitive decline, mood or anxiety disorders) of sports-related traumatic brain injury (TBI). Autopsy studies of brains from a limited number of former athletes have described characteristic, pathologic changes of chronic traumatic encephalopathy (CTE) leading to questions about the relationship between these pathologic and the neuropsychiatric disturbances seen in former athletes. Research in this area will depend on in vivo methods that characterize molecular changes in the brain, linking CTE and other sports-related pathologies with delayed emergence of neuropsychiatric symptoms. In this pilot project we studied former National Football League (NFL) players using new neuroimaging techniques and clinical measures of cognitive functioning. We hypothesized that former NFL players would show molecular and structural changes in medial temporal and parietal lobe structures as well as specific cognitive deficits, namely those of verbal learning and memory. We observed a significant increase in binding of [(11)C]DPA-713 to the translocator protein (TSPO), a marker of brain injury and repair, in several brain regions, such as the supramarginal gyrus and right amygdala, in 9 former NFL players compared to 9 age-matched, healthy controls. We also observed significant atrophy of the right hippocampus. Finally, we report that these same former players had varied performance on a test of verbal learning and memory, suggesting that these molecular and pathologic changes may play a role in cognitive decline. These results suggest that localized brain injury and repair, indicated by increased [(11)C]DPA-713 binding to TSPO, may be linked to history of NFL play. [(11)C]DPA-713 PET is a promising new tool that can be used in future study design to examine further the relationship between TSPO expression in brain injury and repair, selective regional brain atrophy, and the potential link to deficits in verbal learning and memory after NFL play. PMID- 25447242 TI - Routes of administration and dose optimization of soluble antigen arrays in mice with experimental autoimmune encephalomyelitis. AB - Soluble antigen arrays (SAgAs) were developed for treating mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. SAgAs are composed of hyaluronan with grafted EAE antigen and LABL peptide (a ligand of ICAM-1). SAgA dose was tested by varying injection volume, SAgA concentration, and administration schedule. Routes of administration were explored to determine the efficacy of SAgAs when injected intramuscularly, subcutaneously, intraperitoneally, intravenously, or instilled into lungs. Injections proximal to the central nervous system (CNS) were compared with distal injection sites. Intravenous dosing was included to determine if SAgA efficiency results from systemic exposure. Pulmonary instillation (p.i.) was included as reports suggest T cells are licensed in the lungs before moving to the CNS. Decreasing the volume of injection or SAgA dose reduced treatment efficacy. Treating mice with a single injection on day 4, 7, and 10 also reduced efficacy compared with injecting on all three days. Surprisingly, changing the injection site did not lead to a significant difference in efficacy. Intravenous administration showed efficacy similar to other routes, suggesting SAgAs act systemically. When SAgAs were delivered via p.i., however, EAE mice failed to develop any symptoms, suggesting a unique lung mechanism to ameliorate EAE in mice. PMID- 25447243 TI - Gram-positive antimicrobial activity of amino acid-based hydrogels. AB - Antimicrobial hydrogels are prepared based on the co-assembly of commercial Fmoc phenylalanine and Fmoc-leucine, which act as the hydrogelator and antimicrobial building block, respectively. This co-assembled antimicrobial hydrogel is demonstrated to exhibit selective bactericidal activity for gram-positive bacteria while being biocompatible with normal mammalian cells, showing great potential as an antimicrobial coating for clinical anti-infective applications. PMID- 25447244 TI - Tackling obesity: a call to action. PMID- 25447245 TI - Reducing childhood overweight and obesity in New Zealand through setting a clear and achievable target. PMID- 25447246 TI - Health and equity impacts of climate change in Aotearoa-New Zealand, and health gains from climate action. AB - Human-caused climate change poses an increasingly serious and urgent threat to health and health equity. Under all the climate projections reported in the recent Intergovernmental Panel on Climate Change assessment, New Zealand will experience direct impacts, biologically mediated impacts, and socially mediated impacts on health. These will disproportionately affect populations that already experience disadvantage and poorer health. Without rapid global action to reduce greenhouse gas emissions (particularly from fossil fuels), the world will breach its carbon budget and may experience high levels of warming (land temperatures on average 4-7 degrees Celsius higher by 2100). This level of climate change would threaten the habitability of some parts of the world because of extreme weather, limits on working outdoors, and severely reduced food production. However, well planned action to reduce greenhouse gas emissions could bring about substantial benefits to health, and help New Zealand tackle its costly burden of health inequity and chronic disease. PMID- 25447247 TI - Alcohol intake, marijuana use, and sleep deprivation on the risk of falls occurring at home among young and middle-aged adults: a case-crossover study. AB - AIM: This study investigated whether hospitalised fall-related injuries among young and middle-aged adults were associated with short term effects of alcohol intake, marijuana use and sleep deprivation. METHOD: A case-crossover design was used to study 690 adults (aged 20 to 64 years) admitted to public hospitals within 48 hours of a fall-related injury, occurring at home, in three regions of New Zealand during August 2008 to December 2009. A matched-pair interval method of analysis was used to compare alcohol intake, marijuana use and sleep deprivation before the event with similar information in two control periods: 24 hours-before and 1 week-before the time of injury. RESULTS: After adjustment for other paired exposures, the estimated risk of injury was substantially higher after consuming alcohol within the preceding 6 hours, with a dose response gradient. After adjusting for confounding variables, the data did not support a significantly elevated risk of fall-related injury associated with sleep deprivation (<6 hours sleep in the preceding 24 hours), or marijuana use in the preceding 3 hours. CONCLUSION: The findings support the expansion of efforts to reduce the harmful effects of alcohol intake in the home environment. PMID- 25447248 TI - Relationship between fructose and lactose intakes and functional gastrointestinal symptoms in a sample of 50-year-old Cantabrians in New Zealand. AB - AIMS: To examine the relationship between fructose and lactose consumption and irritable bowel syndrome (IBS) symptoms in 50-year-old adults residing in Canterbury, New Zealand. METHODS: The Canterbury Health Ageing and Life Course (CHALICE) study is a study of 50-year-old Cantabrians. A 4-day estimated food and beverage diary (FBD) was completed by 227 participants, 75.7% of those recruited. The Birmingham IBS symptom questionnaire was administered and individual participant scores were calculated for constipation, diarrhoea, pain score, and total symptom score. Associations between symptoms and the intake of fructose and lactose were examined using binary logistic regression. RESULTS: Greater mean daily intakes of fructose (P=0.05) and lactose (P=0.04) were associated with a lower prevalence of IBS pain symptoms after adjusting for demographics and social economic status. However there was no evidence of an association with constipation, diarrhoea or total IBS score. CONCLUSIONS: Although our data show inverse relationships between fructose and lactose intakes and IBS pain symptoms, the use of cross-sectional data do not allow us to determine causality in these relationships. However it is possible that participants may have reduced their intake of fructose and lactose in response to IBS related pain. Follow up of this cohort would allow us to determine if this is the case. Future research could also investigate whether people with IBS could benefit from guidance from a dietitian around consumption of high lactose or fructose-containing foods. PMID- 25447249 TI - Self-monitoring blood glucose test strip use with diabetes medicines in people with types 1 and 2 diabetes in New Zealand. AB - AIMS: (1) To identify actual dispensings of publicly funded blood glucose test strips (SMBG) in New Zealand according to severity of disease, as proxied by the type of medicines prescribed; and (2) To compare these rates with published consensus guidelines on SMBG usage. METHOD: All dispensings of diabetes medicines and blood glucose test strips (SMBG) in 2011 were identified and matched to patients, using encrypted National Health Index numbers (NHIs). Five hierarchical treatment groups were identified, as the use of: -Insulins without oral hypoglycaemic agents (OHs); -Insulins with OHs; -Sulphonylurea-containing OH regimens without insulins (with or without other diabetes medicines); -Metformin alone, with or without glitazones or acarbose; and -No diabetes medication but accessing SMBGs. The average SMBG dispensings to patients in each of these groups was then calculated. The calculation was performed only for 'steady-state' patients, i.e. patients assumed stabilised on the same medication regimen for at least one year. Differences between actual and expected dispensings were calculated from expected daily strip use for each group. RESULTS: An estimated 183,000 patients were dispensed diabetes medicines and/or SMBG during 2011. Of these, 122,000 were identified as 'steady-state' patients. Patient numbers and median ages varied widely across treatment groups and by gender and ethnicity. Dispensing rates for SMBG varied by treatment group, with probable over dispensing in some groups and under-dispensing in others when compared with published guidelines. In particular there appeared to be relatively large under dispensing of SMBG in patients requiring insulin (especially the 25-44 age-group or Maori and Pacific peoples) and a high over-dispensing in those using metformin alone or on no diabetic medication. CONCLUSION: There are appreciable variations in the use of SMBG between treatment groups. Adherence to published guidelines may improve efficacy and health outcomes for those using insulin and reduce pain, anxiety and disruption for those using metformin or diet alone for control of their diabetes. PMID- 25447250 TI - Evaluation of a rural primary-referred cardiac exercise tolerance test service. AB - AIM: To describe the feasibility, clinical impact and cost-effectiveness of a rural generalist-led cardiac exercise tolerance test (ETT) service for primary care patients in two different rural communities. METHOD: For 12 months, from Sept 2011, a generalist-led ETT service was provided in two rural hospitals in New Zealand: Dunstan in Central Otago and Rawene in Northland. Data was collected to describe the patient outcomes of this service. An audit of ETT reports and financial and rural-urban analyses were undertaken. RESULTS: The cost per test of the local ETT service at Dunstan, ($132.50), and Rawene, ($200.00), was less than the national price ($281.13 in 2012). The majority of patients (83% at Dunstan and 70% at Rawene) were not referred to specialist services; the ETT result allowing the GP to continue to manage the patient in primary care. Where the ETT indicated specialist treatment, this was subsequently provided in a timely manner. CONCLUSION: ETT can be provided cost-effectively in a variety of rural settings. Improved access to ETT for rural communities may help address inequities across New Zealand in terms of access to cardiac investigations and early and appropriate treatment. PMID- 25447251 TI - Projecting future smoking prevalence to 2025 and beyond in New Zealand using smoking prevalence data from the 2013 Census. AB - BACKGROUND: We have previously published a forecasting model of future smoking prevalence in New Zealand (NZ). Under business-as-usual (BAU) assumptions NZ's smokefree 2025 goal was not attained by any demographic group. However, the 2013 Census (which included a question on smoking) showed a greater than expected fall in prevalence, especially for Maori. We therefore aimed to provide upgraded projections to inform policy around tobacco endgame planning. METHOD: The previously developed dynamic forecasting model was re-specified using smoking prevalence data from the 2006 and 2013 censuses from NZ. Calculations included changes in initiation by age 20 years, and net annual cessation rates, by sex, age, and ethnicity (Maori vs non-Maori). Projections under 2006-2013 trends (adjusted for no tax rises since 2010), by sex and ethnicity were made out to 2025 and beyond. RESULTS: Between the 2006 and 2013 censuses (adjusted for no tax rises since 2010), initiation of daily smoking by age 20 years decreased annually by 3.4% (95% uncertainty interval 3.2% to 3.6%) and 2.7% (2.5% to 2.8%) for non Maori men and women, and by 2.9% (2.6% to 3.2%) and 3.2% (2.9% to 3.5%) for Maori respectively. Annual net smoking cessation rates ranged from 3.7% to 7.7% across demographic groups. The revised projected smoking prevalence in 2025 (allowing for tax increases that have occurred from 2010 to 2014) was 8.3% and 6.4% for non Maori, and 18.7% and 19.3% for Maori men and women, respectively. CONCLUSIONS: The upgraded smoking prevalence projections still suggests that the NZ Government's smokefree 2025 goal would not be attained by any demographic group. It is likely that more intensive existing interventions, or entirely novel ones, will be needed to achieve the 2025 endgame goal. PMID- 25447252 TI - Is New Zealand water fluoridation justified? AB - Public health programmes extend beyond the clinical context and focus on measures that affect the lives of large subgroups or the population as a whole. An example of this is community water fluoridation (CWF), the altering of fluoride levels in the water supply with the aim of preventing the initiation and slowing the progression of dental caries lesions for the benefit of entire populations. Despite the unfeasibility of randomised controlled trials of CWF, a large volume of evidence is available on the topic. However, CWF remains a polarising and keenly contested issue. CWF is also an intervention where it is difficult to provide everyone affected with a choice. The Nuffield Council on Bioethics is an independent body that examines and reports on ethical questions, and they have provided a useful ethical framework for considering CWF via the 'stewardship' model. This commentary aims to discuss each of the public health aims and how they can be applied and weighed to reach a justified position about CWF. PMID- 25447253 TI - Profits or people? The informative case of alcohol marketing. AB - AIM: To analyse influence on alcohol marketing policy in New Zealand. METHOD: Document and literature review. RESULTS: There is a powerful argument and popular support for restricting alcohol marketing but no significant policy action taken. CONCLUSION: Greater priority has been placed on the profits of influential corporations compared with protecting the health of future generations of New Zealanders. PMID- 25447254 TI - Dog bites, treatment and prevention in New Zealand. PMID- 25447255 TI - Levels of dog control and dog fouling in a large public park: methods issues and survey results. PMID- 25447256 TI - The potential of citizen engagement and empowerment for obesity prevention in New Zealand. PMID- 25447257 TI - What does the 2025 Smokefree Goal mean to the New Zealand public? PMID- 25447258 TI - "Enjoy the future of smoking". PMID- 25447259 TI - Implications of the 2013 ACC/AHA cholesterol guidelines for adults in contemporary cardiovascular practice: insights from the NCDR PINNACLE registry. AB - BACKGROUND: In a significant update, the 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines recommend fixed-dose statin therapy for those at risk and do not recommend nonstatin therapies or treatment to target low-density lipoprotein cholesterol (LDL-C) levels, limiting the need for repeated LDL-C testing. OBJECTIVES: The goal of this study was to examine the impact of the 2013 ACC/AHA cholesterol guidelines on current U.S. cardiovascular practice. METHODS: Using the NCDR PINNACLE (National Cardiovascular Data Registry Practice Innovation and Clinical Excellence) registry data from 2008 to 2012, we assessed current practice patterns as a function of the 2013 cholesterol guidelines. Lipid-lowering therapies and LDL-C testing patterns by patient risk group (atherosclerotic cardiovascular disease [ASCVD], diabetes, LDL-C >=190 mg/dl, or an estimated 10 year ASCVD risk >=7.5%) were described. RESULTS: Among a cohort of 1,174,545 patients, 1,129,205 (96.1%) were statin-eligible (91.2% ASCVD, 6.6% diabetes, 0.3% off-treatment LDL-C >=190 mg/dl, 1.9% estimated 10-year ASCVD risk >=7.5%). There were 377,311 patients (32.4%) not receiving statin therapy and 259,143 (22.6%) receiving nonstatin therapies. During the study period, 20.8% of patients had 2 or more LDL-C assessments, and 7.0% had more than 4. CONCLUSIONS: In U.S. cardiovascular practices, 32.4% of statin-eligible patients, as defined by the 2013 ACC/AHA cholesterol guidelines, were not currently receiving statins. In addition, 22.6% were receiving nonstatin lipid-lowering therapies and 20.8% had repeated LDL-C testing. Achieving concordance with the new cholesterol guidelines in patients treated in U.S. cardiovascular practices would result in significant increases in statin use, as well as significant reductions in nonstatin therapies and laboratory testing. PMID- 25447260 TI - Alice in lipidland: the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol. PMID- 25447262 TI - Blood pressure targets: still struggling for the right answer. PMID- 25447261 TI - Impact of the 2014 expert panel recommendations for management of high blood pressure on contemporary cardiovascular practice: insights from the NCDR PINNACLE registry. AB - BACKGROUND: Since 2003, the Seventh Report of the Joint National Committee (JNC 7) has been the predominant guideline for blood pressure management. A 2014 expert panel recommended increasing the blood pressure targets for patients age 60 years and older, as well as those with diabetes or chronic kidney disease. OBJECTIVES: The purpose of this study was to examine the effect of the 2014 expert panel blood pressure management recommendations on patients managed in U.S. ambulatory cardiovascular practices. METHODS: Using the National Cardiovascular Data Registry PINNACLE Registry, we assessed the proportion of patients who met the 2003 and 2014 panel recommendations, highlighting the populations of patients for whom the blood pressure goals changed. RESULTS: Of 1,185,253 patients in the study cohort, 706,859 (59.6%) achieved the 2003 JNC-7 goals. Using the 2014 recommendations, 880,378 (74.3%) patients were at goal. Among the 173,519 (14.6%) for whom goal achievement changed, 40,323 (23.2%) had a prior stroke or transient ischemic attack, and 112,174 (64.6%) had coronary artery disease. In addition, the average Framingham risk score in this group was 8.5 +/- 3.2%, and the 10-year ASCVD risk score was 28.0 +/- 19.5%. CONCLUSIONS: Among U.S. ambulatory cardiology patients with hypertension, nearly 1 in 7 who did not meet JNC-7 recommendations would now meet the 2014 treatment goals. If the new recommendations are implemented in clinical practice, blood pressure target achievement and cardiovascular events will need careful monitoring, because many patients for whom the target blood pressure is now more permissive are at high cardiovascular risk. PMID- 25447263 TI - Structure of the c-Src-SH3 domain in complex with a proline-rich motif of NS5A protein from the hepatitis C virus. AB - The non-structural hepatitis C virus proteins NS5A and NS5B form a complex through interaction with the SH2 and SH3 domains of the non-receptor Src tyrosine kinase, which seems essential for viral replication. We have crystallized the complex between the SH3 domain of the c-Src tyrosine kinase and the C-terminal proline rich motif of the NS5A protein (A349PPIPPPRRKR359). Crystals obtained at neutral pH belong to the space group I41, with a single molecule of the SH3/NS5A complex at the asymmetric unit. The NS5A peptide is bound in a reverse orientation (class II) and the comparison of this structure with those of the high affinity synthetic peptides APP12 and VSL12 shows some important differences at the salt bridge that drives the peptide orientation. Further conformational changes in residues placed apart from the binding site also seem to play an important role in the binding orientation of this peptide. Our results show the interaction of the SH3 domain of the c-Src tyrosine kinase with a proline rich motif in the NS5A protein and point to their potential interaction in vivo. PMID- 25447264 TI - Epidemiological analysis of an outbreak of foot-and-mouth disease (serotype SAT2) on a large dairy farm in Kenya using regular vaccination. AB - During August-September 2012, an outbreak of Foot-and-mouth Disease (FMD) due to serotype Southern African Territories-2 (SAT2) occurred on a large, extensively grazed dairy farm in Nakuru County, Kenya. Over 29 days, 400/644 (62.1%) cattle were recorded as displaying clinical signs consistent with FMD. Out of the 18 management groups present, 17 had clinical cases (weighted mean incidence rate 3.5 per 100 cattle-days, 95% CI 2.4, 5.1; range 0.064-10.9). Transmission may have been encouraged when an infected group was moved to a designated isolation paddock. A four to five day minimum incubation period was apparent in five groups for which a point source exposure was evident. Further transmission was associated with the movement of individual animals incubating infection, use of a common dip and milking parlour, and grazing of susceptible groups in paddocks neighbouring to infectious cases. Animals over 18 months old appeared to be at highest risk of disease possibly due to milder clinical signs seen among younger animals resulting in reduced transmission or cases not being recorded. Cows with a breeding pedigree containing a greater proportion of zebu appeared to be at lower risk of disease. The outbreak occurred despite regular vaccination (three times per year) last performed approximately three months before the index case. Incidence risk by the lifetime number of doses received indicated limited or no vaccine effectiveness against clinical disease. Reasons for poor vaccine effectiveness are discussed with antigenic diversity of the SAT2 serotype and poor match between the field and vaccine strain as a likely explanation. Detailed field-derived epidemiological data based on individual animals are rarely presented in the literature for FMD, particularly in East-Africa and with the SAT2 serotype. This study provides a detailed account and therefore provides a greater understanding of FMD outbreaks in this setting. Additionally, this is the first study to provide field-derived evidence of poor vaccine effectiveness using a SAT2 vaccine. Further field-based measures of vaccine effectiveness in line with evaluation of human vaccines are needed to inform FMD control policy which has previously relied heavily upon experimental data and anecdotal experience. PMID- 25447266 TI - Identification of the prediction model for dengue incidence in Can Tho city, a Mekong Delta area in Vietnam. AB - The Mekong Delta is highly vulnerable to climate change and a dengue endemic area in Vietnam. This study aims to examine the association between climate factors and dengue incidence and to identify the best climate prediction model for dengue incidence in Can Tho city, the Mekong Delta area in Vietnam. We used three different regression models comprising: standard multiple regression model (SMR), seasonal autoregressive integrated moving average model (SARIMA), and Poisson distributed lag model (PDLM) to examine the association between climate factors and dengue incidence over the period 2003-2010. We validated the models by forecasting dengue cases for the period of January-December, 2011 using the mean absolute percentage error (MAPE). Receiver operating characteristics curves were used to analyze the sensitivity of the forecast of a dengue outbreak. The results indicate that temperature and relative humidity are significantly associated with changes in dengue incidence consistently across the model methods used, but not cumulative rainfall. The Poisson distributed lag model (PDLM) performs the best prediction of dengue incidence for a 6, 9, and 12-month period and diagnosis of an outbreak however the SARIMA model performs a better prediction of dengue incidence for a 3-month period. The simple or standard multiple regression performed highly imprecise prediction of dengue incidence. We recommend a follow up study to validate the model on a larger scale in the Mekong Delta region and to analyze the possibility of incorporating a climate-based dengue early warning method into the national dengue surveillance system. PMID- 25447265 TI - Irrigation in the arid regions of Tunisia impacts the abundance and apparent density of sand fly vectors of Leishmania infantum. AB - The distribution expansion of important human visceral leishmaniasis (HVL) and sporadic cutaneous leishmaniasis (SCL) vector species, Phlebotomus perfiliewi and P. perniciosus, throughout central Tunisia is a major public health concern. This study was designed to investigate if the expansion of irrigation influences the abundance of sand fly species potentially involved in the transmission of HVL and SCL located in arid bioclimatic regions. Geographic and remote sensing approaches were used to predict the density of visceral leishmaniasis vectors in Tunisia. Entomological investigations were performed in the governorate of Sidi Bouzid, located in the arid bioclimatic region of Tunisia. In 2012, sand flies were collected by CDC light traps located at nine irrigated and nine non-irrigated sites to determine species abundance. Eight species in two genera were collected. Among sand flies of the subgenus Larroussius, P. perfiliewi was the only species collected significantly more in irrigated areas. Trap data were then used to develop Poisson regression models to map the apparent density of important sand fly species as a function of different environmental covariates including climate and vegetation density. The density of P. perfiliewi is predicted to be moderately high in the arid regions. These results highlight that the abundance of P. perfiliewi is associated with the development of irrigated areas and suggests that the expansion of this species will continue to more arid areas of the country as irrigation sites continue to be developed in the region. The continued increase in irrigated areas in the Middle East and North Africa region deserves attention, as it is associated with the spread of L. infantum vector P. perfiliewi. Integrated vector management strategies targeting irrigation structures to reduce sand fly vector populations should be evaluated in light of these findings. PMID- 25447267 TI - Role of some biomarkers in placental malaria in women living in Yaounde, Cameroon. AB - Despite intensive research on the immunpathology of placental malaria (PM), the role of some beta-chemokines known to attract inflammatory cells is less known. This study sought to determine the role of CXCL-10, IL-10, IL-19, IL-17A and IL 23 in placental malaria in women at delivery. Between 2010 and 2011, paired peripheral and placental blood specimens were collected from 139 Cameroonian women at delivery. Differential white blood cell counts and malaria parasitaemia were determined microscopically while the accumulation of parasites in the placenta was investigated through histological studies. Plasma levels of CXCL-10, IL-10, IL-17A, IL-19 and Il-23 were determined by ELISA. The cytokines IL-10, IL 17A and IL-23 were predominant in peripheral plasma from both infected and non infected women. While IL-10 associated negatively with parity, IL-23 showed a positive correlation (p<0.05). The production of CXCL-10 was independent of parity and higher in placental plasma. There was an association between the plasma levels of IL-10 and CXCL-10 with malaria parasitaemia in the placenta impression smears, placental and peripheral blood and the presence of malaria pigments in the placenta tissue. Leukocyte accumulation into the intervillous space correlated positively with plasma levels of placental IL-17A (p<0.001). Parity also associated with peripheral IL-17A (p=0.016). The peripheral and placental plasma levels of CXCL-10 and IL-10 also correlated positively with monocyte counts (p=0.011-0.042) while a negative correlation was found with lymphocyte counts (p=0.017 to <0.001) of the impression smear. However, the levels of IL-10 in both peripheral and placental plasma and CXCL-10 in placental plasma only, were higher in low birth weight baby. With regards to IL-17A, its placental plasma level correlated positively with lymphocyte counts of placental blood (p=0.045). During PM, CXCL-10 might attract monocytes and lymphocytes into the placenta where they produce inflammatory cytokines such as IL-10 and IL-17A to modulate the disease, which affect baby weight. PMID- 25447268 TI - Is Fc gamma receptor IIA (FcgammaRIIA) polymorphism associated with clinical malaria and Plasmodium falciparum specific antibody levels in children from Burkina Faso? AB - In the present study, the influences of FcgammaRIIA polymorphism on susceptibility to malaria and antibody responses to Plasmodium falciparum antigens were analyzed in children. We recruited 96 healthy children between 3 and 10 years at the beginning of the high transmission season and we followed up for 5 months through the high transmission season to assess the parasitological, immunological and genetic endpoints in relation to clinical malaria status. There was a similar distribution of homozygous and heterozygous individuals carrying the FcgammaRIIA-131R/R and FcgammaRIIA-131R/H allele, whereas the number of FcgammaRIIA-131H/H homozygous individuals was lower. P. falciparum infection frequency was not associated with the FcgammaRIIa-131R/H polymorphism. Only IgG antibody responses to GLURP R0 showed a significant association between antibody levels and FcgammaRIIA polymorphism (p=0.02). IgG levels to MSP2a were significantly higher in children who did not experience any clinical malaria episode compared to those who experienced at least one malaria episode (p=0.019). Cytophilic and non-cytophylic IgG subclass levels were higher in children without malaria than those who experienced at least one malaria episode. This difference was statistically significant for IgG1 to MSP3 (p=0.003) and to MSP2a (p=0.006); IgG3 to MSP2a (p=0.007) and to GLURP R0 (p=0.044); IgG2 to MSP2b (p=0.007) and IgG4 to MSP3 (p=0.051) and to MSP2a (p=0.049). In this study, homozygous carriers of the FcgammaRIIA-131R/R allele had higher malaria-specific antibody levels compare to the heterozygous carriers FcgammaRIIA-131R/H alleles and to homozygous carriers of FcgammaRIIA-131H/H alleles. The pre-existing antibodies responses were related to a reduced subsequent risk of clinical malaria. PMID- 25447270 TI - Empirical characteristics of family-based linkage to a complex trait: the ADIPOQ region and adiponectin levels. AB - We previously identified a low-frequency (1.1 %) coding variant (G45R; rs200573126) in the adiponectin gene (ADIPOQ) which was the basis for a multipoint microsatellite linkage signal (LOD = 8.2) for plasma adiponectin levels in Hispanic families. We have empirically evaluated the ability of data from targeted common variants, exome chip genotyping, and genome-wide association study data to detect linkage and association to adiponectin protein levels at this locus. Simple two-point linkage and association analyses were performed in 88 Hispanic families (1,150 individuals) using 10,958 SNPs on chromosome 3. Approaches were compared for their ability to map the functional variant, G45R, which was strongly linked (two-point LOD = 20.98) and powerfully associated (p value = 8.1 * 10(-50)). Over 450 SNPs within a broad 61 Mb interval around rs200573126 showed nominal evidence of linkage (LOD > 3) but only four other SNPs in this region were associated with p values < 1.0 * 10(-4). When G45R was accounted for, the maximum LOD score across the interval dropped to 4.39 and the best p value was 1.1 * 10(-5). Linked and/or associated variants ranged in frequency (0.0018-0.50) and type (coding, non-coding) and had little detectable linkage disequilibrium with rs200573126 (r (2) < 0.20). In addition, the two point linkage approach empirically outperformed multipoint microsatellite and multipoint SNP analysis. In the absence of data for rs200573126, family-based linkage analysis using a moderately dense SNP dataset, including both common and low-frequency variants, resulted in stronger evidence for an adiponectin locus than association data alone. Thus, linkage analysis can be a useful tool to facilitate identification of high-impact genetic variants. PMID- 25447271 TI - Clustering of clinical and environmental Escherichia coli O104 isolates using the DiversiLabTM repetitive sequence-based PCR system. AB - The DiversiLabTM rep-PCR system was used to amplify DNA regions of 28 well characterized Escherichia coli O104 strains to generate a digital DNA fingerprint profile for strain differentiation. E. coli O104 strains from human stools and other sources were examined. The results indicate that this system can cluster similar O104 strains rapidly. PMID- 25447269 TI - A 6-month study comparing efficacy, safety, and tolerability of the preservative free fixed combination of tafluprost 0.0015% and timolol 0.5% versus each of its individual preservative-free components. AB - INTRODUCTION: The efficacy, safety and tolerability of the preservative-free (PF) fixed combination (FC) of tafluprost 0.0015% and timolol 0.5% (once daily) were compared to those of the individual components (PF tafluprost 0.0015% once daily and PF timolol 0.5% twice daily) in patients with open-angle glaucoma or ocular hypertension inadequately controlled on prior timolol or prostaglandin monotherapy for 6 months. METHODS: A stratified, double-masked, randomized, multicenter phase III study was conducted. A total of 189 prior timolol users were randomized within the timolol stratum (TS) to receive either FC (n = 95) or timolol 0.5% (TIM; n = 94). Furthermore, a total of 375 prior prostaglandin analog (PGA) users were randomized within the prostaglandin stratum (PS) to receive either FC (n = 188) or tafluprost 0.0015% (TAF; n = 187). To be eligible for participation in the study, the patients were required to have an intraocular pressure (IOP) of >=22 mmHg when on timolol (TIM) or of >=20 mmHg when on PGA in either treated eye at the screening and end-of-run-in visits. In addition to these, the study included visits at baseline, 2 and 6 weeks, 3 and 6 months and at a post-study visit. IOP was measured at 8 a.m., 10 a.m., 4 p.m., and 8 p.m. RESULTS: In the TS, a significant reduction from baseline IOP was seen with FC and TIM throughout the study. Average diurnal IOP change from baseline at month 3 was -8.55 mmHg (32%) for FC and -7.35 mmHg (28%) for TIM. The model-based treatment difference (FC-TIM) was -0.885 mmHg [95% confidence interval (CI) 1.745 to -0.024; p = 0.044] demonstrating the superiority of FC over TIM. In the PS, a significant reduction in IOP was seen with both FC and TAF throughout the study. The average diurnal IOP change from baseline at month 3 was -8.61 mmHg (33%) for FC and -7.23 mmHg (28%) for TAF. The model-based treatment difference (FC-TAF) was -1.516 mmHg (95% CI -2.044 to -0.988; p < 0.001) demonstrating the superiority of FC over TAF. In the TS, related ocular adverse events (AEs) were more frequent for patients treated with FC compared to TIM (16.8% versus 6.4%), whereas related non-ocular AEs were more frequent with TIM compared to FC (2.1% versus 0.0%). In the PS, AEs were similarly distributed between FC and TAF. The frequency of conjunctival hyperemia of FC was low (6.4%). CONCLUSION: The preservative-free fixed combination of tafluprost and timolol provided a substantial and significant IOP reduction in both strata. The IOP reduction was superior to both tafluprost 0.0015% and timolol 0.5% when given as monotherapies. Overall, the study treatments were safe and well tolerated. FUNDING: Santen Oy, Tampere, Finland. PMID- 25447272 TI - Study of Saccharomyces cerevisiae wine strains for breeding through fermentation efficiency and tetrad analysis. AB - One of the issues that most concerns to both winemakers and producers of active dry yeasts is the stuck and sluggish fermentations of grape musts with high levels of sugar, reflecting the inability of inoculated yeast strain to complete the fermentation process. It is difficult to obtain a wine strain that possesses both adequate oenological and technological properties; thus, the correct approach to solving these problems is the application of breeding programs primarily focused on both properties. The first step toward this process is to characterize the phenotypic diversity between potential parental strains. In the present study, we have analyzed the fermentative behavior of 26 Saccharomyces cerevisiae wine strains in high-sugar conditions at 20 degrees C, using a range of tests, such as sporulation ability, spore viability, and tetrad analysis to determine the tolerance of these yeasts to several stress conditions. Most tested strains were homothallic and heterozygous for more than one character. Two auxotrophic derivatives with defects in amino acid or nucleic acid metabolism were obtained, and these strains could potentially be used for the development of hybridization techniques without using laboratory strains. PMID- 25447274 TI - Expression of c-type lysozyme gene in sea cucumber (Apostichopus japonicus) is highly regulated and time dependent after salt stress. AB - Lysozymes have been confirmed to possess varieties of functions in a range of organisms. In the present study, we cloned and sequenced c-type lysozyme cDNAs, constructed the recombinant protein over-expression of c-type lysozyme and analyzed the expression of transcription level in various tissues. The c-type lysozyme cDNA contained an open reading frame of 759 bp encoding a polypeptide of 252 amino acids. The molecular weight of the deduced amino acid of AjcLYZ is 26.7 kDa with an estimated pI of 4.66. Multiple sequence alignments revealed that AjcLYZ had two highly conserved active sites (Glu147 and Asp159) and eight typical Cys residues. The tertiary structure and modeled AjcLYZ showed structural similarity to Meretrix lusoria LYZ. The results of mRNA transcripts showed that the highest expression was found in the tube foot, followed by the muscle, body wall, and coelomic fluid. In contrast, the intestine, tentacle and respiratory tree exhibited very low expression levels. Under salinity stress, significant down-regulation of AjcLYZ was observed in response to salinity stress in the intestine and coelomic fluid. Significant up-regulation and down-regulation of AjcLYZ were observed in response to salinity stress in body wall and respiratory tree. The purified recombinant protein was analyzed by SDS-PAGE and a single band with a molecular mass of 45.09 kDa, which was in agreement with the theoretical size (26.7 kDa for AjcLYZ and 18.39 kDa Trx-His-S tags) of the recombinant protein. Radial diffusion assay was employed to determine the antimicrobial spectrum of recombinant AjcLYZ against three Gram-positive and Gram-negative bacteria, and three sea cucumber pathogenic Vibrio species. From the radius of the antimicrobial zone, it was found that recombinant AjcLYZ harbored remarkable in vitro inhibitive effect on tested Gram-positive bacteria, while lytic activity against Gram-negative bacteria was relatively weak. The results will provide new clues about the molecular mechanisms that regulate the salinity adaption system. PMID- 25447276 TI - Disease severity at the first hospitalization as a predictor for mechanical ventilation dependency in elderly patients with chronic obstructive pulmonary disease. AB - Patients with chronic obstructive pulmonary disease (COPD) are predisposed to respiratory failure with ventilator dependency. This study aims to determine the risk of prolonged mechanical ventilation (PMV), defined as 22 days or more of mechanical ventilation dependency after the first day of hospital admission (index date) in patients diagnosed with COPD. A retrospective cohort was conducted using medical claim data of Taiwan's National Health Insurance Research Database. Eligible study subjects were those who had a diagnosis of COPD made between January 1, 2005 and December 31, 2009. Patients were then followed until being registered as a PMV case, death, or the end of the study. The comorbidities were measured from January 1, 1997 to the index date by the ICD-9 code. The study sample consisted of 6,341 patients with COPD with a mean age of 73.89 (+/- 12.01) years. Over a maximum of 6 years of follow-up, 654 patients developed PMV dependency, with an incidence density of 41.56 per 1,000 person-years. Patients aged 70 years and older were at significantly increased risk for PMV dependency, compared to those aged 40-49 years after adjusting for confounders. Expenses per visit and hospital visits per year, representing the severity of the COPD, were also associated with an elevated risk of PMV. Most patients developed PMV dependency within the first two years after the index date. Physicians should be aware that elderly patients with COPD have a high risk of PMV after first hospitalization, and these patients need to be closely monitored. PMID- 25447277 TI - Designing and troubleshooting immunopanning protocols for purifying neural cells. AB - Purifying and culturing cells from the central nervous system (CNS) has proved to be an incredibly powerful tool for dissecting fundamental neuron and glial properties, and especially powerful in understanding neuronal-glial interactions. In a series of detailed protocols, we have provided step-by-step instructions for purifying and culturing specific types of neurons, glia, and vascular cells from the CNS by immunopanning. This article discusses common pitfalls and errors as well as important design considerations for the immunopanning procedure. PMID- 25447275 TI - Nurr1 blocks the mitogenic effect of FGF-2 and EGF, inducing olfactory bulb neural stem cells to adopt dopaminergic and dopaminergic-GABAergic neuronal phenotypes. AB - The transcription factor Nurr1 is expressed in the mouse olfactory bulb (OB), although it remains unknown whether it influences the generation of dopaminergic neurons (DA) (DA neurons) in cells isolated from this brain region. We found that expressing Nurr1 in proliferating olfactory bulb stem cells (OBSCs) produces a marked inhibition of cell proliferation and the generation of immature neurons immunoreactive for tyrosine hydroxylase (TH) concomitant with marked upregulations of Th, Dat, Gad, and Fgfr2 transcripts. In long-term cultures, these cells develop neurochemical and synaptic markers of mature-like mesencephalic DA neurons, expressing GIRK2, VMAT2, DAT, calretinin, calbindin, synapsin-I, and SV2. Concurring with the increase in both Th and Gad expression, a subpopulation of induced cells was both TH- and GAD-immunoreactive indicating that they are dopaminergic-GABAergic neurons. Indeed, these cells could mature to express VGAT, suggesting they can uptake and store GABA in vesicles. Remarkably, the dopamine D1 receptor agonist SKF-38393 induced c-Fos in TH(+) cells and dopamine release was detected in these cultures under basal and KCl-evoked conditions. By contrast, cotransducing the Neurogenin2 and Nurr1 transcription factors produced a significant decrease in the number of TH-positive neurons. Our results indicate that Nurr1 overexpression in OBSCs induces the formation of two populations of mature dopaminergic neurons with features of the ventral mesencephalon or of the OB, capable of responding to functional dopaminergic stimuli and of releasing dopamine. They also suggest that the accumulation of Fgfr2 by Nurr1 in OBSCs may be involved in the generation of DA neurons. PMID- 25447278 TI - Isolating phagosomes from tissue culture cells. AB - Phagocytosis is the process by which receptors at the plasma membrane are used to engulf a particle such as a bacterium, parasite, or dead cell. Phagosomes can be isolated from tissue culture cells by various centrifugation methods, including the use of differential density gradients or sucrose step gradients, but these methods are time-consuming or otherwise difficult. We describe here a protocol that avoids centrifugation and relies instead on the uptake of magnetic beads to rapidly isolate the phagosomal compartment from tissue culture cells. PMID- 25447273 TI - Biological and biochemical properties of two Xenopus laevis N acetylgalactosaminyltransferases with contrasting roles in embryogenesis. AB - The biosynthesis of mucin-type O-linked glycans in animals is initiated by members of the large family of polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts), which play important roles in embryogenesis, organogenesis, adult tissue homeostasis and carcinogenesis. Until now, the mammalian forms of these enzymes have been the best characterized. However, two N acetylgalactosaminyltransferases (xGalNAc-T6 and xGalNAc-T16) from the African clawed frog (Xenopus laevis), which are most homologous to those encoded by the human GALNT6 and GALNT16 (GALNTL1) genes, were shown to have contrasting roles in TGF-beta/BMP signaling in embryogenesis. In this study we have examined these two enzymes further and show differences in their in vivo function during X. laevis embyrogenesis as evidenced by in situ hybridization and overexpression experiments. In terms of enzymatic activity, both enzymes were found to be active towards the EA2 peptide, but display differential activity towards a peptide based on the sequence of ActR-IIB, a receptor relevant to TGF-beta/BMP signaling. In summary, these data demonstrate that these two enzymes from different branches of the N-acetylgalactosaminyltransferase do not only display differential substrate specificities, but also specific and distinct expression pattern and biological activities in vivo. PMID- 25447279 TI - Purification of schwann cells from the neonatal and injured adult mouse peripheral nerve. AB - This protocol describes the use of immunopanning for acute purification and primary culture of Schwann cells from intact neonatal and injured adult mouse sciatic nerve. PMID- 25447280 TI - Two-dimensional imaging of fast intracellular Ca2+ release. AB - Asynchronous release of calcium (Ca(2+))-for example, the generation of Ca(2+) alternans in cardiac myocytes-is a phenomenon important in the development of cardiac arrhythmogenesis. The development of a failure to release Ca(2+) at individual release sites can be regarded as a major contributor to cardiac pathologies such as hypertrophy. Although confocal linescans provide sufficient temporal resolution to investigate the physiological and pathological cardiac excitation-contraction (EC) coupling, linescans can only image ~1.5% of the cross section of myocytes, which raises doubts about how representative such recordings are, especially in light of nonhomogeneous uncoupling of Ca(2+) channels and ryanodine receptors. Nowadays, the speed of confocal microscopes has been greatly improved, enabling two-dimensional (2D) imaging at sufficient image rates (>100 frames/sec). To understand better the physiological and pathophysiological EC coupling of cardiomyocytes, we describe here a protocol to monitor fast intracellular Ca(2+) signals using fast 2D confocal scanning. PMID- 25447281 TI - Confocal FLIM of genetically encoded FRET sensors for quantitative Ca2+ imaging. AB - Fluorescence lifetime imaging (FLIM) is a powerful imaging mode that can be combined with confocal imaging. Changes in the fluorescence decay time of a donor in an intramolecular Forster resonance energy transfer (FRET)-based biosensor provide intrinsic quantitative data. Here, we describe a protocol using both the Ca(2+) sensor TN-XL, which uses troponin C, as the Ca(2+)-sensing unit, and the FLIM technology based on time-correlated single-photon counting. PMID- 25447282 TI - Mapping RNA-protein interactions using hydroxyl-radical footprinting. AB - The binding of a protein to an RNA sequence protects the region of the RNA from cleavage by chemicals or RNases; this protected region is known as the protein's "footprint." In the footprinting protocol presented here, end-labeled RNAs with and without bound protein are cleaved using chemical methods. Fe(II)-EDTA is used to generate hydroxyl radicals in the presence of a reducing agent. These hydroxyl radicals indiscriminately cleave ribose groups in regions of the ribose-phosphate backbone that are exposed to solvent. After termination of cleavage, the resulting RNA fragments are analyzed by gel electrophoresis on denaturing polyacrylamide gels. Because hydroxyl radicals are smaller and cleave less specifically than RNases, this approach, if feasible, is often the method of choice for monitoring sites of RNA-protein interactions. PMID- 25447283 TI - Mapping RNA-protein interactions using iodine footprinting. AB - Footprinting methods are used to determine the binding site of a protein on an RNA. They are based on the fact that a protein bound to an RNA protects the RNA from cleavage by chemicals or nucleases. The footprinting method described here relies on the ability of iodoethanol to cleave the backbone of RNA when a phosphodiester bond contains sulfur in place of a nonbridging oxygen. A potential advantage of using iodoethanol for cleavage is that one can prepare RNAs that contain selective thiol substitutions such that the resulting cleavage patterns contain fewer bands, making quantification "easier" and the results cleaner. For example, a population of RNAs that only contains nonbridging thiol substitutions 5' to each adenine can be prepared by including alphaS ATP in the transcription reaction. In this protocol, all positions on an RNA are surveyed. First, a series of RNAs is synthesized by transcription in the presence of alphaS ATP, alphaS CTP, alphaS UTP, or alphaS GTP. Each of the selectively substituted RNAs is probed with the binding protein of interest. The portion of the RNA that is not bound by protein is accessible and vulnerable to cleavage by iodoethanol. Finally, the cleavage products are analyzed by gel electrophoresis on denaturing polyacrylamide gels. PMID- 25447284 TI - Generation and analysis of lentivirus expressing a 2A peptide-linked bicistronic fluorescent construct. AB - This weeklong protocol for making and testing lentivirus has been used in the Advanced Topics in Molecular Neuroscience (ATMN) lecture and laboratory course at Cold Spring Harbor Laboratory (CSHL) for nearly a decade. Lentiviruses are derived from HIV-1 and are ideal vehicles for the delivery of multiple genes of interest into target cells. In this protocol, 2A peptide-linked sequences are used to create a bicistronic lentiviral construct containing a ubiquitous promoter (chick beta actin with a cytomegalovirus [CMV] early enhancer) driving dual expression of two fluorescent proteins (FP): H2B-Cerulean (a nuclear localized blue FP) and Dendra2 (a photoactivatable green FP that converts to red after exposure to UV light). Polymerase chain reaction (PCR) amplification of the bicistronic insert is followed by subcloning into a lentiviral vector and transfection into a packaging cell line. The resulting viral supernatants can be used to prepare concentrated stocks and infect cells for imaging via epifluorescent and confocal microscopy. PMID- 25447285 TI - Purification of Schwann cells. AB - This article introduces methods for the acute purification and primary culture of Schwann cells from the mouse sciatic nerve. Immunopanning can be used to isolate Schwann cells from intact nerves during early postnatal development as well as to purify Schwann cells from adult nerves following sciatic nerve injury. These methods facilitate the exploration of mouse Schwann cell biology in the healthy and injured peripheral nerve. PMID- 25447286 TI - Conditional knockout mouse models of cancer. AB - In 2007, three scientists, Drs. Mario R. Capecchi, Martin J. Evans, and Oliver Smithies, received the Nobel Prize in Physiology or Medicine for their contributions of introducing specific gene modifications into mice. This technology, commonly referred to as gene targeting or knockout, has proven to be a powerful means for precisely manipulating the mammalian genome and has generated great impacts on virtually all phases of mammalian biology and basic biomedical research. Of note, germline mutations of many genes, especially tumor suppressors, often result in lethality during embryonic development or at developmental stages before tumor formation. This obstacle has been effectively overcome by the use of conditional knockout technology in conjunction with Cre LoxP- or Flp-Frt-mediated temporal and/or spatial systems to generate genetic switches for precise DNA recombination. Currently, numerous conditional knockout mouse models have been successfully generated and applied in studying tumor initiation, progression, and metastasis. This review summarizes some conditional mutant mouse models that are widely used in cancer research and our understanding of the possible mechanisms underlying tumorigenesis. PMID- 25447287 TI - Molecular characterization of Plasmodium falciparum Bruno/CELF RNA binding proteins. AB - The human malaria parasite Plasmodium falciparum employs intricate post transcriptional regulatory mechanisms in different stages of its life cycle. Despite the importance of post-transcriptional regulation, key elements of these processes, namely RNA binding proteins (RBPs), are poorly characterized. In this study, the RNA binding properties of P. falciparum proteins were characterized including two putative members of the Bruno/CELF family of RBPs (PfCELF1 and PfCELF2), dihydrofolate reductase-thymidylate synthase (PfDHFR-TS), and adenosine deaminase (PfAda). RNA binding activity was tested using UV-crosslinking and electrophoretic mobility shift assays. PfCELF1 and PfDHFR-TS demonstrated RNA binding activity, whereas PfAda and PfCELF2 were RBP-negative. Intracellular protein localization of RBPs was studied using GFP-tagged transgenic parasite lines. PfCELF1 protein may shuttle between nucleus and cytoplasm, as shown by a predominantly nuclear PfCELF1 cell population and another predominantly cytoplasmic. In contrast, PfDHFR-TS protein is predominantly cytoplasmic. PfCELF1 may thus have several roles, including pre-mRNA processing. The mRNA targets of these P. falciparum proteins were investigated by ribonomics using DNA microarrays. A sequence motif similar to that recognized by CELF proteins in other species is common in the introns of target mRNAs identified for PfCELF1, suggesting that nuclear-localized PfCELF1 may regulate pre-mRNA splicing in P. falciparum, as has been found for CELF proteins in other species. In contrast, none or very few mRNA targets were found for the other proteins, suggesting that they do not have biologically relevant roles as RBPs in the asexual stages of P. falciparum. PMID- 25447288 TI - Candidate gene discovery in autoimmunity by using extreme phenotypes, next generation sequencing and whole exome capture. AB - Whole exome sequencing (WES) is a widely used strategy for detection of protein coding and splicing variants associated with inherited diseases. Many studies have shown that the strategy has been broad and proficient due to its ability in detecting a high proportion of disease causing variants, using only a small portion of the genome. In this review we outline the main steps involved in WES, the comprehensive analysis of the massive data obtained including the genomic capture, amplification, sequencing, alignment, curating, filtering and genetic analysis to determine the presence of candidate variants with potential pathogenic/functional effect. Further, we propose that the multiple autoimmune syndrome, an extreme phenotype of autoimmune disorders, is a very well suited trait to tackle genomic variants of major effect underpinning the lost of self tolerance. PMID- 25447289 TI - Integrated psychological care in head and neck cancer: Views from health care providers, patients, and supports. AB - OBJECTIVES/HYPOTHESIS: An evaluation by head-and-neck cancer (HNC) staff, patients, and patient support feedback regarding integrated psychological care and perceived benefit based on patient characteristics. STUDY DESIGN: Cross sectional survey of HNC staff, patients, and their primary supports; and retrospective chart review of psychiatric characteristics of HNC patients. METHODS: HNC staff, patients (who were evaluated by the integrated psychologist), and their primary supports were given questionnaires on their perception of benefit of including a psychologist in the evaluation and treatment of HNC patients. Also, a retrospective chart review on patients who were psychiatrically evaluated by the psychologist on sociodemographics and psychiatric characteristics. RESULTS: Overall, integration of a psychologist was well received by patients, supports, and staff. Younger patients reported greater satisfaction with the availability of the psychologist than older patients (P = .04), and patients with reported psychiatric histories (diagnoses in remission) indicated more satisfaction with the psychologist in relation to managing distress than patients who denied psychiatric histories (P = .03); however, patients who were currently smoking tended to report lower satisfaction with the psychologist helping with distress than those who were past/never smokers (P = .06). CONCLUSIONS: Integrated psychological care has the potential to improve care provided for HNC patients. LEVEL OF EVIDENCE: Level 4. PMID- 25447290 TI - Development characterization and skin permeating potential of lipid based novel delivery system for topical treatment of psoriasis. AB - The aim of this study was to develop, optimize and evaluate the potential of solid lipid nanoparticles (SLNs) as a topical delivery system for targeted and prolonged release of Fluocinolone acetonide (FA). FA loaded SLNs were successfully developed by an emulsification-ultrasonication method and optimized using 17-run, 3-factor, 3-level Box-Behnken design of Design Expert software. SLNs were evaluated for particle size, polydispersity index, zeta potential, drug encapsulation efficiency and drug loading. Shape and surface morphology of the SLNs confirmed spherical shape of nanoparticles when investigated under a transmission electron microscope. Complete encapsulation of drug in the nanoparticles was confirmed by powder X-ray diffraction and differential scanning calorimetry. The drug release study confirmed prolonged release from the SLNs following Higuchi release kinetics with R(2) value of 0.995 where as pure drug suspension exhibited faster drug release following zero order release kinetics with R(2) value of 0.992. Stability study confirmed that SLNs were stable for 3 months at 4 degrees C. Furthermore, in vitro skin distribution studies showed presence of significant amount of FA on the epidermal layer of skin when treated with FA loaded SLNs suspension while plain FA suspension showed minimum amount of FA in the epidermis and dermis. Moreover, selective accumulation of FA in the epidermis might eliminate adverse side effects associated with systemic exposure. Results demonstrated that FA loaded SLNs could be a promising modality for psoriasis treatment but to establish clinical utility of the present system further studies are required in clinically relevant models. PMID- 25447291 TI - Ionic strength and composition govern the elasticity of biological membranes. A study of model DMPC bilayers by force- and transmission IR spectroscopy. AB - Infrared (IR) spectroscopy was used to quantify the ion mixture effect of seawater (SW), particularly the contribution of Mg(2+) and Ca(2+) as dominant divalent cations, on the thermotropic phase behaviour of 1,2-dimyristoyl-sn glycero-3-posphocholine (DMPC) bilayers. The changed character of the main transition at 24 degrees C from sharp to gradual in films and the 1 degrees C shift of the main transition temperature in dispersions reflect the interactions of lipid headgroups with the ions in SW. Force spectroscopy was used to quantify the nanomechanical hardness of a DMPC supported lipid bilayer (SLB). Considering the electrostatic and ion binding equilibrium contributions while systematically probing the SLB in various salt solutions, we showed that ionic strength had a decisive influence on its nanomechanics. The mechanical hardness of DMPC SLBs in the liquid crystalline phase linearly increases with the increasing fraction of all ion-bound lipids in a series of monovalent salt solutions. It also linearly increases in the gel phase but almost three times faster (the corresponding slopes are 4.9 nN/100 mM and 13.32 nN/100 mM, respectively). We also showed that in the presence of divalent ions (Ca(2+) and Mg(2+)) the bilayer mechanical hardness was unproportionally increased, and that was accompanied with the decrease of Na(+) ion and increase of Cl(-) ion bound lipids. The underlying process is a cooperative and competitive ion binding in both the gel and the liquid crystalline phase. Bilayer hardness thus turned out to be very sensitive to ionic strength as well as to ionic composition of the surrounding medium. In particular, the indicated correlation helped us to emphasize the colligative properties of SW as a naturally occurring complex ion mixture. PMID- 25447292 TI - Deciphering archaeal glycolipids of an extremely halophilic archaeon of the genus Halobellus by MALDI-TOF/MS. AB - Polar membrane lipids of an archaeal microorganism recently isolated from the natural salt lake Fuente de Piedra (Malaga, Spain) have been studied by means of TLC in combination with MALDI-TOF mass spectrometry. The major phospholipids are the ether lipids phosphatidylglycerophosphate methyl ester and phosphatidylglycerosulfate, while phosphatidylglycerol is barely detectable; in addition the bisphosphatidylglycerol (archaeal cardiolipin) has been detected for the first time in a representative of the genus Halobellus. The structures of glycolipids, including a glycosyl-cardiolipin, have been elucidated by post source decay (PSD) mass spectrometry analysis. Besides the monosulfated diglycosyl diphytanylglyceroldiether, two variants of a bis-sulfated diglycosyl diphytanylglyceroldiether have been identified; furthermore the glycosyl cardiolipin is found to have the same structure of the analogue present in Halorubrum trapanicum and Haloferax volcanii. The role of the abundant sulfated glycolipids in facing high extracellular salinity is discussed. PMID- 25447293 TI - Assessment of disease-related cognitive impairments using the novel object recognition (NOR) task in rodents. AB - The novel object recognition test (NOR) test is a two trial cognitive paradigm that assesses recognition memory. Recognition memory is disturbed in a range of human disorders and NOR is widely used in rodents for investigating deficits in a variety of animal models of human conditions where cognition is impaired. It possesses several advantages over more complex tasks that involve lengthy training procedures and/or food or water deprivation. It is quick to administer, non-rewarded, provides data quickly, cost effective and most importantly, ethologically relevant as it relies on the animal's natural preference for novelty. A PubMed search revealed over 900 publications in rats and mice using this task over the past 3 years with 34 reviews in the past 10 years, demonstrating its increasing popularity with neuroscientists. Although it is widely used in many disparate areas of research, no articles have systematically examined this to date, which is the subject of our review. We reveal that NOR may be used to study recognition memory deficits that occur in Alzheimer's disease and schizophrenia, where research is extensive, in Parkinson's disease and Autism Spectrum Disorders (ASD) where we observed markedly reduced numbers of publications. In addition, we review the use of NOR to study cognitive deficits induced by traumatic brain injury and cancer chemotherapy, not disorders per se, but situations in which cognitive deficits dramatically reduce the quality of life for those affected, see Fig. 1 for a summary. Our review reveals that, in all these animal models, the NOR test is extremely useful for identification of the cognitive deficits observed, their neural basis, and for testing the efficacy of novel therapeutic agents. Our conclusion is that NOR is of considerable value for cognitive researchers of all disciplines and we anticipate that its use will continue to increase due to its versatility and several other advantages, as detailed in this review. PMID- 25447294 TI - Amantadine preserves dopamine level and attenuates depression-like behavior induced by traumatic brain injury in rats. AB - Traumatic brain injury (TBI) often results in multiple neuropsychiatric sequelae, including cognitive, emotional, and behavioral problems. Among them, depression is a common psychiatric symptom, and links to poorer recovery. Amantadine, as an antiparkinsonian, increases dopamine release, and blocks dopamine reuptake, but has recently received attention for its effectiveness as an antidepressant. In the present study, we first induced a post-TBI depression rat model to probe the efficacy of amantadine therapy in reducing post-TBI depression. The DA concentration in the striatum of the injured rats, as well as the degeneration and apoptosis of dopaminergic neurons in the substantia nigra (SN), were checked along with the depression-like behavior. The results showed that amantadine therapy could significantly ameliorate the depression-like behavior, improving the DA level in the striatum and decreasing the degeneration and apoptosis of dopaminergic neurons in the SN. The results indicated that the anti-depression effect may result from the increase of extracellular DA concentration in the striatum and/or the indirect neuroprotection on the dopaminergic neurons in the SN. We conclude that DA plays a critical role in post-TBI depression, and that amantadine shows its potential value in anti-depression treatment for TBI. PMID- 25447295 TI - Differential effects of alpha7 nicotinic receptor agonist PHA-543613 on spatial memory performance of rats in two distinct pharmacological dementia models. AB - The aim of the present study was to compare the cognitive enhancer potential of a recently identified highly selective alpha7 nicotinic receptor agonist PHA-543613 in scopolamine induced cholinergic and in MK-801 induced glutamatergic transient amnesia models in adult male Wistar rats. Spontaneous alternation paradigm in the T-maze was used as it is considered a reliable measure of spatial working memory and as T-maze performance is highly dependent on the functioning of the hippocampus and the prefrontal cortex. Scopolamine (0.5 mg/kg) and MK-801 (0.1 mg/kg) caused similar decrease of alternation rate and increased locomotion. Prior administration of PHA-543613 (1 or 3 mg/kg) dose dependently and completely reversed scopolamine induced impairment of alternation. However, PHA-543613 had lower efficacy in the MK-801 induced transient amnesia model, as the pharmacologically induced memory deficit was only partially reversed and an inverted U-shaped dose-response was found. PHA-543613 did not modulate either scopolamine or MK-801 induced increased locomotor activity or decreased choice latency. Results suggest that the alpha7 nicotinic receptor agonist had better efficacy to alleviate working memory deficits of rats caused by cholinergic receptor dysfunction, when NMDA receptors were not primarily targeted. On the other hand, the same memory enhancer strategy through alpha7 cholinergic receptors was apparently less effective when glutamatergic transmission (via NMDARs) was directly impaired by MK-801 treatment. The present results provide data supporting the need of parallel comprehensive testing of novel drug candidates for cognitive impairment in distinct preclinical models of memory deficits. PMID- 25447296 TI - Behavioral impairments and changes of nitric oxide and inducible nitric oxide synthase in the brains of molarless KM mice. AB - More studies showed that as a common disorder in senior population, loss of teeth could adversely affect human cognitive function, and nitric oxide (NO) might play an important role in the cognitive function. However, the underlying mechanism has not yet been well-established. The objectives of this study are to evaluate behavior changes of KM mice after loss of molars, and levels of NO and inducible nitric oxide synthase (iNOS) in the brain in molarless condition. It is hypothesized that loss of molars of the mice tested results in the cognitive impairments and that the process is mediated by NO in the brain through the signaling pathways. Morris water maze is used to test the behavioral changes after 8 weeks of the surgery. The changes of NO and iNOS are evaluated by using Griess assay, western blot, and immunohistochemistry method. The results show that 8 weeks after loss of molars, the spatial learning and memory of KM mice impair and the levels of NO and iNOS in mice hippocampus increase. These findings suggest that molar extraction is associated with the behavioral impairment, and that the changes of NO and iNOS in the hippocampus may be involved in the behavioral changes in the molarless condition. PMID- 25447297 TI - A microstructural analysis of schedule-induced polydipsia reveals incentive induced hyperactivity in an animal model of ADHD. AB - Recent research has suggested that frequent short bursts of activity characterize hyperactivity associated with attention deficit hyperactivity disorder (ADHD). This study determined whether such pattern is also visible in schedule-induced polydipsia (SIP) in the spontaneously hypertensive rat (SHR), an animal model of ADHD. Male SHR, Wistar Kyoto (WKY) and Wistar rats were exposed to 40 sessions of SIP using a multiple fixed-time (FT) schedule of food delivery with FT 30-s and FT 90-s components. Stable performance was analyzed to determine the extent to which SIP-associated drinking is organized in bouts. The Bi-Exponential Refractory Model (BERM) of free-operant performance was applied to schedule induced licks. A model comparison analysis supported BERM as a description of SIP episodes: licks were not produced at a constant rate but organized into bouts within drinking episodes. FT 30-s induced similar overall licking rates, latencies to first licks and episode durations across strains; FT 90-s induced longer episode durations in SHRs and reduced licking rate in WKY and Wistar rats to nearly baseline levels. Across schedules, SHRs made more and shorter bouts when compared to the other strains. These results suggest an incentive-induced hyperactivity in SHR that has been observed in operant behaviour and in children with ADHD. PMID- 25447298 TI - Peripherally administered oxytocin modulates latent inhibition in a manner consistent with antipsychotic drugs. AB - BACKGROUND: Peripherally administered oxytocin (OT) has produced antipsychotic drug (APD)-like effects in animal tests that are predictive of APD efficacy. However, these effects have mainly been demonstrated using animal models of schizophrenia-like deficits in prepulse inhibition (PPI) of the startle reflex. Another schizophrenia-relevant abnormality that is the basis of a predictive animal test for APD efficacy is deficient latent inhibition (LI). LI is the normal suppression of a classically conditioned response when the subject is pre exposed to the conditioned stimulus (CS) before it is paired with the unconditioned stimulus (UCS). Conditioned taste aversion (CTA), the normal avoidance of ingesting a food or liquid by animals when its taste is associated with an aversive experience, was used to test whether OT facilitates LI consistent with APDs. METHODS: Brown Norway rats, known to naturally display attenuated LI, were aversively conditioned on two consecutive exposures to flavored drinking water (0.1% saccharin) by pairing it with malaise-inducing lithium chloride injections. Concurrent with conditioning, rats received subcutaneous OT (0.02, 0.1, 0.5mg/kg) or saline. Some rats were pre-exposed to the flavored water prior to its aversive conditioning (pre-exposed) while others were not (non pre-exposed). Two days after aversive conditioning the amount of flavored water consumed during a 20-min session was recorded. RESULTS: As expected, LI, defined as greater consumption by pre-exposed vs. non pre-exposed rats was only weakly exhibited in Brown Norway rats and OT enhanced LI by reducing CTA in pre-exposed rats in a dose-dependent manner, with the 0.02 mg/kg dose producing the strongest effect. CONCLUSIONS: The facilitation of LI by OT is consistent with the effects produced by APDs and provides further support for the notion that OT has therapeutic potential for schizophrenia. PMID- 25447300 TI - ERP correlates of auditory goal-directed behavior of younger and older adults in a dynamic speech perception task. AB - The ability to understand speech under adverse listening conditions deteriorates with age. In addition to genuine hearing deficits, age-related declines in attentional and inhibitory control are assumed to contribute to these difficulties. Here, the impact of task-irrelevant distractors on speech perception was studied in 28 younger and 24 older participants in a simulated "cocktail party" scenario. In a two-alternative forced-choice word discrimination task, the participants responded to a rapid succession of short speech stimuli ("on" and "off") that was presented at a frequent standard location or at a rare deviant location in silence or with a concurrent distractor speaker. Behavioral responses and event-related potentials (mismatch negativity MMN, P3a, and reorienting negativity RON) were analyzed to study the interplay of distraction, orientation, and refocusing in the presence of changes in target location. While shifts in target location decreased performance of both age groups, this effect was more pronounced in the older group. Especially in the distractor condition, the electrophysiological measures indicated a delayed attention capture and a delayed re-focussing of attention toward the task-relevant stimulus feature in the older group, relative to the young group. In sum, the results suggest that a delay in the attention switching mechanism contribute to the age-related difficulties in speech perception in dynamic listening situations with multiple speakers. PMID- 25447299 TI - Delta opioid receptors expressed in forebrain GABAergic neurons are responsible for SNC80-induced seizures. AB - The delta opioid receptor (DOR) has raised much interest for the development of new therapeutic drugs, particularly to treat patients suffering from mood disorders and chronic pain. Unfortunately, the prototypal DOR agonist SNC80 induces mild epileptic seizures in rodents. Although recently developed agonists do not seem to show convulsant properties, mechanisms and neuronal circuits that support DOR-mediated epileptic seizures remain to be clarified. DORs are expressed throughout the nervous system. In this study we tested the hypothesis that SNC80-evoked seizures stem from DOR activity at the level of forebrain GABAergic transmission, whose inhibition is known to facilitate the development of epileptic seizures. We generated a conditional DOR knockout mouse line, targeting the receptor gene specifically in GABAergic neurons of the forebrain (Dlx-DOR). We measured effects of SNC80 (4.5, 9, 13.5 and 32 mg/kg), ARM390 (10, 30 and 60 mg/kg) or ADL5859 (30, 100 and 300 mg/kg) administration on electroencephalograms (EEGs) recorded in Dlx-DOR mice and their control littermates (Ctrl mice). SNC80 produced dose-dependent seizure events in Ctrl mice, but these effects were not detected in Dlx-DOR mice. As expected, ARM390 and ADL5859 did not trigger any detectable change in mice from both genotypes. These results demonstrate for the first time that SNC80-induced DOR activation induces epileptic seizures via direct inhibition of GABAergic forebrain neurons, and supports the notion of differential activities between first and second generation DOR agonists. PMID- 25447302 TI - Positive reinforcing effect of neurotensin microinjection into the ventral pallidum in conditioned place preference test. AB - The ventral pallidum (VP) is innervated by the mesolimbic dopaminergic system and it has a key role in motivation, reward, and memory processes. Neurotensin (NT) is an important neuromodulator which has been shown to modulate reinforcement in the ventral tegmental area, in the ventral mesencephalic region and in the central nucleus of amygdala. Neurotensin receptor 1 (NTR1) has already been detected in the VP in abundance, but its role in rewarding and reinforcing processes is not fully understood yet. In our present experiments, the effects of NT on positive reinforcement were investigated in the VP. In conditioned place preference (CPP) test, male Wistar rats were microinjected bilaterally with 100 ng or 250 ng NT in the volume of 0.4 MUl. In other groups of animals, 35 ng NTR1 antagonist SR 48692 was applied by itself, or microinjected 15 min before 100 ng NT treatment. One hundred ng dose of NT induced CPP, whereas animals injected with 250 ng NT did not exhibit significant differences from the vehicle group. Antagonist pretreatment inhibited the effect of NT, while the antagonist applied by itself had no effect. Our results show that NT injected into the VP is involved in positive reinforcement. This effect is specific to NTR1 receptors because the development of CPP can be prevented by specific antagonist. PMID- 25447301 TI - The effects of energy balance, obesity-proneness and sex on the neuronal response to sweet taste. AB - We have previously shown that propensity for weight gain, energy balance state and sex are important determinants of the neuronal response to visual food cues. It is not clear, though, whether these factors also impact the neuronal response to taste. The objective of this study was to examine the neuronal response to sweet taste during energy imbalance in men and women recruited to be obesity prone (OP) or obesity-resistant (OR). OP (13 men and 12 women) and OR (12 men and 12 women) subjects were studied after 1 day of eucaloric, overfed and underfed conditions in a randomized crossover design. On each test day, fMRI was performed in the respective acute fed state while subjects received in random order 60 trials each of 1M sucrose solution (SU), or artificial saliva (AS) following a visual cue predicting the taste. The neuronal response to SU versus AS expectation was significantly greater in the amygdala, orbitofrontal cortex, putamen and insula in OR versus OP; SU receipt was not different between groups. There were also sex-based differences with men having greater neuronal response to SU versus AS receipt in the caudate than women. The results, however, were not impacted by the state of energy balance. In summary, response to expectation but not receipt of basic sweet taste was different in OR compared to OP, highlighting the importance of learning and conditioning in the propensity to gain weight. Response to sucrose taste receipt was stronger in men than women, raising questions about the effect of sex hormones on brain response to food. PMID- 25447303 TI - Facilitated acquisition of standard but not long delay classical eyeblink conditioning in behaviorally inhibited adolescents. AB - Adolescence is a key age in the development of anxiety disorders. The present study assessed the relationship between behavioral inhibition, a risk factor for anxiety typified by avoidance, and acquisition of the classically conditioned eyeblink response. 168 healthy high school students (mean age 15.7 years, 54% female) were given a battery of self-report measures including the Adult Measure of Behavioural Inhibition (AMBI). The study compared acquisition of three experimental training conditions. Two groups were given paired CS-US training: standard delay of 500-ms or long delay of 1000-ms with CS overlapping and co terminating with a 50-ms airpuff US. A third group received unpaired training of 1000-ms CS and 50-ms airpuff US. Inhibited individuals showed greater acquisition of the conditioned eyeblink response in the 500-ms CS condition, but not in the paired 1000-ms condition. No differences in spontaneous blinks or reactivity to the stimulus were evident in the 1000-ms unpaired CS condition. Results support a relationship between associative learning and anxiety vulnerability that may be mediated by cerebellar functioning in inhibited individuals. PMID- 25447304 TI - Neuropeptide-Y modulates eating patterns and masticatory muscle activity in rats. AB - Neuropeptide Y (NPY) is a powerful orexigenic peptide secreted by hypothalamic neurons. The present study investigates how NPY injection into the lateral ventricle modulates masticatory movements and eating behavior. Behavioral experiments showed that cumulative food intake over a 4-h period and latency to eating were increased and decreased, respectively, in NPY-injected rats compared to saline-injected control rats. The feeding time for 2 g pellets was shorter in NPY-injected rats and resulted in an increased feeding rate, with more potent effects observed at 1 MUg compared to 10 MUg NPY. After injection of 10 MUg NPY, a greater number of bouts with shorter average bout duration for eating 2g, compared to 1 MUg NPY, were observed. Furthermore, 10 MUg NPY injection resulted in prolonged periods of moving and shortened sleep and grooming. Electromyography recordings from the digastric and masseter muscles showed two distinct patterns of bursts corresponding to the gnawing and chewing phases. After the injection of 1 MUg NPY, the burst magnitude of masseter muscle during the gnawing phase increased, reflecting strong jaw-closing muscle activity. The relative integrated EMG of masseter muscle in both phases was smaller following injection of 10 MUg NPY in comparison with that of 1 MUg NPY. The present study indicates that 1 MUg NPY administration promotes feeding behavior together with increased feeding rate and powerful jaw-closing muscle activity; whereas 10 MUg NPY administration lowers jaw-closing muscle activity during biting and produces mastication with shorter and more frequent feeding bouts than 1 MUg NPY. PMID- 25447305 TI - The orexin-1 receptor antagonist SB-334867 decreases anxiety-like behavior and c Fos expression in the hypothalamus of rats exposed to cat odor. AB - Increasing evidence suggests that the orexin system is involved in modulating anxiety, and we have recently shown that cat odor-induced anxiety in rats is attenuated by the orexin receptor antagonist SB-334867. In the current experiment, c-Fos expression was used to map changes in neuronal activation following SB-334867 administration in the cat odor anxiety model. Male Wistar rats were exposed to cat odor with or without SB-334867 pre-treatment (10 mg/kg, i.p.). A naive control group not exposed to cat odor was also used. Following cat odor exposure, brains were processed for c-Fos expression. Vehicle-treated rats showed an increase in anxiety-like behaviors (increased hiding and decreased approach toward the cat odor), and increased c-Fos expression in the posteroventral medial amygdala (MePV), paraventricular hypothalamus (PVN) and dorsal premammillary nucleus (PMd). In rats pretreated with SB-334867, approach scores increased and c-Fos expression decreased in the PVN and PMd. These results provide both behavioral and neuroanatomical evidence for the attenuation of cat odor-induced anxiety in rats via the orexin system. PMID- 25447306 TI - Hypoxia induced E-cadherin involving regulators of Hippo pathway due to HIF 1alpha stabilization/nuclear translocation in bone metastasis from breast carcinoma. AB - The present study deals with the molecular mechanisms involved in the regulation of E-cadherin expression under hypoxia, because the adjustment of the amount of E cadherin due to physical stimuli of the microenvironment might influence the colonization of metastasis to skeleton. We analyzed the effect of 1% oxygen tension, that is similar to that encountered in the bone marrow by metastatic cells spreading from breast carcinoma. The purpose was to evaluate the hypoxia orchestrated control of E-cadherin transactivation via hypoxia inducible factor-1 (HIF-1) and peroxisome proliferator activated receptor-gamma (PPARgamma), and the involvement of Hippo pathway members, as regulators of transcription factors. To give a translational significance to the study, we took into consideration human pair-matched ductal breast carcinoma and bone metastasis: E-cadherin and Wwox were expressed in bone metastasis but not in breast carcinoma, while HIF-1alpha and TAZ seemed localized principally in nuclei of metastasis and were found in all cell compartments of breast carcinoma. A close examination of the regulatory mechanisms underlying E-cadherin expression in bone metastasis was done in 1833 clone derived from MDA-MB231 cells. Hypoxia induced E-cadherin only in 1833 clone, but not in parental cells, through HIF-1 and PPARgamma activities, while Wwox decreased. Since Wwox was highly expressed in bone metastasis, the effect of ectopic Wwox was evaluated, and we showed E-cadherin transactivation and enhanced invasiveness in WWOX transfected 1833 cells. Also, hypoxia was additive with ectopic Wwox remarkably enhancing HIF-1alpha nuclear shuttle and accumulation due to the lengthening of the half-life of HIF-1alpha protein; under this experimental condition HIF-1alpha appeared as a slower migrated band compared with control, in agreement with the phosphorylation state. The in vitro data strongly supported the almost exclusive presence of HIF-1alpha in nuclei of human bone metastasis. Thus, we identified Wwox as a novel molecule in the HIF-1alpha HDM2 regulatory loop, necessary for the dynamic regulation of the HIF-1alpha amount, and we suggested that the reduction of endogenous Wwox free pool under hypoxia might also be due to the interaction with HDM2, sequestering the E3 ubiquitin ligase. We highlighted the importance of nuclear HIF-1alpha in the biology of metastasis for the mesenchymal-epithelial transition: this phenotype was regulated by Wwox plus hypoxia through E-cadherin target gene, playing a pivotal role in bone metastasis colonization. PMID- 25447307 TI - Differential contribution of key metabolic substrates and cellular oxygen in HIF signalling. AB - Changes in availability and utilisation of O2 and metabolic substrates are common in ischemia and cancer. We examined effects of substrate deprivation on HIF signalling in PC12 cells exposed to different atmospheric O2. Upon 2-4h moderate hypoxia, HIF-alpha protein levels were dictated by the availability of glutamine and glucose, essential for deep cell deoxygenation and glycolytic ATP flux. Nuclear accumulation of HIF-1alpha dramatically decreased upon inhibition of glutaminolysis or glutamine deprivation. Elevation of HIF-2alpha levels was transcription-independent and associated with the activation of Akt and Erk1/2. Upon 2h anoxia, HIF-2alpha levels strongly correlated with cellular ATP, produced exclusively via glycolysis. Without glucose, HIF signalling was suppressed, giving way to other regulators of cell adaptation to energy crisis, e.g. AMPK. Consequently, viability of cells deprived of O2 and glucose decreased upon inhibition of AMPK with dorsomorphin. The capacity of cells to accumulate HIF 2alpha decreased after 24h glucose deprivation. This effect, associated with increased AMPKalpha phosphorylation, was sensitive to dorsomorphin. In chronically hypoxic cells, glutamine played no major role in HIF-2alpha accumulation, which became mainly glucose-dependent. Overall, the availability of O2 and metabolic substrates intricately regulates HIF signalling by affecting cell oxygenation, ATP levels and pathways involved in production of HIF-alpha. PMID- 25447308 TI - Quantitative imaging of focal adhesion dynamics and their regulation by HGF and Rap1 signaling. AB - Cell migration is crucial in development, tissue repair and immunity and frequently aberrant in pathological processes including tumor metastasis. Focal adhesions (FAs) are integrin-based adhesion complexes that form the link between the cytoskeleton and the extracellular matrix and are thought to orchestrate cell migration. Understanding the regulation of FAs by (oncogenic) signaling pathways may identify strategies to target pathological cell migration. Here we describe the development of a robust FA tracker that enables the automatic, multi parametric analysis of FA dynamics, morphology and composition from time-lapse image series generated by total internal reflection fluorescence (TIRF) microscopy. In control prostate carcinoma cells, this software recapitulates previous findings that relate morphological characteristics of FAs to their lifetime and their cellular location. We then investigated how FAs are altered when cell migration is induced by the metastasis-promoting hormone HGF and subsequently inhibited by activation of the small GTPase Rap1. We performed a detailed analysis of individual FA parameters, which identified FA size, sliding and intensity as primary targets of Rap1. HGF did not have strong effects on any of the FA parameters within the first hours of its addition. Subsequent Bayesian network inference (BNI), using all measured parameters as input, revealed little correlation between changes in cell migration and FA characteristics in this prostate carcinoma cell line. Instead BNI indicated a concerted coordination of cell size and FA parameters. Thus our results did not reveal a direct relation between the regulation of cell migration and the regulation of FA dynamics. PMID- 25447309 TI - ATF6beta regulates the Wfs1 gene and has a cell survival role in the ER stress response in pancreatic beta-cells. AB - Endoplasmic reticulum (ER) stress is implicated in pancreatic beta-cell dysfunction and death resulting in type 2 diabetes. Activating transcription factor 6 (ATF6) is an essential component of the Unfolded Protein Response (UPR) and consists of two isoforms, ATF6alpha and ATF6beta. Here we investigated the role of ATF6beta. ATF6beta mRNA was detected in pancreatic beta-cell lines and rodent and human islets. We also detected ATF6beta protein and production of the active form (ATF6betap60) in response to ER stress. Knock-down of ATF6beta in INS 1 832/13 insulinoma cells did not affect mRNA induction of several major UPR genes in response to ER stress, suggesting ATF6beta is not essential for the basic UPR. Expressing active ATF6betap60 or ATF6alphap50 followed by microarray analysis showed that they regulate similar UPR genes, although some genes such as Wfs1 are ATF6beta-specific. ATF6beta, but not ATF6alpha, is able to bind the Wfs1 promoter and induce Wfs1 gene and protein expression. Knock-down of ATF6beta increased the susceptibility of beta-cells to ER stress-induced apoptosis, while overexpression of active ATF6betap60 reduced apoptosis. Thus, ATF6beta is not essential for induction of most UPR genes, but is required to maintain cell survival in beta-cells undergoing chronic ER stress, which in part relates to its ability to induce Wfs1, a pro-survival gene. PMID- 25447311 TI - Coagulation factor VII is regulated by androgen receptor in breast cancer. AB - Androgen receptor (AR) is widely expressed in breast cancer; however, there is limited information on the key molecular functions and gene targets of AR in this disease. In this study, gene expression data from a cohort of 52 breast cancer cell lines was analyzed to identify a network of AR co-expressed genes. A total of 300 genes, which were significantly enriched for cell cycle and metabolic functions, showed absolute correlation coefficients (|CC|) of more than 0.5 with AR expression across the dataset. In this network, a subset of 35 "AR-signature" genes were highly co-expressed with AR (|CC|>0.6) that included transcriptional regulators PATZ1, NFATC4, and SPDEF. Furthermore, gene encoding coagulation factor VII (F7) demonstrated the closest expression pattern with AR (CC=0.716) in the dataset and factor VII protein expression was significantly associated to that of AR in a cohort of 209 breast tumors. Moreover, functional studies demonstrated that AR activation results in the induction of factor VII expression at both transcript and protein levels and AR directly binds to a proximal region of F7 promoter in breast cancer cells. Importantly, AR activation in breast cancer cells induced endogenous factor VII activity to convert factor X to Xa in conjunction with tissue factor. In summary, F7 is a novel AR target gene and AR activation regulates the ectopic expression and activity of factor VII in breast cancer cells. These findings have functional implications in the pathobiology of thromboembolic events and regulation of factor VII/tissue factor signaling in breast cancer. PMID- 25447313 TI - Oxygen-dependent acetylation and dimerization of the corepressor CtBP2 in neural stem cells. AB - The transcriptional corepressor CtBP2 is essential for proper development of the nervous system. The factor exerts its repression by interacting in complexes with chromatin-modifying factors such as histone deacetylases (HDAC) 1/2 and the histone demethylase LSD1/KDM1. Notably, the histone acetyl transferase p300 acetylates CtBP2 and this is an important regulatory event of the activity and subcellular localization of the protein. We recently demonstrated an essential role for CtBPs as sensors of microenvironmental oxygen levels influencing the differentiation potential of neural stem cells (NSCs), but it is not known whether oxygen levels influence the acetylation levels of CtBP factors. Here we show by using proximity ligation assay (PLA) that CtBP2 acetylation levels increased significantly in undifferentiated, proliferating NSCs under hypoxic conditions. CtBP2 interacted with the class III HDAC Sirt1 but this interaction was unaltered in hypoxic conditions, and treatment with the Sirt1 inhibitor Ex527 did not result in any significant change in total CtBP2 acetylation levels. Instead, we revealed a significant decrease in PLA signal representing CtBP2 dimerization in NSCs under hypoxic conditions, negatively correlating with the acetylation levels. Our results suggest that microenvironmental oxygen levels influence the dimerization and acetylation levels, and thereby the activity, of CtBP2 in proliferating NSCs. PMID- 25447312 TI - Determining the mechanical properties of plectin in mouse myoblasts and keratinocytes. AB - Plectin is the prototype of an intermediate filament (IF)-based cytolinker protein. It affects cells mechanically by interlinking and anchoring cytoskeletal filaments and acts as scaffolding and docking platform for signaling proteins to control cytoskeleton dynamics. The most common disease caused by mutations in the human plectin gene, epidermolysis bullosa simplex with muscular dystrophy (EBS MD), is characterized by severe skin blistering and progressive muscular dystrophy. Therefore, we compared the biomechanical properties and the response to mechanical stress of murine plectin-deficient myoblasts and keratinocytes with wild-type cells. Using a cell stretching device, plectin-deficient myoblasts exhibited lower mechanical vulnerability upon external stress compared to wild type cells, which we attributed to lower cellular pre-stress. Contrary to myoblasts, wild-type and plectin-deficient keratinocytes showed no significant differences. In magnetic tweezer measurements using fibronectin-coated paramagnetic beads, the stiffness of keratinocytes was higher than of myoblasts. Interestingly, cell stiffness, adhesion strength, and cytoskeletal dynamics were strikingly altered in plectin-deficient compared to wild-type myoblasts, whereas smaller differences were observed between plectin-deficient and wild-type keratinocytes, indicating that plectin might be more important for stabilizing cytoskeletal structures in myoblasts than in keratinocytes. Traction forces strongly correlated with the stiffness of plectin-deficient and wild-type myoblasts and keratinocytes. Contrary to that cell motility was comparable in plectin-deficient and wild-type myoblasts, but was significantly increased in plectin-deficient compared to wild-type keratinocytes. Thus, we postulate that the lack of plectin has divergent implications on biomechanical properties depending on the respective cell type. PMID- 25447310 TI - The MAPK ERK5, but not ERK1/2, inhibits the progression of monocytic phenotype to the functioning macrophage. AB - Intracellular signaling pathways present targets for pharmacological agents with potential for treatment of neoplastic diseases, with some disease remissions already recorded. However, cellular compensatory mechanisms usually negate the initial success. For instance, attempts to interrupt aberrant signaling downstream of the frequently mutated ras by inhibiting ERK1/2 has shown only limited usefulness for cancer therapy. Here, we examined how ERK5, that overlaps the functions of ERK1/2 in cell proliferation and survival, functions in a manner distinct from ERK1/2 in human AML cells induced to differentiate by 1,25D dihydroxyvitamin D3 (1,25D). Using inhibitors of ERK1/2 and of MEK5/ERK5 at concentrations specific for each kinase in HL60 and U937 cells, we observed that selective inhibition of the kinase activity of ERK5, but not of ERK1/2, in the presence of 1,25D resulted in macrophage-like cell morphology and enhancement of phagocytic activity. Importantly, this was associated with increased expression of the macrophage colony stimulating factor receptor (M-CSFR), but was not seen when M-CSFR expression was knocked down. Interestingly, inhibition of ERK1/2 led to activation of ERK5 in these cells. Our results support the hypothesis that ERK5 negatively regulates the expression of M-CSFR, and thus has a restraining function on macrophage differentiation. The addition of pharmacological inhibitors of ERK5 may influence trials of differentiation therapy of AML. PMID- 25447316 TI - The MRE11 complex: an important source of stress relief. PMID- 25447314 TI - Curcumin induces differential expression of cytoprotective enzymes but similar apoptotic responses in fibroblasts and myofibroblasts. AB - Excessive extracellular matrix (ECM) deposition and tissue contraction after injury can lead to esthetic and functional problems. Fibroblasts and myofibroblasts activated by transforming growth factor (TGF)-beta1 play a key role in these processes. The persistence of (myo)fibroblasts and their excessive ECM production and continuous wound contraction have been linked to pathological scarring. The identification of compounds reducing myofibroblast survival and function may thus offer promising therapeutic strategies to optimize impaired wound healing. The plant-derived polyphenol curcumin has shown promising results as a wound healing therapeutic in vivo; however, the exact mechanism is still unclear. In vitro, curcumin induces apoptosis in various cell types via a reactive oxygen species (ROS)-dependent mechanism. Here we treated human dermal fibroblasts with TGF-beta1 to induce myofibroblast differentiation, and compared the responses of fibroblasts and myofibroblasts to 25 uM curcumin. Curcumin induced caspase-independent apoptosis in both fibroblasts and myofibroblasts in a ROS-dependent manner. Oxidative stress leads to the induction of several antioxidant systems to regain cellular homeostasis. We detected stress-induced induction of heme oxygenase (HO)-1 in fibroblasts but not in myofibroblasts following curcumin exposure. Instead, myofibroblasts expressed higher levels of heat shock protein (HSP)72 compared to fibroblasts in response to curcumin, suggesting that TGF-beta1 treatment alters the stress-responses of the cells. However, we did not detect any differences in curcumin toxicity between the two populations. The differential stress responses in fibroblasts and myofibroblasts may open new therapeutic approaches to reduce myofibroblasts and scarring. PMID- 25447315 TI - Cycling with BRCA2 from DNA repair to mitosis. AB - Genetic integrity in proliferating cells is guaranteed by the harmony of DNA replication, appropriate DNA repair, and segregation of the duplicated genome. Breast cancer susceptibility gene BRCA2 is a unique tumor suppressor that is involved in all three processes. Hence, it is critical in genome maintenance. The functions of BRCA2 in DNA repair and homology-directed recombination (HDR) have been reviewed numerous times. Here, I will briefly go through the functions of BRCA2 in HDR and focus on the emerging roles of BRCA2 in telomere homeostasis and mitosis, then discuss how BRCA2 exerts distinct functions in a cell-cycle specific manner in the maintenance of genomic integrity. PMID- 25447317 TI - Cell interactions and cell signaling during hematopoietic development. AB - Hematopoiesis is a key process that leads to the formation of all blood cell lineages from a specialized, multipotent cell, named the hematopoietic stem cell(HSC). During development, the embryo produces several waves of hematopoiesis that produce specialized subsets of hemato- poietic cells. Tissue interactions and cell signaling play an essential role in developmental hematopoiesis by allowing the formation of hematopoietic and endothelial cells(ECs) from the mesoderm particularly in the yolksac and by instructing the different generations of hemato- poietic cells (HCs). The embryonic aortais another site where intissue interaction is essential for the production of the first HSCs that is achieved from a specialized subset of hemogenic endothelial cells. This production is tightly time-and space-controlled with the transcription factor Runx1 and the Notch signaling path way playing a key role in this process and the surrounding tissues controlling the aortics hape and fate. Here we shall briefly review how hemogenic EC differentiates from the mesoderm, how the different aortic components as semble coordinately to establish the dorso-ventral polarity resulting in the initiation of Runx1 expression in hemogenic EC and the initiation of the hematopoietic program through modulation of the Notch-Runx1 axis. These data should help elucidate the first steps in HSC commitment and bring further insights into the manipulation of adult HSCs. PMID- 25447319 TI - Binary behaviour of an oxidation-responsive MRI nano contrast agent. AB - A new nano contrast agent has been prepared incorporating a molecular magnet in oxidation-responsive nanoparticles; this system has shown a remarkable sensitivity to hydrogen peroxide (detection down to at least 40 MUM), which was used as a model reactive oxygen species. Surprisingly, the response had a binary (off/on) character, due to a non-linear cascade relation between extent of oxidation and water permeability in the particles. PMID- 25447318 TI - Cell signaling pathways involved in hematopoietic stem cell specification. PMID- 25447320 TI - Pre-administration of curcumin prevents neonatal sevoflurane exposure-induced neurobehavioral abnormalities in mice. AB - Sevoflurane, a commonly used inhaled anesthetic, can induce neuronal apoptosis in the developing rodent brain and correlate with functional neurological impairment later in life. However, the mechanisms underlying these deleterious effects of sevoflurane remain unclear and no effective treatment is currently available. Herein, the authors investigated whether curcumin can prevent the sevoflurane anesthesia-induced cognitive impairment in mice. Six-day-old C57BL/6 mice were exposed to 3% sevoflurane 2h daily for 3 consecutive days and were treated with curcumin at the dose of 20 mg/kg or vehicle 30 min before the sevoflurane anesthesia from postnatal days 6 (P6) to P8. Cognitive functions were evaluated by open field, Morris water maze, and fear conditioning tests on P61, P63-69, and P77-78, respectively. In another separate experiment, mice were killed on day P8 or P78, and the brain tissues were harvested and then subjected to biochemistry studies. Our results showed that repeated neonatal sevoflurane exposure led to significant cognitive impairment later in life, which was associated with increased neuronal apoptosis, neuroinflammation, oxidative nitrosative stress, and decreased memory related proteins. By contrast, pre-administration of curcumin ameliorated early neuronal apoptosis, neuroinflammation, oxidative nitrosative stress, memory related proteins, and later cognitive dysfunction. In conclusion, our data suggested that curcumin pre-administration can prevent the sevoflurane exposure-induced cognitive impairment later in life, which may be partly attributed to its ability to attenuate the neural apoptosis, inflammation, and oxidative nitrosative stress in mouse brain. PMID- 25447321 TI - Synaptic degeneration in rat brain after prolonged oral exposure to silver nanoparticles. AB - Neurotoxicity of silver nanoparticles has been confirmed in both in vitro and in vivo studies. However, the mechanisms of the toxic action have not been fully clarified. Since nanoparticles are likely to have the ability to enter the brain and significantly accumulate in this organ, it is important to investigate their neurotoxic mechanisms. Here we examine the effect of prolonged exposure of rats to small (10nm) citrate-stabilized silver nanoparticles (as opposed to the ionic silver) on synapse ultrastructure and specific proteins. Administration of both nanosilver and ionic silver over a two-week period resulted in ultrastructural changes including blurred synapse structure and strongly enhanced density of synaptic vesicles clustering in the center of the presynaptic part. Disturbed synaptic membrane leading to liberation of synaptic vesicles into neuropil, which testifies for strong synaptic degeneration, was characteristic feature observed under AgNPs exposure. Also a noteworthy finding was the presence of myelin-like structures derived from fragmented membranes and organelles which are associated with neurodegenerative processes. Additionally, we observed significantly decreased levels of the presynaptic proteins synapsin I and synaptophysin, as well as PSD-95 protein which is an indicator of postsynaptic densities. The present study demonstrates that exposure of adult rats to both forms of silver leads to ultrastructural changes in synapses. However, it seems that small AgNPs lead to more severe synaptic degeneration, mainly in the hippocampal region of brain. The observations may indicate impairment of nerve function and, in the case of hippocampus, may predict impairment of cognitive processes. PMID- 25447322 TI - Inhibition of hippocampal estrogen synthesis by reactive microglia leads to down regulation of synaptic protein expression. AB - Activation of microglia may facilitate age-related impairment in cognitive functions including hippocampal-dependent memory. Considerable evidence indicates that hippocampal-derived estrogen improves hippocampal-dependent learning and memory. We hypothesize that activated microglia may inhibit de novo hippocampal estrogen synthesis and in turn suppress hippocampal synaptic protein expression. The present study aimed to elucidate the role of lipopolysaccharide (LPS) activated microglial HAPI cells on estrogen synthesis and expression of synaptic proteins using H19-7 hippocampal neurons with a neuron-microglia co-culture system. LPS induced expression of the microglial activation markers major histocompatibility complex II (MHC II), CD11b, and ionized calcium-binding adapter molecule 1 (Iba1). Prolonged LPS exposure also enhanced the secretion of interleukin (IL)-6 and nitric oxide (NO) from microglial HAPI cells. Exposure to either LPS-activated microglia or IL-6, significantly suppressed the expression of synaptic proteins and the secretion of de novo hippocampal estrogen in H19-7 hippocampal neurons. In addition, LPS-activated microglia also decreased the expression of estrogen receptors (ERalpha and ERbeta) in H19-7 hippocampal neurons. Our findings demonstrate a potential mechanism of microglia activation underlying the reduction in estrogen-mediated signaling on synaptic proteins in hippocampal neurons, which may be involved in hippocampal-dependent memory formation. PMID- 25447323 TI - Unveiling the role of the pesticides paraquat and rotenone on alpha-synuclein fibrillation in vitro. AB - Epidemiological data have suggested that exposure to environmental toxins might be associated with the etiology of Parkinson's disease (PD). In this context, certain agrochemicals are able to induce Parkinsonism in different animal models via the inhibition of mitochondrial complex I, which leads to an increase in both oxidative stress and the death of nigrostriatal neurons. Additionally, in vitro experiments have indicated that pesticides are capable of accelerating the fibrillation of the presynaptic protein alpha-synuclein (aS) by binding directly to the protein. However, the molecular details of these interactions are poorly understood. In the present work we demonstrate that paraquat and rotenone, two agrochemicals that lead to a Parkinsonian phenotype in vivo, bind to aS via solvent effects rather than through specific interactions. In fact, these compounds produced no significant effects on aS fibrillation under physiological concentrations of NaCl. NMR data suggest that paraquat interacts with the C terminal domain of the disordered aS monomer. This interaction was markedly reduced in the presence of NaCl, presumably due to the disruption of electrostatic interactions between the protein and paraquat. Interestingly, the effects produced by short-term incubation of paraquat with aS on the protein conformation resembled those produced by incubating the protein with NaCl alone. Taken together, our data indicate that the effects of these agrochemicals on PD cannot be explained via direct interactions with aS, reinforcing the idea that the role of these compounds in PD is limited to the inhibition of mitochondrial complex I and/or the up-regulation of aS. PMID- 25447324 TI - The role of parkin in the differential susceptibility of tuberoinfundibular and nigrostriatal dopamine neurons to acute toxicant exposure. AB - Parkinson disease causes degeneration of nigrostriatal dopamine (DA) neurons, while tuberoinfundibular DA neurons remain unaffected. A similar pattern is observed following exposure to 1-methy-4-phenyl-1,2,3,6-tetrahydropyradine (MPTP). The mechanism of tuberoinfundibular neuronal recovery from MPTP is associated with up-regulation of parkin protein. Here we tested if parkin mediates tuberoinfundibular neuronal recovery from MPTP by knocking-down parkin in tuberoinfundibular neurons using recombinant adeno-associated virus (rAAV), expressing a short hairpin RNA (shRNA) directed toward parkin. Following knockdown, axon terminal DA and tyrosine hydroxylase (TH) concentrations were analyzed 24h post-MPTP administration. rAAV-shRNA-mediated knockdown of endogenous parkin rendered tuberoinfundibular neurons susceptible to MPTP induced terminal DA loss, but not TH loss, within 24h post-MPTP. To determine if the neuroprotective benefits of parkin up-regulation could be translated to nigrostriatal neurons, rAAV expressing human parkin was injected into the substantia nigra of mice and axon terminal DA and TH concentrations were analyzed 24h post-MPTP. Nigral parkin over-expression prevented loss of TH in the axon terminals and soma of nigrostriatal neurons, but had no effect on terminal DA loss within 24h post-MPTP. These data show that parkin is necessary for the recovery of terminal DA concentrations within tuberoinfundibular neurons following acute MPTP administration, and parkin can rescue MPTP-induced decreases in TH within nigrostriatal neurons. PMID- 25447327 TI - Neonatal sensitization to ethanol-induced breathing disruptions as a function of late prenatal exposure to the drug in the rat: modulatory effects of ethanol's chemosensory cues. AB - Preclinical and clinical studies have systematically demonstrated abrupt changes in fetal respiratory patterns when the unborn organism is exposed to the effects of maternal ethanol intoxication. In subprimates, chronic exposure to this drug during gestation and infancy results in marked alterations of the plasticity of the respiratory network. These alterations are manifested in terms of an early incapability to overcome deleterious effects of hypoxic events as well as in terms of sensitization to ethanol's depressant effects upon breathing patterns. It has also been demonstrated that near term rat fetuses process ethanol's chemosensory cues when the drug contaminates the amniotic fluid and that associative learning processes occur due to the temporal contiguity existing between these cues and different ethanol-related physiological effects. In the present study during the course of late gestation (gestational days 17-20), pregnant rats were intragastrically administered with either 0.0 or 2.0 g/kg ethanol. Seven-day-old pups derived of these dams were evaluated in terms of respiration rates (breaths/min) and apneas when subjected to different experimental conditions. These conditions were defined by postnatal exposure to the drug (intragastric administrations of either 0.0, 0.5, 1.0 or 2.0 g/kg ethanol), postadministration time of evaluation (5-10 or 30-35 min) and olfactory context at test (no explicit ambient odor or ethanol ambient odor). The results, obtained via whole body plethysmography, indicated that brief prenatal experience with the drug sensitized the organisms to ethanol's depressant effects particularly when employing the higher ethanol doses. In turn, presence of ethanol odor at test potentiated the above mentioned respiratory alterations. Prenatal treatment with ethanol was not found to alter pharmacokinetic profiles resulting from postnatal exposure to the drug or to affect different morphometric parameters related with lung development. These results indicate that even brief exposure to the drug during late gestation is sufficient to sensitize the organism to later disruptive effects of the drug upon breathing responsiveness. These deficits are potentiated through the re-exposure to the olfactory context perceived in utero which is known to be associated with ethanol's unconditioned effects. As a function of these observations it is possible to suggest a critical role of fetal sensory and learning capabilities in terms of modulating later ethanol-related breathing disruptions. PMID- 25447325 TI - The cannabinoid receptor antagonist AM251 increases paraoxon and chlorpyrifos oxon toxicity in rats. AB - Organophosphorus anticholinesterases (OPs) elicit acute toxicity by inhibiting acetylcholinesterase (AChE), leading to acetylcholine accumulation and overstimulation of cholinergic receptors. Endocannabinoids (eCBs, e.g., arachidonoyl ethanolamide [AEA] and 2-arachidonoyl glycerol [2-AG]) are neuromodulators that regulate neurotransmission by reducing neurotransmitter release. The eCBs are degraded by the enzymes fatty acid amide hydrolase (FAAH, primarily involved in hydrolysis of AEA) and monoacylglycerol lipase (MAGL, primarily responsible for metabolism of 2-AG). We previously reported that the cannabinoid receptor agonist WIN 55,212-2 reduced cholinergic toxicity after paraoxon exposure. This study compared the effects of the cannabinoid receptor antagonist AM251 on acute toxicity following either paraoxon (PO) or chlorpyrifos oxon (CPO). CPO was more potent in vitro than PO at inhibiting AChE (~ 2 fold), FAAH (~ 8 fold), and MAGL (~ 19 fold). Rats were treated with vehicle, PO (0.3 and 0.6 mg/kg, sc) or CPO (6 and 12 mg/kg, sc) and subsets treated with AM251 (3mg/kg, ip; 30 min after OP). Signs of toxicity were recorded for 4h and rats were then sacrificed. OP-treated rats showed dose-related involuntary movements, with AM251 increasing signs of toxicity with the lower dosages. PO and CPO elicited excessive secretions, but AM251 had no apparent effect with either OP. Lethality was increased by AM251 with the higher dosage of PO, but no lethality was noted with either dosage of CPO, with or without AM251. Both OPs caused extensive inhibition of hippocampal AChE and FAAH (>80-90%), but only CPO inhibited MAGL (37-50%). These results provide further evidence that eCB signaling can influence acute OP toxicity. The selective in vivo inhibition of MAGL by CPO may be important in the differential lethality noted between PO and CPO with AM251 co-administration. PMID- 25447326 TI - Update on ankylosing spondylitis: current concepts in pathogenesis. AB - Ankylosing spondylitis is an insidiously progressive and debilitating form of arthritis involving the axial skeleton. The long delay in diagnosis and insufficient response to currently available therapeutics both advocate for a greater understanding of disease pathogenesis. Genome-wide association studies of this highly genetic disease have implicated specific immune pathways, including the interleukin (IL)-17/IL-23 pathway, control of nuclear factor kappa B (NF kappaB) activation, amino acid trimming for major histocompatibility complex (MHC) antigen presentation, and other genes controlling CD8 and CD4 T cell subsets. The relevance of these pathways has borne out in animal and human subject studies, in particular, the response to novel therapeutic agents. Genetics and the findings of autoantibodies in ankylosing spondylitis revisit the question of autoimmune vs. autoinflammatory etiology. As environmental partners to genetics, recent attention has focused on the roles of microbiota and biomechanical stress in initiating and perpetuating inflammation. Herein, we review these current developments in the investigation of ankylosing spondylitis pathogenesis. PMID- 25447328 TI - Cortisol and pain-related behavior in disbudded goat kids with and without cornual nerve block. AB - Plasma cortisol and behavior were measured in disbudded goat kids with and without the use of cornual nerve block. A total of 45 kids were used in 5 experimental groups (n=9, males and females). Group LidoD was infiltrated with 1 mL of 2% lidocaine locally at the cornual branches of lacrimal and infratrochlear nerves, 15 min before thermal disbudding. Group Lido was similarly infiltrated and was not disbudded. In group Sim, the disbudding procedure was simulated. A control group (CD) was disbudded without lidocaine infiltration, and group SD was infiltrated with saline before disbudding. The cornual nerve block did not prevent the short-term increase in cortisol levels during and after disbudding. LidoD, CD and SD groups showed higher cortisol concentrations than Lido and Sim (p<0.05) during the first 20 min after the procedure. Frequency of vocalizations during the procedure was significantly different between groups and was higher in SD (29.6 +/- 3.1; mean+/-SE) and CD (28.4 +/- 3.1) than in Sim (16.6 +/- 3.1; p<0.05). Infiltrating lidocaine did not decrease this response to disbudding (21.1 +/- 3.1; p>0.05). Struggles tended to be higher in SD (16.5 +/- 2.5), CD (17.8 +/- 2.5) and LidoD (15.6 +/- 2.5) than Sim (10.6 +/- 2.5; p=0.1). The total behavioral response was different between groups (CD, 59.6 +/- 6.8; LidoD, 52 +/- 6.8; SD, 62.6 +/- 6.8; Sim, 36.8 +/- 6.8; p=0.05), and disbudded animals showed the strongest reactions (disbudded, 58.1 +/- 3.9 vs non-disbudded, 36.8 +/- 6.8; p=0.01). It was concluded that cornual nerve block (lacrimal and infratrochlear) using 2% lidocaine did not prevent pain during thermal disbudding of goat kids. PMID- 25447329 TI - Evaluation of physical and emotional responses to vibrotactile stimulation of the forearm in young adults, the elderly, and transradial amputees. AB - Vibrotactile stimulation (VS) is widely used in the biomedical and biomechanics fields. Most studies have attempted to verify the effects and/or function of VS, but few studies have evaluated emotional response (ER) to VS, although emotions play a critical role in human behavior. This study aimed to evaluate the subjective response (SR) to VS in young, elderly, and amputee adults and to verify whether VS on the forearm evokes displeasure. Twenty-four young adults (YM: male 13, YF: female 11), 31 elderly subjects (EM: male 15, EF: female 16), and 19 transradial amputees (AM: male 11, AF: female 8) participated. Eight equally spaced vibration motors were attached around the circumference of the forearm (channels 1-4 on the lateral site and channels 5-8 on the medial site) and were located 25% of the proximal forearm. Vibration stimuli with frequencies ranging from 37Hz to 258Hz were applied. An SR 10-level test and ER (displeasure or not) test were performed. In all 3 groups, SRs to the lateral site were higher than those to the medial site (YM group, p<0.001; YF group, p=0.002; EM group, p<0.001; EF group, p=0.031; AM group, p<0.001; AF group, p=0.021). Additionally, SRs were saturated at certain frequencies (YM group, 149Hz; YF and EM groups, 198Hz; EF and AM groups, 120Hz; AF group, 176Hz). Several subjects (YM group, 7; YF group, 4; EM group, 2; EF group, 6; AM group, 3; AF group, 1) expressed displeasure, and ERs were different according to sex, age, or amputation. As a result, the lateral site was more sensitive to VS than the medial site, regardless of sex, age, or amputation. Furthermore, VS may evoke displeasure. PMID- 25447330 TI - Intrauterine position as a predictor of postnatal growth and survival in the rabbit. AB - In mammals, body mass at birth is an important predictor of early postnatal growth and survival. Within litters, heavier young are more successful in competing for limited resources and show higher rates of growth and survival than their lighter sibs. In the present study, we investigated the contribution of two aspects of the intrauterine environment to within-litter differences in birth mass, growth and survival in the rabbit (Oryctolagus cuniculus): implantation site along the uterine horns and number of adjacent male fetuses. We used unilaterally ovariectomized mothers in order to infer relative sites of implantation from the birth order of pups from the single functional uterine horn. Pups from the extremities of the horn were significantly heavier at birth and weaning than their siblings from more central positions and had a higher probability of survival. The effect on body mass was still apparent 3 weeks after weaning in pups that had occupied positions at the ovarian end of the horn. The number of adjacent male fetuses did not affect individuals' growth or survival, and there were no differences between females and males. There were also no significant interactions between the different variables considered, indicating that the effects of implantation site on individuals' birth mass, growth and survival relative to littermates were independent of number of male neighbors, sex or litter size. Our study clearly demonstrates that in the rabbit, the site of implantation along the uterine horns is a major contributor to individual differences among littermates in early postnatal growth and survival. PMID- 25447331 TI - The effect of disgust on pain sensitivity. AB - Experiencing the emotion of disgust leads to delayed up-regulation of immune related functions, increased core-body temperature and reduced appetite. These changes parallel those of the acute phase response, which occurs when a pathogen is detected by the immune system. Here we examined whether a further predicted aspect of the acute phase response is evident following disgust induction, namely increased pain sensitivity. Participants attended a two-session experiment. On one session they experienced an emotion induction (being randomly assigned to either disgust, negative or positive groups) and on the other they received a neutral control induction. Before and after each induction, and at 15 and 30min post-induction, participants engaged in a cold-pressor task, rating pain intensity at 10s intervals for 90s on each occasion. Relative to neutral control and pre-test, average pain intensity decreased then increased across time following the disgust induction, with the reverse pattern in the negative and positive emotion inductions. These findings are the first to suggest that disgust may lead to an increase in pain sensitivity over a time course paralleling changes observed for core-body temperature and immune-related function, although the mechanisms underpinning these effects remain to be identified. PMID- 25447332 TI - Increased antidepressant sensitivity after prefrontal cortex glucocorticoid receptor gene deletion in mice. AB - Our laboratory has previously shown that antidepressants regulate glucocorticoid receptor (GR) expression in the prefrontal cortex (PFC). To determine if PFC GR are involved in antidepressant effects on behavior or hypothalamic-pituitary adrenocortical (HPA) axis activity, we treated floxed GR male mice with saline or 15 or 30 mg/kg/d imipramine after PFC injection of adeno-associated virus 2/9 vectors transducing expression of Cre recombinase, to knock-down GR (PFC-GRKD), or green fluorescent protein (PFC-GFP), to serve as a control. The pattern of virally transduced GR deletion, common to all imipramine treatment groups, included the infralimbic, prelimbic, and medial anterior cingulate cortex at its largest extent, but was confined to the prelimbic and anterior cingulate cortex at its smallest extent. PFC GR knock-down increased behavioral sensitivity to imipramine, with imipramine-treated PFC-GRKD but not PFC-GFP mice exhibiting significant decreases in depression-like immobility during forced swim. PFC GR deletion did not alter general locomotor activity. The 30 mg/kg dose of imipramine increased plasma corticosterone levels immediately after a 5-min forced swim, but PFC GR knock-down had no significant effect on plasma corticosterone under these experimental conditions. We conclude that PFC GR knock down, likely limited to the medial prelimbic and anterior cingulate cortices, can increase behavioral sensitivity to antidepressants. These findings indicate a novel role for PFC GR in influencing antidepressant response. PMID- 25447335 TI - Chronic renal insufficiency does not induce behavioral and cognitive alteration in rats. AB - In humans, chronic kidney disease (CKD) is associated with cognitive decline, increase in anxiety, or depression. The underlying mechanisms of these changes remain unclear. The aim of this study was to elucidate whether and how experimentally induced long-term CKD affects cognitive functions in rats. Thirty male Wistar rats underwent 5/6 nephrectomy (5/6 Nx), an established model of CKD, or sham surgery. Development of CKD was monitored using biochemical analyses and confirmed by renal histology. Behavioral tests of anxiety, depression and spatial behavior were performed before, and at 3 and 9 months after the surgery. CKD in 5/6 Nx rats was characterized by significant decrease of renal function, e.g., glomerular filtration rate, and progressive glomerulosclerosis, tubular atrophy, and interstitial fibrosis; and increased plasma uremic toxins. Mortality was higher in 5/6 Nx rats in comparison with controls. Compared to control group, the surviving 5/6 Nx rats presented similar general locomotor activity, depression traits, and spatial abilities (p=0.43, p=0.84, p=0.71, respectively). At 9 months, lower anxiety in the light-dark box test was observed in 5/6 Nx rats if compared with the control group (p=0.02). Despite the development of progressive CKD in 5/6 Nx rats, no expected behavioral changes were observed. Further experimental studies associating behavioral responses to severity of CKD are definitely needed to confirm the solely psychosocial aspect background of CKD associated cognitive impairment in humans. PMID- 25447334 TI - A pilot randomized trial of a cognitive reappraisal obesity prevention program. AB - BACKGROUND/OBJECTIVES: Evaluate a selective obesity prevention program promoting use of cognitive reappraisals to reduce reward region response and increase inhibitory region response to high-fat/high-sugar foods and reduce intake of fat and sugar to prevent blunted reward region response to intake of such foods. SUBJECTS/METHODS: Young adults at risk for future weight gain by virtue of weight concerns (N=148) were randomized to this new prevention program (Minding Health), an alternative prevention program promoting participant-driven gradual reductions in caloric intake and increases in physical activity (Healthy Weight), or an obesity education video control condition, completing assessments at pre-, post-, and 6-month follow-up. A subset of Minding Health and control participants completed an fMRI scan at pre- and post-assessing neural response to images of high-fat/sugar foods and to receipt and anticipated receipt of a high-fat/sugar food. RESULTS: Minding Health participants showed significantly greater reductions in body fat than controls and caloric intake from fat and sugar than Healthy Weight participants. Minding Health participants also showed greater activation of an inhibitory control region and reduced activation of an attention/expectation region in response to palatable food images relative to pretest and controls. However, Healthy Weight participants showed greater reductions in BMI and eating disorder symptoms than Minding Health participants. CONCLUSIONS: Although the Minding Health intervention produced some of the hypothesized effects, it did not produce lasting reductions in body fat or BMI and showed limited effects on neural responsivity, implying it will be vital to increase the efficacy of this new prevention program. PMID- 25447333 TI - Effect of anabolic implants on adrenal cortisol synthesis in feedlot beef cattle implanted early or late in the finishing phase. AB - Implantation of anabolic steroids to increase growth rate in beef cattle impacts adrenal glucocorticoid production. The mechanism by which combination androgen and estrogen implants reduce cortisol biosynthesis in heifers is not clear. The objective of this study was to identify whether pituitary or adrenal gene expression and liver enzyme activity may contribute to altered serum cortisol concentrations in heifers receiving a combination implant. On d 0 of a 122-d finishing phase, 187 predominantly Angus heifers (361 kg) approximately 14 months old were randomly assigned to one of three implant groups: (1) non-implanted control, (2) implanted at the beginning of the finishing phase (d 0; early implant) with a combination implant (200mg TBA+20mg E2; Revalor 200(r)), and (3) implanted during the late stage of the finishing phase (d 56; late implant) with Revalor 200(r). At d 56, body weight (BW) was greater (P<0.0001) for the early implanted heifers (456 +/- 1.9 kg) compared to 437 and 435 (+/- 1.8) kg for control and late implanted heifers, respectively. Final BW (d 122) was similar between both implanted groups and heavier than non-implanted controls (P<0.0001). Serum cortisol was similar among groups at d 0 (P=0.86) however, by d 28 heifers receiving the combination implant had reduced (P<0.05) serum cortisol concentrations (31.2 ng/mL) compared to controls (49.4 ng/mL) and late (48.2 ng/mL) groups. On d 84 cortisol was similar (P=0.75) among implanted heifers and was less (P<0.01) than non-implanted heifers. Expression of pituitary and adrenal genes involved in glucocorticoid synthesis was evaluated at d 28/29 or 84/85; however, despite decreased serum cortisol in implanted heifers, no change in mRNA expression was demonstrated. Liver CYP3A enzyme activity at d 28/29 was decreased 59% in early implanted heifers compared to control heifers (P=0.01). Additionally, at d 84/85 AKR1C activity was greatest (P=0.01) in control heifers compared to both implanted groups. Data suggest that components of hypothalamic pituitary-adrenal axis are influenced by exposure to exogenous hormones and this should be recognized when considering cortisol levels as a marker for stress response. PMID- 25447337 TI - Scaling of free-ranging primate energetics with body mass predicts low energy expenditure in humans. AB - Studies of how a mammal's daily energy expenditure scales with its body mass suggest that humans, whether Westerners, agro-pastoralists, or hunter-gatherers, all have much lower energy expenditures for their body mass than other mammals. However, non-human primates also differ from other mammals in several life history traits suggestive of low energy use. Judging by field metabolic rates of free-ranging strepsirhine and haplorhine primates with different lifestyle and body mass, estimated using doubly labeled water, primates have lower energy expenditure than other similar-sized eutherian mammals. Daily energy expenditure in humans fell along the regression line of non-human primates. The results suggest that thrifty energy use could be an ancient strategy of primates. Although physical activity is a major component of energy balance, our results suggest a need to revise the basis for establishing norms of energy expenditure in modern humans. PMID- 25447336 TI - Cocaine induces state-dependent learning of sexual conditioning in male Japanese quail. AB - State dependent learning effects have been widely studied in a variety of drugs of abuse. However, they have yet to be studied in relation to sexual motivation. The current study investigated state-dependent learning effects of cocaine in male Japanese quail (Coturnix japonica) using a sexual conditioning paradigm. Cocaine-induced state-dependent learning effects were investigated using a 2*2 factorial design with training state as one factor and test state as the other factor. During a 14-day training phase, male quail were injected once daily with 10mg/kg cocaine or saline and then placed in a test chamber after 15min. In the test chamber, sexual conditioning trials consisted of presentation of a light conditioned stimulus (CS) followed by sexual reinforcement. During the state dependent test, half of the birds received a shift in drug state from training to testing (Coc->Sal or Sal->Coc) while the other half remained in the same drug state (Coc->Coc or Sal->Sal). Results showed that male quail that were trained and tested in the same state (Coc->Coc or Sal->Sal) showed greater sexual conditioning than male quail that were trained and tested in different states (Sal->Coc) except when cocaine was administered chronically prior to the test (Coc->Sal). For the latter condition, sexual conditioning persisted from cocaine training to the saline test. The findings suggest that state dependent effects may alter sexual motivation and that repeated exposure to cocaine during sexual activity may increase sexual motivation which, in turn, may lead to high risk sexual activities. An alternative explanation for the findings is also discussed. PMID- 25447338 TI - Integrative physiological and behavioural responses to sudden cold-water immersion are similar in skilled and less-skilled swimmers. AB - We examined the initial physiological responses and subsequent capacity to swim following cold-water immersion. An ecologically-valid model was used whereby immersion was sudden (<2s) and participants had to actively remain afloat. Participants (15 skilled swimmers, 17 less-skilled swimmers) undertook four experimental test sessions: a physiological test and a swimming test in both cold (10 degrees C) water and temperate (27 degrees C) water in a swimming flume (temperature order counter-balanced). For physiological testing, measures of brain perfusion [flow velocity (MCAv, Doppler) and oxygenation (NIRS)] and cardiorespiratory function [ventilation parameters and end-tidal PCO2 (PETCO2)] were recorded whilst treading water for 150s. The swimming test involved treading water (150s) before swimming at 60% (up to 120s) and 90% (to intolerance) of pre determined maximum velocity. Multifactorial analysis revealed that swimming duration was influenced most heavily by water temperature, followed by respiratory variables and MCAv in the first 30s of immersion. The time course and severity of cold shock were similar in both groups (p=0.99), in terms of initial physiological changes (MCAv down ~20 +/- 11%, respiratory frequency increased to 58 +/- 18 breaths.min(-1), PETCO2 dropped to 12 +/- 9 mmHg). Treading water following cold-water immersion increased MCAv by 30% above resting values despite maintained cold-shock-induced hyperventilation. In comparison to temperate water, swimming capacity was also reduced similarly between groups in the cold (i.e., distance decreased by 34 +/- 26% skilled; 41 +/- 33% less-skilled, p=0.99). These integrative findings verify that sudden cold-water immersion followed by physical activity leads to similar physiological responses in humans when contrasting between skilled and less-skilled swimmers. PMID- 25447339 TI - Customized high-dose-rate brachytherapy using MRI planning for vaginal rhabdomyosarcoma. AB - PURPOSE: To report the technical aspects of customized high-dose-rate brachytherapy for vaginal rhabdomyosarcoma using MRI- and CT-based planning in a 20-month-old girl. METHODS AND MATERIALS: An impression of the vaginal cavity at the resection site was taken after adequate lubrication of the vagina with lidocaine jelly. The impression was processed in the dental laboratory to obtain an MRI-compatible device with three imbedded catheters 0.4 mm apart, assuring tumor coverage. An MRI- and CT-based simulation under anesthesia with the applicator in place were performed, and the images were registered for contouring and planning to deliver 40 Gy in 10 fractions daily. Dose to the ovaries was limited to a mean dose less than 4 Gy. Treatment was delivered daily under anesthesia with no acute complications. RESULTS: Brachytherapy using a customized applicator has many advantages over prefabricated vaginal cylinders for young girls. It allows greater dose distribution conformality with the possibility of contralateral vaginal wall sparing and more reproducible daily positioning. MRI based planning is mainly performed to facilitate delineation of the target volume and the ovaries, which are easily identified on MRI. CONCLUSIONS: The customized applicator offers many advantages of which treatment reproducibility, inherent MRI compatibility, and excellent dose distribution conformality. Our brachytherapy technique using MRI and CT scan planning allows precise tumor and normal tissues delineation resulting in excellent tumor coverage and normal tissues sparing. PMID- 25447340 TI - Measuring relief of dysphagia in locally advanced esophageal carcinoma patients submitted to high-dose-rate brachytherapy. AB - BACKGROUND AND PURPOSE: Esophageal neoplasm has a poor prognosis, and palliative care remains an important goal of treatment. The purpose of this study was to assess the ability of high-dose-rate brachytherapy (HDRB) to improve dysphagia in 115 patients treated at our institution. METHODS AND MATERIALS: Patients previously submitted to external beam radiotherapy that at least, 1 month after, presented with residual disease and persistent dysphagia, were given HDRB as palliative treatment. Patients with tumors extending to the level of cardia and those with cervical esophageal lesions were also eligible. HDRB consisted of three fractions of 500 cGy given weekly. Dysphagia was assessed using a food texture-based scale classified according to the type of food patients were able to swallow (absent, solid, pasty, or liquid). At the end of treatment, a single category shift in dysphagia classification was scored as +1 (e.g., liquid to pasty) or -1 (e.g., solid to pasty), and a dual-category shift was scored as +2 (e.g., liquid to solid) or -2 (e.g., absent to pasty). RESULTS: Most patients (51.1%) had improvement of dysphagia, and 55.3% of this group experienced one point improvement. Procedural complications included stricture (38.2%), bleeding (7%), and fistula (8.7%). In the present study, 13 patients with cervical esophageal lesions underwent HDRB without fistula formation. CONCLUSIONS: Esophageal HDRB effectively reduces dysphagia. Tumor location was not related to development of complications. PMID- 25447341 TI - A comparison of inverse optimization algorithms for HDR/PDR prostate brachytherapy treatment planning. AB - PURPOSE: Graphical optimization (GrO) is a common method for high-dose rate/pulsed-dose-rate (PDR) prostate brachytherapy treatment planning. New methods performing inverse optimization of the dose distribution have been developed over the past years. The purpose is to compare GrO and two established inverse methods, inverse planning simulated annealing (IPSA) and hybrid inverse treatment planning and optimization (HIPO), and one new method, enhanced geometric optimization-interactive inverse planning (EGO-IIP), in terms of speed and dose-volume histogram (DVH) parameters. METHODS AND MATERIALS: For 26 prostate cancer patients treated with a PDR brachytherapy boost, an experienced treatment planner optimized the dose distributions using four different methods: GrO, IPSA, HIPO, and EGO-IIP. Relevant DVH parameters (prostate-V100%, D90%, V150%; urethra-D(0.1cm3) and D(1.0cm3); rectum-D(0.1cm3) and D(2.0cm3); bladder D(2.0cm3)) were evaluated and their compliance to the constraints. Treatment planning time was also recorded. RESULTS: All inverse methods resulted in shorter planning time (mean, 4-6.7 min), as compared with GrO (mean, 7.6 min). In terms of DVH parameters, none of the inverse methods outperformed the others. However, all inverse methods improved on compliance to the planning constraints as compared with GrO. On average, EGO-IIP and GrO resulted in highest D90%, and the IPSA plans resulted in lowest bladder D2.0cm3 and urethra D(1.0cm3). CONCLUSIONS: Inverse planning methods decrease planning time as compared with GrO for PDR/high dose-rate prostate brachytherapy. DVH parameters are comparable for all methods. PMID- 25447343 TI - Cyclooxygenase product inhibition with acetylsalicylic acid slows disease progression in the Han:SPRD-Cy rat model of polycystic kidney disease. AB - Renal cyclooxygenase (COX) derived eicosanoids are elevated and lipoxygenase (LOX) products are reduced in the Han:SPRD-Cy rat model of polycystic kidney disease (PKD). Selective COX2 inhibition reduces kidney disease progression, but COX1 levels also are elevated in this model. Since the effect of reducing the products of both COX isoforms and the role of LOX products is not known, weanling normal and diseased Han:SPRD-cy littermates were given either low dose acetylsalicylic acid (ASA), nordihydroguaiaretic (NDGA) or no treatment for eight weeks. Renal eicosanoids were altered in the diseased compared to normal cortex, with COX products being higher and LOX products being lower. ASA reduced COX products, cyst growth and kidney water content, while NDGA reduced LOX products without altering disease progression or kidney function. Hence, a human equivalent ASA dose equal to less than one regular strength aspirin per day slowed disease progression, while further reduction of LOX products did not worsen disease progression. PMID- 25447342 TI - Ethanol at low concentrations protects glomerular podocytes through alcohol dehydrogenase and 20-HETE. AB - Clinical studies suggest cardiovascular and renal benefits of ingesting small amounts of ethanol. Effects of ethanol, role of alcohol dehydrogenase (ADH) or of 20-hydroxyeicosatetraenoic acid (20-HETE) in podocytes of the glomerular filtration barrier have not been reported. We found that mouse podocytes at baseline generate 20-HETE and express ADH but not CYP2e1. Ethanol at high concentrations altered the actin cytoskeleton, induced CYP2e1, increased superoxide production and inhibited ADH gene expression. Ethanol at low concentrations upregulated the expression of ADH and CYP4a12a. 20-HETE, an arachidonic acid metabolite generated by CYP4a12a, blocked the ethanol-induced cytoskeletal derangement and superoxide generation. Ethanol at high concentration or ADH inhibitor increased glomerular albumin permeability in vitro. 20-HETE and its metabolite produced by ADH activity, 20-carboxy-arachidonic acid, protected the glomerular permeability barrier against an ADH inhibitor, puromycin or FSGS permeability factor. We conclude that ADH activity is required for glomerular function, 20-HETE is a physiological substrate of ADH in podocytes and that podocytes are useful biosensors to understand glomeruloprotective effects of ethanol. PMID- 25447345 TI - Effects of left ventricular assist device support on biomarkers of cardiovascular stress, fibrosis, fluid homeostasis, inflammation, and renal injury. AB - OBJECTIVES: The purpose of this study was to examine changes in a broad panel of biomarkers following left ventricular assist device (LVAD) support in advanced heart failure (HF). BACKGROUND: LVAD therapy mechanically unloads the failing heart and may result in reversal of certain aspects of the end-stage HF phenotype. Changes in markers of myocardial stress, fibrosis, inflammation, fluid homeostasis, and renal injury in this setting are unknown. METHODS: Amino terminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3, ST2, copeptin, growth differentiation factor (GDF)-15, C-reactive protein (CRP), and neutrophil gelatinase associated lipocalin (NGAL) levels were measured in frozen plasma collected from 37 individuals prior to continuous flow LVAD implantation and a median of 136 (interquartile range: 94 to 180) days after implantation. RESULTS: The median age of patients was 68 years old. LVAD therapy was associated with significant decreases in NT-proBNP (3,093 to 2,090 pg/ml; p = 0.02), ST2 (67.5 to 45.2 ng/ml, p <0.01), galectin-3 (24.7 to 22.0 ng/ml; p = 0.04), GDF-15 (3,232 to 2,613 ng/l;p <0.001), hs-CRP (22.4 to 11.9 mg/l; p = 0.01), and copeptin (103 to 94 pmol/l; p = 0.003) but not NGAL (132 to 135 ng/ml; p = 0.06). Despite improvement over time, absolute values of each biomarker remained extremely abnormal. Greater reductions in biomarkers were noted in individuals with >25% decrease in NT-proBNP concentrations but reached statistical significance only in the case of galectin-3 (p = 0.01). CONCLUSIONS: The biomarker profile in patients after LVAD placement improves but nonetheless remains significantly abnormal. Our results suggest the need for targeted therapeutic interventions to mitigate such abnormalities and potentially increase rates of myocardial recovery. PMID- 25447347 TI - Revisiting arrhythmic risk after alcohol septal ablation: is the pendulum finally swinging...back to myectomy? PMID- 25447346 TI - Long-term outcomes after medical and invasive treatment in patients with hypertrophic cardiomyopathy. AB - OBJECTIVES: The aim of this study was to determine the long-term outcomes (all cause mortality and sudden cardiac death [SCD]) after medical therapy, alcohol septal ablation (ASA), and myectomy in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: Therapy-resistant obstructive HCM can be treated both surgically and percutaneously. But there is no consensus on the long-term effects of ASA, especially on SCD. METHODS: This study included 1,047 consecutive patients with HCM (mean age 52 +/- 16 years, 61% men) from 3 tertiary referral centers. A total of 690 patients (66%) had left ventricular outflow tract gradients >= 30 mm Hg, of whom 124 (12%) were treated medically, 316 (30%) underwent ASA, and 250 (24%) underwent myectomy. Primary endpoints were all-cause mortality and SCD. Kaplan-Meier graphs and Cox regression models were used for statistical analyses. RESULTS: The mean follow-up period was 7.6 +/- 5.3 years. Ten-year survival was similar in medically treated patients (84%), ASA patients (82%), myectomy patients (85%), and patients with nonobstructive HCM (85%) (log rank p = 0.50). The annual rate of SCD was low after invasive therapy: 1.0%/year in the ASA group and 0.8%/year in the myectomy group. Multivariate analysis demonstrated that the risk for SCD was lower after myectomy compared with the ASA group (hazard ratio: 2.1; 95% confidence interval: 1.0 to 4.4; p = 0.04) and the medical group (hazard ratio: 2.3; 95% confidence interval: 1.0 to 5.2; p = 0.04). CONCLUSIONS: Patients with obstructive HCM who are treated at referral centers for HCM care have good survival and low SCD risk, similar to that of patients with nonobstructive HCM. The SCD risk of patients after myectomy was lower than after ASA or in the medical group. PMID- 25447349 TI - Cardiac rehabilitation in left ventricular assist device recipients: can it bolster the benefits of restored flow? PMID- 25447348 TI - Cardiac rehabilitation improves functional capacity and patient-reported health status in patients with continuous-flow left ventricular assist devices: the Rehab-VAD randomized controlled trial. AB - OBJECTIVES: This study examined the effects of a cardiac rehabilitation (CR) program on functional capacity and health status (HS) in patients with newly implanted left ventricular assist devices (LVADs). BACKGROUND: Reduced functional capacity and HS are independent predictors of mortality in patients with heart failure. CR improves both, and is related to improved outcomes in patients with heart failure; however, there is a paucity of data that describe the effects of CR in patients with LVADs. METHODS: Enrolled subjects (n = 26; 7 women; age 55 +/ 13 years; ejection fraction 21 +/- 8%) completed a symptom-limited cardiopulmonary exercise test, the Kansas City Cardiomyopathy Questionnaire (KCCQ), a 6-min walk test (6MW), and single-leg isokinetic strength test before 2:1 randomization to CR versus usual care. Subjects in the CR group underwent 18 visits of aerobic exercise at 60% to 80% of heart rate reserve. Within-group changes from baseline to follow-up were analyzed with a paired t-test, whereas an independent t-test was used to determine differences in the change between groups. RESULTS: Within-group improvements were observed in the CR group for peak oxygen uptake (10%), treadmill time (3.1 min), KCCQ score (14.4 points), 6MW distance (52.3 m), and leg strength (17%). Significant differences among groups were observed for KCCQ, leg strength, and total treadmill time. CONCLUSIONS: Indicators of functional capacity and HS are improved in patients with continuous flow LVADs who attend CR. Future trials should examine the mechanisms responsible for these improvements, and if such improvements translate into improved clinical outcomes. (Cardiac Rehabilitation in Patients With Continuous Flow Left Ventricular Assist Devices:Rehab VAD Trial [RehabVAD]; NCT01584895). PMID- 25447350 TI - The correlation between mid-brain serotonin transporter availability and intelligence quotient in healthy volunteers. AB - PURPOSE: This study was performed to investigate the association between the mid brain serotonin transporter (SERT) availability and intelligence quotient (IQ). METHODS: One hundred and thirteen healthy participants, including 52 male and 61 female subjects, were recruited. We used SPECT with [(123)I]ADAM images to determine the SERT availability in the mid-brain, and measured the subjects' IQ using the WAIS-R. RESULTS: We found a significant positive correlation between the mid-brain SERT availability and the IQ of the participants. Even when controlling for age and sex, the significant association still existed. CONCLUSION: This result implied that the higher the SERT binding in the mid brain, the better the IQ in healthy participants. PMID- 25447351 TI - SAFE Medication Management for Patients with Physical Impairments of Stroke, Part One. AB - PURPOSE: This article focuses on the extensive impairments of stroke and their influence on medication management. The impairments of motor skills due to paralysis-loss of mobility and balance, lack of hand-to-mouth coordination, and difficulty swallowing-are discussed. A future article will discuss sensory impairments of vision, hearing, cognition, comprehension, communication, and emotional disorders and how these impairments influence medication management. DESIGN: Each of the impairments are presented and discussed, and possible interventions are proposed. Every patient is an individual and requires variable care plans. METHOD: Intervention strategies that include tools for patient assessment, practice tips, and devices available to assist the patient and family in safe medication management are presented. FINDINGS: Patient outcomes and successes vary, but the strategies outlined will return the patient to as close to previous capabilities as possible. CONCLUSION AND CLINICAL RELEVANCE: Teaching SAFE (Systematic, Accurate, Functional, Effective) medication management to the patient, family, and caregivers will increase medication safety and decrease the number of adverse effects. The rehabilitation nurse is charged with evaluating the patients' needs and developing strategies to assist them to manage their medications. PMID- 25447352 TI - The ICD-10 Charlson Comorbidity Index predicted mortality but not resource utilization following hip fracture. AB - OBJECTIVES: To evaluate the performance of the Charlson Comorbidity Index (CCI) in the prediction of mortality, 30-day readmission, and length of stay (LOS) in a hip fracture population using algorithms designed for use in International Classification of Diseases, 10th Revision (ICD-10)--coded administrative data sets. STUDY DESIGN AND SETTING: Hospitalization and death data for 47,698 New South Wales residents aged 65 years and over, admitted for hip fracture, were linked. Comorbidities were ascertained using ICD-10 coding algorithms developed by Sundararajan (2004) and Quan (2005). Regression models were fitted, and area under the receiver operating curve (AUC) and Akaike information criterion were assessed. RESULTS: Both algorithms had acceptable discrimination in predicting in hospital (AUC, 0.72-0.76), 30-day (0.72-0.75), and 1-year mortality (0.69-0.75) but poor ability to predict 30-day readmission (0.54-0.57) or LOS (adjusted R(2), 0.007-0.045). The Quan algorithm provided better model fit than the Sundararajan algorithm. Models incorporating comorbidities as individual variables performed better than the Charlson weighted or updated Quan weighted score. Including a 1 year lookback period increased predictive ability for 1-year mortality only. CONCLUSION: The CCI is a valid tool for predicting mortality but not resource utilization after hip fracture. We recommend the use of the Quan algorithm rather than Sundararajan algorithm and to model individual conditions rather than categorized weighted scores. PMID- 25447353 TI - Tilting for perfusion: head-up position during cardiopulmonary resuscitation improves brain flow in a porcine model of cardiac arrest. AB - INTRODUCTION: Cerebral perfusion is compromised during cardiopulmonary resuscitation (CPR). We hypothesized that beneficial effects of gravity on the venous circulation during CPR performed in the head-up tilt (HUT) position would improve cerebral perfusion compared with supine or head-down tilt (HDT). METHODS: Twenty-two pigs were sedated, intubated, anesthetized, paralyzed and placed on a tilt table. After 6min of untreated ventricular fibrillation (VF) CPR was performed on 14 pigs for 3min with an automated CPR device called LUCAS (L) plus an impedance threshold device (ITD), followed by 5min of L-CPR+ITD at 0 degrees supine, 5min at 30 degrees HUT, and then 5min at 30 degrees HDT. Microspheres were used to measure organ blood flow in 8 pigs. L-CPR+ITD was performed on 8 additional pigs at 0 degrees , 20 degrees , 30 degrees , 40 degrees , and 50 degrees HUT. RESULTS: Coronary perfusion pressure was 19+/-2mmHg at 0 degrees vs. 30+/-3 at 30 degrees HUT (p<0.001) and 10+/-3 at 30 degrees HDT (p<0.001). Cerebral perfusion pressure was 19+/-3 at 0 degrees vs. 35+/-3 at 30 degrees HUT (p<0.001) and 4+/-4 at 30 degrees HDT (p<0.001). Brain-blood flow was 0.19+/ 0.04mlmin(-1)g(-1) at 0 degrees vs. 0.27+/-0.04 at 30 degrees HUT (p=0.01) and 0.14+/-0.06 at 30 degrees HDT (p=0.16). Heart blood flow was not significantly different between interventions. With 0, 10, 20, 30, 40 and 50 degrees HUT, ICP values were 21+/-2, 16+/-2, 10+/-2, 5+/-2, 0+/-2, -5+/-2 respectively, (p<0.001), CerPP increased linearly (p=0.001), and CPP remained constant. CONCLUSION: During CPR, HDT decreased brain flow whereas HUT significantly lowered ICP and improved cerebral perfusion. Further studies are warranted to explore this new resuscitation concept. PMID- 25447354 TI - Improving CPR measurement: are we there yet? PMID- 25447355 TI - Prehospital surface cooling is safe and can reduce time to target temperature after cardiac arrest. AB - PURPOSE: Mild therapeutic hypothermia proved to be beneficial when induced after cardiac arrest in humans. Prehospital cooling with i.v. fluids was associated with adverse side effects. Our primary objective was to compare time to target temperature of out-of hospital cardiac arrest patients cooled non-invasively either in the prehospital setting vs. the in-hospital (IH) setting, to assess surface-cooling safety profile and long term outcome. METHODS: In this retrospective, single center cohort study, a group of adult patients with restoration of spontaneous circulation (ROSC) after out-of hospital cardiac arrest were cooled with a surface cooling pad beginning either in the prehospital or IH setting for 24h. Time to target temperature (33.9 degrees C), temperature on admission, time to admission after ROSC and outcome were compared. Also, rearrests and pulmonary edema were assessed. Neurologic outcome at 12 months was evaluated (Cerebral Performance Category, CPC 1-2, favorable outcome). RESULTS: Between September 2005 and February 2010, 56 prehospital cooled patients and 54 IH-cooled patients were treated. Target temperature was reached in 85 (66-117)min (prehospital) and in 135 (102-192)min (IH) after ROSC (p<0.001). After prehospital cooling, hospital admission temperature was 35.2 (34.2-35.8) degrees C, and in the IH-cooling patients initial temperature was 35.8 (35.2-36.3) degrees C (p=0.001). No difference in numbers of rearrests and pulmonary edema between groups was observed. In both groups, no skin lesions were observed. Favorable outcome was reached in 26.8% (prehospital) and in 37.0% (IH) of the patients (p=0.17). CONCLUSIONS: Using a non-invasive prehospital surface cooling method after cardiac arrest, target temperature can be reached faster without any major complications than starting cooling IH. The effect of early non-invasive cooling on long-term outcome remains to be determined in larger studies. PMID- 25447357 TI - [Guidelines for clinical practice: " Pregnancy losses ". Introduction and legislation]. PMID- 25447356 TI - Understanding the shoot apical meristem regulation: a study of the phytohormones, auxin and cytokinin, in rice. AB - Auxin and cytokinin regulate different critical processes involved in plant growth and environmental feedbacks. These plant hormones act either synergistically or antagonistically to control the organisation, formation and maintenance of meristem. Meristem cells can be divided to generate new tissues and organs at the locations of plant postembryonic development. The aboveground plant organs are created by the shoot apical meristem (SAM). It has been proposed that the phytohormone, cytokinin, plays a positive role in the shoot meristem function, promotes cell expansion and promotes an increasing size of the meristem in Arabidopsis, whereas it has the reverse effects in the root apical meristem (RAM). Over the last few decades, it has been believed that the apically derived auxin suppresses the shoot branching by inactivating the axillary buds. However, it has recently become clear that the mechanism of action of auxinis indirect and multifaceted. In higher plants, the regulatory mechanisms of the SAM formation and organ separation are mostly unknown. This study reviews the effects and functions of cytokinin and auxin at the shoot apical meristem. This study also highlights the merger of the transcription factor activity with the actions of cytokinin/auxin and their complex interactions with the shoot meristem in rice. PMID- 25447358 TI - [Methods used to provide guidelines for clinical practice concerning the management of pregnancy losses]. PMID- 25447359 TI - [Definition of pregnancy losses: Standardization of terminology from the French National College of Obstetricians and Gynecologists (CNGOF)]. AB - OBJECTIVE: While a number of glossaries have been produced by various authorities in different countries, at present there is no internationally accepted common set of definitions for many terms used to describe pregnancy losses. The objective of the current study was to provide a standardized French/English terminology/glossary relating to pregnancy losses. METHODS: Literature review, construction of a glossary and rating of proposals using a formal consensus method. The glossary was subject of a critical comprehensive review by a meeting of professionals (multidisciplinary panel). RESULTS: A miscarriage is a spontaneous evacuation of an intra-uterine pregnancy<22WG. A missed early miscarriage is when ultrasound (<14WG) shows no growth of intra-uterine sac/embryo and/or loss of fetal heart activity. An early miscarriage is when spontaneous evacuation of intra-uterine pregnancy occurs <14WG. A complete early miscarriage is when there is no retained products of conception (empty uterus on ultrasound) and no bleeding nor pain. Incomplete early miscarriage is when ultrasonography shows retained products of conception in the uterine cavity (including cervical canal). Repeat miscarriage or recurrent pregnancy loss is when the woman experiences 3 or more consecutive miscarriages <14WG. A late miscarriage is when there is spontaneous evacuation of pregnancy >=14WG and <22WG. A threatened late miscarriage is when shortening/opening of the cervix+/ uterine contraction occur >=14WG and <22WG. An intra-uterine fetal demise is when there is a spontaneous loss of fetal heart activity >=14 WG. CONCLUSION: The final current terminology should be used by all healthcare professionals. PMID- 25447360 TI - [Epidemiology of loss pregnancy]. AB - OBJECTIVES: Study of epidemiology of pregnancy loss. MATERIALS AND METHOD: A systematic review of the literature was performed using Pubmed and the Cochrane library databases and the guidelines from main international societies. RESULTS: The occurrence of first trimester miscarriage is 12% of pregnancies and 25% of women. Miscarriage risk factors are ages of woman and man, body mass index greater than or equal to 25kg/m(2), excessive coffee drinking, smoking and alcohol consumption, exposure to magnetic fields and ionizing radiation, history of abortion, some fertility disorders and impaired ovarian reserve. Late miscarriage (LM) complicates less than 1% of pregnancies. Identified risk factors are maternal age, low level of education, living alone, history of previous miscarriage, of premature delivery and of previous termination of pregnancy, any uterine malformation, trachelectomy, existing bacterial vaginosis, amniocentesis, a shortened cervix and a dilated cervical os with prolapsed membranes. Fetal death in utero has a prevalence of 2% in the world and 5/1000 in France. Its main risk factors are detailed in the chapter. PMID- 25447361 TI - [French guidelines for diagnostic criteria for nonviable pregnancy early in the first trimester and for management of threatened miscarriage and nonviable pregnancy (except uterine evacuation)]. AB - OBJECTIVE: To assess value of sonography, hCG and progesterone for diagnosis of first trimester nonviable pregnancy and to assess first trimester miscarriage management (except evacuation). METHODS: French and English publications were searched using PubMed, Cochrane Library and international learned societies recommendations. RESULTS: First trimester nonviable pregnancy is established with gestational sac mean diameter and embryo crown-rump length. Mean sac diameter>=25mm without embryo (LE2) or embryo crown-rump length>=7mm without heartbeat (LE2) by transvaginal sonography allows to diagnose pregnancy failure. Intrauterine pregnancy of uncertain viability is defined by intra-uterine gestational sac without embryo with heartbeat or without pregnancy diagnosis failure and requires a new transvaginal sonography. The delay for this second sonography depends on the aspect of intrauterine picture (i.e. presence of yolk sac or not, presence of embryo or not) (LE4). Human chorionic gonadotropin (hCG) and progesterone are useful for pregnancy of unknown location (i.e. no gestational sac at transvaginal sonography): hCG ratio<15% between two-day serum samples when first hCG is<2000UI/mL (LE2) or low serum progesterone level (<3.2ng/mL) (LE2) exclude viable intrauterine pregnancy. There is not known prevention strategy for threatened miscarriage. PMID- 25447362 TI - [Obtaining of uterine vacuity in pregnancy loss]. AB - OBJECTIVE: To assess early and late benefits and harms of different management options for first trimester miscarriage and for induction of labor and obtaining of uterine vacuity in case of fetal death beyond of 14weeks of gestation. METHODS: French and English publications were searched using PubMed and Cochrane Library. RESULTS: Concerning missed miscarriage, expectant management is not recommended (LE1) because it increases the risk of failure, need of unplanned surgical procedure and blood transfusion (LE1). Surgical uterine evacuation remains more effective than medical treatment using misoprostol (LE1), but both techniques involve rare and comparable risks (EL1). When chosen, medical treatment should be a vaginal dose of 800MUg of misoprostol, possibly repeated 24 to 48hours later (EL2). Administration of mifepristone prior to misoprostol is not recommended (EL2). In case of incomplete miscarriage, expectant management can be offered because it does not increase the risk of complications, neither haemorrhagic nor infectious (EL1). Medical treatment using misoprostol is not recommended (EL2) because it does not improve the evacuation rate when compared to our first option, and does not reduce the risk of complications (EL2). Surgical uterine evacuation leads to high evacuation rate (97-98%) and low risk of complications, haemorrhagic and infectious (<5%) (EL1). However, this option should not be the only one because of the good efficiency of the expectant management (more than 75% of evacuation) and comparably low risk of complications (EL1). Surgical aspiration should be favoured to curettage because it is quicker, less painful and leads to less bleeding (EL2). After a first trimester miscarriage future fertility is identical with each treatment (EL2). When a trophoblastic retention is suspected, a diagnostic hysteroscopy is recommended (EL2). In case of late intrauterine foetal death beyond 14weeks of gestation and without a past caesarean section, the most efficient protocol seems to be vaginal administration of misoprostol 200 to 400MUg every 4 to 6hours (EL2). Twenty-four hours prior to misoprostol the administration of 200mg of mifepristone is recommended (EL3) because it improves the induction-expulsion time and diminishes the quantity of needed misoprostol (and so the complications linked to it) (EL3). PMID- 25447363 TI - [Early recurrent miscarriage: Evaluation and management]. AB - OBJECTIVE: To establish recommendations for early recurrent miscarriages (>=3 miscarriages before 14weeks of amenorrhea). MATERIALS AND METHODS: Literature review, establishing levels of evidence and recommendations for grades of clinical practice. RESULTS: Women evaluation includes the search for a diabetes (grade A), an antiphospholipid syndrome (APS) (grade A), a thyroid dysfunction (grade A), a hyperprolactinemia (grade B), a vitamin deficiency and a hyperhomocysteinemia (grade C), a uterine abnormality (grade C), an altered ovarian reserve (grade C), and a couple chromosome analysis (grade A). For unexplained early recurrent miscarriages, treatment includes folic acid and progesterone supplementation, and a reinsurance policy in the first quarter (grade C). It is recommended to prescribe the combination of aspirin and low molecular-weight heparin when APS (grade A), glycemic control in diabetes (grade A), L-Thyroxine in case of hypothyroidism (grade A) or the presence of thyroid antibodies (grade B), bromocriptine if hyperprolactinemia (grade B), a substitution for vitamin deficiency or hyperhomocysteinemia (grade C), sectionning a uterine septum (grade C) and treating an uterine acquired abnormality (grade C). CONCLUSION: These recommendations should improve the management of couples faced with early recurrent miscarriages. PMID- 25447364 TI - [Threatened late miscarriage. French guidelines]. AB - OBJECTIVES: To define guidelines for the management of women diagnosed with threatened late miscarriage (TLM). MATERIALS AND METHODS: A systematic review of the literature was performed using Pubmed and the Cochrane library databases and the guidelines from main international societies. RESULTS: Management of women diagnosed with threatened LM requires a complete history-taking searching for a previous history of LM and/or of premature delivery (Grade B). Speculum examination is required to diagnose membrane prolapse (Grade B) and vaginal ultrasound scan is recommended to measure the cervical length (Grade B). Finally, initial management should allow to rule out chorioamniotitis (Grade B). Vaginal progesterone therapy (90-200mg daily) is recommended for women diagnosed with a sole shortened cervix (<25mm) in mid-pregnancy (Grade A). Cerclage is only recommended in women with both history of previous premature delivery and/or previous LM and shortened cervical length diagnosed before 24 weeks of gestation (Grade A). Finally, cervical cerclage (Mc Donald technique) associated with systematic tocolytic therapy (indometacine) and antibiotics are to be recommended in women diagnosed with TLM with dilated cervical os eventually associated with membrane prolapse (GradeC). PMID- 25447365 TI - [Management of women with a previous late fetal loss (14 to 22weeks of gestation)]. AB - OBJECTIVE: To provide guidelines concerning management after a late fetal pregnancy loss: etiological assessment, follow-up and therapeutic management for subsequent pregnancy. METHODS: French and English publications led to guidelines. RESULTS: In case of a previous late fetal loss, exploration of cavity has to be done (grade C), except hysterosalpingography, which is not recommended (grade A). If uterine anomalies are found, it is recommended to correct them (grade C). In case of stillbirth or unknown foetal vitality before expulsion, antiphospholipid syndrome has to be looked for (grade A). In pregnant women, measurement of cervical length has to be done between 15 and 24weeks of gestation (grade B); in case of singleton pregnancy and short cervix (less than 25mm), a Mc Donald cerclage has to be done (grade A). A cerclage is also recommended in case of three previous fetal loss (grade B). In case of failure of a previous Mc Donald cerclage, a cervico-isthmic cerclage is recommended (grade C). CONCLUSION: In case of a previous fetal loss, uterine cavity has to be explored. In subsequent pregnancy, cervical length has to be evaluated between 15 and 24SA to indicate a cervical cerclage. PMID- 25447367 TI - High resolution neurography of the lumbosacral plexus on 3T magneteic resonance imaging. AB - Magnetic resonance neurography is a technique that complements clinical and electrophysiological study of the peripheral nerves and brachial and lumbosacral plexuses. Numerous focal processes (inflammatory, traumatic, primary tumors, secondary tumors) and diffuse processes (diabetic polyneuropathy, chronic idiopathic demyelinating polyneuropathy due to amyloidosis or Charcot-Marie-Tooth disease) can involve the lumbosacral plexus. This article reviews the anatomy of the lumbosacral plexus, describes the technique for neurography of the plexus at our institution, and shows the diverse diseases that affect it. PMID- 25447366 TI - [Chronic maternal diseases and pregnancy losses. French guidelines]. AB - AIM: To review the available data on maternal chronic diseases and pregnancy losses. MATERIAL AND METHODS: We searched PubMed and the Cochrane library with pregnancy loss, stillbirth, intrauterine fetal demise, intrauterine fetal death, miscarriage and each maternal diseases of this paper. RESULTS: Antiphospholipid antibodies (anticardiolipin, anti-beta-2-glycoprotein, lupus anticoagulant) should be measured in case of miscarriage after 10WG confirmed by ultrasound (grade B) and an antiphospholipid syndrome should be treated by a combination of aspirin and low-molecular-weight heparin during a subsequent pregnancy (grade A). We do not recommend testing for genetic thrombophilia in case of first trimester miscarriage (grade B) or stillbirth (grade C). Glycemic control should be a goal before pregnancy for women with pregestational diabetes to limit the risks of pregnancy loss (grade A) with a goal of prepregnancy HbA1c<7%. Overt and subclinical hypothyroidisms should be treated by L-thyroxin during pregnancy to reduce the risks of pregnancy loss (grade A). Women who are positive for TPOAb should have TSH concentrations follow-up during pregnancy and subsequently treated by L-thyroxin if they develop subclinical hypothyroidism (grade B). CONCLUSIONS: Prepregnancy management of most chronic maternal diseases, ideally through prepregnancy multidisciplinary counseling, reduces the risks of pregnancy loss. PMID- 25447368 TI - A practical introduction to the hemodynamic analysis of the cardiovascular system with 4D Flow MRI. AB - The 4D Flow MRI technique provides a three-dimensional representation of blood flow over time, making it possible to evaluate the hemodynamics of the cardiovascular system both qualitatively and quantitatively. In this article, we describe the application of the 4D Flow technique in a 3T scanner; in addition to the technical parameters, we discuss the advantages and limitations of the technique and its possible clinical applications. We used 4D Flow MRI to study different body areas (chest, abdomen, neck, and head) in 10 volunteers. We obtained 3D representations of the patterns of flow and quantitative hemodynamic measurements. The technique makes it possible to evaluate the pattern of blood flow in large and midsize vessels without the need for exogenous contrast agents. PMID- 25447369 TI - A successful program for training parent mentors to provide assistance with obtaining health insurance for uninsured children. AB - OBJECTIVE: Seven million US children lack health insurance. Community health workers are effective in insuring uninsured children, and parent mentors (PMs) in improving asthmatic children's outcomes. It is unknown, however, whether a training program can result in PMs acquiring knowledge/skills to insure uninsured children. The study aim was to determine whether a PM training program results in improved knowledge/skills regarding insuring uninsured minority children. METHODS: Minority parents in a primary-care clinic who already had Medicaid/Children's Health Insurance Program (CHIP)-covered children were selected as PMs, attending a 2-day training session addressing 9 topics. A 33 item pretraining test assessed knowledge/skills regarding Medicaid/CHIP, the application process, and medical homes. A 46-item posttest contained the same 33 pretest items (ordered differently) and 13 Likert-scale questions on training satisfaction. RESULTS: All 15 PMs were female and nonwhite, 60% were unemployed, and the mean annual income was $20,913. After training, overall test scores (0 100 scale) significantly increased, from a mean of 62 (range 39-82) to 88 (range 67-100) (P < .01), and the number of wrong answers decreased (mean reduction 8; P < .01). Significant improvements occurred in 6 of 9 topics, and 100% of PMs reported being very satisfied (86%) or satisfied (14%) with the training. Preliminary data indicate PMs are significantly more effective than traditional Medicaid/CHIP outreach/enrollment in insuring uninsured minority children. CONCLUSIONS: A PM training program resulted in significant improvements in knowledge and skills regarding outreach to and enrollment of uninsured, Medicaid/CHIP-eligible children, with high levels of satisfaction with the training. This PM training program might be a useful model for training Patient Protection and Affordable Care Act navigators. PMID- 25447370 TI - Your place or mine: shared sensory experiences elicit a remapping of peripersonal space. AB - Our perceptual systems integrate multisensory information about objects that are close to our bodies, which allow us to respond quickly and appropriately to potential threats, as well as act upon and manipulate useful tools. Intriguingly, the representation of this area close to our body, known as the multisensory 'peripersonal space' (PPS), can expand or contract during social interactions. However, it is not yet known how different social interactions can alter the representation of PPS. In particular, shared sensory experiences, such as those elicited by bodily illusions such as the enfacement illusion, can induce feelings of ownership over the other's body which has also been shown to increase the remapping of the other's sensory experiences onto our own bodies. The current study investigated whether such shared sensory experiences between two people induced by the enfacement illusion could alter the way PPS was represented, and whether this alteration could be best described as an expansion of one's own PPS towards the other or a remapping of the other's PPS onto one's own. An audio tactile integration task allowed us to measure the extent of the PPS before and after a shared sensory experience with a confederate. Our results showed a clear increase in audio-tactile integration in the space close to the confederate's body after the shared experience. Importantly, this increase did not extend across the space between participant and confederate, as would be expected if the participant's PPS had expanded. Thus, the pattern of results is more consistent with a partial remapping of the confederate's PPS onto the participant's own PPS. These results have important consequences for our understanding of interpersonal space during different kinds of social interactions. PMID- 25447371 TI - Neuronal bases of peripersonal and extrapersonal spaces, their plasticity and their dynamics: knowns and unknowns. AB - While space is perceived as unitary, experimental evidence indicates that the brain actually contains a modular representation of space, specific cortical regions being involved in the processing of extra-personal space, that is the space that is far away from the subject and that cannot be directly acted upon by the body, while other cortical regions process peripersonal space, that is the space that directly surrounds us and which we can act upon. In the present review, we focus on non-human primate research and we review the single cells, areal and cortical functional network mechanisms that are proposed to underlie extrapersonal and peripersonal space representations. Importantly, the current dominant framework for the study of peripersonal space is centered on the key notion that actions and specifically arm and hand-related actions, shape cortical peripersonal space representations. In the present review, we propose to enlarge this framework to include other variables that have the potential to shape peripersonal space representations, namely emotional and social information. In the initial section of the manuscript, we thus first provide an extensive up-to date review of the low level sensory and oculomotor signals that contribute to the construction of a core cortical far and near space representation, in key parietal, premotor and prefrontal periarcuate cortical regions. We then highlight the key functional properties that are needed to encode peripersonal space and we narrow down our discussion to the specific parietal and periarcuate areas that share these properties: the parieto-premotor peripersonal space network and the parieto-premotor network for grasping. Last, we review evidence for a changing peripersonal space representation. While plastic changes in peripersonal space representation have been described during tool use and their underlying neural bases have been well characterized, the description of dynamical changes in peripersonal space representation as a function of the emotional or social context is quite novel and relies on behavioral human studies. The neural bases of such a dynamic adjustments of peripersonal space coding are yet unknown. We thus review these novel observations and we discuss their putative underlying neural bases. PMID- 25447372 TI - Predictive coding accounts of shared representations in parieto-insular networks. AB - The discovery of mirror neurons in the ventral premotor cortex (area F5) and inferior parietal cortex (area PFG) in the macaque monkey brain has provided the physiological evidence for direct matching of the intrinsic motor representations of the self and the visual image of the actions of others. The existence of mirror neurons implies that the brain has mechanisms reflecting shared self and other action representations. This may further imply that the neural basis self body representations may also incorporate components that are shared with other body representations. It is likely that such a mechanism is also involved in predicting other's touch sensations and emotions. However, the neural basis of shared body representations has remained unclear. Here, we propose a neural basis of body representation of the self and of others in both human and non-human primates. We review a series of behavioral and physiological findings which together paint a picture that the systems underlying such shared representations require integration of conscious exteroception and interoception subserved by a cortical sensory-motor network involving parieto-inner perisylvian circuits (the ventral intraparietal area [VIP]/inferior parietal area [PFG]-secondary somatosensory cortex [SII]/posterior insular cortex [pIC]/anterior insular cortex [aIC]). Based on these findings, we propose a computational mechanism of the shared body representation in the predictive coding (PC) framework. Our mechanism proposes that processes emerging from generative models embedded in these specific neuronal circuits play a pivotal role in distinguishing a self-specific body representation from a shared one. The model successfully accounts for normal and abnormal shared body phenomena such as mirror-touch synesthesia and somatoparaphrenia. In addition, it generates a set of testable experimental predictions. PMID- 25447373 TI - Neural dissociation of automatic and controlled temporal preparation by transcranial magnetic stimulation. AB - Recent neuropsychological evidence suggested a role for the right prefrontal cortex in temporal orienting of attention guided by symbolic cues, and the left prefrontal cortex in preparation guided by rhythms. We tested this hypothesis by comparing the effects of 1-Hz repetitive transcranial magnetic stimulation (TMS) over prefrontal regions on the performances of two temporal preparation tasks, one using symbolic cues (short vs. long lines) and the other using regular rhythms (fast vs. slow pace) to indicate when (early vs. late) a target would be most likely to appear. Stimulation site was either the left dorsolateral prefrontal cortex (DLPFC), right DLPFC, or sham condition. The results showed that frontal TMS produced differential effects as a function of type of cuing. In symbolic cuing, TMS on either left or right frontal sites (vs. sham) increased temporal orienting effects by reducing reaction times in valid trials. In rhythmic cuing, however, frontal TMS did not influence performance. This dissociation between two forms of temporal preparation suggests a specific role for the DLPFC in the ability of temporal orienting, but not in preparation guided by rhythms. PMID- 25447374 TI - Integration of cognitive and affective networks in humor comprehension. AB - Humor comprehension is a complex process that requires the detection and resolution of the incongruity, eliciting a positive feeling of mirth or reward. We conducted a functional magnetic resonance imaging (fMRI) study to identify the key factors involved in this complex process. To reduce the influence of other factors, we utilized a group of sentences that were nearly identical across conditions (i.e., the first two sentences and the punch line were identical, but the third sentence was different). We found that the punch line (target sentence) in the funny condition induced a perception of funniness and elicited greater activation in language and semantic neural networks, which have been implicated in comprehension processing (i.e., incongruity detection and resolution). We also found increased activation in the mesolimbic reward regions, which have been implicated in the experience of positive rewards in the funny condition. Psycho physiological interaction analyses revealed that language and semantic regions, such as inferior frontal gyrus (IFG), middle temporal gyrus (MTG), superior temporal gyrus (STG), superior frontal gyrus (SFG), and inferior parietal lobule (IPL) are simultaneously activated during humor comprehension processing. These analyses also revealed that the right MTG, the left IPL, and IFG showed enhanced connectivity with the midbrain. Our findings suggest that these networks play a central role in incongruity detection and resolution, as well as in positive emotional response. PMID- 25447376 TI - Sleep facilitates learning a new linguistic rule. AB - Natural languages contain countless regularities. Extraction of these patterns is an essential component of language acquisition. Here we examined the hypothesis that memory processing during sleep contributes to this learning. We exposed participants to a hidden linguistic rule by presenting a large number of two-word phrases, each including a noun preceded by one of four novel words that functioned as an article (e.g., gi rhino). These novel words (ul, gi, ro and ne) were presented as obeying an explicit rule: two words signified that the noun referent was relatively near, and two that it was relatively far. Undisclosed to participants was the fact that the novel articles also predicted noun animacy, with two of the articles preceding animate referents and the other two preceding inanimate referents. Rule acquisition was tested implicitly using a task in which participants responded to each phrase according to whether the noun was animate or inanimate. Learning of the hidden rule was evident in slower responses to phrases that violated the rule. Responses were delayed regardless of whether rule knowledge was consciously accessible. Brain potentials provided additional confirmation of implicit and explicit rule-knowledge. An afternoon nap was interposed between two 20-min learning sessions. Participants who obtained greater amounts of both slow-wave and rapid-eye-movement sleep showed increased sensitivity to the hidden linguistic rule in the second session. We conclude that during sleep, reactivation of linguistic information linked with the rule was instrumental for stabilizing learning. The combination of slow-wave and rapid-eye movement sleep may synergistically facilitate the abstraction of complex patterns in linguistic input. PMID- 25447375 TI - Learning to read words in a new language shapes the neural organization of the prior languages. AB - Learning a new language entails interactions with one's prior language(s). Much research has shown how native language affects the cognitive and neural mechanisms of a new language, but little is known about whether and how learning a new language shapes the neural mechanisms of prior language(s). In two experiments in the current study, we used an artificial language training paradigm in combination with an fMRI to examine (1) the effects of different linguistic components (phonology and semantics) of a new language on the neural process of prior languages (i.e., native and second languages), and (2) whether such effects were modulated by the proficiency level in the new language. Results of Experiment 1 showed that when the training in a new language involved semantics (as opposed to only visual forms and phonology), neural activity during word reading in the native language (Chinese) was reduced in several reading related regions, including the left pars opercularis, pars triangularis, bilateral inferior temporal gyrus, fusiform gyrus, and inferior occipital gyrus. Results of Experiment 2 replicated the results of Experiment 1 and further found that semantic training also affected neural activity during word reading in the subjects' second language (English). Furthermore, we found that the effects of the new language were modulated by the subjects' proficiency level in the new language. These results provide critical imaging evidence for the influence of learning to read words in a new language on word reading in native and second languages. PMID- 25447377 TI - Losing track of time? Processing of time reference inflection in agrammatic and healthy speakers of German. AB - BACKGROUND: Individuals with agrammatic aphasia (IWAs) have problems with grammatical decoding of tense inflection. However, these difficulties depend on the time frame that the tense refers to. Verb morphology with reference to the past is more difficult than with reference to the non-past, because a link needs to be made to the past event in discourse, as captured in the PAst DIscourse LInking Hypothesis (PADILIH; Bastiaanse, R., Bamyaci, E., Hsu, C., Lee, J., Yarbay Duman, T., Thompson, C. K., 2011. Time reference in agrammatic aphasia: A cross-linguistic study. J. Neurolinguist. 24, 652-673). With respect to reference to the (non-discourse-linked) future, data so far indicate that IWAs experience less difficulties as compared to past time reference (Bastiaanse, R., Bamyaci, E., Hsu, C., Lee, J., Yarbay Duman, T., Thompson, C. K., 2011. Time reference in agrammatic aphasia: A cross-linguistic study. J. Neurolinguist. 24, 652-673), supporting the assumptions of the PADILIH. Previous online studies of time reference in aphasia used methods such as reaction times analysis (e.g., Faroqi Shah, Y., Dickey, M. W., 2009. On-line processing of tense and temporality in agrammatic aphasia. Brain Lang. 108, 97-111). So far, no such study used eye tracking, even though this technique can bring additional insights (Burchert, F., Hanne, S., Vasishth, S., 2013. Sentence comprehension disorders in aphasia: the concept of chance performance revisited. Aphasiology 27, 112-125, doi:10.1080/02687038.2012.730603). AIMS: This study investigated (1) whether processing of future and past time reference inflection differs between non-brain damaged individuals (NBDs) and IWAs, and (2) underlying mechanisms of time reference comprehension failure by IWAs. METHODS AND PROCEDURES: A visual-world experiment combining sentence-picture matching and eye-tracking was administered to 12 NBDs and 6 IWAs, all native speakers of German. Participants heard German sentences with periphrastic future ('will+V') or periphrastic past ('has+V-d') verb forms while they were presented with corresponding pictures on a computer screen. RESULTS AND DISCUSSION: NBDs scored at ceiling and significantly higher than the IWAs. IWAs had below-ceiling performance on the future condition, and both participant groups were faster to respond to the past than to the future condition. These differences are attributed to a pre-existing preference to look at a past picture, which has to be overcome. Eye movement patterns suggest that both groups interpret future time reference similarly, while IWAs show a delay relative to NBDs in interpreting past time reference inflection. The eye tracking results support the PADILIH, because processing reference to the past in discourse syntax requires additional resources and thus, is problematic and delayed for people with aphasia. PMID- 25447378 TI - Face configuration affects speech perception: Evidence from a McGurk mismatch negativity study. AB - We perceive identity, expression and speech from faces. While perception of identity and expression depends crucially on the configuration of facial features it is less clear whether this holds for visual speech perception. Facial configuration is poorly perceived for upside-down faces as demonstrated by the Thatcher illusion in which the orientation of the eyes and mouth with respect to the face is inverted (Thatcherization). This gives the face a grotesque appearance but this is only seen when the face is upright. Thatcherization can likewise disrupt visual speech perception but only when the face is upright indicating that facial configuration can be important for visual speech perception. This effect can propagate to auditory speech perception through audiovisual integration so that Thatcherization disrupts the McGurk illusion in which visual speech perception alters perception of an incongruent acoustic phoneme. This is known as the McThatcher effect. Here we show that the McThatcher effect is reflected in the McGurk mismatch negativity (MMN). The MMN is an event related potential elicited by a change in auditory perception. The McGurk-MMN can be elicited by a change in auditory perception due to the McGurk illusion without any change in the acoustic stimulus. We found that Thatcherization disrupted a strong McGurk illusion and a correspondingly strong McGurk-MMN only for upright faces. This confirms that facial configuration can be important for audiovisual speech perception. For inverted faces we found a weaker McGurk illusion but, surprisingly, no MMN. We also found no correlation between the strength of the McGurk illusion and the amplitude of the McGurk-MMN. We suggest that this may be due to a threshold effect so that a strong McGurk illusion is required to elicit the McGurk-MMN. PMID- 25447379 TI - Concise reviews: Characteristics and potential applications of human dental tissue-derived mesenchymal stem cells. AB - Recently, numerous types of human dental tissue-derived mesenchymal stem cells (MSCs) have been isolated and characterized, including dental pulp stem cells, stem cells from exfoliated deciduous teeth, periodontal ligament stem cells, dental follicle progenitor cells, alveolar bone-derived MSCs, stem cells from apical papilla, tooth germ progenitor cells, and gingival MSCs. All these MSC like cells exhibit self-renewal, multilineage differentiation potential, and immunomodulatory properties. Several studies have demonstrated the potential advantages of dental stem cell-based approaches for regenerative treatments and immunotherapies. This review outlines the properties of various dental MSC-like populations and the progress toward their use in regenerative therapy. Several dental stem cell banks worldwide are also introduced, with a view toward future clinical application. PMID- 25447381 TI - [In utero fetal death]. AB - OBJECTIVES: To give consistent data of the prevalence of intrauterine fetal death (IUFD), to assess risk factors and causes related to IUFD, to evaluate prevention of IUFD, to evaluate fetal autopsy and MRI and to determine the management of inhibition of lactation. METHODS: French and English publications were searched using PubMed, Cochrane Library. RESULTS: Intrauterine fetal death occurs in 2% of the pregnancies worldwide, and in around 0,5% of pregnancies in France (NP1). Major risk factors related to IUFD are maternal overweight, maternal age, and smoking, small for gestational age fetuses or placental abruption, and pre gestational maternal diseases such as hypertension and diabetes (NP1). The most relevant causes of IUFD are placental anomalies, followed by abnormal karyotypes and congenital malformations (NP3). Data are insufficient to recommend a classification for causes of IUFD. Data concerning primary and secondary prevention do not recommend a specific management for the following of pregnancy. Fetal autopsy is still the gold standard of fetal examination, but fetal post mortem MRI can be offered when fetal autopsy is refused (NP4). Inhibition of lactation should be started within 24hours postpartum with cabergoline, if the patient demands a treatment (NP4). PMID- 25447382 TI - [Psychology and pregnancy loss]. AB - OBJECTIVE: The objective of this study was to evaluate the relationship between psychology and pregnancy loss. METHODS: A literature review was conducted by consulting Medline until April 2014. RESULTS: Psychological factors appear to be significantly associated with the risk of recurrent miscarriage. Depression and anxiety are common symptoms after miscarriage. A return to normal scores of depression and anxiety is frequently found in one year. A systematic psychological treatment after an episode of miscarriage seems to not bring obvious benefits, one year after a miscarriage, in terms of anxiety and depression. After a stillbirth, psychological impacts on the couple, such as anxiety and depressive symptoms, are common. An empathetic and respectful attitude of all medical and paramedical team at the support is associated with better psychological experience. CONCLUSION: After a pregnancy loss, psychological consequences are common and usually reversible. An attitude of empathy is desirable in order to accompany patients and to consider a future pregnancy. PMID- 25447383 TI - [Pregnancy losses: Guidelines for clinical practice. Short text]. PMID- 25447384 TI - [Guidelines for clinical practice: "Post-partum haemorrhage". Introduction]. PMID- 25447385 TI - [Post-partum hemorrhage: Guidelines for clinical practice - Method and organization]. PMID- 25447386 TI - [Epidemiology of post-partum haemorrhage]. AB - OBJECTIVES: To synthesize the available evidence regarding the incidence, causes, risk factors of post-partum haemorrhage (PPH) and the associated maternal morbidity. METHODS: Consultation of the Medline database and of national reports on maternal mortality. RESULTS: PPH is defined as a post-partum blood loss>=500mL, and severe PPH as a post-partum blood loss>=1000mL, whatever the delivery route. In population-based studies, the incidence of PPH is around 5% of deliveries when blood loss is not precisely assessed and around 10% when it is. The incidence of severe PPH is around 2%. Uterine atony if the main cause of PPH. Maternal mortality due to obstetric haemorrhage has decreased in France (currently 1.6 death/100,000 live births) but remained the first cause of maternal death (16%) and the most avoidable (80%). In high-resource countries, PPH is the main cause of acute severe maternal morbidity, and of pregnancy related ICU admissions. In addition to the direct consequences of acute hypovolemia, PPH exposes the women to the complications of transfusion, of intensive care and to infertility in case of hysterectomy. The main risk factors for PPH are factors of uterine atony, but they are globally poorly predictive. CONCLUSION: PPH is the principal cause of severe maternal morbidity, most often due to uterine atony. Risk factors related to components of care during labor and delivery are amenable to change, and the assessment of their risks-benefits balance should take into account the associated risk of PPH. PMID- 25447388 TI - [Clinical and pharmacological procedures for the prevention of postpartum haemorrhage in the third stage of labor]. AB - OBJECTIVES: To describe the clinical and pharmacological procedures for the prevention of Postpartum Haemorrhage (PPH). MATERIALS AND METHODS: We searched the Medline and the Cochrane Library (1st December 2004 to 1st March 2014) and we checked the international guidelines. RESULTS: Vaginal birth: only the use of uterotonics reduces the incidence of PPH. Oxytocin is the treatment of choice if it is readily available (grade A). Oxytocin can be used either after the shoulders expulsion or rapidly after the placental delivery (grade B). A dose of 5 or 10IU must be administrated IV over at least 1minute or directly by an intramuscular injection (professional agreement) except in women with documented cardiovascular disease in which the duration of the IV perfusion should be over at least 5minutes (professional agreement). Mechanical procedures have no significant impact on PPH. The decision to use a collector bag is left to the medical team (professional agreement). A systematic complementary oxytocin perfusion is not recommended (professional agreement). Caesarean delivery: There is no evidence to recommend a particular type of caesarean technique to prevent PPH (professional agreement) but a lower uterine section is recommended (grade B). All types of incision expansion may be used (professional agreement). A controlled cord traction is associated with lower blood losses than manual removal of the placenta (grade B). A dose of 5 or 10IU can be injected (IV) over 1minute, and over 5minutes in women with cardiovascular disease (professional agreement). Carbetocin reduces the incidence of PPH but there is presently no inferiority study comparing oxytocin and carbetocin so that oxytocin remains the gold standard therapy to prevent PPH in C-section (professional agreement). PMID- 25447387 TI - [Antenatal management for patients with increased risk of post-partum hemorrhage (excluding abnormal placentation)]. AB - OBJECTIVES: To describe management and screening for high-risk patients concerning post-partum hemorrhage (PPH) and antenatal management for severe anemia, thrombopenia, bleeding disorders and anticoagulant therapy. METHODS: Bibliographic search restricted to French and English languages using Medline database and recommendations of medical societies. RESULTS: The appropriate place for delivery should be chosen after multidisciplinary concertation based on level of risk (especially past-history of severe PPH and bleeding disorder) and easy access to blood products (Professional Consensus). Prevention for severe anemia is mainly based on oral iron supplementation (grade B). Explorations are required in case of thrombopenia<100Giga/L (grade C). Patients with bleeding disorder require the assistance of a physician skilled in hemostasis for perinatal management (grade C). Preventive anticoagulant therapy has no impact on PPH risk and perimedullar analgesia is usually authorized 12hours after last injection (grade C). Curative anticoagulant therapy slightly increases PPH risk and perimedullar analgesia is authorized only after 24hours since last injection (Professional Consensus). CONCLUSION: Prenatal identification of high-risk patients concerning PPH implies multidisciplinary concertation to determine the most appropriate birthplace where technical and human resources are available. PMID- 25447389 TI - [Initial obstetrical management of post-partum hemorrhage following vaginal delivery]. AB - OBJECTIVES: To define initial steps of obstetrical treatment of post-partum hemorrhage (PPH) after vaginal delivery. MATERIALS AND METHOD: We searched the Medline and the Cochrane Library and checked the international guidelines: HAS, RCOG, SOGC, ACOG and WHO. RESULTS: In case of PPH, the use of a collecting bag is recommended (professional consensus). All the concerned professional (midwife, obstetrician, anesthesiology team) must be warned immediately (professional consensus). If placenta is retained, manual removal needs to be performed and after placental delivery, manual uterine exploration is recommended (professional consensus). At the same time, a dose of 5 or 10 IU of oxytocin must be administrated IV over at least 1minute or directly by an intramuscular injection followed by an infusion of 5 to 10 UI/h during 2hours (professional consensus). In some situations at risk of cervical and high vaginal laceration, the low genital tract needs to be carefully examined (professional consensus). Appropriate management of PPH has to be known by the concerned professional (professional consensus). Retrospective study of each case of PPH should be done (professional consensus). CONCLUSION: The PPH initial treatment involves a team work that, most of times, leads to stop the bleeding in least than 30minutes (professional consensus). PMID- 25447390 TI - [Anesthesiologists at the initial stage of postpartum hemorrhage]. AB - OBJECTIVES: To describe the best practices for management of postpartum hemorrhage (PPH) after vaginal delivery at its initial stage by anesthesiologists. METHODS: Medline, the Cochrane Library, and international guidelines have been exhaustively analyzed, graded, and discussed by the members of the scientific committee. RESULTS: Early recognition of PPH relies on either a perceived or a quantified blood loss of 500mL and over (using a collecting bag), or the presence of clinical signs of shock (hypotension, tachycardia, tachypnea, altered mental status) (professional consensus). Precise timing of the diagnosis of PPH must be annotated (professional consensus). Once the diagnosis is established, appropriate senior professionals, including the anesthesiologist at the early stage, must be called in. The cornerstones of initial resuscitation are restoration of blood volume and oxygen carrying capacity, achieved, with adequate intravenous access, initially with crystalloids, associated with oxygen by facemask (professional consensus). Initial resuscitation is performed, and its efficiency is assessed by continuous monitoring and hemoglobin bedside tests (Hemocue((r))). Adequate anesthetic technique must be performed to enable the obstetricians to perform a diagnostic procedure (manual removal of placenta, uterine revision), and to most frequently obtain the cessation of bleeding. Hemodynamic stability is required for loco-regional anesthesia, while on the other hand, general anesthesia with rapid sequence induction and intubation is recommended (professional consensus). Anesthesiologists must anticipate in case of failure of initial measures, including in alerting the blood transfusion service and calling for additional help (professional consensus). CONCLUSIONS: Adequate management of postpartum hemorrhage (PPH) requires multidisciplinary combined and simultaneous actions. After early recognition, five components are undertaken simultaneously: communication, resuscitation, monitoring, investigating the cause of bleeding, and controlling or stopping the bleeding. Bleeding is usually stopped within 30min in 70 to 80% of cases. PMID- 25447391 TI - [Management of severe or persistent postpartum hemorrhage after vaginal delivery]. AB - INTRODUCTION: This chapter is an update of the 2004 recommendations for the management of persistent or severe postpartum hemorrhage (PPH) after natural childbirth. Severe PPH is defined by estimated blood loss greater than 1000mL (gradeC). Persistent bleeding within 15 to 30minutes after diagnosis and initial treatment (gradeC) or abundant immediately (professional consensus) should lead to a further management. MATERIALS AND METHODS: A systematic review of the literature concerning the management of persistent or severe PPH was conducted on Medline and Cochrane Database, with no specified time period. RESULTS AND DISCUSSION: The initial clinical evaluation is the same whatever initial severity. Each possible cause of bleeding must be evaluated: uterine vacuity must be checked and birth canal lesions must be researched and repaired (gradeC). Sulprostone is effective for the treatment of severe or persistent PPH (EL4) and its use is recommended for the management of PPH resistant to oxytocin administration (grade B). In the current state of the literature, there is no argument for replacing sulprostone in France by dinoprostone or prostaglandins F2alpha (professional consensus). If oxytocin has been administered, it is not recommended to use misoprostol (EL1) as adjuvant treatment because there is no evidence of benefit in this indication (grade A). Balloon intra-uterine tamponade appears to be an efficient mechanical treatment of uterine atony in case of failure of the initial management by sulprostone. Tamponade allows avoiding the need for further interventional radiology or surgery in most cases (EL4). Intra uterine tamponade may be offered in case of failure of sulprostone and prior to surgical management or interventional radiology (professional consensus). Its use is left to the discretion of the practitioner. Tamponade should not delay the implementation of further invasive procedures. PMID- 25447392 TI - [Anesthetic management of severe or worsening postpartum hemorrhage]. AB - INTRODUCTION: Risk factors of maternal morbidity and mortality during postpartum hemorrhage (PPH) include non-optimal anesthetic management. As the anesthetic management of the initial phase is addressed elsewhere, the current chapter is dedicated to the management of severe PPH. METHODS: A literature search was performed using PubMed and Medline databases, and the Cochrane Library, for articles published from 2003 up to and including 2013. Several keywords related to anesthetic and critical care practice, and obstetrical management were used, in various combinations. Guidelines from several societies and organisations were also read. RESULTS: When PPH worsens, one should ask for additional team personnel (professional consensus). Patients should be monitored for heart rate, blood pressure, skin and mucosal pallor, bleeding at skin puncture sites, diuresis and the volume of genital bleeding (grade B). Because of the possible rapid worsening of coagulapathy, patients should undergo regular evaluation of coagulation status (professional consensus). Prevention and management of hypothermia should be considered (professional consensus), by warming intravenous fluids and blood products, and by active body warming (grade C). Antibiotics should be given, if not already administered at the initial phase (professional consensus). Vascular fluids must be given (grade B), the choice being left at the physician discretion. Blood products transfusion should be decided based on the clinical severity of PPH (professional consensus). Priority is given to red blood cells (RBC) transfusion, with the aim to maintain Hb concentration>8g/dL. The first round of products could include 3 units of RBC (professional consensus), and the following round 3 units of RBC, and 3 units of fresh frozen plasma (FFP). The FFP:RBC ratio should be kept between 1:2 and 1:1 (professional consensus). Depending on the etiology of PPH, the early administration of FFP is left at the discretion of the physician (professional consensus). Platelet count should be maintained at>50 G/L (professional consensus). During massive PPH, fibrinogen concentration should be maintained at>2g/L (professional consensus). Fibrinogen can be given without prior fibrinogen measurement in case of massive bleeding (professional consensus). General anesthesia should be considered in case of hemodynamic instability, even when an epidural catheter is in place (professional consensus). CONCLUSION: The anesthetic management aims to restore and maintain optimal respiratory state and circulation, to treat coagulation disorders, and to allow invasive obstetrical and radiologic procedures. Clinical and instrumental monitoring are needed to evaluate the severity of PPH, to guide the choice of therapeutic options, and to assess treatments efficacy. PMID- 25447394 TI - [Surgical treatment of postpartum hemorrhage]. AB - OBJECTIVE: Systematic revue of different conservative and non-conservative surgical treatment of postpartum hemorrhage (PPH). Elaboration of surgical strategy after failed medical treatment of PPH. METHODS: French and English publications were identified through PubMed and Cochrane databases. RESULTS: Each obstetrical unit has to rewrite a full protocol of management of PPH depending on local environment quickly available in theatre (professional consensus). Conservative surgical treatment of PPH: efficacy of vascular ligature (bilateral uterine artery ligation (BUAL) or bilateral hypogastric artery ligation (BHAL)) as a first line of surgical treatment of PPH is about 60 % to 70 % (EL4). Bilateral uterine artery ligation (BUAL) is easy to perform with low rate of immediate severe complication (professional consensus). BUAL as BHAL seems not to affected fertility and obstetrical outcomes of next pregnancies (EL4). Efficacy of haemostatics brace suturing in case of failed medical treatment of PPH is about 75 % (EL3), without risk of major obstetrical complications at the next pregnancy (EL4). Radical surgical treatment of PPH: total hysterectomy is not significantly associated with more urinary tract injury in comparison with subtotal hysterectomy (EL3). Choice of surgical procedure of hysterectomy (total or subtotal) will depend on local consideration and clinicians habits (professional consensus). Surgical strategy: conservative surgical treatment are efficient and associated with low morbidity, they have to be primarily performed in women with further fertility desire. Specific medical consideration as massive PPH or cardiovascular instability has to consider performing haemostatic hysterectomy as the first line surgical treatment of PPH. PPH during caesarean delivery: in case of PPH during caesarean section, embolisation is not recommended, surgical treatment using vascular devascularisation or compression brace suturing should be performed (professional consensus). Surgical conservative technique will depend on local considerations and clinicians habits (professional consensus). PPH diagnosed after caesarean section should indicate relaparotomy. Arterial embolisation, if quickly vacant in the same hospital, may be performed in case of cardiovascular stability without surgical complication diagnoses on intraperitoneal hemorrhage (professional consensus). PPH during vaginal delivery: cardiovascular instability centre indicate the interhospital transfer and must lead to achieve haemostatic surgery on site (professional consensus). In the presence of a unit of embolisation in the maternity delivery, it is preferable to move towards embolisation, if maternal hemodynamic status permits (professional consensus). In case of cardiovascular stability associated with absence of heavy bleeding, the interhospital transfer may be considered for arterial embolisation (professional consensus). CONCLUSION: When medical treatment of PPH failed, conservative surgical treatment has a 70 % efficacy to stop hemorrhage whatever treatment used (vascular ligature or haemostatics brace suturing). In absence of rapid response to conservative medical and surgical treatment, hysterectomy should be performed without delay (professional consensus). PMID- 25447393 TI - [Role of arterial embolization in the management of postpartum hemorrhage]. AB - OBJECTIVES: To provide recommendations regarding the use of arterial embolization in the management of post partum hemorrhage. METHODS: A literature search was conducted using the Pubmed, Medline and Embase databases and the Cochrane Library (study period 1979 to June 2014). RESULTS: Selective embolization of both uterine arteries without microcatheter is recommended (professional consensus). Embolization should be performed using gelatin sponge pledgets rather than gelatin sponge slurry or powder (grade C). Control of hemorrhage can be expected in 70 to 100% of cases after embolization (EL3). Control of hemorrhage is obtained in 85 to 100% of cases (EL3). Arterial embolization is recommended in case of uterine atony after failure of uterotonic drugs particularly after vaginal delivery, in case of cervical hemorrhage, vaginal thrombus of cervico vaginal tear in case of failed surgical repair or if surgery is not feasible (grade C). Pseudoaneurysm of the uterine artery is a good indication for embolization. Major complications related to embolization are reported in 5% of cases (EL4). The presence of coagulation disorders is not a contraindication to embolization (professional consensus). Embolization remains feasible after failed arterial ligations (selective or proximal) or after hysterectomy even if technically more challenging (professional consensus). Embolization can be performed in case of post partum hemorrhage related to abnormal placentation (professional consensus). Prophylactic embolization with the placenta left in place is not routinely recommended (professional consensus). The systematic preoperative placement of arterial occlusion balloons is not recommended in the management of abnormal placentation (professional consensus). Secondary post partum hemorrhage is a good indication for arterial embolization (grade C). After embolization, fertility can be spared (EL3). The risk of recurrent post partum hemorrhage does not seem different after arterial ligations or arterial embolization (EL3). PMID- 25447395 TI - [Obstetric and anesthetic specificities in the management of a postpartum hemorrhage (PPH) associated with cesarean section]. AB - OBJECTIVES: To describe the characteristics of post-partum hemorrhage (PPH) associated with cesarean section (CS), the modalities diagnosis and specific obstetric and anesthetic management. MATERIALS AND METHODS: Bibliographic search restricted to French and English languages using Medline database((r)) and international guidelines of medical societies. RESULTS: Primary PPH associated with CS (incidence 3-15%) is defined as vaginal bleeding >=500mL within 24hours after surgery. Severe PPH is defined by bleeding >=1000mL (professional consensus). The intervention threshold to initiate an active management depends on the flow rate of bleeding, the etiology and the clinical context. It can be higher than 500mL after cesarean (professional consensus). The main risk factor for bleeding is the realization of an emergency CS during labor (EL 3). In the case of persistent or severe intraoperative PPH due to uterine atony, conservative surgical procedures should be initiated in association with maternal resuscitation and second-line uterotonic therapy (sulprostone) (professional consensus). If general anesthesia is required, it is recommended to opt for a maintenance treatment limiting sevoflurane or desflurane in case of uterine atony (professional consensus). Severe bleeding during or after cesarean is a thrombotic risk factor and requires antithrombotic prophylaxis with heparin (the duration of treatment may vary depending on the associated risk factors) after normalization of coagulation (professional consensus). Postoperative hemoperitoneum (ultrasound) or suspected vascular wound require urgent laparotomy under general anesthesia (professional consensus). Otherwise, an uterotonic therapy (oxytocin or sulprostone depending on the severity) should be initiated. Balloon intrauterine tamponade or embolization may be discussed in the absence of hemodynamic instability (professional consensus). CONCLUSION: The occurrence of PPH associated with cesarean delivery requires close collaboration between obstetrician and anesthesiologist to ensure a rapid and coordinated management (professional consensus). PMID- 25447396 TI - [Inter-hospital transfer for severe postpartum hemorrhage]. AB - OBJECTIVES: To elaborate guidelines for inter-hospital transfer for severe postpartum hemorrhage. MATERIALS AND METHODS: Bibliographic search in Medline and Cochrane Database by PubMed. RESULTS: Severe postpartum hemorrhage sometimes needs inter-hospital transfer for arterial embolization or admission in intensive care unit. Validation of this transfer needs multidisciplinary decision, including obstetricians, anesthesiologist-intensivists of primary and tertiary center and prehospital medical team. If bleeding is too important or in case of uncontrolled hemorrhagic shock, inter-hospital transfer may be dangerous and local surgical hemostasis should be preferred. In such situation, prehospital medical team should stay on scene for help especially in small institutions where medical and paramedical resources are sometimes insufficient. In case of inter hospital transportation, organ failure should be controlled and blood transfusion, if needed, should be initiated before. The patient should be transferred to a multidisciplinary center (surgery, anesthesiology and ICU, interventional radiologist, blood bank). CONCLUSION: Inter-hospital transfer for severe postpartum hemorrhage is possible under certain conditions including continuation of blood transfusion and organ failure correction. PMID- 25447397 TI - [Management of blood products in obstetric services]. AB - OBJECTIVES: Define the access conditions and mode of use of blood products in the context of the management of immediate postpartum hemorrhage. METHODS: This text is based on the guidelines published by the French National Authority for Health (HAS) and the French National Security Agency of Medicines and Health Products (ANSM) and a literature search in Medline and Cochrane Library databases. RESULTS: Postpartum bleeding, often unpredictable and potentially severe, may represent a challenge for transfusion management decision within an institution. The efficiency of the decision is based on an emergency protocol widely available in each establishment to secure access to blood products, and coordination between teams of clinical and blood transfusion services (Professional consensus). Blood transfusion is not without infectious and immunological risks, each indication must be carefully considered based on clinical and laboratory criteria (Professional consensus). Availability of blood groups and antibody screening results must be checked upon entry to the delivery unit (Professional consensus). If bleeding risk is identified, RAI less than three days is recommended (Professional consensus). Complex immunological situations, including rare blood groups, should be planned and managed with EFS blood centers throughout prenatal period (Professional consensus). CONCLUSION: Transfusion management in postpartum hemorrhage should be a multidisciplinary approach and requires mastery of emergency circuits to obtain promptly blood products. PMID- 25447399 TI - The 3'UTR 1188A/C polymorphism of IL-12p40 is not associated with susceptibility for developing plaque psoriasis in Mestizo population from western Mexico. AB - Psoriasis is a chronic autoimmune inflammatory disease that affects the skin and the joints. Psoriasis is characterized by the keratinocyte proliferation, which is induced by cytokines Th1 and Th17. Patients with plaque psoriasis present a chronic inflammatory response with high levels of interleukin (IL)-12 and IL-23. Various single-nucleotide polymorphisms (SNP) have been identified in the IL12B gene, such as SNP 3' UTR 1188 A/C (SNP rs3212227), which has been associated with susceptibility to developing plaque psoriasis and with the production of IL-12 and IL-23 in individuals of different ethnic groups. In this study, we determined whether there is an association of SNP rs3212227 with the susceptibility of developing plaque psoriasis and with serum levels of IL-12 and IL-23 in Mestizo population in western Mexico. We included 112 patients with psoriasis and 112 clinical healthy individuals in the study. The frequencies of genotypes A/A, A/C, and C/C in patients with plaque psoriasis were 41, 53, and 6%, respectively, while in the control group, these were 37, 53, and 10%, respectively, without finding statistically significant differences between both groups (p>0.05). Although IL-12 and IL-23 serum levels were higher in patients than in controls, we found no significant differences. The group of patients with genotype CC presented the highest levels of IL-23 (p<0.05). These data suggest that the SNP rs3212227 phenotype is not associated with the risk of developing plaque psoriasis or with IL-12 and IL-23 levels in Mestizo population in western Mexico. PMID- 25447401 TI - Targeting CD44 augments the efficacy of Tregs in autoimmune diabetes. AB - Curing type 1 diabetes (T1D) will require lasting control of the autoimmune response that destroys insulin-producing islet beta-cells. Re-establishing tolerance by restoring/replacing Tregs has significant potential for treatment of T1D but will require strategies to augment and maintain their efficacy. We previously showed that polyclonal in vitro-induced Tregs can reverse recent onset of T1D in ~ 50% of NOD mice. Here we report that treatment of newly hyperglycemic animals with a short course of anti-CD44 at the time of Treg transfer improved diabetes reversal to >90%. Anti-CD44 treatment alone delayed diabetes onset and increased the frequencies of pancreatic CD4(+) T cells producing IL-2 or TGF beta, cytokines that support Treg function and survival, without altering production of IFN-gamma. These anti-CD44 effects on endogenous T cells were also observed in the context of polyclonal Treg transfer, and the combination treatment also reduced pancreatic infiltrates. The results provide compelling evidence that approaches to modulate the pancreatic milieu to support Treg function and counteract inflammation in the pancreas can greatly enhance the efficacy of adoptively transferred Tregs, and suggest that approaches achieving these outcomes hold promise for long-term control of autoimmunity in T1D. PMID- 25447402 TI - Association of the C-type lectin-like domain family-16A (CLEC16A) gene polymorphisms with acute coronary syndrome in Mexican patients. AB - The CLEC16A gene has an important role in the immune activation and regulation inflammatory. This gene encodes to C-type lectin domain that is involved in the recognition of DAMPS. The aim of this study was assess the CLEC16A gene polymorphisms in the risk of developing ACS in a group of patients. Four rs12708716, rs12917716, rs6498142 and rs9925481 (positions 146529 A>G, 155804 G>C, 47905 C>G and 64135 C>T, respectively) single nucleotide polymorphisms of CLEC16A gene were analyzed by TaqMan assays in a group of 452 patients with ACS and 456 healthy controls. The analysis was performed on the total group of individuals and then in groups of men and women separately. Under co-dominant model adjusted by cardiovascular risk factors the rs12708716 (146529 A>G) and rs12917716 (155804 G>C) polymorphisms were significantly associated with decrease risk of ACS in men (OR=0.16, PCo-dom=0.027 and OR=0.37, PCo-dom=0.016, respectively). In summary, our data suggests that two polymorphisms of the CLEC16A gene play an important role in the developing of ACS in men. PMID- 25447403 TI - Aptamers in immunological research. AB - In recent years aptamers, synthetic DNA or RNA single-chain oligonucleotides, have been used in various immunological studies to bind specific ligands. Detailed data on the interactions of an RNA aptamer with a human Fc fragment were obtained by X-ray crystallography. The complex formation involves multiple weak interactions that resemble protein-protein interactions. Aptamers specific to cell surface receptors may serve as antagonists or agonists blocking or stimulating cell activities. As aptamers can modify T-cell reactions, they could be useful in the treatment of chronic diseases such as autoimmune and oncological pathologies. In chimeras constructed for the delivery of active substances to defined targets, aptamers specific to surface proteins may be used to transport constructs directed to targets such as tumor cells. Aptamers are also employed as highly specific reagents in immunological assays after being labeled with reporter groups such as fluorescent dyes or following immobilization on insoluble carriers such as membranes or microspheres. PMID- 25447400 TI - Treatment of IL-21R-Fc control autoimmune arthritis via suppression of STAT3 signal pathway mediated regulation of the Th17/Treg balance and plasma B cells. AB - Interleukin-21 (IL-21) is a T cell-derived cytokine modulating T cell, B cell, and natural killer cell responses. To determine whether IL-21 contributes to pathologic processes, recombinant IL-21 receptor (R) fusion protein (rhIL-21R-Fc) was examined in mice models of autoimmune arthritis (collagen-induced arthritis). DBA/1J mice were immunized with chicken type II collagen and then treated intraperitoneally with rhIL-21R-Fc, which was initiated after the onset of arthritis symptoms in 20% of the cohort. The mice were assessed 3 times per week for signs of arthritis and histologic features as well as serum immunoglobulin. Cytokine messenger RNA levels in the spleen were also examined. STAT3 phosphorylation is dose dependently activated by IL-21 and inhibited by rhIL-21R Fc in vitro using T cells. Treatment of DBA/1J mice with rhIL-21R-Fc reduced the clinical and histologic signs of CIA. The IL-17 and STAT3-expressing CD4(+) splenocytes dramatically decreased in the rhIL-21R-Fc treated mice. IL-21R-Fc treated mice also decreased the production of IgG, STAT3 phosphorylation, and plasma cell transcription factor (Blimp1). These findings demonstrate a pathogenic role of IL-21 in animal models of RA, suggesting IL-21 as a promising therapeutic target among human RA. PMID- 25447398 TI - The oral microbiome and the immunobiology of periodontal disease and caries. AB - The composition of the oral microbiome differs from one intraoral site to another, reflecting in part the host response and immune capacity at each site. By focusing on two major oral infections, periodontal disease and caries, new principles of disease emerge. Periodontal disease affects the soft tissues and bone that support the teeth. Caries is a unique infection of the dental hard tissues. The initiation of both diseases is marked by an increase in the complexity of the microbiome. In periodontitis, pathobionts and keystone pathogens such as Porphyromonas gingivalis appear in greater proportion than in health. As a keystone pathogen, P. gingivalis impairs host immune responses and appears necessary but not sufficient to cause periodontitis. Historically, dental caries had been causally linked to Streptococcus mutans. Contemporary microbiome studies now indicate that singular pathogens are not obvious in either caries or periodontitis. Both diseases appear to result from a perturbation among relatively minor constituents in local microbial communities resulting in dysbiosis. Emergent consortia of the minor members of the respective microbiomes act synergistically to stress the ability of the host to respond and protect. In periodontal disease, host protection first occurs at the level of innate gingival epithelial immunity. Secretory IgA antibody and other salivary antimicrobial systems also act against periodontopathic and cariogenic consortia. When the gingival immune response is impaired, periodontal tissue pathology results when matrix metalloproteinases are released from neutrophils and T cells mediate alveolar bone loss. In caries, several species are acidogenic and aciduric and appear to work synergistically to promote demineralization of the enamel and dentin. Whereas technically possible, particularly for caries, vaccines are unlikely to be commercialized in the near future because of the low morbidity of caries and periodontitis. PMID- 25447404 TI - Effects of number of cagemates on home cage ethanol drinking during proximal cagemate drinking (PCD) procedures in male and female CD-1 mice. AB - The present experiment evaluated the effects of the Number of Cagemates (0 vs 1 vs 2) on home cage ethanol drinking during Proximal Cagemate Drinking (PCD) procedures in Male and Female CD-1 mice. Continuous-access home cage 2-bottle (ethanol vs. water) free-choice procedures were employed. PCD procedures eliminate the distracting effects of direct physical contact between Drinkers and their Cagemates on ethanol drinking by imposing a translucent plastic barrier strip between them. If direct physical contact distracts from drinking, then one Cagemate would drink more ethanol and more water than two Cagemates housed together on the same side of the barrier. This would be the case even if two Cagemates stimulated more ethanol drinking in the Drinker housed on the other side of the barrier, due to the social stimulation effects of additional Cagemates. Results revealed that the ethanol intake of Female Drinkers was directly related to the number of Cagemates on the other side of the barrier strip, but this social stimulation effect was not observed in Male Drinkers. For Male Cagemates and Female Cagemates, the single Cagemate provided elevated ethanol intake and elevated water intake relative to the ethanol intake and water intake of each Cagemate in the two Cagemates condition. The data revealed that direct physical contact between Cagemates reduced their ethanol intake, even while stimulating ethanol intake of the Drinker on the other side of the barrier, indicating that the effects of social stimulation on ethanol drinking are not entirely due to effects of modeling or peer pressure. The PCD procedures allow the evaluation of effects of a broad range of social factors on home cage ethanol drinking in mice. PMID- 25447405 TI - A novel chalcone derivative attenuates the diabetes-induced renal injury via inhibition of high glucose-mediated inflammatory response and macrophage infiltration. AB - Inflammation plays a central role in the development and progression of diabetic nephropathy (DN). Researches on novel anti-inflammatory agents may offer new opportunities for the treatment of DN. We previously found a chalcone derivative L6H21 could inhibit LPS-induced cytokine release from macrophages. The aim of this study was to investigate whether L6H21 could ameliorate the high glucose mediated inflammation in NRK-52E cells and attenuate the inflammation-mediated renal injury. According to the results, L6H21 showed a great inhibitory effect on the expression of pro-inflammatory cytokines, cell adhesion molecules, chemokines, and macrophage adhesion via down-regulation of NF-kappaB/MAPKs activity in high glucose-stimulated renal NRK-52E cells. Further, in vivo oral administration with L6H21 at a dosage of 20 mg/kg/2 days showed a decreased expression of pro-inflammatory cytokines, cell adhesion molecules, which subsequently contributed to the inhibition on renal macrophage infiltration, the reduction of serum creatinine and BUN levels, and the improvement on the fibrosis and pathological changes in the renal tissues of diabetic mice. These findings provided that chalcone derived L6H21 may be a promising anti-inflammatory agent and have the potential in the therapy of diabetic nephropathy, and importantly, MAPK/NF-kappaB signaling system may be a novel therapeutic target for human DN in the future. PMID- 25447406 TI - High level of oxygen treatment causes cardiotoxicity with arrhythmias and redox modulation. AB - Hyperoxia exposure in mice leads to cardiac hypertrophy and voltage-gated potassium (Kv) channel remodeling. Because redox balance of pyridine nucleotides affects Kv function and hyperoxia alters cellular redox potential, we hypothesized that hyperoxia exposure leads to cardiac ion channel disturbances and redox changes resulting in arrhythmias. In the present study, we investigated the electrical changes and redox abnormalities caused by 72h hyperoxia treatment in mice. Cardiac repolarization changes were assessed by acquiring electrocardiogram (ECG) and cardiac action potentials (AP). Biochemical assays were employed to identify the pyridine nucleotide changes, Kv1.5 expression and myocardial injury. Hyperoxia treatment caused marked bradycardia, arrhythmia and significantly prolonged (ms) the, RR (186.2 +/- 10.7 vs. 146.4 +/- 6.2), PR (46.8 +/- 3.1 vs. 39.3 +/- 1.6), QRS (10.8 +/- 0.6 vs. 8.5 +/- 0.2), QTc (57.1 +/- 3.5 vs. 40 +/- 1.4) and JT (13.4 +/- 2.1 vs. 7.0 +/- 0.5) intervals, when compared with normoxia group. Hyperoxia treatment also induced significant increase in cardiac action potential duration (APD) (ex-APD90; 73.8 +/- 9.5 vs. 50.9 +/- 3.1 ms) and elevated levels of serum markers of myocardial injury; cardiac troponin I (TnI) and lactate dehydrogenase (LDH). Hyperoxia exposure altered cardiac levels of mRNA/protein expression of; Kv1.5, Kvbeta subunits and SiRT1, and increased ratios of reduced pyridine nucleotides (NADH/NAD & NADPH/NADP). Inhibition of SiRT1 in H9C2 cells using Splitomicin resulted in decreased SiRT1 and Kv1.5 expression, suggesting that SiRT1 may mediate Kv1.5 downregulation. In conclusion, the cardiotoxic effects of hyperoxia exposure involve ion channel disturbances and redox changes resulting in arrhythmias. PMID- 25447407 TI - Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells. AB - Alpha-tocopherol ether-linked acetic acid (alpha-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether alpha-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of alpha-TEA on vascular endothelial growth factor (VEGF)-induced angiogenesis and matrix metalloproteinase (MMP) expression both in vitro and ex vivo. We found that the alpha-TEA inhibited tube formation, invasion, and migration in human umbilical vein endothelial cells (HUVECs) and that such actions were accompanied by reduced expression of MMP-2. alpha-TEA also inhibited ex vivo angiogenesis, as indicated by chicken egg chorioallantoic membrane assay. We further showed that alpha-TEA attenuated protein expression of VEGF receptor-2 (VEGFR-2)-mediated p38 mitogen activated protein kinase (p38), phosphorylated p38, and focal adhesion kinase (FAK). Moreover, alpha-TEA (30 MUM) significantly up-regulated protein expression of tissue inhibitors of MMP (TIMP)-2 (by 138%) and the metastasis suppressor gene nm23-H1 (by 54%). These results demonstrate that the anti-angiogenic effect of alpha-TEA both in vitro and ex vivo and its possible mechanistic action appears to involve the inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways and through up-regulation of TIMP-2 and nm23-H1 expression. PMID- 25447408 TI - Impact of obesity on 7,12-dimethylbenz[a]anthracene-induced altered ovarian connexin gap junction proteins in female mice. AB - The ovarian gap junction proteins alpha 4 (GJA4 or connexin 37; CX37), alpha 1 (GJA1 or connexin 43; CX43) and gamma 1 (GJC1 or connexin 45; CX45) are involved in cell communication and folliculogenesis. 7,12-dimethylbenz[a]anthracene (DMBA) alters Cx37 and Cx43 expression in cultured neonatal rat ovaries. Additionally, obesity has an additive effect on DMBA-induced ovarian cell death and follicle depletion, thus, we investigated in vivo impacts of obesity and DMBA on CX protein levels. Ovaries were collected from lean and obese mice aged 6, 12, 18, or 24 wks. A subset of 18 wk old mice (lean and obese) were dosed with sesame oil or DMBA (1mg/kg; ip) for 14days and ovaries collected 3days thereafter. Cx43 and Cx45 mRNA and protein levels decreased (P<0.05) after 18 wks while Cx37 mRNA and protein levels decreased (P<0.05) after 24 wks in obese ovaries. Cx37 mRNA and antral follicle protein staining intensity were reduced (P<0.05) by obesity while total CX37 protein was reduced (P<0.05) in DMBA exposed obese ovaries. Cx43 mRNA and total protein levels were decreased (P<0.05) by DMBA in both lean and obese ovaries while basal protein staining intensity was reduced (P<0.05) in obese controls. Cx45 mRNA, total protein and protein staining intensity level were decreased (P<0.05) by obesity. These data support that obesity temporally alters gap junction protein expression and that DMBA-induced ovotoxicity may involve reduced gap junction protein function. PMID- 25447409 TI - Epithelial-mesenchymal transition and cancer stem cells, mediated by a long non coding RNA, HOTAIR, are involved in cell malignant transformation induced by cigarette smoke extract. AB - The incidence of lung diseases, including cancer, caused by cigarette smoke is increasing, but the molecular mechanisms of gene regulation induced by cigarette smoke remain unclear. This report describes a long noncoding RNA (lncRNA) that is induced by cigarette smoke extract (CSE) and experiments utilizing lncRNAs to integrate inflammation with the epithelial-mesenchymal transition (EMT) in human bronchial epithelial (HBE) cells. The present study shows that, induced by CSE, IL-6, a pro-inflammatory cytokine, leads to activation of STAT3, a transcription activator. A ChIP assay determined that the interaction of STAT3 with the promoter regions of HOX transcript antisense RNA (HOTAIR) increased levels of HOTAIR. Blocking of IL-6 with anti-IL-6 antibody, decreasing STAT3, and inhibiting STAT3 activation reduced HOTAIR expression. Moreover, for HBE cells cultured in the presence of HOTAIR siRNA for 24h, the CSE-induced EMT, formation of cancer stem cells (CSCs), and malignant transformation were reversed. Thus, IL 6, acting on STAT3 signaling, which up-regulates HOTAIR in an autocrine manner, contributes to the EMT and to CSCs induced by CSE. These data define a link between inflammation and EMT, processes involved in the malignant transformation of cells caused by CSE. This link, mediated through lncRNAs, establishes a mechanism for CSE-induced lung carcinogenesis. PMID- 25447410 TI - HBCDD-induced sustained reduction in mitochondrial membrane potential, ATP and steroidogenesis in peripubertal rat Leydig cells. AB - Hexabromocyclododecane (HBCDD), a brominated flame retardant added to various consumer products, is a ubiquitous environmental contaminant. We have previously shown that 6-hour exposure to HBCDD disturbs basal and human chorionic gonadotropin (hCG)-induced steroidogenesis in rat Leydig cells. Reduction in mitochondrial membrane potential (DeltaPsim) and cAMP production was also observed. Here, we further expanded research on the effect of HBCDD on Leydig cells by using a prolonged exposure scenario. Cells were incubated in the presence of HBCDD during 24h and then treated with HBCDD+hCG for additional 2h. Results showed that HBCDD caused a sustained reduction in ATP level after 24h of exposure, which persisted after additional 2-hour treatment with HBCDD+hCG. cAMP and androgen accumulations measured after 2h of HBCDD+hCG treatment were also inhibited. Real-time PCR analysis showed significant inhibition in the expression of genes for steroidogenic enzymes, luteinizing hormone receptor, regulatory and transport proteins, and several transcription factors under both treatment conditions. Western blot analysis revealed a decreased level of 30kDa steroidogenic acute regulatory protein (StAR) after HBCDD+hCG treatment. In addition, HBCDD decreased the conversion of 22-OH cholesterol to pregnenolone and androstenedione to testosterone, indicating loss of the activity of cytochrome P450C11A1 (CYP11A1) and 17beta-hydroxysteroid dehydrogenase (HSD17beta). Cell survival was not affected, as confirmed by cytotoxicity and trypan blue tests or DNA fragmentation analysis. In summary, our data showed that HBCDD inhibits ATP supply, most likely through a decrease in DeltaPsim, and targets multiple sites in the steroidogenic pathway in Leydig cells. PMID- 25447411 TI - Analysis of the AHR gene proximal promoter GGGGC-repeat polymorphism in lung, breast, and colon cancer. AB - The aryl hydrocarbon receptor (AhR) regulates expression of numerous genes, including those of the CYP1 gene family. With the goal of determining factors that control AHR gene expression, our studies are focused on the role of the short tandem repeat polymorphism, (GGGGC)n, located in the proximal promoter of the human AHR gene. When luciferase constructs containing varying GGGGC repeats were transfected into cancer cell lines derived from the lung, colon, and breast, the number of GGGGC repeats affected AHR promoter activity. The number of GGGGC repeats was determined in DNA from 327 humans and from 38 samples representing 5 species of non-human primates. In chimpanzees and 3 species of macaques, only (GGGGC)2 alleles were observed; however, in western gorilla, (GGGGC)n alleles with n=2, 4, 5, 6, 7, and 8 were identified. In all human populations examined, the frequency of (GGGGC)n was n=4>5?2, 6. When frequencies of the (GGGGC)n alleles in DNA from patients with lung, colon, or breast cancer were evaluated, the occurrence of (GGGGC)2 was found to be 8-fold more frequent among lung cancer patients in comparison with its incidence in the general population, as represented by New York State neonates. Analysis of matched tumor and non-tumor DNA samples from the same individuals provided no evidence of microsatellite instability. These studies indicate that the (GGGGC)n short tandem repeats are inherited, and that the (GGGGC)2 allele in the AHR proximal promoter region should be further investigated with regard to its potential association with lung cancer susceptibility. PMID- 25447412 TI - Differential regulation of hepatopancreatic vitellogenin (VTG) gene expression by two putative molt-inhibiting hormones (MIH1/2) in Pacific white shrimp (Litopenaeus vannamei). AB - Molt-inhibiting hormone (MIH), a peptide member of the crustacean hyperglycemic hormone (CHH) family, is commonly considered as a negative regulator during the molt cycle in crustaceans. Phylogenetic analysis of CHH family peptides in penaeidae shrimps suggested that there is no significant differentiation between MIH and vitellogenesis-inhibiting hormone (VIH, another peptide member of CHH family), by far the most potent negative regulator of crustacean vitellogenesis known. Thus, MIH may also play a role in regulating vitellogenesis. In this study, two previously reported putative MIHs (LivMIH1 and LivMIH2) in the Pacific white shrimp (Litopenaeus vannamei) were expressed in Escherichia coli, purified by immobilized metal ion affinity chromatography (IMAC) and further confirmed by western blot. Regulation of vitellogenin (VTG) mRNA expression by recombinant LivMIH1 and LivMIH2 challenge was performed by both in vitro hepatopancreatic primary cells culture and in vivo injection approaches. In in vitro primary culture of shrimp hepatopancreatic cells, only LivMIH2 but not LivMIH1 administration could improve the mRNA expression of VTG. In in vivo injection experiments, similarly, only LivMIH2 but not LivMIH1 could stimulate hepatopancreatic VTG gene expression and induce ovary maturation. Our study may provide evidence for one isoform of MIH (MIH2 in L. vannamei) may serve as one of the mediators of the physiological progress of molting and vitellogenesis. Our study may also give new insight in CHH family peptides regulating reproduction in crustaceans, in particular penaeidae shrimps. PMID- 25447415 TI - A review of the anterolateral ligament of the knee: current knowledge regarding its incidence, anatomy, biomechanics, and surgical dissection. AB - PURPOSE: To systematically review current literature on the anterolateral ligament (ALL) of the knee. METHODS: We searched the PubMed/Medline database for publications specifically addressing the ALL. We excluded studies not written in English, studies not using human cadavers or subjects, and studies not specifically addressing the ALL. Data extraction related to the incidence, anatomy, morphometry, biomechanics, and histology of the ALL and its relation to the Segond fracture was performed. RESULTS: The incidence of the ALL ranged from 83% to 100%, and this range occurs because of small discrepancies in the definition of the ALL's bony insertions. The ALL originates anterior and distal to the femoral attachment of the lateral collateral ligament. It spans the joint in an oblique fashion and inserts between the fibular head and Gerdy tubercle on the tibia. Exact anatomic and morphometric descriptions vary in the literature, and there are discrepancies regarding the ALL's attachment to the capsule and lateral meniscus. The ALL is a contributor to tibial internal rotation stability, and histologically, it exhibits parallel, crimped fibers consistent with a ligamentous microstructure. The footprint of the ALL has been shown to be at the exact location of the Segond fracture. CONCLUSIONS: The ALL is a distinct ligamentous structure at the anterolateral aspect of the knee, and it is likely involved in tibial internal rotation stability and the Segond fracture. LEVEL OF EVIDENCE: Level IV, systematic review of anatomic and imaging studies. PMID- 25447414 TI - The protective effect of apelin on ischemia/reperfusion injury. AB - Apelin is the endogenous ligand for the APJ, a member of the G protein coupled receptors family. Apelin/APJ system is widely distributed in central nervous system and peripheral tissues, especially in heart, lung and kidney. Apelin plays important physiological and pathological roles in cardiovascular system, immune system, neuroprotection, etc. This article outlines the protective effect of apelin on ischemia/reperfusion (I/R) injury. Apelin could activate multiple protective mechanisms to prevent heart, brain, liver and kidney I/R injury. Apelin/APJ system may be a promising therapeutic target for ischemic and other related diseases. PMID- 25447413 TI - Functional characterization of five different PRXamide receptors of the red flour beetle Tribolium castaneum with peptidomimetics and identification of agonists and antagonists. AB - The neuropeptidergic system in insects is an excellent target for pest control strategies. One promising biorational approach is the use of peptidomimetics modified from endogenous ligands to enhance biostability and bioavailability. In this study, we functionally characterized five different G protein-coupled receptors in a phylogenetic cluster, containing receptors for PRXamide in the red flour beetle Tribolium castaneum, by evaluating a series of 70 different peptides and peptidomimetics. Three pyrokinin receptors (TcPKr-A, -B, and -C), cardioacceleratory peptide receptor (TcCAPAr) and ecdysis triggering hormone receptor (TcETHr) were included in the study. Strong agonistic or antagonistic peptidomimetics were identified, and included beta-proline (beta(3)P) modification of the core amino acid residue proline and also a cyclo-peptide. It is common for a ligand to act on multiple receptors. In a number of cases, a ligand acting as an agonist on one receptor was an efficient antagonist on another receptor, suggesting complex outcomes of a peptidomimetic in a biological system. Interestingly, TcPK-A was highly promiscuous with a high number of agonists, while TcPK-C and TcCAPAr had a lower number of agonists, but a higher number of compounds acting as an antagonist. This observation suggests that a target GPCR with more promiscuity will provide better success for peptidomimetic approaches. This study is the first description of peptidomimetics on a CAPA receptor and resulted in the identification of peptidomimetic analogs that demonstrate antagonism of CAPA ligands. The PRXamide receptor assays with peptidomimetics provide useful insights into the biochemical properties of receptors. PMID- 25447417 TI - MRI of cholangiocarcinoma. AB - Cholangiocarcinomas are the second most common primary hepatobiliary tumors after hepatocellular carcinomas. They can be categorized either based on their location (intrahepatic/perihilar/extrahepatic distal) or their growth characteristics (mass-forming/periductal-infiltrating/intraductal) because they exhibit varied presentations and outcomes based on their location and or pattern of growth. The increased risk of cholangiocarcinoma in PSC necessitates close surveillance of these patients by means of imaging and laboratory measures; and because currently surgical resection is the only effective treatment for cholangiocarcinoma, the need for accurate pre-operative staging and assessment of resectability has emphasized the role of high quality imaging in management. Today magnetic resonance imaging (MRI) is the modality of choice for detection, pre-operative staging and surveillance of cholangiocarcinoma. PMID- 25447418 TI - A novel technology for automatically obtaining digital facial photographs near simultaneously with portable radiographs. AB - Our objective is to design, implement, and phantom-test a device to automatically obtain point-of-care patient photographs along with portable radiographs. Such photographs could help with detection of wrong-patient errors. Our device consists of a camera controller (CC) and a camera that can be mounted on a portable conventional radiography (CR) machine. Radiation from the CR machine triggers an identification module (IM) embedded in the CR cassette. The IM then sends the cassette identifier--Plate_ID--to the CC along with a trigger to activate the camera. This trigger ensures simultaneous acquisition of radiograph and photograph, and the Plate_ID along with a time stamp ensures binding of the two images. We conducted phantom tests to determine if clinical portable radiography exposure settings (90 to 120 kVp and exposure time ranging from 0.63 to 8.0 ms) are sufficient to trigger the IM. Phantom experiments demonstrate acceptable sensor performance for clinical portable radiography exposures. Simultaneous acquisition of photographs is achieved by integrating a low-cost identification module containing a scintillator-detector into the radiographic cassette. Incident X-rays activate the scintillator-detector triggering photograph acquisition by a camera controller. PMID- 25447416 TI - Accelerated model-based proton resonance frequency shift temperature mapping using echo-based GRAPPA reconstruction. AB - PURPOSE: To develop an acceleration method for MR temperature estimation using model-based proton resonance frequency (PRF) shift method. MATERIALS AND METHODS: Images of 16 different echo times (TE) were acquired in one RF excitation using a multi-echo gradient-recalled echo (GRE) sequence. Fully sampled k-space data were retrospectively under-sampled at a net reduction factor between two and three using the proposed under-sampling strategy. K-spaces of three different TEs were combined together to perform the proposed reconstruction method called Echo-based GRAPPA. Ex vivo goose liver cooling experiment and in vivo breast imaging experiment were performed to investigate the accuracy of Echo-based GRAPPA. Conventional GRAPPA reconstruction was implemented for comparison using the same sampling pattern. RESULTS: The goose liver imaging experiment shows that the reconstruction-induced temperature RMSE of a selected region of interest (ROI) is less than 1.4 degrees C for Echo-based GRAPPA at a net reduction factor of 2.3. The breast imaging experiment shows that the mean temperature error of water-fat mixed ROIs is 2.3 degrees C at a net reduction factor of 2.7. Conventional GRAPPA shows larger temperature RMSE than Echo-based GRAPPA. CONCLUSION: The proposed method can accelerate the MR temperature estimation using model-based PRF at a net reduction factor between two and three with a reconstruction-induced temperature error less than 3 degrees C in water-fat mixed ROIs. PMID- 25447419 TI - Relationship between the contrast effects of raw data projection images from three-dimensional digital subtraction angiography and the optimal volume rendering parameters. AB - Volume rendering (VR) is a technique commonly used for the reconstruction of three-dimensional (3D) digital subtraction angiography (DSA) images, and the rendering parameters greatly affect the characteristics of the 3D image. This study aimed to test whether the optimal VR parameters for 3D DSA could be estimated from the contrast effects in rotational two-dimensional (2D) DSA images acquired using 3D DSA. Simulated blood vessels filled with various concentrations of contrast medium were scanned, and the 3D DSA data sets were reconstructed. The syngo AX vessel analysis software that was able to analyze 3D DSA VR image was used for objective measures. Raw data projection images of the 3D DSA data sets in which the mean diameter was calculated as a true value by the software at nine different thresholds for vessel segmentation were selected. In each image set, five images of all 133 rotational 2D DSA images were selected, and the contrast enhanced area was extracted using a region-growing algorithm. Mean values and standard deviations of each contrast-enhanced area were calculated, and as the thresholds for vessel segmentation of the software increased by 500 every time, significant differences were observed in the mean values (P < 0.01). This optimal threshold can be applied to the window settings of the VR technique. Therefore, the optimal VR parameters for 3D DSA may be determined by analyzing the contrast effects of the raw data projection images, and user-dependent over- and underestimations of 3D DSA VR images also may be prevented. PMID- 25447420 TI - Microbial biotransformation of bioactive flavonoids. AB - The bioactive flavonoids are considered as the most important phytochemicals in food, which exert a wide range of biological benefits for human being. Microbial biotransformation strategies for production of flavonoids have attracted considerable interest because they allow yielding novel flavonoids, which do not exist in nature. In this review, we summarize the existing knowledge on the production and biotransformation of flavonoids by various microbes. The main reactions during microbial biotransformation are hydroxylation, dehydroxylation, O-methylation, O-demethylation, glycosylation, deglycosylation, dehydrogenation, hydrogenation, C ring cleavage of the benzo-gamma-pyrone system, cyclization, and carbonyl reduction. Cunninghamella, Penicillium, and Aspergillus strains are very popular to biotransform flavonoids and they can perform almost all the reactions with excellent yields. Aspergillus niger is one of the most applied microorganisms in the flavonoids' biotransformation; for example, A. niger can transfer flavanone to flavan-4-ol, 2'-hydroxydihydrochalcone, flavone, 3 hydroxyflavone, 6-hydroxyflavanone, and 4'-hydroxyflavanone. The hydroxylation of flavones by microbes usually happens on the ortho position of hydroxyl group on the A ring and C-4' position of the B ring and microbes commonly hydroxylate flavonols at the C-8 position. The microorganisms tend to hydroxylate flavanones at the C-5, 6, and 4' positions; however, for prenylated flavanones, dihydroxylation often takes place on the C4alpha=C5alpha double bond on the prenyl group (the side chain of A ring). Isoflavones are usually hydroxylated at the C-3' position of the B ring by microorganisms. The microbes convert flavonoids to their 7-O-glycosides and 3-O-glycosides (when flavonoids have a hydroxyl moiety at the C-3 position). The demethylation of multimethoxyl flavonoids by microbes tends to happen at the C-3' and C-4' positions of the B ring. Multimethoxyl flavanones and isoflavone are demethylated at the C-7 and C 4' positions. The O-methylation of flavonols happens at the C-3' and C-4' and microorganisms O-methylate flavones at the C-6 position and the O-methylation of flavanones, usually took place on the hydroxyl groups of the A ring. The prenyl flavanones were cyclized at the prenyl side chain to form a new five-member ring attached to the A ring. Chalcones were regioselectively cyclized to flavanones. Hydrogenation of flavonoids was only reported on transformation of chalcones to dihydrochalcones. The dehydrogenation of flavanoids to flavonoids was not comprehensively studied. PMID- 25447421 TI - Fungal treated lignocellulosic biomass as ruminant feed ingredient: a review. AB - In ruminant nutrition, there is an increasing interest for ingredients that do not compete with human nutrition. Ruminants are specialists in digesting carbohydrates in plant cell walls; therefore lignocellulosic biomass has potential in ruminant nutrition. The presence of lignin in biomass, however, limits the effective utilization of cellulose and hemicellulose. Currently, most often chemical and/or physical treatments are used to degrade lignin. White rot fungi are selective lignin degraders and can be a potential alternative to current methods which involve potentially toxic chemicals and expensive equipment. This review provides an overview of research conducted to date on fungal pretreatment of lignocellulosic biomass for ruminant feeds. White rot fungi colonize lignocellulosic biomass, and during colonization produce enzymes, radicals and other small compounds to breakdown lignin. The mechanisms on how these fungi degrade lignin are not fully understood, but fungal strain, the origin of lignocellulose and culture conditions have a major effect on the process. Ceriporiopsis subvermispora and Pleurotus eryngii are the most effective fungi to improve the nutritional value of biomass for ruminant nutrition. However, conclusions on the effectiveness of fungal delignification are difficult to draw due to a lack of standardized culture conditions and information on fungal strains used. Methods of analysis between studies are not uniform for both chemical analysis and in vitro degradation measurements. In vivo studies are limited in number and mostly describing digestibility after mushroom production, when the fungus has degraded cellulose to derive energy for fruit body development. Optimization of fungal pretreatment is required to shorten the process of delignification and make it more selective for lignin. In this respect, future research should focus on optimization of culture conditions and gene expression to obtain a better understanding of the mechanisms involved and allow the development of superior fungal strains to degrade lignin in biomass. PMID- 25447424 TI - Application of nanotechnology for the encapsulation of botanical insecticides for sustainable agriculture: prospects and promises. AB - This review article discusses the use of nanotechnology in combination with botanical insecticides in order to develop systems for pest control in agriculture. The main types of botanical insecticides are described, together with different carrier systems and their potential uses. The botanical insecticides include those based on active principles isolated from plant extracts, as well as essential oils derived from certain plants. The advantages offered by the systems are highlighted, together with the main technological challenges that must be resolved prior to future implementation of the systems for agricultural pest control. The use of botanical insecticides associated with nanotechnology offers considerable potential for increasing agricultural productivity, while at the same time reducing impacts on the environment and human health. PMID- 25447422 TI - Nanoscale drug delivery for taxanes based on the mechanism of multidrug resistance of cancer. AB - Taxanes are one type of the most extensively used chemotherapeutic agents to treat cancers. However, their clinical use is severely limited by intrinsic and acquired resistance. A diverse variety of mechanisms has been implicated about taxane resistance, such as alterations of drug targets, overexpression of efflux transporters, defective apoptotic machineries, and barriers in drug transport. The deepening understanding of molecular mechanisms of taxane resistance has spawned a number of targets for reversing resistance. However, circumvention of taxane resistance would not only possess therapeutic potential, but also face with clinical challenge, which accelerates the development of optimal nanoscale delivery systems. This review highlights the current understanding on the mechanisms of taxane resistance, and provides a comprehensive analysis of various nanoscale delivery systems to reverse taxane resistance. PMID- 25447423 TI - Antimicrobial peptide-based treatment for endodontic infections--biotechnological innovation in endodontics. AB - The presence/persistence of microorganisms in the pulp and periapical area corresponds to the maintenance of an exacerbated immune response that leads to the start of periradicular bone resorption and its perpetuation. In endodontic treatment, the available intracanal medications do not have all the desirable properties in the context of endodontic infection and apical periodontitis; they need to include not only strong antimicrobial performance but also an immunomodulatory and reparative activity, without host damage. In addition, there are various levels of resistance to root canal medications. Thus, antimicrobial agents that effectively eliminate resistant species in root canals could potentially improve endodontic treatment. In the emergence of new therapies, an increasing number of studies on antimicrobial peptides (AMPs) have been seen over the past few years. AMPs are defense biomolecules produced in response to infection, and they have a wide spectrum of action against many oral microorganisms. There are some studies that correlate peptides and oral infections, including oral peptides, neuropeptides, and bacterial, fish, bovine and synthetic peptides. So far, there are around 120 published studies correlating endodontic microbiota with AMPs but, according to our knowledge, there are no registered patents in the American patent database. There are a considerable number of AMPs that exhibit excellent antimicrobial activity against endodontic microbiota at a small inhibitory concentration and modulate an exacerbated immune response, down-regulating bone resorption. All these reasons indicate the antimicrobial peptide-based endodontic treatment as an emerging and promising option. PMID- 25447425 TI - Simultaneous determination of three alkaloids in Huangbo using an ionic liquid as a mobile phase additive in reversed-phase liquid chromatography. AB - A reversed-phase high-performance liquid chromatography method for the simultaneous determination of jatrorrhizine, palmatine, and berberine in Huangbo, the dried bark of Chinese Corktree, was established by using 1-hexyl-3 methylimidazolium tertafluoroborate as a mobile phase additive. The chromatographic behavior of the three compounds on the C18 column was studied with four different types of 1-alkyl-3-methylimidazolium-based ionic liquids as the mobile phase additives. The effect of 1-hexyl-3-methylimidazolium tertafluoroborate was the best in the four investigated ionic liquids. The concentration of 1-hexyl-3-methylimidazolium tertafluoroborate and the pH of the mobile phase, which influenced the chromatographic behaviors of the three bioactive compounds, were investigated. The linearity, precision, accuracy, repeatability, limit of detection, and quantification of the proposed method were found to be satisfactory. To explain the role of ionic liquids as the mobile phase additives, the possible mechanism was also explored and discussed. PMID- 25447426 TI - High versus low fat/sugar food affects the behavioral, but not the cortisol response of marmoset monkeys in a conditioned-place-preference task. AB - The effect of a high (chocolate) versus low fat/sugar (chow) food on a conditioned-place-preference (CPP) task was evaluated in marmoset monkeys. Anxiety-related behaviors and cortisol levels before and after the CPP task were also measured. Subjects were habituated to a two-compartment CPP box and then, on alternate days, had access to only one compartment during daily 15-min conditionings, for a total of 14 trials. Marmosets were provisioned with chocolate chips in the CC-paired compartment on odd-numbered trials and standard chow in the CW-paired compartment on even-numbered trials. They were then tested for preferring the CC-paired context after a 24-h interval. During the conditioning, a significantly greater amount (in kcal/trial) of chocolate was consumed than chow, yet the foraging pattern of both food types was similar. On the test trial, the time spent in the CC-paired context increased significantly compared to pre-CPP levels, yet this response was not readily predicted by baseline behavioral or cortisol levels. Also, the chocolate CPP response was positively correlated with foraging time, rather than the amount of calories consumed. The sudden absence of the food increased exploration, while the chocolate CPP effect was associated with vigilance - both anxiety-related behaviors in marmosets. This behavioral profile occurred regardless of any concomitant change or correlation with cortisol. Therefore, the high fat/sugar food was more prone to be overly consumed by the marmosets, to induce a CPP response and to lead to anxiety-related behavior in its absence. PMID- 25447427 TI - Accuracy rate of lie-detection in China: estimate the validity of CQT on field cases. AB - OBJECTIVE: To explore the accuracy rate of the comparison question test (CQT) by Binomial Distribution way on field cases in Chengdu area of China. In detail, the study revealed the accuracy rate of detecting guilty and innocent examinees, and the rate of False Positive and False Negative. METHOD: The study was built on the field cases with only two examinees that held the opposite opinions to the same single case. The original evaluators and four experienced polygraph specialists independently chose and scored 148 field criminal cases into the final study, among which 111 paired-records were concluded as indicative records and the rest, 37 ones, were ruled as non-indicative. RESULT: Judging from all records, the accuracy rate of detecting guilty examinees was 0.836 with a 0.164 False Negative rate. In addition, the rate to detect innocents was 0.822 with a 0.178 False Positive rate. Judging from indicative cases only excluding the non-indicative, the accuracy rate rose to 0.958 for perceiving guilty examinees with a 0.042 False Negative rate. To innocents, the accuracy rate was 0.859 with a 0.141 False Positive rate. CONCLUSION: The study with non-standard methodology was not limited to mock cases and the final confessions. It was able to estimate validity of other lie-detection ways, GKT, POT, etc., with this method being applied. With high accuracy rate and validity, polygraph examinations were able to give better decisions to real-life investigations. PMID- 25447428 TI - Recurrent ventricular fibrillation: experience with first responders prior to advanced life support interventions. AB - AIM: Following defibrillation, ventricular fibrillation (VF) frequently recurs during out-of-hospital cardiac arrest (OHCA). Prior studies have reported conflicting results regarding its association with survival. The aim of this study was to examine the impact of recurrent VF in the presence of first responders before advanced life support (ALS) interventions. METHODS: Electrocardiographic data from first responder automated external defibrillators (AEDs) were analyzed. A successful shock was defined as termination of VF for 5s or longer. Recurrent VF was defined as any VF that occurred after a successful shock. The primary outcome was neurologically intact survival to hospital discharge (CPC 1-2). RESULTS: 108 patients within our emergency system experienced a witnessed VF arrest. Of these, 73 (68%) had at least one recurrence of VF. Median time to recurrence of VF was 25s [interquartile range (IQR) 11 66s]. Median time in recurrent VF was 180s (IQR 105-266s). Survival was observed in 25 (71%) of patients with no recurrent VF and in 36 (49%) who had recurrence. Recurrent VF was associated with a lower odds of survival on univariate analysis (OR 0.39, 95% CI 0.16-0.92, p=0.0325). After adjusting for bystander CPR, gender and age, recurrent VF had a similar direction of effect but was no longer significantly associated with neurologically intact survival (OR 0.44, 95% CI 0.17-1.11, p=0.081). CONCLUSIONS: In the presence of first responders, VF recurred in 68% of patients. Recurrent VF was associated with a lower odds of survival, though its prognostic significance appeared to be blunted when considered in light of confounding variables. Recurrent VF may have significant survival implications, and further studies to assess its prognostic significance should be performed. PMID- 25447430 TI - Misconceptions about 'do-not-resuscitate (DNR)' orders in the era of social media. PMID- 25447429 TI - Shorter time to target temperature is associated with poor neurologic outcome in post-arrest patients treated with targeted temperature management. AB - INTRODUCTION: Time to achieve target temperature varies substantially for patients who undergo targeted temperature management (TTM) after cardiac arrest. The association between arrival at target temperature and neurologic outcome is poorly understood. We hypothesized that shorter time from initiation of cooling to target temperature ("induction") will be associated with worse neurologic outcome, reflecting more profound underlying brain injury and impaired thermoregulatory control. METHODS: This was a multicenter retrospective study analyzing data from the Penn Alliance for Therapeutic Hypothermia (PATH) Registry. We examined the association between time from arrest to return of spontaneous circulation (ROSC) ("downtime"), ROSC to initiation of TTM ("pre induction") and "induction" with cerebral performance category (CPC). RESULTS: A total of 321 patients were analyzed, of whom 30.8% (99/321) had a good neurologic outcome. Downtime for survivors with good outcome was 11 (IQR 6-27) min vs. 21 (IQR 10-36) min (p=0.002) for those with poor outcome. Pre-induction did not vary between good and poor outcomes (98 (IQR 36-230) min vs. 114 (IQR 34-260) (p=ns)). Induction time in the good outcome cohort was 237 (IQR 142-361) min compared to 180 (IQR 100-276) min (p=0.004). Patients were categorized by induction time (<120min, 120-300min, >300min). Using multivariable logistic regression adjusted for age, initial rhythm, and downtime, induction time >300min was associated with good neurologic outcome when compared to those with an induction time <120min. CONCLUSION: In this multicenter cohort of post-arrest TTM patients, shorter induction time was associated with poor neurologic outcome. PMID- 25447431 TI - Base excess and lactate as prognostic indicators for patients treated by extra corporeal life support after out hospital cardiac arrest due to acute coronary syndrome. AB - OBJECTIVE: To examine whether values of arterial base excess or lactate taken 3 h after starting ECLS indicate poor prognosis and if this can be used as a screening tool to follow Extra Corporeal Life Support after Out Hospital Cardiac Arrest due to acute coronary syndrome. DESIGN: Single Centre retrospective observational study. SETTING: University teaching hospital general adult intensive care unit. PATIENTS: 15 consecutive patients admitted to the intensive care unit after refractory Out Hospital Cardiac Arrest due to acute coronary syndrome treated by Extra Corporeal Life Support. INTERVENTIONS: Arterial base excess and lactate concentrations were measured immediately after starting ECLS and every 3 h after. RESULTS: Both base excess and arterial lactate measured 3 h after starting ECLS effectively predict multi-organ failure occurrence and mortality in the following 21 h (area under the curve on receiver operating characteristic analysis of 0.97, 0.95 respectively). The best predictive values were obtained with a base excess level measured 3 h after starting ECLS of less than -10 mmol/l and lactate concentrations greater than 12 mmol/l. The combination of these two markers measured 3 h after starting ECLS predicted multiorgan failure occurrence and mortality in the following 21 h with a sensitivity of 70% and a specificity of 100%. CONCLUSIONS: Combination of base excess and lactate, measured 3 h after starting ECLS, can be used to predict multiorgan failure occurrence and mortality in the following 21 h in patients admitted to an intensive care unit for refractory Out Hospital Cardiac Arrest due to acute coronary syndrome treated by Extra Corporeal Life Support. These parameters can be obtained simply and rapidly and help in the decision process to continue ECLS for refractory CA. PMID- 25447432 TI - Schoolchildren as BLS instructors for relatives and friends: Impact on attitude towards bystander CPR. AB - INTRODUCTION: We investigated the impact of Cardio-Pulmonary Resuscitation (CPR) instruction by children on the attitude of people to perform bystander CPR. METHODS: In 2012, children from primary and secondary school (age span 11-13 years) received a free individual CPR training package containing an inexpensive manikin and a training video. After a CPR training session by their class teacher, they were invited to teach their relatives and friends. After the training, the trainees of the children were invited to participate in a web survey, containing a test and questions about prior CPR training and about their attitude towards bystander CPR (BCPR) before and after the training. We measured the impact on the attitude to perform BCPR and the theoretical knowledge transfer by the children. RESULTS: A total of 4012 training packages were distributed to 72 schools of which 55 class teachers subscribed their students (n = 822) for the training programme for relatives and friends. After a validation procedure, 874 trainees of 290 children were included in the study. In comparison to trainees of secondary schoolchildren, trainees of primary schoolchildren scored better for the test as well as for a positive change of attitude towards future BCPR (P < 0.001). For every child-instructor 1.7 people changed their attitude towards BCPR positively. CONCLUSIONS: Instructing schoolchildren to teach their relatives and friends in Basic Life Support (BLS) led to a more positive attitude towards BCPR. The results were more positive with trainees from primary schoolchildren than with trainees from secondary schoolchildren. PMID- 25447433 TI - Incidence and outcomes of rearrest following out-of-hospital cardiac arrest. AB - INTRODUCTION: Rearrest occurs when a patient experiences cardiac arrest after successful resuscitation. The incidence and outcomes of rearrest following out-of hospital cardiac arrest have been estimated in limited local studies. We sought provide a large-scale estimate of rearrest incidence and its effect on survival. METHODS: We obtained case data from emergency medical services-treated, out-of hospital cardiac arrest from the Resuscitation Outcomes Consortium, a multi-site clinical research network with clinical centers in 11 regions in the US and Canada. The cohort comprised all cases captured between 2006 and 2008 at 10 of 11 regions with prehospital return of spontaneous circulation. We used three methods to ascertain rearrest via direct signal analysis, indirect signal analysis, and emergency department arrival vital status. Rearrest incidence was estimated as the proportion of cases with return of spontaneous circulation that experience rearrest. Regional rearrest incidence estimates were compared with the chi(2) squared test. Multivariable logistic regression was used to assess the relationship between rearrest and survival to hospital discharge. RESULTS: Out of 18,937 emergency medical services-assessed cases captured between 2006 and 2008, 11,456 (60.5%) cases were treated by emergency medical services and 4396 (38.4%) had prehospital return of spontaneous circulation. Of these, rearrest ascertainment data was available in 3253 cases, with 568 (17.5%) experiencing rearrest. Rearrest differed by region (10.2% to 21.2%, p < 0.001). Rearrest was inversely associated with survival (OR: 0.19, 95% CI: 0.14-0.26). CONCLUSIONS: Rearrest was found to occur frequently after resuscitation and was inversely related to survival. PMID- 25447434 TI - Risk factors for unsuccessful prehospital laryngeal tube placement. AB - INTRODUCTION: Laryngeal tube (LT) airways are commonly used in the prehospital setting, but there are limited data on clinical success rates across emergency medical services (EMS) agencies. We aimed to determine factors associated with unsuccessful LT placement in the prehospital setting. METHODS: We retrospectively reviewed all King LT placement attempts by prehospital providers in 35 ground advanced life support EMS agencies and one air medical critical care service with 17 rotorwing bases, between January 1, 2006 and August 31, 2011. Success of King LT placement and patient, procedural, and agency factors present were identified using descriptive statistics. Factors associated with unsuccessful laryngeal tube placement were identified using multivariable logistic regression. RESULTS: During the study period, we observed 511 attempts at laryngeal tube placement by paramedics or prehospital nurses in 477 patients. Unsuccessful LT placement occurred in 15.1% of first attempts and 9.9% of cases overall. The majority (79.2%) of first attempts occurred as a rescue airway after unsuccessful endotracheal intubation attempt(s), in patients with non-traumatic complaints (70.9%) and in cardiac arrest (60.8%). Gag reflex (OR 4.08, 95% CI 1.72-9.67), ground (versus air) EMS agency (OR 2.49, 95% CI 1.07-5.79), and male gender (OR 1.90, 95% CI 1.04-3.46) were associated with unsuccessful LT placement in our multivariable model. CONCLUSION: The laryngeal tube is an effective airway management tool for both advanced life support and critical care prehospital providers. Gag reflex, ground (versus air) EMS agency, and male gender were associated with unsuccessful laryngeal tube placement by prehospital personnel. PMID- 25447435 TI - Return of consciousness during ongoing cardiopulmonary resuscitation: A systematic review. AB - OBJECTIVES: Cardio-pulmonary resuscitation (CPR) may generate sufficient cerebral perfusion pressure to make the patient conscious. The incidence and management of this phenomenon are not well described. This systematic review aims to identifying cases where CPR-induced consciousness is mentioned in the literature and explore its management options. METHODS: The databases Medline, PubMed, EMBASE, Cinahl and the Cochrane Library were searched from their commencement to the 8th July 2014. We also searched Google (scholar) for grey literature. We combined MeSH terms and text words for consciousness and CPR, and included studies of all types. RESULTS: The search yielded 1997 unique records, of which 50 abstracts were reviewed. Nine reports, describing 10 patients, were relevant. Six of the patients had CPR performed by mechanical devices, three of these patients were sedated. Four patients arrested in the out-of-hospital setting and six arrested in hospital. There were four survivors. Varying levels of consciousness were described in all reports, including purposeful arm movements, verbal communication, and resuscitation interference. Management strategies directed at consciousness were offered to six patients and included both physical and chemical restraints. CONCLUSION: CPR-induced consciousness was infrequently reported in the medical literature, and varied in management. Given the increasing use of mechanical CPR, guidelines to identify and manage consciousness during CPR are required. PMID- 25447436 TI - A tourniquet assisted cardiopulmonary resuscitation augments myocardial perfusion in a porcine model of cardiac arrest. AB - OBJECTIVE: During cardiopulmonary resuscitation (CPR), myocardial blood flow generated by chest compression rarely exceeds 35% of its normal level. Cardiac output generated by chest compression decreases gradually with the prolongation of cardiac arrest and resuscitation. Early studies have demonstrated that myocardial blood flow during CPR is largely dependent on peripheral vascular resistance. In this study, we investigated the effects of chest compression in combination with physical control of peripheral vascular resistance assisted by tourniquets on myocardial blood flow during CPR. METHODS: Ventricular fibrillation was induced and untreated for 7 min in ten male domestic pigs weighing between 33 and 37 kg. The animals were then randomized to receive CPR alone or a tourniquet assisted CPR (T-CPR). In the CPR alone group, chest compression was performed by a miniaturized mechanical chest compressor. In the T CPR group, coincident with the start of resuscitation, the thin elastic tourniquets were wrapped around the four limbs from the distal end to the proximal part. After 2 min of CPR, epinephrine (20 MUg/kg) was administered via the femoral vein. After 5 min of CPR, defibrillation was attempted by a single 150 J shock. If resuscitation was not successful, CPR was resumed for 2 min before the next defibrillation. The protocol was continued until successful resuscitation or for a total of 15 min. Five minutes after resuscitation, the elastic tourniquets were removed. The resuscitated animals were observed for 2h. RESULTS: T-CPR generated significantly greater coronary perfusion pressure, end tidal carbon dioxide and carotid blood flow. There was no difference in both intrathoracic positive and negative pressures between the two groups. All animals were successfully resuscitated with a single shock in both groups. There were no significant changes in hemodynamics observed in the animals treated in the T-CPR group before-and-after the release of tourniquets at post-resuscitation 5 min. CONCLUSIONS: T-CPR improves myocardial and cerebral perfusion during CPR. It may provide a new and convenient method for augmenting myocardial and cerebral blood flow during CPR. PMID- 25447437 TI - Does the sex of a simulated patient affect CPR? AB - INTRODUCTION: While males and females are equally at risk of sudden cardiac arrest (SCA), females are less likely to be resuscitated. Cardiopulmonary Resuscitation (CPR) may be inhibited by socio-cultural norms about exposing female victims' chests. Empirically confirming this hypothesis is limited by lack of patient simulators modeling realistic female physiques. A commercially available patient simulator was transformed to evaluate how physical attributes of a patient's sex might influence lay participants who were asked to resuscitate a female versus a male during simulated cardiac arrest. METHODS: Sixty-nine participants consented to be in the study. Participants were randomly assigned to provide CPR and defibrillation as instructed by a commercially-available automated external defibrillator on a patient simulator presented as either a male or female experiencing cardiac arrest. RESULTS: Rescuers removed significantly more clothing from the male than the female, with men removing less clothing from the female. More rescuers' initial hand placements for CPR were centered between the female's breasts compared to the male, on which placement was distributed across the chest towards the nipples. DISCUSSION: While rescuers had better hand placement for CPR on the female, both men and women rescuers were reluctant to remove the female's clothing, with men significantly more hesitant. Reticence to remove clothing was often articulated relative to social norms during structured interviews. We suggest that using only male simulators will not allow trainees to experience social differences associated with the care of a female simulated patient. Realistic female patient simulators are needed. PMID- 25447438 TI - Histopathological alterations in the kidney of Caspian kutum, Rutilus frisii kutum, larvae and fingerlings exposed to sublethal concentration of atrazine. AB - The use of chemical pesticides has increased environmental pollution and affected ichthyofauna as non target organisms. In the present study, the histopathological alterations in the larvae and fingerlings of the Caspian kutum, Rutilus frisii kutum, were used as a model to investigate the toxic effects of triazine herbicide, atrazine. To investigate toxic effects of atrazine, fish were exposed to sublethal concentration of 1/2 LC50 for 96 h. Histologically, the most significant alterations in kidney tissues were hyperplasia, necrosis, vacuolation, swelling, hypertrophy, aggregation of hyaline droplets, and disruption of the haematopitic tissue of the head kidney. The damage was more severe in larvae than the fingerlings. Results showed that alterations in kidney tissue caused by atrazine were not specific but it could be concluded that atrazine is excessively toxic for Caspian kutum even at sublethal concentration and acute exposure. PMID- 25447439 TI - Modelling microbial dechlorination of trichloroethene: investigating the trade off between quality of fit and parameter reliability. AB - This work puts forth a heuristic approach for investigating compromises between quality of fit and parameter reliability for the Monod-type kinetics employed to model microbial reductive dechlorination of trichloroethene. The methodology is demonstrated with three models of increasing fidelity and complexity. Model parameters were estimated with a stochastic global optimization algorithm, using scarce and inherently noisy experimental data from a mixed anaerobic microbial culture, which dechlorinated trichloroethene to ethene completely. Parameter reliability of each model was assessed using a Monte Carlo technique. Finally, an alternate quantity of applied interest was evaluated in order to assist with model discrimination. Results from the application of our approach suggest that the modeler should examine the implementation of conceptually simple models, even if they are a crude abstraction of reality, as they can be computationally less demanding and adequately accurate when model performance is assessed with criteria of applied interest, such as chloroethene elimination time. PMID- 25447440 TI - Macrophages enhance tumor-derived autophagosomes (DRibbles)-induced B cells activation by TLR4/MyD88 and CD40/CD40L. AB - Our previous studies have showed that tumor-derived autophagosomes (termed "DRibbles") induce B cell activation, resulting in antibody production and cytokine secretion. Unexpectedly, we found that unfractionated splenocytes produced a higher level of antibody and cytokine than that of purified B cells. In the current study, we investigated the role of accessory cells in DRibbles induced B cell activation. We found that cognate macrophages, but not T cells, significantly enhanced the B cell activities. Such an enhancement required cell cell contact. Furthermore, DRibbles stimulation up-regulated CD40L expression on macrophages, resulting in increased level of CD40 expressed on B cells. The accessory role of macrophages in DRibbles-activated B cells is critically dependent on the CD40/CD40L interaction. In addition, the effects of macrophages were found to be largely dependent on TLR4 and MyD88 signaling pathway. Finally, our results showed that macrophages were able to enhance the antigen presentation function of B cells for specific T cell stimulation. Thus, these results suggest that macrophages play an important accessory role for DRibbles-induced B cell immune function. PMID- 25447442 TI - The secreted Frizzled-Related Protein 2 modulates cell fate and the Wnt pathway in the murine intestinal epithelium. AB - The secreted Frizzled-Related Proteins (sFRPs) are generally considered antagonistic to Wnt signaling. However, several studies have described their synergy and/or activation of this pathway. Our own data indicated that in the intestinal epithelium, thyroid hormone induced-expression of sFRP2 stabilizes beta-catenin, leading to induction of Wnt. The aim of this work was to investigate the role of sFRP2 in the intestinal epithelium homeostasis and its specific effect on canonical Wnt pathway. In wild type animals we observed a restricted pattern of sFRP2 protein expression at the level of the intestinal crypts. Interestingly, sFRP2(-/-) mice displayed increased apoptosis within the crypts together with a defect in cell migration. Because of altered proportion of lineage-specific committed progenitors, the sFRP2(-/-) animals also showed a decrease of absorptive differentiation counterbalanced by an increase of secretory differentiation. Regarding the action of sFRP2 on canonical Wnt pathway, the lack of sFRP2 expression in sFRP2(-/-)/TopGal animals in vivo reduced the Wnt activity. This positive action of sFRP2 on Wnt was further confirmed by in vitro studies. In conclusion, in accordance with its restricted expression profile, sFRP2 contributes to the physiology of the intestinal epithelial crypt progenitors by controlling apoptosis, cell fate decisions and the Wnt pathway. PMID- 25447441 TI - Triptolide inhibits TGF-beta1-induced cell proliferation in rat airway smooth muscle cells by suppressing Smad signaling. AB - BACKGROUND: We have reported that triptolide can inhibit airway remodeling in a murine model of asthma via TGF-beta1/Smad signaling. In the present study, we aimed to investigate the effect of triptolide on airway smooth muscle cells (ASMCs) proliferation and the possible mechanism. METHODS: Rat airway smooth muscle cells were cultured and made synchronized, then pretreated with different concentration of triptolide before stimulated by TGF-beta1. Cell proliferation was evaluated by MTT assay. Flow cytometry was used to study the influence of triptolide on cell cycle and apoptosis. Signal proteins (Smad2, Smad3 and Smad7) were detected by western blotting analysis. RESULTS: Triptolide significantly inhibited TGF-beta1-induced ASMC proliferation (P<0.05). The cell cycle was blocked at G1/S-interphase by triptolide dose dependently. No pro-apoptotic effects were detected under the concentration of triptolide we used. Western blotting analysis showed TGF-beta1 induced Smad2 and Smad3 phosphorylation was inhibited by triptolide pretreatment, and the level of Smad7 was increased by triptolide pretreatment. CONCLUSIONS: Triptolide may function as an inhibitor of asthma airway remodeling by suppressing ASMCs proliferation via negative regulation of Smad signaling pathway. PMID- 25447443 TI - Angiopoietin-2 in Bone Marrow milieu promotes Multiple Myeloma-associated angiogenesis. AB - Angiopoietin-2 (Ang-2) is involved in angiogenesis in both solid and hematological malignancies. In Multiple Myeloma (MM), serum Ang-2 correlates with disease progression and response to therapy. To address the patho-physiologic role of Ang-2 in MM associated angiogenesis, we used sera from patients with active MM, which contained significantly higher levels of the molecule, compared to those from patients with smoldering MM and Monoclonal Gammopathy of Undetermined Significance. MM Bone Marrow (BM) sera with high Ang-2 concentration specifically contributed to endothelial cell (EC) activation, while Ang-1 containing sera maintained EC stabilization. The functional dichotomy of Ang-1 and Ang-2 was confirmed by the triggering of distinctive signaling pathways down stream the common Tie-2 receptor, i.e., the Akt or the ERK- phosphorylation pathway. Notably, Ang-2 but not VEGF serum levels correlated with BM micro-vessel density, further underscoring the key role of Ang-2 in angiogenesis. Western Blot, RT-PCR and immunocytochemistry identified MMEC as the major source of Ang 2, at variance with MM cells and CD14(+) BM monocytes. These data suggest that Ang-2 produced in the BM milieu may contribute to MM angiogenesis and suggest that the molecule can be further exploited both as angiogenesis biomarker and as a potential therapeutic target. PMID- 25447444 TI - A comparison among infusion of lidocaine and dexmedetomidine alone and in combination in subjects undergoing coronary artery bypass graft: a randomized trial. AB - BACKGROUND: Previous studies have reported the cardioprotective effect of dexmedetomidine and lidocaine. We compared the effect of lidocaine and dexmedetomidine infusion during off-pump coronary artery bypass graft (OPCAB). METHODS: 153 patients undergoing OPCAB were enrolled. The lidocaine group (n=36, Group LIDO) received an infusion of lidocaine 2 mg/kg/h after bolus 1.5 mg/kg; the dexmedetomidine group (n=40, Group DEX) received dexmedetomidine 0.3-0.7 MUg/kg/h; the combined group (n=39, Group Combined) received infusion of both drugs; and the control group (n=38) received nothing. We measured serum creatinine kinase-myocardial band (CK-MB) and cardiac troponin I (cTnI) concentration before and immediately after the surgery, postoperative day (POD)#1 and #2. The complication rate and clinical outcomes were compared. RESULTS: The concentration of cTnI was significantly lower in the Group LIDO and Group Combined than the control group on POD#2. The concentration of CK-MB was significantly lower in the Group LIDO and Group Combined compared to the control group on POD#1 and #2 [CK-MB on POD#1: 7.67 (5.78-11.92) vs. 7.18 (5.01-11.72) vs. 13.19 (6.85-23.87) in the Group LIDO, combined and control, respectively, Group LIDO vs. control: p=0.003, Group Combined vs. control: p=0.015]. The AUC of CK-MB was significantly lower in the Group LIDO and Group Combined than the control group. However, clinical variables including complication rate, ICU stay and one-year mortality were not different. CONCLUSIONS: Lidocaine infused at 2 mg/kg/h, but not dexmedetomidine infused at 0.3-0.7 MUg/kg/h reduced postoperative myocardial injury marker levels compared with the control group. However, no other clinical benefits were observed. PMID- 25447445 TI - Impaired border zone formation and adverse remodeling after reperfused myocardial infarction in cannabinoid CB2 receptor deficient mice. AB - AIMS: Reperfusion ofmyocardial infarction is associated with inflammatory reaction and subsequentmyocardial remodeling with a rapid scar formation in mice. The cannabinoid receptor CB2 has been associated with cardioprotection and regulation ofmacrophage function.Weinvestigated its role in remodeling of reperfused infarction. MAIN METHODS: One hour LAD-occlusion was followed by reperfusion over 6 h and 1, 3 and 7 days in wild-type C57/BL6J (WT) and CB2 receptor-deficient (Cnr2-/-)mice (n=8/group). Hearts were processed for functional, morphological and mRNA/protein analysis, and tissue concentration of endocannabinoidswas determined using liquid chromatography-multiple reaction monitoring. KEY FINDINGS: In contrast to a rapid formation of granulation tissue and a compacted non-transmural scar inWT mice after 7 days of reperfusion, Cnr2-/ mice showed a non-compacted transmural scar. Millar(r) left ventricular catheter measurements revealed a significantly worse function in Cnr2-/- mice.We found no compensatory elevation of endocannabinoid concentration in Cnr2-/- hearts. Macrophage infiltration was significantly stronger in Cnr2-/- hearts and affected also the remote septum, when compared to WT hearts.We found a cytokine-driven inflammatory response in Cnr2-/- hearts with no significant induction of chemokines. Immunohistochemistry for thrombospondin-1 revealed a dysfunctional infarction border zone formation in Cnr2-/- hearts. Cnr2-/-hearts showed no significant induction of tenascin C, collagen-Ialpha or lysil oxidase, thereby indicating adversemyocardial remodeling. SIGNIFICANCE: Endocannabinoids act via CB2 receptor in the modulation of inflammatory response and myocardial remodeling after infarction. CB2 receptor plays an important role in the formation of infarction border zone, collagen deposition and organization of stable scar during remodeling. PMID- 25447446 TI - The effects of high doses of nandrolone decanoate and exercise on prostate microvasculature of adult and older rats. AB - AIMS: The present study aimed to investigate the effects of the interaction between the abusive use of nandrolone decanoate (ND) and physical activity on the prostate structure of adult and older rats. We evaluated whether the use of ND, associated or not with physical exercise during the post-pubertal stage, interferes with the morphophysiology of the prostate. MAIN METHODS: Fifty-six male Sprague-Dawley rats were divided into eight groups. The animals were treated for eight weeks and divided into sedentary and trained groups, with or without ND use. Four groups were sacrificed 48 h after the end of the eight week experiment (adult groups), and four other groups were sacrificed at 300 days of age (older groups). The prostate was collected and processed for stereological and histopathological analysis and for the expression of AQP1 and VEGF by the Western blotting technique. KEY FINDINGS: Both ND and physical activity altered the ventral prostate structure of the rats; the AQP1 and VEGF expression increased in young animals subjected to physical exercise. SIGNIFICANCE: Thus, it was concluded that the use of ND, associated or not with exercise during the post pubertal stage, interferes with the morphophysiology of the prostate. PMID- 25447447 TI - Gap junctional regulation of pressure, fluid force, and electrical fields in the epigenetics of cardiac morphogenesis and remodeling. AB - Epigenetic factors of pressure load, fluid force, and electrical fields that occur during cardiac contraction affect cardiac development, morphology, function, and pathogenesis. These factors are orchestrated by intercellular communication mediated by gap junctions, which synchronize action potentials and second messengers. Misregulation of the gap junction protein connexin (Cx) alters cardiogenesis, and can be a pathogenic factor causing cardiac conduction disturbance, fatal arrhythmia, and cardiac remodeling in disease states such as hypertension and ischemia. Changes in Cx expression can occur even when the DNA sequence of the Cx gene itself is unaltered. Posttranslational modifications might reduce arrhythmogenic substrates, improve cardiac function, and promote remodeling in a diseased heart. In this review, we discuss the epigenetic features of gap junctions that regulate cardiac morphology and remodeling. We further discuss potential clinical applications of current knowledge of the structure and function of gap junctions. PMID- 25447448 TI - A novel highly potent and selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitor, UI-1499. AB - AIMS: Elevated levels of glucocorticoid hormones cause glucose intolerance, visceral obesity, insulin resistance, hypertension, and dyslipidemia. 11beta Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) represents as an attractive therapeutic target for treatment of metabolic syndrome and type 2 diabetes. This study investigated whether 11beta-HSD1 inhibition by a novel selective inhibitor, (1S,3R,4S,5S,7S)-4-(1-((2-fluoro-N-methylphenylsulfonamido)-methyl) cyclopropanecarboxamido) adamantane-1-carboxamide (UI-1499) ameliorated metabolic abnormalities in diabetic mice. MAIN METHODS: The in vitro activity of 11beta HSD1 was measured using the homogeneous time resolved fluorescence (HTRF) assay. Differentiated adipocytes were used to evaluate cellular 11beta-HSD1 activity. To determine the inhibitory effects on 11beta-HSD1 in tissues, we performed ex vivo studies using liver and epididymal fat isolated from C57BL/6J mice. KKAy mice were administered with UI-1499 to evaluate whether this compound ameliorated metabolic abnormalities in vivo in diabetic animals. KEY FINDINGS: UI-1499 had highly potent inhibitory activity in mouse, monkey and human 11beta-HSD1, derived from liver microsomes. Oral administration of 45 mg/kg UI-1499 significantly inhibited 11beta-HSD1 activity in C57BL/6J mouse liver and epididymal fat tissues. In KKAy mice, oral administration of UI-1499 (10 and 30 mg/kg for 3 weeks) lowered fasting blood glucose and HbA1c levels; these effects were comparable to those of pioglitazone. Further, UI-1499 treatment lowered plasma low-density lipoprotein (LDL) level in KKAy mice. SIGNIFICANCE: These results suggest that the 11beta-HSD1 inhibitor, UI-1499, may serve as a novel drug candidate for the treatment of type 2 diabetes and metabolic syndrome. PMID- 25447450 TI - Cod liver oil ameliorates sodium nitrite-induced insulin resistance and degradation of rat hepatic glycogen through inhibition of cAMP/PKA pathway. AB - AIMS: Sodium nitrite is used to inhibit the growth of microorganisms and is responsible for the desirable red color of meat; however, it can be toxic in high quantities for humans and other animals. Moreover, glycogen, a branched polysaccharide, efficiently stores and releases glucose monosaccharides to be accessible for metabolic and synthetic requirements of the cell. Therefore, we examined the impact of dietary sodium nitrite and cod liver oil on liver glycogen. MAIN METHODS: Thirty-two Sprague-Dawley rats were treated daily with sodium nitrite (80 mg/kg) in the presence/absence of cod liver oil (5 ml/kg). Liver sections were stained with Periodic acid-Schiff. Hepatic homogenates were used for measurements of glycogen, cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), glycogen synthase, glycogen synthase kinase, pyruvate carboxylase, fructose 1,6-diphosphatase, glucose 6-phosphatase, phosphodiesterase and glycogen phosphorylase. Glucose, pyruvate tolerances and HOMA insulin resistance were also determined. KEY FINDINGS: Sodium nitrite significantly increased plasma glucose and insulin resistance. Moreover, sodium nitrite significantly reduced hepatic glycogen content as well as activities of glycogen synthase, glycogen synthase kinase-3, and phosphodiesterase. Sodium nitrite elevated hepatic cAMP, PKA, pyruvate carboxylase, fructose 1,6-diphosphatase, glucose 6-phosphatase and phosphorylase. Cod liver oil significantly blocked all of these except pyruvate carboxylase, fructose 1,6-diphosphatase and glucose 6 phosphatase. SIGNIFICANCE: Sodium nitrite inhibited liver glycogenesis and enhanced liver glycogenolysis and gluconeogenesis, which is accompanied by hyperglycemia and insulin resistance through the activation of cAMP/PKA and the inhibition of phosphodiesterase. Cod liver oil blocked the sodium nitrite effects on glycogenesis and glycogenolysis without affecting gluconeogenesis. PMID- 25447449 TI - Central adenosine A1 and A2A receptors mediate the antinociceptive effects of neuropeptide S in the mouse formalin test. AB - AIMS: The present study aimed to investigate the intraplantar (ipl) and central (icv) effects of neuropeptide S (NPS) in the formalin test and to evaluate the role of adenosine receptors, mainly A1 and A2A, in mediating such effects. MAIN METHODS: The ipl injection of formalin was used to assess the nociceptive activity. Moreover, by pretreating mice with non-selective and selective antagonists of adenosine receptors, the effects of icv NPS on formalin-induced ongoing nociception were assessed. KEY FINDINGS: Morphine-induced antinociceptive effects were observed during phases 1 and 2 of the test, while indomethacin was active only at the later nociceptive phase. The ipl injection of NPS (alone or combined with formalin) did not modify the nociceptive response. However, icv NPS significantly reduced formalin-induced nociception during both phases. Caffeine (3 mg/kg, ip), a non-selective adenosine receptor antagonist, prevented NPS induced antinociceptive effects. Similar to caffeine, icv ZM241385 (0.01 nmol), an A2A receptor antagonist, prevented the antinociceptive effects of NPS. Moreover, icv DPCPX (0.001 nmol), an A1 receptor antagonist, blocked the effects of NPS only during phase 1. SIGNIFICANCE: The above findings suggest that: (i) NPS evokes central antinociceptive effects by activating both A1 and A2A receptors during phase 1, but (ii) only the adenosine A2A receptor during phase 2 of the formalin test. PMID- 25447451 TI - Androgen therapy reverses injuries caused by ethanol consumption in the prostate: testosterone as a possible target to ethanol-related disorders. AB - AIMS: Chronic ethanol consumption leads to reproductive damages, since it can act directly in the tissues or indirectly, causing a hormonal imbalance. Prostate is a hormone-dependent gland and, consequently, susceptible to ethanol. The potential of testosterone therapy in the ethanol-related disorders was investigated in the prostate microenvironment. MAIN METHODS: UChB rats aged 90 days were divided into 2 experimental groups (n=20): C: drinking water only and EtOH: drinking 10% (v/v) ethanol at >2 g/kg body weight/day+water. At 150 days old, 10 rats from each group received subcutaneous injections of testosterone cypionate (5 mg/kg body weight) diluted in corn oil every other day for 4 weeks, constituting T and EtOH+T, while the remaining animals received corn oil as vehicle. Animals were euthanized at 180 days old, by decapitation. Blood was collected to obtain hormone concentrations and ventral prostate was dissected and processed for light microscope and molecular analyses. KEY FINDINGS: Ventral prostate weight, plasma testosterone and DHT and intraprostatic testosterone concentrations were increased after testosterone treatment. Plasma estradiol level was reduced in the EtOH+T. Inflammatory foci, metaplasia and epithelial atrophy were constantly found in the prostate of EtOH and were not observed after hormonal therapy. No differences were found in the expression of AR, ERbeta and DACH-1. Additionally, testosterone treatment down-regulated ERalpha and increased the e-cadherin and alpha-actinin immunoreactivities. SIGNIFICANCE: Testosterone was able to reverse damages caused by ethanol consumption in the prostate microenvironment and becomes a possible target to be investigated to ethanol related disorders. PMID- 25447452 TI - Fungal metabolite myriocin promotes human herpes simplex virus-2 infection. AB - AIMS: Myriocin is a fungal metabolite with antiviral activity, including influenza, hepatitis B, and hepatitis C viruses. We investigated whether myriocin has activity against human HSV-2, one of the most prevalent pathogens of sexually transmitted disease. MAIN METHODS: Cell culture systems were used to evaluate myriocin effect on HSV-2 infection. Plaque forming assay and immunoblotting studies were used to determine virus production and viral protein expression, respectively. KEY FINDINGS: Myriocin showed no cytotoxic effect at up to 5 MUM. Myriocin treatment did not inhibit HSV-2 infection. Instead, the treatment resulted in accelerated replication of HSV-2 and increased titers of infectious virion. The effect was detected at concentrations as low as 3 nM and plateaued at approximately 30 nM. Myriocin at 30 nM increased HSV-2 production by approximately 1.7 logs. Myriocin also promoted HSV-1 infection but required higher concentrations. A time course study revealed that myriocin promoted HSV-2 infection by acceleration of virus replication. Unlike trichostatin A that promotes HSV-2 infection and histone modifications, myriocin treatment did not alter histone modifications. Myriocin is a well characterized inhibitor of sphingolipid biosynthesis pathway. Structurally different inhibitors of the pathway showed no effect on HSV-2 infection. Exogenous sphingolipids did not reverse the effect of myriocin on HSV-2 infection either. SIGNIFICANCE: We found that myriocin promotes HSV-2 replication at nanomolar concentrations with yet unknown mechanisms. Further studies may uncover novel mechanisms regulating HSV replication and targets of myriocin action. This may have potential application in enhancing efficacy of oncolytic HSV for cancer therapy and other diseases. PMID- 25447453 TI - Firefighters' exposure to perfluoroalkyl acids and 2-butoxyethanol present in firefighting foams. AB - The aim of this study was to assess eight firefighters' exposure to Sthamex 3% AFFF (aqueous film forming foam) in the simulation of aircraft accidents at Oulu airport in Finland. Study was conducted in 2010 before limitation for the use of PFOA and PFOS in AFFFs. Due to prospective limitation also eight commercially available AFFFs were evaluated from occupational and environmental point of view to find substitutive AFFFs for future. The firefighters' exposure to twelve perfluoroalkyl acids (PFAS) was analyzed in order to observe the signs of accumulation during three consecutive training sessions. The firefighters' short term exposure to 2-butoxyethanol (EGBE) was analyzed by urinalysis of 2 butoxyacetic acid (2-BAA). For the background information also the concentration of PFAS in used AFFF-liquid was analyzed. Fire fighters' serum PFHxS and PFNA concentrations seemed to increase during the three training sessions although they were not the main PFAS in used AFFF. The statistical significance for the elevations was not able to test due to limited size of test group. In two training sessions, the average urinary excretions of 2-BAA exceeded the reference limit of the occupationally unexposed population. In the evaluations of the firefighting foams, non-fluorine based products were favored and the alcohol resistance properties of foams were recommended for consideration due to the increasing use of biofuels. PMID- 25447454 TI - Metabolic polymorphisms and biomarkers of effect in the biomonitoring of occupational exposure to low-levels of benzene: state of the art. AB - Current levels of occupational exposure to benzene, a genotoxic human carcinogen, in Western countries are reduced by two-three orders of magnitude (from ppm to ppb) as compared to the past. However, as benzene toxicity is strongly dependent on biotransformation and recent evidence underlines a higher efficiency of bio activation pathways at lower levels of exposure, toxic effects at low doses could be higher than expected, particularly in susceptible individuals. Currently, biological monitoring can allow accurate exposure assessment, relying on sensitive and specific enough biomarkers of internal dose. The availability of similarly reliable biomarkers of early effect or susceptibility could greatly improve the risk assessment process to such an extent that risk could even be assessed at the individual level. As to susceptibility biomarkers, functional genetic polymorphisms of relevant biotransformation enzymes may modulate the risk of adverse effects (NQO1) and the levels of biomarkers of internal dose, in particular S-phenylmercapturic acid (GSTM1, GSTT1, GSTA1). Among biomarkers of early effect, genotoxicity indicators, although sensitive in some cases, are too aspecific for routine use in occupational health surveillance programmes. Currently only the periodical blood cell count seems suitable enough to be applied in the longitudinal monitoring of effects from benzene exposure. Novel biomarkers of early effect are expected from higher collaboration among toxicologists and clinicians, also using advanced "omics" techniques. PMID- 25447455 TI - Ethics in biomonitoring for occupational health. AB - Biological monitoring, i.e., the use of biomarkers for the measurement of systemic human exposure, effects and susceptibility to chemicals has increased considerably in recent years. Biomonitoring techniques, originally limited to a few metals and other chemicals in the workplace, are currently applied to a large number of exposure situations and have become a useful tool for occupational and environmental health risk assessment. Almost any biomonitoring program, however, entails a number of relevant ethical issues, which concern all the phases of the entire process, from the selection of the biomarker to the study design, from the collection, storage and analysis of the biological sample to the interpretation, communication and management of the results, from the (truly?) informed consent of the worker to the independence and autonomy of the occupational health professional. These issues require a balanced assessment of the interests and responsibilities of all the parties, the worker primarily, but also the employer, the occupational health professional, the health authorities and, for research studies on new biomarkers, also the scientists involved. Ideally, decisions of ethical relevance concerning biomarkers should be based on, and respectful of the best scientific, legal and ethical evidence available. When, however, a conflict should arise, before any decision is taken a thorough risk-benefit analysis should be done, at the beginning of the process and after listening to the workers and the management involved, by the occupational physician or scientist, based on his/her professional experience, independent judgement and individual responsibility. PMID- 25447456 TI - Were the wrong cells studied? AB - Peripheral blood lymphocytes (PBL) studying the effects of dioxins and dioxin like compounds in vitro is not correct. Peripheral lymphocytes in general (Th1, Th2) do not have an Ah-receptor. Polymorphonuclear leucocytes (PMN's) are more logical to use. PMID- 25447457 TI - Tobacco smoking-response genes in blood and buccal cells. AB - Tobacco smoking is a well-known cause of various diseases, however, its toxic mechanisms for diseases are not completely understood, yet. Therefore, we performed biological monitoring to find tobacco smoking-responsive mechanisms including oxidative stress in Korean men (N=36). Whole genome microarray analyses were performed with peripheral blood from smokers and age-matched nonsmokers. We also performed qRT-PCR to confirm the microarray results and compared the gene expression of blood to those of buccal cells. To assess the effects of tobacco smoking on oxidative stress, we analyzed urinary levels of malondialdehyde (MDA), a lipid peroxidation marker, and performed PCR-based arrays on reactive oxygen species (ROS)-related genes. As results, 34 genes were differently expressed in blood between smokers and nonsmokers (ps<0.01 and >1.5-fold change). Particularly, the genes involved in immune responsive pathways, e.g., the Fcgamma receptor mediated phagocytosis and the leukocyte transendothelial migration pathways, were differentially expressed between smokers and nonsmokers. Among the above genes, the ACTG1, involved in the maintenance of actin cytoskeleton, cell migration and cancer metastasis, was highly expressed by smoking in both blood and buccal cells. Concerning oxidative stress, smokers showed high levels of urinary MDA and down-regulation of expressions of antioxidant related genes including TPO, MPO, GPX2, PTGR1, and NUDT1 as compared to nonsmokers (ps<0.05). In conclusion, these results suggest that systemically altered immune response and oxidative stress can be tobacco-responsive mechanisms for the related diseases. Based on consistent results in blood and buccal cells, expression of the ACTG1 can be a tobacco smoking-responsive biomarker. PMID- 25447459 TI - Studies on potential use of tin(IV) porphyrin in a role of proteins' label. AB - We present an electrochemical and optical characterization of 5,10,15,20 tetraphenylporphyrin tin(IV) dichloride (Sn-tpp) in terms of its potential use as a hybrid proteins' label. Our research comprised Sn-tpp and Sn-tpp in the presence of model proteins selected as to mimic a receptor or surface blocking agents: bovine serum albumin, ovalbumin, and immunoglobulin G. In the course of the study, we determined optimal conditions for analysis by means of differential pulse voltammetry, ultraviolet-visible spectrophotometry, and spectrofluorimetry. In electrochemical detection, the influence of the working electrode, solvent, and supporting electrolyte was examined. Displacements of the received signals along the potential axis (a shift of the potential) and changes in signal intensities due to the addition of proteins were observed and analyzed. Simultaneously, the suitability of Sn-tpp as a label in optical detection mode was assessed by using spectroscopic techniques. The obtained results prove Sn-tpp to be applicable in dual and triple detection systems. Such an approach will improve the reliability of the analysis and, at the same time, will allow for widening the range of the linear response with some overlapping ranges of concentrations. PMID- 25447458 TI - A multifactorial screening strategy to identify anti-idiotypic reagents for bioanalytical support of antibody therapeutics. AB - Antibodies are critical tools for protein bioanalysis; their quality and performance dictate the caliber and robustness of ligand binding assays. After immunization, polyclonal B cells generate a diverse antibody repertoire against constant and variable regions of the therapeutic antibody immunogen. Herein we describe a comprehensive and multifactorial screening strategy to eliminate undesirable constant region-specific antibodies and select for anti-idiotypic antibodies with specificity for the unique variable region. Application of this strategy is described for the therapeutic antibody Mab-A case study. Five different factors were evaluated to select a final antibody pair for the quantification of therapeutics in biological matrices: (i) matrix effect in preclinical and clinical matrices, (ii) assay sensitivity with lower limit of quantification goal of single-digit ng/ml (low pM) at a signal-to-background ratio greater than 5, (iii) epitope distinction or nonbridging antibody pair, (iv) competition with target and inhibitory capacity enabling measurement of free drug, and (v) neutralizing bioactivity using bioassay. The selected antibody pair demonstrated superior assay sensitivity with no or minimal matrix effect in common biological samples, recognized two distinct binding epitopes on the therapeutic antibody variable region, and featured inhibitory and neutralizing effects with respect to quantification of free drug levels. PMID- 25447461 TI - Design of turbulent tangential micro-mixers that mix liquids on the nanosecond time scale. AB - Unravelling (bio)chemical reaction mechanisms and macromolecular folding pathways on the (sub)microsecond time scale is limited by the time resolution of kinetic instruments for mixing reactants and observation of the progress of the reaction. To improve the mixing time resolution, turbulent four- and two-jet tangential micro-mixers were designed and characterized for their mixing and (unwanted) premixing performances employing acid-base reactions monitored by a pH-sensitive fluorescent dye. The mixing performances of the micro-mixers were determined after the mixing chamber in a free-flowing jet. The premixing behavior in the vortex chamber was assessed in an optically transparent glass-silicon replica of a previously well-characterized stainless-steel four-jet tangential micro-mixer. At the highest flow rates, complete mixing was achieved in 160ns with only approximately 9% premixing of the reactants. The mixing time of 160ns is at least 50 times shorter than estimated for other fast mixing devices. Key aspects to the design of ultrafast turbulent micro-mixers are discussed. The integration of these micro-mixers with an optical flow cell would enable the study of the very onset of chemical reactions in general and of enzyme catalytic reactions in particular. PMID- 25447460 TI - Hi-Plex targeted sequencing is effective using DNA derived from archival dried blood spots. AB - Many genetic epidemiology resources have collected dried blood spots (predominantly as Guthrie Cards) as an economical and efficient means of archiving sources of DNA, conferring great value to genetic screening methods that are compatible with this medium. We applied Hi-Plex to screen the breast cancer predisposition gene PALB2 in 93 Guthrie Card-derived DNA specimens previously characterized for PALB2 genetic variants via DNA derived from lymphoblastoid cell lines, whole blood, and buffy coat. Of the 93 archival Guthrie Card-derived DNAs, 92 (99%) were processed successfully and sequenced using approximately half of a MiSeq run. From these 92 DNAs, all 59 known variants were detected and no false-positive variant calls were yielded. Fully 98.13% of amplicons (5417/5520) were represented within 15-fold of the median coverage (2786 reads), and 99.98% of amplicons (5519/5520) were represented at a depth of 10 read-pairs or greater. With Hi-Plex, we show for the first time that a High-Plex amplicon-based massively parallel sequencing (MPS) system can be applied effectively to DNA prepared from dried blood spot archival specimens and, as such, can dramatically increase the scopes of both method and resource. PMID- 25447462 TI - Method for measuring lipid mediators, proteins, and messenger RNAs from a single tissue specimen. AB - This article describes a new method for extracting RNA, protein, and lipid mediators from a single tissue specimen. Specifically, mouse bone fracture callus specimens were extracted into a single solution that was processed using three different procedures to measure messenger RNA (mRNA) levels by reverse transcription-quantitative polymerase chain reaction (RTqPCR), cytokines and growth factors using an xMAP method, and lipid mediators by liquid chromatography tandem mass spectrometry (LC-MS/MS). This method has several advantages because it decreases the number of animals necessary for experimentation, allows division of the sample from a homogeneous mixture that reduces sample variability, and uses a solution that protects the integrity of the macromolecules during storage. PMID- 25447463 TI - Creating highly amplified enzyme-linked immunosorbent assay signals from genetically engineered bacteriophage. AB - For early detection of many diseases, it is critical to be able to diagnose small amounts of biomarkers in blood or serum. One of the most widely used sensing assays is the enzyme-linked immunosorbent assay (ELISA), which typically uses detection monoclonal antibodies conjugated to enzymes to produce colorimetric signals. To increase the overall sensitivities of these sensors, we demonstrate the use of a dually modified version of filamentous bacteriophage Fd that produces significantly higher colorimetric signals in ELISAs than what can be achieved using antibodies alone. Because only a few proteins at the tip of the micron-long bacteriophage are involved in antigen binding, the approximately 4000 other coat proteins can be augmented-by either chemical functionalization or genetic engineering-with hundreds to thousands of functional groups. In this article, we demonstrate the use of bacteriophage that bear a large genomic fusion that allows them to bind specific antibodies on coat protein 3 (p3) and multiple biotin groups on coat protein 8 (p8) to bind to avidin-conjugated enzymes. In direct ELISAs, the anti-rTNFalpha (recombinant human tumor necrosis factor alpha) conjugated bacteriophage show approximately 3- to 4-fold gains in signal over that of anti-rTNFalpha, demonstrating their use as a platform for highly sensitive protein detection. PMID- 25447464 TI - Apoptotic primary normal human dermal fibroblasts for in vitro models of fibrosis. AB - Recent studies show that apoptosis affects surrounding tissue, playing a role in diseases such as fibrosis, a significant global disease burden. Elucidating the mechanisms by which the different apoptotic cells present during fibrotic wound healing affect their environment would enable development of new therapies. We describe here a simple, rapid, and cost-effective method for inducing apoptosis of primary normal human dermal fibroblasts without affecting the overall cell viability of the population. Such population could be used for in vitro models of fibrotic wound healing in co-culture with other cells involved in this process to study events such as apoptosis-induced proliferation. PMID- 25447465 TI - Intact cell mass spectrometry as a progress tracking tool for batch and fed-batch fermentation processes. AB - Penicillin production during a fermentation process using industrial strains of Penicillium chrysogenum is a research topic permanently discussed since the accidental discovery of the antibiotic. Intact cell mass spectrometry (ICMS) can be a fast and novel monitoring tool for the fermentation progress during penicillin V production in a nearly real-time fashion. This method is already used for the characterization of microorganisms and the differentiation of fungal strains; therefore, the application of ICMS to samples directly harvested from a fermenter is a promising possibility to get fast information about the progress of fungal growth. After the optimization of the ICMS method to penicillin V fermentation broth samples, the obtained ICMS data were evaluated by hierarchical cluster analysis or an in-house software solution written especially for ICMS data comparison. Growth stages of a batch and fed-batch fermentation of Penicillium chrysogenum are differentiated by one of those statistical approaches. The application of two matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) instruments in the linear positive ion mode from different vendors demonstrated the universal applicability of the developed ICMS method. The base for a fast and easy-to-use method for monitoring the fermentation progress of P. chrysogenum is created with this ICMS method developed especially for fermentation broth samples. PMID- 25447466 TI - Peptide nucleic acid probe for protein affinity purification based on biotin streptavidin interaction and peptide nucleic acid strand hybridization. AB - We describe a new method for protein affinity purification that capitalizes on the high affinity of streptavidin for biotin but does not require dissociation of the biotin-streptavidin complex for protein retrieval. Conventional reagents place both the selectively reacting group (the "warhead") and the biotin on the same molecule. We place the warhead and the biotin on separate molecules, each linked to a short strand of peptide nucleic acid (PNA), synthetic polymers that use the same bases as DNA but attached to a backbone that is resistant to attack by proteases and nucleases. As in DNA, PNA strands with complementary base sequences hybridize. In conditions that favor PNA duplex formation, the warhead strand (carrying the tagged protein) and the biotin strand form a complex that is held onto immobilized streptavidin. As in DNA, the PNA duplex dissociates at moderately elevated temperature; therefore, retrieval of the tagged protein is accomplished by a brief exposure to heat. Using iodoacetate as the warhead, 8 base PNA strands, biotin, and streptavidin-coated magnetic beads, we demonstrate retrieval of the cysteine protease papain. We were also able to use our iodoacetyl-PNA:PNA-biotin probe for retrieval and identification of a thiol reductase and a glutathione transferase from soybean seedling cotyledons. PMID- 25447468 TI - Exercise improves learning and memory impairments in sleep deprived female rats. AB - Inadequate sleep is a common problem in modern societies. It has been previously shown that female rats are more vulnerable to the deleterious effects of sleep deprivation on cognitive functions. Physical exercise has been suggested to attenuate the cognitive impairments induced by sleep deprivation in male rats. The objective of the current study was to investigate the effects of physical exercise on cognitive functions of female rats following paradoxical sleep deprivation. Intact and ovariectomized (OVX) female Wistar rats were used in the present study. The exercise protocol was 4 weeks of treadmill running. The multiple platform method was applied for the induction of 72h paradoxical sleep deprivation and the cognitive function was evaluated using Morris water maze (MWM). Plasma corticosterone level was evaluated in separate groups of study. ANOVA and repeated measures were used to analyze the data and P<0.05 was considered statistically significant. Throughout the investigation, significant learning impairment was observed in sleep-deprived OVX rats compared to the intact and the other OVX groups. Short term memory impairment was observed in both sleep-deprived OVX and intact groups. Physical exercise alleviated the PSD induced learning and memory impairments in both intact and OVX groups. Corticosterone levels were not statistically significant among the different groups. The results of our study confirmed the negative effects of PSD on cognitive functions in female rats and regular physical exercise seems to protect rats from these effects. Further studies are suggested to be carried out in order to evaluate the possible underlying mechanisms, and also to evaluate the possible interactions between sex hormones and PSD-induced cognitive impairments. PMID- 25447469 TI - The effect of developmental vitamin D deficiency in male and female Sprague Dawley rats on decision-making using a rodent gambling task. AB - Developmental vitamin D (DVD) deficiency is a plausible risk factor for schizophrenia that has been associated with behavioural alterations including disruptions in latent inhibition and response inhibition. The rodent gambling task (rGT) assesses risk-based decision-making, which is a key cognitive deficit observed in schizophrenia patients. The primary aim of this study was to examine risk-based decision-making in DVD-deficient and control rats on the rGT. We also evaluated the performance of female Sprague-Dawley rats on the rGT for the first time. Adult male and female Sprague-Dawley rats from control and vitamin D deficient dams were trained to perform the rGT in standard operant chambers and their performance and choice-preferences were assessed. Female rats were significantly faster to reach rGT training criteria compared with male rats and DVD-deficient rats were faster to reach training criteria than control animals. After reaching stable performance on the rGT DVD-deficient and control rats showed a significant preference for the optimal choice-option in the rGT, but there were no significant effects of sex or diet on these responses. DVD deficiency did not alter the decision-making processes on the rGT because no significant changes in choice-preferences were evident. This is the first study to demonstrate that once established, the performance of females is comparable to male Sprague-Dawley rats on the rGT. PMID- 25447467 TI - Web-enhanced tobacco tactics with telephone support versus 1-800-QUIT-NOW telephone line intervention for operating engineers: randomized controlled trial. AB - BACKGROUND: Novel interventions tailored to blue collar workers are needed to reduce the disparities in smoking rates among occupational groups. OBJECTIVE: The main objective of this study was to evaluate the efficacy and usage of the Web enhanced "Tobacco Tactics" intervention targeting operating engineers (heavy equipment operators) compared to the "1-800-QUIT-NOW" telephone line. METHODS: Operating engineers (N=145) attending one of 25 safety training sessions from 2010 through 2012 were randomized to either the Tobacco Tactics website with nurse counseling by phone and access to nicotine replacement therapy (NRT) or to the 1-800-QUIT-NOW telephone line, which provided an equal number of phone calls and NRT. The primary outcome was self-reported 7-day abstinence at 30-day and 6 month follow-up. The outcomes were compared using chi-square tests, t tests, generalized mixed models, and logistic regression models. RESULTS: The average age was 42 years and most were male (115/145, 79.3%) and white (125/145, 86.2%). Using an intent-to-treat analysis, the Tobacco Tactics website group showed significantly higher quit rates (18/67, 27%) than the 1-800-QUIT NOW group (6/78, 8%) at 30-day follow-up (P=.003), but this difference was no longer significant at 6-month follow-up. There were significantly more positive changes in harm reduction measures (quit attempts, number of cigarettes smoked per day, and nicotine dependence) at both 30-day and 6-month follow-up in the Tobacco Tactics group compared to the 1-800-QUIT-NOW group. Compared to participants in the 1-800 QUIT NOW group, significantly more of those in the Tobacco Tactics website group participated in the interventions, received phone calls and NRT, and found the intervention helpful. CONCLUSIONS: The Web-enhanced Tobacco Tactics website with telephone support showed higher efficacy and reach than the 1-800-QUIT-NOW intervention. Longer counseling sessions may be needed to improve 6-month cessation rates. TRIAL REGISTRATION: Clinicaltrials.gov NCT01124110; http://clinicaltrials.gov/ct2/show/NCT01124110 (Archived by WebCite at http://www.webcitation.org/6TfKN5iNL). PMID- 25447470 TI - Differential effects of quercetin on hippocampus-dependent learning and memory in mice fed with different diets related with oxidative stress. AB - High fat diets induce oxidative stress which may be involved in neurodegenerative diseases. Quercetin is a kind of antioxidant that has neuroprotective effects and potent7ial pro-oxidant effects as well. In this study, we evaluated cognitive function in mice fed with high fat diets and basic diets with or without quercetin. Male Chinese Kunming (KM) mice were randomly assigned to five groups fed with basic diet (Control), basic diet with 0.005% (w/w) quercetin (CQ1), high fat diet (HFD), HFD with 0.005% (w/w) quercetin (HFDQ1) and 0.01% (w/w) quercetin (HFDQ2) for 13weeks. At the end of the study period, fasting blood glucose (FBG), plasma and hippocampal markers of oxidative stress, plasma lipid status, Morris water maze as well as hippocampal relative mRNA expression of akt, bdnf, camkII, creb, gsk-3beta, nrf2 and pi3k were examined. The results suggested that in comparison to the control group, the escape latency was increased and percent time spent in the target quadrant was decreased, with increased reactive carbonyls, malondialdehyde (MDA) and declined expression of pi3k, akt, nrf2, creb and bdnf in the hippocampus of HFD and CQ1 groups. Conversely, higher quercetin supplemented to HFD improved antioxidant capacity and reversed cognitive decline completely. Significant correlations between the redox status and cognition related gene expression were observed as well (P<0.05). Thus, in the case of oxidative stress, an appropriate dose of quercetin can attenuate oxidative stress to improve hippocampus dependent cognition. But under a balanced situation, quercetin exerts pro-oxidant effects to impair cognition. PMID- 25447471 TI - Affective modulation of the startle reflex and the Reinforcement Sensitivity Theory of personality: The role of sensitivity to reward. AB - This study evaluated differences in the amplitude of startle reflex and Sensitivity to Reward (SR) and Sensitivity to Punishment (SP) personality variables of the Reinforcement Sensitivity Theory (RST). We hypothesized that subjects with higher scores in SR would obtain a higher startle reflex when exposed to pleasant pictures than lower scores, while higher scores in SP would obtain a higher startle reflex when exposed to unpleasant pictures than subjects with lower scores in this dimension. The sample consisted of 112 healthy female undergraduate psychology students. Personality was assessed using the short version of the Sensitivity to Punishment and Sensitivity Reward Questionnaire (SPSRQ). Laboratory anxiety was controlled by the State Anxiety Inventory. The startle blink reflex was recorded electromyographically (EMG) from the right orbicularis oculi muscle as a response to the International Affective Picture System (IAPS) pleasant, neutral and unpleasant pictures. Subjects higher in SR obtained a significant higher startle reflex response in pleasant pictures than lower scorers (48.48 vs 46.28, p<0.012). Subjects with higher scores in SP showed a light tendency of higher startle responses in unpleasant pictures in a non parametric local regression graphical analysis (LOESS). The findings shed light on the relationships among the impulsive-disinhibited personality, including sensitivity to reward and emotions evoked through pictures of emotional content. PMID- 25447472 TI - Influence of muscarinic receptor modulators on interacerebroventricular injection of arachydonylcyclopropylamide induced antinociception in mice. AB - The interaction between antinociception induced by CB1 agonist and muscarinic receptor modulators has not been studied yet. In the present study, the effect of pilocarpine (a muscarinic agonist) and atropine (a muscarinic antagonist) on arachidonylcyclopropylamide (ACPA, a CB1 agonist) induced antinociception was studied in mice. In this study the antinociceptive effect of intracerebroventricular administration of ACPA (0.001-2 MUg/mice) or intraperitoneal injection of pilocarpine (2.5-20mg/kg) or atropine (1 and 5mg/kg) were studied individually. Then the effect of co-administration of pilocarine (2.5mg/kg) or atropine (5mg/kg) and ACPA (0.001-2 MUg/mice) were studied as well. ACPA and pilocarpine induced antinociception in mice but atropine did not. Pilocarpine potentiated but atropine antagonized the antinociceptive effect of ACPA. It is concluded that ACPA induced antinociception is influenced by muscarinic receptor modulators in mice. PMID- 25447474 TI - Effects of daytime light exposure on cognitive brain activity as measured by the ERP P300. AB - Exposure to light modulates not only human alertness but also cognitive functions. The present study examined the temporal dynamics of the effects of light exposure on cortical activity related to cognitive processes. Event-related potentials (ERPs) were measured while participants performed an auditory oddball task during exposure to short-, medium- or long-wavelength light or darkness. Experiments were conducted in the daytime. After a 10-min period of darkness, one of the three lights was presented for 28 min. In the control condition, darkness was maintained for the entire session. The ERP component observed approximately 300 ms after the onset of the target stimulus (P300) was analyzed. The amplitude of P300 was larger after 5-20 min of exposure to short-wavelength light than at equivalent time points in the darkness. No differences were observed in the amplitude of P300 between the medium- or long-wavelength light condition and darkness at any time point. These results suggest that the amount of attentional resource allocated to the oddball task was increased by daytime exposure to short wavelength light, and that following approximately 5 min of exposure the impact of light on cortical activity related to cognitive processes was able to be detected. PMID- 25447473 TI - Fear conditioning suppresses large-conductance calcium-activated potassium channels in lateral amygdala neurons. AB - It was previously shown that depression-like behavior is accompanied with suppression of the large-conductance calcium activated potassium (BK) channel in cingulate cortex pyramidal cells. To test whether BK channels are also involved in fear conditioning, we studied neuronal properties of amygdala principal cells in fear conditioned mice. After behavior, we made brain slices containing the amygdala, the structure critically relevant to fear memory. The resting membrane potential in lateral amygdala (LA) neurons obtained from fear conditioned mice (FC group) was more depolarized than in neurons from naive controls. The frequencies of spikes evoked by current injections were higher in neurons from FC mice, demonstrating that excitability of LA neurons was elevated by fear conditioning. The depolarization in neurons from FC mice was shown to depend on BK channels by using the BK channel blocker charybdotoxin. Suppression of BK channels in LA neurons from the FC group was further confirmed on the basis of the spike width, since BK channels affect the descending phase of spikes. Spikes were broader in the FC group than those in the naive control in a manner dependent on BK channels. Consistently, quantitative real-time PCR revealed a decreased expression of BK channel mRNA. The present findings suggest that emotional disorder manifested in the forms of fear conditioning is accompanied with BK channel suppression in the amygdala, the brain structure critical to this emotional disorder. PMID- 25447475 TI - The gustin (CA6) gene polymorphism, rs2274333 (A/G), is associated with fungiform papilla density, whereas PROP bitterness is mostly due to TAS2R38 in an ethnically-mixed population. AB - PROP responsiveness is associated with TAS2R38 haplotypes and fungiform papilla density. Recently, we showed that a polymorphism in the gene coding for the salivary trophic factor, gustin (CA6), affects PROP sensitivity by acting on cell growth and fungiform papillae maintenance, in a genetically homogeneous cohort. Since population homogeneity can lead to over estimation of gene effects, the primary aim of the present work was to confirm gustin's role in PROP bitterness intensity and fungiform papillae density in a genetically diverse population. Eighty subjects were genotyped for both genes by PCR techniques. PROP responsiveness was assessed by a filter paper method and fungiform papilla density was determined in each subject. As expected, PROP bitterness ratings were lower in individuals with the AVI/AVI diplotype of TAS2R38 than in individuals with PAV/PAV and PAV/AVI diplotypes. However, no differences in PROP bitterness among genotypes of the gustin gene, and no differences in the density of fungiform papillae related to TAS2R38 diplotype were found. In contrast, the density of fungiform papillae decreased as the number of minor (G) alleles at the gustin locus increased. In addition, the distribution of TAS2R38 genotypes within each gustin genotype group showed that the occurrence of recessive alleles at both loci was infrequent in the present sample compared to other populations. These findings confirm that papillae density is associated with gustin gene polymorphism, rs2274333 (A/G), in an ancestrally heterogeneous population, and suggest that variations in the frequency of allele combinations for these two genes could provide a salient explanation for discrepant findings for gustin gene effects across populations. PMID- 25447476 TI - Point pressure sensitivity in early stage Parkinson's disease. AB - A number of sensory changes occur in the earliest stages of Parkinson's disease (PD), some of which precede the expression of the classic motor phenotype by years (e.g., olfactory dysfunction). Whether point pressure sensitivity (PPS), a cutaneous measure of light touch mediated by myelinated Abeta fibers, is altered in early PD is not clear. Prior studies on this point are contradictory and are based on non-forced-choice threshold tests that confound the sensitivity measure with the response criterion. While alpha-synuclein pathology, a defining feature of PD, is present in the skin of PD patients, it is restricted to unmyelinated nerve fibers, suggesting PPS may be spared in this disease. We determined PPS thresholds using a state-of-the-art forced-choice staircase threshold test paradigm in 29 early stage PD patients and 29 matched controls at 11 body sites: the center of the forehead and the left and right forearms, index fingers, palms, medial soles of the feet, and plantar halluces. The patients were tested, in counterbalanced sessions, both on and off dopamine-related medications (DRMs). PPS was not influenced by PD and did not correlate with DRM l-DOPA equivalents, scores on the Unified Parkinson's Disease Rating Scale, side of the major motor disturbances, or SPECT imaging of the striatal dopamine transporter, as measured by technetium-99m TRODAT. However, PPS thresholds were lower on the left than on the right side of the body (p=0.008) and on the upper extremities relative to the toes and feet (ps<0.0001). Positive correlations were evident among the thresholds obtained across all body sectors, even though disparate regions of the body differed in terms of absolute sensitivity. This study indicates that PPS is not influenced in early stage PD regardless of whether patients are on or off DRMs. PMID- 25447478 TI - Review: Quantifying animal feeding behaviour with a focus on pigs. AB - The study of animal feeding behaviour is of interest to understand feeding, to investigate the effect of treatments and conditions or to predict illness. This paper reviews the different steps to undertake when studying animal feeding behaviour, with illustrations for group-housed pigs. First, one must be aware of the mechanisms that control feeding and the various influences that can change feeding behaviour. Satiety is shown to largely influence free feeding (ad libitum and without an operant condition) in animals, but 'free' feeding seems a very fragile process, given the many factors that can influence feeding behaviour. Second, a measurement method must be chosen that is compatible with the goal of the research. Several measurement methods exist, which lead to different experimental set-ups and measurement data. Sensors are available for lab conditions, for research on group-housed pigs and also for on-farm use. Most of these methods result in a record of feeding visits. However, these feeding visits are often found to be clustered into meals. Thus, the third step is to choose which unit of feeding behaviour to use for analysis. Depending on the situation, either meals, feeding visits, other raw data, or a combination thereof can be suitable. Meals are more appropriate for analysing short-term feeding behaviour, but this may not be true for disease detection. Further research is therefore needed. To cluster visits into meals, an appropriate analysis method has to be selected. The last part of this paper provides a review and discussion of the existing methods for meal determination. A variety of methods exist, with the most recent methods based on the influence of satiety on feeding. More thorough validation of the recent methods, including validation from a behavioural point of view and uniformity in the applied methods is therefore necessary. PMID- 25447479 TI - Dominance and stress signalling of carotenoid pigmentation in Arctic charr (Salvelinus alpinus): lateralization effects? AB - Social conflicts are usually solved by agonistic interactions where animals use cues to signal dominance or subordinance. Pigmentation change is a common cue used for signalling. In our study, the involvement of carotenoid-based pigmentation in signalling was investigated in juvenile Arctic charr (Salvelinus alpinus). Size-matched pairs were analysed for pigmentation both before and after being tested for competitive ability. We found that dominant individuals had fewer carotenoid-based spots on the right and left sides as well as lower plasma cortisol levels compared to subordinate individuals. Further, the number of spots on both sides was positively associated with plasma cortisol levels. These results indicate that carotenoid-based pigmentation in Arctic charr signals dominance and stress coping style. Further, it also appears as if carotenoid based pigmentation is lateralized in Arctic charr, and that the right side signals aggression and dominance whereas the left side signals stress responsiveness. PMID- 25447477 TI - Voluntary exercise decreases ethanol preference and consumption in C57BL/6 adolescent mice: sex differences and hippocampal BDNF expression. AB - Adolescence is a period of high vulnerability for alcohol use and abuse. Early alcohol use has been shown to increase the risk for alcohol-related problems later in life; therefore effective preventive treatments targeted toward adolescents would be very valuable. Many epidemiological and longitudinal studies in humans have revealed the beneficial effects of exercise for prevention and treatment of alcohol addiction. Pre-clinical studies have demonstrated that access to a running wheel leads to decreased voluntary alcohol consumption in adult mice, hamsters, and rats. However, age and sex may also influence the effects of exercise on alcohol use. Herein, we studied male and female C57BL/6 adolescent mice using a 24-hour two-bottle choice paradigm to evaluate 21 days of concurrent voluntary exercise on alcohol consumption and preference. Given previously known effects of exercise in increasing the expression of brain derived neurotrophic factor (BDNF) in the hippocampus and its role in regulating the reward system, BDNF mRNA and protein levels were measured at the end of the behavioral experiment. Our results demonstrate sex differences in the efficacy of voluntary exercise and its effects on decreasing alcohol consumption and preference. We also report increased BDNF expression after 21 days of voluntary exercise in both male and female mice. Interestingly, the distance traveled played an important role in alcohol consumption and preference in female mice but not in male mice. Overall, this study demonstrates sex differences in the effects of voluntary exercise on alcohol consumption in adolescent mice and points out the importance of distance traveled as a limiting factor to the beneficial effects of wheel running in female mice. PMID- 25447480 TI - Genetic variations in the serotoninergic system and environmental factors contribute to aggressive behavior in Chinese adolescents. AB - Aggressive behavior is a major public health problem worldwide and has been associated with many gene variants, especially those related to the serotonin (5 hydroxytryptamine, 5-HT) system, and environmental factors. However, the overall contribution of serotonin-related genes to aggressive behavior is not well understood. With a sample of 478 healthy Chinese volunteers, this study investigated the relation between aggressive behavior and genetic variations of the serotoninergic system (as characterized by 129 representative polymorphisms) interacting with environmental factors (parental warmth and acceptance; stressful life events). We adopted a system-level approach to identify SNPs and environmental factors associated with aggressive behavior, and estimated their overall contribution to aggressive behavior using multiple regression, which was then verified by permutation analysis. We identified 12 SNPs that made statistically significant contributions to aggressive behavior. Next, main effects, interactions among these SNPs, and interactions between these SNPs and environmental factors were assessed using multiple regression. The final model accounted for approximately 19% of the variance for aggressive behavior. Permutation analysis confirmed that the probability of obtaining these findings by chance was low (p=0.045, permuted for 1000 times). These results showed that genetic variations in the serotoninergic system, combined with environmental risk factors, made a moderate contribution to individual differences in aggressive behavior among a healthy population sample. PMID- 25447481 TI - Differences in eating behaviors and masticatory performances by gender and obesity status. AB - This study aimed to determine whether there might be differences in masticatory performance and eating behaviors by gender and obesity status. Forty eight (24 males; 24 females) non-obese and pre-obese young adults were matched for age, gender, and dental health. Eating behaviors were assessed using the Three-Factor Eating Questionnaire (TFEQ), and chewing performance while eating 152g of boiled rice was measured using electromyography (EMG). Compared with non-obese participants, pre-obese participants had significantly higher levels of disinhibition according to the TFEQ (P<0.05 for males; P<0.01 for females). Microstructures of chewing performance were significantly different by gender but not by obesity status. Males had a greater bite size (P<0.05), greater chewing power (P<0.001) and a faster eating rate (P<0.05) than females. Females habitually chewed more (P<0.05) and had a longer meal duration (P<0.01) than males. Eating rate was positively associated with disinhibition (r=0.490, P<0.05) score in males. Bite size (r=-0.449, P<0.05 for non-obese) and chewing power (r= 0.581, P<0.01 for non-obese and r=-0.446, P<0.05 for pre-obese) were negatively associated with disinhibition score. Results suggest that the effects of gender and, in part, obesity on eating responses may be explained as chewing performance. Therefore, gender-specific interventions and counseling aimed at slowing the rate of ingestion could be promising behavioral treatments for obese persons. PMID- 25447483 TI - Acoustic features of prairie vole (Microtus ochrogaster) ultrasonic vocalizations covary with heart rate. AB - Vocalizations serve as a conspecific social communication system among mammals. Modulation of acoustic features embedded within vocalizations is used by several mammalian species to signal whether it is safe or dangerous to approach conspecific and heterospecific mammals. As described by the Polyvagal Theory, the phylogenetic shift in the evolution of mammals involved an adaptive neuroanatomical link between the neural circuits regulating heart rate and the muscles involved in modulating the acoustic features of vocalizations. However, few studies have investigated the covariation between heart rate and the acoustic features of vocalizations. In the current study, we document that specific features of vocalizations covary with heart rate in a highly social and vocal mammal, the prairie vole (Microtus ochrogaster). Findings with the prairie vole illustrate that higher pitch (i.e., fundamental frequency) and less variability in acoustic features of vocalizations (i.e., less vocal prosody) are associated with elevated heart rate. The study provides the first documentation that the acoustic features of prairie vole vocalizations may function as a surrogate index of heart rate. PMID- 25447484 TI - In vitro and in vivo characterization of PA01, a novel promising triple reuptake inhibitor. AB - Triple reuptake inhibitors (TRIs) that inhibit the reuptake of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) are being developed as a new class of antidepressants, which is hypothesized to produce more rapid onset and better efficacy than conventional antidepressants in part due to the addition of the DA component. 4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)-ethyl]-phenyl benzoate hydrochloride (PA01), a novel compound, potently bound to the human 5-HT, NE, and DA transporters (Ki=105, 644, and 813nM, respectively), and inhibited the reuptake of 5-HT, NE, and DA into recombinant cells (IC50=341, 427, and 753nM, respectively). In vivo, PA01 dose-dependently decreased immobility time in the forced swimming test (FST) in rats, and the tail suspension test (TST) in mice with higher efficacy than desvenlafaxine succinate (DVS), and showed no stimulatory effect on the spontaneous locomotor activity. The anti-immobility effect of PA01 in the TST was significantly prevented by the pretreatment of mice with DL-p-chlorophenylalanine (pCPA, 300mg/kg, an inhibitor of serotonin synthesis), SCH23390 (0.05mg/kg, s.c., dopamine D1 receptor antagonist), and sulpiride (50mg/kg, i.p., dopamine D2 receptor antagonist). PA01 significantly increased head-twitch response induced by 5-hydroxytryptophan (80mg/kg, i.p., a metabolic precursor to serotonin) in rats, potentiated yohimbine (25mg/kg, s.c., a alpha2-adrenoceptor antagonist) toxicity, and antagonized high dose apomorphine induced hypothermia in mice. Taken together, these in vitro and in vivo results indicated that PA01 is a novel triple reuptake inhibitor, and exerts an excellent antidepressant activity in the behavioral despair animal models of depression, with more potent antidepressant activity than DVS at the same dose. PMID- 25447482 TI - Acute effects of light on the brain and behavior of diurnal Arvicanthis niloticus and nocturnal Mus musculus. AB - Photic cues influence daily patterns of activity via two complementary mechanisms: (1) entraining the internal circadian clock and (2) directly increasing or decreasing activity, a phenomenon referred to as "masking". The direction of this masking response is dependent on the temporal niche an organism occupies, as nocturnal animals often decrease activity when exposed to light, while the opposite response is more likely to be seen in diurnal animals. Little is known about the neural mechanisms underlying these differences. Here, we examined the masking effects of light on behavior and the activation of several brain regions by that light, in diurnal Arvicanthis niloticus (Nile grass rats) and nocturnal Mus musculus (mice). Each species displayed the expected behavioral response to a 1h pulse of light presented 2h after lights-off, with the diurnal grass rats and nocturnal mice increasing and decreasing their activity, respectively. In grass rats light induced an increase in cFOS in all retinorecipient areas examined, which included the suprachiasmatic nucleus (SCN), the ventral subparaventricular zone (vSPZ), intergeniculate leaflet (IGL), lateral habenula (LH), olivary pretectal nucleus (OPT) and the dorsal lateral geniculate (DLG). In mice, light led to an increase in cFOS in one of these regions (SCN), no change in others (vSPZ, IGL and LH) and a decrease in two (OPT and DLG). In addition, light increased cFOS expression in three arousal-related brain regions (the lateral hypothalamus, dorsal raphe, and locus coeruleus) and in one sleep-promoting region (the ventrolateral preoptic area) in grass rats. In mice, light had no effect on cFOS in these four regions. Taken together, these results highlight several brain regions whose responses to light suggest that they may play a role in masking, and that the possibility that they contribute to species-specific patterns of behavioral responses to light should be explored in future. PMID- 25447486 TI - Dementia: Vascular comorbidities linked with early-onset dementia. PMID- 25447487 TI - Parkinson disease: Exercise matters in patients with PD-another piece of evidence. PMID- 25447488 TI - Stroke: Cortical connectivity predicts success of stroke rehabilitation. PMID- 25447489 TI - Palladium(0)-catalyzed single and double isonitrile insertion: a facile synthesis of benzofurans, indoles, and isatins. AB - A palladium(0)-catalyzed cascade process consisting of isonitrile insertion and alpha-Csp(3)-H cross-coupling can be achieved for the synthesis of benzofurans and indoles. The construction of isatins by a Pd-catalyzed cascade reaction incorporating double isonitrile insertion, amination, and hydrolysis has also been achieved. The key features of this work include diverse heterocycle synthesis, phosphine-ligand-free reaction conditions, a one-pot procedure, simple and commercially available starting materials, broad functional-group compatibility, and moderate to good reaction yields. PMID- 25447490 TI - Electrophoresis of periodontal pathogens in poly(ethyleneoxide) solutions with uncoated capillary. AB - Periodontitis is a prevalent inflammatory disease caused by different species of anaerobic bacteria such as Porphyromonas gingivalis (P.g), Treponema denticola (T.d), and Tannerella forsythia (T.f). We compared the separation result of DNA ladders in hydroxyethyl cellulose, poly(ethyleneoxide) (PEO), and polyethylene glycol and analyzed the effect of polymer concentration, electric field, and temperature of the background electrolyte on the separation performance. Results demonstrated that there was a linear relationship (R=0.942) for 100 to 700bp of DNA and its migration time. Finally, the polymerase chain reaction products of P.g, T.d, and T.f were successfully identified within 8.5 min in 0.5% PEO with uncoated capillary. PMID- 25447485 TI - The ongoing pursuit of neuroprotective therapies in Parkinson disease. AB - Many agents developed for neuroprotective treatment of Parkinson disease (PD) have shown great promise in the laboratory, but none have translated to positive results in patients with PD. Potential neuroprotective drugs, such as ubiquinone, creatine and PYM50028, have failed to show any clinical benefits in recent high profile clinical trials. This 'failure to translate' is likely to be related primarily to our incomplete understanding of the pathogenic mechanisms underlying PD, and excessive reliance on data from toxin-based animal models to judge which agents should be selected for clinical trials. Restricted resources inevitably mean that difficult compromises must be made in terms of trial design, and reliable estimation of efficacy is further hampered by the absence of validated biomarkers of disease progression. Drug development in PD dementia has been mostly unsuccessful; however, emerging biochemical, genetic and pathological evidence suggests a link between tau and amyloid-beta deposition and cognitive decline in PD, potentially opening up new possibilities for therapeutic intervention. This Review discusses the most important 'druggable' disease mechanisms in PD, as well as the most-promising drugs that are being evaluated for their potential efficiency in treatment of motor and cognitive impairments in PD. PMID- 25447491 TI - Microwave-mediated enzymatic modifications of DNA. AB - Here we report microwave-induced specific cleavage, ligation, dephosphorylation, and phosphorylation of nucleic acids catalyzed by restriction endonucleases, T4 DNA ligase, T4 polynucleotide kinase, and calf intestinal alkaline phosphatase. The microwave-mediated method has dramatically reduced the reaction time to 20 to 50s. In control experiments, the same reactions failed to give the desired reaction products when carried out in the same time periods but without microwave irradiation. Because the microwave method is rapid, it could be a useful alternative to the time-consuming conventional procedure for enzymatic modification of DNA. PMID- 25447492 TI - Liquid chromatography-tandem mass spectrometry determination of human plasma 1 palmitoyl-2-hydroperoxyoctadecadienoyl-phosphatidylcholine isomers via promotion of sodium adduct formation. AB - Accumulation of phosphatidylcholine hydroperoxide (PCOOH), a primary oxidation product of phosphatidylcholine, in blood plasma has been observed in various pathological conditions, including atherosclerosis. In this study, we investigated the use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) to develop a method for accurate quantification of PCOOH (1-palmitoyl-2 hydroperoxyoctadecadienoyl-sn-glycero-3-phosphocholine, 16:0/HpODE PC), focusing on isomers such as 16:0/13-HpODE PC and 16:0/9-HpODE PC. Sodiated PCOOH ([M+Na](+), m/z 812) provided not only a known product ion (m/z 147) but also characteristic product ions (m/z 541 for 16:0/13-HpODE PC and m/z 388 for 16:0/9 HpODE PC). Thus, three multiple reaction monitorings (MRMs) could be performed. MRM (812/147) enabled determination of 16:0/HpODE PC, and MRM (812/541) and MRM (812/388) allowed specific measurement of 16:0/13-HpODE PC and 16:0/9-HpODE PC, respectively. By using this method, we could determine plasma PCOOH concentrations in healthy subjects and patients with angiographically significant stenosis. In healthy subject and patient plasma, the concentration of 16:0/HpODE PC was close to the sum of the concentrations of 16:0/13-HpODE PC and 16:0/9 HpODE PC. This finding shows that radical and/or enzymatic oxidation, rather than singlet oxygen oxidation, is recognized to cause peroxidation of PC. The newly developed LC-MS/MS method appears to be a powerful tool for developing a better understanding of in vivo lipid peroxidation and its involvement in human diseases. PMID- 25447493 TI - Detection of embryonic stem cell lysate biomarkers by surface plasmon resonance with reduced nonspecific adsorption. AB - Surface plasmon resonance imaging (SPRi) has emerged as a versatile biosensor to detect a wide range of biomolecular interactions with divergent potential applications. However, the use of this advanced-level technology for stem cell lysate study is still not much explored. Cell lysates are significant biological analytes used for disease diagnostics and proteomic studies, but their complex nature limits their use as an analyte for SPRi biosensors. Here, we review the problems associated with the use of SPRi for stem cell lysate study and examine the role of surface chemistry, running buffer, and blocking solution in order to minimize nonspecific adsorption (NSA). We detect the expression of Oct4, Sox2, Nanog, Rex1, and Lin28 biomarkers present in mouse embryonic stem cell (mESC) lysate against their corresponding antibodies immobilized on the sensor surface with reduced NSA. The current study shows that the conjunction of SPRi and microarray can be used as a label-free, high-throughput, and rapid technique for detection of biomarkers and their relative abundance in stem cell lysate study. PMID- 25447494 TI - Fetal calf sera can distort cell-based luminescent proteasome assays through heat resistant chymotrypsin-like activity. AB - Luminescence-based proteasome activity assays use specific substrates that are supposed to be cleaved by cellular proteasome activity leading to luciferase substrates. Usually, control wells containing cell culture medium supplemented with antibiotics and fetal calf serum are used as background. Using the Proteasome-Glo chymotrypsin-like cell-based assay from Promega, we show here that fetal calf sera from different manufacturers contain heat-resistant, bortezomib inhibitable, chymotrypsin-like activities that can interfere with proteasome activity assays. These data strongly recommend the use of pure phosphate-buffered saline (PBS) or serum-free medium during proteasome activity assays to diminish background luminescence and, thus, to obtain reliable results. PMID- 25447495 TI - Avidin-biotin capped mesoporous silica nanoparticles as an ion-responsive release system to determine lead(II). AB - We have developed DNAzyme-functionalized silica nanoparticles for the rapid, sensitive, and selective detection of lead ion (Pb(2+)). The specific binding between avidin and biotinylated DNAzymes was used to cap the pore of dye-trapped silica nanoparticles. In the presence of Pb(2+), DNAzymes were catalytically cleaved to uncap the pore, releasing the dye cargo with detectable enhancements of fluorescence signal. This method enables rapid (15 min) and sensitive (limit of detection=8.0 nM) detection. Moreover, the Pb(2+)-responsive behavior shows high selectivity with other metal ions. The superior properties of the as designed DNAzyme-functionalized silica nanoparticles can be attributed to the large loading capacity and highly ordered pore structure of mesoporous silica nanoparticles as well as the catalytical cleaving of DNAzymes with Pb(2+). The recoveries obtained by standard Pb(II) addition to real samples-tap water, commercial mineral water, and lake water-were all from 98 to 101%. Our design serves as a new prototype for metal-ion sensing systems, and it also has promising potential for detection of various targets in stimulus-release systems. PMID- 25447496 TI - Validation of a general method for activity estimation of cyanide evolving oxidoreductases. AB - Ethylene is a key molecule in organic synthesis currently produced by steam cracking of fossil hydrocarbons. In nature, ethylene is produced in higher plants by 1-aminocyclopropane-1-carboxylic acid oxidase (ACCO). Biocatalytic alternatives for ethylene production are still far from being competitive with traditional production plants. Furthermore, data dispersion shown in the literature adds uncertainty to the introduction of ACCO as a biocatalyst, especially when larger numbers of isoforms or mutants are to be compared. Here we propose a new method for measuring ACCO activity based on cyanide detection. Data provided here indicate that cyanide detection is more precise, more responsive, and much more stable than any other method tested for ACCO activity estimation so far. Briefly, enzymatically produced cyanide can be detected by its derivatization with naphthalene-2,3-dicarboxyaldehide (NDA) to generate 1 cyanobenz[f]isoindole (CBI), which is further detected by high-performance liquid chromatography (HPLC) coupled with a fluorescence detector. Cyanide can be detected in the range between 0.99 and 60.17pmol, which is three orders of magnitude more sensitive than the currently used ethylene estimation method. PMID- 25447497 TI - Universal CG cloning of polymerase chain reaction products. AB - Single-insert cloning of DNA fragments without restriction enzymes has traditionally been achieved using TA cloning, with annealing of a polymerase chain reaction (PCR) fragment containing a single overhanging 3' A to a plasmid vector containing a 3' T. In this article, we show that the analogous "CG cloning" is faster and far more efficient, using AhdI to generate a C-vector. For an afternoon ligation, CG cloning achieved double the cloning efficiency and more than 4-fold the number of transformants compared with TA cloning. However, blunt end ligation was markedly more efficient than both. CG cloning could prove to be extremely useful for single-copy high-throughput cloning. PMID- 25447498 TI - Evaluation of bone tissue response to a sealer containing mineral trioxide aggregate. AB - INTRODUCTION: This study analyzed bone tissue reactions to MTA Fillapex (Angelus Industria de Produtos Odontologicos Ltda, Londrina, Brazil) compared with an epoxy resin-based material in the femur of Wistar rats. METHODS: Bone tissue reactions were evaluated in 15 animals after 7, 30, and 90 days (n = 5 per period). Three surgical cavities were prepared on the femur and filled with 0.2 mL MTA Fillapex, AH Plus (Dentsply DeTrey GmbH, Konstanz, Germany), or no sealer (negative control). By the end of each experimental period, 5 animals were randomly euthanized. The samples were histologically processed and analyzed using a light microscope. The presence of inflammatory cells, fibers, and hard tissue barrier formation was evaluated. Differences among the groups and between the 3 experimental periods were evaluated by using 2-way analysis of variance followed by the Bonferroni post hoc test (P <= .05). RESULTS: MTA Fillapex scored significantly higher for neutrophils at 7 days than at 90. At 7 days, the same occurred when comparing MTA Fillapex with AH Plus. The presence of lymphocytes/plasmocytes significantly decreased over time in all groups. Macrophages, giant cells, eosinophils, and fiber condensation presented no differences among groups and periods. Within 90 days, all groups presented complete hard tissue barrier formation. CONCLUSIONS: The presence of mineral trioxide aggregate in MTA Fillapex composition did not improve the bone tissue repair. The presence of sealers provided the re-establishment of the original bone tissue structure and the inflammatory response decreased over time, so they can be considered biocompatible. PMID- 25447499 TI - The effect of canal preparation on fill length in straight root canals obturated with GuttaCore. AB - INTRODUCTION: A common critique of using thermoplasticized carrier-based obturators is the incidence of overextension. It would be of benefit to clinicians to have a technique for canal preparation that would allow for predictable length control. This study compared straight canals instrumented to a size 40 file using a 0.04 standardized taper preparation (STP) and a varied taper preparation (VTP) by evaluating the extension of GuttaCore (GC) obturators (Dentsply Tulsa Dental, Tulsa, OK). METHODS: Eighty extracted mature human premolars with single straight canals were randomly divided into 2 experimental groups (n = 40). The STP group was instrumented to size 40/.04 at the working length (WL). The VTP group was instrumented to size 40/.02 at the WL. Both groups were obturated with a size 40 GC obturator. Extension of the material, in relation to the WL, was evaluated and assessed ordinally. Statistically significant differences were determined by a 2-group chi-square test with a 2 sided P value set at P = .05 and a Fisher exact test of equal proportions. RESULTS: Significant differences in extrusion existed between the STP and VTP groups when controlling for the type of apical preparation (P = .0005). The STP group resulted in a 47.2% incidence of overextension, whereas the VTP group resulted in 10.5% overextension of obturating material. CONCLUSIONS: The results indicate that when filling straight canals with GC obturators the canal can be instrumented using a varied tapered canal preparation with a low likelihood of overextension. PMID- 25447500 TI - The cracked tooth: histopathologic and histobacteriologic aspects. AB - INTRODUCTION: The diagnosis and treatment planning of cracked teeth depend on the understanding of how cracks affect the surrounding tissues. This study evaluated the dentin and pulp conditions in teeth affected by cracks and attrition. METHODS: Specimens under investigation included 12 cracked posterior teeth and 8 teeth with severe attrition. These teeth were obtained consecutively in a private practice and were extracted for reasons not related to this study. Teeth were processed for histopathologic and histobacteriologic analyses. RESULTS: Cracks were histologically detected in all specimens, including the teeth with severe attrition. The cracks in all teeth were colonized by bacterial biofilms. One tooth showed several craze lines in the enamel, one of which reached dentin to a shallow depth. In some teeth, the crack ended in the dentin. Dentinal tubules were invaded by bacteria, especially when the crack extended perpendicularly into the dentin. Severe accumulations of inflammatory cells were present in the pulp zone subjacent to tubules involved with the crack. In many cases, the crack extended to the pulp, leading to reactions with intensities ranging from acute inflammation to total pulpal necrosis. Symptoms occurred in most cases in which the pulp was affected. In some cases, polymorphonuclear neutrophils were seen migrating from the pulp into the crack space and facing the bacterial biofilm located therein. Severe pulp reactions were also observed when the crack extended to the pulp chamber floor. CONCLUSIONS: Cracks are always colonized with bacterial biofilms. The pulp tissue response varies according to the location, direction, and extent of the crack. PMID- 25447501 TI - Implications of endodontic-related sinus aspergillosis in a patient treated by infliximab: a case report. AB - INTRODUCTION: Sinus aspergillosis is a potential complication after root canal therapy of antral teeth. Indeed, zinc oxide-eugenol cement overfilling in the sinus may promote fungal infection. Moreover, if sinus aspergillosis triggers chronic sinusitis with aspergilloma, it may also lead to invasive phenomena, especially for immunocompromised patients. METHODS: We reported a sinus aspergillosis case of a patient treated with infliximab (Remicade; Janssen Biologics BV, Leiden, Netherlands). The purpose of this article was to explore the mechanisms of this pathosis, especially the impact of the root canal sealer overextension, which is a contributing factor for fungal infection. The surgical management and the follow-up are also described. RESULTS: Six months after surgery, the patient showed no clinical signs and presented with a healthy and airy right maxillary sinus on the computed tomography scan. CONCLUSIONS: In conclusion, prevention and screening of aspergillosis of maxillary sinus may be considered before starting an anti-tumor necrosis factor alpha therapy. PMID- 25447502 TI - Removal of filling materials from oval-shaped canals using laser irradiation: a micro-computed tomographic study. AB - INTRODUCTION: The aim of this study was to assess the efficacy of lasers in removing filling remnants from oval-shaped canals after retreatment procedures with rotary instruments using micro-computed tomographic imaging. METHODS: The root canals of 42 mandibular canines were prepared and obturated using the warm vertical compaction technique. Retreatment was performed with rotary instruments, and the specimens were distributed in 3 groups (n = 14) according to the laser device used in a later stage of retreatment procedure: Er:YAG, Er:YAG laser-based photon-induced photoacoustic streaming, and Nd:YAG. The specimens were scanned in a micro-computed tomographic device after root canal filling and each stage of retreatment at a resolution of 13.68 MUm. The percentage differences of the remaining filling material before and after laser application within and between groups were statistically compared using the paired sample t test and 1-way analysis of variance test, respectively. Significance level was set at 5%. RESULTS: Overall, filling residues were located mainly in the apical third and into canal irregularities after the retreatment procedures. After using rotary instruments, the mean percentage volume of the filling remnants ranged from 13% 16%, with no statistical significant difference between groups (P > .05). Within groups, additional laser application had a significant reduction in the amount of the remaining filling materials (P < .05). A comparison between groups showed that Er:YAG laser application after the use of rotary instruments had a significantly higher removal of filling remnants (~13%) than Er:YAG laser-based photon-induced photoacoustic streaming (~4%) and Nd:YAG (~3%) (P < .05). CONCLUSIONS: None of the retreatment procedures completely removed the filling materials. The additional use of lasers improved the removal of filling material after the retreatment procedure with rotary instruments. PMID- 25447503 TI - Comparison of fracture sites and post lengths in longitudinal root fractures. AB - INTRODUCTION: Comparing the epidemiology of fractures originating in the cervical and apical regions may help to understand the causes and risk of a vertical root fracture. We aimed to determine the frequency of vertical root fractures in different fracture sites and how the fracture site relates to fracture direction and post length. METHODS: Teeth diagnosed with a vertical root fracture were retrospectively surveyed for age and sex of the patient, type of tooth, a fracture region in the longitudinal axial direction, site of the fracture, and presence of a post. The fracture region in the longitudinal axial direction was classified as an incomplete fracture, complete fracture, and uncertain. Incomplete fractures were further classified into a fracture originating in the cervical region, a fracture originating in the midregion, and a fracture originating in the apical region. Posts were evaluated by loss of post and length of post. RESULTS: Fractures originating in the cervical and apical region occurred around the same frequency, whereas fractures originating in the midregion were extremely scarce. Of the fractures originating in the cervical region, 36.2% were in a mesial and/or distal site and 57.4% in a buccal and/or lingual site. Of the fractures originating in the apical region, 90.8% were in the buccal and/or lingual site. The number of cases of fractures originating in the apical region decreased with increased post length. CONCLUSIONS: Sites of fracture and post length differed greatly between fractures originating in the cervical region and the apical region, suggesting that risk factors for fractures originating in the cervical and apical regions are different. PMID- 25447504 TI - Apical extrusion of debris in flat-oval root canals after using different instrumentation systems. AB - INTRODUCTION: The purpose of this study was to evaluate the amount of apically extruded debris in flat-oval root canal systems during cleaning and shaping with different instrumentation systems. METHODS: Seventy-two mandibular incisors were randomly assigned to 4 groups (n = 18) according to the instrumentation system to be used: the ProTaper Next rotary system (PTN; Dentsply Tulsa Dental, Tulsa, OK), the WaveOne reciprocating system (WO, Dentsply Tulsa Dental), the Twisted File Adaptive (TFA; SybronEndo, Orange, CA) rotary/reciprocating system, and the Self Adjusting File (SAF) system (ReDent-Nova, Ra'anana, Israel). Debris extruded during the instrumentation was collected and dried in preweighed Eppendorf tubes. Three consecutive weights were obtained for each tube, and the average was calculated. The data were analyzed using the t test and analysis of variance (Games-Howell test). RESULTS: The SAF produced significantly more debris compared with the other systems (P < .05). No significant difference was noted amongst the PTN, WO, and TFA (P > .05). CONCLUSIONS: Regardless of the instrumentation system used, apical extrusion of debris was exhibited at some level, regardless of the instrumentation system used. The SAF was associated with the highest amount of debris extrusion compared with PTN, WO, and TFA. PMID- 25447505 TI - Micro-computed tomographic analysis of the root canal morphology of the distal root of mandibular first molar. AB - INTRODUCTION: The aim of this study was to evaluate the morphologic aspects of the root canal anatomy of the distal root of a mandibular first molar using micro computed tomographic analysis. METHODS: One-hundred distal roots of mandibular first molars were scanned using a micro-computed tomographic device at an isotropic resolution of 19.6 MUm. The percentage frequency distribution of the morphologic configuration of the root canal was performed according to the Vertucci classification system. Two-dimensional parameters (area, perimeter, roundness, aspect ratio, and major and minor diameters) and the cross-sectional shape of the root canal were analyzed in the apical third at every 1-mm interval from the main apical foramen in roots presenting Vertucci types I and II configurations (n = 79). Data were statistically compared using the Kruskal Wallis and Dunn tests with a significance level set at 5%. RESULTS: Seventy-six percent of the distal roots had a single root canal. Two, three, and four canals were found in 13%, 8%, and 3% of the sample, respectively. In 13 specimens, the configuration of the root canal did not fit into Vertucci's classification. Overall, 2-dimensional parameter values significantly increased at the 3-mm level (P < .05). The prevalence of oval canals was higher at the 1-mm level and decreased at the 5-mm level in which long oval and flattened canals were more prevalent. CONCLUSIONS: The distal roots of the mandibular first molars showed a high prevalence of single root canals. The prevalence of long oval and flattened canals increased in the coronal direction. In 13% of the samples, canal configurations that were not included in Vertucci's configuration system were found. PMID- 25447506 TI - Fitness of gutta-percha cones in curved root canals prepared with reciprocating files correlated with tug-back sensation. AB - INTRODUCTION: The purpose of this study was to evaluate the gutta-percha-occupied area (GPOA) and the relationship between GPOA and tug-back sensations in canals instrumented with reciprocating files. METHODS: Twenty curved canals were instrumented using Reciproc R25 (VDW, Munich, Germany) (group R) and WaveOne Primary (Dentsply Maillefer, Ballaigues, Switzerland) (group W), respectively (n = 10 each). The presence or absence of a tug-back sensation was decided for both of #25/.08 and #30/.06 cones in every canal. The percentage of GPOA at 1-, 2-, and 3-mm levels from the working length was calculated using micro-computed tomographic imaging. The correlation between the sum of the GPOA and the presence of a tug-back sensation was also investigated. The data were analyzed statistically at P = .05. RESULTS: A tug-back sensation was present in 45% and 100% canals for #25/.08 and #30/.06 cones, respectively, with a significant difference (P < .05). At the 2- and 3-mm levels, #30/.06 cones produced significantly higher GPOA in groups R and W (P < .05). The sum of the GPOA score was significantly higher in the samples with a strong tug-back sensation (P < .05); however, there was no significant difference between the 2 cone types for this correlation (P > .05). CONCLUSIONS: Under the conditions of this study, the tug-back sensation can be a definitive determinant for indicating higher cone fitness in the curved canal regardless of the cone type. PMID- 25447507 TI - Cell expression patterns of CD147 in N-diethylnitrosamine/phenobarbital-induced mouse hepatocellular carcinoma. AB - Overexpression of CD147/basigin in hepatic cells promotes the progression of hepatocellular carcinoma (HCC). Whether CD147 also expressed in liver non parenchymal cells and associated with HCC development was unknown. The aim of the study was to explore time-dependent cell expression patterns of CD147 in a widely accepted N-diethylnitrosamine/phenobarbital (DEN/PB)-induced HCC mouse model. Liver samples collected at month 1-12 of post-DEN/PB administration were assessed the localization of CD147 in hepatocytes, endothelial cells, hepatic stellate cells, and macrophages. Immunohistochemistry analysis showed that CD147 was upregulated in liver tumors during month 1-8 of DEN/PB induction. Expression of CD147 was positively correlated with cytokeratin 18, a hepatocyte marker (r = 0.7857, P = 0.0279), CD31 (r = 0.9048, P = 0.0046), an endothelial cell marker, and CD68, a macrophage marker (r = 0.7619, P = 0.0368). A significant correlation was also observed between CD147 and alpha-smooth muscle actin (r = 0.8857, P = 0.0333) at DEN/PB initiation and early stage of tumor formation. Immunofluorescence and fluorescence in situ hybridization showed that CD147 co expressed with cytokeratin 18, CD31, alpha-smooth muscle actin, and CD68. Moreover, there existed positive correlations between CD147 and microvessel density (r = 0.7857, P = 0.0279), CD147 and Ki-67 (r = 0.9341, P = 0.0022) in the development of DEN/PB-induced HCC. In conclusion, our results demonstrated that CD147 was upregulated in the liver parenchymal and mesenchymal cells and involved in angiogenesis and tumor cell proliferation in the development of DEN/PB-induced HCC. PMID- 25447508 TI - Long-term test-retest reliability of delayed reward discounting in adolescents. AB - Delay discounting (DD), a decline in subjective value of a reward with increasing temporal delay in receipt of that reward, is an established behavioral indicator of impulsivity. Preference for smaller-immediate over larger-delayed rewards has been implicated in the basic neurobehavioral mechanisms of risk for addictive disorders and related externalizing psychopathology. Establishing long-term stability of DD in adolescence is a necessary step towards its validation as an intermediate phenotype, or marker of risk, in neurobiological and genetic studies. Previous studies have demonstrated moderate to high test-retest reliability of DD, however, these studies utilized adult samples and examined relatively short retest intervals. Due to continuing development of brain and behavior, stability of temporal discounting behavior in adolescence may differ from that in adulthood. Here, two cohorts of adolescents aged 16 (n=126) and 18 (n=111) were administered a computerized test of DD and re-tested two years later. DD rate showed a modest but significant decrease with age, suggesting a reduction in overall impulsivity from middle to late adolescence. Significant test-retest correlations were observed in both cohorts (.67 and .76, respectively, p<.001) indicating longitudinal stability of individual differences in decision-making behavior during middle and late adolescence. This article is part of a Special Issue entitled: insert SI title. PMID- 25447510 TI - Assessment of attachment behaviour to human caregivers in wolf pups (Canis lupus lupus). AB - Previous research suggested that 16-week old dog pups, but not wolf pups, show attachment behaviour to a human caregiver. Attachment to a caregiver in dog pups has been demonstrated by differential responding to a caregiver compared to a stranger in the Ainsworth Strange Situation Test. We show here that 3-7 week old wolf pups also show attachment-like behaviour to a human caregiver as measured by preferential proximity seeking, preferential contact, and preferential greeting to a human caregiver over a human stranger in a modified and counterbalanced version of the Ainsworth Strange Situation Test. In addition, our results show that preferential responding to a caregiver over a stranger is only apparent following brief isolation. In initial episodes, wolf pups show no differentiation between the caregiver and the stranger; however, following a 2-min separation, the pups show proximity seeking, more contact, and more greeting to the caregiver than the stranger. These results suggest intensive human socialization of a wolf can lead to attachment--like responding to a human caregiver during the first two months of a wolf pup's life. PMID- 25447512 TI - Pigeons can learn to make visual category discriminations using either low or high spatial frequency information. AB - Pigeons were trained to discriminate photographs of cat faces from dog faces, using either high- or low-pass spatial frequency filtered stimuli. Each pigeon was trained with multiple exemplars of the categories, but only with either high pass or low-pass filtered stimuli. Not all pigeons reached the discrimination criterion. Successful pigeons were exposed in probe trials to test stimuli: cat and dog faces that had been subjected to the opposite kind of filtering from their training stimuli; the unfiltered original stimuli from which their training stimuli had been derived; and new exemplars of the cat- and dog-face categories, with the same filtering as was used in training. There was no transfer of discrimination to the stimuli with the opposite filtering from those used in training. Discrimination transferred, with some decrement, to the original unfiltered stimuli and to new exemplars with the same type of filtering as used in training. These results provide further evidence that both high and low spatial frequency information can be sufficient for pigeons to make category discriminations, and that there is no clear advantage for high spatial frequency information. They also confirm that high-pass and low-pass spatial frequency filtering produce images that have effectively no information in common. This article is part of a Special Issue entitled: Tribute to Tom Zentall. PMID- 25447511 TI - Endpoint distinctiveness facilitates analogical mapping in pigeons. AB - Analogical thinking necessitates mapping shared relations across two separate domains. We investigated whether pigeons could learn faster with ordinal mapping of relations across two physical dimensions (circle size & choice spatial position) relative to random mapping of these relations. Pigeons were trained to relate six circular samples of different sizes to horizontally positioned choice locations in a six alternative matching-to-sample task. Three pigeons were trained in a mapped condition in which circle size mapped directly onto choice spatial position. Three other pigeons were trained in a random condition in which the relations between size and choice position were arbitrarily assigned. The mapped group showed an advantage over the random group in acquiring this task. In a subsequent second phase, relations between the dimensions were ordinally reversed for the mapped group and re-randomized for the random group. There was no difference in how quickly matching accuracy re-emerged in the two groups, although the mapped group eventually performed more accurately. Analyses suggested this mapped advantage was likely due to endpoint distinctiveness and the benefits of proximity errors during choice responding rather than a conceptual or relational advantage attributable to the common or ordinal mapping of the two dimensions. This potential difficulty in mapping relations across dimensions may limit the pigeons' capacity for more advanced types of analogical reasoning. This article is part of a Special Issue entitled: Tribute to Tom Zentall. PMID- 25447509 TI - Defining value through quantity and quality-Chimpanzees (Pan troglodytes) undervalue food quantities when items are broken. AB - Decision-making largely is influenced by the relative value of choice options, and the value of such options can be determined by a combination of different factors (e.g., the quantity, size, or quality of a stimulus). In this study, we examined the competing influences of quantity (i.e., the number of food items in a set) and quality (i.e., the original state of a food item) of choice items on chimpanzees' food preferences in a two-option natural choice paradigm. In Experiment 1, chimpanzees chose between sets of food items that were either entirely whole or included items that were broken into pieces before being shown to the chimpanzees. Chimpanzees exhibited a bias for whole food items even when such choice options consisted of a smaller overall quantity of food than the sets containing broken items. In Experiment 2, chimpanzees chose between sets of entirely whole food items and sets of initially whole items that were subsequently broken in view of the chimpanzees just before choice time. Chimpanzees continued to exhibit a bias for sets of whole items. In Experiment 3, chimpanzees chose between sets of new food items that were initially discrete but were subsequently transformed into a larger cohesive unit. Here, chimpanzees were biased to choose the discrete sets that retained their original qualitative state rather than toward the cohesive or clumped sets. These results demonstrate that beyond a food set's quantity (i.e., the value dimension that accounts for maximization in terms of caloric intake), other seemingly non-relevant features (i.e., quality in terms of a set's original state) affect how chimpanzees assign value to their choice options. PMID- 25447513 TI - Behavioural responses to olfactory cues in carrion crows. AB - Until recently, the use of olfactory signals in birds has been largely ignored, despite the fact that birds do possess a fully functioning olfactory system and have been shown to use odours in social and foraging tasks, predator detection and orientation. The present study investigates whether carrion crows (Corvus corone corone), a bird species living in complex social societies, respond behaviourally to olfactory cues of conspecifics. During our experiment, carrion crows were observed less often close to the conspecific scent compared to a control side. Because conspecific scent was extracted during handling, a stressful procedure for birds, we interpreted the general avoidance of the 'scent' side as disfavour against a stressed conspecific. However, males, unlike females, showed less avoidance towards the scent of a familiar individual compared to an unfamiliar one, which might reflect a stronger interest in the information conveyed and/or willingness to provide social support. PMID- 25447514 TI - Facial markings in the social cuckoo wasp Polistes sulcifer: No support for the visual deception and the assessment hypotheses. AB - Insect social parasites have to conquer a host colony by overcoming its defensive barriers. In addition to increased fighting abilities, many social parasites evolved sophisticated sensory deception mechanisms to elude host colonies defenses by exploiting host communication channels. Recently, it has been shown that the conspicuous facial markings of a paper wasp social parasite, Polistes sulcifer, decrease the aggressiveness of host foundresses. Two main hypotheses stand as explanations of this phenomenon: visual sensory deception (i.e. the black patterning reduces host aggression by exploiting the host visual communication system) and visual quality assessment (i.e. facial markings reduce aggressiveness as they signal the increased fighting ability of parasites). Through behavioral assays and morphological measurements we tested three predictions resulting from these hypotheses and found no support either for the visual sensory deception or for the quality assessment to explain the reduction in host aggressiveness towards the parasite. Our results suggest that other discrimination processes may explain the observed phenomenon. PMID- 25447516 TI - Interactions with conspecific attenuate conditioned taste aversions in mice. AB - Social animals both increase and decrease their stress levels by interacting with conspecifics. The present study examines the effect of interaction with a conspecific on conditioned taste aversion in 32 male mice. Subjects were injected with lithium chloride immediately after drinking saccharin solution for 30 min. They were then exposed to a male conspecific for 3h following the poisoning. In the subsequent three consecutive days of two-bottle tests involving a choice between saccharin solution and water, they showed attenuated conditioned taste aversion compared with controls exposed to no conspecific after poisoning. These results confirm social interaction with a conspecific reduces conditioned taste aversion in mice. The implications of these findings are discussed with regard to social buffering effect and stress-induced analgesia. PMID- 25447515 TI - Are 50-kHz calls used as play signals in the playful interactions of rats? II. Evidence from the effects of devocalization. AB - During playful interactions, juvenile rats emit many 50-kHz ultrasonic vocalizations, which are associated with a positive affective state. In addition, these calls may also serve a communicative role - as play signals that promote playful contact. Consistent with this hypothesis, a previous study found that vocalizations are more frequent prior to playful contact than after contact is terminated. The present study uses devocalized rats to test three predictions arising from the play signals hypothesis. First, if vocalizations are used to facilitate contact, then in pairs of rats in which one is devocalized, the higher frequency of pre-contact calling should only be present when the intact rat is initiating the approach. Second, when both partners in a playing pair are devocalized, the frequency of play should be reduced and the typical pattern of playful wrestling disrupted. Finally, when given a choice to play with a vocal and a non-vocal partner, rats should prefer to play with the one able to vocalize. The second prediction was supported in that the frequency of playful interactions as well as some typical patterns of play was disrupted. Even though the data for the other two predictions did not produce the expected findings, they support the conclusion that, in rats, 50-kHz calls are likely to function to maintain a playful mood and for them to signal to one another during play fighting. PMID- 25447517 TI - Formation and dimerization of the phosphodiesterase active site of the Pseudomonas aeruginosa MorA, a bi-functional c-di-GMP regulator. AB - Diguanylate cyclases (DGC) and phosphodiesterases (PDE), respectively synthesise and hydrolyse the secondary messenger cyclic dimeric GMP (c-di-GMP), and both activities are often found in a single protein. Intracellular c-di-GMP levels in turn regulate bacterial motility, virulence and biofilm formation. We report the first structure of a tandem DGC-PDE fragment, in which the catalytic domains are shown to be active. Two phosphodiesterase states are distinguished by active site formation. The structures, in the presence or absence of c-di-GMP, suggest that dimerisation and binding pocket formation are linked, with dimerisation being required for catalytic activity. An understanding of PDE activation is important, as biofilm dispersal via c-di-GMP hydrolysis has therapeutic effects on chronic infections. PMID- 25447518 TI - Molecular architecture of the HerA-NurA DNA double-strand break resection complex. AB - DNA double-strand breaks can be repaired by homologous recombination, during which the DNA ends are long-range resected by helicase-nuclease systems to generate 3' single strand tails. In archaea, this requires the Mre11-Rad50 complex and the ATP-dependent helicase-nuclease complex HerA-NurA. We report the cryo-EM structure of Sulfolobus solfataricus HerA-NurA at 7.4A resolution and present the pseudo-atomic model of the complex. HerA forms an ASCE hexamer that tightly interacts with a NurA dimer, with each NurA protomer binding three adjacent HerA HAS domains. Entry to NurA's nuclease active sites requires dsDNA to pass through a 23A wide channel in the HerA hexamer. The structure suggests that HerA is a dsDNA translocase that feeds DNA into the NurA nuclease sites. PMID- 25447520 TI - Up-regulation of p21(WAF1/CIP1) by miRNAs and its implications in bladder cancer cells. AB - We have previously reported that synthetic dsRNA can activate p21 expression by targeting the p21 promoter, thereby suppressing the proliferation of human bladder cancer cells. As complementarity between dsRNA and its target sequences is necessary for RNA activation, miRNAs may also trigger p21 expression through the same mechanism. Here, the expression levels of three miRNAs (miR-370, miR 1180 and miR-1236) decreased in bladder cancer tissues compared to healthy controls and the levels of these mRNAs positively correlated with p21 mRNA levels. The three miRNAs induced nuclear p21 expression through p21-promoter binding. Overexpression of the three miRNAs inhibited the proliferation of bladder cancer cells mainly by regulating p21. Therefore, these miRNAs could be candidates for anti-cancer drugs. PMID- 25447519 TI - C/EBPalpha controls mast cell function. AB - CCAAT/enhancer binding protein alpha (C/EBPalpha) is a transcription factor that influences immune cell fate and differentiation. However, the effect of C/EBPalpha on mast cells is not fully understood. In this study, we showed that C/EBPalpha suppressed granule formation in mast cells and increased macrophage inflammatory protein (MIP)-2 production from mast cells upon bacterial stimulation. These results indicate that C/EBPalpha regulates the balance between the allergic response and the innate immune response of mast cells. Furthermore, we showed that stimulation of mast cells with the Lactobacillus casei JCM1134(T) strain during late differentiation up-regulated C/EBPalpha expression in differentiated mast cells. This suggests that intestinal commensal bacteria modulate C/EBPalpha expression and thereby regulate mast cell function. PMID- 25447521 TI - DNA methylation dynamics of a maternally methylated DMR in the mouse Dlk1-Dio3 domain. AB - The mouse delta-like homolog 1 and type III iodothyronine deiodinase (Dlk1-Dio3) imprinted domain contains three known paternally methylated differentially methylated regions (DMRs): intergenic DMR (IG-DMR), maternally expressed 3-DMR (Gtl2-DMR), and Dlk1-DMR. Here, we report the first maternally methylated DMR, CpG island 2 (CGI-2), is located approximately 800 bp downstream of miR-1188. CGI 2 is highly methylated in sperm and oocytes, de-methylated in pre-implantation embryos, and differentially re-methylated during post-implantation development. CGI-2, similarly to Gtl2-DMR and Dlk1-DMR, acquires differential methylation prior to embryonic day 7.5 (E7.5). Both H3K4me3 and H3K9me3 histone modifications are enriched at CGI-2. Furthermore, CCCTC-binding factor (CTCF) binds to both alleles of CGI-2 in vivo. These results contribute to the investigation of imprinting regulation in this domain. PMID- 25447522 TI - CaMKII isoforms differ in their specific requirements for regulation by nitric oxide. AB - The Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) mediates physiological and pathological functions by its Ca(2+)-independent autonomous activity. Two novel mechanisms for generating CaMKII autonomy include oxidation and S nitrosylation, the latter requiring both Cys280 and Cys289 amino acid residues in the brain-specific isoform CaMKIIalpha. Even though the other CaMKII isoforms have a different amino acid in the position homologous to Cys280, we show here that nitric oxide (NO)-signaling generated autonomy also for the CaMKIIbeta isoform. Furthermore, although oxidation of the Met280/281 residues is sufficient to generate autonomy for most CaMKII isoforms, oxidation-induced autonomy was also prevented by a Cys289-mutation in the CaMKIIalpha isoform. Thus, all CaMKII isoforms can be regulated by physiological NO-signaling, but CaMKIIalpha regulation by oxidation and S-nitrosylation is more stringent. PMID- 25447524 TI - Human ficolin-2 recognition versatility extended: an update on the binding of ficolin-2 to sulfated/phosphated carbohydrates. AB - Ficolin-2 has been reported to bind to DNA and heparin, but the mechanism involved has not been thoroughly investigated. X-ray studies of the ficolin-2 fibrinogen-like domain in complex with several new ligands now show that sulfate and phosphate groups are prone to bind to the S3 binding site of the protein. Composed of Arg132, Asp133, Thr136 and Lys221, the S3 site was previously shown to mainly bind N-acetyl groups. Furthermore, DNA and heparin compete for binding to ficolin-2. Mutagenesis studies reveal that Arg132, and to a lesser extent Asp133, are important for this binding property. The versatility of the S3 site in binding N-acetyl, sulfate and phosphate groups is discussed through comparisons with homologous fibrinogen-like recognition proteins. PMID- 25447523 TI - Calcium release-activated calcium (CRAC) channels mediate the beta(2)-adrenergic regulation of Na,K-ATPase. AB - beta2-Adrenergic agonists have been shown to regulate Na,K-ATPase in the alveolar epithelium by recruiting Na,K-ATPase-containing vesicles to the plasma membrane of alveolar epithelial cells (AEC). Here, we provide evidence that beta2-agonists induce store-operated calcium entry (SOCE) in AECs. This calcium entry is necessary for beta2-agonist-induced recruitment of Na,K-ATPase to the plasma membrane of AECs. Specifically, we show that beta2-agonists induce SOCE via stromal interaction molecule 1 (STIM1)-associated calcium release-activated calcium (CRAC) channels. We also demonstrate that the magnitude of SOCE affects the abundance of Na,K-ATPase at the plasma membrane of AECs. PMID- 25447525 TI - Kinetics of the early events of GPCR signalling. AB - Neurotensin receptor type 1 (NTS1) is a G protein-coupled receptor (GPCR) that affects cellular responses by initiating a cascade of interactions through G proteins. The kinetic details for these interactions are not well-known. Here, NTS1-nanodisc-Galphas and Galphai1 interactions were studied. The binding affinities of Galphai1 and Galphas to NTS1 were directly measured by surface plasmon resonance (SPR) and determined to be 15+/-6 nM and 31+/-18 nM, respectively. This SPR configuration permits the kinetics of early events in signalling pathways to be explored and can be used to initiate descriptions of the GPCR interactome. PMID- 25447528 TI - Wilms' tumor 1 enhances Cisplatin-resistance of advanced NSCLC. AB - Wilms' tumor 1 (WT1) is an oncogene that has been correlated with tumor progression, bad prognosis and chemo-resistance in Non-Small-Cell lung cancer (NSCLC). Here, we found that WT1 expression is significantly higher in NSCLCs than in benign controls, and that Cisplatin-resistant patients display a notable increase in WT1 expression following relapse. In vitro, WT1 levels were associated with the IC50 of NSCLC cells and increased along with treatment time and dose of Cisplatin. Furthermore, WT1 enhanced Major Vault Protein (MVP) transcription via binding to its promoter. Therefore, WT1 may be a potential therapeutic target for solving resistance. PMID- 25447527 TI - GABA-A receptor-dependent mechanisms prevent excessive spine elimination during postnatal maturation of the mouse cortex in vivo. AB - Dendritic spine dynamics are implicated in the structural plasticity of cognition related neuroconnectivity. This study utilized the transcranial in vivo imaging approach to investigate spine dynamics in intact brains of living yellow fluorescent protein-expressing mice. A developmental switch in the net spine loss rate occurred at ~4 months of age. The initially rapid rate slowed down ~6-fold due to substantially reduced spine elimination with minor changes in formation. Furthermore, pharmacological blockade of gamma-aminobutyric acid type A (GABA-A) receptors resulted in significantly increased elimination of pre-existing spines without affecting new spine formation. Spine elimination returned to normal levels following treatment cessation. Thus, GABA-A receptor-dependent mechanisms act as "brakes" - keeping spine elimination in check to prevent over-pruning, thereby preserving the integrity of cognition-related cortical circuits. PMID- 25447529 TI - CD44 variant, but not standard CD44 isoforms, mediate disassembly of endothelial VE-cadherin junction on metastatic melanoma cells. AB - Loss of endothelial adherens junctions is involved in tumor metastasis. Here, we demonstrate that, in the metastatic Lu1205 melanoma cells, expression of the CD44 variant CD44v8-v10 induced junction disassembly and vascular endothelial (VE) cadherin phosphorylation at Y658 and Y731. Short interfering RNA (siRNA)-mediated CD44 knockdown or sialic acid cleavage reversed these effects. Moreover, microspheres coated with recombinant CD44v8-v10 promoted endothelial junction disruption. Overexpression of CD44v8-v10 but not of standard CD44 (CD44s) promoted gap formation in the non-metastatic WM35 melanoma cells, whereas CD44 knockdown or neuraminidase treatment dramatically diminished melanoma transendothelial migration. Endothelial cells transfected with the phosphomimetic VE-cadherin mutant Y658E supported transmigration of CD44-silenced Lu1205 cells. Our findings imply that CD44 variant isoform (CD44v) but not CD44s regulates endothelial junction loss, promoting melanoma extravasation. PMID- 25447530 TI - Segmental isotope-labeling of the intrinsically disordered protein PQBP1. AB - Polyglutamine tract-binding protein 1 (PQBP1) is an intrinsically disordered protein abundantly expressed in the brain. Mutations in the PQBP1 gene are causative for X-linked mental retardation disorders. Here, we investigated the structure of the C-terminal segment within the context of full-length PQBP1. We produced a segmentally isotope-labeled PQBP1 composed of a non-labeled segment (residues 1-219; N-segment) and a (13)C/(15)N-labeled segment (residues 220-265; C-segment). Our results demonstrate that the segmental isotope-labeling combined with NMR spectroscopy is useful for detecting a very weak intra-molecular interaction in an intrinsically disordered protein. PMID- 25447526 TI - Ghrelin augments murine T-cell proliferation by activation of the phosphatidylinositol-3-kinase, extracellular signal-regulated kinase and protein kinase C signaling pathways. AB - Thymic atrophy occurs during normal aging, and is accelerated by exposure to chronic stressors that elevate glucocorticoid levels and impair the naive T cell output. The orexigenic hormone ghrelin was recently shown to attenuate age associated thymic atrophy. Here, we report that ghrelin enhances the proliferation of murine CD4+ primary T cells and a CD4+ T-cell line. Ghrelin induced activation of the ERK1/2 and Akt signaling pathways, via upstream activation of phosphatidylinositol-3-kinase and protein kinase C, to enhance T cell proliferation. Moreover, ghrelin induced expression of the cell cycle proteins cyclin D1, cyclin E, cyclin-dependent kinase 2 (CDK2) and retinoblastoma phosphorylation. Finally, ghrelin activated the above-mentioned signaling pathways and stimulated thymocyte proliferation in young and older mice in vivo. PMID- 25447531 TI - Secondary conformational conversion is involved in glycosaminoglycans-mediated cellular uptake of the cationic cell-penetrating peptide PACAP. AB - Glycosaminoglycans (GAGs) contribute to the cellular uptake of cationic cell penetrating peptides (CPPs). However, molecular details about the contributions of GAGs in CPP internalization remain unclear. In this study, we examined the cellular uptake mechanism of the arginine-rich CPP pituitary adenylate-cyclase activating polypeptide (PACAP). We observed that the uptake efficacy of PACAP is dependent on the expression of cell surface GAGs. As the binding of PACAP to sulfated GAGs induced a random coil-to-alpha-helix conformational conversion, we investigated the role of the helical formation in PACAP internalization. Whereas this secondary structure was not crucial for efficient internalization in GAGs deficient cells, PACAP alpha-helix was essential for GAGs-dependent uptake. PMID- 25447532 TI - Molecular cloning and characterization of drimenol synthase from valerian plant (Valeriana officinalis). AB - Drimenol, a sesquiterpene alcohol, and its derivatives display diverse bio activities in nature. However, a drimenol synthase gene has yet to be identified. We identified a new sesquiterpene synthase cDNA (VoTPS3) in valerian plant (Valeriana officinalis). Purification and NMR analyses of the VoTPS3-produced terpene, and characterization of the VoTPS3 enzyme confirmed that VoTPS3 synthesizes (-)-drimenol. In feeding assays, possible reaction intermediates, farnesol and drimenyl diphosphate, could not be converted to drimenol, suggesting that the intermediate remains tightly bound to VoTPS3 during catalysis. A mechanistic consideration of (-)-drimenol synthesis suggests that drimenol synthase is likely to use a protonation-initiated cyclization, which is rare for sesquiterpene synthases. VoTPS3 can be used to produce (-)-drimenol, from which useful drimane-type terpenes can be synthesized. PMID- 25447534 TI - Molecular exploration of the alpha(1A)-adrenoceptor orthosteric site: binding site definition for epinephrine, HEAT and prazosin. AB - Despite the physiological and pharmacological importance of the alpha1A adrenoreceptor, the mode of interactions of classical agonists and radioactive ligands with this receptor is not yet clearly defined. Here, we used mutagenesis studies and binding experiments to evaluate the importance of 11 receptor sites for the binding of (125)I-HEAT, (3)H-prazosin and epinephrine. Only one residue (F312) commonly interacts with the three molecules, and, surprisingly, D106 interacts only with epinephrine in a moderate way. Our docking model shows that prazosin and HEAT are almost superimposed into the orthosteric pocket with their tetralone and quinazoline rings close to the phenyl ring of the agonist. PMID- 25447533 TI - Crystal structure of phospholipase PA2-Vb, a protease-activated receptor agonist from the Trimeresurus stejnegeri snake venom. AB - Phospholipase A2 (PLA2) is an important component in snake venoms. Here, an acidic PLA2, designated PA2-Vb was isolated from the Trimeresurus stejnegeri snake venom. PA2-Vb acts on a protease-activated receptor (PAR-1) to evoke Ca(2+) release through the inositol 1,4,5-trisphosphate receptor (IP3R) and induces mouse aorta contraction. PAR-1, phospholipase C and IP3R inhibitors suppressed PA2-Vb-induced aorta contraction. The crystal structure reveals that PA2-Vb has the typical fold of most snake venom PLA2. Several PEG molecules bond to a positively charged pocket. The finding offers a novel pharmacological basis of the structure for investigating the PAR-1 receptor and suggests potential applications for PA2-Vb in the vascular system. PMID- 25447535 TI - Enzyme processivity changes with the extent of recalcitrant polysaccharide degradation. AB - Glycoside hydrolases depolymerize polysaccharides. They can subtract single carbohydrate chains from polymer crystals and cleave glycosidic bonds without dissociating from the substrate after each catalytic event. This processivity is thought to conserve energy during polysaccharide degradation. Herein, we compare the processivity of components of the chitinolytic machinery of Serratia marcescens. The two processive chitinases ChiA and ChiB, the ChiB-W97A mutant, and the endochitinase ChiC were analyzed for the extent of degradation of three different chitin substrates. Moreover, enzyme processivity was assessed on the basis of the [(GlcNAc)2]/[GlcNAc] product ratio. The results show that the apparent processivity (Papp) greatly diminishes with the extent of degradation and confirm the hypothesis that Papp is limited by the length of obstacle free path on the substrate. PMID- 25447536 TI - MiR-20a regulates the PRKG1 gene by targeting its coding region in pulmonary arterial smooth muscle cells. AB - Chronic hypoxia triggers pulmonary vascular remodeling, which is associated with de-differentiation of pulmonary artery smooth muscle cells (PASMC). Here, we show that miR-20a expression is up-regulated in response to hypoxia in both mouse and human PASMC. We also observed that miR-20a represses the protein kinase, cGMP dependent, type I (PRKG1) gene and we identified two crucial miR-20a binding sites within the coding region of PRKG1. Functional studies showed that miR-20a promotes the proliferation and migration of human PASMC, whereas it inhibits their differentiation. In summary, we provided a possible mechanism by which hypoxia results in decreased PRKG1 expression and in the phenotypic switching of PASMC. PMID- 25447538 TI - The transcription factor GFI1 negatively regulates NLRP3 inflammasome activation in macrophages. AB - Interleukin-1beta (IL-1beta) secretion downstream of Toll-like receptor (TLR) activation is tightly controlled at the transcriptional and post-translational levels. NLRP3 inflammasome is involved in the maturation of pro-IL-1beta, with NLRP3 expression identified as the limiting factor for inflammasome activation. Previously, we had demonstrated that the zinc-finger protein GFI1 inhibits pro-IL 1beta transcription. Here, we show that GFI1 inhibits NLRP3 inflammasome activation and IL-1beta secretion in macrophages. GFI1 suppressed Nlrp3 transcription via two mechanisms: (1) by binding to the Gli-responsive element 1 (GRE1) in the Nlrp3 promoter; and (2) by antagonizing the nuclear factor-kappaB (NF-kappaB) transcriptional activity. Thus, GFI1 negatively regulates TLR mediated IL-1beta production at both transcriptional and post-translational levels. PMID- 25447537 TI - alpha-Synemin localizes to the M-band of the sarcomere through interaction with the M10 region of titin. AB - alpha-Synemin contains a unique 312 amino acid insert near the end of its C terminal tail. Therefore we set out to determine if the insert is a site of protein-protein interaction that regulates the sub-cellular localization of this large isoform of synemin. Yeast-two hybrid analysis indicated that this region is a binding site for the M10 region of titin. This was confirmed with GST pull-down assays. Co-immunoprecipitation of endogenous proteins indicated close association of the two proteins in vivo and immunostaining of cardiomyocytes demonstrated co localization of the proteins at the M-band of the sarcomere. PMID- 25447539 TI - Respiratory complex I from Escherichia coli does not transport Na(+) in the absence of its NuoL subunit. AB - We investigated H(+) and Na(+) transport by complex I from Escherichia coli devoid of the NuoL subunit, which is probably part of the ion translocating machinery. We observed that complex I devoid of the NuoL subunit still translocates H(+), although to a smaller extension than the complete version of complex I, but does not transport Na(+). Our results unequivocally reinforce the observation that E. coli complex I transports Na(+) in the opposite direction to that of the H+ and show that NuoL subunit is involved in the translocation of both ions by complex I. PMID- 25447540 TI - Mitogen-activated protein kinase p38 induces HDAC4 degradation in hypertrophic chondrocytes. AB - Histone deacetylase 4 (HDAC4) is a critical negative regulator for chondrocyte hypertrophy by binding to and inhibiting Runx2, a critical transcription factor for chondrocyte hypertrophy. It is unclear how HDAC4 expression and stability are regulated during growth plate development. We report here that inhibition of mitogen-activated protein kinase (MAPK) p38 by dominant negative p38 or p38 inhibitor prevents HDAC4 degradation. Mutation of a potential caspase-2 and 3 cleavage site Asp289 stabilizes HDAC4 in chondrocytes. In contrast, constitutively active MAPK kinase 6 (constitutive activator of p38) transgenic mice exhibit decreased HDAC4 content in vivo. We also observed that p38 stimulates caspase-3 activity in chondrocytes. Inhibition of p38 or caspases reduced HDAC4 degradation. HDAC4 inhibited Runx2 promoter activity in a dose dependent manner and caspase inhibitors further enhanced this inhibition by preventing HDAC4 degradation. Overall, these results demonstrate that p38 promotes HDAC4 degradation by increasing caspase-mediated cleavage, which releases Runx2 from a repressive influence of HDAC4 and promotes the chondrocyte hypertrophy and bone formation. PMID- 25447542 TI - Formin mDia1, a downstream molecule of FMNL1, regulates Profilin1 for actin assembly and spindle organization during mouse oocyte meiosis. AB - Mammalian diaphanous1 (mDia1) is a homologue of Drosophila diaphanous and belongs to the Formin-homology family of proteins that catalyze actin nucleation and polymerization. Although Formin family proteins, such as Drosophila diaphanous, have been shown to be essential for cytokinesis, whether and how mDia1 functions during meiosis remain uncertain. In this study, we explored possible roles and the signaling pathway involved for mDia1 using a mouse oocyte model. mDia1 depletion reduced polar body extrusion, which may have been due to reduced cortical actin assembly. mDia1 and Profilin1 had similar localization patterns in mouse oocytes and mDia1 knockdown resulted in reduced Profilin1 expression. Depleting FMNL1, another Formin family member, resulted in reduced mDia1 expression, while RhoA inhibition did not alter mDia1 expression, which indicated that there was a FMNL1-mDia1-Profilin1 signaling pathway in mouse oocytes. Additionally, mDia1 knockdown resulted in disrupting oocyte spindle morphology, which was confirmed by aberrant p-MAPK localization. Thus, these results demonstrated indispensable roles for mDia1 in regulating mouse oocyte meiotic maturation through its effects on actin assembly and spindle organization. PMID- 25447543 TI - Apoptotic human neutrophil peptide-1 anti-tumor activity revealed by cellular biomechanics. AB - Cancer remains a major cause of morbidity and mortality worldwide. Although progress has been made regarding chemotherapeutic agents, new therapies that combine increased selectivity and efficacy with low resistance are still needed. In the search for new anticancer agents, therapies based on biologically active peptides, in particular, antimicrobial peptides (AMPs), have attracted attention for their decreased resistance development and low cytotoxicity. Many AMPs have proved to be tumoricidal agents against human cancer cells, but their mode of action is still controversial. The existence of common properties shared by the membranes of bacteria and tumor cells points to similar lipid-targeting mechanisms in both cases. On the other hand, anticancer peptides (ACPs) also induce apoptosis and inhibit angiogenesis. Human neutrophil peptide-1 (HNP-1) is an endogenous AMP that has been implicated in different cellular phenomena such as tumor proliferation. The presence of HNP-1 in the serum/plasma of oncologic patients turns this peptide into a potential tumor biomarker. The present work reveals the different effects of HNP-1 on the biophysical and nanomechanical properties of solid and hematological tumor cells. Studies on cellular morphology, cellular stiffness, and membrane ultrastructure and charge using atomic force microscopy (AFM) and zeta potential measurements show a preferential binding of HNP-1 to solid tumor cells from human prostate adenocarcinoma when compared to human leukemia cells. AFM also reveals induction of apoptosis with cellular membrane defects at very low peptide concentrations. Understanding ACPs mode(s) of action will certainly open innovative pathways for drug development in cancer treatment. PMID- 25447541 TI - Resveratrol regulates PTEN/Akt pathway through inhibition of MTA1/HDAC unit of the NuRD complex in prostate cancer. AB - Metastasis associated protein 1 (MTA1) is a component of the nucleosome remodeling and deacetylating (NuRD) complex which mediates gene silencing and is overexpressed in several cancers. We reported earlier that resveratrol, a dietary stilbene found in grapes, can down-regulate MTA1. In the present study, we show that PTEN is inactivated by MTA1 in prostate cancer cells. Further, we show that resveratrol promotes acetylation and reactivation of PTEN via inhibition of the MTA1/HDAC complex, resulting in inhibition of the Akt pathway. In addition, we show that MTA1 knockdown is sufficient to augment acetylation of PTEN indicating a crucial role of MTA1 itself in the regulation of PTEN acetylation contributing to its lipid phosphatase activity. Acetylated PTEN preferentially accumulates in the nucleus where it binds to MTA1. We also show that MTA1 interacts exclusively with PTEN acetylated on Lys125 and Lys128, resulting in diminished p-Akt levels. Finally, using orthotopic prostate cancer xenografts, we demonstrate that both resveratrol treatment and MTA1 knockdown enhance PTEN levels leading to a decreased p-Akt expression and proliferation index. Taken together, our results indicate that MTA1/HDAC unit is a negative regulator of PTEN which facilitates survival pathways and progression of prostate cancer and that resveratrol can reverse this process through its MTA1 inhibitory function. PMID- 25447544 TI - Anatomy of an iron-sulfur cluster scaffold protein: Understanding the determinants of [2Fe-2S] cluster stability on IscU. AB - Protein-bound iron sulfur clusters are prosthetic groups involved in several metabolic pathways. Understanding how they interact with the host protein and which factors influence their stability is therefore an important goal in biology. Here, we have addressed this question by studying the determinants of the 2Fe-2S cluster stability in the IscU/Isu protein scaffold. Through a detailed computational study based on a mixed quantum and classical mechanics approach, we predict that the simultaneous presence of two conserved residues, D39 and H105, has a conflicting role in cluster coordination which results in destabilizing cluster-loaded IscU/Isu according to a 'tug-of-war' mechanism. The effect is absent in the D39A mutant already known to host the cluster more stably. Our theoretical conclusions are directly supported by experimental data, also obtained from the H105A mutant, which has properties intermediate between the wild-type and the D39A mutant. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. PMID- 25447546 TI - Do mechanical forces contribute to nanoscale membrane organisation in T cells? AB - Mechanotransduction describes how a cell senses and interacts with its environment. The concept originated in adhesion biology where adhesion receptors, integrins, facilitate force transmission between the extracellular matrix and the intracellular actin cytoskeleton. Indeed, during any adhesive contacts, cells do exert mechanical force. Hence, the probing of the local environment by cells results in mechanical cues that contribute to cellular functions and cell fate decisions such as migration, proliferation, differentiation and apoptosis. On the molecular level, mechanical forces can rearrange proteins laterally within the membrane, regulate their activity by inducing conformational changes and probe the mechanical properties and bond strength of receptor-ligands. From this point of view, it appears surprising that molecular forces have been largely overlooked in membrane organisation and ligand discrimination processes in lymphocytes. During T cell activation, the T cell receptor recognises and distinguishes antigenic from benign endogenous peptides to initiate the reorganisation of membrane proteins into signalling clusters within the immunological synapse. In this review, we asked whether characteristics of fibroblast force sensing could be applied to immune cell antigen recognition and signalling, and outline state of-the-art experimental strategies for studying forces in the context of membrane organisation. This article is part of a Special Issue entitled: Nanoscale membrane orgainisation and signalling. PMID- 25447547 TI - Structural effects of Mg2+ on the regulatory states of three neuronal calcium sensors operating in vertebrate phototransduction. AB - The effects of physiological concentration of magnesium on the switch states of the neuronal calcium sensor proteins recoverin, GCAP1 and GCAP2 were investigated. Isothermal titration calorimetry was applied for binding studies. Circular dichroism spectroscopy was used to characterize protein thermal stability, secondary and tertiary structure in conditions of high and low [Ca2+], mimicking respectively the dark-adapted and light-exposed photoreceptor states during the phototransduction cascade. Further, molecular dynamics (MD) simulations were run to investigate the dynamical structural properties of GCAP1 in its activator, inhibitor and putative transitory states. Our results confirmed that Mg2+ is unable to trigger the typical Ca2+-induced conformational change of recoverin (myristoyl switch) while it decreases its thermal stability. Interestingly, Mg2+ seems to affect the conformation of GCAP2 both at high and low [Ca2+], however the variations are more substantial for myristoylated GCAP2 in the absence of Ca2+. GCAP1 is responsive to Mg2+ only in its low [Ca2+] state and Mg2+-GCAP1 tertiary structure slightly differs from both apo and Ca2+-bound states. Finally, MD simulations suggest that the GCAP1 state harboring one Mg2+ ion bound to EF2 acquires structural characteristics that are thought to be relevant for the activation of the guanylate cyclase. Moreover, all the putative Mg2+-bound states of myristoylated GCAP1 are structurally less flexible than Ca2+ bound states. GCAP1 acquires a more compact tertiary structure that is less accessible to the solvent, thereby inducing a different conformation to the myristoyl moiety, which might be crucial for the activation of the guanylate cyclase. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID- 25447545 TI - Recent advances in the Suf Fe-S cluster biogenesis pathway: Beyond the Proteobacteria. AB - Fe-S clusters play critical roles in cellular function throughout all three kingdoms of life. Consequently, Fe-S cluster biogenesis systems are present in most organisms. The Suf (sulfur formation) system is the most ancient of the three characterized Fe-S cluster biogenesis pathways, which also include the Isc and Nif systems. Much of the first work on the Suf system took place in Gram negative Proteobacteria used as model organisms. These early studies led to a wealth of biochemical, genetic, and physiological information on Suf function. From those studies we have learned that SufB functions as an Fe-S scaffold in conjunction with SufC (and in some cases SufD). SufS and SufE together mobilize sulfur for cluster assembly and SufA traffics the complete Fe-S cluster from SufB to target apo-proteins. However, recent progress on the Suf system in other organisms has opened up new avenues of research and new hypotheses about Suf function. This review focuses primarily on the most recent discoveries about the Suf pathway and where those new models may lead the field. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. PMID- 25447548 TI - Determinants of the membrane orientation of a calcium signaling enzyme CD38. AB - CD38 catalyzes the synthesis of two structurally distinct messengers for Ca2+ mobilization, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), from cytosolic substrates, NAD and NADP, respectively. CD38 is generally thought of as a type II membrane protein with its catalytic site facing outside. We recently showed that CD38 exists, instead, in two opposite membrane orientations. The determinant for the membrane topology is unknown. Here, specific antibodies against type III CD38 were designed and produced. We show that mutating the positively charged residues in the N-terminal tail of CD38 converted its orientation to type III, with the catalytic domain facing the cytosol and it was fully active in producing intracellular cADPR. Changing the serine residues to aspartate, which is functionally equivalent to phosphorylation, had a similar effect. The mutated CD38 was expressed intracellularly and was un-glycosylated. The membrane topology could also be modulated by changing the highly conserved di-cysteine. The results indicate that the net charge of the N-terminal segment is important in determining the membrane topology of CD38 and that the type III orientation can be a functional form of CD38 for Ca2+-signaling. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID- 25447551 TI - May the remodeling of the Ca2+ toolkit in endothelial progenitor cells derived from cancer patients suggest alternative targets for anti-angiogenic treatment? AB - Endothelial progenitor cells (EPCs) may be recruited from bone marrow to sustain the metastatic switch in a number of solid cancers, including breast cancer (BC) and renal cellular carcinoma (RCC). Preventing EPC mobilization causes tumor shrinkage. Novel anti-angiogenic treatments have been introduced in therapy to inhibit VEGFR-2 signaling; unfortunately, these drugs blocked tumor angiogenesis in pre-clinical murine models, but resulted far less effective in human patients. Understanding the molecular mechanisms driving EPC proliferation and tubulogenesis in cancer patients could outline novel targets for alternative anti angiogenic treatments. Store-operated Ca2+ entry (SOCE) regulates the growth of human EPCs, and it is mediated by the interaction between the endoplasmic reticulum Ca2+-sensor, Stim1, and the plasmalemmal Ca2+ channels, Orai1 and TRPC1. EPCs do not belong to the neoplastic clone: thus, unlike tumor endothelium and neoplastic cells, they should not remodel their Ca2+ toolkit in response to tumor microenvironment. However, our recent work demonstrated that EPCs isolated from naive RCC patients (RCC-EPCs) undergo a dramatic remodeling of their Ca2+ toolkit by displaying a remarkable drop in the endoplasmic reticulum Ca2+ content, by down-regulating the expression of inositol-1,4,5-receptors (InsP3Rs), and by up-regulating Stim1, Orai1 and TRPC1. Moreover, EPCs are dramatically less sensitive to VEGF stimulation both in terms of Ca2+ signaling and of gene expression when isolated from tumor patients. Conversely, the pharmacological abolition of SOCE suppresses proliferation in these cells. These results question the suitability of VEGFR-2 as a therapeutically relevant target for anti angiogenic treatments and hint at Orai1 and TRPC1 as more promising alternatives. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID- 25447553 TI - Effects of some extrusion variables on physicochemical characteristics of extruded corn starch-passion fruit pulp (Passiflora edulis) snacks. AB - The aim of this work was to study the effect of the addition of passion fruit pulp (PFP: 0-7%), the variation of barrel temperature in the third zone extruder (BT: 80-140 degrees C) and feed moisture (FM:16-30%) in a blend of corn starch and passion fruit pulp on different physicochemical characteristics of directly expanded snacks by extrusion technology. Single-screw laboratory extruder and a central, composite, rotatable experimental design were used. Expansion index of extrudates ranged between 1.0 and 1.8. Decreasing of feed moisture (18%), passion fruit pulp concentration (1.42%) and the increasing of barrel temperature (127 degrees C) resulted in higher expansion index. The increasing of feed moisture and passion fruit pulp concentration resulted in higher penetration force values of extrudates. The passion fruit pulp concentration showed a highly significant effect (p <= 0.01) on the L *, a * and b * parameters. Passion fruit pulp has a reasonable source of beta-carotene, proteins and dietary fibers that can be added to expanded snacks. PMID- 25447552 TI - STIM1 phosphorylation triggered by epidermal growth factor mediates cell migration. AB - STIM1 is a key regulator of store-operated calcium entry (SOCE), and therefore a mediator of Ca2+ entry-dependent cellular events. Phosphorylation of STIM1 at ERK1/2 target sites has been described as enhancing STIM1 activation during intracellular Ca2+ emptying triggered by the inhibition of the sarco(endo)plasmic Ca2+ -ATPase with thapsigargin. However, no physiological function is known for this specific phosphorylation. The present study examined the role of STIM1 phosphorylation in cell signaling triggered by EGF. Using a human endometrial adenocarcinoma cell line (Ishikawa cells) EGF or H-Ras(G12V), an active mutant of H-Ras, was found to trigger STIM1 phosphorylation at residues Ser575, Ser608, and Ser621, and this process was sensitive to PD0325901, an inhibitor of ERK1/2. Both, ERK1/2 activation and STIM1 phosphorylation took place in the absence of extracellular Ca2+, indicating that both events are upstream steps for Ca2+entry activation. Also, EGF triggered the dissociation of STIM1 from EB1 (a regulator of microtubule plus-ends) in a manner similar to that reported for the activation of STIM1 by thapsigargin. Migration of the Ishikawa cells was impaired when STIM1 phosphorylation was targeted by Ser-to-Ala substitution mutation of ERK1/2 target sites. This effect was also observed with the Ca2+ channel blocker SKF96365. Phosphomimetic mutation of STIM1 restored the migration to levels similar to that found for STIM1-wild type. Finally, the increased vimentin expression and relocalization of E-cadherin triggered by EGF were largely inhibited by targeting STIM1 phosphorylation, while STIM1-S575E/S608E/S621E normalized the profiles of these two EMT markers. PMID- 25447555 TI - The use of rapid diagnostic tests for transfusion infectious screening in Africa: a literature review. AB - Infectious risk associated with blood transfusion remains a major public health challenge in Africa, where prevalence rates of the major transfusion transmissible infections (ie, hepatitis B, hepatitis C, human immunodeficiency virus, and syphilis) are among the highest in the world. Resource-limited blood services often operate with minimal predonation screening safeguards, prompting exclusive reliance on laboratory testing to mitigate infectious risk. Transfusion screening with rapid diagnostic tests (RDTs) has been adopted in areas that lack the capacity to support the routine use of more sophisticated technologies. However, uncertainty surrounding the performance of some RDTs in the field has spurred debate regarding their application to blood donation screening. Our review of the literature identified 17 studies that evaluated RDTs for the infectious screening of blood donors in Africa. The review highlights the variable performance of available RDTs and the importance of their use in a quality-assured manner. Deficiencies in performance observed with some RDTs underscore the need to validate test kits prior to use under field conditions with locally acquired samples. Suboptimal sensitivities of some available tests, specifically hepatitis B virus rapid assays, question their suitability in single test algorithms, particularly in high-prevalence regions. Although RDTs have limitations, many of which can be addressed through improved training and quality systems, they are frequently the only viable option for infectious screening in resource-poor African countries. Therefore, additional studies and specific guidelines regarding the use of RDTs in the context of blood safety are needed. PMID- 25447554 TI - Discipline matters: embedding academic literacies into an undergraduate nursing program. AB - In recent years the higher education sector in Australia has been increasingly concerned with ensuring that the English language proficiency levels of students are commensurate with the academic and professional tasks that they must perform. In many universities, this heightened attention to language proficiency has driven changes to teaching and learning practices. This paper reports on a project to embed academic literacies development into a core first year subject within a Bachelor of Nursing program in a large, culturally and linguistically diverse, metropolitan university. Prior to the commencement of their nursing program 747 students completed a Post Enrolment Language Assessment. Students who required additional support were advised to enroll in tutorials which included an additional literacy focus. These tutorials were part of the normal tutorial program for this nursing subject. Students with lower level language skills who attended the streamed tutorial with additional literacy support showed a greater improvement in their written communication than those with similar language proficiency who attended non-streamed tutorials. Evidence suggests that this improvement was transferred into writing tasks in other non-streamed subjects. The findings reported in this paper highlights that discipline specific embedded strategies are an effective approach to the development of academic literacies. PMID- 25447550 TI - Quantitative analysis of mitochondrial morphology and membrane potential in living cells using high-content imaging, machine learning, and morphological binning. AB - Understanding the processes of mitochondrial dynamics (fission, fusion, biogenesis, and mitophagy) has been hampered by the lack of automated, deterministic methods to measure mitochondrial morphology from microscopic images. A method to quantify mitochondrial morphology and function is presented here using a commercially available automated high-content wide-field fluorescent microscopy platform and R programming-language-based semi-automated data analysis to achieve high throughput morphological categorization (puncta, rod, network, and large & round) and quantification of mitochondrial membrane potential. In conjunction with cellular respirometry to measure mitochondrial respiratory capacity, this method detected that increasing concentrations of toxicants known to directly or indirectly affect mitochondria (t-butyl hydroperoxide [TBHP], rotenone, antimycin A, oligomycin, ouabain, and carbonyl cyanide-p trifluoromethoxyphenylhydrazone [FCCP]), decreased mitochondrial networked areas in cultured 661w cells to 0.60-0.80 at concentrations that inhibited respiratory capacity to 0.20-0.70 (fold change compared to vehicle). Concomitantly, mitochondrial swelling was increased from 1.4- to 2.3-fold of vehicle as indicated by changes in large & round areas in response to TBHP, oligomycin, or ouabain. Finally, the automated identification of mitochondrial location enabled accurate quantification of mitochondrial membrane potential by measuring intramitochondrial tetramethylrhodamine methyl ester (TMRM) fluorescence intensity. Administration of FCCP depolarized and administration of oligomycin hyperpolarized mitochondria, as evidenced by changes in intramitochondrial TMRM fluorescence intensities to 0.33- or 5.25-fold of vehicle control values, respectively. In summary, this high-content imaging method accurately quantified mitochondrial morphology and membrane potential in hundreds of thousands of cells on a per-cell basis, with sufficient throughput for pharmacological or toxicological evaluation. PMID- 25447556 TI - Including frequent emergency department users with severe alcohol use disorders in research: assessing capacity. AB - STUDY OBJECTIVE: Frequent emergency department (ED) users with severe alcohol use disorders are often excluded from research, in part because assessing capacity to provide consent is challenging. We aim to assess the feasibility of using the University of California, San Diego Brief Assessment of Capacity to Consent, a 5 minute, easy-to-use, validated instrument, to screen for capacity to consent for research in frequent ED users with severe alcohol use disorders. METHODS: We prospectively enrolled a convenience sample of 20 adults to assess their capacity to provide consent for participation in 30-minute mixed-methods interviews using the 10-question University of California, San Diego Brief Assessment of Capacity to Consent. Participants were identified through an administrative database, had greater than 4 annual ED visits for 2 years, and had severe alcohol use disorders. The study was conducted with institutional review board approval from March to July 2013 in an urban, public, university ED receiving approximately 120,000 visits per year. Blood alcohol concentration and demographic data were extracted from the medical record. RESULTS: We completed assessments for 19 of 20 participants. One was removed because of agitation. Sixteen of 19 participants passed each question and were deemed capable of providing informed consent. Interventions to improve understanding (prompting and material review) were required for 15 of 19 participants. The mean duration to describe the study and perform the assessment was 10.4 minutes (SD 3 minutes). The mean blood alcohol concentration was 211.5 mg/dL (SD 137.4 mg/dL). The 3 patients unable to demonstrate capacity had blood alcohol concentrations of 226 and 348 mg/dL, with 1 not obtained. CONCLUSION: This pilot study supports the feasibility of using the University of California, San Diego Brief Assessment of Capacity to Consent to assess capacity of frequent ED users with severe alcohol use disorders to participate in research. Blood alcohol concentration was not correlated with capacity. PMID- 25447549 TI - Sense and specificity in neuronal calcium signalling. AB - Changes in the intracellular free calcium concentration ([Ca2+]i) in neurons regulate many and varied aspects of neuronal function over time scales from microseconds to days. The mystery is how a single signalling ion can lead to such diverse and specific changes in cell function. This is partly due to aspects of the Ca2+ signal itself, including its magnitude, duration, localisation and persistent or oscillatory nature. The transduction of the Ca2+ signal requires Ca2+binding to various Ca2+ sensor proteins. The different properties of these sensors are important for differential signal processing and determine the physiological specificity of Ca(2+) signalling pathways. A major factor underlying the specific roles of particular Ca2+ sensor proteins is the nature of their interaction with target proteins and how this mediates unique patterns of regulation. We review here recent progress from structural analyses and from functional analyses in model organisms that have begun to reveal the rules that underlie Ca2+ sensor protein specificity for target interaction. We discuss three case studies exemplifying different aspects of Ca2+ sensor/target interaction. This article is part of a special issue titled the 13th European Symposium on Calcium. PMID- 25447557 TI - The PICHFORK (Pain in Children Fentanyl or Ketamine) trial: a randomized controlled trial comparing intranasal ketamine and fentanyl for the relief of moderate to severe pain in children with limb injuries. AB - STUDY OBJECTIVE: We compare the analgesic effectiveness of intranasal fentanyl and ketamine in children. METHODS: This was a double-blind, randomized, controlled trial comparing fentanyl at 1.5 MUg/kg with ketamine at 1 mg/kg in children aged 3 to 13 years and weighing less than 50 kg, with isolated limb injury and pain of more than 6 of 10 at triage. The sample size was 40 in each arm. Subjects were coadministered oral ibuprofen at 10 mg/kg. The primary outcome was median pain rating reduction at 30 minutes. Secondary outcomes were pain rating reduction at 15 and 60 minutes, subjective improvement and satisfaction, University of Michigan Sedation Score, adverse events, and rescue analgesia. RESULTS: Eighty children enrolled, and 73 were available for analysis: 37 fentanyl and 36 ketamine. Median age was 8 years; 63% were male children; median baseline pain rating was 80 mm. At 30 minutes, median reductions for ketamine and fentanyl were 45 and 40 mm, respectively (difference 5 mm; 95% confidence interval [CI] -10 to 20 mm). Reductions exceeded 20 mm for ketamine and fentanyl in 82% and 79% of patients, respectively (difference 3%; 95% CI -22% to 16%). Pain rating reduction was maintained to 60 minutes in both groups. Satisfaction was reported for ketamine and fentanyl by 83% and 72% of patients, respectively (difference 11%; 95% CI -9% to 30%). Adverse events, mainly mild, were reported for ketamine and fentanyl by 78% and 40% of patients, respectively (difference 38%; 95% CI -58% to 16%). Three ketamine patients had a moderate degree of sedation by University of Michigan Sedation Score. CONCLUSION: Intranasal fentanyl and ketamine were associated with similar pain reduction in children with moderate to severe pain from limb injury. Ketamine was associated with more minor adverse events. PMID- 25447558 TI - Should nerve blocks be used for pain control in children with femur fractures? PMID- 25447559 TI - Delayed sequence intubation: a prospective observational study. AB - STUDY OBJECTIVE: We investigate a new technique for the emergency airway management of patients with altered mental status preventing adequate preoxygenation. METHODS: This was a prospective, observational, multicenter study of patients whose medical condition led them to impede optimal preintubation preparation because of delirium. A convenience sample of emergency department and ICU patients was enrolled. Patients received a dissociative dose of ketamine, allowing preoxygenation with high-flow nonrebreather mask or noninvasive positive pressure ventilation (NIPPV). After preoxygenation, patients were paralyzed and intubated. The primary outcome of this study was the difference in oxygen saturations after maximal attempts at preoxygenation before delayed sequence intubation compared with saturations just before intubation. Predetermined secondary outcomes and complications were also assessed. RESULTS: A total of 62 patients were enrolled: 19 patients required delayed sequence intubation to allow nonrebreather mask, 39 patients required it to allow NIPPV, and 4 patients required it for nasogastric tube placement. Saturations increased from a mean of 89.9% before delayed sequence intubation to 98.8% afterward, with an increase of 8.9% (95% confidence interval 6.4% to 10.9%). Thirty-two patients were in a predetermined group with high potential for critical desaturation (pre-delayed sequence intubation saturations <=93%). All of these patients increased their saturations post-delayed sequence intubation; 29 (91%) of these patients increased their post-delayed sequence intubation saturations to greater than 93%. No complications were observed in the patients receiving delayed sequence intubation. CONCLUSION: Delayed sequence intubation could offer an alternative to rapid sequence intubation in patients requiring emergency airway management who will not tolerate preoxygenation or peri-intubation procedures. It is essentially procedural sedation, with the procedure being preoxygenation. Delayed sequence intubation seems safe and effective for use in emergency airway management. PMID- 25447560 TI - Systematic Reviews Published in Emergency Medicine Journals Do Not Routinely Search Clinical Trials Registries: A Cross-Sectional Analysis. AB - STUDY OBJECTIVE: Publication bias compromises the validity of systematic reviews. This problem can be addressed in part through searching clinical trials registries to identify unpublished studies. This study aims to determine how often systematic reviews published in emergency medicine journals include clinical trials registry searches. METHODS: We identified all systematic reviews published in the 6 highest-impact emergency medicine journals between January 1 and December 31, 2013. Systematic reviews that assessed the effects of an intervention were further examined to determine whether the authors described searching a clinical trials registry and whether this search identified relevant unpublished studies. RESULTS: Of 191 articles identified through PubMed search, 80 were confirmed to be systematic reviews. Our sample consisted of 41 systematic reviews that assessed a specific intervention. Eight of these 41 (20%) searched a clinical trials registry. For 4 of these 8 reviews, the registry search identified at least 1 relevant unpublished study. CONCLUSION: Systematic reviews published in emergency medicine journals do not routinely include searches of clinical trials registries. By helping authors identify unpublished trial data, the addition of registry searches may improve the validity of systematic reviews. PMID- 25447561 TI - Hydroxyl radicals cause fluctuation in intracellular ferrous ion levels upon light exposure during photoreceptor cell death. AB - Iron accumulation is a potential pathogenic event often seen in age-related macular degeneration (AMD) patients. In this study, we focused on the relationship between AMD pathology and concentrations of ferrous ion, which is a highly reactive oxygen generator in biological systems. Murine cone-cells-derived 661 W cells were exposed to white fluorescence light at 2500 lx for 1, 3, 6, or 12 h. Levels of ferrous ions, reactive oxygen species (ROS), and hydroxyl radicals were detected by RhoNox-1, a novel fluorescent probe for the selective detection of ferrous ion, 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H2DCFDA), and 3'-p-(aminophenyl) fluorescein, respectively. Reduced glutathione, total iron levels and photoreceptor cell death were also measured. Two genes related to iron metabolism, transferrin receptor 1 (TfR1) and H ferritin (HFt), were quantified by RT-PCR. The effects of ferrous ion on cell death and hydroxyl radical production were determined by treatment with a ferrous ion chelating agent, 2,2'-bipyridyl. We found that the ferrous ion level decreased with light exposure in the short time frame, whereas it was upregulated during a 6-h light exposure. Total iron, ROS, cell death rate, and expression of TfR and HFt genes were significantly increased in a time-dependent manner in 661 W cells exposed to light. Chelation with 2,2'-bipyridyl reduced the level of hydroxyl radicals and protected against light-induced cell death. These results suggest that light exposure decreases ferrous ion levels and enhances iron uptake in photoreceptor cells. Ferrous ion may be involved in light-induced photoreceptor cell death through production of hydroxyl radicals. PMID- 25447562 TI - The expression of syntaphilin is down-regulated in the optic nerve after axonal injury. AB - The impairment of mitochondrial function is an important pathogenic factor in glaucoma and other optic neuropathies in which retinal ganglion cell (RGC) death is the fundamental pathology. Syntaphilin was recently discovered as a docking protein that affects mitochondrial mobility. However, no reports have investigated the involvement of syntaphilin in the visual system. We investigated the expression of syntaphilin in the rat retina, optic nerve and brain. The expression of syntaphilin exhibited varying patterns in the visual system. Syntaphilin was expressed in retinal ganglion cells in the retina, in the cell bodies of neurons in the superior colliculus and was abundant in the astrocytes of rat optic nerves (similar to the findings that syntaphilin is expressed in human optic nerves). After optic nerve transection, which caused RGC death and axonal degeneration, quantitative real-time RT-PCR was used to assess changes in gene expression in the rat retina and optic nerve. Syntaphilin gene and protein expression in the optic nerve was downregulated 3 and 7 days after optic nerve transection. Our study suggests that syntaphilin expression in astrocytes at the optic nerve might be involved in axonal injury. PMID- 25447563 TI - Correlation between the radial peripapillary capillaries and the retinal nerve fibre layer in the normal human retina. AB - This study aims to provide evidence of the importance of radial peripapillary capillaries (RPCs) by quantitative study of the relationship between the RPCs and retinal nerve fibre layer (RNFL) in normal human donor eyes. The retinal microvasculature in eleven normal human donor eyes was perfused, fixed and labelled after cannulation of the central retinal artery. The retinas were dissected and whole-mounted for confocal microscopy. Six study regions were taken radially from the edge of the optic disc. RPCs from the optic disc edge to a radial distance up to 2.5 mm were imaged and their diameters, inter-capillary distance and volume occupation measured. These were correlated with the study region as well as thickness of the RNFL. It was found that the pooled average diameter of the RPCs in the first 2.5 mm from the optic disk was 8.9 MUm. Significant differences in capillary diameter were present in the six regions, with larger diameter RPCs in the superior, inferior and nasal regions, and significantly smaller diameter in the temporal region. RPCs in the arcuate fibre regions extend the furthest from the optic disc, maintained a close inter capillary distance for a longer distance than other regions, and have the highest RPCs volume occupancy. The RPCs volume was generally correlated with RNFL thickness. In conclusion, a close correlation between RNFL and RPCs presence has been demonstrated which is supportive of their functional reliance/co-dependence. The significantly smaller temporal RPCs may be a result of the greater presence of RPCs in the two bordering arcuate fibre regions and therefore a richer availability of nutrients diffusing from these two regions. PMID- 25447565 TI - Bioflavour: natural flavours and fragrances by yeasts and other microorganisms - the holistic approach of the BIOFLAVOUR Consortium. PMID- 25447564 TI - Retinal vasculature of adult zebrafish: in vivo imaging using confocal scanning laser ophthalmoscopy. AB - Over the past 3 decades the zebrafish (Danio rerio) has become an important biomedical research species. As their use continues to grow additional techniques and tools will be required to keep pace with ongoing research using this species. In this paper we describe a novel method for in vivo imaging of the retinal vasculature in adult animals using a commercially available confocal scanning laser ophthalmoscope (SLO). With this instrumentation, we demonstrate the ability to distinguish diverse vascular phenotypes in different transgenic GFP lines. In addition this technology allows repeated visualization of the vasculature in individual zebrafish over time to document vascular leakage progression and recovery induced by intraocular delivery of proteins that induce vascular permeability. SLO of the retinal vasculature was found to be highly informative, providing images of high contrast and resolution that were capable of resolving individual vascular endothelial cells. Finally, the procedures required to acquire SLO images from zebrafish are non-invasive, simple to perform and can be achieved with low animal mortality, allowing repeated imaging of individual fish. PMID- 25447566 TI - First experience with paclitaxel-coated balloon angioplasty in patients with adult transplant coronary artery disease: is it an alternative to drug-eluting stents? PMID- 25447567 TI - Obese patients with idiopathic pulmonary fibrosis have a higher 90-day mortality risk with bilateral lung transplantation. AB - BACKGROUND: Obese patients with idiopathic pulmonary fibrosis (IPF) have higher 90-day mortality after lung transplantation. We sought to determine whether body mass index (BMI) differentially modified the effect of transplant procedure type on 90-day mortality in IPF patients. METHODS: We analyzed data from the Organ Procurement and Transplantation Network (OPTN) for all patients with IPF who were transplanted between 2000 and 2010. Post-transplant survival was examined using Kaplan-Meier estimates. Multivariable logistic regression modeling was used to determine the difference in 90-day survival. The primary variable of interest was the interaction term between body mass index (BMI) and transplant type. RESULTS: A total of 3,389 (58% single-lung transplant [SLT] and 42% bilateral lung transplant [BLT]) subjects were included. Multivariable logistic regression modeling demonstrated a statistically significant interaction between BMI and transplant type (p = 0.047). Patients with a BMI > 30 kg/m(2) who received a BLT are 1.71 times (95% CI [1.03 to 2.85], p = 0.038) more likely to die within 90 days than BLT recipients with a BMI of 18.5 to 30 kg/m(2). CONCLUSIONS: Our results suggest that obese patients who receive a BLT may be at higher risk of 90 day mortality compared with patients of normal weight. Further study is needed to obtain more detailed information about comorbidities and other risk factors for early death that are not included in the OPTN database. PMID- 25447568 TI - Does pulsatility matter in the era of continuous-flow blood pumps? AB - Despite significant improved survival with continuous flow left ventricular assist devices (LVADs), complications related to aortic valve insufficiency, gastrointestinal bleeding, stroke, pump thrombosis, and hemolysis have dampened the long term success of these pumps. Evolution has favored a pulsatile heart pump to be able to deliver the maximum flow at different levels of systemic vascular resistance, confer kinetic energy to the flow of blood past areas of stenosis and generate low shear stress on blood elements. In this perspective, we suggest that lack of pulsatility may be one factor that has limited the success of continuous flow LVADs and suggest that research needs to focus on methods to generate pulsatility either by the native heart or by various speed modulation algorithms. PMID- 25447569 TI - Thalidomide for treatment of gastrointestinal angiodysplasia in patients with left ventricular assist devices: case series and treatment protocol. PMID- 25447570 TI - A modified implantation technique of the HeartWare ventricular assist device for pediatric patients. PMID- 25447571 TI - Ventricular reconditioning and pump explantation in patients supported by continuous-flow left ventricular assist devices. AB - BACKGROUND: The potential for myocardial reconditioning and device explantation after long-term continuous-flow left ventricular assist device (LVAD) support presents an opportunity to delay or avoid transplantation in select patients. METHODS: Thirty of 657 patients with end-stage heart failure supported with continuous-flow LVADs were assessed for device explantation. Each patient underwent an individualized process of weaning focused on principles of ventricular unloading, gradual reconditioning, and transition to medical therapy. RESULTS: After varying reconditioning periods, 27 patients (16 men, 11 women; age, 39 +/- 12 years) underwent LVAD explant, and 3 patients (2 men, 1 woman; age, 22 +/- 6 years) were evaluated for explantation but could not be weaned. The duration of LVAD support was 533 +/- 424 days (range, 42-1,937 days) for the explant cohort and 1,097 +/- 424 days (range, 643-1,483) for the non-explant cohort. The LV end-diastolic dimension, LV ejection fraction, systolic pulmonary artery pressure, cardiac output, and cardiac index in the explant cohort were significantly improved at explantation (all, p < 0.05). Two late deaths occurred after LVAD explantation despite satisfactory native cardiac function, and 1 patient required resumption of LVAD support 2.7 years after device removal. The remaining explant patients remain in New York Heart Association classes I to II with medical management alone (mean survival post-explant, 1,172 +/- 948 days). The 3 candidates who could not be weaned ultimately underwent transplantation. CONCLUSIONS: The potential for recovery of native LV function after long-term continuous-flow LVAD support should encourage a more aggressive approach to ventricular reconditioning with the goal of device explantation and a return to medical management, particularly in young patients with dilated cardiomyopathy. PMID- 25447572 TI - Prognostic implications of serial risk score assessments in patients with pulmonary arterial hypertension: a Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) analysis. AB - BACKGROUND: Data from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) were used previously to develop a risk score calculator to predict 1-year survival. We evaluated prognostic implications of changes in the risk score and individual risk-score parameters over 12 months. METHODS: Patients were grouped by decreased, unchanged, or increased risk score from enrollment to 12 months. Kaplan-Meier estimates of subsequent 1-year survival were made based on change in the risk score during the initial 12 months of follow-up. Cox regression was used for multivariable analysis. RESULTS: Of 2,529 patients in the analysis cohort, the risk score was decreased in 800, unchanged in 959, and increased in 770 at 12 months post enrollment. Six parameters (functional class, systolic blood pressure, heart rate, 6-minute walk distance, brain natriuretic peptide levels, and pericardial effusion) each changed sufficiently over time to improve or worsen risk scores in >=5% of patients. One-year survival estimates in the subsequent year were 93.7%, 90.3%, and 84.6% in patients with a decreased, unchanged, and increased risk score at 12 months, respectively. Change in risk score significantly predicted future survival, adjusting for risk at enrollment. Considering follow-up risk concurrently with risk at enrollment, follow-up risk was a much stronger predictor, although risk at enrollment maintained a significant effect on future survival. CONCLUSIONS: Changes in REVEAL risk scores occur in most patients with pulmonary arterial hypertension over a 12-month period and are predictive of survival. Thus, serial risk score assessments can identify changes in disease trajectory that may warrant treatment modifications. PMID- 25447574 TI - Pediatric heart transplant waiting list mortality in the era of ventricular assist devices. AB - BACKGROUND: Earlier reviews have reported unacceptably high incidence of pediatric heart transplant (PHT) waiting list mortality. An increase in ventricular assist devices (VAD) suggests a potential positive effect. This study evaluated PHT waiting list mortality in the era of pediatric VADs. METHODS: United Network of Organ Sharing (UNOS) database from 1999 to 2012 showed 5,532 pediatric candidates (aged <= 18 years) actively listed for PHT: 2,191 were listed in 1999 to 2004 (Era 1) and 3,341 were listed in 2005 to 2012 (Era 2). RESULTS: Waiting list mortality was lower in Era 2 (8%) vs Era 1 (16%; p < 0.001). VAD therapy was used more frequently in Era 2 (16%) than in Era 1 (6%; p < 0.001) and was associated with better waiting list survival (p < 0.001). There were more UNOS Status 1A patients in Era 2 (80%) vs Era 1 (68%; p < 0.001). Independent predictors of waiting list mortality included weight < 10 kg (odds ratio [OR], 2.7 95% confidence interval [CI], 1.1-6.9), congenital heart disease diagnosis (OR, 2.4; 95% CI, 1.9-3.0), blood type O (OR, 2.2; 95% CI, 1.8-2.8)], extracorporeal membrane oxygenation (OR, 1.5; 95% CI, 1.1-2.2), mechanical ventilation (OR, 1.8; 95% CI, 1.4-2.3), and renal dysfunction (OR 1.6; 95% CI, 1.2-2.0). Independent predictors of survival on the waiting list included VAD therapy (OR 4.2; 95% CI, 2.4-7.6), cardiomyopathy diagnosis (OR 3.3; 95% CI, 2.4 4.6), blood type A (OR, 2.2; 95% CI, 1.8-2.8), UNOS list Status 1B (OR, 1.9; 95% CI, 1.2-3.0), listed in Era 2 (OR 1.8; 95% CI, 1.4-2.2), and white race (OR 1.3; 95% CI, 1.1-1.6). CONCLUSIONS: Despite an increase in the number of children listed as Status 1A, there was more than a 50% reduction in waiting list mortality in the new era. Irrespective of other factors, patients supported with a VAD were 4 times more likely to survive to transplant. PMID- 25447573 TI - Rotary pump speed modulation for generating pulsatile flow and phasic left ventricular volume unloading in a bovine model of chronic ischemic heart failure. AB - BACKGROUND: Rotary blood pumps operate at a constant speed (rpm) that diminishes vascular pulsatility and variation in ventricular end-systolic and end-diastolic volumes, which may contribute to adverse events, including aortic insufficiency and gastrointestinal bleeding. In this study, pump speed modulation algorithms for generating pulsatility and variation in ventricular end-systolic and end diastolic volumes were investigated in an ischemic heart failure (IHF) bovine model (n = 10) using a clinically implanted centrifugal-flow left ventricular assist device (LVAD). METHODS: Hemodynamic and hematologic measurements were recorded during IHF baseline, constant pumps speeds, and asynchronous (19-60 cycles/min) and synchronous (copulse and counterpulse) pump speed modulation profiles using low relative pulse speed (+/-25%) of 3,200 +/- 800 rpm and high relative pulse speed (+/-38%) of 2,900 +/- 1,100 rpm. End-organ perfusion, hemodynamics, and pump parameters were measured to characterize pulsatility, myocardial workload, and LVAD performance for each speed modulation profile. RESULTS: Speed modulation profiles augmented aortic pulse pressure, surplus hemodynamic energy, and end-organ perfusion (p < 0.01) compared with operation at constant speed. Left ventricular external work and myocardial oxygen consumption were significantly reduced compared with IHF baseline (p < 0.01) but at the expense of higher LVAD power consumption. CONCLUSIONS: Pump speed modulation increases pulsatility and improves cardiac function and end-organ perfusion, but the asynchronous mode provides the technologic advantage of sensorless control. Investigation of asynchronous pump speed modulation during long-term support is warranted to test the hypothesis that operating an LVAD with speed modulation will minimize adverse events in patients supported by an LVAD that may be associated with long-term operation at a constant pump speed. PMID- 25447577 TI - A whole blood-based perfusate provides superior preservation of myocardial function during ex vivo heart perfusion. AB - BACKGROUND: Ex vivo heart perfusion (EVHP) provides the opportunity to resuscitate unused donor organs and facilitates assessments of myocardial function that are required to demonstrate organ viability before transplantation. We sought to evaluate the effect of different oxygen carriers on the preservation of myocardial function during EVHP. METHODS: Twenty-seven pig hearts were perfused ex vivo in a normothermic beating state for 6 hours and transitioned into working mode for assessments after 1 (T1), 3 (T3), and 5 (T5) hours. Hearts were allocated to 4 groups according to the perfusate composition. Red blood cell concentrate (RBC, n = 6), whole blood (RBC+Plasma, n = 6), an acellular hemoglobin-based oxygen carrier (HBOC, n = 8), or HBOC plus plasma (HBOC+Plasma, n = 7) were added to STEEN Solution (XVIVO Perfusion, Goteborg, Sweden) to achieve a perfusate hemoglobin concentration of 40 g/liter. RESULTS: The perfusate composition affected the preservation of systolic (T5 dP/dtmax: RBC+Plasma = 903 +/- 99, RBC = 771 +/- 77, HBOC+Plasma = 691 +/- 82, HBOC = 563 +/- 52 mm Hg/sec; p = 0.047) and diastolic (T5 dP/dtmin: RBC+Plasma = -574 +/- 48, RBC = -492 +/- 63, HBOC+Plasma = -326 +/- 32, HBOC = -268 +/- 22 mm Hg/sec; p < 0.001) function, and the development of myocardial edema (weight gain: RBC+Plasma = 6.6 +/- 0.9, RBC = 6.6 +/- 1.2, HBOC+Plasma = 9.8 +/- 1.7, HBOC = 16.3 +/- 1.9 g/hour; p < 0.001) during EVHP. RBC+Plasma hearts exhibited less histologic evidence of myocyte damage (injury score: RBC+Plasma = 0.0 +/- 0.0, RBC = 0.8 +/- 0.3, HBOC+Plasma = 2.6 +/- 0.2, HBOC = 1.75 +/- 0.4; p < 0.001) and less troponin-I release (troponin-I fold-change T1-T5: RBC+Plasma = 7.0 +/- 1.7, RBC = 13.1 +/- 1.6, HBOC+Plasma = 20.5 +/- 1.1, HBOC = 16.7 +/- 5.8; p < 0.001). Oxidative stress was minimized by the addition of plasma to RBC and HBOC hearts (oxidized phosphatidylcholine compound fold-change T1-T5: RBC+Plasma = 1.83 +/- 0.20 vs RBC = 2.31 +/- 0.20, p < 0.001; HBOC+Plasma = 1.23 +/- 0.17 vs HBOC = 2.80 +/- 0.28, p < 0.001). CONCLUSIONS: A whole blood-based perfusate (RBC+Plasma) minimizes injury and provides superior preservation of myocardial function during EVHP. The beneficial effect of plasma on the preservation of myocardial function requires further investigation. PMID- 25447575 TI - Preemptive treatment with therapeutic plasma exchange and rituximab for early donor-specific antibodies after lung transplantation. AB - OBJECTIVE: De novo donor-specific anti-human leukocyte antigen antibodies develop in a high proportion of lung transplant recipients early after lung transplantation. We recently showed that de novo donor-specific antibodies (DSA) occurrence is associated with significantly increased mortality. Here, we studied the efficacy of a preemptive treatment protocol. METHODS: A retrospective observational study was conducted on all lung transplantations at Hanover Medical School between January 2009 and May 2013. RESULTS: Among the 500 transplant recipients, early DSA developed in 86 (17%). Of these, 56 patients (65%; Group A) received therapeutic plasma exchange, and 30 patients (35%; Group B) did not. Among Group A patients, 51 also received rituximab. Between groups, there was no statistically significant difference in mortality, incidence of pulsed steroid therapies, rejections diagnosed by biopsy specimen, incidence of bronchitis obliterans syndrome (BOS), or infections requiring hospitalization at 1 year and 3 years. Also, there were no statistically significant differences after matching 21 Group A with 21 Group B patients through propensity score analysis. Significantly more Group A patients (65%) than Group B patients (34%) cleared DSA at hospital discharge (p = 0.01). At the last control after transplantation (median, 14 months; interquartile range, 5-24 months), 11 Group A (22%) and 9 Group B patients (33%) still showed DSA (p = 0.28). CONCLUSIONS: Preemptive treatment with therapeutic plasma exchange and rituximab led to improved elimination of DSA early after lung transplantation (p = 0.01). However, spontaneous elimination in untreated Group B patients also occurred frequently. This treatment protocol was not associated with significantly improved outcome. PMID- 25447576 TI - Emergency medical services knowledge and attitudes about non-heart-beating donors: effect of an educational intervention. AB - BACKGROUND: More than 750,000 people die of sudden death each year, and many are potential non-heart-beating donors (NHBDs) for lung transplant. Although critical, the role of emergency medical services (EMS) personnel in assisting with recovery of NHBD lungs has not been studied. The purpose of this study was to assess knowledge of and attitudes about NHBDs among EMS personnel, evaluate the extent to which knowledge and personal experience with organ donation is associated with attitude, and ascertain the effectiveness of an intervention designed to teach EMS professionals about NHBDs. METHODS: EMS professionals (n = 361) completed measures of knowledge of and attitudes about NHBDs and then watched a presentation by a transplant doctor about traditional organ donation, NHBDs, and transplantation. Participants were able to ask questions during and after the presentation. Participants completed the measures again 3 months later. RESULTS: EMS professionals had a high rate of personal experience with organ donation and positive attitudes toward traditional organ donation. However, they showed lack of knowledge about NHBDs and felt less skilled in being part of the NHBD process, consistent with knowledge scores. The educational intervention was somewhat effective in improving knowledge about NHBDs. Scores improved significantly on 5 of 13 items. CONCLUSIONS: Lung recovery from NHBDs offers the potential of a very large supply for transplantation. This research suggests that with additional training, EMS professionals may be willing to be part of a NHBD recovery team. PMID- 25447578 TI - Impact of primary caregivers on long-term outcomes after lung transplantation. AB - BACKGROUND: Current guidelines consider the absence of a dependable social support system as an absolute contraindication to lung transplantation, yet there are varying degrees of social support among those selected for transplantation. We sought to characterize the relationship between a patient's self-reported primary caregiver and long-term outcomes after lung transplantation. METHODS: We conducted a retrospective cohort study of all lung transplant recipients >=18 years of age who had undergone an initial transplant (2000 to 2010). Cox regression was used to explore the relationship between type of caregiver and the long-term risk of death and chronic graft failure while adjusting for potential confounders. RESULTS: There were 452 patients undergoing lung transplantation over the study period who met the inclusion criteria. Five types of primary caregivers were identified, with spouse 60% (270 of 452) being the most common. Compared with spousal caregiver, overall survival was significantly worse for patients who identified an adult child (hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.15 to 3.60) or sibling (HR 3.79, 95% CI 2.48 to 5.78) as their primary caregiver. In addition, risk for long-term graft failure was increased significantly (HR 3.34, 95% CI 1.58 to 7.06) among patients with sibling caregivers. CONCLUSIONS: Type of primary caregiver selected before transplantation was associated with long-term outcomes. These results may be a reflection of the long-term support requirements and/or competing responsibilities of other caregiver types. Interventions to increase support for at-risk patients may include identifying additional caregivers during the pre transplant assessment. As lung allocation is designed to maximize graft potential, risk stratification for listing patients should include type of caregiver and be considered as critically as major organ dysfunction. PMID- 25447579 TI - In-hospital outcomes of a minimally invasive off-pump left thoracotomy approach using a centrifugal continuous-flow left ventricular assist device. AB - BACKGROUND: Minimally invasive left thoracotomy (MILT) and off-pump implantation strategies have been anecdotally reported for implantation of the HeartWare ventricular assist device (HVAD). We analyzed our experience with off-pump MILT implantation techniques and compared early in-hospital outcomes with conventional on-pump sternotomy (CS) implantation strategy. METHODS: Between January 2013 and February 2014, 51 patients underwent HVAD implantation and were included in this study. Thirty-three patients had CS, whereas 18 patients underwent off-pump MILT. To compare outcomes of these techniques, a multivariate analysis using propensity score modeling was performed after adjusting for age, INTERMACS, Kormos and Leitz Miller (LM) scores. RESULTS: Mean age at implant was 57 (range 18 to 69) years, and overall in-hospital mortality was 8%. Univariate analysis revealed a statistically significant reduction in days on inotropes (p = 0.04), and a trend toward reduced intra-operative blood product administration (p = 0.08) in the MILT group. There was no difference in intensive-care-unit length of stay (p = 0.5), total length of stay (p = 0.76), post-operative blood product administration (p = 0.34) and total time on mechanical ventilation (p = 0.32). After adjusting for age, INTERMACS profile and Kormos and LM scores, no statistically significant differences were observed between the MILT and CS groups. CONCLUSIONS: An off-pump MILT implantation strategy can be utilized as a safe surgical approach for patients undergoing HVAD implantation. Further large collaborative studies are needed to identify advantages of the MILT approach. PMID- 25447581 TI - Post-operative kinetics of procalcitonin after lung transplantation. AB - BACKGROUND: Post-operative infections are a major complication after lung transplantation (LT). Early bacterial pneumonia worsens the prognosis of LT. Procalcitonin (PCT) has been proposed as an early and rapid laboratory marker of infection and sepsis. PCT could be a useful biomarker of pulmonary infection after LT, but the early kinetics of PCT in this setting are unknown. We evaluated the kinetics of PCT and the impact of respiratory tract infection on PCT concentrations. METHODS: Over a 12-month period, PCT concentrations were determined daily in each patient admitted to our ICU for LT. Epidemiologic, clinical, laboratory and outcome data were obtained. A diagnosis of respiratory tract infection was suspected on clinical examination and confirmed by microbiologic culture. RESULTS: Twenty-six consecutive patients were included and 397 blood samples were obtained (13 [range 4 to 66] samples per patient). Plasma PCT reached a peak in the first 24 hours post-transplantation (5.72 [0.11 to 93.8] ng/ml), with a progressive decline over the first 7 post-operative days. Doubling of plasma PCT levels after an initial decrease was significantly associated with respiratory tract infection in transplanted patients (RR = 4.2 95% CI [1.95 to 9.03]). CONCLUSIONS: A non-specific increase in PCT values was observed during the first week post-LT. In combination with microbiologic cultures, PCT assays may be useful after the first post-operative week as an aid in the diagnosis of bacterial pulmonary infection. PMID- 25447580 TI - Lung donor treatment protocol in brain dead-donors: A multicenter study. AB - BACKGROUND: The shortage of lung donors for transplantation is the main limitation among patients awaiting this type of surgery. We previously demonstrated that an intensive lung donor-treatment protocol succeeded in increasing the lung procurement rate. We aimed to validate our protocol for centers with or without lung transplant programs. METHODS: A quasi-experimental study was performed to compare lung donor rate before (historical group, 2010 to 2012) and after (prospective group, 2013) the application of a lung management protocol for donors after brain death (DBDs) in six Spanish hospitals. Lung donor selection criteria remained unchanged in both periods. Outcome measures for lung recipients were early survival and primary graft dysfunction (PGD) rates. RESULTS: A total of 618 DBDs were included: 453 in the control period and 165 in the protocol period. Donor baseline characteristics were similar in both periods. Lung donation rate in the prospective group was 27.3%, more than twice that of the historical group (13%; p < 0.001). The number of lungs retrieved, grafts transplanted, and transplants performed more than doubled over the study period. No differences in early recipients' survival between groups were observed (87.6% vs. 84.5%; p = 0.733) nor in the rate of PGD. CONCLUSION: Implementing our intensive lung donor-treatment protocol increases lung procurement rates. This allows more lung transplants to be performed without detriment to either early survival or PGD rate. PMID- 25447583 TI - Outcomes in highly sensitized pediatric heart transplant patients using current management strategies. AB - BACKGROUND: Previous studies have suggested that children with pre-formed anti HLA antibodies (PRA) undergoing orthotopic heart transplantation (OHT) have increased risk for rejection, coronary artery vasculopathy (CAV) and death. In 2005, our program started utilizing aggressive desensitization (including plasmapheresis, IVIg, pulse cytoxan and rituximab) with the goal of improving outcomes for these patients. The purpose of this study was to compare outcomes with this new strategy in recipients with pre-OHT high PRA (>10%) vs low PRA <=10%). METHODS: A retrospective study of 70 consecutive pediatric OHT patients was undertaken between January 2005 and July 2013 to identify patients with pre OHT PRA >10% (high PRA), or PRA <=10% (low PRA). Demographic/data information and detailed post-OHT outcomes, including rejection, 30-day and overall mortality, freedom from significant rejection, and CAV, were analyzed. RESULTS: Fourteen (20%) patients had high PRA and 56 (80%) did not. There was a significant decrease in PRA values before and after desensitization. Thirty-day and overall mortality and the proportion of patients with rejections or CAV were lower in the high PRA group, although the difference was not statistically significant. Kaplan Meier survival analysis revealed no significant difference in survival between the two groups. There was a significant difference in survival in our sensitized patients before 2005 vs after 2005. CONCLUSIONS: We identified no significant differences in outcomes between high or low PRA patients. These preliminary findings may suggest improvement in OHT outcomes for high PRA patients as a result of aggressive desensitization. A larger study is warranted to confirm these findings. PMID- 25447582 TI - Serial monitoring of exhaled nitric oxide in lung transplant recipients. AB - BACKGROUND: Exhaled nitric oxide (FeNO), a marker of airway inflammation, is often elevated in lung transplant recipients (LTxRs) with acute rejection or infection. Isolated measurements in the setting of bronchiolitis obliterans syndrome have been variable. We sought to assess the utility of serial FeNO in predicting chronic allograft dysfunction or the presence of acute rejection or infection. METHODS: Eighty-six LTxRs underwent 325 serial FeNO measurements at an expiratory flow rate of 50 ml/s. The change in FeNO (DeltaFeNO) between two measurements obtained during a stable state (DeltaFeNO-SS) was compared with DeltaFeNO, where the first measurement was taken during a stable state and the second during an unstable state (defined as a subsequent decline in FEV1 > 10% over 3 months [DeltaFeNO-SU]) or an acute complication (acute rejection, lymphocytic bronchiolitis or acute infection [DeltaFeNO-SAC]). The median follow up time after the baseline FeNO was 10 (range 3 to 25) months. RESULTS: DeltaFeNO SS in 117 FeNO pairs was similar to DeltaFeNO-SU in 26 pairs (2.1 +/- 3 ppb vs 2.3 +/- 4 ppb; p = 0.2). DeltaFeNO-SAC in 17 pairs was markedly increased (27 +/- 20 ppb; p < 0.001 vs DeltaFeNO-SS). The area under the receiver-operating characteristic curve for DeltaFeNO in detecting an acute complication was 0.93 (p < 0.001). By applying a cut-off of >10 ppb, the sensitivity and specificity was 82% and 100%, respectively, with positive and negative predictive values of 100% and 97.5%. CONCLUSIONS: Changes in FeNO may serve as a useful adjunct in the detection of acute complications after lung transplantation. In this limited analysis, DeltaFeNO was not predictive of a subsequent decline in allograft function. PMID- 25447584 TI - Contemporary analysis of early outcomes after lung transplantation in the elderly using a national registry. AB - BACKGROUND: With an increasing number of potential recipients and a comparatively static number of donors, lung transplantation (LT) in the elderly has come under significant scrutiny. Previous studies have been limited by single-center experiences with small population sizes and often mixed results. Using a national registry, we sought to evaluate the following: (1) differences in survival outcomes in septuagenarians compared with sexagenarians; and (2) the effect of temporal trends on the development of other comorbidities in this population. METHODS: We analyzed the Scientific Registry of Transplant Recipients (SRTR) data files from the United Network for Organ Sharing (UNOS) database to identify recipients who underwent LT between the years 2000 and 2013. The study period was divided into two equal eras. Using Kaplan-Meier analysis, we compared the 30-day, 3-month, 1-year, 3-year and 5-year patient survival between septuagenarians and sexagenarians in both eras. Separate multivariate analyses were performed to estimate the risk of renal failure, risk of rejection and length of hospital stay (LOS) post-LT in each of these time periods. RESULTS: A total of 6,596 patients were identified comprising 1,726 (26.2%) during 2000 to 2005 and 4,870 (73.8%) during 2006 to 2012. In the "early era," 32 (1.9%) septuagenarians and 1,694 (98.1%) sexagenarians underwent LT, whereas 543 (11.1%) septuagenarians and 4,327 (88.9%) sexagenarians underwent transplantation in the "latter era." A comparison of patient survival between the two groups in the early era revealed no difference at 30 days (95.7% vs 93.8%, p = 0.65). However, 3-month (91.2% vs 75%, p = 0.04) and 1-year patient survival (79.5% vs 62.5%, p = 0.048) were both lower in the septuagenarian group. In the later era, however, there were no differences in 30-day (96.2% vs 96.8, p = 0.5), 3-month (92.7% vs 91.9%, p = 0.56) or 1-year (81.7% vs 78.6%, p = 0.12) patient survival between the two age groups. Survival rates at 3 years (63.7% vs 49.3%, p < 0.001) and 5 years (47.5% vs 28.2%, p < 0.001) were each significantly lower in the septuagenarian group. CONCLUSION: Overall, LT outcomes for the elderly have improved significantly over time and early outcomes in the modern era rival those found in younger recipients. PMID- 25447585 TI - Reliability of diagnostic criteria for bronchiolitis obliterans syndrome after lung transplantation: a survey. AB - BACKGROUND: Long-term outcomes after lung transplantation are limited due to chronic lung allograft dysfunction (CLAD). Bronchiolitis obliterans syndrome (BOS) is the most common form of obstructive CLAD and its definition derives from spirometric measurements. Given the importance of this diagnosis, both the accuracy and reliability of the definition of CLAD are crucial in understanding the pathophysiology of this disease to develop therapeutic options and influence outcome after lung transplantation. METHODS: A web-based survey was designed and distributed to members of the Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT) to better understand the accuracy and reliability of pulmonary function criteria in diagnosing BOS. Spirometric data from five patient scenarios that were discordant among reviewers regarding BOS determination from the Assessment of Immunosuppressive Regimen in Suppressing Acute and Chronic Rejection (AIRSAC) trial were randomly selected and summarized in this survey. Survey questions included the respondent's general understanding of the BOS definition, the determination of BOS, and difficulties with the current BOS definition. RESULTS: Eighty-seven respondents from the Pulmonary Council of the ISHLT responded to this survey. There was an overall 70% interobserver agreement regarding the presence or absence of BOS. Among those who agreed upon the presence of BOS, there was a 41% interobserver agreement regarding its time of onset. Despite this variability, the majority of respondents were not only familiar and agreed with the BOS criteria, they also felt confident in applying these criteria. CONCLUSIONS: Our survey identified potential limitations with the current criteria for diagnosing BOS. With recognition of the various CLAD phenotypes, further refinements of these diagnostic criteria will allow for an improved ability to identify and characterize patients who develop or are at risk for BOS, prognosticate outcomes, and, most importantly, marshal in future strategies directed at treating and preventing chronic lung dysfunction after lung transplantation. PMID- 25447587 TI - Endothelin-Bone morphogenetic protein type 2 receptor interaction induces pulmonary artery smooth muscle cell hyperplasia in pulmonary arterial hypertension. AB - BACKGROUND: Endothelin receptor antagonists improve pulmonary arterial hypertension (PAH). Mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2) predispose to PAH. Here, we sought to determine whether there might exist interactions between these 2 signaling pathways and their effect on the acquisition of the altered phenotype of pulmonary artery smooth muscle cells (PA-SMCs) observed in PAH. METHODS: Expression of BMPR2, of the BMP agonist BMP4, and of the BMP antagonists gremlin1 and gremlin2 was evaluated in lungs and in PA SMCs from 6 PAH patients and 14 controls treated with endothelin-1. Endothelin-1 pre-treated PA-SMCs were assessed for proliferation, apoptosis, and downstream signaling activation of Smad1/5/8 and p38 mitogen-activated protein kinase (p38(MAPK)) after BMP2 treatment. RESULTS: In PA-SMCs from PAH patients, expression of BMPR2 and BMP4 decreased, whereas expression of gremlin1 and gremlin2 increased compared with controls. Treatment of control PA-SMCs with endothelin-1 induced a dose-dependent increase in gremlin1 and gremlin2, whereas BMPR2 and BMP4 expression decreased, reaching similar levels as those observed in PAH cells. In control PA-SMCs, endothelin-1 pre-treatment reduced inhibitor of DNA binding 1 (Id1) expression and Smad1/5/8 activation induced by BMP2, whereas it enhanced p38(MAPK) activation. Moreover, BMP2 decreased serum-induced proliferation and increased the pro-apoptotic Bax/Bcl-2 ratio. These effects were attenuated by endothelin-1 pre-treatment. Endothelin-1 did not alter BMPR2 signaling in PA-SMCs from PAH patients. CONCLUSIONS: Endothelin-1 downregulates canonical BMPR2 signaling. This is related to decreased BMPR2 and increased anti BMP gremlin expression associated with increased activation of p38(MAPK) and results in PA-SMC proliferation. PMID- 25447588 TI - Effects of high selenium and fat supplementation on growth performance and thyroid hormones concentration of broilers. AB - A total of 400, as hatched, broilers were used to investigate the effect of increase of selenium and energy intake on thyroid hormone metabolism, growth and liver fatty acid profile. There were 5 replicates of 4 dietary treatments namely, TA (0.289mg Se per kg diet and adequate energy content), TB (0.583mg Se per kg diet and adequate energy content), TC (0.267mg Se per kg diet and 9% increase of energy content) and TD (0.576mg Se per kg diet and 9% increase of energy content). Diets were isonitrogenous. Zinc L-selenomethionine complex was used to increase Se content and corn oil was used to increase the energy content. The experiment lasted 42 days. Broiler growth performance was not significantly affected by dietary treatments. Liver glutathione peroxidase (GPx) activity increased (P<0.05) in broilers fed high Se and energy diets compared to other ones. Whole blood GPx activity was higher in Se supplemented groups however, it was reduced by age. Thyroid hormone concentrations were unaffected by dietary treatments. A significant increase of linoleic and arachidonic acid concentration (P<0.001) was observed in the liver of broilers fed diets with moderately increased energy content and supplemented with Se compared to those fed diets with moderately increased energy content alone. In conclusion, zinc L selenomethionine complex and moderate increase of energy content did not affect growth rate or thyroid hormone metabolism but led to increased liver fatty acid content and hepatic GPx activity. PMID- 25447589 TI - Excessive iodine intake and thyroid dysfunction among lactating Saharawi women. AB - OBJECTIVES: Excessive iodine intake may lead to thyroid dysfunction, which may be particularly harmful during pregnancy and lactation. The main objective was to describe iodine status and the prevalence of thyroid dysfunction among lactating women in areas with high iodine (HI) and very high iodine (VHI) concentrations in drinking water. DESIGN AND METHODS: A cross-sectional survey was performed among 111 lactating women in the Saharawi refugee camps, Algeria. Breast milk iodine concentration (BMIC), urinary iodine concentration (UIC) and the iodine concentration in the most commonly consumed foods/drinks were measured. A 24-h dietary recall was used to estimate iodine intake. Thyroid hormones and antibodies were measured in serum. RESULTS: Median UIC, BMIC and iodine intake across both areas was 350 MUg/L, 479 MUg/L and 407 MUg/day, respectively. In multiple regression analyses, we discovered that being from VHI area was associated with higher UIC and BMIC. BMIC was also positively associated with iodine intake. Thyroid dysfunction and/or positive thyroid antibodies were found in 33.3% of the women, of which 18.9% had hypothyroidism and 8.1% had hyperthyroidism and 6.3% had positive antibodies with normal thyroid function. Elevated thyroid antibodies were in total found in 17.1%. We found no difference in distribution of thyroid dysfunction or positive antibodies between HI and VHI areas. BMI, BMIC and elevated thyroglobulin (Tg) predicted abnormal thyroid function tests. CONCLUSIONS: The high prevalence of thyroid dysfunction may be caused by excessive iodine intake over several years. PMID- 25447586 TI - Lung size mismatch and primary graft dysfunction after bilateral lung transplantation. AB - BACKGROUND: Donor-to-recipient lung size matching at lung transplantation (LTx) can be estimated by the predicted total lung capacity (pTLC) ratio (donor pTLC/recipient pTLC). We aimed to determine whether the pTLC ratio is associated with the risk of primary graft dysfunction (PGD) after bilateral LTx (BLT). METHODS: We calculated the pTLC ratio for 812 adult BLTs from the Lung Transplant Outcomes Group between March 2002 to December 2010. Patients were stratified by pTLC ratio >1.0 ("oversized") and pTLC ratio <=1.0 ("undersized"). PGD was defined as any ISHLT Grade 3 PGD (PGD3) within 72 hours of reperfusion. We analyzed the association between risk factors and PGD using multivariable conditional logistic regression. As transplant diagnoses can influence the size matching decisions and also modulate the risk for PGD, we performed pre-specified analyses by assessing the impact of lung size mismatch within diagnostic categories. RESULTS: In univariate analyses oversizing was associated with a 39% lower odds of PGD3 (OR 0.61, 95% CI, 0.45-0.85, p = 0.003). In a multivariate model accounting for center-effects and known PGD risks, oversizing remained independently associated with a decreased odds of PGD3 (OR 0.58, 95% CI 0.38 to 0.88, p = 0.01). The risk-adjusted point estimate was similar for the non-COPD diagnosis groups (OR 0.52, 95% CI 0.32 to 0.86, p = 0.01); however, there was no detected association within the COPD group (OR 0.72, 95% CI 0.29 to 1.78, p = 0.5). CONCLUSION: Oversized allografts are associated with a decreased risk of PGD3 after BLT; this effect appears most apparent in non-COPD patients. PMID- 25447591 TI - On pharmacologist and vaccines: present and future challenges. PMID- 25447592 TI - Ongoing pharmacovigilance on vaccines. AB - Vaccines have peculiar characteristics as well as their surveillance. Specific requirements, needs and challenges for the vaccine vigilance are discussed in the perspective to improve the whole system in order to guarantee a safer vaccine use and the keeping of the public confidence in vaccinations. Key elements for the routine safety monitoring, new regulations and some available tools are taken into account. Finally, the Italian experience is shortly described. PMID- 25447590 TI - Clinical audit of patients hospitalized due to COPD exacerbation. MAG-1 Study. AB - Hospitalizations for acute exacerbation of COPD (AECOPD) generate high consumption of health resources, frequent readmissions and high mortality. The MAG -1 study aims to identify critical points to improve the care process of severe AECOPD requiring hospitalization. METHODS: Observational study, with review of clinical records of patients admitted to hospitals of the Catalan public network for AECOPD. The centers were classified into 3 groups according to the number of discharges/year. Demographic and descriptive data of the previous year, pharmacological treatment, care during hospitalization and discharge process and follow-up, mortality and readmission at 30 and 90 days were analyzed. RESULTS: A total of 910 patients (83% male) with a mean age of 74.3 (+10.1) years and a response rate of 70% were included. Smoking habit was determined in only 45% of cases, of which 9% were active smokers. In 31% of cases, no previous lung function data were available. Median hospital stay was 7 days (IQR 4-10), increasing according the complexity of the hospital. Mortality from admission to 90 days was 12.4% with a readmission rate of 49%. An inverse relationship between length of hospital stay and readmission within 90 days was observed. CONCLUSIONS: In a large number of medical records, smoking habit and lung function tests were not appropriately reported. Average hospital stay increases with the complexity of the hospital, but longer stays appear to be associated with lower mortality at follow-up. PMID- 25447593 TI - Lipophilic antioxidants prevent lipopolysaccharide-induced mitochondrial dysfunction through mitochondrial biogenesis improvement. AB - Oxidative stress is implicated in several infectious diseases. In this regard, lipopolysaccharide (LPS), an endotoxic component, induces mitochondrial dysfunction and oxidative stress in several pathological events such as periodontal disease or sepsis. In our experiments, LPS-treated fibroblasts provoked increased oxidative stress, mitochondrial dysfunction, reduced oxygen consumption and mitochondrial biogenesis. After comparing coenzyme Q10 (CoQ10) and N-acetylcysteine (NAC), we observed a more significant protection of CoQ10 than of NAC, which was comparable with other lipophilic and hydrophilic antioxidants such as vitamin E or BHA respectively. CoQ10 improved mitochondrial biogenesis by activating PGC-1alpha and TFAM. This lipophilic antioxidant protection was observed in mice after LPS injection. These results show that mitochondria-targeted lipophilic antioxidants could be a possible specific therapeutic strategy in pharmacology in the treatment of infectious diseases and their complications. PMID- 25447595 TI - Tranilast: a review of its therapeutic applications. AB - Tranilast (N-[3',4'-dimethoxycinnamoyl]-anthranilic acid) is an analog of a tryptophan metabolite. Initially, tranilast was identified as an anti-allergic agent, and used in the treatment of inflammatory diseases, such as bronchial asthma, atypical dermatitis, allergic conjunctivitis, keloids and hypertrophic scars. Subsequently, the results showed that it could be also effective in the management of a wide range of conditions. The beneficial effects of tranilast have also been seen in a variety of disease states, such as fibrosis, proliferative disorders, cancer, cardiovascular problems, autoimmune disorders, ocular diseases, diabetes and renal diseases. Moreover, several trials have shown that it has very low adverse effects and it is generally well tolerated by patients. In this review, we have attempted to accurately summarize previously published studies relating to the use of tranilast for a range of disorders and discuss the drug's possible mode of action. The major mode of the drug's efficacy appears to be the suppression of the expression and/or action of the TGF-beta pathway, but the drug affects other factors as well. The findings presented in this review demonstrate the potential of tranilast for the control of a vast array of pathological situations, furthermore, it is a prescribed drug without severe side effects. PMID- 25447594 TI - Diacerein is a potent and selective inhibitor of palmitoylethanolamide inactivation with analgesic activity in a rat model of acute inflammatory pain. AB - Palmitoylethanolamide (PEA) is produced by mammalian cells from its biosynthetic precursor, N-palmitoyl-phosphatidyl-ethanolamine, and inactivated by enzymatic hydrolysis to palmitic acid and ethanolamine. Apart from fatty acid amide hydrolase (FAAH), the N-acylethanolamine-hydrolyzing acid amidase (NAAA), a lysosomal enzyme, was also shown to catalyze the hydrolysis of PEA and to limit its analgesic and anti-inflammatory action. Here we report the finding of a new potential inhibitor of NAAA, EPT4900 (4,5-diacetyloxy-9,10-dioxo-anthracene-2 carboxylic acid, diacerein). EPT4900 exhibited a high inhibitory activity on human recombinant NAAA over-expressed in HEK293 cells (HEK-NAAA cells). EPT4900 selectively increased the levels of PEA in intact HEK-NAAA cells, and inhibited inflammation as well as hyperalgesia in rats treated with an intraplantar injection of carrageenan. This latter effect was accompanied by elevation of PEA endogenous levels in the paw skin. PMID- 25447596 TI - Amlodipine passage into breast milk in lactating women with pregnancy-induced hypertension and its estimation of infant risk for breastfeeding. AB - BACKGROUND: Few clinical reports have been published on amlodipine passage into breast milk in lactating women. OBJECTIVES: The aims of this study were to evaluate the plasma concentration of amlodipine and its passage into breast milk in lactating women with pregnancy-induced hypertension and to estimate the risk for breastfeeding infants. METHODS: Thirty-one lactating women receiving oral amlodipine once daily for pregnancy-induced hypertension were enrolled. Pre-dose plasma and milk concentrations of amlodipine were determined at day 6 or later after starting the medication. Relative infant dose (RID) as an infant risk for breastfeeding was calculated by dividing the infant dose via milk by the maternal dose. RESULTS: The mean maternal dose of amlodipine was 6.0 mg. The medians of the plasma and milk concentrations of amlodipine were 15.5 and 11.5 ng/mL, respectively. Interindividual variation was observed in the amlodipine dose and body weight-adjusted milk concentrations (interquartile range [IQR], 96.7-205 ng/mL per mg/kg). The median and IQR of the amlodipine concentration ratio of milk to plasma were 0.85 and 0.74 to 1.08, respectively. The medians of infant birth weight and daily amlodipine dose via milk were 2170 g and 4.2 MUg/kg, respectively. The median of the RID of amlodipine was 4.2% (IQR, 3.1%-7.3%). CONCLUSION: Lactating women with pregnancy-induced hypertension had higher plasma concentrations of amlodipine during the early postpartum period. Oral amlodipine transferred into breast milk at the same level as that of plasma. However, the RID of amlodipine in most patients was less than 10%. PMID- 25447597 TI - A thermoresponsive and magnetic colloid for 3D cell expansion and reconfiguration. AB - A dual thermoresponsive and magnetic colloidal gel matrix is described for enhanced stem-cell culture. The combined properties of the material allow enzyme free passaging and expansion of mesenchymal stem cells, as well as isolation of cells postculture by the simple process of lowering the temperature and applying an external magnetic field. The colloidal gel can be reconfigured with thermal and magnetic stimuli to allow patterning of cells in discrete zones and to control movement of cells within the porous matrix during culture. PMID- 25447598 TI - Multivalent nanomaterials: learning from vaccines and progressing to antigen specific immunotherapies. AB - Continued development of multivalent nanomaterials has provided opportunities for the advancement of antigen-specific immunotherapies. New insights emerge when considering the backdrop of vaccine design, which has long employed multivalent presentation of antigen to more strongly engage and enhance an immunogenic response. Additionally, vaccines traditionally codeliver antigen with adjuvant to amplify a robust antigen-specific response. Multivalent nanomaterials have since evolved for applications where immune tolerance is desired, such as autoimmune diseases or allergies. In particular, soluble, linear polymers may be tailored to direct antigen-specific immunogenicity or tolerance by modulating polymer length, ligand valency (number), and ligand density, in addition to incorporating secondary signals. Codelivery of a secondary signal may direct, amplify, or suppress the response to a given antigen. Although the ability of multivalent nanomaterials to enact an immune response through molecular mechanisms has been established, a transport mechanism for biodistribution must also be considered. Both mechanisms are influenced by ligand display and other physical properties of the nanomaterial. This review highlights multivalent ligand display on linear polymers, the complex interplay of physical parameters in multivalent design, and the ability to direct the immune response by molecular and transport mechanisms. PMID- 25447599 TI - Pentraxin-3 and VEGF in POEMS syndrome: a 2-year longitudinal study. AB - Circulating Pentraxin 3 (PTX3) and vascular endothelial growth factor (VEGF) levels were measured longitudinally (mean follow-up 2 years) by ELISA in 6 patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome and 16 controls. Expression of PTX3 was also assessed (immunohistochemistry) on sural nerve biopsies from POEMS and vasculitic neuropathy patients. No correlation was found between PTX3 and VEGF levels in POEMS or controls. Sural nerve biopsies from vasculitic neuropathy patients, but not those from POEMS syndrome, showed strong PTX3 staining. PTX3, expression of vessel inflammation/remodeling, and VEGF, crucial pro-angiogenic cytokine, appear to be independently regulated in POEMS syndrome. PMID- 25447600 TI - Corrigendum: Spatial task context makes short-latency reaches prone to induced Roelofs illusion. AB - [This corrects the article on p. 673 in vol. 8, PMID: 25221500.]. PMID- 25447602 TI - Short (low-dose) ketamine infusion for managing acute pain in the ED: case-report series. PMID- 25447601 TI - Tranexamic acid for traumatic brain injury: a systematic review and meta analysis. AB - OBJECTIVE: The antifibrinolytic agent tranexamic acid (TXA) has demonstrated clinical benefit in trauma patients with severe bleeding, but its effectiveness in patients with traumatic brain injury (TBI) is unclear. We conducted a systematic review to evaluate the following research question: In ED patients with or at risk of intracranial hemorrhage (ICH) secondary to TBI, does TXA compared to placebo improve patients' outcomes? METHODS: MEDLINE, EMBASE, CINAHL, and other databases were searched for randomized controlled trial (RCT) or quasi RCT studies that compared the effect of TXA to placebo on outcomes of TBI patients. The main outcomes of interest included mortality, neurologic function, hematoma expansion, and adverse effects. We used "Grading quality of evidence and strength of recommendations" to assess the quality of trials. Two authors independently abstracted data using a data collection form. Results from studies were pooled when appropriate. RESULTS: Of 1030 references identified through the search, 2 high-quality RCTs met inclusion criteria. The effect of TXA on mortality had a pooled relative risk of 0.64 (95% confidence interval [CI], 0.41 1.02); on unfavorable functional status, a relative risk of 0.77 (95% CI, 0.59 1.02); and on ICH progression, a relative risk of 0.76 (95% CI, 0.58-0.98). No serious adverse effects (such as thromboembolic events) associated with TXA group were reported in the included trials. CONCLUSION: Pooled results from the 2 RCTs demonstrated statistically significant reduction in ICH progression with TXA and a nonstatistically significant improvement of clinical outcomes in ED patients with TBI. Further evidence is required to support its routine use in patients with TBI. PMID- 25447603 TI - Paralytic rabies or postvaccination myelitis: a diagnostic dilemma. PMID- 25447604 TI - The use of thymoquinone in nephrotoxicity related to acetaminophen. AB - AIM: We aimed to investigate efficacy of intraperitoneally administered Thymoquinone (TQ) in acetaminophen (APAP) induced renal toxicity. MATERIAL AND METHOD: Forty Wistar Albino rats were randomly divided into 4 groups of ten rats each. Control group was untreated group while rats in TQ group were treated with single dose TQ. In APAP group rats were treated with single dose acetaminophen. In TQ + APAP group TQ and APAP were administered respectively. Rats were sacrificed at 24th hour; urea, creatinine and nitric oxide levels were measured also malondialdehyde activity were assessed in renal tissue specimens. Tissue damage scores were recorded in histopathological assessment. RESULTS: Urea and creatinine levels were found significantly higher in APAP group than control group (p < 0.003). Urea and creatinine levels in APAP + TQ treated group were significantly lower than APAP treated group (p < 0.01). Serum NO activity and tissue MDA levels were higher in APAP group than control group (p <= 0.002). In contrast to APAP treated group serum NO activity and tissue MDA levels were found significantly lower in TQ + APAP group (p <= 0.03). In APAP group significant histopathological change was found compared with control group (p <= 0.001) where there was no significant change between control and TQ treated groups (p > 0.05). In APAP group we found significantly higher tissue damage scores than control group (p <= 0.001). In APAP + TQ group lower tissue damage scores were found compared with APAP group (p <= 0.001) while higher scores were found compared with control group (p <= 0.001). CONCLUSION: We can conclude that TQ treatment has therapeutical effect in APAP induced nephrotoxicity in rats. PMID- 25447605 TI - Inflammatory diseases of the non-lactating female breasts. AB - Chronic inflammatory diseases of the non-lactating breasts cause considerable difficulty in diagnosis and treatment. There is a spectrum of aetiological factors ranging from infection to autoimmune disorders. The disease causes considerable morbidity and psychological distress in relatively young females. The study aimed to analyse the spectrum of chronic disease and to formulate a treatment protocol. METHOD: Female patients with histological confirmation of inflammatory disease of the breast in the non-lactational phase were included in the study. The patients were categorized based on histological findings supplemented with immunohistochemical staining with CD3 and CD20 antibodies. RESULT: Out of 50 patients included in the study, 38 patients (76%) were diagnosed as idiopathic granulomatous mastitis (IGM) and 12 (24%) patients as periductal mastitis (PD). The possible aetiology of IGM was localized autoimmunity as evidenced by the infiltration of CD3 positive T lymphocyte. Systemic prednisolone was given for 6 months and 95.6% patients were disease-free after 24months. Out of 15 patients who did not receive prednisolone, only 2 patients were disease-free after 24 months (p = .003). CONCLUSION: Idiopathic granulomatous mastitis is an uncommon inflammatory disease of the non-lactating breast. The combination of limited surgical treatment and systemic prednisolone given for 6 months effectively controls the disease as well as prevents recurrence. PMID- 25447606 TI - Cystic adrenal lesions: clinical and surgical management. The experience of a referral centre. AB - BACKGROUND: Cystic adrenal lesions (CALs) represent a rare entity having heterogeneity in etiology and clinical manifestations. Due to their very low incidence and heterogeneity in clinical aspects, many controversials still exist about their management. METHODS: From 1984 to 2012, 21 patients (7 M, 14 F, mean age 48.2 years) underwent adrenalectomy for CALs. 9 patients suffered from hypertension, and 7 were affected by thyroid disorders. RESULTS: 4 patients presented with vague abdominal pain, while in 17 patients the CAL was incidentally identified during imaging examinations. All patients underwent evaluation of adrenal functionality and imaging study. We found 1 case of cystic pheochromocytoma (confirmed by urinary and blood sampling, and MIBG-scan). All patients underwent adrenalectomy (open approach in the first 10 patients treated from 1984 to 1996, laparoscopic lateral transabdominal approach in the other 11 cases). Indication to surgery included: size over 4.5 cm in 16 cases, suspected malignancy at imaging evaluation (not confirmed by histology) in 4 cases, cystic pheochromocytoma in 1 case. Histology revealed 11 endothelial cysts, 3 pseudocysts, 6 epithelial cysts and 1 cystic pheochromocytoma. CONCLUSIONS: The presence of CAL, even asymptomatic, requires complete endocrinological evaluation and imaging study. In the presence of large size, endocrine activity or any suspicion of malignancy, patients must be referred to surgery. PMID- 25447607 TI - Fascial closure after open abdomen: initial indication and early revisions are decisive factors--a retrospective cohort study. AB - BACKGROUND: The surgical treatment method in which the peritoneal cavity is opened anteriorly and deliberately left open, hence often called "open abdomen" has become the standard of care in damage-control procedures as well as in the management of intra-abdominal hypertension and in severe intra-abdominal sepsis. Whereas open abdomen has been closed in two stages traditionally, a modern trend is to close the fascial layers within the initial hospitalization to avoid complications like enterocutaneous fistula and hernia formation. The aim of this study was to determine crucial factors influencing the possibility of fascial closure after open abdomen. METHODS: Between 2003 and 2013, 355 adult patients were treated with open abdomen in our institution. Their data were collected and retrospectively analyzed. They were divided into two groups depending on fascial closure or not (fascial closure, n = 137 (39%) vs. non-fascial closure, n = 218 (61%)). RESULTS: The patients who reached fascial closure had a significantly higher rate of initially performed open abdomen (97 patients (71%) vs. 118 (54%), p = 0.002) and the periods of time until a second and a third look operation were significantly shorter (2.7 +/- 2.5 vs. 4.2 +/- 6.6 days, p = 0.021 and 5.6 +/- 3.7 vs. 8.5 +/- 8.6 days, p = 0.006). Furthermore, the presence of peritonitis (64 patients (47%) vs. 83 patients (38%), p = 0.023) and large bowel resection (74 patients (54%) vs. 90 patients (41%), p = 0.022) were significantly higher in this group. Rates of in-hospital mortality (97 patients (44%) vs. 38 patients (28%), p = 0.002) and the presence of pancreatitis (19 patients (9%) vs. 3 patients (2%), p = 0.013) were significantly higher in the non-fascial closure group. CONCLUSIONS: The probability to reach fascial closure after open abdomen seems to increase when open abdomen is performed initially and when early second and third look operations are performed. The presence of pancreatitis seems to be the only negative prognostic marker concerning fascial closure. PMID- 25447608 TI - Prevalence of thoracic surgical care need in a developing country: results of a cluster-randomized, cross-sectional nationwide survey. AB - BACKGROUND: Developing countries without established surgical capacity face heightened morbidity and mortality from poorly understood, untreated thoracic surgical impairments. This study sought to estimate the prevalence of thoracic surgical need in a low-income country and consider contributing factors involved. METHODS: Cluster-randomized, cross-sectional nationwide survey using the Surgeons OverSeas Assessment of Surgical Need tool in Sierra Leone from January 9-February 3, 2012. RESULTS: Data were collected and analyzed from 3645 respondents (response rate 98.3%). 273 (7.5%) reported >=1 chest (including heart, lungs, and mediastinum) or breast surgical problem during their lifetime; 268 (7.4%) reported >=1 back complaint. Multiple problems could be reported, resulting in a total of 277 chest/breast and 268 back complaints. The majority (184/545) were related to acquired deformities. Most occurred >=12 months ago (364/545) and continued to impact the participant at the time of the interview (339/545). 322/545 sought care; however, 40% (130/322) did not receive care, predominately due to an inability to pay. Adjusted logistic regression found that chest/breast problems were more common among farm workers, older participants, and individuals with minimal education, while back problems were more common in the same groups and males. CONCLUSIONS: The study provides data on the prevalence of thoracic surgical conditions and factors affecting prevalence in one of the world's poorest countries. The results speak to the need for further work to enhance health systems strengthening while offering the opportunity for future training and research in resource-limited settings--an area of thoracic surgery that is not well understood. PMID- 25447609 TI - Should patients with infrainguinal arterial bypasses using autologous vein conduit undergo follow-up surveillance with duplex ultrasound? AB - This best evidence topic was investigated according to a structured format. The question asked was: should duplex ultrasound (DUS) scanning be a routine component of surveillance following infrainguinal arterial bypass using vein conduit? We performed a systematic literature search and identified 4 studies (3 randomised controlled trials and 1 meta-analysis) that provided the best evidence. The highest quality study was a multi-centre randomised controlled trial (n = 594). At 18 months following surgery, it found no difference in patency rates, amputations, vascular mortality or mortality. However it achieved just over half of anticipated recruitment and thus was underpowered. The remaining two randomised controlled trials had smaller sample sizes and methodological weaknesses and found conflicting results. Lundell et al. (n = 106) found improved primary assisted and secondary patency rates and fewer graft occlusions with a routine DUS policy. Ihlberg et al. (n = 152) found no difference in primary assisted patency or amputations although secondary patency was improved. A meta-analysis of mostly observational data (n = 6649) found fewer occlusions with routine DUS surveillance and no effect on amputations or mortality. Results are conflicting. The strongest evidence comes from the single high quality multi-centre trial. It appears as though routine DUS surveillance does not yield benefits in patient important outcomes. Further studies are needed. PMID- 25447611 TI - Required reading for anyone involved in graduate medical education. PMID- 25447610 TI - Impact of aspirin according to type of stable coronary artery disease: insights from a large international cohort. AB - BACKGROUND: Aspirin is recommended in stable coronary artery disease based on myocardial infarction and stroke studies. However, benefit among stable coronary artery disease patients who have not suffered an acute ischemic event is uncertain. The objective of this study was to evaluate the impact of aspirin in stable coronary artery disease. We hypothesized that aspirin's benefit would be attenuated among individuals with stable coronary artery disease but no prior ischemic event. METHODS: An observational study was conducted from the INternational VErapamil-SR/Trandolapril STudy cohort. Ambulatory patients >= 50 years of age with clinically stable coronary artery disease requiring antihypertensive drug therapy (n = 22,576) were classified "ischemic" if they had a history of unstable angina, myocardial infarction, transient ischemic attack, or stroke at the baseline visit. All others were classified "non-ischemic." Aspirin use was updated at each clinic visit and considered as a time-varying covariate in a Cox regression model. The primary outcome was first occurrence of all-cause mortality, myocardial infarction, or stroke. RESULTS: At baseline, 56.7% of all participants used aspirin, which increased to 69.3% at study close out. Among the "non-ischemic" group (n = 13,091), aspirin was not associated with a reduction in risk (hazard ratio [HR] 1.11; 95% confidence interval [CI], 0.97 1.28; P = .13); however, among the "ischemic" group (n = 9485), aspirin was associated with a reduction in risk (HR 0.87; 95% CI, 0.77-0.99; P = .033). CONCLUSIONS: In patients with stable coronary artery disease and hypertension, aspirin use was associated with reduced risk for adverse cardiovascular outcomes among those with prior ischemic events. Among patients with no prior ischemic events, aspirin use was not associated with a reduction in risk. PMID- 25447613 TI - 'The only thing we have to fear is fear itself'. PMID- 25447614 TI - 'Doctor, I think that I might be having a heart attack'. PMID- 25447612 TI - Prognostic comparison of different sensitivity cardiac troponin assays in stable heart failure. AB - BACKGROUND: Cardiac troponin (cTn) levels offer prognostic information for patients with heart failure. Highly sensitive assays detect levels of cTn much lower than the 99th percentile of standard cTn assays. We hypothesize that cardiac troponin levels measured by a high-sensitivity assay provide better prognostic value compared with cTn levels measured by a standard assay in patients with chronic heart failure. METHODS: We measured high-sensitivity cTnT (hs-cTnT) and standard cardiac troponin I (cTnI) levels, as well as amino terminal pro B-type natriuretic peptide (NT-proBNP) in 504 sequential stable patients with a history of heart failure who underwent elective coronary angiography, without acute coronary syndrome, and with 5-year follow-up of all cause mortality. RESULTS: The median hs-cTnT level was 21.2 (interquartile range 12.3-40.9) ng/L and 170 subjects died over 5 years. In a head-to-head overall comparison, hs-cTnT provided increased prognostic utility compared with cTnI (area under the curve [AUC] 66.1% and AUC 69.4%, respectively, P = .03; 9.0% integrated discrimination improvement, P < .001; and 13.6% event-specific reclassification, P < .001), and was independent of NT-proBNP and renal function. Even within the subset of patients where cTn levels by both assays were above the limit of quantification, higher hs-cTnT is associated with a 2-fold increase in 5 year mortality risk after adjusting for traditional risk factors (tertile 1 vs 3: hazard ratio [95% confidence interval] 2.0 [1.3-3.2]; P = .0002). CONCLUSION: Cardiac troponin can be detected by the high-sensitivity assay in more patients with chronic heart failure than the standard assay, and may yield independent and better prognostic accuracy for mortality prediction than standard assay. PMID- 25447617 TI - Resting heart rate: risk indicator and emerging risk factor in cardiovascular disease. AB - Resting heart rate is central to cardiac output and is influenced by changes occurring in numerous diseases. It predicts longevity and cardiovascular diseases, and current evidence suggests that it is also an important marker of outcome in cardiovascular disease, including heart failure. Beta-blockers improve outcomes in heart failure; however, they have effects outside reducing heart rate. Ivabradine has demonstrated efficacy in reducing rehospitalizations and mortality in heart failure and in improving exercise tolerance and reducing angina attacks in patients with coronary artery disease, whereas selective heart rate reduction may also prove to be beneficial in therapeutic areas outside those in which ivabradine has already demonstrated clinical efficacy. This review provides an update on the associations between heart rate and cardiovascular outcomes in various conditions, the experimental effects of heart rate reduction with ivabradine, and the potential new indications in cardiovascular disease. PMID- 25447616 TI - Persistent insomnia is associated with mortality risk. AB - BACKGROUND: Insomnia has been associated with mortality risk, but whether this association is different in subjects with persistent vs intermittent insomnia is unclear. Additionally, the role of systemic inflammation in such an association is unknown. METHODS: We used data from a community-based cohort to determine whether persistent or intermittent insomnia, defined based on persistence of symptoms over a 6-year period, was associated with death during the following 20 years of follow-up. We also determined whether changes in serum C-reactive protein (CRP) levels measured over 2 decades between study initiation and insomnia determination were different for the persistent, intermittent, and never insomnia groups. The results were adjusted for confounders such as age, sex, body mass index, smoking, physical activity, alcohol, and sedatives. RESULTS: Of the 1409 adult participants, 249 (18%) had intermittent and 128 (9%) had persistent insomnia. During a 20-year follow-up period, 318 participants died (118 due to cardiopulmonary disease). In adjusted Cox proportional-hazards models, participants with persistent insomnia (adjusted hazards ratio [HR] 1.58; 95% confidence interval [CI], 1.02-2.45) but not intermittent insomnia (HR 1.22; 95% CI, 0.86-1.74) were more likely to die than participants without insomnia. Serum CRP levels were higher and increased at a steeper rate in subjects with persistent insomnia as compared with intermittent (P = .04) or never (P = .004) insomnia. Although CRP levels were themselves associated with increased mortality (adjusted HR 1.36; 95% CI, 1.01-1.82; P = .04), adjustment for CRP levels did not notably change the association between persistent insomnia and mortality. CONCLUSIONS: In a population-based cohort, persistent, and not intermittent, insomnia was associated with increased risk for all-cause and cardiopulmonary mortality and was associated with a steeper increase in inflammation. PMID- 25447615 TI - The Mediterranean diet, its components, and cardiovascular disease. AB - One of the best-studied diets for cardiovascular health is the Mediterranean diet. This consists of fish, monounsaturated fats from olive oil, fruits, vegetables, whole grains, legumes/nuts, and moderate alcohol consumption. The Mediterranean diet has been shown to reduce the burden, or even prevent the development, of cardiovascular disease, breast cancer, depression, colorectal cancer, diabetes, obesity, asthma, erectile dysfunction, and cognitive decline. This diet is also known to improve surrogates of cardiovascular disease, such as waist-to-hip ratio, lipids, and markers of inflammation, as well as primary cardiovascular disease outcomes such as death and events in both observational and randomized controlled trial data. These enhancements easily rival those seen with more established tools used to fight cardiovascular disease such as aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, and exercise. However, it is unclear if the Mediterranean diet offers cardiovascular disease benefit from its individual constituents or in aggregate. Furthermore, the potential benefit of the Mediterranean diet or its components is not yet validated by concrete cardiovascular disease endpoints in randomized trials or observational studies. This review will focus on the effects of the whole and parts of the Mediterranean diet with regard to both population-based and experimental data highlighting cardiovascular disease morbidity or mortality and cardiovascular disease surrogates when hard outcomes are not available. Our synthesis will highlight the potential for the Mediterranean diet to act as a key player in cardiovascular disease prevention, and attempt to identify certain aspects of the diet that are particularly beneficial for cardioprotection. PMID- 25447618 TI - The association between red cell distribution width and stroke in patients with atrial fibrillation. AB - OBJECTIVE: Red cell distribution width is associated with increased risk of cardiovascular morbidity and mortality. We aimed to assess its association with stroke in patients with atrial fibrillation. METHODS: By using the computerized database of the largest Health Maintenance Organization in Israel, we identified a cohort of adults with atrial fibrillation diagnosed before January 1, 2012. Eligible subjects were not taking anticoagulants at baseline and had at least 1 blood cell count performed in 2011 (41,140 subjects). The cohort was followed for the first occurrence of stroke until December 31, 2012. RESULTS: Overall, 1692 subjects developed stroke during 38,024 person-years of follow-up (stroke rate, 4.45 per 100 person-years). Stroke incidence rate increased across red cell distribution width quartiles: 3.26, 3.71, 5.01, and 6.05 per 100 person-years in the lowest (<= 13.4%), second (13.4%-14.1%), third (14.1%-15.0%), and highest (>15%) red cell distribution width quartiles, respectively. On multivariate analysis adjusting for Congestive heart failure, Hypertension, Age >= 75, Diabetes, and Prior Stroke or TIA (doubled) (CHADS2) score risk factors, the hazard ratio for stroke was 1.29 (95% confidence interval, 1.17-1.42) in subjects with red cell distribution width >14.5% compared with those with values <= 14.5% and was similar in subjects with and without anemia. When analyzed as quartiles, the hazard ratio for stroke was 1.33 (confidence interval, 1.15-1.53) in the highest quartile compared with the lowest quartile and was similar in subjects with and without anemia. The area under the receiver operating characteristic curve was 0.598 for (CHADS2) score and increased to 0.618 when red cell distribution width was included in the model (P < .001). CONCLUSIONS: Red cell distribution width is directly associated with the risk of stroke regardless of anemia status and improves the predictive accuracy for stroke in patients with atrial fibrillation. PMID- 25447619 TI - Diagnostic and prognostic value of high-sensitivity cardiac troponin T in patients with syncope. AB - OBJECTIVE: We examined the diagnostic and predictive value of high-sensitivity cardiac troponin T (cTnThs) in patients with syncope. METHODS: We performed an analysis of consecutive patients with syncope presenting to the emergency department. The primary end point was the accuracy to diagnose a cardiac syncope. In addition, the study explored the prognostic relevance of cTnThs in patients with cardiac and noncardiac syncope. RESULTS: A total of 360 patients were enrolled (median age, 70.5 years; male, 55.8%; 23.9% aged >80 years). Cardiac syncope was present in 22% of patients, reflex syncope was present in 40% of patients, syncope due to orthostatic hypotension was present in 20% of patients, and unexplained syncope was present in 17.5% of patients. A total of 148 patients (41%) had cTnThs levels above the 99% confidence interval (CI) (cutoff point). The diagnostic accuracy for cTnThs levels to determine the diagnosis of cardiac syncope was quantified by the area under the curve (0.77; CI, 0.72-0.83; P < .001). A comparable area under the curve (0.78; CI, 0.73-0.83; P < .001) was obtained for the predictive value of cTnThs levels within 30 days: Patients with increased cTnThs levels had a 52% likelihood for adverse events, patients with cTnThs levels below the cutoff point had a low risk (negative predictive value, 83.5%). Increased cTnThs levels indicate adverse prognosis in patients with noncardiac causes of syncope, but not in patients with cardiac syncope being a risk factor for adverse outcome by itself. CONCLUSIONS: Patients with syncope presenting to the emergency department have a high proportion of life-threatening conditions. cTnThs levels show a limited diagnostic and predictive accuracy for the identification of patients with syncope at high risk. PMID- 25447620 TI - Long-term assessment of fatigue in patients with culture-confirmed Lyme disease. AB - BACKGROUND: Fatigue is a common symptom with numerous causes. Severe fatigue is thought to be an important manifestation of post-treatment Lyme disease syndrome. The frequency with which severe fatigue occurs as a long-term sequela in prospectively followed patients with Lyme disease is unknown. METHODS: Patients with culture-confirmed Lyme disease who originally presented with erythema migrans have been evaluated annually in a prospective study to determine their long-term outcome. In 2011-2013, subjects were evaluated for fatigue using an 11 item Fatigue Severity Scale (FSS-11) that has been used in studies of post treatment Lyme disease syndrome. An FSS-11 score of >=4.0 is indicative of severe fatigue. RESULTS: A total of 100 subjects were assessed, 52% of whom were male; the mean age was 64.9 years (range, 42-86 years). The mean duration of follow-up was 15.4 years (range, 11-20 years). Nine subjects had severe fatigue but in none as a consequence of Lyme disease. Only 3 subjects were thought to possibly have persistent fatigue from Lyme disease. The FSS-11 value for these 3 individuals was less than 4, averaging 2.27, and none had functional impairment. CONCLUSIONS: Severe fatigue was found in 9 patients (9%) with culture-confirmed early Lyme disease at 11 to 20 years after presentation, but was due to causes other than Lyme disease. Fatigue of lesser severity was possibly due to Lyme disease, but was found in only 3% of 100 patients, and therefore is rarely a long-term complication of this infection. PMID- 25447622 TI - A candid discussion of obesity. PMID- 25447621 TI - Noninvasive tests for the diagnostic evaluation of dyspnea among outpatients: the Multi-Ethnic Study of Atherosclerosis lung study. AB - BACKGROUND: Dyspnea on exertion is a common and debilitating symptom, yet evidence for the relative value of cardiac and pulmonary tests for the evaluation of chronic dyspnea among adults without known cardiac or pulmonary disease is limited. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants aged 45 to 84 years who were free of clinical cardiovascular disease from 6 communities; participants with clinical pulmonary disease were excluded from this report. Dyspnea on exertion was assessed via structured interview. Tests included electrocardiograms, cardiac computed tomography (CT) for coronary artery calcium, cardiac magnetic resonance imaging, spirometry, percent emphysema (percent of lung regions <-950 HU) on CT, inflammatory biomarkers, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Logistic regression was used to identify independent correlates of dyspnea after adjustment for age, sex, body mass index, physical activity, anxiety, and leg pain. RESULTS: Among 1969 participants without known cardiopulmonary disease, 9% had dyspnea. The forced expiratory volume in 1 second (FEV1) (P < .001), NT-proBNP (P = .004), and percent emphysema on CT (P = .004) provided independent information on the probability of self-reported dyspnea. Associations with the FEV1 were stronger among smokers and participants with other recent respiratory symptoms or seasonal allergies; associations with NT-proBNP were present only among participants with coexisting symptoms of lower-extremity edema. Only the FEV1 provided a significant improvement in the receiver operating curve. CONCLUSIONS: Among adults without known cardiac or pulmonary disease reporting dyspnea on exertion, spirometry, NT-proBNP, and CT imaging for pulmonary parenchymal disease were the most informative tests. PMID- 25447623 TI - Etiologic and therapeutic analysis in patients with hypokalemic nonperiodic paralysis. AB - BACKGROUND: Hypokalemic nonperiodic paralysis represents a group of heterogeneous disorders with a large potassium (K(+)) deficit. Rapid diagnosis of curable causes with appropriate treatment is challenging to avoid the sequelae of hypokalemia. We prospectively analyzed the etiologies and therapeutic characteristics of hypokalemic nonperiodic paralysis. METHODS: Over an 8-year period, patients with hypokalemic nonperiodic paralysis were enrolled by excluding those with hypokalemic periodic paralysis due to acute shift of K(+) into cells. Blood and spot urine samples were collected for the measurements of electrolytes, pH, and biochemistries. Intravenous potassium chloride (KCl) at a rate of 10-20 mmol/h was administered until muscle strength recovered. RESULTS: We had identified 58 patients with hypokalemic nonperiodic paralysis from 208 consecutive patients with hypokalemic paralysis, and their average K(+) concentration was 1.8 +/- 0.2 mmol/L. Among patients with low urinary K(+) excretion (n = 17), chronic alcoholism, remote diuretic use, and anorexia/bulimia nervosa were the most common causes. Among patients with high urinary K(+) excretion (n = 41) and metabolic acidosis, renal tubular acidosis and chronic toluene abuse were the main causes, while primary aldosteronism, Gitelman syndrome, and diuretics were the leading diagnoses with metabolic alkalosis. The average KCl dose needed to restore muscle strength was 3.8 +/- 0.8 mmol/kg. Initial lower plasma K(+), volume depletion, and high urinary K(+) excretion were associated with higher recovery KCl dosage. During therapy, patients with paradoxical hypokalemia (n = 32) who required more KCl supplementation than patients without (4.1 +/- 0.7 vs 3.4 +/- 0.7 mmol/kg, P < 0.001) often exhibited significantly higher plasma renin activity and received a higher volume of normal saline before its appearance. CONCLUSIONS: Understanding the common etiologies of hypokalemic nonperiodic paralysis may aid in early diagnosis. Patients with initial lower plasma K(+), renal K(+) wasting, and hypovolemia required higher recovery K(+) dosage. Paradoxical hypokalemia is prone to develop in hypovolemic patients even during K(+) supplementation with volume repletion. PMID- 25447624 TI - Hypercalcemic crisis: a clinical review. AB - Hypercalcemia is a common metabolic perturbation. However, hypercalcemic crisis is an unusual endocrine emergency, with little clinical scientific data to support therapeutic strategy. We review the relevant scientific English literature on the topic and review current management strategies after conducting a PubMed, MEDLINE, and Google Scholar search for articles published between 1930 and June 2014 using specific keywords: "hypercalcemic crisis," "hyperparathyroid crisis," "parathyroid storm," "severe primary hyperparathyroidism," "acute hyperparathyroidism," and "severe hypercalcemia" for articles pertaining to the diagnosis, epidemiology, clinical presentation, and treatment strategies. Despite extensive clinical experience, large and well-designed clinical studies to direct appropriate clinical care are lacking. Nonetheless, morbidity and mortality rates have substantially decreased since early series reported almost universal fatality. Improved outcomes can be attributed to modern diagnostic capabilities, leading to earlier diagnosis, along with the recognition that primary hyperparathyroidism is the most common etiology for hypercalcemic crisis. Hypercalcemic crisis is an unusual endocrine emergency that portends excellent outcomes if rapid diagnosis, medical treatment, and definitive surgical treatment are expedited. PMID- 25447625 TI - Management of nipple discharge and the associated imaging findings. AB - Nipple discharge is commonly encountered by health care providers, accounting for 2%-5% of medical visits by women. Because nipple discharge is the presenting symptom in 5% to 12% of breast cancers, it causes considerable anxiety for both patient and providers. Furthermore, the work-up and management of nipple discharge can be confusing. Fortunately, the cause of nipple discharge is usually benign, so the primary goal of evaluation and management is separation of patients with pathologic causes of discharge from those with benign or physiologic causes. The evaluation of nipple discharge requires a thorough history, careful physical examination, and an informed approach that selects the most suitable diagnostic modality. Primary care providers, working with their radiologists and surgeons, are well positioned to design appropriate diagnostic and management protocols to assess and treat nipple discharge. A thoughtful and prudent approach to nipple discharge should alleviate patient anxiety by efficiently and effectively defining the underlying etiology. PMID- 25447626 TI - Venous thromboembolism and cardiovascular risk: results from the NAVIGATOR trial. AB - BACKGROUND: Contemporary studies suggest an association between venous thromboembolism and a higher incidence of major cardiovascular events, mostly attributed to arterial atherothrombosis. Using data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, we assessed the association of venous thromboembolism with major cardiovascular events. METHODS: In NAVIGATOR, patients with impaired glucose tolerance were randomly allocated to receive valsartan or placebo and nateglinide or placebo in addition to lifestyle modification. Baseline characteristics and prior history of venous thromboembolism were assessed. After adjusting for important baseline covariates, Cox proportional hazards regression models were used to assess the association between venous thromboembolism and major cardiovascular outcomes. RESULTS: Of the 9306 patients enrolled, 129 (1.4%) had a history of venous thromboembolism. Patients with venous thromboembolism were older, more frequently white and female, and had a higher body mass index. Patients with venous thromboembolism had higher 5-year event rates for the composite of death, myocardial infarction, and stroke, as compared with patients without venous thromboembolism (10.7% vs 5.9%; P < .001; adjusted hazard ratio 2.12; 95% confidence interval, 1.36-3.31; P = .001). CONCLUSION: In patients with impaired glucose tolerance at high risk for cardiovascular events, the prevalence of venous thromboembolism was rare but associated with worse long-term cardiovascular outcomes, including arterial events. Venous thromboembolism is a marker of risk, and attention should be paid to this high-risk group of patients. PMID- 25447627 TI - Risk of cancer in patients with cholecystitis: a nationwide population-based study. AB - OBJECTIVE: The objective of this study was to evaluate the risk of cancer in patients diagnosed with cholecystitis and possible interactions between cholecystitis and cholecystectomy. METHODS: A retrospective population-based cohort study was conducted among patients diagnosed with cholecystitis that were registered in the National Health Insurance Research Database in Taiwan between January 1, 2000 and December 31, 2010. Standardized incidence ratios (SIRs) were calculated to compare the incidence of cancer in these patients to that of the general population. Adjusted hazard ratios (HRs) were also calculated to investigate whether cholecystitis increased the risk for specific cancers. RESULTS: During a median observation period of 5.4 years, 1541 cancers occurred in 20,431 patients with cholecystitis, yielding a SIR of 1.97 (95% confidence interval [CI], 1.88-2.07). A significantly greater risk of biliary tract cancer (adjusted HR 1.72; 95% CI, 1.08-2.75) was observed after adjusting for potential risk factors. In contrast, cholecystectomy was found to attenuate the cancer risk, with the reduction of adjusted HR from 2.34 (95% CI, 1.62-3.37) to 1.28 (95% CI, 0.76-2.14). CONCLUSION: Cholecystitis is an independent risk factor to extrahepatic biliary tract cancers, whereas cholecystectomy can attenuate the cancer risk of cholecystitis. PMID- 25447628 TI - A patient-centered approach to managing patients with type 2 diabetes. AB - Despite the availability of a number of therapeutic options, management of type 2 diabetes (T2DM) and hyperglycemia remains suboptimal. Evidence shows that physicians are not adequately individualizing incretin-based therapies as there is lack of clear understanding of the similarities and differences between various incretin-based therapies. Additionally, sodium-dependent glucose co transporter 2 (SGLT2) inhibitors, a very recent addition to the therapeutic armamentarium, are not adequately utilized in managing patients with T2DM due to a lack of awareness or an increased concern regarding their safety, efficacy, and the mechanism of action. Insulin therapy is also not initiated or intensified appropriately due to a lack of clear understanding on when to add and how to intensify them and, more importantly, due to fear of increasing the risk of hypoglycemia in patients. To address these gaps, in the first section of this educational activity, the expert faculty will review the current understanding of the risks associated with hypoglycemia-one of the main factors that limit the successful use of insulin therapy-and when to initiate insulin therapy, as well as the available data on the risk of hypoglycemia with emerging agents. The expert faculty will also provide practical strategies on how to minimize the risk of hypoglycemia in patients. In the second section, the expert faculty will highlight the differences between the various incretin-based therapies in addition to providing strategies for physicians to individualize their choice of incretin-based therapy. The expert faculty will also review the mechanism of action, safety, efficacy, and the appropriate place for this class of therapies in the treatment continuum. In the third section, the expert faculty will discuss the mechanism of action, safety, and efficacy of the currently available SGLT2 inhibitors as well as the appropriate use of these newer agents in T2DM management. This CME Multimedia Activity is also available through the Website of The American Journal of Medicine (www.amjmed.com). Click on the CME Multimedia Activity button in the navigation bar for full access. Or access: www.elseviercme.com/537. PMID- 25447629 TI - Update on pharmacological cardiac stress testing: efficacy, risk stratification and patient selection. AB - Despite greater control of risk factors and improved treatments, coronary heart disease (CHD) remains a significant cause of mortality with 1 in every 4 deaths in the United States due to this disorder.(1) Cardiac stress tests have long been one of the most often utilized testing modalities used to identify patients suspected of having CHD, specifically coronary artery disease (CAD). These tests allow for noninvasive assessment of the coronary circulation and its ability to augment flow in response to physiologic demand. As with any diagnostic testing however, potential health risks as well as the financial burden of cardiovascular stress testing, must be weighed against the benefits and utility of the data procured. Given the rapidly evolving field of cardiac stress testing with respect to new risk stratification guidelines, new agents, and new assessment methods, it is difficult for physicians to remain up to date on the latest research and the benefits and risks of different testing modalities. A recent survey of primary care physicians and cardiologists conducted by the Elsevier Office of Continuing Medical Education found that approximately one-quarter of the cardiologists and primary care physicians surveyed do not feel confident identifying the factors which should be considered before ordering a cardiac stress test as part of pre operative screening for a patient. Additionally, this survey also reported that primary care physicians reported a high degree of confidence in ordering the appropriate cardiac screening tests for patients yet, cardiologists reported that they frequently/somewhat frequently felt the need to change the test ordered by the internist. This educational intervention focuses on patient selection, exercise vs. pharmacologic stress testing, pharmacologic agents, and the importance of patient and doctor communication in ensuring the right test is recommended for the right patient. This CME Multimedia Activity is also available through the Website of The American Journal of Cardiology (www.amjmed.com). Click on the Multimedia button in the navigation bar for full access. Or access: http://elseviercme.com/538. PMID- 25447630 TI - Incidence and determinants of sudden infant death syndrome: a population-based study on 37 million births. AB - BACKGROUND: The objective of our study is to measure the incidence of sudden infant death syndrome (SIDS), estimate the birth to death interval, and identify associated maternal and infant risk factors. METHODS: We carried out a population based cohort study on 37 418 280 births using data from the Centers for Disease Control and Prevention's "Linked Birth-Infant Death" and "Fetal Death" data files from 1995 to 2004. Descriptive statistics and cox-proportional hazard models were used to estimate the adjusted effect of maternal and newborn characteristics on the risk of SIDS. RESULTS: There were 24 101 cases of SIDS identified for an overall 10-year incidence of 6.4 cases per 10 000 births. Over the study period, the incidence decreased from 8.1 to 5.6 per 10 000 and appeared to be most common among infants aged 2-4 months. Risk factors included maternal age <20 years, black, non-Hispanic race, smoking, increasing parity, inadequate prenatal care, prematurity and growth restriction. CONCLUSIONS: While the incidence of SIDS in the US has declined, it currently remains the leading cause of post-neonatal mortality, highlighting an important public health priority. Educational campaigns should be targeted towards mothers at increased risk in order to raise their awareness of modifiable risk factors for SIDS such as maternal smoking and inadequate prenatal care. PMID- 25447631 TI - Therapeutic effect of placenta-derived mesenchymal stem cells on hypoxic-ischemic brain damage in rats. AB - BACKGROUND: Oxidative stress is involved in the development of hypoxic-ischemic brain damage (HIBD). In this study, we investigated the therapeutic effects of placenta-derived mesenchymal stem cells (PD-MSCs) and explored the NF-E2-related factor-2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway in treating HIBD. METHODS: P7 rats were subjected to hypoxic-ischemic brain injury and randomly divided into four groups (control, HIBD, HIBD+PD-MSCs, and HIBD+fibroblasts). Forty-eight hours after the induction of HIBD, 5*10(5) of PD-MSCs were injected into cerebral tissue in the HIBD+PD-MSCs group, while the same dose of fibroblasts were injected in the HIBD+fibroblasts group. Morris Water Maze, gross and pathological changes were tested at P28. The level of malondialdehyde (MDA) was detected in rats' hippocampus. RT-PCR and western blot analysis were used to evaluate the changes of Nrf2/HO-1. RESULTS: The HIBD group showed significantly longer escape latency and a lower frequency of original platform crossing in the Morris Water Maze compared with the control group. Rats receiving PD-MSCs showed significant improvement of HIBD. The pathological changes were evident after HIBD, but ameliorated in the PD-MSCs group. Compared with the control group, HO-1 and Nrf2 were up-regulated at gene and protein levels in the HI brain, beginning at 6 hours and peaking at 48 hours (P<0.05). The expression of HO-1 and Nrf2 in the PD-MSCs treatment group was more pronounced than in the HIBD group (P<0.01). PD-MSCs also decreased MDA production in the brain tissue. CONCLUSION: These results demonstrate that PD-MSCs have neuroprotective effect during the treatment of HIBD and that the mechanism may be partly due to alleviating oxidative stress. PMID- 25447633 TI - Diagnosis of pervasive developmental disorders: when and how? An area-based study about health care providers. AB - BACKGROUND: Pervasive developmental disorders (PDDs) can be very difficult to diagnose in children and to communicate such a diagnosis to their parents. Families of children with PDD learn of their child's diagnosis long after the first symptoms are noted in the child's behavior. METHODS: An area-based survey was conducted to assess all social and health care providers taking care of patients with PDDs in the Veneto Region (North-East Italy). RESULTS: Only 28% of health care providers arrived at a definite diagnosis when the child was in his/her first year of age, 51% when the child was 2-3 years old and 21% from age of 4 years and up. On average, the latency between the time of the diagnosis and its communication to the family was 6.9 months. However, a number of families did not ever have a diagnosis communicated to them. Sometimes, 68% of the providers did not communicate a PDDs diagnosis to patient's families, and 4% of them quite commonly. CONCLUSION: The well-known delay in making a diagnosis of PDDs has two distinct components: one relating to the difficulty of confirming a diagnosis of PDDs, the other, hitherto unrecognized, relating to the family being notified. PMID- 25447632 TI - Applicability of various estimation formulas to assess renal function in Chinese children. AB - BACKGROUND: This study was to evaluate the relative applicability of the most commonly used estimation formulas for renal glomerular filtration rate (GFR) of Chinese children with chronic kidney disease (CKD). METHODS: One hundred CKD patients of less than 17 years old were divided into two groups by sex which was further categorized into five subgroups based on CKD staging according to the "reference" GFR (rGFR) determined by Tc-99m-DTPA renal dynamic imaging. Four GFR markers including serum cystatin C (CysC), beta2-microglobulin, creatinine, and blood urea nitrogen were measured. RESULTS: Among all four markers, CysC best reflected the extent of glomerular damages for CKD stage 1. The value for estimation of GFR (eGFR) was derived from five different formulas either over estimated or underestimated GFR as referenced to rGFR, and the extent of deviations was dependent on gender, age and CKD stage. The Counahan-Barratt formula and the Schwartz formula gave the most accurate estimations of GFR for CKD stages 1 and 2-3, respectively regardless of gender and age differences. Receiver operating characteristic analyses indicated that the Counahan-Barratt formula has the highest diagnostic accuracy. CONCLUSION: The Counahan-Barratt formula provides the best approximation to rGFR, thereby the highest applicability to Chinese children with CKD of different genders, ages and CKD stages. PMID- 25447634 TI - UK is urged to introduce standardised tobacco packs as Australia marks policy's second anniversary. PMID- 25447635 TI - Fruitful factors: what limits seed production of flowering plants in the alpine? AB - Predicting demographic consequences of climate change for plant communities requires understanding which factors influence seed set, and how climate change may alter those factors. To determine the effects of pollen availability, temperature, and pollinators on seed production in the alpine, we combined pollen manipulation experiments with measurements of variation in temperature, and abundance and diversity of potential pollinators along a 400-m elevation gradient. We did this for seven dominant species of flowering plants in the Coast Range Mountains, British Columbia, Canada. The number of viable seeds set by plants was influenced by pollen limitation (quantity of pollen received), mate limitation (quality of pollen), temperature, abundance of potential pollinators, seed predation, and combinations of these factors. Early flowering species (n = 3) had higher seed set at high elevation and late-flowering species (n = 4) had higher seed set at low elevation. Degree-days >15 degrees C were good predictors of seed set, particularly in bee-pollinated species, but had inconsistent effects among species. Seed production in one species, Arnica latifolia, was negatively affected by seed-predators (Tephritidae) at mid elevation, where there were fewer frost-hours during the flowering season. Anemone occidentalis, a fly-pollinated, self-compatible species had high seed set at all elevations, likely due to abundant potential pollinators. Simultaneously measuring multiple factors affecting reproductive success of flowering plants helped identify which factors were most important, providing focus for future studies. Our work suggests that responses of plant communities to climate change may be mediated by flowering time, pollination syndrome, and susceptibility to seed predators. PMID- 25447638 TI - Effects of dietary concentrated mannan oligosaccharides supplementation on growth, gut mucosal immune system and liver lipid metabolism of European sea bass (Dicentrarchus labrax) juveniles. AB - The study assesses the effects of dietary concentrated mannan oligosaccharides (cMOS) on fish performance, biochemical composition, tissue fatty acid profiles, liver and posterior gut morphology and gen expression of selected parameters involved on the intestinal immune response and liver lipid metabolism of European sea bass (Dicentrarchus labrax). For that purpose, specimens of 20 g were fed during 8 weeks at 0 and 1.6 g kg(-1) dietary cMOS of inclusion in a commercial sea bass diet. Dietary cMOS enhanced fish length, specific and relative growth without affecting tissue proximate composition. However, cMOS supplementation altered especially liver and muscle fatty acid profiles by reducing levels of those fatty acids that are preferential substrates for beta-oxidation in spite of a preferential retention of long chain polyunsaturated fatty acids (LC-PUFA), such as 20:4n-6 or 22:5n-6, in relation to the down-regulation of delta 6/5 desaturase gene expression found in liver. Besides, dietary cMOS supplementation reduced posterior gut intestinal folds width and induced changes on the gene expression level of certain immune-related genes mainly by down regulating transforming growth factor beta (TGFbeta) and up-regulating immunoglobulin (Ig), major histocompatibility complex class II (MHCII), T cell receptor beta (TCRbeta) and Caspase 3 (Casp-3). Thus, dietary cMOS inclusion at 0.16% promoted European sea bass specific growth rate and length, stimulated selected cellular GALT associated parameters and affected lipid metabolism in muscle and liver pointing to a higher LC-PUFA accumulation and promoted beta-oxidation. PMID- 25447637 TI - Identification of TaWD40D, a wheat WD40 repeat-containing protein that is associated with plant tolerance to abiotic stresses. AB - KEY MESSAGE: TaWD40D that encodes a member of WD40 family proteins is a novel gene involved in the wheat response to abiotic stress. TaWD40D functions as a positive regulator of plant responses to salt stress and osmotic stress in plant. Abiotic stresses can severely affect plant growth and crop productivity. WD40 repeat-containing proteins play a key role in protein-protein or protein-DNA interactions by acting as scaffolding molecules and promoting protein activity. In this study, a stress-inducible gene, TaWD40D, was identified from Chinese spring wheat (Triticum aestivum L.). TaWD40D encodes a protein containing seven WD40 domains. Subcellular localization in Nicotiana benthamiana mesophyll cells and Arabidopsis root cells showed the presence of TaWD40D in the cytoplasm and nucleus. Heterologous overexpression of TaWD40D in Arabidopsis greatly increased plant tolerance to abscisic acid (ABA), salt stress, and osmotic stress during seed germination and seedling development. The expression patterns of two genes from the SOS pathway (SOS2 and SOS3) and three ABA genes (ABI2, RAB18 and DREB2A) functioning in ABA-dependent and ABA-independent pathways were altered in the transgenic lines overexpressing TaWD40D under the treatments. Notably, the basal level of the ABI2 expression was substantially increased in the TaWD40D overexpression lines. The down-regulation of TaWD40D in wheat by virus-induced gene silencing resulted in a decreased relative water content and less vigorous growth compared to non-silenced lines. Our results suggest that TaWD40D functions as a positive regulator of plant responses to salt stress and osmotic stress that could be utilized for the genetic improvement of stress tolerance in crop plants. PMID- 25447636 TI - Nitrate reductase-mediated nitric oxide production is involved in copper tolerance in shoots of hulless barley. AB - KEY MESSAGE: An NR-mediated early NO production in the shoots of hulless barley plays an important role in protecting hulless barley from Cu toxicity through enhanced antioxidant enzyme activities and antioxidant pools. Nitric oxide (NO) has been identified as an important signaling molecule that is involved in multiple plant physiological responses, especially under some abiotic stress. Here, we investigated NO production and its effects on copper (Cu) excess in hulless barley shoots. An early NO burst at 24 h was observed in shoots of hulless barley, and the synthesis of early NO was mediated through nitrate reductase (NR), but not through nitric oxide synthase (NOS). Application of the NO donor sodium nitroprusside (SNP) efficiently alleviated Cu-induced shoot inhibition and decrease in chlorophyll content, as well as oxidative damage and reactive oxygen species (ROS) accumulation, while inhibiting NO accumulation by a specific NO scavenger or a NR inhibitor aggravated shoot inhibition as well as the increase of hydrogen peroxide (H2O2) content, supporting the role of an NR mediated early NO production in hulless barley responses to Cu toxicity. Furthermore, elevated antioxidant enzyme activities were induced by Cu stress in the shoots of hulless barley and further significantly enhanced by NO donor, whereas suppressed by NO scavenger or NR inhibitor. On the other hand, the application of NO scavenger significantly reduced Cu-induced accumulation of glutathione (GSH) and ascorbate (Asc) in the shoots of hulless barley. Taken together, our results indicate that NO may induce hulless barley seedling tolerance to Cu toxicity through modulating antioxidant enzyme activity and antioxidants accumulation. PMID- 25447639 TI - Identification of interferon-gamma-inducible-lysosomal thiol reductase (GILT) gene in goldfish (Carassius auratus) and its immune response to LPS challenge. AB - The interferon-gamma-inducible lysosomal thiol reductase (GILT) has been demonstrated to play an important role in the processing and presentation of MHC class II restricted antigen (Ag) by catalyzing disulfide bond reduction. In this study, we cloned a GILT gene homolog from goldfish (designated gGILT), a kind of precious freshwater fish with high market value. The open reading frame of gGILT consists of 756 bases encoding a protein of 251 amino acids with an estimated molecular mass of 27.8 kDa and a theoretical isoelectric point of 5.24. The deduced protein possesses the typical structural features of known GILT proteins, including an active-site motif, a GILT signature sequence, and 10 conserved cysteines. RT-PCR results showed that gGILT and gIFN-gamma (goldfish IFN-gamma) mRNA were expressed in a tissue-specific manner and obviously up-regulated in splenocytes and the cells from head kidney after induction with LPS. Recombinant gGILT fused with His6 tag was efficiently expressed in Escherichia coli BL21 (DE3) and purified by Ni-NTA affinity chromatography. Further study revealed that gGILT was capable of catalyzing the reduction of the interchain disulfide bonds from intact IgG. This study shows that gGILT may be involved in the immune response to bacteria challenge and maintain first line of innate immune defense at basal level in goldfish. It also provides the basis for investigating on the role of GILT using goldfish as an animal model. PMID- 25447640 TI - Genetic improvement of the microalga Phaeodactylum tricornutum for boosting neutral lipid accumulation. AB - To obtain fast growing oil-rich microalgal strains has been urgently demanded for microalgal biofuel. Malic enzyme (ME), which is involved in pyruvate metabolism and carbon fixation, was first characterized in microalgae here. Overexpression of Phaeodactylum tricornutum ME (PtME) significantly enhanced the expression of PtME and its enzymatic activity in transgenic P. tricornutum. The total lipid content in transgenic cells markedly increased by 2.5-fold and reached a record 57.8% of dry cell weight with a similar growth rate to wild type, thus keeping a high biomass. The neutral lipid content was further increased by 31% under nitrogen-deprivation treatment, still 66% higher than that of wild type. Transgenic microalgae cells exhibited obvious morphological changes, as the cells were shorter and thicker and contained larger oil bodies. Immuno-electron microscopy targeted PtME to the mitochondrion. This study markedly increased the oil content in microalgae, suggesting a new route for developing ideal microalgal strains for industrial biodiesel production. PMID- 25447641 TI - Engineered biosynthesis of medium-chain esters in Escherichia coli. AB - Medium-chain esters such as isobutyl acetate (IBAc) and isoamyl acetate (IAAc) are high-volume solvents, flavors and fragrances. In this work, we engineered synthetic metabolic pathways in Escherichia coli for the total biosynthesis of IBAc and IAAc directly from glucose. Our pathways harnessed the power of natural amino acid biosynthesis. In particular, the native valine and leucine pathways in E. coli were utilized to supply the precursors. Then alcohol acyltransferases from various organisms were investigated on their capability to catalyze esterification reactions. It was discovered that ATF1 from Saccharomyces cerevisiae was the best enzyme for the formation of both IBAc and IAAc in E. coli. In vitro biochemical characterization of ATF1 confirmed the fermentation results and provided rational guidance for future enzyme engineering. We also performed strain improvement by removing byproduct pathways (Deltaldh, DeltapoxB, Deltapta) and increased the production of both target chemicals. Then the best IBAc producing strain was used for scale-up fermentation in a 1.3-L benchtop bioreactor. 36g/L of IBAc was produced after 72h fermentation. This work demonstrates the feasibility of total biosynthesis of medium-chain esters as renewable chemicals. PMID- 25447642 TI - Engineering Propionibacterium freudenreichii subsp. shermanii for enhanced propionic acid fermentation: effects of overexpressing propionyl-CoA:Succinate CoA transferase. AB - Propionibacterium freudenreichii subsp. shermanii naturally forms propionic acid as the main fermentation product with acetate and succinate as two major by products. In this study, overexpressing the native propionyl-CoA:succinate CoA transferase (CoAT) in P. shermanii was investigated to evaluate its effects on propionic acid fermentation with glucose, glycerol, and their mixtures as carbon source. In general, the mutant produced more propionic acid, with up to 10% increase in yield (0.62 vs. 0.56g/g) and 46% increase in productivity (0.41 vs. 0.28g/Lh), depending on the fermentation conditions. The mutant also produced less acetate and succinate, with the ratios of propionate to acetate (P/A) and succinate (P/S) in the final product increased 50% and 23%, respectively, in the co-fermentation of glucose/glycerol. Metabolic flux analysis elucidated that CoAT overexpression diverted more carbon fluxes toward propionic acid, resulting in higher propionic acid purity and a preference for glycerol over glucose as carbon source. PMID- 25447643 TI - Establishing a synthetic pathway for high-level production of 3-hydroxypropionic acid in Saccharomyces cerevisiae via beta-alanine. AB - Microbial fermentation of renewable feedstocks into plastic monomers can decrease our fossil dependence and reduce global CO2 emissions. 3-Hydroxypropionic acid (3HP) is a potential chemical building block for sustainable production of superabsorbent polymers and acrylic plastics. With the objective of developing Saccharomyces cerevisiae as an efficient cell factory for high-level production of 3HP, we identified the beta-alanine biosynthetic route as the most economically attractive according to the metabolic modeling. We engineered and optimized a synthetic pathway for de novo biosynthesis of beta-alanine and its subsequent conversion into 3HP using a novel beta-alanine-pyruvate aminotransferase discovered in Bacillus cereus. The final strain produced 3HP at a titer of 13.7+/-0.3gL(-1) with a 0.14+/-0.0C-molC-mol(-1) yield on glucose in 80h in controlled fed-batch fermentation in mineral medium at pH 5, and this work therefore lays the basis for developing a process for biological 3HP production. PMID- 25447644 TI - Glucocorticoids exert direct toxicity on microvasculature: analysis of cell death mechanisms. AB - Glucocorticoids (GCs) are routinely administered systemically or injected into the eye when treating numerous ocular diseases; however, their toxicity on the retinal microvasculature has not been previously investigated. In this article, the effects of hydrocortisone (Hydro), dexamethasone, dexamethasone-phosphate and triamcinolone acetonide (TA) were evaluated in vitro on human skin microcirculation cells and, bovine endothelial retinal cells, ex-vivo, on flat mounted rat retinas. The degree of GCs induced endothelial cell death varied according to the endothelial cell type and GCs chemical properties. GCs toxicity was higher in skin microvascular endothelial cells and for hydrophobic GC formulations. The mechanism of cell death differed between GCs, Hydro and TA activated the leukocyte elastase inhibitor/L-DNase II pathways but did not activate caspases. The mechanisms of cell death observed in cell cultures were similar to those observed in rat retinal explants. Taken together these results indicate that particular attention should be paid to the potential vascular side effects when administrating GCs clinically and in particular when developing sustained-release intraocular devices. PMID- 25447645 TI - The balance between stress resilience and vulnerability is regulated by corticotropin-releasing hormone during the critical postnatal period for sensory development. AB - Determining whether a stressful event will lead to stress-resilience or vulnerability depends probably on an adjustable stress response set point, which is most likely effective during postnatal sensory development and involves the regulation of corticotrophin-releasing hormone (CRH) expression. During the critical period of thermal-control establishment in 3-day-old chicks, heat stress was found to render resilient or sensitized response, depending on the ambient temperature. These two different responses were correlated with the amount of activation of the hypothalamic-pituitary-adrenal (HPA) axis. The expression of CRH mRNA in the hypothalamic paraventricular nucleus was augmented during heat challenge a week after heat conditioning in chicks which were trained to be vulnerable to heat, while it declined in chicks that were trained to be resilient. To study the role of CRH in HPA-axis plasticity, CRH or Crh-antisense were intracranially injected into the third ventricle. CRH caused an elevation of both body temperature and plasma corticosterone level, while Crh-antisense caused an opposite response. Moreover, these effects had long term implications by reversing a week later, heat resilience into vulnerability and vice versa. Chicks that had been injected with CRH followed by exposure to mild heat stress, normally inducing resilience, demonstrated, a week later, an elevation in body temperature, and Crh mRNA level similar to heat vulnerability, while Crh antisense injected chicks, which were exposed to harsh temperature, responded in heat resilience. These results demonstrate a potential role for CRH in determining the stress resilience/vulnerability balance. PMID- 25447646 TI - Differences and interactions between risk factors for coronary spasm and atherosclerosis--smoking, aging, inflammation, and blood pressure. AB - Objective Coronary spasm as well as atherosclerosis plays an important role in the pathogenesis of coronary heart disease. However, the relationship between coronary spasm and atherosclerosis is not well known. The purpose of the present study was to examine the differences and interactions between risk factors for coronary spasm and atherosclerosis and thereby explore the pathogenesis of coronary spasm. Methods The study subjects consisted of 938 patients with chest discomfort (522 men and 416 women, mean age 65.2+/-11.0) who underwent intracoronary-acetylcholine provocation tests for coronary spasm. Coronary risk factors, including age, gender, body mass index, blood pressure, high-sensitivity C-reactive protein (hsCRP), white blood cells, glucose, lipid profiles, and other laboratory chemistries were examined. Results Four hundred and ninety-six patients (315 men and 181 women, mean age: 65.1+/-11.4) were diagnosed with coronary spastic angina (CSA), while the remaining 442 patients (207 men and 235 women, mean age: 65.3+/-10.7) were diagnosed with non-CSA. A multiple logistic regression analysis revealed men, smoking, hsCRP, and low diastolic blood pressure (DBP) to be predictors (p=0.001, p=0.009, p=0.034, and p=0.041, respectively) for CSA, while age, diabetes mellitus, low high-density lipoprotein cholesterol, systolic blood pressure (SBP), uric acid and male gender were found to be predictors (p<0.001, p<0.001, p<0.001, p=0.002, p=0.006 and p=0.029, respectively) for atherosclerosis. Conclusion Predictors for coronary spasm were smoking, hsCRP and low DBP, whereas those for atherosclerosis were age, diabetes mellitus, high SBP, and uric acid in that order. These findings suggest that the pathogenesis of coronary spasm differs from that of atherosclerosis. PMID- 25447647 TI - Primary small intestinal mucosa-associated lymphoid tissue lymphoma diagnosed by balloon-assisted enteroscopy. AB - A 78-year-old Japanese woman presented with anemia. Oral double-balloon endoscopy (DBE) detected multiple ulcerative lesions covered with coagula extending up to approximately 20 cm from the mid-jejunum. Based on the histopathological findings, the patient's condition was diagnosed as mucosa-associated lymphoid tissue (MALT) lymphoma of the small intestine. During the second DBE examination, a small intestinal perforation occurred in one of the ulcerative lesions, and an emergency segmental small intestinal resection was performed. The present case suggests that in MALT lymphoma, intestinal wall fragility may lead to perforation even though the lesion may appear to be a superficial ulcer on endoscopy. PMID- 25447648 TI - Gastric outlet obstruction induced by a gastric wall abscess after cholecystitis. AB - In December 2011, an 84-year-old Japanese man was admitted with severe cholecystitis. We treated the cholecystitis using antibiotics, and his symptoms improved. In March 2012, he was readmitted after experiencing a sudden bloating sensation and vomiting. We determined that a gastric wall abscess had protruded into the antrum. The gastric wall was adjacent to the gallbladder, and the gastric abscess was related to a known case of cholecystitis. Upper gastrointestinal endoscopy indicated that the abscess was under the mucous membrane of the gastric antrum. Pus, exuding from the abscess, was aspirated with an endoscope. PMID- 25447650 TI - A successful case of transcatheter arterial embolization with n-butyl-2 cyanoacrylate for pancreatic arteriovenous malformation. AB - A 57-year-old man was referred and admitted to our hospital for treatment of a symptomatic pancreatic mass. Pancreatic arteriovenous malformation (AVM) was diagnosed based on the findings of contrast-enhanced computed tomography (CT) and angiography, and transcatheter arterial embolization (TAE) with N-butyl-2 cyanoacrylate (NBCA) was performed without complications. The patient's symptoms subsequently improved after TAE, and resolution of the pancreatic AVM was detected on contrast-enhanced CT performed six months after the embolization procedure. This case indicates that TAE with NBCA is a safe and effective treatment for pancreatic AVM. PMID- 25447649 TI - Heterotopic pancreas in the common bile duct, with a review of the literature. AB - A 65-year-old man presented with upper abdominal pain and was suspected of having choledocholithiasis. Endoscopic extraction of the stone was performed; however, a round filling defect in the common bile duct (CBD) persisted. Subsequent cholangioscopy showed the presence of a papillary tumor in the CBD, and the lesion was removed via the Whipple procedure. Microscopically, the papillary lesion was composed of pancreatic tissue in the submucosal layer of the CBD and therefore diagnosed as reflective of heterotopic pancreas. This is only the seventh case of heterotopic pancreas in the CBD reported in the English literature. PMID- 25447651 TI - Hepatitis C virus (HCV) reactivation caused by steroid therapy for dermatomyositis. AB - A Japanese woman was treated with injectable methylprednisolone and oral prednisolone for dermatomyositis. On admission, her serum was positive for anti hepatitis C virus (HCV) antibodies, although HCV RNA was undetectable on polymerase chain reaction. Glucocorticoid therapy improved the dermatomyositis; however, the serum alanine aminotransferase levels rapidly increased, with positive serum HCV RNA and a high viral titer. Both parameters decreased in association with prednisolone tapering, whereas dermatomyositis subsequently recurred and the administration of glucocorticoid therapy was repeated. The serum alanine aminotransferase and HCV RNA levels subsequently increased in a similar manner to that observed after the first course of therapy. Liver enzymes and the viral load should be monitored in anti-HCV-positive patients receiving immunosuppressives, even if serum HCV RNA is negative. PMID- 25447652 TI - Home parenteral nutrition therapy in seven patients with anorexia nervosa: the role and indications. AB - Home parenteral nutrition (HPN) is a well-established intervention to sustain life in malnourished patients at home. Because it is difficult for patients with anorexia nervosa (AN) to gain weight or stop purging, such patients require repeated hospitalizations. Although HPN has not been commonly used for AN patients in Japan, we utilized this approach to treat seven AN patients. We herein present the clinical course and outcome of these seven patients, the application criteria for HPN in our institution, and the potential problems associated with HPN. Despite its complications, HPN may be a useful measure to help patients with persistent AN avoid multiple hospitalizations. PMID- 25447653 TI - IgG4-related lung disease with organizing pneumonia effectively treated with azathioprine. AB - Immunoglobulin (Ig)-G4-related disease is a multi-organ disease that may affect the lung. We herein describe a patient with IgG4-related lung disease (IgG4-RLD) who was radiologically and pathologically diagnosed with organizing pneumonia. He was successfully treated with a combination of prednisolone (PSL) and azathioprine (AZA), and his clinical course has been uneventful since tapering off PSL. This is a rare case of IgG4-RLD manifesting as organizing pneumonia, and, to our knowledge, this is also the first case showing the effectiveness of AZA in treating IgG4-RLD. PMID- 25447654 TI - An autopsy case of Hermansky-Pudlak syndrome: a case report and review of the literature on treatment. AB - Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder, the most common complication of which influencing the prognosis is pulmonary fibrosis. In the present report, we describe an autopsy case of a Japanese woman with HPS. The patient was diagnosed at 50 years of age based on the presence of oculocutaneous albinism, hemorrhagic diathesis, ceroid-lipofuscin accumulation and pulmonary fibrosis. Although systemic steroids, immunosuppressants and pirfenidone were administered for pulmonary involvement, she died from respiratory failure two years later. Obtaining an early diagnosis and taking into consideration the need for lung transplantation is necessary in order to improve the prognosis of HPS. We herein report this very rare Japanese case of HPS with a review of the treatment approaches for HPS complicated with pulmonary fibrosis. PMID- 25447655 TI - Anaplastic lymphoma kinase gene analysis as a useful tool for identifying primary unknown metastatic lung adenocarcinoma. AB - A 55-year-old woman was admitted for an evaluation of a mediastinal mass, bilateral cervical lymphadenopathy and a left breast tumor. Although pathology revealed a diagnosis of breast cancer, the cervical lymph nodes differed from the breast lesion. An anaplastic lymphoma kinase (ALK) gene analysis revealed ALK rearrangement in the cervical lymph nodes only, which were therefore diagnosed as reflective of metastasis of lung adenocarcinoma. The mediastinal tumor was also diagnosed as an ALK-positive lung adenocarcinoma based on its therapeutic response. ALK gene analyses can be used to identify primary lesions in patients with cancers of unknown primary sites. PMID- 25447656 TI - Spontaneous regression of cutaneous blastic plasmacytoid dendritic cell neoplasm followed by acute monocytic leukemia evolving from myelodysplastic syndrome. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy arising from plasmacytoid dendritic cell precursors. BPDCN typically manifests in the skin, but it can also evolve into a leukemic form or be complicated by acute myeloid leukemia, some cases with a preceding myelodysplastic syndrome (MDS). We herein report the first case of complete spontaneous regression of cutaneous BPDCN followed by acute monocytic leukemia evolving from MDS. This is also the first reported case of gastric BPDCN invasion. PMID- 25447657 TI - Relapse of immune thrombocytopenia associated with varicella 20 years after splenectomy. AB - A 45-year-old man who had undergone splenectomy 20 years earlier for immune thrombocytopenia (ITP) presented with a fever, arthralgia and vesicular skin rash. The skin rash was typical for varicella, as confirmed on serological studies. He exhibited isolated thrombocytopenia and was diagnosed with ITP. In addition, an accessory spleen was detected. The platelet count responded to treatment with prednisolone (PSL), and the varicella subsided uneventfully following therapy with acyclovir. Furthermore, the platelet count was maintained after PSL was discontinued. This case suggests an etiological link between varicella and very late relapse of ITP after initial splenectomy. PMID- 25447659 TI - Pulmonary cryptococcosis with endobronchial lesions and meningitis. AB - A 58-year-old man presented with right chest pain, anorexia, general malaise, and fever. Chest computed tomography showed a mass lesion with right middle lobe atelectasis. The bronchoscopy showed polypoid lesions with a smooth surface in each right middle lobe bronchial lumen. The histopathology revealed the dense accumulation of histiocyte-like cells with foamy cytoplasm under the bronchial epithelium along with yeast-like fungi stained positively with both Alcian blue and Grocott's stains. Cryptococcus neoformans was cultured from the bronchial washings. We diagnosed the patient with pulmonary cryptococcosis with endobronchial lesions. The fluconazole treatment was changed to liposomal amphotericin-B and flucytosine after the diagnosis of cryptococcal meningitis. The minimum inhibitory concentration of the fungi suggested resistance to fluconazole and flucytosine. The lesion regressed after these treatments. PMID- 25447658 TI - Clinical and radiological findings of a cerebrotendinous xanthomatosis patient with a novel p.A335V mutation in the CYP27A1 gene. AB - We herein describe the case of a Japanese cerebrotendinous xanthomatosis (CTX) patient with a novel CYP27A1 gene mutation. The patient had been diagnosed with cataracts at 25 years of age and subsequently developed neurological symptoms in his forties, being referred to our hospital at 47 years of age. Upon admission, Achilles tendon xanthomas, cognitive impairment, dysphagia, dysarthria, dystonia, spasticity, muscle weakness and ataxia were observed. Brain MRI revealed abnormal signals in the dentate nuclei, periventricular white matter and pyramidal tract, and the serum cholestanol level was elevated. A CYP27A1 gene analysis identified compound heterozygosity for p.A335V, a novel mutation, and p.R405Q, a previously reported mutation. Making an early diagnosis of CTX is crucial, as the administration of chenodeoxycholic acid reverses metabolic derangement. PMID- 25447661 TI - Development of intraspinal ectopic endometrial tissue in connection with tethered cord syndrome. AB - We herein report a rare case of intraspinal ectopic endometrial tissue associated with tethered cord syndrome. The patient underwent MR imaging of the lumbar spine and CT spinal angiography. Asymptomatic dysraphism was also detected, including spinal bifida, low-lying conus medullaris, spinal meningocele and a lumbosacral lipoma. Venous reflux obstruction was also suggested. The patient underwent L2-S1 laminectomy and microdecompression of the lesion. The histological and immunohistochemical features were characteristic of ectopic endometrial tissue. Since the surgery, no neurological signs have been noted, either during or outside the patient's menstrual periods. The two-month follow-up MRI scans showed a regression of the lesion. PMID- 25447660 TI - Cavitary pulmonary cryptococcosis with an Aspergillus fungus ball. AB - We herein present the case of a 64-year-old immunocompetent man with a diagnosis of pulmonary cryptococcosis who presented with cavitary nodules, one of which contained a fungus ball, on chest CT. The coincidence of cavitary cryptococcosis and an Aspergillus fungus ball was histologically confirmed on a thoracoscopic lung biopsy. Encapsulated round-to-oval yeasts (Cryptococcus) were observed throughout the entire specimen, including the cavity, cavity wall and lung parenchyma. In contrast, filamentous fungi (Aspergillus) were noted within the cavity only. The probable mechanism of this rare manifestation is that the Cryptococcus formed cavities, after which an Aspergillus fungus ball developed within one cavity. PMID- 25447662 TI - Caffeine intoxication successfully treated by hemoperfusion and hemodialysis. AB - Caffeine is an easily available drug which is generally regarded as being safe. However, it can lead to a lethal outcome in severe cases of caffeine intoxication. We herein report a case of a 32-year-old man who ingested approximately 15.6 g of caffeine in a suicide attempt. He suffered from sustained ventricular tachycardia despite conservative treatment. Therefore, we performed a combined therapy of hemoperfusion and hemodialysis which resulted in rapid improvement of the patient's ventricular tachycardia as well as a reduction of the patient's plasma caffeine level. To the best of our knowledge, this combination has not been previously reported to treat caffeine intoxication. PMID- 25447663 TI - A rare entity: RACAND syndrome. PMID- 25447664 TI - Hypertrophic olivary degeneration with an egg-shaped appearance. PMID- 25447665 TI - Tracheal compression associated with esophageal achalasia. PMID- 25447666 TI - Obstructive shock caused by a giant hiatus hernia. PMID- 25447667 TI - Hypertrophic pulmonary osteoarthropathy in a patient with lung cancer. PMID- 25447668 TI - Cardiac sarcoidosis treatment revisited. PMID- 25447669 TI - Treatment with methotrexate and low-dose corticosteroids in sarcoidosis patients with cardiac lesions. PMID- 25447670 TI - IscS from Archaeoglobus fulgidus has no desulfurase activity but may provide a cysteine ligand for [Fe2S2] cluster assembly. AB - Iron sulfur ([Fe-S]) clusters are essential prosthetic groups involved in fundamental cell processes such as gene expression regulation, electron transfer and Lewis acid base chemistry. Central components of their biogenesis are pyridoxal-5'-phosphate (PLP) dependent l-cysteine desulfurases, which provide the necessary S atoms for [Fe-S] cluster assembly. The archaeon Archaeoglobus fulgidus (Af) has two ORFs, which although annotated as l-cysteine desulfurases of the ISC type (IscS), lack the essential Lys residue (K199 in Af) that forms a Schiff base with PLP. We have previously determined the structure of an Af(IscU D35A-IscS)2 complex heterologously expressed in Escherichia coli and found it to contain a [Fe2S2] cluster. In order to understand the origin of sulfide in that structure we have performed a series of functional tests using wild type and mutated forms of AfIscS. In addition, we have determined the crystal structure of an AfIscS-D199K mutant. From these studies we conclude that: i) AfIscS has no desulfurase activity; ii) in our in vitro [Fe2S2] cluster assembly experiments, sulfide ions are non-enzymatically generated by a mixture of iron, l-cysteine and PLP and iii) the physiological role of AfIscS may be to provide a cysteine ligand to the nascent cluster as observed in the [Fe2S2]-Af(IscU-D35A-IscS)2 complex. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. PMID- 25447671 TI - Shared-intermediates in the biosynthesis of thio-cofactors: Mechanism and functions of cysteine desulfurases and sulfur acceptors. AB - Cysteine desulfurases utilize a PLP-dependent mechanism to catalyze the first step of sulfur mobilization in the biosynthesis of sulfur-containing cofactors. Sulfur activation and integration into thiocofactors involve complex mechanisms and intricate biosynthetic schemes. Cysteine desulfurases catalyze sulfur transfer reactions from l-cysteine to sulfur acceptor molecules participating in the biosynthesis of thio-cofactors, including Fe-S clusters, thionucleosides, thiamin, biotin, and molybdenum cofactor. The proposed mechanism of cysteine desulfurases involves the PLP-dependent cleavage of the C-S bond from l-cysteine via the formation of a persulfide enzyme intermediate, which is considered the hallmark step in sulfur mobilization. The subsequent sulfur transfer reaction varies with the class of cysteine desulfurase and sulfur acceptor. IscS serves as a mecca for sulfur incorporation into a network of intertwined pathways for the biosynthesis of thio-cofactors. The involvement of a single enzyme interacting with multiple acceptors, the recruitment of shared-intermediates partaking roles in multiple pathways, and the participation of Fe-S enzymes denote the interconnectivity of pathways involving sulfur trafficking. In Bacillus subtilis, the occurrence of multiple cysteine desulfurases partnering with dedicated sulfur acceptors partially deconvolutes the routes of sulfur trafficking and assigns specific roles for these enzymes. Understanding the roles of promiscuous vs. dedicated cysteine desulfurases and their partnership with shared-intermediates in the biosynthesis of thio-cofactors will help to map sulfur transfer events across interconnected pathways and to provide insight into the hierarchy of sulfur incorporation into biomolecules. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. PMID- 25447672 TI - Structural changes of the ligand and of the receptor alters the receptor preference for neutrophil activating peptides starting with a formylmethionyl group. AB - Pathogenic Staphylococcus aureus strains produce N-formylmethionyl containing peptides, of which the tetrapeptide fMIFL is a potent activator of the neutrophil formyl peptide receptor 1 (FPR1) and the PSMalpha2 peptide is a potent activator of the closely related FPR2. Variants derived from these two peptide activators were used to disclose the structural determinants for receptor interaction. Removal of five amino acids from the C-terminus of PSMalpha2 gave rise to a peptide that had lost the receptor-independent neutrophil permeabilizing effect, whereas neutrophil activation capacity as well as its preference for FPR2 was retained. Shorter peptides, PSMalpha21-10 and PSMalpha21-5, activate neutrophils, but the receptor preference for these peptides was switched to FPR1. The fMIFL PSM5-16 peptide, in which the N-terminus of PSMalpha21-16 was replaced by the sequence fMIFL, was a dual agonist for FPR1/FPR2, whereas fMIFL-PSM5-10 preferred FPR1 to FPR2. Further, an Ile residue was identified as a key determinant for interaction with FPR2. A chimeric receptor in which the cytoplasmic tail of FPR1 was replaced by the corresponding part of FPR2 lost the ability to recognize FPR1 agonists, but gained function in relation to FPR2 agonists. Taken together, our data demonstrate that the C-terminus of the PSMalpha2 peptide plays a critical role for its cytotoxicity, but is not essential for the receptor-mediated pro inflammatory activity. More importantly, we show that the amino acids present in the C-terminus, which are not supposed to occupy the agonist-binding pocket in the FPRs, are of importance for the choice of receptor. PMID- 25447673 TI - Nucleocytoplasmic shuttling of valosin-containing protein (VCP/p97) regulated by its N domain and C-terminal region. AB - Valosin-containing protein (VCP or p97), a member of the AAA family (ATPases associated with diverse cellular activities), plays a key role in many important cellular activities. A genetic deficiency of VCP can cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). Previous studies showed that the VCP N domain is essential for the regulation of nuclear entry of VCP. Here we report that IBMPFD mutations, which are mainly located in the N domain, suppress the nuclear entry of VCP. Moreover, the peptide sequence G780AGPSQ in the C-terminal region regulates the retention of VCP in the nucleus. A mutant lacking this sequence can increase the nuclear distribution of IBMPFD VCP, suggesting that this sequence is a potential molecular target for correcting the deficient nucleocytoplasmic shuttling of IBMPFD VCP proteins. PMID- 25447674 TI - Indole-3-carbinol inhibits tumorigenicity of hepatocellular carcinoma cells via suppression of microRNA-21 and upregulation of phosphatase and tensin homolog. AB - A major obstacle to successful treatment of hepatocellular carcinoma (HCC) is its high resistance to cytotoxic chemotherapy due to overexpression of multidrug resistance genes. Activation of the AKT pathway is known to be involved in chemoresistance in HCC; however, the underlying mechanisms modulating the AKT pathway by chemopreventive agents remain unclear. In the present study, we found that indole-3-carbinol (I3C) treatment for tumor cells repressed the AKT pathway by increasing the expression of phosphatase and tensin homolog (PTEN) in HCC xenograft tumor and HCC cell lines. qRT-PCR data showed that the expression of miR-21 and miR-221&222 was significantly reduced by I3C in HCC cells in vitro and in vivo. Reactivation of the AKT pathway via restoration of miR-21 was reversed by I3C. Ectopic expression of miR-21 mediated-accelerated wound healing was abrogated by I3C. Moreover, reducing the expression of miR-21 by anti-miR decreased the resistance of HCC cells to I3C. These results provide experimental evidences that I3C could function as a miR-21 regulator, leading to repression of the PTEN/AKT pathway and opening a new avenue for eradication of drug-resistant cells, thus potentially helping to improve the therapeutic outcome in patients diagnosed with HCC. PMID- 25447676 TI - Pro- and antiangiogenic markers in patients with pulmonary complications of systemic scleroderma. AB - Systemic sclerosis (SSc) is an autoimmune disorder characterized by skin and internal organs fibrosis and concomitant vascular abnormalities. Although SSc is considered mainly fibrosing disease, underlying vascular pathology plays a fundamental role in its pathogenesis. We have focused on positive and negative serum markers of angiogenesis and fibrosis (pigment epithelium-derived factor [PEDF], vascular endothelial growth factor [VEGF], and soluble VEGF receptor [sVEGFR]), in progressive SSc patients at baseline and after follow-up in relation to cardiopulmonary complications (systemic hypertension [HT], pulmonary arterial hypertension [PAH] and pulmonary fibrosis [PF]). VEGF and PEDF but not sVEGFR were reciprocally regulated in SSc progression. Moreover, VEGF/PEDF ratio significantly increased during follow up suggesting that it might be used as a biomarker of disease progression. No correlation between the studied markers and cardiopulmonary complications was observed. In conclusion, VEGF and PEDF level, and the VEGF/PEDF ratio are significantly changed in the course of SSc progression and these markers can be used to assess SSc activity. PMID- 25447677 TI - Risk of bronchi obstruction among non-smokers--review of environmental factors affecting bronchoconstriction. AB - In order to find relationship between exposure to traffic and traffic-related air pollutants, pulmonary function tests and a detailed questionnaire were conducted among 3997 selected inhabitants of Warsaw (Poland) and 988 residents of rural areas. Advanced statistical analyses (including GRM models, correspondence analysis and parametrical tests) have been completed. Statistically significant differences between average percentages of predicted values of pulmonary function parameters were found. Among urban area inhabitants the values of FEV1, MEF50 and FEV1/FVC were statistically significant (p<0.05) lower compared with the residents of rural areas (in the non-smoking group this differences were strong (p<0.001)). General linear regression models indicated that residence in the vicinity of urban busy roads fosters a decrease of spirometric parameters. Physical activity however has a positive effect on pulmonary function (exemplified by FEV1) and allows to reduce part of the negative health effects of traffic-related emissions. The results of the presented study demonstrate that long-term residence under the influence of heavy traffic and high concentrations of traffic-related air pollutants reduces respiratory function parameters, which may result in increased bronchial hyperresponsiveness. PMID- 25447679 TI - T3 supplementation affects ventilatory timing & glucose levels in type 2 diabetes mellitus model. AB - Type II diabetes mellitus (T2DM) can affect ventilation, metabolism, and fasting blood glucose levels. Hypothyroidism may be a comorbidity of T2DM. In this study T2DM was induced in 20 female Sprague Dawley rats using Streptozotocin (STZ) and Nicotinamide (N). One of experimental STZ/N groups (N=10 per group) was treated with a low dose of triiodothyronine (T3). Blood glucose levels, metabolism and ventilation (in air and in response to hypoxia) were measured in the 3 groups. STZ/N-treated rats increased fasting blood glucose compared to control rats eight days and 2 months post-STZ/N injections indicating stable induction of T2DM state. Treatments had no effects on ventilation, metabolism or body weight. After one month of T3 supplementation, there were no physiological indications of hyperthyroidism, but T3 supplementation altered ventilatory timing and decreased blood glucose levels compared to STZ/N rats. These results suggest that low levels of T3 supplementation could offer modest effects on blood glucose and ventilatory timing in this T2M model. PMID- 25447680 TI - Does menstrual cycle phase affect lung diffusion capacity during exercise? AB - Resting lung diffusing capacity (DLCO) decreases during the early and late follicular phases of the menstrual cycle presumably due to capillary blood volume (VC) changes; however, it is not known if these differences exist during exercise. We hypothesized that DLCO would increase during the mid-luteal phase of the menstrual cycle due to increases in VC. Eight normally menstruating females (21.4+/-0.7 yrs) were studied. Subjects completed a discontinuous treadmill VO2max test during the early-follicular (EF), late-follicular (LF), and mid luteal (ML) phases of the menstrual cycle. Metabolic measurements were made from a breath-by-breath automated cart, and DLCO via the single-breath exhalation technique during exercise. During exercise, DLCO was lesser during EF compared to ML at 90% and 100%VO2max (p<0.05) (90%: 37.8+/-3.7 EF vs 41.6+/-4.0 ML, 100%: 37.7+/-3.7 EF vs 42.6+/-4.3 ML mL/mmHg/min). VC was significantly greater during the ML phase when compared to the EF at 80%, 90%, and 100%VO2max. These results demonstrate DLCO and VC are influenced by the menstrual cycle during heavy exercise. PMID- 25447678 TI - PGC-1alpha plays a major role in the anti-apoptotic effect of 15-HETE in pulmonary artery endothelial cells. AB - Peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha) has been confirmed as a key regulatory factor in pulmonary artery smooth muscle cells to mediate mitochondrial biogenesis and proliferation during hypoxia. However, the functional role of PGC-1alpha in hypoxic pulmonary artery endothelial cells (PAECs) still needs to be determined. In the present study, we found a marked elevation in the expression of PGC-1alpha under hypoxia, which was predominate in the nucleus of PAECs. This alteration of PGC-1alpha showed a significant association with 15-Hydroxyeicosatetraenoic acid (15-HETE), a regulator known to be protective against apoptosis at the concentration of 1 MUM. By silencing PGC-1alpha, the action against cell viability suppression induced by 15-HETE was blocked, not only in normoxic condition but also in hypoxia stimulated condition. Likewise, the tendency to reduce TUNEL-positive cells, abnormal nuclei and apoptotic cells in response to 15-HETE was depending on PGC 1alpha. Furthermore, 15-HETE and PGC-1alpha siRNA caused significant alterations in related mechanisms including caspase activity, mitochondrial membrane potential, and Bcl-2 expression. Taken together, these results provide the first evidence to confirm the importance of PGC-1alpha in mediating the protective effect of 15-HETE against apoptosis. Therefore, a clear role of PGC-1alpha in hypoxic PAECs is demonstrated, which may be attributed to pulmonary vascular remodeling. PMID- 25447675 TI - Calling in SYK: SYK's dual role as a tumor promoter and tumor suppressor in cancer. AB - SYK (spleen tyrosine kinase) is well-characterized in the immune system as an essential enzyme required for signaling through multiple classes of immune recognition receptors. As a modulator of tumorigenesis, SYK has a bit of a schizophrenic reputation, acting in some cells as a tumor promoter and in others as a tumor suppressor. In many hematopoietic malignancies, SYK provides an important survival function and its inhibition or silencing frequently leads to apoptosis. In cancers of non-immune cells, SYK provides a pro-survival signal, but can also suppress tumorigenesis by restricting epithelial-mesenchymal transition, enhancing cell-cell interactions and inhibiting migration. PMID- 25447681 TI - Physiological mechanisms of dyspnea relief following ivacaftor in cystic fibrosis: a case report. AB - Ivacaftor is a novel oral pharmacologic agent that specifically targets the genetic defect of cystic fibrosis (CF) by augmenting chloride conductance through the CF transmembrane regulator (CFTR) protein. For individuals with CF and at least one copy of the G551D gating mutation, improvements in sweat chloride, nutritional parameters, lung function, respiratory symptoms, and exercise tolerance (i.e., 6-min walk distance) are attained within 2 weeks of initiating ivacaftor. However, there are no reports detailing the physiological and sensory implications of these improvements and their underlying mechanisms. We performed detailed cardiopulmonary exercise testing pre- and post-initiation of ivacaftor in a 27-year old male with CF (CFTR genotype F508del/G551D) and chronic airflow obstruction (FEV1/FVC=0.44). An improvement of FEV1 (by 16%) following ivacaftor was accompanied by clinically significant improvements in exercise capacity (by 14%) and exertional dyspnea (by up to 5 Borg scale units). These improvements were attributable, at least in part, to favorable alterations in the ventilatory response to exercise, including improvements in breathing patterns (e.g., increased tidal volume and reduced breathing frequency) and dynamic operating lung volumes (e.g., increased inspiratory reserve volume and inspiratory capacity) and decreases in dynamic mechanical ventilatory constraints. PMID- 25447682 TI - A new approach to the dynamics of oxygen capture by the human lung. AB - Oxygen capture in the lung results from the intimate dynamic interaction between the space- and time-dependent oxygen partial pressure that results from convection-diffusion and oxygen extraction from the alveolar gas and the space and time dependence of oxygen trapping by the red blood cells flowing in the capillaries. The complexity of the problem can, however, be reduced due to the fact that the systems obey different time scales: seconds for the gas phase transport and tenths of seconds for oxygen trapping by blood. This results first from a dynamical study of gas transport in a moving acinus and second from a new theory of dynamic oxygen trapping in the capillaries. The global solution can be found only through a self-consistent iterative approach linking the two systems. This has been accomplished and used to quantify oxygen capture in various situations: at rest, during exercise, ventilation-perfusion mismatching, high altitude and pulmonary edema. PMID- 25447683 TI - Effect of age-related ventilatory inefficiency on respiratory sensation during exercise. AB - To examine the effect of age-related respiratory function impairment on exertional dyspnea, we compared ventilatory and perceptual responses to incremental exercise under control (CTRL) and added dead space (DS) loading conditions in healthy fit older (55-79 years) and younger (20-39 years) men. Older individuals had higher ventilatory equivalents for CO2 throughout exercise (p<0.05) suggesting greater ventilatory inefficiency but operating lung volumes were similar compared to younger individuals. With added DS compared to CTRL, both groups similarly increased tidal volume (by 0.3-0.6 L) and ventilation (by 8 13 L/min) at submaximal work rates (each p<0.05). At peak exercise with DS, both groups failed to further increase ventilation and had small reductions in peak work rate (p<0.05). Increases in dyspnea intensity ratings with the addition of DS were similar at standardized submaximal work rates in older and younger groups. We conclude that, despite differences in ventilatory efficiency, the respiratory-mechanical and sensory responses to added chemostimulation during exercise were similar in fit older and younger individuals. PMID- 25447685 TI - Bengt Saltin MD DSci (1935-2014), a tribute. PMID- 25447684 TI - Pleural liquid and kinetic friction coefficient of mesothelium after mechanical ventilation. AB - Volume and protein concentration of pleural liquid in anesthetized rabbits after 1 or 3h of mechanical ventilation, with alveolar pressure equal to atmospheric at end expiration, were compared to those occurring after spontaneous breathing. Moreover, coefficient of kinetic friction between samples of visceral and parietal pleura, obtained after spontaneous or mechanical ventilation, sliding in vitro at physiological velocity under physiological load, was determined. Volume of pleural liquid after mechanical ventilation was similar to that previously found during spontaneous ventilation. This finding is contrary to expectation of Moriondo et al. (2005), based on measurement of lymphatic and interstitial pressure. Protein concentration of pleural liquid after mechanical ventilation was also similar to that occurring after spontaneous ventilation. Coefficient of kinetic friction after mechanical ventilation was 0.023+/-0.001, similar to that obtained after spontaneous breathing. PMID- 25447686 TI - Novel regulatory mechanisms in muscle metabolism during exercise. PMID- 25447687 TI - High-altitude adaptation: where Tibetans and Han Chinese agree. PMID- 25447688 TI - Another chapter in the understanding of angiotensin-catecholamine interactions relevant to blood pressure control. PMID- 25447690 TI - Efficacy of bone marrow cytologic evaluations in detecting occult cancellous invasion. AB - OBJECTIVES/HYPOTHESIS: Determine the accuracy of bone marrow cytologic evaluations in detecting occult cancellous invasion by squamous cell carcinomas (SCCa) beyond the original margins of bone resection that would have gone undetected without the use of intraoperative bone-marrow margin analysis. STUDY DESIGN: Retrospective single institution cohort study. METHODS: Retrospective chart review of imaging, clinical, pathological, and follow-up data of 51 patients who underwent mandibular resections with intraoperative bone-marrow cytologic evaluation. The accuracy of bone marrow cytologic evaluations to predict final bone margins was calculated. Five-year survival rates were determined. RESULTS: The accuracy of bone marrow cytologic evaluations in detecting occult cancellous invasion by SCCa beyond the original margins of bone resection was 100%. Twelve percent (6/51) were found to have positive bone margins on cytology and were re-resected to obtain clear margins. Patients with a prior history of radiation had a significantly higher incidence of initially positive bone-marrow margins (P = 0.03). The patients with initially positive bone-margins did not have a significantly different prognosis than the patients with initially negative bone-marrow margins. CONCLUSION: 1) The consistent use of intraoperative bone-marrow cytologic evaluation, when applicable, will improve the ability to obtain clear bone margins. 2) Patients with a history of prior radiation therapy have a significantly higher risk of having occult cancellous invasion of SCCa beyond the original margins of bone resection. 3) The prognosis of patients with initially positive bone-marrow margins is not significantly different than patients with initially negative bone-marrow margins. LEVEL OF EVIDENCE: 4. PMID- 25447691 TI - A novel MYH7 Leu1453pro mutation resulting in Laing distal myopathy in an Irish family. AB - Authors describe clinical, pathological, imaging and genetic findings in the first Irish family with Laing distal myopathy in whom a novel mutation in the human slow beta-myosin heavy chain (MYH7) gene has been identified. A kindred of 14 over 6 generations included 6 individuals with childhood onset distal lower limb weakness in a scapula-peroneal distribution with subsequent proximal upper and lower limb weakness. Finger extensor weakness especially in the 3rd-5th fingers was present in each and two patients had "hanging big toe" sign. Three patients were non-ambulatory by middle-age. One patient developed cardiomyopathy and two patients had respiratory muscle impairment. Intriguingly, brain white matter lesions and epilepsy were present in three patients. Muscle biopsy revealed fibre-size variation, rimmed vacuoles, mild-extensive central nucleation, redundant and folded sarcolemmal membrane and Z band streaming. Genetic analysis revealed a novel heterozygous mutation in the MYH7 gene in one patient which co-segregated perfectly in the remaining 5 affected members and was absent in six unaffected members. PMID- 25447693 TI - Which biomarkers do clinicians need for diagnosis and management of heart failure with reduced ejection fraction? AB - While there have been significant recent advances in the medical management of chronic HF (including the use of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and aldosterone blockers), the ability to characterize, monitor, and predict a patient's response to HF therapy is poor. Risk stratification is important in patients with chronic heart failure and enables informed decisions about treatment and end-of-life care. Clinical parameters, such as advanced age, higher NYHA functional class, reduced left ventricular ejection fraction, lower body mass index, renal dysfunction, and anemia have all been associated with poor outcomes in HF. More recently, heart failure biomarkers have considerably changed the way we take care of our HF patients. BNP and NT-proBNP are endorsed by current guidelines and are now the gold standard biomarkers to confirm the diagnosis and to evaluate the prognosis of heart failure. Studies on natriuretic peptide-guided HF therapy look promising. Novel biomarkers, such soluble ST2, growth differentiation factor-15, highly sensitive troponins and Galectin-3, show potential in assessing prognosis beyond the established natriuretic peptides, but their role in the clinical care of the patient is still partially defined and more studies are needed. PMID- 25447692 TI - A novel m.7539C>T point mutation in the mt-tRNA(Asp) gene associated with multisystemic mitochondrial disease. AB - Mitochondrial transfer RNA (mt-tRNA) mutations are the commonest sub-type of mitochondrial (mtDNA) mutations associated with human disease. We report a patient with multisytemic disease characterised by myopathy, spinal ataxia, sensorineural hearing loss, cataract and cognitive impairment in whom a novel m.7539C>T mt-tRNA(Asp) transition was identified. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX) deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for the mutation whilst single muscle fibre segregation studies revealed statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres. Absence from control databases, hierarchical mt-tRNA mutation segregation within tissues, and occurrence at conserved sequence positions, further confirm this novel mt-tRNA mutation to be pathogenic. To date only three mt-tRNA(Asp) gene mutations have been described with clear evidence of pathogenicity. The novel m.7539C>T mt-tRNA(Asp) gene mutation extends the spectrum of pathogenic mutations in this gene, further supporting the notion that mt-tRNA(Asp) gene mutations are associated with multisystemic disease presentations. PMID- 25447694 TI - Glucagon stability anno 2014. PMID- 25447695 TI - Dried blood spot assay for the quantification of phenytoin using Liquid Chromatography-Mass Spectrometry. AB - Phenytoin (PHT) is one of the most commonly used anticonvulsant drugs for the treatment of epilepsy and bipolar disorders. The large amount of plasma required by conventional methods for drug quantification makes mass spectrometry combined with dried blood spot (DBS) sampling crucial for pediatric patients where therapeutic drug monitoring or pharmacokinetic studies may be difficult to realize. DBS represents a new convenient sampling support requiring minimally invasive blood drawing and providing long-term stability of samples and less expensive shipment and storage. The aim of this study was to develop a LC-MS/MS method for the quantification of PHT on DBS. This analytical method was validated and gave good linearity (r(2)=0.999) in the range of 0-100mg/l. LOQ and LOD were 1.0mg/l and 0.3mg/l, respectively. The drug extraction from paper was performed in a few minutes using a mixture composed of organic solvent for 80%. The recovery ranged from 85 to 90%; PHT in DBS showed to be stable at different storage temperatures for one month. A good correlation was also obtained between PHT plasma and DBS concentrations. This method is both precise and accurate and appears to be particularly suitable to monitor treatment with a simple and convenient sample collection procedure. PMID- 25447696 TI - Personalized biomarkers to monitor disease progression in advanced non-small-cell lung cancer patients treated with icotinib. AB - BACKGROUND: Disease-specific humoral immune response-related protein complexes in blood are associated with disease progression. METHODS: Thirty-one patients with stage IIIB and IV non-small-cell lung cancer (NSCLC) were administered with oral dose of icotinib hydrochloride (150 mg twice daily or 125 mg 3 times daily) for a 28-continuous-day cycle until diseases progressed or unacceptable toxicity occurred. The levels of immunoinflammation-related protein complexes (IIRPCs) in a series of plasma samples from 31 NSCLC patients treated with icotinib hydrochloride were determined by an optimized native polyacrylamide gel electrophoresis. RESULTS: Three characteristic patterns of the IIRPCs, named as patterns a, b, and c, respectively, were detected in plasma samples from 31 patients. Prior to the treatment, there were 18 patients in pattern a consisting of 5 IIRPCs, 9 in pattern b consisting of six IIRPCs, and 4 in pattern c without the IIRPCs. The levels of the IIRPCs in 27 patients were quantified. Our results indicate that the time length of humoral immune and inflammation response (TLHIIR) was closely associated with disease progression, and the median TLHIIR was 22.0 weeks, 95% confidence interval: 16.2 to 33.0 weeks, with a lead time of median 11 weeks relative to clinical imaging evidence confirmed by computed tomography or magnetic resonance imaging (the median progression-free survival, 34.0 weeks, 95% confidence interval: 27.9 to 49.0 weeks). CONCLUSIONS: The complex relationships between humoral immune response, acquired resistance, and disease progression existed. Personalized IIRPCs could be indicators to monitor the disease progression. PMID- 25447697 TI - Reference measurement procedure corrected all method trimmed mean - The best of two worlds. PMID- 25447698 TI - Development of a multimarker assay for differential diagnosis of benign and malignant pelvic masses. AB - BACKGROUND: HE4, a novel tumor marker for detecting ovarian cancer, has been recently applied to clinical practice. However, the comprehensive evaluation of HE4 combined with other markers is still missing. We evaluated an optimal mode of HE4 employment for differential diagnosis of benign and malignant pelvic masses. METHODS: Serum HE4, CA125, CA153, CA199, CA211 and CA724 were measured from 232 patients with pelvic messes (100 malignant masses, 132 benign diseases), and the risk of ovarian malignancy algorithm (ROMA) was also calculated. Receiver operating characteristic curves (ROC), the area under the curve (AUC), sensitivity and specificity were estimated. RESULTS: The combination of HE4 and CA125 (AUC of 0.963, sensitivity of 96.6%, specificity of 65.7%) provided the best differential power in diagnosing ovarian cancer. ROMA performed better in the diagnosis of pelvic masses (AUC of 0.917, sensitivity of 82.0%, specificity of 78.8%) and uterine cancer (AUC of 0.838, sensitivity of 82.0%, specificity of 60.0%) compared with applying HE4 and CA125 individually. CONCLUSION: The optimal cut-off values (CA125: 93.2U/ml, HE4: 87.6 pmol/l, ROMA: 18.1% for pre- and 31.5% for postmenopausal women), simultaneous use of CA125 and HE4 complemented by ROMA showed better performance than the traditional detection modes for differential diagnosis of ovarian cancer. We also observed that ROMA added more accuracy for differentiating the benign and malignant pelvic masses and auxiliary diagnosis of uterine cancer. PMID- 25447699 TI - Effects of growth hormone excess on glycated albumin concentrations: Analysis in acromegalic patients. AB - BACKGROUND: Glycated albumin (GA) does not reflect glycemic control in patients with disorders of albumin metabolism. In the present study, we examined GA concentrations in acromegalic patients with growth hormone (GH) excess. METHODS: We studied the hormonal status of 29 acromegalic patients (10 patients had diabetes mellitus and the remaining 19 patients were non-diabetic), 20 patients with type 2 diabetes mellitus and 38 non-diabetic subjects matched for age, sex and body mass index. RESULTS: Serum GA concentrations, but not those of fasting plasma glucose, 2-h post-load plasma glucose and HbA1c, were significantly higher in non-diabetic acromegalic patients compared with non-diabetic control subjects. Serum GA concentrations, but not those of fasting plasma glucose and HbA1c, were significantly higher in diabetic acromegalic patients compared with patients with type 2 diabetes mellitus. CONCLUSIONS: This is the first report describing higher GA concentrations in acromegalic patients relative to plasma glucose concentrations. Special care should be taken when evaluating glycemic control using GA because acromegaly is frequently complicated with diabetes mellitus. PMID- 25447700 TI - Sepsis biomarkers. AB - Sepsis is the most frequent cause of death in non-coronary intensive care units (ICUs). In the past 10 years, progress has been made in the early identification of septic patients and in their treatment and these improvements in support and therapy mean that the mortality is gradually decreasing but it still remains unacceptably high. Leaving clinical diagnosis aside, the laboratory diagnostics represent a complex range of investigations that can place significant demands on the system given the speed of response required. There are hundreds of biomarkers which could be potentially used for diagnosis and prognosis in septic patients. The main attributes of successful markers would be high sensitivity, specificity, possibility of bed-side monitoring, and financial accessibility. Only a fraction is used in routine clinical practice because many lack sufficient sensitivity or specificity. The following review gives a short overview of the current epidemiology of sepsis, its pathogenesis and state-of-the-art knowledge on the use of specific biochemical, hematological and immunological parameters in its diagnostics. Prospective approaches towards discovery of new diagnostic biomarkers have been shortly mentioned. PMID- 25447701 TI - Association of MTHFR genetic variants C677T and A1298C on predisposition to spontaneous abortion in Slavonic population. AB - AIM: Up to 20% of pregnancies end in the first trimester by spontaneous abortion but the cause of a large proportion remains unexplained. The aim of this study was to investigate the role of two common variants (rs1801133, C677T and rs1801131, A1298C) within the MTHFR gene in the genetic determination of spontaneous abortions. METHODS: DNA from 464 tissue samples of spontaneous abortions and population sample of adults (N=2,486) were genotyped for both MTHFR polymorphisms of interest. RESULTS: The frequencies of the MTHFR polymorphisms in tissues from spontaneous abortions did not differ from the population cohort. However, when combined, carriers of at least three rs1801133 and/or rs1801131 alleles were more common in the spontaneous abortions (61.4%) than in controls (55.4%) and this combination was associated with higher risk of abortion (OR 1.28; 95% CI 1.05-1.57; P=0.017). In contrast, carriers of at least three minor alleles (T677 and C1298) of these polymorphisms were very rare in both groups (0.8% and 0.9% respectively). CONCLUSIONS: Our study suggests that distinct combinations of the MTHFR polymorphisms could be associated with higher risk of spontaneous abortions in Caucasians. PMID- 25447702 TI - Determination of plasma pipecolic acid by an easy and rapid liquid chromatography tandem mass spectrometry method. AB - Pipecolic acid (PA) is an important biochemical marker for the diagnosis of peroxisomal disorders. PA is also a factor responsible for hepatic encephalopathy and a possible biomarker for pyridoxine-dependent seizures. We developed an easy and rapid PA quantification method, by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS), requiring no derivatization and applicable to small sample volumes. Plasma (100 MUl) is extracted with 500 MUl acetonitrile (ACN) containing 2 MUmol/l [(2)H5]-phenylalanine as internal standard, vortexed and centrifuged. The supernatant is analyzed by HPLC-MS/MS in positive-ion mode using multiple reaction monitoring scan type. HPLC column is a Luna HILIC (150*3.0mm; 3 MU 200A): Buffer A: ammonium formate 5 mmol/l; Buffer B: ACN/H20 90:10 containing ammonium formate 5 mmol/l. PA retention time is 4.86 min. Recovery was 93.8%, linearity was assessed between 0.05 and 50 MUmol/l (R(2)=0.998), lower limit of detection was 0.010 MUmol/l and lower limit of quantification was 0.050 MUmol/l. Coefficient of variation was 3.2% intra-assay and 3.4% inter-assay, respectively. Clinical validation was obtained by comparing PA plasma values from 5 patients affected by peroxisomal disorders (mean, 23.38 MUmol/l; range, 11.20-37.1 MUmol/l) to 24 ages related healthy subjects (mean, 1.711 MUmol/l; range, 0.517-3.580 MUmol/l). PMID- 25447703 TI - Early prediction of severe acute pancreatitis by urinary beta-2 microglobulin/saposin B peak ratios on MALDI-TOF. AB - The current methods for predicting severe acute pancreatitis (severe AP) are either complicated or lack efficient sensitivity and specificity. In this study, a simple and practical approach was developed to predict severe AP by using peak intensity ratio of urinary beta-2 microglobulin (B2M) to saposin B (SB) on MALDI TOF MS. Patients with B2M/SB ratio higher than 1.127 present severe AP symptom with a higher Ranson score, computed tomography (CT) grade and longer hospitalization with a sensitivity of 83.7% and specificity of 74.3%. Label-free quantitative proteomics by nanoLC-MS/MS was applied to urine of severe AP patients and found that severe AP is accompanied with kidney injury and inflammation. The measurement of B2M/SB ratios by MALDI-TOF MS could be a simple, accurate and rapid method to diagnose severe AP as well as to monitor AP progression. PMID- 25447704 TI - Rapid and sensitive detection of CALR exon 9 mutations using high-resolution melting analysis. AB - BACKGROUND: Somatic CALR exon 9 mutations have recently been identified in patients with JAK2/MPL-unmutated myeloproliferative neoplasm, and have become an important clonal marker for the diagnosis of essential thrombocythemia (ET) and primary myelofibrosis. In the present study, we sought to use high-resolution melting analysis (HRMA) as a screening method for the detection of CALR mutations. METHODS: 32 JAK2/MPL-unmutated ET patients were retrospectively enrolled and 8 healthy adults were used as wild-type control. CALR exon 9 mutation was independently screened by HRMA with the CFX Connect real-time system and Sanger sequencing. TA-cloning was used to detect CALR exon 9 mutations in patients suspected to have low mutant allele burden. RESULTS: The maximal sensitivity of HRMA in identifying both CALR type 1 and type 2 mutants from patients' genomic DNA was 2.5%. Twenty-two samples were found to have distinct melting curves from wild-type. The presence of CALR mutations in 16 of these 22 samples was confirmed by Sanger sequencing, while the other 6 samples were wild type by sequencing. After TA-cloning, CALR mutations were detected in 5 of 6 patients from 1 (6%) of 16 clones to 1 (2%) of 50 clones. Therefore, HRMA identified CALR mutations in 21 (65.6%) of 32 ET patients compared to 16 (50%) patients by Sanger sequencing, with a false positive rate of 3% and no false negative. CONCLUSION: The HRMA developed in our system is a rapid and sensitive technique for the detection of CALR exon 9 mutations. PMID- 25447705 TI - Effects of sample matrix and storage conditions on full-length visfatin measurement in blood. PMID- 25447706 TI - ROMA, an algorithm for ovarian cancer. AB - Improvement of survival in ovarian cancer may be achieved through early diagnosis and modification of treatment. Although abnormalities in the adnexal region are frequently observed in transvaginal ultrasound, interpretation may be equivocal in some cases. If neoplastic tumor is suspected, a wide range of tests and algorithms may be applied. Risk of Malignancy Algorithm (ROMA), as first described by Moore in 2009, is one of the most popular approaches. The clinical utility of this regression model has been demonstrated in both pre- (75.6% sensitivity and 74.8% specificity) and post-menopausal (92.3% sensitivity and 74.7% specificity) women. These findings have been independently confirmed in a number of publications. The sensitivity and specificity of ROMA may, however, be improved with inclusion of supplemental data, such as age and ultrasound findings. Because of its simplicity, ROMA is a reliable tool characterized by high accuracy and reproducibility to stratify patients into a high or a low ovarian cancer risk. PMID- 25447707 TI - The zymogen of plasmepsin V from Plasmodium falciparum is enzymatically active. AB - Plasmepsin V, a membrane-bound aspartic protease present in Plasmodium falciparum, is involved in the export of malaria parasite effector proteins into host erythrocytes and therefore is a potential target for antimalarial drug development. The present study reports the bacterial recombinant expression and initial characterization of zymogenic and mature plasmepsin V. A 484-residue truncated form of proplasmepsin (Glu37-Asn521) was fused to a fragment of thioredoxin and expressed as inclusion bodies. Refolding conditions were optimized and zymogen was processed into a mature form via cleavage at the Asn80 Ala81 peptide bond. Mature plasmepsin V exhibited a pH optimum of 5.5-7.0 with Km and kcat of 4.6 MUM and 0.24s(-1), respectively, at pH 6.0 using the substrate DABCYL-LNKRLLHETQ-E(EDANS). Furthermore, the prosegment of proplasmepsin V was shown to be nonessential for refolding and inhibition. Unexpectedly, unprocessed proplasmepsin V was enzymatically active with slightly reduced substrate affinity (~ 2-fold), and similar pH optimum as well as turnover compared to the mature form. Both zymogenic and mature plasmepsin V were partially inhibited by pepstatin A as well as several KNI aspartic protease inhibitors while certain metals strongly inhibited activity. Overall, the present study provides the first report on the nonessentiality of the prosegment for plasmepsin V folding and activity, and therefore, subsequent characterization of its structure-function relationships of both zymogen and mature forms in the development of novel inhibitors with potential antimalarial activities is warranted. PMID- 25447708 TI - Dynamic, in vivo, real-time detection of retinal oxidative status in a model of elevated intraocular pressure using a novel, reversibly responsive, profluorescent nitroxide probe. AB - Changes to the redox status of biological systems have been implicated in the pathogenesis of a wide variety of disorders including cancer, Ischemia reperfusion (I/R) injury and neurodegeneration. In times of metabolic stress e.g. ischaemia/reperfusion, reactive oxygen species (ROS) production overwhelms the intrinsic antioxidant capacity of the cell, damaging vital cellular components. The ability to quantify ROS changes in vivo, is therefore essential to understanding their biological role. Here we evaluate the suitability of a novel reversible profluorescent probe containing a redox-sensitive nitroxide moiety (methyl ester tetraethylrhodamine nitroxide, ME-TRN), as an in vivo, real-time reporter of retinal oxidative status. The reversible nature of the probe's response offers the unique advantage of being able to monitor redox changes in both oxidizing and reducing directions in real time. After intravitreal administration of the ME-TRN probe, we induced ROS production in rat retina using an established model of complete, acute retinal ischaemia followed by reperfusion. After restoration of blood flow, retinas were imaged using a Micron III rodent fundus fluorescence imaging system, to quantify the redox-response of the probe. Fluorescent intensity declined during the first 60 min of reperfusion. The ROS-induced change in probe fluorescence was ameliorated with the retinal antioxidant, lutein. Fluorescence intensity in non-Ischemia eyes did not change significantly. This new probe and imaging technology provide a reversible and real-time response to oxidative changes and may allow the in vivo testing of antioxidant therapies of potential benefit to a range of diseases linked to oxidative stress. PMID- 25447710 TI - Bronchoalveolar lavage fluid sample pretreatment with Sputasol((r)) significantly reduces galactomannan levels. PMID- 25447711 TI - Cutaneous leishmaniasis acquired during a brief visit to Cyprus. PMID- 25447709 TI - Predictors of delay in heart failure patients and consequences for outcomes. AB - Persons with heart failure (HF) symptoms delay up to 7 days before seeking treatment. Delay can result in worse symptoms and potentially impact outcomes. The purpose of this review was to describe predictors and outcomes of delay in HF patients. Demographic factors, increased symptom number, social factors, greater HF knowledge, lower anxiety, and depression predicted increased delay. HF patients had difficulty recognizing and interpreting symptoms of HF. Results are conflicting related to symptom pattern, time of care seeking, and history of HF as predictors of delay. The only outcome predicted by delay was length of stay with those delaying longer reporting longer lengths of stay. Future research related to delay should include theoretical frameworks and larger, more ethnically diverse samples from multiple sites and link delay to outcomes. Valid and reliable instruments are needed to measure delay and related factors. HF education should include supportive others. PMID- 25447712 TI - Distribution, virulence-associated genes and antimicrobial resistance of Aeromonas isolates from diarrheal patients and water, China. AB - OBJECTIVES: To determine the prevalence of Aeromonas infections in diarrheal patients, the distribution of virulence-associated genes and antibiotic resistance among different Aeromonas species in China. METHODS: We conducted continual active surveillance aimed on Aeromonas from diarrheal patients and aquatic samples. Aeromonas strains were identified by biochemical tests, further confirmed to species level by a multilocus phylogenetic analysis. Potential virulence genes were detected by PCR. Antibiotics susceptibility testing was carried based on the minimal inhibitory concentration. RESULTS: From 5069 samples (stool specimens, n = 4529; water samples, n = 540) in China, 257 Aeromonas isolates [stools, n = 193 (4.3%); water, n = 64 (11.9%)] were identified by biochemical tests. The most common species from stools and water were Aeromonas veronii (42.5%) and Aeromonas caviae (37.5%), respectively. Distribution of five potential genes were significantly different between stool and water samples, two genes (ast and alt) were higher in stool than in water samples (P < 0.01). Meanwhile, three species (A. veronii, A. caviae and Aeromonas aquariorum) account for the six most prevalent combination patterns of potential genes. Furthermore, strains resistant to nine antibiotics was markedly higher in strains isolated from water than those from stools (P <= 0.003); in contrast, resistance to only two antibiotics was higher in strains isolated from stools compared to those from water. In addition, strains containing multiple antibiotic resistance (MAR) from stools (8.6%; 16/187) and water (30.2%; 19/63) were resistant to ten or more antibiotics. CONCLUSION: Our study highlights the multiple factors involved in the pathogenesis of Aeromonas and reveals that environmental Aeromonas has acquired a wide range of MAR compared to those from clinical sources. PMID- 25447714 TI - Predictors of recurrent cellulitis in five years. Clinical risk factors and the role of PTX3 and CRP. AB - OBJECTIVES: To identify risk factors for recurrence of cellulitis, and to assess the predictive value of pentraxin 3 (PTX3) and C-reactive protein (CRP) measured at baseline. METHODS: A follow up study of 90 hospitalised patients with acute non-necrotising cellulitis was conducted. Clinical risk factors were assessed and PTX3 and CRP values were measured at baseline. Patients were contacted by phone at a median of 4.6 years after the baseline episode and the medical records were reviewed. RESULTS: Overall, 41% of the patients had a recurrence in the follow up. Of the patients with a history of a previous cellulitis in the baseline study 57% had a recurrence in five year follow up as compared to 26% of those without previous episodes (p = 0.003). In multivariate analysis, only the history of previous cellulitis was identified as an independent predicting factor for recurrence. The levels of pentraxin 3 (PTX3) or C-reactive protein (CRP) in the acute phase did not predict recurrence. CONCLUSIONS: Risk of recurrence is considerably higher after a recurrent episode than after the first episode. Clinical risk factors predisposing to the first cellulitis episode plausibly predispose also to recurrences. PMID- 25447713 TI - Characteristics, risk factors and outcomes of carbapenem-resistant Klebsiella pneumoniae infections in the intensive care unit. AB - OBJECTIVE: To study the characteristics, risk factors and outcomes of intensive care unit (ICU) patients with carbapenem-resistant (CRKp) and carbapenem susceptible (CSKp) Klebsiella pneumoniae infections. METHODS: A retrospective cohort of patients with K. pneumoniae infections in an eight-bed ICU between January 2006 and October 2009. RESULTS: During the study period, 104 patients were diagnosed with K. pneumoniae infection (80 CRKp and 24 CSKp). Isolation of CRKp increased gradually during the study period, while isolation of CSKp remained constant. The mean age of patients was 66.3 +/- 14.3 years. The mean APACHE II score was 17.9 +/- 6.9. The median duration of ICU stay until the infection was 15 days. Thirty five patients (33.7%) had primary and 30 (28.8%) had secondary bacteremia. Seventy-two patients (69.2%) died in the ICU. No independent risk factors for development of CRKp infections were identified in the multivariate analysis. Treatment failure (p = 0.001) was the only independent predictor of mortality in the multivariate analysis (APACHE II, shock, multi organ failure, respiratory failure, acute renal failure, acidosis and extensive drug resistance were included in the model). No difference in mortality was found between patients with CRKp and CSKp isolates. CONCLUSIONS: Infection due to K. pneumoniae in the ICU was associated with high mortality. Control of the infection was the most important determinant of the outcome of critically ill patients. PMID- 25447716 TI - The effects of punishment and appeals for honesty on children's truth-telling behavior. AB - This study examined the effectiveness of two types of verbal appeals (external and internal motivators) and expected punishment in 372 children's (4- to 8-year olds) truth-telling behavior about a transgression. External appeals to tell the truth emphasized social approval by stating that the experimenter would be happy if the children told the truth. Internal appeals to tell the truth emphasized internal standards of behavior by stating that the children would be happy with themselves if they told the truth. Results indicate that with age children are more likely to lie and maintain their lie during follow-up questioning. Overall, children in the External Appeal conditions told the truth significantly more compared with children in the No Appeal conditions. Children who heard internal appeals with no expected punishment were significantly less likely to lie compared with children who heard internal appeals when there was expected punishment. The results have important implications regarding the impact of socialization on children's honesty and promoting children's veracity in applied situations where children's honesty is critical. PMID- 25447719 TI - Overview of preparedness and response for Middle East respiratory syndrome coronavirus (MERS-CoV) in Oman. AB - Several countries in the Middle East and around 22 countries worldwide have reported cases of human infection with the Middle East respiratory syndrome coronavirus (MERS-CoV). The exceptionally high fatality rate resulting from MERS CoV infection in conjunction with the paucity of knowledge about this emerging virus has led to major public and international concern. Within the framework of the national acute respiratory illness surveillance, the Ministry of Health in the Sultanate of Oman has announced two confirmed cases of MERS-CoV to date. The aim of this report is to describe the epidemiological aspects of these two cases and to highlight the importance of public health preparedness and response. The absence of secondary cases among contacts of the reported cases can be seen as evidence of the effectiveness of infection prevention and control precautions as an important pillar of the national preparedness and response plan applied in the health care institutions in Oman. PMID- 25447717 TI - Sepsis caused by New Delhi metallo-beta-lactamase (blaNDM-1) and qnrD-producing Morganella morganii, treated successfully with fosfomycin and meropenem: case report and literature review. AB - OBJECTIVES: The objective of this study was to describe the microbiological characteristics of an extensively drug-resistant (XDR) isolate of Morganella morganii obtained from a patient with sepsis of urinary origin and to describe the patient's clinical characteristics. We further aimed to perform a literature review of the situation in Latin America regarding Gram-negative bacillus (GNB) carriers of New Delhi metallo-beta-lactamase (NDM-1) and qnr genes and current reports on the treatment of infections caused by XDR enterobacteria, with particular attention to colistin-resistant isolates. METHODS: The patient's clinical data were obtained from his medical history. Microbiological identification and susceptibility testing were done using the VITEK 2 Compact System. Resistance genes were detected by PCR and sequencing. RESULTS: Blood and urine cultures grew an M. morganii isolate (Mm4232) harboring NDM-1 and qnrD1. The patient was treated successfully with fosfomycin and double doses of meropenem. There are no previous reports of the use of fosfomycin and meropenem to treat infections by XDR enterobacteria harboring NDM-1 carbapenemase. CONCLUSIONS: This is the first report of qnrD1 in South America. We consider that this report could be helpful to physicians implementing treatments for infections caused by XDR GNB, including colistin-carbapenem-resistant GNB. PMID- 25447718 TI - Resurgence of measles in a country of elimination: interim assessment and current control measures in the Republic of Korea in early 2014. AB - Since the beginning of 2014, the Republic of Korea has experienced a resurgence of measles cases. Among the 220 cases confirmed as measles during epidemiological weeks 1-20 (December 29, 2013 to May 17, 2014), 10 imported cases were identified. The predominant genotype was B3, which reflects the circulating measles virus in adjacent countries. Even with the verification of measles elimination in March 2014 by the World Health Organization, recent importation has been related to international travel. Targeted control measures have been implemented in addition to proper isolation and patient care. A vigilant surveillance system and high levels of vaccine coverage should be maintained to sustain the measles elimination status. PMID- 25447721 TI - Spontaneous adult Gram-negative bacillary meningitis in Soweto, South Africa. AB - BACKGROUND: Gram-negative bacillary (GNB) meningitis is a rare cause of meningitis in adults and can occur as a spontaneous infection or as a complication of a neurosurgical procedure or trauma. We aimed to describe the characteristics and outcomes of adults with spontaneous GNB meningitis. METHODS: A retrospective cohort analysis was performed of 26 patients with GNB meningitis seen at a single hospital in Soweto, South Africa. RESULTS: A predisposing condition was found in 24 (92%) patients. The 19 (73%) HIV-infected patients had a median CD4 count of 24/mm(3). Chronic renal disease, diabetes mellitus, myeloma, and alcoholism were other underlying conditions. The HIV-infected had a median cerebrospinal fluid (CSF) neutrophil count of 2/mm(3) compared to the HIV non-infected of 560/mm(3). Common organisms were Escherichia coli, Klebsiella pneumoniae, and non-typhoidal Salmonella in HIV-positive patients and K. pneumoniae in the HIV-negative group. Ten (38%) isolates were resistant to third generation cephalosporins. Mortality was 65%. CONCLUSIONS: A disproportionate burden of GNB meningitis fell on the HIV-infected, among whom absent or low CSF white cells was common. Management was complicated by high rates of resistance to third-generation cephalosporins. PMID- 25447722 TI - Engaging anthropologists in a more systematic way would strengthen our global outbreak response. PMID- 25447720 TI - A feasibility study of the Xpert MTB/RIF test at the peripheral level laboratory in China. AB - OBJECTIVE: To evaluate the performance of Xpert MTB/RIF (MTB/RIF) in the county level tuberculosis (TB) laboratory in China. METHODS: From April 2011 to January 2012, patients with suspected multidrug-resistant tuberculosis (MDR-TB) and non MDR-TB were enrolled consecutively from four county-level TB laboratories. The detection of Mycobacterium tuberculosis (MTB) by MTB/RIF was compared to detection by Lowenstein-Jensen culture. The detection of rifampin resistance was compared to detection by conventional drug-susceptibility testing. The impact of multiple specimens on the performance of MTB/RIF was also evaluated. RESULTS: A total of 2142 suspected non-MDR-TB cases and 312 suspected MDR-TB cases were enrolled. For MTB detection in suspected non-MDR-TB cases, the sensitivity and specificity of MTB/RIF were 94.4% and 90.2%, respectively. The sensitivity in smear-negative patients was 88.8%. For the detection of rifampin resistance in suspected non-MDR-TB cases, the sensitivity and specificity of MTB/RIF were 87.1% and 97.9%, respectively. For the detection of rifampin resistance in suspected MDR-TB cases, the sensitivity and specificity of MTB/RIF were 87.1% and 91.0%, respectively. Using multiple sputum specimens had no significant influence on the performance of MTB/RIF for MTB detection. CONCLUSIONS: The introduction of MTB/RIF could increase the accuracy of detection of MTB and rifampin resistance in peripheral-level TB laboratories in China. One single specimen is adequate for TB diagnosis by MTB/RIF. PMID- 25447723 TI - Outcome of patients over 80 years of age on prolonged suppressive antibiotic therapy for at least 6 months for prosthetic joint infection. AB - OBJECTIVES: To describe elderly patients treated with prolonged suppressive antibiotic therapy for a prosthetic joint infection (PJI) in cases where the infected prosthesis could not be removed. METHODS: All patients aged >=80 years with a documented PJI and treated with prolonged suppressive antibiotic therapy for more than 6 months were included retrospectively in this study. The following events were noted: failure including persisting infection, relapse, new infection, treatment discontinuation due to severe adverse events, and related death, and also unrelated death. RESULTS: Thirty-eight patients with a median age of 84 years (80-95 years) were included; there were 24 hip infections, 13 knee infections, and one shoulder infection. The main causative organisms were Staphylococcus aureus (39%) and Streptococcus agalactiae (16%). The most commonly prescribed antibiotics as prolonged suppressive therapy were penicillins. The median follow-up duration was 24 months; 60% of the patients were event-free at 24 months and were still on prolonged suppressive antibiotic therapy. Fifteen events (six failures and nine unrelated deaths) were observed. Hypoalbuminaemia, the presence of a sinus tract, and a staphylococcal PJI were associated with an increased risk of an event. CONCLUSIONS: Prolonged suppressive antibiotic therapy is an alternative therapy in elderly patients with PJI when surgery is contraindicated and when the bacteria are susceptible to well-tolerated oral antimicrobial therapy such as beta-lactams. PMID- 25447725 TI - Rickettsia africae infection complicated with painful sacral syndrome in an Italian traveller returning from Zimbabwe. AB - We report a case of Rickettsia africae infection complicated with painful sacral syndrome in an Italian traveller returning from Zimbabwe. The patient presented with fever, a tache noire on the left leg, and a neurological syndrome characterized by severe pain of the left leg, predominantly located in the left dorsal thigh and radiating to the calf; she had urinary retention and faecal incontinence. The diagnosis of R. africae was confirmed by polymerase chain reaction on a skin biopsy. The severe left leg pain persisted despite a complete course of doxycycline. A 4-month course of corticosteroids and the addition of carbamazepine was needed to achieve the control of pain. This case highlights the possibility of severe manifestations of R. africae infection and the possibility of a complex pathogenesis of the neurological syndrome, due perhaps to both the direct damage induced by R. africae and an immune-mediated mechanism. PMID- 25447724 TI - Progressive antigenic drift and phylogeny of human influenza A(H3N2) virus over five consecutive seasons (2009-2013) in Hangzhou, China. AB - Vaccine efficacy (VE) can be affected by progressive antigenic drift or any new reassortment of influenza viruses. To effectively track the evolution of human influenza A(H3N2) virus circulating in Hangzhou, China, a total of 65 clinical specimens were selected randomly from outpatients infected by A(H3N2) viruses during the study period from November 2009 to December 2013. The results of reduced VE and antigenic drift of the correspondent epitopes (C-D-E to A-B) suggest that the current vaccine provides suboptimal protection against the A(H3N2) strains circulating recently. Phylogenetic analysis of the entire HA and NA sequences demonstrated that these two genes underwent independent evolutionary pathways during recent seasons. The H3-based phylogenetic tree showed that a special strain A/Hangzhou/A289/2012 fell in a cluster among viruses with reduced VE predominantly circulating in 2013. Our findings underscore a possible early warning for the circulation of A(H3N2) variants with antigenic drift during the previous seasons. PMID- 25447727 TI - IS6110-5'3'FP: an automated typing approach for Mycobacterium tuberculosis complex strains simultaneously targeting and resolving IS6110 5' and 3' polymorphisms. AB - OBJECTIVES: Fingerprinting of Mycobacterium tuberculosis complex strains based on the IS6110 insertion sequence would considerably gain in terms of discriminatory power and versatility if both 5' and 3' polymorphisms were simultaneously targeted, and if it benefited from automated capillary electrophoresis. In response to these requirements, we developed IS6110-5'3'FP (IS6110 5' and 3' fluorescent polymorphisms). METHODS: IS6110-5'3'FP involves the construction of an M. tuberculosis genomic library in a plasmid vector using HincII endonuclease, which cuts within the IS6110 sequence. After amplification in Escherichia coli, the library is subjected to selective and simultaneous PCR amplification of IS6110 5' and 3' polymorphic fragments, using differentially labeled fluorescent primers. The resulting amplicons are then fractionated on a capillary sequencer and the signal peaks analyzed as digital data. RESULTS: IS6110-5'3'FP consistently detected and resolved both 5' and 3' IS6110 polymorphic fragments (35% and 65%, respectively) with a high level of reproducibility. The method differentiated all M. tuberculosis strains, as did IS6110 restriction fragment length polymorphism (RFLP), the gold standard of IS6110-based typing. Strikingly, the potential of IS6110-5'3'FP to resolve more polymorphic fragments than IS6110 RFLP was demonstrated. CONCLUSIONS: IS6110-5'3'FP demonstrated sufficient potential to be a promising automated alternative to IS6110 RFLP, amenable to high throughput analysis and inter-laboratory comparison. PMID- 25447726 TI - First case report of isolated penile mucormycosis in a liver transplantation recipient. AB - Mucormycosis is a rare but potentially lethal complication of liver transplantation. Most reported cases have involved rhinocerebral, pulmonary, gastrointestinal, or disseminated forms. We present herein the case of a 61-year old male patient with hepatocellular carcinoma who developed isolated penile mucormycosis after orthotopic liver transplantation. Such a case has not been reported in the literature to date. Early diagnosis and timely surgical intervention combined with comprehensive treatment are the key factors for improving the survival rate in patients with mucormycosis. PMID- 25447728 TI - Prevalence and type distribution of human papillomavirus among women older than 18 years in Egypt: a multicenter, observational study. AB - OBJECTIVES: Persistent infection with high-risk (HR) human papillomavirus (HPV) is associated with premalignant lesions and cervical cancer, the third most common cancer amongst women globally and the second most frequent in Egypt. We studied the prevalence and type distribution of HPV and documented HPV infection awareness and health-related behaviours for HPV infection. METHODS: This was a multicenter, hospital-based observational study of women >=18 years of age who attended for a gynaecological examination during October 2010-August 2011. Cervical samples were tested using Linear Array HPV genotyping. Two questionnaires on awareness and health-related behaviour were completed. RESULTS: Four hundred and forty-three women with a mean age of 39.3+/-14.0 years were included in the analysis. HPV DNA was detected in 10.4% of women; a single HPV type infection was found in 6.5% and multiple infections in 3.8%. The most prevalent HR types among HPV-positive women were HPV-16 (19.6%) and HPV-31 and HPV-51 (15.2% each); low-risk types included HPV-62 (17.4%) and HPV-84 (10.9%). The prevalence of HPV-18 was low (6.5%). The prevalence of any HR HPV-type was highest in women aged 45-54 years (9.2%). CONCLUSIONS: The overall prevalence of HPV in Egypt was 10.4% and was highest (9.2%) amongst women aged 45-54 years. These data provide important reference information for public health authorities considering HPV prevention in Egypt. PMID- 25447729 TI - Evidence of hepatitis E infection in swine and humans in the East Region of Romania. AB - OBJECTIVE: Swine hepatitis E virus (HEV) is considered to be a new zoonotic agent due to its close genomic resemblance to the human HEV. The aim of this study was to determine human HEV seroprevalence in eastern Romania and to characterize circulating swine HEV sequences. METHODS: Serological investigations of human serum samples were done using a commercial ELISA kit (MP Biomedicals). Swine faecal samples were tested to detect the HEV ORF2 sequence by nested reverse transcription PCR. RESULTS: One hundred and forty-eight human serum samples were tested for anti-HEV IgG of which 22 were found to be positive. Fresh swine faeces (pools) were collected from five farms in eastern Romania. Six out of 19 pooled samples were positive for HEV RNA. Phylogenetic analysis based on alignment of the ORF2 sequence indicated that the Romanian swine HEV isolates belonged to genotype 3. CONCLUSIONS: This is the first study showing HEV to be present in Romanian pig herds and that the human population is exposed. PMID- 25447730 TI - Campylobacter jejuni, an uncommon cause of splenic abscess diagnosed by 16S rRNA gene sequencing. AB - Splenic abscess is a rare disease that primarily occurs in patients with splenic trauma, endocarditis, sickle cell anemia, or other diseases that compromise the immune system. This report describes a culture-negative splenic abscess in an immunocompetent patient caused by Campylobacter jejuni, as determined by 16S rRNA gene sequencing. PMID- 25447731 TI - A pediatric case report and literature review of thelaziosis in China. AB - Thelaziosis is a zoonosis with regional epidemics, mainly present in oriental countries, with a majority of cases reported from China. We report a pediatric case of thelaziosis and present a literature review of Chinese case reports. The epidemiological features and clinical characteristics of thelaziosis in China are presented. PMID- 25447733 TI - Effectiveness of silver-impregnated central venous catheters for preventing catheter-related blood stream infections: a meta-analysis. AB - OBJECTIVES: The purpose of this meta-analysis was to examine the effectiveness of silver-impregnated central venous catheters (CVCs) in preventing catheter bacterial colonization and catheter-related blood stream infections (CRBSIs). METHODS: PubMed, Cochrane, and Embase databases were searched up to April 30, 2014. Studies in which other antiseptic reagents were used (e.g., chlorhexidine, octenidine dihydrochloride, urokinase rinses, benzalkonium chloride, rifampin minocycline) were excluded. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Tests of heterogeneity and publication bias were performed. RESULTS: Twelve studies were included in the meta-analysis. The studies enrolled a total of 2854 patients; 1440 received a standard CVC and 1414 received a silver-impregnated CVC. No significant difference in catheter bacterial colonization rates was found between silver-impregnated and standard CVCs (OR 0.907, 95% CI 0.758-1.087, p=0.290). No significant difference in CRBSI rates was found between silver-impregnated and standard CVCs (pooled OR 0.721, 95% CI 0.476-1.094, p=0.124). No significant heterogeneity or publication bias was noted. CONCLUSIONS: Silver-impregnated CVCs are not associated with reduced rates of bacterial colonization or CRBSI. PMID- 25447734 TI - Helicobacter pylori infection amongst Arab Israeli women with hyperemesis gravidarum--a prospective, controlled study. AB - OBJECTIVE: Helicobacter pylori has been associated with hyperemesis gravidarum in some geographical regions. The prevalence of H. pylori in Arab Israeli women in the Upper Galilee and its association with hyperemesis gravidarum has not been studied previously. We aimed to examine if hyperemesis gravidarum is associated with H. pylori in this population. METHODS: Subjects with hyperemesis gravidarum carrying a singleton fetus were recruited prospectively. Women with an uncomplicated pregnancy served as controls. All patients underwent (13)C-urea breath testing to assess for H. pylori infection. RESULTS: A total of 72 subjects, including 24 patients with hyperemesis gravidarum and 48 controls, aged 28.8+/-5.3 years, were included. H. pylori infection was identified in 75.0% (18/24) of cases and 60.4% (29/48) of controls (p=not significant). H. pylori infection did not correlate with age, fetal sex, or the number of previous pregnancies (p=not significant). CONCLUSION: H. pylori does not seem to increase the likelihood of hyperemesis gravidarum in Arab Israeli women. However, given the high background prevalence of H. pylori in this population, a larger study is required to corroborate these findings. (MOH20110066). PMID- 25447732 TI - Role of innate immunity in the pathogenesis of otitis media. AB - Otitis media (OM) is a public health problem in both developed and developing countries. It is the leading cause of hearing loss and represents a significant healthcare burden. In some cases, acute OM progresses to chronic suppurative OM (CSOM), characterized by effusion and discharge, despite antimicrobial therapy. The emergence of antibiotic resistance and potential ototoxicity of antibiotics has created an urgent need to design non-conventional therapeutic strategies against OM based on modern insights into its pathophysiology. In this article, we review the role of innate immunity as it pertains to OM and discuss recent advances in understanding the role of innate immune cells in protecting the middle ear. We also discuss the mechanisms utilized by pathogens to subvert innate immunity and thereby overcome defensive responses. A better knowledge about bacterial virulence and host resistance promises to reveal novel targets to design effective treatment strategies against OM. The identification and characterization of small natural compounds that can boost innate immunity may provide new avenues for the treatment of OM. There is also a need to design novel methods for targeted delivery of these compounds into the middle ear, allowing higher therapeutic doses and minimizing systemic side effects. PMID- 25447735 TI - Inhibiting the growth of methicillin-resistant Staphylococcus aureus in vitro with antisense peptide nucleic acid conjugates targeting the ftsZ gene. AB - BACKGROUND: The increasing emergence of clinical infections caused by methicillin resistant Staphylococcus aureus (MRSA) challenges existing therapeutic options and highlights the need to develop novel treatment strategies. The ftsZ gene is essential to bacterial cell division. METHODS: In this study, two antisense peptide nucleic acids (PNAs) conjugated to a cell-penetrating peptide were used to inhibit the growth of MRSA. PPNA1, identified with computational prediction and dot-blot hybridization, is complementary to nucleotides 309-323 of the ftsZ mRNA. PPNA2 was designed to target the region that includes the translation initiation site and the ribosomal-binding site (Shine-Dalgarno sequence) of the ftsZ gene. Scrambled PPNA was constructed with mismatches to three bases within the antisense PPNA1 sequence. RESULTS: PPNA1 and PPNA2 caused concentration dependent growth inhibition and had bactericidal effects. The minimal bactericidal concentrations of antisense PPNA1 and PPNA2 were 30MUmol/l and 40MUmol/l, respectively. The scrambled PPNA had no effect on bacterial growth, even at higher concentrations, confirming the sequence specificity of the probes. RT-PCR showed that the antisense PPNAs suppressed ftsZ mRNA expression in a dose dependent manner. CONCLUSION: Our results demonstrate that the potent effects of PNAs on bacterial growth and cell viability were mediated by the down-regulation or even knock-out of ftsZ gene expression. This highlights the utility of ftsZ as a promising target for the development of new antisense antibacterial agents to treat MRSA infections. PMID- 25447736 TI - Baroreflex function in anurans from different environments. AB - Anurans from terrestrial environments have an enhanced ability to maintain mean arterial blood pressure (P(m)) through lymph mobilization in response to desiccation or hemorrhage compared with semiaquatic or aquatic species. Because short term blood pressure homeostasis is regulated by arterial baroreceptors, we compared baroreflex function in three species of anurans that span a range of environments, dehydration tolerance and an ability to maintain P(m) with dehydration and hemorrhage. The cardiac limb of the baroreflex loop was studied using pharmacological manipulation of P(m) with phenylephrine and sodium nitroprusside (20-200 MUg kg(- 1)), and the resulting changes in heart rate (f(H)) were quantitatively analyzed using a four-parameter sigmoidal logistic function. Resting P(m) in the aquatic species, Xenopus laevis, was 3.6 +/- 0.3 kPa and was significantly less (P < 0.005) than for the semiaquatic species, Lithobates catesbeianus (4.1 +/- 0.2 kPa), or the terrestrial species, Rhinella marina (4.7 +/- 0.2 kPa). The maximal baroreflex gain was not different among the three species and ranged from 12.1 to 14.3 beats min( -1) kPa( -1) and occurred at P(m )ranging from 3.0 to 3.8 kPa, which were slightly below the resting P(m) for each species. Mean arterial blood pressures at rest in the three species were near the saturation point of the baroreflex curve which provides the animals with a greater fH response range to hypotensive, rather than hypertensive, changes in P(m). This is consistent with the hypothesis that arterial baroreceptors are key sensory components that allow anurans to maintain P(m) possibly by mobilization of lymphatic return in response to hypotension. PMID- 25447738 TI - Action of thyroxine on the survival and neurite maintenance of cerebellar granule neurons in culture. AB - Developmental hypothyroidism causes severe impairments in the cerebellum. To understand the role of thyroid hormones (THs) in cerebellar development, we examined the effect of three different THs, thyroxine (T4), 3,5,3' triidothyronine (T3), and 3,3',5'-triiodothyronine (reverse T3; rT3), on the survival and morphology of cerebellar granule neurons (CGNs) in culture and found novel actions specific to T4. Rat CGNs obtained at postnatal day 6 were first cultured for 2 days in serum-containing medium with 25 mM K(+) (K25), then switched to serum-free medium with physiological 5 mM K(+) (K5) or with K25 and cultured for an additional 2 or 4 days. CGNs underwent apoptosis in K5 but survived in K25. Addition of T4 at concentrations of 100-200 nM but not T3 or rT3 rescued CGNs from cell death in K5 in a dose-dependent manner. Furthermore, 200 nM T4 was also effective in maintaining the neurites of CGNs in K5. In K5, T4 suppressed tau phosphorylation at two developmentally regulated sites as well as phosphorylation of c-jun N-terminal kinase (JNK) necessary for its activation and localization to axons. These results suggest that, during cerebellar development, T4 exerts its activity in cell survival and neurite maintenance in a manner distinct from the other two thyroid hormones through regulating the activity and localization of JNK. PMID- 25447739 TI - ERP signs of categorical and supra-categorical processing of visual information. AB - BACKGROUND: The aim of the present study was to investigate to what extent shared and distinct brain mechanisms are possibly subserving the processing of visual supra-categorical and categorical knowledge as observed with event-related potentials of the brain. Access time to these knowledge types was also investigated. Picture pairs of animals, objects, and mixed types were presented. Participants were asked to decide whether each pair contained pictures belonging to the same category (either animals or man-made objects) or to different categories by pressing one of two buttons. Response accuracy and reaction times (RTs) were also recorded. RESULTS: Both ERPs and RTs were grand-averaged separately for the same-different supra-categories and the animal-object categories. Behavioral performance was faster for more endomorphic pairs, i.e., animals vs. objects and same vs. different category pairs. For ERPs, a modulation of the earliest C1 and subsequent P1 responses to the same vs. different supra category pairs, but not to the animal vs. object category pairs, was found. This finding supports the view that early afferent processing in the striate cortex can be boosted as a by-product of attention allocated to the processing of shapes and basic features that are mismatched, but not to their semantic quintessence, during same-different supra-categorical judgment. Most importantly, the fact that this processing accrual occurred independent of a traditional experimental condition requiring selective attention to a stimulus source out of the various sources addressed makes it conceivable that this processing accrual may arise from the attentional demand deriving from the alternate focusing of visual attention within and across stimulus categorical pairs' basic structural features. Additional posterior ERP reflections of the brain more prominently processing animal category and same-category pairs were observed at the N1 and N2 levels, respectively, as well as at a late positive complex level, overall most likely related to different stages of analysis of the greater endomorphy of these shape groups. Conversely, an enhanced fronto-central and fronto-lateral N2 as well as a centro-parietal N400 to man-made objects and different-category pairs were found, possibly indexing processing of these entities' lower endomorphy and isomorphy at the basic features and semantic levels, respectively. CONCLUSION: Overall, the present ERP results revealed shared and distinct mechanisms of access to supra-categorical and categorical knowledge in the same way in which shared and distinct neural representations underlie the processing of diverse semantic categories. Additionally, they outlined the serial nature of categorical and supra-categorical representations, indicating the sequential steps of access to these separate knowledge types. PMID- 25447737 TI - Vitamin D and alternative splicing of RNA. AB - The active form of vitamin D (1alpha,25-dihydroxyvitamin D, 1,25(OH)2D) exerts its genomic effects via binding to a nuclear high-affinity vitamin D receptor (VDR). Recent deep sequencing analysis of VDR binding locations across the complete genome has significantly expanded our understanding of the actions of vitamin D and VDR on gene transcription. However, these studies have also promoted appreciation of the extra-transcriptional impact of vitamin D on gene expression. It is now clear that vitamin D interacts with the epigenome via effects on DNA methylation, histone acetylation, and microRNA generation to maintain normal biological functions. There is also increasing evidence that vitamin D can influence pre-mRNA constitutive splicing and alternative splicing, although the mechanism for this remains unclear. Pre-mRNA splicing has long been thought to be a post-transcription RNA processing event, but current data indicate that this occurs co-transcriptionally. Several steroid hormones have been recognized to coordinately control gene transcription and pre-mRNA splicing through the recruitment of nuclear receptor co-regulators that can both control gene transcription and splicing. The current review will discuss this concept with specific reference to vitamin D, and the potential role of heterogeneous nuclear ribonucleoprotein C (hnRNPC), a nuclear factor with an established function in RNA splicing. hnRNPC, has been shown to be involved in the VDR transcriptional complex as a vitamin D-response element-binding protein (VDRE BP), and may act as a coupling factor linking VDR-directed gene transcription with RNA splicing. In this way hnRNPC may provide an additional mechanism for the fine-tuning of vitamin D-regulated target gene expression. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25447740 TI - Spinal cord stimulation alleviates motor deficits in a primate model of Parkinson disease. AB - Although deep brain electrical stimulation can alleviate the motor symptoms of Parkinson disease (PD), just a small fraction of patients with PD can take advantage of this procedure due to its invasive nature. A significantly less invasive method--epidural spinal cord stimulation (SCS)--has been suggested as an alternative approach for symptomatic treatment of PD. However, the mechanisms underlying motor improvements through SCS are unknown. Here, we show that SCS reproducibly alleviates motor deficits in a primate model of PD. Simultaneous neuronal recordings from multiple structures of the cortico-basal ganglia thalamic loop in parkinsonian monkeys revealed abnormal highly synchronized neuronal activity within each of these structures and excessive functional coupling among them. SCS disrupted this pathological circuit behavior in a manner that mimics the effects caused by pharmacological dopamine replacement therapy or deep brain stimulation. These results suggest that SCS should be considered as an additional treatment option for patients with PD. PMID- 25447741 TI - Glial dysfunction causes age-related memory impairment in Drosophila. AB - Several aging phenotypes, including age-related memory impairment (AMI), are thought to be caused by cumulative oxidative damage. In Drosophila, age-related impairments in 1 hr memory can be suppressed by reducing activity of protein kinase A (PKA). However, the mechanism for this effect has been unclear. Here we show that decreasing PKA suppresses AMI by reducing activity of pyruvate carboxylase (PC), a glial metabolic enzyme whose amounts increase upon aging. Increased PC activity causes AMI through a mechanism independent of oxidative damage. Instead, increased PC activity is associated with decreases in D-serine, a glia-derived neuromodulator that regulates NMDA receptor activity. D-serine feeding suppresses both AMI and memory impairment caused by glial overexpression of dPC, indicating that an oxidative stress-independent dysregulation of glial modulation of neuronal activity contributes to AMI in Drosophila. PMID- 25447742 TI - Control and plasticity of the presynaptic action potential waveform at small CNS nerve terminals. AB - The steep dependence of exocytosis on Ca(2+) entry at nerve terminals implies that voltage control of both Ca(2+) channel opening and the driving force for Ca(2+) entry are powerful levers in sculpting synaptic efficacy. Using fast, genetically encoded voltage indicators in dissociated primary neurons, we show that at small nerve terminals K(+) channels constrain the peak voltage of the presynaptic action potential (APSYN) to values much lower than those at cell somas. This key APSYN property additionally shows adaptive plasticity: manipulations that increase presynaptic Ca(2+) channel abundance and release probability result in a commensurate lowering of the APSYN peak and narrowing of the waveform, while manipulations that decrease presynaptic Ca(2+) channel abundance do the opposite. This modulation is eliminated upon blockade of Kv3.1 and Kv1 channels. Our studies thus reveal that adaptive plasticity in the APSYN waveform serves as an important regulator of synaptic function. PMID- 25447743 TI - Selenium as an alternative peptide label - comparison to fluorophore-labelled penetratin. AB - In the present study, the impact on peptide properties of labelling peptides with the fluorophore TAMRA or the selenium (Se) containing amino acid SeMet was evaluated. Three differently labelled variants of the cell-penetrating peptide (CPP) penetratin (Pen) were synthesized, PenM(Se), TAMRA-PenM(Se) and TAMRA-Pen. The labelled peptides were characterized in terms of hydrodynamic radius, secondary structure during peptide-membrane interaction, effect on membrane leakage induction, uptake efficiency in HeLa cells. Furthermore, stability of peptides and identities of degradation products in cell media and cell lysate were evaluated. TAMRA-labelling increased the hydrodynamic radius of Pen and PenM(Se) significantly. Labelling with Se caused no or minimal changes in size, secondary structure and membrane leakage induction in concentration levels relevant for cellular uptake studies. Similar degradation patterns of all labelled peptides were observed in HBSS media; degradation was mainly due to oxidation. Cellular uptake was significantly higher for the TAMRA labelled peptides as compared to Se-labelled Pen. Extensive degradation was observed in media during cellular uptake studies, however, in all cell lysates, primarily the intact peptide (PenM(Se), TAMRA-PenM(Se) or TAMRA-Pen) was observed. Selenium labelling caused minimal alteration of the physicochemical properties of the peptide and allowed for absolute quantitative determination of cellular uptake by inductively coupled plasma mass spectrometry. Selenium is thus proposed as a promising alternative label for quantification of peptides in general, altering the properties of the peptide to a minor extent as compared to commonly used peptide labels. PMID- 25447745 TI - Prediction of skin permeation by chemical compounds using the artificial membrane, Strat-MTM. AB - PURPOSE: The usefulness of the synthetic membrane, Strat-MTM as an alternative to human and animal skins was evaluated by estimating the skin permeabilities of chemical compounds. METHOD: Thirteen chemical compounds with molecular weights (M.W.) of 152-289 and lipophilicities (log Ko/w) of -0.9 to 3.5 were selected. Strat-MTM, excised human skin, or hairless rat skin was set in a Franz-type diffusion cell and a saturated solution of each chemical compound was applied to determine membrane permeation profiles. The obtained permeability coefficients (log P) were compared among these membranes. RESULTS AND DISCUSSION: Elevations were observed in log P for Strat-MTM with an increase in the log Ko/w of the applied compounds, and similar results were observed with the human and hairless rat skins. A correlation was obtained in log P values between Strat-MTM and human or hairless rat skin. Furthermore, the diffusion and partition parameters of chemicals in Strat-MTM were similar to those in the excised human and rat skins. These results suggest that Strat-MTM could be used as an alternative to animal or human skin in permeation studies. PMID- 25447746 TI - ZEB2 and ZEB1 expression in a spontaneous canine model of invasive micropapillary carcinoma of the mammary gland. AB - ZEB1 and ZEB2 have been recently related to cancer prognosis. We investigated their expression and its association with clinicopathological parameters and overall survival in invasive micropapillary carcinoma (IMPC), which is a metastasising neoplasm of the canine mammary gland. Immunohistochemical evaluation showed nuclear and cytoplasmic staining for ZEB2 and nuclear staining for ZEB1. 'In situ' areas presented higher positivity for cytoplasmic ZEB2 than invasive areas of IMPC did (p = 0.03). ZEB1 positivity was associated with a low histological grade (p = 0.01). A shorter overall survival rate was observed in IMPCs that were positive for cytoplasmic ZEB2 (p = 0.04). Antibodies specificity in canine species was confirmed by western blot. Our results indicated that cytoplasmic ZEB2 appears to be an important factor in the early stages of malignancy and predicts a poor overall survival rate for IMPC in this canine mammary cancer model. ZEB1 downregulation appears to be associated with the dedifferentiation process of IMPC. PMID- 25447744 TI - Synthesis, in vitro and in vivo evaluation of 1,3,5-triazines as cannabinoid CB2 receptor agonists. AB - The cannabinoid receptors type 2 (CBR2) are attractive therapeutic targets of the endocannabinoid signaling system (ECS) as they are not displaying the undesired psychotropic and cardiovascular side-effects seen with cannabinoid receptor type 1 (CB1R) agonists. In continuation of our previous work on 2,4,6-trisubstituted 1,3,5-triazines as potent CB2 agonists, we synthesized an additional series of more polar analogues (1-10), which were found to possess high CB2R agonist activity with enhanced water solubility. The most potent compound in the series was N-(adamantan-1-yl)-4-ethoxy-6-(4-(2-fluoroethyl)piperazin-1-yl)-1,3,5-triazin 2-amine (9) with EC50 value of 0.60nM. To further evaluate the biological effects of the compounds, the selected compounds were tested in vitro against four different cell lines. A human retinal pigment epithelial cell line (ARPE-19) was used to evaluate the cytotoxicity of the compounds whereas an androgen-sensitive human prostate adenocarcinoma cell line (LNCaP), a Jurkat leukemia cell line and a C8161 melanoma cell line were used to assess the antiproliferative activity of the compounds. The most interesting results were obtained for N-(adamantan-1-yl) 4-ethoxy-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (6), which induced cell viability decrease in prostate and leukemia cell lines, and diminished proliferation of C8161 melanoma cells. The results could be reversed in leukemia cells with the selective CB2R antagonist AM630, whereas in prostate cells the AM630 induced a significant cell viability decrease with a mechanism probably unlinked to CB2 cannabinoid receptor. The antiproliferative effect of 6 on the melanoma cells seemed not to be mediated via the CB1R or CB2R. No cytotoxicity was detected against ARPE-19 cell line at concentrations of 1 and 10MUM for compound 6. However, at 30MUM concentration the compound 6 decreased the cell viability. Finally, in order to estimate in vivo behavior of these compounds, (18)F labeled PET ligand, N-cyclopentyl-4-ethoxy-6-(4-(2-fluoro-18 ethyl)piperazin-1-yl)-1,3,5-triazin-2-amine ([(18)F]5), was synthesized and its biodistribution was determined in healthy male Sprague-Dawley rats. As a result, the tracer showed a rapid (<15min) elimination in urine accompanied by a slower excretion via the hepatobiliary route. In conclusion, we further demonstrated that 1,3,5-triazine scaffold serves as a suitable template for the design of highly potent CB2R agonists with reasonable water solubility properties. The compounds may be useful when studying the role of the endocannabinoid system in different diseases. The triazine scaffold is also a promising candidate for the development of new CB2R PET ligands. PMID- 25447747 TI - Electroencephalogram-based indices applied to dogs' depth of anaesthesia monitoring. AB - Hypnotic drug administration causes alterations in the electroencephalogram (EEG) in a dose-dependent manner. These changes cannot be identified easily in the raw EEG, therefore EEG based indices were adopted for assessing depth of anaesthesia (DoA). This study examines several indices for estimating dogs' DoA. Data (EEG, clinical end-points) were collected from 8 dogs anaesthetized with propofol. EEG was initially collected without propofol. Then, 100 ml h-1 (1000 mg h-1) of propofol 1% infusion rate was administered until a deep anaesthetic stage was reached. The infusion rate was temporarily increased to 200 ml h-1 (2000 mg h-1) to achieve 80% of burst suppression. The index performance was accessed by correlation coefficient with the propofol concentrations, and prediction probability with the anaesthetic clinical end-points. The temporal entropy and the averaged instantaneous frequency were the best indices because they exhibit: (a) strong correlations with propofol concentrations, (b) high probabilities of predicting anaesthesia clinical end-points. PMID- 25447748 TI - Comparison of the clinical effectiveness of thermal cure and rehabilitation in knee osteoarthritis. A randomized therapeutic trial. AB - OBJECTIVE: To compare the benefits of a thermal cure and non-thermal rehabilitation in treatment of knee osteoarthritis (KOA). METHODS: Randomized therapeutic trial including patients with knee osteoarthritis (American College of Rheumatology criteria). Patients were randomly divided into two groups. Spa treatment consisted of underwater shower, massage-jet showers, hydromassage, pool rehabilitation and peloid therapy. Non-thermal rehabilitation consisted of analgesic physiotherapy, muscle strengthening and group physical rehabilitation. A blinded evaluation was carried out at day 21 and 12months following treatment. It was based on the visual analogic scale of pain (VAS), which represented the primary endpoint. RESULTS: Two hundred and forty patients were included (February June 2005). The spa treatment and non-thermal rehabilitation groups included 119 and 121 patients respectively. Two hundred and thirty-three patients completed their treatments. Significant improvement of the visual analogic scale of pain was noted in the thermal cure group (61.6+/-15 at day 0 versus 46.5+/-22.4 at 12months, P<0.001), but not in the non-thermal group (64.1+/-15 at day 0 versus 62+/-29 at 12months, P=0.68). At day 21, comparison of the two groups revealed no significant difference on the VAS (P=0.08). However, at 12months, the thermal cure group was significantly more improved (P=0.000). CONCLUSION: In our study, crenobalneotherapy had resulted, at 12months, in more pronounced long-term improvement of the painful symptoms of KOA than had non-thermal rehabilitation. PMID- 25447749 TI - Does galvanic vestibular stimulation reduce spatial neglect? A negative study. AB - INTRODUCTION: In spatial neglect, the functional benefit of rehabilitation methods is subject to debate. A few studies have reported that galvanic vestibular stimulation (GVS) is efficacious in spatial neglect. The objective of the present study was to establish whether the effects of GVS persist after the end of stimulation. MATERIALS: Four patients with pathological rightward deviation in a bisection task at least three months after right hemisphere stroke. A single-blind, randomized crossover design was used to assess the effects of GVS on performance in line bisection and star cancellation tasks under three different conditions (cathode-right, cathode-left and sham stimulation). RESULTS: There were no significant differences in the performance of either task following GVS (relative to sham stimulation). CONCLUSION: Galvanic vestibular stimulation did not reduce spatial neglect symptoms in any of the stimulation conditions. Further studies are necessary to understand the disparity between our results and those reported in the literature. Repeated sessions, a higher current intensity and/or alternating-current stimulation may improve this method before it can be used clinically. PMID- 25447750 TI - Lack of repercussions of sleep apnea syndrome on recovery and attention disorders at the subacute stage after stroke: a study of 45 patients. AB - INTRODUCTION: Sleep apnea syndrome (SAS) frequently occurs after a stroke. Its association with a poor prognosis is open to discussion. OBJECTIVE: To study, in a physical and rehabilitation medicine (PRM) unit, the possible repercussions of SAS on neurological and functional recovery as well as attentional abilities following a stroke. PATIENTS AND METHODS: Forty-five patients, all of whom had recently had a stroke without previously documented SAS, were screened using the ApneaLink((r)) system. An apnea-hypopnea index (AHI) score >=10 was considered as indicative of SAS. The NIHSS, Fugl-Meyer (FM) and Functional Independence Measure (FIM) Scales were applied on admission and at two months as means of assessing neurological and functional recovery, which was expressed by the difference between the first and the second scores (delta FM, delta NIHSS, delta FIM). The Battery Attention William Lennox (BAWL) Test was given once in order to evaluate attention disorders. SAS severity was categorized according to the AHI. We compared the groups formed (mild, moderate and severe) using the same method. RESULTS: Twenty-eight patients (62.2%) presented AHI >= 10. Stroke characteristics were comparable in the SAS+ and the SAS- groups, with average post-stroke time lapse of 26 days, initial average FIM score of 71.2 points +/- 26.3 and initial average NIHSS score of 8.9 +/- 4.9. The demographic characteristics of the two groups were likewise comparable with the exception of age, as the SAS+ group was pronouncedly older (65.4 vs. 53.5 years). As for delta FIM, which evaluated functional recovery, it averaged 31.8 +/- 20.6. Cases of SAS were found to be mild (37.1%), moderate (28.6%) or severe (34.3%). No significant difference was observed on admission or at 2 months as regards the clinical scales or the BAWL test between the two groups or according to severity, except for the NIHSS score at 2 months in the severe sub-group. DISCUSSION AND CONCLUSION: This study did not demonstrate the supposed repercussions of SAS on the recovery or attentional abilities of post-stroke patients. The tests were maybe given too early; they should take place at a lengthier time interval after the stroke, and also to be more complete. PMID- 25447752 TI - Inverse effects of lipopolysaccharides on anxiety in pregnant mice and their offspring. AB - This study aimed to evaluate the effects of the bacterial lipopolysaccharide (LPS) exposure during early pregnancy on anxiety-related behaviour of both pregnant female mice and their male offspring. Pregnant NMRI mice were treated with subcutaneous injections of LPS (30, 60, 120, 240 and 480 MUg/kg) on the tenth gestational day of pregnancy. Pro-inflammatory cytokines, such as TNF alpha, IL-1beta, IL-6 and corticosterone levels, were measured in maternal serum 1.5h following the LPS injections. Baseline anxiety levels of pregnant mice (1.5h after LPS administration) and their male offspring (at postnatal days 60-70) were investigated with the elevated plus maze (EPM) test. In addition, anxiety levels in the offspring were measured after 2h restraint stress or TNF-alpha (10 MUg/kg) administration. Our results demonstrate that LPS administration induces anxiety like behaviour and a significant increase in cytokines and corticosterone levels in maternal serum. However, in male offspring, prenatal LPS administration has no significant effects on serum cytokines and corticosterone secretion with an exception of the lowest LPS dose that slightly reduced corticosterone levels. Interestingly, prenatal LPS treatment seemed to decrease the baseline anxiety levels, while pretreatment with restraint stress or TNF-alpha abolished this anxiolytic effects. In summary, our results suggest that prenatal exposure to LPS during early pregnancy may result in reduced baseline anxiety in adult male offspring. PMID- 25447753 TI - Effects of treadmill exercise on the LiCl-induced conditioned taste aversion in rats. AB - Studies have shown that exercise can enhance learning and memory. Conditioned taste aversion (CTA) is an avoidance behavior induced by associative memory of the taste sensation for something pleasant or neutral with a negative visceral reaction caused by the coincident action of a toxic substance that is tasteless or administered systemically. We sought to measure the effects of treadmill exercise on CTA in rats by investigating the effects of exercise on acquisition, extinction and spontaneous recovery of CTA. We made two groups of rats: an exercise group that ran on a treadmill, and a control group that did not have structured exercise periods. To condition rats to disfavor a sweet taste, consumption of a 0.1% saccharin solution in place of drinking water was paired with 0.15M LiCl (2% body weight, i.p.) to induce visceral discomfort. We measured changes of saccharin consumption during acquisition and extinction of CTA. The exercise and no-exercise groups both acquired CTA to similar levels and showed maximum extinction of CTA around 6 days after acquisition. This result indicates that exercise affects neither acquisition nor extinction of CTA. However, in testing for preservation of CTA after much longer extinction periods that included exercise or not during the intervening period, exercising animals showed a significantly lower saccharin intake, irrespective of having exercised or not during the conditioning phase of the trial. This result suggests that exercise may help to preserve aversive memory (taste aversion in this example) as evidence by the significant spontaneous recovery of aversion in exercising animals. PMID- 25447751 TI - Objective assessment of ADHD core symptoms in children with heavy prenatal alcohol exposure. AB - Attention deficits are often observed in children with prenatal alcohol exposure and attention-deficit/hyperactivity disorder (ADHD) is commonly diagnosed in this population. This study used an objective assessment tool to examine differences between alcohol-exposed and non-exposed children on core symptoms of ADHD: inattention, impulsivity, and hyperactivity. Two groups of individuals, aged 7 14years, participated in the study: alcohol-exposed children (AE, n=43), and non exposed children (CON, n=54). Subjects were evaluated with the Quotient ADHD System, which provides objective data on ADHD core symptoms by combining an infrared motion tracking system and a computerized continuous performance task. Twelve separate ANCOVAs controlling for the effects of age and sex, were conducted on attention and motion variables. Results revealed that in comparison to the CON group, the AE group was significantly (p's<.05) less accurate, made an increased number of omission errors, had longer response latencies, and increased variability in response time. Moreover, the AE group spent less time staying still, and made an increased number of head movements, which traveled a larger distance, covered a greater area, and demonstrated a less complex movement pattern. No significant group differences were observed on the number of commission errors and temporal scaling. Our findings provide further support for the notion that inattention is a core deficit in children prenatally exposed to alcohol. Results from this study are also consistent with parent reports of increased hyperactivity. The Quotient ADHD System may be a useful objective measure of ADHD symptomatology in children with FASD. PMID- 25447754 TI - Anti-apoptotic effect of San Huang Shel Shin Tang cyclodextrin complex (SHSSTc) on CCl4 -induced hepatotoxicity in rats. AB - The metabolic loading is heavier in liver especially when injured or inflammation. San Huang Shel Shin Tang (SHSST) was an old traditional herbal decoction, which composed with Rheum officinale Baill, Scutellaria baicalnsis Geprgi and Coptis chinensis Franch (1:1:2 in weight), can provide a liver protection effects. We used a beta-cyclodextrin (beta-CD) drug modification method in reduce of the necessary dose of the SHSST. As the results, the FAS-FADD expressions leaded apoptosis in CCl4 intraperitoneal (IP) injection induced acute liver injury in rats. Silymarin, baicalein, SHSST, and SHSST beta-CD complex (SHSSTc) pretreatments protected liver through the decreasing of the expressions of FAS-FADD and downstream caspase-3 and caspase-8. Particularly, SHSSTc (30 mg/kg day) treatment enhanced cell survival pathway activation through the PI3K, Akt and Bad phosphorylation. Compared with SHSST as well as silymarin and baicalein, SHSSTc provided a magnificent liver protection effect, especially in survival pathway activation/TUNEL-apoptotic cell reduction/serum cholesterol level suppression. All these data suggested that beta-CD complex modified the SHSST and promoted the bioavailability and liver protection effects. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 663-670, 2016. PMID- 25447756 TI - Detection of influenza A virus subtypes using a solid-phase PCR microplate chip assay. AB - A rapid and sensitive microplate chip based on solid PCR was developed to identify influenza A subtypes. A simple ultraviolet cross-linking method was used to immobilize DNA probes on pretreated microplates. Solid-phase PCR was proven to be a convenient method for influenza A screening. The sensitivity of the microplate chip was 10(-3) MUg/mL for the enzymatic colorimetric method and 10( 4) MUg/mL for the fluorescence method. The 10 sets of primers and probes for the microplate chip were highly specific and did not interfere with each other. These results suggest that the microplate chip based on solid PCR can be used to rapidly detect universal influenza A and its subtypes. This platform can also be used to detect other pathogenic microorganisms. PMID- 25447755 TI - Genetically induced cell death in bulge stem cells reveals their redundancy for hair and epidermal regeneration. AB - Adult mammalian epidermis contains multiple stem cell populations in which quiescent and more proliferative stem and progenitor populations coexist. However, the precise interrelation of these populations in homeostasis remains unclear. Here, we blocked the contribution of quiescent keratin 19 (K19) expressing bulge stem cells to hair follicle formation through genetic ablation of the essential histone methyltransferase Setd8 that is required for the maintenance of adult skin. Deletion of Setd8 eliminated the contribution of bulge cells to hair follicle regeneration through inhibition of cell division and induction of cell death, but the growth and morphology of hair follicles were unaffected. Furthermore, ablation of Setd8 in the hair follicle bulge blocked the contribution of K19-postive stem cells to wounded epidermis, but the wound healing process was unaltered. Our data indicate that quiescent bulge stem cells are dispensable for hair follicle regeneration and epidermal injury in the short term and support the hypothesis that quiescent and cycling stem cell populations are equipotent. PMID- 25447757 TI - Evaluation of a commercially available synthetic RNA lipid enveloped control molecule. AB - Detection of viral ribonucleic acid with RT PCR is a useful tool for viral detection. One of the drawbacks of this technique is the difficulty in including an internal control molecule to ensure the validity of the extraction and amplification process. In this study the potential usefulness of a novel lipid enveloped commercially available RNA control molecule is investigated. Initial optimisation of the detection assay was performed by amplification of IC (internal control) spiked into PCR water. Thirty-two clinical respiratory samples were spiked with the IC before and after extraction and RT PCR was then performed. Inefficient extraction was simulated. Inhibition of the RT PCR was achieved by serial dilution of heparin sulfate into samples post extraction. No Targets that matched the IC (Internal Control) primers were identified in 32 extracted sputum samples as determined by the absence of non specific amplification curves. The unextracted IC had an increased CT (cycle threshold) value compared to IC that had been extracted. Inefficient extraction was detected by an increased CT. Increasing concentrations of heparin inhibited the PCR in a predictable fashion. The Bioline IC molecule provides a stable RNA IC that has acceptable performance characteristics. PMID- 25447758 TI - Anti-inflammatory and anti-periductal fibrosis effects of an anthocyanin complex in Opisthorchis viverrini-infected hamsters. AB - The pharmacological activities of herbal extracts can be enhanced by complex formation. In this study, we manipulated cyanidin and delphinidin-rich extracts to form an anthocyanin complex (AC) with turmeric and evaluated activity against inflammation and periductal fibrosis in Opisthorchis viverrini-infected hamsters. The AC was prepared from anthocyanins extracted from cobs of purple waxy corn (70%), petals of blue butterfly pea (20%) and turmeric extract (10%), resulting in an enhanced free-radical scavenging capacity. Oral administration of AC (175 and 700 mg/kg body weight) every day for 1 month to O. viverrini-infected hamsters resulted in reduced inflammatory cells and periductal fibrosis. Fourier transform infrared spectroscopy and partial least square discriminant analysis suggested nucleic acid changes in the O. viverrini-infected liver samples, which were partially prevented by the AC treatment. AC reduced 8-oxodG formation, an oxidative DNA damage marker, significantly decreased levels of nitrite in the plasma and alanine aminotransferase activity and increased the ferric reducing ability of plasma. AC also decreased the expression of oxidant-related genes (NF kappaB and iNOS) and increased the expression of antioxidant-related genes (CAT, SOD, and GPx). Thus, AC increases free-radical scavenging capacity, decreases inflammation, suppresses oxidative/nitrative stress, and reduces liver injury and periductal fibrosis in O. viverrini-infected hamsters. PMID- 25447759 TI - Photooxidative damage in retinal pigment epithelial cells via GRP78 and the protective role of grape skin polyphenols. AB - Blue light induced oxidative damage and ER stress are related to the pathogenesis of age-related macular degeneration (AMD). However, the mechanism of blue light induced damage remained obscure. The objective of this work is to assess the photooxidative damage to retinal pigment epithelial cells (RPE) and oxidation induced changes in expression of ER stress associated apoptotic proteins, and investigate the mechanism underlying the protective effects of grape skin extracts. To mimic lipofuscin-mediated photooxidation in vivo, ARPE-19 cells that accumulated A2E, one of lipofuscin fluorophores, were used as a model system to investigate the mechanism of photooxidative damage and the protective effects of grape skin polyphenols. Exposure of A2E containing ARPE-19 cells to blue light resulted in significant apoptosis and increases in levels of GRP78, CHOP, p-JNK, Bax, cleaved caspase-9, and cleaved caspase-3, indicating that photooxidative damage to RPE cells is mediated by the ER-stress-induced intrinsic apoptotic pathway. Cells in which GRP78 had been knocked down with shRNA were more vulnerable to photooxidative damage. Pre-treatment of blue-light-exposed A2E containing ARPE-19 cells, with grape skin extracts, inhibited apoptosis, in a dose dependent manner. Knockdown GRP78 blocked the protective effect of grape skin extracts. PMID- 25447760 TI - Anti-inflammatory effect of gamma-irradiated genistein through inhibition of NF kappaB and MAPK signaling pathway in lipopolysaccharide-induced macrophages. AB - Genistein was irradiated with gamma-irradiation at doses of 0, 10, 30, 50, 100, and 150 kGy. We observed that the decrease in the genistein peak after gamma irradiation was concomitant with the appearance of several new peaks. 150 kGy gamma-irradiated genistein did not exert cytotoxicity in macrophages, and inhibited inducible nitric oxide synthase-mediated nitric oxide production and pro-inflammatory cytokines level, such as tumor necrosis factor-alpha, interleukin-6 and interleukin-1beta, in lipopolysaccharide (LPS)-induced macrophages. The treatment of LPS-stimulated macrophages with 150 kGy gamma irradiated genistein resulted in a significant decrease in cyclooxygenase-2 levels, as well as the expression of cell surface molecules, such as CD80 and CD86. Furthermore, we also found that the anti-inflammatory action of 150 kGy gamma-irradiated genistein occurred through an inhibition of mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2, p38 and c-Jun N terminal kinase) and nuclear factor-kappaB signaling pathways based on a toll like receptor 4 in macrophages, which may be speculated that several radiolysis products of genistein transformed by gamma-irradiation induce the inhibition of pro-inflammatory mediators. From these findings, it seems likely that gamma irradiated genistein could play a potent role in the treatment of inflammatory disease as a value-added product in the medical industry. PMID- 25447761 TI - Suppression of SOS response in E. coli PQ 37, antioxidant potential and antiproliferative action of methanolic extract of Pteris vittata L. on human MCF 7 breast cancer cells. AB - Pteris vittata L. from the foothills of Kangra district, Himachal Pradesh, India has been investigated for its potential to combat reactive oxygen species and DNA damaging agents. DPPH radical, superoxide anion radical, ABTS(+.) radical cation decolorization, reducing power, deoxyribose degradation, plasmid nicking and lipid peroxidation assays were carried out to evaluate the antioxidant potential of methanolic of P. vittata L. (PME). The extract showed a significant potential in scavenging the free radicals and an IC50 of 64.425 ug/ml and 90.143 ug/ml was obtained in superoxide radical scavenging and reducing power assays respectively. PME inhibited lipid peroxidation with an IC50 of 34.35 ug/ml and protected the plasmid DNA from damage by hydroxyl radicals to varying degrees. Percentage inhibition of 81.22 and 89.36 at a concentration of 160 ug/ml was obtained in non site specific and site specific deoxyribose degradation assays respectively. PME significantly inhibited 4NQO induced mutagenicity in Escherichia coli PQ 37 and a decrease in induction factor was observed with increasing concentration. The amount of total phenolic and flavonoid content were also determined and HPLC analysis was carried out for the identification of phytoconstituents. A dose dependent decrease in viability of MCF-7 cells was observed with GI50 value of 153.967 ug/ml. PMID- 25447762 TI - Exposure assessment of 3-monochloropropane-1, 2-diol esters from edible oils and fats in China. AB - 3-monochoropropane-1, 2-diol (3-MCPD) esters from edible oils are considered to be a possible risk factor for adverse effects in human. In the present study, the exposure assessment of 3-MCPD esters to Chinese population was performed. A total of 143 edible oil and fat samples collected from Chinese markets were determined for the concentrations of 3-MCPD esters. The concentration data together with the data of fats consumed were analyzed by the point evaluation and probabilistic assessment for the exposure assessment. The point evaluation showed that the mean daily intake (DI) of 3-MCPD esters were lower than the value of provisional maximum tolerable daily intake (PMTDI) of 3-MCPD (2 ug/kg BW/d). The mean DI values in different age groups obtained from probabilistic assessment were similar to the results of the point evaluation. However, in high percentiles (95th, 97.5th, 99th), the DI values in all age groups were undesirably higher than the value of PMTDI. Overall, the children and adolescents exposed more to 3 MCPD esters than the adults. Uncertainty was also analyzed for the exposure assessment. Decreasing the level of 3-MCPD esters in edible oils and consuming less oil were top priority to minimize the risk of 3-MCPD esters. PMID- 25447764 TI - The combination of adenosine deaminase inhibition and deoxyadenosine induces apoptosis in a human astrocytoma cell line. AB - Alterations in the functions of astrocytes contribute to the appearance of a variety of neurological pathologies. Gliomas, especially those of astrocytic origin, are particularly resistant to chemotherapy and are often characterized by a poor prognosis. Neuroblastoma is the tumour with the higher incidence in infants. Anticancer drugs can induce apoptosis and their cytotoxic effect is often mediated by this process. We have previously demonstrated that the combination of deoxycoformycin, a strong adenosine deaminase inhibitor, and deoxyadenosine is toxic for a human astrocytoma cell line. In fact, after 15 h of treatment, this combination increases both mitochondrial reactive oxygen species and mitochondrial mass, induces apoptosis as indicated by cytochrome c release from mitochondria and activation of caspase-3. These events are preceded by reduction in lactate release in the medium. In this work we demonstrate that after 8 h of incubation with deoxyadenosine and deoxycoformycin, caspase-8 is activated, mitochondrial mass increases and mitochondrial reactive oxygen species decrease. The addition of baicalein to the incubation medium reduces cell death and caspase-3 activity induced by deoxycoformycin and deoxyadenosine in combination. This protective effect is correlated to an increase of lactate released in the medium, a decrease in the intracellular levels of dATP, and an increase in ATP levels, as compared with the cells subjected to the treatment with deoxycoformycin and deoxyadenosine without any further addition. The effect of baicalein appears to be related to an inhibition of deoxyadenosine phosphorylation, rather than or in addition to the well known antioxidant activity of the compound. This work indicates that an astrocytoma cell line, reported to be resistant to mitochondria-dependent pathways of apoptosis, is indeed very sensitive to a manipulation affecting the balance of cellular purine metabolite concentrations. The same treatment is also cytotoxic on a neuroblastoma cell line, thus suggesting long term implications for cancer therapy. PMID- 25447763 TI - Malibatol A protects against brain injury through reversing mitochondrial dysfunction in experimental stroke. AB - Ischemic stroke is particularly susceptible to free radicals mediated secondary neuronal damage, especially mitochondrial dysfunction. Malibatol A (MA), a novel resveratrol oligomer, has shown potential antioxidant property in vitro. But little is known about its effect on central nervous system (CNS) in vivo. In the present study, the effect of MA was evaluated in focal cerebral ischemia induced by right middle cerebral artery occlusion (MCAO) in mice. MA at the dose of 20 mg/kg was administered by caudal-vein injection within 15 min after reperfusion. At 24 h after cerebral ischemia/reperfusion (I/R) injury, ameliorated neurological scores and reduced infarct volume was observed in MA treated group. Also, MA treatment restored the increased levels of reactive oxygen species (ROS), 3-Nitrotyrosine (3-NT), and 4-Hydroxynonenal (4-HNE) induced by MCAO. The activities of respiratory enzyme complex I, III and mitochondrial transmembrane potential (Deltam) were effectively preserved compared with MCAO group through MA treatment. Western blot analysis showed a marked increase in Bcl-2 and decrease in Bax expression after MA treatment as compared with MCAO group. Moreover, MA treatment prevented release of cytochrome c from mitochondria into cytoplasm and blunted activities of caspase-9 and caspase-3. Collectively, the present study indicates that MA can ameliorate MCAO-induced mitochondrial dysfunction, and this might partially contribute to its protective effect on brain damage after 24 h of I/R injury. PMID- 25447765 TI - Endothelial dysfunction impairs vascular neurotransmission in tail arteries. AB - The present study intends to clarify if endothelium dysfunction impairs vascular sympathetic neurotransmission. Electrically-evoked tritium overflow (100 pulses/5 Hz) was evaluated in arteries (intact and denuded) or exhibiting some degree of endothelium dysfunction (spontaneously hypertensive arteries), pre-incubated with [(3)H]-noradrenaline in the presence of enzymes (nitric oxide synthase (NOS); nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; xanthine oxidase; cyclooxygenase; adenosine kinase) inhibitors and a nucleoside transporter inhibitor. Inhibition of endothelial nitric oxide synthase with L-NIO dihydrochloride reduced tritium overflow in intact arteries whereas inhibition of neuronal nitric oxide synthase with Nomega-Propyl-L-arginine hydrochloride was devoid of effect showing that only endothelial nitric oxide synthase is involved in vascular sympathetic neuromodulation. Inhibition of enzymes involved in reactive oxygen species or prostaglandins production with apocynin and allopurinol or indomethacin, respectively, failed to alter tritium overflow. A facilitation or reduction of tritium overflow was observed in the presence of 8 cyclopentyl-1,3-dipropylxanthine (DPCPX) or of 5-iodotubericidin, respectively, but only in intact arteries. These effects can be ascribed to a tonic inhibitory effect mediated by A1 receptors. In denuded and hypertensive arteries, 7-(2 phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine (SCH 58261) reduced tritium overflow, suggesting the occurrence of a tonic activation of A2A receptors. When endogenous adenosine bioavailability was increased by the nucleoside transporter inhibitor, S-(4-Nitrobenzyl)-6 thioinosine, tritium overflow increased in intact, denuded and hypertensive arteries. Among the endothelium-derived substances studied that could alter vascular sympathetic transmission only adenosine/adenosine receptor mediated mechanisms were clearly impaired by endothelium injury/dysfunction. PMID- 25447766 TI - Interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in minimal hepatic encephalopathy. AB - The cognitive and motor alterations in hepatic encephalopathy (HE) are the final result of altered neurotransmission and communication between neurons in neuronal networks and circuits. Different neurotransmitter systems cooperate to modulate cognitive and motor function, with a main role for glutamatergic and GABAergic neurotransmission in different brain areas and neuronal circuits. There is an interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in HE. This interplay may occur: (a) in different brain areas involved in specific neuronal circuits; (b) in the same brain area through cross-modulation of glutamatergic and GABAergic neurotransmission. We will summarize some examples of the (1) interplay between glutamatergic and GABAergic neurotransmission alterations in different areas in the basal ganglia thalamus-cortex circuit in the motor alterations in minimal hepatic encephalopathy (MHE); (2) interplay between glutamatergic and GABAergic neurotransmission alterations in cerebellum in the impairment of cognitive function in MHE through altered function of the glutamate-nitric oxide-cGMP pathway. We will also comment the therapeutic implications of the above studies and the utility of modulators of glutamate and GABA receptors to restore cognitive and motor function in rats with hyperammonemia and hepatic encephalopathy. PMID- 25447767 TI - Genetic obesity alters recruitment of TANK-binding kinase 1 and AKT into hypothalamic lipid rafts domains. AB - Lipid rafts (LRs) are membrane subdomains enriched in cholesterol, glycosphingolipids and sphingolipids containing saturated fatty acid. Signaling proteins become concentrated in these microdomains mainly by saturated fatty acid modification, thus facilitating formation of protein complexes and activation of specific signaling pathways. High intake of saturated fatty acids promotes inflammation and insulin resistance, in part by disrupting insulin signaling pathway. Here we investigate whether lipid-induced toxicity in obesity correlates with altered composition of insulin signaling proteins in LRs in the brain. Our results showed that insulin receptor (IR) is highly concentrated in LRs fraction in comparison with soluble or postsynaptic density (PSD) fractions. Analysis of LRs domains from hippocampus of obese mouse showed a significant decrease of IR and its downstream signaling protein AKT, while in the PSD fraction we detected partial decrease of AKT and no changes in the IR concentration. No changes were shown in the soluble extract. In hypothalamus, genetic obesity also decreases interaction of AKT, but we did not detect changes in the IR distribution. However, in this structure genetic obesity increases recruitment of the IR negative regulator TANK-binding kinase 1 (TBK1) into LRs and PSD fraction. No changes of AKT, IR and TBK1 were found in soluble fractions of obese in comparison with lean mice. In vitro studies showed that incubation with saturated palmitic acid but not with unsaturated docosahexaenoic acid (DHA) or palmitoleic acid decreases association of IR and AKT and increases TBK1 recruitment into LRs and PSD domains, emulating what happens in the obese mice. TBK1 recruitment to insoluble domains correlates with decreases of IR tyrosine phosphorylation and ser473 AKT phosphorylation, markers of insulin resistance. These data support the hypothesis that hyperlipidemia associated with genetic obesity alters targeting of TBK1 and insulin signaling proteins into insoluble LRs domains. PMID- 25447768 TI - Glutamate: Where does it come from and where does it go? AB - Pyruvate carboxylation, the anaplerotic reaction in the brain, has been demonstrated in astrocytes but not neurons. Since anaplerosis cannot proceed without cataplerosis in a closed system such as the brain, there have to be mechanisms to degrade molecules such as glutamate, glutamine, GABA and aspartate which have more carbon atoms than pyruvate. Pyruvate recycling is a cataplerotic process which is very active in liver. It has also been demonstrated in the brain and has been shown to proceed both in astrocytes and neurons. Increasing recycling as a consequence of increasing glutamate concentration in medium has been shown in astrocytes. In the present study cerebellar granule neurons were incubated with medium containing 0.1, 0.25 or 0.5 mM [U-(13)C]glutamate or [U (13)C]aspartate and pyruvate recycling in combination with tricarboxylic acid (TCA) cycle metabolism was analysed in glutamate, aspartate and malate using mass spectrometry. It could be shown that pyruvate recycling of TCA cycle intermediates as seen in glutamate increased with increasing [U-(13)C]glutamate but not [U-(13)C]aspartate concentration confirming compartmentation of glutamate metabolism and the importance of glutamate in cataplerosis. Partial pyruvate recycling (lactate production from the TCA cycle) was more active in astrocytes than neurons in line with the astrocytes' greater capacity for glutamate uptake. PMID- 25447769 TI - First reported case of systemic envenoming by the Sri Lankan keelback (Balanophis ceylonensis). AB - Envenoming by colubrid snakes is rarely reported. However, some colubrid snakes (e.g. Rhabdophis tigrinus and Rhabdophis subminiatus) have caused severe systemic envenoming. We report here the first case of a bite with systemic envenoming by Balanophis ceylonensis, an opisthoglyphous natricine colubrid, in Sri Lanka. A 33 year-old healthy male field biologist was bitten while handling the snake for photography. Within 5 min of the bite on the dorsum of the right hand, he reported severe occipital headache, photophobia, chills and transient loss of consciousness. He vomited blood-stained gastric contents and bled from venepuncture sites. He had a markedly elevated INR and positive D-dimer test suggestive of significant coagulopathy that was treated with infusions of fresh frozen plasma. He recovered and left hospital after 96 h and subsequent investigations, including electroencephalogram, were normal. We conclude that B. ceylonensis should be regarded as a medically significant venomous snake. This case highlights the need for further studies of the oral secretions (venoms) of colubrid snakes. PMID- 25447771 TI - Nicotinic acetylcholine receptor alpha7 subunit is involved in the cobratoxin induced antinociception in an animal model of neuropathic pain. AB - In this study we report that cobratoxin (CbTX), a long-chain postsynaptic alpha neurotoxin isolated from the Thailand cobra, Naja naja kaouthia, has antinociceptive effect in rats with neuropathic pain. The neuropathic pain model was established in rats with partial sciatic nerve ligature (PSNL) method. The pain response was examined behaviorally with mechanical paw withdrawal and thermal paw withdrawal method. Different doses (0.56, 1.12 and 4.50 MUg/kg) of CbTX were injected intrathecally. Injection of CbTX resulted in a significant dose-dependent antinociception as evidenced by increased mechanical withdrawal threshold and thermal withdrawal latency. CbTX also induces a significant dose dependent inhibition of pain-evoked unit discharges of thalamic parafascicular neurons. Both the behavioral mechanical and thermal antinociception and the inhibition of pain-evoked discharges of neurons in thalamic parafascicular nucleus in PSNL model could be mimicked by PUN282987, selective alpha7 nicotinic AChR (alpha7 nAChR) agonist and reversed by methyllycaconitine (MLA) selective alpha7 nAChR antagonist. In summary, these results suggested that AChR alpha7 subunit was involved in the antinociceptive action of CbTX for neuropathic pain and might be the candidate target for analgesic drug design. PMID- 25447770 TI - Natural mutations change the affinity of MU-theraphotoxin-Hhn2a to voltage-gated sodium channels. AB - MU-Theraphotoxin-Hhn2a (HNTX-III) isolated from the venom of the spider Ornithoctonus hainana is a selective antagonist of neuronal tetrodotoxin sensitive (TTX-S) voltage-gated sodium channels (VGSCs). Intriguingly, previous transcriptomic study revealed HNTX-III family consists of more than 15 precursors, in which the 20(th) and 24(th) residues of the mature sequences are variable. Try20 and Ser24 of HNTX-III are mutated to His20 and Asn24 of other members, respectively. In addition, the alkaline residue His26 of the potent VGSC inhibitor HNTX-III is substituted by acidic residue Asp of the weak VGSC inhibitor HNTX-I. Therefore, four mutants of HNTX-III, HNTX-III-Y20H, -S24N, H26D and -Y20H/24N, were synthesized to examine the effects of these natural mutations on the inhibitory activity of HNTX-III. They were subjected to an electrophysiological screening on five VGSC subtypes (Nav1.3-1.5, Nav1.7 and Nav1.8) expressed on HEK293 cells by whole-cell patch clamp. Like HNTX-III, all mutants only displayed inhibitory activity on Nav1.3 and Nav1.7 among the five subtypes, but the inhibitory potency was much lower than that of HNTX-III. Regarding Nav1.7, the IC50 values of HNTX-III-Y20H, -S24N, -H26D and -Y20H/S24N were increased by approximately 62-, 8.4-, 49- and 19.5-folds compared with that of HNTX-III, respectively. Similar data were obtained for Nav1.3. Our results provide new insights into the activity-related residues of HNTX-III at genic level. Furthermore, the reduced potency of the four mutants probably reflects natural selection might favor and reserve the most potent bioactivity of HNTX-III which is one of the most abundant fractions of the venom. PMID- 25447772 TI - The lethality test used for estimating the potency of antivenoms against Bothrops asper snake venom: pathophysiological mechanisms, prophylactic analgesia, and a surrogate in vitro assay. AB - The potency of antivenoms is assessed by analyzing the neutralization of venom induced lethality, and is expressed as the Median Effective Dose (ED50). The present study was designed to investigate the pathophysiological mechanisms responsible for lethality induced by the venom of Bothrops asper, in the experimental conditions used for the evaluation of the neutralizing potency of antivenoms. Mice injected with 4 LD50s of venom by the intraperitoneal route died within ~25 min with drastic alterations in the abdominal organs, characterized by hemorrhage, increment in plasma extravasation, and hemoconcentration, thus leading to hypovolemia and cardiovascular collapse. Snake venom metalloproteinases (SVMPs) play a predominat role in lethality, as judged by partial inhibition by the chelating agent CaNa2EDTA. When venom was mixed with antivenom, there was a venom/antivenom ratio at which hemorrhage was significantly reduced, but mice died at later time intervals with evident hemoconcentration, indicating that other components in addition to SVMPs also contribute to plasma extravasation and lethality. Pretreatment with the analgesic tramadol did not affect the outcome of the neutralization test, thus suggesting that prophylactic (precautionary) analgesia can be introduced in this assay. Neutralization of lethality in mice correlated with neutralization of in vitro coagulant activity in human plasma. PMID- 25447773 TI - Purification and characterization of two platelet-aggregation inhibitors, named angustatin and H-toxin TA(2), from the venom of Dendroaspis angusticeps. AB - Angustatin and H-toxin TA2 were purified from unfractionated Dendroaspis angusticeps venom (0.3 g) using S-Sepharose fast flow column chromatography, gelfiltration on a Sephadex G-50 column, and reverse-phase HPLC. The purified materials strongly inhibited ADP-induced platelet aggregation. The primary structure of angustatin was determined by the Edman degradation of peptides derived from digestions with endopeptidese Arg-C and alpha-chymotrypsin. Angustatin, which was composed of 59 amino acid residues and an RGD sequence, was identified as a short-length inhibitor similar to mambin, dendroaspin, echistatin, and eristicophin. Angustatin shared 83%, 17%, and 15% homologies with mambin, eristicophin, and echistatin, respectively. On the other hand, H-toxin TA2 did not conserve the RGD sequence in its structure; it was replaced for the Glu-Met-Leu sequence. Furthermore, the amino acid sequence of H-toxin TA2 corresponded to toxin TA2, excluding the amino acid residue of His28Arg. PMID- 25447775 TI - Phage display as a novel promising antivenom therapy: a review. AB - In this work, we present recent advances in the use of phage display technology for the preparation of antivenoms for animal toxin neutralization. Even though classical antivenoms have been used since the early 20th century, envenomation remains a global public health problem. Recently, the phage display technique has been used in an attempt to circumvent some of the difficulties associated with traditional preparations of antivenom. Here, we review studies that developed antibody fragments with potential inhibitory effects against animal toxins and discuss the most current technical issues and perspectives regarding phage display technology in this field. PMID- 25447774 TI - Inhibitory potential of three zinc chelating agents against the proteolytic, hemorrhagic, and myotoxic activities of Echis carinatus venom. AB - Viperbites undeniably cause local manifestations such as hemorrhage and myotoxicity involving substantial degradation of extracellular matrix (ECM) at the site of envenomation and lead to progressive tissue damage and necrosis. The principle toxin responsible is attributed to snake venom metalloproteases (SVMPs). Treatment of such progressive tissue damage induced by SVMPs has become a challenging task for researchers and medical practitioners who are in quest of SVMPs inhibitors. In this study, we have evaluated the inhibitory potential of three specific zinc (Zn(2+)) chelating agents; N,N,N',N'-tetrakis (2 pyridylmethyl) ethane-1,2-diamine (TPEN), diethylene triamine pentaacetic acid (DTPA), tetraethyl thiuram disulfide (TTD) on Echis carinatus venom (ECV) induced hemorrhage and myotoxicity. Amongst them, TPEN has high affinity for Zn(2+) and revealed potent inhibition of ECV metalloproteases (ECVMPs) in vitro (IC50: 6.7 MUM) compared to DTPA and TTD. The specificity of TPEN towards Zn(2+) was confirmed by spectral and docking studies. Further, TPEN, DTPA, and TTD completely blocked the hemorrhagic and myotoxic activities of ECV in a dose dependent manner upon co-injection; whereas, only TPEN successfully neutralized hemorrhage and myotoxicity following independent injection. Histological examinations revealed that TPEN effectively prevents degradation of dermis and basement membrane surrounding the blood vessels in mouse skin sections. TPEN also prevents muscle necrosis and accumulation of inflammatory cells at the site of ECV injections. In conclusion, a high degree of structural and functional homology between mammalian MMPs and SVMPs suggests that specific Zn(2+) chelators currently in clinical practice could be potent first aid therapeutic agents in snakebite management, particularly for local tissue damage. PMID- 25447776 TI - Detection of venom after antivenom administration is largely due to bound venom. AB - Detection of recurrent venom post-antivenom in snake envenoming is commonly reported and thought to be due to insufficient antivenom. However, relatively few reports of recurrence have venom measurement, and in most cases patients clinically improve, despite venom detected post-antivenom. We hypothesized that persistent or recurrent venom detection post-antivenom is due to detecting bound venom. Multiple (>4) serum samples were available from 255 Russell's viper (Daboia russelii) envenomed patients. Enzyme-linked immunosorbent assay was used to measure venom, antivenom and venom-antivenom (VAV) complexes. In 79/255 (31%) there was persistent/recurrent venom detected despite antivenom being present. In these post-antivenom samples, VAV was also detected at the same time as venom was detected. Anti-horse (aH) antiserum was bound to UltraLink (UL) resin and added to in vitro venom-antivenom mixtures, and 15 pre- and post-antivenom samples from patients. There was significantly less free venom detected in in vitro venom antivenom mixtures to which ULaH had been added compared to those without ULaH added. In 9 post-antivenom patient samples the addition of ULaH reduced venom detected by a median of 80% (69%-88%) compared to only 20% in four pre-antivenom samples. This suggests that the detection of persistent/recurrent venom post antivenom is due to bound and not free venom. PMID- 25447777 TI - [Acute fatty liver of pregnancy]. PMID- 25447779 TI - [Perioperative management of patients with systemic scleroderma]. AB - Systemic sclerosis (SSc) is an auto-immune disease characterized by vasculopathy and the combination of microangiopathy and tissue collagen deposit leading to skin, digestive, pulmonary, myocardial and renal injuries. These repercussions could be challenging for anesthesiologists and associated with difficulties in airway management, and occurrence of congestive right heart failure or acute kidney crisis. The aim of this review is to review the physiopathology and the progression of the SSc, as well as to provide a strategy of perioperative management of these patients. PMID- 25447778 TI - [Epidemiology of cerebral perioperative vascular accidents]. AB - OBJECTIVES: Stroke is a well-described postoperative complication, after carotid and cardiac surgery. On the contrary, few studies are available concerning postoperative stroke in general non-cardiac non-carotid surgery. The high morbid mortality of stroke justifies an extended analysis of recent literature. ARTICLE TYPE: Systematic review. DATA SOURCES: Firstly, Medline and Ovid databases using combination of stroke, cardiac surgery, carotid surgery, general non-cardiac non carotid surgery as keywords; secondly, national and European epidemiologic databases; thirdly, expert and French health agency recommendations; lastly, reference book chapters. RESULTS: In cardiac surgery, with an incidence varying from 1.2 to 10% according to procedure complexity, stroke occurs peroperatively in 50% of cases and during the first 48 postoperative hours for the others. The incidence of stroke after carotid surgery is 1 to 20% according to the technique used as well as operator skills. Postoperative stroke is a rare (0.15% as mean, extremes around 0.02 to 1%) complication in general surgery, it occurs generally after the 24-48th postoperative hours, exceptional peroperatively, and 40% of them occurring in the first postoperative week. It concerned mainly aged patient in high-risk surgeries (hip fracture, vascular surgery). Postoperative stroke was associated to an increase in perioperative mortality in comparison to non postoperative stroke operated patients. CONCLUSION: Postoperative stroke is a quality marker of the surgical teams' skill and has specific onset time and induces an increase of postoperative mortality. PMID- 25447780 TI - [Postoperative dissection of the vertebral artery in two steps]. AB - The diagnosis of perioperative vertebral artery dissection can be difficult because of non-specific clinical signs. We report a case revealed by a tegmento thalamic stroke after an abdominal second surgical look. The interest of this observation is related to a particular evolution in two steps separated by a 2 month-interval and an intercurrent cervical manipulation. After the second anesthesia, neck pain associated with a third cranial nerve palsy and a supranuclear ophtalmoplegia revealed a tegmento-thalamic ischemic stroke due to vertebral artery dissection. We discuss here the different factors possibly involved in the pathophysiology of postoperative vertebral artery dissection: positioning, cervical manipulation, subclavian central venous access and cisplatin toxicity. Vertebral artery dissection should be discussed in case of postoperative neck pain, especially with non-typical symptomatology. PMID- 25447781 TI - Production of biofuels and biochemicals by in vitro synthetic biosystems: Opportunities and challenges. AB - The largest obstacle to the cost-competitive production of low-value and high impact biofuels and biochemicals (called biocommodities) is high production costs catalyzed by microbes due to their inherent weaknesses, such as low product yield, slow reaction rate, high separation cost, intolerance to toxic products, and so on. This predominant whole-cell platform suffers from a mismatch between the primary goal of living microbes - cell proliferation and the desired biomanufacturing goal - desired products (not cell mass most times). In vitro synthetic biosystems consist of numerous enzymes as building bricks, enzyme complexes as building modules, and/or (biomimetic) coenzymes, which are assembled into synthetic enzymatic pathways for implementing complicated bioreactions. They emerge as an alternative solution for accomplishing a desired biotransformation without concerns of cell proliferation, complicated cellular regulation, and side product formation. In addition to the most important advantage - high product yield, in vitro synthetic biosystems feature several other biomanufacturing advantages, such as fast reaction rate, easy product separation, open process control, broad reaction condition, tolerance to toxic substrates or products, and so on. In this perspective review, the general design rules of in vitro synthetic pathways are presented with eight supporting examples: hydrogen, n-butanol, isobutanol, electricity, starch, lactate,1,3-propanediol, and poly-3 hydroxylbutyrate. Also, a detailed economic analysis for enzymatic hydrogen production from carbohydrates is presented to illustrate some advantages of this system and the remaining challenges. Great market potentials will motivate worldwide efforts from multiple disciplines (i.e., chemistry, biology and engineering) to address the remaining obstacles pertaining to cost and stability of enzymes and coenzymes, standardized building parts and modules, biomimetic coenzymes, biosystem optimization, and scale-up, soon. PMID- 25447782 TI - Current status and prospects of industrial bio-production of n-butanol in China. AB - n-Butanol is an important bulk chemical. Commercial fermentative production of n butanol has been applied more than 100 years ago but is currently more costly than production from propylene and syngas. Renewed interest in biobutanol as a biofuel has spurred technological advances to the fermentation process. This article reviewed the recent status including the commercialization, pilot production and R&D activities of n-butanol fermentation in China. Long-term bio production of n-butanol as a next generation biofuel and biochemical from biomass waste and steel mill off-gas needs technology breakthroughs and more environmental concerns from policymakers. PMID- 25447783 TI - Halophiles, coming stars for industrial biotechnology. AB - Industrial biotechnology aims to produce chemicals, materials and biofuels to ease the challenges of shortage on petroleum. However, due to the disadvantages of bioprocesses including energy consuming sterilization, high fresh water consumption, discontinuous fermentation to avoid microbial contamination, highly expensive stainless steel fermentation facilities and competing substrates for human consumption, industrial biotechnology is less competitive compared with chemical processes. Recently, halophiles have shown promises to overcome these shortcomings. Due to their unique halophilic properties, some halophiles are able to grow in high pH and high NaCl containing medium under higher temperature, allowing fermentation processes to run contamination free under unsterile conditions and continuous way. At the same time, genetic manipulation methods have been developed for halophiles. So far, halophiles have been used to produce bioplastics polyhydroxyalkanoates (PHA), ectoines, enzymes, and bio-surfactants. Increasing effects have been made to develop halophiles into a low cost platform for bioprocessing with advantages of low energy, less fresh water consumption, low fixed capital investment, and continuous production. PMID- 25447784 TI - 3.0T, time-resolved, 3D flow-sensitive MR in the thoracic aorta: Impact of k-t BLAST acceleration using 8- versus 32-channel coil arrays. AB - PURPOSE: To evaluate the performance of 4D flow MR in the thoracic aorta with 8- and 32-channel coil arrays using k-t BLAST and SENSE acceleration techniques and compare this to a conventional 2D SENSE approach. MATERIALS AND METHODS: Fifteen healthy subjects and eight patients underwent magnetic resonance imaging (MRI) at 3.0T using: 1) 2D SENSE phase contrast velocity mapping as the reference standard and 2) 4D-flow pulse sequences accelerated with SENSE and k-t BLAST, using both 8 and 32-channel coil arrays. Data processing was performed using GT Flow. Image quality of the magnitude images and pathline visualization were graded and mean scan times, flow, peak velocity, stroke volume, and image quality were compared between techniques. RESULTS: Mean scan times were significantly lower for 4D-flow sequences accelerated with k-t BLAST compared to SENSE (5.5 vs. 25.2 min; P < 0.01). 4D k-t BLAST acquisition had greater magnitude and pathline image quality than 4D SENSE acquisition for both 32-channel and 8-channel data (P < 0.001); both 4D SENSE and 4D k-t BLAST acquisitions had significantly greater image quality when 32 channels were utilized compared to 8 (P < 0.05). On Bland-Altman analysis, all 4D flow pulse sequences showed significant agreement with the 2D SENSE reference for peak velocity measurement (P > 0.05); the lowest bias being observed with the 4D 32 channel k-t BLAST sequence. There were no significant differences in measured flow, peak velocity, or stroke volume with any of the four investigated 4D acquisition techniques compared to reference technique values (P > 0.05). In patients, there were no significant differences in flow, peak velocity, or stroke volume measurements between 32-channel 4D k-t BLAST and the reference acquisition. CONCLUSION: 4D flow MR using k-t BLAST and 32 channel coils allows a reduction in total scan time while improving overall image quality compared to a standard 2D SENSE and 4D SENSE acquisitions. The use of 32 channels rather than 8 channels with the 4D k-t BLAST was also preferable in terms of image quality. PMID- 25447785 TI - Isolating EGFR Overexpressing Carcinoma Cells from Human Whole Blood by Bio Ferrography. AB - Background: The epidermal growth factor receptor (EGFR) is overexpressed in carcinoma. In some cases, including in colorectal cancer, it is used as a therapeutic target. Bio-Ferrography is a non-destructive method for isolating magnetized cells and tissues from a fluid onto a glass slide based on their interaction with an external, strong and focused magnetic field. Methods: Here, we implement Bio-Ferrography to separate EGFR positive cancer cells from EGFR negative non-cancer cells, mixed at a ratio of 1 to 1 * 106 , from either PBS or human whole blood (HWB). Incubation of the cells with an anti-EGFR antibody and magnetic microbeads coupled to a secondary antibody was used to magnetize the target cells prior to the ferrographic analysis. Results: A procedure was developed for "a proof of concept" isolation. Recovery values as high as 78% for 1 mL PBS, and 53% for 1 mL HWB, with a limit of detection (LOD) of 30 and 100 target cells, respectively, were achieved. Conclusions: These capture efficiency values are considered significant and therefore warrant further study on isolation of real circulating tumor cells (CTCs) from blood samples of patients, aiming at early diagnosis of EGFR overexpressing tumor types. This article is protected by copyright. All rights reserved. PMID- 25447786 TI - Constructing a recombinant hyaluronic acid biosynthesis operon and producing food grade hyaluronic acid in Lactococcus lactis. AB - Hyaluronic acid (HA), a natural high molecular weight polysaccharide, is produced by Streptococcus zooepidemicus. However, Streptococcus has several drawbacks including its potential to produce exotoxins, so there is demand for an alternative HA source. Here, a recombinant HA biosynthesis operon, as well as the HA biosynthesis operon of S. zooepidemicus were introduced into L. lactis using the nisin-controlled expression system, respectively. HA was successfully synthesized by recombinant L. lactis. Furthermore, overexpression of the endogenous enzymes directing the synthesis of precursor sugars was effective at increasing HA production, and increasing the supply of UDP-activated monosaccharide donors aided synthesis of monodisperse HA polysaccharides. Besides GRAS host strain (L. lactis) and NICE system, the selecting marker (lacF gene) of the recombinant strain is also food grade. Therefore, HA produced by recombinant L. lactis overcomes the problems associated with Streptococcus and provides a source of food-grading HA appropriate for widespread biotechnological applications. PMID- 25447787 TI - Polytocus focus: Uterine position effect is dependent upon horn size. AB - Understanding the variability caused by uterine position effects in polytocus species, such as rats, may enhance prenatal animal models for the study of drug and environmental agents. The primiparous litters of 42 intact female Sprague Dawley rats were studied. Uterine position, fetal body weight, and fetal brain (wet) weight were recorded on gestation day (GD) 20 (GD 0=sperm positive). Uterine position effect for brain and body weight varied depending upon horn size. Furthermore, an inverse relationship between horn size (and, to a lesser extent, litter size) and fetal weight applied to both body and brain weight measures. There were no statistical differences in brain and body weights between the left and right uterine horns. The position of the uterine horn (left vs. right) and litter size did not influence the uterine position effect in the rat. Collectively, the present data suggest the presence of a significant uterine position effect. Prenatal differences based on uterine position provide an untapped opportunity to increase our understanding of developmental neurotoxicological and teratological studies that employ a polytocus species as an animal model. PMID- 25447788 TI - Fenofibrate reduces amyloidogenic processing of APP in APP/PS1 transgenic mice via PPAR-alpha/PI3-K pathway. AB - The peroxisome proliferator-activated receptor alpha (PPAR-alpha), a member of the family of ligand-activated nuclear hormone receptors, plays a relevant role in the development of Alzheimer's disease (AD). To better understand the role of PPAR-alpha in AD, we examined the ability of fenofibrate (a PPAR-alpha agonist) to regulate amyloid precursor protein (APP) processing in APP/PS1 transgenic mice. After intragastric administration of fenofibrate into 3-month-old APP/PS1 transgenic mice for 6 months, and the levels of relative proteins were quantified by quantitative reverse transcription-PCR, Western blotting and ELISA. We found that fenofibrate increased the expression of PPAR-alpha, and decreased beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) mRNA and protein levels, and also reduced soluble APPbeta (sAPPbeta) and amyloid-beta 42 (Abeta42) releases. However. fenofibrate did not modify the levels of APP and presenilin 1 (PS1). Furthermore, LY294002, the phosphoinositide 3-kinase (PI3-K) inhibitor, suppressed the effects of fenofibrate on BACE-1, sAPPbeta, and Abeta42, but not PPAR-alpha. Our data suggest that fenofibrate may reduce the amyloidogenic processing of APP in APP/PS1 transgenic mice via PPAR-alpha/PI3-K pathway. PMID- 25447790 TI - Embryological exposure to valproic acid disrupts morphology of the deep cerebellar nuclei in a sexually dimorphic way. AB - Autism spectrum disorders (ASD) is diagnosed in males at a much higher rate than females. For this reason, the majority of autism research has used male subjects exclusively. However; more recent studies using genetic sex as a factor find that the development of the male and female brain is differentially affected by ASD. That is, the natural sex-specific differences that exist between male and female brains lead to sexually dimorphic expressions of autism. Here we investigate the putative sexual dimorphism that exists in the deep cerebellar nuclei of male and female rats exposed to valproic acid (VPA) on embryological day 12.5. We find natural sex-specific differences in adult nucleus area, length, and estimated cell populations. Therefore VPA exposure during embryology creates some sex specific deficits such as higher cell counts in the VPA males and lower cell counts in the VPA females. At the same time, some effects of VPA exposure occur regardless of sex. That is, smaller nucleus area and length lead to truncated nuclei in both VPA males and females. These deficits are more pronounced in the VPA males suggesting that genetic sex could play a role in teratogenic susceptibility to VPA. Taken together our results suggests that VPA exposure induces sexually dimorphic aberrations in morphological development along a mediolateral gradient at a discrete region of the hindbrain approximate to rhombomere (R) 1 and 2. Sex-specific disruption of the local and long-range projections emanating from this locus of susceptibility could offer a parsimonious explanation for the brain-wide neuroanatomical variance reported in males and females with ASD. PMID- 25447789 TI - Nimodipine enhances neurite outgrowth in dopaminergic brain slice co-cultures. AB - Calcium ions (Ca(2+)) play important roles in neuroplasticity and the regeneration of nerves. Intracellular Ca(2+) concentrations are regulated by Ca(2+) channels, among them L-type voltage-gated Ca(2+) channels, which are inhibited by dihydropyridines like nimodipine. The purpose of this study was to investigate the effect of nimodipine on neurite growth during development and regeneration. As an appropriate model to study neurite growth, we chose organotypic brain slice co-cultures of the mesocortical dopaminergic projection system, consisting of the ventral tegmental area/substantia nigra and the prefrontal cortex from neonatal rat brains. Quantification of the density of the newly built neurites in the border region (region between the two cultivated slices) of the co-cultures revealed a growth promoting effect of nimodipine at concentrations of 0.1MUM and 1MUM that was even more pronounced than the effect of the growth factor NGF. This beneficial effect was absent when 10MUM nimodipine were applied. Toxicological tests revealed that the application of nimodipine at this higher concentration slightly induced caspase 3 activation in the cortical part of the co-cultures, but did neither affect the amount of lactate dehydrogenase release or propidium iodide uptake nor the ratio of bax/bcl-2. Furthermore, the expression levels of different genes were quantified after nimodipine treatment. The expression of Ca(2+) binding proteins, immediate early genes, glial fibrillary acidic protein, and myelin components did not change significantly after treatment, indicating that the regulation of their expression is not primarily involved in the observed nimodipine mediated neurite growth. In summary, this study revealed for the first time a neurite growth promoting effect of nimodipine in the mesocortical dopaminergic projection system that is highly dependent on the applied concentrations. PMID- 25447791 TI - High-performance liquid chromatographic column packings with different particle sizes: chromatographic behavior for the quality analysis of HuanglianShangqing pill. AB - The chromatographic separation of traditional Chinese medicines is still a highly challenging task in analytical science with respect to its hundreds and thousands of chemical compounds, while increase of separation efficiency can greatly improve the separation power of chromatographic column for traditional Chinese medicine. In this study, 13 bioactive components in HuanglianShangqing pill were selected as an index to optimize the separation conditions and evaluate the system suitability of three commercially available columns packed with 1.8, 3.5, and 5.0 MUm particles. The chromatographic separations were obtained by the most appropriate Eclipse Plus C18 column (100 * 2.1 mm, 3.5 MUm) within 45 min using gradient elution with aqueous-ammonium acetate (10 mmol/L, pH 5.0) and acetonitrile, at a flow rate of 0.3 mL/min and an operating temperature of 30 degrees C. The quality of HuanglianShangqing pill was assessed through combining simultaneous quantification of 13 compounds with fingerprint analysis. For the qualitative analysis, mass spectrometry was used to confirm the 13 compounds. All the validation data conformed to the acceptable requirements. For the fingerprint analysis, 32 peaks were selected as the common peaks at 254 nm to evaluate the similarities among HuanglianShangqing pills obtained from ten manufacturers. PMID- 25447792 TI - Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y) tetanus toxoid conjugate vaccine: systematic review and meta-analysis. AB - Meningococcal meningitis represents one of the leading cause of bacterial meningitis in developed countries. Among the thirteen described serogroups, only five are usually responsible of invasive infections making immunisation against multiple serogroups the best strategy to protect individuals from this disease. Herein we carried out a systematic review and meta-analysis, in accordance with the PRISMA statement, of the recently EU-licensed meningococcal ACWY-tetanus toxoid conjugate vaccine (MenACWY-TT). We included 15 randomised clinical trials, comparing MenACWY-TT and Men-PS (ten studies), MenACWY-TT and MenC-CRM197 (four studies) and MenACWY-TT and MenACWY-DT (one study). All studies included in the meta-analysis showed high immunogenicity for MenACWY-TT vaccines in all tested serogroups. Our results suggest that the MenACWY-TT vaccine is as immunogenic as the other commercial available meningococcal vaccines. PMID- 25447793 TI - The emerging role of redox-sensitive Nrf2-Keap1 pathway in diabetes. AB - The pathogenic processes involving in the development of diabetes range from autoimmune destruction of pancreatic beta-cells with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The major contributing factor for excessive beta-cell death includes oxidative stress mediated mitochondrial damage, which creates an imbalance in redox homeostasis. Yet, beta-cells have evolved adaptive mechanisms to endure a wide range of stress conditions to safeguard its potential functions. These include 'Nrf2/Keap1' pathway, a key cellular defense mechanism, to combat oxidative stress by regulating phase II detoxifying and antioxidant genes. During diabetes, redox imbalance provokes defective Nrf2-dependent signaling and compromise antioxidant capacity of the pancreas which turnout beta-cells to become highly vulnerable against various insults. Hence, identification of small molecule activators of Nrf2/Keap1 pathway remains significant to enhance cellular defense to overcome the burden of oxidative stress related disturbances. This review summarizes the molecular mechanism behind Nrf2 activation and the impact of Nrf2 activators in diabetes and its complications. PMID- 25447794 TI - Novel therapeutic approaches for diabetic nephropathy and retinopathy. AB - Diabetes mellitus is a chronic disease that in the long-term increases the microvascular and macrovascular degenerative complications thus being responsible for a large part of death associated with diabetes. During the years, while preventive care for diabetic patients has improved, the increase in the prevalence of diabetes worldwide is continuous. The detrimental effects of diabetes mellitus result in microvascular diseases, which recognize hyperglycemia as major determinant. A significant number of potential therapeutic targets for the treatment of diabetic microvascular complications have been proposed, but the encouraging results obtained in preclinical studies, have largely failed in clinical trials. Currently, the most successful strategy to prevent microvascular complications of diabetes is the intensive treatment of hyperglycemia or the normalization of glycometabolic control achieved with pancreatic and islet transplantation. In this review, we focus on the novel therapeutic targets to prevent the development and progression of diabetic nephropathy and retinopathy microvascular complications. PMID- 25447795 TI - Is narcolepsy a classical autoimmune disease? AB - Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness. It is caused by the loss of orexin producing neurons in the lateral hypothalamus. Current evidences suggest an autoimmune mediated process causing the specific loss of orexin neurons. The high association of the disease with the HLA DQB1*06:02, as well as the link with environmental factors and are important clues supporting this theory. Recently, the association between the occurrence of the disease and vaccination campaign after the 2009 H1N1 pandemic highlighted the importance to increase the knowledge in the Pandora box of the vaccines. This review discusses the last finding regarding the pathogenesis of the disease and its relationship with the H1N1 vaccines. PMID- 25447796 TI - New polyoxypregnane glycosides from the roots of Marsdenia tenacissima. AB - For the first time, a systematic phytochemical study was performed on the roots of Marsdenia tenacissima. Finally, sixteen new polyoxypregnane glycosides, marstenacissides A1-A7 (1-7) and marstenacissides B1-B9 (8-16), were isolated from M. tenacissima roots. The structures of these new compounds were established by various spectroscopic techniques, including 1D and 2D NMR spectroscopy and mass spectrometry. PMID- 25447798 TI - Genistein inhibits glucocorticoid amplification in adipose tissue by suppression of 11beta-hydroxysteroid dehydrogenase type 1. AB - Excess glucocorticoids promote visceral obesity, hyperlipidemia, and insulin resistance. The main regulator of intracellular glucocorticoid levels is 11beta hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which converts inactive glucocorticoids into bioactive forms such as cortisol in humans and corticosterone in rodents. Hexose-6-phosphate dehydrogenase (H6PD), which is colocalized with 11beta-HSD1 in the intralumen of the endoplasmic reticulum, supplies a crucial coenzyme, NADPH, for full reductase activity of 11beta-HSD1. Therefore, it is possible that inhibition of 11beta-HSD1 will become a considerable medical treatment for metabolic diseases including obesity and diabetes. Genistein, a soy isoflavone, has received attention for its therapeutic potential for obesity, diabetes, and cardiovascular disease, and has been proposed as a promising compound for the treatment of metabolic disorders. However, the mechanisms underlying the pleiotropic anti-obesity effects of genistein have not been fully clarified. Here, we demonstrate that genistein was able to inhibit 11beta-HSD1 and H6PD activities within 10 or 20min, in dose- and time-dependent manners. Inhibition of 11beta-HSD2 activity was not observed in rat kidney microsomes. The inhibition was not reversed by two estrogen receptor antagonists, tamoxifen and ICI182,780. A kinetic study revealed that genistein acted as a non-competitive inhibitor of 11beta-HSD1, and its apparent Km value for 11-dehydrocorticosterone was 0.5MUM. Genistein also acted as a non competitive inhibitor of H6PD, and its apparent Km values for G6P and NADP were 0.9 and 3.3MUM, respectively. These results suggest that genistein may exert its inhibitory effect by interacting with these enzymes. PMID- 25447799 TI - Diagnostic accuracy of a urine reagent strip to identify bacterial peritonitis in dogs with ascites. AB - The leukocyte esterase test pad on a urine dipstick has been used as a preliminary test for bacterial peritonitis in humans but has not previously been evaluated in dogs. Here, free abdominal fluid from 60 dogs was tested on the leukocyte esterase test pad and results were compared with culture and microscopic analysis. Depending on the 'gold standard' comparator, the dipstick had sensitivity of ~60-75%, specificity of ~91-92%, positive predictive value of ~69%, and negative predictive value of ~87-94%. Based on these data, it appears that the leukocyte esterase test pad is most useful for tentative identification of cases in which bacterial infection is unlikely. Therefore a negative test may aid in re-directing clinician attention to alternative diagnoses in dogs with free abdominal effusion, whereas a positive result implies the necessity for further diagnostic tests. PMID- 25447800 TI - Monocarboxylate transporter 1 is up-regulated in Caco-2 cells by the methionine precursor DL-2-hydroxy-(4-methylthio)butanoic acid. AB - The methionine precursor, DL-2-hydroxy-(4-methylthio)butanoic acid (HMTBA), is a synthetic source of dietary methionine, which is widely used as a poultry nutritional supplement. In the intestinal epithelium, HMTBA transport across the apical membrane is mediated by monocarboxylate transporter 1 (MCT1). The first step in biological utilisation of this methionine precursor is the stereospecific conversion of HMTBA to the corresponding keto acid. In the present study, the regulation of trans-epithelial HMTBA transport was investigated in Caco-2 cell monolayers. Differentiated Caco-2 cells were maintained under control conditions (apical compartment: 0.2 mmol/L L-methionine) or in a HMTBA-enriched medium (2 mmol/L HMTBA). The effect of culture on HMTBA transport was evaluated from apical and basolateral kinetic parameters. MCT1 and MCT4 immuno-localisation and gene expression were investigated by confocal microscopy and real-time quantitative RT PCR, respectively. The results indicated that apical MCT1 was up-regulated by exposure to HMTBA (1.4-fold increase in Vmax without changes in Km). Moreover, total monolayer MCT1 immunoreactivity increased 1.8-fold in HMTBA-supplemented cultures, this effect mainly being localised at the apical membrane. Functional and immuno-localisation data suggest involvement of MCT1 and MCT4 in basolateral HMTBA transport, although, in this case, no effect was observed for HMTBA enrichment. Molecular analysis confirmed MCT1 mRNA up-regulation (1.8-fold), with no effect on MCT4 mRNA expression. Thus, exposure to HMTBA up-regulates the trans epithelial transport of this methionine precursor by increasing the expression and the transport capacity of apical MCT1. PMID- 25447801 TI - Lameness and hock injuries improve on farms participating in an assessment program. AB - Lameness and hock injuries are recognized welfare and production problems in the dairy industry. The objective of this study was to describe changes in the prevalence of these ailments in 15 freestall herds in the Northeastern United States that participated in an on-farm assessment program. Prevalence was assessed in a high-producing pen in each herd. A confidential report was delivered to each of the farms showing prevalence in relation to other herds assessed within the same region. The average (+/-SD) period between visits was 11.5 +/- 4.4 months (range, 8-25 months). The prevalence of lameness decreased in most herds after the first assessment (mean difference +/- SE [range] = -17 +/- 4 % [-43 to 6]). An even larger improvement was seen in the prevalence of hock injuries with all farms showing a decrease (-38 +/- 6% [-1 to -87]). The degree of improvement observed at the second assessment was greatest for those farms that had higher lameness prevalence when first assessed, but this was not the case for hock injuries. The changes in prevalence of clinical lameness and overall hock lesions were, however, correlated (rho = 0.62). These results suggest that monitoring and reporting the prevalence of lameness and hock injuries to farmers can motivate changes in facilities and management targeted to address these ailments. PMID- 25447797 TI - Impact of physiological levels of chenodeoxycholic acid supplementation on intestinal and hepatic bile acid and cholesterol metabolism in Cyp7a1-deficient mice. AB - Mice deficient in cholesterol 7alpha-hydroxylase (Cyp7a1) have a diminished bile acid pool (BAP) and therefore represent a useful model for investigating the metabolic effects of restoring the pool with a specific BA. Previously we carried out such studies in Cyp7a1(-/-) mice fed physiological levels of cholic acid (CA) and achieved BAP restoration, along with an increased CA enrichment, at a dietary level of just 0.03% (w/w). Here we demonstrate that in Cyp7a1(-/-) mice fed chenodeoxycholic acid (CDCA) at a level of 0.06% (w/w), the BAP was restored to normal size and became substantially enriched with muricholic acid (MCA) (>70%), leaving the combined contribution of CA and CDCA to be <15%. This resulted in a partial to complete reversal of the main changes in cholesterol and BA metabolism associated with Cyp7a1 deficiency such as an elevated rate of intestinal sterol synthesis, an enhanced level of mRNA for Cyp8b1 in the liver, and depressed mRNA levels for Ibabp, Shp and Fgf15 in the distal small intestine. When Cyp7a1(-/-) and matching Cyp7a1(+/+) mice were fed a diet with added cholesterol (0.2%) (w/w), either alone, or also containing CDCA (0.06%) (w/w) or CA (0.03%) (w/w) for 18days, the hepatic total cholesterol concentrations (mg/g) in the Cyp7a1(-/ ) mice were 26.9+/-3.7, 16.4+/-0.9 and 47.6+/-1.9, respectively, vs. 4.9+/-0.4, 5.0+/-0.7 and 6.4+/-1.9, respectively in the corresponding Cyp7a1(+/+) controls. These data affirm the importance of using moderate levels of dietary BA supplementation to elicit changes in hepatic cholesterol metabolism through shifts in BAP size and composition. PMID- 25447803 TI - Risk factors associated with the onset of daptomycin non-susceptibility in Staphylococcus aureus infections in critically ill patients. PMID- 25447802 TI - Nicotinic, glutamatergic and dopaminergic synaptic transmission and plasticity in the mesocorticolimbic system: focus on nicotine effects. AB - Cigarette smoking is currently the leading cause of preventable deaths and disability throughout the world, being responsible for about five million premature deaths/year. Unfortunately, fewer than 10% of tobacco users who try to stop smoking actually manage to do so. The main addictive agent delivered by cigarette smoke is nicotine, which induces psychostimulation and reward, and reduces stress and anxiety. The use of new technologies (including optogenetics) and the development of mouse models characterised by cell-specific deletions of receptor subtype genes or the expression of gain-of-function nAChR subunits has greatly increased our understanding of the molecular mechanisms and neural substrates of nicotine addiction first revealed by classic electrophysiological, neurochemical and behavioural approaches. It is now becoming clear that various aspects of nicotine dependence are mediated by close interactions of the glutamatergic, dopaminergic and gamma-aminobutyric acidergic systems in the mesocorticolimbic system. This review is divided into two parts. The first provides an updated overview of the circuitry of the ventral tegmental area, ventral striatum and prefrontal cortex, the neurotransmitter receptor subtypes expressed in these areas, and their physiological role in the mesocorticolimbic system. The second will focus on the molecular, functional and behavioural mechanisms involved in the acute and chronic effects of nicotine on the mesocorticolimbic system. PMID- 25447805 TI - Recent developments in the management of persistent hypoxemia under veno-venous ECMO. PMID- 25447806 TI - Left upper lobe partial anomalous pulmonary venous return. PMID- 25447804 TI - Volume expansion in the first 4 days of shock: a prospective multicentre study in 19 French intensive care units. AB - PURPOSE: To describe the current practices of volume expansion in French intensive care units (ICU). METHODS: In 19 ICUs, we prospectively observed the prescription and monitoring practices of volume expansion in consecutive adult patients with shock [sustained hypotension and/or need of vasopressor therapy, associated with at least tachycardia and/or sign (s) of hypoperfusion]. Patients were included at the time of prescription of the first fluid bolus (FB). Thereafter, all the FBs administered during the 96 h following shock onset were surveyed. An FB was defined as an intravenous bolus of at least 100 ml of a blood volume expander intended to rapidly improve the patient's circulatory condition. RESULTS: We included 777 patients [age: 63 +/- 15 years; female gender: 274 (35 %); simplified acute physiology score II: 55.9 +/- 20.6; ICU length of stay: 6 days (interquartile range (IQR) 3-13); ICU mortality: 32.8 %] and surveyed 2,694 FBs. At enrolment mean arterial pressure was 63 mmHg (IQR 55-71). The most frequent triggers of FB were hypotension, low urine output, tachycardia, skin mottling and hyperlactataemia. Amount of fluid given at each FB was highly variable between centres. Crystalloids were used in 91 % (2,394/2,635) and synthetic colloids in 3.3 % (87/2,635) of FBs. Overall, clinicians used any kind of haemodynamic assessment (central venous pressure measurement, predictive indices of fluid responsiveness, echocardiography, cardiac output monitoring or a combination of these) in 23.6 % (635/2,694) of all FBs surveyed, with an important between-centre heterogeneity. CONCLUSIONS: High between-centre variability characterised all the aspects of FB prescription and monitoring, but overall haemodynamic exploration to help guide and monitor FB was infrequent. PMID- 25447807 TI - Damage control resuscitation using blood component therapy in standard doses has a limited effect on coagulopathy during trauma hemorrhage. AB - OBJECTIVE: To determine the effectiveness of blood component therapy in the correction of trauma-induced coagulopathy during hemorrhage. BACKGROUND: Severe hemorrhage remains a leading cause of mortality in trauma. Damage control resuscitation strategies target trauma-induced coagulopathy (TIC) with the early delivery of high-dose blood components such as fresh frozen plasma (FFP) and platelet transfusions. However, the ability of these products to correct TIC during hemorrhage and resuscitation is unknown. METHODS: This was an international prospective cohort study of bleeding trauma patients at three major trauma centers. A blood sample was drawn immediately on arrival and after 4, 8 and 12 packed red blood cell (PRBC) transfusions. FFP, platelet and cryoprecipitate use was recorded during these intervals. Samples were analyzed for functional coagulation and procoagulant factor levels. RESULTS: One hundred six patients who received at least four PRBC units were included. Thirty-four patients (32 %) required a massive transfusion. On admission 40 % of patients were coagulopathic (ROTEM CA5 <= 35 mm). This increased to 58 % after four PRBCs and 81 % after eight PRBCs. On average all functional coagulation parameters and procoagulant factor concentrations deteriorated during hemorrhage. There was no clear benefit to high-dose FFP therapy in any parameter. Only combined high-dose FFP, cryoprecipitate and platelet therapy with a high total fibrinogen load appeared to produce a consistent improvement in coagulation. CONCLUSIONS: Damage control resuscitation with standard doses of blood components did not consistently correct trauma-induced coagulopathy during hemorrhage. There is an important opportunity to improve TIC management during damage control resuscitation. PMID- 25447809 TI - Role of activated macrophages in experimental Fusarium solani keratitis. AB - Macrophages under the conjunctival tissue are the first line defender cells of the corneas. Elimination of these cells would lead to aggravation of fungal keratitis. To determine how the course of fungal keratitis would be altered after the activation of these macrophages, a murine model was achieved by intrastromal instillation of latex beads before the corneas were infected with Fusarium solani. The keratitis was observed and clinically scored daily. Infected corneas were homogenized for colony counts. The levels of the IL-12, IL-4, MPO, MIF and iNOS cytokines were measured in the corneas using real-time polymerase chain reactions and enzyme-linked immunosorbent assays. CD3+, CD4+ and CD8+ lymphocytes in the corneas, submaxillary lymph nodes and peripheral blood were detected using immunohistochemistry and flow cytometry, respectively. The latex bead-treated mice exhibited aggravated keratitis. Substantially increased macrophage and polymorphonuclear leukocyte infiltration was detected in the corneas, although few colonies were observed. There was a marked increase in the IL-12, IL-4, MPO, MIF and iNOS expression in the corneas. The numbers of CD3+, CD4+ and CD8+ lymphocytes and the CD4+/CD8+ ratio were significantly enhanced in the corneas and submaxillary lymph nodes. However, the number of CD4+ lymphocytes was decreased in the peripheral blood, while the number of CD8+ lymphocytes increased. Collectively, our data demonstrate that the activation of macrophages in the cornea may cause an excessive immune response. Macrophages appear to play a critical role in regulating the immune response to corneal infections with F. solani. PMID- 25447810 TI - Modeling multispecies biofilms including new bacterial species invasion. AB - A mathematical model for multispecies biofilm evolution based on continuum approach and mass conservation principles is presented. The model can describe biofilm growth dynamics including spatial distribution of microbial species, substrate concentrations, attachment, and detachment, and, in particular, is able to predict the biological process of colonization of new species and transport from bulk liquid to biofilm (or vice-versa). From a mathematical point of view, a significant feature is the boundary condition related to biofilm species concentrations on the biofilm free boundary. These data, either for new or for already existing species, are not required by this model, but rather can be predicted as results. Numerical solutions for representative examples are obtained by the method of characteristics. Results indicate that colonizing bacteria diffuse into biofilm and grow only where favorable environmental conditions exist for their development. PMID- 25447812 TI - Tree-like reticulation networks--when do tree-like distances also support reticulate evolution? AB - Hybrid evolution and horizontal gene transfer (HGT) are processes where evolutionary relationships may more accurately be described by a reticulated network than by a tree. In such a network, there will often be several paths between any two extant species, reflecting the possible pathways that genetic material may have been passed down from a common ancestor to these species. These paths will typically have different lengths but an 'average distance' can still be calculated between any two taxa. In this article, we ask whether this average distance is able to distinguish reticulate evolution from pure tree-like evolution. We consider two types of reticulation networks: hybridisation networks and HGT networks. For the former, we establish a general result which shows that average distances between extant taxa can appear tree-like, but only under a single hybridisation event near the root; in all other cases, the two forms of evolution can be distinguished by average distances. For HGT networks, we demonstrate some analogous but more intricate results. PMID- 25447811 TI - Population dynamics of intraguild predation in a lattice gas system. AB - In the system of intraguild predation (IGP) we are concerned with, species that are in a predator-prey relationship, also compete for shared resources (space or food). While several models have been established to characterize IGP, mechanisms by which IG prey and IG predator can coexist in IGP systems with spatial competition, have not been shown. This paper considers an IGP model, which is derived from reactions on lattice and has a form similar to that of Lotka Volterra equations. Dynamics of the model demonstrate properties of IGP and mechanisms by which the IGP leads to coexistence of species and occurrence of alternative states. Intermediate predation is shown to lead to persistence of the predator, while extremely big predation can lead to extinction of one/both species and extremely small predation can lead to extinction of the predator. Numerical computations confirm and extend our results. While empirical observations typically exhibit coexistence of IG predator and IG prey, theoretical analysis in this work demonstrates exact conditions under which this coexistence can occur. PMID- 25447808 TI - Pathophysiology of ocular surface squamous neoplasia. AB - The incidence of ocular surface squamous neoplasia (OSSN) is strongly associated with solar ultraviolet (UV) radiation, HIV and human papilloma virus (HPV). Africa has the highest incidence rates in the world. Most lesions occur at the limbus within the interpalpebral fissure particularly the nasal sector. The nasal limbus receives the highest intensity of sunlight. Limbal epithelial crypts are concentrated nasally and contain niches of limbal epithelial stem cells in the basal layer. It is possible that these are the progenitor cells in OSSN. OSSN arises in the basal epithelial cells spreading towards the surface which resembles the movement of corneo-limbal stem cell progeny before it later invades through the basement membrane below. UV radiation damages DNA producing pyrimidine dimers in the DNA chain. Specific CC -> TT base pair dimer transformations of the p53 tumour-suppressor gene occur in OSSN allowing cells with damaged DNA past the G1-S cell cycle checkpoint. UV radiation also causes local and systemic photoimmunosuppression and reactivates latent viruses such as HPV. The E7 proteins of HPV promote proliferation of infected epithelial cells via the retinoblastoma gene while E6 proteins prevent the p53 tumour suppressor gene from effecting cell-cycle arrest of DNA-damaged and infected cells. Immunosuppression from UV radiation, HIV and vitamin A deficiency impairs tumour immune surveillance allowing survival of aberrant cells. Tumour growth and metastases are enhanced by; telomerase reactivation which increases the number of cell divisions a cell can undergo; vascular endothelial growth factor for angiogenesis and matrix metalloproteinases (MMPs) that destroy the intercellular matrix between cells. Despite these potential triggers, the disease is usually unilateral. It is unclear how HPV reaches the conjunctiva. PMID- 25447813 TI - Effect of obesity on the reliability of age-at-death indicators of the pelvis. AB - During medicolegal investigations, forensic anthropologists commonly use morphological changes in the auricular surface of the ilium and the symphyseal face of the pubis to estimate age. However, obesity may impact the reliability of age estimations based on pelvic joints. Over the past several decades, the prevalence of obesity has dramatically increased in the United States (US). Since the rate of progression through age-related stages of weight-bearing joints may be influenced by excessive body mass, it is important that anthropologists understand how obesity affects age-related morphological changes in the skeleton. This study investigates the effects of obesity on the validity of the estimated age-at-death based on the Buckberry-Chamberlin and Suchey-Brooks methods by comparing US adults considered normal BMI (BMI 18.5-24.9) and obese (BMI >= 30). The obese group exhibits overall greater bias (overestimation of age) and inaccuracy, less precision, and lower correlations between estimated and known age than the normal BMI group using both methods, although differences in the pubic symphysis are not statistically significant. For the auricular surface the age of transition from one phase to the next is lower and the standard deviations are greater for the obese as compared to normal weight individuals. This study helps to elucidate how obesity affects the rate of age-related skeletal change of the human pelvis, and shows that the pubic symphysis may be a more reliable indicator of age in obese individuals and that greater standard deviations are needed for obese individuals when estimating age-at-death from the pelvis. PMID- 25447814 TI - Tellurite-mediated damage to the Escherichia coli NDH-dehydrogenases and terminal oxidases in aerobic conditions. AB - Escherichia coli exposed to tellurite shows augmented membrane lipid peroxidation and ROS content. Also, reduced thiols, protein carbonylation, [Fe-S] center dismantling, and accumulation of key metabolites occur in these bacteria. In spite of this, not much is known about tellurite effects on the E. coli electron transport chain (ETC). In this work, tellurite-mediated damage to the E. coli ETC's NADH dehydrogenases and terminal oxidases was assessed. Mutant lacking ETC components showed delayed growth, decreased oxygen consumption and increased ROS in the presence of the toxicant. Membranes from tellurite-exposed E. coli exhibited decreased oxygen consumption and dNADH/NADH dehydrogenase activity, showing an impairment of NDH-I but not of NDH-II activity. Regarding terminal oxidases, only the bo oxidase complex was affected by tellurite. When assaying NDH-I and NDH-II activity in the presence of superoxide, the NDH-I complex was preferentially damaged. The activity was partly restored in the presence of reducing agents, sulfide and Fe(2+) under anaerobic conditions, suggesting that damage affects NDH-I [4Fe-4S] centers. Finally, augmented membrane protein oxidation along with reduced oxidase activity was observed in the presence of the toxicant. Also, the increased expression of genes encoding alternative terminal oxidases probably reflects a cell's change towards anaerobic respiration when facing tellurite. PMID- 25447816 TI - The contribution of activating transcription factor 3 to apoptosis of human colorectal cancer cells by protocatechualdehyde, a naturally occurring phenolic compound. AB - Protocatechualdehyde (PCA) is one of the important compounds found in barley, green cavendish bananas and grapevine leaves. PCA shows anti-cancer activities in breast, leukemia and colorectal cancer cells. Previous study reported that PCA exerts anti-cancer activity through down-regulating cyclin D1 and HDAC2 in human colorectal cancer cells. However, the underlying mechanisms for the expression of activating transcription factor 3 (ATF3) by PCA has not been studied. Thus, we performed in vitro study to investigate if treatment of PCA affects ATF3 expression and ATF3-mediated apoptosis in human colorectal cancer cells. PCA decreased cell viability in a dose-dependent manner in HCT116 and SW480 cells. In addition, PCA reduced cell viability in MCF-7, MDA-MB-231 and HepG-2 cells. Exposure of PCA activated the levels of ATF3 protein and mRNA in HCT116 and SW480 cells. Inhibition of ERK1/2/ by PD98059 and p38 by SB203580 inhibited PCA-induced ATF3 expression and transcriptional activation. ATF3-knockdown inhibited PCA induced apoptosis and cell viability. In addition, ATF3 overexpression enhanced PCA-mediated cleavage of PARP. These findings suggest that inhibition of cell viability and apoptosis by PCA may be result of ATF3 expression through ERK1/2 and p38-mediated transcriptional activation. PMID- 25447817 TI - Characterization and identification of three novel aldo-keto reductases from Lodderomyces elongisporus for reducing ethyl 4-chloroacetoacetate. AB - Lodderomyces elongisporus LH703 isolated from soil samples contained three novel aldo-keto reductases (AKRs) (LEAKR 48, LEAKR 49, and LEAKR 50). The three enzymes were cloned, expressed, and purified to homogeneity for characterization. These three AKRs shared <40% amino acid identity with each other. LEAKR 50 was identified as a member of AKR3 family, whereas the other two LEAKRs were identified as members of two novel AKR families, respectively. All the three AKRs required nicotinamide adenine dinucleotide phosphate as a cofactor. However, they showed diverse characteristics, including optimum catalyzing conditions, resistance to adverse reaction conditions, and substrate specificity. LEAKR 50 was estimated to be a promising biocatalyst that could reduce ethyl 4 chloroacetoacetate with high enantiomeric excess (98% e. e.) and high activity residue under adverse conditions. PMID- 25447819 TI - Targeting prion propagation using peptide constructs with signal sequence motifs. AB - Synthetic peptides with sequences derived from the cellular prion protein (PrP(C)) unprocessed N-terminus are able to counteract the propagation of proteinase K resistant prions (PrP(Res), indicating the presence of the prion isoform of the prion protein) in cell cultures (Lofgren et al., 2008). The anti prion peptides have characteristics like cell penetrating peptides (CPPs) and consist of the prion protein hydrophobic signal sequence followed by a polycationic motif (residues KKRPKP), in mouse PrP(C) corresponding to residues 1 28. Here we analyze the sequence elements required for the anti-prion effect of KKRPKP-conjugates. Neuronal GT1-1 cells were infected with either prion strain RML or 22L. Variable peptide constructs originating from the mPrP1-28 sequence were analyzed for anti-prion effects, measured as disappearance of proteinase K resistant prions (PrP(Res)) in the infected cell cultures. We find that even a 5 amino acid N-terminal shortening of the signal peptide abolishes the anti-prion effect. We show that the signal peptide from PrP(C) can be replaced with the signal peptide from the Neural cell adhesion molecule-1; NCAM11-19, with a retained capacity to reduce PrP(Res) levels. The anti-prion effect is lost if the polycationic N-terminal PrP(C)-motif is conjugated to any conventional CPP, such as TAT48-60, transportan-10 or penetratin. We propose a mechanism by which a signal peptide from a secretory or cell surface protein acts to promote the transport of a prion-binding polycationic PrP(C)-motif to a subcellular location where prion conversion occurs (most likely the Endosome Recycling Compartment), thereby targeting prion propagation. PMID- 25447818 TI - Multiple UDP-glucuronosyltransferases in human liver microsomes glucuronidate both R- and S-7-hydroxywarfarin into two metabolites. AB - The widely used anticoagulant Coumadin (R/S-warfarin) undergoes oxidation by cytochromes P450 into hydroxywarfarins that subsequently become conjugated for excretion in urine. Hydroxywarfarins may modulate warfarin metabolism transcriptionally or through direct inhibition of cytochromes P450 and thus, UGT action toward hydroxywarfarin elimination may impact levels of the parent drugs and patient responses. Nevertheless, relatively little is known about conjugation by UDP-glucuronosyltransferases in warfarin metabolism. Herein, we identified probable conjugation sites, kinetic mechanisms and hepatic UGT isoforms involved in microsomal glucuronidation of R- and S-7-hydroxywarfarin. Both compounds underwent glucuronidation at C4 and C7 hydroxyl groups based on elution properties and spectral characteristics. Their formation demonstrated regio- and enantioselectivity by UGTs and resulted in either Michaelis-Menten or substrate inhibition kinetics. Glucuronidation at the C7 hydroxyl group occurred more readily than at the C4 group, and the reaction was overall more efficient for R-7 hydroxywarfarin due to higher affinity and rates of turnover. The use of these mechanisms and parameters to model in vivo clearance demonstrated that contributions of substrate inhibition would lead to underestimation of metabolic clearance than that predicted by Michaelis-Menten kinetics. Lastly, these processes were driven by multiple UGTs indicating redundancy in glucuronidation pathways and ultimately metabolic clearance of R- and S-7-hydroxywarfarin. PMID- 25447820 TI - Heat shock protein 20 (HSPB6) regulates TNF-alpha-induced intracellular signaling pathway in human hepatocellular carcinoma cells. AB - We previously demonstrated that the expression of HSP20, a small heat shock protein, is inversely correlated with the progression of HCC. Inflammation is associated with HCC, and numerous cytokines, including TNF-alpha, act as key mediators in the progression of HCC. In the present study, we investigated whether HSP20 is implicated in the TNF-alpha-stimulated intracellular signaling in HCC using human HCC-derived HuH7 cells in the presence of TNF-alpha. In HSP20 overexpressing HCC cells, the cell growth was retarded compared with that in the control cells under long-term exposure of TNF-alpha. Because NF-kappaB pathway is the main intracellular signaling system activated by TNF-alpha, we investigated the effects of HSP20-overexpression of this pathway. The protein levels of IKK alpha, but not IKK-beta, in the HSP20-overexpressing cells were decreased. Short term exposure to TNF-alpha-induced phosphorylation and degradation of IkappaB, and the phosphorylation and transactivational activity of NF-kappaB were suppressed in the HSP20-overexpressing HCC cells. Furthermore, the increase in IKK-alpha levels was accompanied by a decrease in the HSP20 levels in human HCC tissues. These findings strongly suggest that HSP20 might decrease the IKK-alpha protein level and that it down-regulates the TNF-alpha-stimulated intracellular signaling in HCC, thus resulting in the suppression of HCC progression. PMID- 25447821 TI - Leukotriene signaling in the extinct human subspecies Homo denisovan and Homo neanderthalensis. Structural and functional comparison with Homo sapiens. AB - Mammalian lipoxygenases (LOXs) have been implicated in cell differentiation and in the biosynthesis of pro- and anti-inflammatory lipid mediators. The initial draft sequence of the Homo neanderthalensis genome (coverage of 1.3-fold) suggested defective leukotriene signaling in this archaic human subspecies since expression of essential proteins appeared to be corrupted. Meanwhile high quality genomic sequence data became available for two extinct human subspecies (H. neanderthalensis, Homo denisovan) and completion of the human 1000 genome project provided a comprehensive database characterizing the genetic variability of the human genome. For this study we extracted the nucleotide sequences of selected eicosanoid relevant genes (ALOX5, ALOX15, ALOX12, ALOX15B, ALOX12B, ALOXE3, COX1, COX2, LTA4H, LTC4S, ALOX5AP, CYSLTR1, CYSLTR2, BLTR1, BLTR2) from the corresponding databases. Comparison of the deduced amino acid sequences in connection with site-directed mutagenesis studies and structural modeling suggested that the major enzymes and receptors of leukotriene signaling as well as the two cyclooxygenase isoforms were fully functional in these two extinct human subspecies. PMID- 25447823 TI - Antibacterial properties of laser spinning glass nanofibers. AB - A laser-spinning technique has been used to produce amorphous, dense and flexible glass nanofibers of two different compositions with potential utility as reinforcement materials in composites, fillers in bone defects or scaffolds (3D structures) for tissue engineering. Morphological and microstructural analyses have been carried out using SEM-EDX, ATR-FTIR and TEM. Bioactivity studies allow the nanofibers with high proportion in SiO2 (S18/12) to be classified as a bioinert glass and the nanofibers with high proportion of calcium (ICIE16) as a bioactive glass. The cell viability tests (MTT) show high biocompatibility of the laser spinning glass nanofibers. Results from the antibacterial activity study carried out using dynamic conditions revealed that the bioactive glass nanofibers show a dose-dependent bactericidal effect on Sthaphylococcus aureus (S. aureus) while the bioinert glass nanofibers show a bacteriostatic effect also dose dependent. The antibacterial activity has been related to the release of alkaline ions, the increase of pH of the medium and also the formation of needle-like aggregates of calcium phosphate at the surface of the bioactive glass nanofibers which act as a physical mechanism against bacteria. The antibacterial properties give an additional value to the laser-spinning glass nanofibers for different biomedical applications, such as treating or preventing surgery-associated infections. PMID- 25447822 TI - Intermolecular interactions between salmon calcitonin, hyaluronate, and chitosan and their impact on the process of formation and properties of peptide-loaded nanoparticles. AB - The principal aim of this work was to study the formulation of a ternary complex comprising salmon calcitonin (sCT), hyaluronate (HA), and chitosan (CS) in a nanoparticle (NP) format. As interactions between the constituents are possible, their presence and component mass mixing ratio (MMR) and charge mixing ratio (CMR) were investigated to tune the properties of NPs. Intermolecular interactions between sCT and HA as well as sCT and CS were studied by infrared spectroscopy (FTIR) and dynamic viscosity. The impact of MMR, CMR, and HA molecular weight on the sCT loading capacity in NPs and in vitro release properties was determined. sCT complexes to HA via electrostatic interactions and a support for hydrophobic interactions between sCT and HA as well as sCT and CS was found by FTIR. The sCT/HA complex is soluble but, depending on the mass mixing ratio between sCT and HA, NPs and microparticles were also formed indicative of associative phase separation between HA and sCT. The negatively charged HA/CS/sCT NPs were characterized by very high values (above 90%) of peptide association for the systems tested. Also, high sCT loading up to 50% were achieved. The peptide loading capacity and in vitro release properties were dependent on the NP composition. The zeta potential of the NPs without sCT was negative and ranging from -136 to -36 mV, but increased to -84 to -19 mV when the peptide was loaded. The particle size was found to be smaller and ranging 150-230 nm for sCT/NPs in comparison to NPs without sCT (170-260 nm). Short-term storage studies in liquid dispersions showed that the colloidal stability of NPs was acceptable and no release of sCT was observed for up to 3 days. In conclusion, a range of NP systems comprising sCT, HA, and CS was successfully developed and characterized. Such NPs may be considered as a suitable nanoparticulate format for the delivery of sCT. PMID- 25447824 TI - Antisolvent precipitation of novel xylitol-additive crystals to engineer tablets with improved pharmaceutical performance. AB - The purpose of this work was to develop stable xylitol particles with modified physical properties, improved compactibility and enhanced pharmaceutical performance without altering polymorphic form of xylitol. Xylitol was crystallized using antisolvent crystallization technique in the presence of various hydrophilic polymer additives, i.e., polyethylene glycol (PEG), polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA) at a range of concentrations. The crystallization process did not influence the stable polymorphic form or true density of xylitol. However, botryoidal-shaped crystallized xylitols demonstrated different particle morphologies and lower powder bulk and tap densities in comparison to subangular-shaped commercial xylitol. Xylitol crystallized without additive and xylitol crystallized in the presence of PVP or PVA demonstrated significant improvement in hardness of directly compressed tablets; however, such improvement was observed to lesser extent for xylitol crystallized in the presence of PEG. Crystallized xylitols produced enhanced dissolution profiles for indomethacin in comparison to original xylitol. The influence of additive concentration on tablet hardness was dependent on the type of additive, whereas an increased concentration of all additives provided an improvement in the dissolution behavior of indomethacin. Antisolvent crystallization using judiciously selected type and concentration of additive can be a potential approach to prepare xylitol powders with promising physicomechanical and pharmaceutical properties. PMID- 25447825 TI - Stabilization of amorphous paracetamol based systems using traditional and novel strategies. AB - There is a special interest in having pharmaceutical active ingredients in the amorphous state due to their increased solubility and therefore, higher bioavailability. Nevertheless, not all of them present stable amorphous phases. In particular, paracetamol is an active ingredient widely known for its instability when prepared in the amorphous state. In the present work thermally stable amorphous binary paracetamol based systems were obtained showing stability on a wide range of temperatures: below its glass transition temperature (Tg) as amorphous solids in the glassy state and above their glass transition temperature, where these materials exist as stable supercooled liquids. To achieve stabilization of the binary paracetamol based system several strategies were applied and optimized, being the selection of the container material a key and novel approach to control the mechanical stress during cooling, eliminating cracks which act as nucleation centers leading to crystallization. PMID- 25447815 TI - Mitochondrial maintenance failure in aging and role of sexual dimorphism. AB - Gene expression changes during aging are partly conserved across species, and suggest that oxidative stress, inflammation and proteotoxicity result from mitochondrial malfunction and abnormal mitochondrial-nuclear signaling. Mitochondrial maintenance failure may result from trade-offs between mitochondrial turnover versus growth and reproduction, sexual antagonistic pleiotropy and genetic conflicts resulting from uni-parental mitochondrial transmission, as well as mitochondrial and nuclear mutations and loss of epigenetic regulation. Aging phenotypes and interventions are often sex-specific, indicating that both male and female sexual differentiation promote mitochondrial failure and aging. Studies in mammals and invertebrates implicate autophagy, apoptosis, AKT, PARP, p53 and FOXO in mediating sex-specific differences in stress resistance and aging. The data support a model where the genes Sxl in Drosophila, sdc-2 in Caenorhabditis elegans, and Xist in mammals regulate mitochondrial maintenance across generations and in aging. Several interventions that increase life span cause a mitochondrial unfolded protein response (UPRmt), and UPRmt is also observed during normal aging, indicating hormesis. The UPRmt may increase life span by stimulating mitochondrial turnover through autophagy, and/or by inhibiting the production of hormones and toxic metabolites. The data suggest that metazoan life span interventions may act through a common hormesis mechanism involving liver UPRmt, mitochondrial maintenance and sexual differentiation. PMID- 25447827 TI - Genetic diversity of Dirofilaria spp. isolated from subcutaneous and ocular lesions of human patients in Ukraine. AB - This short communication describes the phylogenetic analysis of 48 Dirofilaria worms isolated from human patients in Ukraine. 102 cases were both of subcutaneous (47; 46.1%) and ocular (54; 52.9%) locations. Worms from 44 patients (15 subcutaneous and 29 ocular) were subjected to DNA extraction and amplification of a specific fragment of the 12S rRNA subunit, and sequences were used for phylogenetic analysis. Results showed that 13.8% of the ocular cases analyzed at molecular level were caused by Dirofilaria immitis. Very few cases of ocular human dirofilariosis due to D. immitis have been described in the literature to date, majority of them attributed to Dirofilaria repens. Our results show that ocular dirofilariosis cannot be excluded in areas of low endemicity for D. repens were D. immitis is also present. PMID- 25447826 TI - Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection. AB - AR-12 has been evaluated in clinical trials as an anti-cancer agent but also has demonstrated host-directed, broad-spectrum clearance of bacteria. We have previously shown that AR-12 has activity in vitro against Salmonella enterica serovar Typhimurium and Francisella species by inducing autophagy and other host immune pathways. AR-12 treatment of S. Typhimurium-infected mice resulted in a 10 fold reduction in bacterial load in the liver and spleen and an increased survival time. However, AR-12 treatment did not protect mice from death, likely due poor formulation. In the current study, AR-12 was encapsulated in a microparticulate carrier formulated from the novel degradable biopolymer acetalated dextran (Ace-DEX) and subsequently evaluated for its activity in human monocyte-derived macrophages (hMDMs). Our results show that hMDMs efficiently internalized Ace-DEX microparticles (MPs), and that encapsulation significantly reduced host cell cytotoxicity compared to unencapsulated AR-12. Efficient macrophage internalization of AR-12 loaded MPs (AR-12/MPs) was further demonstrated by autophagosome formation that was comparable to free AR-12 and resulted in enhanced clearance of intracellular Salmonella. Taken together, these studies provide support that Ace-DEX encapsulated AR-12 may be a promising new therapeutic agent to control intracellular bacterial pathogens of macrophages by targeting delivery and reducing drug toxicity. PMID- 25447828 TI - First overview of the Culicoides Latreille (Diptera: Ceratopogonidae) livestock associated species of Reunion Island, Indian Ocean. AB - This study establishes the first faunistic inventory of livestock associated Culicoides (Diptera: Ceratopogonidae) species of Reunion Island (Indian Ocean), where bluetongue and epizootic hemorrhagic disease are regularly recorded. Single night-catches were performed at 41 sites using light suction traps at altitudes ranging from 0 to 1525 m, from March to April 2005. Five species were recorded: Culicoides imicola, Culicoides bolitinos, Culicoides enderleini, Culicoides grahamii, and Culicoides kibatiensis, among which at least the first three species are known to be involved in virus transmission to ruminants and equids. This is the first record of C. bolitinos, C. kibatiensis, and C. enderleini on the island. C. imicola was the most abundant species along the sea coast. C. bolitinos was more abundant inland and on two sites on the east coast. C. kibatiensis and C. grahamii were less abundant than the other three species and limited to two foci. Spatial distribution analysis of the different species showed that C. bolitinos, C. enderleini and C. imicola were collected at low altitudes, while the other two species were found at higher altitude. A morphological identification key for adult females and males is given, as well as cytochrome oxydase subunit I sequences. Phylogenetic reconstructions showed a clear divergence between C. bolitinos from Reunion Island and mainland Africa. This monograph will help to identify the Culicoides species in the poorly known entomological fauna of the south-western Indian Ocean region. PMID- 25447829 TI - Application of real-time PCR for the detection of Strongyloides spp. in clinical samples in a reference center in Spain. AB - Strongyloidiasis is one of the major intestinal helminthic infections in humans with a worldwide distribution, affecting especially tropical and subtropical regions. This disease can occur without any symptoms or as a potentially fatal hyperinfection or disseminated infection. Definitive diagnosis of Strongyloides stercoralis infection relies mainly on demonstration of larvae in stool, but at present there is no gold standard for this diagnosis. Our main objective was to evaluate a real-time PCR targeting the 18S rRNA gene of Strongyloides spp. and to compare it with routine parasitological methods. DNA from Strongyloides venezuelensis was used to optimize PCR protocols obtaining an analytical sensitivity of 0.1 pg of parasite DNA per sample. Sensitivity and specificity of real-time PCR on fecal samples from 231 patients screened for suspected strongyloidiasis attending two hospitals in Madrid were 93.8% and 86.5%, respectively. No significant differences were found when comparing Ct-values of positive PCR between parasitological positive and negative samples. This study showed that real-time PCR is an effective tool for diagnosing strongyloidiasis and could be applied in association with parasitological methods in epidemiological studies in endemic areas. It would be also important to assess its performance in immunocompromised populations who are at risk of fatal disease. PMID- 25447830 TI - Microcavia australis (Caviidae, Rodentia), a new highly competent host of Trypanosoma cruzi I in rural communities of northwestern Argentina. AB - Rodents are well-known hosts of Trypanosoma cruzi but little is known on the role of some caviomorph rodents. We assessed the occurrence and prevalence of T. cruzi infection in Microcavia australis ("southern mountain, desert or small cavy") and its infectiousness to the vector Triatoma infestans in four rural communities of Tafi del Valle department, northwestern Argentina. Parasite detection was performed by xenodiagnosis and polymerase chain reaction amplification of the hyper-variable region of kinetoplast DNA minicircles of T. cruzi (kDNA-PCR) from blood samples. A total of 51 cavies was captured in traps set up along cavy paths in peridomestic dry-shrub fences located between 25 and 85 m from the nearest domicile. We document the first record of M. australis naturally infected by T. cruzi. Cavies presented a very high prevalence of infection (46.3%; 95% confidence interval, CI=33.0-59.6%). Only one (4%) of 23 cavies negative by xenodiagnosis was found infected by kDNA-PCR. TcI was the only discrete typing unit identified in 12 cavies with a positive xenodiagnosis. The infectiousness to T. infestans of cavies positive by xenodiagnosis or kDNA-PCR was very high (mean, 55.8%; CI=48.4-63.1%) and exceeded 80% in 44% of the hosts. Cavies are highly competent hosts of T. cruzi in peridomestic habitats near human dwellings in rural communities of Tucuman province in northwestern Argentina. PMID- 25447831 TI - Characterization of a Trichinella spiralis 31 kDa protein and its potential application for the serodiagnosis of trichinellosis. AB - The Trichinella spiralis 31 kDa protein (Ts31) was screened from the excretory secretory (ES) proteins of muscle larvae (ML) by immunoproteomics using serum from mice infected with T. spiralis at 18 days post infection (dpi). The aim of this study was to characterize the Ts31 protein and to evaluate the potential of the recombinant Ts31 protein (rTs31) for serodiagnosis of human trichinellosis. Ts31 gene was cloned and rTs31 was produced in an E. coli expression system. An anti-rTs31serum recognized the native protein migrating in a 25-55 kDa range by Western blotting of ML crude or ES antigens. Expression of Ts31 gene was observed at all developmental stages of T. spiralis (adult worms, newborn larvae, pre encapsulated larvae and ML). An immunolocalization analysis identified Ts31 in the cuticle and stichocytes of the parasite. The sensitivity of rTs31-ELISA and ES antigen ELISA for detecting anti-Trichinella IgG antibodies in sera of patients with trichinellosis was 97.83% (45/46) and 86.78% (39/46), respectively (P>0.05); The specificity of rTs31-ELISA was 99.13% (114/115), which was significantly higher than 85.22% (98/115) of ES antigen ELISA (P<0.01). The rTs31 protein of T. spiralis could be considered as a potential diagnostic antigen for trichinellosis. PMID- 25447832 TI - New microsatellite markers for multi-scale genetic studies on Phlebotomus ariasi Tonnoir, vector of Leishmania infantum in the Mediterranean area. AB - The population structure of Phlebotomus ariasi, a proven vector of Leishmania infantum in the Mediterranean area, is still poorly understood. Previously, only two microsatellite loci had been developed to study the population genetics of this species. Herein we use these loci and determined fourteen novel microsatellite loci, useful for the characterization of P. ariasi populations. These loci were tested on three populations of P. ariasi, two from France and one from Portugal. In addition, the usefulness of these markers was also evaluated on seven other sandfly species. We show, that for P. ariasi, 15 of the 16 loci selected were polymorphic, with a mean of 4.25 alleles and an observed heterozygosity of 0.299. Within the P. ariasi population of France, 11 loci were polymorphic, with an average of 2.44 alleles and an observed heterozygosity of 0.2177. The fixation index was moderate among the French populations but high between French and Portuguese populations. In addition, eight loci were also found to be amplifiable in six other Phlebotomus species. These results demonstrate the usefulness of this new set of microsatellite loci for population structure and molecular ecology studies of P. ariasi at various spatial scales, but also of other sandfly species. PMID- 25447833 TI - Testicular cancer: Long-term outcomes of single BEP cycle. PMID- 25447834 TI - Prostate cancer: Integrated test predicts outcome. PMID- 25447836 TI - Kidney cancer: New genomic variation found. PMID- 25447835 TI - Prostate cancer: Identifying sites of recurrence with choline-PET-CT imaging. PMID- 25447837 TI - Characteristics of patient portals developed in the context of health information exchanges: early policy effects of incentives in the meaningful use program in the United States. AB - BACKGROUND: In 2014, the Centers for Medicare & Medicaid Services in the United States launched the second stage of its Electronic Health Record (EHR) Incentive Program, providing financial incentives to providers to meaningfully use their electronic health records to engage patients online. Patient portals are electronic means to engage patients by enabling secure access to personal medical records, communication with providers, various self-management tools, and administrative functionalities. Outcomes of patient portals have mainly been reported in large integrated health systems. This may now change as the EHR Incentive Program enables and supports the use of patient portals in other types of health systems. In this paper, we focus on Health Information Exchanges (HIE): entities that facilitate data exchange within networks of independent providers. OBJECTIVE: In response to the EHR Incentive Program, some Health Information Exchanges in the United States are developing patient portals and offering them to their network of providers. Such patient portals hold high value for patients, especially in fragmented health system contexts, due to the portals' ability to integrate health information from an array of providers and give patients one access point to this information. Our aim was to report on the early effects of the EHR incentives on patient portal development by HIEs. Specifically, we describe the characteristics of these portals, identify factors affecting adoption by providers during the 2013-2014 time frame, and consider what may be the primary drivers of providers' adoption of patient portals in the future. METHODS: We identified four HIEs that were developing patient portals as of spring 2014. We collected relevant documents and conducted interviews with six HIE leaders as well as two providers that were implementing the portals in their practices. We performed content analysis on these data to extract information pertinent to our study objectives. RESULTS: Our findings suggest that there are two primary types of patient portals available to providers in HIEs: (1) portals linked to EHRs of individual providers or health systems and (2) HIE-sponsored portals that link information from multiple providers' EHRs. The decision of providers in the HIEs to adopt either one of these portals appears to be a trade off between functionality, connectivity, and cost. Our findings also suggest that while the EHR Incentive Program is influencing these decisions, it may not be enough to drive adoption. Rather, patient demand for access to patient portals will be necessary to achieve widespread portal adoption and realization of potential benefits. CONCLUSIONS: Optimizing patient value should be the main principle underlying policies intending to increase online patient engagement in the third stage of the EHR Incentive Program. We propose a number of features for the EHR Incentive Program that will enhance patient value and thereby support the growth and sustainability of patient portals provided by Health Information Exchanges. PMID- 25447839 TI - The C-terminal region of the human p23 chaperone modulates its structure and function. AB - The p23 protein is a chaperone widely involved in protein homeostasis, well known as an Hsp90 co-chaperone since it also controls the Hsp90 chaperone cycle. Human p23 includes a beta-sheet domain, responsible for interacting with Hsp90; and a charged C-terminal region whose function is not clear, but seems to be natively unfolded. p23 can undergo caspase-dependent proteolytic cleavage to form p19 (p231-142), which is involved in apoptosis, while p23 has anti-apoptotic activity. To better elucidate the function of the human p23 C-terminal region, we studied comparatively the full-length human p23 and three C-terminal truncation mutants: p231-117; p231-131 and p231-142. Our data indicate that p23 and p19 have distinct characteristics, whereas the other two truncations behave similarly, with some differences to p23 and p19. We found that part of the C-terminal region can fold in an alpha-helix conformation and slightly contributes to p23 thermal stability, suggesting that the C-terminal interacts with the beta-sheet domain. As a whole, our results suggest that the C-terminal region of p23 is critical for its structure-function relationship. A mechanism where the human p23 C-terminal region behaves as an activation/inhibition module for different p23 activities is proposed. PMID- 25447838 TI - Effects of vitexin on the pharmacokinetics and mRNA expression of CYP isozymes in rats. AB - In traditional therapy with Chinese medicine, vitexin has several pharmacological properties, including antinociceptive, antispasmodic, antioxidant, antimyeloperoxidase, and alpha-glucosidase inhibitory activities. Recently, vitexin was shown to protect the heart against ischemia/reperfusion injury in an in vitro model by inhibiting apoptosis. The purpose of this study was to find out whether vitexin influences the effect on rat cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C11, and CYP3A1) by using cocktail probe drugs in vivo; the influence on the levels of CYP mRNA was also studied. A cocktail solution at a dose of 5 mL/kg, which contained phenacetin (10 mg/kg), tolbutamide (1 mg/kg), and midazolam (5 mg/kg), was given as oral administration to rats treated with short or long period of intravenous vitexin via the caudal vein. Blood samples were collected at a series of time points, and the concentrations of probe drugs in plasma were determined by HPLC-mass spectrometry (MS)/MS. The corresponding pharmacokinetic parameters were calculated by the software of DAS 2.0. In addition, real-time reverse transcription-polymerase chain reaction was performed to determine the effects of vitexin on the mRNA expression of CYP1A2, CYP2C11, and CYP3A1 in rat liver. Treatment with short or long period of vitexin had no effects on rat CYP1A2. However, CYP3A1 enzyme activity was inhibited by vitexin in a concentration-dependent and time-dependent manner. Furthermore, CYP2C11 enzyme activity was induced after short period treatment but inhibited after long period of vitexin treatment. The mRNA expression results were in accordance with the pharmacokinetic results. In conclusion, vitexin can either inhibit or induce activities of CYP2C11 and CYP3A1. Therefore, caution is needed when vitexin is co administered with some CYP2C11 or CYP3A1 substrates in clinic, which may result in treatment failure and herb-drug interactions. PMID- 25447840 TI - Membrane protein folding and stability. PMID- 25447841 TI - Isolation and characterization of a protease inhibitor from Acacia karroo with a common combining loop and overlapping binding sites for chymotrypsin and trypsin. AB - By using affinity and reversed-phase HPLC (RP-HPLC) chromatographies two chymotrypsin-trypsin inhibitors were isolated from seeds of Acacia karroo, a legume of the subfamily Mimosoideae. The primary structure of one of these inhibitors, named AkCI/1, was determined. The inhibitor consists of two polypeptide chains, 139 and 44 residues respectively, which are linked by a single disulfide bridge. The amino acid sequence of AkCI/1 is homologous to and showed more than 60% sequence similarity with other protease inhibitors isolated earlier from the group of Mimosoideae. AkCI/1 inhibits both chymotrypsin (EC 3.4.21.1) and trypsin (EC 3.4.21.4) in a 1:1M ratio with Ki values of 2.8 * 10( 12)M and 1.87 * 10(-12)M, respectively. The P1-P1' residues for trypsin were identified as Arg68-Ile69 by selective hydrolysis of the inhibitor at this site, with bovine trypsin and human trypsin IV. The cleavage did not affect the inhibition of trypsin, but fully abolished the chymotrypsin inhibitory activity of AkCI/1. This finding together with our studies on competition of the two enzymes for the same combining loop suggests that the same loop has to contain the binding sites for both proteases. The most likely P1 residue of AkCI/1 for chymotrypsin is Tyr67. PMID- 25447842 TI - Possible implications of Ni(II) on oral IL-1beta-induced inflammatory processes. AB - OBJECTIVES: Nickel (Ni) is one of the main metal elements in orthodontic and prosthetic devices. Different effects of Ni are described ranging from an induction of local inflammation to allergy and cancerous/mutagenic properties. Inflammatory reactions are frequently observed in the oral cavity, but the interrelationship of Ni with those events is still unknown. Therefore, we focused on the impact of Ni on inflammation in vitro. METHODS: In accordance to previous immersion tests of our lab, human gingival fibroblasts (HGFs) (n=6) were exposed to a pro-inflammatory environment using interleukin-1 beta (IL-1beta) and additionally stimulated with different Ni(II) concentrations (400 and 4000ng/ml). At varying time points the expression of pro- and anti-inflammatory as well as matrix degeneration proteins, i.e. MMPs, were analyzed. Furthermore, proliferation assays, wound healing tests and the detection of NF-kappaB activation were conducted. Unstimulated HGFs served as control. RESULTS: Our experiments showed that low clinical average Ni(II) levels did not alter pro inflammatory cytokines significantly compared to control (p>0.05). Instead, a 10 fold higher dose up-regulated these mediators significantly in a time-dependent manner (p<0.01). This was even more pronounced combining both Ni(II) concentrations with an inflammatory condition (p<0.001), MMP expressions were in line with our findings (p<0.001). The mRNA data were supported by proliferation and wound closure assays (p<0.001). However, the combination of both stimuli induced contradictory results. Analyzing NF-kappaB activation revealed that our results may be in part attributed to NF-kappaB. SIGNIFICANCE: Our in vitro study implicated that Ni(II) has various modifying effects on IL-1beta-induced inflammatory processes depending on the concentration. PMID- 25447843 TI - Characterization of urethane-dimethacrylate derivatives as alternative monomers for the restorative composite matrix. AB - OBJECTIVE: The aim was accomplished by a comparative analysis of the physicochemical properties of urethane-dimethacrylate (UDMA) monomers and their homopolymers with regard to the properties of basic dimethacrylates used presently in dentistry. The homologous series of UDMA were obtained from four oligoethylene glycols monomethacrylates (HEMA, DEGMMA, TEGMMA and TTEGMMA) and six diisocyanates (HMDI, TMDI, IPDI, CHMDI, TDI and MDI). METHODS: Photopolymerization was light-initiated with the camphorquinone/tertiary amine system. Monomers were tested for viscosity and density. Flexural strength, flexural modulus, hardness, water sorption and polymerization shrinkage of the polymers were studied. The glass transition temperature and the degree of conversion were also discussed. RESULTS: HEMA/IPDI appeared to be the most promising alternative monomer. The monomer exhibited a lower viscosity and achieved higher degree of conversion, the polymer had lower water sorption as well as higher modulus, glass temperature and hardness than Bis-GMA. The polymer of DEGMMA/CHMDI exhibited lower polymerization shrinkage, lower water sorption and higher hardness, however it exhibited lower modulus when compared to HEMA/TMDI. The remaining monomers obtained from HEMA were solids. Monomers with longer TEGMMA and TTEGMMA units polymerized to rubbery networks with high water sorption. The viscosity of all studied UDMA monomers was too high to be used as reactive diluents. SIGNIFICANCE: The systematic, comparative analysis of the homologous UDMA monomers and corresponding homopolymers along with their physico mechanical properties are essential for optimizing the design process of new components desirable in dental formulations. Some of the studied UDMA monomers may be simple and effective alternative dimethacrylate comonomers. PMID- 25447844 TI - Natural history and therapy of AL cardiac amyloidosis. AB - The natural history of immunoglobulin light chain associated amyloidosis (AL) is determined by the extent of cardiac involvement. Patients with cardiac AL and symptomatic heart failure have a median survival of approximately six months without successful treatment of the underlying plasma cell disorder The outcome in cardiac AL is determined by both the severity of cardiac involvement and the response to treatment. Staging systems using cardiac biomarkers, including NT- proBNP and troponin, have been found to be powerful predictors of prognosis and are used to guide treatment. Arrhythmias are common in cardiac AL and may lead to acute hemodynamic compromise. Sudden cardiac death, often due to pulseless electrical activity, is an important cause of early mortality. Supportive therapy for heart failure is usually limited to diuretics. Beta-blockers, ACE-inhibitors, and angiotensin receptor blockers are poorly tolerated in cardiac AL and should be avoided. Cardiac transplantation is controversial and reserved for highly selected patients with limited extracardiac involvement. The primary target of treatment in cardiac AL is obliteration of the plasma cell clone, using chemotherapy alone or combined with autologous stem cell transplantation. Despite the risk of early mortality, overall survival has improved with advances in disease modifying therapy. Earlier diagnosis and treatment of cardiac AL is crucial to improving survival. PMID- 25447845 TI - Mineralocorticoid receptor antagonists as diuretics: Can congestive heart failure learn from liver failure? AB - Despite significant improvements in diagnosis, understanding the pathophysiology and management of the patients with acute decompensated heart failure (ADHF), diuretic resistance, yet to be clearly defined, is a major hurdle. Secondary hyperaldosteronism is a pivotal factor in pathogenesis of sodium retention, refractory congestion in heart failure (HF) as well as diuretic resistance. In patients with decompensated cirrhosis who suffer from ascites, similar pathophysiological complications have been recognized. Administration of natriuretic doses of mineralocorticoid receptor antagonists (MRAs) has been well established in management of cirrhotic patients. However, this strategy in patients with ADHF has not been well studied. This article will discuss the potential use of natriuretic doses of MRAs to overcome the secondary hyperaldosteronism as an alternative diuretic regimen in patients with HF. PMID- 25447846 TI - Alcohol disrupts levels and function of the cystic fibrosis transmembrane conductance regulator to promote development of pancreatitis. AB - BACKGROUND & AIMS: Excessive consumption of ethanol is one of the most common causes of acute and chronic pancreatitis. Alterations to the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) also cause pancreatitis. However, little is known about the role of CFTR in the pathogenesis of alcohol-induced pancreatitis. METHODS: We measured CFTR activity based on chloride concentrations in sweat from patients with cystic fibrosis, patients admitted to the emergency department because of excessive alcohol consumption, and healthy volunteers. We measured CFTR levels and localization in pancreatic tissues and in patients with acute or chronic pancreatitis induced by alcohol. We studied the effects of ethanol, fatty acids, and fatty acid ethyl esters on secretion of pancreatic fluid and HCO3(-), levels and function of CFTR, and exchange of Cl(-) for HCO3(-) in pancreatic cell lines as well as in tissues from guinea pigs and CFTR knockout mice after administration of alcohol. RESULTS: Chloride concentrations increased in sweat samples from patients who acutely abused alcohol but not in samples from healthy volunteers, indicating that alcohol affects CFTR function. Pancreatic tissues from patients with acute or chronic pancreatitis had lower levels of CFTR than tissues from healthy volunteers. Alcohol and fatty acids inhibited secretion of fluid and HCO3(-), as well as CFTR activity, in pancreatic ductal epithelial cells. These effects were mediated by sustained increases in concentrations of intracellular calcium and adenosine 3',5'-cyclic monophosphate, depletion of adenosine triphosphate, and depolarization of mitochondrial membranes. In pancreatic cell lines and pancreatic tissues of mice and guinea pigs, administration of ethanol reduced expression of CFTR messenger RNA, reduced the stability of CFTR at the cell surface, and disrupted folding of CFTR at the endoplasmic reticulum. CFTR knockout mice given ethanol or fatty acids developed more severe pancreatitis than mice not given ethanol or fatty acids. CONCLUSIONS: Based on studies of human, mouse, and guinea pig pancreata, alcohol disrupts expression and localization of the CFTR. This appears to contribute to development of pancreatitis. Strategies to increase CFTR levels or function might be used to treat alcohol-associated pancreatitis. PMID- 25447849 TI - A 21-year-old patient with a HER2-positive colorectal cancer. PMID- 25447847 TI - Gut-liver axis in alcoholic liver disease. AB - Alcoholic liver disease (ALD) has been among the leading causes of cirrhosis and liver-related death worldwide for decades. Early discoveries in alcoholic liver disease identified increased levels of bacterial endotoxin in the portal circulation, suggesting a role for gut-derived toxins in ALD. Indeed, alcohol consumption can disrupt the intestinal epithelial barrier and result in increased gut permeability that increasingly is recognized as a major factor in ALD. Bacterial endotoxin, lipopolysaccharide, is a prototypic microbe-derived inflammatory signal that contributes to inflammation in ALD through activation of the Toll-like receptor 4. Recent studies also have shown that alcohol consumption is associated with alterations in the gut microbiome, and the dysbalance of pathogenic and commensal organisms in the intestinal microbiome may contribute to the abnormal gut-liver axis in ALD. Indeed, bacterial decontamination improves ALD both in human and animal models. This short review summarizes recent findings and highlights emerging trends in the gut-liver axis relevant to ALD. PMID- 25447850 TI - American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. PMID- 25447848 TI - Hepatitis C virus infection induces autocrine interferon signaling by human liver endothelial cells and release of exosomes, which inhibits viral replication. AB - BACKGROUND & AIMS: Liver sinusoidal endothelial cells (LSECs) make up a large proportion of the nonparenchymal cells in the liver. LSECs are involved in induction of immune tolerance, but little is known about their functions during hepatitis C virus (HCV) infection. METHODS: Primary human LSECs (HLSECs) and immortalized liver endothelial cells (TMNK-1) were exposed to various forms of HCV, including full-length transmitted/founder virus, sucrose-purified Japanese fulminant hepatitis-1 (JFH-1), a virus encoding a luciferase reporter, and the HCV-specific pathogen-associated molecular pattern molecules. Cells were analyzed by confocal immunofluorescence, immunohistochemical, and polymerase chain reaction assays. RESULTS: HLSECs internalized HCV, independent of cell-cell contacts; HCV RNA was translated but not replicated. Through pattern recognition receptors (Toll-like receptor 7 and retinoic acid-inducible gene 1), HCV RNA induced consistent and broad transcription of multiple interferons (IFNs); supernatants from primary HLSECs transfected with HCV-specific pathogen associated molecular pattern molecules increased induction of IFNs and IFN stimulated genes in HLSECs. Recombinant type I and type III IFNs strongly up regulated HLSEC transcription of IFN lambda3 (IFNL3) and viperin (RSAD2), which inhibit replication of HCV. Compared with CD8(+) T cells, HLSECs suppressed HCV replication within Huh7.5.1 cells, also inducing IFN-stimulated genes in co culture. Conditioned media from IFN-stimulated HLSECs induced expression of antiviral genes by uninfected primary human hepatocytes. Exosomes, derived from HLSECs after stimulation with either type I or type III IFNs, controlled HCV replication in a dose-dependent manner. CONCLUSIONS: Cultured HLSECs produce factors that mediate immunity against HCV. HLSECs induce self-amplifying IFN mediated responses and release of exosomes with antiviral activity. PMID- 25447852 TI - American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. PMID- 25447853 TI - Predicting scleral GP lens entrapped tear layer oxygen tensions. AB - BACKGROUND/PURPOSE: Over the past decade, utilization of scleral gas permeable (GP) contact lenses has steadily increased. Scleral GP lenses offer yet another option for patients suffering from visually debilitating corneal and tear conditions. Oxygen delivery to the cornea in the presence of a contact lens system continues to be a subject of interest, and scleral GP lenses are no exception. This paper utilizes an existing model based on simultaneous two lens systems (piggyback lenses) as a resistance to oxygen in series, and applies this model to scleral GP lens systems. METHODS: Theoretical oxygen tensions are calculated for tear layers trapped beneath scleral contact lens systems and the anterior corneal surface with a simple single chamber corneal model using a computer software spreadsheet. RESULTS: Only the best case scenario for current scleral gas permeable lenses (thickness and Dk)/tear layer values allow sufficient tear layer oxygen tension (approximately 100 mmHg) to preclude corneal hypoxia. CONCLUSIONS: The results of the spreadsheet model suggest that clinicians would be prudent to prescribe scleral GP lenses manufactured in the highest Dk materials available and to fit without excessive corneal clearance to minimize anterior segment hypoxia. PMID- 25447854 TI - Decoding soft lens fitting. PMID- 25447855 TI - Comment on 'Contact lens correction for an aphakic patient with megalocornea'. PMID- 25447856 TI - General introduction: recombinant protein production and purification of insoluble proteins. AB - Proteins are synthesized in heterologous systems because of the impossibility to obtain satisfactory yields from natural sources. The production of soluble and functional recombinant proteins is among the main goals in the biotechnological field. In this context, it is important to point out that under stress conditions, protein folding machinery is saturated and this promotes protein misfolding and, consequently, protein aggregation. Thus, the selection of the optimal expression organism and the most appropriate growth conditions to minimize the formation of insoluble proteins should be done according to the protein characteristics and downstream requirements. Escherichia coli is the most popular recombinant protein expression system despite the great development achieved so far by eukaryotic expression systems. Besides, other prokaryotic expression systems, such as lactic acid bacteria and psychrophilic bacteria, are gaining interest in this field. However, it is worth mentioning that prokaryotic expression system poses, in many cases, severe restrictions for a successful heterologous protein production. Thus, eukaryotic systems such as mammalian cells, insect cells, yeast, filamentous fungus, and microalgae are an interesting alternative for the production of these difficult-to-express proteins. PMID- 25447857 TI - Overcoming the solubility problem in E. coli: available approaches for recombinant protein production. AB - Despite the importance of recombinant protein production in academy and industrial fields, many issues concerning the expression of soluble and homogeneous product are still unsolved. Although several strategies were developed to overcome these obstacles, at present there is no magic bullet that can be applied for all cases. Indeed, several key expression parameters need to be evaluated for each protein. Among the different hosts for protein expression, Escherichia coli is by far the most widely used. In this chapter, we review many of the different tools employed to circumvent protein insolubility problems. PMID- 25447858 TI - Optimization of culture parameters and novel strategies to improve protein solubility. AB - The production of recombinant proteins, in soluble form in a prokaryotic expression system, still remains a challenge for the biotechnologist. Innovative strategies have been developed to improve protein solubility in various protein overexpressing hosts. In this chapter, we would focus on methods currently available and amenable to "desired modifications," such as (a) the use of molecular chaperones; (b) the optimization of culture conditions; (c) the reengineering of a variety of host strains and vectors with affinity tags; and (d) optimal promoter strengths. All these parameters are evaluated with the primary objective of increasing the solubilization of recombinant protein(s) during overexpression in Escherichia coli. PMID- 25447859 TI - Cleavable self-aggregating tags (cSAT) for protein expression and purification. AB - Rapid protein expression and purification remains a critical technological need, in particular as the number of proteins being identified is exploding. In this chapter, we describe a simple and rapid scheme for expression and purification of recombinant proteins using Escherichia coli, by taking advantage of two self aggregating peptide fusion tags 18A (EWLKAFYEKVLEKLKELF) and ELK16 (LELELKLKLELELKLK) that can drive target proteins into active protein aggregates in vivo. In practice, a target protein is fused at the N-terminus of the self cleavable Mxe GyrA intein, which is followed by the 18A or ELK16 tag. The fusion protein is first expressed in the form of active aggregate and then separated by centrifugation upon cell lysis. Subsequently, the DTT-mediated intein self cleavage reaction releases the target protein into solution. These cleavable self aggregating tags (cSAT, intein-18A/ELK16) provide a quick and efficient route for the production of proteins with modest purity (around 90% in the case of intein ELK16). Two application examples are included in the chapter. PMID- 25447851 TI - Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus. AB - BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 * 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 * 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 * 10(-9)). CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response. PMID- 25447861 TI - Characterization of amyloid-like properties in bacterial intracellular aggregates. AB - Protein aggregation into amyloid conformations is associated with more than 50 different human disorders. Recent studies demonstrate that the expression in bacteria of amyloid proteins results in the formation of intracellular aggregates structurally related to those underlying human diseases. The ease with which prokaryotic organisms can be genetically and biochemically manipulated makes them useful systems for studying how and why protein aggregates inside the cell, providing a tractable environment to rationally model in vivo amyloid formation. In this chapter we present an overview of the methods used to characterize the kinetic, structural, and functional properties of amyloid-like bacterial intracellular aggregates and how they can be employed to screen for lead compounds that might modulate amyloid deposition. PMID- 25447860 TI - Beyond the cytoplasm of Escherichia coli: localizing recombinant proteins where you want them. AB - Recombinant protein expression in Escherichia coli represents a cornerstone of the biotechnology enterprise. While cytoplasmic expression in this host has received the most attention, achieving substantial yields of correctly folded proteins in this compartment can sometimes be met with difficulties. These issues can often be overcome by targeting protein expression to extracytoplasmic compartments (e.g., membrane, periplasm) or to the culture medium. This chapter discusses various strategies for exporting proteins out of the cytoplasm as well as tools for monitoring and optimizing these different export mechanisms. PMID- 25447862 TI - Co-translational stabilization of insoluble proteins in cell-free expression systems. AB - Precipitation, aggregation, and inclusion body (IB) formation are frequently observed problems upon overexpression of recombinant proteins. The open accessibility of cell-free reactions allows addressing such critical steps by the addition of protein stabilizers such as chemical chaperones or detergents directly into the expression reactions. This approach could therefore reduce or even prevent initial protein precipitation already in the translation environment. The strategy might be considered to generally improve protein sample quality and to rescue proteins that are difficult to refold from IBs or from aggregated precipitates. We describe a protocol for the co-translational stabilization of difficult proteins by their expression in the presence of supplements such as alcohols, poly-ions, or detergents. We compile potentially useful compounds together with their recommended stock and working concentrations. Examples of screening experiments in order to systematically identify compounds or compound mixtures that stabilize particular proteins of interest are given. The method can primarily be considered for the production of unstable soluble proteins or of membrane proteins containing larger soluble domains. PMID- 25447863 TI - Functional expression of plant membrane proteins in Lactococcus lactis. AB - The study of most membrane proteins remains challenging due to their hydrophobicity and their low natural abundance in cells. Lactococcus lactis, a Gram-positive lactic bacterium, has been traditionally used in food fermentations and is nowadays widely used in biotechnology for large-scale production of heterologous proteins. This system has been successfully used for the production of prokaryotic and eukaryotic membrane proteins. The purpose of this chapter is to provide detailed protocols for (1) the expression of plant peripheral or intrinsic membrane proteins and then for (2) their solubilization, from Lactococcus membranes, for further purification steps and biochemical characterization. PMID- 25447864 TI - High cell-density expression system: yeast cells in a phalanx efficiently produce a certain range of "difficult-to-express" secretory recombinant proteins. AB - Yeast's extracellular expression provides a cost-efficient means of producing recombinant proteins of academic or commercial interests. However, depending on the protein to be expressed, the production occasionally results in a poor yield, which is frequently accompanied with a deteriorated growth of the host. Here we describe our simple approach, high cell-density expression, to circumvent the cellular toxicity and achieve in a production of a certain range of "difficult-to express" secretory protein in preparative amount. The system features an ease of performing: (1) precultivate yeast cells to the stationary phase in non-inducing condition, (2) suspend the cells to a small aliquot of inducing medium to form a high cell-density suspension or "a phalanx," and then (3) give a sufficient aeration to the phalanx. Factors and pitfalls that affect the system's performance are also described. PMID- 25447865 TI - Insect cells-baculovirus system for the production of difficult to express proteins. AB - The production of sufficient quantities of homogenous protein not only is an essential prelude for structural investigations but also represents a rate limiting step for many human functional studies. Although technologies for expression of recombinant proteins and complexes have been improved tremendously, in many cases, protein production remains a challenge and can be associated with considerable investment. This chapter describes simple and efficient protocols for expression screening and optimization of protein production in insect cells using the baculovirus expression system. We describe the procedure, starting from the cloning of a gene of interest into an expression transfer baculovirus vector, followed by generation of the recombinant virus by homologous recombination, evaluation of protein expression, and scale-up. Handling of insect cell cultures and preparation of bacmid for co-transfection are also detailed. PMID- 25447867 TI - Recombinant glycoprotein production in human cell lines. AB - The most important properties of a protein are determined by its primary structure, its amino acid sequence. However, protein features can be also modified by a large number of posttranslational modifications. These modifications can occur during or after the synthesis process, and glycosylation appears as the most common posttranslational modification. It is estimated that 50% of human proteins have some kind of glycosylation, which has a key role in maintaining the structure, stability, and function of the protein. Besides, glycostructures can also influence the pharmacokinetics and immunogenicity of the protein. Although the glycosylation process is a conserved mechanism that occurs in yeast, plants, and animals, several studies have demonstrated significant differences in the glycosylation pattern in recombinant proteins expressed in mammalian, yeast, and insect cells. Thus, currently, important efforts are being done to improve the systems for the expression of recombinant glycosylated proteins. Among the different mammalian cell lines used for the production of recombinant proteins, a significant difference in the glycosylation pattern that can alter the production and/or activity of the protein exists. In this context, human cell lines have emerged as a new alternative for the production of human therapeutic proteins, since they are able to produce recombinant proteins with posttranslational modifications similar to its natural counterpart and reduce potential immunogenic reactions against nonhuman epitopes. This chapter describes the steps necessary to produce a recombinant glycoprotein in a human cell line in small scale and also in bioreactors. PMID- 25447866 TI - Transient expression in HEK 293 cells: an alternative to E. coli for the production of secreted and intracellular mammalian proteins. AB - Transient transfection of human embryonic kidney cells (HEK 293) enables the rapid and affordable lab-scale production of recombinant proteins. In this chapter protocols for the expression and purification of both secreted and intracellular proteins using transient expression in HEK 293 cells are described. PMID- 25447869 TI - A screening methodology for purifying proteins with aggregation problems. AB - Many proteins are prone to aggregate or insoluble for different reasons. This poses an extraordinary challenge at the expression level, but even more during downstream purification processes. Here we describe a strategy that we developed for purifying prone-to-aggregate proteins. Our methodology can be easily implemented in small laboratories without the need for automated, expensive platforms. This procedure is especially suitable for intrinsically disordered proteins (IDPs) and for proteins with intrinsically disordered regions (IDRs). Such proteins are likely to aggregate due to their lack of tertiary structure and their extended and flexible conformations. Similar methodologies can be applied to other proteins with comparable tendency to aggregate during the expression or purification steps. In this chapter, we will mainly focus on protein solubility and stability issues during purification and storage, on factors that can prevent aggregation or maintain solubility, and on the importance of the early elimination of aggregates during protein purification. PMID- 25447868 TI - Soluble recombinant protein production in Pseudoalteromonas haloplanktis TAC125. AB - Solubility/activity issues are often experienced when immunoglobulin fragments are produced in conventional microbial cell factories. Although several experimental approaches have been followed to solve, or at least minimize, the accumulation of the recombinant proteins into insoluble aggregates, sometimes the only alternative strategy is changing the protein production platform. In this chapter we describe the use of Antarctic bacterium Pseudoalteromonas haloplanktis TAC125 as host of choice for the production of the heavy-chain antibody fragment VHHD6.1. Combining the use of a regulated psychrophilic gene expression system with an optimized fermentation process in defined growth medium, we obtained the recombinant VHHD6.1 in fully soluble form and correctly translocated into host periplasmic space. PMID- 25447870 TI - Solubilization and refolding of inclusion body proteins. AB - High-level expression of recombinant proteins in Escherichia coli often results in accumulation of protein molecules into aggregates known as inclusion bodies (IBs). Isolation of properly folded, bioactive protein from IBs is a cumbersome task and most of the times results in poor recovery. The process of recovering bioactive proteins from IBs consists of solubilization of IB aggregates using denaturants, followed by refolding of the solubilized protein. Here, we describe a simple protocol for screening of buffers for solubilization of IB proteins. Various IB aggregate solubilization methods including organic solvents have been described. PMID- 25447871 TI - Bacterial inclusion body purification. AB - Purification of bacterial inclusion bodies (IBs) is gaining importance due to the raising of novel applications for this type of submicron particulate protein clusters, with potential uses in the biomedical field among others. Here, we present two optimized methods to purify IBs adapting classical procedures to the material nature as well as the requirements of its final application. PMID- 25447872 TI - Characterization of intracellular aggresomes by fluorescent microscopy. AB - Correct folding of newly synthesized proteins is essential to cellular homeostasis and cells have evolved sophisticated means to fold and modify proteins. When misfolding occurs, the misfolded proteins often expose normally buried hydrophobic domains, causing localized aggregation. Individual small aggregates appear to be transported towards the microtubule-organizing center and there coalesce to form larger aggregates called aggresomes. Both cytoplasmic and nuclear proteins can form aggresomes. The study of aggresomes has progressed rapidly because numerous human diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, various myopathies, and prion disease are characterized by the formation of aggresomes. Importantly, aggresomes sequester many cellular proteins and the pathology of aggresomal disease is at least partially caused by the deregulation of cellular components. Thus, it is essential to identify and characterize the composition of aggresomes formed by different proteins. However, most protein aggregates are insoluble even in buffers with high concentration of detergent, which makes them very difficult to analyze by biochemical approaches. An alternative approach that has been used successfully is the in situ characterization of protein components within aggresomes by immunofluorescent microscopy. Here, we provide detailed protocols to study the characteristic features of aggresomes by fluorescent microscopy. PMID- 25447873 TI - Dialysis: a characterization method of aggregation tendency. AB - All researchers immersed in the world of recombinant protein production are in agreement that often the production and purification process of a protein can become a nightmare due to an unexpected behavior of the protein at different protocol stages. Once the protein is purified, scientists know that they still cannot relax. There is a decisive last step missing: performing a protein dialysis in a suitable buffer for subsequent experimental trials. Here is when we can find proteins that precipitate during dialysis by buffer-related factors (ionic strength, pH, etc.), which are intrinsic to each protein and are difficult to predict. How can we find the buffer in which a protein is more stable and with less tendency to precipitate? In this chapter we go over possible factors affecting the protein precipitation tendency during the dialysis process and describe a general dialysis protocol with tricks to reduce protein aggregation. Furthermore, we propose a fast method to detect the most appropriate buffer for the stability of a particular protein, performing microdialysis on a battery of different buffers to measure afterwards precipitation by a colorimetric method, and thus being able to choose the most suitable buffer for the dialysis of a given protein. PMID- 25447874 TI - Applications of mass spectrometry to the study of protein aggregation. AB - Mass spectrometry is an analytical technique that measures the mass-to-charge ratio of charged particles. Nowadays mass spectrometry-based approaches play a pivotal role in both detection and characterization of proteins. Here we describe two applications to study insoluble proteins: (a) hydrogen/deuterium exchange combined with mass spectrometry to analyze structural properties of amyloid fibrils and (b) the screening for inhibitors of the aggregation process by matrix assisted laser desorption/ionization time-of-flight mass spectrometry. PMID- 25447876 TI - Insoluble protein characterization by circular dichroism (CD) spectroscopy and nuclear magnetic resonance (NMR). AB - Besides misfolded proteins, which still retain the capacity to fold into uniquely defined structures but are misled to "off-pathway" aggregation, there exists a group of proteins which are unrefoldable and insoluble in buffers. Previously no general method was available to solubilize them and consequently their solution conformations could not be characterized. Recently, we discovered that these insoluble proteins could in fact be solubilized in pure water. Circular dichroism (CD) spectroscopy and nuclear magnetic resonance (NMR) characterization led to their classification into three groups, all of which lack the tight tertiary packing and consequently anticipated to unavoidably aggregate in vivo with ~150 mM ions, thus designated as "intrinsically insoluble proteins (IIPs)." It appears that eukaryotic genomes contain many "IIP," which also have a potential to interact with membranes to trigger neurodegenerative diseases. In this chapter, we provide a detailed procedure to express and purify these proteins, followed by CD and NMR spectroscopy characterization of their conformation and interaction with dodecylphosphocholine (DPC). PMID- 25447875 TI - Insoluble protein assemblies characterized by fourier transform infrared spectroscopy. AB - Fourier transform infrared (FTIR) spectroscopy is a useful tool for the structural characterization of insoluble protein assemblies, as it allows to obtain information on the protein secondary structures and on their intermolecular interactions. The protocols for FTIR spectroscopy and microspectroscopy measurements in transmission and attenuated total reflection modes will be presented and illustrated in the following examples: bacterial inclusion bodies, self-assembling peptides, thermal aggregates, and amyloid fibrils. PMID- 25447877 TI - Methods for characterization of protein aggregates. AB - Physicochemical characterization of protein aggregates is important on one hand, due to its large impact in understanding many diseases for which formation of protein aggregates is one of the pathological hallmarks. On the other hand, recently it has been observed that bacterial inclusion bodies (IBs) are also highly pure proteinaceous aggregates of a few hundred nanometers produced by recombinant bacteria supporting the biological activities of the embedded polypeptides. From this fact arises a wide spectrum of uses of IBs as functional and biocompatible materials upon convenient engineering but very few is known about their physicochemical properties. In this chapter we present methods for the characterization of protein aggregates as particulate materials relevant to their physicochemical and nanoscale properties. Specifically, we describe the use of infrared spectroscopy (IR) for the determination of the secondary structure, dynamic light scattering (DLS) for sizing, nanosight for sizing and counting, and Z-potential measurements for the determination of colloidal stability. To study their morphology we present the use of atomic force microscopy (AFM). Cryo transmission electron microscopy will be used for the determination of the internal structuration. Moreover, wettability and nanomechanical characterization can be performed using contact angle (CA) and force spectroscopic AFM measurements of the proteinaceous nanoparticles, respectively. The physical principles of the methods are briefly described and examples of data for real samples and how that data is interpreted are given to help clarify capabilities of each technique. PMID- 25447878 TI - Predicting the solubility of recombinant proteins in Escherichia coli. AB - We describe a statistical model that uses binomial logistic regression for predicting the solubility of heterologous proteins expressed in E. coli. The model is based on a set of proteins reported to have been expressed in E. coli in either soluble or insoluble form. The 22 parameters used in the final model based on proteins' amino acid composition are discussed. The overall accuracy of the model developed is 94%. The way to use this model on the website http://www.ou.edu/ for the prediction of protein solubility is explained. PMID- 25447879 TI - Insoluble protein applications: the use of bacterial inclusion bodies as biocatalysts. AB - Biocatalysis and biotransformations have a broad application in industrial synthetic chemistry. In addition to the whole cell catalysis, purified recombinant enzymes are successfully used for biocatalysis of specific chemical reactions. In this contribution, we report characterization, immobilization, and application of several model target enzymes (D-amino acid oxidase, sialic acid aldolase, maltodextrin phosphorylase, polyphosphate kinase) physiologically aggregated within inclusion bodies (IBs) retaining their biological activity as immobilized biocatalysts. PMID- 25447880 TI - Creating leptin-like biofunctions by active immunization against chicken leptin receptor in growing chickens. AB - In this study, immunization against chicken leptin receptor (cLEPR) extracellular domain (ECD) was applied to investigate leptin regulation and LEPR biofunction in growing chicken pullets. A recombinant protein (cLEPR ECD) based on the cLEPR complemenary DNA sequence corresponding to the 582nd to 796th amino acid residues of cLEPR mature peptide was prepared and used as antigen. Immunization against cLEPR ECD in growing chickens increased anti-cLEPR ECD antibody titers in blood, enhanced proportions of phosphorylated janus kinase 2 (JAK2) and served as signal transducer and activator of transcription 3 (STAT3) protein in liver tissue. Chicken live weight gain and abdominal fat mass were significantly decreased (P < 0.05), but feed intake was stimulated by cLEPR ECD immunization (P < 0.05). The treatment also upregulated the gene expression levels of lepR, AMP-activated protein kinase (AMPK), acetyl CoA carboxylase-2 (ACC2), and uncoupling protein 3 (UCP3) in liver, abdominal fat, and breast muscle (P < 0.05) but decreased fasn expression levels (P < 0.01). Apart from that of lepR, the expression of appetite regulating genes, such as orexigenic genes, agouti-related peptide (AgRP) and neuropeptide Y (NPY), were upregulated (P < 0.01), whereas the anorexigenic gene proopiomelanocortin (POMC) was downregulated in the hypothalamic tissue of cLEPR immunized pullets (P < 0.01). Blood concentrations of metabolic molecules, such as glucose, triglycerides, and very-low-density lipoprotein, were significantly decreased in cLEPR-immunized pullets but those of cholesterol, high-density lipoprotein, and low-density lipoprotein increased. These results demonstrate that antibodies to membrane proximal cLEPR ECD enhance cLEPR signal transduction, which stimulates metabolism and reduces fat deposition in chickens. PMID- 25447881 TI - Expression of variant transcripts of the potassium channel tetramerization domain containing 15 (KCTD15) gene and their association with fatness traits in chickens. AB - The aim of this study was to characterize the structure, expression, and biological functions of potassium channel tetramerization domain containing 15 (KCTD15) in chickens. We compared the KCTD15 expression level in samples of hypothalamic, adipose, and liver tissue of Xinghua chickens that were maintained on different dietary status. An association analysis of KCTD15 gene variant transcripts with fatness traits in a F2 resource population of chickens was performed. Three KCTD15 transcripts were identified in which the complete transcript was predominantly expressed in adipose tissue and the hypothalamus. The chicken KCTD15 gene was regulated by both feeding and fasting and consumption of a high-fat diet. The expression level of KCTD15 gene was markedly decreased in hypothalamus and liver of fasted and refed chickens (P < 0.05) and significantly downregulated in adipose tissue by the high-fat diet (P < 0.05). Three single nucleotide polymorphisms of the KCTD15 gene were significantly associated with a number of fatness traits in chicken (P < 0.05). These results suggest that KCTD15 have a potential role regulation of obesity and fat metabolism in chickens. PMID- 25447882 TI - Relationship between plasma and tissue corticosterone in laying hens (Gallus gallus domesticus): implications for stress physiology and animal welfare. AB - This study directly compared the dynamics of change in plasma corticosterone concentration with the dynamics of change in tissue corticosterone concentration in laying hens. In concert, we measured the rate of gluconeogenesis, glycogenesis, and glycolysis in the liver, kidney, skeletal muscle, and heart. We evaluated these changes acutely, over 3 h in response to an adrenocorticotropic hormone (ACTH) injection, and chronically, over 24 h in response to food and water deprivation. In response to ACTH injection, there was a significant (P < 0.05) increase in plasma corticosterone concentration and a parallel significant increase in corticosterone concentration in the skeletal muscle, kidney, and heart. However, the change in corticosterone concentration in the liver did not parallel the plasma, at times it was greater than the plasma, and there was a second significant increase (P < 0.05) in corticosterone concentration in the liver after 180 min. Under these conditions, the rate of gluconeogenesis in the liver decreased and the rate of glycogenesis increased. In contrast, after 12 h and 24 h of food and water deprivation plasma corticosterone concentration was increased, and this was paralleled by increased corticosterone concentration in the liver, an increase in the rate of gluconeogenesis and a decrease in the rate of glycogenesis. After ACTH injection, glucose concentration in the liver was not significantly depleted but after 12 h or 24 h of food and water deprivation it was significantly depleted (P < 0.05). Plasma corticosterone concentration provided different insight into the effect of the stressor on hen physiology under acute and chronic conditions. Our data suggest that extending our evaluation of stress to the site of corticosterone action, that is, the target tissue, may enhance our ability to evaluate stress and the welfare of laying hens. PMID- 25447883 TI - Modulation of periovulatory endocrine profiles in beef cows: consequences for endometrial glucose transporters and uterine fluid glucose levels. AB - In beef cattle, proestrus estradiol and subsequent progesterone (P4) concentrations can regulate the endometrial characteristics and thereby determine maternal receptivity toward the embryo. However, the underlying mechanisms linking periovulatory endocrine profiles to receptivity, which is crucial to obtain pregnancy, need to be elucidated. We hypothesized that the size of the preovulatory follicle (POF) and subsequent circulating P4 concentrations, during early diestrus, modulate endometrial levels of glucose transporter transcripts and proteins, and subsequently affect the luminal glucose availability in the uterus. Therefore, follicle growth of Nelore cows was manipulated, and cows were assigned to 2 experimental groups: (1) large follicle and large corpus luteum (LF LCL) group with a large POF and corpus luteum (CL); and (2) small follicle and small corpus luteum (SF-SCL) group with a small POF and CL. At day 7 post gonadotropin-releasing hormone induced ovulation (gonadotropin-releasing hormone treatment = day 0), animals were slaughtered (n = 18 per group), and uterine tissues and washings were collected for characterization of glucose transporters and glucose levels, respectively. The diameter of POF was larger (P < 0.05) in the LF-LCL cows compared with their SF-SCL counterparts (12.8 +/- 0.4 vs 11.1 +/- 0.4 mm). Furthermore, CL size (17.49 +/- 0.88 vs 14.48 +/- 0.52 mm) and circulating P4 concentrations at day 7 (4.5 +/- 1.0 vs 3.3 +/- 1.1 ng/mL, P < 0.05) were significantly higher in the LF-LCL cows compared with the SF-SCL cows. No differences (P > 0.05) were detected in gene expression patterns of SLC2A1, SLC2A3, SLC2A4, SLC2A5, SLC5A1, ATP1A2, ATP1B2, and SLC37A4. However, the protein abundance of endometrial SLC2A1was increased in the LF-LCL group compared with the SF-SCL group (P < 0.05). SLC2A1 and SLC2A4 protein products were mainly identified at the endometrial luminal and glandular epithelium membranes as well as in the endometrial stroma. Glucose concentrations in uterine washings were similar between groups. In conclusion, we provided information on the potential link between endocrine profiles and glucose transport pathways in the bovine endometrium. More specifically, our data reveal that the size of the POF, and subsequent P4 concentrations, do not functionally affect the main endometrial glucose transporter pathways or uterine fluid glucose concentrations during diestrus. PMID- 25447885 TI - Mini-Tn7 vectors for studying post-transcriptional gene expression in Pseudomonas. AB - We describe the construction and validation of five mini-Tn7 vectors for analysis of post-transcriptional gene expression in Pseudomonas. Four vectors allow construction of translational fusions to beta-galactosidase (lacZ), while the fifth is designed for functional analysis of noncoding RNA genes. Translational fusions can be constructed without a functional promoter in the vector or from an inducible promoter of either P(tac) or P(dctA). We show that promoterless fusions have value for determining levels of translation, whereas fusions to inducible promoters have utility in the analysis of mRNA-binding factors. PMID- 25447884 TI - Anxiety and worry when coping with cancer treatment: agreement between patient and proxy responses. AB - PURPOSE: Assess agreement between proxy respondents (caregivers) and children/adolescents related to the impact of cancer on children's/adolescents' health-related quality of life, with respect to anxiety and worry issues. METHODS: A cross-sectional study was conducted among 83 Brazilian children/adolescents, of both genders, diagnosed with cancer, aged 5-18 years and their proxy respondents. Anxiety and worry were assessed through items of the instrument Pediatric Quality of Life InventoryTM Cancer Module Scale. Participants were recruited from the pediatric hematology/oncology centers at two public hospitals. All individuals were receiving medical care. Descriptive statistics were performed as well as a weighted kappa coefficient, Spearman's correlation coefficient, Wilcoxon signed-rank test and Bland-Altman plots. The magnitude of the difference between the mean scores obtained from children/adolescents and that of their proxy respondents was evaluated through effect size. RESULTS: The proxy respondents underestimated the feelings of worry among children (8-12 years) (p < 0.001; effect size 0.71) and overestimated adolescents' (13-18 years) treatment anxiety (p < 0.05; effect size 0.57). The comparison between the three age groups (5-7, 8-12, 13-18 years) showed a tendency for children/adolescents to report increasing feelings of worry as they got older. In the 'treatment anxiety' subscale, there was a tendency for proxy respondents to present higher mean scores, revealing that proxy respondents believed the children's/adolescents' treatment anxiety decreased as they aged. CONCLUSIONS: Discrepancies between the reports of children/adolescents and their proxy respondents were observed. Children's/adolescents' reports should not be ignored nor replaced by proxy reports; both reports should be analyzed together. PMID- 25447886 TI - Improvement in the DNA sequencing of genomes bearing long repeated elements. AB - When using next-generation sequencing methods, obtaining a single and complete bacterial chromosomic sequence may be challenging especially for bacteria harboring multiple repeated sequences. Here we present a one-step procedure to optimize the sequencing process in order to obtain a single chromosomic scaffold. PMID- 25447888 TI - Molecular analysis of Staphylococcus aureus pathogenicity islands (SaPI) and their superantigens combination of food samples. AB - Staphylococcus aureus produces a wide variety of superantigenic activity Staphylococcal enterotoxins (SE) and they are a major cause of food poisoning. These superantigens are associated with mobile genetic elements such as plasmids, prophages and S. aureus pathogenicity islands (SaPI). The presence of well-known eight SaPI integrase and 13 enterotoxin genes (sea, seb, sec, sed, see, seg, seh, sei, sej, sel, sek, seq, and tst) in 93 S. aureus strains were investigated. All S. aureus isolates were characterized by pulsed-field gel electrophoresis (PFGE), and the genes were detected using five sets of multiplex PCR (mPCR). The most predominant toxin genes were sea (19%), seb (15%), sec (54%), sell (48%), selk (46%), selq (52%), seg (22%), and sei (19%). Analysis showed that many S. aureus isolates harbored multiple toxin genes. An mPCR-based assay was developed for the determination of all SaPI and their superantigen gene combinations. Twenty three isolates revealed the gene combination sec, sell and tst, typical of the SaPIbov1 and SaPIn1/m1 pathogenicity islands. Twelve isolates revealed the selk and selq gene combination consistent with SaPI3. Eight isolates exhibited the sec and sell genes without the tst gene typical of SaPImw2. We established a correlation between superantigenic toxin genotypes in S. aureus in terms of combinations of toxin gene-encoding SaPI. These results provide a rapid method for determining superantigenic toxin genotypes in S. aureus strains. A total of 24 PFGE patterns were generated. To our knowledge, this is a first study analyzing the correlation of all known SaPI and their enterotoxins in S. aureus using mPCR. PMID- 25447887 TI - Prevalence and phylogenetic analysis of haemoplasmas from cats infected with multiple species. AB - Mycoplasma haemofelis (Mhf), 'Candidatus Mycoplasma haemominutum' (CMhm) and 'Candidatus Mycoplasma turicensis' (CMt) are agents of feline haemoplasmosis and can induce anaemia in cats. This study aimed to determine the prevalence and phylogeny of haemoplasma species in cats from Brazil's capital and surrounding areas, and whether correlation with haematological abnormalities existed. Feline haemoplasmas were found in 13.8% of 432 cats. CMhm was the most prevalent species (in 13.8% of cats), followed by Mhf (11.1%) and CMt (4.4%). Over 80% of haemoplasma-infected cats harboured two or more feline haemoplasma species: 7.1% of cats were co-infected with Mhf/CMhm, 0.4% with CMhm/CMt and 3.9% with Mhf/CMhm/CMt. Male gender was significantly associated with haemoplasma infections. No association was found between qPCR haemoplasma status and haematological variables, however CMhm relative copy numbers were correlated with red blood cell (RBC) numbers and packed cell volume (PCV). Haemoplasma 16S rRNA gene sequences (> 1 Kb) were derived from co-infected cats using novel haemoplasma species-specific primers. This allowed 16S rRNA gene sequences to be obtained despite the high level of co-infection, which precluded the use of universal 16S rRNA gene primers. Within each species, the Mhf, CMhm and CMt sequences showed > 99.8%, > 98.5% and > 98.8% identity, respectively. The Mhf, CMhm and CMt sequences showed > 99.2%, > 98.4% and > 97.8% identity, respectively, with GenBank sequences. Phylogenetic analysis showed all Mhf sequences to reside in a single clade, whereas the CMhm and CMt sequences each grouped into three distinct subclades. These phylogeny findings suggest the existence of different CMhm and CMt strains. PMID- 25447889 TI - Monoclonal antibody-based competitive enzyme-linked immunosorbent assay to detect antibodies to O:4 Salmonella in the sera of livestock and poultry. AB - Serotyping is an important element for surveillance of Salmonella. In this study, an anti-O:4 Salmonella monoclonal antibody-based competitive enzyme-linked immunosorbent assay that could identify Salmonella infection in cow, pig, horse, and chicken was developed. This detection system can therefore be useful for a wide range of animals and for humans. PMID- 25447890 TI - Comparison of PCR and serotyping of Group B Streptococcus in pregnant women: the Oslo GBS-study. AB - Streptococcus agalactiae (GBS) is a leading cause of invasive neonatal infection. Serotyping of GBS is important in following epidemiological trends and vaccine development. Capsular serotyping of GBS by latex agglutination has been the predominant typing method, but more recently capsular genotyping has been introduced as an alternative method. The purpose of this study was to compare the relative performance of these methods in a contemporary population of pregnant women. We typed isolates from an unselected population of 426 colonized women at delivery using latex agglutination and a combination of four PCR methods. Antibiotic resistance was tested in 449 isolates. Capsular genotyping gave a result in all except three of 426 isolates. Fifty-nine of 426 isolates could not be typed by latex agglutination. Agreement between serotyping and genotyping was shown in 303 (71.1%) of the isolates. 10.2% of the isolates were resistant to erythromycin, 9.6% to clindamycin, 76.6% to tetracycline and none to penicillin. In conclusion, a substantial proportion of the colonizing strains were non typeable by serotyping, but typeable by genotyping. This suggests that a diagnostic genotyping strategy is preferable to serotyping of the GBS polysaccharide capsule in colonized, pregnant women. PMID- 25447891 TI - The allele frequency of T920C mutation in butyrylcholinesterase gene is high in an Indian population. AB - The genetic variants of butyrylcholinesterase (BChE) are the cause of concern in individuals experiencing prolonged apnea on administration of muscle relaxants. In an Indian community called Vysya, a variant (L307P; T920C) was associated with imperceptible plasma BChE. Since BChE has several pharmacological significances in humans, the identification of its variants having altered activity is very important. Previous studies for identifying the mutants in a population were based only on its functional attributes (phenotypic characters) such as esterase activity, dibucaine number and fluoride number. Generally phenotyping method is not considered as the accurate methodology till date though it might be used as a primary screening tool. Molecular biology provides a better technique in identifying these variants. Our aim was to screen this particular community living in South India for the heterozygosity of T920C mutation by phenotypic and genotypic analysis and to find the reliability between the two methods. We analysed 266 individuals for the heterozygosity of T920C. Based on BChE phenotypes, we found that 95% of the individuals are heterozygous. Real-time PCR based genotyping revealed that 96% of individuals are heterozygous. The allele frequency for the mutant allele C was 0.52 which confirmed that the genetic pool of this allele is much higher in Vysya. Also, we observed that genotyping correlates 97% with the phenotype in our study. Further, both phenotype and genotype of age matched other ethnic group do not show any preponderance to this mutation authenticating the vulnerability of Vysyas to this mutation is dominant. PMID- 25447892 TI - Identification of human-specific AluS elements through comparative genomics. AB - Mobile elements are responsible for ~45% of the human genome. Among them is the Alu element, accounting for 10% of the human genome (>1.1million copies). Several studies of Alu elements have reported that they are frequently involved in human genetic diseases and genomic rearrangements. In this study, we investigated the AluS subfamily, which is a relatively old Alu subfamily and has the highest copy number in primate genomes. Previously, a set of 263 human-specific AluS insertions was identified in the human genome. To validate these, we compared each of the human-specific AluS loci with its pre-insertion site in other primate genomes, including chimpanzee, gorilla, and orangutan. We obtained 24 putative human-specific AluS candidates via the in silico analysis and manual inspection, and then tried to verify them using PCR amplification and DNA sequencing. Through the PCR product sequencing, we were able to detect two instances of near-parallel Alu insertions in nearby sites that led to computational false negatives. Finally, we computationally and experimentally verified 23 human-specific AluS elements. We reported three alternative Alu insertion events, which are accompanied by filler DNA and/or Alu retrotransposition mediated-deletion. Bisulfite sequencing was carried out to examine DNA methylation levels of human specific AluS elements. The results showed that fixed AluS elements are hypermethylated compared with polymorphic elements, indicating a possible relation between DNA methylation and Alu fixation in the human genome. PMID- 25447893 TI - Deep sequencing analyses of pine wood nematode Bursaphelenchus xylophilus microRNAs reveal distinct miRNA expression patterns during the pathological process of pine wilt disease. AB - Bursaphelenchus xylophilus is known as the causative agent of pine wilt disease with complex life cycles. In this research, four small RNA libraries derived from different infection stages of pine wilt disease were constructed and sequenced. Consequently, we obtained hundreds of evolutionarily conserved miRNAs and novel miRNA candidates. The analysis of miRNA expression patterns showed that most miRNAs were expressed at extraordinarily high levels during the middle stage of pine wilt disease. Functional analysis revealed that expression levels of miR-73 and miR-239 were mutually exclusive with their target GH45 cellulase genes. In addition, another set of atypical miRNAs, termed mirtrons, was also identified in this study. Thus, our research has provided detailed characterization of B. xylophilus miRNA expression patterns during the pathological process of pine wilt disease. These findings would contribute to more in-depth understanding of this devastating plant disease. PMID- 25447894 TI - The functional Q84R polymorphism of TRIB3 gene is associated with diabetic nephropathy in Chinese type 2 diabetic patients. AB - Increased oxidative stress and circulating free fatty acids (FFA) has been suggested to involve in the pathogenesis of diabetic nephropathy. TRIB3 can inhibit FFA and reactive oxygen species (ROS) stimulated podocyte production of MCP-1. Smoking increases the production of reactive oxygen species, which accelerates oxidative stress under hyperglycemia. To determine whether the Q84R polymorphism (rs2295490), alone or in combination with smoking, contributes to the development of diabetic nephropathy, a case-control study was performed in 812 Chinese patients with type 2 diabetes. Among patients, 214 had diabetic nephropathy with microalbuminuria (n=156) or overt albuminuria (n=58), and 598 did not show either of these symptoms but had diabetes for >=10 years and were not undergoing antihypertension treatment. After adjustment for confounders, TRIB3 single-nucleotide polymorphism rs2295490 was associated with DN (OR 1.318, 95% CI 1.075, 1.653, p=0.017); smoking was also an independent risk factor for diabetic nephropathy (1.42 [1.25-2.04], p<0.001). In addition, we identified possible synergistic effects; i.e., the high-risk group (smokers with the AG+GG genotype) showed 2.13 times higher risk (1.51-3.96, p<0.001) of diabetic nephropathy than the low-risk group (nonsmokers with the AA genotype) in a multiple logistic regression analysis controlled for the confounders, but no departure from additivity was found. Our results indicate that smoking and the TRIB3 G-allele is associated with an increased risk of diabetic nephropathy, which supports the hypothesis that oxidative stress contributes to the development of diabetic nephropathy. PMID- 25447895 TI - Silkmapin of Hyriopsis cumingii, a novel silk-like shell matrix protein involved in nacre formation. AB - Understanding the role of matrix proteins in nacre formation and biomineralization in mollusks is important for the pearl industry. In this study, the gene encoding the novel Hyriopsis cumingii shell matrix protein silkmapin was characterized. The gene encodes a protein of 30.89kDa in which Gly accounts for 34.41% of the amino acid content, and the C-terminal region binds Ca(2+). Secondary structure prediction indicated a predominantly beta-fold and a structure typical of filamentous proteins. Real-time quantitative PCR and in situ hybridization showed that silkmapin was expressed in epithelial cells at the edge and pallial of mantle tissue, indicated that silkmapin play roles in the shell nacreous and prismatic layer formation. Further real-time PCR results indicated an involvement in pearl formation via nucleation of calcium carbonate prior to formation of the nacre. PMID- 25447896 TI - The molecular characterization and temporal-spatial expression of myocyte enhancer factor 2 genes in the goat and their association with myofiber traits. AB - The myocyte enhancer factor-2 (MEF2) gene family in vertebrates includes MEF2A, MEF2B, MEF2C, and MEF2D, which have important functions in the regulation of muscular growth and development. To investigate their temporal-spatial expression and functions in the goat, these genes were cloned (accession nos. JN967621-24) and their expression patterns characterized at five postnatal stages (3, 30, 60, 90, and 120days). Association analysis was then applied regarding MEF2 expression levels and myofiber diameter and density. MEF2B was shown to be weakly homologous with other species, the distant branches with other members and the lowest expression levels, suggesting that it is distinct from other family members. Expression of the other three MEF2 genes was widely distributed, but this was largely accumulated in the skeletal muscle and myocardium compared with the viscera at all developmental stages. MEF2A and MEF2D expression levels were higher overall than MEF2B and MEF2C in six tissues, and were significantly positively correlated with the myofiber diameter of the longissimus dorsi. These findings suggest that goat MEF2 genes mainly function in the skeletal muscle and myocardium, and that MEF2A and MEF2D are likely to effectively promote muscular growth and development during postnatal stages. MEF2A expression was highest in the myocardium, where MEF2C expression increased with age, implying that both gene products are related to the growth and development of postnatal myocardium. PMID- 25447897 TI - TNIP1 reduction of HSPA6 gene expression occurs in promoter regions lacking binding sites for known TNIP1-repressed transcription factors. AB - TNFalpha-induced protein 3-interacting protein 1 (TNIP1) represses signaling pathways initiated by specific nuclear and transmembrane receptors. This effect results in reduced activity of distinct transcription factors such as retinoic acid receptors (RAR), peroxisome-proliferator-activated receptors (PPAR), and NFkappaB. TNIP1-null and TNIP1-knockin defective for ubiquitin-binding mice show increased liver apoptosis, and enlarged spleen and lymph nodes, respectively. To complement current knowledge of TNIP1's broad physiologic functions as interpreted from in vivo studies and specific expression consequences from transcription factor repression, we determined effects of excess TNIP1 on global gene regulation. Following experimentally increased expression of TNIP1 in cultured keratinocytes, our gene expression microarray analysis not only confirmed TNIP1's association in previously known pathways and functions but also found a novel TNIP1-regulated pathway - the cell stress response. Under standard culture conditions, expression of several heat shock proteins, including HSPA1A, HSPA6, DNAJA1 and DNAJB1, was reduced. In heat-stressed conditions, differential regulation of HSPA1A and HSPA6 was observed, where only HSPA6 expression was reduced after heat-shock. Using HSPA6 as a model to elucidate the mechanism of the TNIP1-mediated HSP repression, we determined that TNIP1 likely represses HSPs through factors other than RAR, PPAR or NFkappaB despite the presence of these factors' binding sites in the HSPA6 promoter. These results indicate that regulation of HSPs may be through a yet unknown TNIP1-associated pathway. Additionally, these results suggest that TNIP1's reduction of HSP expression levels could negatively impact HSP chaperone capacity or their participation in the cell stress response. PMID- 25447898 TI - A ripening associated peroxidase from papaya having a role in defense and lignification: heterologous expression and in-silico and in-vitro experimental validation. AB - Fruit ripening associated full length cDNA of a peroxidase from papaya was cloned and heterologously expressed. The expressed peroxidase was activated by in-vitro re-folding in the presence of hemin and calcium. The purified recombinant peroxidase exhibited broad substrate affinity in the order of o dianisidine>pyrogallol>guaiacol and was found to be a homotetramer of 155kDa with each subunit having a size of 38kDa. The basis of the distinctive preferences for various substrates was investigated through in-silico molecular modeling approaches. Thus, when the modeled papaya peroxidase-heme complex was docked with these substrates, the in-silico binding efficiency was found to be in agreement with those of wet lab results with the involvement of Arg37, Phe40, His41, Pro137, Asn138, His139, His167, and Phe239 as the common interacting residues in all the cases. However, the binding of the different substrates were found to be associated with conformational changes in the peroxidase. Thus, in the case of o dianisidine (the most efficient substrate), the protein was folded in the most compact fashion when compared to guaiacol (the least efficient substrate). Protein function annotation analyses revealed that the papaya peroxidase may have biological roles in oxidation-reduction processes, stresses, defense responses etc. In order to further validate its role in lignifications, the papaya peroxidase was compared with a lignin biosynthetic peroxidase from Leucaena leucocephala, a tree legume. Thus, based on 3D structure superimposition and docking, both peroxidases exhibited a great extent of similarity suggesting the papaya peroxidase having a role in lignification (defense response) too. The predicted functions of papaya peroxidase in defense response and lignification were further validated experimentally using qRT-PCR analyses and measurement of oxidation of coniferyl alcohol. PMID- 25447899 TI - Expression and functional analysis of novel molecule - Latcripin-13 domain from Lentinula edodes C91-3 produced in prokaryotic expression system. AB - The shiitake mushroom Lentinula edodes has health benefits and is used to treat various diseases due to its immunomodulatory and antineoplastic properties. In the present study, the Latcripin-13 domain, isolated from L. edodes, was expressed in Escherichia coli Rosetta-gami(DE3) in the form of inclusion bodies. The Latcripin-13 domain was purified by Ni-His affinity chromatography with high purity and refolded by urea gradient dialysis. The product showed biological activity in A549 cells, a human lung cancer cell line, by flow cytometry and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) method. The MTT assay and the flow cytometry results revealed that there was a great difference between the Latcripin-13 domain-treated group and the control group (p<0.05). Similarly, cell apoptosis observed by transmission electron microscopy (TEM) supported the flow cytometry results. This work demonstrated that the Latcripin-13 domain can induce apoptosis of A549 cells, which will bring new insights into the development of new antitumor drugs in the future. PMID- 25447900 TI - Genetic determinants in ischaemic stroke subtypes: seven year findings and a review. AB - Stroke is a global health problem and a leading cause of disability worldwide. There have been numerable studies undertaking research on different aspects of ischaemic stroke employing various epidemiological, clinical and molecular parameters. Nevertheless ischaemic stroke being a complex disorder with different subtypes demands equal attention towards its subtypes too. Since there has been enough evidence that disposition to certain subtype is genetically determined and there is a distinct mechanism that influences its development, association studies should focus on subtypes simultaneously while studying specific genes. Data from such studies will thus provide better and intricate findings with regard to heterogenous ischaemic stroke. In the present review we discuss the genes studied by our group over a period of seven years in association with stroke subtypes in a South Indian population and correlate the findings with similar genetic studies from other populations so as to provide an overview of various genes involved in the pathogenesis of ischaemic stroke subtypes. PMID- 25447901 TI - Identification, phylogenetic evolutionary analysis of GDQY orf virus isolated from Qingyuan City, Guangdong Province, southern China. AB - Infection with the orf virus (ORFV) leads to contagious ecthyma, also called contagious pustular dermatitis, which usually affects sheep, goats and other small ruminants. It has a great distribution throughout the world and has also been reported to infect humans. Though many strains have been isolated from differing parts of mainland China, rarely has any strain been reported from the southern provinces of China. We studied a case of orf virus infection that occurred at Qingyuan City, Guangdong Province in southern China. An orf virus strain, GDQY, was successfully isolated and identified through cell culture techniques and transmission electron microscopy. Complete genes of ORFV011, ORFV059, ORFV106 and ORFV107 were amplified for the sequence analysis based on their nucleotide or amino acid level. In order to discuss the genetic variation, precise sequences were used to compare to other reference strains isolated from different districts or countries. Phylogenetic trees based on those strains were built up and evolutionary distances were calculated based on the alignment of their complete sequences. The typical structure of the orf virus was observed in cell-culture suspensions inoculated with GDQY, and the full-length of four genes was amplified and sequenced. Phylogenetic analysis indicated that GDQY is homologous to FJ-DS and CQ/WZ on ORFV011 nucleotides. ORFV059 may be more variable than ORFV011 based on the comparison between GDQY and other isolates. Genetic studies of ORFV106 and 107 are reported for the first time in the presented study. PMID- 25447902 TI - MicroRNA biogenesis pathway from the salmon louse (Caligus rogercresseyi): emerging role in delousing drug response. AB - Despite the increasing evidence of the importance of microRNAs (miRNAs) in the regulation of multiple biological processes, the molecular bases supporting this regulation are still barely understood in crustaceans. Therefore, the molecular characterization and transcriptome modulation of the miRNA biogenesis pathway were evaluated in the salmon louse Caligus rogercresseyi, an ectoparasite that constitutes one of the biggest concerns for salmonid aquaculture industry. Hence, RNA-Seq analysis was conducted from six different developmental stages, and also after bioassays with delousing drugs Deltamethrin and Azamethiphos using adult individuals. In silico analysis evidenced 24 putative genes involved in the miRNA pathway such as biogenesis, transport, maturation and miRNA-target interaction. Moreover, 243 putative single nucleotide polymorphisms (SNPs) were identified, 15 of which showed non-synonym mutations. RNA-Seq analysis revealed that CCR4-Not complex subunit 3 (CNOT3) was upregulated at earlier developmental stages (nauplius I-II and copepodid), and also after the exposure to Azamethiphos, but not to Deltamethrin. In contrast, the subunit 7 (CNOT7) showed an inverse expression pattern. Different Argonaute transcripts were associated to chalimus and adult stages, revealing specific expression patterns in response to antiparasitic drugs. Our results suggest novel insights into the regulatory network of the post-transcriptional gene regulation in C. rogercresseyi mediated by miRNAs, evidencing a putative role during the ontogeny and drug response. PMID- 25447903 TI - RNA-Seq-based transcriptome analysis of dormant flower buds of Chinese cherry (Prunus pseudocerasus). AB - Bud dormancy is a critical biological process allowing Chinese cherry (Prunus pseudocerasus) to survive in winter. Due to the lake of genomic information, molecular mechanisms triggering endodormancy release in flower buds have remained unclear. Hence, we used Illumina RNA-Seq technology to carry out de novo transcriptome assembly and digital gene expression profiling of flower buds. Approximately 47million clean reads were assembled into 50,604 sequences with an average length of 837bp. A total of 37,650 unigene sequences were successfully annotated. 128 pathways were annotated by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and metabolic, biosynthesis of second metabolite and plant hormone signal transduction accounted for higher percentage in flower bud. In critical period of endodormancy release, 1644, significantly differentially expressed genes (DEGs) were identified from expression profile. DEGs related to oxidoreductase activity were especially abundant in Gene Ontology (GO) molecular function category. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis demonstrated that DEGs were involved in various metabolic processes, including phytohormone metabolism. Quantitative real-time PCR (qRT-PCR) analysis indicated that levels of DEGs for abscisic acid and gibberellin biosynthesis decreased while the abundance of DEGs encoding their degradation enzymes increased and GID1 was down-regulated. Concomitant with endodormancy release, MADS-box transcription factors including P. pseudocerasus dormancy-associated MADS-box (PpcDAM), Agamous-like2, and APETALA3-like genes, shown remarkably epigenetic roles. The newly generated transcriptome and gene expression profiling data provide valuable genetic information for revealing transcriptomic variation during bud dormancy in Chinese cherry. The uncovered data should be useful for future studies of bud dormancy in Prunus fruit trees lacking genomic information. PMID- 25447904 TI - Alteration of BRCA1 expression affects alcohol-induced transcription of RNA Pol III-dependent genes. AB - Emerging evidence has indicated that alcohol consumption is an established risk factor for breast cancer. Deregulation of RNA polymerase III (Pol III) transcription enhances cellular Pol III gene production, leading to an increase in translational capacity to promote cell transformation and tumor formation. We have reported that alcohol intake increases Pol III gene transcription to promote cell transformation and tumor formation in vitro and in vivo. Studies revealed that tumor suppressors, pRb, p53, PTEN and Maf1 repress the transcription of Pol III genes. BRCA1 is a tumor suppressor and its mutation is tightly related to breast cancer development. However, it is not clear whether BRCA1 expression affects alcohol-induced transcription of Pol III genes. At the present studies, we report that restoring BRCA1 in HCC 1937 cells, which is a BRCA1 deficient cell line, represses Pol III gene transcription. Expressing mutant or truncated BRCA1 in these cells does not affect the ability of repression on Pol III genes. Our analysis has demonstrated that alcohol induces Pol III gene transcription. More importantly, overexpression of BRCA1 in estrogen receptor positive (ER+) breast cancer cells (MCF-7) decreases the induction of tRNA(Leu) and 5S rRNA genes by alcohol, whereas reduction of BRCA1 by its siRNA slightly increases the transcription of the class of genes. This suggests that BRCA1 is associated with alcohol-induced deregulation of Pol III genes. These studies for the first time demonstrate the role of BRCA1 in induction of Pol III genes by alcohol and uncover a novel mechanism of alcohol-associated breast cancer. PMID- 25447906 TI - Two novel NIPBL gene mutations in Chinese patients with Cornelia de Lange syndrome. AB - Cornelia de Lange syndrome (CdLS) is a dominantly inherited developmental disorder characterized by distinctive facial features, mental retardation, and upper limb defects, with the involvement of multiple organs and systems. To date, mutations have been identified in five genes responsible for CdLS: NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Here, we present a clinical and molecular characterization of five unrelated Chinese patients whose clinical presentation is consistent with that of CdLS. There were no chromosomal abnormalities in the five children. In three patients, DNA sequencing revealed a previously reported frameshift mutation c.2479delA (p.Arg827GlyfsX20), and two novel mutations including a heterozygous mutation c.6272 G>T (p.Cys2091Phe) and a frameshift mutation c.1672delA (p.Thr558LeufsX7) in NIPBL. For the remaining patients, large deletions and/or duplications within the NIPBL gene were excluded as playing a role in the pathogenesis, by Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. These findings broaden the mutation spectrum of NIPBL and further our understanding of the diverse and variable effects of NIPBL mutations on CdLS. PMID- 25447905 TI - Regulation of rDNA transcription in response to growth factors, nutrients and energy. AB - Exquisite control of ribosome biogenesis is fundamental for the maintenance of cellular growth and proliferation. Importantly, synthesis of ribosomal RNA by RNA polymerase I is a key regulatory step in ribosome biogenesis and a major biosynthetic and energy consuming process. Consequently, ribosomal RNA gene transcription is tightly coupled to the availability of growth factors, nutrients and energy. Thus cells have developed an intricate sensing network to monitor the cellular environment and modulate ribosomal DNA transcription accordingly. Critical controllers in these sensing networks, which mediate growth factor activation of ribosomal DNA transcription, include the PI3K/AKT/mTORC1, RAS/RAF/ERK pathways and MYC transcription factor. mTORC1 also responds to amino acids and energy status, making it a key hub linking all three stimuli to the regulation of ribosomal DNA transcription, although this is achieved via overlapping and distinct mechanisms. This review outlines the current knowledge of how cells respond to environmental cues to control ribosomal RNA synthesis. We also highlight the critical points within this network that are providing new therapeutic opportunities for treating cancers through modulation of RNA polymerase I activity and potential novel imaging strategies. PMID- 25447907 TI - Revisiting the essentiality of glutamate racemase in Mycobacterium tuberculosis. AB - Glutamate racemase (MurI) converts l-glutamate into d-glutamate which is an essential component of peptidoglycan in bacteria. The gene encoding glutamate racemase, murI has been shown to be essential for the growth of a number of bacterial species including Escherichia coli. However, in some Gram-positive species d-amino acid transaminase (Dat) can also convert l-glutamate into d glutamate thus rendering MurI non-essential for growth. In a recent study the murI gene of Mycobacterium tuberculosis was shown to be non-essential. As d glutamate is an essential component of peptidoglycan of M. tuberculosis, either Dat or MurI has to be essential for its survival. Since, a Dat encoding gene has not been reported in M. tuberculosis genome sequence, the reported non essentiality of murI was unexplainable. In order to resolve this dilemma we tried to knockout murI in the presence of single and two copies of murI, in wild type and merodiploid strains respectively. It was found that murI could not be inactivated in the wild type background indicating that it could be an essential gene. Also, inactivation of murI could not be achieved in the presence of externally supplied d-glutamate in 7H9 medium suggesting that M. tuberculosis is unable to take up d-glutamate under the conditions tested. However we could generate murI knockout strains at high frequency when two copies of the gene were present indicating that at least one murI gene is required for cellular viability. The essential nature of MurI in M. tuberculosis H37Rv suggests that it could be a potential drug target. PMID- 25447909 TI - Insertion sequence elements in Lactococcus garvieae. AB - Insertion sequences are the simplest intracellular Mobile Genetic Elements which can occur in very high numbers in prokaryotic genomes, where they play an important evolutionary role by promoting genome plasticity. As such, the studies on the diversity and distribution of insertion sequences in genomes not yet investigated can contribute to improve the knowledge on a bacterial species and to identify new transposable elements. The present work describes the occurrence of insertion sequences in Lactococcus garvieae, an opportunistic emerging zoonotic and human pathogen, also associated with different food matrices. To date, no insertion elements have been described for L. garvieae in the IS element database. The analysis of the twelve published L. garvieae genomes identified 15 distinct insertion sequences that are members of the IS3, IS982, IS6, IS21 and IS256 families, including five new elements. Most of the insertion sequences in L. garvieae show substantial homology to the Lactococcus lactis elements, suggesting the movement of IS between these two species phylogenetically closely related. ISLL6 elements belonging to IS3 family were most abundant, with several copies distributed in 9 of the 12 genomes analyzed. An alignment analysis of two complete genomes carrying multi-copies of this insertion sequence indicates a possible involvement of ISLL6 in chromosomal rearrangement. PMID- 25447908 TI - Genome-wide identification and analysis of the MADS-box gene family in apple. AB - The MADS-box gene family is one of the most widely studied families in plants and has diverse developmental roles in flower pattern formation, gametophyte cell division and fruit differentiation. Although the genome-wide analysis of this family has been performed in some species, little is known regarding MADS-box genes in apple (Malus domestica). In this study, 146 MADS-box genes were identified in the apple genome and were phylogenetically clustered into six subgroups (MIKC(c), MIKC*, Malpha, Mbeta, Mgamma and Mdelta) with the MADS-box genes from Arabidopsis and rice. The predicted apple MADS-box genes were distributed across all 17 chromosomes at different densities. Additionally, the MADS-box domain, exon length, gene structure and motif compositions of the apple MADS-box genes were analysed. Moreover, the expression of all of the apple MADS box genes was analysed in the root, stem, leaf, flower tissues and five stages of fruit development. All of the apple MADS-box genes, with the exception of some genes in each group, were expressed in at least one of the tissues tested, which indicates that the MADS-box genes are involved in various aspects of the physiological and developmental processes of the apple. To the best of our knowledge, this report describes the first genome-wide analysis of the apple MADS box gene family, and the results should provide valuable information for understanding the classification, cloning and putative functions of this family. PMID- 25447910 TI - Identification and expression characterization of the myostatin (MSTN) gene and association analysis with growth traits in the razor clam Sinonovacula constricta. AB - Myostatin (MSTN) is a member of the transforming growth factor-beta superfamily (TGF-beta) and is an important negative regulator of muscle growth in vertebrates. In this study, we cloned and analyzed the MSTN gene (Sc-MSTN) from razor clam (Sinonovacula constricta). The full length of Sc-MSTN cDNA sequence consists of 4226 base pairs (bp), comprising a 522-bp 5' untranslated region (UTR), a 2342-bp 3'UTR, and an open reading frame (ORF) that is 1362 in length. The ORF encodes 453 amino acids with a RXXR proteolytic site and nine conserved cysteines. Quantitative real-time PCR analysis revealed that the Sc-MSTN transcript was expressed in a wide range of tissues but appeared to exhibit the greatest level of expression in the foot. The transcript was widely detected in early developmental stages, showing the highest expression in the trochophore stage. Furthermore, six SNPs were identified in the coding region of the Sc-MSTN gene using direct sequencing. SNP-1 is non-synonymous and involves an amino acid change from Leu to Ser. Association analysis showed that SNP-1 and SNP-6 had significant influences on shell length (SL). The results suggested that MSTN could be selected as a candidate gene for the future molecular breeding of razor clam strains. PMID- 25447911 TI - Huntington's disease: an update of therapeutic strategies. AB - Huntington's disease (HD) is an autosomal dominant triplet repeat genetic disease, which results in progressive neuronal degeneration in the neostriatum and neocortex, and associated functional impairments in motor, cognitive, and psychiatric domains. Although the genetic mutation caused by abnormal CAG expansion within the htt gene on chromosome 4p16.3 is identified, the mechanism by which this leads to neuronal cell death and the question of why striatal neurones are targeted both remain unknown. Patients manifest a typical phenotype of sporadic, rapid, involuntary control of limb movement, stiffness of limbs, impaired cognition and severe psychiatric disturbances. There have been a number of therapeutic advances in the treatment of HD, such as fetal neural transplantation, RNA interference (RNAi) and transglutaminase inhibitors (Tgasei). Although there is intensive research into HD and recent findings seem promising, effective therapeutic strategies may not be developed until the next few decades. PMID- 25447913 TI - Eight SNVs in NF-kappaB pathway genes and their different performances between subclinical mastitis and mixed Chinese Holstein cows. AB - The nuclear factor-kappa B (NF-kappaB) pathway proteins are key players in controlling both innate and adaptive immunity. However, the information on NF kappaB pathway genes is very limited in mastitis resistance and milk production of Chinese Holstein cows. In this study, we examine the association of the NF kappaB pathway gene variants with milk quality traits and somatic cell score (SCS) in Chinese Holstein cows. Eight single nucleotide variants (SNVs) were identified within the bovine NF-kappaB pathway genes, using DNA pooled sequencing, PCR-RFLP, and forced PCR-RFLP methods. These SNVs include SNV1: g. 536 C>T (exon 10 of Rel), SNV2: g. 94 G>A (exon 20 of p100), SNV3: g. 43 T>C (intron 6 of p105), SNV4: g. 2397 T>G (intron 9 of p105), SNV5: g. 382 G>C (intron 1 of IkappaBdelta), SNV6: g. 21 C>T (exon 5 of IkappaBzeta), SNV7: g. 272 G>A (intron 6 of IkappaBzeta), and SNV8: g. 18 C>T (intron 10 of IkappaBzeta). The association analysis in mixed Chinese Holstein population showed that SNV1 was significantly or highly significantly associated (P<0.01 and P<0.05) with fat rate, protein rate and SCS. Furthermore, the SNV1-CC (wild genotype) determined serine showed the significantly lower SCS and higher milk production traits compared to TT and TC. SNV2 was significantly associated (P<0.05) with SCS; SNV3 was significantly associated (P<0.05) with fat rate; and SNV4 was significantly associated (P<0.05) with fat rate and SCS. In 199 subclinical mastitis Chinese Holstein cows, the statistical results absolutely differed from the mixed Chinese Holstein individuals. Splice-site prediction by SplicePort showed that single nucleotide difference at eight SNVs results in the acceptor score and donor score changing obviously that may lead to alternative splicing. In brief, SNV1, SNV2, SNV3 and SNV4 could be useful genetic markers for mastitis resistance selection and breeding in Chinese Holstein cows. Furthermore, whether these SNVs lead to alternative splicing need further research. PMID- 25447912 TI - RNA-Seq analysis of differentially expressed genes in rice under varied nitrogen supplies. AB - Ammonium is the main inorganic nitrogen source in paddy soil. Rice (Oryza sativa), an ammonium-preferring and -tolerant grain crop, is a valuable resource for researching ammonium-uptake mechanism and understanding the molecular networks that the plant copes with ammonium variation. To generate a broad survey of early responses affected by varied ammonium supplies in rice, RNA samples were prepared from the roots and shoots of rice plants subjected to nitrogen-free (0mM ammonium), 1mM ammonium and high ammonium (10mM ammonium) for a short period of 4h (1mM ammonium treatment as the control), respectively, and the transcripts were sequenced using the Illumina/HiSeqTM 2000 RNA sequencing (RNA-Seq) platform. By comparative analysis, 394 differentially expressed genes (DEGs) were identified in roots, among which, 143 and 251 DEGs were up- and down-regulated under nitrogen-free condition, respectively. In shoots, 468 (119 up-regulated/349 down-regulated) DEGs were found under such condition. However, with high ammonium treatment, only 63 genes (6 up-regulated/57 down-regulated) in roots and 115 genes in shoots (93 up-regulated/22 down-regulated) were differentially expressed. According to KEGG analysis, when exposed to nitrogen-free condition, DEGs participating in the carbohydrate and amino acid metabolisms were down regulated (with 1 exception) in roots as well as in shoots, implying reduced carbohydrate and nitrogen metabolisms. Under high ammonium supply, all DEGs associated with carbohydrate and amino acid metabolisms were down-regulated in roots and to the contrary, up-regulated in shoots. Aldehyde dehydrogenase (ALDH, NAD(+)) [EC: 1.2.1.3] seemed to have played an important role in rice shoots under high ammonium condition, analysis results implicated a coordinative regulation of carbohydrate with amino acid metabolisms under nitrogen deficiency as well as the high ammonium conditions during a short period of several hours in rice. Moreover, transcripts with abundance variation might be precious gene resources in responding to different ammonium supplies in rice. PMID- 25447914 TI - Genetic assessment of ornamental fish species from North East India. AB - Ornamental fishes are traded with multiple names from various parts around the world, including North East India. Most are collected from the wild, due to lack of species-specific culture or breeding, and therefore, such unmanaged collection of the wild and endemic species could lead to severe threats to biodiversity. Despite many regulatory policies, trade of threatened species, including the IUCN listed species have been largely uncontrolled, due to species identification problems arising from the utilization of multiple trade names. So, the development of species-specific DNA marker is indispensable where DNA Barcoding is proved to be helpful in species identification. Here, we investigated, through DNA Barcoding and morphological assessment, the identification of 128 ornamental fish specimens exported from NE India from different exporters. The generated sequences were subjected to similarity match in BOLD-IDS as well as BLASTN, and analysed using MEGA5.2 for species identification through Neighbour-Joining (NJ) clustering, and K2P distance based approach. The analysis revealed straightforward identification of 84 specimens into 35 species, while 44 specimens were difficult to distinguish based on CO1 barcode alone. However, these cases were resolved through morphology, NJ and distanced based method and found to be belonging to 16 species. Among the 51 identified species, 14 species represented multiple trade names; 17 species belonged to threatened category. Species-level identification through DNA Barcoding along with traditional morphotaxonomy reflects its efficacy in regulating ornamental fish trade and therefore, appeals for their conservation in nature. The use of trade names rather than the zoological name created the passage for trafficking of the threatened species and demands immediate attention for sustaining wildlife conservation. PMID- 25447916 TI - Molecular cloning, characterisation and mRNA expression of the ryanodine receptor from the peach-potato aphid, Myzus persicae. AB - The peach potato aphid, Myzus persicae, is one of the most important agricultural pests of temperate climates. It is mainly controlled through the judicious application of insecticides; however, over time, aphids have developed resistance to many insecticidal classes. The recent introduction of synthetic diamide insecticides, with a novel mode of action, potentially offers new tools to control aphid populations. These diamides act on the ryanodine receptor (RyR), a large endoplasmic calcium release channel. In this study we have cloned cDNAs encoding the complete open reading frame of the RyR from M. persicae. The open reading frame is 15,306 base pairs long and encodes a protein of 5101 amino acids. The aphid RyR shares many of the features of other insect and vertebrate RyRs, including a highly conserved transmembrane region. However, unlike the other RyRs characterised to date, the M. persicae channel does not display alternative splicing at any stage of its developmental cycle, so it cannot generate functional variants of the channel. PMID- 25447917 TI - The investigation of miR-221-3p and PAK1 gene expressions in breast cancer cell lines. AB - The most common malignancy in women is breast cancer. Drug resistance in the treatment of cancer still remains a major clinical concern. Resistance to tamoxifen is seen in half of the recurrences in breast cancer. The anti-estrogen tamoxifen gains agonistic property by transactivating ERalpha. PAK1-mediated phosphorylation of serine 305 (S305) of ERalpha leads to resistance to tamoxifen. In our study, PAK1-induced suggestive tamoxifen resistance was designed. According to our hypothesis, phosphorylation of ERalpha-S305 by PAK1 may be reversed by PAK1 transcriptional inhibition by miR-221-3p due to miR-221-3p targeting the 3' UTR of PAK1. For this purpose, we used Real-time PCR (qRT-PCR) to measure the expression level of miR-221-3p in ER-positive breast cancer cell lines (ZR-75-1, MCF7) and breast epithelial cell line, hTERT-HME1, as control in the laboratory in our department. The increase in the expression of PAK1 depending on miR-221-3p may be related to ZR-75-1 cell line which has invasive characteristic but other two ER+ cancer cell lines, MCF7 and HCC1500, have milder cancer severity. miR-221-3p may have a role on regulation of PAK1 expression because miR-221-3p expression level decreases while PAK1 expression level increases in SKBR3 cell line. miR-221-3p and PAK1 expressions in MDA-MB-231 cell line are higher than that of hTERT-HME1 cell line. This may mean that miR-221-3p has no regulatory effect on of PAK1 expression in this cell line. According to these results, miR-221-3p may give crucial information about molecular mechanism of the disease upon PAK1 activity or different mechanisms with respect to histopathology and severity of breast cancer. PMID- 25447920 TI - Editorial to the Special Issue Historical Medical Genetics II. PMID- 25447919 TI - Medaka vasa gene has an exonic enhancer for germline expression. AB - Enhancers are DNA sequences that enhance gene transcription in a position- and orientation-independent manner. Many enhancers controlling somatic gene expression have been described. Enhancers controlling germline expression have remained rare. Here we report the identification of V35 as a first exonic germline enhancer in vertebrates. V35 constitutes the first 35bp of exon 1 of the medaka vasa gene. V35 is required for vasa promoter function and sufficient to increase transcriptional activity of a heterologous promoter by ~13 fold in either forward or reverse orientation. V35 contains CAGCAGCACGAG for two paired E box-like motifs. Upon incubation with nuclear extract from spermatogonial cells, V35 formed three DNA-protein complexes. We show that complex formation is inhibited partially by oligos containing an E box or E box-like motif but completely by V35 and oligos that contain overlapped E box and E box-like motifs. Most importantly, V35 is sufficient to drive transgene expression in germ cells of developing embryos. These results establish V35 as the first exonic germline enhancer in a lower vertebrate, and provide evidence for the importance of exonic sequences in controlling germ gene expression. PMID- 25447918 TI - Identification and validation of reference genes for normalization of gene expression analysis using qRT-PCR in Helicoverpa armigera (Lepidoptera: Noctuidae). AB - BACKGROUND: Recent studies have focused on determining functional genes and microRNAs in the pest Helicoverpa armigera (Lepidoptera: Noctuidae). Most of these studies used quantitative real-time PCR (qRT-PCR). Suitable reference genes are necessary to normalize gene expression data of qRT-PCR. However, a comprehensive study on the reference genes in H. armigera remains lacking. RESULTS: Twelve candidate reference genes of H. armigera were selected and evaluated for their expression stability under different biotic and abiotic conditions. The comprehensive stability ranking of candidate reference genes was recommended by RefFinder and the optimal number of reference genes was calculated by geNorm. Two target genes, thioredoxin (TRX) and Cu/Zn superoxide dismutase (SOD), were used to validate the selection of reference genes. Results showed that the most suitable candidate combinations of reference genes were as follows: 28S and RPS15 for developmental stages; RPS15 and RPL13 for larvae tissues; EF and RPL27 for adult tissues; GAPDH, RPL27, and beta-TUB for nuclear polyhedrosis virus infection; RPS15 and RPL32 for insecticide treatment; RPS15 and RPL27 for temperature treatment; and RPL32, RPS15, and RPL27 for all samples. CONCLUSION: This study not only establishes an accurate method for normalizing qRT-PCR data in H. armigera but also serve as a reference for further study on gene transcription in H. armigera and other insects. PMID- 25447915 TI - A methods review on use of nonsense suppression to study 3' end formation and other aspects of tRNA biogenesis. AB - Suppressor tRNAs bear anticodon mutations that allow them to decode premature stop codons in metabolic marker gene mRNAs, that can be used as in vivo reporters of functional tRNA biogenesis. Here, we review key components of a suppressor tRNA system specific to Schizosaccharomyces pombe and its adaptations for use to study specific steps in tRNA biogenesis. Eukaryotic tRNA biogenesis begins with transcription initiation by RNA polymerase (pol) III. The nascent pre-tRNAs must undergo folding, 5' and 3' processing to remove the leader and trailer, nuclear export, and splicing if applicable, while multiple complex chemical modifications occur throughout the process. We review evidence that precursor-tRNA processing begins with transcription termination at the oligo(T) terminator element, which forms a 3' oligo(U) tract on the nascent RNA, a sequence-specific binding site for the RNA chaperone, La protein. The processing pathway bifurcates depending on a poorly understood property of pol III termination that determines the 3' oligo(U) length and therefore the affinity for La. We thus review the pol III termination process and the factors involved including advances using gene specific random mutagenesis by dNTP analogs that identify key residues important for transcription termination in certain pol III subunits. The review ends with a 'technical approaches' section that includes a parts lists of suppressor-tRNA alleles, strains and plasmids, and graphic examples of its diverse uses. PMID- 25447921 TI - Characterization of E3 ubiquitin ligase neuregulin receptor degradation protein-1 (Nrdp1) in the large yellow croaker (Larimichthys crocea) and its immune responses to Cryptocaryon irritans. AB - Neuregulin receptor degradation protein-1 (Nrdp1) was recently identified in humans as an important immune factor responding to the challenge of virus, LPS or cytokine. Its role in fish immune defense and whether it is involved in anti parasite immunity have not been proven yet. In this report, the full-length cDNA sequence and genomic structure of Nrdp1 in the large yellow croaker Larimichthys crocea (LcNrdp1) were identified and characterized. The full-length cDNA of LcNrdp1 was 1248bp, including a 5' untranslated region (UTR) of 32bp, a 3' UTR of 259bp and an open reading frame (ORF) of 937bp, encoding a polypeptide of 318 amino acid residues. The full-length genomic DNA sequence of LcNrdp1 was composed of 2635 nucleotides, including four exons and three introns. The putative LcNrdp1 protein had no signal peptide sequence and contained a characteristic Nrdp1 consensus motif C3HC3D ring finger and a Coiled-coil domain. Phylogenetic analysis showed that Nrdp1 in fish was closer with that in other vertebrates (79% 90% amino acid identity) than in invertebrates and bacteria (27%-65%). In fishes, Nrdp1 in large yellow croaker was closer with that in Takifugu rubripes. The expression profile showed that LcNrdp1 was constitutively expressed in all tested tissues, especially highly expressed in brain, muscle and kidney. Post-infection (PI) with Cryptocaryon irritans, an increased expression of LcNrdp1 was induced in infection sites (skin and gill), whereas in immune organs, the expression of LcNrdp1 was up-regulated in spleen (except the 1st d and 10th d PI) but suppressed in head kidney. These results suggested that LcNrdp1 might play an important immune role in the finfish L. crocea in the defense against the parasite C. irritans. PMID- 25447922 TI - A rice DEAD-box RNA helicase protein, OsRH17, suppresses 16S ribosomal RNA maturation in Escherichia coli. AB - DEAD-box proteins comprise a large protein family. These proteins function in all types of processes in RNA metabolism and are highly conserved among eukaryotes. However, the precise functions of DEAD-box proteins in rice physiology and development remain unclear. In this study, we identified a rice DEAD-box protein, OsRH17, that contains a DEAD domain and all of the common conserved motifs of DEAD-box RNA helicases. OsRH17 was specifically expressed in pollen and differentiated callus and upregulated by application of the plant hormones naphthyl acetic acid (NAA) and abscisic acid (ABA). The OsRH17:GFP fusion protein was localized to the nucleus. Tiny amounts of OsRH17 and partial fragments (N-427 and C-167) were detected when they were expressed in Escherichia coli, a prokaryote. Growth of the host cells was suppressed in E. coli by OsRH17, N-427 or C-167, and this suppression was independent of the concentration of the NaCl in the medium. Expression analysis of rRNAs in E. coli revealed that the 16S rRNA precursor accumulated in transgenic E. coli cells, and the relative growth rate was inversely proportional to the levels of pre-16S rRNA accumulation. Results suggested that OsRH17 may play a role in ribosomal biogenesis and suppress 16S rRNA maturation in E. coli. No visible phenotype was observed in transgenic yeast and rice (overexpressing OsRH17, N-427, and C-167, as well as OsRH17 knockdown), and even in some abiotic and biotic stresses, which could be due to the redundancy in rice under normal conditions. PMID- 25447923 TI - Comparisons of isomiR patterns and classification performance using the rank based MANOVA and 10-fold cross-validation. AB - Next generation sequencing technology has identified a series of miRNA variants (named "isomiRs"), which might be associated with cancer progression. We provide a new strategy to reanalyze the miR-seq datasets through a view of the isomiR spectrum. Firstly, differentially expressed (DE) isomiRs were detected with the DESeq algorithm based on negative binomial distribution. Secondly, the rank-based MANOVA was adopted to compare the isomiR patterns between normal and tumor tissues. Moreover, a comprehensive survey on classification performance of three features was conducted, including the logistic regression, k-nearest neighbors and Random Forest. Finally, functional enrichment analysis was performed with the putative targets of specific isomiRs to elucidate their biological functions. Furthermore, the methods were applied to the downloaded miR-seq datasets of breast invasive carcinoma from TCGA. We found that the expression levels of multiple isomiRs derived from the same miRNA locus showed significant inconsistency between normal and tumor samples. In most cases, logistic regression with multiple DE isomiRs was superior to the others, with highest AUC and lowest AIC. Similarly, DE isomiRs performed best in the average accuracy of standard classifiers. Integrated targets were significantly enriched in some cancer-related pathways, including MAPK signaling pathway, and focal adhesion. Collectively, we could recommend the rank-based MANOVA for comparing different isomiR patterns, and further investigation on isomiRs needs to be considered in miRNA sequencing research. PMID- 25447924 TI - Evaluation of cardio-protective effect of soybean oligosaccharides. AB - The aim of the present study was to investigate whether soybean oligosaccharides (SO) protects heart function against myocardium ischemia reperfusion (MIR) injury. Hearts were 20min global ischemia and 50min reperfusion. Rats were fed for 30days with saline (sham and MIR groups) or the SO (200 or 400mg/kg body weight, daily). At the end of 30days, the left main coronary artery was occluded for 30min, followed by 24h reperfusion, in anesthetized rats. Sham operated animals were subjected to the same surgical procedures, except that the suture under the left anterior descending coronary artery was not tied. Results showed that SO decreased malondialdehyde (MDA) level and increased antioxidant enzymes activities in the SO-treatment group. Pre-treated with SO it showed a significant recovery in cardiac contractile function, reduction in infarct size, and decrease in creatine kinase (CK), aspartate transaminase (AST) and lactate dehydrogenase (LDH) activities. Moreover, SO also significantly increased the expression of p JAK2 and p-STAT3 proteins in rat heart. However, no significant change in JAK2 and STAT3 levels was observed. Activation of JAK2/STAT3 pathway showed a significant protective role in the SO-treatment group. Perhaps, the altered activation of the JAK2/STAT3 pathway in ischemic myocardium is one mechanism by which SO is cardioprotective. PMID- 25447925 TI - Analysis of spatiotemporal expression and function of the single-minded homolog in the branchiopod crustacean Daphnia magna. AB - In insect Drosophila melanogaster, ventral midline cells are crucial to formation of the central nervous system (CNS) and have roles in the specification of ectodermal neuroblasts. Notably, midline cells also have more recently recognized roles in the formation of the higher crustacean Parhyale dorso-ventral axis. The single-minded is a master regulator of ventral midline cells and is required for these functions. Recently sim expression patterns have been reported in various arthropods. These results suggest that the midline precursors evolved from ventral neuroectoderm of common ancestor Mandibulata. However, sim function has been only analyzed in few organisms. To investigate whether these functions of sim, the gene encoding Single-minded, are conserved among insects and crustaceans, we examined the embryonic expression pattern of a lower crustacean Daphnia sim homolog (dma sim) and analyzed the function of dma sim during embryonic development. The Dma Sim protein was expressed in the ventral neuroectoderm (like in onychophoran and chelicerate) and midline (like in mandibulatan). In addition to this conserved ventral neuroectoderm and midline expression, Dma Sim was expressed outside the ventral midline; it was expressed in maxilla 2, presumptive shell glands, and other tissues. To investigate dma sim function, we used RNA interference (RNAi) to inhibit dma sim in Daphnia embryos. Embryos subjected to dma sim RNAi exhibited improper axon tract formation and abnormal limb and ventral development. Furthermore, RNAi-mediated knockdown of dma slit, a putative Dma Sim target gene, resulted in similar embryonic phenotypes. These results indicated that dma sim might be required for proper dma slit-mediated ventral development in addition to being required for a conserved role in the ventral midline. Our findings indicated that sim homologs might have provided different developmental functions to ventral midline cells during metazoan evolution. PMID- 25447926 TI - To pill or not to pill in GnRH antagonist cycles: that is the question! AB - Worldwide, gonadotrophin-releasing hormone (GnRH) antagonists are gaining ground, and the number of patients being treated for IVF with a GnRH antagonist is increasing. Cycle planning in GnRH antagonist IVF cycles has been a challenge. During the past 2 years, debate has been ongoing about the possible disadvantages of oral contraceptive pill (OCP) pre-treatment in GnRH antagonist IVF cycles. A recent meta-analysis clearly showed a significant decrease in ongoing pregnancy rates between patients who received OCP pre-treatment and those who did not. In this review, the published meta-analysis are is evaluated. It is argued that caution must be exercised in drawing conclusions too quckly on whether or not OCP pre-treatment might have a negative effect on outcome in GnRH antagonist IVF cycles. PMID- 25447927 TI - Response: anogenital distance in newborns. PMID- 25447928 TI - Composite biomarkers for assessing Duchenne muscular dystrophy: an initial assessment. AB - BACKGROUND: Compared with individual parameters, composite biomarkers may provide a more effective means for monitoring disease progression and the effects of therapy in clinical trials than single measures. In this study, we built composite biomarkers for use in Duchenne muscular dystrophy by combining values from two objective measures of disease severity: electrical impedance myography and quantitative ultrasound and evaluating how well they correlated to standard functional measures. METHODS: Using data from an ongoing study of electrical impedance myography and quantitative ultrasound in 31 Duchenne muscular dystrophy and 26 healthy boys aged 2-14 years, we combined data sets by first creating z scores based on the normal subject data and then using simple mathematical operations (addition and multiplication) to create composite measures. These composite scores were then correlated to age and standard measures of function including the 6-minute walk test, the North Star Ambulatory Assessment, and handheld dynamometry. RESULTS: Combining data sets resulted in stronger correlations with all four outcomes than for either electrical impedance myography or quantitative ultrasound alone in six of eight instances. These improvements reached statistical significance (P < 0.05) in several cases. For example, the correlation coefficient for the composite measure with the North Star Ambulatory Assessment was 0.79 but was only 0.66 and 0.67 (respectively) for gray scale level and electrical impedance myography separately. CONCLUSIONS: Arithmetically derived composite scores can provide stronger correlations to functional measures than isolated biomarkers. Longitudinal study of such composite markers in Duchenne muscular dystrophy clinical trials is warranted. PMID- 25447929 TI - Hypoxic-ischemic encephalopathy mimicking acute necrotizing encephalopathy. AB - BACKGROUND: Acute necrotizing encephalopathy is a rare childhood syndrome associated with distinct and unifying neuroimaging features that are often used for the diagnosis of this entity. PATIENT: We describe a previously healthy 9 month-old girl who presented with upper respiratory symptoms, suspected seizures, and positive nasopharyngeal rapid antigen test for influenza A virus. Magnetic resonance imaging revealed signal abnormality in both thalami, bilateral caudate nuclei, brainstem tegmentum, subcortical white matter, and cerebellar hemispheres, suggestive of acute necrotizing encephalopathy. She subsequently had a cardiac arrest, was placed on extracorporeal membrane oxygenation, and treated with methylprednisone, intravenous immunoglobulin, and plasmapheresis without apparent clinical response. On autopsy, neuropathology showed evidence of hypoxic ischemic injury but lacked evidence of hemorrhagic necrosis, which is typically associated with acute necrotizing encephalopathy. CONCLUSION: Combined clinical and neuroimaging features may be suggestive but not sufficient for the diagnosis of acute necrotizing encephalopathy. PMID- 25447931 TI - Out-of-pocket costs for childhood stroke: the impact of chronic illness on parents' pocketbooks. AB - OBJECTIVE: Direct costs for children who had stroke are similar to those for adults. There is no information regarding the out-of-pocket costs families encounter. We described the out-of-pocket costs families encountered in the first year after a child's ischemic stroke. METHODS: Twenty-two subjects were prospectively recruited at four centers in the United States and Canada in 2008 and 2009 as part of the "Validation of the Pediatric NIH Stroke Scale" study; families' indirect costs were tracked for 1 year. Every 3 months, parents reported hours they did not work, nonreimbursed costs for medical visits or other health care, and mileage. They provided estimates of annual income. We calculated total out-of-pocket costs in US dollars and reported costs as a proportion of annual income. RESULTS: Total median out-of-pocket cost for the year after an ischemic stroke was $4354 (range, $0-$28,666; interquartile range, $1008-$8245). Out-of-pocket costs were greatest in the first 3 months after the incident stroke, with the largest proportion because of lost wages, followed by transportation, and nonreimbursed health care. For the entire year, median costs represented 6.8% (range, 0%-81.9%; interquartile range, 2.7%-17.2%) of annual income. CONCLUSIONS: Out-of-pocket expenses are significant after a child's ischemic stroke. The median costs are noteworthy provided that the median American household had cash savings of $3650 at the time of the study. These results with previous reports of direct costs provide a more complete view of the overall costs to families and society. Childhood stroke creates an under recognized cost to society because of decreased parental productivity. PMID- 25447930 TI - The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia Parkinsonism, CAPOS and beyond. AB - BACKGROUND: ATP1A3 mutations have now been recognized in infants and children presenting with a diverse group of neurological phenotypes, including Rapid-onset Dystonia-Parkinsonism (RDP), Alternating Hemiplegia of Childhood (AHC), and most recently, Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss (CAPOS) syndrome. METHODS: Existing literature on ATP1A3-related disorders in the pediatric population were reviewed, with attention to clinical features and associated genotypes among those with RDP, AHC, or CAPOS syndrome phenotypes. RESULTS: While classically defined phenotypes associated with AHC, RDP, and CAPOS syndromes are distinct, common elements among ATP1A3-related neurological disorders include characteristic episodic neurological symptoms and signs that vary in severity, duration, and frequency of occurrence. Affected children typically present in the context of an acute onset of paroxysmal, episodic neurological symptoms ranging from oculomotor abnormalities, hypotonia, paralysis, dystonia, ataxia, seizure-like episodes, or encephalopathy. Neurodevelopmental delays or persistence of dystonia, chorea, or ataxia after resolution of an initial episode are common, providing important clues for diagnosis. CONCLUSIONS: The phenotypic spectrum of ATP1A3-related neurological disorders continues to expand beyond the distinct yet overlapping phenotypes in patients with AHC, RDP, and CAPOS syndromes. ATP1A3 mutation analysis is appropriate to consider in the diagnostic algorithm for any child presenting with episodic or fluctuating ataxia, weakness or dystonia whether they manifest persistence of neurological symptoms between episodes. Additional work is needed to better identify and classify affected patients and develop targeted treatment approaches. PMID- 25447932 TI - Validation of polyvinylidene fluoride nasal sensor to assess nasal obstruction in comparison with subjective technique. AB - OBJECTIVE: The aim of this study is to validate the applicability of the PolyVinyliDene Fluoride (PVDF) nasal sensor to assess the nasal airflow, in healthy subjects and patients with nasal obstruction and to correlate the results with the score of Visual Analogue Scale (VAS). METHODS: PVDF nasal sensor and VAS measurements were carried out in 50 subjects (25-healthy subjects and 25 patients). The VAS score of nasal obstruction and peak-to-peak amplitude (Vp-p) of nasal cycle measured by PVDF nasal sensors were analyzed for right nostril (RN) and left nostril (LN) in both the groups. Spearman's rho correlation was calculated. The relationship between PVDF nasal sensor measurements and severity of nasal obstruction (VAS score) were assessed by ANOVA. RESULTS: In healthy group, the measurement of nasal airflow by PVDF nasal sensor for RN and LN were found to be 51.14+/-5.87% and 48.85+/-5.87%, respectively. In patient group, PVDF nasal sensor indicated lesser nasal airflow in the blocked nostrils (RN: 23.33+/ 10.54% and LN: 32.24+/-11.54%). Moderate correlation was observed in healthy group (r=-0.710, p<0.001 for RN and r=-0.651, p<0.001 for LN), and moderate to strong correlation in patient group (r=-0.751, p<0.01 for RN and r=-0.885, p<0.0001 for LN). CONCLUSION: PVDF nasal sensor method is a newly developed technique for measuring the nasal airflow. Moderate to strong correlation was observed between PVDF nasal sensor data and VAS scores for nasal obstruction. In our present study, PVDF nasal sensor technique successfully differentiated between healthy subjects and patients with nasal obstruction. Additionally, it can also assess severity of nasal obstruction in comparison with VAS. Thus, we propose that the PVDF nasal sensor technique could be used as a new diagnostic method to evaluate nasal obstruction in routine clinical practice. PMID- 25447933 TI - Mortality in Parkinson's disease: a 38-year follow-up study. AB - BACKGROUND: In this study we report on the outcome including overall and cause specific mortality of Parkinson's disease (PD) patients subsequent to 38 years of surveillance. This is an extension study of our previous report on mortality. METHODS: Two hundred thirty-seven patients with a symptom onset between 1974 and 1984 were followed until the date of December 31, 2012 or death, representing a follow-up period of up to 38 years. Overall and cause-specific standardized mortality ratios (SMRs) were calculated, and predictors for survival at disease onset were estimated. RESULTS AND CONCLUSION: Two hundred thirty patients had died by December 31, 2012; a total of 3,489 person-years were available for observation. The SMR at 38 years of follow-up was 2.02 (1.76-2.29). Employing Cox's proportional hazard modeling, male sex, gait disorder, absence of classical rest tremor, and absence of asymmetry predicted poor survival in this cohort. Increased cause-specific SMRs were found for pneumonia and cerebrovascular and cardiovascular diseases. PMID- 25447934 TI - Mannan-conjugated myelin peptides prime non-pathogenic Th1 and Th17 cells and ameliorate experimental autoimmune encephalomyelitis. AB - Antigen presenting cells (APC) are critical for regulating immune responses. We tested mannan-peptide conjugates for targeting myelin peptides to APC to induce T cell tolerance and resistance to experimental autoimmune encephalomyelitis (EAE). Myelin peptides conjugated to mannan in oxidized (OM) or reduced (RM) forms protected mice against EAE in prophylactic and therapeutic protocols, with OM conjugated peptides giving best results. Protection was peptide-specific and associated with reduced antigen-specific T cell proliferation, but not alterations in Th1, Th17 and Treg cell differentiation or T cell apoptosis compared to EAE controls. Bone marrow-derived dendritic cells (DC) loaded with OM MOG showed up-regulated expression of co-stimulatory molecules, reduced PD-L1 expression and enhanced CD40-inducible IL-12 and IL-23 production compared to MOG DC, features consistent with immunogenic DC. OM-MOG induced active T cell tolerance because i.d. administration or passive transfer of OM-MOG DC suppressed ongoing EAE, while OM-MOG-vaccinated mice did not reduce the proliferation of transferred MOG-specific T cells. As in vivo, MOG-specific T cells cultured with OM-MOG DC showed reduced proliferation and equal Th1 and Th17 cell differentiation compared to those with MOG DC, but surprisingly cytokine production was unresponsive to CD40 engagement. Impaired effector T cell function was further evidenced in spinal cord sections from OM-MOG-vaccinated EAE mice, where markedly reduced numbers of CD3(+) T cells were present, restricted to leptomeninges and exceptional parenchymal lesions. Our results show that mannan conjugated myelin peptides protect mice against EAE through the expansion of antigen-specific Th1 and Th17 cells with impaired proliferation responses and APC induced co-stimulatory signals that are required for licensing them to become fully pathogenic T cells. PMID- 25447936 TI - Stress hormone corticosterone enhances susceptibility to cortical spreading depression in familial hemiplegic migraine type 1 mutant mice. AB - Stress is a putative migraine trigger, but the pathogenic mechanisms involved are unknown. Stress and stress hormones increase neuronal excitability by enhancing glutamatergic neurotransmission, but inhibitory effects have also been reported. We hypothesise that an acute rise in stress hormones, such as corticosteroids which are released after stress, increase neuronal excitability and thereby may increase susceptibility to cortical spreading depression (CSD), the mechanism underlying the migraine aura. Here we investigated effects of acute restraint stress and of the stress hormone corticosterone on CSD susceptibility as surrogate migraine marker, in a transgenic mouse model of familial hemiplegic migraine type 1 (FHM1), which displays increased glutamatergic cortical neurotransmission and increased propensity for CSD. We found that 20-min and 3-h restraint stress did not influence CSD susceptibility in mutant or wild-type mice, despite elevated levels of plasma corticosterone. By contrast, subcutaneous administration of 20mg/kg corticosterone increased CSD frequency exclusively in mutant mice, while corticosterone plasma levels were similarly elevated in mutants and wild types. The effect of corticosterone on CSD frequency was normalised by pre-administration of the glucocorticoid receptor (GR) antagonist mifepristone. These findings suggest that corticosteroid-induced GR activation can enhance susceptibility to CSD in genetically susceptible individuals, and may predispose to attacks of migraine. Although corticosterone levels rise also during acute stress, the latter likely triggers a spatiotemporally more complex biological response with multiple positive and negative modulators which may not be adequately modeled by exogenous administration of corticosterone alone. PMID- 25447935 TI - Pharmacologically inhibiting kinesin-5 activity with monastrol promotes axonal regeneration following spinal cord injury. AB - While it is well established that the axons of adult neurons have a lower capacity for regrowth, some regeneration of certain CNS populations after spinal cord injury (SCI) is possible if their axons are provided with a permissive substrate, such as an injured peripheral nerve. While some axons readily regenerate into a peripheral nerve graft (PNG), these axons almost always stall at the distal interface and fail to reinnervate spinal cord tissue. Treatment of the glial scar at the distal graft interface with chondroitinase ABC (ChABC) can improve regeneration, but most regenerated axons need further stimulation to extend beyond the interface. Previous studies demonstrate that pharmacologically inhibiting kinesin-5, a motor protein best known for its essential role in mitosis but also expressed in neurons, with the pharmacological agent monastrol increases axon growth on inhibitory substrates in vitro. We sought to determine if monastrol treatment after an SCI improves functional axon regeneration. Animals received complete thoracic level 7 (T7) transections and PNGs and were treated intrathecally with ChABC and either monastrol or DMSO vehicle. We found that combining ChABC with monastrol significantly enhanced axon regeneration. However, there were no further improvements in function or enhanced c-Fos induction upon stimulation of spinal cord rostral to the transection. This indicates that monastrol improves ChABC-mediated axon regeneration but that further treatments are needed to enhance the integration of these regrown axons. PMID- 25447937 TI - The role of the nitric oxide pathway in brain injury and its treatment--from bench to bedside. AB - Nitric oxide (NO) is a key signalling molecule in the regulation of cerebral blood flow. This review summarises current evidence regarding the role of NO in the regulation of cerebral blood flow at rest, under physiological conditions, and after brain injury, focusing on subarachnoid haemorrhage, traumatic brain injury, and ischaemic stroke and following cardiac arrest. We also review the role of NO in the response to hypoxic insult in the developing brain. NO depletion in ischaemic brain tissue plays a pivotal role in the development of subsequent morbidity and mortality through microcirculatory disturbance and disordered blood flow regulation. NO derived from endothelial nitric oxide synthase (eNOS) appears to have neuroprotective properties. However NO derived from inducible nitric oxide synthase (iNOS) may have neurotoxic effects. Cerebral NO donor agents, for example sodium nitrite, appear to replicate the effects of eNOS derived NO, and therefore have neuroprotective properties. This is true in both the adult and immature brain. We conclude that these agents should be further investigated as targeted pharmacotherapy to protect against secondary brain injury. PMID- 25447938 TI - Emergence of cognitive deficits after mild traumatic brain injury due to hyperthermia. AB - Mild elevations in core temperature can occur in individuals involved in strenuous activities that are risky for potentially sustaining a mild traumatic brain injury (mTBI) or concussion. Recently, we have discovered that mild elevations in brain temperature can significantly aggravate the histopathological consequences of mTBI. However, whether this exacerbation of brain pathology translates into behavioral deficits is unknown. Therefore, we investigated the behavioral consequences of elevating brain temperature to mildly hyperthermic levels prior to mTBI. Adult male Sprague Dawley rats underwent mild fluid percussion brain injury or sham surgery while normothermic (37 degrees C) or hyperthermic (39 degrees C) and were allowed to recover for 7 days. Animals were then assessed for cognition using the water maze and cue and contextual fear conditioning. We found that mTBI alone at normothermia had no effect on long-term cognitive measures whereas mTBI animals that were hyperthermic for 15 min prior to and for 4h after brain injury were significantly impaired on long-term retention for both the water maze and fear conditioning. In contrast, hyperthermic mTBI animals cooled within 15 min to normothermia demonstrated no significant long-term cognitive deficits. Mild TBI irrespective of temperature manipulations resulted in significant short-term working memory deficits. Cortical atrophy and contusions were detected in all mTBI treatment groups and contusion volume was significantly less in hyperthermic mTBI animals that were cooled as compared to hyperthermic mTBI animals that remained hyperthermic. These results indicate that brain temperature is an important variable for mTBI outcome and that mildly elevated temperatures at the time of injury result in persistent cognitive deficits. Importantly, cooling to normothermia after mTBI prevents the development of long-term cognitive deficits caused by hyperthermia. Reducing temperature to normothermic levels soon after mTBI represents a rational approach to potentially mitigate the long-term consequences of mTBI. PMID- 25447939 TI - Upregulation of the GEF-H1 pathway after transient cerebral ischemia. AB - The microtubule-dependent GEF-H1 pathway controls synaptic re-networking and overall gene expression via regulating cytoskeleton dynamics. Understanding this pathway after ischemia is essential to developing new therapies for neuronal function recovery. However, how the GEF-H1 pathway is regulated following transient cerebral ischemia remains unknown. This study employed a rat model of transient forebrain ischemia to investigate alterations of the GEF-H1 pathway using Western blotting, confocal and electron microscopy, dephosphorylation analysis, and pull-down assay. The GEF-H1 activity was significantly upregulated by: (i) dephosphorylation and (ii) translocation to synaptic membrane and nuclear structures during the early phase of reperfusion. GEF-H1 protein was then downregulated in the brain regions where neurons were destined to undergo delayed neuronal death, but markedly upregulated in neurons that were resistant to the same episode of cerebral ischemia. Consistently, GTP-RhoA, a GEF-H1 substrate, was significantly upregulated after brain ischemia. Electron microscopy further showed that neuronal microtubules were persistently depolymerized in the brain region where GEF-H1 protein was downregulated after brain ischemia. The results demonstrate that the GEF-H1 activity is significantly upregulated in both vulnerable and resistant brain regions in the early phase of reperfusion. However, GEF-H1 protein is downregulated in the vulnerable neurons but upregulated in the ischemic resistant neurons during the recovery phase after ischemia. The initial upregulation of GEF-H1 activity may contribute to excitotoxicity, whereas the late upregulation of GEF-H1 protein may promote neuroplasticity after brain ischemia. PMID- 25447940 TI - Deficiency in monocarboxylate transporter 1 (MCT1) in mice delays regeneration of peripheral nerves following sciatic nerve crush. AB - Peripheral nerve regeneration following injury occurs spontaneously, but many of the processes require metabolic energy. The mechanism of energy supply to axons has not previously been determined. In the central nervous system, monocarboxylate transporter 1 (MCT1), expressed in oligodendroglia, is critical for supplying lactate or other energy metabolites to axons. In the current study, MCT1 is shown to localize within the peripheral nervous system to perineurial cells, dorsal root ganglion neurons, and Schwann cells by MCT1 immunofluorescence in wild-type mice and tdTomato fluorescence in MCT1 BAC reporter mice. To investigate whether MCT1 is necessary for peripheral nerve regeneration, sciatic nerves of MCT1 heterozygous null mice are crushed and peripheral nerve regeneration was quantified electrophysiologically and anatomically. Compound muscle action potential (CMAP) recovery is delayed from a median of 21 days in wild-type mice to greater than 38 days in MCT1 heterozygote null mice. In fact, half of the MCT1 heterozygote null mice have no recovery of CMAP at 42 days, while all of the wild-type mice recovered. In addition, muscle fibers remain 40% more atrophic and neuromuscular junctions 40% more denervated at 42 days post crush in the MCT1 heterozygote null mice than wild-type mice. The delay in nerve regeneration is not only in motor axons, as the number of regenerated axons in the sural sensory nerve of MCT1 heterozygote null mice at 4 weeks and tibial mixed sensory and motor nerve at 3 weeks is also significantly reduced compared to wild-type mice. This delay in regeneration may be partly due to failed Schwann cell function, as there is reduced early phagocytosis of myelin debris and remyelination of axon segments. These data for the first time demonstrate that MCT1 is critical for regeneration of both sensory and motor axons in mice following sciatic nerve crush. PMID- 25447942 TI - An in vitro assay to study induction of the regenerative state in sensory neurons. AB - After injury, peripheral neurons activate a pro-regenerative program that facilitates axon regeneration. While many regeneration-associated genes have been identified, the mechanism by which injury activates this program is less well understood. Furthermore, identifying pharmacological methods to induce a pro regenerative state could lead to novel treatments to repair the injured nervous system. Therefore, we have developed an in vitro assay to study induction of the pro-regenerative state following injury or pharmacological treatment. First, we took advantage of the observation that dissociating and culturing sensory neurons from dorsal root ganglia activates a pro-regenerative program. We show that cultured neurons activate transcription factors and upregulate regeneration associated genes common to the pro-regenerative program within the first hours after dissection. In a paradigm similar to pre-conditioning, neurons injured by dissociation display enhanced neurite outgrowth when replated as early as 12h after being removed from the animal. Furthermore, stimulation of the pro regenerative state improves growth on inhibitory substrates and requires DLK/JNK signaling, both hallmarks of the pro-regeneration response in vivo. Finally, we modified this assay in order to identify new methods to activate the pro regenerative state in an effort to mimic the pre-conditioning effect. We report that after several days in culture, neurons down-regulate many molecular hallmarks of injury and no longer display enhanced neurite outgrowth after replating. Hence, these neurons are functionally naive and are a useful tool for identifying methods to induce the pro-regenerative state. We show that both injury and pre-treatment with forskolin reactivate the pro-regenerative state in this paradigm. Hence, this assay is useful for identifying pharmacological agents that induce the pro-regenerative state in the absence of injury. PMID- 25447944 TI - Role of synucleins in traumatic brain injury - an experimental in vitro and in vivo study in mice. AB - Synucleins are small prone to aggregate proteins associated with several neurodegenerative diseases (NDDs), however their role in traumatic brain injury (TBI) is an emerging area of investigation. Using in vitro scratch injury model and in vivo mouse weight-drop model we have found that the injury causes alterations in the expression and localization of synucleins near the damaged area. Before injury, alpha-synuclein is diffused in the cytoplasm of neurons and gamma-synuclein is both in the cytoplasm and nucleus of oligodendrocytes. After the scratch injury of the mixed neuronal and glial culture, alpha-synuclein forms punctate structures in the cytoplasm of neurons and gamma-synuclein is almost completely localized to the nucleus of the oligodendrocytes. Furthermore, the amount of post-translationally modified Met38-oxidized gamma-synuclein is increased 3.8 fold 24 h after the scratch. alpha- and gamma-synuclein containing cells increased in the initially cell free scratch zone up to 24 h after the scratch.Intracellular expression and localization of synucleins are also changed in a mouse model of focal closed head injury, using a standardized weight drop device. gamma-Synuclein goes from diffuse to punctate staining in a piriform cortex near the amygdala, which may reflect the first steps in the formation of deposits/inclusions. Surprisingly, oxidized gamma-synuclein co-localizes with cofilin-actin rods in the thalamus, which are absent in all other regions of the brain. These structures reach their peak amounts 7 days after injury. The changes in gamma-synuclein localization are accompanied by injury-induced alterations in the morphology of both astrocytes and neurons. PMID- 25447943 TI - Vascular pathology of 20-month-old hypercholesterolemia mice in comparison to triple-transgenic and APPSwDI Alzheimer's disease mouse models. AB - Several studies have shown that elevated plasma cholesterol levels (i.e. hypercholesterolemia) serve as a risk factor for late-onset Alzheimer's disease (AD). However, it remains unclear how hypercholesterolemia may contribute to the onset and progression of AD pathology. In order to determine the role of hypercholesterolemia at various stages of AD, we evaluated the effects of high cholesterol diet (5% cholesterol) in wild-type (WT; C57BL6) and triple-transgenic AD (3xTg-AD; Psen1, APPSwe, tauB301L) mice at 7, 14, and 20 months. The transgenic APP-Swedish/Dutch/Iowa AD mouse model (APPSwDI) was used as a control since these animals are more pathologically-accelerated and are known to exhibit extensive plaque deposition and cerebral amyloid angiopathy. Here, we describe the effects of high cholesterol diet on: (1) cognitive function and stress, (2) AD-associated pathologies, (3) neuroinflammation, (4) blood-brain barrier disruption and ventricle size, and (5) vascular dysfunction. Our data show that high dietary cholesterol increases weight, slightly impairs cognitive function, promotes glial cell activation and complement-related pathways, enhances the infiltration of blood-derived proteins and alters vascular integrity, however, it does not induce AD-related pathologies. While normal-fed 3xTg-AD mice display a typical AD-like pathology in addition to severe cognitive impairment and neuroinflammation at 20 months of age, vascular alterations are less pronounced. No microbleedings were seen by MRI, however, the ventricle size was enlarged. Triple-transgenic AD mice, on the other hand, fed a high cholesterol diet do not survive past 14 months of age. Our data indicates that cholesterol does not markedly potentiate AD-related pathology, nor does it cause significant impairments in cognition. However, it appears that high cholesterol diet markedly increases stress-related plasma corticosterone levels as well as some vessel pathologies. Together, our findings represent the first demonstration of prolonged high cholesterol diet and the examination of its effects at various stages of cerebrovascular- and AD-related disease. PMID- 25447941 TI - Gene expression profiling studies in regenerating nerves in a mouse model for CMT1X: uninjured Cx32-knockout peripheral nerves display expression profile of injured wild type nerves. AB - X-linked Charcot-Marie-Tooth disease (CMT1X) is an inherited peripheral neuropathy caused by mutations in GJB1, the human gene for Connexin32 (Cx32). This present study uses Ilumina Ref8-v2 BeadArray to examine the expression profiles of injured and uninjured sciatic nerves at 5, 7, and 14 days post-crush injury (dpi) from Wild Type (WT) and Cx32-knockout (Cx32KO) mice to identify the genes and signaling pathways that are dysregulated in the absence of Schwann cell Cx32. Given the assumption that loss of Schwann cell Cx32 disrupts the regeneration and maintenance of myelinated nerve leading to a demyelinating neuropathy in CMT1X, we initially hypothesized that nerve crush injury would result in significant increases in differential gene expression in Cx32KO mice relative to WT nerves. However, microarray analysis revealed a striking collapse in the number of differentially expressed genes at 5 and 7 dpi in Cx32KO nerves relative to WT, while uninjured and 14 dpi time points showed large numbers of differentially regulated genes. Further comparisons within each genotype showed limited changes in Cx32KO gene expression following crush injury when compared to uninjured Cx32KO nerves. By contrast, WT nerves exhibited robust changes in gene expression at 5 and 7 dpi with no significant differences in gene expression by 14dpi relative to uninjured WT nerve samples. Taken together, these data suggest that the gene expression profile in uninjured Cx32KO sciatic nerve strongly resembles that of a WT nerve following injury and that loss of Schwann cell Cx32 leads to a basal state of gene expression similar to that of an injured WT nerve. These findings support a role for Cx32 in non-myelinating and regenerating populations of Schwann cells in normal axonal maintenance in re-myelination, and regeneration of peripheral nerve following injury. Disruption of Schwann cell axonal communication in CMT1X may cause dysregulation of signaling pathways that are essential for the maintenance of intact myelinated peripheral nerves and to establish the necessary conditions for successful regeneration and remyelination following nerve injury. PMID- 25447946 TI - Serial coupling of ion-exchange and size-exclusion chromatography to determine aggregation levels in mAbs in the presence of a proteinaceous excipient, recombinant human serum albumin. AB - Aggregation levels of therapeutic proteins may be difficult to determine in mixtures containing other proteinaceous excipients. We performed a feasibility study of using serial coupling of an anion exchange and size exclusion column to determine the aggregation levels of four different model monoclonal antibodies (mAb) mixed with the model proteinaceous excipient recombinant human serum albumin (rHSA). For three of the four mAbs suitable elution conditions could be established. From the limitations imposed by the pI of the rHSA, the pI of the mAb and the nature of the columns used, it was possible to propose a set of general conditions that allows quantification of the aggregation level of a therapeutic protein in the presence of a proteinaceous excipient: The excipient protein and protein of interest should differ in pI by a minimum of 0.5 units, and the pI of the protein of interest should not be higher than ca. 8.5. PMID- 25447947 TI - Cystic fibrosis--what are the prospects for a cure? AB - Significant improvements in the treatment of cystic fibrosis over the last few decades have altered this lethal disease in children to a multisystem disorder with survival into adult life now common. In most developed countries the numbers of adult cystic fibrosis patients outnumber children. This is mainly due to improvements in care during early life. The principal cause of morbidity and mortality is pulmonary disease, and so the focus of new treatments has targeted the lungs. Identification of the underlying gene defect in the cystic fibrosis transmembrane conductance regulator has ushered in a new era in cystic fibrosis research, with prospects of a cure. In this article, we review the most exciting recent advances that correct defects in cellular processing, chloride channel function and gene therapy. PMID- 25447945 TI - Modulation of CaV2.1 channels by neuronal calcium sensor-1 induces short-term synaptic facilitation. AB - Facilitation and inactivation of P/Q-type Ca2+ currents mediated by Ca2+/calmodulin binding to Ca(V)2.1 channels contribute to facilitation and rapid depression of synaptic transmission, respectively. Other calcium sensor proteins displace calmodulin from its binding site and differentially modulate P/Q-type Ca2 + currents, resulting in diverse patterns of short-term synaptic plasticity. Neuronal calcium sensor-1 (NCS-1, frequenin) has been shown to enhance synaptic facilitation, but the underlying mechanism is unclear. We report here that NCS-1 directly interacts with IQ-like motif and calmodulin-binding domain in the C terminal domain of Ca(V)2.1 channel. NCS-1 reduces Ca2 +-dependent inactivation of P/Q-type Ca2+ current through interaction with the IQ-like motif and calmodulin-binding domain without affecting peak current or activation kinetics. Expression of NCS-1 in presynaptic superior cervical ganglion neurons has no effect on synaptic transmission, eliminating effects of this calcium sensor protein on endogenous N-type Ca2+ currents and the endogenous neurotransmitter release machinery. However, in superior cervical ganglion neurons expressing wild type Ca(V)2.1 channels, co-expression of NCS-1 induces facilitation of synaptic transmission in response to paired pulses and trains of depolarizing stimuli, and this effect is lost in Ca(V)2.1 channels with mutations in the IQ-like motif and calmodulin-binding domain. These results reveal that NCS-1 directly modulates Ca(V)2.1 channels to induce short-term synaptic facilitation and further demonstrate that CaS proteins are crucial in fine-tuning short-term synaptic plasticity. PMID- 25447948 TI - Evolutionary neurology, responsive equilibrium, and the moral brain. AB - The relation between morality and the brain is a topic usefully examined through the evolutionary neurology of John Hughlings-Jackson, who considered higher mental function to be progressively inclusive integration of sensori-motor processes. His view, based on careful observations of patients with neurological disorders, implies that moral reasoning involves integration and coordination of behaviour through a process of representation and re-representation encompassing broader and broader types of information sensitive to environmental contingencies. The relevant information is processed in diverse brain areas: superior temporal sulcus (STS), inferior parietal lobule (IPL), inferior frontal gyrus (IFG), dorsolateral prefrontal (DLPF) areas, as well as anterior temporal (AT) structures. Moral function can be regarded as maximally integrating emotion, social cognition, and other-regarding sensibilities using propositionally organised cognitive structures that map a shared world of human activity and relationships so that they take account of what in social and personal life counts as something. PMID- 25447949 TI - Tension pneumoperitoneum in a lung cancer patient with intestinal metastases. PMID- 25447950 TI - Psychological screening for the children with habitual snoring. AB - OBJECTIVES: Adenotonsillar hypertrophy is the major determinants of habitual snoring in pediatric population. Behavioral hyperactivity and schooling problems have been repeatedly reported in these children, and it may underlie more extensive behavioral disturbances, particularly for the obese children. The aim of the present study is to evaluate the incidence and characteristics of emotional and behavioral problems using outpatient-based psychological screening tools in the children with habitual snoring. METHODS: Total 235 patients and 170 controls, who aged 4-9 years were enrolled. Body mass index (BMI) z-score was obtained for age and gender and parental sleep-related breathing disorder (SRBD) questionnaire was used to assess severity of sleep-disordered breathing (SBD). Psychological assessment was performed using standardized questionnaires including Strength and Difficulties Questionnaire (SDQ), Children's Depression Inventory (CDI) and Screen for Child Anxiety Related Emotional Disorders (SCARED). RESULTS: Children presenting habitual snoring had significantly higher mean scores on almost all scales of SDQ, and SCARED than community controls. Around 20% of the children with habitual snoring, compared with 10-11% of controls had significant levels of distress that could adversely impact treatment outcomes. There was no interaction between obstructive sleep apnea severity and behavioral ratings. The scores for emotional distress and hyperactivity were more prominent in the obese children. Significant psychological distress or impairment in social interactions was observed in children with higher SRBD scores. CONCLUSIONS: Our findings suggest that the presence of habitual snoring in young children is associated wide spectrum of behavioral problems and the level of psychological distress might be evaluated at the time of the diagnosis. PMID- 25447951 TI - Indications for tonsillectomy: a 10 year retrospective review. AB - OBJECTIVE: Recurrent tonsillitis and obstructive sleep apnea (OSA) are the most common indications for tonsillectomy. This study was undertaken to determine if recurrent tonsillitis is increasing as an indication for tonsillectomy by reviewing the recent trend at a single institution. METHODS: A retrospective chart review of patients undergoing tonsillectomy from 2003 to 2012 was performed. Data was gathered from pre-operative symptoms and sleep study results. Patients were categorized by the following indications: (1) obstructive sleep apnea, (2) recurrent tonsillitis and OSA, (3) recurrent tonsillitis alone and (4) other. Literature review was conducted to find similar studies; the results of the literature review were compared to our results. RESULTS: A total of 2369 patients were included, 52% were boys. Over the study period OSA was the indication for surgery for 67% of patients. There was an increasing trend in OSA as the indication for tonsillectomy (p<0.0001). Girls were more likely to have tonsillitis as an indication for tonsillectomy (21% vs. 17%, OR: 1.32, p<0.0001). Children younger than 2 or 2-5 are less likely than those older than 5 to have tonsillitis as an indication for surgery (2.30% and 6.26% vs. 27.46%, OR=0.06 and 0.18, p<0.0001). 987 of 2370 (42%) patients undergoing tonsillectomy had a pre operative sleep study. Younger children were more likely to have had a sleep study. CONCLUSION: There were mild variations from year to year; however, obstructive sleep apnea is the most common reason for tonsillectomy. PMID- 25447952 TI - Elevated B cell-activating factor (BAFF) in children with allergic rhinitis. AB - OBJECTIVE: To evaluate the possible role of B cell-activating factor (BAFF) in children with allergic rhinitis (AR). METHODS: Twenty-four AR children and 20 normal children were enrolled in this study and nasal lavage and serum were collected. The nasal and serum levels of BAFF were measured using enzyme-linked immunosorbent assay (ELISA). The relationship between serum BAFF and immunoglobulin A (IgA) was evaluated in AR children. RESULTS: Our results showed that the nasal and serum levels of BAFF were significantly increased in AR children compared with controls (p<0.05). The nasal and serum levels of BAFF in AR children were significantly associated with disease severity (p<0.05). Moreover, the level of serum BAFF was negatively related to serum IgA level (p<0.05). CONCLUSION: Our findings show BAFF expression was significantly increased and related to disease severity, indicating BAFF may be implicated in new treatment modalities for AR children. PMID- 25447953 TI - Intratemporal and intracranial complications of acute otitis media in a pediatric population. AB - OBJECTIVE: To review all cases intratemporal and intracranial complications of acute otitis media (AOM) in infants and children from 1998 to 2013. METHODS: Retrospective chart review of 109 consecutive patients admitted for complications of AOM during a 15-year period at a tertiary-care children's hospital. The main outcomes are: (1) complications of AOM, (2) bacteriology, (3) management strategies. RESULTS: In our population, complications included mastoiditis (86.1%), subperiosteal abscess (38%), facial nerve palsy (16.7%), sigmoid sinus thrombosis (8.3%) and epidural abscess (7.4%). Other complications included post auricular cellulitis, otic hydrocephalus and elevated intracranial pressure, internal jugular thrombosis, cranial nerve VI palsy and Gradenigo's syndrome, labyrinthine fistula, sensorineural hearing loss, and cerebellar infarct. Sixty one patients (56%) received antibiotics prior to presentation. Cultures revealed Streptococcus pneumoniae in 36 patients (33.3%), other bacteria in 30 patients (27.8%), and "no growth" in 33 patients (30.5%). Nine patients (8.3%) did not undergo culture. Of the patients with S. pneumoniae, 20 cultures (55%) were found to be multidrug-resistant. Eleven patients (10.2%) were treated non-surgically, 31 (31%) were treated with myringotomy and intravenous antibiotics. Forty patients (97.5%) presenting with subperiosteal abscess required mastoid surgery. Thirteen of 18 (72.2%) patients with facial paralysis had full recovery. Eight of 10 (80%) patients with epidural abscess empyema required mastoid surgery and incision and drainage of the abscess. CONCLUSION: Complications of AOM are uncommon, yet continue to have potentially serious consequences. The bacteriology in this population reveals an increasing trend of multi-drug resistant S. pneumoniae as the causative organism. PMID- 25447954 TI - Letter to the Editor regarding 'honey for reduction of post tonsillectomy pain'. PMID- 25447955 TI - Response to the letter to the editor regarding "efficacy of honey in reduction of post tonsillectomy pain, randomized clinical trial" [Int. J. Pediatr. Otorhinolaryngol. (2014), doi:10.1016/j.ijporl.2014.07.023]. PMID- 25447956 TI - Functional disability among older women with fecal incontinence. AB - OBJECTIVE: The prevalence of functional disability for basic activities of daily living (ADLs) in older women with fecal incontinence (FI) is not well characterized. Our objective was to determine the prevalence of functional disability among community-dwelling older women with FI. STUDY DESIGN: We conducted a secondary database analysis of the 2005-2006 National Social Life, Health and Aging Project, a cross-sectional study of community-dwelling older adults that had been conducted by single in-home interviews. FI was defined as an affirmative answer to the question, "Have you lost control of your bowels (stool incontinence or anal incontinence)?" with a frequency of "at least monthly." We then examined functional status. Women were asked about 7 basic ADLs. Statistical analyses with percentage estimates and 95% confidence intervals (CIs) were performed. RESULTS: We included 1412 women in our analysis. FI, at least monthly, was reported by 5.5% of community-dwelling older women (n = 77); 63.2% (95% CI, 50.1-76.4) of the women with FI reported difficulty or dependence with >=1 ADLs, and 31.2% (95% CI, 18.9-43.6) of the women specifically reported difficulty or dependence with using the toilet. After adjustment for age category, race/ethnicity, education level, women with FI had 2.6 increased odds (95% CI, 1.26-5.35) of difficulty or dependence compared with women with no FI. Other significant risk factors for increased functional difficulty/dependence included obesity (body mass index, >=30 kg/m(2)) and depressive symptoms. CONCLUSION: Consistent with other large epidemiologic studies, we found monthly FI was reported by 5.5% of older women (n/N = 77/1412). More than 60% of community dwelling older women with FI report functional difficulty or dependence with >=1 ADL and specifically; more than 30% of women with FI report difficulty or dependence using/reaching the toilet. Because of the high prevalence of functional disability in older women with FI, we purpose that initial evaluation and treatment of FI may be improved by considering functional status. PMID- 25447957 TI - Sterilization as last resort in women with intellectual disabilities: protection or disservice? AB - The legacy of the eugenics movement in the United States, including the involuntary sterilization of those deemed unfit to reproduce, has created a profound backlash against sterilization among certain populations. Particularly in treating women with intellectual disabilities, the field of obstetrics and gynecology has widely adopted an antisterilization stance. When treating women with intellectual disabilities, sterilization is generally considered a last resort. This essay revisits the issue of sterilization in women with intellectual disabilities, asking whether the field's stance of sterilization as a last resort is best viewed as a protection of this vulnerable population or one that actually does significant harm. We use a hypothetical but realistic patient case to examine the potential risks and benefits of sterilization. After reviewing the arguments against sterilization as a first-line treatment, we defend the controversial position that, in some cases, sterilization should be presented as an equally legitimate choice to reversible contraceptives. PMID- 25447958 TI - Diagnosing placenta accreta. PMID- 25447959 TI - Reply: To PMID 25077458. PMID- 25447960 TI - Detection of triploid, molar, and vanishing twin pregnancies by a single nucleotide polymorphism-based noninvasive prenatal test. AB - OBJECTIVE: We sought to determine the ability of single-nucleotide polymorphism based noninvasive prenatal testing (NIPT) to identify triploid, unrecognized twin, and vanishing twin pregnancies. STUDY DESIGN: The study included 30,795 consecutive reported clinical cases received for NIPT for fetal whole-chromosome aneuploidies; known multiple gestations were excluded. Cell-free DNA was isolated from maternal blood samples, amplified via 19,488-plex polymerase chain reaction, and sequenced. Sequencing results were analyzed to determine fetal chromosome copy number and to identify the presence of additional fetal haplotypes. RESULTS: Additional fetal haplotypes, indicative of fetal triploidy, vanishing twin, or undetected twin pregnancy, were identified in 130 (0.42%) cases. Clinical confirmation (karyotype for singleton pregnancies, ultrasound for multifetal pregnancies) was available for 58.5% (76/130) of cases. Of the 76 cases with confirmation, 42.1% were vanishing twin, 48.7% were viable twin, 5.3% were diandric triploids, and 3.9% were nontriploid pregnancies that lacked evidence of co-twin demise. One pregnancy had other indications suggesting triploidy but lacked karyotype confirmation. Of the 5 vanishing twin cases with a known date of demise, 100% of losses occurred in the first trimester; up to 8 weeks elapsed between loss and detection by NIPT. CONCLUSION: This single-nucleotide polymorphism-based NIPT successfully identified vanished twin, previously unrecognized twin, and triploid pregnancies. As vanishing twins are more likely to be aneuploid, and undetected residual cell-free DNA could bias NIPT results, the ability of this method to identify additional fetal haplotypes is expected to result in fewer false-positive calls and prevent incorrect fetal sex calls. PMID- 25447961 TI - The association between fetal Doppler and admission to neonatal unit at term. AB - OBJECTIVE: Fetal cerebroplacental ratio is emerging as a better proxy than birthweight for placental insufficiency and as a marker of fetal compromise at term. The extent to which these fetal Doppler changes are related to neonatal outcomes has not been systematically assessed. The main aim of this study was to evaluate the association between estimated fetal weight percentile, cerebroplacental ratio recorded at 34(+0)-35(+6) weeks' gestation, and neonatal unit admission at term. STUDY DESIGN: This was a retrospective cohort study in a tertiary referral center over an 11 year period from 2002 to 2012. The umbilical artery pulsatility index (PI), middle cerebral artery PI, and cerebroplacental ratio were recorded at 34(+0)-35(+6) weeks. Weight values were converted into percentiles and Doppler parameters into multiples of the median (MoM), adjusting for gestational age. Logistic regression analysis was performed to identify, and adjust for, potential confounders. RESULTS: We identified 2518 pregnancies in which a scan was performed at 34(+0)-35(+6) weeks and delivery occurred at or beyond 37 weeks. In the 2485 pregnancies included in the analysis, the umbilical artery PI MoM was significantly higher, and the middle cerebral artery PI and cerebroplacental ratio MoM significantly lower in the babies requiring neonatal unit admission (P < .05). However, the estimated fetal weight percentile was not significantly different between those who required neonatal unit admission and those who did not (P = .087). According to multivariate logistic regression, cerebroplacental ratio MoM (odds ratio, 0.39; 95% confidence interval, 0.19-0.79; P = .008) and gestational age at delivery (odds ratio, 0.70; 95% confidence interval, 0.61-0.80; P < .001) were significantly associated with the risk of neonatal unit admission, whereas maternal age and birthweight percentile were not (P = .183 and P = .460, respectively). Irrespective of birthweight or estimated fetal weight percentile, the fetal cerebroplacental ratio appears to be a better predictor of the need for neonatal unit admission (P < .001). CONCLUSION: Lower cerebroplacental ratio and gestational age at delivery, but not fetal size, were independently associated with the need for admission to the neonatal unit at term in a high-risk patient group. The extent to which fetal hemodynamic assessment could be used to predict perinatal morbidity and optimize the timing of delivery merits further investigation. PMID- 25447963 TI - Water-triggered luminescent "nano-bombs" based on supra-(carbon nanodots). AB - Novel luminescent "nano-bombs" based on a self-assembled system of carbon nanodots, termed supra-CDs, are developed. The luminescence of these luminescent "nano-bombs" depends strongly on water contact; they show weak emission in toluene and decompose in contact with water, resulting in strong photoluminescence. Paper coated with these "nano-bombs" is successfully applied for water-jet printing of luminescence patterns and the mapping of human sweat pore patterns. PMID- 25447964 TI - Use of PET-CT for the assessment of treatment results in patients with sarcoidosis. AB - BACKGROUND AND AIM: Sarcoidosis is a multisystem disease of unknown origin. Determining the involvement and the response to the treatment is important. The aim of this study was to identify the effects of methylprednisolone and indomethacine on metabolic activity and pulmonary function test parameters in patients with sarcoidosis. MATERIAL AND METHODS: A total of 24 pulmonary sarcoidosis patients were enrolled in the study. All the patients underwent spirometry and [(18)F]fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) scan before treatment and were divided into two groups according to the necessity of corticosteroid treatment or not. Patients who did not have corticosteroid indication were treated with indomethacine. Symptomatic patients and patients who did not respond to indomethacine treatment received methylprednisolone. Patients were followed up on a monthly basis to determine the response. FDG uptakes as the disease activity were re-evaluated before ending the treatment at the sixth month. RESULTS: Mean age of patients (16 male, 8 female) was 39.79 (9.3) years. Besides mediastinum and pulmonary parenchyma, extrapulmonary sites were also involved in patients with pulmonary sarcoidosis (distant lymph nodes (upper abdominal, supraclavicular, inguinal, and axillary), liver, and spleen). Although maximum standard uptake values of methylprednisolone group regressed significantly (p < 0.001) after treatment, indomethacine group did not have significant regression (p = 0.345). Despite metabolic regressions, spirometry values of patients did not significantly increase (p > 0.005). CONCLUSION: FDG PET-CT may be useful for determining activity and the efficacy of treatments. Methylprednisolone is effective in reducing metabolic activity but does not lead to improvement in functional parameters. PMID- 25447962 TI - Evaluation of strategies regarding management of imminent preterm delivery before 32 weeks of gestation: a regional cohort study among 1375 women in the Netherlands. AB - OBJECTIVE: To evaluate the management of imminent preterm delivery with respect to prescription of antenatal corticosteroids (ACS) and referral to a tertiary center. STUDY DESIGN: A retrospective cohort study existing of 1 perinatal center and 9 referring hospitals. All women who received their first dose of ACS in 1 of the 10 hospitals between 24+0 and 32+0 weeks of gestation and/or delivered before 32 weeks of gestation from 2005 until 2010. Patients were identified using the electronic database of hospital pharmacies. Main outcome measures were time interval from administration to delivery for different indications and number of women who were not referred in time to a tertiary center. RESULTS: In total, 1375 women received ACS. Main indications were suspected preterm labor (44.7%), preterm prelabor rupture of membranes (15.9%), maternal indication (12.8%), fetal indication (9.2%) and vaginal blood loss (8.4%). Overall, 467 (34.0%) women delivered <=7 days after ACS administration; 8.7% of women with vaginal blood loss and 54.5% of women with maternal indication. Among the 931 women who received ACS in the secondary hospitals, 452 (48.5%) women were referred to a tertiary hospital and 89 (6.5%) women delivered in a secondary hospital with a gestational age of less than 32 weeks. CONCLUSION: One-third of all women receiving ACS delivered within 7 days and half of the women who received ACS in a secondary hospital were referred to a tertiary center. There seems to be room for improvement regarding the timing of ACS administration and subsequently referral to a tertiary center. PMID- 25447965 TI - Complete rupture of the right upper lobe bronchus due to blunt thoracic trauma. PMID- 25447966 TI - Supraclavicular approach for removal of apical thoracic schwannoma. PMID- 25447967 TI - Patient's behavior and attitudes toward the management of benign prostatic hyperplasia among patients with the risk of disease progression: prospective study by "Prostate and Expectations of Treatment Epidemiology Research (PETER) study group". AB - BACKGROUND: The aim of the study was to evaluate patients attitudes with benign prostatic hyperplasia at the risk of progression during a 12-month period of observation. MATERIALS AND METHODS: A total of 426 patients from 45 outpatients centers were included and prospectively followed. Inclusion criteria were: age > 50 years, International Prostate Symptom Score (IPSS) > 8, prostate volume > 30 cm(3) (transabdominal ultrasound) and PSA > 1.5 to < 10 ng/ml. RESULTS: In all, 28.6% patients were naive, 62.9% used monotherapy (alpha-blocker), and 8.5% combined treatment (alpha-blocker/5alpha-reductase inhibitor/dutasteride). The most bothersome symptoms were the weak urine stream (60.8%) and nocturia (59.2%). Patients expectations from the treatment were stabilization of the disease and reducing the risk of surgery rather than rapid resolution of symptoms. Despite the presence of symptoms, 2.3% patients claimed that benign prostatic hyperplasia/lower urinary tract symptoms had no impact on their quality of life (QoL), in 48.1 % only little impact on QoL, and 47.9% patients percepted their symptoms as severe. Out of 71.4% patients treated previously, 26.5% patients were indecisive about the satisfaction of present treatment. Visual analog score was percepted more optimistically rather than the IPSS. Pearson's correlation r = 0.68 at the beginning and r = 0.83 at the end of the study. CONCLUSIONS: Prostate and Expectations of Treatment Epidemiology Research study highlights and reflects on patients behavior and self-perception, patients self-perception of the disease and therapeutic priorities during the 1 year of observation. PMID- 25447968 TI - An outbreak of acute gastroenteritis associated with group A Rotavirus in long term care facility in Slovenia. AB - BACKGROUND: In April 2013, an outbreak of acute gastroenteritis was reported in a residential long-term care facility (LTCF) in Ljubljana. We carried out an outbreak investigation to describe the outbreak, identify factors associated with contracting infection and to recommend control measures. METHODS: We conducted descriptive epidemiology of the outbreak and a case-control study among residents; a case was a resident or staff member of the LTCF with acute diarrhoea and at least one of the following symptoms: fever, vomiting, nausea, fatigue, headache and abdominal pain between 11 and 23 April 2013. Controls had no gastrointestinal symptoms during the outbreak period. Stool specimens were tested for enteric pathogens, including Rotavirus. RESULTS: Of 244, 33 (13.5 %) and 4 of 106 staff (3.8 %) were affected. Twenty-eight (84.8 %; median age 85 years; range 71-95 years) among affected residents and four (100 %; median age 35 years; range 30-45 years) among affected staff were women. The main symptoms besides acute diarrhoea were fatigue (54.1 %) and nausea (45.9 %). The average duration of gastroenteritis symptoms was 3.6 days in residents and 1.3 days in staff. None of the affected persons was hospitalized. Rotavirus group A was detected in a single stool specimen. In the multivariable analysis, being ambulant (aOR = 12.3; 95 % CI: 1.14-133.1), and having more than two comorbidities (aOR = 4.7; 95 % CI: 1.14 19.0) were significantly associated with acute gastroenterocolitis. CONCLUSIONS: Contact precautions of affected persons and controlled staff interactions between outbreak ward and unaffected ward are recommended in times of outbreak, with additional effort in targeting mobile residents and those with comorbidities. PMID- 25447969 TI - Liver fatty acid-binding protein as a diagnostic marker for non-alcoholic fatty liver disease. AB - BACKGROUND AND AIMS: Liver fatty acid-binding protein (L-FABP) is a small cytoplasmic protein. The aim of the current study was to investigate L-FABP levels and to determine their diagnostic value for non-alcoholic fatty liver disease (NAFLD). METHODS: We enrolled in this study 24 consecutive patients with NAFLD who were diagnosed with elevated transaminases and with steatosis by ultrasonograph. The control group consisted of 22 healthy control subjects matched for age and gender. Serum levels of L-FABP were determined by enzyme linked immunosorbent assay. RESULTS: L-FABP levels in NAFLD patients were higher than in the control group (levels were 41,976 +/- 18,998 and 17048 +/- 5021 pg/mL, respectively). A strong correlation was found between serum L-FABP concentrations and aspartate aminotransferase, alanine aminotransferase, body mass index, glucose and gamma-glutamyltransferase levels. A level of 284,000 pg/mL L-FABP had 73% sensitivity and 100% specificity. Positive and negative predictive values for L-FABP were 100 and 79%, respectively. CONCLUSIONS: Serum L-FABP can be considered as a new diagnostic marker for detecting non-alcoholic fatty liver disease. PMID- 25447970 TI - The addiction-related gene ANKK1 in Parkinsonian patients with impulse control disorder. AB - Impulse control disorders (ICDs) comprise a wide spectrum of abnormal behaviors frequently found in patients with Parkinson's disease (PD) receiving antiparkinsonian treatment. Some ICDs share several essential features with substance use disorders. In this work, we have studied the addiction-related gene ankyrin repeat and kinase domain containing I (ANKK1) in a sample of PD patients involved in a multicenter study on ICD. We carried out the TaqIA ANKK1 single nucleotide polymorphism (SNP) genotyping in PD patients. Clinical assessment of ICD was performed using the Questionnaire for impulsive-compulsive disorders in PD. We found no association between TaqIA SNP and ICD in PD patients (p = 0.565). However, when PD patients were grouped according the diagnosis of any ICD with a potentially addictive reinforcement (ICDARs), A1- TaqIA genotype showed significant association (p = 0.036). No association was found for the presence of punding in PD patients (p = 0.289). A logistic regression analysis confirmed the independent effect of the A1- genotype upon ICDARs (OR 8.76, 95 % CI 1.3-57.8, Wald = 5.805, p = 0.024). The TaqIA genotype A1- is associated to ICDAR in our sample and it may differentiate two types of disorders which are part of the ICD definition in PD patients. PMID- 25447971 TI - Contrast enhancement pattern on multidetector CT predicts malignancy in pancreatic endocrine tumours. AB - OBJECTIVES: Preoperative suspicion of malignancy in pancreatic neuroendocrine tumours (pNETs) is mostly based on tumour size. We retrospectively reviewed the contrast enhancement pattern (CEP) of a series of pNETs on multiphasic multidetector computed tomography (MDCT), to identify further imaging features predictive of lesion aggressiveness. METHODS: Sixty pNETs, diagnosed in 52 patients, were classified based on CEP as: type A showing early contrast enhancement and rapid wash-out; type B presenting even (B1) or only (B2) late enhancement. All tumours were resected allowing pathologic correlations. RESULTS: Nineteen pNETs showed type A CEP (5-20 mm), 29 type B1 CEP (5-80 mm) and 12 type B2 (15-100 mm). All tumours were classified as well differentiated tumours, 19 were benign (WDt-b), 15 with uncertain behaviour (WDt-u) and 26 carcinomas (WDC). None of A lesions were malignant (12 WDt-b; 7 WDt-u), all B2 lesions were WDC, 7 B1 lesions were WDt-b, 8 WDt-u and 14 WDC; 4/34 (12 %) lesions <=2cm were WDC. CEP showed correlation with all histological prognostic indicators. CONCLUSIONS: Correlating with the lesion grading and other histological prognostic predictors, CEP may preoperatively suggest the behaviour of pNETs, assisting decisions about treatment. Moreover CEP allows recognition of malignant small tumours, incorrectly classified on the basis of their dimension. PMID- 25447972 TI - Transluminal attenuation gradient in coronary computed tomography angiography for determining stenosis severity of calcified coronary artery: a primary study with dual-source CT. AB - OBJECTIVES: To evaluate the diagnostic accuracy of transluminal attenuation gradient (TAG) for stenosis severity of calcified lesions assessed by coronary computed tomography angiography (CCTA). METHODS: One hundred seven patients who underwent CCTA and coronary angiography (CAG) were enrolled. TAGs of 309 major epicardial coronary arteries were measured. The impact of plaque composition, Agatston scores, and lesion length ratio on TAG were analyzed. Diagnostic performance vs. CAG of TAG, CCTA, and combined TAG/CCTA were evaluated, and incremental value of TAG for reclassification of CCTA stenosis severity in calcified lesions was also analyzed. RESULTS: TAG decreased consistently with stenosis severity. TAG was significantly lower in coronary arteries with calcification scores >300 and lesion length ratios >2/3. TAG improved diagnostic accuracy of CCTA (c-statistic =0.982 vs. 0.942, P = 0.0001) in calcified lesions, and the sensitivity, specificity, positive, and negative predictive values of TAG cutoff <= -11.33 were 72 %, 91 %, 88 %, and 78 %, respectively. The addition of TAG to CCTA resulted in significant reclassification (NRI =0.093, P = 0.022) in calcified vessels. CONCLUSIONS: Measurement of TAG may improve diagnostic performance and reclassification of CCTA in coronary stenosis caused by calcified lesions. KEY POINTS: * TAG decreased as calcification scores and lesion length increased. * TAG markedly improved the diagnostic performance of CCTA for calcified lesions. * TAG improved reclassification of coronary artery stenosis severity in CCTA. PMID- 25447974 TI - Correction to "Network Analysis of Cancer-focused Association Network Reveals Distinct Network Association Patterns". AB - [This corrects the article on p. 45 in vol. 13, PMID: 25368509.]. PMID- 25447973 TI - Imaging-based evaluation of liver function: comparison of 99mTc-mebrofenin hepatobiliary scintigraphy and Gd-EOB-DTPA-enhanced MRI. AB - OBJECTIVES: To compare Gd-EOB-enhanced MRI and (99m)Tc-mebrofenin hepatobiliary scintigraphy (HBS) as imaging-based liver function tests for separate evaluation of right (RLL) and left liver lobe (LLL) function. METHODS: Fourteen patients underwent Gd-EOB-enhanced MRI and (99m)Tc-mebrofenin HBS after portal vein embolization within 24 h. Relative enhancement (RE) and hepatic uptake index (HUI) were determined from MRI; and T max, T 1/2 and mebrofenin uptake were determined from HBS, all values separately for RLL and LLL. RESULTS: Mebrofenin uptake correlated significantly with HUI and RE for both liver lobes. There was strong correlation of mebrofenin uptake with HUI for RLL (r (2) = 0.802, p = 0.001) and RE for LLL (r (2) = 0.704, p = 0.005) and moderate correlation with HUI for LLL (r (2) = 0.560, p = 0.037) and RE for RLL (r (2) = 0.620, p = 0.018). Correlating the percentage share of RLL function derived from MRI (with HUI) with the percentage of RLL function derived from mebrofenin uptake revealed a strong correlation (r (2) = 0.775, p = 0.002). CONCLUSIONS: Both RE and HUI correlate with mebrofenin uptake in HBS. The results suggest that Gd-EOB-enhanced MRI and (99m)Tc-mebrofenin HBS may equally be used to separately determine right and left liver lobe function. KEY POINTS: * Information about liver function can be acquired with routine Gd-EOB-MRI. * Gd-EOB-MRI and (99m) Tc-mebrofenin HBS show elevated function of non-embolized lobe. * Gd-EOB-MRI and (99m) Tc-mebrofenin HBS can determine lobar liver function. PMID- 25447975 TI - Biomechanical effects of valgus knee bracing: a systematic review and meta analysis. AB - To review and synthesize the biomechanical effects of valgus knee bracing for patients with medial knee osteoarthritis (OA). Electronic databases were searched from their inception to May 2014. Two reviewers independently determined study eligibility, rated study quality and extracted data. Where possible, data were combined into meta-analyses and pooled estimates with 95% confidence intervals (CI) for standardized mean differences (SMD) were calculated. Thirty studies were included with 478 subjects tested while using a valgus knee brace. Various biomechanical methods suggested valgus braces can decrease direct measures of medial knee compressive force, indirect measures representing the mediolateral distribution of load across the knee, quadriceps/hamstring and quadriceps/gastrocnemius co-contraction ratios, and increase medial joint space during gait. Meta-analysis from 17 studies suggested a statistically significant decrease in the external knee adduction moment (KAM) during walking, with a moderate-to-high effect size (SMD = 0.61; 95% CI: 0.39, 0.83; P < 0.001). Meta regression identified a near-significant association for the KAM effect size and duration of brace use only (beta, -0.01; 95% CI: -0.03, 0.0001; P = 0.06); with longer durations of brace use associated with smaller treatment effects. Minor complications were commonly reported during brace use and included slipping, discomfort and poor fit, blisters and skin irritation. Systematic review and meta analysis suggests valgus knee braces can alter knee joint loads through a combination of mechanisms, with moderate-to-high effect sizes in biomechanical outcomes. PMID- 25447978 TI - NHS trusts have new duty to be honest about mistakes. PMID- 25447976 TI - Current evidence on risk factors for knee osteoarthritis in older adults: a systematic review and meta-analysis. AB - Osteoarthritis (OA) is a leading cause of pain and disability and leads to a reduced quality of life. The aim was to determine the current evidence on risk factors for onset of knee pain/OA in those aged 50 and over. A systematic review and meta-analysis was conducted of cohort studies for risk factors for the onset of knee pain. Two authors screened abstracts and papers and completed data extraction. Where possible, pooled odds ratios (OR) were calculated via random effects meta-analysis and population attributable fractions (PAFs) derived. 6554 papers were identified and after screening 46 studies were included. The main factors associated with onset of knee pain were being overweight (pooled OR 1.98, 95% confidence intervals (CI) 1.57-2.20), obesity (pooled OR 2.66 95% CI 2.15 3.28), female gender (pooled OR 1.68, 95% CI 1.37-2.07), previous knee injury (pooled OR 2.83, 95% CI 1.91-4.19). Hand OA (pooled OR 1.30, 95% CI 0.90-1.87) was found to be non-significant. Smoking was found not to be a statistically significant risk or protective factor (pooled OR 0.92, 95% CI 0.83-1.01). PAFs indicated that in patients with new onset of knee pain 5.1% of cases were due to previous knee injury and 24.6% related to being overweight or obese. Clinicians can use the identified risk factors to identify and manage patients at risk of developing or increasing knee pain. Obesity in particular needs to be a major target for prevention of development of knee pain. More research is needed into a number of potential risk factors. PMID- 25447977 TI - High-throughput viability assay using an autonomously bioluminescent cell line with a bacterial Lux reporter. AB - Cell viability assays are extensively used to determine cell health, evaluate growth conditions, and assess compound cytotoxicity. Most existing assays are endpoint assays, in which data are collected at one time point after termination of the experiment. The time point at which toxicity of a compound is evident, however, depends on the mechanism of that compound. An ideal cell viability assay allows the determination of compound toxicity kinetically without having to terminate the assay prematurely. We optimized and validated a reagent-addition free cell viability assay using an autoluminescent HEK293 cell line that stably expresses bacterial luciferase and all substrates necessary for bioluminescence. This cell viability assay can be used for real-time, long-term measurement of compound cytotoxicity in live cells with a signal-to-basal ratio of 20- to 200 fold and Z-factors of ~0.6 after 24-, 48- 72-, or 96-h incubation with compound. We also found that the potencies of nine cytotoxic compounds correlated well with those measured by four other commonly used cell viability assays. The results demonstrated that this kinetic cell viability assay using the HEK293(lux) autoluminescent cell line is useful for high-throughput evaluation of compound cytotoxicity. PMID- 25447980 TI - [Series of studies concerning group B streptococci with reduced penicillin susceptibility (PRGBS)]. AB - Group B Streptococcus (GBS, Streptococcus agalactiae) is the cause of neonatal sepsis and meningitides. Moreover, this bacterium causes invasive infections to elderly people and patients suffering from diabetes et al. All clinical isolates of GBS, similar to other beta-hemolytic streptococci, have been considered to be uniformly susceptible to beta-lactams since 1940s, when penicillin was introduced to clinical setting. However, we analyzed clinical isolates of group B streptococci with reduced penicillin susceptibility (PRGBS), recovered in Japan during 1995-2005, and established their existence. Moreover, we promote series of studies concerning PRGBS. In this review, we describe series of studies concerning PRGBS. PMID- 25447981 TI - [Regulation of determination of bacterial shape]. AB - Bacteria show various cell shape such as round, rod, helical, and so on. However, each bacterium has its own shape and their length and width are kept in a narrow range in a population. Abnormal cell shape often results in death of the cells. Therefore, it is important to maintain their shape. Rod-shaped bacterium Escherichia coli needs to regulate cell polarity, length and width in order to form rod shape. Bacterial shape is genetically regulated. Especially, MreB, a bacterial actin, and its interacting proteins are involved in the regulation. We have identified rodZ as a novel cell shape determinant and have been analyzing RodZ protein in the past few years. The rodZ mutant is round. We isolated suppressor mutants of the rodZ mutant. The shape of the suppressors was rod shape. By analyzing the rodZ mutant and the suppressors, we concluded that RodZ helps assembly of MreB filaments. MreB plays roles in regulation of cell polarity, length, and width, whereas RodZ is involved in regulation of length and width. In this review, I summarize our research and research from other groups on bacterial cell shape. PMID- 25447979 TI - Human papillomavirus testing 2007-2012: co-testing and triage utilization and impact on subsequent clinical management. AB - In the United States, high-risk human papillomavirus (HPV) testing is recommended for women with atypical squamous cells of unknown significance (ASC-US) cytology, and co-testing with cytology and HPV is a recommended option for screening women aged >= 30 years. No population-based data are available to examine utilization of HPV testing in the United States. Using the New Mexico HPV Pap Registry data resource, we describe population trends (2007-2012) in utilization and positivity rates for HPV testing as a routine co-testing screening procedure and for triage of ASC-US and other cytologic outcomes. For women aged 30-65 years co-testing increased from 5.2% in 2007 to 19.1% in 2012 (p < 0.001). Overall 82% of women with ASC-US cytology who did not receive co-testing also had an HPV test. HPV positivity was age and cytology result dependent but did not show time trends. For women with negative cytology, 64% received an additional screening test within 3 years if no co-test was done or if it was positive, but this was reduced to 47% with a negative co-test. Reflex HPV testing for ASC-US cytology is well established and occurs in most women. Evidence for reflex testing is also observed following other abnormal cytology outcomes. Co-testing in women aged 30 65 years has more than tripled from 2007 to 2012, but was still only used in 19.1% of women aged 30-65 years attending for screening in 2012. Women receiving co-testing had longer repeat screening intervals, but rescreening within 3 years is still very common even with co-testing. PMID- 25447982 TI - [Study of infection strategies of Helicobacter pylori and host cell response against CagA oncoprotein]. AB - Chronic infection with Helicobacter pylori is involved in a variety of clinical outcomes including gastric cancer. In the present study, we focused on the infection strategies of H. pylori associated with establishment of chronic infection. As a result, the following four findings revealed. 1) alpha ketoglutarate oxidoreductase (KOR) is an essential survival enzyme for energy metabolism in the coccoid form of H. pylori, and inactivation of the KOR activity exerted a potent bactericidal action against H. pylori by preventing induction of the coccoid form. 2) SodB expression is derepressed by amino acids mutation of ferric uptake regulator (Fur), which is associated with the development of Metronidazole resistance. 3) FecA1 is an important determinant of the host colonization ability through Fe(2+) supply to SodB, suggesting that FecA1 may be a possible target for the development of a novel bactericidal drug. 4) Intracellular CagA oncoprotein is degraded by autophagy and therefore short lived. However, in the CD44v9-expressing gastric cells, CagA specifically accumulated through the repression of autophagy induction. PMID- 25447983 TI - [Virulence determinant of Chromobacterium violaceum]. AB - Chromobacterium violaceum is a Gram-negative bacterium that infects humans and animals with fatal sepsis. The infection with C. violaceum is rare in case of those who are healthy, but once established, C. violaceum causes sever disease accompanied by abscess formation in the lungs, liver and spleen. Furthermore, C. violaceum is resistant to a broad range of antibiotics, which in some cases renders the antimicrobial therapy for this infection difficult. Thus, the infection with C. violaceum displays high mortality rates unless initial proper antimicrobial therapy. In contrast, the infection mechanism had completely remained unknown. To this end, we have tried to identify virulence factors associated with C. violaceum infection. Two distinct type III secretion systems (TTSSs) were thought to be one of the most important virulence factors, which are encoded by Chromobacterium pathogenicity island 1/1a and 2 (Cpi-1/-1a and -2) respectively. Our results have shown that Cpi-1/-1a-encoded TTSS, but not Cpi-2, is indispensable for the virulence in a mouse infection model. C. violaceum caused fulminant hepatitis in a Cpi-1/-1a-encoded TTSS-dependent manner. We next have identified 16 novel effectors secreted from Cpi-1/-1a-encoded TTS machinery. From these effectors, we found that CopE (Chromobacterium outer protein E) has similarities to a guanine nucleotide exchange factor (GEF) for Rho GTPases. CopE acts as GEF for Rac1 and Cdc42, leading to induction of actin cytoskeletal rearrangement. Interestingly, C. violaceum invades cultured human epithelial cells in a CopE-dependent manner. Finally, an inactivation of CopE by disruption of copE gene or amino acid point mutation leading to loss of GEF activity attenuates significantly the mouse virulence of C. violaceum. These results suggest that Cpi-1/-1a-encoded TTSS is a major virulence determinant for C. violaceum infection, and that CopE contributes to the virulence in part of this pathogen. PMID- 25447984 TI - [Leptospirosis now-the centennial of the discovery of Weil's disease pathogen]. AB - This year, 2014, marks the centennial of the discovery of Leptospira as the Weil's disease pathogen by Ryokichi Inada, Yutaka Ido and their colleagues. Leptospirosis is a worldwide zoonosis especially in countries with tropical and subtropical climates. Recently, the number of patients with leptospirosis dramatically decreased in Japan because public hygiene has greatly improved, the mechanization of agriculture was introduced, and farmers started using rubber boots and gloves while working in the field. The opportunities for percutaneous infection with Leptospira was reduced, but have not been totally eliminated in Japan.We previously reported a novel combination of five antimicrobial agents for selective isolation of Leptospira from contaminated samples. This cocktail, after being incorporated into Leptospira growth medium, inhibited the growth of contaminants and allowed successful detection of leptospires in environmental samples. We collected soil and environmental water and cultured them using this selective medium. It was revealed that not only saprophytic Leptospira but also pathogenic Leptospira are widely living in the environment. We hypothesized that soil serves as reservoir for Leptospira and infectious source for leptospirosis. In this review, we also discuss the Leptospira-rat-human relationship in the Philippines, natural defense of host against oral and percutaneous infection by Leptospira, the mechanism of jaundice in leptospirosis, and the development of immunochromatography-based methods for detection of leptospiral antigen in urine. PMID- 25447985 TI - Regulation of microglial migration, phagocytosis, and neurite outgrowth by HO 1/CO signaling. AB - Clearance of infected and apoptotic neuronal corpses during inflammatory conditions is a fundamental process to create a favorable environment for neuronal recovery. Microglia are the resident immune cells and the predominant phagocytic cells of the CNS, showing a multitude of cellular responses upon activation. Here, we investigated in functional assays how the CO generating enzyme heme oxygenase 1 (HO-1) influences BV-2 microglial migration, clearance of debris, and neurite outgrowth of human NT2 neurons. Stimulation of HO-1 activity attenuated microglial migration in a scratch wound assay, and phagocytosis in a cell culture model of acute inflammation comprising lipopolysaccharide (LPS) activated microglia and apoptosis-induced neurons. Application of a CO donor prevented the production of NO during LPS stimulation, and reduced microglial migration and engulfment of neuronal debris. LPS-activated microglia inhibited neurite elongation of human neurons without requiring direct cell-cell surface contact. The inhibition of neurite outgrowth was totally reversed by application of exogenous CO or increased internal CO production through supply of the substrate hemin to HO. Our results point towards a vital cytoprotective role of HO-1/CO signaling after microglial activation. In addition, they support a therapeutic potential of CO releasing chemical agents in the treatment of excessive inflammatory conditions in the CNS. PMID- 25447986 TI - Advances in the surgical approach to congenital diaphragmatic hernia. AB - Congenital diaphragmatic hernia is a birth defect that affects about one in 2500 live births. Although the overall survival has improved over the last several decades thanks to advancements in postnatal resuscitation and intensive care treatment, morbidity and mortality remain high. The surgical management of these infants is far from being standardized, and many aspects are still disputed among experts. The timing of surgical repair remains controversial and the indications for the ideal time for surgery have not been validated. The main novelty in the surgical treatment is related to the use of minimally invasive techniques, although these have been associated with intraoperative blood gas disturbances and higher recurrence rates. Herein, we report and comment on the main controversies of postnatal CDH repair in this rapidly evolving field. PMID- 25447987 TI - Prenatal management of the fetus with isolated congenital diaphragmatic hernia in the era of the TOTAL trial. AB - Congenital diaphragmatic hernia (CDH) may be isolated or associated with other structural anomalies, the latter with poor prognosis. The defect allows viscera to herniate through the defect into the chest, competing for space with the developing lungs. At birth, pulmonary hypoplasia leads to respiratory insufficiency and persistent pulmonary hypertension that is lethal in up to 30% of patients. When isolated, survival chances can be predicted by antenatal measurement of lung size and liver herniation. Chromosomal microarrays and exome sequencing contribute to understanding genetic factors underlying isolated CDH. Prenatal intervention aims at stimulating lung development, clinically achieved by percutaneous fetal endoscopic tracheal occlusion (FETO) under local anesthesia. The Tracheal Occlusion To Accelerate Lung growth trial (www.totaltrial.eu) is an international randomized trial investigating the role of fetal therapy for severe and moderate pulmonary hypoplasia. Despite an apparent increase in survival following FETO, the search for lesser invasive and more potent prenatal interventions must continue. PMID- 25447990 TI - A modular zinc finger adaptor accelerates the covalent linkage of proteins at specific locations on DNA nanoscaffolds. AB - A modular adaptor consisting of a sequence-specific DNA binding zinc finger protein and a self-ligating protein-tag was developed to expedite efficient formation of a covalent linkage between an individual protein molecule and the programmed address modified with a tag-substrate on the DNA nanostructure. PMID- 25447989 TI - Dual renin-angiotensin-aldosterone blockade: promises and pitfalls. AB - Single renin-angiotensin-aldosterone system (RAAS) blockade has been shown to be effective and safe for the treatment of hypertension, coronary heart disease (CHD), heart failure (HF), diabetes, and chronic kidney disease (CKD) with proteinuria. Due to the action of RAAS blockers at various levels of the RAAS cascade, it was hypothesized that dual RAAS blockade would result in more complete inhibition of angiotensin II (Ang II) production and be more effective in blocking its detrimental cardiovascular remodeling effects. Unfortunately, several clinical trials in patients with hypertension, CHD, HF, and CKD with proteinuria have demonstrated no superiority of dual versus single RAAS blockade, but a higher incidence of adverse events. Based on these findings, dual RAAS blockade is no longer recommended for the routine treatment of various cardiovascular diseases, except diabetic nephropathy with proteinuria and HF with reduced ejection fraction. All the new information gathered from studies within the last 3 years will be presented in this review. PMID- 25447988 TI - Genetic causes of congenital diaphragmatic hernia. AB - Congenital diaphragmatic hernia (CDH) is a moderately prevalent birth defect that, despite advances in neonatal care, is still a significant cause of infant death, and surviving patients have significant morbidity. The goal of ongoing research to elucidate the genetic causes of CDH is to develop better treatment and ultimately prevention. CDH is a complex developmental defect that is etiologically heterogeneous. This review summarizes the recurrent genetic causes of CDH including aneuploidies, chromosome copy number variants, and single gene mutations. It also discusses strategies for genetic evaluation and genetic counseling in an era of rapidly evolving technologies in clinical genetic diagnostics. PMID- 25447991 TI - Genome-wide ancestry patterns in Rapanui suggest pre-European admixture with Native Americans. AB - BACKGROUND: Rapa Nui (Easter Island), located in the easternmost corner of the Polynesian Triangle, is one of the most isolated locations on the planet inhabited by humans. Archaeological and genetic evidence suggests that the island was first colonized by Polynesians around AD 1200, during their eastward expansion. Although it remains contentious whether Polynesians reached South America, suggestive evidence has been brought forward supporting the possibility of Native American contact prior to the European "discovery" of the island in AD 1722. RESULTS: We generated genome-wide data for 27 Rapanui. We found a mostly Polynesian ancestry among Rapanui and detected genome-wide patterns consistent with Native American and European admixture. By considering the distribution of local ancestry tracts of eight unrelated Rapanui, we found statistical support for Native American admixture dating to AD 1280-1495 and European admixture dating to AD 1850-1895. CONCLUSIONS: These genetic results can be explained by one or more pre-European trans-Pacific contacts. PMID- 25447993 TI - The role of reward in word learning and its implications for language acquisition. AB - The exact neural processes behind humans' drive to acquire a new language--first as infants and later as second-language learners--are yet to be established. Recent theoretical models have proposed that during human evolution, emerging language-learning mechanisms might have been glued to phylogenetically older subcortical reward systems, reinforcing human motivation to learn a new language. Supporting this hypothesis, our results showed that adult participants exhibited robust fMRI activation in the ventral striatum (VS)--a core region of reward processing--when successfully learning the meaning of new words. This activation was similar to the VS recruitment elicited using an independent reward task. Moreover, the VS showed enhanced functional and structural connectivity with neocortical language areas during successful word learning. Together, our results provide evidence for the neural substrate of reward and motivation during word learning. We suggest that this strong functional and anatomical coupling between neocortical language regions and the subcortical reward system provided a crucial advantage in humans that eventually enabled our lineage to successfully acquire linguistic skills. PMID- 25447992 TI - Myo19 ensures symmetric partitioning of mitochondria and coupling of mitochondrial segregation to cell division. AB - During animal cell division, an actin-based ring cleaves the cell into two. Problems with this process can cause chromosome missegregation and defects in cytoplasmic inheritance and the partitioning of organelles, which in turn are associated with human diseases. Although much is known about how chromosome segregation is coupled to cell division, the way organelles coordinate their inheritance during partitioning to daughter cells is less well understood. Here, using a high-content live-imaging small interfering RNA screen, we identify Myosin-XIX (Myo19) as a novel regulator of cell division. Previously, this actin based motor was shown to control the interphase movement of mitochondria. Our analysis shows that Myo19 is indeed localized to mitochondria and that its silencing leads to defects in the distribution of mitochondria within cells and in mitochondrial partitioning at division. Furthermore, many Myo19 RNAi cells undergo stochastic division failure--a phenotype that can be mimicked using a treatment that blocks mitochondrial fission and rescued by decreasing mitochondrial fusion, implying that mitochondria can physically interfere with cytokinesis. Strikingly, using live imaging we also observe the inappropriate movement of mitochondria to the poles of spindles in cells depleted for Myo19 as they enter anaphase. Since this phenocopies the results of an acute loss of actin filaments in anaphase, these data support a model whereby the Myo19 actin-based motor helps to control mitochondrial movement to ensure their faithful segregation during division. The presence of DNA within mitochondria makes their inheritance an especially important aspect of symmetrical cell division. PMID- 25447994 TI - A migrating ciliary gate compartmentalizes the site of axoneme assembly in Drosophila spermatids. AB - BACKGROUND: In most cells, the cilium is formed within a compartment separated from the cytoplasm. Entry into the ciliary compartment is regulated by a specialized gate located at the base of the cilium in a region known as the transition zone. The transition zone is closely associated with multiple structures of the ciliary base, including the centriole, axoneme, and ciliary membrane. However, the contribution of these structures to the ciliary gate remains unclear. RESULTS: Here we report that, in Drosophila spermatids, a conserved module of transition zone proteins mutated in Meckel-Gruber syndrome (MKS), including Cep290, Mks1, B9d1, and B9d2, comprise a ciliary gate that continuously migrates away from the centriole to compartmentalize the growing axoneme tip. We show that Cep290 is essential for transition zone composition, compartmentalization of the axoneme tip, and axoneme integrity and find that MKS proteins also delimit a centriole-independent compartment in mouse spermatids. CONCLUSIONS: Our findings demonstrate that the ciliary gate can migrate away from the base of the cilium, thereby functioning independently of the centriole and of a static interaction with the axoneme to compartmentalize the site of axoneme assembly. PMID- 25447995 TI - Neurological and robot-controlled induction of an apparition. AB - Tales of ghosts, wraiths, and other apparitions have been reported in virtually all cultures. The strange sensation that somebody is nearby when no one is actually present and cannot be seen (feeling of a presence, FoP) is a fascinating feat of the human mind, and this apparition is often covered in the literature of divinity, occultism, and fiction. Although it is described by neurological and psychiatric patients and healthy individuals in different situations, it is not yet understood how the phenomenon is triggered by the brain. Here, we performed lesion analysis in neurological FoP patients, supported by an analysis of associated neurological deficits. Our data show that the FoP is an illusory own body perception with well-defined characteristics that is associated with sensorimotor loss and caused by lesions in three distinct brain regions: temporoparietal, insular, and especially frontoparietal cortex. Based on these data and recent experimental advances of multisensory own-body illusions, we designed a master-slave robotic system that generated specific sensorimotor conflicts and enabled us to induce the FoP and related illusory own-body perceptions experimentally in normal participants. These data show that the illusion of feeling another person nearby is caused by misperceiving the source and identity of sensorimotor (tactile, proprioceptive, and motor) signals of one's own body. Our findings reveal the neural mechanisms of the FoP, highlight the subtle balance of brain mechanisms that generate the experience of "self" and "other," and advance the understanding of the brain mechanisms responsible for hallucinations in schizophrenia. PMID- 25447996 TI - A Golgi-localized pool of the mitotic checkpoint component Mad1 controls integrin secretion and cell migration. AB - Mitotic arrest deficient 1 (Mad1) plays a well-characterized role in the major cell-cycle checkpoint that regulates chromosome segregation during mitosis, the mitotic checkpoint (also known as the spindle assembly checkpoint). During mitosis, Mad1 recruits Mad2 to unattached kinetochores, where Mad2 is converted into an inhibitor of the anaphase-promoting complex/cyclosome bound to its specificity factor, Cdc20. During interphase, Mad1 remains tightly bound to Mad2, and both proteins localize to the nucleus and nuclear pores, where they interact with Tpr (translocated promoter region). Recently, it has been shown that interaction with Tpr stabilizes both proteins and that Mad1 binding to Tpr permits Mad2 to associate with Cdc20. However, interphase functions of Mad1 that do not directly affect the mitotic checkpoint have remained largely undefined. Here we identify a previously unrecognized interphase distribution of Mad1 at the Golgi apparatus. Mad1 colocalizes with multiple Golgi markers and cosediments with Golgi membranes. Although Mad1 has previously been thought to constitutively bind Mad2, Golgi-associated Mad1 is Mad2 independent. Depletion of Mad1 impairs secretion of alpha5 integrin and results in defects in cellular attachment, adhesion, and FAK activation. Additionally, reduction of Mad1 impedes cell motility, while its overexpression accelerates directed cell migration. These results reveal an unexpected role for a mitotic checkpoint protein in secretion, adhesion, and motility. More generally, they demonstrate that, in addition to generating aneuploidy, manipulation of mitotic checkpoint genes can have unexpected interphase effects that influence tumor phenotypes. PMID- 25447997 TI - Nonpolitical images evoke neural predictors of political ideology. AB - Political ideologies summarize dimensions of life that define how a person organizes their public and private behavior, including their attitudes associated with sex, family, education, and personal autonomy. Despite the abstract nature of such sensibilities, fundamental features of political ideology have been found to be deeply connected to basic biological mechanisms that may serve to defend against environmental challenges like contamination and physical threat. These results invite the provocative claim that neural responses to nonpolitical stimuli (like contaminated food or physical threats) should be highly predictive of abstract political opinions (like attitudes toward gun control and abortion). We applied a machine-learning method to fMRI data to test the hypotheses that brain responses to emotionally evocative images predict individual scores on a standard political ideology assay. Disgusting images, especially those related to animal-reminder disgust (e.g., mutilated body), generate neural responses that are highly predictive of political orientation even though these neural predictors do not agree with participants' conscious rating of the stimuli. Images from other affective categories do not support such predictions. Remarkably, brain responses to a single disgusting stimulus were sufficient to make accurate predictions about an individual subject's political ideology. These results provide strong support for the idea that fundamental neural processing differences that emerge under the challenge of emotionally evocative stimuli may serve to structure political beliefs in ways formerly unappreciated. PMID- 25447998 TI - Single serotonergic neurons that modulate aggression in Drosophila. AB - Monoamine serotonin (5HT) has been linked to aggression for many years across species. However, elaboration of the neurochemical pathways that govern aggression has proven difficult because monoaminergic neurons also regulate other behaviors. There are approximately 100 serotonergic neurons in the Drosophila nervous system, and they influence sleep, circadian rhythms, memory, and courtship. In the Drosophila model of aggression, the acute shut down of the entire serotonergic system yields flies that fight less, whereas induced activation of 5HT neurons promotes aggression. Using intersectional genetics, we restricted the population of 5HT neurons that can be reproducibly manipulated to identify those that modulate aggression. Although similar approaches were used recently to find aggression-modulating dopaminergic and Fru(M)-positive peptidergic neurons, the downstream anatomical targets of the neurons that make up aggression-controlling circuits remain poorly understood. Here, we identified a symmetrical pair of serotonergic PLP neurons that are necessary for the proper escalation of aggression. Silencing these neurons reduced aggression in male flies, and activating them increased aggression in male flies. GFP reconstitution across synaptic partners (GRASP) analyses suggest that 5HT-PLP neurons form contacts with 5HT1A receptor-expressing neurons in two distinct anatomical regions of the brain. Activation of these 5HT1A receptor-expressing neurons, in turn, caused reductions in aggression. Our studies, therefore, suggest that aggression may be held in check, at least in part, by inhibitory input from 5HT1A receptor-bearing neurons, which can be released by activation of the 5HT-PLP neurons. PMID- 25447999 TI - Augmin triggers microtubule-dependent microtubule nucleation in interphase plant cells. AB - Microtubule (MT)-dependent MT nucleation by gamma-tubulin is required for interphase plant cells to establish a highly dynamic cortical MT network underneath the plasma membrane, which influences the deposition of cell wall materials and consequently governs patterns of directional cell expansion. Newly formed MTs either assume 40 degrees angles or are parallel to the extant ones. To date, it has been enigmatic how the gamma-tubulin complex is recruited to the sidewall of cortical MTs and initiates MT nucleation. Here, we discovered that the augmin complex was recruited to cortical MTs and initiated MT nucleation in both branching and parallel forms. The augmin complex overwhelmingly colocalized with the gamma-tubulin complex. When the function of the augmin complex was compromised, MT nucleation frequency was drastically reduced, most obviously for the branching nucleation. Consequently, the augmin knockdown cells displayed highly parallel and bundled MTs, replacing the fine and mesh-like MT network in the wild-type cells. Our findings uncovered a mechanism by which the augmin complex functions in recruiting the gamma-tubulin complex to cortical MTs and initiating MT nucleation, and they shifted the paradigm of the commonly perceived mitotic-specific function of augmin and established its crucial function in MT dependent MT nucleation in interphase plant cells. PMID- 25448000 TI - Temporal control of leaf complexity by miRNA-regulated licensing of protein complexes. AB - The tremendous diversity of leaf shapes has caught the attention of naturalists for centuries. In addition to interspecific and intraspecific differences, leaf morphologies may differ in single plants according to age, a phenomenon known as heteroblasty. In Arabidopsis thaliana, the progression from the juvenile to the adult phase is characterized by increased leaf serration. A similar trend is seen in species with more complex leaves, such as the A. thaliana relative Cardamine hirsuta, in which the number of leaflets per leaf increases with age. Although the genetic changes that led to the overall simpler leaf architecture in A. thaliana are increasingly well understood, less is known about the events underlying age-dependent changes within single plants, in either A. thaliana or C. hirsuta. Here, we describe a conserved miRNA transcription factor regulon responsible for an age-dependent increase in leaf complexity. In early leaves, miR319-targeted TCP transcription factors interfere with the function of miR164 dependent and miR164-independent CUC proteins, preventing the formation of serrations in A. thaliana and of leaflets in C. hirsuta. As plants age, accumulation of miR156-regulated SPLs acts as a timing cue that destabilizes TCP CUC interactions. The destabilization licenses activation of CUC protein complexes and thereby the gradual increase of leaf complexity in the newly formed organs. These findings point to posttranslational interaction between unrelated miRNA-targeted transcription factors as a core feature of these regulatory circuits. PMID- 25448001 TI - B. subtilis GS67 protects C. elegans from Gram-positive pathogens via fengycin mediated microbial antagonism. AB - Studies on Caenorhabditis elegans have provided detailed insight into host pathogen interactions. Usually, the E. coli strain OP50 is used as food source for laboratory studies, but recent work has shown that a variety of bacteria have dramatic effects on C. elegans physiology, including immune responses. However, the mechanisms by which different bacteria impact worm resistance to pathogens are poorly understood. Although pathogen-specific immune priming is often discussed as a mechanism underlying such observations, interspecies microbial antagonism might represent an alternative mode of action. Here, we use several natural Bacillus strains to study their effects on nematode survival upon pathogen challenge. We show that B. subtilis GS67 persists in the C. elegans intestine and increases worm resistance to Gram-positive pathogens, suggesting that direct inhibition of pathogens might be the primary protective mechanism. Indeed, chemical and genetic analyses identified the lipopeptide fengycin as the major inhibitory molecule produced by B. subtilis GS67. Specifically, a fengycin defective mutant of B. subtilis GS67 lost inhibitory activity against pathogens and was unable to protect C. elegans from infections. Furthermore, we found that purified fengycin cures infected worms in a dose-dependent manner, indicating that it acts as an antibiotic. Our results reveal a molecular mechanism for commensal-mediated C. elegans protection and highlight the importance of interspecies microbial antagonism for the outcome of animal-pathogen interactions. Furthermore, our work strengthens C. elegans as an in vivo model to reveal protective mechanisms of commensal bacteria, including those relevant to mammalian hosts. PMID- 25448002 TI - Aip1 destabilizes cofilin-saturated actin filaments by severing and accelerating monomer dissociation from ends. AB - BACKGROUND: Depolymerization of actin filaments is vital for the morphogenesis of dynamic cytoskeletal arrays and actin-dependent cell motility. Cofilin is necessary for actin disassembly in cells, and it severs filaments most efficiently at low cofilin to actin ratios, whereas higher concentrations of cofilin suppress severing. However, the cofilin concentration in thymocytes is too high to allow the severing of single-actin filaments. RESULTS: We observed that filaments sever efficiently in thymus cytosol. We identified Aip1 as a critical factor responsible for the severing and destabilization of actin filaments even in the presence of high amounts of cofilin. By fluorescence resonance energy transfer (FRET)-based spectroscopy and single-filament imaging of actin, we show that, besides driving the rapid severing of cofilin-actin filaments, Aip1 also augments the monomer dissociation rate at both the barbed and pointed ends of actin. Our results also demonstrate that Aip1 does not cap the barbed ends of actin filaments, as was previously thought. CONCLUSIONS: Our results indicate that Aip1 is a cofilin-dependent actin depolymerization factor and not a barbed-end-capping factor as was previously thought. Aip1 inverts the rules of cofilin-mediated actin disassembly such that increasing ratios of cofilin to actin now result in filament destabilization through faster severing and accelerated monomer loss from barbed and pointed ends. Aip1 therefore offers a potential control point for disassembly mechanisms in cells to switch from a regime of cofilin-saturation and stabilization to one that favors fast disassembly and destabilization. PMID- 25448004 TI - Directional auxin transport mechanisms in early diverging land plants. AB - The emergence and radiation of multicellular land plants was driven by crucial innovations to their body plans. The directional transport of the phytohormone auxin represents a key, plant-specific mechanism for polarization and patterning in complex seed plants. Here, we show that already in the early diverging land plant lineage, as exemplified by the moss Physcomitrella patens, auxin transport by PIN transporters is operational and diversified into ER-localized and plasma membrane-localized PIN proteins. Gain-of-function and loss-of-function analyses revealed that PIN-dependent intercellular auxin transport in Physcomitrella mediates crucial developmental transitions in tip-growing filaments and waves of polarization and differentiation in leaf-like structures. Plasma membrane PIN proteins localize in a polar manner to the tips of moss filaments, revealing an unexpected relation between polarization mechanisms in moss tip-growing cells and multicellular tissues of seed plants. Our results trace the origins of polarization and auxin-mediated patterning mechanisms and highlight the crucial role of polarized auxin transport during the evolution of multicellular land plants. PMID- 25448003 TI - Plasma membrane-targeted PIN proteins drive shoot development in a moss. AB - BACKGROUND: Plant body plans arise by the activity of meristematic growing tips during development and radiated independently in the gametophyte (n) and sporophyte (2n) stages of the life cycle during evolution. Although auxin and its intercellular transport by PIN family efflux carriers are primary regulators of sporophytic shoot development in flowering plants, the extent of conservation in PIN function within the land plants and the mechanisms regulating bryophyte gametophytic shoot development are largely unknown. RESULTS: We have found that treating gametophytic shoots of the moss Physcomitrella patens with exogenous auxins and auxin transport inhibitors disrupts apical function and leaf development. Two plasma membrane-targeted PIN proteins are expressed in leafy shoots, and pin mutants resemble plants treated with auxins or auxin transport inhibitors. PIN-mediated auxin transport regulates apical cell function, leaf initiation, leaf shape, and shoot tropisms in moss gametophytes. pin mutant sporophytes are sometimes branched, reproducing a phenotype only previously seen in the fossil record and in rare natural moss variants. CONCLUSIONS: Our results show that PIN-mediated auxin transport is an ancient, conserved regulator of shoot development. PMID- 25448006 TI - Neuronal K(ATP) channels mediate hypoxic preconditioning and reduce subsequent neonatal hypoxic-ischemic brain injury. AB - Neonatal hypoxic-ischemic brain injury and its related illness hypoxic-ischemic encephalopathy (HIE) are major causes of nervous system damage and neurological morbidity in children. Hypoxic preconditioning (HPC) is known to be neuroprotective in cerebral ischemic brain injury. K(ATP) channels are involved in ischemic preconditioning in the heart; however the involvement of neuronal K(ATP) channels in HPC in the brain has not been fully investigated. In this study, we investigated the role of HPC in hypoxia-ischemia (HI)-induced brain injury in postnatal seven-day-old (P7) CD1 mouse pups. Specifically, TTC (2,3,5 triphenyltetrazolium chloride) staining was used to assess the infarct volume, TUNEL (Terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling) to detect apoptotic cells, Western blots to evaluate protein level, and patch-clamp recordings to measure K(ATP) channel current activities. Behavioral tests were performed to assess the functional recovery after hypoxic-ischemic insults. We found that hypoxic preconditioning reduced infarct volume, decreased the number of TUNEL-positive cells, and improved neurobehavioral functional recovery in neonatal mice following hypoxic-ischemic insults. Pre-treatment with a K(ATP) channel blocker, tolbutamide, inhibited hypoxic preconditioning-induced neuroprotection and augmented neurodegeneration following hypoxic-ischemic injury. Pre-treatment with a K(ATP) channel opener, diazoxide, reduced infarct volume and mimicked hypoxic preconditioning-induced neuroprotection. Hypoxic preconditioning induced upregulation of the protein level of the Kir6.2 isoform and enhanced current activities of K(ATP) channels. Hypoxic preconditioning restored the HI-reduced PKC and pAkt levels, and reduced caspase-3 level, while tolbutamide inhibited the effects of hypoxic preconditioning. We conclude that K(ATP) channels are involved in hypoxic preconditioning-induced neuroprotection in neonatal hypoxic-ischemic brain injury. K(ATP) channel openers may therefore have therapeutic effects in neonatal hypoxic-ischemic brain injury. PMID- 25448005 TI - G-CSF ameliorates neuronal apoptosis through GSK-3beta inhibition in neonatal hypoxia-ischemia in rats. AB - Granulocyte-colony stimulating factor (G-CSF), a growth factor, has known neuroprotective effects in a variety of experimental brain injury models. Herein we show that G-CSF administration attenuates neuronal apoptosis after neonatal hypoxia-ischemia (HI) via glycogen synthase kinase-3beta (GSK-3beta) inhibition. Ten day old Sprague-Dawley rat pups (n=157) were subjected to unilateral carotid artery ligation followed by 2.5h of hypoxia or sham surgery. HI animals received control siRNA, GSK-3beta siRNA (4 MUL/pup), G-CSF (50 MUg/kg), G-CSF combined with 0.1 or 0.4 nM G-CSF receptor (G-CSFR) siRNA, phosphatidylinositol 3-kinase (PI3K) inhibitor Wortmannin (86 ng/pup), or DMSO (vehicle for Wortmannin). Pups were euthanized 48 h post-HI to quantify brain infarct volume. G-CSFR, activated Akt (p-Akt), activated GSK-3beta (p-GSK-3beta), Cleaved Caspase-3 (CC3), Bcl-2, and Bax were quantified using Western blot analysis and the localizations of each was visualized via immunofluorescence staining. Neuronal cell death was determined using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Our results showed p-GSK-3beta increased after HI until its peak at 48 h post-ictus, and both GSK-3beta siRNA and G-CSF administration reduced p-GSK-3beta expression, as well as infarct volume. p-GSK-3beta and CC3 were generally co-localized in neurons. Furthermore, G-CSF increased p-Akt expression and the Bcl-2/Bax ratio and also decreased p-GSK-3beta and CC3 expression levels in the ipsilateral hemisphere, which were all reversed by G CSFR siRNA, Wortmannin, and GSK-3beta siRNA. In conclusion, G-CSF attenuated caspase activation and reduced brain injury by inhibiting GSK-3beta activity after experimental HI in rat pups. This neuroprotective effect was abolished by both G-CSFR siRNA and Wortmannin. PMID- 25448008 TI - Cell replacement therapy: lessons from teleost fish. AB - Many disorders of the CNS are characterized by a massive loss of neurons. A promising therapeutic strategy to cure such conditions is based on the activation of endogenous stem cells. Implementation of this strategy will benefit from a better understanding of stem cell dynamics and the local CNS microenvironment in regeneration-competent vertebrate model systems. Using a spinal cord injury paradigm in zebrafish larvae, Briona and Dorsky (2014) have provided evidence for the existence of two distinct neural stem cell populations. One population has the characteristics of radial glia and expresses the homeobox transcription factor Dbx. The other lacks Dbx but expresses Olig2. These results are placed in the context of other studies that also support the notion of heterogeneity of adult stem cells in the CNS. The implication that differences among stem cell populations, in combination with specific factors from the local cellular microenvironment, might have a decisive impact on the fate choices of the new cells, is discussed. Reviewed evidence suggests that rather few modifications in the signaling pathways involved in the control of stem cell behavior have led, in the course of evolution, to the pronounced differences between mammals and regeneration-competent organisms. As a consequence, rather minor pharmacological manipulations may be sufficient to reactivate the hidden neurogenic potential of the mammalian CNS, and thus make it available for therapeutic applications. PMID- 25448007 TI - Axonal Charcot-Marie-Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties. AB - OBJECTIVE: Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies associated with mutations or copy number variations in over 70 genes encoding proteins with fundamental roles in the development and function of Schwann cells and peripheral axons. Here, we used iPSC-derived cells to identify common pathophysiological mechanisms in axonal CMT. METHODS: iPSC lines from patients with two distinct forms of axonal CMT (CMT2A and CMT2E) were differentiated into spinal cord motor neurons and used to study axonal structure and function and electrophysiological properties in vitro. RESULTS: iPSC-derived motor neurons exhibited gene and protein expression, ultrastructural and electrophysiological features of mature primary spinal cord motor neurons. Cytoskeletal abnormalities were found in neurons from a CMT2E (NEFL) patient and corroborated by a mouse model of the same NEFL point mutation. Abnormalities in mitochondrial trafficking were found in neurons derived from this patient, but were only mildly present in neurons from a CMT2A (MFN2) patient. Novel electrophysiological abnormalities, including reduced action potential threshold and abnormal channel current properties were observed in motor neurons derived from both of these patients. INTERPRETATION: Human iPSC-derived motor neurons from axonal CMT patients replicated key pathophysiological features observed in other models of MFN2 and NEFL mutations, including abnormal cytoskeletal and mitochondrial dynamics. Electrophysiological abnormalities found in axonal CMT iPSC-derived human motor neurons suggest that these cells are hyperexcitable and have altered sodium and calcium channel kinetics. These findings may provide a new therapeutic target for this group of heterogeneous inherited neuropathies. PMID- 25448010 TI - Signaling pathway profiling by reverse-phase protein array for personalized cancer medicine. AB - Deregulation of intracellular signaling through accumulation of genetic alterations is a hallmark of cancer. In the past few decades, concerted and systematic efforts have been made to identify key genetic alterations and to develop therapeutic agents targeting active signaling molecules. However, the efficacy of molecular therapeutics often varies among individuals, and precise mapping of active molecules in individual patients is now considered an essential for therapy optimization. Reverse-phase protein array or microarray (RPPA or RPPM) is an emerging antibody-based highly quantitative proteomic technology, especially suitable for profiling of expression and modification of signaling proteins in low abundance. Because the supply of clinical materials is often limited, RPPA technology is highly advantageous for clinical proteomics in view of its high sensitivity as well as accurate quantification. RPPA has now begun to be incorporated into various clinical trials employing molecular-targeted therapeutics. In this article we review and discuss the application of RPPA technology in the fields of basic, preclinical, and clinical research. The RPPA Global Workshop was recently launched to accelerate the exchange of rapidly expanding knowledge of this fascinating technology among academic laboratories and industries worldwide. This article is part of a Special Issue entitled: Medical Proteomics. PMID- 25448011 TI - A structured proteomic approach identifies 14-3-3Sigma as a novel and reliable protein biomarker in panel based differential diagnostics of liver tumors. AB - Hepatocellular carcinoma (HCC) is a major lethal cancer worldwide. Despite sophisticated diagnostic algorithms, the differential diagnosis of small liver nodules still is difficult. While imaging techniques have advanced, adjuvant protein-biomarkers as glypican3 (GPC3), glutamine-synthetase (GS) and heat-shock protein 70 (HSP70) have enhanced diagnostic accuracy. The aim was to further detect useful protein-biomarkers of HCC with a structured systematic approach using differential proteome techniques, bring the results to practical application and compare the diagnostic accuracy of the candidates with the established biomarkers. After label-free and gel-based proteomics (n=18 HCC/corresponding non-tumorous liver tissue (NTLT)) biomarker candidates were tested for diagnostic accuracy in immunohistochemical analyses (n=14 HCC/NTLT). Suitable candidates were further tested for consistency in comparison to known protein-biomarkers in HCC (n=78), hepatocellular adenoma (n=25; HCA), focal nodular hyperplasia (n=28; FNH) and cirrhosis (n=28). Of all protein-biomarkers, 14-3-3Sigma (14-3-3S) exhibited the most pronounced up-regulation (58.8*) in proteomics and superior diagnostic accuracy (73.0%) in the differentiation of HCC from non-tumorous hepatocytes also compared to established biomarkers as GPC3 (64.7%) and GS (45.4%). 14-3-3S was part of the best diagnostic three-biomarker panel (GPC3, HSP70, 14-3-3S) for the differentiation of HCC and HCA which is of most important significance. Exclusion of GS and inclusion of 14-3-3S in the panel (>1 marker positive) resulted in a profound increase in specificity (+44.0%) and accuracy (+11.0%) while sensitivity remained stable (96.0%). 14-3-3S is an interesting protein biomarker with the potential to further improve the accuracy of differential diagnostic process of hepatocellular tumors. This article is part of a Special Issue entitled: Medical Proteomics. PMID- 25448009 TI - Hypoxia triggers short term potentiation of phrenic motoneuron discharge after chronic cervical spinal cord injury. AB - Repeated exposure to hypoxia can induce spinal neuroplasticity as well as respiratory and somatic motor recovery after spinal cord injury (SCI). The purpose of the present study was twofold: to define the capacity for a single bout of hypoxia to trigger short-term plasticity in phrenic output after cervical SCI and to determine the phrenic motoneuron (PhrMN) bursting and recruitment patterns underlying the response. Hypoxia-induced short term potentiation (STP) of phrenic motor output was quantified in anesthetized rats 11 weeks following lateral spinal cord hemisection at C2 (C2Hx). A 3-min hypoxic episode (12-14% O2) always triggered STP of inspiratory burst amplitude, the magnitude of which was greater in phrenic bursting ipsilateral vs. contralateral to C2Hx. We next determined if STP could be evoked in recruited (silent) PhrMNs ipsilateral to C2Hx. Individual PhrMN action potentials were recorded during and following hypoxia using a "single fiber" approach. STP of bursting activity did not occur in cells initiating bursting at inspiratory onset, but was robust in recruited PhrMNs as well as previously active cells initiating bursting later in the inspiratory effort. We conclude that following chronic C2Hx, a single bout of hypoxia triggers recruitment of PhrMNs in the ipsilateral spinal cord with bursting that persists beyond the hypoxic exposure. The results provide further support for the use of short bouts of hypoxia as a neurorehabilitative training modality following SCI. PMID- 25448014 TI - Proteome-based bacterial identification using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS): A revolutionary shift in clinical diagnostic microbiology. AB - Rapid and accurate identification of microorganisms, a prerequisite for appropriate patient care and infection control, is a critical function of any clinical microbiology laboratory. Matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) is a quick and reliable method for identification of microorganisms, including bacteria, yeast, molds, and mycobacteria. Indeed, there has been a revolutionary shift in clinical diagnostic microbiology. In the present review, the state of the art and advantages of MALDI TOF MS-based bacterial identification are described. The potential of this innovative technology for use in strain typing and detection of antibiotic resistance is also discussed. This article is part of a Special Issue entitled: Medical Proteomics. PMID- 25448015 TI - Functional annotation and biological interpretation of proteomics data. AB - Proteomics experiments often generate a vast amount of data. However, the simple identification and quantification of proteins from a cell proteome or subproteome is not sufficient for the full understanding of complex mechanisms occurring in the biological systems. Therefore, the functional annotation analysis of protein datasets using bioinformatics tools is essential for interpreting the results of high-throughput proteomics. Although large-scale proteomics data have rapidly increased, the biological interpretation of these results remains as a challenging task. Here we reviewed basic concepts and different programs that are commonly used in proteomics data functional annotation, emphasizing the main strategies focused in the use of gene ontology annotations. Furthermore, we explored the characteristics of some tools developed for functional annotation analysis, concerning the ease of use and typical caveats on ontology annotations. The utility and variations between different tools were assessed through the comparison of the resulting outputs generated for an example of proteomics dataset. PMID- 25448013 TI - Combining solvent isotope effects with substrate isotope effects in mechanistic studies of alcohol and amine oxidation by enzymes. AB - Oxidation of alcohols and amines is catalyzed by multiple families of flavin- and pyridine nucleotide-dependent enzymes. Measurement of solvent isotope effects provides a unique mechanistic probe of the timing of the cleavage of the OH and NH bonds, necessary information for a complete description of the catalytic mechanism. The inherent ambiguities in interpretation of solvent isotope effects can be significantly decreased if isotope effects arising from isotopically labeled substrates are measured in combination with solvent isotope effects. The application of combined solvent and substrate (mainly deuterium) isotope effects to multiple enzymes is described here to illustrate the range of mechanistic insights that such an approach can provide. This article is part of a Special Issue entitled: Enzyme Transition States from Theory and Experiment. PMID- 25448016 TI - A conserved tryptophan (W91) at the barrel-lid junction modulates the packing and stability of Kunitz (STI) family of inhibitors. AB - beta-trefoil fold, consisting of a six stranded beta-barrel capped at one end by a lid comprising of another six beta-strands, is one of the most important folds among proteins. Important classes of proteins like Interleukins (ILs), Fibroblast Growth Factors (FGFs), Kunitz (STI) family of inhibitors etc. belong to this fold. Their core is packed by hydrophobic residues contributed by the 6 stranded beta-barrel and three beta-hairpins that make essential contacts with each other and keep the protein in 'topologically minimal frustrated state'. A complete database analysis of the core residues of the beta-trefoil fold proteins presented here identified a conserved tryptophan (W91) residue in the Kunitz (STI) family of inhibitors that projects from the lid and interacts with the bottom layer residues of the barrel. This kind of interactions is unique in Kunitz (STI) family because no other families of beta-trefoil fold have such a shear sized residue at the barrel lid junction; suggesting its possible importance in packing and stability. We took WCI as a representative of this family and prepared four cavity creating mutants W91F-WCI, W91M-WCI, W91I-WCI & W91A-WCI. CD experiments show that the secondary structure of the mutants remains indistinguishable with the wild type. Crystal structures of the mutants W91F-WCI, W91M-WCI & W91A-WCI also show the same feature. However, slight readjustments of the side chains around the site of mutation have been observed so as to minimize the cavity created due to mutation. Comparative stability of these mutants, estimated using heat denaturation CD spectroscopy, indicates that stability of the mutants inversely correlates with the size of the cavity inside the core. Interestingly, although we mutated at the core, mutants show varying susceptibility against tryptic digestion that grossly follow their instability determined by CD. Our findings suggest that the W91 residue plays an important role in determining the stability and packing of the core of WCI. PMID- 25448017 TI - The role of proline substitutions within flexible regions on thermostability of luciferase. AB - Improving the stability of firefly luciferase has been a critical issue for its wider industrial applications. Studies about hyperthermophile proteins show that flexibility could be an effective indicator to find out weak spots to engineering thermostability of proteins. However, the relationship among flexibility, activity and stability in most of proteins is unclear. Proline is the most rigid residue and can be introduced to rigidify flexible regions to enhance thermostability of proteins. We firstly apply three different methods, molecular dynamics (MD) simulation, B-FITTER and framework rigidity optimized dynamics algorithm (FRODA) to determine the flexible regions of Photinus pyralis luciferase: Fragment 197-207; Fragment 471-481 and Fragment 487-495. Then, introduction of proline is used to rigidify these flexible regions. Two mutants D476P and H489P within most flexible regions are finally designed. In the results, H489P mutant shows improved thermostability while maintaining its catalytic efficiency compared to that of wild type luciferase. Flexibility analysis confirms that the overall rigidity and local rigidity of H489P mutant are greatly strengthened. D476P mutant shows decreased thermosatbility and the reason for this is elucidated at the molecular level. S307P mutation is randomly chosen outside the flexible regions as a control. Thermostability analysis shows that S307P mutation has decreased kinetic stability and enhanced thermodynamic stability. PMID- 25448012 TI - Mass spectrometric analysis of spatio-temporal dynamics of crustacean neuropeptides. AB - Neuropeptides represent one of the largest classes of signaling molecules used by nervous systems to regulate a wide range of physiological processes. Over the past several years, mass spectrometry (MS)-based strategies have revolutionized the discovery of neuropeptides in numerous model organisms, especially in decapod crustaceans. Here, we focus our discussion on recent advances in the use of MS based techniques to map neuropeptides in the spatial domain and monitoring their dynamic changes in the temporal domain. These MS-enabled investigations provide valuable information about the distribution, secretion and potential function of neuropeptides with high molecular specificity and sensitivity. In situ MS imaging and in vivo microdialysis are highlighted as key technologies for probing spatio temporal dynamics of neuropeptides in the crustacean nervous system. This review summarizes the latest advancement in MS-based methodologies for neuropeptide analysis including typical workflow and sample preparation strategies as well as major neuropeptide families discovered in decapod crustaceans. This article is part of a Special Issue entitled: Neuroproteomics: Applications in Neuroscience and Neurology. PMID- 25448018 TI - Specificity studies on Kallikrein-related peptidase 7 (KLK7) and effects of osmolytes and glycosaminoglycans on its peptidase activity. AB - KLK7 substrate specificity was evaluated by families of fluorescence resonance energy transfer (FRET) peptides derived from Abz-KLFSSK-Q-EDDnp (Abz=ortho aminobenzoic acid and Q-EDDnp=glutaminyl-N-[2,4-dinitrophenyl] ethylenediamine), by one bead-one peptide FRET peptide library in PEGA resin, and by the FRET peptide libraries Abz-GXX-Z-XX-Q-EDDnp (Z and X are fixed and random natural amino acids, respectively). KLK7 hydrolyzed preferentially F, Y or M, and its S1' and S2' subsites showed selectivity for hydrophilic amino acids, particularly R and K. This set of specificities was confirmed by the efficient kininogenase activity of KLK7 on Abz-MISLM(?)KRPPGFSPF(?)RSSRI-NH2 ((?)indicates cleavage), hydrolysis of somatostatin and substance P and inhibition by kallistatin. The peptide Abz-NLY(?)RVE-Q-EDDnp is the best synthetic substrate so far described for KLK7 [kcat/Km=455 (mMs)(-1)] that was designed from the KLK7 substrate specificity analysis. It is noteworthy that the NLYRVE sequence is present in human semaphorin 6B. KLK7 is activated by GAGs, inhibited by neutral salts, and activated by high concentration of kosmotropic salt. Pyroglutamic acid inhibited KLK7 (Ki=33mM) and is present in skin moisturizing factor (124mM). The KLK7 specificity described here and elsewhere reflects its participation in patho physiological events in skin, the gastrointestinal tract and central nervous system, where KLK7 is significantly expressed. PMID- 25448019 TI - Off-target responses in the HeLa proteome subsequent to transient plasmid mediated transfection. AB - Transient transfection of mammalian cells with plasmid expression vectors and chemical transfection reagents is widely used to study protein transport and dynamics as well as phenotypic alterations mediated by the overexpressed protein. Despite the undisputed impact of this technique, surprisingly little is known about the cellular effects mediated by the transfection process per se. Conceivably, off-target effects could have implications upon proteins or processes being studied and understanding the molecular pathways affected would add value to the interpretation of experimental observations subsequent to cell transfection. Here we have used a SILAC-based proteomic approach to study differentially expressed proteins after transfection of HeLa cells with ECFP vector using a commonly employed non-liposome based transfection reagent, Fugene(r)HD. Whereas the transfection reagent itself mediated minimal effects upon protein expression, 11 proteins were found to be significantly upregulated after transfection, all of which were associated with an interferon type I/II response. The upregulated proteins might potentially inflict major cellular processes such as RNA splicing, chromatin remodeling, post-translational protein modification and cell cycle control. The results were validated by western analysis as well as quantitative RT-PCR and this demonstrated that an essentially identical response was induced in HeLa by transfection using an empty pUC18 vector, which does not contain a mammalian virus promoter, as well as a liposome based transfection reagent, Lipofectamine(TM)2000. Notably, no induction of the interferon response was observed in HEK293 cells, suggesting that these cells might be preferable to HeLa to avoid undesired off-target effects in transfection studies encompassing interferon-signaling and antiviral responses. PMID- 25448021 TI - A high throughput MATLAB program for automated force-curve processing using the AdG polymer model. AB - Research in understanding biofilm formation is dependent on accurate and representative measurements of the steric forces related to brush on bacterial surfaces. A MATLAB program to analyze force curves from an AFM efficiently, accurately, and with minimal user bias has been developed. The analysis is based on a modified version of the Alexander and de Gennes (AdG) polymer model, which is a function of equilibrium polymer brush length, probe radius, temperature, separation distance, and a density variable. Automating the analysis reduces the amount of time required to process 100 force curves from several days to less than 2min. The use of this program to crop and fit force curves to the AdG model will allow researchers to ensure proper processing of large amounts of experimental data and reduce the time required for analysis and comparison of data, thereby enabling higher quality results in a shorter period of time. PMID- 25448022 TI - Simultaneous quantification of sporangia and zoospores in a biotrophic oomycete with an automatic particle analyzer: disentangling dispersal and infection potentials. AB - Quantitative pathogenicity traits drive the fitness and dynamics of pathogens in agricultural ecosystems and are key determinants of the correct management of crop production over time. However, traits relating to infection potential (i.e. zoospore production) have been less thoroughly investigated in oomycetes than traits relating to dispersal (i.e. sporangium production). We simultaneously quantified sporangium and zoospore production in a biotrophic oomycete, for the joint assessment of life-cycle traits relating to dispersal and infection potentials. We used an automatic particle analyzer to count and size the sporangia and/or zoospores produced at t = 0 min (no zoospore release) and t = 100 min (zoospore release) in 43 Plasmopara viticola isolates growing on the susceptible Vitis vinifera cv. Cabernet Sauvignon. We were able to differentiate and quantify three types of propagules from different stages of the pathogen life cycle: full sporangia, empty sporangia and zoospores. The method was validated by comparing the sporangium and zoospore counts obtained with an automatic particle analyzer and under a stereomicroscope (manual counting). Each isolate produced a mean of 5.8 +/- 1.9 (SD) zoospores per sporangium. Significant relationships were found between sporangium production and sporangium size (negative) and between sporangium size and the number of zoospores produced per sporangium (positive). However, there was a significant positive correlation between total sporangium production and total zoospore production. This procedure can provide a valid quantification of the production of both sporangia and zoospores by oomycetes in large numbers of samples, facilitating joint estimation of the dispersal and infection potentials of plant pathogens in various agro-ecological contexts. PMID- 25448023 TI - A novel method to characterize bacterial communities affected by carbon source and electricity generation in microbial fuel cells using stable isotope probing and Illumina sequencing. AB - Stable isotope probing and high throughput sequencing were used to characterize the microbial communities involved in carbon uptake in microbial fuel cells at two levels of electricity generation. With acetate, the dominant phylotypes involved in carbon uptake included Geobacter and Rhodocyclaceae. With glucose, both Enterobacteriaceae and Geobacter were dominant. PMID- 25448024 TI - Comparison of two partial middle turbinectomy techniques for the treatment of a concha bullosa. AB - OBJECTIVES/HYPOTHESIS: To assess the nasal functions, nasal resistance, and olfactory function in middle turbinate surgery. STUDY DESIGN: Randomized controlled trial. METHODS: This prospective controlled study was carried out on patients who underwent laminectomy for aeration of the middle turbinate. Patients participating in the study were divided into two groups-group 1: medial laminectomy (n = 34) and group 2: lateral laminectomy (n = 38). Patients underwent the preoperative visual analogue score, sinonasal outcome test-22 (SNOT 22), peak nasal inspiratory flowmeter, and Connecticut Chemosensory Clinical Research Center smell test. All patients were reevaluated 3 months after the operation. RESULTS: The study group comprised 72 consecutive patients. The mean age of the patients was 31.03 +/- 9.7, with a range of 17 to 54 years. A total of 47.2 % (n = 34) had medial and 52.8% (n = 38) had lateral laminectomy. Bilateral turbinate intervention was performed in 27.8% (n = 20), whereas unilateral middle turbinate intervention was performed in 72.3% (n = 52). Overall, both groups showed strong significant improvement over time in visual analogue scale results, SNOT-22 scores, peak flowmeter results, and olfactory function between preoperative and postoperative scores (P < 0.001). There was no significant difference between the groups for all parameters (P > 0.05). CONCLUSIONS: This study revealed that medial laminectomy for aeration of the middle turbinate was as effective as lateral laminectomy. LEVEL OF EVIDENCE: 1b. Laryngoscope, 125:1062-1066, 2015. PMID- 25448025 TI - Clinical Biochemistry year in review - the clinical "good", the analytical "bad", and the "ugly" laboratory practices. PMID- 25448026 TI - Bi-variate approach to negative interference of bilirubin towards an acetaminophen assay. AB - BACKGROUND: It is well known that enzymatic assays for acetaminophen are positively interfered by bilirubin. The effect on acetaminophen not only depends on the concentration of bilirubin but also on that of acetaminophen. We demonstrated a negative interference instead of a positive one in a commonly used routine analyzer and investigated the recovery of acetaminophen in an enzymatic assay by a bi-variate regression. METHODS: Commercially available blank serum specimens were spiked with acetaminophen and bilirubin at various concentrations, and were analyzed in the Beckman Coulter AU5822 analyzer. The specimens were run in duplicates. The results were then analyzed by least-square analysis and was built into a bi-variate quadratic model. RESULTS: The recovery of acetaminophen in this experiment ranged from 38.9% to 100% throughout a range of 23 MUmol/L to 2052 MUmol/L (for acetaminophen) and 19 MUmol/L to 570 MUmol/L (for bilirubin). A contour map, as well as a bi-variate equation was established, describing the relationship between acetaminophen recovery, acetaminophen concentration, and bilirubin concentration. CONCLUSION: It was shown that the degree of bilirubin interference in a commercially available acetaminophen assay is dependent on both bilirubin and acetaminophen concentrations. There was a decrease in the apparent acetaminophen concentration by an average of 30% at a bilirubin concentration of 420 MUmol/L in the Beckman Coulter AU5822 analyzer. The complex relationship can be modeled by mathematical means. This allows the laboratory staff to estimate the recovery of acetaminophen when bilirubin level is concurrently measured. PMID- 25448028 TI - Simplified sample preparation in the simultaneous measurement of whole blood antimony, bismuth, manganese, and zinc by inductively coupled plasma mass spectrometry. AB - OBJECTIVES: We developed and validated a simplified sample preparation for the analysis of antimony (Sb), bismuth (Bi), manganese (Mn), and zinc (Zn) in whole blood. This simplification included a reduction in sample volume, removal of a lengthy acidic digestion, and optimization of the internal standard. DESIGN AND METHODS: Measurement of Sb, Bi, Mn and Zn in whole blood was conducted using inductively coupled-plasma mass spectrometry. Method performance characteristics, including intra- and inter-assay imprecision, accuracy, linearity, AMR, sensitivity, carryover, sample stability and assay stability were determined in accordance with clinical laboratory standards. In addition, analytical and clinical recoveries were assessed to investigate comparability between goat blood matrix and pooled patient blood. RESULTS: Established assay performance characteristics included inter- and intra-assay imprecision <4.5% and carryover of <0.04% for all four elements, analytical measurement range of 1 to 25 MUg/L (Sb and Bi), 1 to 80 MUg/L (Mn), and 50 to 1500 MUg/dL (Zn), limit of quantification of 1 MUg/L (Sb, Bi, Mn) and 50 MUg/dL (Zn) (coefficient of variation <14%), proportional bias of 0.96 and constant bias of -0.28 (Sb), 0.94 and -0.45 (Bi), 1.07 and -0.37 (Mn) and 0.96 and +18.05 (Zn) based upon repeat patient samples, proficiency testing samples, and comparison to an outside reference laboratory. CONCLUSION: This method overcomes the laborious acidic heat digestion previously used and replaces it with a simplified sample preparation involving an alkaline dilution. The method requires minimal sample preparation with the dilution of alkaline diluent and is validated to quantify Sb and Bi from 1 to 25 MUg/L, Mn from 1 to 80 MUg/L, and Zn from 50 to 1500 MUg/dL in whole blood. PMID- 25448027 TI - An approach to rule-out an acute cardiovascular event or death in emergency department patients using outcome-based cutoffs for high-sensitivity cardiac troponin assays and glucose. AB - OBJECTIVES: The application of "undetectable" high-sensitivity cardiac troponin (hs-cTn) concentrations to "rule-out" myocardial infarction is appealing, but there are analytical concerns and a lack of consensus on what concentration should be used to define the lower reportable limit; i.e., limit of detection (LoD) or limit of blank. An alternative approach is to utilize a measurable hs cTn concentration that identifies patients at low-risk for a future cardiovascular event combined with another prognostic test, such as glucose. We assessed both of these approaches in different emergency department (ED) cohorts to rule-out an event. DESIGN AND METHODS: We used cohort 1 (all-comer ED population, n=4773; derivation cohort) to determine the most appropriate approach at presentation (i.e., Dual Panel test: hs-cTn/glucose vs. LoD vs. LoD/glucose) for an early rule-out of hospital death using the Abbott ARCHITECT hs-cTnI assay. We used cohort 2 (n=144) and cohort 3 (n=127), both early chest pain onset ED populations as the verification datasets (outcome: composite cardiovascular event at 72h) with three hs-cTn assays assessed (Abbott Laboratories, Beckman Coulter, Roche Diagnostics). RESULTS: In cohort 1, the sensitivity was >99% for all three approaches; however the specificity (11%; 95% CI: 10-12%) was significantly higher for the Dual Panel as compared to the LoD approach (specificity=5%; 95% CI: 4-6%). Verification of the Dual Panel in cohort 2 and cohort 3 revealed 100% sensitivity and negative predictive values for all three hs-cTn assays. CONCLUSIONS: The combination of a "healthy" hs-cTn concentration with glucose might effectively rule-out patients for an acute cardiovascular event at ED presentation. PMID- 25448029 TI - Evidence based application of BNP/NT-proBNP testing in heart failure. AB - BACKGROUND: The B-type natriuretic peptides are now available on many automated clinical analysers. Clinical practice guidelines for heart failure include recommendations for where the B-type natriuretic peptides are possibly useful for clinical practice. A number of systematic reviews considering B-type natriuretic peptides in relation to heart failure patients have been published. METHODS: This review will consider the evidence presented in the systematic reviews and how this can be applied to clinical practice. RESULTS: Twenty-six systematic reviews are summarised in tables considering applications to diagnostic, prognostic and guiding therapy. Important clinical considerations for these applications are discussed to facilitate appropriate implementation in the clinical laboratory. CONCLUSION: Most clinical laboratories should be considering the appropriate implementation of the B-type natriuretic peptide as a diagnostic test to assist in ruling out heart failure. In the application of prognosis and guiding therapy a number of questions remain to be answered. PMID- 25448030 TI - Using a simulation model to assess risk of false negative point-of-care urinary human chorionic gonadotropin device results due to high-dose hook interference. AB - BACKGROUND: It is unclear if the point-of-care (POC) Clinitest hCG device is subject to high-dose hook interference from physiological concentrations of intact human chorionic gonadotropin (hCG), beta-core fragment of hCG (hCGbetacf), and hCG free beta-subunit (hCGbeta) found in urine during pregnancy. We used a simulation model to address this question and related our findings to our institution's pregnant population in order to assess risk for potential false negative hCG results. METHODS: The expected distribution of days relative to ovulation during routine POC hCG testing was estimated from 182 patients. Clinitest-Clinitek Status hCG device susceptibility to high-dose hook interference from hCG variants and potential risk of false-negative results as it relates to this population were evaluated by testing increasing concentrations of hCG, hCGbetacf, hCGbeta as well as urine simulating physiological hCG, hCGbetacf and hCGbeta concentrations expected during early pregnancy (<=44 days post ovulation). RESULTS: The Clinitest-Clinitek Status hCG device exhibited high-dose hook interference from hCGbetacf alone, but not from hCG, hCGbeta, or simulated physiological urinary concentrations of combined hCG, hCGbetacf and hCGbeta expected during early pregnancy. The majority of our patient population had urinary hCG testing conducted during early pregnancy. CONCLUSION: The Clinitest Clinitek Status hCG device is unlikely to exhibit false-negative urinary hCG results due to high-dose hook interference for women in early healthy pregnancy, although additional studies are necessary to determine potential risk in other patient populations. Visual interpretation of POC urinary hCG device results is an important failure mode to consider in risk analyses for erroneous urinary hCG device results. PMID- 25448031 TI - Evaluation of antibody levels over 3 years after 23-valent pneumococcal polysaccharide vaccination in patients with pulmonary diseases receiving steroids and immunosuppressive agents. AB - OBJECTIVES: Pneumococcal capsular polysaccharide vaccine is a mainstay for prevention of Streptococcus pneumoniae infection in adults. There is the possibility that this vaccine is less effective in patients undergoing immunosuppressive therapy. In the present study, we aimed to evaluate the immune response following 23-valent pneumococcal polysaccharide vaccination in pulmonary disease patients receiving steroids and immunosuppressive agents (immunosuppressive group). DESIGN AND METHODS: Antibody levels were measured over 3 years in the immunosuppressive group (median age: 68.5 years) and in aged-match pulmonary disease patients not being treated with immunosuppressive therapy (control group) using enzyme-linked immunosorbent assays. RESULTS: The geometric mean antibody levels were significantly increased after vaccination in both groups (p < 0.05) and remained above baseline for 3 years. The fold increases 1 month after vaccination were 9.4 (95% confidence interval [CI]: 5.7-15.6) and 8.8 (95% CI: 5.8-13.2) in the immunosuppressive and control groups, respectively (p = 0.813). There was no significant difference in the proportion of subjects with a >= two-fold increase of antibody level between the immunosuppressive and control groups at any point. CONCLUSIONS: These results suggest that immunization with the 23-valent pneumococcal polysaccharide vaccine was effective, even in patients undergoing immunosuppressive therapy and should be recommended for such patients. PMID- 25448032 TI - cp-R, an interface the R programming language for clinical laboratory method comparisons. AB - BACKGROUND AND OBJECTIVE: Clinical scientists frequently need to compare two different bioanalytical methods as part of assay validation/monitoring. As a matter necessity, regression methods for quantitative comparison in clinical chemistry, hematology and other clinical laboratory disciplines must allow for error in both the x and y variables. Traditionally the methods popularized by 1) Deming and 2) Passing and Bablok have been recommended. While commercial tools exist, no simple open source tool is available. The purpose of this work was to develop and entirely open-source GUI-driven program for bioanalytical method comparisons capable of performing these regression methods and able to produce highly customized graphical output. METHODS: The GUI is written in python and PyQt4 with R scripts performing regression and graphical functions. The program can be run from source code or as a pre-compiled binary executable. The software performs three forms of regression and offers weighting where applicable. Confidence bands of the regression are calculated using bootstrapping for Deming and Passing Bablok methods. Users can customize regression plots according to the tools available in R and can produced output in any of: jpg, png, tiff, bmp at any desired resolution or ps and pdf vector formats. Bland Altman plots and some regression diagnostic plots are also generated. Correctness of regression parameter estimates was confirmed against existing R packages. RESULTS: The program allows for rapid and highly customizable graphical output capable of conforming to the publication requirements of any clinical chemistry journal. Quick method comparisons can also be performed and cut and paste into spreadsheet or word processing applications. CONCLUSIONS: We present a simple and intuitive open source tool for quantitative method comparison in a clinical laboratory environment. PMID- 25448033 TI - Evaluation of the performance of an immunoturbidimetric HbA1c reagent applied to the Siemens ADVIA 2400 automatic analyzer. AB - OBJECTIVES: A new immunochemical reagent based on latex particles and antibodies against HbA1c (Axis-Shield), using Siemens ADVIA 2400 Instrument was evaluated. DESIGN AND METHODS: Intra-assay and total imprecision, interferences studies (bilirubin ~850 MUmol/L, triglycerides ~16.9 mmol/L, total protein ~140 g/L, sodium cyanate ~50 mg/dL, ascorbic acid ~50 mg/dL, urea ~24.99 mmol/L, glucose ~105.46 mmol/L, rheumatoid factor ~600 U/mL), method comparison vs Capillary Electrophoresis (Sebia), Lot to Lot reproducibility, linearity and carry over were conducted on ADVIA 2400 according to CLSI protocols. Additionally, 40 samples were measured by the two methods and also by a NGSP reference lab. RESULTS: CVs % obtained by intra-assay imprecision, on 3 human HbA1c specimens at different concentrations (48, 48-64 and >64 mmol/mol) in 20 replicates, were <4%. CVs % by total imprecision, performed over 20 days with 4 calibrations on 3 human HbA1c samples (48, 48-64 and >64 mmol/mol), resulted <4%. Interferences were studied on two human samples (42-53 and>64 mmol/mol) without obtaining significant biases (<10%). Methods comparison vs Capillary Electrophoresis, performed on 120 samples ranging 23-137 mmol/mol, obtaining r = 0.974 as regression coefficient and a mean bias at decision level (48 mmol/mol) <3%. The results obtained with the NGSP samples have allowed the certification of the new reagent. CONCLUSIONS: The ASD reagent met the needs of clinical laboratories, fulfilling both NGSP and IFCC requirements and it is robust to endogenous interferences. PMID- 25448034 TI - Comparison of two point of care devices for capillary lipid screening in fasting and postprandial adults. AB - OBJECTIVES: The aim of this study was to assess the performance of two point of care (POC) devices for capillary lipid screening in fasting and post-prandial adults. DESIGN AND METHODS: Fasting and post-prandial capillary whole blood samples collected from 57 adult donors were analyzed simultaneously on Cholestech LDX Lipid Profile (Alere San Diego, Inc., San Diego, CA) cassettes and CardioChek Lipid Panel (Polymer Technology Systems, Indianapolis, IN) strips. Paired serum samples were collected from the same donors and analyzed with CDC-certified methods for total cholesterol, high density lipoprotein cholesterol (HDL-C) and non-blanked triglycerides. Non-HDL-C (total cholesterol minus HDL-C) and low density lipoprotein cholesterol (LDL-C) were calculated. Mean bias between capillary whole blood and serum laboratory lipids was calculated. RESULTS: HDL-C measurements were not affected by triglyceride content on either device. However, both devices exhibited significant variability in triglyceride measurement relative to the reference method. Compared to reference methods, Cholestech was more accurate than CardioChek for non-HDL-C while CardioChek was more accurate for HDL-C. Among the calculated cardiovascular risk parameters (LDL-C and non-HDL C), Cholestech-calculated non-HDL-C exhibited the least average bias in both fasting and postprandial samples. CONCLUSIONS: The optimal approach to capillary lipid screening may be to use Cholestech non-HDL cholesterol; as it exhibited little bias relative to CDC reference methods in both fasting and postprandial samples, facilitating lipid screening in non-fasting adults. PMID- 25448035 TI - Structure-function analysis of NEET proteins uncovers their role as key regulators of iron and ROS homeostasis in health and disease. AB - A novel family of 2Fe-2S proteins, the NEET family, was discovered during the last decade in numerous organisms, including archea, bacteria, algae, plant and human; suggesting an evolutionary-conserved function, potentially mediated by their CDGSH Iron-Sulfur Domain. In human, three NEET members encoded by the CISD1 3 genes were identified. The structures of CISD1 (mitoNEET, mNT), CISD2 (NAF-1), and the plant At-NEET uncovered a homodimer with a unique "NEET fold", as well as two distinct domains: a beta-cap and a 2Fe-2S cluster-binding domain. The 2Fe-2S clusters of NEET proteins were found to be coordinated by a novel 3Cys:1His structure that is relatively labile compared to other 2Fe-2S proteins and is the reason of the NEETs' clusters could be transferred to apo-acceptor protein(s) or mitochondria. Positioned at the protein surface, the NEET's 2Fe-2S's coordinating His is exposed to protonation upon changes in its environment, potentially suggesting a sensing function for this residue. Studies in different model systems demonstrated a role for NAF-1 and mNT in the regulation of cellular iron, calcium and ROS homeostasis, and uncovered a key role for NEET proteins in critical processes, such as cancer cell proliferation and tumor growth, lipid and glucose homeostasis in obesity and diabetes, control of autophagy, longevity in mice, and senescence in plants. Abnormal regulation of NEET proteins was consequently found to result in multiple health conditions, and aberrant splicing of NAF-1 was found to be a causative of the neurological genetic disorder Wolfram Syndrome 2. Here we review the discovery of NEET proteins, their structural, biochemical and biophysical characterization, and their most recent structure function analyses. We additionally highlight future avenues of research focused on NEET proteins and propose an essential role for NEETs in health and disease. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. PMID- 25448037 TI - Review of human butyrylcholinesterase structure, function, genetic variants, history of use in the clinic, and potential therapeutic uses. AB - Phase I clinical trials have shown that pure human butyrylcholinesterase (BChE) is safe when administered to humans. A potential therapeutic use of BChE is for prevention of nerve agent toxicity. A recombinant mutant of BChE that rapidly inactivates cocaine is being developed as a treatment to help recovering cocaine addicts avoid relapse into drug taking. These clinical applications rely on knowledge of the structure, stability, and properties of BChE, information that is reviewed here. Gene therapy with a vector that sustains expression for a year from a single injection is a promising method for delivering therapeutic quantities of BChE. PMID- 25448036 TI - The effect of glucose concentration and sodium phenylbutyrate treatment on mitochondrial bioenergetics and ER stress in 3T3-L1 adipocytes. AB - While the 3T3-L1 adipocyte model is routinely used for the study of obesity and diabetes, the mitochondrial respiratory profile in normal versus high glucose has not been examined in detail. We matured adipocytes in normal (5mM) or high (30 mM) glucose and insulin and examined the mitochondrial bioenergetics. We also assessed the requirement for the Unfolded Protein Response (UPR) and ER stress under these conditions. Basal respiration was ~1.7-fold greater in adipocytes that had matured in 30 mM glucose; however, their ability to increase oxygen consumption in response to stress was impaired. Adipogenesis proceeded in both normal and high glucose with concomitant activation of the UPR, but only high glucose was associated with increased levels of ER stress and mitochondrial stress as observed by parallel increases in CHOP and protein succination. Treatment of adipocytes with sodium phenylbutyrate relieved mitochondrial stress through a reduction in mitochondrial respiration. Our data suggests that mitochondrial stress, protein succination and ER stress are uniquely linked in adipocytes matured in high glucose. PMID- 25448038 TI - Emerging roles of the gamma-secretase-notch axis in inflammation. AB - gamma-Secretase is a distinct proteolytic complex required for the activation of many transmembrane proteins. The cleavage of substrates by gamma-secretase plays diverse biological roles in producing essential products for the organism. More than 90 transmembrane proteins have been reported to be substrates of gamma secretase. Two of the most widely known and studied of these substrates are the amyloid precursor protein (APP) and the Notch receptor, which are precursors for the generation of amyloid-beta (Abeta) and the Notch intracellular domain (NICD), respectively. The wide spectrum of gamma-secretase substrates has made analyses of the pathology of gamma-secretase-related diseases and underlying mechanisms challenging. Inflammation is an important aspect of disease pathology that requires an in-depth analysis. gamma-Secretase may contribute to disease development or progression by directly increasing and regulating production of pro-inflammatory cytokines. This review summarizes recent evidence for a role of gamma-secretase in inflammatory diseases, and discusses the potential use of gamma-secretase inhibitors as an effective future treatment option. PMID- 25448039 TI - Putative targeting of matrix metalloproteinase-8 in atherosclerosis. AB - There is compelling evidence indicating that some members of the matrix metalloproteinase (MMP) family play important roles in the pathogenesis of atherosclerosis and related vascular and cardiac conditions such as atherosclerotic plaque rupture leading to myocardial infarction, heart failure after myocardial infarction, neointima formation following angioplasty, and abdominal aortic aneurysm. Studies have shown that administration of MMP inhibitors can deter some of these conditions in experimental animal models, but few pertinent human clinical trials have been reported to date. Clinical studies of broad-spectrum MMP inhibitors in cancers and arthritis, however, have reported considerable side effects that are likely to be related to the lack of selectivity of these inhibitors. Since different members of the MMP family can have divergent and even opposing functions, it is believed that selective MMP inhibitors that specifically target particular MMPs that are key in the disease pathogenesis will likely have greater efficacy and less adverse effects. In recent years there has been accumulating evidence indicating an important role of MMP8 in atherosclerosis and the associated conditions mentioned above. This article will review findings from studies examining MMP8 in relation to these conditions and discuss rationale of targeting MMP8 as a potential therapeutic strategy. PMID- 25448042 TI - Infections and antineutrophil cytoplasmic antibodies: triggering mechanisms. AB - The precise cause of the antineutrophil cytoplasmic antibodies (ANCA) autoimmunity is not known and is likely to be multifactorial. Infections may trigger formation of ANCA and a fraction of the patients with infection-triggered ANCA develop ANCA-associated vasculitis. Here we discuss some of the proposed mechanisms of ANCA formation during the course of infection. They include initiation of autoimmune response by microbial peptides that are complementary to autoantigens; epigenetic silencing and antigen complementarity leading to upregulation of autoantigen genes; molecular mimicry between bacterial and self antigens; formation of neutrophil extracellular traps that stimulate immune processes including production of ANCA; and interaction of bacterial components with Toll-like receptors, which leads to formation of mediators affecting the immune responses to infections and can trigger ANCA production. Further work is needed to clarify these mechanisms and develop preventive measures and therapeutic interventions. PMID- 25448043 TI - Tau, amyloid, and hypometabolism in a patient with posterior cortical atrophy. AB - Determining the relative contribution of amyloid plaques and neurofibrillary tangles to brain dysfunction in Alzheimer disease is critical for therapeutic approaches, but until recently could only be assessed at autopsy. We report a patient with posterior cortical atrophy (visual variant of Alzheimer disease) who was studied using the novel tau tracer [(18) F]AV-1451 in conjunction with [(11) C]Pittsburgh compound B (PIB; amyloid) and [(18) F]fluorodeoxyglucose (FDG) positron emission tomography. Whereas [(11) C]PIB bound throughout association neocortex, [(18) F]AV-1451 was selectively retained in posterior brain regions that were affected clinically and showed markedly reduced [(18) F]FDG uptake. This provides preliminary in vivo evidence that tau is more closely linked to hypometabolism and symptomatology than amyloid. PMID- 25448045 TI - Hippocampal phosphoproteomics of F344 rats exposed to 1-bromopropane. AB - 1-Bromopropane (1-BP) is neurotoxic in both experimental animals and human. To identify phosphorylated modification on the unrecognized post-translational modifications of proteins and investigate their role in 1-BP-induced neurotoxicity, changes in hippocampal phosphoprotein expression levels were analyzed quantitatively in male F344 rats exposed to 1-BP inhalation at 0, 400, or 1000 ppm for 8 h/day for 1 or 4 weeks. Hippocampal protein extracts were analyzed qualitatively and quantitatively by Pro-Q Diamond gel staining and SYPRO Ruby staining coupled with two-dimensional difference in gel electrophoresis (2D DIGE), respectively, as well as by matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) to identify phosphoproteins. Changes in selected proteins were further confirmed by Manganese II (Mn(2+))-Phos tag SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Bax and cytochrome c protein levels were determined by western blotting. Pro-Q Diamond gel staining combined with 2D-DIGE identified 26 phosphoprotein spots (p<0.05), and MALDI TOF/MS identified 18 up-regulated proteins and 8 down-regulated proteins. These proteins are involved in the biological process of response to stimuli, metabolic processes, and apoptosis signaling. Changes in the expression of phosphorylated 14-3-3 theta were further confirmed by Mn(2+)-Phos-tag SDS-PAGE. Western blotting showed overexpression of Bax protein in the mitochondria with down-regulation in the cytoplasm, whereas cytochrome c expression was high in the cytoplasm but low in the mitochondria after 1-BP exposure. Our results suggest that the pathogenesis of 1-BP-induced hippocampal damage involves inhibition of antiapoptosis process. Phosphoproteins identified in this study can potentially serve as biomarkers for 1-BP-induced neurotoxicity. PMID- 25448044 TI - An integrated QSAR-PBK/D modelling approach for predicting detoxification and DNA adduct formation of 18 acyclic food-borne alpha,beta-unsaturated aldehydes. AB - Acyclic alpha,beta-unsaturated aldehydes present in food raise a concern because the alpha,beta-unsaturated aldehyde moiety is considered a structural alert for genotoxicity. However, controversy remains on whether in vivo at realistic dietary exposure DNA adduct formation is significant. The aim of the present study was to develop physiologically based kinetic/dynamic (PBK/D) models to examine dose-dependent detoxification and DNA adduct formation of a group of 18 food-borne acyclic alpha,beta-unsaturated aldehydes without 2- or 3-alkylation, and with no more than one conjugated double bond. Parameters for the PBK/D models were obtained using quantitative structure-activity relationships (QSARs) defined with a training set of six selected aldehydes. Using the QSARs, PBK/D models for the other 12 aldehydes were defined. Results revealed that DNA adduct formation in the liver increases with decreasing bulkiness of the molecule especially due to less efficient detoxification. 2-Propenal (acrolein) was identified to induce the highest DNA adduct levels. At realistic dietary intake, the predicted DNA adduct levels for all aldehydes were two orders of magnitude lower than endogenous background levels observed in disease free human liver, suggesting that for all 18 aldehydes DNA adduct formation is negligible at the relevant levels of dietary intake. The present study provides a proof of principle for the use of QSAR-based PBK/D modelling to facilitate group evaluations and read-across in risk assessment. PMID- 25448040 TI - Leukocyte integrins: role in leukocyte recruitment and as therapeutic targets in inflammatory disease. AB - Infection or sterile inflammation triggers site-specific attraction of leukocytes. Leukocyte recruitment is a process comprising several steps orchestrated by adhesion molecules, chemokines, cytokines and endogenous regulatory molecules. Distinct adhesive interactions between endothelial cells and leukocytes and signaling mechanisms contribute to the temporal and spatial fine-tuning of the leukocyte adhesion cascade. Central players in the leukocyte adhesion cascade include the leukocyte adhesion receptors of the beta2-integrin family, such as the alphaLbeta2 and alphaMbeta2 integrins, or of the beta1 integrin family, such as the alpha4beta1-integrin. Given the central involvement of leukocyte recruitment in different inflammatory and autoimmune diseases, the leukocyte adhesion cascade in general, and leukocyte integrins in particular, represent key therapeutic targets. In this context, the present review focuses on the role of leukocyte integrins in the leukocyte adhesion cascade. Experimental evidence that has implicated leukocyte integrins as targets in animal models of inflammatory disorders, such as experimental autoimmune encephalomyelitis, psoriasis, inflammatory bone loss and inflammatory bowel disease as well as preclinical and clinical therapeutic applications of antibodies that target leukocyte integrins in various inflammatory disorders are presented. Finally, we review recent findings on endogenous inhibitors that modify leukocyte integrin function, which could emerge as promising therapeutic targets. PMID- 25448046 TI - In vivo doses of butadiene epoxides as estimated from in vitro enzyme kinetics by using cob(I)alamin and measured hemoglobin adducts: an inter-species extrapolation approach. AB - 1,3-Butadiene (BD) is a rodent and human carcinogen. In the cancer tests, mice have been much more susceptible than rats with regard to BD-induced carcinogenicity. The species-differences are dependent on metabolic formation/disappearance of the genotoxic BD epoxy-metabolites that lead to variations in the respective in vivo doses, i.e. "area under the concentration time curve" (AUC). Differences in AUC of the most gentoxic BD epoxy-metabolite, diepoxybutane (DEB), are considered important with regard to cancer susceptibility. The present work describes: the application of cob(I)alamin for accurate measurements of in vitro enzyme kinetic parameters associated with BD epoxy-metabolites in human, mouse and rat; the use of published data on hemoglobin (Hb) adduct levels of BD epoxides from BD exposure studies on the three species to calculate the corresponding AUCs in blood; and a parallelogram approach for extrapolation of AUC of DEB based on the in vitro metabolism studies and adduct data from in vivo measurements. The predicted value of AUC of DEB for humans from the parallelogram approach was 0.078 nM . h for 1 ppm . h of BD exposure compared to 0.023 nM . h/ppm . h as calculated from Hb adduct levels observed in occupational exposure. The corresponding values in nM . h/ppm . h were for mice 41 vs. 38 and for rats 1.26 vs. 1.37 from the parallelogram approach vs. experimental exposures, respectively, showing a good agreement. This quantitative inter-species extrapolation approach will be further explored for the clarification of metabolic rates/pharmacokinetics and the AUC of other genotoxic electrophilic compounds/metabolites, and has a potential to reduce and refine animal experiments. PMID- 25448041 TI - Epigenetic targets for novel therapies of lung diseases. AB - In spite of substantial advances in defining the immunobiology and function of structural cells in lung diseases there is still insufficient knowledge to develop fundamentally new classes of drugs to treat many lung diseases. For example, there is a compelling need for new therapeutic approaches to address severe persistent asthma that is insensitive to inhaled corticosteroids. Although the prevalence of steroid-resistant asthma is 5-10%, severe asthmatics require a disproportionate level of health care spending and constitute a majority of fatal asthma episodes. None of the established drug therapies including long-acting beta agonists or inhaled corticosteroids reverse established airway remodeling. Obstructive airways remodeling in patients with chronic obstructive pulmonary disease (COPD), restrictive remodeling in idiopathic pulmonary fibrosis (IPF) and occlusive vascular remodeling in pulmonary hypertension are similarly unresponsive to current drug therapy. Therefore, drugs are needed to achieve long acting suppression and reversal of pathological airway and vascular remodeling. Novel drug classes are emerging from advances in epigenetics. Novel mechanisms are emerging by which cells adapt to environmental cues, which include changes in DNA methylation, histone modifications and regulation of transcription and translation by noncoding RNAs. In this review we will summarize current epigenetic approaches being applied to preclinical drug development addressing important therapeutic challenges in lung diseases. These challenges are being addressed by advances in lung delivery of oligonucleotides and small molecules that modify the histone code, DNA methylation patterns and miRNA function. PMID- 25448047 TI - Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent. AB - Beta-lapachone (beta-Lp) derived from the Lapacho tree is a potentially novel anticancer agent currently under clinical trials. Previous studies suggested that redox activation of beta-Lp catalyzed by NAD(P)H: quinone oxidoreductase 1 (NQO1) accounted for its killing of cancer cells. However, the exact mechanisms of this effect remain largely unknown. Using chemiluminescence and electron paramagnetic resonance (EPR) spin-trapping techniques, this study for the first time demonstrated the real-time formation of ROS in the redox activation of beta lapachone from cancer cells mediated by mitochondria and NQO1 in melanoma B16-F10 and hepatocellular carcinoma HepG2 cancer cells. ES936, a highly selective NQO1 inhibitor, and rotenone, a selective inhibitor of mitochondrial electron transport chain (METC) complex I were found to significantly block beta-Lp meditated redox activation in B16-F10 cells. In HepG2 cells ES936 inhibited beta Lp-mediated oxygen radical formation by ~80% while rotenone exerted no significant effect. These results revealed the differential contribution of METC and NQO1 to beta-lapachone-induced ROS formation and cancer cell killing. In melanoma B16-F10 cells that do not express high NQO1 activity, both NOQ1 and METC play a critical role in beta-Lp redox activation. In contrast, in hepatocellular carcinoma HepG2 cells expressing extremely high NQO1 activity, redox activation of beta-Lp is primarily mediated by NQO1 (METC plays a minor role). These findings will contribute to our understanding of how cancer cells are selectively killed by beta-lapachone and increase our ability to devise strategies to enhance the anticancer efficacy of this potentially novel drug while minimizing its possible adverse effects on normal cells. PMID- 25448048 TI - Pivotal roles of p53 transcription-dependent and -independent pathways in manganese-induced mitochondrial dysfunction and neuronal apoptosis. AB - Chronic exposure to excessive manganese (Mn) has been known to lead to neuronal loss and a clinical syndrome resembling idiopathic Parkinson's disease (IPD). p53 plays an integral role in the development of various human diseases, including neurodegenerative disorders. However, the role of p53 in Mn-induced neuronal apoptosis and neurological deficits remains obscure. In the present study, we showed that p53 was critically involved in Mn-induced neuronal apoptosis in rat striatum through both transcription-dependent and -independent mechanisms. Western blot and immunohistochemistrical analyses revealed that p53 was remarkably upregulated in the striatum of rats following Mn exposure. Coincidentally, increased level of cleaved PARP, a hallmark of apoptosis, was observed. Furthermore, using nerve growth factor (NGF)-differentiated PC12 cells as a neuronal cell model, we showed that Mn exposure decreased cell viability and induced apparent apoptosis. Importantly, p53 was progressively upregulated, and accumulated in both the nucleus and the cytoplasm. The cytoplasmic p53 had a remarkable distribution in mitochondria, suggesting an involvement of p53 mitochondrial translocation in Mn-induced neuronal apoptosis. In addition, Mn induced impairment of mitochondrial membrane potential (DeltaPsim) could be partially rescued by pretreatment with inhibitors of p53 transcriptional activity and p53 mitochondrial translocation, Pifithrin-alpha (PFT-alpha) and Pifithrin-MU (PFT-MU), respectively. Moreover, blockage of p53 activities with PFT-alpha and PFT-MU significantly attenuated Mn-induced reactive oxidative stress (ROS) generation and mitochondrial H2O2 production. Finally, we observed that pretreatment with PFT-alpha and PFT-MU ameliorated Mn-induced apoptosis in PC12 cells. Collectively, these findings implicate that p53 transcription-dependent and -independent pathways may play crucial roles in the regulation of Mn-induced neuronal death. PMID- 25448050 TI - The olive flounder (Paralichthys olivaceus) Pax3 homologues are highly conserved, encode multiple isoforms and show unique expression patterns. AB - Pax genes encode a highly conserved family of transcription factors that play crucial roles in the formation of tissues and organs during development. Pax3 plays crucial roles in patterning of the dorsal central nervous system (CNS), neural crest and skeletal muscle. Here, we identified two spliced isoforms of Pax3a and three spliced isoforms of Pax3b and characterized their expression patterns. Both of flounder Pax3a-1 and Pax3b-1 contain the conserved paired domain (PD), an octapeptide motif (OP), and a paired type homeodomain (HD). But the PD domain in Pax3a-2 and Pax3b-3 is not intact and there is no HD in Pax3b-2 and Pax3b-3. Pax3a and Pax3b show distinct temporal expression patterns during embryogenesis. Whole-mount in situ hybridization demonstrates that Pax3a and Pax3b are expressed in overlapping patterns in the dorsal central nervous system, with some subtle regional differences between the two genes. In addition, Pax3a is scattered in the somites while Pax3b is specifically expressed in the newly forming somites. RT-PCR results have shown that there were different expression patterns between the different isoforms. These results indicate subfunction partitioning of the duplicated Pax3 genes. The duplicated Pax3 may provide additional flexibility in fine-tuning neurogenesis and somitogenesis. PMID- 25448049 TI - Characterization of acute biliary hyperplasia in Fisher 344 rats administered the indole-3-carbinol analog, NSC-743380. AB - NSC-743380 (1-[(3-chlorophenyl)-methyl]-1H-indole-3-carbinol) is in early stages of development as an anticancer agent. Two metabolites reflect sequential conversion of the carbinol functionality to a carboxaldehyde and the major metabolite, 1-[(3-chlorophenyl)-methyl]-1H-indole-3-carboxylic acid. In an exploratory toxicity study in rats, NSC-743380 induced elevations in liver associated serum enzymes and biliary hyperplasia. Biliary hyperplasia was observed 2 days after dosing orally for 2 consecutive days at 100mg/kg/day. Notably, hepatotoxicity and biliary hyperplasia were observed after oral administration of the parent compound, but not when major metabolites were administered. The toxicities of a structurally similar but pharmacologically inactive molecule and a structurally diverse molecule with a similar efficacy profile in killing cancer cells in vitro were compared to NSC-743380 to explore scaffold versus target-mediated toxicity. Following two oral doses of 100mg/kg/day given once daily on two consecutive days, the structurally unrelated active compound produced hepatic toxicity similar to NSC-743380. The structurally similar inactive compound did not, but, lower exposures were achieved. The weight of evidence implies that the hepatotoxicity associated with NSC-743380 is related to the anticancer activity of the parent molecule. Furthermore, because biliary hyperplasia represents an unmanageable and non-monitorable adverse effect in clinical settings, this model may provide an opportunity for investigators to use a short-duration study design to explore biomarkers of biliary hyperplasia. PMID- 25448051 TI - Cloning and characterization of SREBP-1 and PPAR-alpha in Japanese seabass Lateolabrax japonicus, and their gene expressions in response to different dietary fatty acid profiles. AB - In the present study, putative cDNA of sterol regulatory element-binding protein 1 (SREBP-1) and peroxisome proliferator-activated receptor alpha (PPAR-alpha), key regulators of lipid homoeostasis, were cloned and characterized from liver of Japanese seabass (Lateolabrax japonicus), and their expression in response to diets enriched with fish oil (FO) or fatty acids such as palmitic acid (PA), stearic acid (SA), oleic acid (OA), alpha-linolenic acid (ALA), and n-3 long chain polyunsaturated fatty acid (n-3 LC-PUFA), was investigated following feeding. The SREBP-1 of Japanese seabass appeared to be equivalent to SREBP-1a of mammals in terms of sequence feature and tissue expression pattern. The stimulation of the mRNA expression level of SREBP-1 in liver of Japanese seabass by dietary fatty acids significantly ranked as follows: PA, OA>SA, ALA, and n-3 LC-PUFA>FO. A new PPAR-alpha subtype in Japanese seabass, PPAR-alpha2, was cloned in this study, which is not on the same branch with Japanese seabass PPAR-alpha1 and mammalian PPAR-alpha in the phylogenetic tree. Liver gene expression of PPAR alpha1 of Japanese seabass was inhibited by diets enriched with ALA or FO compared to diets enriched with PA or OA, while the gene expression of PPAR alpha2 of Japanese seabass was up-regulated by diets enriched with ALA or n-3 LC PUFA compared to diets enriched with OA or FO. This was the first evidence for the great divergence in response to dietary fatty acids between PPAR-alpha1 and PPAR-alpha2 of fish, which indicated probable functional distribution between PPAR-alpha isotypes of fish. PMID- 25448053 TI - The odds of small things. Interview by Sophia Hafner. PMID- 25448054 TI - Recognizing global disparities in health and in health transitions in the 21st century: what can nurses do? AB - PURPOSE: To examine changes in patterns of health and disease in global context between rich countries (USA, Korea, South Africa) and poor countries (Cambodia, Malawi) by using the framework of epidemiology theory developed by Orman (1971, 2005), and to raise awareness of global health disparities thereby prompting actions to reduce such disparities. FINDINGS: 1) Life expectancy has increased across all selected countries except South Africa; 2) Korea and the USA have substantially lower mortality rates than other countries; 3) Infant and maternal mortality are still high in the poor countries; 4) The major cause of mortality in the poor countries is still communicable disease with evidence of the onset of non-communicable disease; and 5) The health transition theory provides a description and explanation of the differences in progress in economic development between countries but fails to explain differences in health status within and between countries. CONCLUSIONS: Life expectancy and mortality are enormously different among the five selected countries. This excessive health disparity is primarily due to the higher risk of communicable diseases in low income countries. Social determinants of health are mainly responsible for the health disparities observed within and between countries. CLINICAL RELEVANCE: Future health care development and global research priorities will not be the same for all countries because the pattern of health transitions in the developing countries is not the same as the developed countries. Actions to reduce global health disparities need to recognize the conditions and social context in which persons live. An effective strategic approach to global health equality should develop a shared system of values, priorities, and delivery infrastructures with the populations who are targeted, aligning delivery within the local social contexts. PMID- 25448052 TI - Trypanosoma cruzi invasion is associated with trogocytosis. AB - Trogocytosis was originally thought to be restricted to the interaction of cells of the immune system with cancer cells. Such membrane exchanges are probably a general process in cell biology, and membrane exchange has been demonstrated to occur between non-immune cells within an organism. Herein, we report that membrane and protein exchange, consistent with trogocytosis, between Trypanosoma cruzi (both the Brazil and Tulahuen strains) and the mammalian cells it infects. Transfer of labeled membrane patches was monitored by labeling of either parasites or host cells, i.e. human foreskin fibroblasts and rat myoblasts. Trypomastigotes and amastigotes transferred specific surface glycoproteins to the host cells along with membranes. Exchange of membranes between the parasite and host cells occurred during successful invasion. Extracellular amastigotes did not transfer membrane patches and were did not transfer either membranes or proteins to the host cells. Membrane exchange was also found to occur between interacting epimastigotes in cell-free culture and may be important in parasite-parasite interactions as well. Further studies should provide new insights into pathogenesis and provide targets for therapeutic intervention. PMID- 25448055 TI - Comparison of parent-child communication patterns and parental role satisfaction among mothers with and without breast cancer. AB - PURPOSE: This study compared parent-child communication (PCC) patterns and parental role satisfaction (PRS) between women with breast cancer and healthy women. BACKGROUND: A limited number of studies have examined PCC and the impact of PRS between cancer patients and their children. METHODS: It was a descriptive survey design comprising the Parent-Adolescent Communication Scale and a PRS measure. Data from 202 participants in total were analysed with two-way analyses of variance and t-tests. RESULTS: Closed communication was higher in both groups than open communication, but higher still in children of women with breast cancer than in children of healthy women. PRS was lower in women with breast cancer than in healthy women. Educational programs should be developed to support parents and children during the post-treatment adjustment period for mothers with breast cancer. CONCLUSION: Such programs should take a practical approach toward increasing open parent-child communication while considering personal characteristics and cultural backgrounds. PMID- 25448056 TI - A comprehensive literature review on hypothermia and early extubation following coronary artery bypass surgery. AB - PURPOSE: The purpose of this study was to comprehensively review the literature addressing the physiological effects of hypothermia and its association with the appropriate core body temperature for extubation following coronary artery bypass surgery. METHODS: The electronic databases MEDLINE, CINAHL and Web of Science via OVID were used to identify studies for the literature review. Search words used included 'core temperature', 'arrhythmia', 'cardiac', 'cardiac surgery', 'hypothermia', 'extubation', 'temperature', 'rewarming', and 'shivering'. RESULTS: The literature search yielded 55 articles that met our inclusion criteria. No studies specifically identified the benefit of extubation at 36.5 degrees C. Although temperatures varied, arrhythmias resulting from hypothermia were not reported until core body temperature dropped below 33 degrees C. CONCLUSION: This comprehensive literature review suggests extubation at lower temperatures (between 34 degrees C and 36 degrees C) may be viable if shivering and other factors known to contribute to myocardial stress can be controlled. These findings offer the possibility of earlier extubation which may promote beneficial health outcomes. PMID- 25448057 TI - Contributors to shift work tolerance in South Korean nurses working rotating shift. AB - Shift workers have rapidly increased in South Korea; however, there is no published research exploring shift work tolerance among South Korean workers. This study aimed to investigate factors related to shift work tolerance in South Korean nurses. The sample comprised of 660 nurses who worked shifts in a large hospital in South Korea. A structured questionnaire included following comprehensive variables: demographic (age and number of children), individual (morningness and self-esteem), psychosocial (social support and job stress), lifestyle (alcohol consumption, physical activity, and BMI), and working condition factors (number of night shifts and working hours). Shift work tolerance was measured in terms of insomnia, fatigue, and depression. The results of hierarchical regressions indicate that all variables, except for three, number of children, BMI, and working hours, were related to at least one of the symptoms associated with shift work tolerance. Based on these results, we offer some practical implications to help improve shift work tolerance of workers. PMID- 25448058 TI - Factors affecting the level of burden of caregivers of children with type 1 diabetes. AB - AIM: To analyze the correlations between factors associated with the family and child and the level of burden involved in care. BACKGROUND: The management of diabetes places substantial demands on families and direct caregivers. METHODS: 112 direct caregivers of children with type 1 diabetes from 4 clinics in Poland evaluated their level of burden using the Caregiver's Burden Scale. The additional data were collected through interviews. RESULTS: The highest level of burden was associated with general strain and disappointment. The level of burden correlated with the child's age and the professional status and level of education of the parents, and also with the number of glycemic tests at nighttime, the frequency of hyperglycemic episodes, and the number of hospitalizations. CONCLUSIONS: Measuring the impact of factors influencing the level of burden in care makes it possible to develop effective programs supporting parents in providing care for children with type 1 diabetes. PMID- 25448059 TI - Process evaluation of an exercise counseling intervention using motivational interviewing. AB - AIM: To describe the results of the process evaluation of an exercise counseling intervention using motivational interviewing (MI). BACKGROUND: Exercise can safely be incorporated into heart failure self-care, but many lack access to cardiac rehabilitation. One alternative is to provide exercise counseling in the clinical setting. METHODS: This process evaluation was conducted according to previously established guidelines for health promotion programs. This includes an assessment of recruitment and retention, implementation, and reach. RESULTS: Desired number of subjects were recruited, but 25% dropped out during study. Good fidelity to the intervention was achieved; the use of MI was evaluated with improvement in adherence over time. Dose included initial session plus 12 weekly phone calls. Subjects varied in participation of daily diary usage. Setting was conducive to recruitment and data collection. CONCLUSIONS: Evaluating the process of an intervention provides valuable feedback on content, delivery and fidelity. PMID- 25448060 TI - Trends in outpatient MRI seem to reflect recent reimbursement cuts. AB - PURPOSE: To determine whether recent reimbursement cuts have resulted in a shift of outpatient MRI from private offices to hospital outpatient departments (HOPDs); and to study office MRI utilization trends among radiologists and other specialists. METHODS: The Medicare Part B Physician/Supplier Procedure Summary Master Files were used. MRI codes were aggregated, and total MRI volumes from 2002 to 2012 were studied. Medicare place-of-service codes were used to identify studies performed in private offices and HOPDs and create trend lines. Specialty codes were used to categorize private office MRI users as radiologists, orthopedic surgeons, other physicians, and independent diagnostic testing facilities. RESULTS: Medicare office and HOPD utilization of MRI (all specialties) rose rapidly from 2002 to 2006, reaching 2,727,807 in offices and 2,355,641 in HOPDs. Thereafter, office volume steadily declined, whereas HOPD volume steadily increased. By 2012, more studies were done in HOPDs than in offices. Over the entire period from 2002 and 2012, office MRI volume among radiologists increased 27%, compared with 216% among orthopedic surgeons and 124% among other physicians. CONCLUSIONS: Although the majority of Medicare outpatient MRI studies had previously been performed in private offices, recent years brought a shift, with more now being performed in HOPDs. This change will increase costs to payers, because reimbursements to HOPDs are generally higher than those to offices. Although radiologists perform the majority of MRI exams that are conducted in private offices, the rate of growth for such exams from 2002 to 2012 was considerably higher among orthopedic surgeons and other physicians than among radiologists. PMID- 25448061 TI - Adapting to the new radiology landscape: challenges and solutions discussed at the 2014 AMCLC open-microphone sessions. AB - Every year, multiple open-microphone sessions are hosted at the ACR AMCLC. These sessions allow members of the College to offer opinions, experiences, and questions regarding challenges facing radiologists and the future of the profession. At the 2014 AMCLC, 3 such sessions focused, respectively, on radiology's workforce, the obstacles slowing the shift from volume to value, and alternative reimbursement models and the shifting physician employment landscape. These open-microphone sessions framed contemporary obstacles and emerging challenges that professional radiology societies, such as the ACR, should target with new initiatives and use of resources; in addition, the sessions revealed opportunities for members, councilors, and state chapters to respond with meaningful resolutions and policy proposals. PMID- 25448062 TI - US Preventive Services Task Force CT lung cancer screening recommendations: community awareness and perceptions. PMID- 25448063 TI - NF-kappaB increased expression of 17beta-hydroxysteroid dehydrogenase 4 promotes HepG2 proliferation via inactivating estradiol. AB - Hepatocellular carcinoma (HCC) arises in a setting of chronic inflammation induced by inflammatory cytokines, such as nuclear factor-kappaB (NF-kappaB). HCC is a male-predominant cancer that can be attenuated by estradiol (E2) in vitro and in vivo. Although 17beta-hydroxysteroid dehydrogenase 4 (HSD17B4) has been implicated as an estradiol-inactivating enzyme, and its promoter sequence contains two putative NF-kappaB elements: it is currently unknown whether HSD17B4 is the link between inflammation, estradiol and proliferation in hepatoma cells. In this study, HepG2 cells were used to investigate the role of HSD17B4 in the proliferation of liver cancer cells treated with the NF-kappaB activator, tumor necrosis factor-alpha (TNF-alpha), with the inhibitor of NF-kappaB activation, pyrrolidinedithiocarbamate (PDTC), or with a related specific siRNA. We demonstrated that the human HSD17B4 gene is a target for NF-kappaB activation in inflammation-stimulated HepG2 cells. HSD17B4 is up-regulated via the binding of activated NF-kappaB to the distal NF-kappaB-responsive element via TNF-alpha stimulation, which then promotes cell proliferation by decreasing the levels of E2 and enhancing the expression of interleukin 6 (IL-6), cyclin D1 and proliferating cell nuclear antigen (PCAN). These results from HepG2 cells are consistent with the observation that HSD17B4 is highly expressed and activated NF kappaB is highly co-localized with the NF-kappaB-responsive element of HSD17B4 in liver tumor tissues from HCC patients. Our findings indicate for the first time that HSD17B4 plays an important role in aggravated HCC progression and provides a novel therapeutic target for HCC. PMID- 25448064 TI - Nephrin, a transmembrane protein, is involved in pancreatic beta-cell survival signaling. AB - Nephrin, a cell surface signaling receptor, regulates podocyte function in health and disease. We study the role of nephrin in beta-cell survival signaling. We report that in mouse islet beta-cells and the mouse pancreatic beta-cell line (betaTC-6 cells) nephrin is associated and partly co-localized with PI3-kinase. Incubation of cells with functional anti-nephrin antibodies induced nephrin clustering at the plasma membrane, nephrin phosphorylation and recruitment of PI3 kinase to nephrin thus resulting in increased PI3K-dependent Akt phosphorylation and augmented phosphorylation/inhibition of pro-apoptotic Bad and FoxO. Nephrin silencing abolished Akt activation and increased susceptibility of cells to apoptosis. High glucose impaired nephrin signaling, increased nephrin internalization and up-regulated PKCalpha expression. Interestingly, a marked decrease in nephrin expression and phosphorylated Akt was observed in pancreatic islets of db/db lepr-/- diabetic mice. Our findings revealed that nephrin is involved in beta-cell survival and suggest that glucose-induced changes in nephrin signaling may contribute to gradual pancreatic beta-cell loss in type 2 diabetes. PMID- 25448066 TI - A CRISPR/Cas9-based system for reprogramming cell lineage specification. AB - Gene activation by the CRISPR/Cas9 system has the potential to enable new approaches to science and medicine, but the technology must be enhanced to robustly control cell behavior. We show that the fusion of two transactivation domains to Cas9 dramatically enhances gene activation to a level that is necessary to reprogram cell phenotype. Targeted activation of the endogenous Myod1 gene locus with this system led to stable and sustained reprogramming of mouse embryonic fibroblasts into skeletal myocytes. The levels of myogenic marker expression obtained by the activation of endogenous Myod1 gene were comparable to that achieved by overexpression of lentivirally delivered MYOD1 transcription factor. PMID- 25448065 TI - Purification and ex vivo expansion of fully functional salivary gland stem cells. AB - Hyposalivation often leads to irreversible and untreatable xerostomia. Salivary gland (SG) stem cell therapy is an attractive putative option to salvage these patients but is impeded by the limited availability of adult human tissue. Here, using murine SG cells, we demonstrate single-cell self-renewal, differentiation, enrichment of SG stem cells, and robust in vitro expansion. Dependent on stem cell marker expression, SG sphere-derived single cells could be differentiated in vitro into distinct lobular or ductal/lobular organoids, suggestive of progenitor or stem cell potency. Expanded cells were able to form miniglands/organoids containing multiple SG cell lineages. Expansion of these multipotent cells through serial passaging resulted in selection of a cell population, homogenous for stem cell marker expression (CD24(hi)/CD29(hi)). Cells highly expressing CD24 and CD29 could be prospectively isolated and were able to efficiently restore radiation-damaged SG function. Our approach will facilitate the use of adult SG stem cells for a variety of scientific and therapeutic purposes. PMID- 25448068 TI - Multipotent hematopoietic progenitors divide asymmetrically to create progenitors of the lymphomyeloid and erythromyeloid lineages. AB - Hematopoietic stem and progenitor cells (HSPCs) can self-renew and create committed progenitors, a process supposed to involve asymmetric cell divisions (ACDs). Previously, we had linked the kinetics of CD133 expression with ACDs but failed to detect asymmetric segregation of classical CD133 epitopes on fixed, mitotic HSPCs. Now, by using a novel anti-CD133 antibody (HC7), we confirmed the occurrence of asymmetric CD133 segregation on paraformaldehyde-fixed and living HSPCs. After showing that HC7 binding does not recognizably affect biological features of human HSPCs, we studied ACDs in different HSPC subtypes and determined the developmental potential of arising daughter cells at the single cell level. Approximately 70% of the HSPCs of the multipotent progenitor (MPP) fraction studied performed ACDs, and about 25% generated lymphoid-primed multipotent progenitor (LMPP) as wells as erythromyeloid progenitor (EMP) daughter cells. Since MPPs hardly created daughter cells maintaining MPP characteristics, our data suggest that under conventional culture conditions, ACDs are lineage instructive rather than self-renewing. PMID- 25448069 TI - Comparison of in vitro toxicity of silver ions and silver nanoparticles on human hepatoma cells. AB - Scientific information on the potential harmful effects of silver nanoparticles (AgNPs) on human health severely lags behind their exponentially growing applications in consumer products. In assessing the toxic risk of AgNP usage, liver, as a detoxifying organ, is particularly important. The aim of this study was to explore the toxicity mechanisms of nano and ionic forms of silver on human hepatoblastoma (HepG2) cells. The results showed that silver ions and citrate coated AgNPs reduced cell viability in a dose-dependent manner. The IC50 values of silver ions and citrate-coated AgNPs were 0.5 and 50 mg L(-1) , respectively. The LDH leakage and inhibition of albumin synthesis, along with decreased ALT activity, indicated that treatment with either AgNP or Ag ions resulted in membrane damage and reduced the cell function of human liver cells. Evaluation of oxidative stress markers demonstrating depletion of GSH, increased ROS production, and increased SOD activity, indicated that oxidative stress might contribute to the toxicity effects of nano and ionic forms of silver. The observed toxic effect of AgNP on HepG2 cells was substantially weaker than that caused by ionic silver, while the uptake of nano and ionic forms of silver by HepG2 cells was nearly the same. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 679-692, 2016. PMID- 25448070 TI - Ion milling coupled field emission scanning electron microscopy reveals current misunderstanding of morphology of polymeric nanoparticles. AB - Nanoparticles (NPs) are currently used as drug delivery systems for numerous therapeutic macromolecules, e.g. proteins or DNA. Based on the preparation by double emulsion solvent evaporation a sponge-like structure was postulated entrapping hydrophilic drugs inside an internal aqueous phase. However, a direct proof of this hypothesized structure is still missing today. NPs were prepared from different polymers using a double-emulsion method and characterized for their physicochemical properties. Combining ion milling with field emission scanning electron microscopy allowed to cross section single NP and to visualize their internal morphology. The imaging procedure permitted cross-sectioning of NPs and visualization of the internal structure as well as localizing drugs associated with NPs. It was observed that none of the model actives was encapsulated inside the polymeric matrix when particle diameters were below around 470 nm but predominantly adsorbed to the particle surface. Even at larger diameters only a minority of particles of a diameter below 1 MUm contained an internal phase. The properties of such drug loaded NPs, i.e. drug release or the observations in cellular uptake or even drug targeting needs to be interpreted carefully since in most cases NP surface properties are potentially dominated by the 'encapsulated' drug characteristics. PMID- 25448067 TI - Tenascin C promotes hematoendothelial development and T lymphoid commitment from human pluripotent stem cells in chemically defined conditions. AB - The recent identification of hemogenic endothelium (HE) in human pluripotent stem cell (hPSC) cultures presents opportunities to investigate signaling pathways that are essential for blood development from endothelium and provides an exploratory platform for de novo generation of hematopoietic stem cells (HSCs). However, the use of poorly defined human or animal components limits the utility of the current differentiation systems for studying specific growth factors required for HE induction and manufacturing clinical-grade therapeutic blood cells. Here, we identified chemically defined conditions required to produce HE from hPSCs growing in Essential 8 (E8) medium and showed that Tenascin C (TenC), an extracellular matrix protein associated with HSC niches, strongly promotes HE and definitive hematopoiesis in this system. hPSCs differentiated in chemically defined conditions undergo stages of development similar to those previously described in hPSCs cocultured on OP9 feeders, including the formation of VE Cadherin(+)CD73(-)CD235a/CD43(-) HE and hematopoietic progenitors with myeloid and T lymphoid potential. PMID- 25448071 TI - Influence of formulation composition and process on the characteristics and in vitro release from PLGA-based sustained release injectables. AB - Understanding and controlling the in vitro release behavior of a formulation is a first step toward rationalized selection of a solubility enhancing formulation strategy with a desired release profile in vivo. Therefore six model formulations, representing three different formulation strategies, were physicochemically analyzed and their in vitro release was determined. Solid dispersions based on a PLGA/PVP matrix were compared to solid dispersions in a pure PLGA matrix. Additionally these solid dispersion strategies were compared to the strategy of particle size reduction by means of an API microsuspension. Depending on composition and manufacturing method, formulations varied in particle size, porosity, phase behavior, surface coverage and physical state of the API. This resulted in observed differences in their in vitro release profile. For the various formulation strategies tested both a porous PLGA-based formulation and PLGA/PVP-based formulations, resulted in vitro in sustained release of the poorly soluble API with over 50% of drug released after 24h. For PLGA-based formulations the porosity was identified as a critical parameter influencing in vitro drug release. For the PLGA/PVP-based formulations the release rate can be tailored by the amount of PLGA present. Particle size reduction resulted in immediate total drug release. PMID- 25448072 TI - Spectroscopic insight for tablet compression. AB - Tablet compression process has been studied over the years from various perspectives. However what exactly happens to material during compression is still unknown. In this study a novel compression die which enables real-time spectroscopic measurements during the compression of material is represented. Both near infrared and Raman spectroscope probes can be attached to the die. In this study the usage of the die is demonstrated by using Raman spectroscopy. Eicosane, d-glucose anhydrate, alpha-lactose monohydrate and xylitol were used in the study because their compression behavior and bonding properties during compression were assumed to be different. The intensity of the Raman signal changed during compression with all of the materials. However, the intensity changes were different within the materials. The biggest differences were within the xylitol spectra. It was noticed that some peaks disappeared with higher compression pressures indicating that the pressure affected variously on different bonds in xylitol structure. These reversible changes were supposed to relate the changes in conformation and crystal structure. As a conclusion, the die was found to be a significant addition for studying compression process in real-time. It can help to reveal Process induced transformations (PITs) occurring during powder compaction. PMID- 25448073 TI - Floating lipid beads for the improvement of bioavailability of poorly soluble basic drugs: in-vitro optimization and in-vivo performance in humans. AB - The challenge in developing oral drug delivery systems of poorly soluble basic drugs is primarily due to their pH dependent solubility. Cinnarizine (CNZ), a model for a poorly soluble basic drug, has pH dependent solubility; where it dissolves readily at low pH in the stomach and exhibits a very low solubility at pH values greater than 4. It is also characterized by a short half life of 3-6h, which requires frequent daily administration resulting in poor patient compliance. In an attempt to solve these problems, extended release floating lipid beads were formulated. A 2(4) full factorial design was utilized for optimization of the effects of various independent variables; lipid:drug ratio, % Pluronic F-127, % Sterotex, and Gelucire 43/01:Gelucire 50/13 ratio, on the loading efficiency and release of CNZ from the lipid beads. In-vivo pharmacokinetic study of the optimized CNZ-lipid beads compared to Stugeron(r) (reference standard) was performed in healthy human volunteers. A promising approach for enhancing the bioavailability of the poorly soluble basic drug, CNZ, utilizing novel and simple floating lipid beads was successfully developed. Zero order release profile of CNZ was achieved for 12h. Mean AUC0-24 and AUC0-infinity of the optimized CNZ-loaded lipid beads were 4.23 and 6.04 times that of Stugeron(r) tablets respectively. PMID- 25448074 TI - A comparative study between conventional pan coater and quasi-continuous small batch coater on the stability of tablets containing acetylsalicylic acid. AB - The Supercell coater was developed as an in-line small batch tablet coater which uses air-fluidization for tablet coating. Coating time is very much reduced, with improved heat and mass transfer. It was hypothesized that the quasi-continuous Supercell coating process was more suitable for the aqueous coating of tablets containing moisture-sensitive drugs. Acetylsalicylic acid (ASA) was used as the model drug in this study. The extent of ASA degradation in Supercell coating was compared against that of tablets coated using the conventional pan coater. Less than 0.3% of ASA was degraded at the end of the coating process using either coater. The extent of ASA degradation was found to be more pronounced during storage. The Supercell coated tablets exhibited comparable or smaller percentage of ASA degradation than the pan coated tablets at the end of a storage period of 6 months under accelerated stability conditions (40 degrees C/75% RH) and 3 years under ambient conditions (25 degrees C/50% RH). The extent and rate of ASA degradation during storage were dependent on the processing conditions employed during Supercell coating. Increase in temperature generally led to a reduction in ASA degradation, while increase in spray rate and coating level caused more degradation. Greater extent of ASA degradation was observed on the surface of pan coated tablets compared with Supercell coated tablets due to greater moisture contact and the slower and wetter coating process. Changes to the processing conditions also influenced the residual moisture content (0.55-2.86%) of the tablets. However, no direct correlation between the residual moisture content of the tablets after coating and the extent of ASA degradation during storage was found. PMID- 25448076 TI - Fine tuning of mixed ionic and hydrogen bond interactions for plasmid delivery using lipoplexes. AB - Non viral gene transfection has been mostly reached via cationic polymer and lipid, required for DNA complexation and cell internalisation. However, cationic charges often induce cytotoxicity and limit the efficacy of the lipoplexes in vivo due to their fast elimination from the blood stream. Few years ago, we had developed noncationic lipid interacting with DNA via hydrogen bond interactions. To take advantage of both the internalisation efficacy of cationic complexes and the higher DNA release efficacy of non cationic lipids, we chose to mix both ionic and hydrogen bond interactions within one lipoplex. The idea behind this strategy would be to reduce the overall charge while maintaining a high level of transfection. Four mixed formulations of cationic lipid and thiourea lipid were prepared. We found that decreasing ionic interactions and increasing hydrogen bond interactions improved cationic lipoplexes properties. Indeed, we showed that replacement of net positive charges by hydrogen bond interactions with DNA phosphates led to efficient lipoplexes for in vitro DNA transfection at lower cationic charge content, which consequently reduced lipoplex cytotoxicity. PMID- 25448075 TI - Thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding. AB - This study evaluated thermoplastic polyurethanes (TPUR) as matrix excipients for the production of oral solid dosage forms via hot melt extrusion (HME) in combination with injection molding (IM). We demonstrated that TPURs enable the production of solid dispersions - crystalline API in a crystalline carrier - at an extrusion temperature below the drug melting temperature (Tm) with a drug content up to 65% (wt.%). The release of metoprolol tartrate was controlled over 24h, whereas a complete release of diprophylline was only possible in combination with a drug release modifier: polyethylene glycol 4000 (PEG 4000) or Tween 80. No burst release nor a change in tablet size and geometry was detected for any of the formulations after dissolution testing. The total matrix porosity increased gradually upon drug release. Oral administration of TPUR did not affect the GI ecosystem (pH, bacterial count, short chain fatty acids), monitored via the Simulator of the Human Intestinal Microbial Ecosystem (SHIME). The high drug load (65 wt.%) in combination with (in vitro and in vivo) controlled release capacity of the formulations, is noteworthy in the field of formulations produced via HME/IM. PMID- 25448077 TI - Time lasting S-nitrosoglutathione polymeric nanoparticles delay cellular protein S-nitrosation. AB - Physiological S-nitrosothiols (RSNO), such as S-nitrosoglutathione (GSNO), can be used as nitric oxide (NO) donor for the treatment of vascular diseases. However, despite a half-life measured in hours, the stability of RSNO, limited by enzymatic and non-enzymatic degradations, is too low for clinical application. So, to provide a long-lasting effect and to deliver appropriate NO concentrations to target tissues, RSNO have to be protected. RSNO encapsulation is an interesting response to overcome degradation and provide protection. However, RSNO such as GSNO raise difficulties for encapsulation due to its hydrophilic nature and the instability of the S-NO bound during the formulation process. To our knowledge, the present study is the first description of the direct encapsulation of GSNO within polymeric nanoparticles (NP). The GSNO-loaded NP (GSNO-NP) formulated by a double emulsion process, presented a mean diameter of 289 +/- 7 nm. They were positively charged (+40 mV) due to the methacrylic acid and ethylacrylate polymer (Eudragit(r) RL) used and encapsulated GSNO with a satisfactory efficiency (i.e. 54% or 40 mM GSNO loaded in the NP). In phosphate buffer (37 degrees C; pH 7.4), GSNO-NP released 100% of encapsulated GSNO within 3h and remained stable still 6h. However, in contact with smooth muscle cells, maximum protein nitrosation (a marker of NO bioavailability) was delayed from 1h for free GSNO to 18h for GSNO-NP. Therefore, protection and sustained release of NO were achieved by the association of a NO donor with a drug delivery system (such as polymeric NP), providing opportunities for vascular diseases treatment. PMID- 25448078 TI - Synergistic effect of pendant hydroxypropyl and pyrrolidine moieties randomly distributed along polymethacrylamide backbones on in vitro DNA-transfection. AB - In this work, the cationic monomer N-ethyl pyrrolidine methacrylamide (EPA) was copolymerized with the neutral monomer N-hydroxypropyl methacrylamide (HPMA) at different molar ratios obtaining linear random copolymers that were characterized and evaluated in vitro as non-viral gene carriers using murine Swiss 3T3 fibroblasts. The copolymers with excess or equimolar amount of EPA were able to complex DNA forming stable polyplexes with an average size between 50 and 200 nm, while the copolymers with an excess of HPMA do not. Cell viability was shown to depend on the EPA/HPMA molar ratio, exhibiting the equimolar copolymer poly (EPA co-HPMA) 50:50 (EPA50) a full cytocompatibility, similar to the HPMA-rich systems. This copolymer EPA50 has also shown significantly higher transfection levels than the systems with other compositions and the positive controls poly L lysine (PLL) and poly EPA (pEPA). This statistical equimolar copolymer EPA50 has unique properties related to its composition and microstructure, which allows it to complex DNA, showing an excellent biocompatibility and high transfection efficiency. PMID- 25448079 TI - Tuning the architecture of polymeric conjugate to mediate intracellular delivery of pleiotropic curcumin. AB - To precisely manipulate the intracellular delivery of pleiotropic curcumin, this work reports two types of acid-responsive polymer-curcumin conjugates with different structures. One or two amphiphilic poly(ethylene glycol)-co-poly(lactic acid) (PEG-PLA) copolymer(s) were linked to curcumin via pH-liable hydrazone, producing a linear or phospholipid-like conjugate, respectively. Both conjugates efficiently self-assembled into micellar nanocarriers with enhanced stability in contrast to the paralleling PEG-PLA micelles. In comparison to the micelles assembled by phospholipid-like conjugates, the linear conjugate micelles exhibited similar size, doubled loading dose, higher release rate, and hence enhanced cellular uptake and cytotoxicity at the cost of increased critical micelle concentration. This work highlighted the importance of precise tuning of polymer-drug conjugate architecture in determining the pharmaceutical properties and thus delivery efficiency of the corresponding conjugate micelles. PMID- 25448080 TI - Progenitors of secondary crest myofibroblasts are developmentally committed in early lung mesoderm. AB - Development of the mammalian lung is predicated on cross-communications between two highly interactive tissues, the endodermally derived epithelium and the mesodermally derived pulmonary mesenchyme. While much attention has been paid for the lung epithelium, the pulmonary mesenchyme, partly due to lack of specific tractable markers remains under-investigated. The lung mesenchyme is derived from the lateral plate mesoderm and is the principal recipient of Hedgehog (Hh) signaling, a morphogenetic network that regulates multiple aspects of embryonic development. Using the Hh-responsive Gli1-cre(ERT2) mouse line, we identified the mesodermal targets of Hh signaling at various time points during embryonic and postnatal lung development. Cell lineage analysis showed these cells serve as progenitors to contribute to multiple lineages of mesodermally derived differentiated cell types that include parenchymal or interstitial myofibroblasts, peribronchial and perivascular smooth muscle as well as rare populations of cells within the mesothelium. Most importantly, Gli1-cre(ERT2) identified the progenitors of secondary crest myofibroblasts, a hitherto intractable cell type that plays a key role in alveolar formation, a vital process about which little is currently known. Transcriptome analysis of Hh targeted progenitor cells transitioning from the pseudoglandular to the saccular phase of lung development revealed important modulations of key signaling pathways. Among these, there was significant downregulation of canonical WNT signaling. Ectopic stabilization of beta-catenin via inactivation of Apc by Gli1 cre(ERT2) expanded the Hh-targeted progenitor pools, which caused the formation of fibroblastic masses within the lung parenchyma. The Gli1-cre(ERT2) mouse line represents a novel tool in the analysis of mesenchymal cell biology and alveolar formation during lung development. PMID- 25448083 TI - The relation between resting heart rate and cancer incidence, cancer mortality and all-cause mortality in patients with manifest vascular disease. AB - BACKGROUND: Previous studies suggest that elevated resting heart rate (RHR) is related to an increased risk of cancer mortality. The aim of this study was to evaluate the relation between RHR and cancer incidence and mortality in patients with vascular disease. METHODS: Patients with manifest vascular disease (n=6007) were prospectively followed-up for cancer incidence and mortality. At baseline, RHR was obtained from an electrocardiogram. The relation between RHR and cancer incidence, cancer mortality and total mortality was assessed using competing risks models. RESULTS: During a median follow-up of 6.0 years (interquartile range: 3.1-9.3) 491 patients (8%) were diagnosed with cancer and 907 (15%) patients died, 248 (27%) died from cancer. After adjustment for potential confounders, the hazard ratio (HR) for incident cancer per 10 beats/min increase in RHR was 1.00 (95% confidence interval [CI]: 0.93-1.07). There was a trend toward an increased risk of colorectal cancer in patients with higher RHR (HR 1.15, 95% CI 0.97-1.36). The risk of all-cause mortality was increased in patients in the highest quartile of RHR compared to the lowest quartile (HR 1.86, 95% CI 1.53-2.27), but no effect of RHR on cancer mortality was observed (HR 1.01, 95% CI 0.70-1.46). CONCLUSIONS: In patients with manifest vascular disease, elevated RHR was related to a higher risk of premature all-cause mortality, but this was not due to increased cancer mortality. RHR was not related to risk of overall cancer incidence, although a relation between elevated RHR and incident colorectal cancer risk could not be ruled out. PMID- 25448082 TI - Retention and its predictors among methadone maintenance treatment clients in China: a six-year cohort study. AB - BACKGROUND: To investigate factors associated with retention among the first cohort of drug users attending methadone maintenance treatment (MMT) clinics in China. METHODS: A six-year cohort of 1511 drug users was enrolled in the first 8 MMT clinics in China in 2004 and followed between March, 2004 and December, 2010. Six-year retention rates were calculated and compared by methadone dosage, clinic location, and length of follow-up. Factors associated with retention were evaluated using Cox proportional hazard regression models. RESULTS: The overall retention rate over 6-year was 35.7%. Highest drop-out occurred within the first 12 months of treatment. The retention rates for the 6-year by low (<= 30 mg/day), medium (31-60 mg/day), and high (>60 mg/day) methadone dosage groups were 20.8%, 34.8% and 53.2%, respectively (p < 0.001). The highest 6-year retention rate among eight clinics was 43.8%, while the lowest one was 17.7% (p < 0.001). The results from Cox proportional hazard models indicate that clients having >30 mg daily methadone dosage (p < 0.001), having relatives receiving MMT (p = 0.027), and having >10% urine morphine positive result (p < 0.001) were more likely to be retained in MMT over the six-year period. It has also found that drug injection (p = 0.005) and needle sharing (p < 0.0001) were significantly associated with better retention. CONCLUSIONS: Health workers should adjust individuals' methadone dosages as a method to prevent early treatment termination. Further studies are needed to explore the impact of severity of opiate addiction on long term retention of MMT clients. Careful assessment of drug users upon MMT enrollment may be helpful for providing additional care to clients. PMID- 25448084 TI - Resveratrol suppresses the proliferation of breast cancer cells by inhibiting fatty acid synthase signaling pathway. AB - In breast cancer cells, overexpression of human epidermal growth factor receptor 2 (HER2) increases the translation of fatty acid synthase (FASN) by altering the activity of PI3K/Akt signaling pathways. Cancer chemotherapy causes major side effects and is not effective enough in slowing down the progression of the disease. Earlier studies showed a role for resveratrol in the inhibition of FASN, but the molecular mechanisms of resveratrol-induced inhibition are not known. In the present study, we examined the novel mechanism of resveratrol on Her2 overexpressed breast cancer cells. The effect of resveratrol on the growth of breast cancer cells was assessed as percent cell viability by cytotoxicity-based MTT assay and the induction of apoptosis was determined by cell-death detection ELISA and flow cytometric analysis of Annexin-V-PI binding. Western immunobloting was used to detect signaling events in human breast cancer (SKBR-3) cells. Data showed that resveratrol-mediated down-regulation of FASN and HER2 genes synergistically induced apoptotic death in SKBR-3 cells. This concurrently caused a prominent up-regulation of PEA3, leads to down-regulation of HER2 genes. Resveratrol also alleviated the PI3K/Akt/mTOR signaling by down-regulation of Akt phosphorylation and up-regulation of PTEN expression. These findings suggest that resveratrol alters the cell cycle progression and induce cell death via FASN inhibition in HER2 positive breast cancer. PMID- 25448081 TI - Altered neural correlates of reward and loss processing during simulated slot machine fMRI in pathological gambling and cocaine dependence. AB - BACKGROUND: Individuals with gambling or substance-use disorders exhibit similar functional alterations in reward circuitry suggestive of a shared underlying vulnerability in addictive disorders. Additional research into common and unique alterations in reward-processing in substance-related and non-substance-related addictions may identify neural factors that could be targeted in treatment development for these disorders. METHODS: To investigate contextual reward processing in pathological gambling, a slot-machine fMRI task was performed by three groups (with pathological gambling, cocaine dependence and neither disorder; N = 24 each) to determine the extent to which two groups with addictions (non-substance-related and substance-related) showed similarities and differences with respect to each other and a non-addicted group during anticipatory periods and following the delivery of winning, losing and 'near miss' outcomes. RESULTS: Individuals with pathological gambling or cocaine dependence compared to those with neither disorder exhibited exaggerated anticipatory activity in mesolimbic and ventrocortical regions, with pathological gambling participants displaying greater positive possible-reward anticipation and cocaine-dependent participants displaying more negative certain-loss anticipation. Neither clinical sample exhibited medial frontal or striatal responses that were observed following near-miss outcomes in healthy comparison participants. CONCLUSIONS: Alterations in anticipatory processing may be sensitive to the valence of rewards and content-disorder-specific. Common and unique findings in pathological gambling and cocaine dependence with respect to anticipatory reward and near-miss loss processing suggest shared and unique elements that might be targeted through behavioral or pharmacological interventions in the treatment of addictions. PMID- 25448085 TI - Evaluation of the cytotoxic and mutagenic potential of three ginkgolic acids. AB - Ginkgolic acids (GAs) are alkylphenols which can be found in the fruits and leaves of Ginkgo biloba L. (Ginkgoaceae) used in herbal teas, drugs and food supplements. Standardized leaf extracts of G. biloba are widely used in the therapy of cognitive decline including Alzheimer's diseases. However, GAs are known to have cytotoxic and allergenic potential and are suspected to possess genotoxic properties. Therefore, we examined in this study the cytotoxicity and mutagenicity of three major GAs with different alkyl or alkenyl groups (13:0, 15:1, 17:1). Cytotoxicity was assessed in male Chinese hamster lung fibroblasts (V79 cells) using the resazurin reduction assay. The substances showed concentration dependent cytotoxic effects after 24h of incubation at concentrations of 50MUM and higher. Mutagenicity was determined by using the Ames fluctuation assay in different Salmonella typhimurium strains (TA97a, TA98, TA100 and TA102) with and without exogenous metabolic activation (S9 mix). Furthermore, we analyzed the mutagenic potency of the three major GAs in V79 cells by performing the hypoxanthine phosphoribosyl transferase (HPRT) assay which detects gene mutations at the HPRT locus. None of the mutagenic assays showed any increase in mutagenicity above background. Therefore, these data provide evidence that the GAs tested have some cytotoxic potency but are not mutagenic. Thus, our findings contribute to the risk assessment of preparations containing plant extracts from G. biloba. PMID- 25448086 TI - BPR-3P0128 inhibits RNA-dependent RNA polymerase elongation and VPg uridylylation activities of Enterovirus 71. AB - Enterovirus 71 (EV71) infections can cause hand, foot, and mouth disease with severe neurological complications. Because no clinical drug is available for treating EV71 infections, developing an efficient antiviral medication against EV71 infection is crucial. This study indicated that 6-bromo-2-[1-(2,5 dimethylphenyl)-5-methyl-1H-pyrazol-4-yl] quinoline-4-carboxylic acid (BPR 3P0128) exhibits excellent antiviral activity against EV71 (EC50 = 0.0029 MUM). BPR-3P0128 inhibits viral replication during the early post infection stage, targets EV71 RNA-dependent RNA polymerase and VPg uridylylation, and also reduces viral RNA accumulation levels and inhibits viral replication of EV71. PMID- 25448087 TI - Small molecule inhibitors of Ago2 decrease Venezuelan equine encephalitis virus replication. AB - Venezuelan equine encephalitis virus (VEEV) is classified as a Category B Select Agent and potential bioterror weapon for its severe disease course in humans and equines and its potential for aerosol transmission. There are no current FDA licensed vaccines or specific therapies against VEEV, making identification of potential therapeutic targets a priority. With this aim, our research focuses on the interactions of VEEV with host microRNA (miRNA) machinery. miRNAs are small non-coding RNAs that act as master regulators of gene expression by downregulating or degrading messenger RNA, thus suppressing production of the resultant proteins. Recent publications implicate miRNA interactions in the pathogenesis of various viral diseases. To test the importance of miRNA processing for VEEV replication, cells deficient in Ago2, an important component of the RNA-induced silencing complex (RISC), and cells treated with known Ago2 inhibitors, notably acriflavine (ACF), were utilized. Both conditions caused decreased viral replication and capsid expression. ACF treatment promoted increased survival of neuronal cells over a non-treated, infected control and reduced viral titers of fully virulent VEEV as well as Eastern and Western Equine Encephalitis Viruses and West Nile Virus, but not Vesicular Stomatitis Virus. ACF treatment of VEEV TC-83 infected mice resulted in increased in vivo survival, but did not affect survival or viral loads when mice were challenged with fully virulent VEEV TrD. These results suggest that inhibition of Ago2 results in decreased replication of encephalitic alphaviruses in vitro and this pathway may be an avenue to explore for future therapeutic development. PMID- 25448089 TI - The influence of pleiotropy between viability and pollen fates on mating system evolution. AB - Floral displays are functionally and genetically integrated structures, so modifications to display will likely affect multiple fitness components (pleiotropy), including pollen export and self-pollination, and therefore selfing rate. Consequently, the great diversities of floral displays and of mating systems found among angiosperms have likely co-evolved. I extend previous models of mating system evolution to determine how pleiotropy that links viability (e.g., probability of survival to reproduction) and the allocation of pollen for export and selfing affects the evolution of selfing, outcrossing, and in particular, mixed mating. I show that the outcome depends on how pollen shifts from being exported, unused, or used for selfing. Furthermore, pleiotropy that affects viability can explain observations not addressed by previous theory, including the evolution of mixed mating despite high inbreeding depression in the absence of pollen-limitation. Therefore, pleiotropy may play a key role in explaining selfing rates for such species that exhibit otherwise enigmatic mating systems. PMID- 25448088 TI - Animal models of viral hemorrhagic fever. AB - The term "viral hemorrhagic fever" (VHF) designates a syndrome of acute febrile illness, increased vascular permeability and coagulation defects which often progresses to bleeding and shock and may be fatal in a significant percentage of cases. The causative agents are some 20 different RNA viruses in the families Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae, which are maintained in a variety of animal species and are transferred to humans through direct or indirect contact or by an arthropod vector. Except for dengue, which is transmitted among humans by mosquitoes, the geographic distribution of each type of VHF is determined by the range of its animal reservoir. Treatments are available for Argentine HF and Lassa fever, but no approved countermeasures have been developed against other types of VHF. The development of effective interventions is hindered by the sporadic nature of most infections and their occurrence in geographic regions with limited medical resources. Laboratory animal models that faithfully reproduce human disease are therefore essential for the evaluation of potential vaccines and therapeutics. The goal of this review is to highlight the current status of animal models that can be used to study the pathogenesis of VHF and test new countermeasures. PMID- 25448090 TI - Development and introduction of inactivated poliovirus vaccines derived from Sabin strains in Japan. AB - During the endgame of global polio eradication, the universal introduction of inactivated poliovirus vaccines is urgently required to reduce the risk of vaccine-associated paralytic poliomyelitis and polio outbreaks due to wild and vaccine-derived polioviruses. In particular, the development of inactivated poliovirus vaccines (IPVs) derived from the attenuated Sabin strains is considered to be a highly favorable option for the production of novel IPV that reduce the risk of facility-acquired transmission of poliovirus to the communities. In Japan, Sabin-derived IPVs (sIPVs) have been developed and introduced for routine immunization in November 2012. They are the first licensed sIPVs in the world. Consequently, trivalent oral poliovirus vaccine was used for polio control in Japan for more than half a century but has now been removed from the list of vaccines licensed for routine immunization. This paper reviews the development, introduction, characterization, and global status of IPV derived from attenuated Sabin strains. PMID- 25448091 TI - Vaccine schedule compliance among very low birth weight infants in Lima, Peru. AB - OBJECTIVE: There is little information about vaccine schedule compliance in very low-birth-weight infants in developing countries. The aim of the study was to describe the compliance with the vaccine schedule among this population in Lima, Peru. PATIENTS AND METHODS: We conducted a prospective cohort study in four hospitals in Lima in infants with a birth-weight of less than 1500 g, followed from birth up to 12 months of age every 2 weeks. The date and age at administration of each vaccine was recorded RESULTS: 222 infants were enrolled. The median birth-weight was 1250 g (range 550-1499 g) and the median gestational age was 30.0 weeks (range 23-37 weeks). The mean age for the first pentavalent (DPT, Hib, HepB) and oral polio vaccine administration was 4.3 +/- 1.4 months in infants with a birth-weight of < 1000 g vs. 3.1 +/- 1.0 in infants with a birth weight 1000-1500 g (p < 0.001); 4.1 +/- 0.9 vs. 3.3 +/- 1.1 for rotavirus (p < 0.05); and 5.1 +/- 2.1 vs. 4.3 +/- 1.8 for the 7-valent pneumococcal conjugated vaccine. Only 35% had received the three doses of oral polio and pentavalent vaccine by seven months, although by nine months 81% had received these vaccines. CONCLUSIONS: Vaccination of very-low-birth-weight infants in Peru is significantly delayed, especially in infants with a birth-weight of < 1000 g and lower gestational age. Urgent educational interventions targeting physicians and nurses should be implemented in order to improve vaccination rates and timing in these high risk populations. PMID- 25448092 TI - Immunogenicity of heterologous H5N1 influenza booster vaccination 6 or 18 months after primary vaccination in adults: a randomized controlled clinical trial. AB - BACKGROUND: Highly pathogenic avian influenza A/H5N1 viruses continue to circulate in birds and infect humans causing serious illness and death. METHODS: In this randomized, observer-blinded study, adults >=18 years of age (n=841) received 3.75 or 7.5 MUg hemagglutinin antigen (HA) of an AS03-adjuvanted (AS03A or AS03B) A/Indonesia/5/2005 H5N1 (subclade 2.1) vaccine (priming), followed by the same HA dose of AS03-adjuvanted A/turkey/Turkey/1/05 H5N1 (clade 2.2) influenza vaccine as a booster 6 or 18 months after priming; an unprimed group received placebo at Day 0, and 3.75 MUg HA of AS03A-adjuvanted booster vaccine at 6 and 18 months. Antibody responses were assessed by hemagglutination-inhibition assay (HI). Microneutralization (MN) antibody and cellular immunoassays were assessed in a subset of participants. RESULTS: Geometric mean titers (GMTs) and seroconversion rates (SCRs) were higher in primed vs. unprimed subjects against the booster strain 10 days following booster vaccination at month 6 and month 18. After the booster at 18 months, the lower limit of the 97.5% confidence interval for the difference in SCR and GMT ratios between primed and unprimed subjects was >15% and >2.0, respectively, fulfilling the primary endpoint criteria for superiority against the booster strain. MN and cellular immune responses corresponded with the immunogenicity seen in HI measures. CONCLUSIONS: Adults primed with a dose-sparing oil-in-water adjuvanted H5N1 subclade vaccine had rapid and durable antibody responses to a heterologous subclade boosting vaccine given 6 or 18 months later. PMID- 25448093 TI - Understanding influenza vaccine protection in the community: an assessment of the 2013 influenza season in Victoria, Australia. AB - BACKGROUND: The influenza virus undergoes frequent antigenic drift, necessitating annual review of the composition of the influenza vaccine. Vaccination is an important strategy for reducing the impact and burden of influenza, and estimating vaccine effectiveness (VE) each year informs surveillance and preventative measures. We aimed to describe the influenza season and to estimate the effectiveness of the influenza vaccine in Victoria, Australia, in 2013. METHODS: Routine laboratory notifications, general practitioner sentinel surveillance (including a medical deputising service) data, and sentinel hospital admission surveillance data for the influenza season (29 April to 27 October 2013) were collated in Victoria, Australia, to describe influenza-like illness or confirmed influenza during the season. General practitioner sentinel surveillance data were used to estimate VE against medically-attended laboratory confirmed influenza. VE was estimated using the case test negative design as 1-adjusted odds ratio (odds of vaccination in cases compared with controls) * 100%. Cases tested positive for influenza while non-cases (controls) tested negative. Estimates were adjusted for age group, week of onset, time to swabbing and co morbidities. RESULTS: The 2013 influenza season was characterised by relatively low activity with a late peak. Influenza B circulation preceded that of influenza A(H1)pdm09, with very little influenza A(H3) circulation. Adjusted VE for all influenza was 55% (95%CI: -11, 82), for influenza A(H1)pdm09 was 43% (95%CI: 132, 86), and for influenza B was 56% (95%CI: -51, 87) Imputation of missing data raised the influenza VE point estimate to 64% (95%CI: 13, 85). CONCLUSIONS: Clinicians can continue to promote a positive approach to influenza vaccination, understanding that inactivated influenza vaccines prevent at least 50% of laboratory-confirmed outcomes in hospitals and the community. PMID- 25448094 TI - Development of a DNA vaccine for chicken infectious anemia and its immunogenicity studies using high mobility group box 1 protein as a novel immunoadjuvant indicated induction of promising protective immune responses. AB - Chicken infectious anaemia (CIA) is an economically important and emerging poultry disease reported worldwide. Current CIA vaccines have limitations like, the inability of the virus to grow to high titres in embryos/cell cultures, possession of residual pathogenicity and a risk of reversion to virulence. In the present study, a DNA vaccine, encoding chicken infectious anaemia virus (CIAV) VP1 and VP2 genes, was developed and co-administered with truncated chicken high mobility group box 1 (HMGB1DeltaC) protein in young chicks for the evaluation of vaccine immune response. CIAV VP1 and VP2 genes were cloned in pTARGET while HMGB1DeltaC in PET32b vector. In vitro expression of these gene constructs was evaluated by Western blotting. Further, recombinant HMGB1DeltaC was evaluated for its biological activity. The CIAV DNA vaccine administration in specific pathogen free chicks resulted in moderately protective ELISA antibody titres in the range of 4322.87 +/- 359.72 to 8288.19 +/- 136.38, increased CD8(+) cells, and a higher titre was observed by co-administration of novel adjuvant (HMGB1DeltaC) and booster immunizations. The use of vaccine with adjuvant showed achieving antibody titres nearly 8500, titre considered as highly protective, which indicates that co-immunization of HMGB1DeltaC may have a strong adjuvant activity on CIAV DNA vaccine induced immune responses. The able potential of HMGB1 protein holding strong adjuvant activity could be exploited further with trials with vaccines for other important pathogens for achieving the required protective immune responses. PMID- 25448096 TI - The need for a multi-disciplinary perspective on vaccine hesitancy and acceptance. PMID- 25448095 TI - Effectiveness of a provider-focused intervention to improve HPV vaccination rates in boys and girls. AB - BACKGROUND: HPV vaccination is universally recommended for boys and girls, yet vaccination rates remain low nationwide. METHODS: We conducted a provider-focused intervention that included repeated contacts, education, individualized feedback, and strong quality improvement incentives to raise HPV vaccination rates at two federally qualified community health centers. To estimate the effectiveness of the intervention, rates of initiation of vaccination, and completion of the next needed HPV vaccination (dose 1, 2 or 3) among boys and girls ages 11-21 were compared at baseline and two follow-up periods in two intervention health centers (n4093 patients) and six control health centers (n9025 patients). We conducted multivariable logistic regression accounting for clustering by practice. RESULTS: Girls and boys in intervention practices significantly increased HPV vaccine initiation during the active intervention period relative to control practices (girls OR 1.6, boys OR 11; p<0.001 for both). Boys at intervention practices were also more likely to continue to initiate vaccination during the post intervention/maintenance period (OR 8.5; p<0.01). Girls and boys at intervention practices were more also likely to complete their next needed HPV vaccination (dose 1, 2 or 3) than those at control practices (girls OR 1.4, boys OR 23; p<0.05 for both). These improvements were sustained for both boys and girls in the post-intervention/maintenance period (girls OR 1.6, boys OR 25; p<0.05 for both). CONCLUSIONS: Provider-focused interventions including repeated contacts, education, individualized feedback, and strong quality improvement incentives have the potential to produce sustained improvements in HPV vaccination rates. PMID- 25448097 TI - Influenza vaccine effectiveness against laboratory confirmed influenza in Greece during the 2013-2014 season: a test-negative study. AB - BACKGROUND: In 2013-2014 Greece experienced a resurgence of severe influenza cases, coincidental with a shift to H1N1pdm09 predominance. We sought to estimate Vaccine Effectiveness (VE) for this season using available surveillance data from hospitals (including both inpatients and outpatients). METHODS: Swab samples were sent by hospital physicians to one of three laboratories, covering the entire country, to be tested for influenza using RT-PCR. The test-negative design was employed, with patients testing positive serving as cases and those testing negative serving as controls. VE was estimated using logistic regression, adjusted for age group, sex, region and calendar time, with further adjustment for unknown vaccination status using inverse response propensity weights. Additional age group stratified estimates and subgroup estimates of VE against H1N1pdm09 and H3N2 were calculated. RESULTS: Out of 1310 patients with known vaccination status, 124 (9.5%) were vaccinated, and 543 patients (41.5%) tested positive for influenza. Adjusted VE was 34.5% (95% CI: 4.1-55.3%) against any influenza, and 56.7% (95% CI: 22.8-75.7%) against H1N1pdm09. VE estimates appeared to be higher for people aged 60 and older, while in those under 60 there was limited evidence of effectiveness. Isolated circulating strains were genetically close to the vaccine strain, with limited evidence of antigenic drift. CONCLUSIONS: These results suggest a moderate protective effect of the 2013-2014 influenza vaccine, mainly against H1N1pdm09 and in people aged 60 and over. Vaccine coverage was very low in Greece, even among groups targeted for vaccination, and substantial efforts should be made to improve it. VE can and should be routinely monitored, and the results taken into account when deciding on influenza vaccine composition for next season. PMID- 25448098 TI - Increasing uptake of live attenuated influenza vaccine among children in the United States, 2008-2014. AB - The Advisory Committee on Immunization Practices (ACIP) recommends annual influenza vaccination for all persons in the United States aged >=6 months. On June 25, 2014, ACIP preferentially recommended live attenuated influenza vaccine (LAIV) for healthy children aged 2-8 years. Little is known about national LAIV uptake. To determine uptake of LAIV relative to inactivated influenza vaccine, we analyzed vaccination records from six immunization information system sentinel sites (approximately 10% of US population). LAIV usage increased over time in all sites. Among children 2-8 years of age vaccinated for influenza, exclusive LAIV usage in the collective sentinel site area increased from 20.1% (2008-09 season) to 38.0% (2013-14). During 2013-14, at least half of vaccinated children received LAIV in Minnesota (50.0%) and North Dakota (55.5%). Increasing LAIV usage suggests formulation acceptability, and this preexisting trend offers a favorable context for implementation of ACIP's preferential recommendation. PMID- 25448099 TI - A Vero-cell-adapted vaccine donor strain of influenza A virus generated by serial passages. AB - A cell culture-based vaccine production system is preferred for the large-scale production of influenza vaccines and has advantages for generating vaccines against highly pathogenic influenza A viruses. Vero cells have been widely used in human vaccine manufacturing, and the safety of these cells has been well demonstrated. However, the most commonly used influenza-vaccine donor virus, A/Puerto Rico/8/1934 (PR8) virus, does not grow efficiently in Vero cells. Therefore, we adapted the PR8 virus to Vero cells by continuous passaging, and a high-growth strain was obtained after 20 passages. Sequence analysis and virological assays of the adapted strain revealed that mutations in four viral internal genes (NP, PB1, PA and NS1) were sufficient for adaptation. The recombinant virus harboring these mutations (PR8-4mut) displayed accelerated viral transport into the nucleus and increased RNP activity. Importantly, the PR8 4mut could serve as a backbone donor virus to support the growth of the H7N1, H9N2 and H5N1 avian viruses and the H1N1 and H3N2 human viruses in Vero cells without changing its pathogenicity in either chicken embryos or mice. Thus, our work describes the generation of a Vero-adapted, high-yield PR8-4mut virus that may serve as a promising candidate for an influenza-vaccine donor virus. PMID- 25448100 TI - Cross-protection against H7N9 influenza strains using a live-attenuated H7N3 virus vaccine. AB - In 2013, avian H7N9 influenza viruses were detected infecting people in China resulting in high mortality. Influenza H7 vaccines that provide cross-protection against these new viruses are needed until specific H7N9 vaccines are ready to market. In this study, an available H7N3 cold-adapted, temperature sensitive, live attenuated influenza vaccine (LAIV) elicited protective immune responses in ferrets against H7N9 viruses. The H7N3 LAIV administered alone (by intranasal or subcutaneous administration) or in a prime-boost strategy using inactivated H7N9 virus resulted in high HAI titers and protected 100% of the animals against H7N9 challenge. Naive ferrets passively administered immune serum from H7N3 LAIV infected animals were also protected. In contrast, recombinant HA protein or inactivated viruses did not protect ferrets against challenge and elicited lower antibody titers. Thus, the H7N3 LAIV vaccine was immunogenic in healthy seronegative ferrets and protected these ferrets against the newly emerged H7N9 avian influenza virus. PMID- 25448101 TI - The large-scale production of an artificial influenza virus-like particle vaccine in silkworm pupae. AB - We successfully established a mass production system for an influenza virus-like particle (VLP) vaccine using a synthetic H5 hemagglutinin (HA) gene codon optimized for the silkworm. A recombinant baculovirus containing the synthetic gene was inoculated into silkworm pupae. Four days after inoculation, the hemagglutination titer in homogenates from infected pupae reached a mean value of 0.8 million hemagglutination units (HAU), approximately 2,000 MUg HA protein per pupa, more than 50-fold higher than that produced with an embryonated chicken egg. VLPs ranging from 30 nm to 300 nm in diameter and covered with a large number of spikes were detected in the homogenates. The spikes were approximately 14 nm long, similar to an authentic influenza HA spike. Detailed electron micrographs indicated that the VLP spike density was similar to that of authentic influenza virus particles. The results clearly show that the expression of a single HA gene can efficiently produce VLPs in silkworm pupae. When chickens were immunized with the pupae homogenate, the hemagglutination inhibition titer in their sera reached values of 2,048-8,192 after approximately 1 month. This is the first report demonstrating that a large amount of VLP vaccine could be produced by single synthetic HA gene in silkworm pupae. Our system might be useful for future vaccine development against other viral diseases. PMID- 25448103 TI - Improving immunity to Haemophilus influenzae in children with chronic suppurative lung disease. AB - BACKGROUND: Endobronchial infections related to non-typeable Haemophilus influenzae (NTHi) are common in children and adults with suppurative airway disease such as bronchiectasis and COPD. Impaired cell mediated immune responses to NTHi have been described in these patients. Currently there are no interventions known to correct the deficiency in cell mediated immune responses to NTHi. The aim of this study was to determine if receipt of a conjugate vaccine containing protein D from H. influenzae is associated with improvement in NTHi specific cytokine responses in children with chronic suppurative lung disease. METHODS: Blood mononuclear cells from 107 young children with chronic suppurative lung disease and 32 healthy control children were stimulated in vitro with NTHi. We compared the cytokine production of stimulated mononuclear cells from children who had received the pneumococcal H. influenzae protein D conjugate vaccine with cells from children who received pneumococcal vaccines without protein D. Protein D-specific IgG1 was quantified in plasma. RESULTS: Children with chronic suppurative lung disease who received >= 3 doses of the protein D conjugate vaccine produced significantly more IFNgamma than children who received the alternative vaccines without protein D (median 939 versus 338 pg/ml; p = 0.007). Importantly, the amount of IFNgamma produced by those vaccinated with the conjugate vaccine approached the levels observed in cells from healthy children. The conjugate vaccine was also associated with small but significant increases in IL-13 (p < 0.001) and IL-5 (p = 0.007). Protein D-specific IgG1 levels correlated with the number of PHiD-CV doses (p = 0.02). CONCLUSION: Vaccination with PHiD-CV is associated with improvements in NTHi-specific cell-mediated and humoral immune responses in children with chronic suppurative lung disease. PMID- 25448102 TI - Comparison of the immunogenicity and safety of polysaccharide and protein conjugated pneumococcal vaccines among the elderly aged 80 years or older in Japan: an open-labeled randomized study. AB - An open-labeled randomized study was conducted to compare the immunogenicity and safety of polysaccharide (PPV23) or protein-conjugated pneumococcal vaccine (PCV7) among the elderly aged 80 years or older. A total of 105 nursing home residents were enrolled in this study. We analyzed the geometric mean concentration (GMC) of serotype-specific immunoglobulin G (IgG) and the geometric mean titer (GMT) of the opsonization index (OI) for serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. The GMCs of serotype-specific IgG and the GMTs of the OI significantly increased one month after vaccination in both groups for all seven serotypes evaluated. In the PCV7 group, study subjects with serotypes 4, 9V, 18C, and 23F exhibited statistically significant elevations in both serotype-specific IgGs and OIs compared to those of the PPV23 group. Both vaccines were tolerated without any severe adverse events, and no differences in systemic adverse events were observed between the two groups, although adverse reactions such as redness and localized swelling were more common in the PCV7 group. Our data demonstrated that the GMCs of serotype-specific IgG and the GMTs of the OI were higher in the PCV7 group compared to those in the PPV23 group. Our study also confirmed the safety of both the PCV7 and PPV23 vaccines in elderly people aged 80 years or older. PMID- 25448104 TI - Development of a subunit vaccine containing recombinant Riemerella anatipestifer outer membrane protein A and CpG ODN adjuvant. AB - Riemerella anatipestifer, a Gram-negative bacillus, causes septicemia that can result in high mortality for ducklings. In this study, we evaluated the immune response and protective efficacy provided by a subunit vaccine containing recombinant outer membrane protein A (rOmpA) and plasmid constructs containing CpG oligodeoxynucleotides (ODN). Results showed that CpG ODN enhanced both humoral and cell-mediated immunity elicited by rOmpA as early as two weeks after primary immunization. When compared to ducks immunized with rOmpA, ducks immunized with rOmpA+CpG ODN showed higher levels (p<0.05) of antibody titer, T cell proliferation, and percentages of CD4(+) and CD8(+) T cell in peripheral blood mononuclear cells (PBMCs). The relative fold inductions of mRNA expression of Th1-type (IFN-gamma and IL-12), and Th2-type (IL-6) cytokines in PBMCs isolated from ducks immunized with rOmpA+CpG ODN were significantly higher than those of the rOmpA group. Homologous challenge result showed that the rOmpA+CpG ODN vaccine reduced the pathological score by 90% in comparison with the saline control. In conclusion, our study found that CpG ODN can enhance both humoral and cellular immunity elicited by a rOmpA vaccine. The rOmpA+CpG ODN vaccine can be further developed as a subunit vaccine against R. anatipestifer. PMID- 25448106 TI - Development of a Salmonella cross-protective vaccine for food animal production systems. AB - Intensive livestock production is associated with increased Salmonella exposure, transmission, animal disease, and contamination of food and water supplies. Modified live Salmonella enterica vaccines that lack a functional DNA adenine methylase (Dam) confer cross-protection to a diversity of salmonellae in experimental models of murine, avian, ovine, and bovine models of salmonellosis. However, the commercial success of any vaccine is dependent upon the therapeutic index, the ratio of safety/efficacy. Herein, secondary virulence-attenuating mutations targeted to genes involved in intracellular and/or systemic survival were introduced into Salmonella dam vaccines to screen for vaccine candidates that were safe in the animal and the environment, while maintaining the capacity to confer cross-protective immunity to pathogenic salmonellae serotypes. Salmonella dam mgtC, dam sifA, and dam spvB vaccine strains exhibited significantly improved vaccine safety as evidenced by the failure to give rise to virulent revertants during the infective process, contrary to the parental Salmonella dam vaccine. Further, these vaccines exhibited a low grade persistence in host tissues that was associated with reduced vaccine shedding, reduced environmental persistence, and induction of cross-protective immunity to pathogenic serotypes derived from infected livestock. These data indicate that Salmonella dam double mutant vaccines are suitable for commercial applications against salmonellosis in livestock production systems. Reducing pre-harvest salmonellae load through vaccination will promote the health and productivity of livestock and reduce contamination of livestock-derived food products, while enhancing overall food safety. PMID- 25448105 TI - Impact of the pneumococcal conjugate vaccines on invasive pneumococcal disease in France, 2001-2012. AB - CONTEXT AND AIMS: Vaccination with the 7-valent pneumococcal conjugate vaccine (PCV7) was recommended in France in 2003 for children <2 years. The 13-valent conjugate vaccine (PCV13) replaced PCV7 in 2010. We assessed the impact of PCVs vaccination on the incidence of invasive pneumococcal diseases (IPD) in French children (0-15 years) and adults (>15 years). METHODS: IPD rates were calculated using cases reported from 2001 to 2012 to Epibac, a laboratory network. The distribution of serotypes was assessed from invasive isolates serotyped at the National reference Centre for Pneumococci. IPD incidence rates were compared between the pre-PCV7 (2001-2002), late PCV7 (2008-2009) and post PCV13 (2012) periods. RESULTS: The PCVs coverage increased from 56% in the 2004 birth-cohort to 94% in the 2008 and following birth-cohorts. Following PCV7 introduction, IPD incidence decreased by 19% between 2001-2002 and 2008-2009 in children <2 years, but increased in children aged 2-15 years and adults, despite a sharp decline in PCV7-IPD in all age-groups. After PCV13 introduction, IPD incidence decreased by 34% in children <5 years, by 50% in those aged 5-15 years and 15% in adults from 2008-2009 to 2012. The incidence of PCV13-Non PCV7-IPD decreased by 74% in children <5 years and by 60% in those aged 5-15 years. CONCLUSIONS: Vaccination with PCV13 was rapidly followed by a decrease in the incidence of all-type IPD in children, in relation with a sharp decrease in the incidence of PCV13-Non PCV7 IPD. Moreover, all-type IPD decreased after PCV13 introduction in older non vaccinated age-groups, with a shift in the distribution of serotypes. Considering the whole 2001-2012 period, the vaccination with PCV7 and PCV13 resulted in a decline in the incidence of IPD in children up to the age of 5 but not in older children and adults. PMID- 25448107 TI - BCG vaccination-induced long-lasting control of Mycobacterium tuberculosis correlates with the accumulation of a novel population of CD4+IL-17+TNF+IL-2+ T cells. AB - Mycobacterium bovis Bacille Calmette-Guerin (BCG) is the only vaccine in use to prevent Mycobacterium tuberculosis (Mtb) infection. Here we analyzed the protective efficacy of BCG against Mtb challenges 21 or 120 days after vaccination. Only after 120 days post-vaccination were mice able to efficiently induce early Mtb growth arrest and maintain long-lasting control of Mtb. This protection correlated with the accumulation of CD4(+) T cells expressing IL 17(+)TNF(+)IL-2(+). In contrast, mice challenged with Mtb 21 days after BCG vaccination exhibited only a mild and transient protection, associated with the accumulation of CD4(+) T cells that were mostly IFN-gamma(+)TNF(+) and to a lesser extent IFN-gamma(+)TNF(+)IL-2(+). These data suggest that the memory response generated by BCG vaccination is functionally distinct depending upon the temporal proximity to BCG vaccination. Understanding how these responses are generated and maintained is critical for the development of novel vaccination strategies against tuberculosis. PMID- 25448108 TI - Effect of cationic liposomes on BCG trafficking and vaccine-induced immune responses following a subcutaneous immunization in mice. AB - While formulating Mycobacterium bovis BCG in lipid-based adjuvants has been shown to increase the vaccine's protective immunity, the biological mechanisms responsible for the enhanced potency of lipid encapsulated BCG are unknown. To assess whether mixing BCG in adjuvant increases its immunogenicity by altering post-vaccination organ distribution and persistence, mice were immunized subcutaneously with conventional BCG Pasteur or BCG formulated in DDA/TDB adjuvant and the bio-distribution of BCG bacilli was evaluated in mouse lungs, spleens, lymph nodes, and livers for up to 1 year. Although BCG was rarely detected in mouse livers, mycobacteria were found in mouse lungs, spleens, and lymph nodes for at least 1 year post-vaccination. However, at various time points during the 1 year study, the frequency of lung and spleen infections and the number of mycobacteria in infected organs of individual mice were highly variable. In contrast, mycobacteria were nearly always detected in the lymph nodes of vaccinated mice. While the frequency and extent of lymph node infections generally were not significantly different between mice vaccinated with adjuvanted or nonadjuvanted BCG preparations, multiparameter flow cytometry analysis of lymph node cells showed significantly higher frequencies of CD4+ and CD8+ T cells expressing IFN-gamma and IFN-gamma/TNF-alpha in mice immunized with adjuvanted BCG. Overall, our data suggest that the relationship between lymph node infection and the generation of anti-tuberculosis protective responses following BCG vaccination should be further investigated. PMID- 25448109 TI - Immune responses after fractional doses of inactivated poliovirus vaccine using newly developed intradermal jet injectors: a randomized controlled trial in Cuba. AB - INTRODUCTION: The World Health Organization recommends that, as part of the new polio endgame, a dose of inactivated poliovirus vaccine (IPV) be introduced by the end of 2015 in all countries using only oral poliovirus vaccine (OPV). Administration of fractional dose (1/5th of full dose) IPV (fIPV) intradermally may reduce costs, but its administration is cumbersome with BCG needle and syringe. We evaluated performance of two newly developed intradermal-only jet injectors and compared the immune response induced by fIPV with that induced by full-dose IPV. METHODS: Children between 12 and 20 months of age, who had previously received two doses of OPV, were enrolled in Camaguey, Cuba. Subjects received a single dose of IPV (either full-dose IPV intramuscularly with needle and syringe or fIPV intradermally administered with one of two new injectors or with BCG needle or a conventional needle-free injector). Serum was tested for presence of poliovirus neutralizing antibodies on day 0 (pre-IPV) and on days 3, 7 and 21 (post-vaccination). RESULTS: Complete data were available from 74.2% (728/981) subjects. Baseline median antibody titers were 713, 284, and 113 for poliovirus types 1, 2, and 3, respectively. Seroprevalence at study end were similar across the intervention groups (>= 94.8%). The immune response induced with one new injector was similar to BCG needle and to the conventional injector; and superior to the other new injector. fIPV induced significantly lower boosting response compared to full-dose IPV. No safety concerns were identified. INTERPRETATION: One of the two new injectors demonstrated its ability to streamline intradermal fIPV administration, however, further investigations are needed to assess the potential contribution of fIPV in the polio endgame plan. PMID- 25448110 TI - Carrier priming with CRM 197 or diphtheria toxoid has a different impact on the immunogenicity of the respective glycoconjugates: biophysical and immunochemical interpretation. AB - Glycoconjugate vaccines play an enormous role in preventing infectious diseases. The main carrier proteins used in commercial conjugate vaccines are the non-toxic mutant of diphtheria toxin (CRM197), diphtheria toxoid (DT) and tetanus toxoid (TT). Modern childhood routine vaccination schedules include the administration of several vaccines simultaneously or in close sequence, increasing the concern that the repeated exposure to conjugates based on these carrier proteins might interfere with the anti-polysaccharide response. Extending previous observations we show here that priming mice with CRM197 or DT does not suppress the response to the carbohydrate moiety of CRM197 meningococcal serogroup A (MenA) conjugates, while priming with DT can suppress the response to DT-MenA conjugates. To explain these findings we made use of biophysical and immunochemical techniques applied mainly to MenA conjugates. Differential scanning calorimetry and circular dichroism data revealed that the CRM197 structure was altered by the chemical conjugation, while DT and the formaldehyde-treated form of CRM197 were less impacted, depending on the degree of glycosylation. Investigating the binding and avidity properties of IgGs induced in mice by non-conjugated carriers, we found that CRM197 induced low levels of anti-carrier antibodies, with decreased avidity for its MenA conjugates and poor binding to DT and respective MenA conjugates. In contrast, DT induced high antibody titers able to bind with comparable avidity both the protein and its conjugates but showing very low avidity for CRM197 and related conjugates. The low intrinsic immunogenicity of CRM197 as compared to DT, the structural modifications induced by glycoconjugation and detoxification processes, resulting in conformational changes in CRM197 and DT epitopes with consequent alteration of the antibody recognition and avidity, might explain the different behavior of CRM197 and DT in a carrier priming context. PMID- 25448111 TI - Particle quantification of influenza viruses by high performance liquid chromatography. AB - The influenza virus continuously undergoes antigenic evolution requiring manufacturing, validation and release of new seasonal vaccine lots to match new circulating strains. Although current production processes are well established for manufacturing seasonal inactivated influenza vaccines, significant limitations have been underlined in the case of pandemic outbreaks. The World Health Organization called for a global pandemic influenza vaccine action plan including the development of new technologies. A rapid and reliable method for the quantification of influenza total particles is crucially needed to support the development, improvement and validation of novel influenza vaccine manufacturing platforms. This work presents the development of an ion exchange high performance liquid chromatography method for the quantification of influenza virus particles. The method was developed using sucrose cushion purified influenza viruses A and B produced in HEK 293 suspension cell cultures. The virus was eluted in 1.5 M NaCl salt with 20 mM Tris-HCl and 0.01% Zwittergent at pH 8.0. It was detected by native fluorescence and the total analysis time was 13.5 min. A linear response range was established between 1 * 10(9) and 1 * 10(11) virus particle per ml (VP/ml) with a correlation coefficient greater than 0.99. The limit of detection was between 2.07 * 10(8) and 4.35 * 10(9) whereas the limit of quantification was between 6.90 * 10(8) and 1.45 * 10(10)VP/ml, respectively. The coefficient of variation of the intra- and inter-day precision of the method was less than 5% and 10%. HPLC data compared well with results obtained by electron microscopy, HA assay and with a virus counter, and was used to monitor virus concentrations in the supernatant obtained directly from the cell culture production vessels. The HPLC influenza virus analytical method can potentially be suitable as an in-process monitoring tool to accelerate the development of processes for the manufacturing of influenza vaccines. PMID- 25448113 TI - Canine zona pellucida glycoprotein-3: up-scaled production, immunization strategy and its outcome on fertility. AB - Zona pellucida (ZP) glycoproteins based contraceptive vaccines have been proposed for the management of wildlife population. In the present study, a fusion protein encompassing promiscuous T cell epitope of tetanus toxoid [TT; amino acid (aa) residues 830-844] followed by a dilysine linker and an ectodomain of dog ZP3 (ZP3; aa residues 23-348) without any affinity tag (TT-KK-ZP3) has been expressed in Escherichia coli. The recombinant protein was successfully produced in fed batch fermentor and purified. The average yield of purified refolded protein was 12.20 +/- 0.61 mg/2g wet cell pellet. Female FvB/J mice immunized with the varying doses of recombinant TT-KK-ZP3 supplemented with alum/PetGel A as adjuvants following a three injection schedule, showed dose dependent increase in serum IgG titer. Antibodies against TT-KK-ZP3 recognized native mouse/dog ZP and significantly inhibited mouse in-vitro fertilization (p=0.012). Immunized mice showed significant reduction in fertility (p<0.05). Higher antibody titers were associated with a decrease in the number of pups born to the immunized female mice. To reduce the number of injections, two injection schedule using various dose combinations of TT-KK-ZP3 supplemented with alum revealed lower immunogenicity and contraceptive efficacy as compared to the three injection schedule. To overcome this, CpG motif was included in addition to alum and both intraperitoneal and intranasal route of immunization following the two injection schedule was investigated. Inclusion of CpG significantly enhanced the antibody titer and improved contraceptive efficacy. In the mice immunized following intraperitoneal route, serum/vaginal IgG and in the mice immunized through intranasal route, vaginal IgA seemed to be important for curtailment in fertility. To conclude, the recombinant protein described herein may be a good candidate for developing contraceptive vaccine for the wildlife population management, in particular street dogs. PMID- 25448112 TI - Activation of the NLRP3 inflammasome by vault nanoparticles expressing a chlamydial epitope. AB - The full potential of vaccines relies on development of effective delivery systems and adjuvants and is critical for development of successful vaccine candidates. We have shown that recombinant vaults engineered to encapsulate microbial epitopes are highly stable structures and are an ideal vaccine vehicle for epitope delivery which does not require the inclusion of an adjuvant. We studied the ability of vaults which were engineered for use as a vaccine containing an immunogenic epitope of Chlamydia trachomatis, polymorphic membrane protein G (PmpG), to be internalized into human monocytes and behave as a "natural adjuvant". We here show that incubation of monocytes with the PmpG-1 vaults activates caspase-1 and stimulates IL-1beta secretion through a process requiring the NLRP3 inflammasome and that cathepsin B and Syk are involved in the inflammasome activation. We also observed that the PmpG-1-vaults are internalized through a pathway that is transiently acidic and leads to destabilization of lysosomes. In addition, immunization of mice with PmpG-1-vaults induced PmpG-1 responsive CD4(+) cells upon re-stimulation with PmpG peptide in vitro, suggesting that vault vaccines can be engineered for specific adaptive immune responses. We conclude that PmpG-1-vault vaccines can stimulate NLRP3 inflammasomes and induce PmpG-specific T cell responses. PMID- 25448114 TI - Evaluation of the immune response and protective efficacy of Schistosoma mansoni Cathepsin B in mice using CpG dinucleotides as adjuvant. AB - Schistosomiasis is the most important human helminth infection due to its impact on public health. Worldwide, schistosomiasis is estimated to infect at least 200 million individuals while 700 million are at risk. The clinical manifestations are chronic and significantly decrease an individual's quality of life. Infected individuals suffer from long-term organ pathologies including fibrosis which eventually leads to organ failure. The development of a vaccine against this parasitic disease would contribute to a long-lasting decrease in disease spectrum and transmission. Our group has chosen to target Schistosoma mansoni Cathepsin B as a prospective vaccine candidate. The recombinant protein was tested in the presence of synthetic oligodeoxynucleotides containing unmethylated CpG dinucleotides, which are Toll-like receptor 9 agonists known to stimulate a Th1 response. This formulation conferred a 59% decrease in worm burden as well as a reduction in egg burden. Hepatic egg burden and intestinal egg burden were decreased by 56% and 54% respectively. Immunizations with the formulation elicited robust production of Sm-Cathepsin B specific antibodies, both IgG1 and IgG2c but with the latter predominating. Furthermore, splenocytes isolated from the immunized animals, compared to control animals, had increased secretion levels of key Th1 cytokines, IFN-gamma and TNF-alpha, as well as the chemokine CCL5 when stimulated with recombinant Sm-Cathepsin B. These results highlight the potential of Sm-Cathepsin B/CpG as a vaccine candidate against schistosomiasis. PMID- 25448115 TI - Augmented saliency model using automatic 3D head pose detection and learned gaze following in natural scenes. AB - Previous studies have shown that gaze direction of actors in a scene influences eye movements of passive observers during free-viewing (Castelhano, Wieth, & Henderson, 2007; Borji, Parks, & Itti, 2014). However, no computational model has been proposed to combine bottom-up saliency with actor's head pose and gaze direction for predicting where observers look. Here, we first learn probability maps that predict fixations leaving head regions (gaze following fixations), as well as fixations on head regions (head fixations), both dependent on the actor's head size and pose angle. We then learn a combination of gaze following, head region, and bottom-up saliency maps with a Markov chain composed of head region and non-head region states. This simple structure allows us to inspect the model and make comments about the nature of eye movements originating from heads as opposed to other regions. Here, we assume perfect knowledge of actor head pose direction (from an oracle). The combined model, which we call the Dynamic Weighting of Cues model (DWOC), explains observers' fixations significantly better than each of the constituent components. Finally, in a fully automatic combined model, we replace the oracle head pose direction data with detections from a computer vision model of head pose. Using these (imperfect) automated detections, we again find that the combined model significantly outperforms its individual components. Our work extends the engineering and scientific applications of saliency models and helps better understand mechanisms of visual attention. PMID- 25448117 TI - A neural model of border-ownership from kinetic occlusion. AB - Camouflaged animals that have very similar textures to their surroundings are difficult to detect when stationary. However, when an animal moves, humans readily see a figure at a different depth than the background. How do humans perceive a figure breaking camouflage, even though the texture of the figure and its background may be statistically identical in luminance? We present a model that demonstrates how the primate visual system performs figure-ground segregation in extreme cases of breaking camouflage based on motion alone. Border ownership signals develop as an emergent property in model V2 units whose receptive fields are nearby kinetically defined borders that separate the figure and background. Model simulations support border-ownership as a general mechanism by which the visual system performs figure-ground segregation, despite whether figure-ground boundaries are defined by luminance or motion contrast. The gradient of motion- and luminance-related border-ownership signals explains the perceived depth ordering of the foreground and background surfaces. Our model predicts that V2 neurons, which are sensitive to kinetic edges, are selective to border-ownership (magnocellular B cells). A distinct population of model V2 neurons is selective to border-ownership in figures defined by luminance contrast (parvocellular B cells). B cells in model V2 receive feedback from neurons in V4 and MT with larger receptive fields to bias border-ownership signals toward the figure. We predict that neurons in V4 and MT sensitive to kinetically defined figures play a crucial role in determining whether the foreground surface accretes, deletes, or produces a shearing motion with respect to the background. PMID- 25448118 TI - From shunting inhibition to dynamic normalization: Attentional selection and decision-making in brief visual displays. AB - Normalization models of visual sensitivity assume that the response of a visual mechanism is scaled divisively by the sum of the activity in the excitatory and inhibitory mechanisms in its neighborhood. Normalization models of attention assume that the weighting of excitatory and inhibitory mechanisms is modulated by attention. Such models have provided explanations of the effects of attention in both behavioral and single-cell recording studies. We show how normalization models can be obtained as the asymptotic solutions of shunting differential equations, in which stimulus inputs and the activity in the mechanism control growth rates multiplicatively rather than additively. The value of the shunting equation approach is that it characterizes the entire time course of the response, not just its asymptotic strength. We describe two models of attention based on shunting dynamics, the integrated system model of Smith and Ratcliff (2009) and the competitive interaction theory of Smith and Sewell (2013). These models assume that attention, stimulus salience, and the observer's strategy for the task jointly determine the selection of stimuli into visual short-term memory (VSTM) and the way in which stimulus representations are weighted. The quality of the VSTM representation determines the speed and accuracy of the decision. The models provide a unified account of a variety of attentional phenomena found in psychophysical tasks using single-element and multi-element displays. Our results show the generality and utility of the normalization approach to modeling attention. PMID- 25448119 TI - The perception of gloss: a review. AB - Gloss is a relatively little studied visual property of objects' surfaces. The earliest recorded scientific reference to gloss appears to have been by Ingersoll in 1921: studies at this time were based on the assumption that gloss could be understood as an inherent physical property of a surface, and the priority was to devise a satisfactory method and scale to measure it reliably. As awareness of the complexity of perception grew, efforts were made to distinguish different types of gloss, although these generally still took the form of a search for objective physical measures to be solved within the visual system by means of inverse optics. It became more widely recognised approximately 20 years ago that models of gloss perception based on inverse optics were intractable and failed to explain experimental findings adequately. A temporary decline in the number of published studies followed; however the last decade or so has seen a renewal of interest in the perception of gloss, in an effort to map what is now understood to be a complex interaction of variables including illumination, surface properties and observer. This appears to have been driven by a number of factors, as the study of gloss re-emerged from research into other surface properties such as colour and texture, with technological advances paving the way for new experimental techniques and measurements. This review describes the main strands of research, tracking the changes in approach and theory which have triggered new avenues of research, to the current state of knowledge. PMID- 25448120 TI - [Show me your nails!]. PMID- 25448116 TI - Microsaccade production during saccade cancelation in a stop-signal task. AB - We obtained behavioral data to evaluate two alternative hypotheses about the neural mechanisms of gaze control. The "fixation" hypothesis states that neurons in rostral superior colliculus (SC) enforce fixation of gaze. The "microsaccade" hypothesis states that neurons in rostral SC encode microsaccades rather than fixation per se. Previously reported neuronal activity in monkey SC during the saccade stop-signal task leads to specific, dissociable behavioral predictions of these two hypotheses. When subjects are required to cancel partially-prepared saccades, imbalanced activity spreads across rostral and caudal SC with a reliable temporal profile. The microsaccade hypothesis predicts that this imbalance will lead to elevated microsaccade production biased toward the target location, while the fixation hypothesis predicts reduced microsaccade production. We tested these predictions by analyzing the microsaccades produced by 4 monkeys while they voluntarily canceled partially prepared eye movements in response to explicit stop signals. Consistent with the fixation hypothesis and contradicting the microsaccade hypothesis, we found that each subject produced significantly fewer microsaccades when normal saccades were successfully canceled. The few microsaccades escaping this inhibition tended to be directed toward the target location. We additionally investigated interactions between initiating microsaccades and inhibiting normal saccades. Reaction times were longer when microsaccades immediately preceded target presentation. However, pre-target microsaccade production did not affect stop-signal reaction time or alter the probability of canceling saccades following stop signals. These findings demonstrate that imbalanced activity within SC does not necessarily produce microsaccades and add to evidence that saccade preparation and cancelation are separate processes. PMID- 25448121 TI - [Ingrown nails or onychocryptosis]. AB - Ingrown nails come down to a conflict between the nail plate and the periungual tissue, causing pain, morbidity and impairment. The feet are mainly affected. The treatments are numerous: medical, podiatric, or surgical. Surgical management has two approaches: the techniques focused on the periungual skin and those on the nail plate. Among the latter, partial nail avulsion followed by matrix phenolization, known as "Boll's technique", is still highly regarded. PMID- 25448122 TI - [From COPD definitions to COPD phenotypes]. AB - COPD is characterized by incompletely reversible airflow limitation (FEV1/FVC < 70%). The historical classification of COPD, which was based on the severity of airflow limitation assessed by the level of FEV1, did not take into account the various aspects of COPD patients. At comparable levels of FEV1, COPD patients show marked heterogeneity in clinical manifestations (dyspnea, rates of exacerbations, exercise capacity, and quality of life), leading to the proposal of the current COPD classification based not only on FEV1, but also on symptoms (dyspnea or quality of life) and history of exacerbations. Limitations of this novel classification of COPD include its relative complexity and the absence of age and comorbidities. Recent identification of clinical COPD phenotypes (i.e., subgroups of COPD patients sharing not only clinical characteristics, but also natural history and/response to therapy) could result in progresses in the pathophysiology of the disease, in the development of specific biomarkers, and could facilitate evaluation of drugs in clinical trials. The development of simple algorithms, using easily available clinical data, will allow identification of phenotypes in clinical practice and may lead to individualized therapies. PMID- 25448123 TI - [Impact of COPD: from disability to exacerbations]. AB - COPD is a common disease characterized by health status impairment and disability that is usually progressive. Exacerbations of COPD, an acute event in the course of the disease, have effects on symptoms and patient's quality of life. Assessment of symptoms and risk of exacerbations is useful to guide strategy management of the disease. COPD disability includes different aspects. Its assessment needs to consider the classification of severity of airflow limitation, symptoms, comorbidities and impairment of patient's health-related quality of life. The rate at which exacerbations occur varies between patients. History of previous exacerbations and severity of airflow limitation are the best predictors of the frequency and severity of exacerbations. Severity of the symptoms is associated with an increased risk of exacerbations. Exacerbations increase deterioration in health status and leads to severe disability, inducing a vicious circle from disability to exacerbations. At an individual patient level, an understanding of the impact of COPD requires to assess the patient's disability, the risk of future exacerbations, and the identification of comorbidities. PMID- 25448124 TI - Origin and immunoescape of uterine cervical cancer. AB - Human papillomavirus associated uterine cervical cancer is an important public health problem since it is classified as the fourth most common cancer in women worldwide with more than 500,000 recorded cases. This review is focused on where and why HPV infection induces cervical cancers and how this virus avoids the host immune response. Immunological therapeutic approaches are also addressed. PMID- 25448125 TI - Automated detection and measurement of uterine peristalsis in cine MR images. AB - PURPOSE: To evaluate the ability of automated software to quantify uterine peristalsis on cine magnetic resonance imaging (MRI). MATERIALS AND METHODS: At 1.5T, half-Fourier acquisition single-shot turbo spin echo (HASTE) techniques were used to obtain 60 serial images over 3 minutes (TR/TE 3000/80 msec) in a midsagittal plane of the uterus. Thirty-two cine MR datasets, obtained from 16 healthy females, were analyzed. Uterine peristalsis was defined as the traveling waves of decreasing signal intensity on the endometrium-junctional zone border. The software detected traveling waves by identifying the neighboring areas showing similar patterns of signal intensity decrease in a different timing. Quantification of uterine peristaltic wave using the fully automated software was compared to qualitative visual evaluation by two readers. RESULTS: The mean number (and standard deviation) of peristaltic waves detected by the fully automated software and visual evaluations (readers 1 and 2) were 5.4 (3.0), 4.7 (3.1), and 4.5 (3.1) per 3 minutes, respectively. Quantification by fully automated software demonstrated excellent agreement with repeated measurement (weighted kappa 0.99) and with qualitative visual evaluations (range 0.89-0.95), comparable to interreader agreement by visual evaluations (range 0.89-0.93). CONCLUSION: The fully automated software can be used to quantify uterine peristalsis comparable to visual evaluation. PMID- 25448127 TI - Bone healing around nanocrystalline hydroxyapatite, deproteinized bovine bone mineral, biphasic calcium phosphate, and autogenous bone in mandibular bone defects. AB - The individual healing profile of a given bone substitute with respect to osteogenic potential and substitution rate must be considered when selecting adjunctive grafting materials for bone regeneration procedures. In this study, standardized mandibular defects in minipigs were filled with nanocrystalline hydroxyapatite (HA-SiO), deproteinized bovine bone mineral (DBBM), biphasic calcium phosphate (BCP) with a 60/40% HA/beta-TCP (BCP 60/40) ratio, or particulate autogenous bone (A) for histological and histomorphometric analysis. At 2 weeks, percent filler amongst the test groups (DBBM (35.65%), HA-SiO (34.47%), followed by BCP 60/40 (23.64%)) was significantly higher than the more rapidly substituted autogenous bone (17.1%). Autogenous bone yielded significantly more new bone (21.81%) over all test groups (4.91%-7.74%) and significantly more osteoid (5.53%) than BCP 60/40 (3%) and DBBM (2.25%). At 8 weeks, percent filler amongst the test groups (DBBM (31.6%), HA-SiO (31.23%), followed by BCP 60/40 (23.65%)) demonstrated a similar pattern and was again significantly higher as compared to autogenous bone (9.29%). Autogenous bone again exhibited statistically significantly greater new bone (55.13%) over HA-SiO (40.62%), BCP 60/40 (40.21%), and DBBM (36.35%). These results suggest that the osteogenic potential of HA-SiO and BCP is inferior when compared to autogenous bone. However, in instances where a low substitution rate is desired to maintain the volume stability of augmented sites, particularly in the esthetic zone, HA SiO and DBBM may be favored. PMID- 25448128 TI - [Spotted fever and the invention of its serodiagnosis and vaccination in the Austro-Hungarian army in World War I]. AB - After description of the medical institutions and epidemiological situations of the Austro-Hungarian army in World War I the provisions against spotted fever focused on louse control are discussed. The letter specified for the army had to be adjusted for the local populations. 1915 in the k.u.k. military service in Galicia Edmund Weil and Arthur Felix cultivated Proteus strains from urine of soldiers with spotted fever. As sera of such patients agglutinated these bacteria in considerable titers the investigators developed the reliable diagnostic "Weil Felix-Test" used still today. In the same military area and time Rudolf Weigl invented the anal infection of lice. This enabled him to harvest a great amount of louse intestines containing the spotted fever Rickettsiae in their epithelial cells. Lots with defined numbers of intestines were homogenized, sterilized and used with success as vaccine for medical staff. This sort of vaccine still was used in World War II. PMID- 25448126 TI - Developmental changes in hypothalamic toll-like-receptor 4 mRNA expression and the effects of lipopolysaccharide on such changes in female rats. AB - Hypothalamic pro-inflammatory cytokine expression exhibits a weaker response to lipopolysaccharides (LPS) during the early neonatal period than during the later developmental period. Although toll-like receptor 4 (TLR4), which recognizes bacterial molecules, activates pro-inflammatory cytokine responses, the developmental changes in hypothalamic TLR4 expression have not been evaluated. In this study, the hypothalamic TLR4 mRNA levels of saline-injected and LPS-injected rats were measured during the neonatal, pre-pubertal, and post-pubertal periods. The rats' hypothalamic TLR4 mRNA levels gradually increased from the neonatal to pubertal period and were altered by the injection of LPS at all examined ages (postnatal day (PND) 5, 15, 25, and 42). LPS injection resulted in decreased hypothalamic TLR4 mRNA expression at PND5, whereas it increased hypothalamic TLR4 mRNA expression at PND15, 25, and 42. After the injection of LPS, the hypothalamic mRNA levels of the pro-inflammatory cytokines interleukin (IL) 1beta, tumor necrosis factor alpha, and IL-6 were attenuated during the early developmental period and increased acutely on PND42. The expression profiles of these pro-inflammatory cytokines exhibited similar, but not entirely consistent, changes to those displayed by TLR4 during the developmental period. Hypothalamic TLR4 mRNA expression gradually increased throughout the developmental period, whereas the mRNA expression levels of the pro-inflammatory cytokines increased acutely at PND42. Thus, it is assumed that hypothalamic TLR4 hypoactivity contributes to the low sensitivity of pro-inflammatory cytokines to LPS during the early developmental period. PMID- 25448129 TI - Simultaneous multi-parametric analysis of Leishmania and of its hosting mammal cells: A high content imaging-based method enabling sound drug discovery process. AB - Leishmaniasis is a vector-borne disease for which only limited therapeutic options are available. The disease is ranked among the six most important tropical infectious diseases and represents the second-largest parasitic killer in the world. The development of new therapies has been hampered by the lack of technologies and methodologies that can be integrated into the complex physiological environment of a cell or organism and adapted to suitable in vitro and in vivo Leishmania models. Recent advances in microscopy imaging offer the possibility to assess the efficacy of potential drug candidates against Leishmania within host cells. This technology allows the simultaneous visualization of relevant phenotypes in parasite and host cells and the quantification of a variety of cellular events. In this review, we present the powerful cellular imaging methodologies that have been developed for drug screening in a biologically relevant context, addressing both high-content and high-throughput needs. Furthermore, we discuss the potential of intra-vital microscopy imaging in the context of the anti-leishmanial drug discovery process. PMID- 25448130 TI - Integrons in uropathogenic Escherichia coli and their relationship with phylogeny and virulence. AB - Uropathogenic Escherichia coli (UPEC) comprise a heterogeneous group of strains. In a previous epidemiological survey performed on 230 UPEC isolates, five virulence profiles were described, each one defined by the presence of some virulence determinants and by the absence of others. Phylogenetic groups and antibiotic resistances distributed non-randomly among the isolates with different profiles. Based on these results, the presence of class 1 and 2 integrons was now investigated in these UPEC isolates in order to analyze the distribution of integrons among the phylogenetic groups and virulence profiles. As detected by PCR reactions targeted to the corresponding integrase genes, the class 1 integrons prevailed (22%) followed by those of class 2 (8%). Integrons distributed unevenly among the four main E. coli phylogenetic groups: class 1 integrons predominated in the isolates belonging to group D while class 2 were almost absent in this group. In relation to virulence, integrons frequently appeared in some virulence profiles and were particularly scarce in others. Concerning the class 1 integrons, the most notable findings were that they highly concentrated in isolates presenting one of the virulence profiles (profile V) and were absent in isolates bearing the K1 capsule. The analysis of the Pc promoter variants of the class 1 integrons revealed that all isolates with virulence profile V contained the same Pc version; PcH1. Findings in this work support the idea that, among UPEC strains, integrons would encounter constraints for their installation in some genetic backgrounds while other backgrounds would be propitious for their permanence. PMID- 25448131 TI - Lineage variability in surface components expression within Porphyromonas gingivalis. AB - The periodontopathogen Porphyromonas gingivalis is represented by a spectrum of phenotypes ranging from commensals to pathogenic lineages. Capsule and fimbriae are considered key virulence factors in this specie, involved in colonization and host defenses evasion. Since these virulence traits may not be expressed by certain strains, we aimed to test the hypothesis that certain clusters or genotypes of P. gingivalis correlate with the production of capsule and fimbriae. Sixteen P. gingivalis isolates were evaluated. Capsule (K) was detected by optical microscopy of negatively stained cells. The presence of fimbriae (F) was determined by TEM. Genotypes were determined by NotI macrorestriction fragments analysis through Pulsed-Field Gel Electrophoresis (PFGE) and Multi-locus sequence typing (MLST) based on seven house-keeping genes. The phenotypes included F(+)K(+) (n = 4), F(-)K(+) (n = 5), F(+)K(-) (n = 5) and F(-)K(-) (n = 2). The analysis of whole genome macrorestriction fragments revealed 14 different clusters. MLST data also revealed extensive genetic diversity; however, PFGE and MLST profiles showed evident differences. There was no association between P. gingivalis clusters and encapsulated and/or fimbriated phenotypes. Genotyping methods were not able to discriminate isolates according to the production of virulence factors such as capsule and major fimbriae, indicating that recombination played a key role in the expression of capsule and fimbriae in P. gingivalis. PMID- 25448134 TI - Neural correlates of response-effector switching using event-related potentials. AB - The primary aim of the present study was to explore whether response-effector shifts can be considered as a cognitive component in models of task switching. The secondary aim was to provide some information regarding the issue of whether the two types of task shifts, stimulus-dimension shift and response-effector shift, share common and/or distinct switch-related ERP modulations. The tertiary aim was to illuminate the organization of task-set components by comparing the performance of a concurrent shift of both stimulus dimensions and response effectors to that of a single shift. Two experiments with two different types of judgment tasks (Experiment 1: a same-match-to-sample task; Experiment 2: a categorical-judgment task) were conducted. Intermittently cued task switching was employed. Each trial was composed of a series of stimulus displays following a transition-cue display, which indicated whether the current trial was identical to (repeat) or different from the previous trial (switch). There were stimulus dimension (color and shape) and response-effector (hand and foot) variables that could be repeated or switched independently with an equal probability from the previous trial. Regarding the primary issue, the results of the two experiments reported in this study consistently showed significant RT switch costs as well as switch-related ERP modulations for a shift of response effectors. Yet, one of the switch-related ERPs, i.e., the cue-locked P3b, observed in this study was found to be reduced rather than increased in amplitudes. As to the secondary issue, the two experiments consistently showed that the two single shifts share some common switch-related ERPs. Finally, this study also provides ERP evidence for the integrated model of task-set organization. PMID- 25448132 TI - Endocytosis of human immunodeficiency virus 1 (HIV-1) in astrocytes: a fiery path to its destination. AB - Despite successful suppression of peripheral HIV-1 infection by combination antiretroviral therapy, immune activation by residual virus in the brain leads to HIV-associated neurocognitive disorders (HAND). In the brain, several types of cells, including microglia, perivascular macrophage, and astrocytes have been reported to be infected by HIV-1. Astrocytes, the most abundant cells in the brain, maintain homeostasis. The general consensus on HIV-1 infection in astrocytes is that it produces unproductive viral infection. HIV-1 enters astrocytes by pH-dependent endocytosis, leading to degradation of the virus in endosomes, but barely succeeds in infection. Here, we have discussed endocytosis mediated HIV-1 entry and viral programming in astrocytes. PMID- 25448133 TI - Circulating miR-21, miR-146a and Fas ligand respond to postmenopausal estrogen based hormone replacement therapy--a study with monozygotic twin pairs. AB - Biological aging is associated with physiological deteriorations, which are partly due to changes in the hormonal profile. MicroRNAs regulate various processes associated with cell senescence; differentiation, replication and apoptosis. Serum microRNAs have potential to serve as noninvasive markers for diagnostics/prognostics and therapeutic targets. We analysed the association of estrogen-based hormone replacement therapy (HRT) with selected microRNAs and inflammation markers from the serum, leukocytes and muscle biopsy samples from 54 to 62 year-old postmenopausal monozygotic twins (n=11 pairs) discordant for HRT usage. Premenopausal 30-35 year-old women (n=8) were used as young controls. We focused on the hormonal aging and on the interaction between HRT use and the modulation of miR-21, miR-146a and classical inflammation markers. Fas-ligand was analysed since it functions in both apoptosis and inflammation. The inflammatory profile was healthier among the premenopausal women compared to the postmenopausal twins. Serum miR-21 and miR-146a levels and FasL concentrations were lower in HRT users compared to their non-using co-twins, demonstrating their responsiveness to HRT. Based on the pairwise FasL analysis, FasL concentration is likely to be genetically controlled. Overall, we suggest that postmenopausal estrogen deficiency sustains the development of "inflamm-aging". Estrogen sensitive, specific circulating microRNAs could be potential, early biomarkers for age-associated physiological deteriorations. PMID- 25448136 TI - Navigation forces during wrist arthroscopy: assessment of expert levels. AB - PURPOSE: To facilitate effective and efficient training in skills laboratory, objective metrics can be used. Forces exerted on the tissues can be a measure of safe tissue manipulation. To provide feedback during training, expert threshold levels need to be determined. The purpose of this study was to define the magnitude and the direction of navigation forces used during arthroscopic inspection of the wrist. METHODS: We developed a set-up to mount a cadaver wrist to a 3D force platform that allowed measurement of the forces exerted on the wrist. Six experts in wrist arthroscopy performed two tasks: (1) Introduction of the camera and visualization of the hook. (2) Navigation through the wrist with visualization of five anatomic structures. The magnitude (Fabs) and direction of force were recorded, with the direction defined as alpha being the angle in the vertical plane and beta being the angle in the horizontal plane. The 10th-90th percentile of the data were used to set threshold levels for training. RESULTS: The results show distinct force patterns for each of the anatomic landmarks. Median Fabs of the navigation task is 3.8 N (1.8-7.3), alpha is 3.60 (-54-44) and beta is 260 (0-72). CONCLUSION: Unique expert data on navigation forces during wrist arthroscopy were determined. The defined maximum allowable navigation force of 7.3 N (90th percentile) can be used in providing feedback on performance during skills training. The clinical value is that this study contributes to objective assessment of skills levels. PMID- 25448137 TI - RETRACTED ARTICLE: Comparison of double-bundle anterior cruciate ligament reconstruction with and without autologous conditioned serum application. PMID- 25448135 TI - History of rotator cuff surgery. AB - PURPOSE: Rotator cuff surgery is a rapidly evolving branch in orthopaedics, which has raised from a minor niche to a fully recognized subspecialty. This article summarizes its history, examining the development of its key principles and the technical advancements. METHODS: Literature was thoroughly searched, and few senior surgeons were interviewed in order to identify the significant steps in the evolution of rotator cuff surgery. RESULTS: A wide variety of surgical options is available to reduce pain and restore function after rotator cuff tears. Rotator cuff repair surgical techniques evolved from open to arthroscopic and are still in development, with new fixation techniques and biological solutions to enhance tendon healing being proposed, tested in laboratory and in clinical trials. Although good or excellent results are often obtained, there is little evidence that the results of rotator cuff repair are improving with the decades. An overall high re-tear rate remains, but patients with failed rotator cuff repairs can experience outcomes comparable with those after successful repairs. CONCLUSIONS: Rotator cuff repair techniques evolve at a fast pace, with new solutions often being used without solid clinical evidence of superiority. It is necessary to conduct high-level clinical studies, in which data relating to anatomical integrity, patient self-assessed comfort and function, together with precise description of patient's condition and surgical technique, are collected. LEVEL OF EVIDENCE: IV. PMID- 25448138 TI - Ultrasound-guided dry needling with percutaneous paratenon decompression for chronic Achilles tendinopathy. AB - PURPOSE: Chronic Achilles tendinopathy is a common overuse injury. There are several modalities of treatment, reflecting difficulties in management. In particular, due to the well-recognised surgical morbidity, treatment has steered towards less invasive routes. Previous studies have targeted pathology either inside or outside the tendon in isolation with varying results. This study aimed to target both pathological sites by combining dry needling with percutaneous hydrostatic decompression as a novel treatment. METHODS: Twenty-one patients with 26 chronic, non-insertional Achilles tendinopathy were prospectively enrolled. Ultrasound-guided dry needling of neovascular areas and small-volume hydrostatic paratenon decompression was performed 6-weekly. Sonographic assessment of tendon thickness and neovascularity was undertaken. Following treatment, a standardised physiotherapy regime was adopted. Visual analogue scores (VAS) were used as the primary outcome measure. Telephonic interviews were carried out 12 and 24 months post-treatment. RESULTS: Twenty-four tendons (in 19 patients) were successfully treated. The mean treatment session was 2. There was no significant change in neovascularity or tendon thickness. Therapeutic intervention led to a significant improvement in VAS at rest (42.4 +/- 24.4 vs. 18.4 +/- 26.0, p = 0.0005) and during activity (72.8 +/- 16.0 vs. 33.7 +/- 23.2, p < 0.0001). At 12 and 24 months, >75 % of patients were highly satisfied with their outcome with nearly half reporting complete resolution of their symptoms. >85 % were also able to return to their sporting interests. CONCLUSION: Combined therapy of dry needling with percutaneous hydrostatic paratenon decompression under ultrasound guidance is a well-tolerated procedure with good short- and long-term pain and functional outcomes. LEVEL OF EVIDENCE: Prospective case series, Level IV. PMID- 25448139 TI - Biomechanical evaluation of anatomic single- and double-bundle anterior cruciate ligament reconstruction techniques using the quadriceps tendon. AB - PURPOSE: Quadriceps tendon grafts have renewed interest for ACL reconstruction; however, biomechanical studies comparing anatomic single-bundle (SB) and double bundle (DB) reconstruction techniques are rare. The purpose of this study was to compare the knee biomechanics in four different types of anatomic ACL reconstruction techniques, using the quadriceps tendon in a human cadaver. METHODS: Four different tibial (T) and femoral (F) tunnel configurations, (a) DB 2F-2T, (b) DB-2F-1T, (c) SB-1F-1T and (d) DB-1F-2T, were used for ACL reconstruction using the split quadriceps tendon with patella bone. Ten cadaver knees were subjected to an 89 N anterior tibial load and combined 7 N m valgus and 5 N m internal torques. The anterior tibial translation (ATT) and in situ force were measured using a robotic system for the ACL-intact, ACL-deficient and ACL-reconstructed knees. RESULTS: DB reconstructions mostly restored ATT to the intact ACL. The in situ forces under the anterior load in the DB reconstructions were similar to the intact ACL, but that of the SB reconstruction was different at 30 degrees , 60 degrees and 90 degrees of flexion (P < 0.05). Under combined torques, the in situ force of the SB graft was less than that of intact ACL at 0 degrees , 15 degrees and 30 degrees of knee flexion (P < 0.05), while that of the ACL DB reconstruction was similar to the intact ACL. CONCLUSION: DB ACL reconstruction using quadriceps tendon can restore biomechanics of the knee to that of the intact ACL regardless of whether three or four tunnels are used, but SB reconstruction does not. PMID- 25448140 TI - Arthroscopic stabilisation of an acute acromioclavicular dislocation grade III in a patient with ectopic insertion of the pectoralis minor: technical considerations. AB - The different approaches used in arthroscopic stabilisation of the acromioclavicular joint are well known. However, and despite a great incidence of ectopic pectoralis minor insertion, an alternative choice for the use of arthroscopic portal has not being sufficiently described. Here, we describe a case of acute acromioclavicular dislocation grade III. The arthroscopic stabilisation was achieved using the TightRope (Arthrex, Naples, USA) implant. Through this technique, the approach to the articular portion of the coracoid process can be made intra-articularly or from the subacromial space. We accessed intra-articularly, by opening the rotator interval to reach the coracoid process from the joint cavity. After opening the rotator interval, an ectopic insertion of the pectoralis minor was observed. The choice of approach of the coracoid process from the subacromial space would have complicated the intervention, making it necessary to sever the ectopic tendon to complete the technique, lengthening the surgical time and increasing the chance of complications. For this reason, the use of a standard posterior portal providing intra-articular arthroscopic access through the rotator interval is recommended since the aforementioned anatomical variation is not infrequent. Level of evidence Therapeutic studies-investigating the results of treatment, Level V. PMID- 25448141 TI - The effect of repeated measurements and the use of topical anesthetic on rebound tonometry values in children. AB - Measurement of intraocular pressure (IOP) in children is important in the management of pediatric glaucoma. Availability of the Icare rebound tonometer has greatly facilitated our ability to obtain awake IOP in infants and children, but little has been reported on either the effect of repeated sequential IOP measurements with Icare or the effect of topical anesthetic on subsequent Icare tonometry. This prospective study of 20 eyes of 10 cooperative children (12 normal eyes, 8 with suspected or known glaucoma) found that neither 8 sequential Icare measurements nor application of topical anesthetic produced a statistically or clinically signficant change in measured IOP by rebound tonometry. PMID- 25448143 TI - Bilateral familial nevus of Ota. AB - Nevus of Ota is a benign congenital melanocytic lesion found most commonly in people of Asian ancestry. It is associated with an increased risk of glaucoma and uveal melanomas. Most cases are sporadic and unilateral. We present the first reported case of a brother and sister with familial, bilateral nevus of Ota. PMID- 25448142 TI - Pull-string technique for recovering subconjunctival short-tag noose adjustable sutures. AB - The "short tag noose" technique is used to adjust sutures after strabismus surgery. The pole and noose sutures are buried below conjunctiva for possible use in later adjustment; however, they are not always easily recoverable. We report a "pull string" modification of the technique that permits retrieval of the pole and noose sutures without the need to enlarge the conjunctival wound or explore the subconjunctival space. If suture adjustment proves unnecessary, the pull string can be removed effortlessly under topical anesthesia, even in uncooperative children. PMID- 25448144 TI - Using video indirect ophthalmoscopy to demonstrate retinopathy of prematurity findings. PMID- 25448145 TI - An unusual ophthalmic finding in Lane-Hamilton syndrome. AB - Lane-Hamilton syndrome is a rare condition that is characterized by idiopathic pulmonary hemosiderosis and celiac disease. We report the case of an 18-month-old girl with Lane-Hamilton syndrome who had unilateral pigmentary retinopathy. PMID- 25448146 TI - Infantile esotropia with cross-fixation, inability to abduct, and underlying horizontal gaze palsy with progressive scoliosis. PMID- 25448147 TI - A simple technique for temporary eyelid closure in severe exposure keratopathy. AB - We describe a novel and simple technique for temporary lid closure in severe bilateral corneal exposure keratopathy, where a rapid method for corneal protection is required. The aim is to create a stable dressing base for secure closure of the eyelids that also allows instillation of medication and examination of the eye. PMID- 25448148 TI - Unusual retinal abnormalities in sisters with tetralogy of Fallot. AB - Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease and can occur in the setting of chromosomal aberrations or multisystem malformation syndromes. We report unusual focal bilateral retinal defects in sisters with TOF. PMID- 25448149 TI - Rapid onset of severe ocular injury after exposure to a button battery. AB - Button batteries are commonly used in many household electronic items and are a potential health hazard, especially in children. We present the case of a 2-year old girl presented with swelling and redness of her right eye of 3 hours' duration. Examination revealed a button battery that had became lodged in the superior fornix of her right eye. After the intact battery was removed, the patient was found to have suffered an alkali burn to the underlying conjunctiva and sclera. The burn healed with symblepharon formation. PMID- 25448150 TI - Using cost-effective intra-arterial chemotherapy to treat retinoblastoma in Chile. AB - Intra-arterial chemotherapy (IAC) has proved to be an effective treatment for retinoblastoma, but can be very expensive in developing countries. We report 2 patients from Chile in whom IAC resulted in globe salvation. Both patients had their medical care provided by the public health system and had failed standard therapy. PMID- 25448151 TI - An unusual case of Coats disease associated with Takayasu arteritis. AB - A 3-year-old Malay boy with strabismus in the left eye was found to have Coats disease in the same eye and underlying Takayasu arteritis. Coats disease is usually idiopathic but can be associated with systemic and ocular conditions. To our knowledge, this is the first reported case of Coats disease associated with Takayasu arteritis. PMID- 25448152 TI - Thermal macular injury from a 154 mW green laser pointer. AB - We report a case of accidental thermal injury due to improper use of a laser pointer obtained outside of the United States. A 13-year-old received a laser pointer as a gift and looked at a reflection of the beam. The patient underwent full ophthalmologic examination with fundus photography, spectral domain optical coherence tomography, and fluorescein angiography. Visual acuity in the left eye was 20/100 at presentation. Fundus examination and ancillary tests were consistent with thermal macular injury. The laser pointer was analyzed and found to be a green diode laser with average power output of 154 mW. PMID- 25448153 TI - Scleral perforations during routine traction test in a patient with osteogenesis imperfecta. AB - Osteogenesis imperfecta comprises a rare group of genetic disorders caused by abnormal collagen that results in increased bone fragility and other sequelae. We describe a 37-year-old woman with osteogenesis imperfecta in whom two full thickness scleral perforations were created by adjacent teeth of 0.5 mm forceps during traction testing while undergoing routine strabismus surgery. This case reviews the ocular findings of osteogenesis imperfecta and highlights the potential risk of ocular surgical complications in these patients. PMID- 25448154 TI - Reply: To PMID 24969490. PMID- 25448155 TI - Hypoxanthine uptake by skeletal muscle microvascular endothelial cells from equilibrative nucleoside transporter 1 (ENT1)-null mice: effect of oxidative stress. AB - Adenosine is an endogenous regulator of vascular tone. This activity of adenosine is terminated by its uptake and metabolism by microvascular endothelial cells (MVEC). The predominant transporter involved is ENT1 (equilibrative nucleoside transporter subtype 1). MVEC also express the nucleobase transporter (ENBT1) which is involved in the cellular flux of adenosine metabolites such as hypoxanthine. Changes in either of these transport systems would impact the bioactivity of adenosine and its metabolism, including the formation of oxygen free radicals. MVEC isolated from skeletal muscle of ENT1(+/+) and ENT1(-/-) mice were subjected to oxidative stress induced by simulated ischemia/reperfusion or menadione. The functional activities of ENT1 and ENBT1 were assessed based on zero-trans influx kinetics of radiolabeled substrates. There was a reduction in the rate of ENBT1-mediated hypoxanthine uptake by ENT1(+/+) MVEC treated with menadione or after exposure to conditions that simulate ischemia/reperfusion. In both cases, the superoxide dismutase mimetic MnTMPyP attenuated the loss of ENBT1 activity, implicating superoxide radicals in the response. In contrast, MVEC isolated from ENT1(-/-) mice showed no reduction in ENBT1 activity upon treatment with menadione or simulated ischemia/reperfusion, but they did have a significantly higher level of catalase activity relative to ENT1(+/+) MVEC. These data suggest that ENBT1 activity is decreased in MVEC in response to the increased superoxide radical that is associated with ischemia/reperfusion injury. MVEC isolated from ENT1(-/-) mice do not show this reduction in ENBT1, possibly due to increased catalase activity. PMID- 25448156 TI - Fluoxetine is neuroprotective in slow-channel congenital myasthenic syndrome. AB - The slow-channel congenital myasthenic syndrome (SCS) is an inherited neurodegenerative disease that caused mutations in the acetylcholine receptor (AChR) affecting neuromuscular transmission. Leaky AChRs lead to Ca(2+) overload and degeneration of the neuromuscular junction (NMJ) attributed to activation of cysteine proteases and apoptotic changes of synaptic nuclei. Here we use transgenic mouse models expressing two different mutations found in SCS to demonstrate that inhibition of prolonged opening of mutant AChRs using fluoxetine not only improves motor performance and neuromuscular transmission but also prevents Ca(2+) overload, the activation of cysteine proteases, calpain, caspase 3 and 9 at endplates, and as a consequence, reduces subsynaptic DNA damage at endplates, suggesting a long term benefit to therapy. These studies suggest that prolonged treatment of SCS patients with open ion channel blockers that preferentially block mutant AChRs is neuroprotective. PMID- 25448158 TI - Sulf1 and Sulf2 expression in the nervous system and its role in limiting neurite outgrowth in vitro. AB - Sulf1 and Sulf2 are endosulfatases that cleave 6-O-sulphate groups from Heparan Sulphate Proteoglycans (HSPGs). Sulfation levels of HSPGs are critical for their role in modulating the activity of various growth factor receptors. Sulf1 and Sulf2 mRNAs were found to be widely expressed in the rodent nervous system and their full-length proteins were found in many types of neuronal perikarya and axons in the cerebral cortex, cerebellum, spinal cord and dorsal root ganglia (DRG) of adult rats. Sulf1/2 were also strongly expressed by cultured DRG neurons. To determine if blocking Sulf1 or Sulf2 activity affected neurite outgrowth in vitro, cultured DRG neurons were treated with neutralising antibodies to Sulf1 or Sulf2. Blocking Sulf1 and Sulf2 activity did not affect neurite outgrowth from cultured DRG neurons grown on a laminin/polylysine substrate but ameliorated the inhibitory effects of chondroitin sulphate proteoglycans (CSPGs) on neurite outgrowth. Blocking epidermal growth factor receptor (ErbB1) activity also improved neurite outgrowth in the presence of CSPGs, but the effects of ErbB1 antagonists and blocking SULFs were not additive. It is proposed that Sulf1, Sulf2 and ErbB1 are involved in the signalling pathway from CSPGs that leads to inhibition of neurite outgrowth and may regulate structural plasticity and regeneration in the nervous system. PMID- 25448157 TI - Defining the critical hypoxic threshold that promotes vascular remodeling in the brain. AB - In animal models, hypoxic pre-conditioning confers protection against subsequent neurological insults, mediated in part through an extensive vascular remodeling response. In light of the therapeutic potential of this effect, the goal of this study was to establish the dose-response relationship between level of hypoxia and the extent of cerebrovascular modeling, and to define the mildest level of hypoxia that promotes remodeling. Mice were exposed to different levels of continuous hypoxia (8-21% O2) for seven days before several aspects of vascular remodeling were evaluated, including endothelial proliferation, total vascular area, arteriogenesis, and fibronectin/alpha5beta1 integrin expression. For most events, the threshold level of hypoxia that stimulated remodeling was 12-13% O2. Interestingly, many parameters displayed a biphasic dose-response curve, with peak levels attained at 10% O2, but declined thereafter. Further analysis in the 12-13% O2 range revealed that vascular remodeling occurs by two separate mechanisms: (i) endothelial hyperplasia, triggered by a hypoxic threshold of 13% O2, which leads to increased capillary growth, and (ii) endothelial hypertrophy, triggered by a more severe hypoxic threshold of 12% O2, which leads to expansion of large vessels and arteriogenesis. Taken together, these results define the hypoxic thresholds for vascular remodeling in the brain, and point to two separate mechanisms mediating this process. PMID- 25448159 TI - GDNF signaling implemented by GM1 ganglioside; failure in Parkinson's disease and GM1-deficient murine model. AB - GDNF is indispensible for adult catecholaminergic neuron survival, and failure of GDNF signaling has been linked to loss of dopaminergic neurons in Parkinson's disease (PD). This study demonstrates attenuated GDNF signaling in neurons deficient in ganglio-series gangliosides, and restoration of such signaling with LIGA20, a membrane permeable analog of GM1. GM1 is shown to associate in situ with GFRalpha1 and RET, the protein components of the GDNF receptor, this being necessary for assembly of the tripartite receptor complex. Mice wholly or partially deficient in GM1 due to disruption of the B4galnt1 gene developed PD symptoms based on behavioral and neuropathological criteria which were largely ameliorated by gene therapy with AAV2-GDNF and also with LIGA20 treatment. The nigral neurons of PD subjects that were severely deficient in GM1 showed subnormal levels of tyrosine phosphorylated RET. Also in PD brain, GM1 levels in the occipital cortex, a region of limited PD pathology, were significantly below age-matched controls, suggesting the possibility of systemic GM1 deficiency as a risk factor in PD. This would accord with our finding that mice with partial GM1 deficiency represent a faithful recapitulation of the human disease. Together with the previously demonstrated age-related decline of GM1 in human brain, this points to gradual development of subthreshold levels of GM1 in the brain of PD subjects below that required for effective GDNF signaling. This hypothesis offers a dramatically different explanation for the etiology of sporadic PD as a manifestation of acquired resistance to GDNF. PMID- 25448160 TI - Activity dependent therapies modulate the spinal changes that motoneurons suffer after a peripheral nerve injury. AB - Injury of a peripheral nerve not only leads to target denervation, but also induces massive stripping of spinal synapses on axotomized motoneurons, with disruption of spinal circuits. Even when regeneration is successful, unspecific reinnervation and the limited reconnection of the spinal circuits impair functional recovery. The aim of this study was to describe the changes that axotomized motoneurons suffer after peripheral nerve injury and how activity dependent therapies and neurotrophic factors can modulate these events. We observed a marked decrease in glutamatergic synapses, with a maximum peak at two weeks post-axotomy, which was only partially reversed with time. This decrease was accompanied by an increase in gephyrin immunoreactivity and a disintegration of perineuronal nets (PNNs) surrounding the motoneurons. Direct application of neurotrophins at the proximal stump was not able to reverse these effects. In contrast, activity-dependent treatment, in the form of treadmill running, reduced the observed destructuring of perineuronal nets and the loss of glutamatergic synapses two weeks after injury. These changes were proportional to the intensity of the exercise protocol. Blockade of sensory inputs from the homolateral hindlimb also reduced PNN immunoreactivity around intact motoneurons, and in that case treadmill running did not reverse that loss, suggesting that the effects of exercise on motoneuron PNN depend on increased sensory activity. Preservation of motoneuron PNN and reduction of synaptic stripping by exercise could facilitate the maintenance of the spinal circuitry and benefit functional recovery after peripheral nerve injury. PMID- 25448161 TI - First report of a family outbreak of Chagas disease in French Guiana and posttreatment follow-up. AB - The outbreak of acute Chagas disease due to oral transmission of the parasite is a well-known phenomenon mainly occurring in the Amazon. Such an event is described here for the first time in French Guiana. Eight patients of the same family, presenting epidemiological and clinical histories compatible with recent Trypanosoma cruzi infection of Chagas disease due to the ingestion of palm Oenocarpus bacaba juice were, rather late after the putative date of infection, underwent four parasitological and two serological specific tests for confirmation of the diagnosis. Real-time PCR results were positive for all the patients; strains were isolated by hemoculture from four patients, PCR identification of TcI DTU was made for six patients, while parasites were not detected in any of the patients by direct microscopic examination. The results of two serologic tests were positive. All patients were treated with benznidazole, and two patients were additionally given nifurtimox. A 6-year follow-up was possible for six patients. Real-time PCR was negative for these patients after 1 year, while the antibody rates decreased slowly and serology results were negative only after several years (1-5 years). Our findings confirm the occurrence of an outbreak of Chagas infection in members of the same family, with the oral mode of infection being the most likely hypothesis to explain this group of cases. Our results show the successful treatment of patients infected by TcI and the usefulness of real-time PCR for the emergency diagnosis of recent Chagas disease cases and in posttreatment follow-up. PMID- 25448162 TI - Empathy: what does it mean for GPs? A qualitative study. AB - BACKGROUND: Research has highlighted empathy as an important and effective factor in patient-physician communication. GPs have extensive practical experience with empathy. However, little is known about the personal views of GPs regarding the meaning and application of empathy in daily practice. OBJECTIVES: To explore GP's experiences and the application of empathy in daily practice and to investigate the practical use of empathy. Facts such as preconditions, barriers and facilitating possibilities are described. METHODS: Qualitative interview study; 30 in-depth interviews were performed between June 2012 and January 2013 with a heterogeneous sample of Dutch GPs. Interviews were recorded and transcribed verbatim; content analysis was performed with the help of ATLAS-ti. RESULTS: Empathy was seen as an important quality-increasing element during the patient-GP consultation. The application of non-verbal and verbal techniques was described. Attention to cues and references to previous consults were reported separately. Required preconditions were: being physically and mentally fit, feeling no time pressure and having an efficient practice organization. Not feeling connected to the patient and strict medical guidelines and protocols were identified as obstacles. A key consideration was the positive contribution of empathy to job satisfaction. CONCLUSIONS: The opinions of GPs in this research can be considered as supplementing and strengthening the findings of previous researches. The GPs in this study discussed, in particular, ideas important to the facilitation of empathy. These included: longer consultations, smaller practices, efficient telephonic triage by practice assistants, using intervision to help reflect on their work and drawing financiers' attention to the effectiveness of empathy. PMID- 25448163 TI - Exploring GPs' experiences of using diagnostic tools for cancer: a qualitative study in primary care. AB - BACKGROUND: The UK has an estimated 5-10000 extra cancer deaths each year when compared to other European countries and diagnostic delays are thought to make a significant contribution to this. One of the initiatives in England intended to support primary care professionals has been the development of cancer risk assessment tools (RATs). These tools assist in identifying and quantifying the risk of cancer in symptomatic primary care patients. OBJECTIVE: To explore GPs' experiences of incorporating the RATs for lung and bowel cancers into their clinical practice and in so doing, identify constraints and facilitators to the wider dissemination of the tools in primary care. METHODS: We conducted semi structured interviews over the telephone with 11 project managers who implemented the study and 23 GPs who used the tool. The interviews were digitally recorded, professionally transcribed verbatim and analysed through the construction of a 'thematic framework'. RESULTS: The training and support package was fundamental to the successful integration of the RATs into GPs' daily routines. Ongoing support from cancer networks alongside acknowledgement of the clinical expertize of the GPs by those implementing the study enhanced GPs' uptake of the tool in practice. CONCLUSION: Findings suggest that the embedding of clinical decision support tools into clinical practice is more likely to be achieved when they are perceived to support but not supersede the clinical judgement of their users. This element of our findings is a focal point of this article. PMID- 25448165 TI - Vibrational spectroscopies and bioenergetic systems. PMID- 25448164 TI - New insights into the history of the C-14010 lactase persistence variant in Eastern and Southern Africa. AB - Lactase persistence (LP), the ability to digest lactose into adulthood, is strongly associated with the cultural traits of pastoralism and milk-drinking among human populations, and several different genetic variants are known that confer LP. Recent studies of LP variants in Southern African populations, with a focus on Khoisan-speaking groups, found high frequencies of an LP variant (the C 14010 allele) that also occurs in Eastern Africa, and concluded that the C-14010 allele was brought to Southern Africa via a migration of pastoralists from Eastern Africa. However, this conclusion was based on indirect evidence; to date no study has jointly analyzed data on the C-14010 allele from both Southern African Khoisan-speaking groups and Eastern Africa. Here, we combine and analyze published data on the C-14010 allele in Southern and Eastern African populations, consisting of haplotypes with the C-14010 allele and four closely-linked short tandem repeat loci. Our results provide direct evidence for the previously hypothesized Eastern African origin of the C-14010 allele in Southern African Khoisan-speaking groups. In addition, we find evidence for a separate introduction of the C-14010 allele into the Bantu-speaking Xhosa. The estimated selection intensity on the C-14010 allele in Eastern Africa is lower than that in Southern Africa, which suggests that in Eastern Africa the dietary changes conferring the fitness advantage associated with LP occurred some time after the origin of the C-14010 allele. Conversely, in Southern Africa the fitness advantage was present when the allele was introduced, as would be expected if pastoralism was introduced concomitantly. PMID- 25448166 TI - PET-imaging of brain plasticity after cochlear implantation. AB - In this article, we review the PET neuroimaging literature, which indicates peculiarities of brain networks involved in speech restoration after cochlear implantation. We consider data on implanted patients during stimulation as well as during resting state, which indicates basic long-term reorganisation of brain functional architecture. On the basis of our analysis of neuroimaging literature and considering our own studies, we indicate that auditory recovery in deaf patients after cochlear implantation partly relies on visual cues. The brain develops mechanisms of audio-visual integration as a strategy to achieve high levels of speech recognition. It turns out that this neuroimaging evidence is in line with behavioural findings of better audiovisual integration in these patients. Thus, strong visually and audio-visually based rehabilitation during the first months after cochlear implantation would significantly improve and fasten the functional recovery of speech intelligibility and other auditory functions in these patients. We provide perspectives for further neuroimaging studies in cochlear implanted patients, which would help understand brain organisation to restore auditory cognitive processing in the implanted patients and would potentially suggest novel approaches for their rehabilitation. This article is part of a Special Issue entitled . PMID- 25448168 TI - Ezetimibe use remains common among medical inpatients. AB - OBJECTIVES: The US Food and Drug Administration licensed ezetimibe in 2002 because of its ability to lower low-density lipoprotein cholesterol levels, a surrogate marker for the risk of coronary artery disease. The negative results of the Effect of Ezetimibe Plus Simvastatin Versus Simvastatin Alone on Atherosclerosis in the Carotid Artery trial were published in 2008. Since then, we have seen 6 additional years without a landmark study in favor of ezetimibe. Furthermore, the new American Heart Association/American College of Cardiology guidelines (2013) now strongly downplay the use of nonstatin agents. We sought to determine whether ezetimibe use remains common in 2014 using a new cohort that we have created to teach residents how to perform clinically relevant research. METHODS: The McGill Teaching Unit Cohort is an anonymized prospective cohort study enrolling all patients admitted to the medical clinical teaching units of the Royal Victoria Hospital in Montreal, Quebec, Canada, as of 2014. Information collected includes the receipt of cholesterol-lowering medications and other important demographics. RESULTS: Of the 783 patients enrolled on the date of analysis, 331 (42.7%) were receiving treatment for hypercholesterolemia. Of these, 156 (47%) were receiving primary prophylaxis. Overall, 323 patients (98%) were receiving a statin, 17 patients (5.1%) were receiving ezetimibe, and 5 patients (1.5%) were receiving a fibrate. Users of ezetimibe were more likely to be active smokers than nonusers (6/17 vs 42/314, P = .01); however, there were no other significant differences between important covariates or recent low-density lipoprotein measurements. CONCLUSIONS: Ezetimibe use remains common amongst medical inpatients despite a lack of evidence supporting its efficacy. PMID- 25448169 TI - Myocardial infarction related to a coronary artery aneurysm. PMID- 25448167 TI - Voice emotion recognition by cochlear-implanted children and their normally hearing peers. AB - Despite their remarkable success in bringing spoken language to hearing impaired listeners, the signal transmitted through cochlear implants (CIs) remains impoverished in spectro-temporal fine structure. As a consequence, pitch-dominant information such as voice emotion, is diminished. For young children, the ability to correctly identify the mood/intent of the speaker (which may not always be visible in their facial expression) is an important aspect of social and linguistic development. Previous work in the field has shown that children with cochlear implants (cCI) have significant deficits in voice emotion recognition relative to their normally hearing peers (cNH). Here, we report on voice emotion recognition by a cohort of 36 school-aged cCI. Additionally, we provide for the first time, a comparison of their performance to that of cNH and NH adults (aNH) listening to CI simulations of the same stimuli. We also provide comparisons to the performance of adult listeners with CIs (aCI), most of whom learned language primarily through normal acoustic hearing. Results indicate that, despite strong variability, on average, cCI perform similarly to their adult counterparts; that both groups' mean performance is similar to aNHs' performance with 8-channel noise-vocoded speech; that cNH achieve excellent scores in voice emotion recognition with full-spectrum speech, but on average, show significantly poorer scores than aNH with 8-channel noise-vocoded speech. A strong developmental effect was observed in the cNH with noise-vocoded speech in this task. These results point to the considerable benefit obtained by cochlear-implanted children from their devices, but also underscore the need for further research and development in this important and neglected area. This article is part of a Special Issue entitled . PMID- 25448170 TI - Neck mass in rural Africa. PMID- 25448171 TI - Paradoxical presentation of glucagonoma with delayed onset of necrolytic migratory erythema. PMID- 25448173 TI - Recurrent pancreatitis, rash, and diarrhea: Crohn's disease. PMID- 25448172 TI - The Next Accreditation System: a strategy for implementing new reporting standards using a Hematology/Oncology model. PMID- 25448174 TI - Hypothermia in systemic lupus erythematosus. PMID- 25448175 TI - Music as medicine. PMID- 25448176 TI - Dangerous proximity: splenic infarction after abdominal abscess. PMID- 25448177 TI - The physical therapist's leg pain: Paget's disease. PMID- 25448178 TI - CrossTalk proposal: De novo capillary recruitment in healthy muscle is necessary. PMID- 25448179 TI - CrossTalk opposing view: De novo capillary recruitment in healthy muscle is not necessary to explain physiological outcomes. PMID- 25448180 TI - Rebuttal from Eugene J. Barrett, Michelle A. Keske, Stephen Rattigan and Etto C. Eringa. PMID- 25448181 TI - Rebuttal from David C. Poole. PMID- 25448182 TI - Novel intracellular mediator of adiponectin secretion from adipocytes. PMID- 25448183 TI - Ribosomes 'muscle up' postnatal muscle growth. PMID- 25448184 TI - Proteases, ENaCs and cystic fibrosis. PMID- 25448185 TI - Fibre type-specific hypertrophy mechanisms in human skeletal muscle: potential role of myonuclear addition. PMID- 25448186 TI - Bengt Saltin (1935-2014). PMID- 25448187 TI - MiR-200c regulates ROS-induced apoptosis in murine BV-2 cells by targeting FAP-1. AB - Objective:Reactive oxygen species (ROS) are significantly upregulated after spinal cord injury (SCI). MicroRNAs (miRNAs) are reported to be widely involved in regulating gene expression. This paper aims to explore the correlation between ROS-induced cell apoptosis and abnormal miRNA expression after SCI.Methods:To profile the expression of miRNAs after SCI, miRNA microarray was applied and the result was verified by reverse transcription quantitative PCR (RT-qPCR). ROS production following H2O2 stimulation was examined using dihydroethidium staining and flow cytometry. The levels of miR-200c after H2O2 treatment were determined using RT-qPCR. Cell viability and apoptosis were examined in murine BV-2 cells transfected with miR-200c mimics, inhibitor or negative control. Immunofluorescence and western blot were used to further explore the effects of miR-200c on Fas-associated phosphatase-1 (FAP-1) expression.Results:MiR-200c was showed to be significantly increased after SCI by miRNA microassay and RT-qPCR. ROS production enhanced miR-200c expression in a dose-dependent manner and induced significant apoptosis in BV-2 cells. The upregulation of miR-200c reduced cell viability and induced BV-2 cell apoptosis. MiR-200c negatively regulated the expression of FAP-1, thereby inducing FAS signaling-induced apoptosis. RT-qPCR analysis showed that the FAP-1-targeting small interfering RNA (siRNA) did not affect the level of miR-200c in murine BV-2 cells. In addition, suppression of FAP-1 by siRNA promoted apoptosis, even in cells that were co-transfected with the miR-200c inhibitor.Conclusions:The current data suggested that miR-200c contributes to apoptosis in murine BV-2 cells by regulating the expression of FAP 1. This proposes a therapeutic target for enhancing neural cell functional recovery after SCI.Spinal Cord advance online publication, 2 December 2014; doi:10.1038/sc.2014.185. PMID- 25448188 TI - Eye-tracking computer systems for inpatients with tetraplegia: findings from a feasibility study. AB - Study design:A longitudinal, prospective, self-controlled cohort study.Objectives:To determine (1) the preliminary benefits of using eye-tracking computer systems (ETCSs) among inpatients with tetraplegia and (2) the feasibility of carrying out a well-powered randomized controlled trial.Setting:Specialist Spinal Cord Injuries Centre, United Kingdom; 6 months during 2013-2014.Methods:Individuals with tetraplegia who were admitted to the center and enrolled in this study were trained and allowed to use the ETCS (Tobii Eyegaze C15 System) twice a week for a duration of 10 weeks. Standardized training modules were developed and offered to all study participants. Study feasibility indicators as well as the Appraisals of Disability: Primary and Secondary Scale, Hospital Anxiety and Depression Scale and the Assistive Technology Device Predisposition Assessment questionnaire scores were taken before and after study enrollment.Results:A total of 31 inpatients with tetraplegia were screened. Although 14 patients (45%) met the study eligibility criteria, 6 patients (19%) consented to be enrolled in the study. Three participants did not complete the planned training schedule because of medical, technical and logistic reasons. Although half of the participants agreed that the ETCS under study was easy to use, no substantial improvements were seen in terms of psychological outcomes, appraisals of disability or independence.Conclusions:The conduct of a controlled trial evaluating the benefits of using ETCSs among newly injured patients with tetraplegia comes with considerable feasibility challenges. Until substantial technical improvements of ETCSs have been implemented, future research should initially focus on those individuals with tetraplegia who are living in the community and who have expressed a need to enhance their computer access and communication skills.Spinal Cord advance online publication, 2 December 2014; doi:10.1038/sc.2014.219. PMID- 25448189 TI - Reliability of surface EMG as an assessment tool for trunk activity and potential to determine neurorecovery in SCI. AB - STUDY DESIGN: Reliability and validity study. OBJECTIVE: This study investigates the responsiveness and reliability of the brain motor control assessment (BMCA) as a standardized neurophysiological assessment tool to: (i) characterize trunk neural activity in neurologically-intact controls; (ii) measure and quantify neurorecovery of trunk after spinal cord injury (SCI). SETTING: Kessler Foundation Research Center, West Orange, NJ. METHODS: A standardized BMCA protocol was performed to measure surface electromyography (sEMG) recordings for seven bilateral trunk muscles on 15 able-bodied controls during six maneuvers (inhalation, exhalation, neck flexion, jendrassik, unilateral grip). Additionally, sEMG recordings were analyzed for one chronic SCI individual before electrical stimulation (ES), after ES of the lower extremities while supine, and after active stand training using body-weight support with bilateral ES. sEMG recordings were collected on bilateral erector spinae, internal and external obliques, upper and middle trapezius, biceps and triceps. For each maneuver a voluntary response index was calculated: incorporating the magnitude of sEMG signal and a similarity index (SI), which quantifies the distribution of activity across all muscles. RESULTS: Among all maneuvers, the SI presented reproducible assessment of trunk-motor function within (ICC: 0.860-0.997) and among (P?0.22) able-bodied individuals. In addition, potential changes were measured in a chronic SCI individual after undergoing two intensive ES protocols. CONCLUSION: The BMCA provides reproducible characterization of trunk activity in able-bodied individuals, lending credence for its use in neurophysiological assessment of motor control. Additionally, the BMCA as an assessment tool to measure neurorecovery in an individual with chronic SCI after intense ES interventions was demonstrated. PMID- 25448191 TI - Myelotomy reduces spinal cord edema and inhibits aquaporin-4 and aquaporin-9 expression in rats with spinal cord injury. AB - OBJECTIVE: Spinal cord edema contributes to the pathophysiological mechanisms underlying spinal cord injury (SCI) and is associated with functional recovery after SCI. Early myelotomy may be a promising surgical intervention for reducing SCI-induced edema. However, it remains unclear whether myelotomy can reduce SCI induced edema. In addition, aquaporin-4 (AQP4) and aquaporin-9 (AQP9) have important roles in the regulation of water homeostasis. Here, we aimed to determine the effects of myelotomy on AQP4 and AQP9 expression and spinal cord edema in a rat model of moderate SCI. METHODS: Rats were randomly assigned to three groups: the sham control group (n=22) receiving laminectomy alone; the contusion group (n=44) receiving laminectomy plus contusion; and the myelotomy group (n=44) receiving laminectomy plus contusion followed by myelotomy at 24 h. Functional recovery was estimated by the open-field and inclined plane tests. Spinal cord edema was determined by measuring the water content. The expression of AQP4 and AQP9 was determined by western blot. RESULTS: Compared with the contusion group, myelotomy significantly improved the Basso, Beattie and Bresnahan scores in the open-field test and resulted in a higher mean angle value in the incline plane test. Myelotomy significantly reduced SCI-induced edema at 4 and 6 days after SCI, which was accompanied by downregulation of AQP4 and AQP9 expression. CONCLUSION: Myelotomy improves locomotor function, reduces edema in rats with SCI and is associated with decreased expression of AQP4 and AQP9. PMID- 25448194 TI - Nikola Tesla, humble genius. PMID- 25448190 TI - Pharmacokinetics of the ghrelin agonist capromorelin in a single ascending dose Phase-I safety trial in spinal cord-injured and able-bodied volunteers. AB - STUDY DESIGN: Single centre, single ascending dose study. OBJECTIVES: To compare the pharmacokinetics and assess the safety of capromorelin, a compound that has potential to treat constipation following spinal cord injury (SCI), in groups of able-bodied and SCI volunteers. SETTING: Local population from Victoria, Australia. METHODS: Following initial screening and baseline blood collections, participants received ascending oral doses (20, 50 and then 100 mg at least 1 week apart) of capromorelin after pre-dose blood collection, followed by blood collections over the following 12 h for pharmacokinetic analysis and 1-week and 4 week follow-up blood collections for safety evaluations. Blood pressure and heart rate were monitored. RESULTS: No serious adverse events were recorded following any dose in either the able-bodied group or the SCI group. There were no abnormal blood pressure or heart rate changes. Minor adverse events resolved quickly without the need for treatment. Pharmacokinetic behaviour was broadly similar between groups, with both exhibiting dose-dependent increases in Cmax and AUC0 infinity. The SCI participants showed greater variance in pharmacokinetic parameters and had a slightly delayed Tmax and half-life. CONCLUSION: Capromorelin at the doses tested was safe and well tolerated in both SCI and able bodied participants and also showed similar pharmacokinetics with dose-dependent increases in concentration and drug exposure. PMID- 25448193 TI - Art of neurosurgery. PMID- 25448195 TI - Byzantium period water architecture and a masterpiece in Istanbul: the big basilica cistern. PMID- 25448196 TI - Neurosurgery apps: novel knowledge boosters. AB - AIM: The utilization of technology for purpose of imparting knowledge, especially in high-end branches like neurosurgery, has gained prominence in the contemporary academic scenario. The technological advancements have brought about outstanding transformation to education and patient care. The connectivity through smartphone applications (apps) has transcended the spatial and temporal limitations, thereby enabling easy access to virtually infinite storehouse of knowledge. Although there are numerous neurosurgery related apps, yet there is still a dearth of quality apps that may serve the purpose. MATERIAL AND METHODS: Relevant apps were searched and evaluated on PlayStore and Apple App store, based on their content, user interface, performance, and utility in routine practice and compared with their cost, size and popularity. They were categorized into apps related to textbooks, scoring systems, patient education, operative procedures, blogs, journals, conferences and promotional. RESULTS: 159 relevant apps were hosted on App stores; 54.7% apps were free of cost. "Neuromind" was the most downloaded app because of its simplicity, free access and applicability. Students and practitioners prefer various apps linked to scoring systems, textbooks and operative illustrations. Apps have helped patients in better understanding of their diseases and management options. CONCLUSION: Development of web-based technologies has divided medical professionals into traditional and modernized learners. Mobile apps permit knowledge to be structured visually to facilitate its easy diffusion in the peer community. A technologically demanding branch like Neurosurgery inevitably needs innovative, cost effective apps with trust worthy content. Relevant apps have a high potential to be used as an excellent resource for effectual neurosurgical education beyond the limitations of time and place. PMID- 25448192 TI - Web-based assessments of physical activity in youth: considerations for design and scale calibration. AB - This paper describes the design and methods involved in calibrating a Web-based self-report instrument to estimate physical activity behavior. The limitations of self-report measures are well known, but calibration methods enable the reported information to be equated to estimates obtained from objective data. This paper summarizes design considerations for effective development and calibration of physical activity self-report measures. Each of the design considerations is put into context and followed by a practical application based on our ongoing calibration research with a promising online self-report tool called the Youth Activity Profile (YAP). We first describe the overall concept of calibration and how this influences the selection of appropriate self-report tools for this population. We point out the advantages and disadvantages of different monitoring devices since the choice of the criterion measure and the strategies used to minimize error in the measure can dramatically improve the quality of the data. We summarize strategies to ensure quality control in data collection and discuss analytical considerations involved in group- vs individual-level inference. For cross-validation procedures, we describe the advantages of equivalence testing procedures that directly test and quantify agreement. Lastly, we introduce the unique challenges encountered when transitioning from paper to a Web-based tool. The Web offers considerable potential for broad adoption but an iterative calibration approach focused on continued refinement is needed to ensure that estimates are generalizable across individuals, regions, seasons and countries. PMID- 25448197 TI - Lipopolysaccharide preconditioning induces neuroprotection against early brain injury after experimental subarachnoid hemorrhage. AB - AIM: Subarachnoid hemorrhage (SAH) is a devastating neurological injury associated with significant morbidity and mortality. We postulated that lipopolysaccharide (LPS) preconditioning induces neuroprotection against early brain injury (EBI) after experimental SAH. MATERIAL AND METHODS: 72 male Sprague Dawley rats (250 to 300 g) were used. SAH was produced by injecting autologous arterial blood into the pre-chiasmatic cistern. Rats were given an intraperitoneal injection of LPS 24 hours prior SAH. Matrix metalloproteinase 9 (MMP-9) protein expression was measured by western blot; apoptosis in the cerebral cortex were studied by terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) and 4'6-diamidino-2 phenylindole dihydrochloride (DAPI) staining at 24 h after SAH. Brain water content was also examined. RESULTS: MMP-9 expression was increased after SAH and decreased by LPS preconditioning at 24 h after SAH. The number of neuronal death in cortex was increased after SAH and decreased by LPS preconditioning. In addition, brain water content was attenuated by LPS preconditioning. CONCLUSION: LPS preconditioning could modulate MMP-9 and therefore induce neuroprotection against EBI after experimental SAH. PMID- 25448198 TI - Altered neurotransmitter levels with post-traumatic stress disorder. AB - AIM: The aim of this study was to observe the changes in the monoamine neurotransmitter levels of patients with post-traumatic stress disorder (PTSD) and explore whether the neurotransmitter level is correlated with the severity of PTSD. MATERIAL AND METHODS: A total of 15 PTSD patients without any physical injuries were enrolled into the study. Another 15 cases of pre-restoration patients were recruited as controls who experienced traumatic events but did not experience PTSD or had a Posttraumatic stress disorder Check List-Civilian version (PCL-C) score lower than 12 points. The levels of plasma monoamine neurotransmitters, including norepinephrine, 5-hydroxytryptamine, and dopamine, were tested using enzyme-linked immunosorbent assays. RESULTS: No significant differences were found between the monoamine neurotransmitter levels of the PTSD and the control groups (p > 0.05). A correlation study confirmed that the monoamine neurotransmitter levels and the PCL-C scores of the PTSD group were not significantly correlated (p > 0.05). CONCLUSION: No neurotransmitter changes are seen in PTSD caused by simple mental trauma, and the PCL-C scores do not associate with PTSD. PMID- 25448199 TI - "Honey" can prevent epidural fibrosis development after laminectomy: an experimental study. AB - AIM: One of the most important causes of failed back surgery is the development of epidural fibrosis. Many methods and substances have been used to prevent the development of epidural fibrosis after laminectomy. In this study, effects of "manuka honey" on epidural fibrosis development after laminectomy was evaluated in rats. MATERIAL AND METHODS: Subjects were divided into two groups:In Group-1 (n=8);only laminectomy was carried out in the L1 level; in group-2 (n=8), laminectomy was carried out in the L1 level and manuka honey was applied to the area. The related vertebral columns were removed en bloc 6 weeks later. Leveled sections with thicknesses of 6 mm were obtained from paraffin blocks. RESULTS: In the grading made based on the fibroblast count and scar tissue degree, it was found that epidural fibrosis developed significantly less in the group-2 as compared to the group-1, and the difference was statistically significant. CONCLUSION: It was shown in our study that manuka honey reduces the degree of epidural fibrosis in rats following laminectomy. We believe that manuka honey, which can be used safely in the clinic for surgical wounds, can be used routinely to prevent development of epidural fibrosis following laminectomy. PMID- 25448200 TI - Management of hydrocephalus after decompressive craniectomy. AB - AIM: We set out to investigate the optimal timing for shunt placement in patients with hydrocephalus after decompressive craniectomy (DC). MATERIAL AND METHODS: We studied 63 consecutive patients that underwent DC because of traumatic brain injury, middle cerebral artery infarct or intracerebral hemorrhage. Hydrocephalus was diagnosed in 23/63 patients. The 23 patients were divided into two groups. The first group (A) consisted of 11 patients in whom a ventriculoperitoneal shunt was placed simultaneously or before cranioplasty. In the second group (B) of 12 patients, we performed cranioplasty and a ventriculostomy with monitoring of intracranial pressure was placed simultaneously. After 3 to 5 days, a ventriculoperitoneal shunt was placed with the most appropriate opening pressure. RESULTS: In group A, nine out of the eleven patients experienced complications, mainly hygromas or hematomas that required reoperation. In group B, none of the patients was reoperated. The use of programmable valves allowed for non-invasive revision of the opening pressure when required. CONCLUSION: Cranioplasty and ventriculostomy followed by a second stage placement of a ventriculoperitoneal shunt are associated with fewer complications in the treatment of hydrocephalus after DC. PMID- 25448201 TI - Surgical strategies for the removal of sphenoorbital meningiomas. AB - AIM: Surgical removal of sphenoorbital meningiomas is challenging for neurosurgeons. The aim of study is to share our experience on sphenoorbital meningiomas and to provide a picture of the current state of the art in surgical treatment of these tumors. MATERIAL AND METHODS: The data of 13 cases of sphenoorbital meningioma who were operated between 2006 and 2013 was reviewed retrospectively. Intraorbital extension was present in 10 cases while sphenoid bone invasion was detected in 9 cases. All patients underwent surgical treatment after the radiological evaluation with magnetic resonance imaging and computed tomography. The degree of resection and the clinical outcome of all patients were analyzed. RESULTS: Extended pterional approach with a large frontotemporal craniotomy was performed in all cases. Simpson's grade I and II excision was achieved in 4 (31%) cases while subtotal excision (Simpson's grade III or higher) was performed in 9 cases. The main reason for subtotal excision was the cavernous sinus invasion. Optic canal decompression was performed in patients with intraorbital invasion. CONCLUSION: Although total removal is the main objective of surgery, the sphenoorbital meningiomas are difficult to resect especially with cavernous sinus invasion. But in the meantime, it is not recommended to take any excessive risks to achieve a greater degree of resection for a benign tumor. Endoscopic approach is an option for inferomedial orbital parts of these tumors. PMID- 25448202 TI - Supraclavicular surgical approach for thoracic outlet syndrome: 10 years of experience. AB - AIM: Symptoms of thoracic outlet syndrome (TOS) may be vascular, neurological or combined symptoms involving both. Treatment of TOS is generally conservative. Surgical treatment is required when radiological results indicate anatomical abnormality. This study aims to present the surgical outcomes of TOS patients treated with supraclavicular approach via microsurgery. MATERIAL AND METHODS: 41 patients with thoracic outlet syndrome were rewieved retrospectively. The pain was determined using both on visual analogue scale (VAS) and Oswestry score both in the preoperative and postoperative period. All patients underwent electromyography including brachial plexus, ulnar and median nerves. Computed Tomography (CT) angiographic examination was applied dynamically with required manoeuvres. RESULTS: Post-op VAS scores were recorded as 0.8 for the arm, 0.6 for the shoulder and 0.5 for the neck, while pre-op VAS scores were 6.3 for the arm, 6.0 for the shoulder and 5.2 for the neck. Post-op Oswestry disability index (ODI) average was found as 14,2, while this figure was 67,4 during the pre operative period. CONCLUSION: Accurate patient selection is imperative for increasing the success of TOS surgery. Microscopic TOS surgery yields satisfactory results with smaller incision, safer surgery and a lower rate of complication. PMID- 25448203 TI - Beneficial effects of moxonidine on cerebral vasospasm after experimental subarachnoid hemorrhage. AB - AIM: This study was designed to examine the efficacy of moxonidine, a centrally acting antihypertensive agent that is a selective ligand for I1-imidazoline sites, in a rabbit cerebral vasospasm model. MATERIAL AND METHODS: Twenty-four white, male New-Zealand rabbits weighing 2500-3200 gr. were randomly allocated into three groups as group 1= control group, group 2=subarachnoid hemorrhage (SAH) alone group, and group 3=SAH + moxonidine (treatment) group. Cerebral angiography was performed to all rabbits before (Day=0, basal angiography) and 72 hours after the induction of SAH. Intraperitoneal moxonidine (0.5 mg/kg) treatment was started after the induction of SAH and continued once a day for 72 hours in the treatment group. RESULTS: No statistically significant difference was determined in basal angiographic luminal diameter of the basilar artery between groups (p > 0.005). After SAH, the follow-up angiographic basilar artery luminal diameter significantly changed in treatment group when compared with the SAH alone group (p < 0.001). The pathologically examined basilar artery luminal area was different between these groups (p < 0.005). CONCLUSION: Moxonidine treatment as a centrally acting antihypertensive agent was found to be very beneficial in the treatment of vasospasm by increasing the angiographic diameter and the pathologic luminal area and reducing muscular wall thickness. PMID- 25448204 TI - Spinal nerve root compositions of musculocutaneous nerve: an anatomical study. AB - AIM: This study was aimed to investigate the variations in the spinal nerve root compositions of musculocutaneous nerve and to confirm which spinal nerve root is the main ingredient in participating amount. MATERIAL AND METHODS: A total of 20 fresh cadavers were dissected. Brachial plexus and its branches were extracted. Musculocutaneous nerve stump was traced back to the roots to identify its fascicular origin. The number of fascicles originating from a particular nerve root and their axial location with in the nerve were noted. RESULTS: The most frequent type of spinal nerve compositions of musculocutaneous nerve was C5, C6, and C7 with incidence of 60%. Musculocutaneous nerve had bundles from C5 root in all specimens, 90% of the specimens had contribution from C6 and only 70% of them had bundles from C7 root. There were a total of 46 (37.7%) bundles in C5 fascicles, 48 (39.3%) bundles in C6 fascicles, and 28 (22.9%) bundles in C7 fascicles. CONCLUSIONS: In electrophysiological studies it should be remembered that C7 or C6 lesions may not impair musculocutaneous nerve functions. The success of musculocutaneous nerve neurotization may be improved if care is taken to ensure whether or not C7 root is contributing to the musculocutaneous nerve. PMID- 25448205 TI - The therapeutic value of proanthocyanidin in experimental cerebral vasospasm following subarachnoid hemorrhage. AB - AIM: We aimed to examine the basilar artery in an experimental subarachnoid hemorrhage (SAH) model both from the ultrastructural and radiological aspects and tried to evaluate the benefit of proanthocyanidin (PC), an antioxidant matter, in reducing vasospasm. MATERIAL AND METHODS: A total of 21 male New Zealand rabbits were divided into three groups after performing angiography. Group I: Control group, Group II: Subarachnoid hemorrhage group, Group III: Subarachnoid hemorrhage and Proanthocyanidin group (100 mg/kg/ day). Rabbits were sacrificed on the 5th day after angiography. A segment of the basilar artery, 4 mm in length, was prepared for ultrastructural examination. RESULTS: There was no ultrastructural or radiological abnormality in the basilar artery in Group 1. In the basilar artery digital subtraction angiography (DSA) of Group 2, a statistically significant decrease in basilar artery calibration was found (p < 0.05). There was no damage in the endothelium, subendothelium, tunica media and adventitia of the basilar artery ultrastructurally but a statistically significant narrowing in lumen diameter was seen. There was also no difference in basilar artery calibration in the DSA of Group 3 (p > 0.05). No damage was seen in the basilar artery ultrastructurally. CONCLUSION: Proanthocyanidin with its strong antioxidant effect and possible vasomotor action can significantly attenuate SAH-induced vasospasm. PMID- 25448206 TI - Single institute experience on 108 consecutive cases of type II odontoid fractures: surgery versus conservative treatment. AB - AIM: The incidence of cervical fractures in industrialized countries is about 11.000 cases per year. The objective of our study was to determine which of two treatments was more effective for the management of Type II odontoid fractures. MATERIAL AND METHODS: This study involved 108 cervical fractures treated at the "Department of Neurosurgery of Policlinico Umberto I" in Rome between 2002 and 2013. Sixty of the 108 axis fractures were treated conservatively with external immobilization, and the remaining 48 were treated surgically. RESULTS: Patients undergoing surgery had a higher rate of fusion (91.67% vs. 46.67%) and shorter bone healing times (17 weeks compared to 21 weeks) than the patients who received conservative treatment. CONCLUSION: All fractures of the odontoid process, without dislocation, should be treated with rigid external immobilization (preferably with a "Halo-vest"). All fractures of the odontoid process with dens dislocation > 5 mm should be considered as candidates for surgery. Type II odontoid fractures in patients over 50 years old should also be candidates for surgical treatment, while the outcome of such fractures, as regards conservative treatment, is better for patients under 50 years old. PMID- 25448207 TI - Neurosurgical treatment of cerebrovascular complications of heart surgeries and interventions. AB - AIM: Intracerebral haematoma and brain ischaemia are rare life-threatening complications of cardiovascular surgery. The aim of this study is to present the experience with the neurosurgical treatment of patients with cerebrovascular complications of heart surgery. MATERIAL AND METHODS: Patients with brain ischaemia or intracerebral haematoma in the acute phase after heart surgery or invasive intervention operated on between 2002 and 2011 were reviewed. There were 3 patients with middle cerebral artery infarction requiring decompressive craniectomy (2 males, 1 female; mean age 54.3 years) and 5 patients with intracerebral haematoma (3 males, 2 females; mean age 55 years). The type of surgery for intracerebral haematoma was selected individually preferring minimally invasive techniques: stereotactic aspiration (2 patients), neuroendoscopy (1 patient), stereotactic craniotomy (1 patient) or classical craniotomy (1 patient). RESULTS: The results of decompressive craniectomy were unsatisfactory: GOS 1, 3 and 4 in 1 patient each. The results of surgery for intracerebral haematoma were GOS 5 in 1 patient, GOS 4 in 2 patients, and lethal in 2 patients. CONCLUSION: Minimally invasive neurosurgery techniques appear to be beneficial for selected patients with intracerebral haematoma after heart surgeries even when considering the limited number of patients. Decompressive craniectomy should be considered strictly individually. PMID- 25448209 TI - Description of the response of a new multi-parametric brain sensor to physiological and pathophysiological challenges in the cortex of juvenile pigs. AB - AIM: Monitoring of intracranial pressure (ICP), local cerebral blood flow (CBF) and oxygen is part of modern intensive critical care medicine. Preclinical evaluation of newly developed catheters that should monitor several parameters simultaneously is reported poorly in the literature. The goal of our study was (1) to evaluate a new multi-parametric sensor in brain tissue and (2) to establish a testing protocol using pathophysiological challenges that target measured parameters of the sensor and autoregulatory boundaries and could be used as preclinical standard protocol in future studies. MATERIAL AND METHODS: We describe data from 12 new multi-parametric brain sensors (MPBS) that were implanted into 3 porcine brains and combined measurement of brain tissue oxygenation (ptiO2), ICP, CBF and brain temperature for the first time. Pigs were treated with a period of hyperoxygenation, hypercapnia, hypoxia, dobutamine, and norepinephrine. RESULTS: None of the 12 MPBS failed. Our testing protocol induced standardized pathophysiological changes that were picked up by the new MPBS as significant alterations in brain ptiO2, ICP and CBF. The magnitude of changes was >20% in most tested MPBS. CONCLUSION: An experimental protocol with pre-defined end-points for O2, CO2, blood pressure and cardiac output should be standardized and reported if new sensors for multi-parametric brain monitoring are evaluated. The use of several sensors per brain of only a few animals is sufficient to determine functionality of new sensors in vivo as basis for a larger study with reference sensors and brain injury. PMID- 25448208 TI - Endoscopic endonasal transsphenoidal treatment for acromegaly: 2010 consensus criteria for remission and predictors of outcomes. AB - AIM: Acromegaly is a chronic disorder characterized by enhanced growth hormone (GH) secretion and elevated insulin-like growth factor-I (IGF-I) levels, usually caused by pituitary adenomas. In this retrospective study, we reviewed our experience with endoscopic endonasal transsphenoidal surgery (EETS) with in remission rates using the 2010 consensus criteria, predictors of remission and associated complications. MATERIAL AND METHODS: The authors retrospectively analyzed data from 56 acromegalic patients who underwent pure EETS. Tumors were classified according to size and suprasellar/parasellar extension. The criteria of remission were GH levels < 1 ng/mL randomly, < 0.4 ng/mL after oral glucose tolerance test and normal IGF-I levels for age and sex within the first 3 and 6 months after surgery. RESULTS: Biochemical remission was achieved in 4 of 5 microadenomas (80%) and in 33 of 51 macroadenomas (64.7%). The total remission rate was 66.1% (37 of 56 adenomas). Age, gender and suprasellar extension did not affect the remission rate. However, cavernous sinus invasion, sphenoid sinus invasion and history of prior surgery were associated with lower rates of disease control. CONCLUSION: EETS represents an effective and safe option for the treatment of patients with acromegaly. High disease control rates and a small number of complications are some of the most important points related to the technique. PMID- 25448210 TI - Biomechanical effect of graded facetectomy on asymmetrical finite element model of the lumbar spin. AB - AIM: Facetectomy is a leading surgical method for stenosis treatment. The objective of this study was to investigate biomechanical effect of graded facetectomy on the lumbar spine using an asymmetrical finite element model. MATERIAL AND METHODS: A validated 3-dimensional asymmetrical finite element model of lumbar L1-L5 was developed based on computerized tomography (CT) scans. All components were assigned material properties mimicking original spinal components. Graded facetectomy was performed by removing facet elements along with surrounding capsular ligaments. RESULTS: All three planes of motion were simulated and resulting range of motion at the index level, L4-L5, was compared with the intact model. Left unilateral facetectomy caused increase in range of motion by 14.6%, 87.4%, 94.5%, 10.5%, 6.3% and 8.8% for flexion, extension, left and right axial rotation, and left and right lateral bending, respectively. Total bilateral facetectomy resulted in an increase in motion by 33.6%, 238.7%, 120.4, 151.3%, 15.6% and 12.4% for flexion, extension, left and right axial rotation, and left and right lateral bending, respectively. CONCLUSION: Extension and axial rotation were found to be affected by the facet removal whereas flexion and lateral bending were mildly affected. PMID- 25448211 TI - Intra-arterial infusion of tirofiban and urokinase for thromboembolic complications during coil embolization of ruptured intracranial aneurysms. AB - AIM: To investigate the effectiveness and safety of intra-arterial tirofiban and urokinase for thromboembolic complications during detachable coil treatment of ruptured intracranial aneurysms. MATERIAL AND METHODS: Fourteen patients who had a thromboembolic complication during detachable coil treatment of ruptured cerebral aneurysms from May 2011 to October 2013 were enrolled in this study. Within one hour of thrombus formation, patients underwent intra-arterial infusion of tirofiban plus urokinase with digital subtraction angiography monitoring. Blood flow was checked every 5 min with angiography until complete or partial recanalization of the occluded artery occurred. RESULTS: Of the 14 patients, 10 exhibited complete recanalization immediately after the thrombolytic treatment, and had no neurological dysfunction except one patient with mild hemiplegia. Two patients with partial recanalization exhibited mild neurological dysfunction and one died of cardiac infarction during the recovery period. Two patients had intracranial hemorrhage. In one of these, this was caused by rupture of the aneurysm and the patient died during the thrombolytic treatment. In the remaining patient, intracranial hemorrhage was caused by a puncture of the left posterior internal frontal artery caused by mechanical thrombolysis. CONCLUSION: Intra arterial administration of tirofiban plus urokinase is an effective and safe treatment for thromboembolism during detachable coil treatment of ruptured intracranial aneurysms. PMID- 25448212 TI - Bilateral ophthalmic segment aneurysm clipping with one craniotomy: operative technique and results. AB - AIM: Surgical indications for ophthalmic segment aneurysms are getting narrower due in part to success of endovascular techniques like flow diverters. Wide necks, large size, intraluminal thrombus, optic nerve compression or recurrence after endovascular therapy make the case for surgical treatment. Bilateral aneurysms are less established but worth considering surgical indication. Our objective is to review a series of bilateral ophthalmic segment aneurysms managed through a single craniotomy, describe the surgical technique and evaluate the results. MATERIAL AND METHODS: Between 1997 and 2012, 11 patients with bilateral ophthalmic segment aneurysms were treated through a single craniotomy at UCSF Medical Center. An intradural clinoidectomy was performed to expose and clip the ipsilateral aneurysm. Medially and superiorly projecting contralateral aneurysm could be clipped through the interoptic triangle without clinoidectomy. Indocyanin green videoangiography was performed routinely. RESULTS: Eleven patients harboring 22 ophthalmic segment aneurysms were treated with a single craniotomy. Complete neck occlusion was achieved in 96 % of aneurysms. One patient presenting with subarachnoid hemorrhage Hunt-Hess grade 5 died from vasospasm complications. The remaining 10 patients had good outcomes (mRS <= 2) after a mean 2.2 years follow up. There were no recurrences after surgical treatment. CONCLUSION: Decompressing the optic nerve, completely occluding the aneurysm neck, providing a durable repair and avoiding antiplatelet agents are the well established advantages of microsurgical management. This experience demonstrates safety and feasibility of contralateral clipping of carefully selected ophthalmic segment aneurysms, thus pointing another advantage of surgical clipping when bilateral aneurysms are diagnosed. PMID- 25448213 TI - A difficult Endoscopic Third Ventriculostomy procedure: perforation of a thick Liliequist membrane with high basilar artery location. AB - Endoscopic Third Ventriculostomy (ETV) is a minimally invasive and safe method used in the treatment of obstructive hydrocephalus. However, arterial bleeding episodes that arise from narrowing of the safe perforation area due to a higher location of the basilar artery (BA) may have tragic consequences. Liliequist membrane (LM) or other membranous structures located in the prepontine cistern also affect the success rates with ETV and complicate the procedure. We present herein a safe and successful perforation of the thick LM after retracting BA in a triventricular hydrocephalus case having a high BA protruding into the third ventricle. ETV is an effective and minimally invasive treatment modality in selected cases. Although some case-specific factors may affect the procedural success and feasibility, favorable and safe outcomes are certainly achievable by overcoming these obstacles with increasing experience. PMID- 25448214 TI - Hemangiopericytoma of the cervicothoracic spine: a case report and literature review. AB - A case of hemangiopericytoma in the cervicothoracic spine is reported. A 43-year old man was admitted to our hospital with pain in the scapular region radiating to the left upper extremity, numbness, and weakness of the legs. Magnetic resonance image revealed an intraspinal, extradural mass at the level of the C6 T2 vertebral bodies. The lesion also involved the dorsal paraspinal area with a giant mass. A total resection of the tumor was performed and histopathological findings revealed a malignant hemangiopericytoma. The patient showed rapid neurological function improvement after surgery. It is well-recognized that hemangiopericytoma is an aggressive tumor with a high risk of recurrence and propensity to metastasize. The tumor is rarely found in the central nervous system, and only a few reports could be found in the literature. We present a case of cericothoracic spinal hemangiopericytoma with an intensive review of the literature. PMID- 25448215 TI - Reversal of paraplegia after anterior decompression in a patient underwent posterior decompression and fusion for thoracic ossification of posterior longitudinal ligament. AB - This report describes a rare clinical entity, thoracic myelopathy due to ossification of the posterior longitudinal ligament (OPLL), and its management. A 40-year-old woman presented with thoracic myelopathy due to OPLL, extending from T2-T9. We performed a posterior laminectomy and instrumented fusion. However, postoperative paraplegia occurred within 36 h post-surgery. Emergent anterior decompression and interbody fusion was performed via the trans-thoracic approach. Neurological deterioration was reversed following this anterior procedure. Posterior decompression and instrumented fusion for thoracic OPLL is less technically demanding and presents a lower risk of neurological complications. However, some controversies remain regarding the prevalence and management of postoperative neurological deterioration associated with this technique. Our patient showed recovery with subsequent anterior decompression when paraplegia occurred after posterior decompression and fusion to treat thoracic OPLL. Additional anterior decompression should be considered when posterior decompression and fusion lead to neurological deterioration. PMID- 25448216 TI - Intraventricular lymphoplasmacyte-rich meningioma: a case report. AB - Lymphoplasmacyte-rich meningioma (LPM) is one of the rarest variants of meningioma and those LPMs that arise in the intraventricular space are even rarer. LPMs are classified as grade I (benign) tumors with a low proliferative rate and diagnosis is made through the histological identification of high numbers of inflammatory cells (lymphocytes and plasma cells) in the resected tumor tissue. In the current case, magnetic resonance imaging of a 37-year-old woman who presented at our neurosurgery department following a generalized tonic clonic seizure revealed a partially mortified intraventricular mass, which had caused pronounced peritumoral edema and had a relatively rough surface. Surgical resection was performed. Histological analysis revealed large numbers of inflammatory cells, confirming the diagnosis of LPM, but also indicated that the lesion was positive for the proliferation marker Ki-67. Follow-up magnetic resonance imaging 3 months after surgery revealed no residual tumor or recurrence. PMID- 25448217 TI - Pituitary atypical adenoma or carcinoma sensitive to temozolomide combined with radiation therapy: a case report of early identification and management. AB - Pituitary carcinoma is extremely rare and difficult to diagnose early. Here we present a case of highly suspected pituitary malignant adenoma with early chemotherapy and radiation. A 30-year-old woman was admitted for headache and impaired vision, MRI found a sellar mass. Since there was no disturbance in serum hormone levels, she was diagnosed with non-functioning pituitary adenoma before surgery. Transsphenoidal removal of tumor was attempted but only partial resection of tumor was achieved. Pathology findings suggested a diagnosis of adenocarcinoma. PET-CT scan showed the tumor had elevated max standardized uptake value. No other abnormal sites were found, which excluded metastasis to pituitary. After surgery, the patient was treated with temozolomide assisted with radiation and tumor disappeared on MRI. No recurrence was observed on 1-year follow up. In conclusion, early temozolomide with radiation therapy for highly suspected pituitary carcinoma might be beneficial. PMID- 25448218 TI - Pituitary stone: a case report and review of the literature. AB - A 39-year-old male without any significant complaints or symptoms presented with a calcified lesion located at the sellar region. Total removal of the lesion has been achieved via an endoscopic endonasal transsphenoidal approach. Histopathological examination of the lesion revealed a pituitary stone. This report describes the first pituitary stone formed within a plurihormonal pituitary adenoma and also differs from previous studies in means of chosen surgical method that is the first endoscopic approach to a pituitary stone. Additionally, by reviewing previous cases, a classification has been proposed and possible pathophysiological mechanisms behind this rare entity have been discussed. PMID- 25448219 TI - An unusual and complex congenital heart disease in a patient with a ruptured cerebral aneurysm. AB - A 38-year-old woman had complex, congenital heart anomalies, including double outlet right ventricle with mitral atresia, severe left ventricle hypoplasia, atrial septal defect, and severe pulmonary stenosis, for which she had not received appropriate treatment. She presented to our institution with an intense sudden-onset headache that had initiated while sleeping. Brain computed tomography indicated the presence of spontaneous subarachnoid hemorrhage. Cerebral angiography revealed a left middle cerebral artery aneurysm. Two days later, she underwent a craniotomy for aneurysm clipping. According to the pathological analysis, culture, and clinical presentation, the aneurysm was not mycotic. The patient regained consciousness after a few days postoperatively. Despite the complex and rare congenital heart disease, it is especially notable that the patient survived 38 years without treatment and later had a ruptured cerebral aneurysm that was successfully managed operatively. Our literature review indicated that some congenital heart diseases such as aortic coarctation may correlate with the presence of intracranial aneurysms. Our case is novel because there are no similar cases of complex congenital heart disease combined with a ruptured intracranial aneurysm successfully resolved operatively. We believe that this case would help clinicians deal with such complicated cases of congenital heart disease combined with intracranial aneurysms. PMID- 25448220 TI - Leptomeningeal dissemination of pilocytic astrocytoma in a 17-year-old boy. AB - Pilocytic astrocytoma with leptomeningeal dissemination is a rare phenomenon and can be associated with obstructive hydrocephalus and an unfavorable prognosis. Herein, we report a seventeen-year-old boy with a history of ventriculo peritoneal shunt insertion due to severe hydrocephalus who presented with progressive headache and vomiting together with ocular and cerebellar signs and symptoms. Neuroimaging confirmed the presence of multiple intracranial masses in the cerebellum and thalamus. Intracranial dissemination of tumor to the the leptomeninges was seen during neuroendoscopy. Simultaneous biopsy and endoscopic third ventriculostomy were performed and the diagnosis of low-grade pilocytic astrocytoma with leptomeningeal dissemination was made by histological examination. The patient underwent chemotherapy in combination with radiotherapy to reduce the risk of reoccurrence of the primary tumor and was followed for one year. PMID- 25448221 TI - Lumbar intraosseous schwannoma: case report and review of the literature. AB - Intraosseous schwannomas of the mobile spine are extremely rare. To our knowledge, only 21 cases have been reported in the literature. In this report, we present a case of schwannoma involving the lumbar spine, with a review of the literature and discussion of this rare tumor. A 44 year old male presented with a 3 year history of intermittent low back pain, with radiation into the right lower extremity during the last 2 years. Radiographs revealed an approximately 4 x 4 cm irregular mass with marginal sclerosis located at the L5 vertebra, involving the right pedicle and extruding into the spinal canal. The tumor was resected completely and was confirmed as schwannoma by histological examination. At follow up after 12 months, the patient was free of pain and with no recurrence. Despite its low incidence, intraosseous schwannomas should be considered as the differential diagnosis of an extradural mass involving the vertebrae. Surgery is the preferred treatment method and usually carries a good prognosis. PMID- 25448222 TI - Intraventricular pleomorphic xanthoastrocytoma: a case report. AB - Pleomorphic xanthoastrocytoma (PXA), an uncommon glial neoplasm, typically affects adolescents and young adults and accounts for less than 1% of all astrocytic neoplasms. The authors present a case of PXA located entirely in the third ventricle in a 24-year-old male patient. The patient presented with a 6 month history of headaches, progressive decline in cognitive function and profound behavioral disturbances. He was admitted to the hospital with signs of increased intracranial pressure. Magnetic resonance imaging showed a well enhanced solid tumor, located entirely inside the third ventricle. The tumor was totally removed via a right fronto-pterional trans-lamina terminalis approach and neuropathology report confirmed PXA diagnosis. No further treatment was indicated. To the best of our knowledge, this is the first case report of a solid PXA confined to the third ventricle. PMID- 25448223 TI - Intracranial dural metastasis presenting as chronic subdural hematoma: a case report and review of literature. AB - Intracranial dural metastasis presenting as chronic subdural hematoma is a relatively rare clinical scenario. There are different theories explaining the formation of subdural hematoma in such cases. In this report we present a case of chronic subdural hematoma in a 44-year old lady who did not have any clinical evidence of primary tumour anywhere in the body. This lady died in spite of two emergency surgeries. During second surgery, the subdural membrane was sent for histopathological examination which revealed presence of metastatic tumour. We discuss the case along with a review of literature and recommend subdural membrane biopsy in all cases of chronic subdural hematoma. PMID- 25448224 TI - Chronic subdural hematoma: drainage versus no drainage. PMID- 25448225 TI - Noninvasive MRI and multilineage differentiation capability of ferritin transduced human mesenchymal stem cells. AB - Molecular imaging can be a breakthrough tool for the investigation of the behavior and ultimate feasibility of transplanted human mesenchymal stem cells (hMSCs) inside the body, and for the development of guidelines and recommendations based on the treatment and evaluation of stem cell therapy for patients. The goals of this study were to evaluate the multilineage differentiation ability of hMSCs expressing an MRI reporter, human ferritin heavy chain (FTH) and to investigate the feasibility of using FTH-based MRI to provide noninvasive imaging of transplanted hMSCs. The transduction of FTH and green fluorescence protein (GFP) did not influence the expression of the mesenchymal stem cell surface markers (CD29+/CD105+/CD34-/CD45-) or the self-renewal marker genes [octamer-binding transcription factor 4 (OCT-4) and SRY (sex determining region Y)-box 2 (Sox-2)], cell viability, migration ability and the release of cytokines [interleukin-5 (IL-5), IL-10, IL-12p70, tumor necrosis factor-alpha (TNF-alpha)]. FTH-hMSCs retained the capacity to differentiate into adipogenic, chondrogenic, osteogenic and neurogenic lineages. The transduction of FTH led to a significant enhancement in cellular iron storage capacity and caused hypointensity and a significant increase in R2 * values of FTH-hMSC-collected phantoms and FTH-hMSC-transplanted sites of the brain, as shown by in vitro and in vivo MRI performed at 9.4 T, compared with control hMSCs. This study revealed no differences in biological characteristics between hMSCs and FTH-hMSCs and, therefore, these cells could be used for noninvasive monitoring with MRI during stem cell therapy for brain injury. Our study suggests the use of FTH for in vivo long-term tracking and ultimate fate of hMSCs without alteration of their characteristics and multidifferentiation potential. PMID- 25448226 TI - Reviewing and reconsidering invasion assays in head and neck cancer. AB - Head and neck squamous cell carcinomas (HNSCC) are malignant tumors that arise from the surface epithelium of the oral cavity, oropharynx and larynx, primarily due to exposure to chemical carcinogens or the human papilloma virus. Due to their location, dental practitioners are well-positioned to detect the lesions. Deadlier than lymphoma or melanoma, HNSCC is incompletely understood. For these reasons, dental practitioners and researchers are focused on understanding HNSCC and the processes driving it. One of these critical processes is invasion, the degradation of the basement membrane by HNSCC cells with subsequent movement into the underlying connective tissue, blood vessels or nerves. Cancer cells metastasize to distant sites via the blood vessels, lymphatics and nerves. Metastasis is associated with poor survival. Since invasion is essential for development and metastasis of HNSCC, it is essential to understand the mechanism(s) driving this process. Elucidation of the mechanisms involved will facilitate the development of targeted treatment, thereby accelerating development of precision/personalized medicine to treat HNSCC. Robust in vitro and in vivo assays are required to investigate the mechanistic basis of invasion. This review will focus on in vitro and in vivo assays used to study invasion in HNSCC, with special emphasis on some of the latest assays to study HNSCC. PMID- 25448227 TI - Patient-reported outcomes following parotid-sparing intensity-modulated radiotherapy for head and neck cancer. How important is dysphagia? AB - OBJECTIVES: Swallowing can be significantly affected during and following radiotherapy for head and neck cancer (HNC). The purpose of this study was to understand: (1) the trajectory of swallowing recovery following parotid-sparing intensity-modulated radiotherapy (IMRT) and (2) overall physical and social emotional wellbeing and how patients prioritise swallowing following treatment. MATERIALS AND METHODS: Sixty-one HNC patients completed questionnaires as part of a prospective study exploring patient-reported swallowing outcomes following parotid-sparing IMRT. Participants were asked to complete the M.D. Anderson Dysphagia Inventory (MDADI) and University of Washington Quality of Life Questionnaire (UW-QoL) v.04 before treatment and 3, 6 and 12months after treatment. Given the rise in human papilloma virus (HPV) and associated oropharyngeal cancers, we completed a sub analysis of the data in those participants. RESULTS: There was a significant reduction in the MDADI composite scores 3months after completion of treatment. Improvements were observed by 12months, however, scores did not recover to baseline. The recovery in physical function was limited in comparison to social-emotional recovery at 12months. When oropharyngeal cancer scores were analysed, there was not a substantial difference to the whole group results. There was a shift in priorities following treatment. Swallowing was highlighted as a concern by 44% of HNC patients up to 12months after treatment with swallowing-related factors (saliva, taste and chewing) rated highly. CONCLUSIONS: Patient reported swallowing outcomes were significantly affected from baseline to all follow-up time points and remained a priority concern at 12months following treatment. Overall social-emotional functioning does improve, suggesting that patients have the potential to adapt to their "new normal" following IMRT for HNC. PMID- 25448228 TI - Novel opportunities for next-generation probiotics targeting metabolic syndrome. AB - Various studies have described the beneficial effects of specific bacteria on the characteristics of metabolic syndrome. Intestinal microbiota might therefore represent a modifiable trait for translational intervention to improve the metabolic profiles of obese and type 2 diabetic patients. However, identifying potential probiotic strains that can effectively colonize the gastrointestinal tract and significantly affect host metabolism has been challenging. This review aims to summarize the notable advances and contributions in the field that may prove useful for identifying next-generation probiotics that target metabolic syndrome and its related disorders. PMID- 25448229 TI - Novel opportunities for the exploitation of host-microbiome interactions in the intestine. AB - New sequencing technologies have dramatically increased our knowledge on the composition of the human intestinal microbiota in health and disease. In parallel, various omics as well as focused molecular studies have revealed novel insights in host-microbiome interactions at the cellular and molecular level. Although these studies are mainly descriptive, advanced microbiota-targeting intervention strategies are being explored, ranging from the selection of novel probiotic strains and synthetic stool substitutes, toward the better monitoring of prebiotic and dietary interventions. It can be envisaged that the efficacy of microbiota interventions will depend on the status of the microbiota of an individual at baseline, but also on genetic and physiological host parameters that determine the capacity to interact with microbes via specific receptors. PMID- 25448230 TI - Gut brain axis: diet microbiota interactions and implications for modulation of anxiety and depression. AB - The human gut microbiome is composed of an enormous number of microorganisms, generally regarded as commensal bacteria. Without this inherent microbial community, we would be unable to digest plant polysaccharides and would have trouble extracting lipids from our diet. Resident gut bacteria are an important contributor to healthy metabolism and there is significant evidence linking gut microbiota and metabolic disorders such as obesity and diabetes. In the past few years, neuroscience research has demonstrated the importance of microbiota in the development of brain systems that are vital to both stress reactivity and stress related behaviours. Here we review recent literature that examines the impact of diet-induced changes in the microbiota on stress-related behaviours including anxiety and depression. PMID- 25448231 TI - Recent developments in prebiotics to selectively impact beneficial microbes and promote intestinal health. AB - Prebiotics are non-digestible food ingredients that have a specific stimulatory effect upon selected populations of gut bacteria. The usual target microorganisms for prebiotic approaches are bifidobacteria. Numerous human feeding studies have shown the prebiotic influences that galactans and fructans can exert. Other candidate prebiotics are under investigation. The field is now moving towards identifying the health aspect associated with their use. Many avenues of gut related health are being researched, including reduction of diarrhoea, immune stimulation, and improved mineral bioavailability. Most current emphasis appears to be towards various parameters associated with metabolic syndrome. These include markers of insulin resistance, appetite, satiety, blood lipids and inflammatory status. PMID- 25448232 TI - Plant genome editing by novel tools: TALEN and other sequence specific nucleases. AB - Genome editing technologies using sequence specific nucleases (SSNs) became a tremendously powerful and precise tool for reverse genetic approaches and applied biology. Transcription activator-like effector nucleases (TALENs) in particular, consisting of a free designable DNA binding domain and a nuclease, have been exploited today by a huge number of approaches in many different organisms. The convenience of designing the DNA binding domain and straightforward protocols for their assembly, as well as the broad number of applications in different scientific fields made it Natures method of the year 2011. TALENs act as molecular scissors by introducing double strand breaks (DSBs) to the DNA at a given location. The DSBs are subsequently repaired by the cell itself using different repair pathways such as non-homologous end joining (NHEJ) or homologous recombination (HR). These mechanisms can lead to deletions, insertions, replacements or larger chromosomal rearrangements. By offering a template DNA it is possible to channel the repair in direction of HR. In this article we review the recent findings in the field of SSN approaches with emphasis on plants. PMID- 25448233 TI - Knowledge-driven approaches for engineering complex metabolic pathways in plants. AB - Plant metabolic pathways are complex and often feature multiple levels of regulation. Until recently, metabolic engineering in plants relied on the laborious testing of ad hoc modifications to achieve desirable changes in the metabolic profile. However, technological advances in data mining, modeling, multigene engineering and genome editing are now taking away much of the guesswork by allowing the impact of modifications to be predicted more accurately. In this review we discuss recent developments in knowledge-based metabolic engineering strategies, that is the gathering and mining of genomic, transcriptomic, proteomic and metabolomic data to generate models of metabolic pathways that help to define and refine optimal intervention strategies. PMID- 25448234 TI - Means to optimize protein expression in transgenic plants. AB - The biotechnological production of proteins is currently achieved via expression systems derived from different lineages. In the past years transgenic plants have proven to be able to compete with bacteria or mammalian cell systems. Gene engineering approaches exist to raise yields by controlling mandatory processes in the course of biopharmaceutical protein production. Here we review and discuss the current status and recent improvements of parameters influencing recombinant protein production in transgenic plants. In particular, this review focuses on the so-called inside (mRNA sequence and structure) and outside factors (host and production system/conditions), which are adjustable and allow to optimize protein production via gene engineering. PMID- 25448235 TI - Regulation of plant root system architecture: implications for crop advancement. AB - Root system architecture (RSA) plays a major role in plant fitness, crop performance, and grain yield yet only recently has this role been appreciated. RSA describes the spatial arrangement of root tissue within the soil and is therefore crucial to nutrient and water uptake. Recent studies have identified many of the genetic and environmental factors influencing root growth that contribute to RSA. Some of the identified genes have the potential to limit crop loss caused by environmental extremes and are currently being used to confer drought tolerance. It is hypothesized that manipulating these and other genes that influence RSA will be pivotal for future crop advancements worldwide. PMID- 25448236 TI - Etiologies of acute undifferentiated fever and clinical prediction of scrub typhus in a non-tropical endemic area. AB - Scrub typhus usually presents as acute undifferentiated fever. This cross sectional study included adult patients presenting with acute undifferentiated fever defined as any febrile illness for <= 14 days without evidence of localized infection. Scrub typhus cases were defined by an antibody titer of a >= fourfold increase in paired sera, a >= 1:160 in a single serum using indirect immunofluorescence assay, or a positive result of the immunochromatographic test. Multiple regression analysis identified predictors associated with scrub typhus to develop a prediction rule. Of 250 cases with known etiology of acute undifferentiated fever, influenza (28.0%), hepatitis A (25.2%), and scrub typhus (16.4%) were major causes. A prediction rule for identifying suspected cases of scrub typhus consisted of age >= 65 years (two points), recent fieldwork/outdoor activities (one point), onset of illness during an outbreak period (two points), myalgia (one point), and eschar (two points). The c statistic was 0.977 (95% confidence interval = 0.960-0.994). At a cutoff value >= 4, the sensitivity and specificity were 92.7% (79.0-98.1%) and 90.9% (86.0-94.3%), respectively. Scrub typhus, the third leading cause of acute undifferentiated fever in our region, can be identified early using the prediction rule. PMID- 25448237 TI - Hepatitis E as a cause of acute jaundice syndrome in northern Uganda, 2010-2012. AB - Hepatitis E virus (HEV) is a common cause of acute viral hepatitis in developing countries; however, its contribution to acute jaundice syndrome is not well described. A large outbreak of hepatitis E occurred in northern Uganda from 2007 to 2009. In response to this outbreak, acute jaundice syndrome surveillance was established in 10 district healthcare facilities to determine the proportion of cases attributable to hepatitis E. Of 347 acute jaundice syndrome cases reported, the majority (42%) had hepatitis E followed by hepatitis B (14%), malaria (10%), hepatitis C (5%), and other/unknown (29%). Of hepatitis E cases, 72% occurred in Kaboong district, and 68% of these cases occurred between May and August of 2011. Residence in Kaabong district was independently associated with hepatitis E (adjusted odds ratio = 13; 95% confidence interval = 7-24). The findings from this surveillance show that an outbreak and sporadic transmission of hepatitis E occur in northern Uganda. PMID- 25448238 TI - Rethinking the discharge policy for Ebola convalescents in an accelerating epidemic. AB - The outbreak of Ebola virus disease (EVD) in West Africa has outstripped available resources. Novel strategies are desperately needed to streamline operations. The present norm of requiring negative results on polymerase chain reaction for EVD convalescent patients to be discharged is not evidence-based and often results in asymptomatic patients competing for beds in dangerously crowded Ebola Treatment Units, posing risks to ward staff and patients and the community if infected persons are turned away. We summarize the relevant data and call for a change in discharge criteria for convalescent patients that can safely help reduce the strain on resources and direct energies where they are most needed. In the longer term, research is needed to assess the true infectivity of EVD convalescent patients to establish evidence-based criteria and guidelines for discharge. PMID- 25448240 TI - [The elaboration of aggressiveness in adolescence: Comparative structural study based on the Rorschach test]. AB - BACKGROUND: In adolescence, a component of a successful identity quest consists in elaborating the aggressiveness, be it endured or acted out, in an imaginary and symbolic manner. We will present a comparative study between anxious and violent adolescents, based on the Rorschach test. As the handling of aggressiveness by means of various defense mechanisms and coping strategies contributes to the construction of a sense of reality and of coherent representations of oneself and the others, the Rorschach test is a pertinent tool to study the vicissitudes of the identity quest of medium adolescence. On the other hand, many studies demonstrate that it is also a precious tool allowing diagnosis of the risks of evolution towards character pathology and personality disorders belonging to cluster B of the DSM, or towards emotional disorders and suicidal tendencies. Thus, it can help initiating appropriate therapeutic measures in a spirit of tertiary prevention. METHODS: We present a comparative study between a sample of 20 adolescents suffering from anxiety and inhibition of aggressiveness (subgroup anxiety) and a second sample of 20 adolescents suffering from exteriorized aggressiveness and violent behavior (subgroup violence). The inclusion into the subgroups was based on clinical interviews and a thorough psychological assessment, using the criteria of categorical psychopathology. The comparative study between the two subgroups is based on an original rating scale constructed in the phenomenological and structural tradition, reflecting the global judgment of the experienced clinical psychologist. It permits using the Rorschach test as a research tool by making the step from qualitative analysis towards quantification and the use of inferential and multidimensional statistics. It also allows computing correlations between the Rorschach test and psychometric scales or other projective tests, using specific rating scales of the same type. RESULTS: After showing the descriptive demographic data, we present the results of the comparative between groups study (computed by means of Mann-Whitney's U test) and those of the multidimensional study (computed by means of the optimal scaling procedure HOMALS). The comparative study indicates that, with adolescents suffering from anxiety and inhibition, the emotional and relational needs are much greater, as is the tendency to direct one's aggressiveness against one self. Mentalization, documented by the richness, the originality, the level of integration and the maturity of associations is better developed in this subgroup. In the subgroup of adolescents characterized by exteriorized aggressiveness and violent behavior, the ambiguity of the stimulus causes perplexity, slowing down executive functions. The latent dimensions, extracted with the help of optimal scaling procedures, are meaningful at the light of current clinical psychology and create a typology of the adjustment to aggressive drives. They tend to illustrate the pertinence of the rating scale as a research tool and contribute in demonstrating its construct validity. DISCUSSION AND CONCLUSION: The data of the comparative and multidimensional study are discussed in relationship with open questions in developmental and clinical psychology of adolescence. They highlight the role of the Rorschach test as a means to differentiate between temporary and long-term difficulties related to aggressiveness, as well as to show similarities and differences at the structural level of personality functioning between subgroups with interiorized and exteriorized aggressiveness. The psychological meaning of the latent dimensions, extracted with the help of optimal scaling techniques, are discussed in light of the recent research literature. Rorschach profiles can help indicate risks of evolution towards personality pathology at adult age. Let us stress that our latent dimensions are not focused on aggressiveness itself but rather on control functions liable to modulate its expression. Using the Rorschach test in pretest and posttest situation and exploring the change occurring during the psychotherapeutic interventions with the help of the rating scale (application of optimal scaling on Delta values) could open interesting tracks for future research in the realm of outcome and process evaluation of psychotherapies. PMID- 25448239 TI - Risk factors for leprosy reactions in three endemic countries. AB - The objective of this study was to ascertain risk factors for complications (reactions or neuritis) in leprosy patients at the time of diagnosis in three leprosy-endemic countries. Newly diagnosed patients were enrolled in Brazil, the Philippines, and Nepal, and risk factors for reactions and neuritis were assessed using a case-control approach: "cases" were patients with these complications, and controls were patients without complications. Of 1,972 patients enrolled in this study, 22% had complications before treatment. Type 1 reaction was diagnosed in 13.7% of patients, neuritis alone in 6.9.%, and type 2 reaction in 1.4%. The frequency of these complications was higher in Nepal, in lepromatous patients, in males, and in adults versus children. Reactions and neuritis were seen in patients at diagnosis, before treatment was started. Reactions were seen in adults and children, even in patients with only a single lesion. Neuritis was often present without other signs of reaction. Reactions and neuritis were more likely to occur in lepromatous patients, and were more likely to be seen in adults than in children. PMID- 25448241 TI - [Addiction and reduction in consummation: From epidemiology to evidence based medicine. In response to F. Limosin article]. PMID- 25448243 TI - Epidural steroids for lumbosacral radicular syndrome compared to usual care: quality of life and cost utility in general practice. AB - OBJECTIVE: To investigate the effect of adding segmental epidural steroid injections (SESIs) to usual care compared with usual care alone on quality of life and cost utility in lumbosacral radicular syndrome (LRS) in general practice. DESIGN: A pragmatic randomized controlled trial. Results were analyzed using mixed models. SETTING: Primary care. PARTICIPANTS: Patients (N=50) in the acute phase of LRS. INTERVENTIONS: One epidural injection containing 80mg of triamcinolone in normal saline. MAIN OUTCOME MEASURE: Back pain at 4 weeks after the start of the treatment. RESULTS: Both groups experienced a significant increase in quality of life in (especially) the physical domains of the Medical Outcomes Study 36-Item Short-Form Health Survey. The intervention group scored significantly better than the control group at certain time points in the physical domain. The differences were small. The cost-utility analysis showed that with a negligible loss of utility (3d in perfect health), societal costs (193,354 euros per quality-adjusted life year lost) would be saved because of more productivity in the intervention group. CONCLUSIONS: Although the beneficial effects of SESIs are small and the natural course of LRS is predominantly favorable, we think decision makers can consider implementing SESIs in daily practice with the purpose of saving resources. Caution must be taken, and further research should be directed at identifying patient subgroups who might benefit from SESIs, with additional focus on (costs of) complications and adverse effects. PMID- 25448245 TI - Effectiveness, usability, and cost-benefit of a virtual reality-based telerehabilitation program for balance recovery after stroke: a randomized controlled trial. AB - OBJECTIVES: First, to evaluate the clinical effectiveness of a virtual reality (VR)-based telerehabilitation program in the balance recovery of individuals with hemiparesis after stroke in comparison with an in-clinic program; second, to compare the subjective experiences; and third, to contrast the costs of both programs. DESIGN: Single-blind, randomized, controlled trial. SETTING: Neurorehabilitation unit. PARTICIPANTS: Chronic outpatients with stroke (N=30) with residual hemiparesis. INTERVENTIONS: Twenty 45-minute training sessions with the telerehabilitation system, conducted 3 times a week, in the clinic or in the home. MAIN OUTCOME MEASURES: First, Berg Balance Scale for balance assessment. The Performance-Oriented Mobility Assessment balance and gait subscales, and the Brunel Balance Assessment were secondary outcome measures. Clinical assessments were conducted at baseline, 8 weeks (posttreatment), and 12 weeks (follow-up). Second, the System Usability Scale and the Intrinsic Motivation Inventory for subjective experiences. Third, cost (in dollars). RESULTS: Significant improvement in both groups (in-clinic group [control] and a home-based telerehabilitation group) from the initial to the final assessment in the Berg Balance Scale (etap(2)=.68; P=.001), in the balance (etap(2)=.24; P=.006) and gait (etap(2)=.57, P=.001) subscales of the Tinetti Performance-Oriented Mobility Assessment, and in the Brunel Balance Assessment (control: chi(2)=15.0; P=.002; experimental: chi(2)=21.9; P=.001). No significant differences were found between the groups in any balance scale or in the feedback questionnaires. With regard to subjective experiences, both groups considered the VR system similarly usable and motivating. The in-clinic intervention resulted in more expenses than did the telerehabilitation intervention ($654.72 per person). CONCLUSIONS: First, VR based telerehabilitation interventions can promote the reacquisition of locomotor skills associated with balance in the same way as do in-clinic interventions, both complemented with a conventional therapy program; second, the usability of and motivation to use the 2 interventions can be similar; and third, telerehabilitation interventions can involve savings that vary depending on each scenario. PMID- 25448242 TI - Toward a translational approach to targeting the endocannabinoid system in posttraumatic stress disorder: a critical review of preclinical research. AB - Despite the lack of clinical research, marijuana and synthetic cannabinoids have been approved to treat posttraumatic stress disorder (PTSD) in several states in the United States. This review critically examines preclinical research on the endocannabinoid system (ECS) in order to evaluate three key questions that are relevant to PTSD: (1) Does ECS dysfunction impact fear extinction? (2) Can stress related symptoms be prevented by ECS modulation? (3) Is the ECS a potential target for enhancing PTSD treatment? Disruption of the ECS impaired fear extinction in rodents, and ECS abnormalities have been observed in PTSD. Targeting fear memories via the ECS had mixed results in rodents, whereas augmented cannabinoid receptor activation typically facilitated extinction. However, the translational value of these findings is limited by the paucity and inconsistency of human research. Further investigation is necessary to determine whether incorporating cannabinoids in treatment would benefit individuals with PTSD, with cautious attention to risks. PMID- 25448246 TI - Smoking and physical activity: examining health behaviors and 15-year mortality among individuals with multiple sclerosis. AB - OBJECTIVES: To examine 2 modifiable health behaviors-smoking and physical activity-and their relationship to mortality among individuals with multiple sclerosis (MS). DESIGN: Secondary analysis of Large Health Survey. SETTING: Data were obtained from a linkage of the Veterans Affairs (VA) MS National Data Repository, containing information on service provision to all individuals with MS receiving health services within the U.S. Department of Veterans Affairs; the VA 1999 Large Health Survey, containing information on smoking and physical activity; and the VA Vital Status File. All-cause mortality was examined for the 15-year period from 1999 through 2013. PARTICIPANTS: Participants (N=2994) with MS who completed the Large Health Survey containing information on smoking and physical activity. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Survival. RESULTS: There were 1500 deaths (50.1%) during the study period. Cox proportional hazard analyses were conducted to examine the association between smoking and physical activity and 15-year mortality. After adjusting for demographic factors, physical functioning, mental health, and comorbid medical conditions, baseline smoking was associated with greater mortality (hazard ratio [HR]=1.38; 95% confidence interval [CI], 1.184-1.60). Higher levels of baseline physical activity were associated with lower mortality (activity 1-2 times/wk: HR=.64; 95% CI, .518-.798; activity >=3 times/wk: HR=.53; 95% CI, .388-.715). CONCLUSIONS: Results suggest that modifiable health behaviors represent a promising opportunity for intervention to improve the lives of individuals with MS. PMID- 25448248 TI - Noninvasive brain stimulation: the potential for use in the rehabilitation of pediatric acquired brain injury. AB - Noninvasive brain stimulation (NIBS) offers the potential to modulate neural activity and recovery after acquired brain injury. There are few studies of NIBS in children, but a survey of those studies might provide insight into the potential for NIBS to modulate motor rehabilitation, seizures, and behavior in children. We surveyed the published literature prior to July 2014 for articles pertaining to children and NIBS with a focus on case series or trials. We also reviewed selected articles involving adults to illustrate specific points where the literature in children is lacking. A limited number of articles suggest that NIBS can transiently improve motor function. The evidence for an effect on seizures is mixed. Two open-label studies reported improvement of mood in adolescents with depression. NIBS may serve as a tool for pediatric neurorehabilitation, but many gaps in our knowledge must be filled before NIBS can be adopted as a clinical intervention. To move forward, the field needs adequately powered trials that can answer these questions. Such trials will be challenging to perform, will likely require multicenter collaboration, and may need to adopt novel trial designs that have been used with rare disorders. PMID- 25448244 TI - Improving motor control in walking: a randomized clinical trial in older adults with subclinical walking difficulty. AB - OBJECTIVE: To test the proposed mechanism of action of a task-specific motor learning intervention by examining its effect on measures of the motor control of gait. DESIGN: Single-blinded randomized clinical trial. SETTING: University research laboratory. PARTICIPANTS: Adults (N=40) aged >=65 years with gait speed >1.0m/s and impaired motor skill (figure-of-8 walk time >8s). INTERVENTIONS: The 2 interventions included a task-oriented motor learning and a standard exercise program; both interventions included strength training. Both lasted 12 weeks, with twice-weekly, 1-hour, physical therapist-supervised sessions. MAIN OUTCOME MEASURES: Two measures of the motor control of gait, gait variability and smoothness of walking, were assessed pre- and postintervention by assessors masked to the treatment arm. RESULTS: Of 40 randomized subjects, 38 completed the trial (mean age +/- SD, 77.1+/-6.0y). The motor learning group improved more than the standard group in double-support time variability (.13m/s vs .05m/s; adjusted difference [AD]=.006, P=.03). Smoothness of walking in the anteroposterior direction improved more in the motor learning than standard group for all conditions (usual: AD=.53, P=.05; narrow: AD=.56, P=.01; dual task: AD=.57, P=.04). Smoothness of walking in the vertical direction also improved more in the motor learning than standard group for the narrow-path (AD=.71, P=.01) and dual task (AD=.89, P=.01) conditions. CONCLUSIONS: Among older adults with subclinical walking difficulty, there is initial evidence that task-oriented motor learning exercise results in gains in the motor control of walking, while standard exercise does not. Task-oriented motor learning exercise is a promising intervention for improving timing and coordination deficits related to mobility difficulties in older adults, and needs to be evaluated in a definitive larger trial. PMID- 25448247 TI - Effects of patient-controlled abdominal compression on standing systolic blood pressure in adults with orthostatic hypotension. AB - OBJECTIVE: To assess the effects of patient-controlled abdominal compression on postural changes in systolic blood pressure (SBP) associated with orthostatic hypotension (OH). Secondary variables included subject assessments of their preferences and the ease-of-use. DESIGN: Randomized crossover trial. SETTING: Clinical research laboratory. PARTICIPANTS: Adults with neurogenic OH (N=13). INTERVENTIONS: Four maneuvers were performed: moving from supine to standing without abdominal compression; moving from supine to standing with either a conventional or an adjustable abdominal binder in place; application of subject determined maximal tolerable abdominal compression while standing; and while still erect, subsequent reduction of abdominal compression to a level the subject believed would be tolerable for a prolonged period. MAIN OUTCOME MEASURES: The primary outcome variable included postural changes in SBP. Secondary outcome variables included subject assessments of their preferences and ease of use. RESULTS: Baseline median SBP in the supine position was not affected by mild (10mmHg) abdominal compression prior to rising (without abdominal compression: 146mmHg; interquartile range, 124-164mmHg; with the conventional binder: 145mmHg; interquartile range, 129-167mmHg; with the adjustable binder: 153mmHg, interquartile range, 129-160mmHg; P=.85). Standing without a binder was associated with an -57mmHg (interquartile range, -40 to -76mmHg) SBP decrease. Levels of compression of 10mmHg applied prior to rising with the conventional and adjustable binders blunted these drops to -50mmHg (interquartile range, -33 to 70mmHg; P=.03) and -46mmHg (interquartile range, -34 to -75mmHg; P=.01), respectively. Increasing compression to subject-selected maximal tolerance while standing did not provide additional benefit and was associated with drops of 53mmHg (interquartile range, -26 to -71mmHg; P=.64) and -59mmHg (interquartile range, -49 to -76mmHg; P=.52) for the conventional and adjustable binders, respectively. Subsequent reduction of compression to more tolerable levels tended to worsen OH with both the conventional (-61mmHg; interquartile range, -33 to 80mmHg; P=.64) and adjustable (-67mmHg; interquartile range, -61 to -84mmHg; P=.79) binders. Subjects reported no differences in preferences between the binders in terms of preference or ease of use. CONCLUSIONS: These results suggest that mild (10mmHg) abdominal compression prior to rising can ameliorate OH, but further compression once standing does not result in additional benefit. PMID- 25448249 TI - Physical activity in primary versus secondary prevention indication implantable cardioverter defibrillator recipients 6-12 months after implantation - a cross sectional study with register follow up. AB - OBJECTIVES: To describe physical activity status among patients with implantable cardioverter defibrillators (ICDs) according to the indication for ICD implant compared with international guidelines and compared with a matched healthy reference population to detect potential for improved physical outcomes; to describe patients' beliefs regarding participation in physical exercise by ICD indication; to describe factors predicting low physical activity; and to describe physical activity as a predictor of mortality. DESIGN: National survey with register follow-up. Comparisons were made to a matched healthy reference population, and patients were followed in registers for 15 months. SETTING: Patients are identified from national registers and questionnaires are distributed by postal mail. PARTICIPANTS: All diagnostic profiles and indications were included as were both single-chamber ICD and biventricular ICD (N=499). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Questions regarding physical activity and the International Physical Activity Questionnaire-Short Form were used to assess physical activity. RESULTS: The response rate was 71.7%. The mean age of participants was 65.5 years, with 82% of participants being men. Of the participants, 37% participated in a rehabilitation program, and 21% were sedentary compared with 8% in the reference population (P<.0001). Only 13% of patients followed physical exercise guidelines. Low physical activity was predicted by primary prevention indication (odds ratio [OR]=2.5; 95% confidence interval [CI], 1.3-4.7) and higher comorbidity (OR=2.1; 95% CI, 1.0-4.1; P<.05). Finally, low physical activity was associated with increased mortality (OR=3.9; 95% CI, 1.11-13.71; P<.05); however, it was not statistically significant when adjusted for age, sex, marital status, and comorbidity. CONCLUSIONS: Guidelines for exercise and participation in rehabilitation are not met for this population, leaving a great potential for future interventions to improve the clinical outcomes, which are modifiable by exercise. PMID- 25448251 TI - Consumption of tyrosine in royal jelly increases brain levels of dopamine and tyramine and promotes transition from normal to reproductive workers in queenless honey bee colonies. AB - Dopamine (DA) and tyramine (TA) have neurohormonal roles in the production of reproductive workers in queenless colonies of honey bees, but the regulation of these biogenic amines in the brain are still largely unclear. Nutrition is an important factor in promoting reproduction and might be involved in the regulation of these biogenic amines in the brain. To test this hypothesis, we examined the effect of oral treatments of tyrosine (Tyr; a common precursor of DA, TA and octopamine, and a component of royal jelly) in queenless workers and quantified the resulting production of biogenic amines. Tyrosine treatments enhanced the levels of DA, TA and their metabolites in the brain. Workers fed royal jelly had significantly larger brain levels of Tyr, DA, TA and the metabolites in the brains compared with those bees fed honey or sucrose (control). Treatment with Tyr also inhibited the behavior of workers outside of the hive and promoted ovarian development. These results suggest that there is a link between nutrition and the regulation of DA and TA in the brain to promote the production of reproductive workers in queenless honey bee colonies. PMID- 25448252 TI - Significant fluctuations in ecdysteroid receptor gene (EcR) expression in relation to seasons of molt and reproduction in the grapsid crab, Metopograpsus messor (Brachyura: Decapoda). AB - Metopograpsus messor, a brachyuran crab inhabiting the estuaries of North Kerala (India), is a prolific breeder releasing approximately 14-16 broods a year. The present paper reports the sequence information on the DNA binding domain (C domain, DBD), linker (D domain) and ligand binding domain (E domain, LBD) of M. messor ecdysteroid receptor (MmEcR) gene, the first grapsid brachyuran crab EcR examined. We have also measured MmEcR transcript levels in the ovary and the hepatopancreas throughout the annual cycle, with special reference to seasons of molt and reproduction. MmEcR expression in both the tissues is found to be at its peak (P<0.05) in late premolt crabs (January/May, molt/reproduction season); the expression levels are lowest (P<0.05) during June/July, when the females would neither molt nor reproduce (season for molt/reproduction repose). Intermediate levels of expression were found during the breeding season (August/December). Interestingly, this pattern of gene expression is in concordance with the fluctuating ecdysteroid levels of the hemolymph and Y organ secretory activity. The significant levels of fluctuation in the ovarian expression of MmEcR strongly suggest the ovary as a potential target for ecdysteroid action. A season-wise comparison of the gene expression reveals that ovarian MmEcR transcript levels are higher in breeding crabs (August/December) than the non-breeding animals (June/July), implicating a possible ecdysteroid role in reproduction in M. messor. PMID- 25448253 TI - Neuropeptide discovery in Eucyclops serrulatus (Crustacea, Copepoda): in silico prediction of the first peptidome for a member of the Cyclopoida. AB - Crustaceans of the subclass Copepoda are key components of essentially all aquatic ecosystems as they serve both as the primary consumers of phytoplankton and/or as major food sources for a wide variety of higher-level consumers. The dominant group of copepods in most freshwater ecosystems is the Cyclopoida; members of this order are routinely used as environmental indicators, and some predatory species are used for the biological control of disease-causing mosquitoes. Given their ecological and disease control importance, it is surprising that little is known about endocrine control in cyclopoids. Here, as part of an ongoing effort to identify and characterize the neurochemical signaling systems of members of the Copepoda, the extant transcriptome shotgun assembly for Eucyclops serrulatus, a member of the Cyclopoida, was mined for transcripts encoding putative peptide hormone-encoding transcripts. Via queries using known arthropod pre/preprohormone sequences, primarily ones from other copepod species, 36 E. serrulatus peptide-encoding transcripts were identified. The proteins deduced from these sequences allowed for the prediction of 160 unique mature neuropeptides, including the first copepod isoform of pigment dispersing hormone, as well as isoforms of adipokinetic hormone-corazonin-like peptide, allatostatin A, allatostatin B, allatostatin C, allatotropin, crustacean hyperglycemic hormone, diuretic hormone 31, DXXRLamide, FLRFamide, FXGGXamide, GSEFLamide, insulin-like peptide, intocin, leucokinin, myosuppressin, neuroparsin, neuropeptide F and tachykinin-related peptide. These peptides are currently the only ones known from any member of the Cyclopoida, and as such, provide a new resource for investigating peptidergic signaling in this important copepod order. PMID- 25448250 TI - Enhanced elimination of dabigatran through extracorporeal methods. AB - Several pharmacokinetic studies have suggested that dabigatran possesses a number of ideal properties for expedited removal via extracorporeal methods. However, this practice has not been prospectively evaluated in patients with life threatening bleeding or requiring emergency surgery secondary to dabigatran associated coagulopathy. The purpose of this literature review is to evaluate the published evidence surrounding extracorporeal removal of dabigatran in the setting of emergency surgery or life-threatening bleeding. A query of MEDLINE, Web of Science, International Pharmaceutical Abstracts, and Google Scholar using the terms dabigatran, dabigatran etexilate, hemodialysis, renal replacement therapy, hemorrhage, and atrial fibrillation was used to retrieve relevant literature. Furthermore, a manual search of the references of the identified literature was performed to capture additional data. Current evidence suggests that extracorporeal removal of dabigatran may play a role in the setting of life threatening bleeding and emergent surgery. Conflicting evidence exists with regard to the potential for redistribution based on serum dabigatran concentrations. In addition, a number of practicalities must be considered before incorporating this technique in the clinical setting. Extracorporeal removal of dabigatran may be a treatment modality in selected patients who require emergency reversal. PMID- 25448254 TI - Plasticizer endocrine disruption: Highlighting developmental and reproductive effects in mammals and non-mammalian aquatic species. AB - Due to their versatility, robustness, and low production costs, plastics are used in a wide variety of applications. Plasticizers are mixed with polymers to increase flexibility of plastics. However, plasticizers are not covalently bound to plastics, and thus leach from products into the environment. Several studies have reported that two common plasticizers, bisphenol A (BPA) and phthalates, induce adverse health effects in vertebrates; however few studies have addressed their toxicity to non-mammalian species. The aim of this review is to compare the effects of plasticizers in animals, with a focus on aquatic species. In summary, we identified three main chains of events that occur in animals exposed to BPA and phthalates. Firstly, plasticizers affect development by altering both the thyroid hormone and growth hormone axes. Secondly, these chemicals interfere with reproduction by decreasing cholesterol transport through the mitochondrial membrane, leading to reduced steroidogenesis. Lastly, exposure to plasticizers leads to the activation of peroxisome proliferator-activated receptors, the increase of fatty acid oxidation, and the reduction in the ability to cope with the augmented oxidative stress leading to reproductive organ malformations, reproductive defects, and decreased fertility. PMID- 25448255 TI - Goldfish neurokinin B: Cloning, tissue distribution, and potential role in regulating reproduction. AB - Neurokinin B (NKB) is a member of the tackykinin (TAC) family known to play a critical role in the neuroendocrine regulation of reproduction in mammals. However, its biological functions in teleosts are less clear. The aim of this study was to determine the role of NKB in fish reproduction using goldfish as a model. Two transcripts, TAC3a and TAC3b, which encode several NKBs, including NKBa-13, NKBa-10, NKBb-13, and NKBb-11, were cloned. Phylogenetic analysis revealed that NKBa-10 and NKBb-11 are closely related to mammalian NKB, while NKB 13s are more conserved in teleosts. Quantitative real-time PCR analyses in various tissues showed that TAC3a and TAC3b mRNAs were mainly expressed in the brain. In situ hybridization further detected TAC3a and TAC3b mRNAs in several regions of the brain known to be involved in the regulation of reproduction and metabolism, as well as in the neurohypophysis of the pituitary. To investigate the potential role of NKBs in reproduction, goldfish were injected intraperitoneally with synthetic NKBa-13, -10, NKBb-13, or -11 peptides and the mRNA levels of hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary gonadotropin subunits were measured. NKBa-13, -10, or NKBb-13, but not -11, significantly increased hypothalamic salmon GnRH and pituitary FSHbeta and LHbeta mRNA levels in both female and male goldfish. Finally, ovariectomy increased, while estradiol replacement reduced, TAC3a mRNA levels without affecting TAC3b expression in the hypothalamus. These data suggest that NKBa-13, -10, and NKBb-13 play a role in mediating the estrogen negative feedback regulation of gonadotropins. PMID- 25448256 TI - Changes in gastric sodium-iodide symporter (NIS) activity are associated with differences in thyroid gland sensitivity to perchlorate during metamorphosis. AB - We investigated stage-dependent changes in sensitivity of the thyroid gland to perchlorate during development of African clawed frog tadpoles (Xenopus laevis) in relation to non-thyroidal iodide transporting tissues. Perchlorate-induced increases in thyroid follicle cell size and colloid depletion were blunted when exposures began at Nieuwkoop-Faber (NF) stage 55 compared to when exposures began at NF stages 49 or 1-10. To determine if the development of other iodide transporting tissues may contribute to this difference we first examined which tissues expressed transcripts for the sodium dependent iodide symporter (NIS). RT PCR analysis revealed that NIS was expressed in stomach and small intestine in addition to the thyroid gland of X. laevis tadpoles. NIS mRNA was not detected in lung, kidney, skin, gill, muscle, heart or liver. Perchlorate sensitive (125)I uptake was found in stomach, lung, kidney, gill, and small intestine but not muscle, liver, or heart. Perchlorate-sensitive (125)I uptake by stomach was 6-10 times greater than in any other non-thyroidal tissue in tadpoles. While NF stage 49 tadpoles exhibited perchlorate-sensitive uptake in stomach it was roughly 4 fold less than that observed in NF stage 55 tadpoles. Although abundance of NIS gene transcripts was greater in stomachs from NF stage 55 compared to NF stage 49 tadpoles this difference was not statistically significant. We conclude that gastric iodide uptake increases between NF stages 49 and 55, possibly due to post translational changes in NIS glycosylation or trafficking within gastric mucosal cells. These developmental changes in gastric NIS gene expression may affect iodide availability to the thyroid gland. PMID- 25448257 TI - Covariation in stress and immune gene expression in a range expanding bird. AB - The enemy release hypothesis (ERH) posits that hosts encounter fewer infectious parasites when they arrive in new areas, so individuals that adjust their immune defenses most effectively should thrive and even expand the range of that species. An important aspect of vertebrate immune defense is inflammation, as it provides rapid defense against diverse parasites. Glucocorticoids (GCs) are integral to the regulation of inflammation, so here we investigated whether and how covariation in the expression of genes affecting the regulation of inflammation and GCs might have impacted the house sparrow (Passer domesticus) invasion of Kenya. Toll-like receptors 2 and 4 (TLRs) detect microbial threats and instigate inflammatory responses, whereas the glucocorticoid receptor (GR) is integral to resolving inflammation via both local and systemic pathways. As with a previous study on circulating leukocytes, we found that splenic TLR-4 and TLR-2 (the latter marginally non-significant) expression was higher in younger than older populations but only when differences in spleen size were considered; birds at the range edge had larger spleens. In regards to covariation, we found that TLR-2, TLR-4 and GR expression were closely inter-related within individuals, but covariation did not differ among populations. Subsequently, our data suggest that house sparrows are using variants of a common stress-immune regulatory mechanism to expand their Kenyan range. PMID- 25448258 TI - Autocrine/paracrine roles of extrapituitary growth hormone and prolactin in health and disease: An overview. AB - Growth hormone (GH) and prolactin (PRL) are both endocrines that are synthesized and released from the pituitary gland into systemic circulation. Both are therefore hormones and both have numerous physiological roles mediated through a myriad of target sites and both have pathophysiological consequences when present in excess or deficiency. GH or PRL gene expression is not, however, confined to the anterior pituitary gland and it occurs widely in many of their central and peripheral sites of action. This may reflect "leaky gene" phenomena and the fact that all cells have the potential to express every gene that is present in their genome. However, the presence of GH or PRL receptors in these extrapituitary sites of GH and PRL production suggests that they are autocrine or paracrine sites of GH and PRL action. These local actions often occur prior to the ontogeny of pituitary somatotrophs and lactotrophs and they may complement or differ from the roles of their pituitary counterparts. Many of these local actions are also of physiological significance, since they are impaired by a blockade of local GH or PRL production or by an antagonism of local GH or PRL action. These local actions may also be of pathophysiological significance, since autocrine or paracrine actions of GH and PRL are thought to be causally involved in a number of disease states, particularly in cancer. Autocrine GH for instance, is thought to be more oncogenic than pituitary GH and selective targeting of the autocrine moiety may provide a therapeutic approach to prevent tumor progression. In summary, GH and PRL are not just endocrine hormones, as they have autocrine and/or paracrine roles in health and disease. PMID- 25448259 TI - Effects of nutritional status on plasma leptin levels and in vitro regulation of adipocyte leptin expression and secretion in rainbow trout. AB - As leptin has a key role on appetite, knowledge about leptin regulation is important in order to understand the control of energy balance. We aimed to explore the modulatory effects of adiposity on plasma leptin levels in vivo and the role of potential regulators on leptin expression and secretion in rainbow trout adipocytes in vitro. Fish were fed a regular diet twice daily ad libitum or a high-energy diet once daily at two ration levels; satiation (SA group) or restricted (RE group) to 25% of satiation, for 8weeks. RE fish had significantly reduced growth (p<0.001) and adipose tissue weight (p<0.001), and higher plasma leptin levels (p=0.022) compared with SA fish. Moreover, plasma leptin levels negatively correlated with mesenteric fat index (p=0.009). Adipocytes isolated from the different fish were treated with insulin, ghrelin, leucine, eicosapentaenoic acid or left untreated (control). In adipocytes from fish fed regular diet, insulin and ghrelin increased leptin secretion dose-dependently (p=0.002; p=0.033, respectively). Leptin secretion in control adipocytes was significantly higher in RE than in SA fish (p=0.022) in agreement with the in vivo findings, indicating that adipose tissue may contribute to the circulating leptin levels. No treatment effects were observed in adipocytes from the high energy diet groups, neither in leptin expression nor secretion, except that leptin secretion was significantly reduced by leucine in RE fish adipocytes (p=0.025). Overall, these data show that the regulation of leptin in rainbow trout adipocytes by hormones and nutrients seems to be on secretion, rather than at the transcriptional level. PMID- 25448261 TI - Systemic and flap inflammatory response associates with thrombosis in flap venous crisis. AB - Venous crisis represents the most common complication in flap surgery and often results in flap failure. The gold standard for free flap monitoring is frequent clinical examination. The current study examined the systemic inflammatory response during the immediate post-operative period following flap venous crisis. Superficial epigastric artery perforator flap transplantation was performed in a total of 30 rabbits. Fifteen animals received venous obstruction by vein ligation (venous crisis group, n = 15) and others were sham treated (control group, n = 15). Venous thrombosis was examined by immunohistochemistry staining. Plasma levels of inflammatory response markers (IL-6, IL-8, TNF-alpha, and C-reactive protein) and thrombosis biomarkers (von Willebrand factor and tissue factor) were measured at 0, 2, and 4 h post-operation by enzyme-linked immunosorbent assay. The mRNA levels of relevant biomarkers in the flap were analyzed with quantitative real-time PCR. Flap histopathological examination showed erythrocyte and neutrophil aggregations in venous lumen and erythrocyte diapedesis. At 8 h post-operation, serious edema and fibrinoid necrosis were observed and the venous lumen was almost blocked by thrombus. The venous crisis group had higher plasma levels of IL-8, TNF-alpha, and thrombosis biomarkers. Vein ligation also increased the mRNA levels of IL-8, TNF-alpha, C-reactive protein, von Willebrand factor, and tissue factor in the flap. No significant change in IL-6 levels was observed between the control group and the venous crisis group. Flap venous crisis was accompanied by the increase in a number of inflammatory and thrombosis markers, both in the peripheral blood and the flaps. PMID- 25448260 TI - Perchlorate disrupts embryonic androgen synthesis and reproductive development in threespine stickleback without changing whole-body levels of thyroid hormone. AB - Perchlorate, an environmental contaminant, disrupts normal functioning of the thyroid. We previously showed that perchlorate disrupts behavior and gonad development, and induces external morphological changes in a vertebrate model organism, the threespine stickleback. Whether perchlorate alters these phenotypes via a thyroid-mediated mechanism, and the extent to which the effects depend on dose, are unknown. To address these questions, we chronically exposed stickleback to control conditions and to three concentrations of perchlorate (10, 30 and 100ppm) at various developmental stages from fertilization to reproductive maturity. Adults chronically exposed to perchlorate had increased numbers of thyroid follicles and decreased numbers of thyrocytes. Surprisingly, T4 and T3 levels in larval, juvenile, and adult whole fish chronically exposed to perchlorate did not differ from controls, except at the lowest perchlorate dose, suggesting a non-monotonic dose response curve. We found no detectable abnormalities in external phenotype at any dose of perchlorate, indicating that the increased number of thyroid follicles compensated for the disruptive effects of these doses. In contrast to external morphology, gonadal development was altered substantially, with the highest dose of perchlorate causing the largest effects. Perchlorate increased the number both of early stage ovarian follicles in females and of advanced spermatogenic stages in males. Perchlorate also disrupted embryonic androgen levels. We conclude that chronic perchlorate exposure may not result in lasting adult gross morphological changes but can produce lasting modifications to gonads when compensation of T3 and T4 levels occurs by thyroid follicle hyperplasia. Perchlorate may therefore affect vertebrate development via both thyroidal and non-thyroidal mechanisms. PMID- 25448262 TI - Upregulation of HO-1 Attenuates LPS-Stimulated Proinflammatory Responses Through Downregulation of p38 Signaling Pathways in Rat Ovary. AB - Heme oxygenase-1 (HO-1) plays a key role in the regulation of the inflammatory response. However, the specific mechanism underlying the anti-inflammatory role of HO-1 in the reproductive system is unclear. The aim of this study was to evaluate the role of the mechanism of HO-1 in the regulation of the inflammatory response stimulated by lipopolysaccharide (LPS) in rat ovary. LPS-stimulated inflammatory models were established. Rats were pretreated with HO-1 activator (hemin) or inhibitor (ZnPP) before LPS stimulation, and we evaluated the expression of HO-1 by real-time PCR and Western blot. The messenger RNA (mRNA) expression and secretion of IL-1beta and IL-6 in rat ovary were analyzed using real-time PCR and ELISA. In addition, we also analyzed the p38 and p-p38 protein expression in the ovary. Our results demonstrate that HO-1 is an anti inflammatory factor in LPS-stimulated ovary, which regulates the inflammatory response through downregulation of p38 signaling pathways in rat ovary. PMID- 25448263 TI - Generation of outbred Ace2 knockout mice by RNA transfection of TALENs displaying colitis reminiscent pathophysiology and inflammation. AB - The angiotensin I converting enzyme 2 (ACE2) is a key factor in the maintenance of intestinal homeostasis. Dysregulation of homeostasis can lead to inflammation of the colon (colitis), which can cause life-threatening enfeeblement or even cancer. Animal models are valuable surrogates in deciphering the pathology behind such human conditions and for screening of putative therapeutic targets or treatment paradigms. However, development of disease models can be time-consuming and technical demanding, which might hamper their application-value. In this study, we genetically disrupted the mouse Ace2 gene by direct injection of in vitro transcribed mRNA coding for transcription activator-like effector nucleases (TALENs) into the cytoplasm of outbred Kunming mouse zygotes. Consequently, somatic mutations were induced with an efficiency of 57%, of which 39% were frameshift mutations. Moreover, all modifications were stably transferred during germline transmission. In Ace2-knockout male mice (Ace2(-/y)), we observed severe chemical induced colitis, characterized by considerable weight loss, diarrhea and a shortened colon length. Histologically, Ace2 mutations resulted in the infiltration of leukocytes and the overt damage of the intestinal mucosal barrier. In addition, we detected an increased expression of inflammatory cytokines in the colon tissue of Ace2(-/y) mice. Collectively, the data indicate that high targeting efficiency and heritability can be achieved in an outbred mouse model by zygote injection of TALEN mRNA. Furthermore, the generated Ace2( /y) mice display phenotypic traits reminiscent of colitis and we anticipate that such mice can be of value in studies of the intestinal microbiome or fecal transplantation. PMID- 25448266 TI - The impact of cue learning, trait anxiety and genetic variation in the serotonin 1A receptor on contextual fear. AB - In everyday life, aversive events are usually associated with certain predictive cues. Normally, the acquisition of these contingencies enables organisms to appropriately respond to threat. Presence of a threat cue clearly signals 'danger', whereas absence of such cues signals a period of 'safety'. Failure to identify threat cues may lead to chronic states of anxious apprehension in the context in which the threat has been imminent, which may be instrumental in the pathogenesis of anxiety disorders. In this study, existing data from 150 healthy volunteers in a cue and context virtual reality fear conditioning paradigm were reanalyzed. The aim was to further characterize the impact of cue acquisition and trait anxiety, and of a single nucleotide polymorphism in the serotonin 1A receptor gene (5-HTR1A, rs6295), on cued fear and contextual anxiety before and after fear contingencies were explicitly introduced. Fear conditioned responding was quantified with fear potentiation of the eyeblink startle reflex and subjective fear ratings. First, we replicated previous findings that the inability to identify danger cues during acquisition leads to heightened anxious apprehension in the threat context. Second, in subjects who did not identify the danger cue initially, contextual fear was associated with trait anxiety after the contingencies were explicitly instructed. Third, genetic variability within 5 HTR1A (rs6295) was associated with contextual fear independent of awareness or trait anxiety. These findings confirm that failure to acquire cue contingencies impacts contextual fear responding, in association with trait anxiety. The observed 5-HTR1A effect is in line with models of anxiety, but needs further replication. PMID- 25448265 TI - Aversive startle potentiation and fear pathology: Mediating role of threat sensitivity and moderating impact of depression. AB - Enhanced startle reactivity during exposure to unpleasant cues (aversive startle potentiation; ASP) appears in the RDoC matrix as a physiological index of acute threat response. Increased ASP has been linked to focal fear disorders and to scale measures of dispositional fearfulness (i.e., threat sensitivity; THT+). However, some studies have reported reduced ASP for fear pathology accompanied by major depressive disorder (MDD) or pervasive distress. The current study evaluated whether (a) THT+ as indexed by reported dispositional fearfulness mediates the relationship between fear disorders (when unaccompanied by depression) and ASP, and (b) depression moderates relations of THT+ and fear disorders with ASP. Fear disorder participants without MDD showed enhanced ASP whereas those with MDD (or other distress conditions) showed evidence of reduced ASP. Continuous THT+ scores also predicted ASP, and this association: (a) was likewise moderated by depression/distress, and (b) accounted for the relationship between ASP and fear pathology without MDD. These findings point to a role for the RDoC construct of acute threat, operationalized dispositionally, in enhanced ASP shown by individuals with fear pathology unaccompanied by distress pathology. PMID- 25448267 TI - Modulation of cortical activity in 2D versus 3D virtual reality environments: an EEG study. AB - There is a growing empirical evidence that virtual reality (VR) is valuable for education, training, entertaining and medical rehabilitation due to its capacity to represent real-life events and situations. However, the neural mechanisms underlying behavioral confounds in VR environments are still poorly understood. In two experiments, we examined the effect of fully immersive 3D stereoscopic presentations and less immersive 2D VR environments on brain functions and behavioral outcomes. In Experiment 1 we examined behavioral and neural underpinnings of spatial navigation tasks using electroencephalography (EEG). In Experiment 2, we examined EEG correlates of postural stability and balance. Our major findings showed that fully immersive 3D VR induced a higher subjective sense of presence along with enhanced success rate of spatial navigation compared to 2D. In Experiment 1 power of frontal midline EEG (FM-theta) was significantly higher during the encoding phase of route presentation in the 3D VR. In Experiment 2, the 3D VR resulted in greater postural instability and modulation of EEG patterns as a function of 3D versus 2D environments. The findings support the inference that the fully immersive 3D enriched-environment requires allocation of more brain and sensory resources for cognitive/motor control during both tasks than 2D presentations. This is further evidence that 3D VR tasks using EEG may be a promising approach for performance enhancement and potential applications in clinical/rehabilitation settings. PMID- 25448264 TI - The use of current source density as electrophysiological correlates in neuropsychiatric disorders: A review of human studies. AB - The use of current source density (CSD), the Laplacian of the scalp surface voltage, to map the electrical activity of the brain is a powerful method in studies of cognitive and affective phenomena. During the last few decades, mapping of CSD has been successfully applied to characterize several neuropsychiatric conditions such as alcoholism, schizophrenia, depression, anxiety disorders, childhood/developmental disorders, and neurological conditions (i.e., epilepsy and brain lesions) using electrophysiological data from resting state and during cognitive performance. The use of CSD and Laplacian measures has proven effective in elucidating topographic and activation differences between groups: i) patients with a specific diagnosis vs. healthy controls, ii) subjects at high risk for a specific diagnosis vs. low risk or normal controls, and iii) patients with specific symptom(s) vs. patients without these symptom(s). The present review outlines and summarizes the studies that have employed CSD measures in investigating several neuropsychiatric conditions. The advantages and potential of CSD-based methods in clinical and research applications along with some of the limitations inherent in the CSD-based methods are discussed in the review, as well as future directions to expand the implementation of CSD to other potential clinical applications. As CSD methods have proved to be more advantageous than using scalp potential data to understand topographic and source activations, its clinical applications offer promising potential, not only for a better understanding of a range of psychiatric conditions, but also for a variety of focal neurological disorders, including epilepsy and other conditions involving brain lesions and surgical interventions. PMID- 25448268 TI - Neurophysiological responses to gun-shooting errors. AB - The present study investigated the neural responses to errors in a shooting game and how these neural responses may relate to behavioral performance - by examining the ERP components related to error detection (error-related negativity; ERN) and error awareness (error-related positivity; Pe). The participants completed a Shooter go/no-go task, which required them to shoot at armed targets using a gaming gun, and avoid shooting innocent non-targets. The amplitude of the ERN and Pe was greater for shooting errors than correct shooting responses. The ERN and Pe amplitudes elicited by incorrect shooting appeared to have good internal reliability. The ERN and Pe amplitudes elicited by shooting behaviors also predicted better behavioral sensitivity towards shoot/don't-shoot stimuli. These results suggest that it is possible to obtain online brain response measures to shooting responses and that neural responses to shooting are predictive of behavioral responses. PMID- 25448269 TI - Alterations in attention capture to auditory emotional stimuli in job burnout: an event-related potential study. AB - Job burnout is a significant cause of work absenteeism. Evidence from behavioral studies and patient reports suggests that job burnout is associated with impairments of attention and decreased working capacity, and it has overlapping elements with depression, anxiety and sleep disturbances. Here, we examined the electrophysiological correlates of automatic sound change detection and involuntary attention allocation in job burnout using scalp recordings of event related potentials (ERP). Volunteers with job burnout symptoms but without severe depression and anxiety disorders and their non-burnout controls were presented with natural speech sound stimuli (standard and nine deviants), as well as three rarely occurring speech sounds with strong emotional prosody. All stimuli elicited mismatch negativity (MMN) responses that were comparable in both groups. The groups differed with respect to the P3a, an ERP component reflecting involuntary shift of attention: job burnout group showed a shorter P3a latency in response to the emotionally negative stimulus, and a longer latency in response to the positive stimulus. Results indicate that in job burnout, automatic speech sound discrimination is intact, but there is an attention capture tendency that is faster for negative, and slower to positive information compared to that of controls. PMID- 25448270 TI - An attentional inhibitory deficit for irrelevant information in obsessive compulsive disorder: evidence from ERPs. AB - Previous studies on attentional bias have demonstrated that patients with obsessive-compulsive disorder (OCD) have an overall longer reaction time (RT) for various stimuli. It was hypothesized that this general slowness may indicate the presence of an attentional inhibition deficit in OCD. To test the hypothesis, event-related potentials (ERPs) were recorded in 31 non-medicated OCD patients and 29 age-, handedness- and sex-matched healthy controls while they performed an emotional Stroop task (EST). Relative to the control subjects, the OCD patients had similar interference effects for negative words, but an overall longer RT and larger P2 and P3 amplitudes to all words. These results support the notion that OCD is characterized by an attentional inhibitory dysfunction for irrelevant information. PMID- 25448271 TI - GBA-associated Parkinson's disease: reduced survival and more rapid progression in a prospective longitudinal study. AB - BACKGROUND: Parkinson's disease (PD) patients with GBA mutations show an earlier age at onset and more severe non-motor symptoms compared with PD patients without GBA mutations. OBJECTIVE: This study was undertaken to evaluate progression of motor and non-motor symptoms in sporadic PD patients depending on the mutational GBA status. METHODS: We used regression analysis to evaluate independent effects of the mutational GBA status, age at onset, age at examination, and disease duration on motor (Unified Parkinson's Disease Rating Scale [UPDRS]-III, Hoehn and Yahr [H&Y] stage, Levodopa [L-dopa]-equivalent-dosage) and non-motor characteristics (cognition and mood). Disease progression was assessed prospectively over 3 years. RESULTS: The GBA-associated PD patients compared with non-mutation PD patients, although younger and with an earlier age at onset, show (1) a more rapid disease progression of motor impairment and cognitive decline and (2) reduced survival rates. CONCLUSIONS: The mutational GBA status, rather than older age and age at onset, presents an important predictor for disease progression in this specific subgroup of PD patients. PMID- 25448272 TI - Abstracts from the 2014 research poster session at the american massage therapy association annual convention. PMID- 25448273 TI - Equipment and analytical companies meeting continuous challenges. May 20-21, 2014 Continuous Manufacturing Symposium. AB - This white paper focuses on equipment, and analytical manufacturers' perspectives, regarding the challenges of continuous pharmaceutical manufacturing across five prompt questions. In addition to valued input from several vendors, commentary was provided from experienced pharmaceutical representatives, who have installed various continuous platforms. Additionally, a small medium enterprise (SME) perspective was obtained through interviews. A range of technical challenges is outlined, including: the presence of particles, equipment scalability, fouling (and cleaning), technology derisking, specific analytical challenges, and the general requirement of improved technical training. Equipment and analytical companies can make a significant contribution to help the introduction of continuous technology. A key point is that many of these challenges exist in batch processing and are not specific to continuous processing. Backward compatibility of software is not a continuous issue per se. In many cases, there is available learning from other industries. Business models and opportunities through outsourced development partners are also highlighted. Agile smaller companies and academic groups have a key role to play in developing skills, working collaboratively in partnerships, and focusing on solving relevant industry challenges. The precompetitive space differs for vendor companies compared with large pharmaceuticals. Currently, there is no strong consensus around a dominant continuous design, partly because of business dynamics and commercial interests. A more structured common approach to process design and hardware and software standardization would be beneficial, with initial practical steps in modeling. Conclusions include a digestible systems approach, accessible and published business cases, and increased user, academic, and supplier collaboration. This mirrors US FDA direction. The concept of silos in pharmaceutical companies is a common theme throughout the white papers. In the equipment domain, this is equally prevalent among a broad range of companies, mainly focusing on discrete areas. As an example, the flow chemistry and secondary drug product communities are almost entirely disconnected. Control and Process Analytical Technologies (PAT) companies are active in both domains. The equipment actors are a very diverse group with a few major Original Equipment Manufacturers (OEM) players and a variety of SME, project providers, integrators, upstream downstream providers, and specialist PAT. In some cases, partnerships or alliances are formed to increase critical mass. This white paper has focused on small molecules; equipment associated with biopharmaceuticals is covered in a separate white paper. More specifics on equipment detail are provided in final dosage form and drug substance white papers. The equipment and analytical development from laboratory to pilot to production is important, with a variety of sensors and complexity reducing with scale. The importance of robust processing rather than overcomplex control strategy mitigation is important. A search of nonacademic literature highlights, with a few notable exceptions, a relative paucity of material. Much focuses on the economics and benefits of continuous, rather than specifics of equipment issues. The disruptive nature of continuous manufacturing represents either an opportunity or a threat for many companies, so the incentive to change equipment varies. Also, for many companies, the pharmaceutical sector is not actually the dominant sector in terms of sales. PMID- 25448274 TI - Preface. Advances in Biological Monitoring for Occupational and Environmental Health--II. PMID- 25448275 TI - In vitro and in vivo toxicological studies of V nerve agents: molecular and stereoselective aspects. AB - In vitro inhibition data of cholinesterases (ChEs) and reactivation with HI 6 are presented for separated VX and VR enantiomers with high purity (enantiomer excess >99.999%). Inhibition rate constants for (-)-VR were fourfold higher than for (-) VX. Marked higher stereoselectivity of ChEs inhibition was observed for VR compared with VX enantiomers. Low/no reactivation was determined for respective (+)-enantiomers. Results were related to orientation of (-)- and (+)-enantiomers in ChEs active sites. In vivo in swine, absorption rate constants were practically identical for VX and VR enantiomers after percutaneous application of 3xLD50 underlining relevance of amine group and postulated equilibria shifts between charged, uncharged, open and cyclic form (skin depot). In vivo toxicokinetics of VX and VR enantiomers differed markedly after 4h. Elimination of VX was much slower compared with VR. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition in vivo differed for VX and VR. In vivo spontaneous reactivation was not observed for VX-inhibited AChE while VR inhibited AChE was much faster spontaneously reactivated than expected and AChE inhibition by VR was slower than expected. Progredient BChE inhibition was detected after VX application while VR inhibited BChE weakly. Possible explanation may be impact of the agents on hemodynamics and different metabolisms. Thus, due to increase of the V agents' blood concentration after atropine administration (depot release) the present standard therapy should be thoroughly reconsidered. PMID- 25448276 TI - Checkpoint kinase 1 is activated and promotes cell survival after exposure to sulphur mustard. AB - Sulphur mustard (SM) is a vesicating agent that has been used several times as a weapon during military conflict and continues to pose a threat as an agent of warfare/terrorism. After exposure, SM exerts both acute and delayed long-term toxic effects principally to the skin, eyes and respiratory system. These effects are thought to be mediated, at least in part, by direct interaction of SM with DNA, forming a myriad of DNA lesions and initiating effects on cell cycle and cell death pathways. Previous studies have demonstrated that a complex network of cellular DNA damage response pathways are utilised in cells exposed to SM, consistent with SM causing multiple forms of DNA damage. The present study focused on the role of Checkpoint kinase 1 (CHK1), a protein with putative roles in homologous recombination repair, p53 activation and the initiation of cell cycle checkpoints after certain forms of DNA damage. The data showed that SM caused robust activation of CHK1, monitored by multi-site phosphorylation analysis and that this activation was dependent on the ataxia telangiectasia and Rad3-related (ATR) protein kinase. Furthermore, specific inhibition of CHK1 increased SM toxicity in multiple human cell lines, with concomitant increases in markers of apoptosis, DNA damage and mitosis. Finally, the effect of CHK1 inhibition on SM toxicity was much more marked in cells with non-functional p53. PMID- 25448277 TI - Glucocorticoid-like activity of propylparaben, butylparaben, diethylhexyl phthalate and tetramethrin mixtures studied in the MDA-kb2 cell line. AB - Endocrine-disrupting compounds can interfere with the endocrine organs or hormone system and cause tumors, birth defects and developmental disorders in humans. The estrogen-like activity of compounds has been widely studied but little is known concerning their possible modulation of the glucocorticoid receptor. Steroidal (synthetic and natural) and non-steroidal endocrine-active compounds commonly occur as complex mixtures in human environments. Identification of such molecular species, which are responsible for modulating the glucocorticoid receptor are necessary to fully assess their risk. We have used the MDA-kb2 cell line, which expresses endogenous glucocorticoid receptor and a stably transfected luciferase reporter gene construct, to quantify the glucocorticoid-like activity of four compounds present in products in everyday use - propylparaben (PP), butylparaben (BP), diethylhexyl phthalate (DEHP) and tetramethrin (TM). We tested all possible combinations of these compounds at two concentrations (1 MUM and 10 nM) and compared their glucocorticoid-like activity. At the concentration of 1 MUM seven mixtures were identified to have glucocorticoid-like activity except: DEHP+TM, BP+TM, DEHP+PP+TM, BP+PP+TM. At the concentration of 10 nM only three mixtures have glucocorticoid modulatory activity: DEHP+PP, BP+PP, DEHP+BP+PP+TM. Identified glucocorticoid-like activities were between 1.25 and 1.51 fold at the concentration of 1 MUM and between 1.23 and 1.44 fold at the concentration of 10 nM in comparison with the solvent control. Individually BP, PP, and DEHP had glucocorticoid-like activity of 1.60, 1.57 and 1.50 fold over the solvent control at the concentration of 1 MUM. On the other hand PP and DEHP, at the concentration of 10nM, showed no glucocorticoid-like activity, while BP showed 1.44 fold. The assertion that individual glucocorticoid-like compounds do not produce harm because they are present at low, ineffective levels in humans may be irrelevant when we include mixed exposures. This study emphasizes that risk assessment of compounds should take mixture effects into account. PMID- 25448278 TI - Pifithrin-alpha has a p53-independent cytoprotective effect on docosahexaenoic acid-induced cytotoxicity in human hepatocellular carcinoma HepG2 cells. AB - Pifithrin-alpha (PFT) is an inhibitor of p53 and is known to protect against a variety of p53-mediated genotoxic agents. In this report, we examined the inhibitory effects of PFT against docosahexaenoic acid (DHA)-induced cytotoxicity in the human hepatocellular carcinoma (HCC) cell line HepG2. PFT significantly abrogated DHA-induced cytotoxicity in wild-type HepG2 cells (normal expression of p53) and after p53-knockdown by siRNA, as well as in Hep3B (p53 null) and Huh7 (p53 mutant) cells. DHA-induced cytotoxicity is mediated by induction of oxidative stress, and PFT inhibited this event, but it does not exert antioxidant effects. PFT significantly suppressed the release of cytochrome c from mitochondria to cytosol, as well as changes in the mitochondrial membrane potential (DeltaPsiM) by DHA. Therefore, protection of mitochondria by PFT is crucial for its inhibition of DHA-induced cytotoxicity. Although it has been reported that PFT is able to block p53 function, our data suggest that PFT also has a p53-independent inhibition mechanism. This work provided insights into the mechanisms of PFT action on DHA-induced cytotoxicity in HCC. PMID- 25448279 TI - In vitro selective inhibition of human UDP-glucuronosyltransferase (UGT) 1A4 by finasteride, and prediction of in vivo drug-drug interactions. AB - In the present study, we evaluated the inhibitory potentials of finasteride for the major human hepatic UDP-glucuronosyltransferases (UGTs) (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15) in vitro using LC-MS/MS by specific marker reactions in human liver microsomes (except for UGT2B15) or recombinant supersomes (UGT2B15). Of the seven tested UGTs, finasteride potently, selectively, and competitively inhibited UGT1A4-mediated trifluoperazine-N glucuronidation in human liver microsomes with an IC50 value of 11.5 +/- 1.78 MUM and Ki value of 6.03 +/- 0.291 MUM. This inhibitory potency was similar to that of hecogenin, a well-known inhibitor of UGT1A4. However, finasteride did not seem to inhibit any of the other six UGTs: UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B7, or UGT2B15. Similarly, finasteride markedly inhibited UGT1A4 activity in recombinant human UGT1A4 supersomes, with a Ki value of 6.05 +/- 0.410 MUM. In addition, finasteride strongly inhibited UGT1A4-catalyzed imipramine-N-beta-D glucuronidation. However, on the basis of an in vitro-in vivo extrapolation, our data strongly suggested that finasteride is unlikely to cause clinically significant drug-drug interactions mediated via inhibition of the hepatic UGT enzymes involved in drug metabolism in vivo. PMID- 25448280 TI - Metallothionein deletion exacerbates intermittent hypoxia-induced renal injury in mice. AB - As a main clinical feature of obstructive sleep apnea (OSA), intermittent hypoxia (IH) induces oxidative stress, leading to damage to a variety of organs, including kidney. Metallothionein (MT) is a potent antioxidant that protects kidney against oxidative damage. Our previous studies demonstrated that MT prevented IH-induced cardiomyopathy in mice. However, the role of MT in protecting against IH-induced renal injury is unknown. Therefore, MT knockout (MT KO) mice and wild type (WT) control mice (129S) were culled for exposure to intermittent air as control or IH for a time course of 3 days, 1 week, 3 weeks and 8 weeks. MT KO mice developed higher urinary albumin to creatinine ratio (UACR) after exposure to IH for 8 weeks. Compared with either MT KO control or WT IH mice, MT deletion significantly aggravated IH-induced renal oxidative damage and inflammation at all four time points, along with significant acceleration of renal fibrosis after exposure to IH for 3 weeks and 8 weeks. Antioxidants including MT, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase 1 (HO1) and NAD (P) H dehydrogenase [quinone] 1 (NQO1) were increased in response to short-term IH (3 days, 1 week and 3 weeks) but decreased after long-term IH (8 weeks) in WT mice. Interestingly, Nrf2, HO1 and NQO1 were significantly attenuated under IH conditions in the absence of MT, which were in parallel with the inactivation of protein kinase B (Akt) and extracellular signal-regulated kinase (ERK). These findings demonstrated that MT played a key role in preventing IH-induced renal injury possibly via preserving Nrf2 signaling pathway. PMID- 25448282 TI - Methionine and cystine double deprivation stress suppresses glioma proliferation via inducing ROS/autophagy. AB - Cancer cells are highly dependent on methionine and cystine (Met-Cys) for survival and proliferation. However, the molecular mechanism is not fully clear. The present study is to investigate the effects of Met-Cys deprivation on glioma cells proliferation. The results showed that Met-Cys double deprivation had synergistic action on elevating ROS level, decreased GSH level and inhibition of glioma cell proliferation. Moreover, both of them deprivation triggered autophagy of glioma cells both in vitro and in vivo. Importantly, Met-Cys double restriction diet inhibited growth of glioma. These results provided a new regulation mechanism of Met-Cys metabolism on affecting glioma cell proliferation, suggesting that targeting Met-Cys metabolism may be a potential strategy for glioma therapy. PMID- 25448281 TI - A transcriptomics-based hepatotoxicity comparison between the zebrafish embryo and established human and rodent in vitro and in vivo models using cyclosporine A, amiodarone and acetaminophen. AB - The zebrafish embryo (ZFE) is a promising alternative, non-rodent model in toxicology, which has an advantage over the traditionally used models as it contains complete biological complexity and provides a medium to high-throughput setting. Here, we assess how the ZFE compares to the traditionally used models for liver toxicity testing, i.e., in vivo mouse and rat liver, in vitro mouse and rat hepatocytes, and primary human hepatocytes. For this comparison, we analyzed gene expression changes induced by three model compounds for cholestasis, steatosis, and necrosis. The three compounds, cyclosporine A, amiodarone, and acetaminophen, were chosen because of their relevance to human toxicity and these compounds displayed hepatotoxic-specific changes in the mouse in vivo data. Compound induced expression changes in the ZFE model shared similarity with both in vivo and in vitro. Comparison on single gene level revealed the presence of model specific changes and no clear concordance across models. However, concordance was identified on the pathway level. Specifically, the pathway "regulation of metabolism - bile acids regulation of glucose and lipid metabolism via FXR" was affected across all models and compounds. In conclusion, our study with three hepatotoxic model compounds shows that the ZFE model is at least as comparable to traditional models in identifying hepatotoxic activity and has the potential for use as a pre-screen to determine the hepatotoxic potential of compounds. PMID- 25448283 TI - Activation of the anticancer drugs cyclophosphamide and ifosfamide by cytochrome P450 BM3 mutants. AB - Cyclophosphamide (CPA) and ifosfamide (IFA) are widely used anticancer agents that require metabolic activation by cytochrome P450 (CYP) enzymes. While 4 hydroxylation yields DNA-alkylating and cytotoxic metabolites, N dechloroethylation results in the generation of neuro- and nephrotoxic byproducts. Gene-directed enzyme prodrug therapies (GDEPT) have been suggested to facilitate local CPA and IFA bioactivation by expressing CYP enzymes within the tumor cells, thereby increasing efficacy. We screened bacterial CYP BM3 mutants, previously engineered to metabolize drug-like compounds, for their ability to catalyze 4-hydroxylation of CPA and IFA. Two CYP BM3 mutants showed very rapid initial bioactivation of CPA and IFA, followed by a slower phase of product formation. N-dechloroethylation by these mutants was very low (IFA) to undetectable (CPA). Using purified CYP BM3 as an extracellular bioactivation tool, cytotoxicity of CPA and IFA metabolism was confirmed in U2OS cells. This novel application of CYP BM3 possibly provides a clean and catalytically efficient alternative to liver microsomes or S9 for the study of CYP-mediated drug toxicity. To our knowledge, the observed rate of CPA and IFA 4-hydroxylation by these CYP BM3 mutants is the fastest reported to date, and might be of potential interest for CPA and IFA GDEPT. PMID- 25448284 TI - In vitro metabolism of 2-ethylhexyldiphenyl phosphate (EHDPHP) by human liver microsomes. AB - 2-ethylhexyl diphenyl phosphate (EHDPHP) is used as flame retardant and plasticizer additive in a variety of consumer products. Since EHDPHP is toxic to aquatic organisms and has been detected in environmental samples, concerns about human exposure and toxicity are emerging. With the aim of identifying human specific metabolites, the biotransformation of EHDPHP was investigated using human liver microsomes. Using an in silico program (Meteor) for the prediction of metabolites, untargeted screening tools (agilent Mass Hunter) and a suitable analysis platform based on ultra-high performance liquid chromatography (UPLC) and quadrupole time-of-flight high resolution mass spectrometer (QTOF-MS), for the first time a wide variety of phases-I and II metabolites of EHDPHP were identified. Mono- and di-hydroxylated metabolites, keto metabolites, mixed keto and hydroxylated metabolites and diphenyl phosphate were the major phase-I metabolites of EHDPHP. Glucuronidated metabolites of phase-I metabolites of EHDPHP were also formed by human liver microsomes. Using these results, we propose a general metabolism pathway for EHDPHP in humans and a number of candidate biomarkers for assessing the human exposure to this ubiquitous phosphate flame retardant and plasticizer in future biomonitoring studies. Furthermore, we provide a template analytical approach based on the combination of untargeted and targeted screening and UPLC-QTOF-MS analysis suitable for use in future metabolism studies. PMID- 25448286 TI - iTRAQ-based proteomic analysis of combination therapy with taurine, epigallocatechin gallate, and genistein on carbon tetrachloride-induced liver fibrosis in rats. AB - Combination therapy with taurine, epigallocatechin gallate, and genistein was effective in alleviating the progression of liver fibrosis in our previous study. To better understand the anti-fibrotic mechanisms of combination therapy, an iTRAQ-based proteomics approach was used to study the expression profiles of proteins in carbon tetrachloride-induced liver fibrosis rats following combination therapy. The anti-fibrotic effects of combination therapy were assessed directly by liver histology, and indirectly by measurement of serum biochemical markers and antioxidant enzymes. The results showed that combination therapy could significantly improve the liver function, as indicated by decreasing levels of alanine aminotransferase (ALT), aspartate transaminase (AST), transforming growth factor-beta1 (TGF-beta1), and collagen I, increasing levels of total antioxidative capacity (T-AOC), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), and reducing the pathological tissue damage. A total of 89 differential expressed proteins in response to combination therapy were identified by iTRAQ, which were interacted with each other and involved in different biological processes and pathways. Four differentially expressed proteins (Tpi1, Txn1, Fgb, and F7) involved in antioxidant defense system, glycolysis pathway and coagulation cascade pathway were validated by enzyme linked immunosorbent assay. Our work provided valuable insights into the molecular mechanism of combination therapy against liver fibrosis, and the identified targets may be useful for treatment of liver fibrosis in future. PMID- 25448285 TI - Combined effects of current-smoking and the aldehyde dehydrogenase 2*2 allele on the risk of myocardial infarction in Japanese patients. AB - Aldehyde dehydrogenase 2 (ALDH2) detoxifies toxic aldehydes, e.g. acetaldehyde in cigarette smoke; however, the interactive effects between smoking status and the ALDH2 genotype on coronary artery disease (CAD) have not been reported. We investigated the effects of smoking status and the ALDH2 genotype, and assessed their interactive and combined effects on the risk of myocardial infarction (MI) or stable angina (SA), including 221 MI and 175 SA subjects and 473 age- and sex matched controls without CAD. Current-smoking and the ALDH2*2 allele additively increased the risk of MI (adjusted odds ratio 4.54, 95% confidence interval 2.25 9.15), although this combination was not associated with the risk of SA. This combination also increased the peak creatine kinase (CK) level synergistically in the acute MI (AMI) subjects. Moreover, current-smoking was found to be a significant risk factor for an increased peak CK level in the ALDH2*2 allele carriers (B 2220.2IU/L, p=0.008), but not the non-carriers. Additionally, a synergistic effect of this combination on the triglycerides levels was also found in the AMI subjects. These preliminary findings suggest that the combination of current-smoking and the inactive ALDH2*2 allele may increase the risk of MI additively and the infarct size synergistically. PMID- 25448289 TI - QuantiFERON-TB Gold In-Tube test performance in Denmark. AB - BACKGROUND: Little is known about the QuantiFERON-TB Gold In-Tube Test (QFT) in extreme age groups. The test performance has been reported to be impaired in children and elderly, but reports are diverging. The aim of this study was to evaluate QFT performance in patients with and without Tuberculosis (TB). METHODS: A retrospective study analysing the results of 18,850 QFT performed in Denmark 2005-2010. The effect of age, sex, localisation of TB, and result of culture on QFT performance (positive, negative and indeterminate results) was determined. RESULTS: Among 383 patients with TB, indeterminate rate was low (3.9%, 15/383). Sensitivity was high (86.1%, 317/368) and not affected by sex or localization of TB disease, but declined with increasing age (p < 0.0001). In children 1-4 years old, sensitivity was high (100%, 9/9). Among 15,709 persons without TB, the indeterminate rate was 5.1% (804/15,709) and significantly higher in infants <1 year (15.6%, 5/32) and elderly >65 years (8.1%, 219/2715) compared to the adult population 15-64 years (4.5%, 552/12,317). Indeterminate results were due to a low positive control in 99.6% (801/804). CONCLUSION: In Denmark, a TB low incidence country, the overall QFT performance was good. The sensitivity in children (>= 1) was high although few children were included, whereas sensitivity declined with increasing age. Indeterminate rates were higher in infants and elderly. In contrast to current guidelines, our data suggest that the QFT performs well in children >= 1 years in low endemic regions but that the test should be used with care among the elderly. PMID- 25448287 TI - 17-beta estradiol attenuates ovariectomy-induced changes in cardiomyocyte contractile function via activation of AMP-activated protein kinase. AB - Menopause increases the risk of cardiometabolic diseases in women. This circumstance is usually attributed to a deficiency in circulating estrogen levels although the underlying mechanism remains elusive. Given the pivotal role of AMP activated protein kinase (AMPK) in the regulation of energy metabolism and cardiac function, this study was designed to examine the role of AMPK in estrogen deficiency and replacement-exerted cardiomyocyte responses. Adult female WT and AMPK kinase dead (KD) mice were subjected to bilateral ovariectomy (OVX) or sham operation. A cohort of ovariectomized mice received 17beta-estradiol (E2) (40MUg/kg/day, i.p.) for 6 weeks. Mechanical and intracellular Ca(2+) properties were evaluated including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90), and maximal velocity of shortening/relengthening (+/ dL/dt). Levels of AMPK, Akt JNK, ACC, SERCA, membrane Glut4, AS160 and PGC-1alpha were assessed using Western blot. OVX significantly decreased PS, +/-dL/dt and intracellular Ca(2+) rise in responsible to electric stimulus, prolonged TR90 and intracellular Ca(2+) decay without affecting TPS and resting intracellular Ca(2+), the effects of which were reconciled by E2 replacement. Western blot analysis depicted that OVX suppressed phosphorylation of Akt AMPK and ACC although it promoted JNK phosphorylation, the effects of which were mitigated or significantly attenuated by E2 treatment in WT but not KD mice. Moreover, OVX procedure downregulated SERCA2a and membrane Glut4 while inhibiting AS160 phosphorylation without affecting PGC-1alpha levels. In vitro study revealed that E2 corrected cardiomyocyte contractile dysfunction elicited by OVX in cardiomyocytes from WT but not the AMPK kinase dead mice. Taken together, these data suggest that E2 treatment ameliorates estrogen deficiency-induced changes in cardiac contractile function possibly through an AMPK-dependent mechanism. PMID- 25448291 TI - Free-living amoebae: ecology, phylogeny, pathogenicity, susceptibility and interactions with other cells. PMID- 25448288 TI - Exposure to swainsonine impairs adult neurogenesis and spatial learning and memory. AB - Swainsonine (SW) is an indolizidine triol plant alkaloid isolated from the species Astragalus, colloquially termed locoweed. Ingestion induces severe neurological symptoms of livestock and wildlife, including ataxia, trembling, exaggerated fright reactions. Toxicity to the central and peripheral nervous system is caused by inhibition of lysosomal a-mannosidase (AMA) and accumulation of intracellular oligosaccharide. However, the effects of SW on adult neurogenesis and cognition have remained unclear. Therefore, the present study was conducted to examine the effects of SW on adult neurogenesis and learning as well as memory performance in adult mice. SW (10MUg/mL in drinking water) was administered orally to mice for 4 weeks. Our results showed that SW reduced proliferation and survival of neural progenitor cells (NPCs) in culture, and in the hippocampus of adult mice. In addition, exposure to SW led to down-regulation of doublecortin (DCX) and synaptophysin (SYP) in the hippocampus. However, caspase 3 and glial fibrillary acidic protein (GFAP) levels were significantly increased in SW-treated mice. Finally, SW-treated mice exhibited deficits in hippocampus-dependent spatial learning and memory. Our findings suggest that SW affects adult neurogenesis and cognitive function. PMID- 25448290 TI - Chemical composition and acaricidal activity of the essential oil of Baccharis dracunculifolia De Candole (1836) and its constituents nerolidol and limonene on larvae and engorged females of Rhipicephalus microplus (Acari: Ixodidae). AB - Baccharis dracunculifolia DC (common name "alecrim-do-campo" in Brazil) is a plant with widespread distribution in South America that is the botanical origin of green propolis. The aim of this study was to evaluate the chemical composition and acaricidal activity of the essential oil of B. dracunculifolia and its constituents nerolidol and limonene on unengorged larvae and engorged females of Rhipicephalus microplus (Acari: Ixodidae). The essential oil yield was 0.8% of dry mass and the major constituents were nerolidol (22.3%), germacrene D (7.2%), limonene (6.9%), beta-pinene (6.7) and bicyclogermacrene (6.5%). The acaricidal activity of the essential oil and the pure compounds nerolidol and (R)-(+) limonene were assessed in the laboratory through the modified larval packet test (LPT) and the female immersion test (FIT). In the LPT, the essential oil and nerolidol were both active, causing more than 90% mortality at concentrations from 15.0 and 10.0 mg mL(-1), respectively, whereas (R)-(+)-limonene was not active. In the FIT, the oil and nerolidol caused reduction in the quantity and quality of eggs produced, with control percentages of 96.3% and 90.3% at concentrations of 60.0 and 50.0 mg mL(-1), respectively. It can be concluded that the essential oil obtained from the aerial parts of B. dracunculifolia and its major component nerolidol have high activity on R. microplus larvae and engorged females. PMID- 25448292 TI - Question answering for biology. AB - Biologists often pose queries to search engines and biological databases to obtain answers related to ongoing experiments. This is known to be a time consuming, and sometimes frustrating, task in which more than one query is posed and many databases are consulted to come to possible answers for a single fact. Question answering comes as an alternative to this process by allowing queries to be posed as questions, by integrating various resources of different nature and by returning an exact answer to the user. We have surveyed the current solutions on question answering for Biology, present an overview on the methods which are usually employed and give insights on how to boost performance of systems in this domain. PMID- 25448293 TI - The Hitchhiker's guide to Hi-C analysis: practical guidelines. AB - Over the last decade, development and application of a set of molecular genomic approaches based on the chromosome conformation capture method (3C), combined with increasingly powerful imaging approaches, have enabled high resolution and genome-wide analysis of the spatial organization of chromosomes. The aim of this paper is to provide guidelines for analyzing and interpreting data obtained with genome-wide 3C methods such as Hi-C and 3C-seq that rely on deep sequencing to detect and quantify pairwise chromatin interactions. PMID- 25448294 TI - Combining MeDIP-seq and MRE-seq to investigate genome-wide CpG methylation. AB - DNA CpG methylation is a widespread epigenetic mark in high eukaryotes including mammals. DNA methylation plays key roles in diverse biological processes such as X chromosome inactivation, transposable element repression, genomic imprinting, and control of gene expression. Recent advancements in sequencing-based DNA methylation profiling methods provide an unprecedented opportunity to measure DNA methylation in a genome-wide fashion, making it possible to comprehensively investigate the role of DNA methylation. Several methods have been developed, such as Whole Genome Bisulfite Sequencing (WGBS), Reduced Representation Bisulfite Sequencing (RRBS), and enrichment-based methods including Methylation Dependent ImmunoPrecipitation followed by sequencing (MeDIP-seq), methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq), methyltransferase-directed Transfer of Activated Groups followed by sequencing (mTAG), and Methylation-sensitive Restriction Enzyme digestion followed by sequencing (MRE-seq). These methods differ by their genomic CpG coverage, resolution, quantitative accuracy, cost, and software for analyzing the data. Among these, WGBS is considered the gold standard. However, it is still a cost prohibitive technology for a typical laboratory due to the required sequencing depth. We found that by integrating two enrichment-based methods that are complementary in nature (i.e., MeDIP-seq and MRE-seq), we can significantly increase the efficiency of whole DNA methylome profiling. By using two recently developed computational algorithms (i.e., M&M and methylCRF), the combination of MeDIP-seq and MRE-seq produces genome-wide CpG methylation measurement at high coverage and high resolution, and robust predictions of differentially methylated regions. Thus, the combination of the two enrichment-based methods provides a cost-effective alternative to WGBS. In this article we describe both the experimental protocols for performing MeDIP-seq and MRE-seq, and the computational protocols for running M&M and methylCRF. PMID- 25448296 TI - Calorespirometry of terrestrial organisms and ecosystems. AB - Calorespirometry is the simultaneous measurement of heat and gas exchange from biological systems. Such measurements can be used to assess fundamental properties of many different types of systems from small ecosystems to isolated tissues. Techniques for calorespirometric measurements on terrestrial (non aquatic) samples are described. Methods and models for evaluation of carbon conversion efficiencies, growth rates, and responses to environmental variables from calorespirometric measurements are described. A realistic model of the system under study is essential in the evaluation. Calorespirometry allows testing of models for tissues, individual organisms, and ecosystems. PMID- 25448295 TI - Building the Connectivity Map of epigenetics: chromatin profiling by quantitative targeted mass spectrometry. AB - Epigenetic control of genome function is an important regulatory mechanism in diverse processes such as lineage commitment and environmental sensing, and in disease etiologies ranging from neuropsychiatric disorders to cancer. Here we report a robust, high-throughput targeted, quantitative mass spectrometry (MS) method to rapidly profile modifications of the core histones of chromatin that compose the epigenetic landscape, enabling comparisons among cells with differing genetic backgrounds, genomic perturbations, and drug treatments. PMID- 25448298 TI - Protein-protein interaction predictions using text mining methods. AB - It is beyond any doubt that proteins and their interactions play an essential role in most complex biological processes. The understanding of their function individually, but also in the form of protein complexes is of a great importance. Nowadays, despite the plethora of various high-throughput experimental approaches for detecting protein-protein interactions, many computational methods aiming to predict new interactions have appeared and gained interest. In this review, we focus on text-mining based computational methodologies, aiming to extract information for proteins and their interactions from public repositories such as literature and various biological databases. We discuss their strengths, their weaknesses and how they complement existing experimental techniques by simultaneously commenting on the biological databases which hold such information and the benchmark datasets that can be used for evaluating new tools. PMID- 25448297 TI - Clinical application of plasma thermograms. Utility, practical approaches and considerations. AB - Differential scanning calorimetry (DSC) studies of blood plasma are part of an emerging area of the clinical application of DSC to biofluid analysis. DSC analysis of plasma from healthy individuals and patients with various diseases has revealed changes in the thermal profiles of the major plasma proteins associated with the clinical status of the patient. The sensitivity of DSC to the concentration of proteins, their interactions with other proteins or ligands, or their covalent modification underlies the potential utility of DSC analysis. A growing body of literature has demonstrated the versatility and performance of clinical DSC analysis across a range of biofluids and in a number of disease settings. The principles, practice and challenges of DSC analysis of plasma are described in this article. PMID- 25448299 TI - Text as data: using text-based features for proteins representation and for computational prediction of their characteristics. AB - The current era of large-scale biology is characterized by a fast-paced growth in the number of sequenced genomes and, consequently, by a multitude of identified proteins whose function has yet to be determined. Simultaneously, any known or postulated information concerning genes and proteins is part of the ever-growing published scientific literature, which is expanding at a rate of over a million new publications per year. Computational tools that attempt to automatically predict and annotate protein characteristics, such as function and localization patterns, are being developed along with systems that aim to support the process via text mining. Most work on protein characterization focuses on features derived directly from protein sequence data. Protein-related work that does aim to utilize the literature typically concentrates on extracting specific facts (e.g., protein interactions) from text. In the past few years we have taken a different route, treating the literature as a source of text-based features, which can be employed just as sequence-based protein-features were used in earlier work, for predicting protein subcellular location and possibly also function. We discuss here in detail the overall approach, along with results from work we have done in this area demonstrating the value of this method and its potential use. PMID- 25448300 TI - Modelling multi-protein complexes using PELDOR distance measurements for rigid body minimisation experiments using XPLOR-NIH. AB - Crystallographic and NMR approaches have provided a wealth of structural information about protein domains. However, often these domains are found as components of larger multi domain polypeptides or complexes. Orienting domains within such contexts can provide powerful new insight into their function. The combination of site specific spin labelling and Pulsed Electron Double Resonance (PELDOR) provide a means of obtaining structural measurements that can be used to generate models describing how such domains are oriented. Here we describe a pipeline for modelling the location of thio-reactive nitroxyl spin locations to engineered sties on the histone chaperone Vps75. We then use a combination of experimentally determined measurements and symmetry constraints to model the orientation in which homodimers of Vps75 associate to form homotetramers using the XPLOR-NIH platform. This provides a working example of how PELDOR measurements can be used to generate a structural model. PMID- 25448301 TI - Analysis of chromatin binding dynamics using the crosslinking kinetics (CLK) method. AB - Transcription factor binding sites in chromatin are routinely inventoried by the chromatin immunoprecipitation assay, and these binding patterns can provide precise and detailed information about cell state. However, some fundamental molecular questions regarding transcription factor function require an understanding of in vivo binding dynamics as well as location information. Here we describe the crosslinking kinetics (CLK) assay, in which the time-dependence of formaldehyde crosslinking is used to extract on- and off-rates for chromatin binding in vivo. PMID- 25448303 TI - Biofilms, medical devices, and antibiofilm technology: key messages from a recent public workshop. PMID- 25448304 TI - Health care workers' knowledge and practices regarding the prevention of central venous catheter-related infection. AB - BACKGROUND: Central venous catheter-related infection (CVC-RI) is considered a common cause of increased morbidity, mortality, and medical care costs in intensive care units (ICUs). The objective in this descriptive study was to assess the knowledge of health care workers in ICUs about guidelines for the prevention of CVC-RI and their adherence to these guidelines in practices. METHODS: Health care workers were assessed for their actual practices during central venous catheter (CVC) insertion and care. Then a questionnaire was distributed to the health care workers to assess their knowledge regarding the prevention of CVC-RI. RESULTS: All the health care workers (N = 100; 40 physicians, 60 nurses) in the ICUs (levels I and III and triage) of Alexandria Main University Hospital participated in the present study. The response rate was 100%. The total percentage of correct answers of the health care workers about the guidelines for the prevention of CVC-RI was low. There was no significant difference between physicians' and nurses' knowledge regarding the total score on the questionnaire (P = .134). However, physicians had a significantly higher knowledge about the pathophysiology of CVC-RI and skin antisepsis items than nurses. There were no significant differences between the knowledge of physicians and nurses in other items except for CVC care, where nurses showed significantly higher knowledge than physicians (P = .001). CONCLUSION: The results of the present study revealed health care worker's low knowledge regarding the prevention of CVC-RI and low compliance with the standard guidelines of CVC care. Therefore, health care workers should be periodically evaluated for their knowledge and practices regarding guidelines for the prevention of CVC-RI. PMID- 25448302 TI - Spatial mapping of structural and connectional imaging data for the developing human brain with diffusion tensor imaging. AB - During human brain development from fetal stage to adulthood, the white matter (WM) tracts undergo dramatic changes. Diffusion tensor imaging (DTI), a widely used magnetic resonance imaging (MRI) modality, offers insight into the dynamic changes of WM fibers as these fibers can be noninvasively traced and three dimensionally (3D) reconstructed with DTI tractography. The DTI and conventional T1 weighted MRI images also provide sufficient cortical anatomical details for mapping the cortical regions of interests (ROIs). In this paper, we described basic concepts and methods of DTI techniques that can be used to trace major WM tracts noninvasively from fetal brain of 14 postconceptional weeks (pcw) to adult brain. We applied these techniques to acquire DTI data and trace, reconstruct and visualize major WM tracts during development. After categorizing major WM fiber bundles into five unique functional tract groups, namely limbic, brain stem, projection, commissural and association tracts, we revealed formation and maturation of these 3D reconstructed WM tracts of the developing human brain. The structural and connectional imaging data offered by DTI provides the anatomical backbone of transcriptional atlas of the developing human brain. PMID- 25448305 TI - Factors affecting changes in compliance with infection control practices by dentists in Japan. AB - We surveyed compliance with infection control practices (ICPs) and factors associated with ICPs reported by dentists in Japan in 2008 and 2011. ICPs improved during this period as did the proportion of dentists specializing in oral surgery, the proportion of dentists reporting a willingness to treat HIV and AIDS patients, and the proportion of dentists reporting knowledge about universal and standard precautions. Stronger associations between ICPs and these 3 factors were found in 2011 than in 2008. PMID- 25448306 TI - The kallikrein system in retinal damage/protection. AB - Kallikrein is a serine protease involved in the kallikrein-kinnin system. Kallikrein is derived from the blood plasma or tissue, and is correlated with aggravation and improvement in eye diseases, such as, glaucoma, diabetic retinopathy, age-related macular degeneration, and ocular ischemic syndrome. The plasma kallikrein stimulates retinal vascular permeability and intraocular hemorrhage. On the other hand, we had reported that the tissue kallikrein normalizes retinal vasopermeability and inhibited retinal neovascularization and retinal ischemic injury. The protective mechanisms of the tissue-derived kallikrein include the cleavage of vascular endothelial growth factor (VEGF), which suggests that the tissue kallikrein could be potentially-effective against any disease involving the VEGF production. PMID- 25448307 TI - Gemigliptin, a novel dipeptidyl peptidase-4 inhibitor, exhibits potent anti glycation properties in vitro and in vivo. AB - This study evaluated the inhibitory effects of gemigliptin, a highly selective dipeptidyl peptidase-4 inhibitor, on the formation of advanced glycation end products (AGEs) and AGE cross-links with proteins in in vitro as well as in type 2 diabetic db/db mice. In in vitro assay, gemigliptin dose-dependently inhibited methylglyoxal-modified AGE-bovine serum albumin (BSA) formation (IC50=11.69 mM). AGE-collagen cross-linking assays showed that gemigliptin had a potent inhibitory effect (IC50=1.39 mM) on AGE-BSA cross-links to rat tail tendon collagen, and its activity was stronger than aminoguanidine (IC50=26.4 mM). In addition, gemigliptin directly trapped methylglyoxal in a concentration-dependent manner in vitro. To determine whether gemigliptin inhibits the in vivo glycation processes, gemigliptin (100 mg/kg/day) was orally administered into type 2 diabetic db/db mice for 12 weeks. Elevated serum levels of AGEs in db/db mice were suppressed by the administration of gemigliptin. These inhibitory effects of gemigliptin on the glycation process in both in vitro and in vivo suggest its therapeutic potential for ameliorating AGE-related diabetic complications. PMID- 25448308 TI - Berberine alters epigenetic modifications, disrupts microtubule network, and modulates HPV-18 E6-E7 oncoproteins by targeting p53 in cervical cancer cell HeLa: a mechanistic study including molecular docking. AB - Increased evidence of chemo-resistance, toxicity and carcinogenicity necessitates search for alternative approaches for determining next generation cancer therapeutics and targets. We therefore tested the efficacy of plant alkaloid berberine on human papilloma virus (HPV) -18 positive cervical cancer cell HeLa systematically-involving certain cellular, viral and epigenetic factors. We observed disruptions of microtubule network and changes in membrane topology due to berberine influx through confocal and atomic force microscopies (AFM). We examined nuclear uptake, internucleosomal DNA damages, mitochondrial membrane potential (MMP) alterations and cell migration assays to validate possible mode of cell death events. Analytical data on interactions of berberine with pBR322 through fourier transform infrared (FTIR) and gel migration assay strengthen berberine's biologically significant DNA binding abilities. We measured cellular uptake, DNA ploidy and DNA strand-breaks through fluorescence activated cell sorting (FACS). To elucidate epigenetic modifications, in support of DNA binding associated processes, if any, we conducted methylation-specific restriction enzyme (RE) assay, methylation specific-PCR (MSP) and expression studies of histone proteins. We also analyzed differential interactions and localization of cellular tumor suppressor p53 and viral oncoproteins HPV-18 E6-E7 through siRNA approach. We further made in-silico approaches to determine possible binding sites of berberine on histone proteins. Overall results indicated cellular uptake of berberine through cell membrane depolarization causing disruption of microtubule networks and its biological DNA binding abilities that probably contributed to epigenetic modifications. Results of modulation in p53 and viral oncoproteins HPV-18 E6-E7 by berberine further proved its potential as a promising chemotherapeutic agent in cervical cancer. PMID- 25448309 TI - Midregional proadrenomedullin for prognosis in community-acquired pneumonia: a systematic review. AB - INTRODUCTION: The initial prognostic assessment of patients with community acquired pneumonia( CAP) has important clinical implications. We hypothesized that midregional proadrenomedullin(MR-proADM) is a valuable test for the prediction of outcomes in patients with CAP.Methods: We performed a systemic review of the literature and a meta-analysis to evaluate the prognostic value of MR-proADM for short and long-term mortality in patients with CAP.Results: Twelve studies were included in the systematic review. Elevated MR-proADM was associated with an increase in short-term mortality (OR Z 6.8; 95% CI: 4.65-10.13; P value < 0.001) and complications (OR = 5.0; 95% CI: 3.86-6.49; P value < 0.001). The pooled analysis of 4 studies showed an improvement in the discriminant ability by 8% (95% CI: 2%e14%)when MR-proADM was added to CURB-65/CRB-65. Studies that reported long-term prognosis indicated an increased risk of death in patients with elevated MR-proADM.Conclusion: Elevated level of MR-proADM is significantly associated with both short-term mortality and complications in patients with CAP. Studies also indicate that MR-proADM has prognostic value for prediction of long term mortality in these patients. The addition of MR-proADM improves the discriminant ability of CURB-65/CRB-65. PMID- 25448310 TI - Serum and bal beta-D-glucan for the diagnosis of Pneumocystis pneumonia in HIV positive patients. AB - BACKGROUND/PURPOSE: The diagnosis of patients with pulmonary infiltrates and human immunodeficiency virus (HIV) infection remains a challenge. In current clinical practice the gold standard for Pneumocystis jirovecii pneumonia (PCP) diagnosis remains the identification of the organism in bronco alveolar lavage (BAL) using microscopy (e.g., silver stain). (1->3)-beta -d-glucan (BG) is a polysaccharide that is present within the cell wall of Pneumocystis and other fungi. METHODS: We analyzed serum and BAL lavage fluid from a cohort of 119 patients that did have HIV, a diagnosis of pneumonia and underwent bronchoscopy (FOB) for diagnosis of PCP. RESULTS: The discriminative power of serum BG for the diagnosis of PCP in this group of patients was very high. Using a cutoff of 300 pg/mL, the sensitivity, specificity, positive predictive value(PPV) and negative predictive value (NPV) were 91%, 92%, 89% and 93% respectively. A model for ROC with just serum BG (N = 108) had an AUC of 0.95. Serum procalcitonin (PCT) and BAL BG were not as accurate for the diagnosis of PCP. For BAL BG using a cutoff of 783 pg/mL, the sensitivity,specificity, positive predictive value (PPV) and negative predictive value (NPV) were 72%, 79%,72% and 79% respectively. The differences between the medians for serum PCT between the group with a without PCP did not reach statistical significance (p = 0.6137). CONCLUSION: The measurement of serum BG should be incorporated in the diagnostic work up of HIV positive patients with dyspnea and infiltrates on chest X X-ray. Our study confirms the diagnostic value of serum BG previously reported by others but we add a cutoff value that we believe is more accurate for patients with AIDS and suspicion of PCP. PMID- 25448311 TI - Association of lung function with coronary heart disease and cardiovascular disease outcomes in elderly: the Rancho Bernardo study. AB - INTRODUCTION: Lung function is inversely associated with coronary heart disease (CHD) and cardiovascular disease (CVD). We evaluated the prospective association of reduced lung function by spirometry and CHD or CVD events in older community dwelling adults. METHODS: We studied 1548 participants (mean age 73.6 +/- 9.2 years, 42% males) from the Rancho Bernardo Study using age, sex, and risk-factor adjusted Cox regression to assess pulmonary function (FEV1, FVC, and FEV1/FVC ratio) as a predictor of CHD and CVD events followed for up to 22 years. RESULTS: Of CVD risk factors, older age, male sex, current/past smoking, physical exercise (<3* a week), and prevalent CVD predicted an increased risk of CHD and CVD. Higher FEV1 and FVC were each associated with a decreased risk of CHD [HR 0.80 (0.73-0.88) for both FEV1 and FVC, per SD, p < 0.01] and CVD [HR 0.82 (0.74-0.91) for both FEV1 and FVC, per SD, p < 0.01]. Those in the lowest quartiles of FEV1 and FVC had hazard ratios of 1.68 (1.33-2.13) and 1.55 (1.21-2.00) respectively for CHD and 1.74 (1.34-2.25) and 1.49 (1.13-1.96) respectively for CVD (all p < 0.01, relative to those in the highest quartile). Similar findings were observed for CHD and CVD mortality. Sex- and age-stratified analyses showed the strongest associations for CHD and CVD events in women and in the oldest participants. CONCLUSIONS: FEV1 and FVC are inversely associated with risk of future CHD and CVD events in older community-dwelling adults and may add to CVD risk stratification in the elderly. PMID- 25448312 TI - "Should I prioritize medical problem solving or attentive listening?": the dilemmas and challenges that medical students experience when learning to conduct consultations. AB - OBJECTIVE: Communication skills can be trained alongside clinical reasoning, history taking or clinical examination skills. This is advocated as a solution to the low transfer of communication skills. Still, students have to integrate the knowledge/skills acquired during different curriculum parts in patient consultations at some point. How do medical students experience these integrated consultations within a simulated environment and in real practice when dealing with responsibility? METHODS: Six focus groups were conducted with (pre )/clerkship students. RESULTS: Students were motivated to practice integrated consultations with simulated patients and felt like 'real physicians'. However, their focus on medical problem solving drew attention away from improving their communication skills. Responsibility for real patients triggered students' identity development. This identity formation guided the development of an own consultation style, a process that was hampered by conflicting demands of role models. CONCLUSION: Practicing complete consultations results in the dilemma of prioritizing medical problem solving above attention for patient communication. Integrated consultation training advances this dilemma to the pre-clerkship period. During clerkships this dilemma is heightened because real patients trigger empathy and responsibility, which invites students to define their role as doctor. PRACTICE IMPLICATIONS: When training integrated consultations, educators should pay attention to students' learning priorities and support the development of students' professional identity. PMID- 25448314 TI - JSGE Clinical Practice Guidelines 2014: standards, methods, and process of developing the guidelines. PMID- 25448313 TI - Patient-centered priorities for improving medication management and adherence. AB - OBJECTIVE: The Centers for Education and Research on Therapeutics convened a workshop to examine the scientific evidence on medication adherence interventions from the patient-centered perspective and to explore the potential of patient centered medication management to improve chronic disease treatment. METHODS: Patients, providers, researchers, and other stakeholders (N = 28) identified and prioritized ideas for future research and practice. We analyzed stakeholder voting on priorities and reviewed themes in workshop discussions. RESULTS: Ten priority areas emerged. Three areas were highly rated by all stakeholder groups: creating tools and systems to facilitate and evaluate patient-centered medication management plans; developing training on patient-centered prescribing for providers; and increasing patients' knowledge about medication management. However, priorities differed across stakeholder groups. Notably, patients prioritized using peer support to improve medication management while researchers did not. CONCLUSION: Engaging multiple stakeholders in setting a patient-centered research agenda and broadening the scope of adherence interventions to include other aspects of medication management resulted in priorities outside the traditional scope of adherence research. PRACTICE IMPLICATIONS: Workshop participants recognized the potential benefits of patient-centered medication management but also identified many challenges to implementation that require additional research and innovation. PMID- 25448315 TI - Transparent conductive electrodes from graphene/PEDOT:PSS hybrid inks for ultrathin organic photodetectors. AB - A novel solution fabrication of large-area, highly conductive graphene films by spray-coating of a hybrid ink of exfoliated graphene (EG)/poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) (PH1000) is demonstrated. The fabricated graphene films exhibit excellent mechanical properties, thus enabling their application as bottom electrodes in ultrathin organic photodetector devices with performance comparable to that of the state-of the-art Si-based inorganic photodetectors. PMID- 25448316 TI - What is biased efficacy? Defining the relationship between intrinsic efficacy and free energy coupling. AB - A G protein-coupled receptor (GPCR) is only biologically active when associated with a transduction protein, but it can also switch function by interacting with different types of transduction proteins. Biased agonism arises when the ligand induces the receptor to engage distinct transduction proteins with different efficacies. We briefly review the concept of ligand efficacy, from the classical empirical idea to the current mechanistic views of allosteric regulation in proteins. A combination of these theoretically distinct ideas and methodologies allows us to distinguish true ligand bias from divergences of signalling caused by the system. We also demonstrate a rigorous mathematical connection between the intrinsic efficacy of classical receptor theory and the energetic effect that makes a ligand capable of stabilizing receptor-transducer association in the ternary complex model. This relationship unifies different definitions of efficacy and provides a rational basis for quantifying biased agonism. PMID- 25448317 TI - Paradoxical sleep: A vigilance state to gate long-term brain plasticity? AB - Memory consolidation is the process for long-term storage of information and protection against interferences. It has been proposed that long-term potentiation (LTP), the long-lasting enhancement of synaptic transmission, is a cellular model for memory consolidation. Since consolidation of several forms of memory is facilitated by paradoxical sleep (PS) we ask whether PS modulates the cellular and molecular pathways underlying LTP. The long-lasting form of LTP (L LTP) is dependent on the activation of transcription factors, enzymatic cascades and the secreted neurotrophin BDNF. By using PS deprivation, immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR), we showed that an increase in PS amount (produced by rebound in PS deprived rats) is able to up regulate the expression level of transcription factors Zif268 and c-Fos as well as Arc and BDNF in the CA1 and CA3 areas of the hippocampus. Several studies involved these factors in dendritic protein synthesis and in long-term structural changes of synapses underlying L-LTP. The present study together with the work of others (Ribeiro et al., 2002) suggest that by this mechanism, a post-learning increase in PS quantity (post-learning PS window) could convert a transient form of LTP to L-LTP. PMID- 25448319 TI - Swept-source optical coherence tomography features of choroidal nevi. AB - PURPOSE: To investigate the morphologic characteristics of choroidal nevi using swept-source optical coherence tomography and compare this with enhanced-depth optical coherence tomography. DESIGN: Retrospective observational case series. METHODS: One choroidal nevus each from 30 eyes of 30 patients was included and received imaging with swept-source OCT (SS-OCT) and enhanced-depth imaging OCT (EDI-OCT). For SS-OCT, a scan acquisition protocol was used involving 12 mm horizontal and vertical scans in the posterior fundus. The main outcome measures were morphologic features of choroidal nevi obtained with SS-OCT imaging. These features were compared to images obtained with EDI-OCT. A 2-tailed Fisher exact test was the statistical method used. RESULTS: SS-OCT allowed for an appreciation of intralesional details: Of the 30 nevi imaged, intralesional vessels were apparent in 30 (100%), intralesional cavities in 6 (20%), intralesional granularity in 14 (47%), abnormal choriocapillaris in 25 (83%), and abnormal choriocapillaris confined to the tumor apex in 17 (58%). Distended bordering vessels were identified in 22 nevi (73%) and were significantly associated with the presence of previous or persistent subretinal fluid. Intrinsic hyperreflectivity with hyporeflective shadowing was significantly (P = .05) more apparent in 14 of 21 melanotic nevi (67%) compared with 2 of 9 amelanotic nevi (22%). Visualization of the complete nevus-scleral interface was significantly (P = .02) more apparent in 7 of 9 amelanotic nevi (78%) compared with 6 of 21 melanotic nevi (29%), and was not significantly related to tumor thickness (measured by ultrasound) or to tumor configuration. Tumor diameter (but not tumor height) was statistically significantly associated with secondary retinal changes (P = .05) and configuration (P = .01). EDI-OCT was equivalent at determining secondary retinal changes (P = .29), the presence of distended bordering vessels (P = 1), visualization of the nevus-scleral interface (P = .6), and hyporeflective gradation at the nevus-scleral interface (P = .33). However, in melanotic lesions, SS-OCT was significantly superior at visualizing intralesional vessels (P = .0002), intralesional granularity (P = .0005), and abnormal choriocapillaris (P = .0001). CONCLUSION: Imaging of choroidal nevi with SS-OCT enables visualization of intralesional details such as vessels (present in 100% of tumors imaged), cavities, and granularity. For melanotic lesions, SS-OCT is significantly better at depicting certain intralesional characteristics compared to EDI-OCT. Distended bordering vessels were recognized in over two thirds of the nevi imaged and were significantly associated with previous or persistent subretinal fluid. PMID- 25448318 TI - Contralateral eye comparison of descemet membrane endothelial keratoplasty and descemet stripping automated endothelial keratoplasty. AB - PURPOSE: To compare objective and subjective outcomes after Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping automated endothelial keratoplasty (DSAEK) in the fellow eye of the same patients. STUDY DESIGN: Single center, retrospective case series. METHODS: Seventeen patients with bilateral Fuchs endothelial dystrophy who underwent DSAEK earlier in 1 eye, and later underwent DMEK in the contralateral eye, composed study population. A chart review was completed to obtain follow-up data for at least 6 months after each surgery. Outcome measures included best spectacle-corrected visual acuity (BSCVA) and endothelial cell density (ECD). Subjective questionnaires were used to assess patients' satisfaction. RESULTS: Preoperative BSCVA (logMAR) was similar in both groups, 0.66 +/- 0.4 in DMEK and 0.59 +/- 0.4 in DSAEK (P = .6). The DMEK group showed better BSCVA than the DSAEK group at the 6-month time point (0.25 +/- 0.1 and 0.39 +/- 0.1, for DMEK and DSAEK, respectively, P = .02). Preoperative ECD (cells/mm(2)) was similar in both groups (2647 +/- 249 and 2768 +/- 404, P = .3) in DMEK and DSAEK, respectively. There was statistically significant difference found in ECD at 6 months (2227 +/- 565 for DMEK and 1780 +/- 433 for DSAEK, P = .049). Subjective level of average satisfaction after DMEK was 6 and after DSAEK was 4.87 +/- 1.19 (P = .002). CONCLUSIONS: DMEK provided better visual outcome and lower endothelial cell loss than DSAEK and a higher level of patient satisfaction when assessed at 6 months after surgery. Our results comparing the 2 procedures in the same patients support the benefits of DMEK, and suggest the need for long-term studies observing this new surgical procedure. PMID- 25448320 TI - Long-term follow-up in preperimetric open-angle glaucoma: progression rates and associated factors. AB - PURPOSE: To investigate the rate of progressive visual field (VF) loss and associated factors for structural or functional progression in preperimetric open angle glaucoma (OAG). DESIGN: Longitudinal, observational study. METHODS: We included 127 eyes of 127 preperimetric OAG patients who were treated with topical medication and followed for more than 5 years. All patients underwent stereo optic disc photography, red-free retinal nerve fiber layer (RNFL) photography, frequency doubling technology perimetry, and standard automated perimetry (SAP). Progression was defined as a structural (glaucomatous change confirmed by stereo optic disc and red-free RNFL photography) or functional (new glaucomatous defect on SAP) deterioration. The progression rate of SAP mean deviation (dB/year) and factors associated with progression were evaluated. RESULTS: Glaucoma progression was detected in 72 of 127 eyes (56.7%). Mean rate of VF progression was -0.39 +/- 0.64 dB/year in all patients; -0.66 +/- 0.60 dB/year in progressors and -0.03 +/- 0.24 dB/year in nonprogressors. A multivariate Cox proportional hazard model revealed that optic disc hemorrhage (hazard ratio [HR] = 1.718, P = .031) and the percentage reduction in intraocular pressure (IOP; HR = 0.964, P = .002) were significantly associated with disease progression. Patients with disc hemorrhage had a greater cumulative probability of progression than those without disc hemorrhage (P = .014 by log-rank test). CONCLUSIONS: Our results support the importance of lowering IOP, even at the preperimetric stage. Preperimetric glaucoma patients with disc hemorrhage and insufficient IOP control should be carefully monitored for greater risk of progression. PMID- 25448321 TI - [Therapy of intermediate uveitis]. AB - Intermediate uveitis is a form of intraocular inflammation in which the vitreous body is the major site of inflammation. Intermediate uveitis is primarily treated medicinally and systemic corticosteroids are the mainstay of therapy. When recurrence of uveitis or side effects occur during corticosteroid therapy an immunosuppressive treatment is required. Cyclosporine A is the only immunosuppressive agent that is approved for therapy of uveitis in Germany; however, other immunosuppressive drugs have also been shown to be effective and well-tolerated in patients with intermediate uveitis. In severe therapy refractory cases when conventional immunosuppressive therapy has failed, biologics can be used. In patients with unilateral uveitis or when the systemic therapy is contraindicated because of side effects, an intravitreal steroid treatment can be carried out. In certain cases a vitrectomy may be used. PMID- 25448323 TI - Opening tight junctions may be key to opening the blood-prostate barrier. AB - The blood-prostate barrier could be the major factor that preventing delivery of drugs to prostate tissue and leads to the failure of treatment. Studies indicate that ultrasonic sonoporation can break the blood-prostate barrier and increase the concentration of drugs, but the mechanism is still unclear. Tight junctions exist widely in the endothelial and epithelial cells of mammalians, and form the biological barrier, along with other factors. Through studies on the mechanism of ultrasound microbubbles opening the blood-brain barrier, researchers found that the main mechanism is to change the expression level of TJs proteins. Since there might be some similarities between the blood-brain barrier and the blood-prostate barrier, changing the expression level of TJs proteins may also be the main mechanism by which ultrasound microbubbles opens the blood-prostate barrier, which is worth further study. PMID- 25448324 TI - Medicolegal sidebar: the law and social values: res ipsa loquitur. PMID- 25448322 TI - Language impairment and dyslexia genes influence language skills in children with autism spectrum disorders. AB - Language and communication development is a complex process influenced by numerous environmental and genetic factors. Many neurodevelopment disorders include deficits in language and communication skills in their diagnostic criteria, including autism spectrum disorders (ASD), language impairment (LI), and dyslexia. These disorders are polygenic and complex with a significant genetic component contributing to each. The similarity of language phenotypes and comorbidity of these disorders suggest that they may share genetic contributors. To test this, we examined the association of genes previously implicated in dyslexia, LI, and/or language-related traits with language skills in children with ASD. We used genetic and language data collected in the Autism Genome Research Exchange (AGRE) and Simons Simplex Collection (SSC) cohorts to perform a meta-analysis on performance on a receptive vocabulary task. There were associations with LI risk gene ATP2C2 and dyslexia risk gene MRPL19. Additionally, we found suggestive evidence of association with CMIP, GCFC2, KIAA0319L, the DYX2 locus (ACOT13, GPLD1, and FAM65B), and DRD2. Our results show that LI and dyslexia genes also contribute to language traits in children with ASD. These associations add to the growing literature of generalist genes that contribute to multiple related neurobehavioral traits. Future studies should examine whether other genetic contributors may be shared among these disorders and how risk variants interact with each other and the environment to modify clinical presentations. PMID- 25448325 TI - No sex differences exist in posterior condylar offsets of the knee. AB - BACKGROUND: Restoration of posterior condylar offset during TKA is believed to be important to improving knee kinematics, maximizing ROM, and minimizing flexion instability. However, controversy exists regarding whether there are important anatomic differences between sexes and whether a unisex knee prosthesis can restore the anatomy of knees in males and females. QUESTIONS/PURPOSES: The purposes of our study were to determine if sex differences exist in (1) absolute posterior condylar offset size, (2) relative posterior condylar offset size in relation to total condylar height, and (3) posterior condylar articular cartilage thickness. METHODS: We identified 100 patients (50 men and 50 women) without a history of arthritis, deformity, dysplasia, osteochondral defect, fracture, or surgery about the knee who had MRI of the knee performed. All MR images were ordered by primary care medical physicians for evaluation of nonspecific knee pain. Using a previously described three-dimensional MRI protocol, we measured posterior condylar offset, total condylar height, and articular cartilage thickness at the medial and lateral femoral condyles and compared values to evaluate for potential sex differences. We performed an a priori power calculation using a 2-mm posterior condylar offset difference as the minimum clinically important difference; with 2n = 100, our power to detect such a difference was 99.8%. RESULTS: Compared with females, males had greater medial posterior condylar offset (30 mm [95% CI, 29.3-30.7 mm; SD, 2.5 mm] vs 28 mm [95% CI, 27.0-28.5 mm; SD, 2.7 mm]), lateral posterior condylar offset (27 mm [95% CI, 26.2-27.3 mm; SD, 2.0 mm] vs 25 mm [95% CI, 24.2-25.4 mm; SD, 2.0 mm]), medial condylar height (63 mm [SD, 3.2 mm] vs 57 mm [SD, 4.4 mm]), and lateral condylar height (71 mm [SD, 5.2 mm] vs 65 mm [SD: 4.0 mm]) (all p values < 0.001). However, the mean ratio of medial posterior condylar offset to medial condylar height (0.48 [SD, 0.04] vs 0.49 [SD, 0.05]) and the mean ratio of lateral posterior condylar offset to lateral condylar height (0.38 [SD, 0.05] vs 0.38 [SD, 0.03]) were not different between sexes (p = 0.08 and p = 0.8, respectively). There also was no sex difference in mean articular cartilage thickness at either condyle (medial condyle: 2.7 mm [SD, 0.5 mm] vs 2.5 mm [SD, 0.7 mm]; lateral condyle: 2.6 mm [SD, 0.6 mm] vs 2.5 mm [SD, 0.8 mm]) (both p values >= 0.1). CONCLUSIONS: Results of our study showed that knees in males exhibited greater posterior condylar offset and greater total condylar height at the medial and lateral femoral condyles, however, there were no sex differences in the ratio of posterior condylar offset to condylar height at either condyle. CLINICAL RELEVANCE: These findings suggest that a unisex knee prosthesis design is adequate to recreate the normal posterior condylar offsets for men and women. PMID- 25448326 TI - Twelve percent of hips with a primary cam deformity exhibit a slip-like morphology resembling sequelae of slipped capital femoral epiphysis. AB - BACKGROUND: In some hips with cam-type femoroacetabular impingement (FAI), we observed a morphology resembling a more subtle form of slipped capital femoral epiphysis (SCFE). Theoretically, the morphology in these hips should differ from hips with a primary cam-type deformity. QUESTIONS/PURPOSES: We asked if (1) head neck offset; (2) epiphyseal angle; and (3) tilt angle differ among hips with a slip-like morphology, idiopathic cam, hips after in situ pinning of SCFE, and normal hips; and (4) what is the prevalence of a slip-like morphology among cam type hips? METHODS: We retrospectively compared the three-dimensional anatomy of hips with a slip-like morphology (29 hips), in situ pinning for SCFE (eight hips), idiopathic cam deformity (171 hips), and 30 normal hips using radial MRI arthrography. Normal hips were derived from 17 asymptomatic volunteers. All other hips were recruited from a series of 277 hips (243 patients) seen at a specialized academic hip center between 2006 and 2010. Forty-one hips with isolated pincer deformity were excluded. Thirty-six of 236 hips had a known cause of cam impingement (secondary cam), including eight hips after in situ pinning of SCFE (postslip group). The 200 hips with a primary cam were separated in hips with a slip-like morphology (combination of positive fovea sign [if the neck axis did not intersect with the fovea capitis] and a tilt angle [between the neck axis and perpendicular to the basis of the epiphysis] exceeding 4 degrees ) and hips with an idiopathic cam. We evaluated offset ratio, epiphyseal angle (angle between the neck axis and line connecting the center of the femoral head and the point where the physis meets the articular surface), and tilt angle circumferentially around the femoral head-neck axis. Prevalence of slip-like morphology was determined based on the total of 236 hips with cam deformities. RESULTS: Offset ratio was decreased anterosuperiorly in idiopathic cam, slip like, and postslip (eg, 1 o'clock position with a mean offset ranging from 0.00 to 0.14; p < 0.001 for all groups) compared with normal hips (0.25 +/- 0.06 [95% confidence interval, 0.13-0.37]) and increased posteroinferiorly in slip-like (eg, 8 o'clock position, 0.5 +/- 0.09 [0.32-0.68]; p < 0.001) and postslip groups (0.55 +/- 0.12 [0.32-0.78]; p < 0.001) and did not differ in idiopathic cam (0.32 +/- 0.09 [0.15-0.49]; p = 0.323) compared with normal (0.31 +/- 0.07 [0.18-0.44]) groups. Epiphyseal angle was increased anterosuperiorly in the slip-like (eg, 1 o'clock position, 70 degrees +/- 9 degrees [51 degrees -88 degrees ]; p < 0.001) and postslip groups (75 degrees +/- 13 degrees [49 degrees -100 degrees ]; p = 0.008) and decreased in idiopathic cam (50 degrees +/- 8 degrees [35 degrees -65 degrees ]; p < 0.001) compared with normal hips (58 degrees +/- 8 degrees [43 degrees -74 degrees ]). Posteroinferiorly, epiphyseal angle was decreased in slip-like (eg, 8 o'clock position, 54 degrees +/- 10 degrees [34 degrees -74 degrees ]; p < 0.001) and postslip (44 degrees +/- 11 degrees [23 degrees -65 degrees ]; p < 0.001) groups and did not differ in idiopathic cam (76 degrees +/- 8 degrees [61 degrees -91 degrees ]; p = 0.099) compared with normal (73 degrees +/- 7 degrees [59 degrees -88 degrees ]) groups. Tilt angle increased in slip-like (eg, 2/8 o'clock position, 14 degrees +/- 8 degrees [-1 degrees to 30 degrees ]; p < 0.001) and postslip hips (29 degrees +/- 10 degrees [9 degrees -48 degrees ]; p < 0.001) and decreased in hips with idiopathic cam (-7 degrees +/- 5 degrees [-17 degrees to 4 degrees ]; p < 0.001) compared with normal (-1 degrees +/- 5 degrees [-10 degrees to 8 degrees ]) hips. The prevalence of a slip-like morphology was 12%. CONCLUSIONS: The slip-like morphology is the second most frequent pathomorphology in hips with primary cam deformity. MRI arthrography of the hip allows identifying a slip-like morphology, which resembles hips after in situ pinning of SCFE and distinctly differs from hips with idiopathic cam. These results support previous studies reporting that SCFE might be a risk factor for cam-type FAI. PMID- 25448328 TI - Editor's spotlight/take 5: do patient race and sex change surgeon recommendations for TKA? PMID- 25448329 TI - A dedicated research program increases the quantity and quality of orthopaedic resident publications. AB - BACKGROUND: Programs seek to expose trainees to research during residency. However, little is known in any formal sense regarding how to do this effectively, or whether these efforts result in more or better-quality research output. QUESTIONS/PURPOSES: The objective of our study was to evaluate a dedicated resident research program in terms of the quantity and quality of resident research peer-reviewed publications. Specifically we asked: (1) Did residents mentored through a dedicated resident research program have more peer reviewed publications in higher-impact journals with higher citation rates compared with residents who pursued research projects under a less structured approach? (2) Did this effect continue after graduation? METHODS: In 2006, our department of orthopaedic surgery established a dedicated resident research program, which consisted of a new research policy and a research committee to monitor quality and compliance with this policy. Peer-reviewed publications (determined from PubMed) of residents who graduated 6 years before establishing the dedicated resident research program were compared with publications from an equal period of the research-program-directed residents. The data were assessed using descriptive statistics and regression analysis. Twenty-four residents graduated from 2001 to 2006 (before implementation of the dedicated resident research program); 27 graduated from 2007 to 2012 (after implementation of the dedicated resident research program). There were 74 eligible publications as defined by the study inclusion and exclusion criteria. RESULTS: Residents who trained after implementation of the dedicated resident research program published more papers during residency than did residents who trained before the program was implemented (1.15 versus 0.79 publications per resident; 95% CI [0.05,0.93]; p = 0.047) and the journal impact factor was greater in the group that had the research program (1.25 versus 0.55 per resident; 95% CI [0.2,1.18]; p = 0.005). There were no differences between postresidency publications by trainees who graduated with versus without the research program in the number of publications, citations, and average journal impact factor per resident. A regression analysis showed no difference in citation rates of the residents' published papers before and since implementation of the research program. CONCLUSIONS: Currently in the United States, there are no standard policies or requirements that dictate how research should be incorporated in orthopaedic surgery residency training programs. The results of our study suggest that implementation of a dedicated resident research program improves the quantity and to some extent quality of orthopaedic resident research publications, but this effect did not persist after graduation. PMID- 25448327 TI - Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells. AB - BACKGROUND: Heterotopic ossification (HO) may occur after musculoskeletal trauma, traumatic brain injury, and total joint arthroplasty. As such, HO is a compelling clinical concern in both military and civilian medicine. A possible etiology of HO involves dysregulated signals in the bone morphogenetic protein osteogenic cascade. Contemporary treatment options for HO (ie, nonsteroidal antiinflammatory drugs and radiation therapy) have adverse effects associated with their use and are not biologically engineered to abrogate the molecular mechanisms that govern osteogenic differentiation. QUESTIONS/PURPOSES: We hypothesized that (1) nanogel mediated short interfering RNA (siRNA) delivery against Runt-related transcription factor 2 (Runx2) and osterix (Osx) genes will decrease messenger RNA expression; (2) inhibit activity of the osteogenic marker alkaline phosphatase (ALP); and (3) inhibit hydroxyapatite (HA) deposition in osteoblast cell cultures. METHODS: Nanogel nanostructured polymers delivered siRNA in 48 hour treatment cycles against master osteogenic regulators, Runx2 and Osx, in murine calvarial preosteoblasts (MC3T3-E1.4) stimulated for osteogenic differentiation by recombinant human bone morphogenetic protein (rhBMP-2). The efficacy of RNA interference (RNAi) therapeutics was determined by quantitation of messenger RNA knockdown (by quantitative reverse transcription-polymerase chain reaction), downstream protein knockdown (determined ALP enzymatic activity assay), and HA deposition (determined by OsteoImageTM assay). RESULTS: Gene expression assays demonstrated that nanogel-based RNAi treatments at 1:1 and 5:1 nanogel:short interfering RNA weight ratios reduced Runx2 expression by 48.59% +/ 19.53% (p < 0.001) and 43.22% +/- 18.01% (both p < 0.001). The same 1:1 and 5:1 treatments against both Runx2 and Osx reduced expression of Osx by 51.65% +/- 10.85% and 47.65% +/- 9.80% (both p < 0.001). Moreover, repeated 48-hour RNAi treatment cycles against Runx2 and Osx rhBMP-2 administration reduced ALP activity after 4 and 7 days. ALP reductions after 4 days in culture by nanogel 5:1 and 10:1 RNAi treatments were 32.4% +/- 12.0% and 33.6% +/- 13.8% (both p < 0.001). After 7 days in culture, nanogel 1:1 and 5:1 RNAi treatments produced 35.9% +/- 14.0% and 47.7% +/- 3.2% reductions in ALP activity. Osteoblast mineralization data after 21 days suggested that nanogel 1:1, 5:1, and 10:1 RNAi treatments decreased mineralization (ie, HA deposition) from cultures treated only with rhBMP-2 (p < 0.001). However, despite RNAi attack on Runx2 and Osx, HA deposition levels remained greater than non-rhBMP-2-treated cell cultures. CONCLUSIONS: Although mRNA and protein knockdown were confirmed as a result of RNAi treatments against Runx2 and Osx, complete elimination of mineralization processes was not achieved. RNAi targeting mid- and late-stage osteoblast differentiation markers such as ALP, osteocalcin, osteopontin, and bone sialoprotein) may produce the desired RNAi-nanogel nanostructured polymer HO prophylaxis. CLINICAL RELEVANCE: Successful HO prophylaxis should target and silence osteogenic markers critical for heterotopic bone formation processes. The identification of such markers, beyond RUNX2 and OSX, may enhance the effectiveness of RNAi prophylaxes for HO. PMID- 25448330 TI - West Nile virus seroprevalence and behavioral risks in HIV-1 infected individuals, Northern Greece, 2011. AB - OBJECTIVES: This study sought to assess the West Nile Virus (WNV) seroprevalence and behavioral risk factors for WNV infection in HIV-1 infected individuals in Northern Greece in 2011. METHODS: We prospectively enrolled 91 HIV-1 consecutive patients followed up in the HIV clinic of the AHEPA University Hospital in the period from November to December 2011. Serum samples were tested for the presence of WNV IgG antibodies. All subjects were administered a standardized questionnaire to evaluate for risk factors for WNV infection. RESULTS: WNV IgG antibodies were detected in three subjects (3.3%, 95% CI 0.7-9.3%), two of whom were of African origin. The prevalence of WNV antibodies in HIV patients of Greek origin was 1.2% (95% CI: 0.03% - 6.3%). In the sample surveyed, 53.6% (95% CI: 42.4% to 64.5%) were aware of WNV prevention measures; 2.2% reported no implementation of prevention measures, whereas 46.1% implemented at least three measures. Approximately one half of the patients reported outdoor activities for more than two hours from dusk to dawn. None of the IgG-positive patients reported any symptoms compatible with WNV disease during the season at risk. CONCLUSIONS: Among native Greek HIV patients, the WNV seroprevalence is 1.2%. A considerable proportion of patients was aware of WNV prevention measures and implemented some of these. HIV patients and other categories of immunocompromised patients are at increased risk of neuroinvasive disease, and widespread implementation of prevention measures should be strongly encouraged in this patient population. PMID- 25448333 TI - Two-family outbreak of botulism associated with the consumption of smoked ribs in Sichuan Province, China. AB - BACKGROUND: On September 22, 2013, two patients from Sichuan Province, China presented with symptoms of food-borne botulism, a rare but fatal illness caused by the consumption of foods containing Clostridium botulinum neurotoxins. METHODS: Investigators reviewed the medical charts and food consumption histories, and interviewed patients and family members. Food samples and clinical specimens were tested for botulinum toxin and neurotoxin-producing Clostridium species by standard methods. RESULTS: The first two index cases presented with cranial neuropathies and flaccid paralysis, and required mechanical ventilation. There were 12 confirmed outbreak-associated cases. Botulinum toxin type A was identified in the smoked ribs, and all of the patients had consumed the smoked ribs from the same local restaurant. The smoked ribs contained no added salt, sugar, or preservative. Botulinum toxin production likely resulted from the cold smoking preparation method and inappropriate refrigeration. CONCLUSIONS: Smoked ribs produced by a local restaurant, contaminated with type A botulism, was the contributor to this outbreak. The supervision of food safety should be strengthened to prevent future outbreaks in China. PMID- 25448332 TI - A randomized phase 2 study comparing two doses of delafloxacin with tigecycline in adults with complicated skin and skin-structure infections. AB - BACKGROUND: A randomized, double-blind, multicenter trial was done to compare two doses of delafloxacin with tigecycline in patients with various complicated skin and skin-structure infections (wound infections following surgery, trauma, burns, or animal/insect bites, abscesses, and cellulitis). METHODS: Patients were randomized 1:1:1 to receive delafloxacin 300mg intravenous (IV) every 12h, delafloxacin 450mg IV every 12h, or tigecycline 100mg IV*1, followed by 50mg IV every 12h; randomization was stratified by infection type. Duration of therapy was 5-14 days. The primary efficacy analysis, performed on the clinically evaluable (CE) population at the test-of-cure (TOC) visit (14-21 days after the final dose of study drug), compared clinical response rates in the delafloxacin and tigecycline arms. Clinical response rates in the two delafloxacin arms were also compared. RESULTS: Among CE patients, clinical cure rates at TOC visit were similar in the delafloxacin and tigecycline arms (94.3%, 92.5%, and 91.2%, respectively in delafloxacin 300-mg, delafloxacin 450-mg, and tigecycline arms). Overall, the most frequent adverse events were nausea, vomiting, and diarrhea; the 300-mg delafloxacin arm was the best-tolerated regimen. CONCLUSIONS: Delafloxacin was similarly effective as tigecycline for a variety of complicated skin and skin-structure infections and was well tolerated. (Clinicaltrials.gov NCT 0719810). PMID- 25448334 TI - The changing pattern of hepatitis A in Lebanese adults. AB - OBJECTIVE: A shift in the age of hepatitis A virus (HAV) infection from early childhood to adulthood has been observed in many developing countries. This epidemiological shift has been attributed to improved socioeconomic status and sanitary conditions resulting in growing cohorts of susceptible young people and hence an increased risk of HAV outbreaks. The aim of this study was to investigate the evolutionary trend of anti-HAV seroprevalence in Lebanon in a cohort of Lebanese adults. METHODS: This was a cross-sectional study employing a convenience sample (voluntary blood donors) along with secondary data analysis. Sera from 283 healthy blood donors were tested for anti-HAV IgG antibodies. Moreover, we analyzed the national reports of HAV cases published by the Lebanese Ministry of Public Health since 2001. RESULTS: Anti-HAV seropositivity increased steadily from 60% in the younger age group (19-29 years) to 91% in the older age group (50-59 years), leaving the younger group at higher risk of acquiring HAV. The national data show that the number of acute hepatitis A infections is higher in the age groups 5-9 and 10-19 years. CONCLUSION: Our seroprevalence data reveal that young adults are becoming more at risk of acquiring HAV infection. Thus the introduction of hepatitis A vaccine is highly recommended. PMID- 25448331 TI - Staphylococcus aureus bacteraemia in Gauteng academic hospitals, South Africa. AB - INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) infections are responsible for longer hospital stays, increased hospital costs, and poorer outcomes compared to methicillin-sensitive S. aureus (MSSA) infections. We aimed to describe the epidemiology of S. aureus bacteraemia (SAB) and to determine factors associated with MRSA infection in South Africa. METHODS: Cases of SAB were reported from September 2012 to September 2013 from three sentinel sites. A case was defined as the isolation of S. aureus from a blood culture during a 21 day period. Detailed clinical information was collected. Multivariable logistic regression was done to determine factors associated with MRSA infection and mortality. RESULTS: There were 442 cases of SAB reported; antimicrobial susceptibility testing was performed on 240 isolates (54%). Thirty-six percent (86/240) of cases had an MRSA infection. A longer hospital stay before positive specimen collection (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.02 1.13, p=0.004), hospitalization in the last year (OR 15.7, 95% CI 2.5-99.5, p=0.003), HIV infection (OR 4.9, 95% CI 1.05-22.90, p=0.044), and antibiotic use in the previous 2 months (OR 0.1, 95% CI 0.01-0.68, p=0.022) were independent predictors of MRSA. Older age, and in particular age 25-44 years (OR 22.2, 95% CI 2.7-185.5, p=0.004, compared to those aged<5 years), was the only independent predictor of mortality amongst cases with SAB. MRSA isolates were non-susceptible to more antimicrobial agents compared to MSSA isolates. CONCLUSIONS: HIV infection was an independent risk factor for MRSA infection. The selection of appropriate empirical antimicrobial treatment is essential in patients with MRSA infections because of non-susceptibility to many other antimicrobial classes. PMID- 25448335 TI - Middle East respiratory syndrome coronavirus (MERS-CoV) viral shedding in the respiratory tract: an observational analysis with infection control implications. AB - BACKGROUND: Since the first description of Middle East respiratory syndrome coronavirus (MERS-CoV), it has not been known how long patients shed the virus in respiratory secretions. Thus, we analyzed the available data on time to negative MERS-CoV test in patients with confirmed MERS-CoV infection and asymptomatic positive contacts. METHODS: Data from repeated laboratory testing of respiratory samples received at the Saudi Arabian virology reference laboratory in Jeddah, Kingdom of Saudi Arabia from September 1, 2012 to September 31, 2013 were recorded. A real-time RT-PCR test for MERS-CoV was used. Data were analyzed by origin of sample, sample type, and MERS-CoV PCR test results. RESULTS: Twenty-six individuals (13 patients and 13 contacts) had repeated testing done until a negative test was obtained. Most samples from MERS-CoV cases were tracheal aspirate/sputum (p=0.0006) and most samples from contacts were nose and throat swabs (p=0.0002). Kaplan-Meier curve analysis showed that contacts cleared the virus at a much earlier time than patients. On day 12, 30% of contacts and 76% of cases were still positive for MERS-CoV by PCR. CONCLUSIONS: Contacts cleared MERS CoV earlier than ill patients. This finding could be related to the types of sample as well as the types of patient studied. More ill patients with significant comorbidities shed the virus for a significantly longer time. The results of this study could have critical implications for infection control guidance and its application in healthcare facilities handling positive cases. PMID- 25448336 TI - Identification of severe fever with thrombocytopenia syndrome virus in ticks collected from patients. AB - The cases of two patients (a husband and wife) with thrombocytopenia syndrome (SFTS) are reported herein. Both patients had a history of recent tick bite and displayed typical clinical SFTS symptoms including fever, thrombocytopenia, and leukopenia. The diagnosis was laboratory-confirmed by the provincial Center for Disease Control and Prevention (CDC). The husband died while the wife survived. SFTS virus was eventually identified in ticks collected from the couple. PMID- 25448337 TI - Spleen-preserving surgery is effective for the treatment of spleen cystic echinococcosis. AB - OBJECTIVE: This study evaluated two surgical procedures, total splenectomy and spleen-preserving surgery, for the treatment of spleen cystic echinococcosis (CE). METHODS: A total of 21 patients who underwent surgery for removal of spleen CE were evaluated retrospectively. Patients were divided into two groups, those who received a total splenectomy (n=7) and those who underwent spleen-preserving surgery (n=14). RESULTS: Total splenectomy surgery took 127.1+/-11.1min and spleen-preserving surgery took 104.3+/-25.3min (p<0.05). The length of hospital stay was the same for both patient groups (10.6 days on average). No patient suffered from recurrence during follow-up and all of the patients made a good recovery. No patient developed post-splenectomy sepsis or serious infectious complications. No patient suffered recurrence. CONCLUSIONS: The spleen-saving approach is likely an effective method for the removal of CE spleen cysts given that it is a quick procedure and preserves the function of the spleen. Total splenectomy procedures may be performed particularly for larger, centrally located cysts. PMID- 25448338 TI - Haemolysis associated with the treatment of malaria with artemisinin derivatives: a systematic review of current evidence. AB - BACKGROUND: Artemisinin derivatives are the mainstay of antimalarial treatment, both for uncomplicated malaria and for severe disease. Artemisinins are known for their rapid onset of action, good tolerability, and safety. However, besides the sporadic but worrying reports of delayed parasite clearance after treatment with artemisinins, there have been an increasing number of reports of acute haemolytic anaemia following their use and the safety of this class of antimalarials is being questioned. METHODS: In this systematic review, all reports of patients experiencing haemolysis following the use of artemisinins for the treatment of malaria were identified and collated into an electronic database. Summary statistics were calculated to characterize the epidemiology and clinical features of this safety concern related to artemisinin derivatives. RESULTS: A total of 37 patients were identified suffering from haemolysis following the treatment of severe malaria with artemisinin derivatives. Thirty-one cases had received intravenous artesunate, while the remaining cases were attributed to other parenteral or oral regimens of artemisinin derivatives. The majority of patients were returning travellers (n=30), and six clinical cases had been reported in paediatric patients. The median onset of haemolysis was 15 (interquartile range (IQR) 13-15) days after the initiation of treatment for the 'delayed-onset' pattern and 17 (IQR 13-22) days for the 'persistent' haemolysis pattern. The median reduction in haemoglobin due to haemolysis was 6 g/dl (IQR 4-8 g/dl). The estimated proportion of patients suffering from severe malaria experiencing haemolysis after treatment with artemisinin derivatives was 13% (95% confidence interval 9-18%), and 73% of these (i.e., 9% of the total population) required blood transfusions. No fatal outcome has been reported in the literature to date. CONCLUSIONS: Haemolysis is commonly associated with the class of artemisinin drugs when used for the treatment of severe malaria. Potential causes of this safety issue are discussed. Although no deaths attributed to haemolysis have been reported so far, this safety issue may lead to life-threatening anaemia and is particularly worrying for regions where safe blood products are not readily available. PMID- 25448339 TI - An outbreak of Mycobacterium tuberculosis infection associated with acupuncture in a private clinic of Zhejiang Province, China, 2012. AB - BACKGROUND: Acupuncture carries the potential risk of transmission of pathogenic microorganisms from the environment to the patient, and from one patient to another. An outbreak of tuberculosis at a private clinic in eastern China was investigated to identify the source of infection, mode of transmission, and risk factors for infection. METHODS: A probable case was one who had the onset of unexplained pain, swelling, or abscess in the area of invasive treatment between January 1, 2011 and February 23, 2012. A confirmed case was a probable case with positive laboratory test results for Mycobacterium tuberculosis. Patient history and the frequency of invasive treatment were compared between 56 probable and confirmed cases and 98 controls in a case-control study. RESULTS: Fifty-six of 2561 patients (2.2%) who had visited the clinic developed tuberculosis. The odds ratio (OR) of M. tuberculosis infection increased with the frequency of clinic visits (Chi-square for trend=28.943, p=0.000). Multivariate analysis showed that the frequency of acupuncture (Chi-square=24.258, adjusted p-value=0.000) and sharing acupuncture needles (Chi-square=8.936, adjusted p-value=0.003) were risk factors for M. tuberculosis infection. Thirty-two pus sample and nine sputum sample cultures were M. tuberculosis-positive. CONCLUSIONS: This outbreak was caused by acupuncture and was transmitted through sharing acupuncture needles contaminated with M. tuberculosis. PMID- 25448341 TI - Idiopathic bilateral vocal cord paralysis in infants: Case series and literature review. AB - OBJECTIVES/HYPOTHESIS: Vocal fold paralysis is the second most common congenital laryngeal anomaly in newborns. Bilateral paralysis is a severe condition and often remains of unknown etiology. We report our experience of congenital idiopathic bilateral vocal fold paralysis in newborns and infants, and discuss the therapeutic options. STUDY DESIGN: Retrospective review. METHODS: A retrospective review was carried out at a single tertiary referral center over a 15-year period of children presenting with congenital idiopathic bilateral laryngeal paralysis (CIBP). RESULTS: Twenty-six patients were identified and managed over period of the study (mean follow-up, 6.7 years). A tracheostomy was eventually performed in 14 patients, 12 during the neonatal period. Endoscopic treatment was performed in 16 patients and an external approach in five patients after endoscopic failure. Three patients were managed by watchful waiting. Spontaneous recovery occurred in 16 patients (median age, 14.5 months), including nine with a tracheostomy. Decannulation was achieved in 12 patients (median age, 42 months), and noninvasive positive pressure ventilation (NPPV) was applied in six patients. CONCLUSIONS: Only inhomogeneous series of pediatric bilateral laryngeal palsies have been published so far, making it difficult to identify prognostic and predictive markers, as well as therapeutic guidelines. Focusing on CIBP, our data suggest that the management strategy must take into account the possibility of a delayed spontaneous recovery. NPPV is an interesting therapeutic tool in this situation. A systematic somatic assessment is mandatory to look for associated conditions. PMID- 25448342 TI - Force-controlled dynamic wear testing of total ankle replacements. AB - Currently, our knowledge of wear performance in total ankle replacements is limited. The aim of this study is to develop a scenario for force-controlled testing and wear testing of total ankle replacements. A force-controlled wear test was developed: based on cadaver measurements, the passive stabilization (ligaments and soft tissue) of the ankle joint was characterized and a restraint model for ankle stabilization was developed. Kinematics and kinetics acting at the replaced ankle joint were defined based on literature data and gait analysis. Afterwards, force-controlled wear testing was carried out on a mobile, three component, total ankle replacement design. Wear was assessed gravimetrically and wear particles were analyzed. Wear testing resulted in a mean wear rate of 18.2+/ 1.4mm(3)/10(6) cycles. Wear particles showed a mean size of 0.23MUm with an aspect ratio of 1.61+/-0.96 and a roundness of 0.62+/-0.14. Wear testing of total ankle replacement shows that a relevant wear mass is generated with wear particles in a biologically relevant size range. The developed wear test provides a basis for future wear testing of total ankle replacements. PMID- 25448343 TI - Elastin-like recombinamer-covered stents: Towards a fully biocompatible and non thrombogenic device for cardiovascular diseases. AB - We explored the use of recently developed gels obtained by the catalyst free click reaction of elastin-like recombinamers (ELRs) to fabricate a new class of covered stents. The approach consists in embedding bare metal stents in the ELR gels by injection molding, followed by endothelialization under dynamic pressure and flow conditions in a bioreactor. The mechanical properties of the gels could be easily tuned by choosing the adequate concentration of the ELR components and their biofunctionality could be tailored by inserting specific sequences (RGD and REDV). The ELR-covered stents exhibited mechanical stability under high flow conditions and could undergo crimping and deployment without damage. The presence of RGD in the ELR used to cover the stent supported full endothelialization in less than 2weeks in vitro. Minimal platelet adhesion and fibrin adsorption were detected after exposure to blood, as shown by immunostaining and scanning electron microscopy. These results prove the potential of this approach towards a new and more effective generation of covered stents which exclude the atherosclerotic plaque from the blood stream and have high biocompatibility, physiological hemocompatibility and reduced response of the immune system. PMID- 25448345 TI - Drug delivery from injectable calcium phosphate foams by tailoring the macroporosity-drug interaction. AB - In this work, novel injectable calcium phosphate foams (CPFs) were combined with an antibiotic (doxycycline) to design an innovative dosage form for bone regeneration. The material structure, its drug release profile and antibiotic activity were investigated, while its clinical applicability was assessed through cohesion and injectability tests. Doxycycline had a clear effect on both the micro and macro structure of the CPFs, owing to its role as a nucleating agent of hydroxyapatite and to a drying effect on the paste. Doxycycline-loaded CPFs presented interconnected macroporosity, which increased drug availability compared with calcium phosphate cements, and was a critical parameter controlling the release kinetics which followed a non-Fickian diffusion model. Up to 55% (1mg) of the drug was released progressively in 5days, the percentage released being proportional to the macroporosity of the CPFs. All doxycycline-containing foams had immediate cohesion and were injectable. Moreover, antibacterial activity was observed against Staphylococcus aureus and Escherichia coli. Thus, in addition to enhancing osteoconduction and material resorption, macroporosity enables tuning of the local delivery of drugs from injectable calcium phosphates. PMID- 25448344 TI - Phenotypic stability, matrix elaboration and functional maturation of nucleus pulposus cells encapsulated in photocrosslinkable hyaluronic acid hydrogels. AB - Degradation of the nucleus pulposus (NP) is an early hallmark of intervertebral disc degeneration. The capacity for endogenous regeneration in the NP is limited due to the low cellularity and poor nutrient and vascular supply. Towards restoring the NP, a number of biomaterials have been explored for cell delivery. These materials must support the NP cell phenotype while promoting the elaboration of an NP-like extracellular matrix in the shortest possible time. Our previous work with chondrocytes and mesenchymal stem cells demonstrated that hydrogels based on hyaluronic acid (HA) are effective at promoting matrix production and the development of functional material properties. However, this material has not been evaluated in the context of NP cells. Therefore, to test this material for NP regeneration, bovine NP cells were encapsulated in 1%w/vol HA hydrogels at either a low seeding density (20*10(6)cellsml(-1)) or a high seeding density (60*10(6)cellsml(-1)), and constructs were cultured over an 8week period. These NP cell-laden HA hydrogels showed functional matrix accumulation, with increasing matrix content and mechanical properties with time in culture at both seeding densities. Furthermore, encapsulated cells showed NP-specific gene expression profiles that were significantly higher than expanded NP cells prior to encapsulation, suggesting a restoration of phenotype. Interestingly, these levels were higher at the lower seeding density compared to the higher seeding density. These findings support the use of HA-based hydrogels for NP tissue engineering and cellular therapies directed at restoration or replacement of the endogenous NP. PMID- 25448346 TI - First insight on the impact of an osteoblastic layer on the bio-tribocorrosion performance of Ti6Al4V hip implants. AB - In uncemented Ti6Al4V hip implants, the bone-stem interface is subjected to cyclic loading motion driven by the daily activities of the patients, which may lead to the complete failure of the implant in the long term. It may also compromise the proliferation and differentiation processes of osteoblastic cells (bone-forming cells). The main objective of this work is to approach for the first time the role of these organic materials on the bio-tribocorrosion mechanisms of cultured Ti6Al4V alloys. The colonized materials with MG63 osteoblastic-like cells were characterized through cell viability/proliferation and enzymatic activity. Tribocorrosion tests were performed under a reciprocating sliding configuration and low contact pressure. Electrochemical techniques were used to measure the corrosion kinetics of the system, under free potential conditions. All tests were performed at a controlled atmosphere. The morphology and topography of the wear scar were evaluated. The results showed that the presence of an osteoblastic cell layer on the implant surface significantly influences the tribocorrosion behavior of Ti6Al4V alloy. It was concluded that the cellular material was able to form an extra protective layer that inhibits further wear degradation of the alloy and decreases its corrosion tendency. PMID- 25448347 TI - Functional fabrication of recombinant human collagen-phosphorylcholine hydrogels for regenerative medicine applications. AB - The implant-host interface is a critical element in guiding tissue or organ regeneration. We previously developed hydrogels comprising interpenetrating networks of recombinant human collagen type III and 2-methacryloyloxyethyl phosphorylcholine (RHCIII-MPC) as substitutes for the corneal extracellular matrix that promote endogenous regeneration of corneal tissue. To render them functional for clinical application, we have now optimized their composition and thereby enhanced their mechanical properties. We have demonstrated that such optimized RHCIII-MPC hydrogels are suitable for precision femtosecond laser cutting to produce complementing implants and host surgical beds for subsequent tissue welding. This avoids the tissue damage and inflammation associated with manual surgical techniques, thereby leading to more efficient healing. Although we previously demonstrated in clinical testing that RHCIII-based implants stimulated cornea regeneration in patients, the rate of epithelial cell coverage of the implants needs improvement, e.g. modification of the implant surface. We now show that our 500MUm thick RHCIII-MPC constructs comprising over 85% water are suitable for microcontact printing with fibronectin. The resulting fibronectin micropatterns promote cell adhesion, unlike the bare RHCIII-MPC hydrogel. Interestingly, a pattern of 30MUm wide fibronectin stripes enhanced cell attachment and showed the highest mitotic rates, an effect that potentially can be utilized for faster integration of the implant. We have therefore shown that laboratory-produced mimics of naturally occurring collagen and phospholipids can be fabricated into robust hydrogels that can be laser profiled and patterned to enhance their potential function as artificial substitutes of donor human corneas. PMID- 25448348 TI - In vivo performance of novel soybean/gelatin-based bioactive and injectable hydroxyapatite foams. AB - Major limitations of calcium phosphate cements (CPCs) are their relatively slow degradation rate and the lack of macropores allowing the ingrowth of bone tissue. The development of self-setting cement foams has been proposed as a suitable strategy to overcome these limitations. In previous work we developed a gelatine based hydroxyapatite foam (G-foam), which exhibited good injectability and cohesion, interconnected porosity and good biocompatibility in vitro. In the present study we evaluated the in vivo performance of the G-foam. Furthermore, we investigated whether enrichment of the foam with soybean extract (SG-foam) increased its bioactivity. G-foam, SG-foam and non-foamed CPC were implanted in a critical-size bone defect in the distal femoral condyle of New Zealand white rabbits. Bone formation and degradation of the materials were investigated after 4, 12 and 20weeks using histological and biomechanical methods. The foams maintained their macroporosity after injection and setting in vivo. Compared to non-foamed CPC, cellular degradation of the foams was considerably increased and accompanied by new bone formation. The additional functionalization with soybean extract in the SG-foam slightly reduced the degradation rate and positively influenced bone formation in the defect. Furthermore, both foams exhibited excellent biocompatibility, implying that these novel materials may be promising for clinical application in non-loaded bone defects. PMID- 25448349 TI - The influence of titania-zirconia-zirconium titanate nanotube characteristics on osteoblast cell adhesion. AB - Studies of biomaterial surfaces and their influence on cell behavior provide insights concerning the design of surface physicochemical and topography properties of implant materials. Fabrication of biocompatible metal oxide nanotubes on metallic biomaterials, especially titanium alloys such as Ti50Zr via anodization, alters the surface chemistry as well as surface topography of the alloy. In this study, four groups of TiO2-ZrO2-ZrTiO4 nanotubes that exhibit diverse nanoscale dimensional characteristics (i.e. inner diameter Di, outer diameter Do and wall thicknesses Wt) were fabricated via anodization. The nanotubes were annealed and characterized using scanning electron microscopy and 3-D profilometry. The potential applied during anodization influenced the oxidation rate of titanium and zirconium, thereby resulting in different nanoscale characteristics for the nanotubes. The different oxidation and dissolution rates both led to changes in the surface roughness parameters. The in vitro cell response to the nanotubes with different nanoscale dimensional characteristics was assessed using osteoblast cells (SaOS2). The results of the MTS assay indicated that the nanotubes with inner diameter (Di)~40nm exhibited the highest percentage of cell adhesion of 41.0%. This result can be compared to (i) 25.9% cell adhesion at Di~59nm, (ii) 33.1% at Di~64nm, and (iii) 33.5% at Di~82nm. The nanotubes with Di~59nm exhibited the greatest roughness parameter of Sa (mean roughness), leading to the lowest ability to interlock with SaOS2 cells. PMID- 25448350 TI - In situ quasi-static and dynamic nanoindentation tests on calcified nodules formed by osteoblasts: Implication of glucocorticoids responsible for osteoblast calcification. AB - The functional requirements of regenerated calcified tissues are that they enable the tissues to bear a variety of imposed stress and consequent contact-induced strain without substantial fracture. Here we demonstrate the effects of glucocorticoid hormones such as dexamethasone and hydrocortisone on the nanomechanical properties of calcified nodules formed by mouse osteoblastic MC3T3 E1 cells in differentiation-inducing medium containing ascorbic acid and beta glycerophosphate. Neither cell proliferation nor calcium deposition, evaluated using alizarin red and von Kossa staining, was affected by dexamethasone. On the other hand, calcified nodules formed in the presence of dexamethasone were significantly harder and stiffer than those formed in their absence. In particular, a series of nanoindentation tests revealed that the calcified nodules formed in the presence of dexamethasone showed enhanced stiffness against dynamic strain as compared to a quasi-static load. Furthermore, Raman spectroscopy revealed that dexamethasone and hydrocortisone increased the apatite/matrix ratio and lowered that of carbonate in the nodules. Our results suggest that glucocorticoids are required for in vitro formation by osteoblasts of more mature calcified nodules containing apatite/phosphate. PMID- 25448351 TI - A general strategy to prepare different types of polysaccharide-graft poly(aspartic acid) as degradable gene carriers. AB - Owing to their unique properties such as low cytotoxicity and excellent biocompatibility, poly(aspartic acid) (PAsp) and polysaccharides are good candidates for the development of new biomaterials. In order to construct better gene delivery systems by combining polysaccharides with PAsp, in this work, a general strategy is described for preparing series of polysaccharide-graft-PAsp (including cyclodextrin (CD), dextran (Dex) and chitosan (CS)) gene vectors. Such different polysaccharide-based vectors are compared systematically through a series of experiments including degradability, pDNA condensation capability, cytotoxicity and gene transfection ability. They possess good degradability, which would benefit the release of pDNA from the complexes. They exhibit significantly lower cytotoxicity than the control 'gold-standard' polyethylenimine (PEI, ~25kDa). More importantly, the gene transfection efficiency of Dex- and CS-based vectors is 12-14-fold higher than CD-based ones. This present study indicates that properly grafting degradable PAsp from polysaccharide backbones is an effective means of producing a new class of degradable biomaterials. PMID- 25448354 TI - In vitro evaluation of (-)alpha-bisabolol as a promising agent against Leishmania amazonensis. AB - Current treatments for leishmaniasis present some difficulties due to their toxicity, the use of the intravenous route for administration and therapy duration, which may lead to treatment discontinuation. The aim of this study is to investigate new treatment alternatives to improve patients well being. Therefore, we evaluated the inhibitory effect of (-)alpha-bisabolol, a sesquiterpene alcohol found in various essential oils of different plant species, against the promastigotes and intracellular amastigotes forms of Leishmania amazonensis, as well as the cytotoxic, morphological and ultrastructural alterations of treated cells. Promastigotes forms of L. amazonensis were incubated with (-)alpha-bisabolol to determine the antileishmanial activity of this compound. The cytotoxicity effect was evaluated by testing against J774.G8 cells. After these tests, the infected and uninfected cells with L. amazonensis were used to determine if the (-)alpha-bisabolol was able to kill intracellular parasites and to cause some morphological changes in the cells. The (-)alpha bisabolol compound showed significant antileishmanial activity against promastigotes with a 50% effective concentration of 8.07 ug/ml (24 h) and 4.26 ug/ml (48 h). Against intracellular amastigotes the IC50 (inhibitory concentration) of (-)alpha-bisabolol (24 h) was 4.15 ug/ml. The (-)alpha bisabolol also showed a cytotoxic effect against the macrophage strain J774.G8. The value of 50% cytotoxic concentration was 14.82 ug/ml showing that (-)alpha bisabolol is less toxic to macrophages than to the parasite. Ultrastructural studies of treated promastigotes and amastigotes showed several alterations, such as loss of cytoplasmic organelles, including the nucleus, and the presence of lipid inclusions. This study showed that (-)alpha-bisabolol has promising antileishmanial properties, as it can act against the promastigote forms and is able to penetrate the cell, and is also active against the amastigote forms. About 69% of the promastigotes forms suffered mitochondrial membrane damage after treatment with IC50 of (-)alpha-bisabolol, suggesting inhibition of the metabolic activity of parasites. These results open new prospects for research that can contribute to the development of products based on essential oils or isolated compounds from plants for the treatment of cutaneous leishmaniasis. PMID- 25448353 TI - Reprogramming the genome to totipotency in mouse embryos. AB - Despite investigative interest, the artificial derivation of pluripotent stem cells remains inefficient and incomplete reprogramming hinders its potential as a reliable tool in regenerative medicine. By contrast, fusion of terminally differentiated gametes at fertilization activates efficient epigenetic reprogramming to ensure totipotency of early embryos. Understanding the epigenetic mechanisms required for the transition from the fertilized egg to the embryo can improve efforts to reprogram differentiated cells to pluripotent/totipotent cells for therapeutic use. We review recent discoveries that are providing insight into the molecular mechanisms required for epigenetic reprogramming to totipotency in vivo. PMID- 25448355 TI - A 78 kDa host cell invasion protein of Neospora caninum as a potential vaccine candidate. AB - Neosporosis is an intracellular protozoan disease caused by Neospora caninum. Until now, there is no effective vaccine to prevent neosporosis. The host cell binding protein has the potential as neosporosis vaccine. In the present study, a T7 phage display library was constructed and screened using Vero cells to obtain host cell binding protein of N. caninum. Two host cell binding proteins, a hypothetical protein of 78 kDa (named as NcP78) homologous to the acylglycerol lipase of Toxoplasma gondii ME49 (XP_002370319.1) and NcGRA7 (known as a dense granules protein that is involved in the invasion of N. caninum to the host cells), were identified. Immune responses induced by recombinant NcP78 and NcGRA7 proteins and their protective efficacies against homologous challenge in BALB/c mice were evaluated respectively. Results showed that recombinant NcP78 and NcGRA7 could elicit both Th1 and Th2 immune responses (with the elevated levels of IgG1 and IgG2a antibody), but predominately a Th2 immune response with a high level of IgG1. The ani-NcP78 and anti-NcGRA7 serum also had inhibitory effects on N. caninum invasion to Vero cells in vitro, which indicated that both NcP78 and NcGRA7 proteins were involved in host cell invasion. Recombinant NcP78 and NcGRA7 could not prolong the survival times and improve the survival rates of dams, but could prolong the survival times and improve the survival rates of offspring significantly. Moreover, the recombinant NcP78 and NcGRA7 could reduce the brain parasite load of dams and offspring. Though these protein vaccines could not effectively alleviate the symptom of abortion, they could increase the number of born offspring significantly, indicating that Nc78 and NcGRA7 recombinant proteins could provide a partial protection against N. caninum infection in mice. PMID- 25448352 TI - The effects of glycosaminoglycan degradation on the mechanical behavior of the posterior porcine sclera. AB - Pathological changes in scleral glycosaminoglycan (GAG) content and in scleral mechanical properties have been observed in eyes with glaucoma and myopia. The purpose of this study is to investigate the effect of GAG removal on the scleral mechanical properties to better understand the impact of GAG content variations in the pathophysiology of glaucoma and myopia. We measured how the removal of sulphated GAG (s-GAG) affected the hydration, thickness and mechanical properties of the posterior sclera in enucleated eyes of 6-9 month-old pigs. Measurements were made in 4 regions centered on the optic nerve head (ONH) and evaluated under 3 conditions: no treatment (control), after treatment in buffer solution alone, and after treatment in buffer containing chondroitinase ABC (ChABC) to remove s GAGs. The specimens were mechanically tested by pressure-controlled inflation with full-field deformation mapping using digital image correlation (DIC). The mechanical outcomes described the tissue tensile and viscoelastic behavior. Treatment with buffer alone increased the hydration of the posterior sclera compared to controls, while s-GAG removal caused a further increase in hydration compared to buffer-treated scleras. Buffer-treatment significantly changed the scleral mechanical behavior compared to the control condition, in a manner consistent with an increase in hydration. Specifically, buffer-treatment led to an increase in low-pressure stiffness, hysteresis, and creep rate, and a decrease in high-pressure stiffness. ChABC-treatment on buffer-treated scleras had opposite mechanical effects than buffer-treatment on controls, leading to a decrease in low-pressure stiffness, hysteresis, and creep rate, and an increase in high-pressure stiffness and transition strain. Furthermore, s-GAG digestion dramatically reduced the differences in the mechanical behavior among the 4 quadrants surrounding the ONH as well as the differences between the circumferential and meridional responses compared to the buffer-treated condition. These findings demonstrate a significant effect of s-GAGs on both the stiffness and time-dependent behavior of the sclera. Alterations in s-GAG content may contribute to the altered creep and stiffness of the sclera of myopic and glaucoma eyes. PMID- 25448356 TI - Morphological and molecular characterization of Eimeria paludosa coccidian parasite (Apicomplexa:Eimeriidae) in a dusky moorhen (Gallinula tenebrosa, Gould, 1846) in Australia. AB - An Eimeria species is described from a dusky moorhen (Gallinula tenebrosa). Sporulated oocysts (n = 40) are ovoid, with a pitted single-layered oocyst wall in young oocysts and a relatively smooth wall in the mature oocysts. Oocyst wall was 1.0 um thick, oocysts measured 17.3 * 13.3 (16.3-17.9 * 12.7-13.9) um, oocyst length/width (L/W) ratio, 1.3. Oocyst residuum was absent. A large polar granule was always observed in the centre of the micropyle and many small polar granules were observed when the focus was on the wall. Sporocysts are elongate-ovoid, 8.4 * 5.1 (8.0-8.9 * 4.9-5.5) um, sporocyst L/W ratio, 1.6 (1.5-1.8), sporocyst residuum was present, composed of numerous granules in a spherical or ovoid mass. Each sporocyst contained 2 elongate sporozoites, 7.7 * 2.6 (7-10 * 2.2-3) um. A spherical-ellipsoid posterior refractile body was found in the sporozoites. A nucleus is located immediately anterior to the posterior refractile body. When the oocyst measurements and features were compared with valid Eimeria species from hosts in the Rallidae family, this Eimeria species was identified as E. paludosa. This is the first report of E. paludosa in Australia and the dusky moorhen (Gallinula tenebrosa) in a new host for this species. Molecular analysis was conducted at three loci; the 18S and 28S ribosomal RNA genes and the mitochondrial cytochrome oxidase gene (COI). At the 18 S locus, E. paludosa shared 97.3% genetic similarity with Eimeria gruis (GenBank accession number: AB544336). It also shared 99.2% genetic similarity with Eimeria crecis (GenBank accession numbers: HE653904 and HE653905) and 98.5% similarity with Eimeria nenei (GenBank accession numbers: HE653906), both of which were identified from a corncrake (Crex crex) in the United Kingdom. At the 28S locus, E. paludosa shared 91.4% similarity with E. papillata from a chicken (Gallus gallus) in the USA. At COI locus, E. paludosa was in a clade by itself and shared 87.2% similarity with E. irresidua, from a European rabbit (Oryctolagus cuniculus) from the Czech Republic. This is the first molecular characterization of E. paludosa. PMID- 25448358 TI - An in vitro model of infection of chicken embryos by Cryptosporidium baileyi. AB - Cryptosporidiosis is one of the most prevalent parasitic infections in domesticated, caged and wild birds. Cryptosporidium baileyi is the most common species reported in a wide range of avian hosts. Although this parasite is well investigated, there is no adequate in vitro model for its endogenous development, and therefore, knowledge of each life cycle phase is scarce. In the present study, an in vitro model for C. baileyi in chicken embryos was developed and the complete life cycle investigated by light and electron microscopy, including both the sexual and asexual reproduction stages. The complete life cycle of C. baileyi was observed during 1-96 h post inoculation (PI), and the average reproduction number of C. baileyi oocysts in allantoic fluid of each chicken embryo was greatest at 168 h PI. These results suggest that chicken embryos could adequately represent the natural host cells and support the development of all the endogenous life cycle stages of C. baileyi, and also provide a new and effective in vitro cultivation system for further studies on antigens, virulence, infectivity, metabolites, and sensitivity of drugs against parasites. PMID- 25448357 TI - Piperaquine and Lumefantrine resistance in Plasmodium berghei ANKA associated with increased expression of Ca2+/H+ antiporter and glutathione associated enzymes. AB - We investigated the mechanisms of resistance of two antimalarial drugs piperaquine (PQ) and lumefantrine (LM) using the rodent parasite Plasmodium berghei as a surrogate of the human parasite, Plasmodium falciparum. We analyzed the whole coding sequence of Plasmodium berghei chloroquine resistance transporter (Pbcrt) and Plasmodium berghei multidrug resistance gene 1(Pbmdr-1) for polymorphisms. These genes are associated with quinoline resistance in Plasmodium falciparum. No polymorphic changes were detected in the coding sequences of Pbcrt and Pbmdr1 or in the mRNA transcript levels of Pbmdr1. However, our data demonstrated that PQ and LM resistance is achieved by multiple mechanisms that include elevated mRNA transcript levels of V-type H(+) pumping pyrophosphatase (vp2), Ca(2+)/H(+) antiporter (vcx1), gamma glutamylcysteine synthetase (ggcs) and glutathione-S-transferase (gst) genes, mechanisms also known to contribute to chloroquine resistance in P. falciparum and rodent malaria parasites. The increase in ggcs and gst transcript levels was accompanied by high glutathione (GSH) levels and elevated activity of glutathione-S-transferase (GST) enzyme. Taken together, these results demonstrate that Pbcrt and Pbmdr1 are not associated with PQ and LM resistance in P. berghei ANKA, while vp2, vcx1, ggcs and gst may mediate resistance directly or modulate functional mutations in other unknown genes. PMID- 25448359 TI - Mini-FLOTAC for counting Toxoplasma gondii oocysts from cat feces--comparison with cell counting plates. AB - Oocysts of Toxoplasma gondii represent one of the most common environmental contaminants causing the zoonotic infection toxoplasmosis. The aim of the present study was to compare the Mini-FLOTAC device with traditional cell counting plates (Kova Slide) for the detection of T. gondii oocysts from feline feces. Two types of experiments were performed: (i) purified oocysts were counted in different dilutions and (ii) specific pathogen free T. gondii-negative cat feces was inoculated with numbers of purified oocysts and counting was performed directly from feces. Our analysis showed a thousand times higher sensitivity of Mini FLOTAC (5 * 10(2) oocysts) compared to Kova Slide (5 * 10(5) oocysts). Also, when compared by McNemar's test, counting of the purified oocysts showed a higher sensitivity of Mini-FLOTAC compared to Kova Slide, for a dilution of 10(3) oocysts/ml (chi(2) = 6.1; P < 0.05). A better sensitivity was also found with Mini-FLOTAC in dilutions of 10(5) and 10(4) oocysts/ml, when counted from feces (chi(2) = 4.2 and 8.1, respectively, P < 0.05). Our results show that Mini-FLOTAC is more sensitive than traditional methods of T. gondii oocysts detection and quantification is more accurate. Furthermore, Mini-FLOTAC simplicity and cost effectiveness allow it to be used with light microscopes in any laboratory or field conditions. We therefore recommend its use for regular screening. Further studies are needed to validate Mini-FLOTAC for the detection of oocysts in soil and water samples in field conditions. PMID- 25448360 TI - Production of MMP-9 and inflammatory cytokines by Trypanosoma cruzi-infected macrophages. AB - Matrix metalloproteinases (MMPs) constitute a large family of Zn(2+) and Ca(2+) dependent endopeptidases implicated in tissue remodeling and chronic inflammation. MMPs also play key roles in the activation of growth factors, chemokines and cytokines produced by many cell types, including lymphocytes, granulocytes, and, in particular, activated macrophages. Their synthesis and secretion appear to be important in a number of physiological processes, including the inflammatory process. Here, we investigated the interaction between human and mouse macrophages with T. cruzi Colombian and Y strains to characterize MMP-9 and cytokine production in this system. Supernatants and total extract of T. cruzi infected human and mouse macrophages were obtained and used to assess MMP-9 profile and inflammatory cytokines. The presence of metalloproteinase activity was determined by zymography, enzyme-linked immunosorbent assay and immunoblotting assays. The effect of cytokines on MMP-9 production in human macrophages was verified by previous incubation of cytokines on these cells in culture, and analyzed by zymography. We detected an increase in MMP-9 production in the culture supernatants of T. cruzi infected human and mouse macrophages. The addition of IL-1beta or TNF-alpha to human macrophage cultures increased MMP-9 production. In contrast, MMP-9 production was down-modulated when human macrophage cultures were treated with IFN-gamma or IL-4 before infection. Human macrophages infected with T. cruzi Y or Colombian strains produced increased levels of MMP-9, which was related to the production of cytokines such as IL 1beta, TNF-alpha and IL-6. PMID- 25448361 TI - Stimuli-responsive bile acid-based metallogels forming in aqueous media. AB - The synthesis and gelation properties of a picolinic acid conjugated bile acid derivative in the presence of metal salts along with the stimuli-responsiveness of the systems are reported. The gels are formed in the presence of Cu(2+) ions in the solvent systems composed of 30-50% of organic solvent (MeOH, acetonitrile, or acetone) in water. The gels respond to various stimuli: they can be formed upon sonication or shaking, and their gel-sol transformation can be triggered by a variety of chemical species. NMR, MS, and SEM techniques are exploited in order to gain a deeper insight on the self-assembled systems. PMID- 25448362 TI - Synthesis and biological evaluation of nandrolone-bodipy conjugates. AB - Here, we report synthesis and biological evaluation of fluorescent nandrolone-3 carboxymethyloxime derivatives conjugated with green-emitting bodipy dye via PEG linkers. All the newly-synthesized compounds were evaluated for their effect on cell proliferation in vitro in MCF-7, LNCaP, PC-3 and HEK 293T model cell lines using WST-1 assay. By means of live-cell fluorescence microscopy, the intracellular localization of nandrolone-bodipy conjugates was revealed in endoplasmic reticulum. Moreover, we performed competitive localization study with nonfluorescent nandrolone, metandrolone, boldenone, trenbolone, and testosterone. PMID- 25448363 TI - Synthesis and antibacterial activity evaluation of two androgen derivatives. AB - In this study two androgen derivatives were synthesized using several strategies; the first stage an aza-steroid derivative (3) was developed by the reaction of a testosterone derivative (1) with thiourea (2) in presence of hydrogen chloride. The second step, involves the synthesis of an amino-steroid derivative (4) by the reaction of 1 with 2 using boric acid as catalyst. The third stage was achieved by the preparation of an aminoaza-androgen derivative (6) by the reaction of 3 with ethylenediamine using boric acid as catalyst. In addition, the compound 6 was made reacting with dihydrotestosterone to form a new androgen derivative (7) in presence of boric acid. The following step was achieved by the reaction of 7 with chloroacetyl chloride to synthesize an azetidinone-androgen derivative (8) using triethylamine as catalyst. Additionally, a thiourea-androgen derivative (9) was synthetized by the reaction of 4 with dihydrotestosterone using boric acid as catalyst. Finally, the compound 9 was made reacting with chloroacetyl chloride in presence of triethylamine to synthesize a new azetidinone-androgen derivative (10). On the other hand, antibacterial activity of compounds synthesized was evaluated on Gram negative (Escherichia coli and Vibrio cholerae) and Gram positive (Staphylococos aureus) bacteria. The results indicate that only the compound 3 and 8 decrease the growth bacterial of E. coli and V. cholerae. Nevertheless, growth bacterial of S. aureus was not inhibited by these compounds. These data indicate that antibacterial activity exerted by the compounds 3 and 8 depend of their structure chemical in comparison with the controls and other androgen derivatives that are involved in this study. PMID- 25448364 TI - Quantification of the effect of Lipo-PGE1 on angiogenesis. AB - Fifteen rabbits were used to assess the effect of Lipo-PGE1 on neovascularization. Merocel((r)) and Alloderm((r)) of the same size were implanted separately under the back skin to act as matrices for vessel growth. Lipo-PGE1 was injected intravenously for 2 weeks in an experimental group of eight rabbits, and they were compared with a control group of seven untreated animals. Blood flow was measured using the (99m)TcO4(-) clearance technique. The mean blood clearance halftime (T1/2) and washout radioactivity were measured. Newly formed vessels were counted by CD31. The mean clearance halftime was 4005 +/- 2161.3 and 13840 +/- 4644.6 s in the experimental and control group, respectively, in the 1 * 2 * 1.5-cm-sized implants (p = 0.0125), and 1560 +/- 1174.7 and 3405 +/- 807.03 s, respectively, in the 2 * 2 * 1.5-cm-sized implants (p = 0.0413). Histological examinations revealed that the mean numbers of newly formed vessels in the experimental and control groups were 11 +/- 1.58 and 7.8 +/ 1.71, respectively, in the 1 * 2 * 1.5-cm-sized implants (p = 0.0501), and 20.19 +/- 12.47 and 12.33 +/- 3.25, respectively, in the 2 * 2 * 1.5-cm-sized implants (p = 0.02679). Lipo-PGE1 was found to be effective in promoting angiogenesis in a rabbit matrix model. PMID- 25448365 TI - The use of polypropylene mesh in chest wall reconstruction; a novel approach. PMID- 25448366 TI - Experience and anatomical study of modified lengthening temporalis myoplasty for established facial paralysis. AB - Lengthening temporalis myoplasty, reported by Daniel Labbe in 1997, is a unique and definite facial reanimation procedure that involves moving the whole temporal muscle anteroinferiorly and inserting its tendon directly into the nasolabial fold. In the present article, we report our experience in the use of his modified method of the procedure, which preserves the zygomatic arch by transecting the coronoid process through the nasolabial fold incision. We also describe our cadaveric study that aimed to elucidate a secure approach for coronoid process transection. We performed this procedure in five patients with permanent facial paralysis. To improve facial symmetry, we also performed several additional static reconstructions such as T-shaped double-sleeve fascia grafts for lower lip deformities. We were successful in achieving considerable static improvement at rest, immediately after the surgery, and the recovery of facial movement was apparent approximately 3 months after the surgery. With regard to the cadaveric study, we noted that the entry to the buccal fat region, which is also the pathway of the temporal fascia, was a narrow space, and a short transection of the medial upper edge of the masseter fascia would make it easy to locate the coronoid process. Therefore, for a safe and secure access to the coronoid process from the nasolabial fold, we believe that we should first expose the cranial side and continue to dissect along the side and lower edge of the maxilla to locate the medial upper edge of the masseter fascia. By transecting along its edge, we could easily access the coronoid process, located immediately behind it, and widen the pathway of the temporal fascia. This modified method is less invasive and simpler compared to the original procedure, and understanding the detailed anatomy for dissection would help surgeons perform this procedure more confidently. PMID- 25448367 TI - Precision nipple positioning after nipple sparing mastectomy with hydrocolloid nipple adjuster. PMID- 25448368 TI - Reconstruction of complex soft-tissue defects around the knee joint with distally based split vastus lateralis musculocutaneous flap: a new technique. AB - AIMS: The aim of this study was to report our experience of using distally based spilt vastus lateralis musculocutaneous flaps for soft-tissue defects around the knee joint - a new technique. MATERIAL AND METHODS: Cadaver dissection studies were conducted in three cadavers to demonstrate perforators entering the lower third of the vastus lateralis muscle arising from the superior lateral genicular artery. Its application in eight clinical cases for the reconstruction of soft tissue defects around the knee joint is reported. RESULTS: Seven out of eight flaps survived well without any flap loss. One flap with a skin island measuring 12 * 20 cm suffered a loss of 2 cm distally. This was later treated with skin grafting. Six out of eight donor sites were closed primarily. Six patients achieved full functional range of motion by 3 months. One patient had a 10 degrees limitation of knee extension. One patient had foot drop due to primary injury and walks with a limping gait. CONCLUSIONS: This flap is a new reconstructive option for knee defects. It can reach distally up to the tibial tuberosity and does not require an intraoperative change of position. The donor site can be closed primarily and is hidden inside the clothing. The function of the knee is not affected as the majority of the muscle is kept in continuity. PMID- 25448369 TI - Anatomical basis of a proximal fasciocutaneous extension of the distal-based posterior interosseous flap that allows exclusion of the proximal posterior interosseous artery. AB - OBJECTIVE: The objective of this study was to provide anatomical information for the repair of small tissue defects in the hand with posterior interosseous artery chain-link perforator flaps, a proximal fasciocutaneous extension of the distal based posterior interosseous flap, which allows the exclusion of the proximal posterior interosseous artery. METHODS: Fourteen posterior interosseous artery chain-link perforator flaps taken from human cadavers were studied by the following three methods: latex perfusion for microanatomy analysis, denture material and vinyl chloride mixed packing for cast analysis, and latex perfusion for the production of clearance specimens. Statistical analysis was performed on cutaneous perforators coming from the intermuscular septum of the extensor carpi ulnaris and the extensor digitorum communis. A cluster analysis was conducted to determine the overall distribution of perforators. RESULTS: There are two main clusters of perforators at a relative distance of 21% and 48% along the ulnar head-to-lateral epicondyle interval. On average, the posterior interosseous artery extends six cutaneous perforators through the intermuscular septum of the extensor carpi ulnaris and the extensor digitorum communis. Of these six arteries, two are clinically significant perforators (0.5 mm or more in diameter) and are located 6 +/- 2 cm proximal to the head of the ulna and 10 +/- 1 cm distal to the lateral epicondyle of the humerus. Their mean diameters are 0.5 +/- 0.1 and 0.6 +/- 0.1 mm, with pedicle lengths of 16.8 +/- 5.1 and 21.2 +/- 12.3 mm, respectively. At the two main clusters of perforator-intensive sites, the vessel chains formed by adjacent perforators are parallel to the intermuscular septum of the extensor carpi ulnaris and the extensor digitorum communis. CONCLUSIONS: This study demonstrates that the posterior interosseous artery has two main clusters of perforators in the middle and distal one-fifth of the forearm, which can be used for repairing hand defects with posterior interosseous artery chain-link perforator flaps. PMID- 25448371 TI - Warning! The rice test using weight may underestimate implant size by 18% or 2 implant sizes. PMID- 25448370 TI - Prognostic factors for outcome after median, ulnar, and combined median-ulnar nerve injuries: a prospective study. AB - BACKGROUND: A major problem in the surgical treatment of peripheral nerve injuries of the upper extremities is the unpredictable final outcome. More insight and understanding of the prognostic factors is necessary to improve functional outcome after repair of the peripheral nerves. The objective of this study was to identify prognostic factors for the functional recovery of peripheral nerve injury of the forearm and their independent contribution in the outcome in the first year after reconstruction. METHODS: A multicentered prospective study in the Netherlands resulted in the inclusion of 61 patients with a median, ulnar, or combined median-ulnar nerve injury. The age, level of injury, type of nerve injury, number of damaged structures, number of damaged arteries, education, smoking, and posttraumatic stress were analyzed as prognostic factors for functional outcome after repair of the peripheral nerves. The outcome parameters were sensory recovery (Semmes-Weinstein monofilament test) and motor recovery (Medical Research Council (MRC) score, power grip, and pinch grip) and the ability to perform daily activities. RESULTS: Gender, age, level of education, number of injured arteries and structures, damaged nerve, location of the injury, type of the nerve injury, and posttraumatic stress at 1 and 3 months after repair of the peripheral nerve injury were found to be predictors of functional recovery. CONCLUSIONS: Our prospective analysis of prognostic factors shows several factors to be predictive for the functional recovery after peripheral nerve injuries of the median and/or ulnar nerve of the forearm. Sensibility of the hand, power grip, and DASH score (DASH, Disabilities of Arm, Shoulder and Hand) have proven to be the three best prognostic factors in this study. Of these prognostic factors, only posttraumatic stress can be influenced to optimize functional outcome. PMID- 25448372 TI - Simple anchoring suture to minimise asymmetric nipple-areola complex (NAC) in immediate unilateral breast reconstruction with implant. PMID- 25448373 TI - Large heel soft tissue defects managed successfully with reverse medial crural fasciocutaneous flap: a 7-year single-center experience with 21 consecutive cases. AB - The medial crural fasciocutaneous flap is a reliable cutaneous flap that can be used for soft tissue reconstruction in the extremities. The purpose of this article is to evaluate the application and clinical significance of this surgical technique in the reconstruction of heel soft tissue defects. Twenty-one cases of heel soft tissue defect between March 2005 and March 2012 were included in this study. Wound sizes varied from 5.0 * 5.5 to 7.5 * 10.0 cm. All cases were managed with a reverse medial crural fasciocutaneous flap. Patient demographics and case information were analyzed and are reported. The sizes of the reverse medial crural fasciocutaneous flap varied from 6.5 * 10.0 to 9.0 * 15.0 cm; the average size was 7.7 * 13.8 cm. Out of the 21 consecutive cases, 20 flaps survived intact and one flap underwent partial necrosis. Follow-up observations were conducted for 6-36 months. The cosmetic results were satisfactory, without apparent bulkiness; the weight-bearing outcomes were satisfactory. The donor site can be closed primarily or by skin graft. Reverse medial crural fasciocutaneous flap transfer is appropriate for the reconstruction of heel soft tissue defects. The method is safe and can cover large heel defects. PMID- 25448374 TI - Neuroanatomic correlates of poststroke hyperglycemia. AB - OBJECTIVE: A study was undertaken to determine associations between ischemic stroke sites and poststroke hyperglycemia (PSH). METHODS: Nondiabetic patients with first ever ischemic stroke confirmed by imaging were prospectively included. Blood glucose level (BGL), National Institute of Health Stroke Scale (NIHSS) score, and clinical parameters were assessed on admission. BGL was dichotomized for elevated versus normal levels using a cutoff value of >7.0 mmol/l. Clinical parameters were correlated with BGL and were compared between patient groups with elevated versus normal glucose values. A voxel-based lesion symptom mapping (VLSM) analysis adjusted for confounding variables was performed correlating sites of ischemic lesions with PSH. RESULTS: Of 1,281 stroke patients screened, 229 (mean age = 66.3 +/- 15.9 years) met the inclusion criteria. Patients with elevated BGL were older, had higher NIHSS scores, and had larger infarcts compared to those without elevated glucose levels. Spearman rank analysis showed correlations between BGL and age, infarct size, heart rate (HR), and NIHSS scores (p <= 0.05). The VLSM analysis adjusted for these confounding factors demonstrated associations between PSH and damaged voxels in right hemispheric insular and opercular areas. INTERPRETATION: The data indicate that damage in the right insulo-opercular areas contributes to PSH. The association between sympathetically mediated increase of HR and BGL suggests disinhibition of sympathetic outflow as a possible mechanism for PSH. PMID- 25448375 TI - Early brain changes associated with psychotherapy in major depressive disorder revealed by resting-state fMRI: evidence for the top-down regulation theory. AB - BACKGROUND: Major depressive disorder (MDD) is associated with dysfunction of the emotional circuitry in the brain. Psychotherapy and antidepressant treatment both aid in modulating this dysfunction, albeit probably through different mechanisms. A plausible "top-down" emotional regulation mechanism for psychotherapy has been described in previous studies, but the underlying findings are still contradictory. METHODS: A total of 23 MDD patients and 20 healthy controls were enrolled. The early neural effects within 5 weeks of guided imagery-a psychotherapeutic method for treating depression-were assessed through resting state functional magnetic resonance imaging using the regional homogeneity analytical method. RESULTS: At baseline, regional homogeneity was reduced in cortical regions and increased in limbic areas in the pre-treatment scans of MDD patients as compared to controls. After 5 weeks of guided imagery therapy, regional homogeneity in the ventromedial prefrontal cortex and the anterior cingulate gyrus both increased. Higher pre-treatment regional homogeneity in the dorsal anterior cingulate gyrus was positively correlated with an improved response to guided imagery therapy. CONCLUSION: The changes in regional homogeneity induced by guided imagery therapy demonstrate that this method of psychotherapy takes effect through a "top-down" mechanism. Future studies comparing various psychotherapeutic methodologies across multiple time points in the treatment course should yield more valuable insights on this topic. PMID- 25448376 TI - Analysis of EEG activity in response to binaural beats with different frequencies. AB - When two coherent sounds with nearly similar frequencies are presented to each ear respectively with stereo headphones, the brain integrates the two signals and produces a sensation of a third sound called binaural beat (BB). Although earlier studies showed that BB could influence behavior and cognition, common agreement on the mechanism of BB has not been reached yet. In this work, we employed Relative Power (RP), Phase Locking Value (PLV) and Cross-Mutual Information (CMI) to track EEG changes during BB stimulations. EEG signals were acquired from 13 healthy subjects. Five-minute BBs with four different frequencies were tested: delta band (1 Hz), theta band (5 Hz), alpha band (10 Hz) and beta band (20 Hz). We observed RP increase in theta and alpha bands and decrease in beta band during delta and alpha BB stimulations. RP decreased in beta band during theta BB, while RP decreased in theta band during beta BB. However, no clear brainwave entrainment effect was identified. Connectivity changes were detected following the variation of RP during BB stimulations. Our observation supports the hypothesis that BBs could affect functional brain connectivity, suggesting that the mechanism of BB-brain interaction is worth further study. PMID- 25448377 TI - Examining the N400 semantic context effect item-by-item: relationship to corpus based measures of word co-occurrence. AB - With increasing availability of digital text, there has been an explosion of computational methods designed to turn patterns of word co-occurrence in large text corpora into numerical scores expressing the "semantic distance" between any two words. The success of such methods is typically evaluated by how well they predict human judgments of similarity. Here, I examine how well corpus-based methods predict amplitude of the N400 component of the event-related potential (ERP), an online measure of lexical processing in brain electrical activity. ERPs elicited by the second words of 303 word pairs were analyzed at the level of individual items. Three corpus-based measures (mutual information, distributional similarity, and latent semantic analysis) were compared to a traditional measure of free association strength. In a regression analysis, corpus-based and free association measures each explained some of the variance in N400 amplitude, suggesting that these may tap distinct aspects of word relationships. Lexical factors of concreteness of word meaning, word frequency, number of semantic associates, and orthographic similarity also explained variance in N400 amplitude at the single-item level. PMID- 25448378 TI - Evaluation of fast-track diagnostics and TaqMan array card real-time PCR assays for the detection of respiratory pathogens. AB - Several commercial assays are now available to detect the nucleic acid of multiple respiratory pathogens from a single specimen. Head-to-head comparisons of such assays using a single set of standard specimens provide additional information about key assay parameters such as sensitivity, specificity and lower limits of detection, and help to inform the decision regarding which method to use. We evaluated two real-time PCR platforms: the Fast-track Diagnostics(r) (FTD) multiplex respiratory panel and a TaqMan array card (TAC) for simultaneous uniplex detection of multiple respiratory pathogens. Two sets of samples were used to evaluate the assays. One set was created by spiking pooled nasal wash or phosphate buffered saline with specified volumes of known concentrations of virus and/or bacteria. Clinical nasal wash specimens from children with lower respiratory tract illness comprised the other set. Thirteen pathogen targets were compared between the two platforms. Testing with a validation panel of spiked samples revealed a sensitivity of 96.1% and 92.9% for the FTD and TAC assays, respectively. Specificity could not be reliably calculated due to a suspected contamination of the sample substrate. Inter-assay agreement was high (> 95%) for most targets. Previously untested clinical specimens tested by both assays revealed a high percent agreement (> 95%) for all except rhinovirus, enterovirus and Streptococcus pneumoniae. Limitations of this evaluation included extraction of the validation samples by two different methods and the evaluation of the assays in different laboratories. However, neither of these factors significantly impacted inter-assay agreement for these sets of samples, and it was demonstrated that both assays could reliably detect clinically relevant concentrations of bacterial and viral pathogens. PMID- 25448379 TI - Cryotolerance of Day 2 or Day 6 in vitro produced ovine embryos after vitrification by Cryotop or Spatula methods. AB - This study was conducted to evaluate the cryotolerance of in vitro produced ovine embryos submitted to vitrification at different developmental stages using two methods of minimum volume and rapid cooling rate. Embryos were vitrified at early stage (2 to 8-cells) on Day 2 or at advanced stage (morulae and blastocysts) on Day 6 after in vitro fertilization. Vitrification procedure consisted of the Cryotop (Day 2, n=165; Day 6, n=174) or the Spatula method (Day 2, n=165; Day 6, n=175). Non vitrified embryos were maintained in in vitro culture as a control group (n=408). Embryo survival was determined at 3h and 24h after warming, development and hatching rates were evaluated on Day 6 and Day 8 after fertilization, and total cell number was determined on expanded blastocysts. Embryo survival at 24h after warming increased as the developmental stage progressed (P<0.05) and was not affected by the vitrification method. The ability for hatching of survived embryos was not affected by the stage of the embryos at vitrification or by the vitrification method. Thus, the proportion of hatching from vitrified embryos was determined by the survival rate and was lower for Day 2 than Day 6 vitrified embryos. The percentage of blastocysts on Day 8 was lower for the embryos vitrified on Day 2 than Day 6 (P<0.05), and was lower for both days of vitrification than for non-vitrified embryos (P<0.05). No interaction of embryo stage by vitrification method was found (P=NS) and no significant difference was found in the blastocyst cell number among vitrified and non vitrified embryos. In conclusion, both methods using minimum volume and ultra rapid cooling rate allow acceptable survival and development rates in Day 2 and Day 6 in vitro produced embryos in sheep. Even though early stage embryos showed lower cryotolerance, those embryos that survive the vitrification-warming process show high development and hatching rates, similar to vitrification of morulae or blastocysts. PMID- 25448380 TI - Autoregressive model in the Lp norm space for EEG analysis. AB - The autoregressive (AR) model is widely used in electroencephalogram (EEG) analyses such as waveform fitting, spectrum estimation, and system identification. In real applications, EEGs are inevitably contaminated with unexpected outlier artifacts, and this must be overcome. However, most of the current AR models are based on the L2 norm structure, which exaggerates the outlier effect due to the square property of the L2 norm. In this paper, a novel AR object function is constructed in the Lp (p<=1) norm space with the aim to compress the outlier effects on EEG analysis, and a fast iteration procedure is developed to solve this new AR model. The quantitative evaluation using simulated EEGs with outliers proves that the proposed Lp (p<=1) AR can estimate the AR parameters more robustly than the Yule-Walker, Burg and LS methods, under various simulated outlier conditions. The actual application to the resting EEG recording with ocular artifacts also demonstrates that Lp (p<=1) AR can effectively address the outliers and recover a resting EEG power spectrum that is more consistent with its physiological basis. PMID- 25448381 TI - A non-invasive head-holding device for chronic neural recordings in awake behaving monkeys. AB - BACKGROUND: We have developed a novel head-holding device for behaving non-human primates that affords stability suitable for reliable chronic electrophysiological recording experiments. The device is completely non invasive, and thus avoids the risk of infection and other complications that can occur with the use of conventional, surgically implanted head-fixation devices. NEW METHOD: The device consists of a novel non-invasive head mold and bar clamp holder, and is customized to the shape of each monkey's head. The head-holding device that we introduce, combined with our recording system and reflection-based eye-tracking system, allows for chronic behavioral experiments and single electrode or multi-electrode recording, as well as manipulation of brain activity. RESULTS AND COMPARISON WITH EXISTING METHODS: With electrodes implanted chronically in multiple brain regions, we could record neural activity from cortical and subcortical structures with stability equal to that recorded with conventional head-post fixation. Consistent with the non-invasive nature of the device, we could record neural signals for more than two years with a single implant. Importantly, the monkeys were able to hold stable eye fixation positions while held by this device, demonstrating the possibility of analyzing eye movement data with only the gentle restraint imposed by the non-invasive head holding device. CONCLUSIONS: We show that the head-holding device introduced here can be extended to the head holding of smaller animals, and note that it could readily be adapted for magnetic resonance brain imaging over extended periods of time. PMID- 25448382 TI - Improving AM ester calcium dye loading efficiency. AB - BACKGROUND: Calcium imaging has unraveled the calcium-dependent mechanisms underlying neuronal function. Acetoxymethyl ester (AM) dyes are widely employed for calcium imaging. Pluronic F127 (PF127) as a surfactant and dimethyl sulfoxide (DMSO) as a solvent are used to dissolve the dyes, but concentrations vary between protocols. How these substances affect loading efficiency is not well characterized. NEW METHOD: We aimed to characterize dye loading in slice cultures. We determined minimum concentrations of surfactant, solvent and dye. The current study shows that the efficiency of AM dye loading depends on the initial stock concentration of PF127. Lowering the PF127 and DMSO concentrations can improve the loading efficiency. RESULTS: Both, pluronic and DMSO are required for successful dye loading. However, dissolving the dyes in lower concentrations of PF127 yielded better staining efficiency. Moreover, lowering the DMSO concentration to ~0.25% improves the efficiency. The strategy allows standard two photon or confocal microscope monitoring of neuronal activity. The labeled cells display spontaneous and evoked calcium transients, and repetitive measurements for up to 24h after loading indicate that the method is not deleterious to neuronal function. COMPARISON WITH EXISTING METHOD(S): Dissolving the AM dyes in lower concentrations of PF127 combines the advantages of high loading efficiency, preserves cell viability and functional integrity, and allows repetitive measures over hours and days. Moreover, we found that the dye itself can be diluted to a final concentration of 1MUM which reduces the experimental costs. CONCLUSION: The method is optimal for calcium imaging in slice cultures. PMID- 25448384 TI - Extra tree forests for sub-acute ischemic stroke lesion segmentation in MR sequences. AB - BACKGROUND: To analyse the relationship between structure and (dys-)function of the brain after stroke, accurate and repeatable segmentation of the lesion area in magnetic resonance (MR) images is required. Manual delineation, the current gold standard, is time consuming and suffers from high intra- and inter-observer differences. NEW METHOD: A new approach is presented for the automatic and reproducible segmentation of sub-acute ischemic stroke lesions in MR images in the presence of other pathologies. The proposition is based on an Extra Tree forest framework for voxel-wise classification and mainly intensity derived image features are employed. RESULTS: A thorough investigation of multi-spectral variants, which combine the information from multiple MR sequences, finds the fluid attenuated inversion recovery sequence to be both required and sufficient for a good segmentation result. The accuracy can be further improved by adding features extracted from the T1-weighted and the diffusion weighted sequences. The use of other sequences is discouraged, as they impact negatively on the results. COMPARISON WITH EXISTING METHODS: Quantitative evaluation was carried out on 37 clinical cases. With a Dice coefficient of 0.65, the method outperforms earlier published methods. CONCLUSIONS: The approach proves especially suitable to differentiate between new stroke and other white matter lesions based on the FLAIR sequence alone. This, and the high overlap, renders it suitable for automatic screening of large databases of MR scans, e.g. for a subsequent neuropsychological investigation. Finally, each feature's importance is assessed in detail and the approach's statistical dependency on clinical and image characteristics is investigated. PMID- 25448383 TI - Neurons can be labeled with unique hues by helper virus-free HSV-1 vectors expressing Brainbow. AB - BACKGROUND: A central problem in neuroscience is elucidating synaptic connections, the connectome. Because mammalian forebrains contain many neurons, labeling specific neurons with unique tags is desirable. A novel technology, Brainbow, creates hundreds of hues by combinatorial expression of multiple fluorescent proteins (FPs). NEW METHOD: We labeled small numbers of neurons, and their axons, with unique hues, by expressing Brainbow from a helper virus-free Herpes Simplex Virus (HSV-1) vector. RESULTS: The vector expresses a Brainbow cassette containing four FPs from a glutamatergic-specific promoter. Packaging HSV-Brainbow produced arrays of seven to eight Brainbow cassettes, and using Cre, each FP gene was in a position to be expressed, in different cassettes. Delivery into rat postrhinal (POR) cortex or hippocampus labeled small numbers of neurons with different, often unique, hues. An area innervated by POR cortex, perirhinal (PER) cortex, contained axons with different hues. Specific axons in PER cortex were matched to specific cell bodies in POR cortex, using hue. COMPARISON WITH EXISTING METHODS: HSV-Brainbow is the only technology for labeling small numbers of neurons with unique hues. In Brainbow mice, many neurons contain the same hue. Brainbow-adeno-associated virus vectors require transduction of the same neuron with multiple vector particles, confounding neuroanatomical studies. Replication competent Brainbow-pseudorabies virus vectors label multiple neurons with the same hue. CONCLUSIONS: Attractive properties of HSV-Brainbow include each vector particle contains multiple cassettes, representing numerous hues, recombination products are stabile, and experimental control of the number of labeled neurons. Labeling neurons with unique hues will benefit mapping forebrain circuits. PMID- 25448386 TI - Toxin profile in samples collected in fresh and brackish water in Germany. AB - The simultaneous detection of cyanotoxins is an important issue in order to prevent intoxications. In the present paper an Ultra Performance liquid Chromatography tandem mass spectrometry UPLC-MS/MS method was developed in order to simultaneously identify and quantify cylindrospermopsin (CYN), several microcystins (MC-LR, MC-RR, MC-YR) and some anatoxin-a (ATX-a) analogues. By using this new method all these toxins can be quickly separate. In addition the amino acid phenylalanine (Phe) can also be separate and therefore misidentifications with ATX-a can be avoided. By using this new method the presence of these toxins was studied in samples collected in several German localizations within the sampling program of the European Project MUAqua (Universal microarrays for the evaluation of fresh-water quality based on detection of pathogens and their toxins). In these conditions, several ATX-a analogues, Phe, MC-LR and MC-RR were reported in samples collected. PMID- 25448385 TI - Nonparametric variogram modeling with hole effect structure in analyzing the spatial characteristics of fMRI data. AB - When analyzing functional neuroimaging data, it is particularly important to consider the spatial structure of the brain. Some researchers have applied geostatistical methods in the analysis of functional magnetic resonance imaging (fMRI) data to enhance the detection of activated brain regions. In this paper, we propose a nonparametric variogram model for the complicated spatial characteristics of fMRI data. The new periodic variogram model can well describe the fluctuating spatial structure of fMRI data, considering both the nonlinear physical relationship between the proximate voxels and the functional relationship between distant voxels. We demonstrate the effectiveness of the new variogram model using fMRI data from a saccade study. PMID- 25448388 TI - Soluble prokaryotic expression and purification of crotamine using an N-terminal maltose-binding protein tag. AB - Crotamine is a peptide toxin found in the venom of the rattlesnake Crotalus durissus terrificus. Interestingly, crotamine demonstrates promising anticancer, antimicrobial, and antifungal activities. The crotamine peptide can also deliver plasmids into rapidly dividing cells, such as cancer and stem cells, and demonstrates potent analgesic effects. Efficiently producing crotamine in mammalian cells is difficult because it is both cell-permeable and cytotoxic. Prokaryotic expression of this peptide is also difficult to maintain because it does not fold properly in the cytoplasm, resulting in aggregation and in the formation of inclusion bodies. In our current study, we show for the first time that N-terminal fusion with three protein tags-N-utilization substance protein A (NusA), protein disulfide isomerase b'a' domain (PDIb'a'), and maltose-binding protein (MBP)-enables the soluble overexpression of crotamine in the cytoplasm of Escherichia coli. MBP-tagged crotamine was purified using Ni affinity, anion exchange, and MBP chromatography. The tag was cleaved using TEV protease, and the final product was pure on a silver-stained gels. In total, 0.9 mg pure crotamine was obtained from each liter of bacterial culture with endotoxin level approximately 0.15 EU/MUg, which is low enough to use in biomedical applications. The identity and intramolecular disulfide bonds were confirmed using MALDI-TOF MS analysis. Purified crotamine inhibited the hKv1.3 channel (but not hKv1.5) in a dose-dependent manner with IC50 value of 67.2 +/- 44.7 nM (n = 10), indicating the correct protein folding. The crotamine product fused with MBP at its N terminus also inhibited the hKv1.3 channel, suggesting that the N-terminus is not involved in the channel binding of the toxin. PMID- 25448387 TI - Poisoning by Ipomoea asarifolia in lambs by the ingestion of milk from ewes that ingest the plant. AB - Two experiments, each with 10 pregnant ewes (8 treated and 2 controls) were performed to determine if nursing lambs of lactating ewes become intoxicated when the ewes ingest Ipomoea asarifolia but do not show clinical signs themselves. In the first experiment the sheep grazed I. asarifolia in the field while in the second, sheep were maintained in individual bays consuming dry I. asarifolia at 10% and 20% into their ration. In both experiments the lambs remained confined, consuming only their mother's milk. Four of 8 lambs in the grazing experiment and the 4 nursing lambs from the ewes given 20% I. asarifolia showed signs of I. asarifolia poisoning. These results confirm that the tremorgenic compound of I. asarifolia or its toxic metabolites are eliminated in milk and can intoxicate nursing lambs. PMID- 25448389 TI - Diversity of peptide toxins from stinging ant venoms. AB - Ants (Hymenoptera: Formicidae) represent a taxonomically diverse group of arthropods comprising nearly 13,000 extant species. Sixteen ant subfamilies have individuals that possess a stinger and use their venom for purposes such as a defence against predators, competitors and microbial pathogens, for predation, as well as for social communication. They exhibit a range of activities including antimicrobial, haemolytic, cytolytic, paralytic, insecticidal and pain-producing pharmacologies. While ant venoms are known to be rich in alkaloids and hydrocarbons, ant venoms rich in peptides are becoming more common, yet remain understudied. Recent advances in mass spectrometry techniques have begun to reveal the true complexity of ant venom peptide composition. In the few venoms explored thus far, most peptide toxins appear to occur as small polycationic linear toxins, with antibacterial properties and insecticidal activity. Unlike other venomous animals, a number of ant venoms also contain a range of homodimeric and heterodimeric peptides with one or two interchain disulfide bonds possessing pore-forming, allergenic and paralytic actions. However, ant venoms seem to have only a small number of monomeric disulfide-linked peptides. The present review details the structure and pharmacology of known ant venom peptide toxins and their potential as a source of novel bioinsecticides and therapeutic agents. PMID- 25448390 TI - Bactrian camel nanobody-based immunoassay for specific and sensitive detection of Cry1Fa toxin. AB - The variable domain of the heavy-chain-only antibody (VHH) or nanobody (Nb), derived from camelids, begins to play an important role on the detection of protein markers. In this study, we constructed a phage-displayed library of VHHs against Cry1Fa by immunizing a healthy Bactrian camel with Cry1Fa toxin. After a series of bio-panning and screening by phage display technology, three anti Cry1Fa nanobodies (Nbs) with great difference in complementarity determining region 3 (CDR3) were obtained and they were highly specific to Cry1Fa as well as showed full of activity when exposed to 70 degrees C for 3 h. Through modifying Nbs with Horseradish Peroxidase (HRP) and biotin, two Nbs which can recognize the different epitopes of Cry1Fa were determined and they were used to establish a novel sandwich immune ELISA based on biotin-SA interaction for Cry1Fa detection. The immunoassay exhibited a linear range from 1 to 100 ng/mL with a detection limit of 0.88 ng/mL. The recoveries from spiked corn and soybean samples were ranged from 83.33 to 117.17%, with a coefficient of variation (C.V) less than 6.0%. All together, the proposed immunoassay will be a promising way for sensitive and accurate determination of Cry1Fa toxin. PMID- 25448391 TI - Toxins and drug discovery. AB - Components from venoms have stimulated many drug discovery projects, with some notable successes. These are briefly reviewed, from captopril to ziconotide. However, there have been many more disappointments on the road from toxin discovery to approval of a new medicine. Drug discovery and development is an inherently risky business, and the main causes of failure during development programmes are outlined in order to highlight steps that might be taken to increase the chances of success with toxin-based drug discovery. These include having a clear focus on unmet therapeutic needs, concentrating on targets that are well-validated in terms of their relevance to the disease in question, making use of phenotypic screening rather than molecular-based assays, and working with development partners with the resources required for the long and expensive development process. PMID- 25448392 TI - Venom gland transcriptomics for identifying, cataloging, and characterizing venom proteins in snakes. AB - Snake venoms are cocktails of protein toxins that play important roles in capture and digestion of prey. Significant qualitative and quantitative variation in snake venom composition has been observed among and within species. Understanding these variations in protein components is instrumental in interpreting clinical symptoms during human envenomation and in searching for novel venom proteins with potential therapeutic applications. In the last decade, transcriptomic analyses of venom glands have helped in understanding the composition of various snake venoms in great detail. Here we review transcriptomic analysis as a powerful tool for understanding venom profile, variation and evolution. PMID- 25448393 TI - Anti-loxoscelic horse serum produced against a recombinant dermonecrotic protein of Brazilian Loxosceles intermedia spider neutralize lethal effects of Loxosceles laeta venom from Peru. AB - In this work, an anti-loxoscelic serum was produced by immunizing horses with a recombinant dermonecrotic protein from Loxosceles intermedia (rLiD1). Anti-rLiD1 antibodies were able to recognize different species of Loxosceles venoms by Western Blot and ELISA. The efficacy of anti-rLiD1 serum against the toxic effects of Loxosceles laeta (Peru) venom was tested, showing that anti-rLiD1 serum can neutralize those effects. This study confirms that recombinant proteins can be good candidates to replace crude venoms for antivenom production. PMID- 25448394 TI - Diaphragm dysfunction caused by sphingomyelinase requires the p47(phox) subunit of NADPH oxidase. AB - Sphingomyelinase (SMase) activity is elevated in inflammatory states and may contribute to muscle weakness in these conditions. Exogenous SMase depresses muscle force in an oxidant-dependent manner. However, the pathway stimulated by SMase that leads to muscle weakness is unclear. In non-muscle cells, SMase activates the Nox2 isoform of NADPH oxidase, which requires the p47(phox) subunit for enzyme function. We targeted p47(phox) genetically and pharmacologically (apocynin) to examine the role of NADPH oxidase on SMase-induced increase in oxidants and diaphragm weakness. SMase increased cytosolic oxidants (arbitrary units: control 203+/-15, SMase 276+/-22; P<0.05) and depressed maximal force in wild type mice (N/cm(2): control 20+/-1, SMase 16+/-0.6; P<0.05). However, p47(phox) deficient mice were protected from increased oxidants (arbitrary units: control 217+/-27, SMase 224+/-17) and loss of force elicited by SMase (N/cm(2): control 20+/-1, SMase 19+/-1). Apocynin appeared to partially prevent the decrease in force caused by SMase (n=3 mice/group). Thus, our study suggests that NADPH oxidase plays an important role on oxidant-mediated diaphragm weakness triggered by SMase. These observations provide further evidence that NADPH oxidase modulates skeletal muscle function. PMID- 25448395 TI - Orexin-B antagonized respiratory depression induced by sevoflurane, propofol, and remifentanil in isolated brainstem-spinal cords of neonatal rats. AB - Orexins (hypocretins) play a crucial role in arousal, feeding, and endocrine function. We previously reported that orexin-B activated respiratory neurons in the isolated brainstem-spinal cords of neonatal rats. We herein determined whether orexin-B antagonized respiratory depression induced by sevoflurane, propofol, or remifentanil. We recorded C4 nerve bursts as an index of inspiratory activity in a brainstem-spinal cord preparation. The preparation was superfused with a solution equilibrated with 3% sevoflurane alone for 10 min and the superfusate was then switched to a solution containing sevoflurane plus orexin-B. Sevoflurane decreased the C4 burst rate and the integrated C4 amplitude. The C4 burst rate and amplitude were reversed by 0.5 MUM orexin-B, but not by 0.1 MUM orexin-B. The decrease induced in the C4 burst rate by 10 MUM propofol or 0.01 MUM remifentanil was significantly antagonized by 0.1 MUM orexin-B. Respiratory depression induced by a higher concentration (0.1 MUM) of remifentanil was not restored by 0.1 MUM orexin-B. These results demonstrated that orexin-B antagonized respiratory depression induced by sevoflurane, propofol, or remifentanil. PMID- 25448396 TI - Role of posterior hypothalamus in hypobaric hypoxia induced pulmonary edema. AB - To investigate the role of posterior hypothalamus and central neurotransmitters in the pulmonary edema due to hypobaric hypoxia, rats were placed in a high altitude simulation chamber (barometric pressure-294.4 mmHg) for 24 h. Exposure to hypobaric hypoxia resulted in increases in mean arterial blood pressure, renal sympathetic nerve activity, right ventricular systolic pressure, lung wet to dry weight ratio and Evans blue dye leakage. There was a significant attenuation in these responses to hypobaric hypoxia (a) after lesioning posterior hypothalamus and (b) after chronic infusion of GABAA receptor agonist muscimol into posterior hypothalamus. No such attenuation was evident with the chronic infusion of the nitric oxide donor SNAP into the posterior hypothalamus. It is concluded that in hypobaric hypoxia, there is over-activity of posterior hypothalamic neurons probably due to a local decrease in GABA-ergic inhibition which increases the sympathetic drive causing pulmonary hypertension and edema. PMID- 25448397 TI - Electrical activity of the diaphragm during progressive cycling exercise in endurance-trained men. AB - The study aimed to investigate diaphragm respiratory drive modulation through electrical activity of the diaphragm (EADi) during progressive cycling in endurance-trained men (N=7) and to test day-to-day measurement reliability. Normalized EADi increased at exercise intensities from 40% workload (WL) to 70% and 85%WL but plateaued from 70% to 85% (p<0.05). VO2, VCO2, VE, increased at all exercise intensities, where Vt and BF increased from 40% to 55% WL and from 70% to 85% and RER increased at 70% and 85% (p<0.05). Bland-Altman plots of normalized EADi showed bias of 0.9% and -6.4% and limits of agreement of +/-36.0% and +/-30.4% for absolute measurements and relative changes from 40% WL, respectively. Within-day variability appeared constant indicating that measurements within a trial are reliable. Results suggest that diaphragm respiratory drive increases at moderate exercise intensities, but plateaus at high intensities where other respiratory muscles might contribute significantly to the breathing effort, perhaps to "protect" against diaphragm fatigue. PMID- 25448398 TI - The neural correlates of emotional face-processing in adolescent depression: a dimensional approach focusing on anhedonia and illness severity. AB - Deficits in emotion processing, a known clinical feature of major depressive disorder (MDD), have been widely investigated using emotional face paradigms and neuroimaging. However, most studies have not accounted for the high inter-subject variability of symptom severity. Similarly, only sparse research has focused on MDD in adolescence, early in the course of the illness. Here we sought to investigate neural responses to emotional faces using both categorical and dimensional analyses with a focus on anhedonia, a core symptom of MDD associated with poor outcomes. Nineteen medication-free depressed adolescents and 18 healthy controls (HC) were scanned during presentation of happy, sad, fearful, and neutral faces. ANCOVAs and regressions assessed group differences and relationships with illness and anhedonia severity, respectively. Findings included a group by valence interaction with depressed adolescents exhibiting decreased activity in the superior temporal gyrus (STG), putamen and premotor cortex. Post-hoc analyses confirmed decreased STG activity in MDD adolescents. Dimensional analyses revealed associations between illness severity and altered responses to negative faces in prefrontal, cingulate, striatal, and limbic regions. However, anhedonia severity was uniquely correlated with responses to happy faces in the prefrontal, cingulate, and insular regions. Our work highlights the need for studying specific symptoms dimensionally in psychiatric research. PMID- 25448399 TI - Prefrontal GABA and glutathione imbalance in posttraumatic stress disorder: preliminary findings. AB - Although posttraumatic stress disorder (PTSD) is associated with a variety of structural and functional brain changes, the molecular pathophysiological mechanisms underlying these macroscopic alterations are unknown. Recent studies support the existence of an altered excitation-inhibition balance in PTSD. Further, there is preliminary evidence from blood-sample studies suggesting heightened oxidative stress in PTSD, potentially leading to neural damage through excessive brain levels of free radicals. In this study we investigated PTSD (n=12) and non-PTSD participants (n=17) using single-voxel proton magnetic resonance spectroscopy (MRS) in dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). We found significantly higher levels of gamma amino butyric acid (GABA) (a primary inhibitory neurotransmitter) and glutathione (a marker for neuronal oxidative stress) in PTSD participants. Atypically high prefrontal inhibition as well as oxidative stress may be involved in the pathogenesis of PTSD. PMID- 25448401 TI - SUMOylation of insulin-like growth factor 1 receptor, promotes proliferation in acute myeloid leukemia. AB - Current valid treatments for acute myeloid leukemia (AML) include chemotherapy and hematopoietic stem cell transplantation, which are defective and limited respectively. The insulin-like growth factor 1 receptor (IGF-1R) is up-regulated in many solid tumors; therefore, it may be a target for tumor therapy. Interestingly, IGF-1R is modified by SUMOylation, a type of reversible post translational modification. In this study, we found that IGF-1R was increased in both cell lines and clinical samples of AML and was modified by SUMO-1. Furthermore, IGF-1, ligand of IGF-1R, induced the up-regulation of IGF-1R and increased the proliferation of leukemia cell line. After mutation of Lys(1025) and Lys(1100) in IGF-1R, the evolutionarily conserved lysine residues were identified as the SUMOylation sites of IGF-1R, because the SUMOylation of IGF-1R in these mutants was significantly inhibited. Furthermore, the cell proliferation mediated by IGF-1 was also reduced. After inhibition of UBC9, the activating enzyme of SUMOylation, co-expression of IGF-1R and SUMO-1 was down-regulated, and cell proliferation was also inhibited. However, cell apoptosis was not significantly affected. These results suggest that IGF-1R and its SUMOylation may be a new therapeutic target for strategy of AML. PMID- 25448402 TI - Anchorage-dependent multicellular aggregate formation induces CD44 high cancer stem cell-like ATL cells in an NF-kappaB- and vimentin-dependent manner. AB - Adult T-cell leukemia/lymphoma (ATL) is an intractable T-cell malignancy accompanied by massive invasion of lymphoma cells into various tissues. We demonstrate here that ATL cells cultured on a layer of epithelial-like feeder cells form anchorage-dependent multicellular aggregates (Ad-MCAs) and that a fraction of MCA-forming ATL cells acquire CD44 high cancer stem cell-like phenotypes. ATL cells forming Ad-MCAs displayed extracellular microvesicles with enhanced expression of CD44v9 at cell synapses, augmented expression of multidrug resistance protein 1, and increased NF-kappaB activity. Blockade of the NF-kappaB pathway dramatically reduced Ad-MCA formation by ATL cells and the emergence of CD44 high ATL cells, but left a considerable number of ATL cells adhering to the feeder layer. Disruption of vimentin cytoskeleton by treatment with withaferin A, a natural steroidal lactone, suppressed not only the adhesion of ATL cells to the feeder layer but also subsequent Ad-MCA formation by ATL cells, suggesting the involvement of vimentin in anchoring ATL cells to the feeder layer. Ad-MCA formation by ATL cells on a layer of epithelial-like feeder cells may mimic critical events that occur in metastatic colonization. PMID- 25448403 TI - Regulators of carcinogenesis: emerging roles beyond their primary functions. AB - Cancers are characterized by aberrant cell signaling that results in accelerated proliferation, suppressed cell death, and reprogrammed metabolism to provide sufficient energy and intermediate metabolites for macromolecular biosynthesis. Here, we summarize the emerging "unconventional" roles of these regulators based on their newly identified interaction partners, different subcellular localizations, and/or structural variants. For example, the epidermal growth factor receptor (EGFR) regulates DNA synthesis, microRNA maturation and drug resistance by interacting with previously undescribed partners; cyclins and cyclin-dependent kinases (CDKs) crosstalk with multiple canonical pathways by phosphorylating novel substrates or by functioning as transcriptional factors; apoptosis executioners play extensive roles in necroptosis, autophagy, and in the self-renewal of stem cells; and various metabolic enzymes and their mutants control carcinogenesis independently of their enzymatic activity. These recent findings will supplement the systemic functional annotation of cancer regulators and provide new rationales for potential molecular targeted cancer treatments. PMID- 25448404 TI - Silicon dioxide nanoparticles increase macrophage atherogenicity: Stimulation of cellular cytotoxicity, oxidative stress, and triglycerides accumulation. AB - Nanoparticle research has focused on their toxicity in general, while increasing evidence points to additional specific adverse effects on atherosclerosis development. Arterial macrophage cholesterol and triglyceride (TG) accumulation and foam cell formation are the hallmark of early atherogenesis, leading to cardiovascular events. To investigate the in vitro atherogenic effects of silicon dioxide (SiO2 ), J774.1 cultured macrophages (murine cell line) were incubated with SiO2 nanoparticle (SP, d = 12 nm, 0-20 ug/mL), followed by cellular cytotoxicity, oxidative stress, TG and cholesterol metabolism analyses. A significant dose-dependent increase in oxidative stress (up to 164%), in cytotoxicity (up to 390% measured by lactate dehydrogenase (LDH) release), and in TG content (up to 63%) was observed in SiO2 exposed macrophages compared with control cells. A smaller increase in macrophage cholesterol mass (up to 22%) was noted. TG accumulation in macrophages was not due to a decrease in TG cell secretion or to an increased TG biosynthesis rate, but was the result of attenuated TG hydrolysis secondary to decreased lipase activity and both adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) protein expression (by 42 and 25%, respectively). Overall, SPs showed pro-atherogenic effects on macrophages as observed by cytotoxicity, increased oxidative stress and TG accumulation. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 713-723, 2016. PMID- 25448405 TI - Does the presence of an unerupted lower third molar influence the risk of mandibular angle and condylar fractures? AB - It has been suggested that unerupted lower third molars (M3) increase the fragility of the mandibular angle and simultaneously decrease the risk of condylar fracture. However, it is unknown whether this applies regardless of the direction and point of impact of the traumatic force. The aim of this study was to investigate the impact of an unerupted M3 on the fragility of the angle and condyle in terms of a force acting from different directions and affecting different regions of the mandible. Computed tomography scans of a human mandible and finite element methodology were used to obtain two three-dimensional models: a model with, and the other without an unerupted M3. A force of 2000N was applied to three different regions of the models: the symphysis, ipsilateral body, and contralateral body, respectively. When the force was applied to the mandibular body, the results revealed increased angle fragility in cases with unerupted M3. When the force was applied to the symphysis, the condyle region showed higher fragility, irrespective of the presence of an unerupted M3. In summary, fragility of the angle and condyle regions depends on the presence of an unerupted M3 and on the direction and point of impact of the force. PMID- 25448406 TI - Effects of low-intensity pulsed ultrasound on healing of mandibular bone defects: an experimental study in rabbits. AB - Research evidence suggests that low-intensity pulsed ultrasound (LIPU) produces significant osteoinductive effects, accelerating the healing of bone defects. The authors investigated the effects of LIPU on mandibular bone defects in a rabbit model. Fifty-six adult Dutch rabbits were divided randomly into control, LIPU-1 (1MHz), and LIPU-3 (3MHz) groups. A mandibular defect was created in all rabbits. The effect of LIPU on mandibular defects was assessed by frequency (1 or 3MHz) and timing (2 and 4 weeks). Bone mineral density (BMD) was measured and stereology and histology performed; results were compared at the end of 2 and 4 weeks. LIPU-3 resulted in significantly higher bone formation compared to the control group at the end of week 4 on histological assessment (P=0.008). BMD was significantly higher at 4 weeks than at 2 weeks (P=0.03). LIPU-3 increased the numerical density of osteoblasts and osteocytes at the end of week 4 (P=0.05 and P=0.001, respectively). The results of this study are in favour of using LIPU 3MHz to accelerate mandibular bone healing. However, this study suggests that a frequency of 3MHz and the longer application of LIPU 3MHz for 4 weeks can only promote 8% mandibular bone healing in rabbits. Therefore, the use of LIPU has no really convincing, consistent clinical effects on maxillofacial bone healing. PMID- 25448407 TI - Closed reduction of the isolated anterior frontal sinus fracture via percutaneous screw placement. AB - Fractures of the frontal sinus are a common maxillofacial trauma and constitute 5 15% of all maxillofacial fractures. Conventional surgical approaches include the coronal flap, direct cutaneous incision, and endoscopic techniques. Minimally invasive techniques have recently been described for the reduction of the isolated anterior frontal sinus fracture via a closed approach. The medical records and radiological findings of all patients who underwent surgical treatment for anterior frontal sinus fractures from January 2009 to December 2013 at the study hospital in Florence, Italy, were reviewed. The final study sample consisted of 15 patients (13 males and two females) with isolated anterior frontal sinus fractures who were treated with closed reduction using percutaneous screws. The mean age was 32.1 years. The skin incisions healed without any visible scarring, and no depressions of the frontal sinuses were evident in the postoperative period. Computed tomography scans performed at 6 months postoperatively showed adequate reduction of the displaced fragments. This closed technique is a good option for displaced isolated fractures of the anterior frontal sinus. However, the technique is not adequate for complex fractures of the frontal sinus. PMID- 25448409 TI - Predictors for good therapeutic outcome and drop-out in technology assisted guided self-help in the treatment of bulimia nervosa and bulimia like phenotype. AB - OBJECTIVE: Technology assisted guided self-help has been proven to be effective in the treatment of bulimia nervosa (BN). The aim of this study was to determine predictors of good long-term outcome as well as drop-out, in order to identify patients for whom these interventions are most suitable. METHODS: One hundred and fifty six patients with BN were assigned to either 7 months internet-based guided self-help (INT-GSH) or to conventional guided bibliotherapy (BIB-GSH), both guided by e-mail support. Evaluations were taken at baseline, after 4, 7, and 18 months. As potential predictors, psychiatric comorbidity, personality features, and eating disorder psychopathology were considered. RESULTS: Higher motivation, lower frequency of binge eating, and lower body dissatisfaction at baseline predicted good outcome after the end of treatment. Lower frequency of binge eating predicted good outcome at long-term follow-up. Factors prediciting drop out were higher depression and lower self-directedness at baseline. CONCLUSION: Technology assisted self-help can be recommended for patients with a high motivation to change, lower binge-eating frequency and lower depression scores. PMID- 25448408 TI - Extracellular matrix presentation modulates vascular smooth muscle cell mechanotransduction. AB - The development of atherosclerosis involves phenotypic changes among vascular smooth muscle cells (VSMCs) that correlate with stiffening and remodeling of the extracellular matrix (ECM). VSMCs are highly sensitive to the composition and mechanical state of the surrounding ECM, and ECM remodeling during atherosclerosis likely contributes to pathology. We hypothesized that ECM mechanics and biochemistry are interdependent in their regulation of VSMC behavior and investigated the effect of ligand presentation on certain stiffness mediated processes. Our findings demonstrate that substrate stiffening is not a unidirectional stimulus-instead, the influence of mechanics on cell behavior is highly conditioned on ligand biochemistry. This "stiffness-by-ligand" effect was evident for VSMC adhesion, spreading, cytoskeletal polymerization, and focal adhesion assembly, where VSMCs cultured on fibronectin (Fn)-modified substrates showed an augmented response to increasing stiffness, whereas cells on laminin (Ln) substrates showed a dampened response. By contrast, cells on Fn substrates showed a decrease in myosin light chain (MLC) phosphorylation and elongation with increasing stiffness, whereas Ln supported an increase in MLC phosphorylation and no change in cell shape with increasing stiffness. Taken together, these findings show that identical cell populations exhibit opposing responses to substrate stiffening depending on ECM presentation. Our results also suggest that the shift in VSMC phenotype in a developing atherosclerotic lesion is jointly regulated by stromal mechanics and biochemistry. This study highlights the complex influence of the blood vessel wall microenvironment on VSMC phenotype and provides insight into how cells may integrate ECM biochemistry and mechanics during normal and pathological tissue function. PMID- 25448400 TI - Review of methods to probe single cell metabolism and bioenergetics. AB - Single cell investigations have enabled unexpected discoveries, such as the existence of biological noise and phenotypic switching in infection, metabolism and treatment. Herein, we review methods that enable such single cell investigations specific to metabolism and bioenergetics. Firstly, we discuss how to isolate and immobilize individuals from a cell suspension, including both permanent and reversible approaches. We also highlight specific advances in microbiology for its implications in metabolic engineering. Methods for probing single cell physiology and metabolism are subsequently reviewed. The primary focus therein is on dynamic and high-content profiling strategies based on label free and fluorescence microspectroscopy and microscopy. Non-dynamic approaches, such as mass spectrometry and nuclear magnetic resonance, are also briefly discussed. PMID- 25448410 TI - Skin regeneration: the complexities of translation into clinical practise. AB - The integration of engineering into biological science has resulted in the capacity to provide tissue engineered solutions for tissue damage. Skin regeneration remains the goal of skin repair to reduce the long term consequences of scarring to the individual. A scar is abnormal in its architecture, chemistry and cell phenotype, tissue engineering of scaffolds and cells opens up the potential of tissue regeneration into the future. Tissue engineering solutions have been applied to skin many decades despite technical success the clinical application has been modest. To realise the potential of the developing technologies needs alignment of not only the science and engineering but also the commercial upscaling of production in a safe and regulated framework for clinical use. In addition the education and training for the introduction of new technology within the health system is essential, bringing together the technology and systems for utilisation to optimise the patient outcome. This article is part of a Directed Issue entitled: Regenerative Medicine: The challenge of translation. PMID- 25448411 TI - Tumour progression and cancer-induced pain: a role for protease-activated receptor-2? AB - The role of proteases in modifying the microenvironment of tumour cells has long been recognised. With the discovery of the protease-activated receptor family of G protein-coupled receptors a mechanism for cells to sense and respond directly to proteases in their microenvironment was revealed. Many early studies described the roles of protease-activated receptors in the cellular events that occur during blood coagulation and inflammation. More recently, studies have begun to focus on the roles of protease-activated receptors in the establishment, progression and metastasis of a variety of tumours. This review will focus on the expression of protease-activated receptor-2 and its activators by normal and neoplastic tissues, and describe current evidence that activation of protease activated receptor-2 is an important event at multiple stages of tumour progression and in pain associated with cancer. PMID- 25448413 TI - Age-dependent neuron loss is associated with impaired adult neurogenesis in forebrain neuron-specific Dicer conditional knockout mice. AB - Impairment in the microRNA (miRNA) network causes a number of neurodegenerative diseases. Endoribonuclease Dicer is a key RNase to produce mature miRNAs. It has been shown that Dicer is important for the maintenance of excitatory neuron survival during early postnatal period. However, the role of Dicer in adult mature excitatory neuron survival is not clear. In this study, we generated a mouse model in which Dicer is conditionally inactivated in forebrain excitatory neurons from a mature stage, and this line is termed Dicer conditional knockout (cKO). Significant age-dependent neurodegeneration was observed in the cortex of Dicer cKO mice, indicating an important role of Dicer in the maintenance of mature excitatory neuron survival in the adult cortex. Impairment in adult neurogenesis was found in 6-month but not in young Dicer cKO mice. However, astrocytosis was detected in young Dicer cKO mice displaying no apparent neuron loss. Overall, neurogenesis impairment and neuroinflammation may play pivotal roles in the progression of neurodegeneration. PMID- 25448412 TI - Ubiquitination of the transcription factor c-MAF is mediated by multiple lysine residues. AB - The transcription factor c-MAF could be polyubiquitinated and subsequently degraded in the proteasomes. Theoretically, any lysine residues in c-MAF could be ubiquitinated. In the present study, we tried to find out the specific lysine residue(s) mediating c-MAF ubiquitination. Through a series of mutational screens from lysine (K) to arginine (R), we found that any single lysine mutation (K to R) failed to prevent c-MAF ubiquitination, and any single lysine residue alone could not mediate c-MAF ubiquitination, which indicated that multiple lysine residues were required for c-MAF ubiquitination. Bioinformatics and computing analyses revealed that K85 and K350 could mediate c-MAF ubiquitination, which was confirmed by the cell-based assays. However, this duo was not the only pair because the K85R/K350R mutant could also be ubiquitinated. Functionally, both M12 (K85/K350) and W12 (K85R/K350R) mutants increased cyclin D2 promoter-driven luciferase activity, but they were less potent than the lysine-free counterpart (M14). In addition, M14 induced a higher level of expression of cyclin D2 at both mRNA and protein levels. Therefore, we demonstrated that c-MAF ubiquitination is mediated by multiple lysine residues, of which K85 and K350 were sufficient but not the only residues in mediating c-MAF ubiquitination. Moreover, c-MAF was found to be degraded by lysosomes. This study added a novel insight for c-MAF ubiquitination and degradation, suggesting that c-MAF stability is strictly regulated. PMID- 25448414 TI - Centchroman suppresses breast cancer metastasis by reversing epithelial mesenchymal transition via downregulation of HER2/ERK1/2/MMP-9 signaling. AB - Metastatic spread during carcinogenesis worsens disease prognosis and accelerates the cancer progression. Therefore, newer therapeutic options with higher specificity toward metastatic cancer are required. Centchroman (CC), a female oral contraceptive, has previously been reported to possess antiproliferative and proapoptotic activities in human breast cancer cells. Here, we investigated the effect of CC-treatment against breast cancer metastasis and associated molecular mechanism using in vitro and in vivo models. CC significantly inhibited the proliferation of human and mouse mammary cancer cells. CC-treatment also inhibited migration and invasion capacities of highly metastatic MDA-MB-231 and 4T1 cells, at sub-IC50 concentrations. Inhibition of cell migration and invasion was found to be associated with the reversal of epithelial-to-mesenchymal transition (EMT) as observed by the upregulation of epithelial markers and downregulation of mesenchymal markers as well as decreased activities of matrix metalloproteinases. Experimental EMT induced by exposure to TGFbeta/TNFalpha in nontumorigenic human mammary epithelial MCF10A cells was also reversed by CC as evidenced by morphological changes and modulation in the expression levels of EMT markers. CC-mediated inhibition of cellular migration was, at least partially, mediated through inhibition of ERK1/2 signaling, which was further validated by using MEK1/2 inhibitor (PD0325901). Furthermore, CC-treatment resulted in suppression of tumor growth and lung metastasis in 4T1-syngeneic mouse model. Collectively, our findings suggest that CC-treatment at higher doses specifically induces cellular apoptosis and inhibits cellular proliferation; whereas at lower doses, it inhibits cellular migration and invasion. Therefore, CC could further be developed as an effective drug candidate against metastatic breast cancer. PMID- 25448416 TI - A CHIPotle in physiology and disease. AB - The carboxy-terminus of Hsc70 interacting protein (CHIP) is known to function as a chaperone associated E3 ligase for several proteins and regulates a variety of physiological processes. Being a connecting link between molecular chaperones and 26S proteasomes, it is widely regarded as the central player in the cellular protein quality control system. Recent analyses have provided new insights on the biochemical and functional dynamics of CHIP. In this review article, we give a comprehensive account of our current knowledge on the biology of CHIP, which apart from shedding light on fundamental biological questions promises to provide a potential target for therapeutic intervention. PMID- 25448415 TI - Podocytes protect glomerular endothelial cells from hypoxic injury via deSUMOylation of HIF-1alpha signaling. AB - Hypoxia can cause severe tubulointerstitial injury and peritubular capillary loss. However, hypoxia-induced injury in glomerular capillaries is far milder than tubulointerstitium, but the reason for this difference is unclear. We hypothesized that the phenomenon is due to the protective crosstalk among intrinsic glomerular cells. To mimic the microenvironment and investigate the crosstalk process temporally, we established co-culture models of glomerular endothelial cells (GEnCs) with podocytes or with mesangial cells. We found that podocytes rather than mesangial cells prevented GEnCs from injury and hypoxia induced apoptosis and promoted migration and angiogenesis of GEnCs under hypoxic conditions. We then identified that increased activation of the hypoxia inducible factor 1alpha (HIF-1alpha) pathway as the major mechanism enabling podocytes to protect GEnCs against hypoxia. HIF-1alpha stabilization during hypoxia is known to be dependent on SUMO-specific protease 1 (SENP1)-mediated deSUMOylate modifications. Therefore, we further targeted deSUMOylation, regulated by SENP1, by short hairpin RNA (shRNA) knockdown of SENP1 mRNA in vitro and measured expression of HIF-1alpha and its downstream gene VEGF in hypoxic podocytes. Our results showed that SENP1 was essential for HIF-1alpha deSUMOylation in podocytes. The blockade of deSUMOylation by SENP1 shRNA successfully abolished the activation of HIF-1alpha signaling and consequently suppressed the protective effects of podocytes on GEnCs. In conclusion, we demonstrate for the first time that hypoxia may promote HIF-1alpha stabilization and activation by increasing SENP1 expression in podocytes, which induce GEnCs survival and angiogenesis to resist hypoxia. Thus, deSUMOylation of HIF-1alpha signaling is a potentially novel therapeutic target for treating hypoxic renal disorders. PMID- 25448417 TI - Belatacept-based, ATG-Fresenius-induction regimen for kidney transplant recipients: a proof-of-concept study. AB - Belatacept provides effective immunosuppression while avoiding the nephrotoxicities associated with calcineurin inhibitors (CNIs). However, existing belatacept-based regimens still have high rates of acute rejection. We hypothesized that therapy with belatacept, mycophenolic acid (MMA), steroids and induction therapy with rabbit anti-thymocyte globulin Fresenius (ATGF), rejection rate could be reduced. Prospective, single center, proof-of-concept study including males and females aged >=18years, Epstein-Barr virus (EBV)-seropositive recipients of a first, HLA non-identical, live or deceased donor kidney allograft. Only patients with a calculated panel reactive antibody score of 0% were included. Three donors were positive for Chagas disease. Six of twelve patients had at least one infection and five were readmitted to the hospital for treatment. One patient had a Trypanosoma cruzi infection via the graft treated successfully. Median cold ischemia time for the transplant patients with a deceased donor was 21.5h. Mean serum creatinine levels at 1, 3 and 6months were 1.76+/-0.59, 1.55+/-0.60 and 1.49+/-0.60mg/dl, respectively. Two of twelve patients experienced clinical, biopsy-proven rejection, successfully treated with methylprednisolone. No patient developed post-transplant lymphoproliferative disorder (PTLD) or any other malignancy and no patient lost their graft or died during follow-up. The potential of this approach makes it worthy of further investigation. PMID- 25448418 TI - Sigmoid colon metastasis from metaplastic breast carcinoma mimicking primary sigmoid colon cancer. PMID- 25448419 TI - [Utility of SPECT/CT scan for anatomical localization of pararectal and presacral sentinel nodes in prostate cancer]. AB - AIM: This study has aimed to evaluate the added value of SPECT-CT scan in the preoperative assessment of sentinel nodes of the presacral and pararectal regions localized outside the standard area of extended pelvic lymphadenectomy for the staging of the pelvis in prostate cancer. SPECT-CT scan can serve as a guide for the excision of these nodes by lymphadenectomy by open surgery or laparoscopy. MATERIAL AND METHODS: We evaluated 4 patients with prostate cancer presenting sentinel nodes in the pararectal and presacral regions on SPECT-CT scan performed in addition to lymphoscintigraphy. These patients underwent lymphadenectomy with robot-assisted laparoscopy together with prostatectomy. All of the excised lymph nodes were sent for histopathology study. RESULTS: An average of 6 sentinel nodes per patient were found on SPECT-CT scan with a mean of 2 sentinel nodes in presacral/pararectal region. Lymphadenectomy including these areas was performed. Pararectal/presacral sentinel nodes of all patients depicted by SPECT-CT scan were tumor free on histopathology study. Sentinel nodes (no pararectal/presacral) were positive for malignancy in only one patient. CONCLUSION: Preoperative SPECT CT scan is a useful tool to localize the sentinel nodes in pararectal/presacral regions. It can be an anatomic guide for new modalities of laparoscopic surgery such as robot-assisted procedures that can access the pelvic areas visualized with SPECT-CT scan, making excision of these nodes possible. PMID- 25448421 TI - Continuing increase of tick bites and Lyme disease between 1994 and 2009. AB - BACKGROUND: Nationwide cross-sectional retrospective studies have shown a continuous increase in general practitioner (GP) consultations for tick bites and diagnoses of erythema migrans between 1994 and 2005 in the Netherlands. In this paper, we report incidence estimates for GP consultations for tick bites and erythema migrans diagnoses in 2009, and we compare the observed increase in GP consultations to reports of tick bites in two retrospective cross-sectional surveys of the general population. METHODS: All GPs in the Netherlands were asked to complete a postal questionnaire on the number of consultations for tick bites and erythema migrans diagnoses in 2009, and the size of their practice populations. To investigate how the incidence of GP consultation rates for tick bites and erythema migrans relate to the incidence of tick bites in the general population, questionnaire data on tick bites were analyzed from two large population surveys conducted to evaluate the national immunization program in 1995/1996 and 2006/2007. RESULTS: The 2009 GP survey revealed a further increase, to 564 tick bite consultations per 100,000 inhabitants, and 134 erythema migrans diagnoses per 100,000 inhabitants of the Netherlands. The two population surveys from 1995/1996 and 2006/2007 exhibited an almost twofold increase of the incidence of tick bites in the general population from 4099 per 100,000 population in 1996, to 7198 per 100,000 population in 2007. People nationwide noticed approximately 1.1 million tick bites in 2007. CONCLUSIONS: Our observation of increases in GP consultations for tick bites and erythema migrans diagnoses between 1994 and 2009 are confirmed by the parallel increase of tick bites reported by the general population, although consultation rates slightly increased. For every sixty tick bites in the general population in 2007, we observed one GP consult for erythema migrans. The increase in tick bites poses a progressive threat to public health. PMID- 25448420 TI - Epidemiology and cost of hospital care for Lyme borreliosis in Germany: lessons from a health care utilization database analysis. AB - To date, relatively little is known about the economic and medical impact of Lyme borreliosis (LB) on European health care systems, especially for the inpatient sector. This retrospective analysis is based on data provided for the years 2007 2011 by a German statutory health insurance company (DAK-Gesundheit) covering approximately 6 million insured. Total cost was calculated for a 1-year period both from the third-party payers and from the societal perspective, respectively. In our cohort the incident diagnosis of LB was coded for 2163 inpatient cases during the years 2008-2011. The median inpatient time was 9 days resulting in a median direct medical cost per hospital stay of 3917? for adolescents and 2843? for adults. Based on extrapolation of our findings to the German population, we would expect an average hospital admission of 5200 adults and 2300 adolescents (<18 years) for LB treatment incurring direct medical costs of more than 23 million Euro annually. The annual indirect costs due to loss of productivity would add up to more than 7 million Euro as assessed by the human capital method. Cases tended to accumulate between June and September with remarkable changes in disease manifestations in the course of the year documented in the coded secondary diagnoses. Also specific differences in the disease pattern of adolescents and adults became obvious. Age-specific incidence showed male predominance and a bimodal distribution. Incidence was highest in children aged between 3 and 17 (highest mean incidence of 29 cases/100,000 inhabitants in 6-9 year olds) with a second peak in 60-79 year old individuals. During the study period the nationwide inpatient incidence was 9/100,000 with marked regional variability. In summary, our study is one of the first European investigations on hospital care for LB inpatients and identifies LB as a possibly underestimated socioeconomic factor for health care in Germany. PMID- 25448422 TI - Theileria sp. OT3 and other tick-borne pathogens in sheep and ticks in Italy: molecular characterization and phylogeny. AB - PCR Reverse Line Blot (RLB) hybridization and sequencing were used to determine the dynamics of infection with tick-borne pathogens in one hundred apparently healthy sheep in Italy. Blood samples were tested once prior to the onset of the grazing season (June 2010) and once after the end of the grazing season (August 2010). Ticks collected from sheep and from the vegetation were also tested by PCR/RLB. Before grazing, 56% of the sheep harbored several tick-borne pathogens: Anaplasma ovis was the most prevalent (41%), followed by A. ovis co-infected with Theileria sp. OT3 (14%). After grazing, 87% of sheep were positive for A. ovis alone (41%), co-infected with Theileria sp. OT3 (8%) or co-infected with Babesia motasi (5%). Other sheep were infected with Anaplasma phagocytophilum alone (20%), co-infected with B. motasi (7%) or with Theileria sp. OT3 (5%) (p<0.001). After grazing, sheep were significantly more infected with tick-borne pathogens than before grazing. Ticks collected were all Haemaphysalis punctata (n-89) and 36% were positive for A. ovis, Ehrlichia ovina and A. ovis combined with A. phagocytophilum. Phylogenetic analysis including isolates from countries in the Mediterranean Basin show circulation of the same variants of Theileria sp. OT3, whereas two different geographical origins for the isolates of A. ovis and A. phagocytophilum were identified. This is the first report from Italy of Theileria sp. OT3 in sheep, whereas the detection of Ehrlichia ovina in ticks is worth noting, and the presence of A. phagocytophilum in sheep and in ticks poses a potential public health risk. PMID- 25448424 TI - Ultrafast acoustics. Preface. PMID- 25448423 TI - Comparative microarray analyses of adult female midgut tissues from feeding Rhipicephalus species. AB - The cattle tick, Rhipicephalus microplus, has a debilitating effect on the livestock industry worldwide, owing to its being a vector of the causative agents of bovine babesiosis and anaplasmosis. In South Africa, co-infestation with R. microplus and R. decoloratus, a common vector species on local livestock, occurs widely in the northern and eastern parts of the country. An alternative to chemical control methods is sought in the form of a tick vaccine to control these tick species. However, sequence information and transcriptional data for R. decoloratus is currently lacking. Therefore, this study aimed at identifying genes that are shared between midgut tissues of feeding adult female R. microplus and R. decoloratus ticks. In this regard, a custom oligonucleotide microarray comprising of 13,477 R. microplus sequences was used for transcriptional profiling and 2476 genes were found to be shared between these Rhipicephalus species. In addition, 136 transcripts were found to be more abundantly expressed in R. decoloratus and 1084 in R. microplus. Chi-square analysis revealed that genes involved in lipid transport and metabolism are significantly overrepresented in R. microplus and R. decoloratus. This study is the first transcriptional profiling of R. decoloratus and is an additional resource that can be evaluated further in future studies for possible tick control. PMID- 25448425 TI - Alignment of an acoustic manipulation device with cepstral analysis of electronic impedance data. AB - Acoustic particle manipulation is an emerging technology that uses ultrasonic standing waves to position objects with pressure gradients and acoustic radiation forces. To produce strong standing waves, the transducer and the reflector must be aligned properly such that they are parallel to each other. This can be a difficult process due to the need to visualise the ultrasound waves and as higher frequencies are introduced, this alignment requires higher accuracy. In this paper, we present a method for aligning acoustic resonators with cepstral analysis. This is a simple signal processing technique that requires only the electrical impedance measurement data of the resonator, which is usually recorded during the fabrication process of the device. We first introduce the mathematical basis of cepstral analysis and then demonstrate and validate it using a computer simulation of an acoustic resonator. Finally, the technique is demonstrated experimentally to create many parallel linear traps for 10 MUm fluorescent beads inside an acoustic resonator. PMID- 25448426 TI - A time-domain synthetic aperture ultrasound imaging method for material flaw quantification with validations on small-scale artificial and natural flaws. AB - A direct time-domain reconstruction and sizing method of synthetic aperture focusing technique (SAFT) is developed to improve the spatial resolution and sizing accuracy for phased-array ultrasonic inspections. The basic idea of the reconstruction algorithm is to coherently superimpose multiple A-scan measurements, incorporating the phase information of the sampling points. The algorithm involves data mapping and in-phase summation according to time-of flight (TOF). Data mapping refers to the process of placing each of the sampling points to a two-/three-dimensional grid that represents the geometry model of the object being inspected. The value for each of the cells of the grid is a summation of all sampling points mapped into the cell. A sizing method based on the concept of 6 dB-drop is proposed to characterize the flaw boundary. The extents, orientation and the shape of the flaw can then be inferred to provide more information for life assessment calculations. Lab experiments are performed using a 10 MHz phased-array ultrasonic transducer to collect data from a cylinder material block with closely spaced artificial flaws and from a material block with a natural flaw. The developed method is used to process the experimental data to characterize the flaws. Using the developed method, the improvement of spatial resolution is observed. Results indicate that four closely spaced 0.794 mm-diameter flat-bottomed holes are clearly identified, and the quantification of size and orientation of the natural flaw is very close to the actual measurement made from digital microscopy after cutting the testing piece apart. PMID- 25448427 TI - Modeling of the acoustic field of thermally induced ultrasonic emission from a spherical cavity surface. AB - Thermo-acoustic (TA) ultrasound has attracted considerable interest during the last decade for its many advantages over the conventional electro-acoustic ultrasound. In this paper, a general expression of the acoustic pressure field of thermally induced ultrasonic emission from a spherical cavity surface is derived by using a fully thermally-mechanically coupled TA model. The characteristics and regularities of ultrasound from spherical focusing TA emitter can therefore be studied in detail. It is found that, for the TA emission in sphere shell, wideband flat amplitude-frequency response pattern, the most important feature of TA ultrasound in an open space from a technical standpoint, is seriously disrupted by wave interference occurring in spherical cavity. The dependences of sound pressure of TA ultrasound in spherical cavity on the heating frequency, the inner radius of spherical cavity, the location in spherical cavity, and the thickness of TA sample layer, as well as the type and filling pressure of gas in cavity are given and discussed. The currently used planar TA solution is only the special case for spherical cavity with infinite radius of the analytical solution developed in this work, which would be of significance for more comprehensive guide to understanding and using TA ultrasound. PMID- 25448428 TI - Simultaneously measuring thickness, density, velocity and attenuation of thin layers using V(z,t) data from time-resolved acoustic microscopy. AB - To meet the need of efficient, comprehensive and automatic characterization of the properties of thin layers, a nondestructive method using ultrasonic testing to simultaneously measure thickness, density, sound velocity and attenuation through V(z,t) data, recorded by time-resolved acoustic microscopy is proposed. The theoretical reflection spectrum of the thin layer at normal incidence is established as a function of three dimensionless parameters. The measured reflection spectrum R(theta,omega) is obtained from V(z,t) data and the measured thickness is derived from the signals when the lens is focused on the front and back surface of the thin layer, which are picked up from the V(z,t) data. The density, sound velocity and attenuation are then determined by the measured thickness and inverse algorithm utilizing least squares method to fit the theoretical and measured reflection spectrum at normal incidence. It has the capability of simultaneously measuring thickness, density, sound velocity and attenuation of thin layer in a single V(z,t) acquisition. An example is given for a thin plate immersed in water and the results are satisfactory. The method greatly simplifies the measurement apparatus and procedures, which improves the efficiency and automation for simultaneous measurement of basic mechanical and geometrical properties of thin layers. PMID- 25448429 TI - Combined serotonin (5-HT)1A agonism, 5-HT(2A) and dopamine D2 receptor antagonism reproduces atypical antipsychotic drug effects on phencyclidine-impaired novel object recognition in rats. AB - Subchronic administration of an N-methyl-D-aspartate receptor (NMDAR) antagonist, e.g. phencyclidine (PCP), produces prolonged impairment of novel object recognition (NOR), suggesting they constitute a hypoglutamate-based model of cognitive impairment in schizophrenia (CIS). Acute administration of atypical, e.g. lurasidone, but not typical antipsychotic drugs (APDs), e.g. haloperidol, are able to restore NOR following PCP (acute reversal model). Furthermore, atypical APDs, when co-administered with PCP, have been shown to prevent development of NOR deficits (prevention model). Most atypical, but not typical APDs, are more potent 5-HT(2A) receptor inverse agonists than dopamine (DA) D2 antagonists, and have been shown to enhance cortical and hippocampal efflux and to be direct or indirect 5-HT(1A) agonists in vivo. To further clarify the importance of these actions to the restoration of NOR by atypical APDs, sub effective or non-effective doses of combinations of the 5-HT(1A) partial agonist (tandospirone), the 5-HT(2A) inverse agonist (pimavanserin), or the D2 antagonist (haloperidol), as well as the combination of all three agents, were studied in the acute reversal and prevention PCP models of CIS. Only the combination of all three agents restored NOR and prevented the development of PCP-induced deficit. Thus, this triple combination of 5-HT(1A) agonism, 5-HT(2A) antagonism/inverse agonism, and D2 antagonism is able to mimic the ability of atypical APDs to prevent or ameliorate the PCP-induced NOR deficit, possibly by stimulating signaling cascades from D1 and 5-HT(1A) receptor stimulation, modulated by D2 and 5-HT(2A) receptor antagonism. PMID- 25448430 TI - The neural circuitry and molecular mechanisms underlying delay and trace eyeblink conditioning in mice. AB - Classical eyeblink conditioning (EBC), a simple form of associative learning, has long been served as a model for motor learning and modulation. The neural circuitry of EBC has been studied in detail in rabbits. However, its underlying molecular mechanisms remain unclear. The advent of mouse transgenics has generated new perspectives on the studies of the neural substrates and molecular mechanisms essential for EBC. Results about EBC in mice differ in some aspects from those obtained in other mammals. Here, we review the current studies about the neural circuitry and molecular mechanisms underlying delay and trace EBC in mice. We conclude that brainstem-cerebellar circuit plays an essential role in DEC while the amygdala modulates this process, and that the medial prefrontal cortex (mPFC) as a candidate is involved in the extra-cerebellar mechanism underlying delay eyeblink conditioning (DEC) in mice. We propose the Amygdala Cerebellum-Prefrontal Cortex-Dynamic-Conditioning Model (ACPDC model) for DEC in mice. As to trace eyeblink conditioning (TEC), the forebrain regions may play an essential role in it, whereas cerebellar cortex seems to be out of the neural circuitry in mice. Moreover, the molecular mechanisms underlying DEC and TEC in mice differ from each other. This review provides some new information and perspectives for further research on EBC. PMID- 25448432 TI - Evidence for the involvement of extinction-associated inhibitory learning in the forced swimming test. AB - The forced swimming test (FST) remains one of the most used tools for screening antidepressants in rodent models. Nonetheless, the nature of immobility, its main behavioral measure, is still a matter of debate. The present study took advantage of our recent finding that mice of the inbred DBA/2J strain require a functioning left dorsolateral striatum (DLS) to consolidate long-term memory of FST to test whether immobility is the outcome of stress-related learning. Infusion of the GABA-A agonist muscimol in the left DLS immediately after a single experience of FST prevented and infusion in the left or the right amygdala impaired recall of the acquired levels of immobility in a probe test performed 24h later. Post training left DLS infusion of muscimol, at a dose capable of preventing retention of FST-induced immobility, did not influence 24h retention of inhibitory avoidance training or of the escape response acquired in a water T-maze. However, this same treatment prevented 24h retention of the extinction training of the consolidated escape response. These results indicate that a left DLS-centered memory system selectively mediates memory consolidation of FST and of escape extinction and support the hypothesis that immobility is the result of extinction like inhibitory learning involving all available escape responses due to the inescapable/unavoidable nature of FST experience. PMID- 25448433 TI - Chronic unpredictable stress during adolescence causes long-term anxiety. AB - Exposure to stress during adolescence can cause long-term changes in behavior and cognition. Anxiety diagnoses rise during adolescence and are increased by adverse experiences. Currently, it is unknown how long stress during adolescence alters anxiety in adulthood. We found that rats exposed to chronic unpredictable stress during adolescence expressed altered behavior 6.5 months later; showing increased anxiety in a feeding test in a novel environment. Although behavioral changes indicative of anxiety were detected in late adulthood, the basal levels of fecal corticoid metabolites in prior-stressed rats did not differ from unstressed, control rats. PMID- 25448434 TI - Prevention of palatable diet-induced hyperphagia in rats by central injection of a VEGFR kinase inhibitor. AB - Our previous studies have demonstrated a critical role of a VEGFR-like signaling pathway in hunger-driven overeating of sugar-rich food in Drosophila larvae. In the current study, we investigate whether the VEGFR signaling mechanism plays a similar role in the feeding behavior of vertebrates using male Sprague Dawley rats. Young rats were treated intracerebroventrically (i.c.v.) with a single dose (2 MUg) of VEGFR2 Tyrosine Kinase Inhibitor V (VTKI-V), an N cyclopropylnaphthamide compound that selectively inhibits the kinase activity of VEGFR2 at subnanomolar concentrations. We find that animals treated with VTKI-V showed markedly attenuated overconsumption of palatable food that is sweet and fatty. The subsequent meal pattern analysis reveals that is achieved by consumption of smaller, shorter meals. Furthermore, i.c.v. injection of VTKI-V decreased body weight gain in animals fed with CHOW or palatable food. These inhibitory effects of the drug were detectable within 24h and persisted for at least five days. Given that body weight was affected by the drug regardless of diet while food intake was selectively altered in palatable diet fed animals, these results raise the possibility that i.c.v. injection of VTKI-V may interfere the functions of two separate VEGFR-mediated mechanisms: one promotes overconsumption of palatable food, and the other mediates body weight gain. PMID- 25448431 TI - Brain structure and cognitive correlates of body mass index in healthy older adults. AB - Obesity, commonly measured with body mass index (BMI), is associated with numerous deleterious health conditions including alterations in brain integrity related to advanced age. Prior research has suggested that white matter integrity observed using diffusion tensor imaging (DTI) is altered in relation to high BMI, but the integrity of specific white matter tracts remains poorly understood. Additionally, no studies have examined white matter tract integrity in conjunction with neuropsychological evaluation associated with BMI among older adults. The present study examined white matter tract integrity using DTI and cognitive performance associated with BMI in 62 healthy older adults (20 males, 42 females) aged 51-81. Results revealed that elevated BMI was associated with lower fractional anisotropy (FA) in the uncinate fasciculus, though there was no evidence of an age by BMI interaction relating to FA in this tract. No relationships were observed between BMI and other white matter tracts or cognition after controlling for demographic variables. Findings suggest that elevated BMI is associated with lower structural integrity in a brain region connecting frontal and temporal lobes and this alteration precedes cognitive dysfunction. Future studies should examine biological mechanisms that mediate the relationships between BMI and white matter tract integrity, as well as the evolution of these abnormalities utilizing longitudinal designs. PMID- 25448436 TI - Strain measurements and fracture resistance of endodontically treated premolars restored with all-ceramic restorations. AB - OBJECTIVES: The aim of this study was to investigate the recovery of cuspal stiffness and fracture resistance in endodontically treated maxillary premolars restored with bonded ceramic inlays and onlays of various designs. METHODS: Seventy intact premolars were selected for this study; six cavity designs were investigated: (i) mesio-occlusal-distal (MOD) inlay (I), (ii) MOD inlay with palatal cusp coverage (IPC), (iii) MOD onlay (O), (iv) MOD inlay with pulp chamber extension (IPE), (v) MOD inlay with palatal cusp coverage and pulp chamber extension (IPCPE), and (vi) MOD onlay with pulp chamber extension (OPE). Intact teeth acted as control. Strain gauges were attached to the buccal and palatal surfaces of the teeth to measure cuspal stiffness under static loading. All specimens were eventually subjected to compressive load to failure. Cuspal stiffness and fracture resistance data were analyzed using ANOVA and Tukey test. RESULTS: The I and IPE restorations restored cuspal stiffness to 75% of the sound tooth value. The O and OPE restored teeth had stiffness values greater than that of a sound tooth. The I, IPC, O, IPE, IPCPE and OPE restored teeth demonstrated fracture strength values of 938N+/-113 N (s.d.), 1073N+/-176 N and 1317N+/-219 N, 893N+/-129 N, 1062N+/-153 N and 1347N+/-191 N respectively. CONCLUSIONS: Within the limitations of this study, it was concluded that the all-ceramic onlay or inlay with palatal cusp coverage provided best biomechanical advantage in restoring an endodontically treated maxillary premolar tooth. CLINICAL SIGNIFICANCE: The onlay approach which is more conservative compared to full coverage restoration is considered an appropriate approach to the restoration of endodontically treated maxillary premolars. The addition of a pulpal extension to the all-ceramic restorations, apart from being technically challenging, was not found to offer any biomechanical advantage to the restored teeth. PMID- 25448435 TI - Gabaergic and opioid receptors mediate the facilitation of NaCl intake induced by alpha2-adrenergic activation in the lateral parabrachial nucleus. AB - Alpha2-adrenergic, gabaergic or opioidergic activation in the lateral parabrachial nucleus (LPBN) increases sodium intake. In the present study, we investigated the effects of single or combined blockade of opioidergic and gabaergic receptors in the LPBN on the increase of 0.3M NaCl intake induced by alpha2-adrenoceptor activation in the LPBN. Male Holtzman rats (n=5-9/group) with cannulas implanted bilaterally in the LPBN were treated with the diuretic furosemide (10 mg/kg b wt.) combined with low dose of the angiotensin converting enzyme inhibitor captopril (5 mg/kg b wt.) subcutaneously. Bilateral injections of moxonidine (alpha2-adrenergic/imidazoline receptor agonist, 0.5 nmol) into the LPBN increased furosemide+captopril-induced 0.3M NaCl intake (25.8+/-1.4, vs. vehicle: 3.8+/-1.1 ml/60 min). The opioidergic receptor antagonist naloxone (100 nmol) or the GABAA receptor antagonist bicuculline (5 nmol) injected into the LPBN partially reduced the increase of 0.3M NaCl intake produced by LPBN moxonidine (11.8+/-4.0 and 22.8+/-4.5, respectively, vs. vehicle+moxonidine: 31.6+/-4.0 ml/60 min, respectively). Similar to the treatment with each antagonist alone, the combined injections of naloxone (100 nmol) and bicuculline (5 nmol) into the LPBN also partially reduced moxonidine effects on 0.3M NaCl intake (15.5+/-6.5 ml/60 min). The GABAB receptor antagonist saclofen (5 nmol) injected into the LPBN did not change the effects of moxonidine on 0.3M NaCl intake (24.3+/-7.8 ml/120 min). These results suggest that the increase of 0.3M NaCl intake by alpha2-adrenergic receptor activation in the LPBN is partially dependent on GABAA and opioid receptor activation in this area. PMID- 25448437 TI - Prevention of early childhood caries (ECC) through parental toothbrushing training and fluoride varnish application: a 24-month randomized controlled trial. AB - OBJECTIVES: To investigate the effectiveness of hands-on training in parental toothbrushing, with or without semi-annual applications of 5% sodium fluoride varnish in preventing ECC. METHODS: Study was conducted in Hong Kong where water is optimally fluoridated. Children aged 8-23 months were recruited and randomly allocated to one of three groups: Gp 1 - control, one-off oral health education talk to parents; Gp 2 - oral health education talk and parental toothbrushing training, reinforced every 6 months; Gp 3 - semi-annual application of fluoride varnish onto child's teeth in addition to the intervention provided to Gp 2. Clinical examinations of the children and interviews were conducted at baseline and after 24 months to assess the children's dental caries status and toothbrushing behaviour. RESULTS: Out of the 450 child-parent dyads recruited at baseline, 415 (92%) remained after 24 months. At baseline, 2% of the children had non-cavitated enamel caries lesions and the mean dmft score was 0.03 +/- 0.24. Most of the children did not have daily parental toothbrushing (65-73%) and self toothbrushing (86-90%). At 24-month follow-up, including both non-cavitated and cavitated carious lesions, the incidences of ECC in Gp 1 to Gp 3 were 11.9%, 11.8%, and 17.5%, respectively (p>0.05); and the mean new dmft scores in Gp 1 to Gp 3 were 0.3, 0.2, and 0.3, respectively (p>0.05). Proportions of parents who practiced parental toothbrushing twice daily were 62.7%, 60.4%, and 65.7% in Gp 1 to Gp 3, respectively (p>0.05). CONCLUSIONS: In a water fluoridated area, hands on training in parental toothbrushing, with or without semi-annual application of 5% sodium fluoride varnish may not have additional effect on preventing ECC in young children with low risk of dental caries compared to provision of oral health education to parents. CLINICAL SIGNIFICANCE: In a water fluoridated area, provision of individual oral health education to parents may be sufficient for preventing ECC in young children below age 3. Supplemental training in parental toothbrushing and semi-annual applications of fluoride varnish may not have additional caries prevention effect in young children with low risk of dental caries. PMID- 25448438 TI - Early biomarkers of doxorubicin-induced heart injury in a mouse model. AB - Cardiac troponins, which are used as myocardial injury markers, are released in plasma only after tissue damage has occurred. Therefore, there is a need for identification of biomarkers of earlier events in cardiac injury to limit the extent of damage. To accomplish this, expression profiling of 1179 unique microRNAs (miRNAs) was performed in a chronic cardiotoxicity mouse model developed in our laboratory. Male B6C3F1 mice were injected intravenously with 3mg/kg doxorubicin (DOX; an anti-cancer drug), or saline once a week for 2, 3, 4, 6, and 8weeks, resulting in cumulative DOX doses of 6, 9, 12, 18, and 24mg/kg, respectively. Mice were euthanized a week after the last dose. Cardiac injury was evidenced in mice exposed to 18mg/kg and higher cumulative DOX dose whereas examination of hearts by light microscopy revealed cardiac lesions at 24mg/kg DOX. Also, 24 miRNAs were differentially expressed in mouse hearts, with the expression of 1, 1, 2, 8, and 21 miRNAs altered at 6, 9, 12, 18, and 24mg/kg DOX, respectively. A pro-apoptotic miR-34a was the only miRNA that was up-regulated at all cumulative DOX doses and showed a significant dose-related response. Up regulation of miR-34a at 6mg/kg DOX may suggest apoptosis as an early molecular change in the hearts of DOX-treated mice. At 12mg/kg DOX, up-regulation of miR 34a was associated with down-regulation of hypertrophy-related miR-150; changes observed before cardiac injury. These findings may lead to the development of biomarkers of earlier events in DOX-induced cardiotoxicity that occur before the release of cardiac troponins. PMID- 25448439 TI - Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways. AB - Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5MUM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1alpha, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1beta, IL-6, IL-8, TNF-alpha) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF kappaB, COX-2, STAT-3, iNOS, TNF-alpha) and angiogenesis (HIF-1alpha, VEGF, MMP 9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis. PMID- 25448442 TI - Through the smoke: use of in vivo and in vitro cigarette smoking models to elucidate its effect on female fertility. AB - A finite number of oocytes are established within the mammalian ovary prior to birth to form a precious ovarian reserve. Damage to this limited pool of gametes by environmental factors such as cigarette smoke and its constituents therefore represents a significant risk to a woman's reproductive capacity. Although evidence from human studies to date implicates a detrimental effect of cigarette smoking on female fertility, these retrospective studies are limited and present conflicting results. In an effort to more clearly understand the effect of cigarette smoke, and its chemical constituents, on female fertility, a variety of in vivo and in vitro animal models have been developed. This article represents a systematic review of the literature regarding four of experimental model types: 1) direct exposure of ovarian cells and follicles to smoking constituents' in vitro, 2) direct exposure of whole ovarian tissue with smoking constituents in vitro, 3) whole body exposure of animals to smoking constituents and 4) whole body exposure of animals to cigarette smoke. We summarise key findings and highlight the strengths and weaknesses of each model system, and link these to the molecular mechanisms identified in smoke-induced fertility changes. PMID- 25448443 TI - Transfluthrin: comparative efficacy and toxicity of reference and generic versions. AB - Stringent requirements are in place for the evaluation and registration of new compounds with biocidal or pesticidal activities. However, the registration requirements for established compounds from new suppliers or for established compounds produced by a different manufacturing process have been less clear and ambiguity exists as to how 'equivalence of health hazards' can unequivocally be demonstrated analytically and by toxicological assays. The case presented in this analysis focuses on the chiral pyrethroid transfluthrin (TFL) synthesized by esterification of an acid chloride and alcoholic moiety. According to any modifications of the process of synthesis and purification, new potentially highly toxic and yet chemically reactive impurities in low concentrations (<0.1%) may be formed. Amongst these, that with the structural alert 'organic acid anhydride' was given heightened concern as the most potent putative toxicologically significant impurity. The course taken in this analysis focused on the comparison of reference TFL with commercialized generic TFL from two alternative manufacturing sources in India and China. Despite their apparent high racemic purity, TFLs from generic sources were biologically less effective, genotoxic in the Ames' assay, demonstrated sensory lung irritation and lung/skin sensitization in specialized bioassays. While the off-patent reference TFL was unequivocally negative in all assays (anhydride content not detectable, LOQ <0.01%), positive results with high batch-to-batch variability were a frequent outcome in generic TFLs. Tier I analytical assays failed to detect this relevant impurity in the absence of impurity-specific optimized analytical procedures. This finding suggests that a well-balanced combined approach of analytical and toxicological assays provides the best means to assure that all critical impurities are identified and accounted for. Similarly, putative 'structural alert'-based toxicity tests proved to be more predictive than any indiscriminant battery of standard bioassays commonly applied to demonstrate equivalence, such as acute oral/dermal toxicity and/or eye/skin irritation assays. PMID- 25448441 TI - A comprehensive evaluation of the efficacy of leading oxime therapies in guinea pigs exposed to organophosphorus chemical warfare agents or pesticides. AB - The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection at the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1 min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl2, TMB-4, MMB4-DMS, HLo-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24 h post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman's method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLo-7 DMS were the two most consistently efficacious oximes. PMID- 25448440 TI - Arsenic inhibits hedgehog signaling during P19 cell differentiation. AB - Arsenic is a toxicant found in ground water around the world, and human exposure mainly comes from drinking water or from crops grown in areas containing arsenic in soils or water. Epidemiological studies have shown that arsenic exposure during development decreased intellectual function, reduced birth weight, and altered locomotor activity, while in vitro studies have shown that arsenite decreased muscle and neuronal cell differentiation. The sonic hedgehog (Shh) signaling pathway plays an important role during the differentiation of both neurons and skeletal muscle. The purpose of this study was to investigate whether arsenic can disrupt Shh signaling in P19 mouse embryonic stem cells, leading to changes muscle and neuronal cell differentiation. P19 embryonic stem cells were exposed to 0, 0.25, or 0.5 MUM of sodium arsenite for up to 9 days during cell differentiation. We found that arsenite exposure significantly reduced transcript levels of genes in the Shh pathway in both a time and dose-dependent manner. This included the Shh ligand, which was decreased 2- to 3-fold, the Gli2 transcription factor, which was decreased 2- to 3-fold, and its downstream target gene Ascl1, which was decreased 5-fold. GLI2 protein levels and transcriptional activity were also reduced. However, arsenic did not alter GLI2 primary cilium accumulation or nuclear translocation. Moreover, additional extracellular SHH rescued the inhibitory effects of arsenic on cellular differentiation due to an increase in GLI binding activity. Taken together, we conclude that arsenic exposure affected Shh signaling, ultimately decreasing the expression of the Gli2 transcription factor. These results suggest a mechanism by which arsenic disrupts cell differentiation. PMID- 25448444 TI - Effect of porcine circovirus type 2 (PCV2) load in serum on average daily weight gain during the postweaning period. AB - Porcine circovirus type 2 (PCV2) is a ubiquitous virus that mainly affects nursery and fattening pigs causing systemic disease (PCV2-SD) or subclinical infection. A characteristic sign in both presentations is reduction of average daily weight gain (ADWG). The present study aimed to assess the relationship between PCV2 load in serum and ADWG from 3 (weaning) to 21 weeks of age (slaughter) (ADWG 3-21). Thus, three different boar lines were used to inseminate sows from two PCV2-SD affected farms. One or two pigs per sow were selected (60, 61 and 51 piglets from Pietrain, Pietrain*Large White and Duroc*Large White boar lines, respectively). Pigs were bled at 3, 9, 15 and 21 weeks of age and weighted at 3 and 21 weeks. Area under the curve of the viral load at all sampling times (AUCqPCR 3-21) was calculated for each animal according to standard and real time quantitative PCR results; this variable was categorized as "negative or low" (<10(4.3) PCV2 genome copies/ml of serum), "medium" (>=10(4.3) to <=10(5.3)) and "high" (>10(5.3)). Data regarding sex, PCV2 antibody titre at weaning and sow parity was also collected. A generalized linear model was performed, obtaining that paternal genetic line and AUCqPCR 3-21 were related to ADWG 3-21. ADWG 3-21 (mean+/-typical error) for "negative or low", "medium" and "high" AUCqPCR 3-21 was 672+/-9, 650+/-12 and 603+/-16 g/day, respectively, showing significant differences among them. This study describes different ADWG performances in 3 pig populations that suffered from different degrees of PCV2 viraemia. PMID- 25448446 TI - Linear epitope recognition antibodies strongly respond to the C-terminal domain of HP-PRRSV GP5. AB - A total of 155 peptides derived from the highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) glycoprotein 5 (GP5) were printed on a chip to reveal the antigen reaction characteristics of the protein. The reactions of these peptides to HP-PRRSV-specific pig serum were scanned and quantified using fluorescence intensity via the PepSlide((r)) Analyzer software. The intensity plots showed different reactions in the different sectors of GP5. The highest reaction intensity value reached 3894.5, with a peptide sequence of IVEKGGKVEVEGHLI. Seventeen peptides that showed relatively high reaction levels with HP-PRRSV-specific pig serum were selected as epitope candidates. Furthermore, the antigenic character was predicted using a software and was compared with the peptide scan results. In contrast to the software prediction, the HP-PRRSV-specific antibodies strongly responded to the C-terminal domain of GP5. The acquired data may be useful for understanding the antigenic characteristics of HP-PRRSV GP5. PMID- 25448445 TI - Temporal evolution and potential recombination events in PRRSV strains of Sonora Mexico. AB - The aim of this work was to examine the evolution and potential existence of intragenic recombinations of PRRSV strains in Sonora, Mexico. In this study, 142 serum samples from farms located in Hermosillo (HMO), Cd. Obregon (OBR) and Navojoa (NAV) were sequenced from 2002 to 2012. Ninety non-redundant sequences of ORF5 gene were analyzed for temporal and spatial relationships among strains and the probability of a recombination event. The phylogenetic analysis showed 30 strains grouped into eight groups; 16 strains were closely related among the farms, while 14 were un-related. The first strain in this study was observed in 2002. A number of farms were infected with one or more strains, and in the majority of the strains, the virus was replaced by a new strain. The recombination analysis suggested the presence of four viruses as products of a recombination event; in one case, a virus close related with MLV vaccine was involved as the parent virus. This work shows the evolution of PRRSV in the field, the viral dissemination between farms and the potential recombination events. Our data suggest that PRRSV in Sonora has a specific genetic nature compared with other PRRSV. PMID- 25448447 TI - Application of cattle slurry containing Mycobacterium avium subsp. paratuberculosis (MAP) to grassland soil and its effect on the relationship between MAP and free-living amoeba. AB - Slurry from dairy farms is commonly used to fertilize crops and pastures. This mixture of manure, urine and water can harbor multiple microbial pathogens among which Mycobacterium avium subsp. paratuberculosis (MAP) is a major concern. Persistence of MAP in soil and infection of soil Acanthamoeba was evaluated by culture, real-time IS900 PCR, and by staining of amoeba with acid-fast and vital stains comparing soils irrigated with MAP-spiked or control dairy farm slurry. MAP DNA was detected in soil for the 8 month study duration. MAP was detected by PCR from more soil samples for plots receiving MAP-spiked slurry (n=61/66) than from soils receiving control slurry (n=10/66 samples). Vital stains verified that intracellular MAP in amoeba was viable. More MAP was found in amoeba at the end of the study than immediately after slurry application. There was no relationship between MAP presence in soil and in amoeba over time. Infection of amoeba by MAP provides a protected niche for the persistence and even possibly the replication of MAP in soils. As others have suggested, MAP-infected amoeba may act like a "Trojan horse" providing a means for persistence in soils and potentially a source of infection for grazing animals. PMID- 25448448 TI - Experimental nasal colonization of piglets with methicillin-susceptible and methicillin-resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus sequence type (ST)398 is widely spread among livestock. People in contact with livestock have a higher risk of testing positive for MRSA. Several experimental settings have been described to study in vivo colonization of MRSA in pigs, each having its own limitations. The aim of this study was to develop a nose-colonization model in pigs to quantitatively study the colonization of MRSA and the co-colonization of MSSA and MRSA. Two experiments were performed: in the first experiment piglets received an intranasal inoculation with MRSA ST398, spa-type t011, and in the second experiment piglets received an intranasal inoculation with two MSSA strains (ST398, spa-type t011 and t034) and two MRSA strains (also ST398, spa-type t011 and t034) to investigate co-colonization. Colonization was quantitatively monitored for 2 weeks in both experiments. Nasal colonization was successfully established in all piglets with stable numbers of S. aureus between 10(4) and 10(6) CFU. MSSA and MRSA were able to co-colonize. PMID- 25448449 TI - Evaluation of biofilm formation using milk in a flow cell model and microarray characterization of Staphylococcus aureus strains from bovine mastitis. AB - It was hypothesized that biofilm could play an important role in the establishment of chronic Staphylococcus aureus bovine mastitis. The in vitro evaluation of biofilm formation can be performed either in closed/static or in flow-based systems. Efforts have been made to characterize the biofilm-forming ability of S. aureus mastitis isolates, however most authors used static systems and matrices other than UHT milk. It is not clear whether such results could be extrapolated to the mammary gland environment. Therefore, the present study aimed to investigate the biofilm-forming ability of S. aureus strains from subclinical bovine mastitis using the static method and a flow-based one. One hundred and twelve strains were tested by the classic tissue culture plate assay (TCP) and 30 out of them were also tested by a dynamic semi-quantitative assay using commercial UHT milk as culture medium (Milk Flow Culture, MFC) or Tryptic Soy Broth as control medium (TS Flow Culture, TSFC). Only 6 (20%) strains formed biofilm in milk under flow conditions, while 36.6% were considered biofilm producers in TCP, and 93.3% produced biofilm in TSFC. No agreement was found between TCP, MFC and TSFC results. The association between strain genetic profile, determined by microarray, and biofilm-forming ability in milk was evaluated. Biofilm formation in MFC was significantly associated with the presence of those genes commonly found in bovine-associated strains, assigned to clonal complexes typically detected in mastitis. Based on our results, biofilm forming potential of bovine strains should be critically analysed and tested applying conditions similar to mammary environment. PMID- 25448451 TI - Repeated isolation of Salmonella enterica Goverdhan, a very rare serovar, from Danish poultry surveillance samples. AB - We report here the appearance of a very rare serovar of Salmonella, S. enterica subsp. enterica serovar Goverdhan, in routine Salmonella surveillance samples from Danish poultry production. S. Goverdhan was found on nine occasions: in one broiler breeder farm in October 2010, four broiler farms and one broiler breeder farm in June-September 2012, two broiler breeder flocks simultaneously in June 2013, and one layer flock in July 2013. The five isolates from 2012 and the three isolates from 2013 had identical pulsed-field gel electrophoresis profiles, whereas the profile of the isolate from 2010 deviated in a single band. It is the first time this serovar has been described in samples from poultry. The origin of the bacterium is still unknown, but it is suggested that it may have been a pseudo-outbreak caused by contaminated sampling material. PMID- 25448450 TI - Andrographolide interferes quorum sensing to reduce cell damage caused by avian pathogenic Escherichia coli. AB - Avian pathogenic Escherichia coli (APEC) induce septicemia in chickens by invading type II pneumocytes to breach the blood-air barrier. The virulence of APEC can be regulated by quorum sensing (QS). Andrographolide is a QS inhibitor of Pseudomonas aeruginosa (P. aeruginosa). Therefore, we investigate whether andrographolide inhibits the injury of chicken type II pneumocytes by avian pathogenic E. coli O78 (APEC-O78) by disrupting the bacterial QS system. The results showed that sub-MIC of andrographolide significantly reduced the release of lactate dehydrogenase (LDH), F-actin cytoskeleton polymerization, and the degree of the adherence to chicken type II pneumocytes induced by APEC-O78. Further, we found that andrographolide significantly decreased the autoinducer-2 (AI-2) activity and the expression of virulence factors of APEC-O78. These results suggest that andrographolide reduce the pathogenicity of APEC-O78 in chicken type II pneumocytes by interfering QS and decreasing virulence. These results provide new evidence for colibacillosis prevention methods in chickens. PMID- 25448452 TI - Alternative sampling strategies for passive classical and African swine fever surveillance in wild boar--extension towards African swine fever virus antibody detection. PMID- 25448453 TI - The role of secondary cytoreduction in low-grade serous ovarian cancer or peritoneal cancer. AB - OBJECTIVES: We sought to determine the benefit of secondary cytoreductive surgery (SCRS) in patients with low-grade serous ovarian or peritoneal carcinoma, and whether cytoreduction to no gross residual disease affects survival. METHODS: A single institution retrospective chart review was conducted in patients with recurrent low-grade serous carcinoma who underwent SCRS between 1995 and 2012. Data including demographics, survival, chemotherapy, disease characteristics at the time of surgery, residual disease, and operative complications were collected. Overall survival (OS) and progression-free survival (PFS) were calculated. Kaplan-Meier and log-rank tests were used to examine survival outcomes. RESULTS: Forty-one patients met inclusion criteria. The median time between primary tumor debulking and SCRS was 33.2 months. Of 41 eligible patients who underwent SCRS, 32 (78%) had gross residual disease at the completion of secondary surgery. The median PFS for patients with no gross residual disease after SCRS was 60.3 months, compared to 10.7 months for patients with gross residual disease (p = 0.008). Median OS from diagnosis for patients with no gross residual disease after SCRS was 167.5 months compared to 88.9 months (p = 0.10). Median OS from the time of SCRS for patients with no gross residual disease was 93.6 months compared to 45.8 months (p = 0.04). Complications occurred in 61% of patients after SCRS; there were no deaths directly attributable to surgery. CONCLUSION: Our results suggest a benefit to SCRS in patients with recurrent low grade serous carcinoma. Efforts to maximally cytoreduce patients should be made as patients with no gross residual disease had a better PFS and a trend toward better OS. PMID- 25448455 TI - Treatment of ovarian cancer in the older woman. AB - Half of ovarian cancer patients are over the age of 65, and as the population ages, the number of older women with ovarian cancer is increasing. Older women with ovarian cancer receive less surgery and chemotherapy than younger women, suffer worse toxicity from surgery and chemotherapy than younger women, and have worse survival. Performance status has been shown to be an inadequate tool to predict toxicity of older patients from therapy. Use of formal geriatric assessment tools is a promising direction for stratifying older patients on trials. We review current data on outcomes with surgery and chemotherapy in the older population, and discuss geriatric assessment tools being studied to aid decisions regarding which older patients will tolerate standard therapy and which will not. Modified treatment regimens and interventions to decrease morbidities in the vulnerable older population should be useful. PMID- 25448454 TI - Incidence, risk factors and estimates of a woman's risk of developing secondary lower limb lymphedema and lymphedema-specific supportive care needs in women treated for endometrial cancer. AB - OBJECTIVES: Few studies have assessed the risk and impact of lymphedema among women treated for endometrial cancer. We aimed to quantify cumulative incidence of, and risk factors for developing lymphedema following treatment for endometrial cancer and estimate absolute risk for individuals. Further, we report unmet needs for help with lymphedema-specific issues. METHODS: Women treated for endometrial cancer (n = 1243) were followed-up 3-5 years after diagnosis; a subset of 643 completed a follow-up survey that asked about lymphedema and lymphedema-related support needs. We identified a diagnosis of secondary lymphedema from medical records or self-report. Multivariable logistic regression was used to evaluate risk factors and estimates. RESULTS: Overall, 13% of women developed lymphedema. Risk varied markedly with the number of lymph nodes removed and, to a lesser extent, receipt of adjuvant radiation or chemotherapy treatment, and use of nonsteroidal anti-inflammatory drugs (pre-diagnosis). The absolute risk of developing lymphedema was >50% for women with 15+ nodes removed and 2-3 additional risk factors, 30-41% for those with 15+ nodes removed plus 0-1 risk factors or 6-14 nodes removed plus 3 risk factors, but <= 8% for women with no nodes removed or 1-5 nodes but no additional risk factors. Over half (55%) of those who developed lymphedema reported unmet need(s), particularly with lymphedema-related costs and pain. CONCLUSION: Lymphedema is common; experienced by one in eight women following endometrial cancer. Women who have undergone lymphadenectomy have very high risks of lymphedema and should be informed how to self-monitor for symptoms. Affected women need greater levels of support. PMID- 25448456 TI - Bevacizumab in recurrent, persistent, or advanced stage carcinoma of the cervix: is it cost-effective? AB - OBJECTIVE: Evaluate the cost-effectiveness of incorporating bevacizumab into the treatment regimen for recurrent, persistent, or advanced stage carcinoma of the cervix following publication of a recent phase III trial that demonstrated an overall survival (OS) benefit with the addition of bevacizumab. METHODS: A cost effectiveness decision model was constructed using recently published results from a Gynecologic Oncology Group phase III study, comparing a standard chemotherapy regimen (Chemo) to the experimental regimen (Chemo + Bev) consisting of the standard regimen+bevacizumab. Costs and adverse events were incorporated and sensitivity analyses assessed model uncertainties. RESULTS: The cost of Chemo + Bev was $53,784 compared to $5,688 for the Chemo arm. The 3.7 month OS advantage with Chemo+Bev came at an incremental cost-effectiveness ratio (ICER) of $155K per quality-adjusted life year (QALY). Chemo + Bev becomes cost effective with an ICER <= $100K in sensitivity analysis when the cost of bevacizumab is discounted >37.5% or the dose is reduced from 15 to 7.5 mg/kg, an effective dose in ovarian cancer. CONCLUSIONS: With an ICER of $155K/QALY, the addition of bevacizumab to standard chemotherapy approaches common cost effectiveness standards. Moderately discounting the cost of bevacizumab or using a smaller dose significantly alters its affordability. PMID- 25448457 TI - Nomogram for predicting incomplete cytoreduction in advanced ovarian cancer patients. AB - OBJECTIVE: Accurately predicting cytoreducibility in advanced-ovarian cancer is needed to establish preoperative plans, consider neoadjuvant chemotherapy, and improve clinical trial protocols. We aimed to develop a positron-emission tomography/computed tomography-based nomogram for predicting incomplete cytoreduction in advanced-ovarian cancer patients. METHODS: Between 2006 and 2012, 343 consecutive advanced-ovarian cancer patients underwent positron emission tomography/computed tomography before primary cytoreduction: 240 and 103 patients were assigned to the model development or validation cohort, respectively. After reviewing the detailed surgical documentation, incomplete cytoreduction was defined as a remaining gross residual tumor. We evaluated each individual surgeon's surgical aggressiveness index (number of high-complex surgeries/total number of surgeries). Possible predictors, including surgical aggressiveness index and positron-emission tomography/computed tomography features, were analyzed using logistic regression modeling. A nomogram based on this model was developed and externally validated. RESULTS: Complete cytoreduction was achieved in 120 patients (35%). Surgical aggressiveness index and five positron-emission tomography/computed tomography features were independent predictors of incomplete cytoreduction. Our nomogram predicted incomplete cytoreduction by incorporating these variables and demonstrated good predictive accuracy (concordance index = 0.881; 95% CI = 0.838-0.923). The predictive accuracy of our validation cohort was also good (concordance index = 0.881; 95% CI = 0.790-0.932) and the predicted probability was close to the actual observed outcome. Our model demonstrated good performance across surgeons with varying degrees of surgical aggressiveness. CONCLUSION: We have developed and validated a nomogram for predicting incomplete cytoreduction in advanced ovarian cancer patients which may help stratify patients for clinical trials, establish meticulous preoperative plans, and determine if neoadjuvant chemotherapy is warranted. PMID- 25448458 TI - Genetic and epigenetic changes in vulvar squamous cell carcinoma and its precursor lesions: a review of the current literature. AB - Vulvar cancer is a relatively rare gynecologic malignancy with an annual incidence in developed countries of approximately 2 per 100,000 women. Vulvar squamous cell carcinoma (VSCC) has two etiological pathways: a high risk human papillomavirus (HPV)-dependent route, which has usual vulvar intraepithelial neoplasia (uVIN) as a precursor lesion, and an HPV-independent route, which is associated with differentiated VIN (dVIN), lichen sclerosus, and genetic alterations, such as TP53 mutations. Research on the molecular etiology of vulvar cancer has increased in the past years, not only regarding genetic alterations, but also epigenetic changes. In genetic alterations, a mutation irreversibly changes the nucleotide sequence of the DNA, or the number of copies of chromosomes per cell is altered. In epigenetics, the nucleotide sequence remains the same but genes can be 'switched' on or off by, for example, DNA methylation or histone modification. We searched the current literature on genetic and epigenetic alterations in VSCC and its precursor lesions. Many studies have reported a higher incidence of somatic mutations in HPV-negative tumors compared to HPV-positive tumors, with TP53 mutations being the most frequent. Allelic imbalances or loss of heterozygosity are more frequently found in higher stages of dysplasia and in invasive carcinomas, but it is not exclusive to HPV-negative tumors. A limited number of studies are available on epigenetic changes in vulvar lesions, with hypermethylation of CDKN2A being the most frequently investigated change. For most genes, hypermethylation occurs more frequently in vulvar squamous cell carcinomas than in precursor lesions. As most studies have focused on HPV infection and TP53 mutations, we suggest that more research should be performed using whole genome or next generation sequencing to determine the true landscape of genetic and epigenetic alterations in vulvar squamous cell carcinoma. PMID- 25448459 TI - Risk of second cancers cancer after a first primary breast cancer: a systematic review and meta-analysis. AB - OBJECTIVE: To examine the scientific evidence and the risk of second primary cancers in women diagnosed with a first primary breast cancer. METHODS: The literature was searched in Pubmed and Embase and included studies published up to June 2013, using population-based data and IARC/AICR codification rules for multiple primary cancers. A qualitative synthesis was carried out and the methodological quality of the studies evaluated. Standardised incidence ratios (SIRs) on second cancer risk, weighted by the standard error of each study, were pooled using fixed and random effects models. SIRs were also pooled by age at diagnosis (<50 and >= 50 years), and time since diagnosis of the first breast cancer (<10 and >= 10 years). RESULTS: 15 out of 710 articles fulfilled the inclusion criteria. All of them were retrospective cohort studies either population-based (13 studies) or hospital-based studies (2 studies). The studies varied with respect to number of cases, selection criteria, definition of multiple primary cancers, and the second cancer sites included. SIRs reported in these studies for all cancers combined varied from 1.0 to 1.4. The pooled SIR estimate for second cancer risk was 1.17 (95% CI: 1.10-1.25). By age groups, SIR estimates were 1.51 (95% CI: 1.35-1.70) for women younger than 50 years and 1.11 (95% CI: 1.02-1.21) for those who were older. Women with breast cancer are at risk of second cancers within the first 10 years after the first breast cancer diagnosis (SIR: 1.19; 95% CI: 1.06-1.33), and thereafter (SIR: 1.26; 95% CI: 1.05 1.52). CONCLUSION: This higher risk of second cancers in women diagnosed with a first primary breast cancer with respect to the general population emphasises the importance of prevention and control policies aimed at reducing incidence of second cancers. PMID- 25448460 TI - Dealing With Missing Behavioral Endpoints in Health Promotion Research by Modeling Cognitive Parameters in Cost-Effectiveness Analyses of Behavioral Interventions: A Validation Study. AB - Cost-effectiveness analyses (CEAs) of behavioral interventions typically use physical outcome criteria. However, any progress in cognitive antecedents of behavior change may be seen as a beneficial outcome of an intervention. The aim of this study is to explore the feasibility and validity of incorporating cognitive parameters of behavior change in CEAs. The CEA from a randomized controlled trial on smoking cessation was reanalyzed. First, relevant cognitive antecedents of behavior change in this dataset were identified. Then, transition probabilities between combined states of smoking and cognitions at 6 weeks and corresponding 6 months smoking status were obtained from the dataset. These rates were extrapolated to the period from 6 to 12 months in a decision analytic model. Simulated results were compared with the 12 months' observed cost-effectiveness results. Self-efficacy was the strongest time-varying predictor of smoking cessation. Twelve months' observed CEA results for the multiple tailoring intervention versus usual care showed ? 3188 had to be paid for each additional quitter versus ? 10,600 in the simulated model. The simulated CEA showed largely similar but somewhat more conservative results. Using self-efficacy to enhance the estimation of the true behavioral outcome seems a feasible and valid way to estimate future cost-effectiveness. PMID- 25448461 TI - Canadian Cardiovascular Society position statement on familial hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is the most common genetic disorder causing premature cardiovascular disease and death. Heterozygous FH conservatively affects approximately 1:500 Canadians, and the more serious homozygous form affects approximately 1:1,000,000 Canadians, although these numbers might be underestimated. Of approximately 83,500 Canadians estimated to have FH, most are undiagnosed, which represents a simultaneous public health deficit and opportunity, because early treatment of heterozygous FH can normalize life expectancy. Diagnostic algorithms for FH incorporate increased plasma low-density lipoprotein cholesterol, pathognomonic clinical features, and family history of early cardiovascular disease and hyperlipidemia. DNA-based detection of causative mutations in FH-related genes can help with diagnosis. Maximizing diagnosis and treatment of FH in Canada will involve a multipronged approach, including: (1) increasing awareness of FH among health care providers and patients; (2) creating a national registry for FH individuals; (3) setting standards for screening, including cascade screening in affected families; (4) ensuring availability of standard-of-care therapies, in particular optimization of plasma low-density lipoprotein cholesterol levels and timely access to future validated therapies; (5) promoting patient-based support and advocacy groups; and (6) forming alliances with international colleagues, resources, and initiatives that focus on FH. This document aims to raise awareness of FH nationally, and to mobilize knowledge translation, patient support, and availability of treatment and health care resources for this underrecognized, but important medical condition. PMID- 25448462 TI - The use of antidepressants and the risk of idiopathic pulmonary arterial hypertension. AB - BACKGROUND: Serotonin has been implicated in the development of idiopathic pulmonary arterial hypertension (IPAH). Drugs modulating serotonin pathways, including antidepressants, have been associated with the incidence of IPAH, with conflicting reports as to the direction of the effect. We aimed to determine whether antidepressant exposure is associated with the incidence of IPAH. METHODS: A nested case-control study was conducted using the United Kingdom Clinical Practice Research Datalink and the Hospital Episodes Statistics repository between January 1, 1988 and September 30, 2011. Incident cases of IPAH were identified and matched to all controls in the case's risk set on age, sex, general practice, and date of registration with the practice. Rate ratios (RRs) and 95% confidence intervals (CIs) were estimated for the use of antidepressants on the risk of IPAH, with an 18-month lag period before the diagnosis. RESULTS: One hundred ninety-five IPAH cases were identified (incidence 3.84/million per year). Use of any antidepressant was associated with a 67% increased risk of IPAH (RR, 1.67; 95% CI, 1.17-2.37). The rate of IPAH was similar across antidepressant classes, whether with selective serotonin reuptake inhibitors (SSRIs) (RR, 1.67; 95% CI, 1.09-2.57) or non-SSRI antidepressants (RR, 1.66; 95% CI, 1.07-2.59). In sensitivity and exploratory analyses, no change in risk was observed with different lag times, serotonin transporter affinities, or durations of exposure. CONCLUSIONS: The use of antidepressants was associated with a significantly increased risk of IPAH. However, the consistency of this risk across all antidepressants and absence of a dose-response relationship suggests a noncausal association. PMID- 25448464 TI - The epidemic of heart failure: a lucid approach to stemming the rising tide. AB - At least 1 in 5 Canadians will experience heart failure (HF) during their lifetimes, with an average 1-year mortality rate of 23.4%. Hospitalizations for HF are projected to increase 3-fold from 1996 to 2050. HF can be associated with either reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF), with the latter becoming increasingly common. The prognosis of both groups is equally concerning, but clinical trials testing pharmacologic therapies for HFpEF have been disappointing. We briefly discuss established therapies for HF and then focus on emerging therapies, challenges, and opportunities. Areas covered include practical pathophysiology; health care organization; monitoring and new technologies; pharmacogenomics, biomarkers, and personalized therapy; novel pharmacologic approaches; special considerations in acutely decompensated HF; revascularization; managing valve dysfunction; refining cardiac resynchronization therapy and device therapies; and cell therapy for cardiac repair. Among the novel pharmacologic directions we address are approaches to reducing oxidative stress, improving myocardial metabolism, new mineralocorticoid receptor antagonists, restoring vasoconstrictor-vasodilator balance, increasing cyclic guanosine monophosphate levels, and positive inotropic agents. Modifications in the organization of health care are particularly important, with an emerging hub and-spokes model involving engaged patients cared for by primary care teams, with ready access to specialized HF clinics. Biomarkers have contributed to better understanding of the pathophysiology of HFrEF as well as HFpEF and will eventually allow much more effective and personalized management. Considering the vast array of areas in development, we can look forward to continuing improvements in the care and outcomes of patients with HF in the future. PMID- 25448463 TI - Nonsense mutations in BAG3 are associated with early-onset dilated cardiomyopathy in French Canadians. AB - BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure that may require heart transplantation. Approximately one third of DCM cases are familial. Next-generation DNA sequencing of large panels of candidate genes (ie, targeted sequencing) or of the whole exome can rapidly and economically identify pathogenic mutations in familial DCM. METHODS: We recruited 64 individuals from 26 DCM families followed at the Montreal Heart Institute Cardiovascular Genetic Center and sequenced the whole exome of 44 patients and 2 controls. Both affected and unaffected family members underwent genotyping for segregation analysis. RESULTS: We found 2 truncating mutations in BAG3 in 4 DCM families (15%) and confirmed segregation with disease status by linkage (log of the odds [LOD] score = 3.8). BAG3 nonsense mutations conferred a worse prognosis as evidenced by a younger age of clinical onset (37 vs 48 years for carriers and noncarriers respectively; P = 0.037). We also found truncating mutations in TTN in 5 families (19%). Finally, we identified potential pathogenic mutations for 9 DCM families in 6 candidate genes (DSP, LMNA, MYH7, MYPN, RBM20, and TNNT2). We still need to confirm several of these mutations by segregation analysis. CONCLUSIONS: Screening an extended panel of 41 candidate genes allowed us to identify probable pathogenic mutations in 69% of families with DCM in our cohort of mostly French Canadian patients. We confirmed the prevalence of TTN nonsense mutations in DCM. Furthermore, to our knowledge, we are the first to present an association between nonsense mutations in BAG3 and early-onset DCM. PMID- 25448465 TI - Evaluation of serum PIVKA-II and MIF as diagnostic markers for HCV/HBV induced hepatocellular carcinoma. AB - Viral hepatitis is the most significant predisposing factor for hepatocellular carcinoma (HCC). Liver cancer grows silently with mild or no symptoms until the disease is advanced and with little hope of cure. Early recognition of the onset of HCC would help to select more effective therapies for patients leading to a better prognosis and life span. The current study aims to evaluate two diagnostic and prognostic markers - Prothrombin induced by vitamin K absence-II (PIVKA-II) and macrophage migration inhibitory factor (MIF) in the serum of patients with HCC and those with a high risk of developing hepatic cancers. Serum samples from hepatocellular carcinoma, hepatitis C and normal subjects were subjected to quantitative determinations of different parameters including alpha-fetoprotein (AFP), PIVKA-II and MIF. Significant differences between the various groups were recorded. PIVKA-II and AFP showed a higher specificity and sensitivity compared to MIF, and there was considerable correlation between AFP and both PIVKA and MIF. It is concluded that analysis of PIVKA-II and AFP can serve as useful non invasive markers for the early detection of HCC with good sensitivity and specificity. PMID- 25448466 TI - Sputum containing zinc enhances carbapenem resistance, biofilm formation and virulence of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa chronic lung infections are the leading cause of mortality in cystic fibrosis patients, a serious problem which is notably due to the numerous P. aeruginosa virulence factors, to its ability to form biofilms and to resist the effects of most antibiotics. Production of virulence factors and biofilm formation by P. aeruginosa is highly coordinated through complex regulatory systems. We recently found that CzcRS, the zinc and cadmium-specific two-component system is not only involved in metal resistance, but also in virulence and carbapenem antibiotic resistance in P. aeruginosa. Interestingly, zinc has been shown to be enriched in the lung secretions of cystic fibrosis patients. In this study, we investigated whether zinc might favor P. aeruginosa pathogenicity using an artificial sputum medium to mimic the cystic fibrosis lung environment. Our results show that zinc supplementation triggers a dual P. aeruginosa response: (i) it exacerbates pathogenicity by a CzcRS two-component system-dependent mechanism and (ii) it stimulates biofilm formation by a CzcRS independent mechanism. Furthermore, P. aeruginosa cells embedded in these biofilms exhibited increased resistance to carbapenems. We identified a novel Zn sensitive regulatory circuit controlling the expression of the OprD porin and modifying the carbapenem resistance profile. Altogether our data demonstrated that zinc levels in the sputum of cystic fibrosis patients might aggravate P. aeruginosa infection. Targeting zinc levels in sputum would be a valuable strategy to curb the increasing burden of P. aeruginosa infections in cystic fibrosis patients. PMID- 25448467 TI - The role for TolA in enterohemorrhagic Escherichia coli pathogenesis and virulence gene transcription. AB - Loss of the periplasm spanning protein TolA in Escherichia coli leads to activation of the Rcs phosphorelay, and is required for full virulence in Gram negative pathogens such as Salmonella enterica and Dickeya dadantii. This study explores the role for TolA in the pathogenesis of enterohemorrhagic E. coli (EHEC) and the effect of its mutation on the transcription of key EHEC virulence genes controlled by Rcs phosphorelay, including the type III secretion system (T3SS) (espA and tir), the E. coli common pilus (ecpA), and motility (fliC). Promoter activity for T3SS regulator ler was substantially higher following inactivation of tolA, and corresponded with a similar elevation in espA and tir transcription. Likewise, ecpA transcription was increased in EHECDeltatolA. Conversely, and in-line with previous studies, inactivation of tolA resulted in complete loss of motility and decreased fliC transcription. For all genes examined, altered transcription observed for EHECDeltatolA was dependent on the outer-membrane lipoprotein RcsF. Despite elevated virulence gene transcription, in tolA deleted strains virulence of EHEC in the Galleria mellonella wax worm model was substantially attenuated in a manner at least partly dependent on RcsF, and adherence to cultured HT-29 colonic epithelial cells was markedly reduced. The results of this study broaden the role for TolA in EHEC pathogenesis, and suggest that significant outer-membrane perturbations are able to promote transcription of important EHEC adherence factors. PMID- 25448469 TI - Transcatheter fiber heart valve: Effect of crimping on material performances. AB - Transcatheter aortic valve implantation (TAVI) has become a popular alternative technique to surgical valve replacement. However, the biological valve tissue used in these devices appears to be fragile material in the long term particularly due being folded for low diameter catheter insertion purposes and when released in a calcified environment with irregular geometry. Textile polyester material is characterized by outstanding folding and strength properties combined with proven biocompatibility. It could therefore be considered as a replacement for biological valve leaflets in the TAVI procedure. The folding process associated with crimping, however, may degrade the filaments involved in the fibrous assembly and limit the durability of the device. The purpose of the present work is to study the effect of different crimping conditions on the mechanical performances of textile valve prototypes made from various fabric constructions. Results show that crimping generates some creases in the fabrics, which surface topography varies with fabric construction and crimping configuration. The mechanical properties of the crimped materials are globally slightly reduced. To determine how critical the modifications due to crimping are for prosthesis durability, more detailed long term in vitro and in vivo trials with crimped textile prototypes are needed in addition to this preliminary work. PMID- 25448468 TI - Use of MRI signal intensity of extraocular muscles to evaluate methylprednisolone pulse therapy in thyroid-associated ophthalmopathy. AB - PURPOSE: To quantitatively evaluate the efficacy of methylprednisolone pulse therapy for extraocular muscle inflammation in thyroid-associated ophthalmopathy (TAO) using the short-tau inversion-recovery (STIR) technique of magnetic resonance imaging (MRI). METHODS: The signal intensities of the superior rectus (SR), inferior rectus (IR), lateral rectus (LR), medial rectus (MR), and superior oblique (SO) muscles were measured using the STIR images from 34 eyes of 17 patients with TAO before and after methylprednisolone pulse therapy and 19 eyes of 19 controls. The signal intensity ratio (SIR) of the signal intensity in muscles to that in brain white matter was calculated. RESULTS: The mean SIRs of the controls were 1.08 +/- 0.26 in the SR, 1.32 +/- 0.29 in the IR, 1.34 +/- 0.19 in the LR, 1.47 +/- 0.25 in the MR, and 1.28 +/- 0.22 in the SO muscles. SIRs exceeding 2.0 were out of the normal range. The SIRs of the patients with TAO before treatment were 2.19 +/- 0.64, 2.44 +/- 0.58, 1.96 +/- 0.43, 2.24 +/- 0.47, and 1.91 +/- 0.42, respectively, which was significantly (P < 0.001) higher than those of the controls; after treatment, the mean SIRs were 1.82 +/- 0.57, 1.81 +/ 0.49, 1.64 +/- 0.35, 1.88 +/- 0.43, and 1.54 +/- 0.33, respectively, significantly (P < 0.001) lower in all muscles than those before treatment. However, the SIRs of some muscles remained over 2.0. Moreover, all cases that had deterioration of TAO had one or more muscles with a SIR exceeding 2.5 after treatment. CONCLUSION: Extraocular muscle inflammation in TAO improved with treatment. However, inflammation in some muscles persisted after treatment, and a high SIR in the muscle after treatment suggested the risk of deterioration of TAO. PMID- 25448470 TI - Special issue on children, young people, and families living with long-term conditions. PMID- 25448471 TI - Raising the bar for evidence-based practice within the society of pediatric nurses. PMID- 25448472 TI - Strategies to improve insulin adherence in adolescents with type 1 diabetes. PMID- 25448473 TI - Percutaneous Endoscopic Gastrostomy in Children: Caregivers' Perspectives. AB - We aimed to study caregivers' perspectives on percutaneous endoscopic gastrostomy (PEG). We interviewed the caregivers of 33 children who were fed via PEG and that, of these caregivers, those who believed that they received adequate information prior to and after PEG insertion had a better quality of life. Furthermore, 65% would proceed for an earlier PEG insertion which was associated with several factors including lower educational level, lower household income, and longer traveling time from their residence to our institution. Data from our study may help improve understanding caregivers' perspectives and concerns in children who already or will have PEG. PMID- 25448474 TI - An Analytic Review of Clinical Implications From Nursing and Psychosocial Research Within Swedish Pediatric Oncology. AB - The purpose of this manuscript is to analyze researchers' suggestions for clinical implications of their findings as stated in recent published articles on nursing and psychosocial research within the setting of Swedish pediatric oncology. Identified categories included staff awareness of the effects of child illness on families; systems for care improvement; provision of quality of care, education and support; and empowerment of children and families. In order to be able to realize these clinical suggestions, expanded research is needed as well as continued education and support for staff. PMID- 25448475 TI - Outcomes of a Quality Improvement Project Examining Early Childhood Caries and Improving Identification of At Risk Patients in a Pediatric Medical Home Setting. AB - Early childhood caries (ECC) is a widespread childhood disease that disproportionately affects children with disabilities, those in lower-income households and minority children. The American Academy of Pediatrics (AAP) recommends that all children be screened for ECC and referred to a dentist by the age of one. This quality improvement project took place at a hospital-affiliated pediatric clinic. A caries risk screening tool was implemented at 9-, 12-, and 18 month well child check-ups for 3 months. A retrospective chart review was performed for comparison purposes. The quality improvement project indicated improvement in identification of children at high-risk for ECC. PMID- 25448476 TI - Measurement considerations for achieving equity in research inclusion for transition-aged youth with disabilities. AB - Measuring health for youth with intellectual disabilities (ID) is important for tracking progress toward national health goals. Measures of biophysical and fitness indicators are important but difficult to obtain in youth with ID, particularly in community settings. This paper describes obstacles encountered and strategies used to measure outcomes in a community-based study. Proposed best practices include adaptations in procedures to maximize comprehension; preparation of the environment to provide privacy and predictability; and appropriately sized equipment to obtain accurate readings. Reliable and valid measures, specific to youth with ID, would improve promote research inclusion and reduce health disparities for this population. PMID- 25448477 TI - Deciphering the human microbiome using next-generation sequencing data and bioinformatics approaches. AB - The human microbiome is one of the key factors affecting the host immune system and metabolic functions that are not encoded in the human genome. Culture independent analysis of the human microbiome using metagenomics approach allows us to investigate the compositions and functions of the human microbiome. Computational methods analyze the microbial community by using specific marker genes or by using shotgun sequencing of the entire microbial community. Taxonomy profiling is conducted by using the reference sequences or by de novo clustering of the specific region of sequences. Functional profiling, which is mainly based on the sequence similarity, is more challenging since about half of ORFs predicted in the metagenomic data could not find homology with known protein families. This review examines computational methods that are valuable for the analysis of human microbiome, and highlights the results of several large-scale human microbiome studies. It is becoming increasingly evident that dysbiosis of the gut microbiome is strongly associated with the development of immune disorder and metabolic dysfunction. PMID- 25448478 TI - PTEN-PDZ domain interactions: binding of PTEN to PDZ domains of PTPN13. AB - Protein modular interactions mediated by PDZ domains are essential for the establishment of functional protein networks controlling diverse cellular functions. The tumor suppressor PTEN possesses a C-terminal PDZ-binding motif (PDZ-BM) that is recognized by a specific set of PDZ domains from scaffolding and regulatory proteins. Here, we review the current knowledge on PTEN-PDZ domain interactions and tumor suppressor networks, describe methodology suitable to analyze these interactions, and report the binding of PTEN and the PDZ domain containing protein tyrosine phosphatase PTPN13. Yeast two-hybrid and GST pull down analyses showed that PTEN binds to PDZ2/PTPN13 domain in a manner that depends on the specific PTPN13 PDZ domain arrangement involving the interdomain region between PDZ1 and PDZ2. Furthermore, a specific binding profile of PTEN to PDZ2/PTPN13 domain was observed by mutational analysis of the PTEN PDZ-BM. Our results disclose a PDZ-mediated physical interaction of PTEN and PTPN13 with potential relevance in tumor suppression and cell homeostasis. PMID- 25448479 TI - Engineering PTEN function: membrane association and activity. AB - Many tumors are associated with deficiency of the tumor suppressor, PTEN, a PIP3 phosphatase that turns off PIP3 signaling. The major site of PTEN action is the plasma membrane, where PIP3 is produced by PI3 kinases. However, the mechanism and functional importance of PTEN membrane recruitment are poorly defined. Using the heterologous expression system in which human PTEN is expressed in Dictyostelium discoideum, we defined the molecular mechanisms that regulate the membrane-binding site through inhibitory interactions with the phosphorylated C terminal tail. In addition, we potentiated mechanisms that mediate PTEN membrane association and engineered an enhanced PTEN with increased tumor suppressor functions. Moreover, we identified a new class of cancer-associated PTEN mutations that are specifically defective in membrane association. In this review, we summarize recent advances in PTEN-membrane interactions and methods useful in addressing PTEN function. PMID- 25448480 TI - Structure based virtual screening to discover putative drug candidates: necessary considerations and successful case studies. AB - Drug discovery faces daunting challenges in the current economic situation, which is further exacerbated by resistance against a large group of available drugs. Development of a new drug with traditional approaches generally takes 12-15years and may cost over $800 millions. Therefore, inexpensive and fast alternatives are required for new drug discovery. Various in silico approaches have shown potential for screening chemical databases against the desired biological targets for the development of new potential leads. Among them, the number of publications on structure based virtual screening has been rapidly mounting in recent years. This increase has led a need to evaluate and compare the performance of different virtual screening methodologies. In the present article, we describe some of the work and addresses the important issues for successful structure-based virtual screening. Moreover, few recent case studies are also discussed, where the virtual screening approaches have been applied successfully in designing putative drug candidates. PMID- 25448481 TI - Yeast-based methods to assess PTEN phosphoinositide phosphatase activity in vivo. AB - The PTEN phosphoinositide 3-phosphatase is a tumor suppressor commonly targeted by pathologic missense mutations. Subject to multiple complex layers of regulation, its capital role in cancer relies on its counteracting function of class I phosphoinositide 3-kinase (PI3K), a key feature in oncogenic signaling pathways. Precise assessment of the involvement of PTEN mutations described in the clinics in loss of catalytic activity requires either tedious in vitro phosphatase assays or in vivo experiments involving transfection into mammalian cell lines. Taking advantage of the versatility of the model organism Saccharomyces cerevisiae, we have developed different functional assays by reconstitution of the mammalian PI3K-PTEN switch in this lower eukaryote. This methodology is based on the fact that regulated PI3K expression in yeast cells causes conversion of PtdIns(4,5)P2 in PtdIns(3,4,5)P3 and co-expression of PTEN counteracts this effect. This can be traced by monitoring growth, given that PtdIns(4,5)P2 pools are essential for the yeast cell, or by using fluorescent reporters amenable for microscopy or flow cytometry. Here we describe the methodology and review its application to evaluate the functionality of PTEN mutations. We show that the technique is amenable to both directed and systematic structure-function relationship studies, and present an example of its use for the study of the recently discovered PTEN-L variant. PMID- 25448482 TI - Kinases, tails and more: regulation of PTEN function by phosphorylation. AB - Phosphorylation regulates the conformation, stability, homo- and heterotypic protein interactions, localization, and activity of the tumor suppressor PTEN. From a simple picture, at the beginning of this millennium, recognizing that CK2 phosphorylated PTEN at the C-terminus and thereby impacted on PTEN stability and activity, research has led to a significantly more complex scenario today, where for instance GSK3, Plk3, ATM, ROCK or Src-family kinases are also gaining the spotlight in this evolving play. Here, we review the current knowledge on the kinases that phosphorylate PTEN, and on the impact that specific phosphorylation events have on PTEN function. PMID- 25448484 TI - Transcriptome-wide ribonuclease-mediated protein footprinting to identify RNA protein interaction sites. AB - RNA-binding proteins (RBPs) are intimately involved in all aspects of RNA processing and regulation and are linked to neurodegenerative diseases and cancer. Therefore, investigating the relationship between RBPs and their RNA targets is critical for a broader understanding of post-transcriptional regulation in normal and disease processes. The majority of approaches to study RNA-protein interactions interrogate only individual RBPs. However, there are hundreds of these proteins encoded in the human genome, and each cell type expresses a different repertoire, greatly limiting the ability of current methods to capture the global landscape of RNA-protein interactions. To address this gap, we and others have recently developed methods to globally identify regions of RNAs that are bound by proteins in an unbiased manner. Here, we describe a detailed protocol for performing our ribonuclease-mediated protein footprint sequencing approach, termed protein interaction profile sequencing (PIP-seq). In this protocol, RNA-protein interactions are stabilized by cross-linking, and unbound regions are digested with ribonucleases (RNases), leaving only the protein-bound regions intact. To control for RNase insensitive regions, proteins are first denatured and degraded, then protein-depleted RNAs are subjected to RNase treatment. After high-throughput sequencing of the remaining fragments, peak calling is performed to identify protein-protected sites (PPSs). We describe the application of this protocol to a human embryonic kidney cell line (HEK293T) and perform basic quality control, reproducibility, and benchmarking analyses. Finally, we delineate the landscape of protein-interactions in HEK293T cells, underscoring the value of this approach. Future applications of this method to study the dynamics of RNA-protein interactions in developmental and disease processes will help to further uncover the role of RBPs in post-transcriptional regulation. PMID- 25448483 TI - Eigenanatomy: sparse dimensionality reduction for multi-modal medical image analysis. AB - Rigorous statistical analysis of multimodal imaging datasets is challenging. Mass univariate methods for extracting correlations between image voxels and outcome measurements are not ideal for multimodal datasets, as they do not account for interactions between the different modalities. The extremely high dimensionality of medical images necessitates dimensionality reduction, such as principal component analysis (PCA) or independent component analysis (ICA). These dimensionality reduction techniques, however, consist of contributions from every region in the brain and are therefore difficult to interpret. Recent advances in sparse dimensionality reduction have enabled construction of a set of image regions that explain the variance of the images while still maintaining anatomical interpretability. The projections of the original data on the sparse eigenvectors, however, are highly collinear and therefore difficult to incorporate into multi-modal image analysis pipelines. We propose here a method for clustering sparse eigenvectors and selecting a subset of the eigenvectors to make interpretable predictions from a multi-modal dataset. Evaluation on a publicly available dataset shows that the proposed method outperforms PCA and ICA based regressions while still maintaining anatomical meaning. To facilitate reproducibility, the complete dataset used and all source code is publicly available. PMID- 25448486 TI - Use of patient-reported outcomes to measure symptoms and health related quality of life in the clinic. AB - There is increasing interest in the use of patient-reported outcomes (PROs) in routine practice in cancer care to measure symptoms and health related quality of life (HRQOL). PROs are designed to capture the patient's perspective of their care and treatment, and complement the traditional clinical outcomes of survival and toxicity assessment. Integrating routine collection and feedback of PROs has been found to improve care for patients on both an individual level, through improved communication and management of symptoms, and at an organizational level, by enabling aggregation of data to compare performance. This article reviews the benefits and challenges of introducing patient-reported assessments into routine clinical practice. Methods for choosing a questionnaire; collection and presentation of results; timing and frequency of administration as well as clinician training methods to aid the ability of clinicians to integrate the use of PROs into their own practice are described. Electronic PRO capture and integration with electronic health records seems to provide the most effective method for seamless integration into existing patient care pathways. Case studies from our own practice illustrate the issues raised. Electronic methods enabling immediate collection, scoring and interpretation of the data, as well as real time data capture, email alert systems and individualized, online self-management advice may enable severe symptoms to be managed in a more timely manner. Evaluation methods are described to establish the effectiveness of the PRO intervention. Engaging stakeholders throughout the process of initial consultation and development, during delivery and evaluation is key to success. Future work needs to focus on the effectiveness of PROs in longer-term follow-up of patients in routine care and the relationship between the PRO severity grading and clinician severity grading using the Common Terminology Criteria of Adverse Events (CTCAE). PMID- 25448485 TI - Human placental growth hormone: a potential new biomarker in gestational trophoblastic disease. AB - OBJECTIVES: Gestational trophoblastic disease (GTD) involves a spectrum of abnormal proliferations arising from the placental villous trophoblast. Although the incidence is low, a biomarker with short serum half-life would be a major clinical advance to monitor surgical and medical treatment reducing the socioeconomic burden of multiple control visits as well as patient's anxiety. Placental growth hormone (hGH-V) plays an important role in the regulation of normal placental growth and has shown angiogenic effects. We aimed to determine by immunohistochemistry (IHC) whether hGH-V is expressed in GTD and whether it can be detected in the patient's blood for potential monitoring of surgical or medical treatment procedures. METHODS: Tissue and sera were collected from women undergoing treatment for GTD in a tertiary care university hospital. We evaluated partial and complete hydatidiform moles, invasive moles and choriocarcinoma, n=16. Trophoblast specimens were examined by a newly developed IHC set-up for hGH V in addition to gross morphologic and histopathological examination. Serum samples were analyzed by a highly sensitive hGH-V specific immunoassay. RESULTS: hGH-V was localized in all entities of GTD to the syncytiotrophoblast by immunohistochemistry. Serum hGH-V was detected for the first time in GTD and was present in a high percentage of all analyzed entities. CONCLUSIONS: hGH-V can be detected in all entities of GTD by IHC as well as by serum analysis and may therefore serve as a novel biomarker for the disease. Its clinical utility in diagnosis of GTD and monitoring surgical or medical treatment needs to be determined in further studies. PMID- 25448487 TI - Plasticity of human dedifferentiated adipocytes toward endothelial cells. AB - The process of cellular differentiation in terminally differentiated cells is thought to be irreversible, and these cells are thought to be incapable of differentiating into distinct cell lineages. Our previous study showed that mature adipocytes represent an alternative source of mesenchymal stem cells. Here, results showed the capacity of mature adipocytes to differentiate into endothelial-like cells, using the ability of these cells to revert into an immature phase without any relievable chromosomal alterations. Mature adipocytes were isolated from human omental and subcutaneous fat and were dedifferentiated in vitro. The resulting cells were subcultivated for endothelial differentiation and were analyzed for their expression of specific genes and proteins. Endothelial-like cells were harvested from the differentiation medium and were traditionally cultured to evaluate the endothelial markers and the karyotype. Cells cultured in specific medium formed tube-like structures and expressed several endothelial marker genes and proteins. The endothelial-like cells expressed significantly higher levels of vascular endothelium growth factor receptor 2, vascular endothelial cadherin, Von Willebrand factor, and CD133 than the untreated cells. These cells were positively stained for CD31 and vascular endothelial cadherin, markers of mature endothelial cells. Moreover, the low density lipoprotein-uptake assay demonstrated a functionally endothelial differentiation of these cells. When these cells were harvested and reseeded in basal medium, they lost the endothelial markers and reacquired the typical mesenchymal stem cell markers and the ability to expand in a short time period. Moreover, karyotype analysis showed that these cells reverted into an immature phase without any karyotype alterations. In conclusion, the results showed that adipocytes exhibited a great plasticity toward the endothelial lineage, suggesting their possible use in cell therapy applications for vascular disease. PMID- 25448489 TI - TEMPORARY REMOVAL: Assessment of hematopoietic and neurologic pathophysiology of HCLS1-associated protein X-1 deficiency in a Hax1-knockout mouse model. AB - The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25448488 TI - Dual targeting of the thioredoxin and glutathione antioxidant systems in malignant B cells: a novel synergistic therapeutic approach. AB - B-cell malignancies are a common type of cancer. One approach to cancer therapy is to either increase oxidative stress or inhibit the stress response systems on which cancer cells rely. In this study, we combined nontoxic concentrations of Auranofin (AUR), an inhibitor of the thioredoxin system, with nontoxic concentrations of buthionine-sulfoximine (BSO), a compound that reduces intracellular glutathione levels, and investigated the effect of this drug combination on multiple pathways critical for malignant B-cell survival. Auranofin interacted synergistically with BSO at low concentrations to trigger death in multiple malignant B-cell lines and primary mantle-cell lymphoma cells. Additionally, there was less toxicity toward normal B cells. Low AUR concentrations inhibited thioredoxin reductase (TrxR) activity, an effect significantly increased by BSO cotreatment. Overexpression of TrxR partially reversed AUR+BSO toxicity. Interestingly, the combination of AUR+BSO inhibited nuclear factor kappaB (NF-kappaB) signaling. Moreover, synergistic cell death induced by this regimen was attenuated in cells overexpressing NF-kappaB proteins, arguing for a functional role for NF-kappaB inhibition in AUR+BSO mediated cell death. Together, these findings suggest that AUR+BSO synergistically induces malignant B-cell death, a process mediated by dual inhibition of TrxR and NF-kappaB, and such an approach warrants further investigation in B-cell malignancies. PMID- 25448490 TI - Effective treatment against severe graft-versus-host disease with allele-specific anti-HLA monoclonal antibody in a humanized mouse model. AB - Graft-versus-host disease (GVHD), mediated by donor-derived alloreactive T cells, is a major cause of nonrelapse mortality in allogeneic hematopoietic stem cell transplantation. Its therapy is not well-defined. We established allele-specific anti-human leukocyte antigen (HLA) monoclonal antibodies (ASHmAbs) that specifically target HLA molecules, with steady death of target-expressing cells. One such ASHmAb, against HLA-A*02:01 (A2-kASHmAb), was examined in a xenogeneic GVHD mouse model. To induce fatal GVHD, non-irradiated NOD/Shi-scid/IL 2Rgamma(null) mice were injected with healthy donor human peripheral blood mononuclear cells, some expressing HLA-A*02:01, some not. Administration of A2 kASHmAb promoted the survival of mice injected with HLA-A*02:01-expressing peripheral blood mononuclear cells (p < 0.0001) and, in humanized NOD/Shi-scid/IL 2Rgamma(null) mice, immediately cleared HLA-A*02:01-expressing human blood cells from mouse peripheral blood. Human peripheral blood mononuclear cells were again detectable in mouse blood 2 to 4 weeks after A2-kASHmAb administration, suggesting that kASHmAb may be safely administered to GVHD patients without permanently ablating the graft. This approach, different from those in existing GVHD pharmacotherapy, may open a new door for treatment of GVHD in HLA-mismatched allogeneic hematopoietic stem cell transplantation. PMID- 25448493 TI - Is there a correlation between levator ani and urethral sphincter complex status on 3D ultrasonography? AB - INTRODUCTION AND HYPOTHESIS: To determine the correlation between levator ani deficiency (LAD) and urethral sphincter complex measurements as visualized on 3D endovaginal ultrasonography, and to compare the LAD score with continence status. METHODS: This was a retrospective analysis of patients seen at our institution between January 2011 and August 2013. Patients were dichotomized into those with urodynamic stress urinary incontinence (SUI) and those with no SUI. Levator ani status was evaluated using a validated scoring system yielding scores of 0 - 6 (normal levator ani/mild LAD), 7 - 12 (moderate LAD), and 13 - 18 (severe LAD). The length, horizontal diameter, and cross-sectional area of the urethra, and the length, width, and the area of the rhabdomyosphincter and smooth muscle sphincter were likewise measured using 3D ultrasound volumes. RESULTS: Of the 80 patients included, 54 (67.5%) had SUI and 26 (32.5%) were continent. 18 (22.5%) had evidence of mild LAD, 54 (67.5%) had moderate LAD, and 8 (10.0%) had severe LAD. Among patients with SUI, those with normal levator ani muscles or mild LAD had greater urethral smooth muscle width than those with moderate and severe LAD (p = 0.0238). A greater proportion of patients with SUI also had moderate to severe LAD than continent patients (p = 0.0177, OR 3.59, 95% CI 1.21 - 10.65). There was no difference in LAD distribution by type of stress incontinence (presence or absence of intrinsic sphincter deficiency; p = .2377). CONCLUSIONS: LAD and urethral sphincter complex status, as visualized on 3D ultrasonography, are independent factors. Moderate to severe LAD is more prevalent in patients with SUI. PMID- 25448492 TI - Cellular characterization of thrombocytes in Xenopus laevis with specific monoclonal antibodies. AB - Platelets are produced from megakaryocytes (MKs) in the bone marrow. In contrast, most nonmammalian vertebrates have nucleated and spindle-shaped thrombocytes instead of platelets in their circulatory systems, and the presence of MKs as thrombocyte progenitors has not been verified. In developing a new animal model in adult African clawed frog (Xenopus laevis), we needed to distinguish nucleated thrombocytes and their progenitors from other blood cells, because the cellular morphology of activated thrombocytes resembles lymphocytes and other cells. We initially generated two monoclonal antibodies, T5 and T12, to X. laevis thrombocytes. Whereas T5 recognized both thrombocytes and leukocytes, T12 specifically reacted to spindle-shaped thrombocytes. The T12(+) thrombocytes displayed much higher DNA ploidy than nucleated erythrocytes, and they expressed CD41 and Fli-1. In the presence of CaCl2, adenosine diphosphate, thrombin, or various collagens, T12(+) thrombocytes exhibited aggregation. These thrombocytes were located predominantly in the hepatic sinusoids and the splenic red pulp, suggesting that both organs are the sites of thrombopoiesis. Notably, circulating thrombocytes exhibited lower DNA ploidy than hepatic thrombocytes. Intraperitoneal administration of T12 produced immune thrombocytopenia in frogs, which reached a nadir 4 days postinjection, followed by recovery, suggesting that humoral regulation maintained the number of circulating thrombocytes. Although differences between MKs and thrombocytes in X. laevis remain to be defined, our results provide further insight into MK development and thrombopoiesis in vertebrates. PMID- 25448494 TI - Supra-spinal FAAH is required for the analgesic action of paracetamol in an inflammatory context. AB - Paracetamol (acetaminophen) is the most commonly used analgesic in the world. Recently, a new view of its action has emerged: that paracetamol would be a pro drug that should be metabolized by the FAAH enzyme into AM404, its active metabolite. However, this hypothesis has been demonstrated only in naive animals, a far cry from the clinical pathologic context of paracetamol use. Moreover, FAAH is a ubiquitous enzyme expressed both in the central nervous system and in the periphery. Thus, we explored: (i) the involvement of FAAH in the analgesic action of paracetamol in a mouse model of inflammatory pain; and (ii) the contributions of central versus peripheral FAAH in this action. The analgesic effect of paracetamol was evaluated in thermal hyperalgesia, mechanical allodynia and hyperalgesia induced by an intra-plantar injection of carrageenan (3%) in FAAH knock-out mice or their littermates. Moreover, the contribution of the central and peripheral enzymes was explored by comparing the effect of a global FAAH inhibitor (URB597) to that of a peripherally restricted FAAH inhibitor (URB937) on paracetamol action. Here, we show that in a model of inflammatory pain submitted to different stimuli, the analgesic action of paracetamol was abolished when FAAH was genetically or pharmacologically inhibited. Whereas a global FAAH inhibitor, URB597 (0.3 mg/kg), reduced the anti-hyperalgesic action of paracetamol, a brain-impermeant FAAH inhibitor, URB937 (0.3 mg/kg), had no influence. However, administered intracerebroventricularly, URB937 (5 MUg/mouse) reduced the action of paracetamol. These results demonstrate that the supra spinally-located FAAH enzyme is necessary for the analgesic action of paracetamol. PMID- 25448491 TI - Increased serum tumor necrosis factor alpha levels in patients with lenalidomide induced hypothyroidism. AB - As the use of lenalidomide expands, the poorly understood phenomenon of lenalidomide-induced thyroid abnormalities will increase. In this study, we compared rates of therapy-induced hypothyroidism in 329 patients with diffuse large B-cell lymphoma (DLBCL) treated with conventional chemotherapy (DLBCL-c) or conventional chemotherapy plus lenalidomide (DLBCL-len). We measured serum levels of tumor necrosis factor alpha, interferon gamma, interleukin 6, interleukin 12, and interleukin 15 before and after treatment. We found a significantly higher rate of therapy-induced hypothyroidism in the DLBCL-len group (25.8% vs. 1.3%), and we found a statistically significant increase in serum tumor necrosis factor alpha in patients with lenalidomide-induced hypothyroidism. PMID- 25448495 TI - Gabapentin-induced changes of plasma cortisol level and immune status in hysterectomized women. AB - AIM: We have examined the effects of gabapentin (GBP) on stress-related changes of cortisol and catecholamines in patients who underwent hysterectomy because of uterine fibrinoids. Additionally, we have observed the effect of GBP on the immune status in the acute stress response to surgery. METHODS: Sixty patients scheduled for an abdominal hysterectomy were randomly assigned to the GBP administration 1h before surgery (n=30 pts), or to the placebo group (n=30 pts). Blood samples were collected before and 24h after the surgery. The intensity of pain was assessed by a visual analogue scale (VAS) every 8h at rest. Immunomodulatory effects of GBP were determined by flow cytometry. We followed the total proportion of CD3(+) lymphocytes, CD3(+)CD4(+), CD3(+)CD8(+), CD19(+) B lymphocytes, CD16(+)CD56(+)CD3(-)NK cells and CD16(+)CD56(+)CD3(+) NKT cells before and 24h after hysterectomy. The plasma cortisol and catecholamines concentration was used to estimate the level of the stress response. RESULTS: VAS pain score at rest was significantly lower in the GBP group than in the placebo group (P=0.003). Application of GBP significantly decreased the plasma cortisol level 24h after the operation in comparison to the placebo group (P<0,001). We found significant positive correlation between the VAS pain score and concentration of cortisol in all patients (P=0.025). GBP reduced the concentration of catecholamines (p<0.05). The proportion of CD3(+) (P=0.027) and CD3(+)CD4(+)cells (P=0.006) was significantly lower in the GBP group 24h after operation, while the contribution of CD19(+) (P=0.033) was significantly higher. CONCLUSION: Preoperative administration of GBP reduced the pain scores at rest in patients at 0, 16 and 24h after abdominal hysterectomy. Additionally, GBP reduced the stress response and changed immune parameters in the reaction to surgery. PMID- 25448497 TI - Atorvastatin calcium in combination with methylprednisolone for the treatment of multiple sclerosis relapse. AB - This study aimed to investigate the efficacy of combined atorvastatin calcium and methylprednisolone for the treatment of multiple sclerosis relapse. Patients with multiple sclerosis (MS) at the relapse phase were randomized to receive either combined treatment of atorvastatin calcium and methylprednisolone (n = 19) or methylprednisolone alone (n = 19). Expanded Disability Status Scale (EDSS) was administered at baseline, 1 week, 2 weeks, 4 weeks, 3 months, and 6 months after treatment initiation. The number and volume of brain lesions were evaluated using magnetic resonance imaging at baseline and 6 months. The levels of IL-13, IL-35, IFN-gamma, and IL-10 in the cerebrospinal fluid were examined using the enzyme linked immunosorbent assay method. There was no significant difference in EDSS scores at 1, 2, and 4 weeks. At 3 and 6 months, the combined treatment group showed significantly lower EDSS scores than the monotherapy group (P < 0.05). The number and volume of brain lesions in the combined treatment group were significantly lower than the monotherapy group at 6 months (P < 0.001). The mean time to relapse was significantly extended in the combined treatment group than the monotherapy group (P < 0.001). At 2 and 4 weeks, the combined treatment group had significantly higher levels of IL-13, IL-35, and IL-10 in the cerebrospinal fluid than the monotherapy group (P < 0.05), but significantly lower level of IFN gamma (P < 0.001). The levels of IL-13 and IL-10 in the combined treatment group were positively correlated with EDSS scores (r = 0.632, P = 0.001; r = 0.731, P = 0.002). Combined treatment with atorvastatin calcium and methylprednisolone can improve the outcomes of MS relapse compared with glucocorticosteroid alone. PMID- 25448496 TI - Tamibarotene modulates the local immune response in experimental periodontitis. AB - Tamibarotene (Am80), a synthetic retinoic acid receptor (RAR), is an agonist with high specificity for RARalpha and RARbeta. Retinoid agonists have been shown to inhibit Th17 cell polarization and to enhance forkhead box P3 (Foxp3) expression during the course of inflammatory diseases. The aim of this study was to evaluate the previously unrecognized role of Am80 in regulating the immune responses of periodontitis within the oral microenvironment. The experimental model of periodontitis in mice was induced by oral infection with Porphyromonas gingivalis (P. gingivalis) W83. Our results indicated that Am80 effectively suppressed alveolar bone resorption induced by P. gingivalis W83 and decreased the number of osteoclasts. We clarified that these effects were closely associated with the reduced percentage of CD4(+) retinoid-related orphan receptor (ROR)gammat(+) cells and increased the percentage of CD4(+) Foxp3(+) cells in the gingival tissues, cervical lymph nodes (CLNs), and spleen. Furthermore, in P. gingivalis infected mice, Am80 down-regulated mRNA expression levels of interleukin-17A (IL 17A), receptor activator of nuclear factor-kappa beta ligand (RANKL), monocyte chemotactic protein-1 (MCP-1), IL-6, and IL-1beta. Simultaneously, Am80 up regulated expression levels of IL-10 and transforming growth factor-beta1 (TGF beta1) in gingival tissues and the CLNs. Our results suggest that Am80 could protect against periodontal bone resorption, primarily through the modulation of immune responses in the oral microenvironment, and demonstrate the potential of Am80 as a novel clinical strategy for preventing periodontitis. PMID- 25448498 TI - Regulation of neutrophil phagocytosis of Escherichia coli by antipsychotic drugs. AB - Antipsychotic drugs (APDs) have been used to ease the symptoms of schizophrenia. APDs have recently been reported to regulate the immune response. Our previous studies revealed that the atypical APDs risperidone and clozapine and the typical APD haloperidol can inhibit the phagocytic ability of macrophages. Our research next determined the effects of APDs on the phagocytic ability of neutrophils, which are the most abundant type of white blood cells in mammals. Here we provide evidence that clozapine and haloperidol can induce increased phagocytic uptake of Escherichia coli by differentiated HL-60 cells and by purified human neutrophils. Furthermore, clozapine and haloperidol can increase the myeloperoxidase activity and IL-8 production in neutrophils. Our results also show that clozapine can inhibit E. coli survival within differentiated HL-60 cells. Furthermore, clozapine and haloperidol are shown to enhance cell surface Mac-1 expression and the activated AKT signaling pathway in purified neutrophils exposed to E. coli. These results indicate that clozapine and haloperidol can increase the phagocytic ability of neutrophils by increasing AKT activation when cells are exposed to bacteria. PMID- 25448499 TI - Baicalin from the extract of Scutellaria baicalensis affects the innate immunity and apoptosis in leukocytes of children with acute lymphocytic leukemia. AB - Scutellariae Radix (root of Scutellaria baicalensis) has a long history of application in traditional and in modern herbal medications. The major components of Scutellariae Radix are baicalin, baicalein, wogonoside and wogonin. Accumulating evidence demonstrates that Scutellaria has immunomodulatory effects and possesses compelling anticancer potential. Treatment of peripheral blood leukocytes (PBLs) with Scutellaria extract (SBE) enriched in baicalin, reduced viability of PBLs obtained from patients with acute lymphoblastic leukemia (ALL). SBE had no impact on the survival of healthy, control leukocytes. The immune system modulation by SBE resulted in increased production of IFNgamma in PBLs, and reduced TNFalpha and IL-10 production in bone marrow cells (BMC), in ALL patients. SBE stimulated the nonspecific antiviral immunity, assessed by resistance of PBLs and BMC to vesicular stomatitis virus (VSV) infection. SBE showed pro-apoptotic activity in NALM-6 cell line (B-type human leukemia). The number of cells expressing annexin V increased from 6% in control cultures to 29% and 52% after treatment with 100 MUg/ml and 200 MUg/ml respectively. Increased percentage of apoptotic cells was observed when cells were treated with corresponding concentration of baicalin. SBE enhanced apoptosis of PBLs in BMC of leukemic children. The percentage of PBLs that underwent apoptosis and mean annexin V expression increased from 11% in the control to 17% and 24% for the doses of 100 MUg/ml and 200 MUg/ml respectively. Importantly, SBE did not induce apoptosis of PBLs in the healthy, control group. PMID- 25448500 TI - Anti-neuroinflammatory effect of aurantiamide acetate from the marine fungus Aspergillus sp. SF-5921: inhibition of NF-kappaB and MAPK pathways in lipopolysaccharide-induced mouse BV2 microglial cells. AB - In the course of a search for anti-neuroinflammatory metabolites from marine fungi, aurantiamide acetate (1) was isolated from marine-derived Aspergillus sp. as an anti-neuroinflammatory component. Compound 1 dose-dependently inhibited the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in BV2 microglial cells. It also attenuated inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and other pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). In a further study designed to elucidate the mechanism of its anti-neuroinflammatory effect, compound 1 was shown to block the activation of nuclear factor-kappa B (NF-kappaB) in lipopolysaccharide (LPS) induced BV2 microglial cells by inhibiting the phosphorylation of the inhibitor kappa B-alpha (IkappaB)-alpha. In addition, compound 1 decreased the phosphorylation levels of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs). These results suggest that compound 1 has an anti neuroinflammatory effect on LPS stimulation through its inhibition of the NF kappaB, JNK and p38 pathways. PMID- 25448501 TI - CYP17 genotype modifies the impact of anthropometric variation on salivary estradiol in healthy women. AB - Several studies demonstrate that human ovarian function is responsive to the energetic environment, which has led to the development of theoretical models that explain this phenomenon. Although many genes are involved in ovarian hormone production, the possibility that genetic polymorphism may affect ovarian response to energetic conditions has not been considered. Cytochrome P450c17alpha is an enzyme that produces androgen precursors used to make estrogens during ovarian steroidogenesis, and is encoded by the CYP17 gene. A functionally significant variant within the promoter region of CYP17 has been linked to variation in steroid production, and some evidence suggests that this polymorphism could alter transcription of CYP17 in an insulin-dependent manner. We tested the hypothesis that the CYP17 variant affected the relationship between anthropometric measurements and salivary estradiol in healthy women in the United States (n = 28). PCR-RLFP analysis was used to genotype women for the genetic variant, and estradiol was assayed from saliva by EIA. Moderated regression analysis of these preliminary data revealed a significant interaction between waist-to-hip ratio and CYP17 genotype (P = 0.004). Our study provides evidence that gene-environment interactions should be considered in future adaptive models for human ovarian function. Moreover, our results stand to illuminate possible associations between this genetic variant and reproductive disease. PMID- 25448502 TI - Dynamic analysis of the endogenous metabolites in depressed patients treated with TCM formula Xiaoyaosan using urinary (1)H NMR-based metabolomics. AB - ETHNOPHAMACOLOGICAL RELEVANCE: Xiaoyaosan (XYS), one of the best-known traditional Chinese medicine prescriptions with a long history of use, is composed of Bupleurum chinense DC., Paeonia lactiflora Pall., Poria cocos (Schw.) Wolf, Angelica sinensis (Oliv.) Diels, Zingiber officinale Rosc., Atractylodes macrocephala Koidz., Glycyrrhiza uralensis Fisch., and Mentha haplocalyx Briq. For centuries, XYS has been widely used in China for the treatment of mental disorders such as depression. However, the complicated mechanism underlying the antidepressant activity of XYS is not yet well-understood. This understanding is complicated by the sophisticated pathophysiology of depression and by the complexity of XYS, which has multiple constituents acting on different metabolic pathways. The variations of endogenous metabolites in depressed patients after administration of XYS may help elucidate the anti-depressant effect and mechanism of action of XYS. The aim of this study is to establish the metabolic profile of depressive disorder and to investigate the changes of endogenous metabolites in the depressed patients before and after the treatment of Xiaoyaosan using the dynamic analysis of urine metabolomics profiles based on (1)H NMR. MATERIALS AND METHODS: Twenty-one depressed patients were recruited from the Traditional Chinese Medicine Department of the First Affiliated Hospital of Shanxi Medical University. Small endogenous metabolites present in urine samples were measured by nuclear magnetic resonance (NMR) and analyzed by multivariate statistical methods. The patients then received XYS treatment for six weeks, after which their Hamilton Depression Scale (HAMD) scores were significantly decreased compared with their baseline scores (p<=0.01). Eight components in urine specimens were identified that enabled discrimination between the pre- and post XYS-treated samples. RESULTS: Urinary of creatinine, taurine, 2-oxoglutarate and xanthurenic acid increased significantly after XYS treatment (p<=0.05), while the urinary levels of citrate, lactate, alanine and dimethylamine decreased significantly (p<=0.05) compared with pre-treatment urine samples. These statistically significant perturbations are involved in energy metabolism, gut microbes, tryptophan metabolism and taurine metabolism. CONCLUSIONS: The symptoms of depression had been improved after 6 weeks' treatment of XYS according to evaluation of HAMD scores. The dynamic tendency of the 8 metabolites that changed significantly during the treatment of XYS is consistent with the improvement in symptoms of depression. These metabolites may be used as biomarkers for the diagnosis of depressive disorders or the evaluation of the antidepressant as well as the exploration of the mechanism of depression. PMID- 25448503 TI - Chemical composition, antimicrobial and anti-inflammatory activities of the essential oil from Maqian (Zanthoxylum myriacanthum var. pubescens) in Xishuangbanna, SW China. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Maqian (Zanthoxylum myriacanthum var. pubescens Huang) is widely consumed as an indigenous remedy for digestive disorders, detoxification, detumescence and analgesia by the ethnic groups in Xishuangbanna, SW China. A related species, Huajiao (Zanthoxylum schinifolium Sieb. et Zucc.), has similar uses in traditional Chinese medicine. We aimed to scientifically validate the traditional uses by investigating and comparing the chemical composition, antimicrobial and anti-inflammatory activities of the essential oils of Maqian and Huajiao. MATERIALS AND METHODS: Essential oils were collected from the fruits of Maqian and Huajiao by simultaneous distillation extraction and identified by gas chromatography-mass spectrometry (GC-MS) analysis. To assess antimicrobial activity, the minimum inhibitory and bactericidal concentrations (MIC and MBC) against 7 microbial strains, including 5 food-borne pathogens, were evaluated by serial dilution with a standardized microdilution broth methodology. For anti-inflammatory activity, the cell viability and nitric oxide (NO) production were determined on lipopolysaccharide (LPS)-stimulated RAW 264.7 cells by MTS assay and the Griess reagent system, respectively. RESULTS: The essential oil from Maqian is rich in limonene (67.06%) and has strong antimicrobial activity against the tested pathogens and spoilage organisms, with MIC ranging from 64 to1024ug/ml and MBC ranging from 64 to 2048ug/ml. It also showed anti inflammatory activity by significantly inhibiting nitric oxide (NO) production induced by LPS in RAW 264.7 cells at 0.040/00 without effects on cell viability. Furthermore, it showed relatively stronger antimicrobial and anti-inflammatory activities than the essential oil from Huajiao. CONCLUSIONS: Our findings not only justify the use of Maqian as an indigenous remedy for digestive disorders, detoxification, detumescence and analgesia, but also suggest that it could be promoted as a preferred substitute for Huajiao. PMID- 25448504 TI - Zuo-Gui and You-Gui pills, two traditional Chinese herbal formulas, downregulated the expression of NogoA, NgR, and RhoA in rats with experimental autoimmune encephalomyelitis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Zuo-Gui pills (ZGPs) and You-Gui pills (YGPs) are 2 traditional Chinese herbal formulas used for treating multiple sclerosis (MS) in the clinical setting and have been shown to have neuroprotective effects in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The aim of this study was to explore the mechanisms underlying the neuroprotective functions of ZGPs and YGPs. MATERIALS AND METHODS: Female Lewis rats were randomly divided into normal control, EAE model, 2g/kg ZGP-treated EAE, 3g/kg YGP treated EAE, and prednisone acetate-treated groups. EAE model was induced by subcutaneous injection of MBP68-86 antigen. The neurological function scores were estimated. Histological structures of the brains and spinal cords were observed, and myelinated and axons imaged. NogoA, Nogo receptor (NgR), and RhoA transcript and protein levels were measured by real-time quantitative RT-PCR and western blotting on postimmunization (PI) days 14 (acute stage) and 28 (remission stage). RESULTS: ZGPs and YGPs significantly reduced neurological functions scores and abrogated inflammatory infiltrates, demyelination, and axonal damage. Furthermore, treatment with ZGPs and YGPs inhibited NogoA, NgR, and RhoA mRNA and protein expression in rats at both the acute and remission stages. ZGPs exhibited stronger effects on NogoA and RhoA expressions, as well as neurological function, during the acute stage of EAE, while YGPs caused greater reductions in NogoA expression during the remission stage. CONCLUSIONS: Our findings suggested that ZGPs and YGPs exerted neuroprotective effects by downregulation of NogoA, NgR, and RhoA pathways, with differences in response times and targets observed between ZGPs and YGPs. PMID- 25448505 TI - Ethnomedicinal plants used to treat skin diseases by Tharu community of district Udham Singh Nagar, Uttarakhand, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tharu community is the largest primitive indigenous community of the Uttarakhand, India. In this article we have scientifically enumerated medicinal plants and herbal preparations used by the Tharu community to treat various skin diseases, and discussed dermatological properties of these plants in the light of previous ethnomedicinal, microbiological, pharmacological, toxicological, phytochemical and clinical studies. MATERIALS AND METHODS: Ethnomedicinal survey was conducted in different villages of Tharu community located in district Udham Singh Nagar, Uttarakhand, India. Ethnomedicinal information on plants used to treat various skin diseases was collected from 122 individuals (93 males and 29 females), including 35 experienced herbal practitioners and 87 local villagers. For each of the recorded plant species the use value (UV) and fidelity level (FL) was calculated. The informant consensus factor (Fic) was also calculated to find out the homogeneity in the information given by the informants. RESULTS: A total of 90 plant species belonging to 86 genera and 48 families were used by the Tharu community to treat various skin diseases viz., wounds (38 spp.), boils (32 spp.), cuts (18 spp.), leprosy (11 spp.), eczema (10 spp.), itching (7 spp.), ringworm (5 spp.), burns (4 spp.), leucoderma (4 spp.), cracked heels (2 spp.), dandruff (3 spp.), body infection (2 spp.), chilblains (2 spp.), hair fall (2 spp.) and toes infection (2 spp.). Information on botanical name, family, vernacular name, ailments treated, mode and dose of herbal preparations, UV and FL values are provided for each of the recorded species. According to UV value most preferred plant species used to treat skin diseases by Tharu community was Ricinus communis L. followed by Tridax procumbens (L.) L., Azadirachta indica A. Juss., Ageratum conyzoides and Allium cepa L. CONCLUSIONS: The present study has revealed significant information on various medicinal plants used to treat skin diseases by Tharu community. Literature review has confirmed most of the claims made by the Tharu community regarding treatment of various skin diseases by the reported plants. The literature review has also revealed that products from very few of the reported plants are available in market, while most of the reported plants are still under preclinical or clinical trials. There are various known phytochemicals, and antibiotic, antibacterial, antiviral and antifungal agents present in these plants which may be synthesized or transformed to make pharmaceuticals. Some of the reported plants have shown promising results in preclinical trails and there is a need of clinical trials to see their safety and efficacy in treating various skin diseases. These plants may be targeted for development of new medicines, ointments or drugs for the treatment of skin diseases. However further toxicological, preclinical and clinical studies are needed to validate claims about little worked out plant species reported in the present study viz., Sida cordata (Burm. F.) Borss. Waalk., Millettia extensa (Benth.) Baker, Caesulia axillaris Roxb., Ehretia laevis Roxb., Vanda tessellate (Roxb.) Hook. Ex G.Don. and Eualaliopsis binata (Retz.) C.E. Hubb. Further studies on these plants are recommended to assess their potential in development of new skin care products. PMID- 25448507 TI - Ethnomedicinal plant use value in the Lakki Marwat District of Pakistan. AB - AIM OF THE STUDY: Medicinal plants are regional treasures for the treatment of many ailments. The present research investigated and documented knowledge of indigenous commonly used medicinal plants, including traditional names, preparations and uses, in the Lakki Marwat District of Pakistan. The information gathered was statistically analyzed using the ICF method to establish baseline data for more comprehensive investigations of bioactive compounds of indigenous medicinal plants. MATERIALS AND METHODS: Direct interviews of 78 informants were conducted during 2013-2014 to identify the preparations and uses of indigenous medicinal plants. Data were analyzed using various quantitative tools, such as use value, factor informant consensus and fidelity level. RESULTS: A total of 62 species of flowering plants belonging to 34 families and 57 genera were reportedly used as ethnomedicines in the study area. Fabaceae, Brassicaceae, Apocynaceae, Solanaceae, Apiaceae, Poaceae, Zygophyllaceae, Asteraceae and Euphorbiaceae were the main plant families that comprised ethnobotanically important plant species. Traditional healers most frequently used aerial parts of plants. The following medicinal species were the most important in the present study with the highest use values (UV): Plantago ovata Forsk.(F. Plantaginaceae), Lawsonia inermis L.(F. Lythraceae), Calotropis procera (Aiton) Dryand.(F. Apocynaceae), Peganum harmala L.(F. Zygophyllaceae), Fagonia indica Burm.f. (F. Zygophyllaceae), Carthamus oxyacantha M.Bieb. (F. Asteraceae), Datura metel L. (F. Solanaceae) and Eruca vesicaria (L.) Cav. (F. Brassicaceae). Respiratory, otic, gastrointestinal and neurological ailments were the main categories that were classified as per factor informant consensus (Fic). The greatest number of species was used to cure gastrointestinal and andrological/gynecological problems. The highest fidelity level (Fl=100%) was achieved by Plantago ovata Forsk. (F. Plantaginaceae) to cure cardiovascular disorders. CONCLUSION: The results of present study reveal that this enormous wealth of medicinal plants played an important role in the health care of the villagers in the study area. In addition, species with high use values (UV) might provide valuable leads for further pharmacological investigations. PMID- 25448506 TI - Antidepressant-like effect of the hydroethanolic leaf extract of Alchornea cordifolia (Schumach. & Thonn.) Mull. Arg. (Euphorbiaceae) in mice: involvement of monoaminergic system. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaf of Alchornea cordifolia (Euphorbiaceae) is used in traditional African medicine in the treatment of various neurological and psychiatric disorders including depression. Previous studies have shown its potent antidepressant-like effect in the forced swimming test (FST). Hence, this study sought to investigate the involvement of monoaminergic systems in the antidepressant-like effect elicited by hydroethanolic leaf extract of Alchornea cordifolia (HeAC) in the FST. MATERIALS AND METHODS: HeAC (25-400mg/kg, p.o.) was administered 1h before the FST. To investigate the contribution of monoaminergic systems to antidepressant-like effect, receptors antagonists were injected 15min before oral administration of HeAC (200mg/kg) to mice and 1h thereafter, subjected to FST. RESULTS: HeAC (200 and 400mg/kg, p.o.) produced dose dependent and significant (P<0.001) antidepressant-like effect, in the FST, without accompanying changes in spontaneous locomotor activities in the open-field test. The anti-immobility effect of HeAC (200mg/kg) in the FST was prevented by pretreatment of mice with SCH 23390 (0.05mg/kg, s.c., a dopamine D1 receptor antagonist), sulpiride (50mg/kg, i.p., a dopamine D2 receptor antagonist), prazosin (1mg/kg, i.p., an alpha1-adrenoceptor antagonist), yohimbine (1mg/kg, i.p., an alpha2-adrenoceptor antagonist), and GR 127993 (5-HT1B receptor antagonist). Similarly, 3 days intraperitoneal injection of p-chlorophenylalanine (pCPA, 150mg/kg, i.p., an inhibitor of serotonin synthesis) prevented the antidepressant-like effect elicited by HeAC. The combination of subeffective doses of imipramine (5mg/kg, p.o.) or fluoxetine (5mg/kg, p.o.), with HeAC (25mg/kg, p.o., subeffective dose) produced a synergistic antidepressant-like effect in the FST. CONCLUSION: The hydroethanolic extract of Alchornea cordifolia possesses antidepressant-like effect mediated through interaction with dopamine (D1 and D2), noradrenergic (alpha1 and alpha2 adrenoceptors), and serotonergic (5HT1B receptors) systems. Also, the potentiation of the anti-immobility effect of conventional antidepressants (fluoxetine and imipramine) by Alchornea cordifolia suggest potential therapeutic effect in depression. PMID- 25448508 TI - Expectant management of mild preeclampsia versus superimposed preeclampsia up to 37 weeks. AB - OBJECTIVE: We sought to compare maternal and neonatal outcomes of expectantly managed pregnancies complicated by chronic hypertension with superimposed preeclampsia vs mild preeclampsia up to 37 weeks of gestation. STUDY DESIGN: This was a multicenter retrospective cohort study of all pregnancies complicated by chronic hypertension with superimposed preeclampsia or mild preeclampsia expectantly managed in the hospital from January 2008 through December 2011. The primary outcomes, adverse maternal and neonatal composite morbidities, were compared between these 2 groups. Frequency differences of maternal adverse outcomes were stratified by gestational age at delivery of <34 and 34-36(6/7) weeks of gestation. RESULTS: We found no significant differences in rates of neonatal composite morbidity or latency periods between women with superimposed preeclampsia and mild preeclampsia. Adverse neonatal outcomes were significantly higher at <34 compared to 34-36(6/7) weeks of gestation (97-98% vs 48-50%) in both cohorts. Maternal adverse composite outcome occurred more frequently in women with superimposed preeclampsia compared to mild preeclampsia (15% vs 5%; P = .003; relative risk, 3.0; 95% confidence interval, 1.45-6.29). CONCLUSION: Women with superimposed preeclampsia have similar neonatal outcomes but more maternal complications than women with preeclampsia without severe features who are expectantly managed <37 weeks. PMID- 25448509 TI - A review of sleep-promoting medications used in pregnancy. AB - Approximately 4% of adults who have symptoms of insomnia resort to various hypnotic or sedating medications for acute symptom relief. Although typically a common practice for nonpregnant adults, this is not the case for the thousands of pregnant women who also report substantial sleep issues. Unfortunately, a paucity of randomized controlled trials in this population, scant empiric evidence regarding the appropriateness of prescribing options, and the concern of subsequent teratogenicity restricts the ability of clinicians to make informed decisions. We synthesized the current research regarding hypnotics and sedating medications used (both on- and off-label) during pregnancy and their association with adverse outcomes. Medications that we investigated included benzodiazepines, hypnotic benzodiazepine receptor agonists, antidepressants, and antihistamines. Overall, the examined studies showed no correlation of increased risk of congenital malformations. However, benzodiazepines and hypnotic benzodiazepine receptor agonists may increase rates of preterm birth, low birthweight, and/or small-for-gestational-age infants. The small number of studies and the small number of subjects prohibit any definitive interpretation regarding the consequences of the use of hypnotic or sedating medications in pregnancy. Additional case reports, randomized clinical trials, and epidemiologic studies are needed urgently. PMID- 25448510 TI - Long-term neurologic outcomes after common fetal interventions. AB - OBJECTIVE: Fetal interventions have clearly decreased mortality, but the neurological outcomes of survivors are of critical concern. Here we consolidated available data on long-term neurological outcomes after common fetal interventions to guide counseling, management, and future research. STUDY DESIGN: Published studies assessing long-term neurological outcomes after common fetal interventions from 1990 through 2014 were collected. We included all studies with a cohort of more than 5 patients and with follow-up of 1 year or longer. We divided procedures into those performed for singletons and for multiples. Singleton procedures included amnioinfusion for preterm premature rupture of membranes, intrauterine transfusion for red cell alloimmunization-associated anemia, intrauterine transfusion for parvovirus-associated anemia, vesicoamniotic shunts, thoracoamniotic shunts, ventriculoamniotic shunts, fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia, and open fetal cases by myelomeningocele and others. Multiple procedures included those done for monochorionic twins including serial amnioreduction, selective fetoscopic laser photocoagulation, and selective termination. RESULTS: Of 1341 studies identified, 28 met the inclusion criteria. We combined available literature for all procedures. Studies varied in their length of follow-up and method of assessing neurological status. Neurological outcome after intervention varied by procedure but was normal in 40-93%, mildly impaired in 3-33%, and severely impaired in 1 40%. Follow-up to school age was rare with the exception of procedures for monochorionic twins. CONCLUSION: Fetal treatments have been successful in achieving survival in previously hopeless cases, but success should also be determined by the outcomes of survivors. Except for monochorionic twins, there is a dearth of reported long-term outcomes. Standardized reporting of long-term neurological sequelae is imperative so that meaningful analysis and study comparisons can be made. PMID- 25448511 TI - Recent trends in hepatic diseases during pregnancy in the United States, 2002 2010. AB - OBJECTIVE: While pregnancy-related severe liver disorders are rare, when they occur morbidity and mortality rates are increased for mothers and infants. The objective of this study was to examine the prevalence and trends of hepatic diseases during pregnancy hospitalizations from 2002 through 2010 in the United States. STUDY DESIGN: Hospital discharge data were obtained from the Nationwide Inpatient Sample, the largest all-payer hospital inpatient care database in the United States that provides nationally representative estimates. Pregnancy hospitalizations with the following diagnoses were identified: hepatitis B, hepatitis C, gallbladder disease/cholelithiasis, liver disorders of pregnancy, chronic/alcohol-related liver disease, biliary tract disease, and HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome. Age, insurance status, hospital location, and hospital region were compared among women with and without hepatic diseases using a chi(2) test. Trends in rates of pregnancy hospitalizations and mean charges were analyzed using multivariable logistic and linear regression, respectively. RESULTS: From 2002 through 2010 there were an estimated 41,479,358 pregnancy hospitalizations in the United States. Gallbladder disease and liver disorders of pregnancy were the most common hepatic diseases (rates = 7.18 and 4.65/1000 pregnancy hospitalizations, respectively). Adjusted rates and mean charges significantly increased for all hepatic diseases during pregnancy over the study period. All hepatic diseases were associated with significantly higher charges compared to all pregnancy hospitalizations. HELLP syndrome was associated with the highest mean charges. CONCLUSION: This large study among a representative sample of the US population provides valuable information that can aid policy planning and management of these hepatic diseases during pregnancy in the United States. PMID- 25448512 TI - Creating and selling embryos for "donation": ethical challenges. AB - The commercial creation and sale of embryos has begun, which poses a series of ethical questions that have received little scholarly attention. Some of the concerns that arise are similar to those posed by the sale of gametes, while other issues differ markedly. Questions emerge, first, regarding the rights of the unborn children and their ability to know their biological parents. Companies that create human embryos de novo may wish to keep gamete providers anonymous. Many of these offspring thus will never learn that their parents are not their biologic parents. Yet, such disclosures, regarding not only one but both of these biologic parents, may be important for these individuals; and a lack of this knowledge may impede their physical and psychological health. Second, questions surface regarding the fees that providers should charge for embryos and whether these amounts should vary based on the traits of 1 or both of the gamete donors. Some prospective parents may seek specific traits in a baby (eg, height or eye/hair coloring), which prompts the creation of embryos from 2 gamete donors who possess these characteristics. Third, ownership of embryos created without an advanced directive by patients poses dilemmas (eg, disposition of any remaining embryos). Fourth, guidelines do not yet exist to limit the number of embryos sold from each pair of gamete donors. Hence, unbeknownst to each other, full siblings could potentially meet, get married, and procreate. This discussion has several critical implications for future practice and professional education and policy. Patients with diseases associated with genetic tests may well ask obstetricians, gynecologists, and other physicians about these techniques and practices. Clinicians can refer such patients to assisted reproductive technology specialists; however, familiarity with the basic aspects of the issues and complexities involved could aid these providers and their patients Several of these issues can be addressed relatively easily through guidelines from professional associations (eg, limiting the number of embryos sold from each pair of gamete donors). Because creation and sales of embryos will likely spread, consideration of appropriate responses is critical to establish standards of care to help the future offspring, and ensure ongoing public trust. PMID- 25448513 TI - Reply: To PMID 24662716. PMID- 25448514 TI - Beware the scar: Laparoscopic hysterectomy for 7-week cesarean delivery scar implantation pregnancy. PMID- 25448516 TI - Activation of vestibule-associated lymphoid tissue in localized provoked vulvodynia. AB - OBJECTIVE: Localized provoked vulvodynia (LPV) may have inflammatory etiology. We wanted to find out whether the cell-mediated immune system becomes activated in the vestibular mucosa in LPV. STUDY DESIGN: This was a controlled cross-sectional study. Vestibular mucosal specimens were obtained from 27 patients with severe LPV and 15 controls. Detailed clinical history of the patients was obtained. For immunohistochemistry, antibodies against CD3 (T cells), CD20 (B cells), IgA (mucosal plasma cells), CD163 (dendritic cells [DCs]), CD68 (macrophages), and CD117 (mast cells) were employed. Mann-Whitney U test and chi(2) test were used for statistical analyses. RESULTS: More B lymphocytes and mature mucosal IgA plasma cells were found in patients than in controls (P < .001 and P < .001, respectively). In LPV samples, B and T cells were arranged into germinal centers representing local immune activation. Germinal centers were not seen in controls. Antigen-presenting DCs and macrophages were found both in patients and controls with similar densities. DCs were found to extend their dendrites into the luminal space through an intact epithelium. Similar amounts of mast cells were found evenly scattered throughout the stroma of vestibular mucosa of both patients and controls. CONCLUSION: We demonstrate here local organized vestibule-associated lymphoid tissue analogous to mucosa-associated lymphoid tissue. Vestibule associated lymphoid tissue may emerge as a response to local infection or inflammation in LPV. PMID- 25448515 TI - 17 alpha-hydroxyprogesterone caproate does not prolong pregnancy or reduce the rate of preterm birth in women at high risk for preterm delivery and a short cervix: a randomized controlled trial. AB - OBJECTIVE: The objective of the study was to evaluate the efficacy of 17 alpha hydroxyprogesterone caproate (17OHP-C) in prolonging gestation in patients with a short cervix and other risk factors for preterm delivery, such as previous preterm birth, cervical surgery, uterine anomalies, or prenatal diethylstilbestrol (DES) exposure. STUDY DESIGN: This open-label, multicenter, randomized controlled trial included asymptomatic singleton pregnancies from 20(+0) through 31(+6) weeks of gestation with a cervical length less than 25 mm and a history of preterm delivery or cervical surgery or uterine malformation or prenatal DES exposure. Randomization assigned them to receive (or not) 500 mg of intramuscular 17OHP-C weekly until 36 weeks. The primary outcome was time from randomization to delivery. RESULTS: After enrolling 105 patients, an interim analysis demonstrated the lack of efficacy of 17OHP-C in prolonging pregnancy. The study was discontinued because of futility. The groups were similar for maternal age, body mass index, parity, gestational age at inclusion, history of uterine anomalies, DES syndrome, previous preterm delivery or midtrimester abortion, and cervical length at randomization. The enrollment-to-delivery interval did not differ between patients allocated to 17OHP-C (n = 51) and those allocated to the control group (n = 54) (median [interquartile range] time to delivery: 77 [54-103] and 74 [52-99] days, respectively). The rate of preterm delivery less than 37 (45% vs 44%, P > .99), less than 34 (24% vs 30%, P = .51), or less than 32 (14% vs 20%, P = .44) weeks was similar in patients allocated to 17OHP-C and those in the control group. CONCLUSION: 17OHP-C did not prolong pregnancy in women with singleton gestations, a sonographic short cervix, and other risk factors of preterm delivery (prior history, uterine malformations, cervical surgery, or prenatal DES exposure). PMID- 25448517 TI - The bystander. PMID- 25448519 TI - Reply: To PMID 25218956. PMID- 25448518 TI - Contraception with levonorgestrel system and risks of breast cancer. PMID- 25448520 TI - Risk of critical congenital heart defects by nuchal translucency norms. AB - OBJECTIVE: The purpose of this study was to compare the performance of first trimester nuchal translucency (NT) cutoff of >=3.5 mm with NT percentiles that were calculated for crown-rump length to identify fetuses with critical congenital heart defects (CCHDs). STUDY DESIGN: This was a population-level study of singleton pregnancies in California with NT measurements performed between 11 and 14 weeks of gestation. Eligible cases were those that resulted in live births from 2009-2010 and had information about the presence or absence of CCHDs available in the hospital discharge records through age 1 year (n = 76,089). Logistic binomial regression methods were used to compare the rate of CCHDs by an NT percentile for crown-rump length and millimeter cutpoints. RESULTS: Compared with fetuses with an NT measurement of <90th percentile, fetuses with an NT of >=99th percentile were >5 times as likely to have a CCHD (1.3% vs 0.2%; relative risk, 5.66; 95% confidence interval, 3.19-10.04) and fetuses with an NT measurement >=3.5 mm were >12 times as likely to have a CCHD (2.8% vs 0.2%; relative risk, 12.28; 95% confidence interval, 5.11-29.51). NT >=99th percentile had a sensitivity of 5.8% and a specificity of 98.9% for the detection of CCHDs compared with 2.6% and 99.8% for NT >=3.5 mm. CONCLUSION: Results show that NT measurements of >=99th percentile and >=3.5 mm are not equivalent and that substantial risk for CCHD extends to the less restrictive >=99th percentile cutpoint. Data suggest that the use of this cutpoint compared with the current standard could double the number of CCHDs that are identified based on NT risk. PMID- 25448521 TI - Fetal growth restriction and risk of cerebral palsy in singletons born after at least 35 weeks' gestation. AB - OBJECTIVE: The objective of the study was to improve the understanding of etiological paths to cerebral palsy (CP) that include fetal growth restriction by examining factors associated with growth restriction that modify CP risk. STUDY DESIGN: In a total population of singletons born at or after 35 weeks, there were 493 children with CP and 508 matched controls for whom appropriateness of fetal growth could be estimated. Fetal growth was considered markedly restricted if birthweight was more than 2 SD below optimal for gender, gestation, maternal height, and parity. We examined maternal blood pressure in pregnancy, smoking, birth asphyxia, and major birth defects recognized by age 6 years as potential modifiers of CP risk in growth-restricted births. RESULTS: More than 80% of term and late preterm markedly growth-restricted singletons were born following a normotensive pregnancy and were at statistically significantly increased risk of CP (odds ratio, 4.81; 95% confidence interval, 2.7-8.5), whereas growth restricted births following a hypertensive pregnancy were not. Neither a clinical diagnosis of birth asphyxia nor potentially asphyxiating birth events occurred more frequently among growth-restricted than among appropriately grown infants with CP. Major birth defects, particularly cerebral defects, occurred in an increasing proportion of CP with increasing growth deficit. The factor most predictive of CP in growth-restricted singletons was a major birth defect, present in 53% of markedly growth-restricted neonates with later CP. Defects observed in CP were similar whether growth restricted or not, except for an excess of isolated congenital microcephaly in those born growth restricted. The highest observed CP risk was in infants with both growth restriction and a major birth defect (8.9% of total CP in this gestational age group, 0.4% of controls: odds ratio, 30.9; 95% confidence interval, 7.0-136). CONCLUSION: The risk of CP was increased in antenatally growth-restricted singletons born at or near term to normotensive mothers. In growth-restricted singletons, a major birth defect was the dominant predictor, associated with a 30-fold increase in odds of CP. Identification of birth defects in the growth-restricted fetus or neonate may provide significant prognostic information. PMID- 25448522 TI - Impact of race, socioeconomic status, and the health care system on the treatment of advanced-stage ovarian cancer in California. AB - OBJECTIVE: We sought to investigate the impact of race, socioeconomic status (SES), and health care system characteristics on receipt of specific components of National Comprehensive Cancer Network guideline care for stage IIIC/IV ovarian cancer. STUDY DESIGN: Patients diagnosed with stage IIIC/IV epithelial ovarian cancer between Jan. 1, 1996, through Dec. 31, 2006, were identified from the California Cancer Registry. Multivariate logistic regression analyses evaluated differences in surgery, chemotherapy, and treatment sequence according to race, increasing SES (SES-1 to SES-5), and provider annual case volume. RESULTS: A total of 11,865 patients were identified. Median age at diagnosis was 65.0 years. The overall median cancer-specific survival was 28.2 months. African American race (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.45-2.87) and care by a low-volume physician (OR, 19.72; 95% CI, 11.87-32.77) predicted an increased risk of not undergoing surgery. Patients with SES-1 (OR, 0.71; 95% CI, 0.60-0.85) and those treated at low-volume hospitals (OR, 0.88; 95% CI, 0.77-0.99) or by low volume physicians (OR, 0.80; 95% CI, 0.70-0.92) were less likely to undergo debulking surgery. African American race (OR, 1.55; 95% CI, 1.24-1.93) and SES-1 (OR, 1.80; 95% CI, 1.35-2.39) were both significant predictors of not receiving chemotherapy. African American patients were also more likely than whites to receive no treatment (OR, 2.08; 95% CI, 1.45-2.99) or only chemotherapy (OR, 1.55; 95% CI, 1.10-2.18). Patients with low SES were more likely to receive no treatment (OR, 1.95; 95% CI, 1.44-2.64) or surgery without chemotherapy (OR, 1.67; 95% CI, 1.38-2.03). CONCLUSION: Among patients with advanced-stage ovarian cancer, African American race, low SES, and treatment by low-volume providers are significant and independent predictors of receiving no surgery, no debulking surgery, no chemotherapy, and nonstandard treatment sequences. PMID- 25448523 TI - Measuring the quality of care provided to women with pelvic organ prolapse. AB - OBJECTIVE: Health care providers are increasingly being evaluated by the quality of care they provide. Our aim was to assess the feasibility of recently developed quality indicators (QIs) for pelvic organ prolapse (POP) and identify possible deficits in care. STUDY DESIGN: A panel ranked 14 QIs based on the RAND appropriateness method assessing screening and diagnosis, pessary management, and surgery for POP. Retrospective chart abstraction was performed after identifying patients with a diagnosis of POP evaluated within a hospital-based multispecialty group using International Classification of Diseases, ninth edition, diagnosis codes. RESULTS: Of 283 patients identified, 98% of those with a new complaint of vaginal bulge had a pelvic examination. The POP was described but not staged in 6% and not documented at all in 25.1%. Among those managed with pessaries, 98% had vaginal examinations at least every 6 months. Forty-nine percent of the patients who had surgery had complete preoperative POP staging. Only 20% of women undergoing apical surgery had documentation of counseling regarding different surgical options, and of the women who underwent a hysterectomy for POP, only 48% had a concomitant vault suspension. Although 71% had documentation about the risk of postoperative stress incontinence, only 14.5% had documented counseling regarding risks of mesh. Only 37% of patients implanted with mesh for POP had documented follow-up at 1 year. An intraoperative cystoscopy was performed in 86% undergoing cystocele repair or apical surgery. CONCLUSION: The quality of care for women with POP can be feasibly measured with QIs. Processes of care were deficient in many areas, and our findings can serve as a basis for quality improvement interventions. PMID- 25448525 TI - The effectiveness of using reinforcements in the classroom on the academic achievement of students with intellectual disabilities. AB - The purpose of this study was to compare the effectiveness of two kinds of reinforcements, tangible reinforcements and social reinforcements, on the academic achievement of eighth-grade female students with intellectual disabilities in the science subject. The study was an experimental method by pretest, with a control group. The participants of the study comprised 45 female students with intellectual disabilities from three different middle schools in the province of Tehran. The multistage cluster method was chosen to determine the sample. The Wechsler intelligence test for matching the groups in terms of IQ and teacher-applied tests were used for all students to measure the progress of students in science. Data were analyzed by one-way analysis of variance. The results showed that (a) there was a significant difference in the academic achievement scores of the groups after applying the intervention and (b) the mean difference in achievement scores for the tangible reinforcements group was significantly higher than the social reinforcement group and the control group. Also the mean scores for the social reinforcement group were significantly higher than the control group. PMID- 25448524 TI - Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: a systematic review with metaanalysis. AB - OBJECTIVE: The purpose of this study was to provide an updated summary of the literature regarding the effects of tocolysis with indomethacin on neonatal outcome by systematically reviewing previously and recently reported data. STUDY DESIGN: All previously reported studies pertaining to indomethacin tocolysis and neonatal outcomes along with recently reported data were identified with the use of electronic databases that had been supplemented with references that were cited in original studies and review articles. Observational studies that compared neonatal outcomes among preterm infants who were exposed and not exposed to indomethacin were included in this systematic review. Data were extracted and quantitative analyses were performed on those studies that assessed the neonatal outcomes of patients that received antenatal tocolysis with indomethacin. RESULTS: Twenty-seven observational studies that met criteria for systematic review and metaanalysis were identified. These studies included 8454 infants, of whom 1731 were exposed to antenatal indomethacin and 6723 were not exposed. Relative risks with 95% confidence intervals were calculated for dichotomous outcomes with the use of random and fixed-effects models. Metaanalysis revealed no statistically significant differences in the rates of respiratory distress syndrome, patent ductus arteriosus, neonatal mortality rate, neonatal sepsis, bronchopulmonary dysplasia, or intraventricular hemorrhage (all grades). However, antenatal exposure to indomethacin was associated with an increased risk of severe intraventricular hemorrhage (grade III-IV based on Papile's criteria; relative risk, 1.29; 95% confidence interval, 1.06-1.56), necrotizing enterocolitis (relative risk, 1.36; 95% confidence interval, 1.08-1.71), and periventricular leukomalacia (relative risk, 1.59; 95% confidence interval, 1.17 2.17). CONCLUSION: The use of indomethacin as a tocolytic agent for preterm labor is associated with an increased risk for severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia. PMID- 25448526 TI - Is EMDR an effective treatment for people diagnosed with both intellectual disability and post-traumatic stress disorder? AB - This study aimed to critically review all studies that have set out to evaluate the use of eye movement desensitization and reprocessing (EMDR) for people diagnosed with both intellectual disability (ID) and post-traumatic stress disorder (PTSD). Searches of the online databases Psych Info, The Cochrane Database of Systematic Reviews, The Cochrane Database of Randomized Control Trials, CINAHL, ASSIA and Medline were conducted. Five studies are described and evaluated. Key positive points include the high clinical salience of the studies and their high external validity. Several common methodological criticisms are highlighted, however, including difficulty in the definition of the terms ID and PTSD, lack of control in design and a lack of consideration of ethical implications. Overall, the articles reviewed indicate cause for cautious optimism about the utility of EMDR with this population. The clinical and research implications of this review are discussed. PMID- 25448529 TI - Poster Abstracts from the 34(th) Annual Scientific Meeting of the Canadian Geriatrics Society, Edmonton, April 2013. PMID- 25448527 TI - Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer's disease. AB - Learning and memory and the underlying cellular correlate, long-term synaptic plasticity, involve regulation by posttranslational modifications (PTMs). Here we demonstrate that conjugation with the small ubiquitin-like modifier (SUMO) is a novel PTM required for normal synaptic and cognitive functioning. Acute inhibition of SUMOylation impairs long-term potentiation (LTP) and hippocampal dependent learning. Since Alzheimer's disease (AD) prominently features both synaptic and PTM dysregulation, we investigated SUMOylation under pathology induced by amyloid-beta (Abeta), a primary neurotoxic molecule implicated in AD. We observed that SUMOylation is dysregulated in both human AD brain tissue and the Tg2576 transgenic AD mouse model. While neuronal activation normally induced upregulation of SUMOylation, this effect was impaired by Abeta42 oligomers. However, supplementing SUMOylation via transduction of its conjugating enzyme, Ubc9, rescued Abeta-induced deficits in LTP and hippocampal-dependent learning and memory. Our data establish SUMO as a novel regulator of LTP and hippocampal dependent cognition and additionally implicate SUMOylation impairments in AD pathogenesis. PMID- 25448528 TI - A search engine to access PubMed monolingual subsets: proof of concept and evaluation in French. AB - BACKGROUND: PubMed contains numerous articles in languages other than English. However, existing solutions to access these articles in the language in which they were written remain unconvincing. OBJECTIVE: The aim of this study was to propose a practical search engine, called Multilingual PubMed, which will permit access to a PubMed subset in 1 language and to evaluate the precision and coverage for the French version (Multilingual PubMed-French). METHODS: To create this tool, translations of MeSH were enriched (eg, adding synonyms and translations in French) and integrated into a terminology portal. PubMed subsets in several European languages were also added to our database using a dedicated parser. The response time for the generic semantic search engine was evaluated for simple queries. BabelMeSH, Multilingual PubMed-French, and 3 different PubMed strategies were compared by searching for literature in French. Precision and coverage were measured for 20 randomly selected queries. The results were evaluated as relevant to title and abstract, the evaluator being blind to search strategy. RESULTS: More than 650,000 PubMed citations in French were integrated into the Multilingual PubMed-French information system. The response times were all below the threshold defined for usability (2 seconds). Two search strategies (Multilingual PubMed-French and 1 PubMed strategy) showed high precision (0.93 and 0.97, respectively), but coverage was 4 times higher for Multilingual PubMed French. CONCLUSIONS: It is now possible to freely access biomedical literature using a practical search tool in French. This tool will be of particular interest for health professionals and other end users who do not read or query sufficiently in English. The information system is theoretically well suited to expand the approach to other European languages, such as German, Spanish, Norwegian, and Portuguese. PMID- 25448530 TI - Chemical differentiation and quality evaluation of commercial Asian and American ginsengs based on a UHPLC-QTOF/MS/MS metabolomics approach. AB - INTRODUCTION: Asian and American ginsengs are widely used medicinal materials and are being used more and more in health products. The two materials look alike but function differently. Various forms of both types of ginseng are found in the market, causing confusion for consumers in their choice. OBJECTIVE: To evaluate the overall quality of commercial Asian and American ginsengs and investigate the characteristic chemical markers for differentiating between them. METHODS: This article investigated 17 Asian and 21 American ginseng samples using an ultra-HPLC combined with quadrupole time-of-flight MS/MS technique. The data were processed by principal component analysis and orthogonal partial least squared discriminant analysis. RESULTS: In the chromatograms, a total of 40 peaks were detected. Among them, six were positively identified, and all of the remainder were tentatively identified. According to statistical results, ginsenosides Rf, Rb2 and Rc together with their isomers and derivatives were more likely to be present in Asian ginsengs, whereas ginsenoside Rb1 , pseudoginsenoside F11 and ginsenoside Rd together with their isomers and derivatives tended to be present in American ginsengs. For Asian ginsengs, ginsenoside Ra3 and 20-beta-D-glucopyranosyl ginsenoside-Rf were more likely to be present in forest samples, whereas contents of floralquinquenoside B, ginsenosides Ro and Rc, and zingibroside R1 were higher in sun-dried ginsengs. For American ginseng, wild samples often had more of the notoginsenosides R1 and Rw2 and less of the ginsenosides Rd, Rd isomer and 20 (S) Rg3 than cultivated samples. CONCLUSION: The method provided important fingerprint information for authentication and evaluation of Asian and American ginsengs from various commercial products. PMID- 25448531 TI - Methamphetamine-enhanced female sexual motivation is dependent on dopamine and progesterone signaling in the medial amygdala. AB - Methamphetamine (METH) is a psychomotor stimulant strongly associated with increases in sexual drive and impulsive sexual behaviors that often lead to unsafe sexual practices. In women METH users, such practices have been associated with increases in unplanned pregnancies and sexually transmitted diseases. Despite this significant heath concern, the neural mechanisms underlying this drug-sex association are not known. We previously established a rodent model of METH-facilitated female sexual behavior in which estradiol and progesterone interact with METH to increase motivational components of female behavior and neuronal activation in the posterodorsal medial amygdala (MePD) (Holder et al., 2010; Holder and Mong, 2010). The current study more directly examines the mechanisms underlying the drug-sex interaction. Here, we hypothesize that METH induced increases in MePD dopamine signaling bridge the METH-hormone interaction. In support of this hypothesis, we found that excitotoxic lesions targeted to the MePD attenuated the METH-induced increases in proceptive behavior. Furthermore, infusion of a D1 agonist into the MePD increased proceptive behavior, while infusion of a D1 antagonist blocked the ability of METH to increase proceptive behaviors. Additionally, we found that METH-treatment increased progesterone receptor (PR) immunoreactivity in the MePD, suggesting an interaction between dopamine and progesterone signaling. Indeed, infusions of the PR antagonist, RU486, prevented METH-induced increases in sexual behavior. Thus, taken together, the current findings suggest that dopamine in the MePD modulates enhanced sexual motivation via an amplification of progesterone signaling and contributes to a better understanding of the neurobiology of drug-enhanced sexual behaviors. PMID- 25448533 TI - The prudent parent meets old age: a high stress response in very old seabirds supports the terminal restraint hypothesis. AB - The reproductive success of wild animals usually increases with age before declining at the end of life, but the proximate mechanisms underlying those patterns remain elusive. Young animals are expected to invest less in current reproduction due to high prospects for future reproduction (the "restraint" hypothesis). The oldest animals may also show restraint when conditions are sub optimal where even a small increase in reproductive investment may lead to death ("terminal restraint"). Alternatively, reproduction may be constrained by lack of experience and senescence (the "constraint" hypothesis). In two species of breeding seabirds, behavioural (time to return the offspring, calmness during restraint) and physiological (metabolism, glucose and corticosterone) parameters responded similarly to stress with advancing age, implying a generalized stress response. Across those parameters, birds were "shy" (high stress response) when young or old, and "bold" (low stress response) when middle-aged. Specifically, free corticosterone, the principal avian glucocorticoid responsible for directing energy away from reproduction and towards immediate survival following stress, was highest in both young and very old stressed birds. All age groups had a similar adrenal capacity to produce corticosterone, implying that middle-aged birds were showing restraint. Because the stress response, was highest at ages when the probability of current reproduction was lowest rather than at ages when the probability of future reproduction was highest we concluded that birds restrained reproductive investment based on current conditions rather than potential future opportunities. In particular, old birds showed terminal restraint when stressed. Hormonal cues promoted investment in adult survival over reproductive output at both the start and end of life consistent with the restraint hypothesis. PMID- 25448534 TI - Evaluation of pig production practices, constraints and opportunities for improvement in smallholder production systems in Kenya. AB - This study evaluated pig production practices by smallholder farmers in two distinct production systems geared towards addressing their constraints and prospects for improvement. The production systems evaluated were semi-intensive and extensive and differed in remoteness, market access, resource availability and pig production intensity. Data were collected using structured questionnaires where a total of 102 pig farmers were interviewed. Qualitative and quantitative research methods were employed to define the socioeconomic characteristics of the production systems, understanding the different roles that pigs play, marketing systems and constraints to production. In both systems, regular cash income and insurance against emergencies were ranked as the main reasons for rearing pigs. Marketing of pigs was mainly driven by the type of production operation. Finances, feeds and housing were identified as the major constraints to production. The study provides important parameters and identifies constraints important for consideration in design of sustainable production improvement strategies. Feeding challenges can be improved through understanding the composition and proper utilization of local feed resources. Provision of adequate housing would improve the stocking rates and control mating. PMID- 25448532 TI - Environmental exposure to di-2-ethylhexyl phthalate is associated with low interest in sexual activity in premenopausal women. AB - Phthalates, a ubiquitous class of environmental chemicals, may interfere with typical reproductive hormone production both in utero and in adulthood. Although they are best known as anti-androgens, increasingly, evidence suggests that phthalates, particularly di-2-ethylhexyl phthalate (DEHP), may also suppress estrogen production. Given that both androgens and estrogens are essential for sexual function, particularly sexual interest, it is plausible that adult exposure to phthalates alters sexual function. To this end, we used data from 360 women participating in a pregnancy cohort study (the Study for Future Families) to examine whether urinary phthalate metabolite concentrations were associated with two dimensions of self-reported sexual dysfunction in the months prior to conception: lack of sexual interest and vaginal dryness. Women in the highest quartile of urinary concentrations of mono-2-ethyl-5-hydroxyhexyl phthalate, a DEHP metabolite, had 2.58 (95% CI 1.33, 5.00) times the adjusted odds of reporting that they almost always or often lacked interest in sexual activity, and results were similar for mono-2-ethyl-5-oxohexyl phthalate (aOR: 2.56, 95% CI 1.32, 4.95), another DEHP metabolite. Self-reported vaginal dryness was not associated with any phthalate metabolite concentration. This study is novel in its focus on sexual function in relation to environmentally relevant (rather than occupational) exposure to phthalates in adult women and these preliminary findings merit replication in a large, prospective study. Better understanding how adult exposure to phthalates may affect reproductive health, including sexual function, is of public health interest given that virtually all Westerners are exposed to phthalates. PMID- 25448535 TI - Electron-transfer kinetics in cyanobacterial cells: methyl viologen is a poor inhibitor of linear electron flow. AB - The inhibitor methyl viologen (MV) has been widely used in photosynthesis to study oxidative stress. Its effects on electron transfer kinetics in Synechocystis sp. PCC6803 cells were studied to characterize its electron accepting properties. For the first hundreds of flashes following MV addition at submillimolar concentrations, the kinetics of NADPH formation were hardly modified (less than 15% decrease in signal amplitude) with a significant signal decrease only observed after more flashes or continuous illumination. The dependence of the P700 photooxidation kinetics on the MV concentration exhibited a saturation effect at 0.3 mM MV, a concentration which inhibits the recombination reactions in photosystem I. The kinetics of NADPH formation and decay under continuous light with MV at 0.3 mM showed that MV induces the oxidation of the NADP pool in darkness and that the yield of linear electron transfer decreased by only 50% after 1.5-2 photosystem-I turnovers. The unexpectedly poor efficiency of MV in inhibiting NADPH formation was corroborated by in vitro flash-induced absorption experiments with purified photosystem-I, ferredoxin and ferredoxin-NADP(+)-oxidoreductase. These experiments showed that the second-order rate constants of MV reduction are 20 to 40-fold smaller than the competing rate constants involved in reduction of ferredoxin and ferredoxin NADP(+)-oxidoreductase. The present study shows that MV, which accepts electrons in vivo both at the level of photosystem-I and ferredoxin, can be used at submillimolar concentrations to inhibit recombination reactions in photosystem-I with only a moderate decrease in the efficiency of fast reactions involved in linear electron transfer and possibly cyclic electron transfer. PMID- 25448536 TI - Spermine selectively inhibits high-conductance, but not low-conductance calcium induced permeability transition pore. AB - The permeability transition pore (PTP) is a large channel of the mitochondrial inner membrane, the opening of which is the central event in many types of stress induced cell death. PTP opening is induced by elevated concentrations of mitochondrial calcium. It has been demonstrated that spermine and other polyamines can delay calcium-induced swelling of isolated mitochondria, suggesting their role as inhibitors of the mitochondrial PTP. Here we further investigated the mechanism by which spermine inhibits the calcium-induced, cyclosporine A (CSA) -sensitive PTP by using three indicators: 1) calcium release from the mitochondria detected with calcium green, 2) mitochondrial membrane depolarization using TMRM, and 3) mitochondrial swelling by measuring light absorbance. We found that despite calcium release and membrane depolarization, indicative of PTP activation, mitochondria underwent only partial swelling in the presence of spermine. This was in striking contrast to the high-amplitude swelling detected in control mitochondria and in mitochondria treated with the PTP inhibitor CSA. We conclude that spermine selectively prevents opening of the high-conductance state, while allowing activation of the lower conductance state of the PTP. We propose that the existence of lower conductance, stress-induced PTP might play an important physiological role, as it is expected to allow the release of toxic levels of calcium, while keeping important molecules (e.g., NAD) within the mitochondrial matrix. PMID- 25448538 TI - Cystatin C as an early marker of acute kidney injury in septic shock. AB - OBJECTIVE: To describe the utility of determining plasma cystatinC concentrations in the diagnosis of acute incident kidney injury in septic shock. PATIENTS AND METHODS: Prospective series of 50 patients with septic shock and plasma creatinine levels <2mg/dL hospitalized in an intensive care unit. Clinical and laboratory follow-ups were conducted, with measurements of cystatinC, urea and plasma creatinine levels from the diagnosis of septic shock to 5days later. The severity of the septic shock was assessed with the RIFLE scale. RESULTS: Twenty patients (40%) developed acute kidney injury: 8 (16%) were categorized as RIFLE R, 5 (10%) as RIFLE-I and 7 (14%) as RIFLE-F. All patients categorized as RIFLE-F required extracorporeal renal clearance. Eighteen (36%) patients died, 8 (20%) of whom had developed acute kidney injury in their evolution. There was poor correlation between plasma creatinine and cystatin C levels (r=.501; P=.001), which disappeared upon reaching any degree of renal impairment on the RIFLE scale. CystatinC levels increased earlier and were better able to identify patients who would develop serious renal function impairment (RIFLE-F) than creatinine and urea levels. The initial cystatinC levels were related to mortality at 30days (OR=1.16; 95%CI: 03-.85). CONCLUSIONS: For patients who developed acute septic kidney injury, the plasma cystatinC levels increased before the classical markers of renal function. CystatinC also constitutes a severity biomarker that correlates with progression to RIFLE-F, the need for extrarenal clearance and, ultimately, mortality. This precocity could be useful for starting measures that prevent the progression of renal dysfunction. PMID- 25448537 TI - Stress fracture of the pelvis and lower limbs including atypical femoral fractures-a review. AB - Stress fractures, that is fatigue and insufficiency fractures, of the pelvis and lower limb come in many guises. Most doctors are familiar with typical sacral, tibial or metatarsal stress fractures. However, even common and typical presentations can pose diagnostic difficulties especially early after the onset of clinical symptoms. This article reviews the aetiology and pathophysiology of stress fractures and their reflection in the imaging appearances. The role of varying imaging modalities is laid out and typical findings are demonstrated. Emphasis is given to sometimes less well-appreciated fractures, which might be missed and can have devastating consequences for longer term patient outcomes. In particular, atypical femoral shaft fractures and their relationship to bisphosphonates are discussed. Migrating bone marrow oedema syndrome, transient osteoporosis and spontaneous osteonecrosis are reviewed as manifestations of stress fractures. Radiotherapy-related stress fractures are examined in more detail. An overview of typical sites of stress fractures in the pelvis and lower limbs and their particular clinical relevance concludes this review. Teaching Points * Stress fractures indicate bone fatigue or insufficiency or a combination of these. * Radiographic visibility of stress fractures is delayed by 2 to 3 weeks. * MRI is the most sensitive and specific modality for stress fractures. * Stress fractures are often multiple; the underlying cause should be evaluated. * Infratrochanteric lateral femoral fractures suggest an atypical femoral fracture (AFF); endocrinologist referral is advisable. PMID- 25448539 TI - Following cancer viruses through the laboratory, clinic, and society. AB - These essays in this special issue follow cancer viruses as a means of better understanding the history of biomedicine. Spanning the worlds of chronic and infectious disease research, the history of cancer viruses touches upon an enormous diversity of settings and scientific disciplines. Cancer viruses appeared during the twentieth century as vaccine targets, vaccine contaminants, laboratory anomalies, and tools for molecular biology. Rather than picking one discipline or setting to privilege above others, this issue suggests what can be learned, not only about cancer viruses but also about the character of modern biomedicine, from following these viruses through their different historical trajectories. PMID- 25448540 TI - "Happily ever after" for cancer viruses? AB - This essay discusses three common issues arising from the special collection "100 Years of Cancer and Viruses." The first is the tension between small-scale and big-scale approaches to cancer research; the second is the difference between how physicians and biologists regarded cancer, and how they assessed the value of investigating viruses as a causative agent; and the third is how the pace and temporality of science have varied over the century of research on cancer viruses. An unpublished piece written by C. H. Andrewes in 1935, "A Christmas Fairy-Story for Oncologists," provides the touchstone for the commentary. PMID- 25448541 TI - Comparison of anaesthesia 'Day 1 skills' expectations between veterinary anaesthetists and general practitioners. AB - Day One Skills (DOS) were introduced by the Royal College of Veterinary Surgeons (RCVS) in 2006 as a guideline for minimum skills required by a veterinary graduate. However, the RCVS anaesthesia DOS are broad and do not specify differences in skills required for different species. The aims of this study were: (1) to determine which anaesthesia skills were considered essential for day one practice by UK-based veterinary practitioners (GPs) and anaesthetists; and (2) to explore current opinions on veterinary undergraduate anaesthesia training. Questionnaires for veterinary GPs (QGPs) and veterinary anaesthetists (QVAs) were developed which asked general information on expectations of anaesthesia skills as well as specific expectations for the common veterinary species. Fifty-five UK based members of the Association of Veterinary Anaesthetists responded, with a random sample of veterinary practices stratified by UK county generating 234 responses and a convenience sample targeted at more specialist veterinary specialities in the UK generating 161 responses. There was close overall agreement between the two groups of GPs and anaesthetists on essential anaesthesia DOS. However, expectations varied with species-greatest in cats and dogs, lowest in exotics. Many respondents commented that new veterinary graduates lack practical skills and should not be expected to be omnicompetent across all species. In conclusion, anaesthesia undergraduate training should prioritise essential practical DOS. PMID- 25448542 TI - Development of a thermostable microneedle patch for influenza vaccination. AB - The goal of this study is to develop thermostable microneedle patch formulations for influenza vaccine that can be partially or completely removed from the cold chain. During vaccine drying associated with microneedle patch manufacturing, ammonium acetate and 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer salts stabilized influenza vaccine, surfactants had little effect during drying, drying temperature had weak effects on vaccine stability, and drying on polydimethylsiloxane (PDMS) led to increased stability compared with drying on stainless steel. A number of excipients, mostly polysaccharides and some amino acids, further stabilized the influenza vaccine during drying. Over longer time scales of storage, combinations of stabilizers preserved the most vaccine activity. Finally, dissolving microneedle patches formulated with arginine and calcium heptagluconate had no significant activity loss for all three strains of seasonal influenza vaccine during storage at room temperature for 6 months. We conclude that appropriately formulated microneedle patches can exhibit remarkable thermostability that could enable storage and distribution of influenza vaccine outside the cold chain. PMID- 25448544 TI - Efferent and afferent connections of the ventromedial hypothalamic nucleus determined by neural tracer analysis: implications for lordosis regulation in female rats. AB - Neural connections of the ventromedial hypothalamic nucleus (VMN) to and from forebrain and midbrain structures, which are involved in the neuroendocrine regulation of reproduction, were investigated. A retrograde (fluoro-gold [FG]) or an anterograde neural tracer (phaseolus vulgaris-leucoagglutinin [PHA-L]) was injected into the left side of the VMN in ovariectomized rats. Six days after injection with FG or 11 days after injection with PHA-L, brains were fixed and sectioned. After immunohistochemistry, digital images of FG-labeled neural cell bodies (FG-cells) or PHA-L-labeled fibers (PHA-L-fibers) were analyzed. Injection sites of FG and PHA-L were mainly in the ventrolateral VMN. Considerable numbers of FG-cells and PHA-L-fibers were present in the left side of the medial amygdala, ventral lateral septum, preoptic area, bed nucleus of stria terminalis, dorsomedial hypothalamic nucleus, arcuate nucleus, periventricular nucleus of thalamus, and midbrain central gray. The lateral dorsal raphe nuclei contained many PHA-L-fibers but few FG-cells. By contrast, both sides of the median raphe nucleus contained many FG-cells but few PHA-L-fibers. Reciprocal direct neural connection between the right and left side of the VMN were observed. The present results provide an anatomical basis for functional relationships between the VMN and these nuclei. PMID- 25448543 TI - Ten years and counting: moving leucine-rich repeat kinase 2 inhibitors to the clinic. AB - The burden that Parkinson's disease (PD) exacts on the population continues to increase year after year. Though refinement of symptomatic treatments continues at a reasonable pace, no accepted therapies are available to slow or prevent disease progression. The leucine-rich repeat kinase 2 (LRRK2) gene was identified in PD genetic studies and offers new hope for novel therapeutic approaches. The evidence linking LRRK2 kinase activity to PD susceptibility is presented, as well as seminal discoveries relevant to the prosecution of LRRK2 kinase inhibition. Finally, suggestions are made for predictive preclinical modeling and successful first-in-human trials. PMID- 25448545 TI - Morphological characterization of mammalian timeless in the mouse brain development. AB - Timeless was originally identified in Drosophila as an essential component of circadian cycle regulation. In mammals, the ortholog of Timeless (Tim) has also implicated in cell cycle control and embryonic development. In this study, we generated a specific antibody against Tim, and carried out expression and localization analyses of Tim during mouse brain development. In Western blotting, Tim was detected throughout the developmental stage. In immunohistochemical analyses, Tim was detected strongly in neurons in the ventricular zone/subventricular zone and moderately in cortical neurons during corticogenesis. In adult mouse brain, Tim was observed moderately in cortical neurons. Notably, Tim was enriched in the nucleus of cortical neurons from embryonic to early postnatal stages while it was distributed in the cytoplasm in the adult stage. Similar distribution change from nucleus to cytoplasm was observed in the hippocampal neurons between P0 and P30. In situ hybridization revealed that the tissue expression profile of Tim-mRNA was similar to that of the protein. In differentiated primary cultured mouse hippocampal neurons, Tim was detected in cell body, axon and dendrites. The obtained results suggest that Tim is expressed in neuronal tissues in a spatiotemporally regulated manner and involved in developmental stage-specific neuronal functions. PMID- 25448546 TI - Ambulatory assessment as a means of longitudinal phenotypes characterization in psychiatric disorders. AB - Ambulatory Assessment (AA) comprises the use of in-field methods to assess individuals' behavior, physiology, and the experience as they unfold in naturalistic settings. We propose that AA is favorable for the investigation of gene-environment interactions and for the search for endophenotypes, being able to assess the experienced environment and to track basic regulatory processes, such as stress reactivity, affective instability, and reward experience, which are potential common factors that underlie psychiatric disorders. In this article, we (a) first describe briefly the rationale of AA and summarize the key advantages of the approach, (b) highlight within-subject regulatory processes, such as stress reactivity, affective instability, and reward experience, (c) describe studies that used AA to examine genetic influences in psychiatric disorders, and (d) briefly review longitudinal studies that have investigated phenotypes of psychiatric disorders. The reported studies yielded promising, although sometimes inconclusive evidence for genetic effects on endophenotypes of psychiatric disorders. Moreover, most studies were twin or family studies, especially in stress-sensitivity research; thus, it is unclear which specific single nucleotide polymorphisms contribute to the endophenotypes of psychiatric disorders. We do hope that within-subject regulatory processes will enable us to clarify the fundamental psychological dimensions that cut across traditional disorders and link them to their genetic underpinnings. PMID- 25448547 TI - Intra-amygdala microinjection of TNF-alpha impairs the auditory fear conditioning of rats via glutamate toxicity. AB - During an inflammatory or infectious process, innate immune cells produce large amount of pro-inflammatory cytokines that act on the brain to cause cognitive dysfunctions. Tumor necrosis factor alpha (TNF-alpha) is one of the main pro inflammatory cytokines. Thus, it is important to study how the excessive TNF alpha affects the cognitive functions of central nervous system and possible antagonists to its effects. In the present study, we conducted behavioral experiments of rats to determine whether murine TNF-alpha administered directly into the brain would elicit behavioral effects related to learning and memory impairments. Rats subjected to single-dose intra-amygdala TNF-alpha infusion showed a significant delay in the acquisition and extinction of auditory fear conditioning. Accordingly, the glutamate level of the tissue samples from amygdala was elevated after the TNF-alpha treatment. Furthermore, pharmacological blockade of NMDAR before the TNF-alpha treatment reversed the TNF-alpha induced impairments in fear learning. Our findings suggest that TNF-alpha can impair the learning and memory functions through glutamate-NMDAR neurotoxicity, and present the possibility to develop therapeutic modalities directing at glutamate transmission for the treatment of neuro-inflammative dysfunctions. PMID- 25448548 TI - Monocyte chemoattractant protein-1-induced excitation and sensitization to mechanical stimulation of mechanosensitive C-fiber afferents in rat skin. AB - It has been previously demonstrated that chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) increases the excitability of nociceptive neurons after peripheral nerve injury or inflammation. Moreover, decreased nocifensive mechanical threshold in behavioral tests and increased calcium influx in cultured dorsal root ganglion neurons by MCP-1 application have been reported. However, the effects of MCP-1 on peripheral afferent terminals have not been studied yet. The present study aimed to examine the effect of MCP-1 on the response of cutaneous unmyelinated afferents. For this purpose, single fiber recordings of mechanosensitive C-afferents were made in vitro from skin-saphenous nerve preparations excised from rats euthanized by CO2. Since IB4-positive neurons were previously implicated in MCP-1 induced mechanical hyperalgesia, sensitivity to alpha,beta-methylene ATP (metATP), an indicator of IB4-positive neurons, was also studied. Application of MCP-1 100 ng/ml to the receptive field elicited excitation in one half of mechanosensitive unmyelinated afferents in the skin. MCP-1 also sensitized metATP insensitive fibers to mechanical stimulation, but not metATP sensitive fibers. The incidence of heat sensitive fibers was decreased in the MCP-1 treated group with a decrease in the response threshold. These results demonstrate MCP-1 is an effective stimulant of mechanosensitive unmyelinated peripheral afferents in the rat skin. PMID- 25448550 TI - Flavonoid nanocrystals produced by ARTcrystal(r)-technology. AB - ARTcrystal((r))-technology is a novel technique for a more efficient production of nanocrystals. It consists of a high speed stirring (HSS) step as pre-milling and subsequent high pressure homogenization (HPH) at reduced pressure and cycle numbers. In this study, three antioxidants, rutin, hesperidin and apigenin, were processed by ARTcrystal((r))-technology, the results were compared to sizes obtained for the production of nanocrystals produced by classical HPH. By using the ARTcrystal((r))-process, all three substances could be transformed into nanosuspensions with mean sizes and PdIs of 431 nm/0.27, 717 nm/0.21 and 262 nm/0.31, respectively. Depending on the properties of the raw material the ARTcrystal((r))-technology revealed similar or even better results than classical HPH. Further optimization of the setup of the HSS process might lead to an optimized process with higher efficacy than classical HPH. PMID- 25448549 TI - Gemcitabine-based therapy for pancreatic cancer using the squalenoyl nucleoside monophosphate nanoassemblies. AB - Gemcitabine is currently the most effective agent against advanced pancreatic cancer. However, the major therapeutic hurdles using gemcitabine include rapid inactivation by blood deaminases and fast development of cell chemoresistance, induced by down-regulation of deoxycytidine kinase or nucleoside transporters. To overcome the above drawbacks we designed recently a novel nanomedicine strategy based on squalenoyl prodrug of 5'-monophosphate gemcitabine (SQdFdC-MP). This amphiphilic conjugate self-organized in water into unilamellar vesicles with a mean diameter of 100 nm. In this study the antitumor efficacy of SQdFdC-MP nanoassemblies (NAs) on chemoresistant and chemosensitive pancreatic adenocarcinoma models have been investigated. Cell viability assays showed that SQdFdC-MP NAs displayed higher antiproliferative and cytotoxic effects, particularly in chemoresistant pancreatic tumor cells. In in vivo studies, SQdFdC MP NAs decreased significantly the growth (~70%) of human MiaPaCa2 xenografts, also preventing tumor cell invasion, whereas native dFdC did not display any anticancer activity when tumor growth inhibition was only 35% with SQdFdC NAs. These results correlated with a reduction of Ki-67 antigen and the induction of apoptosis mediated by caspase-3 activation in tumor cells. These findings demonstrated the feasibility of utilizing SQdFdC-MP NAs to make tumor cells more sensitive to gemcitabine and thus providing an efficient new therapeutic alternative for pancreatic adenocarcinoma. PMID- 25448552 TI - Development of an ultrasound sensitive oxygen carrier for oxygen delivery to hypoxic tissue. AB - Radiation therapy is frequently used in the treatment of malignancies, but tumors are often more resistant than the surrounding normal tissue to radiation effects, because the tumor microenvironment is hypoxic. This manuscript details the fabrication and characterization of an ultrasound-sensitive, injectable oxygen microbubble platform (SE61O2) for overcoming tumor hypoxia. SE61O2 was fabricated by first sonicating a mixture of Span 60 and water-soluble vitamin E purged with perfluorocarbon gas. SE61O2 microbubbles were separated from the foam by flotation, then freeze dried under vacuum to remove all perfluorocarbon, and reconstituted with oxygen. Visually, SE61O2 microbubbles were smooth, spherical, with an average diameter of 3.1 MUm and were reconstituted to a concentration of 6.5 E7 microbubbles/ml. Oxygen-filled SE61O2 provides 16.9 +/- 1.0 dB of enhancement at a dose of 880 MUl/l (5.7 E7 microbubbles/l) with a half-life under insonation of approximately 15 min. In in vitro release experiments, 2 ml of SE61O2 (1.3 E8 microbubbles) triggered with ultrasound was found to elevate oxygen partial pressures of 100ml of degassed saline 13.8 mmHg more than untriggered bubbles and 20.6 mmHg more than ultrasound triggered nitrogen-filled bubbles. In preliminary in vivo delivery experiments, triggered SE61O2 resulted in a 30.4 mmHg and 27.4 mmHg increase in oxygen partial pressures in two breast tumor mouse xenografts. PMID- 25448551 TI - Novel oral phosphate binder with nanocrystalline maghemite-phosphate binding capacity and pH effect. AB - Hyperphosphatemia is one of the main risk factors contributing to morbidity and mortality in patients with end stage renal disease. The demand for a new phosphate binder is continuously increasing since the number of patients suffering under hyperphosphatemia is growing. However, side effects and high pill burden of currently available phosphate binders are the main reasons for low compliance and uncontrolled serum phosphate levels. Therefore, the aim of this study was to develop a novel phosphate binder with a high phosphate binding capacity over the entire gastrointestinal (GI) pH range. This novel phosphate binder C-PAM-10 is based on d-mannose coated nanocrystalline maghemite and belongs to the new class of phosphate binders, called the "iron based agents". It was possible to obtain a phosphate binding product that showed very high phosphate binding capacities with the characteristic of being pH independent at relevant pH ranges. The simulation of a GI passage ranging from pH 1.2 to pH 7.5 showed a 2.5 times higher phosphate binding capacity compared to the commonly used phosphate binder sevelamer carbonate. The simulation of a pH sensitive coating that releases the iron based phosphate binder at pH values >=4.5 still showed a very high phosphate binding capacity combined with very low iron release which might decrease iron related side effects in vivo. Therefore, C-PAM-10 and its variations may be very promising candidates as a superior phosphate binder. PMID- 25448553 TI - Surface coating mediates the toxicity of polymeric nanoparticles towards human like macrophages. AB - The purpose of this study was to investigate the toxicity of a series of poly(lactide-co-glycolic) (PLGA) nanoparticles on human-like THP-1 macrophages. Positively-, negatively-charged and neutral nanoparticles (200 nm) were prepared using chitosan (CS), poloxamer 188 (PF68) and poly(vinyl alcohol) (PVA) as stabilizer. Stabilizer-free PLGA nanoparticles were obtained as well. When used at therapeutically relevant concentrations (up to 0.1 mg/mL in vitro), all tested nanoparticles showed no or scarce signs of toxicity, as assessed by cell mitochondrial activity, induction of apoptosis and necrosis, production of intracellular reactive oxygen species (ROS) and secretion of pro-inflammatory cytokines. At high concentrations (above 1mg/mL), cytotoxicity was found to be induced by the presence of stabilizers, whatever the toxicological pattern of the stabilizer itself. While stabilizer-free PLGA nanoparticles exerted no cytotoxicity, the slightly cytotoxic CS polymer conferred PLGA nanoparticles significant cytotoxicity when used as nanoparticle stabilizer; more surprisingly, the otherwise innocuous PVA and PF68 polymers also conferred a significant cytotoxicity to PLGA nanoparticles. These results unveiled the critical toxicological contribution played by stabilizers used for the formulation of PLGA nanoparticles when used at high concentrations, which may have implications for local toxicities of PLGA-based nanomedicine, and provided additional insight in cytotoxic effects of internalized nanoparticles. PMID- 25448554 TI - Sunitinib-eluting beads for chemoembolization: methods for in vitro evaluation of drug release. AB - Drug-eluting microspheres are used for embolization of hypervascular tumors and allow for local controlled drug release. Although the drug release from the microspheres relies on fast ion-exchange, so far only slow-releasing in vitro dissolution methods have been correlated to in vivo data. Three in vitro release methods are assessed in this study for their potential to predict slow in vivo release of sunitinib from chemoembolization spheres to the plasma, and fast local in vivo release obtained in an earlier study in rabbits. Release in an orbital shaker was slow (t50%=4.5h, 84% release) compared to fast release in USP 4 flow through implant cells (t50%=1h, 100% release). Sunitinib release in saline from microspheres enclosed in dialysis inserts was prolonged and incomplete (t50%=9 days, 68% release) due to low drug diffusion through the dialysis membrane. The slow-release profile fitted best to low sunitinib plasma AUC following injection of sunitinib-eluting spheres. Although limited by lack of standardization, release in the orbital shaker fitted best to local in vivo sunitinib concentrations. Drug release in USP flow-through implant cells was too fast to correlate with local concentrations, although this method is preferred to discriminate between different sphere types. PMID- 25448555 TI - Establishment and first characterization of a sublingual epithelial and immune cell co-culture model. AB - We describe here the establishment and first characterization of a co-culture model of human epithelial sublingual cells (HO-1-u-1 cell line) and human dendritic cells derived from human peripheral blood monocytes (PBMC). Cell culture conditions for HO-1-u-1 cells were optimized. First characterization of phenotypic features by electron microscopy and fluorescence imaging revealed resemblance to sublingual tissue specimen from healthy donors. Successful co culturing of epithelial and dendritic cells (DCs) was confirmed by confocal laser scanning microscopy. Stimulation of HO-1-u1 cells alone and the epithelial/DC co culture by incubation with liposomes, virosomes and influenza virus lead reproducibly to the release of inflammatory cytokine GM-CSF. This co-culture model may be suitable for elucidation of mechanisms involved in the immune response at the sublingual epithelium as well as for the evaluation of novel topical vaccines, potentially replacing cumbersome ex vivo and in vivo methods currently in place. PMID- 25448556 TI - Industrial concentrates of dermal hesperidin smartCrystals(r)--production, characterization & long-term stability. AB - Industrial concentrates of hesperidin nanocrystals (5.0% nominal concentration) were produced applying the smartCrystal((r)) combination technology of wet bead milling and subsequent high pressure homogenization. Stabilization was performed by Kolliphor((r)) P 188, preservation by Euxyl PE 9010 and glycerol. Physical and chemical stability were monitored over 1.5 years of storage at 4-6 degrees C. The size of the bulk population stayed unchanged with about 250 nm (photon correlation spectroscopy). Absence of crystal growth by Ostwald ripening and absence of agglomerates were shown by laser diffraction (LD) and light microscopy. The LD diameter 90% was still 0.7 MUm after 1.5 years. Despite the large surface of the nanosuspension in contact with the water phase, the chemical content proved also stable, only a reduction by 0.15% from 5.70% to 5.55% content was observed. The nanocrystals kept their crystalline state unchanged as shown by X-ray diffraction. The saturation solubility of the nanosuspension was more than triple compared to the raw drug powder in water. The data show the availability of a stable hesperidin concentrate as intermediate for industry to produce dermal formulations. PMID- 25448557 TI - Size and diffusion phenomena of AOT/alcohol/water system in the presence of morin by dynamic light scattering. AB - Presented paper is a continuation of our studies on morin interaction with AOT (sodium bis(2-ethylhexyl) sulfosuccinate) reversed micelles solutions in two solvents: ethanol and n-decanol. Now we focused on morin influence on size and diffusion phenomena in the system morin/solvent/AOT/water. In this paper precise measurements of dynamic light scattering (DLS) of the effects of temperature, solvents (alcohols), water on the size and diffusion of AOT reversed micelles in the morin/AOT/alcohol/water system are reported. The concentrations of AOT were varied from 0.51 to 0.78mol/L. Morin concentration in during auto-correlation function registration was not the same in each solvent because of its different solubility depending on the solvent. Water concentration in the studied systems was defined by R parameter according to relation: R=(H2O)/(AOT) and was equal 0 and 30 in ethanol, and 0 in n-decanol. DLS measurements were done at 298.15 and 308.15K. DLS experiment involved on detection two relaxation modes (fast and slow) in the systems containing AOT reversed micelles, water, morin and solvents (ethanol and n-decanol). The DLS data clearly show the solvent influence as well as morin presence on AOT reversed micelles size and consequently their diffusion coefficients. Contrary to n-decanol strong competition between morin and ethanol molecules in AOT reversed micelles palisade layer has been found. It suggests that morin molecules replaced ethanol in AOT reversed micelles and locate in their palisade layer strongly increasing AOT reversed micelles size. Furthermore, it was found a sharp increase in correlation radii of slow modes of AOT reversed micelles containing morin molecules and their diffusion coefficients diminishing. PMID- 25448558 TI - Development of an injectable PHBV microparticles-GG hydrogel hybrid system for regenerative medicine. AB - Uncontrollable displacements that greatly affect the concentration of active agents at the target tissues are among a major limitation of the use of microparticulate drug delivery systems (DDS). Under this context a biphasic injectable DDS combining poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) microparticles (MPs) and a gellan gum (GG) injectable hydrogel is herein proposed for the localized delivery and long-term retention of MPs carrying hydrophilic and hydrophobic model active agents. A double emulsion-solvent evaporation method was adopted to develop the PHBV MPs, carrying bovine serum albumin (BSA) or dexamethasone (Dex) as hydrophilic and hydrophobic active agents' models, respectively. Moreover, this method was modified, together with the properties of the hydrogel to tailor the delivery profile of the active agents. Variations of the composition of the organic phase during the process allowed tuning surface topography, particle size distribution and core porosity of the PHBV MPs and, thus, the in vitro release profile of Dex but not of BSA. Besides, after embedding hydrogels of higher GG concentration led to a slower and more sustained release of both active agents, independently of the processing conditions of the microparticulate system. PMID- 25448560 TI - Novel applications of ubiquinone biopolymer nanocarriers for preventive and regenerative therapeutics: The Saccharomyces cerevisiae paradigm. AB - Since the last decade, nanodispersed drug delivery systems gain increasingly more importance for therapeutic research fields. The forced transport to the centers of inflammation is supposed to take advantage as a novel strategic approach. Thus, the focus of this study was to investigate the applicability of ubiquinone nanoformulations against oxidative stress. The physiological reduction of reactive oxygen species (ROS) seems to be a promising treatment to point out the potential effects of these sophisticated nano-constructs. Therefore, the yeast strain Saccharomyces cerevisiae N34 was used for in vitro studies as a representative for eukaryotic organisms. Growth parameters during sequential fed batch-cultivation were monitored online using focused beam reflectance measurement (FBRM) method. The ability to control diverse cellular processes makes this yeast strain to a valuable tool for the initial investigation by understanding the fundamental mechanisms of nanoparticulate formulations onto eukaryotic cells. Furthermore, the characteristic stress response of yeast cell culture was examined, so that drug effects could be determined quantitatively. As a chemical stressor, diamide was tested in the range of 1-1000 mg diamide per g cell dry weight (CDW). The ubiquinone nanoformulation demonstrated a total stress reduction of approximately 14% in the yeast culture, confirming the potential applicability of ubiquinone. PMID- 25448559 TI - In situ perfusion in rodents to explore intestinal drug absorption: challenges and opportunities. AB - The in situ intestinal perfusion technique in rodents is a very important absorption model, not only because of its predictive value, but it is also very suitable to unravel the mechanisms underlying intestinal drug absorption. This literature overview covers a number of specific applications for which the in situ intestinal perfusion set-up can be applied in favor of established in vitro absorption tools, such as the Caco-2 cell model. Qualities including the expression of drug transporters and metabolizing enzymes relevant for human intestinal absorption and compatibility with complex solvent systems render the in situ technique the most designated absorption model to perform transporter metabolism studies or to evaluate the intestinal absorption from biorelevant media. Over the years, the in situ intestinal perfusion model has exhibited an exceptional ability to adapt to the latest challenges in drug absorption profiling. For instance, the introduction of the mesenteric vein cannulation allows determining the appearance of compounds in the blood and is of great use, especially when evaluating the absorption of compounds undergoing intestinal metabolism. Moreover, the use of the closed loop intestinal perfusion set-up is interesting when compounds or perfusion media are scarce. Compatibility with emerging trends in pharmaceutical profiling, such as the use of knockout or transgenic animals, generates unparalleled possibilities to gain mechanistic insight into specific absorption processes. Notwithstanding the fact that the in situ experiments are technically challenging and relatively time-consuming, the model offers great opportunities to gain insight into the processes determining intestinal drug absorption. PMID- 25448561 TI - Holmium-lipiodol-alginate microspheres for fluoroscopy-guided embolotherapy and multimodality imaging. AB - Embolotherapy is a minimally invasive transcatheter technique aiming at reduction or complete obstruction of the blood flow by infusion of micro-sized particles in order to induce tumor regression. A major drawback of the current commercially available and clinically used microspheres is that they cannot be detected in vivo with medical imaging techniques, impeding intra- and post-procedural feedback. It can be expected that real-time monitoring of microsphere infusion and post-procedural imaging will result in better predictability and higher efficacy of the treatment. In this study, a novel microsphere formulation has been developed that can be visualized with fluoroscopy, X-ray computed tomography (CT) and magnetic resonance imaging (MRI). The microspheres were prepared with the JetCutter technique and consist of alginate (matrix-forming polymer), holmium (cross-linking and MRI contrast agent), lipiodol (radiopaque contrast agent) and Pluronic F-68 (surfactant). The mean size (+/-SEM) of the hydrated holmium lipiodol-alginate microspheres (Ho-lip-ams) was 570+/-12 MUm with a holmium content of 0.38+/-0.01% (w/w). Stability studies showed that the microspheres remained intact during incubation for two weeks in fetal calf serum (FCS) at 37 degrees C. The inclusion of lipiodol in the microspheres rendered excellent visualization capabilities for fluoroscopy and CT, whereas the holmium ions, which keep the alginate network together, also allow MR imaging. In this study it was shown that single sphere detection was possible by fluoroscopy, CT and MRI. The Ho-lip-ams were visualized in real-time, during infusion in a porcine kidney using fluoroscopy, and post-procedural, the deposition of the microspheres was examined with fluoroscopy, (cone beam rotational) CT and MRI. The different imaging modalities showed similar deposition patterns of the microspheres within the organ. The combination of intra-procedural visualization, multimodality imaging for patient follow-up and the possibility of quantification offers a new and promising method for more safe, efficient and successful embolization treatment. PMID- 25448562 TI - Sylysia 350/Eudragit S100 solid nanomatrix as a promising system for oral delivery of cyclosporine A. AB - Cyclosporine A (CyA) is a poorly soluble peptide and the available preparation is the surfactant based Sandimmum Neoral((r)). In this study, we developed a novel pH-sensitive nanomatrix system of CyA with medical-grade nanoporous silica and Eudragit((r)) to enhance the oral absorption of CyA as well as to improve the potential nephrotoxicity caused by the pronounced initial plasma peak of Neoral((r)). The nanomatrixs were prepared by an absolutely simple conventional process. The scanning electron microscopy (SEM), X-ray powder diffraction analysis (XRD), differential thermal analysis (DSC) and specific surface area and pore size analysis were used to analyze the physicochemical characterization of the nanomatrix. The nanomatrix, consisted of CyA, Eudragit((r)) S100 and Sylysia 350 (1/5/5, w/w/w %), not only increased the dissolution of CyA in vitro but also exhibited excellent enteric behavior. The characterization of CyA nanomatrix showed the CyA was highly dispersed in the nanomatrix in a molecular or amorphous state and partly filled into the nanopores of Sylysia 350. The results of comparative pharmacokinetic study showed that the optimized nanomatrix had a relative bioavailability of 90.8% with Neoral((r)) but a lower Cmax than that of Neoral((r)). In conclusion, the novel nanomatrix of CyA, composed of pharmaceutical excipients of biological safety and easily prepared, is expected to become a promising marketed product for the oral delivery of CyA. PMID- 25448563 TI - Overcoming drug crystallization in electrospun fibers--Elucidating key parameters and developing strategies for drug delivery. AB - For the development of novel therapeutics, uncontrolled crystallization of drugs within delivery systems represents a major challenge. Especially for thin and flexible polymeric systems such as oral films or dermal wound dressings, the formation and growth of drug crystals can significantly affect drug distribution and release kinetics as well as physical storage stability. In this context, electrospinning was introduced as a fabrication technique with the potential to encapsulate drugs within ultrafine fibers by rapid solvent evaporation overcoming drug crystallization during fabrication and storage. However, these effects could so far only be shown for specific drug-polymer combinations and an in-depth understanding of the underlying processes of drug-loaded fiber formation and influencing key parameters is still missing. In this study, we systematically investigated crystal formation of caffeine as a model drug in electrospun fibers comparing different polymers. The solvent polarity was found to have a major impact on the drug crystal formation, whereas only a minor effect was attributed to the electrospinning process parameters. Based on an in-depth understanding of the underlying processes determining drug crystallization processes in electrospun fibers, key parameters could be identified which allow for the rational development of drug-loaded electrospun fibers overcoming drug crystallization. PMID- 25448564 TI - Enhanced gene delivery efficiency of cationic liposomes coated with PEGylated hyaluronic acid for anti P-glycoprotein siRNA: a potential candidate for overcoming multi-drug resistance. AB - RNA interference is an effective method to achieve highly specific gene regulation. However, the commonly used cationic liposomes have poor biocompatibility, which may lead to systematic siRNA delivery of no avail. PEGylation is a good strategy in shielding the positive charge of cationic liposomes, but the enhanced serum stability is often in company with compromised cellular uptake and endosome escape. In this study, PEG was covalently linked to negatively charged hyaluronic acid and it was used to coat the liposome-siRNA nanoparticles. The resulting PEG-HA-NP complex had a diameter of 188.6 +/- 10.8 nm and a dramatically declined zeta-potential from +34.9 +/- 4.0 mV to -18.2 +/- 2.2 mV. Owing to the reversed surface charge, PEG-HA-NP could remain stable in fetal bovine serum (FBS) to up to 24h. In contrast with normal PEGylation, hyaluronic acid and PEG co-modified PEG-HA-NP provided comparable cellular uptake and P-glycoprotein downregulation efficacy in MCF-7/ADR cells compared with Lipofectamine RNAiMAX and naked NP regardless of its anionic charged surface. Because of its good biocompatibility in serum, PEG-HA-NP possessed the best tumor accumulation, cellular uptake and subsequently the strongest P-glycoprotein silencing capability in tumor bearing mice compared with naked NP and HA-NP after i.v. injection, with a 34% P-glycoprotein downregulation. Therefore, PEG-HA coated liposomal complex was demonstrated to be a promising siRNA delivery system in adjusting solid tumor P-glycoprotein expression, which may become a potential carrier in reversing MDR for breast cancer therapy. PMID- 25448565 TI - Preformulation study of fiber formation and formulation of drug-loaded microfiber based orodispersible tablets for in vitro dissolution enhancement. AB - Preformulation study of rotary spun hydroxypropyl cellulose fibers was carried out using the combination of textural characterization of gels in the concentration range of 42-60% w/w and optical microscopic evaluation of formed fibers. High adhesiveness values resulted in bead formation at lower polymer concentration, meanwhile fiber formation was hindered when high adhesiveness values were associated with high polymer content. The optimum gel concentration for fiber formation was given to 50% w/w. Drug loaded microfibers were prepared using a model drug of biopharmaceutical drug classification system class II. Fibers were milled, sieved and mixed with tableting excipients in order to directly compress orodispersible tablets. Hardness, friability, in vitro disintegration time values complied with the pharmacopoeial requirements. In vitro dissolution profiles obtained from three distinct dissolution media (pH 1.0; 4.5; 6.8) were quite differentiated compared to the compressed physical mixture of the same composition. Difference and similarity factors confirmed that the drug dissolution from microfiber based formula was almost independent from the pH value of the media. X-ray diffraction patterns indicated that the drug embedded in microfibers was in amorphous state, and the decrease of o-Ps lifetime values suggested that fiber formation enabled the development of a more ordered fibrous system. PMID- 25448566 TI - A novel potential biocompatible hyperbranched polyspermine for efficient lung cancer gene therapy. AB - The clinical successful application of gene therapy critically depends upon the development of non-toxic and efficient delivery system. Although polycationic non viral vectors hold great promise in nanomedicine, the exploring of application in clinics still remains a big challenge. To develop a non-toxic and efficient non viral gene delivery system, two kinds of endogenous substance, citric acid (CA) and spermine (SPE), were used to prepare a new low charge density hyperbranched polyspermine (HPSPE) by one-pot polymerization. The biocompatibility evaluated by hemolytic activity and red blood cell (RBC) aggregation indicated that HPSPE was highly biocompatible without causing hemolysis and RBC aggregation compared with PEI as well as SPE. The MTS assay also demonstrated that the cell viability of HPSPE was above 90% even at 200 MUg/mL at different time (24 and 72 h), which much higher than PEI 25K. Besides, HPSPE showed high transfection efficiency without any toxic effect after aerosol delivery to the mice. Moreover, aerosol delivery of HPSPE/Akt1 shRNA significantly reduced tumor size and numbers and efficiently suppressed lung tumorigenesis ultimately in K-ras(LA1) lung cancer model mice. These results suggest that low charge density as well as endogenous substance skeleton endow HPSPE with great potential for toxicity-free and efficient gene therapy. PMID- 25448567 TI - Extrinsic lactose fines improve dry powder inhaler formulation performance of a cohesive batch of budesonide via agglomerate formation and consequential co deposition. AB - The aim of the study was to investigate how the fine particle content of lactose carriers prepared with different types of lactose fines regulates dry powder inhaler (DPI) formulation performance of a cohesive batch of micronised budesonide. Budesonide formulations (0.8 wt%) were prepared with three different lactose carriers (Lactohale (LH) LH100, 20 wt% LH210 in LH100 and 20 wt% LH300 in LH100). Fine particle fraction of emitted dose (FPFED) and mean mass aerodynamic diameter (MMAD) of budesonide was assessed with a Next Generation Impactor (NGI) using a Cyclohaler at 90 l/min. Morphological and chemical characteristics of particles deposited on Stage 2 were determined using a Malvern Morphologi G3-ID. The results indicate that increasing concentration of lactose fines (<4.5 MUm) not only increased the FPFED but also the MMAD of budesonide, suggesting drug deposition in agglomerates. Presence of agglomerates on Stage 2 was confirmed by morphological analysis of particles. Raman analysis of material collected on Stage 2 indicated that the more fine lactose particles were available the more agglomerates of budesonide and lactose were delivered to Stage 2. These results suggest drug-fines agglomerate formation is an important mechanism for how lactose fines improve and regulate DPI formulation performance. PMID- 25448568 TI - Optimization of process variables of zanamivir-loaded solid lipid nanoparticles and the prediction of their cellular transport in Caco-2 cell model. AB - The aim of this study was to optimize the process variables of zanamivir-loaded solid lipid nanoparticles (SLNs) and to predict their cellular transport across Caco-2 cell monolayers. Zanamivir-loaded SLNs were prepared by a double emulsion solvent evaporation method. The effects of process variables on the mean particle size and zeta potential of SLNs were investigated and the physicochemical properties of SLNs were characterized. In addition, the cytotoxicity and transport ability of SLNs were also studied in Caco-2 cell model. The mean particle size of drug-loaded SLNs was significantly affected by the process variables. The SLNs were prepared using glyceryl monosterate (1% polyvinyl alcohol (PVA) or 1.5% poloxamer 188 as surfactant) had a regular shape with a relatively lower mean particle size (324.2 and 224.9 nm, respectively), higher encapsulation efficacy (55.7 and 42.4%, respectively) and sustained drug release over 12h. The crystalline form of drug had been partly changed and no physicochemical interaction had occurred between drug and carriers in SLNs. The cell viability was approximately 100% even at a high concentration of blank SLNs. There was no remarkable difference in drug permeation between drug-loaded SLNs and drug solution at 2h, while drug-loaded SLNs showed a significant decrease in drug permeation compared with the drug solution at 4h. The process variables of zanamivir-loaded SLNs were successfully optimized in this study. However, these SLNs significantly reduced the transport ability of zanamivir across Caco-2 cell monolayers. Further studies are needed to fully understand the real absorption mechanism of developed SLNs. PMID- 25448569 TI - A polycarboxylic/amino functionalized hyaluronic acid derivative for the production of pH sensible hydrogels in the prevention of bacterial adhesion on biomedical surfaces. AB - A graft copolymer derivative of hyaluronic acid bearing pendant amino and short polymethacrylate portions (HA-EDA-BMP-MANa) has been employed for the production of a pH sensible vancomycin releasing hydrogel and studied in vitro to test its potential anti adhesive property against Staphylococcus aureus colonization. The copolymer obtained through atom transfer radical polymerization bears chargeable (carboxyl and amino groups) portions and it could be formulated as a hydrogel at a concentration of 10%w/v. The HA-EDA-BMP-MANa hydrogels, produced at three different pH values (5, 6 and 7, respectively), were formulated with or without the addition of vancomycin (2%w/v). The vancomycin release profiles were detected and related to the starting hydrogel pH values, demonstrating that the systems were able to sustain the release of drug for more than 48 h. S. aureus adhesion tests were performed on glass culture plates and hydroxyapatite doped titanium surfaces, comparing the performances of HA-EDA-BMP-MANa hydrogel formulations (obtained with and without vancomycin) with similar formulations obtained using unmodified hyaluronic acid. The non fouling property of a selected HA-EDA-BMP MANa hydrogel (without vancomycin) was also assayed with a BSA adsorption test. We found that the HA-EDA-BMP-MANa hydrogel even without vancomycin prevented bacterial adhesion on investigated surfaces. PMID- 25448571 TI - Reduction of glycine particle size by impinging jet crystallization. AB - The parameters of crystallization processes determine the habit and particle size distribution of the products. A narrow particle size distribution and a small average particle size are crucial for the bioavailability of poorly water-soluble pharmacons. Thus, particle size reduction is often required during crystallization processes. Impinging jet crystallization is a method that results in a product with a reduced particle size due to the homogeneous and high degree of supersaturation at the impingement point. In this work, the applicability of the impinging jet technique as a new approach in crystallization was investigated for the antisolvent crystallization of glycine. A factorial design was applied to choose the relevant crystallization factors. The results were analysed by means of a statistical program. The particle size distribution of the crystallized products was investigated with a laser diffraction particle size analyser. The roundness and morphology were determined with the use of a light microscopic image analysis system and a scanning electron microscope. Polymorphism was characterized by differential scanning calorimetry and powder X-ray diffraction. Headspace gas chromatography was utilized to determine the residual solvent content. Impinging jet crystallization proved to reduce the particle size of glycine. The particle size distribution was appropriate, and the average particle size was an order of magnitude smaller (d(0.5)=8-35 MUm) than that achieved with conventional crystallization (d(0.5)=82-680 MUm). The polymorphic forms of the products were influenced by the solvent ratio. The quantity of residual solvent in the crystallized products was in compliance with the requirements of the International Conference on Harmonization. PMID- 25448570 TI - A substrate pharmacophore for the human sodium taurocholate co-transporting polypeptide. AB - Human sodium taurocholate co-transporting polypeptide (NTCP) is the main bile acid uptake transporter in the liver with the capability to translocate xenobiotics. While its inhibitor requirements have been recently characterized, its substrate requirements have not. The objectives of this study were (a) to elucidate NTCP substrate requirements using native bile acids and bile acid analogs, (b) to develop the first pharmacophore for NTCP substrates and compare it with the inhibitor pharmacophores, and (c) to identify additional NTCP novel substrates. Thus, 18 native bile acids and two bile acid conjugates were initially assessed for NTCP inhibition and/or uptake, which suggested a role of hydroxyl pattern and steric interaction in NTCP binding and translocation. A common feature pharmacophore for NTCP substrate uptake was developed, using 14 native bile acids and bile acid conjugates, yielding a model which featured three hydrophobes, one hydrogen bond donor, one negative ionizable feature and three excluded volumes. This model was used to search a database of FDA approved drugs and retrieved the majority of the known NTCP substrates. Among the retrieved drugs, irbesartan and losartan were identified as novel NTCP substrates, suggesting a potential role of NTCP in drug disposition. PMID- 25448572 TI - Improving the API dissolution rate during pharmaceutical hot-melt extrusion I: Effect of the API particle size, and the co-rotating, twin-screw extruder screw configuration on the API dissolution rate. AB - The dissolution rate of the active pharmaceutical ingredients in pharmaceutical hot-melt extrusion is the most critical elementary step during the extrusion of amorphous solid solutions - total dissolution has to be achieved within the short residence time in the extruder. Dissolution and dissolution rates are affected by process, material and equipment variables. In this work, we examine the effect of one of the material variables and one of the equipment variables, namely, the API particle size and extruder screw configuration on the API dissolution rate, in a co-rotating, twin-screw extruder. By rapidly removing the extruder screws from the barrel after achieving a steady state, we collected samples along the length of the extruder screws that were characterized by polarized optical microscopy (POM) and differential scanning calorimetry (DSC) to determine the amount of undissolved API. Analyses of samples indicate that reduction of particle size of the API and appropriate selection of screw design can markedly improve the dissolution rate of the API during extrusion. In addition, angle of repose measurements and light microscopy images show that the reduction of particle size of the API can improve the flowability of the physical mixture feed and the adhesiveness between its components, respectively, through dry coating of the polymer particles by the API particles. PMID- 25448573 TI - Novel non-viral gene delivery systems composed of carbosilane dendron functionalized nanoparticles prepared from nano-emulsions as non-viral carriers for antisense oligonucleotides. AB - The development of novel and efficient delivery systems is often the limiting step in fields such as antisense therapies. In this context, poly(d,l-lactide-co glycolide) acid (PLGA) nanoparticles have been obtained by a versatile and simple technology based on nano-emulsion templating and low-energy emulsification methods, performed in mild conditions, providing good size control. O/W polymeric nano-emulsions were prepared by the phase inversion composition method at 25 degrees C using the aqueous solution/polysorbate80/[4 wt% PLGA in ethyl acetate] system. Nano-emulsions formed at oil-to-surfactant (O/S) ratios between 10/90 90/10 and aqueous contents above 70 wt%. Nano-emulsion with 90 wt% of aqueous solution and O/S ratio of 70/30 was chosen for further studies, since they showed the appropriate characteristics to be used as nanoparticle template: hydrodynamic radii lower than 50 nm and enough kinetic stability. Nanoparticles, prepared from nano-emulsions by solvent evaporation, showed spherical shape, sizes about 40 nm, negative surface charges and high stability. The as-prepared nanoparticles were functionalized with carbosilane cationic dendrons through a carbodiimide-mediated reaction achieving positively charged surfaces. Antisense oligonucleotides were electrostatically attached to nanoparticles surface to perform gene-silencing studies. These complexes were non-haemolytic and non-cytotoxic at the concentrations required. The ability of the complexes to impart cellular uptake was also promising. Therefore, these novel nanoparticulate complexes might be considered as potential non-viral carriers in antisense therapy. PMID- 25448574 TI - Self-assembled drug delivery systems. Part 8: In vitro/in vivo studies of the nanoassemblies of cholesteryl-phosphonyl gemcitabine. AB - A lipid derivative of gemcitabine (Gem), cholesteryl-phosphonyl gemcitabine (CPNG) was synthesized in this study. The amphiphilicity of CPNG was confirmed using a Langmuir monolayer method. Nanoassemblies were formed when the mixture of CPNG and a long-circulating material, CHS-PEG1500 (9:1, mol/mol) were injected into water. The nanoassemblies could be spherical vesicles according to the transmission electron microscopic images. Their mean size was 71.1 nm and the zeta potential was -17.6 mV. CPNG maintained stable in the weakly acidic and neutral environments although mouse plasma quickly degraded CPNG. The cytotoxicity of the nanoassemblies was 3-6 folds of Gem's cytotoxicity on five human cancer cell lines including 95C, 95D, A549, SW620, PANC-1 probably because of the phosphonyl substitution and amphiphilicity of CPNG. CPNG mainly distributed into the mononuclear macrophage system (including liver and spleen) after bolus intravenous administration of the nanoassemblies into mice though the expected significant long-circulating effect was not shown. The nanoassemblies with the high dose of CPNG showed the statistically higher in vivo anticancer effect than Gem. This study indicates that the N-substituted lipid derivative of Gem and the true long-circulating function are necessary for preparing a successful nanoassembly of Gem. PMID- 25448576 TI - Evaluation of transdermal salidroside delivery using niosomes via in vitro cellular uptake. AB - Span 40-based niosomes were employed as nanocarriers to improve cutaneous absorption of salidroside. The niosomal formulation with a molar proportion of Span 40 to cholesterol of 4:3 showed the highest transdermal flux and skin deposition of salidroside. The transdermal flux of the 4:3 niosomal formulation was significantly greater than that of the aqueous solution. Salidroside-loaded niosomes showed good biocompatibility with skin tissue, human epidermal immortal keratinocytes (HaCaT), and human embryonic skin fibroblasts (CCC-ESF). The fluorescence intensity of HaCaT cells after uptake of coumarin 6-labeled niosomes was similar to that observed after uptake of the aqueous suspension. The fluorescence intensity of CCC-ESF cells was greater than that of the aqueous suspension after incubation for 10 min, but was not significantly different after 60 min. Further investigation revealed that internalization of niosomes by HaCaT cells may be achieved through pinocytotic vesicles and macropinocytosis, which consumes energy, rather than via lysosomes. In CCC-ESF cells, pinocytotic vesicles and lysosomes were both important mediators of endocytosis. The niosome formulations reported here could improve the dermal and transdermal salidroside delivery, and the in vitro cell uptake evaluation results serve as a basis for further research into the mechanisms through which niosomes enhance drug permeability. PMID- 25448575 TI - Preparation and in vitro-in vivo evaluation of teniposide nanosuspensions. AB - Teniposide (TEN) is a potent, broad spectrum antitumor agent, especially for cerebroma. But the application in clinic was limited because of its poor solubility. In this paper, teniposide nanosuspensions drug delivery system (TEN NSDDS) for intravenous administration was developed for the first time. Specifically, TEN nanosuspensions were prepared by an anti-solvent sonication precipitation method and evaluated in comparison with teniposide injection (VUMON) in vitro and in vivo. TEN nanosuspensions prepared showed rod-like morphology and the size was 151 +/- 11 nm with a narrow poly dispersion index 0.138 determined by dynamic light scattering. The obtained TEN nanosuspensions were physically stable at least 10 days at 4 degrees C. And the freeze-drying preparations were stable during 3 months. The cytotoxicity of TEN nanosuspensions were considerable to that of VUMON against U87MG and C6 cells in vitro. When tested in rats bearing C6 tumors, the TEN concentration in the tumors treated by the nanosuspensions was more than 20 times than that by the TEN solution at 2h. The TEN nanosuspensions exhibited significant tumor growth inhibition. Overall, the results suggested that nanosuspensions was an alternative formulation for teniposide to be administered intravenously, and it would be a promising formulation in clinic. PMID- 25448577 TI - Orodispersible films in individualized pharmacotherapy: The development of a formulation for pharmacy preparations. AB - Orodispersible films (ODFs) are promising drug delivery systems for customized small scale pharmacy preparations. The aim of the present study was to develop a versatile casting solution suitable for the extemporaneous production of ODFs to which active pharmaceutical ingredients (APIs) can be added. Different combinations of film forming agents and other excipients and different casting heights were tested for their suitability for production of ODFs. The best suitable casting solution contained hypromellose, carbomer, glycerol, disodium EDTA and trometamol. This casting solution was used to prepare ODFs containing water-soluble APIs (enalapril maleate and prednisolone disodium phosphate) and a poorly water-soluble API (diazepam) for which ethanol 96% was used as co solvent.The water-soluble APIs as well as ethanol influenced the viscosity of the casting solution, mechanical properties and disintegration time of the ODFs. All ODFs containing API met the requirements on uniformity of mass and uniformity of content set by the European Pharmacopoeia (2014) (Ph. Eur.) 8th edition. In conclusion, ODFs of good pharmaceutical quality can be prepared on small scale. Hereby opening the perspective of using ODFs for individualized pharmacotherapy. PMID- 25448578 TI - The influence of the adsorption of metoclopramide on the surface ionization of fumed silica. AB - The effect of adsorbed metoclopramide on the surface ionization of fumed silica was studied using potentiometric titration. Adsorption isotherms of metoclopramide to unionized and negatively-charged silica surfaces were generated and compared to the titration data. The adsorption of metoclopramide caused the silica surface charge to become more negative with increasing pH that was independent of ionic strength which suggested that specific adsorbate-surface interactions were occurring. Adsorption studies showed that metoclopramide adsorbs to the unionized silica surface. Ionization caused drug adsorption to increase which was consistent with at least two distinct surface adsorption sites. The ratio of the additional amount of metoclopramide adsorbed to the surface ionized group density determined from the titration curves was approximately unity which showed conclusively that the negatively-charged silanols constitute one of the surface adsorption sites. Potentiometric titration has been shown to be a useful technique for determining the number and types of adsorption sites on the silica surface. PMID- 25448579 TI - Formation of hydrophilic nanofibers from nanoemulsions through electrospinning. AB - This study presents a method for one step incorporation of lipophilic compounds in hydrophilic nanofibers. By this method nanodroplets of oil and of volatile solvent are entrapped within polymer nanofibers during an electrospinning process. While performing the process with a volatile oil with dissolved lipophilic material, such as the drug celecoxib, nanofiber-nanoparticle composites are formed. The polymer used to form the fibers is a high molecular weight poly(vinyl alcohol) which enables rapid dissolution and release of the incorporated lipophilic material. The resulting celecoxib nanoparticles that are embedded within the nanofiber are amorphous and their average size is in between 21 and 93 nm, thus potentially lead to their increased dissolution rate. The preparation of such a solid matrix containing nanodroplets or nanoparticles may be applied as a fast dissolving delivery system for water insoluble materials. PMID- 25448580 TI - Cationic solid lipid nanoparticles enhance ocular hypotensive effect of melatonin in rabbit. AB - The study was aimed at evaluating whether the ocular hypotensive effect of melatonin (MEL) was enhanced by its encapsulation in cationic solid lipid nanoparticles (cSLN), as well as at determining the tolerability of these formulations on the ocular surface. MEL was loaded in cSLN that had already been shown to be suitable for ophthalmic use. The formulations were prepared using Softisan((r)) 100 as the main lipid matrix, with the presence of either stearic (SA) or palmitic acid (PA) as lipid modifiers. A fixed positive charge was provided by the addition of a cationic lipid (didecyldimethylammonium bromide). The ocular hypotensive effect was evaluated by measuring the intraocular pressure (IOP) during 24h in albino rabbits. MEL elicited a significant (p<0.01) IOP reduction in rabbit eye. All the formulations tested in vivo demonstrated a good tolerability. The nanocarrier containing SA was the most effective in terms of IOP reduction (maximum IOP reduction: -7 mmHg), and its effect lasted approximately 24h. The experimental data indicate that the new formulations based on cSLN loaded with MEL represent a potent anti-glaucoma treatment with a safe profile, warranting further clinical evaluation of the proposed nanotechnological strategy. PMID- 25448581 TI - Stability studies of As4S4 nanosuspension prepared by wet milling in Poloxamer 407. AB - In this paper the stability of the arsenic sulfide (As4S4) nanosuspension prepared by wet milling in a circulation mill in the environment of copolymer Poloxamer 407 was studied. The obtained As4S4 particles in nanosuspension were of ~ 100 nm in size. The influence of temperature and UV irradiation on the changes in physical and/or chemical properties was followed. Long-term stability was observed via particle size distribution and zeta potential measurements. Influence of UV irradiation was studied via UV-vis spectroscopy (UV-vis), photoluminicsence (PL) technique and Fourier transform infrared spectroscopy (FTIR) measurements. The best stability of the nanosuspension (24 weeks) was achieved when stored at 4 degrees C and in the dark. PMID- 25448582 TI - Preparation and characterization of spironolactone-loaded nano-emulsions for extemporaneous applications. AB - In neonates as well as in adults having swallowing difficulty, oral medication is given through a nasogastric tube making liquid formulations preferable. In this study, we present the high potential of nanometric emulsions formulated by spontaneous surfactant diffusion, as extemporaneous formulations of hydrophobic drug. Spironolactone used as hydrophobic drug model, was incorporated in oil before formulation at a concentration of 13.5mg/g oil. Then, all formulations were evaluated from pharmacotechnical and clinical standpoints, for their use in hospital or community pharmacy. The strength of this new liquid formulation lies on the simplicity, efficiency and reproducibility of their low energy process as on clinical aspects: high dose uniformity, facility to be administered through in nasogastric tube without any retention and a stability of 2 months at least compatible for an extemporaneous use. Moreover, this emulsion presented spironolactone content of 3.75 mg/ml among the most concentrated formulations published. PMID- 25448583 TI - Formulation, characterization and anti-malarial activity of homolipid-based artemether microparticles. AB - The anti-malarial activity of artemether is dependent on its bioavailability. The purpose of the research is to improve the solubility, bioavailability and therapeutic efficacy of lipophilic artemether using homolipid-based microparticles. Irvingia fat was extracted from Irvingia gabonensis var. excelsa (Irvingia wombolu), and its lipid matrices (LM) with Phospholipon((r)) 90G (P90G) were characterized by differential scanning calorimetry (DSC) and wide angle X ray diffraction (WAXD). Solid lipid microparticles were formulated, characterized, filled and compressed into capsules and tablets, respectively, and drug release studied. In vivo anti-plasmodial activity of artemether SLMs was evaluated in mice. The crystallinity of the phyto-lipid reduced in the presence of P90G, which was integrated into the irvingia fat crystal lattice. SLM dispersions with 3:1 irvingia fat/P90G composition showed higher diffusion and permeability through dialysis membrane while lower proportion of P90G (9:1 LM) favored increased dissolution rate of artemether from capsules (p<0.05). Significant increase (p<0.05) in % plasmodial growth inhibition and reduced parasitemia were observed in mice administered with the SLM dispersions compared with the controls. Therefore, SLMs prepared with composite mixtures of a homolipid and P90G could be used to improve the solubility, dissolution, permeability, bioavailability and anti-malarial efficacy of artemether. PMID- 25448585 TI - Effect of carbamazepine on viscoelastic properties and hot melt extrudability of Soluplus (r). AB - The purpose of this study was to apply viscoelastic properties of polymer and drug-polymer mixtures to determine processing conditions for the preparation of amorphous solid dispersion by melt extrusion. A poorly water-soluble drug, carbamazepine (CBZ), was mixed with Soluplus((r)) as the carrier. Torque analysis using a melt extruder was performed at 10, 20 and 30% w/w drug concentrations and the effect of barrel temperature was studied. Viscosity of the mixtures either at fixed temperatures with different angular frequencies or as a function of temperature with the same frequency was studied using a rheometer. The viscosity of Soluplus((r)) and the torque exerted on the twin screws decreased with the increase in CBZ concentration. The viscosity versus temperature plots for different CBZ concentrations were parallel to each other, without the drug melting transition, indicating complete drug-polymer miscibility. Thus, the drug polymer mixtures could be extruded at temperature as low as 140 degrees C with 10% w/w drug load, 135 degrees C with 20% w/w drug and 125 degrees C with 30% w/w drug, which were, respectively, ~ 50 degrees C, 55 degrees C and 65 degrees C below the melting point of 191 degrees C for CBZ. The differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD) analyses of the binary mixtures extruded at 125-150 degrees C showed absence of crystalline drug. A systematic study of miscibility and extrudability of drug-polymer mixtures by rheological and torque analysis as a function of temperature will help formulators select optimal melt extrusion processing conditions to develop solid dispersions. PMID- 25448584 TI - Population pharmacokinetics of ketamine in children with heart disease. AB - This study aims at developing a population pharmacokinetic model for ketamine in children with cardiac diseases in order to rationalize an effective 2-h anesthetic medication, personalized based on cardiac function and age. Twenty-one children (6 months to 18 years old) were enrolled in this prospective, open label study. Ketamine 2mg/kg IV was administered and blood samples were then collected over 8h for ketamine assay. Pharmacokinetic data analysis using NONMEM, was undertaken. Ketamine pharmacokinetics was adequately described by a two compartment linear disposition model. Typical population parameters were: total clearance: 60.6 *(weight/70)(0.75)L/h, intercompartmental clearance: 73.2 *(weight/70)(0.75)L/h, central distribution volume: 57.3 *(weight/70)L, and peripheral distribution volume: 152 *(weight/70)L. Ketamine clearance in children with pre-existing congenital heart disease was comparable to values reported in healthy subjects. Computer simulations indicated that an initial loading dose of ketamine 2mg/kg IV over 1 min followed by a constant rate infusion of 6.3mg/kg/h for 29 min, 4.5mg/kg/h from 30 to 80 min, and 3.9 mg/kg/h from 80 to 120 min achieves and maintains anesthetic plasma level for 2h in children 1 year or older (weight >= 10 kg). PMID- 25448586 TI - Tumor homing cell penetrating peptide decorated nanoparticles used for enhancing tumor targeting delivery and therapy. AB - Specific targeting ability and good tissue penetration are two critical requirements for tumor targeted delivery systems. Systematical selected peptides from a library may meet these two requirements. RLW was such a cell penetrating peptide that could specifically target to non-small cell lung cancer cells (A549). In this study, RLW was linked onto nanoparticles (RNPs) and then the RNPs were used for lung cancer targeting delivery. A traditional cell penetrating peptide, R8 (RRRRRRRR), was used as control. In vitro cellular uptake study demonstrated that modification with RLW specifically enhanced the uptake by A549 cells rather than human umbilical vein endothelial cells, while modification with R8 increased the uptake by both cells. Furthermore, the modification with RLW specifically elevated the penetration into A549 tumor spheroids rather than glioma cell (U87, used as in vivo control) spheroids. And the in vivo imaging further demonstrated RNPs could target to A549 xenografts rather than U87 xenografts. Importantly, the distribution of RNPs in normal organs was approximately the same as that of unmodified nanoparticles. However, R8 modified nanoparticles elevated the distribution in almost all the tissues. These results demonstrated that RLW was superior in A549 tumor targeted delivery. After loaded with docetaxel, an anti-microtube agent, different formulations could effectively induce the A549 cell apoptosis, and inhibit the growth of A549 spheroids in vitro. While in vivo, RNPs displayed the best antitumor effect. The tumor volume was significantly lower than other groups, which was only 33.3% as that of saline group. In conclusion, in vitro RLW could specifically target to A549 cells and enhance the cytotoxicity of docetaxel. In vivo, RLW could significantly enhance the A549 xenografts targeting delivery and led to improved antitumor effect. PMID- 25448587 TI - Intestinal uptake and toxicity evaluation of acetazolamide and its multicomponent complexes with hidroxypropyl-beta-cyclodextrin in rats. AB - Large oral doses of ACZ lower the intraocular pressure (IOP), but usually lead to a multitude of systemic side effects, including gastrointestinal upset. The present study was undertaken to evaluate the effect of ACZ on the histological structure of rat duodenal mucosa and to assess a possible protective role of the complex formation of ACZ with HP-beta-CD, either separately or in combination with a third compound, on the gut epithelial layer by histological and ultrastructural examinations of sections of rat duodenum exposed to ACZ or its formulations. In addition, the transport process of ACZ and its binary or ternary complexes across the duodenal mucosa by means of the single-pass intestinal perfusion (SPIP) method in rats was evaluated. Evidence was found that ACZ alters intestinal permeability and induces damage to the rat small intestine. In contrast, ACZ-induced intestinal injury may be abrogated by ACZ complexation. In addition, the complexation of ACZ with HP-beta-CD, alone or in combination with a third compound, facilitated significant levels of ACZ uptake across the rat duodenal segment. Ternary complexes of ACZ with HP-beta-CD in combination with TEA (triethanolamine) or calcium ions were found to provide an excellent approach that enabled an increased apparent permeability of ACZ across the duodenal epithelium, with a concomitant ability to preserve the integrity of the gut epithelium from ACZ-induced injury. These results could be useful for the design and development of novel ACZ formulations that can reduce GI toxicity, while still maintaining their essential therapeutic efficacies. PMID- 25448588 TI - Low molecular weight poly (2-dimethylamino ethylmethacrylate) polymers with controlled positioned fluorescent labeling: Synthesis, characterization and in vitro interaction with human endothelial cells. AB - Poly (2-dimethylamino ethylmethacrylate) (PDMAEMA) is an attractive non degradable polymer studied as nonviral vector for gene delivery but it can be also adopted for delivery of other biopharmaceutical drugs. As a parenteral carrier, the PDMAEMA free form (FF) might interact with tissues and cells. Few data are available on its selective internalization and efflux from cells, while the majority of studies published have followed the distribution of DNA complexed with PDMAEMA. In order to address polycation safety, the first aim was to synthesize by atom transfer radical polymerisation (ATRP) fluorescent labeled PDMAEMA of low molecular weight (Mw) (below 15 kDa), controlling the position and density of fluorescein. The second goal was to analyze the possible difference in uptake and subcellular distribution of this labeled FF polycation between human umbilical vein endothelial cells (HUVEC) and hCMEC/D3 cells. These two cell lines have been chosen in order to detect selectivity towards the blood-brain barrier (BBB). In both cases, polycation was detected along the plasma membrane followed by progressive migration to the peri-nuclear region, where it overlapped with lysosomal structures. The analysis by fluorescence-activated cell sorting (FACS) of the PDMAEMA uptake by hCMEC/D3 cells showed a significant (p<0.05) inhibition (40%) in presence of 2-dexoxy-D-glucose inhibitor, a result supporting an energy dependence mechanism(s). Cytotoxicity study showed that low Mw PDMAEMA (10 kDa) lead to a minor cytotoxicity compared to the higher ones. As main conclusion this study highlights the similitude in cell trafficking of FF PDMAEMA and data previously reported for PDMAEMA/DNA complexes. PMID- 25448589 TI - Botulinum injection is useless on fibrotic neuropathic bladders. AB - OBJECTIVE: Studies on the use of intradetrusor botulinum toxin A injection for children with neuropathic bladders are insufficient and the results are controversial. The aim of the present study was to evaluate the effect of intradetrusor botulinum toxin A injection for children with neuropathic bladders that are resistant to anticholinergic treatment, and to reveal any criteria indicating treatment success. PATIENTS/METHODS: Hospital records were reviewed of 16 children with neuropathic bladders due to myelomeningocele, and who had botulinum toxin A injections between 2007 and 2010. Botulinum toxin A (10 units/kg) was injected endoscopically into various sites of the detrusor, except the trigone. The success was defined as complete dryness between clean intermittent catheterizations. Urodynamic studies before and after the application were evaluated and parameters, including bladder capacity (measured/expected) and compliance, were also analyzed. Reviewing the results, patients were then classified into two groups: as having fibrotic bladders (noncompliant, acontractile bladders with high pressures) or overactive bladders. Urodynamic findings and therapy success were then compared between the groups. RESULTS: A total of 19 injections, including repeat injections in three patients, were performed. Results of the 16 initial injections were evaluated. Nine patients had detrusor overactivity, and five out of nine (56%) applications in this group resulted in complete dryness between clean intermittent catheterizations. In bladders with typical detrusor overactivity, there was a significant increase in both the capacity (from 0.53 to 0.74) and compliance (from 4.7 to 8.6 ml/cm H2O). Looking at the seven patients that displayed fibrotic bladders with very low compliance and no contraction at all, none of them presented with notable clinical improvement from injections. Comparing the urodynamic findings, there was no significant difference in compliance (3.1 ml/cm H2O before and 3.5 ml/cm H2O after) and bladder capacity (0.58 before and 0.52 after the treatment) in the fibrotic bladders. DISCUSSION: Despite its worldwide usage and FDA approval, studies on the effectiveness of botulinumtoxin A on neuropathic bladders in children are controversial. There are now numerous studies attesting to the good results of BoNTA in neuropathic detrusor overactivity; however, only scarce reports comment on the specific features of the disease process among patients and reasons for failure in some. In our study, reviewing the urodynamic findings carefully, it was observed that the patients who did not respond to injections were the ones with no contractions, despite high pressures and low compliance. Therefore, describing the indications of BoNTA as neuropathic detrusor overactivity and urinary incontinence despite anticholinergic medications may lead to mistreatment of patients in the decompensated phase of a hyper-reflexive detrusor. Pretreatment urodynamic evaluation might be a good indicator, without biopsies, of estimating the degree of fibrosis and the patients who will benefit from the injection. CONCLUSION: Botulinum toxin A injection in the neuropathic bladder of myelomeningocele patients was found to be ineffective if the detrusor was fibrotic, of low compliance and had lost contractility. Urodynamic findings should be carefully analyzed in order to select appropriate patients that may benefit from Botulinum injection. PMID- 25448590 TI - Production of functional human insulin-like growth factor binding proteins (IGFBPs) using recombinant expression in HEK293 cells. AB - Insulin-like growth factor binding proteins (IGFBPs) display many functions in humans including regulation of the insulin-like growth factor (IGF) signaling pathway. The various roles of human IGFBPs make them attractive protein candidates in drug discovery. Structural and functional knowledge on human proteins with therapeutic relevance is needed to design and process the next generation of protein therapeutics. In order to conduct structural and functional investigations large quantities of recombinant proteins are needed. However, finding a suitable recombinant production system for proteins such as full-length human IGFBPs, still remains a challenge. Here we present a mammalian HEK293 expression method suitable for over-expression of secretory full-length human IGFBP-1 to -7. Protein purification of full-length human IGFBP-1, -2, -3 and -5 was conducted using a two-step chromatography procedure and the final protein yields were between 1 and 12mg protein per liter culture media. The recombinant IGFBPs contained PTMs and exhibited high-affinity interactions with their natural ligands IGF-1 and IGF-2. PMID- 25448591 TI - Expression, purification of IL-38 in Escherichia coli and production of polyclonal antibodies. AB - Members of the interleukin-1 (IL-1) family play important roles in inflammation and host defense against pathogens. Here, we describe a novel member of the IL-1 family, interleukin-38 (IL-38, IL-1F10, or IL-1HY2), which was discovered in 2001. Although the functional role of IL-38 remains unclear, recent reports show that IL-38 binds to the IL-36 receptor (IL-36R) which is also targeted by the IL 36 receptor antagonist (IL-36Ra). Consequently, these two molecules have similar effects on immune cells. Here, we describe the expression of soluble and active recombinant IL-38 in Escherichia coli (E. coli). The IL-38 gene sequence was optimized for expression in E. coli and then cloned into a pEHISTEV expression vector, which has an N-terminal 6-His affinity tag under control of the T7 lac strong promoter. Optimization of culture conditions allowed induction of the recombinant fusion protein with 0.1 mM isopropyl beta-D-1-thio galactoside (IPTG) at 37 degrees C for 4h. The recombinant fusion protein was purified using an Ni affinity column and was further digested with TEV protease; the cleaved protein was purified by molecular-exclusion chromatography. Next, we measured IL-38 binding ability using functional ELISA. The purified proteins were used to immunize a New Zealand white rabbit four times to enable the production of polyclonal antibodies. The specificity of the prepared polyclonal antibodies was determined using Western blot, and the results showed they have high specificity against IL-38. Here, we describe the development of an effective and reliable method to express and purify IL-38 and anti-IL-38 antibodies. This will enable the function and structure of IL-38 to be determined. PMID- 25448593 TI - Cloning, expression and purification of the human Islet Amyloid Polypeptide (hIAPP) from Escherichia coli. AB - Type II diabetes is characterized by deposition of the hormone human Islet Amyloid Polypeptide (hIAPP). Formation of hIAPP amyloid fibrils and aggregates is considered to be responsible for pancreatic beta-cell losses. Therefore, insight into the structure of hIAPP in the solid-state and in solution is of fundamental importance in order to better understand the action of small molecules, which can potentially dissolve protein aggregates and modulate cell toxicity. So far, no procedure has been described that allows to obtain the native human IAPP peptide at high yields. We present here a cloning, expression and purification protocol that permits the production of 2.5 and 3mg of native peptide per liter of minimal and LB medium, respectively. In the construct, hIAPP is fused to a chitin binding domain (CBD). The CBD is subsequently cleaved off making use of intein splicing reaction which yield amidation of the C-terminus. The N-terminus contains a solubilization domain which is cleaved by V8 protease, avoiding additional residues at the N-terminus. The correct formation of the disulfide bond is achieved by oxidation with H2O2. PMID- 25448592 TI - Isolation and characterization of recombinant murine Wnt3a. AB - Wnt proteins are a family of morphogens that possess potent biological activity. Structure-function studies have been impeded by poor yield of biologically active recombinant Wnt as well as a propensity of isolated Wnt to self-associate in the absence of detergent. Using stably transfected Drosophila S2 cells, studies have been conducted to improve recovery of recombinant murine Wnt3a, establish conditions for a detergent-free Wnt preparation and examine the effects of limited proteolysis. S2 cell culture conditioned media was subjected to a 3-step protocol including dye-ligand chromatography, immobilized metal affinity chromatography and gel filtration chromatography. Through selective pooling of column fractions, homogeneous and purified Wnt3a preparations were obtained. Limited proteolysis of Wnt3a with thrombin resulted in site-specific cleavage within the N-terminal saposin-like motif. To generate detergent-free protein, Wnt3a was immobilized on Cu(2+)-charged, iminodiacetic acid-derivatized Sepharose beads, detergent-free buffer was applied and Wnt3a eluted from the beads with buffer containing imidazole plus 30mM methyl-beta-cyclodextrin (MbetaCD). Wnt3a recovered in MbetaCD-containing buffer was soluble and biologically active. Insofar as MbetaCD is a member of a family of non-toxic, low molecular weight compounds capable of binding and solubilizing small hydrophobic ligands, Wnt cyclodextrin complexes may facilitate structure-activity studies in the absence of adverse detergent effects. PMID- 25448594 TI - Optimization of pancreatic trypsin extraction in PEG/citrate aqueous two-phase systems. AB - Enzyme extraction using aqueous two-phase systems (ATPS) has been increasingly used as a primary recovery technique which integrates the clarification, concentration and partial purification of important biomolecules from their natural source in a single step. The goal of this work was to optimize the extraction of trypsin from pancreas homogenate with polyethylene glycol and sodium citrate (PEG/NaCit) ATPS by using the tools of experimental design. The variables NaCl concentration - added inert salt -, the top/bottom phase volume ratio - Vr - and the biomass loaded into the system - in percentage - were selected as the main factors in the trypsin extraction. The yield (%) and the purification factor of trypsin were considered the responses to be optimized. The central composite design and the response surface analysis proved to be suitable tools for a quick and efficient study. As a result, the optimal extraction conditions in PEG3350/NaCit system were 3.34% wt/wt for NaCl concentration, a biomass load which represented 9.30% wt/wt of the total ATPS mass and 6.37 top/bottom volume ratio giving a purification factor of 2.55 and a yield of 99.7% in top phase. PMID- 25448595 TI - Investigation on solubilization protocols in the refolding of the thioredoxin TsnC from Xylella fastidiosa by high hydrostatic pressure approach. AB - The lack of efficient refolding methodologies must be overcome to take full advantage of the fact that bacteria express high levels of aggregated recombinant proteins. High hydrostatic pressure (HHP) impairs intermolecular hydrophobic and electrostatic interactions, dissociating aggregates, which makes HHP a useful tool to solubilize proteins for subsequent refolding. A process of refolding was set up by using as a model TsnC, a thioredoxin that catalyzes the disulfide reduction to a dithiol, a useful indication of biological activity. The inclusion bodies (IB) were dissociated at 2.4 kbar. The effect of incubation of IB suspensions at 1-800 bar, the guanidine hydrochloride concentration, the oxidized/reduced glutathione (GSH/GSSG) ratios, and the additives in the refolding buffer were analyzed. To assess the yields of fully biologically active protein obtained for each tested condition, it was crucial to analyze both the TsnC solubilization yield and its enzymatic activity. Application of 2.4 kbar to the IB suspension in the presence of 9 mM GSH, 1mM GSSG, 0.75 M guanidine hydrochloride, and 0.5M arginine with subsequent incubation at 1 bar furnished high refolding yield (81%). The experience gained in this study shall help to establish efficient HHP-based protein refolding processes for other proteins. PMID- 25448596 TI - Chemical activation of the cyanobacterial orange carotenoid protein. AB - The effects of the Hofmeister series of ions on the activation of the orange carotenoid protein (OCP) from the inactive orange form to the active red form were tested. Kosmotropes led to lower OCP activation, whereas chaotropes led to greater OCP activation. Concentrations of thiocyanate exceeding 1.5M dark activate the orange carotenoid protein to its red form. This chemically activated OCP was studied by UV-vis and circular dichroism spectroscopies. The chemically activated OCP quenches the fluorescence of phycobilisomes in vitro, to a level comparable to that of the light-activated OCP. PMID- 25448597 TI - More than an adaptor molecule: the emerging role of tRNA in cell signaling and disease. PMID- 25448598 TI - Backbone cyclization of a recombinant cystine-knot peptide by engineered Sortase A. AB - Cyclotides belong to the family of cyclic cystine-knot peptides and have shown promise as scaffolds for protein engineering and pharmacological modulation of cellular protein activity. Cyclotides are characterized by a cystine-knotted topology and a head-to-tail cyclic polypeptide backbone. While they are primarily produced in plants, cyclotides have also been obtained by chemical synthesis. However, there is still a need for methods to generate cyclotides in high yields to near homogeneity. Here, we report a biomimetic approach which utilizes an engineered version of the enzyme Sortase A to catalyze amide backbone cyclization of the recombinant cyclotide MCoTI-II, thereby allowing the efficient production of active homogenous species in high yields. Our results provide proof of concept for using engineered Sortase A to produce cyclic MCoTI-II and should be generally applicable to generating other cyclic cystine-knot peptides. PMID- 25448599 TI - MiR-92a inhibits porcine ovarian granulosa cell apoptosis by targeting Smad7 gene. AB - Smad7 has a key role in apoptosis of mammalian ovarian granulosa cells (GCs), as it antagonizes and fine-tunes transforming growth factor beta (TGFbeta) signaling. This study demonstrates that miR-92a regulates GC apoptosis in pig ovaries by targeting Smad7 directly. The expression level of miR-92a was down regulated in atretic porcine follicles, whereas miR-92a expression led to inhibition of GC apoptosis. The Smad7 gene was identified as a direct target of miR-92a using a dual-luciferase reporter assay. Transfection of GCs with miR-92a mimics decreased Smad7 mRNA and protein levels, whereas expression of an miR-92a inhibitor in GCs had the opposite effect. In addition, knockdown of Smad7 prevented GC apoptosis in cells that expressed the miR-92a inhibitor. PMID- 25448600 TI - MiR-199a-3p promotes gastric cancer progression by targeting ZHX1. AB - Accumulating evidence has indicated that microRNAs (miRNAs) act as critical epigenetic regulators in tumor carcinogenesis. Here, we report that miR-199a-3p was significantly upregulated in gastric cancer (GC) cell lines and tissues. Functional studies demonstrated that miR-199a-3p dramatically increased cell proliferation and suppressed cell apoptosis both in vitro and in vivo. Furthermore, the transcriptional regulator zinc fingers and homeoboxes 1 (ZHX1) was identified as one of the direct downstream targets of miR-199a-3p, miR-199a 3p bound to the ZHX1 3' untranslated region (3'UTR) to regulate ZHX1 protein expression. In addition, the expression of miR-199a-3p was inversely associated with that of ZHX1 in GC cell lines. Overexpression of miR-199a-3p in SGC-7901 cells inhibited ZHX1 expression, while reduction in miR-199a-3p by inhibitors in NCI-N87 cells enhanced ZHX1 expression. Moreover, restoring ZHX1 expression in SGC-7901/miR-199a-3p cells inhibited the cell proliferation induced by miR-199a 3p. Taken together, these findings suggest that miR-199a-3p may function as a novel tumor promoter in GC and its oncogenic activity may involve the direct targeting and inhibition of ZHX1. PMID- 25448601 TI - Alzheimer's disease is associated with altered expression of genes involved in immune response and mitochondrial processes in astrocytes. AB - Alzheimer's disease (AD) is characterized by deficits in cerebral metabolic rates of glucose in the posterior cingulate (PC) and precuneus in AD subjects, and in APOEepsilon4 carriers, decades before the onset of measureable cognitive deficits. However, the cellular and molecular basis of this phenotype remains to be clarified. Given the roles of astrocytes in energy storage and brain immunity, we sought to characterize the transcriptome of AD PC astrocytes. Cells were laser capture microdissected from AD (n = 10) and healthy elderly control (n = 10) subjects for RNA sequencing. We generated >5.22 billion reads and compared sequencing data between controls and AD patients. We identified differentially expressed mitochondria-related genes including TRMT61B, FASTKD2, and NDUFA4L2, and using pathway and weighted gene coexpression analyses, we identified differentially expressed immune response genes. A number of these genes, including CLU, C3, and CD74, have been implicated in beta amyloid generation or clearance. These data provide key insights into astrocyte-specific contributions to AD, and we present this data set as a publicly available resource. PMID- 25448604 TI - Advanced glycation end products are mitogenic signals and trigger cell cycle reentry of neurons in Alzheimer's disease brain. AB - Neurons that reenter the cell cycle die rather than divide, a phenomenon that is associated with neurodegeneration in Alzheimer's disease (AD). Reexpression of cell-cycle related genes in differentiated neurons in AD might be rooted in aberrant mitogenic signaling. Because microglia and astroglia proliferate in the vicinity of amyloid plaques, it is likely that plaque components or factors secreted from plaque-activated glia induce neuronal mitogenic signaling. Advanced glycation end products (AGEs), protein-bound oxidation products of sugar, might be one of those mitogenic compounds. Cyclin D1 positive neurons are colocalized with AGEs or directly surrounded by extracellular AGE deposits in AD brain. However, a direct proof of DNA replication in these cells has been missing. Here, we report by using fluorescent in situ hybridization that consistent with the expression of cell cycle proteins, hyperploid neuronal cells are in colocalization with AGE staining in AD brains but not in nondemented controls. To complement human data, we used apolipoprotein E-deficient mice as model of neurodegeneration and showed that increased oxidative stress caused an intensified neuronal deposition of AGEs, being accompanied by an activation of the MAPK cascade via RAGE. This cascade, in turn, induced the expression of cyclin D1 and DNA replication. In addition, reduction of oxidative stress by application of alpha-lipoic acid decreased AGE accumulations, and this decrease was accompanied by a reduction in cell cycle reentry and a more euploid neuronal genome. PMID- 25448602 TI - Association of CD33 polymorphism rs3865444 with Alzheimer's disease pathology and CD33 expression in human cerebral cortex. AB - Recent findings identified the minor A allele present in the single-nucleotide polymorphism rs3865444 in the CD33 gene as being associated with the reduced risk of developing Alzheimer's disease (AD). CD33 (Siglec-3) is an immune function protein with anti-inflammatory signaling, cell adhesion, and endocytosis functions with sialic acid-modified proteins or lipids as ligands. Its involvement in AD pathologic mechanisms is still unclear; so, the goal of this study was to investigate if the rs3865444 polymorphism affects the development of AD pathology and the expression of CD33 messenger RNA (mRNA) and protein. For this study, we used DNA from 96 nondemented (ND) and 97 AD neuropathologically diagnosed cases to identify the different rs3865444 alleles and correlate with different measures of AD pathology. Using semiquantitative histologic measures of plaque and tangle pathology, we saw no significant differences between the different genotypes within these disease groups. However, increased expression of CD33 mRNA was associated with increasing AD pathology in temporal cortex brain samples. We also showed that cases with A/A alleles had reduced levels of CD33 protein in temporal cortex but increased levels of the microglia protein IBA-1. Using immunohistochemistry on temporal cortex sections, CD33 was selectively localized to microglia, with greater expression in activated microglia. The factors causing increased CD33 expression by microglia in brain are still unclear, although both genetic and disease factors are involved. Treatment of human microglia isolated from autopsy brains with amyloid-beta peptide and a range of other inflammatory activating agents resulted in reduced CD33 mRNA and protein levels. PMID- 25448603 TI - Loss of NEIL1 causes defects in olfactory function in mice. AB - Oxidative DNA damage accumulation has been implicated in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The base excision repair pathway is a primary responder to oxidative DNA damage. Effects of loss of base excision repair on normal brain function is a relatively nascent area of research that needs further exploration for better understanding of related brain diseases. Recently, we found that loss of a versatile DNA glycosylase endonuclease 8-like 1 (NEIL1) causes deficits in spatial memory retention using the Morris water maze test. Furthermore, we found that there is a significant loss of NEIL1 enzyme levels and its activity in postmortem Alzheimer's disease brains. Based on the Allen Brain Atlas in situ hybridization data, the expression levels of Neil1 messenger RNA are higher in the olfactory bulb compared with other areas of the brain. Olfaction in mice is a central brain function that involves many central nervous system pathways. Here, we studied the effect of complete loss of Neil1 gene on olfactory function. We explored olfactory function in mice with 3 different behavioral tests namely, olfactory sensitivity, performance, and buried food tests. Neil1(-/-) mice performed poorly compared with wild-type mice in all 3 tests. Our data indicate that loss of Neil1 causes olfactory function deficits supporting our previous findings and that normal brain function requires robust DNA repair. PMID- 25448605 TI - Estrogen receptor-mediated resveratrol actions on blood-brain barrier of ovariectomized mice. AB - To test whether resveratrol provides benefits via estrogen receptors (ERs) in the blood-brain barrier of estrogen-deficient females, ovariectomized mice were treated with resveratrol then were subjected to transient middle cerebral artery occlusion (MCAO). Compared with vehicle treatment, resveratrol reduced infarct volume and neurologic deficits after MCAO. Basal tight junction (TJ) protein levels in the brain were increased by resveratrol. After MCAO, blood-brain barrier breakdown reduced levels of TJ proteins, and induction of HIF-1alpha and VEGF were attenuated by resveratrol. These effects were reversed by the ERs antagonist, ICI182,780. In mouse brain, endothelial cells (bEnd.3) exposed to hypoxia, resveratrol treatment protected the cells against cytotoxicity, increases of paracellular permeability and changes in levels of TJ protein and HIF-1alpha/VEGF proteins. These effects were reversed by ICI182,780 but not by specific ERalpha or ERbeta antagonists, indicating nonspecific ER mediated effects. Altogether, these results showed that neuroprotective effects of resveratrol in ovariectomized mice were mediated by ERs and associated with tightening of blood-brain barrier, suggesting that resveratrol can be an alternative to estrogens to protect the brains of estrogen-deficient females against ischemic insult. PMID- 25448606 TI - Role of miRNAs in endometrial cancer. AB - Endometrial cancer (EC) is the most common gynecologic malignancy. MicroRNAs (miRNAs) were recently associated with carcinogenesis and progression of EC. In this review, we discuss recent advances and the emerging role of miRNAs in EC and their clinical implications, with special emphasis on the differences between deregulated miRNAs in type I and type II EC, as well as the impact of this dysregulation on EC initiation and progression. PMID- 25448607 TI - Differential effects of triacylglycerol positional isomers containing n-3 series highly unsaturated fatty acids on lipid metabolism in C57BL/6J mice. AB - The present study investigated the effects of binding position of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to triacylglycerol (TAG) on lipid metabolism in C57BL/6J mice. Mice were treated with pure TAG positional isomers, including 1,2(2,3)-dipalmitoyl-3(1)-eicosapentaenoyl glycerol, 1,3-dipalmitoyl-2-eicosapentaenoyl glycerol, 1,2(2,3)-dipalmitoyl-3(1) docosahexaenoyl glycerol, and 1,3-dipalmitoyl-2-docosahexaenoyl glycerol. Compared to DHA bound to the alpha-position of TAG, DHA bound to the beta position more effectively inhibited fatty acid synthetic enzymes and cholesterol metabolism enzymes and thus reduced TAG and cholesterol concentrations in the serum and liver. EPA bound to the alpha-position of TAG, but not EPA bound to the beta-position of TAG, significantly decreased hepatic cholesterol concentrations. Additionally, EPA bound to the alpha-position of TAG increased the ratio of PGI2 to TXA2 to a higher degree than EPA bound to the beta-position. These results suggested that the binding position of EPA and DHA to TAG affected TAG and cholesterol metabolism as well as eicosanoid production in C57BL/6J mice. PMID- 25448609 TI - The development of diet-induced obesity and associated metabolic impairments in Dj-1 deficient mice. AB - DJ-1 constitutes a ubiquitously expressed, oxidative stress-responsive protein with multiple functions. DJ-1 emerged as a candidate from our previous proteome analysis investigating alterations in the hypothalamus in three mouse strains differing in their susceptibility to diet-induced obesity (DIO). Validation studies demonstrated a high-fat diet (HFD)-induced shift in the DJ-1 isoform pattern in the hypothalamus and several other tissues of mice. Others found HFD induced alterations in DJ-1 protein abundance in adipose tissue and pancreatic islets in wild-type rodents. Here, we investigated the gene-diet interaction by challenging Dj-1(-/-) mice with a HFD. We demonstrate that the development of diet-induced obesity (DIO) Dj-1(-/-) mice is according to wild-type mice with the exception of transient higher gains in fat mass at the expense of lean mass after 14 weeks of feeding. PMID- 25448610 TI - Polyunsaturated fatty acid supplementation reverses cystic fibrosis-related fatty acid abnormalities in CFTR-/- mice by suppressing fatty acid desaturases. AB - Cystic fibrosis patients and model systems exhibit consistent abnormalities in metabolism of polyunsaturated fatty acids that appear to play a role in disease pathophysiology. Recent in vitro studies have suggested that these changes are due to overexpression of fatty acid desaturases that can be reversed by supplementation with the long-chain polyunsaturated fatty acids docosahexaenoate and eicosapentaenoate. However, these findings have not been tested in vivo. The current study aimed to test these results in an in vivo model system, the CFTR(-/ ) knockout mouse. When compared with wild-type mice, the knockout mice exhibited fatty acid abnormalities similar to those seen in cystic fibrosis patients and other model systems. The abnormalities were confined to lung, ileum and pancreas, tissues that are affected by the disease. Similar to in vitro models, these fatty acid changes correlated with increased expression of Delta5- and Delta6 desaturases and elongase 5. Dietary supplementation with high-dose free docosahexaenoate or a combination of lower-dose docosahexaenoate and eicosapentaenoate in triglyceride form corrected the fatty acid abnormalities and reduced expression of the desaturase and elongase genes in the ileum and liver of knockout mice. Only the high-dose docosahexaenoate reduced histologic evidence of disease, reducing mucus accumulation in ileal sections. These results provide in vivo support for the hypothesis that fatty acid abnormalities in cystic fibrosis result from abnormal expression and activity of metabolic enzymes in affected cell types. They further demonstrate that these changes can be reversed by dietary n-3 fatty acid supplementation, highlighting the potential therapeutic benefit for cystic fibrosis patients. PMID- 25448608 TI - Polyphenol-enriched cocoa protects the diabetic retina from glial reaction through the sirtuin pathway. AB - Cocoa is rich in flavonoids, which are potent antioxidants with established benefits for cardiovascular health but unproven effects on neurodegeneration. Sirtuins (SIRTs), which make up a family of deacetylases, are thought to be sensitive to oxidation. In this study, the possible protective effects of cocoa in the diabetic retina were assessed. Rat Muller cells (rMCs) exposed to normal or high glucose (HG) or H2O2 were submitted to cocoa treatment in the presence or absence of SIRT-1 inhibitor and small interfering RNA The experimental animal study was conducted in streptozotocin-induced diabetic rats randomized to receive low-, intermediate-, or high-polyphenol cocoa treatments via daily gavage for 16 weeks (i.e., 0.12, 2.9 or 22.9 mg/kg/day of polyphenols). The rMCs exposed to HG or H2O2 exhibited increased glial fibrillary acidic protein (GFAP) and acetyl RelA/p65 and decreased SIRT1 activity/expression. These effects were cancelled out by cocoa, which decreased reactive oxygen species production and PARP-1 activity, augmented the intracellular pool of NAD(+), and improved SIRT1 activity. The rat diabetic retinas displayed the early markers of retinopathy accompanied by markedly impaired electroretinogram. The presence of diabetes activated PARP-1 and lowered NAD(+) levels, resulting in SIRT1 impairment. This augmented acetyl RelA/p65 had the effect of up-regulated GFAP. Oral administration of polyphenol cocoa restored the above alterations in a dose dependent manner. This study reveals that cocoa enriched with polyphenol improves the retinal SIRT-1 pathway, thereby protecting the retina from diabetic milieu insult. PMID- 25448611 TI - Obesity and metabolic parameters in adolescents: a school-based intervention program in French Polynesia. AB - PURPOSE: The prevalence of overweight/obesity among French Polynesian adolescents is alarming. This study aims to prevent rises in obesity by modifying school food and the physical environment of French Polynesian adolescents. METHODS: During the 5-month study, 240 adolescents from a Tubuai island college (in French Polynesia) received a balanced diet based almost exclusively on local agricultural products and fishing by the island community. They were divided into three subgroups according to their college attendance status: external (n = 14), half residents (n = 155), and residents (n = 71). To increase energy expenditure, weekly physical activity was augmented by 2-4 hours of training in Polynesian Va'a canoes. Anthropometric parameters were recorded, and blood samples collected at baseline and after 5 months. Collegians from Rurutu, a neighboring island, were considered as controls (N = 90). RESULTS: At baseline, overweight/obesity prevalence was 60% (with 28% obesity) in the intervention group. After 5 months, adjusted weight gain was -.76 kg for residents (95% confidence interval [CI], 1.59 to .08), 1.34 kg for half residents (95% CI, .84-1.83), 1.82 kg for externs (95% CI, .66-2.97), and 4.2 kg (95% CI, 3.4-5.0) in the controls. Our results indicate that the more adolescents were subjected to food and physical activity commitments, the higher was the rate among those who lost weight. We noted that the weight change magnitude predicted insulin, glucose, and visceral obesity modifications. CONCLUSIONS: This 5-month school-based intervention slowed weight gain and improved the health of Polynesian collegians. The implementation of longer school-based interventions deserves evaluation. PMID- 25448612 TI - Maternal and childhood psychological factors predict chronic disabling fatigue at age 13 years. AB - PURPOSE: To investigate whether premorbid maternal and childhood psychological problems are risk factors for chronic disabling fatigue at age 13 years among children in the Avon Longitudinal Study of Parents and Children birth cohort. METHODS: Chronic disabling fatigue was defined as fatigue of at least 3-month, and up to 5-year, duration that prevented school attendance or hobbies/sport/leisure activities, and for which other causes were not identified. Maternal psychological factors were symptoms of anxiety and depression assessed up to eight times between pregnancy and age 6 years. We investigated critical periods for maternal effects and effects of paternal depression at three time points. Child psychological factors included internalizing and externalizing problems and upsetting life events occurring at age 7-8 years. RESULTS: Of 5,657 children, 110 (1.9%) had chronic disabling fatigue at age 13 years. Maternal anxiety (adjusted odds ratio [AOR], 1.19; 95% confidence interval [CI], 1.09-1.31 per episode), maternal depression (AOR, 1.24; CI, 1.11-1.39 per episode), child psychological problems (AOR, 1.19; CI, 1.00-1.41 per problem), and upsetting events (AOR, 1.22; CI, .99-1.58 per event) were associated with chronic disabling fatigue. Associations of child psychological problems and upsetting events were attenuated (AOR, 1.12; CI, .93-1.33 per problem; AOR, 1.19; CI, .94-1.52 per event) after further adjusting for maternal anxiety and depression. CONCLUSIONS: Pediatricians need to be aware that children whose mothers experience anxiety and/or depression between pregnancy and child's age 6 years have an increased risk of developing chronic disabling fatigue in early adolescence. Conversely, clinicians need to be alert to fatigue in children whose mothers have longstanding anxiety and depression. These findings suggest the importance of family-based approaches to treatment. PMID- 25448613 TI - Long-term health and medical cost impact of smoking prevention in adolescence. AB - PURPOSE: To estimate smoking progression probabilities from adolescence to young adulthood and to estimate long-term health and medical cost impacts of preventing smoking in today's adolescents. METHODS: Using data from the National Longitudinal Study of Adolescent Health (Add Health), we first estimated smoking progression probabilities from adolescence to young adulthood. Then, using the predicted probabilities, we estimated the number of adolescents who were prevented from becoming adult daily smokers as a result of a hypothetical 1 percentage point reduction in the prevalence of ever smoking in today's adolescents. We further estimated lifetime medical costs saved and quality adjusted life years (QALYs) gained as a result of preventing adolescents from becoming adult daily smokers. All costs were in 2010 dollars. RESULTS: Compared with never smokers, those who had tried smoking at baseline had higher probabilities of becoming current or former daily smokers at follow-up regardless of baseline grade or sex. A hypothetical 1 percentage point reduction in the prevalence of ever smoking in 24.5 million students in 7th-12th grades today could prevent 35,962 individuals from becoming a former daily smoker and 44,318 individuals from becoming a current daily smoker at ages 24-32 years. As a result, lifetime medical care costs are estimated to decrease by $1.2 billion and lifetime QALYs is estimated to increase by 98,590. CONCLUSIONS: Effective smoking prevention programs for adolescents go beyond reducing smoking prevalence in adolescence; they also reduce daily smokers in young adulthood, increase QALYs, and reduce medical costs substantially in later life. This finding indicates the importance of continued investment in effective youth smoking prevention programs. PMID- 25448614 TI - Web-based personalized feedback: is this an appropriate approach for reducing drinking among high school students? AB - Research indicates that brief Web-based personalized feedback interventions are effective in reducing alcohol use and the negative associated consequences among college students. It is not clear, however, that this is an appropriate strategy for high school students. This study examined high school students' perceptions of a brief Web-based personalized feedback program to assess the appropriateness of this approach for this age group. Results indicated that the majority of students found the program to be user-friendly and to have high utility. Additionally, students reporting alcohol use found the program more useful and indicated that they would be more likely to recommend the program to other students relative to non-drinkers. Findings support the appropriateness of this approach for high school students, and suggest that Web-based personalized feedback may be more positively perceived by students who have initiated drinking. PMID- 25448616 TI - Expert's comment concerning Grand Rounds case entitled "bilateral reconstructive costoplasty for Razorback deformity correction in adolescent idiopathic scoliosis" (Eyal Behrbalk, Ofir Uri, Jonathan A. Clamp, Marcus Rickert, Bronek M. Boszczyk). PMID- 25448617 TI - Comment concerning Grand Rounds case entitled "Intercostal aneurysm causing spinal cord compression in an NF1 patient" (V. Puvanesarajah, I.A. Lina, J.A. Liauw, A.L. Coon, T.F. Witham). PMID- 25448618 TI - Soluble organic semiconductor precursor with specific phase separation for high performance printed organic transistors. AB - A soluble precursor of dinaphtho[2,3-b:2',3'-f]thieno[3,2-b]thiophene (DNTT) is developed for high-performance printed organic thin-film transistors (OTFTs). The DNTT precursor enables excellent thin-film formation and can induce specific phase separations when blended with inert polymers. The DNTT OTFTs processed from the precursor/polymer blend exhibit field-effect mobilities of up to 1.1 cm(2) V( 1) s(-1) and excellent durability against air exposure and thermal stress. PMID- 25448619 TI - Congenital visual pathway abnormalities: a window onto cortical stability and plasticity. AB - Sensory systems project information in a highly organized manner to the brain, where it is preserved in maps of the sensory structures. These sensory projections are altered in congenital abnormalities, such as anophthalmia, albinism, achiasma, and hemihydranencephaly. Consequently, these abnormalities, profoundly affect the organization of the visual system. Surprisingly, visual perception remains largely intact, except for anophthalmia. Recent brain imaging advances shed light on the mechanisms that underlie this phenomenon. In contrast to animal models, in humans the plasticity of thalamocortical connections appears limited, thus demonstrating the importance of cortical adaptations. We suggest that congenital visual pathway abnormalities provide a valuable model to investigate the principles of plasticity that make visual representations available for perception and behavior in humans. PMID- 25448620 TI - Finegoldia magna, not a well-known infectious agent of bacteriemic post sternotomy mediastinitis. AB - Post-sternotomy mediastinitis, a nosocomial infection mostly caused by staphylococci, can be life-threatening. A case of mediastinitis due to Finegoldia magna after a coronary artery bypass graft surgery was reviewed. Although this bacterium is difficult to be isolated from routine blood cultures, a F. magna bacteriemia associated with mediastinitis was diagnosed. PMID- 25448621 TI - Quantitation of protein S-glutathionylation by liquid chromatography-tandem mass spectrometry: correction for contaminating glutathione and glutathione disulfide. AB - Protein S-glutathionylation is a posttranslational modification that links oxidative stimuli to reversible changes in cellular function. Protein-glutathione mixed disulfide (PSSG) is commonly quantified by reduction of the disulfide and detection of the resultant glutathione species. This methodology is susceptible to contamination by free unreacted cellular glutathione (GSH) species, which are present in 1000-fold greater concentration. A liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method was developed for quantification of glutathione and glutathione disulfide (GSSG), which was used for the determination of PSSG in biological samples. Analysis of rat liver samples demonstrated that GSH and GSSG coprecipitated with proteins similar to the range for PSSG in the sample. The use of [(13)C2,(5)N]GSH and [(13)C4,(5)N2]GSSG validated these results and demonstrated that the release of GSH from PSSG did not occur during sample preparation and analysis. These data demonstrate that GSH and GSSG contamination must be accounted for when determining PSSG content in cellular/tissue preparations. A protocol for rinsing samples to remove the adventitious glutathione species is demonstrated. The fragmentation patterns for glutathione were determined by high-resolution mass spectrometry, and candidate ions for detection of PSSG on protein and protein fragments were identified. PMID- 25448622 TI - Label electrochemical immunosensor for prostate-specific antigen based on graphene and silver hybridized mesoporous silica. AB - Prostate-specific antigen (PSA), as the specificity of prostate cancer markers, has been widely used in prostate cancer diagnosis and screening. In this study, we fabricated an electrochemical immunosensor for PSA detection using the amino functionalized graphene sheet-ferrocenecarboxaldehyde composite materials (NH2 GS@FCA) and silver hybridized mesoporous silica nanoparticles (Ag@NH2-MCM48). Under optimal conditions, the fabricated immunosensor showed a wide linear range with PSA concentration (0.01-10.0ng.ml(-1)). Low detection limit (2pg.ml(-1)) proved the high sensitivity. In addition, the immunosensor possessed good stability and reproducibility. Moreover, the application to PSA analysis in serum samples yielded satisfactory results. PMID- 25448623 TI - Miniaturization of gene transfection assays in 384- and 1536-well microplates. AB - The miniaturization of gene transfer assays to either 384- or 1536-well plates greatly economizes the expense and allows much higher throughput when transfecting immortalized and primary cells compared with more conventional 96 well assays. To validate the approach, luciferase and green fluorescent protein (GFP) reporter gene transfer assays were developed to determine the influence of cell seeding number, transfection reagent to DNA ratios, transfection time, DNA dose, and luciferin dose on linearity and sensitivity. HepG2, CHO, and NIH 3T3 cells were transfected with polyethylenimine (PEI)-DNA in both 384- and 1536-well plates. The results established optimal transfection parameters in 384-well plates in a total assay volume of 35MUl and in 1536-well plates in a total assay volume of 8MUl. A luciferase assay performed in 384-well plates produced a Z' score of 0.53, making it acceptable for high-throughput screening. Primary hepatocytes were harvested from mouse liver and transfected with PEI DNA and calcium phosphate DNA nanoparticles in 384-well plates. Optimal transfection of primary hepatocytes was achieved on as few as 250cellsperwell in 384-well plates, with CaPO4 proving to be 10-fold more potent than PEI. PMID- 25448624 TI - Transport stress induces apoptosis in rat myocardial tissue via activation of the mitogen-activated protein kinase signaling pathways. AB - The present study aimed to elucidate the mechanism of myocardial damage induced by simulated transport stress. Sprague-Dawley rats were subjected to 35 degrees C and 60 rpm (0.1*g rcf) on a constant temperature shaker. The blood samples were prepared for detection of epinephrine (E), norepinephrine (NE), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and serum cardiac troponin T (cTNT); myocardium samples were prepared for morphological examination and signaling protein quantitative. The result showed that plasma norepinephrine (NE) and epinephrine (E) concentrations increased in all stressed groups (P < 0.01). Levels of serum cardiac troponin T (cTNT) were elevated in both the S2d (P < 0.05) and S3d groups (P < 0.01). The concentration of plasma BNP was increased significantly in S3d group (P < 0.05); the difference in ANP was not remarkable. Morphological observation demonstrated obvious microstructure and ultrastructure damage after simulated transport stress. There was also a significant increase in the number of TUNEL-positive cardiomyocytes in stressed hearts. Western blot analysis found that the mitogen-activated protein kinase (MAPK) pathways were activated by strengthening phosphorylation of ASK-1, JNK, P38 and ERK in rat myocardial tissue after simulated transport stress (P < 0.05, P < 0.01). In addition, the ratio of pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins was increased in stressed rats (P < 0.01), and the amount of cleaved-caspase3 increased in all stressed rats (P < 0.01). The expression of cleaved-caspase9 protein was also elevated in S2d and S3d groups (P < 0.01). Consequently simulated transport stress induced obvious myocardial damage, which may be attributed to the activation of caspase 9-mediated mitochondrial apoptotic pathway and MAPK pathways. PMID- 25448625 TI - The current provision of community-based teaching in UK medical schools: an online survey and systematic review. AB - OBJECTIVE: To evaluate the current provision and outcome of community-based education (CBE) in UK medical schools. DESIGN AND DATA SOURCES: An online survey of UK medical school websites and course prospectuses and a systematic review of articles from PubMed and Web of Science were conducted. Articles in the systematic review were assessed using Rossi, Lipsey and Freeman's approach to programme evaluation. STUDY SELECTION: Publications from November 1998 to 2013 containing information related to community teaching in undergraduate medical courses were included. RESULTS: Out of the 32 undergraduate UK medical schools, one was excluded due to the lack of course specifications available online. Analysis of the remaining 31 medical schools showed that a variety of CBE models are utilised in medical schools across the UK. Twenty-eight medical schools (90.3%) provide CBE in some form by the end of the first year of undergraduate training, and 29 medical schools (93.5%) by the end of the second year. From the 1378 references identified, 29 papers met the inclusion criteria for assessment. It was found that CBE mostly provided advantages to students as well as other participants, including GP tutors and patients. However, there were a few concerns regarding the lack of GP tutors' knowledge in specialty areas, the negative impact that CBE may have on the delivery of health service in education settings and the cost of CBE. CONCLUSIONS: Despite the wide variations in implementation, community teaching was found to be mostly beneficial. To ensure the relevance of CBE for 'Tomorrow's Doctors', a national framework should be established, and solutions sought to reduce the impact of the challenges within CBE. STRENGTHS AND LIMITATIONS OF THIS STUDY: This is the first study to review how community-based education is currently provided throughout Medical Schools in the UK. The use of Rossi, Lipsey and Freeman's method of programme evaluation means that the literature was analysed in a consistent and comprehensive way. However, a weakness is that data from the online survey was obtained from online medical school prospectuses. This means the data may be incomplete or out of date. Data in the literature review may also be skewed by publication bias. PMID- 25448626 TI - Examining the reliability and validity of a modified version of the International Physical Activity Questionnaire, long form (IPAQ-LF) in Nigeria: a cross sectional study. AB - OBJECTIVES: To investigate the reliability and an aspect of validity of a modified version of the long International Physical Activity Questionnaire (Hausa IPAQ-LF) in Nigeria. DESIGN: Cross-sectional study, examining the reliability and construct validity of the Hausa IPAQ-LF compared with anthropometric and biological variables. SETTING: Metropolitan Maiduguri, the capital city of Borno State in Nigeria. PARTICIPANTS: 180 Nigerian adults (50% women) with a mean age of 35.6 (SD=10.3) years, recruited from neighbourhoods with diverse socioeconomic status and walkability. OUTCOME MEASURES: Domains (domestic physical activity (PA), occupational PA, leisure-time PA, active transportation and sitting time) and intensities of PA (vigorous, moderate and walking) were measured with the Hausa IPAQ-LF on two different occasions, 8 days apart. Outcomes for construct validity were measured body mass index (BMI), systolic blood pressure (SBP) and diastolic blood pressure (DBP). RESULTS: The Hausa IPAQ-LF demonstrated good test retest reliability (intraclass correlation coefficient, ICC>75) for total PA (ICC=0.79, 95% CI 0.65 to 0.82), occupational PA (ICC=0.77, 95% CI 0.68 to 0.82), active transportation (ICC=0.82, 95% CI 0.75 to 0.87) and vigorous intensity activities (ICC=0.82, 95% CI 0.76 to 0.87). Reliability was substantially higher for total PA (ICC=0.80), occupational PA (ICC=0.78), leisure-time PA (ICC=0.75) and active transportation (ICC=0.80) in men than in women, but domestic PA (ICC=0.38) and sitting time (ICC=0.71) demonstrated more substantial reliability coefficients in women than in men. For the construct validity, domestic PA was significantly related mainly with SBP (r=-0.27) and DBP (r=-0.17), and leisure time PA and total PA were significantly related only with SBP (r=-0.16) and BMI (r=-0.29), respectively. Similarly, moderate-intensity PA was mainly related with SBP (r=-0.16, p<0.05) and DBP (r=-0.21, p<0.01), but vigorous-intensity PA was only related with BMI (r=-0.11, p<0.05). CONCLUSIONS: The modified Hausa IPAQ-LF demonstrated sufficient evidence of test-retest reliability and may be valid for assessing context specific PA behaviours of adults in Nigeria. PMID- 25448627 TI - Improving physical functional and quality of life in older adults with multiple sclerosis via a DVD-delivered exercise intervention: a study protocol. AB - INTRODUCTION: There is a need to identify innovative, low-cost and broad-reaching strategies for promoting exercise and improving physical function in older adults with multiple sclerosis (MS). METHODS AND ANALYSIS: This randomised controlled pilot trial will test the efficacy of a 6-month, DVD-delivered exercise intervention to improve functional performance and quality of life in older adults with MS. Participants will be randomised either into a DVD-delivered exercise condition or an attentional control condition. This novel approach to programme delivery provides participants with detailed exercise instructions which are presented in a progressive manner and includes a variety of modifications to better meet varying levels of physical abilities. The targeted exercises focus on three critical elements of functional fitness: flexibility, strength and balance. It is hypothesised that participants who are randomised to the exercise DVD condition will demonstrate improvements in physical function compared with participants assigned to the attentional control condition. Data analysis will include a 2 (condition)*2 (time) mixed factor analysis of variance (ANOVA) that follows intent-to-treat principles, as well as an examination of effect sizes. Participants will take part in qualitative interviews about perspectives on physical activity and programme participation. ETHICS AND DISSEMINATION: The study protocol was approved by a university institutional review board and registered with a federal database. Participants will be asked to read and sign a detailed informed consent document and will be required to provide a physician's approval to participate in the study. The exercise DVDs include an overview of safety-related concerns and recommendations relative to exercise participation, as well as detailed instructions highlighting the proper execution of each exercise presented on screen. Following completion of this trial, data will be immediately analysed and results will be presented at scientific meetings and published in scholarly journals. TRIAL REGISTRATION NUMBER: Clinical Trials NCT01993095. PMID- 25448629 TI - Concerted modulation of paxillin dynamics at focal adhesions by Deleted in Liver Cancer-1 and focal adhesion kinase during early cell spreading. AB - Deleted in Liver Cancer-1 (DLC1) is a RhoGTPase-activating protein (GAP) and a tumor suppressor often downregulated in cancers. It is localized to the focal adhesions (FAs) and its absence leads to enhanced cell migration, invasion, and metastasis. Although DLC1 interacts with focal adhesion kinase (FAK), talin, and tensin, its role in focal adhesions dynamics remains unclear. We examined the effect of DLC1 in Human Foreskin Fibroblasts and determined its localization, dynamics and impact on paxillin by Fluorescence Recovery After Photobleaching at both nascent and mature focal adhesions. During early cell spreading, DLC1 is preferentially localized at the inner/mature adhesions whereas phosphorylated paxillin occupies the outer/nascent FAs. In addition, DLC1 downregulates paxillin turnover in a process, that does not require its GAP activity. Instead, it requires the presence of FAK. Acting in concert, both DLC1 and FAK could provide a unique spatio-temporal mechanism to regulate paxillin function in tissue homeostasis. PMID- 25448628 TI - Protocol investigating the clinical utility of an objective measure of activity and attention (QbTest) on diagnostic and treatment decision-making in children and young people with ADHD-'Assessing QbTest Utility in ADHD' (AQUA): a randomised controlled trial. AB - INTRODUCTION: The National Institute for Health and Care Excellence (NICE) guidelines for attention deficit/hyperactivity disorder (ADHD) state that young people need to have access to the best evidence-based care to improve outcome. The current 'gold standard' ADHD diagnostic assessment combines clinical observation with subjective parent, teacher and self-reports. In routine practice, reports from multiple informants may be unavailable or contradictory, leading to diagnostic uncertainty and delay. The addition of objective tests of attention and activity may help reduce diagnostic uncertainty and delays in initiating treatment leading to improved outcomes. This trial investigates whether providing clinicians with an objective report of levels of attention, impulsivity and activity can lead to an earlier, and more accurate, clinical diagnosis and improved patient outcome. METHODS AND ANALYSIS: This multisite randomised controlled trial will recruit young people (aged 6-17 years old) who have been referred for an ADHD diagnostic assessment at Child and Adolescent Mental Health Services (CAMHS) and Community Paediatric clinics across England. Routine clinical assessment will be augmented by the QbTest, incorporating a continuous performance test (CPT) and infrared motion tracking of activity. The participant will be randomised into one of two study arms: QbOpen (clinician has immediate access to a QbTest report): QbBlind (report is withheld until the study end). Primary outcomes are time to diagnosis and diagnostic accuracy. Secondary outcomes include clinician's diagnostic confidence and routine clinical outcome measures. Cost-effective analysis will be conducted, alongside a qualitative assessment of the feasibility and acceptability of incorporating QbTest in routine practice. ETHICS AND DISSEMINATION: The findings from the study will inform commissioners, clinicians and managers about the feasibility, acceptability, clinical utility and cost-effectiveness of incorporating QbTest into routine diagnostic assessment of young people with ADHD. The results will be submitted for publication in peer-reviewed journals. The study has received ethical approval. TRIAL REGISTRATION NUMBER: NCT02209116. PMID- 25448631 TI - Capture of carbon dioxide from ethanol fermentation by liquid absorption for use in biological production of succinic acid. AB - Previously, it was shown that the gas produced in an ethanol fermentor using either corn or barley as feedstock could be sparged directly into an adjacent fermentor as a feedstock for succinic acid fermentation using Escherichia coli AFP184. In the present investigation, it was demonstrated that the CO2 produced in a corn ethanol fermentor could be absorbed in a base solution and the resultant carbonate solution used both for pH control and supply of the CO2 requirement in succinic acid fermentation. Thus, the CO2 produced in a 5-L corn mash containing 30 wt% total solids was absorbed in a packed column containing 2 L of either 5 M NaOH, 5 M KOH, or 15 wt% NH4OH, and the resultant carbonate solutions were used for pH control in a succinic acid fermentor. The results obtained indicated no significant differences between succinic acid production in these experiments and when 2.5 M solutions of Na2CO3, K2CO3, and (NH4)2CO3 from commercial sources were used. In a commercial setting, the demonstrated capture of CO2 in liquid form will allow transportation of the carbonate solutions to locations not in the immediate vicinity of the ethanol plant, and excess carbonate salts can also be recovered as value-added products. PMID- 25448632 TI - Identification of proteins in Streptococcus pneumoniae by reverse vaccinology and genetic diversity of these proteins in clinical isolates. AB - Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide. Virulence-associated proteins common and conserved among all capsular types now represent the best strategy to combat pneumococcal infections. Our aim was to identify conserved targets in pneumococci that showed positive prediction for lipoprotein and extracellular subcellular location using bioinformatics programs and verify the distribution and the degree of conservation of these targets in pneumococci. These targets can be considered potential vaccine candidate to be evaluated in the future. A set of 13 targets were analyzed and confirmed the presence in all pneumococci tested. These 13 genes were highly conserved showing around >96 % of amino acid and nucleotide identity, but they were also present and show high identity in the closely related species Streptococcus mitis, Streptococcus oralis, and Streptococcus pseudopneumoniae. S. oralis clusters away from S. pneumoniae, while S. pseudopneumoniae and S. mitis cluster closer. The divergence between the selected targets was too small to be observed consistently in phylogenetic groups between the analyzed genomes of S. pneumoniae. The proteins analyzed fulfill two of the initial criteria of a vaccine candidate: targets are present in a variety of different pneumococci strains including different serotypes and are conserved among the samples evaluated. PMID- 25448634 TI - Capsular polysaccharide of Group B Streptococcus mediates biofilm formation in the presence of human plasma. AB - Group B Streptococcus (GBS) is an asymptomatic colonizer of human mucosal surfaces that is responsible for sepsis and meningitis in neonates. Bacterial persistence and pathogenesis often involves biofilm formation. We previously showed that biofilm formation in medium supplemented with glucose is mediated by the PI-2a pilus. Here, biofilm formation was tested in cell culture medium supplemented with human plasma. GBS strains were able to form biofilms in these conditions unlike Group A Streptococcus (GAS) or Staphylococcus aureus. Analysis of mutants impaired for various surface components revealed that the GBS capsule is a key component in this process. PMID- 25448633 TI - Oriented immobilization and characterization of a poly-lysine-tagged cephalosporin C acylase on glyoxyl agarose support. AB - Cephalosporin C acylase (CCA), an important industrial enzyme for the production of 7-aminocephalosporanic acid, has very limited and scattered surface lysine residues. A mutant of cephalosporin C acylase (mCCA) has been designed to fuse a poly-lysine tag to the C-terminal of the beta-subunit, which is far away from the active site. The free mCCA showed a near equal specific activity with the wild type CCA, while a much higher activity recovery was obtained for the mCCA than its wild-type counterpart after immobilization on glyoxyl agarose support (73.3 versus 53.3 %). The mCCA's oriented immobilization enables it to obtain a higher substrate affinity and even a higher thermal stability than the wild-type enzyme. The improvement of stability might be attributed to the multipoint covalent attachment by the oriented enzyme immobilization via the adhered poly-lysine tag, which prevents the dissociation of the beta-subunit of CCA from the support. PMID- 25448630 TI - Human cytomegalovirus infection is associated with essential hypertension in Kazakh and Han Chinese populations. AB - BACKGROUND: We aimed to study the association between cytomegalovirus (CMV) infection and hypertension in Kazakh and Han populations from Xinjiang Province, China. MATERIAL/METHODS: We analyzed data on 800 Kazakhs (467 hypertension patients and 333 healthy control participants) and 800 Hans (482 hypertension patients and 318 healthy control participants) aged 18-84 years old. ELISA and real-time quantitative PCR coupled with restriction fragment length polymorphism analysis were applied for determining CMV infection and glycoprotein B (gB) genotypes, respectively. RESULTS: Serologic evidence of CMV infection was obtained for 95.4% and 90.1% of the Kazakhs and Hans, respectively. The CMV seroprevalence rates among the Kazakh and Han participants with hypertension were 96.8% and 89.8%, respectively. Multiple logistic regression analyses revealed statistically significant independent associations between CMV seropositivity and hypertension in Kazakh males and between CMV antibody titers and hypertension in Hans; significant relationships also existed between CMV antibody titers and blood pressure in Hans. In Kazakhs, 3 CMV gB genotypes were identified: gB2 and genotype mixtures gB1+gB2 and gB2+gB3. In Hans, 4 CMV gB genotypes were identified: gB1, gB2, gB1+gB2, and gB2+gB3. Of the 4 studied genotypes, gB2+gB3 showed a significant independent association with hypertension in Kazakh females. CONCLUSIONS: CMV infection is associated with essential hypertension in Kazakh males and Hans in Xinjiang. CMV seropositivity is associated with hypertension in Kazakh males, and CMV antibody titers are associated with blood pressure and hypertension in Han males and females. Moreover, the CMV gB2+gB3 genotype mixture is associated independently with essential hypertension in Kazakh females. PMID- 25448635 TI - Schistosomiasis mass drug administration in the Philippines: lessons learnt and the global implications. AB - Schistosomiasis was first reported in the Philippines in 1906. A variety of treatments have been deployed to cure infection and to control the disease in the long-term. We discuss the journey to combat the disease in the Philippines and the lessons learnt which have implications for schistosomiasis control globally. PMID- 25448636 TI - Spatial and temporal colonization dynamics of segmented filamentous bacteria is influenced by gender, age and experimental infection with Helicobacter hepaticus in Swiss Webster mice. AB - In this study, we examined colonization dynamics of segmented filamentous bacteria (SFB) in intestine of Swiss Webster (SW) mice infected with Helicobacter hepaticus (Hh). At 8 weeks post-inoculation with Hh (WPI), cecal and colonic SFB levels in the control males were significantly lower compared to those at 16 WPI. Hh infection in both genders did not alter SFB levels in the jejunum and ileum, but increased SFB levels in the cecum and colon of males compared to the controls (P < 0.05) at 8 WPI. At 16 WPI, the Hh-infected females contained lower levels of SFB in the jejunum, cecum and colon compared to the female controls. Irrespective of gender, aging and Hh infection, the Il-17A mRNA levels decreased from the small intestine to the cecum and then to the colon, whereas the Foxp3 mRNA levels were comparable in these intestinal regions. There were significant differences in Il-17A mRNA levels in the ileum (P < 0.05, R(2) = 0.31), with females having greater Il-17A mRNA levels than males, and higher SFB colonization levels related to more Il-17A mRNA. These results indicate that aging and gender play an important role in colonization dynamics of intestinal SFB and ileal SFB associated Th17 response. PMID- 25448638 TI - The effects of specific athletic training on path selection while running. AB - Apertures that are smaller than 1.3 times the shoulder width (SW) require that individuals make an adjustment to their normal walking behavior [6]. When given a choice, individuals will choose to avoid apertures smaller than this ratio, rather than rotate their shoulders and walk through [7]. Research has yet to determine whether this choice in path selection can be influenced by the speed at which one approaches the aperture or by experience/training. Therefore, the current study investigated whether approach speed and/or specific athletic training influences the choice in path selection. Specifically-trained athletes (n=6) and non-trained (n=6) young adults ran toward a visible goal placed at the end of the path and avoided an aperture (created by two poles) placed along the midline of the path. The separation between the poles ranged between 0.6 and 1.8 times each participant's SW, in increments of 0.2. Participants were permitted to either run through or around the aperture to get to the end goal. Results demonstrated that regardless of training experience, participants ran around apertures smaller than 1.4* the SW and ran through apertures larger than this ratio. Increased approach speed (i.e., running) therefore appears to elicit similar aperture crossing behaviors as walking [2,3,6,7]. Additionally, when faced with the choice to run around or to run through apertures, individuals who are specifically-training to run through small spaces chose similar paths as individuals who are not trained to do so. Therefore, specific training does not appear to influence voluntary path selection. PMID- 25448637 TI - Management of tumors arising from the parapharyngeal space: A systematic review of 1,293 cases reported over 25 years. AB - OBJECTIVES: We present a systematic review of 1,252 lesions published in the past 25 years, the largest to date. We also include our own experience of 41 cases. DATA SOURCES: Our data sources were MEDLINE and Embase databases. REVIEW METHODS: A systematic review of the literature (1988-2014) was performed and data on histological diagnosis, presentation, surgical approach, and postoperative complications were reviewed. RESULTS: In total, 22 studies (including our own institution) revealed 82% of lesions were benign. The most common presentation was an intraoral mass (52%) followed by a cervical mass (48%), and the most common primary lesion was a pleomorphic adenoma (29%). Ninety-six percent of patients underwent surgery. The cervical approach was most frequently used (46%), and the most common complication was vagus nerve injury (13%). Within our institution, 5-year progression-free survival for benign and malignant disease was 93% and 61%, respectively (P = .196). CONCLUSIONS: A parapharyngeal space mass is an uncommon tumor and requires careful preoperative assessment. Definitive treatment is usually surgery, and these patients should be counseled appropriately about the potential for permanent cranial nerve deficits. LEVEL OF EVIDENCE: NA. PMID- 25448639 TI - Effect of natural trunk inclination on variability in soleus inhibition and tibialis anterior activation during gait initiation in young adults. AB - BACKGROUND: Anticipatory postural adjustments (APAs) of gait initiation (GI) permit first step execution. APAs are characterized by a structured pattern of soleus (SOL) inhibition followed by tibialis anterior (TA) activation. This pattern shows variability among young adults where SOL is not always inhibited before TA activation. Initial posture preceding GI could explain a part of this variability. The aim of the study was to investigate the effect of natural trunk inclination on APAs during GI. METHODS: Two groups of twelve subjects divided by natural trunk inclination angle performed five gait initiation trials. A regression model was computed to predict SOL inhibition and TA activation. RESULTS: Backward leaners showed less SOL inhibition in stance leg (25.8% of trials) compared to forward leaners (55.6% of trials). Regression model revealed that high tonic EMG activity in SOL in the stance leg is the variable that best explains SOL inhibition variation within trials but not TA activation. CONCLUSION: Slight variations in APAs are due to natural trunk inclination but more contribution in APAs is due to initial posture, future step speed and initial tonic soleus activity. Absence of SOL inhibition could be in part explained by natural trunk inclination, where the backward inclination leads to lower tonic SOL activity in quiet standing. These effects could be due to inherent and functional variability, which depend on postural variation, muscular coordination and limb roles. PMID- 25448640 TI - Health level seven interoperability strategy: big data, incrementally structured. AB - OBJECTIVES: Describe how the HL7 Clinical Document Architecture (CDA), a foundational standard in US Meaningful Use, contributes to a "big data, incrementally structured" interoperability strategy, whereby data structured incrementally gets large amounts of data flowing faster. We present cases showing how this approach is leveraged for big data analysis. METHODS: To support the assertion that semi-structured narrative in CDA format can be a useful adjunct in an overall big data analytic approach, we present two case studies. The first assesses an organization's ability to generate clinical quality reports using coded data alone vs. coded data supplemented by CDA narrative. The second leverages CDA to construct a network model for referral management, from which additional observations can be gleaned. RESULTS: The first case shows that coded data supplemented by CDA narrative resulted in significant variances in calculated performance scores. In the second case, we found that the constructed network model enables the identification of differences in patient characteristics among different referral work flows. DISCUSSION: The CDA approach goes after data indirectly, by focusing first on the flow of narrative, which is then incrementally structured. A quantitative assessment of whether this approach will lead to a greater flow of data and ultimately a greater flow of structured data vs. other approaches is planned as a future exercise. CONCLUSION: Along with growing adoption of CDA, we are now seeing the big data community explore the standard, particularly given its potential to supply analytic en- gines with volumes of data previously not possible. PMID- 25448641 TI - Skeletonized versus pedicled bilateral internal mammary artery grafting: outcomes and concerns analyzed through a meta-analytical approach. AB - BACKGROUND: It is suggested that the internal thoracic artery (ITA) harvesting technique influences the incidence of sternal wound infection (SWI) after coronary artery bypass graft (CABG) surgery when both right and left ITAs are used. We conducted a meta-analysis to determine whether there is any difference between skeletonized versus pedicled bilateral ITA in terms of SWI after CABG. METHODS: We performed a systematic-review using MEDLINE, EMBASE, CENTRAL/CCTR, SciELO, LILACS, Google Scholar and reference lists of relevant articles to search for studies that compared the incidence of SWI after CABG between skeletonized versus pedicled bilateral ITA until May 2014. The principal summary measures were odds ratio (OR) with 95% Confidence Interval (CI) and P values (statistically significant when <0.05). The ORs were combined across studies using weighted DerSimonian-Laird random effects model. Meta-analysis, sensitivity analysis and meta-regression were carried out by using the software Comprehensive Meta Analysis version 2 (Biostat Inc., Englewood, New Jersey). RESULTS: Eight studies involving 2633 patients (1698 skeletonized; 935 pedicled) met the eligibility criteria. There was no evidence for important heterogeneity of the effects among the studies. The overall OR (95% CI) of SWI showed statistical significant difference in favor to skeletonized ITA (random effect model: OR 0.327; 95% CI 0.217-0.492; P < 0.001). In sensitivity analysis, the difference in favor to skeletonized ITA was observed mainly in the presence of diabetes. In meta regression, we observed no modulation of the effects. CONCLUSION: When both ITAs are used, the skeletonized technique appears to reduce the incidence of SWI after CABG in comparison to the pedicled technique. PMID- 25448642 TI - The clinical efficacy of vertebroplasty on osteoporotic vertebral compression fracture: a meta-analysis. AB - We investigated the clinical efficacy of vertebroplasty (VP) for the treatment of osteoporotic vertebral compression fracture (OVCF). We searched the online databases such as MEDLINE, EMBASE, EBSCO, Springer, Ovid and Cochrane library citations up to May 2012 and 5 eligible studies were included in this study. The meta-analysis was conducted using software RevMan 5.0. For the continuous data, the weighted mean difference (WMD) and its 95% confidence interval (CI) were calculated and the odds ratio (OR) and the corresponding 95% CI were calculated for the dichotomous data. The results demonstrated that the Visual Analogue Scale (VAS) score of patients treated with VP was significantly lower than that treated with traditional treatment at each time point (one week: WMD = -2.55, 95% CI, 3.08 to -2.02, P < 0.0001; 12 weeks: WMD = -0.90, 95% CI, -1.22 to -0.57, P < 0.0001; 24 weeks: WMD = -1.75, 95% CI, -2.30 to -1.19, P < 0.0001; 48 weeks: WMD = -1.75, 95% CI, -2.30 to -1.19, P < 0.001). For The incidence of adjacent vertebral fracture, the overall estimate (OR = 2.06, 95% CI: 0.26 to 16.29, P = 0.50) indicated that there was no statistically significant difference between VP and traditional treatment. In conclusion, the OVCF patients treated by VP had statistically significant improvements in pain relief compared with the traditional treatment and there was the similar incidence of adjacent vertebral fracture between the patients treated by VP and traditional treatment. PMID- 25448643 TI - The reporting quality of systematic reviews and meta-analyses in vascular surgery needs improvement: a systematic review. AB - INTRODUCTION: Systematic reviews and meta-analyses are important in shaping clinical practice, but the underlying quality of these studies is critical. The PRISMA guidelines for the reporting of systematic reviews, published in 2009, aimed to improve the quality of reporting of these studies. We looked at whether the reporting of systematic reviews relevant to vascular surgery had improved since the introduction of these guidelines. METHODS: All systematic reviews and meta-analyses published in the top five general and top five vascular surgery journals in the years 2008 (pre-PRIMSA) and 2012 (post-PRISMA) were included. We examined the proportion of concordance of each individual paper with the 27 PRISMA statements. RESULTS: A total of 74 studies were found (n = 37 in 2008, n = 37 in 2012), most of which were found in the specific vascular surgery journals. The average proportion of concordance of systematic reviews to the PRISMA guidance increased between 2008 and 2012 (from 65% to 73%, p < 0.01), indicating some improvement in reporting quality. DISCUSSION: Since the publication of the PRISMA guidance, there has been a marginal improvement in the quality of reporting of systematic reviews and meta-analyses in the field of vascular surgery. However, given the importance of these studies, this needs to be improved, especially as poor reporting may reflect poor methodology in conduct. Journals' instructions to authors should insist on submissions following the published guidance, and this intervention would likely improve both the methodology and quality of reporting of published systematic reviews. PMID- 25448644 TI - Learning curve for gasless endoscopic thyroidectomy using the trans-axillary approach: CUSUM analysis of a single surgeon's experience. AB - BACKGROUND: Endoscopic thyroidectomy and endoscopic parathyroidectomy were first reported in the 1990s. However, there have been few studies reporting on the learning curve of endoscopic thyroidectomy. We used the moving average method and cumulative sum (CUSUM) analysis to assess the learning curve of gasless endoscopic thyroidectomy. METHODS: Three hundred consecutive patients with thyroid carcinoma underwent gasless endoscopic thyroidectomy between September 2008 and February 2012. Patients were divided into two groups according to the type of operation they underwent; group L included hemithyroidectomy patients, and group T included total thyroidectomy patients. Endoscopic total thyroidectomy was performed mostly after the time endoscopic lobectomy could be done without difficulty. The results of surgical outcome were analyzed for changes over the case sequence in each group by using the moving average method and CUSUM analysis. RESULTS: The mean operation time of group T (131 +/- 41 min) was longer than that of group L (102 +/- 33 min; p < 0.05). The moving average method showed that the operation time began to decrease from the 60th case and the 38th case in groups L and T, respectively. However, other factors such as transient hypocalcemia, transient vocal cord palsy and the number of the retrieved lymph nodes had no learning curves based on the moving average method and CUSUM analysis. CONCLUSIONS: The learning curve duration of gasless endoscopic thyroidectomy is about 60 cases for unilateral lobectomy. Thereafter, the learning curve of endoscopic total thyroidectomy is 38 cases. Careful dissections must be carried out to avoid surgical complications even after the surgeon mastered endoscopic thyroidectomy. PMID- 25448645 TI - Pulsed electromagnetic fields accelerate functional recovery of transected sciatic nerve bridged by chitosan conduit: an animal model study. AB - INTRODUCTION: Effect of whole body exposure to pulsed electromagnetic fields (PEMF) on nerve regeneration in a rat sciatic nerve transection model was assessed. METHODS: Sixty male white Wistar rats were divided into four experimental groups (n = 15), randomly: In transected group (TC) left sciatic nerve was transected and stumps were fixed in adjacent muscle. In chitosan group (CHIT) the defect was bridged using a chitosan conduit filled with phosphate buffered saline. In treatment group (CHIT/PEMF) the whole body was exposed to PEMF (0.3 mT, 2 Hz) for 4 h/day within 1-5 days. In normal control group (NC) sciatic nerve was only dissected and manipulated. Each group was subdivided into three subgroups of five animals each and nerve fibers were studied 4, 8 and 12 weeks after surgery. RESULTS: Behavioral, functional, electrophysiological, biomechanical, gastrocnemius muscle mass findings and morphometric indices confirmed faster recovery of regenerated axons in CHIT/PEMF than in CHIT group (p < 0.05). Immunohistochemical reactions to S-100 in CHIT/PEMF were more positive than that in CHIT group. DISCUSSION: Whole body exposure to PEMF improved functional recovery and morphometric indices of sciatic nerve. Detailed mechanism of neuroprotective action remains to be investigated. CONCLUSION: PEMF combine with chitosan grafting could be considered as an effective, safe and tolerable treatment for peripheral nerve repair in clinical practice. PMID- 25448646 TI - Autotransplantation of Inferior Parathyroid glands during central neck dissection for papillary thyroid carcinoma: a retrospective cohort study. AB - INTRODUCTION: The management of inferior parathyroid glands during central neck dissection (CND) for papillary thyroid carcinoma (PTC) remains controversial. Most surgeons preserve inferior parathyroid glands in situ. Autotransplantation is not routinely performed unless devascularization or inadvertent parathyroidectomy occurs. This retrospective study aimed to compare the incidence of postoperative hypoparathyroidism and central neck lymph node (CNLN) recurrence in patients with PTC who underwent inferior parathyroid glands autotransplantation vs preservation in situ. METHODS: This is a retrospective study which was conducted in a tertiary referral hospital. A total of 477 patients with PTC (pN1) who underwent total thyroidectomy (TT) and bilateral CND with/without lateral neck dissection were included. Patients' demographical characteristics, tumor stage, incidence of hypoparathyroidism, CNLN recurrence and the number of resected CNLN were analyzed. RESULTS: Three hundred and twenty one patients underwent inferior parathyroid glands autotransplantation (autotransplantation group). Inferior parathyroid glands were preserved in situ among 156 patients (preservation group). Permanent hypoparathyroidism rate was 0.9% (3/321) versus 3.8% (6/156) respectively (p = 0.028). Mean numbers of resected CNLN were 15 +/- 3 (6-23) (autotransplantation group) versus 11 +/- 3 (7 21) (preservation group) (p < 0.001). CNLN recurrence rate was 0.3% (1/321) versus 3.8% (6/156) respectively (p = 0.003). CONCLUSION: Inferior parathyroid glands autotransplantation during CND of PTC (pN1) might reduce permanent hypoparathyroidism and CNLN recurrence. Further study enrolling more patients with long-term follow-up is needed to support this conclusion. PMID- 25448648 TI - Routine preoperative restaging CTs after neoadjuvant chemoradiation for locally advanced rectal cancer are low yield: a retrospective case study. AB - INTRODUCTION: Pre-operative restaging CT scans are often performed routinely following neoadjuvant chemoradiotherapy for locally advanced rectal cancer. There is a paucity of data on the utility of this common practice. We sought to determine how often restaging CTs identified disease progression or regression that altered management. METHODS: We performed a single-institution retrospective study. From 2007 to 2011, 182 patients had newly-diagnosed, non-metastatic rectal adenocarcinoma, of which 96 were surgical candidates with clinical stage II/III disease. Ninety-one of these patients (95%) completed neoadjuvant chemoradiation. RESULTS: Eighty-three out of 91 patients (91%) had restaging CTs. Four patients (5%) had new lesions suspicious for distant metastasis (2 lung, 2 liver) on restaging CT scan reports (1 of these was present on initial staging CT but not reported). All 4 patients had node-positive disease. In no case did restaging CT result in a change in surgical management. DISCUSSION: Because of the financial costs and established risks of intravenous contrast and cumulative radiation exposure, it may be advisable to take a more selective approach to preoperative imaging. Larger, prospective studies may enable identification of an at-risk cohort who would benefit most from restaging CT. CONCLUSION: Routine restaging CT scans are low yield in the management of locally advanced rectal cancer. PMID- 25448647 TI - Solitary fibrous tumor of the liver: report of two cases and review of the literature. AB - A solitary fibrous tumor (SFT) of the liver is a rare neoplasm of mesenchymal origin. 59 cases have been reported in the literature. We report 2 patients who presented with a hepatic solitary fibrous tumor. The first case is a 65-year-old man who presented with an accidental finding of a large mass in the left liver. Biopsy revealed an SFT and left hepatectomy was performed. The diagnosis was confirmed by histopathology. The second case is an 87-year-old woman who presented with disturbances in her liver function tests. A Computed Tomography (CT) scan showed a large mass in the right liver. Surgery was contraindicated because of the patient's poor general condition. A biopsy was done and SFT was diagnosed histopathologically. SFT are usually benign but the risk of malignant transformation always exists, which mandates surgical resection as the optimal management of these tumors. However, because of the small sample size and the rarity of the entity, it is difficult to define the evolution, the risk factors and the malignant potential of these tumors. PMID- 25448649 TI - A review of prophylactic antibiotics use in plastic surgery in China and a systematic review. AB - The purpose of this study was to investigate the use of antibiotic prophylaxis for plastic surgical procedures at our hospital, and to perform a systematic literature review of randomized controlled trials evaluating the use of prophylactic antibiotics in plastic surgery. The records of patients who received plastic surgical procedures with Class I surgical incisions between 2009 and 2010 were retrospectively reviewed. A systematic literature review was conducted for studies examining the use of prophylactic antibiotics for Class I surgical wounds. A total of 13,997 cases with Class I surgical incisions were included. Prophylactic antibiotics were given in 13,865 cases (99.1%). The antibiotics used were primarily cefuroxime, clindamycin, metronidazole, cefoxitin sodium, and gentamicin. The average duration of administration was 4.84 +/- 3.07 (range, 1 51) days. Antibiotics were administered postoperatively in >99% of cases while preoperative antibiotic administration was only given in 32 cases (0.23%). Wound infections occurred in 21 cases for an overall infection rate of 0.15%. Fourteen studies met the inclusion criteria of the systematic review. There was marked variation in the timing of antibiotic administration with antibiotics given pre-, peri-, and postoperatively. Of studies that compared the use of prophylactic antibiotics with placebo, a reduction in wound infections was noted in 4 trials and no difference was noted in 6 trials. No significant difference in infection rates was shown between the prophylactic and postoperative arms. In conclusion, prophylactic antibiotics are overused in plastic surgical procedures. Evidence based guidelines for the use of prophylactic antibiotics in plastic surgical procedures are needed. PMID- 25448650 TI - Minimal-access video-assisted thyroidectomy for benign disease: a retrospective analysis of risk factors for postoperative complications. AB - BACKGROUND: Minimal-access video-assisted thyroidectomy (MIVAT) has now become a widespread technique in the treatment of benign thyroid disease. No studies systematically investigate risk factors for postoperative complications. The aim of our study was to investigate possible risk factors for postoperative complications in MIVAT in patients with benign disease. METHODS: One-hundred eighty-nine patients who underwent MIVAT for benign disease were retrospectively identified in a prospectively-maintained institutional register of thyroid surgery. Exclusion criteria were: (1) thyroid volume>45 mL; (2) malignant disease; (3) prior neck surgery; (4) prior neck irradiation; (5) nodule size>3 cm; (6) intrathoracic component; (7) follow-up<1 year. Age, sex, comorbidities, body mass index, existence of symptoms, duration of disease evolution, thyroid volume, hyperthyroidism, thyroiditis, and the duration of surgery were analyzed as risk factors for complications. We applied both bivariate and multivariate logistic regression analyses in order to identify risk factors associated with postoperative complications. RESULTS: Complications were presented by 28 patients (14.8%). The variables associated as independent risk factors with these complications were hyperthyroidism (OR = 4.31; P = 0.003) and thyroiditis (OR = 3.59; P = 0.035). Age, sex and thyroid volume up to 45 mL do not seem to be independent risk factors. CONCLUSIONS: In endocrine surgery units, two independent risk factors for postoperative complications could be identified in MIVAT patients: hyperthyroidism and thyroiditis. Surgeons operating on patients presenting these factors should be aware of the potential augmented risk in order to correctly adapt intraoperative and postoperative care. PMID- 25448651 TI - The potential role of BMI, plasma leptin, nesfatin-1 and ghrelin levels in the early detection of pancreatic necrosis and severe acute pancreatitis: a prospective cohort study. AB - BACKGROUND: Early prediction of disease severity in acute pancreatitis (AP) is crucial. The aim of this study was to investigate the body-mass index (BMI), plasma leptin, nesfatin-1 and ghrelin levels as potential markers predicting peripancreatic necrosis and severity in acute pancreatitis. METHODS: In the study period, 97 consecutive patients with AP were prospectively analysed. Severe AP was defined according to the Atlanta Criteria. BMI was also calculated. To measure plasma Leptin, Nesfatin-1 and Ghrelin concentrations, the blood samples were obtained from patients within 24 hours of admission. RESULTS: Out of 97 patients, 92(70 females, 22 males) were considered eligible for analysis. Of the 92 patients, 30 patients (32.6%) were assessed as severe pancreatitis. BMI and leptin levels were significantly higher in patients with severe pancreatitis. The pooled sensitivity and specificity of BMI as a predictor for the development of pancreatic necrosis were 0.90(95%CI = 0.56-0.99) and 0.70(95%CI = 0.58-0.79), respectively; with an overall area under curve value of 0.78.The pooled sensitivity and specificity of leptin levels as a predictor for development of pancreatic necrosis were 1(95%CI = 0.69-1) and 0.73(95%CI = 0.62 0.82),respectively; with an overall area under curve value of 0.82.Nesfatin-1 and ghrelin levels showed no significant difference in patients with mild pancreatitis (6.97 +/- 0.84 ng/ml and 2.3(1.0-9.9);respectively) and severe pancreatitis (6.74 +/- 0.65 ng/ml and 2.0(1.9-9.9); respectively) (p = 0.1923 and 0.8531;respectively). CONCLUSION: BMI and plasma leptin levels both were correlated with the severity of pancreatitis. Leptin levels showed better area under the curve, sensitivity and specificity values compared to BMI in prediction of pancreatic necrosis.Nesfatin-1 and ghrelin levels were not found to be predictors of the severity of disease. PMID- 25448652 TI - An overview of the use and implementation of checklists in surgical specialities a systematic review. AB - INTRODUCTION: Surgical procedures present an immense risk to patients, and adverse patient outcomes are frequently due to substandard non-technical skills amongst surgical staff. The implementation of a 19-item Surgical Safety Checklist, developed by the World Health Organization, is being enforced in operating theatres globally. The objective is to systematically analyze published literature to assess the use of the WHO Surgical Safety Checklist and their impact in on patient safety. METHODS: An English literature search was carried out using MEDLINE, EMBASE and PsycINFO databases. Relevant information was extracted relating to surgical specialities, compliance with the checklist, effects of checklist use on patient outcomes, and staff perceptions of the checklist. Selection was restricted to articles that used the WHO Surgical Safety Checklist. RESULTS: The literature search found 916 potentially relevant articles, which were narrowed down following an abstract review and a full text review. A final total of 16 studies were identified that observed the use of checklists in various surgical specialties; all surgical specialities (n-10), pediatric surgery (n-2), orthopedic surgery (n-2), otorhinolaryngology surgery (n 2). DISCUSSION: Surgical checklists have been shown to significantly improve patient outcomes subsequent to surgery, and therefore their use is being widely encouraged and accepted. Continual feedback could be given to maintain high checklist compliance, and thus high patient safety. SUMMARY: The recent use of checklists in surgery has shown improvements in patient outcomes post operatively. A review was conducted to establish the impact of the checklist on different surgical specialities. PMID- 25448653 TI - The prognostic value of the number of lymph nodes removed in patients with node negative colorectal cancer. AB - BACKGROUND: To investigate the prognostic significance of the number of lymph nodes removed in colorectal cancer (CRC) patients with no metastatic lymph node. PATIENTS AND METHODS: The clinicopathological data of 461 CRC patients was analyzed. In order to compare the survival of patients who had fewer lymph nodes removed versus the survival of patients who had 1-3 metastatic lymph node(s), a separate group of 74 N1 disease patients were also included in the study. All patient data were collected prospectively. Kaplan-Meier method was used for calculation and plotting of the survival curves of the patient groups, and log rank test was used for the comparison of the survival curves. RESULTS: Cancer specific survival (CSS) rates of patients who had 1-7 lymph node(s) and 8-11 lymph nodes removed were significantly worse than those who had 12 or more lymph nodes removed (p = 0.006 and p = 0.037, respectively), while CSS was not significantly different between those who had 1-7 versus 8-11 lymph node(s) removed (p = 0.647); this grouping had independent prognostic significance in Cox analysis (p = 0.006). CSS of patients with N1 disease was not significantly different from those who had 1-7 and 8-11 lymph node(s) removed (p = 0.312 and p = 0.165, respectively), while it was significantly worse than CSS of patients who had 12 or more lymph nodes removed (p = 0.001). CONCLUSION: In colorectal cancer patients whose removed lymph nodes are non-metastatic, removal of at least 12 lymph nodes will determine the lymph node status reliably. PMID- 25448654 TI - Anterior cervical discectomy and fusion with "mini-invasive" harvesting of iliac crest graft versus polyetheretherketone (PEEK) cages: a retrospective outcome analysis. AB - BACKGROUND: Limited outcome data suggested a minimal evidence for better clinical and radiographic outcome of polyetheretherketone cages compared with bone grafts in the anterior cervical discectomy and fusion. We proposed a "mini-invasive" surgical technique for harvesting iliac crest grafts that provides bicortical autografts of sufficient size to be used in multilevel cervical procedures and is not associated with long-term significant donor site pain. METHODS: All patients undergoing discectomy and fusion during a three years period were consecutively extracted from computer database and retrospectively evaluated by means of telephonic interview, independently from surgical procedure (iliac crest autograph or prosthesis). Two procedure-blinded neurologists retrieved baseline clinical-demographic data and pre-surgical scores of routinely performed scales for pain and functional abilities. Afterwards, a third blinded neurologist performed clinical follow up by a semi-structured interview including Verbal Analog Scale for pain and Neck Disability Scale for discomfort. RESULTS: 80 patients out of 115 selected cases completed the follow up. 40 patients had been treated by mini-invasive bone graft harvesting and 40 with PEEK cages for cervical fusion. VAS for both neck and arm pain were significantly reduced within groups. Patients did not complaint any significant pain and/or paraesthesias at donor site from the first week after intervention. Neck Disability Scale was significantly lower at the end of follow up in both groups. CONCLUSIONS: "Miniinvasive" bicortical autografts is a less invasive, inexpensive technique to harvest iliac graft that may produce a reduced amount of general and local donor site complications without outcome differences with prosthetic cages. PMID- 25448655 TI - Is it safe the reversal of a diverting stoma during adjuvant chemotherapy in elderly rectal cancer patients? AB - INTRODUCTION: The aim of this study was to investigate the clinical outcomes between 2 groups of elderly rectal cancer patients according to the time duration after which their diverting stoma can be reversed. METHODS: We recruited 124 patients who were >=65 years old and had undergone diverting stoma after rectal cancer surgery. In Group 1, the reversal of the stoma was predominantly performed after the sixth adjuvant chemotherapy. In Group 2, the reversal was predominantly performed after the third adjuvant chemotherapy. RESULTS: The mean duration for which patients had a stoma was 28.6 +/- 9.9 weeks in Group 1 and 17.1 +/- 7.4 weeks in Group 2. The interval between stoma formation and stoma formation related complications was slightly longer in Group 1 than in Group 2 (13.5 +/- 9.7 vs. 8.0 +/- 4.9 weeks, p = 0.075). There were 16 stoma-related complications in Group 1 (23.2%) and 10 in Group 2 (18.2%) (p = 0.516). There were 6 stoma closure-related complications in Group 1 (8.8%) and 6 in Group 2 (10.9%) (p = 0.766). DISCUSSION: This study shows that stoma closure during adjuvant chemotherapy is no more harmful than stoma closure after termination of adjuvant chemotherapy. CONCLUSION: It may be possible to limit the duration of diverting stoma following rectal cancer surgery, even if patients are elderly and undergoing adjuvant chemotherapy. PMID- 25448656 TI - Predicting blood transfusion in patients undergoing minimally invasive oesophagectomy. AB - AIM: To evaluate predictors of allogenic blood transfusion requirements in patients undergoing minimal invasive oesophagectomy at a tertiary high volume centre for oesophago-gastric surgery. METHODS: Retrospective analysis of all patients undergoing minimal access oesophagectomy in our department between January 2010 and December 2011. Patients were divided into two groups depending on whether they required a blood transfusion at any time during their index admission. Factors that have been shown to influence perioperative blood transfusion requirements in major surgery were included in the analysis. Binary logistic regression analysis was performed to determine the impact of patient and perioperative characteristics on transfusion requirements during the index admission. RESULTS: A total of 80 patients underwent minimal access oesophagectomy, of which 61 patients had a laparoscopic assisted oesophagectomy and 19 patients had a minimal invasive oesophagectomy. Perioperative blood transfusion was required in 28 patients at any time during hospital admission. On binary logistic regression analysis, a lower preoperative haemoglobin concentration (p < 0.01), suffering a significant complication (p < 0.005) and laparoscopic assisted oesophagectomy (p < 0.05) were independent predictors of blood transfusion requirements. DISCUSSION: It has been reported that requirement for blood transfusion can affect long-term outcomes in oesophageal cancer resection. Two factors which could be addressed preoperatively; haemoglobin concentration and type of oesophageal resection, may be valuable in predicting blood transfusions in patients undergoing minimally invasive oesophagectomy. CONCLUSION: Our analysis revealed that preoperative haemoglobin concentration, occurrence of significant complications and type of minimal access oesophagectomy predicted blood transfusion requirements in the patient population examined. PMID- 25448657 TI - Clarification of the circulatory patho-physiology of anaesthesia - implications for high-risk surgical patients. AB - The paper examines the effects of anaesthesia on circulatory physiology and their implications regarding improvement in perioperative anaesthetic management. Changes to current anaesthetic practice, recommended recently, such as the use of flow monitoring in high risk patients, are already beginning to have an impact in reducing complications but not mortality [1]. Better understanding of the patho physiology should help improve management even further. Analysis of selected individual clinical trials has been used to illustrate particular areas of patho physiology and how changes in practice have improved outcome. There is physiological support for the importance of achieving an appropriate rate of oxygen delivery (DO2), particularly following induction of anaesthesia. It is suggested that ensuring adequate DO2 during anaesthesia will avoid development of oxygen debt and hence obviate the need to induce a high, compensatory, DO2 in the post-operative period. In contrast to the usual assumptions underlying strategies requiring a global increase in blood flow [1] by a stroke volume near maximization strategy, blood flow control actually resides entirely at the tissues not at the heart. This is important as the starting point for understanding failed circulatory control as indicated by 'volume dependency'. Local adjustments in blood flow at each individual organ - auto-regulation - normally ensure the appropriate local rate of oxygen supply, i.e. local DO2. Inadequate blood volume leads to impairment of the regulation of blood flow, particularly in the individual tissues with least capable auto-regulatory capability. As demonstrated by many studies, inadequate blood flow first occurs in the gut, brain and kidney. The inadequate blood volume which occurs with induction of anaesthesia is not due to blood volume loss, but probably results from redistribution due to veno-dilation. The increase in venous capacity renders the existing blood volume inadequate to maintain venous return and pre-load. Blood volume shifted to the veins will, necessarily, also reduce the arterial volume. As a result stroke volume and cardiac output fall below normal with little or no change in peripheral resistance. The resulting pre-load dependency is often successfully treated with colloid infusion and, in some studies, 'inotropic' agents, particularly in the immediate post-operative phase. Treatment during the earliest stage of anaesthesia can avoid the build up of oxygen debt and may be supplemented by drugs which maintain or restore venous tone, such as phenylephrine; an alternative to volume expansion. Interpretation of circulatory patho-physiology during anaesthesia confirms the need to sustain appropriate oxygen delivery. It also supports reduction or even elimination of supplementary crystalloid maintenance infusion, supposedly to replace the "mythical" third space loss. As a rational evidence base for future research it should allow for further improvements in anaesthetic management. PMID- 25448659 TI - Laparoscopic gastrectomy for gastric cancer: current evidences. AB - Nowadays, our understanding of gastric cancer has been improved. The major hope is to increase the survival rates of this aggressive, enigmatic and heterogeneous disease, especially in Western population. Over the past decades, conventional surgery has been the cornerstone of treatment for non metastatic gastric cancer patients. Adequate gastrectomy is recommended for at least T2-4a tumors, while T4b tumors require resection of involved structures. However, in the era of advanced technology, minimally invasive surgical approaches are in the top of the scientific interest. Notably, the laparoscopic approach for gastric cancer is a topic that remain controversial. In this review, we summarize the standard of care according to the current evidences and we provide the latest scientific information assessing safety and efficacy of laparoscopic gastrectomy for gastric cancer. PMID- 25448658 TI - Simultaneous cholecystectomy during gastric and oesophageal resection: a retrospective analysis and critical review of literature. AB - The higher incidence of gallstone formation after gastrectomy for cancer has been reported as a common complication in many studies but the management strategies are still controversial and need further evaluation. We retrospectivaly analysed between 2007 and 2013, 206 patients who underwent gastric and or oesophageal resection. In 29/93 patients receiving an oesophagectomy a simultaneous cholecystectomy was performed, respectively 31 from 111 patients who underwent a gastrectomy received an incidental cholecystectomy. In 2 patients with an extended gastrectomy, the gallblader removing was performed simultaneously in one case. A subsequent cholecystectomy was performed in 11 cases. The increased surgical mortality was significant higher correlated with an intervention at a later stage point. That suggest that the prohylactic cholecystectomy can be safely performed during a major intervention in order to reduce complication and a reoperation. PMID- 25448660 TI - Population level analysis of diagnostic laparoscopy versus normal appendicectomy for acute lower abdominal pain. AB - BACKGROUND: There is virtually no evidence to guide surgeons and patients when faced with an absence of pathology for acute lower abdominal pain. This study aimed to compare diagnostic laparoscopy alone to laparoscopic removal of a normal appendix in patients with acute lower abdominal pain but an absence of pathology. METHOD: Retrospective analysis of routinely collected hospital data from all English acute hospitals performing emergency appendicectomy between 01/04/2002 and 31/03/2012. Patients admitted as emergencies with lower abdominal pain undergoing diagnostic laparoscopy (with no other procedure or associated diagnosis) were compared to those undergoing laparoscopic normal appendicectomy. The primary outcome measure was emergency readmission for abdominal pain during the 12 period after index surgery. Multivariable binary logistic regression was used to produce adjusted odds ratios (OR and bootstrapped 95% confidence intervals). RESULT: 10,072 patients undergoing diagnostic laparoscopy were compared to 9665 undergoing laparoscopic normal appendicectomy. Overall, 32.9% (n = 6499/19,737) were readmitted as an emergency for abdominal pain during the 12 months after index surgery. Following risk-adjustment, laparoscopic normal appendicectomy was associated with 44% reduced odds of readmission (adjusted OR 0.56, 0.50-61). In the diagnostic laparoscopy group, 2.1% of patients (213) required subsequent appendicectomy, which was abnormal in 47.4% (101/213) cases. CONCLUSION: This study suggests that removal of a laparoscopically normal appendix, when no other pelvic pathology is visible, may reduce one-year readmission rates. Although limited through selection bias from routinely collected data, this study provides evidence for practicing surgeons and information for methodologists to power a future trial. PMID- 25448661 TI - Standard polypropylene mesh vs lightweight mesh for Lichtenstein repair of primary inguinal hernia: a randomized controlled trial. AB - PURPOSE: The aim of the present clinical study was to compare early and late outcomes after inguinal hernia repair with the heavyweight mesh (HW) and lightweight mesh (LW) during a 3 year follow-up period. METHODS: 226 patients were randomized into LW and HW mesh groups, both of which underwent unilateral primary inguinal hernia repair via the Lichtenstein technique. Wound complications (infection, hematoma, seroma), hernia recurrence, pain and feeling of foreign body in inguinal area were determined in patients. Pain was measured by visual analogue scale. RESULTS: No statistical difference has been found between LW and HW groups by wound complication (P = 0.80). One case of hernia recurrence has been mentioned in both groups one year after hernioplasty. But there was no detectable difference between the two groups. No significant difference has been found between LW and HW groups by frequency of chronic pain 7 days, 1 and 3 months, 1, 2, and 3 years after surgery. As for the feeling of foreign body in groin it is similar in both groups after 1 and 3 months. Level of feeling of foreign body was significantly lower in LW group 1, 2, and 3 years after surgery, than in HW group (P = 0.03, P = 0.02, P = 0.02, respectively). CONCLUSION: Our research shows no significant difference in wound complications, hernia recurrence and chronic pain after Lichtenstein hernioplasty, by using of LW and HW meshes. The usage of the LW mesh was associated with less feeling of foreign body than that of the HW mesh, what can be considered as prevalence of LW mesh hernioplasty. PMID- 25448662 TI - Totally hand-sewn anastomosis using barbed suture device during laparoscopic gastric bypass in obese. A feasibility study and preliminary results. AB - INTRODUCTION: Barbed sutures are routinely used for laparotomy, peritoneal and mesenteric closure, but few studies have reported their use for intestinal anastomosis. We proposed their use for totally hand-sewn anastomosis during laparoscopic gastric bypass secured at the end of the suture with an absorbable clip. MATERIALS AND METHOD: Two totally hand-sewn single-layer extramucosal running sutures were performed for side-to-side gastrojejunal and jejuno-jejunal anastomosis during laparoscopic gastric bypass. Each run (anterior and posterior layer) was locked at the end by an absorbable poly-p-dioxanone suture clip. RESULTS: A total of 96 hand-sewn anastomoses were performed. A total of two leaks occurred originating from the jejunaljejunal anastomosis. No cases of leakage from gastrojejunostomy were recorded. Two stenoses of the gastrojejunal anastomosis were recorded. They were successfully treated with three sessions of endoscopic balloon dilatation. No bleeding occurred. CONCLUSION: In our experience, the suture-related complication rate is comparable with the data reported in the literature. Further studies are needed to address the safety and efficacy of the self-maintained suture in digestive surgery. PMID- 25448663 TI - Effect of in situ delivery of acetyl-L-carnitine on peripheral nerve regeneration and functional recovery in transected sciatic nerve in rat. AB - The repair of peripheral nerve injuries is still one of the most challenging tasks and concerns in neurosurgery, plastic and orthopedic surgery. Effect of acetyl-L-carnitine (ALC) loaded chitosan conduit as an in situ delivery system of ALC in bridging the defects was studied using a rat sciatic nerve regeneration model. A 10-mm sciatic nerve defect was bridged using a chitosan conduit (CHIT/ALC) filled with 10 MUL ALC (100 ng/mL). In control group (CHIT), the conduit was filled with the same volume of the phosphate buffered solution. The regenerated fibers were studied 4, 8, 12 and 16 weeks after surgery. The functional and electrophysiological studies confirmed faster recovery of the regenerated axons in ALC treated than control group (P < 0.05). The mean ratios of gastrocnemius muscles weight were measured. There was statistically significant difference between the muscle weight ratios of CHIT/ALC and CHIT groups (P<0.05). Morphometric indices of regenerated fibers showed number and diameter of the myelinated fibers in CHIT/ALC were significantly higher than in control group. In immuohistochemistry, the location of reactions to S-100 in CHIT/ALC was clearly more positive than CHIT group. ALC when loaded in a chitosan conduit resulted in improvement of functional recovery and quantitative morphometric indices of sciatic nerve. PMID- 25448664 TI - Weight based heparin dosing for thromboembolic disease is associated with earlier anticoagulation in surgical patients. AB - INTRODUCTION: Achievement of early therapeutic anticoagulation with unfractionated heparin (UFH) is associated with improved outcomes in thromboembolic disease. Weight based UFH expedites time to therapeutic anticoagulation. Treatment with UFH is challenging in surgical patients due to their high propensity for bleeding. We sought to test the hypothesis that an initial weight based UFH infusion in surgical patients increases the percentage of patients who achieve early therapeutic anticoagulation without increasing the risk of hemorrhagic events. METHODS: Using a non-concurrent retrospective cohort study design, adult surgical patients receiving UFH for venous thromboembolism (VTE) at a tertiary care center were included. Two groups were identified: the weight based (WB) and the under-dosed (UD) heparin groups. For our primary outcome, we compared percentage of patients in each group that achieved a therapeutic PTT within 24 h. Secondary outcomes included the incidence of supratherapeutic PTT levels, hemorrhagic events, and complications associated with VTE. RESULTS: 73 subjects met study criteria, which included 8 subjects in the WB group and 65 in the UD group. The demographic, baseline laboratory, admitting service and type of VTE were similar between the 2 groups. The percentages of WB and UD subjects who achieved a therapeutic PTT within 24 h were 75% and 28%, respectively (p < 0.01). There was no difference in the incidence of supratherapeutic PTT or hemorrhagic events. CONCLUSION: Surgical patients who received an initial weight based UFH infusion achieved earlier therapeutic anticoagulation compared to under-dosed UFH without increasing the occurrence of supratherapeutic PTT levels or hemorrhagic events. PMID- 25448665 TI - An exploration of the use of social media by surgical colleges. AB - BACKGROUND: Social media use has become common for organisations in surgery, however the nature and reach of these communications is unknown. This study aimed to characterise and compare the use of "Twitter" by five prominent organisations in surgery. STUDY DESIGN: Data were collected from Twitter and the scale, reach, nature and sentiment of messages analysed. Message influence was determined and content analysed by frequency and association using hierarchical clustering and network analysis. Poisson regression was used to compare institutional message and "re-tweet" counts. RESULTS: 7712 messages were analysed from a four-year period up to 13th April 2013. The American College of Surgeons (ACS) had tweeted most and posted the greatest number of messages per day (3.3/day). The number of followers reflects social reach and the Royal College of Surgeons of England (RCSEng) had the greatest number (11,600) followed by the ACS (7320). The number of "retweets" a message receives is a measure of influence with the RCSEng (2.0) demonstrating a significantly greater count than the Royal College of Surgeons of Ireland (RCSI; 0.8, p < 0.001) and the ACS (1.3, p < 0.001). Followers of the RCSEng and ACS appeared most influential. Terms relating to education feature prominently in messages posted by the RCSEng and RCSEd, but less so in those from the RCSI and ACS. Education and training terms were highly correlated with "events". CONCLUSIONS: Surgical colleges have significant international reach through social media. UK colleges frequently communicate about education/training opportunities while the ACS focuses on patient-related matters. Only one organisation was found to have an explicit social media policy, which would be considered best practice and can focus on-line activity. PMID- 25448666 TI - Laparoscopic splenectomy for medically refractory immune thrombocytopenia (ITP): a retrospective cohort study on longtime response predicting factors based on consensus criteria. AB - BACKGROUND: Laparoscopic splenectomy has been proposed to be the standard therapy for adult patients with medically refractory immune thrombocytopenia (ITP). However, due to inconsistent definitions of response, variable rates of long term response have been reported. Furthermore, new medical treatment options are currently challenging the role of splenectomy. The aims of this study were to (1) analyze long term response after splenectomy according to recently defined consensus criteria, (2) identify possible predictive response factors. METHODS: A case series of 72 consecutive patients with ITP undergoing laparoscopic splenectomy was retrospectively studied using univariate and multivariate analysis as well as logrank tests. RESULTS: Median follow-up was 32 (2-110) months. Mortality was 0% and morbidity was 8.2%. Response to splenectomy was achieved in of 63/72 patients (87.5%). Loss of response occurred in 19/63 (30.2%) in median after 3 (range 2-42) months. Preoperative platelet counts after boosting with steroids and immunoglobulins as well as the postoperative rise in platelet counts were statistically significant factors for response upon both univariate and multivariate analysis, whereas age, gender, body mass index, ASA classification, disease duration, accessory spleens, splenic weight, conversion to open surgery, or perioperative complications were not. Patients with a postoperative rise in platelet counts >150,000/MUL had a significant better chance on stable long term response than those with a smaller increment (P < 0.001). CONCLUSIONS: Laparoscopic splenectomy is an effective and safe treatment option in order to obtain stable long term response in patients with ITP. Perioperative platelet counts are predictive factors of long term response. PMID- 25448667 TI - The effect of relaparotomy timing on wound healing in an animal model. AB - BACKGROUND: The effect of the timing of the second laparotomy on wound healing is not clear. In an experimental study in rats, we aimed to investigate the effect of timing on wound healing after reoperations on the same surgical site. MATERIAL AND METHODS: Forty-eight rats were divided into four groups. The control group (GC) didn't have another laparotomy whereas the relaparotomies on the same surgical site were performed either on the 3rd, 15th or the 30th postoperative days in the three study groups (G3, G15, G30 respectively). The midline tension pressure, collagen types I, III and, histological analysis were performed from the specimens in order to assess the wound healing and strength. RESULTS: The tensile strength was the highest in GC and decreased gradually in G3, G15 and G30, the difference between the groups did not reach statistical significance. Higher collagen levels, increased fibrosis, and large defects were observed in relaparotomy groups than CG. The musculoaponeurotic gap was shortest in GC when compared to other three relaparotomy groups (P < 0.001) and, it was the longest in G30 (P = 0.004 between G3 and G30). CONCLUSIONS: Although non-statistically significant the gradual decrease in the tensile strength and the statistically significant increase in the musculoaponeurotic gap with time point out the importance of the timing of relaparotomy in the healing process. Early relaparotomies do not disrupt the healing process as much as relaparotomy performed later. PMID- 25448668 TI - Evaluation of digital infra-red thermal imaging as an adjunctive screening method for breast carcinoma: a pilot study. AB - BACKGROUND: Early screening plays a pivotal role in management of breast cancer. Given the socio-economic situation in India, there is a strong felt need for a screening tool which reaches the masses rather than waiting for the masses to reach tertiary centers to be screened. Digital infra-red thermal imaging (DITI) or breast thermography as a screening test offers this possibility and needs to be carefully assessed in Indian scenario. METHODS: The study involved 1008 female patients of age 20-60 years that had not been diagnosed of cancer of breast earlier. All the subjects in this population were screened for both the breasts using DITI. Based on the measured temperature gradients (DeltaT) in thermograms, the subjects were classified in one of the three groups, normal (DeltaT <= 2.5), abnormal (DeltaT > 2.5, <3) and potentially having breast cancer (DeltaT >= 3). All those having (DeltaT > 2.5) underwent triple assessment that consisted of clinical examination, radiological and histopathological examination. Those with normal thermograms were subjected to only clinical examination. RESULTS: Forty nine female breasts had thermograms with temperature gradients exceeding 2.5 and were subjected to triple assessment. Forty one of these which had DeltaT >= 3 were proven to be having cancer of breast and were offered suitable treatment. Eight thermograms had temperature gradients exceeding 2.5 but less than 3. Most of these were lactating mothers or had fibrocystic breast diseases. As a screening modality, DITI showed sensitivity of 97.6%, specificity of 99.17%, positive predictive value 83.67% and negative predictive value 99.89%. CONCLUSION: Based on the results of this study involving 1008 subjects for screening of breast cancer, thermography turns out to be a very useful tool for screening. Because it is non-contact, pain-free, radiation free and comparatively portable it can be used in as a proactive technique for detection of breast carcinoma. PMID- 25448669 TI - Pancreaticogastrostomy or pancreaticojejunostomy? Methods of digestive continuity reconstruction after pancreaticodudenectomy: a meta-analysis of randomized controlled trials. AB - BACKGROUND AND AIMS: Reconstruction of digestive tract after pancreaticodudenectomy now has been proved associated with pancreatic fistula and complication incidence. The meta-analysis was conducted at the appropriate time enough randomized controlled trials were reported. METHODS: Systematically literature search was performed through PubMed, EMBASE and Cochrane Library database without restriction to regions, or languages, only randomized controlled trials was included. 7 studies compared pancreatogastrostomy with pancreaticojejunostomy were included for meta-analysis. Fixed and random-effects models were used to measure the pooled estimates. RESULTS: Patient underwent pancreatogastrostomy after pancreatoduodenectomy suffered less pancreatic fistula(p = 0.001) and bile leakage (p = 0.02), while the operative time, hospital stay, delayed gastric emptying and overall morbidity were comparable. CONCLUSION: Pancreatogastrostomy is a recommended anastomosis technique according to the meta-analysis due to minimize incidence of pancreatic fistula and bile leakage. PMID- 25448670 TI - Sleeve gastrectomy. A point of technique. PMID- 25448671 TI - Life and work of professor Zofia Umiastowska-Sawicka in perspective of development of Polish pediatric surgery after World War Two - 'Hinc itur ad astra/thus one goes to the stars'. PMID- 25448672 TI - Combining interscalene brachial plexus block with intravenous-inhalation combined anesthesia for upper extremity fractures surgery: a randomized controlled trial. AB - BACKGROUND: A parallel-group randomized controlled trial (RCT) was conducted to evaluate the effect of combining the interscalene brachial plexus block (IBPB) with Intravenous-inhalation combined anesthesia to isolated Intravenous inhalation anesthesia in the upper extremity fractures surgery of elderly patients. METHODS: One hundred elderly patients who underwent upper extremity surgery were randomly assigned to received isolated Intravenous-inhalation combined anesthesia (group CI, n = 50) and IBPB associated with Intravenous inhalation combined anesthesia (group NB, n = 50). Associated side effects, recovery time after operation, as well as the dose of intraoperative vasoactive agents and auxiliary drugs were noted. RESULTS: The two groups were not significantly different in gender (P = 0.539), ages (P = 0.683) and weight (P = 0.212). Five patients (10%) in the group NB and 17 patients (34%) in the group CI suffered from preoperative hypotension (P = 0.004). Besides, lower incidence of other adverse effects such as mental stress, incision pain and hypertension were also found in the group NB; however, the differences were not statistically significant (P > 0.05). The consumption of general anesthetics in the group NB was significantly less than that of the group CI (propofol, P = 0.004; lsoflurane, P < 0.001), and the recovery time of the group NB was significantly shorter than that of the group CI (P = 0.020). CONCLUSION: Combining IBPB with Intravenous-inhalation combined anesthesia in elderly patients hold a greater potential for upper extremity fractures surgery due to its improved clinical effectiveness and fewer side effects. PMID- 25448674 TI - Molecular recognition in the interaction of chloroplast 2-Cys peroxiredoxin with NADPH-thioredoxin reductase C (NTRC) and thioredoxin x. AB - In addition to the standard NADPH thioredoxin reductases (NTRs), plants hold a plastidic NTR (NTRC), with a thioredoxin module fused at the C-terminus. NTRC is an efficient reductant of 2-Cys peroxiredoxins (2-Cys Prxs). The interaction of NTRC and chloroplastic thioredoxin x with 2-Cys Prxs has been confirmed in vivo, by bimolecular fluorescence complementation (BiFC) assays, and in vitro, by isothermal titration calorimetry (ITC) experiments. In comparison with thioredoxin x, NTRC interacts with 2-Cys Prx with higher affinity, both the thioredoxin and NTR domains of NTRC contributing significantly to this interaction, as demonstrated by using the NTR and thioredoxin modules of the enzyme expressed separately. The presence of the thioredoxin domain seems to prevent the interaction of NTRC with thioredoxin x. PMID- 25448675 TI - FERM domain-containing protein FRMD5 regulates cell motility via binding to integrin beta5 subunit and ROCK1. AB - FRMD5 is a novel FERM domain-containing protein depicted in tumor progression. However, the mechanisms underlying FRMD5 inhibition of cell migration is largely unknown. Here, we show that FRMD5 regulates cell migration by interacting with integrin beta5 cytoplasmic tail and ROCK1 in human lung cancer cells. FRMD5 promotes cell-matrix adhesion and cell spreading on vitronectin, and thus inhibits cell migration. Furthermore, FRMD5 interacts with ROCK1 and inhibits its activation that leads to the inhibition of myosin light chain phosphorylation and the actin stress fiber formation. Taken together, these findings demonstrate that the putative tumor suppressive protein FRMD5 regulates tumor cell motility via a dual pathway involving FRMD5 binding to integrin beta5 tail and to ROCK1. PMID- 25448676 TI - The vertebrate muscle-specific RING finger protein family includes MuRF4--a novel, conserved E3-ubiquitin ligase. AB - Muscle-specific RING finger (MuRF) proteins are E3-ubiquitin ligases and key regulators of muscle growth and turnover. Here, using a range of phylogenomic approaches, we established the complete-definitive MuRF family of vertebrates. Adding to recognized MuRF1, 2 and 3, we describe a novel family member, hereafter MuRF4, which was independently lost during placental mammal and bird evolution, but is otherwise conserved. MuRF4 transcripts were expressed in heart and skeletal muscles of zebrafish, but were barely detectable in striated muscles of adult anole lizards. We also demonstrate that MuRF1 underwent retrotransposition in the teleost fish ancestor, before the retrogene fully replaced the original gene and muscle-specific function. PMID- 25448673 TI - Colonic diverticulitis in chemotherapy patients: should operative indications change? A retrospective cohort study. AB - INTRODUCTION: Management of the immunosuppressed patient with diverticular disease remains controversial. We report the largest series of colon cancer patients undergoing chemotherapy and hospitalized for acute diverticulitis, to determine whether recent treatment with systemic chemotherapy is associated with increased risk for/increased severity of recurrent diverticulitis. METHODS: Retrospective cohort study of adult patients hospitalized for an initial episode of acute colonic diverticulitis at Memorial Sloan Kettering Cancer Center, 1988 2004. Outcomes in patients receiving systemic chemotherapy within one month of admission for diverticulitis ("Chemo") were compared to outcomes of patients not receiving chemotherapy within the past month ("No-chemo"). RESULTS: A total 131 patients met inclusion criteria. Chemo patients did not differ significantly from No-chemo group in terms of severity of acute diverticulitis at index admission (13.2% vs. 4.4%, respectively, p = 0.12), resumption of chemotherapy (median 2 months), failure of non-operative management (13.2% vs 4.4%, respectively, p = 0.12), frequency of recurrence (20.5% vs 18.5%), hospital length of stay (p = 0.08), and likelihood of interval resection (24.0% vs. 16.2%, respectively, p = 0.39). Chemo patients recurred with more severe disease, were more likely to undergo emergent surgery (75.0% vs. 23.5%, respectively, p = 0.03), and were more likely to be diverted (100.0% vs. 25.0%, respectively, p = 0.03). Chemo patients were significantly more likely to incur a postoperative complication (100% vs 9.1% p < 0.01) following interval resection. Overall mortality was significantly higher in the Chemo vs. No-chemo group. Median survival in Chemo patients was 3.4 years; in No-chemo patients, median survival was not reached at 10 years. CONCLUSION: Our data do not support routine elective surgery for acute diverticulitis in patients receiving chemotherapy. Non-operative management in the acute or interval setting appears preferable whenever possible. PMID- 25448677 TI - Sites and functional consequence of VDAC-alkylphenol anesthetic interactions. AB - General anesthetics have previously been shown to bind mitochondrial VDAC. Here, using a photoactive analog of the anesthetic propofol, we determined that alkylphenol anesthetics bind to Gly56 and Val184 on rat VDAC1. By reconstituting rat VDAC into planar bilayers, we determined that propofol potentiates VDAC gating with asymmetry at the voltage polarities; in contrast, propofol does not affect the conductance of open VDAC. Additional experiments showed that propofol also does not affect gramicidin A properties that are sensitive to lipid bilayer mechanics. Together, this suggests propofol affects VDAC function through direct protein binding, likely at the lipid-exposed channel surface, and that gating can be modulated by ligand binding to the distal ends of VDAC beta-strands where Gly56 and Val184 are located. PMID- 25448678 TI - Oxytocinergic circuit from paraventricular and supraoptic nuclei to arcuate POMC neurons in hypothalamus. AB - Intracerebroventricular injection of oxytocin (Oxt), a neuropeptide produced in hypothalamic paraventricular (PVN) and supraoptic nuclei (SON), melanocortin dependently suppresses feeding. However, the underlying neuronal pathway is unclear. This study aimed to determine whether Oxt regulates propiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus. Intra-ARC injection of Oxt decreased food intake. Oxt increased cytosolic Ca(2+) in POMC neurons isolated from ARC. ARC POMC neurons expressed Oxt receptors and were contacted by Oxt terminals. Retrograde tracer study revealed the projection of PVN and SON Oxt neurons to ARC. These results demonstrate the novel oxytocinergic signaling from PVN/SON to ARC POMC, possibly regulating feeding. PMID- 25448679 TI - Reactive oxygen species increase HEPN1 expression via activation of the XBP1 transcription factor. AB - Hepatocellular carcinoma downregulated 1 (HEPN1), a cell growth arrest- and apoptosis-related gene, is suppressed in hepatocellular carcinoma (HCC). However, transcriptional control of HEPN1 has not been characterized. Here, we show that exposure to reactive oxygen species (ROS) leads to upregulation of the mRNA expression of HEPN1 in HCC cell lines. Mechanistically, ROS increase production of an alternately spliced form of X-box binding protein 1 (XBP1s) and XBP1s increases HEPN1 expression by binding to the HEPN1 promoter, thereby acting as a transcriptional activator. Finally, HEPN1 overexpression increases the expression of p53, p21, and Bax, all of which are ROS-upregulated proteins. PMID- 25448680 TI - Mode of substrate recognition by the Josephin domain of ataxin-3, which has an endo-type deubiquitinase activity. AB - Ataxin-3, which is encoded by a gene that has been associated with Machado-Joseph disease, contains a catalytic N-terminal Josephin domain with deubiquitinase activity. Here, we show that the Josephin domain of ataxin 3 catalyzes endo-type cleavage of Lys48-linked polyubiquitin. Furthermore, NMR data obtained following site-specific paramagnetic spin labeling of Lys48-linked di-ubiquitin revealed that both ubiquitin units interact with the Josephin domain, with the C-terminal Gly76 of the proximal unit being situated in the vicinity of the catalytic triad of Josephin domain. Our results help to elucidate how the substrate is recognized by the Josephin domain and properly positioned for an endo-type deubiquitination reaction. PMID- 25448681 TI - Expanding the SRI domain family: a common scaffold for binding the phosphorylated C-terminal domain of RNA polymerase II. AB - The SRI domain is a small three-helix domain originally discovered near the C terminus of both histone methyltransferase SETD2 and helicase RECQL5. The SRI domain binds to the C-terminal repeat domain of the largest subunit of RNA polymerase II, allowing SETD2 and RECQL5 to regulate various mechanisms associated with RNA transcription. Using original tools to detect common patterns in distantly related sequences, we have identified SRI domains in several additional proteins, most of which are involved in RNA metabolism. Combining sequence analysis with structural prediction, we show that this domain family is more diverse than previously thought and we predict critical structural and functional features. PMID- 25448682 TI - Suppression of NF-kappaB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone. AB - Inflammatory bowel disease (IBD) affects millions of people worldwide. Although the etiology of this disease is uncertain, accumulating evidence indicates a key role for the activated mucosal immune system. In the present study, we examined the effects of the natural compound fraxinellone on dextran sulfate sodium (DSS) induced colitis in mice, an animal model that mimics IBD. Treatment with fraxinellone significantly reduced weight loss and diarrhea in mice and alleviated the macroscopic and microscopic signs of the disease. In addition, the activities of myeloperoxidase and alkaline phosphatase were markedly suppressed, while the levels of glutathione were increased in colitis tissues following fraxinellone treatment. This compound also decreased the colonic levels of interleukin (IL)-1beta, IL-6, IL-18 and tumor necrosis factor (TNF)-alpha in a concentration-dependent manner. These effects of fraxinellone in mice with experimental colitis were attributed to its inhibition of CD11b(+) macrophage infiltration. The mRNA levels of macrophage-related molecules in the colon, including intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2), were also markedly inhibited following fraxinellone treatment. The results from in vitro assays showed that fraxinellone significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide (NO), IL-1beta and IL 18 as well as the activity of iNOS in both THP-1 cells and mouse primary peritoneal macrophages. The mechanisms responsible for these effects were attributed to the inhibitory role of fraxinellone in NF-kappaB signaling and NLRP3 inflammasome activation. Overall, our results support fraxinellone as a novel drug candidate in the treatment of colonic inflammation. PMID- 25448684 TI - Eryptosis in lead-exposed workers. AB - Eryptosis is a physiological phenomenon in which old and damaged erythrocytes are removed from circulation. Erythrocytes incubated with lead have exhibited major eryptosis. In the present work we found evidence of high levels of eryptosis in lead exposed workers possibly via oxidation. Blood samples were taken from 40 male workers exposed to lead (mean blood lead concentration 64.8MUg/dl) and non exposed workers (4.2MUg/dl). The exposure to lead produced an intoxication characterized by 88.3% less delta-aminolevulinic acid dehydratase (deltaALAD) activity in lead exposed workers with respect to non-lead exposed workers. An increment of oxidation in lead exposed workers was characterized by 2.4 times higher thiobarbituric acid-reactive substance (TBARS) concentration and 32.8% lower reduced/oxidized glutathione (GSH/GSSG) ratio. Oxidative stress in erythrocytes of lead exposed workers is expressed in 192% higher free calcium concentration [Ca(2+)]i and 1.6 times higher MU-calpain activity with respect to non-lead exposed workers. The adenosine triphosphate (ATP) concentration was not significantly different between the two worker groups. No externalization of phosphatidylserine (PS) was found in non-lead exposed workers (<0.1%), but lead exposed workers showed 2.82% externalization. Lead intoxication induces eryptosis possibly through a molecular pathway that includes oxidation, depletion of reduced glutathione (GSH), increment of [Ca(2+)], MU-calpain activation and externalization of PS in erythrocytes. Identifying molecular signals that induce eryptosis in lead intoxication is necessary to understand its physiopathology and chronic complications. PMID- 25448683 TI - Post-exposure administration of diazepam combined with soluble epoxide hydrolase inhibition stops seizures and modulates neuroinflammation in a murine model of acute TETS intoxication. AB - Tetramethylenedisulfotetramine (TETS) is a potent convulsant poison for which there is currently no approved antidote. The convulsant action of TETS is thought to be mediated by inhibition of type A gamma-aminobutyric acid receptor (GABAAR) function. We, therefore, investigated the effects of post-exposure administration of diazepam, a GABAAR positive allosteric modulator, on seizure activity, death and neuroinflammation in adult male Swiss mice injected with a lethal dose of TETS (0.15mg/kg, ip). Administration of a high dose of diazepam (5mg/kg, ip) immediately following the second clonic seizure (approximately 20min post-TETS injection) effectively prevented progression to tonic seizures and death. However, this treatment did not prevent persistent reactive astrogliosis and microglial activation, as determined by GFAP and Iba-1 immunoreactivity and microglial cell morphology. Inhibition of soluble epoxide hydrolase (sEH) has been shown to exert potent anti-inflammatory effects and to increase survival in mice intoxicated with other GABAAR antagonists. The sEH inhibitor TUPS (1mg/kg, ip) administered immediately after the second clonic seizure did not protect TETS intoxicated animals from tonic seizures or death. Combined administration of diazepam (5mg/kg, ip) and TUPS (1mg/kg, ip, starting 1h after diazepam and repeated every 24h) prevented TETS-induced lethality and influenced signs of neuroinflammation in some brain regions. Significantly decreased microglial activation and enhanced reactive astrogliosis were observed in the hippocampus, with no changes in the cortex. Combining an agent that targets specific anti inflammatory mechanisms with a traditional antiseizure drug may enhance treatment outcome in TETS intoxication. PMID- 25448686 TI - The evaluation of new multi-material human soft tissue simulants for sports impact surrogates. AB - Previous sports impact reconstructions have highlighted the inadequacies in current measures to evaluate the effectiveness of personal protective equipment (PPE) and emphasised the need for improved impact surrogates that provide a more biofidelic representation of human impact response. The skin, muscle and subcutaneous adipose tissues were considered to constitute the structures primarily governing the mechanical behaviour of the human body segment. A preceding study by Payne et al. (in press) investigated the formulation and characterisation of muscle tissue simulants. The present study investigates the development of bespoke blends of additive cure polydimethysiloxane (PDMS) silicones to represent both skin and adipose tissues using the same processes previously reported. These simulants were characterised mechanically through a range of strain rates and a range of hyperelastic and viscoelastic constitutive models were evaluated to describe their behaviour. To explore the worth of the silicone simulants, finite element (FE) models were developed using anthropometric parameters representative of the human thigh segment, derived from the Visible Human Project. The multi-material silicone construction was validated experimentally and compared with both organic tissue data from literature and commonly used single material simulants: Dow Corning Silastic 3480 series silicones and ballistics gelatin when subject to a representative sports specific knee impact. Superior biofidelic performance is reported for the PDMS silicone formulations and surrogate predictions. PMID- 25448685 TI - Enhanced susceptibility of ovaries from obese mice to 7,12 dimethylbenz[a]anthracene-induced DNA damage. AB - 7,12-Dimethylbenz[a]anthracene (DMBA) depletes ovarian follicles and induces DNA damage in extra-ovarian tissues, thus, we investigated ovarian DMBA-induced DNA damage. Additionally, since obesity is associated with increased offspring birth defect incidence, we hypothesized that a DMBA-induced DNA damage response (DDR) is compromised in ovaries from obese females. Wild type (lean) non agouti (a/a) and KK.Cg-Ay/J heterozygote (obese) mice were dosed with sesame oil or DMBA (1mg/kg; intraperitoneal injection) at 18weeks of age, for 14days. Total ovarian RNA and protein were isolated and abundance of Ataxia telangiectasia mutated (Atm), X-ray repair complementing defective repair in Chinese hamster cells 6 (Xrcc6), breast cancer type 1 (Brca1), Rad 51 homolog (Rad51), poly [ADP-ribose] polymerase 1 (Parp1) and protein kinase, DNA-activated, catalytic polypeptide (Prkdc) were quantified by RT-PCR or Western blot. Phosphorylated histone H2AX (gammaH2AX) level was determined by Western blotting. Obesity decreased (P<0.05) basal protein abundance of PRKDC and BRCA1 proteins but increased (P<0.05) gammaH2AX and PARP1 proteins. Ovarian ATM, XRCC6, PRKDC, RAD51 and PARP1 proteins were increased (P<0.05) by DMBA exposure in lean mice. A blunted DMBA-induced increase (P<0.05) in XRCC6, PRKDC, RAD51 and BRCA1 was observed in ovaries from obese mice, relative to lean counterparts. Taken together, DMBA exposure induced gammaH2AX as well as the ovarian DDR, supporting that DMBA causes ovarian DNA damage. Additionally, ovarian DDR was partially attenuated in obese females raising concern that obesity may be an additive factor during chemical-induced ovotoxicity. PMID- 25448688 TI - Motor imagery of voluntary muscle relaxation induces temporal reduction of corticospinal excitability. AB - Voluntary muscle relaxation is an "active process" requiring cortical activation. However, cortical activation during motor imagery of muscle relaxation has not been well understood. The purpose of this study was to clarify time-dependent changes in corticospinal excitability during the imagery of muscle relaxation. Ten participants imagined volitional muscle relaxation from an imagined pinching with their right index finger and thumb in response to an auditory cue. Transcranial magnetic stimulation was applied at the left primary motor area of the first dorsal interosseous (FDI) muscle at different time intervals after the auditory cue. Motor evoked potentials (MEPs) were recorded from the right hand and forearm muscles. The MEP amplitudes of the FDI and the synergist temporally decreased after the auditory cue as compared with those present in the resting condition. Our finding indicates that motor imagery of muscle relaxation induces a temporal reduction of the corticospinal excitability related to the targeted muscle. PMID- 25448687 TI - Salience network and parahippocampal dopamine dysfunction in memory-impaired Parkinson disease. AB - OBJECTIVE: Patients with Parkinson disease (PD) and mild cognitive impairment (MCI) are vulnerable to dementia and frequently experience memory deficits. This could be the result of dopamine dysfunction in corticostriatal networks (salience, central executive networks, and striatum) and/or the medial temporal lobe. Our aim was to investigate whether dopamine dysfunction in these regions contributes to memory impairment in PD. METHODS: We used positron emission tomography imaging to compare D2 receptor availability in the cortex and striatal (limbic and associative) dopamine neuron integrity in 4 groups: memory-impaired PD (amnestic MCI; n = 9), PD with nonamnestic MCI (n = 10), PD without MCI (n = 11), and healthy controls (n = 14). Subjects were administered a full neuropsychological test battery for cognitive performance. RESULTS: Memory impaired patients demonstrated more significant reductions in D2 receptor binding in the salience network (insular cortex and anterior cingulate cortex [ACC] and the right parahippocampal gyrus [PHG]) compared to healthy controls and patients with no MCI. They also presented reductions in the right insula and right ACC compared to nonamnestic MCI patients. D2 levels were correlated with memory performance in the right PHG and left insula of amnestic patients and with executive performance in the bilateral insula and left ACC of all MCI patients. Associative striatal dopamine denervation was significant in all PD patients. INTERPRETATION: Dopaminergic differences in the salience network and the medial temporal lobe contribute to memory impairment in PD. Furthermore, these findings indicate the vulnerability of the salience network in PD and its potential role in memory and executive dysfunction. PMID- 25448689 TI - A function for the Joubert syndrome protein Arl13b in ciliary membrane extension and ciliary length regulation. AB - Cilia perform a variety of functions in a number of developmental and physiological contexts, and are implicated in the pathogenesis of a wide spectrum of human disorders. While the ciliary axoneme is assembled by intraflagellar transport, how ciliary membrane length is regulated is not completely understood. Here, we show that zebrafish embryos as well as mammalian cells overexpressing the ciliary membrane protein Arl13b, an ARF family small GTPase that is essential for ciliary differentiation, showed pronounced increase in ciliary length. Intriguingly, this increase in cilia length occurred as a function of the amounts of overexpressed Arl13b. While the motility of Arl13b overexpressing excessively long motile cilia was obviously disrupted, surprisingly, the abnormally long immotile primary cilia seemed to retain their signaling capacity. arl13b is induced by FoxJ1 and Rfx, and these ciliogenic transcription factors are unable to promote ciliary length increase when Arl13b activity is inhibited. Conversely, overexpression of Arl13b was sufficient to restore ciliary length in zebrafish embryos deficient in FoxJ1 function. We show that Arl13b increases cilia length by inducing protrusion of the ciliary membrane, which is then followed by the extension of the axonemal microtubules. Using mutant versions of Arl13b, one of which has been shown to be causative of the ciliopathy Joubert syndrome, we establish that the GTPase activity of the protein is essential for ciliary membrane extension. Taken together, our findings identify Arl13b as an important effector of ciliary membrane biogenesis and ciliary length regulation, and provide insights into possible mechanisms of dysfunction of the protein in Joubert syndrome. PMID- 25448690 TI - A method for using direct injection of plasmid DNA to study cis-regulatory element activity in F0 Xenopus embryos and tadpoles. AB - The ability to express exogenous reporter genes in intact, externally developing embryos, such as Xenopus, is a powerful tool for characterizing the activity of cis-regulatory gene elements during development. Although methods exist for generating transgenic Xenopus lines, more simplified methods for use with F0 animals would significantly speed the characterization of these elements. We discovered that injecting 2-cell stage embryos with a plasmid bearing a phiC31 integrase-targeted attB element and two dual beta-globin HS4 insulators flanking a reporter transgene in opposite orientations relative to each other yielded persistent expression with sufficiently high penetrance for characterizing the activity of the promoter without having to coinject integrase RNA. Expression began appropriately during development and persisted into swimming tadpole stages without perturbing the expression of the cognate endogenous gene. Coinjected plasmids having the same elements but expressing different reporter proteins were reliably coexpressed within the same cells, providing a useful control for variations in injections between animals. To overcome the high propensity of these plasmids to undergo recombination, we developed a method for generating them using conventional cloning methods and DH5alpha cells for propagation. We conclude that this method offers a convenient and reliable way to evaluate the activity of cis-regulatory gene elements in the intact F0 embryo. PMID- 25448691 TI - Mechanics of blastopore closure during amphibian gastrulation. AB - Blastopore closure in the amphibian embryo involves large scale tissue reorganization driven by physical forces. These forces are tuned to generate sustained blastopore closure throughout the course of gastrulation. We describe the mechanics of blastopore closure at multiple scales and in different regions around the blastopore by characterizing large scale tissue deformations, cell level shape change and subcellular F-actin organization and by measuring tissue force production and structural stiffness of the blastopore during gastrulation. We find that the embryo generates a ramping magnitude of force until it reaches a peak force on the order of 0.5MUN. During this time course, the embryo also stiffens 1.5 fold. Strain rate mapping of the dorsal, ventral and lateral epithelial cells proximal to the blastopore reveals changing patterns of strain rate throughout closure. Cells dorsal to the blastopore, which are fated to become neural plate ectoderm, are polarized and have straight boundaries. In contrast, cells lateral and ventral to the blastopore are less polarized and have tortuous cell boundaries. The F-actin network is organized differently in each region with the highest percentage of alignment occurring in the lateral region. Interestingly F-actin was consistently oriented toward the blastopore lip in dorsal and lateral cells, but oriented parallel to the lip in ventral regions. Cell shape and F-actin alignment analyses reveal different local mechanical environments in regions around the blastopore, which was reflected by the strain rate maps. PMID- 25448692 TI - Ptch2 shares overlapping functions with Ptch1 in Smo regulation and limb development. AB - Ptch1 and Ptch2 are highly conserved vertebrate homologs of Drosophila ptc, the receptor of the Hedgehog (Hh) signaling pathway. The vertebrate Ptch1 gene encodes a potent tumor suppressor and is well established for its role in embryonic development. In contrast, Ptch2 is poorly characterized and dispensable for embryogenesis. In flies and mice, ptc/Ptch1 controls Hh signaling through the regulation of Smoothened (Smo). In addition, Hh pathway activation also up regulates ptc/Ptch1 expression to restrict the diffusion of the ligand. Recent studies have implicated Ptch2 in this ligand dependent antagonism, however whether Ptch2 encodes a functional Shh receptor remains unclear. In this report, we demonstrate that Ptch2 is a functional Shh receptor, which regulates Smo localization and activity in vitro. We also show that Ptch1 and Ptch2 are co expressed in the developing mouse limb bud and loss of Ptch2 exacerbates the outgrowth defect in the limb-specific Ptch1 knockout mutants, demonstrating that Ptch1 and Ptch2 co-operate in regulating cellular responses to Shh in vivo. PMID- 25448694 TI - PLR-1, a putative E3 ubiquitin ligase, controls cell polarity and axonal extensions in C. elegans. AB - During embryonic development neurons differentiate and extend axons and dendrites that have to reach their appropriate targets. In Caenorhabditis elegans the AVG neuron is the first neuron to extend an axon during the establishment of the ventral nerve cord, the major longitudinal axon tract in the animal. In genetic screens we isolated alleles of plr-1, which caused polarity reversals of the AVG neuron as well as outgrowth and navigation defects of the AVG axon. In addition plr-1 mutants show outgrowth defects in several other classes of neurons as well as the posterior excretory canals. plr-1 is predicted to encode a transmembrane E3 ubiquitin ligase and is widely expressed in the animal including the AVG neuron and the excretory cell. plr-1 has recently been shown to negatively regulate Wnt signalling by removing Wnt receptors from the cell surface. We observed that mutations in a gene reducing Wnt signalling as well as mutations in unc-53/NAV2 and unc-73/Trio suppress the AVG polarity defects in plr-1 mutants, but not the defects seen in other cells. This places plr-1 in a Wnt regulation pathway, but also suggests that plr-1 has Wnt independent functions and interacts with unc-53 and unc-73 to control cell polarity. PMID- 25448693 TI - Sox21 regulates the progression of neuronal differentiation in a dose-dependent manner. AB - Members of the SoxB transcription factor family play critical roles in the regulation of neurogenesis. The SoxB1 proteins are required for the induction and maintenance of a proliferating neural progenitor population in numerous vertebrates, however the role of the SoxB2 protein, Sox21, is less clear due to conflicting results. To clarify the role of Sox21 in neurogenesis, we examined its function in the Xenopus neural plate. Here we report that misexpression of Sox21 expands the neural progenitor domain, and represses neuron formation by binding to Neurogenin (Ngn2) and blocking its function. Conversely, we found that Sox21 is also required for neuron formation, as cells lacking Sox21 undergo cell death and thus are unable to differentiate. Together our data indicate that Sox21 plays more than one role in neurogenesis, where a threshold level is required for cell viability and normal differentiation of neurons, but a higher concentration of Sox21 inhibits neuron formation and instead promotes progenitor maintenance. PMID- 25448695 TI - Quantitative methods for analyzing cell-cell adhesion in development. AB - During development cell-cell adhesion is not only crucial to maintain tissue morphogenesis and homeostasis, it also activates signalling pathways important for the regulation of different cellular processes including cell survival, gene expression, collective cell migration and differentiation. Importantly, gene mutations of adhesion receptors can cause developmental disorders and different diseases. Quantitative methods to measure cell adhesion are therefore necessary to understand how cells regulate cell-cell adhesion during development and how aberrations in cell-cell adhesion contribute to disease. Different in vitro adhesion assays have been developed in the past, but not all of them are suitable to study developmentally-related cell-cell adhesion processes, which usually requires working with low numbers of primary cells. In this review, we provide an overview of different in vitro techniques to study cell-cell adhesion during development, including a semi-quantitative cell flipping assay, and quantitative single-cell methods based on atomic force microscopy (AFM)-based single-cell force spectroscopy (SCFS) or dual micropipette aspiration (DPA). Furthermore, we review applications of Forster resonance energy transfer (FRET)-based molecular tension sensors to visualize intracellular mechanical forces acting on cell adhesion sites. Finally, we describe a recently introduced method to quantitate cell-generated forces directly in living tissues based on the deformation of oil microdroplets functionalized with adhesion receptor ligands. Together, these techniques provide a comprehensive toolbox to characterize different cell-cell adhesion phenomena during development. PMID- 25448696 TI - Differential pleiotropy and HOX functional organization. AB - Key studies led to the idea that transcription factors are composed of defined modular protein motifs or domains, each with separable, unique function. During evolution, the recombination of these modular domains could give rise to transcription factors with new properties, as has been shown using recombinant molecules. This archetypic, modular view of transcription factor organization is based on the analyses of a few transcription factors such as GAL4, which may represent extreme exemplars rather than an archetype or the norm. Recent work with a set of Homeotic selector (HOX) proteins has revealed differential pleiotropy: the observation that highly-conserved HOX protein motifs and domains make small, additive, tissue specific contributions to HOX activity. Many of these differentially pleiotropic HOX motifs may represent plastic sequence elements called short linear motifs (SLiMs). The coupling of differential pleiotropy with SLiMs, suggests that protein sequence changes in HOX transcription factors may have had a greater impact on morphological diversity during evolution than previously believed. Furthermore, differential pleiotropy may be the genetic consequence of an ensemble nature of HOX transcription factor allostery, where HOX proteins exist as an ensemble of states with the capacity to integrate an extensive array of developmental information. Given a new structural model for HOX functional domain organization, the properties of the archetypic TF may require reassessment. PMID- 25448699 TI - Mechanisms of boundary formation by Eph receptor and ephrin signaling. AB - The formation of sharp borders, across which cell intermingling is restricted, has a crucial role in the establishment and maintenance of organized tissues. Signaling of Eph receptors and ephrins underlies formation of a number of boundaries between and within tissues during vertebrate development. Eph-ephrin signaling can regulate several types of cell response-adhesion, repulsion and tension-that can in principle underlie the segregation of cells and formation of sharp borders. Recent studies have implicated each of these cell responses as having important roles at different boundaries: repulsion at the mesoderm ectoderm border, decreased adhesion at the notochord-presomitic mesoderm border, and tension at boundaries within the hindbrain and forebrain. These distinct responses to Eph receptor and ephrin activation may in part be due to the adhesive properties of the tissue. PMID- 25448697 TI - Mapping the dynamic expression of Wnt11 and the lineage contribution of Wnt11 expressing cells during early mouse development. AB - Planar cell polarity (PCP) signaling is an evolutionarily conserved mechanism that coordinates polarized cell behavior to regulate tissue morphogenesis during vertebrate gastrulation, neurulation and organogenesis. In Xenopus and zebrafish, PCP signaling is activated by non-canonical Wnts such as Wnt11, and detailed understanding of Wnt11 expression has provided important clues on when, where and how PCP may be activated to regulate tissue morphogenesis. To explore the role of Wnt11 in mammalian development, we established a Wnt11 expression and lineage map with high spatial and temporal resolution by creating and analyzing a tamoxifen inducible Wnt11-CreER BAC (bacterial artificial chromosome) transgenic mouse line. Our short- and long-term lineage tracing experiments indicated that Wnt11 CreER could faithfully recapitulate endogenous Wnt11 expression, and revealed for the first time that cells transiently expressing Wnt11 at early gastrulation were fated to become specifically the progenitors of the entire endoderm. During mid gastrulation, Wnt11-CreER expressing cells also contribute extensively to the endothelium in both embryonic and extraembryonic compartments, and the endocardium in all chambers of the developing heart. In contrast, Wnt11-CreER expression in the myocardium starts from late-gastrulation, and occurs in three transient, sequential waves: first in the precursors of the left ventricular (LV) myocardium from E7.0 to 8.0; subsequently in the right ventricular (RV) myocardium from E8.0 to 9.0; and finally in the superior wall of the outflow tract (OFT) myocardium from E8.5 to 10.5. These results provide formal genetic proof that the majority of the endocardium and myocardium diverge by mid gastrulation in the mouse, and suggest a tight spatial and temporal control of Wnt11 expression in the myocardial lineage to coordinate with myocardial differentiation in the first and second heart field progenitors to form the LV, RV and OFT. The insights gained from this study will also guide future investigations to decipher the role of non-canonical Wnt/PCP signaling in endoderm development, vasculogenesis and heart formation. PMID- 25448698 TI - The ABC transporter, AbcB3, mediates cAMP export in D. discoideum development. AB - Extracellular cAMP functions as a primary ligand for cell surface cAMP receptors throughout Dictyostelium discoideum development, controlling chemotaxis and morphogenesis. The developmental consequences of cAMP signaling and the metabolism of cAMP have been studied in great detail, but it has been unclear how cells export cAMP across the plasma membrane. Here we show pharmacologically and genetically that ABC transporters mediate cAMP export. Using an evolutionary developmental biology approach, we identified several candidate abc genes and characterized one of them, abcB3, in more detail. Genetic and biochemical evidence suggest that AbcB3 is a component of the cAMP export mechanism in D. discoideum development. PMID- 25448700 TI - Obesity and FTO: Changing Focus at a Complex Locus. AB - The fat mass and obesity-associated (FTO) gene was placed center stage when common intronic variants within the gene were robustly associated with human obesity. Murine models of perturbed Fto expression have shown effects on body weight and composition. However, a clear understanding of the link between FTO intronic variants and FTO activity has remained elusive. Two recent reports now indicate that obesity-associated SNPs appear functionally connected not with FTO but with two neighboring genes: IRX3 and RPGRIP1L. Here, we review these new findings and consider the implications for future analysis of GWAS hits. PMID- 25448701 TI - The FOXO transcription factor DAF-16 bypasses ire-1 requirement to promote endoplasmic reticulum homeostasis. AB - The unfolded protein response (UPR) allows cells to adjust the capacity of the endoplasmic reticulum (ER) to the load of ER-associated tasks. We show that activation of the Caenorhabditis elegans transcription factor DAF-16 and its human homolog FOXO3 restore secretory protein metabolism when the UPR is dysfunctional.We show that DAF-16 establishes alternative ER-associated degradation systems that degrade misfolded proteins independently of the ER stress sensor ire-1 and the ER-associated E3 ubiquitin ligase complex sel-11/sel 1. This is achieved by enabling autophagy-mediated degradation and by increasing the levels of skr-5, a component of an ER associated ubiquitin ligase complex. These degradation systems can act together with the conserved UPR to improve ER homeostasis and ER stress resistance, beyond wild-type levels. Because there is no sensor in the ER that activates DAF-16 in response to intrinsic ER stress, natural or artificial interventions that activate DAF-16 may be useful therapeutic approaches to maintain ER homeostasis. PMID- 25448703 TI - Association of TCR/CD3, PTPN22, CD28 and ZAP70 gene polymorphisms with type 1 diabetes risk in Tunisian population: family based association study. AB - Type 1 diabetes (T1D) is caused by an immune-mediated destruction of the insulin producing beta-cells. Several studies support the involvement of T cell activation molecules in the pathogenesis of T1D. In order to underline the role of the genes involved in this activation pathway, we investigated, using the Sequenom MassARRAY platform, 45 single-nucleotide polymorphisms (SNPs) belonging to TCR/CD3, CD28, ZAP70, and PTPN22 genes in 59 T1D Tunisian families. In the current study, we identified an association with rs706 (Z score=2.782; p=0.005) of TCRbeta gene. We also demonstrated that rs10918706 in the intron of the CD3z gene was associated with increased risk of T1D (Z score 2.137; p=0.032). In the same region, rs2949655 (Z score=2.101; p=0.035) and rs1214611 (Z score=4.036; p=0.00005) showed a genotype association with the risk of T1D. When haplotypes were constructed, GAA haplotype displayed significant association with T1D (Z score=2.135; p=0.032), while GGA haplotype (Z score=-1.988; p=0.046) was negatively associated with the disease. We also identified an association with rs3181096 (Z score=2.177; p=0.029), rs17695937 (Z score =2.111; p=0.034) and rs2488457 (Z score=2.219; p=0.026), respectively of CD28, ZAP70 and PTPN22 genes. In addition, our results suggest a significant effect on T1D susceptibility for AC (Z score=2.30; p=0.02) and CTGGC (Z score=2.309, p=0.02) haplotypes of ZAP70 and PTPN22 genes, respectively. While, the GTCT (Z score=-2.114, p=0.034) and CTAGG (Z score=-2.121, p=0.033) haplotypes of CD28 and PTPN22 genes, may confer protection against T1D. These findings confirm the role of PTPN22 and CD28 involved in the T cell activation pathway in the development of T1D in Tunisian families. Interestingly, ZAP70 and TCRbeta/CD3z seem to contribute to the susceptibility to the disease in our population. However, this finding has to be confirmed in further studies. PMID- 25448705 TI - 1alpha,25-Dihydroxyvitamin D3 upregulates HIF-1 and TREM-1 via mTOR signaling. AB - Triggering receptor expressed on myeloid cells-1 (TREM-1) is induced by 1alpha,25 dihydroxyvitamin D3 (1,25(OH)2D3) in human monocytes/macrophages and epithelial cells. However, little information is available regarding the mechanism of 1,25(OH)2D3-induced TREM-1 expression in human monocytes/macrophages. In this study, 1,25(OH)2D3 was shown to strongly upregulate hypoxia-inducible transcription factor (HIF) in PMA-differentiated U937 cells. However, HIF was not mainly involved in 1,25(OH)2D3-induced TREM-1 expression. Instead, 1,25(OH)2D3 induced expression of TREM-1 was inhibited by rapamycin, a specific inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, indicating the involvement of mTOR. Induction of HIF proteins by 1,25(OH)2D3 was also inhibited by rapamycin. In addition, 1,25(OH)2D3 induced the phosphorylation of p70S6 kinase, a target of mTOR complex 1 (mTORC1). Our results suggest that 1,25(OH)2D3 induces the expression of TREM-1 through the mTOR signaling pathway in human macrophages. PMID- 25448707 TI - A comparative examination of thrombocyte/platelet immunity. AB - Among the cells in the blood vascular system, platelets in mammals and thrombocytes in lower vertebrates are the source of crucial mediators in hemostatic functions. Although these cells have been known to be primarily involved in thrombosis and hemostasis, platelets and thrombocytes have been shown recently to have roles in inflammatory functions and the immune response in general. Thrombocytes/platelets are widely recognized contributors to inflammatory responses upon stimulation with various microbial stimulants. In recent years, the role of platelets has been shown in adaptive immune responses. Therefore, thrombocytes/platelets should be considered as specialized immune cells that not only resemble innate effector cells in function but also have a role in affecting adaptive immunity through cellular contact and interaction with antigen presenting cells and lymphocytes. PMID- 25448704 TI - Single-chain anti-idiotypic antibody retains its specificity to porcine reproductive and respiratory syndrome virus GP5. AB - Monoclonal anti-idiotypic antibody (Mab2-5G2) raised against idiotypic antibodies to membrane glycoprotein GP5 of porcine reproductive and respiratory syndrome virus (PRRSV). The variable regions of the heavy chain (VH) and light chain (VL) of Mab2-5G2 were cloned and connected with a (Gly4Ser)3 linker. The recombinant scFv gene was cloned into the pEasy-E1 vector and expressed in E. coli as inclusion bodies. The expressed scFv-His proteins renatured in a pH and urea gradient buffer retained the same immunological properties as that of Mab2-5G2. Renatured scFv-His protein retained the same characteristics as that of Mab2-5G2 by recognizing and binding to Marc-145 cells. Furthermore, renatured scFv-His along with Mab2-5G2 were used to immunize rabbits to produce anti-anti-idiotypic antibodies (Ab3) that neutralized PRRSV infection of Marc-145 cells. These results demonstrated that the expressed scFv-His protein possessed the same characteristics of Mab2-5G2 and will be suitable for future investigations of Mab2-5G2 antibody structure and its ability to interact with potential PRRSV cellular receptor as well as immunological properties against PRRSV infection. PMID- 25448706 TI - Differential requirements of MyD88 and TRIF pathways in TLR4-mediated immune responses in murine B cells. AB - LPS stimulates the TLR4/Myeloid differentiation protein-2 (MD-2) complex and promotes a variety of immune responses in B cells. TLR4 has two main signaling pathways, MyD88 and Toll/IL-1R (TIR)-domain-containing adaptor-inducing interferon-beta (TRIF) pathways, but relatively few studies have examined these pathways in B cells. In this study, we investigated MyD88- or TRIF-dependent LPS responses in B cells by utilizing their knockout mice. Compared with wild-type (WT) B cells, MyD88(-/-) B cells were markedly impaired in up-regulation of CD86 and proliferation induced by lipid A moiety of LPS. TRIF(-/-) B cells were also impaired in these responses compared with WT B cells, but showed better responses than MyD88(-/-) B cells. Regarding class switch recombination (CSR) elicited by lipid A plus IL-4, MyD88(-/-) B cells showed similar patterns of CSR to WT B cells. However, TRIF(-/-) B cells showed the impaired in the CSR. Compared with WT and MyD88(-/-) B cells, TRIF(-/-) B cells exhibited reduced cell division, fewer IgG1(+) cells per division, and decreased activation-induced cytidine deaminase (Aicda) mRNA expression in response to lipid A plus IL-4. Finally, IgG1 production to trinitrophenyl (TNP)-LPS immunization was impaired in TRIF(-/-) mice, while MyD88(-/-) mice exhibited increased IgG1 production. Thus, MyD88 and TRIF pathways differently regulate TLR4-induced immune responses in B cells. PMID- 25448702 TI - AMPK--sensing energy while talking to other signaling pathways. AB - The AMP-activated protein kinase (AMPK) is a sensor of cellular energy and nutrient status, expressed almost universally in eukaryotes as heterotrimeric complexes comprising catalytic (alpha) and regulatory (beta and gamma) subunits. Along with the mechanistic target of rapamycin complex-1 (mTORC1), AMPK may have been one of the earliest signaling pathways to have arisen during eukaryotic evolution. Recent crystal structures have provided insights into the mechanisms by which AMPK is regulated by phosphorylation and allosteric activators. Another recent development has been the realization that activation of AMPK by the upstream kinase LKB1 may primarily occur not in the cytoplasm, but at the surface of the lysosome, where AMPK and mTORC1 are regulated in a reciprocal manner by the availability of nutrients. It is also becoming clear that there is a substantial amount of crosstalk between the AMPK pathway and other signaling pathways that promote cell growth and proliferation, and this will be discussed. PMID- 25448708 TI - Thymic precursors of TCRalphabeta(+)CD8alphaalpha(+) intraepithelial lymphocytes are negative for CD103. AB - CD5(+)TCRalphabeta(+) cells in CD4(-)CD8(-) double negative (DN) thymocytes are generally regarded as the thymic precursors of TCRalphabeta(+)CD8alphaalpha(+) intestinal intraepithelial lymphocytes (IELs). However, this population is not homogenous and can be subdivided based on the expression of cell surface markers such as CD103. In this study, we aimed to define a cell population that is enriched in thymic IEL precursors. Here we report that only CD103(-) but not CD103(+)cells in the CD5(+)TCRalphabeta(+) DN thymocyte population can give rise to TCRalphabeta(+)CD8alphaalpha(+) IELs or IEL-like cells in in vivo injections and in vitro cultures, respectively. In addition, we demonstrate that IL-15 stimulation alone is sufficient for upregulation of CD8alphaalpha in CD103( )CD5(+)TCRalphabeta(+) DN thymocytes. We also found that the CD103( )CD5(+)TCRalphabeta(+) DN population can be further separated into two fractions: CD69(-/lo) and CD69(+). Of these two fractions, only CD69(-/lo) cells can give rise to CD8alphaalpha IEL-like cells in the presence of IL-15 in in vitro cultures. Based on these results, we conclude that a CD69(-/lo)CD103( )CD5(+)TCRalphabeta(+) DN population is highly enriched in thymic IEL precursors. PMID- 25448709 TI - Evidence supporting an altered immune response in ASD. AB - Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by deficits in social interactions, communication, and increased stereotypical repetitive behaviors. The immune system plays an important role in neurodevelopment, regulating neuronal proliferation, synapse formation and plasticity, as well as removing apoptotic neurons. Immune dysfunction in ASD has been repeatedly described by many research groups across the globe. Symptoms of immune dysfunction in ASD include neuroinflammation, presence of autoantibodies, increased T cell responses, and enhanced innate NK cell and monocyte immune responses. Moreover these responses are frequently associated with more impairment in core ASD features including impaired social interactions, repetitive behaviors and communication. In mouse models replacing immune components in animals that exhibit autistic relevant features leads to improvement in behavior in these animals. Taken together this research suggests that the immune dysfunction often seen in ASD directly affects aspects of neurodevelopment and neurological processes leading to changes in behavior. Discussion of immune abnormalities in ASD will be the focus of this review. PMID- 25448711 TI - The amblyopic deficit for 2nd order processing: Generality and laterality. AB - A number of previous reports have suggested that the processing of second-order stimuli by the amblyopic eye (AE) is defective and that the fellow non-amblyopic eye (NAE) also exhibits an anomaly. Second-order stimuli involve extra-striate as well as striate processing and provide a means of exploring the extent of the cortical anomaly in amblyopia using psychophysics. We use a range of different second-order stimuli to investigate how general the deficit is for detecting second-order stimuli in adult amblyopes. We compare these results to our previously published adult normative database using the same stimuli and approach to determine the extent to which the detection of these stimuli is defective for both amblyopic and non-amblyopic eye stimulation. The results suggest that the second-order deficit affects a wide range of second-order stimuli, and by implication a large area of extra-striate cortex, both dorsally and ventrally. The NAE is affected only in motion-defined form judgments, suggesting a difference in the degree to which ocular dominance is disrupted in dorsal and ventral extra-striate regions. PMID- 25448712 TI - Special issue: The function of contextual modulation. PMID- 25448710 TI - Active confocal imaging for visual prostheses. AB - There are encouraging advances in prosthetic vision for the blind, including retinal and cortical implants, and other "sensory substitution devices" that use tactile or electrical stimulation. However, they all have low resolution, limited visual field, and can display only few gray levels (limited dynamic range), severely restricting their utility. To overcome these limitations, image processing or the imaging system could emphasize objects of interest and suppress the background clutter. We propose an active confocal imaging system based on light-field technology that will enable a blind user of any visual prosthesis to efficiently scan, focus on, and "see" only an object of interest while suppressing interference from background clutter. The system captures three dimensional scene information using a light-field sensor and displays only an in focused plane with objects in it. After capturing a confocal image, a de cluttering process removes the clutter based on blur difference. In preliminary experiments we verified the positive impact of confocal-based background clutter removal on recognition of objects in low resolution and limited dynamic range simulated phosphene images. Using a custom-made multiple-camera system based on light-field imaging, we confirmed that the concept of a confocal de-cluttered image can be realized effectively. PMID- 25448715 TI - Coding depth perception from image defocus. AB - As a result of the spider experiments in Nagata et al. (2012), it was hypothesized that the depth perception mechanisms of these animals should be based on how much images are defocused. In the present paper, assuming that relative chromatic aberrations or blur radii values are known, we develop a formulation relating the values of these cues to the actual depth distance. Taking into account the form of the resulting signals, we propose the use of latency coding from a spiking neuron obeying Izhikevich's 'simple model'. If spider jumps can be viewed as approximately parabolic, some estimates allow for a sensory-motor relation between the time to the first spike and the magnitude of the initial velocity of the jump. PMID- 25448714 TI - Fourier decomposition of spatial localization errors reveals an idiotropic dominance of an internal model of gravity. AB - Given its conspicuous nature, gravity has been acknowledged by several research lines as a prime factor in structuring the spatial perception of one's environment. One such line of enquiry has focused on errors in spatial localization aimed at the vanishing location of moving objects - it has been systematically reported that humans mislocalize spatial positions forward, in the direction of motion (representational momentum) and downward in the direction of gravity (representational gravity). Moreover, spatial localization errors were found to evolve dynamically with time in a pattern congruent with an anticipated trajectory (representational trajectory). The present study attempts to ascertain the degree to which vestibular information plays a role in these phenomena. Human observers performed a spatial localization task while tilted to varying degrees and referring to the vanishing locations of targets moving along several directions. A Fourier decomposition of the obtained spatial localization errors revealed that although spatial errors were increased "downward" mainly along the body's longitudinal axis (idiotropic dominance), the degree of misalignment between the latter and physical gravity modulated the time course of the localization responses. This pattern is surmised to reflect increased uncertainty about the internal model when faced with conflicting cues regarding the perceived "downward" direction. PMID- 25448713 TI - The rate of change of vergence-accommodation conflict affects visual discomfort. AB - Stereoscopic (S3D) displays create conflicts between the distance to which the eyes must converge and the distance to which the eyes must accommodate. Such conflicts require the viewer to overcome the normal coupling between vergence and accommodation, and this effort appears to cause viewer discomfort. Vergence accommodation coupling is driven by the phasic components of the underlying control systems, and those components respond to relatively fast changes in vergence and accommodative stimuli. Given the relationship between phasic changes and vergence-accommodation coupling, we examined how the rate of change in the vergence-accommodation conflict affects viewer discomfort. We used a stereoscopic display that allows independent manipulation of the stimuli to vergence and accommodation. We presented stimuli that simulate natural viewing (i.e., vergence and accommodative stimuli changed together) and stimuli that simulate S3D viewing (i.e., vergence stimulus changes but accommodative stimulus remains fixed). The changes occurred at 0.01, 0.05, or 0.25 Hz. The lowest rate is too slow to stimulate the phasic components while the highest rate is well within the phasic range. The results were consistent with our expectation: somewhat greater discomfort was experienced when stimulus distance changed rapidly, particularly in S3D viewing when the vergence stimulus changed but the accommodative stimulus did not. These results may help in the generation of guidelines for the creation and viewing of stereo content with acceptable viewer comfort. PMID- 25448716 TI - Stabilization of polymer lipid complexes prepared with lipids of lactic acid bacteria upon preservation and internalization into eukaryotic cells. AB - The physicochemical characterization of polymer liposome complexes (PLCs) prepared with lipids of lactic acid bacteria and poly(N,N-dimethylaminoethyl methacrylate) covalently bound to cholesterol (CHO-PDMAEMA) was carried out in an integrated approach, including their stability upon preservation and incorporation into eukaryotic cells. PLCs were prepared with different polymer:lipid molar ratios (0, 0.05 and 0.10). Zeta potential, particle size distribution and polydispersity index were determined. The optimal polymer:lipid ratio and the stability of both bare liposomes and PLCs were evaluated at 37 degrees C and at different pHs, as well as after storage at 4 degrees C, -80 degrees C and freeze-drying in the presence or absence of trehalose 250 mM. Internalization of PLCs by eukaryotic cells was assessed to give a complete picture of the system. Incorporation of CHO-PDMAEMA onto bacterial lipids (ratio 0.05 and 0.10) led to stabilization at 37 degrees C and pH 7. A slight decrease of pH led to their strong destabilization. Bacteria PLCs showed to be more stable than lecithin (LEC) PLCs (used for comparison) upon preservation at 4 and -80 degrees C. The harmful nature of the preservation processes led to a strong decrease in the stability of PLCs, bacterial formulations being more stable than LEC PLCs. The addition of trehalose to the suspension of liposomes stabilized LEC PLC and did not have effect on bacterial PLCs. In vitro studies on Raw 264.7 and Caco-2/TC7 cells demonstrated an efficient incorporation of PLCs into the cells. Preparations with higher stability were the ones that showed a better cell uptake. The nature of the lipid composition is determinant for the stability of PLCs. Lipids from lactic acid bacteria are composed of glycolipids and phospholipids like cardiolipin and phosphatidylglycerol. The presence of negatively charged lipids strongly improves the interaction with the positively charged CHO-PDMAEMA, thus stabilizing liposomes. In addition, glycolipids and phosphatidylglycerol act as intrinsic protectants of PLCs upon preservation. This particular lipid composition of lactic acid bacteria makes them natural formulations potentially useful as drug delivery systems. PMID- 25448717 TI - Interaction of 5-fluoro-5'-deoxyuridine with human serum albumin under physiological and non-physiological condition: a biophysical investigation. AB - Uridine analogs 5'dFUrd (a cytotoxic metabolite of a prodrug capecitabine that enzymatically converted into 5'dFUrd) commonly used in the treatment of advanced human cancers, especially gastrointestinal tract, ovary, colorectal, breast cancers etc. Drugs/metabolites are transported in the blood by transporter proteins like human serum albumin (HSA). Here we investigate the interaction of 5'dFUrd to HSA by spectroscopic and calorimetric techniques at physiological (pH 7.4) and non-physiological (pH 9.0) conditions. The binding constant (Kb), enthalpy change (DeltaH degrees ), entropy change (DeltaS degrees ) and Gibbs free energy change (DeltaG degrees ) were also calculated under both conditions. The secondary structure of HSA showed greater alteration in helicity at physiological pH. ITC measurement reveals that HSA have high binding affinity at physiological pH as compares to non-physiological conditions. The thermostability of HSA alone as well of the HSA-drug complex was found to be higher at physiological pH. The binding study was also explored through molecular docking studies which revealed that 5'dFUrd was bound to subdomain IIA of Sudlow's site I through multiple mode of interaction. These results suggest that 5'dFUrd have high binding affinity at physiological condition or "N" isoform so lower drug concentrations are required in compare to non-physiological or "B" isoform of HSA to completely occupied the binding site of the protein. PMID- 25448718 TI - Adhesion and proliferation of HeLa and fibroblast cells on chemically-modified gold surfaces. AB - The development of materials that allow proper functioning of cells on solid supports is directly relevant to the construction of living-cell biosensors. Both physical and chemical properties of the surfaces have been shown to be critical in this field. Our aim is to report correlations between chemical properties of surfaces and cell behavior by studying adhesion, viability and proliferation of fibroblasts and HeLa cells. Neither fibroblasts nor HeLa cells adhered to a hydrophobic surface. Fibroblasts were able to attach and proliferate well on all other surfaces tested. In contrast, on some surfaces where HeLa cells adhered and were viable, proliferation decreased by half while on others proliferation was not affected. Proliferation was significantly correlated with the level of adsorption of serum proteins on the surface (quantified by surface plasmon resonance), but not with surface wettability (water contact angle). Interestingly, surfaces modified with COOH and HSO3 groups were the ones that favored most protein adsorption and allowed the best measures for HeLa cell proliferation. The decrease of HeLa cell proliferation on surfaces covered with poly-L-lysine (PL) was related with the profile of integrin expression. Compared to a polystyrene control surface, there was an increase in alphaV and alphaVbeta3 and a decrease in alpha2 and alpha3, indicating that migration rather than proliferation could be favored on PL functionalized surfaces. These results indicate that charge is more important than wettability to determine biocompatibility. PMID- 25448719 TI - Lethal drug combination: arsenic loaded multiple drug mesoporous silica for theranostic applications. AB - Simultaneous delivery of multiple therapeutic agents is of great importance for effective chemotherapy due of its well-known drug synergism and suppression to chemoresistance. We report a new theranostic nanoformulation to shuttle multiple chemotherapeutic agents for successfully exterminating cancer cells. This strategy is based on the fabrication of magnetite doped mesoporous silica nanoparticles (MSNs) in which both internal porous and external surface of MSN are respectively exploited to load two different kinds of cytotoxic cargoes. Notably, an exceptionally high quantity (29%) of poorly hydrophobic drug camptothecin (CPT) is loaded into the nanopores of MSNs; however, in previous reports less than 1% loading efficiency is reported. Following CPT loading in the pores of MSNs, another unconventional but FDA approved arsenic trioxide (ATO) is conjugated onto the surface of nanocomposite via exploiting the thiophilic nature of ATO. Cell inhibition performance of dual drug nanoformulation is significantly higher than single drug formulation, possibly due to additional or synergistic effect, as low as 3 MUg/ml of double drug nanocarrier were found effective to exterminate cancer cells. Besides drug delivery, the presence of superparamagnetic magnetite nanocrystals additionally empowers this system to be used as a contrast agent in magnetic resonance (MR) imaging for either monitoring diseased tissues or feedback of chemotherapy. We anticipate that the integration of combination therapy with nanotechnology coupled with versatile magnetic manipulation feature may prove a significant step forward toward the development of effective theranostic agents. PMID- 25448720 TI - Sodium hydroxide-mediated hydrogel of citrus pectin for preparation of fluorescent carbon dots for bioimaging. AB - The citrus process industry produces annually a huge amount of pomace, which is a rich source of citrus pectin. Here, we report the hydrogel of citrus pectin mediated by sodium hydroxide can be used to prepare fluorescent carbon dots (CDs). The introduction of hydrogel can not only make the temperature of the hydrothermal reaction down to 100 degrees C, but also avoid visually carbonized precipitates in the synthesis process even up to 180 degrees C. The as synthesized CDs are well dispersed in water with an average size of 2.7 nm and show cyan fluorescence with high photostability, good biocompatibility. Furthermore, the CDs can act as a potential fluorescent probe for cell imaging. Citrus pectin as a non-toxic carbonaceous precursor for preparation of fluorescent CDs provides a new approach for the efficient utilization of citrus germplasm in future. PMID- 25448721 TI - Comparison of the transport of Bacteroides fragilis and Escherichia coli within saturated sand packs. AB - Pathogens in groundwater accounted for ~50% of waterborne disease outbreaks in the United States between 1971 and 2006. The fast and reliable detection of groundwater microbial contamination and the identification of the contamination sources are of critical importance to the protection of public health. Recent studies suggested that fecal anaerobe Bacteriodes spp. could be employed as an effective tool for surface water microbial source tracking (MST). The usefulness of Bacteroides spp. for groundwater MST depends strongly on its mobility within the subsurface system. This research provides laboratory results comparing transport and attachment of E. coli K12 and B. fragilis within packed quartz sands. The results indicate that at low ionic strengths both E. coli K12 and B. fragilis are readily transported through saturated sand packs. At higher ionic strengths such as may be found near concentrated sources of fecal contamination, B. fragilis displayed significantly higher mobility than E. coli K12. Analysis of the extended Derjaguin-Landau-Verweu-Overbeek (XDLVO) energy interactions for both types of bacteria showed a significant repulsive energy barrier exists between the sand surface and the bacteria, precluding attachment directly to the sand surface. However a secondary minimum energy level exists under higher ionic strength conditions. The depth of this energy low is greater for E. coli K12, which results in greater attachment of E. coli K12 than of B. fragilis. The high mobility of B. fragilis suggests that it represents a promising tool for the detection of groundwater fecal contamination as well as the identification of the microbial sources. PMID- 25448723 TI - Associations between clinical characteristics and chronic complications in latent autoimmune diabetes in adults and type 2 diabetes. AB - BACKGROUND: This study aimed to assess the associations between clinical characteristics and chronic complications in latent autoimmune diabetes in adults (LADA) and type 2 diabetes. METHODS: This is a retrospective study. Our diabetes registry included 6975 patients aged 30-75 years old with phenotypic type 2 diabetes who underwent islet autoantibody screening between 2003 and 2012; 384 patients were identified to have LADA. Rates of chronic complications for LADA and type 2 diabetes were compared using a 1 : 2 matched design. Logistic models were fitted to identify the presence of chronic diabetic complications using clinical characteristics including gender, age, duration of diabetes, glycemic control and metabolic syndrome. RESULTS: When duration of diabetes is <5 years, the prevalence of diabetic nephropathy (nephropathy; 12.2% versus 21.8%, p = 0.018) and diabetic retinopathy (retinopathy; 8.1% versus 15.9%, p = 0.011) were significantly lower in patients with LADA than in patients with type 2 diabetes; the prevalence of nephropathy and retinopathy were comparable between both groups when duration is >=5 years. There was no significant difference in the prevalence of macrovascular complications between groups. The areas under the receiver operating characteristic curves based on the nephropathy and retinopathy models were larger for LADA than for type 2 diabetes (0.72 versus 0.61, p = 0.013; 0.76 versus 0.68, p = 0.056). CONCLUSIONS: Patients with LADA had a lower prevalence of microvascular complications than patients with type 2 diabetes when the duration of diabetes was <5 years. Regression equation fitted by clinical characteristics can better predict the risk of microvascular complications in LADA than in type 2 diabetes. PMID- 25448724 TI - Clostridium thermocellum thermostable lichenase with circular permutations and modifications in the N-terminal region retains its activity and thermostability. AB - The Clostridium thermocellum lichenase (endo-beta-1,3;1,4-glucan-D-glycosyl hydrolase) displays a high thermostability and specific activity and has a compact protein molecule, which makes it attractive, in particular, for protein engineering. We have utilized in silico analysis to construct circularly permuted (CP) variants and estimated the retained activity and thermostability. New open termini in the region of residues 53 or 99 in two lichenase CP variants (CN-53 and CN-99) had no effect on their activity and thermal tolerance versus another variant CP variant, CN-140 (cut in the region of residue 140), which displayed a dramatic decrease in the activity and thermostability. Construction and further activity and thermostability testing of the modified lichenase variants (M variants) and CP variants with peptides integrated via insertion fusion have demonstrated that the N-terminal regions in the lichenase catalytic domain (53 and 99 amino acid residues) that permit circular permutations with retention of activity and thermostability of the enzyme as well as the region between the C and N termini of the native lichenase in thermostable and active lichenase variants (CN-53 and CN-99) may be used for integrating small peptides without the loss of activity and thermostability. These findings not only suggest that CP predictions can be used in search for internal integration sites within protein molecule, but also form the background for further enzymatic engineering of the C. thermocellum thermostable lichenase aiming to create new fusion proteins. PMID- 25448722 TI - Proteins, platelets, and blood coagulation at biomaterial interfaces. AB - Blood coagulation and platelet adhesion remain major impediments to the use of biomaterials in implantable medical devices. There is still significant controversy and question in the field regarding the role that surfaces play in this process. This manuscript addresses this topic area and reports on state of the art in the field. Particular emphasis is placed on the subject of surface engineering and surface measurements that allow for control and observation of surface-mediated biological responses in blood and test solutions. Appropriate use of surface texturing and chemical patterning methodologies allow for reduction of both blood coagulation and platelet adhesion, and new methods of surface interrogation at high resolution allow for measurement of the relevant biological factors. PMID- 25448725 TI - Structural analysis and binding properties of isoforms of tarin, the GNA-related lectin from Colocasia esculenta. AB - The lectins, a class of proteins that occur widely in animals, plants, fungi, lichens and microorganisms, are known for their ability to specifically bind to carbohydrates. Plant lectins can be classified into 12 families including the Galanthus nivalis agglutinin (GNA)-related lectin superfamily, which is widespread among monocotyledonous plants and binds specifically to mannose, a behavior that confers remarkable anti-tumor, anti-viral and insecticidal properties on these proteins. The present study characterized a mitogenic lectin from this family, called tarin, which was purified from the crude extract from taro (Colocasia esculenta). The results showed that tarin is a glycoprotein with 2-3% carbohydrate content, composed of least 10 isoforms with pIs ranging from 5.5 to 9.5. The intact protein is a heterotetramer of 47kDa composed of two non identical and non-covalently associated polypeptides, with small subunits of 11.9kDa and large subunits of 12.6kDa. The tarin structure is stable and recovers or maintains its functional structure following treatments at different temperatures and pH. Tarin showed a complex carbohydrate specificity, binding with high affinity to high-mannose and complex N-glycans. Many of these ligands can be found in viruses, tumor cells and insects, as well as in hematopoietic progenitor cells. Chemical modifications confirmed that both conserved and non conserved amino acids participate in this interaction. This study determined the structural and ligand binding characteristics of a GNA-related lectin that can be exploited for several different purposes, particularly as a proliferative therapeutic molecule that is able to enhance the immunological response. PMID- 25448726 TI - Dual-hemisphere transcranial direct current stimulation over primary motor cortex enhances consolidation of a ballistic thumb movement. AB - Transcranial direct current stimulation (tDCS) is a noninvasive technique that modulates motor performance and learning. Previous studies have shown that tDCS over the primary motor cortex (M1) can facilitate consolidation of various motor skills. However, the effect of tDCS on consolidation of newly learned ballistic movements remains unknown. The present study tested the hypothesis that tDCS over M1 enhances consolidation of ballistic thumb movements in healthy adults. Twenty eight healthy subjects participated in an experiment with a single-blind, sham controlled, between-group design. Fourteen subjects practiced a ballistic movement with their left thumb during dual-hemisphere tDCS. Subjects received 1mA anodal tDCS over the contralateral M1 and 1mA cathodal tDCS over the ipsilateral M1 for 25min during the training session. The remaining 14 subjects underwent identical training sessions, except that dual-hemisphere tDCS was applied for only the first 15s (sham group). All subjects performed the task again at 1h and 24h later. Primary measurements examined improvement in peak acceleration of the ballistic thumb movement at 1h and 24h after stimulation. Improved peak acceleration was significantly greater in the tDCS group (144.2+/-15.1%) than in the sham group (98.7+/-9.1%) (P<0.05) at 24h, but not 1h, after stimulation. Thus, dual-hemisphere tDCS over M1 enhanced consolidation of ballistic thumb movement in healthy adults. Dual-hemisphere tDCS over M1 may be useful to improve elemental motor behaviors, such as ballistic movements, in patients with subcortical strokes. PMID- 25448727 TI - Risk factors for coronary artery calcification in Japanese patients. AB - BACKGROUND: Because the prevalence of coronary artery calcification is lower among Japanese than among Western individuals, aspects of the Japanese lifestyle might be related to the development of calcification. We aimed to clarify the relationship between coronary artery calcium scores in Japanese patients and various lifestyle factors among the Japanese population. METHODS: Study subjects were patients aged >=20 years who underwent multidetector-row computed tomography. A total of 201 patients agreed to take part in this study and answered a questionnaire regarding lifestyle, medical history, and other factors. RESULTS: Old age, current and former smoking, sedentary work, short sleep time, coronary artery stenosis, treatment with statins, medical history of cerebrovascular disease, medical history of angina pectoris, medical history of ischemic heart disease, and medical history of dyslipidemia were associated with higher odds ratios than the other factors examined, while the Japanese-style breakfast (e.g. boiled rice, miso soup, grilled fish) was associated with lower odds ratios. CONCLUSIONS: In this study, smoking, sedentary work, short sleep time, and the Japanese-style breakfast were lifestyle factors related to coronary artery calcification. The lifestyle of Japanese people may be related to coronary calcification. PMID- 25448728 TI - We should pay more attention to renal function before initiation of warfarin therapy. PMID- 25448730 TI - Influence of maternal diet enrichment with conjugated linoleic acids on lipoxygenase metabolites of polyunsaturated fatty acids in serum of their offspring with 7,12-dimethylbenz[a]anthracene induced mammary tumors. AB - Conjugated linoleic acids (CLA), which are a group of naturally occurring in food isomers of linoleic acid, seem to be active in each step of cancer development. There are many possible mechanisms of this action, and interactions with polyunsaturated fatty acids (PUFA) in lipoxygenase (LOX) and cyclooxygenase (COX) pathways are among the most likely ones. The aim of this study was to assess the influence of diet supplementation with CLA of pregnant and breastfeeding Sprague Dawley female rats on selected polyunsaturated fatty acids and their LOX metabolites concentrations in serum of the progeny with chemically induced mammary tumors. We confirmed that higher supply of CLA in the diet of female rats corresponded with the lower susceptibility to chemically induced mammary tumors in their female offspring. It also influenced the polyunsaturated n-3 and n-6 fatty acid concentrations in serum, as well as the concentrations of their LOX metabolites. The significant negative correlation between the concentrations of two CLA isomers in serum and linoleic acid (p=0.0144, p=0.0098), eicosapentaenoic acid (p=0.0158, p=0.0124), and 5-HEPE (p=0.0014, p=0.01690) and between cis-9, trans-11 CLA and 15-HEPE was detected, whereas arachidonic acid concentration positively correlated with CLA concentration in serum (p=0.0150, p=0.0231). Our results indicate that CLA can compete with PUFA and influence serum concentration of PUFA and their LOX metabolites, which could partly explain the anticancerogenic action of CLA. PMID- 25448729 TI - Additional value of the red blood cell distribution width to the Mehran risk score for predicting contrast-induced acute kidney injury in patients with ST elevation acute myocardial infarction. AB - BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) after percutaneous coronary intervention in patients with ST-elevation myocardial infarction (STEMI) is a common complication associated with worse outcome. Considering the prognostic predictive value of the red cell distribution width (RDW), we aimed to measure the usefulness of RDW for predicting CI-AKI. METHODS: All consecutive STEMI patients without hemodialysis from June 2011 to September 2013 admitted to St. Luke's International Hospital were enrolled. We performed primary percutaneous coronary intervention in all patients. CI-AKI was defined as a >25% increase or an absolute increase in serum creatinine of 0.5mg/dl within 3 days after percutaneous coronary intervention. The potential additional predictive value of RDW with the Mehran risk score (MRS) on admission was estimated. RESULTS: A total of 102 patients (78.4% males) were analyzed - 10 of the 102 (10%) STEMI patients developed CI-AKI. Multivariate analysis showed that RDW was an independent variable predicting CI-AKI in these patients [odds ratio, 2.029; 95% confidence interval (95% CI), 1.029-3.999; p=0.041]. The areas under the receiver operating characteristic curves for MRS only, RDW only, and the combined model (MRS and RDW) for the prediction of CI-AKI were 0.806 (95% CI, 0.696 0.917), 0.719 (95% CI, 0.536-0.902), and 0.846 (95% CI, 0.744-0.949), respectively. CONCLUSION: We showed the potential predictive ability of RDW, only if used with MRS, for CI-AKI in STEMI patients. Further evaluation of RDW for predicting CI-AKI in patients with STEMI is needed. PMID- 25448731 TI - Multifunctional adamantane derivatives as new scaffolds for the multipresentation of bioactive peptides. AB - The remarkable structural and chemical properties of adamantane afford attractive opportunities to design various adamantane-based scaffolds for biomedical applications. A wide range of mono-functionalized adamantane compounds have already been investigated and reviewed, mostly as anti-viral agents. The four bridgehead positions of adamantane provide many possibilities to design poly functional derivatives, and the recent conception of adamantane building blocks with multiple substituents has shown promising applications in several domains. In this review, we provide a detailed description of the different ways to synthesize multifunctional derivatives starting from adamantane molecule as the main core. We will then describe the interesting biological activity of the diverse multivalent scaffolds, focusing in particular on peptide-based systems. The results reported here will certainly encourage the development of novel adamantane-based structures for biological purposes. PMID- 25448733 TI - Updated survey of the steroid-converting enzymes in human adipose tissues. AB - Over the past decade, adipose tissues have been increasingly known for their endocrine properties, that is, their ability to secrete a number of adipocytokines that may exert local and/or systemic effects. In addition, adipose tissues have long been recognized as significant sites for steroid hormone transformation and action. We hereby provide an updated survey of the many steroid-converting enzymes that may be detected in human adipose tissues, their activities and potential roles. In addition to the now well-established role of aromatase and 11beta-hydroxysteroid dehydrogenase (HSD) type 1, many enzymes have been reported in adipocyte cell lines, isolated mature cells and/or preadipocytes. These include 11beta-HSD type 2, 17beta-HSDs, 3beta-HSD, 5alpha reductases, sulfatases and glucuronosyltransferases. Some of these enzymes are postulated to bear relevance for adipose tissue physiology and perhaps for the pathophysiology of obesity. This elaborate set of steroid-converting enzymes in the cell types of adipose tissue deserves further scientific attention. Our work on 20alpha-HSD (AKR1C1), 3alpha-HSD type 3 (AKR1C2) and 17beta-HSD type 5 (AKR1C3) allowed us to clarify the relevance of these enzymes for some aspects of adipose tissue function. For example, down-regulation of AKR1C2 expression in preadipocytes seems to potentiate the inhibitory action of dihydrotestosterone on adipogenesis in this model. Many additional studies are warranted to assess the impact of intra-adipose steroid hormone conversions on adipose tissue functions and chronic conditions such as obesity, diabetes and cancer. PMID- 25448735 TI - Ethnicity and social deprivation contribute to vitamin D deficiency in an urban UK population. AB - We receive a large number of 25 hydroxyvitamin D (25OHD) assay requests from General Medical Practitioners (GPs) in primary care. We have investigated whether this rate of requesting is related to the ethnicity of the local urban population based in Central Manchester or Trafford areas with very different ethnic populations. Data on assay requesting was collected from January-December 2013. Samples were assayed using an ABSciex 5500 tandem mass spectrophotometer and the Chromsystems 25OHD kit for LC-MS/MS. 11,291 requests for 25OHD measurement received from Central Manchester GPs and 5176 requests from Trafford GPs. Overall 29% of patients were profoundly deficient (<25nmol/L) and a further 32% were insufficient (25-50nmol/L). Using the 2011 Census data we have analysed our data by ethnicity (categorized here as white, Asian, black, Chinese, other) based on patient's home postcode and related this to the Index of Multiple Deprivation (IMD). In areas where >70% of the population were non-white (NW), 69% had 25OHD <50nmol/L. Areas where <5% of patients were NW, 42% of patients were still insufficient. There was a significant correlation between the Index of Social Deprivation (IMD) and the percentage of patients with 25OHD <50nmol/L (p<0.0001). Areas with the highest Index of Social Deprivation (IMD ranking <16,000) showed no association between ethnicity and IMD (p=0.69). We have shown that over 61% of all patients in these urban areas of Manchester and Trafford showed increased risk of bone, and potentially other diseases, based on their 25OHD assay results alone and that social deprivation, as well as ethnicity, contribute to the poor 25OHD levels seen in these patients. PMID- 25448734 TI - Post-hoc comparison of vitamin D status at three timepoints during pregnancy demonstrates lower risk of preterm birth with higher vitamin D closer to delivery. AB - There have been observational reports that maternal vitamin D status at baseline and not closest to delivery is a better predictor of pregnancy outcomes, suggesting that a cascade of events is set into motion that is not modifiable by vitamin D supplementation during later pregnancy. To address this issue, in this exploratory post-hoc analysis using correlation and logistic regression, we sought to measure the strength of the association between serum 25(OH)D concentrations at 3 timepoints during pregnancy: baseline, 1st trimester (<16 weeks); 2nd trimester (16-26 weeks); and 3rd trimester (>=27 weeks) and preterm birth. It was hypothesized that the 25(OH)D value closest to delivery would be most significantly associated with preterm birth. To accomplish this objective, the datasets from NICHD (n=333) and Thrasher Research Fund (n=154) vitamin D supplementation pregnancy studies were combined. The results of this analysis were that 25(OH)D values closer to delivery were more strongly correlated with gestational age at delivery than earlier values: 1st trimester: r=0.11 (p=0.02); 2nd trimester: r=0.08 (p=0.09); and 3rd trimester: r=0.15 (p=0.001). When logistic regression was performed with preterm birth (<37 weeks) as the outcome and 25(OH)D quartiles as the predictor variable, adjusting for study and participant race/ethnicity, as with the correlation analysis, the measurements closer to delivery were more significantly associated and had a higher magnitude of effect. That is, at baseline, those who had serum concentrations <50nmol/L (20ng/mL) had 3.3 times of odds of a preterm birth compared to those with serum concentrations >=100nmol/L (40ng/mL; p=0.27). At 2nd trimester, the odds were 2.0 fold (p=0.21) and at the end of pregnancy, the odds were 3.8 fold (p=0.01). The major findings from this exploratory analysis were: (1) maternal vitamin D status closest to delivery date was more significantly associated with preterm birth, suggesting that later intervention as a rescue treatment may positively impact the risk of preterm delivery, and (2) a serum concentration of 100nmol/L (40ng/mL) in the 3rd trimester was associated with a 47% reduction in preterm births. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25448736 TI - Regulation of human 3-beta-hydroxysteroid dehydrogenase type-2 (3betaHSD2) by molecular chaperones and the mitochondrial environment affects steroidogenesis. AB - Human 3-beta-hydroxysteroid dehydrogenase/isomerase types 1 and 2 (3betaHSD1 and 3betaHSD2, respectively) are expressed in a tissue-specific pattern by different genes. Site-directed mutagenesis studies have confirmed the function of the catalytic amino acids (Tyr154, Lys 158, Ser124 in both isoenzymes), substrate/inhibitor isoform-specific residues (His156 and Arg195 in 3betaHSD1) and cofactor binding residues (Asp36 provides NAD(+) specificity in both isoenzymes). However, detailed analysis of isoform-specific organelle localization and characterization is difficult due to the 93% amino acid identity between the two isoforms. With recent advances in the knowledge of mitochondrial architecture and localization of the various translocases, our laboratory has studied the mechanisms regulating mitochondrial 3betaHSD2 localization. The mitochondrial N-terminal leader sequence of 3betaHSD2 directs its entry into the mitochondria where it is localized to the intermembrane space (IMS). Unlike other mitochondrial proteins, the N-terminal signal sequence of 3betaHSD2 is not cleaved upon mitochondrial import. 3betaHSD2 interacts with the mitochondrial translocase, Tim50, to regulate progesterone and androstenedione formation. Our studies suggest that its activity at the IMS is facilitated in a partially unfolded "molten globule" conformation by the proton pump between the matrix and IMS. The unfolded protein is refolded by the mitochondrial chaperones. The protons at the IMS are absorbed by the lipid vesicles, to maintain the proton pump and recycle 3betaHSD2. As a result, one molecule of 3betaHSD2 may participate in multiple catalytic reactions. In summary, the steroidogenic cell recycles 3betaHSD2 to catalyze the reactions needed to produce androstenedione, progesterone and 17alpha-hydroxyprogesterone on demand in coordination with the mitochondrial translocase, Tim50. This article is part of a Special Issue entitled 'Steroid/Sterol signaling'. PMID- 25448738 TI - Dissecting high from low responders in a vitamin D3 intervention study. AB - Vitamin D3 is a pleiotropic signaling molecule that has via activation of the transcription factor vitamin D receptor (VDR) a direct effect on the expression of more than 100 genes. The aim of this study was to find transcriptomic and clinical biomarkers that are most suited to identify vitamin D3 responders within 71 pre-diabetic subjects during a 5-month intervention study (VitDmet). In hematopoietic cells, the genes ASAP2, CAMP, CD14, CD97, DUSP10, G0S2, IL8, LRRC8A, NINJ1, NRIP1, SLC37A2 and THBD are known as primary vitamin D targets. We demonstrate that each of these 12 genes carries a conserved VDR binding site within its genomic region and is expressed in human peripheral blood mononuclear cells (PBMCs). The changes in the expression of these genes in human PBMCs at the start and the end of the vitamin D-intervention were systematically correlated with the alteration in the circulating form of vitamin D3, 25-hydroxyvitamin D3 (25(OH)D3). Only 39-44 (55-62%) of the study subjects showed a highly significant response to vitamin D3, i.e., we considered them as "responders". In comparison, we found for 37-53 (52-75%) of the participants that only 12 biochemical and clinical parameters, such as concentrations of parathyroid hormone (PTH) and insulin, or computed values, such as homeostatic model assessment and insulin sensitivity index, show a correlation with serum 25(OH)D3 levels that is as high as that of the selected VDR target genes. All 24 parameters together described the pleiotropic vitamin D response of the VitDmet study subjects. Interestingly, they demonstrated a number of additional correlations that define a network, in which PTH plays the central role. In conclusion, vitamin D3-induced changes in human PBMCs can be described by transcriptomic and serum biomarkers and allow a segregation into high and low responders. This article is part of a Special Issue entitled '17th Vitamin D Workshop' . PMID- 25448732 TI - Novel activities of CYP11A1 and their potential physiological significance. AB - CYP11A1, found only in vertebrates, catalyzes the first step of steroidogenesis where cholesterol is converted to pregnenolone. The purified enzyme, also converts desmosterol and plant sterols including campesterol and beta-sitosterol, to pregnenolone. Studies, initially with purified enzyme, reveal that 7 dehydrocholesterol (7DHC), ergosterol, lumisterol 3, and vitamins D3 and D2 also serve as substrates for CYP11A1, with 7DHC being better and vitamins D3 and D2 being poorer substrates than cholesterol. Adrenal glands, placenta, and epidermal keratinocytes can also carry out these conversions and 7-dehydropregnenolone has been detected in the epidermis, adrenal glands, and serum, and 20-hydroxyvitamin D3 was detected in human serum and the epidermis. Thus, this metabolism does appear to occur in vivo, although its quantitative importance and physiological role remain to be established. CYP11A1 action on 7DHC in vivo is further supported by detection of Delta(7)steroids in Smith-Lemli-Opitz syndrome patients. The activity of CYP11A1 is affected by the structure of the substrate with sterols having steroidal or Delta(7)-steroidal structures undergoing side chain cleavage following hydroxylations at C22 and C20. In contrast, metabolism of vitamin D involves sequential hydroxylations that start at C20 but do not lead to cleavage. Molecular modeling using the crystal structure of CYP11A1 predicts that other intermediates of cholesterol synthesis could also serve as substrates for CYP11A1. Finally, CYP11A1-derived secosteroidal hydroxy-derivatives and Delta(7)steroids are biologically active when administered in vitro in a manner dependent on the structure of the compound and the lineage of the target cells, suggesting physiological roles for these metabolites. This article is part of a special issue entitled 'SI: Steroid/Sterol signaling'. PMID- 25448737 TI - Membrane-mediated actions of 1,25-dihydroxy vitamin D3: a review of the roles of phospholipase A2 activating protein and Ca(2+)/calmodulin-dependent protein kinase II. AB - The secosteroid 1alpha,25-dihydroxy vitamin D3 [1alpha,25(OH)2D3] acts on cells via classical steroid hormone receptor-mediated gene transcription and by initiating rapid membrane-mediated signaling pathways. In its membrane-initiated pathway, after 1alpha,25(OH)2D3 interacts with protein disulfide isomerase, family A, member 3 (Pdia3) in caveolae, phospholipase A2 (PLA2) and protein kinase C (PKC) are activated. Recent efforts to determine the signaling proteins involved in the 1alpha,25(OH)2D3 signal from Pdia3 to PLA2 have indicated that phospholipase A2 activating protein (PLAA) and Ca(2+)/calmodulin-dependent kinase II (CaMKII) are required. PLAA is located in caveolae, where it interacts with Pdia3 and caveolin-1 (Cav-1) to initiate rapid signaling via CaMKII, activating PLA2, leading to activation of protein kinase C (PKC) and PKC-dependent responses. PMID- 25448739 TI - Vitamin D and the brain: key questions for future research. AB - Over the last decade a convergent body of evidence has emerged from epidemiology, animal experiments and clinical trials which links low vitamin D status with a range of adverse neuropsychiatric outcomes. This research demonstrates that the timing of exposure to low vitamin D influences the nature of brain phenotypes, as exposures during gestation versus adulthood result in different phenotypes. With respect to early life exposures, there is robust evidence from rodent experiments indicating that transient developmental vitamin D (DVD) deficiency is associated with changes in brain structure, neurochemistry, gene and protein expression and behavior. In particular, DVD deficiency is associated with alterations in the dopaminergic neurotransmitter systems. In contrast, recently published animal experiments indicate that adult vitamin D (AVD) deficiency is associated with more subtle neurochemical and behavioral phenotypes. This paper explores key issues that need to be addressed in future research. There is a need to define the timing and duration of the 'critical window' during which low vitamin D status is associated with differential and adverse brain outcomes. We discuss the role for 'two-hit hypotheses', which propose that adult vitamin D deficiency leaves the brain more vulnerable to secondary adverse exposures, and thus may exacerbate disease progression. Finally, we explore the evidence implicating a role for vitamin D in rapid, non-genomic mechanisms that may involve L-type calcium channels and brain function. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25448740 TI - Suppression of epithelial ovarian cancer invasion into the omentum by 1alpha,25 dihydroxyvitamin D3 and its receptor. AB - Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death in women, mainly because it has spread to intraperitoneal tissues such as the omentum in the peritoneal cavity by the time of diagnosis. In the present study, we established in vitro assays, ex vivo omental organ culture system and syngeneic animal tumor models using wild type (WT) and vitamin D receptor (VDR) null mice to investigate the effects of 1alpha,25-dihydroxyvitamin D3 (1,25D3) and VDR on EOC invasion. Treatment of human EOC cells with 1,25D3 suppressed their migration and invasion in monolayer scratch and transwell assays and ability to colonize the omentum in the ex vivo system, supporting a role for epithelial VDR in interfering with EOC invasion. Furthermore, VDR knockdown in OVCAR3 cells increased their ability to colonize the omentum in the ex vivo system in the absence of 1,25D3, showing a potential ligand-independent suppression of EOC invasion by epithelial VDR. In syngeneic models, ID8 tumors exhibited an increased ability to colonize omenta of VDR null over that of WT mice; pre-treatment of WT, not VDR null, mice with EB1089 reduced ID8 colonization, revealing a role for stromal VDR in suppressing EOC invasion. These studies are the first to demonstrate a role for epithelial and stromal VDR in mediating the activity of 1,25D3 as well as a 1,25D3-independent action of the VDR in suppressing EOC invasion. The data suggest that VDR-based drug discovery may lead to the development of new intervention strategies to improve the survival of patients with EOC at advanced stages. This article is part of a Special Issue entitled "Vitamin D Workshop". PMID- 25448742 TI - Automated immunoassays for 25-hydroxyvitamin D (25-OHD): do plasticisers interfere? AB - The international quality assessment scheme for vitamin D metabolites (DEQAS) was established in 1989. The scheme involves the quarterly distribution of 5 serum samples prepared from blood collected in plain plastic bags. Following transfer of the donors to a clinic using different bags, sera were found to contain a contaminant that interfered in both the local LC-MS/MS assay and the NIST reference measurement procedure for 25-OHD. It seemed likely that the contaminant was a substance, possibly a plasticiser, leached from the plastic bag. It was subsequently suggested that the unidentified contaminant might also cause interference in certain automated non-extraction assays for 25-OHD. This was investigated in 3 automated immunoassays by comparing serum 25-OHD results from blood collected simultaneously into plain glass tubes and plastic bags. There was no significant difference in results, indicating that the leached substance had no effect on any of the 3 immunoassays examined. PMID- 25448743 TI - CYP11A1 in skin: an alternative route to photoprotection by vitamin D compounds. AB - Topical 1,25-dihydroxyvitamin D (1,25D) and other vitamin D compounds have been shown to protect skin from damage by ultraviolet radiation (UVR) in a process that requires the vitamin D receptor. Yet, while mice which do not express the vitamin D receptor are more susceptible to photocarcinogenesis, mice unable to 1alpha-hydroxylate 25-hydroxyvitamin D to form 1,25D do not show increased susceptibility to UVR-induced skin tumors. A possible explanation is that an alternative pathway, which does not involve 1alpha-hydroxylation, may produce photoprotective compounds from vitamin D. The cholesterol side chain cleavage enzyme CYP11A1 is expressed in skin and produces 20-hydroxyvitamin D3 (20OHD) as a major product of vitamin D3. We examined whether topical 20OHD would affect UVR induced DNA damage, inflammatory edema or immune suppression produced in Skh:hr1 mice. Photoprotection by 20OHD at 23 or 46pmol/cm(2) against cyclobutane pyrimidine dimers (DNA lesions) after UVR in mice was highly effective, up to 98+/-0.8%, (p<0.001) and comparable to that of 1,25D. Sunburn edema measured as skinfold thickness 24h after UVR was also significantly reduced by 20OHD (p<0.001). In studies of contact hypersensitivity (CHS), which is suppressed by UVR, topical application of 20OHD to mice protected against UVR-induced immunosuppression (p<0.05), similar to the effect of 1,25D at similar doses (46+/ 0.6% protection with 20OHD, 44+/-0.5% with 1,25D). Both UVR-induced DNA damage and immunosuppression contribute to increased susceptibility to UVR-induced skin tumors. This study indicates a potentially anti-photocarcinogenic role of the naturally occurring vitamin D metabolite, 20OHD, which does not depend on 1alpha hydroxylation for generation. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25448744 TI - Calciotrophic hormones and hyperglycemia modulate vitamin D receptor and 25 hydroxyy vitamin D 1-alpha hydroxylase mRNA expression in human vascular smooth muscle cells. AB - Estrogen receptors (ERalpha and ERbeta), the vitamin D receptor (VDR) and 25 hydroxyy vitamin D 1-alpha hydroxylase (1OHase) mRNA are expressed in vascular smooth muscle cells (VSMC). In these cells estrogenic hormones modulate cell proliferation as measured by DNA synthesis (DNA). In the present study we determined whether or not the calciotrophic hormones PTH 1-34 (PTH) and less- calcemic vitamin D analog QW as well as hyperglycemia can regulate DNA synthesis and CK. E2 had a bimodal effect on VSMC DNA synthesis, such that proliferation was inhibited at 30nM but stimulated at 0.3nM. PTH at 50nM increased, whereas QW at 10nM inhibited DNA synthesis. Hyperglycemia inhibited the effects on high E2, QW and PTH on DNA only. Both QW and PTH increased ERalpha mRNA expression, but only PTH increased ERbeta expression. Likewise, both PTH and QW stimulated VDR and 1OHase expression and activity. ERbeta, VDR and 1OHase expression and activity were inhibited by hyperglycemia, but ERalpha expression was unaffected by hyperglycemia. In conclusion, calcitrophic hormones modify VSMC growth and concomitantly affect ER expression in these cells as well as the endogenous VSMC vitamin D system elements, including VDR and 1OHase. Some of the later changes may likely participate in growth effects. Of importance in the observation is that several regulatory effects are deranged in the presence of hyperglycemia, particularly the PTH- and vitamin D-dependent up regulation of VDR and 1OHase in these cells. The implications of these effects require further studies. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25448741 TI - 1,25-Dihydroxyvitamin D3 induces monocytic differentiation of human myeloid leukemia cells by regulating C/EBPbeta expression through MEF2C. AB - Myogenic enhancer factor2 (Mef2) consists of a family of transcription factors involved in morphogenesis of skeletal, cardiac and smooth muscle cells. Among the four isoforms (Mef2A, 2B, 2C, and 2D), Mef2C was also found to play important roles in hematopoiesis. At myeloid progenitor level, Mef2C expression favors monocytic differentiation. Previous studies from our laboratory demonstrated that ERK5 was activated in 1,25-dihydroxyvitamin D3 (1,25D)-induced monocytic differentiation in AML cells and ERK5 activation was accompanied by increased Mef2C phosphorylation. We therefore examined the role of Mef2C in 1,25D-induced monocytic differentiation in AML cell lines (HL60, U937 and THP1) and found that knockdown of Mef2C with small interfering RNA (siRNA) significantly decreases the expression of the monocytic marker, CD14, without affecting the expression of the general myeloid marker, CD11b. CCAAT/enhancer-binding protein (C/EBP) beta, which can bind to CD14 promoter and increase its transcription, has been shown to be the downstream effector of 1,25D-induced monocytic differentiation in AML cells. When Mef2C was knocked down, expression of C/EBPbeta was reduced at both mRNA and protein levels. The protein expression levels of cell cycle regulators, p27(Kip1) and cyclin D1, were not affected by Mef2C knockdown, nor the monopoiesis related transcription factor, ATF2 (activating transcription factor 2). Thus, we conclude that 1,25D-induced monocytic differentiation, and CD14 expression in particular, are mediated through activation of ERK5-Mef2C-C/EBPbeta signaling pathway, and that Mef2C does not seem to modulate cell cycle progression. PMID- 25448745 TI - Epigenetic modifications of gene promoter DNA in the liver of adult female mice masculinized by testosterone. AB - Testosterone (T) is known to masculinize the female phenotype of the liver, evidenced as up- and down-regulated expressions of male- and female-predominant genes, respectively, involved in hepatic metabolism. This study is aimed at identifying epigenetic modifications of promoters of these differently expressed genes in the liver after masculinization by T of adult female C57BL/6 mice using methylated DNA immunoprecipitation and NimbleGen microarrays. Among the 17,354 promoters examined, 82 promoters in the liver have been identified to be significantly changed by T (p<0.05), with 47 and 35 promoters exhibiting increased and decreased DNA methylation, respectively. Most of these promoters display the changes of DNA methylation in their Ups-regions, which are between +500 and +2000 bp upstream from the transcription start site (TSS) of the genes. Less T-induced modifications have been detected in the Cor-regions of the promoters, i.e., +500 to -500 bp around the TSS. Only 13 and 7 Cor-promoters are hyper- and hypo-methylated, respectively, among which are 10 hyper- and 5 hypo methylated promoters of genes with annotated functions. Surprisingly, the promoters are largely unmethylated in those genes whose expression has been previously found to be permanently deregulated by T in the liver, as e.g. the T upregulated male-predominant genes Cyp7b1, Cyp2d9, Cyp4a10, Ugt2b1, Ugt2b38, Hsd3b5, Slco1a1 as well as the T-downregulated female-predominant genes Cyp2b9, Cyp2b13, Cyp3a41, Cyp3a44, Fmo3, Sult2a2, respectively. Though methylatable, the promoter DNA of Ar, Esr1, and Esr2 remained unaffected by T. However, T decreases DNA-methylation of the Cor-promoter region of Ddc encoding the AR-coactivator dopa decarboxylase. Among the identified 15 Cor-promoters of genes with annotated functions are also those of Defb43, Cst11, and Sele involved in innate immunity. Our data support the view that T may exert long-lasting epigenetic effects on functions of the liver-inherent immune system. PMID- 25448747 TI - Immunomodulatory effects of 25-hydroxyvitamin D3 on monocytic cell differentiation and influence of vitamin D3 polymorphisms in type 1 diabetes. AB - BACKGROUND: Preventive measures and a causal therapy for type 1 diabetes (T1D) remain elusive. An imbalance between different dendritic cells (DC) with increased immunogenic DC and decreased tolerogenic DC (tDC) may lead to T1D. Furthermore, 25(OH)D3 is associated with less adverse effects than 1,25(OH)2D3. PURPOSE: The present study was performed to clarify the remaining issues about the cellular effects of 25(OH)D3 in patients with T1D and the role of genetic polymorphisms of the vitamin D3 (VD3) metabolism on a functional cellular level. MATERIALS AND METHODS: Twelve patients with T1D were case-matched to twelve healthy controls (HC). Monocytes (MC) were either not supplemented or supplemented with 25(OH)D3 in vitro and phenotyped with fluorescence-activated cell sorting. In vitro synthesis and plasma levels of 25(OH)D3 and 1,25(OH)2D3 were analyzed as well as twelve gene polymorphisms of the VD3 metabolism. RESULTS: 25(OH)D3 significantly inhibited differentiation of MC into DC and led to an increase of intermediate cells (IC), which show a similar phenotype as tDC. The patient with a recent onset of T1D showed a higher increase in MC and IC compared to patients with long-standing T1D. There were significant differences for the increase of IC with supplementation of 25(OH)D3 between different genotypes within the polymorphisms of VDR-BsmI-rs1544410, VDR-TaqI-rs731236 and CYP24A1-rs927650. CONCLUSION: This study suggests that 25(OH)D3 shows immunomodulatory effects on a cellular level in patients with T1D and HC by inhibiting the differentiation of MC into DC and promoting the formation of IC, which are similar to tDC, thereby shifting immunity to self-tolerance. The potency of 25(OH)D3 did not differ between patients with T1D and HC. Increased plasma levels of 25(OH)D3 may inhibit a proinflammatory cell milieu. Despite of the limited patient number, this study generates the hypothesis that the immunmodulatory effects may be influenced by genotypes of the VDR and CYP24A1 illustrating their functional role in T1D susceptibility, which is worth further investigation. PMID- 25448746 TI - Significant role of estrogen in maintaining cardiac mitochondrial functions. AB - Increased susceptibility to stress-induced myocardial damage is a significant concern in addition to decreased cardiac performance in postmenopausal females. To determine the potential mechanisms underlying myocardial vulnerability after deprivation of female sex hormones, cardiac mitochondrial function is determined in 10-week ovariectomized rats (OVX). Significant mitochondrial swelling in the heart of OVX rats is observed. This structural alteration can be prevented with either estrogen or progesterone supplementation. Using an isolated mitochondrial preparation, a decrease in ATP synthesis by complex I activation in an OVX rat is completely restored by estrogen, but not progesterone. At basal activation, reactive oxygen species (ROS) production from the mitochondria is not affected by the ovariectomy. However, after incubated in the presence of either high Ca(2+) or antimycin-A, there is a significantly higher mitochondrial ROS production in the OVX sample compared to the control. This increased stress-induced ROS production is not observed in the preparation isolated from the hearts of OVX rats with estrogen or progesterone supplementation. However, deprivation of female sex hormones has no effect on the protein expression of electron transport chain complexes, mitofusin 2, or superoxide dismutase 2. Taken together, these findings suggest that female sex hormones, estrogen and progesterone, play significant regulatory roles in maintaining normal mitochondrial properties by stabilizing the structural assembly of mitochondria as well as attenuating mitochondrial ROS production. Estrogen, but not progesterone, also plays an important role in modulating mitochondrial ATP synthesis. PMID- 25448748 TI - Cytochrome P450 1 family and cancers. AB - The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor that dimerizes with aryl hydrocarbon receptor nuclear translocator (ARNT). This complex binds to xenobiotics response element (XREs), and then starts the expressions of downstream genes including cytochrome P450 (CYP) 1 family members: CYP1A1, CYP1A2 and CYP1B1. Role of CYP1 family is involved in the metabolism of endogenous hormones, xenobiotics and drug. The expression of CYP1 family is regulated by estradiol (E2) or xenobiotics in diverse cancers. In breast cancers expressing estrogen receptors (ERs), level of CYP1B1 is increased by E2 and reversed by an estrogen receptor antagonist, ICI 182,780 or 4-hydrotamoxifen, which indicates that the expression of CYP1 family in downstream region of AhR is regulated by an activation of ERalpha. In metabolic pathways, E2 is converted into 4-hydroxyestradiol by CYP1B1, which can be converted into mainly estradiol 3,4-quinone, a potential carcinogen, by peroxidase. Increased expression of CYP1 family indicates the possibility of carcinogenesis by exposure of xenobiotics in endometrial and ovarian cancers. Apart from roles of CYP1 family in relation with ER pathway, CYP1 family is over-expressed in ER independent cancers. CYP1A1 exhibits hydroxylase activity in oxidation of arachidonic acid, which has been transformed to 12(R)-hydrxyeicosatetraenoic (HETEs), a potent activator of AhR activity. On the basis of results, phytoestrogens and dexamethasone are provided as cancer therapy regulating the expression of CYP1 family. Thus, this review focuses on the role(s) of CYP1 family in ER-dependent or ER-independent cancers and the potential for cancer therapy to target CYP1 family in these cancers. PMID- 25448749 TI - Progesterone-induced down-regulation of hormone sensitive lipase (Lipe) and up regulation of G0/G1 switch 2 (G0s2) genes expression in inguinal adipose tissue of female rats is reflected by diminished rate of lipolysis. AB - Decreased lipolytic activity in adipose tissue may be one of the reasons behind excess accumulation of body fat during pregnancy. The aim of this study was to analyze the effect of progesterone on the expression of: (a) Lipe (encoding hormone-sensitive lipase, HSL), (b) Pnpla2 (encoding adipose triglyceride lipase, ATGL), (c) abhydrolase domain containing 5 (Abhd5), and (d) G0/G1 switch 2 (G0s2) genes in white adipose tissue (WAT), as potential targets for progesterone action during the course of pregnancy. Administration of progesterone to female rats, which was reflected by approximately 2.5-fold increase in circulating progesterone concentration, is associated with a decrease in Lipe gene expression in the inguinal WAT. The expression of Pnpla2 gene in all main fat depots of females and males remained unchanged after progesterone administration. Administration of progesterone resulted in an increase in the expression of Abhd5 gene (whose product increases ATGL activity) and G0s2 gene (whose product decreases ATGL activity) in the inguinal WAT of female rats. Mifepristone, a selective antagonist of progesterone receptor, abolished the effect of progesterone on Lipe, Abhd5 and G0s2 genes expression in the inguinal WAT. The decrease in Lipe and the increase in Abhd5 and G0s2 genes expression was associated with lower rate of stimulated lipolysis. Administration of progesterone exerted no effect on Lipe, Abhd5 and G0s2 genes expression and stimulated lipolysis in the retroperitoneal WAT of females, as well as in the inguinal, epididymal and retroperitoneal WAT of males. In conclusion, our findings suggest that progesterone decreases the rate of lipolysis in the inguinal WAT of female rats, inhibiting the activity of both ATGL (by stimulating synthesis of G0S2 - specific inhibitor of the enzyme) and HSL (due to inhibition of Lipe gene expression). PMID- 25448750 TI - In vivo and in vitro estrogenic profile of 17beta-amino-1,3,5(10)estratrien-3-ol. AB - 17beta-amino-1,3,5(10)estratrien-3-ol (17betaAE2), is the 17beta-aminoestrogens prototype possessing anticoagulant activity, contrasting with the procoagulant effects of 17beta-estradiol (17betaE2). Its estrogenicity profile has not been reported, and it was evaluated by uterotrophic assay, estrogen receptor binding affinity and its ability to induce gene transcription of the human estrogen receptor (hER)alpha mediated in a Saccharomyces cerevisiae yeast expression system. Additionally, 17betaAE2 and 17alphaAE2 were compared with 17betaE2 in HeLa cells co-transfected with expression vectors for hERalpha or hERbeta subtypes and for an estrogen-responsive reporter gene. Immature female CD1 mice and Wistar rats (21 days old) were treated for three days with 17betaAE2 (10-5000 MUg/kg), 17betaE2 (0.001-1000 MUg/kg) or vehicle (propylenglycol 10 ml/kg) and uterine weights were estimated. 17betaAE2 increased uterine weight in a dose dependent manner. The effective dose (ED)50 uterine weight values: 17betaAE2=552 and 764 MUg/kg (17betaE2=4.8 and 16 MUg/kg) and their relative uterotrophic potency were 0.86 and 2.1 (17betaE2=100) in mice and rats, respectively. 17betaAE2 competed with [(3)H]E2 for the estrogen receptor. The 17betaAE2 relative binding affinities (RBAs) were: 0.074; Ki=2.2*10(-6)M (17betaE2=100; Ki=1.6*10(-9)M); 0.029 and Ki=3.8*10(-6)M (17betaE2=100; Ki=1.1*10(-9)M) for mice and rats uteri respectively. 17betaAE2 activated hERalpha-mediated beta galactosidase transcription activity in the yeast system co-transfected with hERalpha gene. 17betaAE2 effective concentration (EC)50=1.82 MUM (17betaE2=2.14 nM) with a relative potency of 0.12 (17betaE2=100). These transactivation effects were abolished by the antagonist fulvestrant (ICI 182,780), similarly to 17betaE2. 17betaAE2 and 17alphaAE2 bind with low relative affinity to hERalpha and hERbeta. Both induced hER-mediated reporter gene transactivation in a dose response manner. The overall results provide evidence that 17betaAE2 has a weak agonist estrogenic action greatly mediated through the hERbeta and to a lesser extent the hERalpha at genomic level. PMID- 25448752 TI - Therapeutic strategies of diabetic nephropathy: recent progress and future perspectives. AB - Diabetic nephropathy (DN) is one of the most common complications of diabetes with high mortality rates worldwide. The treatment of DN has posed a formidable challenge to the scientific community. Simple control of risk factors has been insufficient to cope with the progression of DN. During the process of anti-DN drug discovery, multiple pathogeneses such as oxidative stress, inflammation and fibrosis should all be considered. In this review, the pathogenesis of DN is summarized. The major context focuses on a few small molecules toward the pathogenesis available in animal models and clinical trials for the treatment of DN. The perspectives of novel anti-DN agents and the future directions for the prevention of DN are discussed. PMID- 25448753 TI - Racing to define pharmaceutical R&D external innovation models. AB - The pharmaceutical industry continues to face fundamental challenges because of issues with research and development (R&D) productivity and rising customer expectations. To lower R&D costs, move beyond me-too therapies, and create more transformative portfolios, pharmaceutical companies are actively capitalizing on external innovation through precompetitive collaboration with academia, cultivation of biotech start-ups, and proactive licensing and acquisitions. Here, we review the varying innovation strategies used by pharmaceutical companies, compare and contrast these models, and identify the trends in external innovation. We also discuss factors that influence these external innovation models and propose a preliminary set of metrics that could be used as leading indicators of success. PMID- 25448751 TI - Vitamin D deficiency in pregnant women impairs regulatory T cell function. AB - Regulatory T cells and IgE receptors (CD23 and CD21) on B cells were assessed in vitamin D deficient pregnant women. For this, 153 pregnant women were recruited from a government hospital and were categorized into three groups based on 25 hydroxyvitamin D3 (25(OH)D3) status. Regulatory T cell population (Treg cells) and CD23/CD21 expression on B cells were quantified by FACS ARIA II in maternal blood at third trimester; and the same parameters were evaluated in cord blood soon after delivery. In addition, TGF beta and IL-10 were quantified in maternal and cord blood by using Milliplex kits. In a representative sample of eight women from each group (vitamin D sufficient, insufficient and deficient), placental tissues were processed for mRNA expressions of vitamin D receptor (VDR), retinoic acid receptor (RXR), vitamin D binding protein (VDBP) and vitamin D regulating enzymes. Of the 153 pregnant women, 18 were sufficient (>=30 ng/mL), 55 were insufficient (20-29 ng/mL) and 80 were deficient (<=19 ng/mL) for 25(OH)D3 status. The maternal blood Treg cell population (mean (%)+/- SE) was lower (p<0.05) in 25(OH)D3 deficient (0.2 +/- 0.01) pregnant women compared to insufficient (0.34 +/- 0.01) and sufficient (0.45 +/- 0.02) pregnant women. Similarly, cord blood Treg cell population (mean (%)+/- SE) was also lower (p<0.05) in 25(OH)D3 deficient (0.63 +/- 0.03) pregnant women when compared to insufficient (1.05 +/- 0.04) and sufficient (1.75 +/- 0.02) pregnant women. Mean (%) +/- SE of B cells with CD23 and CD21 in maternal blood was higher (p<0.05) in 25(OH)D3 deficient pregnant women (0.35 +/- 0.02; 1.65 +/- 0.04) when compared to insufficient (0.22 +/- 0.02; 0.55 +/- 0.05) and sufficient (0.15 +/- 0.02; 0.21 +/- 0.01) pregnant women. Similarly, mean (%)+/- SE of B cell population with CD23 and CD21 in cord blood was also higher (p<0.05) in 25(OH)D3 deficient (0.41 +/- 0.02; 1.2 +/- 0.03) when compared to insufficient (0.32 +/- 0.01; 0.6 +/- 0.05) and sufficient (0.2 +/- 0.01; 0.4 +/- 0.02) pregnant women. Regulatory cytokines, TGF beta and IL-10 were lower (p<0.05) in 25(OH)D3 insufficient and deficient subjects. In the placenta tissue of women with 25(OH)D3 deficiency, the regulatory T cell transcription factor FOXP3, vitamin D receptor (VDR) and retinoic acid receptor (RXR) expressions were downregulated. In contrast, CD23, CD21 and VDBP expressions were upregulated in 25(OH)D3 deficient and insufficient women. Vitamin D regulating enzymes (CYP24A1, CYP2R1 and CYP27B1) expression were also altered in women with 25(OH)D3 deficiency. The current study shows that impaired maternal 25(OH)D3 during pregnancy influences the spectrum of immune cells such as regulatory T cells and B cells with IgE receptors and this in turn may be linked to allergy and asthma in neonates. PMID- 25448754 TI - A new application of value-stream mapping in new drug development: a case study within Novartis. AB - In this case study, we evaluated the effect of colocation on the drug development process using value-stream mapping (VSM) on the Novartis Campus in Basel, Switzerland. We compared a colocated team with a control group that was not colocated. The data showed that colocation was not associated with increased process speed in terms of lead lines. However, the colocated team communicated more and reported beneficial experiences, such as faster working processes or improved mutual understanding. VSM workshops revealed not only performance indicators about colocation, but also enhanced communication and cooperation through the evolving discussion. PMID- 25448755 TI - The suprachoroidal pathway: a new drug delivery route to the back of the eye. AB - The development of safe and convenient drug delivery strategies for treatment of posterior segment eye diseases is challenging. Although intravitreal injection has wide acceptance amongst clinicians, its use is associated with serious side effects. Recently, the suprachoroidal space (SCS) has attracted the attention of ophthalmologists and pharmaceutical formulators as a potential site for drug administration and delivery to the posterior segment of the eye. This review highlights the major constraints of drug delivery to the posterior eye segment, key anatomical and physiological features of the SCS and drug delivery applications of this route with emphasis on microneedles along with future perspectives. PMID- 25448756 TI - A low-cost, high-quality new drug discovery process using patient-derived induced pluripotent stem cells. AB - Knockout, knock-in and conditional mutant gene-targeted mice are routinely used for disease modeling in the drug discovery process, but the human response is often difficult to predict from these models. It is believed that patient-derived induced pluripotent stem cells (iPSCs) could replace millions of animals currently sacrificed in preclinical testing and provide a route to new safer pharmaceutical products. In this review, we discuss the use of IPSCs in the drug discovery process. We highlight how they can be used to assess the toxicity and clinical efficacy of drug candidates before the latter are moved into costly and lengthy preclinical and clinical trials. PMID- 25448757 TI - Cell-laden microfibers for bottom-up tissue engineering. AB - Bottom-up tissue engineering, which utilizes hundred-micrometer-scale cellular constructs as building blocks, is a promising approach to reconstructing 3D, macroscopic and spatially organized tissues in vitro. Among the various types of cellular building blocks for reconstruction, cell-laden microfibers (CLMs) are recognized as an appropriate shape because many important human tissues and organs are composed of fiber-shaped or network-like structures. This review covers the current techniques in forming CLMs and typical cell culture conditions on or within the microfibers. We summarize CLMs for in vitro 3D tissue construction, in vitro pseudo tissue models for drug testing and in vivo implantation. Additionally, we discuss current challenges regarding CLM technologies and their potential applications. PMID- 25448759 TI - Machine-learning approaches in drug discovery: methods and applications. AB - During the past decade, virtual screening (VS) has evolved from traditional similarity searching, which utilizes single reference compounds, into an advanced application domain for data mining and machine-learning approaches, which require large and representative training-set compounds to learn robust decision rules. The explosive growth in the amount of public domain-available chemical and biological data has generated huge effort to design, analyze, and apply novel learning methodologies. Here, I focus on machine-learning techniques within the context of ligand-based VS (LBVS). In addition, I analyze several relevant VS studies from recent publications, providing a detailed view of the current state of-the-art in this field and highlighting not only the problematic issues, but also the successes and opportunities for further advances. PMID- 25448758 TI - New drugs from ancient natural foods. Oleocanthal, the natural occurring spicy compound of olive oil: a brief history. AB - Extra-virgin olive oil (EVOO), a principal component of the Mediterranean diet (Med diet), is one of the most ancient known foods and has long been associated with health benefits. Many phenolic compounds extracted from Olea europea L. have attracted attention since their discovery. Among these phenolic constituents, oleocanthal has recently emerged as a potential therapeutic molecule for different diseases, showing relevant pharmacological properties in various pathogenic processes, including inflammation, cancers and neurodegenerative diseases. Here, we discuss and summarize the most recent pharmacological evidence for the medical relevance of oleocanthal, focusing our attention on its anti inflammatory and chemotherapeutic roles. PMID- 25448760 TI - Post-approval fate of pharmaceutical companies. AB - For a fortunate subset of pharmaceutical companies, a regulatory approval is the culmination of massive investment in time, work and money. What happens next? Some companies proceed to build a pipeline and obtain additional approvals. Others do not. In this present report, post-approval fate is evaluated and it was found that most companies are ultimately acquired. A subset achieved a second approval six-to-eight years after the first approval, whereas a shrinking subset, designated as 'singlets', remains active in drug discovery with only a single approval. The likelihood that a company will remain a singlet or be acquired relates to therapeutic indication, with oncology associated with increased acquisition potential and infectious-disease-based companies being less commonly acquired. PMID- 25448762 TI - PET, MRI, and simultaneous PET/MRI in the development of diagnostic and therapeutic strategies for glioma. AB - Glioma is the most aggressive brain tumour, resulting in death often within 1-2 years. Current treatment strategies involve surgical resection followed by chemoradiation therapy. Despite continuing improvements in the delivery of adjuvant therapies, there has not been a dramatic increase in survival for glioma. Molecular imaging techniques have become central in the development of new therapeutic strategies in recent years. The multimodal imaging technology of positron emission tomography/magnetic resonance imaging (PET/MRI) has recently been realised on a preclinical scale and the effect of this technology is starting to be observed in preclinical drug development for glioma. Here, we propose that PET/MRI will play an integral part in the development of new diagnostic and therapeutic strategies for glioma. PMID- 25448763 TI - Reprint of "Structural and functional correlates of epileptogenesis--does gender matter?". AB - In the majority of neuropsychiatric conditions, marked gender-based differences have been found in the epidemiology,clinical manifestations, and therapy of disease. One possible reason is that sex differences in cerebral morphology, structural and functional connections, render men and women differentially vulnerable to various disease processes. The present review addresses this issue with respect to the functional and structural correlates to some forms of epilepsy. PMID- 25448764 TI - Injured adult retinal axons with Pten and Socs3 co-deletion reform active synapses with suprachiasmatic neurons. AB - Despite advances in promoting axonal regeneration after adult central nervous system injury, elicitation of a large number of lesion-passing axons reform active synaptic connections with natural target neurons remains limited. By deleting both Pten and Socs3 in retinal ganglion cells, we report that optic nerve axons after prechiasm lesion robustly reinnervate the hypothalamus, form new synapses with neurons in the suprachiasmatic nucleus (SCN), and re-integrate with the existing circuitry. Photic or electric stimulation of the retinal axons induces neuronal response in SCN. However both the innervation pattern and evoked responses are not completely restored by the regenerating axons, suggesting that combining with other strategies is necessary to overcome the defective rewiring. Our results support that boosting the intrinsic growth capacity in injured neurons promotes axonal reinnervation and rewiring. PMID- 25448761 TI - Improving the predictive value of interventional animal models data. AB - For many chronic diseases, translational success using the animal model paradigm has reached an impasse. Using Alzheimer's disease as an example, this review employs a networks-based method to assess repeatability of outcomes across species, by intervention and mechanism. Over 75% of animal studies reported an improved outcome. Strain background was a significant potential confounder. Five percent of interventions had been tested across animals and humans, or examined across three or more animal models. Positive outcomes across species emerged for donepezil, memantine and exercise. Repeatable positive outcomes in animals were identified for the amyloid hypothesis and three additional mechanisms. This approach supports in silico reduction of positive outcomes bias in animal studies. PMID- 25448767 TI - Gastric bypass using barbed suture (with video). PMID- 25448765 TI - Focal disturbances in the blood-brain barrier are associated with formation of neuroinflammatory lesions. AB - Early changes in the normal appearing white matter of multiple sclerosis (MS) patients precede the appearance of gadolinium-enhancing lesions. Although these findings suggest blood-brain barrier (BBB) breakdown as an important feature in MS pathogenesis, limited information is available on the BBB alterations during lesion genesis. Here, we perform a longitudinal characterization of the vascular, neuropathological and immunological changes before lesion formation in mice developing spontaneous relapsing-remitting experimental autoimmune encephalomyelitis (sRR-EAE). We found a significant upregulation of Th1 and Th17 cytokines in the periphery of sRR-EAE mice before any evident neuropathology. In the CNS, BBB and astroglial activations were the first pathological changes occurring after 45days of age and were followed by immune cell infiltration by day 50. These pathological alterations subsequently led to perivascular demyelination and disease onset. In MS, (p)reactive lesions mirrored the changes seen in early sRR-EAE by displaying considerable BBB disruption, perivascular astrogliosis, redistribution of junctional proteins and increased expression of endothelial cell adhesion molecules. Our findings suggest that BBB breach occurs before significant immune cell infiltration and demyelination. In addition, peripheral immune activation during sRR-EAE precedes CNS pathology, suggesting that outside in signaling mechanisms play a role in the development of neuroinflammatory lesions. PMID- 25448766 TI - Bisphenol diglycidyl ethers and bisphenol A and their hydrolysis in drinking water. AB - Epoxy coatings are commonly used to protect the interior (and exterior) surfaces of water mains and storage tanks and can be used on the interior surfaces of water pipes in homes, hospitals, hotels, and other buildings. Common major components of epoxies include bisphenols, such as bisphenol A (BPA) or bisphenol F (BPF), and their reactive prepolymers, bisphenol A diglycidyl ether (BADGE) and bisphenol F diglycidyl ether (BFDGE), respectively. There currently are health concerns about the safety of BPA and BPF due to known estrogenic effects. Determination of key bisphenol leachates, development of a hydrolysis model, and identification of stable hydrolysis products will aid in assessment of human bisphenol exposure through ingestion of drinking water. Liquid chromatography/mass spectrometry (LC/MS/MS) was used for quantitation of key analytes, and a pseudo-first order kinetic approach was used for modeling. In fill-and-dump studies on epoxy-coated pipe specimens, BADGE and a BPA-like compound were identified as leachates. The BADGE hydrolysis model predicts BADGE half-lives at pH 7 and 15, 25, 35, and 40 degrees C to be 11, 4.6, 2.0, and 1.4 days respectively; the BFDGE half-life was 5 days at pH 7 and 25 degrees C. The two identified BADGE hydrolysis products are BADGE-H2O and BADGE 2H2O, with BADGE 2H2O being the final end product under the conditions studied. PMID- 25448768 TI - Accessory liver lobes: anatomical description and clinical implications. AB - Accessory liver lobes are a rare condition and appear to be due to excessive development of the liver. The presence of an accessory hepatic lobe is often diagnosed incidentally and sometimes revealed if it develops torsion, especially in pedunculated forms. In most cases, the accessory lobe is located below the liver, i.e., infrahepatic. Riedel's lobe is the best-known example of an accessory lobe, corresponding to hypertrophy of segments V and VI. While accessories lobes can simulate tumors, there have also been reports of hepatocellular tumor(s) that developed in these accessory lobes. Based on a review of the literature, this update focuses on accessory hepatic lobes. PMID- 25448769 TI - Comparative biochemistry of Giardia, Hexamita and Spironucleus: Enigmatic diplomonads. AB - The diplomonad genera are here represented by three highly diverse species, both free-living (Hexamita inflata), and parasitic (Spironucleus vortens and Giardia intestinalis). All three are moderately aerotolerant flagellates, inhabiting environments where O2 tensions are low and fluctuating. Many diplomonads are opportunistic pathogens of avian, terrestrial and aquatic animals. Hexamitids inhabit deep waters and sediments of lakes and marine basins, S. vortens commonly infects the intestinal tract of ornamental fish, particularly of cichlids and cyprinids, and G. intestinalis, the upper intestinal tracts of humans as well as domestic and farm animals. Despite these very different habitats, their known physiological and biochemical characteristics are similar, but they do differ in significant respects as their lifestyles and life cycles demand. They have efficient O2 scavenging systems, and are highly effective at countering rapid O2 fluctuations, or clustering away from its source (except for G. intestinalis when attached to the jejunal villi). Their core metabolic pathways (glycolysis using pyrophosphate), incomplete tricarboxylic acid cycle (lacking alpha-ketoglutarate dehydrogenase), and amino acid metabolism (with an alternative energy-generating arginine dihydrolase pathway as a possibility in some cases), largely conform to those of other protists inhabiting low-O2 environments. Mitochondrial evolutionary reduction to give hydrogenosomes as seen in Spironucleus spp. has proceeded further to its minimal state in the mitosomes of G. intestinalis. Understanding of essential redox reactions and the maintentence of redox state, especially in the infective encysted stage of G. intestinalis provide increasing possibilities for parasite control. To this aim a plethora of new synthetic chemicals and natural products (especially those from garlic, Allium sativum) show promise as replacements for the highly effective (but potentially toxic to higher organisms) 5-nitroimidazoles (e.g., metronidazole) in the treatment and/or prevention of dimplomonad infection in humans and animals. PMID- 25448770 TI - Contribution of lipid environment to NADPH oxidase activity: influence of sterol. AB - The NADPH-oxidase complex, which plays beneficial or detrimental role in the inflammatory and degenerative diseases, is a membrane multi-subunit complex tightly regulated in order to produce superoxide anions, precursor of oxygen reactive species (ROS), in cells. The flavocytochrome b(558) (Cytb(558)) is the catalytic core of the NADPH oxidase which consists of two membrane proteins gp91(phox) (highly glycosylated) and p22(phox). In this work we took advantage of heterologous yeast cells engineered to express wild-type bovine Cytb(558) to analyze the properties of the NADPH oxidase activity during the biosynthesis processing steps of gp91(phox) and p22(phox) within endoplasmic reticulum (ER) and plasma membrane (Pmb). Our data showed that, in yeast, the heterodimerization at the endoplasmic reticulum membranes was concomitant with high level glycosylation of gp91(phox) and the heme acquisition. This study also demonstrated that the phagocyte NADPH oxidase was active at ER membranes and that this activity was surprisingly higher at the ER compared to the Pmb membranes. We have correlated these findings with the presence of sterols in the plasma membranes and their absence in ER membranes. This correlation was confirmed by decreased superoxide anion production rates in proteoliposomes supplemented with ergosterol or cholesterol. Our data support the idea that membrane environment might be determinant for ROS regulation and that sterols could directly interact with the membrane proteins of the NADPH oxidase constraining its capacity to produce superoxide anions. PMID- 25448771 TI - Ciguatera fish poisoning: a first epidemic in Germany highlights an increasing risk for European countries. AB - Toxin-producing microalgae are thriving worldwide due to coral reef destruction and global warming with major consequences on ecosystems, international trade and human health. Microalgae belonging to the family of flagellate protists, in particular dinoflagellates, secrete a variety of high-molecular-weight polyether toxins that accumulate through the marine food chain to cause disease in humans by acting as sodium channel activator toxins; ciguatera is the most frequent seafood-borne illness worldwide with 50,000 to 500,000 global incidences per annum and is usually limited to endemic areas located between 35 degrees northern and 35 degrees southern latitude. The rising global incidence frequency renders it a major human health problem, because no curative treatment is available yet and reliable detection assays are lacking. During the last decade ciguatera has increasingly become endemic in previously unaffected areas for two reasons: first global warming has contributed to the emergence of dinoflagellate species in subtropical and even temperate regions that previously had been constrained to tropical areas and second: in Europe globalization of fishing industry and tourism has led to a progressive increase in the number of ciguatera cases and a lack of awareness among medical personnel contributes to under reporting. We review, through a recent ciguatera outbreak in Germany, the risk for ciguatera poisoning in Europe and highlight characteristic symptoms, current knowledge about disease pathomechanisms and treatment options. PMID- 25448772 TI - Rothstein Roundtable podcast--"Interprofessionalism: is it Campfire Kumbaya, or the means to the triple aim (better health, better care, lower cost)?". PMID- 25448773 TI - On "Identifying items to assess methodological quality..." Armio-Olivo A, Cummings GC, Fuentes J, et al. Phys Ther. 2014;94:1272-1284. PMID- 25448774 TI - On "Application of LSVT BIG intervention..." Janssens J, Malfroid KN, Myffeler T, et al. Phys Ther. 2014;94:1014-1023. PMID- 25448776 TI - Intramuscular long-acting paliperidone palmitate in acute patients with schizophrenia unsuccessfully treated with oral antipsychotics. AB - In this prospective multicentre, open-label, 6-month study (Paliperidone Palmitate Flexible Dosing in Schizophrenia [PALMFlexS]), tolerability, safety and treatment response with paliperidone palmitate (PP) were explored in patients with acute symptoms of schizophrenia following switching from previously unsuccessful treatment with oral antipsychotics. This pragmatic study was conducted in a large, more representative sample of the general schizophrenia population compared to randomized controlled pivotal trials, to specifically mimic real-world clinical situations. After initiation on Day 1 and Day 8, patients received PP once monthly at flexible doses (50-150mgeq.) intramuscularly. The primary efficacy outcome was defined as the percentage of patients achieving >=30% improvement in PANSS total score from baseline (BL) to last-observation-carried-forward (LOCF) endpoint (EP). Safety and tolerability assessments included Extrapyramidal Symptom Rating Scale (ESRS) total score and treatment-emergent adverse events (TEAEs). Overall, 212 patients received PP at least once after switching from oral antipsychotics, primarily due to lack of efficacy (45.8%). Significant improvements from BL in mean (SD) PANSS total score were observed from Day 8 onwards (BL to LOCF EP: -31.0 [29.0]; p<0.0001). At endpoint, two-thirds (66.7%) and 43.5% of patients achieved a >=30% and >=50% improvement in mean PANSS total score, respectively. PP was associated with significant improvements across secondary measures of symptom severity, subjective well-being, medication satisfaction, illness-related disorders of activity and participation, and patient functioning (p<0.0001; BL to LOCF EP). PP was generally well tolerated, with significant reductions in ESRS total score (p<0.0001) and mainly mild-to-moderate TEAEs. TEAEs reported in >=5% of patients were injection-site pain (13.7%), insomnia (10.8%), psychotic disorder (10.4%), headache and anxiety (both 6.1%). The PALMFlexS study findings provide valuable pragmatic clinical data on PP treatment in patients with acute schizophrenia previously unsuccessfully treated with oral antipsychotics. PMID- 25448777 TI - Involvement of PPAR receptors in the anticonvulsant effects of a cannabinoid agonist, WIN 55,212-2. AB - Cannabinoid and PPAR receptors show well established interactions in a set of physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study aimed to evaluate the roles of the PPAR gamma, PPAR-alpha and CB1 receptors on the anticonvulsant effects of WIN 55,212-2 (WIN, a non selective cannabinoid agonist). The clonic seizure thresholds after intravenous administration of pentylenetetrazole (PTZ) were assessed in mice weighing 23-30 g. WIN increased the seizure threshold dose dependently. Pretreatment with pioglitazone, as a PPARgamma agonist, potentiated the anticonvulsant effects of WIN, while PPARgamma antagonist inhibited these anticonvulsant effects partially. On the other hand PPARalpha antagonist reduced the anticonvulsant effects of WIN significantly. Finally the combination of CB1 antagonist and PPARalpha antagonist could completely block the anticonvulsant properties of WIN. Taken together, these results show for the first time that a functional interaction exists between cannabinoid and PPAR receptors in the modulation of seizure susceptibility. PMID- 25448778 TI - AMN082, a metabotropic glutamate receptor 7 allosteric agonist, attenuates locomotor sensitization and cross-sensitization induced by cocaine and morphine in mice. AB - Previous studies have indicated that metabotropic glutamate receptors 7 (mGluR7s) are involved in drug addiction. However, the role of these receptors in drug induced behavioral sensitization is unknown. The aim of the present study was to determine whether systemic injection of AMN082, a selective mGluR7 allosteric agonist, reduces the cocaine- and morphine-induced hyperactivity and the development and expression of locomotor sensitization, and also affects the reciprocal cross-sensitization to the stimulant effect of cocaine and morphine in mice. AMN082 (1.25-10.0 mg/kg, i.p.) did not have an impact on locomotion of naive mice and did not affect the acute cocaine- or morphine-induced hyperactivity, except the dose of 10 mg/kg that suppressed the locomotor effect of both drugs. Repeated exposure to cocaine or morphine (10 mg/kg, 5* every 3 days) gradually increased locomotion during induction of sensitization and after 4 (cocaine) or 7 day (morphine) withdrawal phase when challenged with cocaine (10 mg/kg, i.p.) or morphine (10 mg/kg, i.p.) on day 17 or 20, respectively. Pretreatment of animals with the lower doses of AMN082 (1.25-5.0 mg/kg, i.p.), 30 min before every cocaine or morphine injection during repeated drug administration or before cocaine or morphine challenge, dose-dependently attenuated the development, as well as the expression of cocaine or morphine locomotor sensitization. AMN082 also inhibited the reciprocal cross-sensitization between these drugs. Prior to administration of MMPIP (10 mg/kg, i.p.), a selective mGluR7 antagonist reversed the inhibitory effect of AMN082 on the development or expression of cocaine or morphine sensitization. These data indicate that AMN082 attenuated the development and expression of cocaine and morphine sensitization, and the reciprocal cross-sensitization via a mechanism that involves mGluR7s. Thus, AMN082 might have therapeutic implications not only in the treatment of cocaine or opioid addiction but also in the treatment of cocaine/opioid polydrug-abusers. PMID- 25448779 TI - Altered gray matter density and disrupted functional connectivity of the amygdala in adults with Internet gaming disorder. AB - OBJECTIVES: The aim of this study was to evaluate the altered brain structure and functional connectivity (FC) among subjects with Internet gaming disorder (IGD). METHODS: We recruited 30 males with IGD and 30 controls and evaluated their gray matter density (GMD) and FC using resting fMRI. The severities of IGD, gaming urge, and impulsivity were also assessed. RESULTS: The results demonstrated that the subjects with IGD had a higher impulsivity and a greater severity of IGD. The subjects with IGD had a lower GMD over the bilateral amygdala than the controls. Further, the subjects with IGD had lower FC with the left amygdala over the left dorsolateral prefrontal lobe (DLPFC) and with the right amygdala over the left DLPFC and orbital frontal lobe (OFL). They also had higher FC with the bilateral amygdala over the contralateral insula than the controls. The FC between the left amygdala and DLPFC was negatively correlated with impulsivity. The FC of the right amygdala to the left DLPFC and orbital frontal lobe was also negatively correlated with impulsivity. Our results indicated that the altered GMD over the amygdala might represent vulnerability to IGD, such as impulsivity. Further analysis of the amygdala demonstrated impaired FC to the frontal lobe, which represents impulsivity. CONCLUSION: The results of this study suggested that the amygdala plays a very influential role in the mechanism of IGD. Its detailed role should be further evaluated in future study and should be considered in the treatment of IGD. PMID- 25448781 TI - Abdominal wall defects. AB - Abdominal wall defects in foetuses include gastroschisis, exomphalos, bladder exstrophy complex, cloacal exstrophy and body stalk syndrome. The defects that occur more commonly are gastroschisis and exomphalos. In this review we assess the current evidence regarding the incidence, perinatal risk factors, antenatal and postnatal management and outcome for both these conditions. A review of the current surgical practices for management of gastroschisis and exomphalos is discussed. PMID- 25448782 TI - Malrotation and intestinal atresias. AB - This review encompasses four congenital conditions which present with symptoms of bowel obstruction in the neonatal period. The antenatal and postnatal features of malrotation, jejuno-ileal atresia, duodenal atresia and colonic atresia are discussed. Each condition is outlined including the classification, epidemiology, aetiology and presentation, and a summary of the surgical management is described. PMID- 25448783 TI - Hirschsprung disease and anorectal malformation. AB - Hirschsprung disease and Anorectal Malformations are congenital disorders presenting in neonates with distal intestinal obstruction. Hirschsprung disease is associated with a functional distal bowel obstruction resulting from the abnormal development of the enteric nervous system and ensuing aganglionosis of the distal gut. Anorectal Malformations comprise a spectrum of anatomical anomalies causing a mechanical bowel obstruction. Both conditions are frequently associated with congenital abnormalities/syndromes, which require careful assessment and evaluation. Surgical intervention is usually required for both conditions with careful preparation and meticulous technique. Long-term follow-up allows early identification and treatment of potentially debilitating symptoms, which include faecal incontinence. PMID- 25448780 TI - Kindergarten classroom functioning of extremely preterm/extremely low birth weight children. AB - BACKGROUND: Cognitive, behavioral, and learning problems are evident in extremely preterm/extremely low birth weight (EPT/ELBW, <28 weeks gestational age or <1000 g) children by early school age. However, we know little about how they function within the classroom once they start school. AIMS: To determine how EPT/ELBW children function in kindergarten classrooms compared to termborn normal birth weight (NBW) classmates and identify factors related to difficulties in classroom functioning. METHODS: A 2001-2003 birth cohort of 111 EPT/ELBW children and 110 NBW classmate controls were observed in regular kindergarten classrooms during a 1-hour instructional period using a time-sample method. The groups were compared on frequencies of individual teacher attention, competing or offtask behaviors, task management/preparation, and academic responding. Regression analysis was also conducted within the EPT/ELBW group to examine associations of these measures with neonatal and developmental risk factors, kindergarten neuropsychological and behavioral assessments, and classroom characteristics. RESULTS: The EPT/ELBW group received more individual teacher attention and was more often off-task than the NBW controls. Poorer classroom functioning in the EPT/ELBW group was associated with higher neonatal and developmental risk, poorer executive function skills, more negative teaching ratings of behavior and learning progress, and classroom characteristics. CONCLUSION: EPT/ELBW children require more teacher support and are less able to engage in instructional activities than their NBW classmates. Associations of classroom functioning with developmental history and cognitive and behavioral traits suggest that these factors may be useful in identifying the children most in need of special educational interventions. PMID- 25448784 TI - Neonatal surgical conditions. PMID- 25448785 TI - Congenital cystic lesions of the lung. AB - Congenital cystic lesions of the lung are present in 1 in 10,000-35,000 births and present as a spectrum of anomalies. Majority of these cystic lesions comprise congenital cystic adenomatoid malformations, pulmonary sequestrations, congenital lobar emphysema, and bronchogenic cysts. Most of these lesions are nowadays detected antenatally, however some will present either in the newborn or during later childhood. A review of the aetiology, classification, natural history, investigations, and treatment of congenital cystic lung lesions is discussed. PMID- 25448786 TI - Congenital diaphragmatic hernia. AB - There is a paucity of level 1 and level 2 evidence for best practice in surgical management of CDH. Antenatal imaging and prognostication is developing. Observed to expected lung-to-head ratio on ultrasound allows better predictive value over simple lung-to-head ratio. Based on 2 randomised studies, the verdict is still out in terms the best group and indication for antenatal intervention and their outcome. Tracheal occlusion is best suited for prospective randomised studies of benefit and outcome. Only one pilot randomised controlled study of thoracoscopic repair exists, suggesting increased acidosis; blood gases and CO2 levels should be closely monitored. Only poorly controlled retrospective studies suggest higher recurrence rates. Randomised studies on the outcome of thoracoscopic repair are needed. Careful selection, anaesthetic vigilance, monitoring and follow-up of these cases are required. There is no evidence to suggest the best patch material to decrease recurrences. Evidence suggests no benefit from routine fundoplication based on the one randomised study. Multi-disciplinary follow-up is required. This can be visits to different specialities, but may be best served by a multi disciplinary one-stop clinic. PMID- 25448787 TI - Oesophageal atresia and tracheo-oesophageal fistula. AB - Oesophageal atresia with tracheo-oesophageal fistula is a relatively common congenital anomaly occurring in around 1:2500 births. The aetiology and embryology of the condition remain unclear, whilst associations with other significant anomalies are common. Studies in rodent models are contributing to our understanding of the condition. Advances in surgical care and neonatal management have improved survival considerably to around 90%. Long-gap and isolated oesophageal atresia present significant management challenges. Post operative and long-term complications including oesophageal stricture, gastro oesophageal reflux and respiratory compromise however remain relatively common and continue to pose a challenge for the ongoing management of patients. PMID- 25448789 TI - Male sexual dysfunction and ankylosing spondylitis: a systematic review and metaanalysis. AB - OBJECTIVE: No consensus has been reached on sexual dysfunction in men with ankylosing spondylitis (AS). Our study aimed to derive a more precise estimation of the sexual function and its clinical correlations in men with AS. METHODS: A metaanalysis was performed and the related literature were searched in PubMed, Elsevier Science Direct, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and in reference lists of articles and systematic reviews. Score of the International Index of Erectile Function (IIEF) was used as the outcome measurement, and standardized mean differences (SMD) with 95% CI were calculated. RESULTS: Eleven studies were included, including 535 men with AS and 430 male controls. Each domain of the IIEF score (erectile function: SMD -0.52, 95% CI -0.68 - -0.37; orgasmic function: -0.72, -1.03 - -0.42; sexual drive: 0.40, -0.62 - -0.18; intercourse satisfaction: -0.86, -1.15 - -0.56; and overall satisfaction: -0.61, -0.91 - -0.32) were lower in men with AS than in controls. In the subgroup analysis, the results did not change except for the sexual drive in the Asians group (-0.15, -0.42-0.13). At metaregression, no study characteristics were significantly associated with effect size of the IIEF score. CONCLUSION: Sexual function is impaired in male patients with AS and further studies are necessary to better understand risk factors for sexual dysfunction in this population. PMID- 25448790 TI - Polymyositis/dermatomyositis and malignancy risk: a metaanalysis study. AB - OBJECTIVE: To investigate the association between polymyositis (PM)/dermatomyositis (DM) and risks of malignancy. METHODS: We searched Pubmed for articles dated before August 16, 2013. Studies were included if they met the following criteria: (1) a cohort or observational study; (2) PM or DM as one of the exposures of interest; (3) cancer as an outcome of interest; and (4) the rate ratio (RR) or standardized incidence ratio (SIR) were available with their 95% CI. We used random-effects or fixed-effects models to calculate the pooled RR according to the heterogeneity test. RESULTS: Twenty publications were included. Compared with the general population, the pooled RR for patients with PM, DM, and PM/DM were 1.62 (95% CI 1.19-2.04), 5.50 (4.31-6.70), and 4.07 (3.02-5.12), respectively. The increased risks were more significant in patients within the first year of myositis diagnosis, male patients, and population-based studies (for DM). A significant association was also found between PM or DM and most site specific malignancies. However, both PM and DM were not associated with stomach and prostate cancers. Significant heterogeneity was found between studies on association between PM/DM and overall malignancy, but not between PM/DM and the majority of site-specific malignancies, suggesting that that inherent malignancy difference may be a major source of heterogeneity. CONCLUSION: The present metaanalysis indicates that PM and DM are significantly associated with increased risks of overall malignancy and most site-specific malignancies. The number of studies on association between PM or DM and some malignancies is too small to draw a firm conclusion. Accordingly, more research is needed for these malignancies. PMID- 25448788 TI - The hypothalamic photoreceptors regulating seasonal reproduction in birds: a prime role for VA opsin. AB - Extraretinal photoreceptors located within the medio-basal hypothalamus regulate the photoperiodic control of seasonal reproduction in birds. An action spectrum for this response describes an opsin photopigment with a lambdamax of ~ 492 nm. Beyond this however, the specific identity of the photopigment remains unresolved. Several candidates have emerged including rod-opsin; melanopsin (OPN4); neuropsin (OPN5); and vertebrate ancient (VA) opsin. These contenders are evaluated against key criteria used routinely in photobiology to link orphan photopigments to specific biological responses. To date, only VA opsin can easily satisfy all criteria and we propose that this photopigment represents the prime candidate for encoding daylength and driving seasonal breeding in birds. We also show that VA opsin is co-expressed with both gonadotropin-releasing hormone (GnRH) and arginine-vasotocin (AVT) neurons. These new data suggest that GnRH and AVT neurosecretory pathways are endogenously photosensitive and that our current understanding of how these systems are regulated will require substantial revision. PMID- 25448791 TI - Genetic polymorphisms of Foxp3 in patients with rheumatoid arthritis. AB - OBJECTIVE: The aim of the study was to identify 2 polymorphic variants in the promoter region of the Foxp3 gene and their possible association with susceptibility to and severity of rheumatoid arthritis (RA). The association between genetic factors and pathogenesis suggests that T cells take part in the induction of RA. The CD4+CD25highFoxp3+ subset of regulatory T cells plays an essential role in preventing autoimmunity and maintaining immune homeostasis. METHODS: Patients with RA (n = 274) and healthy individuals (n = 295) were examined for -3279 C/A and -924 A/G Foxp3 gene polymorphisms by the polymerase chain reaction-restriction fragment-length polymorphism method. Serum Foxp3 levels in patients with RA and controls were measured with ELISA. RESULTS: Foxp3 3279 A and -924 G alleles were associated with significantly elevated risk of RA in the population tested (p = 0.003 and p = 0.004, respectively) compared to the wild-type alleles. Overall, -3279 C/A and -924 A/G Foxp3 gene polymorphisms were in indistinct linkage disequilibrium with D' = 0.481 and r(2) = 0.225. From 4 possible haplotypes, frequencies of 2 (AG and CA) showed significant differences between both examined groups (respectively, p < 0.001 and p = 0.007). After appropriate adjustment of Bonferroni correction for multiple testing, the genotype-phenotype analysis showed no significant correlation of the Foxp3 -3279 C/A and -924 A/G polymorphisms with the disease activity, joint damage, laboratory variables, and extraarticular manifestation in patients with RA. Serum Foxp3 level was significantly higher in patients than in controls (p < 0.0001). CONCLUSION: Current findings indicated that the Foxp3 genetic polymorphism and the Foxp3 protein level may be associated with susceptibility to RA in the Polish population. PMID- 25448793 TI - Trabecular bone score in female patients with systemic sclerosis: comparison with rheumatoid arthritis and influence of glucocorticoid exposure. AB - OBJECTIVE: Systemic sclerosis (SSc) is associated with an increased risk of osteoporosis and fractures. To date, the etiology of bone loss in SSc is unclear. Trabecular bone score (TBS) provides an indirect measurement of bone microarchitecture, independent of areal bone mineral density (aBMD). The aims were to assess bone involvement in SSc using TBS in comparison with a "high-risk" population with rheumatoid arthritis (RA) and controls, and to investigate the determinants of a low TBS. METHODS: This was a cross-sectional study of 65 women with SSc, 138 age-matched female patients with RA, and 227 age-matched female controls. Spine and hip aBMD were assessed using dual-energy X-ray absorptiometry. TBS was calculated from the anteroposterior image of the spine aBMD. RESULTS: TBS was significantly lower in SSc compared to controls (p < 0.0001) and did not differ from RA (p = 0.128), despite lower cumulative and daily glucocorticoid (GC) dose (p < 0.0001). Further, patients with SSc receiving GC >= 5 mg/day had a significantly lower TBS than those receiving GC < 5 mg/day (p = 0.001). Multivariate analysis revealed that a low TBS was independently associated with daily GC dose (OR 5.6, 95% CI 1.7-19.2) and a T score <= -2.5 SD (OR 5.0, 95% CI 1.5-7.0) in SSc. No association between GC and TBS was found in RA. CONCLUSION: Our results support the development of a combined approach using both TBS and aBMD for the assessment of bone microarchitecture in inflammatory rheumatic diseases. Our study showed that SSc-related bone involvement is characterized by an impairment in bone quality in addition to reduced bone quantity, and highlights that TBS can identify the negative effect of GC on bone microarchitecture. PMID- 25448792 TI - PTPN22 R620W polymorphism and ANCA disease risk in white populations: a metaanalysis. AB - OBJECTIVE: No clear consensus has been reached on the PTPN22 R620W polymorphism and anti-neutrophil cytoplasmic antibody (ANCA) disease, especially when stratified by ANCA specificity and disease phenotypes. METHODS: A metaanalysis was conducted on the PTPN22 R620W polymorphism across 4 studies in 1399 white patients with ANCA disease and 9934 normal control subjects. RESULTS: Overall, metaanalysis showed a statistically significant association between the A allele and ANCA disease in all subjects (OR 1.44, 95% CI 1.26-1.64, p < 0.00001), and stratification by disease category indicated the A allele was associated with granulomatosis with polyangiitis (Wegener's; GPA; OR 1.72, 95% CI 1.35-2.20, p < 0.0001) and microscopic polyangiitis (MPA; OR 1.53, 95% CI 1.08-2.15, p = 0.02) as compared to controls. However, when stratified by ANCA specificity, the association of the A allele was statistically evident among those with proteinase 3 (PR3) ANCA disease (OR 1.74, 95% CI 1.25-2.430, p = 0.001), with the same trend but not statistically associated with myeloperoxidase ANCA disease (OR 1.94, 95% CI 0.64-5.85, p = 0.24). The marked associations were also demonstrated between this allele with lung (OR 1.69, 95% CI 1.21-2.36, p = 0.002), ENT (OR 2.03, 95% CI 1.45-2.84, p < 0.0001), skin (OR 2.55, 95% CI 1.69-3.84, p < 0.0001), and peripheral neuropathy involvement (OR 2.12, 95% CI 1.39-3.22, p = 0.0005). CONCLUSION: The PTPN22 620W allele confers susceptibility to the occurrence and development of ANCA disease in whites, with specific evidence among subsets with GPA, MPA, and PR3 ANCA. PMID- 25448794 TI - Syncope in a febrile state: A case report of Brugada syndrome. AB - In 1992, Brugada and Brugada first described a new entity, which became known as Brugada syndrome, that is associated with a high risk of ventricular arrhythmias and sudden cardiac death in patients without structural heart disease. This syndrome is characterized by a distinct electrocardiographic phenotype, type 1 Brugada pattern, consisting of a coved ST-segment elevation (>=0.2 mV) followed by a negative T wave in more than one right precordial lead. This pattern is dynamic, and can be spontaneous or concealed, but is unmasked under certain circumstances, like febrile states. The authors report a case in which the diagnosis of Brugada syndrome was made in the course of etiologic investigation of recurrent syncope in a febrile state. PMID- 25448796 TI - High levels of high-sensitivity C-reactive protein and uric acid can predict disease severity in patients with mitral regurgitation. AB - INTRODUCTION: Both high-sensitivity CRP (hs-CRP) and uric acid (UA) levels are known to be increased in heart failure patients and are associated with poorer functional capacity and adverse outcome. The role of these markers in patients with mitral regurgitation (MR) is less clear. The aim of this study was to assess the relationship between hs-CRP, UA and organic MR. We also assessed whether hs CRP and UA levels are correlated with symptoms of MR, severity of MR, LV remodeling and outcome during follow-up. METHODS: A total of 200 consecutive patients (87 men [43.5%]; mean age 61.6+/-12.5 years) with moderate or severe isolated and organic MR were included in the study. All the patients were assessed clinically and were managed and treated with standard medical therapy according to evidence-based practice guidelines. Patients were categorized according to New York Heart Association (NYHA) functional class. We assessed and graded the severity of MR using a multiparametric approach. hs-CRP was measured with chemiluminescent immunometric assay using an IMMULITE(r) 1000 autoanalyzer (Siemens, Germany). Serum UA levels were analyzed using a Cobas(r) 6000 autoanalyzer (Roche Diagnostics, Mannheim, Germany). RESULTS: Mean UA levels increased significantly with NYHA class: 4.46+/-1.58 mg/dl for patients in NYHA class I, 5.91+/-1.69 mg/dl for class II, 6.31+/-2.16 mg/dl for class III and 8.86+/-3.17 mg/dl for class IV (p<0.001). Mean UA levels also increased significantly with increased severity of MR (moderate 5.62+/-1.9 mg/dl, moderate to severe 5.56+/-1.2 mg/dl, severe 7.38+/-3.4 mg/dl, p<0.001). There was a significant correlation between UA level and left ventricular end-diastolic diameter (r=0.40; p<0.001), left ventricular end-systolic diameter (r=0.297; p=0.001) and left ventricular ejection fraction (LVEF) (r=0.195, p=0.036), whereas hs-CRP was not correlated with these parameters. In multivariate Cox proportional hazards analysis LVEF, NYHA class and UA levels were the only independent predictors of death. CONCLUSION: UA and hs-CRP levels can help identify patients with asymptomatic moderate or severe mitral regurgitation. UA levels may be useful to assess the extent of left ventricular remodeling and in the optimal timing of mitral valve surgery in certain subsets of patients. PMID- 25448795 TI - Pro-inflammatory triggers in childhood obesity: correlation between leptin, adiponectin and high-sensitivity C-reactive protein in a group of obese Portuguese children. AB - INTRODUCTION: Pediatric obesity is increasingly prevalent in the Portuguese population. Adipocyte dysfunction results in the expression of pro-inflammatory mediators that are responsible for the low-grade inflammatory process that characterizes obesity. OBJECTIVES: The aim of this study was to investigate the relationship between markers of adiposity, inflammation and adipokines in a Portuguese obese pediatric population. METHODS: One hundred and twenty children of both sexes, aged 6-17 years, were included in this study. The control group consisted of 41 healthy normal-weight children. The variables analyzed were age, gender, body mass index, waist circumference, fat mass percentage, high sensitivity C-reactive protein (hs-CRP), leptin and adiponectin. RESULTS: There were significant differences between controls and obese children for all parameters analyzed. In the obese group, after controlling for age and gender, hs CRP (p=0.041), adiponectin (p=0.019) and leptin (p<0.001) still showed significant statistical differences. A direct correlation was found between hs CRP, leptin, body mass index and waist circumference, the strongest being with leptin (r=0.568; p<0.001). This trend remained statistically significant, regardless of gender or pubertal age. CONCLUSIONS: Considering the role of leptin, adiponectin and hs-CRP in the genesis of endothelial dysfunction, they may be used in clinical practice for risk stratification, as well as in the assessment of weight control programs. PMID- 25448798 TI - The Canadian Coalition for Seniors' Mental Health (CCSMH) and Canadian Academy of Geriatric Psychiatry (CAGP) Joint Scientific Meeting. PMID- 25448799 TI - Systematic review and meta-analysis of feasibility, safety, and efficacy of a novel procedure: associating liver partition and portal vein ligation for staged hepatectomy. AB - BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a novel strategy to resect liver tumors despite the small size of the liver remnant. It is an hepatectomy in two stages, with PVL and parenchymal transection during the first stage, which induces rapid growth of the remnant liver exceeding any other technique. Despite high postoperative morbidity and mortality in most reports, the technique was adopted by a number of surgeons. MATERIALS AND METHODS: This systematic review explores current data regarding the feasibility, safety, and oncologic efficacy of ALPPS; the search strategy has been published online. A meta-analysis of hypertrophy, feasibility (ALPPS stage 2 performed), mortality, complications, and R0 (complete) resection was performed. RESULTS: A literature search revealed a total of 13 publications that met the search criteria, reporting data from 295 patients. Evidence levels were low, with the highest Oxford evidence level being 2c. The most common indication was colorectal liver metastasis in 203 patients. Hypertrophy in the meta-analysis was 84 %, feasibility (ALPPS stage 2 performed) 97 % (CI 94-99 %), 90-day mortality 11 % (CI 8-16 %), and complications grade IIIa or higher occured in 44 % (CI 38 50 %) of patients. A standardized reporting format for complications is lacking despite the widespread use of the Clavien-Dindo classification. Oncological outcome is not well-documented. The most common topics in the selected studies published were technical feasibility and indications for the procedures. Publication bias due to case-series and single-center reports is common. CONCLUSION: A systematic exploration of this novel operation with a rigid methodology, such as registry analyses and a randomized controlled trial, is highly advised. PMID- 25448801 TI - Determining the role of gene expression assays in local therapy for breast cancer: first steps with a positive impression. PMID- 25448797 TI - Phase transformation of dental zirconia following artificial aging. AB - AIMS: Low-temperature degradation (LTD) of yttria-stabilized zirconia can produce increased surface roughness with a concomitant decrease in strength. This study determined the effectiveness of artificial aging (prolonged boiling/autoclaving) to induce LTD of Y-TZP (yttria-tetragonal zirconia-polycrystals) and used artificial aging for transformation depth progression analyses. The null hypothesis is aging techniques tested produce the same amount of transformation, transformation is not time/temperature dependent and LTD causes a constant transformation throughout the Y-TZP samples. METHODS: Dental-grade Y-TZP samples were randomly divided into nine subgroups (n = 5): as received, 3.5 and 7 day boiling, 1 bar autoclave (1, 3, 5 h), and 2 bar autoclave (1, 3, 5 h). A 4-h boil treatment (n = 2) was performed post-experiment for completion of data. Transformation was measured using traditional X-ray diffraction and low-angle X ray diffraction. RESULTS: The fraction of t -> m transformation increased with aging time. The 3.5 day boil and 2 bar 5 h autoclave produced similar transformation results, while the 7 day boiling treatment revealed the greatest transformation. The surface layer of the aged specimen underwent the most transformation while all samples displayed decreasing transformation with depth. SIGNIFICANCE: Surface transformation was evident, which can lead to rougher surfaces and increased wear of opposing dentition/materials. Therefore, wear studies addressing LTD of Y-TZP are needed utilizing accelerated aging. PMID- 25448800 TI - Breast cancer screening at the Breast Examination Center of Harlem. AB - BACKGROUND: This study was designed to describe patient, disease, and treatment characteristics of women diagnosed with breast cancer at the Breast Examination Center of Harlem (BECH) and to determine whether these characteristics have changed over time. METHODS: Retrospective chart review of women diagnosed with breast cancer at BECH from 2000 to 2008 was performed. Comparisons were made to data from an earlier study period (1995-2000). RESULTS: From 2000 to 2008, 339 women were diagnosed with breast cancer following attendance at BECH-55 % were black, 39 % Hispanic, 5 % of other race/ethnicity; 52 % had no health insurance. Hispanic patients were significantly more likely to have no health insurance compared with black patients (p = 0.0091); 29 % of patients had preinvasive disease and 36.5 % had stage I disease. Almost 40 % of the entire group was followed for <1 year. Five-year overall survival for the entire group was 83 % (95 % CI, 75-89 %) and 79 % for 188 Black women (95 % CI, 68-87 %). Compared with the earlier study period (1995-2000), fewer patients presented with palpable masses (45.4 vs. 67 %), and more had either stage 0 or stage I disease (65.6 vs. 46 %). CONCLUSIONS: Women diagnosed with breast cancer at BECH are predominantly Black and Hispanic, and most of these patients do not have health insurance. An increasing proportion of women diagnosed with breast cancer are presenting with nonpalpable, early-stage disease. Despite improved access to breast cancer screening, early stage at diagnosis, and access to appropriate management, these ethnic minorities continue to have poor outcomes and are poorly compliant with follow-up. PMID- 25448802 TI - Erratum to: Papilloma on Core Biopsy: Excision vs. Observation. PMID- 25448803 TI - TGFBI Expression in Cancer Stromal Cells is Associated with Poor Prognosis and Hematogenous Recurrence in Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an important cause of cancer-related death worldwide. To improve prognoses in patients with ESCC, we evaluated the potential of transforming growth factor-beta-induced protein (TGFBI), which is overexpressed in ESCC, as a therapeutic candidate. METHODS: We examined the clinical significance of TBFBI in 102 ESCC samples using real-time RT-PCR. Immunohistochemical studies were conducted to examine the localization of TGFBI. Knockdown of TGFBI in cocultured fibroblasts was performed to determine the roles of TGFBI in migration and invasion. RESULTS: The level of TGFBI in ESCC tissues was higher than that in normal tissues. The high TGFBI expression group (n = 16) had higher TGFB1 expression and more frequent hematogenous recurrence than the low-expression group (n = 86). High TGFBI expression was an independent prognostic factor in patients with ESCC. TGFBI was mainly localized in stromal cells of ESCC. Moreover, suppression of TGFBI in fibroblasts inhibited the migration and invasion capacity of TE8 ESCC cells. CONCLUSIONS: High TGFBI expression in ESCC tissues could be a powerful biomarker of poor prognosis and hematogenous recurrence. TGFBI in stromal cells might be a promising molecular target for ESCC treatment. PMID- 25448804 TI - Comparison of complete pathologic response and hepatic injuries between hepatic arterial infusion and systemic administration of oxaliplatin in patients with colorectal liver metastases. AB - BACKGROUND: Whether hepatic arterial infusion (HAI) of oxaliplatin influences the rates of complete pathologic response (CPR) and severe oxaliplatin-related lesions (SOxL) in patients with colorectal liver metastases (CRLM) is unknown. This study aimed to compare the incidence of CPR and SOxL between systemic (intravenous, IV) and HAI administration. METHODS: All patients with initially unresectable CRLM who had undergone hepatic resection in two expert centers between 2004 and 2010 after at least 6 cycles of oxaliplatin-based chemotherapy administered either via HAI (n = 18) or IV (n = 50) were included. The presence of CPR and SOxL were evaluated by two pathologists. A 1:2 case match using a propensity score was used. RESULTS: A CPR was observed significantly more often after HAI (33 vs. 10 %, P = 0.03). However, SOxL had occurred more frequently in patients in the HAI group versus the IV group, 66 and 20 %, respectively (P < 0.001). On a well-balanced cohort, HAI was associated with higher chance of CPR (odds ratio 9.33, 95 % confidence interval 1.59-54.7) but also higher risk of SOxL (odds ratio 13.7, 95 % confidence interval 3.08-61.3). A CPR markedly enhanced overall survival (OS) and disease-free survival (median OS of 114 vs. 42 months, P = 0.02; median disease-free survival of 51 vs. 12 months, P = 0.002). Patients with SOxL did not experience different outcome (median OS of 42 vs. 50 months, respectively; P = 0.92) CONCLUSIONS: HAI of oxaliplatin increases the likelihood of a CPR at the cost of a higher incidence of SOxL in patients with initially unresectable CRLM. PMID- 25448805 TI - Toxicity assessment of aggregated/agglomerated cerium oxide nanoparticles in an in vitro 3D airway model: the influence of mucociliary clearance. AB - We investigated the toxicity of aggregated nanoparticles of cerium oxide (CeO2) using an in vitro 3D human bronchial epithelial model that included a mucociliary apparatus (MucilAirTM). CeO2 was dispersed in saline and applied to the apical surface of the model. CeO2 did not induce distinct effects in the model, whereas it did in BEAS-2B and A549 cell cultures. The absence of effects of CeO2 was not because of the model's insensitivity. Nanoparticles of zinc oxide (ZnO) elicited positive responses in the toxicological assays. Respiratory mucus (0.1% and 1%) added to dispersions increased aggregation/agglomeration to such an extent that most CeO2 sedimented within a few minutes. Also, the mucociliary apparatus of the model removed CeO2 from the central part of the apical surface to the borders. This 'clearance' may have prevented the majority of CeO2 from reaching the epithelial cells. Chemical analysis of cerium in the basal tissue culture medium showed only minimal translocation of cerium across the 3D barrier. In conclusion, mucociliary defence appeared to prevent CeO2 reaching the respiratory epithelial cells in this 3D in vitro model. This model and approach can be used to study compounds of specific toxicological concern in airway defence mechanisms in vitro. PMID- 25448806 TI - Lipid antigen presentation through CD1d pathway in mouse lung epithelial cells, macrophages and dendritic cells and its suppression by poly-dispersed single walled carbon nanotubes. AB - Effect of poly-dispersed acid-functionalized single-walled carbon nanotubes (AF SWCNTs) was examined on lipid antigen presentation through CD1d pathway on three cell lines, LA4, MHS, and JAWSII used as prototype antigen presenting cells (APCs). CD1d molecule was expressed on 80-90% MHS (prototype macrophages) and JAWSII (prototype dendritic cells) cells whereas <5% LA4 cells (lung epithelial cells, non-classical APCs) expressed CD1d. Treatment with AF-SWCNTs but not with pristine SWCNTs resulted in a significant decline in the level of CD1d mRNA as well as mRNA levels of some other intracellular proteins involved in lipid antigen presentation pathway (MTP, ApoE, prosaposin, SR-BI and LDLr). Lipid antigen presentation was assessed by first incubating the cells with a prototype lipid antigen (alpha-Glactosylceramide or alphaGC) and then staining with L363 monoclonal antibody that detects alphaGC bound to CD1d molecule. While 100% MHS and JAWSII cells presented alphaGC, only 20% LA4 cells presented the CD1d antigen. Treatment with AF-SWCNTs resulted in a 30-40% decrease in alphaGC antigen presentation in all three cell lines. These results show that AF-SWCNT treatment down regulated the lipid antigen presentation pathway in all three cell lines and significantly lowered the ability of these cell lines to present alphaGC antigen. PMID- 25448807 TI - Toxicity, genotoxicity and proinflammatory effects of amorphous nanosilica in the human intestinal Caco-2 cell line. AB - Silica (SiO2) in its nanosized form is now used in food applications although the potential risks for human health need to be evaluated in further detail. In the current study, the uptake of 15 and 55nm colloidal SiO2 NPs in the human intestinal Caco-2 cell line was investigated by transmission electron microscopy. The ability of these NPs to induce cytotoxicity (XTT viability test), genotoxicity (gammaH2Ax and micronucleus assay), apoptosis (caspase 3), oxidative stress (oxidation of 2,7-dichlorodihydrofluorescein diacetate probe) and proinflammatory effects (interleukin IL-8 secretion) was evaluated. Quartz DQ12 was used as particle control. XTT and cytokinesis-block micronucleus assays revealed size- and concentration-dependent effects on cell death and chromosome damage following exposure to SiO2 nanoparticles, concomitantly with generation of reactive oxygen species (ROS), SiO2-15nm particles being the most potent. In the same way, an increased IL-8 secretion was only observed with SiO2-15nm at the highest tested dose (32MUg/ml). TEM images showed that both NPs were localized within the cytoplasm but did not enter the nucleus. SiO2-15nm, and to a lower extent SiO2-55nm, exerted toxic effects in Caco-2 cells. The observed genotoxic effects of these NPs are likely to be mediated through oxidative stress rather than a direct interaction with the DNA. Altogether, our results indicate that exposure to SiO2 NPs may induce potential adverse effects on the intestinal epithelium in vivo. PMID- 25448808 TI - Involvement of PPARgamma in emodin-induced HK-2 cell apoptosis. AB - Emodin, a major compound in total rhubarb anthraquinones (TRAs), has exhibited nephrotoxicity in Sprague Dawley rats and cytotoxicity to HK-2 cells, a human proximal tubular epithelial cell line, in our previous study. However, the exact molecular mechanisms underlying emodin-induced cytotoxicity remain undefined. In this study, the exposure of HK-2 cells to emodin led to decreased cell viability, caspase 3 cleavage and activation, loss of mitochondrial membrane potential (DWm), and cytochrome c release from mitochondria to cytosol. Meanwhile, the levels of peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA and protein expression were elevated. GW9662, an antagonist of PPARgamma, dramatically ameliorated the release of cytochrome c, the activation of caspase 3, and the reduction of cell viability induced by emodin. Importantly, emodin at the concentration causing apoptosis enhanced the stability of PPARgamma mRNA. Taken together, these findings suggest that PPARgamma might mediate, at least in part, emodin-induced HK-2 cell apoptosis via mitochondrial pathway. PMID- 25448809 TI - A coculture model of the lung-blood barrier: the role of activated phagocytic cells. AB - We developed a coculture model of the lung-blood barrier using human bronchial epithelial cells(16HBE14o-), monocytes (THP-1) and human lung microvascular endothelial cells (HLMVEC) in which several parameters can be assessed simultaneously. The epithelial and endothelial cells were grown on opposite sides of a microporous membrane. Electron and confocal microscopic pictures show the presence of the cells in their appropriate compartment and both cell types do not show evidence of growing through the pores. Out of three endothelial cell types (EAhy.926, HUVEC and HLMVEC), the last was chosen as the most appropriate cell type, best resembling the pulmonary endothelium and allowing the expression of functional tight junctions in the 16HBE14o- monolayer with sufficiently high transepithelial electrical resistance (TEER) values. Finally, monocytes were added to the apical compartment. PMA-activated macrophages significantly affected barrier integrity (73% TEER reduction compared to control after 24 h) and disrupted the epithelial tight junctions as shown by redistribution of ZO-1 labeling. Alternatively, monocytes could be activated using lipopolysaccharide, at a sub-toxic level int he apical compartment and only induced a small, though significant, reduction in TEER.This coculture system is a representative model of the lung-blood barrier with barrier integrity as the main toxicity endpoint. PMID- 25448810 TI - Epigenetic marks responsible for cadmium-induced melanoma cell overgrowth. AB - Cadmium (Cd) is a human carcinogen that likely acts via epigenetic mechanisms. However, the precise role of Cd in melanoma remains to be defined. The goals of this study are to: (i) examine the effect of Cd on the proliferation rate of cutaneous and uveal melanoma cells; (ii) identify the genes affected by Cd exposure; (iii) understand whether epigenetic changes are involved in the response to Cd. The cell growth capacity increased at 48 h after Cd treatment at doses ranging from 0.5 to 10 MUM. The research on the key genes regulating proliferation has shown that aberrant methylation is responsible for silencing of p16(INK4A) and caspase 8 in uveal and cutaneous melanoma cells, respectively. The methylation and expression patterns of p14(ARF), death receptors 4/5, and E cadherin remained unmodified after Cd treatment in all the cell lines analyzed. Ectopic expression of p16(INK4A) abolished the overgrowth of uveal melanoma cells in response to Cd and the overexpression of caspase 8 drastically increased the apoptotic rate of Cd-treated cutaneous melanoma cells. In conclusion, our data suggest that hypermethylation of p16(INK4A) and caspase 8 represents the most common event linked to Cd-induced stimulation of cell growth and inhibition of cell death pathway in melanoma. PMID- 25448811 TI - Intracellular concentrations determine the cytotoxicity of adefovir, cidofovir and tenofovir. AB - Lack of in vitro to in vivo translation is a major challenge in safety prediction during early drug discovery.One of the most common in vitro assays to evaluate the probability of a compound to cause adverse effects is a cytotoxicity assay. Cytotoxicity of a compound is often measured by dose-response curves assuming the administered doses and intracellular exposures are equal at the time of measurement.However, this may not be true for compounds with low membrane permeability or those which are substrates for drug transporters as intracellular concentrations are determined both by passive permeability and active uptake through drug transporters. We show here that three antiviral drugs, adefovir, cidofovir and tenofovir exhibit significantly increased cytotoxicity in HEK293 cells transfected with organic anion transporter (OAT) 1 and 3 compared to a lack of cytotoxicity in HEK293 wildtype cells. A further look at the media and intracellular drug concentrations showed that 24 h after dosing, all three drugs had higher intracellular drug concentrations than that of media in the HEK-OAT1 cells whereas the intracellular drug concentrations in the wildtype cells were much lower than the administered doses. Comparing cytotoxicity IC(50) values of adefovir, cidofovir and tenofovir based on administered doses and measured intracellular concentrations in HEK-OAT1 cells revealed that intracellular drug concentrations have significant impact on calculated IC(50) values. Tenofovir showed much less intrinsic cytotoxicity than adefovir and cidofovir using intracellular concentrations rather than media concentration. Our data suggest that for low permeable drugs or drugs that are substrates for drug transporters, the choice of cellular model is critical for providing an accurate determination of cytotoxicity. PMID- 25448812 TI - Systematic evaluation of non-animal test methods for skin sensitisation safety assessment. AB - The need for non-animal data to assess skin sensitisation properties of substances, especially cosmetics ingredients, has spawned the development of many in vitro methods. As it is widely believed that no single method can provide a solution, the Cosmetics Europe Skin Tolerance Task Force has defined a three phase framework for the development of a non-animal testing strategy for skin sensitization potency prediction. The results of the first phase - systematic evaluation of 16 test methods - are presented here. This evaluation involved generation of data on a common set of ten substances in all methods and systematic collation of information including the level of standardisation, existing test data,potential for throughput, transferability and accessibility in cooperation with the test method developers.A workshop was held with the test method developers to review the outcome of this evaluation and to discuss the results. The evaluation informed the prioritisation of test methods for the next phase of the non-animal testing strategy development framework. Ultimately, the testing strategy - combined with bioavailability and skin metabolism data and exposure consideration - is envisaged to allow establishment of a data integration approach for skin sensitisation safety assessment of cosmetic ingredients. PMID- 25448814 TI - Fifty ways to inhibit motility via cyclic di-GMP: the emerging Pseudomonas aeruginosa swarming story. AB - There are numerous ways by which cyclic dimeric GMP (c-di-GMP) inhibits motility. Kuchma et al. (S. L. Kuchma, N. J. Delalez, L. M. Filkins, E. A. Snavely, J. P. Armitage, and G. A. O'Toole, J. Bacteriol. 197:420-430, 2015, http://dx.doi.org/10.1128/JB.02130-14) offer a new, previously unseen way of swarming motility inhibition in Pseudomonas aeruginosa PA14. This bacterium possesses a single flagellum with one rotor and two sets of stators, only one of which can provide torque for swarming. The researchers discovered that elevated levels of c-di-GMP inhibit swarming by skewing stator selection in favor of the nonfunctional, "bad" stators. PMID- 25448813 TI - Characterization and localization of the Campylobacter jejuni transformation system proteins CtsE, CtsP, and CtsX. AB - The human pathogen Campylobacter jejuni is naturally competent for transformation with its own DNA. Genes required for efficient transformation in C. jejuni include those similar to components of type II secretion systems found in many Gram-negative bacteria (R. S. Wiesner, D. R. Hendrixson, and V. J. DiRita, J Bacteriol 185:5408-5418, 2003, http://dx.doi.org/10.1128/JB.185.18.5408 5418.2003). Two of these, ctsE and ctsP, encode proteins annotated as putative nucleotide binding nucleoside triphosphatases (NTPases) or nucleoside triphosphate (NTP) binding proteins. Here we demonstrate that the nucleotide binding motifs of both proteins are essential for their function in transformation of C. jejuni. Localization experiments demonstrated that CtsE is a soluble protein while CtsP is membrane associated in C. jejuni. A bacterial two hybrid screen identified an interaction between CtsP and CtsX, an integral membrane protein also required for transformation. Topological analysis of CtsX by the use of LacZ and PhoA fusions demonstrated it to be a bitopic, integral membrane protein with a cytoplasmic amino terminus and a periplasmic carboxyl terminus. Notwithstanding its interaction with membrane-localized CtsX, CtsP inherently associates with the membrane, requiring neither CtsX nor several other Cts proteins for this association. PMID- 25448815 TI - Evolution of aromatic beta-glucoside utilization by successive mutational steps in Escherichia coli. AB - The bglA gene of Escherichia coli encodes phospho-beta-glucosidase A capable of hydrolyzing the plant-derived aromatic beta-glucoside arbutin. We report that the sequential accumulation of mutations in bglA can confer the ability to hydrolyze the related aromatic beta-glucosides esculin and salicin in two steps. In the first step, esculin hydrolysis is achieved through the acquisition of a four nucleotide insertion within the promoter of the bglA gene, resulting in enhanced steady-state levels of the bglA transcript. In the second step, hydrolysis of salicin is achieved through the acquisition of a point mutation within the bglA structural gene close to the active site without the loss of the original catabolic activity against arbutin. These studies underscore the ability of microorganisms to evolve additional metabolic capabilities by mutational modification of preexisting genetic systems under selection pressure, thereby expanding their repertoire of utilizable substrates. PMID- 25448816 TI - One-carbon metabolic pathway rewiring in Escherichia coli reveals an evolutionary advantage of 10-formyltetrahydrofolate synthetase (Fhs) in survival under hypoxia. AB - In cells, N(10)-formyltetrahydrofolate (N(10)-fTHF) is required for formylation of eubacterial/organellar initiator tRNA and purine nucleotide biosynthesis. Biosynthesis of N(10)-fTHF is catalyzed by 5,10-methylene-tetrahydrofolate dehydrogenase/cyclohydrolase (FolD) and/or 10-formyltetrahydrofolate synthetase (Fhs). All eubacteria possess FolD, but some possess both FolD and Fhs. However, the reasons for possessing Fhs in addition to FolD have remained unclear. We used Escherichia coli, which naturally lacks fhs, as our model. We show that in E. coli, the essential function of folD could be replaced by Clostridium perfringens fhs when it was provided on a medium-copy-number plasmid or integrated as a single-copy gene in the chromosome. The fhs-supported folD deletion (DeltafolD) strains grow well in a complex medium. However, these strains require purines and glycine as supplements for growth in M9 minimal medium. The in vivo levels of N(10)-fTHF in the DeltafolD strain (supported by plasmid-borne fhs) were limiting despite the high capacity of the available Fhs to synthesize N(10)-fTHF in vitro. Auxotrophy for purines could be alleviated by supplementing formate to the medium, and that for glycine was alleviated by engineering THF import into the cells. The DeltafolD strain (harboring fhs on the chromosome) showed a high NADP(+)-to-NADPH ratio and hypersensitivity to trimethoprim. The presence of fhs in E. coli was disadvantageous for its aerobic growth. However, under hypoxia, E. coli strains harboring fhs outcompeted those lacking it. The computational analysis revealed a predominant natural occurrence of fhs in anaerobic and facultative anaerobic bacteria. PMID- 25448818 TI - Recombinant reporter assay using transcriptional machinery of Mycobacterium tuberculosis. AB - Development of an in vivo gene reporter assay to assess interactions among the components of the transcription machinery in Mycobacterium tuberculosis remains a challenge to scientists due to the tediousness of generation of mutant strains of the extremely slow-growing bacterium. We have developed a recombinant mCherry reporter assay that enables us to monitor the interactions of Mycobacterium tuberculosis transcriptional regulators with its promoters in vivo in Escherichia coli. The assay involves a three-plasmid expression system in E. coli wherein two plasmids are responsible for M. tuberculosis RNA polymerase (RNAP) production and the third plasmid harbors the mCherry reporter gene expression cassette under the control of either a sigma factor or a transcriptional regulator-dependent promoter. We observed that the endogenous E. coli RNAP and sigma factor do not interfere with the assay. By using the reporter assay, we found that the functional interaction of M. tuberculosis cyclic AMP receptor protein (CRP) occurs with its own RNA polymerase, not with the E. coli polymerase. Performing the recombinant reporter assay in E. coli is much faster than if performed in M. tuberculosis and avoids the hazard of handling the pathogenic bacterium. The approach could be expanded to develop reporter assays for other pathogenic and slow-growing bacterial systems. PMID- 25448817 TI - The Staphylococcus aureus NuoL-like protein MpsA contributes to the generation of membrane potential. AB - In aerobic microorganisms, the entry point of respiratory electron transfer is represented by the NADH:quinone oxidoreductase. The enzyme couples the oxidation of NADH with the reduction of quinone. In the type 1 NADH:quinone oxidoreductase (Ndh1), this reaction is accompanied by the translocation of cations, such as H(+) or Na(+). In Escherichia coli, cation translocation is accomplished by the subunit NuoL, thus generating membrane potential (Deltapsi). Some microorganisms achieve NADH oxidation by the alternative, nonelectrogenic type 2 NADH:quinone oxidoreductase (Ndh2), which is not cation translocating. Since these enzymes had not been described in Staphylococcus aureus, the goal of this study was to identify proteins operating in the NADH:quinone segment of its respiratory chain. We demonstrated that Ndh2 represents a NADH:quinone oxidoreductase in S. aureus. Additionally, we identified a hypothetical protein in S. aureus showing sequence similarity to the proton-translocating subunit NuoL of complex I in E. coli: the NuoL-like protein MpsA. Mutants with deletion of the nuoL-like gene mpsA and its corresponding operon, mpsABC (mps for membrane potential-generating system), exhibited a small-colony-variant-like phenotype and were severely affected in Deltapsi and oxygen consumption rates. The MpsABC proteins did not confer NADH oxidation activity. Using an Na(+)/H(+) antiporter-deficient E. coli strain, we could show that MpsABC constitute a cation-translocating system capable of Na(+) transport. Our study demonstrates that MpsABC represent an important functional system of the respiratory chain of S. aureus that acts as an electrogenic unit responsible for the generation of Deltapsi. PMID- 25448819 TI - New tools for comparing microscopy images: quantitative analysis of cell types in Bacillus subtilis. AB - Fluorescence microscopy is a method commonly used to examine individual differences between bacterial cells, yet many studies still lack a quantitative analysis of fluorescence microscopy data. Here we introduce some simple tools that microbiologists can use to analyze and compare their microscopy images. We show how image data can be converted to distribution data. These data can be subjected to a cluster analysis that makes it possible to objectively compare microscopy images. The distribution data can further be analyzed using distribution fitting. We illustrate our methods by scrutinizing two independently acquired data sets, each containing microscopy images of a doubly labeled Bacillus subtilis strain. For the first data set, we examined the expression of srfA and tapA, two genes which are expressed in surfactin-producing and matrix producing cells, respectively. For the second data set, we examined the expression of eps and tapA; these genes are expressed in matrix-producing cells. We show that srfA is expressed by all cells in the population, a finding which contrasts with a previously reported bimodal distribution of srfA expression. In addition, we show that eps and tapA do not always have the same expression profiles, despite being expressed in the same cell type: both operons are expressed in cell chains, while single cells mainly express eps. These findings exemplify that the quantification and comparison of microscopy data can yield insights that otherwise would go unnoticed. PMID- 25448820 TI - Ethylmalonyl coenzyme A mutase operates as a metabolic control point in Methylobacterium extorquens AM1. AB - The metabolism of one- and two-carbon compounds by the methylotrophic bacterium Methylobacterium extorquens AM1 involves high carbon flux through the ethylmalonyl coenzyme A (ethylmalonyl-CoA) pathway (EMC pathway). During growth on ethylamine, the EMC pathway operates as a linear pathway carrying the full assimilatory flux to produce glyoxylate, malate, and succinate. Assimilatory carbon enters the ethylmalonyl-CoA pathway directly as acetyl-CoA, bypassing pathways for formaldehyde oxidation/assimilation and the regulatory mechanisms controlling them, making ethylamine growth a useful condition to study the regulation of the EMC pathway. Wild-type M. extorquens cells were grown at steady state on a limiting concentration of succinate, and the growth substrate was then switched to ethylamine, a condition where the cell must make a sudden switch from utilizing the tricarboxylic acid (TCA) cycle to using the ethylmalonyl-CoA pathway for assimilation, which has been an effective strategy for identifying metabolic control points. A 9-h lag in growth was observed, during which butyryl CoA, a degradation product of ethylmalonyl-CoA, accumulated, suggesting a metabolic imbalance. Ethylmalonyl-CoA mutase activity increased to a level sufficient for the observed growth rate at 9 h, which correlated with an upregulation of RNA transcripts for ecm and a decrease in the levels of ethylmalonyl-CoA. When the wild-type strain overexpressing ecm was tested with the same substrate switchover experiment, ethylmalonyl-CoA did not accumulate, growth resumed earlier, and, after a transient period of slow growth, the culture grew at a higher rate than that of the control. These findings demonstrate that ethylmalonyl-CoA mutase is a metabolic control point in the EMC pathway, expanding our understanding of its regulation. PMID- 25448821 TI - Identification of heat shock cognate protein 70 gene (Alhsc70) of Apolygus lucorum and its expression in response to different temperature and pesticide stresses. AB - Heat shock cognate protein 70 (Hsc70) is a very important stress-resistance protein of insects against environmental stresses. We employed fluorescent real time quantitative polymerase chain reaction and Western-blot techniques to analyze the transcriptional and translational expression profiles of AlHSC70 under extreme temperature (4 degrees C and 40 degrees C) or 4 pesticide stresses in Apolygus lucorum. The results showed that the expression of AlHSC70 were significantly induced by cyhalothrin or extremely high temperature (40 degrees C) in both transcriptional and translational levels (P < 0.05), while the transcriptional and translational level of AlHSC70 decreased significantly in treatments of chlorpyrifos or extreme cold temperature (4 degrees C) (P < 0.05). Moreover, after Apolygus lucorum treated by imidacloprid or emamectin benzoate, the expression of AlHSC70 was only up-regulated significantly at the transcriptional level (P < 0.05), although obviously up-regulated at the translational level of AlHSC70. Therefore, this study confirmed that the Alhsc70 gene played important roles in response to both temperature and pesticide stresses, especially for cyhalothrin or extremely high temperature (40 degrees C). In addition, the significant polynomial regression correlations between temperature and the Alhsc70 expression level were shown in all the nymph and adult stages (P < 0.01), indicating temperature was an important factor to affect the relative expression of Alhsc70. PMID- 25448822 TI - Contemplative spaces in social work practice. AB - Exploring contemplative practices and spirituality in social work has developed a new impetus as the understanding of the importance of those variables in patient care has increased. Social work brings its historical attention to the whole person and the many ways the social worker and patient understand their respective roles in assisting in the process of healing and coping with loss. It is essential that social workers attend to their own understanding of the space for contemplative practice in their lives. This article sets the context for this important work and provides an example of a program designed to increase the social worker's awareness and practice skills that reflect the particular dynamics of engaging spirituality in the clinical relationship. PMID- 25448823 TI - Variability in response to drugs. PMID- 25448824 TI - Large scale expression and purification of the rat 5-HT2c receptor. AB - 5-HT2c G-protein coupled receptors located in the central nervous system bind the endogenous neurotransmitters serotonin and couple to G protein to mediate excitatory neurotransmission, which inhibits dopamine and norepinephrine release in the brain. Thus, 5-HT2c receptors play important roles in cognitive function and are potent drug targets. Structural information is needed to elucidate the molecular mechanism of ligand-binding and receptor-activation of the 5-HT2c receptor. Lacking of an efficient expression system that produces sufficient amounts of active and homogenous receptors hinders progress in the functional and structural characterization of the 5-HT2c receptor. We present here a protocol which can be used easily to obtain milligram amount of purified rat 5-HT2c receptors. We established this protocol by protein engineering and optimization of expression and purification based on radioligand-binding assay. The purified and well-characterized rat 5-HT2c receptors are active, stable, homogenous, and ready for 2-dimensional and 3-dimensional crystallization experiments. PMID- 25448825 TI - Development of a recombinant hCG-specific single chain immunotoxin cytotoxic to hCG expressing cancer cells. AB - A large number of cancers express human chorionic gonadotropin (hCG) or its subunits ectopically. Patients harboring such cancers have poor prognosis and adverse survival. PiPP is a monoclonal antibody of high affinity and specificity for hCGbeta/hCG. Work was carried out to develop a PiPP based recombinant immunotoxin for the immunotherapy of hCG expressing cancers. Recombinant PiPP antibody was constructed in scFv format in which gene encoding the VH and VL domains were joined through a linker. This scFv gene was fused to the gene expressing Pseudomonas exotoxin (PE38), and cloned in a Escherichia coli based expression vector under the control of strong bacteriophage T7 promoter. Immunotoxin conjugating scFv(PiPP) and PE38, was expressed in E. coli as recombinant protein. Recombinant PiPP immunotoxin was purified from the bacterial cell lysate and tested for binding and killing of hCGbeta expressing lymphoma, T lymphoblastic leukemia and lung carcinoma cells in vitro. Immunotoxin showed nearly 90% killing on the cells. This is the first ever report on recombinant immunotoxin for binding and cytotoxicity to hCG expressing cancer cells, and thus can be a potential candidate for the immunotherapy of hCG expressing cells. PMID- 25448826 TI - Design and construction of a chimeric multi-epitope gene as an epitope-vaccine strategy against ALV-J. AB - In the present study, we designed and constructed a chimeric multi-epitope gene of ALV-J to develop a potential multi-epitope vaccine using a reverse vaccinology approach. The chimeric gene includes 4 multi-epitope concentrated fragments (Gag (278-376aa), Pol (784-855aa), Env (Gp85:145-156aa and Gp37:412-538aa) screened from major structural proteins of ALV-J using epitope prediction software. The recombinant chimeric multi-epitope protein (rCMEPX) encoded by the cloned chimeric gene was successfully expressed using an Escherichia coli expression system. The rCMEPX was induced optimally at 37 degrees C for 4.0 h with 0.5mM IPTG. The identity and purity of the expressed rCMEPX was analyzed on a SDS-PAGE. The specific recognition of the purified rCMEPX by the chicken anti-ALV-J serum on a western analysis demonstrated a good immunoreactivity of the expressed rCMEPX, which indicates that the construction and expression of the multi-epitope based chimeric gene for ALV-J vaccine development is successful. The antigenicity and reactionogenicity of the rCMEPX were evaluated by western blot and indirect ELISA. Our results showed good reactionogenicity, specificity, and sensitivity for the expressed rCMEPX, suggesting that it may be a promising vaccine candidate against ALV-J infections. PMID- 25448827 TI - Improved expression and purification of the Helicobacter pylori adhesin BabA through the incorporation of a hexa-lysine tag. AB - Helicobacter pylori is a pathogenic bacterium that has the remarkable ability to withstand the harsh conditions of the stomach for decades. This is achieved through unique evolutionary adaptations, which include binding Lewis(b) antigens found on the gastric epithelium using the outer membrane protein BabA. We show here the yield of a recombinant form of BabA, comprising its putative extracellular binding domain, can be significantly increased through the addition of a hexa-lysine tag to the C-terminus of the protein. BabA was expressed in the periplasmic space of Escherichia coli and purified using immobilised metal ion affinity and size exclusion chromatography - yielding approximately 1.8 mg of protein per litre of culture. The hexa-lysine tag does not inhibit the binding activity of BabA as the recombinant protein was found to possess affinity towards HSA-Lewis(b) glycoconjugates. PMID- 25448828 TI - The role of kinship in the formation of a primate multilevel society. AB - A small number of mammalian species live in a modular or multilevel society in which several individual social/reproductive units called one-male units (OMUs) are embedded within a large cohesive band. Factors that affect band composition and stability are poorly understood. In this study we examined the role of kinship in the formation and maintenance of a multilevel society in an endangered population of golden snub-nosed monkeys (Rhinopithecus roxellana). From 2005 to 2011, we obtained genetic samples from 86 individuals (including 88.9% of leader males and 80.5% of adult females) living in a band of 8-10 OMUs. We used microsatellite genotyping to identify patterns of relatedness and individual transfer. We found that adult females residing in the same OMU were more closely related to each other than to a random set of females drawn from the band and that females tended to disperse into OMUs that contained female relatives. In addition, adult females who transferred were not more closely related to their previous leader male than to the leader male of their new OMU. These results support the contention that kin bonds contribute importantly to the formation and stability of this primate multilevel society by influencing a female's decision to remain in her current OMU, or during transfer, which new OMU to enter. PMID- 25448829 TI - Video game genre preference, physical activity and screen-time in adolescent boys from low-income communities. AB - The primary aim of this study was to examine the association between the types of video games played by adolescent boys and their participation in physical activity and recreational screen-time. Participants were 320 boys (mean age = 12.7, +/-0.5 years) from 14 secondary schools located in low-income areas of New South Wales, Australia. Outcomes included height, weight, physical activity (accelerometers), total screen-time, and video game genre preference. Significant differences in both weekday and weekend screen-time were found between video game genre groups. In addition, significant differences in overall activity and moderate-to-vigorous physical activity were found between genre groups on weekdays. Between-group differences in physical activity on weekends were not statistically significant. This cross-sectional study has demonstrated that video game genre preference is associated with physical activity and screen-time in adolescent boys from low-income communities. PMID- 25448831 TI - Parental efficacy, parental monitoring efficacy, and monitoring among Asian Indian parents of adolescents living in Chennai, India. AB - The purpose of this study was to investigate the relationship between parental efficacy and a new concept entitled parental monitoring efficacy, and to examine the association between parental monitoring efficacy and monitoring. We conducted two studies on two samples of Asian-Indian parents and adolescents living in Chennai, India. In the first study of 241 parents of adolescents in grades, 9-12, we constructed a new measure of parental efficacy that included two factors. The first factor, responding competently to negative adolescent behavior was more strongly predictive of parental monitoring efficacy than the second factor, instilling positive behavior. In the second study of 215 parents and adolescents in grades 10 and 12, parental monitoring efficacy predicted monitoring, especially adolescent disclosure and parental control. The importance of parental control as a monitoring technique among traditional Indian parents was discussed. PMID- 25448830 TI - Adolescent risk behaviours and protective factors against peer influence. AB - This study examined the relationships between protective factors and involvement in risk behaviour of Italian adolescents with friends involved in risk. Protective factors were drawn from models of peers and from individual skills (perceived regulatory self-efficacy, intolerant attitudes about deviance) and orientation (to health, school, religion). The data are from two waves, 1 year apart, of a questionnaire survey of adolescents in northwestern Italy. Participants were 908 adolescents (42% boys) ages 14-16 years. Results of a hierarchical regression revealed that religiosity is a protective factor and that friends' models for conventional behaviours and positive attitude about health can mitigate the influence of deviant friends on adolescent risk behaviour 1 year later, even after controlling for prior levels of risk behaviour. Possible implications of this study suggest the importance of implementing preventive interventions by involving the peer group, especially at about 16 years, and working with heterogeneous (deviant and nondeviant) groups. PMID- 25448832 TI - Adolescent Stress Questionnaire: reliability and validity of the Greek version and its description in a sample of high school (lyceum) students. AB - Adolescence is a crucial phase of human life characterized by enhanced exposure and vulnerability to various stressful stimuli. The Adolescent Stress Questionnaire (ASQ) is a useful measure to evaluate possible sources of stressors affecting the adolescent equilibrium. The present study examines the scientific properties of the Greek version of ASQ to measure perceived stress among 250 Greek adolescents. The confirmatory factor analysis (CFA) results showed a good fit of the original structure of ASQ to the observed data in the Greek sample. A good internal reliability was also confirmed by high Cronbach's alpha values. In line with previous research, girls reported more stress than boys. Overall, the Greek ASQ is a valid and reliable instrument for evaluating adolescent stress. PMID- 25448833 TI - Adolescent trust and trustworthiness: role of gender and social value orientation. AB - Trusting others is an essential feature of adolescent development. The aim of this study was to investigate gender differences in trusting behavior using an experimental game and relate these to the underlying social preferences. 206 adolescents (Mage = 15.1 years, 51% girls) performed a series of one-shot Trust Games to measure their levels of trust and trustworthiness. Social value orientation, or the preference to maximize one's own outcomes (proself) or both the outcomes of self and other (prosocial) was assessed using the Triple Dominance Measure. Boys were more trusting than girls, but no gender differences on trustworthiness were found. Prosocials were more trusting and trustworthy than proselfs. In addition, gender and social value orientation were independent predictors of trust (but not trustworthiness). These findings show that the higher levels of trust in boys are not the result of a gender difference in prosocial orientation. PMID- 25448834 TI - Brief report: The association between adolescents' characteristics and engagement in sexting. AB - The potential emotional and legal consequences of adolescents' engagement in sending sexually explicit pictures through the internet or the mobile phone (i.e., sexting) have caused significant concern about the behavior among practitioners and academics. The present study compares the characteristics of students who engage in sexting to those who do not. A survey among 1028 adolescents of 11 secondary schools in Belgium was administered. Logistic regression analyses suggest that sexting is significantly linked with sensation seeking, experiential thinking styles and depression, while controlling for gender, age, family status and students' response to economic stress. The results are of importance to practitioners who could adapt their prevention and intervention campaigns to better reach this complex youth. Differences with the findings of previous studies highlight the importance of continuing research on sexting and the need to pay attention to the specific context in which adolescent sexting takes place. PMID- 25448835 TI - Brief report: Cyberbullying perpetration and its associations with socio demographics, aggressive behaviour at school, and mental health outcomes. AB - Relatively little is known about those who cyberbully others, especially in a UK context. We drew on data from 1144 young people aged 12-13 in eight English secondary schools to examine the prevalence of cyberbullying perpetration and its associations with sociodemographics, other behaviours, and health outcomes. Overall, 14.1% of respondents reported ever cyberbullying others with no significant differences by gender or socioeconomic status. Drawing on mixed effects logistic regression models, first we found a strong, dose-response relationship between aggressive behaviour at school and cyberbullying others, suggesting that cyberbullying may not only be a facet of wider patterns of bullying but also of aggression more broadly. Second, cyberbullying others was associated with poorer quality of life and with psychological difficulties but not with peer/social problems or worse mental wellbeing. Longitudinal studies are needed to assess whether such associations are causal. PMID- 25448836 TI - Emotion regulation styles as longitudinal predictors of compulsive exercise: a twelve month prospective study. AB - Exercise can be used as a mood regulator but, in the eating disorder literature, exercise has sometimes been found to be compulsive, detrimental to physical health, and regarded as one maladaptive strategy used to regulate emotions. This study examined longitudinal associations between emotion regulation styles and this compulsive exercise in 572 adolescents who completed measures of compulsive exercise and emotion regulation. Twelve months later they completed measures of compulsive exercise. Compulsive exercise was predicted by Internal Dysfunctional emotion regulation in girls and boys, even after controlling for initial levels of compulsive exercise. Adolescents displaying compulsivity to exercise may require intervention programmes to alter their emotion regulation strategies. PMID- 25448838 TI - An evidence-based perspective on vitamin D and the growing skeleton. PMID- 25448839 TI - Vitamin D and bone development. PMID- 25448840 TI - Farmers, mechanized work, and links to obesity. AB - OBJECTIVE: In a contemporary sample of Saskatchewan farm people, to relate the degree of mechanized and also non-mechanized farm work to the occurrence of being overweight or obese. Secondarily to determine the prevalence of being overweight or obese, and to compare these prevalence levels with those reported for general populations. METHOD: Cross-sectional analyses of baseline survey data provided for 2849 individuals (2619 adults) from 1216 Saskatchewan farms in 2013. Age/sex standardized prevalence levels of overweight and obesity were compared between the farm cohort and general populations. Durations of specific types of work were described by metabolic equivalent scoring. Multi-level binomial regression was used to study relations between mechanized and also non-mechanized farm work with overweight and obesity. RESULTS: Overall, 65.1% of the adult farm cohort was overweight (39.6%) or obese (25.5%), with prevalence levels that exceeded estimated norms for Canada but not the province of Saskatchewan. Increases in risks for obesity were related to higher amounts of mechanized but not non mechanized farm work. CONCLUSION: While the mechanization of farm work has obvious benefits in terms of productivity, its potential effects on risks for overweight and obesity must be recognized. PMID- 25448837 TI - Incorporating bazedoxifene into the treatment paradigm for postmenopausal osteoporosis in Japan. AB - The incidence of osteoporosis-related fractures in Asian countries is steadily increasing. Optimizing osteoporosis treatment is especially important in Japan, where the rate of aging is increasing rapidlyelderly population is increasing rapidly and life expectancy is among the longest in the world. There are several therapies currently available in Japan for the treatment of postmenopausal osteoporosis, each with a unique risk/benefit profile. A novel selective estrogen receptor modulator, bazedoxifene (BZA), was recently approved for the treatment of postmenopausal osteoporosis in Japan. Results from a 2-year, phase 2 trial in postmenopausal Japanese women showed that BZA significantly improved lumbar spine and total hip bone mineral density compared with placebo, while maintaining endometrial and breast safety, consistent with results from 2 global, phase 3 trials including a 2-year osteoporosis prevention study and a 3-year osteoporosis treatment study. In the pivotal 3-year treatment study, BZA significantly reduced the incidence of new vertebral fractures compared with placebo; in a post hoc analysis of a subgroup of women at higher risk of fractures, BZA significantly reduced the risk of nonvertebral fractures compared with placebo and raloxifene. A 2-year extension of the 3-year treatment study demonstrated the sustained efficacy of BZA over 5 years of treatment. BZA was generally safe and well tolerated in these studies. In a "super-aging" society such as Japan, long-term treatment for postmenopausal osteoporosis is a considerable need. BZA may be considered as a first choice for younger women anticipating long-term treatment, and also an appropriate option for older women who are unable or unwilling to take bisphosphonates. PMID- 25448841 TI - Primary care physician smoking screening and counseling for patients with chronic disease. AB - BACKGROUND: Evidence-based guidelines recommend smoking cessation treatment, including screening and counseling, for all smokers, including those with chronic diseases exacerbated by smoking. Physician treatment improves smoking cessation. Little data describes smoking treatment guideline uptake for patients with chronic cardiopulmonary smoking-sensitive diseases. OBJECTIVE: Describe U.S. primary care physician (PCP) smoking cessation treatment during patient visits for chronic cardiopulmonary smoking-sensitive diseases. METHODS: The National (Hospital) Ambulatory Medical Care Survey captured PCP visits. We examined smoking screening and counseling time trends for smokers with chronic diseases. Multivariable logistic regression assessed factors associated with smoking counseling for smokers with chronic smoking-sensitive diseases. RESULTS: From 2001-2009 smoking screening and counseling for smokers with chronic smoking sensitive cardiopulmonary diseases were unchanged. Among smokers with chronic smoking-sensitive diseases, 50%-72% received no counseling. Smokers with chronic obstructive pulmonary disease (COPD) (odds ratio (OR)=6.54, 95% confidence interval (CI) 4.85-8.83) and peripheral vascular disease (OR=4.50, 95% CI 1.72 11.75) were more likely to receive smoking counseling at chronic/preventive care visits, compared with patients without smoking-sensitive diseases. Other factors associated with increased smoking counseling included non-private insurance, preventive and longer visits, and an established PCP. Asthma and cardiovascular disease showed no association with counseling. CONCLUSIONS: Smoking cessation counseling remains infrequent for smokers with chronic smoking-sensitive cardiopulmonary diseases. New strategies are needed to encourage smoking cessation counseling. PMID- 25448842 TI - Long live the Italians! PMID- 25448843 TI - A systematic review of standing and treadmill desks in the workplace. AB - OBJECTIVES: Standing and treadmill desks are intended to reduce the amount of time spent sitting in today's otherwise sedentary office. Proponents of these desks suggest that health benefits may be acquired as standing desk use discourages long periods of sitting, which has been identified as an independent health risk factor. Our objectives were thus to analyze the evidence for standing and treadmill desk use in relation to physiological (chronic disease prevention and management) and psychological (worker productivity, well-being) outcomes. METHODS: A computer-assisted systematic search of Medline, PubMed, PsycINFO, SPORTDiscus, CINAHL, CENTRAL, and EMBASE databases was employed to identify all relevant articles related to standing and treadmill desk use. RESULTS: Treadmill desks led to the greatest improvement in physiological outcomes including postprandial glucose, HDL cholesterol, and anthropometrics, while standing desk use was associated with few physiological changes. Standing and treadmill desks both showed mixed results for improving psychological well-being with little impact on work performance. DISCUSSION: Standing and treadmill desks show some utility for breaking up sitting time and potentially improving select components of health. At present; however, there exist substantial evidence gaps to comprehensively evaluate the utility of each type of desk to enhance health benefits by reducing sedentary time. PMID- 25448844 TI - The effects of perfluorinated chemicals on adipocyte differentiation in vitro. AB - The 3T3-L1 preadipocyte culture system has been used to examine numerous compounds that influence adipocyte differentiation or function. The perfluoroalkyl acids (PFAAs), used as surfactants in a variety of industrial applications, are of concern as environmental contaminants that are detected worldwide in human serum and animal tissues. This study was designed to evaluate the potential for PFAAs to affect adipocyte differentiation and lipid accumulation using mouse 3T3-L1 cells. Cells were treated with perfluorooctanoic acid (PFOA) (5-100 uM), perfluorononanoic acid (PFNA) (5-100 uM), perfluorooctane sulfonate (PFOS) (50-300 uM), perfluorohexane sulfonate (PFHxS) (40-250 uM), the peroxisome proliferator activated receptor (PPAR) PPARalpha agonist Wyeth-14,643 (WY-14,643), and the PPARgamma agonist rosiglitazone. The PPARgamma agonist was included as a positive control as this pathway is critical to adipocyte differentiation. The PPARalpha agonist was included as the PFAA compounds are known activators of this pathway. Cells were assessed morphometrically and biochemically for number, size, and lipid content. RNA was extracted for qPCR analysis of 13 genes selected for their importance in adipocyte differentiation and lipid metabolism. There was a significant concentration-related increase in cell number and decreased cell size after exposure to PFOA, PFHxS, PFOS, and PFNA. All four PFAA treatments produced a concentration-related decrease in the calculated average area occupied by lipid per cell. However, total triglyceride levels per well increased with a concentration-related trend for all compounds, likely due to the increased cell number. Expression of mRNA for the selected genes was affected by all exposures and the specific impacts depended on the particular compound and concentration. Acox1 and Gapdh were upregulated by all six compounds. The strongest overall effect was a nearly 10-fold induction of Scd1 by PFHxS. The sulfonated PFAAs produced numerous, strong changes in gene expression similar to the effects after treatment with the PPARgamma agonist rosiglitazone. By comparison, the effects on gene expression were muted for the carboxylated PFAAs and for the PPARalpha agonist WY-14,643. In summary, all perfluorinated compounds increased cell number, decreased cell size, increased total triglyceride, and altered expression of genes associated with adipocyte differentiation and lipid metabolism. PMID- 25448847 TI - The circadian clock machinery controls adiponectin expression. AB - Adiponectin, an adipokine involved in glucose and lipid metabolism, exhibits a circadian manner of expression. Adiponectin expression is mediated by the helix loop-helix transcription factor sterol regulatory element binding protein (SREBP) 1c. In this study, we tested whether the circadian clock helix-loop-helix transcription factors CLOCK and BMAL1 regulate adiponectin expression. We found that adiponectin expression is regulated by the clock through the circadian expression of its transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) and its co-activator PPARgamma co-activator 1alpha (PGC1alpha) in mouse white adipose tissue and differentiated adipocytes. In addition, reconstitution of the core clock mechanism and siRNA experiments in cell culture suggest that the clock directly activates the adiponectin promoter and mediates its expression. In summary, adiponectin expression is regulated by the circadian clock and through the circadian expression of its transcription factor PPARgamma and its co-activator PGC1alpha. PMID- 25448845 TI - TGFbeta2 regulates hypothalamic Trh expression through the TGFbeta inducible early gene-1 (TIEG1) during fetal development. AB - The hypothalamus regulates the homeostasis of the organism by controlling hormone secretion from the pituitary. The molecular mechanisms that regulate the differentiation of the hypothalamic thyrotropin-releasing hormone (TRH) phenotype are poorly understood. We have previously shown that Klf10 or TGFbeta inducible early gene-1 (TIEG1) is enriched in fetal hypothalamic TRH neurons. Here, we show that expression of TGFbeta isoforms (1-3) and both TGFbeta receptors (TbetaRI and II) occurs in the hypothalamus concomitantly with the establishment of TRH neurons during late embryonic development. TGFbeta2 induces Trh expression via a TIEG1 dependent mechanism. TIEG1 regulates Trh expression through an evolutionary conserved GC rich sequence on the Trh promoter. Finally, in mice deficient in TIEG1, Trh expression is lower than in wild type animals at embryonic day 17. These results indicate that TGFbeta signaling, through the upregulation of TIEG1, plays an important role in the establishment of Trh expression in the embryonic hypothalamus. PMID- 25448846 TI - Regulation of cytokine-inducible SH2-containing protein (CIS) by ubiquitination and Elongin B/C interaction. AB - Cytokine-inducible SH2-containing protein (CIS) inhibits prolactin receptor (PRLR) signaling and acts as part of an E3 ubiquitin ligase complex through interactions with Elongin B/C proteins. This study aimed to identify CIS lysine ubiquitination sites and determine roles of ubiquitination and Elongin B/C interactions on CIS protein stability and PRLR signaling inhibition. Site directed mutations revealed that CIS can be ubiquitinated on all six lysine residues. Elongin B/C interaction box mutation had no influence on CIS ubiquitination. CIS stability was increased by mutation of lysine residues and further enhanced by co-mutation of Elongin B/C interaction domain. CIS inhibition of STAT5B phosphorylation and casein promoter activation was dependent on CIS interactions with Elongin B/C, but not on CIS ubiquitination. These data indicate CIS protein stability is regulated through multiple mechanisms, including ubiquitination and interaction with Elongin B/C proteins, whereas CIS functional inhibition of PRLR signaling is dependent on the Elongin B/C interaction. PMID- 25448848 TI - Telomerase in differentiated thyroid cancer: promoter mutations, expression and localization. AB - Telomerase-reverse-transcriptase (TERT) promoter mutations have been recently described in tumors. In the present large series, TERT mutations were found in 12% of papillary thyroid cancers (PTCs) and in 14% of follicular thyroid cancers (FTCs), and were found to significantly correlate with older age at diagnosis and poorer outcome. Interestingly, the prognostic value of TERT mutations resulted to be significantly stronger than that of BRAF(V600E). Moreover, the outcome was not different among tumors with isolated TERT mutation and those with coexistent mutations (TERT/BRAF in PTCs or TERT/RAS in FTCs). TERT rs2853669 polymorphism was found in 44.4% of tumors. At WB, TERT was significantly more expressed in tumors than in normal samples, being the highest levels of expression recorded in TERT mutated cases. At IHC, in tumors and in metastatic lymph-nodes TERT staining was significantly higher in the cytoplasm than in the nucleus, whereas in normal tissue the degree of staining did not differ in the two cellular compartments. In conclusion, TERT mutations were shown to strongly correlate with a poorer outcome in differentiated thyroid tumors, and neither BRAF nor RAS mutation were found to confer an additional effect in the disease persistence. TERT protein was found to be more expressed in neoplastic than in normal tissues, and to display a different cellular localization, suggesting that it could contribute to thyroid cancer progression by mechanisms taking place in the cytoplasm. PMID- 25448849 TI - Triptolide inhibits osteoclast formation, bone resorption, RANKL-mediated NF-?B activation and titanium particle-induced osteolysis in a mouse model. AB - The RANKL-induced NF-kappaB signaling pathway is required for osteoclast formation and function. By screening for compounds that inhibit RANKL-induced NF kappaB activation using a luciferase reporter gene assay in RAW264.7 cells, we identified triptolide (PG490), as a candidate compound targeting osteoclast differentiation and osteoclast-mediated osteolysis. Triptolide (PG490) is an active compound of the medicinal herb Tripterygium wilfordii Hook F (TWHF) or Lei Gong Teng with known anti-inflammatory properties. We found that triptolide inhibited osteoclastogenesis and bone resorption, as well as RANKL-induced NF-?B activities as monitored by luciferase reporter gene assays and the nuclear translocation of p65. In vivo studies showed that triptolide attenuates titanium induced osteolysis and osteoclast formation in a mouse calvarial model. Considering that drugs which protect against localized bone loss are critically needed for the effective treatment of particle-induced osteolysis, our data suggest that triptolide might have therapeutic potential for the treatment of bone lytic diseases caused by prosthetic wear particles. PMID- 25448850 TI - Abdominal obesity: what does it mean in an adolescent? PMID- 25448851 TI - Using a combination of fMRI and anterior temporal lobe rTMS to measure intrinsic and induced activation changes across the semantic cognition network. AB - By developing and applying a method which combines fMRI and rTMS to explore semantic cognition, we identified both intrinsic (related to automatic changes in task/stimulus-related processing) and induced (i.e., associated with the effect of TMS) activation changes in the core, functionally-coupled network elements. Low-frequency rTMS applied to the human anterior temporal lobe (ATL) induced: (a) a local suppression at the site of stimulation; (b) remote suppression in three other ipsilateral semantic regions; and (c) a compensatory up-regulation in the contralateral ATL. Further examination of activity over time revealed that the compensatory changes appear to be a modulation of intrinsic variations that occur within the unperturbed network. As well as providing insights into the dynamic collaboration between core regions, the ability to observe intrinsic and induced changes in vivo may provide an important opportunity to understand the key mechanisms that underpin recovery of function in neurological patient groups. PMID- 25448852 TI - When your arm becomes mine: pathological embodiment of alien limbs using tools modulates own body representation. AB - Previous evidence has shown that active tool-use can reshape one's own body schema, extend peripersonal space and modulate the representation of related body parts. Here we investigate the effect of tool-use training on length representation of the contralesional forearm in brain-damaged hemiplegic patients who manifested a pathological embodiment of other people body parts. Four patients and 20 aged-matched healthy-controls were asked to estimate the mid point of their contralesional forearm before and after 15 min of tool-use training (i.e. retrieving targets with a garbage plier). In the case of patients, training was always performed by the examiner's (alien) arm acting in two different positions, aligned (where the pathological embodiment occurs; E+ condition) or misaligned (where the pathological embodiment does not occur; E- condition) relative to the patients' shoulder. Healthy controls performed tool use training either with their own arm (action condition) or observing the examiner's arm performing the task (observation condition), handling (observation with-tool condition) or not (observation without-tool condition) a similar tool. Crucially, in the E+ condition, when patients were convinced to perform the tool use training with their own paralyzed arm, a significant overestimation effect was found (as in the Action condition with normal subjects): patients mislocated their forearm midpoint more proximally to the hand in the post- than in the pre training phase. Conversely, in the E- condition, they did not show any overestimation effect, similarly to healthy subjects in the observation condition (neither in the with-tool nor in the without-tool condition significant overestimation effects were found). These findings show the existence of a tight link between spatial, motor and bodily representations and provide strong evidence that a pathological sense of body ownership can extend to intentional motor processes and modulate the sensory map of action-related body parts. PMID- 25448853 TI - Evidence that transcranial direct current stimulation (tDCS) generates little-to no reliable neurophysiologic effect beyond MEP amplitude modulation in healthy human subjects: A systematic review. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a form of neuromodulation that is increasingly being utilized to examine and modify a number of cognitive and behavioral measures. The theoretical mechanisms by which tDCS generates these changes are predicated upon a rather large neurophysiological literature. However, a robust systematic review of this neurophysiological data has not yet been undertaken. METHODS: tDCS data in healthy adults (18-50) from every neurophysiological outcome measure reported by at least two different research groups in the literature was collected. When possible, data was pooled and quantitatively analyzed to assess significance. When pooling was not possible, data was qualitatively compared to assess reliability. RESULTS: Of the 30 neurophysiological outcome measures reported by at least two different research groups, tDCS was found to have a reliable effect on only one: MEP amplitude. Interestingly, the magnitude of this effect has been significantly decreasing over the last 14 years. CONCLUSION: Our systematic review does not support the idea that tDCS has a reliable neurophysiological effect beyond MEP amplitude modulation - though important limitations of this review (and conclusion) are discussed. This work raises questions concerning the mechanistic foundations and general efficacy of this device - the implications of which extend to the steadily increasing tDCS psychological literature. PMID- 25448854 TI - How many peripersonal spaces? AB - Several studies in humans and non-human primates have explored and characterised the features of the cortical representation of the portion of space immediately surrounding the body - the peripersonal space. In this paper we ask the following question: is it legitimate to assume that there is a single representation of peripersonal space? This issue has rarely been addressed in the literature, leading to much confusion, especially when one compares results reported in social psychology and in cognitive neuroscience. Indeed, studies in both fields explore and refer to more or less the same portion of space, but the terminology used to describe it differs greatly. Therefore, the definition of this portion of space immediately surrounding the body has remained quite vague, allowing for many variations. Here, we propose a dual model of peripersonal space, based on a clear functional distinction between bodily protection and goal-directed action. We argue that the two functions of peripersonal space require distinct sensory and motor processes that obey different principles. Furthermore, we highlight that the effects of anxiety and tool use on peripersonal space provide empirical support to our distinction. PMID- 25448855 TI - Timing of spatial priming within the fronto-parietal attention network: A TMS study. AB - The posterior parietal cortex (PPC) and the dorsolateral prefrontal cortex (DLPFC) are known to be part of a cortical network involved in visual spatial attention. Top-down control can modulate processing at target and distractor positions over a sequence of trials, leading to positive priming at prior target positions and negative priming at prior distractor positions. In order to elucidate the exact time course of this top-down mechanism we here propose a transcranial magnetic stimulation (TMS) protocol. Single-pulses were applied over the right PPC, the right DLPFC or over the vertex (sham stimulation) at five time intervals (50, 100, 150, 200, 250 ms) after onset of a probe display during a spatial negative priming paradigm. Both suppression of the negative priming effect at a previous distractor position and enhancement of positive priming at a previous target position was found if a TMS pulse was applied 100 ms after the probe display onset either over the right DLPFC or the right PPC. We suggest that top-down mechanisms within the right fronto-parietal attention network are compromised during TMS interference in this time window. PMID- 25448856 TI - Autobiographical memory in children with Idiopathic Generalised Epilepsy. AB - Autobiographical memory involves the recall of both personal facts (semantic memory) and the re-experiencing of past personal events (episodic memory). The recall of autobiographical episodic details has been associated with a specific network, which involves the prefrontal and medial temporal lobes, in addition to posterior regions of the brain. Seizure activity has been previously shown to disrupt the consolidation of newly-learned information into long-term memory, but it is not yet known whether primary generalised seizures alone are also associated with deficits in the recall of autobiographical memories. Here we examined this recall in children who experience generalised rather than localisation-related seizures: children with Idiopathic Generalised Epilepsy (IGE). In this study, 18 children with IGE and 42 healthy controls of comparable age (6-16 years), sex and socio-economic status were administered the Children's Autobiographical Interview (CAI). Compared with controls, children with IGE recalled significantly fewer episodic details, even when retrieval prompts were provided. In contrast, no group difference was found for the recall of semantic autobiographic details. Within the IGE group, hierarchical regression analyses showed that patient age and earlier age of diagnosis were significantly related to the recall of episodic autobiographical details over different conditions of the CAI, explaining up to 37% of variance. To our knowledge, this study provides the first evidence of autobiographical episodic memory deficits in patients with primary generalised seizures. As no evidence of localisation-related epilepsy is apparent in patients with IGE, our findings suggest that generalised seizures alone, especially when developed at an early age, could compromise memories for personally-experienced events. PMID- 25448857 TI - A robust index of lexical representation in the left occipito-temporal cortex as evidenced by EEG responses to fast periodic visual stimulation. AB - Despite decades of research on reading, including the relatively recent contributions of neuroimaging and electrophysiology, identifying selective representations of whole visual words (in contrast to pseudowords) in the human brain remains challenging, in particular without an explicit linguistic task. Here we measured discrimination responses to written words by means of electroencephalography (EEG) during fast periodic visual stimulation. Sequences of pseudofonts, nonwords, or pseudowords were presented through sinusoidal contrast modulation at a periodic 10 Hz frequency rate (F), in which words were interspersed at regular intervals of every fifth item (i.e., F/5, 2 Hz). Participants monitored a central cross color change and had no linguistic task to perform. Within only 3 min of stimulation, a robust discrimination response for words at 2 Hz (and its harmonics, i.e., 4 and 6 Hz) was observed in all conditions, located predominantly over the left occipito-temporal cortex. The magnitude of the response was largest for words embedded in pseudofonts, and larger in nonwords than in pseudowords, showing that list context effects classically reported in behavioral lexical decision tasks are due to visual discrimination rather than decisional processes. Remarkably, the oddball response was significant even for the critical words/pseudowords discrimination condition in every individual participant. A second experiment replicated this words/pseudowords discrimination, and showed that this effect is not accounted for by a higher bigram frequency of words than pseudowords. Without any explicit task, our results highlight the potential of an EEG fast periodic visual stimulation approach for understanding the representation of written language. Its development in the scientific community might be valuable to rapidly and objectively measure sensitivity to word processing in different human populations, including neuropsychological patients with dyslexia and other reading difficulties. PMID- 25448858 TI - Interaction of memory systems during acquisition of tool knowledge and skills in Parkinson's disease. AB - Previous research suggests that different aspects of tool knowledge are mediated by different memory systems. It is believed that tool attributes (e.g., function, color) are represented as declarative memory while skill learning is supported by procedural memory. It has been proposed that other aspects (e.g., skilled tool use) may rely on an interaction of both declarative and procedural memory. However, the specific form of procedural memory underlying skilled tool use and the nature of interaction between declarative and procedural memory systems remain unclear. In the current study, individuals with Parkinson's disease (PD) and healthy controls were trained over 2 sessions, 3 weeks apart, to use a set of novel complex tools. They were also tested on their ability to recall tool attributes as well as their ability to demonstrate grasp and use of the tools to command. Results showed that, compared to controls, participants with PD showed intact motor skill acquisition and tool use to command within sessions, but failed to retain performance across sessions. In contrast, people with PD showed equivalent recall of tool attributes and tool grasping relative to controls, both within and across sessions. Current findings demonstrate that the frontal striatal network, compromised in PD, mediates long-term retention of motor skills. Intact initial skill learning raises the possibility of compensation from declarative memory for frontal-striatal dysfunction. Lastly, skilled tool use appears to rely on both memory systems which may reflect a cooperative interaction between the two systems. Current findings regarding memory representations of tool knowledge and skill learning may have important implications for delivery of rehabilitation programs for individuals with PD. PMID- 25448859 TI - Transcranial direct current stimulation (tDCS) of the parietal cortex leads to increased false recognition. AB - A robust finding is that brain activity in the lateral posterior parietal cortex (PPC) correlates with successful recognition. Here we test whether the PPC has a causal role in memory retrieval using transcranial direct current stimulation (tDCS). Participants were given a modified version of the Deese-Roediger McDermott (DRM) paradigm, a well-established method for producing false recognition with high confidence. In Experiment 1, false recognition was significantly greater for active compared to sham tDCS when the anode was placed over left parietal cortex (CP3) and the cathode over right parietal cortex (CP4). These findings were replicated in Experiment 2, with both anode CP3/cathode CP4 and anode CP4/cathode CP3 active stimulation leading to greater false recognition. Differences also emerged, with anode CP4/cathode CP3 active stimulation leading to greater hits. Our findings support the proposal that the lateral PPC plays a causal role in episodic memory retrieval and can lead to enhanced subjective aspects of memory. PMID- 25448860 TI - The role of executive control in bilingual language production: A study with Parkinson's disease individuals. AB - The basal ganglia are critically involved in language control (LC) processes, allowing a bilingual to utter correctly in one language without interference from the non-requested language. It has been hypothesized that the neural mechanism of LC closely resembles domain-general executive control (EC). The purpose of the present study is to investigate the integrity of bilingual LC and its overlap with domain-general EC in a clinical population such as individuals with Parkinson's disease (PD), notoriously associated with structural damage in the basal ganglia. We approach these issues in two ways. First, we employed a language switching task to investigate the integrity of LC in a group of Catalan Spanish bilingual individuals with PD, as compared to a group of matched healthy controls. Second, to test the relationship between domain-general EC and LC we compared the performances of individuals with PD and healthy controls also in a non-linguistic switching task. We highlight that, compared to controls, individuals with PD report decreased processing speed, less accuracy and larger switching costs in terms of RT and errors in the language switching task, whereas in the non-linguistic switching task PD patients showed only increased switching cost in terms of errors. However, we report a positive correlation between the magnitudes of linguistic and non-linguistic mixing costs in individuals with PD. Taken together, these results support the notion of a critical role of the basal ganglia and connected structures in LC, and suggest a possible link between LC and domain-general EC. PMID- 25448862 TI - Peripersonal space in the brain. AB - Research in neuroscience reveals that the brain constructs multiple representation of space. Here, we primarily focus on peripersonal space (PPS) representation, the region of space immediately surrounding our bodies and in which objects can be grasped and manipulated. We review convergent results from several generations of studies, including neurophysiological studies in animals, neuropsychological investigations in monkeys and brain-damaged patients with spatial cognition disorders, as well as recent neuroimaging experiments in neurologically normal individuals. Collectively, these studies show that the primate brain constructs multiple, rapidly modifiable representations of space, centered on different body parts (i.e., hand-centered, head-centered, and trunk centered), which arise through extensive multisensory interactions within a set of interconnected parietal and frontal regions. PPS representations are pivotal in the sensory guidance of motor behavior, allowing us to interact with objects and, as demonstrated by recent studies, with other people in the space around us. PMID- 25448863 TI - Neuropsychological parameters indexing executive processes are associated with independent components of ERPs. AB - Lesion studies have indicated that at least the three executive processes can be differentiated in the frontal lobe: Energization, monitoring and task setting. Event related potentials (ERPs) in Go/NoGo tasks have been widely used in studying executive processes. In this study, ERPs were obtained from EEG recorded during performance of a cued Go/NoGo task. The Contingent Negative Variation (CNV) and P3NoGo waves were decomposed into four independent components (ICs), by applying Independent Component Analysis (ICA) to a collection of ERPs from 193 healthy individuals. The components were named IC CNVearly, IC CNVlate, IC P3NoGoearly and IC P3NoGolate according to the conditions and time interval in which they occurred. A sub-group of 28 individuals was also assessed with neuropsychological tests. The test parameters were selected on the basis of studies demonstrating their sensitivity to executive processes as defined in the ROtman-Baycrest Battery for Investigating Attention (ROBBIA) model. The test scores were categorized into the domain scores of energization, monitoring and task setting and correlated with the amplitudes of the individual ICs from the sub-group of 28 individuals. The energization domain correlated with the IC CNVlate and IC P3NoGoearly. The monitoring domain correlated with the IC P3NoGolate, while the task setting domain correlated with the IC CNVlate. The IC CNVearly was not correlated with any of the neuropsychological domain scores. The correlations between the domains and ICs remained largely unchanged when controlling for full-scale IQ. This is the first study to demonstrate that executive processes, as indexed by neuropsychological test parameters, are associated with particular event-related potentials in a cued Go/NoGo paradigm. PMID- 25448864 TI - Bilingualism modulates dual mechanisms of cognitive control: Evidence from ERPs. AB - Recent behavioral findings with the AX-Continous Performance Task (AX-CPT; Morales et al., 2013) show that bilinguals only outperform monolinguals under conditions that require the highest adjustment between monitoring (proactive) and inhibitory (reactive) control, which supports the idea that bilingualism modulates the coordination of different control mechanisms. In an ERP experiment we aimed to further investigate the role that bilingualism plays in the dynamic combination of proactive and reactive control in the AX-CPT. Our results strongly indicate that bilingualism facilitates an effective adjustment between both components of cognitive control. First, we replicated previous behavioral results. Second, ERP components indicated that bilingualism influences the conflict monitoring, response inhibition and error monitoring components of control (as indexed by the N2 and P3a elicited by the probe and the error-related negativity following incorrect responses, respectively). Thus, bilinguals exerted higher reactive control than monolinguals but only when they needed to overcome the competing cue-information. These findings join others in suggesting that a better understanding of the cognitive benefits of bilingualism may require consideration of a multi-component perspective. PMID- 25448861 TI - Similarity between remembering the past and imagining the future in Alzheimer's disease: Implication of episodic memory. AB - Recent studies suggest that common cognitive processes and neuroanatomical substrates underlie the ability to remember the past and imagine the future. We studied these cognitive processes in patients with Alzheimer's Disease (AD). We asked 27 participants with AD and 30 older controls, matched by age, sex, and educational level, to generate past and future autobiographical events. Autobiographical generation was analyzed with respect to theme, general autobiographical performance, contextual performance, self-defining memories, and autonoetic reliving/re-experiencing. Unlike older controls, most AD participants evoked similar themes when generating past and future events (n=23/30 participants). These participants also showed similar autobiographical and contextual performance, similar amount of self-defining memories, and similar autonoetic states when generating past and future events. Further, significant correlations were detected between hippocampal-dependent memory decline in AD participants and their ability to relive past and future events. These outcomes suggest striking similarities between remembering the past and imagining the future in AD. Due to their memory decline, imagining the future in AD patients is likely to draw heavily from the little amount of available information from past episodes, resulting in striking similarities between remembering the past and imagining the future. Finally, and unlike AD participants, older controls mentally "try out" alternative approaches to upcoming situations without replicating the same schemes of past events. PMID- 25448865 TI - Neural correlates of second-language communication and the effect of language anxiety. AB - Communicative speech is a type of language use that involves goal-directed action targeted at another person based on social interactive knowledge. Previous studies regarding one's first language (L1) have treated the theory of mind system, which is associated with understanding others, and the sensorimotor system, which is associated with action simulation, as important contributors to communication. However, little is known about the neural basis of communication in a second language (L2), which is limited in terms of its use as a communication tool. In this fMRI study, we manipulated the type of speech (i.e., communication vs. description) and the type of language (L1 vs. L2) to identify the specific brain areas involved in L2 communication. We also attempted to examine how the cortical mechanisms underlying L2 speech production are influenced by oral proficiency and anxiety regarding L2. Thirty native Japanese speakers who had learned English as an L2, performed communicative and descriptive speech-production tasks in both L1 and L2 while undergoing fMRI scanning. We found that the only the L2 communication task recruited the left posterior supramarginal gyrus (pSMG), which may be associated with the action simulation or prediction involved in generating goal-directed actions. Furthermore, the neural mechanisms underlying L2 communication, but not L2 description, were sensitive to both oral proficiency and anxiety levels; (a) activation in the left middle temporal gyrus (MTG) increased as oral proficiency levels increased, and (b) activation in the orbitofrontal cortex (OFC), including the left insula, decreased as L2 anxiety levels increased. These results reflect the successful retrieval of lexical information in a pragmatic context and an inability to monitor social behaviors due to anxiety. Taken together, the present results suggest that L2 communication relies on social skills and is mediated by anxiety and oral proficiency. PMID- 25448866 TI - The Iterative Protein Redesign and Optimization (IPRO) suite of programs. AB - Proteins are an important class of biomolecules with applications spanning across biotechnology and medicine. In many cases, native proteins must be redesigned to improve various performance metrics by changing their amino acid sequences. Algorithms can help sharpen protein library design by focusing the library on sequences that optimize computationally accessible proxies. The Iterative Protein Redesign and Optimization (IPRO) suite of programs offers an integrated environment for (1) altering protein binding affinity and specificity, (2) grafting a binding pocket into an existing protein scaffold, (3) predicting an antibody's tertiary structure based on its sequence, (4) enhancing enzymatic activity, and (5) assessing the structure and binding energetics for a specific mutant. This manuscript provides an overview of the methods involved in IPRO, input language terminology, algorithmic details, software implementation specifics and application highlights. IPRO can be downloaded at http://maranas.che.psu.edu. PMID- 25448867 TI - Robust assessment of the expansion and retreat of Mediterranean climate in the 21st century. AB - The warm-temperate regions of the globe characterized by dry summers and wet winters (Mediterranean climate; MED) are especially vulnerable to climate change. The potential impact on water resources, ecosystems and human livelihood requires a detailed picture of the future changes in this unique climate zone. Here we apply a probabilistic approach to quantitatively address how and why the geographic distribution of MED will change based on the latest-available climate projections for the 21st century. Our analysis provides, for the first time, a robust assessment of significant northward and eastward future expansions of MED over both the Euro-Mediterranean and western North America. Concurrently, we show a significant 21st century replacement of the equatorward MED margins by the arid climate type. Moreover, future winters will become wetter and summers drier in both the old and newly established MED zones. Should these projections be realized, living conditions in some of the most densely populated regions in the world will be seriously jeopardized. PMID- 25448868 TI - Surgical procedure of extracting teeth for obtaining dental pulp for regenerative medicine in swine. AB - Dental pulp is a potential source of cells that can be used in cell replacement therapy for various nerve disorders, including stroke, spinal cord injury, and peripheral nerve defect. However, the validation of an animal model closely related to humans is needed in translational research. The miniature pig is a suitable experimental model in maxillofacial surgery, because its anatomical structure and size are similar to those of humans. However, the swine tooth is extremely long. The routine closed extraction procedure for harvesting dental pulp tissue causes root fracture. This report describes the details of a surgical procedure for tooth extraction. Four healthy 7-8-month-old male NIBS miniature pigs were used. Two mandibular deciduous right incisors (Di1 and Di2) were extracted in order to obtain dental pulp tissue. Gingival envelope incision with vertical-releasing incision was performed, and a full-thickness mucoperiosteal flap was made. The buccal alveolar bone was exposed and removed by osteotomy. Di1 and Di2 were extracted. Dental pulp tissue was obtained from these extracted teeth by splitting hard tissue. In this procedure, 9.8 +/- 2.5 * 10(5) cells were obtained from the mandibular Di1 and Di2 (n = 4). PMID- 25448870 TI - Defining and measuring quality in endoscopy. PMID- 25448869 TI - Quality indicators for ERCP. PMID- 25448872 TI - Quality indicators for EGD. PMID- 25448871 TI - Quality indicators for EUS. PMID- 25448874 TI - Quality indicators common to all GI endoscopic procedures. PMID- 25448876 TI - Cardiotoxic Electrophysiological Effects of the Herbicide Roundup((r)) in Rat and Rabbit Ventricular Myocardium In Vitro. AB - Roundup (R), a glyphosate (G)-based herbicide (GBH), containing unknown adjuvants is widely dispersed around the world. Used principally by farmers, intoxications have increasingly been reported. We have studied R effects (containing 36 % of G) on right ventricular tissues (male Sprague-Dawley rats, up to 20,000 ppm and female New Zealand rabbits, at 25 and 50 ppm), to investigate R cardiac electrophysiological actions in vitro. We tested the reduced Ca(++) intracellular uptake mechanism as one potential cause of the electrical abnormalities after GBH superfusion, using the Na(+)/K(+)-ATPase inhibitor ouabain or the 1,4 dihydropyridine L-type calcium channel agonist BAY K 8644 which increases I Ca. R concentrations were selected based on human blood ranges found after acute intoxication. The study showed dose-dependent V max, APD50 and APD90 variations during 45 min of R superfusion. At the highest concentrations tested, there was a high incidence of conduction blocks, and 30-min washout with normal Tyrode solution did not restore excitability. We also observed an increased incidence of arrhythmias at different doses of R. Ouabain and BAY K 8644 prevented V max decrease, APD90 increase and the cardiac inexcitability induced by R 50 ppm. Glyphosate alone (18 and 180 ppm) had no significant electrophysiological effects. Thus, the action potential prolonging effect of R pointing to I Ca interference might explain both conduction blocks and proarrhythmia in vitro. These mechanisms may well be causative of QT prolongation, atrioventricular conduction blocks and arrhythmias in man after GBH acute intoxications as reported in retrospective hospital records. PMID- 25448875 TI - The association of proopiomelanocortin polymorphisms with the risk of major depressive disorder and the response to antidepressants via interactions with stressful life events. AB - Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is among the most consistent neuroendocrine abnormalities in major depressive disorder (MDD). The peptide adrenocorticotropin hormone (ACTH) mediates HPA axis function during stress and is encoded by the proopiomelanocortin (POMC) gene polycistronically. After screening 39 POMC polymorphisms, we evaluated the association of polymorphisms with susceptibility to MDD in 145 MDD patients and 193 normal subjects; in patients, we also evaluated the response to treatment with antidepressants. Additionally, we investigated the role of gene-environment interaction between POMC haplotypes and stressful life events (SLE) in the treatment response. Although genotypes and haplotypes were not significantly associated with the risk of MDD, non-remitters were more likely to carry haplotype 1 (ht1) and to have no ht2 than were remitters (corrected P = 0.010 0.035). Although observations were limited in patients without SLE, a significant haplotype-SLE interaction was observed (P = 0.020). Additionally, at 1, 2, and 8 weeks of treatment, the 21-item Hamilton Depression Rating scores of MDD subjects with POMC ht2 were significantly (P = 0.003-0.044) lower than those of patients with ht1 in subjects those did not experience SLE. MDD subjects possessing POMC ht2 achieved remission significantly (P = 0.013; survival analysis) faster than patients with ht1. This study suggests that POMC haplotypes, via an interaction with SLE, are associated with antidepressant treatment outcomes in MDD patients. Regarding SLE, haplotypes of the POMC gene could be useful markers for predicting the response to antidepressant treatment in MDD patients. PMID- 25448873 TI - Quality indicators for colonoscopy. PMID- 25448877 TI - Evolving Electrocardiographic Changes in Lamotrigine Overdose: A Case Report and Literature Review. AB - Lamotrigine overdose usually follows a benign pattern, and the majority of cases reported involve a co-ingestant. Prior reports have suggested the possible use of intravenous lipid emulsion in cases of severe sodium channel blockade. We describe the electrocardiographic changes in a massive lamotrigine overdose treated with intravenous lipid emulsion. A 36-year-old male with bipolar disorder ingested 13.5 g of lamotrigine in a suicidal attempt. The lamotrigine level was 78.0 MUg/mL. Comprehensive drug screen was negative for all screened compounds. The electrocardiogram demonstrated a prolonged QRS complex and signs suggestive of sodium channel blockade. Refractory to treatment with sodium bicarbonate was treated with intravenous lipid emulsion, with immediate resolution of the electrocardiographic changes. Lamotrigine inhibits the voltage-gated sodium channel opening, attenuating the release of excitatory neurotransmitters. Cardiac intraventricular conduction could be delayed in cases of lamotrigine overdose resulting in QRS and QTc prolongation and R waves >3 mm in leads I and aVR. A potential role for intravenous lipid emulsion therapy has been described in patients with toxic levels of lamotrigine and electrocardiographic changes refractory to the treatment with sodium bicarbonate. Intravenous lipid emulsion has been successfully used in the treatment of lamotrigine cardiac toxicity. PMID- 25448878 TI - The mitochondrial voltage-dependent anion channel 1 in tumor cells. AB - VDAC1 is found at the crossroads of metabolic and survival pathways. VDAC1 controls metabolic cross-talk between mitochondria and the rest of the cell by allowing the influx and efflux of metabolites, ions, nucleotides, Ca2+ and more. The location of VDAC1 at the outer mitochondrial membrane also enables its interaction with proteins that mediate and regulate the integration of mitochondrial functions with cellular activities. As a transporter of metabolites, VDAC1 contributes to the metabolic phenotype of cancer cells. Indeed, this protein is over-expressed in many cancer types, and silencing of VDAC1 expression induces an inhibition of tumor development. At the same time, along with regulating cellular energy production and metabolism, VDAC1 is involved in the process of mitochondria-mediated apoptosis by mediating the release of apoptotic proteins and interacting with anti-apoptotic proteins. The engagement of VDAC1 in the release of apoptotic proteins located in the inter membranal space involves VDAC1 oligomerization that mediates the release of cytochrome c and AIF to the cytosol, subsequently leading to apoptotic cell death. Apoptosis can also be regulated by VDAC1, serving as an anchor point for mitochondria-interacting proteins, such as hexokinase (HK), Bcl2 and Bcl-xL, some of which are also highly expressed in many cancers. By binding to VDAC1, HK provides both a metabolic benefit and apoptosis-suppressive capacity that offer the cell a proliferative advantage and increase its resistance to chemotherapy. Thus, these and other functions point to VDAC1 as an excellent target for impairing the re-programed metabolism of cancer cells and their ability to evade apoptosis. Here, we review current evidence pointing to the function of VDAC1 in cell life and death, and highlight these functions in relation to both cancer development and therapy. In addressing the recently solved 3D structures of VDAC1, this review will point to structure-function relationships of VDAC as critical for deciphering how this channel can perform such a variety of roles, all of which are important for cell life and death. Finally, this review will also provide insight into VDAC function in Ca2+ homeostasis, protection against oxidative stress, regulation of apoptosis and involvement in several diseases, as well as its role in the action of different drugs. We will discuss the use of VDAC1-based strategies to attack the altered metabolism and apoptosis of cancer cells. These strategies include specific siRNA able to impair energy and metabolic homeostasis, leading to arrested cancer cell growth and tumor development, as well VDAC1-based peptides that interact with anti-apoptotic proteins to induce apoptosis, thereby overcoming the resistance of cancer cell to chemotherapy. Finally, small molecules targeting VDAC1 can induce apoptosis. VDAC1 can thus be considered as standing at the crossroads between mitochondrial metabolite transport and apoptosis and hence represents an emerging cancer drug target. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25448879 TI - Atomically detailed lipid bilayer models for the interpretation of small angle neutron and X-ray scattering data. AB - We present a new atom density profile (ADP) model and a statistical approach for extracting structural characteristics of lipid bilayers from X-ray and neutron scattering data. Models for five lipids with varying head and tail chemical composition in the fluid phase, 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC), 1,2 dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), 1-palmitoyl-2-oleoyl-sn glycero-3-phosphatidylserine (POPS), and 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphatidylglycerol (POPG), are optimized using a simplex based method to simultaneously reproduce both neutron and X-ray scattering data. Structural properties are determined using statistical analysis of multiple optimal model structures. The method and models presented make minimal assumptions regarding the atomic configuration, while taking into account the underlying physical properties of the system. The more general model and statistical approach yield data with well defined uncertainties, indicating the precision in determining density profiles, atomic locations, and bilayer structural characteristics. Resulting bilayer structures include regions exhibiting large conformational variation. Due to the increased detail in the model, the results demonstrate the possibility of a distinct hydration layer within the interfacial (backbone) region. PMID- 25448880 TI - Early treatment response to sorafenib for rabbit VX2 orthotic liver tumors: evaluation by quantitative contrast-enhanced ultrasound. AB - The aim of our study was to investigate the application of contrast-enhanced ultrasound (CEUS) and its quantification analysis for the prediction of early treatment response of sorafenib on rabbit VX2 liver tumor model. Rabbits were implanted VX2 tumor mass to establish a liver tumor model. Fourteen days after tumor implantation, rabbits presented with single liver tumor were randomly divided into two groups. Rabbits in treatment group were given by gavage once a day for 14 days with sorafenib suspension at a dose of 30 mg/kg, whereas rabbits in control group were given saline by gavage of the same volume. CEUS was performed before treatment and 3, 7, 14 days after treatment for the analysis of tumor size, enhancement pattern, and necrosis range. The time intensity curve (TIC) was used to obtain quantitative parameters of enhancement patterns. Before sorafenib administration, tumor volumes ranged from 0.24 to 0.75 cm(3) (mean 0.49 +/- 0.18 cm(3)) in treatment group and 0.24 to 0.44 cm(3) (mean 0.30 +/- 0.12 cm(3)) in control group. The dynamic enhancement patterns of tumors were homogeneous hyper-enhancement (n = 8), heterogeneous hyper-enhancement (n = 4), and peripheral rim-like enhancement (n = 2). All tumors of the treatment group presented with peripheral rim-like enhancement with large necrotic area after sorafenib administration, whereas tumors of the control group showed heterogeneous hyper-enhancement (n = 5) and peripheral rim-like enhancement (n = 2). There was a significant difference in area under the curve (AUC) before and after sorafenib treatment (P = 0.045). CEUS may be of value in the evaluation of early therapeutic response after sorafenib administration. PMID- 25448882 TI - Two decades of publishing excellence in pharmaceutical biotechnology. PMID- 25448883 TI - Stepwise combination of NH3 with BH4(-) in metal borohydride ammoniate. AB - Step-wise combination of NH3 with BH4(-) was found to proceed in the AlCl3.mNH3 nLiBH4 system. Firstly, only two N-H bonds of the NH3 groups combined with B-H bonds at low temperature. Secondly, the residual N-H bonds could react further with excess B-H bonds at elevated temperature. This process is believed to be a common feature for many metal borohydride ammoniates. PMID- 25448881 TI - Bone morphogenetic protein 2 mediates epithelial-mesenchymal transition via AKT and ERK signaling pathways in gastric cancer. AB - Although deregulation of bone morphogenetic protein 2 (BMP2) signaling has been linked to various types of cancers, the relationships between abnormal activation of these signaling pathways and tumorigenesis are not clear in gastric cancer. We hypothesized that BMP2 might be involved in epithelial-mesenchymal transition (EMT) process of gastric cancer. Here, BMPR-II activation and inhibition in gastric cancer cell line AGS were induced with exogenous BMP2 and with BMPR-II small interfering RNA (siRNA), respectively. BMPR-II downstream signal molecules AKT, ERK phosphorylation, and EMT biomarkers (vimentin, snail, N-cadherin, and E cadherin) were tested using the Western blot. In the present study, our results showed that BMP2 can induce AKT and ERK phosphorylation in a dose-dependent method, and endogenous BMPR-II can be inhibited completely by BMPR-II siRNA in AGS. Notably BMP2 alone treatment can induce the up-regulation of vimentin, snail, and N-cadherin in AGS cells, besides, the down-regulation of E-cadherin also occurred. On the contrary, BMPR-II siRNA significantly prohibited BMP2 induced AKT and ERK phosphorylation, at the same time, EMT biomarkers changes were not observed. On the other hand, BMPR-II knockdown could significantly affect AGS wound closure and the migration ability (p < 0.001) compared to control siRNA and BMP2 alone. In conclusion, this study suggested that EMT process can be triggered by the BMP2/BMPR axis in gastric cancer and then involved in the tumor cell migration, invasion, and metastasis via the activation of PI3K/AKT and MEK/ERK pathways. Our study lays a new foundation for the treatment of gastric cancer through antagonizing BMP2 system. PMID- 25448884 TI - Variation in fluorosis and caries experience among Lithuanian 12 year olds exposed to more than 1 ppm F in tap water. AB - AIM: The aim of the present study was to analyze caries experience in relation to the occurrence of fluorosis in 12 year olds in a natural fluoride area. METHODS: This cross-sectional study was conducted among 12-year-old lifetime residents (n = 301) of Klaipeda, Lithuania, where the natural fluoride content is 1.7-2.2 ppm F. Data collection included a clinical dental examination and an inquiry about toothbrushing habits. Dental caries was diagnosed according to the World Health Organization criteria and described in terms of decayed, missing, and filled teeth (DMFT)/decayed, missing and filled surfaces (DMFS) indices and decayed, filled surfaces (DFS) on selected proximal surfaces. Dental fluorosis was diagnosed according to the Thylstrup-Fejerskov (TF) index and categorized as none (TF = 0), mild (TF = 1-2), moderate (TF = 3-7), or severe (TF = 8-9). The chi(2) , Kruskal-Wallis, and Mann-Whitney tests, Pearson's correlation, and linear regression served for statistical analyses. RESULTS: A total of 34% of the 12 year olds studied had no signs of fluorosis, while the rest had mild (42%) or moderate (24%) fluorosis. Caries experience was negatively related to the presence of fluorosis. When present (TF > 0), the mean DMFT was 1.8 (standard deviation [SD]: 1.7) versus 2.6 (SD: 2.3) in the absence of fluorosis (TF = 0, P = 0.008). The corresponding mean DMFS values were 2.6 (SD: 3.1) versus 3.8 (SD: 4.3, P = 0.014). CONCLUSION: The presence of fluorosis associates with lesser caries experience in 12-year-old lifetime residents of an area with moderately elevated natural fluoride. PMID- 25448887 TI - Biogenic nanospheres of amorphous carbonated Ca-Mg phosphate within the periostracum of the green mussel Perna viridis. AB - Recently there is increasing evidence that the shell biomineralization proceeds via an amorphous precursor route. Therefore, the search for and investigation of amorphous biominerals in bivalve shells are of great importance and interest. Here, using a scanning electron microscope (SEM), transmission electron microscope (TEM), X-ray diffractometer (XRD), and Fourier transform infrared spectrometer (FTIR), we investigate the microstructure and mineralogy of the periostracum in Perna viridis. We find that: (1) the periostracum has three layers, of which the inner and outer layer are of proteins, while the middle layer is mineralized with nanospheres of amorphous biominerals; (2) the nanospheres are of amorphous carbonated Ca-Mg phosphate (ACCP), where the CO3(2)( )/PO4(3)(-) weight ratio is estimated to be ~0.3, and the Ca/P and Ca/Mg atomic ratio is ~1.4 and 1.6, respectively; (3) the nanospheres, with a diameter of 43 106nm, are found to assemble into spherules with a diameter of 160-500nm, which are further organized into parallel microlayers separated by the proteins; and (4) the nanospheres are assumed to function as the pH stabilizer to facilitate the shell's initial mineralization. Finally, we expect that these findings will advance our understanding of the shell's biomineralization process. PMID- 25448885 TI - Quantitative analysis of mouse pancreatic islet architecture by serial block-face SEM. AB - We have applied serial block-face scanning electron microscopy (SBF-SEM) to measure parameters that describe the architecture of pancreatic islets of Langerhans, microscopic endocrine organs that secrete insulin and glucagon for control of blood glucose. By analyzing entire mouse islets, we show that it is possible to determine (1) the distributions of alpha and beta cells, (2) the organization of blood vessels and pericapillary spaces, and (3) the ultrastructure of the individual secretory cells. Our results show that the average volume of a beta cell is nearly twice that of an alpha cell, and the total mitochondrial volume is about four times larger. In contrast, nuclear volumes in the two cell types are found to be approximately equal. Although the cores of alpha and beta secretory granules have similar diameters, the beta granules have prominent halos resulting in overall diameters that are twice those of alpha granules. Visualization of the blood vessels revealed that every secretory cell in the islet is in contact with the pericapillary space, with an average contact area of 9+/-5% of the cell surface area. Our data show that consistent results can be obtained by analyzing small numbers of islets. Due to the complicated architecture of pancreatic islets, such precision cannot easily be achieved by using TEM of thin sections. PMID- 25448886 TI - Analysis of acute brain slices by electron microscopy: a correlative light electron microscopy workflow based on Tokuyasu cryo-sectioning. AB - Acute brain slices are slices of brain tissue that are kept vital in vitro for further recordings and analyses. This tool is of major importance in neurobiology and allows the study of brain cells such as microglia, astrocytes, neurons and their inter/intracellular communications via ion channels or transporters. In combination with light/fluorescence microscopies, acute brain slices enable the ex vivo analysis of specific cells or groups of cells inside the slice, e.g. astrocytes. To bridge ex vivo knowledge of a cell with its ultrastructure, we developed a correlative microscopy approach for acute brain slices. The workflow begins with sampling of the tissue and precise trimming of a region of interest, which contains GFP-tagged astrocytes that can be visualised by fluorescence microscopy of ultrathin sections. The astrocytes and their surroundings are then analysed by high resolution scanning transmission electron microscopy (STEM). An important aspect of this workflow is the modification of a commercial cryo ultramicrotome to observe the fluorescent GFP signal during the trimming process. It ensured that sections contained at least one GFP astrocyte. After cryo sectioning, a map of the GFP-expressing astrocytes is established and transferred to correlation software installed on a focused ion beam scanning electron microscope equipped with a STEM detector. Next, the areas displaying fluorescence are selected for high resolution STEM imaging. An overview area (e.g. a whole mesh of the grid) is imaged with an automated tiling and stitching process. In the final stitched image, the local organisation of the brain tissue can be surveyed or areas of interest can be magnified to observe fine details, e.g. vesicles or gold labels on specific proteins. The robustness of this workflow is contingent on the quality of sample preparation, based on Tokuyasu's protocol. This method results in a reasonable compromise between preservation of morphology and maintenance of antigenicity. Finally, an important feature of this approach is that the fluorescence of the GFP signal is preserved throughout the entire preparation process until the last step before electron microscopy. PMID- 25448888 TI - Amino acid sequence homologies in the hard keratins of birds and reptiles, and their implications for molecular structure and physical properties. AB - Avian and reptilian epidermal appendages such as feathers, claws and scales exhibit a filament-matrix texture. Previous studies have established that both components reside within the same single-chain molecule. In the present study the homology in a wide range of aligned sequences is used to gain insights into the structure and function of the molecular segments associated with the filament and with the matrix. The notion that all molecules contain a beta-rich 34-residue segment associated with the framework of the filament is reinforced by the present study. In addition, the residues involved in the polymerization of the molecules to form filaments are identified. In the Archosaurs (birds, crocodiles and turtles), and the Squamates (snakes and lizards) segments rich in glycine and tyrosine can be identified in the C-terminal domain. In Rhynocephalians (tuataras) and Squamates a similar segment is inserted at a specific point in the N-terminal domain. In some Archosaurian appendages (both avian and reptilian) segments rich in charged residues and cysteine are found in the N-terminal domain. The likely effect of these segments will be to soften the tissue without compromising its insolubility. The structure and role of the various molecular segments identified in this study and the way in which they might manifest themselves in terms of the physical properties of the particular epidermal appendage in which they appear are also discussed. PMID- 25448889 TI - Thalidomide mimics uridine binding to an aromatic cage in cereblon. AB - Thalidomide and its derivatives lenalidomide and pomalidomide are important anticancer agents but can cause severe birth defects via an interaction with the protein cereblon. The ligand-binding domain of cereblon is found, with a high degree of conservation, in both bacteria and eukaryotes. Using a bacterial model system, we reveal the structural determinants of cereblon substrate recognition, based on a series of high-resolution crystal structures. For the first time, we identify a cellular ligand that is universally present: we show that thalidomide and its derivatives mimic and compete for the binding of uridine, and validate these findings in vivo. The nature of the binding pocket, an aromatic cage of three tryptophan residues, further suggests a role in the recognition of cationic ligands. Our results allow for general evaluation of pharmaceuticals for potential cereblon-dependent teratogenicity. PMID- 25448890 TI - A reason for intermittent fasting to suppress the awakening of dormant breast tumors. AB - For their growth, dormant tumors, which lack angiogenesis may critically depend on gradients of nutrients and oxygen from the nearest blood vessel. Because for oxygen depletion the distance from the nearest blood vessel to depletion will generally be shorter than for glucose depletion, such tumors will contain anoxic living tumor cells. These cells are dangerous, because they are capable of inducing angiogenesis, which will "wake up" the tumor. Anoxic cells are dependent on anaerobic glucose breakdown for ATP generation. The local extracellular glucose concentration gradient is determined by the blood glucose concentration and by consumption by cells closer to the nearest blood vessel. The blood glucose concentration can be lowered by 20-40% during fasting. We calculated that glucose supply to the potentially hazardous anoxic cells can thereby be reduced significantly, resulting in cell death specifically of the anoxic tumor cells. We hypothesize that intermittent fasting will help to reduce the incidence of tumor relapse via reducing the number of anoxic tumor cells and tumor awakening. PMID- 25448891 TI - Biological wires, communication systems, and implications for disease. AB - Microtubules, actin, and collagen are macromolecular structures that compose a large percentage of the proteins in the human body, helping form and maintain both intracellular and extracellular structure. They are biological wires and are structurally connected through various other proteins. Microtubules (MTs) have been theorized to be involved in classical and quantum information processing, and evidence continues to suggest possible semiconduction through MTs. The previous Dendritic Cytoskeleton Information Processing Model has hypothesized how MTs and actin form a communication network in neurons. Here, we review information transfer possibilities involving MTs, actin, and collagen, and the evidence of an organism-wide high-speed communication network that may regulate morphogenesis and cellular proliferation. The direct and indirect evidence in support of this hypothesis, and implications for chronic diseases such as cancer and neurodegenerative diseases are discussed. PMID- 25448893 TI - Physarum polycephalum: towards a biological controller. AB - Microbial fuels cells (MFCs) are bio-electrochemical transducers that generate energy from the metabolism of electro-active microorganisms. The organism Physarum polycephalum is a slime mould, which has demonstrated many novel and interesting properties in the field of unconventional computation, such as route mapping between nutrient sources, maze solving and nutrient balancing. It is a motile, photosensitive and oxygen-consuming organism, and is known to be symbiotic with some, and antagonistic with other microbial species. In the context of artificial life, the slime mould would provide a biological mechanism (along with the microbial community) for controlling the performance and behaviour of artificial systems (MFCs, robots). In the experiments it was found that P. polycephalum did not generate significant amounts of power when inoculated in the anode. However, when P. polycephalum was introduced in the cathode of MFCs, a statistically significant difference in power output was observed. PMID- 25448892 TI - The effect of nanoparticles on plankton dynamics: a mathematical model. AB - A simple modification of the Rosenzweig-MacArthur predator (zooplankton)-prey (phytoplankton) model with the interference of the predators by adding the effect of nanoparticles is proposed and analyzed. It is assumed that the effect of these particles has a potential to reduce the maximum physiological per-capita growth rate of the prey. The dynamics of nanoparticles is assumed to follow a simple Lotka-Volterra uptake term. Our study suggests that nanoparticle induce growth suppression of phytoplankton population can destabilize the system which leads to limit cycle oscillation. We also observe that if the contact rate of nanoparticles and phytoplankton increases, then the equilibrium densities of phytoplankton as well as zooplankton decrease. Furthermore, we observe that the depletion/removal of nanoparticles from the aquatic system plays a crucial role for the stable coexistence of both populations. Our investigation with various types of functional response suggests that Beddington functional response is the most appropriate representation of the interaction of phytoplankton-nanoparticles in comparison to other widely used functional responses. PMID- 25448894 TI - Effects of reciprocal inhibitory coupling in model neurons. AB - Central pattern generators are neuron networks that produce vital rhythmic motor outputs such as those observed in mastication, walking and breathing. Their activity patterns depend on the tuning of their intrinsic ionic conductances, their synaptic interconnectivity and entrainment by extrinsic neurons. The influence of two commonly found synaptic connectivities--reciprocal inhibition and electrical coupling--are investigated here using a neuron model with subthreshold oscillation capability, in different firing and entrainment regimes. We study the dynamics displayed by a network of a pair of neurons with various firing regimes, coupled by either (i) only reciprocal inhibition or by (ii) electrical coupling first and then reciprocal inhibition. In both scenarios a range of coupling strengths for the reciprocal inhibition is tested, and in general the neuron with the lower firing rate stops spiking for strong enough inhibitory coupling, while the faster neuron remains active. However, in scenario (ii) the originally slower neuron stops spiking at weaker inhibitory coupling strength, suggesting that the electrical coupling introduces an element of instability to the two-neuron network. PMID- 25448895 TI - Synovial membrane asks for independence. AB - Synovial membrane is traditionally considered as a part of the joint capsule. It, however, differs from fibrous part of the capsule in development, structure, function, vascularisation, innervation and involvement in pathological processes. Moreover, in some areas, it even does not contact with the fibrous capsule. Thus, it appears that the synovial membrane should be considered as an independent organ and not as the lining of the joint capsule. PMID- 25448897 TI - Determination of the median nerve safe-zone in the carpal tunnel using the distal forearm bony prominences. AB - BACKGROUND: The compression of the median nerve (MN) in the carpal tunnel (CT) is one of the most common aetiologies of entrapment neuropathy syndromes in clinical practice. The aim of this study was to investigate the relationship of the palpable bony prominences of the distal forearm (radial styloid process [RSP] and ulnar styloid process [USP]) with MN in the CT, in order to determine a safe-zone of the MN during carpal tunnel procedures. MATERIALS AND METHODS: This study involved the bilateral dissection of the CT region of 30 adult cadaveric specimens (n = 60). RESULTS: The mean distance between the RSP and USP was 49.34 mm. The mean distance of the MN from the RSP and the USP were 22.44 mm and 26.66 mm, respectively. The mean diameter of the MN within the CT deep to the flexor retinaculum was 5.93 mm. In addition, the MN was located postero-lateral and postero-medial to palmaris longus tendon (PLT) in 78.33% and 21.67% of specimens, respectively. CONCLUSIONS: This study found that the MN was located less than 60% of the RSP-USP distance from the RSP. Furthermore, the MN was mostly located postero-lateral to the PLT. Therefore, injection or surgical incision made at/medial to a point 60% of the RSP-USP distance from the RSP will be outside the safe-zone of the MN. The knowledge of this surface anatomical relationship of the MN may be useful during decompression for CT syndrome. PMID- 25448896 TI - Effect of prenatal exposure to bisphenol a on the vagina of albino rats: immunohistochemical and ultrastructural study. AB - BACKGROUND: Bisphenol-A (BPA) is an industrial chemical, used to manufacture polycarbonate and numerous plastic articles. It has been found to cause biological effects, mimic that of oestrogen. It belongs to a group of chemicals termed "endocrine disruptors" able to disrupt the chemical messenger system in the body. Aim of the study was to demonstrate the biological effects of BPA on the vagina of female rats, with the prediction of the neoplastic changes in relation to its potential impact. MATERIALS AND METHODS: Sprague-Dawley gravid dams were divided into three groups (10 per group): G1 - control group had an equivalent volume of sesame oil to that taken in the treated groups, G2 - group was administered by gavage 0.1 mg BPA/kg body weight (low-dose group) per day, and G3 - group was administered 50 mg BPA/kg body weight (high-dose group) per day, dissolved in sesame oil. Treatment was carried out on gestation days 10 through 20. The female offsprings of each group were weaned at day 21 and the vagina was dissected when became 3 months old for histological, immunohistochemical analysis (for detection of oestrogen receptors a [ERa], and the proliferation marker Ki-67), and ultrastructural study. RESULTS: The low dose group showed degeneration of the epithelial lining with focal patches of decreased epithelial layers. The high dose group revealed cytoplasmic hydropic degeneration, and the pyknotic nuclei of epithelial cells. Oestrogen receptors demonstrated a significant decrease of positive cells in low dose treated group and this decrease markedly accentuated in the high dose one. Positive nuclei for Ki-67 were markedly increased with increasing doses of BPA. Electron microscopic study revealed cytoplasmic degeneration, vacuolation and mitochondrial degeneration in both treated groups. CONCLUSIONS: BPA showed an obvious mix of degenerative and proliferative histological changes and clear damage of the cellular organelles. This stressful condition may predispose to neoplastic changes of the vagina. PMID- 25448898 TI - Vascularisation of the geniculate ganglion. AB - BACKGROUND: Lack of the relevant data in the literature and possible clinical significance of the geniculate ganglion vasculature inspired us to examine the vessels of this ganglion. MATERIALS AND METHODS: Twelve temporal bones were taken during autopsy and microdissected. Four geniculate ganglions were taken as well, serially sectioned and used for haematoxylin-eosin and trichrome staining, and for CD34 immunostaining. RESULTS: The geniculate ganglion was supplied by the petrosal artery, which averaged 1.1 in number, 0.44 mm in the outer diameter, 0.24 mm in the luminal diameter, and 17.1 mm in length. The artery approached the greater petrosal nerve, giving off 1-3 twigs to it with a mean diameter of 24 MUm, and entered the nerve hiatus or a small bone opening close to the ganglion. Before the artery continued to the tympanic segment of the facial nerve, it gave rise to 1 (8.33%), 2 (75.00%) or 3 (16.67%) branches to the geniculate ganglion, which ranged in diameter between 18 MUm and 56 MUm (mean 29 MUm). From the formed superficial network, several twigs penetrated the ganglion and built an intraganglionic plexus. The counting, performed in microscopic fields, each measuring 341.7 MUm * 250.0 MUm in size, contained between 20 and 38 (mean 28.1) ganglion cells, as well as from 87 to 143 microvessels (mean 99.8), so that the neuron/vessel ratio was 1:3.6. CONCLUSIONS: This is the first detailed examination of the geniculate ganglion vasculature. The obtained data could be of clinical importance, especially in relation to the Bell's palsy, ganglionitis, geniculate neuralgia, petrous bone imaging, and operations in the same region. PMID- 25448900 TI - Variations in the squamous part of the occipital bone in medieval and contemporary cranial series from Bulgaria. AB - The squamous part of the occipital bone is a place of many different variations. They are a result of faulty ossification in the occipital squama or due to the presence of sutural bones in the lambda region. As their differentiation is intricate because of the various criteria used, the issue of their recognition in the adult skull still remains difficult even though they can be clearly distinguished at a younger age. The aim of the present study was to compare the frequency of interparietal, preinterparietal and sutural bones in the lambda region in medieval male and female cranial series as well as between medieval and contemporary male series from Bulgaria. We also discuss the development of the occipital squama in order to set clearer criteria for further differentiation of such variations in the adult skull. In the reviewed 3 cranial series, the variations in the squamous portion of the occipital bone were observed with a low frequency. The incidence of preinterparietal bones was more common than the interparietal ones. The sutural bones in the lambda region were numerous in the series. No statistically significant sex or intergroup differences were established. So even if these anatomical variations are relatively rare, the understanding of them is of significance for many disciplines like anthropology, comparative and developmental anatomy, clinical and forensic medicine. PMID- 25448899 TI - Three dimensional visualisation and morphometry of bone samples studied in microcomputed tomography (micro-CT). AB - This article highlights the utility of micro-computed tomography (micro-CT) for characterisingmicroscale bone morphology. For this purpose we tested selected samplesof the human bones (Wormian bone, rib, lumbar vertebra) to reconstruct externaland internal morphological features. Selected bony samples were investigatedusing a micro-CT scanner (Skyscan 1172, N.V., Aartselaar, Belgium). The imageresolution of scans varied from 5 to 27 MUm/pixel depending on the bone sample.We used CTvox software (by Skyscan) to perform volume rendering of the samples.Further, 3-dimensional geometrical models were reconstructed using theCTvol application. Such models enabled graphical distinction between osseouscomponents of various morphology and were used to visualise the Haversian canalsystem inside the compact bone of the rib. Applying a modified transfer functionfor volume rendering we presented the overall morphology of the Wormian boneand small vascular channels penetrating its interior. As an example of quantitativeanalysis based on micro-CT scans we compared the trabecular structure of thelumbar vertebrae with CTAn software. Significant differences in percent bonevolume (BV/TV) were determined. Micro-CT was found to be a very accurate andhelpful method to study small anatomical structures of the bones in micro scale. PMID- 25448901 TI - The stratigraphical organisation of the microvascular systems of the porcine vocal folds. AB - The cranial and caudal vocal folds (CraF, CauF) of the glottis of adult minipigs (11-27 months; n = 12) were examined after immunohistochemical application of polyclonal anti-von-Willebrand-Factor and anti-Smooth-Muscle-Actin in serial paraffin sections. This examination aimed at a stratigraphical analysis of microvessels; data were compared with findings in humans which had been reported in the literature. (1) The distribution of the microvessels was very heterogeneous in the CraF and in the CauF, but a common pattern existed in both. (2) Characteristic vascular zones and rows were detected; each of them displayed a specific distribution and density of blood capillaries, arterioles, venules, lymphatic capillaries, and lymphatic precollectors. (3) A striking feature was the presence of a subepithelial Avascular Band and of a focal Avascular Area within the lamina propria of the fold's crests. (4) The vascular zones, the rows, the Avascular Band, and the Avascular Area could be allocated to specific layers of the lamina propria: subepithelial, superficial, intermediate, deep layer. (5) The loose Avascular Area at the level of the superficial layer of the lamina propria (in both CraF and CauF) corresponded to Reinke's space in humans in terms of structure and location. (6) The direction/course of blood and lymphatic microvessels shared common features with that of the human vocal fold. PMID- 25448902 TI - Radiographic appearance and clinical implications of the presence of radix entomolaris and radix paramolaris. AB - BACKGROUND: The variation in mandibular molars' anatomy is not as rare as it might appear to be. Depending on the location of the additional root found in a mandibular molar, it may be referred to as either radix entomolaris (RE) or radix paramolaris (RP). The aim of the study was to present radiographic appearance of RE and RP and indicate the clinical implications of its presence. MATERIALS AND METHODS: The material consisted of 3,000 panoramic and 300 periapical radiographs of first and second mandibular molars taken in the Department of Dental and Maxillofacial Radiodiagnostics of the Medical University in Lublin which were screened for RE and RP. RESULTS: Among panoramic and periapical radiographs only 14 cases of additional roots were found: 11 teeth with RE/RP in the Polish population and 3 in Taiwanese. Only 2 panoramic radiographs revealed the presence of RE and surprisingly the occurrence was bilateral. CONCLUSIONS: Dentists should not be taken by surprise at finding an additional root in mandibular molars. They should be aware of the anatomical diversity of these teeth and know how to recognise possible extra roots during radiograph reading. PMID- 25448903 TI - Fatty foci within the heart and the accompanying changes in the coronary arteries diagnosed in electrocardiogram-gated multislice computed tomography of the heart. AB - BACKGROUND: The purpose of our study was to analyse the relationship between fatty foci within the heart and the accompanying changes in the coronary arteries supplying the relevant heart chambers in a large group of patients referred to multi-slice computed tomography with electrocardiogram-gating examinations (ECG MSCT) for various clinical reasons. MATERIALS AND METHODS: The ECG-MSCT examinations of 1,830 consecutive patients were analysed. The examinations were performed using 8-row (1,015 patients) and 64-row (815 patients) MSCT, in pre- and postcontrast scanning. In the group of patients with fatty foci within the heart the concomitant changes in the coronary arteries were assessed. It was analysed: the type of changes in the arteries; the relationship between the locations of the fatty deposits and the occurrence and type of changes in the coronary arteries. RESULTS: In 200 (10.9%) subjects fatty foci within the heart (112 men; 88 women; mean age 57.8) were detected. The distribution of the fat was as follows: right ventricle (RV) - 32.5%, left ventricle (LV) - 22.0%, biventricular - 45.5%. One hundred and seventy-two patients had concomitant changes in the coronary arteries. In patients with normal coronary arteries, significantly more often fatty deposits were localised within RV. Fat was primarily located subendocardially in the LV in patients with atherosclerosis in the left anterior descending artery (p < 0.001), in the right coronary artery (RCA) (p = 0.003), and in the left circumflex artery (LCX) (p < 0.001). Subpericardial locations of fatty deposits in RV significantly correlated with RCA bridging (p < 0.02); the subpericardial location of fat in LV significantly correlated with LCX bridging (p = 0.001). CONCLUSIONS: Fatty replacement of the myocardium is common, occurring in up to 10% of diagnosed patients and the majority of this group had concomitant changes in the coronary arteries. However, in the group of patients without changes in the coronary arteries, the fatty deposits locate themselves significantly more frequently within the RV. PMID- 25448904 TI - Sex determination based on the analysis of a contemporary Polish population's palatine bones: a computed tomography study of 1,200 patients. AB - BACKGROUND: The aims of the present study were to assess whether the hard palate reveals any measurable sex-related differences, and to create a mathematical model which would differentiate between males and females using hard palate measurements alone. MATERIALS AND METHODS: The present study was conducted on 1,200 archived sinus computed tomography (CT) scans. Each cranial measurement was taken twice by the same observer, and in cases of any discrepancies, the mean of the two values was recorded. Twenty per cent of randomly chosen samples were re measured by an observer who did not partake in assessing the samples the first time. Logistic regression was used to derivate two mathematical formulas which would calculate the probability of a skull being male. RESULTS: The studied group comprised 1,200 head CT's (627 female; 52.3%). The mean age of the group was 43.5 +/- 17.4 years - no age difference between sexes was noted (p = 0.37). All of the performed measurements were significantly (p < 0.0001) larger in males than in females. The mathematical formula based on the "orale-spina nasalis posterior" (O SNP) distance alone had a reliability rate of 68.35%. The equation based on the depth of the right greater palatine canal (GPC), the O-SNP distance and the anterior width of the palatal arch (AWPA) had a reliability rate of 78.37%. CONCLUSIONS: The most prominent sexually dimorphic parameters were the O-SNP, the GPC depth and the AWPA. The mathematical models presented in the current study can be used to successfully distinguish between sexes during forensic examination. PMID- 25448905 TI - Single coronary artery incidence in 215,140 patients undergoing coronary angiography. AB - BACKGROUND: The aim of our study is to determine the incidence of single coronary artery (SCA). SCA is a rarely seen coronary anomaly in which the right coronary artery and the left main coronary artery arise from single aortic sinus. Although SCA has a benign course in most cases and its clinical significance is unknown, in some autopsy studies it was shown to be related to sudden cardiac death. MATERIALS AND METHODS: SCA patients detected among 215,140 coronary angiographies (CAG) performed between 1998 and 2013 in SANKO Hospital were included in our study. The classification of CAG was made according to the two different classifications defined by Smith and Lipton and colleagues. RESULTS: A total number of 215,140 patients who underwent routine CAG were included in the study, and SCA was detected in 67 (0.031%) patients. There were 6 (9%) type R-I, 23 (34%) type R-II, 10 (15%) type R-III, 16 (24%) type L-I and 12 (18%) type L-II patients according to the angiographic classification. CONCLUSIONS: SCA is rarely seen during routine cardiac catheterisation and its incidence is 0.014-0.066% in angiographic series. In our study, the incidence was shown to be similar to the previous studies. PMID- 25448906 TI - Corrosion cast study of the canine hepatic veins. AB - This study presents a detailed description of the distribution, diameters and drainage patterns of hepatic veins on the basis of the corrosion cast analysis in 18 dogs. We classified the hepatic veins in three main groups: the right hepatic veins of the caudate process and right lateral liver lobe, the middle hepatic veins of the right medial and quadrate lobes and the left hepatic veins of both left liver lobes and the papillary process. The corrosion cast study showed that the number of the veins in the Nomina Anatomica Veterinaria and most anatomical textbooks is underestimated. The number of various-sized hepatic veins of the right liver division ranged from 3 to 5 and included 1 to 4 veins from the caudate process and 2 to 4 veins from the right lateral liver lobe. Generally, in all corrosion casts, one middle-sized vein from the right part of the right medial lobe, which emptied separately in the caudal vena cava, was established. The other vein was a large-sized vein from the remainder of the central division, which frequently joined the common left hepatic vein from the left liver lobes. The common left hepatic vein was the largest of all the aforementioned hepatic veins. PMID- 25448907 TI - Incidence of bone formation by whole bone marrow cell suspensions and by its stromal cell cultures injected into kidney parenchyma of Balb/c mice. AB - The evaluation of incidence of bone formation by whole syngeneic bone marrow cell suspension and by bone marrow stromal cell cultured in vitro injection into kidney parenchyma was done. Bone tissue was found in 26 kidneys out of 100 injected with whole bone marrow cells suspension. Cultured stromal bone marrow cells grafted into kidney parenchyma produced ossicles in only 4 out of 101 injected kidneys. Such low incidence of bone forming ability of the marrow stromal cell cultures grafted into kidney indicate their useless for study on bone histogenesis in the kidney by murine marrow stromal cell cultures. PMID- 25448908 TI - Origin of the subscapular artery in the South African Black population. AB - There is great variability in the branching patterns of the axillary artery (AA). Racial differences have been reported to play a role in this variability. The subscapular artery (SA) is the largest and most variable branch of the AA. It usually arises from the third part of the AA at the inferior border of the subscapularis muscle. Approximately 4 cm from its origin, the SA divides into the circumflex scapular and thoracodorsal arteries. Two types of the SA have been described, depending on the site of its origin from the AA in relation to the point where the AA passes between the lateral and medial roots of the median nerve. It is referred to as the superficial SA (SSA), when proximal, and the deep SA (DSA), when distal to this point, respectively. This study aimed to determine the site and distance of origin of the SA from the outer border of the first rib in the South African Black population. The study comprised bilateral gross anatomical dissections of 50 adult Black South African cadavers (n = 100 AAs). The site and distance of origin of each vessel from the outer border of the first rib were recorded. Additional branches and variations were also noted. The SSA and DSA were found in 52.8% and 47.2% of cases, respectively. In 16.8% of cases, the SA gave rise to the posterior circumflex humeral artery and the lateral thoracic artery in 33.7% cases. The SA was absent in 11% of the cases. The prevalence of the SSA reported in this study differs from values ranging between 1.7% and 16% reported in the literature. The high incidence of the SSA in this study may have clinical significance as a superficial course of the arteries make them vulnerable to injury during surgical procedures. PMID- 25448909 TI - Study of the human ligamentum flavum in old age: a histological and morphometric study. AB - BACKGROUND: Ageing is associated with many changes in the ligamentum flavum (LF): ossification, diminish of the cross-sectional area of the elastic fibres, increase of the collagen fibres and change in its mineral and matrix elements. There are limited data about the influence of the ageing process on the structure of the LF at different spinal levels. The aim of the study was to clarify the effect of the ageing process on the LF at different spinal levels. This was done through histological study and morphometric analysis using the image analyser. MATERIALS AND METHODS: Vertebral column specimens were obtained from 10 human cadavers preserved in a mixture of formaldehyde and carbol. Their average age ranged 60-70 years. The vertebral blocks included 4 vertebrae at cervical level (C 3, 4, 5, 6), thoracic level (T 5, 6, 7, 8) and lumbar level (L 2, 3, 4, 5). Sections were stained with haematoxylin and eosin, Masson's trichrome, Orcein and Verhoeff stains. The morphometric measurements included the relative collagen area, relative elastic area, collagen area [%] and elastic area [%]. RESULTS: The relative elastic areas reduced in all the spinal levels. The relative collagen areas increased to become 46.1 +/- 2.9 in the cervical region, 51.8 +/- 1.3 in the thoracic region, and 49.7 +/- 2.5 in the lumbar region. The average elastic area was highest in the cervical region, and lowest in the thoracic region. The ratio of elastic area to collagen area was 1.16:1 in the cervical region, 1.01:1 in the lumbar region and 0.93:1 in the thoracic region. The elastic fibres were regular, diffuse and organised in parallel order in the cervical and thoracic regions. Their orientations were craniocaudal with a variation of some fibres in the cervical region. Most of the elastic fibres in the lumbar region were regular and organized in parallel order. Nevertheless, rupture, fragmentation, and abnormal organization of the elastic fibres were discovered in a few specimens of the lumbar region. Increase of the vasculature and degeneration with abnormal body formations within the lumbar ligaments were observed. The LF midline gaps were present in the cervical, thoracic and lumbar regions. In 10% of lumbar specimens, the ligaments fused in the midline with absence of the midline gaps. Ossification was discovered in the thoracic and lumbar ligaments. CONCLUSIONS: Structural differences have been observed among the LF at the different spinal levels, and all these changes were caused by the ageing process. Decrease of the relative elastic area, an increase of the relative collagen area and reduction of the elastic to collagen area ratio affected all the spinal levels of the ligaments. Many changes took place in the lumbar ligaments such as ossification, increase vasculature, degeneration with abnormal body formation, absence of the midline gaps, fragmentation and rupture of the elastic fibres. PMID- 25448910 TI - Urinary bladder diverticulum as an unusual content of the inguinal canal. AB - The inguinal urinary bladder hernia is a rare pathology observed mostly in males. A new case of asymptomatic reducible acquired inguinal hernia was revealed in a 54-year-old male during computed tomography (CT) undertaken for oncological follow-up. The right nephrectomy was previously performed due to clear cell carcinoma. The hernia was not visible on the CT 6 months before and on ultrasound performed after voiding. Slight herniation with a wide invagination of transversalis fascia but with empty bladder was seen on CT 4 months after the initial detection of hernia. PMID- 25448911 TI - Fat herniation through the canal of Schwalbe. AB - The authors report a case of fat herniation through the canal of Schwalbe noted in a female cadaver during abdominopelvic dissection. Perineal hernias are rare hernias, and herniations through the hiatus of Schwalbe represent a rare posterior lateral perineal hernia. While these hernias are extremely rare, anatomists and surgeons should be aware of them, and the clinical significance and manifestations which may occur with these hernias. PMID- 25448912 TI - Thyroid lymphoepithelial nodule. AB - Thyroid benign lymphoepithelial lesions are rare in adults, reported as associated with thyroiditis or adjacent to tumours. Here we report a unique case of a thyroid solid nodule with benign lymphoepithelial morphology. A 56-year-old woman presented with a thyroid nodule increasing in size. Thyroid function was normal. On the surgical resection specimen, in addition to a 2-cm follicular adenoma, there was, at distance, a 0.5-cm solid nodule with lymphoepithelial morphology, without Hassal's corpuscles or calcifications. On immunohistochemistry, the epithelial component was cytokeratin 5/6 positive and very focally cytokeratin 7 positive, the immunophenotype of the lymphoid tissue confirming the benign nature. The diagnosis of thyroid benign lymphoepithelial nodule was proposed. In conclusion, recognition of thyroid solid benign lymphoepithelial nodules is important since they can be misdiagnosed with other thyroid micronodule types including carcinoma, primary or metastatic. PMID- 25448913 TI - Bilateral asymmetrical multiple renal arteries associated with the left testicular artery. AB - We found 3 right and 2 left renal arteries with asymmetrical origins in a 61-year old Korean male cadaver, whose cause of death was 'laryngeal carcinoma'. According to a previous classification, the first and second right renal arteries correspond to the early division and other renal arteries - to the extra renal arteries, except the first left renal artery as a typical renal artery. The third right renal artery ran anterior to the inferior vena cava to the inferior pole of the kidney. The first and second left renal arteries were associated with the inferior suprarenal artery and the testicular artery, respectively. The bilateral asymmetry in the number of renal arteries can be explained by the embryological development, degeneration and persistence of the renal artery in the process of ascending of kidneys. PMID- 25448914 TI - Bilateral coronary artery to pulmonary trunk fistulae detected by coronary angiography and evaluated by ECG-gated SPECT myocardial perfusion imaging: report of two cases. AB - Coronary artery fistulae (CAF) are anomalies related to coronary artery abnormal termination. This is a very rare congenital malformation accounting for about 0.2 0.4% of congenital cardiac anomalies, but in some patients it can be haemodynamically important. Single-photon emission computed tomography or positron emission tomography myocardial perfusion imaging (MPI) using radioactive agents is widely used in clinical practice for cardiac ischaemia detection as a very sensitive and non-invasive tool. We are going to present 2 patients with bilateral CAFs to the pulmonary trunk without signs of the rest or stress ischaemia in MPI. PMID- 25448915 TI - The influence of atherosclerotic abdominal aorta on the shape of duplicated inferior vena cava: its potential clinical implications and vascular complications. AB - Duplication of the inferior vena cava (IVC) is a congenital condition where there are 2 large vessels: right IVC (RIVC) and left IVC (LIVC) on both sides of the abdominal aorta. Here, we present 2 cases of duplicated inferior cava coexisting with rare morphology of left gonadal (ovarian/testicular) vein. Both were observed during multidetector 64-row computer tomography. In first case atherosclerotic, tortuous abdominal aorta models both inferior venae cavae. The shape of veins were more- (RIVC) and less-arcuate (LIVC). Two years ago, the patient had been diagnosed with pulmonary thromboembolism. In second case abdominal aortic aneurysm models both large veins. The RIVC has a highly right arcuate shape, while the LIVC has a less left-arcade shape. Our observation would seem to be especially important, because the tortuous abdominal aorta changes the shape of both IVC, and may predispose them for thrombosis formation. The presented report precisely describes the topography and measurements of the vessels in the retroperitoneal area. The literature concerning this anomaly, potential clinical implications and vascular complications are reviewed and the possible practical aspects are discussed. A familiarity with the anatomy of the most common types of venous anomalies is crucial for all surgeons, urologists and oncologists to reduce the risk of severe haemorrhage during all abdominal procedures. PMID- 25448916 TI - Supraclavicularis proprius muscle associated with supraclavicular nerve entrapment. AB - Entrapment neuropathy of the supraclavicular nerve is rare and, when it occurs, is usually attributable to branching of the nerve into narrow bony clavicular canals. We describe another mechanism for entrapment of this nerve with the aberrant muscle; supraclavicularis being found during the routine dissection of an embalmed 82-year-old cadaver. Our report details a unique location for this rare muscular variation whereby the muscle fibres originated posteriorly on the medial aspect of the clavicle before forming a muscular arch over the supraclavicular nerve and passing laterally towards the trapezius and acromion. We recommend that in clinical instances of otherwise unexplained unilateral clavicular pain or tenderness, nerve compression from the supraclavicularis muscle must be borne in mind. PMID- 25448917 TI - Rare variations of hepatic arteries in association with variable origin of gastroduodenal artery found in multidetector computed tomography angiography. AB - Three rare anatomical variations were found during study on hepatic arterial vascularisation in multidetector computed tomography angiography. In the first described variation the common hepatic artery (CHA) arises from the celiac trunk (CTr) and supplies right hepatic lobe. The left lobe of the liver is supplied by aberrant left hepatic artery originating as a common trunk with the left gastric artery and the splenic artery. This variation may correspond to the type 2 in Michels' classification coexisting with one of three possible patterns of the CTr division (when the CHA is the first branch of the CTr and the gastrosplenic trunk is the second one). The second variation corresponds to the very early bifurcation of the CHA arising from the CTr. Both, the right and left hepatic arteries originate separately from the CTr. The gastroduodenal artery (GDA) originates from the left hepatic artery. It may be regarded as the variation of most common type 1 according to Michels. In the third case the CHA gives raise to the GDA and terminates as the right hepatic artery supplying the right lobe of the liver only. The proper hepatic artery is missing and the left hepatic artery arises from the GDA. This variation does not correspond to any types of Michels' classification. PMID- 25448918 TI - Higher education experiences of students with autism spectrum disorder: challenges, benefits and support needs. AB - The transition into higher education constitutes a precarious life stage for students with autism spectrum disorder (ASD). Research on how students with ASD navigate college life is needed for the development of adequate support. This study investigated the challenges and support needs of 23 students with ASD in higher education through semi-structured interviews. Data were analyzed following the principles of Grounded Theory. Students faced difficulties with new situations and unexpected changes, social relationships, problems with information processing and time management and had doubts about disclosure. Facing these challenges simultaneously in the domains of education, student life and daily (independent) living, had a major impact on students' well being. Besides these challenges, students also reported benefits that contributed to success in the three domains. They pointed out to a set of recommendations for support. These findings are linked with previous research and implications for higher education institutions are extrapolated on the basis of these findings. PMID- 25448921 TI - Imaging retinal ganglion cells: enabling experimental technology for clinical application. AB - Recent advances in clinical ophthalmic imaging have enhanced patient care. However, the ability to differentiate retinal neurons, such as retinal ganglion cells (RGCs), would advance many areas within ophthalmology, including the screening and monitoring of glaucoma and other optic neuropathies. Imaging at the single cell level would take diagnostics to the next level. Experimental methods have provided techniques and insight into imaging RGCs, however no method has yet to be translated to clinical application. This review provides an overview of the importance of non-invasive imaging of RGCs and the clinically relevant capabilities. In addition, we report on experimental data from wild-type mice that received an in vivo intravitreal injection of a neuronal tracer that labelled RGCs, which in turn were monitored for up to 100 days post-injection with confocal scanning laser ophthalmoscopy. We were able to demonstrate efficient and consistent RGC labelling with this delivery method and discuss the issue of cell specificity. This type of experimental work is important in progressing towards clinically applicable methods for monitoring loss of RGCs in glaucoma and other optic neuropathies. We discuss the challenges to translating these findings to clinical application and how this method of tracking RGCs in vivo could provide valuable structural and functional information to clinicians. PMID- 25448920 TI - Different mechanisms of ripple-like oscillations in the human epileptic subiculum. AB - OBJECTIVE: Transient high-frequency oscillations (HFOs; 150-600Hz) in local field potentials generated by human hippocampal and parahippocampal areas have been related to both physiological and pathological processes. The cellular basis and effects of normal and abnormal forms of HFOs have been controversial. This lack of agreement is clinically significant, because HFOs may be good markers of epileptogenic areas. Better defining the neuronal correlate of specific HFO frequency bands could improve electroencephalographic analyses made before epilepsy surgery. METHODS: Here, we recorded HFOs in slices of the subiculum prepared from human hippocampal tissue resected for treatment of pharmacoresistant epilepsy. With combined intra- or juxtacellular and extracellular recordings, we examined the cellular correlates of interictal and ictal HFO events. RESULTS: HFOs occurred spontaneously in extracellular field potentials during interictal discharges (IIDs) and also during pharmacologically induced preictal discharges (PIDs) preceding ictal-like events. Many of these events included frequencies >250Hz and so might be considered pathological, but a significant proportion were spectrally similar to physiological ripples (150 250Hz). We found that IID ripples were associated with rhythmic gamma aminobutyric acidergic and glutamatergic synaptic potentials with moderate neuronal firing. In contrast, PID ripples were associated with depolarizing synaptic inputs frequently reaching the threshold for bursting in most pyramidal cells. INTERPRETATION: Our data suggest that IID and PID ripple-like oscillations (150-250Hz) in human epileptic hippocampus are associated with 2 distinct population activities that rely on different cellular and synaptic mechanisms. Thus, the ripple band could not help to disambiguate the underlying cellular processes. PMID- 25448919 TI - Reading and phonological skills in boys with fragile X syndrome. AB - Although reading skills are critical for the success of individuals with intellectual disabilities, literacy has received little attention in fragile X syndrome (FXS). This study examined the literacy profile of FXS. Boys with FXS (n = 51; mean age 10.2 years) and mental age-matched boys with typical development (n = 35) participated in standardized assessments of reading and phonological skills. Phonological skills were impaired in FXS, while reading was on-par with that of controls. Phonological awareness predicted reading ability and ASD severity predicted poorer phonological abilities in FXS. Boys with FXS are capable of attaining reading skills that are commensurate with developmental level and phonological awareness skills may play a critical role in reading achievement in FXS. PMID- 25448922 TI - Patient-specific induced pluripotent stem cells (iPSCs) for the study and treatment of retinal degenerative diseases. AB - Vision is the sense that we use to navigate the world around us. Thus it is not surprising that blindness is one of people's most feared maladies. Heritable diseases of the retina, such as age-related macular degeneration and retinitis pigmentosa, are the leading cause of blindness in the developed world, collectively affecting as many as one-third of all people over the age of 75, to some degree. For decades, scientists have dreamed of preventing vision loss or of restoring the vision of patients affected with retinal degeneration through drug therapy, gene augmentation or a cell-based transplantation approach. In this review we will discuss the use of the induced pluripotent stem cell technology to model and develop various treatment modalities for the treatment of inherited retinal degenerative disease. We will focus on the use of iPSCs for interrogation of disease pathophysiology, analysis of drug and gene therapeutics and as a source of autologous cells for cell transplantation and replacement. PMID- 25448923 TI - Mucosal impedance discriminates GERD from non-GERD conditions. AB - BACKGROUND & AIMS: Current diagnostic tests for gastroesophageal reflux disease (GERD) are suboptimal and do not accurately and reliably measure chronicity of reflux. A minimally invasive device has been developed to assess esophageal mucosal impedance (MI) as a marker of chronic reflux. We performed a prospective longitudinal study to investigate MI patterns in patients with GERD and common nonreflux conditions, to assess MI patterns before and after treatment with proton pump inhibitors and to compare the performance of MI and wireless pH tests. METHODS: We evaluated MI in 61 patients with erosive esophagitis, 81 with nonerosive but pH-abnormal GERD, 93 without GERD, 18 with achalasia, and 15 with eosinophilic esophagitis. MI was measured at the site of esophagitis and at 2, 5, and 10 cm above the squamocolumnar junction in all participants. MI was measured before and after acid suppressive therapy, and findings were compared with those from wireless pH monitoring. RESULTS: MI values were significantly lower in patients with GERD (erosive esophagitis or nonerosive but pH-abnormal GERD) or eosinophilic esophagitis than in patients without GERD or patients with achalasia (P < .001). The pattern of MI in patients with GERD differed from that in patients without GERD or patients with eosinophilic esophagitis; patients with GERD had low MI closer to the squamocolumnar junction, and values increased axially along the esophagus. These patterns normalized with acid suppressive therapy. MI patterns identified patients with esophagitis with higher levels of specificity (95%) and positive predictive values (96%) than wireless pH monitoring (64% and 40%, respectively). CONCLUSIONS: Based on a prospective study using a prototype device, measurements of MI detect GERD with higher levels of specificity and positive predictive values than wireless pH monitoring. Clinical Trials.gov, Number: NCT01556919. PMID- 25448924 TI - Comparative effectiveness of immunosuppressants and biologics for inducing and maintaining remission in Crohn's disease: a network meta-analysis. AB - BACKGROUND & AIMS: There is controversy regarding the best treatment for patients with Crohn's disease because of the lack of direct comparative trials. We compared therapies for induction and maintenance of remission in patients with Crohn's disease, based on direct and indirect evidence. METHODS: We performed systematic reviews of MEDLINE, EMBASE, and Cochrane Central databases, through June 2014. We identified randomized controlled trials (N = 39) comparing methotrexate, azathioprine/6-mercaptopurine, infliximab, adalimumab, certolizumab, vedolizumab, or combined therapies with placebo or an active agent for induction and maintenance of remission in adult patients with Crohn's disease. Pairwise treatment effects were estimated through a Bayesian random effects network meta-analysis and reported as odds ratios (OR) with a 95% credible interval (CrI). RESULTS: Infliximab, the combination of infliximab and azathioprine (infliximab + azathioprine), adalimumab, and vedolizumab were superior to placebo for induction of remission. In pair-wise comparisons of anti tumor necrosis factor agents, infliximab + azathioprine (OR, 3.1; 95% CrI, 1.4 7.7) and adalimumab (OR, 2.1; 95% CrI, 1.0-4.6) were superior to certolizumab for induction of remission. All treatments were superior to placebo for maintaining remission, except for the combination of infliximab and methotrexate. Adalimumab, infliximab, and infliximab + azathioprine were superior to azathioprine/6 mercaptopurine: adalimumab (OR, 2.9; 95% CrI, 1.6-5.1), infliximab (OR, 1.6; 95% CrI, 1.0-2.5), infliximab + azathioprine (OR, 3.0; 95% CrI, 1.7-5.5) for maintenance of remission. Adalimumab and infliximab + azathioprine were superior to certolizumab: adalimumab (OR, 2.5; 95% CrI, 1.4-4.6) and infliximab + azathioprine (OR, 2.6; 95% CrI, 1.3-6.0). Adalimumab was superior to vedolizumab (OR, 2.4; 95% CrI, 1.2-4.6). CONCLUSIONS: Based on a network meta-analysis, adalimumab and infliximab + azathioprine are the most effective therapies for induction and maintenance of remission of Crohn's disease. PMID- 25448925 TI - Efficacy of transoral fundoplication vs omeprazole for treatment of regurgitation in a randomized controlled trial. AB - BACKGROUND & AIMS: Transoral esophagogastric fundoplication (TF) can decrease or eliminate features of gastroesophageal reflux disease (GERD) in some patients whose symptoms persist despite proton pump inhibitor (PPI) therapy. We performed a prospective, sham-controlled trial to determine if TF reduced troublesome regurgitation to a greater extent than PPIs in patients with GERD. METHODS: We screened 696 patients with troublesome regurgitation despite daily PPI use with 3 validated GERD-specific symptom scales, on and off PPIs. Those with at least troublesome regurgitation (based on the Montreal definition) on PPIs underwent barium swallow, esophagogastroduodenoscopy, 48-hour esophageal pH monitoring (off PPIs), and high-resolution esophageal manometry analyses. Patients with GERD and hiatal hernias <=2 cm were randomly assigned to groups that underwent TF and then received 6 months of placebo (n = 87), or sham surgery and 6 months of once- or twice-daily omeprazole (controls, n = 42). Patients were blinded to therapy during follow-up period and reassessed at 2, 12, and 26 weeks. At 6 months, patients underwent 48-hour esophageal pH monitoring and esophagogastroduodenoscopy. RESULTS: By intention-to-treat analysis, TF eliminated troublesome regurgitation in a larger proportion of patients (67%) than PPIs (45%) (P = .023). A larger proportion of controls had no response at 3 months (36%) than subjects that received TF (11%; P = .004). Control of esophageal pH improved after TF (mean 9.3% before and 6.3% after; P < .001), but not after sham surgery (mean 8.6% before and 8.9% after). Subjects from both groups who completed the protocol had similar reductions in GERD symptom scores. Severe complications were rare (3 subjects receiving TF and 1 receiving the sham surgery). CONCLUSIONS: TF was an effective treatment for patients with GERD symptoms, particularly in those with persistent regurgitation despite PPI therapy, based on evaluation 6 months after the procedure. Clinicaltrials.gov no: NCT01136980. PMID- 25448928 TI - Spectroscopic (FT-IR and FT-Raman) investigation, first order hyperpolarizability, NBO, HOMO-LUMO and MEP analysis of 6-nitrochromone by ab initio and density functional theory calculations. AB - The vibrational spectral analysis is carried out using FT-Raman and FT-IR spectroscopy in the range 3500-50 cm(-1) and 4000-400 cm(-1), respectively, for 6 nitrochromone (6NC). The molecular structure, fundamental vibrational frequencies and intensity of the vibrational bands are interpreted with the aid of structure optimization and normal coordinates force field calculation based on ab initio HF and DFT gradient calculations employing the HF/6-311++G(d,p) and B3LYP/6 311++G(d,p) basis set. Stability of the molecule has been analyzed using NBO analysis. The calculated HOMO and LUMO energies show that charge transfer occurs within the molecule. Thermodynamic properties like entropy, heat capacity, zero point energy and Mulliken's charge analysis have been calculated for the 6NC. The complete assignments were performed on the basis of total energy distribution (TED) of the vibrational modes with scaled quantum mechanical (SQM) method. The MEP map shows the negative potential sites are on oxygen atoms as well as the positive potential sites are around the hydrogen atoms. PMID- 25448927 TI - Acetabular cup liner and prosthetic head exchange to increase the head diameter for management of recurrent luxation of a prosthetic hip in two dogs. AB - Component malalignment and impingement are possible causes of recurrent luxation following total hip replacement in the dog. In the two cases presented in this report, luxation that was probably due to impingement was managed by exchanging the standard 17 mm prosthetic head for a 24 mm prosthetic head. This required removal of the original acetabular cup liner and placement of a new polyethylene liner that would accept the 24 mm head into the stable acetabular shell. In the first case, a 50 kg Malamute dog, recurrent luxation was initially managed by component alignment revision, iliofemoral suture, triple pelvic osteotomy and a novel lasso technique, without long-term success. After exchanging the head and cup liner, luxation did not recur over a 12-month period. In the second case, a 65 kg Newfoundland dog, impingement was suspected after a second luxation event. Luxation did not recur during the nine months after exchange of the head and cup liner. The larger prosthetic head used in these two cases increased the impingement-free range-of-motion of the joint and increased the translation distance required for luxation (jump distance). PMID- 25448929 TI - Spectroscopic studies on covalent functionalization of single-walled carbon nanotubes with glycine. AB - Single-walled carbon nanotubes (SWCNTs) have a great potential in a wide range of applications, but faces limitation in terms of dispersion feasibility. The functionalization process of SWCNTs with the amino acid, glycine involves oxidation reaction using a mild aqueous acid mixture of HNO3 and H2SO4 (1:3), via ultrasonication technique and the resulted oxidized SWCNTs were again treated with the amino acid glycine suspension. The resulted glycine functionalized carbon nanotubes have been characterized by XRD, UV-Vis, FTIR, EPR, SEM, and EDX, spectroscopic techniques. The enhanced XRD peak (002) intensity was observed for glycine functionalized SWCNTs compared with oxidized SWCNTs, which is likely due to sample purification by acid washing. The red shift was observed in the UV-Vis spectra of glycine functionalized SWCNTs, which reveals that the covalent bond formation between glycine molecule and SWCNTs. The functional groups of oxidized SWCNTs and glycine functionalized SWCNTs were identified and assigned. EPR results indicate that the unpaired electron undergoes reduction process in glycine functionalized SWCNTs. SEM images show that the increase in the diameter of the SWCNTs was observed for glycine functionalized SWCNTs, which indicates that the adsorption of glycine molecule on the sidewalls of oxidized SWCNTs. EDX elemental micro analysis confirms that the nitrogen element exists in glycine functionalized SWCNTs. The functionalization has been chosen due to CONH bioactive sites in glycine functionalized SWCNTs for future applications. PMID- 25448931 TI - Colorimetric detection of mercury ion based on unmodified gold nanoparticles and target-triggered hybridization chain reaction amplification. AB - A novel unmodified gold nanoparticles (AuNPs)-based colorimetric strategy for label-free, specific and sensitive mercury ion (Hg(2+)) detection was demonstrated by using thymine-Hg(2)(+)-thymine (T-Hg(2)(+)-T) recognition mechanism and hybridization chain reaction (HCR) amplification strategy. In this protocol, a structure-switching probe (H0) was designed to recognize Hg(2+) and then propagated a chain reaction of hybridization events between two other hairpin probes (H1 and H2). In the absence of Hg(2+), all hairpin probes could stably coexist in solution, the exposed sticky ends of hairpin probes were capable of stabilizing AuNPs. As a result, salt-induced AuNPs aggregation could be effectively prevented. In the presence of Hg(2+), thymine bases of H0 could specifically interact with Hg(2+) to form stable T-Hg(2)(+)-T complex. Consequently, the hairpin structure of H0 probe was changed. As H1/H2 probes were added, the HCR process could be triggered and nicked double-helixes were formed. Since it was difficult for the formed nicked double-helixes to inhibit salt induced AuNPs aggregation, a red-to-blue color change was observed in the colloid solution as the salt concentration increased. With the elegant amplification effect of HCR, a detection limit of around 30 nM was achieved (S/N=3), which was about 1-2 orders of magnitudes lower than that of previous unmodified AuNPs-based colorimetric methods. By using the T-Hg(2)(+)-T recognition mechanism, high selectivity was also obtained. As an unmodified AuNPs-based colorimetric strategy, the system was simple in design, convenient in operation, and eliminated the requirements of separation processes, chemical modifications, and sophisticated instrumentations. PMID- 25448926 TI - Liver-specific deletion of augmenter of liver regeneration accelerates development of steatohepatitis and hepatocellular carcinoma in mice. AB - BACKGROUND & AIMS: Augmenter of liver regeneration (ALR, encoded by GFER) is a widely distributed pleiotropic protein originally identified as a hepatic growth factor. However, little is known about its roles in hepatic physiology and pathology. We created mice with liver-specific deletion of ALR to study its function. METHODS: We developed mice with liver-specific deletion of ALR (ALR-L KO) using the albumin-Cre/LoxP system. Liver tissues were collected from ALR-L-KO mice and ALR(floxed/floxed) mice (controls) and analyzed by histology, reverse transcription polymerase chain reaction, immunohistochemistry, electron microscopy, and techniques to measure fibrosis and lipids. Liver tissues from patients with and without advanced liver disease were determined by immunoblot analysis. RESULTS: Two weeks after birth, livers of ALR-L-KO mice contained low levels of ALR and adenosine triphosphate (ATP); they had reduced mitochondrial respiratory function and increased oxidative stress, compared with livers from control mice, and had excessive steatosis, and hepatocyte apoptosis. Levels of carbamyl-palmitoyl transferase 1a and ATP synthase subunit ATP5G1 were reduced in livers of ALR-L-KO mice, indicating defects in mitochondrial fatty acid transport and ATP synthesis. Electron microscopy showed mitochondrial swelling with abnormalities in shapes and numbers of cristae. From weeks 2-4 after birth, levels of steatosis and apoptosis decreased in ALR-L-KO mice, and numbers of ALR expressing cells increased, along with ATP levels. However, at weeks 4-8 after birth, livers became inflamed, with hepatocellular necrosis, ductular proliferation, and fibrosis; hepatocellular carcinoma developed by 1 year after birth in nearly 60% of the mice. Hepatic levels of ALR were also low in ob/ob mice and alcohol-fed mice with liver steatosis, compared with controls. Levels of ALR were lower in liver tissues from patients with advanced alcoholic liver disease and nonalcoholic steatohepatitis than in control liver tissues. CONCLUSIONS: We developed mice with liver-specific deletion of ALR, and showed that it is required for mitochondrial function and lipid homeostasis in the liver. ALR-L-KO mice provide a useful model for investigating the pathogenesis of steatohepatitis and its complications. PMID- 25448930 TI - Spectroscopic analysis of the impact of oxidative stress on the structure of human serum albumin (HSA) in terms of its binding properties. AB - Oxygen metabolism has an important role in the pathogenesis of rheumatoid arthritis (RA). Reactive oxygen species (ROS) are produced in the course of cellular oxidative phosphorylation and by activated phagocytic cells during oxidative bursts, exceed the physiological buffering capacity and result in oxidative stress. ROS result in oxidation of serum albumin, which causes a number of structural changes in the spatial structure, may influence the binding and cause significant drug interactions, particularly in polytherapy. During the oxidation modification of amino acid residues, particularly cysteine and methionine may occur. The aim of the study was to investigate the influence of oxidative stress on human serum albumin (HSA) structure and evaluate of possible alterations in the binding of the drug to oxidized human serum albumin (oHSA). HSA was oxidized by a chloramine-T (CT). CT reacts rapidly with sulfhydryl groups and at pH 7.4 the reaction was monitored by spectroscopic techniques. Modification of free thiol group in the Cys residue in HSA was quantitatively determined by the use of Ellman's reagent. Changes of albumin conformation were examined by comparison of modified (oHSA) and nonmodified human serum albumin (HSA) absorption spectra, emission spectra, red-edge shift (REES) and synchronous spectroscopy. Studies of absorption spectra indicated that changes in the value of absorbance associated with spectral changes in the region of 200-250 nm involve structural alterations in peptide backbone conformation. Synchronous fluorescence spectroscopy technique confirmed changes of position of tryptophanyl and tyrosyl residues fluorescent band caused by CT. Moreover analysis of REES effect allowed to observe structural changes caused by CT in the region of the hydrophobic pocket containing the tryptophanyl residue. Effect of oxidative stress on binding of anti-rheumatic drugs, sulfasalazine (SSZ) and sulindac (SLD) in the high and low affinity binding sites was investigated by spectrofluorescence, ITC and (1)H NMR spectroscopy, respectively. SSZ and SLD change the affinity of each other to the binding site in non- and modified human serum albumin. The presence of SLD causes the increase of association constant (Ka) of SSZ-oHSA system and the strength of binding and the stability of the complexes has been observed while in the presence of SSZ a displacement of SLD from the SLD-HSA has been recorded. The analysis of (1)H NMR spectral parameters i.e. changes of chemical shifts of the drug indicate that the presence of SSZ and SLD have a mutual influence on changes in the affinity of human serum albumin binding site and this competition takes place not only due to the additional drug but also to the oxidation of HSA. PMID- 25448932 TI - Investigation on the trioctylphosphine oxide-based super-concentrated HCl system. AB - We report a new super-concentrated HCl system prepared by using trioctylphosphine oxide (TOPO)-based reverse micelles. The observed molar ratio between acid and water (nHCl/nH2O) in the super-concentrated HCl are much higher than that in the saturated aqueous HCl solution (0.28). Moreover, FT-IR spectroscopic results reveal that a significant amount of HCl remains in the molecular form rather than being ionized into H(+) and Cl(-). As a result, two H-Cl stretching bands can be observed in the FT-IR spectrum. The super-concentrated HCl provides a unique chemical environment in which many chemical substances occur in unusual states. For example, the color of super-concentrated HCl solution containing copper ion was found to be reddish brown rather than green as in conventional state. UV-Vis NIR spectral results indicate that both d-d transition band of Cu(2+) and charge transfer band of Cl-Cu in super-concentrated HCl underwent significant variation. Additionally, copper ions bring about remarkable variation on the hydrogen bond network among HCl in the super-concentrated HCl solution as demonstrated by FT-IR spectra. According to the EXAFS results, we suggest that copper ion may occur as HCuCl3 in the super-concentrated HCl. PMID- 25448933 TI - Conformational analysis, spectroscopic study (FT-IR, FT-Raman, UV, 1H and 13C NMR), molecular orbital energy and NLO properties of 5-iodosalicylic acid. AB - In this study, 5-iodosalicylic acid (5-ISA, C7H5IO3) is structurally characterized by FT-IR, FT-Raman, NMR and UV spectroscopies. There are eight conformers, Cn, n=1-8 for this molecule therefore the molecular geometry for these eight conformers in the ground state are calculated by using the ab-initio density functional theory (DFT) B3LYP method approach with the aug-cc-pVDZ-PP basis set for iodine and the aug-cc-pVDZ basis set for the other elements. The computational results identified that the most stable conformer of 5-ISA is the C1 form. The vibrational spectra are calculated DFT method invoking the same basis sets and fundamental vibrations are assigned on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method with PQS program. Total density of state (TDOS) and partial density of state (PDOS) and also overlap population density of state (COOP or OPDOS) diagrams analysis for C1 conformer were calculated using the same method. The energy and oscillator strength are calculated by time-dependent density functional theory (TD-DFT) results complement with the experimental findings. Besides, charge transfer occurring in the molecule between HOMO and LUMO energies, frontier energy gap, molecular electrostatic potential (MEP) are calculated and presented. The NMR chemical shifts ((1)H and (13)C) spectra are recorded and calculated using the gauge independent atomic orbital (GIAO) method. Mulliken atomic charges of the title molecule are also calculated, interpreted and compared with salicylic acid. The optimized bond lengths, bond angles and calculated NMR and UV, vibrational wavenumbers showed the best agreement with the experimental results. PMID- 25448935 TI - Study on the interaction characteristics of cefamandole with bovine serum albumin by spectroscopic technique. AB - The interaction of cefamandole with bovine serum albumin (BSA) was studied by fluorescence quenching in combination with UV-Vis spectroscopic method under near physiological conditions. The fluorescence quenching rate constants and binding constants for BSA-cefamandole system were determined at different temperatures. The fluorescence quenching of BSA by cefamandole is due to static quenching and energy transfer. The results of thermodynamic parameters, DeltaH (-268.0 kJ mol( 1)), DeltaS (-810.0 J mol(-1) K(-1)) and DeltaG (-26.62 to -8.52 kJ mol(-1)), indicated that van der Waals interaction and hydrogen bonding played a major role for cefamandole-BSA association. The competitive experiments demonstrated that the primary binding site of cefamandole on BSA was located at site III in sub domain IIIA of BSA. The distance between cefamandole and a tryptophane unit was estimated to be 1.18 nm based on the Forster resonance energy transfer theory. The binding constant (KA) of BSA-cefamandole at 298 K was 2.239*10(4) L mol(-1). Circular dichroism spectra, synchronous fluorescence and three-dimensional fluorescence studies showed that the presence of cefamandole could change the conformation of BSA during the binding process. PMID- 25448934 TI - DFT calculations and experimental FT-IR, FT-Raman, NMR, UV-Vis spectral studies of 3-fluorophenylboronic acid. AB - The spectroscopic (FT-IR, FT-Raman, (1)H and (13)C NMR, UV-Vis), structural, electronic and thermodynamical properties of 3-fluorophenylboronic acid (C6H4FB(OH)2), 3FPBA) were submitted by using both experimental techniques and theoretical methods (quantum chemical calculations) in this work. The experimental infrared and Raman spectra were obtained in the region 4000-400 cm( 1) and 3500-10 cm(-1), respectively. The equilibrium geometry and vibrational spectra were calculated by using DFT (B3LYP) with 6-311++G(d,p) basis set. The vibrational wavenumbers were also corrected with scale factor to take better results for the calculated data. The total energy distributions (TED) of the vibrational modes were performed for the assignments of the title molecule by using scaled quantum mechanics (SQM) method. The NMR chemical shifts ((1)H and (13)C) were recorded in DMSO solution. The (1)H and (13)C NMR spectra were computed by using the gauge-invariant atomic orbital (GIAO) method, showing a good agreement with the experimental ones. The last one UV-Vis absorption spectra were analyzed in two solvents (ethanol and water), saved in the range of 200-400 nm. In addition these, HOMO and LUMO energies, the excitation energies, density of states (DOS) diagrams, thermodynamical properties and molecular electrostatic potential surface (MEPs) were presented. Nonlinear optical (NLO) properties and thermodynamic features were performed. The experimental results are combined with the theoretical calculations using DFT calculations to fortification of the paper. At the end of this work, the results were proved our paper had been indispensable for the literature backing. PMID- 25448936 TI - Cytotoxicity and cellular uptake of ZnS:Mn nanocrystals biofunctionalized with chitosan and aminoacids. AB - Highly luminescent, manganese doped, zinc sulphide (ZnS:Mn) nanocrystals biofunctionalized with chitosan and various aminoacids such as L-citrulline, L lysine, L-arginine, L-serine, L-histidine and glycine were synthesized by chemical capping co-precipitation method at room temperature, which is a simple and cost effective technique. The synthesized nanocrystals were structurally characterized by TEM, XRD, EDXS and FT-IR spectroscopy techniques. They possess high colloidal stability with strong orange red photoluminescence emission at 598 nm. The intensity of orange red emission has been observed to be maximum in L citrulline capped ZnS:Mn nanocrystals in which the emission at 420 nm is effectively quenched by surface passivation due to capping. Taking into consideration the prospects of these highly luminescent, bio-compatible ZnS:Mn nanocrystals in bio-imaging applications, cytotoxicity studies were conducted to identify the capping combination which would accomplish minimum toxic effects. ZnS:Mn nanocrystals biofunctionalized with chitosan, L-citrulline, glycine, L artginine, L-serine and L-histidine showed least toxicity up to 10 nM concentrations in mouse fibroblast L929 cells, which further confirms their cytocompatibility. Also the ZnS:Mn nanocrystals biofunctionalized with l-arginine showed maximum uptake in in vitro studies carried out in human embryonic kidney cells, HEK-293T, which shows the significant role of this particular amino acid in fetoplacental nutrition. The present study highlights the suitability of aminoacid conjugated ZnS:Mn nanocrystals, as promising candidates for biomedical applications. PMID- 25448937 TI - Density functional theory (DFT) and natural bond orbital (NBO) study of vibrational spectra and intramolecular hydrogen bond interaction of L-ornithine-L aspartate. AB - In this study, exhaustive conformations of (S)-4-amino-4-carboxybutan-1-aminium (S)-3-amino-3-carboxypropanoate (LOLA) have been scanned. Experimental and theoretical studies on the structure and vibrations of the title compound are presented. The optimized molecular structure, vibrational wavenumbers, Mulliken atomic charges, natural bond orbital (NBO) and molecular electrostatic potential studies have been performed by density functional theory (DFT) using B3LYP method with the 6-311++G(d,p) basis set. Computed X-ray powder diffraction (XRPD) data has been carried out by DFT calculations and ab initio from measured XRPD finding. The LOLA molecular geometry has been determined which exists in the form of salt by intramolecular H-bonds and ionic bonding. Moreover, calculated vibrational frequencies were applied to simulate IR and Raman spectra of the title compound which showed excellent agreement with observed spectra. Reliable vibrational assignments have been made on the basis of potential energy distribution (PED) and 0.992 has been obtained by least squares method which is the uniform scaled factor for theoretical frequencies at 6-311++G(d,p) basis set. In addition, the hydrogen bonding in LOLA molecule has been explored by calculation of the hyperconjugative charge transfer interaction on [LP X sigma(*)(Y-H)], under NBO analysis, Mulliken atomic charge analysis, molecular electrostatic potential map (MEP) and vibrational spectra. Finally, HOMO-LUMO of the title compound has been plotted for predicting reactive sites. PMID- 25448938 TI - Comment on "Assessment of new DFT methods for predicting vibrational spectra and structure of cisplatin: which density functional should we choose for studying platinum(II) complexes?" [Spectrochim. Acta A125 (2014) 431-439]. PMID- 25448939 TI - Facile synthesis of PbWO4: applications in photoluminescence and photocatalytic degradation of organic dyes under visible light. AB - Stolzite polymorph of PbWO4 catalyst was prepared by the facile room temperature precipitation method. Structural parameters were refined by the Rietveld analysis using powder X-ray data. PbWO4 was crystallized in the scheelite-type tetragonal structure with space group I41/a (No. 88). Field emission scanning electron microscopy revealed leaf like morphology. Photoluminescence spectra exhibit broad blue emission (425 nm) under the excitation of 356 nm. The photocatalytic degradation of Methylene blue, Rhodamine B and Methyl orange dyes were measured under visible illumination. The 100% dye degradation was observed for MB and RhB dyes within 60 and 105 min. The rate constant was found to be in the decreasing order of MB>RhB>MO which followed the 1st order kinetic mechanism. Therefore, PbWO4 can be a potential candidate for blue component in white LEDs and also acts as a catalyst for the treatment of toxic and non-biodegradable organic pollutants in water. PMID- 25448940 TI - Role of flux on morphology and luminescence properties of Sm(3+) doped Y2SiO5 nanopowders for WLEDs. AB - The study involves preparation of samarium doped Y2SiO5 (YSO) nano powders by solution combustion method using urea as a fuel for the first time. Effect of different fluxes on the crystallization behavior, morphology and photoluminescence (PL) properties of YSO:Sm(3+) (1-9 mol%) were investigated. The final product was characterized by Powder X-ray diffraction (PXRD), Scanning Electron Microscopy (SEM) and UV-Vis spectroscopy. The average crystallite size estimated by Debye-Scherer's and Williamson-Hall plots were found to be in the range of 10-50 nm. Samples calcined at 1100 degrees C show pure monoclinic X1 phase; whereas, samples calcined at 1200 and 1300 degrees C show pure X2 phase of YSO. Photoluminescence (PL) studies of Sm(3+) (1-9 mol%) doped YSO for near ultra violet (NUV) excitation (407 nm) was studied in order to investigate the possibility of its use in white light emitting diode (WLED) applications. The emission spectra consists of intra 4f transitions of Sm(3+), such as (4)G5/2 >(6)H5/2 (~560 nm), (4)G5/2->(6)H7/2 (600-613 nm), (4)G5/2->(6)H9/2 (~650 nm), (4)G5/2->(6)H11/2 (715 nm) and (4)G5/2->(6)H13/2 (763 nm) respectively. The emission intensity of the phosphor was found to be enhancing after addition of fluxes. Further, the emission at 600-613 nm show strong orange-red emission and can be applied to the orange-red emission of phosphor for near ultra violet excitation. PMID- 25448942 TI - Antimicrobial and antioxidant activity evaluation of Co(II), Ni(II), Cu(II) and Zn(II) complexes with 15-thia-3,4,9,10-tetraazabicyclo[10.2.1]pentadeca 1(14),2,10,12-tetraene-5,8-dione. AB - A new mixed thia-aza macrocyclic complexes with Schiff base viz. 15-thia-3,4,9,10 tetraazabicyclo[10.2.1]pentadeca-1(14),2,10,12-tetraene-5,8-dione containing transition metals, M = Co(II), Ni(II), Cu(II) and Zn(II) and X = Cl(-), NO3(-), OAc(-), has been synthesized, resulting in the final constitution of 1:1:1 M ratio, by the condensation of succinyldihydrazide and thiophenedicarboxaldehyde. The metal complexes have been investigated with the help of various physico chemical techniques viz. elemental analyses, magnetic susceptibility, thermal, conductivity measurements, spectral (IR, UV, ESR, NMR and mass) and X-ray diffraction techniques. The low value of molar conductivity indicates the non electrolytic nature of the complexes and a distorted octahedral geometry has been proposed on the basis of various physico-chemical studies. X-ray diffraction indicates the presence of monoclinic crystal system. The complexes have been investigated for in vitro antibacterial, antifungal and antioxidant activity. All the complexes show moderate to significant activity. PMID- 25448941 TI - Spectroscopic and electrical studies on Nd(3+), Zr(4+) ions doped nano-sized BaTiO3 ferroelectrics prepared by sol-gel method. AB - Lead free ferroelectric ceramics in the form of Ba(1-3x)Nd(2x)Ti(1-y)ZryO3 ((where x=0.025, y=0 (BT1), 0.025 (BT2), 0.05 (BT3)) were prepared using sol-gel method. The surface morphology and the orientation of grains of the present ceramics were examined using Field Emission Scanning Electron Microscope (FESEM) images. The effect of Nd(3+), Zr(4+) ions content on the BaTiO3 was studied using Raman and Fourier Transform Infrared (FTIR) spectroscopies. From the Raman analysis the band observed at ~838 cm(-1) was attributed due to the presence of Nd(3+)-barium vacancy pairs. The FTIR studies suggested that the addition of Nd(3+) ions in A-site of BaTiO3 (ABO3) perovskite create lattice distortion by forming A-site vacancies and Zr(4+) ions in B-site of BaTiO3 induce the lattice distortion by forming ZrO6 octahedra in the place of TiO6 octahedra. Dielectric measurements of the samples were done at different frequencies from RT-150 degrees C. Charge transportation phenomenon is explained using DC conductivity, which is found to increase with temperature. PMID- 25448944 TI - Studies of the interaction between FNC and human hemoglobin: a spectroscopic analysis and molecular docking. AB - FNC (2'-deoxy-2'-bfluoro-4'-azidocytidine) is a novel nucleoside analogue with pharmacologic effects on several human diseases. In this work, the binding of FNC to human hemoglobin (HHb) have been investigated by absorption spectroscopy, fluorescence quenching technique, synchronous fluorescence, three-dimensional fluorescence and molecular modeling methods. Analysis of fluorescence data showed that the binding of FNC to HHb occurred via a static quenching mechanism. Thermodynamic analysis and molecular modeling suggest that hydrogen bond and van der Waals force are the mainly binding force in the binding of FNC to HHb. PMID- 25448943 TI - Computational and spectral studies of 6-phenylazo-3-(p-tolyl)-2H-chromen-2-one. AB - 6-Phenylazo-3-(p-tolyl)-2H-chromen-2-one 4 was prepared and characterized by IR, (1)H, and (13)C NMR spectral studies. The optimized structure of the chromen-2 one 4 was investigated by the Gaussian 03 B3LYP density functional method calculations at 6-31G(d,p) basis set. The gauge-independent atomic orbital (GIAO) (13)C and (1)H chemical shift calculations for the synthesized chromen-2-one in CDCl3 were also made by the same method. The computed IR frequencies of the chromen-2-one and the corresponding vibrational assignments were analyzed by means of potential energy distribution (PED%) calculation using vibrational energy distribution analysis (VEDA) program. The first order hyperpolarizability (betatot), polarizability (alpha) and dipole moment (MU) were calculated using 6 311G(d,p) basis set and the nonlinear optical (NLO) properties are also addressed theoretically. Stability of the chromen-2-one 4 molecule has been analyzed by calculating the intramolecular charge transfer using natural bond order (NBO) analysis. The molecular electrostatic potentials, HOMO-LUMO energy gap and geometrical parameters were also computed. Topological properties of the electronic charge density in chromen-2-one 4 were analyzed employing the Bader's Atoms in Molecule (AIM) theory which indicated the presence of intramolecular hydrogen bond in the molecule. PMID- 25448945 TI - Comparison of adsorption and photo-Fenton processes for phenol and paracetamol removing from aqueous solutions: single and binary systems. AB - In the present study, adsorption and photo-Fenton processes have been compared for the removal of phenol and paracetamol from aqueous solutions in a single and binary systems. NaX nanozeolites and cobalt ferrite nanoparticles were used during adsorption and photo-Fenton processes, respectively. Both nanoparticles were synthesized using microwave heating method. The synthesized nanoparticles were characterized using powder X-ray diffraction (XRD) and scanning electronic microscopy (SEM) analysis. Based on results, more than 99% removing percentages of phenol and paracetamol were obtained during photo-Fenton process at initial concentrations of 10, 20, 50, 100 and 200 mg/L of phenol and paracetamol. Moreover, the complete removing of phenol and paracetamol was only achieved at lower initial concentrations than 10 mg/L for phenol and paracetamol during adsorption process. The results showed a significant dependence of the phenol and paracetamol removing on the initial concentrations of phenol and paracetamol for selection of process. The photo-Fenton process could be considered an alternative method in higher initial concentrations of phenol and paracetamol. However, the adsorption process due to economical issue was preferred for phenol and paracetamol removing at lower initial concentrations. The kinetic data of photo Fenton and adsorption processes were well described using first-order and pseudo second-order kinetic models. The results of phenol and paracetamol removing in a binary system confirmed the obtained results of single removing of phenol and paracetamol in selection of process. PMID- 25448946 TI - Spectroscopic investigation, natural bond orbital analysis, HOMO-LUMO and thermodynamic functions of 2-tert-butyl-5-methyl anisole using DFT (B3LYP) calculations. AB - The optimized molecular structure and corresponding vibrational assignments of 2 tert-butyl-5-methyl anisole (TBMA) have been investigated using density functional theory (DFT)/B3LYP with 6-31G(d,p) and 6-311++G(d,p) basis sets investigation of the relative orientation of the methoxy group has shown two conformers (O-cis) and (O-trans) exist. The vibrational analysis of the stable conformer of the title compound is performed by means of infrared absorption and Raman spectroscopy in combination with theoretical simultaneously. The natural bond orbital (NBO) analysis is useful to understand the intra-molecular hyper conjugative interaction lone pair and pi(*)(C-C), sigma(*)(C-H) bond orbital. HOMO and LUMO energies show that charge transfer occurs in the molecule, therefore; HOMO, LUMO and molecular electrostatic potential (MEP) were calculated and analyzed. (1)H and (13)C NMR spectra by using gauge including atomic orbital (GIAO) method of studied compound were compared with experimental data. The thermodynamic functions of TBMA were calculated by B3LYP/6-311+G(d,p) basis set. PMID- 25448947 TI - FT-IR and FT-Raman spectra, MEP and HOMO-LUMO of 2,5-dichlorobenzonitrile: DFT study. AB - The experimental FT-IR and FT-Raman spectra of 2,5-dichlorobenzonitrile molecule were recorded at room temperature, and the results compared with quantum chemical theoretical values using MP2 and DFT methods. Molecular geometry, vibrational wavenumbers and thermodynamic parameters were calculated. With the help of specific scaling procedures for the computed wavenumbers, the experimentally observed FTIR and FT-Raman bands were analyzed and assigned to different normal modes of the molecule. Most of the modes have wavenumbers in the expected range and the error obtained was in general very low. Several general conclusions were deduced. The NBO analysis has been done and Molecular Electrostatic Potential (MEP) has been plotted. PMID- 25448948 TI - Molecular structure, FT-IR, vibrational assignments, HOMO-LUMO analysis and molecular docking study of 1-[5-(4-Bromophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H pyrazol-1-yl]ethanone. AB - The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 1-[5-(4-bromophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H pyrazol-1-yl]ethanone have been investigated experimentally and theoretically using Gaussian09 software package. The title compound was optimized using the HF/6-31G(d) (6D, 7F), B3LYP/6-31G (6D, 7F) and B3LYP/6-311++G(d,p) (5D, 7F) calculations. The B3LYP/6-311++G(d,p) (5D, 7F) results and in agreement with experimental infrared bands. The geometrical parameters are in agreement with XRD data. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. The HOMO and LUMO analysis is used to determine the charge transfer within the molecule. Molecular electrostatic potential was also performed. From the MEP it is evident that the negative charge covers the C=O group and the positive region is over the rings. First hyperpolarizability is calculated in order to find its role in nonlinear optics. Molecular docking studies suggest that the compound might exhibit inhibitory activity against TPII and may act as anti-neoplastic agent. PMID- 25448949 TI - FT-IR, NBO, HOMO-LUMO, MEP analysis and molecular docking study of 1-[3-(4 Fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]ethanone. AB - The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 1-[3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol 1-yl]ethanone have been investigated experimentally and theoretically. The geometrical parameters are in agreement with XRD data. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. The HOMO and LUMO analysis is used to determine the charge transfer within the molecule. From the MEP it is evident that the negative charge covers the carbonyl group and the positive region is over the remaining groups. The more electronegativity in the carbonyl group makes it the most reactive part in the molecule. First hyperpolarizability is calculated in order to find its role in nonlinear optics. From the molecular docking studies, it is evident that the fluorine atom attached to benzene ring and ethanone attached to the pyrazoline ring are crucial for binding and the compound might exhibit inhibitory activity against TPII and may act as anti-neoplastic agent. PMID- 25448950 TI - DFT studies on vibrational spectra, HOMO-LUMO, NBO and thermodynamic function analysis of cyanuric fluoride. AB - In this work, the theoretical vibrational spectral characteristics of cyanuric fluoride (C3N3F3) have been investigated and compared with existing experimental results. The density functional theoretical (DFT) computations were performed at the B3LYP level with the basis sets 6-31G(d,p) and 6-311++G(d,p) levels to derive the optimized geometry, vibrational wavenumbers with IR intensities of cyanuric fluoride. In addition, the molecular orbital calculations such as Natural Bond Orbitals (NBOs), HOMO-LUMO energy gap and Mapped molecular Electrostatic Potential (MEP) surfaces were also performed with the same level of DFT. Electronic stability of the compound arising from hyper conjugative interactions and charge delocalization were also investigated based on the natural bond orbital (NBO) analysis. Effective stabilization energy E((2)) connected with the interactions of the pi and the lone pair of electrons was determined by the NBO analysis. Mulliken population analysis on atomic charges is also calculated. The thermodynamic properties of the cyanuric fluoride at different temperatures have also been calculated for the range of temperature 50-1000 K. PMID- 25448951 TI - Spectroscopic analyses of the photocatalytic behavior of nano titanium dioxide. AB - Nano titanium dioxide TiO2 was synthesized using hydrolysis method then subjected to several characterizations. XRD revealed that the as-prepared sample is pure anatase phase and after calcinations at 500 degrees C for 3 h the crystallinity has increased. The crystallite size calculated by Debye-Scherrer's formula is 8 nm. The HRTEM image shows an average size of about 9 nm, which is close to the XRD calculation from Scherrer's formula. PM3 semiempirical quantum mechanical calculations were conducted to present the electronic as well as thermal properties for TiO2. FTIR spectra between 800 and 400 cm(-1) are the verification for the lattice vibrations of anatase TiO2. The photo catalytic degradation of methylene blue (MB) was tested by the prepared nano TiO2. Results indicate that, the maximum degradation efficiency reached 94.4% after 120 min of UV irradiation. This increase in the degradation efficiency of TiO2 could be attributed to the reduction in particle size that enhanced the crystallinity as a result of heat treatment. PMID- 25448952 TI - Synthesis, structural, optical and anti-rheumatic activity of metal complexes derived from (E)-2-amino-N-(1-(2-aminophenyl)ethylidene)benzohydrazide (2-AAB) with Ru(III), Pd(II) and Zr(IV). AB - Three new metal complexes derived from Pd(II), Ru(III) and Zr(IV) with (E)-2 amino-N-(1-(2-aminophenyl)ethylidene)benzohydrazide (2-AAB) have been synthesized. The isolated complexes were characterized by elemental analyses, FT IR, UV-Vis, ES-MS, (1)H NMR, XRD, thermal analyses (TGA and DTA) and conductance. The morphology and the particle size were determined by transmittance electron microscope (TEM). The results showed that, the ligand coordinates to Pd(II) in the enol form, while it coordinates to Ru(III) and Zr(IV) in the keto form. A square planar geometry is suggested for Pd(II) complex and octahedral geometries are suggested for Ru(III) and Zr(IV) complexes. The optical band gaps of the isolated complexes were measured and indicated the semi-conductivity nature of the complexes. The anti-inflammatory and analgesic activities of the ligand and its complexes showed that, Ru(III) complex has higher effect than the well known drug "meloxicam". PMID- 25448953 TI - Spectroscopic investigation (FT-IR, FT-Raman), HOMO-LUMO, NBO analysis and molecular docking study of 2-[(4-chlorobenzyl)sulfanyl]-4-(2-methylpropyl)-6-[3 trifluoromethyl)-anilino]pyrimidine-5-carbonitrile, a potential chemotherapeutic agent. AB - FT-IR and FT-Raman spectra of 2-[(4-chlorobenzyl)sulfanyl]-4-(2-methylpropyl)-6 [3-trifluoromethyl)-anilino]pyrimidine-5-carbonitrile were recorded and analyzed. The vibrational wave numbers were computed using DFT quantum chemical calculations. The data obtained from wave number calculations are used to assign vibrational bands obtained in infrared and Raman spectra. Potential energy distribution was done using GAR2PED program. The NH stretching wave number is red shifted by 102 cm(-1) in IR from the computed wave number, which indicates the weakening of the NH bond. The geometrical parameters (DFT) of the title compound are in agreement with the XRD results. NBO analysis, HOMO-LUMO, first hyperpolarizability and molecular electrostatic potential results are also reported. From the MEP map it is evident that the negative electrostatic potential regions are mainly localized over the CN and CF3 groups and are possible sites for electrophilic attack and positive regions are localized around NH group, indicating possible sites for nucleophilic attack. The preliminary docking results suggest that the title compound might exhibit inhibitory activity against GPb and may act as a potential anti-diabetic compound. PMID- 25448954 TI - DFT calculations, spectroscopy and antioxidant activity studies on (E)-2-nitro-4 [(phenylimino)methyl]phenol. AB - We have reported synthesis and characterization of (E)-2-nitro-4 [(phenylimino)methyl]phenol by using X-ray crystallographic method, FT-IR and UV vis spectroscopies and density functional theory (DFT). Optimized geometry and vibrational frequencies of the title compound in the ground state have been computed by using B3LYP with the 6-311G+(d,p) basis set. HOMO-LUMO energy gap, Non-linear optical properties and NBO analysis of the compound are performed at B3LYP/6-311G+(d,p) level. Additionally, as remarkable properties, antioxidant activity of the title compound (CMPD) has been determined by using different antioxidant test methods i.e. ferric reducing antioxidant power (FRAP), hydrogen peroxide scavenging (HPSA), free radical scavenging (FRSA) and ferrous ion chelating activities (FICA). When compared with standards (BHA, BHT, and alpha tocopherol), we have concluded that CPMD has effective FRAP, HPSA, FRSA and FICA. PMID- 25448955 TI - Raman scattering investigation of the high temperature phase transition in [N(C3H7)4]2SnCl6. AB - The phase transition at high temperature of bis tetrapropylammoniumhexachlorostannate compound has been investigated by Raman spectroscopy as a function of temperature from 303 K to 393 K. While the bands mainly associated with the internal modes of the SnCl6 anions only undergo weak changes, strong evolutions of wavenumbers, widths and intensities of many lines associated with the organic cations are observed with discontinuities in the vicinity of the phase transition at 362 K. The most important changes are observed for two lines at 1137.5 cm(-1) and 1159.4 cm(-1) (at room temperature) issued from twisting of CH2 groups and skeletal deformation of the cations. The spectral characteristics of these lines are analyzed and consistently described in the framework of an order-disorder model for the phase transition. The temperature dependency of the reduced peak intensity allowed to determine the critical exponents and evolution of the correlation length on approaching the transition. PMID- 25448956 TI - Molecular structure, spectroscopic (FTIR, FT-Raman, 13C and 1H NMR, UV), polarizability and first-order hyperpolarizability, HOMO-LUMO analysis of 2,4 difluoroacetophenone. AB - The FTIR and FT-Raman spectra of 2,4-difluoroacetophenone (DFAP) have been recorded in the regions 4000-400 cm(-1) and 3500-50 cm(-1), respectively. Utilizing the observed FTIR and FT-Raman data, a complete vibrational assignment and analysis of the fundamental modes of the compound were carried out. The optimum molecular geometry, harmonic vibrational frequencies, infrared intensities and Raman scattering activities, were calculated by density functional theory (DFT/B3LYP) method with 6-31+G(d,p) and 6-311++G(d,p) basis sets. The difference between the observed and scaled wavenumber values of most of the fundamentals is very small. A detailed interpretation of the infrared and Raman spectra of DFAP is also reported based on total energy distribution (TED). Stability of the molecule arising from hyperconjugative interactions, charge delocalization have been analyzed using natural bond orbital (NBO) analysis. The MEP map shows the negative potential sites are on oxygen atom as well as the positive potential sites are around the hydrogen atoms. The UV-Vis spectral analysis of DFAP has also been done which confirms the charge transfer of DFAP. The chemical shifts of H atoms and C atoms were calculated using NMR analysis. Furthermore, the polarizability, the first hyperpolarizability and total dipole moment of the molecule have been calculated. PMID- 25448957 TI - Vibrational, UV spectra, NBO, first order hyperpolarizability and HOMO-LUMO analysis of carvedilol. AB - In this work, we have investigated experimentally and theoretically on the molecular structure, vibrational spectra, UV spectral analysis and NBO studies of cardio-protective drug carvedilol. The FT-Raman and FT-IR spectra for carvedilol in the solid phase have been recorded in the region 4000-100 cm(-1) and 4000-400 cm(-1) respectively. Theoretical calculations were performed by using density functional theory (DFT) method at B3LYP/6-31G(d,p) and B3LYP/6-31++G(d,p) basis set levels. The harmonic vibrational frequencies, the optimized geometric parameters have been interpreted and compared with the reported experimental values. The complete vibrational assignments were performed on the basis of potential energy distribution (PED) of the vibrational modes. The thermodynamic properties and molecular electrostatic potential surfaces of the molecule were constructed. The electronic absorption spectrum was recorded in the region 400 200 nm and electronic properties such as HOMO and LUMO energies were calculated. The stability of the molecule arising from hyper conjugative interactions and charge delocalization have been analyzed from natural bond orbital (NBO) analysis. The first order hyperpolarizability of the title molecule was also calculated. The photo stability of carvedilol under different storage conditions were analyzed using UV-Vis spectral technique. PMID- 25448958 TI - Molecular structure and vibrational spectroscopic studies on 2-furanacetic acid monomer and dimer. AB - In this work, molecular geometries and fundamental vibrational frequencies of 2 furanacetic acid (2FAA) and its hydrogen bonded dimer were investigated using DFT/B3LYP method with 6-311++G(d,p) as basis set. The FT-infrared and FT-Raman spectra of the 2FAA compound were recorded in the region 4000-400 cm(-1). The theoretical wavenumbers were scaled and compared with experimental FT-IR and FT Raman spectra. Complete vibrational assignments and analysis of the fundamental modes of monomer and dimer structures were performed on the basis of the potential energy distribution (PED) calculations. A study on the electronic properties, such as excitation energies, oscillator strength, wavelengths, HOMO and LUMO energies, are performed by time-dependent DFT (TD-DFT) approach. Molecular stability arising from hyperconjugative interactions and charge delocalization has been analyzed using Natural Bond Orbital (NBO) analysis. Topological parameters such an electron density and its Laplacian at bond critical points (BCP) of O-H and O?H contact bonds were analyzed in details with the help of the atoms in molecules (AIM) approach in order to study the intermolecular hydrogen bonding. The nonlinear optical properties of the title molecule have been investigated. Moreover, molecular electrostatic potential (MEP) surface was plotted for predicting sites and relative reactivities towards electrophilic and nucleophilic attack. The nonlinear optical properties were reported and compared with that of the urea. The thermodynamic properties like heat capacity, entropy, and enthalpy have been calculated for the molecule at different temperatures. PMID- 25448959 TI - Pigment characterization of important golden age panel paintings of the 17th century. AB - Samples were obtained from two world-famous 17th century panel paintings of the Gdansk school of panting: 'Seven Acts of Charity' (1607, in St. Mary's Church in Gdansk, Poland) by Anton Moller and 'Angelic Concert' (1611, in Diocesan Museum in Pelplin, Poland) by Hermann Han. Micro-Raman spectroscopy (MRS), optical microscopy (OM), and X-ray fluorescence (XRF) spectroscopy studies of the samples were performed to characterize the pigments present in the individual painting layers (a rich palette of white, black, blue, red, and yellow pigments) and the pictorial techniques used by the artists. PMID- 25448961 TI - Synthesis and DFT calculation of a novel 5,17-di(2-antracenylazo)-25,27 di(ethoxycarbonylmethoxy)-26,28-dihydroxycalix[4]arene. AB - In this study, 5,17-di(2-antracenylazo)-25,27-di(ethoxycarbonylmethoxy)-26,28 dihydroxycalix[4]arene has been synthesized from 2-aminoantracene and 25,27 dihydroxy-26,28-diethylacetate calix[4]arene. In order to identify the molecular structure and vibrational features of the prepared azocalix[4]arene, FT-IR and (1)H NMR spectral data have been used. FT-IR spectrum of the studied molecule is recorded in the region 4000-400 cm(-1). (1)H NMR spectrum is recorded for 0.1-0.2 M solutions in DMSO-d6 solution. The molecular geometry, infrared spectrum are calculated by the density functional method employing B3LYP level with different basis sets, including 6-31G(d) and LanL2DZ. The chemical shifts calculation for (1)H NMR of the title molecule is calculated by using by Gauge-Invariant Atomic Orbital method by utilizing the same basis sets. The total density of state, the partial density of state and the overlap population density of state diagram analysis are done via GaussSum 3.0 program. Frontier molecular orbital (HOMO LUMO) and molecular electrostatic potential surface on the title molecule are carried out for various intramolecular interactions that are responsible for the stabilization of the molecule. The experimental results and theoretical calculations have been compared, and they are found to be in good agreement. PMID- 25448960 TI - The effect of sarafloxacin on Cu/ZnSOD structure and activity. AB - The effect of sarafloxacin to Cu/ZnSOD was evaluated via investigating the change in Cu/ZnSOD structure and the structure basis activity upon sarafloxacin binding. Multi-spectroscopic methods, isothermal titration microcalorimetry (ITC) and molecular docking method were adopted in this study. Sarafloxacin binds to Cu/ZnSOD mainly through hydrophobic and hydrogen bond forces and tends to be saturated as the molar ratio of sarafloxacin to Cu/ZnSOD reaches 4. The binding changed the microenvironment around Tyr and the secondary structure of Cu/ZnSOD but did not affect the activity of Cu/ZnSOD. Molecular docking study revealed that sarafloxacin binds into a hydrophobic area with possibility to form hydrogen bonds with Tyr 108, Asp 25, Pro 100 and Ser 103 of Cu/ZnSOD. The binding area locates on the surface of beta-barrel close to the second Greek key loop (GK2) and V-loop but far away from the active site and active site channel of Cu/ZnSOD. These promoted the understanding of the experiment phenomenons. The binding of sarafloxacin does not affect the activity of Cu/ZnSOD should attribute to the binding not to change the microenvironment of Cu/ZnSOD active site and active site channel. PMID- 25448962 TI - Structural investigation of oxovanadium(IV) Schiff base complexes: X-ray crystallography, electrochemistry and kinetic of thermal decomposition. AB - A series of new VO(IV) complexes of tetradentate N2O2 Schiff base ligands (L(1) L(4)), were synthesized and characterized by FT-IR, UV-vis and elemental analysis. The structure of the complex VOL(1)?DMF was also investigated by X-ray crystallography which revealed a vanadyl center with distorted octahedral coordination where the 2-aza and 2-oxo coordinating sites of the ligand were perpendicular to the "-yl" oxygen. The electrochemical properties of the vanadyl complexes were investigated by cyclic voltammetry. A good correlation was observed between the oxidation potentials and the electron withdrawing character of the substituents on the Schiff base ligands, showing the following trend: MeO5-H>5-Br>5-Cl. Furthermore, the kinetic parameters of thermal decomposition were calculated by using the Coats-Redfern equation. According to the Coats-Redfern plots the kinetics of thermal decomposition of studied complexes is of the first-order in all stages, the free energy of activation for each following stage is larger than the previous one and the complexes have good thermal stability. The preparation of VOL(1)?DMF yielded also another compound, one kind of vanadium oxide [VO]X, with different habitus of crystals, (platelet instead of prisma) and without L(1) ligand, consisting of a V10O28 cage, diaminium moiety and dimethylamonium as a counter ions. Because its crystal structure was also new, we reported it along with the targeted complex. PMID- 25448963 TI - Ab-initio and DFT calculations on molecular structure, NBO, HOMO-LUMO study and a new vibrational analysis of 4-(Dimethylamino) Benzaldehyde. AB - The experimental and theoretical study on the molecular structure and a new vibrational analysis of 4-(Dimethylamino) Benzaldehyde (DMABA) is presented. The IR and Raman spectra were recorded in solid state. Optimized geometry, vibrational frequencies and various thermodynamic parameters of the title compound were calculated using DFT methods and are in agreement with the experimental values. A detailed interpretation of the IR and Raman spectra of the title compound were reported. The stability of the molecule arising from hyper conjugative interactions and charge delocalization has been analyzed using NBO analysis and AIM approach. The HOMO and LUMO analysis were used to determine the charge transfer within the molecule and some molecular properties such as ionization potential, electron affinity, electronegativity, chemical potential, hardness, softness and global electrophilicity index. The TD-DFT approach was applied to assign the electronic transitions observed in the UV-visible spectrum measured experimentally. Molecular electrostatic potential map was performed by the DFT method. According to DSC measurements, the substance presents a melting point of 72.34 degrees C and decomposes at temperatures higher than 193 degrees C. PMID- 25448964 TI - The effects of electronegative substituent atoms on structural, vibrational, electronic and NLO properties of some 4-nitrostilbene derivates. AB - Organic compounds which have one or more aromatic systems in conjugated positions show charge transfer interactions which are responsible for the non-linear properties of the compounds. A conjugated pi electron system enables a pathway for the entire length of conjugation under the perturbation of an external electric field. When electron donating and withdrawing moieties are located at terminal position of conjugated backbone, nonlinear optical (NLO) properties have been increased significantly which involve the correlated and high delocalized pi electron states. Recently synthesized organic complexes, 1-(4-fluorostyryl)-4 nitrostilbene (1), 4-Chloro 4-nitrostilbene (2), 4-Bromo 4-nitrostilbene (3) and 4-Iodo 4-nitrostilbene (4), were simulated using density functional theory (DFT). Based on the optimized geometries, spectroscopic and NLO properties of these complexes were discussed as compared with each other. PMID- 25448965 TI - Unsymmetrical Schiff base (ON) ligand on complexation with some transition metal ions: synthesis, spectral characterization, antibacterial, fluorescence and thermal studies. AB - A series of eight metal Schiff base complexes were synthesized by the thermal reaction of Cu(II), Ni(II), Fe(III), Co(II), Zn(II), Hg(II), La(III) or Sm(III) with a Schiff base "L" produced by the condensation of furfuraldehyde and 1,2 diaminobenzene. These compounds were characterized by elemental analysis, UV-Vis, FT-IR, molar conductance, mass spectrometry, thermal and fluorescence studies. The studies suggested the coordination of the ligand L to metal through azomethine imine nitrogen and furan oxygen atoms of Schiff base moiety. Thermogravimetric (TG/DTG) analyses data were studied and indicated high stability for all complexes and suggested the presence of lattice and/or coordinated water molecules in the complexes. Coats-Redfern method has been used to calculate the kinetic and thermodynamic parameters of the metal complexes. The spectral and thermal analysis reveal that all complexes have octahedral geometry except Cu(II) and Ni(II) complexes which can attain a square planner arrangements. The ligand and its complexes exhibited intraligand (pi-pi(*)) fluorescence and can potentially serve as photoactive materials. Both the ligand and its complexes have been screened for antibacterial activities. PMID- 25448966 TI - Study on the spectral and inclusion properties of a sensitive dye, 3-naphthyl-1 phenyl-5-(5-fluoro-2-nitrophenyl)-2-pyrazoline, in solvents and beta cyclodextrin. AB - 3-Naphthyl-1-phenyl-5-(5-fluoro-2-nitrophenyl)-2-pyrazoline (NPFP), a fluorogenic probe and its derivative NPFP-Phenylephrine were synthesized and their absorption and fluorescence properties were recorded in solvents of varying polarity. Spectroscopic studies reveal that, the solvatochromic behavior of the compounds depend not only on the polarity but also on the hydrogen-bonding properties of the solvents. The effects of beta-cyclodextrin on the fluorescence properties of both compounds were studied. It was found that there is an enhancement in the fluorescence intensity of labeled drug (NPFP-Phenylephrine) in the presence of beta-cyclodextrin. In the present study, the molecular motions of NPFP Phenylephrine embedded in a beta-cyclodextrin cavity have been investigated by fluorescence techniques in steady-state and time resolved modes. PMID- 25448968 TI - Spectroscopic and molecular structure investigations of 9-vinylcarbazole by DFT and ab initio method. AB - Fourier transform infrared (FT-IR) and FT-Raman spectra have been recorded and widespread spectroscopic investigations have been carried out on 9-vinylcarbazole (9VC). The optimized geometries, vibrational wavenumbers, intensity of vibrational bands and various atomic charges of 9VC have been investigated using Hartree-Fock (HF) and density functional theory (DFT-B3LYP) method using 6 31G(d,p) as basis set. Experimental fundamental vibrational modes are scrutinized and compared with the calculated results. (13)C and (1)H NMR spectra were recorded and the chemical shifts of the molecule have been computed using GIAO method. The nonlinear property of the title compound was confirmed by hyperpolarizability. Molecular stability and bond strength was analyzed by Natural Bond Orbital analysis. Electronic structure properties such as UV and frontier molecular orbital examination have been reported. PMID- 25448967 TI - Coordination mode of pentadentate ligand derivative of 5-amino-1,3,4-thiadiazole 2-thiol with nickel(II) and copper(II) metal ions: synthesis, spectroscopic characterization, molecular modeling and fungicidal study. AB - Complexes of nickel(II), and copper(II) were synthesized with pantadentate ligand i.e. 3,3'-thiodipropionicacid-bis(5-amino-1,3,4-thiadiazole-2-thiol) (L). The ligand was synthesized by the condensation of thiodipropionic acid and 5-amino 1,3,4-thiadiazole-2-thiol in 1:2 ratio, respectively. Synthesized ligand was characterized by elemental analysis, mass, (1)H NMR, IR, and molecular modeling. All the complexes were characterized by elemental analysis, molar conductance, magnetic moment, IR, electronic spectra, ESR, and molecular modeling. The newly synthesized complexes possessed general composition [M(L)X2] where M = Ni(II), Cu(II), L = pantadentate ligand and X = Cl(-), CH3COO(-). The IR spectral data indicated that the ligand behaved as a pantadentate ligand and coordinated to the metal ion through N2S3 donor atoms. The molar conductance value of Ni(II), and Cu(II) complexes in DMSO corresponded to their electrolytic behavior. On the basis of spectral study, octahedral and tetragonal geometry was assigned for Ni(II) and Cu(II) complexes, respectively. In vitro fungicidal study of ligand and its complexes was investigated against fungi Candida albicans, Candida parapsilosis, Candidia krusei, and Candida tropicalis by means of well diffusion method. PMID- 25448969 TI - Synthesis, crystal growth and physiochemical characterization of organic NLO crystal: L-ornithinium dipicrate (LODP). AB - L-ornithinium dipicrate (LODP) has been synthesized and good quality single crystals were grown by slow evaporation method at room temperature. Single crystal XRD confirms that the grown crystal belongs to the monoclinic system with the noncentrosymmetric space group P21. Powder X-ray diffraction study confirms the crystalline nature of the compound. FTIR spectral analysis confirms the functional group in the synthesized compound. Thermogravimetric and differential thermal analyses reveal the thermal stability of the crystal. The optical absorption spectrum shows the absence of absorption between 475 nm and 800 nm. The dielectric measurements were carried out to estimate the dielectric parameters of the grown crystal in the frequency range from 50 Hz to 5 MHz at various temperatures. The second harmonic property has been investigated by Kurtz Perry powder technique. The relative SHG efficiency of LODP is found to be 14.57 times greater than that of the reference material KDP. PMID- 25448970 TI - Novel spectrophotometric determination of flumethasone pivalate and clioquinol in their binary mixture and pharmaceutical formulation. AB - This work is concerned with development and validation of three simple, specific, accurate and precise spectrophotometric methods for determination of flumethasone pivalate (FP) and clioquinol (CL) in their binary mixture and ear drops. Method A is a ratio subtraction spectrophotometric one (RSM). Method B is a ratio difference spectrophotometric one (RDSM), while method C is a mean center spectrophotometric one (MCR). The calibration curves are linear over the concentration range of 3-45 MUg/mL for FP, and 2-25 MUg/mL for CL. The specificity of the developed methods was assessed by analyzing different laboratory prepared mixtures of the FP and CL. The three methods were validated as per ICH guidelines; accuracy, precision and repeatability are found to be within the acceptable limits. PMID- 25448971 TI - Spectrophotometric, voltammetric and cytotoxicity studies of 2-hydroxy-5 methoxyacetophenone thiosemicarbazone and its N(4)-substituted derivatives: a combined experimental-computational study. AB - In this study, 2-hydroxy-5-methoxyacetophenone thiosemicarbazone (HMAT) and its novel N(4) substituted derivatives were synthesized and characterized by different techniques. The optical band gap of the compounds and the energy of HOMO were experimentally examined by UV-vis spectra and cyclic voltammetry measurements, respectively. Furthermore, the conformational spaces of the compounds were scanned with molecular mechanics method. The geometry optimization, HOMO and LUMO energies, the energy gap of the HOMO-LUMO, dipole moment of the compounds were theoretically calculated by the density functional theory B3LYP/6-311++G(d,p) level. The minimal electronic excitation energy and maximum wavelength calculations of the compounds were also performed by TD DFT//B3LYP/6-311++G(d,p) level of theory. Theoretically calculated values were compared with the related experimental values. The combined results exhibit that all compounds have good electron-donor properties which affect anti-proliferative activity. The cytotoxic effects of the compounds were also evaluated against HeLa (cervical carcinoma), MCF-7 (breast carcinoma) and PC-3 (prostatic carcinoma) cell lines using the standard MTT assay. All tested compounds showed antiproliferative effect having IC50 values in different range. In comparison with that of HMAT, it was obtained that while ethyl group on 4(N)-substituted position decreased in potent anti-proliferative effect, the phenyl group on the position increased in anti-proliferative effect for the tested cancer cell line. Considering the molecular energy parameters, the cytotoxicity activities of the compounds were discussed. PMID- 25448972 TI - Hydrogen bond strength and vibrational assignment of the enol form of 3-(ortho methoxyphenylthio) and 3-(para-methoxyphenylthio)pentane-2,4-dione. AB - The molecular structure of 3-(ortho-methoxyphenylthio) pentane-2,4-dione (o MPTPD) and 3-(para-methoxyphenylthio) pentane-2,4-dione (p-MPTPD) has been investigated by means of Density Functional Theory (DFT) calculations. The results were compared with 3-(phenylthio) pentane-2,4-dione (PTPD), 3 (methylthio) pentane-2,4-dione (MTPD), and their parent, pentane-2,4-dione (known as acetylacetone, AA). The full optimized geometry, the IR and Raman frequencies and their intensities has been calculated at the B3LYP/6-311++G(**) level of theory. The calculated frequencies were compared with the experimental results. The IR and Raman spectra of o-MPTPD and p-MPTPD and their deuterated analogs are recorded in the 3200-200 cm(-1) range. The quantum theory of atoms in molecules (QTAIM) was applied to calculate the topological parameters of electron density distributions and charge transfer energy associated with the intramolecular hydrogen bond (IHB). Natural bond orbital analysis (NBO) was performed for investigation of electron delocalization in these compounds. According to the theoretical and experimental data, the hydrogen bond strength in the 3-thio pentane-2,4-dione derivatives is much stronger than that in AA. The results of theoretical calculations are in excellent agreement with the vibrational and NMR spectroscopy data. PMID- 25448973 TI - L-tryptophan L-tryptophanium chloride. AB - L-tryptophan L-tryptophanium chloride is a new salt with (A?A(+)) type dimeric cation. It crystallizes in the monoclinic system (space group P2(1), Z=2). The asymmetric unit contains one zwitterionic L-tryptophan molecule, one L tryptophanium cation and one chloride anion. The dimeric cation is formed by a O H?O hydrogen bond with the O?O distance equal to 2.5556(18) A. The infrared and Raman spectra of the crystal are studied and compared with the spectra of L tryptophanium chloride. PMID- 25448974 TI - A novel approach for the synthesis of SnO2 nanoparticles and its application as a catalyst in the reduction and photodegradation of organic compounds. AB - Tin oxide (SnO2) nanoparticles of sizes ~4.5, ~10 and ~30 nm were successfully synthesized by a simple chemical precipitation method using amino acid, glycine which acts as a complexing agent and surfactant, namely sodium dodecyl sulfate (SDS) as a stabilizing agent, at various calcination temperatures of 200, 400 and 600 degrees C. This method resulted in the formation of spherical SnO2 nanoparticles and the size of the nanoparticles was found to be a factor of calcination temperature. The spherical SnO2 nanoparticles show a tetragonal rutile crystalline structure. A dramatic increase in band gap energy (3.8-4.21 eV) was observed with a decrease in grain size (30-4.5 nm) due to three dimensional quantum confinement effect shown by the synthesized SnO2 nanoparticles. SnO2 nanoparticles were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), selected area electron diffraction (SAED) and fourier transformed infrared spectroscopy (FT-IR). The optical properties were investigated using UV-visible spectroscopy. These SnO2 nanoparticles were employed as catalyst for the reduction of p-nitro phenol to p-amino phenol in aqueous medium for the first time. The synthesized SnO2 nanoparticles act as an efficient photocatalyst in the degradation of methyl violet 6B dye under direct sunlight. For the first time, methyl violet 6B dye was degraded by SnO2 nanoparticles under direct sunlight. PMID- 25448975 TI - New water-soluble copper (II) complexes including 4,7-dimethyl-1,10 phenanthroline and L-tyrosine: synthesis, characterization, DNA interactions and cytotoxicities. AB - Two new water-soluble copper(II) complexes, [Cu(dmphen)2(NO3)]NO3 (1), [Cu(dmphen)(tyr)(H2O)]NO3.H2O (2) and the diquarternary salt of dmphen (dmphen = 4,7-dimethyl-1,10-phenanthroline and tyr = L-tyrosine), have been synthesized and characterized by elemental analysis, (1)H NMR, (13)C NMR and IR spectroscopy, thermal analysis and single crystal X-ray diffraction techniques. The CT-DNA binding properties of these compounds have been investigated by absorption, emission spectroscopy and thermal denaturation measurements. The supercoiled pBR322 plasmid DNA cleavage activity of these compounds has been explored by agarose gel electrophoresis. The cytotoxicity of these compounds against MCF-7, Caco-2, A549 cancer cells and BEAS-2B healthy cells was also studied by the XTT method. Complexes 1 and 2 exhibit significant cytotoxicity, with lower IC50 values than those of cisplatin. PMID- 25448976 TI - Spectroscopic (FT-IR, FT-Raman) and quantum mechanical studies of 3t-pentyl-2r,6c diphenylpiperidin-4-one thiosemicarbazone. AB - In this study, the molecular structure and vibrational spectra of 3t-pentyl2r,6c diphenylpiperidin-4-one thiosemicarbazone (PDPOTSC) were studied. The ground state molecular geometry was ascertained by using the density functional theory (DFT)/B3LYP method using 6-31++G(d,p) as a basis set. The vibrational (FT-IR and FT-Raman) spectra of PDPOTSC were computed using DFT/B3LYP and HF methods with 6 31++G(d,p) basis set. The fundamental vibrations were assigned on the basis of the total energy distribution (TED?10%) of the vibrational modes, calculated with scaled quantum mechanics (SQM) methods PQS program. The electrical dipole moment (MU) and first hyperpolarizability (betao) values have been computed using DFT/B3LYP and HF methods. The calculated result (betao) shows that the title molecule might have nonlinear optical (NLO) behavior. Atomic charges of C, N, S and molecular electrostatic potential (MEP) were calculated using B3LYP/6 31G++(d,p). The HOMO-LUMO energies were calculated and natural bonding orbital (NBO) analysis has also been carried out. PMID- 25448977 TI - Raman spectroscopic signatures of the yellow and ochre paints from artist palette of J. Matejko (1838-1893). AB - The Raman and complementary spectroscopic analyses were performed using the exceptional possibility of research on the XIX c. original paint materials of the artist palette of J. Matejko stored in the National Museum in Cracow. The yellow and ochre-based paints characteristic for Matejko's workshop and selected from the ensemble of 273 labelled tubes (brand of R. Aine/Paris) supplied during the period of 1880-1893 were investigated. Highly specific Raman spectra were obtained for paints containing mixtures of the Zn- and Sn-modified Pb-Sb pigment, and also for the ochre-based ones. A clear pigment discrimination of the mixture of cadmium yellow (CdS), cinnabar (HgS) and lead white (2PbCO3?Pb(OH)2) was possible by means of Raman data collected under different excitations at 514 nm and 785 nm. It was shown that the Raman spectra complemented by the XRF, SEM-EDX and in some cases also by the LIPS and FTIR data ensure reliable pigment identification in multi-component paints containing secondary species and impurities. The reported spectral signatures will be used for non-destructive investigation of the collection of about 300 oil paintings of J. Matejko. In view of the comparative research on polish painting which point out that richness of modified Naples yellows clearly distinguish Matejko's artworks from other ones painted in the period of 1850-1883, the Raman data of these paints can provide support in the authentication studies. PMID- 25448978 TI - Development of a cloud point extraction and spectrophotometry-based microplate method for the determination of nitrite in human urine and blood. AB - A novel and simple method for the sensitive determination of trace amounts of nitrite in human urine and blood has been developed by combination of cloud point extraction (CPE) and microplate assay. The method is based on the Griess reaction and the reaction product is extracted into nonionic surfactant Triton-X114 using CPE technique. In this study, decolorization treatment of urine and blood was applied to overcome the interference of matrix and enhance the sensitivity of nitrite detection. Multi-sample can be simultaneously detected thanks to a 96 well microplate technique. The effects of different operating parameters such as type of decolorizing agent, concentration of surfactant (Triton X-114), addition of (NH4)2SO4, extraction temperature and time, interfering elements were studied and optimum conditions were obtained. Under the optimum conditions, a linear calibration graph was obtained in the range of 10-400 ng mL(-1) of nitrite with limit of detection (LOD) of 2.5 ng mL(-1). The relative standard deviation (RSD) for determination of 100 ng mL(-1) of nitrite was 2.80%. The proposed method was successfully applied for the determination of nitrite in the urine and blood samples with recoveries of 92.6-101.2%. PMID- 25448979 TI - Oxidation of phenyl propyne catalyzed by copper(II) complexes of a benzimidazolyl schiff base ligand: effect of acid/base, oxidant, surfactant and morphology. AB - Copper(II) complexes with a new N-Substituted benzimidazolyl schiff base ligand are used as catalyst for the oxidation of 1-phenyl propyne. The oxidation is carried out under mild conditions using stoichiometric amounts of oxidant and catalytic amounts of Cu(II) complex as catalyst. Effect of acid/base, oxidant, morphology and surfactant has been studied. Two major products of phenyl propyne oxidation are the alpha-diketonic product and a terminal aldehyde. Diketone is the major product under acidic conditions while aldehyde formation is highest under basic conditions. The maximum conversion is found with the NO3(-) bound complex. GC-MS is used to find the percentage yields of products. SEM and PXRD of the reused complexes as catalyst suggest that morphology affects the catalytic efficiency. PMID- 25448980 TI - Synthesis, characterization, PL properties, photocatalytic and antibacterial activities of nano multi-metal oxide NiO?CeO2?ZnO. AB - A novel multi-metal nanocomposite, NiO?CeO2?ZnO has been prepared by co precipitation of their carbonates from aqueous solutions of the metal nitrates following calcination and annealing 5 h at 450 degrees C and 10 h at 950 degrees C. NiO?CeO2?ZnO has been characterized by XRD, SEM, EDS, IR and PL spectra. The crystallite size of the as-synthesized sample varies in the range of 14-23 nm and those of the annealed sample in the range of 17-50 nm. Emissions of NiO?CeO2?ZnO have been observed in UV (NBE emission) and visible region at different excitations. Excitation wavelength dependent PL behavior of NiO?CeO2?ZnO has been observed in acetone at room temperature. This PL property is in disagreement with Kasha's rule of excitation wavelength dependence of emission spectrum. Photocatalytic as well as anti-bacterial activities were studied. PMID- 25448981 TI - Sol-gel based optical sensor for determination of Fe (II): a novel probe for iron speciation. AB - A highly selective optical sensor for Fe (II) ions was developed based on entrapment of a sensitive reagent, 2,4,6-tri(2-pyridyl)-s-triazine (TPTZ), in a silica sol-gel thin film coated on a glass substrate. The thin films fabricated based on tetraethoxysilane (TEOS) as precursor, sol-gel pH~3, water:alkoxyde ratio of 4:1 and TPTZ concentration of 0.112 mol L(-1). The influence of sol-gel parameters on sensing behavior of the fabricated sensor was also investigated. The fabricated sensor can be used for determination of Fe (II) ion with an outstanding high selectivity over a dynamic range of 5-115 ng mL(-1) and a detection limit of 1.68 ng mL(-1). It also showed reproducible results with relative standard deviation of 3.5% and 1.27% for 10 and 90 ng mL(-1) of Fe (II), respectively, along with a fast response time of ~120 s. Total iron also was determined after reduction of Fe (III) to Fe (II) using ascorbic acid as reducing agent. Then, the concentration of Fe (III) was calculated by subtracting the concentration of Fe (II) from the total iron concentration. Interference studies showed a good selectivity for Fe (II) with trapping TPTZ into sol-gel matrix and appropriately adjusting the structure of doped sol-gel. The sensor was compared with other sensors and was applied to determine iron in different water samples with good results. PMID- 25448982 TI - Spectral features, electric properties, NBO analysis and reactivity descriptors of 2-(2-Benzothiazolylthio)-Ethanol: Combined experimental and DFT studies. AB - Quantum chemical calculations of ground state energy, geometrical structure and vibrational wavenumbers, nuclear magnetic behaviors, electronic absorption spectra along with the nonlinear optical properties of 2-(2-benzothiazolylthio) ethanol (BTZTE) were carried out using density functional (DFT/B3LYP) method with 6-311++G(d,p) as basis set. The FT-IR and FT-Raman spectra were measured in the condensed state. The fundamental vibrational wavenumbers as well as their intensities were calculated, and a good correlation between experimental and scaled calculated wavenumbers was accomplished. The electric dipole moment, polarizability and the first hyperpolarizability values of the BTZTE were calculated at the same level of theory and basis set. The results show that the BTZTE molecule possesses nonlinear optical (NLO) behavior with non-zero values. Stability of the molecule arising from hyper-conjugative interactions and charge delocalization was analyzed using natural bond orbital (NBO) analysis. UV spectrum of the studied molecule was recorded in the region 200-500nm and the electronic properties were predicted by time-dependent DFT approach. The calculated transition energies are in good concurrency with the experimental data. (1)H nuclear magnetic resonance (NMR) chemical shifts of the title molecule were calculated by the gauge independent atomic orbital (GIAO) method and compared with experimental results. The thermodynamic properties of the studied compound at different temperatures were calculated. Global and local reactivity descriptors were computed to predict reactivity and reactive sites on the molecule. PMID- 25448984 TI - MiR-185 is involved in human breast carcinogenesis by targeting Vegfa. AB - MiR-185 expression has been associated with many cancers. However, the roles of miR-185 in human breast cancer remain elusive. Here, we found that miR-185 expression was decreased in human breast cancer tissues compared with healthy tissue controls. Up-regulation of miR-185 inhibited breast cancer cell proliferation and invasion and vice versa. MiR-185 was shown to bind to the 3' untranslated region (UTR) of vascular endothelial growth factor a (Vegfa), and a significant inverse correlation was found between miR-185 and Vegfa. Vegfa overexpression partially restored the inhibition of cell proliferation and invasion that was induced by miR-185, and vice versa. Additionally, Vegfa expression was found to be high in human breast cancer tissues. Thus, miR-185 mediated Vegfa targeting may be involved in breast cancer formation. PMID- 25448985 TI - Hypoxia triggers endothelial endoplasmic reticulum stress and apoptosis via induction of VLDL receptor. AB - Endothelial cells express very low density lipoprotein receptor (VLDLr). Beyond the function as peripheral lipoprotein receptor, other roles of VLDLr in endothelial cells have not been completely unraveled. In the present study, human umbilical vein endothelial cells were subjected to hypoxia, and VLDLr expression, endoplasmic reticulum (ER) stress, and apoptosis were assessed. Hypoxia triggered endothelial ER stress and apoptosis, and induced VLDLr expression. Silencing or stabilization of HIF-1alpha reduced and enhanced VLDLr expression, respectively. HIF-1alpha affected vldlr promoter activity by interacting with a hypoxia responsive element (HRE). Knockdown or overexpression of VLDLr alleviated and exacerbated hypoxia-induced ER stress and apoptosis, respectively. Thus, hypoxia induces VLDLr expression through the interaction of HIF-1alpha with HRE at the vldlr promoter. VLDLr then mediates ER stress and apoptosis. PMID- 25448983 TI - TALEN-mediated mutagenesis in zebrafish reveals a role for r-spondin 2 in fin ray and vertebral development. AB - R-spondin (Rspo) encodes a multi-domain protein that modulates the Wnt-signaling pathway. Two distinct rspo2 zebrafish mutants were generated by TALEN-mediated mutagenesis: a null mutant, rspo2(null), lacking all functional domains, and a hypomorphic mutant, rspo2(tsp), lacking the two N-terminal domains. Mutants were analyzed mainly for abnormalities in the skeletal system. Fin ray skeletons were formed normally in the rspo2(tsp) mutants, but were absent from the rspo2(null) mutants. Hypoplasia of the neural/hemal arches and ribs was observed in both mutants. Thus, the two rspo2 mutants help to identify the functions of Rspo2 in skeletogenesis, as well as functional differences among multiple Rspo2 domains. PMID- 25448986 TI - Membrane interactions and fibrillization of alpha-synuclein play an essential role in membrane disruption. AB - We studied alpha-synuclein (alphaS) aggregation in giant vesicles, and observed dramatic membrane disintegration, as well as lipid incorporation into micrometer sized suprafibrillar aggregates. In the presence of dye-filled vesicles, dye leakage and fibrillization happen concurrently. However, growing fibrils do not impair the integrity of phospholipid vesicles that have a low affinity for alphaS. Seeding alphaS aggregation accelerates dye leakage, indicating that oligomeric species are not required to explain the observed effect. The evolving picture suggests that fibrils that appear in solution bind membranes and recruit membrane-bound monomers, resulting in lipid extraction, membrane destabilization and the formation of lipid-containing suprafibrillar aggregates. PMID- 25448987 TI - Juxtamembrane tryptophans have distinct roles in defining the OmpX barrel-micelle boundary and facilitating protein-micelle association. AB - Defining the span of the transmembrane region, a key requirement to ensure correct folding, stability and function of bacterial outer membrane beta-barrels, is assisted by the amphipathic property of tryptophan. We demonstrate the unique and distinctive properties of the interface Trp76 and Trp140 of outer membrane protein X, and map their positional relevance to the refolding process, barrel formation and the resulting stability in dodecylphosphocholine micelles. The solvent-exposed Trp76 displays a rigid interfacial localization, whereas Trp140 is relatively micelle-solvated and contributes to barrel folding and global OmpX stability. Kinetic contribution to OmpX stability is influenced by the two tryptophans. Differential associations of the indoles with the detergent milieu therefore contribute to micelle-assisted beta-barrel folding and concomitant OmpX stability. PMID- 25448988 TI - Subunit unbinding mechanics of dimeric wheat germ agglutinin (WGA) studied by atomic force microscopy. AB - Wheat germ agglutinin (WGA) is an oligomeric lectin widely used as a model of sugar moieties in biochemistry. Subunit association is important for the crosslinking function of WGA, so we used atomic force microscopy to measure the subunit unbinding force of dimeric WGA. We found that the average unbinding force of dimeric WGA is ~55 pN at ~1 nN/s loading rate, whereas this unbinding force is increased at least up to 100 pN when WGA is bound to glycophorin A. Moreover, the dissociation rate constant of WGA was calculated to be 1-2 * 10(-2) s(-1), suggesting that dimer dissociation is relatively fast. PMID- 25448989 TI - Crystal structures of Entamoeba histolytica lysyl-tRNA synthetase reveal conformational changes upon lysine binding and a specific helix bundle domain. AB - The class II lysyl-tRNA synthetases (KRS) are conserved aminoacyl-tRNA synthetases that attach lysine to the cognate tRNA in a two-step mechanism. The enzyme from the parasitic protozoan Entamoeba histolytica was crystallized in the presence of small ligands to generate snapshots of the lysine-adenylate formation. The residues involved in lysine activation are highly conserved and the active site closes around the lysyl-adenylate, as observed in bacterial KRS. The Entamoeba EMAPII-like polypeptide is not resolved in the crystals, but another Entamoeba-specific insertion could be modeled as a small helix bundle that may contribute to tRNA binding through interaction with the tRNA hinge. PMID- 25448990 TI - Comparison of outcomes of primary anterior chamber versus secondary scleral fixated intraocular lens implantation in complicated cataract surgeries. AB - PURPOSE: To compare the outcome of primary anterior chamber vs secondary scleral fixated intraocular lens (IOL) implantation in complicated cataract surgeries. DESIGN: Retrospective, comparative study. METHODS: A consecutive series of complicated cataract surgeries with primary anterior chamber (ACIOL) or secondary scleral-fixated IOL implantation from January 1, 2004 to December 31, 2009 was analyzed. Main outcome measures included the postoperative best-corrected visual acuity (BCVA) and postoperative complications. RESULTS: There were 89 eyes in the primary ACIOL group and 74 eyes in the secondary scleral-fixated IOL group. The mean follow-up duration was 64.1 +/- 36.7 months. The mean postoperative logarithm of minimal angle of resolution (logMAR) BCVA at 1 year was 0.32 +/- 0.54 and 0.34 +/- 0.21 in the primary ACIOL group and the secondary scleral fixated IOL group, respectively (P = .734). The mean latest logMAR BCVA was 0.68 +/- 0.54 and 0.61 +/- 0.47 in the primary ACIOL group and the secondary scleral fixated IOL group, respectively (P = .336). The primary ACIOL group had more early postoperative complications (P < .001). No difference in late postoperative complications was observed between the 2 groups (P = .100). Regression analysis showed that primary ACIOL and secondary scleral-fixated IOL implantation had similar latest postoperative logMAR BCVA (P = .927), while the presence of late complications was associated with a worse final visual outcome (P = .000). CONCLUSIONS: This study shows that there are no long-term differences in the visual outcomes and complication profiles after primary ACIOL or secondary scleral-fixated IOL implantation in a complicated cataract operation when capsular support is inadequate. PMID- 25448992 TI - Multimodal imaging in handheld laser-induced maculopathy. AB - PURPOSE: To describe the clinical and imaging findings in 3 patients with maculopathy secondary to handheld laser exposure. DESIGN: Retrospective, observational case series. METHODS: We evaluated the multimodal imaging including fundus autofluorescence and spectral-domain optical coherence tomography (OCT) for 3 patients with histories of exposure to handheld lasers. RESULTS: An 18-year old woman with a history of repetitive self-inflicted handheld laser exposure was found to have bilateral outer retinal streaks in the macula and the superior peripheral retina on both ophthalmoscopy and multimodal imaging. Initial spectral domain OCT revealed vertical hyper-reflective bands at the level of the outer retina corresponding to the streaks. An 11-year-old boy who played with a green laser developed a yellow foveal lesion and outer retinal streaks in the superior macula. Spectral-domain OCT showed vertical hyper-reflective bands in the outer retina corresponding to the streaks. A 14-year-old boy developed bilateral focal foveal lesions and ellipsoid loss on spectral-domain OCT following peer-inflicted laser injury. CONCLUSIONS: In a series of 3 patients, outer retinal streaks were associated with self-inflicted handheld laser injury. In contrast, accidental and peer-inflicted laser injuries were found to result in focal foveal lesions. PMID- 25448991 TI - Diagnostic ability of retinal nerve fiber layer imaging by swept-source optical coherence tomography in glaucoma. AB - PURPOSE: To evaluate the diagnostic accuracies of swept-source optical coherence tomography (OCT) wide-angle and peripapillary retinal nerve fiber layer (RNFL) thickness measurements for glaucoma detection. DESIGN: Cross-sectional case control study. METHODS: In this study we enrolled 144 glaucomatous eyes of 106 subjects and 66 eyes of 42 healthy subjects from the Diagnostic Innovations in Glaucoma Study. Glaucoma was defined by the presence of repeatable abnormal standard automated perimetry results and/or progressive glaucomatous optic disc change on masked grading of stereophotographs. Wide-angle and peripapillary RNFL thicknesses were assessed using swept-source OCT. Peripapillary RNFL thickness was also evaluated using spectral-domain OCT. Areas under the receiver operating characteristic (ROC) curves were calculated to evaluate the ability of the different swept-source OCT and spectral-domain OCT parameters to discriminate between glaucomatous and healthy eyes. RESULTS: Mean (+/- standard deviation) average spectral-domain OCT wide-angle RNFL thicknesses were 50.5 +/- 5.8 MUm and 35.0 +/- 9.6 MUm in healthy and glaucomatous eyes, respectively (P < 0.001). Corresponding values for swept-source OCT peripapillary RNFL thicknesses were 103.5 +/- 12.3 MUm and 72.9 +/- 16.5 MUm, respectively (P < 0.001). Areas under the ROC curves of swept-source OCT wide-angle and peripapillary RNFL thickness were 0.88 and 0.89, respectively. Swept-source OCT performed similar to average peripapillary RNFL thickness obtained by spectral-domain OCT (area under the ROC curve of 0.90). CONCLUSION: Swept-source OCT wide-angle and peripapillary RNFL thickness measurements performed well for detecting glaucomatous damage. The diagnostic accuracies of the swept-source OCT and spectral-domain OCT RNFL imaging protocols evaluated in this study were similar. PMID- 25448993 TI - Correlation among lens opacities classification system III grading, visual function index-14, pentacam nucleus staging, and objective scatter index for cataract assessment. AB - PURPOSE: To investigate the relationship among Lens Opacities Classification System III (LOCS III) grading score, Visual Function Index-14 (VF-14) score, average lens density by the Pentacam Nucleus Staging system, and the objective scatter index measured by the Optical Quality Analysis System in age-related cataract patients. DESIGN: Prospective, single-center, cross-sectional study. METHODS: Thirty-six subjects (60 eyes) with age-related cataract were recruited. Subjects with any corneal anomaly potentially affecting intraocular scatter were excluded. The best-corrected visual acuity (BCVA), LOCS III nuclear opalescence score and cortical cataract score, VF-14 score, average lens density, and objective scatter index were obtained. Correlations among these parameters were analyzed. RESULTS: The LOCS III nuclear opalescence score was correlated with the BCVA (r = 0.438; P = .001), objective scatter index (r = 0.543; P < .001), and average lens density (r = 0.621; P < .001). The objective scatter index was also correlated with the BCVA (r = 0.779; P < .001) and the average lens density (r = 0.320; P = .013). The VF-14 score had the strongest correlation with the objective scatter index (r = -0.712; P < .001). The difference between groups with objective scatter index<3.0 and >=3.0 was significant with regard to BCVA, average lens density, LOCS III nuclear opalescence score, and VF-14 score. CONCLUSIONS: LOCS III grading remains an economical and effective method to assess lens opacities, especially in the formation of early cortex cataracts. The objective scatter index can be a useful parameter to objectively analyze the correlation between ocular examination findings and patient concerns. Furthermore, the objective scatter index scores >=3.0 can be a possible objective cut-off for preoperative decision making. PMID- 25448994 TI - Frequency and implications of discordant gene expression profile class in posterior uveal melanomas sampled by fine needle aspiration biopsy. AB - PURPOSE: To determine the frequency of discordant gene expression profile (GEP) classification of posterior uveal melanomas sampled at 2 tumor sites by fine needle aspiration biopsy (FNAB). DESIGN: Prospective single-institution longitudinal study performed in conjunction with a multicenter validation study of the prognostic value of GEP class of posterior uveal melanoma cells for metastasis and metastatic death. METHODS: FNAB aspirates of 80 clinically diagnosed primary choroidal and ciliochoroidal melanomas were obtained from 2 tumor sites prior to or at the time of initial ocular tumor treatment and submitted for independent GEP testing and classification. Frequency of discordant GEP classification of these specimens was determined. RESULTS: Using the support vector machine learning algorithm favored by the developer of the GEP test employed in this study, 9 of the 80 cases (11.3% [95% confidence interval: 9.0% 13.6%]) were clearly discordant. If cases with a failed classification at 1 site or a low confidence class assignment by the support vector machine algorithm at 1 or both sites are also regarded as discordant, then this frequency rises to 13 of the 80 cases (16.3% [95% confidence interval: 13.0%-19.6%]). CONCLUSION: Sampling of a clinically diagnosed posterior uveal melanoma at a single site for prognostic GEP testing is associated with a substantial probability of misclassification. Two-site sampling of such tumors with independent GEP testing of each specimen may be advisable to lessen the probability of underestimating an individual patient's prognostic risk of metastasis and metastatic death. PMID- 25448995 TI - Binocular visual function of modified pseudophakic monovision. AB - PURPOSE: To compare binocular visual function of pseudophakic patients having modified monovision (0.75 diopter [D] anisometropia) with that of patients having conventional monovision (1.75 D anisometropia). DESIGN: Prospective observational study. METHODS: Eighty-two patients that underwent bilateral implantation of a monofocal intraocular lens were recruited at 3 months postoperatively. Modified monovision was simulated by adding a +0.75 D spherical lens to the nondominant eye, while conventional monovision was simulated by adding a +1.75 D spherical lens. Binocular corrected visual acuity (VA) at various distances, binocular contrast VA (contrast VA) and that with glare (glare VA), and stereoacuity were evaluated. RESULTS: With modified monovision, mean binocular corrected intermediate VA at 1.0 m was 20/19 and near VA at 0.3 m was 20/51, and stereoacuity was 125 +/- 100 seconds of arc. Mean binocular intermediate VA at 1.0 m was significantly better with modified monovision than with conventional monovision (P = .0001), while near VA and intermediate VA at 0.5 m were significantly worse (P < .0001). Mean binocular photopic and mesopic contrast VA and glare VA tended to be better with modified monovision than with conventional monovision, but the difference was not significant. Mean stereoacuity was significantly better with modified monovision than with conventional monovision (P = .0020). CONCLUSIONS: Modified pseudophakic monovision provided excellent binocular VA from far to intermediate distances, although near VA was worse than that with conventional monovision. Contrast VA with and without glare tended to be better and stereoacuity was significantly better with modified monovision, suggesting that this method is useful for correcting presbyopia without marked impairment of binocular function. PMID- 25448996 TI - Predictive value of heidelberg retina tomograph parameters for the development of glaucoma in the European glaucoma prevention study. AB - PURPOSE: To determine whether baseline Heidelberg Retina Tomograph (HRT) measurements of the optic disc are associated with the development of open-angle glaucoma (OAG) in individuals with ocular hypertension in the European Glaucoma Prevention Study (EGPS). DESIGN: Retrospective analysis of a prospective, randomized, multicenter, double-masked, controlled clinical trial. METHODS: There were 489 participants in the HRT Ancillary Study to the EGPS. Each baseline HRT parameter was assessed in univariate and multivariate proportional hazards models to determine its association with the development of OAG. Proportional hazards models were used to identify HRT variables that predicted which participants in the EGPS had developed OAG. Development of OAG was based on visual field and/or optic disc changes. RESULTS: At a median follow-up time of about 5 years, 61 participants developed OAG. In multivariate analyses, adjusting for randomization arm, age, baseline IOP, central corneal thickness, pattern standard deviation, and HRT disc area, the following HRT parameters were associated with the development of OAG: the "outside normal limits" classification of the Frederick Mikelberg (FSM) discriminant function (hazard ratio [HR] 2.51, 95% confidence interval [CI]: 1.45-4.35), larger mean cup depth (HR 1.64, 95% CI: 1.21-2.23), cup-to-disc area ratio (HR 1.43, 95% CI: 1.14-1.80), linear cup-to-disc ratio (HR 1.43, 95% CI: 1.13-1.80), cup area (HR 1.33, 95% CI: 1.08-1.64), smaller rim area (HR 1.33, 95% CI: 1.07-1.64), larger cup volume (HR 1.30, 95% CI: 1.05-1.61), smaller rim volume (HR 1.25, 95% CI: 1.01-1.54), larger maximum cup depth (HR 1.18, 95% CI: 1.01-1.36), and cup shape measure (HR 1.18, 95% CI: 1.01-1.36). CONCLUSIONS: Several baseline HRT parameters, alone or in combination with baseline clinical and demographic factors, were significantly associated with the development of OAG among the EGPS participants. PMID- 25448997 TI - Endoscopic medial orbital fat decompression for proptosis in type 1 graves orbitopathy. AB - PURPOSE: To describe the surgical technique for endoscopic medial orbital fat decompression in type 1 (lipogenic) Graves orbitopathy and report outcomes. DESIGN: Retrospective interventional case review. METHODS: We reviewed 108 patients (206 orbits) with inactive, type 1 Graves orbitopathy without diplopia, who underwent endoscopic medial orbital fat decompression solely for proptosis reduction. Following endoscopic transethmoid medial orbital wall decompression, extraconal and intraconal orbital fat was removed with a low-suction cutting instrument. All patients were followed up for at least 12 months. Surgical time, preoperative and postoperative Hertel exophthalmometry, incidence of postoperative diplopia within 30-degree visual field in the primary gaze, and other complications were analyzed. RESULTS: The mean surgical time was 97.7 +/- 16.7 minutes (67-136 minutes). The mean follow-up was 16.0 +/- 4.2 months (12-24 months). Preoperative and postoperative proptosis values at final review were 21.1 +/- 2.3 mm (17-26 mm) and 13.0 +/- 0.9 mm (12-15 mm), respectively (P < .001). Median reduction in proptosis was 8.0 mm with mean of 8.2 +/- 1.8 mm (4-11 mm). Symmetry to within 2 mm was achieved in 106 of 108 patients (98.1%). Twenty five of 108 patients (23.1%) had diplopia within 30-degree visual field of the gaze, and 23 of these had complete resolution within 3 months, while the remaining 2 patients required squint surgery. CONCLUSIONS: Endoscopic medial orbital fat decompression may be an effective technique for proptosis in selected patients with type 1 Graves orbitopathy and is associated with a low rate of surgically induced diplopia. PMID- 25448998 TI - Uveitis in Behcet disease in a tertiary center over 25 years: the KKESH Uveitis Survey Study Group. AB - PURPOSE: To describe the features of Behcet-associated uveitis over a 25-year period. DESIGN: Retrospective observational case series. METHODS: A chart review of patients with Behcet-associated uveitis who were evaluated from January 1986 to December 2011 at King Khaled Eye Specialist Hospital, Saudi Arabia. Demographic data, symptoms, type of uveitis, treatment, and complications were evaluated. The main outcome measures were presenting symptoms, types of uveitis, treatment, and complications. RESULTS: There were 132 patients (232 eyes; 102 male [77.3%]) evaluated with age of onset of 36.9 +/- 11.4 years. Panuveitis was the most common presentation, affecting 118 patients (89.4%). Episodes were bilateral in 100 patients (75.8%). Baseline best-corrected visual acuity (BCVA) was 20/125 in both eyes. Retinal vasculitis at presentation occurred in 61 eyes (26.3%), occlusive vasculitis in 59 eyes (25.4%), and macular edema in 42 eyes (18.1%). Common therapeutic management included oral corticosteroids in 123 patients (93.2%), intravenous steroid therapy in 35 patients (26.5%), cyclosporine in 98 patients (74.2%), and azathioprine in 65 patients (49.2%). Common anterior segment complications included glaucoma (44 eyes, 19%) and cataracts (34 eyes, 14.7%). The most common posterior segment complication was optic nerve atrophy. Cataract surgery was the most common surgery. At last visit, BCVA was better than 20/50 in 131 eyes (56.5%). CONCLUSIONS: Behcet-associated uveitis predominantly affects young men in Saudi Arabia. Bilateral panuveitis associated with retinal vasculitis was the most common manifestation. More than 50% of patients maintained 20/50 or better BCVA at final follow-up and were primarily managed with oral corticosteroids and other immunosuppressive agents. PMID- 25448999 TI - Retinal detachment associated with AIDS-related cytomegalovirus retinitis: risk factors in a resource-limited setting. AB - PURPOSE: To determine risk factors predictive of retinal detachment in patients with cytomegalovirus (CMV) retinitis in a setting with limited access to ophthalmic care. DESIGN: Case-control study. METHODS: Sixty-four patients with CMV retinitis and retinal detachment were identified from the Ocular Infectious Diseases and Retina Clinics at Chiang Mai University. Three control patients with CMV retinitis but no retinal detachment were selected for each case, matched by calendar date. The medical records of each patient were reviewed, with patient level and eye-level features recorded for the clinic visit used to match cases and controls, and also for the initial clinic visit at which CMV retinitis was diagnosed. Risk factors for retinal detachment were assessed separately for each of these time points using multivariate conditional logistic regression models that included 1 eye from each patient. RESULTS: Patients with a retinal detachment were more likely than controls to have low visual acuity (odds ratio [OR], 1.24 per line of worse vision on the logMAR scale; 95% confidence interval [CI], 1.16-1.33) and bilateral disease (OR, 2.12; 95% CI, 0.92-4.90). Features present at the time of the initial diagnosis of CMV retinitis that predicted subsequent retinal detachment included bilateral disease (OR, 2.68; 95% CI, 1.18 6.08) and lesion size (OR, 2.64 per 10% increase in lesion size; 95% CI, 1.41 4.94). CONCLUSION: Bilateral CMV retinitis and larger lesion sizes, each of which is a marker of advanced disease, were associated with subsequent retinal detachment. Earlier detection and treatment may reduce the likelihood that patients with CMV retinitis develop a retinal detachment. PMID- 25449000 TI - Factors affecting therapeutic decisions in intermediate and posterior uveitis. AB - PURPOSE: To evaluate whether cost, insurance prior authorization, pregnancy considerations, and subspecialty practice lead to changes in therapeutic decisions among uveitis and retina specialists in the treatment of intermediate and posterior uveitis. DESIGN: Prospective cross-sectional study. METHODS: A total of 934 uveitis and retina specialists across the United States were surveyed via e-mail regarding their choice in long-term therapy for 3 hypothetical patients with uveitic conditions (Behcet disease, birdshot retinochoroiditis, and intermediate uveitis). Respondents were asked to select first- and second-choice therapies and then reselect first and second choices assuming cost of all options was equal to the patient and there would be no issues with insurance prior authorization. In 1 case, they were additionally asked for their treatment preferences if the patient desired a pregnancy. Outcomes of interest were differences in therapy choice based on cost/prior authorization, pregnancy, and subspecialty practice. RESULTS: One hundred and six respondents (11.3%) completed the survey; 44 were uveitis specialists and 62 retina specialists. Cost and prior authorization affected the therapy choices of uveitis specialists treating ocular Behcet disease (P = .008). Uveitis specialists and retina specialists differed in their first choice in therapy for each vignette when cost and prior authorization were equalized (P = .0018, P = .0049, and P = .0156). Both uveitis specialists and retina specialists changed their therapeutic choices for intermediate uveitis when pregnancy was a consideration (P = .00001 for uveitis specialists, P = .0044 for retina specialists). CONCLUSIONS: Physician decision making in intermediate and posterior uveitis is affected by cost and prior authorization concerns, pregnancy considerations, and subspecialty practice. PMID- 25449001 TI - Exogenous fungal endophthalmitis: an analysis of isolates and susceptibilities to antifungal agents over a 20-year period (1990-2010). AB - PURPOSE: To describe the isolates and susceptibilities to antifungal agents for patients with culture-proven exogenous fungal endophthalmitis. DESIGN: Noncomparative case series. METHODS: The clinical records of all patients treated for culture-proven exogenous fungal endophthalmitis at a university referral center from 1990 to 2010 were reviewed. Specimens initially used for diagnosis were recovered from the microbiology department and then underwent antifungal sensitivity analysis. RESULTS: The antifungal susceptibilities of 47 fungal isolates from culture-positive fungal endophthalmitis are reported. Included are 14 isolates from yeast and 33 from mold. The mean (+/-standard deviation) minimum inhibitory concetrations (MICs) for amphotericin B (2.6 +/- 3.5 MUg/mL), fluconazole (36.9 +/- 30.7 MUg/mL), and voriconazole (1.9 +/- 2.9 MUg/mL) are reported. Presumed susceptibility to oral fluconazole, intravenous amphotericin B, intravitreal amphotericin B, oral voriconazole, and intravitreal voriconazole occurred in 34.8%-43.5%, 0-8.3%, 68.8%, 69.8%, and 100% of isolates, respectively. CONCLUSIONS: Based on this laboratory study of isolates from exogenous fungal endophthalmitis, intravitreal voriconazole appears to provide the broadest spectrum of antifungal coverage and, as such, may be considered for empiric therapy of endophthalmitis caused by yeast or mold. PMID- 25449003 TI - The child with pediculosis capitis. PMID- 25449002 TI - Moderate-to-Severe Traumatic Brain Injury in Children: Complications and Rehabilitation Strategies. AB - Traumatic brain injury (TBI) is the leading cause of death in children in the United States. Each year 37,200 children sustain a severe TBI, with up to 1.3 million life-years potentially adversely affected. Severe pediatric TBI is associated with significant mortality and morbidity. Of the children who survive their injury, more than 50% experience unfavorable outcomes 6 months after the injury. Although TBI-associated death rates decreased between 1997-2007, disabilities for TBI survivors continue to have both a direct and indirect impact on the economic and human integrity of our society. The degree of disability varies with the severity and mechanism of the injury, but a realm of physical and emotional deficits may be evident for years after the injury occurs. This article describes the pathophysiology of moderate to severe TBI, its associated complications, and opportunities to improve patient outcomes through use of acute management and rehabilitation strategies. To address the many challenges for TBI survivors and their families, including significant financial and emotional burdens, a collaborative effort is necessary to help affected children transition seamlessly from acute care through long-term rehabilitation. PMID- 25449004 TI - The bird beak configuration has no adverse effect in a magnetic resonance functional analysis of thoracic stent grafts after traumatic aortic transection. AB - BACKGROUND: This study used magnetic resonance imaging (MRI) to analyze functional long-term outcome after endovascular repair of blunt aortic injury. METHODS: This prospective study enrolled 27 of 53 patients who were treated between 1999 and 2008. Patients underwent functional multidimensional contrast enhanced MRI with flow analysis or compliance measurements of the aorta, or both. Ten patients were treated with the Medtronic Valiant (Medtronic World Medical, Sunrise, Fla), 14 patients received a Gore TAG (W. L. Gore & Associates, Flagstaff, Ariz), and two received a C (conformable)-TAG (W. L. Gore & Associates) stent graft. For several patients, repetitive measurements over time could be done. Median follow-up was 3.92 +/- 2.7 years. The MRI parameters were: three-dimensional flow: echo time/repetition time = 3.1/5.3 ms, Deltax(pixel density) = 2.5 * 2.5 * 3 mm(3); respiratory navigator, alpha = 15 degrees , venc(encoding velocity) = 200 cm/s along anterior-posterior, right-left, and foot head direction, 40 cardiac phases. Cine: echo time/repetition time = 1.7/3.4 ms, Deltax(pixel density) = 1.2 * 1.2 * 6 mm(3), breathhold, alpha = 60 degrees , 40 cardiac phases. RESULTS: The flow analysis showed flow acceleration at the proximal end of the stent graft, with higher values in patients with a nonoptimal alignment of the stent graft. No differences were found between different devices (median acceleration was 75.99 +/- 37.98 cm/s for Gore and 71.59 +/- 17.22 cm/s for Medtronic). The values were stable during follow-up. In the compliance analysis, the part of the aorta covered with the stent graft showed nearly no expansion, whereas the ascending and descending aorta showed normal expansion. This behavior did not change over the time. At the proximal end of the stent graft, a slight compression could be noted (-0.5 +/- 0.14 mm), except in those patients with a C-TAG device from Gore. CONCLUSIONS: Functional analysis showed no adverse long-term outcome of the bird beak configuration of stent grafts in the aortic arch after endovascular repair after blunt aortic injury. PMID- 25449005 TI - Technique and results of femoral bifurcation endarterectomy by eversion. AB - OBJECTIVE: This study evaluated, in a contemporary prospective series, the safety and efficacy of femoral endarterectomy using the eversion technique and compared our results with results obtained in the literature for the standard endarterectomy with patch closure. METHODS: Between 2010 and 2012, 121 patients (76% male; mean age, 68.7 years; diabetes, 28%; renal insufficiency, 20%) underwent 147 consecutive femoral bifurcation endarterectomies using the eversion technique, associating or not inflow or outflow concomitant revascularization. The indications were claudication in 89 procedures (60%) and critical limb ischemia in 58 (40%). Primary, primary assisted, and secondary patency of the femoral bifurcation, clinical improvement, limb salvage, and survival were assessed using Kaplan-Meier life-table analysis. Factors associated with those primary end-points were evaluated with univariate analysis. RESULTS: The technical success of eversion was of 93.2%. The 30-day mortality was 0%, and the complication rate was 8.2%; of which, half were local and benign. Median follow up was 16 months (range, 1.6-31.2 months). Primary, primary assisted, and secondary patencies were, respectively, 93.2%, 97.2%, and 98.6% at 2 years. Primary, primary assisted, and secondary maintenance of clinical improvement were, respectively, 79.9%, 94.6%, and 98.6% at 2 years. The predictive factors for clinical degradation were clinical stage (Rutherford category 5 or 6, P = .024), platelet aggregation inhibitor treatment other than clopidogrel (P = .005), malnutrition (P = .025), and bad tibial runoff (P = .0016). A reintervention was necessary in 18.3% of limbs at 2 years: 2% involving femoral bifurcation, 6.1% inflow improvement, and 9.5% outflow improvement. The risk factors of reintervention were platelet aggregation inhibitor (other than clopidogrel, P = .049) and cancer (P = .011). Limb preservation at 2 years was 100% in the claudicant population. Limb salvage was 88.6% in the critical limb ischemia population, with a statistically higher rate for patients with malnutrition (P = .029), preoperative platelet count >450 *10(9)/L (P = .0071), platelet aggregation inhibitor treatment other than clopidogrel (P = .022), preoperative deep femoral artery occlusion or stenosis >75% (P = .0064), and poor tibial runoff (P = .00042). CONCLUSIONS: Eversion femoral bifurcation endarterectomy is a safe, efficient, and reproducible technique for the treatment of atherosclerotic femoral lesions. Advantages are notable, especially the lack of need for prosthetic angioplasty, eliminating the risk of patch infection or pseudoaneurysms and permitting direct puncture if endovascular procedures are needed for assisted patency. PMID- 25449006 TI - Staged endovascular repair of thoracoabdominal aortic aneurysms limits incidence and severity of spinal cord ischemia. AB - OBJECTIVE: Neurologic dysfunction remains a persistent complication of extensive aortic repair owing to disruption of the spinal collateral network. We hypothesized that staged repair might mitigate the incidence and severity of this spinal cord ischemia (SCI). METHODS: We conducted a retrospective cohort study of patients undergoing a Crawford type II repair of a thoracoabdominal aortic aneurysm between January 2008 and July 2013. Baseline demographics, incidence of prior aortic surgery, comorbidities, and outcomes were prospectively recorded. Staged repair was defined as intentional completion of the endovascular repair as two temporally separate procedures, referred to as a two-stage repair. Extent of aortic cover was calculated by three-dimensional imaging and reported as the proportion of the aorta covered between the left subclavian artery and the aortic bifurcation. Primary outcome measures were incidence and severity of SCI and mortality. RESULTS: The study included 87 patients, divided into the following subgroups: single-stage repair (n = 32; repair in a single procedure, without prior aortic surgery), two-stage repair (n = 27; repair in two separate procedures, without prior aortic surgery), and unintentionally staged repair (n = 28; those with prior aortic surgery, without an intention to stage). Median time between stages was 5 months (range, 1-60 months). All groups were equivalent in terms of demographics and risk factors; however, the staged group had significantly greater proximal aortic cover (P = .001). The overall rates of SCI in the nonstaged and staged groups were 37.5% (12 of 32) and 11.1% (3 of 27), respectively (P = .03). Furthermore, all neurologic injuries in the staged group were temporary. The 30-day survival in the single-stage, two-stage, and unintentionally staged repairs was 18.8%, 0%, and 10.7%, respectively (P = .52). CONCLUSIONS: Staged repair appears both to protect against SCI and to enhance overall survival in extensive aortic repair. PMID- 25449007 TI - Arthur Hendley Blakemore's life and contributions to vascular surgery. PMID- 25449008 TI - Cost analysis of endovascular versus open repair in the treatment of thoracic aortic aneurysms. AB - OBJECTIVE: For descending thoracic aortic aneurysms (TAAs), it is generally considered that thoracic endovascular aortic repairs (TEVARs) reduce operative morbidity and mortality compared with open surgical repair. However, long-term differences in survival of patients have not been demonstrated, and an increased need for aortic reintervention has been observed. Many assume that TEVAR becomes less cost-effective through time because of higher rates of reintervention and surveillance imaging. This study investigated midterm outcomes and hospital costs of TEVAR compared with open TAA repair. METHODS: This was a retrospective, single institution review of elective TAA repairs between 2005 and 2012. Patient demographics, operative outcomes, reintervention rates, and hospital costs were assessed. The literature was also reviewed to determine commonly observed complication and reintervention rates for TEVAR and open repair. Monte Carlo simulation was used to model and to forecast hospital costs for TEVAR and open TAA repair up to 3 years after intervention. RESULTS: Our cohort consisted of 131 TEVARs and 27 open repairs. TEVAR patients were significantly older (67.2 vs 58.7 years old; P = .02) and trended toward a more severe comorbidity profile. Operative mortality for TEVAR and open repair was 5.3% and 3.7%, respectively (P = 1.0). There was a trend toward more complications in the TEVAR group, although not statistically significant (all P > .05). In-hospital costs were significantly greater in the TEVAR group ($52,008 vs $37,172; P = .001). However, cost modeling by use of reported complication and reintervention rates from the literature overlaid with our cost data produced a higher cost for the open group in-hospital ($55,109 vs $48,006) and at 3 years ($58,426 vs $52,825). Interestingly, TEVAR hospital costs, not reintervention rates, were the most significant driver of cost in the TEVAR group. CONCLUSIONS: Our institutional data showed a trend toward lower mortality and complication rates with open TAA repair, with significantly lower costs within this cohort compared with TEVAR. These findings were likely, at least in part, to be due to the milder comorbidity profile of these patients. In contrast, cost modeling by Monte Carlo simulation demonstrated lower costs with TEVAR compared with open repair at all time points up to 3 years after intervention. Our institutional data show that with appropriate selection of patients, open repair can be performed safely with low complication rates comparable to those of TEVAR. The cost model argues that despite the costs associated with more frequent surveillance imaging and reinterventions, TEVAR remains the more cost-effective option even years after TAA repair. PMID- 25449010 TI - Simulating the dual-peak excitation pattern produced by bipolar stimulation of a cochlear implant: effects on speech intelligibility. AB - Several electrophysiological and psychophysical studies have shown that the spatial excitation pattern produced by bipolar stimulation of a cochlear implant (CI) can have a dual-peak shape. The perceptual effects of this dual-peak shape were investigated using noise-vocoded CI simulations in which synthesis filters were designed to simulate the spread of neural activity produced by various electrode configurations, as predicted by a simple cochlear model. Experiments 1 and 2 tested speech recognition in the presence of a concurrent speech masker for various sets of single-peak and dual-peak synthesis filters and different numbers of channels. Similarly as results obtained in real CIs, both monopolar (MP, single-peak) and bipolar (BP + 1, dual-peak) simulations showed a plateau of performance above 8 channels. The benefit of increasing the number of channels was also lower for BP + 1 than for MP. This shows that channel interactions in BP + 1 become especially deleterious for speech intelligibility when a simulated electrode acts both as an active and as a return electrode for different channels because envelope information from two different analysis bands are being conveyed to the same spectral location. Experiment 3 shows that these channel interactions are even stronger in wide BP configuration (BP + 5), likely because the interfering speech envelopes are less correlated than in narrow BP + 1. Although the exact effects of dual- or multi-peak excitation in real CIs remain to be determined, this series of experiments suggest that multipolar stimulation strategies, such as bipolar or tripolar, should be controlled to avoid neural excitation in the vicinity of the return electrodes. PMID- 25449011 TI - Comparative proteomics analysis of high n-butanol producing metabolically engineered Clostridium tyrobutyricum. AB - The acidogenic Clostridium tyrobutyricum has recently been metabolically engineered to produce n-butanol. The objective of this study was to obtain a comprehensive understanding as to how butanol production was regulated in C. tyrobutyricum to guide the engineering of next-generation strains. We performed a comparative proteomics analysis, covering 78.1% of open reading frames and 95% of core enzymes, using wild type, ACKKO mutant (Deltaack) producing 37.30 g/L of butyrate and ACKKO-adhE2 mutant (Deltaack-adhE2) producing 16.68 g/L of butanol. In ACKKO-adhE2, the expression of most glycolytic enzymes was decreased, the thiolase (thl), acetyl-CoA acetyltransferase (ato), 3-hydroxybutyryl-CoA dehydrogenase (hbd) and crotonase (crt) that convert acetyl-CoA to butyryl-CoA were increased, and the heterologous bifunctional acetaldehyde/alcohol dehydrogenase (adhE2) catalyzing butanol formation was highly expressed. The apparent imbalance of energy and redox was observed due to the downregulation of acids production and the addition of butanol synthesis pathway, which also resulted in increased expression of chaperone proteins and glycerol-3-phosphate dehydrogenase (glpA) and the silence of sporulation transcription factor Spo0A (spo0A) as the cellular responses to butanol production. This study revealed the mechanism of carbon redistribution, and limiting factors and rational metabolic cell and process engineering strategies to achieve high butanol production in C. tyrobutyricum. PMID- 25449009 TI - Auditory implant research at the House Ear Institute 1989-2013. AB - The House Ear Institute (HEI) had a long and distinguished history of auditory implant innovation and development. Early clinical innovations include being one of the first cochlear implant (CI) centers, being the first center to implant a child with a cochlear implant in the US, developing the auditory brainstem implant, and developing multiple surgical approaches and tools for Otology. This paper reviews the second stage of auditory implant research at House - in-depth basic research on perceptual capabilities and signal processing for both cochlear implants and auditory brainstem implants. Psychophysical studies characterized the loudness and temporal perceptual properties of electrical stimulation as a function of electrical parameters. Speech studies with the noise-band vocoder showed that only four bands of tonotopically arrayed information were sufficient for speech recognition, and that most implant users were receiving the equivalent of 8-10 bands of information. The noise-band vocoder allowed us to evaluate the effects of the manipulation of the number of bands, the alignment of the bands with the original tonotopic map, and distortions in the tonotopic mapping, including holes in the neural representation. Stimulation pulse rate was shown to have only a small effect on speech recognition. Electric fields were manipulated in position and sharpness, showing the potential benefit of improved tonotopic selectivity. Auditory training shows great promise for improving speech recognition for all patients. And the Auditory Brainstem Implant was developed and improved and its application expanded to new populations. Overall, the last 25 years of research at HEI helped increase the basic scientific understanding of electrical stimulation of hearing and contributed to the improved outcomes for patients with the CI and ABI devices. This article is part of a Special Issue entitled . PMID- 25449012 TI - Proteomics analysis of E-cadherin knockdown in epithelial breast cancer cells. AB - E-cadherin is the core protein of the epithelial adherens junction. Through its cytoplasmic domain, E-cadherin interacts with several signaling proteins; among them, alpha- and beta-catenins mediate the link of E-cadherin to the actin cytoskeleton. Loss of E-cadherin expression is a crucial step of epithelial mesenchymal transition (EMT) and is involved in cancer invasion and metastatization. In human tumors, down-regulation of E-cadherin is frequently associated with poor prognosis. Despite the critical role of E-cadherin in cancer progression, little is known about proteome alterations linked with its down regulation. To address this point, we investigated proteomics, biophysical and functional changes of epithelial breast cancer cell lines upon shRNA-mediated stable knockdown of E-cadherin expression (shEcad). shEcad cells showed a distinct proteomic signature including altered expression of enzymes and proteins involved in cytoskeletal dynamic and migration. Moreover, these results suggest that, besides their role in mechanical adhesion, loss of E-cadherin expression may contribute to cancer progression by modifying a complex network of pathways that tightly regulate fundamental processes as oxidative stress, immune evasion and cell metabolism. Altogether, these results extend our knowledge on the cellular modifications associated with E-cadherin down-regulation in breast cancer cells. PMID- 25449013 TI - Plasmid DNA nanogels as photoresponsive materials for multifunctional bio applications. AB - This study provides a detailed description on the synthesis and characterization of novel polyamine plasmid DNA nanogels. Ethylene glycol diglycidyl ether was used as cross-linker, in conjugation with polyamines to promote pDNA condensation. The biocompatible nanovectors exhibit a unique swelling behavior in water and salt solutions. These systems are light photodegradable allowing their use in a broad range of biotechnological applications. Different plasmids, pVAX1 LacZ and pcDNA3-FLAG-p53, and anticancer drugs were, thus, efficiently loaded in the nanogels and their controlled release was demonstrated. Furthermore, the dual delivery of pcDNA3-FLAG-p53 gene and anticancer drugs illustrates the possibility of the combination of chemical and gene therapies. This new versatile and easy method of nanohydrogels preparation provides a potential synthetic approach for the design of tunable systems which can display multiple functions, sensitivity to different stimuli and exhibit programmed responses as well. PMID- 25449014 TI - Quantitative analysis of NRF2 pathway reveals key elements of the regulatory circuits underlying antioxidant response and proliferation of ovarian cancer cells. AB - Cells are constantly exposed to Reactive Oxygen Species (ROS) produced both endogenously to meet physiological requirements and from exogenous sources. While endogenous ROS are considered as important signalling molecules, high uncontrollable ROS are detrimental. It is unclear how cells can achieve a balance between maintaining physiological redox homeostasis and robustly activate the antioxidant system to remove exogenous ROS. We have utilised a Systems Biology approach to understand how this robust adaptive system fulfils homeostatic requirements of maintaining steady-state ROS and growth rate, while undergoing rapid readjustment under challenged conditions. Using a panel of human ovarian and normal cell lines, we experimentally quantified and established interrelationships between key elements of ROS homeostasis. The basal levels of NRF2 and KEAP1 were cell line specific and maintained in tight correlation with their growth rates and ROS. Furthermore, perturbation of this balance triggered cell specific kinetics of NRF2 nuclear-cytoplasmic relocalisation and sequestration of exogenous ROS. Our experimental data were employed to parameterise a mathematical model of the NRF2 pathway that elucidated key response mechanisms of redox regulation and showed that the dynamics of NRF2-H2O2 regulation defines a relationship between half-life, total and nuclear NRF2 level and endogenous H2O2 that is cell line specific. PMID- 25449015 TI - Enhanced enzyme stability through site-directed covalent immobilization. AB - Breakthroughs in enzyme immobilization have enabled increased enzyme recovery and reusability, leading to significant decreases in the cost of enzyme use and fueling biocatalysis growth. However, current enzyme immobilization techniques suffer from leaching, enzyme stability, and recoverability and reusability issues. Moreover, these techniques lack the ability to control the orientation of the immobilized enzymes. To determine the impact of orientation on covalently immobilized enzyme activity and stability, we apply our PRECISE (Protein Residue Explicit Covalent Immobilization for Stability Enhancement) system to a model enzyme, T4 lysozyme. The PRECISE system uses non-canonical amino acid incorporation and the Huisgen 1,3-dipolar cycloaddition "click" reaction to enable directed enzyme immobilization at rationally chosen residues throughout an enzyme. Unlike previous site-specific systems, the PRECISE system is a truly covalent immobilization method. Utilizing this system, enzymes immobilized at proximate and distant locations from the active site were tested for activity and stability under denaturing conditions. Our results demonstrate that orientation control of covalently immobilized enzymes can provide activity and stability benefits exceeding that of traditional random covalent immobilization techniques. PRECISE immobilized enzymes were 50 and 73% more active than randomly immobilized enzymes after harsh freeze-thaw and chemical denaturant treatments. PMID- 25449016 TI - Elimination of polyamine N-acetylation and regulatory engineering improved putrescine production by Corynebacterium glutamicum. AB - Corynebacterium glutamicum has been engineered for production of the polyamide monomer putrescine or 1,4-diaminobutane. Here, N-acetylputrescine was shown to be a significant by-product of putrescine production by recombinant putrescine producing C. glutamicum strains. A systematic gene deletion approach of 18 (putative) N-acetyltransferase genes revealed that the cg1722 gene product was responsible for putrescine acetylation. The encoded enzyme was purified and characterized as polyamine N-acetyltransferase. The enzyme accepted acetyl-CoA and propionyl-CoA as donors for acetylation of putrescine and other diamines as acceptors, but showed highest catalytic efficiency with the triamine spermidine and the tetraamine spermine and, hence, was named SnaA. Upon deletion of snaA in the putrescine producing strain PUT21, no acteylputrescine accumulated, but about 41% more putrescine as compared to the parent strain. Moreover, a transcriptome approach identified increased expression of the cgmAR operon encoding a putative permease and a transcriptional TetR-family repressor upon induction of putrescine production in C. glutamicum PUT21. CgmR is known to bind to cgmO upstream of cgmAR and gel mobility shift experiments with purified CgmR revealed that putrescine and other diamines perturbed CgmR-cgmO complex formation, but not migration of free cgmO DNA. Deletion of the repressor gene cgmR resulted in expression changes of a number of genes and increased putrescine production of C. glutamicum PUT21 by 19% as compared to the parent strain. Overexpression of the putative transport gene cgmA increased putrescine production by 24% as compared to the control strain. However, cgmA overexpression in PUT21DeltasnaA did not further improve putrescine production, hence, the beneficial effects of both targets were not synergistic at the highest described yield of 0.21 g g(-1). PMID- 25449017 TI - The intracellular proton gradient enables anaerobic ammonia oxidizing (anammox) bacteria to tolerate NO2 - inhibition. AB - Anammox bacteria are inhibited by nitrite, which is one of their substrates. By utilizing 2,4 dinitrophenol and carbonyl cyanide m-chlorophenyl hydrazone, two uncouplers of respiration, we demonstrate that nitrite tolerance of anammox cells is strongly dependent on their ability to maintain a proton gradient, which may be the driving force for active nitrite transport system. PMID- 25449018 TI - Myostatin knockout using zinc-finger nucleases promotes proliferation of ovine primary satellite cells in vitro. AB - Myostatin (MSTN) has previously been shown to negatively regulate the proliferation and differentiation of skeletal muscle cells. Satellite cells are quiescent muscle stem cells that promote muscle growth and repair. Because the mechanism of MSTN in the biology of satellite cells is not well understood, this study was conducted to generate MSTN mono-allelic knockout satellite cells using the zinc-finger nuclease mRNA (MSTN-KO ZFN mRNA) and also to investigate the effect of this disruption on the proliferation and differentiation of sheep primary satellite cells (PSCs). Nineteen biallelic and four mono-allelic knockout cell clones were obtained after sequence analysis. The homologous mono-allelic knockout cells with 5-bp deletion were used to further evaluations. The results demonstrated that mono-allelic knockout of MSTN gene leads to translation inhibition. Real-time quantitative PCR results indicated that knockout of MSTN contributed to an increase in CDK2 and follistatin and a decrease in p21 at the transcript level in proliferation conditions. Moreover, MSTN knockout significantly increased the proliferation of mutant clones (P < 0.01). Consistent with the observed increase in CDK2 and decrease in p21 in cells lacking MSTN, cell cycle analysis showed that MSTN negatively regulated the G1 to S progression. In addition, knockout of myostatin resulted in a remarkable increase in MyoD and MyoG expression under differentiating conditions but had no effect on Myf5 expression. These results expanded our understanding of the regulation mechanism of MSTN. Furthermore, the MSTN-KO ZFN mRNA system in PSCs could be used to generate transgenic sheep in the future. PMID- 25449020 TI - High-performance and environmentally stable planar heterojunction perovskite solar cells based on a solution-processed copper-doped nickel oxide hole transporting layer. AB - An effective approach to significantly increase the electrical conductivity of a NiOx hole-transporting layer (HTL) to achieve high-efficiency planar heterojunction perovskite solar cells is demonstrated. Perovskite solar cells based on using Cu-doped NiOx HTL show a remarkably improved power conversion efficiency up to 15.40% due to the improved electrical conductivity and enhanced perovskite film quality. General applicability of Cu-doped NiOx to larger bandgap perovskites is also demonstrated in this study. PMID- 25449019 TI - Type II thioesterase improves heterologous biosynthesis of valinomycin in Escherichia coli. AB - Heterologous expression of secondary metabolite biosynthesis pathways in a surrogate host, e.g. Escherichia coli, has emerged in recent years as an effective way to produce complex natural products. The nonribosomal peptide (NRP) antibiotic valinomycin has been recombinantly produced in E. coli through reconstitution of its biosynthetic pathway from the native producer Streptomyces tsusimaensis. In this study, a discrete protein type II thioesterase (TEII) encoded in the valinomycin gene cluster was coexpressed in the valinomycin producing E. coli strain. Valinomycin titers were significantly improved from 0.5 (without TEII coexpression) to 3.3 mg L(-1), which demonstrates the reconstitutive function of TEII involved in NRP biosynthesis. Based on a flask scale fed-batch cultivation system, repeated feeding of the glucose polymer during the cultivation further increased cell density and valinomycin titer up to 55 (OD600) and 13 mg L(-1), respectively. This indicates scalable high cell density cultivation in a bioreactor for overproduction of valinomycin will be a potential and feasible approach. In this work we present an in vivo example to show that TEII plays a positive role in heterologous valinomycin production. PMID- 25449021 TI - Mark Warren Babyatsky, MD (June 29, 1959-August 25, 2014). PMID- 25449022 TI - Michael Field, MD (1933-2014). PMID- 25449024 TI - FDA perspective on sofosbuvir therapy for patients with chronic hepatitis C virus genotype 1 infection who did not respond to treatment with pegylated interferon and ribavirin. PMID- 25449025 TI - Building bridges and providing transparency to the hepatitis C virus drug approval process. PMID- 25449026 TI - Improving quality of health care for patients with cirrhosis. PMID- 25449028 TI - Reply: To PMID 24704526. PMID- 25449027 TI - Reply: To PMID 24786894. PMID- 25449030 TI - Dynamic changes in maternal decidual leukocyte populations from first to second trimester gestation. AB - INTRODUCTION: Decidual leukocytes are critical to the development of the fetomaternal interface, regulating tolerance to the semi-allogeneic fetus and vascular transformation of the uterine spiral arteries. Despite the continuation of these processes beyond the first trimester of pregnancy, the second trimester has largely been unstudied, with investigation focusing on early gestation and term tissues. We sought to characterize changes in decidual leukocyte populations from first to second trimester. METHODS: Multicolor flow cytometry was performed on isolated decidual leukocytes from elective terminations of pregnancy between 6 and 20 weeks of gestation for study of first (6-12 weeks) and second trimesters (13-20 weeks). Specific subpopulations were identified by comparison to isotype and fluorescent-minus-one (FMO) controls. RESULTS: Decidual natural killer cells (CD56(+)CD16(-)CD3(-)) did not change in number, although a population of dNK with decreased CD56 brightness was observed in second trimester decidua. CD14(+)HLA-DR(+) macrophage numbers declined from first to second trimester (p = 0.031), yet a CD163(+)CD206(+) subset designating alternatively activated M2-like macrophages increased during the same period (p = 0.015). Intermediate CD205(+) dendritic cells demonstrated significant decline (p = 0.022), but immature CD209(+) and mature CD83(+) dendritic cells did not differ between trimesters. Total CD3(+) and CD3(+)CD4(+) T lymphocytes increased (p = 0.0079, p = 0.0028); CD3(+)CD8(+) T cells trended towards increase but did not differ significantly. CONCLUSION: Several changes in leukocyte subsets are observed in the second trimester that promote a tolerogenic and angiogenic decidual microenvironment through mid-gestation. PMID- 25449029 TI - RNA-seq analysis of the rat placentation site reveals maternal obesity-associated changes in placental and offspring thyroid hormone signaling. AB - INTRODUCTION: In animal models, maternal obesity (OB) leads to augmented risk of offspring OB. While placental function is influenced by maternal habitus, the effect of maternal obesity on the interacting zones of the placenta [the labyrinth (LZ), junctional (JZ) and metrial gland (MG)] remains unknown. METHODS: Using a rat maternal obesity model, we conducted transcriptomic profiling of the utero-placental compartments and fetal liver (FL) at dpc 18.5, in conjunction with analyses of mRNA expression of key thyroid hormone (TH) signaling genes in the placenta, fetus and weanling offspring. RESULTS AND DISCUSSION: Gene expression analysis of placenta and offspring revealed that each utero-placental compartment responds distinctly to maternal OB with changes in inflammatory signaling, lipid metabolism and hormone stimulus being the predominant effects. OB-induced alterations in 17 genes were confirmed by qPCR, including reductions in thyrotropin-releasing hormone (Trh) in JZ. We further characterized mRNA and protein expression of TH signaling regulators including deiodinases (Dio), TH receptors (Tr), and downstream targets (uncoupling proteins (Ucp)). A concerted down-regulation of multiple facets of thyroid hormone signaling in the JZ and FL was observed. JZ expression of thyroid hormone signaling components Trh, Dio2, Tralpha, and Ucp2 were negatively associated with maternal leptin. mRNA expression of TRH, TRbeta and UCP1 were also decreased in term placenta from OB women. Finally, our studies identified persistent impairments in expression of TH related genes in tissues from offspring of obese dams. CONCLUSIONS: The role of lower placental thyroid expression is worthy of further study as a possible pathway that leads to low energy metabolism and obesity in animals born to obese mothers. PMID- 25449031 TI - Placental share and hemoglobin level in relation to birth weight in twin anemia polycythemia sequence. AB - INTRODUCTION: Twin anemia-polycythemia sequence (TAPS) is a newly described form of chronic twin transfusion. Previous observational studies noted a discordance between birth weight and individual placental share in TAPS. The purpose of this study was to investigate if fetal growth in monochorionic (MC) twins with TAPS is determined by placental share or by the net inter-twin blood transfusion. METHODS: All consecutive MC twin placentas of live-born twin pairs with and without TAPS examined at our center between June 2002 and February 2014 were included in this study. Hemoglobin (Hb) levels and individual placental share were evaluated at birth and correlated with birth weight share. We excluded MC twin pregnancies with twin-twin transfusion syndrome. RESULTS: A total of 270 MC twin pregnancies (TAPS group, n = 20; control group without TAPS, n = 250) were included in this study. Donors with TAPS had a lower birth weight than recipients in 90% (18/20) of cases, but a larger placental share in 65% (13/20) of cases. In the TAPS group, birth weight share was positively correlated with Hb share at birth (P < 0.01) but not with placental share (P = 0.54). In the control group without TAPS, birth weight share was strongly correlated with placental share (P < 0.01) but not with Hb share (P = 0.14). DISCUSSION: A relatively larger placental share may enable the survival of the anemic twin in TAPS. CONCLUSION: In contrast with uncomplicated MC twins, fetal growth in MC twins with TAPS is determined primarily by the net inter-twin blood transfusion instead of placental share. PMID- 25449032 TI - Differential effects of thioridazine enantiomers on action potential duration in rabbit papillary muscle. AB - The antipsychotic drug thioridazine has potential for treatment of multidrug resistant microbes including tuberculosis but also causes cardiotoxic QT interval prolongation. Both thioridazine enantiomers have potent antimicrobial effects, but the neuroleptic effect primarily resides with (+)-thioridazine. In this study we for the first time investigate the cardiotoxicity of the isolated thioridazine enantiomers and show their effects on ventricular repolarization. The effects of (+)-thioridazine, (-)-thioridazine, and racemate on the rabbit ventricular action potential duration (APD) were investigated in a randomized controlled blinded experiment. Action potentials were measured in papillary muscles isolated from 21 female rabbits, and the drug effect on 90% APD in comparison with control (DeltaDelta-APD90) was evaluated. Increasing concentrations of (+)-thioridazine and the racemate caused significant dose-dependent DeltaDelta-APD90 prolongation, while (-)-thioridazine did not. At 0.5 and 2Hz pacing, (+)-thioridazine caused 19.5% and 20.1% DeltaDelta-APD90 prolongation, the racemate caused 8.0% and 12.9%, and (-)-thioridazine caused 1.5% and 1.1%. The effect of (-)-thioridazine on APD90 was significantly less than that of the other drugs at both pacing rates (P<0.01 in all cases), and there was no significant difference between (-) thioridazine and control. The results of this study indicate that the APD prolonging effect of thioridazine is primarily due to the (+)-thioridazine enantiomer. If these results are valid in humans, (-)-thioridazine may be a safer drug for treatment of multidrug-resistant tuberculosis and other microbes. PMID- 25449033 TI - The organic anion transport inhibitor probenecid increases brain concentrations of the NKCC1 inhibitor bumetanide. AB - Bumetanide is increasingly being used for experimental treatment of brain disorders, including neonatal seizures, epilepsy, and autism, because the neuronal Na-K-Cl cotransporter NKCC1, which is inhibited by bumetanide, is implicated in the pathophysiology of such disorders. However, use of bumetanide for treatment of brain disorders is associated with problems, including poor brain penetration and systemic adverse effects such as diuresis, hypokalemic alkalosis, and hearing loss. The poor brain penetration is thought to be related to its high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, but more recently brain efflux transporters have been involved, too. Multidrug resistance protein 4 (MRP4), organic anion transporter 3 (OAT3) and organic anion transporting polypeptide 2 (OATP2) were suggested to mediate bumetanide brain efflux, but direct proof is lacking. Because MRP4, OAT3, and OATP2 can be inhibited by probenecid, we studied whether this drug alters brain levels of bumetanide in mice. Probenecid (50 mg/kg) significantly increased brain levels of bumetanide up to 3-fold; however, it also increased its plasma levels, so that the brain:plasma ratio (~0.015-0.02) was not altered. Probenecid markedly increased the plasma half-life of bumetanide, indicating reduced elimination of bumetanide most likely by inhibition of OAT-mediated transport of bumetanide in the kidney. However, the diuretic activity of bumetanide was not reduced by probenecid. In conclusion, our study demonstrates that the clinically available drug probenecid can be used to increase brain levels of bumetanide and decrease its elimination, which could have therapeutic potential in the treatment of brain disorders. PMID- 25449035 TI - Neuroprotective potential of sesamol and its loaded solid lipid nanoparticles in ICV-STZ-induced cognitive deficits: behavioral and biochemical evidence. AB - Neuroinflammation is a prominent feature of Alzheimer disease (AD) and other chronic neurodegenerative disorders. Intracerebroventricular (ICV) streptozotocin (STZ) induced-cognitive impairment has been widely used as an experimental paradigm of Alzheimer's disease. Sesamol is a potent inhibitor of cytokine production as well as an antioxidant. The present study was designed to evaluate the effectiveness of sesamol in ICV-STZ-induced cognitive deficits in rats by incorporating it into solid lipid nanoparticles (SLNs). ICV-STZ administration produced significant cognitive deficits as assessed by both Morris water maze and elevated plus maze task which is accompanied by significantly enhanced nitrodative stress, altered acetylcholinesterase in rat brain along with significantly increased serum TNF-alpha levels. Chronic treatment with sesamol and sesamol loaded SLNs dose dependently restored cognitive deficits in ICV-STZ rats along with mitigation of nitrodative stress and cytokine release. Effectiveness of SLNs to deliver sesamol to the brain was shown by a significantly better alleviation of the oxidative stress parameters. Our findings demonstrate that loading of sesamol in SLNs is an effective strategy to mitigate ICV-STZ-induced neuronal dysfunction and memory deficits. PMID- 25449034 TI - Inhibitory effects of cortisone and hydrocortisone on human Kv1.5 channel currents. AB - Glucocorticoids are the primary hormones that respond to stress and protect organisms from dangerous situations. The glucocorticoids hydrocortisone and its dormant form, cortisone, affect the cardiovascular system with changes such as increased blood pressure and cardioprotection. Kv1.5 channels play a critical role in the maintenance of cellular membrane potential and are widely expressed in pancreatic beta-cells, neurons, myocytes, and smooth muscle cells of the pulmonary vasculature. We examined the electrophysiological effects of both cortisone and hydrocortisone on human Kv1.5 channels expressed in Xenopus oocytes using a two-microelectrode voltage clamp technique. Both cortisone and hydrocortisone rapidly and irreversibly suppressed the amplitude of Kv1.5 channel current with IC50 values of 50.2+/-4.2MUM and 33.4+/-3.2MUM, respectively, while sustained the current trace shape of Kv1.5 current. The inhibitory effect of cortisone on Kv1.5 decreased progressively from -10mV to +30mV, while hydrocortisone's inhibition of the channel did not change across the same voltage range. Both cortisone and hydrocortisone blocked Kv1.5 channel currents in a non use-dependent manner and neither altered the channel's steady-state activation or inactivation curves. These results show that cortisone and hydrocortisone inhibited Kv1.5 channel currents differently, and that Kv1.5 channels were more sensitive to hydrocortisone than to cortisone. PMID- 25449036 TI - The xanthine oxidase inhibitor Febuxostat reduces tissue uric acid content and inhibits injury-induced inflammation in the liver and lung. AB - Necrotic cell death in vivo induces a robust neutrophilic inflammatory response and the resulting inflammation can cause further tissue damage and disease. Dying cells induce this inflammation by releasing pro-inflammatory intracellular components, one of which is uric acid. Cells contain high levels of intracellular uric acid, which is produced when purines are oxidized by the enzyme xanthine oxidase. Here we test whether a non-nucleoside xanthine oxidase inhibitor, Febuxostat (FBX), can reduce intracellular uric acid levels and inhibit cell death-induced inflammation in two different murine tissue injury models; acid induced acute lung injury and acetaminophen liver injury. Infiltration of inflammatory cells induced by acid injection into lungs or peritoneal administration of acetaminophen was evaluated by quantification with flow cytometry and tissue myeloperoxidase activity in the presence or absence of FBX treatment. Uric acid levels in serum and tissue were measured before giving the stimuli and during inflammation. The impact of FBX treatment on the peritoneal inflammation caused by the microbial stimulus, zymosan, was also analyzed to see whether FBX had a broad anti-inflammatory effect. We found that FBX reduced uric acid levels in acid-injured lung tissue and inhibited acute pulmonary inflammation triggered by lung injury. Similarly, FBX reduced uric acid levels in the liver and inhibited inflammation in response to acetaminophen-induced hepatic injury. In contrast, FBX did not reduce inflammation to zymosan, and therefore is not acting as a general anti-inflammatory agent. These results point to the potential of using agents like FBX to treat cell death-induced inflammation. PMID- 25449037 TI - Evaluation of antiglypican-3 therapy as a promising target for amelioration of hepatic tissue damage in hepatocellular carcinoma. AB - In Egypt, hepatocellular carcinoma (HCC) was predicted to continue to rise over the next few decades causing a national problem. Meanwhile, glypican-3 (GPC3), a highly expressed glypican, has emerged as a potential target for HCC immunotherapy. Therefore, we aimed to identify the impact of blocking GPC3 on liver damage in HCC as well as a possible mechanism. Fifty four HCC patients, 20 cirrhotic patients and 10 healthy subjects were recruited. Serum levels of GPC3, sulfatase-2 (SULF-2), heparan sulfate proteoglycan (HSPG), insulin-like growth factor-II (IGF-II) were measured by ELISA. In parallel, HCC was induced in 40 male Sprague-Dawley rats in presence/absence of antiGPC-3. Liver impairment was detected by investigating liver sections stained with hematoxylin/eosin and serum alpha-fetoprotein (AFP). Liver homogenates of GPC3, SULF-2, and HSPG were measured by ELISA. Gene expression of caspase-3 and IGF-II were assayed by RT PCR. HCC patients showed significant elevated serum levels of GPC3, IGF-II and SULF-2 accompanied by decreased HSPG. However, treatment of HCC rats with antiGPC 3 significantly reduced serum AFP and showed nearly normal hepatocytes. In addition, antiGPC-3 significantly reduced elevated liver homogenates protein levels of GPC3 and SULF-2 and gene expression of IGF-II and caspase-3. antiGPC-3 restored the reduced hepatic HSPG. antiGPC-3 showed anti-tumor activity as well as hepatoprotective effects. antiGPC-3-chemoprotective effect can be explained by forced reduction of IGF-II expression, restoration of HSPGs, deactivation of SULF 2 and reduction of gene expression of caspase-3. Targeting GPC3 is a promising therapeutic approach for HCC. PMID- 25449038 TI - Hinokitiol, a tropolone derivative, inhibits mouse melanoma (B16-F10) cell migration and in vivo tumor formation. AB - Invasion and metastasis are the major causes of treatment failure in patients with cancer. Hinokitiol, a natural bioactive compound found in Chamacyparis taiwanensis, has been used in hair tonics, cosmetics, and food as an antimicrobial agent. In this study, we investigated the effects and possible mechanisms of action of hinokitiol on migration by the metastatic melanoma cell line, B16-F10, in which matrix metalloproteinase-1 (MMP-1) is found to be highly- expressed. Treatment with hinokitiol revealed a concentration-dependent inhibition of migration of B16-F10 melanoma cells. Hinokitiol appeared to achieve this effect by reducing the expression of MMP-1 and by suppressing the phosphorylation of mitogen- activated protein kinase (MAPK) signaling molecules such as extracellular signal-regulated kinase (ERK) 1/2, p38 MAPK and c-Jun N terminal kinases (JNK). On the other hand, hinokitiol treatment reversed IkappaB alpha degradation and inhibited the phosphorylation of p65 nuclear factor kappa B (NF-kappaB) and cJun in B16-F10 cells. In addition, hinokitiol suppressed the translocation of p65 NF-kappaB from the cytosol to the nucleus, suggesting reduced NF-kappaB activation. Consistent with these in vitro findings, our in vivo study demonstrated that hinokitiol treatment significantly reduced the total number of mouse lung metastatic nodules and improved histological alterations in B16-F10 injected C57BL/6 mice. These findings suggest that treatment of B16-F10 cells with hinokitiol significantly inhibits metastasis, possibly by blocking MMP 1 activation, MAPK signaling pathways and inhibition of the transcription factors, NF-kappaB and c-Jun, involved in cancer cell migration. These results may accelerate the development of novel therapeutic agents for the treatment of malignant cancers. PMID- 25449039 TI - TRPV1 and TRPV4 channels: potential therapeutic targets for ischemic conditioning induced cardioprotection. AB - Besides the involvement of TRPV channels in exhibiting various cellular functions including thermoregulation, pain perception, maintenance of bone homeostasis and gastrointestinal function; certain studies have also implicated the putative role of these channels in mediating ischemic conditioning-induced cardioprotection. The potential role of TRPV1 channels in different forms of ischemic conditioning (pre/post/remote)-induced cardioprotection has been described by employing TRPV1 knockout mice and various pharmacological modulators. The cardioprotective effects of TRPV1 activation during ischemic conditioning have been linked with increased CGRP, substance P release and augmented ALOX expression. Furthermore, the role of TRPV4 channels in mediating preconditioning-induced preservation of vascular function in terms restoring NO- and further improving EDH(F)-mediated endothelial relaxation has been described. The present review discusses the putative role of TRPV1 and TRPV4 channels in mediating different forms of conditioning (pre/post/remote)-induced cardioprotection along with the possible mechanisms. Future perspectives have also been described to fully understand the cascade of signaling and contribution of TRPV channel activation during myocardial ischemic conditioning. PMID- 25449041 TI - Hypoxia/ischemia a key player in early post stroke seizures: modulation by opioidergic and nitrergic systems. AB - Stroke is a leading cause of death, disability, and socioeconomic loss worldwide. All attempts at pharmacological reduction of the complications of stroke (e.g. post-stroke seizure, and brain's vulnerability to hypoxic/ischemic injury) have failed. Endogenous opioids and nitric oxide (NO) overproduction has been documented in brain hypoxia/ischemia (H/I), which can exert pro-convulsive effects. In this study, we aimed to examine the possible involvement of opioidergic and nitrergic pathways in the pathogenesis of post-stroke seizure. H/I was induced by right common carotid ligation and sham-operated mice served as controls. We demonstrated that right common carotid ligation decreases the threshold for clonic seizures induced by pentylenetetrazole (PTZ), a GABA antagonist. Furthermore, pro-convulsive effect of H/I following right common carotid ligation was blocked by naltrexone (NTX) (3mg/kg), NG-Nitro-l-arginine methyl ester (l-NAME) (10mg/kg), and aminoguanidine (AG) (100mg/kg) administration (P<0.001). Interestingly, co-administration of non-effective doses of NTX and l-NAME (1 and 0.5mg/kg, respectively) reverses epileptogenesis of H/I (P<0.001). In the same way, co-administration of non-effective doses of NTX and AG (1 and 5mg/kg, respectively), reverses epileptogenesis of H/I (P<0.001). Indeed, the histological studies performed on mice exposed to H/I confirmed our previous data. These findings suggest hyper-susceptibility to PTZ induced seizure following H/I is mediated by interaction of opioidergic, and iNOS/NO pathways. Therefore, our results identify new pharmacological targets and provide the rationale for a novel strategy to promote recovery after stroke and possibly other brain injuries. PMID- 25449040 TI - Polydatin prevents hypertrophy in phenylephrine induced neonatal mouse cardiomyocytes and pressure-overload mouse models. AB - Recent evidence suggests that polydatin (PD), a resveratrol glucoside, may have beneficial actions on the cardiac hypertrophy. Therefore, the current study focused on the underlying mechanism of the PD anti-hypertrophic effect in cultured cardiomyocytes and in progression from cardiac hypertrophy to heart failure in vivo. Experiments were performed on cultured neonatal rat, ventricular myocytes as well as adult mice subjected to transverse aortic constriction (TAC). Treatment of cardiomyocytes with phenylephrine for three days produced a marked hypertrophic effect as evidenced by significantly increased cell surface area and atrial natriuretic peptide (ANP) protein expression. These effects were attenuated by PD in a concentration-dependent manner with a complete inhibition of hypertrophy at the concentration of 50 uM. Phenylephrine increased ROCK activity, as well as intracellular reactive oxygen species production and lipid peroxidation. The oxidizing agent DTDP similarly increased Rho kinase (ROCK) activity and induced hypertrophic remodeling. PD treatment inhibited phenylephrine-induced oxidative stress and consequently suppressed ROCK activation in cardiomyocytes. Hypertrophic remodeling and heart failure were demonstrated in mice subjected to 13 weeks of TAC. Upregulation of ROCK signaling pathway was also evident in TAC mice. PD treatment significantly attenuated the increased ROCK activity, associated with a markedly reduced hypertrophic response and improved cardiac function. Our results demonstrated a robust anti hypertrophic remodeling effect of polydatin, which is mediated by inhibition of reactive oxygen species dependent ROCK activation. PMID- 25449042 TI - The supplement-drug interaction of quercetin with tamsulosin on vasorelaxation. AB - The food supplement quercetin is used as self-medication for prostate disorders and is known to induce vasorelaxation. The drug tamsulosin is used in the treatment of benign prostatic hyperplasia. A major side effect of tamsulosin is orthostatic hypotension, mediated by vasorelaxation resulting from alpha1 adrenoceptor blockade. The overlapping profile prompted us to investigate the pharmacodynamic interaction of quercetin with tamsulosin. Since quercetin is extensively metabolized in the intestines and the liver, the metabolites quercetin-3-glucuronide and 4'O-methyl-quercetin were also examined. Vasorelaxation induced by the compounds was tested in rat mesenteric arteries (average diameter: 360+/-MUm) constricted by the alpha1-adrenoceptor agonist phenylephrine. Tamsulosin (0.1nM) decreased phenylephrine sensitivity 17-fold (n=10). Quercetin (5, 10 and 20uM) also caused a decrease (2-, 4- and 6-fold respectively) of phenylephrine sensitivity, while 10uM of quercetin-3-glucuronide and 4'O-methyl-quercetin decreased this sensitivity (1.5- and 2-fold) only slightly (n=6). The combination of tamsulosin with quercetin or quercetin metabolites proved to be far more potent than the compounds in isolation. The combination of quercetin, quercetin-3-glucuronide or 4'O-methyl-quercetin with tamsulosin decreased the phenylephrine sensitivity approximately 200-, 35- and 150-fold (n=6). The strong pharmacodynamic interaction between the food supplement quercetin and tamsulosin underlines the potential of the impact of supplement-drug interactions that warrant more research. PMID- 25449043 TI - Genetic evidence for hybridisation between Haemonchus contortus and Haemonchus placei in natural field populations and its implications for interspecies transmission of anthelmintic resistance. AB - Genetic hybridisation between parasitic nematode species has potentially important consequences. It could lead to the introgression of genes between species including those involved in pathogenicity, host specificity, transmission and drug resistance. It could also complicate diagnosis and control. However, there are few compelling examples of its occurrence in parasites in the field. Haemonchus contortus and Haemonchus placei are two closely related parasitic nematode species that predominantly infect small ruminants and cattle, respectively. They are capable of experimental hybridisation when adult worms of each species are transplanted into the same individual host. Given that co infection occurs in both small ruminants and cattle, there is potential for hybridisation in the field. However, this has not been definitively demonstrated and its extent is unknown. We investigated the occurrence of co-infection and interspecies hybridisation in H. contortus and H. placei in field populations from small ruminants from Pakistan and southern India using a number of independent genetic markers. Haemonchus contortus and H. placei co-infections were common in Pakistan but not in southern India where H. placei appeared to be absent in small ruminant hosts. In the former region, a number of worms were identified that were heterozygous for fixed, species-specific rDNA internal transcribed spacer 2 (ITS-2) single nucleotide polymorphisms. Genotyping of these ITS-2 heterozygotes with an additional four nuclear markers conclusively demonstrated them to be F1 interspecies hybrids. Mitochondrial NADH dehydrogenase subunit 4 haplotype analysis demonstrated that four of the hybrid worms had a H. placei maternal parent and one had a H. contortus maternal parent showing that hybridisation could occur in either direction. Interestingly, one of these hybrids contained an H. contortus isotype-1 beta-tubulin benzimidazole resistance allele, suggesting there is a potential for interspecies introgression of drug resistance loci. We believe this is the first definitive genetic evidence of hybridisation between H. contortus and H. placei in the field and represents the most comprehensive genetic evidence of F1 hybrids between any human or livestock parasitic nematode species to date. Further, it suggests that interspecies transmission of anthelmintic resistance mutations warrants further investigation. PMID- 25449044 TI - The onset of nonmotor symptoms in Parkinson's disease (the ONSET PD study). AB - Nonmotor symptoms (NMS) in Parkinson's disease (PD) can precede onset of motor symptoms. Relationship between premotor symptoms onset and motor features is limited. Our aim is to describe the presence and perceived onset of NMS in PD as well as their possible association with motor phenotype. Presence and onset of NMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls from 11 Spanish and Austrian centers. Seventeen of thirty-one NMS were more common in patients than controls (P < 0.05). They were usually mild and frequently reported to occur at different time-spans before motor symptoms. Anhedonia, apathy, memory complaints, and inattention occurred more frequently during the 2-year premotor period. Those reported more frequently in the 2- to 10-year premotor period were smell loss, mood disturbances, taste loss, excessive sweating, fatigue, and pain. Constipation, dream-enacting behavior, excessive daytime sleepiness, and postprandial fullness were frequently perceived more than 10 years before motor symptoms. No correlation between NMS burden and motor severity, age, or gender was observed. NMS associated in four clusters: rapid eye movement sleep behavior disorder symptoms-constipation, cognition-related, mood-related, and sensory clusters. No cluster was associated with a specific motor phenotype or severity. NMS are common in early unmedicated PD and frequently reported to occur in the premotor period. They are generally mild, but a patient subgroup showed high NMS burden mainly resulting from cognition-related symptoms. Certain NMS when present at the time of assessment or in the premotor stage, either alone or in combination, allowed discriminating PD from controls. PMID- 25449045 TI - Stem cell tourism--a web-based analysis of clinical services available to international travellers. AB - BACKGROUND: Stem cell therapies are advertised through online resources which describe a range of treatments with diverse clinical indications. Stem cell tourists may not be aware of the information they should seek when consulting these clinics, or of the potential risks involved. The aim of this study was to characterise the therapies offered by online stem cell clinics. METHODS: A web based search utilising five search terms was employed. The first twenty pages of each search result were screened against 340 variables. RESULTS: 224 out of 1091 websites advertised stem cell clinics. 68 eligible sites covering 21 countries were evaluated. The top five clinical indications for stem cell therapy were multiple sclerosis, anti-ageing, Parkinson's disease, stroke and spinal cord injury. Adult, autologous stem cells were the most commonly utilised stem cell, and these were frequently sourced from bone marrow and adipose tissue and administered intravenously. Thirty-four per cent of sites mentioned the number of patients treated while one quarter of clinics provided outcome data. Twenty-nine per cent of clinics had an internationally recognised accreditation. Fifteen per cent of clinics stated that their therapies posed no risk. Eighty-eight per cent of clinics claimed treatment effectiveness, with 16% describing their curative potential. Over 40% of sites did not specify the number or duration of treatments. Fifty-three per cent of clinics requested access to patients' medical records, and 12% recommended patients discuss the proposed therapy with their doctor. No clinic recommended that travellers consult a travel medicine specialist or receive vaccinations prior to their intended travel. One quarter of sites discussed contraindications to treatment, with 41% of sites detailing follow up patient care. CONCLUSIONS: There is potential for stem cell tourists to receive misleading or deficient information from online stem cell clinics. Both the stem cell tourist and travel medicine practitioner should be educated on the potential risks associated with stem cell clinical services advertised online. PMID- 25449046 TI - Malaria control in military forces. PMID- 25449047 TI - Chronic thromboembolic pulmonary hypertension is not associated with iron overload. AB - BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized as the incomplete resolution of emboli after pulmonary embolism (PE) and the subsequent fibrotic organization and remodeling of pulmonary vascular bed. It has been reported that abnormal fibrin probably contributes to the incomplete resolution of emboli. And there is evidence that free iron could convert fibrinogen into fibrin which is remarkably resistant to lysis. Thus, we hypothesized that persistent iron overload might participate in the development of CTEPH. MATERIALS AND METHODS: A case-control study was conducted. Forty-five CTEPH patients were enrolled as cases, and 36 age and sex frequency-matched chronic PE patients without pulmonary hypertension were selected as controls. Levels of free iron, soluble transferrin receptor (sTfR), ferritin, sTfR/ferritin ratio, hepcidin-25, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and malondialdehyde (MDA) were compared between the two groups. Logistic regression analysis was carried out to estimate odds ratios. RESULTS: There was no difference of the levels of free iron, hepcidin-25, sTfR, ferritin, sTfR/ferritin ratio, TNF-alpha, and MDA between CTEPH patients and the controls. Levels of sTfR and ferritin in both groups were within the normal limits. Levels of IL-6 in CTEPH patients were significantly higher than that in the controls. A negative correlation was observed between hepcidin-25 and sTfR (Spearman's r= 0.438, P<.001), and a positive correlation was observed between hepcidin-25 and ferritin (Spearman's r=0.503, P<.001). In the univariate logistic regression model, there was no association observed between CTEPH and free iron, hepcidin 25, sTfR, ferritin, sTfR/ferritin ratio, TNF-alpha, IL-6, and MDA. CONCLUSIONS: CTEPH has no association with iron overload. The iron status evaluated by sTfR and ferritin is within the normal limits in this CTEPH population. PMID- 25449048 TI - Older Adult Hill Transition Strategies are Determined by Task Demands and Cautious Gait Patterns. AB - Falls are the leading cause of injury for all age groups. However, adults over 65 are at a higher risk, with one-third falling each year. Transitioning between level and hill surfaces poses a greater fall risk than walking on either surface alone. Previous studies found that young adults adopted a cautious gait pattern to mitigate this risk. As older adults typically employ a cautious pattern during level walking, we investigated how they modify their gait pattern to safely transition between surfaces. Twenty adults over the age of 65 transitioned onto and off of a 15 degrees ramp while we recorded kinematics and muscle activity. During the level-to-downhill and uphill-to-level transitions, participants took slower, shorter steps indicative of an exaggerated cautious gait pattern. The older adults also exhibited greater muscle activity during the transitions, which may be due to muscle weakness requiring compensatory strategies to meet the greater demands of the task. However, the slower, shorter steps when transitioning from uphill to level suggest that these compensations may not always be adequate. Thus, it is important to consider the relationship between physical abilities and task demands in evaluating walking terrains that may be excessively difficult or dangerous for older adults. PMID- 25449049 TI - Arthritogenic alphaviruses: new insights into arthritis and bone pathology. AB - Arthritogenic alphaviral infection begins as a febrile illness and often progresses to joint pain and rheumatic symptoms that are described as polyarthritis. Alphaviral arthritis and classical arthritides share many similar cellular and immune mediators involved in their pathogenesis. Recent in vitro and in vivo evidence suggests that bone loss resulting from increased expression of bone resorption mediators may accompany alphaviral infection. In addition, several longitudinal studies have reported more severe and delayed recovery of alphaviral disease in patients with pre-existing arthritic conditions. This review aims to provide insights into alphavirus-induced bone loss and focuses on aspects of disease exacerbation in patients with underlying arthritis and on possible therapeutic targets. PMID- 25449051 TI - Changing academic culture to improve undergraduate STEM education. AB - Improving undergraduate science, technology, engineering, and math (STEM) education requires faculty with the skills, resources, and time to create active learning environments that foster student engagement. Current faculty hiring, promotion, and tenure practices at many universities do not measure, reward, nor encourage faculty pursuit of these skills. A cultural change is needed to foster improvement. PMID- 25449050 TI - Bridging the gap between viable but non-culturable and antibiotic persistent bacteria. AB - Microbial dormancy is a widespread phenomenon employed by bacteria to evade environmental threats including antibiotics. This intrinsic mechanism of antibiotic tolerance has drawn special attention to the role of dormancy in human disease, particularly in regards to recurrent infections. Two dormancy states, the viable but non-culturable state and bacterial persistence, both produce antibiotic-tolerant populations capable of withstanding prolonged lethal treatment. Currently described as two distinct forms of dormancy, they are rarely discussed in the same context. We argue here that these two dormant states are closely related phenomena which are part of a shared 'dormancy continuum'. This discussion is intended to stimulate discourse about these seemingly different but very similar dormant states. PMID- 25449052 TI - Social and recovery capital amongst homeless hostel residents who use drugs and alcohol. AB - BACKGROUND: Homeless people who use drugs and alcohol have been described as one of the most marginalised groups in society. In this paper, we explore the relationships of homeless drug and alcohol users who live in hostels in order to ascertain the nature and extent of their social and recovery capital. METHODS: Data were collected during 2013 and 2014 from three hostels. Each hostel was in a different English city and varied in size and organisational structure. Semi structured interviews were conducted with 30 residents (21 men; 9 women) who self reported current drink and/or drug problems. Follow-up interviews were completed after 4-6 weeks with 22 residents (16 men; 6 women). Audio recordings of all interviews were transcribed verbatim, systematically coded and analysed using Framework. RESULTS: Participants' main relationships involved family members, professionals, other hostel residents, friends outside of hostels, current and former partners, and enemies. Social networks were relatively small, but based on diverse forms of, often reciprocal, practical and emotional support, encompassing protection, companionship, and love. The extent to which participants' contacts provided a stable source of social capital over time was, nonetheless, uncertain. Hostel residents who used drugs and alcohol welcomed and valued interaction with, and assistance from, hostel staff; women appeared to have larger social networks than men; and hostels varied in the level of enmity between residents and antipathy towards staff. CONCLUSION: Homeless hostel residents who use drugs and alcohol have various opportunities for building social capital that can in turn foster recovery capital. Therapies that focus on promoting positive social networks amongst people experiencing addiction seem to offer a valuable way of working with homeless hostel residents who use drugs and alcohol. Gains are, however, likely to be maximised where hostel management and staff are supportive of, and actively engage with, therapy delivery. PMID- 25449053 TI - Sex work amongst people who inject drugs in England, Wales and Northern Ireland: findings from a National Survey of Health Harms and Behaviours. PMID- 25449054 TI - Drug analysis of residual content of used syringes: a new approach for improving knowledge of injected drugs and drug user practices. AB - BACKGROUND: Since their inception, harm reduction services, including needle exchange programs, have aimed to improve and update knowledge about illicit drug consumption and injection practices in order to assess and regularly revise the effectiveness of preventive strategies. METHODS: In this paper we describe the development of a scientific approach to obtaining this type of information through analysis of the residual content of used syringes. This was done using a validated liquid chromatography method with mass spectrometry detection to identify different molecules. Used syringes were collected from automatic injection kit dispensers at 17 sites in Paris and the surrounding suburbs each month for one year. RESULTS: In total, 3489 syringes were collected. No compounds were detected in 245 syringes. Heroin was the most commonly observed compound (42%), followed by cocaine (41%), buprenorphine (29%) and 4-methylethylcathinone (23%). These analyses also showed the increased appearance of 4 methylethylcathinone between the summer and winter of 2012. CONCLUSIONS: Despite the bias involved in this approach, the method can provide rapid data on patterns of drug consumption for specific time periods and for well-defined locations. This kind of analysis enables the detection of new substances being injected and thus enables harm reduction services to revise and adapt prevention strategies. PMID- 25449055 TI - Illicit drugs in Central Asia: what we know, what we don't know, and what we need to know. PMID- 25449056 TI - Controlling HIV among people who inject drugs in Eastern Europe and Central Asia: insights from modeling. AB - BACKGROUND: Although there is evidence of the effectiveness of needle and syringe programme (NSP), opioid substitution therapy (OST) and antiretroviral therapy (ART) in reducing HIV prevalence, most Central and Eastern European sub-regions still have low or no coverage of most or all of these interventions. METHODS: We conducted a modelling analysis to consider the potential impact on HIV incidence and prevalence of OST, NSP and ART in three illustrative epidemic scenarios: Russia (St. Petersburg); Estonia (Tallinn) and Tajikistan (Dushanbe). For each intervention, we consider the coverage needed of each intervention separately or in combination to: (1) achieve a 30% or 50% relative reduction in HIV incidence or prevalence over 10 years; and (2) reduce HIV incidence to below 1% or HIV prevalence below 10% after 20 years. A sensitivity analysis for St. Petersburg considered the implications of greater on no risk heterogeneity, none or more sexual HIV transmission, like-with-like mixing, different injecting cessation rates and assuming a lower HIV acute phase cofactor. RESULTS: For St. Petersburg, when OST, NSP and ART are combined, only 14% coverage of each intervention is required to achieve a 30% reduction in HIV incidence over 10 years. Similar findings are obtained for Tallinn and Dushanbe. In order to achieve the same reductions in HIV prevalence over 10 years, over double the coverage level is required relative to what was needed to achieve the same reduction in HIV incidence in that setting. To either reduce HIV incidence to less than 1% or HIV prevalence to less than 10% over 20 years, with all interventions combined, projections suggest that very high coverage levels of 74-85% are generally required for the higher prevalence settings of Tallinn and St. Petersburg, whereas lower coverage levels (23-34%) are needed in Dushanbe. Coverage requirements are robust to increased sexual HIV transmission, risk heterogeneity and like-with-like mixing, as well as to assuming a lower HIV acute phase cofactor or different injecting cessation rate. CONCLUSION: The projections suggest that high but achievable coverage levels of NSP can result in large decreases (30%) in HIV incidence in settings with high HIV prevalence among PWID. Required coverage levels are much lower when interventions are combined or in lower prevalence settings. However, even when all three interventions are combined, the targets of reducing HIV incidence to less than 1% or prevalence to less than 10% in 20 years may be hard to achieve except in lower prevalence settings. PMID- 25449058 TI - The cradle of the Journal of International Urology and Nephrology: foundations of our journal. PMID- 25449057 TI - Drug scene, drug use and drug-related health consequences and responses in Kulob and Khorog, Tajikistan. AB - BACKGROUND: Tajikistan and other Central Asian republics are facing intertwined epidemics of injecting drug use and HIV. This paper aims to examine drug scene, drug use, drug-related infectious diseases, drug treatment and other responses to health consequences of drug injecting in two Tajik cities of Kulob (Khatlon Region) and Khorog (Gorno-Badakhshan Autonomous Oblast). METHODS: We conducted 12 focus group discussions in Kulob and Khorog and analysed peer-reviewed literature, published and unpublished programme and country reports and other publications that focused on substance use and/or HIV/AIDS in Tajikistan and included the Khatlon and Gorno-Badakhshan regions. RESULTS: In both Kulob and Khorog, heroin is used by the overwhelming majority of people who inject drugs (PWID), with one dose of heroin in Khorog costing less than a bottle of vodka. Opioid overdose among PWID in Tajikistan is a serious issue that appears to be substantially underestimated and inadequately addressed at the policy and practice levels. In integrated bio-behavioural surveys (IBBS), HIV and HCV prevalence in both Kulob and Khorog varied widely over a short period of time, raising questions over the quality and reliability of these data. Access to opioid substitution therapy (OST) and antiretroviral therapy (ART) by PWID is either lacking or inadequate. Very few women who inject drugs access needle and syringe programmes in Kulob and Khorog. HCV treatment cannot be afforded by the overwhelming majority of PWID due to high costs. CONCLUSION: Tajikistan IBBS data point to the potential problems in using composite national prevalence as an adequate reflection of the HIV epidemic among PWID in the country and highlight the importance of examining site-specific prevalence rates for better understanding of the dynamics of the epidemic over time as well as potential problems related to the reliability of data. Furthermore, our analysis highlights that in a country where almost all PWID inject opiates, agonist treatment should be an intervention of choice. Scaling-up both OST and ART coverage must be seen as the top priority for reducing HIV prevalence and incidence in Tajikistan. Naloxone distribution programmes need to be expanded and drug treatment, harm reduction and HIV services that meet the specific needs of female injecting drug users should be put in place. PMID- 25449059 TI - Effect of tiotropium on neural respiratory drive during exercise in severe COPD. AB - BACKGROUND: Studies have shown that tiotropium once daily reduces lung hyperinflation and dyspnea during exercise and improves exercise tolerance in patients with COPD. Mechanisms underlying the effects of the muscarinic receptor antagonist tiotropium on COPD have not been fully understood. OBJECTIVE: In this study, we investigated whether improvement in neural respiratory drive is responsible for reducing dyspnea during exercise and improving exercise tolerance in COPD. METHODS: Twenty subjects with severe COPD were randomized into two groups: no treatment (Control, n = 10, 63.6 +/- 4.6 years, FEV1 29.6 +/- 13.3%pred) or inhaled tiotropium 18 MUg once daily for 1 month (n = 10, 66.5 +/- 5.4 years, FEV1 33.0 +/- 11.1%pred). All subjects were allowed to continue their daily medications other than anti-cholinergics during the study. Constant cycle exercise with 75% of maximal workload and spirometry were performed before and 1 month after treatment. Diaphragmatic EMG (EMGdi) and respiratory pressures were recorded with multifunctional esophageal catheter. Efficiency of neural respiratory drive, defined as the ratio of minute ventilation (VE) and diaphragmatic EMG (VE/EMGdi%max), was calculated. Modified British Medical Research Council Dyspnea Scale (mMRC) was used for the evaluation of dyspnea before and after treatment. RESULTS: There was no significant difference in spirometry before and after treatment in both groups. Diaphragmatic EMG decreased significantly at rest (28.1 +/- 10.9% vs. 22.6 +/- 10.7%, P < 0.05) and mean efficiency of neural respiratory drive at the later stage of exercise increased (39.8 +/- 2.9 vs. 45.2 +/- 3.9, P < 0.01) after 1-month treatment with tiotropium. There were no remarkable changes in resting EMGdi and mean efficiency of neural respiratory drive post-treatment in control group. The score of mMRC decreased significantly (2.5 +/- 0.5 vs. 1.9 +/- 0.7, P < 0.05) after 1-month treatment with tiotropium, but without significantly difference in control group. CONCLUSION: Tiotropium significantly reduces neural respiratory drive at rest and improves the efficiency of neural respiratory drive during exercise, which might account for the improvement in exercise tolerance in COPD. PMID- 25449060 TI - The Impact of Oversampling with SMOTE on the Performance of 3 Classifiers in Prediction of Type 2 Diabetes. AB - OBJECTIVE: To evaluate the impact of the synthetic minority oversampling technique (SMOTE) on the performance of probabilistic neural network (PNN), naive Bayes (NB), and decision tree (DT) classifiers for predicting diabetes in a prospective cohort of the Tehran Lipid and Glucose Study (TLGS). METHODS: . Data of the 6647 nondiabetic participants, aged 20 years or older with more than 10 years of follow-up, were used to develop prediction models based on 21 common risk factors. The minority class in the training dataset was oversampled using the SMOTE technique, at 100%, 200%, 300%, 400%, 500%, 600%, and 700% of its original size. The original and the oversampled training datasets were used to establish the classification models. Accuracy, sensitivity, specificity, precision, F-measure, and Youden's index were used to evaluated the performance of classifiers in the test dataset. To compare the performance of the 3 classification models, we used the ROC convex hull (ROCCH). RESULTS: Oversampling the minority class at 700% (completely balanced) increased the sensitivity of the PNN, DT, and NB by 64%, 51%, and 5%, respectively, but decreased the accuracy and specificity of the 3 classification methods. NB had the best Youden's index before and after oversampling. The ROCCH showed that PNN is suboptimal for any class and cost conditions. CONCLUSIONS: To determine a classifier with a machine learning algorithm like the PNN and DT, class skew in data should be considered. The NB and DT were optimal classifiers in a prediction task in an imbalanced medical database. PMID- 25449061 TI - Bovine serum albumin with glycated carboxyl groups shows membrane-perturbing activities. AB - The aim of the present study aimed to investigate whether glycated bovine serum albumin (BSA) showed novel activities on the lipid-water interface. Mannosylated BSA (Man-BSA) was prepared by modification of the carboxyl groups with p aminophenyl alpha-d-mannopyranoside. In contrast to BSA, Man-BSA notably induced membrane permeability of egg yolk phosphatidylcholine (EYPC)/egg yolk sphingomyelin (EYSM)/cholesterol (Chol) and EYPC/EYSM vesicles. Noticeably, Man BSA induced the fusion of EYPC/EYSM/Chol vesicles, but not of EYPC/EYSM vesicles. Although BSA and Man-BSA showed similar binding affinity for lipid vesicles, the lipid-bound conformation of Man-BSA was distinct from that of BSA. Moreover, Man BSA adopted distinct structure upon binding with the EYPC/EYSM/Chol and EYPC/EYSM vesicles. Man-BSA could induce the fusion of EYPC/EYSM/Chol vesicles with K562 and MCF-7 cells, while Man-BSA greatly induced the leakage of Chol-depleted K562 and MCF-7 cells. The modified BSA prepared by conjugating carboxyl groups with p aminophenyl alpha-d-glucopyranoside also showed membrane-perturbing activities. Collectively, our data indicate that conjugation of carboxyl groups with monosaccharide generates functional BSA with membrane-perturbing activities on the lipid-water interface. PMID- 25449062 TI - Polycomb chromobox (Cbx) 7 modulates activation-induced CD4+ T cell apoptosis. AB - CD4(+) T cell polarization plays a critical role in a number of immune disorders; the pathogenesis is unclear. Chromobox homolog 7 (Cbx7) is involved in the gene transcription of several cell types. This study aims to investigate the mechanism by which Cbx7 modulates the CD4(+) T cell polarization. Expression of Cbx7 was assessed by quantitative RT-PCR and Western blotting. Apoptosis of CD4(+) T cell was analyzed by flow cytometry. The FasL promoter methylation was evaluated by the methylation specific PCR. The results showed that CD4(+) CD25(-) T cells express Cbx7 that was increased significantly after activation by exposing to anti-CD3/CD28 Ab, but suppressed by exposing to specific antigens. More apoptotic cells were detected in CD4(+) T cells with the Cbx7 gene knockdown. Exposure to insulin-like growth factor-1 up regulated the expression of Cbx7 in CD4(+) T cells. After antigen-specific TCR activation, Cbx7-deficient CD4(+) T cells expressed more FasL and showed the FasL gene promoter hyper demethylation than wild CD4(+) T cells. In addition, CD4(+) T cells with overexpression of Cbx7 showed lower levels of FasL gene promoter demethylation. We conclude that CD4(+) T cells express Cbx7; the latter prevents FasL expression and the activation induced CD4(+) T cell apoptosis. PMID- 25449063 TI - Cholesteryl ester diffusion, location and self-association constraints determine CETP activity with discoidal HDL: excimer probe study. AB - The transfer of cholesteryl ester by recombinant cholesteryl ester transfer protein (CETP) between reconstituted discoidal high-density lipoprotein (rHDL) was studied. Particles contained apolipoprotein A-I, unsaturated POPC or saturated DPPC and cholesteryl ester as cholesteryl 1-pyrenedecanoate (CPD) or cholesteryl laurate (CL) in donor and acceptor rHDL, respectively. Probe dynamics fulfilled the quenching sphere-of-action model. The cholesteryl ester exchange between donor and acceptor particles was characterized by a heterogeneous kinetics; the fast exchanging CPD pool was much higher in a case of POPC compared to DPPC complexes. Probe fraction accessible to CETP increased with temperature, suggesting a more homogeneous probe distribution. Noncompetitive inhibition of probe transfer by acceptor particles was observed. The values of Vmax (0.063MUMmin(-1)) and catalytic rate constant kcat (0.42s(-1)) together with a similarity of Km (0.9MUM CPD) and KI (2.8MUM CL) values for POPC-containing rHDL suggest the efficient cholesteryl ester transfer between nascent HDL with unsaturated phosphatidylcholine in vivo. The phospholipid matrix in discoidal HDL may underlie CETP activity through the self-association, diffusivity and location of cholesteryl ester in the bilayer, the accessibility of cholesteryl ester to cholesterol-binding site in apoA-I structure and the binding of cholesteryl ester, positionable by apoA-I, to CETP. PMID- 25449064 TI - A partial least squares analysis of seizure outcomes following resective surgery for tuberous sclerosis complex in children with intractable epilepsy. AB - INTRODUCTION: Previous studies aimed at identifying predictors of seizure outcomes following resective surgery for tuberous sclerosis complex (TSC) are limited by multicollinearity among predictors, whereby the high degree of correlation between covariates precludes detection of potentially significant findings. PURPOSE: Here, we apply a data-driven method, partial least squares (PLS) to model multidimensional variance and study significant patterns in data that are associated with seizure outcomes. METHODS: Post hoc analysis of 186 children with TSC who underwent resective epilepsy surgery derived from an individual participant data meta-analysis was performed. PLS was used to derive a latent variable (component) that relates clinical covariates with Engel classification. Permutation testing was performed to evaluate the significance of the component, and bootstrapping was used to identify significant contributors to the component. RESULTS: A significant component was identified, which represents the pattern of covariates related to Engel class. The strongest and significant factors contributing to this component were focal ictal electroencephalogram and concordance of electroencephalography (EEG)-magnetic resonance imaging (MRI) abnormality. Interestingly, covariates contributing the least to the seizure-free patient phenotype were continent of treatment and age at the time of surgery. CONCLUSION: Using a data-driven, multivariate method, PLS, we describe patient phenotypes that are associated with seizure-freedom following resective surgery for TSC. PMID- 25449065 TI - Comment on: Gastroesophageal reflux in laparoscopic sleeve gastrectomy: hiatal findings and their management influence outcome. PMID- 25449066 TI - Gastrointestinal bleeding from the excluded stomach: a proposed algorithmic approach to management. PMID- 25449067 TI - [Clinical features and PRRT2 mutations in infantile convulsions with paroxysmal choreoathetosis]. AB - OBJECTIVE: To analyze the phenotypes and proline-rich transmenbrane protein 2 (PRRT2) gene mutations in patients of infantile convulsions with paroxysmal choreoathetosis (ICCA). METHODS: Clinical data were collected from ICCA patients and their family members. Genomic DNA was extracted from peripheral blood samples with standard protocol. Mutations of PRRT2 were screened using PCR amplification and Sanger sequencing. RESULTS: Eleven families and one sporadic case with ICCA were recruited in this study. In 11 ICCA families, 49 family members were affected, of which 15 individuals had benign infantile convulsions (BIC) alone, 18 individuals had only paroxysmal kinesigenic dyskinesia(PKD), and 16 individuals had BIC followed by PKD. The seizure onset age of infantile convulsions was between 3 and 12 months. The onset age of PKD was ranging from 5 to 17 years old. Four affected members in two ICCA families had PKD or ICCA co existing with migraine. The one sporadic ICCA case had afebrile seizures between 3.5 and 4 months, and developed paroxysmal twists of limbs after 3 years and 9 months of age. He had good response to treatment with oxcarbazepine at the age of 4 years and 10 months. PRRT2 mutations were identified in all 11 ICCA families. The most common mutation, c.649_650insC (p.R217PfsX8), was detected in 6 of the 11 families (54.5%). PRRT2 mutation (c.649_650insC) was also found in the sporadic ICCA case, and was identified as de novo mutation. CONCLUSION: The phenotype of PKD in ICCA families occurred in childhood or adolescence. Few affected members in some ICCA families may have migraine. PRRT2 is the causative gene of ICCA and the mutation c.649_650insC was the hotspot of PRRT2 mutations. PRRT2 mutation was also found in sporadic case with ICCA. PMID- 25449068 TI - [The mutation analysis of PAH gene and prenatal diagnosis in classical phenylketonuria family]. AB - OBJECTIVE: To characterize the mutation spectrum of phenylalanine hydroxylase (PAH) gene and perform prenatal diagnosis for families with classical phenylketonuria. METHODS: By stratified sequencing, mutations were detected in the exons and flaking introns of PAH gene of 44 families with classical phenylketonuria. 47 fetuses were diagnosed by combined sequencing with linkage analysis of three common short tandem repeats (STR) (PAH-STR, PAH-26 and PAH-32) in the PAH gene. RESULTS: Thirty-one types of mutations were identified. A total of 84 mutations were identified in 88 alleles (95.45%), in which the most common mutation have been R243Q (21.59%), EX6-96A>G (6.82%), IVS4-1G>A (5.86%) and IVS7+2T>A (5.86%). Most mutations were found in exons 3, 5, 6, 7, 11 and 12. The polymorphism information content (PIC) of these three STR markers was 0.71 (PAH STR), 0.48 (PAH-26) and 0.40 (PAH-32), respectively. Prenatal diagnosis was performed successfully with the combined method in 47 fetuses of 44 classical phenylketonuria families. Among them, 11 (23.4%) were diagnosed as affected, 24 (51.1%) as carriers, and 12 (25.5%) as unaffected. CONCLUSION: Prenatal diagnosis can be achieved efficiently and accurately by stratified sequencing of PAH gene and linkage analysis of STR for classical phenylketonuria families. PMID- 25449069 TI - [Regulation of PI3K-Akt-GSK3beta signaling pathway in U251 cells by risperidone]. AB - OBJECTIVE: To investigate the effect of risperidone, an antipsychotic drug, on the Akt-GSK3beta pathway and the role of PI3K in dopamine D2 receptor (DRD2) expression and Akt-GSK3beta signal pathway. METHODS: Human glioma cells (U251) were cultured in vitro. Cells without any treatment as control, Western blotting was used for measuring the expression of Akt (Thr308 and Ser473) and GSK3beta (Ser9) protein phosphorylation by risperidone and LY294002 in U251 cell, and real time PCR was used for detecting the expression of DRD2 mRNA. RESULTS: Risperidone has significantly enhanced the expression of phosphorylated Akt and phosphorylated GSK3beta (P< 0.05), but did not alter the mRNA expression of DRD2. LY294002 could reduce the phosphorylation of Akt and GSK3beta (P< 0.01, P< 0.05), and also decrease the DRD2 mRNA (P<0 .05). CONCLUSION: Risperidone can activate the Akt-GSK3beta signaling pathway in the U251 cells, and PI3K is a common regulatory site in Akt-GSK3beta signaling and D2 receptor gene expression. PMID- 25449070 TI - [Study of a Bethlem myopathy pedigree resulted from a novel mutation of COL6A3 gene]. AB - OBJECTIVE: To determine the molecular etiology for a muscular dystrophy pedigree with target region sequencing platform using hereditary myopathy capture array. METHODS: Specific gene testing was performed based on the clinical diagnosis. Since no pathogenic mutation was found, target region sequencing with hereditary myopathy capture array combined with Sanger sequencing and bioinformatics analysis were employed in turn. PolyPhen and NCBI were used to evaluate the pathogenicity of identified mutation and conservation of the gene. RESULTS: Target region sequencing indicated the proband has carried a heterozygous c.3353 A>C mutation of COL6A3 gene, which was confirmed by Sanger-sequencing in 4 affected individuals from the family. The same mutation was not detected in healthy members of the pedigree. Bioinformatics analysis suggested that the mutation has caused a highly pathogenic amino acid substitution from Histidine to Proline. The affected patients featured normal intelligence with mild myogenic damage by muscle biopsy, slightly increased serum creatine kinase and slow disease progression, which was consistent with Bethlem myopathy. CONCLUSION: Target region sequencing is an effective and efficient method for genetic testing. The heterozygous c.3353A>C mutation in exon 8 of the COL6A3 gene probably underlies the Bethlem myopathy with autosomal dominant inheritance. PMID- 25449071 TI - [Analysis of copy number variations in 66 children with unexplained mental retardation/developmental delay using chromosomal microarrays]. AB - OBJECTIVE: To investigate clinically relevant copy number variations (CNV) in patients with unexplained mental retardation/developmental delay (MR/DD) through chromosomal microarray analysis (CMA). METHODS: Sixty-six patients with unexplained MR/DD were analyzed with CMA. All identified CNVs were verified with database of genomic variations (DGV), DECIPHER, ISCA and the literature. RESULTS: Nineteen clinically relevant CNVs were detected among the 16 individuals. The diagnostic yield for the MR/DD patients was 24.2%. The most common abnormality was Phelan-McDermid syndrome (3/16, 18.8%), which was followed by Prader-Willi syndrome/Angelman syndrome (2/16, 12.5%) and Wolf-Hirschhorn syndrome (2/16, 12.5%). CONCLUSION: CNVs are one of the most common causes for unexplained MR/DD. CMA can improve the detection rate of CNVs and confer genetic testing with greater sensitivity in elucidating the diagnosis for unexplained MR/DD. PMID- 25449072 TI - [Phenotype-genotype correlation analysis of 12 cases with Angelman/Prader-Willi syndrome]. AB - OBJECTIVE: To investigate the genotype-phenotype correlation in patients with Angelman syndrome/Prader-Willi syndrome (AS/PWS) and assess the application value of high-resolution single nucleotide polymorphism microarrays (SNP array) for such diseases. METHODS: Twelve AS/PWS patients were diagnosed through SNP array, fluorescence in situ hybridization (FISH) and karyotype analysis. Clinical characteristics were analyzed. RESULTS: Deletions ranging from 4.8 Mb to 7.0 Mb on chromosome 15q11.2-13 were detected in 11 patients. Uniparental disomy (UPD) was detected in only 1 patient. Patients with deletions could be divided into 2 groups, including 7 cases with class I and 4 with class II. The two groups however had no significant phenotypic difference. The UPD patient had relatively better development and language ability. Deletions of 6 patients were confirmed by FISH to be of de novo in origin. The risk to their sibs was determined to be less than 1%. CONCLUSION: The phenotypic differences between AS/PWS patients with class I and class II deletion need to be further studied. SNP array is useful in detecting and distinguishing of patients with deletion or UPD. This method may be applied for studying the genotype-phenotype association and the mechanism underlying AS/PWS. PMID- 25449073 TI - [Expression of Musashi2 gene in de novo acute myeloid leukemia and its clinical implications]. AB - OBJECTIVE: To explore the expression and clinical significance of Musashi2 (MSI2) gene in de novo acute myeloid leukemia (AML). METHODS: Real-time quantitative PCR (RQ-PCR) was used to measure the expression of MSI2 gene in 181 de novo AML patients. Correlation between the expression level and clinical features of such patients was explored. RESULTS: Transcript of the MSI2 gene was detected in 181 AML patients, with the median expression level being 2.341 (0.1124-58.8566). By contrast, CD34+ cells from 10 healthy controls had a much lower expression level (P=0.012), and the expression level of MSI2 in 24 patients with complete remission was significant lower than de novo patients (P=0.021). Based on the median expression level, such patients were divided into low expression group and high expression group. Patients from the high expression group had significantly higher rate of high white blood cell count (78% vs. 63%, P=0.034). Compared with MSI2-low group, FLT3-ITD mutation were much more common in MSI2-high group (28% vs. 7%, P=0.002). The expression level of MSI2 in aberrant karyotypes was much higher than that in favorable karyotypes (the median expression level was 2.7726 and 2.0733, P=0.035). Kaplan-Meier analysis showed that the overall survival in high expression group of MSI2 was lower than the low expression group, with the median survival time being 28 months and 12 months, respectively (P=0.045). CONCLUSION: De novo AML patients have a higher level of MSI2 gene expression. And the latter is much more common in those with high white blood cell count and aberrant karyotypes, and has a positive correlation with FLT3-ITD mutation. High expression of MSI2 gene may be a predictor for poorer prognosis among AML patients. PMID- 25449074 TI - [Association between -1296T/C and -915A/G polymorphisms of matrix metalloproteinase inhibitor-3 gene and atherosclerotic cerebral infarction in an ethnic Han Chinese population]. AB - OBJECTIVE: To assess the association between -1296T/C and -915A/G polymorphisms in the promoter region of matrix metalloproteinase inhibitor-3 gene (TIMP-3) and atherosclerotic cerebral infarction in an ethnic Han Chinese population. METHODS: Peripheral blood samples were collected from 485 patients with atherosclerotic cerebral infarction and 525 healthy controls. Serum levels of TIMP-3 were measured with an enzyme-linked immunosorbent assay (ELISA). The polymorphisms of the TIMP-3 gene were analyzed with DNA sequencing. RESULTS: There were significant differences in genotype and allele frequencies in -1296T/C and 915A/G between the patients and healthy controls (chi-square: 5.227 and 5.869; P: 0.022 and 0.015, respectively). Besides, there was a strong linkage disequilibrium between -1296T/C and -915A/G (D'=1.0, r(2)=0.991). The serum levels of TIMP-3 in patients were significantly higher than the control group [(248.90 +/- 97.10) pg/mL vs. (200.17 +/- 79.70) pg/mL, t=2.098, P=0.039]. CONCLUSION: The -1296T/C and -915A/G polymorphisms of the TIMP-3 gene are associated with increased risk for atherosclerotic cerebral infarction in ethnic Han Chinese and may be used as molecular markers for the disease. There is also strong linkage disequilibrium between the two loci. PMID- 25449075 TI - [A microdeletion of chromosome 9q34.11 may cause suspected cerebral palsy]. AB - OBJECTIVE: To identify the genetic cause for a child with mental retardation and dyskinesia. METHODS: After the routine genetic counseling for the child and the core family members, conventional peripheral blood karyotyping with G-banding and tandem mass spectrometry were applied to find the common genetic problems. Array comparative genomic hybridization (aCGH) based on the whole genome level was performed to detect minor chromosomal structural abnormalities and the result was confirmed by multiplex ligation dependent probe amplification (MLPA). RESULTS: The proband's karyotype was normal. There were not obvious abnormalities for the testing of 26 types of congenital metabolic diseases. A -2.11 Mb microdeletion of chromosome 9q34.11 region was found though aCGH, which including SPTAN1, TOR1A and other nearly 50 genes related to mental retardation, early infantile spasms, epileptic encephalopathy, myelin dysplasia and dystonia. The -2.11 Mb chromosomal microdeletion was identified by MLPA. CONCLUSION: The 2.11 Mb microdeletion of chromosome 9q34.11 region may lead to suspected cerebral palsy. Cytogenetic methods combined with MLPA and aCGH can efficiently identify genetic etiology and provide accurate results for clinical diagnosis. PMID- 25449076 TI - [Mutation analysis and prenatal diagnosis of COL1A1 gene in a Chinese family with type I osteogenesis imperfecta]. AB - OBJECTIVE: To detect mutation of COL1A1 gene in a Chinese family affected with type I osteogenesis imperfecta (OI) and to provide prenatal diagnosis for a fetus at 17th gestational week. METHODS: Polymerase chain reaction, DNA sequencing and restriction endonuclease analysis were used to verify the detected mutation among other members of the family and 100 healthy controls. RESULTS: No mutation has been detected in the COL1A2 gene in all of the subjects. A heterozygous mutation c.104-1G>C was identified in the COL1A1 gene among all patients from this family. The same mutation was not found in other members from the family and the 100 healthy controls. The mutation was not found in the fetus, and was verified to be a new mutation according to the type I collagen mutation database. CONCLUSION: The c.104-1G>C mutation of the COL1A1 gene probably underlies the type I osteogenesis imperfecta in this family. Under the premise of a clear genetic diagnosis, prenatal diagnosis may be provided to reduce the risk for the disease. PMID- 25449077 TI - [Detection of dystrophin gene mutation in a Chinese pedigree affected with Duchenne muscular dystrophy]. AB - OBJECTIVE: To identify mutations of dystrophin gene in a Chinese pedigree affected with Duchenne muscular dystrophy (DMD). METHODS: Clinical data from the pedigree was collected. Subsequently, polymerase chain reaction and DNA sequencing analysis were applied to detect the potential mutations. Restriction enzyme digestion was carried out to determine whether the mutation was present in 118 healthy controls. Clustal software was applied for analyzing the conservation of altered amino acids. RESULTS: DNA sequencing analysis has identified a heterozygous missense mutation c.7578G>C (p.Gln2526His) mutation in exon 52 of the dystrophin gene in the proband and his mother. The same mutation was absent in the 118 healthy controls. Restriction enzyme digestion has confirmed above result. Clustal analysis indicated that the altered amino acid is highly conserved in mammals. CONCLUSION: The results revealed a novel missense mutation (c.7578G>C) of the dystrophin gene in DMD patients. PMID- 25449078 TI - [Applied research of combined G-banding and array-CGH in the prenatal diagnosis of ultrasonographic abnormalities in fetuses]. AB - OBJECTIVE: To use combined comparative genome hybridization (array-CGH) and conventional karyotype analysis to study the relationship between ultrasonographic abnormalities of fetuses and chromosomal aberrations. METHODS: One hundred twenty two fetuses with ultrasonographic abnormalities in middle and late trimesters suspected with chromosomal abnormalities were collected between March 2012 and February 2013. RESULTS: The pregnant women had an average age of 31 yr (22-38), among whom 35 were above the age of 35. The average gestational age was 27(+5) weeks (18-37 weeks), and the most common abnormal findings have involved heart, central nervous system and bones. Multiple malformations were found in 49 cases. The success rate of the combined methods was 100%. In 24 (19.7%) of the cases, a chromosomal abnormality was detected. Among all cases, 16 (13.1%) were detected by the combined method (12.3%). Seventeen cases (13.9%) of chromosomal abnormalities and 4 cases (3.3%) of polymorphic variation were detected by karyotype analysis, and 23 cases (8.9%) of abnormalities were detected by array-CGH. Meanwhile, 7 cases (5.7%) of abnormalities were detected by array-CGH, but the results of karyotype analysis were normal. One case (0.8%) with low level of chromosome chimerism detected by the karyotype analysis was missed by array-CGH. CONCLUSION: The results suggested that multiple congenital deformity of the fetus has a strong correlation with chromosomal abnormalities. For fetuses with ultrasonographic abnormalities, array-CGH can improve the detection sensitivity of the chromosomal disease. PMID- 25449079 TI - [Mutation analysis of EXT2 gene in a family with hereditary multiple exostosis]. AB - OBJECTIVE: To investigate EXT1 and EXT2 genes mutations in a family with hereditary multiple osteochondromas (HME). METHODS: A four-generation family with HME from Linyi city of Shandong Province was studied. There were 6 affected individuals among the 17 family members. Physical examination and radiographical evaluations were carried out for all family members. Genomic DNA was extracted from peripheral venous blood and the samples were subjected to mutation screening by PCR of the coding regions of EXT1 and EXT2 genes. RESULTS: The family has featured an autosomal dominant inheritance pattern. Sequencing of the EXT1 and EXT2 genes suggested the causative gene in this family was in linkage with the second exon of EXT2. A c.244delG mutation was detected, which has resulted in a frameshift mutation p.Asp81IlefsX30. The mutation was found in all of the 6 affected individuals but not in normal family members. And the mutation has co segregated with the phenotype. CONCLUSION: The mutation c.244delG in the EXT2 gene is the probably the cause of the disease in this family. PMID- 25449080 TI - [Cytogenetic and molecular genetic diagnosis of a neonate with partial 13q trisomy and partial 5p monosomy]. AB - OBJECTIVE: To diagnose a neonate presenting with multiple dysmorphic features, Cri-du-chat signs and hypoglycemia and to correlate the phenotype with the genotype. METHODS: The patient was diagnosed with conventional cytogenetics and real-time fluorescence quantitative PCR (QF-PCR). The phenotype was then correlated with the genotype through a review of literature. RESULTS: The neonate was diagnosed with a partial 13q trisomy (q12 -> qter) and partial 5p monosomy (p15 ->pter). CONCLUSION: A rare diagnosis has been established with combined cytogenetic and molecular genetic techniques. QF-PCR has a broad application in genetic diagnosis. PMID- 25449081 TI - [Investigation of a family with Kennedy disease by genetic analysis]. AB - OBJECTIVE: To report on a Chinese family from Wenzhou with genetically confirmed Kennedy disease and describe its clinical and genetic features. METHODS: The clinical phenotype and the level of relevant biochemical markers were assessed. To determine the number of CAG repeats in the exon 1 of androgen receptor (AR) gene, genomic DNA was extracted from peripheral blood samples of the family members, amplified by PCR and identified by DNA sequencing. RESULTS: The proband showed predominantly proximal limb weakness, fasciculation, muscle atrophy, gynecomastia, sexual dysfunction and increased serum creatine kinase. Myopathy and neuropathy were identified by electromyography. Two other affected males and 2 affected female carriers were identified to carry an expanded CAG repeat in the AR gene. The numbers of CAG repeats were found to be 43 in the proband, 43 and 42 in the other two affected males, one of which had similar clinical symptoms to the proband. CONCLUSION: The family was diagnosed with Kennedy disease by analysis of the AR gene. PMID- 25449082 TI - [Molecular diagnosis for a patient with Kennedy disease]. AB - OBJECTIVE: To screen for potential mutations of androgen receptor (AR) gene in a patient clinically diagnosed as Kennedy disease. METHODS: Polyglutamine expansion (PQE) induced by a duplication of CAG trinucleotide tandem-repeat in exon 1 of the AR gene was detected with PCR and T-clone sequencing. RESULTS: Compared with the number of CAG repeat of 22 in the normal allele, the number of CAG repeats has increased to 45 in the mutant allele carried by the patient. This has fit with the diagnostic criteria for Kennedy disease. CONCLUSION: A mutation of PQE has been detected in the patient with Kennedy disease. Detection of PQE in AR gene can be used as reliable method to identify the Kennedy disease. PMID- 25449083 TI - [Analysis of APC gene mutation in a familial adenomatous polyposis pedigree]. AB - OBJECTIVE: To analyze mutation of adenomatous polyposis coli (APC) gene in a family affected with familial adenomatous polyposis. METHODS: The diagnosis was made based on clinical manifestations, family history, presence of numerous polyps in the colon as well as pathological examination. Peripheral blood samples were collected, and genomic DNA was extracted. Potential mutation of the APC gene was detected by polymerase chain reaction (PCR) and DNA sequencing. After finding the mutation in the proband, the same mutation was screened among other family members. The mutation was also confirmed with PCR-restriction fragment length polymorphism (RFLP), with which 100 unrelated healthy controls were examined. RESULTS: A novel heterozygous nonsense mutation c.2891T>G (L964X) of the APC gene was identified in this pedigree. The mutation has led to premature termination of translation. The same mutation was not detected among the 100 healthy controls. CONCLUSION: The c.2891T>G (L964X) of the APC gene probably underlies the familial adenomatous polyposis in this pedigree. The combined DNA sequencing and PCR-RFLP method is efficient and accurate for the diagnosis. PMID- 25449084 TI - [Analysis of a infertile female with ring 21 chromosome using combined techniques]. AB - OBJECTIVE: To investigate clinical phenotype and genetic characteristics of a 30 year-old infertile female carrying a mosaic ring 21 chromosome. METHODS: A combination of techniques including G-banding, C-banding, fluorescence in situ hybridization (FISH) and SNP array were performed to investigate the breaking point of the r(21). RESULTS: The karyotype of the patient was mos 46,XX,r(21)[166]/46, XX,der(21)[60]/45, XX, -21[20]/46, XX,dic r(21)[4].ish del(21)(q22.2?)(21qter-, AML1+, D21S259/D21S341/D21S342+). arr 21q22.3(43 457 934 48 093 361) * 1, 21q22.2q22.3(40 218 429-43 457 934)* 1-2. The karyotypes of her parents were both normal. CONCLUSION: Clinical phenotypes of patients carrying a ring 21 mainly depends on the percentage of abnormal cells and the deleted chromosomal fragment. The small uterus and oligomenorrhea in our patient may be attributed to the mosaic ring 21 chromosome. PMID- 25449085 TI - [Studies on the association of single nucleotide polymorphisms of HLA-DP and DQ genes with the outcome of chronic hepatitis B virus infection]. AB - OBJECTIVE: To investigate the association of single nucleotide polymorphisms in the HLA-DP and DQ genes with the outcome of chronic hepatitis B virus infection. METHODS: Two hundred and four healthy subjects, 255 clearance subjects, 204 asymptomatic HBV carriers (AsC), 136 chronic hepatitis B (CHB), 68 liver cirrhosis (LC) and hepatocellular carcinoma (HCC) were enrolled. Genotypes of rs3077, rs9277535 and rs2647050 were determined by sequence specific primers-PCR (PCR-SSP). RESULTS: By using healthy subjects and clearance subjects as the control groups, rs3077 and rs9277535 were significantly associated with chronic HBV infection under additive and dominant models (P< 0.05). Meanwhile, haplotypes GGA, AGA, AAA appeared to be protective factors against chronic HBV infection (P < 0.05). By using AsC as the control group, comparison with the CHB, LC and HCC groups showed no association of the 3 SNPs or haplotypes with the clinical outcome (P > 0.05). CONCLUSION: HLA-DP gene polymorphisms are strongly associated with chronic HBV infection. The presence of A allele at rs3077 and rs9277535 of the HLA-DP gene may decreased the risk for chronic HBV infection. PMID- 25449086 TI - [Gene diagnosis for a child with tuberous sclerosis]. AB - OBJECTIVE: To identify the pathogenic mutation in a family affected with tuberous sclerosis. METHODS: For the proband and its parents, mutational hotspots in the 11 exons of TSC1 and TSC2 gene were analyzed with DNA sequencing and bioinformatics tools. RESULTS: A heterozygous c.4493G>C missense mutation was identified in the proband. The same mutation was however not found in the parents. CONCLUSION: The missense mutation c.4493G>C probably underlie the tuberous sclerosis complex seen in the child. PMID- 25449087 TI - [Analysis of genomic copy number variation for a Chinese patient with split hand/split foot malformation]. AB - OBJECTIVE: To employ single nucleotide polymorphisms (SNP) microarray to detect copy number variations (CNVs) for the diagnosis of disease and molecular classification. METHODS: For a patient with split-hand/split-foot malformation, genome-wide copy number variants SNP microarray was applied. Tiny copy number variations were verified by real-time fluorescent quantitative PCR. RESULTS: The results of SNP microarray has revealed that the patient has carried a 0.39 Mb duplication in 10q24.31-24.32 (102 955 122-103 348 688), which has encompassed genes including LBX1, BTRC and POLL. By real-time fluorescent quantitative PCR, duplicate area encompassing the pathogenic genes have been verified. The results for LBX1, BTRC, POLL genes were all consistent with the SNP microarray test. Moreover, a duplication was detected in exon 9 of FBXW4 gene which is in nearby. CONCLUSION: SNP chips can efficiently identify tiny CNVs (< 1.0 Mb). In combination with real-time fluorescence quantitative PCR, this may provide valuable information for prenatal diagnosis. PMID- 25449088 TI - [Analysis of two false positive cases from noninvasive prenatal testing]. AB - OBJECTIVE: To track and analyze two false positive cases from non-invasive prenatal testing for potential fetal aneuploidy. METHODS: The two cases, respectively reported to have XO (+++) and T18 (1/20) XO(+), were analyzed with conventional karyotyping, fluorescence in situ hybridization (FISH) and massively parallel genomic sequencing (MPS). RESULTS: The first fetus, who was suspected for XO(+++), was verified to have super female syndrome (47,XXX/46,XX) due to confined placental mosaicism by karyotyping of amniotic fluid cells, FISH analysis of placenta and massively parallel sequencing (MPS) of fetal tissue. The second fetus, suspected to have trisomy 18 (1/20) XO(+), was verified to have Turner syndrome by karyotyping, FISH and MPS analyses of umbilical cord blood cells. And the karyotype was 45,X[48]/46, X, der(X) del(X) (p11.21) del(X) (q13.3)[62]. CONCLUSION: Non-invasive prenatal testing carries a risk for false positive diagnosis of fetal sex chromosome and trisomy 18. Combined cytogenetic and molecular techniques are required to ensure an accurate diagnosis. PMID- 25449089 TI - [Analysis of linkage disequilibrium and linkage for 12 short tandem repeat loci on chromosome X]. AB - OBJECTIVE: To analyze linkage disequilibrium of 12 short tandem repeat loci on chromosome X (X-STR) among an ethnic Han population from Guilin, Guangxi, and to study the genetic linkage and haplotype distributions of such loci in 2 linkage groups. METHODS: 12 X-STR loci including DXS8378, DXS10159, DXS10162, DXS10164, DXS981, DXS6789, DXS7424, DXS101, DXS7133, GATA165B12, GATA31E08 and DXS7423 were genotyped using an AGCU X12 STR PCR Amplification kit. A total of 119 pedigrees were analyzed for linkage and linkage disequilibrium. RESULTS: Two mutations were found at DXS7424, and 1 mutation was found at DXS10164. A total of 93 haplotypes of DXS10159-DXS10162-DXS10164 were constructed for 261 unrelated males and females, in addition with 167 haplotypes of DXS6789-DXS7424-DXS101-DXS7133. The values of recombination fraction between DXS10159 and DXS10162, DXS10162 and DXS10164, DXS6789 and DXS7424, and DXS7424 and DXS101 were 0.0269, 0.0236, 0.0505 and 0.0438, respectively. CONCLUSION: Linkage disequilibrium of X-STR does not only depend on physical and genetic distances. There was incomplete linkage relationship between loci on DXS10159-DXS1016-DXS10164 and DXS6789-DXS7424-DXS101 linkage groups. PMID- 25449090 TI - [Molecular genetic analysis of a weak D phenotype]. AB - OBJECTIVE: To explore the molecular basis for an individual with a rare weak D phenotype. METHODS: Serological methods were used to characterize the RhD blood group phenotype. The exons of RHD gene were amplified with PCR and sequenced. The presence of Rhesus box was tested by PCR to determine the homozygosity of RHD gene. RESULTS: The RhD blood group of the proband was detected as weak D. The 10 exons of the RHD gene and Rhesus box could be amplified by PCR, and the genotype of RHD alleles was determined as RHD+/RHD-. The exons of the RHD gene were sequenced, and a 365C>T mutation in exon 3 was detected. Therefore, the RhD blood group of the proband was confirmed as weak D type 54 by both serological methods and DNA sequencing. CONCLUSION: A weak D type 54 has been detected. A 365C>T mutation in RHD gene is responsible for the low expression of D antigen. PMID- 25449091 TI - [Nucleotide sequence analysis for a new HLA-B allele HLA-B*13:01:06*]. AB - OBJECTIVE: To confirm a new allele HLA-B*13:01:06 and analyze its nucleotide sequence. METHODS: Genomic DNA was extracted using a Qiagen DNA extraction kit. Nucleotide sequences of HLA-A, HLA-B, HLA-C and HLA-DRB1 were analyzed by polymerase chain reaction-sequence based typing (PCR-SBT). HLA high-resolution results were assigned, and the nucleotide sequences of HLA-B locus was compared with that of HLA-B*13:01:01. RESULTS: The nucleotide sequence of the new allele shows a strong similarity to that of HLA-B*13:01:01. One nucleotide in exon 2 has changed from G to A at position 219 (codon 49 GCG>GCA), which however did not result in amino acid change. CONCLUSION: The novel allele verified by sequencing has been submitted to GenBank and officially named as HLA-B*13:01:06 by the World Health Organization HLA Nomenclature Committee. PMID- 25449092 TI - [Analysis of frequency of a RHD1227A allele in Chinese Hans]. AB - OBJECTIVE: To determine the frequency of RHD1227A allele in Chinese Hans. METHODS: For a total of 890403 ethnic Han blood donors, the D antigen was determined with a saline method and indirect antiglobulin test. The RHD1227A allele and number and type of zygosity of RHD gene were determined with PCR sequence specific primer (PCR-SSP). Allelic frequency was calculated through statistics. RESULTS: In total 2385 donors were found to be Rh-negative, 108 individuals were found to be weakly positive for D antigen (including weak D and partial D phenotypes). The remaining 887 910 individuals were Rh-positive. Among the Rh-negative individuals, 516 were found with RHD1227A. Among these, 467 were RHD1227A/d and 49 were RHD1227A/RHD1227A. Two of 108 D antigen weak-positive individuals were found as RHD1227A/RHD+. In addition, 8 of 1073 random Rh positive samples were found to be RHD1227A/RHD+. The allele frequency of RHD1227A in the population was calculated as 0.004 036. The figure should be 0.006 682 if calculated based on the detected rate of the allele in Rh-negative individuals, and 0.007 884 if calculated based on the reported average phenotype rate of DEL in Rh-negative individuals. CONCLUSION: By taking main influencing factors such as the RHD zygosity, the rate of RHD1227A and DEL phenotype may be determined. The allele frequency of RHD1227A in Chinese Hans is between 0.004 036 and 0.007 884. PMID- 25449093 TI - [A pedigree with familial cortical myoclonic epilepsy]. PMID- 25449094 TI - Effects of Tityus serrulatus scorpion venom on thromboelastogram in rats. AB - Thromboelastometry was used to evaluate blood coagulation in anesthetized rats after intravenous administration of Tityus serrulatus scorpion venom (Tx). Tracheostomy followed by catheterization of the left jugular vein and right carotid artery were performed for Tx or Ringer's lactate solution injection and blood sample harvesting, respectively. Blood samples were obtained at the beginning of the experiments (baseline) and at two, five, 15, 30, and 60 min after intoxication. The following coagulation parameters were analyzed: CT (Clotting Time), CFT (Clotting Formation Time), Alpha Angle (alpha), MCF (Maximum Clot Firmness) and TPI (Thrombodynamic Potential Index). Toxin-induced hypercoagulability was demonstrated at the 15 and 60 min. We hypothesize Tx induced hypercoagulability and enhanced clot formation could be explained by catecholamine release, systemic inflammatory response, and complement system activation, at least in the first hour after envenomation. Further studies are needed to determine the molecular mechanism of Tx-induced coagulopathy. PMID- 25449095 TI - Isolation, purification and functional characterization of alpha-BnIA from Conus bandanus venom. AB - We report the isolation and characterization by proteomic approach of a native conopeptide, named BnIA, from the crude venom of Conus bandanus, a molluscivorous cone snail species, collected in the South central coast of Vietnam. Its primary sequence was determined by matrix-assisted laser desorption/ionization time-of flight tandem mass spectrometry using collision-induced dissociation and confirmed by Edman's degradation of the pure native fraction. BnIA was present in high amounts in the crude venom and the complete sequence of the 16 amino acid peptide was the following GCCSHPACSVNNPDIC*, with C-terminal amidation deduced from Edman's degradation and theoretical monoisotopic mass calculation. Sequence alignment revealed that its -C1C2X4C3X7C4- pattern belongs to the A-superfamily of conopeptides. The cysteine connectivity of BnIA was 1-3/2-4 as determined by partial-reduction technique, like other alpha4/7-conotoxins, reported previously on other Conus species. Additionally, we found that native alpha-BnIA shared the same sequence alignment as Mr1.1, from the closely related molluscivorous Conus marmoreus venom, in specimens collected in the same coastal region of Vietnam. Functional studies revealed that native alpha-BnIA inhibited acetylcholine-evoked currents reversibly in oocytes expressing the human alpha7 nicotinic acetylcholine receptors, and blocked nerve-evoked skeletal muscle contractions in isolated mouse neuromuscular preparations, but with ~200-times less potency. PMID- 25449096 TI - High-throughput quantitative analysis of domoic acid directly from mussel tissue using Laser Ablation Electrospray Ionization - tandem mass spectrometry. AB - Eliminating sample extraction or liquid chromatography steps from methods for analysis of the neurotoxin Domoic Acid (DA) in shellfish could greatly increase throughput in food safety testing laboratories worldwide. To this end, we have investigated the use of Laser Ablation Electrospray Ionization (LAESI) with tandem mass spectrometry (MS/MS) detection for DA analysis directly from mussel tissue homogenates without sample extraction, cleanup or separation. DA could be selectively detected directly from mussel tissue homogenates using MS/MS in selected reaction monitoring scan mode. The quantitative capabilities of LAESI MS/MS for DA analysis from mussel tissue were evaluated by analysis of four mussel tissue reference materials using matrix-matched calibration. Linear response was observed from 1 mg/kg to 40 mg/kg and the method limit of detection was 1 mg/kg. Results for DA analysis in tissue within the linear range were in good agreement with two established methods, LC-UV and LC-MS/MS (recoveries from 103 to 125%). Beyond the linear range, extraction and clean-up were required to achieve good quantitation. Most notable is the extremely rapid analysis time of about 10 s per sample by LAESI-MS/MS, which corresponds to a significant increase in sample throughput compared with existing methodology for routine DA analysis. PMID- 25449097 TI - DisBa-01 inhibits angiogenesis, inflammation and fibrogenesis of sponge-induced fibrovascular tissue in mice. AB - Integrins are involved in a number of physio-pathological processes including wound healing, chronic inflammation and neoplasias. Blocking its activity is potentially of therapeutic value in these conditions. We investigated whether DisBa-01, a recombinant His-tag RGD-disintegrin from Bothrops alternatus snake venom, could modulate key events (inflammatory cell recruitment/activation, neovascularization and extracellular matrix deposition) of the proliferative fibrovascular tissue induced by polyether polyurethane sponge implants in mice. The hemoglobin content (MUg/mg wet tissue), blood flow measurements (laser Doppler perfusion imaging) and number of vessels in the implants, used as indices of vascularization, showed that the disintegrin dose-dependently reduced angiogenesis in the implants relative to the Saline-treated group. DisBa-01 inhibited neutrophil and macrophage content as determined by the myeloperoxidase (MPO) and N-acetyl-beta-D-glucosaminidase (NAG) activities, respectively. Similarly, down regulation of the fibrogenic component studied (collagen deposition) was observed in DisBa-01-treated implants. VEGF, bFGF, TNF-alpha, CXCL1 and CCL2 levels were also decreased by the disintegrin. The inhibitory effect of this alphavbeta3-blocking disintegrin on the angiogenic, inflammatory, and fibrogenic components of the fibrovascular tissue induced by the synthetic matrix extends the range of DisBa-01 actions and may indicate its therapeutic potential in controlling angiogenesis in fibroproliferative diseases. PMID- 25449098 TI - Jingzhaotoxin-35, a novel gating-modifier toxin targeting both Nav1.5 and Kv2.1 channels. AB - Jingzhaotoxin-35 (JZTX-35), a 36-residue polypeptide, was purified from the venom of the Chinese tarantula Chilobrachys jingzhao. JZTX-35 inhibited Nav1.5 and Kv2.1 currents with the IC50 value of 1.07 MUM and 3.62 MUM, respectively, but showed no significant effect on either Na(+) currents or Ca(2+) currents evoked in hippocampal neurons. It shifted the activation of the Nav1.5 and Kv2.1 channels to more depolarized voltages, and markedly shifted the steady-state inactivation of Nav1.5 currents toward more hyperpolarized potentials. Moreover, JZTX-35 can bind to a close state of Nav1.5 and Kv2.1 channels. These results indicate that JZTX-35 is a new gating modifier toxin. JZTX-35 shares high sequence similarity with Jingzhaotoxins (JZTXs) targeting Nav1.5 or Kv2.1 channels, but they showed different ion channel selectivity. Structure-function analysis in this study would provide important clues for the exploration of ion channel selectivity of JZTXs. PMID- 25449099 TI - Maturity-related changes in venom toxicity of the freshwater stingray Potamotrygon leopoldi. AB - Aquatic venomous animals such as stingrays represent a largely untapped source for venom-based drug development. However, the major challenge for a potential drug development pipeline is the high inter- and intraspecific variability in toxicity and venom composition. As of today, little is known about maturity driven changes in these traits in stingrays. The present study investigates the differences in toxicity and venom composition in different maturity stages of the freshwater stingray Potamotrygon leopoldi. This species can be found in the Xingu River basin (Brazil), where it mainly feeds on invertebrates, while being predated by other stingrays or large catfishes. P. leopoldi, as commonly known for stingrays, can cause severe injuries with the venomous dentine spine located at its tails. The toxicity of tissue extracts of juvenile and mature specimens was recorded on a myoblast cell culture bioassay. Venom composition and bioactivity of compounds were analyzed with planar chromatography linked to an Aliivibrio fischeri bioassay. Results revealed a decrease in venom toxicity during maturation, but no changes in venom composition. These findings may indicate that toxicity in mature specimens becomes evolutionary less important, probably due to a decrease in predation pressure. PMID- 25449100 TI - Modulated mechanism of phosphatidylserine on the catalytic activity of Naja naja atra phospholipase A2 and Notechis scutatus scutatus notexin. AB - Phosphatidylserine (PS) externalization is a hallmark for apoptotic death of cells. Previous studies showed that Naja naja atra phospholipase A2 (NnaPLA2) and Notechis scutatus scutatus notexin induced apoptosis of human cancer cells. However, NnaPLA2 and notexin did not markedly disrupt the integrity of cellular membrane as evidenced by membrane permeability of propidium iodide. These findings reflected that the ability of NnaPLA2 and notexin to hydrolyze membrane phospholipids may be affected by PS externalization. To address that question, this study investigated the membrane-interacted mode and catalytic activity of NnaPLA2 and notexin toward outer leaflet (phosphatidylcholine/sphingomyelin/cholesterol, PC/SM/Chol) and inner leaflet (phosphatidylserine/phosphatidylethanolamine/cholesterol, PS/PE/Chol) of plasma membrane-mimicking vesicles. PS incorporation promoted enzymatic activity of NnaPLA2 and notexin on PC and PC/SM vesicles, but suppressed NnaPLA2 and notexin activity on PC/SM/Chol and PE/Chol vesicles. PS incorporation increased the membrane fluidity of PC vesicles but reduced membrane fluidity of PC/SM, PC/SM/Chol and PE/Chol vesicles. PS increased the phospholipid order of all the tested vesicles. Moreover, PS incorporation did not greatly alter the binding affinity of notexin and NnaPLA2 with phospholipid vesicles. Acrylamide quenching studies and trinitrophenylation of Lys residues revealed that membrane-bound mode of notexin and NnaPLA2 varied with the targeted membrane compositions. The fine structure of catalytic site in NnaPLA2 and notexin in all the tested vesicles showed different changes. Collectively, the present data suggest that membrane inserted PS modulates PLA2 interfacial activity via its effects on membrane structure and membrane-bound mode of NnaPLA2 and notexin, and membrane compositions determine the effect of PS on PLA2 activity. PMID- 25449101 TI - Confirmation of extensive natural distribution of azaspiracids in the tissue compartments of mussels (Mytilus edulis). AB - Liquid chromatography multiple tandem mass spectrometry (LC-MS/MS) has been applied to demonstrate that azaspiracid (AZA1), its isomer, AZA6, and its methyl- and demethyl-analogues, AZA2 and AZA3 respectively, are distributed throughout mussel (Mytilus edulis) tissue compartments. Large differences in both the toxin content and the toxin profiles were observed in 20 individual mussels from the same batch. The toxin levels found in the hepatopancreas of mussels were, AZA1 (0.02-5.0 MUg/g); AZA2 (0.12-1.9 MUg/g), AZA3 (0.06-0.88 MUg/g) and AZA6 (0.05 2.0 MUg/g). This study also examined the toxin content in mussel tissue compartments and it was found that the gills contributed significantly to the overall level of toxins in mussels. Although polyether toxins are usually concentrated in the hepatopancreas of shellfish this is not always the situation with azaspiracids. The mean distribution of azaspiracids in mussels was; hepatopancreas (60.6%), gills (12.0%) and adductor muscle (27.4%). PMID- 25449102 TI - Epithelium specific ETS transcription factor, ESE-3, of Protobothrops flavoviridis snake venom gland transactivates the promoters of venom phospholipase A2 isozyme genes. AB - Protobothrops flavoviridis (habu) (Crotalinae, Viperidae) is a Japanese venomous snake, and its venom contains the enzymes with a variety of physiological activities. The phospholipases A2 (PLA2s) are the major components and exert various toxic effects. They are expressed abundantly in the venom gland. It is thought that the venom gland-specific transcription factors play a key role for activation of PLA2 genes specifically expressed in the venom gland. Thus, the full-length cDNA library for P. flavoviridis venom gland after milking of the venom was made to explore the transcription factors therein. As a result, three cDNAs encoding epithelium-specific ETS transcription factors (ESE)-1, -2, and -3 were obtained. Among them, ESE-3 was specifically expressed in the venom gland and activated the proximal promoters of venom PLA2 genes, which are possibly regarded as the representatives of the venom gland-specific protein genes in P. flavoviridis. Interestingly, the binding specificity of ESE-3 to the ETS binding motif located near TATA box is well correlated with transcriptional activities for the venom PLA2 genes. This is the first report that venom gland-specific transcription factor could actually activate the promoters of the venom protein genes. PMID- 25449103 TI - Testing the Toxicofera: comparative transcriptomics casts doubt on the single, early evolution of the reptile venom system. AB - The identification of apparently conserved gene complements in the venom and salivary glands of a diverse set of reptiles led to the development of the Toxicofera hypothesis - the single, early evolution of the venom system in reptiles. However, this hypothesis is based largely on relatively small scale EST based studies of only venom or salivary glands and toxic effects have been assigned to only some putative Toxicoferan toxins in some species. We set out to examine the distribution of these proposed venom toxin transcripts in order to investigate to what extent conservation of gene complements may reflect a bias in previous sampling efforts. Our quantitative transcriptomic analyses of venom and salivary glands and other body tissues in five species of reptile, together with the use of available RNA-Seq datasets for additional species, shows that the majority of genes used to support the establishment and expansion of the Toxicofera are in fact expressed in multiple body tissues and most likely represent general maintenance or "housekeeping" genes. The apparent conservation of gene complements across the Toxicofera therefore reflects an artefact of incomplete tissue sampling. We therefore conclude that venom has evolved multiple times in reptiles. PMID- 25449104 TI - Effects of nitrogen and phosphorus on anatoxin-a, homoanatoxin-a, dihydroanatoxin a and dihydrohomoanatoxin-a production by Phormidium autumnale. AB - Anatoxins are powerful neuromuscular blocking agents produced by some cyanobacteria. Consumption of anatoxin-producing cyanobacterial mats or the water containing them has been linked to numerous animal poisonings and fatalities worldwide. Despite this health risk, there is a poor understanding of the environmental factors regulating anatoxin production. Non-axenic Phormidium autumnale strain CAWBG557 produces anatoxin-a (ATX), homoanatoxin-a (HTX) and their dihydrogen-derivatives dihydroanatoxin-a (dhATX) and dihydrohomoanatoxin-a (dhHTX). The effects of varying nitrogen and phosphorus concentrations on the production of these four variants were examined in batch monocultures. The anatoxin quota (anatoxin per cell) of all four variants increased up to four fold in the initial growth phase (days 0-9) coinciding with the spread of filaments across the culture vessel during substrate attachment. Dihydroanatoxin-a and dhHTX, accounted for over 60% of the total anatoxin quota in each nitrogen and phosphorus treatment. This suggests they are being internally synthesised and not just derived following cell lysis and environmental degradation. The four anatoxin variants differed in their response to varying nitrogen and phosphorus concentrations. Notably, dhATX quota significantly decreased (P <= 0.03) when nitrogen and phosphorus concentrations were elevated (nitrogen = 21 mg L(-1); phosphorus = 3 mg L(-1)), while HTX quota increased when the phosphorus concentrations were reduced (ca. < 0.08 mg L(-1)). This is of concern as HTX has a high toxicity and anatoxin producing P. autumnale blooms in New Zealand usually occur in rivers with low water column dissolved reactive phosphorus. PMID- 25449105 TI - Not as docile as it looks? Loxosceles venom variation and loxoscelism in the Mediterranean Basin and the Canary Islands. AB - The medical importance of Loxosceles spiders has promoted extensive research on different aspects of their venoms. Most of the reported cases of loxoscelism have occurred in the Americas, and thus, much work has focused on North and South American Loxosceles species. Interestingly, loxoscelism cases are rare in the Mediterranean Basin although Loxosceles rufescens, endemic to the Mediterranean, is an abundant spider even in human-altered areas. Thus, it has been suggested that the venom of L. rufescens could be of less medical relevance than that of its congeners. In this study, we challenge this hypothesis by using multiple approaches to study venom variation in selected species and lineages from the Mediterranean Basin and the Canary Islands. We found that SMase D activity, the key bioactive component of Loxosceles venom, is comparable to American species that are confirmed to have medically relevant bites. The venom protein composition using SDS-PAGE presents some differences among regional Loxosceles taxa in banding pattern and intensity, mostly between the Canarian and L. rufescens lineages. Differences between these species also exist in the expression of different paralogs of the SicTox gene family, with the Canarian species being less diverse. In conclusion, our results do not support the challenged hypothesis, and suggest that venom of these species may indeed be as potent as other Loxosceles species. Pending confirmation of loxoscelism with direct evidence of Loxosceles bites with species identification by professionals, Loxosceles in the Mediterranean region should conservatively be considered medically relevant taxa. PMID- 25449106 TI - CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes. AB - Cancer-specific splice variants gain significant interest as they generate neo antigens that could be targeted by immune cells. CD20, a membrane antigen broadly expressed in mature B cells and in B cell lymphomas, is subject to an alternative splicing named D393-CD20 leading to loss of membrane expression of the spliced isoform. D393-CD20 expression is detectable in transformed B cells and upregulated in various lymphoma B cells. In this study, we show that D393-CD20 is translated in malignant B cells and that D393-CD20 specific CD4 T cells producing IFN-gamma are present in B-cell lymphoma patients. Then, we have investigated whether the 20mer D393-CD20 peptide spanning the splicing site might be targeted by the immune system and we have shown that D393-CD20-specific CD4 Th1 clones could directly recognize malignant B cell lines and kill autologous lymphoma B cells indicating that D393-CD20-derived epitopes are naturally processed and presented on tumor cells. Finally, D393-CD20 peptide-based vaccination induced specific CD8 and CD4 T cell responses in HLA-humanized transgenic mice suggesting the presentation of D393-CD20 derived peptides on both HLA Class-I and -II. These findings support further investigations on the potential use of D393-CD20 directed specific immunotherapy in B cell malignancies. PMID- 25449107 TI - The development of an industrial-scale fed-batch fermentation simulation. AB - This paper describes a simulation of an industrial-scale fed-batch fermentation that can be used as a benchmark in process systems analysis and control studies. The simulation was developed using a mechanistic model and validated using historical data collected from an industrial-scale penicillin fermentation process. Each batch was carried out in a 100,000 L bioreactor that used an industrial strain of Penicillium chrysogenum. The manipulated variables recorded during each batch were used as inputs to the simulator and the predicted outputs were then compared with the on-line and off-line measurements recorded in the real process. The simulator adapted a previously published structured model to describe the penicillin fermentation and extended it to include the main environmental effects of dissolved oxygen, viscosity, temperature, pH and dissolved carbon dioxide. In addition the effects of nitrogen and phenylacetic acid concentrations on the biomass and penicillin production rates were also included. The simulated model predictions of all the on-line and off-line process measurements, including the off-gas analysis, were in good agreement with the batch records. The simulator and industrial process data are available to download at www.industrialpenicillinsimulation.com and can be used to evaluate, study and improve on the current control strategy implemented on this facility. PMID- 25449108 TI - Enhancement of protocatechuate decarboxylase activity for the effective production of muconate from lignin-related aromatic compounds. AB - The decarboxylation reaction of protocatechuate has been described as a bottleneck and a rate-limiting step in cis,cis-muconate (ccMA) bioproduction from renewable feedstocks such as sugar. Because sugars are already in high demand in the development of many bio-based products, our work focuses on improving protocatechuate decarboxylase (Pdc) activity and ccMA production in particular, from lignin-related aromatic compounds. We previously had transformed an Escherichia coli strain using aroY, which had been used as a protocatechuate decarboxylase encoding gene from Klebsiella pneumoniae subsp. pneumoniae A170-40, and inserted other required genes from Pseudomonas putida KT2440, to allow the production of ccMA from vanillin. This recombinant strain produced ccMA from vanillin, however the Pdc reaction step remained a bottleneck during incubation. In the current study, we identify a way to increase protocatechuate decarboxylase activity in E. coli through enzyme production involving both aroY and kpdB; the latter which encodes for the B subunit of 4-hydroxybenzoate decarboxylase. This permits expression of Pdc activity at a level approximately 14-fold greater than the strain with aroY only. The expression level of AroY increased, apparently as a function of the co-expression of AroY and KpdB. Our results also imply that ccMA may inhibit vanillate demethylation, a reaction step that is rate limiting for efficient ccMA production from lignin-related aromatic compounds, so even though ccMA production may be enhanced, other challenges to overcome vanilate demethylation inhibition still remain. PMID- 25449109 TI - Acyl-CoA sensing by FasR to adjust fatty acid synthesis in Corynebacterium glutamicum. AB - Corynebacterium glutamicum, like Mycobacterium tuberculosis, is a member of the Corynebacteriales, which have linear fatty acids and as branched fatty acids the mycolic acids. We identified accD1 and fasA as key genes of fatty acid synthesis, encoding the beta-subunit of the acetyl-CoA carboxylase and a type-I fatty acid synthase, respectively, and observed their repression during growth on minimal medium with acetate. We also identified the transcriptional regulator FasR and its binding sites in the 5' upstream regions of accD1 and fasA. In the present work we establish by co-isolation and gel-mobility shifts oleoyl-CoA and palmitoyl-CoA as effectors of FasR, and show by DNA microarray analysis that in presence of exogeneous fatty acids accD1 and fasA are repressed. These results are evidence that acyl-CoA derivatives derived from extracellular fatty acids interact with FasR to repress the genes of fatty acid synthesis. This model also explains the observed repression of accD1 and fasA during growth on acetate, where apparently the known high intracellular acetyl-CoA concentration during growth on this substrate requires reduced accD1 and fasA expression for fine control of de novo fatty acid synthesis. Consequently, this mechanism ensures that membrane lipid homeostasis is maintained when specific nutrients are available resulting in increased acetyl-CoA concentration, as is the case with acetate, or when fatty acids are directly available from the extracellular environment. However, the genes specific to mycolic acid synthesis, which are in part shared with linear fatty acid synthesis, are not controlled by FasR, which is in agreement with the fact that they can not be supplied from the extracellular environment but that their synthesis fully depends on a constant supply of linear fatty acid chains. PMID- 25449110 TI - Co-expression of disulfide oxidoreductases DsbA/DsbC markedly enhanced soluble and functional expression of reteplase in Escherichia coli. AB - Reteplase is the third generation of thrombolytic medicine and has many advantages over commercial t-PA. However, over-expressing recombinant reteplase in E. coli always accumulates as inclusion bodies due to nine pairs of disulfide bonds formation that is the main obstacle for correct folding. In this paper, in order to enhance soluble expression of recombinant reteplase in E. coli, DsbA/DsbC foldases were used to introduce disulfide bonds into the reduced polypeptide chain and catalyze their isomerization to the native disulfide linkage during the folding process. Firstly multiple E. coli protein expression systems, i.e. DsbA, DsbC and DsbA/DsbC co-expression were constructed. Subsequently, IPTG and l-arabinose were added to induce expression of foldases and reteplase accordingly, and experimental parameters such as culture temperature and inducer concentration were optimized. As a result, the co expression system markedly enhanced soluble expression of recombinant reteplase, and up to 60% of reteplase achieved soluble expression especially for the DsbC co expression system. The fibrin plate method for active reteplase quantification showed that ~70 mg soluble reteplase per liter fermentation broth was obtained with 2.35 * 105 IU/mg thrombolytic activity. Finally, fluorescence spectra indicated that the structural conformation of soluble reteplase was identical to its native state. The soluble expression of recombinant reteplase in E. coli was accomplished by co-expression with DsbA/DsbC, which contributes to further research in clinical application and folding mechanism, and provides guidance for production of other proteins with disulfide bonds. PMID- 25449111 TI - Improvement of the stability and activity of the BPO-A1 haloperoxidase from Streptomyces aureofaciens by directed evolution. AB - Haloperoxidases are oxygenases that catalyze the halogenation of a range of organic compounds without the need for additional high-cost cofactors. Thus, haloperoxidases with high activity and stability are desired for industrial application. In this study, a directed evolution approach was adopted to improve the thermostability of the homodimeric BPO-A1 haloperoxidase from Streptomyces aureofaciens. Among 1000 mutant BPO-A1 haloperoxidases, 2 mutants HT177 and HT507, having higher thermostabilities than the wild-type BPO-A1 haloperoxidase, were obtained by directed evolution. The residual activities of mutants HT177 and HT507 were 2.3- and 5.1-fold higher than that of wild-type BPO-A1, respectively, after incubation at 80 degrees C for 1 h. In addition, mutant HT177 showed higher stability in organic solvents, such as methanol, ethanol, dimethyl sulfoxide, and N,N-dimethylformamide, than the wild-type BPO-A1 haloperoxidase. Furthermore, mutant HT507 showed higher specific activity. Based on the evaluation of single-amino-acid-substituted mutants, stabilization of the alpha helix conformation, substitution of amino acid residues located at the surface of the protein molecule, and enhancement of the interaction between subunits may account for the improvement in thermostability, organic solvent stability, and specific activity. Consequently, the thermostability, organic solvent stability, and specific activity of S. aureofaciens BPO-A1 haloperoxidase were successfully improved by a directed evolution approach. PMID- 25449112 TI - A rapid method of accurate detection and differentiation of Newcastle disease virus pathotypes by demonstrating multiple bands in degenerate primer based nested RT-PCR. AB - A rapid and accurate method of detection and differentiation of virulent and avirulent Newcastle disease virus (NDV) pathotypes was developed. The NDV detection was carried out for different domestic avian field isolates and pigeon paramyxo virus-1 (25 field isolates and 9 vaccine strains) by using APMV-I "fusion" (F) gene Class II specific external primer A and B (535bp), internal primer C and D (238bp) based reverses transcriptase PCR (RT-PCR). The internal degenerative reverse primer D is specific for F gene cleavage position of virulent strain of NDV. The nested RT-PCR products of avirulent strains showed two bands (535bp and 424bp) while virulent strains showed four bands (535bp, 424bp, 349bp and 238bp) on agar gel electrophoresis. This is the first report regarding development and use of degenerate primer based nested RT-PCR for accurate detection and differentiation of NDV pathotypes by demonstrating multiple PCR band patterns. Being a rapid, simple, and economical test, the developed method could serve as a valuable alternate diagnostic tool for characterizing NDV isolates and carrying out molecular epidemiological surveillance studies for this important pathogen of poultry. PMID- 25449113 TI - Quantitative RT-PCR evaluation of a rapid influenza antigen test for efficient diagnosis of influenza virus infection. AB - Influenza virus infection is diagnosed in most cases using a rapid influenza antigen diagnostic test (RIDT). However, false-negative results are a major concern. By contrast, the nucleic acid amplification test offers high sensitivity and therefore can aid the interpretation of negative RIDT results. In this study, influenza viral loads were quantified with quantitative reverse transcription polymerase chain reaction (qRT-PCR) using viral suspensions left over after RIDT, and the performance of both methods was evaluated. qRT-PCR detected as few as 10(3)copies/mL of influenza viruses A and B, whereas RIDT showed negative results for viral loads less than 10(7) and 10(5)copies/mL of influenza viruses A and B, respectively. These results indicate that small quantities of the virus that cause false-negative RIDT results can be detected efficiently with qRT-PCR follow up. In addition, influenza A virus subtype was determined using qRT-PCR. PMID- 25449114 TI - What will be the role of first-trimester ultrasound if cell-free DNA screening for aneuploidy becomes routine? PMID- 25449115 TI - Re: influence of parity on fetal hemodynamics and amniotic fluid volume at term. T. Prior, E. Mullins, P. Bennett and S. Kumar. Ultrasound Obstet Gynecol 2014; 44: 688-692. PMID- 25449116 TI - Re: Office gel sonovaginography for the prediction of posterior deep infiltrating endometriosis: a multicenter prospective observational study. S. Reid, C. Lu, N. Hardy, I. Casikar, G. Reid, G. Cario, D. Chou, D. Almashat and G. Condous. Ultrasound Obstet Gynecol 2014; 44: 710-718. PMID- 25449117 TI - How to perform an amniocentesis. PMID- 25449120 TI - Dimethyl fumarate attenuates 6-OHDA-induced neurotoxicity in SH-SY5Y cells and in animal model of Parkinson's disease by enhancing Nrf2 activity. AB - Oxidative stress is central to the pathology of several neurodegenerative diseases, including Parkinson's disease (PD), and therapeutics designed to enhance antioxidant potential could have clinical value. In this study, we investigated whether dimethyl fumarate (DMF) has therapeutic effects in cellular and animal model of PD, and explore the role of nuclear transcription factor related to NF-E2 (Nrf2) in this process. Treatment of animals and dopaminergic SH SY5Y cells with DMF resulted in increased nuclear levels of active Nrf2, with subsequent upregulation of antioxidant target genes. The cytotoxicity of 6 hydroxydopamine (6-OHDA) was reduced by pre-treatment with DMF in SH-SY5Y cells. The increase in the reactive oxygen species caused by 6-OHDA treatment was also attenuated by DMF in SH-SY5Y cells. The neuroprotective effects of DMF against 6 OHDA neurotoxicity were dependent on Nrf2, since treatment with Nrf2 siRNA failed to block against 6-OHDA neurotoxicity and induce Nrf2-dependent cytoprotective genes in SH-SY5Y cells. In vivo, DMF oral administration was shown to upregulate mRNA and protein levels of Nrf2 and Nrf2-regulated cytoprotective genes, attenuate 6-OHDA induced striatal oxidative stress and inflammation in C57BL/6 mice. Moreover, DMF ameliorated dopaminergic neurotoxicity in 6-OHDA-induced PD animal models as evidenced by amelioration of locomotor dysfunction, loss in striatal dopamine, and reductions in dopaminergic neurons in the substantia nigra and striatum. Taken together, these data strongly suggest that DMF may be beneficial for the treatment of neurodegenerative diseases like PD. PMID- 25449121 TI - Injectable radiopaque and bioactive polycaprolactone-ceramic composites for orthopedic augmentation. AB - The aim of this study was to develop and characterize an injectable bone void filler by incorporating baghdadite (Ca3 ZrSi2 O9 ) particles (average size of 1.7 um) into polycaprolactone (PCL). A series of PCL composites containing different volume percentages of baghdadite [1 (PCL-1%Bag), 5 (PCL-5%Bag), 10 (PCL-10%Bag), 20 (PCL-20%Bag), and 30 (PCL-30%Bag)] were prepared, and their injectability, setting time, mechanical properties, radiopacity, degradation, and cytocompatibility were investigated. PCL, PCL-1%Bag, PCL-5%Bag, and PCL-10%Bag were able to be injected through a stainless steel syringe (Length: 9.0 mm, nozzle diameter: 2.2 mm) at 75 degrees C at injection forces of below 1.5 kN. The core temperature of the injected material at the nozzle exit ranged between 55 and 60 degrees C and was shown to set after 2.5-3.5 min postinjection in a 37 degrees C environment. Injection force, melt viscosity, and radiopacity of the composites increased with increasing baghdadite content. Incorporation of 10-30 vol % baghdadite into PCL increased the compressive strength of the composites from 36 to 47.1 MPa, compared with that for pure PCL (31.4 MPa). Similar trend was found for the compressive modulus of the composites, which increased from 203.8 to 741 MPa, compared with that for pure PCL (205 MPa). Flexural strain of PCL, PCL-5%Bag, and PCL-10%Bag exceeded 30%, and PCL-10%Bag showed the highest flexural strength (29.8 MPa). Primary human osteoblasts cultured on PCL-10%Bag showed a significant upregulation of osteogenic genes compared with pure PCL. In summary, our results demonstrated that PCL-10%Bag could be a promising injectable material for orthopedic and trauma application. PMID- 25449122 TI - Functional characterization of a type 3 metallolthionein isoform (OsMTI-3a) from rice. AB - Metallothioneins (MTs) are low-molecular weight proteins with high Cys content and a high affinity for metals. Plant MTs are classified into four types based on the arrangement of Cys in their amino acid sequences. In the present study, the gene encoding OsMTI-3a, a type 3 MT found in rice, was cloned into pET41a vector. The resulting construct was transformed into the Escherichia coli strain Rosetta (DE3). Following the induction with isopropyl beta-D-1-thiogalactopyranoside, the OsMTI-3a was expressed as glutathione-S-transferase (GST)-tagged fusion protein. In comparison to control strain, the cells expressing GST-OsMTI-3a accumulated more Cd(2+), Ni(2+) and Zn(2+) when they were grown in the medium containing CdCl2, NiCl2 or ZnSO4. The recombinant GST-OsMTI-3a was purified using affinity chromatography. The UV absorption spectra recorded after the reconstitution of the apo-protein with different metals confirmed that GST-OsMTI-3a was able to form complexes with Cd(2+), Ni(2+), and Zn(2+). The reaction of the protein-metal complexes with 5-5-dithiobis (2-nitrobenzoic) revealed that the order of affinity of GST-OsMTI-3a toward different metals was Ni(2+)>=Cd(2+)>Zn(2+)>Cu(2+). PMID- 25449123 TI - Development and optimization of modified release IPN macromolecules of oxcarbazepine using natural polymers. AB - The study shows development and optimization of modified release interpenetrating polymer network (IPN) macromolecules (beads) of oxcarbazepine using sodium alginate-egg albumin prepared by ionotropic gelation method and CaCl2 as a cross linker. Independent variables were identified based on preliminary study of investigation. The effect of amount of both polymers on drug entrapment efficiency (DEE,%), bead size (MUm) and cumulative drug release at 8 h (Q8h, %) were optimized using 3(2) factorial design. The DEE, average size and Q8h were found in the range of 65.08-91.02%, 976-1084 MUm and 73.50-94.06% respectively. The beads were also characterized by FTIR, DSC, SEM and XRD. The experiential responses were coincided well with predicted values obtained by Design Expert((r)) 8.0.6.1 software. The swelling of beads were influenced by the pH of a release medium. The in vitro drug release from IPN beads exhibited sustained release Hixson-Crowell pattern with anomalous non-Fickian diffusion mechanism concluding that the developed sodium alginate-egg albumin IPN composite beads are suitable for sustained delivery of oxcarbazepine for desired period. PMID- 25449124 TI - Transcriptional upregulation centra of HO-1 by EGB via the MAPKs/Nrf2 pathway in mouse C2C12 myoblasts. AB - Long-term abuse of alcohol results in chronic alcoholic myopathy which is associated with increased oxidative stress. Ginkgo biloba extract (EGB) is widely used as a therapeutic agent to treat certain cardiovascular and neurological disorders. Although EGB is known to possess antioxidant functions and potent cytoprotective effects, its protective mechanism on alcohol-induced oxidative damage in C2C12 myoblasts remains unclear. In this study, we investigated the cytoprotective mechanisms of EGB against alcohol-derived oxidative stress in mouse C2C12 myoblasts. Challenge with alcohol (100mM) caused an increase in intracellular reactive oxygen species in mouse C2C12 myoblasts, which was not alleviated by treatment with EGB. These results indicate that EGB does not seem to act as an ROS scavenger in this experimental model. Additionally, EGB produced activation of ERK and JNK [two major mitogen-activated protein kinases (MAPKs)], an increase in the nuclear level of nuclear factor erythroid-2-related factor 2 (Nrf2) and upregulation of heme oxygenase-1 (HO-1, a stress-responsive protein with antioxidant function). Pretreatment with inhibitors of MAPKs PD98059 (a specific inhibitor of ERK), SP600125 (a specific inhibitor of JNK) abolished both EGB-induced Nrf2 nuclear translocation and HO-1 up-regulation. We conclude that EGB confers cytoprotective effects from oxidative stress induced by alcohol in mouse C2C12 myoblasts depend on transcriptional upregulation of HO-1 by EGB via the MAPKs/Nrf2 pathway. PMID- 25449125 TI - Endocrine disruptor activity of multiple environmental food chain contaminants. AB - Industrial chemicals, antimicrobials, drugs and personal care products have been reported as global pollutants which enter the food chain. Some of them have also been classified as endocrine disruptors based on results of various studies employing a number of in vitro/vivo tests. The present study employed a mammalian reporter gene assay to assess the effects of known and emerging contaminants on estrogen nuclear receptor transactivation. Out of fifty-nine compounds assessed, estrogen receptor agonistic activity was observed for parabens( n = 3), UV filters (n = 6), phthalates (n = 4) and a metabolite, pyrethroids (n = 9) and their metabolites (n = 3). Two compounds were estrogen receptor antagonists while some of the agonists enhanced 17b-estradiol mediated response.This study reports five new compounds (pyrethroids and their metabolites) possessing estrogen agonist activity and highlights for the first time that pyrethroid metabolites are of particular concern showing much greater estrogenic activity than their parent compounds. PMID- 25449126 TI - Melanogenesis and antioxidant defense system in normal human melanocytes cultured in the presence of chlorpromazine. AB - Chlorpromazine is used in the treatment of schizophrenia and psychotic disorders and belongs to phenothiazine class of neuroleptic drugs. It shows severe side effects such as extrapyramidal symptoms as well as ocular and skin disorders, but the mechanism is still not fully established. The aim of this study was to examine the effect of chlorpromazine on cell viability, melanogenesis and antioxidant defense system in normal human melanocytes. It has been demonstrated that chlorpromazine induces concentration dependent loss in cell viability. The value of EC(50) was calculated to be 2.53 MUM. Chlorpromazine in lower concentrations (0.0001, 0.001 and 0.01 MUM) increased the melanin and microphthalmia-associated transcription factor (MITF) content and tyrosinase activity, while changes of antioxidant enzymes activity were not observed. It suggests that long-term chlorpromazine therapy, even with low drug doses, may lead to hyperpigmentation disorders in skin and/or eye. The use of the analyzed drug in higher concentrations (0.1 and 1.0 MUM) caused significant alterations of antioxidant enzymes activity in normal melanocytes, what may explain a potential role of chlorpromazine in the depletion of cellular antioxidant status leading to other adverse effects associated with the high-dose and/or long-term therapy. PMID- 25449127 TI - Tweedle cuticular protein BmCPT1 is involved in innate immunity by participating in recognition of Escherichia coli. AB - Bombyx mori, a lepidopteran insect, is one of the earliest models for pattern recognition of Gram-negative bacteria, which may induce the IMD pathway for production of antibacterial peptides. So far, several recognition proteins have been reported in B. mori. However, the connection between pattern recognition of Gram negative bacteria and activation of BmRelish1, a transcription factor controlled by the IMD pathway remains largely unknown. In the present study, we identify BmCPT1, a cuticle protein bearing a Tweedle domain. Its gene expression is co-regulated by NF-kappaB and juvenile hormone signals. BmCPT1 is induced by Escherichia coli in fat bodies and hemocytes, but is constitutively expressed in the epidermis. In vitro binding assays indicate that BmCPT1 protein recognizes and binds to E. coli peptidoglycan. Post-transcriptionally modified BmCPT1 in the hemolymph binds to E. coli cells through interactions with peptidoglycan recognition protein-5 (BmPGRP5) and lipopolysaccharide binding protein (BmLBP). Transgenic overexpression of BmCPT1 causes the upregulated expression of BmRelish1 and clear induction of two gloverin genes. Therefore, BmCPT1 may work along with BmPGRP-S5 and BmLBP to recognize E. coli in the hemolymph and indirectly activate BmRelish1 to induce antimicrobial peptide synthesis. PMID- 25449128 TI - Pharmacological and signalling properties of a D2-like dopamine receptor (Dop3) in Tribolium castaneum. AB - Dopamine is an important neurotransmitter in the central nervous system of vertebrates and invertebrates. Despite their evolutionary distance, striking parallels exist between deuterostomian and protostomian dopaminergic systems. In both, signalling is achieved via a complement of functionally distinct dopamine receptors. In this study, we investigated the sequence, pharmacology and tissue distribution of a D2-like dopamine receptor from the red flour beetle Tribolium castaneum (TricaDop3) and compared it with related G protein-coupled receptors in other invertebrate species. The TricaDop3 receptor-encoding cDNA shows considerable sequence similarity with members of the Dop3 receptor class. Real time qRT-PCR showed high expression in both the central brain and the optic lobes, consistent with the role of dopamine as neurotransmitter. Activation of TricaDop3 expressed in mammalian cells increased intracellular Ca(2+) signalling and decreased NKH-477 (a forskolin analogue)-stimulated cyclic AMP levels in a dose-dependent manner. We studied the pharmacological profile of the TricaDop3 receptor and demonstrated that the synthetic vertebrate dopamine receptor agonists, 2 - amino- 6,7 - dihydroxy - 1,2,3,4 - tetrahydronaphthalene hydrobromide (6,7-ADTN) and bromocriptine acted as agonists. Methysergide was the most potent of the antagonists tested and showed competitive inhibition in the presence of dopamine. This study offers important information on the Dop3 receptor from Tribolium castaneum that will facilitate functional analyses of dopamine receptors in insects and other invertebrates. PMID- 25449129 TI - Chitin is a necessary component to maintain the barrier function of the peritrophic matrix in the insect midgut. AB - In most insects, the peritrophic matrix (PM) partitions the midgut into different digestive compartments, and functions as a protective barrier against abrasive particles and microbial infections. In a previous study we demonstrated that certain PM proteins are essential in maintaining the PM's barrier function and establishing a gradient of PM permeability from the anterior to the posterior part of the midgut which facilitates digestion (Agrawal et al., 2014). In this study, we focused on the effects of a reduction in chitin content on PM permeability in larvae of the red flour beetle, Tribolium castaneum. Oral administration of the chitin synthesis inhibitor diflubenzuron (DFB) only partially reduced chitin content of the larval PM even at high concentrations. We observed no nutritional effects, as larval growth was unaffected and neutral lipids were not depleted from the fat body. However, the metamorphic molt was disrupted and the insects died at the pharate pupal stage, presumably due to DFB's effect on cuticle formation. RNAi to knock-down expression of the gene encoding chitin synthase 2 in T. castaneum (TcCHS-2) caused a complete loss of chitin in the PM. Larval growth was significantly reduced, and the fat body was depleted of neutral lipids. In situ PM permeability assays monitoring the distribution of FITC dextrans after DFB exposure or RNAi for TcCHS-2 revealed that PM permeability was increased in both cases. RNAi for TcCHS-2, however, led to a higher permeation of the PM by FITC dextrans than DFB treatment even at high doses. Similar effects were observed when the chitin content was reduced by feeding DFB to adult yellow fever mosquitos, Aedes aegypti. We demonstrate that the presence of chitin is necessary for maintaining the PM's barrier function in insects. It seems that the insecticidal effects of DFB are mediated by the disruption of cuticle synthesis during the metamorphic molt rather than by interfering with larval nutrition. However, as DFB clearly affects PM permeability, it may be suitable to increase the efficiency of pesticides targeting the midgut. PMID- 25449130 TI - LIM-homeodomain transcription factor Awh is a key component activating all three fibroin genes, fibH, fibL and fhx, in the silk gland of the silkworm, Bombyx mori. AB - In the silkworm Bombyx mori, three fibroin genes, fibroin-heavy-chain (fibH), fibroin-light-chain (fibL) and fibrohexamerin (fhx), are coexpressed only in the posterior silk gland (PSG) cells, while the sericin genes encoding silk glue proteins are expressed in the middle silk gland (MSG) cells. Silk gland factor-2 (SGF-2) is a PSG-specific activator complex of fibH, composed of a LIM homeodomain protein, Awh, and its cofactors, Ldb and Lcaf. We investigated whether SGF-2 can activate other fibroin genes using transgenic silkworms. The genes for Ldb and Lcaf were expressed ubiquitously in various tissues, while the gene for Awh was expressed strictly specific in PSG of the wild type silkworms. Misexpression of Awh in transgenic silkworms induced ectopic expression of fibL and fhx as well as fibH in MSG. Coincidently with the induction of fibL and fhx by Awh, binding of SGF-2 to the promoter of fibL and fhx was detected in vitro, and SGF-2 binds directly to the fhx core promoter. Ectopic expression of the fibroin genes was observed at high levels in the middle part of MSG. Moreover, fibL and fhx were induced in the anterior silk gland (ASG) of the transgenic silkworms, but fibH was not. These results indicate that Awh is a key activator of all three fibroin genes, and the activity is probably regulated in conjunction with additional factors. PMID- 25449131 TI - Adenosine activates thermogenic adipocytes. AB - Brown or beige fat activation can cause potent anti-obesity and anti-diabetic effects. In a study recently published in Nature, Gnad et al. show that adenosine is a novel activator of brown and beige fat that acts through the A2A receptor. PMID- 25449132 TI - Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition. AB - Target competition (ceRNA crosstalk) within miRNA-regulated gene networks has been proposed to influence biological systems. To assess target competition, we characterize and quantitate miRNA networks in two cell types. Argonaute iCLIP reveals that hierarchical binding of high- to low-affinity miRNA targets is a key characteristic of in vivo activity. Quantification of cellular miRNA and mRNA/ncRNA target pool levels indicates that miRNA:target pool ratios and an affinity partitioned target pool accurately predict in vivo Ago binding profiles and miRNA susceptibility to target competition. Using single-cell reporters, we directly test predictions and estimate that ?3,000 additional high-affinity target sites can affect active miRNA families with low endogenous miRNA:target ratios, such as miR-92/25. In contrast, the highly expressed miR-294 and let-7 families are not susceptible to increases of nearly 10,000 sites. These results show differential susceptibility based on endogenous miRNA:target pool ratios and provide a physiological context for ceRNA competition in vivo. PMID- 25449133 TI - Strand-specific analysis shows protein binding at replication forks and PCNA unloading from lagging strands when forks stall. AB - In eukaryotic cells, DNA replication proceeds with continuous synthesis of leading-strand DNA and discontinuous synthesis of lagging-strand DNA. Here we describe a method, eSPAN (enrichment and sequencing of protein-associated nascent DNA), which reveals the genome-wide association of proteins with leading and lagging strands of DNA replication forks. Using this approach in budding yeast, we confirm the strand specificities of DNA polymerases delta and epsilon and show that the PCNA clamp is enriched at lagging strands compared with leading-strand replication. Surprisingly, at stalled forks, PCNA is unloaded specifically from lagging strands. PCNA unloading depends on the Elg1-containing alternative RFC complex, ubiquitination of PCNA, and the checkpoint kinases Mec1 and Rad53. Cells deficient in PCNA unloading exhibit increased chromosome breaks. Our studies provide a tool for studying replication-related processes and reveal a mechanism whereby checkpoint kinases regulate strand-specific unloading of PCNA from stalled replication forks to maintain genome stability. PMID- 25449134 TI - Oscillators and Oscillations in the Basal Ganglia. AB - What is the meaning of an action potential? There must be different answers for neurons that fire spontaneously, even in the absence of synaptic input, and those driven to fire from a resting membrane potential. In spontaneously firing neurons, the occurrence of the next action potential is guaranteed; only variations in its timing can carry the message. In the basal ganglia, the globus pallidus, the substantia nigra, and the subthalamic nucleus consist of neurons firing spontaneously. They each receive thousands of synaptic inputs, but these are not required to maintain their background firing. Instead, synaptic interactions among basal ganglia nuclei comprise a system of coupled oscillators that produces a complex resting pattern of activity. Normally, this pattern is highly irregular and uncorrelated, so that the firing of each cell is statistically independent of the others. This maximizes the potential information that may be transmitted by the basal ganglia to its target structures. In Parkinson's disease, the resting pattern of activity is dominated by a slow oscillation shared by nearly all of the neurons. Treatment with deep brain stimulation may gain its therapeutic value by disrupting this shared pathological oscillation, and restoring independent action by each neuron in the network. PMID- 25449135 TI - Differences in affinities between the homologous and the heterologous rabbit prolactin-receptor interaction with respect to proliferation and differentiation activities. AB - Interspecies differences in PRL-receptor binding and their relationship with bioactivity deserve investigation since cross-reactivity is relevant to the design of many experiments. We have previously shown that the lower affinity of rabbit prolactin (rbPRL) binding to its homologous receptor is due to its faster and more complete dissociation compared with that of ovine PRL (oPRL). In order to obtain sufficient amounts of rbPRL to study the functional consequences of its low affinity homologous interaction, rbPRL was expressed recombinantly in Escherichia coli (rec rbPRL) as insoluble inclusion bodies, refolded and purified to homogeneity, yielding electrophoretically pure, over 98% monomeric rec rbPRL. Proper renaturation of rec rbPRL was evidenced by comparison of its CD spectra, binding parameters and bioactivity with those determined for the rbPRL. The binding potency of rec rbPRL to its receptor, expressed either endogenously in the mammary gland or recombinantly in mammalian cells is one log unit lower than that to the receptor expressed recombinantly in insect cells. This difference is probably related to differences in cell-dependent receptor densities. The proliferation potency of rbPRL or rec rbPRL was one log unit lower than that of oPRL, consistent with its lower binding affinity, but the differentiation potencies of these PRLs were similar. Thus, the proliferation activity is sensitive to PRL-receptor affinity and dissociation kinetics, whereas the differentiation response is marginally modulated. PMID- 25449136 TI - Molecular characterization, tissue distribution, and ultrastructural localization of adipokinetic hormones in the CNS of the firebug Pyrrhocoris apterus (Heteroptera, Insecta). AB - Adipokinetic hormones (AKHs) are a group of insect metabolic neurohormones, synthesized and released from an endocrine retrocerebral gland, the corpus cardiacum (CC). Small amounts of AKH have also been identified in the brain, although their role in this organ is not clear. To address this gap in the knowledge about insect brain biology, we studied the nucleotide sequence, tissue distribution, and subcellular localization of AKHs in the brain and CC of the firebug Pyrrhocoris apterus. This insect expresses two AKHs; the octapeptides Pyrap-AKH and Peram-CAH-II, the presence of which was documented in the both studied organs. In situ hybridization and quantitative reverse-transcription (q RT)-PCR revealed the expression of the genes encoding for both AKHs not only in the CC, but also in brain. Electron microscopy analysis of the brain revealed the presence of these hormones in specialized secretory granules localized predominantly in the cellular bodies of neurons. The hormones might be transported from the granules into the axons, where they could play a role in neuronal signaling. Under acute stress induced by the injection of 3MUmol KCl, the level of AKHs in the brain increased to a greater extent than that in the CC. These results might indicate an enhanced role of brain-derived AKHs in defence reaction under acute stress situations. PMID- 25449137 TI - The TORC1/P70S6K and TORC1/4EBP1 signaling pathways have a stronger contribution on skeletal muscle growth than MAPK/ERK in an early vertebrate: Differential involvement of the IGF system and atrogenes. AB - Knowledge about the underlying mechanisms, particularly the signaling pathways that account for muscle growth in vivo in early vertebrates is still scarce. Fish (Paralichthys adspersus) were fasted for 3weeks to induce a catabolic period of strong muscle atrophy. Subsequently, fish were refed for 2weeks to induce compensatory muscle hypertrophy. During refeeding, the fish were treated daily with either rapamycin (TORC blocker), PD98059 (MEK blocker), or PBS (V; vehicle), or were untreated (C; control). Rapamycin and PD98059 differentially impaired muscle cellularity in vivo, growth performance, and the expression of growth related genes, and the inhibition of TORC1 had a greater impact on fish muscle growth than the inhibition of MAPK. Blocking TORC1 inhibited the phosphorylation of P70S6K and 4EBP1, two downstream components activated by TORC1, thus affecting protein contents in muscle. Concomitantly, the gene expression in muscle of igf 1, 2 and igfbp-4, 5 was down-regulated while the expression of atrogin-1, murf-1, and igfbp-2, 3 was up-regulated. Muscle hypertrophy was abolished and muscle atrophy was promoted, which finally affected body weight. TORC2 complex was not affected by rapamycin. On the other hand, the PD98059 treatment triggered ERK inactivation, a downstream component activated by MEK. mRNA contents of igf-1 in muscle were down-regulated, and muscle hypertrophy was partially impaired. The present study provides the first direct data on the in vivo contribution of TORC1/P70S6K, TORC1/4EBP1, and MAPK/ERK signaling pathways in the skeletal muscle of an earlier vertebrate, and highlights the transcendental role of TORC1 in growth from the cellular to organism level. PMID- 25449138 TI - Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. AB - The Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with various diseases (vascular, cancers, neurology, diabetes, psoriasis, etc) with the epidemiology of the polymorphism of the C677T that varies dependent on the geography and ethnicity. The 5,10-Methylenetetrahydrofolate reductase (MTHFR) locus is mapped on chromosome 1 at the end of the short arm (1p36.6). This enzyme is important for the folate metabolism which is an integral process for cell metabolism in the DNA, RNA and protein methylation. The mutation of the MTHFR gene which causes the C677T polymorphism is located at exon 4 which results in the conversion of valine to alanine at codon 222, a common polymorphism that reduces the activity of this enzyme. The homozygous mutated subjects have higher homocysteine levels while the heterozygous mutated subjects have mildly raised homocysteine levels compared with the normal, non-mutated controls. Hyperhomocysteinemia is an emerging risk factor for various cardiovascular diseases and with the increasing significance of this polymorphism in view of the morbidity and mortality impact on the patients, further prevention strategies and nutritional recommendations with the supplementation of vitamin B12 and folic acid which reduces plasma homocysteine level would be necessary as part of future health education. This literature review therefore focuses on the recent evidence based reports on the associations of the MTHFR C677T polymorphism and the various diseases globally. PMID- 25449139 TI - Building treasures for rare disorders. AB - The internet pre-eminently marks an era with unprecedented chances for patient care. Especially individuals with rare disorders and their families can benefit. Their handicap of low numbers vanishes and can become a strength, as small, motivated and well-organized international support groups allow easily fruitful collaborations with physicians and researchers. Jointly setting research agendas and building wikipedias has eventually led to building of multi-lingual databases of longitudinal data on physical and behavioural characteristics of individuals with several rare disorders which we call waihonapedias (waihona meaning treasure in Hawaiian). There are hurdles to take, like online security and reliability of diagnoses, but sharing experiences and true collaborations will allow better research and patient care for fewer costs to patients with rare disorders. PMID- 25449140 TI - A study of familial Mediterranean Fever (MEFV) gene mutations in Egyptian children with type 1 diabetes mellitus. AB - BACKGROUND/AIMS: An association of type 1 DM and familial Mediterranean fever (FMF) has been newly reported in the medical literature. The aim of the present work was to investigate frequency of MEFV gene mutations in Egyptian children with type 1 diabetes mellitus. METHODS: Forty five children with type 1 DM were screened for Mediterranean Fever (MEFV) gene mutation. Forty one healthy control subjects were included. Identification of FMF gene mutation was done based on polymerase chain reaction (PCR) and reverse hybridization. The assay covers 12 mutations in the FMF gene: E148Q - P369S - F479L - M680I (G/C) - M680I (G/A) - I692del - M694V - M694I - K695R-V726A - A744S and R761H. RESULTS: Among the screened diabetics, the overall frequency of MEFV gene mutations was 42.2% and among the control group it was 34.1% with no significant difference. Fourteen out of 45 diabetic children (31.1%) were heterozygous (E148Q in 7 children, A744S in 3 children, V726A in 2 children, M680I (G/C) in 1 child and P369S in1 child), while 5 children (11.1%) were compound heterozygous (M694V/M694I in 2 children, E148Q/K695R mutations in 1 child, E148Q/M694I in 1 child and E148Q/V726A in 1 child). The control group showed heterozygous mutation in 34.1% of cases (E148Q mutation in 14.6%, V726A in 12.2%, M680I (G/C) in 4.9% and M694V in 2.4%). CONCLUSION: No significant difference in mutation frequency between diabetic and non-diabetic children. We have high carrier rate of MEFV gene mutations among Egyptian population probably due to high consanguinity. PMID- 25449142 TI - Simplified tandem polymer solar cells with an ideal self-organized recombination layer. AB - A new tandem architecture for printable photovoltaics using a versatile organic nanocomposite containing photoactive and interfacial materials is demonstrated. The nanocomposite forms an ideal self-organized recombination layer via a spontaneous vertical phase separation, which yields a simplified tandem structure fabricated with only four component layers and a high tandem efficiency of 10.8%. PMID- 25449141 TI - Nucleic acid spot hybridization based species-specific detection of Sclerotium rolfsii associated with collar rot disease of Amorphophallus paeoniifolius. AB - Collar rot is one of the most destructive and prevalent disease of Amorphophallus paeoniifolius, resulting in heavy yield losses. The causative organism, Sclerotium rolfsii is a soil-borne polyphagous fungus characterized by prolific growth and ability to produce persistent sclerotia. The pathogen propagules surviving in soil and planting material are the major sources of inoculum. This study presents the suitability of DNA hybridization technique for species specific detection of S. rolfsii in soil and planting material. The detection limit of the probe was 10-15 pg of pure pathogen DNA. The developed probe was found to be highly specific and could be used for accurate identification of pathogen up to the species level. The protocol was standardized for detection of the pathogen in naturally infected field samples. PMID- 25449143 TI - Lifestyle of metabolically healthy obese individuals. AB - AIMS: The aim of this study is to find factors associated with metabolic syndrome in obese individuals and thus offer guidance to stay metabolically healthy if obese. METHODS: A cardiovascular screening programme performed in Finland during the years 2005-2007, identified 901 obese white individuals. Of them, 269 (30%) were metabolically healthy according to the Harmonization criteria of metabolic syndrome. RESULTS: In multivariate logistic regression analysis, male sex [odds ratio (OR) 1.44 (95% CI 1.01-2.07)], living alone [OR 1.77 (95% CI 1.18-2.65)], physical inactivity [OR 3.73 (95% CI 1.24-11.24)], and use of betablockers [OR 2.63 (95% CI 1.75-3.95)] were associated with metabolic syndrome. CONCLUSIONS: Even mild or occasional physical exercise is beneficial to health in obese individuals. Betablockers may not be the antihypertensive agents of choice when treating obese hypertensive individuals. PMID- 25449145 TI - Visual processing and social cognition in schizophrenia: relationships among eye movements, biological motion perception, and empathy. AB - Schizophrenia patients have impairments at several levels of cognition including visual attention (eye movements), perception, and social cognition. However, it remains unclear how lower-level cognitive deficits influence higher-level cognition. To elucidate the hierarchical path linking deficient cognitions, we focused on biological motion perception, which is involved in both the early stage of visual perception (attention) and higher social cognition, and is impaired in schizophrenia. Seventeen schizophrenia patients and 18 healthy controls participated in the study. Using point-light walker stimuli, we examined eye movements during biological motion perception in schizophrenia. We assessed relationships among eye movements, biological motion perception and empathy. In the biological motion detection task, schizophrenia patients showed lower accuracy and fixated longer than healthy controls. As opposed to controls, patients exhibiting longer fixation durations and fewer numbers of fixations demonstrated higher accuracy. Additionally, in the patient group, the correlations between accuracy and affective empathy index and between eye movement index and affective empathy index were significant. The altered gaze patterns in patients indicate that top-down attention compensates for impaired bottom-up attention. Furthermore, aberrant eye movements might lead to deficits in biological motion perception and finally link to social cognitive impairments. The current findings merit further investigation for understanding the mechanism of social cognitive training and its development. PMID- 25449146 TI - Y-maze avoidance: an automated and rapid associative learning paradigm in zebrafish. AB - Adult zebrafish are gaining attention in behavioral neuroscience. By combining video tracking and computer-controlled visual cue presentations on a liquid crystal display screen under the tank, we have developed a new method by which zebrafish can be trained to avoid one arm of a Y-shaped tank by presenting a specific color on the floor paired with an electric shock. Within two hours, zebrafish learn to choose the correct arm at an efficiency of 89.0%. In addition, we also developed a graphical user interface to modify the paradigm assessment parameters such as shape of the tank and time schedules. PMID- 25449144 TI - Persistent lipid abnormalities in statin-treated patients: Portuguese diabetic subpopulation of the Dyslipidaemia International Study (DYSIS). AB - AIMS: To assess the treatment patterns and prevalence of persistent lipid abnormalities in Portuguese statin-treated patients with diabetes. METHODS: DYSIS was an epidemiological, cross-sectional and multicentre international study. Outpatients >= 45 years old seen at primary and secondary care centres and treated with statins for at least three months were enrolled. This study presents the results for the Portuguese subpopulation, focusing on lipid control of the diabetic patients. RESULTS: Of the 916 patients recruited, 348 (38%) had diabetes mellitus (DM). The majority of the diabetic patients (58%) failed to attain an LDL-C < 2.5 mmol/L, and 77% did not reach the optional goal of LDL-C < 2.0 mmol/L set by the 2007 recommendations of the European Society of Cardiology. The most frequently used statin was simvastatin, both in patients with and without diabetes (55.7% vs. 57.1%, p = 0.68). The mean (SD) statin dose in simvastatin equivalent units was 26.1 (9.2) mg in diabetics and 25.3 (8.8 mg) in non diabetics (p = 0.19). CONCLUSIONS: The majority of Portuguese diabetic patients treated with statins failed to attain the recommended LDL cholesterol goals. Relatively low doses of medium potency statins were the prevailing therapy. There seems to be considerable room for improvement through the use of more potent statins, dose up-titration and/or the addition of other lipid-modifying therapies. PMID- 25449148 TI - Emerging trends in heart valve engineering: Part II. Novel and standard technologies for aortic valve replacement. AB - The engineering of technologies for heart valve replacement (i.e., heart valve engineering) is an exciting and evolving field. Since the first valve replacement, technology has progressed by leaps and bounds. Innovations emerge frequently and supply patients and physicians with new, increasingly efficacious and less invasive treatment options. As much as any other field in medicine the treatment of heart valve disease has experienced a renaissance in the last 10 years. Here we review the currently available technologies and future options in the surgical and transcatheter treatment of aortic valve disease. Different valves from major manufacturers are described in details with their applications. PMID- 25449147 TI - Dual optical modality endoscopic imaging of cancer development in the mouse colon. AB - BACKGROUND AND OBJECTIVE: We utilize a miniature, dual-modality endoscope that combines fluorescence-based surface magnifying chromoendoscopy (SMC) and optical coherence tomography (OCT) to follow the anatomical changes that occur during adenoma development in the mouse colon. MATERIALS AND METHODS: Twenty-five mice were treated with the carcinogen azoxymethane (AOM) to induce tumor development in the distal colon, or were treated with saline as control, and were imaged over six months. OCT detects adenoma number with high sensitivity and specificity and can measure lesion size. In methylene blue-lavaged colons, SMC detects changes in the colonic crypts. SMC images of control mouse colons exhibit reticulated patterns of crypts of equal size, forming either a dot or honeycomb pattern. RESULTS: Images of AOM-treated colons show mild crypt irregularities even in grossly normal tissue. Images of small to medium adenoma exhibit larger crypts, more intense signal, and irregular spacing whereas those of large adenoma have heterogeneous, intense signal and loss of crypt structure. CONCLUSIONS: The combination of OCT and SMC permits the detection of neoplastic events from the earliest stages of crypt irregularities before gross tissue changes are noted, through to measuring the growth of protruding adenoma. PMID- 25449150 TI - Assessment of daily-life reaching performance after stroke. AB - For an optimal guidance of the rehabilitation therapy of stroke patients in an in home setting, objective, and patient-specific performance assessment of arm movements is needed. In this study, metrics of hand movement relative to the pelvis and the sternum were estimated in 13 stroke subjects using a full body ambulatory movement analysis system, including 17 inertial sensors integrated in a body-worn suit. Results were compared with the level of arm impairment evaluated with the upper extremity part of the Fugl-Meyer Assessment scale (uFMA). Metrics of arm movement performance of the affected side, including size of work area, maximum reaching distance and movement range in vertical direction, were evaluated during a simulated daily-life task. These metrics appeared to strongly correlate with uFMA scores. Using this body-worn sensor system, metrics of the performance of arm movements can easily be measured and evaluated while the subject is ambulating in a simulated daily-life setting. Suggested metrics can be used to objectively assess the performance of the arm movements over a longer period in a daily-life setting. Further development of the body-worn sensing system is needed before it can be unobtrusively used in a daily-life setting. PMID- 25449149 TI - A Pre-computed Brain Response Atlas for Instantaneous Strain Estimation in Contact Sports. AB - Finite element models of the human head play an important role in investigating the mechanisms of traumatic brain injury, including sports concussion. A critical limitation, however, is that they incur a substantial computational cost to simulate even a single impact. Therefore, current simulation schemes significantly hamper brain injury studies based on model-estimated tissue-level responses. In this study, we present a pre-computed brain response atlas (pcBRA) to substantially increase the simulation efficiency in estimating brain strains using isolated rotational acceleration impulses parameterized with four independent variables (peak magnitude and duration, and rotational axis azimuth and elevation angles) with values determined from on-field measurements. Using randomly generated testing datasets, the partially established pcBRA achieved a 100% success rate in interpolation based on element-wise differences in accumulated peak strain ([Formula: see text]) according to a "double-10%" criterion or average regional [Formula: see text] in generic regions and the corpus callosum. A similar performance was maintained in extrapolation. The pcBRA performance was further successfully validated against directly simulated responses from two independently measured typical real-world rotational profiles. The computational cost to estimate element-wise whole-brain or regional [Formula: see text] was 6 s and <0.01 s, respectively, vs. ~50 min directly simulating a 40 ms impulse. These findings suggest the pcBRA could substantially increase the throughput in impact simulation without significant loss of accuracy from the estimation itself and, thus, its potential to accelerate the exploration of the mechanisms of sports concussion in general. If successful, the pcBRA may also become a diagnostic adjunct in conjunction with sensors that measure head impact kinematics on the field to objectively monitor and identify tissue-level brain trauma in real-time for "return-to-play" decision-making on the sideline. PMID- 25449152 TI - Challenges in the Modeling of Wound Healing Mechanisms in Soft Biological Tissues. AB - Numerical models have become one of the most powerful tools in biomechanics and mechanobiology allowing highly detailed simulations. One of the fields in which they have broadly evolved during the last years is in soft tissue modeling. Particularly, wound healing in the skin is one of the processes that has been approached by computational models due to the difficulty of performing experimental investigations. During the last decades wound healing simulations have evolved from numerical models which considered only a few number of variables and simple geometries to more complex approximations that take into account a higher number of factors and reproduce more realistic geometries. Moreover, thanks to improved experimental observations, a larger number of processes, such as cellular stress generation or vascular growth, that take place during wound healing have been identified and modeled. This work presents a review of the most relevant wound healing approximations, together with an identification of the most relevant criteria that can be used to classify them. In addition, and looking towards the actual state of the art in the field, some future directions, challenges and improvements are analyzed for future developments. PMID- 25449151 TI - Evaluation of a Multiscale Modelling Methodology to Predict the Mechanical Properties of PCL/beta-TCP Sintered Scaffold Materials. AB - A multiscale modelling methodology to predict the macroscale stiffness of selective laser sintered polycaprolactone (PCL)/beta-tricalcium phosphate (beta TCP) materials is evaluated. The relationship between a micromechanics-evaluated composite material elastic modulus (E eff) and segment grey-value (GVave) is established for a 90/10 wt% PCL/beta-TCP material and compared to the previously established E eff vs. GVave relationship for a 50/50 wt% PCL/beta-TCP material. The increase in E eff with GVave was found to be greater for the 90/10 wt% material than for the 50/50 wt% material. Differences in the material microstructures are visible with greater local conglomerations of beta-TCP in the 90/10 wt% material compared to the 50/50 wt% material. These results indicate that the relationship between E eff and GVave is material-specific and that one definition cannot be used to describe both materials. We have used the E eff and GVave relationship specific to the 90/10 wt% material to assign element-specific elastic properties in a high resolution macroscale strut finite element model to successfully predict the experimentally-evaluated strut effective stiffness of the 90/10 wt%. These results combined indicate that this multiscale modelling methodology reasonably predicts the effective elastic modulus of selective laser sintering struts with different material configurations, and that it can be used to determine the material-specific definition of the relationship between E eff and GVave for a particular material. PMID- 25449153 TI - A plant-derived anti-nociceptive spray for reduction of pain with photodynamic therapy. AB - BACKGROUND: Photodynamic therapy is an effective tool in the management of some forms of skin cancer and generalized solar dermopathy and can be beneficial in the management of acne vulgaris. When used as an area treatment one of the main limiters is the quite severe burning pain that patients feel during the illumination phase of the treatment. OBJECTIVE: To examine the effectiveness of a plant derived anti-nociceptive spray applied prior to and during large area photodynamic therapy. METHODS: A split face or left arm versus right arm, placebo controlled trial was performed on 60 patients to assess the effectiveness of the spray in reducing pain perception. RESULTS: There was a statistically significant reduction in pain at all illumination points during the illumination phase but no significant difference in discomfort levels in the first 72 h post illumination. LIMITATIONS: Only large area photodynamic therapy treatment was performed during the study. No conclusions can be drawn for small area treatments. CONCLUSION: Use of a simple, plant derived anti-nociceptive spray can reduce the discomfort experienced by patients undergoing photodynamic therapy to large areas. PMID- 25449154 TI - Polymeric micelles for enhanced Photofrin II (r) delivery, cytotoxicity and pro apoptotic activity in human breast and ovarian cancer cells. AB - BACKGROUND: Searching for photodynamic therapy (PDT) - effective nanocarriers which enable a photosensitizer to be selectively delivered to tumor cells with enhanced bioavailability and diminished dark cytotoxicity is of current interest. The main objective of this study is to evaluate newly designed mixed polymeric micelles based on Pluronics P123 and F127 for the improved delivery of Photofrin II((r)) (Ph II((r))) to circumvent unfavorable effects overcoming multidrug resistance (MDR) in tumor cells - in breast MCF-7/WT (caspase-3 deficient) and ovarian SKOV-3 (resistant to chemotherapy). METHODS: Ph II((r))-loaded micelles were obtained and analyzed for size and morphology, solubilization efficiency, physical stability and in vitro drug release. Intracellular uptake, reactive oxygen species (ROS) generation, mitochondrial oxidoreductive potential and proapoptotic activity (TUNEL assay) studies were evaluated in the examined cancer cells. The preliminary biocompatibility characteristics of all nanocarriers was determined by assessment of their hemolytic activity in human erythrocytes and dark toxicity in cancer cells. RESULTS: Dynamic light scattering (DLS) and atomic force microscopy (AFM) confirmed that almost monodisperse, sphere-shaped and nanosized (DH<20 nm) carriers were developed. Biological studies after photodynamic reaction (PDR) with encapsulated Ph II((r)) revealed increased ROS level, malondialdehyde (MDA) concentration and protein damage in SKOV-3 and MCF 7/WT cells in comparison to treatment with free Ph II((r)). Numerous apoptotic cells were detected after nano-therapy in both cell lines, with observed significant morphological disorders in ovarian cancer cells. In the case of encapsulated Ph II((r)) only negligible disruption of human erythrocytes and cancer cells was observed. CONCLUSIONS: The obtained biocompatible long-lasting nanocarriers significantly enhance the Photofrin II((r)) photodynamic effect and apoptosis in both SKOV-3 and MCF-7/WT cell lines. PMID- 25449155 TI - Does fluorescence diagnosis have a role in follow up of response to therapy in mycosis fungoides? AB - BACKGROUND: Monitoring of tumor burden during mycosis fungoides (MF) treatment, is crucial to adjust therapy accordingly. This is usually achieved through combined by clinical assessment with histopathological and immunohistochemical evaluation. AIM: To assess the validity of fluorescence diagnosis (FD) in the measurement of response to therapy in early MF, using in comparison flow cytometric technique of skin biopsies for CD4+/CD7- malignant T-cell count before and after therapy. PATIENTS AND METHODS: Twenty-two patients of histologically proven early MF (stages Ia, Ib, IIa) were subjected to fluorescence diagnosis of their most affected skin lesion before and after 12 weeks of phototherapy with or without combination therapy. In comparison flow cytometric assessment of skin biopsies for CD4+/CD7- malignant T-cell count was evaluated before and after therapy from skin biopsy of the same lesion. RESULTS: All tested MF lesions showed varying degrees of fluorescence by FD at week zero, with a mean accumulation factor (AF), which is the fluorescence ratio between the tumor tissue and normal skin, of 2.2. After 12 weeks of therapy, the mean AF showed significant reduction to 1.94 (p=0.009). The percent of CD4+/CD7- cells dropped significantly after treatment (p=0.029). No correlation between CD4+/CD7- cell counts and the mean AF could be deduced. CONCLUSION: In cases of mycosis fungoides, fluorescence diagnosis can represent an effective tool for evaluating the response to therapy. Changes in accumulation factor values can be used for follow-up of therapy in the same patient, but it should not be used as an absolute value. PMID- 25449157 TI - ImpastoR: a realistic surface display system. AB - In this paper we describe our efforts to create a surface display system that produces realistic representations of real-world surfaces. Our system, based on a desktop PC with GPU hardware, LCD display, light and position sensors, and custom graphics software, supports the photometrically accurate and visually realistic real-time simulation and display of surfaces with complex color, gloss, and textural properties in real-world lighting environments, and allows users to interact with and manipulate these virtual surfaces as naturally as if they were real ones. We explain the system design, illustrate its capabilities, describe experiments we conducted to validate its fidelity, and discuss potential applications in material appearance research and computer-aided appearance design. PMID- 25449156 TI - Combination of photodynamic therapy and temozolomide on glioma in a rat C6 glioma model. AB - BACKGROUND: For glioma, temozolomide (TMZ) is a commonly used chemotherapy drug and photodynamic therapy (PDT) is an important adjuvant therapy. The aim of this study was to evaluate the effect of their combination for the treatment of glioma. METHODS: A rat C6 glioma model using male Wistar rats (n=180) weighing 280-300 g was established. Glioma-bearing rats (n=100) were treated with mock, hematoporphyrin monomethyl ether (HMME), laser or PDT. The expression of P glycoprotein (P-gp) in endothelial cells of the blood-tumor-barrier and in glioma tissues was detected using immunohistochemistry and western blot, respectively. Glioma-bearing rats (n=40) were treated with normal saline, TMZ (60 mg/m(2) for five consecutive days), PDT (630 nm for 10 min) or a combination of TMZ and PDT. TMZ concentration in glioma tissues was detected using liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) and cell death was observed using transmission microscopy. Concurrently, another batch of 40 glioma-bearing rats was subjected to the same treatment, and the survival of these rats was estimated using Kaplan-Meier analysis. RESULTS: PDT significantly decreased the expression of P-gp in endothelial cells comprising the blood-tumor-barrier and in glioma tissues. The combination of TMZ with PDT significantly increased TMZ concentration in glioma tissues, enhanced glioma cell apoptosis and prolonged the median survival of glioma-bearing rats. CONCLUSION: The combination of PDT with TMZ shows synergistic effect in rat C6 glioma model, indicating its potential clinical use in glioma treatment. PMID- 25449158 TI - Size of the foveal blue scotoma related to the shape of the foveal pit but not to macular pigment. AB - When the eye is covered with a filter that transmits light below 480 nm and a blue field is observed on a computer screen that is modulated in brightness at about 1 Hz, the fovea is perceived as small irregular dark spot. It was proposed that the "foveal blue scotoma" results from the lack of S-cones in the foveal center. The foveal blue scotoma is highly variable among subjects. Possible factors responsible for the variability include differences in S-cone distribution, in foveal shape, and in macular pigment distribution. Nine young adult subjects were instructed to draw their foveal blue scotomas on a clear foil that was attached in front of the computer screen. The geometry of their foveal pit was measured in OCT images in two dimensions. Macular pigment distribution was measured in fundus camera images. Finally, blue scotomas were compared with Maxwell's spot which was visualized with a dichroic filter and is commonly assumed to reflect the macular pigment distribution. The diameters of the foveal blue scotomas varied from 15.8 to 76.4 arcmin in the right eyes and 15.5 to 84.7 arcmin in the left and were highly correlated in both eyes. It was found that the steeper the foveal slopes and the narrower the foveal pit, the larger the foveal blue scotoma. There was no correlation between foveal blue scotoma and macular pigment distribution or Maxwell's spot. The results are therefore in line with the assumption that the foveal blue scotoma is a consequence of the lack of S cones in the foveal center. Unlike the foveal blue scotoma, Maxwell's spot is based on macular pigment as previously proposed. PMID- 25449159 TI - Is a unified model of contrast and constancy possible? Reply to Gilchrist. PMID- 25449160 TI - Correlation of vision loss with tactile-evoked V1 responses in retinitis pigmentosa. AB - Neuroimaging studies have shown that the visual cortex of visually impaired humans is active during tactile tasks. We sought to determine if this cross-modal activation in the primary visual cortex is correlated with vision loss in individuals with retinitis pigmentosa (RP), an inherited degenerative photoreceptor disease that progressively diminishes vision later in life. RP and sighted subjects completed three tactile tasks: a symmetry discrimination task, a Braille-dot counting task, and a sandpaper roughness discrimination task. We measured tactile-evoked blood oxygenation level dependent (BOLD) responses using functional magnetic resonance imaging (fMRI). For each subject, we quantified the cortical extent of the tactile-evoked response by the proportion of modulated voxels within the primary visual cortex (V1) and its strength by the mean absolute modulation amplitude of the modulated voxels. We characterized vision loss in terms of visual acuity and the areal proportion of V1 that corresponds to the preserved visual field. Visual acuity and proportion of the preserved visual field both had a highly significant effect on the cortical extent of the V1 BOLD response to tactile stimulation, while visual acuity also had a significant effect on the strength of the V1 response. These effects of vision loss on cross modal responses were reliable despite high inter-subject variability. Controlling for task-evoked responses in the primary somatosensory cortex (S1) across subjects further strengthened the effects of vision loss on cross-model responses in V1. We propose that such cross-modal responses in V1 and other visual areas may be used as a cortically localized biomarker to account for individual differences in visual performance following sight recovery treatments. PMID- 25449162 TI - Target frequency influences antisaccade endpoint bias: evidence for perceptual averaging. AB - Perceptual judgments related to stimulus-sets are represented computationally different than individual items. In particular, the perceptual averaging hypothesis contends that the visual system represents target properties (e.g., eccentricity) via a statistical summary of the individual targets included within a stimulus-set. Here we sought to determine whether perceptual averaging governs the visual information mediating an oculomotor task requiring top-down control (i.e., antisaccade). To that end, participants completed antisaccades (i.e., saccade mirror-symmetrical to a target) - and complementary prosaccades (i.e., saccade to veridical target location) - to different target eccentricities (10.5 degrees , 15.5 degrees and 20.5 degrees ) located left and right of a common fixation. Importantly, trials were completed in blocks wherein eccentricities were presented with equal frequency (i.e., control condition) and when the 'proximal' (10.5 degrees : i.e., proximal-weighting condition) and 'distal' (20.5 degrees : i.e., distal-weighting condition) targets were respectively presented five times as often as the other eccentricities. If antisaccades are governed by a statistical summary then amplitudes should be biased in the direction of the most frequently presented target within a block. As expected, pro- and antisaccade across each target eccentricity were associated with an undershooting bias and prosaccades were refractory to the manipulation of target frequency. Most notably, antisaccades in the proximal-weighting condition had a larger undershooting bias than the control condition, whereas the converse was true for the distal-weighing condition; that is, antisaccades were biased in the direction of the most frequently presented target. Thus, we propose that perceptual averaging extends to motor tasks requiring top-down cognitive control. PMID- 25449161 TI - Perceived depth in non-transitive stereo displays. AB - The separation between the eyes shapes the distribution of binocular disparities and gives a special role to horizontal disparities. However, for one-dimensional stimuli, disparity direction, like motion direction, is linked to stimulus orientation. This makes the perceived depth of one-dimensional stimuli orientation dependent and generally non-veridical. It also allows perceived depth to violate transitivity. Three stimuli, A, B, and C, can be arranged such that A > B (stimulus A is seen as farther than stimulus B when they are presented together) and B > C, yet A ? C. This study examines how the visual system handles the depth of A, B, and C when they are presented together, forming a pairwise inconsistent stereo display. Observers' depth judgments of displays containing a grating and two plaids resolved transitivity violations among the component stimulus pairs. However, these judgments were inconsistent with judgments of the same stimuli within depth-consistent displays containing no transitivity violations. To understand the contribution of individual disparity signals, observers were instructed in subsequent experiments to judge the depth of a subset of display stimuli. This attentional instruction was ineffective; relevant and irrelevant stimuli contributed equally to depth judgments. Thus, the perceived depth separating a pair of stimuli depended on the disparities of the other stimuli presented concurrently. This context dependence of stereo depth can be approximated by an obligatory pooling and comparison of the disparities of one and two-dimensional stimuli along an axis defined locally by the stimuli. PMID- 25449163 TI - Brain mechanisms underlying behavioral specificity and generalization of short term texture discrimination learning. AB - In this study, we used high-density event-related potentials (ERPs) to investigate the brain mechanisms underlying behavioral specificity and generalization of short-term learning of texture discrimination task (TDT). Human adults were trained with TDT for a single session of 1.5 h and their ERPs were measured on the following day. Behavioral performance showed that, after a same amount of exposure of the trained and untrained conditions during EEG session, learning effects were specific to the trained background orientation but generalized across target locations. ERP data, however, revealed both target location and background-orientation specific changes. While the behavioral background-orientation specificity mainly involved amplitude enhancement of early N2pc over occipital cortex, behavioral target-location generalization was associated with modulation of tempo-spatial configurations of the N2pc component (early-occipital vs. late-parietal/temporal pattern) and decrease of frontal P2 amplitudes for the trained relative to the untrained condition. The earliest visual component C1 did not show specific effects for either background orientation or target location. These results indicated different brain mechanisms underlying the behavioral specificity and generalization of TDT learning. Based on the present findings and literatures, we propose that perceptual learning may induce not only enhancement of relatively early visual selection of the trained target among distractors but also decreases of top-down attention originating from high-level brain center. The reactivation of top-down attention control in some conditions (e.g., the untrained target-location condition) may compensate for the specific effect induced by the early visual selective attention mechanism, leading to generalization or less specificity of perceptual learning in behavioral performance. PMID- 25449164 TI - Effects of face feature and contour crowding in facial expression adaptation. AB - Prolonged exposure to a visual stimulus, such as a happy face, biases the perception of subsequently presented neutral face toward sad perception, the known face adaptation. Face adaptation is affected by visibility or awareness of the adapting face. However, whether it is affected by discriminability of the adapting face is largely unknown. In the current study, we used crowding to manipulate discriminability of the adapting face and test its effect on face adaptation. Instead of presenting flanking faces near the target face, we shortened the distance between facial features (internal feature crowding), and reduced the size of face contour (external contour crowding), to introduce crowding. We are interested in whether internal feature crowding or external contour crowding is more effective in inducing crowding effect in our first experiment. We found that combining internal feature and external contour crowding, but not either of them alone, induced significant crowding effect. In Experiment 2, we went on further to investigate its effect on adaptation. We found that both internal feature crowding and external contour crowding reduced its facial expression aftereffect (FEA) significantly. However, we did not find a significant correlation between discriminability of the adapting face and its FEA. Interestingly, we found a significant correlation between discriminabilities of the adapting and test faces. Experiment 3 found that the reduced adaptation aftereffect in combined crowding by the external face contour and the internal facial features cannot be decomposed into the effects from the face contour and facial features linearly. It thus suggested a nonlinear integration between facial features and face contour in face adaptation. PMID- 25449165 TI - Role of syllable segmentation processes in peripheral word recognition. AB - Previous studies of foveal visual word recognition provide evidence for a low level syllable decomposition mechanism occurring during the recognition of a word. We investigated if such a decomposition mechanism also exists in peripheral word recognition. Single words were visually presented to subjects in the peripheral field using a 6 degrees square gaze-contingent simulated central scotoma. In the first experiment, words were either unicolor or had their adjacent syllables segmented with two different colors (color/syllable congruent condition). Reaction times for correct word identification were measured for the two different conditions and for two different print sizes. Results show a significant decrease in reaction time for the color/syllable congruent condition compared with the unicolor condition. A second experiment suggests that this effect is specific to syllable decomposition and results from strategic, presumably involving attentional factors, rather than stimulus-driven control. PMID- 25449166 TI - Liquid nitrogen cryotherapy for lip mucous membrane venous malformation in infants. AB - OBJECTIVE: Lip mucous membrane venous malformations are common benign lesions in infants. This clinical study evaluates the efficacy and safety of liquid nitrogen cryotherapy used to treat this condition. METHODS: A total of 84 pediatric patients undergoing liquid nitrogen cryotherapy for venous malformations involving the lips were reviewed, with 45 males and 39 females treated. The overall median age at mucous membrane venous malformation diagnosis was 5.6 months (range 2-18 months). The venous malformations involved the vermilion of the lower lip in 44 cases, the vermilion of the upper lip in 31 cases, and both vermilions in 9 cases. RESULTS: No complications due to anesthesia occurred. After a follow-up period of 2-38 months (mean 25 months), 65 lesions (77.4 %) were completely involuted, 14 lesions (16.7 %) were mostly involuted, and 5 lesions (5.9 %) were partially involuted; no lesions showed a minor amount of involution. CONCLUSIONS: Liquid nitrogen cryotherapy is an effective, simple, and safe management tool for mucous membrane venous malformations of the lip in infants. PMID- 25449167 TI - The life and work of Geoffrey Tyndale Young. AB - Geoffrey Tyndale Young was born in England's Peak District in 1915: his father and both grandfathers were pharmaceutical chemists. He graduated from the Universities of Birmingham and Bristol and was a transatlantic scientific liaison officer in the Second World War, shortly after which he was elected to a Fellowship at Jesus College Oxford. He combined peptide synthesis research, undergraduate teaching, and College administration with leadership in European peptide science and was universally respected for his integrity, wisdom, and unflappable diplomacy. A close friend of Josef Rudinger, he attended almost all of the first two dozen European Peptide Symposia 1958-1996. When he retired in 1982, he was appointed an Officer of the Order of the British Empire and was elected an Emeritus Fellow of Jesus College, of which he had been Acting Principal 1973-1977. In retirement, he was instrumental in setting up this journal and steered the formation of the European Peptide Society, of which he was the first chairman. In 1950, he married Janet Mary Baker, later Baroness Young of Farnworth, Leader of the British House of Lords 1982-1983, who died in 2002: they had three daughters who survive him. He died at home in Oxford on 24 May 2014 aged 98. PMID- 25449168 TI - Discovery of novel vitamin D-regulated proteins in INS-1 cells: a proteomic approach. AB - BACKGROUND: Experimental evidence indicates that vitamin D may have a beneficial role in pancreatic beta-cell function. Global gene expression studies have shown that the active metabolite 1,25-dihydroxyvitamin D3 [1,25-(OH)2 D3 ] modulates genes involved in ion transport, lipid metabolism and insulin secretion. METHODS: We employed stable isotope labelling by amino acids in cell culture in combination with liquid chromatography-tandem mass spectrometry to quantitatively assess the impact of two vitamin D metabolites, 1,25-(OH)2 D3 and 25 hydroxyvitamin D3 [25-(OH)D3 ], on global protein expression on a model rat beta cell line, insulinoma-derived INS-1 cells. RESULTS: Although treatment with 1,25 (OH)2 D3 resulted in 31 differentially expressed proteins, 25-(OH)D3 had no impact on protein expression. Of these 31 proteins, 29 were upregulated, whereas two showed a decrease in abundance. Proteins whose expression levels markedly increased in the presence of 1,25-(OH)2 D3 included Crat, Hmgn2, Protein Tmsbl1 and Gdap1. One of the most important findings in this study is upregulation of proteins implicated in insulin granule motility and insulin exocytosis, suggesting a positive effect on insulin secretion. Moreover, modulation of several membrane transport proteins suggests that 1,25-(OH)2 D3 has an impact on the homeostatic regulation of ions, which is critical for most functions in the beta-cell. CONCLUSIONS: In this study, we discovered a number of novel 1,25-(OH)2 D3 -regulated proteins, which may contribute to a better understanding of the reported beneficial effects of vitamin D on pancreatic beta-cells. All in all, our findings should pave the way for future studies providing insights into molecular mechanisms by which 1,25-(OH)2 D3 regulates protein expression in pancreatic beta-cells. PMID- 25449169 TI - Pseudoaneurysm of head and neck vessels has been frequently observed in road side bomb blast victims. AB - BACKGROUND: Due to recent war situation in neighboring country we have witnessed large number of victims with post-traumatic false (pseudo) aneurysms of head and neck in roadside bomb blast victims in Pakistan. Thus through this observational retrospective study we aim to share our experience of managing these patients. METHOD: 5 years patients' case records, from June 2008-June 2013, were reviewed from the hospital's records. 14 cases of roadside bomb blast victims, developing false aneurysms of major or minor vessels of head and neck, were studied. We excluded the post-traumatic pseudoaneurysms involving other sites and vessels of the body. We observed the mechanism, the duration of presentation, symptoms/signs, vessels involved, complications and the management done. RESULTS: All 14 cases presented with a localized pulsatile swelling with tenderness in the course of a known artery and with an overlying entry site wound from bomb blast sharp nails. Men were affected more as compared to women. All (14) cases had 2-12 weeks of duration between the injury and presentation. Temporal artery (4) was involved in most cases followed by common carotid artery (3). Open surgery was treatment of choice in 12 (85.7%) of cases; however 2 (14.3%) patients had endovascular intervention to correct the pathology. Post-operatively all patients recovered completely, without any major or minor complications. CONCLUSION: Surgical intervention remains the management of choice for post-traumatic false aneurysms of head and neck in Pakistan. Despite the benefits of endovascular procedures, improvements must be weighed against the added costs on the patients. PMID- 25449170 TI - Total knee replacement under tourniquet control: A prospective study of the peripheral arterial vasculature using colour-assisted duplex ultrasonography. AB - BACKGROUND AND PURPOSE: A tourniquet may potentiate rare and devastating arterial complications after total knee replacement (TKR) in patients with peripheral vascular disease (PVD). Most prior studies that evaluated peripheral arterial blood flow primarily used the ankle-brachial index (ABI). METHODS: We assessed the prevalence and risk factors for PVD in a cohort undergoing TKR. Clinical and radiological evaluations, including duplex ultrasonography, were performed one week prior to, and six weeks post-TKR performed under tourniquet control. Forty patients were analysed (20 male, 20 female; mean age 67 yrs, range: 53-80 yrs). MAIN FINDINGS: Hypertension (50%) and hypercholesterolaemia (50%) were the most common co-morbidities. Distal pulses were present in all patients preoperatively. Six patients (15%) had arterial calcification on their preoperative knee X-rays. Three patients (7.5%) had moderate PVD. There was no change in blood flow postoperatively in patients with or without PVD (p > 0.05). Vascular stenosis was less than 50% in all patients preoperatively and postoperatively. No postoperative vascular complications occurred. CONCLUSIONS: Severe PVD is not common in patients undergoing TKR. Performing total knee replacement under tourniquet control does not adversely affect the vasculature in patients with less than 50% vascular occlusion. PMID- 25449171 TI - Confusing mumps serology during an outbreak. PMID- 25449173 TI - Human enterovirus co-infection in severe HFMD patients in China. PMID- 25449172 TI - Identification of a novel intertypic recombinant species D human adenovirus in a pediatric stem cell transplant recipient. AB - BACKGROUND: Human adenoviruses (HAdV) are known opportunistic pathogens in hematopoietic stem cell transplant (SCT) recipients. The detection of HAdV infection in children after SCT has been implicated as a determinant of poor outcome but specific associations between HAdV species or individual HAdV types and disease are poorly understood. OBJECTIVES: Characterization of a HAdV-D strain isolated from multiple clinical specimens of an 11-year-old female recipient of a matched unrelated donor peripheral SCT for T-cell lymphoma and case report. STUDY DESIGN: Archived HAdV PCR-positive plasma, urine, and stool specimens were processed for virus isolation and detailed molecular typing. Complete genomic sequencing was carried out on 2 isolates. RESULTS: The patient tested positive for HAdV DNA by real-time PCR of a stool specimen at 44 days after initiation of a SCT conditioning regimen. In the subsequent 3 months, HAdV was detected in plasma, urine and stool specimens in association with symptoms of gastroenteritis and hemorrhagic cystitis. A novel HAdV-D with a HAdV20-like hexon gene was isolated from both urine and stool specimens. All isolates yielded identical restriction profiles with endonucleases BamHI, BglII, BstEII, HindIII, PstI and SmaI. Analysis of 2 complete genomic sequences further identified the virus as a novel intertypic recombinant HAdV-D (P20/H20/F42) closely related to HAdV42. CONCLUSIONS: This case highlights the identification of a previously unknown HAdV-D from an immunocompromised host. In this patient, the course of adenovirus infection is compatible with reactivation of a latent virus or a primary opportunistic infection. Adenoviremia in this patient resolved without definitive adenovirus-directed antiviral therapy. PMID- 25449174 TI - A self-assembly induced emission system constructed by the host-guest interaction of AIE-active building blocks. AB - Dibenzo[24]crown-8 (host) and benzylamine (guest) modified tetraphenylethenes are prepared and used to construct supramolecular polymers, which demonstrate the merits of reversible assembling-disassembling and tunable aggregation-induced emission by acid-base treatments. PMID- 25449175 TI - Gene expression alterations in chronic hypoxic MCF7 breast cancer cell line. AB - Hypoxia plays a significant role in tumor progression and aggressiveness and implicated in resistance to radiotherapy and chemotherapy. This study aims to characterize the changes in gene expression associated with chronic hypoxia in MCF7 breast cancer cell line and identify a possible biomarker for hypoxia in breast cancer. Breast cancer cells (MCF7) were exposed to 8-hour hypoxic episodes (<1% oxygen) three times a week for a total of 38 episodes. Gene expression changes were profiled using RT- PCR array after 19 and 38 episodes of hypoxia and compared to normoxic cells. Chemoresistance of hypoxic cells toward doxorubicin was assessed using MTT cell proliferation assay. Marked gene expression changes were indentified after 19 and 38 episodes of hypoxia. Only few changes were common in both stages with most genes rebounding at the level of 38 episodes. A notable gene (HNF4A) has been up-regulated by 2 folds after 19 hypoxic shots and further up-regulated by 6.43 folds after 38 hypoxic shots. The half maximal inhibitory concentration (IC50) of doxorubicin in MCF7 cells has increased in a trend proportional to the number of hypoxic episodes then totally rebounded after incubation under normoxia for 3 weeks. This study provides evidence that exposing cells to prolonged periods of hypoxia (weeks) results in different expression changes than those induced by short-term hypoxia (less than 72h). PMID- 25449176 TI - Development and characterization of simple sequence repeat (SSR) markers based on a full-length cDNA library of Scutellaria baicalensis. AB - Scutellaria baicalensis Georgi is an herbaceous perennial plant used as one of the staple Chinese herbal medicines in China with a long officinal history. However, research on S. baicalensis is currently limited due to the lack of genome and gene expression information. A full-length cDNA library from leaves and roots of S. baicalensis subjected to water deficit and heat, conditions that have been shown to affect baicalein accumulation, was constructed. There were 6491 expressed sequence tags (ESTs) obtained. UniGenes were assembled by BLAST similarity searches and annotated with Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). A total of 78 simple sequence repeats (SSRs) were identified and SSR markers associated with the active ingredients of S. baicalensis were selected. EST-SSR transferability was determined from 5 populations from different areas. This study is the first to produce a large volume of gene expression data from S. baicalensis to facilitate gene discovery in S. baicalensis and provide an important resource for molecular genetic and functional genomic studies in this species. PMID- 25449177 TI - Adaptive evolution of a novel avian-origin influenza A/H7N9 virus. AB - In China, the recent outbreak of novel influenza A/H7N9 virus has been assumed to be severe, and it may possibly turn brutal in the near future. In order to develop highly protective vaccines and drugs for the A/H7N9 virus, it is critical to find out the selection pressure of each amino acid site. In the present study, six different statistical methods consisting of four independent codon-based maximum likelihood (CML) methods, one hierarchical Bayesian (HB) method and one branch-site (BS) method, were employed to determine if each amino acid site of A/H7N9 virus is under natural selection pressure. Functions for both positively and negatively selected sites were inferred by annotating these sites with experimentally verified amino acid sites. Comprehensively, the single amino acid site 627 of PB2 protein was inferred as positively selected and it function was identified as a T-cell epitope (TCE). Among the 26 negatively selected amino acid sites of PB2, PB1, PA, HA, NP, NA, M1 and NS2 proteins, only 16 amino acid sites were identified to be involved in TCEs. In addition, 7 amino acid sites including, 608 and 609 of PA, 480 of NP, and 24, 25, 109 and 205 of M1, were identified to be involved in both B-cell epitopes (BCEs) and TCEs. Conversely, the function of positions 62 of PA, and, 43 and 113 of HA was unknown. In conclusion, the seven amino acid sites engaged in both BCEs and TCEs were identified as highly suitable targets, as these sites will be predicted to play a principal role in inducing strong humoral and cellular immune responses against A/H7N9 virus. PMID- 25449179 TI - Regulation of TRP channels by steroids: Implications in physiology and diseases. AB - While effects of different steroids on the gene expression and regulation are well established, it is proven that steroids can also exert rapid non-genomic actions in several tissues and cells. In most cases, these non-genomic rapid effects of steroids are actually due to intracellular mobilization of Ca(2+)- and other ions suggesting that Ca(2+) channels are involved in such effects. Transient Receptor Potential (TRP) ion channels or TRPs are the largest group of non-selective and polymodal ion channels which cause Ca(2+)-influx in response to different physical and chemical stimuli. While non-genomic actions of different steroids on different ion channels have been established to some extent, involvement of TRPs in such functions is largely unexplored. In this review, we critically analyze the literature and summarize how different steroids as well as their metabolic precursors and derivatives can exert non-genomic effects by acting on different TRPs qualitatively and/or quantitatively. Such effects have physiological repercussion on systems such as in sperm cells, immune cells, bone cells, neuronal cells and many others. Different TRPs are also endogenously expressed in diverse steroid-producing tissues and thus may have importance in steroid synthesis as well, a process which is tightly controlled by the intracellular Ca(2+) concentrations. Tissue and cell-specific expression of TRP channels are also regulated by different steroids. Understanding of the crosstalk between TRP channels and different steroids may have strong significance in physiological, endocrinological and pharmacological context and in future these compounds can also be used as potential biomedicine. PMID- 25449178 TI - The Valley-of-Death: reciprocal sign epistasis constrains adaptive trajectories in a constant, nutrient limiting environment. AB - The fitness landscape is a powerful metaphor for describing the relationship between genotype and phenotype for a population under selection. However, empirical data as to the topography of fitness landscapes are limited, owing to difficulties in measuring fitness for large numbers of genotypes under any condition. We previously reported a case of reciprocal sign epistasis (RSE), where two mutations individually increased yeast fitness in a glucose-limited environment, but reduced fitness when combined, suggesting the existence of two peaks on the fitness landscape. We sought to determine whether a ridge connected these peaks so that populations founded by one mutant could reach the peak created by the other, avoiding the low-fitness "Valley-of-Death" between them. Sequencing clones after 250 generations of further evolution provided no evidence for such a ridge, but did reveal many presumptive beneficial mutations, adding to a growing body of evidence that clonal interference pervades evolving microbial populations. PMID- 25449180 TI - Changes in glucose metabolism and reversion of genes expression in the liver of insulin-resistant rats exposed to malathion. The protective effects of N acetylcysteine. AB - Organophosphorus pesticides are known to disturb glucose homeostasis and increase incidence of metabolic disorders and diabetes via insulin resistance. The current study investigates the influence of malathion on insulin signaling pathways and the protective effects of N-acetylcysteine (NAC). Malathion (200 mg/kg) and NAC (2 g/l) were administered orally to rats, during 28 consecutive days. Malathion increases plasma glucose, plasma insulin and glycated hemoglobin levels. Further, we observed an increase of insulin resistance biomarkers and a decrease of insulin sensitivity indices. The GP, GSK3beta and PEPCK mRNA expressions were amplified by malathion while, the expression of glucokinase gene is down regulated. On the basis of biochemical and molecular findings, it is concluded that malathion impairs glucose homeostasis through insulin resistance and insulin signaling pathways disruptions in a way to result in a reduced function of insulin into hepatocytes. Otherwise, when malathion-treated rats were compared to NAC supplemented rats, fasting glucose and insulin levels, as well as insulin resistance indices were reduced. Furthermore, NAC restored liver GP and PEPCK expression. N-acetylcysteine showed therapeutic effects against malathion-induced insulin signaling pathways disruption in liver. These data support the concept that antioxidant therapies attenuate insulin resistance and ameliorate insulin sensitivity. PMID- 25449181 TI - Tissue distribution and developmental changes of ghrelin and GOAT expression in broiler chickens during embryogenesis. AB - Ghrelin plays important roles, such as regulating growth hormone release and energy metabolism, but little is known about its developmental changes in the proventriculi of chicken embryos. This study was designed to elucidate the distributions and developmental changes of ghrelin and ghrelin-O-acyltransferase (GOAT) expression in broiler embryos using qRT-PCR and immunohistochemistry. Our results demonstrated the following: (1) on E18, ghrelin and GOAT are ubiquitously expressed in every tissue examined. The expression level of ghrelin mRNA was the highest in the proventriculus, reaching a level that was 50-fold higher than that in the hypothalamus, while GOAT mRNA expression was low in the proventriculus and it was only 67.6% as high as that of hypothalamus; (2) ghrelin and GOAT mRNA expression were detected in the proventriculus on E9, but only at 1.9% and 1.7% of the level expressed on E18, respectively, and their expression levels increased rapidly from E18 to E21. There was similar developmental pattern in the ghrelin and GOAT mRNA expression; and (3) ghrelin-immunopositive cells were first detected in the proventriculus on E15, were located only in the compound tubular glands of the proventriculus, and were of the closed-cell type. The density of ghrelin-immunopositive cells increased significantly from E15 to E21. These results suggest that ghrelin may be an important regulating factor that plays a vital role during the development of chicken embryos. PMID- 25449182 TI - Protracted treatment with corticosterone reduces breeding success in a long-lived bird. AB - Determining the physiological mechanisms underpinning life-history decisions is essential for understanding the constraints under which life-history strategies can evolve. In long-lived species, where the residual reproductive value of breeders is high, adult survival is a key contributor to lifetime reproductive success. We therefore expect that when adult survival is compromised during reproduction, mechanisms will evolve to redirect resources away from reproduction, with implications for reproductive hormones, adult body mass, nest attendance behaviour and breeding success. We investigated whether manipulating corticosterone, to simulate exposure to an environmental stressor, affected the secretion of prolactin and breeding success in the black-legged kittiwake Rissa tridactyla. We used implanted Alzet(r) osmotic pumps to administer corticosterone to incubating kittiwakes at a constant rate over a period of approximately 8days. Manipulated birds were compared with sham implanted birds and control birds, which had no implants. There was no significant difference in the body mass of captured individuals at the time of implantation and implant removal. Corticosterone-implanted males showed lower nest attendance during the chick rearing period compared to sham-implanted males; the opposite pattern was found in females. Corticosterone treated birds showed a marginally significant reduction in breeding success compared to sham-implanted individuals, with all failures occurring at least 1week after implant removal. However, prolactin concentrations at implant removal were not significantly different from initial values. We were unable to measure the profile of change in corticosterone during the experiment. However, our results suggest a delayed effect of elevated corticosterone on breeding success rather than an immediate suppression of prolactin concentrations causing premature failure. PMID- 25449183 TI - Role of olfaction in Octopus vulgaris reproduction. AB - The olfactory system in any animal is the primary sensory system that responds to chemical stimuli emanating from a distant source. In aquatic animals "Odours" are molecules in solution that guide them to locate food, partners, nesting sites, and dangers to avoid. Fish, crustaceans and aquatic molluscs possess sensory systems that have anatomical similarities to the olfactory systems of land-based animals. Molluscs are a large group of aquatic and terrestrial animals that rely heavily on chemical communication with a generally dispersed sense of touch and chemical sensitivity. Cephalopods, the smallest class among extant marine molluscs, are predators with high visual capability and well developed vestibular, auditory, and tactile systems. Nevertheless they possess a well developed olfactory organ, but to date almost nothing is known about the mechanisms, functions and modulation of this chemosensory structure in octopods. Cephalopod brains are the largest of all invertebrate brains and across molluscs show the highest degree of centralization. The reproductive behaviour of Octopus vulgaris is under the control of a complex set of signal molecules such as neuropeptides, neurotransmitters and sex steroids that guide the behaviour from the level of individuals in evaluating mates, to stimulating or deterring copulation, to sperm-egg chemical signalling that promotes fertilization. These signals are intercepted by the olfactory organs and integrated in the olfactory lobes in the central nervous system. In this context we propose a model in which the olfactory organ and the olfactory lobe of O. vulgaris could represent the on off switch between food intake and reproduction. PMID- 25449184 TI - In silico characterization of the neuropeptidome of the Western black widow spider Latrodectus hesperus. AB - Technological advancements in high-throughput sequencing have resulted in the production/public deposition of an ever-growing number of arthropod transcriptomes. While most sequencing projects have focused on hexapods, transcriptomes have also been generated for members of the Chelicerata. One chelicerate for which a large transcriptome has recently been released is the Western black widow Latrodectus hesperus, a member of the Araneae (true spiders). Here, a neuropeptidome for L. hesperus was predicted using this resource. Thirty eight peptide-encoding transcripts were mined from the L. hesperus transcriptome, with 216 distinct peptides predicted from the deduced pre/preprohormones. The identified peptides included members of the allatostatin A, allatostatin B, allatostatin C, allatotropin, bursicon alpha, bursicon beta, CAPA/periviscerokinin/pyrokinin, CCHamide, corazonin, crustacean cardioactive peptide, crustacean hyperglycemic hormone/ion transport peptide, diuretic hormone 31, diuretic hormone 44, FMRFamide-like peptide (FLP), GSEFLamide, insulin-like peptide, neuropeptide F (NPF), orcokinin, proctolin, short neuropeptide F, SIFamide, sulfakinin and tachykinin-related peptide (TRP) families. Of particular note were the identifications of a carboxyl (C)-terminally extended corazonin, FLPs possessing -IMRFamide, -MMYFamide, and -MIHFamide C-termini, a NPF and a sulfakinin each ending in -RYamide rather than -RFamide, a precursor whose orcokinins include C-terminally amidated isoforms, and a collection of TRPs possessing -FXPXLamide rather than the stereotypical -FXGXLamide C-termini. The L. hesperus peptidome is by far the largest thus far published for any member of the Chelicerata. Taken collectively, these data serve as a reference for future neuropeptide discovery in the Araneae and provide a foundation for future studies of peptidergic control in L. hesperus and other spiders. PMID- 25449186 TI - Microbial transformation of 8:2 fluorotelomer acrylate and methacrylate in aerobic soils. AB - Biotransformation of fluorotelomer (FT) compounds, such as 8:2 FT alcohol (FTOH) is now recognized to be a source of perfluorooctanoic acid (PFOA) as well as other perfluoroalkyl acids. In this study, microbially mediated hydrolysis of FT industrial intermediates 8:2 FT acrylate (8:2 FTAC) and 8:2 FT methacrylate (8:2 FTMAC) was evaluated in aerobic soils for up to 105d. At designated times, triplicate microcosms were sacrificed by sampling the headspace for volatile FTOHs followed by sequential extraction of soil for the parent monomers as well as transient and terminal degradation products. Both FTAC and FTMAC were hydrolyzed at the ester linkage as evidenced by 8:2 FTOH production. 8:2 FTAC and FTMAC degraded rapidly with half-lives ?5d and 15d, respectively. Maximum 8:2 FTOH levels were 6-13mol% within 3-6d. Consistent with the known biotransformation pathway of 8:2 FTOH, FT carboxylic acids and perfluoroalkyl carboxylic acids were subsequently generated including up to 10.3mol% of PFOA (105d). A total mass balance (parent plus metabolites) of 50-75mol% was observed on the last sampling day. 7:2 sFTOH, a direct precursor to PFOA, unexpectedly increased throughout the incubation period. The likely, but unconfirmed, concomitant production of acrylic acids was proposed as altering expected degradation patterns. Biotransformation of 8:2 FTAC, 8:2 FTMAC, and previously reported 8:2 FT-stearate for the same soils revealed the effect of the non fluorinated terminus group linked to the FT chain on the electronic differences that affect microbially-mediated ester cleavage rates. PMID- 25449185 TI - Effects of yoga on cancer-related fatigue and global side-effect burden in older cancer survivors. AB - BACKGROUND: Sixty percent of cancer survivors are 65years of age or older. Cancer and its treatments lead to cancer-related fatigue and many other side effects, in turn, creating substantial global side-effect burden (total burden from all side effects) which, ultimately, compromises functional independence and quality of life. Various modes of exercise, such as yoga, reduce cancer-related fatigue and global side-effect burden in younger cancer survivors, but no studies have specifically examined the effects of yoga on older cancer survivors. OBJECTIVES: The purpose of this study was to assess the effects of a 4-week yoga intervention (Yoga for Cancer Survivors: YOCAS(c)(r)) on overall cancer-related fatigue, and due to its multidimensional nature, the subdomains of cancer-related fatigue (general, physical, emotional, and mental) and global side-effect burden in older cancer survivors. MATERIALS AND METHODS: We conducted a secondary analysis on data from a multicenter phase III randomized controlled clinical trial with 2 arms (standard care and standard care plus a 4-week YOCAS(c)(r) intervention). The sample for this secondary analysis was 97 older cancer survivors (>=60years of age), between 2months and 2years post-treatment, who participated in the original trial. RESULTS: Participants in the YOCAS(c)(r) intervention arm reported significantly lower cancer-related fatigue, physical fatigue, mental fatigue, and global side-effect burden than participants in the standard care arm following the 4-week intervention period (p<0.05). CONCLUSIONS: YOCAS(c)(r) is an effective standardized yoga intervention for reducing cancer-related fatigue, physical fatigue, mental fatigue, and global side-effect burden among older cancer survivors. PMID- 25449187 TI - The molecular-kinetic approach to wetting dynamics: Achievements and limitations. AB - The molecular-kinetic theory (MKT) of dynamic wetting was formulated almost 50 years ago. It explains the dependence of the dynamic contact angle on the speed of a moving meniscus by estimating the non-hydrodynamic dissipation in the contact line. Over the years it has been refined to account explicitly for the influence of (bulk) fluid viscosity and it has been applied successfully to both solid-liquid-vapour and solid-liquid-liquid systems. The free energy barrier for surface diffusion has been related to the energy of adhesion. The MKT provides a qualitative explanation for most effects in dynamic wetting. The theory is simple, flexible, and it is widely used to rationalize the physics of wetting dynamics and fit experimental data (dynamic contact angle versus contact line speed). The MKT predicts an intermediate wettability as optimal for high-speed coating as well as the maximum speeds of wetting and dewetting. Nevertheless, the values of the molecular parameters derived from experimental data tend to be scattered and not particularly reliable. This review outlines the main achievements and limitations of the MKT and highlights some common cases of misinterpretation. PMID- 25449188 TI - Pedicle digital pad transfer and negative pressure wound therapy for reconstruction of the weight-bearing surface after complete digital loss in a dog. AB - A young Labrador Retriever was presented for treatment of severe distal hindlimb necrosis caused by bandage ischemia. During digit amputation at the metatarsophalangeal joints, the third and fourth digital pads were salvaged and transferred to the metatarsal stump to create a weight-bearing surface. Negative pressure wound therapy (NPWT) was utilized for flap immobilization and to promote granulation tissue in the remaining wound defect. Sturdy adherence of the digital pads was achieved after only four days. The skin defect healed completely by second intention and the stump was epithelialized with a thin pad after three months. At the nine month follow-up examination, the stump had a thick hyperkeratinized pad. The dog walked and ran without any apparent signs of discomfort and compensated for the loss of limb length by extending the stifle and tarsocrural joints. Despite a challenging wound in a difficult anatomical location, digital pad flap transfer and NPWT proved successful in restoring long term ambulation in an active large breed dog. PMID- 25449190 TI - Toning it down: selecting outcome measures for spasticity management using a modified Delphi approach. AB - OBJECTIVE: To identify a set of clinically useful outcome measures for assessment of adults receiving treatment for spasticity. DESIGN: A modified Delphi process was conducted. In round 1, key areas of spasticity assessment and associated outcome measures were identified. In round 2, participants were presented with reviews of eligible outcome measures and were asked to select the tool they believed to be the "best" in each area. Consensus was achieved if there was at least 70% agreement among participants. In round 3, participants rated measures based on feasibility, ability to capture change, and usefulness of information gained for areas where consensus was not achieved in round 2. SETTING: The Modified Delphi process was conducted online using survey software. PARTICIPANTS: Clinicians (N=32) from centers across Canada participated in this study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Not applicable. RESULTS: Of 51 tools identified initially, 8 were selected. Tools related to body structure and function included the visual analog scale, manual muscle testing, Penn Spasm Frequency Scale, and goniometry. Activity level measures included the Berg Balance Scale, Goal Attainment Scaling (GAS), and the FIM. The Modified Caregiver Strain Index was selected for the assessment of caregiver burden, while GAS was selected for participation level outcomes. CONCLUSIONS: A standardized set of outcome measures will assist with better documentation and standardization of assessment practices of clinicians who manage spasticity. PMID- 25449189 TI - Psychometric properties of the Young Children's Participation and Environment Measure. AB - OBJECTIVE: To evaluate the psychometric properties of the newly developed Young Children's Participation and Environment Measure (YC-PEM). DESIGN: Cross sectional study. SETTING: Data were collected online and by telephone. PARTICIPANTS: Convenience and snowball sampling methods were used to survey caregivers of children (N=395, comprising children with [n=93] and without [n=302] developmental disabilities and delays) between the ages of 0 and 5 years (mean age+/-SD, 35.33+/-20.29 mo) and residing in North America. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The YC-PEM includes 3 participation scales and 1 environment scale. Each scale is assessed across 3 settings: home, daycare/preschool, and community. Data were analyzed to derive estimates of internal consistency, test-retest reliability, and construct validity. RESULTS: Internal consistency ranged from .68 to .96 and .92 to .96 for the participation and environment scales, respectively. Test-retest reliability (2-4 wk) ranged from .31 to .93 for participation scales and from .91 to .94 for the environment scale. One of 3 participation scales and the environment scale demonstrated significant group differences by disability status across all 3 settings, and all 4 scales discriminated between disability groups for the daycare/preschool setting. The participation scales exhibited small to moderate positive associations with functional performance scores. CONCLUSIONS: Results lend initial support for the use of the YC-PEM in research to assess the participation of young children with disabilities and delays in terms of (1) home, daycare/preschool, and community participation patterns; (2) perceived environmental supports and barriers to participation; and (3) activity-specific parent strategies to promote participation. PMID- 25449191 TI - Falls among adults aging with disability. AB - OBJECTIVE: To investigate the prevalence of and risk factors for falling among individuals aging with multiple sclerosis (MS), muscular dystrophy (MD), postpolio syndrome (PPS), and spinal cord injury (SCI). DESIGN: Cross-sectional survey data from 2009 to 2010 were analyzed. We used forward logistic regression models to examine whether risk factors such as age, sex, mobility level, years since diagnosis, vision, balance, weakness, number of comorbid conditions, and physical activity could distinguish participants who reported falling from those who did not. SETTING: Surveys were mailed to community-dwelling individuals who had 1 of 4 diagnoses (MS, MD, PPS, or SCI). The survey response rate was 91%. PARTICIPANTS: A convenience sample of community-dwelling individuals (N=1862; age, 18-94y) with MS, MD, PPS, or SCI in the United States. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Self-reported fall within the last 6 months. RESULTS: Fall prevalence for people with MS (54%), MD (70%), PPS (55%), and SCI (40%). Across all 4 groups, fall rates peaked in middle age (45-64y) and among people with moderate mobility limitations. Seven risk factors differentiated participants who fell from those who did not: mobility level, imbalance, age, curvilinear age (age(2)), number of comorbid conditions, duration of diagnosis, and sex. The models differed across diagnostic groups. CONCLUSIONS: People aging with long-term physical disabilities experience unique challenges that affect their risk of falls. A better understanding of the frequency, severity, and risk factors of falls across diagnostic groups is needed to design and implement customized, effective fall prevention and management programs for these individuals. PMID- 25449192 TI - Diagnosis and decision making for patients with disorders of consciousness: a survey among family members. AB - OBJECTIVES: To examine the perceptions of family members of patients with disorders of consciousness (DOC) in regard to the patients' level of consciousness, communicative status, and prognosis as compared with the objective medical categories, and to elicit the family members' self-reported practice of treatment decision-making. DESIGN: Cross-sectional semiquantitative survey. SETTING: Five specialized neurologic rehabilitation facilities. PARTICIPANTS: Consecutive sample of primary family members (N=44) of patients with DOC as determined by the Coma Recovery Scale-Revised, surveyed 6 months after the patient's brain injury. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Perception of level of consciousness as compared with the medical diagnosis; assessment of communicative status and prognosis; and practice of treatment decision-making. RESULTS: The study included 44 family members of patients, most of whom had sustained global cerebral ischemia. Six months after brain injury, 36% were in a vegetative state (VS), 20% were in a minimally conscious state (MCS), and 39% had emerged from an MCS. In 76% of cases, the relatives assumed the same level of consciousness that diagnostic tests showed. In the other cases, consciousness was mostly underestimated. While relatives of patients in a VS, and to a lesser extent of those in an MCS, were more skeptical about the patients' chances to advance to an independent life, all had high hopes that the patients would regain the ability to communicate. Yet, 59% of family members had thought about limiting life-sustaining treatment. Most of them base treatment decisions on the patient's well-being; very few relied on previously expressed patient wishes. CONCLUSIONS: According to our sample, family members of patients with DOC largely assess the level of consciousness correctly and express high hopes to reestablish communication with the patient. PMID- 25449193 TI - Nonpharmacologic management of orthostatic hypotension: a systematic review. AB - OBJECTIVE: To systematically review the literature on nonpharmacologic treatment of orthostatic hypotension. DATA SOURCES: MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Embase, Cochrane Central Register of Controlled Trials, and SPORTDiscus were searched for human studies written in the English language between January 1980 and April 2013. Reference lists of relevant articles were reviewed for citations to expand the data set. STUDY SELECTION: Prospective experimental studies assessing nonpharmacologic interventions for management of orthostatic drop in blood pressure in various patient populations were included. All studies identified through the literature search were reviewed independently in duplicate. Of the 642 studies, 23 met the selection criteria. DATA EXTRACTION: Two reviewers independently extracted data for analysis, including systolic and diastolic blood pressure and orthostatic symptoms in response to postural challenge before and after the intervention. All 23 studies were assessed in duplicate for risk of bias using the Physiotherapy Evidence Database scale for randomized controlled trials and the Downs and Black tool for nonrandomized trials. DATA SYNTHESIS: There were 8 identified nonpharmacologic interventions for management of orthostatic hypotension under 2 general categories: physical modalities (exercise, functional electrical stimulation, compression, physical countermaneuvers, compression with physical countermaneuvers, sleeping with head up) and dietary measures (water intake, meals). Owing to the clinically diverse nature of the studies, statistical comparison (meta-analysis) was deemed inappropriate. Instead, descriptive comparisons were drawn. Levels of evidence were assigned. CONCLUSIONS: Strong levels of evidence were found for 4 of the 8 interventions: functional electrical stimulation in spinal cord injury, compression of the legs and/or abdomen, physical countermaneuvers in various patient populations, and eating smaller and more frequent meals in chronic autonomic failure. However, this conclusion is based on a limited number of studies with small sample sizes. Further research into all interventions is warranted. PMID- 25449194 TI - Visual scapular dyskinesis: kinematics and muscle activity alterations in patients with subacromial impingement syndrome. AB - OBJECTIVE: To characterize scapular kinematics and shoulder muscle activity in patients with subacromial impingement syndrome, with and without visually identified scapular dyskinesis. DESIGN: Cross-sectional study. SETTING: Laboratory. PARTICIPANTS: Participants with subacromial impingement syndrome (N=38) were visually classified using a scapular dyskinesis test with obvious scapular dyskinesis (n=19) or normal scapular motion (n=19). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: An electromagnetic motion capture system measured 3-dimensional kinematics of the thorax, humerus, and scapula. Simultaneously, surface electromyography was used to measure muscle activity of the upper, middle, and lower trapezius; serratus anterior; and infraspinatus during ascending and descending phases of weighted shoulder flexion. Separate mixed-model analyses of variance for the ascending and descending phases of shoulder flexion compared kinematics and muscle activity between the 2 groups. Shoulder disability was assessed with the Pennsylvania Shoulder Score (Penn). RESULTS: The group with obvious dyskinesis reported 6 points lower on Penn shoulder function (0-60 points), exhibited a main group effect of less scapular external rotation of 2.1 degrees during ascent and 2.5 degrees during descent, and had 12.0% higher upper trapezius muscle activity during ascent in the 30 degrees to 60 degrees interval. CONCLUSIONS: Patients with obvious dyskinesis and subacromial impingement syndrome have reduced scapular external rotation and increased upper trapezius muscle activity, along with a greater loss of shoulder function compared with those without dyskinesis. These biomechanical alterations can lead to or be caused by scapular dyskinesis. Future studies should determine if correction of these deficits will eliminate scapular dyskinesis and improve patient-rated shoulder use. PMID- 25449195 TI - Functional electrical stimulation-assisted active cycling--therapeutic effects in patients with hemiparesis from 7 days to 6 months after stroke: a randomized controlled pilot study. AB - OBJECTIVE: To determine whether functional electrical stimulation (FES)-assisted active cycling is more effective than active cycling without FES concerning walking and balance. Specifically, walking ability was classified as to the amount of personal assistance needed to be able to walk and balance was evaluated for static and dynamic balance tasks. DESIGN: Monocentric, randomized, single blinded, controlled trial. SETTING: Neurologic rehabilitation hospital. PARTICIPANTS: Patients with severe hemiparesis due to stroke (N=40). INTERVENTIONS: Twenty minutes of active leg cycling with or without FES applied to the paretic vastus medialis and rectus femoris of quadriceps and to the biceps femoris and semitendinosus muscles, 3 times/wk for 4 weeks. MAIN OUTCOME MEASURES: Functional ambulation classification (FAC) and performance-oriented mobility assessment (POMA) were the primary outcome measures. The leg subscale of the motricity index (MI) and the modified Ashworth scale were the secondary outcome measures. Evaluation was done before and after the intervention period and after an additional 2 weeks. RESULTS: After the intervention, the FAC, POMA, and the MI (P<.016) for both intervention groups improved significantly. The FAC of the control group increased by a median of 1 category and that of the FES group by 2 categories. The median change in POMA was 2 and 4 points for the control group and the FES group, respectively. The Mann-Whitney U test between group comparisons revealed that these gains were significantly better in the FES group for both the FAC (U=90; z=-2.58; P=.013; r=-.42) and the POMA (U=60; z= 3.43; P<.0004; r=-.56). Because of missing data and slightly decreased effect sizes during the follow-up phase (FAC, r=-.33; POMA, r=-.41), differences did not reach statistically significant P values. The MI leg subscale showed significant improvements in both groups. However, there were no significant differences between the groups at any time. No changes were observed on the modified Ashworth scale. CONCLUSIONS: FES-assisted active cycling seems to be a promising intervention during rehabilitation in patients with stroke. PMID- 25449196 TI - Do overhead sports increase risk for rotator cuff tears in wheelchair users? AB - OBJECTIVE: To analyze whether frequent overhead-sports activity increases the risk for rotator cuff disease in patients with spinal cord injuries (SCIs) who are wheelchair dependent. DESIGN: Cross-sectional study, risk analysis. SETTING: Department of Orthopaedic Surgery, Trauma Surgery and Spinal Cord Injury. PARTICIPANTS: Patients (N=296) with SCI requiring the full-time use of a manual wheelchair were recruited for this study. The total population was divided into 2 groups (sports vs no sports), among them 103 patients playing overhead sports on a regular basis (at least 1-2 times/wk) and 193 patients involved in overhead sports less than once a week or in no sports activity at all. The mean age of the sports group was 49.1 years. The mean duration of wheelchair dependence was 26.5 years. The mean age of the no-sports group was 48 years. The mean duration of wheelchair dependence was 25.2 years. Each individual completed a questionnaire designed to identify overhead-sports activity on a regular basis and was asked about shoulder problems. Magnetic resonance imaging scans of both shoulders were performed in each patient and analyzed in a standardized fashion. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Possible differences in continuous data between patients with and without rotator cuff tear were evaluated. The relative risk of suffering from a rotator cuff tear between patients playing overhead sports and those not playing overhead sports was calculated. RESULTS: One hundred three patients played overhead sports regularly and 193 did not. There was no difference between groups regarding age, sex, level of SCI, and duration of wheelchair dependence. The body mass index was significantly lower in the sports group than in the no-sports group (P<.0001). A rotator cuff tear was present in 75.7% of the patients in the sports group and in 36.3% of the patients in the no sports group (P<.0001). Rotator cuff tears were symptomatic in 92.6% of the patients. The estimated risk increase for the sports group to develop rotator cuff tears was twice as high as for the no-sports group (95% confidence interval, 1.7-2.6; P<.001). Similar results were found for the neurological level of lesion (T2-7/ 0.05) concentrations between different milk types were observed, with the exception of specific metabolites of DDT in some milk types. Exposure assessment scenarios were developed for children aged 1, 3, 5, 7 and 12 years old based on estimated body weights and daily milk consumption. Hazard Indices for non-carcinogenic effects were below 0.109 covering also carcinogenic effects according to WHO approach. The cancer risk values for carcinogenic effects according to the US EPA Cancer Benchmark Concentration approach, ranged from 0.4 to 18. For both effects the highest values were calculated for the 1- to 3-year-old age groups. PMID- 25449199 TI - Steviol glycoside safety: are highly purified steviol glycoside sweeteners food allergens? AB - Steviol glycoside sweeteners are extracted from the plant Stevia rebaudiana (Bertoni), a member of the Asteraceae (Compositae) family. Many plants from this family can induce hypersensitivity reactions via multiple routes of exposure (e.g., ragweed, goldenrod, chrysanthemum, echinacea, chamomile, lettuce, sunflower and chicory). Based on this common taxonomy, some popular media reports and resources have issued food warnings alleging the potential for stevia allergy. To determine if such allergy warnings are warranted on stevia-based sweeteners, a comprehensive literature search was conducted to identify all available data related to allergic responses following the consumption of stevia extracts or highly purified steviol glycosides. Hypersensitivity reactions to stevia in any form are rare. The few cases documented in the peer-reviewed literature were reported prior to the introduction of high-purity products to the market in 2008 when many global regulatory authorities began to affirm the safety of steviol glycosides. Neither stevia manufacturers nor food allergy networks have reported significant numbers of any adverse events related to ingestion of stevia-based sweeteners, and there have been no reports of stevia-related allergy in the literature since 2008. Therefore, there is little substantiated scientific evidence to support warning statements to consumers about allergy to highly purified stevia extracts. PMID- 25449200 TI - High dose of maternal folic acid supplementation is associated to infant asthma. AB - Maternal folic acid supplementation had a positive effect on preventing neural tube defects (NTDs), but its effects in infant asthma remained unclear. A hospital-based case-control study was conducted with outpatients between March 2010 and March 2011 including 150 onset infant asthma cases and 212 controls, together with a meta-analysis involving 14,438 participants, was performed. The association between maternal folic acid supplementation and the risk of infant asthma was not significant either in the meta-analysis (OR = 1.06, 95% CI =0.99 1.14) or in the case-control study (OR = 0.72, 95% CI =0.37-1.39). However, quantitative analysis of the supplementation dose demonstrated that the risk of infant asthma significantly increased for the infants whose mother were with high dose supplementation (>72,000 ug*d; OR = 3.16, 95% CI =1.15-8.71) after adjusting for confounding factors in the case-control study. Meanwhile, the risk of infant asthma significantly decreased for the infants whose mother were with low-dose supplementation (<36,000 ug*d; OR = 0.36, 95% CI =0.17-0.77). A high dose of folic acid supplementation for mother during pregnancy was associated with an increased risk of infant asthma, whereas supplementation with a relatively low dose was associated with a decreased risk of infant asthma. These findings should be further investigated in a large population. PMID- 25449198 TI - Chemopreventive effects of standardized ethanol extract from the aerial parts of Artemisia princeps Pampanini cv. Sajabal via NF-kappaB inactivation on colitis associated colon tumorigenesis in mice. AB - Chronic inflammation is an underlying risk factor of colon cancer, and NF-kappaB plays a critical role in the development of inflammation-associated colon cancer in an AOM/DSS mouse model. The aim of this study was to determine whether the standardized ethanol extract obtained from the aerial parts of Artemisia princeps Pampanini cv. Sajabal (EAPP) is effective at preventing inflammation-associated colon cancer, and if so, to identify the signaling pathways involved. In the present study, protective efficacy of EAPP on tumor formation and the infiltrations of monocytes and macrophages in colons of an AOM/DSS mouse model were evaluated. It was found that colitis and tumor burdens showed statistically meaningful improvements after EAPP administration. Furthermore, these improvements were accompanied by a reduction in NF-kappaB activity and in the levels of NF-kappaB-dependent pro-survival proteins, that is, survivin, cFLIP, XIAP, and Bcl-2. In vitro, EAPP significantly reduced NF-kappaB activation and the levels of IL-1beta and IL-8 mRNA and pro-survival proteins in HT-29 and HCT 116 colon cancer cells. Furthermore, EAPP caused caspase-dependent apoptosis. Based on these results, the authors suggest EAPP suppresses inflammatory responses and induces apoptosis partly via NF-kappaB inactivation, and that EAPP could be useful for the prevention of colitis-associated tumorigenesis. PMID- 25449201 TI - Strain differences in contact hypersensitivity reaction to dinitrochlorobenzene (DNCB) in rats. AB - Genetic factors are among the most important determinants of susceptibility to induction of allergic contact dermatitis. A limited number of studies of experimental contact hypersensitivity (CHS) in animals has shown differences in the severity of CHS; however, the underlying mechanisms are unknown. In this study comparative analysis of CHS to low and high dinitrochlorobenzene (DNCB) doses regimen of sensitization/challenge in inbred Dark Agouti (DA) and Albino Oxford (AO) rats was examined. Basic aspects of draining lymph node (dLN) activity (cellularity, proliferation), proinflammatory (IFN-gamma, IL-17) and anti-inflammatory (IL-10) cytokine gene expression and production, as well as IL 12 and IL-23 subunits mRNA expression, were examined in challenge and sensitization phase of CHS reaction. Lower (compared to DA) intensity of CHS in AO rats was associated with lack of (or negligible) dLN responses in challenge phase (ex vivo, hapten- or IL-2-stimulated cell proliferation and proinflammatory cytokine mRNA and production levels) but with lack of changes in IL-10 response. Less pronounced dLN activity of sensitized animals of this strain was observed as well. Higher proliferative activity and more pronounced proinflammatory cytokine response during challenge and sensitization phase suggest these activities as underlying mechanisms of higher susceptibility of DA rats to CHS response to DNCB. PMID- 25449202 TI - Effects of aflatoxin B1, fumonisin B1 and their mixture on the aryl hydrocarbon receptor and cytochrome P450 1A induction. AB - Aflatoxin B1 (AFB1) and fumonisin B1 (FB1) are mycotoxins widely found as cereal contaminants and their co-occurrence in corn has been associated with a high incidence of liver cancer. Both toxins are immunotoxic, with AFB1 being a procarcinogen, and its bioactivation through specific cytochrome P450 (Cyp) enzymes, such as Cyp1A, being a requirement for hepatocarcinogenic and toxic activities. This study evaluated the effects of these mycotoxins, alone or combined, on activation and expression of Cyp1A and its transcription factor aryl hydrocarbon receptor (Ahr) in hepatoma cell line H4IIE and spleen mononuclear cells of rats. The results demonstrate that in H4IIE cells, AFB1 induced an increase in Cyp1A activity and cyp1A transcription, associated with an enhanced Ahr activity, which suggests that this toxin can act as an Ahr agonist. Moreover, FB1 caused a small rise in Cyp1A activity and cyp1A expression. Similarly in spleen cells, AFB1 and FB1 induced overexpression of cyp1A and ahr genes. This work shows that the response potency was significantly higher for the mixture, indicating the existence of an interaction between both toxins. This study proposes the Ahr pathway activation as a toxicity mechanism of AFB1 and FB1, and highlights that FB1 may increase AFB1 bioactivation. PMID- 25449203 TI - The extended version of restriction analysis approach for the examination of the ability of low-molecular-weight compounds to modify DNA in a cell-free system. AB - One of the primary requirements in toxicology is the assessment of ability of chemicals to induce DNA covalent modification. There are several well-established methods used for this purpose such as (32)P-Postlabeling or HPLC-MS. However, all of these approaches have difficult to overcome limitations, which prevents their use in genotoxin screening. Here, we describe the simple protocol exploiting specificity of restriction enzymes for the detection of DNA modification. It uses a specifically designed DNA amplicon, which contains two restriction sites recognized by Tru1I or MspI/HapII endonucleases. Modification of a restriction site abolishes its recognition and thus cleavage by the corresponding enzyme. The inhibition of cleavage indicates the occurrence of DNA modification of the restriction site(s), simultaneously pointing at the kind of base pairs (AT or GC) involved in DNA adduct formation. Previously, the application of this method was demonstrated for two antitumor compounds. Current study shows the extended version, that includes different ways of activation of tested compounds. Moreover, we propose an array of applications being of interest in toxicological research such as monitoring the kinetics of DNA adduct formation, detection of oxidative DNA damage, as well as assessment of the ability of antioxidative phytochemicals to prevent the latter DNA lesions. PMID- 25449205 TI - Standardization of patient-centered outcomes: less is more. PMID- 25449204 TI - Systematic review and meta-analysis of the clinical effectiveness of shock wave lithotripsy, retrograde intrarenal surgery, and percutaneous nephrolithotomy for lower-pole renal stones. AB - The prevalence of urolithiasis is increasing. Lower-pole stones (LPS) are the most common renal calculi and the most likely to require treatment. A systematic review comparing shock wave lithotripsy (SWL), retrograde intrarenal surgery (RIRS), and percutaneous nephrolithotomy (PNL) in the treatment of <=20 mm LPS in adults was performed. Comprehensive searches revealed 2741 records; 7 randomised controlled trials (RCTs) recruiting 691 patients were included. Meta-analyses for stone-free rate (SFR) at <=3 mo favoured PNL over SWL (risk ratio [RR]: 2.04; 95% confidence interval [CI], 1.50-2.77) and RIRS over SWL (RR: 1.31; 95% CI, 1.08 1.59). Stone size subgroup analyses revealed PNL and RIRS were considerably more effective than SWL for >10 mm stones, but the magnitude of benefit was markedly less for <=10 mm stones. The quality of evidence (Grading of Recommendations Assessment, Development, and Evaluation [GRADE]) for SFR was moderate for these comparisons. The median SFR from reported RCTs suggests PNL is more effective than RIRS. The findings regarding other outcomes were inconclusive because of limited and inconsistent data. Well-designed, prospective, comparative studies that measure these outcomes using standardised definitions are required, particularly for the direct comparison of PNL and RIRS. This systematic review, which used Cochrane methodology and GRADE quality-of-evidence assessment, provides the first level 1a evidence for the management of LPS. PATIENT SUMMARY: We thoroughly examined the literature to compare the benefits and harms of the different ways of treating kidney stones located at the lower pole. PNL and RIRS were superior to SWL in clearing the stones within 3 mo, but we were unable to make any conclusions regarding other outcomes. More data is required from reliable studies before firm recommendations can be made. PMID- 25449206 TI - International variations and trends in renal cell carcinoma incidence and mortality. AB - CONTEXT: Renal cell carcinoma (RCC) incidence rates are higher in developed countries, where up to half of the cases are discovered incidentally. Declining mortality trends have been reported in highly developed countries since the 1990s. OBJECTIVE: To compare and interpret geographic variations and trends in the incidence and mortality of RCC worldwide in the context of controlling the future disease burden. EVIDENCE ACQUISITION: We used data from GLOBOCAN, the Cancer Incidence in Five Continents series, and the World Health Organisation mortality database to compare incidence and mortality rates in more than 40 countries worldwide. We analysed incidence and mortality trends in the last 10 yr using joinpoint analyses of the age-standardised rates (ASRs). EVIDENCE SYNTHESIS: RCC incidence in men varied in ASRs (World standard population) from approximately 1/100,000 in African countries to >15/100,000 in several Northern and Eastern European countries and among US blacks. Similar patterns were observed for women, although incidence rates were commonly half of those for men. Incidence rates are increasing in most countries, most prominently in Latin America. Although recent mortality trends are stable in many countries, significant declines were observed in Western and Northern Europe, the USA, and Australia. Southern European men appear to have the least favourable RCC mortality trends. CONCLUSIONS: Although RCC incidence is still increasing in most countries, stabilisation of mortality trends has been achieved in many highly developed countries. There are marked absolute differences and opposing RCC mortality trends in countries categorised as areas of higher versus lower human development, and these gaps appear to be widening. PATIENT SUMMARY: Renal cell cancer is becoming more commonly diagnosed worldwide in both men and women. Mortality is decreasing in the most developed settings, but not in low- and middle-income countries, where access to and the availability of optimal therapies are likely to be limited. PMID- 25449208 TI - Metastatic malignant phyllodes tumor involving the cerebellum. AB - Brain metastases from malignant phyllodes tumors of the breast are a rare occurrence. We report a patient with a malignant phyllodes tumor of the right breast which subsequently metastasized to the right lower lobe of the lung 1 year after initial presentation, and to the right cerebellar hemisphere 2 years after diagnosis of her breast mass. After both chemotherapy and whole brain radiotherapy the patient is tumor free at most recent follow-up, 116 months after the breast tumor diagnosis was made. The literature is briefly reviewed and the differential diagnosis of malignant spindle cell brain tumors is discussed. PMID- 25449209 TI - Surgical anatomy of the minimally invasive lateral lumbar approach. AB - The lateral lumbar interbody fusion approach (LLIF), which encompasses the extreme lateral interbody fusion or direct lateral interbody fusion techniques, has gained popularity as an alternative to traditional posterior approaches. With rapidly expanding applications, this minimally invasive surgery (MIS) approach is now utilized in basic degenerative pathologies as well as complex lumbar degenerative deformities and tumors. Given the intimate relationship of the psoas muscle, and hence the lumbar plexus, to this MIS approach, several authors have examined the surgical anatomy of this approach. Understanding this regional neural anatomy is imperative given the potential for serious injuries to both the motor and sensory nerves of the lumbar plexus. In this review, we critically and comprehensively discuss all published studies detailing the surgical anatomy of the lateral lumbar approach with respect to the MIS LLIF techniques. This is a timely review given the rapidly growing number of surgeons utilizing this technique. PMID- 25449207 TI - Bone-related Parameters are the Main Prognostic Factors for Overall Survival in Men with Bone Metastases from Castration-resistant Prostate Cancer. AB - BACKGROUND: Previous studies have reported on prognostic factors for castration resistant prostate cancer (CRPC); however, most of these studies were conducted before docetaxel chemotherapy was approved for CRPC. OBJECTIVE: To evaluate the prognostic value of multiple parameters in men with bone metastases due to CRPC using a contemporary dataset. DESIGN, SETTING, AND PARTICIPANTS: The analysis included 1901 patients with metastatic CRPC enrolled in an international, multicenter, randomized, double-blind phase 3 trial conducted between May 2006 and October 2009. OUTCOME MEASURES AND STATISTICAL ANALYSIS: We developed multivariate validated Cox proportional hazards models and nomograms to estimate 12-mo and 24-mo survival probabilities and median survival time. RESULTS AND LIMITATIONS: The median (95% confidence interval) overall survival was 20 (18, 21) mo. The final model included 12 of the 15 potential prognostic variables evaluated (concordance index 0.72). Seven bone-related variables were associated with longer survival in the final model: alkaline phosphatase <=143 U/l (p<0.0001); bone-specific alkaline phosphatase (BSAP) <146 U/l (p<0.0001); corrected urinary N-telopeptide (uNTx) <=50 nmol/mmol (p=0.0008); mild or no pain (Brief Pain Inventory-Short Form [BPI-SF] score <=4) (p<0.0001); no previous skeletal-related event (SRE; p=0.0002); longer time from initial diagnosis to first bone metastasis (p<0.0001); and longer time from first bone metastasis to randomization (p<0.0001). Other significant predictors of improved survival included prostate-specific antigen (PSA) level <10 ng/ml (p<0.0001), hemoglobin >128g/l (p<0.0001), absence of visceral metastases (p<0.0001), Eastern Co operative Oncology Group (ECOG) score <=1 (p=0.017), and younger age (p=0.008). Nomograms were generated based on the parameters included in the final validated models (with/without uNTx and BSAP). One limitation was that lactate dehydrogenase (LDH) levels, a known prognostic factor, were not available in this study. CONCLUSIONS: Bone-related parameters are strong prognostic variables for overall survival in patients with bone metastases from CRPC. PATIENT SUMMARY: Survival time is variable in patients with bone metastases from prostate cancer. We found that factors related to bone help to predict how long a patient will live. PMID- 25449210 TI - Levodopa therapy for Parkinson's disease: Pharmacokinetics and pharmacodynamics. AB - For all its imperfections at treating Parkinson's disease (PD), orally administered levodopa (l-dopa) can be regarded as the "platinum" standard of PD therapeutics for its impact on disability and discomfort and its cost effectiveness. The past half-century has confirmed that the typical l-dopa treated patient gains improvement for most Parkinsonian features, presumably by conversion of this amino acid into dopamine in the striatum. However, fundamental questions remain as to its full mechanism of action and how adverse reactions evolve. Various aspects of clinical phenomenology associated with chronic l-dopa use (such as dyskinesias and the long-duration anti-Parkinsonian response) present a continuing challenge for better understanding of its pharmacology. The pharmacokinetics of l-dopa tend to predict some of problems that can emerge during chronic therapy, which can be linked with its irregular uptake and marked dose-by-dose variability in plasma concentrations. Several new pharmaceutical approaches are targeted at the unique physiology of l-dopa uptake and are likely to improve the consistency of its anti-Parkinsonian effect. PMID- 25449214 TI - Restructuring the patient's history: enhancing the consultant's role as a teacher. PMID- 25449213 TI - The long intergenic noncoding RNA UFC1, a target of MicroRNA 34a, interacts with the mRNA stabilizing protein HuR to increase levels of beta-catenin in HCC cells. AB - BACKGROUND & AIMS: Altered activities of long noncoding RNAs (lncRNAs) have been associated with cancer development. We investigated the mechanisms by which the long intergenic noncoding RNA UFC1 (lincRNA-UFC1) promotes progression of hepatocellular carcinoma (HCC), using human tissues and cell lines. METHODS: We used microarrays to compare expression profiles of lncRNAs in HCC samples and adjacent nontumor tissues (controls) from 7 patients. HCC and nontumor tissues were collected from 2006 through 2012 from patients in Guangzhou, China. We used quantitative real-time polymerase chain reaction to measure levels of lincRNA UFC1 in tissues from 49 patients, and in situ hybridization to measure levels in samples from 131 patients; clinical data were collected from patients for up to 5 years. The lincRNA-UFC1 was expressed transgenically, or knocked down with short hairpin RNAs, in BEL-7402, SK-Hep1, Huh7, and MHCC-97H HCC cell lines; luciferase reporter and RNA immunoprecipitation and pull-down assays were performed. We also analyzed growth of xenograft tumors from these cells in BALB/c nude mice. RESULTS: Levels of the lincRNA-UFC1 were increased in HCC tissues compared with controls, and associated with tumor size, Barcelona Clinic Liver Cancer stage, and patient outcomes. Transgenic expression of the lincRNA-UFC1 in HCC cells promoted their proliferation and cell-cycle progression and inhibited apoptosis, whereas short hairpin RNA knockdown of lincRNA-UFC1 had opposite effects. Xenograft tumors grown from cells overexpressing lincRNA-UFC1 had larger mean volumes and weights, and formed more rapidly, than tumors grown from control cells. Tumors grown from lincRNA-UFC1 knockdown were smaller than controls. The lincRNA-UFC1 interacted directly with the messenger RNA (mRNA) stabilizing protein HuR (encoded by ELAVL1) to increase levels of beta-catenin mRNA (encoded by CTNNB1) and protein. Levels of lincRNA-UFC1 correlated with those of beta catenin in HCC tissues. In contrast, there was a negative correlation between levels of microRNA 34a and lincRNA-UFC1 in HCC tissues; microRNA 34a reduced the stability of lincRNA-UFC1. CONCLUSIONS: The lincRNA-UFC1, a target of microRNA 34a, promotes proliferation and reduces apoptosis in HCC cells to promote growth of xenograft tumors in mice. It interacts directly with the mRNA stabilizing protein HuR to regulate levels of beta-catenin in HCC cells. PMID- 25449215 TI - Hemophagocytic lymphohistiocytosis induced by monocytic ehrlichiosis. PMID- 25449216 TI - Transitioning youth with congenital heart disease from pediatric to adult health care. PMID- 25449217 TI - A lumbosacral hemangioma with spinal dysraphism. PMID- 25449218 TI - Pitfalls in food allergy diagnosis: serum IgE testing. PMID- 25449220 TI - Airway metabolome and chronic lung disease of prematurity. PMID- 25449219 TI - Retinopathy of prematurity risk prediction for infants with birth weight less than 1251 grams. AB - OBJECTIVE: To predict retinopathy of prematurity (ROP) exam findings among infants with birth weight <1251 g from 32-40 weeks postmenstrual age (PMA). STUDY DESIGN: Secondary analysis of 3714 eye exams from 1239 infants. RESULTS: The likelihood of developing type 1 ROP by 40 weeks PMA varied by gestational age (GA) (P < .001), from 33% for <=25 weeks, 10% for 26 or 27 weeks, 4% for 28 or 29 weeks, and none for >=30 weeks. By 40 weeks PMA, 51% with GA <=27 weeks still needed subsequent exams. Previous exam findings, GA, and PMA were predictive of the development of type 1 ROP (area under the curve, 0.78) or mature retina (area under the curve, 0.85). CONCLUSIONS: This analysis provides the opportunity for development of an ROP approach to estimate resource needs in the neonatal intensive care unit and to facilitate communication with families when planning discharge or transfer. PMID- 25449222 TI - The effect of the Infant Health and Development Program on special education use at school age. AB - OBJECTIVES: To evaluate the effect of an intensive early intervention on special service use at school-age. STUDY DESIGN: The Infant Health and Development Program was a randomized controlled trial of an intervention for low birth weight (<2500 g) infants ages 0-3 years. We used multivariate logistic regression to test the association between intervention and risk of special education, remedial reading and math, and speech therapy at age 8 years. We also compared rates of service use between study arms among those with learning disabilities (LDs). RESULTS: There were 875 complete cases at 8-year follow-up. There were no statistically significant differences between groups in risk of special education (risk ratio [RR] 0.86, 95% CI 0.64-1.15), remedial reading (RR 0.88, 95% CI 0.68 1.14), remedial math (RR 0.92, 95% CI 0.63-1.34), or speech therapy (RR 0.87, 95% CI 0.62-1.23). The treatment arms did not differ in rates of LDs, and service use for those with LDs was low and unaffected by study group. CONCLUSIONS: Early gains in IQ from infant interventions may not protect children as they face the educational demands of grade school. Only a fraction of those having a LD were receiving school-based support services, indicating a high level of unmet need among low birth weight children with disabilities. PMID- 25449223 TI - Pharmacologic treatment in pediatric functional abdominal pain disorders: a systematic review. AB - OBJECTIVE: To systematically review literature assessing efficacy and safety of pharmacologic treatments in children with abdominal pain-related functional gastrointestinal disorders (AP-FGIDs). STUDY DESIGN: MEDLINE and Cochrane Database were searched for systematic reviews and randomized controlled trials investigating efficacy and safety of pharmacologic agents in children aged 4-18 years with AP-FGIDs. Quality of evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation approach. RESULTS: We included 6 studies with 275 children (aged 4.5-18 years) evaluating antispasmodic, antidepressant, antireflux, antihistaminic, and laxative agents. Overall quality of evidence was very low. Compared with placebo, some evidence was found for peppermint oil in improving symptoms (OR 3.3 (95% CI 0.9-12.0) and for cyproheptadine in reducing pain frequency (relative risk [RR] 2.43, 95% CI 1.17-5.04) and pain intensity (RR 3.03, 95% CI 1.29-7.11). Compared with placebo, amitriptyline showed 15% improvement in overall quality of life score (P = .007) and famotidine only provides benefit in global symptom improvement (OR 11.0; 95% CI 1.6-75.5; P = .02). Polyethylene glycol with tegaserod significantly decreased pain intensity compared with polyethylene glycol only (RR 3.60, 95% CI 1.54 8.40). No serious adverse effects were reported. No studies were found concerning antidiarrheal agents, antibiotics, pain medication, anti-emetics, or antimigraine agents. CONCLUSIONS: Because of the lack of high-quality, placebo-controlled trials of pharmacologic treatment for pediatric AP-FGIDs, there is no evidence to support routine use of any pharmacologic therapy. Peppermint oil, cyproheptadine, and famotidine might be potential interventions, but well-designed randomized controlled trials are needed. PMID- 25449225 TI - Initial respiratory support with cold, dry gas versus heated humidified gas and admission temperature of preterm infants. AB - OBJECTIVE: To assess whether the addition of heated humidified gas (HHG) at delivery and until neonatal unit arrival improved admission temperatures of preterm infants. STUDY DESIGN: This multicenter, randomized controlled trial was performed in New Zealand and The Netherlands. Infants <32 weeks' gestation who required respiratory support after delivery were randomized to either cold, dry gas or HHG from birth. Standard measures to prevent hypothermia included heated delivery rooms, the use of radiant warmers, body wrap, and head covering. The primary outcome was axillary temperature in the normothermic (36.5-37.5 degrees C) range on admission to a neonatal intensive care unit. Secondary outcomes were measures of respiratory support and neonatal morbidities. The effect of humidification was analyzed by the use of logistic regression. RESULTS: Of 203 randomized infants, 100 received HHG (humidifier set to 37 degrees C) and 103 received cold, dry gas. In the HHG group, 69 (69%) were normothermic compared with 57 (55%) in the cold, dry gas group (unadjusted OR 1.8, 95% CI 1.01-3.19). A greater number of infants <28 weeks were normothermic on admission in the HHG group (24/35; ie, 69%) compared with the cold, dry gas group (16/38; ie, 42%; P = .03). In addition, 2 (2%) infants in the HHG group had admission temperatures <35.5 degrees C compared with 12 (12%) in the cold, dry gas group (P = .007). Respiratory and short-term outcomes were not different. CONCLUSION: Adding HHG during respiratory support in preterm infants from birth increased the incidence of normothermia at admission. PMID- 25449226 TI - Transglutaminase 2 interacts with syndecan-4 and CD44 at the surface of human macrophages to promote removal of apoptotic cells. AB - Tissue transglutaminase (TG2) is a multifunctional protein cross-linking enzyme that has been implicated in apoptotic cell clearance but is also important in many other cell functions including cell adhesion, migration and monocyte to macrophage differentiation. Cell surface-associated TG2 regulates cell adhesion and migration, via its association with receptors such as syndecan-4 and beta1 and beta3 integrins. Whilst defective apoptotic cell clearance has been described in TG2-deficient mice, the precise role of TG2 in apoptotic cell clearance remains ill-defined. Our work addresses the role of macrophage extracellular TG2 in apoptotic cell corpse clearance. Here we reveal TG2 expression and activity (cytosolic and cell surface) in human macrophages and demonstrate that inhibitors of protein crosslinking activity reduce macrophage clearance of dying cells. We show also that cell-impermeable TG2 inhibitors significantly inhibit the ability of macrophages to migrate and clear apoptotic cells through reduced macrophage recruitment to, and binding of, apoptotic cells. Association studies reveal TG2 syndecan-4 interaction through heparan sulphate side chains, and knockdown of syndecan-4 reduces cell surface TG2 activity and apoptotic cell clearance. Furthermore, inhibition of TG2 activity reduces crosslinking of CD44, reported to augment AC clearance. Thus our data define a role for TG2 activity at the surface of human macrophages in multiple stages of AC clearance and we propose that TG2, in association with heparan sulphates, may exert its effect on AC clearance via a mechanism involving the crosslinking of CD44. PMID- 25449224 TI - Randomized trial of occlusive wrap for heat loss prevention in preterm infants. AB - OBJECTIVE: To determine whether the application of occlusive wrap applied immediately after birth will reduce mortality in very preterm infants. STUDY DESIGN: This was a prospective randomized controlled trial of infants born 24 0/7 to 27 6/7 weeks' gestation who were assigned randomly to occlusive wrap or no wrap. The primary outcome was all cause mortality at discharge or 6 months' corrected age. Secondary outcomes included temperature, Apgar scores, pH, base deficit, blood pressure and glucose, respiratory distress syndrome, bronchopulmonary dysplasia, seizures, patent ductus arteriosus, necrotizing enterocolitis, gastrointestinal perforation, intraventricular hemorrhage, cystic periventricular leukomalacia, pulmonary hemorrhage, retinopathy of prematurity, sepsis, hearing screen, and pneumothorax. RESULTS: Eight hundred one infants were enrolled. There was no difference in baseline population characteristics. There were no significant differences in mortality (OR 1.0, 95% CI 0.7-1.5). Wrap infants had statistically significant greater baseline temperatures (36.3 degrees C wrap vs 35.7 degrees C no wrap, P < .0001) and poststabilization temperatures (36.6 degrees C vs 36.2 degrees C, P < .001) than nonwrap infants. For the secondary outcomes, there was a significant decrease in pulmonary hemorrhage (OR 0.6, 95% CI 0.3-0.9) in the wrap group and a significant lower mean one minute Apgar score (P = .007) in the wrap group. The study was stopped early because continued enrollment would not result in the attainment of a significant difference in the primary outcome. CONCLUSION: Application of occlusive wrap to very preterm infants immediately after birth results in greater mean body temperature but does not reduce mortality. PMID- 25449227 TI - Interactions of the hepatitis C virus protease inhibitor faldaprevir with cytochrome P450 enzymes: in vitro and in vivo correlation. AB - The potential inhibition of the major human cytochrome P450 (CYP) enzymes by faldaprevir was evaluated both in vitro and in clinical studies (healthy volunteers and hepatitis C virus [HCV] genotype 1-infected patients). In vitro studies indicated that faldaprevir inhibited CYP2B6, CYP2C9, and CYP3A, and was a weak-to-moderate inactivator of CYP3A4. Faldaprevir 240 mg twice daily in healthy volunteers demonstrated moderate inhibition of hepatic and intestinal CYP3A (oral midazolam: 2.96-fold increase in AUC(0-24 h)), weak inhibition of hepatic CYP3A (intravenous midazolam: 1.56-fold increase in AUC(0-24 h)), weak inhibition of CYP2C9 ([S]-warfarin: 1.29-fold increase in AUC(0-120 h)), and had no relevant effects on CYP1A2, CYP2B6, or CYP2D6. Faldaprevir 120 mg once daily in HCV infected patients demonstrated weak inhibition of hepatic and intestinal CYP3A (oral midazolam: 1.52-fold increase in AUC(0-infinity)), and had no relevant effects on CYP2C9 or CYP1A2. In vitro drug-drug interaction predictions based on inhibitor concentration ([I])/inhibition constant (Ki) ratios tended to overestimate clinical effects and a net-effect model provided a more accurate approach. These studies suggest that faldaprevir shows a dose-dependent inhibition of CYP3A and CYP2C9, and does not induce CYP isoforms. PMID- 25449221 TI - Integrated genomic analyses in bronchopulmonary dysplasia. AB - OBJECTIVE: To identify single-nucleotide polymorphisms (SNPs) and pathways associated with bronchopulmonary dysplasia (BPD) because O2 requirement at 36 weeks' postmenstrual age risk is strongly influenced by heritable factors. STUDY DESIGN: A genome-wide scan was conducted on 1.2 million genotyped SNPs, and an additional 7 million imputed SNPs, using a DNA repository of extremely low birth weight infants. Genome-wide association and gene set analysis was performed for BPD or death, severe BPD or death, and severe BPD in survivors. Specific targets were validated via the use of gene expression in BPD lung tissue and in mouse models. RESULTS: Of 751 infants analyzed, 428 developed BPD or died. No SNPs achieved genome-wide significance (P < 10(-8)), although multiple SNPs in adenosine deaminase, CD44, and other genes were just below P < 10(-6). Of approximately 8000 pathways, 75 were significant at false discovery rate (FDR) <0.1 and P < .001 for BPD/death, 95 for severe BPD/death, and 90 for severe BPD in survivors. The pathway with lowest FDR was miR-219 targets (P = 1.41E-08, FDR 9.5E-05) for BPD/death and phosphorous oxygen lyase activity (includes adenylate and guanylate cyclases) for both severe BPD/death (P = 5.68E-08, FDR 0.00019) and severe BPD in survivors (P = 3.91E-08, FDR 0.00013). Gene expression analysis confirmed significantly increased miR-219 and CD44 in BPD. CONCLUSIONS: Pathway analyses confirmed involvement of known pathways of lung development and repair (CD44, phosphorus oxygen lyase activity) and indicated novel molecules and pathways (adenosine deaminase, targets of miR-219) involved in genetic predisposition to BPD. PMID- 25449228 TI - Severe meningoencephalitis co-infection due to Cryptococcus neoformans and Mycobacterium tuberculosis in a child with systemic lupus erythematosus. AB - The incidences of infection with Mycobacterium tuberculosis and Cryptococcus neoformans in immunocompromised patients have increased, but there are few documented cases of their coexistence. We present the case of a 9-year-old female with systemic lupus erythematosus (SLE), treated with prednisone and cyclophosphamide, who was admitted to the emergency department with a 2-week history of fever, headache, malaise, fatigue, and diplopia 3 years after diagnosis. Physical examination showed limitation of abduction of the right eye, Kernig and Brudzinski signs, and hyporeflexia. Magnetic resonance imaging showed hyperdense lesions located in the caudate nucleus, and lumbar puncture showed pleocytosis, a low glucose level, and increased protein level. Cerebrospinal fluid culture identified C. neoformans and PCR detect M. tuberculosis. Treatment was started with isoniazid, rifampin, pyrazinamide, ethambutol, and amphotericin B. We found two similar reports in adults, but no data were found for either pediatric or SLE patients. PMID- 25449229 TI - Growth and development of children prenatally exposed to telbivudine administered for the treatment of chronic hepatitis B in their mothers. AB - OBJECTIVES: We studied the growth and development of children prenatally exposed to telbivudine used to treat chronic hepatitis B virus (HBV) infection in their mothers. METHODS: Maternal abnormalities during pregnancy and delivery and infant congenital anomalies, physical development status, developmental quotient (DQ), HBV vertical transmission status, and HBV vaccination outcomes of 54 infants were evaluated (2010-2013). RESULTS: No fetal abnormalities were observed during pregnancy or delivery. Postpartum, three infants (5.56%) had abnormalities: ankyloglossia, cutaneous hemangioma, and vaginal canal leak. Height and weight were within the normal range at birth and at 6 weeks, but were higher than the reference at 12 months (p<0.05). Body mass index increased gradually with age (p<0.05). DQ scores were normal (84.81%, 229/270) in 37 children (68.52%), abnormal or suspicious for a developmental delay (15.19%, 41/270) in 17 children (31.48%), and indicated a developmental delay (4.07%, 11/270) in seven children (12.96%). There were no significant differences in developmental delay between children prenatally exposed to telbivudine and controls (p>0.05). HBV vertical transmission was successfully blocked in all infants. The effective HBV vaccination rate was 98.15% (53/54). CONCLUSIONS: The growth and development of children prenatally exposed to telbivudine was normal, indicating that telbivudine treatment during pregnancy is safe and effective. PMID- 25449230 TI - Clinical and laboratory profiles of refractory Mycoplasma pneumoniae pneumonia in children. AB - OBJECTIVES: The purpose of this study was to explore the clinical and laboratory characteristics of children with refractory Mycoplasma pneumoniae pneumonia (RMPP). METHODS: Seventy-six children with RMPP and 26 children with non refractory M. pneumoniae pneumonia (NRMPP), confirmed by both serology and fluorescent quantitation PCR in bronchoalveolar lavage fluid (BALF), were evaluated retrospectively. RESULTS: Compared to those with NRMPP, children with RMPP were older (66.6+/-39.0 vs. 48.4+/-35.4 months, p=0.038) and had a longer duration of fever (12.7+/-2.6 vs. 7.5+/-1.8 days) and hospital stay (12.1+/-3.2 vs. 7.4+/-2.9 days). Children with RMPP presented neutrophil infiltration both in serum and BALF, as well as severe pulmonary lesions with pleural effusion. Children with RMPP had a significantly higher M. pneumoniae DNA load in BALF compared to NRMPP patients, and the M. pneumoniae load in BALF was significantly correlated with neutrophils and inversely correlated with macrophages for both the NRMPP and RMPP groups. The serum concentrations of tumor necrosis factor alpha (median 114.5 pg/ml, range 49.1-897.9 pg/ml) and interferon gamma (median 376.9 pg/ml, range 221.4-1997.6 pg/ml) were significantly higher in children with RMPP compared to children with NRMPP. CONCLUSIONS: This study indicates that a direct microbe effect and the subsequent induced excessive host immune response contribute in part to the progression of RMPP. PMID- 25449232 TI - Recurrent Streptococcus pyogenes genital infection in a woman: test and treat the partner! AB - Group A Streptococcus (GAS) is a well-known cause of vulvovaginitis in prepubescent girls, but it is rarely described in adult women. We describe the case of a 64-year-old woman who presented with endometritis revealed by GAS bacteraemia, followed by recurrent vulvovaginitis due to a wild-type strain of GAS. She relapsed twice despite amoxicillin treatment. Her husband was found to be an asymptomatic carrier after GAS was identified in nasal and rectal swabs. She was cured after eradication of carriage in both herself and her husband with amoxicillin and rifampin. When recurrent Streptococcus pyogenes genital infections occur, test and treat the partner. PMID- 25449231 TI - Immunizations with hepatitis B viral antigens and a TLR7/8 agonist adjuvant induce antigen-specific immune responses in HBV-transgenic mice. AB - BACKGROUND: The capacity of toll-like receptor (TLR) 7/8 agonist-conjugated hepatitis B virus (HBV) proteins (HBV-Ag) to overcome established hepatitis B surface antigen (HBsAg)-specific immune tolerance was explored. METHODS: A TLR7/8 agonist, CL097, was conjugated with alum-absorbed HBsAg and hepatitis B core antigen (HBcAg), as confirmed by ultra performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF MS). Mice from two independently generated HBV-transgenic (HBV-Tg) colonies, C57BL/6J-TgN (AlblHBV) 44Bri/J mice and C57BL/6-HBV-1.3 genome-eq mice, were immunized with CL097 conjugated HBV-Ag every 2 weeks, four times. RESULTS: After immunization, 8/11 (72.7%) of the AlblHBV mice and 10/13 (76.9%) of the HBV-1.3 genome-eq mice generated serum detectable antibodies against HBsAg (anti-HBs). HBsAg-specific interferon gamma (IFN-gamma)-producing CD4(+) and CD8(+) T-cells were detected in splenocytes from these mice. Naive normal mice receiving splenocytes from the mice immunized with CL097-conjugated HBV-Ag generated immediate recall immune responses, e.g., the mice that received CD4(+)CD25(+)-depleted splenocytes generated anti-HBs on day 3 after HBsAg challenge while those receiving cells from sham-immunized mice did not. CONCLUSIONS: Immunization with CL097-conjugated HBV-Ag reversed immune tolerance in HBV-Tg mice and induced antigen-specific immune responses. TLR7/8 agonists appear to be potent adjuvants for the induction of antigen-specific Th1 responses in an immune tolerant state. PMID- 25449233 TI - Generalized edema associated with parvovirus B19 infection. AB - Generalized edema is a rare presentation of human parvovirus B19 infection. The etiology of this edema is unclear, particularly because signs of heart or renal failure are often not present. We report the case of a young adult presenting with generalized edema with serological and PCR evidence of parvovirus B19 infection, and discuss the potential mechanisms of edema based on the previous literature. PMID- 25449234 TI - The current spectrum and prevalence of intestinal parasitosis in Campania (region of southern Italy) and their relationship with migration from endemic countries. AB - BACKGROUND: In Italy, the current clinical-epidemiological features of intestinal parasitosis and the impact of recent massive migration flows from endemic areas on their distribution are not very well known. METHODS: An analysis was carried out involving 1766 patients (720 natives and 1046 immigrants) observed during the period 2009-2010 (the 'current group') and 771 native patients observed during the period 1996-1997 (the 'historical group'), a time at which immigration in the area was minimal. Patients were analyzed for intestinal parasitosis at four healthcare centres in Campania. RESULTS: A wide variety of intestinal parasites was detected in the study subjects. Immigrants had a significantly higher prevalence of parasitosis and multiple simultaneous infections than natives in both groups. In both study groups of natives, the detection of at least one parasite was significantly associated with a history of travel to endemic areas. Among immigrants, we found an inverse correlation between the frequency of parasite detection and the amount of time spent in Italy. No circulation of parasites was found among contacts of parasitized patients. CONCLUSIONS: Intestinal parasites are still a cause of intestinal infection in Campania. Although immigrants have a significantly higher prevalence of parasitosis than natives, this does not increase the risk of infection for that population. This is likely due to the lack of suitable biological conditions in our area. PMID- 25449235 TI - Antimicrobial profiles of bacterial clinical isolates from the Gabonese National Laboratory of Public Health: data from routine activity. AB - BACKGROUND: The present study is one of the first to provide a picture of antimicrobial resistance for a range of bacteria and antimicrobial classes in Gabon, Central Africa. METHODS: During the year 2010, 146 urine cytology, 143 blood cultures, 107 vaginal swabs, 23 urethral swabs, and 18 other culture examinations were positives. All isolates were tested for antibiotic sensitivity. RESULTS: Four hundred thirty-seven microorganisms were isolated: 210 enterobacteria, 166 staphylococci, 38 streptococci, 14 Acinetobacter, and nine Stenotrophomonas. Of the Klebsiella isolates, 18% and 30% were found to be resistant to selected third-generation cephalosporins (3CG) and fourth-generation cephalosporins (4CG), respectively. Sixty-seven percent of Escherichia coli isolates were resistant to amoxicillin with clavulanic acid. Between 3% and 30% of E. coli isolates were resistant to selected 3CG. All Enterobacter cloacae isolates were sensitive to imipenem. Resistance to quinolones/fluoroquinolones was seen in 21-50% of E. coli isolates. Twenty-six percent of E. cloacae showed resistance to ceftazidime and 37% to cefotaxime. The resistance rate to quinolones ranged between 58% and 78%. Thirty-two percent of Staphylococcus isolates were resistant to gentamicin. Low resistance rates to teicoplanin (2-4%) were observed. Thirty-seven percent of isolated Staphylococcus aureus and 61% of isolated Staphylococcus saprophyticus were resistant to both penicillin G and oxacillin. Streptococcus isolates had low resistance rates to erythromycin, ceftriaxone, and ciprofloxacin (5%, 7%, and 14%, respectively) and were highly resistant to tetracycline, gentamicin, and sulfamethoxazole-trimethoprim (92%, 91%, and 62%, respectively). CONCLUSIONS: The antimicrobial resistance profiles seen here are of concern. To control the spread of drug-resistant bacteria, clinicians should be cognizant of their local antimicrobial resistance patterns. PMID- 25449236 TI - What underpins the decline in syphilis in Southern and Eastern Africa? An exploratory ecological analysis. AB - BACKGROUND: AIDS mortality played an important role in the decline in syphilis prevalence in the USA, but its effect on the dramatic reduction in syphilis prevalence in Southern and Eastern Africa has not been explored. In this ecological study, we investigated the extent to which the relationship between syphilis and HIV prevalence at a population level varied between the early and late periods of the HIV epidemic. METHODS: We performed linear regression analysis to measure the association between the national prevalence of syphilis and the peak-HIV prevalence in the early and late phases of the HIV epidemic in 11 countries of Southern and Eastern Africa. RESULTS: Our analysis showed a strong positive association between peak-HIV prevalence and syphilis prevalence early in the HIV epidemic (R(2)=0.59; p=0.006). Although only of borderline statistical significance, this linear relationship between HIV prevalence and syphilis prevalence switched to a negative direction late in the HIV epidemic (R(2)=0.32; p=0.07). CONCLUSIONS: AIDS mortality may have played an important role in the decline in syphilis in this region. Consequently, with AIDS deaths declining in Sub-Saharan Africa, vigilant surveillance of syphilis prevalence will be necessary to detect a potential re-emergence, as has occurred in high income countries, and to render a timely public health response. PMID- 25449237 TI - The case of a new sequence type 7 serogroup X Neisseria meningitidis infection in China: may capsular switching change serogroup profile? AB - Neisseria meningitidis remains the leading cause of bacterial meningitis and septicemia worldwide. We describe a case of invasive meningococcal infection caused by serogroup X N. meningitidis with a unique sequence type (ST-7) in China. The strain may have arisen from locally prevalent hypervirulent serogroup A clones by capsular switching events. PMID- 25449238 TI - Overt and occult hepatitis B virus infection in adult Sudanese HIV patients. AB - OBJECTIVES: Human immunodeficiency virus (HIV) infection in Sub-Saharan Africa is complicated by co-infection with hepatitis B and C viruses (HBV and HCV), which share similar transmission routes. The aims of this study were to determine the prevalence of hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative HBV infection and of HCV infection among HIV-infected patients. METHODS: A cross sectional study was conducted among treatment-naive HIV-positive adults in Khartoum State. HBV, HCV, and HIV infections were detected using immunoassays for HBsAg, hepatitis B core antibodies (anti-HBc), hepatitis C antibodies (anti-HCV), and HIV antibodies (anti-HIV), while real-time PCR was used to measure HBV DNA. RESULTS: The mean age of the 358 patients was 35.2+/-9.3 years and the male to female ratio was 1.3:1.0. The mean alanine aminotransferase (ALT) level was 10.9+/-18.0 U/l. Evidence of 23, current or past HBV infection was detected in 62.8% of the patients. HBV DNA was detected in 96 patients (26.8%), 42 HBsAg positive (11.7%) and 54 (15.1%) HBsAg-negative, indicating occult hepatitis B infection. Anti-HCV was detected in 1.7%. CONCLUSIONS: Evidence of HBV infection was detected in 26.8% of HIV patients with HBsAg-negative infection, with viraemia detected in 15.1% of the patients. All HIV-infected patients should be screened carefully for HBV infection with HBsAg and anti-HBc IgG antibodies prior to starting antiretroviral therapy. PMID- 25449239 TI - Invasive actinomycosis: surrogate marker of a poor prognosis in immunocompromised patients. AB - OBJECTIVES: Actinomycosis is a rare disease favored by disruption of the mucosal barrier. In order to investigate the impact of immunosuppression on outcome we analyzed the most severe cases observed in patients hospitalized in three tertiary care centers. METHODS: We reviewed all cases of proven invasive actinomycosis occurring over a 12-year period (1997 to 2009) in three teaching hospitals in the Paris area. RESULTS: Thirty-three patients (16 male) were identified as having an invasive actinomycosis requiring hospitalization. The diagnosis was made by microbiological identification in 26 patients, pathological examination in eight patients, and by both methods in one. Twenty patients (61%) were immunocompromised. Actinomycosis localization was abdominal or pelvic in 17 patients, thoracic in 11, cervicofacial in three, and neurological in two. Twenty patients (61%) underwent surgery. All strains were susceptible to amoxicillin. All patients were treated with a beta-lactam antibiotic, for a median length of 82 days. Twenty-eight patients (85%) were considered as cured. Overall mortality at hospital discharge was 21% (7/33). Mortality was higher in immunocompromised patients (7/20; 21%) compared to non-immunocompromised patients (0/13) (p=0.027). However, six of seven deaths were directly related to the underlying disease. CONCLUSIONS: Actinomycosis is a cause of severe infection in immunocompromised patients and a surrogate marker of a poor prognosis in this specific population. PMID- 25449240 TI - First report of NDM-1-producing Pseudomonas aeruginosa in Egypt. AB - This work reports the occurrence of New Delhi metallo-beta-lactamase 1 (NDM-1) in metallo-beta-lactamase-producing Pseudomonas aeruginosa in Egypt for the first time, and the presence of more than one blaMBL gene in carbapenem-resistant P. aeruginosa. PMID- 25449241 TI - Disease burden of intensive care unit-acquired pneumonia in China: a systematic review and meta-analysis. AB - BACKGROUND: Intensive care unit (ICU)-acquired pneumonia and ventilator associated pneumonia (VAP) are associated with poor clinical and economic outcomes. Data regarding ICU-acquired pneumonia and VAP are not readily available from developing countries, including China. The objective of this meta-analysis was to evaluate the incidence, mortality rate, length of stay, and pathogens associated with ICU-acquired pneumonia in China. METHODS: A meta-analysis and systematic review of 334 publications published between January 2007 and May 2012 and retrieved from the Chinese BioMedical database, China National Knowledge Infrastructure, VIP Chinese Science and Technique Journals database, Wanfang database, and PubMed was conducted. RESULTS: The incidences of ICU-acquired pneumonia and VAP were 16.2% (95% confidence interval (CI) 12.8-20.4%) and 33.7% (95% CI 31.4-36.1%), respectively; mortality rates were 37.4% (95% CI 24.6-52.2%) and 34.5% (95% CI 29.2-40.1%), respectively. The durations of stay in the ICU and hospital were 12.4 (95% CI 9.6-15.3) and 17.7 (95% CI 15.6-19.7) days and 18.0 (95% CI 16.5-19.6) and 30.5 (95% CI 26.4-34.7) days for ICU-acquired pneumonia and VAP, respectively. Pseudomonas aeruginosa (19.9%) and Acinetobacter baumannii (13.9%) were the most frequently isolated pathogens, followed by Klebsiella pneumoniae (11.9%) and Staphylococcus aureus (10.4%); 82.9% of S. aureus isolates were reported to be methicillin-resistant. CONCLUSIONS: ICU-acquired pneumonia/VAP remains a major cause of morbidity and mortality in patients in the ICU in China. Data on organisms causing disease in this population could help guide appropriate prevention strategies and treatment. PMID- 25449242 TI - Healthcare-associated respiratory tract infection and colonization in an intensive care unit caused by Burkholderia cepacia isolated in mouthwash. AB - OBJECTIVES: Burkholderia cepacia has been linked to healthcare-associated infections and colonization caused by contamination of alcohol-free mouthwash used in patients undergoing mechanical ventilation. The purpose of our study was to establish the source of a clustering of healthcare-associated B. cepacia isolates in patients on mechanical ventilation in the intensive care unit (ICU). METHODS: During April 2012 the Infection Control Committee became concerned when B. cepacia was isolated from tracheal aspirate cultures of three ICU patients. The medical records for the years 2011 and 2012 were reviewed to identify further cases. Cultures of potential reservoirs were done. Isolates from patients and an alcohol-free mouthwash were submitted to multilocus sequence typing (MLST) analysis and antimicrobial resistance testing. RESULTS: Four patients with positive cultures for B. cepacia were identified before the review of the medical records for the years 2011 and 2012. Nine further cases were identified in the review, defined as a patient with pneumonia who had a culture of respiratory secretions that was positive for B. cepacia. Three were cases of infection and 10 were colonizations. All of the isolates from patients (J, K, L, and M) and mouthwash samples (B19, B20, and B21) were genetically identical by MLST analysis. CONCLUSIONS: Our findings strongly suggest that alcohol-free mouthwash solution intrinsically contaminated with B. cepacia was the source of these colonizations and infections involving adults in the ICU. PMID- 25449244 TI - Changing trends in the epidemiology, clinical presentation, and diagnosis of Leishmania-HIV co-infection in India. AB - Following the HIV epidemic, several countries have reported co-infections of Leishmania with HIV. Co-infection with these two pathogens results in rapid disease progression, more severe disease, and a poor response to treatment. A systematic review of the literature from India is presented herein. Since the first case of visceral leishmaniasis (VL) and HIV was published from India in 1999, a number of cases of HIV-Leishmania co-infection have been reported, but the proportion has been low (0.029-0.4%), as also reported in other countries where these two diseases are co-endemic. More than 89 cases of VL-HIV and 10 cases of cutaneous leishmaniasis (CL)-HIV have been published since 1999. Of these latter 10 cases, five had simple CL and five cases manifested with diffuse cutaneous leishmaniasis (DCL). In addition, one case of post-kala-azar mucocutaneous leishmaniasis in a patient with full-blown AIDS has also been reported. In two cases, it could not be ascertained whether they were cases of DCL or post-kala-azar dermal leishmaniasis from the description. Although the first case of VL-HIV co-infection was reported from the sub-Himalayan state of Uttarakhand, most cases have been reported from the VL endemic state of Bihar. HIV-Leishmania is not alarmingly high in India. Most cases were found to have occurred during 1997-2007. After that, the number of new cases decreased. This is most probably due to the low prevalence of HIV in VL and CL endemic regions and to the free supply of highly active antiretroviral therapy for HIV-infected patients. PMID- 25449245 TI - Revisiting leishmaniasis in the time of war: the Syrian conflict and the Lebanese outbreak. AB - BACKGROUND: Leishmaniasis is a neglected tropical disease, endemic in many worldwide foci including the Middle East. Several outbreaks have occurred in the Middle East over the past decades, mostly related to war-associated population migration. With the start of the Syrian war, the frequency and magnitude of these outbreaks increased alarmingly. We describe the epidemiology of Leishmania infection in Lebanon and the most recent outbreak relevant to the Syrian war. METHODS: We reviewed all leishmaniasis cases reported to the Epidemiologic Surveillance Department at the Lebanese Ministry of Public Health between 2001 and the first quarter of 2014. The demographics and distribution of Syrian refugees in Lebanon were linked to reports of new Leishmania cases. RESULTS: In total, 1033 new cases of leishmaniasis were reported in 2013 compared to a previous annual number in the range of 0-6 cases. The majority of cases reported in 2013 involved Syrian refugees and their relevant areas of concentration. CONCLUSIONS: This new outbreak of leishmaniasis in Lebanon is the first of its kind for more than a decade. The sudden increase in Leishmania cases in Lebanon in 2013 is attributed to the increasing numbers and wide distribution of Syrian refugees in Lebanon. This serves as an example of the risks associated with military conflicts and the ability of communicable diseases to cross borders. PMID- 25449243 TI - Sustained virological response after ten days of triple anti-hepatitis C virus (HCV) therapy with telaprevir plus pegylated interferon and ribavirin in an HIV/HCV co-infected cirrhotic woman. AB - The introduction of first-generation protease inhibitors for the treatment of chronic hepatitis C in subjects infected with hepatitis C virus (HCV) genotype 1 has significantly improved the sustained virological response (SVR) rate. As liver cirrhosis reduces the probability of achieving SVR, current guidelines discourage response-guided therapy in cirrhotic patients. We report the first case of a cirrhotic woman with chronic HCV and HIV co-infection achieving virological response after an ultra-short course of therapy. A 40-year-old HIV/HCV co-infected woman with compensated liver cirrhosis was treated with anti HCV triple therapy containing telaprevir plus pegylated interferon and ribavirin. Baseline plasma HCV RNA was 3.6 log IU/ml and transaminases were within the normal range. She harboured IL28B rs12979860C/C alleles. Ten days after starting therapy, the patient stopped treatment because of mild anorexia and nausea. Virological response was detected at treatment discontinuation and was maintained up to 24 weeks. This case describes an unexpected SVR after a 10-day course of antiviral therapy in a cirrhotic HIV/HCV co-infected woman presenting positive predictive factors for a response (low viral load, IL28B genotype). Nonetheless, there is no evidence to suggest a shorter duration of treatment in this subset of patients. PMID- 25449246 TI - Genotyping and virological characteristics of hepatitis B virus in HIV-infected individuals in Sudan. AB - OBJECTIVES: Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) share common routes of blood-borne transmission. In HBV mono-infected Sudanese individuals, genotypes D, E, and A circulate. The objective of this study was to molecularly characterize HBV from HBV/HIV co-infected individuals. METHODS: The polymerase overlapping the S region and the basic core promoter (BCP/PC) of HBV from 32 hepatitis B surface antigen (HBsAg)-positive and 18 HBsAg-negative serum samples were amplified and sequenced. RESULTS: HBV from 37 samples was successfully genotyped and the genotype distribution was 46.0% D, 21.6% E, 18.9% A, and 13.5% D/E recombinant. Compared to mono-infected individuals, the frequencies of the D/E recombinant and genotype A were higher in HBV/HIV co infected patients, as was the intra-group divergence of genotype E. BCP/PC mutations affecting hepatitis B e antigen (HBeAg) expression at the transcriptional and translational levels were detected. Two HBsAg-positive individuals had pre-S deletion mutants. The following mutations in the S region could account for the HBsAg negativity: sM133T, sE164G, sV168G, and sS174N. No primary drug resistance mutations were found. CONCLUSIONS: In HBV/HIV co-infected Sudanese patients, the ratio of genotype A to non-A was higher than that in mono infected patients. The genotype E intra-group divergence in HBV/HIV co-infected individuals was significantly higher than that in HBV mono-infected patients. PMID- 25449247 TI - Historic and current hepatitis B viral DNA and quantitative HBsAg level are not associated with cirrhosis in non-Asian women with chronic hepatitis B. AB - BACKGROUND: Some studies done in Asian patients have shown that serum levels of hepatitis B virus (HBV) DNA predict the development of cirrhosis. However, it is unclear whether this also applies for non-Asian patients. This study investigated historic and current HBV DNA and quantitative hepatitis B surface antigen (HBsAg) levels as predictors of cirrhosis in non-Asian women with chronic HBV. METHODS: A retrospective cohort study of non-Asian women with chronic HBV was performed. Among other variables, HBV DNA and quantitative HBsAg levels were measured in stored historic serum samples obtained during pregnancy (period 1990-2004) and current serum samples (period 2011-2012) to determine any association with liver cirrhosis by liver stiffness measurement (LSM). RESULTS: One hundred and nineteen asymptomatic, treatment-naive non-Asian women were included; the median number of years between the historic sample and the current sample was 17 (interquartile range (IQR) 13-20). The median historic log HBV DNA and quantitative log HBsAg levels were 2.5 (IQR 1.9-3.4) IU/ml and 4.2 (IQR 3.6-4.5) IU/ml, respectively. LSM diagnosed 14 patients (12%) with F3-F4 fibrosis, i.e. stiffness >8.1kPa. No association of cirrhosis was found with historic HBV DNA (relative risk (RR) 0.34, 95% confidence interval (CI) 0.05-2.44) or with the quantitative HBsAg level (HBsAg level >1000 IU/ml, RR 0.35, 95% CI 0.11-1.11). Multivariable analysis identified alcohol consumption (odds ratio (OR) 6.4, 95% CI 1.3-30.1), aspartate aminotransferase >0.5 times the upper limit of normal (OR 15.4, 95% CI 1.9-122.6), and prothrombin time (OR 12.0, 95% CI 1.2-120.4), but not HBV DNA or quantitative HBsAg level, to be independent predictors of the presence of cirrhosis. CONCLUSIONS: Neither historic nor current HBV DNA or the quantitative HBsAg level is associated with the development of HBV-related cirrhosis in non Asian women. PMID- 25449248 TI - Countrywide spread of OXA-48 carbapenemase in Lebanon: surveillance and genetic characterization of carbapenem-non-susceptible Enterobacteriaceae in 10 hospitals over a one-year period. AB - OBJECTIVES: To detect, characterize, and assess the genetic clonality of carbapenem-non-susceptible Enterobacteriaceae in 10 Lebanese hospitals in 2012. METHODS: Selected Enterobacteriaceae isolates with reduced susceptibility to carbapenems were subject to phenotypic study including antibiotic susceptibility, cloxacillin effect, modified Hodge test, and activity of efflux pump inhibitor. Carbapenemase genes were detected using PCR; clonal relatedness was studied by pulsed field gel electrophoresis. RESULTS: Out of 8717 Enterobacteriaceae isolated in 2012, 102 (1.2%) showed reduced susceptibility to carbapenems. Thirty one (70%) of the 44 studied clinical isolates harbored blaOXA-48, including 15 Klebsiella pneumoniae, eight Escherichia coli, four Serratia marcescens, three Enterobacter cloacae, and one Morganella morganii. The majority of OXA-48 producers co-secreted an extended-spectrum beta-lactamase, while one had an acquired AmpC of the ACC type. In the non-OXA-48 producers, carbapenem resistance was attributed to the production of acquired AmpC cephalosporinases of MOX or CIT type, outer membrane impermeability, and/or efflux pump overproduction. DNA fingerprints revealed that OXA-48 producers were different, except for clonal relatedness among four K. pneumoniae, two E. coli, two E. cloacae, and three S. marcescens. CONCLUSIONS: Nosocomial carbapenem-non-susceptible Enterobacteriaceae are moderately spread in Lebanon and the predominant mechanism is OXA-48 production. PMID- 25449249 TI - Molecular epidemiology of Staphylococcus aureus in post-earthquake northern Haiti. AB - BACKGROUND: Knowledge of nasal carriage is important in predicting staphylococcal infection, and no information exists regarding the endemicity of Staphylococcus aureus in Haiti. METHODS: We performed a cross-sectional analysis of S. aureus nasal screening in an acute care, a subacute rehabilitation, and a community setting, with a brief medical and epidemiological history. PCR-positive S. aureus screening nasal cultures underwent molecular analysis for spa type, SCCmec type, and virulence genes (Panton-Valentine leukocidin (PVL), toxic shock syndrome toxin (TSST), and arginine catabolic mobile element (ACME)), and were evaluated for antibiotic susceptibility using commercial tests. RESULTS: Overall carriage rates of 8.4% methicillin-susceptible S. aureus (MSSA) and 2.8% methicillin resistant S. aureus (MRSA) were identified, with a high rate of tetracycline resistance. TSST and PVL genes were identified in MSSA. MRSA isolates contained no virulence markers. Unique MSSA phenotypes (i.e., linezolid-resistant, vancomycin-sensitive/daptomycin non-susceptible) were identified, as were two PVL positive ST152 MSSA colonization isolates, previously geographically limited to Africa. CONCLUSIONS: We found a low S. aureus carriage rate with complete vancomycin susceptibility and high tetracycline resistance, which has important public health implications with regard to treatment. Additionally, the finding of PVL-positive MSSA isolates, including the expansion of a previously described limited 'divergent' clone, ST152, warrants further evaluation. PMID- 25449250 TI - Severity and frequency of community-onset Clostridium difficile infection on an Australian tertiary referral hospital campus. AB - BACKGROUND: Clostridium difficile infection (CDI) is increasingly being found in populations without traditional risk factors. We compared the relative frequency, risk factors, severity, and outcomes of community-onset CDI with hospital acquired infection. METHODS: This was a retrospective, observational study of CDI at a tertiary hospital campus in Sydney, Australia. Patients aged 15 years and older with a first episode of CDI from January 1 to December 31, 2011 were included. CDI was defined as the presence of diarrhoea with a positive enzyme immunoassay in conjunction with a positive cell cytotoxicity assay, toxin culture, or organism culture. Main outcome measures were onset of infection (hospital or community), risk factors, markers of severity, and outcomes for the two groups. RESULTS: One hundred and twenty-nine cases of CDI infection were identified, of which 38 (29%) were community-onset. The community-onset infection group were less likely to have a recent history of antibiotic use (66% vs. 98%; p<0.001) or proton pump inhibitor use (38% vs. 69%; p=0.03) than the hospital acquired infection group. Markers of severity and outcomes were similar in the two groups, with an overall mortality of 9%. CONCLUSIONS: Community-onset CDI accounts for a large proportion of C. difficile infections and has a similar potential for severe disease as hospital-acquired infection. Using a history of previous antibiotic use, proton pump inhibitor use, or recent hospitalization to predict cases is unreliable. We recommend that patients with diarrhoea being investigated in emergency departments and community practice are tested for Clostridium difficile infection. PMID- 25449251 TI - Imaging findings of cryptococcal infection of the thoracic spine. AB - Cryptococcosis with thoracic spine involvement is extremely rare, with most cases occurring in immunosuppressed patients. We report a case of cryptococcosis of the thoracic vertebrae confirmed by histopathology. The immunocompetence of the patient is a most interesting feature of this case. Laboratory investigations were normal, but the erythrocyte sedimentation rate was raised. A computed tomography scan showed an eccentric lytic lesion with a clear boundary at T2-T3. Magnetic resonance imaging showed the endplates of the T2 and T3 vertebral bodies to be involved, but without significant loss of the intervertebral disk height. A prespinal and large paraspinal soft tissue component was spreading along T1-T4, and the pleura and dural sac at the level of T2-T3 had thickened abnormally. (18)F-fluorodeoxyglucose positron emission tomography/computed tomography showed abnormal uptake in the lesion. The above-mentioned clinical and imaging information will help improve our understanding of this rare disease. PMID- 25449252 TI - A case report of Mycoplasma hominis brain abscess identified by MALDI-TOF mass spectrometry. AB - We report the case of a 43-year-old man with a Mycoplasma hominis brain abscess occurring after a cranial trauma, which was identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The presence of colonies on classic blood agar plates and the use of MALDI-TOF MS, a valuable diagnostic tool that identified M. hominis due to its presence in the VITEK MS database, allowed the rapid diagnosis of this infection. PMID- 25449253 TI - Candida glabrata meningitis and endocarditis: a late severe complication of candidemia. AB - We report an unusual case of Candida glabrata meningitis and endocarditis in a young Caucasian woman with a prosthetic aortic valve and suffering from a dissecting thoraco-abdominal aortic aneurysm. C. glabrata was isolated from culture of the cerebrospinal fluid. Candida infection of the central nervous system is an uncommon manifestation of disseminated infection due to Candida species. Our case report also highlights the intrinsic resistance of C. glabrata to azoles. PMID- 25449254 TI - Bartonella quintana detection in Demodex from erythematotelangiectatic rosacea patients. AB - We report here the presence of Bartonella quintana in a demodex. Demodex are arthropods associated with acnea. Bartonella quintana was found by broad Spectrum 16rDNA PCR amplification and sequencing, and confirmed by specific PCR. Bartonella quintana may parasite several arthropods and not only lice. PMID- 25449255 TI - Ecthyma: a potential mimicker of zoonotic infections in a returning traveler. AB - The cutaneous ulcer in a patient with a history of international travel poses a vexing diagnostic dilemma for the clinician. While Streptococcus and Staphylococcus are common causes of cutaneous ecthyma, the necrotizing ulcer can have a vast differential diagnosis including ulcerating zoonoses. PMID- 25449256 TI - Molecular characterization of macrolide resistance of a Mycoplasma pneumoniae strain that developed during therapy of a patient with pneumonia. AB - The development of macrolide resistance that occurred during 3 days of therapy with azithromycin to treat Mycoplasma pneumoniae pneumonia in a paediatric patient is reported. After extended molecular characterization of strains, the parallel occurrence of clones showing the non-mutated wild-type 23S rRNA sequence as well as mutations A2063G and A2064G, which are both responsible for phenotypic resistance, was confirmed for the first time. PMID- 25449257 TI - Detection of virulence genes in Escherichia coli isolated from patients with cystitis and pyelonephritis. AB - BACKGROUND: Uropathogenic Escherichia coli (UPEC) is a common cause of ascending urinary tract infections including cystitis and pyelonephritis. The purpose of this study was to investigate virulence genes among Escherichia coli isolated from patients with cystitis and pyelonephritis. METHODS: Between December 2012 and June 2013, 150 E. coli isolates from hospitalized patients with pyelonephritis (n = 72) and cystitis (n=78) were collected at Shahid Beheshti Hospital in Kashan. A PCR assay was used to evaluate the presence of virulence genes including pap, hly, aer, sfa, cnf, afa, traT, and pathogenicity island (PAI) markers in isolates. RESULTS: Of the total 150 UPEC isolates, 130 (86.7%) were found to carry the virulence genes studied. Nineteen different virulence patterns were identified. The most prevalent virulence pattern was UPEC including traT-PAI operons. The pap, traT, aer, hly, and PAI operons were more prevalent among patients with pyelonephritis than cystitis, and the sfa, afa, and cnf genes were not detected in any of the isolates. CONCLUSIONS: Higher virulence gene diversity was found among pyelonephritis UPEC isolates in comparison to cystitis UPEC isolates, showing that UPEC strains that cause pyelonephritis need more virulence factors. PMID- 25449258 TI - Influence of preoperative skin sealing with cyanoacrylate on microbial contamination of surgical wounds following trauma surgery: a prospective, blinded, controlled observational study. AB - OBJECTIVE: Intraoperative bacterial contamination is a risk factor for surgical site infections (SSIs). This prospective, randomized, blinded, controlled trial (Reg. No. BB08/12) investigated the effect of a cyanoacrylate-based skin sealant (InteguSeal) on intraoperative wound contamination during trauma surgery. METHODS: A total of 128 patients undergoing trauma surgery were assigned randomly to an intervention (n=62) or a control group (n=66). Surgical sites were investigated at three locations: maximum incision depth (base), wound margin prior to wound closure (margin), and the surgical sutures (suture). Colony forming units (CFU) were counted after 48h of incubation. RESULTS: Overall, significantly lower CFU counts were obtained for samples from the intervention group at all three sample sites compared to the control group. The difference, however, was only significant for the suture site (p=0.040). CONCLUSIONS: Preoperative sealing reduced microbial contamination on sutures during surgery, while the overall wound contamination remained unchanged. Hence, prevention of the clinically more relevant deep SSIs may not be expected. However, this study was not designed to detect differences in the rate of SSI. The role of the reduction in suture contamination with regard to the prevention of SSI remains to be evaluated. PMID- 25449259 TI - Analysing regenerative potential in zebrafish models of congenital muscular dystrophy. AB - The congenital muscular dystrophies (CMDs) are a clinically and genetically heterogeneous group of muscle disorders. Clinically hypotonia is present from birth, with progressive muscle weakness and wasting through development. For the most part, CMDs can mechanistically be attributed to failure of basement membrane protein laminin-alpha2 sufficiently binding with correctly glycosylated alpha dystroglycan. The majority of CMDs therefore arise as the result of either a deficiency of laminin-alpha2 (MDC1A) or hypoglycosylation of alpha-dystroglycan (dystroglycanopathy). Here we consider whether by filling a regenerative medicine niche, the zebrafish model can address the present challenge of delivering novel therapeutic solutions for CMD. In the first instance the readiness and appropriateness of the zebrafish as a model organism for pioneering regenerative medicine therapies in CMD is analysed, in particular for MDC1A and the dystroglycanopathies. Despite the recent rapid progress made in gene editing technology, these approaches have yet to yield any novel zebrafish models of CMD. Currently the most genetically relevant zebrafish models to the field of CMD, have all been created by N-ethyl-N-nitrosourea (ENU) mutagenesis. Once genetically relevant models have been established the zebrafish has several important facets for investigating the mechanistic cause of CMD, including rapid ex vivo development, optical transparency up to the larval stages of development and relative ease in creating transgenic reporter lines. Together, these tools are well suited for use in live-imaging studies such as in vivo modelling of muscle fibre detachment. Secondly, the zebrafish's contribution to progress in effective treatment of CMD was analysed. Two approaches were identified in which zebrafish could potentially contribute to effective therapies. The first hinges on the augmentation of functional redundancy within the system, such as upregulating alternative laminin chains in the candyfloss fish, a model of MDC1A. Secondly high-throughput small molecule screens not only provide effective therapies, but also an alternative strategy for investigating CMD in zebrafish. In this instance insight into disease mechanism is derived in reverse. Zebrafish models are therefore clearly of critical importance in the advancement of regenerative medicine strategies in CMD. This article is part of a Directed Issue entitled: Regenerative Medicine: The challenge of translation. PMID- 25449260 TI - Vascularisation to improve translational potential of tissue engineering systems for cardiac repair. AB - Cardiac tissue engineering is developing as an alternative approach to heart transplantation for treating heart failure. Shortage of organ donors and complications arising after orthotopic transplant remain major challenges to the modern field of heart transplantation. Engineering functional myocardium de novo requires an abundant source of cardiomyocytes, a biocompatible scaffold material and a functional vasculature to sustain the high metabolism of the construct. Progress has been made on several fronts, with cardiac cell biology, stem cells and biomaterials research particularly promising for cardiac tissue engineering, however currently employed strategies for vascularisation have lagged behind and limit the volume of tissue formed. Over ten years we have developed an in vivo tissue engineering model to construct vascularised tissue from various cell and tissue sources, including cardiac tissue. In this article we review the progress made with this approach and others, together with their potential to support a volume of engineered tissue for cardiac tissue engineering where contractile mass impacts directly on functional outcomes in translation to the clinic. It is clear that a scaled-up cardiac tissue engineering solution required for clinical treatment of heart failure will include a robust vascular supply for successful translation. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation. PMID- 25449261 TI - Exploiting the unique regenerative capacity of the liver to underpin cell and gene therapy strategies for genetic and acquired liver disease. AB - The number of genetic or acquired diseases of the liver treatable by organ transplantation is ever-increasing as transplantation techniques improve placing additional demands on an already limited organ supply. While cell and gene therapies are distinctly different modalities, they offer a synergistic alternative to organ transplant due to distinct architectural and physiological properties of the liver. The hepatic blood supply and fenestrated endothelial system affords relatively facile accessibility for cell and/or gene delivery. More importantly, however, the remarkable capacity of hepatocytes to proliferate and repopulate the liver creates opportunities for new treatments based on emerging technologies. This review will summarise current understanding of liver regeneration, describe clinical and experimental cell and gene therapeutic modalities and discuss critical challenges to translate these new technologies to wider clinical utility. This article is part of a Directed Issue entitled: "Regenerative Medicine: the challenge of translation". PMID- 25449262 TI - Cbl-family ubiquitin ligases and their recruitment of CIN85 are largely dispensable for epidermal growth factor receptor endocytosis. AB - Members of the casitas B-lineage lymphoma (Cbl) family (Cbl, Cbl-b and Cbl-c) of ubiquitin ligases serve as negative regulators of receptor tyrosine kinases (RTKs). An essential role of Cbl-family protein-dependent ubiquitination for efficient ligand-induced lysosomal targeting and degradation is now well accepted. However, a more proximal role of Cbl and Cbl-b as adapters for CIN85 endophilin recruitment to mediate ligand-induced initial internalization of RTKs is supported by some studies but refuted by others. Overexpression and/or incomplete depletion of Cbl proteins in these studies is likely to have contributed to this dichotomy. To address the role of endogenous Cbl and Cbl-b in the internalization step of RTK endocytic traffic, we established Cbl/Cbl-b double-knockout (DKO) mouse embryonic fibroblasts (MEFs) and demonstrated that these cells lack the expression of both Cbl-family members as well as endophilin A, while they express CIN85. We show that ligand-induced ubiquitination of EGFR, as a prototype RTK, was abolished in DKO MEFs, and EGFR degradation was delayed. These traits were reversed by ectopic human Cbl expression. EGFR endocytosis, assessed using the internalization of (125)I-labeled or fluorescent EGF, or of EGFR itself, was largely retained in Cbl/Cbl-b DKO compared to wild type MEFs. EGFR internalization was also largely intact in Cbl/Cbl-b depleted MCF-10A human mammary epithelial cell line. Inducible shRNA-mediated knockdown of CIN85 in wild type or Cbl/Cbl-b DKO MEFs had no impact on EGFR internalization. Our findings, establish that, at physiological expression levels, Cbl, Cbl-b and CIN85 are largely dispensable for EGFR internalization. Our results support the model that Cbl-CIN85-endophilin complex is not required for efficient internalization of EGFR, a prototype RTK. PMID- 25449264 TI - Cyanide does more to inhibit heme enzymes, than merely serving as an active-site ligand. AB - The toxicity of cyanide is hitherto attributed to its ability to bind to heme proteins' active site and thereby inhibit their activity. It is shown herein that the long-held interpretation is inadequate to explain several observations in heme-enzyme reaction systems. Generation of cyanide-based diffusible radicals in heme-enzyme reaction milieu could shunt electron transfers (by non-active site processes), and thus be detrimental to the efficiency of oxidative outcomes. PMID- 25449265 TI - Basolateral sorting of the Mg2+ transporter CNNM4 requires interaction with AP-1A and AP-1B. AB - Ancient conserved domain protein/cyclin M (CNNM) 4 is an evolutionarily conserved Mg(2+) transporter that localizes at the basolateral membrane of the intestinal epithelia. Here, we show the complementary importance of clathrin adaptor protein (AP) complexes AP-1A and AP-1B in basolateral sorting of CNNM4. We first confirmed the basolateral localization of both endogenous and ectopically expressed CNNM4 in Madin-Darby Canine Kidney cells, which form highly polarized epithelia in culture. Single knockdown of MU1B, a cargo-recognition subunit of AP 1B, did not affect basolateral localization, but simultaneous knockdown of the MU1A subunit of AP-1A abrogated localization. Mutational analyses showed the importance of three conserved dileucine motifs in CNNM4 for both basolateral sorting and interaction with MU1A and MU1B. These results imply that CNNM4 is sorted to the basolateral membrane by the complementary function of AP-1A and AP 1B. PMID- 25449263 TI - Radiation persistently promoted oxidative stress, activated mTOR via PI3K/Akt, and downregulated autophagy pathway in mouse intestine. AB - While acute effects of toxic radiation doses on intestine are well established, we are yet to acquire a complete spectrum of sub-lethal radiation-induced chronic intestinal perturbations at the molecular level. We investigated persistent effects of a radiation dose (2 Gy) commonly used as a daily fraction in radiotherapy on oxidants and anti-oxidants, and autophagy pathways, which are interlinked processes affecting intestinal homeostasis. Six to eight weeks old C57BL/6J mice (n=10) were exposed to 2 Gy gamma-ray. Mice were euthanized two or twelve months after radiation, intestine surgically removed, and flushed using sterile PBS. Parts of the intestine from jejunal-ilial region were fixed, frozen, or used for intestinal epithelial cell (IEC) isolation. While oxidant levels and mitochondrial status were assessed in isolated IEC, autophagy and oxidative stress related signaling pathways were probed in frozen and fixed samples using PCR-based expression arrays and immunoprobing. Radiation exposure caused significant alterations in the expression level of 26 autophagy and 17 oxidative stress related genes. Immunoblot results showed decreased Beclin1 and LC3-II and increased p62, PI3K/Akt, and mTOR. Flow cytometry data showed increased oxidant production and compromised mitochondrial integrity in irradiated samples. Immunoprobing of intestinal sections showed increased 8-oxo-dG and nuclear PCNA, and decreased autophagosome marker LC3-II in IEC after irradiation. We show that sub-lethal radiation could persistently downregulate anti-oxidants and autophagy signaling, and upregulate oxidant production and proliferative signaling. Radiation-induced promotion of oxidative stress and downregulation of autophagy could work in tandem to alter intestinal functions and have implications for post radiation chronic gastrointestinal diseases. PMID- 25449266 TI - An ultrasensitive system for measuring the USPs and OTULIN activity using Nanoluc as a reporter. AB - The deubiquitinating enzymes (DUBs) are a family of isopeptidases responsible for removing the ubiquitin from the ubiquitinated proteins. Identification of inhibitors for DUBs is emerging as an efficient way for discovering potential medicines for disease treatment. However, the high throughput screening (HTS) assay is still not available for all USPs, especially OTULIN. Here, we described a novel steadily quantifiable DUBs assay platform using Nanoluc (Nluc) as reporter. We further demonstrated that the Ub-Nluc assay could be used for HTS of DUBs inhibitors. Moreover, we generated a sensitive system for OTULIN inhibitors screening using Nluc as a reporter. In summary, our data indicate that Ub-Nluc and the improved Ub-Ub-GS-Nluc assay are efficient systems for measuring activities and screening inhibitors of USPs and OTULIN. PMID- 25449267 TI - Morphology and vasoactive hormone profiles from endothelial cells derived from stem cells of different sources. AB - Endothelial cells form a highly specialised lining of all blood vessels where they provide an anti-thrombotic surface on the luminal side and protect the underlying vascular smooth muscle on the abluminal side. Specialised functions of endothelial cells include their unique ability to release vasoactive hormones and to morphologically adapt to complex shear stress. Stem cell derived-endothelial cells have a growing number of applications and will be critical in any organ regeneration programme. Generally endothelial cells are identified in stem cell studies by well-recognised markers such as CD31. However, the ability of stem cell-derived endothelial cells to release vasoactive hormones and align with shear stress has not been studied extensively. With this in mind, we have compared directly the ability of endothelial cells derived from a range of stem cell sources, including embryonic stem cells (hESC-EC) and adult progenitors in blood (blood out growth endothelial cells, BOEC) with those cultured from mature vessels, to release the vasoconstrictor peptide endothelin (ET)-1, the cardioprotective hormone prostacyclin, and to respond morphologically to conditions of complex shear stress. All endothelial cell types, except hESC-EC, released high and comparable levels of ET-1 and prostacyclin. Under static culture conditions all endothelial cell types, except for hESC-EC, had the typical cobblestone morphology whilst hESC-EC had an elongated phenotype. When cells were grown under shear stress endothelial cells from vessels (human aorta) or BOEC elongated and aligned in the direction of shear. By contrast hESC-EC did not align in the direction of shear stress. These observations show key differences in endothelial cells derived from embryonic stem cells versus those from blood progenitor cells, and that BOEC are more similar than hESC-EC to endothelial cells from vessels. This may be advantageous in some settings particularly where an in vitro test bed is required. However, for other applications, because of low ET-1 release hESC-EC may prove to be protected from vascular inflammation. PMID- 25449268 TI - Glucosylceramides are required for mycelial growth and full virulence in Penicillium digitatum. AB - Glucosylceramides (GlcCers) are important lipid components of the membrane systems of eukaryotes. Recent studies have suggested the roles for GlcCers in regulating fungal growth and pathogenesis. In this study, we report the identification and functional characterization of PdGcs1, a gene encoding GlcCer synthase (GCS) essential for the biosynthesis of GlcCers, in Penicilliumdigitatum genome. We demonstrated that the deletion of PdGcs1 in P. digitatum resulted in the complete loss of production of GlcCer (d18:1/18:0 h) and GlcCer (d18:2/18:0 h), a decrease in vegetation growth and sporulation, and a delay in spore germination. The virulence of the PdGcs1 deletion mutant on citrus fruits was also impaired, as evidenced by the delayed occurrence of water soaking lesion and the formation of smaller size of lesion. These results suggest that PdGcs1 is a bona fide GCS that plays an important role in regulating cell growth, differentiation, and virulence of P. digitatum by controlling the biosynthesis of GlcCers. PMID- 25449269 TI - Transgenic silkworms expressing human insulin receptors for evaluation of therapeutically active insulin receptor agonists. AB - We established a transgenic silkworm strain expressing the human insulin receptor (hIR) using the GAL4/UAS system. Administration of human insulin to transgenic silkworms expressing hIR decreased hemolymph sugar levels and facilitated Akt phosphorylation in the fat body. The decrease in hemolymph sugar levels induced by injection of human insulin in the transgenic silkworms expressing hIR was blocked by co-injection of wortmannin, a phosphoinositide 3-kinase inhibitor. Administration of bovine insulin, an hIR ligand, also effectively decreased sugar levels in the transgenic silkworms. These findings indicate that functional hIRs that respond to human insulin were successfully induced in the transgenic silkworms. We propose that the humanized silkworm expressing hIR is useful for in vivo evaluation of the therapeutic activities of insulin receptor agonists. PMID- 25449270 TI - Exosome-associated hepatitis C virus in cell cultures and patient plasma. AB - Hepatitis C virus (HCV) infects its target cells in the form of cell-free viruses and through cell-cell contact. Here we report that HCV is associated with exosomes. Using highly purified exosomes and transmission electron microscopic imaging, we demonstrated that HCV occurred in both exosome-free and exosome associated forms. Exosome-associated HCV was infectious and resistant to neutralization by an anti-HCV neutralizing antibody. There were more exosome associated HCV than exosome-free HCV detected in the plasma of HCV-infected patients. These results suggest exosome-associated HCV as an alternative form for HCV infection and transmission. PMID- 25449271 TI - Alpha lipoic acid induces hepatic fibroblast growth factor 21 expression via up regulation of CREBH. AB - Hepatic expression of fibroblast growth factor 21 (FGF21), one of the most promising therapeutic candidates for metabolic syndrome, is induced by multiple factors associated with fasting, including cyclic AMP response element-binding protein H (CREBH). Alpha lipoic acid (ALA), a naturally occurring thiol antioxidant, has been shown to induce metabolic changes that are similar to those induced by FGF21, including weight loss and increased energy expenditure. Here, we investigated the effect of ALA on hepatic FGF21 expression. ALA treatment enhanced CREBH and FGF21 mRNA expression and protein abundance in cultured hepatocytes. ALA increased FGF21 promoter activity by up-regulating CREBH expression and increasing CREBH binding to the FGF21 promoter, indicating that ALA up-regulates FGF21 at the transcriptional level. Moreover, inhibition of endogenous CREBH expression by siRNA attenuated ALA-induced FGF21 expression. Finally, treatment of mice with ALA enhanced fasting-induced up-regulation of CREBH and FGF21 in the liver and inhibited feeding-induced suppression of their expression. Consistently, ALA increased serum FGF21 levels in both fasted and fed mice. Collectively, these results indicate that ALA increases hepatic FGF21 expression via up-regulation of CREBH, identifying ALA as a novel positive regulator of FGF21. PMID- 25449272 TI - An alternative method of enhancing the expression level of heterologous protein in Escherichia coli. AB - Though numerous strategy options are available for achieving high expression levels of genes in Escherichia coli, not every gene can be efficiently expressed in this organism. By investigating the relationship between the mRNA secondary structure of translational initiation region (TIR) and gene expression in E.coli, we establish a simple method to design sequences of appropriate TIR (from -35 to +36) that meet a specific expression level as we need. Using this method, overexpression of native human humor necrosis factor alpha and extracellular domain of Her2/neu protein (aa 23-146) in E. coli were achieved. Differences in expression appeared was mainly related to the efficiency of translation initiation and the stability of mRNA secondary structure, because the intracellular mRNA levels analyzed by real-time RT-PCR were quite similar. Our approach can overcome the steric hindrance of translation startup, and therefore promote translation smoothly to acquire high expression of exogenous protein. PMID- 25449273 TI - A polymorphism of the TIM-1 IgV domain: implications for the susceptibility to filovirus infection. AB - Filoviruses, including Ebola and Marburg viruses, cause severe hemorrhagic fever in humans and nonhuman primates with mortality rates of up to 90%. Human T-cell immunoglobulin and mucin domain 1 (TIM-1) is one of the host proteins that have been shown to promote filovirus entry into cells. In this study, we cloned TIM-1 genes from three different African green monkey kidney cell lines (Vero E6, COS 1, and BSC-1) and found that TIM-1 of Vero E6 had a 23-amino acid deletion and 6 amino acid substitutions compared with those of COS-1 and BSC-1. Interestingly, Vero E6 TIM-1 had a greater ability to promote the infectivity of vesicular stomatitis viruses pseudotyped with filovirus glycoproteins than COS-1-derived TIM-1. We further found that the increased ability of Vero E6 TIM-1 to promote virus infectivity was most likely due to a single amino acid difference between these TIM-1s. These results suggest that a polymorphism of the TIM-1 molecules is one of the factors that influence cell susceptibility to filovirus infection, providing a new insight into the molecular basis for the filovirus host range. PMID- 25449274 TI - Tight junction protein claudin-4 is modulated via DeltaNp63 in human keratinocytes. AB - In the epidermis, tight junction (TJ) structure is specifically located in the stratum granulosum, where the expression of DeltaNp63, a p53 family transcription factor, is attenuated. Since the relationship between DeltaNp63 and barrier function has not been fully uncovered, we assessed expression profiles of TJ proteins in skin tissues and cultured keratinocytes. The results showed that expression of DeltaNp63 and that of claudin-4 were inversely correlated in healthy human epidermis. In vitro studies using HaCaT keratinocytes revealed functional relevance of DeltaNp63 and claudin-4. Curiously, Toll-like receptor (TLR)-3 ligand, which is known to be liberated from damaged cells, suppressed DeltaNp63 expression and concomitantly upregulated claudin-4 expression in primary keratinocytes. More interestingly, a broad expression pattern of claudin 4 was found in the epidermis of atopic dermatitis (AD), a barrier defect disorder, which contains DeltaNp63-lacking keratinocytes as we reported previously. Therefore, upregulation of claudin-4 expression regulated by DeltaNp63 might be associated with complementary or repair responses of damaged keratinocytes with AD. PMID- 25449275 TI - Varenicline aggravates plaque formation through alpha7 nicotinic acetylcholine receptors in ApoE KO mice. AB - Varenicline is one of the most widely used drugs for smoking cessation. However, whether an adverse effect of varenicline is associated with the risk of serious cardiovascular events remains controversial. In this study, we determined if varenicline increases the risk of cardiovascular events using apolipoprotein E knockout (ApoE KO) mice. ApoE KO mice (8 weeks old) were injected with varenicline 0.5 mg kg(-1)day(-1) for 3 weeks. Varenicline aggravated atherosclerotic plaque formation in whole aorta from ApoE KO mice compared with vehicle. Methyllycaconitine, an alpha7 nicotinic acetylcholine receptor (nAChR) antagonist, inhibited varenicline-induced aggravated plaque formation. Our findings show that varenicline progresses atherosclerotic plaque formation through alpha7 nAChR, and thereby increases the risk of cardiovascular events. PMID- 25449276 TI - Pretreatment with wortmannin alleviates lipopolysaccharide/d-galactosamine induced acute liver injury. AB - Intestinal endotoxemia-induced liver injury is a common clinical disease which leads to liver failure and death. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, could be used for suppressing autophagy in vitro and in vivo. Autophagy is an evolutionarily conserved and lysosome dependent protein degradation pathway, which participates in various physiological and pathological processes. The present study aims to explore the effect of pretreatment with wortmannin on acute liver injury and the autophagy in acute liver injury. We demonstrated that wortmannin could downregulate the expression of phosphorylated extracellular regulated protein kinase and p65, decrease the production and release of hepatic inflammatory cytokines, and then reduce hepatocytes apoptosis and necrosis. More importantly, we found that autophagy was induced to increase in LPS/D-GalN-induced acute liver injury, and pretreatment with wortmannin could effectively inhibit increased autophagy in acute liver injury. In conclusion, these results indicate that wortmannin plays a protective role in LPS/D-GalN induced hepatocytotoxity maybe by inhibiting autophagy and could be acted as a target for the treatment of acute liver injury. PMID- 25449277 TI - SAMHD1 is down regulated in lung cancer by methylation and inhibits tumor cell proliferation. AB - The function of dNTP hydrolase SAMHD1 as a viral restriction factor to inhibit the replication of several viruses in human immune cells was well established. However, its regulation and function in lung cancer have been elusive. Here, we report that SAMHD1 is down regulated both on protein and mRNA levels in lung adenocarcinoma compared to adjacent normal tissue. We also found that SAMHD1 promoter is highly methylated in lung adenocarcinoma, which may inhibit its gene expression. Furthermore, over expression of the SAMHD1 reduces dNTP level and inhibits the proliferation of lung tumor cells. These results reveal the regulation and function of SAMHD1 in lung cancer, which is important for the proliferation of lung tumor cells. PMID- 25449278 TI - Prevention of aberrant protein aggregation by anchoring the molecular chaperone alphaB-crystallin to the endoplasmic reticulum. AB - The chaperone alphaB-crystallin (alphaBC) is a member of the small heat shock protein family and its point or truncated mutants cause the muscular disorder alpha-crystallinopathy. The illness is histologically characterized by accumulation of protein aggregates in muscle cells. Expression of the myopathy causing R120G mutant of alphaBC, harboring an arginine-to-glycine mutation at position 120, results in aggregate formation. We demonstrated that tethering alphaBC to the endoplasmic reticulum (ER) membrane represses the protein aggregation mediated by the R120G mutant. ER-anchored alphaBC decreased the amount of the R120G mutant through autophagic proteolysis. In contrast, knockdown of ATG5, an E3 ligase essential for autophagy, in ER-anchored alphaBC-transfected cells restored the quantity of the R120G mutant. In this context, aggregate formation was still suppressed, indicating that ER-anchored alphaBC profoundly constrains aggregation competency of the R120G mutant separately from downregulating the abundance of the mutant. We have proposed that protein aggregation is prevented by manipulation of the ER microenvironment with alphaBC, and have shed light on a novel aspect of the ER as a therapeutic target. PMID- 25449279 TI - COH-203, a novel microtubule inhibitor, exhibits potent anti-tumor activity via p53-dependent senescence in hepatocellular carcinoma. AB - 5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiol-3-one (COH-203) is a novel synthesized analogue of combretastatin A-4 that can be classified as a microtubule inhibitor. In this study, we evaluated the anti hepatoma effect of COH-203 in vitro and in vivo and explored the underlying molecular mechanisms. COH-203 was shown to be more effective in inhibiting the proliferation of liver cancer cells compared with normal liver cells. COH-203 also displayed potent anti-tumor activity in a hepatocellular carcinoma xenograft model without significant toxicity. Mechanistic studies demonstrated that treatment with COH-203 induced mitotic arrest by inhibiting tubulin polymerization in BEL-7402 liver cancer cells. Long-term COH-203 treatment in BEL 7402 cells led to mitotic slippage followed by senescence via the p14(Arf)-p53 p21 and p16(INK4alpha)-Rb pathways. Furthermore, suppression of p53 via pifithrin alpha (p53 inhibitor) and p53-siRNA attenuated COH-203-induced senescence in BEL 7402 cells, suggesting that COH-203 induced senescence p53-dependently. In conclusion, we report for the first time that COH-203, one compound in the combretastatin family, promotes anti-proliferative activity through the induction of p-53 dependent senescence. Our findings will provide a molecular rationale for the development of COH-203 as a promising anti-tumor agent. PMID- 25449280 TI - Stem cell factor (SCF) protects osteoblasts from oxidative stress through activating c-Kit-Akt signaling. AB - Osteoblasts regulate bone formation and remodeling, and are main target cells of oxidative stress in the progression of osteonecrosis. The stem cell factor (SCF) c-Kit pathway plays important roles in the proliferation, differentiation and survival in a range of cell types, but little is known about its functions in osteoblasts. In this study, we found that c-Kit is functionally expressed in both osteoblastic-like MC3T3-E1 cells and primary murine osteoblasts. Its ligand SCF exerted significant cyto-protective effects against hydrogen peroxide (H2O2). SCF activated its receptor c-Kit in osteoblasts, which was required for its cyto protective effects against H2O2. Pharmacological inhibition (by Imatinib and Dasatinib) or shRNA-mediated knockdown of c-Kit thus inhibited SCF-mediated osteoblast protection. Further investigations showed that protection by SCF against H2O2 was mediated via activation of c-Kit-dependent Akt pathway. Inhibition of Akt activation, through pharmacological or genetic means, suppressed SCF-mediated anti-H2O2 activity in osteoblasts. In summary, we have identified a new SCF-c-Kit-Akt physiologic pathway that protects osteoblasts from H2O2-induced damages, and might minimize the risk of osteonecrosis caused by oxidative stress. PMID- 25449281 TI - Vinculin negatively regulates transcription of MT1-MMP through MEK/ERK pathway. AB - Vinculin regulates a variety of cellular functions partly through stabilization of tumor suppressor PTEN. In order to study the role of vinculin in tumor progression other than PTEN stabilization, vinculin was knocked down in PTEN deficient squamous cell carcinoma HSC-4 cells. Knockdown of vinculin induced phenotypical change by reducing cell-cell and cell-extracellular matrix adhesions, and enhanced MT1-MMP expression at transcription level and subsequent cell migration. Up-regulation of MT1-MMP transcription by vinculin knockdown was abrogated by ERK inhibition. These results suggest that vinculin negatively regulates malignant phenotype of tumor cells including MT1-MMP transcription through MEK/ERK pathway. PMID- 25449282 TI - Improved tumor-targeting MRI contrast agents: Gd(DOTA) conjugates of a cycloalkane-based RGD peptide. AB - Two new MRI contrast agents, Gd-DOTA-c(RGD-ACP-K) (1) and Gd-DOTA-c(RGD-ACH-K) (2), which were designed by incorporating aminocyclopentane (ACP)- or aminocyclohexane (ACH)-carboxylic acid into Gd-DOTA (gadolinium-tetraazacyclo dodecanetetraacetic acid) and cyclic RGDK peptides, were synthesized and evaluated for tumor-targeting ability in vitro and in vivo. Binding affinity studies showed that both 1 and 2 exhibited higher affinity for integrin receptors than cyclic RGDyK peptides, which were used as a reference. These complexes showed high relaxivity and good stability in human serum and have the potential to improve target-specific signal enhancement in vivo MR images. PMID- 25449283 TI - Microphthalmia-associated transcription factor as the molecular target of cadmium toxicity in human melanocytes. AB - Dietary intake of cadmium is inevitable, causing age-related increase in cadmium accumulation in many organs, including hair, choroid and retinal pigment epithelium (RPE). Cadmium has been implicated in the pathogenesis of hearing loss and macular degeneration. The functions of cochlea and retina are maintained by melanocytes and RPE, respectively, and the differentiation of these pigment cells is regulated by microphthalmia-associated transcription factor (MITF). In the present study, we explored the potential toxicity of cadmium in the cochlea and retina by using cultured human melanocytes and human RPE cell lines. MITF consists of multiple isoforms, including melanocyte-specific MITF-M and widely expressed MITF-H. Levels of MITF-M protein and its mRNA in human epidermal melanocytes and HMV-II melanoma cells were decreased significantly by cadmium. In parallel with the MITF reduction, mRNA levels of tyrosinase, the key enzyme of melanin biosynthesis that is regulated by MITF-M, were also decreased. In RPE cells, however, the levels of total MITF protein, constituting mainly MITF-H, were not decreased by cadmium. We thus identify MITF-M as the molecular target of cadmium toxicity in melanocytes, thereby accounting for the increased risk of disability from melanocyte malfunction, such as hearing and vision loss among people with elevated cadmium exposure. PMID- 25449284 TI - Ligand induced stabilization of the melting temperature of the HSV-1 single strand DNA binding protein using the thermal shift assay. AB - We have adapted the thermal shift assay to measure the ligand binding properties of the herpes simplex virus-1 single-strand DNA binding protein, ICP8. By measuring SYPRO Orange fluorescence in microtiter plates using a fluorescence enabled thermal cycler, we have quantified the effects of oligonucleotide ligands on the melting temperature of ICP8. We found that single-stranded oligomers raise the melting temperature of ICP8 in a length- and concentration-dependent manner, ranging from 1 degrees C for (dT)5 to a maximum of 9 degrees C with oligomers ?10 nucleotides, with an apparent Kd of <1MUM for (dT)20. Specifically, the results indicate that ICP8 is capable of interacting with oligomers as short as 5 nucleotides. Moreover, the observed increases in melting temperature of up to 9 degrees C, indicates that single-strand DNA binding significantly stabilizes the structure of ICP8. This assay may be applied to investigate the ligand binding proteins of other single-strand DNA binding proteins and used as a high throughput screen to identify compounds with therapeutic potential that inhibit single-strand DNA binding. As proof of concept, the single-strand DNA binding agent ciprofloxacin reduces the ligand induced stabilization of the melting temperature of ICP8 in a dose-dependent manner. PMID- 25449285 TI - Microalgal lipids biochemistry and biotechnological perspectives. AB - In the last few years, there has been an intense interest in using microalgal lipids in food, chemical and pharmaceutical industries and cosmetology, while a noteworthy research has been performed focusing on all aspects of microalgal lipid production. This includes basic research on the pathways of solar energy conversion and on lipid biosynthesis and catabolism, and applied research dealing with the various biological and technical bottlenecks of the lipid production process. In here, we review the current knowledge in microalgal lipids with respect to their metabolism and various biotechnological applications, and we discuss potential future perspectives. The committing step in fatty acid biosynthesis is the carboxylation of acetyl-CoA to form malonyl-CoA that is then introduced in the fatty acid synthesis cycle leading to the formation of palmitic and stearic acids. Oleic acid may also be synthesized after stearic acid desaturation while further conversions of the fatty acids (i.e. desaturations, elongations) occur after their esterification with structural lipids of both plastids and the endoplasmic reticulum. The aliphatic chains are also used as building blocks for structuring storage acylglycerols via the Kennedy pathway. Current research, aiming to enhance lipogenesis in the microalgal cell, is focusing on over-expressing key-enzymes involved in the earlier steps of the pathway of fatty acid synthesis. A complementary plan would be the repression of lipid catabolism by down-regulating acylglycerol hydrolysis and/or beta oxidation. The tendency of oleaginous microalgae to synthesize, apart from lipids, significant amounts of other energy-rich compounds such as sugars, in processes competitive to lipogenesis, deserves attention since the lipid yield may be considerably increased by blocking competitive metabolic pathways. The majority of microalgal production occurs in outdoor cultivation and for this reason biotechnological applications face some difficulties. Therefore, algal production systems need to be improved and harvesting systems need to be more effective in order for their industrial applications to become more competitive and economically viable. Besides, a reduction of the production cost of microalgal lipids can be achieved by combining lipid production with other commercial applications. The combined production of bioactive products and lipids, when possible, can support the commercial viability of both processes. Hydrophobic compounds can be extracted simultaneously with lipids and then purified, while hydrophilic compounds such as proteins and sugars may be extracted from the defatted biomass. The microalgae also have applications in environmental biotechnology since they can be used for bioremediation of wastewater and to monitor environmental toxicants. Algal biomass produced during wastewater treatment may be further valorized in the biofuel manufacture. It is anticipated that the high microalgal lipid potential will force research towards finding effective ways to manipulate biochemical pathways involved in lipid biosynthesis and towards cost effective algal cultivation and harvesting systems, as well. PMID- 25449286 TI - Global distribution of polymorphisms associated with delayed Plasmodium falciparum parasite clearance following artemisinin treatment: genotyping of archive blood samples. AB - The recent emergence and spread of artemisinin-resistant Plasmodium falciparum isolates is a growing concern for global malaria-control efforts. A recent genome wide analysis study identified two SNPs at genomic positions MAL10-688956 and MAL13-1718319, which are linked to delayed clearance of parasites following artemisinin combination therapy (ACT). It is expected that continuous artemisinin pressure will affect the distribution of these SNPs. Here, we investigate the worldwide distribution of these SNPs using a large number of archived samples in order to generate baseline data from the period before the emergence of ACT resistance. The presence of SNPs in MAL10-688956 and MAL13-1718319 was assessed by nested PCR RFLP and direct DNA sequencing using 653 global P. falciparum samples obtained before the reported emergence of ACT resistance. SNPs at MAL10 688956 and MAL13-1718319 associated with delayed parasite clearance following ACT administration were observed in 8% and 3% of parasites, respectively, mostly in Cambodia and Thailand. Parasites harbouring both SNPs were found in only eight (1%) isolates, all of which were from Cambodia and Thailand. Linkage disequilibrium was detected between MAL10-688956 and MAL13-1718319, suggesting that this SNP combination may have been selected by ACT drug pressure. Neither of the SNPs associated with delayed parasite clearance were observed in samples from Africa or South America. Baseline information of the geographical difference of MAL10-688956 and MAL13-1718319 SNPs provides a solid basis for assessing whether these SNPs are selected by artemisinin-based combination therapies. PMID- 25449287 TI - First report of a fatal autochthonous canine Angiostrongylus vasorum infection in Belgium. AB - Canine angiostrongylosis is considered as an emergent disease in Europe and Canada. A fatal case of Angiostrongylus vasorum infection is described in a four and a half month old puppy born in Belgium. The dog was presented with marked neurological disorders, body weight loss, a profound weakness and mild respiratory signs. The dog was given antibiotics and mucolytic compounds with very little improvement and consequently was referred to a specialist for additional examinations. As the general condition of the dog was rapidly declining, the animal was euthanized shortly after on its owners' request and a necropsy was carried out. Extensive gross pulmonary lesions were observed and histopathological examination revealed the presence of numerous larvae with morphology compatible with A. vasorum. Larvae were also found in the product of a bronchoalveolar lavage but fecal material was not examined. The presence of A. vasorum circulating serum antigen was demonstrated through ELISA; additionally an A. vasorum specific PCR was performed on brain material and yielded a positive result. This case confirms that the clinical diagnosis of canine angiostrongylosis can be very challenging especially when respiratory signs are absent or very mild such in the present case. This is the first reported case of canine angiostrongylosis in Belgium. PMID- 25449288 TI - Composition, structure and pattern of helminth assemblages associated with central European herons (Ardeidae). AB - Helminths parasitizing the ardeid birds are poorly understood, and the majority of studies are limited to checklists and records of novel host-parasite interactions. Here we analyzed the prevalence, intensity and diversity of the helminth component communities associated with an extensive cohort of the five most common Czech herons (Ardea cinerea, Ardea alba, Nycticorax nycticorax, Botaurus stellaris and Ixobrychus minutus) collected in the years 1962-2013. Comparison with Ukrainian datasets supports the existence of local helminth component communities, subject to strong geographic variation. The diversity of the component communities ranged between 37.3+/-9.6 (A. cinerea) and 2.5+/-1.1 (I. minutus) species. Similarly, the frequency of particular helminths differed by over one order of magnitude, whereas the helminth load differed by over two orders of magnitude. Typically, the dominant species (Echinochasmus beleocephalus, Uroproctepisthmium bursicola, Posthodiplostomum cuticola, Apharyngostrigea cornu, Desmidocercella numidica and Neogryporhynchus cheilancristrotus) were considered local, with intermediate host species available onsite, as represented by freshwater mollusks. Of the digeneans, 52% of the species likely infected their definitive hosts outside the study area, frequently utilizing invertebrates of salt or brackish waters. For A. cinerea, the largest number of species was in adult males; however the helminth load of the adults was lower than in their juvenile counterparts. This study provides the first systematically collected evidence for the intra-annual changes of the helminth assemblages in herons. PMID- 25449289 TI - Bioactivity-guided isolation of antiplasmodial constituents from Conyza sumatrensis (Retz.) E.H. Walker. AB - Conyza sumatrensis (Retz.) E.H. Walker (Cs) leaves are used for traditional treatment of malaria in Cameroon. However, the antimalarial activity of the leaf constituents of this plant is still unexplored. The aim of our investigation was to evaluate the antiplasmodial activity of some bioactive constituents from Cs leaves. Compounds were isolated from Cs leaves and structurally elucidated using extensive spectroscopic analysis. The in vitro antiplasmodial activity of the extracts and pure compounds were evaluated on chloroquine-sensitive strain (NF54) of Plasmodium falciparum. The in vivo assay was done by administering seven doses of extracts in mice infected with Plasmodium berghei K173 through oral route. Cytotoxicity of pure compounds on murine macrophage cells was performed through [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] (MTT) test. Hemolysis and lactate dehydrogenase assays were also carried out using standard procedures. The in silico prediction of bioactive constituents was performed through Autodock Vina. Polarity-based extracts from Cs were found to be active against P. falciparum (NF54) and P. berghei (K173) in vitro and in vivo respectively. Further, bioactivity-guided isolation of n-hexane fraction yielded three compounds, (1), (2) and (3) with IC50 of 34, 17.9 and 18MUg/ml, respectively, while the ethyl acetate fraction afforded the fourth compound with an IC50 of 25MUg/ml, indicating anti-malarial potential of Cs through PfLDH interaction without compromising normal cell growth. This study reports for the first time, the antiplasmodial activity of bioactive constituents from Cs and confirms its traditional use. PMID- 25449290 TI - Functional analysis of iron superoxide dismutase-A in wild-type and antimony resistant Leishmania braziliensis and Leishmania infantum lines. AB - In this work, we characterized the gene encoding iron superoxide dismutase-A (FeSOD-A) in wild-type (WTS) and antimony-resistant (SbR) L. (Viannia) braziliensis and L. (Leishmania) infantum lines, which were selected in vitro. FeSOD-A transcript and protein expression were similar in all tested lines; however, specific enzyme activity analysis revealed higher superoxide dismutase activity in SbIII-resistant LbSbR and LiSbR lines than in the corresponding WTS lines. These parasites were also more tolerant to oxidative stress generated by the herbicide paraquat. Functional analysis showed that in comparison to non transfected lines, wild-type LbWTS and LiWTS clones overexpressing the FeSOD-A enzyme are 1.6- and 1.7-fold more resistant to SbIII, respectively. Our results suggest that FeSOD-A is involved in the antimony resistance phenotype in L. (V.) braziliensis and L. (L.) infantum. PMID- 25449291 TI - Clinical outcomes from mature oocytes derived from preovulatory and antral follicles: reflections on follicle physiology and oocyte competence. AB - PURPOSE: The aim of this retrospective study was to compare the competence of oocytes obtained from preovulatory and antral follicles. METHODS: Mature oocytes from preovulatory follicles were retrieved from women selected for standard IVF treatment (Group A). Mature oocytes from antral follicles were recovered from women undergoing hCG-primed in vitro maturation (IVM) treatment (Group B). Patients groups were matched for age, BMI, FSH, AMH and antral follicle count (AFC) values. In vivo matured oocytes from both groups were microinjected and resulting embryos were culture and selected on day 3 for embryo transfer. RESULTS: Oocyte pick-ups (OPU) were 315 and 204 in Groups A and B, respectively. Fertilization rates were comparable (72.8 and 75.9 %, respectively; P = 0.137). In Group A, in which the average number of embryos transferred was higher, clinical pregnancy rates per OPU (37.5 %) and embryo transfer (38.4 %) were superior in comparison to Group B (27.0 %, P = 0.013; 29.4 %, P = 0.041; respectively). On the other hand, implantation rates (Group A, 23.7 %; Group B, 20.8 %) and proportions of babies born per transferred embryo (Group A, 19.5 %; Group B, 16.9 %) were similar (P = 0.528 and 0.332, respectively). CONCLUSIONS: Overall, this suggests that oocyte competence is already achieved at the antral stage of follicle development. PMID- 25449292 TI - Azoospermia and ring chromosome 9--a case report. PMID- 25449293 TI - Enhancing acquisition of health care management skills in youth living with HIV prior to transition: a pilot study. PMID- 25449294 TI - HIV as chronic illness: caregiving and social networks in a vulnerable population. AB - We sought to understand the support networks of people living with HIV (PLWH) in the Canadian cities of Winnipeg and Regina, particularly of their network of caregivers and with a focus on people from disadvantaged and/or stigmatized communities. Using a variation of the Photovoice method, 31 study participants took photographs of their everyday realities and were then interviewed. Among the findings was the heavy reliance on institutional caregivers and on nonhuman sources of support. There was evidence of peer-to-peer networks of care, but the strongest connections were with their formal caregivers. HIV as a chronic condition among disadvantaged and/or stigmatized groups requires paying special attention to informal and formal care dynamics and to where social or family networks cannot meet the basic needs. Honing in on and enhancing these features through programs and services can only improve the situation of stigmatized yet hopeful and resilient PLWH. PMID- 25449295 TI - Residency in urology and training in kidney transplantation. Results of a national survey. AB - OBJECTIVES: To determine the current state of kidney transplantation (KT) training in a country that is leader in organ donation and transplantation. MATERIAL AND METHODS: We conducted an online survey by e-mail to 138 urology residents. The survey contained 5 sections: affiliation, training in KT, interest in KT, residents of transplant centers and residents of nontransplant centers. RESULTS: Sixty-five residents responded, 47.1% of the urologists in training surveyed, representing 28 cities and 15 provinces. Fifty-five percent (n=36) of the respondents deemed the KT training offered during their residency as insufficient, and 85% (n=55) demanded more resources. More than half were not confident in their abilities to perform transplantation surgery over the course of their residency (n=35). Nineteen percent of the residents considered KT an important discipline in their residency, with a mean score of 56.2 (1-100). Among the residents of the transplant centers (69.2%, n=45), 73% (n=33) considered KT when choosing a center for their residency. Of the surveyed residents from nontransplant centers (30.7%, n=20), 45% (n=9) do not perform an external rotation in KT. CONCLUSIONS: The surveyed residents demand more training in KT. The most common situation is to end a residency without having performed a complete KT. KT is considered an asset when selecting a resident medical intern position and commonly they are part of the transplantation team. The majority of residents are trained in centers with less than 75 transplants/year. External rotations in KT are not the rule in centers where transplantation is not performed. PMID- 25449296 TI - LRIG1 improves chemosensitivity through inhibition of BCL-2 and MnSOD in glioblastoma. AB - We have reported that Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) can improve the chemosensitivity in U251 cells. However, the underlying mechanisms how LRIG1 improves the chemosensitivity remain unknown. In this study, we reported that LRIG1 can improve the chemosensitivity through the inhibition of B cell lymphoma 2 (BCL-2) and manganese superoxide dismutase (MnSOD). In addition, we showed that the expression level of LRIG1 was significantly negatively correlated with BCL-2 and MnSOD expression in glioma. Our research demonstrated that overexpression of LRIG1 can enhance the chemosensitivity. BCL-2 and MnSOD were inhibited in LRIG1 overexpressing cells. On the other hand, when BCL-2 and MnSOD were knocked down, the chemosensitivity of U251 cells decreased, and the effect of LRIG1 in regulating chemosensitivity was compromised. For the first time, our results showed that LRIG1 can enhance chemosensitivity in glioblastoma by inhibition of BCL-2 and MnSOD. PMID- 25449297 TI - Lower Serum Bilirubin and Uric Acid Concentrations in Patients with Parkinson's Disease in China. AB - The objective of the study is to investigate the correlation between bilirubin and uric acid (UA) concentrations and symptoms of Parkinson's disease (PD) in Chinese population. A total of 425 PD patients and 460 controls were included in the current study. Patients were diagnosed by a neurologist and assessed using the Hoehn & Yahr (H&Y) scale. Venous blood samples were collected, and bilirubin and UA concentrations were analyzed. Compared to controls, indirect bilirubin (IBIL) and UA concentrations were lower in PD patients (P IBIL = 0.015, P UA = 0.000). Serum IBIL in different age subgroups and H&Y stage subgroups were also lower compared to the control group (P IBIL = 0.000, P UA = 0.000) but were not significantly different among these subgroups. Females in the control group had significantly lower serum IBIL and UA concentrations than males (P IBIL = 0.000, P UA = 0.000) and the PD group (P IBIL = 0.027, P UA = 0.000). In early PD (patients with <2-year medical history and no treatment), serum IBIL and UA concentrations were also lower than the controls (P IBIL = 0.013, P UA = 0.000). Although IBIL concentration was positively correlated with UA concentration in controls (R IBIL = 0.229, P IBIL = 0.004), this positive association was not observed in the PD group (R IBIL = -0.032, P IBIL = 0.724). Decreased levels of serum IBIL and UA were observed in PD patients. It is possible that individuals with decreased serum bilirubin and UA concentrations lack the endogenous defense system to prevent peroxynitrite and other free radicals from damaging and destroying dopaminergic cells in the substantia nigra. Our results provide a basis for further investigation into the role of bilirubin in PD. PMID- 25449298 TI - A primer of NAADP-mediated Ca(2+) signalling: From sea urchin eggs to mammalian cells. AB - Since the discovery of the Ca(2+) mobilizing effects of the pyridine nucleotide metabolite, nicotinic acid adenine dinucleotide phosphate (NAADP), this molecule has been demonstrated to function as a Ca(2+) mobilizing intracellular messenger in a wide range of cell types. In this review, I will briefly summarize the distinct principles behind NAADP-mediated Ca(2+) signalling before going on to outline the role of this messenger in the physiology of specific cell types. Central to the discussion here is the finding that NAADP principally mobilizes Ca(2+) from acidic organelles such as lysosomes and it is this property that allows NAADP to play a unique role in intracellular Ca(2+) signalling. Lysosomes and related organelles are small Ca(2+) stores but importantly may also initiate a two-way dialogue with other Ca(2+) storage organelles to amplify Ca(2+) release, and may be strategically localized to influence localized Ca(2+) signalling microdomains. The study of NAADP signalling has created a new and fruitful focus on the lysosome and endolysosomal system as major players in calcium signalling and pathophysiology. PMID- 25449300 TI - A simple and cost-effective solid-phase protein nano-assay using polyacrylamide coated glass plates. AB - A new solid-phase protein nano-assay is suggested for simple and sensitive estimation of protein content in sample buffers (a 1-MUl sample is sufficient for analysis). The assay is different from conventional "on-filter" assays in that it uses inexpensive fully transparent polyacrylamide gel (PAAG)-coated glass plates as solid support and, thus, combines the convenience of "on-membrane" staining with the sensitivity and ease of documentation of "in-gel" staining (and, therefore, is especially suited for standard lab gel documentation systems). The PAAG plates assay is compatible with all dyes for in-gel protein staining. Depending on the sensitivity of the staining protocol, the assay can be used in macro-, micro-, and nano-assay formats. We also describe a low-cost two-component colloidal Coomassie brilliant blue G-250 (CBB G-250) staining protocol for fast quantitative visualization of proteins spotted on a PAAG plate (the detection limit is up to 2 ng of proteins even when using a Nikon CoolPix digital camera and white light transilluminator instead of a gel scanner). The suggested colloidal CBB G-250 protocol could also be used for visualizing nano-amounts of proteins in polyacrylamide gels. The PAAG plate assay could be useful for proteomic applications and, in general, for all cases where a fast, sensitive, and easily documentable cost-effective solid-phase protein assay is required. PMID- 25449299 TI - The sorting of a small potassium channel in mammalian cells can be shifted between mitochondria and plasma membrane. AB - The two small and similar viral K(+) channels Kcv and Kesv are sorted in mammalian cells and yeast to different destinations. Analysis of the sorting pathways shows that Kcv is trafficking via the secretory pathway to the plasma membrane, while Kesv is inserted via the TIM/TOM complex to the inner membrane of mitochondria. Studies with Kesv mutants show that an N-terminal mitochondrial targeting sequence in this channel is neither necessary nor sufficient for sorting of Kesv the mitochondria. Instead the sorting of Kesv can be redirected from the mitochondria to the plasma membrane by an insertion of >=2 amino acids in a position sensitive manner into the C-terminal transmembrane domain (TMD2) of this channel. The available data advocate the presence of a C-terminal sorting signal in TMD2 of Kesv channel, which is presumably not determined by the length of this domain. PMID- 25449301 TI - Determining binding sites of polycyclic aromatic small molecule-based amyloid beta peptide aggregation modulators using sequence-specific antibodies. AB - Numerous aromatic small molecule modulators of amyloid-beta peptide (Abeta) monomer aggregation and neurotoxicity have been identified with the ultimate goal of Alzheimer's disease (AD) treatment. Determining binding sites of these modulators on Abeta monomer is an important topic in the mechanistic understanding of AD pathology and drug development. However, Abeta monomer binding sites have been reported for only a very limited number of Abeta modulators. In this article, we present a convenient method for determining aggregation-modulating polycyclic aromatic small molecule ligand binding sites on Abeta monomer using immunostaining with a panel of Abeta sequence-specific antibodies. To validate our technique, we first examined one modulating aromatic ligand, Congo Red, with known binding sites, which yielded consistent results with previous findings. Then, using the same technique, binding sites on Abeta of four known Abeta monomer aggregation modulators, Erythrosin B, Eosin Y, Phloxine B, and Rose Bengal, were determined. The identified ligand binding sites were also confirmed by a separate fluorescence quenching-based assay using a panel of overlapping Abeta sub-fragments. The technique described here greatly increases researchers' ability to determine the Abeta monomer binding site(s) of aggregation-modulating aromatic small molecule ligands and to screen for new ligands that bind specific regions on Abeta. PMID- 25449302 TI - Beta-hydroxymyristic acid as a chemical marker to detect endotoxins in dialysis water. AB - An analytical chemical method has been developed for determination of beta hydroxymyristic acid (beta-HMA), a component of lipopolysaccharides (LPSs/endotoxins) in dialysis water. In our investigation, the beta-HMA component was used as a chemical marker for endotoxin presence in dialysis water because it is available in the molecular subunit (lipid A) and responsible for toxicity. It is the most abundant saturated fatty acid in that subunit. The developed method is based on fluorescence derivatization with 4-nitro-7-piperazino-2,1,3 benzoxadiazole (NBD-PZ). A high-performance liquid chromatographic separation of the beta-HMA derivative was achieved using an octadecyl silica column in gradient elution. A wide dynamic range of beta-HMA was tested and a calibration curve was constructed with accuracy of 90% and variability of less than 10%. The limits of detection and quantification obtained were 2 and 5MUM, respectively. The developed method was applied to detect endotoxins in dialysis water by alkaline hydrolysis of LPS using NaOH (0.25M) at 60 degrees C for 2h. After hydrolysis, free acid was detected as its NBD-PZ derivative using high-performance liquid chromatography/mass spectrometry (HPLC/MS). Good recovery rates ranging from 98 to 105% were obtained for beta-HMA in dialysis water. PMID- 25449303 TI - Improving the odorant sensitivity of olfactory receptor-expressing yeast with accessory proteins. AB - Olfaction depends on the selectivity and sensitivity of olfactory receptors. Previous attempts at constructing a mammalian olfactory receptor-based artificial odorant sensing system in the budding yeast Saccharomyces cerevisiae suffered from low sensitivity and activity. This result may be at least in part due to poor functional expression of olfactory receptors and/or limited solubility of some odorants in the medium. In this study, we examined the effects of two types of accessory proteins, receptor transporting protein 1 short and odorant binding proteins, in improving odor-mediated activation of olfactory receptors expressed in yeast. We found that receptor transporting protein 1 short enhanced the membrane expression and ligand-induced responses of some olfactory receptors. Coexpression of odorant binding proteins of the silkworm moth Bombyx mori enhanced the sensitivity of a mouse olfactory receptor. Our results suggest that different classes of accessory proteins can confer sensitive and robust responses of olfactory receptors expressed in yeast. Inclusion of accessory proteins may be essential in the future development of practical olfactory receptor-based odorant sensors. PMID- 25449304 TI - A highly sensitive and accurate gene expression analysis by sequencing ("bead seq") for a single cell. AB - Analyses of gene expressions in single cells are important for understanding detailed biological phenomena. Here, a highly sensitive and accurate method by sequencing (called "bead-seq") to obtain a whole gene expression profile for a single cell is proposed. A key feature of the method is to use a complementary DNA (cDNA) library on magnetic beads, which enables adding washing steps to remove residual reagents in a sample preparation process. By adding the washing steps, the next steps can be carried out under the optimal conditions without losing cDNAs. Error sources were carefully evaluated to conclude that the first several steps were the key steps. It is demonstrated that bead-seq is superior to the conventional methods for single-cell gene expression analyses in terms of reproducibility, quantitative accuracy, and biases caused during sample preparation and sequencing processes. PMID- 25449306 TI - Insights into the functional characteristics of geminivirus rolling-circle replication initiator protein and its interaction with host factors affecting viral DNA replication. AB - Geminiviruses are DNA viruses that infect several economically important crops, resulting in a reduction in their overall yield. These plant viruses have circular, single-stranded DNA genomes that replicate mainly by a rolling-circle mechanism. Geminivirus infection results in crosstalk between viral and cellular factors to complete the viral life cycle or counteract the infection as part of defense mechanisms of host plants. The geminiviral replication initiator protein Rep is the only essential viral factor required for replication. It is multifunctional and is known to interact with a number of host factors to modulate the cellular environment or to function as a part of the replication machinery. This review provides a holistic view of the research related to the viral Rep protein and various host factors involved in geminiviral DNA replication. Studies on the promiscuous nature of geminiviral satellite DNAs are also reviewed. PMID- 25449305 TI - Taxonomic reorganization of the family Bornaviridae. AB - Knowledge of bornaviruses has expanded considerably during the last decade. A possible reservoir of mammalian Borna disease virus has been identified, divergent bornaviruses have been detected in birds and reptiles, and endogenous bornavirus-like elements have been discovered in the genomes of vertebrates of several species. Previous sequence comparisons and alignments have indicated that the members of the current family Bornaviridae are phylogenetically diverse and are not adequately classified in the existing bornavirus taxonomy supported by the International Committee on Taxonomy of Viruses (ICTV). We provide an update of these analyses and describe their implications for taxonomy. We propose retaining the family name Bornaviridae and the genus Bornavirus but reorganizing species classification. PAirwise Sequence Comparison (PASC) of bornavirus genomes and Basic Local Alignment Search Tool (BLAST) comparison of genomic and protein sequences, in combination with other already published phylogenetic analyses and known biological characteristics of bornaviruses, indicate that this genus should include at least five species: Mammalian 1 bornavirus (classical Borna disease virus and divergent Borna disease virus isolate No/98), Psittaciform 1 bornavirus (avian/psittacine bornaviruses 1, 2, 3, 4, 7), Passeriform 1 bornavirus (avian/canary bornaviruses C1, C2, C3, LS), Passeriform 2 bornavirus (estrildid finch bornavirus EF), and Waterbird 1 bornavirus (avian bornavirus 062CG). This classification is also in line with biological characteristics of these viruses and their vertebrate hosts. A snake bornavirus, proposed to be named Loveridge's garter snake virus 1, should be classified as a member of an additional species (Elapid 1 bornavirus), unassigned to a genus, in the family Bornaviridae. Avian bornaviruses 5, 6, MALL, and another "reptile bornavirus" ("Gaboon viper virus") should stay unclassified until further information becomes available. Finally, we propose new virus names and abbreviations when necessary to achieve clear differentiation and unique identification. PMID- 25449307 TI - Disparities in endometrial cancer outcomes between non-Hispanic White and Hispanic women. AB - OBJECTIVE: To compare demographics, tumor characteristics, the first course of treatment, and cancer-specific survival of non-Hispanic White and Hispanic women with endometrial cancer. METHODS: We used public-use data from the Surveillance, Epidemiology, and End Results (SEER) Program. The study included 69,764 non Hispanic White and Hispanic women diagnosed with endometrial cancer between 2000 and 2010. Using Cox proportional hazards models, demographics, tumor characteristics, and treatment were assessed as potential explanatory variables for the survival disparity between non-Hispanic Whites and Hispanics. RESULTS: Kaplan-Meier estimation with Bonferroni correction showed statistically different cancer-specific survival for U.S.-born and foreign-born Hispanics compared to non Hispanic Whites, but no difference between birthplace-unknown Hispanics and non Hispanic Whites. In 2000-2005, U.S.-born and foreign-born Hispanics had a higher risk of endometrial cancer death compared to non-Hispanic Whites after full adjustment (hazard rate (HR)=1.61, 95% Confidence Interval (CI):1.44-1.79 and 1.27, 95% CI:1.13-1.43). In 2006-2010, the risk of endometrial death was not statistically significant for U.S.-born Hispanics (HR=1.16, 95% CI:0.99-1.36), but increased for foreign-born Hispanics (HR=1.31, 95% CI:1.12-1.52). Most of the survival disparity between Hispanic and non-Hispanic White women was mediated by cancer characteristics, specifically, stage and node involvement. CONCLUSIONS: Hispanic women have higher cancer-specific mortality compared to non-Hispanic Whites. Compared to 2000-2005, more Hispanics were diagnosed at later stages and fewer received combination therapy in 2006-2010. Early detection is vital to improving endometrial cancer survival as most of the disparity was mediated by stage. Increased efforts are needed to improve education and access to care for Hispanic women. PMID- 25449308 TI - Uterine adenosarcoma: an analysis on management, outcomes, and risk factors for recurrence. AB - OBJECTIVES: Uterine adenosarcoma is a rare malignancy with little data on optimal management. We aimed to clarify the impact of adjuvant therapy in patients with uterine adenosarcoma and identify risk factors for recurrence and death. METHODS: We performed a retrospective review of patients undergoing primary evaluation and treatment for uterine adenosarcoma at a single institution from July 1982 through December 2011. Univariate and multivariate analyses were used to identify prognostic factors for progression-free survival (PFS) and overall survival (OS). RESULTS: We identified 100 patients with uterine adenosarcoma, and 74 patients met the inclusion criteria. On multivariate analysis, sarcomatous overgrowth (SO) and lymphovascular space invasion (LVSI) were predictors of worse PFS and OS. Median PFS and OS were 29.4 and 55.4 months for patients with SO, compared to 105.9 and 112.4 months for patients without SO (PFS HR 2.58, 95% CI 1.37-4.84, p=0.003; OS HR 2.45, 95% CI 1.26-4.76, p=0.008). Among patients with stage I disease, 17 of 22 patients (77%) with SO and 8 of 37 patients (22%) without SO had a recurrence (p<0.001). Among patients with stage I disease with SO, adjuvant therapy appeared to be associated with longer PFS and OS, but these differences were not statistically significant (PFS, 46.7 vs. 29.4 months, p=0.28; OS, 97.3 vs. 55.4 months, p=0.18). CONCLUSION: In patients with uterine adenosarcoma, the presence of SO or LVSI confers a higher risk of recurrence. We did not identify an optimal treatment strategy for patients with SO, but adjuvant therapy may be associated with prolonged PFS. PMID- 25449309 TI - Predictive markers of chemoresistance in advanced stages epithelial ovarian carcinoma. AB - OBJECTIVE: DNA repair mechanisms, environment-mediated drug resistance and cancer initiating cells (CIC) are three major research concepts that can explain the chemoresistance of epithelial ovarian cancer (EOC). The objective was to test if changes in the expression of potential markers associated with drug resistance before and after chemotherapy would correlate with platinum resistance, defined as a recurrence within the first year after chemotherapy cessation, and with survival, in advanced EOC. METHODS: We included 32 patients with stage IIIC-IV EOC who underwent laparoscopy to evaluate the extent of carcinomatosis, neoadjuvant chemotherapy (carboplatin/taxol) and interval surgery. Biopsies taken during the initial laparoscopies and interval surgeries were evaluated using immunohistochemistry for the expression of 7 proteins: CD117, CD44 and ALDH1 to evaluate CIC; IL-6, IL-8 and BMP2 to evaluate environment-mediated drug resistance; and ERCC1 to evaluate DNA repair. Expression measurements were correlated with platin resistance and survival. The markers' relevance was confirmed in vitro using chemoresistance tests and flow cytometric measurements of the proportion of CD44+ cells. RESULTS: 17 patients were chemoresistant and 15 patients were chemosensitive. We observed increases in CD44, IL-6 and ERCC1 expression and stable ALDH1, CD117, IL-8, and BMP2 expression. Reduced expression of cancer initiating cell markers and increased expression of environment mediated drug resistance markers were associated with poor prognosis. We also demonstrated that CD44+ cells had survival advantages in vitro. CONCLUSIONS: Changes in CD44 and IL-8 expression on tumor cells appeared to correlate with overall survival and should be further tested as predictors of chemoresistance using larger cohort. PMID- 25449310 TI - Efficacy of acupuncture in prevention of delayed chemotherapy induced nausea and vomiting in gynecologic cancer patients. AB - OBJECTIVE: To compare the efficacy between acupuncture and ondansetron in the prevention of delayed chemotherapy induced nausea and vomiting (CINV). METHODS: 70 patients were randomized to receive either 1) acupuncture at P6 point before chemotherapy infusion or 2) ondansetron 8 mg intravenously 30 min before chemotherapy infusion in their first cycle with cross-over of antiemetic regimen in the consecutive cycle. All patients received dexamethasone 5mg orally twice a day for 3 days. Patients were given additional does of ondansetron 4 mg orally every 12h if they experienced emesis. Emetic episode, severity of nausea score of 0-10 and adverse events were recorded. Complete response was defined as no nausea, no vomiting and no requirement of additional antiemetic drugs. FACT-G scale was used to evaluate quality of life (QOL) 7 days after each cycle of chemotherapy. RESULTS: The acupuncture group had a significantly higher rate of complete response in the prevention of delayed CINV (52.8% and 35.7%, P = 0.02). Compared to another group, the acupuncture group reported significantly lower delayed nausea (45.7% and 65.7%, P = 0.004), nausea score (P < 0.001) and fewer dosages of additional oral ondansetron (P = 0.002). Adverse effects were also significantly lower in the acupuncture group with less frequent constipation (P = 0.02) and insomnia (P = 0.01). Overall FACT-G scores were significantly higher in the acupuncture group. CONCLUSION: Acupuncture is effective in preventing delayed CINV and in promoting better QOL. With fewer adverse effects, it may be used as an alternative treatment option for CINV. PMID- 25449312 TI - Relevance of sentinel lymph node procedure for patients with high-risk endometrial cancer. AB - OBJECTIVE: While the accuracy of the Sentinel Lymph Node (SLN) procedure has been validated in patients with early-stage endometrial cancer (EC) at low and intermediate risk of recurrence, its relevance for high-risk EC remains unknown. The aim of this study was to evaluate the contribution of SLN biopsy in staging patients with presumed high-risk EC. METHODS: This retrospective multicenter study, conducted from January 2001 to December 2012, included 180 patients with early-stage EC undergoing SLN biopsy. Detection rate and false negative rate were assessed according to risk groups of recurrence. RESULTS: SLNs were detected in 159/180 patients (88%) and were bilateral in 63% of cases. Of the 180 patients, 41 (22%) had a positive lymph node. Ultrastaging detected metastases undiagnosed by conventional histology in 17/41 patients (41%). The false negative rate was 6% (9/159); 2.3% in the low/intermediate risk group and 20% in the high-risk group (p = 0.0008). Lymphovascular space invasion (LVSI) was present in 48 patients (27%). Preoperative findings classified 146 patients as ESMO low/intermediate risk (81%) and 34 as high risk (19%). Ten of the 34 patients (29%) in the presumed high-risk group were downstaged on final histology and 5/18 patients (28%) initially diagnosed with type 2 were finally classified as having type 1 EC. Classification was more likely discordant for patients with preoperative type 2 EC (p = 0.03) and in the initial high-risk group (p = 0.02). CONCLUSIONS: SLN biopsy associated with LVSI status can select which high-risk patients with EC would benefit from comprehensive staging. PMID- 25449311 TI - Ovarian cancer in the United States: contemporary patterns of care associated with improved survival. AB - BACKGROUND: Ovarian cancer (OC) requires complex multidisciplinary care with wide variations in outcome. We sought to determine the impact of institutional and process of care factors on overall survival (OS) and delivery of guideline care nationally. METHODS: This was a retrospective cohort study of primary OC diagnosed from 1998 to 2007 using the National Cancer Data Base (NCDB) capturing 80% of all U.S. cases. Patient- (demographics, comorbidities, stage/grade), process of care (adherence to guidelines) and institutional- (facility type, case volume) factors were evaluated. Primary outcomes were OS and delivery of guideline therapy. Multivariable logistic regression and Cox proportional hazards models were used for analysis. RESULTS: We analyzed 96,802 consecutive cases. Five-year OS was 84%, 66.3%, 32% and 15.7% for stages I, II, III and IV, respectively. The annual mean facility case volumes varied by cancer center type (range: 5.7 to 26.7), with 25% of cases spread over 65% of centers--all treating fewer than 8 cases. Overall, 56% of cases received non-guideline care. Low facility case volume and higher comorbidity index independently predicted non guideline care; high volume centers were less likely to deliver non-guideline care (OR: 0.44, 95% CI: 0.41-0.47). Delivery of non-guideline care (OR: 1.4, 95% CI: 1.36-1.44), and higher facility case volume (OR: 0.91, 95% CI: 0.86-0.96) were both independent predictors of OS. CONCLUSIONS: Delivery of guideline care and facility case volume are important drivers of overall survival. Most cancer centers treat very few women with OC. National efforts should focus on improved access to centers with expertise in OC and ensuring delivery of guideline care. PMID- 25449313 TI - Phase II trial of oral etoposide plus intravenous irinotecan in patients with platinum-resistant and taxane-pretreated ovarian cancer (JCOG0503). AB - OBJECTIVE: To assess the safety and efficacy of the combination of oral etoposide and intravenous irinotecan in patients with platinum-resistant and taxane pretreated ovarian cancer. METHODS: Eligible patients (age, 20-75years; platinum free interval, <=28weeks) with an adequate organ function received oral etoposide (50mg/m(2) once a day) from day 1 to day 21 and intravenous irinotecan (70mg/m(2)) on days 1 and 15. The regimen was repeated every 28days up to 6cycles. The primary endpoint was the response rate (RR) with a threshold of 20%. The response was evaluated according to RECIST 1.0 and Gynecologic Cancer Intergroup CA-125 Response Definition, and toxicities were evaluated according to CTCAE version 3.0. This trial was registered at UMIN-CTR as UMIN000001837. RESULTS: Between April 1, 2009 and January 20, 2012, 61 patients were enrolled. Sixty patients were eligible. 1 CR and 12 PRs were confirmed; RR was 21.7% (p=0.42, the exact binomial test). PFS and OS were 4.1 and 11.9months, respectively. Major toxicities of >=grade 3 were neutropenia (60%), anemia (36.7%), thrombocytopenia (11.7%), febrile neutropenia (18.3%), fatigue (13.3%), anorexia (11.7%), and nausea (11.7%). Three patients died from treatment related death (interstitial pneumonia, a pulmonary embolism, and DIC due to infection). Two of these patients were aged >=65years. CONCLUSIONS: Oral etoposide and intravenous irinotecan had a moderate RR but did not meet the primary endpoint. Because of toxicity, we do not recommend this regimen outside of clinical trials. In particular, when considering this regimen for elderly patients, extreme caution is advised. PMID- 25449315 TI - Crystal structure of Legionella pneumophila dephospho-CoA kinase reveals a non canonical conformation of P-loop. AB - Dephospho-CoA kinase (DPCK; EC 2.7.1.24) catalyzes the final step in the coenzyme A biosynthetic pathway. DPCK transfers a phosphate group from ATP to the 3 hydroxyl group of the ribose of dephosphocoenzyme A (dCoA) to yield CoA and ADP. Upon the binding of ligands, large conformational changes is induced in DPCKs, as well as in many other kinases, to shield the bound ATP in their catalytic site from the futile hydrolysis by bulk water molecules. To investigate the molecular mechanisms underlying the phosphoryl transfer during DPCK catalytic cycle, we determined the crystal structures of the Legionellapneumophila DPCK (LpDPCK) both in its apo-form and in complex with ATP. The structures reveal that LpDPCK comprises of three domains, the classical core domain, the CoA domain, and the LID domain, which are packed together to create a central cavity for substrate binding and enzymatic catalysis. The binding of ATP induces large conformational changes, including a hinge-bending motion of the CoA binding domain and the "helix to loop" conformational change of the P-loop. Finally, modeling of a dCoA molecule to the enzyme provides insights into the catalytic mechanism of DPCK. PMID- 25449316 TI - Dark-field transmission electron microscopy of cortical bone reveals details of extrafibrillar crystals. AB - In a previous study we showed that most of the mineral in bone is present in the form of "mineral structures", 5-6nm-thick, elongated plates which surround and are oriented parallel to collagen fibrils. Using dark-field transmission electron microscopy, we viewed mineral structures in ion-milled sections of cortical human bone cut parallel to the collagen fibrils. Within the mineral structures we observe single crystals of apatite averaging 5.8+/-2.7nm in width and 28+/-19nm in length, their long axes oriented parallel to the fibril axis. Some appear to be composite, co-aligned crystals as thin as 2nm. From their similarity to TEM images of crystals liberated from deproteinated bone we infer that we are viewing sections through platy crystals of apatite that are assembled together to form the mineral structures. PMID- 25449314 TI - The leucine-rich amelogenin protein (LRAP) is primarily monomeric and unstructured in physiological solution. AB - Amelogenin proteins are critical to the formation of enamel in teeth and may have roles in controlling growth and regulating microstructures of the intricately woven hydroxyapatite (HAP). Leucine-rich amelogenin protein (LRAP) is a 59 residue splice variant of amelogenin and contains the N- and C-terminal charged regions of the full-length protein thought to control crystal growth. Although the quaternary structure of full-length amelogenin in solution has been well studied and can consist of self-assemblies of monomers called nanospheres, there is limited information on the quaternary structure of LRAP. Here, sedimentation velocity analytical ultracentrifugation (SV) and small angle neutron scattering (SANS) were used to study the tertiary and quaternary structure of LRAP at various pH values, ionic strengths, and concentrations. We found that the monomer is the dominant species of phosphorylated LRAP (LRAP(+P)) over a range of solution conditions (pH 2.7-4.1, pH 4.5-8, 50 mmol/L(mM) to 200 mM NaCl, 0.065-2 mg/mL). The monomer is also the dominant species for unphosphorylated LRAP (LRAP( P)) at pH 7.4 and for LRAP(+P) in the presence of 2.5 mM calcium at pH 7.4. LRAP aggregates in a narrow pH range near the isoelectric point of pH 4.1. SV and SANS show that the LRAP monomer has a radius of ~2.0 nm and an asymmetric structure, and solution NMR studies indicate that the monomer is largely unstructured. This work provides new insights into the secondary, tertiary, and quaternary structure of LRAP in solution and provides evidence that the monomeric species may be an important functional form of some amelogenins. PMID- 25449317 TI - Particle migration analysis in iterative classification of cryo-EM single particle data. AB - Recently developed classification methods have enabled resolving multiple biological structures from cryo-EM data collected on heterogeneous biological samples. However, there remains the problem of how to base the decisions in the classification on the statistics of the cryo-EM data, to reduce the subjectivity in the process. Here, we propose a quantitative analysis to determine the iteration of convergence and the number of distinguishable classes, based on the statistics of the single particles in an iterative classification scheme. We start the classification with more number of classes than anticipated based on prior knowledge, and then combine the classes that yield similar reconstructions. The classes yielding similar reconstructions can be identified from the migrating particles (jumpers) during consecutive iterations after the iteration of convergence. We therefore termed the method "jumper analysis", and applied it to the output of RELION 3D classification of a benchmark experimental dataset. This work is a step forward toward fully automated single-particle reconstruction and classification of cryo-EM data. PMID- 25449318 TI - Visualizing the uncertainty in the relationship between seasonal average climate and malaria risk. AB - Around $1.6 billion per year is spent financing anti-malaria initiatives, and though malaria morbidity is falling, the impact of annual epidemics remains significant. Whilst malaria risk may increase with climate change, projections are highly uncertain and to sidestep this intractable uncertainty, adaptation efforts should improve societal ability to anticipate and mitigate individual events. Anticipation of climate-related events is made possible by seasonal climate forecasting, from which warnings of anomalous seasonal average temperature and rainfall, months in advance are possible. Seasonal climate hindcasts have been used to drive climate-based models for malaria, showing significant skill for observed malaria incidence. However, the relationship between seasonal average climate and malaria risk remains unquantified. Here we explore this relationship, using a dynamic weather-driven malaria model. We also quantify key uncertainty in the malaria model, by introducing variability in one of the first order uncertainties in model formulation. Results are visualized as location-specific impact surfaces: easily integrated with ensemble seasonal climate forecasts, and intuitively communicating quantified uncertainty. Methods are demonstrated for two epidemic regions, and are not limited to malaria modeling; the visualization method could be applied to any climate impact. PMID- 25449320 TI - Ciliate species diversity and host-parasitoid codiversification in Pseudocollinia infecting krill, with description of Pseudocollinia similis sp. nov. AB - All parasitoid apostome ciliates infecting krill in the northeastern Pacific are currently assigned to the genus Pseudocollinia. Each krill specimen is apparently infected by only 1 Pseudocollinia species. We describe Pseudocollinia similis sp. nov., discovered infecting the krill Thysanoessa spinifera off Oregon, USA. Its protomite-tomite stage resembles that of P. beringensis, which infects T. inermis (type host species), T. longipes, and T. raschii females in the Bering Sea. These ciliates have similar numbers of somatic kineties (18-21 vs. 16-20) and typically have 3 oral kineties. Furthermore, these 2 apostomes are sister species on gene trees based on sequences of small subunit rRNA (0.06% difference) and cytochrome c oxidase subunit 1 (cox1; 30% difference). P. brintoni and P. oregonensis are closely related as a separate group from P. similis and P. beringensis. The similar tree topologies based on the cox1 sequences of 21 host krill individuals representing 6 krill species (Euphausia pacifica, Nyctiphanes simplex, T. inermis, T. longipes, T. raschii, and T. spinifera) and the apostomes isolated from these krill suggest host-parasitoid codiversification. However, this hypothesis was statistically rejected by an approximately unbiased test in which the host tree topology was used to model parasitoid evolution (p <= 0.05). PMID- 25449321 TI - Prevalence and quantification of pathogenic Vibrio parahaemolyticus during shrimp culture in Thailand. AB - Vibrio parahaemolyticus is a major cause of seafood-borne gastroenteritis. The human pathogenic strains possess tdh or trh or both genes. In Thai shrimp farming, the level of pathogenic V. parahaemolyticus contamination has not been completely characterized, although it has been identified as a risk for people who consume undercooked shrimp. In this study, the prevalence and concentration of V. parahaemolyticus (total Vp) and pathogenic V. parahaemolyticus (tdh+ Vp and trh+ Vp) were investigated during shrimp culture cycles using the most probable number (MPN) method and were confirmed by PCR and the loop-mediated isothermal amplification (LAMP) techniques. The prevalence and concentration of total Vp were high in broodstock and egg samples at the start of the hatchery cycle, but the organism decreased in the subsequent larval and postlarval stages. In contrast, total Vp was low at the beginning of the pond cycle and dramatically increased during the later stages of culture. Broodstock and fresh feed were important sources of V. parahaemolyticus. Numbers of tdh+ Vp and trh+ Vp detected by the LAMP technique were much greater than those detected by the PCR technique, especially in the late stages of the pond cycle. A direct correlation between total Vp and pathogenic Vp was demonstrated only during the harvest stage. This study will be useful as a guideline to establish levels of V. parahaemolyticus presence which can be considered as safe during shrimp culture. In addition, it could be used to identify the source of V. parahaemolyticus, which has recently been reported to be one of the etiologic agents of acute hepatopancreatic necrosis disease. PMID- 25449322 TI - Simulated hatchery system to assess bacteriophage efficacy against Vibrio harveyi. AB - Vibriosis caused by luminous Vibrio harveyi commonly contributes to poor survival in shrimp hatcheries and aquaculture ponds. Lytic bacteriophages pathogenic for V. harveyi are currently being investigated as an alternative to antibiotics to prevent vibriosis. Here, 8 bacteriophages were isolated from oysters and clams using V. harveyi strains as baiting hosts. Among these bacteriophages, 1 strain (VHP6b) identified as broadly pathogenic for 27 V. harveyi strains examined was further characterized by electron microscopy and genome sequence analysis. Phage VHP6b possessed a tail and morphology consistent with it being a member of the family Siphoviridae, and its genome and proteome were most closely related to the Vibrio phages SSP02 and MAR10. An integrase gene essential for lysogeny was not evident. The ability of bacteriophage VHP6b to protect shrimp postlarvae against vibriosis caused by V. harveyi strain VH6 was demonstrated in a model system designed to simulate typical hatchery conditions. Bacteriophage treatment improved survival of postlarvae by 40 to 60% under these conditions, so therapies based on this or other bacteriophages may be useful in shrimp hatcheries. PMID- 25449323 TI - Genetic diversity and associated pathology of rhabdovirus infections in farmed and wild perch Perca fluviatilis in Ireland. AB - Rhabdovirus infections are an emerging problem for both wild and farmed freshwater fish in Northern Europe. In October 2005, a clinical outbreak with an approximate mortality rate of 40% occurred in a single batch of juvenile perch on a farm in the Republic of Ireland. Clinical signs developed slowly and were consistent with a perch rhabdovirus infection: signs included haemorrhages at the base of the fins and apparent impairment of the central nervous system (manifested as loss of equilibrium and erratic swimming behaviour). Studies suggest that the infected fish originated from a hatchery within the country which relied on wild fish broodstock to supplement the production of perch juveniles. A related rhabdovirus was subsequently isolated from this hatchery. Virus isolation studies have shown that rhabdoviruses were often isolated from wild fish in the vicinity of the hatchery between 1993 and 2005. All isolates were analysed using a generic primer set specific for the L gene of fish vesiculotype viruses. Phylogenetic analysis revealed that all isolates recovered from perch clustered together with the European lake trout rhabdovirus (903/87) of the genus Perhabdovirus. In addition to this, anguillid rhabdovirus was isolated from eel, and the partial L-gene sequence of a previously reported isolate from tench clustered with the pike fry rhabdoviruses, in the genus Sprivivirus. PMID- 25449324 TI - Isolation and characterization of a novel reovirus from white bream Blicca bjoerkna. AB - During a fish health inspection in the Viennese waterway 'Old Danube', a virus was isolated exclusively from white bream Blicca bjoerkna (L.) (formerly Abramis bjoerkna L.), one of the most abundant cyprinids present and not known as a host species for this virus. The virus preferentially replicated in cultures of the epithelioma papulosum cyprini cell line where focal plaques of infection developed slowly. Examination of infected cell cultures by electron microscopy revealed non-enveloped 60 to 70 nm icosahedral virions that had characteristic multiple segregated protrusions of their outer capsid. A partial RNA-dependent RNA polymerase gene sequence was obtained and a BLAST search indicated 76% identity to golden shiner reovirus and grass carp reovirus. These results suggested that the virus belonged to the genus Aquareovirus (Family Reoviridae). Phylogenetic analysis placed the isolated virus within a clade of the species Aquareovirus C species. Accordingly, the virus was tentatively designated as white bream reovirus (WBRV) strain A-127/06 within the species Aquareovirus C. PMID- 25449325 TI - Ultrastructure and phylogeny of the parasite Henneguya carolina sp. nov. (Myxozoa), from the marine fish Trachinotus carolinus in Brazil. AB - Microscopic and molecular procedures are used to describe a new myxosporean species, Henneguya carolina sp. nov., found infecting the intestine of the marine teleost fish Trachinotus carolinus on the southern Atlantic coast of Brazil. Spherical to ellipsoid cysts, measuring up to ~750 um, display synchronous development. Mature myxospores are ellipsoidal with a bifurcated caudal process. Myxospore body length, width, and thickness are 12.7 +/- 0.8 (12.0-13.4) um, 8.8 +/- 0.6 (7.5-9.6) um, and 5.8 +/- 0.4 (5.0-6.4) um, respectively; 2 equal caudal processes are 16.8 +/- 1.1 (15.9-18.0) um long, and the total myxospore length is 29.4 +/- 0.8 (28.4-30.4) um. Two pyriform polar capsules measure 5.0 +/- 0.5 (4.6 5.6) * 2.4 +/- 0.4 (1.9-2.9) um, and each contains a polar filament forming 3 to 4 coils. Sporoplasm is binucleated and presents a spherical vacuole surrounded by numerous globular sporoplasmosomes. Molecular analysis of the small subunit rRNA gene by maximum parsimony, neighbor joining, and maximum likelihood reveals the parasite clustering together with other myxobolids that are histozoic in marine fish of the order Perciformes, thereby strengthening the contention that the host phylogenetic relationships and aquatic environment are the strongest evolutionary signal for myxosporeans of the family Myxobolidae. PMID- 25449326 TI - Genetically divergent Symbiodinium sp. display distinct molecular responses to pathogenic Vibrio and thermal stress. AB - Global climate change and anthropogenic activities are threatening the future survival of coral reef ecosystems. The ability of reef-building zooxanthellate coral to survive these stressors may be determined through fundamental differences within their symbiotic dinoflagellates (Symbiodinium sp.). We define the in vitro apoptotic response of 2 evolutionarily distant Symbiodinium sp., subtypes B2 and C1, to determine the synergistic effects of disease and temperature on cell viability using flow cytometry. The putative yellow band disease (YBD) consortium of Vibrio spp. bacteria and temperature (33 degrees C) had a positive synergistic effect on C1 apoptosis, while B2 displayed increased apoptosis to elevated temperature (29 and 33 degrees C), the Vibrio consortium, and a lone virulent strain of V. alginolyticus, but no synergistic effects. Additionally, heat shock protein 60 expression revealed differential cell mediated temperature sensitivity between subtypes via western blotting. This result marks the first evidence of Symbiodinium sp. apoptotic variations to YBD pathogens and emphasizes the potential impact of synergistic stress on globally distributed coral-Symbiodinium symbioses. PMID- 25449319 TI - Systematic review of sleep disorders in cancer patients: can the prevalence of sleep disorders be ascertained? AB - Although sleep is vital to all human functioning and poor sleep is a known problem in cancer, it is unclear whether the overall prevalence of the various types of sleep disorders in cancer is known. The purpose of this systematic literature review was to evaluate if the prevalence of sleep disorders could be ascertained from the current body of literature regarding sleep in cancer. This was a critical and systematic review of peer-reviewed, English-language, original articles published from 1980 through 15 October 2013, identified using electronic search engines, a set of key words, and prespecified inclusion and exclusion criteria. Information from 254 full-text, English-language articles was abstracted onto a paper checklist by one reviewer, with a second reviewer randomly verifying 50% (k = 99%). All abstracted data were entered into an electronic database, verified for accuracy, and analyzed using descriptive statistics and frequencies in SPSS (v.20) (North Castle, NY). Studies of sleep and cancer focus on specific types of symptoms of poor sleep, and there are no published prevalence studies that focus on underlying sleep disorders. Challenging the current paradigm of the way sleep is studied in cancer could produce better clinical screening tools for use in oncology clinics leading to better triaging of patients with sleep complaints to sleep specialists, and overall improvement in sleep quality. PMID- 25449327 TI - Review of historical unusual mortality events (UMEs) in the Gulf of Mexico (1990 2009): providing context for the multi-year northern Gulf of Mexico cetacean UME declared in 2010. AB - An unusual mortality event (UME) was declared for cetaceans in the northern Gulf of Mexico (GoM) for Franklin County, Florida, west through Louisiana, USA, beginning in February 2010 and was ongoing as of September 2014. The 'Deepwater Horizon' (DWH) oil spill began on 20 April 2010 in the GoM, raising questions regarding the potential role of the oil spill in the UME. The present study reviews cetacean mortality events that occurred in the GoM prior to 2010 (n = 11), including causes, durations, and some specific test results, to provide a historical context for the current event. The average duration of GoM cetacean UMEs prior to 2010 was 6 mo, and the longest was 17 mo (2005-2006). The highest number of cetacean mortalities recorded during a previous GoM event was 344 (in 1990). In most previous events, dolphin morbillivirus or brevetoxicosis was confirmed or suspected as a causal factor. In contrast, the current northern GoM UME has lasted more than 48 mo and has had more than 1000 reported mortalities within the currently defined spatial and temporal boundaries of the event. Initial results from the current UME do not support either morbillivirus or brevetoxin as primary causes of this event. This review is the first summary of cetacean UMEs in the GoM and provides evidence that the most common causes of previous UMEs are unlikely to be associated with the current UME. PMID- 25449328 TI - mPLR-Loc: an adaptive decision multi-label classifier based on penalized logistic regression for protein subcellular localization prediction. AB - Proteins located in appropriate cellular compartments are of paramount importance to exert their biological functions. Prediction of protein subcellular localization by computational methods is required in the post-genomic era. Recent studies have been focusing on predicting not only single-location proteins but also multi-location proteins. However, most of the existing predictors are far from effective for tackling the challenges of multi-label proteins. This article proposes an efficient multi-label predictor, namely mPLR-Loc, based on penalized logistic regression and adaptive decisions for predicting both single- and multi location proteins. Specifically, for each query protein, mPLR-Loc exploits the information from the Gene Ontology (GO) database by using its accession number (AC) or the ACs of its homologs obtained via BLAST. The frequencies of GO occurrences are used to construct feature vectors, which are then classified by an adaptive decision-based multi-label penalized logistic regression classifier. Experimental results based on two recent stringent benchmark datasets (virus and plant) show that mPLR-Loc remarkably outperforms existing state-of-the-art multi label predictors. In addition to being able to rapidly and accurately predict subcellular localization of single- and multi-label proteins, mPLR-Loc can also provide probabilistic confidence scores for the prediction decisions. For readers' convenience, the mPLR-Loc server is available online (http://bioinfo.eie.polyu.edu.hk/mPLRLocServer). PMID- 25449329 TI - Aminocella lysinolytica gen. nov., sp. nov., a L-lysine-degrading, strictly anaerobic bacterium in the class Clostridia isolated from a methanogenic reactor of cattle farms. AB - A strictly anaerobic bacterial strain (WN037(T)) was isolated from a methanogenic reactor. Cells were Gram-positive rods. Strain WN037(T) was asaccharolytic. The strain fermented L-lysine in the presence of B-vitamin mixture or vitamin B12 and produced acetate and butyrate. L-arginine and casamino acids poorly supported the growth. Strain WN037(T) used neither other amino acids nor organic acids examined. The strain had C18:1 omega7c, C16:0 and C18:1 omega7c DMA as the predominant cellular fatty acids. The genomic DNA G + C content was 44.2 mol %. Phylogenetic analysis based on the 16S rRNA gene sequence placed strain WN037(T) in the family Eubacteriaceae in the class Clostridia. The closest relative was Eubacterium pyruvativorans (sequence similarity, 92.8 %). Based on the comprehensive analyses, the novel genus and species, Aminocella lysinolytica gen. nov., sp. nov. was proposed to accommodate the strain. The type strain is WN037(T) (= JCM 19863(T) = DSM 28287(T)). PMID- 25449330 TI - Differential expression of pentraxin 3 in neutrophils. AB - Pentraxins belong to the superfamily of conserved proteins that are characterized by a cyclic multimeric structure. Pentraxin 3 (PTX3) is a long pentraxin which can be produced by different cell types upon exposure to various inflammatory signals. Inside the neutrophil PTX3 is stored in form of granules localized in the cytoplasm. Neutrophilic granules are divided into three types: azurophilic (primary) granules, specific (secondary) granules and gelatinase (tertiary) granules. PTX3 has been considered to be localized in specific (secondary) granules. Immunofluorescent analyses using confocal laser microscopic examination were performed to clarify the localization of all three groups of granules within the cytoplasm of the mature neutrophils and neutrophils stimulated with IL-8. Furthermore, PTX3 was localized in primary granules of promyelocyte cell line HL 60. As a result, we suggest that PTX3 is localized not only in specific granules, but is also partly expressed in primary and tertiary granules. After the stimulation with IL-8, irregular reticular structures called neutrophil extracellular traps (NETs) were formed, three types of granules were trapped by NETs and PTX3 showed partial colocalization with these granular components. PTX3 localized in all three types of granules in neutrophils may play important roles in host defense. PMID- 25449331 TI - Exploring the genes associated with the response to intravenous immunoglobulin in patients with Kawasaki disease using DNA microarray analysis. AB - In this study we aimed to screen genes associated with intravenous immunoglobulin (IVIG) responding in patients with Kawasaki disease (KD) and thus explore the underlying molecular mechanism of IVIG resistance. The differentially expressed genes (DEGs) were identified by samr package in R. Then, protein-protein interaction (PPI) networks were constructed by STRING software. We further collected the regulatory data from TRANSFAC database, followed by regulatory interaction network construction. A total 194 of DEGs, including 185 up- and 9 down-regulated DEGs, were identified between IVIG-responding and non-responding patients with KD at acute stage. In contrast, no DEGs were found at convalescent stage. PPI networks and regulatory networks were constructed based on the 185 up regulated genes at acute stage. The degrees of TFRC (transferrin receptor protein 1) and GADD45A (growth arrest and DNA-damage-inducible alpha) were higher than other genes, and meanwhile MYC (V-Myc Myelocytomatosis Viral Oncogene Homolog) and E2F1 (E2F Transcription Factor 1) were found to be two TFs (transcription factors) with the highest degrees. In conclusions, the response to IVIG in Kawasaki disease patients may be involved in the expression of TFRC, GADD45A, MYC and E2F1. PMID- 25449332 TI - The T29C (rs1800470) polymorphism of the transforming growth factor-beta1 (TGF beta1) gene is associated with restenosis after coronary stenting in Mexican patients. AB - The aim of the present study was to establish the role of IL-6 and TGF-beta1 gene polymorphisms in the risk of developing in-stent restenosis. Two IL-6 [rs1800796 (-572 G>C), rs2069827 (-1426 T>G)] and two TGF-beta1 [rs1800469 (-509 T>C), rs1800470 (T29C)] gene polymorphisms were analyzed by 5' exonuclease TaqMan genotyping assays in a group of 244 patients, who underwent coronary artery stenting. Basal and procedure coronary angiography were analyzed, looking for angiographic predictors of restenosis and follow-up angiography was performed to screen for binary restenosis. Under the dominant and additive models adjusted for hypertension, stable angina, stent used, and diameter of stent, the TGF-beta1 T29C (rs1800470) polymorphism was significantly associated with an increase risk of restenosis when compared to patients without restenosis (OR=2.06, 95% CI: 1.03 4.11, P(Dom)=0.034 and OR=1.64, 95% CI: 1.09-2.45, PAdd=0.016). TGF-beta1 polymorphisms were in linkage disequilibrium and one haplotype (TT) was significantly increased in patients with restenosis when compared to patients without restenosis (OR=2.03, P=0.041). In summary, our results suggest that the TGF-beta1 T29C gene polymorphism could be involved in the risk of developing restenosis after coronary stent placement. PMID- 25449333 TI - Pyrazine, 2-ethylpyridine, and 3-ethylpyridine are cigarette smoke components that alter the growth of normal and malignant human lung cells, and play a role in multidrug resistance development. AB - Lung cancer is one of the few human diseases for which the primary etiological agent, cigarette smoke (CS), has been described; however, the precise role of individual cigarette smoke toxicant in tumor development and progression remains to be elusive. The purpose of this study was to assess in vitro the effects of previously identified cigarette smoke components, pyrazine, 2-ethylpyridine, and 3-ethylpyridine, on non-tumorigenic (MRC5) and adenocarcinomic (A549) human lung cell lines. Our data showed that the administration of three cigarette smoke components in combination perturbed the proliferation of both normal and adenocarcinomic cells. Study of malignant cells revealed that CS components were cytotoxic at high concentration (10(-6) M) and stimulatory in a dose-dependent manner at lower concentrations (10(-8) M to 10(-10) M). This adverse effect was enhanced when adenocarcinomic cells were maintained in hypoxia resembling intratumoral environment. Furthermore, exposure to pyrazine, 2-ethylpyridine, and 3-ethylpyridine induced oxidative stress in both normal and malignant cells. Finally, assessment of P-gp activity revealed that multidrug resistance was induced in CS component exposed adenocarcinomic lung cells and the induction was augmented in hypoxia. Taken together, pyrazine, 2-ethylpyridine, and 3 ethylpyridine adversely altered both normal and diseased lung cells in vitro and data collected from this study may help lung cancer patients to understand the importance of quitting smoking during lung cancer treatment. PMID- 25449334 TI - Prolonged survival after neoadjuvant chemotherapy related with specific molecular alterations in the patients with nonsmall-cell lung carcinoma. AB - Lung cancer is the most common cause of neoplasia-related death worldwide. Accounting for approximately 80% of all lung carcinomas, the non-small cell lung carcinoma (NSCLC) is the most common clinical form with its two predominant histological types, adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Although surgical resection is the most favorable treatment for patients with NSCLC, relapse is still high, so neoadjuvant chemotherapy (NAC) is an accepted treatment modality. In this study we examined whether some of the key molecules associated with the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways could have predictive and prognostic value for the NAC application. To that end we examined the expression status of PTEN, pAKT, pERK and loss of heterozygosity (LOH) of PTEN in two groups of NSCLC patients, those who received and those who did not receive NAC. LOH PTEN and low pERK expression is shown to be correlated with the longest survival of patients with SCC and ADC, respectively, who received NAC. These results point that the application of NAC is beneficial in the NSCLC patients with specific molecular alterations which could further help to improve constant search for the druggable molecular targets used in personalized therapy. PMID- 25449335 TI - Cortical magnification plus cortical plasticity equals vision? AB - Most approaches to visual prostheses have focused on the retina, and for good reasons. The earlier that one introduces signals into the visual system, the more one can take advantage of its prodigious computational abilities. For methods that make use of microelectrodes to introduce electrical signals, however, the limited density and volume occupying nature of the electrodes place severe limits on the image resolution that can be provided to the brain. In this regard, non retinal areas in general, and the primary visual cortex in particular, possess one large advantage: "magnification factor" (MF)-a value that represents the distance across a sheet of neurons that represents a given angle of the visual field. In the foveal representation of primate primary visual cortex, the MF is enormous-on the order of 15-20 mm/deg in monkeys and humans, whereas on the retina, the MF is limited by the optical design of the eye to around 0.3m m/deg. This means that, for an electrode array of a given density, a much higher resolution image can be introduced into V1 than onto the retina (or any other visual structure). In addition to this tremendous advantage in resolution, visual cortex is plastic at many different levels ranging from a very local ability to learn to better detect electrical stimulation to higher levels of learning that permit human observers to adapt to radical changes to their visual inputs. We argue that the combination of the large magnification factor and the impressive ability of the cerebral cortex to learn to recognize arbitrary patterns, might outweigh the disadvantages of bypassing earlier processing stages and makes V1 a viable option for the restoration of vision. PMID- 25449337 TI - Contextual modulation and stimulus selectivity in extrastriate cortex. AB - Contextual modulation is observed throughout the visual system, using techniques ranging from single-neuron recordings to behavioral experiments. Its role in generating feature selectivity within the retina and primary visual cortex has been extensively described in the literature. Here, we describe how similar computations can also elaborate feature selectivity in the extrastriate areas of both the dorsal and ventral streams of the primate visual system. We discuss recent work that makes use of normalization models to test specific roles for contextual modulation in visual cortex function. We suggest that contextual modulation renders neuronal populations more selective for naturalistic stimuli. Specifically, we discuss contextual modulation's role in processing optic flow in areas MT and MST and for representing naturally occurring curvature and contours in areas V4 and IT. We also describe how the circuitry that supports contextual modulation is robust to variations in overall input levels. Finally, we describe how this theory relates to other hypothesized roles for contextual modulation. PMID- 25449338 TI - Spatial and temporal aspects of chromatic adaptation and their functional significance for colour constancy. AB - Illumination in natural scenes changes at multiple temporal and spatial scales: slow changes in global illumination occur in the course of a day, and we encounter fast and localised illumination changes when visually exploring the non uniform light field of three-dimensional scenes; in addition, very long-term chromatic variations may come from the environment, like for example seasonal changes. In this context, I consider the temporal and spatial properties of chromatic adaptation and discuss their functional significance for colour constancy in three-dimensional scenes. A process of fast spatial tuning in chromatic adaptation is proposed as a possible sensory mechanism for linking colour constancy to the spatial structure of a scene. The observed middlewavelength selectivity of this process is particularly suitable for adaptation to the mean chromaticity and the compensation of interreflections in natural scenes. Two types of sensory colour constancy are distinguished, based on the functional differences of their temporal and spatial scales: a slow type, operating at a global scale for the compensation of the ambient illumination; and a fast colour constancy, which is locally restricted and well suited to compensate region-specific variations in the light field of three dimensional scenes. PMID- 25449336 TI - Surround suppression supports second-order feature encoding by macaque V1 and V2 neurons. AB - Single neurons in areas V1 and V2 of macaque visual cortex respond selectively to luminance-modulated stimuli. These responses are often influenced by context, for example when stimuli extend outside the classical receptive field (CRF). These contextual phenomena, observed in many sensory areas, reflect a fundamental cortical computation and may inform perception by signaling second-order visual features which are defined by spatial relationships of contrast, orientation and spatial frequency. In the anesthetized, paralyzed macaque, we measured single unit responses to a drifting preferred sinusoidal grating; low spatial frequency sinusoidal contrast modulations were applied to the grating, creating contrast modulated, second-order forms. Most neurons responded selectively to the orientation of the contrast modulation of the preferred grating and were therefore second-order orientation-selective. Second-order selectivity was created by the asymmetric spatial organization of the excitatory CRF and suppressive extraclassical surround. We modeled these receptive field subregions using spatial Gaussians, sensitive to the modulation of contrast (not luminance) of the preferred carrier grating, that summed linearly and were capable of recovering asymmetrical receptive field organizations. Our modeling suggests that second-order selectivity arises both from elongated excitatory CRFs, asymmetrically organized extraclassical surround suppression, or both. We validated the model by successfully testing its predictions against conventional surround suppression measurements and spike-triggered analysis of second-order form responses. Psychophysical adaptation measurements on human observers revealed a pattern of second-order form selectivity consistent with neural response patterns. We therefore propose that cortical cells in primates do double duty, providing signals about both first- and second-order forms. PMID- 25449339 TI - Effects of spatial congruency on saccade and visual discrimination performance in a dual-task paradigm. AB - The present study investigated the coupling of selection-for-perception and selection-for-action during saccadic eye movement planning in three dual-task experiments. We focused on the effects of spatial congruency of saccade target (ST) location and discrimination target (DT) location and the time between ST-cue and Go-signal (SOA) on saccadic eye movement performance. In two experiments, participants performed a visual discrimination task at a cued location while programming a saccadic eye movement to a cued location. In the third experiment, the discrimination task was not cued and appeared at a random location. Spatial congruency of ST-location and DT-location resulted in enhanced perceptual performance irrespective of SOA. Perceptual performance in spatially incongruent trials was above chance, but only when the DT-location was cued. Saccade accuracy and precision were also affected by spatial congruency showing superior performance when the ST- and DT-location coincided. Saccade latency was only affected by spatial congruency when the DT-cue was predictive of the ST-location. Moreover, saccades consistently curved away from the incongruent DT-locations. Importantly, the effects of spatial congruency on saccade parameters only occurred when the DT-location was cued; therefore, results from experiments 1 and 2 are due to the endogenous allocation of attention to the DT-location and not caused by the salience of the probe. The SOA affected saccade latency showing decreasing latencies with increasing SOA. In conclusion, our results demonstrate that visuospatial attention can be voluntarily distributed upon spatially distinct perceptual and motor goals in dual-task situations, resulting in a decline of visual discrimination and saccade performance. PMID- 25449340 TI - Influence of higher order aberrations and retinal image quality in myopisation of emmetropic eyes. AB - Refractive error, higher order aberrations (HOA), axial length (AL), anterior chamber depth (ACD) and average corneal radius of curvature were measured after cycloplegia from 166 emmetropic participants at the Sydney Myopia Study (SMS, 2004-2005, age 12.63 +/- 0.48 years). Measurements were repeated approximately 5 years later at the Sydney Adolescent Vascular and Eye Study (SAVES, 2009-2010, age 17.08 +/- 0.67 years). The baseline spherical equivalent (M) did not differ significantly between the participants lost to follow-up (65%) and the participants enrolled in SAVES study (p = 0.932). Refractive error and HOA were measured using a Shack-Hartmann aberrometer for a pupil diameter of 5 mm and AL, ACD and average corneal curvature measured using IOL Master at both visits. Retinal image quality in terms of Visual Strehl ratio (VSOTF) for a 5 mm pupil diameter was determined using on-axis lower and HOA. General linear model was used to determine the association of HOA and retinal image quality with change in refraction. Of the 166 emmetropes, 41 (25%) had myopic change (change in M > 0.50 D) and 125 (75%) had no change in refraction (change in M between +0.49 D and -0.49 D). Change in C[4, 0] (p < 0.001, R2 = 0.236), fourth order RMS (p = 0.003, R2 = 0.097) and coma RMS (p = 0.004, R2 = 0.056) from baseline were significantly correlated with change in refraction. More positive change in C[4, 0] was associated with lesser myopic change in refraction. The eyes with myopic change in refraction decreased in positive C[4, 0] (at baseline = +0.049 +/- 0.05 MUm, at follow-up = +0.024 +/- 0.05 MUm, p < 0.05). In comparison, eyes with no change increased in positive C[4, 0] (at baseline = +0.033 +/- 0.04 MUm, at follow-up = +0.047 +/- 0.04 MUm, p < 0.05). Thus in conclusion, no significant association was observed between HOA and retinal image quality at baseline and development and progression of myopia among emmetropic eyes. The change in spherical aberration (C[4, 0]) with myopic change is possibly associated with changes occurring in crystalline lens during ocular growth. PMID- 25449341 TI - Embracing the digital future. PMID- 25449342 TI - Performance of chest compressions with the use of a new audio-visual feedback device: a randomized manikin study in health care professionals. AB - AIM: Optimal depth (50-60mm) and rate (100-120min(-1)) of chest compressions (CC) is the prerequisite of effective cardiopulmonary resuscitation (CPR). However, insufficient CC during CPR are common even among health care professionals. We sought to evaluate if CC are more effective with the use of a novel feedback device compared to standard CC. Primary endpoints were absolute percentage of correct CC of all CC (correct rate and correct depth, classified as "optimal" CC), and the percentage of CC in target rate and percentage of CC in target depth. METHODS: 63 healthcare professionals performed CC on a manikin with the use of a novel feedback device. The device provides audio-visual information about compression depth and rate. Each participant performed two minutes of CC with and without feedback. Participants were randomized into two groups that performed either CC with feedback first, followed by a trial without feedback, or vice versa. All participants answered a short questionnaire on self-estimation of CC performance. RESULTS: The absolute percentage of optimal compressions of all compressions has increased from 27.9+/-28.8% to 47.6+/-33.5% (p<0.001) with use of the device. Furthermore, a significant increase of the percentage of CC in target depth (35.9+/-30.6% without vs. 54.8+/-33.5% with the device, p=0.003) and in target rate (70.5+/-37.7% without vs. 82.7+/-27.8 with the device, p=0.039) were observed. CONCLUSION: This novel feedback device significantly improved the quality of CC in health care professionals. PMID- 25449344 TI - Two decades of British newspaper coverage regarding do not attempt cardiopulmonary resuscitation decisions: Lessons for clinicians. AB - OBJECTIVE: To review UK newspaper reports relating to Do Not Attempt Cardiopulmonary Resuscitation (DNACPR) decisions in order to identify common themes and encourage dialogue. METHODS: An online media database (LexisNexis((r))) was searched for UK Newspaper articles between 1993 and 2013 that referenced DNACPR decisions. Legal cases, concerning resuscitation decisions, were identified using two case law databases (Lexis Law((r)) and Westlaw((r))), and referenced back to newspaper publications. All articles were fully reviewed. RESULTS: Three hundred and thirty one articles were identified, resulting from 77 identifiable incidents. The periods 2000-01 and 2011-13 encompassed the majority of articles. There were 16 high-profile legal cases, nine of which resulted in newspaper articles. Approximately 35 percent of newspaper reports referred to DNACPR decisions apparently made without adequate patient and/or family consultation. "Ageism" was referred to in 9 percent of articles (mostly printed 2000-02); and "discrimination against the disabled" in 8 percent (mostly from 2010-12). Only five newspaper articles (2 percent) discussed patients receiving CPR against their wishes. Eighteen newspaper reports (5 percent) associated DNACPR decisions with active euthanasia. CONCLUSIONS: Regarding DNACPR decision-making, the predominant theme was perceived lack of patient involvement, and, more recently, lack of surrogate involvement. Negative language was common, especially when decisions were presumed unilateral. Increased dialogue, and shared decision-making, is recommended. PMID- 25449343 TI - Characteristics of ventricular fibrillation in relation to cardiac aetiology and shock success: A waveform analysis study in ICD-patients. AB - BACKGROUND: Ventricular fibrillation (VF) waveform characteristics are associated with cardiac arrest duration and defibrillation success. Recent animal studies found that VF characteristics and shock success also depend on the presence of myocardial infarction (MI). In patients, VF induction after implantable cardioverter defibrillator (ICD) implantation offers a unique setting to study early VF characteristics: we studied the relation with cardiac disease--either presence or absence of a previous MI--and with shock success. METHODS: Retrospective cohort study of ICD-patients who underwent defibrillation testing, 117 (63%) with and 69 (37%) without a previous MI. Intracardiac recordings of induced VF were analysed using Fourier analysis. RESULTS: In previous MI patients, the fundamental frequency and organisation index of the VF signal were significantly lower as compared with patients without a previous MI: 4.9 Hz +/- 0.6 vs. 5.2 Hz +/- 0.6 (p = 0.005) and 56% +/- 10 vs. 60% +/- 9 (p = 0.001), respectively. The median frequency was not different (p = 0.25). We found no association between VF characteristics and ICD shock success. CONCLUSIONS: In analogy with observations in animals, we found that a history of a previous MI was associated with slower and less organised VF. In our cohort of ICD-patients, early VF waveform characteristics were not associated with shock outcomes. Further study is warranted to determine to what extent VF characteristics are influenced by the underlying aetiology on the one hand, and time delay on the other. These findings could improve insight into the potential value of VF analysis to guide shock delivery. PMID- 25449346 TI - Public access defibrillation-results from the Victorian Ambulance Cardiac Arrest Registry. AB - AIM: To assess the impact of automated external defibrillator (AED) use by bystanders in Victoria, Australia on survival of adults suffering an out-of hospital cardiac arrest (OHCA) in a public place compared to those first defibrillated by emergency medical services (EMS). METHODS: We analysed data from the Victorian Ambulance Cardiac Arrest Registry for individuals aged >15 years who were defibrillated in a public place between 1 July 2002 and 30 June 2013, excluding events due to trauma or witnessed by EMS. RESULTS: Of 2270 OHCA cases who arrested in a public place, 2117 (93.4%) were first defibrillated by EMS and 153 (6.7%) were first defibrillated by a bystander using a public AED. Use of public AEDs increased almost 11-fold between 2002/2003 and 2012/2013, from 1.7% to 18.5%, respectively (p < 0.001). First defibrillation occurred sooner in bystander defibrillation (5.2 versus 10.0 min, p < 0.001). Unadjusted survival to hospital discharge for bystander defibrillated patients was significantly higher than for those first defibrillated by EMS (45% versus 31%, p < 0.05). Multivariable logistic regression analysis showed that first defibrillation by a bystander using an AED was associated with a 62% increase in the odds of survival to hospital discharge (adjusted odds ratio 1.62, 95% CI: 1.12-2.34, p = 0.010) compared to first defibrillation by EMS. CONCLUSION: Survival to hospital discharge is improved in patients first defibrillated using a public AED prior to EMS arrival in Victoria, Australia. Encouragingly, bystander AED use in Victoria has increased over time. More widespread availability of AEDs may further improve outcomes of OHCA in public places. PMID- 25449345 TI - Resuscitative extracorporeal membrane oxygenation for in hospital cardiac arrest: a Canadian observational experience. AB - BACKGROUND: Among patients with reversible conditions who sustain cardiac arrest, extracorporeal membrane oxygenation (ECMO) may support end organ perfusion while bridging to definitive therapy. METHODS: A single center retrospective review (February 2008-September 2013) of adults receiving ECMO for cardiac arrest >=15 min duration refractory to conventional management (E-CPR) or profound cardiogenic shock following IHCA (E-CS) was conducted. The primary outcome was 30 day survival with good neurologic function defined as a cerebral performance category (CPC) of 1-2. Secondary outcomes included intensive care unit (ICU) and hospital length of say, duration of mechanical ventilation, and univariate predictors of 30-day survival with favorable neurologic function. RESULTS: Thirty two patients (55 +/- 11 years, 66% male) were included of which 22 (69%) received E-CPR and 10 (31%) received E-CS following return of spontaneous circulation (ROSC). Cardiac arrest duration was 48.8 +/- 21 min for those receiving E-CPR and 25 +/- 23 min for the E-CS group. Patients received ECMO support for 70.7 +/- 47.6 h. Death on ECMO support occurred in 7 (21.9%) patients, while 7 (21.9%) were bridged to another form of mechanical circulatory support, and 18 (56.3%) were successfully decannulated. ICU length of stay was 7.5 [3.3-14] days and ICU survival occurred in 16 (50%) of patients. 30-Day survival was 5 (50%) in the E CS group, 10 (45.4%) in the E-CPR group, and 15 (47%) overall. All survivors had CPC 1-2 neurologic status. CONCLUSION: In this single center experience, the use of resuscitative ECMO was associated with neurologically favorable 30-day survival in 47% of patients with prolonged IHCA (H2012:172). PMID- 25449347 TI - Errors in the management of cardiac arrests: an observational study of patient safety incidents in England. AB - OBJECTIVE: The aim of this qualitative study is to better understand the types of error occurring during the management of cardiac arrests that led to a death. METHODS: All patient safety incidents involving management of cardiac arrests and resulting in death which were reported to a national patient safety database over a 17-month period were analysed. Structured data from each report were extracted and these together with the free text, were subjected to content analysis which was inductive, with the coding scheme emerged from continuous reading and re reading of incidents. RESULTS: There were 30 patient safety incidents involving management of cardiac arrests and resulting in death. The reviewers identified a main shortfall in the management of each cardiac arrest and this resulted in 12 different factors being documented. These were grouped into four themes that highlighted systemic weaknesses: miscommunication involving crash number (4/30, 13%), shortfalls in staff attending the arrest (4/30, 13%), equipment deficits (11/30, 36%), and poor application of knowledge and skills (11/30, 37%). CONCLUSION: The factors identified represent serious shortfalls in the quality of response to cardiac arrests resulting in death in hospital. No firm conclusion can be drawn about how many deaths in the study population would have been averted if the emergency had been managed to a high standard. The effective management of cardiac arrests should be considered as one of the markers of safe care within a healthcare organisation. PMID- 25449348 TI - The emergency cardiac arrest response team (eCART): a novel strategy for improving therapeutic hypothermia utilization following out-of-hospital cardiac arrest. AB - BACKGROUND: Out-of hospital cardiac arrest (OHCA) is associated with significant mortality. Therapeutic hypothermia is one of the few interventions that have been shown to increase post-arrest survival as well as enhance neurologic recovery. Despite clinical guidelines recommending the use of therapeutic hypothermia (TH) following cardiac arrest, utilization rates by physicians remain low. We hypothesized that the development of a multi-disciplinary emergency cardiac arrest response team (eCART) would enhance therapeutic hypothermia utilization in the emergency department for OHCA. METHODS AND RESULTS: An eCART (emergency department cardiac arrest response team) was created at a single site academic urban emergency department. The eCART team consisted of a physician hypothermia consultant, a cardiologist, a clinical pharmacist, a respiratory therapist and a chaplain. These providers were notified by page prior to the arrival of an OHCA patient and responded to the ED in person or by phone to support the resuscitation. Analysis of pre- and post-intervention data demonstrated a significant increase in the rate of TH utilization (64% to 96%). There was a non significant decrease in the time to target temperature. CONCLUSIONS: The creation of a coordinated, multi-disciplinary care team, providing real-time support for OHCA patients increased TH utilization in an emergency department. PMID- 25449349 TI - Mouth-to-mouth: an obstacle to cardiopulmonary resuscitation for lay-rescuers. PMID- 25449351 TI - Thermodynamic aspects of therapeutic hypothermia. AB - Therapeutic hypothermia (TH) is an important treatment for post-cardiac arrest syndrome. Despite its widespread practice, only limited data describe the thermodynamic aspects of heat transfer during TH. This paper reviews the principles of human body heat balance and provides a conceptual model for characterizing heat exchange during TH. The model may provide a framework for computer simulation for improving training in or clinical methods of TH. PMID- 25449350 TI - Microcirculatory perfusion and vascular reactivity are altered in post cardiac arrest patients, irrespective of target temperature management to 33 degrees C vs 36 degrees C. AB - AIM: In previous reports both microcirculatory alterations and impaired vascular reactivity have been described in post cardiac arrest patients treated with mild therapeutic hypothermia. As of now it is unknown whether these alterations are related to the temperature management or to the cardiac arrest itself. Aim of the present study was to investigate the potential difference in microcirculatory alterations and vascular reactivity in comatose patients after out of hospital cardiac arrest treated with target temperature management of 33 degrees C (TTM33) in comparison to patients treated with 36 degrees C (TTM36). METHODS: Our study was designed as a predefined substudy of the open label randomized controlled TTM trial in 2 Dutch mixed ICU's. Sublingual microvascular flow index (MFI) was assessed by Side Stream Darkfield imaging and vascular reactivity at the thenar region of the hand by near infrared spectroscopy. Variables, including systemic hemodynamics were recorded at start study (T1), after 12h (T2) and after 24h (T3). RESULTS: 22 patients were included, 13 in TTM33 and 9 in TTM36. At T1 MFI between groups did not differ significantly (1.08 [0.4-1.9] versus 1.67 [0.7 2.4] respectively, p = 0.59). The difference between groups remained insignificant over time. At T1 tissue oxygenation (StO2) was significantly lower in TTM36 in comparison to TTM33: (44.6 +/- 15.8 versus 58.9 +/- 13.5, p = 0.03). Over time this difference between groups disappeared. However, vascular reactivity, expressed as the descending and ascending slope of StO2 after a standardized ischemic occlusion test was similar between groups. CONCLUSIONS: In this relatively small sample size study microcirculatory blood flow and vascular reactivity did not differ nor change between TTM33 and TTM36. PMID- 25449352 TI - Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains. AB - Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES. Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18. Mice were examined at birth, and on 5-120 days postnatal to evaluate ExG malformations. Of 23 adult (>60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias (see text for definitions) ranged from 18% to 100% in prenatally DES-exposed CD-1 males and 31% to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed only slightly in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral-vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations. For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral-vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal. Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation. PMID- 25449354 TI - Strain-dependent differential behavioral responses of zebrafish larvae to acute MK-801 treatment. AB - The zebrafish is a relatively new model organism and has become a valuable tool in genetic, developmental, and pharmacological researches. Zebrafish larvae, compared with adult, are particularly suitable for high-throughput screening of drug effects. AB and TU are well established in-bred zebrafish strains. The behavioral responses to acute MK-801 treatments (0, 5, 20, 100, and 200MUM) under illumination at 50lx were studied using zebrafish larvae of both AB and TU strains at 7dpf with ZebraLab software. Two behavioral parameters, traveling distance and activity counts, were analyzed. "Traveling distance" represents locomotor activity, whereas "activity count" is any activity including small, non ambulatory movements. Zebrafish larvae of TU strain demonstrated inhibitory effects in both behavioral parameters in response to MK-801 treatment. Zebrafish larvae of AB strain showed lack of responses to MK-801 treatments in traveling distance, and showed increases in activity counts. Therefore, zebrafish larvae of AB and TU strains demonstrated opposite responses in activity counts towards MK 801 treatment. Differences in the level of neurotransmitters and their respective metabolites (NE and MHPG, DA and DOPAC, 5-HT and 5-HIAA) between AB and TU strain zebrafish larvae were discovered by HPLC analysis, which was related to the strain-dependent differential behavioral responses to MK-801 treatment. CONCLUSION: Under the influences of MK-801, in contrast with TU strain, AB strain zebrafish larvae demonstrated activity changes similar to previous studies on rodents. AB strain larvae are better model organisms than TU strain larvae in MK 801 related behavioral studies. PMID- 25449353 TI - Comparative effects of neonatal diethylstilbestrol on external genitalia development in adult males of two mouse strains with differential estrogen sensitivity. AB - The effect of neonatal exposure to diethylstilbestrol (DES), a potent synthetic estrogen, was examined to evaluate whether the CD-1 (estrogen insensitive, outbred) and C57 (estrogen sensitive, inbred) mouse strains differ in their response to estrogen disruption of male ExG differentiation. CD-1 and C57BL/6 litters were injected with sesame oil or DES (200 ng/g/5 MUl in sesame oil vehicle) every other day from birth to day 10. Animals were sacrificed at the following time points: birth, 5, 10 and 60 days postnatal. Neonatally DES-treated mice from both strains had many ExG abnormalities that included the following: (a) severe truncation of the prepuce and glans penis, (b) an abnormal urethral meatus, (c) ventral tethering of the penis, (d) reduced os penis length and glans width, (e) impaired differentiation of cartilage, (f) absence of urethral flaps, and (g) impaired differentiation of erectile bodies. Adverse effects of DES correlated with the expression of estrogen receptors within the affected tissues. While the effects of DES were similar in the more estrogen-sensitive C57BL/6 mice versus the less estrogen-sensitive CD-1 mice, the severity of DES effects was consistently greater in C57BL/6 mice. We suggest that many of the effects of DES, including the induction of hypospadias, are due to impaired growth and tissue fusion events during development. PMID- 25449355 TI - Potential of novel phytoecdysteroids isolated from Vitex doniana in the treatment depression: involvement of monoaminergic systems. AB - Vitex doniana Sweet (Verbanaceae) is used in traditional African medicine for the treatment of neurological disorders including depression. In our previous studies, three new phytoecdysteroids were isolated from methanol stem bark extract of V. doniana (VD) (11beta-hydroxy-20-deoxyshidasterone, 21 hydroxyshidasterone, and 2,3-acetonide-24-hydroxyecdysone) along with known ecdysteroids. This study was designed to investigate antidepressant-like effect of VD and the isolated phytoecdysteroids in behavioral models of despair, forced swim test (FST) and tail-suspension test (TST) in mice. VD (100 and 200mg/kg, p.o.) treatment reduced (P<0.05) the duration of immobility in both tests without affecting the locomotor activity and exploratory behavior as observed in the open field test. Similarly, 21-hydroxyshidasterone, 11beta-hydroxy-20 deoxyshidasterone, ajugasterone and 24-hydroxyecdysone acute oral treatments significantly reduced immobility time with peak effect at 10mg/kg, which was similar to the effect of conventional antidepressants (imipramine and fluoxetine) in the FST. Conversely, pretreatment of mice with yohimbine (1mg/kg, i.p., alpha2 adrenoceptor antagonist), ketanserin (5mg/kg, i.p., 5-HT2A/2C receptor antagonist) or sulpiride (dopamine D2 receptor antagonist) prevented the antidepressant-like effect of 21-hydroxyshidasterone while the effects of 11beta hydroxy-20-deoxyshidasterone and 24-hydroxyecdysone were blocked by yohimbine or ketanserin in the FST. Moreover, the anti-immobility effect elicited by ajugasterone was prevented by prazosin (62.5MUg/kg, i.p., alpha1-adrenoceptor antagonist) pretreatment. Our findings demonstrated that V. doniana and its phytoecdysteroids constituents elicited antidepressant-like effect in behavioral paradigm of despair. Furthermore, 21-hydroxyshidasterone produces its antidepressant-like effect through interaction with alpha2-adrenoceptor, 5 HT2A/2C receptor and dopamine D2-receptors but 11beta-hydroxy-20 deoxyshidasterone and 24-hydroxyecdysone effects depend on interaction with alpha2-adrenoceptor and 5-HT2A/2C receptors while ajugasterone produces its action through interaction with post-synaptic alpha1-adrenoceptors. Thus, phytoecdysteroids could play a pivotal role in the treatment of major depression. PMID- 25449356 TI - Naringin ameliorates memory deficits in experimental paradigm of Alzheimer's disease by attenuating mitochondrial dysfunction. AB - RATIONALE: Mitochondrial dysfunction has been well documented in age related disorders like Alzheimer's disease. Alterations in mitochondrial membrane potential lead to neuronal death by excessive generation of free radicals, inflammatory cytokines, and excitotoxins. Intracerebroventricular (ICV) streptozotocin (STZ) induced-cognitive impairment has been widely used as an experimental model of Alzheimer's disease. Naringin is a potent antioxidant, which can cross the blood brain barrier protecting brain tissue and modulating brain chemistry. OBJECTIVES: The present study was designed to evaluate the effect of naringin, in ICV STZ-induced mitochondrial dysfunction and memory loss in rats. METHODS: Streptozotocin (3mg/kg, ICV) was injected bilaterally in two divided doses on first and third day followed by treatment with different doses of naringin (50, 100 and 200mg/kg; p.o.) for twenty one days. Behavioral alterations were monitored using Morris water maze paradigm and elevated plus maze test. Animals were sacrificed to evaluate various biochemical and mitochondrial parameters in brain. Rivastigmine was used as a standard drug. RESULTS: ICV-STZ administration produced significant cognitive deficits as assessed by both Morris water maze and elevated plus maze task which is accompanied by significantly enhanced oxidative-nitrosative stress, altered acetylcholinesterase and mitochondrial enzyme activities in cerebral cortex and hippocampus of rats brain along with significantly increased brain TNF-alpha and IL-1beta levels. Chronic treatment with naringin dose dependently restored cognitive deficits in ICV-STZ rat along with mitigation of mitochondrial dysfunction mediated oxido-nitrosative stress and cytokine release. CONCLUSIONS: Our findings demonstrate that naringin ameliorates mitochondrial dysfunction mediated oxido-nitrosative stress and inflammatory surge in ICV-STZ rats. PMID- 25449357 TI - Tanshinone IIA attenuates neuropathic pain via inhibiting glial activation and immune response. AB - Neuropathic pain, characterized by spontaneous pain, hyperalgesia and allodynia, is a devastating neurological disease that seriously affects patients' quality of life. We have previously shown that tanshinone IIA (TIIA), an important lipophilic component of Danshen, had significant anti-nociceptive effect in somatic and visceral pain, it is surprisingly noted that few pharmacological studies have been carried out to explore the possible analgesic action of TIIA on neuropathic pain and the underlying mechanisms. Therefore, in the present study, by using spinal nerve ligation (SNL) pain model, the antinociceptive and antihyperalgesic effects of TIIA on neuropathic pain were evaluated by intraperitoneal administration in rats. The results indicated that TIIA dose dependently inhibited SNL-induced mechanical hyperalgesia. As revealed by OX42 levels, TIIA effectively repressed the activation of spinal microglial activation in SNL-induced neuropathic pain. Meanwhile, TIIA also decreased the expressions of inflammatory cytokines TNF-alpha and IL-1beta in the spinal cord. Furthermore, TIIA inhibited oxidative stress by significantly rescuing the superoxide dismutase (SOD) activity and decreasing the malondialdehyde (MDA). Moreover, TIIA depressed SNL-induced MAPKs activation in spinal cord. CONCLUSION: Taken together, our study provides evidence that TIIA inhibited SNL-induced neuropathic pain through depressing microglial activation and immune response by the inhibition of mitogen-activated protein kinases (MAPKs) pathways. Our findings suggest that TIIA might be a promising agent in the treatment of neuropathic pain. PMID- 25449358 TI - Participation of peripheral P2Y1, P2Y6 and P2Y11 receptors in formalin-induced inflammatory pain in rats. AB - Metabotropic P2Y receptors subfamily consists of eight functional mammalian receptors. Specifically, P2Y1, P2Y6 and P2Y11 receptors have been described in the sensory nervous system, but their participation, at peripheral level, in behavioral pain models is scarcely understood. This study assessed the role of peripheral P2Y1, P2Y6 and P2Y11 receptors in formalin-induced inflammatory pain. Ipsilateral, but not contralateral peripheral pre-treatment with the endogenous P2Y1 (ADP, 100-1000nmol/paw), P2Y6 (UDP, 180-300nmol/paw) and P2Y11 (ATP, 100 1000nmol/paw), or selective P2Y1 (MRS2365, 0.1-10nmol/paw), P2Y6 (PSB0474, 0.1 0.10pmol/paw) and P2Y11 (NF546, 0.3-3nmol/paw) receptor agonists increased 0.5% formalin-induced flinching behavior. Concordantly, peripheral pre-treatment with the selective P2Y1 (MRS2500, 0.01-10pmol/paw), P2Y6 (MRS2578, 3-30nmol/paw) and P2Y11 (NF340, 1-10nmol/paw) receptor antagonists significantly decreased 1% formalin-induced flinching behavior. Furthermore, the pronociceptive effect of ADP (100nmol/paw) or MRS2365 (10nmol/paw), UDP (300nmol/paw) or PSB0474 (10pmol/paw) and ATP (1000nmol/paw) or NF546 (3nmol/paw) was blocked by the selective P2Y1 (MRS2500, 0.01nmol/paw), P2Y6 (MRS2578, 3nmol/paw), and P2Y11 (NF340, 1nmol/paw) receptor antagonists, respectively. Western blot analysis confirmed the presence of P2Y1 (66kDa), P2Y6 (36kDa) and P2Y11 (75kDa) receptors in dorsal root ganglia (DRG) and sciatic nerve. Results suggest that peripheral activation of P2Y1, P2Y6 and P2Y11 receptors plays a pronociceptive role in formalin-induced pain. PMID- 25449360 TI - Effects of methylphenidate on the behavior of male 5xFAD mice. AB - Alzheimer's disease is a neurodegenerative disorder characterized by a loss of memory and spatial orientation. It is also reported that the dopamine system is affected. Dopamine plays a prominent role in motor functions, motivation, emotion, arousal and reward, and it is important for learning and memory. One model that represents characteristic hallmarks of Alzheimer's disease is the 5xFAD mouse model, in which parenchymal plaque load starts at 2months of age. Transgenic 5xFAD mice show the first behavioral deficits at 6months, which are evident at 9months of age. In this study, we investigated the pharmacological influence of methylphenidate (MPH) on behavioral deficits of 5xFAD mice. Using a battery of behavioral tests, we observed no influence of MPH on anxiety in the elevated plus maze, whereas the locomotion and explorative activity in the open field was increased in transgenic and non-transgenic 5xFAD mice after the application of MPH. Further MPH inhibits habituation in the open field in healthy 5xFAD littermates after the application of 10mg/kg MPH. On the other hand, 10mg/kg MPH improved spatial memory in 6-month-old transgenic 5xFAD males, i.e., at a time point when deficits start to occur. However, in 9-month-old transgenic mice, MPH did not improve persisting learning and memory deficits. We concluded that MPH might improve the non-cognitive, apathy-like behavior (indicated by a reduced exploration), but it has no influence on sustained Alzheimer typical learning and memory deficits. PMID- 25449359 TI - GABA and 5-HT systems are implicated in the anxiolytic-like effect of spinosin in mice. AB - The present study investigated the anxiolytic-like effects of spinosin, one of the major flavonoids in Ziziphi Spinosae Semen (ZSS), in experimental models of anxiety compared with a known anxiolytic, diazepam. Repeated treatment with spinosin (2.5 and 5mg/kg/day, p.o.) significantly increased the percentage of entries into and time spent on the open arms of the elevated plus maze compared with the control group. In the light/dark box test, spinosin exerted an anxiolytic-like effect at 5mg/kg. In the open-field test, 5mg/kg spinosin increased the number of central entries. Spinosin did not affect spontaneous activity. The anxiolytic-like effects of spinosin in the elevated plus maze, light/dark box test, and open field test were blocked by the gamma-aminobutyric acid-A (GABAA) receptor antagonist flumazenil (3mg/kg, i.p.) and 5 hydroxytryptamine-1A (5-HT1A) receptor antagonist WAY-100635 (1mg/kg, i.p.). These results suggest that spinosin exerts anxiolytic-like effects, and its mechanism of action appears to be modulated by GABAA and 5-HT1A receptors. PMID- 25449361 TI - A substitution in nsP1 combined with a double substitution in E2 glycoprotein renders Sindbis-like virus XJ-160 fully neurovirulent for adult mice. AB - Sindbis virus (SV) can be rendered neurovirulent for adult mice by a double substitution within the E2 glycoprotein, including replacing Gln at position 55 of E2 with a His (E2-55: Gln-His) and E2-70: Glu to Lys. However, the mutant Sindbis-like virus XJ-160 with the double substitution (BR-E5570) does not show neurovirulence for adult mice, although the mutant apparently reduced the average survival time of neonatal mice. To produce an XJ-160 virus neurovirulent for adult mice, the BR-E5570 virus containing the double substitution was provided with another substitution in the nsP1 region (nsP1-173: Thr-Ile), which could enhance viral infectivity and neurovirulence for neonatal mice. The mutant containing these three substitutions was accordingly designated as BR-5570-ns173. Like the BR-XJ160 virus derived from the wild-type clone, BR-E5570 and BR-E5570 ns173 were both virulent for newborn mice, between which BR-E5570-ns173 virus showed the greatest neurovirulence. Furthermore, only BR-E5570-ns173 virus was fully neurovirulent for 14-day-old mice, and this fatal adult mouse-virulence was dependent on the E2 double substitutions at positions 55 and 70. Compared with BR XJ160, both the mutants showed a higher capacity for propagation both in cultured cells and in the mouse brain. In particular, BR-E5570-ns173 virus showed a more persistent existence and higher titer in the brains of 7-day-old mice. These findings indicate that the substitution at nsP1-173 combination with a double substitution in the E2 region renders the XJ-160 virus fully neurovirulent for adult mice, and this neurovirulence may be related to the increased efficiency and persistence of propagation of this virus. PMID- 25449362 TI - The pregenome/C RNA of duck hepatitis B virus is not used for translation of core protein during the early phase of infection in vitro. AB - Over the course of duck hepatitis B virus (DHBV) replication, one type of RNA (pregenome/C RNA, 3.5 kb) that corresponds to the whole genome of DHBV is generated from the transcription of viral cccDNA. Previous work has proposed three functions for the pregenome/C RNA: it can serve as the pregenome and be packaged into the core protein during the process of replication, and it encodes the mRNA for both the capsid protein and the viral polymerase. However, little is known about the timing of these functions during the different stages of viral infection. In this study, a reverse transcription quantitative real-time PCR assay was developed to analyze the dynamic transcription process of the pregenome/C RNA. The dynamic expression of the core protein was investigated using an indirect immunofluorescence assay (IFA) and by western blot analysis. The generation of pregenome/C RNA began at 12 h post infection and peaked at 20 h post infection; however, the core protein was not detectable until 24h post infection. These results demonstrate that the core protein appeared approximately 12h later than the pregenome/C RNA. These results suggest that the DHBV pregenome/C RNA is not used for the translation of the viral core protein during the early stages of infection. PMID- 25449363 TI - Computational study on the drug resistance mechanism of HCV NS5B RNA-dependent RNA polymerase mutants V494I, V494A, M426A, and M423T to Filibuvir. AB - Filibuvir, a potent non-nucleoside inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp), has shown great promise in phase IIb clinical trial. However, drug resistant mutations towards Filibuvir have been identified. In the present study, the drug resistance mechanism of wild-type (WT) and mutant NS5B polymerases (including V494I, V494A, M426A, and M423T) toward Filibuvir was investigated by molecular modeling methods. The predicted binding free energy of these five complexes is highly consistent with the experimental EC50 values of Filibuvir to the wild-type and mutant NS5B RdRps, V494I 10, and LR < 10 and LR > 10 to better understand the effect of lice burden per se. As expected, expression patterns were influenced both by genetic background and the number of attached parasites. Higher number of lice (>10) negatively affected gene expression in both HR and LR families. In general, strongest down-regulation was seen in LR > 10 and lesser down-regulation in HR < 10. HR in general and especially HR < 10 fish were better at resisting suppression of expression of both Th1 and Th2 genes. However, the best inverse correlation with infection level was seen for the prototypical Th1 genes, including several members from the interferon pathways. In addition, skin histomorphometry suggests that infected LR salmon had thicker epidermis in the area behind the dorsal fin and larger mucous cell size compared to infected HR fish, however marginally significant (p = 0.08). This histomorphometric finding was in line with the immune response being skewed in LR towards the Th2 rather than a Th1 profile. Our findings suggest that the ability to resist lice infection depends on the ability to avoid immunosuppression and not as much on the physical tissue barrier functions. PMID- 25449369 TI - Cascading effects from survival to physiological activities, and gene expression of heat shock protein 90 on the abalone Haliotis discus hannai responding to continuous thermal stress. AB - Increasing temperatures can be a significant stressor for aquatic organisms. Abalones, a type of large marine gastropods, are the most commercially important species in aquaculture for Asia. To evaluate the potential ecological risk posed by temperature stress, we measured biological responses such as survival rate, adhesion ability (falling rate), and foot abnormalities in the abalone Haliotis discus hannai. Additionally, biochemical and molecular responses were evaluated in H. discus hannai exposed to various temperature gradients. The survival rate was reduced in abalones exposed to relative high temperatures (more than 26 degrees C). Increased temperature stress induced a higher falling rate and abnormal foot structure. Furthermore, increased antioxidant enzyme activities were observed in abalones exposed to relative high temperatures (26 and 28 degrees C). The activities of superoxide dismutase were induced in a time dependent manner after high temperature stress. Generally, heat shock protein 90 also increased significantly in H. discus hannai exposed to temperature gradients (more than 24 degrees C) for 12 h. These results provide valuable information regarding stress responses to increased temperatures, in H. discus hannai: adverse biological and molecular outcomes could be utilized as risk assessments and stress monitoring of marine ecosystems under increased water temperatures. PMID- 25449371 TI - The role of Cu/Zn-SOD and Mn-SOD in the immune response to oxidative stress and pathogen challenge in the clam Meretrix meretrix. AB - The copper/zinc superoxide dismutase (Cu/Zn-SOD) and manganese superoxide dismutase (Mn-SOD) could effectively eliminate reactive oxygen species (ROS) and maintain the redox balance of immune system. In the present study, the potential synergy of Cu/Zn-SOD and Mn-SOD in immune system was investigated in the clam Meretrix meretrix. The expression of Cu/Zn-SOD mainly distributed in hepatopancreas and that of Mn-SOD was higher in gill of M. meretrix, and their mRNA and protein activity paralleled with each other. In response to H2O2 challenge, Cu/Zn-SOD mRNA showed significantly higher level at 24 h post challenge and Mn-SOD mRNA was significantly higher at 12 and 24 h post-challenge in the experimental clams than in the control clams (P<0.05). After injection with Vibrio-parahaemolyticus-related bacterium (MM21), the Cu/Zn-SOD mRNA was significantly up-regulated at 24 h and 48 h post-injection and Mn-SOD mRNA was significantly higher at 24 h post-injection in MM21-injected clams than in control clams (P<0.05), suggesting that both of them might involve in the immune defense to Vibrio challenge. The mRNA expression of Cu/Zn-SOD and Mn-SOD was examined in a Vibrio-resistant population and a control population after MM21 immersion challenge. The increased transcription of Cu/Zn-SOD and Mn-SOD in the resistant population suggested both of them could benefit the immune system to defend against pathogen infection. As expression of Mn-SOD mRNA depended on stimuli and was more easily inducible, its response to H2O2 and Vibrio challenge was earlier than Cu/Zn-SOD. Our study suggested the redox balance might play an important role in M. meretrix to resist pathogen infection. PMID- 25449370 TI - The roles of Na+/K+-ATPase alpha-subunit gene from the ridgetail white prawn Exopalaemon carinicauda in response to salinity stresses. AB - Na(+)/K(+)-ATPase (NAK) is one important transporter protein and plays a key role in maintaining osmotic homeostasis in low and high salinity acclimation in variety of crustacean species. The ridgetail white prawn Exopalaemon carinicauda is an euryhaline and economic shrimp species in China, but it remains unclear about its mechanism of salinity adaption. In this study, a full-length of Na(+)/K(+)-ATPase alpha-subunit (alpha-NAK) cDNA was cloned from E. carinicauda by using rapid amplification of cDNA ends (RACE) approaches. The full-length cDNA of alpha-NAK was of 3680 bp, containing an open reading frame (ORF) of 3030 bp encoding a polypeptide of 1009 amino acids with the predicted molecular weight of 112.27 kDa. Eight transmembrane domains and two sites of phosphorylation and ATP binding were identified in E. carinicauda alpha-NAK. BLAST analysis revealed that the sequence of alpha-NAK amino acids of E. carinicauda shared more than 75% homologies with those of other crustacean. Real time quantitative RT-PCR analysis indicated that E. carinicauda alpha-NAK gene could be detected in all the tested tissues with highest expression level in gill. The expression profiles of E. carinicauda alpha-NAK transcripts were analyzed in gill and hepatopancreas tissues after salinity stresses. The results showed that the expression level of E. carinicauda alpha-NAK gene in both gill and hepatopancreas reached peak at different time after low and high salinity stresses, and showed different expression profiles. The expression profiles of proPO transcripts in gills after salinity stresses also indicated alpha-NAK and proPO played synergistic actions for salinity responses in E. carinicauda. These results indicated that E. carinicauda alpha-NAK involved in stress responses against salinity. PMID- 25449372 TI - Involvement of a Serpin serine protease inhibitor (OoSerpin) from mollusc Octopus ocellatus in antibacterial response. AB - Serpin is an important member of serine protease inhibitors (SPIs), which is capable of regulating proteolytic events and involving in a variety of physiological processes. In present study, a Serpin homolog was identified from Octopus ocellatus (designated as OoSerpin). Full-length cDNA of OoSerpin was of 1735 bp, containing a 5' untranslated region of 214 bp, a 3' UTR of 282 bp, and an open reading frame of 1239 bp. The open reading frame encoded a polypeptide of 412 amino acids which has a predicted molecular weight of 46.5 kDa and an isoelectric point of 8.52. The OoSerpin protein shares 37% sequence identity with other Serpins from Mus musculus (NP_941373) and Ixodes scapularis (XP_002407493). The existence of a conserved SERPIN domain strongly suggested that OoSerpin was a member of the Serpin subfamily. Expression patterns of OoSerpin, both in tissues and towards bacterial stimulation, were then characterized. The mRNA of OoSerpin was constitutively expressed at different levels in all tested tissues of untreated O. ocellatus, including mantle (lowest), muscle, renal sac, gill, hemocyte, gonad, systemic heart, and hepatopancreas (highest). The transcriptional level of OoSerpin was significantly up-regulated (P<0.01) in O. ocellatus upon bacterial challenges with Vibrio anguillarum and Micrococcus luteus, indicating its involvement in the antibacterial immune response. Furthermore, rOoSerpin, the recombinant protein of OoSerpin, exhibited strong abilities to inhibit proteinase activities of trypsin and chymotrypsin as well as the growth of Escherichia coli. Our results demonstrate that OoSerpin is a potential antibacterial factor involved in the immune response of O. ocellatus against bacterial infection. PMID- 25449373 TI - The known and unknown sources of reactive oxygen and nitrogen species in haemocytes of marine bivalve molluscs. AB - Reactive oxygen and nitrogen species (ROS and RNS) are naturally produced in all cells and organisms. Modifications of standard conditions alter reactive species generation and may result in oxidative stress. Because of the degradation of marine ecosystems, massive aquaculture productions, global change and pathogenic infections, oxidative stress is highly prevalent in marine bivalve molluscs. Haemocytes of bivalve molluscs produce ROS and RNS as part of their basal metabolism as well as in response to endogenous and exogenous stimuli. However, sources and pathways of reactive species production are currently poorly deciphered in marine bivalves, potentially leading to misinterpretations. Although sources and pathways of ROS and RNS productions are highly conserved between vertebrates and invertebrates, some uncommon pathways seem to only exist in marine bivalves. To understand the biology and pathobiology of ROS and RNS in haemocytes of marine bivalves, it is necessary to characterise their sources and pathways of production. The aims of the present review are to discuss the currently known and unknown intracellular sources of reactive oxygen and nitrogen species in marine bivalve molluscs, in light of terrestrial vertebrates, and to expose principal pitfalls usually encountered. PMID- 25449374 TI - Comprehensive and comparative transcription analyses of the complement pathway in rainbow trout. AB - The complement system is one of the most ancient and most essential innate immune cascades throughout the animal kingdom. Survival of aquatic animals, such as rainbow trout, depends on this early inducible, efficient immune cascade. Despite increasing research on genes coding for complement components in bony fish, some complement-related genes are still unknown in salmonid fish. In the present study, we characterize the genes encoding complement factor D (CFD), CD93 molecule (CD93), and C-type lectin domain family 4, member M (CLEC4M) from rainbow trout (Oncorhynchus mykiss). Subsequently, we performed comprehensive and comparative expression analyses of 36 complement genes including CFD, CD93, and CLEC4M and further putative complement-associated genes to obtain general information about the functional gene interaction within the complement pathway in fish. These quantification analyses were conducted in liver, spleen and gills of healthy fish of two rainbow trout strains, selected for survival (strain BORN) and growth (Import strain), respectively. The present expression study clearly confirms for rainbow trout that liver represents the primary site of complement expression. Spleen and gills also express most complement genes, although the mean transcript levels were generally lower than in liver. The transcription data suggest a contribution of spleen and gills to complement activity. The comparison of the two rainbow trout strains revealed a generally similar complement gene expression. However, a significantly lower expression of numerous genes especially in spleen seems characteristic for the BORN strain. This suggests a strain-specific complement pathway regulation under the selected rearing conditions. PMID- 25449375 TI - Nuclear factor of activated T cells (NFAT) in pearl oyster Pinctada fucata: molecular cloning and functional characterization. AB - Nuclear factor of activated T cells (NFAT) plays an important role in nonimmune cells and also in T cells and many other cells of the immune system, by regulating the expression of a variety of genes involved in the immune response, organ development, developmental apoptosis and angiogenesis. In the present study, the NFAT homology gene, PfNFAT, from the pearl oyster Pinctada fucata was cloned and its genomic structure and promoter were analyzed. PfNFAT encodes a putative protein of 1226 amino acids, and contains a highly conserved Rel homology region (RHR) with DNA-binding specificity, and a regulatory domain (NFAT homology region, NHR) containing a potent transactivation domain (TAD). The PfNFAT gene consists of 12 exons and 11 introns, and its promoter contains potential binding sites for transcription factors such as NF-kappaB (Nuclear factor kappaB), STATx (signal transducer and activator of transcription), AP-1 (activator protein-1) and Sox-5/9 (SRY type HMG box-5/9), MyoD (Myogenic Differentiation Antigen) and IRF (Interferon regulatory factor). Comparison and phylogenetic analysis revealed that PfNFAT shows high identity with other invertebrate NFAT, and clusters with the NFAT5 subgroup. Furthermore, gene expression analysis revealed that PfNFAT is involved in the immune response to lipopolysaccharide (LPS) and Polyinosinic-polycytidylic acid (poly I:C) stimulation and in the nucleus inserting operation. The study of PfNFAT may increase understanding of molluscan innate immunity. PMID- 25449376 TI - Nitric oxide as an antimicrobial molecule against Vibrio harveyi infection in the hepatopancreas of Pacific white shrimp, Litopenaeus vannamei. AB - Nitric oxide (NO) is a key effector molecule produced in the innate immune systems of many species for antimicrobial defense. However, how NO production is regulated during bacterial infection in invertebrates, especially crustaceans, remains poorly understood. Vibrio harveyi, a Gram-negative marine pathogen, is among the most prevalent and serious threats to the world's shrimp culture industry. Its virulence typically manifests itself through shrimp hepatopancreas destruction. In the current study, we found that NO generated by an in vitro donor system (NOC-18) could rapidly and effectively kill V. harveyi. In addition, injection of heat-killed V. harveyi increased the concentration of NO/nitrite and the mRNA expression of nitric oxide synthase (NOS) in the hepatopancreas of Pacific white shrimp (Litopenaeus vannamei), the commercially most significant shrimp species. Live V. harveyi challenge also induced NO/nitrite production and NOS gene expression in primary L. vannamei hepatopancreatic cells in a time- and dose-dependent manner. Co-incubation of l-NAME, an inhibitor selective for mammalian constitutive NOSs, dose-dependently blocked V. harveyi-induced NO/nitrite production, without affecting V. harveyi-induced NOS mRNA expression. Furthermore, l-NAME treatment significantly increased the survival rate of infecting V. harveyi in cultured primary hepatopancreatic cells of L. vannamei. As a whole, we have demonstrated that endogenous NO produced by L. vannamei hepatopancreatic cells occurs in enzymatically regulated manners and is sufficient to act as a bactericidal molecule for V. harveyi clearance. PMID- 25449377 TI - Transcriptome analysis of medaka following epinecidin-1 and TH1-5 treatment of NNV infection. AB - Nervous necrosis virus (NNV) infects a wide range of larval and juvenile fish species, thereby causing enormous economic losses in the aquaculture industry. Possible solutions to this problem include the use of antimicrobial peptides (AMPs), which directly inhibit bacterial growth, and also modulate host signaling mechanisms. The AMPs epinecidin (Epi)-1 and Tilapia hepcidin (TH) 1-5 have been demonstrated to be effective against Nervous necrosis virus infection in medaka (Oryzias latipes). However, the underlying molecular mechanisms are yet to be explored. Here, microarray analyses were performed to examine how NNV infection and/or epinecidin-1 or TH1-5 treatment affects gene expression in medaka; such analyses enabled the prediction of host signaling pathways affected by virus infection and/or regulated by epinecidin-1 and TH1-5. Transcriptome analysis revealed altered expression of genes involved in B cell activation, T cell activation, adipocytokine signaling, and mast cell activation. We subsequently used real-time PCR to analyze expression of key genes involved in these signaling mechanisms. Medaka infected with NNV exhibited up-regulation of PVALB, CEBPA, IFIM, IFN, IL-6ST, NF-kB2, SOC3, SP1, and TGFB1, and such increases were prevented by pre-treatment with epinecidin-1 or TH1-5. Immunohistochemistry using the anti-NNV antibody to stain brain and eye sections revealed that epinecidin-1 treatment during or after infection clears viral load, while TH1-5 treatment only reduces viral numbers if applied during infection. These observations demonstrate that epinecidin-1 and TH1-5 modulate NNV-induced host signaling mechanisms, thereby preventing viral multiplication in host organisms. PMID- 25449378 TI - The effects of Ficus carica polysaccharide on immune response and expression of some immune-related genes in grass carp, Ctenopharyngodon idella. AB - The present study investigated the effect of Ficus carica polysaccharide (FCP), isolated from the fruit of F. carica L., at 0%, 0.1%, 0.5% and 1.0% doses supplementation with feed on genes Interleukin 1-beta (IL-1beta), Tumor Necrosis Factor alpha (TNF-alpha) and heat shock protein 70 (HSP70) gene expression in blood, humoral innate immune parameters and resistant to Flavobacterium columnare of grass carp at weeks 1, 2 and 3. The results revealed that administration of FCP significantly (P<0.05) up regulated IL-1beta and TNF-alpha gene expression. HSP70 gene expression was significantly (P<0.05) lower in FCP-fed fish at the end of trial. The serum total protein, albumin and globulin did not significantly increased in any diet on the first week whereas it was significantly enhanced in 0.5% and 1.0% supplementation diets on weeks 2 and 3 when compared to control. The serum complement C3 was significantly (P<0.05) increased on weeks 1 and 2 when compared to control, however, no significant difference was found in this activity after 3 weeks of treatment. All diets significantly enhanced the serum lysozyme activity, bactericidal activity from weeks 1-2 as compared to control. Grass carp fed with FCP showed remarkably higher resistance against F. columnare (60% survival) compared to the control group (30% survival). These results confirm that FCP can up regulate immune related genes expression, stimulates immune response that per se enhances disease resistance in grass carp. PMID- 25449379 TI - Ferritin protect shrimp Litopenaeus vannamei from WSSV infection by inhibiting virus replication. AB - Iron is considered as an essential element for all living organisms. Therefore, limiting iron availability may be key part of the host's innate immune response to various pathogens. Ferritin is a major iron storage protein in living cells and plays an important role in iron homeostasis. One way the host can transiently reduce iron bioavailability is by ferritin over expression. In invertebrates, ferritin was found to be up-regulated after pathogens challenge and is considered to be an important element in the innate immune system. This study was designed to investigate the involvement of ferritin in shrimp Litopenaeus vannamei defense against WSSV. We discovered that the viral load of shrimp injected with recombinant ferritin protein was lower than that of control group. The suppression of ferritin by dsRNA increased susceptibility to WSSV with 3-fold high viral copies. The present study documented that ferritin protected shrimp L. vannamei from WSSV by inhibiting virus replication. We presume that ferritin reduce iron availability, leading to inhibit the activity of ribonucleotide reductase and delay the replication of virus genome. This study provided new insights into the understanding of molecular responses and defense mechanisms in shrimp against WSSV. PMID- 25449380 TI - Effects of recombinant flagellin B and its ND1 domain from Vibrio anguillarum on macrophages from gilthead seabream (Sparus aurata L.) and rainbow trout (Oncorhynchus mykiss, W.). AB - Flagellin is the principal component of flagellum in Gram negative and positive bacteria, and it is also the ligand that activates the Toll-like receptor 5 (TLR5) in mammals and fish. In higher vertebrates, flagellin induces the activation of the membrane-bound TLR5 (TLR5M), which promotes the expression of proinflammatory cytokines and chemokines and the co-stimulatory molecules present in antigen-presenting cells needed for the activation of T cells. In the present study, we report the production of two recombinant proteins of Vibrio anguillarum: i) a full length flagellin B (FlaB) (rFla) and ii) the amino terminus of the D1 domain (rND1) of the same protein, the region mainly responsible for binding to TLR5 and for the immunostimulatory activity of flagellin. The effects of these recombinant proteins were assessed in vitro using head kidney macrophages of gilthead seabream (Sparus aurata L., Perciformes, Sparidae) and rainbow trout (Oncorhynchus mykiss W., Salmoniformes, Salmonidae). In both species, 3 h of stimulation with rFla and rND1 induced expression of the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha), and of the chemokine IL-8. In gilthead seabream macrophages stimulated with rFla and rND1, a 900- and 6-fold increase were observed for IL 1beta transcription, while a 900- and 3-fold increase were recorded for IL-8 transcription, respectively, as compared to non-stimulated macrophages. In rainbow trout, rFla increased expression of IL-8 40-fold in macrophages, whereas rND1 increased expression of the chemokine 3-fold, as compared to non-stimulated cells. The results obtained for rFla and rND1 demonstrate their modulatory capabilities in vitro, suggesting that rFla and rND1 could be evaluated as immunostimulatory candidates for use in farmed fish. However, further in vivo studies are needed to confirm and expand on the present results. PMID- 25449381 TI - Grouper (Epinephelus coioides) MyD88 and Tollip: intracellular localization and signal transduction function. AB - Myeloid differentiation factor 88 (MyD88) and Toll-interacting protein (Tollip) are two important regulatory proteins of the Toll-like receptor (TLR) signaling pathways. In this paper, a Tollip sequence of grouper (Epinephelus coioides) was identified and the signal transduction functions of Tollip and MyD88 were studied. The full length of E. coioides Tollip (EcTollip) cDNA with an open reading frame (ORF) of 1734 nucleotides encoded a putative protein of 274 amino acid residues. The EcTollip protein had conservative domains with mammalian homologous proteins, and high identity (78%-95%) with other vertebrates. MyD88 and Tollip were distributed in the HeLa cytoplasm in a highly condensed form. Over-expression of MyD88 could activate nuclear factor-kappaB (NF-kappaB) and its function was dependent on the death domain and ID domain on the N-terminal. Some important functional sites of mammalian MyD88 also affected fish MyD88 signal transduction. Tollip impaired NF-kappaB signals activated by MyD88, and its activity was dependent on the coupling of ubiquitin to the endoplasmic reticulum degradation (CUE) domain on the C-terminal. These results suggest that MyD88 and Tollip of fish and mammals are conservative on function during evolution. PMID- 25449382 TI - The effects of combined dietary probiotics Lactococcus lactis BFE920 and Lactobacillus plantarum FGL0001 on innate immunity and disease resistance in olive flounder (Paralichthys olivaceus). AB - The effects of a dietary probiotic mixture containing Lactococcus (Lc.) lactis BFE920 isolated from bean sprout and autochthonous Lactobacillus (Lb.) plantarum FGL0001 originally isolated from the hindgut of olive flounder (Paralichthys olivaceus) were investigated for the purpose of improving the probiotic effects of Lc. lactis BFE920 on the olive flounder. The immunostimulatory, disease protective, and weight gain effects of Lc. lactis BFE920 were significantly improved when olive flounder (average weight 37.5+/-1.26 g) were fed the probiotic mixture (log10 7.0 CFU each/g feed pellet) for 30 days. Flounder fed the mixture showed improved skin mucus lysozyme activity and phagocytic activity of innate immune cells compared to flounder fed a single probiotic agent or a control diet. While the levels of neutrophil activity in flounder fed the single probiotic agent or the mixture were similar, they were significantly higher than levels in a control group. Additionally, probiotic-fed flounder showed significantly increased expressions of IL-6, IL-8, and TNF-alpha in the intestine compared to the control group. Following a 30-day period of being fed probiotics or a control diet, the olive flounder were challenged with an i.p. injection of Streptococcus iniae (log10 6.0 CFU/fish). The groups fed the mixed probiotics, Lc. lactis BFE920, Lb. plantarum FGL0001, and the control diet had survival rates of 55%, 45%, 35%, and 20%, respectively. Flounder fed the probiotic mixture gained 38.1+/-2.8% more body weight compared to flounder fed the control diet during the 30-day study period. These data strongly suggest that a mixture of Lc. lactis BFE920 and Lb. plantarum FGL0001 may serve as an immunostimulating feed additive useful for disease protection in the fish farming industry. PMID- 25449383 TI - A multidisciplinary study of the extracutaneous pigment system of European sea bass (Dicentrarchus labrax L.). A possible relationship between kidney disease and dopa oxidase activity level. AB - Infectious diseases and breeding conditions can influence fish health status. Furthermore it is well known that human and animal health are strongly correlated. In lower vertebrates melano-macrophage centres, clusters of pigment containing cells forming the extracutaneous pigment system, are widespread in the stroma of the haemopoietic tissue, mainly in kidney and spleen. In fishes, melano macrophage centres play an important role in the immune response against antigenic stimulants and pathogens. Hence, they are employed as biomarker of fish health status. We have investigated this cell system in the European sea bass (Dicentrarchus labrax L.) following the enzyme activities involved in melanin biosynthesis. We have found a possible relationship between kidney disease of farmed fishes and dopa oxidase activity level, suggesting it as an indicator of kidney disease. Moreover variations of dopa oxidase activity in extracutaneous pigment system have been observed with respect to environmental temperature. At last, for the first time, using femtosecond transient absorption spectroscopy (Femto-TA), we pointed out that pigment-containing cells of fish kidney tissue present melanin pigments. PMID- 25449384 TI - N-hexanoyl-L-homoserine lactone-degrading Pseudomonas aeruginosa PsDAHP1 protects zebrafish against Vibrio parahaemolyticus infection. AB - Four strains of N-hexanoyl-L-homoserine lactone (AHL)-degrading Pseudomonas spp., named PsDAHP1, PsDAHP2, PsDAHP3, and PsDAHP4 were isolated and identified from the intestine of Fenneropenaeus indicus. PsDAHP1 showed the highest AHL-degrading activity among the four isolates. PsDAHP1 inhibited biofilm-forming exopolysaccharide and altered cell surface hydrophobicity of virulent green fluorescent protein (GFP)-tagged Vibrio parahaemolyticus DAHV2 (GFP-VpDAHV2). Oral administration of PsDAHP1 significantly reduced zebrafish mortality caused by GFP-VpDAHV2 challenge, and inhibited colonisation of GFP-VpDAHV2 in the gills and intestine of zebrafish as evidence by confocal laser scanning microscope and selective plating. Furthermore, zebrafish receiving PsDAHP1-containing feed had increased phagocytic cells of its leucocytes, increased serum activities of superoxide dismutase and lysozyme. The results suggest that Pseudomonas aeruginosa PsDAHP1 could protect zebrafish from V. parahaemolyticus infection by inhibiting biofilm formation and enhancing defence mechanisms of the fish. PMID- 25449386 TI - Physiological changes in response to hearing female voices recorded at high fertility. AB - The human voice transmits pertinent information regarding health status and age, with recent evidence suggesting that it plays an important role in mate selection. However, the mechanism that drives preferences for voices of fertile females has yet to be elucidated. The current study examined the physiological changes that occur when listening to voices recorded from naturally cycling females at high and low fertility phases of the menstrual cycle, as well as from females using hormonal contraception. We found the voices of naturally cycling females recorded during a high fertility phase were rated as more attractive and produced the greatest increase in galvanic skin response (GSR). Heart rate (HR) also showed a trend towards the highest increase when listening to naturally cycling, high fertility female voices. There were no differences in ratings of voice attractiveness, GSR, or HR between the voices recorded from females using hormonal contraception. Analyzed separately, male and female listeners both showed a preference for naturally cycling, high fertility voices. Female listeners additionally showed increased GSR and HR responses to naturally cycling, high fertility voices. We discuss the adaptive benefits of detecting vocal changes for male as well as female listeners, and also discuss the role that the nervous system plays during human mate assessments. PMID- 25449387 TI - Repeated nicotine exposure in adolescent rats: Reduction of medial habenular activity and augmentation of nicotine preference. AB - Adolescence is a critical period for the initiation of tobacco use. Nicotine not only stimulates brain reward circuits to establish and maintain the tobacco smoking habit, but also produces aversive reactions to nicotine after initial exposure, due to its noxious properties. Although new insights into the mechanisms that regulate nicotine avoidance could result in an advantageous treatment strategy for addiction, little is known about the mechanism of nicotine aversion in adolescence. Because growing evidences suggest that the habenula to interpeduncular nucleus circuitry plays a critical role in nicotine aversion, we investigated the effects of repeated nicotine exposure on the electrical activity of medial habenular neurons in adolescent rats, using extracellular recordings. Nicotine strongly increased the frequency of spontaneous spike activity in the medial habenula of naive rats. In repeated nicotine-injected rats, we found a reduction in nicotine-induced spontaneous spike frequency, such that these neurons displayed a significantly lower basal activity and reduced spontaneous activity upon re-exposure to nicotine. Moreover, nicotine intake preference in repeated nicotine-injected rats is significantly more increased than that in saline-injected rats. These results demonstrate that repeated phases of nicotine exposure induce a functional switch in the activity of medial habenular neurons in adolescent rats and suggest that medial habenular activity is one of mediators for an inhibitory motivational signal that limits nicotine consumption. PMID- 25449388 TI - The relationship between working memory, reinvestment, and heart rate variability. AB - There is growing evidence illustrating the negative aspects of reinvestment on everyday life, however its underlying mechanisms remain unclear. The main aim of this study was to empirically clarify the relationship between reinvestment and working memory (WM). A secondary aim was to investigate the contribution of high frequency heart rate variability (HF-HRV) to WM. Sixty-two participants took part in a within-subject design in which we measured their WM capacity in a low pressure and a high-pressure condition while their HF-HRV was measured. In addition, they had to fill out scales assessing their dispositional reinvestment. Results showed that the correlation between reinvestment and WM is negative, exists only in the high-pressure condition, and is specific to the decision component of reinvestment and not the movement component. Moreover, a hierarchical regression analysis revealed that under high pressure resting HF-HRV predicted WM performance above DSRS, whereas DSRS did not predict WM performance above resting HF-HRV. PMID- 25449385 TI - Impaired gait pattern as a sensitive tool to assess hypoxic brain damage in a novel mouse model of atherosclerotic plaque rupture. AB - Apolipoprotein E deficient (ApoE(-/-)) mice with a heterozygous mutation in the fibrillin-1 gene (Fbn1(C1039G+/-)) show spontaneous atherosclerotic plaque ruptures, disturbances in cerebral flow and sudden death when fed a Western-type diet (WD). The present study focused on motor coordination and spatial learning of ApoE(-/-) Fbn1(C1039G+/-) mice on WD for 20 weeks (n=21). ApoE(-/-) mice on WD (n=24) and ApoE(-/-) Fbn1(C1039G+/-) mice on normal diet (ND, n=21) served as controls. Starting from 10 weeks of diet, coordination was assessed every two weeks by the following tests: gait analysis, stationary beam, wire suspension and accelerating rotarod. The Morris water maze test was performed after 13 weeks of diet to study spatial learning. At the end of the experiment (20 weeks of WD), the mice were sacrificed and the brachiocephalic artery and brain were isolated. From 12 weeks onward, gait analysis of ApoE(-/-) Fbn1(C1039G+/-) mice on WD revealed a progressive increase in track width as compared to ApoE(-/-) mice on WD and ApoE(-/-) Fbn1(C1039G+/-) mice on ND (at 20 weeks: 29.8+/-0.6 mm vs. 25.8+/-0.4 mm and 26.0+/-0.5 mm). Moreover, the stationary beam test showed a decrease in motor coordination of ApoE(-/-) Fbn1(C1039G+/-) mice on WD at 18 and 20 weeks. The wire suspension test and accelerating rotarod could not detect signs of motor impairment. Spatial learning was also not affected. Histological analysis of the brachiocephalic artery showed larger and more stenotic plaques in ApoE(-/-) Fbn1(C1039G+/-) mice on WD. Furthermore, the parietal cortex of ApoE(-/ ) Fbn1(C1039G+/-) mice on WD showed pyknotic nuclei as a sign of hypoxia and the percentage of pyknosis correlated with track width. In conclusion, gait analysis may be an efficient method for analyzing hypoxic brain damage in the ApoE(-/-) Fbn1(C1039G+/-) mouse model. This test could be of value to assess the effect of potential anti-atherosclerotic therapies in mice. PMID- 25449389 TI - Chronic psychological stress in high-anxiety rats induces sustained bladder hyperalgesia. AB - OBJECTIVE: To evaluate whether anxiety-prone rats exposed to chronic water avoidance stress (WAS) develop visceral bladder hyperalgesia in addition to increased voiding frequency and anxiety-related behaviors. MATERIALS AND METHODS: Female Wistar-Kyoto (WKY) rats were exposed to chronic (10-day) WAS or sham paradigms. Referred hyperalgesia and tactile allodynia were tested using von Frey filaments applied to the suprapubic region and plantar region of the hindpaw, respectively. To confirm that suprapubic nociception represented referred visceral bladder hyperalgesia, we recorded abdominal visceromotor responses (VMR) to slow (100 MUl/min) and fast (1 cc/sec) bladder filling with room temperature or ice-cold saline. We assessed the development of hyperalgesia over the 10-day WAS protocol and the durability of increased pain sensations over time. RESULTS: Animals exposed to chronic WAS had significantly lower hindpaw withdrawal thresholds post-stress and significant differences in referred hyperalgesia. Rats exposed to chronic WAS demonstrated an increased pain response to suprapubic stimulation and decreased response threshold to mechanical hindpaw stimulation by day 8 of the stress protocol, which persisted for more than one month. Animals exposed to chronic WAS showed increased VMR to fast filling and ice water testing in comparison to sham animals. Cystometry under anesthesia did not show increases in the frequency of non-voiding contractions. CONCLUSION: Chronic WAS induces sustained bladder hyperalgesia, lasting over a month after exposure to stress. The urinary frequency demonstrated previously in anxiety-prone rats exposed to chronic WAS seems to be associated with bladder hyperalgesia, suggesting that this is a potential model for future studies of bladder hypersensitivity syndromes such as interstitial cystitis/painful bladder syndrome (IC/PBS). PMID- 25449390 TI - Thirst interoception and its relationship to a Western-style diet. AB - Less sensitive interoception for hunger and fullness has been observed in people who consume a diet rich in saturated fat and added sugar. In this study we examined whether healthy young people who routinely consume such diets, also demonstrate less sensitive thirst interoception. Participants, varying primarily in diet, were made thirsty by consuming salted chips and later provided with ad libitum access to water, with thirst ratings obtained throughout. A self-report measure of interoceptive awareness was also included plus measures to determine eating habits, memory and executive function. A diet reported as richer in saturated fat and added sugar (an HFS diet) was associated both with less sensitive thirst interoception and with greater attention to somatic signs. Evidence of poorer hippocampal-sensitive learning and memory was also detected. Poorer sensitivity to interoceptive cues appears to be a reliable correlate of an HFS diet and its causal origins are discussed. PMID- 25449391 TI - Voluntary alcohol consumption and plasma beta-endorphin levels in alcohol preferring rats chronically treated with lamotrigine. AB - Several recent studies have indicated that lamotrigine, similarly to other antiepileptic drugs, may be useful in the therapy of alcohol dependence. The rationale for using lamotrigine in the treatment of alcohol addiction is based on its multiple mechanisms of action which include inhibition of voltage-sensitive sodium channels, modulation voltage-gated calcium currents and transient potassium outward current. However, the known mechanism of lamotrigine does not fully explain its efficacy in alcohol addiction therapy. For this reason we have decided to examine the effect of lamotrigine on the opioid system. Our previous studies showed that topiramate and levetiracetam (antiepileptic drugs) as well as the most effective drugs in alcohol addiction therapy i.e. naltrexone and acamprosate, when given repeatedly, all increased plasma beta endorphin (an endogenous opioid peptide) level, despite operating through different pharmacological mechanisms. It is known that low beta-endorphin level is often associated with alcohol addiction and also that alcohol consumption elevates the level of this peptide. This study aims to assess the effect of repeated treatment with lamotrigine on voluntary alcohol intake and beta-endorphin plasma level in alcohol preferring rats (Warsaw high preferring (WHP) rats). We observed a decrease in alcohol consumption in rats treated with lamotrigine. However we didn't observe significant changes in beta-endorphin level during withdrawal of alcohol, which may indicate that the drug does not affect the opioid system. We suppose that lamotrigine may be useful in alcohol dependence therapy and presents a potential area for further study. PMID- 25449394 TI - Analysis of extinction acquisition to attenuated tones in prenatally stressed and non-stressed offspring following auditory fear conditioning. AB - Stimulus generalization occurs when stimuli with characteristics similar to a previously conditioned stimulus (CS) become able to evoke a previously conditioned response. Experimental data (Lissek et al., 2005) indicate that patients with post-traumatic stress disorder (PTSD), more often show stimulus generalization following fear conditioning when tested under laboratory conditions. Factors surrounding this observation may contribute to two common features of PTSD: 1) hyper-responsiveness to sensory stimuli reminiscent of those associated with the original trauma, and 2) resistance of PTSD to extinction based therapies. Adverse early experience is considered a risk factor for the later development of PTSD and in the present experiments we hypothesized that stimulus generalization would occur in an animal model of adverse early experience, the prenatally stressed (PS) rat. Adult PS and control (CON) rats underwent extensive pre-habituation to a conditioning chamber followed by conventional auditory fear conditioning. The next day both groups began an extinction regimen where a series of quieter (attenuated), CSs were administered prior to the full 75 dB training CS. When tested in this manner, PS rats froze at significantly lower tone amplitudes than did CON offspring on the first day of extinction training. This suggests that the PS rats had stimulus-generalized the CS to lower decibel tones. In addition to this finding, we also observed that PS rats froze more often and longer during three ensuing days of extinction training to attenuated tones. Group differences vanished when PS and CON rats were extinguished under conventional conditions. Thus, it appears that the two extinction regimens differed in their aversive cue saliency for the PS vs. CON rats. Follow-up prefrontal cortex transcriptome probing suggests that cholinergic and dopaminergic alterations may be involved. PMID- 25449393 TI - Ascent to moderate altitude impairs overnight memory improvements. AB - Several studies showed beneficial effects of sleep on memory performance. Slow waves, the electroencephalographic characteristic of deep sleep, reflected on the neuronal level by synchronous slow oscillations, seem crucial for these benefits. Traveling to moderate altitudes decreases deep sleep. In a randomized cross-over design healthy male subjects performed a visuo-motor learning task in Zurich (490 m) and at Davos Jakobshorn (2590 m) in random order. Memory performance was assessed immediately after learning, before sleep, and in the morning after a night of sleep. Sleep EEG recordings were performed during the nights. Our findings show an altitude induced reduction of sleep dependent memory performance. Moreover, this impaired sleep dependent memory performance was associated with reduced slow wave derived measures of neuronal synchronization. Our results are consistent with a critical role of slow waves for the beneficial effects of sleep on memory that is susceptible to natural environmental influences. PMID- 25449392 TI - Naproxen attenuates sensitization of depressive-like behavior and fever during maternal separation. AB - Early life stress can increase susceptibility for later development of depressive illness though a process thought to involve inflammatory mediators. Isolated guinea pig pups exhibit a passive, depressive-like behavioral response and fever that appear mediated by proinflammatory activity, and which sensitize with repeated separations. Treatment with an anti-inflammatory can attenuate the behavioral response during the initial separation and separation the following day. Here we used the cyclooxygenase inhibitor naproxen to examine the role of prostaglandins in mediating the depressive-like behavior and core body temperature of young guinea pigs during an initial separation, separation the next day, and separation 10 days after the first. The passive, depressive-like behavior as well as fever sensitized with repeated separation. Three days of injection with 14 mg/kg of naproxen prior to the initial separation reduced depressive-like behavior during all three separations. A 28 mg/kg dose of naproxen, however, had minimal effect on behavior. Fever during the early separations was moderated by naproxen, but only at the higher dose. These results suggest a role of prostaglandins in the behavioral and febrile response to maternal separation, and particularly in the sensitization of depressive-like behavior following repeated separation. PMID- 25449395 TI - Cholecystokinin regulates satiation independently of the abdominal vagal nerve in a pig model of total subdiaphragmatic vagotomy. AB - The vagal nerve and gut hormones CCK and GLP-1 play important roles in the control of food intake. However, it is not clear to what extent CCK and GLP-1 increase satiation by stimulating receptors located on abdominal vagal nerve endings or via receptors located elsewhere. This study aimed to further explore the relative contribution of the abdominal vagal nerve in mediating the satiating effects of endogenous CCK and GLP-1. Total subdiaphragmatic vagotomy or sham operation was combined with administration of CCK1 and GLP-1 receptor antagonists devazepide and exendin (9-39) in 12 pigs, applying an unbalanced Latin Square within-subject design. Furthermore, effects of vagotomy on preprandial and postprandial acetaminophen absorption, glucose, insulin, GLP-1 and CCK plasma concentrations were investigated. Ad libitum liquid meal intake (mean+/-SEM) was similar in sham and vagotomized pigs (4180+/-435 and 3760+/-810 g/meal). Intake increased by about 20% after blockade of CCK1 receptors, independently of the abdominal vagal nerve. Food intake did not increase after blockade of GLP-1 receptors. Blockade of CCK1 and GLP-1 receptors increased circulating CCK and GLP 1 concentrations in sham pigs only, suggesting the existence of a vagal reflex mechanism in the regulation of plasma CCK1 and GLP-1 concentrations. Vagotomy decreased acetaminophen absorption and changed glucose, insulin, CCK and GLP-1 concentrations indicating a delay in gastric emptying. Our data show that at liquid feeding, satiation is decreased effectively by pharmacological blockade of CCK1 receptors. We conclude that regulation of liquid meal intake appears to be primarily regulated by CCK1 receptors not located on abdominal vagal nerve endings. PMID- 25449396 TI - Disgust in pregnancy and fetus sex--longitudinal study. AB - Disgust, an emotion triggering behavioral avoidance of pathogens, serves as a first line of defense against infections. Since behavior related to disgust involves some cost, the aversive reaction should be adjusted to the level of an individual's immunocompetence, and raise only when immunological function is lower (e.g. during pregnancy). We studied changes in disgust sensitivity in pregnant women, and tested if disgust sensitivity is related to a fetus's sex. 92 women participated in a three-stage research, answering the Disgust Scale-Revised questionnaire at each trimester of pregnancy. The result showed that total disgust and disgust sensitivity in the Core Domain were the highest in the first trimester (when maternal immunosuppression is also the highest), and decreased during pregnancy in women bearing daughters. Women bearing sons had relatively high disgust sensitivity persisting in the first and in the second trimester. The elevation in disgust sensitivity during the second trimester for mothers bearing male fetus can be explained by the necessity to protect for a longer time, a more ecologically sensitive fetus, and also herself when bearing a more energetically costly sex. The proximate mechanism may involve the differences in maternal testosterone and cortisol concentrations in the second trimester of pregnancy. PMID- 25449397 TI - My stress, our stress: blunted cortisol response to stress in isolated housed zebrafish. AB - Here, we show that individually housed zebrafish presented a reduced cortisol response to an acute stressor (persecution with a pen net for 120 s) compared to zebrafish housed in groups of 10. We hypothesized that the cortisol response to stress was reduced in individually housed zebrafish because they depend solely on their own perceptions of the stressor, whereas among grouped zebrafish, the stress response might be augmented by chemical and/or behavioral cues from the other members of the shoal. This hypothesis was based on previous described chemical communication of stress in fish as well on individual variation in stressor perception and potential individual differences in fish personality. PMID- 25449398 TI - Central administration of chicken growth hormone-releasing hormone decreases food intake in chicks. AB - Growth hormone-releasing hormone (GHRH) is well known as a stimulator of growth hormone (GH) secretion. GHRH not only stimulates GH release but also modifies feeding behavior and energy homeostasis in rodents. In chickens (Gallus gallus domesticus), on the other hand, two types of GHRH, namely, chicken GHRH (cGHRH) and cGHRH-like peptide (cGHRH-LP), have been identified. The purpose of the present study was to investigate the effect of central injection of cGHRH and cGHRH-LP on feeding behavior in chicks. Intracerebroventricular (ICV) injection of both cGHRH and cGHRH-LP (0.04 to 1 nmol) significantly decreased food intake without any abnormal behavior in chicks. Furthermore, the feeding-inhibitory effect was not abolished by co-injection of the antagonist for pituitary adenylate cyclase-activating polypeptide (PACAP) or corticotropin-releasing hormone (CRH) receptors, suggesting that the anorexigenic effect of cGHRH and cGHRH-LP might not be related to the PACAP and CRH systems in the brain of chicks. Finally, 24-h food deprivation increased mRNA expression of cGHRH but not cGHRH-LP in the diencephalon. These results suggest that central cGHRH is related to inhibiting feeding behavior and energy homeostasis in chicks. PMID- 25449399 TI - Effects of sugar solutions on hypothalamic appetite regulation. AB - Several hypotheses for the causes of the obesity epidemic in the US have been proposed. One such hypothesis is that dietary intake patterns have significantly shifted to include unprecedented amounts of refined sugar. We set out to determine if different sugars might promote changes in the hypothalamic mechanisms controlling food intake by measuring several hypothalamic peptides subsequent to overnight access to dilute glucose, sucrose, high fructose corn syrup, or fructose solutions. Rats were given access to food, water and a sugar solution for 24h, after which blood and tissues were collected. Fructose access (as opposed to other sugars that were tested) resulted in a doubling of circulating triglycerides. Glucose consumption resulted in upregulation of 7 satiety-related hypothalamic peptides whereas changes in gene expression were mixed for remaining sugars. Also, following multiple verification assays, 6 satiety related peptides were verified as being affected by sugar intake. These data provide evidence that not all sugars are equally effective in affecting the control of intake. PMID- 25449400 TI - Antidepressant-like effect of n-3 PUFAs in CUMS rats: role of tPA/PAI-1 system. AB - BDNF is strongly implicated in the development of depression. Recent evidence has indicated that tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) are related to the cleavage of pro-brain-derived neurotrophic factor (BDNF) into its mature form. Chronic unpredicted mild stress (CUMS) is widely used to induce depressive behaviors in rodents. Therefore, we investigated the effects of PUFAs and sertraline on tPA/PAI-1 system in CUMS rats. After 5 weeks of CUMS procedures, the rats were induced to a depressive-like state. The expressions of PAI-1 and proBDNF were increased in the prefrontal cortex and hippocampus of CUMS rats. N-3 polyunsaturated fatty acids (PUFAs) or sertraline administration reversed the changes in behavioral test and induced the expression of tPA in certain brain areas, but failed to restore the CUMS-induced PAI-1 expression. Meanwhile, the antidepressant treatment also accelerated the extracellular conversion of proBDNF into mature BDNF in CUMS rats. Our results firstly showed the synchronously altered balance of tPA/PAI-1 system in the prefrontal cortex and hippocampus of CUMS rats, which was partly ameliorated by PUFAs and sertraline medication, providing new evidence for the involvement of tPA/PAI-1 system in the progression and treatment of depression. PMID- 25449402 TI - The role of calcitonin gene-related peptide in post-stroke depression in chronic mild stress-treated ischemic rats. AB - Poststroke depression (PSD) is the most common psychological sequel after stroke. Although the neurological mechanisms of PSD remain to be fully elucidated, numerous studies have implicated the calcitonin gene-related peptide (CGRP), a potent vasodilatory neuropeptide, as key modulator of the depression. A PSD rat model, which was established by middle cerebral artery occlusion (MCAO) and following chronic unpredictable mild stress (CUMS) procedures, was used to investigate the role of CGRP in post-stroke mood disturbances. In the present study, depressive-like state such as anhedonia and behavioral despair was found in CUMS-treated ischemic rat, as measured by sucrose preference test, open-field test and forced swimming test. Moreover, CGRP immunoreactivity (CGRP-ir) concentration in CSF and hippocampus were increased in the PSD rats, compared to the MCAO or CUMS subjects. The other separate groups were implanted chronically with unilateral cannulae in the lateral cerebral ventricle. GABA and its receptor antagonist alphaGABA(8-37) were administrated centrally into ischemic and PSD rats, respectively. Administration of CGRP into the ischemic rat increased depression-like behaviors in a dose-dependent manner, whereas icv infusion of alphaCGRP(8-37) produced antidepressant effects in PSD rats, implying that the PSD is mediated, at least partially, by endogenous CGRP receptor activation. Taken together, these results suggest a pivotal role for central CGRP signaling in the modulation of PSD. PMID- 25449401 TI - Cocaine-induced suppression of saccharin intake and morphine modulation of Ca2+ channel currents in sensory neurons of OPRM1 A118G mice. AB - Several studies have shown that human carriers of the single nucleotide polymorphism of the MU-opioid receptor, OPRM1 A118G, exhibit greater drug and alcohol use, increased sensitivity to pain, and reduced sensitivity to the antinociceptive effects of opiates. In the present study, we employed a 'humanized' mouse model containing the wild-type (118AA) or variant (118GG) allele to examine behavior in our model of drug-induced suppression of a natural reward cue and to compare the morphine pharmacological profile in acutely isolated sensory neurons. Compared with 118AA mice, our results demonstrate that homozygous 118GG mice exhibit greater avoidance of the cocaine-paired saccharin cue, a behavior linked to an aversive withdrawal-like state. Electrophysiological recordings confirmed the reduced modulation of Ca(2+) channels by morphine in trigeminal ganglion (TG) neurons from 118GG mice compared to the 118AA control cells. However, repeated cocaine exposure in 118GG mice led to a leftward shift of the morphine concentration-response relationship when compared with 118GG control mice, while a rightward shift was observed in 118AA mice. These results suggest that cocaine exposure of mice carrying the 118G allele leads to a heightened sensitivity of the reward system and a blunted modulation of Ca(2+) channels by morphine in sensory neurons. PMID- 25449403 TI - Preliminary evidence that abscisic acid improves spatial memory in rats. AB - Abscisic acid (ABA) is a crucial phytohormone that exists in a wide range of animals, including humans, and has multiple bioactivities. As direct derivatives of carotenoids, ABA and retinoic acid (RA) share similar molecular structures, and RA has been reported to improve spatial memory in rodents. To explore the potential effects of ABA on spatial learning and memory in rodents, 20mg/kg ABA was administered to young rats for 6weeks, and its effects on behaviour performance were evaluated through a series of behavioural tests. ABA pharmacokinetic analysis revealed that the exogenous ABA was distributed widely in the rat brain, characterised by rapid absorption and slow elimination. The behavioural tests showed that ABA increased both the duration spent in the target quadrant and the frequency it was entered in the probe test of the Morris water maze (MWM) and decreased the latency to locate the target quadrant. Moreover, ABA decreased the latency to enter the novel arm in the Y-maze test, accompanied by increases in the total entries and distance travelled in the three arms. However, there were no significant differences between the ABA-treated and control rats in the open field test and elevated plus-maze test. These results preliminarily indicate that ABA improves spatial memory in MWM and exploratory activity in Y maze in young rats. PMID- 25449404 TI - Interaction of smoking and obesity on type 2 diabetes risk in a Chinese cohort. AB - The aim of this study was to examine the independent and combined effects of current smoking and obesity on risk of type 2 diabetes (T2DM) in a Chinese cohort. We analyzed the data from a population-based prospective cohort of 3598 participants aged 35-74 years from Jiangsu, China. A Cox proportional hazards regression model was used to calculate the hazard ratio (HR) of T2DM and corresponding 95% confidence interval (CI), and to examine the interaction between current smoking and obesity on risk of T2DM. Compared with non-smokers, the hazard ratio of T2DM for current smokers was 4.16 (2.77-6.24). There was a significant interaction between current smoking and abdominal obesity on T2DM. RERI=2.84 (0.02-5.67), suggesting that there would be 2.84 relative excess risk due to the additive interaction; AP=0.48 (0.20-0.76), indicating that 48% of T2DM exposed to both risk factors was attributable to the additive interaction; and SI was 2.36 (1.15-4.87), suggesting that the risk of T2DM in obese smokers was 2.36 times as high as the sum of risks in the participants exposed to a single risk factor alone. We did not find a significant interaction between smoking and overall obesity on T2DM, but the incidence of T2DM in overall obese smokers was also highest. Both current smoking and abdominal obesity are strong risk factors of T2DM in the Chinese population. This study further demonstrates an additive interaction of current smoking and abdominal obesity on T2DM risk. PMID- 25449405 TI - Do I turn left or right? Effects of sex, age, experience and exit route on maze test performance in sheep. AB - Brain development and function are susceptible to perturbation by environmental factors. Sheep are increasingly being used as a neurodevelopmental model due to timing similarities with humans, but effects of age, experience and sex on cognition are not well characterised in this species. We therefore studied memory and reversal learning in sheep using a modified Y-maze at two ages: naive 18 weeks old (18N: 23 male, 17 female), experienced 40 week old sheep that had previously been tested at 18 weeks (40E: 22 male, 17 female), and naive 40 weeks old (40N: 4 male, 10 female). Younger naive animals (18N) required more trials and time to solve the first reversal task (task R1) than 40E (P=0.007 and P<0.001 respectively). Experience also improved outcomes, with 40N sheep requiring more time to solve tasks L (P=0.034) and R1 (P=0.002) than 40E. Increasing age (40N cf. 18N) decreased bleat frequency in tasks R1, M2 and R2 (each P<0.05). In 40N females, outcomes also differed by exit method in task R1, with those that exited via an indirect route taking less time to pass tasks R1 (P=0.009) and R2 (P=0.015) than those that used a direct route. Age plus experience improved learning outcomes, demonstrating knowledge retention for 22 weeks in this species, whilst age alone affected mostly behavioral responses. These results provide comparison data, and can be utilised to improve experimental design, for studies of neurodevelopment in the sheep. PMID- 25449406 TI - Site selective activation of lateral hypothalamic mGluR1 and R5 receptors elicits feeding in rats. AB - Recent findings from our lab indicate that metabotropic glutamate receptor (mGluR) activation elicits eating, and the goal of the current study was to specify whether the lateral hypothalamus (LH) is the actual brain site mediating this effect. To examine this issue we injected the selective mGluR group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) unilaterally into the LH and surrounding regions (n=5-8 subjects/brain site) of satiated adult male Sprague Dawley rats and measured elicited feeding. We determined that 1.0 nmol elicited food intake only within the LH. Increasing the dose to 10 or 25 nmol produced a more sustained effect in the LH, and also elicited eating in several other brain sites. These results, demonstrating that the LH mediates the eating elicited by low doses of DHPG, suggest that the LH may contain mGluR whose activation can produce eating behavior. PMID- 25449407 TI - TRPA1, NMDA receptors and nitric oxide mediate mechanical hyperalgesia induced by local injection of magnesium sulfate into the rat hind paw. AB - Previous studies have shown that while magnesium, an antagonist of the glutamate subtype of N-methyl-D-aspartate receptors, possesses analgesic properties, it can induce writhing in rodents. The aim of this study was to determine the effect and mechanism of action of local (intraplantar) administration of magnesium sulfate (MS) on the paw withdrawal threshold (PWT) to mechanical stimuli. The PWT was evaluated by the electronic von Frey test in male Wistar rats. Tested drugs were either co-administered intraplantarly (i.pl.) with MS or given into the contralateral paw to exclude systemic effects. MS at doses of 0.5, 1.5, 3 and 6.2 mg/paw (i.pl.) induced a statistically significant (as compared to 0.9% NaCl) and dose-dependent mechanical hyperalgesia. Only isotonic MS (250 mmol/l or 6.2% or 6.2 mg/paw) induced mechanical hyperalgesia that lasted at least six hours. Isotonic MS-induced mechanical hyperalgesia was reduced in a dose-dependent manner by co-injection of camphor, a non-selective TRPA1 antagonist (0.3, 1 and 2.5 MUg/paw), MK-801, a NMDA receptor antagonist (0.001, 0.025 and 0.1 MUg/paw), L-NAME, a non-selective nitric oxide (NO) synthase inhibitor (20, 50 and 100 MUg/paw), ARL 17477, a selective neuronal NOS inhibitor (5.7 and 17 MUg/paw), SMT, a selective inducible NOS inhibitor (1 and 2.78 MUg/paw), and methylene blue, a guanylate cyclase inhibitor (5, 20 and 125 MUg/paw). Drugs injected into the contralateral hind paw did not produce significant effects. These results suggest that an i.pl. injection of MS produces local peripheral mechanical hyperalgesia via activation of peripheral TRPA1 and NMDA receptors and peripheral production of NO. PMID- 25449408 TI - Influence of music on performance and psychophysiological responses during moderate-intensity exercise preceded by fatigue. AB - PURPOSE: We examined the effects of listening to music on time to exhaustion and psychophysiological responses during moderate-intensity exercise performed in fatigued and non-fatigued conditions. METHODS: Fourteen healthy men performed moderate-intensity exercise (60% Wmax) until exhaustion under four different conditions: with and without pre-fatigue (induced by 100 drop jumps) and listening and not listening to music. RESULTS: Time to exhaustion was lower in the fatigued than the non-fatigued condition regardless listening to music. Similarly, RPE was higher in the fatigued than the non-fatigued condition, but music had no effect. On the other hand, listening to music decreased the associative thoughts regardless of fatigue status. Heart rate was not influenced by any treatment. CONCLUSION: These results suggest that listening to music changes attentional focus but is not able to reverse fatigue-derived alteration of performance. PMID- 25449409 TI - Heart rate and heart rate variability in multiparous dairy cows with unassisted calvings in the periparturient period. AB - Behavioural changes before calving can be monitored on farms; however, predicting the onset of calving is sometimes difficult based only on clinical signs. Heart rate (HR) and heart rate variability (HRV) as non-invasive measures of autonomic nervous system (ANS) activity were investigated in Holstein-Friesian cows (N=20) with unassisted calvings in the periparturient period to predict the onset of calving and assess the stress associated with calving. R-R-intervals were analysed in 5-min time windows during the following three main periods of measurement: 1) between 0 and 96 h before the onset of calving restlessness (prepartum period); 2) during four stages of calving: (I) early first stage; between the onset of calving restlessness and the first abdominal contractions; (II) late first stage (between the first abdominal contractions and the appearance of the amniotic sac); (III) early second stage (between the appearance of the amniotic sac and the appearance of the foetal hooves); (IV) late second stage (between the appearance of the foetal hooves and delivery of the calf), and 3) over 48 h following calving (postpartum period). Data collected between 72 and 96 h before calving restlessness was used as baseline. Besides HR, Poincare measures [standard deviation 1 (SD1) and 2 (SD2) and SD2/SD1 ratio], the root mean square of successive differences (RMSSD) in R-R intervals, the high frequency (HF) component of HRV and the ratio between the low-frequency (LF) and the HF components (LF/HF ratio) were calculated. Heart rate increased only following the onset of the behavioural signs, peaked before delivery of the calf, then decreased immediately after calving. Parasympathetic indices of HRV (RMSSD, HFnorm and SD1) decreased, whereas sympathovagal indices (LF/HF ratio and SD2/SD1 ratio) increased significantly from baseline between 12 and 24 before the onset of calving restlessness. The same pattern was observed between 0 and 1h before calving restlessness. Following the onset of behavioural signs, parasympathetic activity increased gradually with a parallel shift in sympathovagal balance towards parasympathetic tone, which was possibly a consequence of oxytocin release, which induces an increase in vagus nerve activity. Parasympathetic activity decreased rapidly between 0 and 0.5h following calving and was lower than measured during all other stages of the study, while sympathetic activity peaked during this stage and was higher than measured during any other stages. Between 0 and 4h after calving vagal tone was lower than baseline, whereas sympathovagal balance was higher, reflecting a prolonged physiological challenge caused by calving. Vagal activity decreased, whereas sympathovagal balance shifted towards sympathetic tone with increased live body weight of the calf during the late second stage of calving, suggesting higher levels of stress associated with the higher body weight of calves. All HRV indices, measured either at the late second stage of calving and between 12 and 24h after calving, were affected by the duration of calving. Our results indicate that ANS activity measured by HRV indices is a more immediate indicator of the onset of calving than behaviour or HR, as it changed earlier than when restlessness or elevation in HR could be observed. However, because of the possible effects of other physiological mechanisms (e.g. oxytocin release) on ANS activity it seems to be difficult to measure stress associated with calving by means of HRV between the onset of calving restlessness and delivery. Further research is needed to enable more precise interpretation of the prepartum changes in HR and HRV in dairy cattle. PMID- 25449410 TI - Large portion sizes increase bite size and eating rate in overweight women. AB - OBJECTIVE: Larger food portions lead to increased intake but the mechanism behind this effect is unclear. We investigated the effect of portion size on bite size, eating rate, deceleration rate, and meal duration. DESIGN AND METHODS: Thirty seven overweight women attended 5 visits after a 3 h fast and consumed a 229, 303, 400, 529 or 700 g portion of a lunch meal in random order. Meal eating parameters were measured with the Sussex Ingestion Pattern Monitor. Data were analyzed with mixed effects models. RESULTS: Average bite size increased by 0.22 g for every 100 g increase in portion size (p=0.001); portion size had a non linear effect on eating rate, increasing with portion sizes up to about 540 g (p=0.01). Deceleration rate (reduction in speed of eating) decreased by 20% (p<0.001) and meal duration increased by 22.5% for every 100 g increase in portion size (p<0.001), relative to the smallest portion. CONCLUSIONS: Increasing portion size led to a larger bite size and faster eating rate, but a slower reduction in eating speed during the meal. These changes may underlie greater energy intakes with exposure to large portions. Interventions to reduce bite size and slow eating rate may provide individuals with strategies to reduce the risk of overconsumption. PMID- 25449412 TI - Arginine vasotocin reduces levels of cooperative behaviour in a cleaner fish. AB - Cooperation between unrelated individuals usually involves investments that often mean a decrease in immediate payoffs, but ensure future benefits. Here we investigated the potential role of the neuropeptides Arginine-vasotocin (AVT) and Isotocin (IT) as proximate agents affecting individuals' cooperative levels in the Indo-pacific bluestreak cleaner wrasse Labroides dimidiatus. Their 'client' reef fish partners only benefit from interacting if cleaners eat ectoparasites and refrain from gleaning preferred client mucus. Thus, cleaners must control their impulse to eat according to their preference, and eat less preferred items to maintain ongoing interactions and avoid clients' leaving or punishing. We found that solely the experimental transient higher dosage of AVT led to a decrease of cleaners' willingness to feed against their preference, while IT and AVT antagonists had no significant effects. The sole effect of AVT on cleaner's performance may imply a link between AVT's influence and a potential activation of a stress response. Our results confirm the importance of the AVT/AVP system as an agent affecting levels of cooperation, offering a potential mechanistic pathway for the reported flexible service quality that cleaners provide their clients. PMID- 25449411 TI - Physically active rats lose more weight during calorie restriction. AB - Daily physical activity shows substantial inter-individual variation, and low physical activity is associated with obesity and weight gain. Elevated physical activity is also associated with high intrinsic aerobic capacity, which confers considerable metabolic health benefits. Rats artificially selected for high intrinsic aerobic capacity (high-capacity runners, HCR) are more physically active than their low-capacity counterparts (low-capacity runners, LCR). To test the hypothesis that physical activity counters metabolic thriftiness, we measured physical activity and weight loss during three weeks of 50% calorie restriction (CR) in the HCR and LCR rat lines. At baseline, HCR ate more and were more active than LCR; this was seen in male rats, where LCR are considerably heavier than HCR, as well as in a set of female rats where body weight did not differ between the lines, demonstrating that this effect is consistent across sex and not secondary to body weight. We show for the first time that HCR lose more weight than LCR relative to baseline. Physical activity levels declined throughout CR, and this was more pronounced in HCR than in LCR, yet some aspects of activity remained elevated in HCR relative to LCR even during CR. This is consistent with the idea that low physical activity contributes to metabolic thriftiness during food restriction, allowing LCR to defend body mass, particularly lean mass. This has implications for physical activity during diet-induced weight loss, the genetic underpinnings of individual differences in weight loss during a diet, and the potential evolutionary opposition between metabolic thriftiness and aerobic capacity. PMID- 25449413 TI - The oxytocin receptor impairs ethanol reward in mice. AB - It is well established that oxytocin, and its receptor (OxtR), play a crucial role in addiction and that the stimulation of oxytocin neurotransmission reduces addictive behaviors to ethanol in laboratory animals. However, the impact of OxtR modulation on acquisition, extinction and reinstatement of drug-elicited ethanol conditioned place preference (EtOH-CPP) has not yet been investigated. In this study, we evaluated the effects of OxtR pharmacological modulation, using the oxytocin analog Carbetocin, and genetic overexpression in the nucleus accumbens (NAcc), using lentiviral-mediated gene transfer technology, of the OxtR on acquisition, extinction and reinstatement of drug-elicited EtOH-CPP in mice. In the first experiment, results showed that Carbetocin administration and NAcc OxtR overexpression (LV-OxtR) reduced EtOH-CPP establishment. In the second experiment, systemic Carbetocin treatment and OxtR overexpression resulted in decreased time spent in the ethanol-paired compartment following completion of a 7-day extinction protocol. Finally, the third experiment showed that Carbetocin and LV-OxtR suppressed primed reinstatement of EtOH-CPP. It is concluded that pharmacological and genetic modulation of the OxtR can modulate the acquisition, extinction, and reinstatement of conditioned reinforcing effects of ethanol. Taken together, the current findings add to the growing literature on oxytocin neurotransmission modulation in the pharmacotherapy of ethanol addiction and alcoholism. PMID- 25449414 TI - Feeding behavior and digestive physiology in sea cucumber Apostichopus japonicus. AB - The feeding behavior and digestive physiology of the sea cucumber, Apostichopus japonicus are not well understood. A better understanding may provide useful information for the development of the aquaculture of this species. In this article the tentacle locomotion, feeding rhythms, ingestion rate (IR), feces production rate (FPR) and digestive enzyme activities were studied in three size groups (small, medium and large) of sea cucumber under a 12h light/12h dark cycle. Frame-by-frame video analysis revealed that all size groups had similar feeding strategies using a grasping motion to pick up sediment particles. The tentacle insertion rates of the large size group were significantly faster than those of the small and medium-sized groups (P<0.05). Feeding activities investigated by charge coupled device cameras with infrared systems indicated that all size groups of sea cucumber were nocturnal and their feeding peaks occurred at 02:00-04:00. The medium and large-sized groups also had a second feeding peak during the day. Both IR and FPR in all groups were significantly higher at night than those during the daytime (P<0.05). Additionally, the peak activities of digestive enzymes were 2-4h earlier than the peak of feeding. Taken together, these results demonstrated that the light/dark cycle was a powerful environment factor that influenced biological rhythms of A. japonicus, which had the ability to optimize the digestive processes for a forthcoming ingestion. PMID- 25449416 TI - How genomic studies have improved our understanding of the mechanisms of transcriptional regulation by NR5A nuclear receptors. AB - SF-1 and LRH-1 are transcription factors that belong to the NR5A family of nuclear receptors that both have an essential role during development. Recent studies at the genome-wide scale have enabled the characterization of the cistrome and transcriptome regulated by SF-1 and LRH-1 in different cell lines and tissues. Those studies have allowed us to make a significant leap forward in our understanding of the mechanisms of transcriptional regulation of NR5A nuclear receptors in stem cells and cancer. PMID- 25449415 TI - Emergency healthcare worker sleep, fatigue, and alertness behavior survey (SFAB): development and content validation of a survey tool. AB - BACKGROUND: Workplace safety is a recognized concern in emergency medical services (EMS). Ambulance crashes are common and injury rates exceed that of the general working public. Fatigue and sleepiness during shift work pose a safety risk for patients and EMS workers. Changing EMS worker behaviors and improving alertness during shift work is hampered by a lack of instruments that reliably and accurately measure multidimensional beliefs and habits that predict alertness behavior. OBJECTIVES: We sought to test the reliability and validity of a survey tool (the sleep, fatigue, and alertness behavior survey [SFAB]) designed to identify the cognitions of EMS workers concerning sleep, fatigue, and alertness behaviors during shift work. METHODS: We operationalized the integrative model of behavioral prediction (IMBP) and developed a pool of 97 candidate items and sub items to measure eight domains of the IMBP. Five sleep scientists judged the content validity of each item and a convenience sample of EMS workers completed a paper-based version of the SFAB. We retained items judged content valid by five sleep scientists and performed exploratory factor analysis (EFA), confirmatory factor analysis (CFA), and tests of reliability and internal consistency. We identified a simple factor structure for each scale and calculated means and standard deviations for each item and scale. RESULTS: We received 360 completed SFAB surveys from a convenience sample of 800 EMS workers attending two regional continuing education conferences (45% participation rate). Forty-seven candidate items and sub-items/options were removed following content validation, EFA, and CFA testing. Analyses revealed a simple factor structure for seven of eight domains and a final pool of 50 items and sub-items/options. Domains include: attitudes, normative beliefs, knowledge, salience, habits, environmental constraints, and intent. EFA tests of self-efficacy items failed to identify a simple factor structure. We retained two self-efficacy items based on Spearman Brown correlation of 0.23 (p<0.0001). CONCLUSIONS: Measurement of sleep, fatigue, and alertness behavior among EMS workers is challenging. We describe the development and psychometric testing of a survey tool that may be useful in a variety of applications addressing sleep, fatigue, and alertness behavior among EMS workers. PMID- 25449417 TI - Botanical compounds and their regulation of nuclear receptor action: the case of traditional Chinese medicine. AB - Nuclear receptors (NRs) are major pharmacological targets that allow an access to the mechanisms controlling gene regulation. As such, some NRs were identified as biological targets of active compounds contained in herbal remedies found in traditional medicines. We aim here to review this expanding literature by focusing on the informative articles regarding the mechanisms of action of traditional Chinese medicines (TCMs). We exemplified well-characterized TCM action mediated by NR such as steroid receptors (ER, GR, AR), metabolic receptors (PPAR, LXR, FXR, PXR, CAR) and RXR. We also provided, when possible, examples from other traditional medicines. From these, we draw a parallel between TCMs and phytoestrogens or endocrine disrupting chemicals also acting via NR. We define common principle of action and highlight the potential and limits of those compounds. TCMs, by finely tuning physiological reactions in positive and negative manners, could act, in a subtle but efficient way, on NR sensors and their transcriptional network. PMID- 25449418 TI - Effects of perfluorooctane sulfuric acid on placental PRL-family hormone production and fetal growth retardation in mice. AB - Perfluorooctane sulfuric acid (PFOS) is a persistent organic pollutant, causes fetal growth retardation but the mechanism is still unclear. This study focused on PFOS-induced toxicity such as placental trophoblast cell histopathological changes, endocrine function (i.e., prolactin (PRL)-family hormone production) and subsequent fetal growth retardation in mice. Maternal body weight gain, placental and fetal weights were significantly decreased in proportion to PFOS dosage. Placental efficiency (fetal weight/placental weight) was significantly reduced dose-dependently. Necrotic changes were observed in PFOS-treated placental tissues, and the area of injury increased dose-dependently. Finally, mRNA levels and maternal serum concentrations of the PRL-family hormones (mPL-II, mPLP Calpha, mPLP-K) were significantly reduced dose-dependently. In addition, the changing pattern between PRL-family hormone concentrations and fetal body weight was positively correlated. These results suggest that gestational PFOS treatment induces placental histopathological changes and disruption of endocrine function, finally may lead to fetal growth retardation in mice. PMID- 25449419 TI - 4-hydroxy estrogen induces DNA damage on codon 130/131 of PTEN in endometrial carcinoma cells. AB - Catechol estrogens, such as 4-hydroxyestradiol (4-OHE2), are estrogen metabolites that form DNA adducts and may induce mutations and subsequent cell transformation in mammary cells; however, little is known about their roles in endometrial carcinogenesis. Furthermore, it remains unclear whether 4-OHE2 is able to induce DNA damage on specific genes involved in carcinogenesis or a 'pro'-mutation status such as microsatellite instability (MSI). Therefore, we modified terminal transferase-dependent PCR by the application of a capillary sequencer to detect DNA damage at the single base level. Using this method, we demonstrated that 4 OHE2 directly induced DNA damage on codon 130/131 in exon 5 of PTEN, which is a mutation hot spot for PTEN in endometrial carcinoma. Whereas, both estradiol and 4-OHE2 treatment did not affect MSI status in immortalized endometrial glandular cells. 4-OHE2 might contribute to endometrial carcinogenesis by inducing PTEN mutation on codon 130/131. PMID- 25449420 TI - Antagonism of gastric inhibitory polypeptide (GIP) by palmitoylation of GIP analogues with N- and C-terminal modifications improves obesity and metabolic control in high fat fed mice. AB - Compromise of gastric inhibitory polypeptide (GIP) receptor signalling represents a possible therapeutic strategy for the treatment of obesity-related diabetes. This study has characterised and evaluated the C-terminally fatty acid derivatised GIP analogues, GIP(3-30)Cex-K(40)[Pal] and Pro(3)GIP(3-30)Cex K(40)[Pal], as potential GIP inhibitors. Both GIP analogues lack the two N terminal amino acids cleaved by DPP-4 and have addition of nine amino acids from the C-terminal of exendin(1-39), Cex. GIP(3-30)Cex-K(40)[Pal] and Pro(3)GIP(3 30)Cex-K(40)[Pal] effectively (p < 0.01 to p < 0.001) inhibited GIP-induced cAMP production and insulin secretion in vitro. In normal mice, GIP(3-30)Cex K(40)[Pal] and Pro(3)GIP(3-30)Cex-K(40)[Pal] displayed a significant (p < 0.05 to p < 0.001) and prolonged inhibitory effect on GIP-induced glucose-lowering and insulin-releasing actions. When injected once daily for 21 days in obese-diabetic high fat fed mice, both GIP(3-30)Cex-K(40)[Pal] and Pro(3)GIP(3-30)Cex-K(40)[Pal] significantly reduced body weight (p < 0.01 to p < 0.001) and lowered circulating glucose (p < 0.001) and insulin (p < 0.01 to p < 0.001) concentrations. The observed beneficial changes were independent of effects on energy intake, locomotor activity or metabolic rate. Oral and intraperitoneal glucose tolerance were significantly (p < 0.05 to p < 0.001) improved in both treatment groups at the end of the study, despite reduced glucose-induced plasma insulin concentrations. This improvement of metabolic control was accompanied by enhanced (p < 0.05 to p < 0.01) insulin sensitivity compared with high fat controls. These data demonstrate the potential offered by GIP(3-30)Cex-K(40)[Pal] and Pro(3)GIP(3 30)Cex-K(40)[Pal] for the treatment of obesity-related diabetes. PMID- 25449421 TI - Involvement of insulin-like growth factor binding protein-3 in peroxisome proliferator-activated receptor gamma-mediated inhibition of breast cancer cell growth. AB - We have previously reported that insulin-like growth factor binding protein-3 (IGFBP-3), a protein with dichotomous effects on both cell proliferation and cell survival, interacts with peroxisome proliferator-activated receptor gamma (PPARgamma) and inhibits adipogenic PPARgamma signaling. We now show that IGFBP-3 and PPARgamma interact in breast cancer cells, through amino- and carboxyl terminal residues of IGFBP-3. IGFBP-3 and the PPARgamma ligands, rosiglitazone or 15-deoxy-Delta(12,14)-prostaglandin J2, separately inhibited the proliferation of MCF-7, MDA-MB-231 and MDA-MB-468 breast cancer cells. However, growth inhibition by IGFBP-3 and PPARgamma ligand combined was greater than by either alone. Two IGFBP-3 mutants with reduced PPARgamma binding caused no growth inhibition when used alone and abolished the inhibitory effect of rosiglitazone when used in combination with PPARgamma ligand. Cell growth inhibition by PPARgamma ligands was substantially blocked by IGFBP-3 siRNA and restored by exogenous IGFBP-3. We conclude that the interaction between IGFBP-3 and PPARgamma is important for the growth-inhibitory effect of PPARgamma ligands in human breast cancer cells, suggesting that IGFBP-3 expression by breast tumors may regulate their sensitivity toward PPARgamma ligands. PMID- 25449422 TI - Identification of transmembrane domains that regulate spatial arrangements and activity of prokineticin receptor 2 dimers. AB - The chemokine prokineticin 2 (PK2) activates its cognate G protein-coupled receptor (GPCR) PKR2 to elicit various downstream signaling pathways involved in diverse biological processes. Many GPCRs undergo dimerization that can modulate a number of functions including membrane delivery and signal transduction. The aim of this study was to elucidate the interface of PKR2 protomers within dimers by analyzing the ability of PKR2 transmembrane (TM) deletion mutants to associate with wild type (WT) PKR2 in yeast using co-immunoprecipitation and mammalian cells using bioluminescence resonance energy transfer. Deletion of TMs 5-7 resulted in a lack of detectable association with WT PKR2, but could associate with a truncated mutant lacking TMs 6-7 (TM1-5). Interestingly, TM1-5 modulated the distance, or organization, between protomers and positively regulated Galphas signaling and surface expression of WT PKR2. We propose that PKR2 protomers form type II dimers involving TMs 4 and 5, with a role for TM5 in modulation of PKR2 function. PMID- 25449423 TI - New vobasinyl-ibogan type bisindole alkaloids from Tabernaemontana corymbosa. AB - Ten vobasinyl-ibogan type bisindole alkaloids, including three new ones, tabercorines A-C (1-3), and a new natural product, 17-acetyl-tabernaecorymbosine A (4), were isolated from the twigs and leaves of Tabernaemontana corymbosa. Their structures were elucidated on the basis of spectroscopic data, and the NMR data of 17-acetyl-tabernaecorymbosine A (4) was assigned and reported for the first time. The absolute configurations of 1-4 were determined by CD exciton chirality method. All new compounds were evaluated for in vitro cytotoxicity against various human cancer cell lines. Compounds 1 and 4 showed significant inhibitory effects with IC50 values comparable to those of cisplatin. PMID- 25449424 TI - Cytotoxic rotenoid glycosides from the seeds of Amorpha fruticosa. AB - Four new rotenoid glycosides, namely amorphaside A-D (1-4), along with four known ones (5-8) were isolated from the seeds of Amorpha fruticosa. Their chemical structures and absolute configurations were elucidated by HRESIMS, NMR and CD spectra, as well as deduction from biosynthesis route. The sugar units were determined by acid hydrolysis, appropriate derivatization and HPLC analysis. The in vitro anti-proliferative activities of all compounds were evaluated against MCF-7 and HCT-116 cell lines. The results showed that compounds 1-3 had no effect on cell proliferation in the two cell lines even with the concentration of 50 MUM, and compounds 4, 7 and 8 had selective cytotoxicity against MCF-7 with IC50 values of 3.90, 0.95 and 34.08 MUM, respectively, while compounds 5 and 6 both showed significant cytotoxicity to the two cell lines with IC50 values less than 2.00 MUM, even better than the positive control cisplatin. These preliminary results indicated that compounds 5 and 6 might be valuable to anticancer drug candidates. PMID- 25449425 TI - A review of biotransformation and pharmacology of ginsenoside compound K. AB - As an intestinal bacterial metabolite of ginseng protopanaxadiol saponins, ginsenoside compound K (20-O-beta-d-glucopyranosyl-20(S)-protopanaxadiol, CK) is a major deglycosylated metabolite form of ginsenosides which is absorbed into the systemic circulation. And it has demonstrated such diverse intriguing biological properties as anticarcinogenic, anti-inflammation, antiallergic, anti-diabetic, anti-angiogenesis, anti-aging, neuroprotective and hepatoprotective effects. The present review shall summarize recent studies on various biotransformation and pharmacological activities of CK. PMID- 25449426 TI - Natural phosphodiesterase-4 inhibitors from the leaf skin of Aloe barbadensis Miller. AB - The ethanolic extract of Aloe barbadensis Miller leaf skin showed inhibitory activity against phosphodiesterase-4D (PDE4D), which is a therapeutic target of inflammatory disease. Subsequent bioassay-guided fractionation led to the isolation of two new anthrones, 6'-O-acetyl-aloin B (9) and 6'-O-acetyl-aloin A (11), one new chromone, aloeresin K (8), together with thirteen known compounds. Their chemical structures were elucidated by spectroscopic methods including UV, IR, 1D and 2D NMR, and HRMS. All of the isolates were screened for their inhibitory activity against PDE4D using tritium-labeled adenosine 3',5'-cyclic monophosphate ((3)H-cAMP) as substrate. Compounds 13 and 14 were identified as PDE4D inhibitors, with their IC50 values of 9.25 and 4.42 MUM, respectively. These achievements can provide evidences for the use of A. barbadensis leaf skin as functional feed additives for anti-inflammatory purpose. PMID- 25449427 TI - The protein kinase C agonist prostratin induces differentiation of human myeloid leukemia cells and enhances cellular differentiation by chemotherapeutic agents. AB - As acute myeloid leukemia (AML) cells are characterized by uncontrolled self renewal and impaired cellular differentiation, induction of terminal differentiation of leukemia cells by differentiating agents has been proposed as an attractive therapeutic strategy to treat AML. Here, we demonstrated that prostratin, a potent protein kinase C (PKC) activator, inhibited the growth of myeloid leukemia cells by a predominant G1 arrest with variable induction of apoptosis. Conversely, prostratin induced significant differentiation of AML cell lines and primary AML blasts as evidenced by morphology and immunophenotyping. The effects of prostratin were PKC dependent, and activation of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2 by PKC was required for prostratin-induced cell differentiation. Consequently, prostratin reprogrammed transcriptional factor expression, and ectopic expression of c-Myc in HL-60 cells significantly eliminated prostratin-mediated cellular differentiation and cell cycle arrest, indicating an essential role for c-Myc suppression in the differentiation-inducing effects of prostratin. Finally, prostratin was able to potentiate cellular differentiation induced by chemotherapeutic agents such as Ara-C. Together, we proposed that prostratin alone or administered with other anticancer agents may be effective in differentiation therapy of AML. PMID- 25449428 TI - A loss of antitumor therapeutic activity of CEA DNA vaccines is associated with the lack of tumor cells' antigen presentation to Ag-specific CTLs in a colon cancer model. AB - Human colon cancers express carcinoembryonic antigen (CEA). Thus, CEA has been considered as a potential vaccine target for immune therapy against colon cancer. In this study, CEA DNA vaccines plus anti-4-1BB Abs treatment was found to increase Ag-specific CTL activity and antitumor protective responses to MC32 cells. However, CEA DNA vaccines alone displayed few antitumor therapeutic effects while significantly inducing Ag-specific CTL responses. Anti-4-1BB Abs alone displayed antitumor therapeutic effects. Intratumoral electroporation with IL-12 cDNA also showed antitumor therapeutic activity against MC32 cells in a CD8+ T cell-dependent and CEA-non-specific manner, suggesting that established MC32 cells are still susceptible to CTL-mediated killing. Finally, our in vitro assays (Western blot assay, IFN-gamma, CTL and apoptosis assays, FACS analysis) and animal studies demonstrated that a lack of antitumor therapeutic activity of CEA DNA vaccines might result from acquisition of tumor cell resistance to Ag specific CTL-mediated killing through the loss of tumor cells' antigen presentation to Ag-specific CTLs. Taken together, these data show that MC32 cells may resist CEA DNA vaccination by their loss of antigen presentation to CEA specific CTLs in the therapeutic model. PMID- 25449429 TI - The role of exosomes and "exosomal shuttle microRNA" in tumorigenesis and drug resistance. AB - How are intracellular proteins and nucleic acids transported to the appropriate sites, and how do they function at the proper time? This problem has plagued scientists for a long time. The roles of vesicles, and nanovesicles called exosomes, as carriers were revealed in 2013. Many types of cells can release exosomes, particularly tumor cells. Tumor-derived (TD) exosomes are rich in proteins and nucleic acids derived from parental cells. With the activity of signal transmission, these exosomes can guide communication between cells and induce cancer-related disorders in many signaling pathways. TD-exosomes can be a source of tumor antigen to induce an anti-tumor immune response but can also suppress the immune system. TD-exosomes are especially rich in microRNAs (miRNAs), which are in various pathological and physiological states. Therefore, exosomal miRNA can serve as a new diagnostic marker for cancers. Moreover, miRNAs in exosomes can shuttle between cells to communicate and exchange genetic material. Thus, TD-exosomes can be used as targeted therapies. Cell-type specificity, stability and accessibility from body fluids make exosomes valuable candidates for tumor diagnosis and targeted treatment. PMID- 25449430 TI - The toxicity of anti-VEGF agents when coupled with standard chemotherapeutics. AB - Bevacizumab (Avastin(r), Genentech, CA) was granted accelerated approval by the FDA for metastatic breast cancer in 2008. This occurred after the initial clinical trial, E2100, demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) with the addition of bevacizumab to a standard chemotherapy. Unfortunately, the approval was rescinded in 2011 when two subsequent trials, AVADO and RIBBON-1, failed to show survival benefit. We compare and analyze the landmark trials E2100, AVADO and RIBBON-1, and suggest that the present-day clinical trial model may not be suited for the investigation of targeted therapies such as bevacizumab. The existing clinical trial model does not allow for modification of chemotherapeutic doses in a manner that maximizes the effect of biologic response modifiers and does not account for its "chemosensitizing" effect. The E2100, AVADO, and RIBBON-1 trials differed in the type and dose of chemotherapy, the dose and frequency of bevacizumab, and in the trial design, making it difficult to effectively compare and evaluate the results. The efficacy of combining bevacizumab with a maximum tolerated dose (MTD) of chemotherapy is also discussed in view of the observation that increased tumor response did not translate to an increase in survival. We suggest that even though angiogenesis inhibitors are non-toxic as monotherapies, they increase the toxicity of standard chemotherapy, and consequently a re-design of the now classic clinical trial model should be considered. Modifying the existing clinical trial model will lead to a more accurate evaluation of the safety and efficacy of bevacizumab and other biological agents in treating metastatic cancer. PMID- 25449431 TI - MiR-22 regulates 5-FU sensitivity by inhibiting autophagy and promoting apoptosis in colorectal cancer cells. AB - Autophagy has become one of the most important mechanisms of chemotherapy resistance by supporting the survival of tumor cells under metabolic and therapeutic stress. Here, we showed that miR-22 inhibited autophagy and promoted apoptosis to increase the sensitivity of colorectal cancer (CRC) cells to 5 fluorouracil (5-FU) treatment both in vitro and in vivo. B-cell translocation gene 1 (BTG1) was identified as a new target of miR-22, which could reverse the inhibition of autophagy induced by miR-22. Thus, miR-22 may function as an important switch between autophagy and apoptosis to regulate 5-FU sensitivity through post-transcriptional silencing of BTG1. Promisingly, miR-22 could be considered as both a predictor of 5-FU sensitivity for personalized treatment and a therapeutic target for colorectal cancer. PMID- 25449432 TI - Proton pump inhibitor pantoprazole abrogates adriamycin-resistant gastric cancer cell invasiveness via suppression of Akt/GSK-beta/beta-catenin signaling and epithelial-mesenchymal transition. AB - The effect of proton pump inhibitor (PPI) on cancer risk has received much attention recently. In this study, we investigated the mechanism underlying multidrug resistance and the effect of a PPI pantoprazole using an adriamycin resistant gastric cancer cell model (SGC7901/ADR). Compared with the parental cell line, SGC7901/ADR cells showed reduced proliferation rate, but higher resistance to adriamycin under both anchorage-dependent and -independent conditions. Notably, SGC7901/ADR cells underwent epithelial to mesenchymal transition (EMT) and showed increased migrating and invading capabilities. At molecular level, SGC7901/ADR cells showed strong activation of Wnt/beta-catenin signaling pathway compared with parental sensitive cells. Interestingly, we found that a PPI pantoprazole can effectively reverse the aggressiveness and EMT marker expression of SGC7901/ADR cells. Furthermore, pantoprazole treatment resulted in a profound reduction of both total and phosphorylated forms of Akt and GSK-3beta, which in turn suppressed the adriamycin-induced Wnt/beta-catenin signaling in SGC7901/ADR cells. Taken together, we demonstrate that the aggressive phenotype of adriamycin-resistant SGC7901/ADR cells is mediated by induction of EMT and activation of the canonical Wnt/beta-catenin signaling pathway. And for the first time, we show that it is possible to suppress the invasiveness of SGC7901/ADR cells by pantoprazole which targets the EMT and Akt/GSK-3beta/beta-catenin signaling. PMID- 25449433 TI - Protein kinase CK2 inhibition is associated with the destabilization of HIF 1alpha in human cancer cells. AB - Screening for protein kinase CK2 inhibitors of the structural diversity compound library (DTP NCI/NIH) led to the discovery of 4-[(E)-(fluoren-9 ylidenehydrazinylidene)-methyl]benzoic acid (E9). E9 induces apoptotic cell death in various cancer cell lines and upon hypoxia, the compound suppresses CK2 catalyzed HSP90/Cdc37 phosphorylation and induces HIF-1alpha degradation. Furthermore, E9 exerts a strong anti-tumour activity by inducing necrosis in murine xenograft models underlining its potential to be used for cancer treatment in future clinical studies. Crystal structure analysis of human and maize CK2alpha in complex with E9 reveals unique binding properties of the inhibitor to the enzyme, accounting for its affinity and selectivity. PMID- 25449434 TI - Collagen type V promotes the malignant phenotype of pancreatic ductal adenocarcinoma. AB - Excessive matrix production by pancreatic stellate cells promotes local growth and metastasis of pancreatic ductal adenocarcinoma and provides a barrier for drug delivery. Collagen type V is a fibrillar, regulatory collagen up-regulated in the stroma of different malignant tumors. Here we show that collagen type V is expressed by pancreatic stellate cells in the stroma of pancreatic ductal adenocarcinoma and affects the malignant phenotype of various pancreatic cancer cell lines by promoting adhesion, migration and viability, also after treatment with chemotherapeutic drugs. Pharmacological and antibody-mediated inhibition of beta1-integrin signaling abolishes collagen type V-induced effects on pancreatic cancer cells. Ablation of collagen type V secretion of pancreatic stellate cells by siRNA reduces invasion and proliferation of pancreatic cancer cells and tube formation of endothelial cells. Moreover, stable knock-down of collagen type V in pancreatic stellate cells reduces metastasis formation and angiogenesis in an orthotopic mouse model of ductal adenocarcinoma. In conclusion, paracrine loops involving cancer and stromal elements and mediated by collagen type V promote the malignant phenotype of pancreatic ductal adenocarcinoma and underline the relevance of epithelial-stromal interactions in the progression of this aggressive neoplasm. PMID- 25449435 TI - Hepatic stellate cells activated by acidic tumor microenvironment promote the metastasis of hepatocellular carcinoma via osteopontin. AB - Extracellular pH of solid tumor is generally acidic due to excessive glycolysis and poor perfusion. But whether acidic tumor microenvironment influenced the stromal cells infiltrating in tumor remains unknown. As the predominant progenitor of stromal cells in liver, the number of activated hepatic stellate cells (HSCs) was found positively correlated to the acidification level in the tumor tissues of HCC patients in our study. Whereas, in vitro acidic culture condition and in vivo co-implanting xenograft model were adopted to study the response of HSCs and its influence on HCC progression. HSCs were activated under acidic culture condition depending on the phosphorylation of cellular signal regulated kinase (ERK). Acidity-activated HSCs promoted HCC metastasis in vitro and in vivo. Osteopontin (OPN) excretion from HSCs was increased under acidic condition and proved to promote the migration of HCC cells. Furthermore, the expression level of OPN was significantly associated with myofibroblasts and the combination of alpha-SMA with OPN was a powerful predictor for poor prognosis of HCC patients. Activation of HSCs in acidic tumor microenvironment represents a novel mechanism for HCC metastasis and provides a potential therapeutic strategy for HCC. PMID- 25449436 TI - Low-dose cisplatin converts the tumor microenvironment into a permissive state for HSVtk-induced antitumor immunity in HPV16-related tonsillar carcinoma. AB - An adenovirus harboring the HSV thymidine kinase (HSVtk) gene under the regulation of a trans-splicing ribozyme that targets telomerase is cytotoxic to cancer cells because it inhibits DNA replication (Ad5mTR). Furthermore, it induces anti-tumor immunity by activating cytotoxic T cells. Because multiple chemotherapeutic agents also activate cytotoxic T-cell immunity during the direct killing process of tumor cells, we herein explored whether low-dose cisplatin could synergize with cytotoxic Ad5mTR to potentiate its therapeutic effect by boosting anti-tumor immunity in a murine HPV16-associated tonsillar carcinoma model. Tumor regression was enhanced when low-dose (1 mg/kg) cisplatin was added to suicide gene therapy using Ad5mTR. Meanwhile, 1 mg/kg cisplatin alone had no tumor-suppressive effects and did not result in any systemic toxicity. Thus, cisplatin along with Ad5mTR improved tumor clearance by increasing the number of E7-specific CD8+ T cells. Specifically, analysis of the tumors and lymph nodes supported improved immune clearance by increasing the number of E7-specific CD8+ T cells inside tumors (40%, P < 0.05) as a result of the combination of suicide gene and cisplatin therapy. These results suggest that a low dose of cisplatin potentiates CD8+ T-cell-mediated anti-tumor immunity, and its addition to the HSVtk-based adenovirus results in additional therapeutic benefits for HPV16 positive head and neck cancer patients. PMID- 25449437 TI - Epstein-Barr virus miR-BART20-5p regulates cell proliferation and apoptosis by targeting BAD. AB - Although Epstein-Barr virus (EBV) BamHI A rightward transcript (BART) microRNAs (miRNAs) are ubiquitously expressed in EBV-associated tumors, the role of most BART miRNAs is unclear. In this study, we showed that Bcl-2-associated death promoter (BAD) expression was significantly lower in EBV-infected AGS-EBV cells than in EBV-negative AGS cells and investigated whether BART miRNAs target BAD. Using bioinformatics analysis, five BART miRNAs showing seed match with the 3' untranslated region (3'-UTR) of BAD were selected. Of these, only miR-BART20-5p reduced BAD expression when individually transfected into AGS cells. A luciferase assay revealed that miR-BART20-5p directly targets BAD. The expression of BAD mRNA and protein was decreased by miR-BART20-5p and increased by an inhibitor of miR-BART20-5p. PE-Annexin V staining and cell proliferation assays showed that miR-BART20-5p reduced apoptosis and enhanced cell growth. Furthermore, miR-BART20 5p increased chemoresistance to 5-fluorouracil and docetaxel. Our data suggest that miR-BART20-5p contributes to tumorigenesis of EBV-associated gastric carcinoma by directly targeting the 3'-UTR of BAD. PMID- 25449438 TI - Enhanced anticancer activity of a protein phosphatase 2A inhibitor on chemotherapy and radiation in head and neck squamous cell carcinoma. AB - The aim of this study is to eliminate more cancer cells by promoting them from quiescence into cell cycle or by changing their molecular events, leading them to be sensitive to radiation or chemotherapy. Protein phosphatase 2A plays an important role in many cellular functions and regulates various biological processes. It is unclear that LB1, which is an inhibitor of protein phosphatase 2A, has enhanced anticancer activity on chemotherapy (cisplatin and 5 fluorourcil) and radiation in head and neck squamous cell carcinoma (HNSCC). Herein, we performed both in vitro and in vivo studies to determine the anticancer activity of LB1 on chemotherapy and radiation in HNSCC, with detection of p53 expression, AKT and MDM2 phosphorylation. In vitro studies indicated that, LB1 could significantly enhance the cytotoxicity of cisplatin, 5-fluorourcil, and radiation; LB1 could also significantly enhance the treatment effect of cisplatin in nude mice. The anticancer activity of LB1 was mediated by increased AKT phosphorylation and decreased p53 expression with increased MDM2 phosphorylation, especially when combined with cisplatin. Our data suggest a strategy of improving treatment effect through the enhanced anticancer activity of LB1 on cisplatin based chemotherapy and radiation in HNSCC. PMID- 25449439 TI - Arsenic trioxide induces programmed cell death through stimulation of ER stress and inhibition of the ubiquitin-proteasome system in human sarcoma cells. AB - Sarcoma is a rare form of cancer that differs from the much more common carcinomas because it occurs in a distinct type of tissue. Many patients of sarcoma have poor response to chemotherapy and an increased risk for local recurrence. Arsenic trioxide (ATO) is used to treat certain types of leukemia. Recently, data have revealed that ATO induces sarcoma cell death in several types of solid tumor cell lines. In the present study, we investigated whether ATO induces cancer cell death and elucidated the underlying anti-cancer mechanisms. Our results showed that ATO caused concentration- and time-dependent cell death in human osteosarcoma and fibrosarcoma cells. The types of cell death that were induced by ATO were primarily autophagy and apoptosis. Furthermore, ATO activated p38, JNK and AMPK and inhibited the Akt/mTOR signaling pathways. Specifically, we found that ATO induced endoplasmic reticulum (ER) stress and suppressed proteasome activation in two types of sarcoma cell lines. However, the level of proteasome inhibition in osteosarcoma cells was lower than in fibrosarcoma cells. Thus, we used combined treatment with ATO and a proteasome inhibitor to examine the antitumor activity in fibrosarcoma cells. The data indicated showed that the combination treatment of ATO and MG132 (a proteasome inhibitor) resulted in synergistic cytotoxicity. In a fibrosarcoma xenograft mouse model, the combined treatment significantly reduced tumor progression. Immunohistochemical studies revealed that combined treatment induced autophagy and apoptosis. In summary, our results suggest a potential clinical application of ATO in sarcoma therapy and that combined treatment with a proteasome inhibitor can increase the therapeutic efficacy. PMID- 25449440 TI - Lansoprazole induces sensitivity to suboptimal doses of paclitaxel in human melanoma. AB - Tumor acidity is now considered an important determinant of drug-resistance and tumor progression, and anti-acidic approaches, such as Proton Pump inhibitors (PPIs), have demonstrated promising antitumor and chemo-sensitizing efficacy. The main purpose of the present study was to evaluate the possible PPI-induced sensitization of human melanoma cells to Paclitaxel (PTX). Our results show that PTX and the PPI Lansoprazole (LAN) combination was extremely efficient against metastatic melanoma cells, as compared to the single treatments, both in vitro and in vivo. We also showed that acidity plays an important role on the anti tumor activity of these drugs, being detrimental for PTX activity, while crucial for the synergistic effect of PTX following pretreatment with LAN, due to its nature of pro-drug needing protonation for a full activation. We obtained straightforward results in a human melanoma xenograft model combining well tolerated LAN doses with suboptimal and poorly toxic doses of PTX. With this study we provide a clear evidence that the PPI LAN may be included in new combined therapy of human melanoma together with low doses of PTX. PMID- 25449442 TI - [Finger in the door: it is possible to prevent it!]. PMID- 25449441 TI - Quantitative laser diffraction method for the assessment of protein subvisible particles. AB - Laser diffraction (LD) has been recognized as a method for estimating particle size distribution. Here, a recently developed quantitative LD (qLD) system, which is an LD method with extensive deconvolution analysis, was employed for the quantitative assessment of protein particles sizes, especially aimed at the quantification of 0.2-10 MUm diameter subvisible particles (SVPs). The qLD accurately estimated concentration distributions for silica beads with diameters ranging from 0.2 to 10 MUm that have refractive indices similar to that of protein particles. The linearity of concentration for micrometer-diameter silica beads was confirmed in the presence of a fixed concentration of submicrometer diameter beads. Similarly, submicrometer-diameter silica beads could be quantified in the presence of micrometer-diameter beads. Subsequently, stir- and heat-stressed intravenous immunoglobulins were evaluated by using the qLD, in which the refractive index of protein particles that was determined experimentally was used in the deconvolution analysis. The results showed that the concentration distributions of protein particles in SVP size range differ for the two stresses. The number concentration of the protein particles estimated using the qLD agreed well with that obtained using flow microscopy. This work demonstrates that qLD can be used for quantitative estimation of protein aggregates in SVP size range. PMID- 25449443 TI - [Epidemiological profile of snake bites in a pediatric intensive care unit at the Children's Hospital of Marrakech, Morocco]. AB - Snake bites are a serious medical emergency. They are most commonly associated with substantial morbidity and mortality in many parts of the world. This study aimed to determine the epidemiological profile of snake bites, as well as their severity and treatment in children in the Marrakech pediatric intensive care unit. The clinicobiological picture, physiopathology, the toxicokinetics of the venom, and the risk factors are discussed. Treatment of confirmed envenomation is based on antivenom administration via the venous route as soon as possible after the bite. Its efficacy and tolerance have been established by several studies. In our context, no specific immunotherapy is available, and the management of snake bites is based on symptomatic measures. Hence, the local health institutions must ensure the availability of antivenom specific to the Moroccan snake species, the only proven specific therapy against snake bite envenomation. The administration of highly purified immunoglobulin appears to improve the prognosis of envenomation, reduce morbidity and mortality, and reduce the length of the hospital stay. PMID- 25449444 TI - [Medical fault or professional negligence? Case studies in two recovery nutrition centers in Niger]. AB - In developing countries such as Niger, the risk of medical malpractice is ubiquitous in health, jeopardizing patient safety. The aim of this work was to contribute to patients' safety and respect of code of ethics and conduct in the exercise of the medical profession. The reported cases involved two children under 5 years who were admitted to nutrition rehabilitation centers, died as a result of medical malpractice. In Niger, there are no statistics on this phenomenon and a few cases found have always been considered "accident" or "fate." The establishment of an observatory collections of such information should improve their frequency, consequences and propose a prevention plan. PMID- 25449446 TI - [Gastric volvulus in children: five case reports]. AB - Gastric volvulus is an abnormal rotation of all or a part of the stomach around one of its axes. It is a rare cause of intestinal obstruction in children. This anomaly can be primary, due to abnormalities of the gastric ligaments, or secondary to other congenital malformations. We report on the cases of five children treated between January 1994 and December 2011, four boys and one girl, with a medium age of 7 months. Diagnosis was based on clinical features, particularly in the upper gastrointestinal Rx contrast study, which confirmed the diagnosis. Four out of the five children underwent laparoscopic surgery with fixation of the stomach. A diaphragmatic hernia was associated in one case. Antireflux surgery was performed in three cases, and a diaphragmatic defect was closed in one case. The follow-up was uneventful after a medium period of 7 years. CONCLUSION: good knowledge of this anomaly is the guarantee of early diagnosis and optimum treatment to ameliorate the prognosis. PMID- 25449445 TI - [Nephropathy due to Puumala hantavirus]. AB - Hemorrhagic fever with renal syndrome (HFRS) is due to an infection by the virus of the Hantavirus genus. Rodent hosts of Hantavirus are present in restricted areas in France; consequently, there are ecological niches and microepidemics of human Hantavirus infections. A HFRS case was diagnosed in the Paris region. The 11-year-old child had an acute debut fever-persistent despite antipyretic medication-asthenia, headache, abdominal pain, myalgia, thrombocytopenia, as well as renal failure with proteinuria. The diagnosis was made with a relevant clinical history and the specific serology of Puumala hantavirus. Therefore, a kidney biopsy was not necessary. What was interesting was the diagnostic approach because of the difference between the place and time of contamination and where the child became ill and developed the symptoms. The child was infected by Puumala hantavirus in Les Ardennes, a high-risk area, but became ill in the Paris region, an area with no prevalence. We review Hantavirus infections in France and its differential diagnosis. PMID- 25449447 TI - [Psychological violences]. AB - Among the various forms of violence inflicted on a child, psychological violence holds a significant place in terms of frequency, diversity and damage done, as serious and pervasive consequences can be observed on the child's development. This article highlights and assesses the psychological consequences provoked by psychological violences perpetrated by parents, teachers or other children in different situations, such as domestic violence, divorce and school bullying. It also gives some indications for intervention and prevention in those situations. PMID- 25449448 TI - Use of traditional Chinese medicine reduces exposure to corticosteroid among atopic dermatitis children: a 1-year follow-up cohort study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Atopic dermatitis is a prevalent dermatologic disease in children. Corticosteroid is an important treatment but side effects caused by long-term and excessive use heavily concern patients. Traditional Chinese medicine (TCM) is potentially an alternative treatment and might cause less adverse effects. This nationwide retrospective cohort study aimed to examine the hypothesis that TCM use is associated with lower exposure to corticosteroid. MATERIALS AND METHODS: Children under 12 years of age with ICD-9 codes 691.8 and 692.x were identified as atopic dermatitis patients from 2007/1/1 to 2007/12/31. Corticosteroid use was compared between TCM users and non-users for one-year follow-up by using a general estimation equation model with propensity-score matching. RESULTS: A total of 9012 TCM users were identified and the use of corticosteroid after treatment was compared with matched TCM non-users. Use of TCM significantly reduced exposure to corticosteroids after 1-year follow-up. Among TCM users, the exposure to any corticosteroids was lower (42.1% reduction in TCM users versus 34.5% increase in TCM non-users, relative risk: 0.36; p Value<0.001), the duration was shorter (relative risk for using corticosteroid more than 14 days: 0.37; p-Value<0.001), and the rate of frequent visits with steroid prescription was also lower. CHM was the most commonly used TCM modality (98.5% of all visits) and Xiao-Feng-San was the most commonly used CHM (33% of all prescriptions) with extensive coverage for pathogenesis of atopic dermatitis. CONCLUSIONS: Lower use rate of corticosteroid can be found after TCM treatment, which can be considered as an integrative therapy for atopic dermatitis. Further studies are warranted on the basis of this study. PMID- 25449449 TI - Alkaline phosphatase activity-guided isolation of active compounds and new dammarane-type triterpenes from Cissus quadrangularis hexane extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The stem of Cissus quadrangularis L. (CQ) is used in traditional medicine to treat bone fractures and swelling. Anti-osteoporotic activity of CQ hexane extract has been reported, but the active compounds in this extract remain unknown. Thus, we aimed to identify the active compounds in CQ hexane extract using bioassay-guided isolation. MATERIALS AND METHODS: The CQ hexane extract was fractionated sequentially with benzene, dichloromethane, ethyl acetate, and methanol. The examination of CQ extract and its fractions was guided by bioassays for alkaline phosphatase (ALP) activity during the differentiation of MC3T3-E1 osteoblastic cells. The cells were treated with or without the CQ extract and its fractions for a period of time, and then the stimulatory effect of the alkaline phosphatase enzyme, a bone differentiation marker, was investigated. The compounds obtained were structurally elucidated using spectroscopic techniques and re-evaluated for activity during bone differentiation. RESULTS: A total of 29 compounds were isolated, viz., triterpenes, fatty acid methyl esters, glycerolipids, steroids, phytols, and cerebrosides. Four new dammarane-type triterpenes were isolated for the first time from nature, and this report is the first to identify this group of compounds from the Vitaceae family. Seven compounds, viz., glycerolipids and squalene, stimulated ALP activity at a dose of 10MUg/mL. Moreover, the synergistic effect of these compounds on bone formation was demonstrated. CONCLUSION: This report describes, for the first time, the isolation of active compounds from CQ hexane extract; these active compounds will be useful for the quality control of extracts from this plant used to treat osteoporosis. PMID- 25449450 TI - Banana (Musa spp) from peel to pulp: ethnopharmacology, source of bioactive compounds and its relevance for human health. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Banana is a fruit with nutritional properties and also with acclaimed therapeutic uses, cultivated widely throughout the tropics as source of food and income for people. Banana peel is known by its local and traditional use to promote wound healing mainly from burns and to help overcome or prevent a substantial number of illnesses, as depression. AIM OF THE STUDY: This review critically assessed the phytochemical properties and biological activities of Musa spp fruit pulp and peel. MATERIALS AND METHODS: A survey on the literature on banana (Musa spp, Musaceae) covering its botanical classification and nomenclature, as well as the local and traditional use of its pulp and peel was performed. Besides, the current state of art on banana fruit pulp and peel as interesting complex matrices sources of high-value compounds from secondary metabolism was also approached. RESULTS: Dessert bananas and plantains are systematic classified into four sections, Eumusa, Rhodochlamys, Australimusa, and Callimusa, according to the number of chromosomes. The fruits differ only in their ploidy arrangement and a single scientific name can be given to all the edible bananas, i.e., Musa spp. The chemical composition of banana's peel and pulp comprise mostly carotenoids, phenolic compounds, and biogenic amines. The biological potential of those biomasses is directly related to their chemical composition, particularly as pro-vitamin A supplementation, as potential antioxidants attributed to their phenolic constituents, as well as in the treatment of Parkinson's disease considering their contents in l-dopa and dopamine. CONCLUSION: Banana's pulp and peel can be used as natural sources of antioxidants and pro-vitamin A due to their contents in carotenoids, phenolics, and amine compounds, for instance. For the development of a phytomedicine or even an allopathic medicine, e.g., banana fruit pulp and peel could be of interest as raw materials riches in beneficial bioactive compounds. PMID- 25449451 TI - Ethnobotanical survey of medicinal plants used for pregnant women's health conditions in Menoua division-West Cameroon. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Cameroon, most women use traditional medicine for the treatment of pregnancy and childbirth complaints. In order to identify some of the medicinal plants locally used to alleviate these complaints, an ethnobotanical survey was undertaken in five villages of Menoua Division (West Cameroon). MATERIALS AND METHODS: Interviews were conducted through structured questionnaires among 24 traditional healers and 179 women living either in the town of Dschang or in 4 neighboring villages. After having recorded the interviewee personal information on issues related to medicinal plants utilization, a literature investigation on their therapeutic or pharmacological effects and phytochemical composition was conducted. RESULTS: A total of 88 medicinal plants species used to treat 24 conditions occurring during or after pregnancy and belonging to 70 genera or 34 families were recorded. Maximum medicinal uses of plants are reported for the treatment of the following ailments: swelling of legs and ankles (23%), facilitation of delivery (22%), cleaning of the baby (12%). Most herbal remedies are prepared with the leaves (30%), leaves+stems (28%) and whole plant (23%) as maceration (76%). The majority of women who used medicinal plants were very satisfied (75 %) and it is reported that most of these plants are used in the treatment of women health conditions. CONCLUSION: Many herbal remedies used for the treatment of pregnant women's health conditions in Menoua division-West Cameroon have been revealed. It would therefore be judicious for our government and research institution to evaluate the therapeutic and toxicological potentials of these plants in order to valorize their use. PMID- 25449452 TI - A study of medicinal plants used as ethnoveterinary: harnessing potential phytotherapy in Bheri, District Muzaffarabad (Pakistan). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants are utilized for handling health care system and in preventing a variety of diseases. A survey was conducted to document the rapidly disappearing traditional knowledge of medicinal plants in union council Bheri, District Muzaffarabad, Azad Kashmir, Pakistan. MATERIALS AND METHODS: Questionnaire format was used to collect the medicinal uses of plants. The 180 informants were interviewed from six villages in total, 30 from each village (20 male and 10 female) regarding the ethnoveterinary uses of plants in several ailments. For the reliability of ethnoveterinary knowledge, the informant consensus factor (FIC), and fidelity level (FL) were calculated and the literature cited was surveyed. The medicinal information was gathered from local inhabitants, healers, shepherds and old men and women of different age groups. RESULTS: A total of 24 medicinal plant species used as ethnoveterinary were found belonging to 22 genera and 19 families. The most dominant family was Polygonaceae (3 species) followed by Araceae, Asteraceae, Lamiaceae each with 2 species and remaining families having one species. The important medicinal plant species showed the highest fidelity level (FL) such as: Rumex nepalensis, Primula denticulata, (100%) used for dysuria, red urination, Skimmia laureola (100%), Swertia paniculata (99%), and Angelica glauca (97%), used for ague, cold, shivering, gastric ailments, Melia azedarach (100%), used to reduce intestinal worm load in cattle showing the conformity of knowledge on these species. Highest FIC was recorded for foot and mouth diseases and ectoparasite (1) followed by ague (0.98) and dysuria (0.99) depicting that a few species were used to cure various animals' ailments. CONCLUSIONS: The findings of the research revealed that merely a few species are used as ethnoveterinary medicine supported by pharmacology study. Due to anthropogenic pressure the extinction of each species from the areas could result in disappearing knowledge regarding century's old traditional methods of curing diseases from these plant species. PMID- 25449453 TI - Attenuation of neuroinflammatory responses and behavioral deficits by Ligusticum officinale (Makino) Kitag in stimulated microglia and MPTP-induced mouse model of Parkinson's disease. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ligusticum officinale (Makino) Kitag (L. officinale) is one of the important traditional herbs used in traditional Oriental medicine for the treatment of various disorders including pain and inflammation. However, there is limited scientific basis for its activity and mechanism in brain inflammation. AIM OF THE STUDY: This study aimed to evaluate the effects of L. officinale on microglia-mediated neuroinflammation and behavioral impairments using in vitro cellular and in vivo mouse model of PD, as well as investigate the molecular mechanisms involved including the finger printing analysis of its ethanol extract. MATERIALS AND METHODS: Lipopolysaccharide (LPS) was used to stimulate BV-2 microglial cells. The changes in neuroinflammatory expressional levels were measured by Western blotting and immunofluorescence techniques. 1-methyl-4 phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-intoxicated mice model of PD was developed to evaluate the behavioral impairments and the brain tissues were used for immunohistochemical studies. High performance liquid chromatography (HPLC) technique was performed for finger printing analysis of L. officinale extract used in the study. RESULTS: L. officinale significantly attenuated the LPS-stimulated increase in inflammatory mediators in BV-2 cells. L. officinale also inhibited the LPS-induced activation of nuclear factor-kappa beta by blocking the degradation of IkappaB-alpha and suppressing the increase in p38-mitogen-activated protein kinase phosphorylation in BV-2 cells. Furthermore, L. officinale exhibited significant antioxidant properties by inhibiting the 1-diphenyl-2-picrylhydrazyl radicals. An in vivo evaluation in MPTP (20mg/kg, four times, 1 day, i.p.) intoxicated mice resulted in brain microglial activation and significant behavioral deficits. Prophylactic treatment with L. officinale prevented microglial activation and attenuated PD like behavioral changes as assessed by the pole test. HPLC finger printing analysis revealed that L. officinale extract contained ferulic acid (FA) as one of the major constituents compared with reference standard. FA also inhibited the LPS-stimulated excessive release of NO and suppressed the increased the expressional levels of proinflammatory mediators in BV-2 microglia. CONCLUSIONS: The findings observed in this study indicated that L. officinale extract significantly attenuated the neuroinflammatory processes in stimulated microglia and restored the behavioral impairments in a mouse model of PD providing a scientific basis for its traditional claims. PMID- 25449454 TI - Medicinal plants used by traditional healers for the treatment of malaria in the Chipinge district in Zimbabwe. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Because about 50% of the Zimbabwean population is at risk of contracting malaria each year, the majority of people, especially in rural areas, use traditional plant-based medicines to combat malaria. This explorative ethnobotanical survey was undertaken to document how malaria is conceptualized and diagnosed by traditional healers, and to record the medicinal plants used in the prevention and treatment of malaria, their mode of preparation and administration. MATERIALS AND METHODS: The research was conducted in three villages in Headman Muzite's area and in Chiriga village. These villages are located in the Chipinge district in the Manicaland Province in Zimbabwe.Traditional healers were selected with the assistance of the headman of the Muzite area and a representative of the Zimbabwe National Traditional Healers Association. Semi-structured interviews were conducted with 14 traditional healers from four villages in the Chipinge district in Zimbabwe. RESULTS: In total, 28 plants from 16 plant families are used by the healers who manage malaria with medicinal plants. The most cited plant is Cassia abbreviata Oliv. (Leguminosae) followed by Aristolochia albida Duch (Aristolociaceae) and Toddalia asiatica (L.) Lam. (Rutaceae). Roots (55.3%) are the most common part used. Most of the plant parts used to treat malaria are stored as dried powders in closed bottles. The powders are soaked in hot or cold water and the water extract is taken as the active medicine. The healers consider their medicinal knowledge as a spiritual family heritage. Only 25% of the healers refer the malaria patients that do not respond to their treatment to hospital - they believe evil spirits cause their remedies to failure and they would rather try a different plant or perform a cleansing ceremony. CONCLUSIONS: Local knowledge of medicinal plants in the treatment of malaria still exists in all four villages surveyed and traditional healers appear to play an important role in primary health care services in this remote rural area in Zimbabwe. This explorative survey underscores the need to preserve and document traditional healing for managing malaria and for more future scientific research on the plants to determine their efficacy and their safety. This could improve their traditional anti-malarial recipes and might contribute to a better integration of Zimbabwean traditional medicine into the national health system in the future. PMID- 25449455 TI - Effects of Dictamnus dasycarpus Turcz., root bark on ICAM-1 expression and chemokine productions in vivo and vitro study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The root bark of Dictamnus dasycarpus Turcz., family Rutaceae is a well known anti-inflammatory agent for skin diseases such as eczema, pruritus and urticaria in Eastern countries. MATERIALS AND METHODS: We investigated the effects of methanol extract of Dictamnus dasycarpus root bark (MEDD) on Intercellular Adhesion Molecule-1 (ICAM-1) expression, epidermal hyperplasia and immune cell infiltration in 1-fluoro-2,4-dinitrofluorobenzene (DNFB)-induced contact dermatitis (CD) mice. We also investigated its effects on the expression of ICAM-1, binding capacity to THP-1 cells, cytokine and chemokine production, and phosphorylation of NF-kappaB in human keratinocytes (HaCaT cells). RESULTS: Topical application of MEDD effectively inhibited ICAM-1 expression and epidermal hyperplasia in inflamed tissues. MEDD treatment also inhibited immune cell infiltration induced by DNFB. In addition, treatment with MEDD reduced surface expression and total amount of ICAM-1in HaCaT cells and effectively lowered the capacity to bind to THP-1 cells. MEDD also lowered the levels of IL-6, IL-8, monokine induced by gamma interferon (MIG), monocyte chemotactic protein-1 (MCP-1) and regulated on activation, normal T cell expressed and secreted (RANTES). Finally, MEDD treatment prevented activation of the NF-kappaB pathway induced by TNF-alpha in HaCaT cells. CONCLUSIONS: These data indicate that root bark of Dictamnus dasycarpus has the potential for treatment of inflammatory skin diseases as a complementary or alternative medicine to corticosteroids. In addition, they suggest that the anti-inflammatory effects of Dictamnus dasycarpus on CD are involved in the regulation of ICAM-1 expression and cytokine and chemokine secretion through down-regulation of the NF kappaB signaling pathway in keratinocytes. PMID- 25449456 TI - Influence of JuA in evoking communication changes between the small intestines and brain tissues of rats and the GABAA and GABAB receptor transcription levels of hippocampal neurons. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Jujuboside A (JuA) is a main active ingredient of semen ziziphi spinosae, which can significantly reduce spontaneous activity in mammals, increase the speed of falling asleep, prolong the sleeping time as well as improve the sleeping efficiency. In this study, the mechanism and the pathway of the sedative and hypnotic effect of JuA were investigated. MATERIALS AND METHODS: After being treated with JuA (in vitro), the rat's small intestine tissues cultures were used to stimulate the brain tissues. Then 27 cytokine levels were detected in the two kinds of tissue culture via liquid protein chip technology; In addition, the cultured hippocampal neurons of rat were treated with JuA, and gamma-aminobutyric acid (GABA) receptor subunits (GABAAalpha1, GABAAalpha5, GABAAbeta1 and GABABR1) mRNAs were evaluated by Real-time PCR. RESULTS: The levels of IL-1alpha, MIP-1alpha, IL-1beta and IL-2 were reduced significantly after 3h of treating the small intestine tissues with JuA (200ul/ml), and the concentration change rates, in order, were -59.3%, -3.59%, 50.1% and -49.4%; these cytokines were transmitted to brain tissues 2h later, which could lead to significant levels of reduction of IL-1alpha, IFN-gamma, IP 10 and TNF-alpha; the concentration change rates were -62.4%, -25.7%, -55.2% and 38.5%, respectively. Further, the intercellular communication network diagram was mapped out, which could suggest the mechanism and the pathway of the sedative and hypnotic effect of JuA. The results also indicated that JuA (50ul/ml) increased significantly GABAAalpha1 receptor mRNAs and reduced GABABR1, mRNAs in hippocampal neurons after 24h of stimulation; however, all the mRNA transcription levels of GABAAalpha1,GABAAalpha5, GABAAbeta1 and GABABR1 receptors increased significantly after 48h. CONCLUSION: JuA performed its specific sedative and hypnotic effect through not only adjusting GABA receptors subunit mRNAs expression, but also down-regulating the secretion of relevant inflammation cytokines on the intestinal mucosal system to affect the intercellular cytokine network between nerve cells in the brain. This mechanism is similar to that of melatonin. PMID- 25449457 TI - Suppressive effects of total alkaloids of Lycopodiastrum casuarinoides on adjuvant-induced arthritis in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Lycopodiastrum casuarinoides is a folk medicine used to treat inflammation-associated diseases including rheumatoid arthritis in South China. Since the major secondary metabolites in Lycopodiastrum casuarinoides are alkaloids, the present study aims to investigate the suppressive effects of total alkaloids of Lycopodiastrum casuarinoides (ALC) on adjuvant-induced arthritis (AA) in rats. MATERIALS AND METHODS: AA was induced (day 0) in male Sprague-Dawley rats by intradermal injection of complete Freund's adjuvant (CFA) in right hind footpad. Diclofenac sodium (SD) was chosen as the positive drug. SD (10mg/kg) and ALC (20 and 40 mg/kg) administration started from day 1 and continued for 28 days. Paw swelling, arthritis scores, and histopathological changes were evaluated. In addition, the serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and prostaglandin E2 (PGE2), as well as cyclooxygenase-2 (COX-2) and nuclear factor (NF)-kappaB expressions in joint synovial tissues were detected. RESULTS: ALC administration significantly suppressed the inflammatory responses in the joints of AA rats. It also decreased the serum levels of TNF-alpha, IL-6 and PGE2. Moreover, Western blot analysis showed that COX-2 and NF-kappaB expressions in synovial tissues of AA rats were significantly reduced. CONCLUSION: These results indicated that ALC prevented the pathological development of AA in rats. ALC may be a potential candidate for the treatment of inflammation and arthritis. PMID- 25449458 TI - Medicinal plants of the genus Betula--traditional uses and a phytochemical pharmacological review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Trees and shrubs of the genus Betula (Betulaceae) inhabit various ecosystems in temperate and boreal climate zones of the northern hemisphere. The healing properties of Betula bark and bark extracts have been known for a long time in traditional medicine in different parts of the world. Several species of Betula have traditionally been used for the treatment of various inflammatory diseases including arthritis. The purpose of this review is to provide updated, comprehensive and categorized information on the botany, traditional uses, phytochemistry and pharmacological and toxicological research of Betula species in order to explore their therapeutic potential and evaluate future research opportunities. MATERIALS AND METHODS: All the available information on various species belonging to the genus Betula was collected via electronic search (using Pubmed, SciFinder, Scirus, Google Scholar, JCCC@INSTIRC and Web of Science) and a library search for articles published in peer-reviewed journals. RESULTS: Although over a hundred Betula species are found distributed globally, about 7 different species of Betula have been documented for their traditional uses. Phytochemical research on Betula species has led to the isolation of triterpenoids, diarylheptanoids, phenylbutanoids, lignans, phenolics and flavonoids. Crude extracts, fractions and phytochemical constituents isolated from Betula showed a wide spectrum of in vitro and in vivo pharmacological activities like immunomodulatory, anti-inflammatory, antimicrobial, antiviral, antioxidant, antidiabetic, dermatological, gastroprotective and hepatoprotective. Antiarthritic and anticancer are the two major areas of research conducted on these species. The anti-carcinogenic effects of Betula bark, betulin as well as betulinic acid have been extensively studied. CONCLUSIONS: Several species belonging to the genus Betula are widely used in traditional medicine. Betula platyphylla and Betula pendula have specifically been found to be potentially useful in the treatment of degenerative joint disease. There is convincing evidence in experimental animal models in support of their anti-carcinogenic effects. However, it would be worthwhile to investigate the biochemical and physiological mechanisms as well as detailed preclinical toxicity, bioavailability, pharmacokinetics and pharmacodynamics of the different biologically active extracts as well as molecules in sufficient detail. An integrated and holistic approach is required for tapping the full potentials of this important genus. PMID- 25449459 TI - Shexiang Tongxin dropping pill attenuates atherosclerotic lesions in ApoE deficient mouse model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Shexiang Tongxin dropping pill (STDP) is a formulation of Traditional Chinese Medicine mainly used for clinical treatment of stable angina pectoris in China. AIM OF THE STUDY: To investigate the effects and mechanisms of STDP treatment on atherosclerosis. MATERIALS AND METHODS: ApoE deficient (ApoE(-/-)) mice were utilized to evaluate the effect of STDP treatment (30 mg/kg/day) on atherosclerotic lesions. Histopathological features of atherosclerotic lesions, serum levels of lipid proteins, parameters of oxidative stress and pro-inflammatory cytokines were measured by H&E staining, Masson's trichrome staining and ELISA, respectively. Real-time PCR analyses were performed to examine the aortic expression of atherosclerosis-associated microRNAs. RESULTS: The STDP treatment resulted in attenuated atherosclerotic lesion manifested by reduced lipid deposition, fibrosis and oxidative stress. It also led to increase in serum levels of GSH and SOD, decrease in MDA, decrease in CHO, TG, LDL, ox-LDL and increase in HDL, respectively. Additionally, the levels of pro-inflammatory cytokines including IL-2, IL-6, TNF-alpha and gamma-IFN were markedly reduced by STDP treatment. Furthermore, STDP treatment was associated with a significant reduction in the aortic expression of miR-21a, miR-132, miR 126a, miR-155 and increased expression of miR-20a. CONCLUSION: Our results demonstrated for the first time that STDP attenuated atherosclerotic lesions in ApoE(-/-) mouse model. Moreover, STDP treatment exhibited multi-targeting effects on pathological, biochemical and molecular aspects of atherosclerosis implicating lipid regulation, fibrosis, inflammation and oxidative stress. Findings from the current study warrant further evaluation of the clinical application of STDP in atherosclerosis treatment. PMID- 25449460 TI - Neuroprotective effect of modified Chungsimyeolda-tang, a traditional Korean herbal formula, via autophagy induction in models of Parkinson's disease. AB - AIM OF THE STUDY: Previous studies in our laboratory revealed the neuroprotective effect of modified Yeoldahanso-tang (MYH) in models of Parkinson's disease (PD). In this study, we investigated another traditional Korean herbal formula, modified Chungsimyeolda-tang (termed DG), as a potential treatment for PD. Chungsimyeolda-tang has been used in Korea to treat cerebrovascular diseases, such as stroke. Here, we verify the neuroprotective and autophagy-inducing effects of DG to evaluate any potential anti-parkinsonian properties. MATERIALS AND METHODS: 1-Methyl-4-phenylpyridinium (MPP(+)) and rotenone were used to induce cytotoxicity in nerve growth factor (NGF)-differentiated rat pheochromocytoma (PC12) cells. Cell viability was measured using an MTT assay. Induction of autophagy by DG in NGF-differentiated PC12 cells was measured using an immunoblotting assay with an LC3 antibody. The proteasomal inhibitor lactacystin was used to induce ubiquitin-proteasome system (UPS) dysfunction in NGF-differentiated PC12 cells. DG-mediated clearance of aggregated proteins was measured using an immunoblotting assay with a ubiquitin antibody. RESULTS AND CONCLUSIONS: Our findings indicate that DG robustly protects NGF-differentiated PC12 cells against the neurotoxic effects of MPP(+) and rotenone in an in vitro model. Furthermore, DG protects NGF-differentiated PC12 cells against lactacystin induced cell death. This effect is partially mediated by an increased autophagy associated with the enhanced degradation of aggregated proteins. This study suggests that DG is an attractive candidate drug for inducing autophagy and, therefore, may represent a promising strategy to prevent diseases associated with misfolded/aggregated proteins in various neurodegenerative disorders, including Parkinson's disease. PMID- 25449461 TI - Anti-inflammatory effects of Antrodia camphorata, a herbal medicine, in a mouse skin ischemia model. AB - ETHNOPHARMACOLOGICAL EVIDENCE: Antrodia camphorata, a highly valued polypore mushroom native only to Taiwan, has been traditionally used as a medicine for anti-inflammation. AIM OF THE STUDY: In this study, anti-inflammatory effects of Antrodia camphorata (AC) and its active compound, ergostatrien-3beta-ol (ST1), were investigated in a mouse skin ischemia model induced by skin flap surgery on the dorsal skin. MATERIALS AND METHODS: A U-shaped flap was elevated on the dorsal skin of the nine-week-old male mice. Mice were randomly assigned to six groups for treatment (n=6) including normal skin/propylene glycol (PG), surgical skin flap/PG, solid-state-cultured AC (S/AC), wood-cultured AC (W/AC), high-dose ST1 (H-ST1), low-dose ST1 (L-ST1). Antrodia camphorata was dissolved in 25MUL PG and smeared on the skin flap every six hours for 24h. At the end of the experiment, each mouse was anesthetized, and skin tissues were collected from their back for histopathological analysis, extracting RNA and protein according to our previous reports. RESULTS: Skin-flap-induced ischemia damage significantly increased the expression of the iNOS, COX2, and IL-6 proteins and decreased the expression of IkappaB protein. In addition, focal, moderate coagulative necrosis with inflammatory cell infiltration was found in the epidermis, and moderate inflammatory cells and necrosis with slight edema was noted in the sub-dermis at 24h after skin flap surgery. However, treatment with solid-state-cultured or wood cultured AC, or with its derived ST1 active compound, significantly reduced the necrosis and inflammatory cell infiltration in both the epidermis and sub-dermis of the skin flap. The treatments also reduced the inflammatory response by decreasing the expression of inflammation-related genes including iNOS, IL-6, TNF alpha, and NF-kappaB, as shown by changes in RNA and protein expression, when compared with the surgical skin flap procedure alone. CONCLUSIONS: These results demonstrated that methanolic extracts of wood-cultured fruiting bodies and solid state-cultured mycelia from Antrodia camphorata have excellent anti-inflammatory activities and thus have great potential as an addition for hydrocolloid dressings. PMID- 25449462 TI - Traditional usages, botany, phytochemistry, pharmacology and toxicology of Polygonum multiflorum Thunb.: a review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum Thunb., which is known as Heshouwu ( in Chinese) in China. It is traditionally valued and reported for hair blacking, liver and kidney-tonifying and anti-aging effects as well as low toxicity. The aim of this review is to provide comprehensive information on the botany, traditional uses, phytochemistry, pharmacological research and toxicology of Polygonum multiflorum, based on the scientific literature. Moreover, trends and perspectives for future investigation of this plant are discussed. It will build up a new foundation for further study on Polygonum multiflorum. MATERIALS AND METHODS: A systematic review of the literature on Polygonum multiflorum was performed using several resources, including classic books on Chinese herbal medicine and various scientific databases, such as PubMed, SciFinder, the Web of Science, Science Direct, China Knowledge Resource Integrated (CNKI). RESULTS: Polygonum multiflorum is widely distributed throughout the world and has been used as a traditional medicine for centuries in China. The ethnomedical uses of Polygonum multiflorum have been recorded in many provinces of China and Japan for nine species of adulterants in six families. More than 100 chemical compounds have been isolated from this plant, and the major components have been determined to be stilbenes, quinones, flavonoids and others. Crude extracts and pure compounds of this plant are used as effective agents in pre-clinical and clinical practice due to their anti-aging, anti-hyperlipidaemia, anti-cancer and anti inflammatory effects and to promote immunomodulation, neuroprotection, and the curing of other diseases. However, these extracts can also lead to hepatotoxicity, nephrotoxicity and embryonic toxicity. Pharmacokinetic studies have demonstrated that the main components of Polygonum multiflorum, such as 2,3,5,4'-tetrahydroxystilbene-2-O-beta-d-glucopyranoside and emodin are distributed among many organs and tissues. CONCLUSION: Therapeutic potential of Polygonum multiflorum has been demonstrated in the conditions like Alzheimer's disease, Parkinson's disease, hyperlipidaemia, inflammation and cancer, which is attributed to the presence of various stilbenes, quinones, flavonoids, phospholipids and other compounds in the drug. On the other hand, the adverse effects (hepatotoxicity, nephrotoxicity, and embryonic toxicity) of this plant were caused by the quinones, such as emodin and rhein. Thus more pharmacological and toxicological mechanisms on main active compounds are necessary to be explored, especially the combined anthraquinones (Emodin-8-O-beta-d glucopyranoside, Physcion-8-O-beta-d-glucopyranoside, etc.) and the variety of stilbenes. PMID- 25449463 TI - Effect of traditional Uyghur medicine abnormal Savda Munziq extract on rabbit platelet aggregation in vitro and rat arteriovenous shunt thrombosis in vivo. AB - OBJECTIVE: Abnormal Savda Munziq (ASMq) is a standard herbal preparation used in Uyghur traditional medicine to fight chronic diseases including cardiovascular, but its specific effects on thrombosis and platelet aggregation are unknown. METHODS: Rabbit platelets were incubated with ASMq extract (10, 20, 40 ug/ml) for 15, 30, or 60 min, and aggregation was induced with ADP and collagen. In vivo, ASMq extract 2.97 g/kg, 5.94g/kg, 11.88 g/kg per os daily for 15 days were tested on thrombus wet weight in a rat model of arterio-venous bypass thrombosis. Plasma thromboxane B2 (TXB2) and 6-keto-PGF1a (6PG) were measured by radioimmunoassay. Aspirin (12 ug/ml and 5mg/kg) and saline were used as control in both experiments. RESULTS: ASMq inhibited ADP and collagen-induced aggregation in vitro in a dose-dependent manner that increased over time, to a maximum of 6.4 +/ 1.3% and 21.6 +/- 4.0% for ADP and collagen, respectively, at one hour's incubation with the highest concentration, whereas the effects of aspirin (34.5 +/- 2.2% and 41.9 +/- 2.5%, respectively) were stable over time. In vivo, ASMq inhibited thrombus formation dose-dependently, by 70% at the highest dose, compared to 67% with aspirin. ASMq essentially did not change prostaglandin production, compared to the clear inhibition by aspirin. CONCLUSION: Abnormal Savda Munziq extract inhibits dose-dependent platelet aggregation with ADP or collagen in vitro and thrombosis in vivo to values similar to those of aspirin, though unlike aspirin this effect does not seem mediated by an inhibition of cyclo-oxygenase. PMID- 25449466 TI - Traditional acupuncture and myocardial ischemia. PMID- 25449465 TI - Letter by Zagatina et al. regarding the article, "three-dimensional speckle strain echocardiography is more accurate and efficient than 2D strain in the evaluation of left ventricular function". PMID- 25449468 TI - Noncompaction in alleged motor neuron disease suggests myopathy. PMID- 25449467 TI - Infective endocarditis in elderly: an Italian prospective multi-center observational study. PMID- 25449464 TI - Intricacies of cardiac damage in coxsackievirus B3 infection: implications for therapy. AB - Heart disease is the leading cause of death in humans, and myocarditis is one predominant cause of heart failure in young adults. Patients affected with myocarditis can develop dilated cardiomyopathy (DCM), a common reason for heart transplantation, which to date is the only viable option for combatting DCM. Myocarditis/DCM patients show antibodies to coxsackievirus B (CVB)3 and cardiac antigens, suggesting a role for CVB-mediated autoimmunity in the disease pathogenesis; however, a direct causal link remains to be determined clinically. Experimentally, myocarditis can be induced in susceptible strains of mice using the human isolates of CVB3, and the disease pathogenesis of postinfectious myocarditis resembles that of human disease, making the observations made in animals relevant to humans. In this review, we discuss the complex nature of CVB3 induced myocarditis as it relates to the damage caused by both the virus and the host's response to infection. Based on recent data we obtained in the mouse model of CVB3 infection, we provide evidence to suggest that CVB3 infection accompanies the generation of cardiac myosin-specific CD4 T cells that can transfer the disease to naive recipients. The therapeutic implications of these observations are also discussed. PMID- 25449469 TI - High-sensitivity C-reactive protein mediates in part the impact of ABO blood group on coronary artery disease. PMID- 25449470 TI - Parameters influencing LVEF improvement with intracoronary bone marrow stem cell delivery in acute myocardial infarction. PMID- 25449472 TI - Adult Fontan failure - distinct disease entity. PMID- 25449471 TI - M3 muscarinic acetylcholine receptor in cardiology and oncology. PMID- 25449473 TI - Leisure-time physical activity over four seasons in chronic heart failure patients. PMID- 25449474 TI - Meta-analysis of efficacy and safety of genotype-guided pharmacogenetic dosing of warfarin. PMID- 25449476 TI - Axillary artery cannulation for aortic valve replacement through right anterior minithoracotomy. PMID- 25449475 TI - Functional capacity and risk stratification by the Six-minute Walk Test in Chagas heart disease: comparison with Cardiopulmonary Exercise Testing. PMID- 25449477 TI - Clinical risk factors and subclinical target organ damage as predictors of new onset of atrial fibrillation: the Catanzaro atrial fibrillation project. PMID- 25449478 TI - Blood pressure and autonomic responses to electrical stimulation of the renal arterial nerves before and after ablation of the renal artery. PMID- 25449479 TI - Heart rate recovery and physical fitness. PMID- 25449480 TI - Association of serum bicarbonate with long-term outcomes in patients hospitalized with heart failure. PMID- 25449481 TI - Transcutaneous electrical stimulation of auricular branch of vagus nerve: a noninvasive therapeutic approach for post-ischemic heart failure. PMID- 25449482 TI - When it comes down to the wire: iatrogenic coronary lesion disruption due to passage of a pressure wire. PMID- 25449483 TI - Improved prognosis following renin-angiotensin-aldosterone system blockade in patients undergoing concomitant aortic and mitral valve replacement. PMID- 25449484 TI - Heart failure having little effect on the progression of Parkinson's disease: direct evidence from mouse model. PMID- 25449485 TI - Prognostic impact of early glucose variability in acute heart failure patients: a pilot study. PMID- 25449486 TI - Impact of folic acid administration in homocysteine levels, inflammation and in atherosclerotic plaque area in apoE deficient mice. PMID- 25449487 TI - Acute stent thrombosis due to Kounis syndrome. PMID- 25449488 TI - Long-term risks of cardiac and cerebral vascular diseases increased following winter swimming in the cold seawater. PMID- 25449489 TI - Comparison of field questionnaires with the ankle-brachial index for the detection of peripheral artery disease. A population-based study in rural Ecuador. PMID- 25449490 TI - Impact of the oral adsorbent AST-120 on oxidative stress and uremic toxins in high-risk chronic kidney disease patients. PMID- 25449491 TI - Ultrasound carotid intima-media thickness, carotid plaque and cardiac calcium incrementally add to the Framingham Risk Score for the prediction of angiographic coronary artery disease: a multicenter prospective study. PMID- 25449492 TI - Beneficial effects of intravenous beta-blockers in Tako-Tsubo syndrome with dynamic left ventricular outflow tract obstruction and severe haemodynamic impairment. PMID- 25449493 TI - Kounis syndrome after ingestion of undercooked fish: new role of intracoronary imaging techniques. PMID- 25449494 TI - A case of Takotsubo syndrome following 5-fluorouracil chemotherapy. PMID- 25449495 TI - The chance finding of an atrial septal defect in a cancer patient. PMID- 25449496 TI - Resistant or recurrent acute pericarditis: a new therapeutic opportunity? PMID- 25449497 TI - Spontaneous healing of life-threatening iatrogenic type A aortic dissection. PMID- 25449498 TI - Lone or idiopathic atrial fibrillation, messenger of misery in sight. AB - This editorial refers to 'Gender-related differences in risk of cardiovascular morbidity and all-cause mortality in patients hospitalized with incident atrial fibrillation without concomitant diseases: a nationwide cohort study of 9519 patients' by T. Andersson et al. In order to adequately describe root causes and adverse consequences of apparently idiopathic AF, the requested study population has to be large and be followed for a very long time. Andersson et al. adequately deployed the excellent national Swedish health registries in order to cover the hiatus of aforementioned studies in the current idiopathic AF literature. Considering the notion that patients with idiopathic or lone AF have comparable prospects as AF patients overall but are only caught early in their 'arrhythmia and vascular career', the study by Andersson et al. should trigger physicians to give high priority to exposing predisposing factors or early stages of underlying cardiovascular disease in such a way that preventative measures can be accurately deployed in these patients. PMID- 25449499 TI - Hypertrophic cardiomyopathy: genotype-positive, phenotype-"almost" negative. Diagnostic role of exercise in provocation of left ventricular outflow tract gradient. AB - It has been proposed to use exercise stress echocardiography in the upright position with left ventricular outflow tract gradient monitoring both during and after exercise as a marker of genotype-positive/phenotype negative hypertrophic cardiomyopathy (HCM). Doppler measurement of gradient has been a very helpful and diagnostic examination in several subgroups of subjects (especially in young persons, athletes). Recently, many noninvasive (bio)markers have been found to be very helpful in screening patients suspected of HCM before full expression of phenotype. PMID- 25449500 TI - Longitudinal necrotic shafts near TCFAs--a potential novel mechanism for plaque rupture to trigger ACS? AB - It has been questioned for over 15 years why only less than 20% of TCFAs trigger ACS. We illustrate TCFA rupture into adjacent longitudinal necrotic shafts of massive amounts of thrombogenic material into the blood, leading to catastrophic clot formation. This is the potential mechanism for TCFAs triggering ACS. One case presented also illustrates the dangers of stent edges rupturing TCFAs. PMID- 25449501 TI - Addressing discrepancies: personal experience of a cardiac mission programme in Africa. AB - The worldwide incidence of cardiovascular disease (CVD) is increasing, reflecting a combination of ongoing infective diseases and a rapid rise in traditional 'western' risk factors. It is estimated that in the next 20 years that CVD be the leading cause of death in developing nations. There are high incidences of rheumatic heart disease, coronary artery disease, cardiomyopathies, uncorrected congenital heart disease and human immunodeficiency virus (HIV) associated disease in many low-income countries. Such high levels combined with a lack of diagnostic tests and therapeutic options means mortality and morbidity rates are high. A number of charities and organizations have tried to address the discrepancy of cardiac care within developing areas although the needs remain great. However there is no one global cardiac organization that coordinates such humanitarian work. The challenges of missionary work include the need for appropriate facilities, financial constraints of clinical consumables, and lack of education of local healthcare staff, making the move away from the mission model difficult. The strategy for delivery of care in developing countries should be long term educational and technical support, so that local case volumes increase. However it must be realized that there are many different levels of local services within developing nations with different health and educational needs, including some countries with very high facilities and skills levels, yet high case loads. This paper highlights the personal experience of our organization and the types of diseases encountered in developing countries. PMID- 25449502 TI - Impact of stent strut design in metallic stents and biodegradable scaffolds. AB - Advances in the understanding of healing mechanisms after stent implantation have led to the recognition of stent strut thickness as an essential factor affecting re-endothelialization and overall long term vessel healing response after Percutaneous Coronary Interventions (PCI). Emergence of Drug-eluting stents (DESs) with anti-proliferative coating has contributed to reducing the incidence of restenosis and Target Lesion Revascularization (TVR), while progress and innovations in stent materials have in the meantime facilitated the design of newer platforms with more conformability and thinner struts, producing lesser injury and improving integration into the vessel wall. Recent advances in biodegradable metal and polymer materials now also allow for the design of fully biodegradable platforms, which are aimed at scaffolding the vessel only temporarily to prevent recoil and constrictive remodeling of the vessel during the initial period required, and are then progressively resorbed thereby avoiding the drawback of leaving an unnecessary implant permanently in the vessel. The aim of this article is to review recent evolution in stent material and stent strut design while understanding their impact on PCI outcomes. The article describes the different metallic alloys and biodegradable material properties and how these have impacted the evolution of stent strut thickness and ultimately outcomes in patients. PMID- 25449503 TI - MicroRNA-505 identified from patients with essential hypertension impairs endothelial cell migration and tube formation. AB - OBJECTIVES: MicroRNAs are potent regulators of gene expression and may serve as disease markers. This study aimed to identify the plasma microRNA signature in hypertensive patients, which may help better understand the mechanisms underlying the pathogenesis of hypertension and target organ impairment. METHODS AND RESULTS: Plasma samples from three independent cohorts were analyzed to identify circulating microRNA candidates associated with hypertension in patients. The results revealed that the plasma level of hsa-miR-505, a previously reported tumor suppressive microRNA, was significantly elevated in hypertensive patients. Further studies were carried out in endothelial cells to elucidate the functional significance of the enhanced level of hsa-miR-505. The results showed that hsa miR-505 expression markedly impaired the migration and tube formation of all three types of endothelial cells examined. Moreover, gene expression analyses and luciferase reporter assay revealed that FGF18, a proangiogenic factor, is a target directly regulated by hsa-miR-505 in endothelial cells, which may in part underlie the function of hsa-miR-505 in angiogenic processes. CONCLUSIONS: Our findings indicate that hsa-miR-505 is a novel circulating signature of hypertension, which may play a role in angiogenesis. Our results provide mechanistic insights into hypertension-associated pathogenesis and point hsa-miR 505 as a potential target for intervention of hypertension. PMID- 25449504 TI - Intracoronary injection of adenosine before reperfusion in patients with ST segment elevation myocardial infarction: a randomized controlled clinical trial. AB - BACKGROUND: The effect of intracoronary adenosine (ADO) on ST-segment elevation myocardial infarction (STEMI) size and adverse remodeling is not well established. METHODS: In a double-blind trial, 201 patients with STEMI were randomized to receive percutaneous coronary intervention (PCI) within 6 hours of symptom onset, 4.5mg ADO or saline immediately prior to reperfusion. Primary end point: percentage of total myocardial necrotic mass by cardiac magnetic resonance (CMR) 2-7 days post-reperfusion. Secondary end-points: changes in left ventricular volumes and ejection fraction (LVEF) at baseline and at 6 months. RESULTS: Baseline CMR could not be performed in 20 patients. Overall, no significant differences were observed between ADO and placebo regarding infarct size (20.8% vs. 22.5%; p=0.40). However, infarct size was significantly reduced (19.4% vs. 25.7%; p for interaction=0.031) in those with ischemia duration below the median (200 min). CMR at 6 months, performed in 138 patients, did not show statistically significant differences between groups in the rate of LVEF increase (3.3 units (SD 9.6) in ADO group vs. 1.5 units (SD 9) in placebo group; p=0.25). In the subgroup analysis, among patients with ischemia time below 200 min, the increase in LVEF was slightly higher with ADO (3.59% vs. 0.43%; p for interaction=0.06). CONCLUSIONS: Although our study failed to demonstrate that intracoronary administration of ADO prior to PCI limits infarct size, in patients receiving early PCI ADO might enhance myocardial salvage and has a favorable effect on LVEF evolution, which may help to reconcile apparently contradictory results of previous studies. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov (NCT00781404). PMID- 25449505 TI - Influence of renal impairment on myocardial function in outpatients with systolic heart failure: an echocardiographic and cardiac biomarker study. AB - BACKGROUND: Renal dysfunction (RD) is associated with poor outcome in systolic heart failure (HF). Left ventricular ejection fraction (LVEF) is not depressed to a greater extent in patients with RD compared to patients with normal renal function, but it is relatively unknown whether other measures of myocardial function are impaired by RD. The objective of the present study is to evaluate whether RD in systolic HF is associated with excessive impairment of myocardial function, evaluated by strain analysis and cardiac biomarkers. METHODS: Patients with LVEF <0.45% were enrolled from an outpatient HF clinic. The patients underwent advanced echocardiography. Glomerular filtration rate was estimated by the CKD-EPI equation (eGFR) and patients grouped by eGFR: eGFR group-I, >= 90 ml/min/1.73 m(2); eGFR group-II, 60-89 ml/min/1.73 m(2); and eGFR group-III, <= 59 ml/min/1.73 m(2). Multivariate regression models were developed to evaluate the associations between eGFR groups, echocardiographic measures and cardiac biomarkers. RESULTS: A total of 149 patients participated in the study. Median age was 69 years, 26% were female; LVEF was 33%. Patients with a low eGFR were older (P < 0.001), but there were no differences in frequency of atrial fibrillation, hypertension, diabetes and ischemic heart disease between eGFR groups (P > 0.05 for all). RD was associated with impaired global longitudinal strain (P = 0.018), increased E/e' (P = 0.032), larger left atria (P = 0.038) and increased levels of proANP (P < 0.001), NT-proBNP (P < 0.001) and troponin I (P = 0.019) after adjustment for traditional confounders. CONCLUSIONS: Echocardiographic measures and biomarkers reflecting different aspects of myocardial function are impaired in systolic HF patients with RD and the increased mortality risk in these patients may partly be explained by a depressed cardiac function. PMID- 25449506 TI - A high normal thyroid-stimulating hormone is associated with arterial stiffness, central systolic blood pressure, and 24-hour systolic blood pressure in males with treatment-naive hypertension and euthyroid. AB - BACKGROUND: We compared the results of laboratory examinations, echocardiography, arterial stiffness, central blood pressure (BP) and ambulatory BP monitoring (ABPM) between treatment-naive patients with low normal thyroid-stimulating hormone (TSH) and those with high normal TSH levels. METHODS: A total of 285 consecutively-eligible patients with both treatment-naive hypertension and euthyroid were divided into two groups: those with low-normal TSH (0.40-1.99 MUIU/mL, group 1) and high-normal TSH (2.00-4.50 MUIU/mL, group 2) and compared according to group and gender. RESULTS: Males were divided into group 1 (n = 113, 68.9%) and group 2 (n = 51, 31.1%) and females were divided into group 1 (n = 71, 58.7%) and group 2 (n = 50, 41.3%). Multivariate analyses revealed that the augmentation index (71.0 [adjusted mean] +/- 1.7 [standard error] vs. 78.8 +/- 2.5%, P = 0.045), central systolic BP (SBP) (143.3 +/- 2.1 vs. 153.0 +/- 3.2 mmHg, P = 0.013), systemic vascular resistance (SVR, 21.4 +/- 0.6 vs. 23.9 +/- 0.9 mmHg/L/min, P = 0.027), SBP during daytime (144.1 +/- 1.4 vs. 151.6 +/- 2.1 mmHg, P=0.004) and nighttime (130.4 +/- 1.6 vs. 138.5 +/- 2.5 mmHg, P=0.008), and nighttime pulse pressure (PP, 47.2 +/- 0.9 vs. 51.7 +/- 1.4 mmHg, P = 0.010) were significantly higher while cardiac output (5.4 +/- 0.1 vs. 4.8 +/- 0.2L/min, P = 0.043) and PP amplification (1.02 +/- 0.02 vs. 0.94 +/- 0.03, P = 0.039) were significantly lower in the male group 2 than in the male group 1. However, there were no significant differences between the two groups in females. CONCLUSIONS: Treatment-naive hypertensive males with high normal TSH and euthyroid showed higher arterial stiffness, central SBP, SVR, and SBP in ABPM and lower cardiac output and PP amplification as compared to the the low normal TSH group, but not females. PMID- 25449507 TI - Percutaneous left atrial appendage closure with a novel self-modelizing device: a pre-clinical feasibility study. AB - The aim of the study is to evaluate the feasibility and safety of a new left atrial appendage (LAA) occluder. Twelve pigs were included. In 2 pigs the implantation process failed due to pericardial tamponade in 1 pig and device embolization in the other pig. The placement of the devices was controlled via TEE and fluoroscopy. After 6 weeks of implantation the hearts were explanted. The devices were found to be easy to deploy and showed a very good adaptation to the LAA tissue. Eight out of 10 pigs had full closure of the LAA directly after implantation. After six weeks, due to the self-modelizing properties of the device, all pigs had a full closure of the LAA. The macroscopic evaluation of the explanted hearts showed that all devices were securely integrated in LAA tissues. There was one case of mild pericarditis but no macroscopic signs of inflammation on the device surrounding endocardium. The explantation revealed that device loops had penetrated the LAA tissue in three pigs. However, no signs of bleeding, pericardial effusion, or other damage to the LAA wall could be detected and the pigs were in good condition with normal weight gain and no clinical symptoms. The Occlutech(r) LAA occluder achieved complete closure of the LAA in all pigs, and remained in the LAA, with benign healing and no evidence of new thrombus or damage to surrounding structures. Moreover, the uncompromised survival of all implanted pigs demonstrates the feasibility and safety of the device. PMID- 25449508 TI - Atrial fibrillation increases medical cost and complicates hospital outcome of traffic accident-related physical trauma--a nationwide population-based study. AB - BACKGROUND: Traffic accidents account substantially for premature disability and deaths in the modern world. Whether atrial fibrillation complicates the outcome of traffic injury remains under-investigated. METHODS: From 1998 to 2010, all inpatient records stored in the Taiwan National Health Insurance database were screened. Those related with traffic accidents were aggregated to individuals and enrolled. The medical expenses and hospital outcomes were compared between patients with atrial fibrillation (AF group) and either the rest patients (No-AF group) or the propensity-matched patients without atrial fibrillation (No-AF matched group). Prognostic predictive variables for adverse in-hospital events were further identified by multivariate regression analysis. RESULTS: Within the 13-year time span, of the 776,620 individuals ever admitted for traffic accidents, there were 1233 patients with AF. Compared with No-AF and No-AF matched groups respectively, AF patients stayed longer in hospital (10.9 +/- 10.6 vs. 6.8 +/- 7.2 and vs. 8.2 +/- 8.7 days, both p < 0.001), more often required surgical operations (73.2% vs. 69.5%, p = 0.006 and vs. 68.9%, p = 0.021), and consumed larger medical expenses (US$ 2384 +/- 3174 vs. 1246 +/- 2024, or 91.3% higher; and vs. 1406 +/- 2172, or 69.6% higher, both p < 0.001), yet developed more postoperative complications (8.8% vs. 1.2% and vs. 3.2%, both p<0.001) and deaths (2.5% vs. 0.9%, p < 0.001 and vs. 1.6%, p = 0.015). Identified by regression analysis, CHA2DS2-VASC score and representative demographic/injury related variables predict in-hospital adverse events in these AF group patients. CONCLUSIONS: For patients suffering traffic accidents, those with AF consume more surgical resources and medical expenses yet end up with poorer hospital outcome, especially those with higher CHA2DS2-VASC scores and other relevant variables. PMID- 25449509 TI - Operator-blinded contact force monitoring during pulmonary vein isolation using conventional and steerable sheaths. AB - BACKGROUND: We performed contact force (CF) monitoring during pulmonary vein (PV) isolation to evaluate CF according to sheath type, catheter position, and inadequate ablation. METHODS: Thirty consecutive patients (paroxysmal atrial fibrillation, 23; CHADS2 score, 0.5 +/- 0.7; age, 56 +/- 10 years) who underwent PV isolation using a CF-sensing catheter were included. Data for operator-blinded CF, impedance, and duration of the "first touch" (first round of ablation in each PV) was collected. We compared the CF, maximum CF, force-time integral, average impedance, and impedance drop (Delta impedance) between different sheaths (SwartzTM vs. AgilisTM) in 12 different catheter positions, and in inadequate first touches requiring additional ablation. RESULTS: A total of 1283 ablation points (SwartzTM, 620 points; AgilisTM, 663 points) were evaluated. The average CF was significantly higher in the AgilisTM group (17.8 +/- 13.0 g) than the SwartzTM group (15.0 +/- 12.4 g; P < 0.001), especially in the anterior, inferior anterior, and inferior-posterior sections of the right PV, and the top of the roof, and calina of the left PV. The Delta impedance showed a mildly significant negative relationship with the average CF (r=-0.206; P<0.001) and with the force time integral (r = -0.279; P < 0.001). Compared to first touches, the average CF and Delta impedance were significantly smaller in inadequate first touches in the SwartzTM group, but not in the AgilisTM group. CONCLUSIONS: CF for PV isolation was significantly different depending on the position of the catheter and the type of sheath. PMID- 25449510 TI - Electrocardiographic identification of prior myocardial infarction during right ventricular pacing--effect of septal versus apical pacing. AB - BACKGROUND: Electrocardiographic (ECG) identification of prior myocardial infarction (MI) during right ventricular (RV) pacing is of clinical importance. Proposed ECG criteria have been evaluated only during apical pacing. We evaluated the effect of pacing site on the predictive performance of ECG signs of prior MI. METHODS: The present study is a secondary analysis of a prospective, multicenter study which randomized recipients of an implantable cardioverter defibrillator to an apical versus septal RV lead positioning. ECGs of patients with or without prior MI were analyzed for the presence of the following criteria: Cabrera sign, Chapman sign, QR pattern in leads I, aVL, V5 or V6, QR in inferior leads and notching in the descending slope of the QRS complex in inferior leads. RESULTS: The MI group included 89 patients (55.1% apically paced), while 99 patients had no prior MI (50.5% apically paced). In the total population, the Cabrera sign presented the highest specificity (97%) and diagnostic accuracy (62.2%), with a sensitivity of 23.6%. The Cabrera sign was the only significant predictor of a prior MI [OR=9.9, (95%CI:2.8-34.5), p<0.001], among all ECG markers. Pacing site did not significantly influence the sensitivity and specificity of the Cabrera sign for detection of prior MI. CONCLUSIONS: In our study, the Cabrera sign was the only ECG marker that predicted the presence of prior MI during ventricular paced rhythm. Septal RV lead positioning did not affect the predictive performance of the Cabrera sign. PMID- 25449512 TI - Incidence and predictors of appropriate therapies delivered by the implantable cardioverter defibrillator in patients with ischemic cardiomyopathy: a systematic review. AB - BACKGROUND: Although the implantable cardioverter defibrillator (ICD) improves the survival of patients at increased risk of sudden cardiac death due to systolic heart failure, ICD shocks have been associated with both worse survival and quality of life. We performed a systematic review of primary prevention ICD studies to evaluate the incidence and clinical predictors of appropriate ICD shocks or anti-tachycardia pacing (ATP) in patients with ischemic cardiomyopathy. METHODS: We performed a literature search in MEDLINE. Eligible studies had to be full text, written in the English language, performed in adults aged >= 19, and published from 1999 through April 2014. RESULTS: Of 289 identified studies, 9 met all our inclusion criteria. The mean length of follow up ranged from 17 to 45.5 months. The incidence of appropriate ICD therapy varied from 17% to 31%. Among those studies, only 4 included data on the clinical characteristics of appropriate ICD therapy recipients. Characteristics associated with appropriate ICD therapy included male sex, advanced New York Heart Association class, non sustained ventricular tachycardia, and lower serum creatinine. Patients who received appropriate therapy were also less likely to be on a beta-blocker. Left ventricular ejection fraction was not significantly different between patients who received appropriate ICD therapy and those who did not. CONCLUSION: The incidence of appropriate ICD therapy is not trivial in patients with ischemic cardiomyopathy and a primary prevention ICD. Predictors of appropriate ICD therapy have not been adequately assessed in large patient populations. As such, large prospective studies of predictors of appropriate ICD therapies are needed. PMID- 25449511 TI - Histone deacetylase inhibition reduces pulmonary vein arrhythmogenesis through calcium regulation. AB - Pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation (AF). Histone deacetylases (HDACs) are vital to calcium homeostasis and AF genesis. However, the electrophysiological effects of HDAC inhibition were unclear. This study evaluated whether HDAC inhibition can regulate PV electrical activity through calcium modulation. Whole-cell patch-clamp, confocal microscopic with fluorescence, and Western blot were used to evaluate electrophysiological characteristics and Ca(2+) dynamics in isolated rabbit PV cardiomyocytes with and without MPT0E014 (a pan HDAC inhibitor), MS-275 (HDAC1 and 3 inhibitor), and MC 1568 (HDAC4 and 6 inhibitor) for 5~8h. Atrial electrical activity and induced-AF (rapid atrial pacing and acetylcholine infusion) were measured in rabbits with and without MPT0E014 (10mg/kg treated for 5 hours) in vivo. MPT0E014 (1 MUM) treated PV cardiomyocytes (n=12) had slower beating rates (2.1 +/- 0.2 vs. 2.8 +/ 0.1 Hz, p < 0.05) than control PV cardiomyocytes. However, control (n=11) and MPT0E014 (1 MUM)-treated (n = 12) SAN cardiomyocytes had similar beating rates (3.2 +/- 0.2 vs. 2.9 +/- 0.3 Hz). MS-275-treated PV cardiomyocytes (n = 12, 2.3 +/- 0.2 Hz), but not MC-1568-treated PV cardiomyocytes (n=14, 3.1 +/- 0.3 Hz) had slower beating rates than control PV cardiomocytes. MPT0E014-treated PV cardiomyocytes (n=14) had a lower frequency (2.4 +/- 0.6 vs. 0.3 +/- 0.1 spark/mm/s, p < 0.05) of Ca(2+) sparks than control PV (n=17) cardiomyocytes. As compared to control, MPT0E014-treated PV cardiomyocytes had reduced Ca(2+) transient amplitudes, sodium-calcium exchanger currents, and ryanodine receptor expressions. Moreover, MPT0E014-treated rabbits had less AF and shorter AF duration than control rabbits. In conclusions, HDAC inhibition reduced PV arrhythmogenesis and AF inducibility with modulation on calcium homeostasis. PMID- 25449513 TI - The prognostic value of long-term visit-to-visit blood pressure variability on stroke in real-world practice: a dynamic cohort study in a large representative sample of Chinese hypertensive population. AB - BACKGROUND: The prognostic significance of long-term visit-to-visit blood pressure variability (BPV) has not yet been validated in "real world" hypertensive patients. The aim of the current study is to explore the prognostic value of BPV on stroke in hypertensive patients. METHODS: This was a dynamic prospective cohort study based on electronic medical records in Shanghai, China. Hypertensive patients (N=122,636) without history of stroke at baseline, were followed up from 2005 to 2011. The cohort comprised of 4522 stroke patients and 118,114 non-stroke patients during a mean follow-up duration of 48 months. BPV was measured by standard deviation (SD) and the coefficient of variation (CV) of blood pressure. RESULTS: The visit-to-visit variability of both systolic blood pressure (SBP) and diastolic blood pressure (DBP) was independently associated with the occurrence of stroke [SD: the hazard ratios (95% confidence intervals) of SBP and DBP were 1.042 (1.021 to 1.064) and 1.052 (1.040 to 1.065); CV: the hazard ratios (95% confidence intervals) of SBP and DBP were 1.183 (1.010 to 1.356) and 1.151 (1.005 to 1.317), respectively]. The hazard ratio values increased along with an increase of the BPV levels of SBP and DBP. The increment effect remained significant after controlling the blood pressure control status of subjects. CONCLUSIONS: Increased BPV of both SBP and DBP, independent of the average blood pressure, is a predictor of stroke among community hypertensive patients in real-world clinical practice. The risk of stroke increased along with increased BPV. Stabilizing BPV might be a therapeutic target in hypertension. PMID- 25449514 TI - Detection of significant stenosis in the left anterior descending artery by 'virtual myocardial perfusion' bolus tracking, 320 slice computed tomography. AB - PURPOSE: We used bolus-tracking CT-images, which are usually used only to detect contrast-material in target organs for optimal-starting of acquisition, as virtual first pass myocardial perfusion images. METHODS: Retrospective-analysis of 14 patients (10 male, 63 +/- 10 years) diagnosed with >= 75% stenosis confined to left-anterior-descending-artery (LAD) (7 patients, Group-1) or insignificant stenosis of any coronary artery (7 patients Group-2) diagnosed using invasive coronary-angiograms (ICA) and enhanced 320-slice-CT within 3-months and without incident between examinations. Bolus-tracking CT-images were acquired at mid level left-ventricle (LV) until CT-attenuation of descending-aorta increased to 200 HU. We measured CT-attenuation (HU) in the LV anterior-wall (AW), the basal inter-ventricular-septum (BIVS), and LV basal lateral-wall (BLW) in end-systole using both bolus-tracking images and routine, enhanced, early-phase CT-images. RESULTS: In the bolus-tracking images, the Group-1 LV AW, BIVS, BLW CT attenuation and ratio of LV AW CT attenuation to the average of BIVS and BLW were 36 +/- 7HU, 62 +/- 11HU, 58 +/- 25HU, and 0.6 +/- 0.1 respectively. In Group-2, they were 53 +/- 14HU, 56 +/- 9HU, 54 +/- 15HU, and 1.0 +/- 0.3 respectively. LV AW CT attenuation and the ratio of LV AW CT values to the average of BIVS and BLW, were significantly lower in Group-1 (both P < 0.05). These values were not significant using routine, enhanced, early-phase CT-images. CONCLUSIONS: Bolus tracking CT-images may be useful to detect the LAD-confined stenosis that cannot be detected using routine, enhanced, early-phase CT-images. This can be achieved by measuring the local-reduction in CT-attenuation of the LV AW compared with the average of those of the BIVS and BLW and without the need for drugs, exercise or additional radiation-exposure. PMID- 25449515 TI - Anti-platelet or anti-coagulant agent for the prevention of ischemic stroke in patients with end-stage renal disease and atrial fibrillation--a nation-wide database analyses. AB - OBJECTIVE: The risk/benefit profiles of anti-coagulant or anti-platelet agents in patients with end-stage renal disease (ESRD) and atrial fibrillation (AF) remained unclear. We aimed to investigate the stroke risks in these patients with or without anti-coagulant/anti-platelet therapy by using our national database. METHOD: By using our national health insurance ESRD claim database, we searched patients with AF, more than 18 years old and without prior history of ischemic stroke. Medication information as well as the events of ischemic stroke, hemorrhagic stroke, and transient ischemic accident during follow-up were identified from the database. Propensity score method was used to match all the potential confounders between patients with and without anti-platelets/warfarin treatment. RESULT: A total of 134,410 ESRD patients were identified in the database. Among them, patients with non-valvular AF, over 18 years old, without prior history of ischemic stroke and received monotherapy with anti-platelets (1622) or warfarin (294) served as case groups while patients (2983) without taking any anti-platelets and warfarin served as control groups. The incidences of ischemic stroke or transient ischemic attack (TIA) were not different among the control (6.6%), anti-platelet (6.2%) and warfarin (5.1%) groups in a follow up period of approximately 4 years. The results remained unchanged after propensity match. Cox-regression analyses also showed no beneficial effect of anti-platelet or warfarin therapy in overall and any subgroups. CONCLUSION: In this nationwide cohort analyses, we found that anti-platelet or warfarin treatment could not lower the risk of ischemic stroke in patients with ESRD. PMID- 25449517 TI - Marked sympathetic activation and baroreflex dysfunction in true resistant hypertension. AB - BACKGROUND: An increase in sympathetic drive to the heart and the peripheral circulation characterizes mild and severe essential hypertension. However, it remains unsettled whether sympathetic cardiovascular influences are potentiated in true resistant hypertension (RHT). METHODS: In 32 RHT patients treated with 4.6 +/- 0.3 drugs (mean +/- SEM) and aged 58.6 +/- 2.1 years, 35 non-resistant treated hypertensives (HT) and 19 normotensive controls (NT), all age-matched with RHT, we measured clinic, 24-hour ambulatory and beat-to-beat blood pressures (BP), heart rate (HR, EKG), muscle sympathetic nerve traffic (MSNA, microneurography) and spontaneous baroreflex MSNA-sensitivity. RESULTS: BP values were markedly greater in RHT patients than in NT and HT (172.2 +/- 1.7/100.7 +/- 1.2 vs 132.1 +/- 1.3/82.1 +/- 0.9 and 135.5 +/- 1.2/83.6 +/- 0.9 mmHg, P < 0.01). This was paralleled by a significant and marked increase in MSNA (87.8 +/- 2.0 vs 46.8 +/- 2.6 and 59.3 +/- 1.7 and bursts/100 heartbeats, P < 0.01). In multiple regression analysis the MSNA increase observed in RHT was significantly related to hemodynamic, hormonal and metabolic variables. It was also significantly related to plasma aldosterone values as well as spontaneous baroreflex MSNA sensitivity, which were the variables that at the multivariate analysis were more closely related to the adrenergic activation of RHT after adjustment for confounders, including antihypertensive treatment (r(2)partial=0.04405 and r(2)partial=0.00878, P<0.05 for both). CONCLUSIONS: These data represent the first evidence that RHT is a state of marked adrenergic overdrive, greater for magnitude than that detectable in HT. They also suggest that impaired baroreflex mechanisms, along with hemodynamic and neurohumoral factors, may be responsible for the phenomenon. PMID- 25449516 TI - Different patterns of myocardial iron distribution by whole-heart T2* magnetic resonance as risk markers for heart complications in thalassemia major. AB - BACKGROUND: The multislice multiecho T2* cardiovascular magnetic resonance (CMR) technique allows to detect different patterns of myocardial iron overload (MIO). The aim of this cross-sectional study was to verify the association between cardiac complications (heart failure and arrhythmias), biventricular dysfunction and myocardial fibrosis with different patterns of MIO in thalassemia major (TM) patients. METHODS: We considered 812 TM patients enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network. The T2* value in all the 16 cardiac segments was evaluated. RESULTS: We identified 4 groups of patients: 138 with homogeneous MIO (all segments with T2* < 20 ms), 97 with heterogeneous MIO (some segments with T2* < 20 ms, others with T2* >= 20 ms) and significant global heart iron (global heart T2* < 20 ms), 238 with heterogeneous MIO and no significant global heart iron, and 339 with no MIO (all segments with T2* >= 20 ms). Compared to patients with no MIO, patients with homogeneous MIO were more likely to have cardiac complications (odds ratio-OR = 2.67), heart failure (OR = 2.54), LV dysfunction (OR = 5.59), and RV dysfunction (OR = 2.26); patients with heterogeneous MIO and significant global heart iron were more likely to have heart failure (OR = 2.38) and LV dysfunction (OR = 2.39). CONCLUSIONS: Cardiac complications, heart failure and dysfunction were correlated with MIO distribution with an increasing risk from the TM patients with no MIO to those with homogeneous MIO. Using a segmental approach, early iron deposit or homogeneous MIO patterns can be characterized to better tailor chelation therapy. PMID- 25449519 TI - Mistaken inference caused by reliance on and misinterpretation of a significance test. PMID- 25449518 TI - Clinical and prognostic implications of plasma NGAL and NT-proBNP in adult patients with congenital heart disease. AB - BACKGROUND: Prognostic value of NT-proBNP is well established in patients with congenital heart disease. Growing evidence suggests that plasma NGAL is elevated in heart failure but data is limited in congenital heart disease. This study investigates the combined prognostic value of plasma NGAL with plasma NT-proBNP in adult patients with congenital heart disease. METHODS: Plasma levels of NT proBNP and NGAL were measured in 76 consecutive adult patients (33 men, mean age 31.7 +/- 14 yrs) with congenital heart disease and normal values of serum creatinine. Patients were divided in three groups: A: simple cardiac lesions, B: complex cardiac lesions and C: cyanotic lesions. Patients were also monitored for long-term major cardiovascular events: death, hospitalization, NYHA class worsening, new onset of arrhythmias, surgical or percutaneous intervention. RESULTS: NGAL value was significantly different between groups: In group A median NGAL value was 64.5 +/- 36.7 ng/ml, in group B median NGAL value was 88.77 +/- 36.17 ng/ml and in group C median NGAL value was 121 +/- 40 ng/ml (group A vs. group B: p = 0.048, group B vs. group C: p = 0.037, group A vs. group C: p = 0.003). Plasma NT-proBNP predicted all events (HR = 1.001, CI = 1.001-1.002, p = 0.0006) as well as cardiovascular death alone (HR = 1.001, CI = 1.001-1.002, p = 0.0004); plasma NGAL was the only predictor of cardiovascular death (HR = 1.017, CI = 1.001-1.033, p = 0.037). CONCLUSION: Plasma NGAL levels were lower in patients with simple congenital disease compared to patients with complex congenital heart disease and cyanotic congenital heart disease. Plasma NGAL levels correlated with NT-proBNP and could predict cardiovascular death in this small cohort of patients. PMID- 25449520 TI - Patterns of cardiovascular drugs prescribed for an elderly Swedish population. PMID- 25449521 TI - Risk stratification for prediction of adverse coronary events in emergency department chest pain patients with a machine learning score compared with the TIMI score. PMID- 25449522 TI - Multiple mechanisms of SDF-1 promoting VEGF-induced endothelial differentiation of mesenchymal stem cells. PMID- 25449523 TI - The relationship between serum vitamin D and HOMA-IR in overweight elderly patients. PMID- 25449524 TI - Transesophageal echocardiography guidance is essential in the management of prosthetic valve thrombosis. PMID- 25449525 TI - Bicuspid aortic valve syndrome: a heterogeneous and still unknown condition. PMID- 25449526 TI - Gradual staple line disruption presenting with subtle multidiverticular pocket syndrome after STARR. PMID- 25449528 TI - Chemotherapy of WAP-T mouse mammary carcinomas aggravates tumor phenotype and enhances tumor cell dissemination. AB - In this study, the effects of the standard chemotherapy, cyclophosphamide/adriamycin/5-fluorouracil (CAF) on tumor growth, dissemination and recurrence after orthotopic implantation of murine G-2 cells were analyzed in the syngeneic immunocompetent whey acidic protein-T mouse model (Wegwitz et al., PLoS One 2010; 5:e12103; Schulze-Garg et al., Oncogene 2000; 19:1028-37). Single dose CAF treatment reduced tumor size significantly, but was not able to eradicate all tumor cells, as recurrent tumor growth was observed 4 weeks after CAF treatment. Nine days after CAF treatment, residual tumors showed features of regressive alterations and were composed of mesenchymal-like tumor cells, infiltrating immune cells and some tumor-associated fibroblasts with an intense deposition of collagen. Recurrent tumors were characterized by coagulative necrosis and less tumor cell differentiation compared with untreated tumors, suggesting a more aggressive tumor phenotype. In support, tumor cell dissemination was strongly enhanced in mice that had developed recurrent tumors in comparison with untreated controls, although only few disseminated tumor cells could be detected in various organs 9 days after CAF application. In vitro experiments revealed that CAF treatment of G-2 cells eliminates the vast majority of epithelial tumor cells, whereas tumor cells with a mesenchymal phenotype survive. These results together with the in vivo findings suggest that tumor cells that underwent epithelial-mesenchymal transition and/or exhibit stem-cell like properties are difficult to eliminate using one round of CAF chemotherapy. The model system described here provides a valuable tool for the characterization of the effects of chemotherapeutic regimens on recurrent tumor growth and on tumor cell dissemination, thereby enabling the development and preclinical evaluation of novel therapeutic strategies to target mammary carcinomas. PMID- 25449529 TI - Imaging neuroinflammation in Alzheimer's disease and other dementias: Recent advances and future directions. AB - Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal dementia (FTD), and Huntington's disease (HD) are the main neurodegenerative causes of dementia. Causes and mechanisms of these diseases remain elusive. Neuroinflammation is increasingly emerging as an important pathological factor in their development. Positron emission tomography (PET) using [11C]PK11195 represents a method of visualizing the microglial component of neuroinflammation via the translocator protein (TSPO) and we discuss the valuable insights this has yielded in neurodegenerative diseases. We discuss the limitations of this method and the development of second generation TSPO PET ligands which hope to overcome these limitations. We also discuss other methods of visualizing neuroinflammation and review the state of current dementia treatments targeted at neuroinflammation. It is our view that a multimodal investigation into neuroinflammation in AD, Parkinson's disease dementia, FTD and HD will yield valuable pathological insights which will usefully inform development of therapeutic targets and biomarkers. PMID- 25449530 TI - Transcranial direct current stimulation in mild cognitive impairment: Behavioral effects and neural mechanisms. AB - INTRODUCTION: The long preclinical phase of Alzheimer's disease provides opportunities for potential disease-modifying interventions in prodromal stages such as mild cognitive impairment (MCI). Anodal transcranial direct current stimulation (anodal-tDCS), with its potential to enhance neuroplasticity, may allow improving cognition in MCI. METHODS: In a double-blind, cross-over, sham controlled study, anodal-tDCS was administered to the left inferior frontal cortex during task-related and resting-state functional magnetic resonance imaging (fMRI) to assess its impact on cognition and brain functions in MCI. RESULTS: During sham stimulation, MCI patients produced fewer correct semantic word-retrieval responses than matched healthy controls, which was associated with hyperactivity in bilateral prefrontal regions. Anodal-tDCS significantly improved performance to the level of controls, reduced task-related prefrontal hyperactivity and resulted in "normalization" of abnormal network configuration during resting-state fMRI. DISCUSSION: Anodal-tDCS exerts beneficial effects on cognition and brain functions in MCI, thereby providing a framework to test whether repeated stimulation sessions may yield sustained reversal of cognitive deficits. PMID- 25449527 TI - Food and addiction among the ageing population. AB - Obesity among the elderly is a growing public health concern. Among the various factors that may contribute to the current rates of obesity is the rewarding aspect of highly palatable foods and beverages, which may lead to overconsumption and excess caloric intake. The present review describes recent research supporting the hypothesis that, for some individuals, the consumption these highly palatable foods and beverages may lead to the development of addictive like behaviors. In particular, the authors consider the relevance of this hypothesis to the ageing population. PMID- 25449532 TI - Isolation of high-affinity, neutralizing anti-idiotype antibodies by phage and ribosome display for application in immunogenicity and pharmacokinetic analyses. AB - Anti-idiotype antibodies against a therapeutic antibody are key reagents for the development of immunogenicity and pharmacokinetic (PK) assays during pre-clinical and clinical development. Here we have used a combination of phage and ribosome display to isolate a panel of monoclonal anti-idiotype antibodies with sub nanomolar affinity and high specificity to a human anti-IgE monoclonal antibody. Anti-idiotype antibodies were enriched from scFv libraries using phage display, and a biochemical epitope competition assay was used to identify anti-idiotypes which neutralized IgE binding, which was essential for the intended use of the anti-idiotypes as positive controls in neutralizing anti-drug antibody (Nab) assays. The phage display-derived anti-idiotype antibodies were rapidly affinity matured using a random point mutagenesis approach in ribosome display. Ten anti idiotype antibodies with improved neutralizing activity relative to the parent antibodies displayed sub-nanomolar affinity for the anti-IgE antibody, representing up to 20-fold improvements in affinity from just two rounds of affinity-based selection. The optimized anti-idiotype antibodies retained the specificity of the parent antibodies, and importantly, were fit for purpose for use in PK and anti-drug antibody (ADA) assays. The approach we describe here for generation of anti-idiotype antibodies to an anti-IgE antibody is generically applicable for the rapid isolation and affinity maturation of anti-idiotype antibodies to any antibody-based drug candidate. PMID- 25449531 TI - Self-rated and informant-rated everyday function in comparison to objective markers of Alzheimer's disease. AB - It is recognized that individuals with mild cognitive impairment (MCI) already demonstrate difficulty in aspects of daily functioning, which predicts disease progression. This study examined the relationship between self- versus informant report of functional ability, and how those reports relate to objective disease measures across the disease spectrum (i.e. cognitively normal, MCI, Alzheimer's disease). A total of 1080 subjects with self- and/or informant-rated Everyday Cognition questionnaires were included. Objective measures included cognitive functioning, structural brain atrophy, cerebrospinal fluid abnormalities, and a marker of amyloid deposition using positron emission tomography with [18F]AV45 (florbetapir). Overall, informant-report was consistently more associated with objective markers of disease than self-report although self-reported functional status may still have some utility in early disease. PMID- 25449534 TI - Metaphor: finding bi-directional best hit homology relationships in (meta)genomic datasets. AB - As the number of assembled genome and metagenome sequences continue to grow at an ever-increasing pace, so does the need for fast, flexible and automated pipelines for generating meaningful homologous relationships within and between these (meta)genomes. Such relationships, or lack thereof, are crucial for differentiating between microbial organisms and environments at compositional, functional and phylogenetic levels. Metaphor is a standalone application that identifies core genes, unique genes, orthologs and paralogs in complex genomic datasets. It is not only limited to isolate genomes, but can also be applied to metagenomes due to its flexible implementation of Bi-directional Best Hit analysis. Thus, Metaphor can be used for a variety of functional and phylogenetic applications on a multitude of (meta)genome datasets. PMID- 25449535 TI - Genomics special issue on 5-hydroxymethylation. PMID- 25449536 TI - Genes associated with antibody-dependent cell activation are overexpressed in renal biopsies from patients with antibody-mediated rejection. AB - INTRODUCTION: Antibody-mediated rejection (ABMR) is dependent on complement activating donor-specific anti-HLA antibodies (DSA). This is commonly detected by C4d deposition in allografts. However, recent data define a C4d negative ABMR phenotype suggesting a role for complement-independent DSA injury, antibody dependent cellular cytotoxicity (ADCC). METHODS: Here, we established an in vitro ADCC model that identified human ADCC-activated genes using microarray analysis. We subsequently interrogated renal allograft biopsies from patients with ABMR and controls for mRNA expression of the ADCC-activated gene set. RESULTS: We identified 13 ADCC-activated genes. Six gene expression assays including 8 of the 13 genes (CCL3, CCL4/CCL4L1/CCL4L2, CD160, IFNG, NR4A3 and XCL1/XCL2) were analyzed in 127 kidney biopsies obtained from HLA-sensitized (HS), non-HS patients and control individuals. Most ADCC-activated genes showed significantly higher expression in the transplant samples compared to the controls (p<0.0005). The gene expression levels were significantly higher in HS and non-HS transplant patients who developed ABMR compared to those who did not (p=0.04-0.002). There was no difference in the gene expression levels between C4d positive and negative ABMR (p=0.26-0.99). Samples from high PRA (>80%) or positive DSA patients showed higher gene expression levels for the ADCC-activated genes compared to low PRA (<80%) and negative DSA patients (p=0.04-0.001). CONCLUSION: ADCC pathways are active in transplant patients with ABMR, and likely mediate allograft injury, providing a potential mechanism for C4d negative ABMR. PMID- 25449533 TI - Inoculation stress hypothesis of environmental enrichment. AB - One hallmark of psychiatric conditions is the vast continuum of individual differences in susceptibility vs. resilience resulting from the interaction of genetic and environmental factors. The environmental enrichment paradigm is an animal model that is useful for studying a range of psychiatric conditions, including protective phenotypes in addiction and depression models. The major question is how environmental enrichment, a non-drug and non-surgical manipulation, can produce such robust individual differences in such a wide range of behaviors. This paper draws from a variety of published sources to outline a coherent hypothesis of inoculation stress as a factor producing the protective enrichment phenotypes. The basic tenet suggests that chronic mild stress from living in a complex environment and interacting non-aggressively with conspecifics can inoculate enriched rats against subsequent stressors and/or drugs of abuse. This paper reviews the enrichment phenotypes, mulls the fundamental nature of environmental enrichment vs. isolation, discusses the most appropriate control for environmental enrichment, and challenges the idea that cortisol/corticosterone equals stress. The intent of the inoculation stress hypothesis of environmental enrichment is to provide a scaffold with which to build testable hypotheses for the elucidation of the molecular mechanisms underlying these protective phenotypes and thus provide new therapeutic targets to treat psychiatric/neurological conditions. PMID- 25449537 TI - Kinetics of B, T, NK lymphocytes and isoagglutinin titers in ABO incompatible living donor liver transplantation using rituximab and basiliximab. AB - BACKGROUND: The kinetics of isoagglutinin titers and lymphocyte subpopulations including B, T, and natural killer (NK) cells after ABO incompatible (ABO-I) living donor liver transplantation (LDLT) have not been evaluated. METHODS: From January 2012 to July 2013, consecutive ABO-I LDLT patients were enrolled at the National Cancer Center. Our desensitizing protocol included rituximab, plasma exchanges, basiliximab, and intravenous immune globulin without splenectomy. RESULTS: Twenty patients (14 males, 6 females) underwent ABO-I LDLT due to HCC (n=15) or liver cirrhosis (n=5). There was no hyperacute and antibody-mediated rejection. The isoagglutinin titers were effectively lowered less than 1:16 before operation. CD 19+ B cells were rapidly eliminated after rituximab and suppressed during 6months postoperatively. CD3+ and CD4+ T cells were elevated higher than CD8+ T cells. CD4/CD8 ratio was increased during first 1month postoperatively and decreased thereafter. CD16+CD56+ NK cells were lowered and restored after 4months of LDLT. Among 15 patients with HCC, 5 patients (33.3%) experienced early tumor recurrence (1/8 within Milan and 4/7 beyond Milan). CONCLUSIONS: Our protocol showed effective results in preventing antibody mediated rejection and suppressing B lymphocytes. Application to advanced hepatocellular carcinoma should be considered due to decreased natural immunity after ABO-I LDLT. PMID- 25449538 TI - Iota-carrageenan/chitosan/gelatin scaffold for the osteogenic differentiation of adipose-derived MSCs in vitro. AB - In this study, we have developed iota-carrageenan/chitosan/gelatin (CCG) scaffold containing multiple functional groups (-NH2 , -OH, -COOH, and -SO3 H) to resemble the native extracellular matrix (ECM), using the ion-shielding technology and ultrasonic dispersion method. Fourier transform infrared spectroscopy (FTIR) of the CCG scaffolds suggests that the formation of CCG network involves electrostatic interactions between iota-carrageenan (iota-CA) and chitosan/gelatin, and the covalent cross-linking among amino groups of chitosan and/or gelatin. Scanning electron microscopic (SEM) observation reveals that the porous structure of scaffolds can be modulated by the ratio of iota-CA to chitosan/gelatin. The swelling ratio of the hydrogels increases as the iota-CA contents increase. Using differential scanning calorimetry, we found that the double helix structure of iota-CA is only stabilized at low contents of iota-CA in the CCG scaffolds (e.g., 5 wt %). The scaffolds containing 5% iota-CA showed the best protein adsorption capacity (4.46 +/- 0.63 MUg protein/mg scaffold) and elastic modulus (5.37 +/- 1.03 MPa). In addition, the CCG scaffolds exhibit excellent support for adipose-derived mesenchymal stem cells (ADMSCs) attachment and proliferation, and they can improve the osteogenic differentiation and neovascularization capacities of ADMSCs. Overall, we conclude that the CCG may represent an ideal scaffold material for bone tissue engineering. PMID- 25449539 TI - Turn-on fluorescence and unprecedented encapsulation of large aromatic molecules within a manganese(II)-triazole metal-organic confined space. AB - For the purpose of investigating the coordination behavior of sterically congested alkenes and exploring the possibility of cofacial complexation in the polycyclic aromatic system for the formation of extended polymeric networks, a new tetradentate ligand, 1,1,2,2-tetrakis[4-(1H-1,2,4-triazol-1 yl)phenyl]ethylene (TTPE), has been designed and synthesized. By using TTPE as a building block with regard to the self-assembly with MnCl2 ?4 H2 O, a novel two dimensional coordination framework {[Mn(TTPE)Cl2 ]?4 CHCl3 }n (1) can be isolated. Anion-exchange and organic-group-functionalized aromatic guest TTPE loaded host-guest complex experimental results indicate that coordinated Cl(-) anions in the 2D framework of 1 can be completely replaced with dissociative ClO4 (-) groups in an irreversible single-crystal-to-single-crystal transformation fashion, as evidenced by the anion-exchange products of {[Mn(TTPE)(H2 O)2 ](ClO4 )2 ?0.5 TTPE?5.25 H2 O}n (2). Interestingly, TTPE, acting as an organic template, was encapsulated in the confined space of the 2D grid of 2. To the best of our knowledge, such large organic molecules encapsulated in the reactive organic group-functionalized aromatic-guest-loaded host-guest complex are unprecedented up to now. Luminescence measurements illustrate that 1 and 2 represent novel examples of sensing materials based on triazole derivatives. Further, 2 has been demonstrated by tuning the fluorescence response of porous metal-organic frameworks as a function of adsorbed small analytes. PMID- 25449541 TI - 115-year-old society knows how to reach young scientists: ASM Young Ambassador Program. AB - With around 40,000 members in more than 150 countries, American Society for Microbiology (ASM) faces the challenge of meeting very diverse needs of its increasingly international members base. The newly launched ASM Young Ambassador Program seeks to aid the Society in this effort. Equipped with ASM conceptual support and financing, Young Ambassadors (YAs) design and pursue country-tailored approaches to strengthen the Society's ties with local microbiological communities. In a trans-national setting, the active presence of YAs at important scientific events, such as 16th European Congress on Biotechnology, forges new interactions between ASM and sister societies. The paper presents an overview of the Young Ambassadors-driven initiatives at both global and country levels, and explores the topic of how early-career scientists can contribute to science diplomacy and international relations. PMID- 25449543 TI - DC-Analyzer-facilitated combinatorial strategy for rapid directed evolution of functional enzymes with multiple mutagenesis sites. AB - Iterative saturation mutagenesis (ISM) has been shown to be a powerful method for directed evolution. In this study, the approach was modified (termed M-ISM) by combining the single-site saturation mutagenesis method with a DC-Analyzer facilitated combinatorial strategy, aiming to evolve novel biocatalysts efficiently in the case where multiple sites are targeted simultaneously. Initially, all target sites were explored individually by constructing single site saturation mutagenesis libraries. Next, the top two to four variants in each library were selected and combined using the DC-Analyzer-facilitated combinatorial strategy. In addition to site-saturation mutagenesis, iterative saturation mutagenesis also needed to be performed. The advantages of M-ISM over ISM were that the screening effort is greatly reduced, and the entire M-ISM procedure was less time-consuming. The M-ISM strategy was successfully applied to the randomization of halohydrin dehalogenase from Agrobacterium radiobacter AD1 (HheC) when five interesting sites were targeted simultaneously. After screening 900 clones in total, six positive mutants were obtained. These mutants exhibited 4.0- to 9.3-fold higher k(cat) values than did the wild-type HheC toward 1,3 dichloro-2-propanol. However, with the ISM strategy, the best hit showed a 5.9 fold higher k(cat) value toward 1,3-DCP than the wild-type HheC, which was obtained after screening 4000 clones from four rounds of mutagenesis. Therefore, M-ISM could serve as a simple and efficient version of ISM for the randomization of target genes with multiple positions of interest. PMID- 25449542 TI - A novel D-mandelate dehydrogenase used in three-enzyme cascade reaction for highly efficient synthesis of non-natural chiral amino acids. AB - A novel NAD(+)-dependent D-mandelate dehydrogenase was identified from Lactobacillus brevis (LbDMDH). After purified to homogeneity, the optimum pH and temperature for oxidation of D-mandelate were pH 10.0 and 40 degrees C, and the Km and kcat were 1.1 mM and 355 s(-1) respectively. Employing the LbDMDH together with a mandelate racemase from Pseudomonas putida and a leucine dehydrogenase (EsLeuDH) from Exiguobacterium sibiricum, we established a three-step one-pot domino reaction system for preparing chiral L-phenylglycine from racemic mandelic acid with internal cofactor recycling. Under the optimum conditions, 30.4 g rac mandelic acid (0.2 M) at 1L scale had been converted into chiral L-phenylglycine, with 96.4% conversion, 86.5% isolation yield, >99% eep and 50.4 gL(-1)d(-1) space time yield. PMID- 25449544 TI - Conjugation of alginate to a synthetic peptide containing T- and B-cell epitopes as an induction for protective immunity against Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a major cause of respiratory tract infections worldwide, particularly in hospitalized patients with immunosuppressed conditions and cystic fibrosis (CF). Excessive use of antibiotics means that there is currently resistance among bacterial infections to many drugs. Vaccination is a strategy that can reduce mortality and morbidity rates in infections such as those caused by P. aeruginosa. Alginate has a critical role in such infections and affects pathogenicity of the bacterium. In this work, the bioinformatics approach was used to design and synthesis a carrier peptide (ERRANAVRDVLVNEY), derived from OMP F P. aeruginosa. This peptide contained both B- and T-cell epitopes based on prediction models. Conjugation of alginate to carrier peptide was performed and then analyzed by Fourier transform infrared spectroscopy (FTIR). Results of this study on mice showed that the conjugate elicited anti alginate-IgG that were not detected after immunization with naive alginate. The effect of the antibodies to alginate conjugate was evaluated as highly opsonic and showed moderate to high-level killing activity against two mucoid strains. IgG1 was also dominant among IgG subclasses. Mice vaccinated with the conjugate vaccine survived lethal challenges (2 *LD 50). Furthermore, using an acute pneumonia model of infection in mice, determined that levels of P. aeruginosa in mice were significantly reduced in the vaccinated group. Thus, tests confirmed ability of this conjugate to elicit protective and opsonophagocytic antibodies that candidate our vaccine for further studies. PMID- 25449545 TI - Complete genome sequence of the caprolactam-degrading bacterium Pseudomonas mosselii SJ10 isolated from wastewater of a nylon 6 production plant. AB - Pseudomonas mosselii strain SJ10 is a caprolactam-degrading bacterium belonging to the class Gammaproteobacteria, which was isolated from wastewater of the nylon 6 producing Seongseo industrial complex in Daegu, Republic of Korea. Here, we report the complete genome sequence of the strain, providing genetic information for biodegradation of aromatic compounds. PMID- 25449546 TI - Efficient backsplicing produces translatable circular mRNAs. AB - While the human transcriptome contains a large number of circular RNAs (circRNAs), the functions of most circRNAs remain unclear. Sequence annotation suggests that most circRNAs are generated from splicing in reversed orders across exons. However, the mechanisms of this backsplicing are largely unknown. Here we constructed a single exon minigene containing split GFP, and found that the pre mRNA indeed produces circRNA through efficient backsplicing in human and Drosophila cells. The backsplicing is enhanced by complementary introns that form double-stranded RNA structure to bring splice sites in proximity, but such structure is not required. Moreover, backsplicing is regulated by general splicing factors and cis-elements, but with regulatory rules distinct from canonical splicing. The resulting circRNA can be translated to generate functional proteins. Unlike linear mRNA, poly-adenosine or poly-thymidine in 3' UTR can inhibit circular mRNA translation. This study revealed that backsplicing can occur efficiently in diverse eukaryotes to generate circular mRNAs. PMID- 25449547 TI - Using UHF proximity loggers to quantify male-female interactions: a scoping study of estrous activity in cattle. AB - Reproductive efficiency is an important determinant of profitable cattle breeding systems and the success of assisted reproductive techniques (ART) in wildlife conservation programs. Methods of estrous detection used in intensive beef and dairy cattle systems lack accuracy and remain the single biggest issue for improvement of reproductive rates and such methods are not practical for either large-scale extensive beef cattle enterprises or free-living mammalian species. Recent developments in UHF (ultra high frequency) proximity logger telemetry devices have been used to provide a continuous pair-wise measure of associations between individual animals for both livestock and wildlife. The objective of this study was to explore the potential of using UHF telemetry to identify the reproductive cycle phenotype in terms of intensity and duration of estrus. The study was conducted using Belmont Red (interbred Africander Brahman Hereford Shorthorn) cattle grazing irrigated pasture on Belmont Research Station, northeastern Australia. The cow-bull associations from three groups of cows each with one bull were recorded over a 7-week breeding season and the stage of estrus was identified using ultrasonography. Telemetry data from bull and cows, collected over 4 8-day logger deployments, were log transformed and analyzed by ANOVA. Both the number and duration of bull-cow affiliations were significantly (P<0.001) greater in estrous cows compared to anestrus cows. These results support the development of the UHF technology as a hands-off and noninvasive means of gathering socio-sexual information on both wildlife and livestock for reproductive management. PMID- 25449548 TI - Semen collection using phantom in dromedary camel. AB - Semen collection is relatively long, unsafe, and tedious procedure in dromedary camel. The innovation of safe, hygienic, and simple approach to collect semen could make great progress in development of AI program in this species. This study investigated two methods of semen collection using phantom and artificial vagina in dromedary camel. Semen was collected using phantom (n = 4 bulls; 26 collections) and artificial vagina (n = 6 bulls; 11 collections) and diluted with INRA96 at the ratio of 1:10. The duration of semen collection, semen parameters, and morphometric features of sperm were evaluated. For specimen collected through phantom and AV, the respected duration of semen collection (411.2 +/- 48.19 vs 326 +/- 37.05 sec), volume (6.6 +/- 0.87 vs 6 +/- 1.57 ml), osmolarity (328 +/- 1.6 vs 319.4 +/- 3.21 mOsm/kg H2O), pH (7.7 +/- 0.06 vs 7.9 +/- 0.16) of semen, concentration (161.4 +/- 44.05 * 10(6)/mL vs 160.2 +/- 58.42 * 10(6)/mL), total motility (84.1 +/- 1.89 vs 78.3 +/- 3.97%), progressive forward motility (45.5 +/ 3.69 vs 44.3 +/- 6.41%), live percentage (72.2 +/- 3.11 vs 76 +/- 2.53%), and plasma membrane integrity (61.5 +/- 2.49 vs 58.9 +/- 4.19%) of sperm were similar (P > 0.05). The number of specimens contaminated with visible particles was greater using AV (72.7%) compared to phantom (0%; P < 0.05). Total length, head, middle-piece, and tail length of sperm were 45.9 +/- 0.1, 5.6 +/- 0.01, 7 +/- 0.02, and 34.2 +/- 0.16 MUm, respectively. The frequency of abnormal sperm was 13.28% among which coiled tail, detached head, and proximal protoplasmic droplets had greater incidence. In conclusion, phantom could be considered as a suitable approach to collect semen due to simplicity, safety, and lack of specimen contamination in dromedary camel. PMID- 25449549 TI - Manifestation of estrous behavior and subsequent progesterone concentration at timed-embryo transfer in cattle are positively associated with pregnancy success of recipients. AB - Plasma estradiol and progesterone (P4) concentrations during the peri-ovulatory period are positively correlated with pregnancy success in cattle. The aims of this study were to assess the effects of estrus occurrence and early diestrus P4 concentrations on pregnancy per timed-embryo transfer (P/TET). A total of 267 crossbred beef heifers [222 with corpus luteum (CL) and 45 without a CL but with a follicle >8mm at beginning of the estrous synchronization protocol) received an intra-vaginal P4 device and intramuscular administration of estradiol benzoate. Progesterone devices were removed 8 days later (Day 0), and heifers received d cloprostenol, eCG and estradiol cypionate. Estrous behavior was monitored twice daily for 3 days after P4 device removal. Plasma P4 concentration was measured by radioimmunoassay at Day 7 and Day 9. At Day 9, heifers with a CL (n=236; i.e. submission rate of 85.5%; 236/276) undergoing TET received an in vitro-produced embryo. Heifers expressing a standing behavioral estrus had a greater P/TET than heifers that did not express a standing estrus [62.4% (106/170) compared with 47.0% (31/66)]. The probability of pregnancy was positively correlated with plasma P4 concentration at TET. When heifers were grouped by quartiles of P4 concentration at TET (Q1=0.64+/-0.16, Q2=1.70+/-0.04, Q3=2.90+/-0.07 and Q4=5.52+/-0.27ng/mL) the P/TET were 45.8% (Q1; 27/59)(c), 52.25% (Q2; 31/59)(bc), 66.1% (Q3; 39/59)(ab) and 67.8% (Q4; 40/59)(a). Additionally, heifers that became pregnant had greater P4 concentrations at TET (2.87+/-0.16ng/mL; n=137) than heifers that did not become pregnant (2.45+/-0.24ng/mL; n=99). No statistical difference was observed regarding P4 concentrations on Day 7, regardless of standing estrus or pregnancy status. In cattle, manifestation of estrous behavior and plasma P4 concentration at TET increase the probability of pregnancy in in vitro-produced embryo recipients. PMID- 25449550 TI - Detecting child abuse based on parental characteristics: does the Hague Protocol cause parents to avoid the emergency department? AB - OBJECTIVES: The Hague Protocol is used by professionals at the adult Emergency Departments (ED) in The Netherlands to detect child abuse based on three parental characteristics: (1) domestic violence, (2) substance abuse or (3) suicide attempt or self-harm. After detection, a referral is made to the Reporting Center for Child Abuse and Neglect (RCCAN). This study investigates whether implementing this Protocol will lead parents to avoid medical care. METHOD: We compared the number of patients (for whom the Protocol applied) who attended the ED prior to implementation with those attending after implementation. We conducted telephone interviews (n = 14) with parents whose children were referred to the RCCAN to investigate their experience with the procedure. RESULTS: We found no decline in the number of patients, included in the Protocol, visiting the ED during the 4 year implementation period (2008-2011). Most parents (n = 10 of the 14 interviewed) were positive and stated that they would, if necessary, re-attend the ED with the same complaints in the future. CONCLUSION: ED nurses and doctors referring children based on parental characteristics do not have to fear losing these families as patients. PMID- 25449551 TI - Emergency nurses practices in assessing and administering continuous intravenous sedation for critically ill adult patients: a retrospective record review'. AB - AIM: To generate an initial profile of emergency nurses' practices in and factors influencing the assessment and administration of continuous intravenous sedation and analgesia for critically ill mechanically ventilated adult patients. BACKGROUND: Emergency nurses are relied upon to assess and manage critically ill patients, some of whom require continuous intravenous sedation. Balancing sedation is a highly complex activity. There is however little evidence relating to how emergency nurses manage continuous intravenous analgesia and sedation for the critically ill intubated patients. DESIGN: Descriptive study. METHOD: A 12 month retrospective medical record review was undertaken from January to December 2009 of patients (>16 years) administered continuous intravenous sedation in ED. RESULTS: Fifty-five patients received ongoing intravenous sedation within the ED during a median length of stay of 3.4 h. Assessment of patient depth/quality of sedation and pain-relief varied and were rarely documented. Adverse events were documented, majority (16%) drug administration related. Thematic analysis identified three themes: 'Maintaining sedation', 'Directionless-directions', and 'Navigating the balance'. CONCLUSION: Emergency nurses provide continuity of patient care and optimisation of analgesia and sedation for critically ill sedated patients. The safety and effectiveness of continuous intravenous sedation for the critically ill adult patient in ED are dependent on the expertise and decision-making abilities of the nurse. PMID- 25449553 TI - The Canadian Diabetes Association, Canadian Society, is funding CDN $7.5 million in research in 2014-2015 to support excellent researchers and research trainees. PMID- 25449554 TI - Circulating cell free DNA testing: are some test failures informative? AB - OBJECTIVE: The proportion of circulating cell free DNA derived from the feto placental unit (fetal fraction or FF) correlates with test success and interpretation reliability. Some fetal disorders are associated with systematically lower FF, sometimes resulting in noninformative results. METHODS: We analyzed results from pregnancies tested in a nested case/control study derived from a cohort of 4664 high-risk pregnancies. Low FF was defined before and after adjusting for maternal weight and gestational age. RESULTS: Compared with euploid pregnancies, the median FF was significantly higher in Down syndrome pregnancies (ratio 1.17) and significantly lower in trisomy 18 and triploid pregnancies (ratios 0.71 and 0.19, respectively). Among 2157 pregnancies tested, 13 (0.6%) had FF <3.0% (all noninformative), including three trisomy 18 and three triploidy fetuses. After adjustment, 16 pregnancies (0.7%) had FF <0.3 multiples of the median (six informative), including one trisomy 18 and three triploidy fetuses. Modeled positive predictive values for low and high-risk populations were 7% and 30%, respectively. CONCLUSION: Among women with noninformative results attributable to low FF, trisomy 18 and/or triploidy risk are sufficiently high to warrant offering additional assessments (e.g. ultrasound). If the testing indication is ultrasound abnormality, amniocentesis and karyotype/microarray should be considered. (c) 2014 John Wiley & Sons, Ltd. PMID- 25449552 TI - On the Efficacy and Mediation of a One-on-One HIV Risk-Reduction Intervention for African American Men Who Have Sex with Men: A Randomized Controlled Trial. AB - We examined the efficacy and mediation of Being Responsible for Ourselves (BRO), an HIV/STI risk-reduction intervention for African American men who have sex with men (MSM), the population with the highest HIV-diagnosis rate in the US. We randomized African American MSM to one of two interventions: BRO HIV/STI risk reduction, targeting condom use; or attention-matched control, targeting physical activity and healthy diet. The interventions were based on social cognitive theory, the reasoned-action approach, and qualitative research. Men reporting anal intercourse with other men in the past 90 days were eligible and completed pre-intervention, immediately post-intervention, and 6 and 12 months post intervention surveys. Of 595 participants, 503 (85 %) completed the 12-month follow-up. Generalized-estimating-equations analysis indicated that, compared with the attention-matched control intervention, the BRO intervention did not increase consistent condom use averaged over the 6- and 12-month follow-ups, which was the primary outcome. Although BRO did not affect the proportion of condom-protected intercourse acts, unprotected sexual intercourse, multiple partners, or insertive anal intercourse, it did reduce receptive anal intercourse compared with the control, a behavior linked to incident HIV infection. Mediation analysis using the product-of-coefficients approach revealed that although BRO increased seven of nine theoretical constructs it was designed to affect, it increased only one of three theoretical constructs that predicted consistent condom use: condom-use impulse-control self-efficacy. Thus, BRO indirectly increased consistent condom use through condom-use impulse-control self-efficacy. In conclusion, although BRO increased several theoretical constructs, most of those constructs did not predict consistent condom use; hence, the intervention did not increase it. Theoretical constructs that interventions should target to increase African American MSM's condom use are discussed. PMID- 25449555 TI - Cortical connectivity in fronto-temporal focal epilepsy from EEG analysis: A study via graph theory. AB - OBJECTIVE: It is believed that effective connectivity and optimal network structure are essential for proper information processing in the brain. Indeed, functional abnormalities of the brain are found to be associated with pathological changes in connectivity and network structures. The aim of the present study was to explore the interictal network properties of EEG signals from temporal lobe structures in the context of fronto-temporal lobe epilepsy. METHODS: To complete this aim, the graph characteristics of the EEG data of 17 patients suffering from focal epilepsy of the fronto-temporal type, recorded during interictal periods, were examined and compared in terms of the affected versus the unaffected hemispheres. EEG connectivity analysis was performed using eLORETA software in 15 fronto-temporal regions (Brodmann Areas BAs 8, 9, 10, 11, 20, 21, 22, 37, 38, 41, 42, 44, 45, 46, 47) on both affected and unaffected hemispheres. RESULTS: The evaluation of the graph analysis parameters, such as 'global' (characteristic path length) and 'local' connectivity (clustering coefficient) showed a statistically significant interaction among side (affected and unaffected hemisphere) and Band (delta, theta, alpha, beta, gamma). Duncan post hoc testing showed an increase of the path length in the alpha band in the affected hemisphere with respect to the unaffected one, as evaluated by an inter hemispheric marker. The affected hemisphere also showed higher values of local connectivity in the alpha band. In general, an increase of local and global graph theory parameters in the alpha band was found in the affected hemisphere. It was also demonstrated that these effects were more evident in drug-free patients than in those undergoing pharmacological therapy. CONCLUSIONS: The increased measures in the affected hemisphere of both functional local segregation and global integration could result from the combination of overlapping mechanisms, including reactive neuroplastic changes seeking to maintain constant integration and segregation properties. SIGNIFICANCE: This reactive neuroplastic mechanism seeking to maintain constant integration and segregation properties seems to be more evident in the absence of antiepileptic treatment. PMID- 25449556 TI - Role of multimodal intraoperative neurophysiological monitoring during positioning of patient prior to cervical spine surgery. AB - OBJECTIVE: To determine the use of multimodal intraoperative neurophysiological monitoring (IONM) during positioning procedures in cervical spine surgery. METHODS: IONM data was collected from 75 patients from the onset of positioning to the end of the surgical procedure. These included: transcranial motor evoked potentials (TcMEP), somatosensory evoked potentials (SEP) and free running electromyography (EMG) recordings. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (PNV) were calculated. RESULTS: IONM warnings were given in 5 cases during neck positioning. These consisted of the disappearance of TcMEP in all the cases, while two cases showed a loss of SEPs as well. Four of these patients presented a complete recovery of TcMEP and SEPs after neck repositioning. The patient in which this recovery was not present, woke up with new postoperative neurological deficits. Sensitivity, specificity, PPV and NPV of TcMEP during cervical positioning were all 100%. Sensitivity of SEPs was 40%; specificity and PPV were 100%; and the NPV of SEPs was 95.9%. CONCLUSION: Multimodal IONM is a useful method to prevent spinal cord injury during neck positioning in cervical spine surgical procedures. TcMEPs showed the highest sensitivity in detecting injuries to cervical spine related to neck positioning. SIGNIFICANCE: Multimodal IONM should not only be considered for detecting intra-operative warnings, but also during positioning. PMID- 25449557 TI - Disinhibitory shift of recovery curve of somatosensory-evoked response in elderly: A magnetoencephalographic study. AB - OBJECTIVE: The aim of the study was to investigate the functional differences between N20m and P30m components of somatosensory-evoked magnetic cortical field (SEF) in young and senior subjects. METHODS: Twenty-nine healthy subjects, 13 younger (mean age: 21.8years) and 16 senior (63.8 years), participated. Magnetic fields were measured using a 160-channel, whole head MEG. Single- and paired pulse stimulations of 200 artifact-free MEG signal epochs were averaged separately. We calculated how aging affects recovery function of SEFs. RESULTS: The senior showed a prolonged N20m peak latency compared to the younger, although the P30m peak latency was not significantly different between groups. The N20m ratios at 60 and 80 ms in the senior were significantly increased compared to the ratios in the younger (60 ms: P<0.05, 80 ms: P<0.001). The P30m ratios at inter stimulus interval (ISI) of 80 and 100 ms showed even disinhibition in the senior than in the younger (P<0.05). The younger also showed a significantly negative correlation between P30m and N20m components' recovery curves (R=0.72, P<0.05). CONCLUSION: Aging-related changes that occurred in recovery functioning were the decrease in N20m component suppression and the increase in P30m component recovery, indicating that the N20m and P30m components have different functions in aging-related recovery changes. SIGNIFICANCE: Our results show that the N20m ratio at an ISI of 80 ms was significantly increased in the senior group, indicating that the second stimulus-evoked SEF was less inhibited by the initial stimulus at this ISI, suggesting less refractory effect or increased disinhibition. PMID- 25449558 TI - Brain-computer interfaces in amyotrophic lateral sclerosis: A metanalysis. AB - OBJECTIVE: Despite recent groundbreaking findings on the genetic causes of amyotrophic lateral sclerosis (ALS), and improvements on neuroimaging techniques for ALS diagnosis have been reported, the main clinical intervention in ALS remains palliative care. Brain-computer interfaces (BCIs) have been proposed as a channel of communication and control for ALS patients. The present metanalysis was performed to test the evidence of BCI effectiveness in ALS, and to investigate whether the promising aims emerged from the first studies have been reached. METHODS: Studies on ALS patients tested with BCIs, until June 2013, were searched in PubMed and PsychInfo. The random-effect approach was used to compute the pooled effectiveness of BCI in ALS. A meta-regression was performed to test whether there was a BCI performance improvement as a function of time. Finally, BCI effectiveness for complete paralyzed ALS patients was tested. Twenty-seven studies were eligible for metanalysis. RESULTS: The pooled classification accuracy (C.A.) of ALS patients with BCI was about 70%, but this estimation was affected by significant heterogeneity and inconsistency. C.A. did not significantly increase as a function of time. C.A. of completely paralyzed ALS patients with BCI did not differ from that obtained by chance. CONCLUSIONS: After 15 years of studies, it is as yet not possible to reliably establish the effectiveness of BCIs. SIGNIFICANCE: Methodological issues among the retrieved studies should be addressed and new well-powered studies should be conducted to confirm BCI effectiveness for ALS patients. PMID- 25449560 TI - Combining cutaneous silent periods with quantitative sudomotor axon reflex testing in the assessment of diabetic small fiber neuropathy. AB - OBJECTIVE: Routine electrophysiological testing is often normal in the evaluation of painful diabetic neuropathy, as it is unable to detect dysfunction of thinly myelinated (Adelta) and unmyelinated (C) small fibers. Although cutaneous silent periods (CSP) and quantitative sudomotor axon reflex testing (QSART) respectively evaluate these fiber types in the extremities, these two tests have yet to be assessed together. METHODS: 26 patients with a clinical diagnosis of small fiber neuropathy (SFN) and 26 age-matched controls were assessed. Nine patients had Type I diabetes, nine had Type II diabetes, and eight had impaired glucose tolerance. The CSP onset latency and duration were recorded in each extremity. QSART was performed on the right side. RESULTS: 58% (15/26) of patients had abnormal sweat volumes obtained from QSART, while 50% (13/26) of patients had abnormal CSP responses. Combining these two tests increased the sensitivity of testing to 77% (20/26). Abnormalities were seen equally across all patient groups. CONCLUSIONS: Combining CSP with QSART significantly increases the sensitivity of testing when assessing patients with SFN related to diabetes, or prediabetes. SIGNIFICANCE: For clinically suspected SFN, it is preferable to test more than one small fiber type, as each possess different structural and functional properties and may be heterogeneously affected between patients. PMID- 25449559 TI - Effects of robotic-locomotor training on stretch reflex function and muscular properties in individuals with spinal cord injury. AB - OBJECTIVE: We sought to determine the therapeutic effect of robotic-assisted step training (RAST) on neuromuscular abnormalities associated with spasticity by characterization of their recovery patterns in people with spinal cord injury (SCI). METHODS: Twenty-three motor-incomplete SCI subjects received one-hour RAST sessions three times per week for 4 weeks, while an SCI control group received no training. Neuromuscular properties were assessed using ankle perturbations prior to and during the training, and a system-identification technique quantified stretch reflex and intrinsic stiffness magnitude and modulation with joint position. Growth-mixture modeling classified subjects based on similar intrinsic and reflex recovery patterns. RESULTS: All recovery classes in the RAST group presented significant (p<0.05) reductions in intrinsic and reflex stiffness magnitude and modulation with position; the control group presented no changes over time. Subjects with larger baseline abnormalities exhibited larger reductions, and over longer training periods. CONCLUSIONS: Our findings demonstrate that RAST can effectively reduce neuromuscular abnormalities, with greater improvements for subjects with higher baseline abnormalities. SIGNIFICANCE: Our findings suggest, in addition to its primary goal of improving locomotor patterns, RAST can also reduce neuromuscular abnormalities associated with spasticity. These findings also demonstrate that these techniques can be used to characterize neuromuscular recovery patterns in response to various types of interventions. PMID- 25449561 TI - Clinical correlates of rapid eye movement sleep without atonia in Parkinson's disease. AB - OBJECTIVE: The aim of the present study was to investigate the relationship between rapid eye movement (REM) sleep without atonia (RWA) and Parkinson's disease (PD) progression. METHODS: We quantified tonic and phasic RWA by performing polysomnography in 198 PD patients. We then correlated the extent of RWA with clinical patient characteristics. RESULTS: PD patients were categorized into quartiles of tonic and phasic RWA. We found that patients with more RWA tended to be older and have longer PD duration, a greater likelihood of REM sleep behavior disorder (RBD), more advanced Hoehn & Yahr (H&Y) stage, a higher dose of parkinsonian medication, poorer cognitive performance, worse quality of life, and more severe sleep disturbance. After adjusting for age, sex, and PD duration, patients in the highest two RWA quartile were more likely to have severe PD (H&Y stage ? 3.0) than those in the lowest RWA quartile. CONCLUSIONS: These findings provide evidence that RWA, especially with regard to tonic muscle activity, is associated with PD severity. SIGNIFICANCE: Further studies are warranted to determine the importance and utility of assessing RWA to evaluate sleep in PD patients. PMID- 25449562 TI - Chemical synthesis and biophysical applications of membrane proteins. AB - Chemical synthesis or semi-synthesis of membrane proteins can provide unique molecular tools, such as site-specific isotope labeling or post-translationally modified membrane proteins to gain insight into their biophysical and functional characteristics. However, during preparation, purification, and ligation of transmembrane peptides, tremendous challenges are encountered owing to their hydrophobic nature. This review focuses on the recent advances in chemical synthesis strategies of membrane proteins. These strategies help to solubilize the hydrophobic transmembrane peptide sequences under standard purification and chemical ligation conditions to improve their handling properties. Biophysical and functional studies of synthetic membrane proteins are reviewed as well. PMID- 25449563 TI - Comparison of three human papillomavirus DNA assays and one mRNA assay in women with abnormal cytology. AB - OBJECTIVE: To compare the clinical characteristics of four human papillomavirus (HPV) assays: hybrid capture 2 (HC2), cobas, CLART, and APTIMA in Danish women with abnormal cytology. METHODS: SurePath samples from 367 consecutive women from Copenhagen, with atypical squamous cells of undetermined significance or worse, were tested with the four assays. These women were routinely recommended for repeated testing or were referred for colposcopy. Their worst histological diagnosis in 29 months from baseline was retrieved from the Danish National Pathology Data Bank. RESULTS: Of the 367 women, 16 (4%) had no follow-up, 232 (63%) had =CIN3 was 95% (95% CI: 88-99) for HC2, 94% (95% CI: 87-98) for cobas, 93% (95% CI: 85-97) for CLART, and 87% (95% CI: 78-93) for APTIMA. In women of age above 30 years, the sensitivities were 98% (95% CI: 87 100), 93% (95% CI: 80-98), 90% (95% CI: 77-97), and 93% (95% CI: 80-98), respectively. One woman with cervical cancer tested negative on CLART and one on cobas; HC2 and APTIMA were positive in all three cancer cases. The specificity for =CIN2. CONCLUSIONS: Small differences in clinical characteristics were found for the four HPV assays in Danish women with abnormal cytology aged >=30 years. At younger ages, APTIMA was somewhat less sensitive for high-grade CIN than the three HPV DNA assays. PMID- 25449564 TI - Continuous epidural infusion anesthesia and analgesia in gynecologic oncology patients: less pain, more gain? AB - OBJECTIVE: There is a lack of consistent data regarding gynecologic oncology (GO) patients and the use of neuraxial anesthesia for post-operative pain management. Our objective was to compare the use of continuous epidural infusion (CEI) as part of post-operative pain management to more traditional management schemes. METHODS: GO patients undergoing laparotomy from July 1st, 2011 through July 31st, 2012 were identified. Patient demographic data and peri-operative details were abstracted from the medical record. The primary outcome was a mean patient visual analog pain score. Secondary outcomes included length of stay, post-operative urinary tract infection (UTI) and venous thromboembolic (VTE) events. RESULTS: There were 237 laparotomies during the study time period. Fifty-six women had CEI for post-operative pain management and 181 did not. Patients with CEI had lower pain scores on POD #0 (3.8 vs 5.3, p < 0.01), #1 (2.6 vs 4.0, p < 0.01) and #2 (2.5 vs 3.5, p < 0.01) compared to women without CEI. There was no difference in the length of stay between those with and without CEI (103 vs 94 h, p = 0.32). Women with CEI did have a longer length of urinary catheterization (56 vs 26 h, p = 0.01) but not an increased rate of UTI (5.5% vs 1.8%, p = 0.24). There was a higher rate of post-operative VTE events among women with CEI (8.9% vs 1.7%, p = 0.02). CONCLUSIONS: In this small series, GO patients undergoing laparotomy had improved post-operative pain control when their analgesia regimen included CEI. However, the higher rate of VTE events among CEI users is concerning and merits further investigation. PMID- 25449565 TI - Position-related injury is uncommon in robotic gynecologic surgery. AB - OBJECTIVE: To assess the rate and risk factors for position-related injury in robotic gynecologic surgery. METHODS: A prospective database from 12/2006 to 1/2014 of all planned robotic gynecologic procedures was retrospectively reviewed for patients who experienced neurologic injury, musculoskeletal injury, or vascular compromise related to patient positioning in the operating room. Analysis was performed to determine risk-factors and incidence for position related injury. RESULTS: Of the 831 patients who underwent robotic surgery during the study time period, only 7 (0.8%) experienced positioning-related injury. The injuries included minor head contusions (n=3), two lower extremity neuropathies (n=2), brachial plexus injury (n=1) and one large subcutaneous ecchymosis on the left flank and thigh (n=1). There were no long term sequelae from the positioning related injuries. The only statistically significant risk factor for positioning related injury was prior abdominal surgery (P=0.05). There were no significant associations between position-related injuries and operative time (P=0.232), body mass index (P=0.847), age (P=0.152), smoking history (P=0.161), or medical comorbidities (P=0.229-0.999). CONCLUSIONS: The incidence of position-related injury among women undergoing robotic surgery was extremely low (0.8%). Due to the low incidence we were unable to identify modifiable risk factors for position related injury following robotic surgery. A standardized, team-oriented approach may significantly decrease position-related injuries following robotic gynecologic surgery. PMID- 25449567 TI - Robotic resection of bulky aorto-caval lymphadenopathy in a patient with serous fallopian tube carcinoma. PMID- 25449566 TI - DNA methylation as a biomarker for the detection of hidden carcinoma in endometrial atypical hyperplasia. AB - OBJECTIVE: Women with atypical hyperplasia (AH) are often found to have endometrial carcinoma (EC) at hysterectomy. The purpose of this study was to evaluate whether the hypermethylation of specific genes found by methylomic approaches to the study of gynecologic cancers is a biomarker for EC in women with AH. METHODS: We evaluated the methylation of AJAP1, HS3ST2, SOX1, and PTGDR from 61 AH patients undergoing hysterectomy. Endometrial biopsy samples were analyzed by bisulfite conversion and quantitative methylation-specific polymerase chain reaction. A methylation index was used to predict the presence of cancer. To confirm the silencing effects of DNA methylation, immunohistochemical analysis of AJAP1, HS3ST2, and SOX1 was performed using tissue microarray. RESULTS: Fourteen (23%) patients had EC at hysterectomy. AJAP1, HS3ST2, and SOX1 were highly methylated in the EC patients' biopsy samples (p<=0.023). AJAP1, HS3ST2, and SOX1 protein expression was significantly higher in patients with AH only (p<=0.038). The predictive value of AJAP1, HS3ST2, and SOX1 methylation for EC was 0.81, 0.72, and 0.70, respectively. Combined testing of both AJAP1 and HS3ST2 methylation had a positive predictive value of 56%, methylation of any one of AJAP1, SOX1, or HS3ST2 had a 100% negative predictive value. CONCLUSIONS: Hypermethylation of AJAP1, HS3ST2, and SOX1 is predictive of EC in AH patients. Testing for methylation of these genes in endometrial biopsy samples may be a hysterectomy-sparing diagnostic tool. Validation of these new genes as biomarkers for AH screening in a larger population-based study is warranted. PMID- 25449568 TI - A cost-utility analysis of NRG Oncology/Gynecologic Oncology Group Protocol 218: incorporating prospectively collected quality-of-life scores in an economic model of treatment of ovarian cancer. AB - OBJECTIVE: To estimate quality-of-life (QOL)-adjusted cost-utility with addition of bevacizumab (B) to intravenous paclitaxel/carboplatin (PC) for primary treatment of advanced-stage epithelial ovarian cancer. METHODS: A modified Markov state transition model of 3 regimens evaluated in GOG 218 (PC, PC+concurrent B [PCB], and PCB+maintenance B [PCB+B]) was populated by prospectively collected survival, adverse event, and QOL data from GOG 218. Progression-free survival (PFS) and overall survival (OS) were modeled using primary event data. Costs of grade 4 hypertension, grade 3-5 bowel events, and growth factor support were incorporated. QOL scores were converted to utilities and incorporated into the model. Monte Carlo probabilistic sensitivity analysis was performed to account for uncertainty in estimates. RESULTS: PC was the least expensive ($4044) and least effective (mean 1.1 quality-adjusted progression-free years [QA-PFY]) regimen. PCB ($43,703 and 1.13 QA-PFY) was dominated by a combination of PC and PCB+B. PCB+B ($122,700 and 1.25 QA-PFY) was the most expensive regimen with an incremental cost-effectiveness ratio of $792,380/QA-PFY compared to PC. In a model not incorporating QOL, the incremental cost-effectiveness ratio (ICER) of PCB+B was $632,571/PFY compared to PC. CONCLUSIONS: In this cost-utility model, incorporation of QOL into an analysis of GOG 218 led to less favorable ICER (by >$150,000/QA-PFY) in regimens containing B compared with those that do not include B. Continued investigation of populations with ovarian cancer in whom the efficacy of treatment with bevacizumab is expected to be increased (or in whom QOL is expected to increase with use) is critical. PMID- 25449569 TI - Combining clinical assessment and the Risk of Ovarian Malignancy Algorithm for the prediction of ovarian cancer. AB - OBJECTIVES: ACOG guidelines for the evaluation of women with a pelvic mass employ a combination of physical exam, imaging, and CA125 to guide physicians in the triage of women to gynecologic oncologists. We studied the use of ROMA with clinical assessment for cancer risk assessment in women with a pelvic mass. METHODS: This was a prospective, multicenter trial evaluating women with a pelvic mass who had an initial clinical risk assessment (ICRA) performed by a generalist. ROMA scores were calculated and sensitivity, specificity, PPV and NPV were determined for ICRA and ICRA+ROMA. RESULTS: A total of 461 women were entered into the study. There were 375 benign tumors, 48 EOC, 18 LMP tumors and 20 non-ovarian malignancies. For detection of ovarian cancer alone, ICRA had a sensitivity of 85.4%, a specificity of 84.3%, and a NPV of 97.8%. Adding ROMA to ICRA produced a significant improvement of 8.4% in sensitivity, achieving a sensitivity of 93.8% with a specificity of 67.2% and a NPV of 98.8%. Examination of all malignancies (ovarian & non-ovarian) provided a sensitivity of 89.7% for ROMA+ICRA in comparison to 77.9% for ICRA alone, a significant increase in sensitivity of 11.8%. The NPV also significantly increased from 95.5% to 97.3%. Overall, ROMA detected 13 additional malignancies missed by ICRA. CONCLUSIONS: Adjunctive use of ROMA with clinical assessment improves the stratification of women with a pelvic mass into low and high risk groups for ovarian cancer. The combination is particularly effective in ruling out malignant disease. PMID- 25449570 TI - Synthetic prions and other human neurodegenerative proteinopathies. AB - Transmissible spongiform encephalopathies (TSE) are a heterogeneous group of neurodegenerative disorders. The common feature of these diseases is the pathological conversion of the normal cellular prion protein (PrP(C)) into a beta structure-rich conformer-termed PrP(Sc). The latter can induce a self perpetuating process leading to amplification and spreading of pathological protein assemblies. Much evidence suggests that PrP(Sc) itself is able to recruit and misfold PrP(C) into the pathological conformation. Recent data have shown that recombinant PrP(C) can be misfolded in vitro and the resulting synthetic conformers are able to induce the conversion of PrP(C) into PrP(Sc)in vivo. In this review we describe the state-of-the-art of the body of literature in this field. In addition, we describe a cell-based assay to test synthetic prions in cells, providing further evidence that synthetic amyloids are able to template conversion of PrP into prion inclusions. Studying prions might help to understand the pathological mechanisms governing other neurodegenerative diseases. Aggregation and deposition of misfolded proteins is a common feature of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other disorders. Although the proteins implicated in each of these diseases differ, they share a common prion mechanism. Recombinant proteins are able to aggregate in vitro into beta-rich amyloid fibrils, sharing some features of the aggregates found in the brain. Several studies have reported that intracerebral inoculation of synthetic aggregates lead to unique pathology, which spread progressively to distal brain regions and reduced survival time in animals. Here, we review the prion-like features of different proteins involved in neurodegenerative disorders, such as alpha synuclein, superoxide dismutase-1, amyloid-beta and tau. PMID- 25449572 TI - Light-dependent segregation of begomoviruses in Asystasia gangetica leaves. AB - Asystasia gangetica (Acanthaceae) from tropical Africa and Asia is used as source of food and for medical applications. Plants collected in West Africa in the 1980s with typical geminivirus symptoms showed an unusual symptom segregation that included vein yellowing, curling and mosaic, which were present simultaneously or separately on different leaves of the same plant or on different plants propagated as cuttings from a single plant. Rolling-circle amplification in combination with restriction fragment length polymorphism analysis followed by deep sequencing of the RCA products identified two geminiviruses in these plants. One with a bipartite genome, Asystasia begomovirus 1, and the other with a monopartite genome together with its defective DNA, Asystasia begomovirus 2. The relationship between leaf symptoms and virus distribution under different light regimes was investigated, and showed for the first time an unusual segregation of symptoms and viruses, either within a single plant, or even within a leaf. PMID- 25449571 TI - The DEAD-box RNA helicase 5 positively regulates the replication of porcine reproductive and respiratory syndrome virus by interacting with viral Nsp9 in vitro. AB - The nonstructural protein 9 (Nsp9) of porcine reproductive and respiratory syndrome virus (PRRSV) has been recognized to play important roles in viral replication. The present study first screened that the DEAD-box RNA helicase 5 (DDX5) was a cellular protein interacting with the Nsp9 of PRRSV by a yeast two hybrid method in a pulmonary alveolar macrophages (PAMs) cDNA library. Next, DDX5 was shown to interact with viral Nsp9 in the co-transfected HEK293 cells with the DDX5- and Nsp9-expressing plasmids, and the interaction between endogenous DDX5 and Nsp9 was also confirmed in MARC-145 cells infected with the Nsp9-expressing lentiviruses. Then, the interacting domains between DDX5 and Nsp9 were determined to be the DEXDc and HELICc domains in DDX5 and the RdRp domain in Nsp9, respectively. Moreover, in the HEK293 cells, MARC-145 cells and PAM cell lines co transfected with the DDX5- and Nsp9-expressing plasmids, Nsp9 was shown to co localize with DDX5 in the cytoplasm with a perinuclear pattern, and meanwhile in PRRSV-infected MARC-145 cells and PAMs, endogenous DDX5 was also found to co localize with Nsp9. Finally, silencing the DDX5 gene in MARC-145 cells significantly impacted the replication of PRRSV, and while the over-expression of DDX5 could slightly enhance viral replication. These findings indicate that DDX5 positively regulates the replication of PRRSV via its interaction with viral Nsp9 in vitro. PMID- 25449573 TI - Hepatitis B virus X protein increases the IL-1beta-induced NF-kappaB activation via interaction with evolutionarily conserved signaling intermediate in Toll pathways (ECSIT). AB - Hepatitis B virus X protein (HBx) transactivates multiple transcription factors including nuclear factor-kappa B (NF-kappaB) that regulates inflammatory-related genes. However, the regulatory mechanism of HBx in NF-kappaB activation remains largely unknown. This study reports that HBx augments the interleukin-1beta (IL 1beta)-induced NF-kappaB activation via interaction with a Toll-like receptor (TLR) adapter protein, ECSIT (evolutionarily conserved signaling intermediate in Toll pathways). GST pull-down and co-immunoprecipitation analyses showed that HBx interacted with ECSIT. Deletion analysis of HBx in a CytoTrap two-hybrid system revealed that the interaction region of HBx for ECSIT was attributed to aa 51-80. Co-transfection of HBx and ECSIT in IL-1beta-stimulated cells appeared to activate IKK and IkappaB signaling pathway as phosphorylation of both IKK alpha/beta and IkappaBalpha was increased whereas knockdown of ECSIT or HBxDelta51-80 mutant attenuated the phosphorylation. As a consequence of IkappaBalpha degradation, NF-kappaB was activated as evidenced by increases in NF kappaB transcriptional activity and the nuclear translocation of p65 and p50 that resulted in the induction of IL-10. In contrast, knockdown of ECSIT by siRNA or treatment with an NF-kappaB selective inhibitor (helenalin) abolished the NF kappaB activation and IL-10 expression. We conclude that ECSIT appears to be a novel HBx-interacting signal molecule and their interaction is mechanistically important in IL-1beta induction of NF-kappaB activation. PMID- 25449574 TI - Identification of conserved and HLA-A*2402-restricted epitopes in Dengue virus serotype 2. AB - In this study, we set out to identify dengue virus serotype 2 (DENV-2)-specific HLA-A*2402-restricted epitopes and determine the characteristics of T cells generated to these epitopes. We screened the full-length amino-acid sequence of DENV-2 to find potential epitopes using the SYFPEITHI algorithm. Twelve putative HLA-A*2402-binding peptides conserved in hundreds of DENV-2 strains were synthesized, and the HLA restriction of peptides was tested in HLA-A*2402 transgenic mice. Nine peptides (NS4b(228-237), NS2a(73-81), E(298-306), M(141 149), NS4a(96-105), NS4b(159-168), NS5(475-484), NS1(162-171), and NS5(611-620)) induced high levels of peptide-specific IFN-gamma-secreting cells in HLA-A*2402 transgenic mice. Apart from IFN-gamma, NS4b(228-237-), NS2a(73-81-) and E(298 306)-specific CD8(+) cells produced TNF-alpha and IL-6 simultaneously, whereas M(141-149-) and NS5(475-484-) CD8(+) cells produced only IL-6. Moreover, splenic mononuclear cells (SMCs) efficiently recognized and killed peptide-pulsed splenocytes. Furthermore, each of nine peptides could be recognized by splenocytes from DENV-2-infected HLA-A*2402 transgenic mice. The SMCs from HLA A*2402 transgenic mice immunized with nine immunogenic peptides efficiently killed DENV-2-infected splenic monocytes. The present identified epitopes have the potential to be new diagnostic tools for characterization of T-cell immunity in DENV infection and may serve as part of a universal epitope-based vaccine. PMID- 25449575 TI - Phylogenetic analysis of feline immunodeficiency virus strains from naturally infected cats in Belgium and The Netherlands. AB - Feline immunodeficiency virus (FIV) is a major pathogen in feline populations worldwide, with seroprevalences up to 26%. Virus strains circulating in domestic cats are subdivided into different phylogenetic clades (A-E), based on the genetic diversity of the V3-V4 region of the env gene. In this report, a phylogenetic analysis of the V3-V4 env region, and a variable region in the gag gene was made for 36 FIV strains isolated in Belgium and The Netherlands. All newly generated gag sequences clustered together with previously known clade A FIV viruses, confirming the dominance of clade A viruses in Northern Europe. The same was true for the obtained env sequences, with only one sample of an unknown env subtype. Overall, the genetic diversity of FIV strains sequenced in this report was low. This indicates a relatively recent introduction of FIV in Belgium and The Netherlands. However, the sample with an unknown env subtype indicates that new introductions of FIV from unknown origin do occur and this will likely increase genetic variability in time. PMID- 25449576 TI - Understanding inflammation, its regulation, and relevance for health: a top scientific and public priority. PMID- 25449577 TI - Alterations in microglial phenotype and hippocampal neuronal function in transgenic mice with astrocyte-targeted production of interleukin-10. AB - Interleukin-10 (IL-10) is a cytokine classically linked with anti-inflammatory and protective functions in the central nervous system (CNS) in different neurodegenerative and neuroinflammatory conditions. In order to study the specific role of local CNS produced IL-10, we have created a new transgenic mouse line with astrocyte-targeted production of IL-10 (GFAP-IL10Tg). In the present study, the effects of local CNS IL-10 production on microglia, astrocytes and neuronal connectivity under basal conditions were investigated using immunohistochemistry, molecular biology techniques, electrophysiology and behavioural studies. Our results showed that, in GFAP-IL10Tg animals, microglia displayed an increase in density and a specific activated phenotype characterised by morphological changes in specific areas of the brain including the hippocampus, cortex and cerebellum that correlated with the level of transgene expressed IL-10 mRNA. Distinctively, in the hippocampus, microglial cells adopted an elongated morphology following the same direction as the dendrites of pyramidal neurons. Moreover, this IL-10-induced microglial phenotype showed increased expression of certain molecules including Iba1, CD11b, CD16/32 and F4/80 markers, "de novo" expression of CD150 and no detectable levels of either CD206 or MHCII. To evaluate whether this specific activated microglial phenotype was associated with changes in neuronal activity, the electrophysiological properties of pyramidal neurons of the hippocampus (CA3-CA1) were analysed in vivo. We found a lower excitability of the CA3-CA1 synapses and absence of long term potentiation (LTP) in GFAP-IL10Tg mice. This study is the first description of a transgenic mouse with astrocyte-targeted production of the cytokine IL-10. The findings indicate that IL-10 induces a specific activated microglial phenotype concomitant with changes in hippocampal LTP responses. This transgenic animal will be a very useful tool to study IL-10 functions in the CNS, not only under basal conditions, but also after different experimental lesions or induced diseases. PMID- 25449579 TI - Stromal cell-derived CCL2 drives neuropathic pain states through myeloid cell infiltration in injured nerve. AB - Neuropathic pain resulting from peripheral nerve injury involves many persistent neuroinflammatory processes including inflammatory chemokines that control leukocyte trafficking and activate resident cells. Several studies have shown that CCL2 chemokine, a potent attractant of monocytes, and its cognate receptor, CCR2, play a critical role in regulating nociceptive processes during neuropathic pain. However, the role of CCL2 in peripheral leukocyte infiltration-associated neuropathic pain remains poorly understood. In particular, the contribution of individual CCL2-expressing cell populations (i.e. stromal and leukocytes) to immune cell recruitment into the injured nerve has not been established. Here, in preclinical model of peripheral neuropathic pain (i.e. chronic constriction injury of the sciatic nerve), we have demonstrated that, CCL2 content was increased specifically in nerve fibers. This upregulation of CCL2 correlated with local monocyte/macrophage infiltration and pain processing. Furthermore, sciatic intraneural microinjection of CCL2 in naive animals triggered long-lasting pain behavior associated with local monocyte/macrophage recruitment. Using a specific CCR2 antagonist and mice with a CCL2 genetic deletion, we have also established that the CCL2/CCR2 axis drives monocyte/macrophage infiltration and pain hypersensitivity in the CCI model. Finally, specific deletion of CCL2 in stromal or immune cells respectively using irradiated bone marrow-chimeric CCI mice demonstrated that stromal cell-derived CCL2 (in contrast to CCL2 immune cell derived) tightly controls monocyte/macrophage recruitment into the lesion and plays a major role in the development of neuropathic pain. These findings demonstrate that in chronic pain states, CCL2 expressed by sciatic nerve cells predominantly drove local neuro-immune interactions and pain-related behavior through CCR2 signaling. PMID- 25449580 TI - Neonatal glucocorticoid treatment: long-term effects on the hypothalamus pituitary-adrenal axis, immune system, and problem behavior in 14-17 year old adolescents. AB - Neonatal glucocorticoid (GC) treatment is used to prevent bronchopulmonary dysplasia (BPD) in prematurely born babies. In the 1990s, treatment regimens with relatively high doses of dexamethasone (DEX) were common. As an alternative, hydrocortisone (HC) was used. Earlier, we compared long-term effects of both GCs in children aged 7-10 and detected adverse effects of neonatal DEX treatment, but not of HC, on a range of outcomes. The aim of the current cohort study was to investigate whether long-term effects of neonatal DEX were maintained and whether effects of HC remained absent at adolescent age (14-17years). We compared 71 DEX treated and 67 HC-treated adolescents. In addition, 71 adolescents who were not neonatally treated with GCs participated. All were born <32weeks of gestation. DEX-treated girls showed increased adrenocorticotropic hormone (ACTH) and cortisol responses in the Trier Social Stress Test. The cortisol awakening response was lower in HC-treated participants compared to untreated participants. Negative feedback function of the HPA-axis in the dexamethasone suppression test did not differ between groups. In contrast to our observations at the age of 7 10years, we did not observe group differences in mitogen-induced cytokine production at the age of 14-17years. DEX-treated girls showed more social problems and anxious/depressed behavior than HC-treated girls. Untreated girls showed more problem behavior as well. In conclusion, our results suggest that, especially in girls, neonatal DEX has a programming effect on the HPA-axis and on the ability to adjust to the environment. The loss of group differences on immune system measures indicate that potentially negative effects detected at a younger age subsided. PMID- 25449581 TI - Cytotoxic chemotherapy increases sleep and sleep fragmentation in non-tumor bearing mice. AB - Sleep disruption ranks among the most common complaints of breast cancer patients undergoing chemotherapy. Because of the complex interactions among cancer, treatment regimens, and life-history traits, studies to establish a causal link between chemotherapy and sleep disruption are uncommon. To investigate how chemotherapy acutely influences sleep, adult female c57bl/6 mice were ovariectomized and implanted with wireless biotelemetry units. EEG/EMG biopotentials were collected over the course of 3days pre- and post-injection of 13.5mg/kg doxorubicin and 135mg/kg cyclophosphamide or the vehicle. We predicted that cyclophosphamide+doxorubicin would disrupt sleep and increase central proinflammatory cytokine expression in brain areas that govern vigilance states (i.e., hypothalamus and brainstem). The results largely support these predictions; a single chemotherapy injection increased NREM and REM sleep during subsequent active (dark) phases; this induced sleep was fragmented and of low quality. Mice displayed marked increases in low theta (5-7Hz) to high theta (7 10Hz) ratios following chemotherapy treatment, indicating elevated sleep propensity. The effect was strongest during the first dark phase following injection, but mice displayed disrupted sleep for the entire 3-day duration of post-injection sleep recording. Vigilance state timing was not influenced by treatment, suggesting that acute chemotherapy administration alters sleep homeostasis without altering sleep timing. qPCR analysis revealed that disrupted sleep was accompanied by increased IL-6 mRNA expression in the hypothalamus. Together, these data implicate neuroinflammation as a potential contributor to sleep disruption after chemotherapy. PMID- 25449578 TI - The neuron-specific interleukin-1 receptor accessory protein is required for homeostatic sleep and sleep responses to influenza viral challenge in mice. AB - Interleukin-1beta (IL1) is involved in sleep regulation and sleep responses induced by influenza virus. The IL1 receptor accessory protein (AcP) and an alternatively spliced isoform of AcP found primarily in neurons, AcPb, form part of the IL1 signaling complex. IL1-induced sleep responses depend on injection time. In rat cortex, both IL1 mRNA and AcPb mRNA peak at Zeitgeber Time (ZT) 0 then decline over the daylight hours. Sleep deprivation enhances cortical IL1 mRNA and AcPb mRNA levels, but not AcP mRNA. We used wild type (WT) and AcPb knockout (KO) mice and performed sleep deprivation between ZT10 and 20 or between ZT22 and 8 based on the time of day expression profiles of AcPb and IL1. We hypothesized that the magnitude of the responses to sleep loss would be strain- and time of day-dependent. In WT mice, NREMS and REMS rebounds occurred regardless of when they were deprived of sleep. In contrast, when AcPbKO mice were sleep deprived from ZT10 to 20 NREMS and REMS rebounds were absent. The AcPbKO mice expressed sleep rebound if sleep loss occurred from ZT22 to 8 although the NREMS responses were not as robust as those that occurred in WT mice. We also challenged mice with intranasal H1N1 influenza virus. WT mice exhibited the expected enhanced sleep responses. In contrast, the AcPbKO mice had less sleep after influenza challenge compared to their own baseline values and compared to WT mice. Body temperature and locomotor activity responses after viral challenge were lower and mortality was higher in AcPbKO than in WT mice. We conclude that neuron-specific AcPb plays a critical role in host defenses and sleep homeostasis. PMID- 25449584 TI - Implant survival and patient-reported outcomes after total hip arthroplasty in young patients with juvenile idiopathic arthritis. AB - Juvenile Idiopathic Arthritis (JIA) is a common rheumatologic disease that frequently involves the hip joint and requires treatment with total hip arthroplasty (THA). A retrospective study with prospective follow-up was conducted to determine implant survival and patient-reported outcomes in JIA patients aged 35 or younger treated with THA. This study included 56 patients, and the mean time to follow-up was 12 years. The 10-year implant survival was 85%, and implant survival was significantly longer in older patients (P value=0.04). Hip disability and osteoarthritis outcome (HOOS) scores were favorable at follow-up, but significantly worse in women and patients with custom implants or history of revision THA. Overall, patient factors and implant characteristics predict implant survival and outcomes after THA in young patients with JIA. PMID- 25449583 TI - Programming of formalin-induced nociception by neonatal LPS exposure: Maintenance by peripheral and central neuroimmune activity. AB - The immune and nociceptive systems are shaped during the neonatal period where they undergo fine-tuning and maturation. Painful experiences during this sensitive period of development are known to produce long-lasting effects on the immune and nociceptive responses. It is less clear, however, whether inflammatory pain responses are primed by neonatal exposure to mild immunological stimuli, such as with lipopolysaccharide (LPS). Here, we examine the impact of neonatal LPS exposure on inflammatory pain responses, peripheral and hippocampal interleukin-1beta (IL-1beta), as well as mast cell number and degranulation in preadolescent and adult rats. Wistar rats were injected with LPS (0.05mg/kg IP, Salmonella enteritidis) or saline on postnatal days (PNDs) 3 and 5 and later subjected to the formalin test at PNDs 22 and 80-97. At both time-points, and one hour after formalin injection, blood and hippocampus were collected for measuring circulating and central IL-1beta levels using ELISA and Western blot, respectively. Paw tissue was also isolated to assess mast cell number and degree of degranulation using Toluidine Blue staining. Behavioural analyses indicate that at PND 22, LPS-challenged rats displayed enhanced flinching (p<.01) and licking (p<.01) in response to formalin injection. At PNDs 80-97, LPS-challenged rats exhibited increased flinching (p<.05), an effect observed in males only. Furthermore, neonatal LPS exposure enhanced circulating IL-1beta and mast cell degranulation in preadolescent but not adult rats following formalin injection. Hippocampal IL-1beta levels were increased in LPS-treated adult but not preadolescent rats in response to formalin injection. These data suggest neonatal LPS exposure produces developmentally regulated changes in formalin-induced behavioural responses, peripheral and central IL-1beta levels, as well as mast cell degranulation following noxious stimulation later in life. These findings highlight the importance of immune activation during the neonatal period in shaping immune response and pain sensitivity later in life. This is of clinical relevance given the high prevalence of bacterial infection during the neonatal period, particularly in the vulnerable population of preterm infants admitted to neonatal intensive care units. PMID- 25449582 TI - Gut microbiome composition is associated with temperament during early childhood. AB - BACKGROUND: Understanding the dynamics of the gut-brain axis has clinical implications for physical and mental health conditions, including obesity and anxiety. As such disorders have early life antecedents, it is of value to determine if associations between the gut microbiome and behavior are present in early life in humans. METHODS: We used next generation pyrosequencing to examine associations between the community structure of the gut microbiome and maternal ratings of child temperament in 77 children at 18-27months of age. It was hypothesized that children would differ in their gut microbial structure, as indicated by measures of alpha and beta diversity, based on their temperamental characteristics. RESULTS: Among both boys and girls, greater Surgency/Extraversion was associated greater phylogenetic diversity. In addition, among boys only, subscales loading on this composite scale were associated with differences in phylogenetic diversity, the Shannon Diversity index (SDI), beta diversity, and differences in abundances of Dialister, Rikenellaceae, Ruminococcaceae, and Parabacteroides. In girls only, higher Effortful Control was associated with a lower SDI score and differences in both beta diversity and Rikenellaceae were observed in relation to Fear. Some differences in dietary patterns were observed in relation to temperament, but these did not account for the observed differences in the microbiome. CONCLUSIONS: Differences in gut microbiome composition, including alpha diversity, beta diversity, and abundances of specific bacterial species, were observed in association with temperament in toddlers. This study was cross-sectional and observational and, therefore, does not permit determination of the causal direction of effects. However, if bidirectional brain-gut relationships are present in humans in early life, this may represent an opportunity for intervention relevant to physical as well as mental health disorders. PMID- 25449585 TI - Effect of heterotopic ossification on hip range of motion and clinical outcome. AB - The utility of heterotopic ossification (HO) classification systems is debatable. The range of motion and Harris hip score (HHS) were calculated in 104 patients with known HO after total hip arthroplasty and 208 matched controls without HO. The patients with HO were radiographically divided into high and low grade HO groups. There was no statistically significant association of HHS with high or low grade HO. High grade HO had a statistically significant 6 degrees loss of terminal hip flexion, 4 degrees loss of abduction, and 6 degrees loss of internal rotation at the hip. The small changes in terminal hip range of motion and lack of association with HHS may be the result of false radiographic continuity resulting in an overestimation of the disability in high grade HO. PMID- 25449586 TI - Third-generation alumina-on-alumina total hip arthroplasty: 14 to 16-year follow up study. AB - Ceramic-on-ceramic articulation has the lowest wear with little osteolysis. However, the wear and osteolysis in long-term follow-up are not known. Another concern is ceramic fracture, which might occur after repeated stress during a long period. Ninety hips (76 patients with a mean age of 47 years) that underwent cementless total hip arthroplasty using third-generation ceramic-on-ceramic articulation were followed for 14-16 years. At final follow-up, there was no measurable ceramic wear and no periprosthetic osteolysis was identified. No ceramic fracture occurred during the follow-up. One hip was revised because of late infection. All prostheses were bone-ingrown. Two patients experienced a grinding sensation. However, no patient had squeak. The mean Harris hip score at the final evaluation was 89 points and the survival rate was 98.9%. PMID- 25449587 TI - Incidence of perioperative events in single setting bilateral direct anterior approach total hip arthroplasty. AB - The peri-operative complication rates of a single setting bilateral direct anterior approach (DAA) total hip arthroplasty (THA) are not well known. All single setting (90) bilateral DAA THA patients were reviewed. Blood loss was 632 mL for single setting bilateral DAA procedures. Intra-operative and post operative complication rates for single setting bilateral DAA THA were low. PMID- 25449588 TI - The effect of surface morphology on the primary fixation strength of uncemented femoral knee prosthesis: a cadaveric study. AB - We investigated the effect of surface morphology on the mechanical performance of uncemented femoral knee prosthesis. Eighteen implants were implanted on nine paired femurs and then pushed-off (left legs: a novel surface morphology; right legs: Porocoat as baseline). Bone mineral density (BMD) and anteroposterior dimension were not significantly different between groups. The insertion force was not significantly different, however, the loosening force was significantly higher in the novel group (P=0.007). BMD had a direct relationship with the insertion and loosening force (P<0.001). The effect of surface morphology on implant alignment was very small. We conclude that the surface properties create a higher frictional resistance, thereby providing a better inherent stability of implants featuring the novel surface morphology. PMID- 25449589 TI - Development and verification of a cementless novel tapered wedge stem for total hip arthroplasty. AB - Most current tapered wedge hip stems were designed based upon the original Mueller straight stem design introduced in 1977. These stems were designed to have a single medial curvature and grew laterally to accommodate different sizes. In this preclinical study, the design and verification of a tapered wedge stem using computed tomography scans of 556 patients are presented. The computer simulation demonstrated that the novel stem, designed for proximal engagement, allowed for reduced distal fixation, particularly in the 40-60 year male population. Moreover, the physical micromotion testing and finite element analysis demonstrated that the novel stem allowed for reduced micromotion. In summary, preclinical data suggest that the computed tomography based stem design described here may offer enhanced implant fit and reduced micromotion. PMID- 25449590 TI - No difference in clinical and radiologic outcomes after total knee arthroplasty with a new ultra-congruent mobile bearing system and rotating platform mobile bearing systems after minimum 5-year follow-up. AB - We retrospectively compared the clinical and radiographic results between 76 primary total knee arthroplasties (TKAs) using the e.motion Ultra-Congruent prosthesis and 155 primary TKAs using the Low Contact Stress rotating platform. All patients had a minimum 5-year follow-up. Range of motion, Hospital for Special Surgery score, Knee Society Knee Score and Knee Society Functional Score significantly increased in both groups postoperatively, but there was no significant difference between the two groups. The mechanical femorotibial angle improved in both groups postoperatively. Coronal and sagittal component angles were well maintained at the final follow-up. This study demonstrates that a new mobile-bearing prosthesis, designed to be highly congruent with a rotating bearing, could be considered with theoretical advantages and comparable outcomes of established mobile-bearing prostheses. PMID- 25449591 TI - Responsiveness of patient reported outcome measures in total joint arthroplasty patients. AB - This study reports the responsiveness to change and minimal clinically important difference (MCID) of three patient reported outcome measures following total hip arthroplasty (THA) and total knee arthroplasty (TKA). Patient-reported outcome measures were collected preoperatively and 3 months postoperatively for 391 patients enrolled in the California Joint Replacement Registry. Effect size, standardized response means, and MCID were calculated for each measure. The WOMAC and the SF12v2 physical component summary (PCS) score were the most responsive to perioperative changes. The MCID was 4.97 for the SF12v2 PCS and 10.21 for the WOMAC. THA patients were more likely to exhibit improvements above the MCID than TKA patients. The WOMAC and SF12v2 PCS are useful to measure health status changes in TJA patients. LEVEL OF EVIDENCE: Prognostic Level II. PMID- 25449592 TI - The impact of total joint arthroplasty on sexual function in young, active patients. AB - There is limited information regarding sexual function following total hip (THA) and knee arthroplasty (TKA). A multicenter study of 806 THA, 542 TKA, and 181 control patients less than 60 years of age was conducted using an independent survey center to question subjects about their sexual function. Only 1.3% of THA and 1.6% of TKA patients stated they were not sexually active due to their operation. No significant differences were noted in sexual function based on the bearing surface, femoral head size, or use of surface replacement arthroplasty in the hip cohort. Multivariate analysis revealed no difference in the percentage of patients sexually active following a THA or TKA (OR 1.19, P=0.38). Most young active patients return to sexual activity after hip and knee arthroplasty. PMID- 25449593 TI - Clinical outcomes, survivorship and adverse events with mobile-bearings versus fixed-bearings in hip arthroplasty-a prospective comparative cohort study of 143 ADM versus 130 trident cups at 2 to 6-year follow-up. AB - The principle of dual mobility cups, often called "tripolar", has been developed to overcome the problem of instability following primary hip arthroplasty. We prospectively compared two cohorts which differed only by the type of bearings, i.e." mobile bearing hip" (MBH) in a 143-study cohort of ADM cups versus "fixed bearing hip" (FBH) of 130 Trident PSL cups, at a follow-up at 2-6years. The survival rates at 4.13-years, with instability as endpoint was significantly (P=0.0176) in favor of mobile bearings at 100% with no dislocation reported, versus 94.8% with fixed bearings. These mobile bearings, matching both "modern" dual mobility cups and annealed highly crossed polyethylene, would appear to offer at longer follow-up a valuable solution to clinical outcomes in acetabular arthroplasty. PMID- 25449595 TI - Hormone replacement with 17beta-estradiol plus dihydrotestosterone restores male sexual behavior in rats treated neonatally with clomipramine. AB - Male sexual behavior (MSB) in rodents, in both its consummatory and motivational components, is regulated by hormones such as testosterone, 17beta-estradiol and 5 alpha-dihydrotestosterone. In experiments, neonatal treatment with clomipramine (CMI; a serotonin reuptake inhibitor) reproduces some of the signs of depression in adult age, including reduced sexual behavior manifested in a lower percentage of subjects that mount, intromit and ejaculate, although their testosterone levels were not altered. However, the effect of this treatment on estrogen levels and the consequences of hormone substitution using 17beta-estradiol and 5-alpha dihydrotestosterone on the expression of male sexual behavior are still unknown. Therefore, the objective of the present study was to analyze the effect of neonatal treatment with CMI on plasma testosterone and 17beta-estradiol levels, and the role of testosterone, 17beta-estradiol and 5-alpha-dihydrotestosterone in altering the consummatory and motivational components of sexual behavior in male rats. To this end, it analyzed the copulatory parameters and sexual incentive motivation (SIM) of rats treated with CMI under two conditions: basal and post hormone replacements. Neonatal treatment with CMI did not affect plasma testosterone or 17beta-estradiol concentrations, but did decrease both the consummatory component and sexual motivation according to the results of the SIM test. These aspects were recovered after administering 17beta-estradiol +5-alpha dihydrotestosterone, but not testosterone. PMID- 25449596 TI - Polyoxometalates--potent and selective ecto-nucleotidase inhibitors. AB - Polyoxometalates (POMs) are inorganic cluster metal complexes that possess versatile biological activities, including antibacterial, anticancer, antidiabetic, and antiviral effects. Their mechanisms of action at the molecular level are largely unknown. However, it has been suggested that the inhibition of several enzyme families (e.g., phosphatases, protein kinases or ecto nucleotidases) by POMs may contribute to their pharmacological properties. Ecto nucleotidases are cell membrane-bound or secreted glycoproteins involved in the hydrolysis of extracellular nucleotides thereby regulating purinergic (and pyrimidinergic) signaling. They comprise four distinct families: ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs), alkaline phosphatases (APs) and ecto 5'-nucleotidase (eN). In the present study, we evaluated the inhibitory potency of a series of polyoxometalates as well as chalcogenide hexarhenium cluster complexes at a broad range of ecto-nucleotidases. [Co4(H2O)2(PW9O34)2](10-) (5, PSB-POM142) was discovered to be the most potent inhibitor of human NTPDase1 described so far (Ki: 3.88 nM). Other investigated POMs selectively inhibited human NPP1, [TiW11CoO40](8-) (4, PSB-POM141, Ki: 1.46 nM) and [NaSb9W21O86](18-) (6, PSB-POM143, Ki: 4.98 nM) representing the most potent and selective human NPP1 inhibitors described to date. [NaP5W30O110](14-) (8, PSB-POM144) strongly inhibited NTPDase1-3 and NPP1 and may therefore be used as a pan-inhibitor to block ATP hydrolysis. The polyoxoanionic compounds displayed a non-competitive mechanism of inhibition of NPPs and eN, but appeared to be competitive inhibitors of TNAP. Future in vivo studies with selected inhibitors identified in the current study are warranted. PMID- 25449594 TI - Pharmacogenomics of cisplatin sensitivity in non-small cell lung cancer. AB - Cisplatin, a platinum-based chemotherapeutic drug, has been used for over 30 years in a wide variety of cancers with varying degrees of success. In particular, cisplatin has been used to treat late stage non-small cell lung cancer (NSCLC) as the standard of care. However, therapeutic outcomes vary from patient to patient. Considerable efforts have been invested to identify biomarkers that can be used to predict cisplatin sensitivity in NSCLC. Here we reviewed current evidence for cisplatin sensitivity biomarkers in NSCLC. We focused on several key pathways, including nucleotide excision repair, drug transport and metabolism. Both expression and germline DNA variation were evaluated in these key pathways. Current evidence suggests that cisplatin-based treatment could be improved by the use of these biomarkers. PMID- 25449597 TI - Chemical inhibitor targeting the replication protein A-DNA interaction increases the efficacy of Pt-based chemotherapy in lung and ovarian cancer. AB - Platinum-based chemotherapeutics exert their therapeutic efficacy via the formation of DNA adducts which interfere with DNA replication, transcription and cell division and ultimately induce cell death. Repair and tolerance of these Pt DNA lesions by nucleotide excision repair (NER) and homologous recombination (HR) can substantially reduce the effectiveness of therapy. Inhibition of these repair pathways, therefore, holds the potential to sensitize cancer cells to Pt treatment and increase clinical efficacy. Replication Protein A (RPA) plays essential roles in both NER and HR, along with its role in DNA replication and DNA damage checkpoint activation. Each of these functions is, in part, mediated by RPA binding to single-stranded DNA (ssDNA). Here we report the synthesis and characterization of novel derivatives of RPA small molecule inhibitors and their activity in models of epithelial ovarian cancer (EOC) and non-small cell lung cancer (NSCLC). We have synthesized analogs of our previously reported RPA inhibitor TDRL-505 and determined the structure-activity relationships. These data led us to the identification of TDRL-551, which exhibited a greater than 2 fold increase in in vitro activity. TDRL-551 showed synergy with Pt in tissue culture models of EOC and in vivo efficacy, as a single agent and in combination with platinum, in a NSCLC xenograft model. These data demonstrate the utility of RPA inhibition in EOC and NSCLC and the potential in developing novel anticancer therapeutics that target RPA-DNA interactions. PMID- 25449598 TI - New functional activity of aripiprazole revealed: Robust antagonism of D2 dopamine receptor-stimulated Gbetagamma signaling. AB - The dopamine D2 receptor (DRD2) is a G protein-coupled receptor (GPCR) that is generally considered to be a primary target in the treatment of schizophrenia. First generation antipsychotic drugs (e.g. haloperidol) are antagonists of the DRD2, while second generation antipsychotic drugs (e.g. olanzapine) antagonize DRD2 and 5HT2A receptors. Notably, both these classes of drugs may cause side effects associated with D2 receptor antagonism (e.g. hyperprolactemia and extrapyramidal symptoms). The novel, "third generation" antipsychotic drug, aripiprazole is also used to treat schizophrenia, with the remarkable advantage that its tendency to cause extrapyramidal symptoms is minimal. Aripiprazole is considered a partial agonist of the DRD2, but it also has partial agonist/antagonist activity for other GPCRs. Further, aripiprazole has been reported to have a unique activity profile in functional assays with the DRD2. In the present study the molecular pharmacology of aripiprazole was further examined in HEK cell models stably expressing the DRD2 and specific isoforms of adenylyl cyclase to assess functional responses of Galpha and Gbetagamma subunits. Additional studies examined the activity of aripiprazole in DRD2-mediated heterologous sensitization of adenylyl cyclase and cell-based dynamic mass redistribution (DMR). Aripiprazole displayed a unique functional profile for modulation of G proteins, being a partial agonist for Galphai/o and a robust antagonist for Gbetagamma signaling. Additionally, aripiprazole was a weak partial agonist for both heterologous sensitization and dynamic mass redistribution. PMID- 25449600 TI - Ferulic acid suppresses activation of hepatic stellate cells through ERK1/2 and Smad signaling pathways in vitro. AB - Hepatic stellate cells (HSCs) are the primary source of matrix components in hepatic fibrosis. Ferulic acid (FA) has antifibrotic potential in renal and cardiac disease. However, whether FA comprises inhibitive effects of HSCs activation remains to be clarified. This study aims at evaluating the hypothesis that FA inhibits extracellular matrix (ECM)-related gene expression by the interruption of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) or/and Smad signaling pathways in HSC-T6. Our results indicated that FA significantly inhibited both viability and activation of HSC-T6 cells in vitro. In addition, we demonstrated, for the first time, that FA dramatically inhibited the expression of alpha1(I) collagen (Col-I) and fibronectin at levels of transcription and translation. Moreover, FA treatment inhibited Smad transcriptional activity, as evaluated by transient transfection with a plasmid construction containing SMAD response element and the luciferase reporter gene. Furthermore, FA inhibition of HSCs activation involved in both focal adhesion kinase (FAK)-dependent ERK1/2 and Smad signaling pathways with independent manner. Blocking transforming growth factor-beta by a neutralizing antibody caused a marked reduction in both ERK1/2 and Smad signaling. These results support FA as an effective therapeutic agent for the prevention and treatment of hepatic fibrosis. PMID- 25449599 TI - Myricetin prevents titanium particle-induced osteolysis in vivo and inhibits RANKL-induced osteoclastogenesis in vitro. AB - Titanium (Ti) particle-induced periprosthetic osteolysis and subsequent aseptic loosening are a primary reason for total hip arthroplasty failure. The aim of this study was to assess the effect of myricetin on Ti particle-induced osteolysis and osteoclastogenesis. We demonstrated that myricetin, a natural plant extract, exerts potent inhibitory effects on Ti particle-induced osteolysis in a mouse calvarial model. Further histological analysis indicated that the inhibition of osteoclast formation and function, and the secretion of inflammatory factors, are key targets for therapeutic agents in the treatment of wear particle-induced osteolysis. In vitro, we found that myricetin suppressed receptor activator of nuclear factor-kappaB ligand (RANKL)-mediated osteoclast differentiation, bone resorption, and F-actin ring formation in a dose-dependent manner. Moreover, myricetin significantly reduced the expression of osteoclast specific markers in mouse bone marrow-derived macrophages, including tartrate resistant acid phosphatase (TRAP), cathepsin K, the calcitonin receptor, V-ATPase d2, c-fos, and nuclear factor of activated T cells (NFAT) c1. Further investigation revealed that myricetin inhibited osteoclastogenesis through the suppression of the nuclear factor-kappaB (NF-kappaB) signaling pathway and mitogen-activated protein kinase (MAPK) pathways involving extracellular signal regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase 1/2 (JNK1/2). While, the inhibition of TNF-alpha and IL-1beta secretion was another reason for the suppressive effect of myricetin on Ti particle-induced osteolysis. Collectively, these findings suggest that myricetin is a potential natural agent for the treatment of periprosthetic osteolysis and other osteoclast-related osteolytic diseases. PMID- 25449601 TI - Upregulation of FLJ10540, a PI3K-association protein, in rostral ventrolateral medulla impairs brain stem cardiovascular regulation during mevinphos intoxication. AB - FLJ10540, originally identified as a microtubule-associated protein, induces cell proliferation and migration during tumorigenesis via the formation of FLJ10540 PI3K complex and enhancement of PI3K kinase activity. Interestingly, activation of PI3K/Akt cascade, leading to upregulation of nitric oxide synthase II (NOS II)/peroxynitrite signaling in the rostral ventrolateral medulla (RVLM), the brain stem site that maintains blood pressure and sympathetic vasomotor tone, mediates the impairment of brain stem cardiovascular regulation induced by the pesticide mevinphos. We evaluated the hypothesis that upregulation of FLJ10540 in the RVLM is upstream to this repertoire of signaling cascade that underpins mevinphos-induced circulatory depression. Microinjection bilaterally of mevinphos (10nmol) into the RVLM of anesthetized Sprague-Dawley rats induced a progressive hypotension that was accompanied by an increase (Phase I), followed by a decrease (Phase II) of an experimental index for baroreflex-mediated sympathetic vasomotor tone. There was augmentation in FLJ10540 mRNA in the RVLM or FLJ10540 protein in RVLM neurons, both of which were causally and temporally related to an augmentation of binding between the catalytic subunit (p110) and regulatory subunit (p85) of PI3K, phosphorylation of Akt at Thr308 site, and NOS II, superoxide or peroxynitrite level in the RVLM. Immunoneutralization of FJL10540 in the RVLM significantly antagonized those biochemical changes, and blunted the progressive hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during mevinphos intoxication. We conclude that upregulation of FLJ10540 in the RVLM elicits impairment of brain stem cardiovascular regulation that underpins circulatory depression during mevinphos intoxication via activation of PI3K/Akt/NOS II/peroxynitrite signaling cascade in the RVLM. PMID- 25449602 TI - Coumestrol inhibits carotid sinus baroreceptor activity by cAMP/PKA dependent nitric oxide release in anesthetized male rats. AB - Phytoestrogens could offer multiple beneficial effects on the cardiovascular system. Here, we have examined the effects of coumestrol (CMT) on carotid baroreceptors activity (CBA) and the possible mechanisms in male rats. The functional parameters of carotid baroreceptors were measured by recording sinus nerve afferent discharge in anesthetized male rats with perfused isolated carotid sinus. The levels of protein expression were determined by using ELISA and Western blotting. CMT (1 to 100MUmolL(-1)) inhibited CBA, which shifted the functional curve of the carotid baroreceptor to the right and downward, with a marked decrease in the peak slope and the peak integral value of carotid sinus nerve discharge in a concentration dependent manner. These effects were not blocked by a specific estrogen receptor antagonist ICI 182,780, but were completely abolished by nitric oxide (NO) synthase inhibitor l-NAME (N(G)-nitro-l arginine methyl ester). Furthermore, a NO donor, SIN-1(3-morpholion-sydnon imine), could potentiate these inhibitory effects of CMT. CMT stimulated the phosphorylation of Ser(1176)-eNOS (endothelial nitric oxide synthase) in a dose dependent manner in carotid bifurcation tissue over a perfusion period of 15min. The rapid activation of eNOS by CMT was blocked by a highly selective PKA (protein kinase A) inhibitor H89. In addition, inhibition of PI3K (phosphatidylinositol-3-kinase) and ERK (extracellular signal-regulated kinase) pathways had no effect on eNOS activation by CMT. CMT inhibited CBA via eNOS activation and NO synthesis. These effects were mediated by the cAMP/PKA pathway and were unrelated to the estrogenic effect. PMID- 25449603 TI - Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Galphaq pathway. AB - The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) and an important target in the treatment of type 2 diabetes mellitus (T2DM). Upon stimulation with agonist, the GLP-1R signals through both Galphas and Galphaq coupled pathways to stimulate insulin secretion. The agonist-induced GLP-1R internalisation has recently been shown to be important for insulin secretion. However, the molecular mechanisms underlying GLP-1R internalisation remain unknown. The aim of this study was to determine the role of GLP-1R downstream signalling pathways in its internalisation. Agonist-induced human GLP 1R (hGLP-1R) internalisation and activity were examined using a number of techniques including immunoblotting, ELISA, immunofluorescence and luciferase assays to determine cAMP production, intracellular Ca(2+) accumulation and ERK phosphorylation. Agonist-induced hGLP-1R internalisation is dependent on caveolin 1 and dynamin. Inhibition of the Galphaq pathway but not the Galphas pathway affected hGLP-1R internalisation. Consistent with this, hGLP-1R mutant T149M and small-molecule agonists (compound 2 and compound B), which activate only the Galphas pathway, failed to induce internalisation of the receptor. Chemical inhibitors of the Galphaq pathway, PKC and ERK phosphorylation significantly reduced agonist-induced hGLP-1R internalisation. These inhibitors also suppressed agonist-induced ERK1/2 phosphorylation demonstrating that the phosphorylated ERK acts downstream of the Galphaq pathway in the hGLP-1R internalisation. In summary, agonist-induced hGLP-1R internalisation is mediated by the Galphaq pathway. The internalised hGLP-1R stimulates insulin secretion from pancreatic beta-cells, indicating the importance of GLP-1 internalisation for insulin secretion. PMID- 25449604 TI - Receptor proximal kinases in NF-kappaB signaling as potential therapeutic targets in cancer and inflammation. AB - Many signaling pathways leading to activation of transcription factors and gene expression are characterized by phosphorylation events mediated by specific kinases. The transcription factor NF-kappaB plays a key role in multiple cellular processes, including immune signaling, inflammation, development, proliferation and survival. Dysregulated NF-kappaB activation is associated with autoimmunity, chronic inflammation and cancer. Activation of NF-kappaB requires IkappaB kinase (IKK)alpha or beta, the activity of which is regulated via phosphorylation by specific IKK kinases and by autophosphorylation. Receptor specificity is further obtained by the use of multiple upstream receptor proximal kinases. We review the identities of several IKK regulatory kinases as well as the proposed molecular mechanisms. In addition, we discuss the potential for therapeutic targeting of some of these kinases in the context of inflammatory diseases and cancer. PMID- 25449605 TI - A review of canine atlantoaxial joint subluxation. AB - Atlantoaxial subluxation was first reported in dogs nearly fifty years ago. Since that time a better understanding of the aetiologies predisposing to joint laxity and instability has been achieved. Surgeons however are still trying to address the problems associated with stabilizing this joint which by nature is often required in small juvenile dogs. This review describes the various techniques used, discussing the associated benefits and complications thereby allowing the clinician to make an informed decision on the best treatment for the individual patient. PMID- 25449606 TI - Separation of polyethylene terephthalate from municipal waste plastics by froth flotation for recycling industry. AB - Recycling is an effective way to manage plastic wastes and receives considerable attention. Since plastic mixtures are difficult to recycle because of their intrinsic characteristics, separation of mixed plastics is the key problem for recycling. Separation of polyethylene terephthalate (PET) from municipal waste plastics (MWP) by froth flotation combined with alkaline pretreatment was investigated for recycling industry. The effect of process variables was estimated by L9 (3(4)) orthogonal array of experiments and single factor experiments. The optimum conditions of alkaline pretreatment are 10 wt% sodium hydroxide, 20 min and 70 degrees C. After alkaline pretreatment under optimum conditions, flotation separation PET from acrylonitrile-butadiene-styrene, polystyrene, polycarbonate or polyvinyl chloride was achieved with high purity and efficiency. The purity of PET is up to 98.46% and the recovery is above 92.47%. A flow sheet of separation PET from MWP by a combination of froth flotation and sink float separation was designed. This study facilitates industrial application of plastics flotation and provides technical insights into recycling of waste plastics. PMID- 25449607 TI - Performance and kinetic study of semi-dry thermophilic anaerobic digestion of organic fraction of municipal solid waste. AB - Anaerobic digestion (AD) of the organic fraction of municipal solid waste (OFMSW) is promoted as an energy source and waste disposal. In this study semi dry anaerobic digestion of organic solid wastes was conducted for 45 days in a lab scale batch experiment for total solid concentration of 100g/L for investigating the start-up performances under thermophilic condition (50 degrees C). The performance of the reactor was evaluated by measuring the daily biogas production and calculating the degradation of total solids and the total volatile solids. The biogas yield at the end of the digestion was 52.9L/kg VS (volatile solid) for the total solid (TS) concentration of 100g/L. About 66.7% of the volatile solid degradation was obtained during the digestion. A first order model based on the availability of substrate as the limiting factor was used to perform the kinetic studies of batch anaerobic digestion system. The value of reaction rate constant, k, obtained was 0.0249 day(-1). PMID- 25449609 TI - [Oral health in dementia: Results of a telephone helpline]. AB - BACKGROUND: The complexity of dental care and oral hygiene for people with dementia increases with increasing numbers of residual teeth. AIM: This study was carried out to determine whether the offer of a telephone helpline on oral health and dementia would be utilized. MATERIAL AND METHODS: Over a period of 1 year contacts received by a telephone helpline manned by three oral healthcare staff were collected and analyzed. RESULTS: From 01 June 2012 to 31 May 2013 a total of 355 callers (180 healthcare staff and 175 relatives) presented and discussed 2535 problems. The average duration of a call was 21 min. Almost one quarter of the callers were looking for mobile dental care services and 14.4 % were looking for a dentist specialized in caring for patients with dementia. Oral disease, oral care and conflicts between stakeholders on aspects of oral health were discussed. Of the healthcare staff three quarters asked about training to improve the oral health of people with dementia. CONCLUSION: The demand on the specialists of the helpline showed a substantial knowledge deficit of healthcare staff and relatives. The study confirmed a wide range of oral health issues of people with dementia. Knowledge on oral and denture hygiene and on oral disease could be introduced into primary training and continued professional education. In addition to the lack of knowledge, deficits also exist in the oral healthcare system for people with dementia. Politicians and healthcare stakeholders are encouraged to incorporate oral healthcare for people with dementia into strategies and dementia networks. PMID- 25449608 TI - A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations. AB - Arctic populations live in an environment characterized by extreme cold and the absence of plant foods for much of the year and are likely to have undergone genetic adaptations to these environmental conditions in the time they have been living there. Genome-wide selection scans based on genotype data from native Siberians have previously highlighted a 3 Mb chromosome 11 region containing 79 protein-coding genes as the strongest candidates for positive selection in Northeast Siberians. However, it was not possible to determine which of the genes might be driving the selection signal. Here, using whole-genome high-coverage sequence data, we identified the most likely causative variant as a nonsynonymous G>A transition (rs80356779; c.1436C>T [p.Pro479Leu] on the reverse strand) in CPT1A, a key regulator of mitochondrial long-chain fatty-acid oxidation. Remarkably, the derived allele is associated with hypoketotic hypoglycemia and high infant mortality yet occurs at high frequency in Canadian and Greenland Inuits and was also found at 68% frequency in our Northeast Siberian sample. We provide evidence of one of the strongest selective sweeps reported in humans; this sweep has driven this variant to high frequency in circum-Arctic populations within the last 6-23 ka despite associated deleterious consequences, possibly as a result of the selective advantage it originally provided to either a high-fat diet or a cold environment. PMID- 25449610 TI - Immediate rehabilitation of the posterior maxilla with extensive sinus pneumatization with one axial and one trans-sinus tilted implant: a 3-year clinical report and a classification. AB - Implant rehabilitation of the posterior maxilla can entail difficulties due to reduced bone quantity and poor bone quality, especially after long-term edentulism. In some patients, multiple surgeries are necessary, which may lead to higher patient morbidity and longer treatment times before a prosthetic rehabilitation can be achieved. This article presents an immediate fixed prosthesis in a posterior atrophic maxilla supported by 1 anterior axial implant and 1 posterior tilted fixture placed with an intrasinus insertion. Additionally, a classification scheme for immediate treatment for the posterior maxilla based on the available residual bone is provided. PMID- 25449611 TI - Clinical tooth preparations and associated measuring methods: a systematic review. AB - STATEMENT OF PROBLEM: The geometries of tooth preparations are important features that aid in the retention and resistance of cemented complete crowns. The clinically relevant values and the methods used to measure these are not clear. PURPOSE: The purpose of this systematic review was to retrieve, organize, and critically appraise studies measuring clinical tooth preparation parameters, specifically the methodology used to measure the preparation geometry. MATERIAL AND METHODS: A database search was performed in Scopus, PubMed, and ScienceDirect with an additional hand search on December 5, 2013. The articles were screened for inclusion and exclusion criteria and information regarding the total occlusal convergence (TOC) angle, margin design, and associated measuring methods were extracted. The values and associated measuring methods were tabulated. RESULTS: A total of 1006 publications were initially retrieved. After removing duplicates and filtering by using exclusion and inclusion criteria, 983 articles were excluded. Twenty-three articles reported clinical tooth preparation values. Twenty articles reported the TOC, 4 articles reported margin designs, 4 articles reported margin angles, and 3 articles reported the abutment height of preparations. A variety of methods were used to measure these parameters. CONCLUSIONS: TOC values seem to be the most important preparation parameter. Recommended TOC values have increased over the past 4 decades from an unachievable 2- to 5-degree taper to a more realistic 10 to 22 degrees. Recommended values are more likely to be achieved under experimental conditions if crown preparations are performed outside of the mouth. We recommend that a standardized measurement method based on the cross sections of crown preparations and standardized reporting be developed for future studies analyzing preparation geometry. PMID- 25449612 TI - Closed-eye orbital prosthesis: a clinical report. AB - One of the most challenging prostheses to fabricate is an acceptable orbital prosthesis. Successful reconstruction of the complex missing tissues, the globe, muscle, skin, and bony elements requires time and high levels of practical skill. A good match to the contralateral nondefect side will help mask the underlying defect and give the patient confidence to return to normal, routine life. The contralateral eye opening will commonly dictate the eye opening of such a prosthesis, but because of the expressive nature of the eye and its high levels of mobility, this can be difficult to achieve. This clinical report presents a patient who had an extended orbital exenteration and right maxillectomy to remove a maxillary squamous cell carcinoma. An alternative approach to constructing an orbital prosthesis was undertaken with the eye closed. Compared to the normal method of fabrication, this process was less complex and quicker, made the prosthesis less "staring," camouflaged the defect, and reduced the detection of the prosthesis because of movements in the remaining eye. The patient engaged in his routine daily life, which reinforced his self-esteem, confidence, and reintegration into the community. PMID- 25449614 TI - Model structures for C-(A)-S-H(I). AB - C-(A)-S-H(I) is a calcium silicate hydrate that is studied extensively as a model for the main binding phase in concrete. It is a structurally imperfect form of 14 A tobermorite that has variable composition and length of (alumino)silicate anions. New structural-chemical formulae are presented for single- and double chain tobermorite-based phases and equations are provided that can be used to calculate a number of useful quantities from (29)Si NMR data. It is shown that there are no interlayer calcium ions when the silicate chains are of infinite length and that one is added for each tetrahedral 'bridging' site that is vacant. Preparations that have Ca/Si greater than about 1.4 include an intermixed Ca-rich phase. It is not possible to generate a structural model for a dimer that is crystal-chemically consistent with known calcium silicate hydrates if the starting structure is an orthotobermorite, i.e. of the type that has been used in all previous studies. Crystal-chemically plausible models are developed that are based instead on clinotobermorite. A number of models that represent different mean chain lengths are developed using crystal-chemical and geometrical reasoning. The models account for experimental observations, including variations in Ca/Si, H2O/Si, (alumino)silicate anion structure and layer spacing. PMID- 25449613 TI - Intraoral angiosarcoma: treatment with a brachytherapy prosthesis. AB - Angiosarcomas are rare, malignant neoplasms of vascular origin that account for less than 1% of all soft tissue tumors. Angiosarcomas of the oral cavity are especially rare, and brachytherapy may be prescribed as a localized treatment to manage these malignancies. Intraoral brachytherapy requires collaboration between the radiation oncologist and a dental professional for the fabrication of the brachytherapy delivery prosthesis. This clinical report describes an intraoral angiosarcoma and the fabrication of an intraoral brachytherapy prosthesis to manage this malignancy. PMID- 25449615 TI - Reconstructive phase transition in (NH4)3TiF7 accompanied by the ordering of TiF6 octahedra. AB - An unusual phase transition P4/mnc -> Pa?bar 3 has been detected after cooling the (NH4)3TiF7 compound. Some TiF6 octahedra, which are disordered in the room temperature tetragonal structure, become ordered in the low-temperature cubic phase due to the disappearance of the fourfold axis. Other TiF6 octahedra undergo large rotations resulting in huge displacements of the F atoms by 1.5-1.8 A that implies a reconstructive phase transition. It was supposed that phases P4/mbm and Pm?bar 3m could be a high-temperature phase and a parent phase, respectively, in (NH4)3TiF7. Therefore, the sequence of phase transitions can be written as Pm?bar 3m -> P4/mbm -> P4/mnc -> Pa?bar 3. The interrelation between (NH4)3TiF7, (NH4)3GeF7 and (NH4)3PbF7 is found, which allows us to suppose phase transitions in relative compounds. PMID- 25449616 TI - Metal distribution and disorder in the crystal structure of [NH2Et2][Cr7MF8((t)BuCO2)16] wheel molecules for M = Mn, Fe, Co, Ni, Cu, Zn and Cd. AB - The homometallic wheel compound [Cr8F8(O2CCMe3)16] formed with fluorine and pivalic acid ligands can be modified by introducing in the synthesis process a divalent cation M capable of octahedral coordination instead of one of the trivalent Cr centres in the ring. Heterometallic mono-anionic species [Cr7MF8(O2CCMe3)16](-) can form diethylammonium salts and be crystallized from ethylacetate solution as compounds with the general formula [NH2Et2][Cr7MF8((t)BuCO2)16][C4H8O2]0.5 for M = Mn, Fe, Co, Ni, Cu, Zn and Cd. Their structures are isomorphous, belonging to the space group P21/c. The study has determined the degree of order for the individual M heterometal over the possible metal positions of the ring in the crystal structure by modelling based on X-ray diffraction data. The model took into account disorder in tert-butyl groups of the pivalate ligands and in the position and orientation of the ethylacetate solvent molecule. The heterometal turned out to be partly ordered in the crystal structure. PMID- 25449617 TI - Unusual crystal structure of N-substituted maleamic acid - very strong effect of intramolecular hydrogen bonds. AB - N-Carbamylmaleamic acid (malur) undergoes cyclodehydration under favourable conditions, as expected, to give N-carbamyl maleimide. N-(Carboxymethyl) maleamic acid (malgly), however, does not undergo a similar cyclization reaction. Strong pi bonding between the C and N of the amide group as well as two intramolecular hydrogen bonds makes malgly a planar molecule, as revealed by single-crystal X ray studies. PMID- 25449619 TI - Refinement of cronstedtite-1M. AB - The structure of cronstedtite-1M was refined using a crystal from Eisleben (Saxony-Anhalt, Germany). The space group is Cm, a = 5.5033 (3), b = 9.5289 (6), c = 7.3328 (5) A, beta = 104.493 (7) degrees , composition (Fe(2+)2.461Fe(3+)0.539)(Si1.461Fe(3+)0.539)O5(OH)4, Z = 2. Despite diffusely streaked characteristic polytype reflections, the refinement converged to Robs = 0.0242 for 1117 independent reflections. Separate Robs values of 0.0183 and 0.0553 were obtained for 415 subfamily and 702 characteristic reflections, respectively. The structure is built of one edge-sharing octahedral (Oc) and one corner-sharing tetrahedral (Tet) sheet forming the 1:1 layer by sharing apical corners of the Tet sheet. Consecutive layers are shifted by a/3 of the hexagonal cell, the polytype belongs to the subfamily (Bailey's group) A. There are two octahedral sites M1 (at m), M2 (in a general position) both fully occupied by Fe. Since the M2 octahedron is larger than M1, the Oc sheet is meso-octahedral. The Tet sheet contains one tetrahedral position, T1, occupied by Si and Fe in the ratio 0.731:0.269 (9). The ring of tetrahedra is strongly ditrigonalized, alpha = +12.7 degrees ; Franzini type A. Of three H atoms localized, two are involved in hydrogen bonds, linking OH groups of the Oc sheet with basal O atoms of the Tet sheet. The basal O atoms (acceptors) of the Tet sheet are rotated close to OH groups (donors) of the Oc sheet of an adjacent layer in order to achieve reasonable lengths and geometries of hydrogen bonds. The structure is interpreted as an example of the order-disorder (OD) structure of more than one kind of layer with a very low degree of desymmetrization. PMID- 25449618 TI - Structure, hydrogen bonding and thermal expansion of ammonium carbonate monohydrate. AB - We have determined the crystal structure of ammonium carbonate monohydrate, (NH4)2CO3.H2O, using Laue single-crystal diffraction methods with pulsed neutron radiation. The crystal is orthorhombic, space group Pnma (Z = 4), with unit-cell dimensions a = 12.047 (3), b = 4.453 (1), c = 11.023 (3) A and V = 591.3 (3) A(3) [rhocalc = 1281.8 (7) kg m(-3)] at 10 K. The single-crystal data collected at 10 and 100 K are complemented by X-ray powder diffraction data measured from 245 to 273 K, Raman spectra measured from 80 to 263 K and an athermal zero-pressure calculation of the electronic structure and phonon spectrum carried out using density functional theory (DFT). We find no evidence of a phase transition between 10 and 273 K; above 273 K, however, the title compound transforms first to ammonium sesquicarbonate monohydrate and subsequently to ammonium bicarbonate. The crystallographic and spectroscopic data and the calculations reveal a quite strongly hydrogen-bonded structure (EHB ? 30-40 kJ mol(-1)), on the basis of H...O bond lengths and the topology of the electron density at the bond critical points, in which there is no free rotation of the ammonium cation at any temperature. The barrier to free rotation of the ammonium ions is estimated from the observed librational frequency to be ~ 36 kJ mol(-1). The c-axis exhibits negative thermal expansion, but the thermal expansion behaviour of the a and b axes is ormal. PMID- 25449620 TI - Isomorphism and solid solution as shown by an accurate high-resolution diffraction experiment. AB - High-resolution crystal structure determination and spherical and multipolar refinement enabled an organic solid solution of 1-(4'-chlorophenyl)-2-methyl-4 nitro-1H-imidazole-5-carbonitrile and 5-bromo-1-(4'-chlorophenyl)-2-methyl-4 nitro-1H-imidazole to be found, which would not normally be revealed using only standard resolution data (ca 0.8 A), as the disordered part is only visible at high resolution. Therefore, this new structure would have been reported as just another polymorphic form, even more reasonably as isostructural with other derivatives. To the best of our knowledge this is the first example of organic solid solution modelled via charge density Hansen-Coppens formalism and analysed by means of quantum theory of atoms in molecules (QTAIM) theory. PMID- 25449621 TI - Reassessment of the electron density in Cu2O using gamma-ray diffraction. AB - The electron-density distribution in Cu2O has been critically reexamined to test controversial conclusions from earlier experimental and theoretical studies. The electron density is derived via multipole refinement of high-quality single crystal diffraction data, collected at room temperature with 316.5 keV gamma radiation. Four gamma-lines in the energy range 200-600 keV have been used to extrapolate extinction-free low-order structure factors. The remaining extinction corrections refine to a crystal mosaicity identical to the observed one. There is no support for anharmonic contributions to the thermal parameters. Important features of the derived electron density are (i) a partially filled d_{z^2} orbital, (ii) an incomplete ionization of Cu and O, and (iii) no interstitial Cu Cu charge pileup, thereby refuting the covalent bonding hypothesis. PMID- 25449622 TI - Enantiopure and racemic alanine as bridging ligands in Ca and Mn chain polymers. AB - Under accelerated and controlled evaporation, chain polymers crystallize from aqueous solutions of Ca(II) and Mn(II) halides with enantiopure L-alanine or racemic DL-alanine. In all ten solids thus obtained zwitterionic amino acid ligands bridge neighbouring cations. The exclusively O-donor-based coordination sphere around the metal cations is completed by aqua ligands; the halides remain uncoordinated and act as counter-anions for the cationic strands. Despite the differences in ionic radii and electronic structure between the main group and the transition metal cation, their derivatives with L-alanine share a common structure type. In contrast, the solids derived from DL-alanine differ and adopt structures depending on the metal cation and the halide. Homochiral chains of either chirality or heterochiral chains with different arrangements of crystallographic inversion centres along the polymer strands are encountered. On average, the six-coordinated Ca(II) cations, devoid of any ligand field effect, show more pronounced deviation from idealized octahedral geometry than the d block cation Mn(II). PMID- 25449623 TI - Atomic structure solution of the complex quasicrystal approximant Al77Rh15Ru8 from electron diffraction data. AB - The crystal structure of the novel Al77Rh15Ru8 phase (which is an approximant of decagonal quasicrystals) was determined using modern direct methods (MDM) applied to automated electron diffraction tomography (ADT) data. The Al77Rh15Ru8 E-phase is orthorhombic [Pbma, a = 23.40 (5), b = 16.20 (4) and c = 20.00 (5) A] and has one of the most complicated intermetallic structures solved solely by electron diffraction methods. Its structural model consists of 78 unique atomic positions in the unit cell (19 Rh/Ru and 59 Al). Precession electron diffraction (PED) patterns and high-resolution electron microscopy (HRTEM) images were used for the validation of the proposed atomic model. The structure of the E-phase is described using hierarchical packing of polyhedra and a single type of tiling in the form of a parallelogram. Based on this description, the structure of the E phase is compared with that of the epsilon6-phase formed in Al-Rh-Ru at close compositions. PMID- 25449624 TI - Assembled structures of tetrakis(biimidazole)dirhodium complexes hydrogen-bonded with common inorganic anions. AB - Eight new structures of dirhodium complexes, each with four biimidazole (H2bim) ligands, were obtained: [Rh2(H2bim)4(H2O)2](NO3)4.4H2O (I), [Rh2(H2bim)4(H2O)2](ClO4)4.5H2O (II), [Rh2(H2bim)4(MeOH)2](ClO4)4 (III), [Rh2(H2bim)4(DMF)2](BF4)4 (IV), [Rh2(H2bim)4(Mepy)2](SiF6)2.8H2O (V), [{Rh2(H2bim)4(pz)}2(MU-pz)](SiF6)(ClO4)6.12.7H2O (VI), [{Rh2(H2bim)4(pz)}2(MU pz)](ClO4)8.11.4H2O (VII) and [Rh2(H2bim)4(MU-pz)](SiF6)2.6H2O (VIII). The unbridged Rh-Rh bond distances range between 2.6313 (8) and 2.7052 (5) A. The dirhodium units adopt a staggered conformation with torsion angles N-Rh-Rh-N of 37.6 (4)-48.98 (8) degrees . Various assembled structures were constructed by hydrogen bonding between the complexes and the anions: a discrete structure in (IV), one-dimensional structure in (II), two-dimensional structures in (I), (III), (VI), (VII) and (VIII) and a three-dimensional structure in (V). PMID- 25449626 TI - Diamond structure cannot be stable in nm-sized particles. AB - The observed and calculated densities of nanodiamond cannot be reconciled, and the stability of diamond structure explained, if nanodiamond is regarded as a form of pure carbon. The surface-terminating hydrogen and functional groups are an integral part in the stability of these particles which therefore need not be as inert and non-toxic as bulk diamond, with important implications for nanomedicine. PMID- 25449627 TI - Frank H. Allen (1944-2014). PMID- 25449625 TI - Validation of molecular crystal structures from powder diffraction data with dispersion-corrected density functional theory (DFT-D). AB - In 2010 we energy-minimized 225 high-quality single-crystal (SX) structures with dispersion-corrected density functional theory (DFT-D) to establish a quantitative benchmark. For the current paper, 215 organic crystal structures determined from X-ray powder diffraction (XRPD) data and published in an IUCr journal were energy-minimized with DFT-D and compared to the SX benchmark. The on average slightly less accurate atomic coordinates of XRPD structures do lead to systematically higher root mean square Cartesian displacement (RMSCD) values upon energy minimization than for SX structures, but the RMSCD value is still a good indicator for the detection of structures that deserve a closer look. The upper RMSCD limit for a correct structure must be increased from 0.25 A for SX structures to 0.35 A for XRPD structures; the grey area must be extended from 0.30 to 0.40 A. Based on the energy minimizations, three structures are re refined to give more precise atomic coordinates. For six structures our calculations provide the missing positions for the H atoms, for five structures they provide corrected positions for some H atoms. Seven crystal structures showed a minor error for a non-H atom. For five structures the energy minimizations suggest a higher space-group symmetry. For the 225 SX structures, the only deviations observed upon energy minimization were three minor H-atom related issues. Preferred orientation is the most important cause of problems. A preferred-orientation correction is the only correction where the experimental data are modified to fit the model. We conclude that molecular crystal structures determined from powder diffraction data that are published in IUCr journals are of high quality, with less than 4% containing an error in a non-H atom. PMID- 25449628 TI - Utility of uroplakin II expression as a marker of urothelial carcinoma. AB - Uroplakins are markers of terminally differentiated urothelium. Uroplakin II (UPII) is a newly described sensitive marker for urothelial carcinoma (UC). The expression profile of UPII in different types of UC and its utility in the diagnostic setting are needed. We evaluated UPII expression in bladder tissue microarrays, including urothelial neoplasm of low malignant potential (n = 8), low-grade papillary UC (n = 72), noninvasive high-grade papillary UC (n = 77), UC in situ (n = 27), and invasive high-grade UC (INVUC) (n = 122). UPII expression in 52 breast carcinomas and 38 high-grade prostate adenocarcinomas was also assessed. UPII expression was compared with GATA binding protein 3 (GATA3) and estrogen receptor for its role in facilitating the differential diagnosis of the above 3 types of malignancy. UPII labeling was seen in 83.0% of UC overall, including 95.7% of noninvasive UC and 65.6% of INVUC. UPII labeling was not found in any breast and prostate carcinomas. In comparison, GATA3 labeling was seen in 91.6% of all UCs, including 96.4% of noninvasive UCs and 85.1% of INVUC, with stronger intensity and extent compared with UPII (P < .005). GATA3 labeled 2 (5%) of 38 high-grade prostate adenocarcinoma. Estrogen receptor nuclear labeling was seen in 13.0% of UCs and 12.5% of prostate carcinomas. UPII was highly specific (100%) but only moderately sensitive for UC and can therefore be a potentially useful marker to identify urothelial lineage and help distinguish UC from prostate cancer or, in conjunction with GATA3, from metastatic breast cancer. PMID- 25449630 TI - Germline PRKACA amplification leads to Cushing syndrome caused by 3 adrenocortical pathologic phenotypes. AB - We describe the pathology of 5 patients with germline PRKACA copy number gain and Cushing syndrome: 4 males and 1 female, aged 2 to 43 years, including a mother and son. Imaging showed normal or slightly enlarged adrenal glands in 4 patients and a unilateral mass in the fifth. Biochemically, the patients had corticotropin independent hypercortisolism. Four underwent bilateral adrenalectomy; unilateral adrenalectomy was performed in the patient with the adrenal mass. Pathologically, 3 patients, including the 1 with the tumor (adenoma), had primary pigmented nodular adrenocortical disease with extranodular cortical atrophy and mild intracapsular and extracapsular extension of cortical cells. The other 2 patients had cortical hyperplasia and prominent capsular and extracapsular micronodular cortical hyperplasia. Immunoperoxidase staining revealed differences for synaptophysin, inhibin-A, and Ki-67 (nuclei) in the atrophic cortices (patients 1, 2, and 3) and hyperplastic cortices (patients 4 and 5) and for Ki-67 (nuclei) and vimentin in the extracortical nodules in the 2 groups of patients. beta Catenin stained the cell membrane, cytoplasm, and nuclei of the adenoma. The patients were well at follow-up (1-23 years); 24-hour urinary cortisol excretion was elevated in the patient who had unilateral adrenalectomy. PMID- 25449629 TI - A comparative study on renal biopsy before and after long-term calcineurin inhibitors therapy: an insight for pathogenesis of its toxicity. AB - Calcineurin inhibitors (CNIs) are effective immunosuppressive agents for the successful treatment of childhood steroid-resistant nephrotic syndrome (SRNS). Because these patients require long-term treatment, the identification of early markers of CNI-induced nephrotoxicity (CNIN) is imperative. The monitoring of CNI trough levels, serum creatinine, and glomerular filtration rate is not an accurate marker of CNIN. The present study has been undertaken to identify early markers of CNIN in SRNS patients. Twenty-four pediatric SRNS patients were included with paired renal biopsies, before initiation (time zero biopsy) and at least 1 year after CNI therapy (protocol renal biopsy) with standard dosage. Semiquantitative morphologic grading of the histologic features was done for assessing CNIN. Immunohistochemical markers for oxidative stress (nitrotyrosine [NT]), fibrogenic cytokine (transforming growth factor beta1 [TGF-beta1]), and endothelial injury (endothelial nitric oxide synthase [eNOS]) were evaluated. In addition, ultrastructural study was done to assess mitochondrial injury in endothelial and tubular epithelial cells. The protocol renal biopsies in comparison with time zero biopsies showed significant increase in glomerulosclerosis, juxtaglomerular apparatus hyperplasia, tubular atrophy, interstitial fibrosis, arteriolar hyalinosis, and smooth muscle vacuolization (P < .05 - P < .001). Significantly higher immunoexpression of eNOS (91.6%), NT (71%), and TGF-beta1 (87.5%) was noted in posttreatment biopsies. Mean mitochondrial injury grade among post-CNI cases in endothelial cells and proximal tubular cells was 2.28 and 1.4, whereas in pre-CNI, it was 0.28 and 0.27, respectively. We propose that immunohistochemical overexpression of NT, eNOS, and TGF-beta1 is an early marker of CNIN. Endothelial and proximal tubular mitochondrial injury may play an important role in the pathogenesis of CNIN. PMID- 25449631 TI - Breast cancer detection in axillary sentinel lymph nodes: the impact of the method of pathologic examination. AB - At Carolinas Medical Center, before 2008, axillary sentinel lymph nodes (SLNs) from breast cancer patients were evaluated with a single hematoxylin and eosin stained slide. In 2008, the protocol changed to include a limited step sectioning at 500 MUm. In this study, we compared the intraoperative and permanent section pathologic findings for SLN biopsies from 2006 to 2007 to those from 2009 to 2010. We hypothesized that evaluating 2 slides would increase the detection of micrometastases and isolated tumor cells (ITCs) on permanent sections and correspondingly decrease the sensitivity of intraoperative touch preparation cytology (IOTPC). From 2006 to 2007, 140 (23.5%) of 597 of SLN permanent sections contained tumor cells: 92 macrometastases (65.7%), 36 micrometastases (25.7%), and 12 ITCs 0.2 mm or less (8.6%). The sensitivity of IOTPC for 2006 to 2007 was 51.4% for any tumor cells and 71.7% for macrometastases. From 2009 to 2010, 160 (21.9%) of 730 SLN permanent sections were positive for any tumor cells: 76 macrometastases (47.5%), 55 micrometastases (34.4%), and 29 ITCs (18.1%). The sensitivity of IOTPC for 2009 to 2010 was 39.4% for any tumor cells and 76.3% for macrometastases. With limited step sectioning, we observed an approximately 10% increase in the detection of both micrometastases and ITCs in SLN. The increased detection of ITCs on permanent sections reached statistical significance (P = .018). However, under current clinical guidelines, patients with limited SLN involvement may not be required to undergo completion axillary lymph node dissection. The ability to detect SLN tumor deposits less than 2 mm must be balanced with the clinical utility of doing so. PMID- 25449632 TI - Development of loop-mediated isothermal amplification assays for rapid and easy detection of Coxiella Burnetii. AB - Q fever is an important worldwide zoonosis that is caused by infection with Coxiella burnetii. We have developed a loop-mediated isothermal amplification (LAMP) assay to detect the presence of the transposase gene insertion element IS1111a of C. burnetii. The sensitivity of this LAMP assay is very similar to quantitative PCR (qPCR) method with a detection limit at 25 copies of the gene, the equivalent of about one C. burnetii organism. Several methods for the detection of LAMP product were also performed to show the diverse way of detection which may be used in different settings depending on the user's infrastructure and resource. PMID- 25449633 TI - Nutritional stress in Northern gannets during an unprecedented low reproductive success year: can extreme sea surface temperature event and dietary change be the cause? AB - Reproductive success of seabirds is tightly associated with availability of their prey for which the spatiotemporal distribution may be influenced by sea surface temperature (SST) fluctuations. The objective of this study was to investigate whether Northern gannets (Morus bassanus) from the largest colony in North America (Bonaventure Island, Quebec, Canada) were in negative nutritional state during the unprecedented low reproductive success year of 2012, and whether this was associated with changes in SST anomalies and diet. The incubation period of gannets in 2012 was characterized by a significant decline, from early to late incubation, in plasma triglyceride levels that was associated with an increase in plasma corticosterone levels. However, no changes in plasma glycerol and beta hydroxybutyrate levels were noted. SST anomalies recorded in this area (south of the Gulf of St. Lawrence) during the breeding period were consistently higher in 2012 compared to the previous year (a better reproductive success year). Based on signatures of stable carbon (delta(13)C) and nitrogen (delta(15)N) isotopes in gannet red blood cells and in whole fish homogenates of three major preys (mackerel, herring, and capelin), a minor dietary shift was noted between those years and incubation periods. In light of these findings, it is suggested that the extreme warm-water perturbation event that prevailed in the Gulf of St. Lawrence during summer 2012 was associated with a rapid deterioration of nutritional condition of Bonaventure Island gannets during the incubation. These suboptimal physiological changes likely contributed to the dramatic decline in reproductive success reported in this colony. PMID- 25449634 TI - Developmental exposure to purity-controlled polychlorinated biphenyl congeners (PCB74 and PCB95) in rats: effects on brainstem auditory evoked potentials and catalepsy. AB - Whereas the effects of dioxin-like polychlorinated biphenyls (DL-PCBs) are well described, less is known about non-dioxin-like PCBs (NDL-PCBs), including influences on the nervous system and related behavioral effects after developmental exposure. Following the examination of the highly purified NDL congeners PCB52 and PCB180, we report here the results of experiments with PCB74 and PCB95. Rat dams were orally exposed to equimolar doses of either congener (40MUmol/kg bw - 11.68mg PCB74/kg bw or 13.06mg PCB95/kg bw) from gestational day (GD) 10 to postnatal day (PND) 7. Control dams were given the vehicle. Adult offspring were tested for cataleptic behavior after induction with haloperidol, a classical neuroleptic drug, and brainstem auditory evoked potentials (BAEPs), using clicks and tone pips of different frequencies for stimulation. Results revealed slight effects on latencies to movement onset in female offspring exposed to PCB74, whereas PCB74 males and offspring exposed to PCB95 were not affected. Pronounced changes were observed in BAEPs at low frequencies in PCB74 offspring, with elevated thresholds in both sexes. PCB95 increased thresholds in males, but not females. Small effects were detected on latency of the late wave IV in both sexes after developmental exposure to PCB74 or PCB95. Compared with the other NDL-PCB congeners tested, PCB74 caused the most pronounced effects on BAEPs. PMID- 25449635 TI - Predictors of alcohol and tobacco use prior to and during pregnancy in the US: the role of maternal stressors. AB - The purpose of the study was to understand the association between stressful life events prior to conception (PSLEs) and women's alcohol and tobacco use prior to and during pregnancy, and the continuation of such use through pregnancy. Data were from the Early Childhood Longitudinal Study-Birth Cohort (n = 9,350). Data were collected in 2001. Exposure to PSLEs was defined by indications of death of a parent, spouse, or previous live born child, divorce or marital separation, or fertility problems prior to conception. Survey data determined alcohol and tobacco usage during the 3 months prior to and in the final 3 months of pregnancy. Weighted regressions estimated the effect of PSLEs on alcohol and tobacco use at each time point and on the continuation of use, adjusting for confounders. Experiencing any PSLE increased the odds of tobacco use prior to (adjusted odds ratio [AOR] 1.52, 95 % confidence interval (CI) 1.23-1.87) and during pregnancy (AOR 1.57, 95 % CI 1.19-2.07). Women exposed to PSLEs smoked nearly five additional packs of cigarettes in the 3 months prior to pregnancy (97 cigarettes, p = 0.011) and consumed 0.31 additional alcoholic drinks during the last 3 months of pregnancy than unexposed women. PSLEs are associated with tobacco use before pregnancy and alcohol and tobacco use during pregnancy. Alcohol and tobacco screening and cessation services should be implemented prior to and during pregnancy, especially for women who have experienced PSLEs. PMID- 25449636 TI - Corneal thickness of eyes with unilateral age-related macular degeneration. AB - PURPOSE: To compare the central corneal thicknesses (CCT), peripheral corneal thicknesses, and corneal volumes (CV) of the 2 eyes of patients with unilateral age-related macular degeneration (AMD). METHODS: Twenty patients who were diagnosed with unilateral AMD were included in this prospective study for the purpose of making comparison between the diseased and healthy eyes. Optical coherence tomography and fundus fluorescein angiography imaging were applied to all patients in order to confirm and reveal the presence of unilateral AMD. Then, the measurements of CCT, peripheral corneal thickness measured 4 mm distant from the center of the cornea (4 mm CT), and CV of each eye of these patients were obtained through the rotating Scheimpflug corneal topographer. RESULTS: Wilcoxon signed-rank test did not demonstrate a statistically significant difference between the 2 eyes of patients with unilateral AMD when we compared the CCT and CV of diseased and healthy eyes (p>0.05). However, 4 mm CT of the diseased eyes of these patients were statistically significantly thicker than the healthy eyes (p<0.05). CONCLUSIONS: The significant difference in terms of 4 mm CT between the diseased and healthy eyes of patients with unilateral AMD may demonstrate the possible effect of peripheral corneal thickness on the development of AMD. PMID- 25449638 TI - Two-year outcome of repeat trabeculectomy with mitomycin C in primary open-angle and PEX glaucoma. AB - PURPOSE: To evaluate the effectiveness of repeat trabeculectomy with risk factor adjusted mitomycin C (MMC) application in primary open-angle glaucoma (POAG) and pseudoexfoliation glaucoma (PEXG) over 2 years. METHODS: A total of 58 patients (43 with POAG, 15 with PEXG) who had undergone repeat trabeculectomy with MMC were included in this retrospective study. Exposure time of MMC 0.3 mg/mL was adjusted according to a standardized protocol. Main outcome measures were best corrected visual acuity (BCVA), intraocular pressure (IOP) reduction, surgical success rate (criteria were defined as A: IOP <=21 mm Hg and a reduction of IOP >=20%; B: IOP <=18 mm Hg and a reduction of IOP of >=30%; C: IOP <=15 mm Hg and a reduction of IOP of >=40% from baseline), and number of medications at baseline, 3 months, and 2 years postoperatively. RESULTS: The BCVA remained stable for 2 years after surgery (0.47 +/- 0.47 at baseline, 0.49 +/- 0.64 logMAR units after 2 years, respectively). Mean IOP decreased from 22.2 +/- 7.0 mm Hg at baseline to 12.7 +/- 3.1 mm Hg at 3 months and 12.9 +/- 4.3 mm Hg 2 years after surgery. The qualified success rate for criterion A was 75.4%, for criterion B 66.6%, and for criterion C45.6%. Complete success rates were 42.9%, 37.5%, and 32.1%, respectively. Two years after repeat trabeculectomy, the mean IOP was reduced by 38.8%, and the number of medications was reduced significantly. CONCLUSIONS: Repeat trabeculectomy with MMC is successful at lowering IOP in POAG and PEXG and permits a significant and safe reduction of antiglaucomatous medication for at least 2 years after surgery. PMID- 25449637 TI - Sequential spontaneous resolution of acute syphilitic posterior placoid chorioretinitis. AB - PURPOSE: Acute syphilitic posterior placoid chorioretinitis (ASPPC) is a distinctive manifestation of ocular syphilis characterized by the development of a placoid macular deposit in the outer retina. Fundus autofluorescence descriptions suggest it may result from subretinal deposition of retinal pigment epithelium (RPE)-photoreceptor complex material and incomplete phagocytosis of outer segments. A 14-day therapy with systemic penicillin is essential for prompt control of the infection and to limit substantial retinal damage and irreversible visual loss. We report on the spontaneous sequential resolution of ASPPC in a patient with HIV coinfection. METHODS: Descriptive case report. RESULTS: A 55 year-old man presented with profound decrease in vision in his left eye secondary to ASPPC. Nine days later, ASPPC resolved, and a similar process developed in the right eye. Four years earlier, HIV infection had been diagnosed, and the patient was maintained on antiretroviral therapy with good immune recovery (CD4+ T-cell count 204 cells/uL). Spontaneous resolution ensued in the right eye and vision was restored. CONCLUSIONS: Ocular immune privilege probably contributed to the spontaneous resolution of ASPPC in this patient, who experienced immune recovery following antiretroviral therapy. The RPE immunologic characteristics likely contained the infectious/inflammatory infiltrate in this patient and prevented extension to inner retina and optic disc. Despite the uniqueness of the present case and the spontaneous resolution and excellent visual outcome, it remains essential to promptly manage patients with ocular syphilis because of the possible sight-threatening complications and to prevent potentially fatal disease. PMID- 25449639 TI - Effect of grid decentration on macular thickness measurements in normal subjects and patients with diabetic macular edema. AB - PURPOSE: To evaluate the effect of optical coherence tomography (OCT) grid decentration on macular thickness measurements in healthy subjects and patients with diabetic macular edema. METHODS: In this prospective study, 3D spectral domain OCT images of 51 eyes with clinically significant diabetic macular edema and 29 healthy eyes were assessed. In each eye, the macular Early Treatment Diabetic Retinopathy Study grid was evaluated for decentration. After grid adjustment, changes in central subfield thickness (CST) and central subfield volume (CSV) measurements were recorded. Changes >1 MUm and >8.5 MUm in CST were considered as grid decentration and clinically significant grid decentration, respectively. RESULTS: Grid decentration was found in 10 normal eyes (34.6%) and 32 clinically significant macular edema (CSME) eyes (62.7%, p = 0.01). Clinically significant CST changes were found in 3 normal eyes (10.3%) and 23 CSME eyes (45%, p = 0.001). The mean change in CST after grid adjustment was 6.4 +/- 5.8 um and 24.7 +/- 27 um in normal and CSME eyes (p = 0.04). Age, sex, and CST had no statistically significant effect on grid decentration in normal and CSME eyes. Best-corrected visual acuity was significantly worse in eyes with grid decentration (0.75 +/- 0.55 vs 0.42 +/- 0.22 logMAR, p = 0.02) and clinically significant grid decentration (0.81 +/- 0.6 vs 0.45 +/- 0.27 logMAR, p = 0.01). Change in CSV was detected in 3 normal eyes (10.3%) and 24 CSME eyes (47%, p = 0.001). CONCLUSIONS: Grid decentration occurs in a large number of OCT thickness maps and leads to significant error in macular thickness measurements. The effect is more prominent in patients with CSME. PMID- 25449640 TI - Long-term follow-up of standard photodynamic therapy with standardized small spot size for diffuse retinal pigment epitheliopathy. AB - PURPOSE: To evaluate the long-term efficacy and safety of standard-fluence photodynamic therapy (PDT) with verteporfin using the minimum PDT spot size in patients with diffuse retinal pigment epitheliopathy (DRPE). METHODS: This is a retrospective study of 67 DRPE cases treated with PDT using a standardized minimum spot size of 850 MUm. Indocyanine green angiography (ICGA) was used to guide and determine the outcome of PDT treatment. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), recurrences, and adverse events were recorded and analyzed. RESULTS: The mean follow-up period of the study was 35.8 +/- 16.6 months. There was a statistically significant difference in BCVA between baseline and the end of the follow-up (p<0.001). The BCVA improved in 41 eyes (61.2%), remained stable in 20 eyes (29.9%), and deteriorated in 6 eyes (9%). Accordingly, there was a statistically significant difference in CRT between the baseline and the last follow-up visit (p<0.001). The recurrence rate was 13.4% and only one eye presented a recurrence at the same site as the laser treatment. No adverse events were noted. CONCLUSIONS: Application of ICGA-guided standard PDT, with a laser spot size of minimum diameter, on the site of active leakage seems to be effective and safe in a long-term follow-up period, presenting improvement in BCVA, decrease in CRT, and low rate of recurrence. PMID- 25449641 TI - Modified scleral suture fixation technique for foldable IOL with fenestrations in the proximal part of the haptics. AB - PURPOSE: To present a modified surgical technique for scleral suture fixation of a new foldable intraocular lens (IOL) design with fenestrations in the proximal part of the haptics. METHODS: An experimental model of a double continuous-loop 4 point scleral suture fixation of IOL with fenestrations in the proximal part of the haptics showed that with conventional techniques, the lens is located in a horizontal plane 90 degrees to the expected iris plane. To achieve proper IOL positioning, we modified the technique so as to perform 2 needle passes through the sclera for each haptic in the same meridian, resulting in the external part of the suture being radial to the limbus. The technique was performed in 14 eyes. Mean follow-up time was 9.8 months. RESULTS: In all cases, the lens was successfully implanted through clear corneal tunnel incision and the scleral fixation, as mentioned above, was performed with the use of Hoffman scleral pockets. Good centration of the IOLs without signs of tilt was achieved. CONCLUSIONS: It is possible to decrease the risk of tilt of the IOL with fenestrations in the proximal part of the haptics by modifying the technique so that the 2 needle passes through the sclera for each haptic are done in the same meridian, resulting in a layout of the external part of the suture being radial to the limbus. PMID- 25449642 TI - Macular edema after uncomplicated cataract surgery: a role for phacoemulsification energy and vitreoretinal interface status? AB - PURPOSE: To study postoperative macular thickness fluctuations measured by spectral-domain optical coherence tomography (SD-OCT) and to investigate a potential correlation among macular edema (ME) incidence, cumulative dissipated energy (CDE) released during phacoemulsification, and vitreoretinal interface status. METHODS: This is a prospective, cross-sectional study of 106 cataract patients with no macular disorder who underwent phacoemulsification. Best corrected visual acuity measurement, slit-lamp examination, OCT scans were performed preoperatively and 30 and 90 days postoperatively. The intraoperative parameters measured were CDE and total phacoemulsification time. The SD-OCT parameters assessed were central subfield thickness (CST), cube average thickness (CAT), cube macular volume, vitreoretinal interface status, and presence of cystoid or diffuse ME. RESULTS: Four patients (3.8%) developed subclinical ME. Regarding ME, there was no significant difference between patients with presence or absence of posterior vitreous detachment (chi-square, p = 0.57), although 75% of ME cases were observed in patients with attached posterior vitreous. With regard to comparison between eyes with and without subclinical CME incidence, CDE (p = 0.05), phacoemulsification time (p = 0.001), CST at month 1 (p = 0.002), cube macular volume at month 1 (p = 0.039), and CAT at month 1 (p = 0.050) were significantly higher in the subclinical CME group. CONCLUSIONS: This study provides evidence that OCT macular thickness parameters increase significantly at first and third month postoperatively and that the incidence of pseudophakic ME can be affected by CDE. PMID- 25449643 TI - Cataract surgery under topical anesthesia in a patient with Parkinson disease and deep brain stimulation: a report of feasibility. AB - PURPOSE: Deep brain stimulation provides benefits for people with Parkinson disease by managing some of their complications. None of the few reports in the current literature establishes the functionality of deep brain stimulation when activated during phacoemulsification. METHODS: A 70-year-old woman with subthalamic deep brain stimulator (DBS) for advanced Parkinson disease was referred to our center for cataract surgery. To evaluate any possible interference between ultrasounds and the DBS, we registered the impedance of the electrodes before and after surgery. RESULTS: The patient underwent uneventful phacoemulsification of her right eye under topical anesthesia with her internal pulse generator device activated. During the surgical procedure, all potential variations of the impedance of the electrodes were recorded. CONCLUSIONS: This report demonstrates that phacoemulsification under topical anesthesia is a feasible procedure in patients with DBS, showing no interference between the ultrasounds and the internal pulse generator. PMID- 25449644 TI - Efficacy and safety of phenylephrine 2.5% with cyclopentolate 0.5% for retinopathy of prematurity screening in 1246 eye examinations. AB - PURPOSE: Retinopathy of prematurity (ROP) is a leading cause of visual loss in infancy that is largely preventable with careful screening. We report the safety and efficacy of the use of phenylephrine 2.5% and cyclopentolate 0.5% eyedrops instilled 3 times 5 minutes apart in ROP screening. METHODS: A total of 1246 ROP screening eye examinations were carried out by the same pediatric ophthalmologist between February 2011 and May 2013. Outcome measures were successful mydriasis (defined as achieving a full screening examination) and any intraprocedural systemic complications (defined as any respiratory, cardiac, or other clinical deterioration severe enough to result in screening abandonment). RESULTS: Of 1246 eyes, 1234 (98.8%) achieved successful dilation to enable complete screening. A fourth application was successful in the remaining 1.2%. No respiratory or cardiac arrest or any other intraprocedural event requiring cessation of screening was encountered during any of the examinations. No retinal bleeding or other intraocular complication occurred. CONCLUSIONS: This is the largest cohort studying the effectiveness and safety of a mydriatic regimen for ROP screening. We have found the combination of phenylephrine 2.5% with cyclopentolate 0.5% to be efficacious and well-tolerated. The absence of any severe intraprocedural complications may be related to reduced indentation time and stress in the infant facilitated by effective pupil dilation. PMID- 25449645 TI - Two week, OCT-based follow-up as guidance for retreatment with ranibizumab for CNV apparently refractory to therapy. AB - PURPOSE: To assess the value of 2-week optical coherence tomography (OCT) follow up for re-treatment decision-making in patients receiving monthly ranibizumab injections for choroidal neovascular membrane (CNV), which was apparently refractory to treatment. METHODS: A total of 25 eyes of 25 consecutive patients with refractory CNV were included. Patients were classified as having refractory disease if no visual acuity (VA) change and no change in the pattern of macular fluid was noticed on OCT after at least 3 consecutive monthly injections, excluding the loading doses. Repeat injection was given and reassessment with VA and OCT was undertaken at 2, 4, 8, and 12 weeks. RESULTS: Complete resolution or marked reduction of macular fluid was noted in 19 patients at 2 weeks (responders). In 18 responders, the fluid increased on 4- and persisted on 8- and 12-week follow-ups, so that further injections were given at these time points. In 6 patients, no significant change was noted at 2 weeks (nonresponders). In all of them, VA and OCT were stable on 4-, 8-, and 12-week follow-ups, without further injections. CONCLUSIONS: As some patients are responding for at least part of the month, injections may be worth continuing or possibly more frequent injections, tailored to the individual's response, may need to be considered. Alternative therapies such as aflibercept may also need to be considered. In nonresponding eyes, other cytokines except for vascular endothelial growth factor are probably involved in the pathogenesis or such cases may have structural damage that will not respond to therapy. PMID- 25449646 TI - Phosphoinositide signalling in Drosophila. AB - Phosphoinositides (PtdInsPs) are lipids that mediate a range of conserved cellular processes in eukaryotes. These include the transduction of ligand binding to cell surface receptors, vesicular transport and cytoskeletal function. The nature and functions of PtdInsPs were initially elucidated through biochemical experiments in mammalian cells. However, over the years, genetic and cell biological analysis in a range of model organisms including S. cerevisiae, D. melanogaster and C. elegans have contributed to an understanding of the involvement of PtdInsPs in these cellular events. The fruit fly Drosophila is an excellent genetic model for the analysis of cell and developmental biology as well as physiological processes, particularly analysis of the complex relationship between the cell types of a metazoan in mediating animal physiology. PtdInsP signalling pathways are underpinned by enzymes that synthesise and degrade these molecules and also by proteins that bind to these lipids in cells. In this review we provide an overview of the current understanding of PtdInsP signalling in Drosophila. We provide a comparative genomic analysis of the PtdInsP signalling toolkit between Drosophila and mammalian systems. We also review some areas of cell and developmental biology where analysis in Drosophila might provide insights into the role of this lipid-signalling pathway in metazoan biology. This article is part of a Special Issue entitled Phosphoinositides. PMID- 25449647 TI - Phosphoinositides in the regulation of actin cortex and cell migration. AB - In order for the cell to function well within a multicellular system, the mechanical properties of the plasma membrane need to meet two different requirements: cell shape maintenance and rearrangement. To achieve these goals, phosphoinositides play key roles in the regulation of the cortical actin cytoskeleton. PI(4,5)P2is the most abundant phosphoinositide species in the plasma membrane. It maintains cell shape by linking the actin cortex to the membrane via interactions with Ezrin/Radixin/Moesin (ERM) proteins and class I myosins. Although the role of D3-phosphoinositides, such as PI(3,4,5)P3, in actin driven cell migration has been a subject of controversy, it becomes evident that the dynamic turnover of the phosphoinositide by the action of metabolizing enzymes, such as 5-phosphatases, is necessary. Recent studies have revealed an important role of PI(3,4)P2in podosome/invadopodia formation, shedding new light on the actin-based organization of membrane structures regulated by phosphoinositide signaling. This article is part of a Special Issue entitled Phosphoinositides. PMID- 25449648 TI - Phosphoinositides: Lipids with informative heads and mastermind functions in cell division. AB - Phosphoinositides are low abundant but essential phospholipids in eukaryotic cells and refer to phosphatidylinositol and its seven polyphospho-derivatives. In this review, we summarize our current knowledge on phosphoinositides in multiple aspects of cell division in animal cells, including mitotic cell rounding, longitudinal cell elongation, cytokinesis furrow ingression, intercellular bridge abscission and post-cytokinesis events. PtdIns(4,5)P2production plays critical roles in spindle orientation, mitotic cell shape and bridge stability after furrow ingression by recruiting force generator complexes and numerous cytoskeleton binding proteins. Later, PtdIns(4,5)P2hydrolysis and PtdIns3P production are essential for normal cytokinesis abscission. Finally, emerging functions of PtdIns3P and likely PtdIns(4,5)P2have recently been reported for midbody remnant clearance after abscission. We describe how the multiple functions of phosphoinositides in cell division reflect their distinct roles in local recruitment of protein complexes, membrane traffic and cytoskeleton remodeling. This article is part of a Special Issue entitled Phosphoinositides. PMID- 25449651 TI - Linking transcription to physiology in lipidomics. PMID- 25449652 TI - Biochemical characterization of Yarrowia lipolytica LIP8, a secreted lipase with a cleavable C-terminal region. AB - Yarrowia lipolytica is a lipolytic yeast possessing 16 paralog genes coding for lipases. Little information on these lipases has been obtained and only the major secreted lipase, namely YLLIP2, had been biochemically and structurally characterized. Another secreted lipase, YLLIP8, was isolated from Y. lipolytica culture medium and compared with the recombinant enzyme produced in Pichia pastoris. N-terminal sequencing showed that YLLIP8 is produced in its active form after the cleavage of a signal peptide. Mass spectrometry analysis revealed that YLLIP8 recovered from culture medium lacks a C-terminal part of 33 amino acids which are present in the coding sequence. A 3D model of YLLIP8 built from the X ray structure of the homologous YLLIP2 lipase shows that these truncated amino acids in YLLIP8 belong to an additional C-terminal region predicted to be mainly helical. Western blot analysis shows that YLLIP8 C-tail is rapidly cleaved upon enzyme secretion since both cell-bound and culture supernatant lipases lack this extension. Mature recombinant YLLIP8 displays a true lipase activity on short-, medium- and long-chain triacylglycerols (TAG), with an optimum activity at alkaline pH on medium chain TAG. It has no apparent regioselectivity in TAG hydrolysis, thus generating glycerol and FFAs as final lipolysis products. YLLIP8 properties are distinct from those of the 1,3-regioselective YLLIP2, acting optimally at acidic pH. These lipases are tailored for complementary roles in fatty acid uptake by Y. lipolytica. PMID- 25449653 TI - Diagnosing PD-MCI by MDS Task Force criteria: how many and which neuropsychological tests? AB - BACKGROUND: The optimal properties of a comprehensive (level II) neuropsychological battery for determining Parkinson's disease mild cognitive impairment (PD-MCI) by Movement Disorder Society (MDS) Task Force criteria remain unresolved. METHODS: Seventy-six nondemented PD patients underwent PD-MCI classification using a consensus diagnosis and level II criteria. We examined the optimal number of tests in each of the five designated cognitive domains, identified the best tests within each domain, and determined the best overall battery for PD-MCI level II diagnosis. RESULTS: A battery with two tests per domain provided a highly practical, robust diagnostic assessment. Level II testing with the two best tests and impairment defined as 2 standard deviations below norms was highly sensitive and specific for PD-MCI diagnosis. CONCLUSIONS: Our findings strongly support the MDS Task Force Level II testing recommendations, provide a framework for creating an optimal, efficient neuropsychological test battery for PD-MCI diagnosis, and offer specific test recommendations. PMID- 25449654 TI - Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib. AB - The induction of CYP2C9 by dabrafenib using S-warfarin as a probe and the effects of a CYP3A inhibitor (ketoconazole) and a CYP2C8 inhibitor (gemfibrozil) on dabrafenib pharmacokinetics were evaluated in patients with BRAF V600 mutation positive tumors. Dabrafenib single- and repeat-dose pharmacokinetics were also evaluated. S-warfarin AUC(0- infinity) decreased 37% and Cmax increased 18% with dabrafenib. Dabrafenib AUC(0- tau) and C(max) increased 71% and 33%, respectively, with ketoconazole. Hydroxy- and desmethyl-dabrafenib AUC(0-tau) increased 82% and 68%, respectively, and AUC for carboxy-dabrafenib decreased 16%. Dabrafenib AUC(0-tau) increased 47%, with no change in C(max), after gemfibrozil co-administration. Gemfibrozil did not affect systemic exposure to dabrafenib metabolites. Single- and repeat-dose dabrafenib pharmacokinetics were consistent with previous reports. All cohorts used the commercial capsules. More frequent monitoring of international normalized ratios is recommended in patients receiving warfarin during initiation or discontinuation of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A or CYP2C8 is recommended during treatment with dabrafenib. PMID- 25449655 TI - Folding and stability of integral membrane proteins in amphipols. AB - Amphipols (APols) are a family of amphipathic polymers designed to keep transmembrane proteins (TMPs) soluble in aqueous solutions in the absence of detergent. APols have proven remarkably efficient at (i) stabilizing TMPs, as compared to detergent solutions, and (ii) folding them from a denatured state to a native, functional one. The underlying physical-chemical mechanisms are discussed. PMID- 25449649 TI - The isoprostanes--25 years later. AB - Isoprostanes (IsoPs) are prostaglandin-like molecules generated independent of the cyclooxygenase (COX) by the free radical-induced peroxidation of arachidonic acid. The first isoprostane species discovered were isomeric to prostaglandin F2alpha and were thus termed F2-IsoPs. Since the initial discovery of the F2 IsoPs, IsoPs with differing ring structures have been identified as well as IsoPs from different polyunsaturated fatty acids, including eicosapentaenoic acid and docosahexanenoic acid. The discovery of these molecules in vivo in humans has been a major contribution to the field of lipid oxidation and free radical research over the course of the past 25 years. These molecules have been determined to be both biomarkers and mediators of oxidative stress in numerous disease settings. This review focuses on recent developments in the field with an emphasis on clinical research. Special focus is given to the use of IsoPs as biomarkers in obesity, ischemia-reperfusion injury, the central nervous system, cancer, and genetic disorders. Additionally, attention is paid to diet and lifestyle factors that can affect endogenous levels of IsoPs. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance." PMID- 25449656 TI - Biological properties of a thermally crosslinked gelatin film as a novel anti adhesive material: Relationship between the biological properties and the extent of thermal crosslinking. AB - In order to prevent postoperative adhesion and the related complications, a thermally crosslinked gelatin (TCG) film was developed and the basic biological properties were examined, paying special attention to the relationship between these properties and the extent of crosslinking of the film. The gelatin films crosslinked thermally for five different time periods (0, 1, 3, 8, and 14 hours) were developed and the following tests were performed. Regarding the material characterization of the films, the water content, the water solubility, and the enzymatic degradation for collagenase were found to be closely related to the duration of thermal crosslinking. In an in vitro study conducted to examine the cell growth of fibroblasts cultured on the films, the degree of cell growth, except no crosslinked film, was less than that observed in the control group, thus suggesting that such effects of the films on fibroblast cell growth may be related with their anti-adhesive effects. In in vivo tests, the films crosslinked for longer time periods (3, 8, and 14 hours) were retained for longer after being implanted into the abdominal cavity in rats and showed a significant anti adhesive effect in the rat cecum adhesion models, indicating that the biodegradability and anti-adhesive effects of the TCG films depend on the duration of thermal crosslinking. In order to develop useful and effective anti adhesive gelatin film, it is very important to optimize duration of the thermal crosslinking. PMID- 25449650 TI - Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid. AB - Arachidonic acid can be oxygenated by a variety of different enzymes, including lipoxygenases, cyclooxygenases, and cytochrome P450s, and can be converted to a complex mixture of oxygenated products as a result of lipid peroxidation. The initial products in these reactions are hydroperoxyeicosatetraenoic acids (HpETEs) and hydroxyeicosatetraenoic acids (HETEs). Oxoeicosatetraenoic acids (oxo-ETEs) can be formed by the actions of various dehydrogenases on HETEs or by dehydration of HpETEs. Although a large number of different HETEs and oxo-ETEs have been identified, this review will focus principally on 5-oxo-ETE, 5S-HETE, 12S-HETE, and 15S-HETE. Other related arachidonic acid metabolites will also be discussed in less detail. 5-Oxo-ETE is synthesized by oxidation of the 5 lipoxygenase product 5S-HETE by the selective enzyme, 5-hydroxyeicosanoid dehydrogenase. It actions are mediated by the selective OXE receptor, which is highly expressed on eosinophils, suggesting that it may be important in eosinophilic diseases such as asthma. 5-Oxo-ETE also appears to stimulate tumor cell proliferation and may also be involved in cancer. Highly selective and potent OXE receptor antagonists have recently become available and could help to clarify its pathophysiological role. The 12-lipoxygenase product 12S-HETE acts by the GPR31 receptor and promotes tumor cell proliferation and metastasis and could therefore be a promising target in cancer therapy. It may also be involved as a proinflammatory mediator in diabetes. In contrast, 15S-HETE may have a protective effect in cancer. In addition to GPCRs, higher concentration of HETEs and oxo ETEs can activate peroxisome proliferator-activated receptors (PPARs) and could potentially regulate a variety of processes by this mechanism. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance". PMID- 25449657 TI - Quantitative high-throughput screening data analysis: challenges and recent advances. AB - In vitro HTS holds much potential to advance drug discovery and provide cell based alternatives for toxicity testing. In quantitative HTS, concentration response data can be generated simultaneously for thousands of different compounds and mixtures. However, nonlinear modeling in these multiple concentration assays presents important statistical challenges that are not problematic for linear models. The uncertainty of parameter estimates obtained from the widely used Hill equation model can be extremely large when using standard designs. Failure to properly consider standard errors of these parameter estimates would greatly hinder chemical genomics and toxicity testing efforts. In this light, optimal study designs should be developed to improve nonlinear parameter estimation; or alternative approaches with reliable performance characteristics should be used to describe concentration-response profiles. PMID- 25449658 TI - Databases and collaboration require standards for human stem cell research. AB - Stem cell research is at an important juncture: despite significant potential for human health and several countries with key initiatives to expedite commercialization, there are gaps in capturing and exploiting the results of past and current research. Here, we propose a concerted plan that could be taken to foster a more collaborative approach and ensure that all research efforts can be leveraged across the community. The creation of a definitive centralized database repository, or at least harmonized data repositories, for stem cell groups in academia and industry, enabling secure selective sharing of data when needed, could provide the core structure that is sought globally and protect intellectual property. The development of minimum information about stem cell experiments (MIASCE) could be key to this development. PMID- 25449659 TI - The role of ovarian steroids in reproductive plasticity in Hoplias malabaricus (Teleostei: Characiformes: Erythrinidae) in tropical reservoirs with different degrees of pollution. AB - Chemicals in aquatic environments may lead to impairment of fish reproduction, but some species display plasticity levels to survive and reproduce in such localities. We investigated the reproductive cycle in a teleost species, Hoplias malabaricus, which inhabits a variety of environments with different degrees of pollution. Adult females were sampled at two locations in Sao Paulo State (Brazil), the reference Ponte Nova (PN) reservoir and the polluted Billings (BIL) reservoir. Metabolic and endocrine processes were analyzed throughout the annual cycle with special attention to ovarian histology, gonadosomatic index (GSI), fecundity, ovarian energetic substrates and plasma steroids analyses, in addition to physical and chemical analyses of the water. Pollutants were frequent in BIL but not in PN. The GSI, including the predominance of vitellogenic oocytes, was higher in spring and summer in both locations, but the oocyte recruitment dynamics was different. During winter, females from BIL presented vitellogenic oocytes and high levels of 11-ketotestosterone, which indicated precocity in the vitellogenic phase in relation to the females from PN. In animals from PN, high deposition of lipids occurred in the ovaries. However, plasma estradiol levels did not vary throughout the annual cycle. In animals from BIL, plasma estradiol levels peaked during the summer, but the ovarian lipid content remained unchanged throughout the year. The data suggest that the presence of pollutants cause various endocrine and metabolic responses and especially affects reproductive plasticity, which could explain why H. malabaricus survives under unfavorable environments. PMID- 25449660 TI - Development of a flatfish-specific enzyme-linked immunosorbent assay for Fsh using a recombinant chimeric gonadotropin. AB - In flatfishes with asynchronous and semicystic spermatogenesis, such as the Senegalese sole (Solea senegalensis), the specific roles of the pituitary gonadotropins during germ cell development, particularly of the follicle stimulating hormone (Fsh), are still largely unknown in part due to the lack of homologous immunoassays for this hormone. In this study, an enzyme-linked immunosorbent assay (ELISA) for Senegalese sole Fsh was developed by generating a rabbit antiserum against a recombinant chimeric single-chain Fsh molecule (rFsh C) produced by the yeast Pichia pastoris. The rFsh-C N- and C-termini were formed by the mature sole Fsh beta subunit (Fshbeta) and the chicken glycoprotein hormone common alpha subunit (CGA), respectively. Depletion of the antiserum to remove anti-CGA antibodies further enriched the sole Fshbeta-specific antibodies, which were used to develop the ELISA using the rFsh-C for the standard curve. The sensitivity of the assay was 10 and 50 pg/ml for Fsh measurement in plasma and pituitary, respectively, and the cross-reactivity with a homologous recombinant single-chain luteinizing hormone was 1%. The standard curve for rFsh-C paralleled those of serially diluted plasma and pituitary extracts of other flatfishes, such as the Atlantic halibut, common sole and turbot. In Senegalese sole males, the highest plasma Fsh levels were found during early spermatogenesis but declined during enhanced spermiation, as found in teleosts with cystic spermatogenesis. In pubertal males, however, the circulating Fsh levels were as high as in adult spermiating fish, but interestingly the Fsh receptor in the developing testis containing only spermatogonia was expressed in Leydig cells but not in the primordial Sertoli cells. These results indicate that a recombinant chimeric Fsh can be used to generate specific antibodies against the Fshbeta subunit and to develop a highly sensitive ELISA for Fsh measurements in diverse flatfishes. PMID- 25449661 TI - Dynamic expression of tgf-beta2, tgf-beta3 and inhibin betaA during muscle growth resumption and satellite cell differentiation in rainbow trout (Oncorhynchus mykiss). AB - Members of the TGF-beta superfamily are involved in numerous cell functions; however, except for myostatin, their roles in the regulation of muscle growth in fish are completely unknown. We measured tgf-beta1, tgf-beta2, tgf-beta3, inhibin betaA (inh) and follistatin (fst) gene expression during muscle growth recovery following a fasting period. We observed that tgf-beta1a and tgf-beta2 expression were quickly down-regulated after refeeding and that tgf-beta3 reached its highest level of expression 7days post-refeeding, mirroring myogenin expression. Inh betaA1 mRNA levels decreased sharply after refeeding, in contrast to fst b2 expression, which peaked at day 2. No significant modification of expression was observed for tgf-beta1a, tgf-beta1b, tgf-beta1c and tgf-beta6 during refeeding. In vitro, tgf-beta2 and inh betaA1 expression decreased during the differentiation of satellite cells, whereas tgf-beta3 expression increased following the same pattern as myogenin. Surprisingly, fst b1 and fst b2 expression decreased during differentiation, whereas no variation was observed in fst a1 and fst a2 expression levels. In vitro analyses also indicated that IGF1 treatment up-regulated tgf-beta3, inh betaA1 and myogenin expression, and that MSTN treatment increased fst b1 and fst b2 expression. In conclusion, we showed that the expression of tgf-beta2, tgf-beta3 and inh betaA1 is dynamically regulated during muscle growth resumption and satellite cell differentiation, strongly suggesting that these genes have a role in the regulation of muscle growth. PMID- 25449662 TI - Characterization of peptide QRFP (26RFa) and its receptor from amphioxus, Branchiostoma floridae. AB - A peptide ending with RFamide (Arg-Phe-amide) was discovered independently by three different laboratories in 2003 and named 26RFa or QRFP. In mammals, a longer version of the peptide, 43 amino acids, was identified and found to bind to the orphan G protein-coupled receptor GPR103. We searched the genome database of Branchiostoma floridae (Bfl) for receptor sequences related to those that bind peptides ending with RFa or RYa (including receptors for NPFF, PRLH, GnIH, and NPY). One receptor clustered in phylogenetic analyses with mammalian QRFP receptors. The gene has 3 introns in Bfl and 5 in human, but all intron positions differ, implying that the introns were inserted independently. A QRFP-like peptide consisting of 25 amino acids and ending with RFa was identified in the amphioxus genome. Eight of the ten last amino acids are identical between Bfl and human. The prepro-QRFP gene in Bfl has one intron in the propeptide whereas the human gene lacks introns. The Bfl QRFP peptide was synthesized and the receptor was functionally expressed in human cells. The response was measured as inositol phosphate (IP) turnover. The Bfl QRFP peptide was found to potently stimulate the receptor's ability to induce IP turnover with an EC50 of 0.28nM. Also the human QRFP peptides with 26 and 43 amino acids were found to stimulate the receptor (1.9 and 5.1nM, respectively). Human QRFP with 26 amino acids without the carboxyterminal amide had dramatically lower potency at 1.3MUM. Thus, we have identified an amphioxus QRFP-related peptide and a corresponding receptor and shown that they interact to give a functional response. PMID- 25449663 TI - Health issues for menopausal women: the top 11 conditions have common solutions. AB - Multiple health issues affect women throughout the life course differently from men, or do not affect men at all. Although attention to women's health is important in all stages in life, health among middle-aged and elderly women has not received sufficient attention by scientists and policy-makers. Related to the menopausal transition and the experiences accumulated until that age, many diseases occur or further develop in middle-aged and elderly women. To improve women's quality of life and guarantee a long-lasting and active role for middle aged and elderly women in society, prevention of chronic diseases and disability is a key aspect. In this manuscript we give an overview of the major health issues for peri- and post-menopausal women, we summarize risk factors and interventions to improve menopausal health. Based on the available scientific literature and the global burden of disease endeavor, we have selected and herein describe the following top 11 key health issues, selected in terms of burden exerted in women's mortality, morbidity, disability and quality of life: cardiovascular disease, musculoskeletal disorders, cancer, cognitive decline and dementia, chronic obstructive pulmonary disease, diabetes mellitus, metabolic syndrome, depression, vasomotor symptoms, sleep disturbances and migraine. PMID- 25449664 TI - Role of cervical screening in older women. AB - OBJECTIVE: To review the literature concerning the role of cervical screening in women 60 years and older. METHODS: Literature review was conducted using PubMed and the search terms cervical neoplasm, cancer, middle aged, elderly, aged, postmenopausal, cervical cytology and screening. To be included in the review, the article must have been in the English language. The search focused on publications from 2000 forward. RESULTS: The case control and modeling studies that addressed the role of cervical cytology screening in women 60 and older were reviewed. The outcomes of interest included: (1) the benefits of screening in terms of decrease rate of cervical cancer incidence (6 studies) and mortality (3 studies); (2) the duration of protection of the last screening test (4 studies); and (3) the harms of screening older women including false positive test results and cost. CONCLUSIONS: Cervical cytology screening is beneficial for women over 60 years in terms of preventing the occurrence and death from cervical cancer. A negative cytology test appears to have 5 years of protection in this age group. Age of last screen with in an organized screening program may differ compared to the goals and wishes of individual women. PMID- 25449665 TI - The Hot Flush Beliefs and Behaviour Scale for Men (HFBBS-Men) undergoing treatment for prostate cancer. AB - OBJECTIVE: Hot flushes and night sweats (HFNS) are commonly experienced by men receiving treatment for prostate cancer. Cognitive behavioural therapy (CBT) has been found to be an effective treatment for HFNS in women, but cognitions and behavioural reactions to HFNS in men are under-researched. This study describes the development of the HFNS beliefs and behaviour scale for men. METHODS: HFNS beliefs and behaviour items were generated from a qualitative study, from pilot interviews with men with prostate cancer and HFNS, and from scales used for women. 118 men with prostate cancer, aged above 18, English-speaking, who had minimum of seven HFNS weekly for at least 1 month, completed the initial measure, and measures of HFNS frequency, problem rating, anxiety and depression (HADS). Principal components analyses with orthogonal rotation determined the most coherent solution. RESULTS: Exploratory factor analysis culminated in a 17-item HFNS beliefs and behaviour scale for men (HFBBS-Men) with three subscales: (1) HFNS social context and sleep, (2) Calm/Acceptance, (3) Humour/Openness. The subscales had reasonable internal consistency (Cronbach alpha 0.56-0.83). Validity was supported, by correlations between subscale 1, HFNS frequency, problem-rating and mood; men with locally advanced cancer more likely to adopt Calm/Acceptance and those with metastatic cancer Humour/Openness. CONCLUSIONS: Preliminary analysis of the HFBBS-Men suggests that it is a psychometrically sound instrument, grounded in men's experiences. As a measure of cognitive and behavioural reactions to HF/NS, the HFBBS-Men should increase understanding of the mediators of outcomes of psychological interventions, such as CBT. PMID- 25449666 TI - Innovation and new trends in critical trauma disease. AB - The management of critical trauma disease (CTD) has always trends the trends in military war experiences. These conflicts have historically revolutionized clinical concepts, clinical practice guidelines and medical devices, and have marked future lines of research and aspects of training and learning in severe trauma care. Moreover, in the civil setting, the development of intensive care, technological advances and the testing of our healthcare systems in the management of multiple victims, hasve also led to a need for innovation in our trauma care systems. PMID- 25449667 TI - [Succinylcholine. Until when?]. PMID- 25449669 TI - Unabridged phase diagram for single-phased FeSe(x)Te(1-x) thin films. AB - A complete phase diagram and its corresponding physical properties are essential prerequisites to understand the underlying mechanism of iron-based superconductivity. For the structurally simplest 11 (FeSeTe) system, earlier attempts using bulk samples have not been able to do so due to the fabrication difficulties. Here, thin FeSe(x)Te(1-x) films with the Se content covering the full range (0 <= x <= 1) were fabricated by using pulsed laser deposition method. Crystal structure analysis shows that all films retain the tetragonal structure in room temperature. Significantly, the highest superconducting transition temperature (T(C) = 20 K) occurs in the newly discovered domain, i.e., 0.6 <= x <= 0.8. The single-phased superconducting dome for the full Se doping range is the first of its kind in iron chalcogenide superconductors. Our results present a new avenue to explore novel physics as well as to optimize superconductors. PMID- 25449670 TI - Acute increases in intramuscular inflammatory cytokines are necessary for the development of mechanical hypersensitivity in a mouse model of musculoskeletal sensitization. AB - Musculoskeletal pain is a widespread health problem in the United States. Back pain, neck pain, and facial pain are three of the most prevalent types of chronic pain, and each is characterized as musculoskeletal in origin. Despite its prevalence, preclinical research investigating musculoskeletal pain is limited. Musculoskeletal sensitization is a preclinical model of muscle pain that produces mechanical hypersensitivity. In a rodent model of musculoskeletal sensitization, mechanical hypersensitivity develops at the hind paws after injection of acidified saline (pH 4.0) into the gastrocnemius muscle. Inflammatory cytokines contribute to pain during a variety of pathologies, and in this study we investigate the role of local, intramuscular cytokines in the development of mechanical hypersensitivity after musculoskeletal sensitization in mice. Local intramuscular concentrations of interleukin-1beta (IL-1), IL-6 and tumor necrosis factor-alpha (TNF) were quantified following injection of normal (pH 7.2) or acidified saline into the gastrocnemius muscle. A cell-permeable inhibitor was used to determine the impact on mechanical hypersensitivity of inhibiting nuclear translocation of the transcription factor nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB) prior to musculoskeletal sensitization. The role of individual cytokines in mechanical hypersensitivity following musculoskeletal sensitization was assessed using knockout mice lacking components of the IL-1, IL-6 or TNF systems. Collectively, our data demonstrate that acidified saline injection increases intramuscular IL-1 and IL-6, but not TNF; that intramuscular pre-treatment with an NF-kappaB inhibitor blocks mechanical hypersensitivity; and that genetic manipulation of the IL-1 and IL-6, but not TNF systems, prevents mechanical hypersensitivity following musculoskeletal sensitization. These data establish that actions of IL-1 and IL-6 in local muscle tissue play an acute regulatory role in the development of mechanical hypersensitivity following musculoskeletal sensitization. PMID- 25449671 TI - Maternal immune activation differentially impacts mature and adult-born hippocampal neurons in male mice. AB - Schizophrenia is associated with deficits in the hippocampus, a brain area important for learning and memory. The dentate gyrus (DG) of the hippocampus develops both before and after birth. To study the relative contribution of mature and adult-born DG granule cells to disease etiology, we compared both cell populations in a mouse model of psychiatric illness resulting from maternal immune activation. Polyriboinosinic-polyribocytidilic acid (PolyIC, 5mg/kg) or saline was given on gestation day 15 to pregnant female C57Bl/6 mice. Male offspring (n=105), was administered systemic bromodeoxyuridine (BrdU, 50mg/kg) (n=52) or intracerebral retroviral injection into the DG (n=53), to label dividing cells at one month of age. Two months later behavioral tests were performed to evaluate disease phenotype. Immunohistochemistry and whole-cell patch clamping were used to assess morphological and physiological characteristics of DG cells. Three-month-old PolyIC exposed male offspring exhibited deficient pre-pulse inhibition, spatial maze performance and motor coordination, as well as increased depression-like behavior. Histological analysis showed reduced DG volume and parvalbumin positive interneuron number. Both mature and new hippocampal neurons showed modifications in intrinsic properties such as increased input resistance and lower current threshold, and decreased action potential number. Reduced GABAergic inhibitory transmission was observed only in mature DG neurons. Differential impairments in mature DG cells and adult-born new neurons may have implications for behavioral deficits associated with maternal immune activation. PMID- 25449674 TI - Novel 4-thiazolidinones as non-nucleoside inhibitors of hepatitis C virus NS5B RNA-dependent RNA polymerase. AB - In continuation of our efforts to develop new derivatives as hepatitis C virus (HCV) NS5B inhibitors, we synthesized novel 5-arylidene-4-thiazolidinones. The novel compounds 29-42, together with their synthetic precursors 22-28, were tested for HCV NS5B inhibitory activity; 12 of these compounds displayed IC50 values between 25.3 and 54.1 uM. Compound 33, an arylidene derivative, was found to be the most active compound in this series with an IC50 value of 25.3 uM. Molecular docking studies were performed on the thumb pocket-II of NS5B to postulate the binding mode for these compounds. PMID- 25449673 TI - S100A8 contributes to postoperative cognitive dysfunction in mice undergoing tibial fracture surgery by activating the TLR4/MyD88 pathway. AB - Neuro-inflammation plays a key role in the occurrence and development of postoperative cognitive dysfunction (POCD). Although S100A8 and Toll-like receptor 4 (TLR4) have been increasingly recognized to contribute to neuro inflammation, little is known about the interaction between S100A8 and TLR4/MyD88 signaling in the process of systemic inflammation that leads to neuro inflammation. Firstly, we demonstrated that C57BL/6 wide-type mice exhibit cognitive deficit 24h after the tibial fracture surgery. Subsequently, increased S100A8 and S100A9 expression was found in the peripheral blood mononuclear cells (PBMCs), spleen, and hippocampus of C57BL/6 wide-type mice within 48h after the surgery. Pre-operative administration of S100A8 antibody significantly inhibited hippocampal microgliosis and improved cognitive function 24h after the surgery. Secondly, we also observed TLR4/MyD88 activation in the PBMCs, spleen, and hippocampus after the surgery. Compared with those in their corresponding wide type mice, TLR4(-/-) and MyD88(-/-) mice showed lower immunoreactive area of microglia in the hippocampal CA3 region after operation. TLR4 deficiency also led to reduction of CD45(hi)CD11b(+) cells in the brain and better performance in both Y maze and open field test after surgery, suggesting a new regulatory mechanism of TLR4-dependent POCD. At last, the co-location of S100A8 and TLR4 expression in spleen after operation suggested a close relationship between them. On the one hand, S100A8 could induce TLR4 activation of CD11b(+) cells in the blood and hippocampus via intraperitoneal or intracerebroventricular injection. On the other hand, TLR4 deficiency conversely alleviated S100A8 protein-induced hippocampal microgliosis. Furthermore, the increased expression of S100A8 protein in the hippocampus induced by surgery sharply decreased in both TLR4 and MyD88 genetically deficient mice. Taken together, these data suggest that S100A8 exerts pro-inflammatory effect on the occurrence and development of neuro-inflammation and POCD by activating TLR4/MyD88 signaling in the early pathological process of the postoperative stage. PMID- 25449675 TI - DNA mechatronic devices switched by K+ and by Sr2+ are structurally, topologically, and electronically distinct. AB - DNAs and RNAs that fold via the formation of guanine quartets form G-quadruplexes that are often highly diverse in terms of architecture and topology. G quadruplexes are specifically stabilized by metal cations such as K(+) and Sr(2+), but not Li(+). DNA duplexes that incorporate two separated clusters of G*G mismatches ("P-duplexes") can function as electronic switches, capable of toggling reversibly from a poorly conductive conformer (E) with only Li(+) in the solution to a G-quadruplex incorporating conformer of higher conductivity (C) in the presence of K(+). Herein, we report results from fluorescence energy transfer, circular dichroism, charge conduction, and chemical footprinting experiments, which cumulatively demonstrate that P-duplex E<->C transitions are genuinely mechatronic, with causally coupled mechanical and electronic states. We show, further, that the K(+) - and the Sr(2+)-fuelled E<->C switching of a given P-duplex are structurally, topologically, and electronically distinct from each other. A single DNA P-duplex can thus exist in at least three distinguishable mechatronic states in aqueous solution. PMID- 25449676 TI - [State of the art in invasive diseases by filamentous fungi]. AB - Invasive fungal infections have become a major cause of morbimortality in intensive care patients, persons suffering from cancer or immune deficiencies, and other diseases with impaired immunity. Candida albicans remains the most frequent fungal pathogen, but advances in the diagnosis, prevention and treatment of invasive candidiasis are leading to important etiological changes. Among the emerging invasive mycoses, are those caused by filamentous fungi, such as Aspergillus, Lomentospora/Scedosporium, Fusarium or the Mucorales. Invasive aspergillosis is difficult to diagnose, and although there are diagnostic tools available, their use is not widespread, and their effectiveness vary depending on the group of patients. Clinical suspicion in high-risk patients, radiological diagnosis and the use of biomarkers, such as 1,3-beta-D-glucan and galactomannan, can be of great help. However, diagnostic resources are limited in other mycoses, but radiology, pathological studies and the microbiological diagnosis can be useful. The high mortality of these mycoses requires early empirical antifungal treatment in many cases. Voriconazole is the first choice for treatment of the majority of aspergillosis, scedosporiasis, fusariosis and other hyalohyphomycoses. The treatment of mucormycoses, Lomentospora prolificans infections or mycoses by dematiaceous fungi are more complicated. Amphotericin B is active against many mucoralean fungi, but the combination of two or more antifungal agents could be a therapeutic alternative in many amphotericin B refractory mycoses. Current clinical challenges include improving the diagnosis and the treatment of these mycoses, along with improving the adequate prevention in patients at high risk of suffering from them. PMID- 25449677 TI - The mechanisms behind helminth's immunomodulation in autoimmunity. AB - The incidence of autoimmune diseases has risen throughout the last half a century, mostly in the industrialized world. Helminths and their derivatives were found to have a protective role in autoimmunity and inflammatory conditions, as they manipulate the immune network, attenuating the host's cellular and humoral responses. Indeed, various helminth species used in several human and animal models were shown to limit inflammatory activity in a variety of diseases including inflammatory bowel disease, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis. Our review will focus on the main mechanisms by which helminths and their secreted molecules modulate the host's immune system. The main pathways induce a shift from Th1 to Th2 phenotype, accelerate T regulatory and B regulatory phenotypes, and attenuate the levels of the inflammatory cytokines, leading to a tolerable scenario. PMID- 25449672 TI - Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications. AB - Individuals living with HIV who are optimally treated with combination antiretroviral therapy (cART) can now lead an extended life. In spite of this remarkable survival benefit from viral suppression achieved by cART in peripheral blood, the rate of mild to moderate cognitive impairment remains high. A cognitive decline that includes impairments in attention, learning and executive function is accompanied by increased rates of mood disorders that together adversely impact the daily life of those with chronic HIV infection. The evidence is clear that cells in the brain are infected with HIV that has crossed the blood brain barrier both as cell-free virus and within infected monocytes and T cells. Viral proteins that circulate in blood can induce brain endothelial cells to release cytokines, invoking another source of neuroinflammation. The difficulty of efficient delivery of cART to the central nervous system (CNS) contributes to elevated viral load in the CNS, resulting in a persistent HIV-associated neurocognitive disorders (HAND). The pathogenesis of HAND is multifaceted, and mounting evidence indicates that immune cells play a major role. HIV-infected monocytes and T cells not only infect brain resident cells upon migration into the CNS but also produce proinflammatory cytokines such as TNF and IL-1beta, which in turn, further activate microglia and astrocytes. These activated brain resident cells, along with perivascular macrophages, are the main contributors to neuroinflammation in HIV infection and release neurotoxic factors such as excitatory amino acids and inflammatory mediators, resulting in neuronal dysfunction and death. Cytokines, which are elevated in the blood of patients with HIV infection, may also contribute to brain inflammation by entering the brain from the blood. Host factors such as aging and co-morbid conditions such as cytomegalovirus co-infection and vascular pathology are important factors that affect the HIV-host immune interactions in HAND pathogenesis. By these diverse mechanisms, HIV-1 induces a neuroinflammatory response that is likely to be a major contributor to the cognitive and behavior changes seen in HIV infection. PMID- 25449678 TI - A PRISMA-driven systematic review for predictive risk factors of digital ulcers in systemic sclerosis patients. AB - Vasculopathy has a major role in the pathogenesis and tissue injury in systemic sclerosis (SSc). Raynaud's phenomenon (RP) is frequently the first clinical manifestation of SSc preceding by years other clinical manifestations. RP in SSc patients is frequent, often very severe and long lasting. The repeated bouts of RP lead to prolonged digital ischemia that may progress to digital ulceration or in extreme to critical digital ischemia with gangrene. Digital ulcers (DU) are a true burden for all patients. They are very painful, with a long and slow healing course, have high risk of infection and are extremely disabling. In adults, up to 40-50% of patients will experience at least one DU in the course of the disease and of these 31-71% will have recurrent ulcers. In order to try to identify predictive risk factors for DU in SSc patients, an extensive literature review was conducted, according to the guidelines proposed at the PRISMA statement. MEDLINE database (PubMed) and Thomson Reuters Web of Knowledge platform were searched for articles published in peer-reviewed journals since 1990 with the last search run on June 2014 and published in English language. The keyword search terms included: digital ulcer/s, systemic sclerosis, scleroderma, digital scars, ischemic complications, autoantibodies, biomarkers, endothelium dysfunction, endothelin-1, vascular endothelial growth factor (VEGF), endostatin, ADMA, endoglin, angiostatin, and capillaroscopy. The following criteria were included: (1) cohorts of SSc patients including patients with DU, (2) endothelium dysfunction and angiogenesis biomarkers compared with a healthy control group, (3) autoantibodies, capillary morphology and distribution, endothelium dysfunction and angiogenesis biomarkers compared between patients with and without digital ulcers, (4) detailed description of the statistical methods used to conclude for predictive factors, and (5) English language. Our search provided a total of 376 citations. Of these, 297 studies were discarded for not meeting the criteria proposed. PMID- 25449679 TI - GITR+ regulatory T cells in the treatment of autoimmune diseases. AB - Autoimmune diseases decrease life expectancy and quality of life for millions of women and men. Although treatments can slow disease progression and improve quality of life, all currently available drugs have adverse effects and none of them are curative; therefore, requiring patients to take immunosuppressive drugs for the remainder of their lives. A curative therapy that is safe and effective is urgently needed. We believe that therapies promoting the in vivo expansion of regulatory T cells (Tregs) or injection of in vitro expanded autologous/heterologous Tregs (cellular therapy) can alter the natural history of autoimmune diseases. In this review, we present data from murine and human studies suggesting that 1) glucocorticoid-induced tumor necrosis factor receptor related protein (GITR) plays a crucial role in thymic Treg (tTreg) differentiation and expansion; 2) GITR plays a crucial role in peripheral Treg (pTreg) expansion; 3) in patients with Sjogren syndrome and systemic lupus erythematosus, CD4(+)GITR(+) pTregs are expanded in patients with milder forms of the disease; and 4) GITR is superior to other cell surface markers to differentiate Tregs from other CD4(+) T cells. In this context, we consider two potential new approaches for treating autoimmune diseases consisting of the in vivo expansion of GITR(+) Tregs by GITR-triggering drugs and in vitro expansion of autologous or heterologous GITR(+) Tregs to be infused in patients. Advantages of such an approach, technical problems, and safety issues are discussed. PMID- 25449681 TI - Role of dendritic cells in the initiation, progress and modulation of systemic autoimmune diseases. AB - Dendritic cells (DCs) play a key role in the activation of the immune response against pathogens, as well as in the modulation of peripheral tolerance to self antigens (Ags). Furthermore, an imbalance in the activating/inhibitory receptors expressed on the surface of DCs has been linked to increased susceptibility to develop autoimmune diseases underscoring their immunogenicity potential. It has been described that modulation of activating or inhibitory molecules expressed by DCs, such as CD86, TLRs, PDL-1 and FcgammaRs, can define the immunogenic phenotype. On the other hand, T cell tolerance can be achieved by tolerogenic DCs, which have the capacity of blocking undesired autoimmune responses in several experimental models, mainly by inducing T cell anergy, expansion of regulatory T cells and limiting B cell responses. Due to the lack of specific therapies to treat autoimmune disorders and the tolerogenic capacity of DCs shown in experimental autoimmune disease models, autologous tolDCs are a potential therapeutic strategy for fine-tuning the immune system and reestablishing tolerance in human autoimmune diseases. New advances in the role of DCs in systemic lupus erythematosus (SLE) pathogenesis and the identification of pathogenic self-Ags may favor the development of novel tolDC based therapies with a major clinical impact. In this review, we discuss recent data relative to the role of DCs in systemic autoimmune pathogenesis and their use as a therapy to restore tolerance. PMID- 25449680 TI - Regulatory T-cells in autoimmune diseases: challenges, controversies and--yet- unanswered questions. AB - Regulatory T cells (Tregs) are central to the maintenance of self-tolerance and tissue homeostasis. Markers commonly used to define human Tregs in the research setting include high expression of CD25, FOXP3 positivity and low expression/negativity for CD127. Many other markers have been proposed, but none unequivocally identifies bona fide Tregs. Tregs are equipped with an array of mechanisms of suppression, including the modulation of antigen presenting cell maturation and function, the killing of target cells, the disruption of metabolic pathways and the production of anti-inflammatory cytokines. Treg impairment has been reported in a number of human autoimmune conditions and includes Treg numerical and functional defects and conversion into effector cells in response to inflammation. In addition to intrinsic Treg impairment, resistance of effector T cells to Treg control has been described. Discrepancies in the literature are common, reflecting differences in the choice of study participants and the technical challenges associated with investigating this cell population. Studies differ in terms of the methodology used to define and isolate putative regulatory cells and to assess their suppressive function. In this review we outline studies describing Treg frequency and suppressive function in systemic and organ specific autoimmune diseases, with a specific focus on the challenges faced when investigating Tregs in these conditions. PMID- 25449682 TI - A volcanic explosion of autoantibodies in systemic lupus erythematosus: a diversity of 180 different antibodies found in SLE patients. AB - Recent research in systemic lupus erythematosus (SLE) yielded new antigens and antibodies in SLE patients. We describe the various autoantibodies that can be detected in patients with SLE. A literature review, using the terms "autoantibody" and "systemic lupus erythematosus", was conducted to search for articles on autoantibodies in SLE, their target antigens, association with disease activity and other clinical manifestations. One hundred and eighty autoantibodies were so far described in SLE patients. These include autoantibodies that target nuclear antigens, cytoplasmic antigens, cell membrane antigens, phospholipid-associated antigens, blood cells, endothelial cells, and nervous system antigens, plasma proteins, matrix proteins, and miscellaneous antigens. The target of an autoantibody, the autoantigen properties, autoantibody frequencies in SLE, as well as clinical associations, and correlation with disease activity are described for all 180 autoantibodies. SLE is so far the autoimmune disease with the largest number of detectable autoantibodies. Their production could be antigen-driven, the result of a polyclonal B cell activation, impaired apoptotic pathways, or the outcome of an idiotypic network dysregulation. PMID- 25449683 TI - Induction of Ras by SAF-1/MAZ through a feed-forward loop promotes angiogenesis in breast cancer. AB - In the majority of breast cancers, overexpression and hyperactivation of Ras in the tumor microenvironment play significant role in promoting cancer cell growth, angiogenesis, and metastasis. We have previously shown that vascular endothelial growth factor (VEGF) expression in triple negative breast cancer cells is regulated, at least in part, by SAF-1 (serum amyloid A activating factor 1) transcription factor. In this study we show that transformation of normal MCF-10A breast epithelial cells by constitutively active, oncogenic Ras, induces the DNA binding activity and transcription function of SAF-1. Furthermore, we show that inhibition of MEK/MAPK-signaling pathway prevents Ras-mediated activation of SAF 1. Interestingly, silencing of SAF-1 expression in breast cancer cells by SAF-1 specific short hairpin RNAs (shRNAs) significantly reduced H-Ras and K-Ras mRNA level. We show that SAF-1 is a direct transcriptional regulator of H-Ras and K Ras and overexpression of SAF-1 increases H-Ras and K-Ras gene expression. Chromatin immunoprecipitation (ChIP) analyses demonstrated in vivo interaction of SAF-1 at highly purine-rich sequences present at the proximal promoter region, upstream of the transcription start site, in H-Ras and K-Ras genes. Previous studies have shown that these sequences are nuclease hypersensitive and capable of forming G4 quadruplex structure. Together, our results show the presence of a novel transactivating loop, in which, Ras and SAF-1 are interconnected. These findings will help defining molecular mechanisms of abnormal overexpression of Ras in breast tumors, which seldom show genetic Ras mutations. PMID- 25449684 TI - IL-1beta increases necrotic neuronal cell death in the developing rat hippocampus after status epilepticus by activating type I IL-1 receptor (IL-1RI). AB - Interleukin-1beta (IL-1beta) is associated with seizure-induced neuronal cell death in the adult brain. The contribution of IL-1beta to neuronal injury induced by status epilepticus (SE) in the immature brain remains unclear. In the present study, we investigated the effects of IL-1beta administration on hippocampal neuronal cell death associated with SE in the immature brain, and the role of the type I receptor of IL-1beta (IL-1RI). SE was induced with lithium-pilocarpine in 14-days-old (P14) rat pups. Six hours after SE onset, pups were i.c.v. injected in the right ventricle with IL-1beta (0, 0.3, 3, 30, or 300 ng), 30 ng of IL-1RI antagonist (IL-1Ra) alone, or 30 ng of IL-1Ra plus 3ng of IL-1beta. As control groups, pups without seizures were injected with 3 ng of IL-1beta or vehicle. Twenty-four hours after SE onset, neuronal cell death in the CA1 field of dorsal hippocampus was assessed by hematoxylin-eosin, Fluoro-Jade B and in vivo propidium iodide (PI) staining; expression of active caspase-3 (aCas-3) was also determined, using immunohistochemistry. The concentration-response curve of IL 1beta showed a bell-shape. Only pups injected with 3 ng of IL-1beta after SE showed a significant increase in the number of cells with eosinophilic cytoplasm and pyknotic nuclei, as well as F-JB positive cells with respect to the vehicle group. This effect was prevented when IL-1beta was injected with IL-1Ra. Injection of 3 ng of IL-1beta increased the number of PI-positive cells in CA1 area after SE. Injection of 3 ng of IL-1beta did not produce hippocampal cell death in rats without seizures. Active caspase-3 expression was not observed after treatments in hippocampus. The activation of the IL-1beta/IL-1RI system increases necrotic neuronal cell death caused by SE in rat pups. PMID- 25449685 TI - How tyrosine kinase inhibitors impair metabolism and endocrine system function: a systematic updated review. AB - Tyrosine kinase inhibitors (TKIs) advent has deeply changed the outcome of chronic myeloid leukemia (CML) patients, with improved rates of response and overall survival. However, for this success some patients paid the price of a number of peculiar side effects, the so-called off-target side effects, specific for each one TKI. These effects are due to non-selective inhibition of other tyrosine kinase receptors, such as PDGFR, c-KIT, Src, VEGF. Consequences of this inhibition, some metabolic changes during the treatment with TKIs are reported. Aim of present review is to report metabolic changes and potential mechanisms involved in the pathogenesis related to imatinib, second (nilotinib and dasatinib) and third generation (bosutinib and ponatinib) TKIs. PMID- 25449686 TI - Thinking outside of ABL1 for resistance to tyrosine kinase inhibitors: a perspective of the SEPT9-ABL1 fusion protein. PMID- 25449687 TI - A phase I/II trial of Erlotinib in higher risk myelodysplastic syndromes and acute myeloid leukemia after azacitidine failure. AB - Survival after azacitidine (AZA) failure in higher-risk myelodysplastic syndromes (MDS) is poor and new treatment options are needed. Erlotinib, an oral inhibitor of the epidermal-growth-factor-receptor (EGFR), has shown in preclinical models some efficacy in higher risk MDS and acute myeloid leukemia (AML). In this phase I/II trial, 30 patients received 100mg/day (n=5) or 150mg/day (n=25) of Erlotinib orally after primary or secondary resistance to AZA treatment. Eighteen MDS and 12 AML patients were treated. This outpatient treatment was well tolerated with limited grade III-IV extra hematological toxicities (skin (n=1), and diarrhea (n=3). Response was observed in 6 patients (20%) including 1 complete remission (CR), 1 marrow CR and 4 hematological improvement (2 erythroid and 2 on platelets). Median duration of response was 5 months. Erlotinib appears to induce a significant number of responses in higher risk MDS/AML having failed AZA treatment. Given the good safety profile of Erlotinib, its combination with other drugs could be tested in the future in MDS and AML. PMID- 25449688 TI - Prevalence and prognostic significance of c-KIT mutations in core binding factor acute myeloid leukemia: a comprehensive large-scale study from a single Chinese center. AB - To clarify the prevalence and prognostic significance of c-KIT mutations in patients with core binding factor acute myeloid leukemia (CBF-AML), a total of 351 patients who were categorized as pediatric t(8;21), adult t(8;21), pediatric inv(16), or adult inv(16) were screened at diagnosis for c-KIT mutations in exons 17 and 8 using direct sequencing. A total of 250 patients underwent follow-up. Overall, 36.5% of the patients had a c-KIT mutation. Adult t(8;21) and inv(16) patients had mutations predominantly in exons 17 and 8, respectively. Higher White blood cell (WBC) count, WBC index, and AML1-ETO transcript levels in adult t(8;21) patients were significantly associated with c-KIT mutations and mutations in exon 17 (P<=0.030). c-KIT mutations in adult t(8;21) patients were significantly correlated with a high cumulative incidence of relapse (CIR, P=0.0070) at 2 years and a low 2-year disease-free survival (DFS, P=0.013) and overall survival (OS, P=0.0055). However, no significant difference was revealed in the effect of c-KIT mutations on outcome of adult inv(16) and pediatric t(8;21) patients (all P>0.05). Multivariate analysis revealed that c-KIT mutation is an independent prognostic factor for relapse, DFS, and OS (P<=0.016) in adult t(8;21) AML patients. Therefore, with regard to c-KIT mutation, CBF-AML is a heterogeneous disease. c-KIT mutations have a strong adverse effect on the relapse and survival of adult t(8;21) AML patients. PMID- 25449689 TI - Salvage therapy with mitoxantrone, etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia. AB - The survival of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) is poor. We performed a retrospective analysis of 40 patients treated with five days of mitoxantrone 8mg/m(2)/day, etoposide 100mg/m(2)/day, and cytarabine 1000mg/m(2)/day (MEC). The complete remission rate was 30% and median remission duration was 11.2 months. Median overall survival was 6.5 months. In univariate analysis, patients in first relapse had improved overall survival compared to >=second relapse (p=0.02). Thirty-day mortality rate was 7.5%. In relapsed or refractory ALL, MEC demonstrated moderate activity, but did not improve survival compared to published salvage chemotherapy regimens. PMID- 25449690 TI - Missed opportunities to intervene with caregivers of young children highly exposed to secondhand tobacco smoke. PMID- 25449691 TI - Sedentary behaviour and health in children - evaluating the evidence. AB - This commentary critically discusses the current evidence on the association between sedentary behaviour and cardiometabolic health in children as well as the methodologically issues that need to be addressed in order to advance this field. We conclude with recommendations for future research. PMID- 25449692 TI - Stair-use interventions in worksites and public settings - a systematic review of effectiveness and external validity. AB - OBJECTIVE: We performed a literature review with the main aims to propose an updated overview of the effectiveness of stair-use interventions and to determine the most effective type of intervention. METHODS: We systematically searched stair-use interventions performed in worksites or public settings, published up to mid 2013. We used a harvest plot approach to visualize the findings in addition to a quantitative synthesis. We also assessed external validity using the Reach, Efficacy, Adoption, Implementation, Maintenance (RE-AIM) framework. RESULTS: Of 8571 articles identified, 50 were included. In worksites (25 studies) and public settings (35 studies), an increase in stair climbing was found during the intervention period in 64% and 76% of studies, respectively. Combining motivational and directional signs in worksites or conducting a second intervention phase in public settings increased stair climbing in 83% and 86% of studies, respectively. Elements of external validity were overall largely under reported. CONCLUSION: There is evidence that stair-use interventions are effective to increase stair climbing in public settings, but evidence of such effect is limited in worksites. Issues regarding the best sequencing of interventions or the potential importance of environmental interventions should be addressed in future studies. Process evaluation should be an integral part of interventions. PMID- 25449693 TI - A "big data" approach to HIV epidemiology and prevention. AB - The recent availability of "big data" from social media and mobile technologies provides promise for development of new tools and methods to address the HIV epidemic. This manuscript presents recent work in this growing area of bioinformatics, digital epidemiology, and disease modeling, describes how it can be applied to address HIV prevention, and presents issues that need to be addressed prior to implementing a mobile technology big-data approach to HIV prevention. PMID- 25449694 TI - Relationships between dog ownership and physical activity in postmenopausal women. AB - BACKGROUND: Positive associations between dog ownership and physical activity in older adults have been previously reported. PURPOSE: The objective of this study was to examine cross-sectional associations between dog ownership and physical activity measures in a well-characterized, diverse sample of postmenopausal women. METHODS: Analyses included 36,984 dog owners (mean age: 61.5years), and 115,645 non-dog owners (mean age: 63.9years) enrolled in a clinical trial or the observational study of the Women's Health Initiative between 1993 and 1998. Logistic regression models were used to test for associations between dog ownership and physical activity, adjusted for potential confounders. RESULTS: Owning a dog was associated with a higher likelihood of walking >=150min/wk (Odds Ratio, 1.14; 95% Confidence Interval, 1.10-1.17) and a lower likelihood of being sedentary >=8h/day (Odds Ratio, 0.86; 95% Confidence Interval, 0.83-0.89) as compared to not owning a dog. However, dog owners were less likely to meet >=7.5MET-h/wk of total physical activity as compared to non-dog owners (Odds Ratio, 1.03; 95% Confidence Interval, 1.00-1.07). CONCLUSIONS: Dog ownership is associated with increased physical activity in older women, particularly among women living alone. Health promotion efforts aimed at older adults should highlight the benefits of regular dog walking for both dog owners and non-dog owners. PMID- 25449695 TI - Ascribing novel functions to the sarcomeric protein, myosin binding protein H (MyBPH) in cardiac sarcomere contraction. AB - Myosin binding protein H (MyBPH) is a protein of unknown function, which shares sequence and structural similarities with myosin binding protein C (cMyBPC), a protein frequently implicated in hypertrophic cardiomyopathy (HCM). Given the similarity between cMyBPC and MyBPH, we proposed that MyBPH, like cMyBPC, could be involved in HCM pathogenesis and we therefore sought to determine its function. We identified MyBPH-interacting proteins by using yeast two-hybrid (Y2H) analysis. The role of MyBPH and cMyBPC in cardiac cell contractility was analysed by measuring the planar cell surface area of differentiated H9c2 rat cardiomyocytes in response to beta-adrenergic stress after siRNA knockdown of MyBPH and cMyBPC. Individual knockdown of either protein had no effect on cardiac contractility, while concurrent knockdowns reduced cardiac contractility. These proteins therefore functionally compensate for one another and are critical for cardiac contractility. We further show that both proteins co-localise with the autophagosomal membrane protein LC3, suggesting that both proteins are involved in autophagosomal membrane maturation processes. The results of this study ascribe novel functions to MyBPH, which may contribute to our understanding of its role in the sarcomere. This study provides evidence for a potential role of MyBPH in HCM, which warrants further investigation. PMID- 25449696 TI - Functional analysis of miR-181a and Fas involved in hepatitis B virus-related hepatocellular carcinoma pathogenesis. AB - The hepatitis B virus (HBV) is responsible for most of hepatocellular carcinoma (HCC). However, whether HBV plays an important role during hepatocarcinogenesis through effecting miRNAs remains unknown. Here, we reported that HBV up-regulated microRNA-181a (miR-181a) by enhancing its promoter activity. Simultaneously, we found that miR-181a inhibited apoptosis in vitro and promoted tumor cell growth in vivo. TNF receptor superfamily member 6 (Fas) was further identified as a target of miR-181a. We also found that Fas could reverse the apoptosis-inhibition effect induced by miR-181a. Moreover, HBV could inhibit cell apoptosis by down regulating Fas expression, which could be reversed by miR-181a inhibitor. Our data demonstrated that HBV suppressed apoptosis of hepatoma cells by up regulating miR-181a expression and down-regulating Fas expression, which may provide a new understanding of the mechanism in HBV-related HCC pathogenesis. PMID- 25449697 TI - Aldosterone up-regulates MMP-9 and MMP-9/NGAL expression in human neutrophils through p38, ERK1/2 and PI3K pathways. AB - Aldosterone and mineralocorticoid receptors are important regulators of inflammation. During this process, chemokines and extracellular matrix degradation by matrix metalloproteases, such as MMP-9, help leukocytes reaching swiftly and infiltrating the injured tissue, two processes essential for tissue repair. Leukocytes, such as neutrophils, are a rich source of MMP-9 and possess mineralocorticoid receptors (MR). The aim of our study was to investigate whether aldosterone was able to regulate proMMP-9, active MMP-9 and MMP-9/NGAL production in human neutrophils. Here we show that aldosterone increased MMP-9 mRNA in a dose- and time-dependent manner. This hormone up-regulated also dose-dependently proMMP-9 and active MMP-9 protein release as well as the MMP-9/NGAL protein complex. PI3K, p38 and ERK1/2 inhibition diminished these aldosterone-induced neutrophil productions. Furthermore, spironolactone, a MR antagonist, counteracted aldosterone-induced increases of proMMP-9, active MMP-9 and MMP 9/NGAL complex. These findings indicate that aldosterone could participate in tissue repair by modulating neutrophil activity and favoring extracellular matrix degradation. PMID- 25449698 TI - Serine protease inhibitors interact with IFN-gamma through up-regulation of FasR; a novel therapeutic strategy against cancer. AB - Among the many immunomodulatory and anti-tumor activities, IFN-gamma up-regulates tumor cell death mediated by Fas receptor (FasR). Our and several other studies have demonstrated the involvement of trypsin-like proteases (TLPs) in the mode of action of IFN-gamma. In the present study, we tried to unravel the role of serine proteases in IFN-gamma induced Fas-mediated cell death. Our present results show that both tosyl-l-Lysine chloromethylketone (TLCK), a trypsin like protease inhibitor and tosyl-l-phenylalanine chloromethylketone (TPCK) - a chymotrypsin like protease (CLP) inhibitor, sensitize HeLa cells to Fas-mediated cell death. The combined effect of these protease inhibitors with anti-Fas was stronger than additive. In contrast, elastase inhibitor III (EI), which also contains the chloromethyl ketone moiety, was not active. Furthermore, co-addition of TLCK or TPCK with IFN-gamma markedly enhanced Fas-induced cell death. IFN-gamma led to up regulation of FasR on its own, which was further enhanced by the co-addition of TLCK or TPCK. This was evident both by increased expression of Fas receptor on cell surface and by elevated Fas mRNA level. This study may provide the basis for the design of a novel combinatory therapeutic strategy that could enhance the eradication of tumors. PMID- 25449700 TI - Neuronal stathmins: a family of phosphoproteins cooperating for neuronal development, plasticity and regeneration. AB - Nervous system development, plasticity and regeneration require numerous, coordinated and finely tuned subcellular mechanisms. Phosphoproteins of the stathmin family, originally identified as intracellular signal relay proteins, are mostly or exclusively expressed in the nervous system with a high level of expression during brain development. Vertebrate stathmins 1-4 all possess a C terminal "stathmin-like domain" that binds or releases tubulin in a phosphorylation dependent way, and hence participates in the control of microtubule dynamics, an essential process for neuronal differentiation. Contrary to stathmin 1, stathmins 2-4 possess an N-terminal extension whose reversible palmitoylation specifically targets them to the Golgi and intracellular membranes. Regulation of stathmins 2-4 palmitoylation is therefore an important regulatory mechanism that controls their shuttling to various neuronal compartments where they can then act locally. Expression of stathmins is upregulated during neuronal differentiation and plasticity, and altered in numerous neurodegenerative diseases. Experimental perturbation of stathmins expression in Drosophila or in neurons in culture revealed their importance in neuronal growth and differentiation, each stathmin fulfilling at least partially distinct and likely complementary roles. On the other hand, knock-out of stathmins in mice, with the exception of stathmin 2, resulted in mostly mild or no detected phenotype, revealing likely compensations among stathmins. Altogether, through their combinatorial expression and regulation by phosphorylation and by palmitoylation, and through their interactions with tubulin and other neuronal protein targets, the various stathmins appear as essential regulators of neuronal differentiation at the various stages during development and plasticity of the nervous system. PMID- 25449699 TI - Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers. AB - RATIONALE: There is now compelling evidence for a link between enteric microbiota and brain function. The ingestion of probiotics modulates the processing of information that is strongly linked to anxiety and depression, and influences the neuroendocrine stress response. We have recently demonstrated that prebiotics (soluble fibres that augment the growth of indigenous microbiota) have significant neurobiological effects in rats, but their action in humans has not been reported. OBJECTIVES: The present study explored the effects of two prebiotics on the secretion of the stress hormone, cortisol and emotional processing in healthy volunteers. METHODS: Forty-five healthy volunteers received one of two prebiotics (fructooligosaccharides, FOS, or Bimuno(r) galactooligosaccharides, B-GOS) or a placebo (maltodextrin) daily for 3 weeks. The salivary cortisol awakening response was sampled before and after prebiotic/placebo administration. On the final day of treatment, participants completed a computerised task battery assessing the processing of emotionally salient information. RESULTS: The salivary cortisol awakening response was significantly lower after B-GOS intake compared with placebo. Participants also showed decreased attentional vigilance to negative versus positive information in a dot-probe task after B-GOS compared to placebo intake. No effects were found after the administration of FOS. CONCLUSION: The suppression of the neuroendocrine stress response and the increase in the processing of positive versus negative attentional vigilance in subjects supplemented with B-GOS are consistent with previous findings of endocrine and anxiolytic effects of microbiota proliferation. Further studies are therefore needed to test the utility of B-GOS supplementation in the treatment of stress-related disorders. PMID- 25449701 TI - Neuropeptides as neuroprotective agents: Oxytocin a forefront developmental player in the mammalian brain. AB - Oxytocin (OT) plays a major role in the establishment of social bonds. Social bonds are linked to the activation of cell signaling pathways that promote neurotrophic and synaptic maturation, plasticity and memory changes. Anti-social behavior is often associated with abnormalities of cell signaling pathways and/or defective function of brain neurotransmitters within behavioral CNS circuits due to unproper environmental and social factors, such as, diet, stress, chemical, air pollution, and noise, during gestational period or/and during early postnatal development. OT exerts an important regulatory functions in maternity and parental behaviors, lactation, attachment, bonding, trust, and sensorial functions such as: homeostatic cardiovascular control, satiety, touch, pain, analgesia and sexual behavior. Noteworthy, OT displays important neuroprotective properties against fetal programmed hypertension when administered during early postnatal life, added to its known anabolic properties shown in adult rats, e.g. body weight control, reduces blood pressure, and increases analgesia. This review focuses on the new evidences supporting OT's role as a major neuroprotective nonapeptide provided by its quality to reverse hypertension programmed in utero by undernutrition. PMID- 25449702 TI - Flightless-I (FliI) is a potential negative regulator of the Toll pathway in Litopenaeus vannamei. AB - Flightless-I (FliI) is a protein negatively modulates the Toll-like receptor (TLR) pathway through interacting with Myeloid differentiation factor 88 (MyD88). To investigate the function of FliI in innate immune responses in invertebrates, Litopenaeus vannamei FliI (LvFliI) was identified and characterized. The full length cDNA of LvFliI is 4, 304 bp long, with an open reading frame (ORF) encoding a putative protein of 1292 amino acids, including 12 leucine-rich repeat (LRR) domains at the N-terminus and 6 gelsolin homology (GEL) domains at the C terminus. The LvFliI protein was located in the cytoplasm and LvFliI mRNA was constitutively expressed in healthy L. vannamei, with the highest expression level in the muscle. LvFliI could be up-regulated in hemocytes after lipopolysaccharide (LPS), poly I:C, CpG-ODN2006, Vibrio parahaemolyticus, Staphylococcus aureus, and white spot syndrome virus (WSSV) challenges, suggesting a stimulation response of LvFliI to bacterial and immune stimulant challenges. Upon LPS stimulation, overexpression of LvFliI in Drosophila Schneider 2 cells led to downregulation of Drosophila and shrimp antimicrobial peptide (AMP) genes. Knockdown of LvFliI by RNA interference (RNAi) resulted in an increase of the expression of three shrimp AMP genes (PEN2, crustin, and Lyz1). However, the mortality rates of LvFliI-knockdown shrimp in response to V. parahaemolyticus, S. aureus or WSSV infections were not significantly different from those of the control group. Taken together, all the results suggested that LvFliI may play a negative role in TLR signaling response in L. vannamei. PMID- 25449703 TI - Immune responses of phenoloxidase and superoxide dismutase in the manila clam Venerupis philippinarum challenged with Vibrio tapetis--Part I: Spatio-temporal evolution of enzymes' activities post-infection. AB - Manila clams, Venerupis philippinarum (Adams and Reeve, 1850), were experimentally challenged with two Vibrio tapetis strains: CECT4600T, the causative agent of Brown Ring Disease (BRD); and LP2 supposedly non-pathogenic in V. philippinarum. Changes in phenoloxidase (PO) and superoxide dismutase (SOD), two major enzymes involved in immunity, were studied in two tissues, the mantle and hemolymph for 30 days after infection in the extrapallial cavity. Bacterial infection in V. philippinarum resulted in modulation of PO and SOD activities that was both tissue- and time-dependent. A response at early times was detected in the mantle and was associated with significant increases in PO and SOD activities in LP2- and CECT4600T-challenged clams 36 h post injection. This first response in the mantle could be explained by the proximity to the injection region (extrapallial cavity). In the hemolymph the response occurred at later times and was associated with an increase in PO activity and a decrease in SOD activity. As hemolymph is a circulating fluid, this response delay could be due to an "integration time" needed by the organism to counteract the infection. Injections also impacted PO and SOD activities in both tissues and confirmed a difference in pathogenicity between the two V. tapetis strains. PMID- 25449704 TI - Determining the monosaccharides of the sea urchin (Paracentrotus lividus) coelomocytes via the CapLC-ESI-MS/MS system and the lectin histochemistry. AB - The essential mechanism within immune systems is the recognition of pathogens and parasites by the immune system cells, which attach to their targets and destroy them. Glycans are fundamental macromolecular components of all cells, and are important in the vertebrate immunity. But, glycans have been investigated rarely in coelomocytes of echinoids. Hence, the aim of this study is to determine the monosaccharides which form glycan chains on the sea urchin immune system cells, coelomocytes, via analytical and lectin histochemistry methods. The study material is the coelomocytes obtained from adult sea urchin Paracentrotus lividus. In order to analyze the monosaccharides with the Capillary Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometry (CapLC-ESI-MS/MS) system, the samples underwent hydrolysation, reacetylation and derivatization steps. In order to determine the monosaccharides with the lectin histochemistry, the cells were incubated with fluorescein isothiocyanate (FITC) conjugated PNA, HPA, WGA-suc, WGA, and PSL lectins and then photographed with the fluorescence microscope. As a result of the CapLC-ESI-MS/MS analysis; mannose, ribose, N acetylglucosamine, glucose, N-acetylgalactosamine, galactose, arabinose, xylose and fucose monosaccharides were detected. A peak area calculation analysis revealed the most prevalent saccharides as glucose, galactose and fucose, respectively. Lectin histochemistry came out with higher intensity emission signals obtained from the FITC-conjugated lectin WGA, which is specific to N acetylglucosamine and sialic acid in comparison to the emission obtained from the sialic acid unspecific WGA-suc lectin. This finding indicates the existence of sialic acid within coelomocytes. Fluorescent emissions from other lectins were detected at lower levels. Determination of the monosaccharides which form glycan chains of the sea urchin coelomocytes and elucidating their similarities among other invertebrate and vertebrate systems is vital in terms of understanding the uncovered complex features of the immune systems of higher vertebrates. PMID- 25449705 TI - The first echinoderm gamma-interferon-inducible lysosomal thiol reductase (GILT) identified from sea cucumber (Stichopus monotuberculatus). AB - Gamma-interferon-inducible lysosomal thiol reductase (GILT) has been described as a key enzyme that facilitating the processing and presentation of major histocompatibility complex class II-restricted antigen in mammals. In this study, the first echinoderm GILT named StmGILT was identified from sea cucumber (Stichopus monotuberculatus). The StmGILT cDNA is 1529 bp in length, containing a 5'-untranslated region (UTR) of 87 bp, a 3'-UTR of 674 bp and an open reading frame (ORF) of 768 bp that encoding a protein of 255 amino acids with a deduced molecular weight of 27.82 kDa and a predicted isoelectric point of 4.73. The putative StmGILT protein possesses all the main characteristics of known GILT proteins, including a signature sequence, a reductase active site CXXC, twelve conserved cysteines, and two potential N-linked glycosylation sites. For the gene structure, StmGILT contains four exons separated by three introns. In the promoter region of StmGILT gene, an NF-kappaB binding site and an IFN-gamma activation site were found. The thiol reductase activity of recombinant StmGILT protein was also demonstrated in this study. In addition, the highest level of mRNA expression was noticed in coelomocytes of S. monotuberculatus. In in vitro experiments performed in coelomocytes, the expression of StmGILT mRNA was significantly up-regulated by lipopolysaccharides (LPS), inactivated bacteria or polyriboinosinic polyribocytidylic acid [poly (I:C)] challenge, suggested that the sea cucumber GILT might play critical roles in the innate immune defending against bacterial and viral infections. PMID- 25449706 TI - Vaccination with outer membrane vesicles from Francisella noatunensis reduces development of francisellosis in a zebrafish model. AB - Infection of fish with the facultative intracellular bacterium Francisella noatunensis remains an unresolved problem for aquaculture industry worldwide as it is difficult to vaccinate against without using live attenuated vaccines. Outer membrane vesicles (OMVs) are biological structures shed by Gram-negative bacteria in response to various environmental stimuli. OMVs have successfully been used to vaccinate against both intracellular and extracellular pathogens, due to an ability to stimulate innate, cell-mediated and humoral immune responses. We show by using atomic force and electron microscopy that the fish pathogenic bacterium F. noatunensis subspecies noatunensis (F.n.n.) shed OMVs both in vitro into culture medium and in vivo in a zebrafish infection model. The main protein constituents of the OMV are IglC, PdpD and PdpA, all known Francisella virulence factors, in addition to the outer membrane protein FopA and the chaperonin GroEL, as analyzed by mass spectrometry. The vesicles, when used as a vaccine, reduced proliferation of the bacterium and protected zebrafish when subsequently challenged with a high dose of F.n.n. without causing adverse effects for the host. Also granulomatous responses were reduced in F.n.n. challenged zebrafish after OMV vaccination. Taken together, the data support the possible use of OMVs as vaccines against francisellosis in fish. PMID- 25449707 TI - Molecular genomic- and transcriptional-aspects of a teleost TRAF6 homolog: Possible involvement in immune responses of Oplegnathus fasciatus against pathogens. AB - Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is a crucial docking molecule for TNFR superfamily and Interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily. As an adaptor protein in pathogen-induced signaling cascades, TRAF6 modulates both adaptive- and innate-immunity. In order to understand the immune responses of teleost TRAF6, Oplegnathus fasciatus TRAF6 like gene (OfTRAF6) was identified and characterized. Genomic length of OfTRAF6 (4 kb), obtained by means of a genomic BAC library, spanned seven exons which represented a putative coding sequence of 1716 bp and encoded 571 amino acids (aa) with an estimated molecular weight of 64 kDa. This putative protein demonstrated the classical tetra-domain architecture composed of a zinc finger RING-type profile, two zinc finger TRAF-type profiles, a coiled-coil region and a MATH domain. While the sequence similarity with human TRAF6 was 66.5%, OfTRAF6 shared a higher overall similarity with teleost homologs (~75-92%). Phylogeny of TRAF-family was examined and TRAF6-subfamily appeared to be the precursor of other subfamilies. In addition, the clustering pattern confirmed that OfTRAF6 is a novel member of TRAF6subfamily. Based on comparative genomic analysis, we found that vertebrate TRAF6 exhibits two distinct structures in teleost and tetrapod lineages. An intron-loss event has probably occurred in TRAF6 gene during the evolution of tetrapods from teleosts. Inspection of putative OfTRAF6 promoter revealed the presence of several immune responsive transcription factor binding sites. Real-time qPCR assay detected OfTRAF6 transcripts in eleven juvenile fish tissues with higher levels in peripheral blood cells followed by liver. Putative role of OfTRAF6 in response to flagellin, LPS, poly I:C, pathogenic bacteria (Edwardsiella tarda and Streptococcus iniae) and rock bream iridovirus (RBIV) was profiled in different tissues and OfTRAF6 revealed up-regulated transcript levels. Altogether, these findings implicate that OfTRAF6 is not only involved in flagellin-induced signaling cascade, but also contributes to the antibacterial- and antiviral-responses. PMID- 25449708 TI - Ciona intestinalis galectin (CiLgals-a and CiLgals-b) genes are differentially expressed in endostyle zones and challenged by LPS. AB - Immunohistochemical and in situ hybridization assays were performed to answer the question whether the endostyle, that is the initial gastro-intestinal trait of Ciona intestinalis pharynx, is involved in galectin (CiLgals-a and CiLgals-b) production during the pharynx inflammatory response to LPS inoculation. Specific anti-CiLgal-a and anti-CiLgals-b antibodies, and oligonucleotide probes, that mark inflammatory hemocytes inside the pharynx vessels and vessel epithelium as shown by a previous paper, were assayed on endostyle histological sections. For the first time, we show that galectins are produced by endostyle zones, and both CiLgals-a and -b genes are upregulated by LPS. CiLgals-a and CiLgals-b are constitutively expressed in the endostyle zone 2 and 3, respectively, both genes are upregulated by LPS in the zone 2, and CiLgals-b in the zone 3 and 4. The antibody-reacting material contained in intracellular and extracellular large vesicles suggest an unexpected vesicle-dependent transporting mechanism of galectins not provided with signal peptide. Differential expression and gene upregulation in not-treated and LPS-treated specimens, support the role of endostyle galectins both in filter feeding and defense responses. PMID- 25449709 TI - Tumor-targeted paclitaxel delivery and enhanced penetration using TAT-decorated liposomes comprising redox-responsive poly(ethylene glycol). AB - To combine the advantage of poly(ethylene gylcol) (PEG) for longer circulation and cell-penetrating peptides (CPPs) for efficient cellular uptake, paclitaxel (PTX)-loaded liposomes functionalized with TAT, the most frequently used CPP, and cleavable PEG via a redox-responsive disulfide linker (PTX-C-TAT-LP) were successfully developed here. Under physiological conditions, TAT was shielded by PEG layer and liposomes exhibited a long blood circulation. At tumor site, PEG could be detached in the presence of exogenous reducing agent [glutathione (GSH)] and TAT was exposed to facilitate cell internalization. In the presence of GSH, the liposomal vesicle C-TAT-LP showed increased cellular uptake and improved three-dimensional tumor spheroids penetration in vitro compared with analogous stable shielded liposomes. C-TAT-LP achieved enhanced tumor distribution and demonstrated superior delivery efficiency in vivo. PTX-C-TAT-LP with GSH strongly inhibited the proliferation of murine melanoma B16F1 tumor cells in vitro and in vivo with the tumor inhibition rate being 69.4% on B16F1-bearing mice. In addition, the serum aspartate transaminase level, alanine transaminase level, and creatine kinase level were almost completely within normal range in the PTX-C-TAT LP with GSH group, revealing PTX-C-TAT-LP with GSH had no obvious drug-related adverse events for liver and heart. Taken together, C-TAT-LP is a promising tumor targeting drug carrier. PMID- 25449710 TI - Validation of mismatch negativity and P3a for use in multi-site studies of schizophrenia: characterization of demographic, clinical, cognitive, and functional correlates in COGS-2. AB - Mismatch negativity (MMN) and P3a are auditory event-related potential (ERP) components that show robust deficits in schizophrenia (SZ) patients and exhibit qualities of endophenotypes, including substantial heritability, test-retest reliability, and trait-like stability. These measures also fulfill criteria for use as cognition and function-linked biomarkers in outcome studies, but have not yet been validated for use in large-scale multi-site clinical studies. This study tested the feasibility of adding MMN and P3a to the ongoing Consortium on the Genetics of Schizophrenia (COGS) study. The extent to which demographic, clinical, cognitive, and functional characteristics contribute to variability in MMN and P3a amplitudes was also examined. Participants (HCS n=824, SZ n=966) underwent testing at 5 geographically distributed COGS laboratories. Valid ERP recordings were obtained from 91% of HCS and 91% of SZ patients. Highly significant MMN (d=0.96) and P3a (d=0.93) amplitude reductions were observed in SZ patients, comparable in magnitude to those observed in single-lab studies with no appreciable differences across laboratories. Demographic characteristics accounted for 26% and 18% of the variance in MMN and P3a amplitudes, respectively. Significant relationships were observed among demographically adjusted MMN and P3a measures and medication status as well as several clinical, cognitive, and functional characteristics of the SZ patients. This study demonstrates that MMN and P3a ERP biomarkers can be feasibly used in multi-site clinical studies. As with many clinical tests of brain function, demographic factors contribute to MMN and P3a amplitudes and should be carefully considered in future biomarker-informed clinical studies. PMID- 25449711 TI - GABAergic mechanisms of hippocampal hyperactivity in schizophrenia. AB - Schizophrenia is associated with abnormalities of hippocampal structure and function. Neuroimaging studies have shown that the hippocampus is hyperactive in schizophrenia. Here we explore GABAergic mechanisms of this hippocampal hyperactivity. The initial evidence for GABAergic abnormalities of the hippocampus in schizophrenia came from post-mortem studies of interneuron number, protein expression, and gene expression. These studies revealed marked decreases in gene and protein expression of somatostatin-positive and parvalbumin-positive interneurons, and indicated reduced interneuron numbers. Animal studies of decreased parvalbumin and NMDA-receptor function have shown that selective abnormalities of hippocampal interneurons mimic some of the cognitive deficits and clinical features of schizophrenia. The post-mortem and animal studies are consistent with the neuroimaging finding of increased hippocampal activity in schizophrenia, which can explain some of the psychotic symptoms and cognitive deficits. Taken together, these findings may guide the development of biomarkers and the development of new treatments for psychosis. PMID- 25449713 TI - Myelin, myelin-related disorders, and psychosis. AB - The neuropathological basis of schizophrenia and related psychoses remains elusive despite intensive scientific investigation. Symptoms of psychosis have been reported in a number of conditions where normal myelin development is interrupted. The nature, location, and timing of white matter pathology seem to be key factors in the development of psychosis, especially during the critical adolescent period of association area myelination. Numerous lines of evidence implicate myelin and oligodendrocyte function as critical processes that could affect neuronal connectivity, which has been implicated as a central abnormality in schizophrenia. Phenocopies of schizophrenia with a known pathological basis involving demyelination or dysmyelination may offer insights into the biology of schizophrenia itself. This article reviews the pathological changes in white matter of patients with schizophrenia, as well as demyelinating diseases associated with psychosis. In an attempt to understand the potential role of dysmyelination in schizophrenia, we outline the evidence from a number of both clinically-based and post-mortem studies that provide evidence that OMR genes are genetically associated with increased risk for schizophrenia. To further understand the implication of white matter dysfunction and dysmyelination in schizophrenia, we examine diffusion tensor imaging (DTI), which has shown volumetric and microstructural white matter differences in patients with schizophrenia. While classical clinical-neuropathological correlations have established that disruption in myelination can produce a high fidelity phenocopy of psychosis similar to schizophrenia, the role of dysmyelination in schizophrenia remains controversial. PMID- 25449712 TI - Differential susceptibility of white matter tracts to inflammatory mediators in schizophrenia: an integrated DTI study. AB - BACKGROUND: The pathophysiological underpinnings of impaired anatomical and functional connectivity are not precisely known. Emerging data suggest that immune mediators may underlie such dysconnectivity. We examined anatomical brain connections using diffusion tensor imaging (DTI) data in relation to interleukin 6 (IL-6) and C-reactive protein (CRP) levels among early-course clinically stable schizophrenia subjects compared to healthy controls (HC). METHODS: DTI data were acquired in 30 directions with 2 averages. Fractional anisotropy (FA) and radial diffusivity (RD) maps were separately processed using FSL4.1.9 and Tract-Based Spatial Statistics (TBSS). Threshold free cluster enhancements (TFCE) were examined employing familywise error (FWE) corrections for multiple testing within linear regression models including age, sex and socioeconomic status as covariates. IL-6 and CRP were assayed using highly sensitive and specific sandwich immunosorbent assays. RESULTS: The groups did not differ in age and sex as well as in the IL-6 and CRP levels. IL-6 levels were negatively correlated with the FA and positively correlated with RD among schizophrenia subjects but not HC. The voxel clusters that showed significant correlations were localized to the forceps major, the inferior longitudinal fasciculus and the inferior fronto occipital fasciculus. CRP levels showed similar pattern except for lack of correlation with RD on any cluster that corresponded to the forceps major. DISCUSSION: Our results suggest that the IL-6 and CRP contribute to impaired anisotropy of water diffusion in selected pathways that have been previously associated with schizophrenia suggesting differential susceptibility of selected neural pathways to immune mediators. PMID- 25449715 TI - The normalities and abnormalities associated with speech in psychometrically defined schizotypy. AB - Speech deficits are thought to be an important feature of schizotypy--defined as the personality organization reflecting a putative liability for schizophrenia. There is reason to suspect that these deficits manifest as a function of limited cognitive resources. To evaluate this idea, we examined speech from individuals with psychometrically-defined schizotypy during a low cognitively-demanding task versus a relatively high cognitively-demanding task. A range of objective, computer-based measures of speech tapping speech production (silence, number and length of pauses, number and length of utterances), speech variability (global and local intonation and emphasis) and speech content (word fillers, idea density) were employed. Data for control (n=37) and schizotypy (n=39) groups were examined. Results did not confirm our hypotheses. While the cognitive-load task reduced speech expressivity for subjects as a group for most variables, the schizotypy group was not more pathological in speech characteristics compared to the control group. Interestingly, some aspects of speech in schizotypal versus control subjects were healthier under high cognitive load. Moreover, schizotypal subjects performed better, at a trend level, than controls on the cognitively demanding task. These findings hold important implications for our understanding of the neurocognitive architecture associated with the schizophrenia-spectrum. Of particular note concerns the apparent mismatch between self-reported schizotypal traits and objective performance, and the resiliency of speech under cognitive stress in persons with high levels of schizotypy. PMID- 25449714 TI - Glucagon-like peptide 1 receptor (GLP1R) haplotypes correlate with altered response to multiple antipsychotics in the CATIE trial. AB - Glucagon-like peptide 1 receptor (GLP1R) signaling has been shown to have antipsychotic properties in animal models and to impact glucose-dependent insulin release, satiety, memory, and learning in man. Previous work has shown that two coding mutations (rs6923761 and rs1042044) are associated with altered insulin release and cortisol levels. We identified four frequently occurring haplotypes in Caucasians, haplotype 1 through haplotype 4, spanning exons 4-7 and containing the two coding variants. We analyzed response to antipsychotics, defined as predicted change in PANSS-Total (dPANSS) at 18 months, in Caucasian subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness treated with olanzapine (n=139), perphenazine (n=78), quetiapine (n=14), risperidone (n=143), and ziprasidone (n=90). Haplotype trend regression analysis revealed significant associations with dPANSS for olanzapine (best p=0.002), perphenazine (best p=0.01), quetiapine (best p=0.008), risperidone (best p=0.02), and ziprasidone (best p=0.007). We also evaluated genetic models for the two most common haplotypes. Haplotype 1 (uniquely including the rs1042044 [Leu(260)] allele) was associated with better response to olanzapine (p=0.002), and risperidone (p=0.006), and worse response to perphenazine (p=.03), and ziprasidone (p=0.003), with a recessive genetic model providing the best fit. Haplotype 2 (uniquely including the rs6923761 [Ser(168)] allele) was associated with better response to perphenazine (p=0.001) and worse response to olanzapine (p=.02), with a dominant genetic model providing the best fit. However, GLP1R haplotypes were not associated with antipsychotic-induced weight gain. These results link functional genetic variants in GLP1R to antipsychotic response. PMID- 25449717 TI - Dexterity as measured with the 9-Hole Peg Test (9-HPT) across the age span. AB - STUDY DESIGN: Cross-sectional observational, clinical measurement. INTRODUCTION: Manual dexterity is an important aspect of motor function across the age span. PURPOSE OF THE STUDY: To present the norms for the 9-Hole Peg Test (9-HPT) across the age span (3-85 years) and compare the 9-HPT performance by age group, gender, dominance, handedness, ethnicity, race, and language preference. METHODS: A population-based sample of 4319 subjects contributed data to this study which was part of the NIH Toolbox Norming Project. RESULTS: The 16-39 age groups demonstrated the shortest completion time (dominant hand, males completed a trial in 19-20 s, and females 18-19 s), and the youngest children 3-5 age groups showed the longest completion time with largest variation (males 32-51 s and females 32 45 s). Across all age groups, females performed slightly better as compared to males (22.5 versus 24.2 s). Dominant hands completed the test more quickly than the non-dominant hands (23.3 versus 25.4 s). Individuals who are not Hispanic or Latino performed slightly better than individuals who are Hispanic or Latino (22.2 versus 25.6 s). The completion time for English speakers was shorter than Spanish speakers (22.3 versus 27.8 s). There were no statistical differences by handedness (P = 0.6) or race (White versus Black or African American, P = 0.4). CONCLUSIONS: We present norms of the 9-HPT established by the NIH Toolbox. The norms can be used to determine the presence of impairments in dexterity across the age span. LEVEL OF EVIDENCE: NA. PMID- 25449718 TI - Establishing expert consensus on the evaluation of pediatric upper extremity function. AB - STUDY DESIGN: Consensus statement. INTRODUCTION: There is a lack of consensus in the literature on the measures of pediatric upper extremity (UE) function for musculoskeletal conditions. PURPOSE: To establish expert consensus on utility, satisfaction and importance of functional outcome measures in children with UE musculoskeletal conditions, across International Classification of Functioning, Disability and Health (ICF) domains. METHODS: Using Delphi Consensus Methodology, expert panelists completed three rounds of questionnaires. RESULTS: Agreement on Body Functions and Structure, Activity, and Participation outcome measures was determined (alpha, ICC range = 0.86-0.96). Mean satisfaction of measures in the respective domains was between 6.93 and 7.94. The Activity domain had lowest satisfaction, however there was consensus it was the most important. DISCUSSION: Consensus on relative importance, but low satisfaction in the Activity domain suggests a need for better outcomes in this domain. CONCLUSIONS: Findings report the status of outcome measure utility and use in pediatric UE function. LEVEL OF EVIDENCE: 5. PMID- 25449719 TI - Evaluation of pediatric upper extremity peripheral nerve injuries. AB - INTRODUCTION: The evaluation of motor and sensory function of the upper extremity after a peripheral nerve injury is critical to diagnose the location and extent of nerve injury as well as document functional recovery in children. PURPOSE: The purpose of this paper is to describe an approach to the evaluation of the pediatric upper extremity peripheral nerve injuries through a critical review of currently used tests of sensory and motor function. METHODS: Outcome studies on pediatric upper extremity peripheral nerve injuries in the Medline database were reviewed. RESULTS: The evaluation of the outcome in children less than 10 years of age with an upper extremity peripheral nerve injury includes careful observation of preferred prehension patterns, examination of muscle atrophy and sudomotor function, provocative tests, manual muscle testing and tests of sensory threshold and tactile gnosis. CONCLUSION: The evaluation of outcome in children with upper extremity peripheral nerve injuries warrants a unique approach. PMID- 25449716 TI - An incongruent reality: the N400 in relation to psychosis and recovery. AB - BACKGROUND: Cognitive impairments and delusions are hallmarks of schizophrenia, and are thought to be due in part to abnormalities in semantic priming. The N400, a neural measure of semantic processing, is found to be reduced in schizophrenia. However, it is unclear if individuals with other psychoses (e.g., mood disorders or substance abuse with psychotic features) also show this impairment, and whether N400 reduction relates to real-world functioning and recovery. METHODS: Eighty-nine individuals from the Suffolk County Mental Health Project, a longitudinal study of first-admission psychosis, and 35 healthy adults were assessed using matched, related, and unrelated picture-word pairs to elicit the N400. Patients' real-world functioning, symptomatology, and recovery were tracked since first hospitalization; EEG assessment was completed during year 15 of the study. RESULTS: Participants with schizophrenia had slower reaction times and reduced N400 to semantically incongruent stimuli relative to healthy participants. Schizophrenia and other psychoses did not differ on N400, suggesting that N400 abnormalities characterize psychosis broadly. When grouped by recovery status, patients who remained ill had a significantly blunted N400, while those who recovered did not differ from healthy adults. Few patients with schizophrenia achieved recovery; therefore recovery results are limited to the other psychosis group. Furthermore, reduced N400 and increased reaction times correlated with greater psychotic symptoms, worse global assessment of functioning scores, unemployment, and impaired social functioning. CONCLUSIONS: Abnormalities in the N400 are not specific to schizophrenia; in addition, the N400 may be a useful neural correlate of recovery and real-world functioning across psychotic disorders. PMID- 25449720 TI - Cell cycle entry, maintenance, and exit during plant development. AB - Growth and development of plants are driven by the continuous production of new cells at the meristems; hence, it is of pivotal importance for plants to precisely regulate the timing and extent of cell proliferation. Although over the past decades the molecular components underlying cell cycle progression have been the subject of intensive research, knowledge remains scarce on how the various elements connect with developmental pathways. Recently, advances have been made that link cell cycle entry with nutrient availability, cell division maintenance with stem cell organization, and cell cycle exit with reactive oxygen species and developmental programs. PMID- 25449721 TI - Polypeptide signaling molecules in plant development. AB - Intercellular communication mediated by small signaling molecules is a key mechanism for coordinating plant growth and development. In the past few years, polypeptide signals have been shown to play prominent roles in processes as diverse as shoot and root meristem maintenance, vascular differentiation, lateral root emergence, and seed formation. Signaling components such as CLV1 and the IDA HAE/HSL2 signaling module have been discovered to regulate distinct developmental processes in different tissues. Recent studies have also uncovered novel polypeptide-receptor interactions, intracellular components and downstream target genes, adding complexity to our picture of polypeptide signaling networks. Finally, new families of plant polypeptides, such as the GLV/RGF/CLEL and ESF factors, are being identified, the functions of which we are only beginning to understand. PMID- 25449722 TI - Polycomb repression in the regulation of growth and development in Arabidopsis. AB - Chromatin state is critical for cell identity and development in multicellular eukaryotes. Among the regulators of chromatin state, Polycomb group (PcG) proteins stand out because of their role in both establishment and maintenance of cell identity. PcG proteins act in two major complexes in metazoans and plants. These complexes function to epigenetically-in a mitotically heritable manner prevent expression of important developmental regulators at the wrong stage of development or in the wrong tissue. In Arabidopsis, PcG function is required throughout the life cycle from seed germination to embryo formation. Recent studies have expanded our knowledge regarding the biological roles and the regulation of the activity of PcG complexes. In this review, we discuss novel functions of Polycomb repression in plant development as well as advances in understanding PcG complex recruitment, activity regulation and removal in Arabidopsis and other plant species. PMID- 25449723 TI - Control of oriented cell division in the Arabidopsis embryo. AB - Multicellular plant development requires strict control of cell division orientation. A key unanswered question is how developmental regulators interact with the generic cell division machinery to trigger oriented divisions. We discuss the Arabidopsis embryo as a model for addressing this question. Recent progress in 3D imaging and computation now allows sketching of a framework for the developmental control of division orientation in which the signaling molecule auxin controls oriented division by preventing a geometrically defined default plane. We expect that the identification of auxin effectors, together with the identification of novel regulators of cell division will help to link developmental regulators to the division machinery. PMID- 25449724 TI - Talking through walls: mechanisms of lateral root emergence in Arabidopsis thaliana. AB - Lateral roots are formed postembryonically and determine the final shape of the root system, a determinant of the plants ability to uptake nutrients and water. The lateral root primordia are initiated deep into the main root and to protrude out the primary root they have to grow through three cell layers. Recent findings have revealed that these layers are not merely a passive physical obstacle to the emergence of the lateral root but have an active role in its formation. Here, we review examples of communication between the lateral root primordium and the surrounding tissues, highlighting the importance of auxin-mediated growth coordination as well as cell and tissue mechanics for the morphogenesis of lateral roots. PMID- 25449725 TI - Epigenetic mechanisms of postzygotic reproductive isolation in plants. AB - Hybrid incompatibility is generally viewed as a consequence of negative epistatic interactions between alleles that do not cause negative fitness effects in their parents. Substantial evidence in support of the model has accumulated over recent years. Nevertheless, there is evidence that hybrid incompatibility can have an epigenetic basis and results from deregulated small RNAs (sRNAs), causing changes in DNA methylation and transposable element (TE) activation. Epigenetically regulated loci can impact on the expression of nearby located genes. Alteration of dosage-sensitive gene expression builds hybridization barriers in the endosperm; however, it may also offer an explanation for transgressive effects in plant hybrids. In this review we highlight recent advances that illuminate the role of epigenetic pathways in establishing hybrid incompatibility in plants. PMID- 25449726 TI - Conserved function of FLOWERING LOCUS T (FT) homologues as signals for storage organ differentiation. AB - Due to their high carbohydrate content and relative low farming demands, tuber bearing species are an important contribution to human dietary needs in many climatic zones, and interest in these staple crops for processed food and other industrial uses is increasing. Over the past years we have seen remarkable advances in our understanding of the signalling mechanisms involved in the differentiation of these organs, partly aided by their conservation with the well characterized photoperiodic control of flowering in Arabidopsis. Recent studies have led to the identification of members of the FT gene family as major component of the tuber-inducing signal and the characterization of circadian and photoperiodic components involved in the regulation of these genes. A relevant role of microRNAs in the control of storage organ formation has been established, and hormonal balance requirements similar to those controlling shoot branching were shown to be implicated in the activation of stolon meristem cells. Hence, the recent finding that FT controls branching through direct interaction with the TCP factors holds great promise for the identification of genes acting as FT signal integrators in the stolon. PMID- 25449728 TI - Compound leaf development in model plant species. AB - Plant leaves develop in accordance with a common basic program, which is flexibly adjusted to the species, developmental stage and environment. Two key stages of leaf development are morphogenesis and differentiation. In the case of compound leaves, the morphogenesis stage is prolonged as compared to simple leaves, allowing for the initiation of leaflets. Here, we review recent advances in the understanding of how plant hormones and transcriptional regulators modulate compound leaf development, yielding a substantial diversity of leaf forms, focusing on four model compound leaf organisms: cardamine (Cardamine hirsuta), tomato (Solanum lycopersicum), medicago (Medicago truncatula) and pea (Pisum sativum). PMID- 25449727 TI - (Pro)cambium formation and proliferation: two sides of the same coin? AB - The body of higher plants is usually pervaded by the (pro)cambium, a reticulate system of meristematic cells harboring the potential for producing vascular tissues at critical times and places. The (pro)cambium thereby provides the basis for the differential modulation of long-distance transport capacities and plant body stability. Distinct regulatory networks responsible for the initiation and proliferation of (pro)cambium cells have been identified. However, although a tight interaction between these networks can be expected, connections have been established only sporadically. Here we highlight recent discoveries of how (pro)cambium development is regulated and discuss possible interfaces between networks regulating two processes: (pro)cambium formation and cambium proliferation. PMID- 25449729 TI - Traversing organizational scales in plant salt-stress responses. AB - Modern society has developed in large part due to our ability to reliably grow plants for food and renewable resources. Predicted increases in environmental variability will impact agricultural productivity and may have extensive secondary effects on the stability of our society. Thus, a concerted effort to understand plant response strategies to stress is needed. High salinity is an agriculturally important environmental stress and generates complex effects on the physiology of the plant. The abiotic-stress-associated hormone, abscisic acid (ABA), mediates a major component of this response. I highlight recent work studying salt-stress responses at different spatial and organizational scales from the action of ABA in specific cell types to global networks of proteins that predict critical regulatory events during acclimation. PMID- 25449730 TI - Understanding plant cell morphogenesis requires real-time monitoring of cell wall polymers. AB - Plant cell development and growth are determined by the expansion pattern of the cell wall, a matrix of mixed polysaccharide polymers and proteins. To understand the different roles of these polymers in the regulation of the morphogenetic process, their spatial dynamics need to be monitored over time. Recent developments in the live cell labeling of polysaccharides include specific dyes whose insertion into the wall does not interfere with wall properties and growth, as well as metabolically inserted labeling. The present review explains the motivation and necessity for novel polysaccharide labeling techniques and provides an overview of the insight gained with these strategies. PMID- 25449731 TI - Lignification: different mechanisms for a versatile polymer. AB - Lignins are cell wall phenolic polymers resulting from monolignol radical coupling. They have characteristically high diversity in their structures which is a direct consequence of the versatile character of the lignification mechanisms discussed in this review. We will relate the latest discoveries regarding the main participants involved in lignin deposition in various tissues. Lignification is often described as a cell autonomous event occurring progressively in all cell wall layers during lignifying cell life and stopping with the cell death. However, recent data combined to old data from studies of tree lignification and zinnia cultures challenged these entrenched views and showed that the lignification process is cell-type dependent and can involve neighboring cells. Therefore, we consider recent data on cell-autonomous and non cell autonomous lignification processes. We conclude that the role of lignins still need to be assessed during plant development and that control of polymerization/lignin deposition remains elusive and need to be investigated. PMID- 25449732 TI - O cell, where art thou? The mechanisms of shoot meristem patterning. AB - Plants develop postembryonically from pools of continuously active stem cells embedded in specialized tissues called meristems, which are located at the growing points of shoot and root. How these stem cells are established, maintained and guided towards differentiation within the highly dynamic shoot apical meristem is only beginning to emerge. At the core of the complex regulatory system are spatially distinct subdomains within the shoot apex, in which cells carry out defined functions, despite highly similar phenotypes. Spatial and temporal control of these domains appears to rely on an elaborate network of phytohormone signaling, transcriptional loops and intercellular trafficking of key regulators. In this review, we aim at summarizing and connecting the mechanisms underlying the spatial organization of the shoot apical meristem and the sequence of molecular events occurring during the life of a shoot cell, from its birth towards its differentiation. PMID- 25449733 TI - From phenotypes to causal sequences: using genome wide association studies to dissect the sequence basis for variation of plant development. AB - Tremendous natural variation of growth and development exists within species. Uncovering the molecular mechanisms that tune growth and development promises to shed light on a broad set of biological issues including genotype to phenotype relations, regulatory mechanisms of biological processes and evolutionary questions. Recent progress in sequencing and data processing capabilities has enabled Genome Wide Association Studies (GWASs) to identify DNA sequence polymorphisms that underlie the variation of biological traits. In the last years, GWASs have proven powerful in revealing the complex genetic bases of many phenotypes in various plant species. Here we highlight successful recent GWASs that uncovered mechanistic and sequence bases of trait variation related to plant growth and development and discuss important considerations for conducting successful GWASs. PMID- 25449734 TI - Complex system modelling for veterinary epidemiology. AB - The use of mathematical models has a long tradition in infectious disease epidemiology. The nonlinear dynamics and complexity of pathogen transmission pose challenges in understanding its key determinants, in identifying critical points, and designing effective mitigation strategies. Mathematical modelling provides tools to explicitly represent the variability, interconnectedness, and complexity of systems, and has contributed to numerous insights and theoretical advances in disease transmission, as well as to changes in public policy, health practice, and management. In recent years, our modelling toolbox has considerably expanded due to the advancements in computing power and the need to model novel data generated by technologies such as proximity loggers and global positioning systems. In this review, we discuss the principles, advantages, and challenges associated with the most recent modelling approaches used in systems science, the interdisciplinary study of complex systems, including agent-based, network and compartmental modelling. Agent-based modelling is a powerful simulation technique that considers the individual behaviours of system components by defining a set of rules that govern how individuals ("agents") within given populations interact with one another and the environment. Agent-based models have become a recent popular choice in epidemiology to model hierarchical systems and address complex spatio-temporal dynamics because of their ability to integrate multiple scales and datasets. PMID- 25449735 TI - Survival analysis of clinical mastitis data using a nested frailty Cox model fit as a mixed-effects Poisson model. AB - Mastitis is a complex disease affecting dairy cows and is considered to be the most costly disease of dairy herds. The hazard of mastitis is a function of many factors, both managerial and environmental, making its control a difficult issue to milk producers. Observational studies of clinical mastitis (CM) often generate datasets with a number of characteristics which influence the analysis of those data: the outcome of interest may be the time to occurrence of a case of mastitis, predictors may change over time (time-dependent predictors), the effects of factors may change over time (time-dependent effects), there are usually multiple hierarchical levels, and datasets may be very large. Analysis of such data often requires expansion of the data into the counting-process format - leading to larger datasets - thus complicating the analysis and requiring excessive computing time. In this study, a nested frailty Cox model with time dependent predictors and effects was applied to Canadian Bovine Mastitis Research Network data in which 10,831 lactations of 8035 cows from 69 herds were followed through lactation until the first occurrence of CM. The model was fit to the data as a Poisson model with nested normally distributed random effects at the cow and herd levels. Risk factors associated with the hazard of CM during the lactation were identified, such as parity, calving season, herd somatic cell score, pasture access, fore-stripping, and proportion of treated cases of CM in a herd. The analysis showed that most of the predictors had a strong effect early in lactation and also demonstrated substantial variation in the baseline hazard among cows and between herds. A small simulation study for a setting similar to the real data was conducted to evaluate the Poisson maximum likelihood estimation approach with both Gaussian quadrature method and Laplace approximation. Further, the performance of the two methods was compared with the performance of a widely used estimation approach for frailty Cox models based on the penalized partial likelihood. The simulation study showed good performance for the Poisson maximum likelihood approach with Gaussian quadrature and biased variance component estimates for both the Poisson maximum likelihood with Laplace approximation and penalized partial likelihood approaches. PMID- 25449736 TI - Distribution of cow-calf producers' beliefs about reporting cattle with clinical signs of foot-and-mouth disease to a veterinarian before or during a hypothetical outbreak. AB - Understanding the prevalence of cattle producers' beliefs regarding disease reporting can help officials improve surveillance programs with passive data collection. A cross-sectional survey was conducted in Texas in 2008 and 2009 to determine beliefs about reporting cattle with clinical signs consistent with foot and-mouth disease (FMD) either prior to (scenario 1) or during an on-going outbreak of FMD (scenario 2). Two questionnaires were developed and distributed to Texas cow-calf producers in order to evaluate their behavioral, control, and normative beliefs related to disease reporting. The context for each behavior was provided through the use of scenarios, and belief strength was measured using a 7 point Likert-like scale. Beliefs were compared across scenarios and demographic categories, and the effect of scenario on belief examined using ordinal logistic regression. Respondents agreed that reporting clinically suspect cases would have positive economic and emotional consequences; however, when an outbreak was known to be present, producers were less likely to agree with many of the positive outcomes of reporting. Important barriers to disease reporting indicated by producers included a lack of knowledge related to clinical signs of highly contagious cattle diseases and which cattle are at risk of contracting FMD. In general, beliefs about barriers to reporting did not differ based on scenario. Veterinarians and regulatory authorities were the groups perceived to most strongly expect disease reporting, regardless of the scenario. Risk education for producers related to clinical signs of reportable livestock diseases, post reporting procedures, and an understanding of FMD introduction and spread may improve the reporting of cattle with clinical signs consistent with FMD. PMID- 25449737 TI - Selective attention effects on early integration of social signals: same timing, modulated neural sources. AB - Humans combine co-emitted social signals to predict other's immediate intentions and prepare an adapted response. However, little is known about whether attending to only one of co-emitted social signals impacts on its combination with other signals. Here, using electroencephalography, we address selective attention effects on early combination of social signals. We manipulated three visual cues: gaze direction, emotional expression, and pointing gesture, while participants performed either emotion or gaze direction judgments. Results showed that a temporal marker of social cues integration emerges 170ms after the stimulus onset, even if the integration of the three visual cues was not required to perform the task, as only one feature at a time was task relevant. Yet in addition to common temporal regions, the relative contribution of specific neural sources of this integration changed as a function of the attended feature: integration during emotion judgments was mainly implemented in classic limbic areas but in the dorsal pathway during gaze direction judgments. Together, these findings demonstrate that co-emitted social cues are integrated as long as they are relevant to the observer, even when they are irrelevant to the ongoing task. PMID- 25449738 TI - Avoiding symmetry-breaking spatial non-uniformity in deformable image registration via a quasi-volume-preserving constraint. AB - The choice of a reference image typically influences the results of deformable image registration, thereby making it asymmetric. This is a consequence of a spatially non-uniform weighting in the cost function integral that leads to general registration inaccuracy. The inhomogeneous integral measure--which is the local volume change in the transformation, thus varying through the course of the registration--causes image regions to contribute differently to the objective function. More importantly, the optimization algorithm is allowed to minimize the cost function by manipulating the volume change, instead of aligning the images. The approaches that restore symmetry to deformable registration successfully achieve inverse-consistency, but do not eliminate the regional bias that is the source of the error. In this work, we address the root of the problem: the non uniformity of the cost function integral. We introduce a new quasi-volume preserving constraint that allows for volume change only in areas with well matching image intensities, and show that such a constraint puts a bound on the error arising from spatial non-uniformity. We demonstrate the advantages of adding the proposed constraint to standard (asymmetric and symmetrized) demons and diffeomorphic demons algorithms through experiments on synthetic images, and real X-ray and 2D/3D brain MRI data. Specifically, the results show that our approach leads to image alignment with more accurate matching of manually defined neuroanatomical structures, better tradeoff between image intensity matching and registration-induced distortion, improved native symmetry, and lower susceptibility to local optima. In summary, the inclusion of this space- and time varying constraint leads to better image registration along every dimension that we have measured it. PMID- 25449741 TI - Role of white-matter pathways in coordinating alpha oscillations in resting visual cortex. AB - In the absence of cognitive tasks and external stimuli, strong rhythmic fluctuations with a frequency ~ 10 Hz emerge from posterior regions of human neocortex. These posterior alpha-oscillations can be recorded throughout the visual cortex and are particularly strong in the calcarine sulcus, where the primary visual cortex is located. The mechanisms and anatomical pathways through which local ?alpha-oscillations are coordinated however, are not fully understood. In this study, we used a combination of magnetoencephalography (MEG), diffusion tensor imaging (DTI), and biophysical modeling to assess the role of white-matter pathways in coordinating cortical alpha-oscillations. Our findings suggest that primary visual cortex plays a special role in coordinating alpha oscillations in higher-order visual regions. Specifically, the amplitudes of alpha-sources throughout visual cortex could be explained by propagation of alpha oscillations from primary visual cortex through white-matter pathways. In particular, alpha-amplitudes within visual cortex correlated with both the anatomical and functional connection strengths to primary visual cortex. These findings reinforce the notion of posterior alpha-oscillations as intrinsic oscillations of the visual system. We speculate that they might reflect a default mode of the visual system during which higher-order visual regions are rhythmically primed for expected visual stimuli by alpha-oscillations in primary visual cortex. PMID- 25449740 TI - Rapid T2- and susceptometry-based CMRO2 quantification with interleaved TRUST (iTRUST). AB - Susceptometry-based oximetry (SBO) and T2-relaxation-under-spin-tagging (TRUST) are two promising methods for quantifying the cerebral metabolic rate of oxygen (CMRO2), a critical parameter of brain function. We present a combined method, interleaved TRUST (iTRUST), which achieves rapid, simultaneous quantification of both susceptometry- and T2-based CMRO2 via insertion of a flow-encoded, dual-echo gradient-recalled echo (OxFlow) module within the T1 recovery portion of the TRUST sequence. In addition to allowing direct comparison between SBO- and TRUST derived venous oxygen saturation (Yv) values, iTRUST substantially improves TRUST temporal resolution for CMRO2 quantification and obviates the need for a separate blood flow measurement following TRUST acquisition. iTRUST was compared directly to TRUST and OxFlow alone in three resting subjects at baseline, exhibiting close agreement with the separate techniques and comparable precision. These baseline data as well as simulation results support the use of two instead of the traditional four T2 preparation times for T2 fitting, allowing simultaneous quantification of susceptometry- and T2-based Yv (and CMRO2) with three- and six second temporal resolution, respectively. In 10 young healthy subjects, iTRUST was applied during a 5% CO2 gas mixture-breathing paradigm. T2-based Yv values were lower at baseline relative to susceptometry (62.3 +/- 3.1 vs. 66.7 +/- 5.1 %HbO2, P<0.05), but increased more in response to hypercapnia. As a result, T2 based CMRO2 decreased from 140.4 +/- 9.7 to 120.0 +/- 9.5 MUMol/100g/min, a significant -14.6 +/- 3.6% response (P < 0.0001), whereas susceptometry-based CMRO2 changed insignificantly from 123.4 +/- 18.7 to 127.9 +/- 25.7, a 3.3 +/- 9.7% response (P = 0.31). These differing results are in accord with previous studies applying the parent OxFlow or TRUST sequences individually, thus supporting the reliability of iTRUST but also strongly suggesting that a systematic bias exists between the susceptometry- and T2-based Yv quantification techniques. PMID- 25449739 TI - Gray matter myelination of 1555 human brains using partial volume corrected MRI images. AB - The myelin content of the cortex changes over the human lifetime and aberrant cortical myelination is associated with diseases such as schizophrenia and multiple sclerosis. Recently magnetic resonance imaging (MRI) techniques have shown potential in differentiating between myeloarchitectonically distinct cortical regions in vivo. Here we introduce a new algorithm for correcting partial volume effects present in mm-scale MRI images which was used to investigate the myelination pattern of the cerebral cortex in 1555 clinically normal subjects using the ratio of T1-weighted (T1w) and T2-weighted (T2w) MRI images. A significant linear cross-sectional age increase in T1w/T2w estimated myelin was detected across an 18 to 35 year age span (highest value of ~ 1%/year compared to mean T1w/T2w myelin value at 18 years). The cortex was divided at mid thickness and the value of T1w/T2w myelin calculated for the inner and outer layers separately. The increase in T1w/T2w estimated myelin occurs predominantly in the inner layer for most cortical regions. The ratio of the inner and outer layer T1w/T2w myelin was further validated using high-resolution in vivo MRI scans and also a high-resolution MRI scan of a postmortem brain. Additionally, the relationships between cortical thickness, curvature and T1w/T2w estimated myelin were found to be significant, although the relationships varied across the cortex. We discuss these observations as well as limitations of using the T1w/T2w ratio as an estimate of cortical myelin. PMID- 25449742 TI - Population receptive field estimates of human auditory cortex. AB - Here we describe a method for measuring tonotopic maps and estimating bandwidth for voxels in human primary auditory cortex (PAC) using a modification of the population Receptive Field (pRF) model, developed for retinotopic mapping in visual cortex by Dumoulin and Wandell (2008). The pRF method reliably estimates tonotopic maps in the presence of acoustic scanner noise, and has two advantages over phase-encoding techniques. First, the stimulus design is flexible and need not be a frequency progression, thereby reducing biases due to habituation, expectation, and estimation artifacts, as well as reducing the effects of spatio temporal BOLD nonlinearities. Second, the pRF method can provide estimates of bandwidth as a function of frequency. We find that bandwidth estimates are narrower for voxels within the PAC than in surrounding auditory responsive regions (non-PAC). PMID- 25449743 TI - Simultaneous EEG-fMRI at ultra-high field: artifact prevention and safety assessment. AB - The simultaneous recording of scalp electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) can provide unique insights into the dynamics of human brain function, and the increased functional sensitivity offered by ultra-high field fMRI opens exciting perspectives for the future of this multimodal approach. However, simultaneous recordings are susceptible to various types of artifacts, many of which scale with magnetic field strength and can seriously compromise both EEG and fMRI data quality in recordings above 3T. The aim of the present study was to implement and characterize an optimized setup for simultaneous EEG-fMRI in humans at 7 T. The effects of EEG cable length and geometry for signal transmission between the cap and amplifiers were assessed in a phantom model, with specific attention to noise contributions from the MR scanner coldheads. Cable shortening (down to 12 cm from cap to amplifiers) and bundling effectively reduced environment noise by up to 84% in average power and 91% in inter-channel power variability. Subject safety was assessed and confirmed via numerical simulations of RF power distribution and temperature measurements on a phantom model, building on the limited existing literature at ultra-high field. MRI data degradation effects due to the EEG system were characterized via B0 and B1(+) field mapping on a human volunteer, demonstrating important, although not prohibitive, B1 disruption effects. With the optimized setup, simultaneous EEG-fMRI acquisitions were performed on 5 healthy volunteers undergoing two visual paradigms: an eyes-open/eyes-closed task, and a visual evoked potential (VEP) paradigm using reversing-checkerboard stimulation. EEG data exhibited clear occipital alpha modulation and average VEPs, respectively, with concomitant BOLD signal changes. On a single-trial level, alpha power variations could be observed with relative confidence on all trials; VEP detection was more limited, although statistically significant responses could be detected in more than 50% of trials for every subject. Overall, we conclude that the proposed setup is well suited for simultaneous EEG-fMRI at 7 T. PMID- 25449744 TI - Out of control: diminished prefrontal activity coincides with impaired motor performance due to choking under pressure. AB - There are three non-exclusive theoretical explanations for the paradoxical collapse of performance due to large financial incentives. It has been proposed that "choking under pressure" is either due to distraction, interference via an increase in top-down control and performance monitoring, or excessive levels of arousal in the face of large losses. Given the known neural architecture involved in executive control and reward, we used fMRI of human participants during incentivized motor performance to provide evidence to support and/or reconcile these competing models in a visuomotor task. We show that the execution of a pre trained motor task during neuroimaging is impaired by high rewards. BOLD activity occurring prior to movement onset is increased in dorsolateral prefrontal cortex and functional connectivity between this region and motor cortex is likewise increased just prior to choking. However, the extent of this increase in functional connectivity is inversely related to a participant's propensity to choke, suggesting that a failure in exerting top-down influence on motor control underlies choking under pressure due to large incentives. These results are consistent with a distraction account of choking and suggest that frontal influences on motor activity are necessary to protect performance from vulnerability under pressure. PMID- 25449746 TI - Separating slow BOLD from non-BOLD baseline drifts using multi-echo fMRI. AB - The functional magnetic resonance (fMRI) baseline is known to drift over the course of an experiment and is often attributed to hardware instability. These ultraslow fMRI fluctuations are inseparable from blood oxygenation level dependent (BOLD) changes in standard single echo fMRI and they are therefore typically removed before further analysis in both resting-state and task paradigms. However, some part of these fluctuations may be of neuronal origin, as neural activity can indeed fluctuate at the scale of several minutes or even longer, such as after the administration of drugs or during the ultradian rhythms. Here, we show that it is possible to separate the slow BOLD and non-BOLD drifts automatically using multi-echo fMRI and multi-echo independent components analysis (ME-ICA) denoising by demonstrating the detection of a visual signal evoked from a flickering checkerboard with slowly changing contrast. PMID- 25449745 TI - Decomposing cerebral blood flow MRI into functional and structural components: a non-local approach based on prediction. AB - We present RIPMMARC (Rotation Invariant Patch-based Multi-Modality Analysis aRChitecture), a flexible and widely applicable method for extracting information unique to a given modality from a multi-modal data set. We use RIPMMARC to improve the interpretation of arterial spin labeling (ASL) perfusion images by removing the component of perfusion that is predicted by the underlying anatomy. Using patch-based, rotation invariant descriptors derived from the anatomical image, we learn a predictive relationship between local neuroanatomical structure and the corresponding perfusion image. This relation allows us to produce an image of perfusion that would be predicted given only the underlying anatomy and a residual image that represents perfusion information that cannot be predicted by anatomical features. Our learned structural features are significantly better at predicting brain perfusion than tissue probability maps, which are the input to standard partial volume correction techniques. Studies in test-retest data show that both the anatomically predicted and residual perfusion signals are highly replicable for a given subject. In a pediatric population, both the raw perfusion and structurally predicted images are tightly linked to age throughout adolescence throughout the brain. Interestingly, the residual perfusion also shows a strong correlation with age in selected regions including the hippocampi (corr = 0.38, p-value <10(-6)), precuneus (corr = -0.44, p < 10(-5)), and combined default mode network regions (corr = -0.45, p < 10(-8)) that is independent of global anatomy-perfusion trends. This finding suggests that there is a regionally heterogeneous pattern of functional specialization that is distinct from that of cortical structural development. PMID- 25449748 TI - Discrimination of voice gender in the human auditory cortex. AB - Discerning a speaker's gender from their voice is a basic and crucial aspect of human communication. Voice pitch height, the perceptual correlate of fundamental frequency, is higher in females and provides a cue for gender discrimination. However, male and female voices are also differentiated by multiple other spectral and temporal characteristics, including mean formant frequency and spectral flux. The robust perceptual segregation of male and female voices is thought to result from processing the combination of discriminating features, which in neural terms may correspond to early sound object analysis occurring in non-primary auditory cortex. However, the specific mechanism for gender perception has been unclear. Here, using functional magnetic resonance imaging, we show that discrete sites in non-primary auditory cortex are differentially activated by male and female voices, with female voices consistently evoking greater activation in the upper bank of the superior temporal sulcus and posterior superior temporal plane. This finding was observed at the individual subject-level in all 24 subjects. The neural response was highly specific: no auditory regions were more activated by male than female voices. Further, the activation associated with female voices was 1) larger than can be accounted for by a sole effect of fundamental frequency, 2) not due to psychological attribution of female gender and 3) unaffected by listener gender. These results demonstrate that male and female voices are represented as distinct auditory objects in the human brain, with the mechanism for gender discrimination being a gender-dependent activation-level cue in non-primary auditory cortex. PMID- 25449747 TI - Probing region-specific microstructure of human cortical areas using high angular and spatial resolution diffusion MRI. AB - Regional heterogeneity in cortical cyto- and myeloarchitecture forms the structural basis of mapping of cortical areas in the human brain. In this study, we investigate the potential of diffusion MRI to probe the microstructure of cortical gray matter and its region-specific heterogeneity across cortical areas in the fixed human brain. High angular resolution diffusion imaging (HARDI) data at an isotropic resolution of 92-MUm and 30 diffusion-encoding directions were acquired using a 3D diffusion-weighted gradient-and-spin-echo sequence, from prefrontal (Brodmann area 9), primary motor (area 4), primary somatosensory (area 3b), and primary visual (area 17) cortical specimens (n=3 each) from three human subjects. Further, the diffusion MR findings in these cortical areas were compared with histological silver impregnation of the same specimens, in order to investigate the underlying architectonic features that constitute the microstructural basis of diffusion-driven contrasts in cortical gray matter. Our data reveal distinct and region-specific diffusion MR contrasts across the studied areas, allowing delineation of intracortical bands of tangential fibers in specific layers-layer I, layer VI, and the inner and outer bands of Baillarger. The findings of this work demonstrate unique sensitivity of diffusion MRI to differentiate region-specific cortical microstructure in the human brain, and will be useful for myeloarchitectonic mapping of cortical areas as well as to achieve an understanding of the basis of diffusion NMR contrasts in cortical gray matter. PMID- 25449749 TI - Extraversion mediates the relationship between structural variations in the dorsolateral prefrontal cortex and social well-being. AB - Social well-being reflects the appraisal of one's circumstance and functioning in society, which is crucial for individuals' mental and physical health. However, little is known about the neural processes associated with social well-being. In this study, we used voxel-based morphometry (VBM) to identify the brain regions underlying individual differences in social well-being, as measured by the Social Well-being Scale (SWBS), in a large sample of young healthy adults. We found that social well-being was negatively correlated with gray matter volume in left mid dorsolateral prefrontal cortex (mid-DLPFC) that is implicated in executive functioning, emotional regulation and social reasoning. The results remained significant even after controlling for the effect of socioeconomic status. Furthermore, although basic personality factors such as neuroticism, extraversion, and conscientiousness (as measured by the NEO Personality Inventory) all contributed to social well-being, only extraversion acted as a mediational mechanism underlying the association between the left mid-DLPFC volume and social well-being. Together, our findings provide the first evidence for the structural basis of individual differences in social well-being, and suggest that the personality trait of extraversion might play an important role in the acquisition and process of social well-being. PMID- 25449750 TI - Broadband Direct UVA irradiance measurement for clear skies evaluated using a smartphone. AB - UVA wavelengths (320-400 nm) have been implicated in recent studies to contribute to melanoma induction and skin photoaging in humans and damage to plants. The use of smartphones in UVA observations is a way to supplement measurements made by traditional radiometric and spectroradiometric technology. Although the smartphone image sensor is not capable of determining broadband UVA irradiances, these can be reconstructed from narrowband irradiances, which the smartphone, with narrowband and neutral density filters, can quantify with discrepancies not exceeding 5 %. Three models that reconstruct direct broadband clear sky UVA were developed from narrowband irradiances derived from smartphone image sensor pixel data with coefficients of determination of between 0.97 and 0.99. Reasonable accuracy and precision in determining the direct broadband UVA was maintained for observations made with solar zenith angles as high as 70 degrees . The developed method has the potential to increase the uptake of the measurement of broadband UVA irradiances. PMID- 25449751 TI - Innate immune sensing of nucleic acids from pathogens. AB - The innate immune system is important as the first line of defense to sense invading pathogens. Nucleic acids represent critical pathogen signatures that trigger a host proinflammatory immune response. Much progress has been made in understanding how DNA and RNA trigger host defense countermeasures, however, several aspects of how cytosolic nucleic acids are sensed remain unclear. This special issue reviews how the host innate immune system senses nucleic acids from Brucella abortus, Mycobacterium sp and Legionella pneumophila, viral DNA, the role of STING in DNA sensing and inflammatory diseases and the mechanism of viral RNA recognition by the small interfering RNA pathway in Drosophila melanogaster. PMID- 25449752 TI - The STING controlled cytosolic-DNA activated innate immune pathway and microbial disease. AB - The innate immune system is critically important for the primary sensing of invading pathogens. Over the past decade, the cellular sensors important for recognizing microbial entry into the host cell have been largely elucidated. These sensors, some of which are evolutionarily conserved, include the Toll-like receptor (TLR) and RIG-I-like helicase family (RLH) pathway that can recognize bacterial and viral non-self nucleic acid. In addition, a cellular sensor referred to as STING (for stimulator of interferon genes) has been shown to be critical for triggering host defense countermeasures, including stimulation of the adaptive immune response, following the detection of cytosolic DNA species. The STING pathway has now been shown to be critical for activating innate immune gene transcription in response to infection by DNA pathogens such as herpes simplex virus 1 (HSV1) as well as retroviruses. In addition, it is clear that chronic STING activation can also cause autoinflammatory disease manifested by self-DNA. Here we review recent developments in our understanding of STING function, including importance in the control of microbial disease. PMID- 25449753 TI - Inflammation-induced DNA damage and damage-induced inflammation: a vicious cycle. AB - Inflammation is the ultimate response to the constant challenges of the immune system by microbes, irritants or injury. The inflammatory cascade initiates with the recognition of microorganism-derived pathogen associated molecular patterns (PAMPs) and host cell-derived damage associated molecular patterns (DAMPs) by the pattern recognition receptors (PRRs). DNA as a molecular PAMP or DAMP is sensed directly or via specific binding proteins to instigate pro-inflammatory response. Some of these DNA binding proteins also participate in canonical DNA repair pathways and recognise damaged DNA to initiate DNA damage response. In this review we aim to capture the essence of the complex interplay between DNA damage response and the pro-inflammatory signalling through representative examples. PMID- 25449754 TI - Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: a systematic review and pooled analysis. AB - Radioembolization with yttrium-90 microspheres offers an alternative treatment option for patients with unresectable intrahepatic cholangiocarcinoma (ICC). However, the rarity and heterogeneity of ICC makes it difficult to draw firm conclusions about treatment efficacy. Therefore, the goal of the current study is to systematically review the existing literature surrounding treatment of unresectable ICCs with yttrium-90 microspheres and provide a comprehensive review of the current experience and clinical outcome of this treatment modality. We performed a comprehensive search of electronic databases for ICC treatment and identified 12 studies with relevant data regarding radioembolization therapy with yttrium-90 microspheres. Based on pooled analysis, the overall weighted median survival was 15.5 months. Tumour response based on radiological studies demonstrated a partial response in 28% and stable disease in 54% of patients at three months. Seven patients were able to be downstaged to surgical resection. The complication profile of radioembolization is similar to that of other intra arterial treatment modalities. Overall survival of patients with ICC after treatment with yttrium-90 microspheres is higher than historical survival rates and shows similar survival to those patients treated with systemic chemotherapy and/or trans-arterial chemoembolization therapy. Therefore, the use of yttrium-90 microspheres should be considered in the list of available treatment options for ICC. However, future randomized trials comparing systemic chemotherapy, TACE and local radiation will be required to identify the optimal treatment modality for unresectable ICC. PMID- 25449755 TI - Dynamics of the microbial community during continuous methane fermentation in continuously stirred tank reactors. AB - Methane fermentation is an attractive technology for the treatment of organic wastes and wastewaters. However, the process is difficult to control, and treatment rates and digestion efficiency require further optimization. Understanding the microbiology mechanisms of methane fermentation is of fundamental importance to improving this process. In this review, we summarize the dynamics of microbial communities in methane fermentation chemostats that are operated using completely stirred tank reactors (CSTRs). Each chemostat was supplied with one substrate as the sole carbon source. The substrates include acetate, propionate, butyrate, long-chain fatty acids, glycerol, protein, glucose, and starch. These carbon sources are general substrates and intermediates of methane fermentation. The factors that affect the structure of the microbial community are discussed. The carbon source, the final product, and the operation conditions appear to be the main factors that affect methane fermentation and determine the structure of the microbial community. Understanding the structure of the microbial community during methane fermentation will guide the design and operation of practical wastewater treatments. PMID- 25449757 TI - Halophilic and halotolerant actinomycetes from a marine saltern of Goa, India producing anti-bacterial metabolites. AB - Marine salterns are estuarine ecosystems in Goa, receiving inputs from riverine and marine waters. The Salinity fluctuates between 0 and 300 psu which makes it a conducive niche for salt tolerant and salt loving Actinomycetales. Halotolerant and halophilic Actinomycetales producing anti-bacterial metabolites were studied from crystallizer pond sediments of Ribandar saltern, Goa. Three media viz. Starch casein, R2A and Inorganic salt starch agar at four different salinities (35, 50, 75 and 100 psu) were used for isolation. R2A agar at 35 psu was the most preferred by hypersaline actinomycetes. The dominant group was halotolerant Streptomyces spp. others being rare actinomycetes viz. Nocardiopsis, Micromonospora and Kocuria spp. More than 50% of the isolates showed anti bacterial activity against one or more of the fifteen human pathogens tested. Eight strains from 4 genera showed consistent anti-bacterial activity and studied in detail. Most halotolerant isolates grew from 0 to 75 psu, with optimum antibiotic production at 35 psu whereas halophiles grew at 20 to 100 psu with optimum antibiotic production at 35 psu. Four Streptomyces strains showed multiple inhibition against test organisms while four rare actinomycetes were specific in their inhibitory activity. This is the first report of a halophilic Kocuria sp., Nocardiopsis sp., and halotolerant Micromonospora sp. producing anti bacterial compound(s) against Staphylococcus aureus, Staphylococcus citreus, and Vibrio cholerae, respectively. Sequential extraction with varying polarity of organic solvents showed that the extracts inhibited different test pathogens. These results suggest that halophilic and halotolerant actinomycetes from marine salterns are a potential source of anti-bacterial compounds. PMID- 25449756 TI - Characterization of cucumber violaxanthin de-epoxidase gene promoter in Arabidopsis. AB - Violaxanthin de-epoxidase (VDE) activates the dissipation of excessive light energy as heat and protects the photosynthetic apparatus from photo-damage. Here we quantitatively analyzed the expression characteristics of cucumber violaxanthin de-epoxidase (CsVDE) promoter using the 1983 bp upstream fragment, and a series of 5'-truncated fragments, to drive beta-glucuronidase (GUS) expression in Arabidopsis. The activity of CsVDE promoter was altered by hormones and abiotic stresses are positively by indole-3-acetic acid and gibberellin, but negatively by polyethylene glycol, abscisic acid, salicylic acid, mannitol and sodium chloride. Quantitative analysis by fluorometry of GUS activity and histochemical localization showed that the CsVDE promoter is green tissue specific. A 334 bp fragment was sufficient to drive the expression of GUS to the same extent as the longest 1983 bp one in green tissue-specific manner. Further analysis of the promoter led to the discovery of one enhancer region and two silencer regions. The activities of GUS driven by the CsVDE promoter fragments were increased when plants were exposed to high light for 4 h, but decreased by 8 h illumination. The high light responsive elements were defined in two positions. The normal-level light-responsive elements were also found in different regions. PMID- 25449758 TI - Production of initial-stage eukaryotic N-glycan and its protein glycosylation in Escherichia coli. AB - N-Glycosylation is a ubiquitous protein post-translational modification mechanism in eukaryotes. In this work, a synthetic pathway containing glycosyltransferases from Saccharomyces cerevisiae was introduced to Escherichia coli to synthesize lipid-linked mannosyl-chitobiose (Man-GlcNAc2) and trimannosyl-chitobiose (Man3 GlcNAc2). Transfer of Man3-GlcNAc2 onto a model periplasmic protein occurred in the engineered E. coli cell using oligosaccharyltransferase PglB from Campylobacter jejuni. Mass spectrometric analysis of the fluorescently labeled N glycan indicated a glycan signal composed of 2 HexNAc and 3 Hex residues. The reversed-phase HPLC analysis suggested that the Hex residues were alpha1,3-, alpha1,6- and beta1,4-linked mannoses. These results indicated that the constructed system synthesizes a Man3-GlcNAc2, identical to that observed in an early eukaryotic dolichol pathway. Finally, glycopeptide mass spectrometry confirmed the transfer of the assembled glycan moiety onto an engineered glycosylation motif of recombinant maltose binding protein. Surprisingly, the Man3-GlcNAc2 structure but not Man-GlcNAc2 was transferred onto maltose binding protein. This work showed that PglB protein might be able to accommodate the transfer of the further engineered glycan with greater complexity. PMID- 25449760 TI - Titer of trastuzumab produced by a Chinese hamster ovary cell line is associated with tricarboxylic acid cycle activity rather than lactate metabolism. AB - Achieving high productivity and quality is the final goal of therapeutic antibody development, but the productivity and quality of antibodies are known to be substantially dependent on the nature of the cell lines expressing the antibodies. We characterized two contrasting cell lines that produce trastuzumab, namely cell line A with a high titer and a low aggregate content and cell line B with a low titer and a high aggregate content to identify the causes of the differences. We observed the following differences: cell growth (A > B), proportion of defucosylated oligosaccharides on antibodies (A < B), and proportion of covalent antibody aggregates (A > B). Our results suggest that the high monoclonal antibody (mAb) titers in cell line A is associated with the high proliferation and is not caused by the lactate metabolism shift (switching from lactate production to net lactate consumption). Rather, these differences can be accounted for by the following: levels of tricarboxylic acid cycle intermediates (A > B), ammonium ion levels (A <= B), and oxidative stress (A > B). PMID- 25449761 TI - [Evaluation and analysis of pain in chronic hemodialysis]. AB - AIM: Pain is an unpleasant experience that deeply affects patients' quality of life and emotional state. Pain's epidemiology and characteristics in chronic hemodialysis are not well known and insufficiently analysed. The aim of our study was to assess the prevalence, characteristics, impact and treatment of pain in our hemodialysis patients and determine its related associated factors. METHODS: We performed a cross-sectional study including 93 chronic hemodialysis patients. We collected demographic data as well as the aspects of the reported pain on the basis of the concise pain questionnaire, and finally inferred the risk factors related to pain occurrence. Chronic pain was defined as a pain that has existed for over three months. RESULTS: The prevalence of pain was 70.9% (n=66), mean age 55.3+/-13.3 years, sex ratio 30 males/36 females, mean duration of hemodialysis 82.4+/-57.29 (6-252) months. This pain was permanent, daily, intermittent and rare in respectively 9%, 28.7%, 48.4% and 13.6% of cases. It was mild, moderate, severe or unbearable in respectively 42.8%, 23.8%, 19% and 14.2% of cases. Pain was multifocal in 57.4% of cases. The most frequently reported pain sites were: shoulders (47.2%), head (41.2%), knee (34.5%) and back (20%). Thus, 53.8% of patients reported using analgesics, with a daily intake, frequent or rare in respectively 28%, 44% and 28% of cases. The comparison between the group of patients reporting pain to the one without pain complaints in univariate statistical analysis found that age, Charlson's score, interdialytic weight gain and the rate of two dialysis sessions per week were linked to pain occurrence. However, in multivariate analysis, only age remained as a pain-associated factor. CONCLUSION: Pain in chronic hemodialysis patients is a very common complaint. Therefore, it is necessary to assess it regularly, using a suitable questionnaire. PMID- 25449759 TI - Type 2C protein phosphatase Ptc6 participates in activation of the Slt2-mediated cell wall integrity pathway in Saccharomyces cerevisiae. AB - The phosphorylation status of cellular proteins results from an equilibrium between the activities of protein kinases and protein phosphatases (PPases). Reversible protein phosphorylation is an important aspect of signal transduction that regulate many biological processes in eukaryotic cells. The Saccharomyces cerevisiae genome encodes 40 PPases, including seven members of the protein phosphatase 2C subfamily (PTC1 to PTC7). In contrast to other PPases, the cellular roles of PTCs have not been investigated in detail. Here, we sought to determine the cellular role of PTC6 in S. cerevisiae with disruption of PTC genes. We found that cells with Deltaptc6 disruption were tolerant to the cell wall-damaging agents Congo red (CR) and calcofluor white (CFW); however, cells with simultaneous disruption of PTC1 and PTC6 were very sensitive to these agents. Thus, simultaneous disruption of PTC1 and PTC6 gave a synergistic response to cell wall damaging agents. The level of phosphorylated Slt2 increased significantly after CR treatment in Deltaptc1 cells and more so in Deltaptc1Deltaptc6 cells; therefore, deletion of PTC6 enhanced Slt2 phosphorylation in the Deltaptc1 disruptant. The level of transcription of KDX1 upon exposure to CR increased to a greater extent in the Deltaptc1Deltaptc6 double disruptant than the Deltaptc1 single disruptant. The Deltaptc1Deltaptc6 double disruptant cells showed normal vacuole formation under standard growth conditions, but fragmented vacuoles were present in the presence of CR or CFW. Our analyses indicate that S. cerevisiae PTC6 participates in the negative regulation of Slt2 phosphorylation and vacuole morphogenesis under cell wall stress conditions. PMID- 25449762 TI - [Vasopressin V2 receptor-related pathologies: congenital nephrogenic diabetes insipidus and nephrogenic syndrome of inappropiate antidiuresis]. AB - Congenital nephrogenic diabetes insipidus is a rare hereditary disease with mainly an X-linked inheritance (90% of the cases) but there are also autosomal recessive and dominant forms. Congenital nephrogenic diabetes insipidus is characterized by a resistance of the renal collecting duct to the action of the arginine vasopressin hormone responsible for the inability of the kidney to concentrate urine. The X-linked form is due to inactivating mutations of the vasopressin 2 receptor gene leading to a loss of function of the mutated receptors. Affected males are often symptomatic in the neonatal period with a lack of weight gain, dehydration and hypernatremia but mild phenotypes may also occur. Females carrying the mutation may be asymptomatic but, sometimes, severe polyuria is found due to the random X chromosome inactivation. The autosomal recessive and dominant forms, occurring in both genders, are linked to mutations in the aquaporin-2 gene. The treatment remains difficult, especially in infants, and is based on a low osmotic diet with increased water intake and the use of thiazides and indomethacin. The main goal is to avoid hypernatremic episodes and maintain a good hydration state. Potentially, specific treatment, in some cases of X-linked congenital nephrogenic diabetes insipidus, with pharmacological chaperones such as non-peptide vasopressin-2 receptor antagonists will be available in the future. Conversely, the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is linked to a constitutive activation of the V(2)-receptor due to activating mutations with clinical and biological features of inappropriate antidiuresis but with low or undetectable plasma arginine vasopressin hormone levels. PMID- 25449763 TI - [Uncontrolled hypertension in chronic kidney disease in patients from black Africa admitted in a renal unit: a retrospective analysis]. AB - The incidence of uncontrolled hypertension (HTN+) in CKD in nephrology could reflect the quality of the management of the patients in a primary care setting. The aim of the present study was to identify factors associated with HTN+ in CKD in order to elaborate a prevention strategy for the health professionals. A retrospective analysis of 479 incidents patients has been performed from 2012/1st to 2012/12th. Sixty-two percent had CKD HTN+. Eighty percent were at stages 4 and 5. Mean value of SBP was 166.5+/-32 mmHg and 96+/-27.3 mmHg for DBP. Mean age was 48.2+/-14.6 years. Mean GFR was 17.4+/-17.1 mL/min and no difference found between groups (17.4+/-17.6 mL/min in CKD HTN+ versus 17.5+/-16.3 mL/min in CKD HTN-, P < 0.9). Alcohol consumption was more in CKD HTN+ as compared to CKD HTN-, but not different between groups (37.2% in CKD HTN+ versus 27.6% in CKD HTN-; P < 0.09). Patients who were taking antihypertensive drugs were significantly more in the CKD HTN- than CKD HTN+ (22% in CKD HT+ versus 41.1% in CKD HTN-; P < 0.0001). Factors associated with HTN+ in CKD were antihypertensive therapy (OR = 0.39; CI 0.20-0.75; P < 0.005); alcohol (OR = 2.19; CI 1.09-4.37; P < 0.02). BP was similar in HN and non-HN patients (173.0+/-26.9 mmHg versus 174.7+/-33.7 mmHg; P = 0.75). But kidney function was a little better in HN (16.9+/-17.7 mL/min and 20.95+/-18.5 mL/min; P < 0.1). Factors associated positively with HN/HTN+ were: history of HTN and age. Factors associated negatively with HN/HTN+ were: history of diabetes and CKD stage. PMID- 25449764 TI - Epimerization of C-22 in (25R)- and (25S)-sapogenins. AB - Most of the naturally occurring steroidal sapogenins (C-23 non-substituted frameworks), possess an R configuration at the spiro C-22 center. Their C-22 epimers have become important targets in biological research. This paper describes a procedure to obtain 22S-spirostans from 22R-sapogenins and pseudosapogenin skeletons, without affecting the chirality at either C-25 or C 20. An optimal way to synthesize the pair of C-22 stereoisomers of 23 acetyldiosgenin is also reported. The latter was obtained from a 22,26 epoxycholestane or from 23-acetylfurostene compounds. PMID- 25449766 TI - Karataviosides G-K, five new bisdesmosidic steroidal glycosides from the bulbs of Allium karataviense. AB - We have analyzed the steroidal glycosides in Allium karataviense bulbs, and isolated five new bisdesmosidic steroidal glycosides: karataviosides G-K (1-5). The structures were elucidated by extensive spectroscopic analysis, including 2D NMR and enzymatic and hydrolytic cleavage. Karatavioside G (1) is an entirely novel furostanol glycoside, which has an O-beta-d-glucopyranosyl-(1->6)-beta-d glucopyranosyl-(1->6)-beta-d-glucopyranosyl unit at C-26 of the aglycone. Although a variety of cholestanol glycosides have been isolated, mainly from Liliaceae and Agavaceae, karataviosides J and K (4 and 5) are also notable because they are the most polar cholestanol bisdesmosides discovered, in which a lycotetraose is attached to C-3 of the aglycone, and a glucose or O-glucosyl-(1 >3)-glucose is attached at C-16. The isolated glycosides were also evaluated for their cytotoxic activities against cultured tumor cell lines. PMID- 25449765 TI - Minor cytotoxic cardenolide glycosides from the root of Streptocaulon juventas. AB - In order to determine new minor natural cardenolide glycosides as cytotoxic candidates, we isolated six new cardenolide glycosides together with four known ones, which had never previously been reported in the genus, by bioassay-guided separation from the 75% ethanol extract of Streptocaulon juventas (Asclepiadaceae). Their structures were elucidated on the basis of spectroscopic analysis, including homo- and heteronuclear correlation NMR experiments (COSY, HSQC and HMBC). The cytotoxic activities of these compounds were evaluated against A549 and NCI-H460 cell lines by MTT assay and compound 7 exhibited inhibitory activity against the two cell lines, while other compounds displayed a range of inhibitory activity against NCI-H460 and A549 cells. Their structure activity relationships were also discussed. PMID- 25449767 TI - Protective effect of dienogest on chemotherapy-induced reduced fertility in female rats. AB - Reduced fertility is one of the main long-term consequences of chemotherapy given for lymphoma, leukemia, and other malignancies in young women. We examined with a female rat model whether and how dienogest, a fourth-generation progestin, modulates reduced fertility following exposure to gonadotoxic chemotherapy. Female rats were administered cyclophosphamide with or without GnRH agonist and different concentrations of dienogest for 20 days. Animals were sacrificed on Day 29, and the numbers of follicle at primordial, preantral and antral stage in the ovaries were counted histologically. Rats treated with sterile saline solution (as control), cyclophosphamide, cyclophosphamide plus GnRH agonist, and cyclophosphamide plus dienogest were also mated with male rats to evaluate their fertility and pregnancy outcomes. Cyclophosphamide significantly reduced the number of primordial follicles, whereas dienogest suppressed depletion of primordial follicle pool induced by chemotherapy. Although the rats exposed to cyclophosphamide alone failed to deliver live births, co-treatment with dienogest improved the pregnancy outcomes of treated rats. The protective effect of dienogest on chemotherapy-induced ovarian damage and reduced fertility was comparable to that of GnRH agonist. The present results suggest that the co administration of dienogest and chemotherapy may be a useful strategy in preserving ovarian function and fertility in premenopausal women facing gonadotoxic chemotherapy. PMID- 25449768 TI - Non-classical effects of androgens on testes from neonatal rats. AB - The intratesticular testosterone concentration is high during the early postnatal period although the intracellular androgen receptor expression (iAR) is still absent in Sertoli cells (SCs). This study aimed to evaluate the non-classical effects of testosterone and epitestosterone on calcium uptake and the electrophysiological effects of testosterone (1MUM) on SCs from rats on postnatal day (pnd) 3 and 4 with lack of expression of the iAR. In addition, crosstalk on the electrophysiological effects of testosterone and epitestosterone with follicle stimulating hormone (FSH) in SCs from 15-day-old rats was evaluated. The isotope (45)Ca(2+) was utilized to evaluate the effects of testosterone and epitestosterone in calcium uptake. The membrane potential of SCs was recorded using a standard single microelectrode technique. No immunoreaction concerning the iAR was observed in SCs on pnd 3 and 4. At this age, both testosterone and epitestosterone increased the (45)Ca(2+) uptake. Testosterone promoted membrane potential depolarization of SCs on pnd 4. FSH application followed by testosterone and epitestosterone reduced the depolarization of the two hormones. Application of epitestosterone 5 min after FSH resulted in a delay of epitestosterone-promoted depolarization. The cell resistance was also reduced. Thus, in SCs from neonatal Wistar rats, both testosterone and epitestosterone act through a non-classical mechanism stimulating calcium uptake in whole testes, and testosterone produces a depolarizing effect on SC membranes. Testosterone and epitestosterone stimulates non-classical actions via a membrane mechanism, which is independent of iAR. FSH and testosterone/epitestosterone affect each other's electrophysiological responses suggesting crosstalk between the intracellular signaling pathways. PMID- 25449769 TI - LC-MS(n) characterization of steroidal saponins in Helleborus niger L. roots and their conversion products during fermentation. AB - Steroidal saponins comprise a substantial part of the secondary metabolite spectrum in the medicinal plant Helleborus niger L. (black hellebore). The saponin fraction from the roots was investigated by LC-MS(n) resulting in 38 saponins and beta-ecdysone. Nine diosgenyl-type glycosides, mainly furostanols consisting of the aglycones diosgenin, macranthogenin, sceptrumgenin, and sarsasapogenin were accompanied by 5 diosgenyl-type saponins exhibiting an aglycone with an additional OH group. However, the most relevant compounds were 24 acetylated polyhydroxy saponins including hellebosaponins A and D. The enzymes glucuronidase, beta-glucosidase, and pectinase were used to obtain an idea on potential fermentative transformation reactions by incubation of the isolated model saponins macranthosid I and hellebosaponin A. In a second step, aqueous H. niger extracts containing a much greater range of saponins were monitored during fermentation and 12months of storage. The metabolites were examined and assigned by LC-MS(n) and targeted extracted ion current (EIC) scan analyses. Good agreement was found among the results from the model compounds and the whole aqueous fermented extracts. The native diosgenyl-type furostanol saponins were converted to spirostanols under scission of hexoses. Alteration of the acetylated polyhydroxy saponins, exclusively spirostanols, took place following cleavage of acetyl groups and terminal deoxyhexoses. Most interestingly, the pentoses of the sugar chain at C(1) were not affected. Conversion of acetylated polyhydroxy saponins resulted in a final structure type which was stable and detectable, even after 12months of fermentation and storage. PMID- 25449770 TI - Cation channels are involved in brassinosteroid signalling in higher plants. AB - Brassinosteroids (BRs) are an important class of plant hormones with a multitude of functions. They have been intensively investigated for their biosynthesis, distribution and physiological functions. The aim of this study was to examine possible effects of BRs on the plant plasma membrane cation conductances and Ca(2+) signalling. The wheat root protoplasts (tested by patch-clamping) and excised arabidopsis roots (analysed by Ca(2+)-aequorin chemiluminometry), were used. In the whole-cell plasma membrane patches, 24-epibrassinolide, 28 homobrassionolide or 24-epicastasterone (1 MUM) were applied exogenously. 24 Epicastasterone increased the activity of the K(+) efflux conductance in 50% of tested protoplasts while 24-epibrassonolide and 28-homobrassionolide did not modify the plasma membrane currents. Addition of 24-epicastasterone at the cytosolic side (to the pipette solution) resulted in dramatic stimulation of a time-dependent K(+) efflux current (in 30% of protoplasts) and an activation of Ca(2+) influx currents (in 30% of protoplasts). Gadolinium ions, which are blockers of cation channels, inhibited the 24-epicastasterone-induced cation channel activities. In Arabidopsis thaliana plants constitutively expressing aequorin, exogenous 24-epibrassonolide, 28-homobrassionolide and 24 epicastasterone induced a transient elevation of the cytosolic free Ca(2+), which was inhibited by Gd(3+) and mediated by Ca(2+) influx from the bathing solution. In Ca(2+)-aequorin tests, 10 MUM of exogenous BRs was the minimal concentration at which statistically significant changes of the cytosolic Ca(2+) were observed. In conclusion, the obtained results suggest that the plasma membrane of root cells contains the brassinosteroid-activated cation-permeable channels, which can probably be involved in rapid regulation of the K(+) homeostasis and Ca(2+) signalling. PMID- 25449771 TI - Use of proper diagnostic methods will provide more reliable results. PMID- 25449772 TI - Cutamesine Overcomes REM Sleep Deprivation-Induced Memory Loss: Relationship to Sigma-1 Receptor Occupancy. AB - PURPOSE: Rapid eye movement (REM) sleep deprivation (SD) decreases cerebral sigma 1 receptor expression and causes cognitive deficits. Sigma-1 agonists are cognitive enhancers. Here, we investigate the effect of cutamesine treatment in the REM SD model. PROCEDURES: Sigma-1 receptor occupancy (RO) in the rat brain by cutamesine was determined using 1-[2-(3,4-dimethoxyphenethyl)]-4-(3 phenylpropyl)piperazine ([(11)C]SA4503) and positron emission tomography (PET), and tissue cutamesine levels were measured by ultra performance liquid chromatography (UPLC)-MS. RO was calculated from a Cunningham-Lassen plot, based on the total distribution volume of [(11)C]SA4503 determined by Logan graphical analysis. Cognitive performance was assessed using the passive avoidance (PA) test. RESULTS: Cutamesine at a dose of 1.0 mg/kg reversed REM SD-induced cognitive deficit and occupied 92 % of the sigma-1 receptor population. A lower dose (0.3 mg/kg) occupied 88 % of the receptors but did not significantly improve cognition. CONCLUSION: The anti-amnesic effect of cutamesine in this animal model may be related to longer exposure at a higher dose and/or drug binding to secondary targets. PMID- 25449773 TI - CD146 mediates VEGF-induced melanoma cell extravasation through FAK activation. AB - CD146 is an adhesion molecule expressed by both melanoma and endothelial cells and thus is well positioned to control melanoma extravasation. Nevertheless, during melanoma metastasis, the involvement of CD146 expressed within tumor microenvironment has never been analyzed. To investigate whether host CD146 mediates the extravasation of melanoma cells across the endothelium, we generated CD146 KO mice. We demonstrated that host CD146 did not affect melanoma growth or tumor angiogenesis but promoted hematogenous melanoma metastasis to the lung. Accordingly, the survival of CD146-deficient mice was markedly prolonged during melanoma metastasis. Interestingly, vascular endothelial growth factor-induced vascular permeability was significantly decreased in CD146 KO mice. We also provided evidence that VEGF-induced transendothelial migration of melanoma cells was significantly reduced across CD146 KO lung microvascular endothelial cells (LMEC). CD146 deficiency decreased the expression of VEGFR-2/Ve-cadherin and altered focal adhesion kinase (FAK) activation in response to VEGF. In addition, inhibition of FAK phosphorylation reduced transmigration of B16 melanoma cells across WT LMEC at the same level that across CD146 KO LMEC. Altogether, we propose a novel mechanism involving the VEGF/CD146/FAK/Ve-cadherin network in melanoma extravasation across the vessel barrier that identifies CD146-targeted therapy as a potential strategy for the treatment of melanoma metastasis. PMID- 25449774 TI - SAHA triggered MET activation contributes to SAHA tolerance in solid cancer cells. AB - Although SAHA is approved for the treatment of cutaneous T-cell lymphoma by the U.S. Food and Drug Administration, clinical trials using SAHA as a monotherapy or in combination with other chemotherapeutic agents in solid tumors have not met with success, and the mechanisms of tolerance remain unknown. In this study, using the prostate cancer cell line PC3 and the non-small lung cancer cell line A549, which have limited sensitivity to SAHA, we found that SAHA triggered MET and AKT phosphorylation at clinical concentrations. siRNA silencing of MET enhanced SAHA induced apoptosis in PC3 and A549 cells. However, MET protein expression and HGF secretion were not affected by SAHA, suggesting that the SAHA induced MET activation was not due to MET over-expression or HGF paracrine secretion. However, mRNA and protein expression of the laminin receptor integrin alpha5beta1 was up-regulated by SAHA prior to MET activation. Silencing of integrin alpha5beta1 abolished SAHA-triggered MET phosphorylation, suggesting the involvement of integrin alpha5beta1 in MET activation. Further, the combination of SAHA and XL184 resulted in a synergistic induction of cancer cell apoptosis and a synergistic inhibition of tumor growth. These data indicate that SAHA triggered MET activation in an HGF independent manner. This effect is partially involved in the resistance to SAHA in solid cancers, warranting further clinical investigation into combining SAHA with MET inhibitors in solid cancer treatment. PMID- 25449775 TI - In vivo molecular imaging of gastric cancer in human-murine xenograft models with confocal laser endomicroscopy using a tumor vascular homing peptide. AB - The early detection of premalignant lesions and cancers are very important for improving the survival of patients with gastric malignancies. Confocal laser endomicroscopy (CLE) is a novel imaging tool for achieving real-time microscopy during the ongoing endoscopy at subcellular resolution. In the present study, to evaluate the feasibility of real-time molecular imaging of GEBP11 by CLE in gastric cancer, CLE was performed on two types of tumor-bearing mice models, as well as surgical specimens of patients with gastric cancer, after the application of GEBP11. A whole-body fluorescent imaging device was first used to screen for the strongest specific fluorescent signal in xenograft models. Next, the tumor sites, as well as human tissues, were scanned with CLE. After this, targeted specimens were obtained for fluorescence microscopy and histology. We confirmed that GEBP11 could specifically bind to co-HUVECs by means of CLE in cell experiments. Thereafter, a specific signal was observed in both subcutaneous and orthotopic xenograft models in vivo after the injection of FITC-GEBP11 via tail vein, whereas the group injected with FITC-URP showed no fluorescent signals. In human tissues, a specific signal of GEBP11 was observed in 26/28 neoplastic specimens and in 8/28 samples of non-neoplastic specimens from the patients (p < 0.01). The findings from ex vivo immunofluorescence microscopy of cryostat sections correlated well with that obtained by CLE. These findings indicate that the peptide, GEBP11, might be a potential candidate for the molecular imaging of gastric cancer. PMID- 25449776 TI - The inhibitor of differentiation isoform Id1b, generated by alternative splicing, maintains cell quiescence and confers self-renewal and cancer stem cell-like properties. AB - Id1 has been shown to play a critical role in tumorigenesis and angiogenesis. Moreover, recent reports have involved Id1 in the maintenance of cancer stem cell features in some tumor types. The Id1 gene generates two isoforms through alternative splicing: Id1a and Id1b. We have investigated the role of each isoform in cancer development. Using lentiviral systems we modified the endogenous expression of each of these isoforms in cancer cells and analyzed their biological effect both in vitro and in vivo. Overexpression of Id1b in murine CT26 and 3LL cells caused a G0/G1 cell cycle arrest and reduced proliferation, clonogenicity and phospho-ERK1/2 levels, while increasing p27 levels. High levels of Id1a had an opposite effect and the proportion of cells in the S phase increased significantly. In vivo models confirmed the inhibitory role of Id1b in primary tumor growth and metastasis. Through microarray analysis we found that the cancer stem cell (CSC) markers ALDH1A1 and Notch-1 were up regulated specifically in Id1b-overexpressing cells. By using qPCR we also found overexpression of Sca-1, Tert, Sox-2 and Oct-4 in these cells. Increased levels of Id1b promoted self-renewal and CSC-like properties, as shown by their high capacity for developing secondary tumorspheres and retaining the PKH26 dye. The acquisition of CSC phenotype was confirmed in human PC-3 cells that overexpressed Id1b. Our results show that Id1b maintains cells in a quiescent state and promotes self-renewal and CSC-like features. On the contrary, Id1a promotes cell proliferation. PMID- 25449777 TI - Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer. AB - We previously reported that activin produces a signal with a tumor suppressive role in pancreatic cancer (PC). Here, the association between plasma activin A and survival in patients with advanced PC was investigated. Contrary to our expectations, however, patients with high plasma activin A levels had a significantly shorter survival period than those with low levels (median survival, 314 days vs. 482 days, P = 0.034). The cellular growth of the MIA PaCa 2 cell line was greatly enhanced by activin A via non-SMAD pathways. The cellular growth and colony formation of an INHBA (beta subunit of inhibin)-overexpressed cell line were also enhanced. In a xenograft study, INHBA-overexpressed cells tended to result in a larger tumor volume, compared with a control. The bodyweights of mice inoculated with INHBA-overexpressed cells decreased dramatically, and these mice all died at an early stage, suggesting the occurrence of activin-induced cachexia. Our findings indicated that the activin signal can promote cancer progression in a subset of PC and might be involved in cachexia. The activin signal might be a novel target for the treatment of PC. PMID- 25449778 TI - Circulating tumour cells and lung microvascular tumour cell retention in patients with metastatic breast and cervical cancer. AB - We have shown that in up to half of the patients with metastatic breast cancer (MBC), higher numbers of circulating tumour cells (CTCs) are present in the central venous blood (CVB) compared to the peripheral venous blood (PVB), suggesting that the lungs might retain a substantial number of CTCs. Here we report the presence of tumour cell emboli (TCE) in the microvasculature of the lungs in three out of eight patients with MBC and one patient with metastatic cervical carcinoma who had markedly elevated numbers of CTCs in the blood. All these patients suffered from symptomatic dyspnoea not easily attributable to other causes. No TCE were observed in five patients with MBC and elevated CTC counts and three patients with MBC who had low CTC counts (<5/7.5 ml). To investigate whether CTCs derived from CVB or PVB exhibit different transcriptional characteristics that might explain selective CTC retention, paired CTC samples from CVB and PVB of 12 patients with advanced breast cancer were subjected to gene expression analysis of 105 genes. No significant differences in CTC gene expression were observed. Together, these data suggest that potentially clinically relevant CTC retention in the microvasculature of the lung can occur in a subset of patients with advanced metastatic breast and cervical cancer, which seems to be transcriptionally non-selectively. PMID- 25449779 TI - A pathway-based approach for identifying biomarkers of tumor progression to trastuzumab-resistant breast cancer. AB - Although trastuzumab is a successful targeted therapy for breast cancer patients with tumors expressing HER2 (ERBB2), many patients eventually progress to drug resistance. Here, we identified subpathways differentially expressed between trastuzumab-resistant vs. -sensitive breast cancer cells, in conjunction with additional transcriptomic preclinical and clinical gene datasets, to rigorously identify overexpressed, resistance-associated genes. From this approach, we identified 32 genes reproducibly upregulated in trastuzumab resistance. 25 genes were upregulated in drug-resistant JIMT-1 cells, which also downregulated HER2 protein by >80% in the presence of trastuzumab. 24 genes were downregulated in trastuzumab-sensitive SKBR3 cells. Trastuzumab sensitivity was restored by siRNA knockdown of these genes in the resistant cells, and overexpression of 5 of the 25 genes was found in at least one of five refractory HER2 + breast cancer. In summary, our rigorous computational approach, followed by experimental validation, significantly implicate ATF4, CHEK2, ENAH, ICOSLG, and RAD51 as potential biomarkers of trastuzumab resistance. These results provide further proof-of-concept of our methodology for successfully identifying potential biomarkers and druggable signal pathways involved in tumor progression to drug resistance. PMID- 25449780 TI - Novel Hsp90 inhibitor FW-04-806 displays potent antitumor effects in HER2 positive breast cancer cells as a single agent or in combination with lapatinib. AB - Human epidermal growth factor receptor 2 (HER2), a member of the HER family of tyrosine kinases and a binding partner of Heat shock protein 90 (Hsp90), is found amplifies in approximately 25% breast cancers. Treatment of HER2+ breast cancers has been greatly improved in recent years, but the accompanying upregulation of HER3 induced by HER2 blockade has subdued the therapeutic effect. FW-04-806, a novel Hsp90 N-terminal inhibitor that disassociates the Hsp90/Cdc37/client complex and degrades Hsp90 clients, was studied alone or in combination with the EGFR/HER2 tyrosine kinase inhibitor lapatinib in HER2+ breast cancer cells. We found that FW-04-806 alone or with laptinib inhibits cell proliferation, induces cell apoptosis and reduces the total and activated HER3 levels in these cells, while lapatinib has been reported to increase HER3 expression followed HER2 inhibition. The combination of FW-04-806 and lapatinib showed synergistic reduction of HER2 expression and the downstream PI3K/Akt and Ras/MEK/ERK pathways, enhanced suppression of Akt-mediated FOXO3a inactivation and augmented antitumor efficacy on SKBR3 xenografts with a favorable toxicity profile, suggesting its viability as a combination therapy for clinical studies in HER2+ breast cancer patients. PMID- 25449781 TI - Ribosomal protein S3 regulates GLI2-mediated osteosarcoma invasion. AB - It has been reported that GLI2 promotes proliferation, migration, and invasion of mesenchymal stem cell and osteosarcoma cells. To examine the molecular mechanisms of GLI2-mediated osteosarcoma metastasis, we performed a microarray analysis. The gene encoding ribosomal protein S3 (RPS3) was identified as a target of GLI2. Real-time PCR revealed that RPS3 was upregulated in osteosarcoma cell lines compared with normal osteoblast cells. Knockdown of GLI2 decreased RPS3 expression, whereas forced expression of a constitutively active form of GLI2 upregulated the expression of RPS3. RPS3 knockdown by siRNA decreased the migration and invasion of osteosarcoma cells. Although forced expression of constitutively active GLI2 increased the migration of human mesenchymal stem cells, knockdown of RPS3 reduced the up-regulated migration. In contrast, forced expression of RPS3 increased migration and invasion of osteosarcoma cells. Moreover, reduction of migration by GLI2 knockdown was rescued by forced expression of RPS3. Immunohistochemical analysis showed that RPS3 expression was increased in primary osteosarcoma lesions with lung metastases compared with those without. These findings indicate that GLI2-RPS3 signaling may be a marker of invasive osteosarcoma and a therapeutic target for patients with osteosarcoma. PMID- 25449782 TI - MicroRNA-362-5p promotes tumor growth and metastasis by targeting CYLD in hepatocellular carcinoma. AB - MicroRNAs are increasingly recognized as playing important roles in hepatocellular carcinoma (HCC) tumorigenesis. Here we identified an essential role for miR-362-5p in the regulation of HCC development. We found that miR-362 5p was significantly up-regulated in HCCs and associated with HCC progression. Inhibition of miR-362-5p in HCC cells dramatically decreased cell proliferation, clonogenicity, migration and invasion in vitro as well as tumor growth and metastasis in vivo. We subsequently identified that CYLD was a target gene of miR 362-5p. Furthermore, knockdown of CYLD expression partially counteracted the tumor suppressive effects of miR-362-5p inhibitors. Finally, we have shown that miR-362-5p acts through CYLD to activate the NF-kappaB signaling pathway, which contributes to HCC progression. Taken together, our findings indicate that miR 362-5p belongs to a new class of oncomiR that regulates HCC cell aggressiveness, thus providing new insight into the molecular mechanisms underlying HCC development. This study also suggests that miR-362-5p may serve as a novel therapeutic target for miRNA based HCC therapy. PMID- 25449783 TI - Hypoxia-induced IL-32beta increases glycolysis in breast cancer cells. AB - IL-32beta is highly expressed and increases the migration and invasion of gastric, lung, and breast cancer cells. Since IL-32 enhances VEGF production under hypoxic conditions, whether IL-32beta is regulated by hypoxia was examined. Hypoxic conditions and a mimetic chemical CoCl2 enhanced IL-32beta production. When cells were treated with various inhibitors of ROS generation to prevent hypoxia-induced ROS function, IL-32beta production was suppressed by both NADPH oxidase and mitochondrial ROS inhibitors. IL-32beta translocated to the mitochondria under hypoxic conditions, where it was associated with mitochondrial biogenesis. Thus, whether hypoxia-induced IL-32beta is associated with oxidative phosphorylation (OXPHOS) or glycolysis was examined. Glycolysis under aerobic and anaerobic conditions is impaired in IL-32beta-depleted cells, and the hypoxia induced IL-32beta increased glycolysis through activation of lactate dehydrogenase. Src is also known to increase lactate dehydrogenase activity, and the hypoxia-induced IL-32beta was found to stimulate Src activation by inhibiting the dephosphorylation of Src. These findings revealed that a hypoxia-ROS-IL 32beta-Src-glycolysis pathway is associated with the regulation of cancer cell metabolism. PMID- 25449785 TI - Prognostic impact of COX-2 in non-small cell lung cancer: a comprehensive compartment-specific evaluation of tumor and stromal cell expression. AB - Cyclooxygenase-2 (COX-2) is an enzyme that has been extensively investigated as a prognostic marker in cancer. In non-small cell lung cancer (NSCLC) previous results regarding the prognostic impact of COX-2 expression are inconsistent. Therefore we evaluated the association between transcript levels and overall survival in nine publicly available gene expression data sets (total n = 1337) and determined in situ compartment-specific tumor and stromal cell protein expression in two independent cohorts (n = 616). Gene expression did not show any correlation with clinical parameters or with overall survival. Protein expression in tumor and stromal cells did not correlate with any clinical parameter or with overall survival in one of the analyzed cohorts, while a significant association of high stromal expression with longer survival was observed in both univariate and multivariate analysis in the other cohort. Stromal expression of COX-2 has not been separately evaluated in NSCLC previously and may be a subject of further investigation, whereas the presented findings from this comprehensive compartment specific evaluation clearly reject the hypothesis of COX-2 tumor cell expression having a prognostic value in NSCLC. PMID- 25449786 TI - CD133+ melanoma subpopulation acquired resistance to caffeic acid phenethyl ester induced apoptosis is attributed to the elevated expression of ABCB5: significance for melanoma treatment. AB - According to the cancer stem-like cell (CSC) hypothesis, neoplastic clones are maintained by a small fraction of cells with stem cell properties. Also, melanoma resistance to chemo- and radiotherapy is thought to be attributed to melanoma stem-like cells (MSCs). Caffeic acid phenethyl ester (CAPE) is a bioactive molecule, whose antitumor activity is approved in different tumor types. CAPE induced both apoptosis and E2F1 expression in CD133(-), but not in CD133(+) melanoma subpopulations. The resistance of CD133(+) melanoma subpopulation is attributed to the enhanced drug efflux mediated by ATP-binding cassette sub family B member 5 (ABCB5), since the knockdown of ABCB5 was found to sensitize CD133(+) cells to CAPE. CAPE-induced apoptosis is mediated by E2F1 as evidenced by the abrogation of apoptosis induced in response to the knockdown of E2F1. The functional analysis of E2F1 in CD133(+) melanoma subpopulation demonstrated the ability of E2F1 gene transfer to trigger apoptosis of CD133(+) cells and to enhance the activation of apoptosis signal-regulating kinase (ASK1), c-Jun N terminal kinase and p38, and the DNA-binding activities of the transcription factors AP-1 and p53. Also, the induction of E2F1 expression was found to enhance the expression of the pro-apoptotic proteins Bax, Noxa and Puma, and to suppress the anti-apoptotic protein Mcl-1. Using specific pharmacological inhibitors we could demonstrate that E2F1 overcomes the chemo-resistance of MSCs/CD133(+) cells by a mechanism mediated by both mitochondrial dysregulation and ER-stress dependent pathways. In conclusion, our data addresses the mechanisms of CAPE/E2F1 induced apoptosis of chemo-resistant CD133(+) melanoma subpopulation. PMID- 25449787 TI - Divalproex sodium enhances the anti-leukemic effects of imatinib in chronic myeloid leukemia cells partly through SIRT1. AB - Imatinib (IM) represents a breakthrough in the treatment of chronic myeloid leukemia (CML) by inhibiting the activity of Bcr-Abl tyrosine kinase. However, many patients exhibit resistance to IM in the clinic. Recent studies have indicated that sirtuin 1 (SIRT1), a class III histone deacetylase (HDAC), plays an important role in leukemogenesis. In addition, some HDAC inhibitors are being tested to determine their anti-cancer activities in clinical trials. Divalproex sodium (DVPX), a first-line treatment for epilepsy, is also a HDAC inhibitor. However, it is unclear whether the anti-leukemic effects of IM in combination with DVPX on CML cells are related to SIRT1. The aim of this study was to investigate the effects of IM in combination with DVPX on cell viability, apoptosis, and cell cycle arrest in CML cells and to explore the underlying mechanisms. It was found that DVPX enhanced IM-induced cell growth inhibition, apoptosis and cell cycle arrest in K562-S and K562-G cells. Surprisingly, the level of p-Bcr-Abl was similar in K562-S and K562-G cells. Moreover, IM combined with DVPX had no effects on the phosphorylation of Bcr-Abl and its downstream target STAT5. Further study revealed that SIRT1 expression was higher in K562-G cells compared with K562-S cells. DVPX enhanced the inhibitory effect of IM on SIRT1 expression in K562-S and K562-G cells. Furthermore, knockdown of SIRT1 promoted apoptosis of K562-G cells treated with IM and DVPX. These results indicate that DVPX may increase the sensitivity of CML cells to IM and reverse IM resistance by regulating SIRT1 expression. PMID- 25449788 TI - Practices related to late-onset sepsis in very low-birth weight preterm infants. AB - OBJECTIVE: To understand the practices related to late-onset sepsis (LOS) in the centers of the Brazilian Neonatal Research Network, and to propose strategies to reduce the incidence of LOS. METHODS: This was a cross-sectional descriptive multicenter study approved by the Ethics Committee. Three questionnaires regarding hand hygiene, vascular catheters, and diagnosis/treatment of LOS were sent to the coordinator of each center. The center with the lowest incidence of LOS was compared with the others. RESULTS: All 16 centers answered the questionnaires. Regarding hand hygiene, 87% use chlorhexidine or 70% alcohol; alcohol gel is used in 100%; 80% use bedside dispensers (50% had one dispenser for every two beds); practical training occurs in 100% and theoretical training in 70% of the centers, and 37% train once a year. Catheters: 94% have a protocol, and 75% have a line insertion team. Diagnosis/treatment: complete blood count and blood culture are used in 100%, PCR in 87%, hematological scores in 75%; oxacillin and aminoglycosides is the empirical therapy in 50% of centers. Characteristics of the center with lowest incidence of LOS: stricter hand hygiene; catheter insertion and maintenance groups; use of blood culture, PCR, and hematological score for diagnosis; empirical therapy with oxacillin and aminoglycoside. CONCLUSION: The knowledge of the practices of each center allowed for the identification of aspects to be improved as a strategy to reduce LOS, including: alcohol gel use, hand hygiene training, implementation of catheter teams, and wise use of antibiotic therapy. PMID- 25449789 TI - Prevalence and factors associated with stunting and excess weight in children aged 0-5 years from the Brazilian semi-arid region. AB - OBJECTIVE: To analyze the prevalence of excess weight and low height, and identify associated factors among children younger than five years. METHODS: Cross-census study. A total of 1,640 children from two municipalities in Piaui, Brazil were included. RESULTS: The prevalence of low height was 10.9% (95% CI: 9.3 to 12.4), inversely associated with mother's younger age and low level of education, lower socioeconomic status, mothers who had fewer than six prenatal consultations, and households that had more than one child younger than 5 years. Excess weight prevalence was 19.1% (95% CI: 17.2 to 21.0), and remained inversely associated with lower maternal age, low maternal education, and cesarean delivery. Stunting was greater in children aged between 12 and 23 months, while excess weight decreased with age. CONCLUSIONS: It is noteworthy that the stunting rate, although decreasing, is still high, while the prevalence of excess weight, even in this very poor area, already exceeds the expected percentage for a population with better socioeconomic level. PMID- 25449790 TI - Characterization of mortality in children with sickle cell disease diagnosed through the Newborn Screening Program. AB - OBJECTIVE: To characterize the deaths of 193 children with sickle cell disease screened by a neonatal program from 1998 to 2012 and contrast the initial years with the final years. METHODS: Deaths were identified by active surveillance of children absent to scheduled appointments in Blood Bank Clinical Centers (Hemominas). Clinical and epidemiological data came from death certificates, neonatal screening database, medical records, and family interviews. RESULTS: Between 1998 and 2012, 3,617,919 children were screened and 2,591 had sickle cell disease (1:1,400). There were 193 deaths (7.4%): 153 with SS/Sbeta(0) thalassemia, 34 SC and 6 Sbeta(+)thalassemia; 76.7% were younger than five years; 78% died in the hospital and 21% at home or in transit. The main causes of death were infection (45%), indeterminate (28%), and acute splenic sequestration (14%). In 46% of death certificates, the term "sickle cell" was not recorded. Seven-year death rate for children born between 1998 and 2005 was 5.43% versus 5.12% for those born between 2005 and 2012 (p = 0.72). Medical care was provided to 75% of children; 24% were unassisted. Medical care was provided within 6 hours of symptom onset in only half of the interviewed cases. In 40.5% of cases, death occurred within the first 24 hours. Low family income was recorded in 90% of cases, and illiteracy in 5%. CONCLUSIONS: Although comprehensive and effective, neonatal screening for sickle cell disease was not sufficient to significantly reduce mortality in a newborn screening program. Economic and social development and increase of the knowledge on sickle cell disease among health professionals and family are needed to overcome excessive mortality. PMID- 25449791 TI - Association of junk food consumption with high blood pressure and obesity in Iranian children and adolescents: the CASPIAN-IV Study. AB - OBJECTIVE: This study aimed to evaluate the association of junk food consumption with hypertension and obesity in a national sample of Iranian children and adolescents. METHODS: This nationwide study was conducted in 2011-2012 among 14,880 students, aged 6-18 years, selected by cluster sampling from 30 provinces. Weight, height, waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), as well as systolic and diastolic blood pressure (BP) were measured. Junk food was divided into four categories, including salty snacks, sweets, sweetened beverages, and fast food. Subjects reported how many times they had consumed each item (daily, weekly, and seldom). RESULTS: The intake of sweets was significantly associated with anthropometric indices and BP levels. Moreover, a significant association was found between fast food consumption, BP levels, and anthropometric indices (except for WHtR and WHR). Sweet beverages consumption was significantly associated with anthropometric indices; however, the consumption of salty snacks was only significantly associated with height, HC, and WHR. The risk of general obesity (OR: 0.75, 95% CI: 0.65-0.87) and abdominal obesity (OR: 0.81, 95% CI: 0.72-0.92) among participants who seldom consumed sweets was less than those who consumed daily. Also, the risk of general obesity (OR: 0.85, 95% CI: 0.74-0.97) among students that seldom consumed sweetened beverages was less than subjects who consumed them on a daily basis. CONCLUSION: It was found that junk food consumption increased the risk of both general and abdominal obesity; therefore, consumption of junk food should be reduced via restricting TV advertisements and increasing taxes on junk foods. PMID- 25449784 TI - Cancer cells remodel themselves and vasculature to overcome the endothelial barrier. AB - Metastasis refers to the spread of cancer cells from a primary tumor to distant organs mostly via the bloodstream. During the metastatic process, cancer cells invade blood vessels to enter circulation, and later exit the vasculature at a distant site. Endothelial cells that line blood vessels normally serve as a barrier to the movement of cells into or out of the blood. It is thus critical to understand how metastatic cancer cells overcome the endothelial barrier. Epithelial cancer cells acquire increased motility and invasiveness through epithelial-to-mesenchymal transition (EMT), which enables them to move toward vasculature. Cancer cells also express a variety of adhesion molecules that allow them to attach to vascular endothelium. Finally, cancer cells secrete or induce growth factors and cytokines to actively prompt vascular hyperpermeability that compromises endothelial barrier function and facilitates transmigration of cancer cells through the vascular wall. Elucidation of the mechanisms underlying metastatic dissemination may help develop new anti-metastasis therapeutics. PMID- 25449792 TI - Association between the Brazilian Breastfeeding Network implementation and breastfeeding indicators. AB - OBJECTIVE: To estimate the association between the implementation of the Brazilian Breastfeeding Network and prevalence of breastfeeding in a medium-size city in southern Brazil. METHODS: This was a cross-sectional study involving 405 children under 1 year who participated in the second phase of the multivaccination campaign in 2012. Children's consumption of food on the day before the interview was obtained through interviews with mothers or guardians. The manager and one health professional from every health facility that joined the Network were interviewed in order to investigate the process of implementation of this initiative. The association between prevalence of breastfeeding and exclusive breastfeeding and adherence to the Network implementation process was tested using Poisson regression with robust variance. RESULTS: Multivariate analysis revealed that among the children assisted by health facilities who joined the Network and those attending services that did not adhere to this strategy, the prevalence of breastfeeding (74% and 70.4% among children under 1 year, respectively) and exclusive breastfeeding (43.3% and 38.1% among children under 6 months, respectively) did not differ significantly. Difficulties in implementing the Network, such as high turnover of professionals, not meeting the criteria for accreditation, and insufficient participation of tutors in the process were identified. CONCLUSION: Contrary to the hypothesis of this study, there was no significant association between the implementation of the Brazilian Breastfeeding Network and prevalence of breastfeeding and exclusive breastfeeding in the studied city. It is possible that the difficulties found in implementing the Network in this city have influenced this result. PMID- 25449793 TI - A template-free method for preparation of cobalt nanoparticles embedded in N doped carbon nanofibers with a hierarchical pore structure for oxygen reduction. AB - Designing and preparing porous materials without using any templates is a challenge. Herein, single-nozzle electrospinning technology coupled with post pyrolysis is applied to prepare cobalt nanoparticles embedded in N-doped carbon nanofibers with a hierarchical pore structure (HP-Co-NCNFs). The resultant HP-Co NCNFs have lengths up to several millimeters with an average diameter of 200 nm and possess abundant micro/meso/macropores on both the surface and within the fibers. Such a microstructure endows the surface area as high as 115 m(2) g(-1) . When used as an electrocatalyst for the oxygen reduction reaction (ORR), the HP Co-NCNFs exhibit outstanding electrochemical performance in terms of activity, methanol tolerance, and durability. The hierarchically porous structure and high surface area can effectively decrease the mass transport resistance and increase the exposed ORR active sites. The sufficient amount of exposed ORR active sites along with accessible transport channel and enhanced electrical conductivity may be responsible for the good electrocatalytic performance. PMID- 25449794 TI - L-DOPA-induced behavioral sensitization of motor activity in the MPTP-treated common marmoset as a Parkinson's disease model. AB - l-DOPA is the gold standard for treatment of Parkinson's disease (PD). However, the drug produces some serious side effects, including dyskinesia, which is characterized by repetitive involuntary movements-including chorea. In the present preclinical study using a nonhuman primate model, dyskinesia caused by repeated l-DOPA administration was investigated in the context of behavioral sensitization by objectively quantifying motor activity in the common marmoset of PD model (the Parkinsonian marmoset). Twelve male Parkinsonian marmosets previously treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and six intact male marmosets were used. The motor activity of each marmoset was measured using infrared sensors attached to each individual living cage. Parkinsonian marmosets (n=6) exhibited behavioral sensitization (enhanced motor activity) in 10weeks upon oral administration of l-DOPA (10mg/kg per day on 3days/week). These animals also exhibited dyskinesia characterized by repetitive rapid movements including chorea in 6-10weeks. Neither behavioral sensitization nor dyskinesia was observed in Parkinsonian marmosets given vehicle and in intact marmosets given l-DOPA at the same dose (both n=6 each). Behavioral sensitization was detected sensitively and objectively on motor activity only in Parkinsonian marmosets given repeated l-DOPA at a similar dose used in PD patients. The behavioral feature of the marmosets was dyskinesia similar to that of PD patients but appeared earlier than would be manifested in humans. In spite of statistically significant behavioral sensitization, some marmosets did not exhibit dyskinesia in the present limited l-DOPA administration period. Although both commonalities and differences may exist between behavioral sensitization and dyskinesia, behavioral sensitization is considered to be an objective, quantitative, sensitive and predictive measure of behavioral mechanism underlying dyskinesia in preclinical studies in evaluating compounds. PMID- 25449795 TI - Antidepressant-like activity of dehydrozingerone: involvement of the serotonergic and noradrenergic systems. AB - Dehydrozingerone (DHZ) is a phenolic compound isolated from ginger rhizomes (Zingiber officinale). It is known for its diverse spectrum of biological activities as an antioxidant, anti-inflammatory and antitumor compound. The present study was designed to assess the antidepressant effect of DHZ and the involvement of the monoaminergic system and to evaluate its in vitro antioxidant activity in the hippocampus, cortex and cerebellum of mice. For this study, the tail suspension test (TST), forced swim test (FST) and yohimbine lethality test were performed. DHZ administered orally 30min prior to testing reduced the immobility time in the TST (1-40mg/kg) and the FST (10-40mg/kg), with no change in locomotor activity in the open field test. The antidepressant-like effect of DHZ (1mg/kg) was prevented by ketanserin (1mg/kg, i.p.; a 5-HT2A/2C receptor antagonist), ondansetron (1mg/kg, i.p.; a 5-HT3 receptor antagonist), prazosin (1mg/kg, i.p., an alpha1-adrenoceptor antagonist) and yohimbine (1mg/kg, i.p., an alpha2-adrenoceptor antagonist) pretreatments. Furthermore, DHZ administered at doses of 10 and 20mg/kg increased the lethality of yohimbine (35mg/kg, i.p.). DHZ had antioxidant activity on in vitro lipid peroxidation induced by sodium nitroprusside in all brain regions tested. The results revealed that DHZ has a potent antidepressant effect, which seems to involve the serotonergic and noradrenergic systems. PMID- 25449796 TI - Hypothalamic control of seasonal changes in food intake and body weight. AB - Seasonal cycles of fattening and body weight reflecting changes in both food intake and energy expenditure are a core aspect of the biology of mammals that have evolved in temperate and arctic latitudes. Identifying the neuroendocrine mechanisms that underlie these cycles has provided new insights into the hypothalamic control of appetite and fuel oxidation. Surprisingly, seasonal cycles do not result from changes in the leptin-responsive and homeostatic pathways located in the mediobasal and lateral hypothalamus that regulate meal timing and compensatory responses to starvation or caloric restriction. Rather, they result from changes in tanycyte function, which locally regulates transport and metabolism of thyroid hormone and retinoic acid. These signals are crucial for the initial development of the brain, so it is hypothesized that seasonal neuroendocrine cycles reflect developmental mechanisms in the adult hypothalamus, manifest as changes in neurogenesis and plasticity of connections. PMID- 25449798 TI - E-cadherin's role in development, tissue homeostasis and disease: Insights from mouse models: Tissue-specific inactivation of the adhesion protein E-cadherin in mice reveals its functions in health and disease. AB - Recent studies uncovered critical roles of the adhesion protein E-cadherin in health and disease. Global inactivation of Cdh1, the gene encoding E-cadherin in mice, results in early embryonic lethality due to an inability to form the trophectodermal epithelium. To unravel E-cadherin's functions beyond development, numerous mouse lines with tissue-specific disruption of Cdh1 have been generated. The consequences of E-cadherin loss showed great variability depending on the tissue in question, ranging from nearly undetectable changes to a complete loss of tissue structure and function. This review focuses on these studies and discusses how they provided important insights into E-cadherin's role in cell adhesion, proliferation and differentiation, and its consequences for biological processes as epithelial-to-mesenchymal transition, vascularization, and carcinogenesis. Lastly, we present some perspectives and possible approaches for future research. PMID- 25449799 TI - Negative pressure wound therapy, silver coated foam dressing and conventional bandages in open wound treatment in dogs. A retrospective comparison of 50 paired cases. AB - OBJECTIVES: To evaluate negative pressure wound therapy (NPWT) for treatment of complicated wounds in dogs. STUDY TYPE: Retrospective multicentre study. MATERIALS AND METHODS: Dogs (n = 50) undergoing open wound treatment were classified according to treatment method used: bandage (Group A, n = 7), NPWT (Group B, n = 18), and foam dressing (Group C, n = 25). Pairs of patients matched based on wound conformation, localization, and underlying cause were compared between Group A and C (n = 7 pairs) and between groups B and C (n = 18 pairs) in terms of duration of previous treatment, time to closure, and complications. RESULTS: Signalment, antibiotic medications, antiseptic treatment, and bacterial status of wounds were comparable between groups. The duration of previous treatment was significantly higher in patients assigned to Group B (p = 0.04) compared to Group C, while no significant difference was found between groups A and B. Total time to wound closure was significantly shorter in Group C compared to Group A (p = 0.02) and in Group B compared to Group C (p = 0.003). Wounds treated with NPWT suffered significantly less complications (p = 0.008) and were significantly less septic during treatment (p = 0.016) than wounds treated with a foam dressing. CONCLUSION: This study shows that time to healing was halved in NPWT treated patients compared to foam dressing treated patients, which in turn healed faster than patients treated with conventional bandage, underlining the value of NPWT therapy for the treatment of complicated wounds. PMID- 25449797 TI - A novel method for inducing nerve growth via modulation of host resting potential: gap junction-mediated and serotonergic signaling mechanisms. AB - A major goal of regenerative medicine is to restore the function of damaged or missing organs through the implantation of bioengineered or donor-derived components. It is necessary to understand the signals and cues necessary for implanted structures to innervate the host, as organs devoid of neural connections provide little benefit to the patient. While developmental studies have identified neuronal pathfinding molecules required for proper patterning during embryogenesis, strategies to initiate innervation in structures transplanted at later times or alternate locations remain limited. Recent work has identified membrane resting potential of nerves as a key regulator of growth cone extension or arrest. Here, we identify a novel role of bioelectricity in the generation of axon guidance cues, showing that neurons read the electric topography of surrounding cells, and demonstrate these cues can be leveraged to initiate sensory organ transplant innervation. Grafts of fluorescently labeled embryological eye primordia were used to produce ectopic eyes in Xenopus laevis tadpoles. Depolarization of host tissues through anion channel activation or other means led to a striking hyperinnervation of the body by these ectopic eyes. A screen of possible transduction mechanisms identified serotonergic signaling to be essential for hyperinnervation to occur, and our molecular data suggest a possible model of bioelectrical control of the distribution of neurotransmitters that guides nerve growth. Together, these results identify the molecular components of bioelectrical signaling among cells that regulates axon guidance, and suggest novel biomedical and bioengineering strategies for triggering neuronal outgrowth using ion channel drugs already approved for human use. PMID- 25449800 TI - Intrathecal injection of a therapeutic gene-containing polyplex to treat spinal cord injury. AB - Spinal cord injury (SCI) is a serious clinical problem that suddenly deprives patients of neurologic function and drastically diminishes their quality of life. Gene introduction has the potential to be effective for various pathological states of SCI because various proteins can be produced just by modifying nucleic acid sequences. In addition, the sustainable protein expression allows to maintain its concentration at an effective level at the target site in the spinal cord. Here we propose an approach using a polyplex system composed of plasmid DNA (pDNA) and a cationic polymer, poly{N'-[N-(2-aminoethyl)-2 aminoethyl]aspartamide} [PAsp(DET)], that has high capacity to promote endosome escape and the long-term safety by self-catalytically degrading within a few days. We applied brain-derived neurotrophic factor (BDNF)-expressing pDNA for SCI treatment by intrathecal injection of PAsp(DET)/pDNA polyplex. A single administration of polyplex for experimental SCI provided sufficient therapeutic effects including prevention of neural cell death and enhancement of motor function recovery. This lasted for a few weeks after SCI, demonstrating the capability of this system to express BDNF in a safe and responsible manner for treatment of various pathological states in SCI. PMID- 25449801 TI - Ultrasound and microbubble mediated drug delivery: acoustic pressure as determinant for uptake via membrane pores or endocytosis. AB - Although promising results are achieved in ultrasound mediated drug delivery, its underlying biophysical mechanisms remain to be elucidated. Pore formation as well as endocytosis has been reported during ultrasound application. Due to the plethora of ultrasound settings used in literature, it is extremely difficult to draw conclusions on which mechanism is actually involved. To our knowledge, we are the first to show that acoustic pressure influences which route of drug uptake is addressed, by inducing different microbubble-cell interactions. To investigate this, FITC-dextrans were used as model drugs and their uptake was analyzed by flow cytometry. In fluorescence intensity plots, two subpopulations arose in cells with FITC-dextran uptake after ultrasound application, corresponding to cells having either low or high uptake. Following separation of the subpopulations by FACS sorting, confocal images indicated that the low uptake population showed endocytic uptake. The high uptake population represented uptake via pores. Moreover, the distribution of the subpopulations shifted to the high uptake population with increasing acoustic pressure. Real-time confocal recordings during ultrasound revealed that membrane deformation by microbubbles may be the trigger for endocytosis via mechanostimulation of the cytoskeleton. Pore formation was shown to be caused by microbubbles propelled towards the cell. These results provide a better insight in the role of acoustic pressure in microbubble-cell interactions and the possible consequences for drug uptake. In addition, it pinpoints the need for a more rational, microbubble behavior based choice of acoustic parameters in ultrasound mediated drug delivery experiments. PMID- 25449802 TI - Stealth CD44-targeted hyaluronic acid supramolecular nanoassemblies for doxorubicin delivery: probing the effect of uncovalent pegylation degree on cellular uptake and blood long circulation. AB - Stealth active targeting nanoparticles (NPs) usually include two types of ligand sites: ligand anchored on distal ends of the polyethylene glycol (PEG) and ligand buried under pegylated layer. The latter typical case is hyaluronic acid (HA) based NPs; however, there is little information available for the latter NPs about effect of the optimal density of surface PEG coating on the blood circulation time, cellular uptake and in vivo anticancer activity. Thus, in this study, in order to optimize the anticancer effects of HA-based NPs, we focus on how uncovalent pegylation degree modulates blood circulation time and cellular uptake of HA-based NPs. We firstly designed a new double-hydrophilic copolymer by conjugating HP-beta-cyclodextrin with HA, and this carrier was further pegylated with adamantyl-peg (ADA-PEG) to form inclusion complex HA-HPCD/ADA-PEG, termed as HCPs. The supramolecular nanoassemblies were fabricated by host-guest and polar interactions between HCPs and doxorubicin (Dox), with vitamin E succinate (VES) being a nanobridge. Despite the active recognition between HA and CD44 receptor, the cellular uptake and targeting efficiency of HA-NPs decreased with the increasing peg density, demonstrating HA was partly buried by high density peg coating. However, the high density of peg coating was beneficial to long circulation time, tumor biodistribution and anticancer activity in vivo. NPs with 5% peg coating had the optimal cellular targeting efficiency in vitro and anticancer effects in vivo. The findings suggest that balancing long circulation property and cellular uptake is important to achieve the optimal antitumor efficacy for pegylated HA-based NPs, and that PEG coating densities cannot be extended beyond a certain density for shielding effect without compromising the efficacy of hyaluronic acid targeted delivery. PMID- 25449803 TI - The topical administration of rhEGF-loaded nanostructured lipid carriers (rhEGF NLC) improves healing in a porcine full-thickness excisional wound model. AB - The development of an effective treatment able to reduce the healing time of chronic wounds is a major health care need. In this regard, our research group has recently demonstrated the in vivo effectiveness of the topical administration of rhEGF-loaded lipid nanoparticles in healing-impaired db/db mice. Here we report the effectiveness of rhEGF-NLC (rhEGF loaded nanostructured lipid carriers) in a more relevant preclinical model of wound healing, the porcine full thickness excisional wound model. The rhEGF-NLC showed a particle size of around 335nm, negative surface charge (-27mV) and a high encapsulation efficiency of 94%. rhEGF plasma levels were almost undetectable, suggesting that no systemic absorption occurred, which may minimise potential side effects and improve treatment safety. In vivo healing experiments carried out in large white pigs demonstrated that 20MUg of rhEGF-NLC topically administered twice a week increased the wound closure and percentage of healed wounds by day 25, compared with the same number of intralesional administrations of 75MUg free rhEGF and empty NLC. Moreover, rhEGF-NLC improved the wound healing quality expressed in terms of number of arranged microvasculature, fibroblast migration and proliferation, collagen deposition and evolution of the inflammatory response. Overall, these findings demonstrated that topically administered rhEGF-NLC may generate de novo intact skin after full thickness injury in a porcine model, thereby confirming their potential clinical application for the treatment of chronic wounds. PMID- 25449805 TI - A photosensitizer delivered by bispecific antibody redirected T lymphocytes enhances cytotoxicity against EpCAM-expressing carcinoma cells upon light irradiation. AB - Recently conducted clinical trials have provided impressive evidence that chemotherapy resistant metastatic melanoma and several hematological malignancies can be cured using adoptive T cell therapy or T cell-recruiting bispecific antibodies. However, a significant fraction of patients did not benefit from these treatments. Here we have evaluated the feasibility of a novel combination therapy which aims to further enhance the killing potential of bispecific antibody-redirected T lymphocytes by using these cells as targeted delivery system for photosensitizing agents. For a first in vitro proof-of-concept study, ex vivo activated human donor T cells were loaded with a poly(styrene sulfonate) (PSS)-complex of the model photosensitizer 5,10,15,20-tetrakis(3 hydroxyphenyl)porphyrin (mTHPP). In the absence of light and when loading with the water-soluble PSS/mTHPP-complex occurred at a tolerable concentration, viability and cytotoxic function of loaded T lymphocytes were not impaired. When "drug-enhanced" T cells were co-cultivated with EpCAM-expressing human carcinoma cells, mTHPP was transferred to target cells. Notably, in the presence of a bispecific antibody, which cross-links effector and target cells thereby inducing the cytolytic activity of cytotoxic T lymphocytes, significantly more photosensitizer was transferred. Consequently, upon irradiation of co-cultures, redirected drug-loaded T cells were more effective in killing A549 lung and SKOV 3 ovarian carcinoma cells than retargeted unloaded T lymphocytes. Particularly, the additive approach using redirected unloaded T cells in combination with appropriate amounts of separately applied PSS/mTHPP was less efficient as well. Thus, by loading T lymphocytes with a stimulus-sensitive anti-cancer drug, we were able to enhance the cytotoxic capacity of carrier cells. Photosensitizer boosted T cells could open new perspectives for adoptive T cell therapy as well as targeted photodynamic therapy. PMID- 25449806 TI - Mathematical model accurately predicts protein release from an affinity-based delivery system. AB - Affinity-based controlled release modulates the delivery of protein or small molecule therapeutics through transient dissociation/association. To understand which parameters can be used to tune release, we used a mathematical model based on simple binding kinetics. A comprehensive asymptotic analysis revealed three characteristic regimes for therapeutic release from affinity-based systems. These regimes can be controlled by diffusion or unbinding kinetics, and can exhibit release over either a single stage or two stages. This analysis fundamentally changes the way we think of controlling release from affinity-based systems and thereby explains some of the discrepancies in the literature on which parameters influence affinity-based release. The rate of protein release from affinity-based systems is determined by the balance of diffusion of the therapeutic agent through the hydrogel and the dissociation kinetics of the affinity pair. Equations for tuning protein release rate by altering the strength (KD) of the affinity interaction, the concentration of binding ligand in the system, the rate of dissociation (koff) of the complex, and the hydrogel size and geometry, are provided. We validated our model by collapsing the model simulations and the experimental data from a recently described affinity release system, to a single master curve. Importantly, this mathematical analysis can be applied to any single species affinity-based system to determine the parameters required for a desired release profile. PMID- 25449804 TI - Effect of surface chemistry on nanoparticle interaction with gastrointestinal mucus and distribution in the gastrointestinal tract following oral and rectal administration in the mouse. AB - It is believed that mucoadhesive surface properties on particles delivered to the gastrointestinal (GI) tract improve oral absorption or local targeting of various difficult-to-deliver drug classes. To test the effect of nanoparticle mucoadhesion on distribution of nanoparticles in the GI tract, we orally and rectally administered nano- and microparticles that we confirmed possessed surfaces that were either strongly mucoadhesive or non-mucoadhesive. We found that mucoadhesive particles (MAP) aggregated in mucus in the center of the GI lumen, far away from the absorptive epithelium, both in healthy mice and in a mouse model of ulcerative colitis (UC). In striking contrast, water absorption by the GI tract rapidly and uniformly transported non-mucoadhesive mucus-penetrating particles (MPP) to epithelial surfaces, including reaching the surfaces between villi in the small intestine. When using high gavage fluid volumes or injection into ligated intestinal loops, common methods for assessing oral drug and nanoparticle absorption, we found that both MAP and MPP became well-distributed throughout the intestine, indicating that the barrier properties of GI mucus were compromised. In the mouse colorectum, MPP penetrated into mucus in the deeply in folded surfaces to evenly coat the entire epithelial surface. Moreover, in a mouse model of UC, MPP were transported preferentially into the disrupted, ulcerated tissue. Our results suggest that delivering drugs in non-mucoadhesive MPP is likely to provide enhanced particle distribution, and thus drug delivery, in the GI tract, including to ulcerated tissues. PMID- 25449807 TI - Probing the extracellular diffusion of antibodies in brain using in vivo integrative optical imaging and ex vivo fluorescence imaging. AB - Antibody-based therapeutics exhibit great promise in the treatment of central nervous system (CNS) disorders given their unique customizable properties. Although several clinical trials have evaluated therapeutic antibodies for treatment of CNS disorders, success to date has likely been limited in part due to complex issues associated with antibody delivery to the brain and antibody distribution within the CNS compartment. Major obstacles to effective CNS delivery of full length immunoglobulin G (IgG) antibodies include transport across the blood-brain and blood-cerebrospinal fluid barriers. IgG diffusion within brain extracellular space (ECS) may also play a role in limiting central antibody distribution; however, IgG transport in brain ECS has not yet been explored using established in vivo methods. Here, we used real-time integrative optical imaging to measure the diffusion properties of fluorescently labeled, non targeted IgG after pressure injection in both free solution and in adult rat neocortex in vivo, revealing IgG diffusion in free medium is ~10-fold greater than in brain ECS. The pronounced hindered diffusion of IgG in brain ECS is likely due to a number of general factors associated with the brain microenvironment (e.g. ECS volume fraction and geometry/width) but also molecule specific factors such as IgG size, shape, charge and specific binding interactions with ECS components. Co-injection of labeled IgG with an excess of unlabeled Fc fragment yielded a small yet significant increase in the IgG effective diffusion coefficient in brain, suggesting that binding between the IgG Fc domain and endogenous Fc-specific receptors may contribute to the hindered mobility of IgG in brain ECS. Importantly, local IgG diffusion coefficients from integrative optical imaging were similar to those obtained from ex vivo fluorescence imaging of transport gradients across the pial brain surface following controlled intracisternal infusions in anesthetized animals. Taken together, our results confirm the importance of diffusive transport in the generation of whole brain distribution profiles after infusion into the cerebrospinal fluid, although convective transport in the perivascular spaces of cerebral blood vessels was also evident. Our quantitative in vivo diffusion measurements may allow for more accurate prediction of IgG brain distribution after intrathecal or intracerebroventricular infusion into the cerebrospinal fluid across different species, facilitating the evaluation of both new and existing strategies for CNS immunotherapy. PMID- 25449808 TI - Chitosan amphiphile coating of peptide nanofibres reduces liver uptake and delivers the peptide to the brain on intravenous administration. AB - The clinical development of neuropeptides has been limited by a combination of the short plasma half-life of these drugs and their ultimate failure to permeate the blood brain barrier. Peptide nanofibres have been used to deliver peptides across the blood brain barrier and in this work we demonstrate that the polymer coating of peptide nanofibres further enhances peptide delivery to the brain via the intravenous route. Leucine(5)-enkephalin (LENK) nanofibres formed from the LENK ester prodrug - tyrosinyl(1)palmitate-leucine(5)-enkephalin (TPLENK) were coated with the polymer - N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6 O-glycolchitosan (GCPQ) and injected intravenously. Peptide brain delivery was enhanced because the GCPQ coating on the peptide prodrug nanofibres, specifically enables the peptide prodrug to escape liver uptake, avoid enzymatic degradation to non-active sequences and thus enjoy a longer plasma half life. Plasma half life is increased 520%, liver AUC0-4 decreased by 54% and brain AUC0-4 increased by 47% as a result of the GCPQ coating. The increased brain levels of the GCPQ coated peptide prodrug nanofibres result in the pharmacological activity of the parent drug (LENK) being significantly increased. LENK itself is inactive on intravenous injection. PMID- 25449810 TI - Investigation of protein distribution in solid lipid particles and its impact on protein release using coherent anti-Stokes Raman scattering microscopy. AB - The aim of this study was to gain new insights into protein distribution in solid lipid microparticles (SLMs) and subsequent release mechanisms using a novel label free chemical imaging method, coherent anti-Stokes Raman scattering (CARS) microscopy. Lysozyme-loaded SLMs were prepared using different lipids with lysozyme incorporated either as an aqueous solution or as a solid powder. Lysozyme distribution in SLMs was investigated using CARS microscopy with supportive structural analysis using electron microscopy. The release of lysozyme from SLMs was investigated in a medium simulating the conditions in the human duodenum. Both preparation method and lipid excipient affected the lysozyme distribution and release from SLMs. Lysozyme resided in a hollow core within the SLMs when incorporated as an aqueous solution. In contrast, lysozyme incorporated as a solid was embedded in clusters in the solid lipid matrix, which required full lipolysis of the entire matrix to release lysozyme completely. Therefore, SLMs with lysozyme incorporated in an aqueous solution released lysozyme much faster than with lysozyme incorporated as a solid. In conclusion, CARS microscopy was an efficient and non-destructive method for elucidating the distribution of lysozyme in SLMs. The interpretation of protein distribution and release during lipolysis enabled elucidation of protein release mechanisms. In future, CARS microscopy analysis could facilitate development of a wide range of protein-lipid matrices with tailor-made controlled release properties. PMID- 25449809 TI - Encapsulation of beraprost sodium in nanoparticles: analysis of sustained release properties, targeting abilities and pharmacological activities in animal models of pulmonary arterial hypertension. AB - Prostaglandin I2 (PGI2) and its analogues (such as beraprost sodium, BPS) are beneficial for the treatment of pulmonary arterial hypertension (PAH). The encapsulation of BPS in nanoparticles to provide sustained release and targeting abilities would improve both the therapeutic effect of BPS on PAH and the quality of life of patients treated with this drug. BPS was encapsulated into nanoparticles prepared from a poly(lactic acid) homopolymer and monomethoxy poly(ethyleneglycol)-poly(lactide) block copolymer. The accumulation of nanoparticles in damaged pulmonary arteries was examined using fluorescence emitting rhodamine S-encapsulated nanoparticles. The monocrotaline-induced PAH rat model and the hypoxia-induced mouse model were used to examine the pharmacological activity of BPS-encapsulated nanoparticles. A nanoparticle, named BPS-NP, was selected among various types of BPS-encapsulated nanoparticles tested; this was based on the sustained release profile in vitro and blood clearance profile in vivo. Fluorescence-emitting rhodamine S-encapsulated nanoparticles were prepared in a similar manner to that of BPS-NP, and showed accumulation and prolonged residence in monocrotaline-damaged pulmonary peripheral arteries. Intravenous administration of BPS-NP (once per week, 20MUg/kg) protected against monocrotaline-induced pulmonary arterial remodeling and right ventricular hypertrophy. The extent of this protection was similar to that observed with oral administration (once per day, 100MUg/kg) of BPS alone. The once per week intravenous administration of BPS-NP (20MUg/kg) also exhibited an ameliorative effect on hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy. The beneficial effects of BPS-NP on PAH animal models seem to be mediated by its sustained release and tissue targeting profiles. BPS NP may be useful for the treatment of PAH patients due to reduced dosages and frequency of BPS administration. PMID- 25449812 TI - Mendelian randomization: present and future of epidemiological studies in cardiology. PMID- 25449811 TI - Early controlled release of peroxisome proliferator-activated receptor beta/delta agonist GW501516 improves diabetic wound healing through redox modulation of wound microenvironment. AB - Diabetic wounds are imbued with an early excessive and protracted reactive oxygen species production. Despite the studies supporting PPARbeta/delta as a valuable pharmacologic wound-healing target, the therapeutic potential of PPARbeta/delta agonist GW501516 (GW) as a wound healing drug was never investigated. Using topical application of polymer-encapsulated GW, we revealed that different drug release profiles can significantly influence the therapeutic efficacy of GW and consequently diabetic wound closure. We showed that double-layer encapsulated GW microparticles (PLLA:PLGA:GW) provided an earlier and sustained dose of GW to the wound and reduced the oxidative wound microenvironment to accelerate healing, in contrast to single-layered PLLA:GW microparticles. The underlying mechanism involved an early GW-mediated activation of PPARbeta/delta that stimulated GPx1 and catalase expression in fibroblasts. GPx1 and catalase scavenged excessive H2O2 accumulation in diabetic wound beds, prevented H2O2-induced ECM modification and facilitated keratinocyte migration. The microparticles with early and sustained rate of GW release had better therapeutic wound healing activity. The present study underscores the importance of drug release kinetics on the therapeutic efficacy of the drug and warrants investigations to better appreciate the full potential of controlled drug release. PMID- 25449814 TI - Current evidence for new oral anticoagulants in the treatment of nonvalvular atrial fibrillation: comparison of substudies. PMID- 25449813 TI - Implantable Cardioverter-defibrillator Therapy for Hypertrophic Cardiomyopathy: Usefulness in Primary and Secondary Prevention. AB - INTRODUCTION AND OBJECTIVES: Hypertrophic cardiomyopathy is a frequent cause of sudden death. Clinical practice guidelines indicate defibrillator implantation for primary prevention in patients with 1 or more risk factors and for secondary prevention in patients with a history of aborted sudden death or sustained ventricular arrhythmias. The aim of the present study was to analyze the follow up of patients who received an implantable defibrillator following the current guidelines in nonreferral centers for this disease. METHODS: This retrospective observational study included all patients who underwent defibrillator implantation between January 1996 and December 2012 in 3 centers in the province of Barcelona. RESULTS: The study included 69 patients (mean age [standard deviation], 44.8 [17] years; 79.3% men), 48 in primary prevention and 21 in secondary prevention. The mean number of risk factors per patient was 1.8 in the primary prevention group and 0.5 in the secondary prevention group (P=.029). The median follow-up duration was 40.5 months. The appropriate therapy rate was 32.7/100 patient-years in secondary prevention and 1.7/100 patient-years in primary prevention (P<.001). Overall mortality was 10.1%. Implant-related complications were experienced by 8.7% of patients, and 13% had inappropriate defibrillator discharges. CONCLUSIONS: In patients with a defibrillator for primary prevention, the appropriate therapy rate is extremely low, indicating the low predictive power of the current risk stratification criteria. PMID- 25449815 TI - Left Main Coronary Artery Atresia in an Asymptomatic Elderly Adult. PMID- 25449816 TI - Prediabetes, diabetes and left heart deformation. PMID- 25449817 TI - Thrombosis of a mechanical tricuspid valve prosthesis resolved with fibrinolysis. PMID- 25449818 TI - Coronary angioplasty with catheter extension following transcatheter aortic valve implantation. PMID- 25449819 TI - Comments on Long-term results of cryoballoon ablation in the treatment of atrial fibrillation in a low-volume center. Response. PMID- 25449820 TI - Physical activity and menopause-related quality of life - a population-based cross-sectional study. AB - The aim of the research was to study the association between engagement in the recommended level of physical activity and quality of life (QoL) among middle aged women. In total, 2606 Finnish women aged 49 years responded to a postal questionnaire on lifestyle, quality of life, and health, wherein QoL was assessed with a shorter version of the menopause-specific Women's Health Questionnaire (WHQ). Proportional odds ratios (PORs) from ordered logistic regression models were used to test the association between the physical-activity and WHQ domains or three quality-of-life variables. Physically inactive women had an increased probability of anxiety/depressed mood (POR 1.44; 95% confidence interval (CI) 1.26-1.65), of decreased well-being (POR 1.96; 95% CI 1.71-2.25), of somatic symptoms (POR 1.61; 95% CI 1.40-1.85), of memory/concentration problems (POR 1.48; 95% CI 1.29-1.70), and of vasomotor symptoms (POR 1.19; 95% CI 1.03-1.36) as compared to physically active women. Women with the recommended level of physical activity had a higher self-perceived health level, better relative health, and better global quality of life in relation to other women their age. Physically active women showed higher quality of life in four menopause-specific WHQ dimensions and in global quality of life when compared to inactive women. PMID- 25449821 TI - The impact of moderate wine consumption on health. AB - Wine is a traditional beverage that has been associated with both healthy and harmful effects. Conceptions like the so-called "French paradox" or the beneficial impact of the Mediterranean diet suggest benefit. Wine has a complex composition, which is affected by whether it is red or white or by other variables, like the variety of grapes or others. Alcohol and phenolic compounds have been attributed a participation in the benefits ascribed to wine. The case of alcohol has been extensively studied, but the key question is whether wine offers additional benefits. Resveratrol, a non-flavonoid compound, and quercetin, a flavonol, have received particular attention. There is much experimental work confirming a beneficial balance for both substances, particularly resveratrol, in various organs and systems. The pharmacological dosages used in many of those experiments have shed doubt, however, on the clinical translation of those findings. Clinical studies are limited by their observational nature as well as for the difficulties to abstract the benefits of wine from other confounders. Notwithstanding the doubts, there is reasonable unanimity in beneficial effects of moderate wine consumption in cardiovascular disease, diabetes, osteoporosis, maybe neurological diseases, and longevity. Observations are less enthusiastic in what refers to cancer. While considering these limitations, clinicians may spread the message that the balance of moderate wine consumption seems beneficial. PMID- 25449822 TI - A systematic review and meta-analysis of tai chi for treating type 2 diabetes. AB - The aim of this review was to update and critically evaluate the evidence from randomised clinical trials (RCTs) of tai chi for patients with type 2 diabetes mellitus (T2DM). Twelve databases were searched by August 2014. Fifteen RCTs met all of the inclusion criteria. One RCT compared the effects of tai chi with sham exercise and failed to show the effectiveness of tai chi on fasting blood glucose (FBG), or HbA1c. The other four RCTs tested the effects of tai chi compared with various types of exercise and the meta-analysis failed to show an FBG-lowering effect. Five RCTs compared the effects of tai chi with an anti-diabetic medication and the meta-analysis showed favourable effects of tai chi on FBG. One RCT showed the positive effects of tai chi plus standard care on HbA1c and FBG compared with standard care alone. Four RCTs compared the effects of tai chi to no treatment and the meta-analysis failed to show the positive effects of tai chi on HbA1c. Three RCTs reported superior effects of tai chi on quality of life. In conclusion, the existing trial evidence is not convincing enough to suggest that tai chi is effective for managing patients with T2DM. PMID- 25449823 TI - Growing evidence for topical mometasone fuoroate in the treatment of Vulvar Lichen Sclerosus. AB - Vulvar lichen sclerosus (VLS) is a chronic inflammatory disease with a huge impact on a person's quality of life. On the basis of the immunologic changes in VLS, treatment with a high potency topical corticosteroid is recommended. The currently available guidelines identified the ultra-potent corticosteroid clobetasol propionate 0.05% (CP) as the first-line recommended treatment but growing evidence supports the use of the potent corticosteroid mometasone furoate 0.1% (MMF). We reviewed the available studies assessing MMF in the treatment of VLS. Both non comparative and comparative studies were included in this review. Findings from clinical trials indicate that MMF is an effective and safe option in the treatment of VLS both in the active phase and in long-term maintenance treatment. Consistent with the findings from the comparative studies, MMF shows similar efficacy and safety to CP. PMID- 25449824 TI - Should placebo be used routinely for chronic pain in older people? AB - As research expands our understanding of underlying placebo mechanisms, interest turns to the clinical application of placebos. Whether placebos are appropriate and effective in the management of chronic pain in older people deserves considerable attention. The evidence suggests that adults of any age are responsive to placebos, and that placebo treatments can be effective for many conditions prevalent in older people. Though placebos in general already seem to be used with some regularity in medical practice, the use of placebos alone for chronic pain is probably unjustified unless other treatments are inadvisable or have been exhausted. However maximising the mechanisms that underpin placebo analgesia such as expectancy or the psychosocial context should be encouraged and would be considered a feature of good clinical practice. It would also be anticipated that older people may see an additional benefit with placebo treatments when such treatments reduce existing or planned medication regimes, as older people typically experience more comorbidities, increased susceptibility to adverse drug reactions, and altered pharmacological responses to drugs. Further research is still needed in placebo-related treatment paradigms for the management of chronic pain in older people. PMID- 25449825 TI - A systematic review of the longitudinal relationships between subjective sleep disturbance and menopausal stage. AB - Sleep disturbance is a common complaint for women going through the menopausal transition. A previous systematic review and meta-analysis of cross-sectional studies showed a small but significant relationship between self-reported sleep disturbance and menopausal stage and highlighted a possible influence of culture. However, the longitudinal relationship between self-reported sleep disturbance and menopausal transition has not been explored. This paper aimed to review literature on the longitudinal relationship between self-reported sleep disturbance and menopausal transition among community dwelling midlife women. Multiple electronic databases were systematically searched. Literature published prior to 2013 was reviewed. A narrative synthesis was used to analyse the results due to high level of heterogeneity across the included studies. Overall, review of eligible studies showed a small increased risk of self-reported sleep disturbance as women go through the menopausal transition after adjustment of potential confounders. Although the methodological quality of the majority of included studies was classified as high, the impact of culture on this relationship could not be explored, as all of the included studies were conducted in western countries. Like vasomotor symptoms, self-reported sleep disturbance is one of the core menopausal symptoms. Management strategies should be put in place to help women manage sleep disturbance to prevent complications and to improve health related quality of life. PMID- 25449826 TI - Effects of supervised whole body vibration exercise on fall risk factors, functional dependence and health-related quality of life in nursing home residents aged 80+. AB - OBJECTIVE: To test the feasibility and effectiveness of whole-body vibration (WBV) therapy on fall risk, functional dependence and health-related quality of life in nursing home residents aged 80+ years. DESIGN: Twenty-nine 80-95 years old volunteers, nursing home residents were randomized to an eight-week WBV intervention group) (n=15) or control group (n=14). Functional mobility was assessed using the timed up and go (TUG) test. Lower limb performance was evaluated using the 30-s Chair Sit to Stand (30-s CSTS) test. Postural stability was measured using a force platform. The Barthel Index was used to assess functional dependence and the EuroQol (EQ-5D) was used to evaluate Health-Related Quality of Life. All outcome measures were assessed at baseline and at a follow up after 8 weeks. RESULTS: At the 8-week follow up, TUG test (p<0.001), 30-s CSTS number of times (p=0.006), EQ-5Dmobility (p<0.001), EQ-5DVAS (p<0.014), EQ 5Dutility (p<0.001) and Barthel index (p=0.003) improved in the WBV intervention group when compared to the control group. CONCLUSIONS: An 8-week WBV-based intervention in a nursing home setting is effective in reducing fall risk factors and quality of life in nursing home residents aged 80+. PMID- 25449827 TI - Interactive communication with the public: qualitative exploration of the use of social media by food and health organizations. AB - OBJECTIVE: To examine the use and impact of social media on 2-way communication between consumers and public organizations in the food safety and nutrition area. METHODS: In-depth qualitative study conducted between October, 2012 and January, 2013, using semi-structured interviews in the United Kingdom and Ireland. Sixteen professionals worked on the public interface within 5 national organizations with a role in communicating on food safety and nutrition issues in this thematic analysis. RESULTS: Five main themes were identified: gradual shift toward social media-based queries and complaints; challenges and limitations of social media to deal with queries and complaints; benefits of using social media in query and complaint services; content redesign driven by social media use; and using social media to learn more about consumers. CONCLUSION AND IMPLICATIONS: Social media penetrated and brought new opportunities to food organizations' interactions with the public. Given the increasing use of social media by the public, food organizations need to explore such new opportunities for communication and research. PMID- 25449828 TI - Construct validity of a single-item, self-rated question of diet quality. AB - OBJECTIVE: To provide evidence of the construct validity of a single-item overall diet question with a nomological network of self-rated and biometric measures of dietary intake and outcomes. METHODS: The authors conducted a secondary analysis of survey and biometric data from a cross-sectional sample of urban-dwelling adults. In addition to self-rated diet quality, they examined dietary behaviors, biomarkers of intake, and related outcomes. Self-rated diet quality was treated as a continuous variable to calculate P for trend using regression analysis. RESULTS: Self-rated diet quality was significantly associated with variation in both subjective and objective measures of dietary intake (fruit and vegetable intake, P < .001; sugar-sweetened beverage intake, P < .001; sodium to potassium ratio, P < .001), behavior (frequency of fast-food dining, P < .001), and related outcomes (systolic blood pressure, P = .010; diastolic blood pressure, P < .001; and body mass index, P < .001). CONCLUSIONS AND IMPLICATIONS: Evidence supports the construct validity of a single-item measure of diet quality. This single-item question may be a useful proxy for more burdensome measures of overall diet quality. PMID- 25449829 TI - Systematic investigation of hierarchical phosphorylation by protein kinase CK2. AB - Although multiple phosphorylation sites are often clustered in substrates, the mechanism of phosphorylation within clusters has not been systematically investigated. Intriguingly, in addition to acidic residues, protein kinase CK2 can use phosphoserine residues as consensus determinants suggesting that CK2 may act in concert with other kinases. We used a peptide array approach to outline optimal consensus sequences for hierarchical phosphorylation by CK2, both in the context of processive, multisite phosphorylation, and in concert with a priming proline-directed kinase. Results suggest that hierarchical phosphorylation involving CK2 requires precise positioning of either multiple phosphodeterminant residues or specific combinations of canonical determinants and phosphodeterminants, and can be as enzymatically favorable as canonical CK2 phosphorylation. Over 1600 human proteins contain at least one CK2 hierarchical consensus motif, and ~20% of these motifs contain at least one reported in vivo phosphorylation site. These motifs occur non-randomly in the human proteome, with significant enrichment in proteins controlling specific cellular processes. Taken together, our results provide strong in vitro evidence that hierarchical phosphorylation may contribute to the regulation of crucial biological processes. In addition, the results suggest a mechanism by which CK2, a constitutively active kinase, can be a regulatory participant in cellular processes. BIOLOGICAL SIGNIFICANCE: Phosphorylation is a crucial regulatory mechanism governing cellular signal transduction pathways, and despite the large number of identified sites to date, most mechanistic studies remain focused on individual phosphorylation sites. This study is the first to systematically determine specific consensus sequences for hierarchical phosphorylation events. The results indicate that individual phosphorylation sites should not be studied in isolation, and that larger, multisite phosphorylation motifs may have profound impact on cellular signaling. This article is part of a Special Issue entitled: Protein dynamics in health and disease. Guest Editors: Pierre Thibault and Anne Claude Gingras. PMID- 25449830 TI - Affinity chromatography revealed insights into unique functionality of two 14-3-3 protein species in developing maize kernels. AB - The 14-3-3 proteins are a group of regulatory proteins of divergent functions in plants. However, little is known about their roles in maize kernel development. Using publically available gene expression profiling data, we found that two 14-3 3 species genes, zmgf14-4 and zmgf14-6, exhibited prominent expression profiles over other 14-3-3 protein genes during maize kernel development. More than 5000 transcripts of these two genes were identified accounting for about 1/10 of the total transcripts of genes correlating to maize kernel development. We constructed a proteomics pipeline based on the affinity chromatography, in combination with 2-DE and LC-MS/MS technologies to identify the specific client proteins of the two proteins for their functional characterization. Consequently, we identified 77 specific client proteins from the developing kernels of the inbred maize B73. More than 60% of the client proteins were commonly affinity identified by the two 14-3-3 species and are predicted to be implicated in the fundamental functions of metabolism, protein destination and storage. In addition, we found ZmGF14-4 specifically bound to the disease- or defense relating proteins, whilst ZmGF14-6 tended to interact with the proteins involving metabolism and cell structure. Our findings provide primary insights into the functional roles of 14-3-3 proteins in maize kernel development. BIOLOGICAL SIGNIFICANCE: Maize kernel development is a complicated physiological process for its importance in both genetics and cereal breeding. 14-3-3 proteins form a multi gene family participating in regulations of developmental processes in plants. However, the correlation between this protein family and maize kernel development has hardly been studied. We have for the first time found 12 14-3-3 protein genes from maize genome and studied in silico the gene transcription profiling of these genes. Comparative studies revealed that maize kernel development aroused a great number of gene expression, among which 14-3-3 protein genes took a significant proportion. We applied affinity chromatographic approach, in combination with 2 DE and LC-MS/MS, to explore the specific client proteins of two crucial 14-3-3 protein species that exhibit prominent gene expression over other members in the family during the kernel development. Assessments of the identified client proteins resulted in important information toward understanding the functional mechanism of 14-3-3 protein family in maize kernel development. PMID- 25449831 TI - Investigation of serum proteome alterations in human endometriosis. AB - Endometriosis is a common benign gynecological disease, characterized by proliferation of functional endometrial glands and stroma outside the uterine cavity. The present study involves investigation of alterations in the serum proteome of endometriosis patients compared to healthy controls using 2DE and 2D DIGE combined with MALDI TOF/TOF-MS. Comparison of serum proteome of endometriosis patients and healthy subjects revealed 25 significant differentially expressed proteins. Gene ontology and network analysis, performed using PANTHER, DAVID, WebGestalt and STRING, revealed that the differentially expressed proteins are majorly involved in response to stimulus, immune system, metabolic, localization and cellular processes. For serum diagnostic marker identification, several robust statistical screening procedures were applied to identify the set of the most significant proteins responsible for successful diagnosis of different endometriosis stages. Partial least squares (PLS) based marker selection tool and orthogonal partial least squares-discriminant analysis (OPLS-DA) were used to identify the most significant proteins for disease prediction. Western blotting validation in a separate cohort of patients revealed that haptoglobin (HP), Ig kappa chain C region (IGKC), alpha-1B-glycoprotein (A1BG) can be considered effective serum protein markers for the diagnosis of Stage II, III and IV endometriosis. For diagnosis of Stage I, only IGKC and HP seemed promising. BIOLOGICAL SIGNIFICANCE: Globally, about 12 in 100 women of reproductive age are diagnosed with endometriosis. The pathogenesis of the disease still remains unclear, leading to non-specific therapeutic approaches for disease management. Moreover, there is a delay of 8-12years in correct diagnosis after the initial onset of symptoms leading to a considerable impact on the woman's lifestyle. Also, the gold standard for diagnosis of endometriosis, laparoscopy, is an invasive procedure. The value of a noninvasive or semi invasive diagnostic test for endometriosis with easily accessible fluids such as plasma, serum, urine, and saliva is, therefore, rightfully recognized. The present study is expected to considerably improve the understanding of the disease pathogenesis along with improved diagnostics and therapeutic approaches leading to better management of the disease. PMID- 25449832 TI - Effect of vancomycin on the proteome of the multiresistant Enterococcus faecium SU18 strain. AB - Enterococci are not highly pathogenic bacteria, but the incidence of vancomycin resistance among clinical isolates of this microbial group is steadily increasing, posing a threat to public health. Vancomycin-resistant enterococci are currently some of the most recalcitrant hospital-associated pathogens against which new therapies are urgently needed. To understand the molecular mechanisms of bacterial resistance to glycopeptides, we obtained proteomic profiles of the vancomycin-resistant Enterococcus faecium SU18 strain treated with and without vancomycin. Fourteen proteins were differentially expressed in SU18, seven of which were up-regulated and seven down-regulated. Proteins involved in the vancomycin resistance mechanism, such as the VanA protein, VanA ligase, VanR and D-Ala-D-Ala dipeptidase, were up-regulated in the presence of vancomycin, while metabolism-related proteins, such as triosephosphate isomerase, guanine monophosphate synthase and glyceraldehyde-3-phosphate dehydrogenase were down regulated. Overall the compensatory response of SU18 to antibiotics is to alter expression of proteins related to antibiotic resistance, cell wall formation and energy metabolism. Some of the differentially expressed proteins might enhance antimicrobial activity and are now being investigated as potential therapeutic drug targets in other pathogenic bacteria. BIOLOGICAL SIGNIFICANCE: This study highlights the power of proteomics in the study of differential protein expression in a multiresistant Enterococcus faecium strain when subjected to vancomycin stress. PMID- 25449834 TI - Proteomic analysis of oil bodies in mature Jatropha curcas seeds with different lipid content. AB - To reveal the difference among three mature Jatropha curcas seeds (JcVH, variant with high lipid content; JcW, wild type and JcVL, variant with low lipid content) with different lipid content, comparative proteomics was employed to profile the changes of oil body (OB) associated protein species by using gels-based proteomic technique. Eighty-three protein species were successfully identified through LTQ ES-MS/MS from mature JcW seeds purified OBs. Two-dimensional electrophoresis analysis of J. curcas OB associated protein species revealed they had essential interactions with other organelles and demonstrated that oleosin and caleosin were the most abundant OB structural protein species. Twenty-eight OB associated protein species showed significant difference among JcVH, JcW and JcVL according to statistical analysis. Complementary transient expression analysis revealed that calcium ion binding protein (CalBP) and glycine-rich RNA binding protein (GRP) were well targeted in OBs apart from the oleosins. This study demonstrated that ratio of lipid content to caleosins abundance was involved in the regulation of OB size, and the mutant induced by ethylmethylsulfone treatment might be related to the caleosin like protein species. These findings are important for biotechnological improvement with the aim to alter the lipid content in J. curcas seeds. BIOLOGICAL SIGNIFICANCE: The economic value of Jatropha curcas largely depends on the lipid content in seeds which are mainly stored in the special organelle called oil bodies (OBs). In consideration of the biological importance and applications of J. curcas OB in seeds, it is necessary to further explore the components and functions of J. curcas OBs. Although a previous study concerning the J. curcas OB proteome revealed oleosins were the major OB protein component and additional protein species were similar to those in other oil seed plants, these identified OB associated protein species were corresponding to the protein bands instead of protein spots in the electrophoresis gels. Furthermore, the interaction of OB associated protein species and their contribution to OB formation and stabilization are still blank. In this study, with the overall object of profiling OB protein species from mature J. curcas seeds with different lipid content, we provided a setting of comparative OB proteomics with biochemical data and transient expression to explore the core of OB associated protein species involved in the regulation of OB size and lipid accumulation. The results were important for biotechnological improvement with the aim to a global modification of lipid storage in J. curcas seeds. Meanwhile, this study gave insight into possible associations between OBs and other organelles in mature J. curcas seeds. It may represent new aspects of the biological functions of the OBs during the oil mobilization. Combined the technique of transient transformation, a newly reported protein species, glycine-rich RNA binding protein (GRP) was successfully targeted in OBs. Therefore, further molecular analysis of these protein species is warranted to verify this association and what role they have in OBs. PMID- 25449835 TI - The SNO/SOH TMT strategy for combinatorial analysis of reversible cysteine oxidations. AB - Redox homeostasis is essential for normal function of cells and redox imbalance has been recognised as a pathogenic factor of numerous human diseases. Oxidative modifications of cysteine thiols modulate function of many proteins, mediate signalling, and fine-tune transcriptional and metabolic processes. In this study we present the SNO/SOH TMT strategy, which enables simultaneous analysis of two different types of cysteine modification: S-nitrosylation (SNO) and S sulfenylation (SOH). The method facilitates quantitation of modification changes corrected by changes in protein abundance levels and estimation of relative modification site occupancy in a single nLC-MSMS run. The approach was evaluated in vivo using an Escherichia coli based model of mild oxidative stress. Bacteria were grown anaerobically on fumarate or nitrate. Short-term treatment with sub millimolar levels of hydrogen peroxide was used to induce SOH. We have identified and quantified 114 SNO and SOH modified peptides. In many instances SNO and SOH occupy the same site, suggesting an association between them. High site occupancy does not equate to a site of modification which responds to redox imbalance. The SNO/SOH TMT strategy is a viable alternative to existing methods for cysteine oxidation analysis and provides new features that will facilitate our understanding of the interplay between SNO and SOH. BIOLOGICAL SIGNIFICANCE: SNO/SOH TMT strategy outperforms other available strategies for cysteine oxidation analysis. It provides quantitative profiling of S-nitrosylation and S sulfenylation changes simultaneously in two experimental conditions. It allows correction of modification levels by protein abundance changes and determination of relative modification site occupancy - all in a single nLC-MSMS experiment based on commercially available reagents. The method has proven precise and sensitive enough to detect and quantify endogenous levels of oxidative stress on proteome-wide scale. PMID- 25449833 TI - Parallel reaction monitoring (PRM) and selected reaction monitoring (SRM) exhibit comparable linearity, dynamic range and precision for targeted quantitative HDL proteomics. AB - High-density lipoprotein (HDL), a lipid nanoparticle containing many different low abundance proteins, is an attractive target for clinical proteomics because its compositional heterogeneity is linked to its cardioprotective effects. Selected reaction monitoring (SRM) is currently the method of choice for targeted quantification of proteins in such a complex biological matrix. However, model system studies suggest that parallel reaction monitoring (PRM) is more specific than SRM because many product ions can be used to confirm the identity of a peptide. We therefore compared PRM and SRM for their abilities to quantify proteins in HDL, using (15)N-labeled apolipoprotein A-I (HDL's most abundant protein) as the internal standard. PRM and SRM exhibited comparable linearity, dynamic range, precision, and repeatability for protein quantification of HDL. Moreover, the single internal standard protein performed as well as protein specific peptide internal standards when quantifying 3 different proteins. Importantly, PRM and SRM yielded virtually identical quantitative results for 26 proteins in HDL isolated from 44 subjects. Because PRM requires less method development than SRM and is potentially more specific, our observations indicate that PRM in concert with a single isotope-labeled protein is a promising new strategy for quantifying HDL proteins in translational studies. BIOLOGICAL SIGNIFICANCE: HDL, a complex matrix composed of lipids and proteins, is implicated in cardioprotection. Its cholesterol content correlates inversely with cardiovascular disease and it is the current metric to assess cardiovascular risk. However, the cholesterol content does not capture HDL's complexity and heterogeneity. Devising metrics that better capture HDL's cardioprotective effects, we developed an optimized method for quantification of HDL proteome, using PRM in concert with a single labeled protein as internal standard. The availability of a method that increases sample throughput without compromising the reproducibility, sensitivity, and accuracy could therefore point to better risk assessment for CVD or other diseases. PMID- 25449836 TI - Comparative physiology and proteomic analysis of two wheat genotypes contrasting in drought tolerance. AB - Comparative physiology and proteomic analyses were conducted to monitor the stress response of two wheat genotypes (SERI M 82 (SE) and SW89.5193/kAu2 (SW)) with contrasting responses to drought stress. Under stress condition, the tolerant genotype (SE) produced higher shoot and root biomasses, longer roots and accumulated higher level of ABA in leaves. Physiological measurements suggested that the SE genotype was more efficient in water absorption and could preserve more water presumably by controlling stomata closure. Proteomic analysis showed an increased abundance of proteins related to defense and oxidative stress responses such as GLPs, GST, and SOD, and those related to protein processing such as small HSPs in roots of both genotypes in response to drought stress. Interestingly, the abundance of proteins such as endo-1,3-beta-glucosidase, peroxidase, SAMS, and MDH significantly increased in roots or leaves of the SE genotype and decreased in that of the SW one. In addition, an increased abundance of APX was detected in leaves and roots of the SE genotype and a decreased abundance of 14-3-3 and ribosomal proteins were noted in the SW one in response to drought stress. Our findings led to a better understanding about the integrated physiology and proteome responses of wheat genotypes with nearly contrasting responses to drought stress. BIOLOGICAL SIGNIFICANCE: We applied a comparative physiology and proteomic analysis to decipher the differential responses of two contrasting wheat genotypes to drought stress. Based on physiological measurements the tolerant genotype (SE) showed better drought response by developing deep root system, higher root and shoot biomasses, and higher level of ABA in leaves. Proteomic analysis showed an increased abundance of proteins related to defense and oxidative stress responses such as GLPs, GST, and SOD, and those related to protein processing such as small HSPs in roots of both genotypes in response to drought stress. In addition, the abundance of proteins such as glucan endo-1,3-beta-glucosidase, peroxidases, SAMS, and MDH increased in roots or leaves of the tolerant genotype (SE) and decreased in that of the sensitive genotype (SW). Overall, proteins related to oxidative stress, protein processing and photosynthesis showed decreased abundance to a greater extent in the sensitive genotype (SW). PMID- 25449837 TI - Quantitative proteomics and transcriptomics reveal key metabolic processes associated with cotton fiber initiation. AB - An iTRAQ-based proteomics of ovules from the upland cotton species Gossypium hirsutum and its fuzzless-lintless mutant was performed, and finally 2729 proteins that preferentially accumulated at anthesis in wild-type ovules were identified. We confirmed that the gene expression levels of 2005 among these proteins also increased by performing an RNA sequencing transcriptomics. Expression of proteins involved in carboxylic acid metabolism, small-molecule metabolic processes, hormone regulation, and lipid metabolism was significantly enhanced in wild-type ovules. Quantitative real-time PCR verified the increased expression of 26 genes involved in these processes. Cotton 3-hydroxyacyl-CoA dehydratase (GhPAS2) catalyzing the third reaction of very long-chain fatty acid (VLCFA) biosynthesis, accumulated at anthesis in wild-type ovules. Heterogeneous expression of GhPAS2 restored viability to the Saccharomyces cerevisiae haploid psh1-deletion strain deficient in PAS2 activity. Application of VLCFA biosynthesis inhibitor acetochlor (2-chloro-N-[ethoxymethyl]-N-[2-ethyl-6-methyl phenyl]-acetamide; ACE) and gibberellic acid to the unfertilized cotton ovules significantly suppressed fiber cell protrusion. In this study, the profiling of gene expression at both transcriptome and proteome levels provides new insights into cotton fiber cell initiation. BIOLOGICAL SIGNIFICANCE: Cotton fiber initiation determines the ultimate number of fibers per ovule, thereby determining fiber yield. In total, 2729 proteins were preferentially accumulated in wild-type ovules at anthesis. The most up-regulated proteins were assigned to carboxylic acid metabolism, small-molecule metabolic processes, hormone regulation, and lipid metabolism. In consistence with these findings, we characterized GhPAS2 gene coding for the enzyme that catalyzes VLCFA production. VLCFA biosynthesis inhibitor, acetochlor, was shown to significantly suppress fiber initiation. This study provides a genome-scale transcriptomic and proteomic characterization of fiber initial cells, laying a solid basis for further investigation of the molecular processes governing fiber cell development. PMID- 25449838 TI - Peptidomics combined with cDNA library unravel the diversity of centipede venom. AB - Centipedes are one of the oldest venomous arthropods using toxin as their weapon to capture prey. But little attention was focused on them and only few centipede toxins were demonstrated with activity on ion channels. Therefore, more deep works are needed to understand the diversity of centipede venom. In the present study, we use peptidomics combined with cDNA library to uncover the diversity of centipede Scolopendra subspinipes mutilans L. Koch. 192 peptides were identified by LC-MS/MS and 79 precursors were deduced by cDNA library. Surprisingly, the signal peptides of centipede toxins were more complicated than any other animal toxins and even exhibited large differences in homologues. Meanwhile, a large number of variants generated by alternative cleavage sites were detected by mass spectra. Odd number of cystein (3, 5, 7) found in the mature peptides were seldom seen in peptide toxins. In additional, two novel cysteine frameworks (C-C-C-CCC, C-C-C-C-CC-CC) were identified from 16 different cysteine frameworks from centipede peptides. Only 29 precursors have clear targets, while others may provide a potential diversity function for centipede. These findings highlight the extensive diversity of centipede toxins and provide powerful tools to understand the capture and defense weapon of centipede. BIOLOGICAL SIGNIFICANCE: Peptide toxins from venomous animal have attracted increasing attentions due to their extraordinary chemical and pharmacological diversity. Centipedes are one of the most used Chinese traditional medicines, but little was known about the active components. The venom of Scolopendra subspinipes mutilans L. Koch is first deeply analyzed in this work and most of peptides were never discovered before. Interestingly, the number and arrangement of cysteine showed a larger different to known peptide toxins such spider or scorpion toxins. Moreover, only 29 peptides from this centipede venom were identified with known function. It suggested that our work not only important to understand the composition of centipede venom, but also provide many valuable peptides for potential biological functions. PMID- 25449840 TI - 5-HT2A/C receptors do not mediate the attenuation of compulsive checking by mCPP in the quinpirole sensitization rat model of obsessive-compulsive disorder (OCD). AB - There is emerging evidence for a dopamine (DA)-serotonin (5-HT) interaction underlying obsessive-compulsive disorder (OCD). In the quinpirole sensitization rat model of OCD, compulsive checking is induced by chronic treatment with the DA agonist quinpirole, and is attenuated by the 5-HT agonist drug mCPP. However, mCPP has affinity for a number of 5-HT receptor subtypes, and it is unknown by which receptors mCPP exerts its effects on quinpirole-treated animals. The present study tested in rats whether mCPP activity at 5-HT2A/C receptors mediates the attenuation of compulsive checking in quinpirole-treated animals. Rats were chronically treated with quinpirole on the open field for the induction of compulsive checking. Following the induction phase, animals were treated with mCPP (1.25 mg/kg) and the selective 5-HT2A/C receptor antagonist ritanserin (1 mg/kg or 5 mg/kg) to test whether blockade of 5-HT2A/C receptors inhibits attenuation of checking by mCPP. Results showed that as expected, quinpirole induced compulsive checking, and mCPP reduced its performance. However, 5-HT2A/C receptor blockade by ritanserin did not inhibit the attenuation of compulsive checking by mCPP. These results suggest that the reduction in compulsive checking by mCPP is not mediated by activity at 5-HT2A/C receptors, but by another receptor subtype. PMID- 25449841 TI - An age-related deficit in spatial-feature reference memory in homing pigeons (Columba livia). AB - Age-related memory decline in mammals has been well documented. By contrast, very little is known about memory decline in birds as they age. In the current study we trained younger and older homing pigeons on a reference memory task in which a goal location could be encoded by spatial and feature cues. Consistent with a previous working memory study, the results revealed impaired acquisition of combined spatial-feature reference memory in older compared to younger pigeons. Following memory acquisition, we used cue-conflict probe trials to provide an initial assessment of possible age-related differences in cue preference. Both younger and older pigeons displayed a similarly modest preference for feature over spatial cues. PMID- 25449839 TI - Multiple faces of BDNF in cocaine addiction. AB - Brain-derived neurotrophic factor (BDNF) has been found to play roles in many types of plasticity including drug addiction. Here, we focus on rodent studies over the past two decades that have demonstrated diverse roles of BDNF in models of cocaine addiction. First, we will provide an overview of studies showing that cocaine exposure alters (and generally increases) BDNF levels in reward-related regions including the ventral tegmental area, nucleus accumbens, prefrontal cortex, and amygdala. Then we will review evidence that BDNF contributes to behavioral changes in animal models of cocaine addiction, focusing on conditioned place preference, behavioral sensitization, maintenance and reinstatement of self administration, and incubation of cocaine craving. Last, we will review the role of BDNF in synaptic plasticity, particularly as it relates to plasticity of AMPA receptor transmission after cocaine exposure. We conclude that BDNF regulates cocaine-induced behaviors in a highly complex manner that varies depending on the brain region (and even among different cell types within the same brain region), the nature of cocaine exposure, and the "addiction phase" examined (e.g., acquisition vs maintenance; early vs late withdrawal). These complexities make BDNF a daunting therapeutic target for treating cocaine addiction. However, recent clinical evidence suggests that the serum BDNF level may serve as a biomarker in cocaine addicts to predict future relapse, providing an alternative direction for exploring BDNF's potential relevance to treating cocaine addiction. PMID- 25449843 TI - Fox urine exposure induces avoidance behavior in rats and activates the amygdalar olfactory cortex. AB - Predator odors represent a group of biologically-relevant chemosignals called kairomones. Kairomones enable prey animals to recognize potential predatory threats in their environment and to initiate appropriate defensive responses. Although the behavioral repertoire of anti-predatory responses (e.g. avoidance, freezing, risk assessment) has been investigated extensively, our knowledge about the neural network mediating these innate fear responses is rather limited. In the present study, the GABAA agonist muscimol was bilaterally injected (2.6 nmol/0.3 MUl) into the amygdalar olfactory cortex (AOC), a brain area that receives massive olfactory input from both olfactory systems and is strongly interconnected with the medial hypothalamic defense circuit. Temporary inactivation of the AOC substantially disrupted avoidance behavior of rats to fox urine that is strongly avoided under control conditions (saline injections). Taken together, these results demonstrate that the AOC is critically involved in fox urine-induced fear behavior. This suggests that the AOC is part of a brain fear circuit that mediates innate fear responses toward predatory odors. PMID- 25449844 TI - Sources of variation in the design of preclinical studies assessing the effects of amphetamine-type stimulants in pregnancy and lactation. AB - The prevalence of drug use during pregnancy has increased in recent years and the amount of drug-exposed babies has therefore increased. In order to assess the risk associated with this there has been an increase in the amount of preclinical studies investigating the effects of prenatal and postnatal drug exposure on the offspring. There are many challenges associated with investigating the developmental and behavioural effects of drugs of abuse in animal models and ensuring that such models are appropriate and clinically relevant. The purpose of this review is to illustrate the variation in the design of preclinical studies investigating the effects of the amphetamine-type stimulants taken during pregnancy and/or lactation in animal models. Methamphetamine, methylendioxymethamphetamine and amphetamine were included in this review. The protocols used for exploring the effects of these drugs when taking during pregnancy and/or lactation were investigated and summarised into maternal experimental variables and offspring experimental variables. Maternal experimental variables include animals used, mating procedures and drug treatment and offspring experimental variables include litter standardisation, cross fostering, weaning and behaviours and parameters assessed. The findings in this paper suggest that there is a large diversity and little consistency among these studies and so the interpretation of these results may not be as clinically relevant as previously thought. For this reason, the importance of steering the preclinical studies in a direction that is most clinically relevant will be an important future recommendation. This will also allow us to be more confident in the results obtained and confident that the human situation is being replicated as closely as possible. PMID- 25449842 TI - Striatal dopamine receptor plasticity in neurotensin deficient mice. AB - Schizophrenia is thought to be caused, at least in part, by dysfunction in striatal dopamine neurotransmission. Both clinical studies and animal research have implicated the dopamine neuromodulator neurotensin (NT) in the pathophysiology of schizophrenia. Utilizing male mice lacking the NT gene (NT(-/ )), these studies examined the consequences of NT deficiency on dopaminergic tone and function, investigating (1) dopamine concentrations and dopamine receptor and transporter expression and binding in dopaminergic terminal regions, and (2) the behavioral effects of selective dopamine receptor agonists on locomotion and sensorimotor gating in adult NT(-/-) mice compared to wildtype (NT(+/+)) mice. NT(-/-) mice did not differ from NT(+/+) mice in concentrations of dopamine or its metabolite DOPAC in any brain region examined. However, NT(-/-) mice showed significantly increased D1 receptor, D2 receptor, and dopamine transporter (DAT) mRNA in the caudate putamen compared to NT(+/+) controls. NT(-/-) mice also showed elevated D2 receptor binding densities in both the caudate putamen and nucleus accumbens shell compared to NT(+/+) mice. In addition, some of the behavioral effects of the D1-type receptor agonist SKF-82958 and the D2-type receptor agonist quinpirole on locomotion, startle amplitude, and prepulse inhibition were dose-dependently altered in NT(-/-) mice, showing altered D1-type and D2-type receptor sensitivity to stimulation by agonists in the absence of NT. The results indicate that NT deficiency alters striatal dopamine receptor expression, binding, and function. This suggests a critical role for the NT system in the maintenance of striatal DA system homeostasis and implicates NT deficiency in the etiology of dopamine-associated disorders such as schizophrenia. PMID- 25449845 TI - Dopamine D2/D3 but not dopamine D1 receptors are involved in the rapid antidepressant-like effects of ketamine in the forced swim test. AB - Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses. The traditional antidepressants often take several weeks, even months, to obtain clinical effects. However, recent clinical studies have shown that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects within 2h and are long-lasting. The aim of the present study was to investigate whether dopaminergic system was involved in the rapid antidepressant effects of ketamine. The acute administration of ketamine (20 mg/kg) significantly reduced the immobility time in the forced swim test. MK 801 (0.1 mg/kg), the more selective NMDA antagonist, also exerted rapid antidepressant-like effects. In contrast, fluoxetine (10 mg/kg) did not significantly reduced the immobility time in the forced swim test after 30 min administration. Notably, pretreatment with haloperidol (0.15 mg/kg, a nonselective dopamine D2/D3 antagonist), but not SCH23390 (0.04 and 0.1 mg/kg, a selective dopamine D1 receptor antagonist), significantly prevented the effects of ketamine or MK-801. Moreover, the administration of sub-effective dose of ketamine (10 mg/kg) in combination with pramipexole (0.3 mg/kg, a dopamine D2/D3 receptor agonist) exerted antidepressant-like effects compared with each drug alone. In conclusion, our results indicated that the dopamine D2/D3 receptors, but not D1 receptors, are involved in the rapid antidepressant-like effects of ketamine. PMID- 25449846 TI - Acute stress affects the global DNA methylation profile in rat brain: modulation by physical exercise. AB - The vulnerability of epigenetic marks of brain cells to environmental stimuli and its implication for health have been recently debated. Thus, we used the rat model of acute restraint stress (ARS) to evaluate the impact of stress on the global DNA methylation and on the expression of the Dnmt1 and Bdnf genes of hippocampus, cortex, hypothalamus and periaqueductal gray (PAG). Furthermore, we verified the potential of physical exercise to modulate epigenetic responses evoked by ARS. Sedentary male Wistar rats were submitted to ARS at the 75th postnatal day (PND), whereas animals from a physically active group were previously submitted to swimming sessions (35-74th PND) and to ARS at the 75th PND. Global DNA methylation profile was quantified using an ELISA-based method and the quantitative expression of the Dnmt1 and Bdnf genes was evaluated by real time PCR. ARS induced a decrease in global DNA methylation in hippocampus, cortex and PAG of sedentary animals and an increased expression of Bdnf in PAG. No change in DNA methylation was associated with ARS in the exercised animals, although it was associated with abnormal expression of Dnmt1 and Bdnf in cortex, hypothalamus and PAG. Our data reveal that ARS evokes adaptive changes in global DNA methylation of rat brain that are independent of the expression of the Dnmt1 gene but might be linked to abnormal expression of the Bdnf gene in the PAG. Furthermore, our evidence indicates that physical exercise has the potential to modulate changes in DNA methylation and gene expression consequent to ARS. PMID- 25449848 TI - The role of DNA methylation in the mechanisms of memory reconsolidation and development of amnesia. AB - Current considerations suggest that the mechanisms of long term memory are based on the changes of the neuronal genetic algorithms. Process of the enzyme DNA methylation have great importance to the differential genes expression, and is likely to be one of the key mechanisms of the consolidation and memory storage. The present study aimed to investigate the DNA methylation processes role in the mechanisms of the conditioned food aversion memory reconsolidation and also in the amnesia development mechanisms, caused by disturbances of the reconsolidation in Helix lucorum. It was found that DNA-methyltransferase inhibitors zebularine and RG108 had no influence on the memory reconsolidation. We investigated the effects of the DNA-methyltransferase inhibitors on different amnesia stage. The amnesia was induced by NMDA glutamate receptors antagonists. At the early stage of amnesia (3rd day after its induction) injections of the DNA-methyltransferase inhibitors in combination with reminder by conditioned food stimuli led to memory recall. Memory was recovered by the DNA-methyltransferase inhibitors injections before the reminder and also 3h, but not 9h after the reminder. In case when enzyme inhibitors or reminders were applied separately, no effect on memory was revealed. At the late stage of amnesia (10th day) the DNA-methyltransferase inhibitors didn't affects amnesia development. It might be hypothesized that presentation of reminding stimuli result in the reactivation/reconsolidation of molecular processes, involved in amnesia development, one of the key mechanisms of which could be the DNA methylation/demethylation of neural cells. PMID- 25449847 TI - Tasting calories differentially affects brain activation during hunger and satiety. AB - An important function of eating is ingesting energy. Our objectives were to assess whether oral exposure to caloric and non-caloric stimuli elicits discriminable responses in the brain and to determine in how far these responses are modulated by hunger state and sweetness. Thirty women tasted three stimuli in two motivational states (hunger and satiety) while their brain responses were measured using functional magnetic resonance imaging in a randomized crossover design. Stimuli were solutions of sucralose (sweet, no energy), maltodextrin (non sweet, energy) and sucralose+maltodextrin (sweet, energy). We found no main effect of energy content and no interaction between energy content and sweetness. However, there was an interaction between hunger state and energy content in the median cingulate (bilaterally), ventrolateral prefrontal cortex, anterior insula and thalamus. This indicates that the anterior insula and thalamus, areas in which hunger state and taste of a stimulus are integrated, also integrate hunger state with caloric content of a taste stimulus. Furthermore, in the median cingulate and ventrolateral prefrontal cortex, tasting energy resulted in more activation during satiety compared to hunger. This finding indicates that these areas, which are known to be involved in processes that require approach and avoidance, are also involved in guiding ingestive behavior. In conclusion, our results suggest that energy sensing is a hunger state dependent process, in which the median cingulate, ventrolateral prefrontal cortex, anterior insula and thalamus play a central role by integrating hunger state with stimulus relevance. PMID- 25449849 TI - Do the effects of adolescent employment differ by employment intensity and neighborhood context? AB - Research on the effects of adolescent employment on primarily middle-class youth suggests that intense employment, working more than 15 or 20 hours during the school year, is associated with increased participation in risky behavior. Despite these findings, scholars who focus on the development of youth living in low-income urban areas often hypothesize that adolescent employment will have beneficial effects on this population. There is some evidence that adolescent employment is associated with increased educational achievement and adult employment for low-income urban youth. The impact of adolescent employment on future engagement in risky behavior across levels of neighborhood deprivation and employment intensity was investigated on a sample of 1,057 adolescents from the Project on Human Development in Chicago Neighborhoods, a longitudinal study of neighborhood effects on development. After controlling for individual characteristics, intense employment during adolescence did predict increased use of cigarettes and alcohol and having a greater number of sexual partners 2 years after employment was measured. There were no significant interactions between neighborhood SES and adolescent employment status on involvement in risky behavior. These findings suggest that intense adolescent employment is associated with detrimental developmental outcomes for youth regardless neighborhood context. PMID- 25449850 TI - Central injection of GalR1 agonist M617 facilitates GLUT4 expression in cardiac muscle of type 2 diabetic rats. AB - Although galanin has been shown to increase GLUT4 expression in the cardiac muscle of rats, there is no literature available about the effect of GalR1 on GLUT4 expression in the cardiac muscle of type 2 diabetic rats. The aim of this study was to determine whether intracerebroventricular injection of GalR1 agonist M617 would elevate GLUT4 expression in the cardiac muscle of type 2 diabetic rats. The rats tested were divided into four groups: rats from healthy and type 2 diabetic drug groups were injected with 10nM/kg/d M617 in 5MUl artificial cerebrospinal fluid for 21days, while control received 5MUl vehicle injections. The blood samples were analyzed for glucose and insulin concentration. Cardiac muscle was collected and processed for determination of GLUT4 mRNA expression and GLUT4 protein levels. The present findings showed that fasting blood glucose levels in both M617 treatment groups were lower compared with each control. The insulin levels in both M617 treatment groups were decreased compared with each control. Moreover, the GLUT4 content in the cardiac muscle in both drug groups was higher compared with each control. M617 treatment increased GLUT4 mRNA expression and GLUT4 protein levels compared with each control group. These observations suggest that GalR1 agonist M617, acting through its central GalR1, can promote GLUT4 expression and enhance GLUT4 content in the cardiac muscle of type 2 diabetic rats. Central GalR1 may play a significant role in regulation of glucose metabolic homeostasis in the cardiac muscle of type 2 diabetic rats. PMID- 25449853 TI - Concurrent strength and endurance training exercise sequence does not affect neuromuscular adaptations in older men. AB - Concurrent training is an effective method for increasing skeletal muscle performance in aging individuals, but controversy exists as to whether chronic neuromuscular and functional adaptations are affected by the intra-session exercise sequence. Therefore the aim of this study was to evaluate the effect of concurrent endurance and power-like strength training exercise sequence on muscular and functional adaptations of older participants. Thirty-six healthy older men not engaged in systematic exercise training programs for at least 6 months were divided into a control group (CON; 65.8+/-5.3 years), or in the training groups: endurance-strength (ES; 63.2+/-3.3 years), or strength-endurance (SE; 67.1+/-6.1 years). Training groups underwent 12 weeks of concurrent endurance and power-like strength training, starting every exercise session with either endurance (in ES) or strength (in SE) exercises. Measurements included knee extension one repetition maximum (1RM), knee extension power, 30 second sit to-stand test (30SS), maximum vastus lateralis surface electromyographic activity, and rectus femoris echo intensity (RFEI). Significant increases in maximal strength (ES +18+/-11.3%; SE +14.2+/-6.0%; p<=0.05), peak power (ES +22.2+/-19.4%; SE +26.3+/-31.3%; p<=0.05), and 30SS performance (ES +15.2+/-7.2%; SE +13.2+/-11.8%; p<=0.05) were observed only in the training groups, with no differences between ES and SE. Maximum muscular activity was greater after 12weeks at training groups (p<=0.05), and reductions in RFEI were found only in ES and SE (p<=0.05). These results demonstrate that concurrent strength and endurance training performed twice a week effectively increases muscular performance and functional capacity in older men, independent of the intra session exercise sequence. Additionally, the RFEI decreases indicate an additional adaptation to concurrent training. PMID- 25449852 TI - Aging disturbs the balance between effector and regulatory CD4+ T cells. AB - Healthy aging requires an optimal balance between pro-inflammatory and anti inflammatory immune responses. Although CD4+ T cells play an essential role in many immune responses, few studies have directly assessed the effect of aging on the balance between effector T (Teff) cells and regulatory T (Treg) cells. Here, we determined if and how aging affects the ratio between Treg and Teff cells. Percentages of both naive Treg (nTreg; CD45RA+CD25(int)FOXP3(low)) and memory Treg (memTreg; CD45RA-CD25(high)FOXP3(high)) cells were determined by flow cytometry in peripheral blood samples of healthy individuals of various ages (20 84 years). Circulating Th1, Th2 and Th17 effector cells were identified by intracellular staining for IFN-gamma, IL-4 and IL-17, respectively, upon in vitro stimulation with PMA and calcium ionophore. Whereas proportions of nTreg cells declined with age, memTreg cells increased. Both Th1 and Th2 cells were largely maintained in the circulation of aged humans, whereas Th17 cells were decreased. Similar to memTreg cells, the 3 Teff subsets resided primarily in the memory CD4+ T cell compartment. Overall, Treg/Teff ratios were increased in the memory CD4+ T cell compartment of aged individuals when compared to that of young individuals. Finally, the relative increase of memTreg cells in elderly individuals was associated with poor responses to influenza vaccination. Taken together, our findings imply that aging disturbs the balance between Treg cells and Teff cells. PMID- 25449851 TI - Aberrant mTOR activation in senescence and aging: A mitochondrial stress response? AB - Unexpected activation of mTOR signaling, measured by ribosomal S6 phosphorylation or ribosomal S6 kinase (p70S6K) activity, has been reported in aging-related settings. Evidence of elevated mTOR activity has been reported in the heart and muscle tissue in aged mice and humans, mouse models of progeria, and senescent human fibroblasts. We explore these reports and the possibility that activation of the mTOR/p70S6K kinase pathway may represent a ROS-mediated response to mitochondrial stress leading to the activation of senescence. This activation is a hallmark of both aged tissue and senescent human cells. PMID- 25449854 TI - Increased intestinal production of alpha-defensins in aged rats with acute pancreatic injury. AB - Acute pancreatitis is a life-threatening situation, frequently associated with uncontrolled local and systemic inflammation, and aging is associated with a worst prognosis. Antimicrobial peptides are ancient molecules that belong to innate immunity, produced by epithelial and immune cells, and are able to trigger a myriad of effector responses. We have hypothesized that antimicrobial peptides could play an important role during serious pancreatic injury. To investigate our hypothesis, alpha-defensin-5, alpha-defensin-7 and CRAMP gene expression levels were measured in the intestinal tissue of old and young rats submitted to chemical pancreatic damage. We found significantly higher levels of alpha defensin-5 and alpha-defensin-7, but not CRAMP, in the samples from old mice. This increase was not associated with a worse systemic inflammatory response. We conclude that alpha-defensins may have a pivotal role during acute pancreatitis and that the elderly develops a more severe local, but not systemic inflammatory process. PMID- 25449855 TI - Attention enhancing effects of methylphenidate are age-dependent. AB - The psychostimulant methylphenidate (MPH, Ritalin(r)) is used to treat a variety of cognitive disorders. MPH is also popular among healthy individuals, including the elderly, for its ability to focus attention and improve concentration, but these effects have not been shown to be comparable between aged and adult subjects. Thus, we tested whether MPH would improve performance in sustained attention in both adult and aged rats. In addition, we tested the impact of visual distraction on performance in this task and the ability of MPH to mitigate the effects of distraction. Adult (6-12 months) and aged (18-22 months) male Sprague-Dawley rats were given oral MPH, and their cognitive and motor abilities were tested. Results suggest that while MPH improves task performance in adults; there is no improvement in the aged animals. These outcomes suggest that the use of MPH for cognitive enhancement in elderly individuals may be ineffective. PMID- 25449856 TI - Thyroid function tests and early outcomes of acute ischemic stroke in older euthyroid patients. AB - Blood thyroid function tests (TFT) are routinely used to screen for thyroid disorders in several clinical settings. TFT on hospital admission may also be useful prognostic predictors of acute IS: according to recent evidence, poststroke outcome is better in patients with lower thyroid function and worse in those with higher thyroid function. However, previous reports are few and mostly compared patients with thyroid disorders to euthyroid patients. Thyroid disorders are known risk factors for cerebrovascular disease. However, hyperthyroidism is related to cardioembolic IS whereas hypothyroidism is related to atherosclerotic risk factors. Therefore, findings from available studies of TFT might just reflect the worse prognosis of cardioembolic IS compared to other IS subtypes. Another limitation of previous studies is the lack of information for older persons, who represent three quarters of all IS patients. In this paper, we investigated whether serum thyroid stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) measured on Stroke Unit (SU) admission are associated with early outcomes of acute IS in 775 euthyroid patients aged >=65 years (mean age 80.1+/-8.7 years). Two composite outcomes were investigated: poor functional outcome (death during SU stay or disability at SU discharge), and unfavorable discharge setting (death during SU stay, transfer from SU to other acute hospital unit or transfer from SU to long-term care-facilities as opposed to direct discharge home). Analyses were performed using logistic regression models. Curvilinear associations were tested including TFT as polynomial terms. Models were adjusted for demographics, prestroke, and IS-related confounders. We found that lower TSH had a complex curvilinear association with poor functional outcome and that the shape of the associations changed with age. At age 65, the curve was U-shaped: outcome risk decreased with increasing TSH, reached its minimum at TSH near 3.00mUI/L and then started to rise. Between ages 70 and 75, however, the shape of the curve straightened and, starting from age 80 took an inverted U-shape: outcome risk rose with increasing TSH, reached its maximum at TSH values that progressively shifted upward with increasing age (from 1.70mU/L at age 80 to about 2.20mUI/L at age 90), then started to decrease. A linear inverse association was found between FT3 and unfavorable discharge setting. Our study suggests that measurement of TFT on SU admission can provide independent prognostic information for early outcomes of acute IS in older euthyroid patients. PMID- 25449857 TI - Skeletal muscle mitochondrial DNA deletions are not increased in CuZn-superoxide dismutase deficient mice. AB - Mitochondrial DNA (mtDNA) deletion mutations are proposed contributors to aging related muscle fiber loss and atrophy, but evidence of a causal role for these mutations in muscle aging is lacking. Elucidating the etiology of in vivo mtDNA deletion mutations will help to better understand and test the possible roles of these mutations in aging. The implication of mtDNA mutations in aging is based on the susceptibility of mtDNA to oxidative damage by reactive oxygen species (ROS) due to residing in mitochondria, the primary source of endogenous ROS. Cells possess many pathways for neutralizing ROSs, including a variety of superoxide dismutases (SOD). Mice lacking CuZnSOD (Sod1(-/-) mice) have high levels of oxidative damage in many tissues including skeletal muscle and are a model for testing the role of oxidative damage in the formation of mtDNA deletion mutations. The increased DNA oxidative damage in Sod1(-/-) mice is associated with increased mtDNA deletion mutations in a variety of tissues, but skeletal muscle mtDNA mutations have not been reported. We hypothesized that a life-long absence of mouse muscle CuZnSOD would increase mtDNA deletion mutation frequency and focal accumulation of these mutations in aging mouse skeletal muscle. Focal accumulations of mtDNA deletion mutations were detected by histochemical staining for cytochrome c oxidase (cytOX) activity and detection of cytOX-negative fibers, a marker of focal mtDNA mutation accumulation, within approximately 20,000 muscle fibers through a distance of 1000MUm. Total DNA was extracted from intervening unstained sections and mtDNA deletion mutation frequency was measured by a droplet digital PCR. Droplet digital PCR quantification of mtDNA deletion mutations showed no difference in mtDNA deletion mutation frequency in Sod1(-/-) mouse muscle compared to wild-type mice and we observed no significant increase in the number of cytOX-negative muscle fibers, in Sod1(-/-) mice compared to wild type mice. These data demonstrate that not all changes in cellular oxidative stress are linked to mtDNA deletion mutations and shift the focus to other etiologies for these mutations that need to be clarified to better test their possible role in aging. PMID- 25449858 TI - Ethanol-induced differential gene expression and acetyl-CoA metabolism in a longevity model of the nematode Caenorhabditis elegans. AB - Previous studies have shown that exposing adults of the soil-dwelling nematode Caenorhabditis elegans to concentrations of ethanol in the range of 100-400mM results in slowed locomotion, decreased fertility, and reduced longevity. On the contrary, lower concentrations of ethanol (0.86-68mM) have been shown to cause a two- to three-fold increase in the life span of animals in the stress resistant L1 larval stage in the absence of a food source. However, little is known about how gene and protein expression is altered by low concentrations of ethanol and the mechanism for the increased longevity. Therefore, we used biochemical assays and next generation mRNA sequencing to identify genes and biological pathways altered by ethanol. RNA-seq analysis of L1 larvae incubated in the presence of 17mM ethanol resulted in the significant differential expression of 649 genes, 274 of which were downregulated and 375 were upregulated. Many of the genes significantly altered were associated with the conversion of ethanol and triglycerides to acetyl-CoA and glucose, suggesting that ethanol is serving as an energy source in the increased longevity of the L1 larvae as well as a signal for fat utilization. We also asked if L1 larvae could sense ethanol and respond by directed movement. Although we found that L1 larvae can chemotax to benzaldehyde, we observed little or no chemotaxis to ethanol. Understanding how low concentrations of ethanol increase the lifespan of L1 larvae may provide insight into not only the longevity pathways in C. elegans, but also in those of higher organisms. PMID- 25449860 TI - Effects of short-term training combining strength and balance exercises on maximal strength and upright standing steadiness in elderly adults. AB - This study investigated the effects of two training programmes of 6 weeks combining strength and balance exercises in different proportions. One training programme [n=10; 71.4 (6.3) years] consisted mainly of strength exercises (ST) and the other programme [n=8; 71.4 (6.4) years] included a majority of balance exercises (BT). Maximal strength of lower leg muscles and centre of pressure (CoP) steadiness during upright stance in various sensory conditions were measured before and after training. The input-output relation of motor evoked potential (MEP) induced by transcranial magnetic stimulation and H reflex was also assessed in soleus during upright standing. The maximal strength of the ankle plantar flexor muscles increased after training programmes (p<0.001) with a trend for greater gain in ST (+35.7%) compared with BT (+20.8%, p=0.055). The gain in strength was positively correlated with the increase in voluntary activation (p<0.001). Both training programmes decreased maximal amplitude and mean fluctuations of CoP displacements recorded in the backward-forward direction when standing on a foam mat (p<0.05) but not on a rigid surface. The electromyographic activity of the ankle plantar flexor muscles during upright standing decreased (p<0.05) after training but not for the tibialis anterior. Results obtained for H reflex and MEP input-output relations suggest an increased efficacy of Ia afferents to activate low-threshold motor neurones and a decrease in corticospinal excitability after training. This study indicates that short term training combining strength and balance exercises increases maximal strength and induces change in the neural control of lower leg muscles during upright standing. PMID- 25449859 TI - Estimation of sarcopenia prevalence using various assessment tools. AB - BACKGROUND: Sarcopenia is defined as a progressive and generalized loss of muscle mass with either a loss of muscle strength or a loss of physical performance but there is no recommendation regarding the diagnostic tools that have to be used. In this study, we compared the prevalence of sarcopenia assessed using different diagnostic tools. METHODS: To measure muscle mass, muscle strength and physical performance, we used for each outcome two different diagnostic tools. For muscle mass, we used Dual Energy X-Ray Absorptiometry (DXA) and bio-electrical impedance analysis (BIA); for muscle strength, we used a hydraulic dynamometer and a pneumatic dynamometer; for physical performance we used the Short Physical Performance Battery test (SPPB test) and the walk speed. Eight diagnostic groups were hereby established. RESULTS: A total of 250 consecutive subjects were recruited in an outpatient clinic in Liege, Belgium. Estimated prevalence of sarcopenia varied from 8.4% to 27.6% depending on the method of diagnosis used. Regarding muscle mass, BIA systematically overestimated muscle mass compared to DXA (mean estimated prevalence with BIA=12.8%; mean prevalence with DXA=21%). For muscle strength, the pneumatic dynamometer diagnosed twice more sarcopenic subjects than the hydraulic dynamometer (mean estimated prevalence with PD=22.4%; mean estimated prevalence with HD=11.4%). Finally, no difference in prevalence was observed when the walking speed or the SPPB test was used. A weak overall kappa coefficient was observed (0.53), suggesting that the 8 methods of diagnosis are moderately concordant. CONCLUSION: Within the same definition of sarcopenia, prevalence of sarcopenia is highly dependent on the diagnostic tools used. PMID- 25449861 TI - Efficacy and tolerability of antidepressants in pediatric anxiety disorders: a systematic review and meta-analysis. AB - BACKGROUND: Randomized controlled trials have demonstrated that antidepressants are efficacious in the treatment of anxiety disorders in youth. However, there are no recent, systematic analyses of the efficacy, safety, or tolerability of these medications in pediatric anxiety disorders. METHODS: A systematic review and meta-analysis of prospective, randomized, parallel-group, controlled trials of selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SSNRIs) in pediatric patients with non obsessive compulsive disorder (OCD) anxiety disorders was undertaken using a search of PubMed/Medline (1966-2014). The meta-analysis utilized random-effects models to evaluate change in the Pediatric Anxiety Rating Scale or similar anxiety scale, suicidality, and adverse events. Additionally, pharmacologic variables were explored with regard to effect size, although no correction for multiple comparisons was made with regard to these relationships. RESULTS: Nine trials involving 1,673 patients and six medications were included. All SSRI/SSNRIs evaluated demonstrated efficacy, and the meta-analytic estimate of effect was of moderate magnitude (Cohen's d = 0.62, confidence interval [CI]: 0.34-0.89, P = .009) and there was evidence of modest heterogeneity (I(2) = 0.29, P = .103). Activation trended toward being more likely with antidepressant treatment (OR: 1.86, CI: 0.98-3.53, P = .054), but no increased risk was observed for nausea/abdominal symptoms (P = .262), discontinuation as a result of an adverse event (P = .132), or suicidality (OR: 1.3, CI: 0.53-3.2, P = .514). Finally, the effect size correlated with the serotonergic specificity of the agent (R = .79, P = .021). CONCLUSIONS: Data for nine SSRI/SSNRIs suggest superiority of antidepressants relative to placebo for the treatment of pediatric anxiety disorders with a moderate effect size. PMID- 25449862 TI - Connexins, gap junctions and peripheral neuropathy. AB - Gap junctions (GJs) have emerged as an important molecular component of peripheral myelinated fibers following the discovery of mutations affecting the GJ protein connexin32 (Cx32) in patients with the X-linked Charcot-Marie-Tooth neuropathy (CMT1X). CMT1X is the second most common CMT form and is caused by over 400 different mutations in the GJB1 gene encoding Cx32. In peripheral nerves, Cx32 is expressed by Schwann cells and forms reflexive GJs through non compact myelin areas, which allow the diffusion of ions and small molecules including second messengers across apposed cell membranes connecting directly the Schwann cell perinuclear cytoplasm with the adaxonal cell compartment inside the myelin sheath. GJs formed by Cx32 play an important role in the homeostasis of myelinated axons. Patients with CMT1X typically present with a progressive peripheral neuropathy characterized by mixed demyelinating and axonal features electrophysiologically and pathologically, which may be accompanied by transient or chronic CNS myelin dysfunction. Both in vitro and in vivo models of the disease indicate that most Cx32 mutations cause loss of function and inability of the mutant Cx32 to form functional GJs. Increased understanding of CMT1X pathogenesis will lead to the development of effective therapies for this currently incurable disease. PMID- 25449863 TI - Gait analysis in three different 6-hydroxydopamine rat models of Parkinson's disease. AB - Gait deficits are important clinical symptoms of Parkinson's disease (PD) but are rarely studied. In this study we made three different rat PD models by administration of 6-hydroxydopamine into caudate putamen (CPU), medial forebrain bundle (MFB) and substantia nigra compact (SNC). We evaluated the gait changes in these models by using a computer-assisted CatWalk system. Correlations of gait parameters with tyrosine hydroxylase protein levels in the CPU and SNC were also investigated. The gait readouts were significantly impaired in both the MFB and SNC groups. However, the MFB group showed a more pronounced impairment than the SNC group. In contrast, only mild and incomplete gait impairment occurred in the CPU group. In addition, some gait parameters demonstrated close correlation with the protein levels of TH. This paper suggests that the 6-hydroxydopamine-induced MFB model is more propitious to study gait dysfunction than the other two models and the CatWalk system can provide reliable and objective criteria to stratify gait changes arising from 6-hydroxydopamine lesioned rats. These findings may hold promise in the study of PD disease progression and new therapeutic methods. PMID- 25449864 TI - The effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) on negative symptoms of schizophrenia and the follow-up study. AB - In this double-blind, randomized controlled study, we assessed the therapeutic effects of high-frequency left dorsolateral prefrontal cortex (DLPFC) repetitive transcranial magnetic stimulation (rTMS) on negative symptoms of schizophrenia. For the study, 117 patients with prominent negative symptoms were randomized to a 20-day course of either active rTMS applied to the left DLPFC (n = 78) or sham rTMS (n = 39). The primary outcome measures were the Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). Secondary outcomes included the Clinical Global Impressions Scale (CGI) and the Udvalg for Kliniske Under sogelser (UKU) Side Effect Rating Scale. We found that treatment with high-frequency rTMS for 6 weeks significantly improved negative symptoms in the active group as compared to the sham group. However, active rTMS was not correlated with significant improvement in the CGI severity of illness scale (CGI-S). The improvement of negative symptoms persisted to the 24-week follow-up assessment. These results indicate that there is a lasting beneficial effect of rTMS on negative symptoms in absence of decrease in CGI scores. We conclude that rTMS may serve as a relatively noninvasive treatment that alleviates negative symptoms in patients with schizophrenia. PMID- 25449865 TI - The temporal reliability of sound modulates visual detection: an event-related potential study. AB - Utilizing the high temporal resolution of event-related potentials (ERPs), we examined the effects of temporal reliability of sounds on visual detection. Significantly faster reaction times to visual target stimuli were observed when reliable temporal information was provided by a task-irrelevant auditory stimulus. Three main ERP components related to the effects of auditory temporal reliability were found: the first at 180-240 ms over a wide central area, the second at 300-400 ms over an anterior area, and the third at 300-380 ms over bilateral temporal areas. Our results support the hypothesis that temporal reliability affects visual detection and indicate that auditory facilitation of visual detection is partly due to spread of attention and thus results from implicit temporal linking of auditory and visual information at a relatively late processing stage. PMID- 25449866 TI - Chronic unpredictable stress impairs endogenous antioxidant defense in rat brain. AB - Many studies have shown that chronic stress can cause neuronal damage and depression, but this exact mechanism still remains unknown. Neurons are vulnerable to lipid peroxidation-induced damage because the major part of neuronal cell membrane is polyunsaturated fatty acids that are substrate for reactive oxygen species. Since endogenous antioxidant defense systems normally eliminate production of reactive oxygen species, deficient antioxidant defense can cause oxidative stress-induced damage. In the present study, to understand the role of endogenous antioxidant defense in chronic stress-induced neuronal damage, we analyzed lipid peroxidation, total antioxidant capacity, and activities of catalase and glutathione peroxidase in frontal cortex, hippocampus and striatum of rats exposed to chronic unpredictable stress. We found that chronic unpredictable stress for four weeks in rats induced depressive-like behaviors such as anhedonia, despair and decreased exploration. Malondialdehyde, a lipid peroxidation product, is increased, but total antioxidant capacity, glutathione peroxidase activity and catalase activity are decreased in brain of rats exposed to chronic unpredictable stress. Our findings suggest that down regulation of endogenous antioxidant defense induces lipid peroxidation contributing a role to chronic stress and depression. PMID- 25449867 TI - Evidence for sustained cortical involvement in peripheral stretch reflex during the full long latency reflex period. AB - Adaptation of reflexes to environment and task at hand is a key mechanism in optimal motor control, possibly regulated by the cortex. In order to locate the corticospinal integration, i.e. spinal or supraspinal, and to study the critical temporal window of reflex adaptation, we combined transcranial magnetic stimulation (TMS) and upper extremity muscle stretch reflexes at high temporal precision. In twelve participants (age 49 +/- 13 years, eight male), afferent signals were evoked by 40 ms ramp and subsequent hold stretches of the m. flexor carpi radialis (FCR). Motor conduction delays (TMS time of arrival at the muscle) and TMS-motor threshold were individually assessed. Subsequently TMS pulses at 96% of active motor threshold were applied with a resolution of 5-10 ms between 10 ms before and 120 ms after onset of series of FCR stretches. Controlled for the individually assessed motor conduction delay, subthreshold TMS was found to significantly augment EMG responses between 60 and 90 ms after stretch onset. This sensitive temporal window suggests a cortical integration consistent with a long latency reflex period rather than a spinal integration consistent with a short latency reflex period. The potential cortical role in reflex adaptation extends over the full long latency reflex period, suggesting adaptive mechanisms beyond reflex onset. PMID- 25449868 TI - The giant miniature endplate potentials frequency is increased in aged rats. AB - At the neuromuscular junction, spontaneous giant events (GMEPPs) are enhanced in different conditions when degenerative and/or remodeling processes take place, but no one investigated their incidence upon aging. In the present work, we evaluated evoked and spontaneous neuromuscular transmission events recorded from single muscle fibers. Phrenic-diaphragm preparations of 3-4, 12-16, 36-40 and 70 80 weeks old rat males were used. We found that the occurrence of GMEPPs significantly increases in aged rats. Moreover, in old rats the neuromuscular transmission was significantly impaired due to a significant decrease in the amplitude and quantal content of evoked endplate potentials. Interestingly, the number of observed EPPs failures were ~ 3 times lower than the predicted value based on the quantal content. This discrepancy was not observed in infant or adult rats. The coincidence of a high GMEPPs frequency with a lower than expected EPPs failure rate suggests that GMEPPs events are needed to preserve effective neuromuscular transmission in aged animals. PMID- 25449869 TI - Fluorocitrate induced the alterations of memory-related proteins and tau hyperphosphorylation in SD rats. AB - Astrocytes provide structural, metabolic and trophic supports for neurons. However, there are no direct evidences whether astrocytes involve in the regulation of synaptic proteins expression and tau phosphorylation until now. Here, we injected 1 nmol fluorocitrate (FC), which preferentially taken up by astrocytes and results in reversible inhibition of the astrocytic tricarboxylic acid cycle, into the left lateral ventricle of the brain in the SD rats for 1h, and found that FC treatment decreased several memory-related proteins levels, such as AMPA receptor GluR1/2, postsynaptic density protein 93/95, Arc and phosphorylated cAMP response element binding proteins, while increased synaptophysin and synapsin I levels in the hippocampus. FC treatment also increased the levels of phosphorylated tau at multiple Alzheimer-related phosphorylation sites, as well as activation of glycogen synthase kinase-3beta and inactivation of protein phosphatase-2A. Similar effects were also observed in the primary hippocampal neurons, which were cultured with the conditioned media from FC-treatment primary astrocytes. Our data suggest that astrocytes regulate neuronal tau phosphorylation and several synaptic proteins expression. PMID- 25449870 TI - Ferumoxytol administration does not alter infarct volume or the inflammatory response to stroke in mice. AB - Ferumoxytol is an ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle that is FDA-approved as an intravenous iron replacement therapy for the treatment of iron deficiency anemia in patients with chronic kidney disease. Ferumoxytol has also been used as a contrast agent for cerebral blood volume mapping by magnetic resonance imaging (MRI), which suggests it could be used for imaging hemodynamic abnormalities after stroke. However, circulating macrophages can internalize USPIOs, and recent data indicate that the accumulation of iron in macrophages can lead them to adopt the M1 pro-inflammatory phenotype. Therefore, the uptake of intravenously administered iron particles by circulating macrophages that home to the stroke core could potentially alter the inflammatory response to stroke. To test this possibility in vivo we administered a dose of ferumoxytol previously used to obtain cerebral blood volume maps in healthy humans by steady-state susceptibility contrast (SSC) MRI to BALB/cJ mice 48h after stroke and examined cytokine levels, microglial/macrophage activation, and lesion volume in the brain 5 days later. Treatment with ferumoxytol did not lead to any differences in these parameters. These data indicate that the use of ferumoxytol as a contrast agent for brain imaging after stroke does not alter the inflammatory response to stroke in mice, and is therefore unlikely to do so in human subjects. PMID- 25449871 TI - The antioxidative, non-psychoactive tricyclic phenothiazine reduces brain damage after experimental traumatic brain injury in mice. AB - Oxidative stress due to free radical formation is an important mechanism of secondary brain damage following traumatic brain injury (TBI). Phenothiazine has been found to be a strong antioxidant in eukaryotic cells in vitro and in invertebrates in vivo. The present study was designed to determine the neuroprotective potency of unsubstituted phenothiazine in a paradigm of acute brain injury. Thirty minutes after pneumatic, controlled cortical impact (CCI) injury, C57BI6 mice were randomly assigned to "low dose" (3 mg/kg, LD) or "high dose" (30 mg/kg, HD) s.c. phenothiazine or vehicle treatment. Brain lesion, neurofunctional impairment, body weight, and markers of cerebral inflammation were determined 24h after the insult. Phenothiazine treatment dose-dependently reduced brain lesion volume (LD: -19.8%; HD: -26.1%) and posttraumatic body weight loss. There were no significant differences in the neurological function score and in markers of cerebral inflammation (Iba-1 positive cells, TNFalpha expression), whereas iNOS expression was significantly lower compared to vehicle treated animals. Phenothiazine appears to modify in a post-treatment protocol certain aspects of secondary brain damage in vivo at unusually low concentrations, in particular the cortical contusion volume after TBI. The potential role of the reduced iNOS expression is unclear at present. PMID- 25449872 TI - Intravenous mesenchymal stem cell administration exhibits therapeutic effects against 6-hydroxydopamine-induced dopaminergic neurodegeneration and glial activation in rats. AB - To explore a novel therapy against Parkinson's disease (PD), we evaluated the therapeutic effects of human bone marrow-derived mesenchymal stem cells (hBM MSCs), pluripotent stromal cells with secretory potential of various neurotrophic and anti-inflammatory factors, in a hemi-parkinsonian rat model. The unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were injected hBM-MSCs (1.0 * 10(7)cells) or PBS intravenously 16 days after lesioning. Administration of hBM-MSCs inhibited methamphetamine-stimulated rotational behavior at 7, 14, 21 and 28 days after transplantation. Immunohistochemical analysis also showed that number of TH-positive neurons in the substantia nigra pars compacta was significantly preserved in hBM-MSCs-transplanted rats compared to sham-operated rats, whereas the immunoreactivity of ionized calcium binding adaptor molecule 1 was markedly inhibited. In this study, we demonstrated the therapeutic effects of intravenous hBM-MSCs administration in parkinsonian model rats presenting distinct parkinsonian phenotype at 16 days after 6-OHDA lesioning. The favorable findings raise the possibility that hBM-MSCs could be a novel therapeutic option to promote survival of dopaminergic neurons in PD. PMID- 25449873 TI - Velocity-dependent suppression of the soleus H-reflex during robot-assisted passive stepping. AB - The amplitude of the Hoffmann (H)-reflex in the soleus (Sol) muscle is known to be suppressed during passive stepping compared with during passive standing. The reduction of the H-reflex is not due to load-related afferent inputs, but rather to movement-related afferent inputs from the lower limbs. To elucidate the underlying neural mechanisms of this inhibition, we investigated the effects of the stepping velocity on the Sol H-reflex during robot-assisted passive stepping in 11 healthy subjects. The Sol H-reflexes were recorded during passive standing and stepping at five stepping velocities (stride frequencies: 14, 21, 28, 35, and 42 min(-1)) in the air. The Sol H-reflexes were significantly inhibited during passive stepping as compared with during passive standing, and reduced in size as the stepping velocity increased. These results indicate that the extent of H reflex suppression increases with increasing movement-related afferent inputs from the lower limbs during passive stepping. The velocity dependence suggests that the Ia afferent inputs from lower-limb muscles around the hip and knee joints are most probably related to this inhibition. PMID- 25449875 TI - The microfluidic chip module for the detection of murine norovirus in oysters using charge switchable micro-bead beating. AB - Sample preparation has recently been an issue in the detection of food poisoning pathogens, particularly viruses such as norovirus (NoV), in food because of the complexity of foods and raw fresh materials. Here, we demonstrate a total analytical microfluidic chip module to automatically perform a series of essential processes (cell concentration, lysis (RNA extraction), nucleic acid amplification, and detection) for the fast but sensitive detection of norovirus in oysters. The murine NoV spiked oyster was stomached using a standard method. The supernatant was first loaded into a shape switchable sample preparation chamber consisting of charge switchable micro-beads. Murine NoV, which was adsorbed on microbeads by electrostatic physisorption, was lysed using bead beating. The extracted RNA was transferred to the detection chamber to be amplified using Nucleic Acid Sequence Based Amplification (NASBA). The optimal surface functionality, size, and number of microbeads were achieved for the virus concentration and the stable RNA extraction in the shape-switchable micro channel. As a result, murine NoV in a single oyster was successfully detected within 4h by the microfluidic chip developed here, and could be directly applied to the large volume environmental sample as well as the food sample. PMID- 25449876 TI - A biomimetic sensor for the detection of lead in water. AB - The monitoring of lead (II) ions (Pb(2+)) in water is essential for both human health and the environment. Herein, a simple yet innovative biosensor for Pb(2+) detection is presented. The sensor is developed by the self-assembly of gold nanoparticles (GNPs) core-satellite structure using naturally occurring tripeptide glutathione (GSH) as linker. The addition of Pb(2+) caused a red-to blue color change and the localized surface plasmon resonance (LSPR) band was shifted to ca. 650 nm. The limit of detection (LOD) is found to be 47.6 nM (9.9 ppb) by UV-vis spectroscopy with high selectivity against other heavy metals. This method offers a new strategy for heavy metal detection using functionalized GNPs. PMID- 25449874 TI - Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia. AB - Aquaporin-4 (AQP4) is a water channel expressed in astrocyte end-feet lining the blood-brain barrier. AQP4 deletion in mice is associated with improved outcomes in global cerebral ischemia produced by transient carotid artery occlusion, and focal cerebral ischemia produced by permanent middle cerebral artery occlusion (MCAO). Here, we investigated the consequences of 1-h transient MCAO produced by intraluminal suture blockade followed by 23 h of reperfusion. In nine AQP4(+/+) and nine AQP4(-/-) mice, infarct volume was significantly reduced by an average of 39 +/- 4% at 24h in AQP4(-/-) mice, cerebral hemispheric edema was reduced by 23 +/- 3%, and Evans Blue extravasation was reduced by 31 +/- 2% (mean +/- SEM). Diffusion-weighted magnetic resonance imaging showed greatest reduction in apparent diffusion coefficient around the occlusion site after reperfusion, with remarkably lesser reduction in AQP4(-/-) mice. The reduced infarct volume in AQP4(-/-) mice following transient MCAO supports the potential utility of therapeutic AQP4 inhibition in stroke. PMID- 25449877 TI - An unconventional approach to impedance microbiology: detection of culture media conductivity variations due to bacteriophage generated lyses of host bacteria. AB - A novel and unconventional approach to impedance microbiology has been under investigation. In our approach, solution conductivity variations are generated from bacteriophage lyses of infected host cells and the consequent release of conductive endoplasmic material. To sensitively detect the lysis, low conductive growth media have been developed. A microchip has been fabricated to perform the analysis. The microchip is made of two bare gold electrodes and PDMS microchamber of 36 nL volume. Escherichia coli and selective phages T4 have been used as case study. Proof-of-principle experiments are here presented and discussed. The method was characterised in a wide range between 10(4) and 10(8) CFU/mL, where linear relation was found between conductivity variation and cell concentration in a log10 vs. log10 plot. The method is suited to integration with sample preparation based on phage-functionalised magnetic beads. It has a potential detection limit below 1 CFU/chamber and a total assay time of less than 1 h. PMID- 25449878 TI - Peptide conjugated chitosan foam as a novel approach for capture-purification and rapid detection of hapten--example of ochratoxin A. AB - A novel bioassay for the detection and monitoring of Ochratoxin A (OTA), a natural carcinogenic mycotoxin produced by Aspergillus and Penicillium fungi, has been developed and applied for the screening of red wine. Here we report the immobilization and orientation of NOF4, a synthetic peptide, onto 3-D porous chitosan supports using a N-terminal histidine tag to allow binding to M(++) ions that were previously adsorbed onto the high surface area biopolymer. Three divalent cations (M(++)=Zn(++), Co(++), Ni(++)) were evaluated and were found to adsorb via a Langmuir model and to have binding capacities in the order Zn(++)>Co(++)>Ni(++). Following Zn(++) saturation and washing, C-terminus vs. the N-terminus His-tagged NOF4 was evaluated. At 1000 ug L(-1) OTA the N-terminus immobilization was more efficient (2.5 times) in the capture of OTA. HRP labeled OTA was added to the antigen solutions (standards or samples) and together competitively incubated on biospecific chitosan foam. The chemiluminescence substrate luminol was then added and after 5 min of enzymatic reaction, light emission signals (lambdamax=425 nm) were analyzed. Calibration curves of %B/B0 vs. OTA concentration in PBS showed that half-inhibition occurred at 1.17 ug L( 1), allowing a range of discrimination of 0.25 and 25 ug L(-1). In red wine, the minimum concentration of OTA that the system can detect was 0.5 ug L(-1) and could detect up to 5 ug L(-1). Assay validation was performed against immunoaffinity column (IAC) tandem reversed-phase high pressure liquid chromatography with fluorescence detection (HPLC-FLD) and provided quite good agreement. The association of chitosan foam and specific peptide represents a new approach with potential for both purification-concentration and detection of small molecules. In the future this assay will be implemented in a solid-sate bioelectronic format. PMID- 25449879 TI - Computed tomography pulmonary angiography: more than a screening tool for pulmonary embolus. AB - BACKGROUND: Traumatically injured patients have multiple causes for acute respiratory decompensation. We reviewed the use of computed tomography pulmonary angiography (CTPA) in critically injured patients to evaluate the results and impact on patient care. METHODS: The charts of trauma patients (age >16 years) admitted to our intensive care unit for greater than 48 hours, who underwent CTPA for acute respiratory decompensation, were reviewed to determine the results of these studies and the effect on patient care. RESULTS: We identified 188 patients who underwent CTPA for acute physiologic changes. Pertinent clinical finding were identified in 95% of studies and included atelectasis/collapse (56%), pleural effusion (18%), pneumonia (15%), and pulmonary embolus (18%). These results prompted interventions designed to improve patient outcome. The most frequent interventions were modifications of ventilator therapy (52%), antibiotic therapy (28%), mini-bronchoalveolar lavage (15%), or bronchoscopy (15%). Diagnostic agreement between chest x-ray and CTPA was poor to moderate (kappa = 0.013 0.512). CONCLUSIONS: Computed tomography pulmonary angiography is valuable in the evaluation of cardiopulmonary deterioration in critically ill traumatically injured patients. Computed tomography pulmonary angiography offers the ability to identify causes of acute physiologic changes not detected using standard chest x ray. The results of these studies provide insight into the underlying pathophysiology and offer an opportunity to direct subsequent patient care. PMID- 25449880 TI - The methodology and pharmacokinetics study of intraventricular administration of vancomycin in patients with intracranial infections after craniotomy. AB - OBJECTIVE: The purpose of the study was to investigate the pharmacokinetics of combined intravenous (i.v.) and intracerebroventricular (i.c.v.) vancomycin for patients with intracranial infections after craniotomy and to provide the basis for establishing the intracranial local administration criterion. METHODS: Fourteen postoperative intracranial infection cases with surgical cavity/ventricular drainages were given vancomycin (1.0 g, i.v. drip for 2 hours, quaque 12 h, and a simultaneous i.c.v. injection of 10 mg). Their blood and cerebral spinal fluid (CSF) specimens were collected at each time point before and after administrations. The concentrations and biochemical properties were measured. RESULTS: The 1-hour serum vancomycin concentration reached a peak of 46.38 +/- 33.39 mg/L; the trough concentration of 48 hours was 8.10 +/- 7.11 mg/L; the CSF vancomycin concentration reached a peak of 382.17 +/- 421.00 mg/L at 0.25 hours, and the 48-hour trough concentration was 30.82 +/- 29.53 mg/L. The inhibitory quotient was calculated at 15.4 by the minimum inhibitory concentration 2 mg/L of target bacteria and had reached the range of 10 to 20 recommended by Infectious Diseases Society of America guidelines. The pH value and osmotic pressure of CSF were found to have no significant changes before and after administration. There was no increasement of seizures and ototoxicity in our study. Before the drug administration and 1 week later, the changes of creatine had no statistically significant, with P > .05. CONCLUSIONS: The combined i.v. and i.c.v. administration may improve CSF vancomycin concentrations without side effects at the same dosage. Our finding suggests that it can be an option for the treatment of severe intracranial infections after craniotomy; however, its safety and effectiveness need to be confirmed by further large-scale studies. PMID- 25449881 TI - The spectrum of psychocognitive morbidity in the critically ill: a review of the literature and call for improvement. AB - OBJECTIVE: The objective of the study is to review the cognitive and psychiatric dysfunction experienced by critically ill patients during and after hospitalization. METHODS: A structured PubMed search identified studies and reports in English pertaining to intensive care unit (ICU)-related cognitive and psychological dysfunction, known risk factors, and treatment modalities. DATA SYNTHESIS: This article summarizes recent literature on psychological sequelae experienced by critically ill patients including delirium, cognitive impairment, acute stress disorder, posttraumatic stress disorder, anxiety, and depression. Known risk factors for cognitive dysfunction and psychological trauma are discussed, encompassing clinical, demographic, socioeconomic, and psychiatric domains as well as the memories of the ICU stay. Specific treatment and prevention modalities are discussed including post-ICU physical rehabilitation and psychotherapeutic interventions as well as interventions available to patients still in the ICU, including early mobilization, minimization of sedation, improved sleep hygiene, and available psychological interventions. CONCLUSIONS: We propose a paradigm change highlighting the need for interventions focused on early psychological support applied in parallel with stabilization of physiologic status in the ICU. PMID- 25449882 TI - A pilot assessment of alpha-stat vs pH-stat arterial blood gas analysis after cardiac arrest. AB - PURPOSE: Resuscitated cardiac arrest (CA) patients typically receive therapeutic hypothermia, but arterial blood gases (ABGs) are often assessed after adjustment to 37 degrees C (alpha-stat) instead of actual body temperature (pH-stat). We sought to compare alpha-stat and pH-stat assessment of PaO2 and PaCO2 in such patients. MATERIALS AND METHODS: Using ABG data obtained during the first 24 hours of intensive care unit admission, we determined the impact of measured alpha vs calculated pH-stat on PaO2 and PaCO2 on patient classification and outcomes for CA patients. RESULTS: We assessed 1013 ABGs from 120 CA patients with a median age of patients 66 years (interquartile range, 50-76). Median alpha stat PaO2 changed from 122 (95-156) to 107 (82-143) mm Hg with pH-stat and median PaCO2 from 39 (34-46) to 35 (30-41) mm Hg (both P < .001). Using the categories of hyperoxemia, normoxemia, and hypoxemia, pH-stat estimation of PaO2 reclassified approximately 20% of patients. Using the categories of hypercapnia, normocapnia, and hypocapnia, pH stat estimation of PaCO2 reclassified approximately 40% of patients. The mortality of patients in different PaO2 and PaCO2 categories was similar for pH-stat and alpha-stat. CONCLUSIONS: Using the pH-stat method, fewer resuscitated CA patients admitted to intensive care unit were classified as hyperoxemic or hypercapnic compared with alpha-stat. These findings suggest an impact of ABG assessment methodology on PaO2, PaCO2 , and patient classification but not on associated outcomes. PMID- 25449883 TI - The role of noninvasive positive pressure ventilation in community-acquired pneumonia. AB - BACKGROUND: Despite the increasing use of noninvasive positive pressure ventilation (NIV) in the treatment of critically ill patients with respiratory failure, its role in the treatment of severe community-acquired pneumonia (CAP) is controversial. The aim of this study was to assess the use of NIV in patients with CAP requiring ventilation who are admitted an intensive care unit. METHODS: A retrospective cohort study of all consecutive patients admitted to 3 tertiary care, university-affiliated, intensive care units from January 2007 to January 2012 with the principal diagnosis of CAP and requiring positive pressure ventilation was carried out. The primary outcome was acute hospital mortality. Univariable and multivariable analysis were performed to assess the association between mode of ventilation and death as well as factors associated with failure of NIV. RESULTS: A total of 229 patients were admitted, with 20 patients excluded from the analysis because of do-not-resuscitate orders. Fifty-six percent of patients were initially treated with NIV. Of those, 76% failed NIV and required intubation and invasive ventilation. After adjusting for confounders, no difference in mortality was seen between patients who received NIV as first-line therapy in comparison with patients who received invasive ventilation (odds ratio [OR], 1.63; 95% confidence interval [CI], 0.81-3.28; P = .17). Multivariable analysis demonstrated a trend toward increased NIV failure for the patients who had higher Acute Physiology and Chronic Health Evaluation II scores (P = .07) and vasopressor use at 2 hours after initiation of positive pressure ventilation (OR, 7.5; 95% CI, 1.8-31.3, P = .006). In an adjusted analysis, patients who failed NIV had an increased odds of death when compared with patients who were treated with invasive ventilation (OR, 2.2; 95% CI, 1.0-4.8; P = .03). CONCLUSION: Noninvasive pressure ventilation is frequently used in CAP but is associated with high failure rates. Mortality was not improved in the group of patients who received NIV as first-line therapy despite clinical characteristics that might have suggested a more favorable prognosis. Given the high rates of NIV use, high failure rates, and the hypothesis generating nature of the data in this study, further randomized studies are needed to better delineate the role of NIV in CAP. PMID- 25449885 TI - Aptasensors based on supramolecular structures of nucleic acid-stabilized Ag nanoclusters. AB - Two-sized luminescent nucleic acid-functionalized Ag nanoclusters (NCs) are implemented for the analysis and multiplexed detection of adenosine monophosphate, AMP, and of cocaine using aptamer-ligand complexes. PMID- 25449884 TI - In vivo gene silencing following non-invasive siRNA delivery into the skin using a novel topical formulation. AB - Therapeutics based on short interfering RNAs (siRNAs), which act by inhibiting the expression of target transcripts, represent a novel class of potent and highly specific next-generation treatments for human skin diseases. Unfortunately, the intrinsic barrier properties of the skin combined with the large size and negative charge of siRNAs make epidermal delivery of these macromolecules quite challenging. To help evaluate the in vivo activity of these therapeutics and refine delivery strategies we generated an innovative reporter mouse model that predominantly expresses firefly luciferase (luc2p) in the paw epidermis--the region of murine epidermis that most closely models the tissue architecture of human skin. Combining this animal model with state-of-the-art live animal imaging techniques, we have developed a real-time in vivo analysis work-flow that has allowed us to compare and contrast the efficacies of a wide range nucleic acid-based gene silencing reagents in the skin of live animals. While inhibition was achieved with all of the reagents tested, only the commercially available "self-delivery" modified Accell-siRNAs (Dharmacon) produced potent and sustained in vivo gene silencing. Together, these findings highlight just how informative reliable reporter mouse models can be when assessing novel therapeutics in vivo. Using this work-flow, we developed a novel clinically-relevant topical formulation that facilitates non-invasive epidermal delivery of unmodified and "self-delivery" siRNAs. Remarkably, a sustained >40% luc2p inhibition was observed after two 1-hour treatments with Accell-siRNAs in our topical formulation. Importantly, our ability to successfully deliver siRNA molecules topically brings these novel RNAi-based therapeutics one-step closer to clinical use. PMID- 25449886 TI - The circadian gene Clock oscillates in the suprachiasmatic nuclei of the diurnal rodent Barbary striped grass mouse, Lemniscomys barbarus: a general feature of diurnality? AB - A major challenge in the field of circadian rhythms is to understand the neural mechanisms controlling the oppositely phased temporal organization of physiology and behaviour between night- and day-active animals. Most identified components of the master clock in the suprachiasmatic nuclei (SCN), called circadian genes, display similar oscillations according to the time of day, independent of the temporal niche. This has led to the predominant view that the switch between night- and day-active animals occurs downstream of the master clock, likely also involving differential feedback of behavioral cues onto the SCN. The Barbary striped grass mouse, Lemniscomys barbarus is known as a day-active Muridae. Here we show that this rodent, when housed in constant darkness, displays a temporal rhythmicity of metabolism matching its diurnal behaviour (i.e., high levels of plasma leptin and hepatic glycogen during subjective midday and dusk, respectively). Regarding clockwork in their SCN, these mice show peaks in the mRNA profiles of the circadian gene Period1 (Per1) and the clock-controlled gene Vasopressin (Avp), which occur during the middle and late subjective day, respectively, in accordance with many observations in both diurnal and nocturnal species. Strikingly, expression of the circadian gene Clock in the SCN of the Barbary striped grass mouse was not constitutive as in nocturnal rodents, but it was rhythmic. As this is also the case for the other diurnal species investigated in the literature (sheep, marmoset, and quail), a hypothesis is that the transcriptional control of Clock within the SCN participates in the mechanisms underlying diurnality and nocturnality. PMID- 25449887 TI - Resonance characteristic and its ionic basis of rat mesencephalic trigeminal neurons. AB - Intrinsic resonant frequency properties of neurons in the brain provide a basis for different behavioral states and determine the responding modality (i.e. excitability) of different neurons. Previously, three types of excitability behaviors in rat Mesencephalic V neurons were found. To investigate the different resonant frequency and ionic current mechanisms underlying different resonances among three types of excitability, we performed whole-cell patch recordings and applied ZAP current on Mesencephalic V cells (N=70) in rat slices. The results show that: Class 2 neurons (30/30) have two resonances with U-shaped voltage dependence. One is a high frequency resonance (75.4 +/- 2.11 Hz) significant at depolarized potentials (about -50 mV) and the other is a low frequency resonance (5.46 +/- 0.31 Hz) significant at hyperpolarized potentials (about -70 mV). Voltage clamp experiments reveal two non-inactivating currents operating in the subthreshold voltage range: (1) 4-aminopyridine sensitive K(+) current, which activates at membrane potentials positive than -60 mV and was blocked by 4-AP (50 uM), was underlying the high frequency resonance of Class 2 neuron; (2) h current, which activates negative than -60mV and was blocked by the hyperpolarization-activated cyclic nucleotide-gated channel blocker ZD7288 (10 uM), was underlying the low frequency resonance. Class 1 neurons do not show voltage-dependence resonant behaviors (10/10). Class 3 neurons (23/30) have two resonances, which are similar with Class 2 in both resonant frequency and currents. Our results provide clear evidence for the existence of multiple kinds of frequency resonances and how the relationship between the resonant frequency and the ionic current is based in Mesencephalic V neurons. PMID- 25449888 TI - Human umbilical cord mesenchymal stem cells protect against ischemic brain injury in mouse by regulating peripheral immunoinflammation. AB - Current treatments for ischemic stroke are limited, stem cell transplantation offers great potential as a therapeutic strategy. The present study was undertaken to determine whether human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) could improve brain injury after middle cerebral artery occlusion (MCAO) through modulating peripheral immunoinflammation. The study showed that neurological deficit was ameliorated and brain edema, infarct volume was significantly decreased from 72 h to 1 week post-MCAO with hUC-MSCs treatment via tail vein injection within 30 mins after stroke; hUC-MSCs attenuated the levels of inflammatory factors including IL-1, TNF-alpha, IL-23, IL-17 and IL-10 in peripheral blood serum and ischemia hemisphere after stroke; hUC-MSCs significantly decreased the level of Th17 cells at 24h and increased the level of Tregs at 72 h post-MCAO in peripheral immune system; the level of TGF-beta in blood serum was enhanced by hUC-MSCs. In conclusion, our findings suggested that hUC-MSCs had neuroprotection in MCAO mice by TGF-beta modulating peripheral immune and hUC-MSCs may be as a potential therapy for ischemic stroke. PMID- 25449889 TI - SUN11602-induced hyperexpression of calbindin D-28k is pivotal for the survival of hippocampal neurons under neurotoxic conditions. AB - Basic fibroblast growth factor (FGF-2/bFGF) possesses neuroprotective activity and promotes cell proliferation. In this study, the novel synthetic compound 4 ({4-[[(4-amino-2,3,5,6-tetramethylanilino)acetyl](methyl)amino]-1 piperidinyl}methyl)benzamide (SUN11602) exhibited neuroprotective activities similar to those of FGF-2 without promoting cell proliferation. In primary cultures of hippocampal neurons, stimulation with SUN11602 or FGF-2 increased calbindin D-28k (CalB) gene expression and prevented glutamate-induced neuronal death. These effects were abolished by pretreatment with PD166866 (FGF receptor 1 [FGFR1] tyrosine kinase-specific inhibitor). This indicated that FGFR1 activation and increased CalB expression were involved in SUN11602-mediated neuroprotection. However, receptor-binding assays revealed that unlike FGF-2, SUN11602 did not alter the binding of (125)I-labeled FGF-2 to FGFR1. To investigate the possible proliferative activity of SUN11602, we utilized BHK21 and SKN cells expressing endogenous FGFR1. FGF-2 promoted cell proliferation whereas SUN11602 did not. In in vivo studies, wild-type (WT) and CalB-deficient (CalB(-/-)) mice were injected with aggregated Abeta1-40 and ibotenate (NMDA receptor agonist) to severely damage the hippocampal tissue. Treatment with SUN11602 (orally) or FGF-2 (intraparenchymally) at the midpoint of Abeta1-40 and ibotenate injections prevented the hippocampal damage in WT mice, however this effect was abolished in CalB(-/-) mice. Thus, SUN11602 exerted protective effects on hippocampal neurons through activation of FGFR1 and increased CalB expression. Moreover, the neuroprotective effects of SUN11602 depended upon the various biological activities of FGF-2. PMID- 25449890 TI - Reduction of epileptic spike-wave activity in WAG/Rij rats fostered by Wistar dams. AB - In WAG/Rij rat genetic model of absence epilepsy, the first spike-wave discharges (EEG hallmark of absence epilepsy) are known to appear after puberty, and their incidence increases with age. WAG/Rij rats are known to have a genetic predisposition to absence epilepsy, and further development of epilepsy might be influenced by epigenetic factors. This preliminary study examined the effect of early postnatal factors on the incidence of epileptic spike-wave discharges in adulthood. The newborn WAG/Rij rats were fostered by Wistar dams (from birth throughout the weaning age), and their EEG was examined continuously from 5 to 13 months of age. It was found that the number and duration of absence seizures was reduced in WAG/Rij rats adopted by Wistar dams as compared with the age-matched control WAG/Rij rats nursed by their own mothers. These data indicate that natural (epigenetic) factors, such as maternal care during suckling period, affect development of seizure activity in genetically prone subjects. It is suggested that improvement of primarily care-giving environment in subjects with genetic predisposition to absence epilepsy is a way to reduce epileptic activity in later life. PMID- 25449891 TI - Localization and characterization of an essential associative memory trace in the mammalian brain. AB - We argue here that we have succeeded in localizing an essential memory trace for a basic form of associative learning and memory - classical conditioning of discrete responses learned with an aversive stimulus - to the anterior interpositus nucleus of the cerebellum. We first identified the entire essential circuit, using eyelid conditioning as the model system, and used reversible inactivation, during training, of critical structures and activation of pathways to localize definitively the essential memory trace. This discovery and the associated studies have: 1) shown that the essential cerebellar circuit applies equally to all mammals studied, including humans; 2) shown that this cerebellar circuit holds for the learning of any discrete behavioral response elicited by an aversive US, not just eyelid closure; 3) identified the essential circuit and process for reinforcement for this form of learning; 4) shown that this form of learning and its essential cerebellar circuitry is phylogenetically very old; 5) solved the long-standing puzzle of where memory traces are formed in the brain when the CS is electrical stimulation of the cerebral cortex in conditioning; 6) shown that this cerebellar circuitry forms the essential neural substrate for the behavioral phenomenon of "blocking", and hence, 7) provides the first clear neural instantiation of the Rescorla-Wagner learning algorithm; 8) shown that the fundamental neural process underlying this form of learning is a strengthening of preexisting pathways, and 9) shown that the basic mechanism underlying this strengthening is the formation of new excitatory synapses. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25449893 TI - Effects of risperidone treatment on the expression of hypothalamic neuropeptide in appetite regulation in Wistar rats. AB - Although the use of atypical antipsychotic drugs has been successful in the treatment of schizophrenia, they can cause some complications in the long-term use, including weight gain. Patients using these drugs tend to disrupt treatment primarily due to side effects. The atypical antipsychotic mechanism of action regulates a number of highly disrupted neurotransmitter pathways in the brains of psychotic patients but may also cause impairment of neurohormonal pathways in different brain areas. In this study, we investigated the circulating levels of hypothalamic neurohormones, which are related to appetite regulation; neuropeptide Y (NPY); alpha melanocyte stimulating hormone (alpha-MSH); cocaine and amphetamine regulated transcript (CART); agouti-related peptide (AgRP); and leptin in male Wistar rats, which were treated with risperidone, a serotonin antagonist, for four weeks. Alterations in the mRNA expression levels of these candidate genes in the hypothalamus were also analyzed. We hypothesized that risperidone treatment might alter both hypothalamic and circulating levels of neuropeptides through serotonergic antagonism, resulting in weight gain. Gene expression studies revealed that the mRNA expression levels of proopiomelanocortin (POMC), AgRP, and NPY decreased as well as their plasma levels, except for NPY. Unexpectedly, CART mRNA levels increased when their plasma levels decreased. Because POMC neurons express the serotonin receptor (5HT2C), the serotonergic antagonism of risperidone on POMC neurons may cause an increase in appetite and thus increase food consumption even in a short-term trial in rats. PMID- 25449892 TI - Time and space in the hippocampus. AB - It has been hypothesized that one of the functions of the hippocampus is to enable the learning of relationships between different stimuli experienced in the environment. These relationships might be spatial ("the bathroom is about 5m down the hall from the bedroom") or temporal ("the coffee is ready about 3 min after the button was pressed"). Critically, these spatial and temporal relationships may exist on a variety of scales from a few hundred milliseconds up to minutes. In order to learn consistent relationships between stimuli separated by a variety of spatial and temporal scales using synaptic plasticity that has a fixed temporal window extending at most a few hundred milliseconds, information about the spatial and temporal relationships of distant stimuli must be available to the hippocampus in the present. Hippocampal place cells and time cells seem well suited to represent the spatial and temporal locations of distant stimuli in order to support learning of these relationships. We review a recent computational hypothesis that can be used to construct both spatial and temporal relationships. We suggest that there is a deep computational connection between spatial and temporal coding in the hippocampus and that both serve the overarching function of learning relationships between stimuli-constructing a "memory space." This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25449894 TI - Distinct cardioprotective mechanisms of immediate, early and delayed ischaemic postconditioning. AB - Cardioprotection against ischaemia/reperfusion injury in mice can be achieved by delayed ischaemic postconditioning (IPost) applied as late as 30 min after the onset of reperfusion. We determined the efficacy of delayed IPost in a rat model of myocardial infarction (MI) and investigated potential underlying mechanisms of this phenomenon. Rats were subjected to 20, 30 or 45 min of coronary artery occlusion followed by 120 min of reperfusion (I/R). Immediate and early IPost included six cycles of I/R (10/10 s) applied 10 s or 10 min after reperfusion onset. In the second series of experiments, the rats were subjected to 30 min of coronary occlusion followed by IPost applied 10 s, 10, 30, 45 or 60 min after the onset of reperfusion. Immediate and early IPost (applied 10 s or 10 min of reperfusion) established cardioprotection only when applied after a period of myocardial ischaemia lasting 30 min. Delayed IPost applied after 30 or 45 min of reperfusion reduced infarct sizes by 36 and 41 %, respectively (both P < 0.01). IPost applied 60 min after reperfusion onset was ineffective. Inhibition of RISK pathway (administration of ERK1/2 inhibitor PD-98059 or PI3K inhibitor LY-294002) abolished cardioprotection established by immediate IPost but had no effect on cardioprotection conferred by early IPost. Blockade of SAFE pathway using JAK/STAT inhibitor AG490 had no effect on the immediate or early IPost cardioprotection. Blockade of mitochondrial KATP (mitoKATP) channels (with 5 Hydroxydecanoate) abolished cardioprotection achieved by immediate and early IPost, but had no effect on cardioprotection when IPost was applied 30 or 45 min into the reperfusion period. Immediate IPost increased phosphorylation of PI3K AKT and ERK1/2. Early or delayed IPost had no effect on phosphorylation of PI3K AKT, ERK1/2 or STAT3. These data show that in the rat model, delayed IPost confers significant cardioprotection even if applied 45 min after onset of reperfusion. Cardioprotection induced by immediate and early postconditioning involves recruitment of RISK pathway and/or mitoKATP channels, while delayed postconditioning appears to rely on a different mechanism. PMID- 25449896 TI - Brain natriuretic peptide is able to stimulate cardiac progenitor cell proliferation and differentiation in murine hearts after birth. AB - Brain natriuretic peptide (BNP) contributes to heart formation during embryogenesis. After birth, despite a high number of studies aimed at understanding by which mechanism(s) BNP reduces myocardial ischemic injury in animal models, the actual role of this peptide in the heart remains elusive. In this study, we asked whether BNP treatment could modulate the proliferation of endogenous cardiac progenitor cells (CPCs) and/or their differentiation into cardiomyocytes. CPCs expressed the NPR-A and NPR-B receptors in neonatal and adult hearts, suggesting their ability to respond to BNP stimulation. BNP injection into neonatal and adult unmanipulated mice increased the number of newly formed cardiomyocytes (neonatal: +23 %, p = 0.009 and adult: +68 %, p = 0.0005) and the number of proliferating CPCs (neonatal: +142 %, p = 0.002 and adult: +134 %, p = 0.04). In vitro, BNP stimulated CPC proliferation via NPR-A and CPC differentiation into cardiomyocytes via NPR-B. Finally, as BNP might be used as a therapeutic agent, we injected BNP into mice undergoing myocardial infarction. In pathological conditions, BNP treatment was cardioprotective by increasing heart contractility and reducing cardiac remodelling. At the cellular level, BNP stimulates CPC proliferation in the non-infarcted area of the infarcted hearts. In the infarcted area, BNP modulates the fate of the endogenous CPCs but also of the infiltrating CD45(+) cells. These results support for the first time a key role for BNP in controlling the progenitor cell proliferation and differentiation after birth. The administration of BNP might, therefore, be a useful component of therapeutic approaches aimed at inducing heart regeneration. PMID- 25449897 TI - Identification of intrinsically disordered regions in PTEN and delineation of its function via a network approach. AB - Intrinsically disordered proteins (IDPs) are proteins that lack stable higher order structures for the entire protein molecule or a significant portion of it. The discovery of IDPs evolved as an antithesis to the conventional structure function paradigm wherein a higher order structure dictates protein function. Over the last decade, a number of proteins with functionally relevant unstructured regions have been discovered, which includes tumor suppressor PTEN. The protein domains that lack structure provide "hot-spots" for post translational modifications (PTMs) and protein-protein interactions (PPIs), which facilitate their regulation and participation in multiple cellular processes. Consequently, dysregulation in IDPs contribute to aberrant cellular pathophysiology. Herein, we present PTEN and its translational isoform PTEN-L as a hybrid protein possessing ordered domain and intrinsically disordered C terminal and an N-terminal tails. We review the role of intrinsic disorder in PTEN function and propose a methodology for the use of intrinsic disorder to study PTEN-regulated higher order protein-networks by associating basic principles of network biology to functional pathway analysis at the systems level. PMID- 25449895 TI - Remote ischemic conditioning: from experimental observation to clinical application: report from the 8th Biennial Hatter Cardiovascular Institute Workshop. AB - In 1993, Przyklenk and colleagues made the intriguing experimental observation that 'brief ischemia in one vascular bed also protects remote, virgin myocardium from subsequent sustained coronary artery occlusion' and that this effect'... may be mediated by factor(s) activated, produced, or transported throughout the heart during brief ischemia/reperfusion'. This seminal study laid the foundation for the discovery of 'remote ischemic conditioning' (RIC), a phenomenon in which the heart is protected from the detrimental effects of acute ischemia/reperfusion injury (IRI), by applying cycles of brief ischemia and reperfusion to an organ or tissue remote from the heart. The concept of RIC quickly evolved to extend beyond the heart, encompassing inter-organ protection against acute IRI. The crucial discovery that the protective RIC stimulus could be applied non-invasively, by simply inflating and deflating a blood pressure cuff placed on the upper arm to induce cycles of brief ischemia and reperfusion, has facilitated the translation of RIC into the clinical setting. Despite intensive investigation over the last 20 years, the underlying mechanisms continue to elude researchers. In the 8th Biennial Hatter Cardiovascular Institute Workshop, recent developments in the field of RIC were discussed with a focus on new insights into the underlying mechanisms, the diversity of non-cardiac protection, new clinical applications, and large outcome studies. The scientific advances made in this field of research highlight the journey that RIC has made from being an intriguing experimental observation to a clinical application with patient benefit. PMID- 25449898 TI - A guide for building biological pathways along with two case studies: hair and breast development. AB - Genomic information is being underlined in the format of biological pathways. Building these biological pathways is an ongoing demand and benefits from methods for extracting information from biomedical literature with the aid of text-mining tools. Here we hopefully guide you in the attempt of building a customized pathway or chart representation of a system. Our manual is based on a group of software designed to look at biointeractions in a set of abstracts retrieved from PubMed. However, they aim to support the work of someone with biological background, who does not need to be an expert on the subject and will play the role of manual curator while designing the representation of the system, the pathway. We therefore illustrate with two challenging case studies: hair and breast development. They were chosen for focusing on recent acquisitions of human evolution. We produced sub-pathways for each study, representing different phases of development. Differently from most charts present in current databases, we present detailed descriptions, which will additionally guide PESCADOR users along the process. The implementation as a web interface makes PESCADOR a unique tool for guiding the user along the biointeractions, which will constitute a novel pathway. PMID- 25449899 TI - Quantitative and dynamic analysis of PTEN phosphorylation by NMR. AB - The dual lipid and protein phosphatase PTEN is a tumor suppressor controlling key biological processes, such as cell growth, proliferation and neuro-survival. Its activity and intracellular trafficking is finely regulated notably by multi-site phosphorylation of its C-terminal tail. The reversible and highly dynamic character of these regulatory events confers a temporal dimension to the cell for triggering crucial decisions. In this review, we describe how a recently developed time-resolved NMR spectroscopy approach unveils the dynamic establishment of the phosphorylation events of PTEN C-terminal tail controlled by CK2 and GSK3beta kinases. Two cascades of reactions have been identified, in vitro and in extracts of human neuroblastoma cells. They are triggered independently on two nearby clusters of sites (S380-S385 and S361-S370) and occur on different timescales. In each cascade, the reactions follow an ordered model with a distributive kinetic mechanism. The vision of these cascades as two delay timers activating distinct or time-delayed regulatory responses gives a temporal dimension on PTEN regulation and is discussed in relation to the known functional roles of each cluster. PMID- 25449900 TI - A method for time-resolved calorespirometry of terrestrial samples. AB - A new vessel for simultaneous isothermal calorimetry and respirometry (calorespirometry) on terrestrial (non-aqueous) samples has been developed. All types of small (<1 g) biological samples (insects, soil, leaves, fungi, etc.) can be studied. The respirometric measurements are made by opening and closing a valve to a vial inside the sample ampoule containing a carbon dioxide absorbent. Typically a 7 h measurement results in seven measurements of heat production rate, oxygen consumption and carbon dioxide production, which can be used to evaluate how the metabolic activity in a sample changes over time. Results from three experiments on leaves, a cut vegetable, and mold are given. As uncertainties--especially in the carbon dioxide production--tend to be quite high, improvements to the technique are also discussed. PMID- 25449901 TI - Visualizing the spatial gene expression organization in the brain through non linear similarity embeddings. AB - The Allen Brain Atlases enable the study of spatially resolved, genome-wide gene expression patterns across the mammalian brain. Several explorative studies have applied linear dimensionality reduction methods such as Principal Component Analysis (PCA) and classical Multi-Dimensional Scaling (cMDS) to gain insight into the spatial organization of these expression patterns. In this paper, we describe a non-linear embedding technique called Barnes-Hut Stochastic Neighbor Embedding (BH-SNE) that emphasizes the local similarity structure of high dimensional data points. By applying BH-SNE to the gene expression data from the Allen Brain Atlases, we demonstrate the consistency of the 2D, non-linear embedding of the sagittal and coronal mouse brain atlases, and across 6 human brains. In addition, we quantitatively show that BH-SNE maps are superior in their separation of neuroanatomical regions in comparison to PCA and cMDS. Finally, we assess the effect of higher-order principal components on the global structure of the BH-SNE similarity maps. Based on our observations, we conclude that BH-SNE maps with or without prior dimensionality reduction (based on PCA) provide comprehensive and intuitive insights in both the local and global spatial transcriptome structure of the human and mouse Allen Brain Atlases. PMID- 25449902 TI - Analysis of survival, gene expression and behavior following chill-coma in the medfly Ceratitis capitata: effects of population heterogeneity and age. AB - The medfly Ceratitis capitata is an agricultural pest distributed worldwide thanks, in part, to its phenotypic plasticity of thermal tolerance. Cold exposure has been shown to reduce C. capitata survival, which may affect its distribution in areas with subfreezing temperatures. When insects are increasingly cooled, they attain a critical thermal threshold and enter a chill-coma state characterized by cessation of movement. It is not clear how a rapid cold exposure affects the physiological state of medflies, and how this is influenced by age and population heterogeneity. In order to approach these questions, C. capitata single-sex laboratory populations of 15 and 30 days old were subjected to a chill coma recovery assay, and separated according to their recovery time in three subgroups: Fast-Subgroups, Intermediate-Subgroups, and Slow-Subgroups. Thereafter, we analyzed their survival, behavioral, and gene expression outputs. In female and old male populations, we found that flies with the slowest recovery time had a reduced life expectancy, a higher initial mortality rate, and a worse climbing performance compared with flies that recovered faster. Therefore, we were able to separate subgroups that developed chilling-injury from subgroups that had a reversible full recovery after cold exposure. The gene expression analysis of the heat shock protein genes hsp70 and hsp83 showed no clear association with the parameters studied. Interestingly, thorax expression levels of the Cu/Zn superoxide dismutase gene were elevated during the recovery phase in the Fast-Subgroups, but remained constant in the Slow-Subgroups that developed chilling-injury. On the other hand, none of the young male subgroups seemed to have suffered irreversible damage. Thus, we concluded that depending on age and population heterogeneity, chill-coma recovery time points out significant differences on individual cold tolerance. Moreover, the inability to properly induce the antioxidant defense system to counteract the oxidative damage caused by cold seems to contribute to the development of chilling-injury. PMID- 25449903 TI - Uncovering deep mysteries: the underwater life of an amphibious louse. AB - Despite the incredible success of insects in colonizing almost every habitat, they remain virtually absent in one major environment--the open sea. A variety of hypotheses have been raised to explain why just a few insect species are present in the ocean, but none of them appears to be fully explanatory. Lice belonging to the family Echinophthiriidae are ectoparasites on different species of pinnipeds and river otters, i.e. they have amphibious hosts, who regularly perform long excursions into the open sea reaching depths of hundreds of meters (thousands of feets). Consequently, lice must be able to support not only changes in their surrounding media, but also extreme variations in hydrostatic pressure as well as breathing in a low oxygen atmosphere. In order to shed some light on the way lice can survive during the diving excursions of their hosts, we have performed a series of experiments to test the survival capability of different instars of Antarctophthirus microchir (Phthiraptera: Anoplura) from South American sea lions Otaria flavescens, when submerged into seawater. These experiments were aimed at analyzing: (a) immersion tolerance along the louse life; (b) lice's ability to obtain oxygen from seawater; (c) physiological responses and mechanisms involved in survival underwater. Our experiments showed that the forms present in non diving pups--i.e. eggs and first-instar nymphs--were unable to tolerate immersion in water, while following instars and adults, all usually found in diving hosts, supported it very well. Furthermore, as long as the level of oxygen dissolved in water was higher, the lice survival capability underwater increased, and the recovery period after returning to air declined. These results are discussed in relation to host ecology, host exploitation and lice functional morphology. PMID- 25449904 TI - A cost benefit analysis of the Luminex xTAG Gastrointestinal Pathogen Panel for detection of infectious gastroenteritis in hospitalised patients. AB - OBJECTIVES: Recent advances in the laboratory detection of infectious diarrhoea allow more rapid and sensitive identification of infected patients. Several commercial multiplex molecular panels are now available and may have significant advantages over culture based techniques. Faster and more sensitive testing of hospitalised patients with suspected infectious gastroenteritis could result in significant efficiencies in the utilisation of isolation facilities, however few studies have examined this potential benefit. We studied the potential clinical and cost benefits of a commercially available molecular panel. METHODS: An eight month parallel diagnostic study was conducted to measure potential economic benefits of testing hospitalised patients with the Luminex xTAG Gastrointestinal Pathogen Panel (GPP) compared with conventional laboratory testing (based on a combination of culture, microscopy and enzyme immunoassay). Laboratory testing costs and patient isolation costs were measured or estimated for 800 patients. RESULTS: Although costing an additional L22,283, use of GPP could enable a reduction in isolation time from 2202 to 1447 days, a saving of L66,765, which more than offsets the additional laboratory testing costs. CONCLUSION: Syndromic testing of patients against a broad panel of organisms using a multiplex molecular panel can both improve detection rates and allow better laboratory workflow practices. Removing patients testing negative using this panel could result in significant patient isolation savings. PMID- 25449905 TI - Changes in total cell numbers of the basal ganglia in patients with multiple system atrophy - A stereological study. AB - Total numbers of neurons, oligodendrocytes, astrocytes, and microglia in the basal ganglia and red nucleus were estimated in brains from 11 patients with multiple system atrophy (MSA) and 11 age- and gender-matched control subjects with unbiased stereological methods. Compared to the control subjects, the MSA patients had a substantially lower number of neurons in the substantia nigra (p=0.001), putamen (p=0.001), and globus pallidus (p<0.001), and, to a lesser extent in the caudate nucleus (p=0.03). A significantly lower number of oligodendrocytes were only observed in the putamen (p=0.04) and globus pallidus (p=0.01). In the MSA brains the total number of astrocytes was significantly higher in the putamen (p=0.04) and caudate nucleus (p=0.01). In all examined regions a higher number of microglia were found in the MSA brains with the greatest difference observed in the otherwise unaffected red nucleus (p=0.001). The results from the stereological study were supported by cell marker expression analyses showing increased markers for activated microglia. Our results suggest that microgliosis is a consistent and severe neuropathological feature of MSA, whereas no widespread and substantial loss of oligodendrocytes was observed. We have demonstrated significant neuronal loss in the substantia nigra, striatum, and globus pallidus of patients with MSA, while neurons in other basal ganglia nuclei were spared, supporting the region-specific patterns of neuropathological changes in MSA. PMID- 25449906 TI - Sigma-1 receptor is involved in degradation of intranuclear inclusions in a cellular model of Huntington's disease. AB - The sigma-1 receptor (SIGMAR1) is one of the endoplasmic reticulum (ER) chaperones, which participate in the degradation of misfolded proteins via the ER related degradation machinery linked to the ubiquitin-proteasome pathway. ER dysfunction in the formation of inclusion bodies in various neurodegenerative diseases has also become evident. Recently, we demonstrated that accumulation of SIGMAR1 was common to neuronal nuclear inclusions in polyglutamine diseases including Huntington's disease. Our study also indicated that SIGMAR1 might shuttle between the cytoplasm and the nucleus. In the present study, we investigated the role of SIGMAR1 in nuclear inclusion (NI) formation, using HeLa cells transfected with N-terminal mutant huntingtin. Cell harboring the mutant huntingtin produced SIGMAR1-positive NIs. SIGMAR1 siRNA and a specific inhibitor of the proteasome (epoxomicin) caused significant accumulation of aggregates in the cytoplasm and nucleus. A specific inhibitor of exportin 1 (leptomycin B) also caused NIs. Huntingtin became insolubilized in Western blot analysis after treatments with SIGMAR1 siRNA and epoxomicin. Furthermore, proteasome activity increased chronologically along with the accumulation of mutant huntingtin, but was significantly reduced in cells transfected with SIGMAR1 siRNA. By contrast, overexpression of SIGMAR1 reduced the accumulation of NIs containing mutant huntingtin. Although the LC3-I level was decreased in cells treated with both SIGMAR1 siRNA and control siRNA, the levels of LC3-II and p62 were unchanged. SIGMAR1 agonist and antagonist had no effect on cellular viability and proteasome activity. These findings suggest that the ubiquitin-proteasome pathway is implicated in NI formation, and that SIGMAR1 degrades aberrant proteins in the nucleus via the ER-related degradation machinery. SIGMAR1 might be a promising candidate for therapy of Huntington's disease. PMID- 25449907 TI - Parallel age-associated changes in brain and plasma neuronal pentraxin receptor levels in a transgenic APP/PS1 rat model of Alzheimer's disease. AB - Neuronal pentraxin receptor (NPR) is a synaptic protein implicated in AMPA receptor trafficking at excitatory synapses. Since glutamate neurotransmission is disrupted in Alzheimer's disease (AD), NPR levels measured from plasma represent a potential biomarker for synaptic dysfunction associated with AD. We sought to determine the relationship between AD pathology and brain and plasma NPR levels by examining age-associated NPR levels in these compartments in a transgenic APP/PS1 rat model of AD. NPR levels in cortical homogenate were similar in wild type (Wt) and APP/PS1 rats at 3 months of age (prior to Abeta plaque deposition), but significantly increased in APP/PS1 rats by 9 and 18-20 months of age (after the onset of plaque deposition). These age-dependent differences were driven by proportional increases in NPR in membrane-associated cortical fractions. Genotype related differences in NPR expression were also seen in the hippocampus, which exhibits significant Abeta pathology, but not in the cerebellum, which does not. Plasma analyses revealed increased levels of a 26 kDa NPR fragment in APP/PS1 rats relative to Wt rats by 18-20 months of age, which correlated with the levels of full-length NPR in cortex. Our findings indicate that cerebral accumulation of NPR and Abeta occurs with similar temporal and regional patterns in the APP/PS1 model, and suggest that a 26 kDa plasma NPR fragment may represent a peripheral biomarker of this process. PMID- 25449908 TI - Hyperactivation of D1 and A2A receptors contributes to cognitive dysfunction in Huntington's disease. AB - Stimulation of dopamine D1 receptor (D1R) and adenosine A2A receptor (A2AR) increases cAMP-dependent protein kinase (PKA) activity in the brain. In Huntington's disease, by essentially unknown mechanisms, PKA activity is increased in the hippocampus of mouse models and patients and contributes to hippocampal-dependent cognitive impairment in R6 mice. Here, we show for the first time that D1R and A2AR density and functional efficiency are increased in hippocampal nerve terminals from R6/1 mice, which accounts for increased cAMP levels and PKA signaling. In contrast, PKA signaling was not altered in the hippocampus of Hdh(Q7/Q111) mice, a full-length HD model. In line with these findings, chronic (but not acute) combined treatment with D1R plus A2AR antagonists (SCH23390 and SCH58261, respectively) normalizes PKA activity in the hippocampus, facilitates long-term potentiation in behaving R6/1 mice, and ameliorates cognitive dysfunction. By contrast, chronic treatment with either D1R or A2AR antagonist alone does not modify PKA activity or improve cognitive dysfunction in R6/1 mice. Hyperactivation of both D1R and A2AR occurs in HD striatum and chronic treatment with D1R plus A2AR antagonists normalizes striatal PKA activity but it does not affect motor dysfunction in R6/1 mice. In conclusion, we show that parallel alterations in dopaminergic and adenosinergic signaling in the hippocampus contribute to increase PKA activity, which in turn selectively participates in hippocampal-dependent learning and memory deficits in HD. In addition, our results point to the chronic inhibition of both D1R and A2AR as a novel therapeutic strategy to manage early cognitive impairment in this neurodegenerative disease. PMID- 25449911 TI - A study of the human bocavirus replicative genome structures. AB - The complete genomes of two human bocavirus 4 (HBoV4) isolates recovered in 2011 in Novosibirsk, Russia have been determined. A set of primers was designed based on the determined and previously published HBoV sequences; this primer pair was able to detect all possible HBoV replicative intermediates. This primer set was used to assay all HBoV genotypes and detected only those structures that correspond to an episomal form of this viral genome. Also, for the first time, head-to-tail nucleotide sequences have been determined for HBoV4. Secondary structures of the terminal noncoding regions (NCRs) of episomal forms have been computed for all HBoV genotypes, as well as for the canine bocavirus. Conserved secondary structures in episomal NCRs, which are likely to play an important part in the replication of bocaviruses, were found. NCR heterogeneity in the genomes of individual HBoV isolates has been shown for the first time. PMID- 25449910 TI - Inhibition of Theiler's virus-induced apoptosis in infected murine macrophages results in necroptosis. AB - In mice Theiler's murine encephalomyelitis virus (TMEV) persists in macrophages that eventually undergo apoptosis. TMEV infection of macrophages in culture induces apoptosis through the intrinsic pathway, restricting virus yields. We show that inhibition of TMEV-induced apoptosis leads to phosphorylation of receptor interacting protein 1 (RIP1), localization of RIP1 and RIP3 to mitochondria, ROS production independent of MAPK activation and programmed necrosis (necroptosis). Blocking both apoptosis and necroptosis restored virus yields. PMID- 25449912 TI - Injectable silk-polyethylene glycol hydrogels. AB - Silk hydrogels for tissue repair are usually pre-formed via chemical or physical treatments from silk solutions. For many medical applications, it is desirable to utilize injectable silk hydrogels at high concentrations (>8%) to avoid surgical implantation and to achieve slow in vivo degradation of the gel. In the present study, injectable silk solutions that formed hydrogels in situ were generated by mixing silk with low-molecular-weight polyethylene glycol (PEG), especially PEG300 and 400 (molecular weight 300 and 400g mol(-1)). Gelation time was dependent on the concentration and molecular weight of PEG. When the concentration of PEG in the gel reached 40-45%, gelation time was less than 30min, as revealed by measurements of optical density and rheological studies, with kinetics of PEG400 faster than PEG300. Gelation was accompanied by structural changes in silk, leading to the conversion from random coil in solution to crystalline beta-sheets in the gels, based on circular dichroism, attenuated total reflection Fourier transform infrared spectroscopy and X-ray diffraction. The modulus (127.5kPa) and yield strength (11.5kPa) determined were comparable to those of sonication-induced hydrogels at the same concentrations of silk. The time-dependent injectability of 15% PEG-silk hydrogel through 27G needles showed a gradual increase of compression forces from ~10 to 50N within 60min. The growth of human mesenchymal stem cells on the PEG-silk hydrogels was hindered, likely due to the presence of PEG, which grew after a 5 day delay, presumably while the PEG solubilized away from the gel. When 5% PEG-silk hydrogel was subcutaneously injected in rats, significant degradation and tissue in-growth took place after 20 days, as revealed by ultrasound imaging and histological analysis. No significant inflammation around the gel was observed. The features of injectability, slow degradation and low initial cell attachment suggests that these PEG-silk hydrogels are of interest for many biomedical applications, such as anti-fouling and anti-adhesion. PMID- 25449909 TI - Ginsenoside Rb1 inhibits fibrillation and toxicity of alpha-synuclein and disaggregates preformed fibrils. AB - Compelling evidence indicates that alpha-synuclein (alpha-syn) aggregation plays a central role in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies. Identification of compounds that inhibit or reverse the aggregation process may thus represent a viable therapeutic strategy against PD and related disorders. Ginseng is a well-known medicinal plant that has been used in East Asia for more than two thousand years to treat several conditions. It is now understood that the pharmacological properties of ginseng can be attributed to its biologically active components, the ginsenosides, which in turn have been shown to have neuroprotective properties. We therefore sought to determine for the first time, the potential of the most frequently used and studied ginsenosides, namely Rg1, Rg3 and Rb1, as anti-amyloidogenic agents. The effect of Rg1, Rg3 and Rb1 on alpha-syn aggregation and toxicity was determined by an array of biophysical, biochemical and cell-culture-based techniques. Among the screened ginsenosides, only Rb1 was shown to be a potent inhibitor of alpha-syn fibrillation and toxicity. Additionally, Rb1 exhibited a strong ability to disaggregate preformed fibrils and to inhibit the seeded polymerization of alpha syn. Interestingly, Rb1 was found to stabilize soluble non-toxic oligomers with no beta-sheet content, that were susceptible to proteinase K digestion, and the binding of Rb1 to those oligomers may represent a potential mechanism of action. Thus, Rb1 could represent the starting point for designing new molecules that could be utilized as drugs for the treatment of PD and related disorders. PMID- 25449914 TI - Mechanical properties and cytocompatibility of oxygen-modified beta-type Ti-Cr alloys for spinal fixation devices. AB - In this study, various amounts of oxygen were added to Ti-10Cr (mass%) alloys. It is expected that a large changeable Young's modulus, caused by a deformation induced omega-phase transformation, can be achieved in Ti-10Cr-O alloys by the appropriate oxygen addition. This "changeable Young's modulus" property can satisfy the otherwise conflicting requirements for use in spinal implant rods: high and low moduli are preferred by surgeons and patients, respectively. The influence of oxygen on the microstructures and mechanical properties of the alloys was examined, as well as the bending springback and cytocompatibility of the optimized alloy. Among the Ti-10Cr-O alloys, Ti-10Cr-0.2O (mass%) alloy shows the largest changeable Young's modulus following cold rolling for a constant reduction ratio. This is the result of two competing factors: increased apparent beta-lattice stability and decreased amounts of athermal omega phase, both of which are caused by oxygen addition. The most favorable balance of these factors for the deformation-induced omega-phase transformation occurred at an oxygen concentration of 0.2mass%. Ti-10Cr-0.2O alloy not only exhibits high tensile strength and acceptable elongation, but also possesses a good combination of high bending strength, acceptable bending springback and great cytocompatibility. Therefore, Ti-10Cr-0.2O alloy is a potential material for use in spinal fixture devices. PMID- 25449913 TI - S-Nitrosothiol-modified nitric oxide-releasing chitosan oligosaccharides as antibacterial agents. AB - S-Nitrosothiol-modified chitosan oligosaccharides were synthesized by reaction with 2-iminothiolane hydrochloride and 3-acetamido-4,4-dimethylthietan-2-one, followed by thiol nitrosation. The resulting nitric oxide (NO)-releasing chitosan oligosaccharides stored ~0.3MUmol NO mg(-1) chitosan. Both the chemical structure of the nitrosothiol (i.e. primary and tertiary) and the use of ascorbic acid as a trigger for NO donor decomposition were used to control the NO-release kinetics. With ascorbic acid, the S-nitrosothiol-modified chitosan oligosaccharides elicited a 4-log reduction in Pseudomonas aeruginosa viability. Confocal microscopy indicated that the primary S-nitrosothiol-modified chitosan oligosaccharides associated more with the bacteria relative to the tertiary S nitrosothiol system. The primary S-nitrosothiol-modified chitosan oligosaccharides elicited minimal toxicity towards L929 mouse fibroblast cells at the concentration necessary for a 4-log reduction in bacterial viability, further demonstrating the potential of S-nitrosothiol-modified chitosan oligosaccharides as NO-release therapeutics. PMID- 25449915 TI - Three-dimensional printed strontium-containing mesoporous bioactive glass scaffolds for repairing rat critical-sized calvarial defects. AB - The development of a new generation of biomaterials with high osteogenic ability for fast osseointegration with host bone is being intensively investigated. In this study, we have fabricated three-dimensional (3-D) strontium-containing mesoporous bioactive glass (Sr-MBG) scaffolds by a 3-D printing technique. Sr-MBG scaffolds showed uniform interconnected macropores (~400MUm), high porosity (~70%) and enhanced compressive strength (8.67+/-1.74MPa). Using MBG scaffolds as a control, the biological properties of Sr-MBG scaffolds were evaluated by apatite-forming ability, adhesion, proliferation, alkaline phosphatase activity and osteogenic gene expression of osteoblast-like cells MC3T3-E1. Furthermore, Sr MBG scaffolds were used to repair critical-sized rat calvarial defects. The results showed that Sr-MBG scaffolds possessed good apatite-forming ability and stimulated MC3T3-E1 cell proliferation and differentiation. Importantly, the in vivo results revealed that Sr-MBG scaffolds had good osteogenic capability and stimulated new blood vessel formation in critical-sized rat calvarial defects within 8 weeks. Therefore, 3-D printed Sr-MBG scaffolds with favorable pore structure and high osteogenic ability have more potential applications in bone regeneration. PMID- 25449916 TI - Aluminum-free low-modulus Ti-C composites that exhibit reduced image artifacts during MRI. AB - Feasibility studies were performed to determine the suitability of a novel synthesis technique for fabricating multifunctional composite materials for orthopedic implants. By blending paramagnetic Ti powder with diamagnetic graphite and consolidating the resulting mixtures, Ti-C composites that cannot be feasibly obtained via conventional alloying techniques or ingot metallurgy were synthesized. The synthesized composite material exhibited extremely low magnetic susceptibility (chi=67.6*10(-6)), and, as a result, exhibited fewer artifacts during magnetic resonance imaging. The strength of the composite material (sigma=770MPa) was such that it could support external loads to which the human body is subjected, but its Young's modulus was low (E=81.9 GPa) such that it could mitigate the stress-shielding effect. The material was also free from toxic elements such as Al and V and, thus, can be considered less harmful. PMID- 25449917 TI - Investigation of magnesium-zinc-calcium alloys and bone marrow derived mesenchymal stem cell response in direct culture. AB - Crystalline Mg-Zn-Ca ternary alloys have recently attracted significant interest for biomedical implant applications due to their promising biocompatibility, bioactivity, biodegradability and mechanical properties. The objective of this study was to characterize as-cast Mg-xZn-0.5Ca (x=0.5, 1.0, 2.0, 4.0wt.%) alloys, and determine the adhesion and morphology of bone marrow derived mesenchymal stem cells (BMSCs) at the interface with the Mg-xZn-0.5Ca alloys. The direct culture method (i.e. seeding cells directly onto the surface of the sample) was established in this study to probe the highly dynamic cell-substrate interface and thus to elucidate the mechanisms of BMSC responses to dynamic alloy degradation. The results showed that the BMSC adhesion density on these alloys was similar to the cell-only positive control and the BMSC morphology appeared more anisotropic on the rapidly degrading alloy surfaces in comparison with the cell-only positive control. Importantly, neither culture media supplemented with up to 27.6mM Mg(2+) ions nor media intentionally adjusted up to alkaline pH 9 induced any detectable adverse effects on BMSC responses. We speculated that degradation-induced dynamic surface topography played an important role in modulating cell morphology at the interface. This study presents a clinically relevant in vitro model for screening bioresorbable alloys, and provides useful design guidelines for determining the degradation rate of implants made of Mg-Zn Ca alloys. PMID- 25449918 TI - Agarose particle-templated porous bacterial cellulose and its application in cartilage growth in vitro. AB - Bacterial cellulose (BC) is a biocompatible hydrogel with a three-dimensional (3 D) structure formed by a dense network of cellulose nanofibers. A limitation of using BC for applications in tissue engineering is that the pore size of the material (~0.02-10MUm) is smaller than the dimensions of mammalian cells and prevents cells from penetrating into the material and growing into 3-D structures that mimic tissues. This paper describes a new route to porous bacterial cellulose (pBC) scaffolds by cultivating Acetobacter xylinum in the presence of agarose microparticles deposited on the surface of a growing BC pellicle. Monodisperse agarose microparticles with a diameter of 300-500MUm were created using a microfluidic technique, layered on growing BC pellicles and incorporated into the polymer as A. xylinum cells moved upward through the growing pellicle. Removing the agarose microparticles by autoclaving produced BC gels containing a continuous, interconnected network of pores with diameters ranging from 300 to 500MUm. Human P1 chondrocytes seeded on the scaffolds, replicated, invaded the 3 D porous network and distributed evenly throughout the substrate. Chondrocytes grown on pBC substrates displayed a higher viability compared to growth on the surface of unmodified BC substrates. The approach described in this paper introduces a new method for creating pBC substrates with user-defined control over the physical dimensions of the pore network, and demonstrates the application of these materials for tissue engineering. PMID- 25449919 TI - A modular peptide-based immobilization system for ZrO2, TiZr and TiO2 surfaces. AB - The present study describes a novel versatile immobilization system for the modification of implant materials with biologically active molecules (BAMs), e.g. antibiotics or growth factors. Specific adsorbing peptides are used as anchor molecules to immobilize oligodesoxynucleotides (ODNs) on the implant surface (anchor strand, AS). The BAM is conjugated to a complementary ODN strand (CS) which is able to hybridize to the AS on the implant surface to immobilize the BAM. The ODN double strand allows for a controlled release of the BAM adjustable by the ODN sequence and length. The immobilization system was developed and proven on three typical implant materials, namely ZrO2, TiZr and Ti, respectively. The parathyroid hormone (PTH) fragment 1-34 was conjugated to the CS and immobilized on these different implant materials. To investigate the biological activity of the immobilized PTH, alkaline phosphatase was quantified after incubation of the osteoblast precursor cells C2C12 on the modified samples. The results demonstrate the successful immobilization of biologically active PTH (1-34) and the high potential of the established surfaces to achieve an increased osseointegration of variable implants, especially for patients with risk factors. PMID- 25449920 TI - Bilayered silk/silk-nanoCaP scaffolds for osteochondral tissue engineering: In vitro and in vivo assessment of biological performance. AB - Novel porous bilayered scaffolds, fully integrating a silk fibroin (SF) layer and a silk-nano calcium phosphate (silk-nanoCaP) layer for osteochondral defect (OCD) regeneration, were developed. Homogeneous porosity distribution was achieved in the scaffolds, with calcium phosphate phase only retained in the silk-nanoCaP layer. The scaffold presented compressive moduli of 0.4MPa in the wet state. Rabbit bone marrow mesenchymal stromal cells (RBMSCs) were cultured on the scaffolds, and good adhesion and proliferation were observed. The silk-nanoCaP layer showed a higher alkaline phosphatase level than the silk layer in osteogenic conditions. Subcutaneous implantation in rabbits demonstrated weak inflammation. In a rabbit knee critical size OCD model, the scaffolds firmly integrated into the host tissue. Histological and immunohistochemical analysis showed that collagen II positive cartilage and glycosaminoglycan regeneration presented in the silk layer, and de novo bone ingrowths and vessel formation were observed in the silk-nanoCaP layer. These bilayered scaffolds can therefore be promising candidates for OCD regeneration. PMID- 25449923 TI - In vitro collagen fibril alignment via incorporation of nanocrystalline cellulose. AB - This study demonstrates a method for producing ordered collagen fibrils on a similar length scale to those in the cornea, using a one-pot liquid-phase synthesis. The alignment persists throughout samples on the mm scale. The addition of nanocrystalline cellulose (NCC), a biocompatible and widely available material, to collagen prior to gelation causes the fibrils to align and achieve a narrow size distribution (36+/-8nm). The effects of NCC loading in the composites on microstructure, transparency and biocompatibility are studied by scanning electron microscopy, ultraviolet-visible spectroscopy and cell growth experiments. A 2% loading of NCC increases the transparency of collagen while producing an ordered microstructure. A mechanism is proposed for the ordering behavior on the basis of enhanced hydrogen bonding during collagen gel formation. PMID- 25449924 TI - The three-dimensional structure of anosteocytic lamellated bone of fish. AB - Fish represent the most diverse and numerous of the vertebrate clades. In contrast to the bones of all tetrapods and evolutionarily primitive fish, many of the evolutionarily more advanced fish have bones that do not contain osteocytes. Here we use a variety of imaging techniques to show that anosteocytic fish bone is composed of a sequence of planar layers containing mainly aligned collagen fibrils, in which the prevailing principal orientation progressively spirals. When the sequence of fibril orientations completes a rotation of around 180 degrees , a thin layer of poorly oriented fibrils is present between it and the next layer. The thick layer of aligned fibrils and the thin layer of non-aligned fibrils constitute a lamella. Although both basic components of mammalian lamellar bone are found here as well, the arrangement is unique, and we therefore call this structure lamellated bone. We further show that the lamellae of anosteocytic fish bone contain an array of dense, small-diameter (1-4 MUm) bundles of hypomineralized collagen fibrils that are oriented mostly orthogonal to the lamellar plane. Results of mechanical tests conducted on beams from anosteocytic fish bone and human cortical bone show that the fish bones are less stiff but much tougher than the human bones. We propose that the unique lamellar structure and the orthogonal hypomineralized collagen bundles are responsible for the unusual mechanical properties and mineral distribution in anosteocytic fish bone. PMID- 25449921 TI - Localized delivery of dexamethasone-21-phosphate via microdialysis implants in rat induces M(GC) macrophage polarization and alters CCL2 concentrations. AB - Microdialysis sampling probes were implanted into the subcutaneous space on the dorsal side of male Sprague Dawley rats to locally deliver dexamethasone-21 phosphate (Dex) with the aim of altering in vivo macrophage polarization. Macrophage polarization is of significant interest in the field of biomaterials since wound-healing macrophages are a possible means to extend implant life as well as improve tissue remodeling to an implant. Quantitative analysis of CCL2 in collected dialysates, gene expression and immunohistochemistry performed on the tissue surrounding the microdialysis implant were used to evaluate if Dex polarized macrophages. Dex infusion down-regulated IL-6 and CCL2 gene expression and decreased CCL2 concentrations in dialysates collected at the implant site. Dex appeared to have no significant effect on the gene regulation of CD163, a commonly used M2c macrophage surface marker; Arg2; and iNOS2. However, Dex infusion was effective at increasing the number of CD163(+) cells surrounding the implanted microdialysis probe. This work demonstrates the use of microdialysis sampling to deliver agents such as Dex to alter macrophage polarization in vivo while allowing the ability to collect cytokines in the surrounding microenvironment. PMID- 25449922 TI - A photosensitive surface capable of inducing electrophysiological changes in NG108-15 neurons. AB - Retinal prostheses promise to be a viable therapy for many forms of blindness. Direct stimulation of neurons using an organic light-sensitive, self-assembled monolayer surface offers a simple alternative to conventional semiconductor technology. For this purpose we have derivatized an indium tin oxide (ITO) substrate with the photosensitive dye, NK5962, using 3 (aminopropyl)trimethoxysilane (APTMS) as cross-linker. The surface was characterized through contact angle goniometry, electrochemical impedance spectroscopy, grazing angle infrared and ultraviolet-visible spectrophotometry. NG108-15 neurons were grown on the ITO-APTMS-NK5962 surface and neural responses from electrical stimulation vs. photostimulation through the ITO-APTMS-NK5962 surface were measured using patch clamp electrophysiology. Under these conditions, photostimulation of depolarized cells caused an approximate 2-fold increase in voltage-gated sodium (Na(+)) current amplitude at a membrane potential of -30mV. Our results demonstrate the feasibility of stimulating neurons, grown on light-sensitive surfaces, with light impulses, which ultimately may facilitate the fabrication of a simple, passive retinal prosthetic. PMID- 25449925 TI - Biodegradable chitosan microparticles induce delayed STAT-1 activation and lead to distinct cytokine responses in differentially polarized human macrophages in vitro. AB - Current data suggest that chitosan activates wound macrophages to release endogenous factors that guide mesenchymal stem cell (MSC) to bone fractures. We tested the hypothesis that chitosan, a polymer containing glucosamine and N acetyl glucosamine, stimulates macrophages in different polarization states to release functional MSC chemokines and mainly anabolic factors. Low-serum conditioned medium was collected from M0, M1 and M2a U937 macrophages previously differentiated with phorbol myristate acetate (PMA) and exposed or not for 24h to chitosan microparticles (80% degree of deacetylation, DDA, 130kDa). Chitosan particles were highly phagocytosed. Chitosan enhanced anabolic factor release from M0 and M2a macrophages (MCP-1, IP-10, MIP-1beta, IL-1ra, IL-10, PDGF), and IL-1beta release, with 25- to 400-fold excess IL-1ra over IL-1beta. In M1 macrophages, chitosan enhanced IL-1beta without enhancing or suppressing inflammatory factor release (IL-6, IP-10, IL-8). M0 and M2a macrophages, with or without chitosan stimulation, produced conditioned medium that promoted 2-fold more MSC chemotaxis than low-serum control medium, while M1-conditioned medium failed to induce MSC chemotaxis. Acetylated chitosan induced U937 macrophages to release IL-1ra without STAT-6 activation, and also induced a delayed STAT-1 activation/IP-10 release response that was not observed using non-biodegradable chitosan (98% DDA, 130kDa). In primary human macrophages, acetylated chitosan enhanced IL-1ra release without inducing IL-1beta, and required PMA priming to elicit STAT-1 activation and IP-10 release. We conclude that biodegradable chitosan particles enhance M0 and M2a macrophage anabolic responses independent of the IL4/STAT-6 axis, by inducing excess IL-1ra over IL-1beta and more chemokine release, without altering their inherent capacity to attract MSCs. PMID- 25449926 TI - Enhanced osseointegration of titanium implants with nanostructured surfaces: an experimental study in rabbits. AB - Titanium and its alloys are commonly used for dental implants because of their good mechanical properties and biocompatibility. The surface properties of titanium implants are key factors for rapid and stable bone tissue integration. Micro-rough surfaces are commonly prepared by grit-blasting and acid-etching. However, proteins and cells interact with implant surfaces in the nanometer range. The aim of this study was to compare the osseointegration of machined (MA), standard alumina grit-blasted and acid-etched (MICRO) and nanostructured (NANO) implants in rabbit femurs. The MICRO surface exhibited typical random cavities with an average roughness of 1.5 MUm, while the NANO surface consisted of a regular array of titanium oxide nanotubes 37+/-11 nm in diameter and 160 nm thick. The MA and NANO surfaces had a similar average roughness of 0.5 MUm. The three groups of implants were inserted into the femoral condyles of New Zealand White rabbits. After 4 weeks, the pull-out test gave higher values for the NANO than for the other groups. Histology corroborated a direct apposition of bone tissue on to the NANO surface. Both the bone-to-implant contact and bone growth values were higher for the NANO than for the other implant surfaces. Overall, this study shows that the nanostructured surface improved the osseointegration of titanium implants and may be an alternative to conventional grit-blasted and acid etched surface treatments. PMID- 25449928 TI - Neuro-ophthalmology: an emerging specialty. PMID- 25449929 TI - Neuro-ophthalmology in India: the way forward. PMID- 25449927 TI - Laughter perception in social anxiety. AB - BACKGROUND: Laughter is a powerful signal of social acceptance or rejection while the fear of being embarrassed and humiliated is central in social anxiety (SA). This type of anxiety is associated with cognitive biases indicating increased sensitivity to social threat as well as with deficits in emotion regulation. Both are thought to be implicated in the maintenance of social anxiety. METHOD: Using laughter as a novel stimulus, we investigated cognitive biases and their modulation through emotion regulation and cue ambiguity in individuals with varying degrees of SA (N = 60). RESULTS: A combination of a negative laughter interpretation bias and an attention bias away from joyful/social inclusive laughter in SA was observed. Both biases were not attributable to effects of general anxiety and were closely correlated with the concept of gelotophobia, the fear of being laughed at. DISCUSSION: Thus, our study demonstrates altered laughter perception in SA. Furthermore, it highlights the usefulness of laughter as a highly prevalent social signal for future research on the interrelations of interpretation and attention biases in SA and their modulation through emotion regulation. PMID- 25449930 TI - Treatment options for atypical optic neuritis. AB - CONTEXT: Optic neuritis (ON) is defined as inflammation of the optic nerve and can have various etiologies. The most common presentation in the US is demyelinating, or "typical" ON, usually associated with multiple sclerosis. This is in contrast to "atypical" causes of ON, which differ in their clinical presentation, management, and prognosis. These atypical cases are characterized by lack of eye pain, exudates, and hemorrhages on exam, very severe, bilateral or progressive visual loss, or with failure to recover vision. AIMS: The aim was to describe the clinical presentations of atypical ON and their treatments. SETTINGS AND DESIGN: Review article. MATERIALS AND METHODS: Literature review. RESULTS: Types of atypical ON identified include neuromyelitis optica, autoimmune optic neuropathy, chronic relapsing inflammatory optic neuropathy, idiopathic recurrent neuroretinitis, and optic neuropathy associated with systemic diseases. Atypical ON usually requires corticosteroid treatment and often will require aggressive immunosuppression. CONCLUSIONS: Unlike demyelinating ON, atypical ON requires treatment to preserve vision. PMID- 25449932 TI - Neuro-ophthalmic manifestations of prematurity. AB - Increasing rates of preterm births coupled with better survival of these infants have resulted in higher prevalence of systemic and ocular complications associated with prematurity. In addition to retinopathy of prematurity, infants who are born preterm may suffer from severe visual impairment as a result of hypoxic ischemic encephalopathy, hypoglycemia, and other metabolic imbalances. The effect of these processes on the anterior visual pathway may result in optic atrophy, optic nerve hypoplasia or optic disc cupping and affection of the posterior visual pathway leads to cortical visual impairment (CVI). Other ocular associations include strabismus, nystagmus, and ocular motor abnormalities such as tonic down gaze and defective saccades and pursuits. Cortical and subcortical involvement also manifests as defects in functional vision and these have not yet been completely understood. Children with CVI may have visual field defects, photophobia, defective visual processing, and deficient color vision. Since most of these children also suffer from additional systemic disabilities, evaluation, and management remains a challenge. However, early diagnosis and initiation of rehabilitation therapy can prove to be of significant benefit in these children. PMID- 25449933 TI - Pseudotumor cerebri: an update on treatment options. AB - AIMS: The aim was to identify Pseudotumor cerebri treatment options and assess their efficacy. SETTING AND DESIGN: Review article. MATERIALS AND METHODS: Existing literature and the authors' experience were reviewed. RESULTS: Treatment options range from observation to surgical intervention. Weight loss and medical treatment may be utilized in cases without vision loss or in combination with surgical treatment. Cerebrospinal fluid shunting procedures and/or optic nerve sheath decompression is indicated for severe vision loss or headache unresponsive to medical management. The recent use of endovascular stenting of transverse sinus stenoses has also demonstrated benefit in patients with pseudotumor cerebri. CONCLUSION: While each treatment form may be successful individually, a multimodal approach is typically utilized with treatments selected on a case-by case basis. PMID- 25449931 TI - Ocular myasthenia gravis: a review. AB - Myasthenia gravis (MG) is a disease that affects the neuro-muscular junction resulting in classical symptoms of variable muscle weakness and fatigability. It is called the great masquerader owing to its varied clinical presentations. Very often, a patient of MG may present to the ophthalmologist given that a large proportion of patients with systemic myasthenia have ocular involvement either at presentation or during the later course of the disease. The treatment of ocular MG involves both the neurologist and ophthalmologist. Thus, the aim of this review was to highlight the current diagnosis, investigations, and treatment of ocular MG. PMID- 25449934 TI - Treatment modalities of thyroid related orbitopathy. AB - AIMS: The aim was to highlight recent advances in the treatment of thyroid eye disease. SETTINGS AND DESIGN: Review article. MATERIALS AND METHODS: Existing literature and the authors' experience was reviewed. RESULTS: Thyroid ophthalmopathy is a disfiguring and vision-threatening complication of autoimmune thyroid disease that may develop or persist even in the setting of well controlled systemic thyroid status. Treatment response can be difficult to predict, and optimized algorithms for disease management do not exist. Thyroid ophthalmopathy should be graded for both severity and disease activity before choosing a treatment modality for each patient. The severity of the disease may not correlate directly with the activity; medical treatment is most effective in active disease, and surgery is usually reserved for quiescent disease with persistent proptosis and/or eyelid changes. CONCLUSIONS: Intravenous pulsed corticosteroids, orbital radiotherapy, and orbital surgical techniques form the mainstay of current management of thyroid ophthalmopathy. Immunosuppressive and biologic agents may have a role in treating active disease although additional safety and efficacy studies are needed. PMID- 25449935 TI - Etiology and clinical profile of childhood optic nerve atrophy at a tertiary eye care center in South India. AB - BACKGROUND: Optic nerve atrophy is an important ophthalmological sign that may be associated with serious systemic conditions having a significant bearing on the overall morbidity of the child. Studies specific to etiology of childhood optic atrophy are scarce, this being the first such study from India to the best of our knowledge. AIM: The aim was to analyze the clinical features and etiology of diagnosed cases of optic nerve atrophy in children <16 years of age. MATERIALS AND METHODS: Retrospective review of records of children diagnosed with optic nerve atrophy between the ages of 0 and 16 years from 2006 to 2011. RESULTS: A total of 324 children (583 eyes) were identified. Among these 160 (49%) presented with defective vision, 71 (22%) with strabismus, 18 (6%) with only nystagmus. Rest had a combination of two or three of the above symptoms. Sixty-five patients (20%) had a unilateral affection. Hypoxic ischemic encephalopathy seen in 133 patients (41%) was the most frequent cause of childhood optic atrophy, followed by idiopathic in 98 (30%), hydrocephalus in 24 (7%), compressive etiology in 18 (5%), infective in 19 (6%), congenital in 6 (2%), inflammatory in 5 (2%) patients, respectively. CONCLUSION: Hypoxic ischemic encephalopathy appears to be the most common cause of optic atrophy in children in this series. The most common presenting complaint was defective vision. PMID- 25449936 TI - The diagnostic yield of neuroimaging in sixth nerve palsy--Sankara Nethralaya Abducens Palsy Study (SNAPS): Report 1. AB - AIMS: The aim was to assess the etiology of sixth nerve palsy and on the basis of our data, to formulate a diagnostic algorithm for the management in sixth nerve palsy. DESIGN: Retrospective chart review. RESULTS: Of the 104 neurologically isolated cases, 9 cases were attributable to trauma, and 95 (86.36%) cases were classified as nontraumatic, neurologically isolated cases. Of the 95 nontraumatic, isolated cases of sixth nerve palsy, 52 cases were associated with vasculopathic risk factors, namely diabetes and hypertension and were classified as vasculopathic sixth nerve palsy (54.7%), and those with a history of sixth nerve palsy from birth (6 cases) were classified as congenital sixth nerve palsy (6.3%). Of the rest, neuroimaging alone yielded a cause in 18 of the 37 cases (48.64%). Of the other 19 cases where neuroimaging did not yield a cause, 6 cases were attributed to preceding history of infection (3 upper respiratory tract infection and 3 viral illnesses), 2 cases of sixth nerve palsy were found to be a false localizing sign in idiopathic intracranial hypertension and in 11 cases, the cause was undetermined. In these idiopathic cases of isolated sixth nerve palsy, neuroimaging yielded no positive findings. CONCLUSIONS: In the absence of risk factors, a suggestive history, or positive laboratory and clinical findings, neuroimaging can serve as a useful diagnostic tool in identifying the exact cause of sixth nerve palsy. Furthermore, we recommend an algorithm to assess the need for neuroimaging in sixth nerve palsy. PMID- 25449937 TI - Neuro-ophthalmology as a career. AB - This essay was written to discuss the reasoning behind the personal decisions made by 2 current neuro-ophthalmology fellows to pursue neuro-ophthalmology as a career. It is meant to enlighten the reader about what role neuro ophthalmologists play in clinical practice, what makes neuro-ophthalmology unique to all other sub-specialties, and how this contributes to making neuro ophthalmology not only one of the most medically interesting, yet rewarding sub specialties in ophthalmology. PMID- 25449938 TI - Controversies: Optic nerve sheath fenestration versus shunt placement for the treatment of idiopathic intracranial hypertension. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) has been increasing in prevalence in the past decade, following the obesity epidemic. When medical treatment fails, surgical treatment options must be considered. However, controversy remains as to which surgical procedure is the preferred surgical option - optic nerve sheath fenestration (ONSF) or cerebrospinal fluid (CSF) shunting - for the long-term treatment of this syndrome. PURPOSE: To provide a clinical update of the pros and cons of ONSF versus shunt placement for the treatment of IIH. DESIGN: This was a retrospective review of the current literature in the English language indexed in PubMed. METHODS: The authors conducted a PubMed search using the following terms: Idiopathic IIH, pseudotumor cerebri, ONSF, CSF shunts, vetriculo-peritoneal shunting, and lumbo-peritoneal shunting. The authors included pertinent and significant original articles, review articles, and case reports, which revealed the new aspects and updates in these topics. RESULTS: The treatment of IIH remains controversial and lacks randomized controlled clinical trial data. Treatment of IIH rests with the determination of the severity of IIH-related visual loss and headache. CONCLUSION: The decision for ONSF versus shunting is somewhat institution and surgeon dependent. ONSF is preferred for patients with visual symptoms whereas shunting is reserved for patients with headache. There are positive and negative aspects of both procedures, and a prospective, randomized, controlled trial is needed (currently underway). This article will hopefully be helpful in allowing the reader to make a more informed decision until that time. PMID- 25449939 TI - Systemic corticosteroids in nonarteritic ischemic optic neuropathy. PMID- 25449940 TI - Commentary. PMID- 25449941 TI - Commentary. PMID- 25449942 TI - Controversies in neuro-ophthalmology: steroid therapy for traumatic optic neuropathy. AB - BACKGROUND: There is an increase in the incidence of traumatic optic neuropathy (TON) due to increasing urbanization and rapid spurt in the number of motor vehicles on the road. Despite early presentation and ease of diagnosis the visual outcomes in TON are still limited. There is also significant confusion about the timing, dose and efficacy of steroid treatment in its management. PURPOSE: To provide a clinical update of the pros and cons of steroid therapy for TON. DESIGN: The paper is a retrospective review of the currently available literature in the English language indexed in PubMed. METHODS: A PubMed search was conducted by the authors using the following terms: Traumatic optic neuropathy, megadose, steroids, methylprednisolone. Relevant original articles, review articles, and case reports related to the topic of discussion were evaluated and discussed in the paper. RESULTS: There is no prospective randomized control trial evaluating the effect of steroids in TON. There are varying reports on the effect of steroid therapy from significant improvement to no difference compared to observation. CONCLUSION: The decision to give steroids to patients with TON has to be on an individual case to case basis and must involve informed consent from the patient. There are documented advantages and disadvantages of steroid therapy and a prospective, randomized, controlled trial is necessary comparing steroids, surgery and observation before definitive management can be evolved. PMID- 25449943 TI - Commentary. PMID- 25449945 TI - A novel mutation in a case of dominant optic atrophy? PMID- 25449944 TI - Unusual case of temporal dermoid cyst presenting as oculomotor nerve palsy. PMID- 25449946 TI - Toxic optic neuropathy: an unusual cause. AB - A 60-year-old woman with a history of chronic alcoholism and tobacco use presented with the complaint of a painless decrease in vision in both eyes. She lost vision first in the left eye then in the right eye. She admitted consuming at least one 16 ounce bottle of over the counter mouthwash daily and denied consumption of any other alcohols, methanol, or antifreeze. She stated that her vision had been continuing to deteriorate in both eyes. Her best-corrected visual acuity was 4/200 in each eye. Color vision was nil in each eye. Her pupils were sluggish bilaterally, and her optic discs were flat and hyperemic with peripapillary hemorrhages. Her visual fields revealed central scotomas bilaterally. The magnetic resonance imaging of the brain and lumbar puncture were within normal limits. Antinuclear antibody, human leukocyte antigen-B27 genotyping, and B12 were normal; serum thiamine was low. While continuing to ingest mouthwash, her vision decreased to count fingers at 2 feet, and maculopapillary bundle pallor developed. She was started on folate and thiamine supplementation. Once she discontinued mouthwash, her vision improved to 20/400 bilaterally, and her central scotomas improved. This case demonstrates an alcohol induced toxic optic neuropathy from mouthwash ingestion with some visual recovery after discontinuation of the offending agent. PMID- 25449947 TI - Morphology and phylogeny of Agmasoma penaei (Microsporidia) from the type host, Litopenaeus setiferus, and the type locality, Louisiana, USA. AB - Since June 2012, samples of wild caught white shrimp, Litopenaeus setiferus, from the Gulf of Mexico, Plaquemines and Jefferson Parishes (Louisiana, USA) with clinical signs of microsporidiosis have been delivered to the Louisiana Aquatic Diagnostic Laboratory for identification. Infection was limited predominantly to female gonads and was caused by a microsporidium producing roundish pansporoblasts with eight spores (3.6*2.1 MUm) and an anisofilar (2-3+4-6) polar filament. These features allowed identification of the microsporidium as Agmasoma penaei Sprague, 1950. Agmasoma penaei is known as a microsporidium with world wide distribution, causing devastating epizootic disease among wild and cultured shrimps. This paper provides molecular and morphological characterisation of A. penaei from the type host and type locality. Comparison of the novel ssrDNA sequence of A. penaei from Louisiana, USA with that of A. penaei from Thailand revealed 95% similarity, which suggests these geographical isolates are two different species. The A. penaei sequences did not show significant homology to any other examined taxon. Phylogenetic reconstructions using the ssrDNA and alpha and beta-tubulin sequences supported its affiliation with the Clade IV Terresporidia sensu Vossbrink 2005, and its association with parasites of fresh and salt water crustaceans of the genera Artemia, Daphnia and Cyclops. PMID- 25449948 TI - Three Anisakis spp. isolated from toothed whales stranded along the eastern Adriatic Sea coast. AB - Knowledge concerning cetacean ecology in the Mediterranean is limited but important for sustainable planning and enforcement of appropriate conservation measures. Any information that might help to elucidate their ecology is essential. We explored the population and genetic structures of Anisakis spp. nematodes isolated from four toothed whale species - bottlenose dolphins (Tursiops truncatus), striped dolphins (Stenella coeruleoalba), Risso's dolphins (Grampus griseus) and Cuvier's beaked whales (Ziphius cavirostris) - stranded along the eastern Adriatic Sea coast (1990-2012) to reveal more information on host ecological patterns. Lower parasite prevalence was observed in resident dolphin species compared with occasionally occurring species, as well as in young compared with adult dolphins, indicating different feeding habits related to age. No unequivocal relationship between the biological traits of a host (age, body length, body mass and blubber depth) and Anisakis population parameters was observed. Phylogenetic analysis revealed a new geographical record of Anisakis simplex sensu stricto (1.96%) and Anisakis physeteris (1.31%) in the Adriatic Sea in addition to resident Anisakis pegreffii (96.73%). In an assessment of the Adriatic Sea and oceans worldwide, the genetic structure of Anisakis revealed that A. pegreffii populations do not differ among various final host species but do differ with respect to geographical location in contrast to previously accepted Anisakis panmixia. PMID- 25449950 TI - Description of the first cryptic avian malaria parasite, Plasmodium homocircumflexum n. sp., with experimental data on its virulence and development in avian hosts and mosquitoes. AB - For over 100 years studies on avian haemosporidian parasite species have relied on similarities in their morphology to establish a species concept. Some exceptional cases have also included information about the life cycle and sporogonic development. More than 50 avian Plasmodium spp. have now been described. However, PCR-based studies show a much broader diversity of haemosporidian parasites, indicating the possible existence of a diverse group of cryptic species. In the present study, using both similarity and phylogenetic species definition concepts, we believe that we report the first characterised cryptic speciation case of an avian Plasmodium parasite. We used sequence information on the mitochondrial cytochrome b gene and constructed phylogenies of identified Plasmodium spp. to define their position in the phylogenetic tree. After analysis of blood stages, the morphology of the parasite was shown to be identical to Plasmodium circumflexum. However, the geographic distribution of the new parasite, the phylogenetic information, as well as patterns of development of infection, indicate that this parasite differs from P. circumflexum. Plasmodium homocircumflexum n. sp. was described based on information about genetic differences from described lineages, phylogenetic position and biological characters. This parasite develops parasitemia in experimentally infected birds - the domestic canary Serinus canaria domestica, siskin Carduelis spinus and crossbill Loxia curvirostra. Anaemia caused by high parasitemia, as well as cerebral paralysis caused by exoerythrocytic stages in the brain, are the main reasons for mortality. Exoerythrocytic stages also form in other organs (heart, kidneys, liver, lungs, spleen, intestines and pectoral muscles). DNA amplification was unsuccessful from faecal samples of heavily infected birds. The sporogonic development initiates, but is abortive, at the oocyst stage in two common European mosquito species, Culex pipiens pipiens (forms pipiens and molestus) and Aedes vexans. Vectors of this Plasmodium sp. remain unknown. PMID- 25449949 TI - Leishmania donovani: impairment of the cellular immune response against recombinant ornithine decarboxylase protein as a possible evasion strategy of Leishmania in visceral leishmaniasis. AB - Ornithine decarboxylase, the rate limiting enzyme of the polyamine biosynthesis pathway, is significant in the synthesis of trypanothione, T(SH)2, the major reduced thiol which is responsible for the modulation of the immune response and pathogenesis in visceral leishmaniasis. Data on the relationship between ornithine decarboxylase and the cellular immune response in VL patients are limited. Therefore, we purified a recombinant ornithine decarboxylase from Leishmania donovani (r-LdODC) of approximately 77kDa and examined its effects on the immunological responses in peripheral blood mononuclear cells of human visceral leishmaniasis cases. For these studies, alpha-difluoromethylornithine was tested as an inhibitor and was used in parallel in all experiments. The r LdODC was identified as having a direct correlation with parasite growth and significantly increased the number of promastigotes as well as axenic amastigotes after 96h of culture. The stimulation of peripheral blood mononuclear cells with r-LdODC up-regulated IL-10 production but not IFN-gamma production from CD4(+) T cells in active as well as cured visceral leishmaniasis cases, indicating a pivotal role for r-LdODC in causing strong immune suppression in a susceptible host. In addition, severe hindrance of the immune response and anti-leishmanial macrophage function due to r-LdODC, as revealed by decreased IL-12 and nitric oxide production, and down-regulation in mean fluorescence intensities of reactive oxygen species, occurred in visceral leishmaniasis patients. There was little impact of r-LdODC in the killing of L. donovani amastigotes in macrophages of visceral leishmaniasis patients. In contrast, when cultures of promastigotes and amastigotes, and patients' blood samples, were directed against alpha difluoromethylornithine, parasite numbers significantly reduced in culture, whereas the levels of IFN-gamma and IL-12, and the production of reactive oxygen species and nitric oxide, were significantly elevated. Therefore, we demonstrated cross-talk with the use of alpha-difluoromethylornithine which can reduce the activity of ornithine decarboxylase of L. donovani, eliminating the parasite induced immune suppression and inducing collateral host protective responses in visceral leishmaniasis. PMID- 25449951 TI - Impact of diamond nanoparticles on neural cells. AB - Diamond nanoparticles (DNPs) are very attractive for biomedical applications, particularly for bioimaging. The aim of this study was to evaluate the impact of DNPs on neural cancer cells and thus to assess the possible application of DNPs for these cells imaging. For this purpose, the neuroblastoma SH-SY5Y cell line was chosen. Cells were cultured in medium with different concentrations (15, 50, 100 and 150 MUg/ml) of DNPs. After 48 h of incubation, cell metabolic activity was evaluated by the XTT assay. For assessment of cellular metabolic activity, cells were also cultured on differently terminated nanocrystalline diamond (NCD) coatings in medium with 150 MUg/ml of DNPs. Cell adhesion and morphology were evaluated by brightfield microscopy. Diamond nanoparticle internalization was determined by confocal microscopy. The obtained results showed that low concentrations (15, 50 and 100 MUg/ml) of nanoparticles did not significantly affect the SH-SY5Y cell metabolic activity. However, a higher concentration (150 MUg/ml) of DNPs statistically significantly reduced SH-SY5Y cell metabolic activity. After 48 h incubation with 150 MUg/ml DNPs, cell metabolic activity was 23% lower than in medium without DNPs on standard tissue culture polystyrene. PMID- 25449952 TI - Variants in TSPYL1 are not associated with sudden infant death syndrome in a cohort of deceased infants from Switzerland. AB - Sudden infant death syndrome (SIDS) is currently the major cause of an unexpected and unexplained death of infants in the first year of lifetime in industrialized countries. Besides environmental factors also genetic factors have been identified as risk factors for SIDS. Notably, the mutation c.457dupG (p.Glu153Glyfs*17) in the TSPYL1 gene has been reported to cause autosomal recessive sudden infant death with dysgenesis of the testes syndrome (SIDDT) in an Old Order Amish community in Pennsylvania. The purpose of this study was to analyze whether variants of TSPYL1 are associated with the sudden infant death syndrome (SIDS) in the area of Europe from which the Amish descended. Mutation analysis of the entire TSPYL1 gene was performed in a cohort of 165 SIDS cases with mostly Swiss ethnic origin, in comparison to 163 German controls. Eight known polymorphisms were detected, none of which was significantly associated with SIDS. One deceased girl was heterozygous for the hitherto unreported TSPYL1 variant c.106C>G (p.Leu36Val), and two affected girls were heterozygous for the rare known TSPYL1 variant rs140756663 (c.1098C>A, p.Phe366Leu). In addition, one deceased boy was heterozygous for the rare common silent nucleotide substitution c.718C>T (p.Leu240Leu, rs150144081), while one control was heterozygous for the rare silent nucleotide substitution rs56190632 (c.760C>T; p.Leu254Leu). In silico analyses predicted a likely non-pathogenic effect for p.Leu36Val and p.Phe366Leu, respectively, although protein features might be affected. The Amish founder mutation was not detected in the analyzed SIDS cases and controls. Mutations and polymorphisms in the TSPYL1 gene were not associated with SIDS in a cohort of 165 deceased Swiss infants. PMID- 25449953 TI - Craniofacial modularity, character analysis, and the evolution of the premaxilla in early African hominins. AB - Phylogenetic analyses require evolutionarily independent characters, but there is no consensus, nor has there been a clear methodology presented on how to define character independence in a phylogenetic context, particularly within a complex morphological structure such as the skull. Following from studies of craniofacial development, we hypothesize that the premaxilla is an independent evolutionary module with two integrated characters that have traditionally been treated as independent. We test this hypothesis on a large sample of primate skulls and find evidence supporting the premaxilla as an independent module within the larger module of the palate. Additionally, our data indicate that the convexity of the nasoalveolar clivus and the contour of the alveolus are integrated within the premaxilla. We show that the palate itself is composed of two distinct modules: the FNP-derived premaxillae and the mxBA1-derived maxillae and palatines. Application of our data to early African hominin facial morphology suggests that at least three separate transitions contributed to robust facial morphology: 1) an increase in the size of the post-canine dentition housed within the maxillae and palatines, 2) modification of the premaxilla generating a concave clivus and reduced incisor alveolus, and 3) modification of the zygomatic, shifting the zygomatic root and lateral face anteriorly. These data lend support to the monophyly of Paranthropus boisei and Paranthropus robustus, and provide mounting evidence in favor of a Paranthropus clade. This study also highlights the utility of applying developmental evidence to studies of morphological evolution. PMID- 25449954 TI - How much more would KNM-WT 15000 have grown? AB - Because of its completeness, the juvenile Homo ergaster/erectus KNM-WT 15000 has played an important role in studies of the evolution of body form in Homo. Early attempts to estimate his adult body size used modern human growth models. However, more recent evidence, particularly from the dentition, suggests that he may have had a more chimpanzee-like growth trajectory. Here we re-estimate his adult stature and body mass using ontogenetic data derived from four African ape taxa: Pan troglodytes troglodytes, Pan troglodytes schweinfurthii, Pan paniscus, and Gorilla gorilla gorilla. The average percentage change in femoral and tibial lengths and femoral head breadth between individuals at the same stage of dental development as KNM-WT 15000 - eruption of M2s but not M3s - and adult individuals with fully fused long bone epiphyses, was determined. Results were then applied to KNM-WT 15000, and his adult size estimated from skeletal dimensions using modern human prediction formulae. Using this approach, adult stature best estimates of 176-180 cm and body mass best estimates of 80-83 kg were obtained. These estimates are close to those estimated directly from longitudinal changes in body length and body mass between 8 and 12 years of age in chimpanzees, the suggested chronological equivalent to KNM-WT 15000's remaining growth period. Thus, even using an African ape growth model, it is likely that KNM-WT 15000 would have attained close to 180 cm in stature (without a slight reduction for his lower cranial height) and 80 kg in body mass as an adult. Other evidence from the East African Early Pleistocene indicates that KNM-WT 15000 was not unusually large-bodied for his time period. PMID- 25449955 TI - Resting heart rate variability and the startle reflex to briefly presented affective pictures. AB - We have previously shown that persons with low HRV showed potentiated startle responses to neutral stimuli. In the present study we replicated our prior findings and extended them to examine the effects of HRV on the startle magnitude to pictures that were presented outside of conscious awareness. A total of 85 male and female students were stratified via median split on their resting HRV. They were presented pictures for 6 s or for 30 ms. Results indicated that the high HRV group showed the context appropriate startle magnitude increase to unpleasant foreground. The low HRV group showed startle magnitude increase from pleasant to neutral pictures but no difference between the neutral and unpleasant pictures. This pattern of results was similar for the 30 ms and the 6 s conditions. These results suggest that having high HRV may allow persons to more efficiently process emotional stimuli and to better recognize threat and safety signals. PMID- 25449956 TI - Polypropylene glycol phosphate methacrylate as an alternative acid-functional monomer on self-etching adhesives. AB - OBJECTIVES: The aim of this study was to synthesize an alternative acidic monomer (polypropylene glycol phosphate methacrylate--Poly-P) to constitute experimental two-step self-etch adhesive systems and also to evaluate its influence on the pH and microshear bond strength (MUSBS) to enamel. METHODS: Primers containing Poly P (10, 15, 30 or 50wt.%), HEMA, ethanol, and water were prepared and allocated in subgroups according to a buffered or non-buffered pH. One experimental control and one commercial (ClearfillTM SE Bond) references were used. MUSBS protocol was performed at human enamel, followed by mechanical testing. Scanning electron microscopy (SEM) was performed after each primer application. Data was analysed by one-way Kruskal-Wallis and Student-Newman-Keuls tests (p<0.05) and by linear regression predictive models. RESULTS: As greater the Poly-P content, the lower the primer's pH. Buffered groups showed lower MUSBS values than non-buffered groups. Groups with Poly-P content equal or higher than 30wt.% showed similar MUSBS results when compared to the controls. SEM images demonstrated that primers with high Poly-P content etched enamel with prisms exposure. CONCLUSIONS: The pH of the primer was directly influenced by the concentration of acidic monomer, which directly affected the adhesion to enamel. Both the acidity and the type of acid-functional monomer present in the adhesive influenced the bond strength results. CLINICAL SIGNIFICANCE: Poly-P synthesis was easy and effective, and considering the good bond strength results obtained, this acid-functional monomer may be potentially used in the formulation of self-etch dental adhesive systems. PMID- 25449957 TI - Measurements and modelling of the influence of dentine colour and enamel on tooth colour. AB - OBJECTIVES: We provide a quantitative predictive model for the extent to which coloured dentine, visible through the enamel, contributes to tooth colour. Our model uses (L(*),a(*),b(*)) measurements rather than spectral measurements. METHODS: We have used a model system, composed of a slice of bovine enamel placed on top of coloured paper. We have measured the colour of the enamel-paper combination, as an analogue for a tooth, and have related this to the colour of the paper, as an analogue for dentine. By changing the paper colour, we have been able to explore how the colour of dentine determines tooth colour, according to our model system. We have also compared hydrated and desiccated samples. RESULTS: In qualitative terms, superimposing the enamel on top of the paper increases the "lightness" for all colours tested except white while simultaneously reducing the chromaticity, a measure of the extent to which the colour differs from grey. Desiccated enamel is much more effective at increasing the lightness and reducing the chromaticity than hydrated enamel. Quantitatively, our measurements are reproduced by the mathematical model we have developed to within 2% in "lightness" and about 8% in chromaticity. CONCLUSIONS: We are able to predict the colour of an analogue for a tooth, composed of bovine enamel and coloured paper, from the colour of an analogue for the dentine, the coloured paper alone, with good accuracy. This understanding provides insights into the role of dentine colour in determining tooth colour. CLINICAL SIGNIFICANCE: Our work helps quantify the importance of dentine colour, compared to other, extrinsic causes of colour, such as staining, in determining the visible colour of teeth. Our predicted colours represent a baseline to which extrinsic sources will add. PMID- 25449958 TI - The relationship between incisal/occlusal wear, dentine hypersensitivity and time after the last acid exposure in vivo. AB - OBJECTIVE: The aim of this study was to investigate the relationship between tooth wear and dentine hypersensitivity on occlusal/incisal tooth surfaces and the time since dietary acid consumption. METHOD: 350 subjects were recruited from hospital and general practice in SE England aged 19-34 years old. The severity of tooth wear and dentine hypersensitivity was calculated on occlusal/incisal tooth surfaces per subject using Basic Erosive Wear Examination (BEWE) and Cumulative Hypersensitivity Index (CHI) scores respectively at each appointment. The CHI score relied on evaporative stimuli applied to each occlusal/incisal tooth surface. The subjects were also asked about the time since their last acidic food or drink consumption. RESULT: Tooth wear was recorded in 93% (n=327) of subjects and dentine hypersensitivity was recorded in 56% (n=196) of subjects. A positive statistically significant relationship existed between the severity of tooth wear and severity of dentine hypersensitivity recorded using BEWE and CHI on occlusal/incisal tooth surfaces (p<0.01). Dentine hypersensitivity and tooth wear were correlated with consumption of acidic beverages (p<0.01). The severity of dentine hypersensitivity on occlusal/incisal tooth surfaces was associated with the time since the subject's last acidic food consumption (p<0.01). Among those subjects who consumed an acidic beverage within 60min of their appointment, 87.2% (n=130) had dentine hypersensitivity. Among subjects who had consumed the acidic beverage more than 1h previously, the prevalence of dentine hypersensitivity was 12.8% (n=19). CONCLUSION: The severity of tooth wear on occlusal/incisal tooth surfaces is associated with the dentine hypersensitivity severity. Subjects who consume dietary acidic beverages more recently are more likely to have dentine hypersensitivity. CLINICAL SIGNIFICANCE: Occlusal tooth surfaces suffer erosive, attritive and abrasive tooth wear. Tooth wear is important in the aetiology of dentine hypersensitivity on these surfaces. Dentine hypersensitivity is more likely initiated if subjects consume acidic beverages more recently. This supports clinically the episodic nature of dentine hypersensitivity caused predominately by active erosive tooth wear. PMID- 25449959 TI - Towards broadly protective polyvalent vaccines against hand, foot and mouth disease. AB - Hand, foot, and mouth disease (HFMD) caused by multiple enterovirus infections is a serious health threat to children in the Asia-Pacific region. This article reviews progresses in the development of vaccines for HFMD and discusses the need for polyvalent HFMD vaccines for conferring broad-spectrum protection. PMID- 25449960 TI - Childhood obesity and in-hospital asthma resource utilization. AB - OBJECTIVE: To examine the relationship between pediatric obesity and inpatient length of stay (LOS), resource utilization, readmission rates, and total billed charges for in-hospital status asthmaticus. DESIGN/METHODS: We conducted a cross sectional study of patients 5 to 17 years old hospitalized with status asthmaticus to 1 free-standing children's hospital system over 12 months. Only hospitalized patients initially treated in the hospital's emergency department were included to ensure all therapies/charges were examined. Patients with complex chronic conditions, pneumonia, or lacking recorded body mass index (BMI) were excluded. The primary exposure was BMI percentile for age. The primary outcome was LOS (in hours). Secondary outcomes were 90-day readmission rate, billed charges, and resource utilization: number of albuterol treatments, chest radiographs, intravenous fluids, intravenous or intramuscular steroids, and intensive care unit admission. Bivariate, adjusted Poisson and logistic regression model analyses were performed. RESULTS: Five hundred eighteen patients met inclusion criteria. Most had a normal BMI (59.7%); 36.7% were overweight or obese. LOS, readmissions, and resource utilization outcomes were not associated with BMI category on bivariate analyses. After adjustment for demographic/clinical characteristics, LOS decreased by 2% for each decile increase in BMI percentile for age. BMI percentile for age was not associated with billed charges, readmissions, or other measures of resource utilization. CONCLUSIONS: Although BMI decile for age is inversely associated with LOS for in hospital pediatric status asthmaticus, the effect likely is not clinically meaningful. PMID- 25449961 TI - Anticonvulsant prescription patterns in patients covered by the Colombian Health System. AB - INTRODUCTION: Epilepsy is a group of long-term neurological disorders characterised by seizures that may respond to pharmacological treatment. OBJECTIVE: Determine the prescribing patterns of anticonvulsants for patients covered by the healthcare system in Colombia. METHODS: Cross-sectional study using a database containing 6.5 million people. From among residents in 88 Colombian cities, we selected patients of both sexes and all ages who were treated continuously with anticonvulsants between June and August 2012. We designed a drug consumption database and performed multivariate analysis for combination treatment and co-medication using SPSS 20.0. RESULTS: A total of 13,793 patients with mean age of 48.9+/-22.0 years were studied; 52.9% of the participants were women. Of the patient total, 74.4% were treated in monotherapy and 25.6% received two or more anticonvulsants. Globally, 72.9% of the patients were initially treated with classic anticonvulsants and 27.1% with new drugs. The most frequently used drugs were valproic acid (33.3%), carbamazepine (30.2%), clonazepam (15.7%), pregabalin (10.3%), phenytoin (10.0%) and levetiracetam (7.9%). Most agents were used in higher doses than recommended. The most common combinations were valproic acid+clonazepam (10.9%), valproic acid+carbamazepine (10.0%), carbamazepine+clonazepam (5.6%), valproic acid+phenytoin (4.4%). The most frequently prescribed co-medications were antihypertensives (61.0%), lipid lowering drugs (45.8%), antidepressants (36.7%), antipsychotics (20.1%), anxiolytics (7.9%), and lithium (1.8%). DISCUSSION: Doctors predominantly prescribe drugs with a high therapeutic value and favour anticonvulsant monotherapy. Most agents were used in higher doses than recommended. This underlines the need to design educational strategies addressing these prescribing habits, and to undertake research on the effectiveness of treatment. PMID- 25449962 TI - Dementia drug consumption in the Basque Country between 2006 and 2011. AB - OBJECTIVE: We evaluated the consumption of specific medications for treating cognitive symptoms associated with AD and other types of dementia in individuals over 60 years of age between 2006 and 2011 in the Basque Country. METHODS: A retrospective descriptive study was conducted. The pharmacy division of the Basque Government Department of Health provided the prescribing data for the following drugs: donepezil, rivastigmine, galantamine, and memantine. The number of defined daily doses (DDDs) and the number of DDDs per 1000 inhabitants/day (DHD) were calculated. RESULTS: Consumption increased by 49.72% between 2006 and 2011. There were marked differences between drugs (13.02% donepezil; 93.18% rivastigmine; 37.79% galantamine; 70.40% memantine) and Basque provinces (16.34% in Araba; 50.49% in Bizkaia; 57.37% in Gipuzkoa). Likewise, expenditure increased from ?11.5 million in 2006 to ? 18.1 million in 2011. CONCLUSIONS: This study shows increased consumption of these drugs, although there are also marked differences by province which may be due to differences in prescribing habits. Spending for these drugs rose parallel to this increase in consumption; drug prices remained stable throughout the study period. PMID- 25449963 TI - Alice in Wonderland syndrome in cerebrovascular disease. PMID- 25449964 TI - Case report of thrombotic microangiopathy associated with subcutaneous interferon beta-1a: an emerging complication? PMID- 25449965 TI - Prevalence of myasthenia gravis in the Catalan county of Osona. AB - INTRODUCTION: The reported prevalence of myasthenia gravis ranges between 5 and 24 cases per 100,000, and people over 65years account for less than 50% of all cases. The prevalence and clinical characteristics of myasthenia gravis in the county of Osona were studied in patients younger and older than 65. METHODS: The study draws from the county-based prospective myasthenia gravis register implemented by the Neurology Department at Hospital General de Vic in 1991. RESULTS: The prevalence of myasthenia gravis was 32.89*105 inhabitants (95%CI, 23.86-41.91). The standardized prevalence (European population) was 35.47*105 inhabitants (95%CI, 26.10-44.84). The ratio of women to men was 1.3. Overall, the group of patients older than 65 accounted for 62.75% of all cases. The prevalence of myasthenia gravis increased considerably in older age groups. No cases were registered among patients under 25years old, prevalence was 21.87*105 in the 25 to 64 age group, and prevalence in patients over 65 years increased to 122.35*105. The clinical characteristics prior to treatment and at the cut-off date are similar (P>.05) in patients younger than 65 and those aged 65 and older. CONCLUSIONS: These figures show the highest prevalence rate reported to date. This high prevalence is due to the rate observed among patients older than 65. These results provide a new warning that myasthenia gravis may be underdiagnosed in the elderly population. PMID- 25449967 TI - Cytochrome bd from Escherichia coli catalyzes peroxynitrite decomposition. AB - Cytochrome bd is a prokaryotic respiratory quinol oxidase phylogenetically unrelated to heme-copper oxidases, that was found to promote virulence in some bacterial pathogens. Cytochrome bd from Escherichia coli was previously reported to contribute not only to proton motive force generation, but also to bacterial resistance to nitric oxide (NO) and hydrogen peroxide (H2O2). Here, we investigated the interaction of the purified enzyme with peroxynitrite (ONOO(-)), another harmful reactive species produced by the host to kill invading microorganisms. We found that addition of ONOO(-) to cytochrome bd in turnover with ascorbate and N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) causes the irreversible inhibition of a small (<=15%) protein fraction, due to the NO generated from ONOO(-) and not to ONOO(-) itself. Consistently, addition of ONOO( ) to cells of the E. coli strain GO105/pTK1, expressing cytochrome bd as the only terminal oxidase, caused only a minor (<=5%) irreversible inhibition of O2 consumption, without measurable release of NO. Furthermore, by directly monitoring the kinetics of ONOO(-) decomposition by stopped-flow absorption spectroscopy, it was found that the purified E. coli cytochrome bd in turnover with O2 is able to metabolize ONOO(-) with an apparent turnover rate as high as ~10 mol ONOO(-) (mol enzyme)(-1) s(-1) at 25 degrees C. To the best of our knowledge, this is the first time that the kinetics of ONOO(-) decomposition by a terminal oxidase has been investigated. These results strongly suggest a protective role of cytochrome bd against ONOO(-) damage. PMID- 25449966 TI - The contributions of respiration and glycolysis to extracellular acid production. AB - BACKGROUND: The rate at which cells acidify the extracellular medium is frequently used to report glycolytic rate, with the implicit assumption that conversion of uncharged glucose or glycogen to lactate(-)+H(+) is the only significant source of acidification. However, another potential source of extracellular protons is the production of CO2 during substrate oxidation: CO2 is hydrated to H2CO3, which then dissociates to HCO3(-)+H(+). METHODS: O2 consumption and pH were monitored in a popular platform for measuring extracellular acidification (the Seahorse XF Analyzer). RESULTS: We found that CO2 produced during respiration caused almost stoichiometric release of H(+) into the medium. With C2C12 myoblasts given glucose, respiration-derived CO2 contributed 34% of the total extracellular acidification. When glucose was omitted or replaced by palmitate or pyruvate, this value was 67-100%. Analysis of primary cells, cancer cell lines, stem cell lines, and isolated synaptosomes revealed contributions of CO2-produced acidification that were usually substantial, ranging from 3% to 100% of the total acidification rate. CONCLUSION: Measurement of glycolytic rate using extracellular acidification requires differentiation between respiratory and glycolytic acid production. GENERAL SIGNIFICANCE: The data presented here demonstrate the importance of this correction when extracellular acidification is used for quantitative measurement of glycolytic flux to lactate. We describe a simple way to correct the measured extracellular acidification rate for respiratory acid production, using simultaneous measurement of oxygen consumption rate. SUMMARY STATEMENT: Extracellular acidification is often assumed to result solely from glycolytic lactate production, but respiratory CO2 also contributes. We demonstrate that extracellular acidification by myoblasts given glucose is 66% glycolytic and 34% respiratory and describe a method to differentiate these sources. PMID- 25449968 TI - Assembly of functional photosystem complexes in Rhodobacter sphaeroides incorporating carotenoids from the spirilloxanthin pathway. AB - Carotenoids protect the photosynthetic apparatus against harmful radicals arising from the presence of both light and oxygen. They also act as accessory pigments for harvesting solar energy, and are required for stable assembly of many light harvesting complexes. In the phototrophic bacterium Rhodobacter (Rba.) sphaeroides phytoene desaturase (CrtI) catalyses three sequential desaturations of the colourless carotenoid phytoene, extending the number of conjugated carbon carbon double bonds, N, from three to nine and producing the yellow carotenoid neurosporene; subsequent modifications produce the yellow/red carotenoids spheroidene/spheroidenone (N=10/11). Genomic crtI replacements were used to swap the native three-step Rba. sphaeroides CrtI for the four-step Pantoea agglomerans enzyme, which re-routed carotenoid biosynthesis and culminated in the production of 2,2'-diketo-spirilloxanthin under semi-aerobic conditions. The new carotenoid pathway was elucidated using a combination of HPLC and mass spectrometry. Premature termination of this new pathway by inactivating crtC or crtD produced strains with lycopene or rhodopin as major carotenoids. All of the spirilloxanthin series carotenoids are accepted by the assembly pathways for LH2 and RC-LH1-PufX complexes. The efficiency of carotenoid-to-bacteriochlorophyll energy transfer for 2,2'-diketo-spirilloxanthin (15 conjugated CC bonds; N=15) in LH2 complexes is low, at 35%. High energy transfer efficiencies were obtained for neurosporene (N=9; 94%), spheroidene (N=10; 96%) and spheroidenone (N=11; 95%), whereas intermediate values were measured for lycopene (N=11; 64%), rhodopin (N=11; 62%) and spirilloxanthin (N=13; 39%). The variety and stability of these novel Rba. sphaeroides antenna complexes make them useful experimental models for investigating the energy transfer dynamics of carotenoids in bacterial photosynthesis. PMID- 25449969 TI - Origin and concentration profile of chromium in a Greek aquifer. AB - In this paper the origin and concentration of chromium (Cr) in an ophiolitic aquifer in Vergina, northern Greece were investigated. The study area has only agricultural activity so that industrial Cr contamination was precluded. Soil sampling included topsoil and drillcore samples collected down to 98 m depth. Groundwater samples were collected from three existing wells and a spring at the area and from different depths of the soil boring using the discrete sampling method. Mineralogical analysis of soils confirmed the presence of ultramafic minerals, including chrysotile and chromite. Soil elemental analysis showed significant concentration of total chromium (Crtot; max 12,000 mg/kg) and hexavalent chromium (Cr(VI); max 7.5mg/kg). Significant Crtot (91 MUg/L) and Cr(VI) (64 MUg/L) concentrations exceeding the drinking water limit of 50 MUg/L were also detected in groundwater. In both the discrete soil and groundwater samples a decreasing trend of Cr(VI) concentration was observed with increasing depth, while Crtot increased. The increasing trend in Crtot is attributed to the increasing contribution of unweathered ultramafic minerals with depth, while the decreasing Cr(VI) may be related to the increasing soil pH that does not favor Cr(III) oxidation by Mn-oxides. PMID- 25449971 TI - How to measure wear following total hip arthroplasty - EBRA not mentioned! Letter to the Editor and Authors' response. PMID- 25449970 TI - Reconnaissance of 47 antibiotics and associated microbial risks in seafood sold in the United States. AB - Aquaculture production has nearly tripled in the last two decades, bringing with it a significant increase in the use of antibiotics. Using liquid chromatography/tandem mass spectrometry (LC-MS/MS), the presence of 47 antibiotics was investigated in U.S. purchased shrimp, salmon, catfish, trout, tilapia, and swai originating from 11 different countries. All samples (n=27) complied with U.S. FDA regulations and five antibiotics were detected above the limits of detection: oxytetracycline (in wild shrimp, 7.7ng/g of fresh weight; farmed tilapia, 2.7; farmed salmon, 8.6; farmed trout with spinal deformities, 3.9), 4-epioxytetracycline (farmed salmon, 4.1), sulfadimethoxine (farmed shrimp, 0.3), ormetoprim (farmed salmon, 0.5), and virginiamycin (farmed salmon marketed as antibiotic-free, 5.2). A literature review showed that sub-regulatory levels of antibiotics, as found here, can promote resistance development; publications linking aquaculture to this have increased more than 8-fold from 1991 to 2013. Although this study was limited in size and employed sample pooling, it represents the largest reconnaissance of antibiotics in U.S. seafood to date, providing data on previously unmonitored antibiotics and on farmed trout with spinal deformities. Results indicate low levels of antibiotic residues and general compliance with U.S. regulations. The potential for development of microbial drug resistance was identified as a key concern and research priority. PMID- 25449973 TI - Bone mineral density distribution in the proximal femur and its relationship to morphologic factors in progressed unilateral hip osteoarthritis. AB - Although an adverse relationship between osteoporosis and osteoarthritis (OA) has been reported, it remains controversial. In most previous reports of OA, bone mineral density (BMD) changes in the subtrochanteric region have not been clarified, whilst BMD of the femoral neck and trochanteric region has been well investigated. In our current study, we investigated the BMD ratio compared to the contralateral side in the whole proximal femurs of hip OA patients. We aimed to clarify the morphologic factor that may influence these BMD ratios. We performed dual energy X-ray absorptiometry (DEXA) analysis of 69 hip joints from unilateral progressed OA cases. The minimum joint space, center edge angle, Sharp angle, acetabular head index, neck-shaft angle, and leg length discrepancy were also measured as radiographic factors. The correlation between BMD ratio and radiographic morphologic factors was then evaluated by logistic regression. The BMD ratio was higher in the femoral neck than in the distal region. In terms of radiographic factors, the neck-shaft angle was revealed to influence the decreased BMD ratio in the distal subtrochanteric part, whilst the leg length discrepancy and Sharp angle showed a relationship with the increased BMD ratio in the proximal neck region. The discrepancy in the BMD ratio between the femoral neck and the distal subtrochanteric region in the proximal femur is influenced by several morphologic factors. PMID- 25449974 TI - Coenzyme Q10 and spinocerebellar ataxias. AB - The aim of this study was to investigate the association between drug exposure and disease severity in SCA types 1, 2, 3 and 6. The Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) enrolled 319 participants with SCA1, 2, 3, and 6 from 12 medical centers in the United States and repeatedly measured clinical severity by the Scale for Assessment and Rating of Ataxia (SARA), the Unified Huntington's Disease Rating Scale part IV (UHDRS-IV), and the 9-item Patient Health Questionnaire during July 2009 to May 2012. We employed generalized estimating equations in regression models to study the longitudinal effects of coenzyme Q10 (CoQ10), statin, and vitamin E on clinical severity of ataxia after adjusting for age, sex, and pathological CAG repeat number. Cross sectionally, exposure to CoQ10 was associated with lower SARA and higher UHDRS-IV scores in SCA1 and 3. No association was found between statins, vitamin E, and clinical outcome. Longitudinally, CoQ10, statins, and vitamin E did not change the rates of clinical deterioration indexed by SARA and UHDRS-IV scores within 2 years. CoQ10 is associated with better clinical outcome in SCA1 and 3. These drug exposures did not appear to influence clinical progression within 2 years. Further studies are warranted to confirm the association. PMID- 25449976 TI - Ultrastructure of mediodorsal setae in biting midge larvae of the genus Atrichopogon Kieffer with notes on their biological significance (Diptera: Ceratopogonidae). AB - The ultrastructure of the strong mediodorsal setae in terrestrial stage IV larvae of Atrichopogon (Meloehelea) oedemerarum and A. (M.) meloesugans was examined using light, scanning and transmission electron microscopy. Serrated setae placed on prominent processes are distributed in pairs on all thoracic and abdominal segments. Setae are innervated by a single dendrite and their surface has no pores. The trichogen cell is not retracted from the setal lumen on completion of the hair-forming process but fills the mediodorsal seta also when the larval cuticle is fully sclerotised. Such a phenomenon was previously reported in terrestrial larvae of the genus Forcipomyia. We suggest that the mediodorsal setae described in Atrichopogon are plesiotypic mechanoreceptors for the subfamily Forcipomyiinae. They are preserved in the truly terrestrial larvae of Atrichopogon, but modified to secretory setae in the genus Forcipomyia. Both genera bearing distinct mediodorsal setae have developed functional tracheal gills, unknown in other biting midges. PMID- 25449975 TI - Continuous indicator fields: a novel universal type of molecular fields. AB - A novel type of molecular fields, Continuous Indicator Fields (CIFs), is suggested to provide 3D structural description of molecules. The values of CIFs are calculated as the degree to which a point with given 3D coordinates belongs to an atom of a certain type. They can be used similarly to standard physicochemical fields for building 3D structure-activity models. One can build CIF-based 3D structure-activity models in the framework of the continuous molecular fields approach described earlier (J Comput-Aided Mol Des 27 (5):427 442, 2013) for the case of physicochemical molecular fields. CIFs are thought to complement and further extend traditional physicochemical fields. The models built with CIFs can be interpreted in terms of preferable and undesirable positions of certain types of atoms in space. This helps to understand which changes in chemical structure should be made in order to design a compound possessing desirable properties. We have demonstrated that CIFs can be considered as 3D analogues of 2D topological molecular fragments. The performance of this approach is demonstrated in structure-activity studies of thrombin inhibitors, multidentate N-heterocyclic ligands for Am(3+)/Eu(3+) separation, and coloring dyes. PMID- 25449977 TI - Lehr's fields of campaniform sensilla in beetles (Coleoptera): functional morphology. II. Wing reduction and the sensory field. AB - Loss of the flight ability and wing reduction has been reported for many taxa of Coleoptera. If elytra are closed, their roots are clenched between the tergum and the pleuron, forces applied to the elytra can not be transmitted to the field of campaniform sensilla situated on the root. That is why it is plausible to assume that the field becomes redundant in non-flying beetles. We examined the relationships between the hind wing reduction and characters of this mechanosensory field in beetles of six families. We measured the size of the elytron, that of the hind wing and counted the number of sensilla in the sensory field. Mesopterous non-flying beetles retain one half to one third of sensilla present in macropterous species of the same body size. Further reduction of the sensory field in brachypterous species is obvious, but sensilla are still present in insects with strongly reduced wings, as long as their elytra are separable and mesothoracic axillaries are present. Complete loss of sensilla coincides with the existence of a permanent sutural lock. However, some beetles with permanently locked elytra and absence of axillaries still retain few campaniform sensilla. A very special case of an extreme wing modification in feather-wing beetles is considered. No sensilla were revealed either on the root of the elytron or on the basal segment of such fringed wings in flying ptiliid species. PMID- 25449978 TI - High energy density asymmetric supercapacitor based on NiOOH/Ni3S2/3D graphene and Fe3O4/graphene composite electrodes. AB - The application of the composite of Ni3S2 nanoparticles and 3D graphene as a novel cathode material for supercapacitors is systematically investigated in this study. It is found that the electrode capacitance increases by up to 111% after the composite electrode is activated by the consecutive cyclic voltammetry scanning in 1 M KOH. Due to the synergistic effect, the capacitance and the diffusion coefficient of electrolyte ions of the activated composite electrode are ca. 3.7 and 6.5 times higher than those of the Ni3S2 electrode, respectively. Furthermore, the activated composite electrode exhibits an ultrahigh specific capacitance of 3296 F/g and great cycling stability at a current density of 16 A/g. To obtain the reasonable matching of cathode/anode electrodes, the composite of Fe(3)O(4) nanoparticles and chemically reduced graphene oxide (Fe(3)O(4)/rGO) is synthesized as the anode material. The Fe(3)O(4)/rGO electrode exhibits the specific capacitance of 661 F/g at 1 A/g and excellent rate capability. More importantly, an asymmetric supercapacitor fabricated by two different composite electrodes can be operated reversibly between 0 and 1.6 V and obtain a high specific capacitance of 233 F/g at 5 mV/s, which delivers a maximum energy density of 82.5 Wh/kg at a power density of 930 W/kg. PMID- 25449979 TI - Stage specific activity of synthetic antimalarial endoperoxides, N-89 and N-251, against Plasmodium falciparum. AB - We have reported that two endoperoxides, N-89 and N-251, synthesized in 2001, possess potent antimalarial activities. Aiming at their eventual use for curing malaria in humans, we have been investigating various aspects of their antimalarial actions. Here we show that N-89 and N-251 inhibit the growth of Plasmodium falciparum within human erythrocytes in vitro at its lifecycle stage 'trophozoite' specifically. It is known that artemisinin compounds, which are currently used for curing malaria, have other stage-specificities. Therefore, it is likely that the antimalarial mechanism of N-89 and N-251 differs from those of artemisinin compounds. As malaria parasites resistant to artemisinin-based combination therapy are currently emerging in some tropical regions, N-89 and N 251 are candidates for overcoming these new problems. PMID- 25449980 TI - Elevated beta2-glycoprotein I-low-density lipoprotein levels are associated with the presence of diabetic microvascular complications. AB - AIMS: To investigate serum beta2-glycoprotein I-low-density lipoprotein (beta2 GPI-LDL) and oxidized low-density lipoprotein (ox-LDL) levels in type 2 diabetes mellitus (T2DM) patients, and to further evaluate the associations of beta2-GPI LDL with ox-LDL in vivo and with the presence of diabetic microvascular complications. METHODS: We determined beta2-GPI-LDL, ox-LDL and small dense low density lipoprotein cholesterol (sdLDL-C) levels in 236 T2DM patients with or without microvascular complications and 75 controls. The correlation analyses, multiple linear regression analyses and logistic regression analyses were performed, respectively. RESULTS: Compared with controls, beta2-GPI-LDL and ox LDL levels were significantly elevated in both groups of T2DM patients and those with microvascular complications exhibited the more significant increase than those without complications. Serum beta2-GPI-LDL levels were positively correlated with ox-LDL as well as sdLDL-C levels in T2DM patients. Multiple linear regression analyses showed that ox-LDL was one of the independent determinants of beta2-GPI-LDL levels. Logistic regression analyses indicated that elevated beta2-GPI-LDL and ox-LDL levels had significant predictive values for diabetic microvascular complications. CONCLUSIONS: Elevated serum beta2-GPI-LDL levels may be a serological hallmark of enhanced LDL oxidation in vivo and closely associated with the presence of diabetic microvascular complications. PMID- 25449981 TI - Effectiveness and safety of basal supported oral therapy with insulin glargine, in Japanese insulin-naive, type 2 diabetes patients, with or without microvascular complications: subanalysis of the observational, non interventional, 24-week follow-up Add-on Lantus(r) to Oral Hypoglycemic Agents (ALOHA) study. AB - AIMS: The aim of this study is to evaluate effectiveness and safety of basal supported oral therapy (BOT) using insulin glargine in insulin-naive Japanese patients, with and without microvascular complications. METHODS: This sub-group analysis of observational, non-interventional ALOHA study, assessed changes in glycemic parameters and glargine dose, at 24weeks or at glargine discontinuation. Count of hypoglycemic episodes was based on physicians' documentation of patient reports. Patients were stratified according to presence/absence of microvascular complications, at baseline. Relationships between baseline patient characteristics and achievement of HbA1c <7% were examined by multivariate regression analysis. RESULTS: A total of 3631 patients, included during 2007 2009, were stratified in sub-groups: no complications (n= 1889), retinopathy (n=318), neuropathy (n=297), nephropathy (n=356), retinopathy+neuropathy (n= 174), retinopathy+nephropathy (n=154), neuropathy+nephropathy (n=142), and retinopathy+neuropathy+nephropathy (n=301). Changes in HbA1c, fasting and postprandial plasma glucose, and glargine daily dose were similar among patients with and without complications. Response-rate for achieving HbA1c <7.0% was highest in patients without complications (19.1%). In multivariate analysis, patients without complications showed significantly higher odds of attaining HbA1c <7%, independent of diabetes duration and baseline HbA1c levels. Patients with retinopathy+nephropathy had the lowest response-rate (8.8%) and highest hypoglycemic-rate (3.2%). CONCLUSION: Japanese insulin-naive patients without complications, on BOT with glargine, show higher chances of attaining HbA1c <7.0% than those with complications. PMID- 25449982 TI - Fistulas in octogenarians: are they beneficial? AB - BACKGROUND: The incidence of end-stage renal disease is increasing most rapidly in patients aged older than 75 years. Meanwhile, their 5-year survival rate remains the lowest of any dialysis cohort. The purpose of this study was to evaluate the benefit of arteriovenous fistula (AVF) construction in octogenarians, as the data regarding the effects of age on fistula success are conflicting. METHODS: Using our hemodialysis database, we performed a retrospective review of all AVFs placed between 1 November, 2007, and 17 July, 2013, in patients aged 80 years or older. Patient demographics, presence of catheters, time to first fistula use, fistula interventions, fistula patency, and time to patient death were all evaluated. RESULTS: We placed 32 fistulas in 31 patients. Our average patient was 82-year-old, men (75%) and Caucasian (71%). Three patients were excluded, as they never required dialysis. One patient required 2 fistulas; the second fistula was excluded from analysis. Of the remaining 28 patients, 22 (78%) were used for hemodialysis and 19 (68%) required catheter-based dialysis before fistula use. The mean length of catheter use was 166 days, and the median time to first fistula use was 109 days. Primary functional patency was 51% at year 1 and 38% at year 2, respectively. Secondary patency was 75% at year 1 and year 2. Of the 22 patients, 17 (77%) required intervention to achieve or maintain patency. The median time to death was 26 months. CONCLUSIONS: With substantial effort, successful fistula utilization can be achieved in an extremely elderly patient population. Our patients experienced significant catheter utilization and over 3 quarters required secondary interventions to achieve or maintain fistula utilization. Given this group's limited survival and the fact that 21% of their survival time was spent dialyzing with a catheter, the benefit of a functioning fistula to a patient older than 80 years can be questioned. PMID- 25449983 TI - Vascular injury is associated with increased mortality in winter sports trauma. AB - BACKGROUND: Trauma is the leading cause of injury and death for individuals aged 1-44 years. Up to 8% of the US population participates in winter sports, and although vascular injuries are uncommon in these activities, little is published in this area. We sought to identify the incidence, injury patterns, and outcomes of vascular injuries resulting from winter sports trauma. METHODS: Patients with winter sports trauma and the subset with vascular injuries were identified by accessing the National Trauma Data Bank querying years 2007-2010. Patients with and without vascular injuries were then compared. Admission variables included transport time, emergency department hypotension (systolic blood pressure < 90), Glasgow Coma Scale <= 8, Injury Severity Score >= 25, fractures, solid organ injury, and vascular injury. Outcomes were analyzed and associations with vascular injuries were determined. RESULTS: A total of 2,298 patients were identified with winter sports-related trauma and 28 (1.2%) had associated vascular injuries. Overall, the top 3 injuries were head trauma (16.7%), thoracic vertebral fractures (5.5%), and lumbar vertebral fractures (5.1%). The most common associated vascular injures were to the popliteal artery (17.7%), splenic artery (14.7%), and brachial blood vessels (14.7%). In the entire cohort, 1 patient (0.04%) suffered an amputation and 15 patients (0.7%) died. There were no amputations in the vascular injury group. Mortality was 0.6% in patients without a vascular injury compared with 7.1% of those with a vascular injury (P = 0.01). CONCLUSIONS: Although vascular injury is an uncommon associated finding in winter sports trauma, it is associated with a significant increase in mortality. These findings highlight the need for rapid identification of traumatic vascular injuries, which predicts worse overall outcomes in this patient population. PMID- 25449984 TI - Functional outcome after resuscitative endovascular balloon occlusion of the aorta of the proximal and distal thoracic aorta in a swine model of controlled hemorrhage. AB - BACKGROUND: Noncompressible torso hemorrhage remains an ongoing problem for both military and civilian trauma. Resuscitative endovascular balloon occlusion of the aorta (REBOA) has been characterized as a potentially life-saving maneuver. The objective of this study was to determine the functional outcomes, paraplegia rates, and survival of 60-min balloon occlusion in the proximal and distal thoracic aorta in a porcine model of controlled hemorrhage. METHODS: Swine (Sus scrofa, 70-110 kg) were subjected to class IV hemorrhagic shock and underwent 60 min of REBOA. Devices were introduced from the left carotid artery and positioned in the thoracic aorta in either the proximal location (pREBOA [n = 8]; just past takeoff of left subclavian artery) or distal location (dREBOA [n = 8]; just above diaphragm). After REBOA, animals were resuscitated with whole blood, crystalloid, and vasopressors before a 4-day postoperative period. End points included evidence of spinal cord ischemia (clinical examination, Tarlov gait score, bowel and bladder dysfunction, and histopathology), gross ischemia-reperfusion injury (clinical examination and histopathology), and mortality. RESULTS: The overall mortality was similar between pREBOA and dREBOA groups at 37.5% (n = 3). Spinal cord-related mortality was 12.5% for both pREBOA and dREBOA groups. Spinal cord symptoms without death were present in 12.5% of pREBOA and dREBOA groups. Average gait scores improved throughout the postoperative period. CONCLUSIONS: REBOA placement in the proximal or distal thoracic aorta does not alter mortality or paraplegia rates as compared with controlled hemorrhage alone. Functional recovery improves in the presence or the absence of REBOA, although at a slower rate after REBOA as compared with negative controls. Additional research is required to determine the ideal placement of REBOA in an uncontrolled hemorrhage model to achieve use compatible with survival outcomes and quality of life. PMID- 25449985 TI - Intraoperative duplex ultrasound criteria for performing interposition bypass in the treatment of popliteal artery entrapment syndrome. AB - We present a case series of 3 surgical procedures (2 patients) in which intraoperative duplex ultrasound (IDUS) was used to determine whether the chronic compression of the popliteal artery caused by popliteal artery entrapment syndrome had injured the artery to such a degree that interposition bypass was required. Patients initially underwent standard clinical evaluation including history and physical examination and noninvasive diagnostic testing including postexercise ankle-brachial indexes and angiography with evocative maneuvers before surgery. IDUS was performed. Doppler was used to calculate peak systolic velocities (PSVs) and velocity ratios (VRs) across areas of suspected injury. B mode was used to assess arterial wall thickness (AWT) and sclerotic changes. Patients were followed in the postoperative period with surveillance duplex ultrasound (US). Three limbs (2 patients) underwent IDUS evaluation after popliteal decompression. Limb 1 demonstrated an elevated intraoperative PSV of 295 cm/sec with an elevated VR of 2.52 (295/117 cm/sec) and AWT of 1.1 mm. Interposition bypass was performed after popliteal decompression. Postoperative surveillance duplex US revealed a reduction of the PSV to 90 cm/sec. Limb 2 showed a mildly elevated intraoperative PSV of 211.5 cm/sec with a VR of 1.86 (211.5/114 cm/sec) and AWT of 0.8 mm. An interposition bypass was not performed. Limb 3 demonstrated an elevated intraoperative PSV of 300 cm/sec with an elevated VR of 2.51 (300/119.5 cm/sec) and AWT of 1.0. Interposition bypass was performed. Postoperative surveillance duplex US revealed a reduction of the PSV to 115 cm/sec. IDUS was very helpful in the operative management and intraoperative decision making process for popliteal artery entrapment. An elevated PSV of 250 275 cm/sec or greater on IDUS and a VR of 2.0 or greater, in conjunction with B mode demonstration of arterial wall injury, was useful in identifying severely injured popliteal arterial segments. Additional prospective studies are warranted to further investigate objective criteria that indicate the need for bypass. PMID- 25449987 TI - Experimental and clinical evidence supporting septectomy in the primary treatment of acute type B thoracic aortic dissection. AB - BACKGROUND: We reviewed the mechanics involved in the aneurysmal dilatation of the false lumen (FL) in type B aortic dissection and the experimental and clinical evidence supporting the proposition that the main agent for this dilatation is a differential of pressure between the false and true lumena. This difference in pressure is the consequence of a restricted outflow of the FL. Our aim was to study the relationship between the size of a septectomy that increases the outflow of the FL and its effect on the values of the differential of pressure. METHODS: A bench-top model of aortic dissection was used to determine the relationship between the area of the tears and the value of the pressure differential. A range of tear sizes was tested. RESULTS: The highest differential of pressure (6.77 mm Hg) was found with a single proximal tear. The addition of a distal tear decreases the pressure difference. The greater the sum of the areas of proximal and distal tears, the lower the pressure difference between true lumen and FL. This pressure difference approached zero, as the sum of the areas approached 250 mm(2). CONCLUSIONS: A septectomy of at least 250 mm(2), initiated from the distal tear to the proximal aorta of an area, should be part of the initial treatment of acute aortic dissection. Concomitant with it, the proximal tear should be occluded with either a bare stent or a stent graft. PMID- 25449988 TI - Biological reaction to small-diameter vascular grafts made of silk fibroin implanted in the abdominal aortae of rats. AB - BACKGROUND: Bombyx mori silk fibroin (SF) is biocompatible and degradable and has been proposed as a new material for small-diameter vascular grafts. We compared biological reactions to vascular grafts made of SF and polyethylene terephthalate (PET) to reveal the potential ability of SF as a base and/or coating materials for vascular prostheses. METHODS: SF was combined with PET or gelatin (G) to make 4 types of vascular grafts (SF/SF, SF/G, PET/SF, and PET/G, shown as "base/coating material," respectively), which are 1.5 mm in diameter and 10 mm in length. The 4 types of grafts (n = 6, respectively) were implanted into rat abdominal aortae and explanted 2 weeks or 3 months later. RESULTS: Two weeks after implantation, there are no significant differences among the 4 kinds of grafts in biological reactions evaluated by histopathologic examination. However, a remarkable difference was observed after 3 months. The area of tissue infiltration into the inside of the graft wall was approximately 2.5 times larger in SF/SF than that in PET/G. The endothelialization was achieved almost 100% in SF/SF, despite only 50% was achieved in PET/G. CONCLUSIONS: Results show that SF has a higher potential as a base of vascular grafts than the commercially available PET/G graft. The larger tissue infiltration area in PET/SF compared with that in PET/G also indicates the potential of SF as a coating material. In the present study, SF delivered promising results as base and coating materials for small-diameter vascular prostheses. PMID- 25449989 TI - Technical and early outcomes using ultrasound-guided reentry for chronic total occlusions. AB - BACKGROUND: Subintimal angioplasty is a common treatment for chronic total occlusions (CTOs) in the iliac and infrainguinal arteries. Although technical success has been described using intravascular ultrasound-guided reentry devices (IVUS-RED), outcomes are still not well defined. This report describes the technical aspects and longitudinal follow-up after intravascular ultrasound guided reentry of iliac and infrainguinal CTOs. METHODS: A retrospective review was performed of 20 patients with lower extremity CTO treated with IVUS-RED from 2011 to 2013. A matched cohort of patients who underwent lower extremity interventions without the use of IVUS-RED was also identified. Procedural success, patency estimates, ankle-brachial indices (ABIs), complications, and limb salvage were analyzed. RESULTS: Twenty patients (mean age, 69 +/- 13 years), including 11 men and 9 women, underwent attempted IVUS-RED-guided recanalization. Median follow-up was 4.3 months (range, 0.4-24). Eleven patients presented with critical limb ischemia (CLI), and 9 presented with claudication. Technical success was achieved in 18 (90%) patients. Ten common iliac arteries, 3 external iliac arteries, and 5 superficial femoral arteries (SFA) were treated. No intraoperative complications resulted from device use. After procedure, ABIs significantly increased (0.5-0.9; P < 0.01) in the 13 patients with follow-up. Primary patency for the entire cohort was 62% at 12 months. No patient treated for claudication required reintervention, whereas 3 (27%) of those treated for CLI required repeat interventions. During follow-up, 2 patients died unrelated to the procedure, 1 patient required an amputation, and 1 patient eventually required open revascularization. When the IVUS-RED group was compared with a cohort matched on Trans-Atlantic Inter-Society Consensus and age, no difference was found in runoff scores and patency between the 2 groups during follow-up (P > 0.05). CONCLUSIONS: Recanalization of CTO using IVUS-RED is safe and effective. Use of IVUS-RED does not adversely impact outcomes in conjunction with other endovascular techniques. Early follow-up demonstrates acceptable patency, especially in patients with claudication, and freedom from reintervention. PMID- 25449990 TI - Biomolecular mechanisms in varicose veins development. AB - Varicose veins (VVs) can be described as tortuous and dilated palpable veins, which are more than 3 mm in diameter. They are one of the clinical presentations of chronic venous disorders, which are a significant cause of morbidity. The prevalence of VVs has been estimated at 25-33% in women and 10-20% in men and is still increasing at an alarming rate. Family history, older age, female, pregnancy, obesity, standing occupations, and a history of deep venous thrombosis are the predominant risk factors. A great amount of factors are implicated in the pathogenesis of VVs, including changes in hydrostatic pressure, valvular incompetence, deep venous obstruction, ineffective function of calf muscle pump, biochemical and structural alterations of the vessel wall, extracellular matrix abnormalities, impaired balance between growth factors or cytokines, genetic alterations, and several other mechanisms. Nevertheless, the issue of pathogenesis in VVs is still not completely known, even if a great progress has been made in understanding their molecular basis. This kind of studies appears promising and should be encouraged, and perhaps the new insight in this matter may result in targeted therapy or possibly prevention. PMID- 25449986 TI - Bone marrow from blotchy mice is dispensable to regulate blood copper and aortic pathologies but required for inflammatory mediator production in LDLR-deficient mice during chronic angiotensin II infusion. AB - BACKGROUND: The blotchy mouse caused by mutations of ATP7A develops low blood copper and aortic aneurysm and rupture. Although the aortic pathologies are believed primarily due to congenital copper deficiencies in connective tissue, perinatal copper supplementation does not produce significant therapeutic effects, hinting additional mechanisms in the symptom development, such as an independent effect of the ATP7A mutations during adulthood. METHODS: We investigated if bone marrow from blotchy mice contributes to these symptoms. For these experiments, bone marrow from blotchy mice (blotchy marrow group) and healthy littermate controls (control marrow group) was used to reconstitute recipient mice (irradiated male low-density lipoprotein receptor -/- mice), which were then infused with angiotensin II (1,000 ng/kg/min) for 4 weeks. RESULTS: By using Mann-Whitney U test, our results showed that there was no significant difference in the copper concentrations in plasma and hematopoietic cells between these 2 groups. And plasma level of triglycerides was significantly reduced in blotchy marrow group compared with that in control marrow group (P < 0.05), whereas there were no significant differences in cholesterol and phospholipids between these 2 groups. Furthermore, a bead-based multiplex immunoassay showed that macrophage inflammatory protein (MIP)-1beta, monocyte chemotactic protein (MCP)-1, MCP-3, MCP-5, tissue inhibitor of metalloproteinases (TIMP)-1, and vascular endothelial growth factor (VEGF)-A production was significantly reduced in the plasma of blotchy marrow group compared with that in control marrow group (P < 0.05). More important, although angiotensin II infusion increased maximal external aortic diameters in thoracic and abdominal segments, there was no significant difference in the aortic diameters between these 2 groups. Furthermore, aortic ruptures, including transmural breaks of the elastic laminae in the abdominal segment and lethal rupture in the thoracic segment, were observed in blotchy marrow group but not in control marrow group; however, there was no significant difference in the incidence of aortic ruptures between these 2 groups (P = 0.10; Fisher's exact test). CONCLUSIONS: Overall, our study indicated that the effect of bone marrow from blotchy mice during adulthood is dispensable in the regulation of blood copper, plasma cholesterol and phospholipids levels, and aortic pathologies, but contributes to a reduction of MIP-1beta, MCP-1, MCP 3, MCP-5, TIMP-1, and VEGF-A production and triglycerides concentration in plasma. Our study also hints that bone marrow transplantation cannot serve as an independent treatment option. PMID- 25449991 TI - Effect of structured home-based exercise on walking ability in patients with peripheral arterial disease: a meta-analysis. AB - BACKGROUND: The present study is designed to investigate the effect of structured home-based exercise (SHE) programs on maximal walking time (MWT), pain-free walking time (PFWT), and self-reported walking ability in patients with peripheral arterial disease (PAD). METHODS: We searched the databases including MEDLINE, EMBASE, ISI Web of Knowledge, and the Cochrane Library from inception to December 2013 for randomized controlled trials (RCTs) that assessed the effect of SHE programs on walking ability in patients with PAD. Meta-analysis was performed based on the searched results, moreover, we made a systemic review regarding the results along with our knowledge. RESULTS: Of all the 348 publications we got from the databases, 5 RCTs covering 547 patients reached the inclusion criteria and were involved in the present study. Both inverse-variance fixed-effects and random-effects model were used to perform meta-analysis. SHE programs improved MWT by mean difference of 66.78 sec (95% confidence interval [CI], 5.15-128.41; P = 0.03), heterogeneity across studies was significant. When the trial accounting for significant heterogeneity was omitted, SHE programs improved MWT by mean difference of 91.21 sec (95% CI, 51.96-130.45; P < 0.0001). In contrast, there was no significant heterogeneity across the studies with regard to PFWT and Walking Impairment Questionnaire (WIQ) score. SHE programs improved both PFWT and WIQ scores (mean difference of PFWT, 57.76s; 95% CI, 20.42-95.10; P = 0.002; mean difference of WIQ distance score, 8.67; 95% CI, 3.86-13.49; P = 0.0004; mean difference of WIQ speed score, 8.05, 95% CI, 4.46-11.64; P < 0.0001; mean difference of WIQ stair-climbing score, 6.44; 95% CI, 2.55-10.34; P = 0.001). CONCLUSIONS: SHE programs improve walking ability in patients with PAD. PMID- 25449992 TI - Endovascular aneurysm repair in nonagenarians: a systematic review. AB - BACKGROUND: Endovascular aortic aneurysm repair (EVAR) has been associated with a reduction in early morbidity and mortality compared with open surgery, creating an opportunity for aneurysm repair in those previously considered unfit for intervention. We determine the published incidence of complications and survival after elective EVAR in nonagenarians. METHODS: A systematic literature search was performed using the PubMed, EMBASE, and Cochrane databases up to December 2012. Two observers independently screened search results and extracted data. RESULTS: Six retrospective reports were identified including 361 patients (81% men) with a mean age of 91.6 years. The mean aneurysm size was 69 mm. Comorbidities include hypertension (81%), ischemic heart disease (50%), peripheral vascular disease (30%), and chronic obstructive pulmonary disease (20%). There was no intraoperative mortality, 22% of patients had perioperative medical or surgical complications, and 24% had endoleaks. Mean duration of hospital stay was 4 days. Thirty-day mortality was 5%, and survival at 1, 3, and 5 years was 82%, 56%, and 17%, respectively. CONCLUSIONS: Although the complication rates and longer term survival after elective EVAR in carefully selected nonagenarians appear acceptable, they are higher than those reported in younger patients. Given the typical life expectancy, careful consideration should be given to individual cases before undertaking EVAR in the nonagenarian. PMID- 25449993 TI - The associations of bedtime, nocturnal, and daytime sleep duration with bone mineral density in pre- and post-menopausal women. AB - To explore the association of sleep patterns with bone mineral density (BMD) in pre- and post-menopausal women, we used a questionnaire to evaluate the sleep patterns and performed calcaneal quantitative ultrasound to estimate BMD, in 6,510 women aged 40 years or older, from June to November 2011 in Nanjing City. We found a 1.7-fold risk of osteoporosis in post-menopausalwomen with bedtime of >=0:00 am (OR = 1.69, 95 % CI 1.39-2.13), compared to those whose bedtime of <0:00 am. post-menopausalwomen with excessive total sleep (>10 h vs. 8-9 h, OR = 1.54, 95 % CI 1.05-2.02) were shown to have a higher risk of osteoporosis, however, this high risk was not detected in those with excessive nocturnal sleep (>10 h vs. 8-9 h, OR = 0.85, 95 % CI 0.62-1.30). By contrast, post menopausalwomen with inadequate nocturnal sleep (<=7 h vs. 8-9 h, OR = 1.68, 95 % CI 1.32-2.75), excessive daytime sleep (>=180 min vs. 0 min, OR = 1.52, 95 % CI 1.08-2.13), and noontime nap (>60 min vs. 0 min: OR = 1.37, 95 % CI 1.06-1.76) were demonstrated to have higher risk of bone loss. Nevertheless, these associations were not found in premenopausal women. We conclude that delayed bedtime, nocturnal sleep deprivation, excessive daytime sleep, and noontime nap, but not reduced total sleep duration, could promote bone loss in post menopausalwomen, which might be related to circadian rhythm disturbances. However, they have limited influences to BMD in women who were still in menstruating. Mechanism responsible for the phenomena warrants further investigation. PMID- 25449994 TI - Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects. AB - All commercially available integrase inhibitors are 2-metal binders and may be affected by co-administration with metal cations. The purpose of this study was to evaluate the effect of calcium and iron supplements on dolutegravir pharmacokinetics and strategies (dose separation and food) to attenuate the effects if significant reductions in dolutegravir exposure were observed. This was an open-label, crossover study that randomized 24 healthy subjects into 1 of 2 cohorts to receive 4 treatments: (1) dolutegravir alone, fasting; (2) dolutegravir with calcium carbonate or ferrous fumarate, fasting; (3) dolutegravir with calcium carbonate or ferrous fumarate with a moderate-fat meal; (4) dolutegravir administered 2 hours before calcium carbonate or ferrous fumarate, fasting. Plasma dolutegravir AUC(0-infinity), Cmax , and C24 were reduced by 39%, 37%, and 39%, respectively, when co-administered with calcium carbonate while fasting and were reduced by 54%, 57%, and 56%, respectively, when co-administered with ferrous fumarate while fasting. Dolutegravir administration 2 hours before calcium or iron supplement administration (fasted), as well as administration with a meal, counteracted the effect. Dolutegravir and calcium or iron supplements can be co-administered if taken with a meal. Under fasted conditions, dolutegravir should be administered 2 hours before or 6 hours after calcium or iron supplements. PMID- 25449995 TI - Proton channels and exchangers in cancer. AB - Although cancer is characterized by an intratumoral genetic heterogeneity, a totally deranged pH control is a common feature of most cancer histotypes. Major determinants of aberrant pH gradient in cancer are proton exchangers and transporters, including V-ATPase, Na+/H+ exchanger (NHE), monocarboxylate transporters (MCTs) and carbonic anhydrases (CAs). Thanks to the activity of these proton transporters and exchangers, cancer becomes isolated and/or protected not only from the body reaction against the growing tumor, but also from the vast majority of drugs that when protonated into the acidic tumor microenvironment do not enter into cancer cells. Proton transporters and exchangers represent a key feature tumor cells use to survive in the very hostile microenvironmental conditions that they create and maintain. Detoxifying mechanisms may thus represent both a key survival option and a selection outcome for cells that behave as unicellular microorganisms rather than belonging to an organ, compartment or body. It is, in fact, typical of malignant tumors that, after a clinically measurable yet transient initial response to a therapy, resistant tumor clones emerge and proliferate, thus bursting a more malignant behavior and rapid tumor progression. This review critically presents the background of a novel and efficient approach that aims to fight cancer through blocking or inhibiting well characterized proton exchangers and transporters active in human cancer cells. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25449996 TI - Eicosapentaenoic acid inhibits glucose-induced membrane cholesterol crystalline domain formation through a potent antioxidant mechanism. AB - Lipid oxidation leads to endothelial dysfunction, inflammation, and foam cell formation during atherogenesis. Glucose also contributes to lipid oxidation and promotes pathologic changes in membrane structural organization, including the development of cholesterol crystalline domains. In this study, we tested the comparative effects of eicosapentaenoic acid (EPA), an omega-3 fatty acid indicated for the treatment of very high triglyceride (TG) levels, and other TG lowering agents (fenofibrate, niacin, and gemfibrozil) on lipid oxidation in human low-density lipoprotein (LDL) as well as membrane lipid vesicles prepared in the presence of glucose (200 mg/dL). We also examined the antioxidant effects of EPA in combination with atorvastatin o-hydroxy (active) metabolite (ATM). Glucose-induced changes in membrane structural organization were measured using small angle x-ray scattering approaches and correlated with changes in lipid hydroperoxide (LOOH) levels. EPA was found to inhibit LDL oxidation in a dose dependent manner (1.0-10.0 uM) and was distinguished from the other TG-lowering agents, which had no significant effect as compared to vehicle treatment alone. Similar effects were observed in membrane lipid vesicles exposed to hyperglycemic conditions. The antioxidant activity of EPA, as observed in glucose-treated vesicles, was significantly enhanced in combination with ATM. Glucose treatment produced highly-ordered, membrane-restricted, cholesterol crystalline domains, which correlated with increased LOOH levels. Of the agents tested in this study, only EPA inhibited glucose-induced cholesterol domain formation. These data demonstrate that EPA, at pharmacologic levels, inhibits hyperglycemia-induced changes in membrane lipid structural organization through a potent antioxidant mechanism associated with its distinct, physicochemical interactions with the membrane bilayer. PMID- 25449997 TI - Comparative genomic analysis of eight Leptospira strains from Japan and the Philippines revealing the existence of four putative novel genomic islands/islets in L. interrogans serovar Lai strain 56601. AB - Leptospirosis is one of the most widespread zoonotic diseases worldwide and can be considered an emerging health problem to both human and animal. Despite the importance of the disease, complete genome sequences are currently available for only three Leptospira interrogans strains: 56601, Fiocruz L1-130, and IPAV. Therefore, intra- and inter-species comparative genomic analyses of Leptospira are limited. Here, to advance current knowledge of the genomic differences within Leptospira species, next-generation sequencing technology was used to examine the genomes of eight L. interrogans strains belonging to six different serogroups isolated from humans and dogs in Japan and the Philippines. The genomic sequences were mapped to that of the reference strain, L. interrogans serovar Lai strain 56601. The results revealed the presence of four novel genomic islands/islets (GIs) in strain 56601. This study provides a deeper insight into the molecular basis and evolutionary perspective of the virulence of leptospires. PMID- 25449999 TI - Arthrographis kalrae soluble antigens present hemolytic and cytotoxic activities. AB - Arthrographis kalrae is a dimorphic, cosmopolitan and neurotropic fungus that has been described as a rare human pathogen. This study investigated the hemolytic and cytotoxic activities of A. kalrae cell-free antigens (CFAs). Total CFAs and their Sephadex chromatography fractions were tested on mouse erythrocytes for hemolysis and on the P3U1 cell line for cytotoxicity. Hemolytic and cytotoxic activities were detected in distinct molecular mass (MM) fractions. Additionally, antibodies against isogenic erythrocytes sensitized with CFAs (anti-E-CFAs) inhibited hemolysis but not cytotoxicity. Hemolysis was not affected by heating, and a higher reactivity was detected in the carbohydrate-rich fractions, which decreased after reduction by periodate treatment. The pioneering nature of this work is due to the demonstration of the cytotoxic activity in A. kalrae and the suggestion that this activity may be due to molecules distinct from the hemolytic factor, with the latter potentially being a component with a high MM. PMID- 25449998 TI - Iron metabolism in hamsters experimentally infected with Leptospira interrogans serovar Pomona: influence on disease pathogenesis. AB - The aim of this study was to analyze the classic iron markers associated to the storage process in hamsters experimentally infected by Leptospira interrogans serovar Pomona. Four groups with six hamsters each were used; two were negative controls (C7 and C14) and two were composed by infected animals (T7 and T14). Blood samples were collected on the seventh (C7 and T7) and fourteenth days (C14 and T14) post-inoculation. Iron availability was determined in sera samples through the assessment of iron, ferritin, transferrin, and iron binding capacity, whereas the bone marrow was also evaluated for the presence of iron by Pearl's reaction. Additionally, the total antioxidant capacity (TAC) and total oxidant status (TOS) were assessed, along with hepcidin and IL-6 levels. Based on the results, it was possible to observe the onset of an anemic profile, predominantly hemolytic and regenerative. Also, The other parameters showed an increase in seric iron (P<0.01) and ferritin (P<0.01), and a positive Pearl's reaction in T7 and T14, when compared with the control groups. Transferrin levels decreased (P<0.05) in animals of T14 with saturation index. TAC was increased in both periods (P<0.01), while TOS was increased only on T14 (P<0.05). Hepcidin and IL-6 were increased on T7 and T14 (P<0.01). Therefore, it was observed that the serum profile from infected animals showed a strong hemolytic pattern, with some demonstration of ferric tissue sequestration when the infection tended to become chronic. The results show that iron metabolism is activated in hamsters infected by L. interrogans serovar Pomona. PMID- 25450000 TI - High affinity anti-Internalin B VHH antibody fragments isolated from naturally and artificially immunized repertoires. AB - The need for rapid and easy technologies for the detection of food-borne and environmental pathogens is essential for safeguarding the health of populations. Furthermore, distribution of tainted food and water can have consequences which can affect whole economies. Antibodies and antibody fragments have been historically used in detection platforms due to their antigen specificity and robust physicochemical properties. In this study, we report the isolation and characterization of antibody fragments from the heavy chain antibody repertoire (VHH) of Camelidae which bind with specificity and high affinity to the Listeria monocytogenes invasin, Internalin B (InlB). To the best of our knowledge, this is the first report of anti-InlB VHHs from camelids. These anti-InlB VHHs were not cross-reactive to the structurally related Listeria invasin Internalin A (InlA) and are potential reagents to be used in the development of detection and medical technologies. PMID- 25450001 TI - CMV specific cytokine release assay in whole blood is optimized by combining synthetic CMV peptides and toll like receptor agonists. AB - BACKGROUND: Interferon gamma release assays (IGRAs) are widely used to detect pathogen specific cellular immunity. Cytomegalovirus (CMV) is the foremost problematic viral infection in immunocompromised patients such as transplant or HIV infected patients. CMV antibody ELISAs are not able to predict CMV specific cellular immunity during immunosuppression. We developed a CMV specific IGRA comparing synthetic CMV peptides, native lysate and recombinant antigen. In addition, TLR agonists were tested to enhance CMV antigen immunogenicity. METHODS: 397 healthy controls (HC) were stratified according to CMV IgM and IgG serostatus and subsequently tested for IFNgamma- and IL2-secretion in whole blood after challenge with synthetic, native or recombinant CMV antigens and TLR agonists by ELISA. The selected TLR agonists were lipopolysaccharide (LPS), lipoteichoic acid (LTA), peptidoglycan (PGN), zymosan (Zym), polyinosinic polycytidylic acid (Poly(I:C)), flagellin (Fla), R848, loxoribine (Lox) and bropirimine (Bro). RESULTS: Synthetic pp65 peptides elicited strong IFNgamma responses in CMV seropositive, but not seronegative HC (6418 vs. 13 pg/ml). Native lysates and recombinant pp65 induced equally high IFNgamma responses in seropositive (35,877 and 26,428 pg/ml) and increased background IFNgamma expression in seronegative HC (43 and 1148 pg/ml). Diagnostic sensitivity and specificity with regard to anti-CMV serology reached 100% for synthetic pp65 and native CMV lysate, but 57% and 100% for recombinant pp65, respectively. TLR agonists LTA and Poly(I:C) augmented IFNgamma responses after challenge with synthetic pp65 peptide, native lysate or recombinant pp65 in seropositive HC. Seronegative HC remained unaffected. IL2 production was negligible compared to IFNgamma. CONCLUSION: IGRAs using synthetic CMV peptides or native lysate showed the best cytokine signal to noise ratio compared to recombinant antigen and TLR agonists LTA and Poly(I:C) constitute potential costimulating reagents. PMID- 25450002 TI - An infected chicken kidney cell co-culture ELISpot for enhanced detection of T cell responses to avian influenza and vaccination. AB - A better understanding of the immune responses of chickens to the influenza virus is essential for the development of new strategies of vaccination and control. We have developed a method incorporating infected chicken kidney cells (CKC) in culture with splenocytes in an IFNgamma ELISpot assay to enumerate ex vivo responses against influenza virus antigens. Splenocytes from birds challenged with influenza showed specific responses to the influenza virus, with responding cells being mainly CD8 positive. The utility of the assay was also demonstrated in the detection of an antigen specific enhancement of IFNgamma producing cells from birds vaccinated with recombinant Fowlpox vectored influenza nucleoprotein and matrix protein. PMID- 25450003 TI - CyTOF supports efficient detection of immune cell subsets from small samples. AB - Analysis of immune cell states is paramount to our understanding of the pathogenesis of a broad range of human diseases. Immunologists rely on fluorescence cytometry for cellular analysis, and while detection of 8 markers is now well established, the overlap of fluorescent signals limits efficiency. Mass cytometry or CyTOF (Cytometry by Time-Of-Flight) is a new technology for multiparameter single cell analysis that overcomes many limitations of fluorescence-based flow cytometry and can routinely detect as many as 40 markers per sample. This technology provides tremendous detail for cellular analysis of multiple cell populations simultaneously and is a powerful technique for translational investigations. Here we present reproducible detection of immune cell subsets starting with as few as 10,000 cells. Our study provides methods to employ CyTOF for small samples, which is especially relevant for investigation of limited patient biopsies in translational and clinical research. PMID- 25450004 TI - Auto-induction for high yield expression of recombinant novel isoallergen tropomyosin from King prawn (Melicertus latisulcatus) for improved diagnostics and immunotherapeutics. AB - Food allergies are increasing worldwide, demonstrating a considerable public health concern. Shellfish allergy is one of the major food groups causing allergic sensitization among adults and children, affecting up to 2% of the general world population. Tropomyosin (TM) is the major allergen in shellfish and frequently used in the diagnosis of allergic sensitization and the detection of cross-contaminated food. To improve and establish better and more sensitive diagnostics for allergies and immunotherapeutics, large quantities of pure allergens are required. To establish a reproducible method for the generation of pure recombinant tropomyosin we utilized in this study different Escherichia coli strains (NM522, TOP10 and BL21(DE3)RIPL). In addition, isopropyl-beta-D thiogalactoside (IPTG) induction was compared with a novel auto-induction system to allow the generation of larger quantities of recombinant allergen. We demonstrated that the B-strain of E. coli is better for the expression of TM compared to the K-strain. Moreover, a higher yield could be achieved when using the auto-induction system, with up to 62 mg/l. High yield expressed recombinant TM from King prawn (KP) was compared to recombinant TM from Black tiger prawn (Pen m 1). We demonstrated that recombinant TM from KP and known isoallergen Pen m 1 have very similar molecular and immunological characteristics. Overall, we demonstrate that auto-induction can be used to express larger quantities of recombinant allergens for the development of diagnostic, to quantify allergens as well as immunotherapeutics employing isoallergens. PMID- 25450005 TI - Flow cytometric evaluation of lymphocyte transformation test based on 5-ethynyl 2'deoxyuridine incorporation as a clinical alternative to tritiated thymidine uptake measurement. AB - In clinical laboratories, the evaluation of lymphocyte proliferative response (lymphocyte transformation test-LTT) is routinely performed by the measurement of [(3)H]-thymidine uptake after stimulation. In this study we evaluated the performances of a recently developed non-radioactive test based on the detection by flow cytometry of 5-ethynyl-2'deoxyuridine (EdU) incorporation for the measurement of LTT in routine lab conditions. After definition of optimal protocol parameters, EdU incorporation test showed good repeatability and reproducibility. Moreover, this assay was flexible enough to fit important clinical laboratory constraints (delayed stimulation, low number of cells and delayed analysis after staining). Importantly, correlations between results obtained with EdU and [(3)H]-thymidine incorporation assays were excellent both in healthy volunteers and pediatric and septic patients. In particular, the two techniques identified patients presenting with altered LTT. Upon confirmation in a larger cohort of patients, EdU incorporation assay may be a relevant non radioactive candidate for LLT in clinic. PMID- 25450006 TI - Development of a sensitive potency assay to measure the anti-proliferation effect of an anti-HER2 antibody. AB - For therapeutic antibodies that inhibit the growth of cancer cells, proliferation assays that measure cell number changes after the antibody treatment are often used to determine the potency of the antibody. Two of the most commonly used non radioactive readout systems for proliferation assays, the ATP bioluminescence assay and the fluorescent dye Alamar Blue assay, were initially tested as potency assays an anti-HER2 antibody. Due to the slow growth of the target cells, these assays only produced less than 3-fold difference after 5 days of antibody treatment. BrdU incorporation-based proliferation assay, which differentiates proliferating cells from arrested cells, was developed, and showed superior sign to-background ratio. Colorimetric, chemiluminescent, and DELFIA readouts were compared for BrdU incorporation assays, and DELFIA-based assay was further optimized using a Design of Experiment (DoE) approach. The final DELFIA-based BrdU incorporation assay demonstrated superior signal-to-background ratio, robustness, accuracy, and precision, and represented significant improvement over traditional proliferation assays. PMID- 25450008 TI - A three-dimensional computed tomography study of distal femoral morphology in Japanese patients: gender differences and component fit. AB - BACKGROUND: Previous anthropometric studies have reported gender differences in distal femoral morphology. However, to date, very few studies have investigated the knee morphology of Japanese adults and possible gender differences. The purpose of this study was to examine the distal femoral morphology of Japanese patients, to characterize anatomical differences between male and female, and to evaluate the need to create gender-specific knee prostheses. MATERIAL AND METHODS: We evaluated 80 knees in 40 male and 40 female Japanese patients scheduled for total knee arthroplasty (TKA). The mediolateral (ML) and anteroposterior (AP) dimensions of the knees at different levels were measured preoperatively using three-dimensional computed tomography, and ML/AP aspect ratios were calculated. RESULTS: On the distal femoral cut surface, the mean ML widths were 74.9 mm for male and 65.1mm for female, and the mean AP lengths were 63.4mm for male and 58.9 mm for female. Such values were generally smaller compared to data from European and North American studies. In this study, the mean ML/AP aspect ratios were 1.31 for male and 1.25 for female, higher than those from non-Asian regions. The ML/AP ratios of Japanese patients were negatively correlated with distal femoral AP length. CONCLUSIONS: Japanese female had a relatively narrower femoral width for a given AP length than male. Our study suggests the utility of Japanese-specific implants and provides useful insights for manufacturers to design components of appropriate sizes and aspect ratios for Japanese TKA patients. PMID- 25450009 TI - Comparison of topical versus intravenous tranexamic acid in primary total knee arthroplasty: a meta-analysis of randomized controlled and prospective cohort trials. AB - BACKGROUND: There has been much debate and controversy about the optimal regimen of tranexamic acid in primary total knee arthroplasty. The purpose of this study was to undertake a meta-analysis to compare the efficacy of topical and intravenous regimen of tranexamic acid in primary total knee arthroplasty. METHODS: A systematic review of the electronic databases PubMed, CENTRAL, Web of Science, and Embase was undertaken. All randomized controlled trials and prospective cohort studies evaluating the effectiveness of topical and intravenous tranexamic acid during primary total knee arthroplasty were included. The focus of the analysis was on the outcomes of blood loss, transfusion rate, and thromboembolic complications. Subgroup analysis was performed when possible. RESULTS: Of 328 papers identified, six trials were eligible for data extraction and meta-analysis comprising 679 patients (739 knees). We found no statistically significant difference between topical and intravenous administration of tranexamic acid in terms of blood loss, transfusion requirements and thromboembolic complications. CONCLUSIONS: Topical tranexamic acid has a similar efficacy to intravenous tranexamic acid in reducing both blood loss and transfusion rate without sacrificing safety in primary total knee arthroplasty. LEVEL OF EVIDENCE: II. PMID- 25450010 TI - Improved alignment and operating room efficiency with patient-specific instrumentation for TKA. AB - BACKGROUND: Achieving accurate alignment in total knee arthroplasty (TKA) remains a concern. Patient-specific instrumentation (PSI) produced using preoperative 3D models was developed to offer surgeons a simplified, reliable, efficient and customised TKA procedure. METHODS: In this prospective study, 60 patients underwent TKA with conventional instrumentation and 71 patients were operated on using PSI. The primary endpoint was surgical time. Secondary endpoints included operating room (OR) time, the number of instrument trays used and postoperative radiographic limb alignment. RESULTS: Compared to conventional instrumentation, PSI significantly reduced total surgical time by 8.9 +/- 3.3 min (p=0.038), OR time by 8.6 +/- 4.2 min (p=0.043), and the number of instrument trays by six trays (p<0.001). Mechanical axis malalignment of the lower limb of >3 degrees was observed in 13% of PSI patients versus 29% with conventional instrumentation (p=0.043). PSI predicted the size of the femoral and tibial components actually used in 85.9% and 78.9% of cases, respectively. CONCLUSION: PSI improves alignment, surgical and OR time, reduces the number of instruments trays used compared to conventional instrumentation in patients undergoing TKA and results in fewer outliers in overall mechanical alignment in the coronal plane. LEVEL OF EVIDENCE II: Prospective comparative therapeutic study. PMID- 25450007 TI - Inhibition of SNW1 association with spliceosomal proteins promotes apoptosis in breast cancer cells. AB - RNA splicing is a fundamental process for protein synthesis. Recent studies have reported that drugs that inhibit splicing have cytotoxic effects on various tumor cell lines. In this report, we demonstrate that depletion of SNW1, a component of the spliceosome, induces apoptosis in breast cancer cells. Proteomics and biochemical analyses revealed that SNW1 directly associates with other spliceosome components, including EFTUD2 (Snu114) and SNRNP200 (Brr2). The SKIP region of SNW1 interacted with the N-terminus of EFTUD2 as well as two independent regions in the C-terminus of SNRNP200. Similar to SNW1 depletion, knockdown of EFTUD2 increased the numbers of apoptotic cells. Furthermore, we demonstrate that exogenous expression of either the SKIP region of SNW1 or the N terminus region of EFTUD2 significantly promoted cellular apoptosis. Our results suggest that the inhibition of SNW1 or its associating proteins may be a novel therapeutic strategy for cancer treatment. PMID- 25450011 TI - Decision-making in classic trigeminal neuralgia concurrent with a pontine cavernous malformation: Causal or coincidental association? AB - Trigeminal neuralgia is classically associated with neurovascular compression of the trigeminal nerve, at the root entry zone (REZ). However, patients are occasionally affected by intra-axial involvement of trigeminal sensory fibers caused by demyelinating diseases, strokes and, rarely, pontine cavernous malformations. We discuss the management strategies and decision-making process in a 55-year-old patient, affected by trigeminal neuralgia with 2 potential causative mechanisms: a neurovascular conflict at the trigeminal REZ and an ipsilateral cavernous malformation at the pontine nucleus of the trigeminal nerve. PMID- 25450013 TI - Dynamic changes in tricuspid annular diameter measurement in relation to the echocardiographic view and timing during the cardiac cycle. AB - BACKGROUND: Tricuspid annular (TA) size and function play important roles in planning the need for associated TA annuloplasty in patients undergoing cardiac surgery for left-sided heart valve diseases. However, TA diameter normative values and the extent of TA dynamic changes during cardiac cycle remain to be established. METHODS: This was a prospective, cross-sectional study of 219 healthy volunteers (mean age, 43 +/- 15 years; 57% women), using conventional two dimensional transthoracic echocardiographic (2DE) imaging to assess the variability of TA diameter measurement in relation to 2DE view and timing during cardiac cycle. TA diameter was obtained from apical right ventricular (RV) focused four-chamber, parasternal long-axis RV inflow, and parasternal short-axis at aortic plane 2DE views at five time points during the cardiac cycle. Right atrial and RV volumes were measured using three-dimensional echocardiography. RESULTS: TA diameters differed significantly among the three 2DE views and changed significantly during the cardiac cycle in all views. Moreover, mean fractional shortening of TA diameter was 24 +/- 6% in the four-chamber view, 20 +/- 7% in the parasternal long-axis RV inflow view, and 29 +/- 11% in the parasternal short-axis at aortic plane view. One multivariate linear regression analysis, age, gender, and right atrial and RV volumes were independently correlated with TA diameters and accounted for 55% of the variance of midsystolic TA diameter in the four-chamber view. CONCLUSIONS: This study provides references values for TA diameters and dynamics using 2DE imaging. Age, gender, and right chamber sizes, as well as the 2DE view and time during the cardiac cycle, significantly influenced TA diameters in healthy individuals. These data may help better identify TA dilatation using 2DE imaging for surgical planning. PMID- 25450012 TI - Improving olefin tolerance and production in E. coli using native and evolved AcrB. AB - Microorganisms can be engineered for the production of chemicals utilized in the polymer industry. However many such target compounds inhibit microbial growth and might correspondingly limit production levels. Here, we focus on compounds that are precursors to bioplastics, specifically styrene and representative alpha olefins; 1-hexene, 1-octene, and 1-nonene. We evaluated the role of the Escherichia coli efflux pump, AcrAB-TolC, in enhancing tolerance towards these olefin compounds. AcrAB-TolC is involved in the tolerance towards all four compounds in E. coli. Both styrene and 1-hexene are highly toxic to E. coli. Styrene is a model plastics precursor with an established route for production in E. coli (McKenna and Nielsen, 2011). Though our data indicates that AcrAB-TolC is important for its optimal production, we observed a strong negative selection against the production of styrene in E. coli. Thus we used 1-hexene as a model compound to implement a directed evolution strategy to further improve the tolerance phenotype towards this alpha-olefin. We focused on optimization of AcrB, the inner membrane domain known to be responsible for substrate binding, and found several mutations (A279T, Q584R, F617L, L822P, F927S, and F1033Y) that resulted in improved tolerance. Several of these mutations could also be combined in a synergistic manner. Our study shows efflux pumps to be an important mechanism in host engineering for olefins, and one that can be further improved using strategies such as directed evolution, to increase tolerance and potentially production. PMID- 25450014 TI - Abnormal left ventricular contractile response to exercise in the absence of obstructive coronary artery disease is associated with resting left ventricular long-axis dysfunction. AB - BACKGROUND: The etiology of reduced left ventricular (LV) ejection fraction after exercise, without obstructive coronary artery disease or other established causes, is unclear. The aims of this study were to determine whether patients undergoing treadmill stress echocardiography with this abnormal LV contractile response to exercise (LVCRE) without established causes have resting LV long-axis dysfunction or microvascular dysfunction and to determine associations with this abnormal LVCRE. METHODS: Of 5,275 consecutive patients undergoing treadmill stress echocardiography, 1,134 underwent cardiac computed tomography angiography or invasive angiography. Having excluded patients with obstructive coronary artery disease, hypertensive response, submaximal heart rate response, resting LV ejection fraction < 50%, and valvular disease, 110 with "abnormal LVCRE" and 212 with "normal LVCRE" were analyzed. Resting mitral annular velocities were measured to assess LV long-axis function. Myocardial blush grade and corrected Thrombolysis In Myocardial Infarction frame count were determined angiographically to assess microvascular function. RESULTS: Comparing normal LVCRE with abnormal LVCRE, age (mean, 59.7 +/- 11.1 vs 61.4 +/- 10.0 years), hypertension (53% vs 55%), diabetes (16% vs 20%), and body mass index (mean, 29.1 +/- 5.4 vs 29.5 +/- 6.4 kg/m(2)) were similar (P > .05). Abnormal LVCRE had reduced resting LV long-axis function with lower septal (mean, 6.1 +/- 1.9 vs 7.7 +/- 2.2 cm/sec) and lateral (mean, 8.1 +/- 2.9 vs 10.4 +/- 3.0 cm/sec) e' velocities (P < .001) and larger resting left atrial volumes (mean, 37.3 +/- 10.1 vs 31.1 +/- 7.2 mL/m(2), P < .001). On multivariate analysis, female gender (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.15-1.99; P < .001), exaggerated chronotropic response (OR, 1.49; 95% CI, 1.09-2.05; P < .001), resting left atrial volume (OR, 2.38; 95% CI, 1.63-3.47; P < .001), and resting lateral e' velocity (OR, 1.70; 95% CI, 1.22-2.49; P = .003) were associated with abnormal LVCRE, but not myocardial blush grade or corrected Thrombolysis In Myocardial Infarction frame count. CONCLUSIONS: An abnormal LVCRE in the absence of established causes is associated with resting LV long-axis dysfunction and is usually seen in women. PMID- 25450015 TI - Effects of right ventricular hemodynamic burden on intraventricular flow in tetralogy of fallot: an echocardiographic contrast particle imaging velocimetry study. AB - BACKGROUND: The purpose of this investigation was to test the hypothesis that flow patterns in the right ventricle are abnormal in patients with repaired tetralogy of Fallot (TOF). High-resolution echocardiographic contrast particle imaging velocimetry was used to investigate rotation intensity and kinetic energy dissipation of right ventricular (RV) flow in patients with TOF compared with normal controls. METHODS: Forty-one subjects (16 with repaired TOF and varying degrees of RV dilation and 25 normal controls) underwent prospective contrast imaging using the lipid-encapsulated microbubble (Definity) on Sequoia systems. A mechanical index of 0.4, three-beat high-frame rate (>60 Hz) captures, and harmonic frequencies were used. Rotation intensity and kinetic energy dissipation of flow in the right and left ventricles were studied (Hyperflow). Ventricular volumes and ejection fractions in all subjects were derived from same-day cardiac magnetic resonance (CMR). RESULTS: Measurable planar maps were obtained for the left ventricle in 14 patients and the right ventricle in 10 patients among those with TOF and for the left ventricle in 23 controls and the right ventricle in 21 controls. Compared with controls, the TOF group had higher RV indexed end diastolic volumes (117.8 +/- 25.5 vs 88 +/- 15.4 mL/m(2), P < .001) and lower RV ejection fractions (44.6 +/- 3.6% vs 51.8 +/- 3.6%, P < .001). Steady-streaming (heartbeat-averaged) flow rotation intensities were higher in patients with TOF for the left ventricle (0.4 +/- 0.13 vs 0.29 +/- 0.08, P = .012) and the right ventricle (0.53 +/- 0.15 vs 0.26 +/- 0.12, P < .001), whereas kinetic energy dissipation in TOF ventricles was lower (for the left ventricle, 0.51 +/- 0.29 vs 1.52 +/- 0.69, P < .001; for the right ventricle, 0.4 +/- 0.24 vs 1.65 +/- 0.91, P < .001). CONCLUSIONS: It is feasible to characterize RV and left ventricular flow parameters and planar maps in adolescents and adults with repaired TOF using echocardiographic contrast particle imaging velocimetry. Intraventricular flow patterns in the abnormal and/or enlarged right ventricle in patients with TOF differ from those in normal young adults. The rotation intensity and energy dissipation trends in this investigation suggest that they may be quantitative markers of RV and left ventricular compliance abnormalities in patients with repaired TOF. This hypothesis merits further investigation. PMID- 25450016 TI - Predicted 10-year risk of developing cardiovascular disease at the state level in the U.S. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in the U.S. State-specific predicted 10-year risk of developing CVD could provide useful information for state health planning and policy. PURPOSE: To estimate state specific 10-year risk of developing CVD. METHODS: Using the updated non laboratory-based Framingham CVD Risk Score (RS), this study estimated 10-year risk of developing CVD; coronary heart disease (CHD); and stroke, stratified by demographic factors and by state among 2009 Behavioral Risk Factors Surveillance System participants aged 30-74 years. Data analysis was completed in June 2014. RESULTS: The age-standardized mean CVD, CHD, and stroke RSs for adults aged 30-74 years were 14.6%, 10.4%, and 2.3% among men, respectively, and 7.5%, 4.5%, and 1.8% among women. RSs increased significantly with age and were highest among non Hispanic blacks, those with less than high school education, and households with incomes <$35,000. State-specific age-standardized CVD, CHD, and stroke RS ranged, among men, from lows in Utah (13.2%, 9.6%, and 2.1%, respectively) to highs in Louisiana (16.2%, 11.7%, and 2.6%), and among women, from lows in Minnesota (6.3%, 3.8%, and 1.5%) to highs in Mississippi (8.7%, 5.3%, and 2.1%). CONCLUSIONS: The predicted 10-year risk of developing CVD varies significantly by age, gender, race/ethnicity, educational attainment, household income, and state of residence. These results support the development and implementation of targeted prevention programs by states to address the risk of developing CVD, CHD, and stroke among their populations. PMID- 25450017 TI - CYP2J2 epoxygenase membrane anchor plays an important role in facilitating electron transfer from CPR. AB - CYP2J2 epoxygenase is a membrane-bound cytochrome P450 primarily expressed in the heart and plays a significant role in cardiovascular diseases. The interactions of CYP2J2 with its redox partner, cytochrome P450 reductase (CPR), and with its substrates are quite complex and can have a significant effect on the kinetics of substrate metabolism. Here we show that the N-terminus of CYP2J2 plays an important role in the formation of CYP-CPR complex for subsequent electron transfer. We demonstrate that when CYP2J2-CPR are pre-incubated before the onset of reduction, the kinetics of reduction is triphasic and is of a similar order of magnitude to previously reported rates in other cytochrome P450 systems. However, when CYP2J2 and CPR form a complex during the time course of the experiment the kinetics of the fastest phase for N-terminus containing full-length CYP2J2 is 200 times faster than the kinetics of reduction of N-terminally truncated CYP2J2. Hence, we show that the N-terminus of CYP2J2 is very important to form a productive CYP-CPR complex to facilitate electron transfer. PMID- 25450018 TI - Pulse radiolysis studies of the reactions of nitrogen dioxide with the vitamin B12 complexes cob(II)alamin and nitrocobalamin. AB - Although now recognized to be an important reactive nitrogen species in biological systems that modifies the structures of proteins, DNA and lipids, there are few studies on the reactivity of NO2, including the reactions between NO2 and transition metal complexes. We report kinetic studies on the reactions of NO2 with two forms of vitamin B12 - cob(II)alamin and nitrocobalamin. UV-visible spectroscopy and HPLC analysis of the product solution show that NO2 cleanly oxidizes the metal center of cob(II)alamin to form nitrocobalamin, with a second order rate constant of (3.5+/-0.3)*10(8)M(-1)s(-1) (pH7.0 and 9.0, room temperature, I=0.20M). The stoichiometry of the reaction is 1:1. No reaction is detected by UV-visible spectroscopy and HPLC analysis of the product solution when nitrocobalamin is exposed to up to 2.0molequiv. NO2. PMID- 25450020 TI - Acid-base characterization, coordination properties towards copper(II) ions and DNA interaction studies of ribavirin, an antiviral drug. AB - We have studied processes of copper(II) ion binding by ribavirin, an antiviral agent used in treating hepatitis C, which is accompanied usually by an increased copper level in the serum and liver tissue. Protonation equilibria and Cu(II) binding were investigated using the UV-visible, EPR and NMR spectroscopic techniques as well as the DFT (density functional theory) calculations. The spectroscopic data suggest that the first complex is formed in the water solution at pH as low as 0.5. In this compound Cu(II) ion is bound to one of the nitrogen atoms from the triazole ring. Above pH6.0, the metal ion is surrounded by two nitrogen and two oxygen atoms from two ligand molecules. The DFT calculations allowed to determine the exact structure of this complex. We found that in the lowest energy isomer two molecules of the ligand coordinate via O and N4 atoms in trans positions. The hypothetical oxidative properties of the investigated system were also examined. It proved not to generate plasmid DNA scission products. However, the calf thymus (CT)-DNA binding studies showed that it reacts with ribavirin and its cupric complex. Moreover, the interaction with the complex is much more efficient. PMID- 25450019 TI - Zinc is the molecular "switch" that controls the catalytic cycle of bacterial leucyl-tRNA synthetase. AB - The Escherichia coli (E. coli) leucyl-tRNA synthetase (LeuRS) enzyme is part of the aminoacyl-tRNA synthetase (aaRS) family. LeuRS is an essential enzyme that relies on specialized domains to facilitate the aminoacylation reaction. Herein, we have biochemically characterized a specialized zinc-binding domain 1 (ZN-1). We demonstrate that the ZN-1 domain plays a central role in the catalytic cycle of E. coli LeuRS. The ZN-1 domain, when associated with Zn(2+), assumes a rigid architecture that is stabilized by thiol groups from the residues C159, C176 and C179. When LeuRS is in the aminoacylation complex, these cysteine residues form an equilateral planar triangular configuration with Zn(2+), but when LeuRS transitions to the editing conformation, this geometric configuration breaks down. By generating a homology model of LeuRS while in the editing conformation, we conclude that structural changes within the ZN-1 domain play a central role in LeuRS's catalytic cycle. Additionally, we have biochemically shown that C159, C176 and C179 coordinate Zn(2+) and that this interaction is essential for leucylation to occur, but is not essential for deacylation. Furthermore, calculated Kd values indicate that the wild-type enzyme binds Zn(2+) to a greater extent than any of the mutant LeuRSs. Lastly, we have shown through secondary structural analysis of our LeuRS enzymes that Zn(2+) is an architectural cornerstone of the ZN-1 domain and that without its geometric coordination the domain collapses. We believe that future research on the ZN-1 domain may reveal a possible Zn(2+) dependent translocation mechanism for charged tRNA(Leu). PMID- 25450021 TI - Association of a Zn(2+) containing metallo beta-lactamase with the anticancer antibiotic mithramycin. AB - Pathogenic bacteria that are resistant to beta-lactam antibiotics mostly utilize serine beta-lactamases to degrade the antibiotics. Current studies have shown that different subclasses of metallo beta-lactamases (E[MBL]) are involved in the defense mechanism of drug resistant bacteria. Here we report that the Zn(2+) containing subclass B1 E[MBL] from Bacillus cereus binds to a naturally occurring anti-cancer drug mithramycin (MTR). Spectroscopic (CD and fluorescence) and isothermal titration calorimetry studies show that MTR forms a high affinity complex with the Zn(2+) ion containing E[MBL]. Abolished interaction of MTR with apo E[MBL] suggests that the formation of this high affinity complex occurs due to the potential of MTR to bind bivalent metal ions like Zn(2+). Furthermore, CD spectroscopy, dynamic light scattering and differential scanning calorimetry studies indicate that the strong association with sub-micromolar dissociation constant leads to an alteration in the enzyme conformation at both secondary and tertiary structural levels. The enzyme activity decreases as a consequence to this conformational disruption arising from the formation of a ternary complex involving MTR, catalytic Zn(2+) and the enzyme. Our results suggest that the naturally occurring antibiotic MTR, a generic drug, has the potential as an E[MBL] inhibitor. PMID- 25450022 TI - DFT study on the oxygen transfer mechanism in nitroethenediamine based H2 receptor antagonists using the bis-dithiolene complex as the model catalyst for N oxide reductase enzyme. AB - Nitroethenediamine is an important functional unit, which is present in H2 receptor antagonists. These drugs show low bioavailability due to the bacterial degradation caused by the N-oxide reductase type of enzymes present in the human colon. Quantum chemical studies have been carried out to elucidate the mechanism of metabolic degradation of nitroethenediamine in the active site of N-oxide reductase. Three different pathways have been explored for the N-oxide bond cleavage by the model system, Mo(IV) bis-dithiolene complex [Mo(OMe)(mdt)2](-), (where mdt=1,2-dimethyl-ethene-1,2-dithiolate) using B3LYP/6-311+G(d,p) and M06/6 311+G(d,p) Density Functional Theory methods. The oxygen atom transfer from the nitrogen atom of nitroethenediamine to the Mo(IV) complex, involves simultaneous weakening of the N-oxide bond and the formation of Mo-O bond through a least motion path. During this transfer, Mo center is converted from a square pyramidal geometry to a distorted octahedral geometry, to facilitate the process of oxygen atom transfer. The energy barrier for the oxygen atom transfer from the imine tautomer has been estimated to be 25.9kcal/mol however, the overall reaction has been found to be endothermic. On the other hand, oxygen transfer reaction from the nitronic acid tautomer requires 30.5kcal/mol energy leading to a highly exothermic metabolite (M-1) directly hence, this path can be considered thermodynamically favorable for this metabolite. The alternative path involving the oxygen atom transfer from the enamine tautomer requires comparatively a higher energy barrier (32.6kcal/mol) and leads to a slightly endothermic metabolite. This study established the structural and energetic details associated with the Mo(IV) bis-dithiolene complex that catalyzes the degradation of nitroethenediamine based drug molecules. PMID- 25450023 TI - Iron-salophen complexes involving azole-derived ligands: A new group of compounds with high-level and broad-spectrum in vitro antitumor activity. AB - A series of iron(II/III) salophen (salph) complexes involving monodentate azole derived ligands, having the composition [Fe(II)(salph)(HL1)] (1) and [Fe(III)(salph)(L)] (2-6), where HL1=imidazole, L=1,2,4-triazol-1-ido (L2), benzo[d][1,2,3]triazol-1-ido (L3), 5-aminotetrazol-1-ido (L4), 5-phenyltetrazol-1 ido (L5), and 5-methyltetrazol-1-ido (L6) ligand, was prepared and characterized by elemental analyses, infrared, Mossbauer and X-ray photolelectron spectroscopy, magnetic data and electrospray-ionization mass spectrometry. X-ray structure of 1 revealed a distorted square-pyramidal geometry in the vicinity of the iron(II) atom. The complexes were evaluated for their in vitro antitumor activity against the panel of six human cancer cell lines (HOS, MCF7, A549, HeLa, A2780 and G-361) and were found to be highly cytotoxic, showing the best IC50 value of 58nM for [Fe(III)(salph)(L6)] (6) against the ovarian carcinoma A2780 cell line, being 200 times more effective than cisplatin. In vitro cytotoxicity of complexes 1-6 on primary culture of human hepatocytes and calf-thymus DNA (CT-DNA) binding studies using the fluorescence titration were also performed. PMID- 25450024 TI - New 8-hydroxyquinoline galactosides. The role of the sugar in the antiproliferative activity of copper(II) ionophores. AB - 8-Hydroxyquinoline derivatives and their metal complexes have recently awakened interest as promising therapeutic agents in cancer therapy. We have previously synthesized and evaluated glucoconjugated 8-hydroxyquinolines as copper ionophores activated by beta-glucosidases. In order to further evaluate the crucial role of the sugar, we designed and synthesized a series of new galactoconjugates of 8-hydroxyquinolines and investigated their biological properties in comparison with the 8-hydroxyquinoline analogs. The effect of copper(II) ions on their biological activities was evaluated. In particular, two compounds possess a pharmacologically relevant antiproliferative activity against specific tumor cells in the presence of copper(II) ions. Furthermore, the antiproliferative activity of the selected galactosides was successfully investigated in the presence of beta-galactosidase as a preliminary model of antibody directed enzyme prodrug therapy. PMID- 25450025 TI - Two novel compounds of vanadium and molybdenum with carnitine exhibiting potential pharmacological use. AB - The reaction of sodium orthovanadate with carnitine hydrochloride molecule results in the precipitation of decavanadate compound of carnitine whereas the reaction of metallic molybdenum with hydrogen peroxide and carnitine results in the peroxo-molybdenum complex of carnitine. The decavanadate compound as well as the molybdenum complex of carnitine have been characterized by means of elemental analysis, IR, electronic spectra, (1)H NMR, 2D-COSY-NMR (=correlation spectroscopy) and thermo-gravimetric analysis (TGA). In addition decavanadate compound of carnitine was fully characterized by X-ray crystallography. The analytical data were in good agreement with the empirical formulae of both, decavanadate compound and molybdenum complex. The two compounds were also evaluated for cell toxicity and their anticancer activity by the MTT(3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)-based assay method, using primary cells and tumor cell lines of both human and murine origins and the results show that compound 1 shows an increased biological activity in comparison with compound 2. Moreover using confocal microscopy and antibodies against cleaved caspase 3 we further analyzed the cell toxicity and we conclude that the apoptotic pathway is triggered efficiently with tumor specificity by compound 1 and not by compound 2. PMID- 25450026 TI - A monofunctional platinum(II)-based anticancer agent from a salicylanilide derivative: Synthesis, antiproliferative activity, and transcription inhibition. AB - Cationic monofunctional platinum(II)-based anticancer agents with a general formula of cis-[Pt(NH3)2(N-donor)Cl](+) have recently drawn significant attention due to their unique mode of action, distinctive anticancer spectrum, and promising antitumor activity both in vitro and in vivo. Understanding the mechanism of action of novel monofunctional platinum compounds through rational drug design will aid in the further development of active agents. In this study, we synthesized and evaluated a monofunctional platinum-based anticancer agent SA Pt containing a bulky salicylanilide moiety. The antiproliferative activity of SA Pt was close to that of cisplatin. Mechanism studies revealed that SA-Pt entered HeLa cells more efficiently than cisplatin, blocked the cell cycle at the S phase, and induced apoptosis. The compound bound to DNA as effectively as cisplatin, but did not block RNA polymerase II-mediated transcription as strongly as cisplatin, indicating that once the compound formed Pt-DNA lesions, the salicylanilide group was more easily recognized and removed. This study not only enriches the family of monofunctional platinum-based anticancer agents but also guides the design of more potent monofunctional platinum complexes. PMID- 25450027 TI - XAS examination of glutathione-cobalt complexes in solution. AB - In the present work, we have investigated the coordination modes of cobalt with glutathione (gamma-l-glutamyl-l-cysteinyl-glycine, GSH). A systematic study of cobalt-GSH complexes at basic and neutral pH has been undertaken with a multi spectroscopic approach combined with quantum chemistry calculations. XAS (x-ray absorption spectroscopy) has been performed at the cobalt K edge in order to shed light into the cation coordination sphere and formal oxidation states. XANES (x ray absorption near edge structure) enabled to show that in basic and neutral media, cobalt oxidation state is equal to +III and +II respectively. EXAFS (extended x-ray absorption fine structure) provided indications on the donor atoms involved in the coordination with cobalt as well as the bond lengths. DFT (density functional theory)-based calculations and NMR experiments have been performed to assess the most stable structure of the cobalt-GSH complex in basic conditions. PMID- 25450028 TI - Silver(I) compounds of the anti-inflammatory agents salicylic acid and p-hydroxyl benzoic acid which modulate cell function. AB - Silver nitrate reacts with salicylic acid (salH2) or p-hydroxy-benzoic acid (p HbzaH2) and equimolar amount of NaOH to yield a white precipitations which are then treated with tri(p-tolyl)phosphine (tptp) or tri(m-tolyl)phosphine (tmtp) to yield the complexes [Ag(tptp)2(salH)] (1), [Ag(tptp)2(p-Hbza)] (2) and [Ag(tmtp)2(salH)] (3). Complexes 1 and 3 are also obtained when aspirin (aspH) is used. The acetic ester of salicylic acid is hydrolyzed to form the complexes 1 and 3. However, when aspirin and tptp are used, a mixture of products was obtained which contains both 1 and an ionic complex of formula {[Ag(tptp)4](+)[(salH)(-)]?[(CH3)2NCHO)]?(H2O)} (1a). The complexes were characterized by m.p., e.a., mid-FT-IR, (1)H-,(31)P-NMR, HRMS, UV-vis spectroscopic techniques and X-ray crystallography. Two phosphorus and one carboxylic oxygen atoms form a trigonal planar geometry around Ag(I) ions in complexes 1-3. Complex 1a consists of a [Ag(tptp)4](+) cation and a deprotonated salH(-) counter anion. The influence of 1-3 on the viability of MCF-7 (breast) and HeLa (cervix) adenocarcinoma cells, is evaluated. DNA binding tests indicate the ability of 1-3 to modify the activity of cells. The binding constants of 1-3 towards calf-thymus DNA, reveal stronger interaction of 2. Changes in fluorescent emission light of ethidium bromide (EB) in the presence of DNA suggest intercalation or electrostatic interactions into DNA for 1 and 3. Docking studies on DNA-complex interactions confirm the binding of 1-3 in the minor groove of B DNA. Moreover, the influence of 1-3 on the peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied. PMID- 25450029 TI - A review of interventional clinical trials in renal cell carcinoma: a status report from the ClinicalTrials.gov WebSite. AB - INTRODUCTION: The treatment of renal cell carcinoma (RCC) has undergone a major shift over the past 10 years and continues to evolve. The objective of this study was to assess the current landscape of clinical trials (CTs) in RCC to identify areas of strength and opportunities for improvement. MATERIALS AND METHODS: ClinicalTrials.gov was queried using 17 prespecified search criteria. Only open, RCC-dedicated, interventional CTs in adult patients were included. Descriptive statistics and Fisher exact tests were used to compare features of CTs. RESULTS: The study cohort consisted of 169 trials. Phase II trials were the most common (67, 39.6%) and 52.7% (89) of CTs examined patients with stage IV disease. Only 26.6% (45) were randomized and 64.5% (109) were single-arm. Targeted therapies (TTs) were studied in 47.9% (81) of CTs overall and 71.1% (81 of 114) of the systemic therapy trials. Immunotherapies (ITs) were the next most common systemic therapy accounting for 5.9% (10) of trials. The primary end point of feasibility or biomarker analysis, progression-free survival, or overall survival was noted in 27.8%, 51.5%, and 2.1% of TT CTs (27, 50, 2 trials, respectively) and 42.9%, 35.7%, and 14.3% of IT CTs (6, 5, 2 trials respectively; P = .037). Biomarkers were assessed in 45% (76) of CTs overall and were more frequently examined in TT and IT CTs (53.6% [52/97] and 64.3% [9/14]) than in surgery and other CTs (22.2% [4/18] and 27.5% [11/40]; P = .002). Sponsorship differed according to treatment type (P = .003). CONCLUSION: Clinical trials in RCC are largely nonrandomized, single-arm, with minimal focus on non-clear-cell RCC. Significant differences were noted in the primary end point, sponsorship, and biomarker assessment between treatment types. PMID- 25450030 TI - Small renal masses managed with active surveillance: predictors of tumor growth rate after long-term follow-up. AB - BACKGROUND: The purpose of the study was to evaluate the relationships between the patients' clinical characteristics and the growth pattern of SRMs, and to investigate the predictive factors of tumor growth rates in patients initially managed with AS. MATERIALS AND METHODS: We retrospectively reviewed data from our prospectively collected database of 70 patients diagnosed with 72 SRMs between 1996 and 2013. Clinical and demographic data, and linear and volumetric growth rates were recorded for each patient. A Pearson correlation test was used to evaluate initial tumor size and linear or volumetric growth rate. Logistic regression models were used to evaluate the predictive factors affecting tumor growth kinetics. RESULTS: The mean age was 76 +/- 6.8 years, and 47 (67.1%) of patients were male. The mean (+/- SD) and the median (interquartile range [IQR]) tumor size at presentation were 2.1 +/- 1.3 and 2.7 (1.8-3.7) cm, respectively. The mean (+/- SD) and the median (IQR) linear growth rate were 0.5 +/- 0.3 and 0.6 (0.4-1.5) cm per year, respectively. Patients treated with delayed surgery experienced a significantly greater mean linear growth rate (1.4 vs. 0.3 cm per year) than those observed in the AS group (P < .001). Male sex (HR, 1.70; P = .04) and symptomatic presentation (HR, 1.85; P = .02) were found to be significant predictors of tumor growth rates during AS. Conversely, age, Charlson Comorbidity Index, and initial tumor size failed to predict growth kinetics. CONCLUSION: Male sex and symptomatic presentation are associated with faster growth rates in patients managed with AS after long-term follow-up. PMID- 25450032 TI - Combining immunotherapy and radiation for prostate cancer. AB - Radiotherapy has conventionally been viewed as immunosuppressive, which has precluded its use in combination with immunotherapy for prostate and other cancers. However, the relationship between ionizing radiation and immune reactivity is now known to be more complex than was previously thought, and data on the use of radiotherapy and immunotherapy are accumulating. Herein, we review this topic in the light of recently available data in the prostate cancer setting. Recent research has shown no significant lymphopenia in patients undergoing radiotherapy for high-risk adenocarcinoma of the prostate. In addition, emerging evidence suggests that radiotherapy can have immunostimulatory effects, and that tumor cell death, coupled with related changes in antigen availability and inflammatory signals, can affect lymphocyte and dendritic cell activation. Initial studies have focused on combinations of tumor irradiation and immunotherapy, such as the autologous cellular immunotherapy sipuleucel-T and the monoclonal antibody ipilimumab, in metastatic castration-resistant prostate cancer. These combinations appear to have clinical promise, and further investigation of the potentially synergistic combination of radiotherapy and immunotherapy is continuing in clinical trials. PMID- 25450031 TI - A phase I study of everolimus and docetaxel in patients with castration-resistant prostate cancer. AB - BACKGROUND: The PTEN tumor suppressor is frequently lost in CRPC, with activation of Akt-mTOR signaling, driving growth. We conducted a phase I trial of the mTOR inhibitor, everolimus, and docetaxel in CRPC. PATIENTS AND METHODS: Eligible patients had progressive, metastatic, chemotherapy-naive CRPC. Patients received everolimus 10 mg daily for 2 weeks and underwent a restaging FDG-PET/computed tomography scan. Patient cohorts were subsequently treated at 3 dose levels of everolimus with docetaxel: 5 mg to 60 mg/m(2), 10 mg to 60 mg/m(2), and 10 mg to 70 mg/m(2). The primary end point was the safety and tolerability of combination therapy. RESULTS: Accrual was 4 patients at level 1, 3 patients at level 2, and 8 patients at level 3. Common toxicities were hematologic and fatigue. Serum concentrations of everolimus when administered with docetaxel were 1.5 to 14.8 ng/mL in patients receiving 5 mg everolimus and 4.5 to 55.4 ng/mL in patients receiving 10 mg everolimus. Four patients had partial metabolic response (PMR) using FDG-PET, 12 had stable metabolic disease, and 2 had progressive metabolic disease after a 2-week treatment with everolimus alone. Five of 12 evaluable patients experienced a prostate-specific antigen (PSA) reduction >= 50% during treatment with everolimus together with docetaxel. All 4 patients with a PMR according to PET imaging experienced a PSA reduction in response to everolimus with docetaxel, and 3 of 4 had PSA declines >= 50%. CONCLUSION: Everolimus 10 mg daily and docetaxel 60 mg/m(2) was safe in CRPC patients and these were the recommended doses in combination. FDG-PET response might serve as a biomarker for target inhibition by mTOR inhibitors. PMID- 25450033 TI - A prospective, multicenter evaluation of predictive factors for positive surgical margins after nephron-sparing surgery for renal cell carcinoma: the RECORd1 Italian Project. AB - BACKGROUND: The purpose of this study was to evaluate the predictors of positive margins in one of the largest available prospective multi-institutional studies. PATIENTS AND METHODS: We evaluated all patients who underwent NSS for radiologically diagnosed kidney tumors between January 2009 and December 2012 at 19 urological Italian centers (Registry of Conservative Renal Surgery [RECORd] project). Preoperative and anthropometric data, comorbidities, intraoperative and postoperative outcomes, and histological findings were analyzed. The negative and PSMs were compared according to the clinical and surgical variables. Multivariable logistic regression models were applied to analyze predictors of PSMs. RESULTS: Eight hundred consecutive patients were evaluated. Seven hundred sixty-one (95.1%) and 39 patients (4.9%) achieved negative and PSMs, respectively. Patients with PSMs were significantly older compared with those with negative margins (median age: 66.6 vs. 61.8 years, respectively; P = .001). A higher incidence of PSMs was observed when NSS was performed for renal masses located in the upper pole (P = .001). A lower rate of PSMs was found in patients treated with simple enucleation rather than standard PN (1.6% vs. 7.4%, respectively; P < .0001). A greater incidence of PSMs was found in Fuhrman 3/4 tumors (11.3%; P < .0001). At multivariable analysis, age (odds ratio [OR], 1.04; P = .01), upper pole tumor location (OR, 2.85; P = .005), standard PN (OR, 3.45; P = .004), and Fuhrman 3-4 nuclear grade (OR, 4.81; P = .001) were found to be independent predictors of PSMs. CONCLUSION: In our multi-institutional report, young age, simple enucleation, middle or lower tumor location, and low-grade tumor were demonstrated to be independent predictors of negative SMs. PMID- 25450034 TI - Delayed antiandrogen withdrawal syndrome after discontinuation of bicalutamide. PMID- 25450035 TI - Cisplatin-based first-line therapy for advanced urothelial carcinoma after previous perioperative cisplatin-based therapy. AB - BACKGROUND: Outcomes with cisplatin-based first-line therapy for advanced UC after previous perioperative cisplatin-based chemotherapy are unclear. In this study we evaluated outcomes with a focus on the effect of time from previous cisplatin-based perioperative chemotherapy. PATIENTS AND METHODS: Data were collected for patients who received cisplatin-based first-line therapy for advanced UC after previous perioperative cisplatin-based therapy. Cox proportional hazards models were used to investigate the prognostic ability of visceral metastasis, ECOG PS, TFPC, anemia, leukocytosis, and albumin on overall survival (OS). RESULTS: Data were available for 41 patients from 8 institutions including 31 men (75.6%). The median age was 61 (range, 41-77) years, most received gemcitabine plus cisplatin (n = 26; 63.4%), and the median number of cycles was 4 (range, 1-8). The median OS was 68 weeks (95% confidence interval [CI], 48.0-81.0). Multivariable Cox regression analysis results showed an independent prognostic effect on OS for PS > 0 versus 0 (hazard ratio [HR], 4.56 [95% CI, 1.66-12.52]; P = .003) and TFPC >= 78 weeks versus < 78 weeks (HR, 0.48 [95% CI, 0.21-1.07]; P = .072). The prognostic model for OS was internally validated with c-index = 0.68. Patients with TFPC < 52 weeks, 52 to 104 weeks, and >= 104 weeks had median survival of 42, 70, and 162 weeks, respectively. CONCLUSION: Longer TFPC >= 78 weeks and ECOG PS = 0 were independently prognostic for better survival with cisplatin-based first-line chemotherapy for advanced UC after previous perioperative cisplatin-based chemotherapy. The data support using TFPC >= 52 weeks to rechallenge with cisplatin-based first-line chemotherapy for metastatic disease. PMID- 25450036 TI - Outcome of patients with metastatic sarcomatoid renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. AB - BACKGROUND: Sarcomatoid renal cell carcinoma is associated with poor prognosis. Data regarding outcome in the targeted therapy era are lacking. PATIENTS AND METHODS: Clinical, prognostic, and treatment parameters in metastatic renal cell carcinoma patients with and without sarcomatoid histology treated with targeted therapy were retrospectively analyzed. RESULTS: Two thousand two hundred eighty six patients were identified (sRCC: n = 230 and non-sRCC: n = 2056). sRCC patients had significantly worse IMDC prognostic criteria compared with non-sRCC (11% vs. 19% favorable risk; 49% vs. 57% intermediate risk, and 40% vs. 24% poor risk; P < .0001). Time from original diagnosis to relapse (excluding synchronous metastatic disease) was shorter in the sRCC group (18.8 vs. 42.9 months; P < .0001). There was no significant difference in the incidence of central nervous system metastases (6%-8%) or underlying clear cell histology (87%-88%). More than 93% of patients received VEGF inhibitors as first-line therapy; objective response was less common in sRCC whereas primary refractory disease was more common (21% vs. 26% and 43% vs. 21%; P < .0001, for both). sRCC patients had significantly less use of second- (P = .018) and third-line (P < .0001) systemic therapy. The median progression-free survival (PFS)/overall survival (OS) was 4.5/10.4 months in sRCC patients and 7.8/22.5 months in non-sRCC patients (P < .0001 for both). Sarcomatoid histology was associated with a significantly worse PFS and OS after adjusting for individual IMDC risk factors in multivariable analysis (hazard ratio, 1.5; P < .0001 for both). CONCLUSION: Patients with sRCC have a shorter time to relapse, worse baseline prognostic criteria, and worse clinical outcome with targeted therapy. Additional insight into the biology of sRCC is needed to develop alternative therapeutics. PMID- 25450038 TI - Treatment patterns and costs for metastatic renal cell carcinoma patients with private insurance in the United States. AB - BACKGROUND: To evaluate the evolution of treatment patterns and associated costs for metastatic renal cell carcinoma (mRCC) in the United States. MATERIALS AND METHODS: The LifeLink Health Plan Claims Database was used to create a cohort of mRCC patients with at least 12 months of continuous enrollment from 2004 to 2011. We summarized treatment patterns over time; we used a nonparametric bootstrapping method to compare costs and logistic regression to examine the association between the likelihood of advancing to third-line therapy and beyond and the number of targeted therapy agents available. RESULTS: A total of 1527 mRCC patients were analyzed. In 2010, nine unique treatment regimens were used for first-line treatment, 8 for second-line treatment, and 8 for third-line treatment. A significant association (odds ratio 1.26; P = .001) between the odds of advancing to third-line therapy or beyond and the number of targeted agents available was noted. For 767 patients receiving modern therapy who were < 65 years old, and stratifying by whether the first-line treatment was oral or intravenous, drug cost per patient with ancillary services was $59,664 versus $86,518, respectively (P = .001). Total costs and drug out-of-pocket costs per patient during the first year increased by the number of switches: $111,680 to $2355 for no switches, $149,994 to $2538 for 1 switch, and $196,706 to $3524 for 2 or more switches. In 2004, the median drug cost was $11,458, while by 2010 it rose to $68,660. CONCLUSION: A marked shift in the management of mRCC has occurred, with wide heterogeneity in treatment patterns. More patients are able to receive more lines of therapy, but treatment costs are high. PMID- 25450037 TI - African-american race is a predictor of seminal vesicle invasion after radical prostatectomy. AB - INTRODUCTION: The purpose of the study was to determine whether racial differences exist in the pattern of local disease progression among men treated with radical prostatectomy (RP) for localized prostate cancer (PCa), which is currently unknown. In this study we evaluated the pattern of adverse pathologic features in an identical cohort of African-American (AA) and Caucasian (CS) men with PCa. PATIENTS AND METHODS: The overall cohort consisted of 1104 men (224 AA, and 880 CS) who underwent RP between 1990 and 2012. We compared preoperative factors and pathologic outcomes after RP across race groups. Multivariate analysis was used to identify factors predictive of adverse pathologic outcomes. The effect of race on adverse pathologic outcomes and biochemical control rate (BCR) was evaluated using multivariate regression model and Kaplan-Meier analysis. RESULTS: The 10-year BCR was 59% versus 82% in AA and CS men, respectively (P = .003). There was no significant difference in extraprostatic spread (P = .14), positive surgical margin (P = .81), lymph node involvement (P = .71), or adverse pathologic features (P = .16) across race groups. However, among patients with >= 1 adverse pathologic features, AA men had higher rate of seminal vesicle invasion (SVI) compared with CS men (51% vs. 30%; P = .01). After adjusting for known predictors of adverse pathologic features AA race remained a predictor of SVI. CONCLUSION: AA men have an increased risk of SVI after RP, particularly among men with Gleason <= 6 disease. This might represent racial differences in the biology of PCa disease progression, which contribute to poorer outcomes in AA men. PMID- 25450040 TI - Hyperlipidemia and hypothyroidism among metastatic renal cell carcinoma patients taking sunitinib malate. Related or unrelated adverse events? AB - BACKGROUND: In recent years, new-onset hypothyroidism was extensively reported in patients receiving sunitinib for malignancy. Effects of sunitinib on serum lipids are not described, however a hyperlipidemic state is commonly observed in hypothyroid patients. Here we report about the incidence and severity of hypercholesterolemia and hypertriglyceridemia in a cohort of patients receiving sunitinib for metastatic renal cell carcinoma. PATIENTS AND METHODS: Thyroid function tests, serum triglycerides, and cholesterol were prospectively evaluated in 39 consecutive metastatic renal cell carcinoma patients, who were receiving sunitinib as a first-line treatment. Incidence of hyperlipidemia, thyroid function impairment, and their possible relationship were investigated. RESULTS: Thyroid function tests, serum cholesterol, and triglycerides were assessed at baseline and before the beginning of each sunitinib cycle. During treatment, median triglyceride levels increased up to 271.3 mg/dL, and median cholesterol increased up to 234.7 mg/dL (+113% and +22%, respectively). A hyperlipidemic state developed in 27 patients (69.2%) within a mean time of 1.8 six-week cycles (range, 1-5 cycles) and persisted during treatment. Hypothyroidism was observed in 20 patients (51.2%) and usually developed within 2.3 cycles. Because hypothyroidism and hyperlipidemia developed at different time points of treatment and among different patients, our results failed to demonstrate a correlation between these adverse events. CONCLUSION: New-onset hyperlipidemia was observed in an increased percentage of patients taking sunitinib. The mechanism of this side effect is still unclear. We recommend careful monitoring of serum lipid levels during sunitinib administration to recognize possible consequences, especially on cardiovascular health. PMID- 25450039 TI - Detection and phenotyping of circulating tumor cells in high-risk localized prostate cancer. AB - BACKGROUND: In this study, we aimed to determine the feasibility of identifying CTCs in patients with HRLPC, using a modified isolation procedure using the CellSearch (Veridex) platform, and to assess the expression of stem cell and epithelial-mesenchymal transition (EMT) markers on the CTCs. PATIENTS AND METHODS: Thirty-five patients with HRLPC who had chosen prostatectomy for definitive management were prospectively identified. After obtaining consent, four 30-mL blood draws were performed, 2 before surgery and 2 after surgery. The CTC-containing fraction was Ficoll-purified and transferred to a CellSave (Veridex) tube containing dilution buffer before standard enumeration using the CellSearch system. Loss of E-cadherin expression, a marker of EMT, and CD133, a putative prostate cancer stem cell marker, were characterized using the open channel of the CellSearch platform. CTC fragments were also enumerated. RESULTS: Using the modified methodology, CTCs were detectable in 49% of patients before surgery. Although no correlation between CTC count and biochemical recurrence (BR) was observed, the percentages of CD133 and E-cadherin-positive CTC fragments were associated with BR at 1 year. CONCLUSION: Our results suggest that further research into the development of CTCs as prognostic biomarkers in HRLPC is warranted. PMID- 25450041 TI - Designer crops: optimal root system architecture for nutrient acquisition. AB - Plant root systems are highly plastic in response to environmental stimuli. Improved nutrient acquisition can increase fertilizer use efficiency and is critical for crop production. Recent analyses of field-grown crops highlighted the importance of root system architecture (RSA) in nutrient acquisition. This indicated that it is feasible in practice to exploit genotypes or mutations giving rise to optimal RSA for crop design in the future, especially with respect to plant breeding for infertile soils. PMID- 25450043 TI - High-throughput screening for integrative biomaterials design: exploring advances and new trends. AB - With the increasing need for biomaterials and tissue engineering alternatives, more accurate, rapid, and cost-saving methods and models to study biomaterial cell interactions must be developed. We review the evolution of microarray platforms used for such studies in order to meet the criteria of complex tissue engineering biological environments. Particular aspects regarding biomaterials processing, data acquisition, and treatment are addressed. Apart from in vitro array-based strategies, we also address emerging in vivo high-throughput approaches and their associated trends, such as the role of inflammation in regeneration. The up-scaling of high-throughput methods using single cell encapsulation systems is also explored. Possible limitations related to the use of such methods, such as spot-to-spot crosstalk, are also discussed. PMID- 25450042 TI - Cellular targets for improved manufacturing of virus-based biopharmaceuticals in animal cells. AB - The past decade witnessed the entry into the market of new virus-based biopharmaceuticals produced in animal cells such as oncolytic vectors, virus-like particle vaccines, and gene transfer vectors. Therefore, increased attention and investment to optimize cell culture processes towards enhanced manufacturing of these bioproducts is anticipated. Herein, we review key findings on virus-host interactions that have been explored in cell culture optimization. Approaches supporting improved productivity or quality of vector preparations are discussed, mainly focusing on medium design and genetic manipulation. This review provides an integrated outline for current and future efforts in exploring cellular targets for the optimization of cell culture manufacturing of virus-based biopharmaceuticals. PMID- 25450044 TI - Structural features and antitumor activity of a purified polysaccharide extracted from Sargassum horneri. AB - A polysaccharide fraction (SHPSA) was obtained from Sargassum horneri by hot water extraction and sequential purification of anion-exchange chromatography and gel-filtration chromatography. SHPSA was found to be a neutral polysaccharide fraction with an average molecular weight of 5.78*10(5) Da and composed of T-D Glcp, 1,3-D-Glcp, 1,6-D-Glcp and 1,3,6-D-Glcp in a molar percentage of 1.00:4.17:1.17:0.89, respectively. Based on the results from chemical analysis, NMR, and SHPSA was determined to be a glucan with beta-(1->6) side chains linked to a beta-(1->3) backbone with relatively few branch points. Moreover, SHPSA could inhibit the growth of human colon cancer DLD cells in a dose-dependent manner by inducing the apoptosis of DLD cells. So, SHPSA was promising for future use as a natural antitumor agent. PMID- 25450045 TI - Characterization of pre-molten globule state of yeast iso-1-cytochrome c and its deletants at pH 6.0 and 25 degrees C. AB - To understand the role of five extra N-terminal residues, we prepared wild type (WT) yeast iso-1-cytochrome c (y-cyt-c) and its deletants by subsequently deleting these residues. Denaturation of all these proteins induced by LiCl was followed by observing changes in molar absorption coefficient at 405 nm (DeltaE405), the mean residue ellipticity at 222 nm ([theta]222), and the difference mean residue ellipticity at 409 nm (Delta[theta]409) near physiological pH and temperature (pH 6.0 and 25 degrees C). It was observed that in each case LiCl induces biphasic transition, N (native) state <-> X (intermediate) state <-> D (denatured) state. The intermediate (X) was characterized by the far-UV, near-UV and Soret circular dichroism, ANS (8-anilino 1-naphthalenesulfonic acid) binding and dynamic light scattering measurements. These measurements led us to conclude that X state of each protein has structural characteristics of PMG (pre-molten globule) state. Thermodynamic stability of all proteins was also determined. It was observed that the N-terminal extension stabilizes the native WT protein but it has no effect on the stability of PMG state. Another state was observed for each protein, in the presence of 0.33 M Na2SO4 at pH 2.1, which when characterized showed all structural characteristics of MG (molten globule) state. PMID- 25450046 TI - Chitosan coated alginate-xanthan gum bead enhanced pH and thermotolerance of Lactobacillus plantarum LAB12. AB - The vulnerability of probiotics at low pH and high temperature has limited their optimal use as nutraceuticals. This study addressed these issues by adopting a physicochemical driven approach of incorporating Lactobacillus plantarum LAB12 into chitosan (Ch) coated alginate-xanthan gum (Alg-XG) beads. Characterisation of Alg-XG-Ch, which elicited little effect on bead size and polydispersity, demonstrated good miscibility with improved bead surface smoothness and L. plantarum LAB12 entrapment when compared to Alg, Alg-Ch and Alg-XG. Sequential incubation of Alg-XG-Ch in simulated gastric juice and intestinal fluid yielded high survival rate of L. plantarum LAB12 (95%) at pH 1.8 which in turn facilitated sufficient release of probiotics (>7 log CFU/g) at pH 6.8 in both time- and pH-dependent manner. Whilst minimising viability loss at 75 and 90 degrees C, Alg-XG-Ch improved storage durability of L. plantarum LAB12 at 4 degrees C. The present results implied the possible use of L. plantarum LAB12 incorporated in Alg-XG-Ch as new functional food ingredient with health claims. PMID- 25450047 TI - Structure and rheological properties of a xyloglucan extracted from Hymenaea courbaril var. courbaril seeds. AB - Hymenaea courbaril var courbaril seed xyloglucan was efficiently extracted with 0.1M NaCl, followed by ethanol precipitation (yield=72+/-5% w/w). Its amorphous structure was identified by the pattern of X-ray diffraction. The monosaccharide composition was determined by GC/MS analysis of the alditol acetates and showed the occurrence of glucose:xylose:galactose:arabinose (40:34:20:6). One-(1D) and two-dimensional-(2D) NMR spectra confirmed a central backbone composed by 4 linked beta-glucose units partially branched at position 6 with non-reducing terminal units of alpha-xylose or beta-galactose-(1->2)-alpha-xylose disaccharides. The xyloglucan solution was evaluated by dynamic light scattering and presents a polydisperse and practically neutral profile, and at 0.5 and 1.0% (w/v) the solutions behave as a viscoelastic fluid. The polysaccharide did not show significant antibacterial or hemolytic activities. Overall our results indicate that xyloglucan from H. courbaril is a promising polysaccharide for food and pharmaceutical industries. PMID- 25450048 TI - Chitosan-PVP-nano silver oxide wound dressing: in vitro and in vivo evaluation. AB - The main aim of this work was to prepare wound healing material with chitosan, poly vinyl pyrrolidone (PVP), silver oxide nanoparticles. The prepared chitosan, chitosan-PVP-nano silver oxide (CPS) films were characterized for their thermal behaviour, morphological properties, mechanical properties, antibacterial properties and wound healing properties. The CPS film found higher antibacterial activity because the materials both chitosan as well as silver oxide poses good antibacterial activity. L929 cell lines were for cytotoxicity study and Adult male albino rats (140-180 g) were used for wound healing study. The prepared film has more wound healing property than of cotton gauge, 100% chitosan and other reported chitosan based dressings. PMID- 25450049 TI - Carboxymethyl cellulose-g-poly(2-(dimethylamino) ethyl methacrylate) hydrogel as adsorbent for dye removal. AB - A novel adsorbent was prepared via crosslinking graft copolymerization of 2 (dimethylamino) ethyl methacrylate (DMAEMA) onto carboxymethyl cellulose (CMC) backbone. Ethylene glycol dimethacrylate and potassium persulphate were used as crosslinker and initiator, respectively. CMC-g-PDMAEMA hydrogel was used to remove methyl orange (MO) from aqueous solutions. The adsorption kinetics and isotherms were found to follow Pseudo-second-order kinetic model and Langmuir model, respectively. The high maximum adsorption capacity (1825 mg/g) implied that CMC-g-PDMAEMA can be used as promising adsorbent for the synthetic dyes removal from wastewater. PMID- 25450050 TI - Development and validation of an LC-ESI-MS/MS method for the triple reuptake inhibitor indatraline enabling its quantification in MS Binding Assays. AB - We herein present the first LC-MS/MS quantification method for indatraline, a highly potent nonselective inhibitor of the three monoamine transporters (for dopamine, DAT; norepinephrine, NET; serotonin, SERT), and its application to MS Binding Assays. For HPLC, an R18 column with a mobile phase composed of acetonitrile and ammonium bicarbonate buffer (5 mmol L(-1), pH 10.0) in a ratio of 90:10 (v/v) at a flow rate of 600 MUL min(-1) was used. Recording indatraline at m/z 292.2/261.0 and ((2)H(7))-indatraline, employed as internal standard, at m/z 299.2/268.0 allowed reliable quantification from 5 pmol L(-1) (LLOQ) to 5 nmol L(-1) in biological matrices without additional sample preparation. Validation of the developed quantification method showed that selectivity, calibration standard curve, accuracy, as well as precision meet the criteria of the CDER guideline. Applying this method to mass spectrometry (MS) Binding Assays, a label-free MS-based alternative to conventional radioligand binding assays, binding of indatraline's eutomer, (1R,3S)-indatraline, towards NET could be characterized directly for the first time, revealing an equilibrium dissociation constant (K d) of 805 pmol L(-1). Additionally, it could be shown that the established MS Binding Assays enable characterization of test compounds in competition experiments. As the established setup is based on a 96-well format and an LC MS/MS method with a short chromatographic cycle time (1.5 min), the developed MS Binding Assays enable considerable throughput and are therefore well suited as substitute for corresponding radioligand binding assays. PMID- 25450051 TI - Certified reference material of volatile organic compounds for environmental analysis: BTEX in methanol. AB - The Brazilian Metrology Institute (National Institute of Metrology, Quality, and Technology, Inmetro) has been developing a certified reference material (CRM) of the volatile organic compounds benzene; toluene; ethylbenzene; and ortho, meta, and para-xylenes (BTEX) in methanol, to ensure quality control for environmental analysis measurements. The objective of this paper is to present the results of certification studies: uncertainty estimates related to characterization, a homogeneity study, and a stability study on a single lot of CRM composed of BTEX in methanol. The method used analysis of variance (ANOVA), a statistical tool, to evaluate the homogeneity and stability of the BTEX CRM, which complies with ISO Guide 30 series. The homogeneity and stability of the BTEX CRM was confirmed for all analytes and their respective properties. All the procedures used in this study complied with ISO GUIDE 34, ISO GUIDE 35, and the guide to the expression of uncertainty of measurement (GUM). PMID- 25450052 TI - Tracking calcification in tissue-engineered bone using synchrotron micro-FTIR and SEM. AB - One novel tissue engineering approach to mimic in vivo bone formation is the use of aggregate or micromass cultures. Various qualitative and quantitative techniques, such as histochemical staining, protein assay kits and RT-PCR, have been used previously on cellular aggregate studies to investigate how these intricate arrangements lead to mature bone tissue. However, these techniques struggle to reveal spatial and temporal distribution of proliferation and mineralization simultaneously. Synchrotron-based Fourier transform infrared microspectroscopy (micro-FTIR) offers a unique insight at the molecular scale by coupling high IR sensitivity to organic matter with the high spatial resolution allowed by diffraction limited SR microbeam. This study is set to investigate the effects of culture duration and aggregate size on the dynamics and spatial distribution of calcification in engineered bone aggregates by a combination of micro-FTIR and scanning electron microscopy (SEM)/energy-dispersive X-ray spectroscopy (EDX). A murine bone cell line has been used, and small/large bone aggregates have been induced using different chemically treated culture substrates. Our findings suggest that bone cell aggregate culturing can greatly increase levels of mineralization over short culture periods. The size of the aggregates influences mineralisation rates with larger aggregates mineralizing at a faster rate than their smaller counterparts. The micro-FTIR mapping has demonstrated that mineralization in the larger aggregates initiated from the periphery and spread to the centre, whilst the smaller aggregates have more minerals in the centre at the early stage and deposited more in the periphery after further culturing, implying that aggregate size influences calcification distribution and development over time. SEM/EDX data correlates well with the micro-FTIR results for the total mineral content. Thus, synchrotron-based micro FTIR can accurately track mineralization process/mechanism in the engineered bone. PMID- 25450053 TI - Longitudinal meta-analysis of NIST pH Standard Reference Materials((r)): a complement to pH key comparisons. AB - This meta-analysis assesses the long-term (up to 70 years) within-laboratory variation of the NIST pH Standard Reference Material(r) (SRM) tetroxalate, phthalate, phosphate, borate, and carbonate buffers. Values of DeltapH(S), the difference between the certified pH value, pH(S), of each SRM issue and the mean of all pH(S) values for the given SRM at that Celsius temperature, t, are graphed as a function of the SRM issue and t. In most cases, |DeltapH(S)| < 0.004. Deviations from the nominal base:acid amount (mole) ratio of a buffer yield t independent, constant shifts in DeltapH(S). The mean DeltapH(S) characterizes such deviations. The corresponding mole fraction of impurity in the conjugate buffer component is generally <0.3 %. Changes in the equipment, personnel, materials, and methodology of the pH(S) measurement yield t-dependent variations. The standard deviation of DeltapH(S) characterizes such changes. Standard deviations of DeltapH(S) are generally 0.0015 or less. The results provide a long term, single-institution complement to the time-specific, multi-institution results of pH key comparisons administered by the Consultative Committee for Metrology in Chemistry and Biology (CCQM). PMID- 25450054 TI - Development of a rapid method for the analysis of trenbolone, nortestosterone, and zeranol in bovine liver using liquid chromatography tandem mass spectrometry. AB - A rapid liquid chromatography tandem mass spectrometry method has been developed and validated for the determination of alpha-trenbolone, beta-trenbolone, alpha nortestosterone, beta-nortestosterone, zeranol, and taleranol in bovine liver. The impact of liquid-liquid extraction with methyl tert-butyl ether and optimized solid phase extraction on silica cartridges significantly reduced effort and time of sample preparation. Electrospray ionization gives a significant signal increase compared with atmospheric pressure chemical ionization and atmospheric pressure photoionization. The HPLC gradient was optimized to separate isobaric analytes and matrix constituents from the hormone molecules. The optimized time and temperature of enzymatic hydrolysis of conjugated trenbolone was 4 h at 52 degrees C. The method validated in the range of 0.5-30 MUg kg(-1) for alpha trenbolone, beta-trenbolone, zeranol, taleranol, and 2-30 MUg kg(-1) for alpha nortestosterone, beta-nortestosterone. Combined uncertainty of measurements was in the range of 4%-23%. The matrix effect was negligible (1%-5%) for all analytes except of alpha-nortestosterone (19%). The developed method with changes concerning sample size and hydrolysis was also applied for the analysis of meat, serum, and urine samples. Graphical Abstract Determination of trenbolone, nortestosterone and zeranol in bovine liver. PMID- 25450055 TI - Sleep medication in patients with attention-deficit/hyperactivity disorder. PMID- 25450056 TI - Restless legs syndrome in dialysis patients: a meta-analysis. AB - BACKGROUND: Restless legs syndrome (RLS) occurs frequently in dialysis patients. However, it remains elusive regarding the risk factors for RLS onset in dialysis patients. METHODS: A meta-analysis was performed to investigate the association between clinical measures (age, gender, diabetes mellitus or DM etc.) and RLS in dialysis patients. We searched electronic databases from January 1990 to February 2014 to identify studies that met inclusion criteria. Either a fixed-effects or, in the presence of heterogeneity, a random-effects model was used to calculate the pooled odds ratios (ORs)/standard mean differences (SMDs) and their corresponding confidence intervals (CIs). RESULTS: Twenty-three studies were included in this study. Dialysis patients with RLS demonstrated significantly higher OR of DM compared with non-RLS in Asians (OR: 1.238, 95% CI: 1.032-1.484, P = 0.021). Dialysis patients with RLS showed markedly lower level of hemoglobin (Hb)/iron compared with non-RLS in overall populations/Caucasians (SMD: -0.178/ 0.104, 95% CI: -0.352/-0.206 to -0.004/-0.002, P = 0.045/0.045; SMD: -0.283/ 0.158, 95% CI: -0.552/-0.304 to -0.013/-0.012, P = 0.04/0.034). No differences of female populations, age, duration of dialysis, body mass index (BMI), blood urea nitrogen (BUN), creatinine, albumin, phosphorus, parathyroid hormone (PTH), and calcium were observed between dialysis patients with RLS and non-RLS in overall populations, Caucasians and Asians. No evidence of publication bias was observed. CONCLUSIONS: Our findings indicate that dialysis patients with DM are nearly 24% more susceptible to RLS in Asians. Decreased Hb/iron is a risk factor for RLS onset in dialysis patients in overall populations including Caucasians. PMID- 25450057 TI - Response to: sleep medication in patients with attention-deficit/hyperactivity disorder. PMID- 25450058 TI - Sleep duration and obesity among adults: a meta-analysis of prospective studies. AB - BACKGROUND: Results from longitudinal studies on sleep duration and incidence of obesity remain controversial. METHODS: PubMed and Web of Science updated on 20 February 2014 were searched for eligible publications. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using a random-effects model. RESULTS: Eleven published articles were included, involving 197,906 participants for short sleep duration and 164,016 participants for long sleep duration. Compared with the normal sleep duration, the pooled OR for obesity was 1.45 (95% CI, 1.25-1.67) for the short sleep duration overall. After removing the three studies that had strong effects on heterogeneity, the pooled OR was 1.25 (95% CI, 1.14-1.38). The positive association was consistent among all subgroups analysis except in the European group (OR, 1.45; 95% CI, 0.79-2.64). No significant association was found between long sleep duration and risk of obesity overall (OR, 1.06; 95% CI, 0.98-1.15) and in subgroup analysis. CONCLUSION: This meta analysis indicated that short sleep duration was significantly associated with incidence of obesity, whereas long sleep duration had no effect on future obesity among adults. PMID- 25450059 TI - Prolonged elevation of intraocular pressure results in retinal ganglion cell loss and abnormal retinal function in mice. AB - The purpose of this study was to assess the impact of prolonged intraocular pressure (IOP) elevation on retinal anatomy and function in a mouse model of experimental glaucoma. IOP was elevated by anterior chamber injection of a fixed combination of polystyrene beads and sodium hyaluronate, and maintained via re injection after 24 weeks. IOP was measured weekly with a rebound tonometer for 48 weeks. Histology was assessed with a combination of retrograde labeling and antibody staining. Retinal physiology and function was assessed with dark-adapted electroretinograms (ERGs). Comparisons between bead-injected animals and various controls were conducted at both 24 and 48 weeks after bead injection. IOP was elevated throughout the study. IOP elevation resulted in a reduction of retinal ganglion cell (RGCs) and an increase in axial length at both 24 and 48 weeks after bead injection. The b-wave amplitude of the ERG was increased to the same degree in bead-injected eyes at both time points, similar to previous studies. The positive scotopic threshold response (pSTR) amplitude, a measure of RGC electrical function, was diminished at both 24 and 48 weeks when normalized to the increased b-wave amplitude. At 48 weeks, the pSTR amplitude was reduced even without normalization, suggesting more profound RGC dysfunction. We conclude that injection of polystyrene beads and sodium hyaluronate causes chronic IOP elevation which results in phenotypes of stable b-wave amplitude increase and progressive pSTR amplitude reduction, as well as RGC loss and axial length elongation. PMID- 25450060 TI - Colocalization of outflow segmentation and pores along the inner wall of Schlemm's canal. AB - All aqueous humor draining through the conventional outflow pathway must cross the endothelium of Schlemm's canal (SC), likely by passing through micron-sized transendothelial pores. SC pores are non-uniformly distributed along the inner wall endothelium, but it is unclear how the distribution of pores relates to the non-uniform or segmental distribution of aqueous humor outflow through the trabecular meshwork. It is hypothesized that regions in the juxtacanalicular tissue (JCT) with higher local outflow should coincide with regions of greater inner wall pore density compared to JCT regions with lower outflow. Three pairs of non-glaucomatous human donor eyes were perfused at 8 mmHg with fluorescent tracer nanospheres to decorate local patterns of outflow segmentation through the JCT. The inner wall was stained for CD31 and/or vimentin and imaged en face using confocal and scanning electron microscopy (SEM). Confocal and SEM images were spatially registered to examine the spatial relationship between inner wall pore density and tracer intensity in the underlying JCT. For each eye, tracer intensity, pore density (n) and pore diameter (D) (for both transcellular "I" and paracellular "B" pores) were measured in 4-7 regions of interest (ROIs; 50 * 150 MUm each). Analysis of covariance was used to examine the relationship between tracer intensity and pore density, as well as the relationship between tracer intensity and three pore metrics (nD, nD(2) and nD(3)) that represent the local hydraulic conductivity of the outflow pathway as predicted by various hydrodynamic models. Tracer intensity in the JCT correlated positively with local pore density when considering total pores (p = 0.044) and paracellular B pores on their own (p = 0.016), but not transcellular I-pores on their own (p = 0.54). Local hydraulic conductivity as predicted by the three hydrodynamic models all showed a significant positive correlation with tracer intensity when considering total pores and B-pores (p < 0.0015 and p < 10(-4)) but not I-pores (p > 0.38). These data suggest that aqueous humor passes through micron-sized pores in the inner wall endothelium of SC. Paracellular B-pores appear to have a dominant contribution towards transendothelial filtration across the inner wall relative to transcellular I-pores. Impaired pore formation, as previously described in glaucomatous SC cells, may thereby contribute to greater outflow heterogeneity, outflow obstruction, and IOP elevation in glaucoma. PMID- 25450061 TI - Local targeting of the CD200-CD200R axis does not promote corneal graft survival. AB - Corneal graft rejection is primarily a CD4(+) T cell-mediated mechanism in which macrophages may play an important inflammatory role. CD200Fc fusion protein is an artificial agonist of CD200R1, a receptor expressed predominantly on myeloid cells, engagement of which is known to down-regulate macrophage function. We therefore wished to test whether CD200Fc could be used as a therapeutic agent to prolong corneal graft survival. The distribution of CD200R1 and CD200, its natural ligand, was examined by immunohistology in the cornea and conjunctiva of unoperated rats and rats that had received corneal allografts. Mouse CD200Fc was injected subconjunctivally into transplanted rats on six occasions from the day of surgery until day 10 after transplantation. Control groups received injections of mouse IgG or diluent PBS. Allo-transplants were also performed in CD200(-/-) and control mice. The ability of CD200Fc to bind rat macrophages in vitro and to inhibit nitric oxide production was tested. Mean day of rejection in CD200Fc, IgG and PBS-treated rats was 12, 10 and 9 respectively (p=0.24). Mean day of rejection in CD200(-/-) and wild type mice was 17.5 and 16.0 respectively (p=0.07). Mouse CD200Fc bound to rat macrophages in a dose-dependent manner, but was unable to inhibit nitric oxide production. The fact that treatment with CD200Fc did not inhibit graft rejection and the failure of CD200 deficiency to affect graft survival suggests that local targeting of the CD200-CD200R axis to suppress macrophage activation is not a useful therapeutic strategy in corneal graft rejection. PMID- 25450062 TI - NFATc1 activity regulates the expression of myocilin induced by dexamethasone. AB - Mutations in the myocilin gene (MYOC) account for 10% of juvenile open-angle glaucoma cases and 3-4% of adult onset primary open-angle glaucoma cases. It is a secreted glycoprotein found in many ocular and non-ocular tissues and has been linked to elevated intraocular pressure. In human trabecular meshwork (HTM) cells, MYOC expression can be induced by the glucocorticoid dexamethasone (DEX). In this study we examined the role of the calcineurin/NFATc1 (Nuclear Factor of Activated T-cells) pathway in the DEX induction of MYOC in HTM cells. In post confluent HTM cells treated with either 500 nM DEX or 0.1% ethanol (EtOH; vehicle control) for 0-6 days both protein and mRNA levels of MYOC were increased while DEX was present. The protein and mRNA levels remained elevated for an additional 12 days after the removal of DEX. Only 1 day of DEX treatment was sufficient to trigger a sustained increase in MYOC mRNA that lasted for 4 days after the removal of DEX. Similar to other studies, myocilin protein expression was not seen until the second day of DEX treatment while mRNA increased within one day of DEX indicating that this is a secondary glucocorticoid response. To determine if MYOC gene expression was regulated by calcineurin/NFATc1, HTM cells were pre treated for 1 h with the calcineurin inhibitors cyclosporin A or INCA-6 prior to the addition of DEX or EtOH for 2 days. NFATc1 siRNA was used to determine if NFATc1 was required for MYOC mRNA expression. Cells were also treated with the ionophone ionomycin to determine if increased cytosolic calcium affected MYOC expression. These studies showed that the DEX induced increase in MYOC mRNA could be inhibited with either cyclosporin A or INCA-6 or by transfection with NFATc1 siRNA and that ionomycin was unable to increase MYOC mRNA. Immunofluorescence microscopy was also performed to determine if DEX caused the nuclear translocation of NFATc1. Immunostaining showed that NFATc1 relocated to the nucleus within 15 min of DEX treatment and remained there for up to 2 h. The data suggest that the DEX-induced increase in MYOC expression activates a calcineurin and NFATc1 pathway in a calcium independent mechanism. PMID- 25450064 TI - Assessment of the immunogenicity of mechanically induced interferon aggregates in a transgenic mouse model. AB - Pump delivery of human interferon alpha-2B (IFNalpha2b) has the potential for inducing immunogenic drug aggregates. We therefore evaluated the immunogenicity of mechanically induced IFNalpha2b aggregates to assess this risk. Transgenic human-IFNalpha2b (TG) and wild-type (WT) FVB/N mice (n = 8 and n = 9/group, respectively) were administered mechanically agitated drug [45 Hz for 6 h (LLA) or 24 h (HLA)], chemically modified drug [low pH (pH 4.0) or metal oxidized (OXD)] or unstressed drug (native). Mice received IFNalpha2b (50 MUg; 100 MUg/mL; s.c.) formulations on days 0, 7, 14, and 21. Drug-binding and neutralizing antibody titers were determined after 28 d. Aggregate concentrations were highest in OXD and HLA formulations but OXD had more dimers/trimers. Geometric mean titers were 1:131, 1:728, 1:1573, 1:871, and 1:10,240 for WT mice (n = 9) and 1:207, 1:587, 1:1810, 1:571, and 1:2,153 for TG mice (n = 8) for native, LLA, HLA, pH4, and OXD groups, respectively. Mechanical agitation of IFNalpha2b induced equivalent titers of immunoglobulin to that of metal oxidation, both capable of binding to or neutralizing the drug in WT and TG mice. Thus, by limiting metal contamination and by inclusion of a stabilizing agent to mitigate drug aggregation, the risk of anti-drug immunoglobulin may be reduced in a pump delivery scenario. PMID- 25450065 TI - Penicillin-binding proteins: evergreen drug targets. AB - The penicillin-binding proteins (PBPs) are well known targets for the beta-lactam antibiotics. They continue to be a focus of interest for pharmaceutical design, as exemplified by the number of new agents under clinical investigation as well as novel experimental molecules. Considerable advances have been made in understanding the structure and function of this family of enzymes, through high resolution structural studies and mechanistic studies in solution. These studies have thrown light on role of the high molecular mass PBPs in mediating beta lactam resistance, although much work remains to be done to enable a full description of the mechanisms by which these proteins modulate their sensitivity towards beta-lactams while retaining their essential activity in cell wall biosynthesis. PMID- 25450066 TI - Progress in the delivery of nanoparticle constructs: towards clinical translation. AB - The application of nanoparticle constructs in drug delivery and nanomedicine is anticipated to have a great impact on future public health. Progress in this area is expected to address some of modern medicine's unresolved problems and recent literature contains many articles discussing this topic. We focus here on recent nanomedicine developments mainly in relation to cancer, which have either being approved for the market or clinical trials. We review nanomedicines in clinical use, nano-construct delivery systems (both non-targeted and targeted), imaging agents, as well as theranostics. PMID- 25450063 TI - The rat retina has five types of ganglion-cell photoreceptors. AB - Intrinsically photosensitive retinal ganglion cells (ipRGCs) are inner retinal photoreceptors that mediate non-image-forming visual functions, e.g. pupillary constriction, regulation of pineal melatonin release, and circadian photoentrainment. Five types of ipRGCs were recently discovered in mouse, but whether they exist in other mammals remained unknown. We report that the rat also has five types of ipRGCs, whose morphologies match those of mouse ipRGCs; this is the first demonstration of all five cell types in a non-mouse species. Through immunostaining and lambdamax measurements, we showed that melanopsin is likely the photopigment of all rat ipRGCs. The various cell types exhibited diverse spontaneous spike rates, with the M1 type spiking the least and M4 spiking the most, just like we had observed for their mouse counterparts. Also similar to mouse, all ipRGCs in rat generated not only sluggish intrinsic photoresponses but also fast, synaptically driven ones. However, we noticed two significant differences between these species. First, whereas we learned previously that all mouse ipRGCs had equally sustained synaptic light responses, rat M1 cells' synaptic photoresponses were far more transient than those of M2-M5. Since M1 cells provide all input to the circadian clock, this rat-versus-mouse discrepancy could explain the difference in photoentrainment threshold between mouse and other species. Second, rat ipRGCs' melanopsin-based spiking photoresponses could be classified into three varieties, but only two were discerned for mouse ipRGCs. This correlation of spiking photoresponses with cell types will help researchers classify ipRGCs in multielectrode-array (MEA) spike recordings. PMID- 25450067 TI - Pharmacological aspects of release from microcapsules - from polymeric multilayers to lipid membranes. AB - This review is devoted to pharmacological applications of principles of release from capsules to overcome the membrane barrier. Many of these principles were developed in the context of polymeric multilayer capsule membrane modulation, but they are also pertinent to liposomes, polymersomes, capsosomes, particles, emulsion-based carriers and other carriers. We look at these methods from the physical, chemical or biological driving mechanisms point of view. In addition to applicability for carriers in drug delivery, these release methods are significant for another area directly related to pharmacology - modulation of the permeability of the membranes and thus promoting the action of drugs. Emerging technologies, including ionic current monitoring through a lipid membrane on a nanopore, are also highlighted. PMID- 25450069 TI - Nanoencapsulated and microencapsulated SERS platforms for biomedical analysis. AB - The problems of layer-by-layer-based surface enhancement Raman scattering (SERS) sensor application for pharmaceutical analysis were discussed. Layer-by-layer (LbL) method allows fabrication of encapsulated SERS platforms with high reproducibility of enhancement factor and increased signal/noise ratio of Raman scattering. LbL encapsulation approach opens an avenue to implement a novel type of theranostic systems combining SERS based sensing and drug delivery in one entity. The area of encapsulation development toward smart multifunctional theranostic systems could bring benefits for personalized medicine and should minimize costs and resources at preclinical and clinical study in pharmacology while testing new bioactive compounds. PMID- 25450068 TI - Spherical and tubule nanocarriers for sustained drug release. AB - We discuss new trends in Layer-by-Layer (LbL) encapsulation of spherical and tubular cores of 50-150 nm diameter and loaded with drugs. This core size decrease (from few micrometers to a hundred of nanometers) for LbL encapsulation required development of sonication assistant non-washing technique and shell PEGylation to reach high colloidal stability of drug nanocarriers at 2-3mg/mL concentration in isotonic buffers and serum. For 120-170 nm spherical LbL nanocapsules of low soluble anticancer drugs, polyelectrolyte shell thickness controls drug dissolution. As for nanotube carriers, we concentrated on natural halloysite clay nanotubes as cores for LbL encapsulation that allows high drug loading and sustains its release over tens and hundreds hours. Further drug release prolongation was reached with formation of the tube-end stoppers. PMID- 25450071 TI - Recurrent abdominal pain accompanied by small intestinal lesions. PMID- 25450070 TI - Patchy colitis and interstitial lung disease. PMID- 25450072 TI - Whitish intestinal epithelium and numerous intussusceptions. PMID- 25450073 TI - An unusual case of acute intestinal hemorrhage. PMID- 25450074 TI - Abdominal distension in an infant. PMID- 25450075 TI - A case of painless jaundice. PMID- 25450076 TI - Multiple tumor-like lesions of the liver in a patient with a history of pancreaticoduodenectomy. PMID- 25450077 TI - A new meaning to butterflies in the stomach. PMID- 25450078 TI - A case of the hiccups in the setting of colonic ulcers. PMID- 25450079 TI - Unexpected cause of acute recurrent vomiting. PMID- 25450080 TI - A woman with spontaneous colonic perforation. PMID- 25450081 TI - A rare primary liver tumor that responded to sorafenib. PMID- 25450082 TI - An unusual perigastric cyst. PMID- 25450083 TI - Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. AB - BACKGROUND & AIMS: Little is known about whether probiotics can affect outcomes of patients with cirrhosis and hepatic encephalopathy (HE). We assessed the efficacy of a probiotic preparation in preventing the recurrence of HE (primary outcome) and reducing the number of hospitalizations and severity of liver disease in patients with cirrhosis. METHODS: We performed a double-blind trial at a tertiary care hospital in India. Patients with cirrhosis who had recovered from an episode of HE during the previous month were assigned randomly (using computer generated allocation) to groups given a probiotic preparation (VSL#3, 9 * 10(11) bacteria; CD Pharma India Private Limited, New Delhi, India) (n = 66) or placebo (n = 64) daily for 6 months. RESULTS: There was a trend toward a reduction in the development of breakthrough HE among patients receiving the probiotic (34.8% in the probiotic group vs 51.6% in the placebo group; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.38-1.11; P = .12). Fewer patients in the probiotic group were hospitalized for HE (19.7% vs 42.2%, respectively; HR, 0.45; 95% CI, 0.23-0.87; P = .02) or for complications of cirrhosis (24.2%) than in the placebo group (45.3%) (HR, 0.52; 95% CI, 0.28-0.95; P = .034). Child-Turcotte-Pugh and model for end-stage liver disease scores improved significantly from baseline to 6 months in the probiotic group, but not in the placebo group. There were no adverse events related to VSL#3. CONCLUSIONS: Over a 6-month period, daily intake of VSL#3 significantly reduced the risk of hospitalization for HE, as well as Child-Turcotte-Pugh and model for end-stage liver disease scores, in patients with cirrhosis. ClinicalTrials.gov number: NCT01110447. PMID- 25450085 TI - Improved prediction of the need for liver transplantation in patients with drug induced liver injury? PMID- 25450084 TI - Race in colorectal cancer screening strategies: a solid determinant factor or a "moving target"? PMID- 25450087 TI - A multicystic tumor causing intermittent pain in a young man. PMID- 25450086 TI - An unusual cause of iron deficiency anemia. PMID- 25450088 TI - Not every ampullary mass is deadly. PMID- 25450089 TI - A case of confusion. PMID- 25450091 TI - An unusual complication after laparoscopic gastric lap band placement. PMID- 25450090 TI - Systemic ulcerative lesions in a patient with ischemic heart disease. PMID- 25450092 TI - Novel compound heterozygous mutations in CTSC gene cause Papillon-Lefevre syndrome with high serum immunoglobulin E. PMID- 25450093 TI - Decreased ATP synthesis and lower pH may lead to abnormal muscle contraction and skin sensitivity in human skin. AB - BACKGROUND: Sensitive skin represents hyperactive sensory symptoms showing exaggerated reactions in response to internal stimulants or external irritants. Although sensitive skin is a very common condition affecting an estimated 50% of the population, its pathophysiology remains largely elusive, particularly with regard to its metabolic aspects. OBJECTIVE: The objective of our study was to investigate the pathogenesis of sensitive skin. METHODS: We recruited healthy participants with 'sensitive' or 'non-sensitive' skin based on standardized questionnaires and 10% lactic acid stinging test, and obtained skin samples for microarray analysis and subsequent experiments. RESULTS: Microarray transcriptome profiling revealed that genes involved in muscle contraction, carbohydrate and lipid metabolism, and ion transport and balance were significantly decreased in sensitive skin. These altered genes could account for the abnormal muscle contraction, decreased ATP amount in sensitive skin. In addition, pain-related transcripts such as TRPV1, ASIC3 and CGRP were significantly up-regulated in sensitive skin, compared with non-sensitive skin. CONCLUSIONS: Our findings suggest that sensitive skin is closely associated with the dysfunction of muscle contraction and metabolic homeostasis. PMID- 25450095 TI - Late psychiatric morbidity in survivors of cancer at a young age: a nationwide registry-based study. AB - Childhood cancer survivors have been shown to be prone to psychosocial adverse outcomes. Data on young adults and their psychiatric late effects are still scarce. In a nationwide, registry-based study, we explored the risk (HR) of new psychiatric diagnoses in 5-year survivors of childhood and young adulthood (YA) cancer (n = 13,860) compared with a sibling cohort (n = 43,392). Hazard ratios (HRs) were calculated using Cox regression models. Patients and siblings were identified from the Finnish Cancer Registry and Central Population Registry, respectively. Outcome diagnoses were retrieved from the national hospital discharge register. The risk of organic memory/brain disorders was significantly increased in both childhood (HR 4.9; 95%CI 2.7-8.9) and YA (HR 2.1; 95%CI 1.4 3.1) cancer survivors compared with siblings. Mood disorders were also more common in childhood (HR 1.3; 95%CI 1.1-1.7) and YA survivors (1.3; 95%CI 1.1-1.5) than in siblings. Radiotherapy did not explain the differences. Female childhood cancer survivors had significantly increased HRs for mood disorders, psychotic disorders, neurotic/anxiety disorders, somatization/eating disorders and personality disorders. In survivors of YA cancers, females had significantly increased HR for neurotic/anxiety disorders, and the difference between female survivors and siblings was significantly (p < 0.05) higher than that between male survivors and male siblings. The effect of treatment era was also analyzed, and the risk of organic memory and brain disorders in childhood cancer survivors did not diminish over time. Despite the trend of decreased use of cranial irradiation in children, the risk of organic memory/brain disorders was elevated, even during the most recent era. Thus, additional research on chemotherapy-only protocols and their impact on mental health, is warranted. PMID- 25450094 TI - Protein kinase D1 deficiency promotes differentiation in epidermal keratinocytes. AB - BACKGROUND: Protein kinase D (PKD or PKD1) is a serine/threonine protein kinase that has been shown to play a role in a variety of cellular processes; however, the function of PKD1 in the skin has not been fully investigated. The balance between proliferation and differentiation processes in the predominant cells of the epidermis, the keratinocytes, is essential for normal skin function. OBJECTIVE: To investigate the effect of PKD1 deficiency on proliferation and differentiation of epidermal keratinocytes. METHODS: We utilized a floxed PKD1 mouse model such that infecting epidermal keratinocytes derived from these mice with an adenovirus expressing Cre-recombinase allowed us to determine the effect of PKD1 gene loss in vitro. Proliferation and differentiation were monitored using qRT-PCR, Western blot, transglutaminase activity assays, [3H]thymidine incorporation into DNA and cell cycle analysis. RESULTS: A significant decrease in PKD1 mRNA and protein levels was achieved in adenoviral Cre-recombinase infected cells. Deficiency of PKD1 resulted in significant increases in the mRNA and protein expression of various differentiation markers such as loricrin, involucrin, and keratin 10 either basally and/or upon stimulation of differentiation. PKD1-deficient keratinocytes also showed an increase in transglutaminase expression and activity, indicating an anti-differentiative role of PKD1. Furthermore, the PKD1-deficient keratinocytes exhibited decreased proliferation. However, PKD1 loss had no effect on stem cell marker expression. CONCLUSIONS: Cre-recombinase-mediated knockdown represents an additional approach demonstrating that PKD1 is an anti-differentiative, pro-proliferative signal in mouse keratinocytes. PMID- 25450096 TI - Genomic variation in a widespread Neotropical bird (Xenops minutus) reveals divergence, population expansion, and gene flow. AB - The demographic and phylogeographic histories of species provide insight into the processes responsible for generating biological diversity, and genomic datasets are now permitting the estimation of species histories with unprecedented accuracy. We used a genomic single nucleotide polymorphism (SNP) dataset generated using a RAD-Seq method to investigate the historical demography and phylogeography of a widespread lowland Neotropical bird (Xenops minutus). As expected, we found that prominent landscape features that act as dispersal barriers, such as Amazonian rivers and the Andes Mountains, are associated with the deepest phylogeographic breaks, and also that isolation by distance is limited in areas between these barriers. In addition, we inferred positive population growth for most populations and detected evidence of historical gene flow between populations that are now physically isolated. Although we were able to reconstruct the history of Xenops minutus with unprecedented resolution, we had difficulty conclusively relating this history to the landscape events implicated in many Neotropical diversification hypotheses. We suggest that even if many traditional diversification hypotheses remain untestable, investigations using genomic datasets will provide greater resolution of species histories in the Neotropics and elsewhere. PMID- 25450097 TI - Applying species-tree analyses to deep phylogenetic histories: challenges and potential suggested from a survey of empirical phylogenetic studies. AB - Coalescent-based methods for species-tree estimation are becoming a dominant approach for reconstructing species histories from multi-locus data, with most of the studies examining these methodologies focused on recently diverged species. However, deeper phylogenies, such as the datasets that comprise many Tree of Life (ToL) studies, also exhibit gene-tree discordance. This discord may also arise from the stochastic sorting of gene lineages during the speciation process (i.e., reflecting the random coalescence of gene lineages in ancestral populations). It remains unknown whether guidelines regarding methodologies and numbers of loci established by simulation studies at shallow tree depths translate into accurate species relationships for deeper phylogenetic histories. We address this knowledge gap and specifically identify the challenges and limitations of species tree methods that account for coalescent variance for deeper phylogenies. Using simulated data with characteristics informed by empirical studies, we evaluate both the accuracy of estimated species trees and the characteristics associated with recalcitrant nodes, with a specific focus on whether coalescent variance is generally responsible for the lack of resolution. By determining the proportion of coalescent genealogies that support a particular node, we demonstrate that (1) species-tree methods account for coalescent variance at deep nodes and (2) mutational variance - not gene-tree discord arising from the coalescent - posed the primary challenge for accurate reconstruction across the tree. For example, many nodes were accurately resolved despite predicted discord from the random coalescence of gene lineages and nodes with poor support were distributed across a range of depths (i.e., they were not restricted to a particular recent divergences). Given their broad taxonomic scope and large sampling of taxa, deep level phylogenies pose several potential methodological complications including difficulties with MCMC convergence and estimation of requisite population genetic parameters for coalescent-based approaches. Despite these difficulties, the findings generally support the utility of species-tree analyses for the estimation of species relationships throughout the ToL. We discuss strategies for successful application of species-tree approaches to deep phylogenies. PMID- 25450098 TI - Re-evaluating the phylogeny of Sipuncula through transcriptomics. AB - Sipunculans (also known as peanut worms) are an ancient group of exclusively marine worms with a global distribution and a fossil record that dates back to the Early Cambrian. The systematics of sipunculans, now considered a distinct subclade of Annelida, has been studied for decades using morphological and molecular characters, and has reached the limits of Sanger-based approaches. Here, we reevaluate their family-level phylogeny by comparative transcriptomic analysis of eight species representing all known families within Sipuncula. Two data matrices with alternative gene occupancy levels (large matrix with 675 genes and 62% missing data; reduced matrix with 141 genes and 23% missing data) were analysed using concatenation and gene-tree methods, yielding congruent results and resolving each internal node with maximum support. We thus corroborate prior phylogenetic work based on molecular data, resolve outstanding issues with respect to the familial relationships of Aspidosiphonidae, Antillesomatidae and Phascolosomatidae, and highlight the next area of focus for sipunculan systematics. PMID- 25450099 TI - A phylogenomic analysis of turtles. AB - Molecular analyses of turtle relationships have overturned prevailing morphological hypotheses and prompted the development of a new taxonomy. Here we provide the first genome-scale analysis of turtle phylogeny. We sequenced 2381 ultraconserved element (UCE) loci representing a total of 1,718,154bp of aligned sequence. Our sampling includes 32 turtle taxa representing all 14 recognized turtle families and an additional six outgroups. Maximum likelihood, Bayesian, and species tree methods produce a single resolved phylogeny. This robust phylogeny shows that proposed phylogenetic names correspond to well-supported clades, and this topology is more consistent with the temporal appearance of clades and paleobiogeography. Future studies of turtle phylogeny using fossil turtles should use this topology as a scaffold for their morphological phylogenetic analyses. PMID- 25450100 TI - Phylogeny, biogeography and evolution of Triglochin L. (Juncaginaceae)- morphological diversification is linked to habitat shifts rather than to genetic diversification. AB - A species-level phylogeny is presented for Triglochin, the largest genus of Juncaginaceae (Alismatales) comprising about 30 species of annual and perennial herbs. Triglochin has an almost cosmopolitan distribution with Australia as centre of species diversity. Trans-Atlantic and trans-African disjunctions exist in the genus. Phylogenetic analyses were conducted based on molecular data obtained from nuclear (ITS, internal transcribed spacer) and chloroplast sequence data (psbA-trnH spacer, matK gene). Based on the phylogeny of the group divergence times were estimated and ancestral distribution areas reconstructed. Our data confirm the monophyly of Triglochin and resolve relationships between the major lineages of the genus. The sister group relationship between the Mediterranean/African T. bulbosa complex and the American T. scilloides (formerly Lilaea s.) is strongly supported. This clade is sister to the rest of the genus which contains two main clades. In the first, the widespread T. striata is sister to a clade comprising annual Triglochin species from Australia. The second clade comprises T. palustris as sister to the T. maritima complex, of which the latter is further divided into a Eurasian and an American subclade. Taxonomic diversity in some clades appears to be linked to habitat shifts and is not present in old but ecologically invariable lineages such as the non-monophyletic T. maritima. Diversification in Triglochin began in the Miocene or Oligocene, and most disjunctions in Triglochin were dated to the Miocene. PMID- 25450101 TI - Mitogenomic phylogenetics of the bank vole Clethrionomys glareolus, a model system for studying end-glacial colonization of Europe. AB - We have revisited the mtDNA phylogeny of the bank vole Clethrionomys glareolus based on Sanger and next-generation Illumina sequencing of 32 complete mitochondrial genomes. The bank vole is a key study species for understanding the response of European fauna to the climate change following the Last Glacial Maximum (LGM) and one of the most convincing examples of a woodland mammal surviving in cryptic northern glacial refugia in Europe. The genomes sequenced included multiple representatives of each of the eight bank vole clades previously described based on cytochrome b (cob) sequences. All clades with the exception of the Basque - likely a misidentified pseudogene clade - were highly supported in all phylogenetic analyses and the relationships between the clades were resolved with high confidence. Our data extend the distribution of the Carpathian clade, the marker of a northern glacial refugium in the Carpathian Mountains, to include Britain and Fennoscandia (but not adjacent areas of continental Europe). The Carpathian sub-clade that colonized Britain and Fennoscandia had a somewhat different history from the sub-clade currently found in or close to the Carpathians and may have derived from a more north-westerly refugial area. The two bank vole populations that colonized Britain at the end of the last glaciation are for the first time linked with particular continental clades, the first colonists with the Carpathian clade and the second colonists with the western clade originating in a more southerly refugium in the vicinity of the Alps. We however found no evidence that a functional divergence of proteins encoded in the mitochondrial genome promoted the partial genetic replacement of the first colonists by the second colonists detected previously in southern Britain. We did identify one codon site that changed more often and more radically in the tree than expected and where the observed amino acid change may affect the reductase activity of the cytochrome bc1 complex, but the change was not specific to a particular clade. We also found an excess of radical changes to the primary protein structure for geographically restricted clades from southern Italy and Norway, respectively, possibly related to stronger selective pressure at the latitudinal extremes of the bank vole distribution. However, overall, we find little evidence of pervasive effects of deviation from neutrality on bank vole mtDNA phylogeography. PMID- 25450102 TI - Recent evolutionary history of Lost World endemics: population genetics, species delimitation, and phylogeography of sky-island treefrogs. AB - The tepuis of South America are massive flattop mountains with cliffs up to 1000m and summits up to 3100m. Tepuis hold enormous endemicity levels, but little is known about the origins of the endemic flora and fauna. Recently diverged lineages offer the possibility of understanding the origins of summit endemicity by examining population dynamics and dispersal. We examine species delimitation, clade relationships, and demographic patterns of three recently diverged lineages of Tepuihyla, an endemic treefrog clade. These three lineages represent two currently recognized species, T. edelcae and T. rodriguezi. Given the low divergences in both nuclear and mitochondrial genes among lineages, we find unexpectedly high numbers of unique nuclear haplotypes and moderate levels of lineage sorting. We also find support from multiple analyses for a cryptic, undescribed summit species within T. edelcae. We suggest that the genetic and distribution patterns of the four most recently diverged Tepuihyla lineages support a concurrent speciation event during the Pliocene, and suggest a biogeographic hypothesis in which a widespread climatic change made mid- and low elevation habitat unsuitable for the common ancestor within the timeframe of their divergence. PMID- 25450103 TI - Multiple origins of subsociality in crab spiders (Thomisidae). AB - Determining factors that facilitate the transition from a solitary to a social lifestyle is a major challenge in evolutionary biology, especially in taxa that are usually aggressive towards conspecifics. Most spiders live solitarily and few species are known to be social. Nevertheless, sociality has evolved multiple times across several families and nearly all studied social lineages have originated from a periodically social (subsocial) ancestor. Group-living crab spiders (Thomisidae) are exclusively found in Australia and differ from most other social spiders because they lack a communal capture web. Three of the group living species were placed in the genus Diaea and another in the genus Xysticus. Most Australian thomisids are, however, difficult to identify as most descriptions are old and of poor quality, and the genera Diaea and Xysticus may not correspond to monophyletic groups. Here, we clarify the phylogenetic relationships of the four group-living Australian thomisids and conclude that amongst these subsociality has evolved two to three times independently. The subsocial Xysticus bimaculatus is not closely related to any of the social Diaea and an independent origin of subsociality is likely in this case. The presented data indicates that within Diaea two origins of subsociality are possible. Our results help to understand the evolution of sociality in thomisids and support the hypothesis that permanent sociality in spiders has evolved multiple times relatively recently from subsocial ancestors. PMID- 25450104 TI - First multilocus and densely sampled timetree of trevallies, pompanos and allies (Carangoidei, Percomorpha) suggests a Cretaceous origin and Eocene radiation of a major clade of piscivores. AB - Carangoid fishes (trevallies, pompanos, jacks, dolphinfishes, cobias and remoras) include about 159 species of marine fishes found in tropical and temperate waters worldwide (Froese and Pauly, 2014). Many carangoids are powerful swimmers and active piscivores in and around coral-reef ecosystems. Some carangoid lineages, such as dolphinfishes, have evolved a pelagic lifestyle, while remoras spend their adult life attached to cetaceans, sharks, manta rays and large teleosts, feeding off skin parasites or leftovers from their host's meals. In spite of their taxonomic diversity, ecological dominance, economic importance to humans, and a rich fossil record dating to the Paleogene, relatively little is currently known about the tempo of evolution of this group. Here we present the results of the first time calibration study of carangoid fishes. Using a fossil-calibrated molecular timetree that includes 133 species of carangoids (~85% of extant species), we show that this group originated in the Late Cretaceous and that several major lineages were already present before the K-Pg extinction. All major clades were in existence by the end of the Eocene, even though significant diversification has continued to occur throughout the history of this group. PMID- 25450105 TI - Middle ear impedance studies in elderly patients implications on age-related hearing loss. AB - INTRODUCTION: Controversies arise with respect to functioning of the middle ear over time. OBJECTIVE: To assess changes in middle ear impedance that may be related to aging, and/or if there was an association of these changes with those of the inner ear in the elderly patients. METHODS: Cross-sectional, comparative study of elderly patients managed in ear, nose and throat clinics. A structured questionnaire was administered to obtain clinical information. Pure tone audiometry, tympanometry, and acoustic reflexes were performed. Comparative analyses were performed to detect intergroup differences between clinico audiometric findings and middle ear measures, viz. tympanograms and acoustic reflexes. RESULTS: One hundred and three elderly patients participated in the study; 52.4% were male, averagely 70.0+/-6.3 years old, age-related hearing loss in 59.2%, abnormal tympanograms in 39.3%, absent acoustic reflex in 37.9%. There was no association between age and gender in patients with abnormal tympanograms and absent acoustic reflex. Significantly more patients with different forms and grades of age-related hearing loss had abnormal tympanometry and absent acoustic reflex. CONCLUSION: Some abnormalities were observed in the impedance audiometric measures of elderly patients, which were significantly associated with parameters connected to age-related hearing loss. PMID- 25450106 TI - Dysphagia progression and swallowing management in Parkinson's disease: an observational study. AB - INTRODUCTION: Dysphagia is relatively common in individuals with neurological disorders. OBJECTIVE: To describe the swallowing management and investigate associated factors with swallowing in a case series of patients with Parkinson's disease. METHODS: It is a long-term study with 24 patients. The patients were observed in a five-year period (2006-2011). They underwent Fiberoptic Endoscopic Evaluation of Swallowing, Functional Oral Intake Scale and therapeutic intervention every three months. In the therapeutic intervention they received orientation about exercises to improve swallowing. The Chi-square, Kruskal-Wallis and Fisher's tests were used. The period of time for improvement or worsening of swallowing was described by Kaplan-Meier analysis. RESULTS: During the follow-up, ten patients improved, five stayed the same and nine worsened their swallowing functionality. The median time for improvement was ten months. Prior to the worsening there was a median time of 33 months of follow-up. There was no associated factor with improvement or worsening of swallowing. The maneuvers frequently indicated in therapeutic intervention were: chin-tuck, bolus consistency, bolus effect, strengthening-tongue, multiple swallows and vocal exercises. CONCLUSION: The swallowing management was characterized by swallowing assessment every three months with indication of compensatory and rehabilitation maneuvers, aiming to maintain the oral feeding without risks. There was no associated factor with swallowing functionality in this case series. PMID- 25450108 TI - Scalp spindles are associated with widespread intracranial activity with unexpectedly low synchrony. AB - In humans, the knowledge of intracranial correlates of spindles is mainly gathered from noninvasive neurophysiologic and functional imaging studies which provide an indirect estimate of neuronal intracranial activity. This potential limitation can be overcome by intracranial electroencephalography used in presurgical epilepsy evaluation. We investigated the intracranial correlates of scalp spindles using combined scalp and intracerebral depth electrodes covering the frontal, parietal and temporal neocortex, and the scalp and intracranial correlates of hippocampal and insula spindles in 35 pre-surgical epilepsy patients. Spindles in the scalp were accompanied by widespread cortical increases in sigma band energy (10-16 Hz): the highest percentages were observed in the frontoparietal lateral and mesial cortex, whereas in temporal lateral and mesial structures only a low or no simultaneous increase was present. This intracranial involvement during scalp spindles showed no consistent pattern, and exhibited unexpectedly low synchrony across brain regions. Hippocampal spindles were shorter and spatially restricted with a low synchrony even within the temporal lobe. Similar results were found for the insula. We suggest that the generation of spindles is under a high local cortical influence contributing to the concept of sleep as a local phenomenon and challenging the notion of spindles as widespread synchronous oscillations. PMID- 25450109 TI - Pre-stimulus neural activity predicts successful encoding of inter-item associations. AB - fMRI was employed to investigate the relationship between pre-stimulus neural activity and associative encoding of words and pictures in humans. While undergoing scanning, subjects studied randomly interleaved word or picture pairs. A pre-stimulus cue preceded the presentation of each study pair and signaled whether it would comprise words or pictures. Memory for the study pairs was later tested with an associative recognition test, which comprised word or picture pairs presented either in the same (intact) or a different (rearranged) pairing as at study, along with pairs of new items. The critical fMRI contrast was between study activity associated with pairs later correctly judged intact and pairs incorrectly judged as rearranged. A key question was whether material selective pre-stimulus encoding effects could be identified which overlapped regions selectively activated by the respective study material. Picture-selective pre-stimulus effects were identified in bilateral fusiform and the intraparietal sulcus (IPS), whereas word-selective effects could not be identified. Material invariant pre-stimulus subsequent memory effects were also identified in several neocortical regions as well as in the hippocampus. Whereas the loci of the neocortical effects suggest that they reflect the benefit to encoding that accrues from engagement of cognitive control processes, their magnitude was negatively correlated across subjects with associative recognition performance and positively related to false alarm rate. Conversely, the hippocampal effects also predicted unique variance in associative memory and were negatively related to hit rate. It is suggested that the neocortical pre-stimulus effects may reflect encoding processes that increase familiarity of single items, whereas the hippocampal pre-stimulus effects are proposed to reflect either the encoding of task-irrelevant features or the retrieval of task-relevant information associated with the pre-stimulus cues. Overall, the results provide evidence that pre stimulus processes may be deleterious, rather than beneficial, to associative encoding. PMID- 25450111 TI - Removing speech artifacts from electroencephalographic recordings during overt picture naming. AB - A number of electroencephalography (EEG) studies have investigated the time course of brain activation during overt word production. The interpretation of their results is complicated by the fact that articulatory movements may mask the cognitive components of interest. The first aim of the present study was to investigate when speech artifacts occur during word production planning and what effects they have on the spatio-temporal neural activation pattern. The second aim was to propose a new method that strongly attenuates speech artifacts during overt picture naming and to compare it with existing methods. EEG and surface electromyograms (EMGs) of the lips were recorded while participants overtly named pictures in a picture-word interference paradigm. The comparison of the raw data with lip EMG and the comparison of source localizations of raw and corrected EEG data showed that speech artifacts occurred mainly from ~400 ms post-stimulus onset, but some earlier artifacts mean that they occur much earlier than hitherto assumed. We compared previously used methods of speech artifacts removal (SAR) with a new method, which is based on Independent Component Analysis (SAR-ICA). Our new method clearly outperformed other methods. In contrast to other methods, there was only a weak correlation between the lip EMG and the corrected data by SAR-ICA. Also, only the data corrected with our method showed activation of cerebral sources consistent with meta-analyses of word production. PMID- 25450112 TI - Formal properties of the probability of fixation: identities, inequalities and approximations. AB - The formula for the probability of fixation of a new mutation is widely used in theoretical population genetics and molecular evolution. Here we derive a series of identities, inequalities and approximations for the exact probability of fixation of a new mutation under the Moran process (equivalent results hold for the approximate probability of fixation under the Wright-Fisher process, after an appropriate change of variables). We show that the logarithm of the fixation probability has particularly simple behavior when the selection coefficient is measured as a difference of Malthusian fitnesses, and we exploit this simplicity to derive inequalities and approximations. We also present a comprehensive comparison of both existing and new approximations for the fixation probability, highlighting those approximations that induce a reversible Markov chain when used to describe the dynamics of evolution under weak mutation. To demonstrate the power of these results, we consider the classical problem of determining the total substitution rate across an ensemble of biallelic loci and prove that, at equilibrium, a strict majority of substitutions are due to drift rather than selection. PMID- 25450113 TI - Dying on the way: the influence of migrational mortality on neutral models of spatial variation. AB - Migrational mortality is introduced into the classical Malecot model for migration, mutation, and random genetic drift. To assess the influence of mortality, its effect on the backward migration rates and on the probabilities of identity in allelic state are studied. Perhaps surprisingly, some of the former may increase, but as is intuitive, their sum always decreases. As expected, in the island model, mortality does not change the migration pattern, but it decreases the migration rate. Furthermore, it decreases the expected heterozygosity, but increases the genetic diversity and differentiation. The circular habitat and the unbounded, linear stepping-stone model also illustrate the general results. Arbitrary migration is also analyzed. If migration is sufficiently weak, then mortality diminishes every migration rate; it decreases the expected heterozygosity and the genetic similarity between demes. In the strong-migration limit, mortality may raise or lower the probability of identity in state. Perhaps unexpectedly, under mild and reasonable biological assumptions, mortality does not alter the diffusion limit of the probabilities of identity. PMID- 25450110 TI - A comparative analysis of mouse and human medial geniculate nucleus connectivity: a DTI and anterograde tracing study. AB - Understanding the function and connectivity of thalamic nuclei is critical for understanding normal and pathological brain function. The medial geniculate nucleus (MGN) has been studied mostly in the context of auditory processing and its connection to the auditory cortex. However, there is a growing body of evidence that the MGN and surrounding associated areas ('MGN/S') have a diversity of projections including those to the globus pallidus, caudate/putamen, amygdala, hypothalamus, and thalamus. Concomitantly, pathways projecting to the medial geniculate include not only the inferior colliculus but also the auditory cortex, insula, cerebellum, and globus pallidus. Here we expand our understanding of the connectivity of the MGN/S by using comparative diffusion weighted imaging with probabilistic tractography in both human and mouse brains (most previous work was in rats). In doing so, we provide the first report that attempts to match probabilistic tractography results between human and mice. Additionally, we provide anterograde tracing results for the mouse brain, which corroborate the probabilistic tractography findings. Overall, the study provides evidence for the homology of MGN/S patterns of connectivity across species for understanding translational approaches to thalamic connectivity and function. Further, it points to the utility of DTI in both human studies and small animal modeling, and it suggests potential roles of these connections in human cognition, behavior, and disease. PMID- 25450115 TI - Response to the letter to the editor. PMID- 25450114 TI - Respiratory physiology & neurobiology. PMID- 25450116 TI - The protective effect of hypercapnia on ischemia-reperfusion injury in lungs. AB - Lifesaving therapy for patients with end-stage lung disease is lung transplantation. However, there are not enough available donors. A relatively new method of transplantation from non-heart-beating donors (NHBDs) allows the treatment of the lung outside the body and could increase the number of suitable lungs. We have focused on hypercapnic ventilation, which has the possibility of reducing reactive oxygen species damage. We used four experimental and two control groups of adult rats. Each experimental group underwent the protocol of NHBD lung harvesting. The lungs were than perfused in an ex vivo model and we measured weight gain, arterial-venous difference in partial pressure of oxygen and perfusion pressure. We observed that hypercapnic ventilation during reperfusion reduces the development of pulmonary oedema and has a protective effect on the oxygen transport ability of the lungs after warm ischemia. The effect of CO2 on pulmonary oedema and on oxygen transport ability after warm ischemia could be of clinical importance for NHBD transplantation. PMID- 25450118 TI - Antihyperalgesic effect of 5-HT7 receptor activation on the midbrain periaqueductal gray in a rat model of neuropathic pain. AB - The 5-HT7 receptor is the most recently discovered receptor for 5 hydroxytryptamine (5-HT), and only little is known about the analgesic potential of this receptor. Adenosine triphosphate (ATP) modulates pain transmission by activating P2X/P2Y receptors, in which the P2X3 subtype is an important target for this effect. This study examined the antihyperalgesic effect of the 5-HT7 receptors in the ventrolateral midbrain periaqueductal gray (vlPAG), a crucial site for endogenous pain inhibition. This study also explored the importance of the interactions between the 5-HT7 and P2X3 receptors in this effect. To address this issue, neuropathic pain was induced through chronic constriction injury (CCI) of the sciatic nerve in Sprague-Dawley (SD) rats. The expression level and distribution of the 5-HT7 receptor were evaluated through Western blot and immunohistochemistry. The mechanical withdrawal threshold (MWT) was measured by using an electronic pressure meter test. Different doses (3, 6, and 12MUmol) of AS-19, a selective agonist of the 5-HT7 receptor, were administered in the vlPAG of CCI rats. The effects of pretreatment with the selective 5-HT7 receptor antagonist SB-269970 or the selective P2X3 receptor antagonist A-317491 on the analgesic effect of AS-19 were observed. Results showed that CCI decreased the MWT values of the rats. The injury also increased the protein level of the 5-HT7 receptor in the vlPAG of neuropathic pain rats. AS-19 microinjection significantly elevated the MWT values in a dose-dependent manner, but SB-269970 pretreatment attenuated the antihyperalgesic effect of AS-19. Furthermore, the antihyperalgesic effect of the 5-HT7 receptor was partially but significantly blocked by A-317491 pretreatment. These data indicate that the 5-HT7 receptor in the vlPAG exerts an antihyperalgesic effect on rats with neuropathic pain. The 5 HT7 and P2X3 receptors interact in the vlPAG and exhibit an analgesic action through the enhanced function of the endogenous analgesic system. PMID- 25450119 TI - Atomoxetine reduces hyperactive/impulsive behaviours in neurokinin-1 receptor 'knockout' mice. AB - BACKGROUND: Mice with functional ablation of the neurokinin-1 receptor gene (NK1R(-/-)) display behavioural abnormalities which resemble the hyperactivity, inattention and impulsivity seen in Attention Deficit Hyperactivity Disorder (ADHD). Here, we investigated whether the established ADHD treatment, atomoxetine, alleviates these abnormalities when tested in the light/dark exploration box (LDEB) and 5-Choice Serial Reaction-Time Task (5-CSRTT). METHODS: Separate cohorts of mice were tested in the 5-CSRTT and LDEB after treatment with no injection, vehicle or atomoxetine (5-CSRTT: 0.3, 3 or 10mg/kg; LDEB: 1, 3 or 10mg/kg). RESULTS: Atomoxetine reduced the hyperactivity displayed by NK1R(-/-) mice in the LDEB at a dose (3mg/kg) which did not affect the locomotor activity of wildtypes. Atomoxetine (10mg/kg) also reduced impulsivity in NK1R(-/-) mice, but not wildtypes, in the 5-CSRTT. No dose of drug affected attention in either genotype. CONCLUSIONS: This evidence that atomoxetine reduces hyperactive/impulsive behaviours in NK1R(-/-) mice consolidates the validity of using NK1R(-/-) mice in research of the aetiology and treatment of ADHD. PMID- 25450120 TI - Effect of scapular stabilization during horizontal adduction stretching on passive internal rotation and posterior shoulder tightness in young women volleyball athletes: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of scapular stabilization during horizontal adduction stretching (cross-body) on posterior shoulder tightness (PST) and passive internal rotation (IR). DESIGN: Randomized controlled trial with single blinding. SETTING: Athletic club. PARTICIPANTS: Asymptomatic volleyball players who are women with glenohumeral internal rotation deficit (N=60). INTERVENTIONS: Subjects were randomly assigned to either horizontal adduction stretching with manual scapular stabilization (n=30) or horizontal adduction stretching without stabilization (n=30). Passive stretching was performed for 3- to 30-second holds in both groups. MAIN OUTCOME MEASURES: Range of motion measurements of PST and IR were performed on the athlete's dominant shoulder prior to and immediately after the intervention. RESULTS: Baseline mean angular measurements of PST and IR for all athletes involved in the study were 62 degrees +/-14 degrees and 40 degrees +/-10 degrees , respectively, with no significant difference between groups (P=.598 and P=.734, respectively). Mean PST measurements were significantly different between groups after the horizontal adduction stretch, with a mean angle of 83 degrees +/-17 degrees among the scapular stabilization group and 65 degrees +/-13 degrees among the nonstabilization group (P<.001). Measurements of IR were also significantly different between groups, with a mean angle of 51 degrees +/-14 degrees among the scapular stabilization group and 43 degrees +/-9 degrees among the nonstabilization group (P=.006). CONCLUSIONS: Horizontal adduction stretches performed with scapular stabilization produced significantly greater improvements in IR and PST than horizontal adduction stretching without scapular stabilization. PMID- 25450117 TI - Ro 04-6790-induced cognitive enhancement: no effect in trace conditioning and novel object recognition procedures in adult male Wistar rats. AB - The evidence for cognitively enhancing effects of 5-hydroxytryptamine6 (5-HT6) receptor antagonists such as Ro 04-6790 is inconsistent and seems to depend on the behavioral test variant in use. Trace conditioning holds promise as a behavioral assay for hippocampus-dependent working memory function. Accordingly, Experiment 1 assessed the effect of Ro 04-6790 (5 and 10mg/kg i.p.) on associating a noise conditioned stimulus paired with foot shock (unconditioned stimulus) at a 3 or 30s trace interval in adult male Wistar rats. Contextual conditioning was measured as suppression to the contextual cues provided by the experimental chambers and as suppression to a temporally extended light background stimulus which provided an experimental context. Experiment 2 assessed the effect of Ro 04-6790 (5 and 10mg/kg i.p.) on recognition memory as tested by the exploration of novel relative to familiar objects in an open arena. In Experiment 1, Ro 04-6790 (5 and 10mg/kg) was without effect on trace and contextual conditioning. In Experiment 2, there was no indication of the expected improvement under Ro 04-6790 at the same doses previously found to enhance recognition memory as measured in tests of novel object exploration. Thus, there was no evidence that treatment with the 5-HT6 receptor antagonist Ro 04-6790 acted as a cognitive enhancer in either trace conditioning or object recognition procedures. We cannot exclude the possibility that the experimental procedures used in the present study would have been sensitive to the cognitive enhancing effects of Ro 04-6790 in a different dose range, behavioral test variant, or in a different strain of rat. Nonetheless the drug treatment was not ineffective in that object exploration was reduced under 10mg/kg Ro 04-6790. PMID- 25450121 TI - Effect of mental health on long-term disability after a road traffic crash: results from the UQ SuPPORT study. AB - OBJECTIVE: To investigate the relation between mental health and disability after a road traffic crash (RTC) up to 24 months for claimants with predominantly minor injuries in an Australian sample. DESIGN: Longitudinal cohort study with survey and telephone interview data collected at approximately 6, 12, and 24 months post RTC. SETTING: Not applicable. PARTICIPANTS: Claimants (N=382) within a common law, fault-based compulsory third-party motor accident insurance scheme in Queensland, Australia, consented to participate when invited and were approached at each wave. Retention was high (65%) at 2-year follow-up. Disability scores from at least 1 wave were known for 363 participants, with the mean age of participants being 48.4 years and 62% being women. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Self-reported disability (via the World Health Organization Disability Assessment Schedule 2). RESULTS: Participants reported higher disability (mean, 10.9+/-9.3) compared with the Australian norms (mean, 3.1+/ 5.3). A multilevel regression analysis found that predictors of disability included present diagnosis of posttraumatic stress disorder (PTSD), anxiety, or depression, mental health history, perceived threat to life, and pain. PTSD moderated the relation between age and disability such that older age predicted higher disability in the PTSD group only, whereas anxiety moderated the relation between expectation to return to work and disability such that those with low expectations and anxiety reported significantly higher disability. CONCLUSIONS: Claimants with predominantly minor physical injuries report high disability, particularly when comorbid psychiatric disorders are present, pain is high, and expectations regarding return to work are low. Developing tools for detecting those at risk of poor recovery after an RTC is necessary for informing policy and practice in injury management and postinjury rehabilitation. PMID- 25450122 TI - Preliminary evidence to support a "boot camp" approach to wheelchair skills training for clinicians. AB - OBJECTIVE: To evaluate the impact of providing intensive large-group training on wheelchair-specific self-efficacy and skill capacity among occupational therapy students. DESIGN: Intervention study using before-after trial. SETTING: Universities. PARTICIPANTS: Volunteer sample of master of occupational therapy students (N=65). INTERVENTIONS: Two instructors provided a total of 4.5 hours of wheelchair skills training to groups of 14 to 19 students in a boot camp format, which included a brief lecture, instruction, demonstration, and hands-on practice. MAIN OUTCOME MEASURES: Wheelchair skill capacity (Wheelchair Skills Test Questionnaire [WST-Q]), with scores ranging from 0 to 64, and wheelchair specific self-efficacy (Wheelchair Use Confidence Scale for Manual Wheelchair Users [WheelCon-M]), with scores ranging from 0 to 10. RESULTS: At postintervention, the mean WST-Q score increased by 24.7 (95% confidence interval, 22.1-27.3; P=.000), reflecting a 38.6% improvement (Cohen d=2.8). The mean WheelCon-M score improved by 3.0 (95% confidence interval, 2.5-3.3; P=.000). CONCLUSIONS: To our knowledge, this is the first study to measure and demonstrate improvement in wheelchair-specific self-efficacy among student clinicians. Participants demonstrated substantively larger improvements and acquired more advanced skills than previous studies using shorter training sessions with smaller groups. This study provides evidence for using a boot camp format as an effective strategy to increase occupational therapy students' confidence and skill with wheelchair mobility, preparing them to place greater emphasis on, and achieve better success in, training future clients. PMID- 25450124 TI - Differences in quality of life outcomes among depressed spinal cord injury trial participants. AB - OBJECTIVE: To assess the role that treatment response plays in a randomized controlled trial of an antidepressant among people with spinal cord injury (SCI) diagnosed with major depressive disorder (MDD) in explaining quality of life (QOL), assessed both globally as life satisfaction and in terms of physical and mental health-related QOL. DESIGN: Multivariable analyses were conducted, controlling for demographic, neurologic, and participatory factors and perceived functional limitations. SETTING: Rehabilitation centers. PARTICIPANTS: Of the 133 persons who were randomized into the Project to Improve Symptoms and Mood after Spinal Cord Injury randomized controlled trial, 124 participated in this study. All participants were between the ages of 18 and 64 years, at least 1 month post SCI, met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for MDD, and completed the core measures used in this study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The Satisfaction with Life Scale and the physical and mental component summary scores of the Medical Outcomes Study 12-Item Short-Form Health Survey. RESULTS: Reduction in depressive symptoms over the course of a 12-week trial was predictive of increased QOL, which was measured as life satisfaction and mental well-being, within the context of other explanatory factors. However, reduction in symptoms did not explain differences in physical well-being among those with MDD. Perceived functional disability explained all 3 indices of QOL. CONCLUSIONS: Greater recognition has been given to QOL outcomes as endpoints of clinical trials because these often reflect participants' reported outcomes. Our findings support the association of QOL to the reduction of depression symptoms among trial participants. This association differs depending on how QOL is defined and measured, with stronger relations observed with life satisfaction and mental well-being among those diagnosed with MDD. The lack of association between depression and physical well being may be explained by participants' subjective interpretation of physical well-being after SCI and their expectations and perceptions of improved physical health-related QOL based on the use of assistive technology. Consistent with our findings, pain is likely to play a role in decreasing physical QOL among those with incomplete injuries. Practicing caution is suggested in using physical well being as an endpoint in trials among people with SCI. PMID- 25450123 TI - Efficacy of progressive muscle relaxation, mental imagery, and phantom exercise training on phantom limb: a randomized controlled trial. AB - OBJECTIVE: To evaluate the reduction in phantom pain and sensation with combined training of progressive muscle relaxation, mental imagery, and phantom exercises. DESIGN: Randomized controlled prospective trial with 2 parallel groups. SETTING: Amputee unit of a rehabilitation hospital. PARTICIPANTS: Subjects with unilateral lower limb amputation (N=51) with phantom limb pain (PLP) and/or phantom limb sensation (PLS). INTERVENTIONS: The experimental group performed combined training of progressive muscle relaxation, mental imagery, and phantom exercises 2 times/wk for 4 weeks, whereas the control group had the same amount of physical therapy dedicated to the residual limb. No pharmacological intervention was initiated during the trial period. MAIN OUTCOME MEASURES: The Prosthesis Evaluation Questionnaire and the Brief Pain Inventory were used to evaluate changes over time in different aspects (intensity, rate, duration, and bother) of PLS and PLP. Blind evaluations were performed before and after treatment and after 1-month follow-up. RESULTS: The experimental group showed a significant decrease over time in all the Prosthesis Evaluation Questionnaire domains (in terms of both PLS and PLP; P<.04 for both) and the Brief Pain Inventory (P<.03). No statistically significant changes were observed in the control group. Between group analyses showed a significant reduction in intensity (average and worst pain) and bother of PLP and rate and bother of PLS at follow-up evaluation, 1 month after the end of the treatment. CONCLUSIONS: Combined training of progressive muscle relaxation, mental imagery, and modified phantom exercises should be taken into account as a valuable technique to reduce phantom limb pain and sensation. PMID- 25450125 TI - Postural control in response to altered sensory conditions in persons with dysvascular and traumatic transtibial amputation. AB - OBJECTIVE: To compare the postural control of persons with a dysvascular transtibial amputation and traumatic transtibial amputation with able-bodied adults with and without a dysvascular condition in altered sensory testing conditions. DESIGN: Cross-sectional study. SETTING: University balance clinic. PARTICIPANTS: The study participants (N=35) included: participants with a dysvascular transtibial amputation (n=9), participants with a traumatic transtibial amputation (n=9), age-matched able-bodied adults without a dysvascular condition (n=9), and able-bodied adults with a dysvascular condition (n=8). INTERVENTIONS: Six Sensory Organization Test (SOT) conditions, which included standing with eyes open (condition 1) and closed (condition 2) on a static force platform with visual surround; standing with eyes open on a static force platform with movable visual surround (condition 3); standing with eyes open (condition 4) and closed (condition 5) on a movable force platform with static visual surround; and standing with eyes open on a movable force platform with movable visual surround (condition 6). MAIN OUTCOME MEASURES: Bilateral anteroposterior (AP) and mediolateral (ML) center of pressure variables, namely root mean square distance (RMSD) and mean velocity (mVel), for each of the 6 SOT conditions. RESULTS: The dysvascular transtibial amputation group demonstrated a higher AP RMSD (P<=.04) on the sound side than did the able-bodied adults without a dysvascular condition and the able-bodied adults with a dysvascular condition in SOT conditions 1 and 2, respectively. Both the dysvascular transtibial amputation group and the traumatic transtibial amputation group demonstrated a higher AP RMSD (P<=.002) than the able-bodied adults without a dysvascular condition in SOT conditions 3 and 4. The dysvascular transtibial amputation group showed higher AP mVel (P<=.002) on the sound side for SOT conditions 2 and 3, whereas both amputation groups showed higher AP mVel for SOT conditions 1 and 4 than the able-bodied adults with and without a dysvascular condition. CONCLUSIONS: Postural control of the dysvascular transtibial amputation group was not different than the traumatic transtibial amputation group in challenging sensory conditions. However, when compared with the groups of able-bodied adults with and without a dysvascular condition, postural strategies distinct with amputation etiology were observed. PMID- 25450126 TI - Pressure changes under the ischial tuberosities during gluteal neuromuscular stimulation in spinal cord injury: a comparison of sacral nerve root stimulation with surface functional electrical stimulation. AB - OBJECTIVE: To compare the magnitude of interface pressure changes during gluteal maximus contraction by stimulating sacral nerve roots with surface electrical stimulations in patients with spinal cord injuries (SCIs). DESIGN: Pilot interventional study. SETTING: Spinal injury research laboratory. PARTICIPANTS: Adults (N=18) with suprasacral complete SCI. INTERVENTIONS: Sacral nerve root stimulation (SNRS) via a functional magnetic stimulator (FMS) or a sacral anterior root stimulator (SARS) implant; and surface functional electrical stimulation (FES). MAIN OUTCOME MEASURES: Interface pressure under the ischial tuberosity (IT) defined as peak pressure, gradient at peak pressure, and average pressure. RESULTS: With optimal FMS, a 29% average reduction of IT peak pressure was achieved during FMS (mean +/- SD: 160.1+/-24.3mmHg at rest vs 114.7+/ 18.0mmHg during FMS, t5=6.3, P=.002). A 30% average reduction of peak pressure during stimulation via an SARS implant (143.2+/-31.7mmHg at rest vs 98.5+/ 21.5mmHg during SARS, t5=4.4, P=.007) and a 22% average decrease of IT peak pressure during FES stimulation (153.7+/-34.8mmHg at rest vs 120.5+/-26.1mmHg during FES, t5=5.3, P=.003) were obtained. In 4 participants who completed both the FMS and FES studies, the percentage of peak pressure reduction with FMS was slightly greater than with FES (mean difference, 7.8%; 95% confidence interval, 1.6%-14.0; P=.04). CONCLUSIONS: SNRS or surface FES can induce sufficient gluteus maximus contraction and significantly reduce ischial pressure. SNRS via an SARS implant may be more convenient and efficient for frequently activating the gluteus maximus. PMID- 25450128 TI - Biomechanical and clinical correlates of swing-phase knee flexion in individuals with spastic cerebral palsy who walk with flexed-knee gait. AB - OBJECTIVE: To identify clinical and biomechanical parameters that influence swing phase knee flexion and contribute to stiff-knee gait in individuals with spastic cerebral palsy (CP) and flexed-knee gait. DESIGN: Retrospective analysis of clinical data and gait kinematics collected from 2010 to 2013. SETTING: Motion and gait analysis laboratory at a children's hospital. PARTICIPANTS: Individuals with spastic CP (N=34; 20 boys, 14 girls; mean age +/- SD, 10.1+/-4.1y [range, 5 20y]; Gross Motor Function Classification System I-III) who walked with flexed knee gait >=20 degrees at initial contact and had no prior surgery were included; the more-involved limb was analyzed. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The magnitude and timing of peak knee flexion (PKF) during swing were analyzed with respect to clinical data, including passive range of motion and Selective Control Assessment of the Lower Extremity, and biomechanical data, including joint kinematics and hamstring, rectus femoris, and gastrocnemius muscle-tendon length during gait. RESULTS: Data from participants demonstrated that achieving a higher magnitude of PKF during swing correlated with a higher maximum knee flexion velocity in swing (rho=.582, P<0.001) and a longer maximum length of the rectus femoris (rho=.491, P=.003). In contrast, attaining earlier timing of PKF during swing correlated with a higher knee flexion velocity at toe off (rho=-.576, P<.001), a longer maximum length of the gastrocnemius (rho=-.355, P=.039), and a greater peak knee extension during single-limb support phase (rho= .354, P=.040). CONCLUSIONS: Results indicate that the magnitude and timing of PKF during swing were independent, and their biomechanical correlates differed, suggesting important treatment implications for both stiff-knee and flexed-knee gait. PMID- 25450127 TI - Validity of physical activity measures in individuals after total knee arthroplasty. AB - OBJECTIVE: To determine the concurrent criterion-related validity of 2 activity monitors in comparison with the criterion method of indirect calorimetry in older adults after total knee arthroplasty (TKA). DESIGN: Validation study. SETTING: Subjects completed 9 increasingly demanding daily activities in a research laboratory; each activity was performed for 7 minutes, for a total of 80 minutes, while the activity monitors and criterion method were used concurrently. PARTICIPANTS: Subjects (N=21, 67% women) had a mean age +/- SD of 68+/-7 years and a body mass index of 29+/-4. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Energy expenditure (in kcal/min) measured by accelerometer-based and multisensor-based monitors and by a criterion method. Validity was assessed by the paired t test, intraclass correlation coefficient (ICC), and Bland-Altman plots comparing the measurements from the activity monitors with those of the criterion method. RESULTS: Measurements from the accelerometer-based monitor were significantly lower than those of the criterion method across all walking and nonwalking activities. The underestimations ranged from 40% to 100%. The accelerometer-based monitor demonstrated small to moderate agreement compared with the criterion method (ICCs from 0 to .38). Measurements from the multisensor based monitor were significantly lower than those of the criterion method during several nonwalking activities; yet, the differences were minor (2%-19%). Measurements from the multisensor-based monitor during walking activities were not different compared with the criterion method. The multisensor-based monitor demonstrated moderate to excellent agreement with the criterion method (ICCs from .48 to .81). CONCLUSIONS: The multisensor-based monitor showed better criterion related validity than the accelerometer-based monitor and should be considered as a tool to measure physical activity in individuals after TKA. PMID- 25450129 TI - Rehabilitation program after mesenchymal stromal cell transplantation augmented by vascularized bone grafts for idiopathic osteonecrosis of the femoral head: a preliminary study. AB - OBJECTIVE: To determine the feasibility and safety of implementing a 12-week rehabilitation program after mesenchymal stromal cell (MSC) transplantation augmented by vascularized bone grafting for idiopathic osteonecrosis (ION) of the femoral head. DESIGN: A prospective case series. SETTING: University clinical research laboratory. PARTICIPANTS: Participants (N=10) with ION who received MSC transplantation augmented by vascularized bone grafting. INTERVENTION: A 12-week exercise program, which included range-of-motion (ROM) exercises, muscle strengthening exercises, and aerobic training. MAIN OUTCOME MEASURES: Measures of ROM, muscle strength, Timed Up and Go test, and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) were collected before surgery and again at 6 and 12 months after surgery. RESULTS: All participants completed the 12-week program. External rotation ROM as well as extensor and abductor muscle strength significantly improved 6 months after treatment compared with that before treatment (P<.05). Significant improvements were also seen in physical function, role physical, and bodily pain subgroup scores of the SF-36 (P<.05). No serious adverse events occurred. CONCLUSIONS: This study demonstrates the feasibility and safety of a multiplex rehabilitation program after MSC transplantation and provides support for further study on the benefits of rehabilitation programs in regenerative medicine. PMID- 25450107 TI - The mediational effects of FDG hypometabolism on the association between cerebrospinal fluid biomarkers and neurocognitive function. AB - Positive cerebrospinal fluid (CSF) biomarkers of tau and amyloid beta42 suggest possible active underlying Alzheimer's disease (AD) including neurometabolic dysfunction and neurodegeneration leading to eventual cognitive decline. But the temporal relationship between CSF, imaging markers of neural function, and cognition has not been described. Using a statistical mediation model, we examined relationships between cerebrospinal fluid (CSF) analytes (hyperphosphorylated tau (p-Tau(181p)), beta-amyloid peptides 1-42 (Abeta(1-42)), total tau (t-Tau), and their ratios); change in cognitive function; and change in [18F]fluorodeoxyglucose (FDG) uptake using positron emission tomography (PET). We hypothesized that a) abnormal CSF protein values at baseline, result in cognitive declines by decreasing neuronal glucose metabolism across time, and b) the role of altered glucose metabolism in the assumed causal chain varies by brain region and the nature of CSF protein alteration. Data from 412 individuals participating in Alzheimer's Disease Neuroimaging (ADNI) cohort studies were included in analyses. At baseline, individuals were cognitively normal (N = 82), or impaired: 241 with mild cognitive impairment, and 89 with Alzheimer's disease. A parallel process latent growth curve model was used to test mediational effects of changes in regional FDG-PET uptake over time in relation to baseline CSF biomarkers and changes in cognition, measured with the 13-item Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-Cog). Findings suggested a causal sequence of events; specifically, FDG hypometabolism acted as a mediator between antecedent CSF biomarker alterations and subsequent cognitive impairment. Higher baseline concentrations of t-Tau, and p-Tau(181p) were more predictive of decline in cerebral glucose metabolism than lower baseline concentrations of Abeta(1-42). FDG-PET changes appeared to mediate t-Tau or t-Tau/Abeta(1-42)-associated cognitive change across all brain regions examined. Significant direct effects of alterations in Abeta(1-42) levels on hypometabolism were observed in a single brain region: middle/inferior temporal gyrus. Results support a temporal framework model in which reduced CSF amyloid-related biomarkers occur earlier in the pathogenic pathway, ultimately leading to detrimental cognitive effects. Also consistent with this temporal framework model, baseline markers of neurofibrillary degeneration predicted changes in brain glucose metabolism in turn causing longitudinal cognitive changes, suggesting that tau-related burden precedes neurometabolic dysfunction. While intriguing, the hypothesized mediational relationships require further validation. PMID- 25450130 TI - Pilot study: evaluation of the effect of functional electrical stimulation cycling on muscle metabolism in nonambulatory people with multiple sclerosis. AB - OBJECTIVE: To investigate the changes in muscle oxygen consumption (mVO2) using near-infrared spectroscopy (NIRS) after 4 weeks of training with functional electrical stimulation (FES) cycling in nonambulatory people with multiple sclerosis (MS). DESIGN: Four-week before-after trial to assess changes in mVO2 after an FES cycling intervention. SETTING: Rehabilitation hospital. PARTICIPANTS: People (N=8; 7 men, 1 women) from a volunteer/referred sample with moderate to severe MS (Expanded Disability Status Scale score>6.0). INTERVENTION: Participants cycled 30 minutes per session, 3d/wk for 4 weeks or a total of 12 sessions. MAIN OUTCOME MEASURES: mVO2 of the right vastus lateralis muscle was measured with NIRS before and within 1 week after the intervention. Six bouts of 15-second electrical stimulation increasing from 2 to 7Hz were used to activate the muscle. mVO2 was assessed by analyzing the slope of the NIRS oxygen signal during a 10-second arterial occlusion after each electrical stimulation bout. RESULTS: Significant FES training by electrical stimulation frequency level interaction was observed (P=.031), with an average increase in mVO2 of 47% across frequencies with a main effect of training (P=.047). CONCLUSIONS: FES cycling for 4 weeks improved mVO2, suggesting that FES cycling is a potential therapy for improving muscle health in people with MS who are nonambulatory. PMID- 25450131 TI - Acute effects of multipath electrical stimulation in patients with total knee arthroplasty. AB - OBJECTIVE: To compare maximal evoked torque, discomfort, and fatigue-related outcomes between multipath neuromuscular electrical stimulation (NMES) and conventional NMES of the quadriceps muscle in patients with total knee arthroplasty (TKA). DESIGN: Randomized, single-blind, crossover study with 2 experimental sessions (multipath NMES, conventional NMES). SETTING: Research laboratory. PARTICIPANTS: Patients (N=20; mean age, 68y) 6 to 12 months after TKA surgery. INTERVENTIONS: None. MAIN OUTCOME MEASURES: We quantified NMES-evoked knee extension torque at the maximally tolerated current intensity, self-reported discomfort, and fatigue induced by NMES intermittent contractions in both conditions. RESULTS: Compared with conventional NMES, multipath NMES resulted in higher evoked torque (33%, P<.001), lower discomfort scores (-39%, P<.001), and less quadriceps muscle fatigue (P=.034). CONCLUSIONS: The use of multiple current pathways distributed to large electrodes allowed multipath NMES to generate stronger contractions and reduce discomfort and fatigue compared with conventional NMES. Therefore, multipath NMES has the potential to be more effective than conventional NMES. PMID- 25450132 TI - Treatment of detrusor external sphincter dyssynergia using ultrasound-guided trocar catheter transurethral botulinum toxin a injection in men with spinal cord injury. AB - OBJECTIVE: To evaluate the effects of transrectal ultrasound-guided trocar catheter transurethral botulinum toxin A (BTX-A) injection into the external urethral sphincter (EUS) for treating detrusor external sphincter dyssynergia (DESD) in men with spinal cord injury (SCI). DESIGN: Descriptive study. SETTING: Hospital rehabilitation department. PARTICIPANTS: Patients (N=15; mean age, 40.5y; range, 22-64y) with suprasacral SCI with confirmed DESD determined by urodynamic study. INTERVENTIONS: A single dose of 100U BTX-A was injected into the EUS via transrectal ultrasound-guided trocar catheter transurethral injection. MAIN OUTCOME MEASURES: Maximal detrusor pressure, detrusor leak point pressure, maximal pressure on static urethral pressure profilometry, postvoid residual volume, and maximal flow rate. RESULTS: After BTX-A transurethral injection, 4 (28.5%) patients showed an excellent result and 7 (46.7%) patients showed an improved result, whereas 4 (28.5%) patients experienced treatment failure. The overall success rate was 75.2%. We observed a significant decrease in static urethral pressure (P<.05) and detrusor leak point pressure after treatment (P<.05), but not in detrusor pressure. The postvoid residual volume were significantly decreased in the fourth week after treatment (P<.05). CONCLUSIONS: Transrectal ultrasound-guided trocar catheter transurethral BTX-A injection into the EUS effectively suppresses or ameliorates DESD. A potential advantage of the method is that ultrasound guidance may not be necessary in the next injection. PMID- 25450134 TI - Computer-assisted training as a complement in rehabilitation of patients with chronic vestibular dizziness--a randomized controlled trial. AB - OBJECTIVE: To compare a computer-assisted home exercise program with conservative home-training following printed instructions in the rehabilitation of elderly patients with vestibular dysfunction. DESIGN: Single-blind, randomized, controlled trial. SETTING: Geriatric department of a university hospital. PARTICIPANTS: Patients with chronic dizziness due to vestibular dysfunction (N=63) were randomly assigned to either rehabilitation in the clinic followed by computer-assisted home exercises (intervention group: n=32) or rehabilitation in the clinic followed by home exercises according to printed instructions (control group: n=31). INTERVENTIONS: Patients in the intervention group received assisted rehabilitation by a computer program. MAIN OUTCOME MEASURES: Measurements at baseline and at 8 and 16 weeks were compared. These included the One Leg Stand Test, Dynamic Gait Index, Chair Stand Test, Motion Sensitivity Test, Short Form 12, Dizziness Handicap Inventory, and visual analog scale. RESULTS: Both groups improved significantly during 16 weeks of rehabilitation. However, neither t tests nor repeated-measures analysis of variance demonstrated any significant differences between the 2 groups. The overall compliance rate to computer program exercises during 16 weeks was 57%. CONCLUSIONS: A computer-assisted program to support the home training of elderly patients with vestibular dysfunction did not improve rehabilitation more than did printed instructions. PMID- 25450133 TI - A shoe insole delivering subsensory vibratory noise improves balance and gait in healthy elderly people. AB - OBJECTIVES: To test whether subsensory vibratory noise applied to the sole of the foot using a novel piezoelectric vibratory insole can significantly improve sensation, enhance balance, and reduce gait variability in elderly people, as well as to determine the optimal level of vibratory noise and whether the therapeutic effect would endure and the user's sensory threshold would remain constant during the course of a day. DESIGN: A randomized, single-blind, crossover study of 3 subsensory noise stimulation levels on 3 days. SETTING: Balance and gait laboratory. PARTICIPANTS: Healthy community-dwelling elderly volunteers (N=12; age, 65-90y) who could feel the maximum insole vibration. INTERVENTIONS: A urethane foam insole with the piezoelectric actuators delivering subsensory vibratory noise stimulation to the soles of the feet. MAIN OUTCOME MEASURES: Balance, gait, and timed Up and Go (TUG) test. RESULTS: The vibratory insoles significantly improved performance on the TUG test, reduced the area of postural sway, and reduced the temporal variability of walking at both 70% and 85% of the sensory threshold and during the course of a day. Vibratory sensation thresholds remained relatively stable within and across study days. CONCLUSIONS: This study provides proof of concept that the application of the principle of stochastic resonance to the foot sole sensory system using a new low-voltage piezoelectric technology can improve measures of balance and gait that are associated with falls. Effective vibratory noise amplitudes range from 70% to 85% of the sensory threshold and can be set once daily. PMID- 25450135 TI - Two-minute walk test performance by adults 18 to 85 years: normative values, reliability, and responsiveness. AB - OBJECTIVES: To provide (1) normative reference values for the 2-minute walk test (2MWT), (2) reference equations for the 2MWT, and (3) information on the reliability and responsiveness of the 2MWT across the adult lifespan. DESIGN: Cross-sectional study. SETTING: General community settings. PARTICIPANTS: A population-based sample of adult participants (N=1137) contributed data to this study, which was part of the National Institutes of Health (NIH) Toolbox for the Assessment of Neurological and Behavioral Function Norming Project. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: 2MWT. RESULTS: Overall, the distance participants walked ranged from 64.6 to 300.8m (mean, 180.9m). Men walked farther than did women (189.4m vs 176.0m; t=6.8; df=1,135; P<.001). Significant correlations were observed between the 2MWT and age (r=-.41), height (r=.29), weight (r=-.16), and body mass index (r=-.32). Age and body mass index were used in the linear regression modeling to predict the 2MWT distance (R(2)=.55-.56). Test-retest reliability of the 2MWT as characterized by the intraclass correlation coefficient was .82 (95% confidence interval, .76-.87). Based on a standard error of measurement of 15.3m, the minimum detectable change for the 2MWT was 42.5m. CONCLUSIONS: The study presents norms of the 2MWT established by the NIH Toolbox. The norms can be used to determine the presence of limitations in walking endurance across the lifespan. PMID- 25450137 TI - Audiovisual congruency and incongruency effects on auditory intensity discrimination. AB - This study used a S1-S2 matching paradigm to investigate the influences of visual (size) change on auditory intensity discrimination. Behavioral results showed that subjects made more errors and spent more time to discriminate change in auditory intensity when it was accompanied by an incongruent visual change, while the performance for congruent audiovisual stimuli was better especially if there is a change in auditory stimuli. Event-related potential difference waves revealed that audiovisual interactions for multimodal mismatched information processing activated the right frontal and left centro-parietal cortices around 300-400 ms post S1-onset. PMID- 25450136 TI - Comparison of self-report sleep measures for individuals with multiple sclerosis and spinal cord injury. AB - OBJECTIVE: To investigate self-report measures of sleep disturbances and sleep related impairments in samples of individuals with multiple sclerosis (MS) or spinal cord injury (SCI). DESIGN: Cross-sectional survey. SETTING: Community based. PARTICIPANTS: Adults (age >=18y) (N=700) with either MS (n=461) or SCI (n=239) who were enrolled in a longitudinal survey of self-reported health outcomes and who completed self-report sleep measures at 1 time point. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Medical Outcomes Study Sleep Scale (MOS-S), Patient Reported Outcomes Measurement Information System (PROMIS) sleep disturbance short form, and PROMIS sleep-related impairments short form. RESULTS: Mean scores on the MOS-S sleep index II were significantly worse for both the MS and SCI samples than those of previously reported samples representative of the U.S. general population (P<.0001 for each group). The PROMIS sleep disturbance short form and PROMIS sleep-related impairments short form scores of the MS sample were also significantly different from those reported for the calibration cohort (P<.0001 on each scale). However, although the scores of the SCI sample were significantly different from those of the comparison cohort for the PROMIS sleep-related impairments short form (P=.045), the differences on the PROMIS sleep disturbance short form were not significant (P=.069). CONCLUSIONS: Although the MOS-S scores for the MS and SCI cohorts clearly indicated significantly high levels of sleep-related problems and were consistent with existing literature, the more ambiguous findings from the PROMIS sleep disturbance short form and PROMIS sleep-related impairments short form suggest that not enough is currently known about how these instruments function when applied to those with chronic neurologic dysfunction. PMID- 25450138 TI - Intraplantar injection of tetrahydrobiopterin induces nociception in mice. AB - Tetrahydrobiopterin (BH4) is implicated in the development and maintenance of chronic pain. After injury/inflammation, the biosynthesis of BH4 is markedly increased in sensory neurons, and the pharmacological and genetic inhibition of BH4 shows analgesic effects in pre-clinical animal pain models. Intrathecal injections of BH4 have been shown to induce and enhance pain-like behaviours in rats, suggesting that under chronic pain conditions BH4 may act by facilitating central sensitisation. So far it is unknown whether BH4 acts on peripheral sites of the somatosensory system or whether BH4 per se provokes nociceptive pain behaviours. The purpose of this study was therefore to investigate the acute nociceptive effects of intraplantar injection of BH4. BH4 was found to induce dose-dependent licking/biting of the paw lasting 5 min, which was not observed following an injection of biopterin (inactive BH4 metabolite). Paw swelling, measured as paw thickness and weight, was not observed after BH4 injection. To explore possible mechanisms of action of BH4, the effect of local pre-treatment with indomethacin, Nomega-nitro-L-arginine methyl ester, Nomega-nitro-L-arginine, capsazepine and ruthenium red was tested. Morphine served as a positive control. Intraplantar pre-injection of morphine dose-dependently inhibited BH4-induced nociception, while none of the other compounds showed any statistical significant antinociception. These results suggest that BH4 exhibits nociceptive properties at peripheral sites of the somatosensory system, proposing an as yet unexplored involvement of BH4 in peripheral nociceptive processes. However, this appears not to be mediated through nitric oxide and prostaglandin release or by activation of the transient receptor potential vanilloid 1. PMID- 25450140 TI - Ca2+ imaging of cricket protocerebrum responses to air current stimulation. AB - Crickets (Gryllus bimaculatus) use the cercal sensory system at the rear of the abdomen to detect air currents and direct predator avoidance behavior. Sensory information regarding the direction and dynamic properties of air currents is processed within the terminal abdominal ganglion, and conveyed by ascending giant interneurons (GIs) to higher centers including the brain. However, the brain region responsible for decoding cercal sensory information has not yet been identified, nor the response properties within the brain characterized. In this study, we performed in vivo Ca(2+) imaging to investigate wind-evoked neural activities within the cricket protocerebrum. Ca(2+) responses to air current stimuli were observed at peripheral regions of the ventrolateral neuropile (VLNP) where projection of GIs' axon terminals has been observed in larvae. The wind evoked Ca(2+) response had temporal dynamics and directional sensitivity that varied with different recorded regions displaying transient or sustained Ca(2+) increases. Individual cells showed Ca(2+) elevation in response to air currents from a specific angle, while stimuli from a different angle evoked decreased signals. Removing the antennae reduced the air-current-evoked responses in VLNP, suggesting contribution of sensory inputs from antennae in addition to the cercal inputs. The VLNP is presumably an integrative center for mechanosensory processing from antennae and cerci where directional information is primarily decoded by protocerebral neurons. PMID- 25450141 TI - Saccadic and smooth pursuit eye movements attenuate postural sway similarly. AB - Saccadic eye movements reduce body sway, yet visually pursuing a moving dot seems to increase body sway. However, how these two types of eye movements affect postural control remains ambiguous, particularly for smooth pursuit eye movements. The aim of this study was to examine the effects of saccade and smooth pursuit eye movements on body sway magnitude during low and high frequencies. Ten young adults (19.5 +/- 1.9 years) participants were required to stand upright, barefoot for 70s using a bipedal stance, with feet hip width apart, fixating or pursuing a target that was displayed on a monitor positioned 100 cm away from their eyes. Each participant performed three trials using both types of eye movements, in particular, slow and fast saccades, and slow and fast smooth pursuit movements. Body sway was obtained using reflective markers attached to a participant's head and trunk, which were recorded by two video cameras. The results indicated that body sway was reduced during both saccadic eye movements and smooth pursuit movements when compared to fixation, independent of visual frequencies. These results suggested similarities in the control of saccades and smooth pursuit on postural control. PMID- 25450139 TI - Preliminary evidence for the interaction of the oxytocin receptor gene (oxtr) and face processing in differentiating prenatal smoking patterns. AB - Prenatal smoking cessation has been described as an empathic action "for the baby," but this has not been empirically demonstrated. We capitalized on a genetically-characterized extant dataset with outstanding measurement of prenatal smoking patterns and maternal face processing data (as an indicator of empathy) to test this hypothesis, and explore how empathy and smoking patterns may be moderated by a genetic substrate of empathy, the oxytocin receptor gene (OXTR). Participants were 143 Caucasian women from the East Boston family study with repeated prospective reports of smoking level, adjusted based on repeated cotinine bioassays. Salivary DNA and face processing (Diagnostic Analysis of Nonverbal Accuracy-2) were assessed 14 years later at an adolescent follow-up of offspring. Two-thirds of participants reported smoking prior to pregnancy recognition. Of these, 21% quit during pregnancy; 56% reduced smoking, and 22% smoked persistently at the same level. A significant interaction between face processing and OXTR variants previously associated with increased sensitivity to social context, rs53576GG and rs2254298A, was found (beta = -.181; p = .015); greater ability to identify distress in others was associated with lower levels of smoking during pregnancy for rs53576(GG)/rs2254298(A) individuals (p = .013), but not for other genotypes (p = .892). Testing this "empathy hypothesis of prenatal smoking cessation" in larger studies designed to examine this question can elucidate whether interventions to enhance empathy can improve prenatal smoking cessation rates. PMID- 25450142 TI - The utility of susceptibility-weighted imaging for differentiating Parkinsonism predominant multiple system atrophy from Parkinson's disease: correlation with 18F-flurodeoxyglucose positron-emission tomography. AB - Our study was intended to demonstrate the different signal intensity (SI) pattern of the putamen seen on susceptibility-weighted imaging (SWI) between that of Parkinson's disease (PD) and Parkinsonism-predominant multiple system atrophy (MSA-P), and to correlate it with (18)F-flurodeoxyglucose positron-emission tomography ((18)F-FDG PET). Thirty patients with PD and 17 with MSA-P underwent SWI, and (18)F-FDG PET were included. The SI was measured on SWI in the anterior and posterior halves of the putamen using a region-of-interest (ROI) on both sides. The normalized regional glucose metabolism (standardized uptake value ratio, SUVR) was measured on co-registered (18)F-FDG PET images using the ROI obtained with SWI. Analysis included a group-level comparison of the SI values obtained on SWI, and these results were correlated with the SUVR on (18)F-FDG PET. The SIs of the bilateral posterior, dominant-side of the posterior, mean values of the bilateral anterior and posterior halves of the putamen on SWI, differed significantly between the two groups (P < 0.001, respectively). The SUVR of the all locations also differed significantly between PD and MSA-P (P < 0.001, respectively). There was a moderate degree of positive correlation between the SI and the SUVR of the left posterior half, and mean value of the bilateral posterior putamen in MSA-P (r = 0.634, P = 0.006, r = 0.492, P = 0.045). In conclusion, the low SI seen on the posterior putamen may differentiate MSA-P from PD. Furthermore, low SI in the putamen correlated with hypometabolism on (18)F FDG PET. Therefore, SWI could be a potential complementary diagnostic tool to (18)F-FDG PET for differentiating these conditions. PMID- 25450143 TI - Decrease of neocortical paired-pulse depression in GAERS and possible implication of gap junctions. AB - Thalamocortical slices are widely used to study thalamocortical relationships and absence epilepsy. However, it is still not known whether (1) intracortical synaptic transmission, in particular neocortical paired-pulse depression (PPD), is maintained in these slices and (2) whether PPD is altered in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS, a model of absence epilepsy for which cortico-thalamic loops are involved). Furthermore, while the involvement of gap junctions (GJ) in the mechanisms leading to epileptiform discharges has been intensively studied, little is known about their effect on intracortical transmission. We first studied intracortical connection efficacy and PPD in thalamocortical slices from GAERS and non-epileptic rats (NER). We then investigated the effects of GJ blockers (carbenoxolone and quinidine) on intracortical response following single or paired-pulse stimulations in coronal slices from Wistar rats. We show that the efficacy of intracortical connections is not impaired in GAERS. We also show that neocortical PPD is preserved in thalamocortical slices of NER, but that its efficacy is strongly decreased in GAERS. Moreover, a NMDA antagonist strongly reduced the PPD in NER but had no effect in GAERS. Cortical responses to white matter stimulation were not modified by quinidine or carbenoxolone in coronal slices of Wistar rats. PPD was recorded in these slices and was decreased by carbenoxolone but not by quinidine. We hypothesize that the decrease of PPD observed in GAERS might be due to a decrease in function of (1) NMDA receptors and/or (2) astrocytic GJ's. PMID- 25450145 TI - Vesicular glutamate transporter 3 is strongly upregulated in cochlear inner hair cells and spiral ganglion cells of developing circling mice. AB - Vesicular glutamate transporter 3 (VGLUT3) plays a major role in hearing, and mice lacking the VGLUT3 are congenitally deaf due to absence of glutamate release at the inner hair cell afferent synapses. However, whether VGLUT3 is expressed normally in the cochleae of developing circling mice (homozygous (cir/cir) mice), the animal model for human deafness type DFNB6, has not been established. In this study, we investigated the developmental expression of VGLUT3 in cochlear inner hair cells (IHCs) and spiral ganglion cells (SGCs) of homozygous (cir/cir) mice from postnatal day (P)1 to P14 using immunofluorescence (IF) staining and Western blot. VGLUT3 immunoreactivity (IR) and protein expression increased progressively with age in homozygous (cir/cir) and control mice (heterozygous (+/cir) mice and ICR mice). The rank order of VGLUT3 IR in IHCs and SGCs in P14 mice was homozygous (cir/cir) mice = heterozygous (+/cir) mice > ICR mice. The rank order of total protein expression was homozygous (cir/cir) mice > heterozygous (+/cir) mice = ICR mice at P14. IF staining and Western blot analysis indicated that developmental VGLUT3 expression in cochleae was most prominent in homozygous (cir/cir) mice. The possible contribution of VGLUT3 upregulation in the cochlear degeneration is discussed. PMID- 25450144 TI - High aggression in rats is associated with elevated stress, anxiety-like behavior, and altered catecholamine content in the brain. AB - The social defeat paradigm involves aggressive encounters between Long-Evans (L E) (resident) and Sprague-Dawley (S-D) (intruder) rats. Successful application of chronic social defeat stress in S-D rats is dependent upon selection of highly aggressive L-E rats. Half of the L-E rats screened for aggression did not meet the criterion for aggression (L-E rats performing a defeat, characterized by the intruder surrendering or acquiring a supine position for at least 3s). The observation of the differences in the level of aggression between age and weight matched L-E rats was quite compelling which led us to the present study. Herein, we measured behavioral differences between aggressor and non-aggressor L-E rats. We analyzed their anxiety-like behavior using open-field and elevated plus maze tests. We also measured aggression/violence-like behavior using two tests. In one, time taken to defeat the intruder S-D rat was recorded. In the second test, time taken to attack a novel object was compared between the two groups. We observed a significant increase in anxiety-like behavior in aggressor rats when compared to the non-aggressive group. Furthermore, time taken to defeat the intruder rat and to attack a novel object was significantly lower in aggressive L E rats. Biochemical data suggests that heightened anxiety-like behavior and aggression is associated with increased plasma levels of corticosterones and elevated oxidative stress. Significant alterations in dopamine (DA), norepinephrine (NE) and epinephrine (EPI) were observed within the hippocampus, amygdala, and the prefrontal cortex, suggesting potential involvement of dopaminergic and noradrenergic systems in regulation of aggressive behaviors. PMID- 25450146 TI - What is the optimal anodal electrode position for inducing corticomotor excitability changes in transcranial direct current stimulation? AB - Transcranial direct current stimulation (tDCS) non-invasively modulates brain function by inducing neuronal excitability. The conventional hot spot for inducing the highest current density in the hand motor area may not be the optimal site for effective stimulation. In this study, we investigated the influence of the center position of the anodal electrode on changes in motor cortical excitability. We considered three tDCS conditions in 16 healthy subjects: (i) real stimulation with the anodal electrode located at the conventional hand motor hot spot determined by motor evoked potentials (MEPs); (ii) real stimulation with the anodal electrode located at the point with the highest current density in the hand motor area as determined by electric current simulation; and (iii) sham stimulation. Motor cortical excitability as measured by MEP amplitude increased after both real stimulation conditions, but not after sham stimulation. Stimulation using the simulation-derived anodal electrode position, which was found to be posterior to the MEP hot spot for all subjects, induced higher motor cortical excitability. Individual positioning of the anodal electrode, based on the consideration of anatomical differences between subjects, appears to be important for maximizing the effects of tDCS. PMID- 25450147 TI - Task-dependent modulation of regions in the left temporal cortex during auditory sentence comprehension. AB - Numerous studies have revealed the essential role of the left lateral temporal cortex in auditory sentence comprehension along with evidence of the functional specialization of the anterior and posterior temporal sub-areas. However, it is unclear whether task demands (e.g., active vs. passive listening) modulate the functional specificity of these sub-areas. In the present functional magnetic resonance imaging (fMRI) study, we addressed this issue by applying both independent component analysis (ICA) and general linear model (GLM) methods. Consistent with previous studies, intelligible sentences elicited greater activity in the left lateral temporal cortex relative to unintelligible sentences. Moreover, responses to intelligibility in the sub-regions were differentially modulated by task demands. While the overall activation patterns of the anterior and posterior superior temporal sulcus and middle temporal gyrus (STS/MTG) were equivalent during both passive and active tasks, a middle portion of the STS/MTG was found to be selectively activated only during the active task under a refined analysis of sub-regional contributions. Our results not only confirm the critical role of the left lateral temporal cortex in auditory sentence comprehension but further demonstrate that task demands modulate functional specialization of the anterior-middle-posterior temporal sub-areas. PMID- 25450148 TI - Light touch and medio-lateral postural stability during short distance gait. AB - While standing, light fingertip touch on an external stable object attenuates sway and improves balance in healthy adults as well as in individuals with poor postural control. The effect of light touch on balance during gait is, however, not well known. Therefore, the purpose of this work was to study the effects of light fingertip touch on balance during gait. We hypothesized that similar to its effect during stance light touch would increase postural stability. Forty healthy young adults were tested under four gait conditions: (1) eyes open (EO), (2) eyes closed (EC), (3) eyes closed while lightly touching a static object on the right side of the walking lane (ECLTS), (4) eyes closed while lightly touching a dynamic object, namely, a stick that was moved forwards by the subject with the right hand (ECLTD). The main outcome measure was medio-lateral step width variability, a well established indicator of gait balance in the medio-lateral plane. During the EC condition, light touch of an external static object (ECLTS) decreased medio-lateral variability (i.e., balance improved); however, this stabilizing effect was not observed with light touch on the stick. The availability of self positional and spatial cues when touching a static external reference, and their absence when touching a stick that is moved forwards by the subject as he walks, can explain the different effects of light touch in the ECLTS vs the ECLTD gait conditions. PMID- 25450149 TI - SORL1 gene polymorphism association with late-onset Alzheimer's disease. AB - We examined the relationship between loci polymorphisms (rs689021, rs3824966, and rs1784933) of the sortilin-related receptor 1 gene (SORL1) and late-onset Alzheimer's disease (LOAD) in the Chinese Han population of the Hunan Changsha region. A case-control association analysis was used. Clinical data and peripheral blood were collected from 201 Alzheimer's disease patients and 257 healthy controls. PCR and MALDI-TOF mass spectrometry detection technologies were used to identify single nucleotide polymorphism (SNP) distribution at SORL1 gene loci. Genotype and allele frequency differences were analyzed and compared between groups. No significant differences were found in genotype frequency distributions of the rs689021 and rs3824966 loci. Similarly, allele frequency distributions of the C and T alleles of rs689021, and the C and G alleles of rs3824966 showed no significant differences. However, the genotype frequency distribution of the rs1784933 locus was significantly different, and the allele frequency distribution of the A and G alleles were also significantly different. Multifactor logistic regression analysis showed that after correcting for confounding factors such as gender, age, and cholesterol, LOAD risk in rs1784933 AA genotype carriers was 1.803 times that in AG+GG genotype carriers. SORL1 gene SNPs at rs689021 and rs3824966 loci show no relationship with LOAD onset in the Chinese Han population of the Hunan Changsha region. Conversely, a SORL1 gene SNP at the rs1784933 locus is associated with LOAD onset, with the A allele being a risk factor. PMID- 25450150 TI - The cost-effectiveness of selective lymphadenectomy based on a preoperative prediction model in patients with endometrial cancer: insights from the US and Korean healthcare systems. AB - OBJECTIVE: The aim of this study was to determine the cost-effectiveness of selective lymphadenectomy using a preoperative prediction model compared to routine lymphadenectomy for patients undergoing surgery for endometrial cancer in the US and Korea. METHODS: We used a modified Markov model to estimate clinical and economic outcomes for newly diagnosed, apparent early-stage endometrial cancer patients under two different strategies: (1) selective lymphadenectomy, where patients classified as low risk based on the preoperative prediction model did not undergo complete surgical staging, and (2) routine lymphadenectomy, where all patients underwent complete surgical staging. Published data were used to estimate the rates of adjuvant therapy and survival. Costs were calculated from the perspective of US or Korean payers. Cost-effectiveness ratios were analyzed separately using data from each country. RESULTS: Base-case analysis indicated that selective lymphadenectomy was less costly ($6454 vs. $7079 in Korea; $23,995 vs. $26,318 in the US) and more effective (6.91 quality-adjusted life years (QALYs) vs. 6.85 QALYs in Korea; 6.87 QALYs vs. 6.81 QALYs in the US) than routine lymphadenectomy in both countries. This result was robust in a deterministic sensitivity analysis, with the exception of when the utility scores for patients with lymphedema were varied. So long as a modest preference for avoiding lymphedema (disutility of 0.04) was obtained, selective lymphadenectomy remained the dominant strategy. CONCLUSIONS: A selective lymphadenectomy strategy based on a preoperative prediction model was shown to be more cost-effective than routine lymphadenectomy for endometrial cancer patients in the US and Korea. PMID- 25450152 TI - Interval debulking surgery following neo-adjuvant chemotherapy for stage IVB ovarian cancer using neutral argon plasma (PlasmaJetTM). AB - OBJECTIVE: We present a novel surgical approach to ovarian cancer debulking using neutral argon plasma (PlasmaJetTM). CASE HISTORY: A 48 year-old woman diagnosed with FIGO stage IVB grade 3 serous epithelial ovarian carcinoma received three cycles of neoadjuvant chemotherapy with carboplatin and paclitaxel. OPERATIVE TECHNIQUE: Dissection and radical debulking surgery were performed using PlasmaJetTM as previously described [1,2]. This included diaphragmatic and abdominal peritoneal stripping, supra-colic omentectomy, tumour ablation on the small and large intestines and mesentery, pelvic and para-aortic lymphadenectomy. RESULTS: The only post-operative complication was a superficial wound breakdown, which healed by secondary intention. She remains well two years after surgery, with no sign of recurrence. CONCLUSION: In this case, PlasmaJetTM facilitated diaphragmatic peritoneal stripping as well as dissection of tissue close to bowel and major vessels. Further study is required to assess whether this device can reduce the need for bowel resection while achieving complete cytoreduction. PMID- 25450151 TI - Sentinel node biopsy for the management of early stage endometrial cancer: long term results of the SENTI-ENDO study. AB - OBJECTIVE: We report the long-term results of the SENTI-ENDO study evaluating the impact of sentinel lymph node (SLN) biopsy on management and survival in patients with early stages of endometrial cancer (EC). METHODS: Patients with FIGO stage I II EC underwent pelvic SLN biopsy after cervical dual injection (technetium and patent blue) and systematic pelvic node dissection. This study is a secondary endpoint reporting the long-term recurrence free survival (RFS) and the impact of the SLN procedure on adjuvant therapies. RESULTS: The median follow-up was 50 months (range: 3-77 months). Eighteen of the 125 patients (14.4%) experienced a recurrence. The 50-month recurrence-free survival (RFS) was 84.7% with no difference between patients with and without detected SLN (p = 0.09). Among patients with detected SLN (111), no difference in RFS was observed between those with and without positive SLN (p = 0.5). In the whole population, adjuvant therapy was performed in low-, intermediate- and high-risk groups in 31 of 64 patients (48.4%), 28 of 37 patients (75.7%) and 14 of 17 patients (82.3%), respectively (p = 0.0001). For the 111 patients with detected SLN, EBRT was performed in 27 of the 89 with negative SLN and in 11 of the 14 with positive SLN (p = 0.001). Chemotherapy was performed more frequently in patients with positive SLN (6/12, 50%) than in patients with negative SLN (7/56, 12.5%) (p = 0.009). CONCLUSIONS: Our results support the impact of SLN biopsy on surgical management and indications for adjuvant therapies. Further studies are required to assess the clinical impact of the SLN biopsy in early stage EC. PMID- 25450153 TI - Beneficial effect of continuous positive airway pressure on lipid profiles in obstructive sleep apnea: a meta-analysis. AB - PURPOSE: Dyslipidemia is considered as one mechanism causing cardiovascular sequelae in obstructive sleep apnea (OSA). Continuous positive airway pressure (CPAP) can reduce cardiovascular morbidities but its effect on lipid profiles is inconclusive. This study aimed to investigate the effects of CPAP on lipid profiles by a meta-analysis of the existing randomized controlled trials. METHODS: Studies were retrieved from MEDLINE/PubMed, EMBASE, CENTRAL, commercial websites, and article references up to August 2013 following the protocols (PROSPERO CRD42012002636). Randomized controlled trials investigating the CPAP effects on changes in lipid profiles in adult patients with OSA were included. Two independent researchers extracted relevant data in duplicate. The pooled effect was analyzed by fixed-effect generic inverse variance, and the heterogeneity was assessed using the I (2) statistic. RESULTS: Six trials with 348 patients and 351 controls were included. CPAP significantly lowered total cholesterol (mean, -6.23 mg/dl; 95% CI, -8.73 to -3.73; I (2), 0%; p < 0.001), triglyceride (mean, -12.60 mg/dl; 95% CI, -18.80 to -6.41; I (2), 25%; p < 0.001), and high-density lipoprotein (mean, -1.05 mg/dl; 95% CI, -1.69 to -0.40; I (2), 0%; p = 0.001), but not low-density lipoprotein (mean, -1.01 mg/dl; 95% CI, -5.04 to 3.02; I (2), 0%; p = 0.62). The lipid-lowering effects were homogeneous across the studies. By subgroup analysis, the reductions of lipid profiles were associated with the cross-over design, subtherapeutic CPAP as placebo, enrolled patients with moderate-to-severe OSA or daytime sleepiness, and CPAP treatment with short-term duration or good compliance. CONCLUSIONS: This meta-analysis validates the observation that CPAP can reduce lipid profiles in patients with OSA. PMID- 25450154 TI - Restless legs syndrome among pregnant women in China: prevalence and risk factors. AB - BACKGROUND: The goal of this study was to identify the prevalence and clinical correlates and severity of restless legs syndrome (RLS) among pregnant women in mainland China. METHODS: This cross-sectional study enrolled 1584 women (18-40 years old) who came to a prenatal outpatient clinic to consult an obstetrician. Pregnant women were studied in each trimester, and assessments included interviews about RLS symptoms and related questions. Standardized questionnaires include the International Restless Syndrome Scale and the Pittsburgh Sleep Quality Questionnaire. Blood tests included levels of hemoglobin and mean corpuscular volume. RESULTS: RLS was diagnosed in 177 of 1584 women (11.2%); 4.2% were categorized as having pre-existing RLS and 54.8% reported onset of RLS symptoms after the 24th week. Multivariate analysis revealed that anemia was positively correlated with RLS. For the participants who first experienced RLS in pregnancy, RLS severity in the third trimester was more severe when compared with the first and second trimesters. Sleep disorders occurred more frequently in the third trimester. CONCLUSIONS: In our study, RLS was frequent in pregnant Chinese women, and anemia was identified as an independent predictor of the disease. Further, most participants reported their symptoms during the third trimester, and the severity of RLS and sleep disorders of participants was more prominent in the third trimester. PMID- 25450155 TI - Influence of calibration protocols for a pressure-sensing walkway on kinetic and temporospatial parameters. AB - OBJECTIVES: To evaluate the influence on the kinetic and temporospatial parameters of calibration protocols with point and step techniques for a pressure sensing walkway. METHODS: Nine Labrador dogs were used. Two protocols of point calibration technique (C1 and C2) and eight protocols of step calibration technique (C3 to C10) were performed. In C1, weight was added to a stool to match the body mass of each dog. In C2, weight was added to the stool to match a 46.1 kg person. The other eight calibration protocols represented combinations of the following factors: 46.1 kg and 96.1 kg persons, barefoot or wearing sneakers, and stepping onto the platform with one or two feet. RESULTS: The calibration protocols did not affect the temporospatial variables or percentages of body weight (%BW) distribution. Significant differences were found in both PVI (peak vertical force) and VI (vertical impulse) between barefoot versus wearing sneakers, 46.1 kg versus 96.1 kg person, and stepping onto the platform with one foot versus two feet. When comparing C1 with other protocols, significant differences were observed in PVF and VI for both forelimbs and hindlimbs. When comparing C2 with other protocols, significant differences were observed in PVF and VI for both forelimbs and hindlimbs in all protocols. CLINICAL SIGNIFICANCE: The PVF and VI were influenced by the calibration protocol used, but the %BW distribution and temporospatial parameters were not. Using the same calibration protocol for all dogs within the same group eliminated the variability of the kinetic data caused by the calibration. PMID- 25450156 TI - Promoter or enhancer, what's the difference? Deconstruction of established distinctions and presentation of a unifying model. AB - Gene transcription is strictly controlled by the interplay of regulatory events at gene promoters and gene-distal regulatory elements called enhancers. Despite extensive studies of enhancers, we still have a very limited understanding of their mechanisms of action and their restricted spatio-temporal activities. A better understanding would ultimately lead to fundamental insights into the control of gene transcription and the action of regulatory genetic variants involved in disease. Here, I review and discuss pros and cons of state-of-the-art genomics methods to localize and infer the activity of enhancers. Among the different approaches, profiling of enhancer RNAs yields the highest specificity and may be superior in detecting in vivo activity. I discuss their apparent similarities to promoters, which challenge the established view of enhancers and promoters as distinct entities, and present a unifying model of regulatory elements in transcriptional regulation, in which activity, transcriptional output and regulatory function is context specific. PMID- 25450157 TI - Superior lithium-ion storage properties of si-based composite powders with unique Si@carbon@void@graphene configuration. AB - Composite powders of the configuration Si@carbon@void@graphene were prepared by a one-step spray pyrolysis process, by adding polyvinylpyrrolidone (PVP) to a precursor solution containing graphene oxide (GO) sheets and silicon nanoparticles (NPs). Morphological analysis indicates that the individual Si NPs are coated with amorphous carbon and encapsulated in a micrometer-sized graphene ball structure that offers a large amount of buffer space. The addition of PVP improves the stability of the colloidal spray solution containing the GO sheets and the Si NPs. Consequently, the prepared Si@C@void@graphene composite powders have a relatively more uniform morphology than the Si@void@graphene composite powders prepared from the spray solution without PVP. The first charge and discharge capacities of the Si@C@void@graphene electrode measured at 0.1 A g(-1) are as high as 3102 and 2215 mA h g(-1) , respectively. With an increase in the current rate from 0.5 to 11 A g(-1) , 46 % of the original capacity (i.e., 2134 mA h g(-1) ) is maintained. After 500 cycles at a high rate of 7 A g(-1) , the Si@C@void@graphene electrode shows 84 % capacity retention and 99.8 % of the average Coulombic efficiency. The superior cycling and rate capabilities of the prepared Si@C@void@graphene electrode could be attributed to the uniform carbon coating of the Si NPs and the graphene ball structure, which facilitates efficient diffusion of Li ions and prevents the penetration of electrolyte into graphene ball during cycling. PMID- 25450158 TI - Space charge frequency shifts of the cyclotron modes in multi-species ion plasmas. AB - Shifts of the cyclotron frequency away from the "bare" cyclotron frequency are observed to be proportional to the total ion density through the E * B rotation frequency, and to the relative concentration of each ion species, in quantitative agreement with analytic theory. These shifts are measured at small excitation amplitudes on the typical center-of-mass m = 1 mode, and also on cyclotron modes with m = 0 and m = 2 azimuthal dependence. The frequency spacing between these modes is proportional to the rotation frequency of the ion cloud, which is controlled and measured using a "rotating wall" and laser-induced fluorescence. These cylindrical ion plasmas consist of Mg(+) isotopes, with H3 O (+) and O2 (+) impurities. It is observed that the shift in the m = 1 cyclotron frequency is larger for the minority species (25)Mg(+) and (26)Mg(+), than for the majority species (24)Mg(+). A simple center-of-mass model is presented, which is in quantitative agreement with these results. It is also shown that this model interprets and expands the intensity dependent calibration equation, (M/q) = A/f + B/f (2) + CI/f (2). PMID- 25450159 TI - Factors associated with the failure of arthroscopic surgery treatment in patients with femoroacetabular impingement: A cohort study. AB - OBJECTIVE: The aim of this study was to evaluate the association of the anatomical and functional characteristics with therapeutic failure in patients with femoroacetabular impingement, who underwent hip arthroscopy. MATERIALS AND METHODS: A cohort study was performed on 179 patients with femoroacetabular impingement who underwent hip arthroscopy between 2004 and 2012. The demographic, anatomical, functional, and clinical information were recorded. A logistic regression model and ANCOVA were used in order to compare the described characteristics with the treatment outcomes of the hip arthroscopy. RESULTS: The median time of follow-up for symptoms was 13 months (8-30), and the mean time of follow-up after surgery was 23.83 +/- 9.8 months. At the end of the follow-up 3.91% of the patients were considered as a therapeutic failure. The WOMAC score in pain and functional branches, as well as the total WOMAC score, showed significant differences (P<.05). The mean WOMAC score was higher (0 to 100 with 0 being a perfect score) in the group of patients who failed after surgery as compared with the group who meet the requirements for a successful treatment, 65.9 vs 48.8, respectively (mean difference 17.0; 95% CI; 1.3-32.6; P=.033). CONCLUSION: The poor functional state prior to arthroscopic treatment of femoroacetabular impingement, mainly due to preoperative pain, assessed using the WOMAC scale, is associated with a higher therapeutic failure rate. PMID- 25450160 TI - Preventive analgesia in hip or knee arthroplasty: a systematic review. AB - OBJECTIVE: To analyze the efficacy and safety of preventive analgesia in patients undergoing hip or knee arthroplasty due to osteoarthritis. METHODS: A systematic literature review was performed, using a defined a sensitive strategy on Medline, Embase and Cochrane Library up to May 2013. The inclusion criteria were: patients undergoing knee and/or hip arthroplasty, adults with moderate or severe pain (>=4 on a Visual Analog Scale). The intervention, the use (efficacy and safety) of pharmacological treatment (preventive) close to surgery was recorded. Oral, topical and skin patch drugs were included. Systematic reviews, meta-analysis, controlled trials and observational studies were selected. RESULTS: A total of 36 articles, of moderate quality, were selected. The patients included were representative of those undergoing knee and/or hip arthroplasty in Spain. They had a mean age >50 years, higher number of women, and reporting moderate to severe pain (>=4 on a Visual Analog Scale). Possurgical pain was mainly evaluated with a Visual Analog Scale. A wide variation was found as regards the drugs used in the preventive protocols, including acetaminophen, classic NSAID, Cox-2, opioids, corticosteroids, antidepressants, analgesics for neuropathic pain, as well as others, such as magnesium, ketamine, nimodipine or clonidine. In general, all of them decreased post-surgical pain without severe adverse events. CONCLUSIONS: The use or one or more pre-surgical analgesics decreases the use of post-surgical drugs, at least for short term pain. PMID- 25450161 TI - Anterior cervical arthrodesis using a vertebral body autograft. AB - OBJECTIVE: To assess fusion rates and functional outcomes in patients undergoing anterior cervical discectomy and fusion by using a vertebral body autograft for interbody filling and anterior cervical plate fixation. MATERIAL AND METHODS: The study included a total of 102 patients, 54 men and 48 women, who underwent surgery between 2006 and 2010 patients with degenerative disease, cervical disc herniation and radiculopathy, and who had failed standard conservative treatment (3 months). The study was limited to patients with fusion levels 1-3. The mean patient follow-up was 44 (24-96) months. Their mean age was 48.8 years. RESULTS: The clinical variables analyzed were: duration of symptoms (> 12 months), smoking (31% smokers), employment status (76% active), average days of hospitalization (2.2 days), operation time (62 min), etiology (100%, degenerative disease), notable comorbidities (28%), fusion levels (42% 1, 49% 2, 9% 3), symptoms (radiculalgia or axial pain). The functional variables analyzed (score pre-and post-operative scores) were: VAS (8.6-1.32), Neck Disability Index (37.7-5.8), and Odom criteria (76% reflected excellent results after surgery). Finally, radiological variables were also analyzed: anterior reactive osteophytosis (16%), significant collapse (0%), and fusion rate (98%). There were 4 cases of acute postoperative complications, and 4 chronic, none of them were related to the surgical technique. DISCUSSION: The use of autograft bone of the vertebral body itself reduces comorbidities associated with the use of the iliac crest of the patient. Our results using the technique described are comparable to those in the literature, with a fusion rate of 98% and a mean of 62 min duration of the procedure. PMID- 25450163 TI - Predicting errors from patterns of event-related potentials preceding an overt response. AB - Everyday actions often require fast and efficient error detection and error correction. For this, the brain has to accumulate evidence for errors as soon as it becomes available. This study used multivariate pattern classification techniques for event-related potentials to track the accumulation of error related brain activity before an overt response was made. Upcoming errors in a digit-flanker task could be predicted after the initiation of an erroneous motor response, ~90ms before response execution. Channels over motor and parieto occipital cortices were most important for error prediction, suggesting ongoing perceptual analyses and comparisons of initiated and appropriate motor programmes. Lower response force on error trials as compared to correct trials was observed, which indicates that this early error information was used for attempts to correct for errors before the overt response was made. In summary, our results suggest an early, automatic accumulation of error-related information, providing input for fast correction processes. PMID- 25450162 TI - Dissociation between arithmetic relatedness and distance effects is modulated by task properties: an ERP study comparing explicit vs. implicit arithmetic processing. AB - Event-related potential (ERP) studies have detected several characteristic consecutive amplitude modulations in both implicit and explicit mental arithmetic tasks. Implicit tasks typically focused on the arithmetic relatedness effect (in which performance is affected by semantic associations between numbers) while explicit tasks focused on the distance effect (in which performance is affected by the numerical difference of to-be-compared numbers). Both task types elicit morphologically similar ERP waves which were explained in functionally similar terms. However, to date, the relationship between these tasks has not been investigated explicitly and systematically. In order to fill this gap, here we examined whether ERP effects and their underlying cognitive processes in implicit and explicit mental arithmetic tasks differ from each other. The same group of participants performed both an implicit number-matching task (in which arithmetic knowledge is task-irrelevant) and an explicit arithmetic-verification task (in which arithmetic knowledge is task-relevant). 129-channel ERP data differed substantially between tasks. In the number-matching task, the arithmetic relatedness effect appeared as a negativity over left-frontal electrodes whereas the distance effect was more prominent over right centro-parietal electrodes. In the verification task, all probe types elicited similar N2b waves over right fronto-central electrodes and typical centro-parietal N400 effects over central electrodes. The distance effect appeared as an early-rising, long-lasting left parietal negativity. We suggest that ERP effects in the implicit task reflect access to semantic memory networks and to magnitude discrimination, respectively. In contrast, effects of expectation violation are more prominent in explicit tasks and may mask more delicate cognitive processes. PMID- 25450164 TI - Microstructural brain abnormalities and symptom dimensions in child and adolescent patients with obsessive-compulsive disorder: a diffusion tensor imaging study. AB - BACKGROUND: The aims of this study were to determine white matter (WM) microstructure abnormalities in obsessive-compulsive disorder (OCD) using diffusion tensor imaging, and to investigate whether these abnormalities differ according to OCD symptom dimensions. METHODS: Sixty-three child and adolescent OCD patients (11-18 years old) and 37 healthy subjects matched for gender, age, and estimated intelligence quotient were assessed by means of psychopathology scales and diffusion tensor magnetic resonance imaging. RESULTS: Compared with healthy controls OCD patients showed a significant decrease (t = 3.79, P = .049 FDR-corrected) in fractional anisotropy (FA) in the anterior region of the corpus callosum (CC). In addition, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values were significantly increased in OCD compared with controls in the CC and in several WM regions of the cingulate, frontal and occipital lobes, basal ganglia, cerebellum, and pons. Compared with healthy controls, OCD patients presenting the harm/checking dimension showed decreased FA in the CC and in the left anterior cingulate gyrus and caudate nucleus, whereas patients with a predominant contamination/washing symptom dimension presented significantly decreased FA in the left midbrain, lentiform nucleus, insula, and thalamus, and increased MD, AD, and RD in both the anterior lobes of cerebellum and in the pons. CONCLUSIONS: The findings suggest WM abnormalities at the microstructural level in the pathogenesis of OCD. Moreover, WM abnormalities in OCD may vary according to the specific OCD symptom dimensions, thus indicating the clinical heterogeneity of the condition. PMID- 25450167 TI - Sex-dependent transcriptome analysis and single nucleotide polymorphism (SNP) discovery in the brine shrimp Artemia franciscana. AB - In order to enhance genomic resources for the brine shrimp Artemia franciscana, RNA-Seq analysis was conducted for adult females and males. Through de novo assembly, 36,896 high quality contigs were obtained, of which 13,749 sequences were annotated with arthropod sequences. Just 4.5% matched against previously reported sequences for Artemia spp. Additionally, different transcriptional patterns between males and females were found, evidencing sex-related transcriptional responses. Furthermore, 221 and 534 putative SNPs were identified exclusively in males and females, respectively. These results will build the foundation for further genomic studies in A. franciscana. PMID- 25450166 TI - Gene discovery in the finger leather coral Sinularia notanda by construction and sequencing of a normalized cDNA library. AB - The transplantation of coral fragments is one of methods that restore coral communities. To form coral colonies, the fragmented corals initiated skeletal extension from the cut-edge of fragment then success the settlement. In order to understand the molecular events underlying fragment adhesion and settlement, we constructed a normalized cDNA library and generated and annotated expressed sequence tags (ESTs) from the fragmented adult polyps of soft coral Sinularia notanda. We generated 3251 high-quality ESTs with an average length of 580 bp and the EST cluster and assembly analyses produced 2796 unigenes, including 2487 singletons and 309 contigs. Of the known genes, 55 genes were sel ected to be involved in polyp fragment adhesion and settlement based on Gene Ontology (GO) classification. Notably, two EST clones were identified to show homology with galaxin gene which was demonstrated as coral specific calcifying protein of organic matrix. These EST sequences can provide utility as molecular markers in molecular and genetic studies of S. notanda and other soft coral. PMID- 25450165 TI - Dataset for metatranscriptome analysis of Prochlorococcus-rich marine picoplankton communities in the Gulf of Aqaba, Red Sea. AB - Regulatory RNAs play a central role in the regulation of gene expression and can act on several regulatory levels from transcriptional initiation and RNA processing to the control of initiation of translation and RNA stability. One class of these molecules is non-coding (nc)RNAs in bacteria that typically lack protein-coding potential, range in size between 50 and 500nt and originate from intergenic regions. Common methods for the identification of these RNAs are either based on computational predictions, or on transcriptomic analyses of laboratory cultures, whereas very little is known about ncRNAs in environmental microbial populations. Here, we have combined a metatranscriptomics approach with a selective enrichment protocol for ncRNAs. The primary objective of this study was the identification of novel, environmentally relevant ncRNAs focusing on the cyanobacterium Prochlorococcus, which was one of the dominant microorganisms of the marine community of the Gulf of Aqaba when samples were taken. PMID- 25450168 TI - Disparities in tobacco use by sexual orientation among high school students. AB - OBJECTIVE: This study examined whether cigarette use is associated with sexual orientation among high school students. METHODS: Data were from a 2012 cross sectional survey of 5994 students in grades 9, 10 and 12 attending public schools in Atlantic Canada. Multilevel logistic regression analysis was used to examine differences in cigarette use by sexual orientation. RESULTS: Lesbian, gay and bisexual adolescents (LGB) reported higher prevalence (22%) of daily cigarette use compared with heterosexuals (11%). Multilevel logistic regression analysis, controlling for standard covariates, found that LGB adolescents were more likely to be daily smokers than non-LGB adolescents (odds ratio 2.00, 95% confidence interval 1.50-2.68). Bisexual adolescents were at least twice more likely to be a smoker compared with heterosexual adolescents. CONCLUSIONS: Prevalence of cigarette use was significantly higher among LGB adolescent students. Our results join a growing body of evidence indicating that sexual minorities are at heightened risk of tobacco use. Smoking cessation measures that specifically target this group may be beneficial given that there is no one size fits all approach. PMID- 25450169 TI - Proximal first metatarsal opening wedge osteotomy: geometric analysis on saw bone models. AB - BACKGROUND: For hallux valgus correction, distal first metatarsal osteotomy is generally used for minor to moderate deformities, diaphyseal osteotomy for moderate deformities and basal osteotomy or arthrodesis for severe deformities. With the advent of locking plates, there has been renewed interest in opening wedge basal osteotomy. OBJECTIVE: We undertook this study in order to understand the power and limitations of this osteotomy. METHOD: Proximal opening wedge osteotomies were performed on saw bone models in four orientations, with three different wedge sizes: (1) perpendicular to the ground (PG); (2) perpendicular to the shaft (PS); (3) perpendicular to shaft with 30 degrees declination (DEC); (4) 30 degrees oblique (OB). Pre- and post-osteotomy measurements were made of axial and plantar translation and inter-metatarsal angle. RESULTS: Plantar translation and intermetatarsal angle correction increased with increasing wedge size. The DEC osteotomy produced the greatest increase in length of metatarsal shaft, while the PS osteotomy gave the least. The most plantar translation was achieved with the DEC osteotomy. Overall, the PS osteotomy gave the largest correction of the intermetatarsal angle. CONCLUSION: Although there are several published clinical case series of the proximal opening wedge osteotomy, this is the first study to fully evaluate its geometry. PMID- 25450170 TI - ROS, thiols and thiol-regulating systems in male gametogenesis. AB - BACKGROUND: During maturation and storage, spermatozoa generate substantial amounts of reactive oxygen species (ROS) and are thus forced to cope with an increasingly oxidative environment that is both needed and detrimental to their biology. Such a janus-faceted intermediate needs to be tightly controlled and this is done by a wide array of redox enzymes. These enzymes not only have to prevent unspecific modifications of essential cellular biomolecules by quenching undesired ROS, but they are also required and often directly involved in critical protein modifications. SCOPE OF REVIEW: The present review is conceived to present an update on what is known about critical roles of redox enzymes, whereby special emphasis is put on the family of glutathione peroxidases, which for the time being presents the best characterized tasks during gametogenesis. MAJOR CONCLUSIONS: We therefore demonstrate that understanding the function of (seleno)thiol-based oxidases/reductases is not a trivial task and relevant knowledge will be mainly gained by using robust systems, as exemplified by several (conditional) knockout studies. We thus stress the importance of using such models for providing unequivocal evidence in the molecular understanding of redox regulatory mechanisms in sperm maturation. GENERAL SIGNIFICANCE: ROS are not merely detrimental by-products of metabolism and their proper generation and usage by specific enzymes is essential for vital functions as beautifully exemplified during male gametogenesis. As such, lessons learnt from thiol-based oxidases/reductases in male gametogenesis could be used as a general principle for other organs as it is most likely not only restricted to this developmental phase. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. PMID- 25450172 TI - Extension of the free energy workflow FEW towards implicit solvent/implicit membrane MM-PBSA calculations. AB - BACKGROUND: The number of high-resolution structures of pharmacologically relevant membrane proteins has been strongly increasing. This makes computing relative affinities of chemically similar compounds binding to a membrane protein possible in order to guide decision making in drug design. However, the preparation step of such calculations is time-consuming and complex. METHODS: We extended the free energy workflow tool FEW, available in AMBER, towards facilitating the setup of molecular dynamics simulations with explicit membrane, and the setup and execution of effective binding energy calculations according to a 1-trajectory implicit solvent/implicit membrane MM-PBSA approach for multiple ligands binding to the same membrane protein. RESULTS: We validated the implemented protocol initially on two model systems, a sodium ion in the presence of an implicit membrane slab and a proton traversing the M2 proton-channel of the influenza A virus. For the latter, we found a good agreement for several important events along the proton pathway with those obtained in a recent computational study. Finally, we performed a case study on effective binding energy calculations for a set of inhibitors binding to the M2 proton-channel. CONCLUSIONS: From the case study, we estimate a considerable speed up in the setup and analysis times for implicit solvent/implicit membrane MM-PBSA calculations by the extended version of FEW compared to a manual preparation. GENERAL SIGNIFICANCE: Together with the overall runtime and the analysis results, this suggests that such type of calculations can be valuable in later stages of drug design projects on membrane proteins. This article is part of a Special Issue entitled Recent developments of molecular dynamics. PMID- 25450171 TI - Enhanced sampling techniques in molecular dynamics simulations of biological systems. AB - BACKGROUND: Molecular dynamics has emerged as an important research methodology covering systems to the level of millions of atoms. However, insufficient sampling often limits its application. The limitation is due to rough energy landscapes, with many local minima separated by high-energy barriers, which govern the biomolecular motion. SCOPE OF REVIEW: In the past few decades methods have been developed that address the sampling problem, such as replica-exchange molecular dynamics, metadynamics and simulated annealing. Here we present an overview over theses sampling methods in an attempt to shed light on which should be selected depending on the type of system property studied. MAJOR CONCLUSIONS: Enhanced sampling methods have been employed for a broad range of biological systems and the choice of a suitable method is connected to biological and physical characteristics of the system, in particular system size. While metadynamics and replica-exchange molecular dynamics are the most adopted sampling methods to study biomolecular dynamics, simulated annealing is well suited to characterize very flexible systems. The use of annealing methods for a long time was restricted to simulation of small proteins; however, a variant of the method, generalized simulated annealing, can be employed at a relatively low computational cost to large macromolecular complexes. GENERAL SIGNIFICANCE: Molecular dynamics trajectories frequently do not reach all relevant conformational substates, for example those connected with biological function, a problem that can be addressed by employing enhanced sampling algorithms. This article is part of a Special Issue entitled Recent developments of molecular dynamics. PMID- 25450173 TI - Molecular dynamic simulations of protein/RNA complexes: CRISPR/Csy4 endoribonuclease. AB - BACKGROUND: Many prokaryotic genomes comprise Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) offering defense against foreign nucleic acids. These immune systems are conditioned by the production of small CRISPR derived RNAs matured from long RNA precursors. This often requires a Csy4 endoribonuclease cleaving the RNA 3'-end. METHODS: We report extended explicit solvent molecular dynamic (MD) simulations of Csy4/RNA complex in precursor and product states, based on X-ray structures of product and inactivated precursor (55 simulations; ~3.7MUs in total). RESULTS: The simulations identify double protonated His29 and deprotonated terminal phosphate as the likely dominant protonation states consistent with the product structure. We revealed potential substates consistent with Ser148 and His29 acting as the general base and acid, respectively. The Ser148 could be straightforwardly deprotonated through solvent and could without further structural rearrangements deprotonate the nucleophile, contrasting similar studies investigating the general base role of nucleobases in ribozymes. We could not locate geometries consistent with His29 acting as general base. However, we caution that the X-ray structures do not always capture the catalytically active geometries and then the reactive structures may be unreachable by the simulation technique. CONCLUSIONS: We identified potential catalytic arrangement of the Csy4/RNA complex but we also report limitations of the simulation technique. Even for the dominant protonation state we could not achieve full agreement between the simulations and the structural data. GENERAL SIGNIFICANCE: Potential catalytic arrangement of the Csy4/RNA complex is found. Further, we provide unique insights into limitations of simulations of protein/RNA complexes, namely, the influence of the starting experimental structures and force field limitations. This article is part of a Special Issue entitled Recent developments of molecular dynamics. PMID- 25450174 TI - Triamcinolone regulated apopto-phagocytic gene expression patterns in the clearance of dying retinal pigment epithelial cells. A key role of Mertk in the enhanced phagocytosis. AB - BACKGROUND: The apopto-phagocytic gene expression patterns during clearance of dying cells in the retina and the effect of triamcinolone (TC) upon these processes have relevance to development of age-related macular degeneration (AMD). METHODS: ARPE-19 cells and primary human retinal pigment epithelium (hRPE) were induced to undergo cell death by anoikis and the clearance of these cells by living hRPE/ARPE-19 or human monocyte-derived macrophages (HMDMs) in the presence or absence of TC was quantified by flow cytometry. TaqMan low-density gene expression array determining known markers of phagocytosis and loss-of-function studies on selected apopto-phagocytic genes was carried out in HMDM engulfing anoikic cells. RESULTS: The glucocorticoid TC had a profound phagocytosis enhancing effect on HMDM engulfing anoikic ARPE-19 or hRPE cells, causing a selective upregulation of the Mer tyrosine kinase (MERTK) receptor, while decreasing the expression of the AXL receptor tyrosine kinase and thrombospondin 1 (THSB-1). The key role of the MERTK could be demonstrated in HMDM engulfing dying cells using gene silencing as well as blocking antibodies. Similar pathways were found upregulated in living ARPE-19 engulfing anoikic ARPE-19 cells. Gas6 treatment enhanced phagocytosis in TC-treated HMDMs. CONCLUSIONS: Specific agonists of the Mertk receptor may have a potential role as phagocytosis enhancers in the retina and serve as future targets for AMD therapy. GENERAL SIGNIFICANCE: The use of Gas6 as enhancer of retinal phagocytosis via the MerTK receptor, alone or in combination with other specific ligands of the tyrosine kinase receptors' family may have a potential role in AMD therapy. PMID- 25450175 TI - The circadian clock and hypoxia in tumor cell de-differentiation and metastasis. AB - BACKGROUND: Cancer is considered to develop due to disruptions in the tissue microenvironment in addition to genetic disruptions in the tumor cells themselves. The two most important microenvironmental disruptions in cancer are arguably tissue hypoxia and disrupted circadian rhythmicity. Endothelial cells, which line the luminal side of all blood vessels transport oxygen or endocrine circadian regulators to the tissue and are therefore of key importance for circadian disruption and hypoxia in tumors. SCOPE OF REVIEW: Here I review recent findings on the role of circadian rhythms and hypoxia in cancer and metastasis, with particular emphasis on how these pathways link tumor metastasis to pathological functions of blood vessels. The involvement of disrupted cell metabolism and redox homeostasis in this context and the use of novel zebrafish models for such studies will be discussed. MAJOR CONCLUSIONS: Circadian rhythms and hypoxia are involved in tumor metastasis on all levels from pathological deregulation of the cell to the tissue and the whole organism. Pathological tumor blood vessels cause hypoxia and disruption in circadian rhythmicity which in turn drives tumor metastasis. Zebrafish models may be used to increase our understanding of the mechanisms behind hypoxia and circadian regulation of metastasis. GENERAL SIGNIFICANCE: Disrupted blood flow in tumors is currently seen as a therapeutic goal in cancer treatment, but may drive invasion and metastasis via pathological hypoxia and circadian clock signaling. Understanding the molecular details behind such regulation is important to optimize treatment for patients with solid tumors in the future. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. PMID- 25450178 TI - In vivo formation of Plasmodium falciparum ribosomal stalk - a unique mode of assembly without stable heterodimeric intermediates. AB - BACKGROUND: The ribosomal stalk composed of P-proteins constitutes a structure on the large ribosomal particle responsible for recruitment of translation factors and stimulation of factor-dependent GTP hydrolysis during translation. The main components of the stalk are P-proteins, which form a pentamer. Despite the conserved basic function of the stalk, the P-proteins do not form a uniform entity, displaying heterogeneity in the primary structure across the eukaryotic lineage. The P-proteins from protozoan parasites are among the most evolutionarily divergent stalk proteins. METHODS: We have assembled P-stalk complex of Plasmodium falciparum in vivo in bacterial system using tricistronic expression cassette and provided its characteristics by biochemical and biophysical methods. RESULTS: All three individual P-proteins, namely uL10/P0, P1 and P2, are indispensable for acquisition of a stable structure of the P stalk complex and the pentameric uL10/P0-(P1-P2)2form represents the most favorable architecture for parasite P-proteins. CONCLUSION: The formation of P. falciparum P-stalk is driven by trilateral interaction between individual elements which represents unique mode of assembling, without stable P1-P2 heterodimeric intermediate. GENERAL SIGNIFICANCE: On the basis of our mass-spectrometry analysis supported by the bacterial two-hybrid assay and biophysical analyses, a unique pathway of the parasite stalk assembling has been proposed. We suggest that the absence of P1/P2 heterodimer, and the formation of a stable pentamer in the presence of all three proteins, indicate a one-step formation to be the main pathway for the vital ribosomal stalk assembly, whereas the P2 homo-oligomer may represent an off-pathway product with physiologically important nonribosomal role. PMID- 25450177 TI - Bridging of a substrate between cyclodextrin and an enzyme's active site pocket triggers a unique mode of inhibition. AB - BACKGROUND: Methionyl-7-amino-4-methylcoumarin (MetAMC) serves as a substrate for the Escherichia coli methionine aminopeptidase (MetAP) catalyzed reaction, and is routinely used for screening compounds to identify potential antibiotic agents. In pursuit of screening the enzyme's inhibitors, we observed that 2-hydroxypropyl beta-cyclodextrin (HP-beta-CD), utilized to solubilize hydrophobic inhibitors, inhibited the catalytic activity of the enzyme, and such inhibition was not solely due to sequestration of the substrate by HP-beta-CD. METHODS: The mechanistic path for the HP-beta-CD mediated inhibition of MetAP was probed by performing a detailed account of steady-state kinetics, ligand binding, X-ray crystallographic, and molecular modeling studies. RESULTS: X-ray crystallographic data of the beta-cyclodextrin-substrate (beta-CD-MetAMC) complex reveal that while the AMC moiety of the substrate is confined within the CD cavity, the methionine moiety protrudes outward. The steady-state kinetic data for inhibition of MetAP by HP-beta-CD-MetAMC conform to a model mechanism in which the substrate is "bridged" between HP-beta-CD and the enzyme's active-site pocket, forming HP beta-CD-MetAMC-MetAP as the catalytically inactive ternary complex. Molecular modeling shows that the scissile bond of HP-beta-CD-bound MetAMC substrate does not reach within the proximity of the enzyme's catalytic metal center, and thus the substrate fails to undergo cleavage. CONCLUSIONS: The data presented herein suggests that the bridging of the substrate between the enzyme and HP-beta-CD cavities is facilitated by interaction of their surfaces, and the resulting complex inhibits the enzyme activity. GENERAL SIGNIFICANCE: Due to its potential interaction with physiological proteins via sequestered substrates, caution must be exercised in HP-beta-CD mediated delivery of drugs under pathophysiological conditions. PMID- 25450179 TI - A novel synthetic luteinizing hormone-releasing hormone (LHRH) analogue coupled with modified beta-cyclodextrin: insight into its intramolecular interactions. AB - BACKGROUND: Cyclodextrins (CDs) in combination with therapeutic proteins and other bioactive compounds have been proposed as candidates that show enhanced chemical and enzymatic stability, better absorption, slower plasma clearance and improved dose-response curves or immunogenicity. As a result, an important number of therapeutic complexes between cyclodextrins and bioactive compounds capable to control several diseases have been developed. RESULTS: In this article, the synthesis and the structural study of a conjugate between a luteinizing hormone releasing hormone (LHRH) analogue, related to the treatment of hormone dependent cancer and fertility, and modified beta-cyclodextrin residue are presented. The results show that both the phenyl group of tyrosine (Tyr) as well as the indole group of tryptophan (Trp) can be encapsulated inside the cyclodextrin cavity. Solution NMR experiments provide evidence that these interactions take place intramolecularly and not intermolecularly. CONCLUSIONS: The study of a LHRH analogue conjugated with modified beta-cyclodextrin via high field NMR and MD experiments revealed the existence of intramolecular interactions that could lead to an improved drug delivery. GENERAL SIGNIFICANCE: NMR in combination with MD simulation is of great value for a successful rational design of peptide cyclodextrin conjugates showing stability against enzymatic proteolysis and a better pharmacological profile. PMID- 25450180 TI - Astaxanthin prevents TGFbeta1-induced pro-fibrogenic gene expression by inhibiting Smad3 activation in hepatic stellate cells. AB - BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a subset of non-alcoholic fatty liver disease, the most common chronic liver disease in the U.S. Fibrosis, a common feature of NASH, results from the dysregulation of fibrogenesis in hepatic stellate cells (HSCs). In this study, we investigated whether astaxanthin (ASTX), a xanthophyll carotenoid, can inhibit fibrogenic effects of transforming growth factor beta1 (TGFbeta1), a key fibrogenic cytokine, in HSCs. METHODS: Reactive oxygen species (ROS) accumulation was measured in LX-2, an immortalized human HSC cell line. Quantitative realtime PCR, Western blot, immunocytochemical analysis, and in-cell Western blot were performed to determine mRNA and protein of fibrogenic genes, and the activation of Smad3 in TGFbeta1-activated LX-2 cells and primary mouse HSCs. RESULTS: In LX-2 cells, ROS accumulation induced by tert butyl hydrogen peroxide and TGFbeta1 was abolished by ASTX. ASTX significantly decreased TGFbeta1-induced alpha-smooth muscle actin (alpha-SMA) and procollagen type 1, alpha 1 (Col1A1) mRNA as well as alpha-SMA protein levels. Knockdown of Smad3 showed the significant role of Smad3 in the expression of alpha-SMA and Col1A1, but not TGFbeta1, in LX-2 cells. ASTX attenuated TGFbeta1-induced Smad3 phosphorylation and nuclear translocation with a concomitant inhibition of Smad3, Smad7, TGFbeta receptor I (TbetaRI), and TbetaRII expression. The inhibitory effect of ASTX on HSC activation was confirmed in primary mouse HSCs as evidenced by decreased mRNA and protein levels of alpha-SMA during activation. CONCLUSION: Taken together, ASTX exerted anti-fibrogenic effects by blocking TGFbeta1 signaling, consequently inhibiting the activation of Smad3 pathway in HSCs. GENERAL SIGNIFICANCE: This study suggests that ASTX may be used as a preventive/therapeutic agent to prevent hepatic fibrosis. PMID- 25450181 TI - Metabolic control analysis of the Trypanosoma cruzi peroxide detoxification pathway identifies tryparedoxin as a suitable drug target. AB - BACKGROUND: The principal oxidative-stress defense in the human parasite Trypanosoma cruzi is the tryparedoxin-dependent peroxide detoxification pathway, constituted by trypanothione reductase (TryR), tryparedoxin (TXN), tryparedoxin peroxidase (TXNPx) and tryparedoxin-dependent glutathione peroxidase A (GPxA). Here, Metabolic Control Analysis (MCA) was applied to quantitatively prioritize drug target(s) within the pathway by identifying its flux-controlling enzymes. METHODS: The recombinant enzymes were kinetically characterized at physiological pH/temperature. Further, the pathway was in vitro reconstituted using enzyme activity ratios and fluxes similar to those observed in the parasites; then, enzyme and substrate titrations were performed to determine their degree of control on flux. Also, kinetic characterization of the whole pathway was performed. RESULTS: Analyses of the kinetic properties indicated that TXN is the less efficient pathway enzyme derived from its high Kmapp for trypanothione and low Vmax values within the cell. MCA established that the TXN-TXNPx and TXN-GPxA redox pairs controlled by 90-100% the pathway flux, whereas 10% control was attained by TryR. The Kmapp values of the complete pathway for substrates suggested that the pathway flux was determined by the peroxide availability, whereas at high peroxide concentrations, flux may be limited by NADPH. CONCLUSION: These quantitative kinetic and metabolic analyses pointed out to TXN as a convenient drug target due to its low catalytic efficiency, high control on the flux of peroxide detoxification and role as provider of reducing equivalents to the two main peroxidases in the parasite. GENERAL SIGNIFICANCE: MCA studies provide rational and quantitative criteria to select enzymes for drug-target development. PMID- 25450176 TI - Prolyl isomerases in gene transcription. AB - BACKGROUND: Peptidyl-prolyl isomerases (PPIases) are enzymes that assist in the folding of newly-synthesized proteins and regulate the stability, localization, and activity of mature proteins. They do so by catalyzing reversible (cis-trans) rotation about the peptide bond that precedes proline, inducing conformational changes in target proteins. SCOPE OF REVIEW: This review will discuss how PPIases regulate gene transcription by controlling the activity of (1) DNA-binding transcription regulatory proteins, (2) RNA polymerase II, and (3) chromatin and histone modifying enzymes. MAJOR CONCLUSIONS: Members of each family of PPIase (cyclophilins, FKBPs, and parvulins) regulate gene transcription at multiple levels. In all but a few cases, the exact mechanisms remain elusive. Structure studies, development of specific inhibitors, and new methodologies for studying cis/trans isomerization in vivo represent some of the challenges in this new frontier that merges two important fields. GENERAL SIGNIFICANCE: Prolyl isomerases have been found to play key regulatory roles in all phases of the transcription process. Moreover, PPIases control upstream signaling pathways that regulate gene-specific transcription during development, hormone response and environmental stress. Although transcription is often rate-limiting in the production of enzymes and structural proteins, post-transcriptional modifications are also critical, and PPIases play key roles here as well (see other reviews in this issue). This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. PMID- 25450182 TI - Mechanism of dopachrome tautomerization into 5,6-dihydroxyindole-2-carboxylic acid catalyzed by Cu(II) based on quantum chemical calculations. AB - BACKGROUND: Tautomerization of dopachrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA) is a biologically crucial reaction relevant to melanin synthesis, cellular antioxidation, and cross-talk among epidermal cells. Since dopachrome spontaneously converts into 5,6-dihydroxyindole (DHI) via decarboxylation without any enzymes at physiologically usual pH, the mechanism of how tautomerization to DHICA occurs in physiological system is a subject of intense debate. A previous work has found that Cu(II) is an important factor to catalyze the tautomerization of dopachrome to DHICA. However, the effect of Cu(II) on the tautomerization has not been clarified at the atomic level. METHODS: We propose the reaction mechanism of the tautomerization to DHICA by Cu(II) from density functional theory-based calculation. RESULTS: We clarified that the activation barriers of alpha-deprotonation, beta-deprotonation, and decarboxylation from dopachrome are significantly reduced by coordination of Cu(II) to quinonoid oxygens (5,6 oxygens) of dopachrome, with the lowest activation barrier of beta-deprotonation among them. In contrast to our previous work, in which beta-deprotonation and quinonoid protonation (O5/O6-protonation) were shown to be important to form DHI, our results show that the Cu(II) coordination to quinonoid oxygens inhibits the quinonoid protonation, leading to the preference of proton rearrangement from beta-carbon to carboxylate group but not to the quinonoid oxygens. CONCLUSION: Integrating these results, we conclude that dopachrome tautomerization first proceeds via proton rearrangement from beta-carbon to carboxylate group and subsequently undergoes alpha-deprotonation to form DHICA. GENERAL SIGNIFICANCE: This study would provide the biochemical basis of DHICA metabolism and the generalized view of dopachrome conversion which is important to understand melanogenesis. PMID- 25450183 TI - Antibacterial effect of silver nanoparticles and the modeling of bacterial growth kinetics using a modified Gompertz model. AB - BACKGROUND: An alternative to conventional antibiotics is needed to fight against emerging multiple drug resistant pathogenic bacteria. In this endeavor, the effect of silver nanoparticle (Ag-NP) has been studied quantitatively on two common pathogenic bacteria Escherichia coli and Staphylococcus aureus, and the growth curves were modeled. METHODS: The effect of Ag-NP on bacterial growth kinetics was studied by measuring the optical density, and was fitted by non linear regression using the Logistic and modified Gompertz models. Scanning Electron Microscopy and fluorescence microscopy were used to study the morphological changes of the bacterial cells. Generation of reactive oxygen species for Ag-NP treated cells were measured by fluorescence emission spectra. RESULTS: The modified Gompertz model, incorporating cell death, fits the observed data better than the Logistic model. With increasing concentration of Ag-NP, the growth kinetics of both bacteria shows a decline in growth rate with simultaneous enhancement of death rate constants. The duration of the lag phase was found to increase with Ag-NP concentration. SEM showed morphological changes, while fluorescence microscopy using DAPI showed compaction of DNA for Ag-NP-treated bacterial cells. CONCLUSIONS: E. coli was found to be more susceptible to Ag-NP as compared to S. aureus. The modified Gompertz model, using a death term, was found to be useful in explaining the non-monotonic nature of the growth curve. GENERAL SIGNIFICANCE: The modified Gompertz model derived here is of general nature and can be used to study any microbial growth kinetics under the influence of antimicrobial agents. PMID- 25450185 TI - Interaction of human telomeric G-quadruplex DNA with thymoquinone: a possible mechanism for thymoquinone anticancer effect. AB - BACKGROUND: Thymoquinone (TQ) has been documented to possess chemo-preventive and chemotherapeutic antitumor effects. Studies reported that TQ inhibits the growth of cancer cells in animal models, culture and xenografted tumors. Molecular mechanisms underlying these anticancer effects were attributed to inductions of cell cycle arrest, apoptosis, oxidative damage of cellular macromolecules, blockade of tumor angiogenesis and inhibitions in migration, invasion and metastasis of cancer cells. On the other hand, human telomere DNA plays a role in regulating genes' transcriptions. It folds up into G-quadruplex structures that inhibit telomerase enzyme over-expressed in cancerous cells. Molecules that selectively stabilize G-quadruplex are potential anticancer agents. Therefore, this work aimed to explore the interaction of TQ with G-quadruplex DNA as a possible underlying mechanism for the anticancer effect of TQ. METHODS: Interactions of TQ with telomeric G-quadruplex (5'-AGGG(TTAGGG)3-3') and duplex DNAs were studied using UV-vis, fluorescence, circular dichroism, liquid and solid NMR (1H and 13C), melting temperature and docking simulation. RESULTS: Changes in UV-vis, CD, fluorescence, 1H NMR and 13C NMR, spectra as well as melting temperatures and docking simulations provided evidences for TQ's interactions with G-quadruplex. TQ was found to interact with G-quadruplex on two binding sites adjacent to the TTA loop with binding constants 1.80*10(5) and 1.12*10(7) M(-1). Melting temperatures indicated that TQ stabilized G-quadruplex by 5.6 degrees C and destabilized ct-DNA by 5.1 degrees C. Selectivity experiment indicated that TQ is preferentially binding to G-quadruplex over duplex with selectivity coefficients of 2.80-3.33*10(-3). Results suggested an intercalation binding mode based on pi-pi stacking. CONCLUSION: Our results propose that TQ can possibly act as a G-quadruplex DNA stabilizer and subsequently contribute to the inhibition of telomerase enzyme and cancer's proliferation. GENERAL SIGNIFICANCE: Our results represent a change in the paradigms reported for structural features of G-quadruplex's stabilizers and anticancer mechanisms of TQ. PMID- 25450187 TI - Transplantation of ovarian tissue. AB - Since the first live birth after orthotopic transplantation of frozen-thawed ovarian tissue, >40 babies have been born. It is time to consider fertility preservation in women as one of the foremost challenges of the next decade and to offer women facing the risk of induced or iatrogenic premature menopause the best chances of becoming mothers. Heterotopic transplantation has also been attempted, with consistent restoration of endocrine function; nonetheless, its clinical value remains questionable as it may not provide an optimal environment for follicular development, possibly because of differences in temperature, pressure, paracrine factors and blood supply. Finally, orthotopic allo-transplantation of fresh human ovarian tissue has been successfully attempted between monozygotic twins and also between genetically different sisters. The next step in this field will be the development of an artificial ovary, using, as a support, a biodegradable scaffold made of an alginate matrigel matrix onto which isolated preantral follicles and ovarian cells can be grafted. PMID- 25450186 TI - Basal Flt1 tyrosine kinase activity is a positive regulator of endothelial survival and vascularization during zebrafish embryogenesis. AB - BACKGROUND: The role of Kdr (VEGFR-2/Flk-1) in vascular formation has been well described, but the role of Flt1 (VEGFR-1) is not well studied and is generally considered as a decoy receptor for trapping VEGF. METHODS: The effects of VEGFR1/2 kinase inhibitor (VRI) and calycosin on Flt1 tyrosine kinase (TK) activity were evaluated by molecular docking, enzymatic inhibition assay, protein co-immunoprecipitation and siRNA gene knock-down analysis in HUVECs. Toxicities of the chemicals were examined using HUVECs viability. Their effects on angiogenesis and vessel formation were furthered studied in HUVECs in vitro and Tg(fli-1:EGFP) zebrafish in vivo. The gene and protein expression of VEGF and VEGF receptors were investigated by quantitative RT-PCR and Western blot. RESULTS: VRI strongly inhibited physiological functions of both VEGF receptors and suppressed endothelial cell survival. This resulted in blood vessel loss in zebrafish embryos. Interestingly, calycosin co-treatment impeded VRI-induced blood vessel loss. Docking and kinase inhibition assay revealed that calycosin competed with VRI for the tyrosine kinase domain of Flt1 without affecting ATP binding. On the contrary, calycosin did not affect the interaction between VRI and Kdr-TK. Consistent with these results, calycosin counteracted the inhibition of Flt1-TK and PI3K phosphorylation induced by VRI in HUVECs. Further studies in vitro and in vivo showed that the minimizing effect of calycosin on VRI-mediated endothelial cytotoxicity was blocked by wortmannin (a PI3K inhibitor). The impeding effect of calycosin on VRI-induced blood vessel loss was absent in zebrafish embryos injected with Flt1 MO. CONCLUSIONS: Flt1-tyrosine kinase (TK) activity contributed significantly in endothelial cells survival and vascular development during embryo angiogenesis in zebrafish by engaging PI3K/Akt pathway. GENERAL SIGNIFICANCE: The roles of Flt1 activity in endothelial cell survival in physiological vascular formation may have been previously under-appreciated. PMID- 25450184 TI - Sialic acids attached to N- and O-glycans within the Nav1.4 D1S5-S6 linker contribute to channel gating. AB - BACKGROUND: Voltage-gated Na+ channels (Nav) are responsible for the initiation and conduction of neuronal and muscle action potentials. Nav gating can be altered by sialic acids attached to channel N-glycans, typically through isoform specific electrostatic mechanisms. METHODS: Using two sets of Chinese Hamster Ovary cell lines with varying abilities to glycosylate glycoproteins, we show for the first time that sialic acids attached to O-glycans and N-glycans within the Nav1.4 D1S5-S6 linker modulate Nav gating. RESULTS: All measured steady-state and kinetic parameters were shifted to more depolarized potentials under conditions of essentially no sialylation. When sialylation of only N-glycans or of only O glycans was prevented, the observed voltage-dependent parameter values were intermediate between those observed under full versus no sialylation. Immunoblot gel shift analyses support the biophysical data. CONCLUSIONS: The data indicate that sialic acids attached to both N- and O-glycans residing within the Nav1.4 D1S5-S6 linker modulate channel gating through electrostatic mechanisms, with the relative contribution of sialic acids attached to N- versus O-glycans on channel gating being similar. GENERAL SIGNIFICANCE: Protein N- and O-glycosylation can modulate ion channel gating simultaneously. These data also suggest that environmental, metabolic, and/or congenital changes in glycosylation that impact sugar substrate levels, could lead, potentially, to changes in Nav sialylation and gating that would modulate AP waveforms and conduction. PMID- 25450188 TI - Reproductive health care after transplantation. AB - Contraception, cervical cancer screening, human papillomavirus (HPV) vaccination, sexually transmitted infection (STI) screening, and menstrual disorders are issues that need to be addressed in all reproductive-aged women, including those with a history of solid organ transplantation. There are specific considerations that may alter routine care in this population. Due to teratogenic immunosuppressive medications, highly effective contraception is important to planning or appropriately timing pregnancy. Estrogen-containing methods (pill, patch, and ring) may be contraindicated. Immunosuppression is also a consideration when screening for and treating STIs including precancerous conditions of the cervix. This chapter will provide a framework to address the specific gynecologic needs of women with a history of solid organ transplantation. PMID- 25450189 TI - Chryseobacterium polytrichastri sp. nov., isolated from a moss (Polytrichastrum formosum), and emended description of the genus Chryseobacterium. AB - A Gram-stain negative, rod-shaped and non-endospore forming bacterium, designated strain YG4-6(T), was isolated from Polytrichastrum formosum collected from Gawalong glacier in Tibet, China and characterized by using a polyphasic taxonomic approach. The predominant fatty acids of strain YG4-6(T) were identified as iso-C15:0 (29.3 %), summed feature 3 (C16:1 omega7c and/or C16:1 omega6c as defined by MIDI, 23.5 %) and iso-C17:0 3-OH (16.5 %). The major polar lipids were found to consist of five unidentified aminolipids and three unidentified lipids. Strain YG4-6(T) was found to contain MK-6 as the dominant menaquinone and the G+C content of its genomic DNA was determined to be 37.3 mol%. The phylogenetic analysis based on 16S rRNA gene sequences showed that strain YG4-6(T) is affiliated to Chryseobacterium species, and its closest related species were Chryseobacterium aahli T68(T) (97.9 % sequence similarity), Chryseobacterium zeae JM-1085(T) (97.8 % sequence similarity), Chryseobacterium yeoncheonense DCY67(T) (97.6 % sequence similarity) and Chryseobacterium soldanellicola NBRC 100864(T) (97.2 % sequence similarity). However, the DNA-DNA relatedness values between these strains and strain YG4-6(T) were found to be clearly below 70 %. Based on the phylogenetic inference and phenotypic data, strain YG4-6(T) is considered to represent a novel species of the genus Chryseobacterium, for which the name Chryseobacterium polytrichastri sp. nov. is proposed. The type strain is YG4-6(T) (=CGMCC 1.12491(T) = DSM 26899(T)). An emended description of the genus Chryseobacterium is also proposed. PMID- 25450191 TI - Synthetic fusion protein design and applications. AB - Synthetic fusion proteins can be designed to achieve improved properties or new functionality by synergistically incorporating multiple proteins into one complex. The fusion of two or more protein domains enhances bioactivities or generates novel functional combinations with a wide range of biotechnological and (bio)pharmaceutical applications. In this review, initially, we summarize the commonly used approaches for constructing fusion proteins. For each approach, the design strategy and desired properties are elaborated with examples of recent studies in the areas of biocatalysts, protein switches and bio-therapeutics. Subsequently, the progress in structural prediction of fusion proteins is presented, which can potentially facilitate the structure-based systematic design of fusion proteins toward identifying the best combinations of fusion partners. Finally, the current challenges and future directions in this field are discussed. PMID- 25450193 TI - WITHDRAWN: The paradox of natural flavonoid C-glycosides and health benefits: When more occurrence is less research. AB - This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25450190 TI - Recent advances in micro/nanotechnologies for global control of hepatitis B infection. AB - The control of hepatitis B virus (HBV) infection is a challenging task, specifically in developing countries there is limited access to diagnostics and antiviral treatment mainly due to high costs and insufficient healthcare infrastructure. Although the current diagnostic technologies can reliably detect HBV, they are relatively laborious, impractical and require expensive resources that are not suitable for resource-limited settings. Advances in micro/nanotechnology are pioneering the development of new generation methodologies in diagnosis and screening of HBV. Owing to combination of nanomaterials (metal/inorganic nanoparticles, carbon nanotubes, etc.) with microfabrication technologies, utilization of miniaturized sensors detecting HBV and other viruses from ultra-low volume of blood, serum and plasma is realized. The state-of-the-art microfluidic devices with integrated nanotechnologies potentially allow for inexpensive HBV screening at low cost. This review aims to highlight recent advances in nanotechnology and microfabrication processes that are employed for developing point-of-care (POC) HBV assays. PMID- 25450194 TI - Recent advances in microbial production of fuels and chemicals using tools and strategies of systems metabolic engineering. AB - The advent of various systems metabolic engineering tools and strategies has enabled more sophisticated engineering of microorganisms for the production of industrially useful fuels and chemicals. Advances in systems metabolic engineering have been made in overproducing natural chemicals and producing novel non-natural chemicals. In this paper, we review the tools and strategies of systems metabolic engineering employed for the development of microorganisms for the production of various industrially useful chemicals belonging to fuels, building block chemicals, and specialty chemicals, in particular focusing on those reported in the last three years. It was aimed at providing the current landscape of systems metabolic engineering and suggesting directions to address future challenges towards successfully establishing processes for the bio-based production of fuels and chemicals from renewable resources. PMID- 25450195 TI - Detection of triatomine infection by Triatoma virus and horizontal transmission: protecting insectaries and prospects for biological control. AB - Triatoma virus (TrV) is the only triatomine entomopathogenic virus identified so far. Propagation of TrV in insectaries depends on handling procedures and triatomine population dynamics. The effects of propagation can be devastating and entire colonies must often be sacrificed to prevent spread of the virus throughout the insectary. This study found that after 41.3 days from TrV ingestion of human blood with 0.04 mg of viral protein by 5th instar Triatomainfestans, viral particles could be detected by RT-PCR; in a second horizontal transmission experiment time to detection resulted in a mean of 42.5 days. These results should rise awareness of TrV dynamics in nature, help estimate the spread of this virus when TrV-infected field-collected insects are incorporated into an insectary, and provide a base for the consideration of TrV as an agent of biological control of some species of triatomines. PMID- 25450196 TI - Characterization and pathogenicity of Vibrio splendidus strains associated with massive mortalities of commercial hatchery-reared larvae of scallop Argopecten purpuratus (Lamarck, 1819). AB - Three strains (VPAP16, VPAP18 and VPAP23 strains) were isolated as the most predominant organisms from 3 different episodes of massive mortalities of larval cultures of the Chilean scallop Argopecten purpuratus occurred in different commercial hatcheries located in northern Chile. The main aims of this study were to identify the pathogenic strains and investigate their pathogenic activity. Based on selected phenotypic features and sequence identity of the 16S rRNA gene and the housekeeping gene, RNA polymerase alpha-chain rpoA, all pathogenic strains were identified as Vibrio splendidus. Healthy 10-day-old scallop larvae cultures exhibited mortality percentages of 69.61+/-3.35%, 79.78+/-6.11% and 61.73+/-3.71% after 48 h when were inoculated with 1*10(6) CFU (colony forming units)mL(-1) of VPAP16, VPAP18 and VPAP23 strains, respectively, and evidenced that concentrations ?10(4) CFU mL(-1) would probably be detrimental for the larval culture. The main clinical signs observed in challenged larvae for 24h were bacterial swarms on the margins of the larvae, extension and disruption of the velum, detachment of velum cilia cells and digestive tissue necrosis. Otherwise, challenge assays using pathogenic strains stained with 5-([4,6 dichlorotriazin-2-yl]amino)fluorescein hydrochloride (5-DTAF)evidenced that after 1h stained bacteria were detected in high density in the digestive gland and the margin of the shell. When larval cultures were inoculated with cell-free extracellular products (ECP) of V. splendidus strains, exhibited larval mortalities higher than 70% (VPAP16), 80% (VPAP18) and 50% (VPAP23) after 24 h, even when ECP were treated with proteinase K or heat, indicating that extracellular pathogenic activity is mainly mediated by non-proteic thermostable compounds. In this study all Koch's postulates were fulfilled and it was demonstrated for the first time the pathogenic activity of V. splendidus strains on reared-larvae of scallop A. purpuratus and prompt the necessity to maintain this species at concentrations lower than 10(4) CFU mL(-1) to avoid episodes of mass mortalities in scallop hatcheries. PMID- 25450192 TI - Rapid prototyping of microbial cell factories via genome-scale engineering. AB - Advances in reading, writing and editing genetic materials have greatly expanded our ability to reprogram biological systems at the resolution of a single nucleotide and on the scale of a whole genome. Such capacity has greatly accelerated the cycles of design, build and test to engineer microbes for efficient synthesis of fuels, chemicals and drugs. In this review, we summarize the emerging technologies that have been applied, or are potentially useful for genome-scale engineering in microbial systems. We will focus on the development of high-throughput methodologies, which may accelerate the prototyping of microbial cell factories. PMID- 25450197 TI - Arginine and NASH--do macrophages deliver the first hit? PMID- 25450198 TI - Partial hepatectomy vs. transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond the Milan criteria: a randomized controlled trial. PMID- 25450199 TI - Prognosis of treated severe alcoholic hepatitis in patients with gastrointestinal bleeding. AB - BACKGROUND & AIMS: All trials on severe alcoholic hepatitis (AH) have included patients with "pure" AH, i.e., without concomitant gastrointestinal bleeding (GIB). Severe AH is often suspected in cirrhotic patients with GIB. We aimed at (1) assessing the prevalence of AH in patients with GIB and Maddrey discriminant function (DF) ?32; (2) comparing the outcome in AH patients with or without GIB (AH-GIB+, AH-GIB-); and (3) assessing the performance of the Lille model for survival in AH-GIB+ patients. METHODS: We retrospectively included all patients with alcoholic cirrhosis admitted between January 2005 and March 2011 with the following: (1) jaundice <3 months; (2) DF ?32 at admission; (3) bilirubin level >50 MUmol/L; and (4) active drinking. Exclusion criteria were advanced hepatocellular carcinoma, other etiology of cirrhosis, severe comorbidities and DF <32 after stabilization. In our centre, we systematically plan a liver biopsy for these patients. Patients with severe AH received prednisolone. RESULTS: We screened 161 patients (86 GIB+, 75 GIB-), and analyzed data for 58 and 47 patients in each group, respectively. The 2 groups did not differ in prevalence of AH (77.3% vs. 81%), demographic data, MELD/Child-Pugh score, or DF. The 2 groups were similar in 6-month probability of survival (73.9 +/- 6.0% vs. 69.9 +/ 7%, p=0.49). The probability of developing infection was lower for AH-GIB+ patients (24.1% vs. 44.7%, p=0.04). The AUC for the Lille model in predicting 6 month survival was 0.71 +/- 0.06 for all patients and 0.74 +/- 0.06 for AH-GIB+ patients (p>0.05). CONCLUSIONS: Prevalence of AH is 80% for patients with cirrhosis and GIB, recent jaundice and DF ?32. Infection was lower for AH-GIB+ patients, which suggests a beneficial role of antibiotic prophylaxis treatment. Survival among subjects with GIB was the same as among subjects without GIB. PMID- 25450200 TI - Reply to: "Ferritin in decompensated cirrhosis: Iron or inflammation?". PMID- 25450202 TI - Target patients for partial hepatectomy and relationship between PLT and prognosis in BCLC B HCC. PMID- 25450201 TI - Performance of PIVKA-II for early hepatocellular carcinoma diagnosis and prediction of microvascular invasion. AB - BACKGROUND & AIMS: Prothrombin induced by vitamin K absence-II (PIVKA-II) is a diagnostic and surveillance marker for HCC mainly used in Asia, and has also been shown to be a predictor of microvascular invasion (MVI), a major prognostic factor in HCC. However, experience with PIVKA-II in Europe remains limited. METHODS: In a French cohort, we conducted a case-control study to compare the performances of alpha-fetoprotein (AFP) and PIVKA-II serum levels for diagnosis of early stage HCC, and we determined the value of PIVKA-II serum and tissue expression in pre-operative detection of MVI. 43 cirrhotic control patients and 85 HCC cases were included, of which 54 (63.5%) had early stage HCC (n=22 very early, n=32 early). PIVKA-II tissue expression was assessed by immunohistochemistry in HCC surgical samples. RESULTS: For the diagnosis of early HCC, PIVKA-II had a sensitivity of 77% and a specificity of 82% at a cut-off of 42 mAU/ml, vs. 61% and 50% for AFP at a cut-off of 5.5 ng/ml (AUC 0.81 vs. 0.58, respectively). A PIVKA-II level >90 mAU/ml was an independent predictor of MVI (HR 3.5; 95% CI 1.08-11.8; p=0.043). High PIVKA-II tissue expression was significantly associated with the presence of MVI (p=0.001). When combining PIVKA II immunostaining with the PIVKA-II serum level, sensitivity and specificity for the diagnosis of MVI increased from 70% to 87% and 63% to 90%, respectively. CONCLUSIONS: PIVKA-II was more efficient than AFP for the diagnosis of early HCC, and could be used as a predictive biomarker of MVI. PMID- 25450203 TI - Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand activated transcription factor belonging, together with PPARgamma and PPARbeta/delta, to the NR1C nuclear receptor subfamily. Many PPARalpha target genes are involved in fatty acid metabolism in tissues with high oxidative rates such as muscle, heart and liver. PPARalpha activation, in combination with PPARbeta/delta agonism, improves steatosis, inflammation and fibrosis in pre clinical models of non-alcoholic fatty liver disease, identifying a new potential therapeutic area. In this review, we discuss the transcriptional activation and repression mechanisms by PPARalpha, the spectrum of target genes and chromatin binding maps from recent genome-wide studies, paying particular attention to PPARalpha-regulation of hepatic fatty acid and plasma lipoprotein metabolism during nutritional transition, and of the inflammatory response. The role of PPARalpha, together with other PPARs, in non-alcoholic steatohepatitis will be discussed in light of available pre-clinical and clinical data. PMID- 25450204 TI - Saikosaponin b2 is a naturally occurring terpenoid that efficiently inhibits hepatitis C virus entry. AB - BACKGROUND & AIMS: A vaccine against hepatitis C virus (HCV) is unavailable and cost-effective antivirals that prevent HCV infection and re-infection, such as in the transplant setting, do not exist. In a search for novel and economical prophylactic agents, we examined the antiviral activity of saikosaponins (SSa, SSb2, SSc, and SSd) from Bupleurum kaoi root (BK) as entry inhibitors against HCV infection. METHODS: Infectious HCV culture systems were used to examine the effect of saikosaponins on the complete virus life cycle (entry, RNA replication/translation, and particle production). Antiviral activity against various HCV genotypes, clinical isolates, and infection of primary human hepatocytes were also evaluated. RESULTS: BK and the saikosaponins potently inhibited HCV infection at non-cytotoxic concentrations. These natural agents targeted early steps of the viral life cycle, while leaving replication/translation, egress, and spread relatively unaffected. In particular, we identified SSb2 as an efficient inhibitor of early HCV entry, including neutralization of virus particles, preventing viral attachment, and inhibiting viral entry/fusion. Binding analysis, using soluble viral glycoproteins, demonstrated that SSb2 acted on HCV E2. Moreover, SSb2 inhibited infection by several genotypic strains and prevented binding of serum-derived HCV onto hepatoma cells. Finally, treatment with the compound blocked HCV infection of primary human hepatocytes. CONCLUSIONS: Due to its potency, SSb2 may be of value for development as an antagonist of HCV entry and could be explored as prophylactic treatment during the course of liver transplantation. PMID- 25450205 TI - Autotaxin activity has a high accuracy to diagnose intrahepatic cholestasis of pregnancy. AB - BACKGROUND & AIMS: Intrahepatic cholestasis of pregnancy (ICP) is defined by pruritus, elevated total fasting serum bile salts (TBS) and transaminases, and an increased risk of adverse fetal outcome. An accurate diagnostic marker is needed. Increased serum autotaxin correlates with cholestasis-associated pruritus. We aimed at unraveling the diagnostic accuracy of autotaxin in ICP. METHODS: Serum samples and placental tissue were collected from 44 women with uncomplicated pregnancies and 105 with pruritus and/or elevated serum transaminases. Autotaxin serum levels were quantified enzymatically and by Western blotting, autotaxin gene expression by quantitative PCR. RESULTS: Serum autotaxin was increased in ICP (mean +/- SD: 43.5 +/- 18.2 nmol ml(-1)min(-1), n=55, p<0.0001) compared to other pruritic disorders of pregnancy (16.8 +/- 6.7 nmol ml(-1)min(-1), n=33), pre-eclampsia complicated by HELLP-syndrome (16.8 +/- 8.9 nmol ml(-1)min(-1), n=17), and pregnant controls (19.6 +/- 5.7 nmol ml(-1)min(-1), n=44). Longitudinal analysis during pregnancy revealed a marked rise in serum autotaxin with onset of ICP-related pruritus. Serum autotaxin was increased in women taking oral contraceptives. Increased serum autotaxin during ICP was not associated with increased autotaxin mRNA in placenta. With a cut-off value of 27.0 nmol ml( 1)min(-1), autotaxin had an excellent sensitivity and specificity in distinguishing ICP from other pruritic disorders or pre-eclampsia/HELLP-syndrome. Serum autotaxin displayed no circadian rhythm and was not influenced by food intake. CONCLUSIONS: Increased serum autotaxin activity represents a highly sensitive, specific and robust diagnostic marker of ICP, distinguishing ICP from other pruritic disorders of pregnancy and pregnancy-related liver diseases. Pregnancy and oral contraception increase serum autotaxin to a much lesser extent than ICP. PMID- 25450206 TI - An extension of STARD statements for reporting diagnostic accuracy studies on liver fibrosis tests: the Liver-FibroSTARD standards. AB - BACKGROUND & AIMS: Chronic liver diseases are highly prevalent and require an accurate evaluation of liver fibrosis to determine patient management. Over the last decade, great effort has been made to develop non-invasive liver fibrosis tests. The ensuing increase of literature is, however, impaired by extensive heterogeneity in the quality of published reports. The Standards for Reporting of Diagnostic Accuracy Studies (STARD), first published in 2003, were developed to improve the quality of research reports on diagnostic studies. We aimed to evaluate STARD statements in the setting of diagnostic studies on non-invasive liver fibrosis tests, and to propose an extended version developed specifically for those studies. METHODS: Eight French experts evaluated STARD statement adequacy in 10 studies on non-invasive liver fibrosis tests and then developed an extended version with a glossary. The new checklist and glossary were independently evaluated by seven international experts. RESULTS: Fourteen of the 25 STARD items were considered only partially adequate for the evaluation of diagnostic studies on non-invasive liver fibrosis tests. Inter-expert agreement was at least very good for 8 STARD items (32%), moderate for 9 (36%), and poor or very poor for 8 (32%). The experts' proposals were developed into the new Liver FibroSTARD standards including a checklist with 62 items/sub-items and a corresponding comprehensive glossary. New proposals were inserted in the 25 STARD items as a complementary module. Independent evaluation of the Liver-FibroSTARD checklist showed at least very good inter-expert agreement for 39 items/sub-items (63%), moderate agreement for 11 (18%), and poor or very poor agreement for only 12 (19%). CONCLUSIONS: As a supplement of the STARD statements, the Liver FibroSTARD checklist and its glossary are new tools specifically designed for the evaluation of diagnostic studies about non-invasive liver fibrosis tests. PMID- 25450207 TI - Reply to: "TERT promoter mutation during development of hepatoblastoma to hepatocellular carcinoma". PMID- 25450209 TI - TERT promoter mutation during development of hepatoblastoma to hepatocellular carcinoma. PMID- 25450208 TI - Sofosbuvir plus ribavirin for the treatment of chronic genotype 4 hepatitis C virus infection in patients of Egyptian ancestry. AB - BACKGROUND & AIMS: We conducted an open-label phase 2 study to assess the efficacy and safety of the oral nucleotide polymerase inhibitor sofosbuvir in combination with ribavirin in patients of Egyptian ancestry, chronically infected with genotype 4 hepatitis C virus (HCV). METHODS: Treatment-naive and previously treated patients with genotype 4 HCV were randomly allocated in a 1:1 ratio to receive sofosbuvir 400mg and weight-based ribavirin, for 12 or 24 weeks. The primary efficacy endpoint was the proportion of patients with sustained virologic response (HCV RNA <25IU/ml) 12 weeks after cessation of therapy (SVR12). RESULTS: Thirty treatment-naive and thirty previously treated patients were enrolled and treated for 12 weeks (n=31) or 24 weeks (n=29). Overall, 23% of patients had cirrhosis and 38% had diabetes. 14% of treatment-naive patients were interferon ineligible and 63% of treatment-experienced patients had prior non-response. SVR12 was achieved by 68% of patients (95% CI, 49-83%) in the 12-week group, and by 93% of patients (95% CI, 77-99%) in the 24-week group. The most common adverse events were headache, insomnia, and fatigue. No patient discontinued treatment due to an adverse event. CONCLUSIONS: The findings from the present study suggest that 24 weeks of sofosbuvir plus ribavirin is an efficacious and well tolerated treatment in patients with HCV genotype 4 infection. PMID- 25450210 TI - Partial hepatectomy vs. transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond Milan criteria: a RCT. PMID- 25450211 TI - Ferritin in decompensated cirrhosis: iron or inflammation? PMID- 25450212 TI - Circulating phospholipid profiling identifies portal contribution to NASH signature in obesity. AB - BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning with fibrosis in severe cases, and high prevalence in obesity. We aimed at defining NASH signature in morbid obesity by mass spectrometry-based lipidomic analysis. METHODS: We analyzed systemic blood before and 12 months after bariatric surgery, along with portal blood and adipose tissue lipid efflux collected from obese women at the time of surgery (9 structural classes, 150 species). RESULTS: Increased concentrations of several glycerophosphocholines (PC), glycerophosphoethanolamines (PE), glycerophosphoinositols (PI), glycerophosphoglycerols (PG), lyso-glycerophosphocholines (LPC), and ceramides (Cer) were detected in systemic circulation of NASH subjects. Post-surgery weight loss (12 months) improved the levels of liver enzymes, as well as several lipids, but most PG and Cer species remained elevated. Analysis of lipids from hepatic portal system at the time of surgery revealed limited lipid alterations compared to systemic circulation, but PG and PE classes were found significantly increased in NASH subjects. We evaluated the contribution of visceral adipose tissue to lipid alterations in portal circulation by measuring adipose tissue lipid efflux ex vivo, and observed only minor alterations in NASH subjects. Interestingly, integration of clinical and lipidomic data (portal and systemic) led us to define a NASH signature in which lipids and clinical parameters are equal contributors. CONCLUSIONS: Circulatory (portal and systemic) phospholipid profiling and clinical data defines NASH signature in morbid obesity. We report weak contribution of visceral adipose tissue to NASH-related portal lipid alterations, suggesting possible contribution from other organs draining into hepatic portal system. PMID- 25450213 TI - Urodynamic characteristics of rats with detrusor instability. AB - The purpose of the present study is to investigate urodynamic characteristics of rats with detrusor instability (DI) induced by different causes. Forty-eight adult female Sprague-Dawly rats were randomly divided into 4 groups: cyclophosphamide group, bladder outlet obstruction group, lipopolysaccharide group and control group. The BL-410 model bio-function experimental system was applied to monitor bladder pressure and a number of urodynamic parameters were recorded and calculated, including the frequency of detrusor instability, maximum voiding pressure (MVP), maximum cystometric capacity (MCC), intercontraction interval (ICI), voiding time (VT), postvoid residual (PVR) and bladder compliance (BC). The positive rates of DI in cyclophosphamide group, bladder outlet obstruction group and lipopolysaccharide group were 83.33%, 75.00% and 58.33%, respectively. And correspondingly the frequency of DI was 10.00+/-2.00, 4.87+/ 1.24 and 3.50+/-1.00tmin(-1), which was significantly higher than those of the control group (P<0.05). Compared with the control group, the decrease of MVP, MCC, ICI, VT and BC was noted in the cyclophosphamide group and lipopolysaccharide group. Increased PVR, MVP, MCC, VT and BC were presented in the bladder outlet obstruction group. Therefore, we suggested that the urodynamic parameters could reflect the pathophysiological characteristics of DI induced by different causes, which could systematically benefit the diagnosis and treatment of overactive bladder. PMID- 25450214 TI - Benefits of a new Metropolis-Hasting based algorithm, in non-linear regression for estimation of ex vivo antimalarial sensitivity in patients infected with two strains. AB - Malaria is one of the world's most widespread parasitic diseases. The parasitic protozoans of the genus Plasmodium have developed resistance to several antimalarial drugs. Some patients are therefore infected by two or more strains with different levels of antimalarial drug sensitivity. We previously developed a model to estimate the drug concentration (IC50) that inhibits 50% of the growth of the parasite isolated from a patient infected with one strain. We propose here a new Two-Slopes model for patients infected by two strains. This model involves four parameters: the proportion of each strain and their IC50, and the sigmoidicity parameter. To estimate the parameters of this model, we have developed a new algorithm called PGBO (Population Genetics-Based Optimizer). It is based on the Metropolis-Hasting algorithm and is implemented in the statistical software R. We performed a simulation study and defined three evaluation criteria to evaluate its properties and compare it with three other algorithms (Gauss-Newton, Levenberg-Marquardt, and a simulated annealing). We also evaluated it using in vitro data and three ex vivo datasets from the French Malaria Reference Center. Our evaluation criteria in the simulation show that PGBO gives good estimates of the parameters even if the concentration design is poor. Moreover, our algorithm is less sensitive than Gauss-Newton algorithms to initial values. Although parameter estimation is good, interpretation of the results can be difficult if the proportion of the second strain is close to 0 or 1. For these reasons, this approach cannot yet be implemented routinely. PMID- 25450216 TI - POTAMOS mass spectrometry calculator: computer aided mass spectrometry to the post-translational modifications of proteins. A focus on histones. AB - Mass spectrometry is a widely used technique for protein identification and it has also become the method of choice in order to detect and characterize the post translational modifications (PTMs) of proteins. Many software tools have been developed to deal with this complication. In this paper we introduce a new, free and user friendly online software tool, named POTAMOS Mass Spectrometry Calculator, which was developed in the open source application framework Ruby on Rails. It can provide calculated mass spectrometry data in a time saving manner, independently of instrumentation. In this web application we have focused on a well known protein family of histones whose PTMs are believed to play a crucial role in gene regulation, as suggested by the so called "histone code" hypothesis. The PTMs implemented in this software are: methylations of arginines and lysines, acetylations of lysines and phosphorylations of serines and threonines. The application is able to calculate the kind, the number and the combinations of the possible PTMs corresponding to a given peptide sequence and a given mass along with the full set of the unique primary structures produced by the possible distributions along the amino acid sequence. It can also calculate the masses and charges of a fragmented histone variant, which carries predefined modifications already implemented. Additional functionality is provided by the calculation of the masses of fragments produced upon protein cleavage by the proteolytic enzymes that are most widely used in proteomics studies. PMID- 25450215 TI - Spike sorting paradigm for classification of multi-channel recorded fasciculation potentials. AB - BACKGROUND: Fasciculation potentials (FPs) are important in supporting the electrodiagnosis of Amyotrophic Lateral Sclerosis (ALS). If classified by shape, FPs can also be very informative for laboratory-based neurophysiological investigations of the motor units. METHODS: This study describes a Matlab program for classification of FPs recorded by multi-channel surface electromyogram (EMG) electrodes. The program applies Principal Component Analysis on a set of features recorded from all channels. Then, it registers unsupervised and supervised classification algorithms to sort the FP samples. Qualitative and quantitative evaluation of the results is provided for the operator to assess the outcome. The algorithm facilitates manual interactive modification of the results. Classification accuracy can be improved progressively until the user is satisfied. The program makes no assumptions regarding the occurrence times of the action potentials, in keeping with the rather sporadic and irregular nature of FP firings. RESULTS: Ten sets of experimental data recorded from subjects with ALS using a 20-channel surface electrode array were tested. A total of 11891 FPs were detected and classified into a total of 235 prototype template waveforms. Evaluation and correction of classification outcome of such a dataset with over 6000 FPs can be achieved within 1-2 days. Facilitated interactive evaluation and modification could expedite the process of gaining accurate final results. CONCLUSION: The developed Matlab program is an efficient toolbox for classification of FPs. PMID- 25450217 TI - A classification study of kinematic gait trajectories in hip osteoarthritis. AB - The clinical evaluation of patients in hip osteoarthritis is often done using patient questionnaires. While this provides important information it is also necessary to continue developing objective measures. In this work we further investigate the studies concerning the use of 3D gait analysis to attain this goal. The gait analysis was associated with machine learning methods in order to provide a direct measure of patient control gait discrimination. The applied machine learning method was the support vector machine (SVM). Applying the SVM on all the measured kinematic trajectories, we were able to classify individual patient and control gait cycles with a mean success rate of 88%. With the use of an ROC curve to establish the threshold number of cycles necessary for a subject to be identified as a patient, this allowed for an accuracy of higher than 90% for discriminating patient and control subjects. We then went on to determine the importance of each trajectory. By ranking the capacity of each trajectory for this discrimination, we provided a guide on their order of importance in evaluating patient severity. In order to be clinically relevant, any measure of patient deficit must be compared with clinically validated scores of functional disability. In the case of hip osteoarthritis (OA), the WOMAC scores are currently one of the most widely accepted clinical scores for quantifying OA severity. The kinematic trajectories that provided the best patient-control discrimination with the SVM were found to correlate well but imperfectly with the WOMAC scores, hence indicating the presence of complementary information in the two. PMID- 25450218 TI - Degrees of separation as a statistical tool for evaluating candidate genes. AB - Selection of candidate genes is an important step in the exploration of complex genetic architecture. The number of gene networks available is increasing and these can provide information to help with candidate gene selection. It is currently common to use the degree of connectedness in gene networks as validation in Genome Wide Association (GWA) and Quantitative Trait Locus (QTL) mapping studies. However, it can cause misleading results if not validated properly. Here we present a method and tool for validating the gene pairs from GWA studies given the context of the network they co-occur in. It ensures that proposed interactions and gene associations are not statistical artefacts inherent to the specific gene network architecture. The CandidateBacon package provides an easy and efficient method to calculate the average degree of separation (DoS) between pairs of genes to currently available gene networks. We show how these empirical estimates of average connectedness are used to validate candidate gene pairs. Validation of interacting genes by comparing their connectedness with the average connectedness in the gene network will provide support for said interactions by utilising the growing amount of gene network information available. PMID- 25450219 TI - Dynamic finite element analysis and moving particle simulation of human enamel on a microscale. AB - BACKGROUND: The study of biomechanics of deformation and fracture of hard biological tissues involving organic matrix remains a challenge as variations in mechanical properties and fracture mode may have time-dependency. Finite element analysis (FEA) has been widely used but the shortcomings of FEA such as the long computation time owing to re-meshing in simulating fracture mechanics have warranted the development of alternative computational methods with higher throughput. The aim of this study was to compare dynamic two-dimensional FEA and moving particle simulation (MPS) when assuming a plane strain condition in the modeling of human enamel on a reduced scale. METHODS: Two-dimensional models with the same geometry were developed for MPS and FEA and tested in tension generated with a single step of displacement. The displacement, velocity, pressure, and stress levels were compared and Spearman's rank-correlation coefficients R were calculated (p<0.001). RESULTS: The MPS and FEA were significantly correlated for displacement, velocity, pressure, and Y-stress. CONCLUSIONS: The MPS may be further developed as an alternative approach without mesh generation to simulate deformation and fracture phenomena of dental and potentially other hard tissues with complex microstructure. PMID- 25450220 TI - Establishing the macular grading grid by means of fovea centre detection using anatomical-based and visual-based features. AB - This paper presents a methodology for establishing the macular grading grid in digital retinal images by means of fovea centre detection. To this effect, visual and anatomical feature-based criteria are combined with the aim of exploiting the benefits of both techniques. First, acceptable fovea centre estimation is obtained by using a priori known anatomical features with respect to the optic disc and the vascular tree. Second, a type of morphological processing is employed in an attempt to improve the obtained fovea centre estimation when the fovea is detectable in the image; otherwise, it is declared indistinguishable and the first result is retained. The methodology was tested on the MESSIDOR and DIARETDB1 databases making use of a distance criterion between the obtained and the real fovea centre. Fovea centres in the brackets between the categories Excellent and Fair (fovea centres primarily accepted as valid in the literature) made up for 98.24% and 94.38% of the cases in the MESSIDOR and DIARETDB1, respectively. PMID- 25450221 TI - A ternary model of decompression sickness in rats. AB - BACKGROUND: Decompression sickness (DCS) in rats is commonly modelled as a binary outcome. The present study aimed to develop a ternary model of predicting probability of DCS in rats, (as no-DCS, survivable-DCS or death), based upon the compression/decompression profile and physiological characteristics of each rat. METHODS: A literature search identified dive profiles with outcomes no-DCS, survivable-DCS or death by DCS. Inclusion criteria were that at least one rat was represented in each DCS status, not treated with drugs or simulated ascent to altitude, that strain, sex, breathing gases and compression/decompression profile were described and that weight was reported. A dataset was compiled (n=1602 rats) from 15 studies using 22 dive profiles and two strains of both sexes. Inert gas pressures in five compartments were estimated. Using ordinal logistic regression, model-fit of the calibration dataset was optimised by maximum log likelihood. Two validation datasets assessed model robustness. RESULTS: In the interpolation dataset the model predicted 10/15 cases of nDCS, 3/3 sDCS and 2/2 dDCS, totalling 15/20 (75% accuracy) and 18.5/20 (92.5%) were within 95% confidence intervals. Mean weight in the extrapolation dataset was more than 2SD outside of the calibration dataset and the probability of each outcome was not predictable. DISCUSSION: This model is reliable for the prediction of DCS status providing the dive profile and rat characteristics are within the range of parameters used to optimise the model. The addition of data with a wider range of parameters should improve the applicability of the model. PMID- 25450222 TI - Three-dimensional semiautomatic liver segmentation method for non-contrast computed tomography based on a correlation map of locoregional histogram and probabilistic atlas. AB - BACKGROUND: We sought to evaluate a new regional segmentation method for use with three-dimensional (3D) non-contrast abdominal CT images and to report the preliminary results. METHODS: The proposed method was evaluated in ten cases. Manually segmented areas were used as the gold standard for evaluation. To compare the standard and the extracted liver regions, the degree of coincidence R% was redefined by transforming a volumetric overlap error. We also evaluated the influence of varying the density window size in terms of setting the starting points. RESULTS: We confirmed in ten cases that our method could segment the liver region more precisely than the conventional method. A size of window 15 voxels was optimal as the starting point in all cases. CONCLUSIONS: We demonstrated the accuracy of a 3D semiautomatic liver segmentation method for non contrast CT. This method promises to offer radiologists a time-efficient segmentation aid. PMID- 25450223 TI - Haemophilus influenzae Genome Database (HIGDB): a single point web resource for Haemophilus influenzae. AB - BACKGROUND: Haemophilus influenzae (H. Influenzae) is the causative agent of pneumonia, bacteraemia and meningitis. The organism is responsible for large number of deaths in both developed and developing countries. Even-though the first bacterial genome to be sequenced was that of H. Influenzae, there is no exclusive database dedicated for H. Influenzae. This prompted us to develop the Haemophilus influenzae Genome Database (HIGDB). METHODS: All data of HIGDB are stored and managed in MySQL database. The HIGDB is hosted on Solaris server and developed using PERL modules. Ajax and JavaScript are used for the interface development. RESULTS: The HIGDB contains detailed information on 42,741 proteins, 18,077 genes including 10 whole genome sequences and also 284 three dimensional structures of proteins of H. influenzae. In addition, the database provides "Motif search" and "GBrowse". The HIGDB is freely accessible through the URL: http://bioserver1.physics.iisc.ernet.in/HIGDB/. DISCUSSION: The HIGDB will be a single point access for bacteriological, clinical, genomic and proteomic information of H. influenzae. The database can also be used to identify DNA motifs within H. influenzae genomes and to compare gene or protein sequences of a particular strain with other strains of H. influenzae. PMID- 25450224 TI - A computational framework for cancer response assessment based on oncological PET CT scans. AB - In this work we present a comprehensive computational framework to help in the clinical assessment of cancer response from a pair of time consecutive oncological PET-CT scans. In this scenario, the design and implementation of a supervised machine learning system to predict and quantify cancer progression or response conditions by introducing a novel feature set that models the underlying clinical context is described. Performance results in 100 clinical cases (corresponding to 200 whole body PET-CT scans) in comparing expert-based visual analysis and classifier decision making show up to 70% accuracy within a completely automatic pipeline and 90% accuracy when providing the system with expert-guided PET tumor segmentation masks. PMID- 25450225 TI - A moonlighting function of Mycobacterium smegmatis Ku in zinc homeostasis? AB - Ku protein participates in DNA double-strand break repair via the nonhomologous end-joining pathway. The three-dimensional structure of eukaryotic Ku reveals a central core consisting of a beta-barrel domain and pillar and bridge regions that combine to form a ring-like structure that encircles DNA. Homologs of Ku are encoded by a subset of bacterial species, and they are predicted to conserve this core domain. In addition, the bridge region of Ku from some bacteria is predicted from homology modeling and sequence analyses to contain a conventional HxxC and CxxC (where x is any residue) zinc-binding motif. These potential zinc-binding sites have either deteriorated or been entirely lost in Ku from other organisms. Using an in vitro metal binding assay, we show that Mycobacterium smegmatis Ku binds two zinc ions. Zinc binding modestly stabilizes the Ku protein (by ~3 degrees C) and prevents cysteine oxidation, but it has little effect on DNA binding. In vivo, zinc induces significant upregulation of the gene encoding Ku (~sixfold) as well as a divergently oriented gene encoding a predicted zinc dependent MarR family transcription factor. Notably, overexpression of Ku confers zinc tolerance on Escherichia coli. We speculate that zinc-binding sites in Ku proteins from M. smegmatis and other mycobacterial species have been evolutionarily retained to provide protection against zinc toxicity without compromising the function of Ku in DNA double-strand break repair. PMID- 25450226 TI - A2A adenosine receptor deletion is protective in a mouse model of Tauopathy. AB - Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies. PMID- 25450227 TI - Transcriptome organization for chronic alcohol abuse in human brain. AB - Alcohol dependence is a heterogeneous psychiatric disorder characterized by high genetic heritability and neuroadaptations occurring from repeated drug exposure. Through an integrated systems approach we observed consistent differences in transcriptome organization within postmortem human brain tissue associated with the lifetime consumption of alcohol. Molecular networks, determined using high throughput RNA sequencing, for drinking behavior were dominated by neurophysiological targets and signaling mechanisms of alcohol. The systematic structure of gene sets demonstrates a novel alliance of multiple ion channels, and related processes, underlying lifetime alcohol consumption. Coordinate expression of these transcripts was enriched for genome-wide association signals in alcohol dependence and a meta-analysis of alcohol self-administration in mice. Further dissection of genes within alcohol consumption networks revealed the potential interaction of alternatively spliced transcripts. For example, expression of a human-specific isoform of the voltage-gated sodium channel subunit SCN4B was significantly correlated to lifetime alcohol consumption. Overall, our work demonstrates novel convergent evidence for biological networks related to excessive alcohol consumption, which may prove fundamentally important in the development of pharmacotherapies for alcohol dependence. PMID- 25450228 TI - Reciprocal causation models of cognitive vs volumetric cerebral intermediate phenotypes for schizophrenia in a pan-European twin cohort. AB - In aetiologically complex illnesses such as schizophrenia, there is no direct link between genotype and phenotype. Intermediate phenotypes could help clarify the underlying biology and assist in the hunt for genetic vulnerability variants. We have previously shown that cognition shares substantial genetic variance with schizophrenia; however, it is unknown if this reflects pleiotropic effects, direct causality or some shared third factor that links both, for example, brain volume (BV) changes. We quantified the degree of net genetic overlap and tested the direction of causation between schizophrenia liability, brain structure and cognition in a pan-European schizophrenia twin cohort consisting of 1243 members from 626 pairs. Cognitive deficits lie upstream of the liability for schizophrenia with about a quarter of the variance in liability to schizophrenia explained by variation in cognitive function. BV changes lay downstream of schizophrenia liability, with 4% of BV variation explained directly by variation in liability. However, our power to determine the nature of the relationship between BV deviation and schizophrenia liability was more limited. Thus, while there was strong evidence that cognitive impairment is causal to schizophrenia liability, we are not in a position to make a similar statement about the relationship between liability and BV. This is the first study to demonstrate that schizophrenia liability is expressed partially through cognitive deficits. One prediction of the finding that BV changes lie downstream of the disease liability is that the risk loci that influence schizophrenia liability will thereafter influence BV and to a lesser extent. By way of contrast, cognitive function lies upstream of schizophrenia, thus the relevant loci will actually have a larger effect size on cognitive function than on schizophrenia. These are testable predictions. PMID- 25450229 TI - The contribution of rare and common variants in 30 genes to risk nicotine dependence. AB - Genetic and functional studies have revealed that both common and rare variants of several nicotinic acetylcholine receptor subunits are associated with nicotine dependence (ND). In this study, we identified variants in 30 candidate genes including nicotinic receptors in 200 sib pairs selected from the Mid-South Tobacco Family population with equal numbers of African Americans (AAs) and European Americans (EAs). We selected 135 of the rare and common variants and genotyped them in the Mid-South Tobacco Case-Control (MSTCC) population, which consists of 3088 AAs and 1430 EAs. None of the genotyped common variants showed significant association with smoking status (smokers vs non-smokers), Fagerstrom Test for ND scores or indexed cigarettes per day after Bonferroni correction. Rare variants in NRXN1, CHRNA9, CHRNA2, NTRK2, GABBR2, GRIN3A, DNM1, NRXN2, NRXN3 and ARRB2 were significantly associated with smoking status in the MSTCC AA sample, with weighted sum statistic (WSS) P-values ranging from 2.42 * 10(-3) to 1.31 * 10(-4) after 10(6) phenotype rearrangements. We also observed a significant excess of rare nonsynonymous variants exclusive to EA smokers in NRXN1, CHRNA9, TAS2R38, GRIN3A, DBH, ANKK1/DRD2, NRXN3 and CDH13 with WSS P values between 3.5 * 10(-5) and 1 * 10(-6). Variants rs142807401 (A432T) and rs139982841 (A452V) in CHRNA9 and variants V132L, V389L, rs34755188 (R480H) and rs75981117 (N549S) in GRIN3A are of particular interest because they are found in both the AA and EA samples. A significant aggregate contribution of rare and common coding variants in CHRNA9 to the risk for ND (SKAT-C: P=0.0012) was detected by applying the combined sum test in MSTCC EAs. Together, our results indicate that rare variants alone or combined with common variants in a subset of 30 biological candidate genes contribute substantially to the risk of ND. PMID- 25450231 TI - Attenuation of ER stress prevents post-infarction-induced cardiac rupture and remodeling by modulating both cardiac apoptosis and fibrosis. AB - Endoplasmic reticulum (ER) stress is implicated in the pathophysiology of various cardiovascular diseases, but the role of ER stress in cardiac rupture and/or remodeling after myocardial infarction (MI) is still unclear. Here we investigated whether ER stress plays a major role for these processes in mice. We ligated the left coronary artery (LCA) without reperfusion in mice and administered either NaCl or 4-phenylbutyric acid (4-PBA, 20 mg/kg/d) intraperitoneally for 4 weeks. Cardiac rupture rates during the first week of MI were 37.5% and 18.2% in the control and 4-PBA groups, respectively. The extent of ventricular aneurysm and fibrosis was less, and the cardiac function better, in the 4-PBA group compared with the control group. The protein levels of ER stress markers in the heart tissues of the control group remained elevated during the entire 4-week period after MI, while pro-apoptotic proteins mainly increased in the early phase, and the pro-fibrotic proteins markedly increased in the late phase post MI; 4-PBA decreased all of these protein levels. In the primary cultured neonatal rat cardiomyocytes or fibroblasts, hypoxia (3% O2) increased the number of apoptotic cardiomyocytes and promoted the proliferation and migration of fibroblasts, all of which were attenuated by 4-PBA (0.5 mM). These findings indicate that MI induces ER stress and provokes cardiac apoptosis and fibrosis, culminating in cardiac rupture and remodeling, and that the attenuation of ER stress could be an effective therapeutic target to prevent post-MI complications. PMID- 25450234 TI - Anti-arthritic activity of luteolin in Freund's complete adjuvant-induced arthritis in rats by suppressing P2X4 pathway. AB - To investigate anti-arthritic activity of luteolin (Lut) in Freund's complete adjuvant (FCA)-induced arthritis (AA) in rats. AA was induced by injecting with Freund's complete adjuvant (FCA). Male rats were randomly divided into five groups with 10 mice in each group: (1) control group (saline), (2) AA group, (3) AA+Diclofenac Sodium (AA+DS, 5 mg/kg), (4) AA+Lut (20 mg/kg), (5) AA+Lut (40 mg/kg). Male SD rats were subjected to treatment with Lut at 10 and 20 mg/kg from days 18 to 24 after immunization. Arthritic scores, tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), interleukin-6 (IL-6), interleukin-17 (IL-17), paw histopathology and the proteins of P2X4 pathway were assessed at the end of the experiment. Lut reduced the severity of arthritic scores during the experimental period as compared with positive control (RA). Lut significantly suppressed TNF-alpha, IL-6, IL-1beta and IL-17 as compared with RA group. Histopathological examination indicated that Lut alleviated infiltration of inflammatory cells and synovial hyperplasia as well as protected joint destruction. Lut significantly suppressed P2X4, NLRP1, ASC, and Caspase-1p10. Lut may be a potential preventive or therapeutic candidate for the treatment of inflammation and arthritis. PMID- 25450232 TI - 15-Oxoeicosatetraenoic acid is a 15-hydroxyprostaglandin dehydrogenase-derived electrophilic mediator of inflammatory signaling pathways. AB - Bioactive lipids govern cellular homeostasis and pathogenic inflammatory processes. Current dogma holds that bioactive lipids, such as prostaglandins and lipoxins, are inactivated by 15-hydroxyprostaglandin dehydrogenase (15PGDH). In contrast, the present results reveal that catabolic "inactivation" of hydroxylated polyunsaturated fatty acids (PUFAs) yields electrophilic alpha,beta unsaturated ketone derivatives. These endogenously produced species are chemically reactive signaling mediators that induce tissue protective events. Electrophilic fatty acids diversify the proteome through post-translational alkylation of nucleophilic cysteines in key transcriptional regulatory proteins and enzymes that govern cellular metabolic and inflammatory homeostasis. 15PGDH regulates these processes as it is responsible for the formation of numerous electrophilic fatty acids including the arachidonic acid metabolite, 15 oxoeicosatetraenoic acid (15-oxoETE). Herein, the role of 15-oxoETE in regulating signaling responses is reported. In cell cultures, 15-oxoETE activates Nrf2 regulated antioxidant responses (AR) and inhibits NF-kappaB-mediated pro inflammatory responses via IKKbeta inhibition. Inhibition of glutathione S transferases using ethacrynic acid incrementally increased the signaling capacity of 15-oxoETE by decreasing 15-oxoETE-GSH adduct formation. This work demonstrates that 15PGDH plays a role in the regulation of cell and tissue homeostasis via the production of electrophilic fatty acid signaling mediators. PMID- 25450233 TI - Development of a high-throughput in vitro assay to identify selective inhibitors for human ALDH1A1. AB - The human aldehyde dehydrogenase (ALDH) superfamily consists of at least 19 enzymes that metabolize endogenous and exogenous aldehydes. Currently, there are no commercially available inhibitors that target ALDH1A1 but have little to no effect on the structurally and functionally similar ALDH2. Here we present the first human ALDH1A1 structure, as the apo-enzyme and in complex with its cofactor NADH to a resolution of 1.75 and 2.1A, respectfully. Structural comparisons of the cofactor binding sites in ALDH1A1 with other closely related ALDH enzymes illustrate a high degree of similarity. In order to minimize discovery of compounds that inhibit both isoenzymes by interfering with their conserved cofactor binding sites, this study reports the use of an in vitro, NAD(+) independent, esterase-based high-throughput screen (HTS) of 64,000 compounds to discover novel, selective inhibitors of ALDH1A1. We describe 256 hits that alter the esterase activity of ALDH1A1. The effects on aldehyde oxidation of 67 compounds were further analyzed, with 30 selectively inhibiting ALDH1A1 compared to ALDH2 and ALDH3A1. One compound inhibited ALDH1A1 and ALDH2, while another inhibited ALDH1A1, ALDH2, and the more distantly related ALDH3A1. The results presented here indicate that this in vitro enzyme activity screening protocol successfully identified ALDH1A1 inhibitors with a high degree of isoenzyme selectivity. The compounds identified via this screen plus the screening methodology itself represent a starting point for the development of highly potent and selective inhibitors of ALDH1A1 that may be utilized to better understand the role of this enzyme in both normal and disease states. PMID- 25450235 TI - Galangin inhibits growth of human head and neck squamous carcinoma cells in vitro and in vivo. AB - Galangin, an active flavonoid component extracted from the propolis and root of Alpinia officinarum Hance, has anti-tumor activity, but the mechanisms by which galangin affects various cancers, including human head and neck squamous cell carcinoma (HNSCC) remain unclear. In this study, we demonstrated for the first time that galangin suppressed the growth of HNSCC in vivo. With the cell culture system, galangin inhibited the proliferation and colony formation of HNSCC cells in a dose-dependent manner. Galangin induced significant cell cycle arrest of the tumor cells at the G0/G1 phase, which was accompanied by reduced AKT phosphorylation and mammalian target of rapamycin and S6 kinase activation. Decreased expression of cyclin D1, cyclin-dependent kinase (CDK)4, CDK6 and phosphorylation of retinoblastoma protein was observed in galangin-treated HNSCC cells. In addition, galangin induced apoptosis of HNSCC cells, downregulating antiapoptotic protein Bcl-2 and Bcl-xL and upregulating proapoptotic protein Bax and cleaved caspase 3. Immunohistochemical analysis showed a dose-dependent reduction in cyclin-D1-positive cancer cells and an increase in TUNEL-positive cancer cells in galangin-administrated mouse tumor sections. Therefore, galangin may be a novel therapeutic option in human HNSCC treatment. PMID- 25450236 TI - Isoliquiritigenin attenuates oxidative hepatic damage induced by carbon tetrachloride with or without buthionine sulfoximine. AB - Glycyrrhizae radix (G. radix) has been demonstrated to have hepatoprotective properties. This study determined the therapeutic effects of isoliquiritigenin (isoLQ) in G. radix, against liver injury induced by CCl4 in rats. CCl4 (0.5 ml/kg/d, twice) or CCl4 plus buthionine sulfoximine exerted severe liver damage assessed by increased plasma levels of alanine aminotransferase and aspartate aminotransferase, in addition to hepatic degeneration and necrosis. These pathological changes were markedly protected by pretreatment with isoLQ (5, 20 mg/kg/d, p.o.) for 3 consecutive days. In addition, pretreatment with isoLQ inhibited CCl4-induced reduction of cytochrome P450 2E1 protein and mRNA expression as well as activity in the liver. Moreover, isoLQ pretreatment reversed the decrease in hepatic antioxidant capacity induced by CCl4 as well as suppressed expression of tumor necrosis factor-alpha and cyclooxigenase-2 in the liver. These results suggest that isoLQ has a protective effect against CCl4 induced liver damage through induction of antioxidant and anti-inflammatory activities. PMID- 25450230 TI - Molecular underpinnings of prefrontal cortex development in rodents provide insights into the etiology of neurodevelopmental disorders. AB - The prefrontal cortex (PFC), seat of the highest-order cognitive functions, constitutes a conglomerate of highly specialized brain areas and has been implicated to have a role in the onset and installation of various neurodevelopmental disorders. The development of a properly functioning PFC is directed by transcription factors, guidance cues and other regulatory molecules and requires the intricate and temporal orchestration of a number of developmental processes. Disturbance or failure of any of these processes causing neurodevelopmental abnormalities within the PFC may contribute to several of the cognitive deficits seen in patients with neurodevelopmental disorders. In this review, we elaborate on the specific processes underlying prefrontal development, such as induction and patterning of the prefrontal area, proliferation, migration and axonal guidance of medial prefrontal progenitors, and their eventual efferent and afferent connections. We furthermore integrate for the first time the available knowledge from genome-wide studies that have revealed genes linked to neurodevelopmental disorders with experimental molecular evidence in rodents. The integrated data suggest that the pathogenic variants in the neurodevelopmental disorder-associated genes induce prefrontal cytoarchitectonical impairments. This enhances our understanding of the molecular mechanisms of prefrontal (mis)development underlying the four major neurodevelopmental disorders in humans, that is, intellectual disability, autism spectrum disorders, attention deficit hyperactivity disorder and schizophrenia, and may thus provide clues for the development of novel therapies. PMID- 25450238 TI - Purification and immunodetection of the complete recombinant HER-2[neu] receptor produced in yeast. AB - For the first time, the full length recombinant HER-2[neu] receptor has been produced in a yeast (Arxula adeninivorans). It is one of the most studied membrane receptors in oncology and is involved in aggressive tumor formation. A yeast integration rDNA cassette containing the human gene coding for the HER 2[neu] protein was constructed and a screening procedure was performed to select the most productive transformant. Different detergents were tested for efficient solubilization of the membrane bound protein, with CHAPS giving the best results. To increase the yield of the recombinant protein from HER-2[neu] producing A. adeninivorans, optimal culture parameters were established for cultivation in bioreactor. The recombinant protein was subsequently assayed using ELISA and SPR immunoassays systems with antibodies raised against two different epitopes of the human receptor. In both cases, elution fractions containing the recombinant HER 2[neu] receptor successfully reacted with the immunoassays with limits of quantification below 100ngml(-1). These results demonstrate that the full length recombinant HER-2[neu] reported here has the potential to be a new standard for the detection of HER-2 type cancer. PMID- 25450239 TI - Challenging the validity of the association between oversleeping and overeating in atypical depression. AB - OBJECTIVE: In this study, we used a strict definition of hypersomnia and tested if the association between overeating-hypersomnia remained positive and significant. Hypersomnia was present if the total sleep time was close to 10h per day or was at least 2h longer than in normothymic periods. METHODS: Cross sectional study using the adult general population of California and New York. The sample was composed of 6694 individuals aged between 18 and 96years. Participants were interviewed by telephone using the Sleep-EVAL system. The interviews included various sleep and health topics and the assessment of DSM-IV sleep and psychiatric disorders. RESULTS: The one-month prevalence of major depressive episode was 6.1%, including a one-month prevalence of atypical depression of 1.6%, in this sample. Atypical depression subjects had a greater number of depressive symptoms and a longer duration of the current depressive episode than the other depressive subjects. Depressive subjects with hypersomnia slept longer (8h, 29min) than the other depressive subjects (6h, 36min) and longer than the subjects "getting too much sleep" (6h, 48min). Furthermore, hypersomnia was not associated with overeating while "getting too much sleep" showed a positive association with overeating. CONCLUSIONS: Hypersomnia needs to be evaluated using a strict definition. Otherwise, it leads to an overestimation of this symptom in major depressive episode subjects and to a false association with overeating. PMID- 25450237 TI - Expression and in vitro functional analyses of recombinant Gam1 protein. AB - Gam1, an early gene product of an avian adenovirus, is essential for viral replication. Gam1 is the first viral protein found to globally inhibit cellular SUMOylation, a critical posttranslational modification that alters the function and cellular localization of proteins. The interaction details at the interface between Gam1 and its cellular targets remain unclear due to the lack of structural information. Although Gam1 has been previously characterized, the purity of the protein was not suitable for structural investigations. In the present study, the gene of Gam1 was cloned and expressed in various bacterial expression systems to obtain pure and soluble recombinant Gam1 protein for in vitro functional and structural studies. While Gam1 was insoluble in most expression systems tested, it became soluble when it was expressed as a fusion protein with trigger factor (TF), a ribosome associated bacterial chaperone, under the control of a cold shock promoter. Careful optimization indicates that both low temperature induction and the chaperone function of TF play critical roles in increasing Gam1 solubility. Soluble Gam1 was purified to homogeneity through sequential chromatography techniques. Monomeric Gam1 was obtained via size exclusion chromatography and analyzed by dynamic light scattering. The SUMOylation inhibitory function of the purified Gam1 was confirmed in an in vitro assay. These results have built the foundation for further structural investigations that will broaden our understanding of Gam1's roles in viral replication. PMID- 25450241 TI - Evacuating a pre-Descemet hematoma through a clear corneal incision during a canaloplasty procedure. AB - We present a surgical technique for evacuating an intracorneal pre-Descemet hematoma that occurred during a canaloplasty procedure. The technique allows both evacuation of the hematoma outside the anterior chamber and preservation of the intact Descemet membrane, and it can be performed within the primary procedure. Intraoperative pre-Descemet hematoma is reported to be a relatively rare complication of canaloplasty; however, to hasten visual recovery and to avoid potentially sight-threatening complications, surgeons should be aware of this possible complication and be prepared to resolve it as early as possible, even within the canaloplasty procedure. PMID- 25450240 TI - Tumour necrosis factor alpha inhibitor therapy and rehabilitation for the treatment of ankylosing spondylitis: a systematic review. AB - OBJECTIVES: To systematically review the evidence for a synergistic effect of combining rehabilitation with biological anti-tumour necrosis factor (TNF) therapy in patients with ankylosing spondylitis (AS). METHODS: Data were analysed to identify the most effective rehabilitation programmes, the best endpoints for effectiveness, and patient subgroups most likely to benefit from combination therapy. Systematic MEDLINE and Embase searches were performed to identify studies evaluating rehabilitation programmes and biological therapy in patients with AS. Evidence was categorised by study type, and efficacy, adverse effects and other outcomes were summarised. RESULTS: Of the 75 studies identified, 13 investigated the combination of a rehabilitation programme with TNF inhibitor therapy, while the remainder studied rehabilitation with standard therapy (often not specified). Data from these few studies suggest that combined rehabilitation plus anti-TNF therapy is more effective in terms of symptom severity, disease activity, disability and quality-of-life indices versus biologic alone or rehabilitation with standard medical therapy, or, in non-comparative studies, compared with baseline. The most effective rehabilitation appears to be supervised or in-patient programmes with an educational component. Available data do not provide guidance on most appropriate endpoints or identify patients most likely to benefit from combination therapy. Combined, TNF inhibitor and rehabilitation therapy appear to have a synergistic effect, possibly due to increased adherence to exercise. Exercise regimes are more effective if supervised and include an education component. CONCLUSIONS: Further randomized, controlled trials comparing endpoints and investigating longer-term benefits of combining TNF inhibitors with rehabilitation in different AS subgroups are needed. PMID- 25450242 TI - Optical coherence tomography and 3-dimensional confocal structured imaging system guided femtosecond laser capsulotomy versus manual continuous curvilinear capsulorhexis. AB - PURPOSE: To compare the features of capsulotomy obtained during femtosecond laser assisted cataract surgery with those of continuous curvilinear capsulorhexis (CCC) obtained using a standard manual technique. SETTING: Ophthalmology Clinic, Department of Medicine and Science of Ageing, University G. D'Annunzio Chieti Pescara, Chieti, Italy. DESIGN: Prospective randomized clinical study. METHODS: Candidates for cataract extraction were randomized into 1 of 3 groups as follows: Lensx femtosecond laser-assisted cataract surgery capsulotomy (laser group 1), Lensar femtosecond laser-assisted cataract surgery capsulotomy (laser group 2), and manual CCC (manual group). RESULTS: Each group comprised 30 eyes (30 patients). The capsulotomies in laser group 1 and laser group 2 showed significantly better circularity than the manual CCCs at 7 days (P<.001). There was a significant correlation between the intended versus achieved capsulotomy size in the 2 laser groups. Both laser groups had better intraocular lens (IOL) centration than the manual group at all timepoints (P<.001). Between-group differences in uncorrected and corrected distance visual acuities were not statistically significant. The residual spherical equivalent and mean absolute error were statistically significantly smaller in the 2 laser groups than in the manual group (P=.038) and increased significantly over time in all the groups (P<.001). CONCLUSIONS: Femtosecond laser capsulotomies showed better circularity with more predictable size than manual CCCs. In addition, IOL centration was better immediately after surgery and over time with better refractive results in the 2 laser groups. PMID- 25450243 TI - Correlation of corneal thickness and volume with intraoperative phacoemulsification parameters using Scheimpflug imaging and optical coherence tomography. AB - PURPOSE: To evaluate post-phacoemulsification corneal edema using central corneal thickness (CCT) and central corneal volume (CCV) derived from Scheimpflug imaging, optical coherence tomography (OCT), and ultrasound (US) pachymetry and to correlate CCV with phacoemulsification parameters. SETTING: Department of Ophthalmology, Boston Medical Center, Boston, Massachusetts, USA. DESIGN: Prospective case study. METHODS: Scheimpflug imaging (Pentacam HR), OCT (Cirrus HD-OCT), and US pachymetry (Pachmate) were used to measure the CCT, CCV, and phacoemulsification parameters after uneventful phacoemulsification over a 1 month follow-up. RESULTS: In the 16 eyes assessed, the Scheimpflug CCT was less than the US CCT preoperatively (P=.01) and 1 week postoperatively (P=.02). The OCT CCT was less than the US CCT at 1 week and 1 month (both P<.01). At 3.0 mm, the CCV was increased at 1 day and 1 week (both P<.01) but returned to preoperative levels by 1 month (P=.09). However, the 7.0 mm CCV remained elevated at 1 month (P<.01). There were strong correlations between the change in the 7.0 mm CCV and the estimated fluid used (r = 0.76) and phacoemulsification time (r = 0.61). CONCLUSIONS: Scheimpflug imaging and OCT underestimated the CCT in normal eyes compared with US pachymetry, with a trend toward thicker measurements in acutely edematous corneas. Although the CCV returned to preoperative values at 1 month, the peripheral cornea remained edematous, possibly because of a correlation with the estimated amount of fluid used and phacoemulsification time. PMID- 25450244 TI - Aqueous reaction quantification after phacoemulsification: Fourier-domain optical coherence tomography versus slitlamp biomicroscopy. AB - PURPOSE: To compare anterior chamber cell detection after phacoemulsification between Fourier-domain optical coherence tomography (OCT) and slitlamp biomicroscopy. DESIGN: Observational prospective comparative case series. SETTING: Dr. Agarwal's Eye Hospital and Eye Research Centre, Chennai, India. METHODS: Eyes with preoperative nuclear opalescence (NO) grades 1 to 3 that had phacoemulsification with posterior chamber intraocular lens implantation were included. Slitlamp biomicroscopy and Fourier-domain OCT (Cirrus HD) of the anterior chamber were performed 1 day postoperatively. The results were evaluated, and a correlation analysis between the results and preoperative NO, effective phacoemulsification time (EPT), postoperative central corneal thickness (CCT), and intraocular pressure (IOP) was performed. RESULTS: The preoperative NO grade was 1 in 20 eyes, 2 in 55 eyes, and 3 in 42 eyes. Anterior chamber grading was possible by slitlamp biomicroscopy and Fourier-domain OCT in 106 eyes (90.5%) and 117 eyes (100.0%), respectively. A positive correlation between slitlamp biomicroscopy and OCT grading was noted (R(2) = 0.986, P=.000). Slitlamp grading was not possible in 11 eyes (9.4%) with corneal edema (mean CCT 754 MUm +/- 44.2 [SD]); OCT detected cells in all 11 eyes. There was a difference in slitlamp grading and OCT grading in 7 eyes (6.6%). There was a significant correlation between the OCT cell count and the EPT (P=.000) and NO (P=.000). CONCLUSION: Fourier-domain OCT was as reliable as slitlamp biomicroscopy in assessing postoperative anterior chamber cells. PMID- 25450245 TI - Comparison of the anterior capsulotomy edge created by manual capsulorhexis and 2 femtosecond laser platforms: Scanning electron microscopy study. AB - PURPOSE: To compare the scanning electron microscopy (SEM) features of the anterior capsule edge created by continuous curvilinear capsulorhexis (CCC) and femtosecond laser-assisted capsulotomy using angular second moment and contrast. SETTING: King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia. DESIGN: Prospective comparative series. METHODS: Anterior capsule specimens following CCC (n = 10) or femtosecond laser-assisted capsulotomy using 2 platforms (Lensx, n = 9, and Victus, n = 10) were studied by SEM. Irregularity of the capsule edge was quantified using 2 parameters (angular second moment and contrast) using ImageJ software. The clinical features and laser parameters were correlated with angular second moment and contrast. RESULTS: By SEM, the femtosecond laser-assisted capsulotomy edge surfaces created by both lasers showed marked irregularity compared with the smooth edge of the CCC. The angular second moment and contrast measures for both lasers differed significantly from those obtained for CCC (P<.001). There was no between-laser difference in angular second moment and contrast measures. The angular second moment showed only a weak negative correlation with increasing laser power, whereas contrast showed a weak positive correlation with increasing power. CONCLUSIONS: Both laser platforms created an irregular capsulotomy edge. The angular second moment and contrast quantified capsule edge irregularities for further comparisons. These measures could be used to quantify efforts to reduce capsule-edge irregularity from femtosecond laser-lens capsule interaction. PMID- 25450246 TI - Comparison of 2 techniques for managing posterior polar cataracts: Traditional phacoemulsification versus femtosecond laser-assisted cataract surgery. AB - We report 2 patients with bilateral, visually significant posterior polar cataracts who had traditional phacoemulsification in 1 eye and femtosecond laser assisted cataract surgery in the fellow eye. In both cases, the eye that had femtosecond laser-assisted cataract surgery developed a posterior capsule rupture during lens removal; in 1 eye, there were also retained nuclear fragments. Although visual outcome was excellent in both eyes of both patients, it appears that traditional phacoemulsification with extensive hydrodelineation is the preferable treatment method for posterior polar cataracts. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 25450247 TI - Hyperoxic gassing with Tiron enhances bradykinin-induced endothelium-dependent and EDH-type relaxation through generation of hydrogen peroxide. AB - Oxygenation with 95%O2 is routinely used in organ bath studies. However, hyperoxia may affect tissue responses, particularly in studies which involve reactive oxygen species (ROS). Here, the effects of the antioxidant, Tiron, were investigated under different gassing conditions in the porcine isolated coronary artery (PCA). Distal PCAs from male and female pigs were mounted in a wire myograph gassed with either 95%O2/5%CO2 or 95% air/5%CO2 and pre-contracted with U46619. Concentration-response curves to bradykinin were constructed in the presence of Tiron (1mM), a cell permeable superoxide scavenger and catalase (1000Uml(-1)) to breakdown H2O2. The H2O2 level in Krebs'-Henseleit solution was detected using Amplex Red. Bradykinin produced concentration-dependent vasorelaxations in male and female PCAs when gassed with either 95%O2 or air, with no differences in the Rmax or EC50. Tiron increased the potency of bradykinin only when gassed with 95%O2 in PCAs from both sexes. At 95%O2, catalase prevented the leftward shift caused by Tiron in both sexes indicating that catalase prevented the formation of H2O2 by Tiron. In female PCAs, addition of catalase to Tiron significantly reduced the Rmax. In the EDH-type response (using L-NAME and indomethacin), Tiron enhanced the potency of the bradykinin induced vasorelaxation when gassed with 95%O2 in PCAs from both sexes. Biochemical analysis using Amplex Red demonstrated that H2O2 was generated in Krebs'-Henseleit solution when gassed with 95%O2, but not with air. Therefore, hyperoxic gassing conditions could alter the environment generating superoxide within the Krebs'-Henseleit buffer, which may, in turn, influence the in vitro pharmacological responses. PMID- 25450248 TI - N-terminal protein modifications: Bringing back into play the ribosome. AB - N-terminal protein modifications correspond to the first modifications which in principle any protein may undergo, before translation is completed by the ribosome. This class of essential modifications can have different nature or function and be catalyzed by a variety of dedicated enzymes. Here, we review the current state of the major N-terminal co-translational modifications, with a particular emphasis to their catalysts, which belong to metalloprotease and acyltransferase clans. The earliest of these modifications corresponds to the N terminal methionine excision, an ubiquitous and essential process leading to the removal of the first methionine. N-alpha acetylation occurs also in all Kingdoms although its extent appears to be significantly increased in higher eukaryotes. Finally, N-myristoylation is a crucial pathway existing only in eukaryotes. Recent studies dealing on how some of these co-translational modifiers might work in close vicinity of the ribosome is starting to provide new information on when these modifications exactly take place on the elongating nascent chain and the interplay with other ribosome biogenesis factors taking in charge the nascent chains. Here a comprehensive overview of the recent advances in the field of N terminal protein modifications is given. PMID- 25450249 TI - Human adenovirus Ad36 and its E4orf1 gene enhance cellular glucose uptake even in the presence of inflammatory cytokines. AB - BACKGROUND: Aging and obesity are associated with elevated pro-inflammatory cytokines such as monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)alpha, which are linked to insulin resistance. Anti-inflammatory agents have marginal effect in improving insulin resistance. Hence, agents are needed to improve glycemic control despite the inflammation. Ad36, a human adenovirus, increases TNFalpha and MCP1 mRNA in adipose tissue, yet improves glycemic control in mice. Ad36 via its E4orf1 gene, up-regulates AKT/glucose transporter (Glut)-4 signaling to enhance cellular glucose uptake. OBJECTIVE: Directly test a role of Ad36, or E4orf1 in enhancing cellular glucose uptake in presence of inflammatory cytokines. METHODS: Experiment 1: 3T3-L1 preadipocytes were treated with 0, 10 or 100 ng/mL lipopolysaccharides (LPS), and infected with 0 or 5 plaque forming units (PFU) of Ad36/cell. 3T3-L1 cells that stably and inducibly express E4orf1 or a null vector (pTRE-E4orf1 or pTRE-null cells), were similarly treated with LPS and then with doxycycline, to induce E4orf1. Experiment 2: 3T3L1 preadipocytes were treated with 25 nM MCP1 or 20 nM TNFalpha for 16 h, followed by infection with 0 or 5 PFU of Ad36/cell. Experiment 3: pTRE E4orf1 or -null cells were similarly treated with MCP1 or TNFalpha followed by doxycycline to induce E4orf1. Cellular glucose uptake and cellular signaling were determined 72 h post-Ad36 infection or E4orf1-induction, in continued presence of MCP1 or TNFalpha. RESULTS: In 3T3-L1 preadipocytes, Ad36, but not E4orf1, increased MCP1 and TNFalpha mRNA, in presence of LPS stimulation. Ad36 or E4orf1 up-regulated AKT-phosphorylation and Glut4 and increased glucose uptake (P < 0.05) in the presence of MCP1 or TNFalpha. CONCLUSIONS: Unlike Ad36, E4orf1 does not appear to stimulate inflammatory response. Ad36 and E4orf1 both enhance cellular glucose uptake even in presence of inflammation. Further research is needed to harness this novel and beneficial property of E4orf1 to improve hyperglycemia despite chronic inflammation that is commonly present in aging and obesity. PMID- 25450250 TI - Kinetic and spectral properties of isovaleryl-CoA dehydrogenase and interaction with ligands. AB - Isovaleryl-CoA dehydrogenase (IVD) catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA and the transfer of electrons to the electron transfer flavoprotein (ETF). Recombinant human IVD purifies with bound CoA-persulfide. A modified purification protocol was developed to isolate IVD without bound CoA persulfide and to protect the protein thiols from oxidation. The CoA-persulfide free IVD specific activity was 112.5 MUmol porcine ETF min(-)(1) mg(-)(1), which was ~20-fold higher than that of its CoA-persulfide bound form. The Km and catalytic efficiency (kcat/Km) for isovaleryl-CoA were 1.0 MUM and 4.3 * 10(6) M( 1) s(-1) per monomer, respectively, and its Km for ETF was 2.0 MUM. Anaerobic titration of isovaleryl-CoA into an IVD solution resulted in a stable blue complex with increased absorbance at 310 nm, decreased absorbance at 373 and 447 nm, and the appearance of the charge transfer complex band at 584 nm. The apparent dissociation constant (KDapp) determined spectrally for isovaleryl-CoA was 0.54 MUM. Isovaleryl-CoA, acetoacetyl-CoA, methylenecyclopropyl-acetyl-CoA, and ETF induced CD spectral changes at the 250-500 nm region while isobutyryl-CoA did not, suggesting conformational changes occur at the flavin ring that are ligand specific. Replacement of the IVD Trp166 with a Phe did not block IVD interaction with ETF, indicating that its indole ring is not essential for electron transfer to ETF. A twelve amino acid synthetic peptide that matches the sequence of the ETF docking peptide competitively inhibited the enzyme reaction when ETF was used as the electron acceptor with a Ki of 1.5 mM. PMID- 25450251 TI - Correlation of transducin photoaffinity labeling with the specific formation of intermolecular disulfide linkages in its alpha-subunit. AB - Transducin (T) is a heterotrimer of Talpha, Tbeta, and Tgamma subunits. In the presence of light-activated rhodopsin, 8-azidoguanosine triphosphate (8-N3GTP) was covalently incorporated into T in a UV-light photodependent manner, with a low stoichiometry of 0.02 mol of 8-N3GTP per mol of T. Although Talpha was preferentially labeled by 8-N3GTP, Tbeta and Tgamma were also modified. Photolabeling of T was specifically inhibited by GDP and GTP, but not by beta,gamma-imido-guanosine 5'-triphosphate (GMP-PNP), indicating that 8-N3GTP was modifying the GDP binding site of the holoenzyme. This was consistent with the observation that the photoaffinity probe was completely hydrolyzed to 8-N3GDP by T activated by illuminated rhodopsin. The formation of intermolecular disulfide associations in T was also determined because photolabeling of T was performed under non-reducing conditions. We established that Cys-347 of Talpha was the major residue involved in the formation of disulfide-linked T oligomers. Other cysteines of Talpha, such as Cys-321, also participated in the formation of disulfide bonds, revealing a complex pattern of intermolecular disulfide cross links that led to the polymerization of T. The spontaneous generation of these cystines in Talpha inhibited the light-dependent GTPase and GMP-PNP binding activities of T. A model was constructed illustrating that when two heterotrimers dimerize through the formation of disulfide bridges between the Cys-347 of their Talpha subunits, the guanine ring of the 8-N3GDP bound to one T molecule might approach to the Tbetagamma-complex of the other heterotrimer. This model provides an explanation for the additional photolabeling of Tbeta and Tgamma by 8-N3GTP. PMID- 25450253 TI - Biochemical properties and substrate recognition mechanism of GH31 alpha glucosidase from Bacillus sp. AHU 2001 with broad substrate specificity. AB - alpha-Glucosidases are ubiquitous enzymes that hydrolyze the alpha-glucosidic linkage at the non-reducing end of substrates. In this study, we characterized an alpha-glucosidase (BspAG31A) belonging to glycoside hydrolase family 31 from Bacillus sp. AHU 2001. Recombinant BspAG31A, produced in Escherichia coli, had high hydrolytic activity toward maltooligosaccharides, kojibiose, nigerose, and neotrehalose. This is the first report of an alpha-glucosidase with high activity toward neotrehalose. The transglucosylation products, nigerose, kojibiose, isomaltose, and neotrehalose, were generated from 440 mm maltose. Substitution of Tyr268, situated on the beta -> alpha loop 1 of BspAG31A, with Trp increased hydrolytic activity toward isomaltose. This mutation reduced the hydrolytic activity toward maltooligosaccharides more than toward kojibiose, nigerose, and neotrehalose. Analysis of the Y173A mutant of BspAG31A showed that Tyr173, situated on the N-terminal domain loop, is associated with the formation of subsite +2. In Y173A, the kcat/Km for maltooligosaccharides slightly decreased with an increasing degree of polymerization compared with wild type. Among the amino acid residues surrounding the substrate binding site, Val543 and Glu545 of BspAG31A were different from the corresponding residues of Bacillus thermoamyloliquefaciens alpha-glucosidase II, which has higher activity toward isomaltose than BspAG31A. The E545G mutation slightly enhanced isomaltase activity without a large reduction of hydrolytic activities toward other substrates. V543A showed 1.8-3.5-fold higher hydrolytic activities toward all substrates other than neotrehalose compared with wild type, although its preference for isomaltose was unchanged. PMID- 25450252 TI - Phospholipid makeup of the breast adipose tissue is impacted by obesity and mammary cancer in the mouse: Results of a pilot study. AB - Obesity, an established risk factor for breast cancer (BC), is associated with systemic inflammation. The breast contains adipose tissue (bAT), yet whether it plays a role in BC progression in obese females is being intensively studied. There is scarce knowledge on the lipid composition of bAT in health and disease. The purpose of this pilot study was: 1) to determine whether obesity and BC are associated with inflammatory changes in bAT 2) to analyze for the first time the lipid profile of bAT in obese and lean mammary tumor-bearing and normal mice. Syngeneic E0771 mammary tumor cells were implanted into the mammary fat pad of lean and diet-induced obese C57BL/6 mice. BATs were analyzed four weeks after tumor cell inoculation by immunohistochemistry and mass spectrometry. Phospholipids were identified and subjected to ratiometric quantification using a TSQ Quantum Access Max triple quadrupole mass spectrometer utilizing precursor ion scan or neutral ion loss scan employing appropriate class specific lipid standards in a two step quantification process. Four main classes of phospholipids were analyzed: phosphatidylcholines phosphatidylserines, phosphatidylethanolamines and phosphatidylinositols. Our results showed that bAT in obese (normal and tumor-bearing) mice contained hypertrophic adipocytes compared with their corresponding samples in lean mice; higher numbers of macrophages and crown-like structures were observed in obese tumor bearers compared to obese normal mice. BAT from normal obese mice revealed higher concentrations of phosphatidylethanolamines. Furthermore, bAT from tumor-bearing mice expressed higher phosphatidylcholines than that from non-tumor bearing mice, suggesting the presence of the tumor is associated with phosphatidylcholines. Conversion of phosphatidylethanolamines to phosphatidylcholines will be investigated in E0771 cells. Additional studies are projected to investigate macrophage activation by these specific classes of phospholipids. Occurrence of triglycerides and free fatty acids will be examined in bAT and similar lipidomic analyses will be carried out visceral adipose tissue, highly inflamed in obesity. PMID- 25450254 TI - Establishment of the first international standard for PEGylated granulocyte colony stimulating factor (PEG-G-CSF): report of an international collaborative study. AB - We assessed the feasibility of developing a suitable international reference standard for determination of in vitro biological activity of human sequence recombinant PEG-G-CSF products with a 20kD linear PEG linked to the N-terminal methionyl residue of G-CSF (INN Filgrastim), produced using a conjugation process and coupling chemistry similar to that employed for the lead PEGfilgrastim product. Based on initial data which showed that the current WHO 2nd international standard, IS for G-CSF (09/136) or alternatively, a PEG-G-CSF standard with a unitage traceable to the G-CSF IS may potentially serve as the IS for PEG-G-CSF products, two candidate preparations of PEG-G-CSF were formulated and lyophilized at NIBSC. These preparations were tested by 23 laboratories using in vitro bioassays in a multi-centre collaborative study. Results indicated that on the basis of parallelism, the current WHO 2nd IS for G-CSF or any of the PEG-G CSF samples could be used as the international standard for PEG-G-CSF preparations. However, because of the variability in potency estimates seen when PEG-G-CSF preparations were compared with the current WHO 2nd IS for G-CSF, a candidate PEG-G-CSF was suitable as the WHO IS. The preparation 12/188 was judged suitable to serve as the WHO IS based on in vitro biological activity data. Therefore, the preparation coded 12/188 was established by the WHO Expert Committee on Biological Standardization (ECBS) in 2013 as the WHO 1st IS for human PEGylated G-CSF with an assigned in vitro bioactivity of 10,000IU per ampoule. PMID- 25450255 TI - A modified immune tolerant mouse model to study the immunogenicity of recombinant human interferon beta. AB - Interferon beta may induce antibodies in multiple sclerosis patients and the incidence of immunogenicity depends on the type of product. These antibodies can reduce the efficacy of interferon beta. Two transgenic immune tolerant mouse models for human interferon beta (hIFNbeta) (C57Bl/6, and C57Bl/6*FVB/N F1 hybrid mice) have been developed previously for studying immunogenicity. These models, however, may not be used for every interferon beta product because of the lack of immunogenicity in the wildtype genetic background. We therefore developed a modified transgenic mouse model by backcrossing the F1 hybrid C57Bl/6*FVB/N transgenic mice with wildtype FVB/N for 10 generations. These F10 offspring (referred to hear as FVB/N) have a genetic background consisting of mostly FVB/N (99.9%) and very little C57Bl/6 (0.1%), and are expected to have the more sensitive antibody producing phenotype of the parental FVB/N strain. The newly generated "FVB/N" strain was assessed for antibody formation against different rhIFNbeta formulations compared to the C57Bl/6, and C57Bl/6*FVB/N transgenic mouse models. The new FVB/N transgenic mouse model was more sensitive for all tested rhIFNbeta products, and the difference in antibody titers between the transgenic and non-transgenic mice of the FVB/N strain was much bigger compared to the antibody levels of the C57Bl/6, and C57Bl/6*FVB/N strains. PMID- 25450256 TI - Applications for an engineered Protein-G variant with a pH controllable affinity to antibody fragments. AB - Immunoglobulin binding proteins (IBPs) are broadly used as reagents for the purification and detection of antibodies. Among the IBPs, the most widely used are Protein-A and Protein-G. The C2 domain of Protein-G from Streptococcus is a multi-specific protein domain; it possesses a high affinity (K(D) ~10 nM) for the Fc region of the IgG, but a much lower affinity (KD~low MUM) for the constant domain of the antibody fragment (Fab), which limits some of its applications. Here, we describe the engineering of the Protein-G interface using phage display to create Protein-G-A1, a variant with 8 point mutations and an approximately 100 fold improved affinity over the parent domain for the 4D5 Fab scaffold. Protein-G A1 is capable of robust binding to Fab fragments for numerous applications. Furthermore, we isolated a variant with pH-dependent affinity, demonstrating a 1,000-fold change in affinity from pH7 to 4. Additional rational mutagenesis endowed Protein-G with significantly enhanced stability in basic conditions relative to the parent domain while maintaining high affinity to the Fab. This property is particularly useful to regenerate Protein-G affinity columns. Lastly, the affinity-matured Protein-G-A1 variant was tethered together to produce dimers capable of providing multivalent affinity enhancement to a low affinity antibody fragment-antigen interaction. Engineered Protein-G variants should find widespread application in the use of Fab-based affinity reagents. PMID- 25450257 TI - Raman spectroscopic modeling of early versus late T-lymphocyte activation via differential spectral detection of receptor expression. AB - The proven efficacy of renal transplantation has made it the definitive treatment for end-stage renal disease. Despite its wide acceptance, transplantation has been limited by organ shortages. In the face of this, preservation of allograft longevity is essential. The predominately T cell-driven process of acute rejection (AR) can lead to graft dysfunction and even graft loss. As a marker for AR screening, serum creatinine has a low sensitivity and specificity. This has warranted the development of more accurate screening/diagnostic tools such as Raman Spectroscopy (RS) which has been demonstrated in previous studies to accurately quantify T cell activation. In this study we further explore its application by modeling the dynamic process of cell surface receptor expression during T cell activation. 50 mitogen (Concanavalin A and pokeweed) activated T cells were stained with CD69, CD25, and CD71 monoclonal antibodies (mAbs) at 48 and 72 hour time points. In parallel, 50 activated T cells were analyzed using RS at these same time periods. At 4 8h there was high expression of the CD69 cell surface receptor detected via mAb staining with no appreciable binding of CD25/CD71 fluorescent tag. In conjunction, 48 hour RS-analyzed T cells demonstrated a significant peak difference at the 1585 cm(-1) position which represented a 63% (p=0.01) increase in peak magnitude when compared with the 72 hour samples. By contrast, the 72 hour data demonstrated an attenuation of the CD69 expression and increased CD25/CD71 expression. The corresponding RS analysis showed two significant peak differences at the 903 cm(-1) and 1449 cm(-1) positions that were not present at 48 h. These differences in Raman shifts resulted in a 40% (p=0.04) and a 59% (p=0.001) increase in peak magnitudes at these positions, respectively. This study serves to further validate RS as a screening modality capable of not only detecting T cells early in the activation process through the spectral signatures associated with CD69, but also quantifying the persistent expression of CD25 and CD71. This provides a foundation for the development of a system capable of the accurate assessment of acute and maintenance immunosuppression efficacy at the molecular level. PMID- 25450258 TI - Post-stained Western blotting, a useful approach in immunoproteomic studies. AB - The precise localisation of immunogenic proteins on stained two-dimensional electrophoresis (2DE) gels is occasionally difficult, contributing to the erroneous identification of unrelated non-immunogenic proteins, which is expensive and time consuming. This inconvenience can be solved by performing immunoblotting using previously stained polyacrylamide gels. This approach was proposed nearly 20 years ago but is now almost forgotten. We have evaluated the suitability of this approach to identify immunogenic proteins from Lactococcus garvieae. Some of the immunogenic proteins identified in L. garvieae, such as Gls24, have been considered important as immunotarget in different bacterial species. Post-staining western blotting facilitated the correct selection of immunogenic proteins of interest in 2D gels before their identification. PMID- 25450259 TI - Recent progress in microRNA delivery for cancer therapy by non-viral synthetic vectors. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. Because of significant changes in their expression in cancer, miRNAs are believed to be key factors in cancer genetics and to have potential as anticancer drugs. However, the delivery of miRNAs is limited by many barriers, such as low cellular uptake, immunogenicity, renal clearance, degradation by nucleases, elimination by phagocytic immune cells, poor endosomal release, and untoward side effects. Nonviral delivery systems have been developed to overcome these obstacles. In this review, we provide insights into the development of non-viral synthetic miRNA vectors and the promise of miRNA-based anticancer therapies, including therapeutic applications of miRNAs, challenges of vector design to overcome the delivery obstacles, and the development of miRNA delivery systems for cancer therapy. Additionally, we highlight some representative examples that give a glimpse into the current trends into the design and application of efficient synthetic systems for miRNA delivery. Overall, a better understanding of the rational design of miRNA delivery systems will promote their translation into effective clinical treatments. PMID- 25450260 TI - Hepatocellular carcinoma and microRNA: new perspectives on therapeutics and diagnostics. AB - Hepatocellular carcinoma (HCC) remains one of the most lethal forms of cancer in the world. In this arena, utilities of microRNA (miRNA) as a sophisticated tool, in therapeutics and diagnostics, remains a prime focus among the leading researchers. It is well known that viral hepatitis, chronic alcoholism and metabolic syndrome are the prime causes of HCCs. Nevertheless, HCCs are usually diagnosed at late stages by using current serum biomarkers. Most epidemiological studies have found the survival rate in HCC cases to be relatively low. Therefore, development of effective noninvasive biomarkers for early detention of HCC and new strategies for HCC treatment remains a high priority research area on the shoulders of liver oncologists. Accumulating evidence in cancer diagnostics and therapeutics indicates that miRNAs involve in HCC progression, which may serve as sensitive biomarkers for detecting carcinogenesis and monitoring therapies of HCC. This review focuses on the role of miRNAs in the diagnostics and therapeutics of HCC. PMID- 25450262 TI - Therapeutic strategies to combat antibiotic resistance. AB - With multidrug resistant bacteria on the rise, new antibiotic approaches are required. Although a number of new small molecule antibiotics are currently in the development pipeline with many more in preclinical development, the clinical options and practices for infection control must be expanded. Biologics and non antibiotic adjuvants offer this opportunity for expansion. Nevertheless, to avoid known mechanisms of resistance, intelligent combination approaches for multiple simultaneous and complimentary therapies must be designed. Combination approaches should extend beyond biologically active molecules to include smart controlled delivery strategies. Infection control must integrate antimicrobial stewardship, new antibiotic molecules, biologics, and delivery strategies into effective combination therapies designed to 1) fight the infection, 2) avoid resistance, and 3) protect the natural microbiome. This review explores these developing strategies in the context of circumventing current mechanisms of resistance. PMID- 25450263 TI - Antimicrobial hydrogels: a new weapon in the arsenal against multidrug-resistant infections. AB - The rapid emergence of antibiotic resistance in pathogenic microbes is becoming an imminent global public health problem. Treatment with conventional antibiotics often leads to resistance development as the majority of these antibiotics act on intracellular targets, leaving the bacterial morphology intact. Thus, they are highly prone to develop resistance through mutation. Much effort has been made to develop macromolecular antimicrobial agents that are less susceptible to resistance as they function by microbial membrane disruption. Antimicrobial hydrogels constitute an important class of macromolecular antimicrobial agents, which have been shown to be effective in preventing and treating multidrug resistant infections. Advances in synthetic chemistry have made it possible to tailor molecular structure and functionality to impart broad-spectrum antimicrobial activity as well as predictable mechanical and rheological properties. This has significantly broadened the scope of potential applications that range from medical device and implant coating, sterilization, wound dressing, to antimicrobial creams for the prevention and treatment of multidrug resistant infections. In this review, advances in both chemically and physically cross-linked natural and synthetic hydrogels possessing intrinsic antimicrobial properties or loaded with antibiotics, antimicrobial polymers/peptides and metal nanoparticles are highlighted. Relationships between physicochemical properties and antimicrobial activity/selectivity, and possible antimicrobial mechanisms of the hydrogels are discussed. Approaches to mitigating toxicity of metal nanoparticles that are encapsulated in hydrogels are reviewed. In addition, challenges and future perspectives in the development of safe and effective antimicrobial hydrogel systems especially involving co-delivery of antimicrobial polymers/peptides and conventional antimicrobial agents for eventual clinical applications are presented. PMID- 25450261 TI - Contribution of bioinformatics prediction in microRNA-based cancer therapeutics. AB - Despite enormous efforts, cancer remains one of the most lethal diseases in the world. With the advancement of high throughput technologies massive amounts of cancer data can be accessed and analyzed. Bioinformatics provides a platform to assist biologists in developing minimally invasive biomarkers to detect cancer, and in designing effective personalized therapies to treat cancer patients. Still, the early diagnosis, prognosis, and treatment of cancer are an open challenge for the research community. MicroRNAs (miRNAs) are small non-coding RNAs that serve to regulate gene expression. The discovery of deregulated miRNAs in cancer cells and tissues has led many to investigate the use of miRNAs as potential biomarkers for early detection, and as a therapeutic agent to treat cancer. Here we describe advancements in computational approaches to predict miRNAs and their targets, and discuss the role of bioinformatics in studying miRNAs in the context of human cancer. PMID- 25450264 TI - The potential role of estrogen receptor beta2 in breast cancer. AB - Endocrine therapy is provided to all patients with estrogen receptor (ER) positive breast cancer, but only a subset of them derives clinical benefit. The discovery of ERbeta and its five isoforms added another layer of complexity in the regulation of estrogen activity in breast cancer cells. Two large retrospective studies showed conflicting results with regard to the prognostic value of the different ERbeta isoforms in patients treated with tamoxifen in an adjuvant setting. This study tested the hypothesis that ERbeta1 and, or ERbeta2 are correlated with clinical outcome. We identified patients with breast cancer who had undergone surgery at Bucheon St. Mary's Hospital, the Catholic University of Korea, between January 2004 and March 2006. We evaluated 101 consecutive cases for ERbeta1 and ERbeta2 expression using immunohistochemical staining and obtained other clinicopathology by reviewing medical records. ERbeta1 was expressed in 81.2% (79 of 97) and ERbeta2 was expressed in 50.5% (51 of 101) of primary breast cancer tissues. Disease-free survival (DFS) and overall survival (OS) of patients with cancers expressing ERbeta2 was significantly worse. Moreover, in subgroup analysis according to the tamoxifen treatment, ERbeta2 expression was significantly associated with shorter DFS of tamoxifen-treated patients. This study indicates that breast cancer with ERbeta2 expression was associated with worse DFS and OS, especially in tamoxifen treated patients. Our results suggest a role for ERbeta2 as an independent prognostic marker and might serve as a new therapeutic target. PMID- 25450265 TI - Different setups of laparoscopic cholecystectomy: conversion and complication rates: a retrospective cohort study. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) is the gold standard treatment for gall bladder disease. METHODS: We retrospectively reviewed charts of patients who underwent LC. Four LC groups were defined: elective LC - Group I; interval LC - Group II; LC during acute cholecystitis - Group III; and LC following percutaneous cholecystostomy (PCC) - Group IV. RESULTS: The study comprised 1658 patients [mean age: 51.0 years (range 17-94)]: Group I: 1221 patients (73.6%); Group II: 271 patients (16.3%); Group III: 125 patients (7.6%); Group IV: 41 patients (2.5%). The operative time was significantly different between the groups (p < 0.05). The conversion rate was highest in Group III (24.8%) and was significantly higher than all the other groups. Group II had a higher conversion rate than Group I (p < 0.05). The length of hospital stay was not significantly different between Groups I and II (1.5 and 1.96 days, respectively), and between Groups III and IV (4.46 and 4.78 days, respectively). The differences between Groups I and II, and between Groups III and IV were significant. Complication rates were significantly different between Groups I (2.2%), II (5.6%), and III (13.6%) (p < 0.05.) There were no differences between Groups III and IV and there were no significant differences in 30-day readmission rates between the groups. CONCLUSIONS: The highest conversion and complication rates were encountered in patients undergoing LC during acute cholecystitis. A gradual increase of conversion and complication rates was noted between the groups of elective LC, interval LC and LC post PCC. PMID- 25450266 TI - Aurora-A kinase: potential tumor marker of osteosarcoma. AB - Aurora kinase family is a group of serine/threonine protein kinase. It is the main regulator in mitosis, including centrosome regulation, spindle formation, and chromosome separation. Aurora-A is an oncogene that is highly expressed in various human tumors, including osteosarcoma. Its high expression level and malignance and tumor metastasis are correlated. Aurora-A is a potential tumor marker. The progress of Aurora-A kinase in tumor research is summarized in this article. PMID- 25450267 TI - Expression of growth arrest and DNA damage inducible 45a in human oral squamous cell carcinoma is associated with tumor progression and clinical outcome. AB - OBJECTIVES: The aim of this study was to examine the growth arrest and DNA damage inducible (Gadd45a) expression and its role in tumor progression, invasion and metastasis in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Growth arrest and DNA damage-inducible 45a distribution was detected by immunohistochemistry in tumor sections of 106 patients with primary OSCC and sections of adjacent pericancerous tissues from 60 patients among the 106. The association between the Gadd45a expression and clinical prognosis of OSCC were performed by statistical analysis. Gadd45a gene knockdown was performed in Tca8113 cells by small interfering ribonucleic acid treatment and its effects on cell cycle, and migration were detected by Flow Cytometric (Becton Dickinson, USA) and transwell chamber assay respectively. RESULTS AND CONCLUSION: The results showed that Gadd45a was redistributed to cytoplasm in poorly differentiated carcinoma from its nucleus location in normal tissue (P < 0.05). The expression of Gadd45a was significantly associated with lymph node metastasis, tumor stage and tumor histological grade (P < 0.05). Knockdown of Gadd45a gene abolished the G2/M arrest and increased migrating ability of Tca8113 cell (P < 0.05). The results indicate that Gadd45a play an important role in OSCC metastasis by affecting the bioactivity of the tumor cells, and its distribution may serve for the prediction of clinical outcome of OSCC. PMID- 25450268 TI - Identification of melanoma biomarkers based on network modules by integrating the human signaling network with microarrays. AB - BACKGROUND: Melanoma is a leading cause of cancer death. Thus, accurate prognostic biomarkers that will assist rational treatment planning need to be identified. METHODS: Microarray analysis of melanoma and normal tissue samples was performed to identify differentially expressed modules (DEMs) from the signaling network and ultimately detect molecular markers to support histological examination. Network motifs were extracted from the human signaling network. Then, significant expression-correlation differential modules were identified by comparing the network module expression-correlation differential scores under normal and disease conditions using the gene expression datasets. Finally, we obtained DEMs by the Wilcoxon rank test and considered the average gene expression level in these modules as the classification features for diagnosing melanoma. RESULTS: In total, 99 functional DEMs were identified from the signaling network and gene expression profiles. The area under the curve scores for cancer module genes, melanoma module genes, and whole network modules are 92.4%, 90.44%, and 88.45%, respectively. The classification efficiency rates for nonmodule features are 71.04% and 79.38%, which correspond to the features of cancer genes and melanoma cancer genes, respectively. Finally, we acquired six significant molecular biomarkers, namely, module 10 (CALM3, Ca 2+ , PKC, PDGFRA, phospholipase-g, PIB5PA, and phosphatidylinositol-3-kinase), module 14 (SRC, Src homology 2 domain-containing [SHC], SAM68, GIT1, transcription factor-4, CBLB, GRB2, VAV2, LCK, YES, PTCH2, downstream of tyrosine kinase [DOK], and KIT), module 16 (ELK3, p85beta, SHC, ZFYVE9, TGFBR1, TGFBR2, CITED1, SH3KBP1, HCK, DOK, and KIT), module 45 (RB, CCND3, CCNA2, CDK4, and CDK6), module 75 (PCNA, CDK4, and CCND1), and module 114 (PSD93, NMDAR, and FYN). CONCLUSION: We explored the gene expression profile and signaling network in a global view and identified DEMs that can be used as diagnostic or prognostic markers for melanoma. PMID- 25450269 TI - The clinical value of lymphatic vessel density, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 expression in patients with oral tongue squamous cell carcinoma. AB - BACKGROUND: Oral tongue squamous cell carcinoma (OTSCC) is an oral carcinoma prone to lymphatic metastasis. Intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) as important adhesion molecules play roles in regulating cell-cell adhesion and tumor cells metastasis. MATERIALS AND METHODS: Lymphatic vessel density (LVD) was evaluated by immunohistochemistry using anti-human D2-40 antibody. The expression of ICAM-1 or VCAM-1 in lymphatic vessels were measured by double immunofluorescence staining. Then both of the LVD and the expression of ICAM-1 or VCAM-1 were compared between in normal tongue and in OTSCC lymphatic vessels. In OTSCC, statistical analyses were performed to determine the prognostic correlation of ICAM-1 or VCAM-1 levels. RESULTS: LVD and expression of ICAM-1 or VCAM-1 in OTSCC lymphatic vessels was higher than those in normal tongue lymphatic vessels (LVD: 21.454 +/- 7.022, 8.498 +/- 1.679; ICAM 1: 30.241 +/- 5.639%, 5.050 +/- 1.227%; VCAM-1: 33.134 +/- 5.127%, 2.113 +/- 0.446%, in OTSCC, normal tongue tissues, respectively). High LVD and high ICAM-1 or VCAM-1 expression in lymphatic vessels was significantly associated with lymphatic node metastasis. Overall survival was significantly shorter in patients with high LVD and ICAM-1 or VCAM-1 expression in lymphatic vessels. CONCLUSIONS: LVD and expression of ICAM-1 or VCAM-1 in OTSCC was higher than that in normal tongue lymphatic vessels. Monitoring changes in the expression of ICAM-1 or VCAM 1 in lymphatic vessels may be a useful technique for assessing prognoses in OTSCC patients. PMID- 25450270 TI - The value of serum Cyfra21-1 as a biomarker in the diagnosis of patients with non small cell lung cancer: a meta-analysis. AB - OBJECTIVE: The serum level of Cyfra21-1 was always elevated in patients with nonsmall cell lung carcinoma. The aim of this meta-analysis was to evaluate the serum Cyfra21-1 as a biomarker in the diagnosis of nonsmall cell lung cancer (NSCLC). METHODS: All the articles associated with serum Cyfra21-1 in the diagnosis of NSCLC were searched in the PubMed, Medline, and CNKI databases. The number of patients for true positive, false positive, false negative and true negative were extracted from each individual study. The pooled sensitivity, specificity, positive likely hood ratio (+lr), negative likely hood ratio (-lr), diagnosis odds ratio (dor) and summary receiver operating characteristic (sroc) curve were calculated by MetaDiSc 1.4 software. RESULTS: After searching the databases, 17 studies with 4221 subjects were met the inclusion criteria and finally included in this meta-analysis. The pooled diagnosis sensitivity, specificity, +lr, -lr and dor were 0.72 (95% confidence interval [CI]: 0.70 0.73), 0.94 (95%CI: 0.93-0.95), 8.81 (95%CI: 6.36-12.22), 0.42 (95%CI: 0.32-0.55) and 22.57 (95%CI: 13.89-36.68) respectively. The area under the sroc curve was 0.95. And significant publication bias was found in this meta-analysis (P = 0.049). CONCLUSION: With published data, the serum Cyfra21-1 was a useful biomarker for diagnosis of NSCLC. OBJECTIVE: The serum level of Cyfra21-1 was always elevated in patients with nonsmall cell lung carcinoma. The aim of this meta-analysis was to evaluate the serum Cyfra21-1 as a biomarker in the diagnosis of nonsmall cell lung cancer (NSCLC). METHODS: All the articles associated with serum Cyfra21-1 in the diagnosis of NSCLC were searched in the PubMed, Medline, and CNKI databases. The number of patients for true positive, false positive, false negative and true negative were extracted from each individual study. The pooled sensitivity, specificity, positive likely hood ratio (+lr), negative likely hood ratio (-lr), diagnosis odds ratio (dor) and summary receiver operating characteristic (sroc) curve were calculated by MetaDiSc 1.4 software. RESULTS: After searching the databases, 17 studies with 4221 subjects were met the inclusion criteria and finally included in this meta-analysis. The pooled diagnosis sensitivity, specificity, +lr, -lr and dor were 0.72 (95% confidence interval [CI]: 0.70-0.73), 0.94 (95%CI: 0.93-0.95), 8.81 (95%CI: 6.36-12.22), 0.42 (95%CI: 0.32-0.55) and 22.57 (95%CI: 13.89-36.68) respectively. The area under the sroc curve was 0.95. And significant publication bias was found in this meta-analysis (P = 0.049). CONCLUSION: With published data, the serum Cyfra21-1 was a useful biomarker for diagnosis of NSCLC. PMID- 25450271 TI - Association between interleukin-4 polymorphisms and environment and nonsmall cell lung cancer in Chinese population. AB - AIM: The aim was to evaluate the influence of interleukin (IL)-4-590 C/T gene polymorphism in the susceptibility to nonsmall cell lung cancer (NSCLC), whether the environment also affects genetic polymorphisms. MATERIALS AND METHODS: A case control study was conducted with 500 NSCLC patients and 500 healthy controls, matched on age and gender. The single nucleotide polymorphisms distributed in IL 4 gene were selected for genotyping. The association between genotype and NSCLC risk was evaluated by computing the odds ratio and 95% confidence interval with multivariate unconditional logistic regression analyses. RESULTS: The allele frequencies were not associated with NSCLC regardless of histological type or gender. The genotype distributions were similar between cases and controls, between adenocarcinoma patients and controls, and between male squamous-cell carcinoma (SCC) patients and male controls. However, genotype (C/C + C/T) frequencies polymorphism of rs2243250 were different between female SCC patients and female controls. CONCLUSIONS: These results suggest that environmental agents might have the potential for interacting with human genetic polymorphisms in NSCLC. IL-4-590 C/T polymorphism (C/C + C/T frequencies) may be a potential susceptibility marker for female SCC patients in China. PMID- 25450272 TI - Serum bone-specific alkaline phosphatase as a biomarker for osseous metastases in patients with malignant carcinomas: a systematic review and meta-analysis. AB - OBJECTIVE: Bone metastasis was common in patients with malignant tumors. The purpose of this study was to investigate the serum bone-specific alkaline phosphatase (B-ALP) as a biomarker in the diagnosis of osseous metastases in patients with cancers. METHODS: We searched the databases of Pubmed, Cochrane Library, Medline, CNKI and Wanfang to screen the relevant articles about the serum B-ALP detection in the diagnosis of osseous metastases in patients with malignant carcinomas. The pooled sensitivity, specificity, summary receiver operating characteristic (SROC) curve were calculated by STATA12.0 software. RESULTS: Nineteen trials with 3 268 subjects were finally included in this study. The mean level of serum B-ALP was 41.50 +/- 26.61 MUg/L (216.90 +/- 139.00U/L) in patients with osseous metastases and 14.49 +/- 5.52 MUg/L (103.30 +/- 39.44 U/L) in patients without osseous metastases. The serum level of B-ALP was significant higher in the osseous metastases group than that in the control group (P < 0.05); The pooled sensitivity and specificity for diagnosis of osseous metastases were 0.74 with its 95% confidence interval (95% CI) of 0.62-0.83 and 0.80 (95% CI: 0.67-0.89), respectively. The area under the SRCO was 0.86 (95% CI: 0.83-0.89). CONCLUSION: Serum B-ALP can be a promising biomarker for detection of osseous metastases in patients with cancers. PMID- 25450274 TI - A comparison of consistency of detecting BRAF gene mutations in peripheral blood and tumor tissue of nonsmall-cell lung cancer patients. AB - OBJECTIVE: The aim was to detect the consistency of the BRAF gene mutation in peripheral blood and tumor tissue of patients with nonsmall-cell lung cancer and discuss the clinical application value of BRAF gene mutation in peripheral blood. MATERIALS AND METHODS: Real-time fluorescent quantitative polymerase chain reaction was used to test the tissues in 257 patients of nonsmall-cell lung cancer (NSCLC) and the peripheral blood samples in 318 patients of NSCLC, of which 185 cases of peripheral blood specimens could match the tissue samples, and detected the BRAF gene mutation in them by comparison of mutations consistency in blood and tissue samples, and analyzed the correlation between BRAF gene mutations and clinical characteristics of patients. RESULTS: The BRAF gene mutation rate was 7.23% in peripheral blood of 23 patients with nonsmall-cell lung cancer, and was 5.45% in 14 cancer tissues, the mutation consistency was 80.00% in peripheral blood-tumor tissue matched samples. The consistency was statistically significant (k =0.710, P = 0.000). CONCLUSION: The consistency of the BRAF gene mutation in peripheral blood and tissue is high. BRAF gene mutations of peripheral blood could be used for clinical diagnosis and treatment in cases when tissue specimen is hard to get. PMID- 25450273 TI - Ultrasonography-guided percutaneous radiofrequency ablation for cervical lymph node metastasis from thyroid carcinoma. AB - PURPOSE: The aim was to explore the efficacy and safety of ultrasonography-guided percutaneous radiofrequency ablation (RFA) for cervical lymph node metastases from thyroid carcinoma. MATERIALS AND METHODS: Eight patients with previous total thyroidectomy and radioiodine therapy were enrolled in this study. A total of 20 cervical lymph node metastases were confirmed by percutaneous biopsy. Participants underwent ultrasonography-guided RFA treatment for all confirmed metastatic lymph nodes. Contrast-enhanced ultrasound (CEUS) and sonoelastography were performed to rapidly evaluate treatment responses before and shortly after RFA. Routine follow-up consisted of conventional US, CEUS, sonoelastography, thyroglobulin level, and necessary fine needle aspiration cytology. RESULTS: All eight patients were successfully treated without obvious complications. Post-RFA CEUS showed that total metastatic lymph nodes were ablated. The sonoelastographic score of ablated area elevated significantly shortly after RFA (P < 0.001). With a mean follow-up of 9.4 +/- 5.1 months, there were no evidences of recurrence at ablated sites; however, two new cervical recurrent lymph nodes occurred in one case, which was successfully ablated as well. The mass volume shrinkages of the ablated nodes were observed in all cases. We found that 5 treated lymph nodes disappeared, 4 were reduced more than 80%, 9 were reduced between 50% and 80%, and 2 were reduced less than 50%. At the last follow-up evaluation, the serum thyroglobulin levels had decreased in 6 of 8 patients. CONCLUSION: Ultrasonography-guided percutaneous RFA for cervical lymph node metastasis of thyroid malignancy is a feasible, effective, and safe therapy. This procedure shows a nonsurgical therapeutic option for metastatic lymph nodes in patients with difficult reoperations or inoperations, it may reduce or delay a large number of highly invasive repeated neck dissections. PMID- 25450275 TI - Efficacy of icotinib versus traditional chemotherapy as first-line treatment for preventing brain metastasis from advanced lung adenocarcinoma in patients with epidermal growth factor receptor-sensitive mutation. AB - OBJECTIVE: This study aimed to investigate the potential use of icotinib as first line treatment to prevent brain metastasis from advanced lung adenocarcinoma. PATIENTS AND METHODS: This investigation was designed as a retrospective nonrandomized controlled study. Enrolled patients received either icotinib or traditional chemotherapy as their first-line treatment. The therapeutic efficacy was compared among patients with advanced (stages IIIB and IV) lung adenocarcinoma with epidermal growth factor receptor (EGFR)-sensitive mutation. The primary endpoint was the cumulative incidence of brain metastasis, whereas the secondary endpoint was overall survival (OS). Death without brain metastasis was considered a competitive risk to calculate the cumulative risk of brain metastasis. Survival analysis was conducted using the Kaplan-Meier method and statistical significance were determined using the log-rank test. RESULTS: The present study included 396 patients with 131 in the icotinib group and 265 in the chemotherapy group. Among those with EGFR-sensitive mutation, the cumulative risk of brain metastasis was lower in the icotinib group than in the chemotherapy group. However, no significant difference in OS was observed between the two groups. CONCLUSION: Icotinib can effectively reduce the incidence of brain metastasis and therefore improve prognosis in advanced lung adenocarcinoma patients with EGFR-sensitive mutation. PMID- 25450276 TI - Prognostic value of circulating C-reactive protein levels in patients with non small cell lung cancer: a systematic review with meta-analysis. AB - BACKGROUND: The clinical and prognostic significance of C-reactive protein (CRP) in nonsmall-cell lung cancer (NSCLC) remains inconsistent. To clarify a precise determinant of the clinical significance of CRP, we conducted a systematic review and meta-analysis to evaluate the overall risk of elevated CRP for survival in NSCLC. MATERIALS AND METHODS: Related studies were identified and evaluated for quality through multiple search strategies. Data were collected from studies comparing overall survival in patients with elevated CRP levels and those having lower levels. The meta-analysis was performed by Review Manager version 5.2 (RevMan; the Cochrane Collaboration, Oxford, England). The pooled hazard ratios (HRs) and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS: Eight eligible studies involved 1649 patients were ultimately identified. Combined HRs suggested that elevated CRP had an unfavorable impact on survival of patients with NSCLC. The HRs (95% CI) was 1.55 (1.19-2.01) overall, 1.78 (1.33-2.38) in Asian patients, 1.33 (1.00-1.77) in non-Asian patients, 1.78 (1.47-2.15) in primary resectable NSCLC, 1.28 (0.95-1.73) in primary unresectable NSCLC, 1.78 (1.33-2.38) in group of cut-off value <5 mg/L, 1.33 (1.00-1.77) in group of cut-off value >=10 mg/L. CONCLUSIONS: With the available evidence, CRP might serve as an efficient prognostic indicator in NSCLC. This marker should be taken into consideration in the development of new diagnostic and therapeutic program for NSCLC. PMID- 25450277 TI - Identification of potential biomarkers for clear cell renal cell carcinoma based on microRNA-mRNA pathway relationships. AB - BACKGROUND: MicroRNAs (miRNAs) play important roles in tumor genesis. miRNA dysregulation has been widely studied and demonstrated in clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: We applied a newly proposed method for selecting miRNAs that discriminate between healthy controls and cancers. We initially extracted different miRNAs and mRNAs and then selected miRNA-mRNA dysregulation pairs. The pathways that involved mRNAs were acquired according to the functional enrichment. We integrated the miRNAs, mRNAs, and pathways and constructed the miRNA-mRNA pathway relationships based on the derived significant miRNAs. RESULTS: We acquired 566 antiregulated miRNA-mRNA pairs including 56 miRNAs and 485 mRNAs. Three significant pathways related to ccRCC, namely, arginine and proline metabolism, aldosterone-regulated sodium reabsorption, and oxidative phosphorylation, were observed. Based on the miRNA-mRNA pathway relationships, five significant miRNAs were identified as potential biomarkers: hsa-miR-425, hsa-miR-136, hsa-miR-335, hsa-miR-340, and hsa-miR-320d. CONCLUSION: This integrative network approach revealed important miRNAs in the ccRCC that can identify specific disease biomarkers, which can be used as targets for cancer treatment. PMID- 25450278 TI - Diagnostic value of circulating microRNAs for nasopharyngeal cancer: a systematic review and meta-analysis. AB - AIM: Circulating microRNAs (miRNA) are a promising diagnostic tool for lung and gastric cancer. However, their diagnostic value in nasopharyngeal cancer remains unknown. Thus, this study aims to systematically evaluate the diagnostic accuracy of circulating miRNA for nasopharyngeal cancer. METHOD: Eligible studies were searched and selected from the PubMed, EMBASE, and Cochrane CENTRAL databases. RESULTS from these included studies were pooled using random-effects models. Sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were calculated to assess the overall performance of miRNA-based assay. Summary receiver operating characteristic (SROC) curves were plotted to evaluate the overall diagnostic accuracy of circulating miRNA detection. RESULTS: Seven publications were considered eligible for this systematic review, and four studies were finally chosen for this meta-analysis. In the diagnostic meta-analysis, the overall pooled results for sensitivity, specificity, PLR, NLR, and DOR were 0.87 (95% confidence interval [CI]: 0.83-0.90), 0.87 (95% CI: 0.82-0.91), 7.529 (95% CI, 2.575-22.013), 0.145 (95% CI, 0.058-0.363), and 64.045 (95% CI, 10.176-403.10), respectively. The area under SROC curve was 0.95. CONCLUSION: Circulating miRNA detection presents an enormous potential in diagnosing nasopharyngeal cancer. Studies with a large sample size of nasopharyngeal cancer patients must be conducted to verify the diagnostic value of circulating miRNA. PMID- 25450279 TI - Clinical significance of preoperative serum tumor markers in esophageal squamous cell carcinoma. AB - BACKGROUND: Serum tumor markers (TMs) were seldom reported in esophageal carcinoma (ESCC), and the results were still unsatisfactory. MATERIALS AND METHODS: We retrospectively analyzed carcinoembryonic antigen, CA125, CA199, CA724 and CA242 in ESCC patients. The preliminary relations between serum TMs and clinicopathological factors or prognosis were analyzed by Fisher's exact test and Kaplan-Meier method firstly. Then, the cut-off values of these serum TMs were delimited according to lymph node metastasis, hematogenic metastasis and 2-year survival or 5-year survival of ESCC by receiver operating characteristic curve. Based on these cut-off values, the relations between the serum TMs and clinicopathological factors or prognosis were analyzed again. Univariate and multivariate analyses of Cox regression proportional hazard model were performed to evaluate the prognostic parameters for survival. RESULTS: We chose 13.65 U/mL, 9.945 U/mL and 6.25 U/mL as new cut-off values of CA125, CA199 and CA724, respectively, and chose 25.35 U/mL as the cut-off value of CA125 for ESCC hematogenous metastasis. with these optimal cut-off values, CA199, CA125 and CA724 were associated with ESCC hematogenous metastasis, and CA199 and CA125 were associated with ESCC lymph node metastasis, but not associated with other clinicopathological factors. The prognosis was better in patients with CA125 <= 13.65 U/mL than those with CA125 > 13.65U/mL. Vascular tumor thrombus, grading, T grade, lymph node metastasis and CA125 were independent prognostic factors. CONCLUSION: CA125 could predict lymph node metastasis, hematogenic metastasis and prognosis with the cut-off value 13.65 U/mL. PMID- 25450280 TI - Analysis of hepatocellular carcinoma and metastatic hepatic carcinoma via functional modules in a protein-protein interaction network. AB - INTRODUCTION: This study aims to identify protein clusters with potential functional relevance in the pathogenesis of hepatocellular carcinoma (HCC) and metastatic hepatic carcinoma using network analysis. MATERIALS AND METHODS: We used human protein interaction data to build a protein-protein interaction network with Cytoscape and then derived functional clusters using MCODE. Combining the gene expression profiles, we calculated the functional scores for the clusters and selected statistically significant clusters. Meanwhile, Gene Ontology was used to assess the functionality of these clusters. Finally, a support vector machine was trained on the gold standard data sets. RESULTS: The differentially expressed genes of HCC were mainly involved in metabolic and signaling processes. We acquired 13 significant modules from the gene expression profiles. The area under the curve value based on the differentially expressed modules were 98.31%, which outweighed the classification with DEGs. CONCLUSIONS: Differentially expressed modules are valuable to screen biomarkers combined with functional modules. PMID- 25450281 TI - Uridine diphosphate glucuronide transferase 1A1FNx0128 gene polymorphism and the toxicity of irinotecan in recurrent and refractory small cell lung cancer. AB - OBJECTIVE: The aim was to investigate the association between uridine diphosphate glucuronide transferase 1A1 (UGT1A1) gene promoter region polymorphism and irinotecan-related adverse effects and efficacy on recurrent and refractory small cell lung cancer (SCLC). MATERIALS AND METHODS: A total of 31 patients with recurrent and refractory SCLC were enrolled in this study from June 2012 to August 2013 and received at least two cycles of single-agent irinotecan chemotherapy. The efficacy and adverse effects of irinotecan were evaluated. DNA was extracted from peripheral blood and direct sequencing method was employed to test UGT1A1FNx0128 polymorphism, thus analyzing the correlation between UGT1A1FNx0128 polymorphism and irinotecan-related side-effects and efficacy. RESULTS: A total of 25 cases (80.6%) were UGT1A1FNx0128 wild-type (TA) 6 /(TA) 6 ; 6 cases (19.4%) were heterozygous mutant (TA) 6 /(TA) 7 , no homozygous mutant genotype (TA) 7 /(TA) 7 was found. The incidences of grade 3/4 neutropenia, diarrhea and thrombocytopenia were 35.5%, 25.8% and 22.6% in all the patients, respectively. The incidence of 3/4 adverse effects in patients with genotype (TA) 6 /(TA) 6 and heterozygous (TA) 6 /(TA) 7 had no statistical difference (P > 0.05 for all). The overall response rate (ORR) was 32.3%. Median progression free survival (PFS) and overall survival (OS) were 4 months and 7.5 months in all patients, respectively. There was no statistical difference in ORR, PFS and OS between genotype (TA) 6 /(TA) 6 patients and heterozygous (TA) 6 /(TA) 7 patients. CONCLUSION: Irinotecan showed efficacy in patients with recurrent and refractory SCLC; UGT1A1 FNx01 28 polymorphism failed to predict the incidence of serious adverse effects and efficacy of irinotecan. PMID- 25450282 TI - Quantitative assessment of the influence of glutathione S-transferase M1 null variant on ovarian cancer risk. AB - OBJECTIVE: Many studies have reported the role of glutathione S-transferase Mu 1 (GST M1) polymorphism with ovary cancer risk, but the results remained controversial. MATERIALS AND METHODS: To derive a more precise estimation of the relationship, a meta-analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between GSTM1 polymorphism and ovary cancer risk. A total of 11 studies including 2709 cases and 3599 controls were also involved in this meta-analysis. RESULTS: When all the eligible studies were pooled into this meta-analysis, no significant association between ovary cancer risk and GSTM1 polymorphism was found (OR = 1.010, 95% CI = 0.911-1.121, P heterogeneity = 0.174, P = 0.848). DISCUSSION: Our meta-analysis supports that the GSTM1 polymorphism is not contributed to the risk of ovary cancer from currently available evidence. PMID- 25450283 TI - Association between P-glycoprotein expression and response to chemotherapy in patients with osteosarcoma: a systematic and meta-analysis. AB - OBJECTIVE: The aim was to investigate the association between p-glycoprotein (Pgp) expression and response to chemotherapy in patients with osteosarcoma. MATERIALS AND METHODS: We searched and included the openly published articles evaluated the correlation between Pgp expression and response to chemotherapy. The odds ratio (OR) of response rate for Pgp positive group versus Pgp negative group was aggregated by random or fixed effect model. RESULTS: Twelve studies were included in our meta-analysis. The mean Pgp positive rate was 0.39 +/- 0.10 with its range of (0.14-0.53). The summary response rate was 0.46 +/- 0.16 in Pgp positive and 0.57 +/- 0.27 in the Pgp negative group, with no statistical difference between two groups (P > 0.05). The pooled OR of response rate for Pgp positive group versus Pgp negative group was 0.75 with its 95% confidence interval of 0.47-1.22, indicating there was no association between Pgp expression and response to chemotherapy in patients with osteosarcoma. CONCLUSION: The present evidence indicated that there was no association between p-glycoprotein expression and chemotherapy response in patients with osteosarcoma. PMID- 25450284 TI - The association between methylenetetrahydrofolate reductase C677 > T polymorphisms and risk of pediatric acute lymphoblastic leukemia in Asia. AB - OBJECTIVE: The association between methylenetetrahydrofolate reductase (MTHFR) C677 > T polymorphisms and pediatric acute lymphoblastic leukemia (ALL) risk in Asia is controversial. The aim of this meta-analysis was to further assess the relationship between MTHFR C677 > T polymorphisms and pediatric ALL for Chinese children. MATERIALS AND METHODS: Studies about the MTHFR C677 > T polymorphisms and pediatric ALL risk were searched in the Medline, PubMed, EMBASE, Wanfang and CNIK databases. The genotype of the case and control group were extracted and pooled by meta-analysis. The association between ALL risk and C677 > T polymorphisms was demonstrated by odds ratio (OR) and its 95% confidence interval (CI). RESULTS: Twelve articles were included in this study with 1803 ALL cases and 4146 controls. In recessive genetic model (TT vs. CC + CT), the OR was 0.37 (95%CI: 0.31-0.43); in dominant genetic model (TT + CT vs. CC) the OR was 0.94 (95%CI: 0.82-1.06); and in the homozygous model the OR was 0.84 (95%CI: 0.69 1.03). CONCLUSION: The results indicated that Asian children with TT genotype of MTHFR gene may have less risk of developing ALL. PMID- 25450285 TI - Serum cyfra21-1 as a biomarker in patients with nonsmall cell lung cancer. AB - OBJECTIVE: The purpose of this retrospective study was to evaluate the clinical value of serum cytokeratin-19-fragment (cyfra21-1) as a biomarker in nonsmall cell lung cancer (NSCLC). METHODS: Sixty-six patients with NSCLC and 48 cases with benign lung disease were retrospectively analyzed in the department of thoracic surgery in our hospital. The serum level of cyfra21-1 was detected in the above patients. The diagnosis sensitivity, specificity and the receiver operating characteristic curve were calculated by using the stata11.0 statistical software to evaluate the clinical diagnosis value of serum Cyfra21-1 as NSCLC serologic biomarker. RESULTS: The mean of serum cyfra21-1 were 8.95 eat. 01 MU/L and 4.28 eat. 89 MU/L in NSCLC patient and control groups respectively, which indicated that the NSCLC group were much higher (P < 0.05). The diagnosis sensitivity and specificity were 77.08% and 63.64% at the threshold of 6.32 MU/L respectively. Moreover, the area under the curve was 0.78 (95% confidence interval: 0.70-0.87). CONCLUSION: Serum cyfra21-1 can be a potential serologic biomarker in evaluation of NSCLC. PMID- 25450286 TI - Prostate cancer antigen 3 as a biomarker in the urine for prostate cancer diagnosis: a meta-analysis. AB - OBJECTIVE: The aim of this study was to investigate the clinical value of urine Prostate cancer antigen 3 (PCA3) test in the diagnosis of prostate cancer by pooling the published data. METHODS: The clinical trials about urine PCA3 test in the diagnosis of prostate cancer were searched in the PubMed (January, 1966-July, 2014). Cochrane library (Section 3, 2013), CNKI (March, 1994-July, 2014). All relevant prospective studies of urine PCA3 test in the diagnosis of prostate cancer were screened. The aggregated sensitivity, specificity, positive likely hood ratio (+LR), negative likely hood ratio (-LR), diagnosis odds ratio (DOR) and area under the area under curve (AUC) were calculated by using Meta-disc 1.4 and STATA 11.0 statistic software. RESULTS: Finally, a total of 13 trials including 3245 subjects were included in this meta-analysis. The pooled sensitivity, specificity, +LR, -LR, DOR and AUC were 0.62 (95% confidence interval [CI]: 0.59-0.65), 0.75 (95% CI: 0.73-0.76), 6.16 (95% CI: 3.39-11.21), 0.50 (95% CI: 0.43-0.59), 5.49 (95% CI: 3.76-8.019) and 0.75 (95% CI: 0.71-0.78), respectively. CONCLUSION: Urine PCA3 test has acceptable sensitivity and specificity in the diagnosis of prostate cancer, which can be used as non invasive method for diagnosis of prostate cancer. PMID- 25450287 TI - A meta-analysis of serum cancer antigen 125 array for diagnosis of ovarian cancer in Chinese. AB - OBJECTIVE: To further evaluation the diagnosis accuracy of serum cancer antigen 125 (CA125) in the diagnosis of ovarian cancer in Chinese patients. MATERIALS AND METHODS: The PubMed, Wanfang and CNKI databases were electric searched and relevant diagnosis trials were reviewed and finally included in this meta analysis. The diagnosis sensitivity, specificity, positive likely hood ratio (+LR), negative likely hood ratio (-LR), diagnostic odds ratio (DOR) and receiver operating characteristic curve were pooled by Meta DiSc 1.4 software. RESULTS: Nineteen studies with a total of 2426 subjects were included in this meta analysis. The pooled sensitivity, specificity, +LR, -LR and DOR were 0.75 (95% confidence interval = 0.73-0.78), 0.80 (0.77-0.82), 4.52 (3.27-6.26), 0.31 (0.28 0.35) and 15.76 (10.45-23.75) respectively. The area under the summary receiver operating characteristic curve was 0.84. CONCLUSION: Serum CA125 was potential biomarker for diagnosis of ovarian cancer with acceptable diagnosis value. PMID- 25450288 TI - Tumor M2-pyruvate kinase in stool as a biomarker for diagnosis of colorectal cancer: A meta-analysis. AB - OBJECTIVE: The aim of this meta-analysis was to evaluate the diagnosis value of tumor M2-pyruvate kinase (M2-PK) in stool as a biomarker for diagnosis of colorectal cancer. MATERIALS AND METHODS: By searching the databases of Cochrane Library, PubMed, China national knowledge Information and Wanfang, the diagnosis study related to tumor M2-PK in stool as a biomarker for diagnosis of colorectal cancer were screened and included in this study. The pooled sensitivity, specificity, positive likelihood ratio (+LR), negative likelihood ratio (-LR) and the receiver operating characteristic curve (ROC) were calculated by stata 11.0 software. RESULTS: According to the including criteria, 14 trials including 1990 subjects were finally included in this meta-analysis. The pooled diagnosis sensitivity, specificity, +LR, -LR and area under curve were 0.78 (95% confidence interval [CI]: 0.74-0.81), 0.77 (95% CI: 0.76-0.79), 4.38 (95% CI: 3.27-5.88), 0.28 (95% CI: 0.23-0.34) and 0.86 (95% CI: 0.834-0.89). No statistical publication bias was found in this study. CONCLUSION: Tumor M2-PK in stool can be a useful biomarker in the diagnosis of colorectal cancer with relative high sensitivity and specificity. PMID- 25450289 TI - Evaluation of computed tomography-guided parapharyngeal mass needle biopsy through mandibular notch for diagnosis of recurrent nasopharygeal carcinoma. AB - OBJECTIVE: The aim was to evaluate the effectiveness of computed tomography (CT) guided fine-needle aspiration biopsy (FNAB) from Mandibular notch and under the zygomatic arch for pathological diagnosis of recurrence nasopharyngeal carcinoma (NPC) after radiotherapy (RT). MATERIALS AND METHODS: Between October 2007 and December 2013, 48 patients with suspected recurrent NPC underwent CT-guided FNAB. A modified coaxial technique was used in all cases, and multiple samples were obtained for histological studies. RESULTS: We obtained a definite histological diagnosis with 87.5% (42/48) overall diagnostic accuracy. In 42 patients the needle aspirate confirmed a clinical suspicion of recurrent disease and the histologic finding was positive (10 cases of squamous cell carcinoma, 3 cases of adenocarcinoma, finding tumor cells tend to squamous cell carcinoma in 24 patients and undifferentiated carcinoma in 5 patients). In the six cases of "no tumor seen" confirmation was made by clinical and imaging follow-up showing 2 tumor relapse and 4 fibrillation. CONCLUSION: CT-guided FNAB from Mandibular notch and under the zygomatic arch is a safe and accurate technique useful for pathological diagnosis of recurrence NPC after RT. PMID- 25450290 TI - Wnt5a/Ca (2+) /calcineurin/nuclear factor of activated T signaling pathway as a potential marker of pediatric melanoma. AB - Melanoma is rare in children, but its incidence appears to be increasing. Melanoma accounts for the highest mortality among all skin cancer types. This disease is characterized by high-grade malignancy, easy metastasis, poor prognosis, and high death rate. Melanoma in children may be biologically different from that in adults. Therefore, novel biomarkers need to be developed to understand the mechanism by which melanoma cells migrate and infiltrate. Such biomarkers will also be useful for the molecular recognition and targeted therapy of melanoma. Ca 2+ regulates the migration, proliferation, infiltration, and metastasis of cancer cells. Consequently, many studies investigated the relationship of the Wnt/Ca 2+ signaling pathway to tumor occurrence and development. This review summarizes and discusses the function of the Wnt5a/Ca 2+ /calcineurin/nuclear factor of the activated T signaling pathway in melanoma and evaluates its potential to be a biomarker of pediatric melanoma. PMID- 25450291 TI - Research progress on bladder cancer molecular genetics. AB - Bladder cancer is a common malignant urinary tumor with a high rate of recurrence and quick progression, which threats human health. With the research on bladder cancer molecular genetics, the knowledge of gene modification and the development of molecular detection methods, more tumor markers have been discovered, which may have potential for early diagnosis, clinical examination and prognosis. This article reviews the research progress on bladder cancer molecular genetics. PMID- 25450292 TI - Advances in the study of serum tumor markers of lung cancer. AB - Lung cancer is among the most prevalently occurring carcinomas worldwide, and reducing lung cancer mortality depends on early detection, diagnosis, and treatment. Given the rapid development of molecular biology and modern techniques for diagnosis and treatment, the study of serum tumor markers has gained extensive application in early diagnosis, treatment effect monitoring, and prognosis evaluation. Serum tumor markers possess the advantages of easy detection, noninvasive operation, and cost-effectiveness. This article reviews the progress in the study of serum tumor markers of lung cancer. PMID- 25450293 TI - Leptin down-regulates gamma-ENaC expression: a novel mechanism involved in low endometrial receptivity. AB - OBJECTIVE: To examine epithelial Na(+) channel (ENaC) expression in endometrium of overweight/obese women with polycystic ovary syndrome (PCOS) during the window of implantation, and to explore the mechanism linking leptin-mediated reduction of gamma-ENaC to low endometrial receptivity. DESIGN: Controlled, prospective, clinical, experimental study. SETTING: University-based infertility center. PATIENT(S): Blood and endometrium samples were collected from 12 control women and 12 overweight/obese PCOS patients. Pregnancy outcomes were obtained from 245 women with male-factor infertility (533 cycles) and 57 infertile women with PCOS (120 cycles) who underwent intrauterine insemination. INTERVENTION(S): Human endometrial biopsies. MAIN OUTCOME MEASURE(S): Expression of ENaC mRNA and protein in endometrium. RESULT(S): The expression of gamma-ENaC decreased in the secretory phase endometrium of PCOS patients who showed increased serum leptin levels. In cultured endometrial cells (Ishikawa cells), leptin dose-dependently down-regulated the expression of gamma-ENaC and reduced the JAr spheroid attachment rate, which could be blocked by knockdown of STAT3, a signal in the pathway of leptin receptor activation. The overweight/obese PCOS patients with increased serum leptin levels showed a significantly increased biochemical pregnancy rate, suggesting that high leptin might attenuate endometrial receptivity and increase very early pregnancy loss. CONCLUSION(S): High serum leptin may reduce endometrial receptivity by activating the STAT3 signal pathway and down-regulating gamma-ENaC expression in the endometrium. These results provide valuable new insights into the molecular mechanisms linking abnormal ENaC gene expression to early pregnancy loss in overweight/obese PCOS patients. PMID- 25450294 TI - Pregnancy outcomes in very advanced maternal age pregnancies: the impact of assisted reproductive technology. AB - OBJECTIVE: To determine whether there are differences in adverse pregnancy outcomes in very advanced maternal age (vAMA) women who conceived with assisted reproductive technologies (ART) compared with spontaneous conceptions. DESIGN: Retrospective cohort study. SETTING: Academic tertiary care medical center. PATIENT(S): A total of 472 women aged >=45 years who delivered at one institution. INTERVENTION(S): Mode of conception. MAIN OUTCOME MEASURE(S): Maternal and neonatal outcomes. RESULT(S): For singleton pregnancies, vAMA women who conceived with ART were significantly older (47.0 +/- 2.3 vs. 45.6 +/- 0.1 years), more likely to be white (88.1% vs. 75.6%), and less parous (0.4 +/- 0.9 vs. 1.2 +/- 1.8) than vAMA women who conceived spontaneously. They were at significantly increased risk for cesarean delivery (CD) (75.1% vs. 49.7%) and were more likely to undergo elective primary CD without labor (25.4% vs. 9.4%). Risk of retained placenta was also significantly higher (2.7% vs. 0%). Rates of other maternal complications and neonatal outcomes were similar. Subgroup analysis of ART singleton pregnancies did not demonstrate differences in women using autologous oocytes versus donor oocytes. CONCLUSION(S): Very advanced maternal age women who conceive after ART are more likely to be white, older, primiparous, and are more likely to proceed with an elective CD compared with vAMA women who conceive spontaneously. The increased risk of retained placenta in women who conceive with ART may indicate an underlying risk for placentation defects. PMID- 25450295 TI - Liability for mismanagement of sperm specimens in fertility practices. PMID- 25450297 TI - Fetal endometriosis: a case report. AB - OBJECTIVE: To report a case of a large fetal pelvic mass diagnosed at 35 weeks' gestation. DESIGN: Report of a unique case of a fetal abdominal mass, emphasizing the wide range of differential diagnoses. Although rare reports of fetal ovarian cysts exist, even fewer describe endometriosis or endometriomas in infants. As of 2014 there have not been any published reports of fetal endometriosis from the United States. SETTING: Large tertiary community hospital. PATIENT(S): An 18-year old pregnant woman diagnosed with a large fetal pelvic mass at 35 weeks' gestation. INTERVENTION(S): Diagnosis of a fetal abdominal mass at 35 weeks with documented enlargement at 37 weeks leading to delivery, with subsequent removal of the mass on day of life 2. MAIN OUTCOME MEASURE(S): On day of life 2, a pediatric surgeon performed an exploratory laparotomy and left salpingo oophorectomy. RESULT(S): Final pathology showed a 7.0 * 4.5 cm cyst-like structure consistent with hemorrhagic ovarian cyst wall and focal endometriosis. CONCLUSION(S): It can be very difficult to counsel patients regarding an abdominal mass in their unborn child. These difficulties stem from the large list of differential diagnoses and the range of prognoses they portend. As more and more of these cases appear in the literature, we are able to gain a better understanding of how each of these diagnoses present and appear on imaging, allowing us to provide a more accurate diagnosis and counseling antenatally. PMID- 25450296 TI - Simple perfusion apparatus for manipulation, tracking, and study of oocytes and embryos. AB - OBJECTIVE: To develop and implement a device and protocol for oocyte analysis at a single cell level. The device must be capable of high resolution imaging, temperature control, perfusion of media, drugs, sperm, and immunolabeling reagents all at defined flow rates. Each oocyte and resultant embryo must remain spatially separated and defined. DESIGN: Experimental laboratory study. SETTING: University and academic center for reproductive medicine. PATIENT(S)/ANIMAL(S): Women with eggs retrieved for intracytoplasmic sperm injection (ICSI) cycles, adult female FVBN and B6C3F1 mouse strains, sea stars. INTERVENTION(S): Real time, longitudinal imaging of oocytes after fluorescent labeling, insemination, and viability tests. MAIN OUTCOME MEASURE(S): Cell and embryo viability, immunolabeling efficiency, live cell endocytosis quantification, precise metrics of fertilization, and embryonic development. RESULT(S): Single oocytes were longitudinally imaged after significant changes in media, markers, endocytosis quantification, and development, all with supreme control by microfluidics. Cells remained viable, enclosed, and separate for precision measurements, repeatability, and imaging. CONCLUSION(S): We engineered a simple device to load, visualize, experiment, and effectively record individual oocytes and embryos without loss of cells. Prolonged incubation capabilities provide longitudinal studies without need for transfer and potential loss of cells. This simple perfusion apparatus provides for careful, precise, and flexible handling of precious samples facilitating clinical IVF approaches. PMID- 25450298 TI - Antimullerian hormone as predictor of implantation and clinical pregnancy after assisted conception: a systematic review and meta-analysis. AB - OBJECTIVE: To assess whether antimullerian hormone (AMH) is a predictor of implantation and/or clinical pregnancy in women undergoing assisted reproductive technology. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Women undergoing IVF/intracytoplasmic sperm injection in nondonor cycles. INTERVENTION(S): Measurement of serum AMH level. MAIN OUTCOME MEASURE(S): Diagnostic odds ratio (OR) and summary receiver operating characteristic curve (AUC) for AMH as a predictor of implantation and/or clinical pregnancy. RESULT(S): A total of 525 observational studies were identified, of which 19 were selected (comprising 5,373 women). Studies reporting clinical pregnancy rates in women with unspecified ovarian reserve (n = 11), diminished ovarian reserve (DOR) (n = 4), and polycystic ovary syndrome (n = 4) were included, together with studies reporting implantation rates (n = 4). The OR for AMH as a predictor of implantation in women with unspecified ovarian reserve (n = 1,591) was 1.83 (95% confidence interval [CI] 1.49-2.25), whereas the AUC was 0.591 (95% CI 0.563 0.618). The OR for AMH as a predictor of clinical pregnancy in these women (n = 4,324) was 2.10 (95% CI 1.82-2.41), whereas the AUC was 0.634 (95% CI 0.618 0.650). The predictive ability of AMH for pregnancy was greatest in women with DOR (n = 615), with OR and AUC of 3.96 (95% CI 2.57-6.10) and 0.696 (95% CI 0.641 0.751), respectively. In contrast, AMH had no significant predictive ability in women with PCOS (n = 414), with OR and AUC of 1.18 (95% CI 0.53-2.62) and 0.600 (95% CI 0.547-0.653), respectively. CONCLUSION(S): Antimullerian hormone has weak association with implantation and clinical pregnancy rates in assisted reproductive technology but may still have some clinical utility in counseling women undergoing fertility treatment regarding pregnancy rates, particularly those with DOR. PMID- 25450299 TI - Status of sperm morphology assessment: an evaluation of methodology and clinical value. AB - OBJECTIVE: To characterize methodological changes in sperm morphology assessment and to correlate sperm morphology with clinical outcome. DESIGN: In this observational study, sperm morphology profiles of patients were analyzed. The percentages of morphologically normal spermatozoa were evaluated with respect to changes in morphology assessment criteria; male aging; and prognostic value for outcomes after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). SETTING: Diagnostic and clinical laboratories. PATIENT(S): A total of 8,846 men who visited the diagnostic laboratory; 133 samples from a sperm bank; and 3,676 IVF/ICSI couples. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The percentage of morphologically normal spermatozoa in semen samples. The regression of the individual morphologically normal cell profiles. The relation between the percentage of normal forms with pregnancy outcome after IVF/ICSI. RESULT(S): The percentage of morphologically normal spermatozoa showed a decrease from roughly 30%-80% in 1984 to 0%-10% since 2004. With added evidence from sperm bank samples, this decrease was found to be attributable mainly to changes in morphology assessment criteria. Furthermore, an intraindividual aging effect of 0.51% per year was observed. A statistically significant relationship was found between decreases in percentage of normal forms and a lower probability of ongoing pregnancies after IVF, although the area under the curve was only 54%. CONCLUSION(S): Methodological changes had a strong effect on the percentage of morphologically normal spermatozoa over the past few decades. In addition, male aging results in decreasing sperm morphology. The percentage of morphologically normal spermatozoa has no prognostic value for individual IVF/ICSI patients. PMID- 25450300 TI - Use of gonadotropin-releasing hormone agonist trigger during in vitro fertilization is associated with similar endocrine profiles and oocyte measures in women with and without polycystic ovary syndrome. AB - OBJECTIVE: To compare endocrine profiles and IVF outcomes after using GnRH agonists (GnRHa) to trigger final oocyte maturation in women with polycystic ovary syndrome (PCOS) with other hyper-responders. DESIGN: Retrospective cohort study. SETTING: Academic center. PATIENT(S): Forty women with PCOS and 74 hyper responders without PCOS. INTERVENTION(S): GnRHa trigger. MAIN OUTCOME MEASURE(S): Number of oocytes. RESULT(S): Serum E2, LH, and P levels on the day of GnRHa trigger and the day after trigger did not differ significantly between groups. There were no significant differences in total number of oocytes or percent mature oocytes obtained between groups after controlling for age, antral follicle count, and total days of stimulation. The overall rate of no retrieval of oocytes after trigger was low (2.6%). Fertilization, implantation, clinical pregnancy, and live-birth rates were similar in the two groups. No patients developed ovarian hyperstimulation syndrome (OHSS). CONCLUSION(S): The similar post-GnRHa trigger hormone profiles and mature oocyte yield support the routine use of GnRHa trigger to prevent OHSS in women with PCOS. PMID- 25450301 TI - Analysis of semen parameters in male referrals: impact of reference limits, stratification by fertility categories, predictors of change, and comparison of normal semen parameters in subfertile couples. AB - OBJECTIVE: To [1] determine the impact of semen reference limits on referrals for male fertility evaluations, [2] analyze the stratification of subjects based on published "normal" thresholds, [3] analyze the odds of changing fertility categories during serial tests and thereby the potential impact of inherent variability of semen parameters on referrals, and [4] determine variable(s) predictive of change. DESIGN: Retrospective chart review. SETTING: Academic referral center for male fertility. PATIENT(S): New encounters in a male fertility clinic over a 5-year period that straddles the publication of World Health Organization (WHO) 2010 reference values. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Demographic and clinical variables, semen values, and fertility categories as follows: BE (below WHO 2010 criteria), BTWN (above WHO 2010 but below WHO 1999 criteria), and N (above WHO 1999 criteria). RESULT(S): A total of 82.3% of initial semen tests were categorized as BE, and the predominance of this category was unchanged by publication of the WHO 2010 criteria. Men with initial semen analysis categorized as BTWN or N represented 16.2% and 1.5% of the referral population, respectively. Subjects initially categorized as BTWN were more likely to change fertility categories, and overwhelmingly this migration was downward. Analysis of normal individual semen parameters revealed statistically worse mean concentration and motility when at least one other parameter fell below the WHO 2010 criteria. CONCLUSION(S): Men with semen results above reference criteria are underrepresented, indicating that reference limits influence referral patterns for male fertility evaluations. Normal mean concentration and motility were lower in men with at least one other individual semen parameter below the 2010 criteria, suggesting global dysfunction in spermatogenesis. PMID- 25450303 TI - Is polycystic ovarian morphology related to a poor oocyte quality after controlled ovarian hyperstimulation for intracytoplasmic sperm injection? Results from a prospective, comparative study. AB - OBJECTIVE: To evaluate the relationship between polycystic ovarian morphology (PCOM) and oocyte quality after controlled ovarian stimulation for intracytoplasmic sperm injection (ICSI). DESIGN: Prospective, comparative study with concurrently treated and age-matched controls. SETTING: Academic IVF unit of the Lille University Hospital. PATIENT(S): A total of 194 women were prospectively included before their first IVF-ICSI attempt for exclusive male infertility. They were classified into PCOM (n = 97) or control groups (n = 97) according to their follicle number per ovary. The nuclear maturation and morphologic aspects of 1,013 oocytes from PCOM patients were assessed and compared with those of 774 oocytes from controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Rate of metaphase II (MII) and morphologically abnormal oocytes. RESULT(S): The mean number of total and MII oocytes retrieved was significantly higher in the PCOM group. The rate of MII and morphologically abnormal oocytes was equivalent between the two groups. The mean number of embryos was significantly higher in the PCOM group. However, the percentage of top-quality embryos on day 3 was similar between the two groups. The implantation and clinical pregnancy rates were significantly higher in the PCOM group. CONCLUSION(S): Polycystic ovarian morphology does not have a negative impact on the quality of oocytes and embryos or the outcome of IVF-ICSI. PMID- 25450304 TI - Sperm functional tests. AB - Several semen parameters are used to discriminate the fertile male from the subfertile male. The most widely used parameters are sperm concentration, motility, progressive motility, and sperm morphology. Semen analysis is usually applied as described in the World Health Organization manual for semen analysis. In addition to a routine semen analysis, sperm functional tests have been described for many years, which in most cases are regarded as research tools and not part of the routine semen testing in an infertility clinic. In this review we report on the value of four sperm function tests: the sperm penetration assay, the sperm-zona pellucida binding tests, the acrosome reaction, and the hyaluronan binding assay. For each test we describe the current value, the indication for performing the test, how to interpret the results, and its therapeutic implications. Our data show that sperm functional assays are highly predictive of IVF outcome results and have the potential to assist in clinical decision making, especially to avoid the current long-standing treatment with IUI and to direct the patients to intracytoplasmic sperm injection without delay when sperm functional testing fails. We believe that advances in molecular biology techniques will allow us to develop simpler sperm function assays in the near future. This will undoubtedly help clinicians in optimizing male factor infertility diagnosis and treatment. PMID- 25450305 TI - Benefit of intraoperative navigation on glenoid component positioning during total shoulder arthroplasty. AB - INTRODUCTION: The objective of this study was to review and synthesize the current best evidence for the use of intraoperative navigation in the implantation of glenoid components in total shoulder prostheses. METHODS: We conducted a systematic, online search using PubMed, EMBASE, CCTR, and CINAHL using "Arthroplasty, Replacement"(Mesh) AND (shoulder) AND (navi* OR computer). Data on study design and quality as well as accuracy of positioning and complications were extracted independently and in duplicate. After assessment of study heterogeneity, DerSimonian-Laird random effect models were used to pool data from the individual studies. RESULTS: The systematic search revealed 359 manuscripts in total. After exclusion of duplicates and irrelevant publications, 6 groups of 247 shoulders from 5 studies were included. The pooled weighted mean difference for deviation from neutral version was -6.4 degrees (95 %CI -7.9 to 5.3) in favor of navigation, which is consistent with a statistically significant difference (p < 0.01). In the navigation group, 2 superior glenoid screws were reported as perforating compared to 5 screws (1 inferior, 4 superior) in the control group. There was no difference in tilt at a WMD of 2.7 (95 %CI -1.4 to 6.8, p = 0.192). CONCLUSIONS: Navigation allows for significantly more accurate glenoid version, but the clinical meaningfulness of the absolute improvement over standard techniques is questionable. However, navigation is a valuable teaching tool that might prove very beneficial not for the patient at hand, but for those treated by the operating surgeon in the future. LEVEL OF EVIDENCE: Level II-meta analysis of non-homogenous controlled trials. PMID- 25450302 TI - A prospective study of prepregnancy serum concentrations of perfluorochemicals and the risk of gestational diabetes. AB - OBJECTIVE: To examine preconception serum concentrations of perfluorooctanoic acid (PFOA) and six other PFCs in relation to gestational diabetes (GDM) risk. DESIGN: Prospective cohort with longitudinal follow-up. SETTING: Not applicable. PATIENT(S): Among 501 women recruited upon discontinuing contraception for the purpose of becoming pregnant, 258 (51%) became pregnant and were eligible for the study, of which 28 (11%) reported having physician-diagnosed GDM during follow up. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The odds ratios (ORs) and 95% confidence intervals (CIs) of GDM associated with each standard deviation (SD) increment of preconception serum PFOA concentration (ng/mL, log-transformed) and six other PFCs were estimated with the use of logistic regression after adjusting for age, prepregnancy body mass index, smoking, and parity conditional on gravidity. RESULT(S): Preconception geometric mean (95% CI) PFOA concentrations (in ng/mL) were higher for women with than without GDM (3.94 [3.15-4.93] vs. 3.07 [2.83-3.12], respectively). Each SD increment in PFOA was associated with a 1.87 fold increased GDM risk (adjusted OR 1.86 [95% CI 1.14-3.02]). A slightly increased risk associated with each SD increment for the six other PFCs was observed as well (all ORs >1.0, range 1.06-1.27), although the associations were not statistically significant. CONCLUSION(S): Our findings suggested that higher environmentally relevant concentrations of PFOA were significantly associated with an increased risk of GDM. If corroborated, these findings may be suggestive of a possible environmental etiology for GDM. PMID- 25450306 TI - Axial view of acetabular anterior column: a new X-ray projection of percutaneous screw placement. AB - INTRODUCTION: To search for a new radiographic view/projection of the acetabular anterior column to provide a safe guide for percutaneous screw placement for acetabular fractures. MATERIALS AND METHODS: Eight pelvic specimens taken from normal adult cadavers were positioned in a supine position on the operating table. First, the ipsilateral ilium-oblique view of the observed side was obtained on C-arm fluoroscopy by tilting the C-arm approximately 35 degrees toward the contralateral hip joint. Then, the tilting angle of the C-arm was changed gradually until an oval track image (acetabular anterior column axial view) appeared. The oval shadow was clear only in one position as the angle of the C-arm was changed toward the caudal side of the operating table. A guide pin was put on the skin of the cadaver, and the location and tilting direction of the guide pin were adjusted under C-arm fluoroscopy until the pin's shadow became a point in the center of the oval track. Then, the guide pin was inserted into the bone using a battery-powered drill. The degree of inclination of the guide pin in the cadaver in the frontal and sagittal planes was measured using computed tomography (CT). RESULTS: Axial views of the anterior column were found successfully in all of the pelvic specimens, and the guide pins were inserted accurately into the acetabular anterior column under C-arm fluoroscopic guidance. On the CT-reconstructed image, the average degree of angle between the guide pin and the sagittal plane was 33.6 degrees (range 29.6 degrees -36.5 degrees ). The average angle between the guide pin and the transverse plane was 59.1 degrees (range 56.4 degrees -63.2 degrees ). CONCLUSION: This axial view of the acetabular anterior column is a novel X-ray projection which provides an optimal method for guiding percutaneous insertion of anterior column screws for acetabular fractures. PMID- 25450308 TI - Capillary-channeled polymer (C-CP) fibers for the rapid extraction of proteins from urine matrices prior to detection with MALDI-MS. AB - PURPOSE: While MS is a powerful tool for biomarker determinations, the high salt content and the small molecules present in urine poses incredible challenges. Separation/extraction methods must be employed for the isolation of target species at relevant concentrations. Micropipette tips packed with capillary channeled polymer (C-CP) fibers are employed for the SPE of proteins from a synthetic and a certified urine matrix. EXPERIMENTAL DESIGN: Extractions are performed utilizing a very simple centrifugation method to spin-down species through the C-CP fiber tips. Proteins adsorb to the hydrophobic polypropylene fibers and are eluted in a solvent suitable for MALDI-MS analysis. Figures of merit are determined for representative compounds beta2-microglobulin, retinol binding protein, and transferrin. RESULTS: The optimum protein processing included a 100 MUL aqueous rinse and an elution solvent composition was 10 MUL of 55:45 ACN:water (with triflouroacetic acid). MALDI-MS responses for the target proteins are improved from nondetectable levels to eventually yield LOD ranging from 5 to 180 nM in 1 MUL aliquots. CONCLUSION AND CLINICAL RELEVANCE: C-CP fiber tips offer a plethora of advantages including low materials costs, high throughput, microvolume processing, and the determination of sub-nanogram quantities of analyte; allowing determination of biomarkers that are otherwise undetectable in urine matrices. PMID- 25450309 TI - A new forensic collection housed at the University of Coimbra, Portugal: The 21st century identified skeletal collection. AB - The purpose of this study is to characterize and contextualize the new collection of identified skeletons housed in the Department of Life Sciences at the University of Coimbra, Portugal. The 21st Century Identified Skeletal Collection, which is still being enlarged, is currently composed of 159 complete adult skeletons (age at death range: 29-99 years) of both sexes. The skeletons consist almost exclusively of Portuguese nationals who died between 1995 and 2008. The state of preservation is good and more detailed antemortem information is presently being collected. This collection constitutes a fundamental tool for forensic anthropology research, including development and validation studies of skeletal aging and sexing methods that target elderly adults. Moreover, this collection can also be used in conjunction with the other reference collections housed in the University of Coimbra to investigate secular trends in skeletal development and aging, among others. PMID- 25450307 TI - Presynaptic effects of levodopa and their possible role in dyskinesia. AB - Levodopa replacement therapy has long provided the most effective treatment for Parkinson's disease (PD). We review how this dopamine (DA) precursor enhances dopaminergic transmission by providing a greater sphere of neurotransmitter influence as a result of the confluence of increased quantal size and decreased DA reuptake, as well as loading DA as a false transmitter into surviving serotonin neuron synaptic vesicles. We further review literature on how presynaptic dysregulation of DA release after l-dopa might trigger dyskinesias in PD patients. PMID- 25450310 TI - Carnosine: effect on aging-induced increase in brain regional monoamine oxidase-A activity. AB - Aging is a natural biological process associated with several neurological disorders along with the biochemical changes in brain. Aim of the present investigation is to study the effect of carnosine (0.5-2.5MUg/kg/day, i.t. for 21 consecutive days) on aging-induced changes in brain regional (cerebral cortex, hippocampus, hypothalamus and pons-medulla) mitochondrial monoamine oxidase-A (MAO-A) activity with its kinetic parameters. The results of the present study are: (1) The brain regional mitochondrial MAO-A activity and their kinetic parameters (except in Km of pons-medulla) were significantly increased with the increase of age (4-24 months), (2) Aging-induced increase of brain regional MAO-A activity including its Vmax were attenuated with higher dosages of carnosine (1.0 2.5MUg/kg/day) and restored toward the activity that observed in young, though its lower dosage (0.5MUg/kg/day) were ineffective in these brain regional MAO-A activity, (3) Carnosine at higher dosage in young rats, unlike aged rats significantly inhibited all the brain regional MAO-A activity by reducing their only Vmax excepting cerebral cortex, where Km was also significantly enhanced. These results suggest that carnosine attenuated the aging-induced increase of brain regional MAO-A activity by attenuating its kinetic parameters and restored toward the results of MAO-A activity that observed in corresponding brain regions of young rats. PMID- 25450312 TI - A novel detachable head-mounted device for simultaneous EEG and photoacoustic monitoring of epilepsy in freely moving rats. AB - The study of neuro-hemodynamic changes in freely moving animals provides for a better understanding of brain dynamics in normal and disease states. While it has been shown that hemodynamic changes are closely related to seizures, methods for detection in freely moving animals are limited. In this work, we integrate photoacoustic sensor technology and electroencephalography into a small portable device that can be attached on the head of wake freely moving animals. We demonstrate chronic simultaneous monitoring of photoacoustic and electroencephalographic signals in an acute seizure model of epilepsy. Our results demonstrate that both the neural and vascular responses during seizures in freely moving rats have characteristics which are observed to be different and more diverse from that of anesthetized rats. This implies that the neurovascular coupling in seizure in free moving animals are more complicated, which calls for more detailed study in future. To the best of our knowledge, this is the first time for hemodynamic monitoring of seizure in free moving animals. This technology also promises for other hemodynamic related research study in freely moving small animals. PMID- 25450311 TI - Binding specificity of anti-HNK-1 IgM M-protein in anti-MAG neuropathy: possible clinical relevance. AB - Anti-myelin-associated-glycoprotein (MAG) neuropathy is an intractable autoimmune polyneuropathy. The antigenic region of MAG is the human natural killer-1 (HNK-1) carbohydrate. We and others previously suggested that the extension of antibody reactivities to HNK-1-bearing proteins other than MAG was associated with treatment resistance, without statistical analyses. In this study, we established an ELISA method with recombinant proteins to test binding specificities of currently available monoclonal antibodies to MAG and another HNK-1-bearing protein, phosphacan. Using this system, we found the distinct binding specificities of anti-MAG antibody in 19 patients with anti-MAG neuropathy. Their clinical relevance was then determined retrospectively with the adjusted 10 points INCAT disability score (0 = normal and 10 = highly disable). The results showed that strong reactivities of anti-MAG antibodies to phosphacan were significantly associated with treatment resistance or progressive clinical courses, indicating a possible clinical relevance of the binding specificities. PMID- 25450313 TI - Three faces of self-face recognition: potential for a multi-dimensional diagnostic tool. AB - The recognition of self-face is a unique and complex phenomenon in many aspects, including its associated perceptual integration process, its emergence during development, and its socio-motivational effect. This may explain the failure of classical attempts to identify the cortical areas specifically responsive to self face and designate them as a unique system related to 'self'. Neuroimaging findings regarding self-face recognition seem to be explained comprehensively by a recent forward-model account of the three categories of self: the physical, interpersonal, and social selves. Self-face-specific activation in the sensory and motor association cortices may reflect cognitive scrutiny due to prediction error or task-induced top-down attention in the physical internal schema related to the self-face. Self-face-specific deactivation in some amodal association cortices in the dorsomedial frontal and lateral posterior cortices may reflect adaptive suppression of the default recruitment of the social-response system during face recognition. Self-face-specific activation under a social context in the ventral aspect of the medial prefrontal cortex and the posterior cingulate cortex may reflect cognitive scrutiny of the internal schema related to the social value of the self. The multi-facet nature of self-face-specific activation may hold potential as the basis for a multi-dimensional diagnostic tool for the cognitive system. PMID- 25450314 TI - BDNF promoter I methylation correlates between post-mortem human peripheral and brain tissues. AB - Several psychiatric disorders have been associated with CpG methylation changes in CG rich promoters of the brain-derived neurotrophic factor (BDNF) mainly by extracting DNA from peripheral blood cells. Whether changes in peripheral DNA methylation can be used as a proxy for brain-specific alterations remains an open question. In this study we aimed to compare DNA methylation levels in BDNF promoter regions in human blood cells, muscle and brain regions using bisulfite pyrosequencing. We found a significant correlation between the levels of BDNF promoter I methylation measured in quadriceps and vPFC tissues extracted from the same individuals (n = 98, Pearson, r = 0.48, p = 4.5 * 10(-7)). In the hippocampus, BDNF promoter I and IV methylation levels were strongly correlated (Pearson, n = 37, r = 0.74, p = 1.4 * 10(-7)). We found evidence for sex dependent effect on BDNF promoter methylation levels in the various tissues and blood samples. Taken together, these data indicate a strong intra-individual correlation between peripheral and brain tissue. They also suggest that sex determines methylation patterns in BDNF promoter region across different types of tissue, including muscle, brain, and blood. PMID- 25450315 TI - Task-specific brain reorganization in motor recovery induced by a hybrid rehabilitation combining training with brain stimulation after stroke. AB - Recently, we have developed a new hybrid-rehabilitation combining 5Hz repetitive transcranial magnetic stimulation and extensor motor training of the paretic upper-limb for stroke patients with flexor hypertonia. We previously showed that the extensor-specific plastic change in M1 was associated with beneficial effects of our protocol (Koganemaru et al., 2010). Here, we investigated whether extensor specific multiregional brain reorganization occurred after the hybrid rehabilitation using functional magnetic resonance imaging. Eleven chronic stroke patients were scanned while performing upper-limb extensor movements. Untrained flexor movements were used as a control condition. The scanning and clinical assessments were done before, immediately and 2 weeks after the hybrid rehabilitation. As a result, during the trained extensor movements, the imaging analysis showed a significant reduction of brain activity in the ipsilesional sensorimotor cortex, the contralesional cingulate motor cortex and the contralesional premotor cortex in association with functional improvements of the paretic hands. The activation change was not found for the control condition. Our results suggested that use-dependent plasticity induced by repetitive motor training with brain stimulation might be related to task-specific multi-regional brain reorganization. It provides a key to understand why repetitive training of the target action is one of the most powerful rehabilitation strategies to help patients. PMID- 25450316 TI - A modeling tool to study the combined effects of drug administration and LVAD assistance in pathophysiological circulatory conditions. AB - The aim of this work is to develop a tool to study the effect of sodium nitroprusside (SNP) on hemodynamics in conjunction with baroreflex and mechanical circulatory assistance. To this aim, a numerical model of the pharmacodynamic effect of SNP was developed and inserted into a cardiovascular circulatory model integrated with baroreflex and LVAD (continuous flow pump with atrio-aortic connection) sub-models.The experiments were carried out in two steps. In the first step the model was verified comparing simulations with experimental data acquired from mongrel dogs on mean arterial pressure (MAP), cardiac output (CO), heart rate (HR), peripheral resistance, and left ventricular properties.In the second step, the combined action of SNP and mechanical circulatory assistance was studied. Data were measured at pump off and at pump on (20000 rpm and 24000 rpm). At pump off, with a 2.5 ug/kg per min SNP infusion in heart failure condition, the MAP was reduced by approximately 8%, CO and HR increased by about 16% and 18%, respectively. In contrast, during assistance (24000 rpm) the changes in MAP, CO and HR were around -9%, +12%, and +20%, respectively. Furthermore, the effects of the drug on hemodynamic parameters at different heart conditions were significantly different. Thus, the model provides insight into the complex interactions between baroreflex, drug infusion, and LVAD and could be a support for clinical decision-making in cardiovascular pathologies. PMID- 25450317 TI - New option for the treatment of hyperbilirubinemia: in vitro direct hemoperfusion with the Lixelle S-35. AB - PURPOSE: Limited options are available to treat critically ill patients with acute liver failure (ALF) and acute-on-chronic liver failure (AoCLF), therefore we set up an in vitro study in order to test the bilirubin adsorption capacity of the Lixelle S-35 cartridge by direct hemoperfusion (DHP). METHODS: Mock DHP was performed for 120 min using hyperbilirubinic human plasma and blood obtained from a plasmapheresis and exchange transfusion, respectively. The total bilirubin (TBIL) and direct bilirubin (DBIL) baseline concentrations were 17.57 +/- 0.53, 12.57 +/- 0.23 mg/dl for plasma and 23.10 +/- 0.47, 15.37 +/- 0.24 mg/dl for blood. Plasma and blood were separately circulated in a closed circuit simulating DHP using an adsorption column (Lixelle S-35) at flow rate of 100 ml/min. TBIL and DBIL levels were measured at 10, 30, 60, and 120 min from arterial and venous ports and assessed with the Jendrassik-Grof method. All tests were performed in triplicate. RESULTS: The total removal subsequent to DHP (120 min) was seen as TBIL in plasma 55.60%, TBIL in blood 62.16%, DBIL plasma 58.87%, DBIL in blood 64.41%, respectively. The estimated mass adsorption of TBIL in plasma 958.20 +/- 5.72 mg, TBIL in blood 1233.60 +/- 10.22 mg, DBIL in plasma 680.70 +/- 10.68, DBIL in blood 818.10 +/- 4.68, respectively. CONCLUSIONS: The bilirubin adsorption rates after DHP were very promising for both hyperbilirubinic plasma and blood. Although further in vitro investigations are required, including comparisons with other techniques, these findings have shown that the Lexille S 35 should represent an option for the management of hyperbilirubinemia in ALF or AoCLF. PMID- 25450318 TI - Measurement of in vitro and in vivo stent geometry and deformation by means of 3D imaging and stereo-photogrammetry. AB - PURPOSE: To quantify variability of in vitro and in vivo measurement of 3D device geometry using 3D and biplanar imaging. METHODS: Comparison of stent reconstruction is reported for in vitro coronary stent deployment (using micro-CT and optical stereo-photogrammetry) and in vivo pulmonary valve stent deformation (using 4DCT and biplanar fluoroscopy). Coronary stent strut length and inter strut angle were compared in the fully deployed configuration. Local (inter-strut angle) and global (dog-boning ratio) measures of stent deformation were reported during stent deployment. Pulmonary valve stent geometry was assessed throughout the cardiac cycle by reconstruction of stent geometry and measurement of stent diameter. RESULTS: Good agreement was obtained between methods for assessment of coronary stent geometry with maximum disagreement of +/- 0.03 mm (length) and +/- 3 degrees (angle). The stent underwent large, non-uniform, local deformations during balloon inflation, which did not always correlate with changes in stent diameter. Three-dimensional reconstruction of the pulmonary valve stent was feasible for all frames of the fluoroscopy and for 4DCT images, with good correlation between the diameters calculated from the two methods. The largest compression of the stent during the cardiac cycle was 6.98% measured from fluoroscopy and 7.92% from 4DCT, both in the most distal ring. CONCLUSIONS: Quantitative assessment of stent geometry reconstructed from biplanar imaging methods in vitro and in vivo has shown good agreement with geometry reconstructed from 3D techniques. As a result of their short image acquisition time, biplanar methods may have significant advantages in the measurement of dynamic 3D stent deformation. PMID- 25450320 TI - Effect of protoconized therapy for renal anemia on adverse events of patients with maintenance hemodialysis. AB - PURPOSE: We evaluate the effect of the protoconized anemia therapy on adverse events using the Hb and ferritin levels of individual patients undergoing maintenance hemodialysis (MHD). METHODS: Design: A randomized, parallel group, multi-center study. PATIENTS: Two hundred sixty-six MHD patients. Intervention group: The doses of erythropoietin, iron, and vitamin C were adjusted every month based on the ferritin and hemoglobin (Hb) levels according to the protocol. Non intervention group: The attending physician determined the doses of erythropoietin and iron. RESULTS: The maintenance rate of target Hb and ferritin levels were significantly higher in the Intervention group than in the Non intervention group. The frequency of hospitalization was significantly lower for patients with a higher maintenance rate of target Hb levels than for those with a lower maintenance rate. CONCLUSIONS: Using an anemia treatment protocol according to the individual Hb and ferritin levels of hemodialysis patients might stabilize the Hb and ferritin levels, which in turn could contribute to the lower frequency of adverse events in MHD patients. PMID- 25450319 TI - Relationship of tricuspid repair at the time of left ventricular assist device implantation and survival. AB - PURPOSE: Tricuspid regurgitation contributes to right ventricular failure (RVF) and is associated with worse clinical outcomes in patients undergoing left ventricular assist device (LVAD) treatment. However, whether tricuspid valve repair (TVR) at the time of LVAD implantation improves outcomes is not clear. METHODS: We identified all patients undergoing initial implantation of a long term continuous-flow LVAD at our institution from March 2006 to August 2011. We assessed the impact of TVR on survival and incidence of RVF using Kaplan-Meier curves and proportional hazards regression adjusted for age, gender, baseline tricuspid regurgitation, RV function, MELD score, albumin, and indication (bridge vs. destination). RESULTS: A total of 101 patients were included in the analysis, of which 14 patients underwent TVR concomitant LVAD. All TVR patients had moderate or severe baseline regurgitation. Crude survival was not different between groups. In multivariable models adjusted for confounding factors, TVR showed a significant association with improved survival (HR = 0.1, p = 0.049). Adjusted models showed no difference in RVF. CONCLUSIONS: In this cohort of patients, TVR at the time of LVAD implantation appears associated with better survival. Additional larger studies are needed to verify the effect of TVR at the time of LVAD implantation, and whether it should be utilized more frequently. PMID- 25450321 TI - Effect of rotary blood pump pulsatility on potential parameters of blood compatibility and thrombosis in inflow cannula tips. AB - PURPOSE: Rotary Blood Pump (RBP) pulsatile strategies relative to the native cardiac cycle have been widely studied because of their benefits to hemodynamics. However, the effects that inducing pulses has on the blood compatibility of ventricular assist device (VAD) support have not yet been understood. Inflow cannulae have been found to be associated with thrombosis under conventional constant speed support of RBPs. To prevent further risks to blood compatibility, it is necessary to understand the relationship between cannula tip design and the induced pulsatility. The purpose of this study was to evaluate the flow field of 5 different tip geometries under RBP pulsatile support using stereo-particle image velocimetry (PIV). METHODS: Inflow cannulae with conventional tip geometries (blunt, blunt with 4 side ports, beveled with 3 side ports, and cage) and a custom designed crown tip were studied. All cannulae were interposed between a mixed-flow RBP and a silicone left ventricle. The contractile function and hemodynamics were reproduced in a mock circulation loop (MCL). The RBP was configured to induce synchronous and counter-synchronous pulses relative to cardiac cycles while supporting the failing ventricle. RESULTS: Between both pulsing strategies, low shear volume (gamma<=100/s, potential parameter of thrombus formation) showed no significant difference. However, counter synchronous pulsatile mode induced less increase of both high shear volume (gamma>=2778/s, potential parameter of platelet activation) and recirculation volume (V(z)>0, potential parameter of thrombus formation). CONCLUSIONS: Although the clinical relationship cannot be inferred from this measurement, when considering the inflow tips only, a necessary trade-off should be made between adverse effects on blood compatibility and benefits for hemodynamics during RBP pulsatile mode. PMID- 25450322 TI - Development of a novel method for decellularizing a nerve graft using a hypertonic sodium chloride solution. AB - PURPOSE: Acellular nerves are a reconstruction material and provide scaffolds for nerve regeneration. Numerous methods to develop acellular nerves have been described. However, these methods pose problems that can be attributed to incomplete acellular processing and destruction of the extracellular matrix (ECM); the former may lead to rejection response, while the latter may damage the scaffold. In order to overcome problems associated with the above-mentioned methods, we developed a novel method that employs a hypertonic sodium chloride solution to decellularize nerve graft material. METHODS: Rat sciatic nerves were harvested, dipped in hypertonic sodium chloride solution (1 M), and shaken for 24 h. We then washed the nerves in phosphate-buffered saline for 7 days with shaking and evaluated the acellular nerves by hematoxylin-eosin (H-E) staining, immunostaining, and electron microscopy. We then transplanted the grafts to the sciatic nerve of another rat and evaluated the outcomes by H-E staining, immunostaining (anti-neurofilament antibody, anti-S-100 antibody), anterograde nerve tracing, and electron microscopy. RESULTS: We found that our method successfully decellularized the grafts, but was mild enough to leave the ECM intact. Two months after transplantation, immunostaining and anterograde nerve tracing confirmed that Schwann cells infiltrated the grafts and induced neurofilament extension. CONCLUSIONS: Our methodology preserves the ECM, is simple to develop, and does not involve substances that harm biogenic tissue. Acellular nerve tissue processed in this way could become a substitute material for bridging nerve gaps. Our method could also aid in the development of other acellular tissues. PMID- 25450323 TI - In situ evolution of the mechanical properties of stretchable and non-stretchable ePTFE vascular grafts and adjacent native vessels. AB - INTRODUCTION: The purpose of this study was to evaluate the evolution of the mechanical properties of stretchable and non-stretchable ePTFE vascular grafts over time following implantation, as well as those of the adjacent native vessels. METHODS: One stretchable and one non-stretchable graft were implanted in either carotid position of six sheep. After twelve weeks, the samples, as well as the distal adjacent native vessel, were explanted and evaluated mechanically by means of uniaxial tensile tests. These tests were performed in the axial as well as in the circumferential direction. Also, patches of these grafts were implanted subcutaneously in the abdominal wall of the same animals. At 2, 4, 6, and 8 weeks, patches were explanted and evaluated mechanically. Baseline mechanical tensile tests were also performed on non-implanted grafts and on native sheep carotid arteries. RESULTS: Statistical analysis shows a significant effect of implantation time on the tensile mechanical properties of ePTFE vascular grafts. This effect is present for stretchable as well as non-stretchable grafts, in axial as well as in circumferential direction of the material. Also the adjacent native vessels have a tendency to lose mechanical stiffness and strength in the circumferential direction, an effect which is most pronounced for stretchable grafts. CONCLUSIONS: The mechanical properties of ePTFE vascular grafts and the adjacent native vessels significantly change as a function of implantation time. Compared to the native vessels, the grafts are still significantly stronger and stiffer, though longer term experiments are needed to evaluate whether and how much the decline would continue in time. PMID- 25450324 TI - Right ventricular infarction and mitral stenosis: a resuscitation challenge. AB - We report the case of a 49-year-old woman who experienced an inferior myocardial infarction with right ventricular extension, poorly tolerated, partly due to a severe rheumatic mitral stenosis discovered during the hospitalization. Following an initial emergent mechanical circulatory support with femoro-femoral extracorporeal life support (ECLS), the patient had the mitral valve replaced, and the arterio-venous ECLS was removed for a right ventricular assistance device. After seven weeks, she was discharged and fully recovered. PMID- 25450325 TI - Clinical evaluation of an expert system for arteriovenous fistula assessment. AB - The monitoring of ionic dialysance in hemodialysis allows early detection of arterio-venous fistula stenosis. One limitation to the practical use of ionic dialysance is that the analysis is very time consuming on a majority of normal cases.The purpose of the study is to evaluate the utility of an expert system reproducing a human analysis and allowing continuous monitoring of the ionic dialysance by helping the physician to focus his or her expertise on the abnormal cases.The method is based on a Bayesian model that analyzes the blood flow rate, the ionic dialysance, and the venous and arterial pressures measured on the extra corporeal circuit.The clinical evaluation was performed on 90 dialysis patients at the hospital dialysis center of Saint Brieux in France with a history of at least four consecutive months of validated recording. The retrospective automated analysis was evaluated in comparison to vascular access problems identified from invasive investigation or treatment. The sensitivity of the automated analysis is 92% with a specificity of 75%.As a conclusion we suggest that this expert system could be used in a continuous vascular access monitoring procedure consisting in a weekly review of the patient population at the dialysis center. The patients with the highest risk score need a further investigation of their historical data and their medical history in order to decide whether or not to perform an invasive intervention. PMID- 25450326 TI - [Atherogenic dyslipidemia and residual risk. State of the art in 2014]. AB - Pandemics of metabolic sindrome, obesity, and type 2 diabetes is a major challenge for the next years and supported the grat burden of cardiovascular diseases. The R3i (Residual Risk Reduction initiative) has previously highlighted atherogenic dyslipidaemia as an important and modifiable contributor to the lipid related residual cardiovascular risk. Atherogenic dyslipidaemia is defined as an imbalance between proatherogenic triglycerides-rich apoB-containing lipoproteins and antiatherogenic AI containing lipoproteins. To improve clinical management of atherogenic dyslipidaemia a despite of lifestyle intervention includes pharmacological approach, and fibrates is the main option for combination with a statin to further reduce non-HDL cholesterol. PMID- 25450329 TI - Moving free radical and redox biology ahead in the next decade(s). PMID- 25450327 TI - Collaboration between mitochondria and the nucleus is key to long life in Caenorhabditis elegans. AB - Recent findings in diverse organisms strongly support a conserved role for mitochondrial electron transport chain dysfunction in longevity modulation, but the underlying mechanisms are not well understood. One way cells cope with mitochondrial dysfunction is through a retrograde transcriptional reprogramming response. In this review, we primarily focus on the work that has been performed in Caenorhabditis elegans to elucidate these mechanisms. We describe several transcription factors that participate in mitochondria-to-nucleus signaling and discuss how they mediate the relationship between mitochondrial dysfunction and life span. PMID- 25450328 TI - Redox regulation of mitophagy in the lung during murine Staphylococcus aureus sepsis. AB - Oxidative mitochondrial damage is closely linked to inflammation and cell death, but low levels of reactive oxygen and nitrogen species serve as signals that involve mitochondrial repair and resolution of inflammation. More specifically, cytoprotection relies on the elimination of damaged mitochondria by selective autophagy (mitophagy) during mitochondrial quality control. This aim of this study was to identify and localize mitophagy in the mouse lung as a potentially upregulatable redox response to Staphylococcus aureus sepsis. Fibrin clots loaded with S. aureus (1*10(7) CFU) were implanted abdominally into anesthetized C57BL/6 and B6.129X1-Nfe2l2tm1Ywk/J (Nrf2(-/-)) mice. At the time of implantation, mice were given vancomycin (6mg/kg) and fluid resuscitation. Mouse lungs were harvested at 0, 6, 24, and 48h for bronchoalveolar lavage (BAL), Western blot analysis, and qRT-PCR. To localize mitochondria with autophagy protein LC3, we used lung immunofluorescence staining in LC3-GFP transgenic mice. In C57BL/6 mice, sepsis-induced pulmonary inflammation was detected by significant increases in mRNA for the inflammatory markers IL-1beta and TNF-alpha at 6 and 24h, respectively. BAL cell count and protein also increased. Sepsis suppressed lung Beclin-1 protein, but not mRNA, suggesting activation of canonical autophagy. Notably sepsis also increased the LC3-II autophagosome marker, as well as the lung's noncanonical autophagy pathway as evidenced by loss of p62, a redox regulated scaffolding protein of the autophagosome. In LC3-GFP mouse lungs, immunofluorescence staining showed colocalization of LC3-II to mitochondria, mainly in type 2 epithelium and alveolar macrophages. In contrast, marked accumulation of p62, as well as attenuation of LC3-II in Nrf2-knockout mice supported an overall decrease in autophagic turnover. The downregulation of canonical autophagy during sepsis may contribute to lung inflammation, whereas the switch to noncanonical autophagy selectively removes damaged mitochondria and accompanies tissue repair and cell survival. Furthermore, mitophagy in the alveolar region appears to depend on activation of Nrf2. Thus, efforts to promote mitophagy may be a useful therapeutic adjunct for acute lung injury in sepsis. PMID- 25450331 TI - Free radical generation from an aniline derivative in HepG2 cells: a possible captodative effect. AB - Xenobiotic metabolism can induce the generation of protein radicals, which are believed to play an important role in the toxicity of chemicals and drugs. It is therefore important to identify chemical structures capable of inducing macromolecular free radical formation in living cells. In this study, we evaluated the ability of four structurally related environmental chemicals, aniline, nitrosobenzene, N,N-dimethylaniline, and N,N-dimethyl-4-nitrosoaniline (DMNA), to induce free radicals and cellular damage in the hepatoma cell line HepG2. Cytotoxicity was assessed using lactate dehydrogenase assays, and morphological changes were observed using phase contrast microscopy. Protein free radicals were detected by immuno-spin trapping using in-cell western experiments and confocal microscopy to determine the subcellular locale of free radical generation. DMNA induced free radical generation, lactate dehydrogenase release, and morphological changes in HepG2 cells, whereas aniline, nitrosobenzene, N,N dimethylaniline did not. Confocal microscopy showed that DMNA induced free radical generation mainly in the cytosol. Preincubation of HepG2 cells with N acetylcysteine and 2,2'-dipyridyl significantly prevented free radical generation on subsequent incubation with DMNA, whereas preincubation with apocynin and dimethyl sulfoxide had no effect. These results suggest that DMNA is metabolized to reactive free radicals capable of generating protein radicals which may play a critical role in DMNA toxicity. We propose that the captodative effect, the combined action of the electron-releasing dimethylamine substituent, and the electron-withdrawing nitroso substituent, leads to a thermodynamically stabilized radical, facilitating enhanced protein radical formation by DMNA. PMID- 25450330 TI - The metabolic state of cancer stem cells-a valid target for cancer therapy? AB - In the 1920s Otto Warburg first described high glucose uptake, aerobic glycolysis, and high lactate production in tumors. Since then high glucose uptake has been utilized in the development of PET imaging for cancer. However, despite a deepened understanding of the molecular underpinnings of glucose metabolism in cancer, this fundamental difference between normal and malignant tissue has yet to be employed in targeted cancer therapy in the clinic. In this review, we highlight attempts in the recent literature to target cancer cell metabolism and elaborate on the challenges and controversies of these strategies in general and in the context of tumor cell heterogeneity in cancer. PMID- 25450335 TI - Development and validation of consensus clustering-based framework for brain segmentation using resting fMRI. AB - BACKGROUND: Clustering methods are increasingly employed to segment brain regions into functional subdivisions using resting-state functional magnetic resonance imaging (rs-fMRI). However, these methods are highly sensitive to the (i) precise algorithms employed, (ii) their initializations, and (iii) metrics used for uncovering the optimal number of clusters from the data. NEW METHOD: To address these issues, we develop a novel consensus clustering evidence accumulation (CC EAC) framework, which effectively combines multiple clustering methods for segmenting brain regions using rs-fMRI data. Using extensive computer simulations, we examine the performance of widely used clustering algorithms including K-means, hierarchical, and spectral clustering as well as their combinations. We also examine the accuracy and validity of five objective criteria for determining the optimal number of clusters: mutual information, variation of information, modified silhouette, Rand index, and probabilistic Rand index. RESULTS: A CC-EAC framework with a combination of base K-means clustering (KC) and hierarchical clustering (HC) with probabilistic Rand index as the criterion for choosing the optimal number of clusters, accurately uncovered the correct number of clusters from simulated datasets. In experimental rs-fMRI data, these methods reliably detected functional subdivisions of the supplementary motor area, insula, intraparietal sulcus, angular gyrus, and striatum. COMPARISON WITH EXISTING METHODS: Unlike conventional approaches, CC-EAC can accurately determine the optimal number of stable clusters in rs-fMRI data, and is robust to initialization and choice of free parameters. CONCLUSIONS: A novel CC-EAC framework is proposed for segmenting brain regions, by effectively combining multiple clustering methods and identifying optimal stable functional clusters in rs-fMRI data. PMID- 25450337 TI - Modulation of TIM-3 expression on NK and T cell subsets in HIV immunological non responders. AB - Highly active antiretroviral therapy (HAART) for the treatment of HIV infection sustains viral suppression and increases CD4(+) T cells in HIV patients. However, in 10-25% of subjects, known as immunological non-responders (INRs), HAART does not increase CD4 count. We investigated a potential role for galectin-9 and TIM-3 in INRs as galectin-9 and TIM-3 have been described to modulate NK and T cell function. PBMCs were isolated from healthy controls, HIV immunological responders (IRs, >350CD4(+) cells/mm(3)) and HIV INRs (<350CD4(+) cells/mm(3)) and TIM-3 and galectin-9 expressions on NK cell subsets and CD4(+) T cells were assessed. HIV INRs and HIV IRs showed increased galectin-9 expression on CD16(-)CD56(bright) and CD16(+)CD56(+) NK cells and CD4(+) T cells. Only HIV INRs showed a reduced frequency of TIM-3-expressing CD16(+)CD56(+), CD16(+)CD56(-) and CD4(+) cells, which correlated with low peripheral CD4 counts. These data suggest that TIM-3 expression may be characteristic for HIV INRs. PMID- 25450336 TI - Preferential M2 macrophages contribute to fibrosis in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease. AB - IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) is characterized by bilateral swelling of glandular tissues with extensive fibrosis, and is immunologically considered a Th2-predominant disease. Recent studies reported that alternatively activated (M2) macrophages enhanced Th2 immune responses and fibrosis by production of pro-fibrotic factors (IL-10, IL-13 and CCL18). Therefore, we examined the association between M2 macrophages and fibrosis in submandibular glands from 7 patients with IgG4-DS, 10 patients with chronic sialoadenitis, 10 patients with Sjogren's syndrome, and 10 healthy subjects. The number of M2 macrophages in SMGs from patients with IgG4-DS was also significantly higher than in the other groups. Double immunofluorescence staining showed that IL-10 and CCL18 expression co-localized with M2 macrophage-marker (CD163). Furthermore, the SMG fibrosis score was positively correlated with the frequency of M2 macrophages in only IgG4-DS. These results indicate that IL-10 and CCL18 secreted by preferential M2 macrophages possibly play a key role in the development of severe fibrosis in IgG4-DS. PMID- 25450338 TI - Systems biology of ion channels and transporters in tumor angiogenesis: An omics view. AB - Solid tumors require the formation of new blood vessels to support their growth, invasiveness and metastatic potential. Tumor neovascularization is achieved by vasculogenesis from endothelial precursors and by sprouting angiogenesis from preexisting vessels. The complex sequence of events driving these processes, including endothelial activation, proliferation, migration and differentiation, is associated with fluxes of ions, water and other small molecules mediated by a great pool of ion channels and transporters (ICT). This 'transportome' is regulated by environmental factors as well as intracellular signaling molecules. In turn, ICT play a prominent role in the response to angiogenesis-related stimuli through canonical and 'unconventional' activities: indeed, there is an increasing recognition of the multifunctionality of several ion channels that could also be annotated as receptors, enzymes, scaffolding proteins, mechanical and chemical sensors. The investigation of ICT structure and function has been far from the experimental oncology for long time and these two domains converged only very recently. Furthermore, the systems biology viewpoint has not received much attention in the biology of cancer transportome. Modulating angiogenesis by interference with membrane transport has a great potential in cancer treatment and the application of an 'omics' logic will hopefully contribute to the overall advancement in the field. This review is an attempt to apply the systems biology approach to the analysis of ICT involved in tumor angiogenesis, with a particular focus on endothelial transportome diversity. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25450339 TI - Ion channels in the regulation of apoptosis. AB - Apoptosis, a type of genetically controlled cell death, is a fundamental cellular mechanism utilized by multicellular organisms for disposal of cells that are no longer needed or potentially detrimental. Given the crucial role of apoptosis in physiology, deregulation of apoptotic machinery is associated with various diseases as well as abnormalities in development. Acquired resistance to apoptosis represents the common feature of most and perhaps all types of cancer. Therefore, repairing and reactivating apoptosis represents a promising strategy to fight cancer. Accumulated evidence identifies ion channels as essential regulators of apoptosis. However, the contribution of specific ion channels to apoptosis varies greatly depending on cell type, ion channel type and intracellular localization, pathology as well as intracellular signaling pathways involved. Here we discuss the involvement of major types of ion channels in apoptosis regulation. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25450340 TI - Understanding the roles of the P2X7 receptor in solid tumour progression and therapeutic perspectives. AB - P2X7 is an intriguing ionotropic receptor for which the activation by extracellular ATP induces rapid inward cationic currents and intracellular signalling pathways associated with numerous physiological processes such as the induction of the inflammatory cascade, the survival and proliferation of cells. In contrast, long-term stimulation of P2X7 is generally associated with membrane permeabilisation and cell death. Recently, P2X7 has attracted great attention in the cancer field, and particularly in the neoplastic transformation and the progression of solid tumours. A growing number of studies were published; however they often appeared contradictory in their results and conclusions. As such, the involvement of P2X7 in the oncogenic process remains unclear so far. The present review aims to discuss the current knowledge and hypotheses on the involvement of the P2X7 receptor in the development and progression of solid tumours, and highlight the different aspects that require further clarification in order to decipher whether P2X7 could be considered as a cancer biomarker or as a target for pharmacological intervention. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25450341 TI - Construction and validation of an atomic model for bacterial TSPO from electron microscopy density, evolutionary constraints, and biochemical and biophysical data. AB - The 18 kDa protein TSPO is a highly conserved transmembrane protein found in bacteria, yeast, animals and plants. TSPO is involved in a wide range of physiological functions, among which the transport of several molecules. The atomic structure of monomeric ligand-bound mouse TSPO in detergent has been published recently. A previously published low-resolution structure of Rhodobacter sphaeroides TSPO, obtained from tubular crystals with lipids and observed in cryo-electron microscopy, revealed an oligomeric structure without any ligand. We analyze this electron microscopy density in view of available biochemical and biophysical data, building a matching atomic model for the monomer and then the entire crystal. We compare its intra- and inter-molecular contacts with those predicted by amino acid covariation in TSPO proteins from evolutionary sequence analysis. The arrangement of the five transmembrane helices in a monomer of our model is different from that observed for the mouse TSPO. We analyze possible ligand binding sites for protoporphyrin, for the high-affinity ligand PK 11195, and for cholesterol in TSPO monomers and/or oligomers, and we discuss possible functional implications. PMID- 25450344 TI - Phospholipid lateral diffusion in phosphatidylcholine-sphingomyelin-cholesterol monolayers; effects of oxidatively truncated phosphatidylcholines. AB - Oxidative stress is involved in a number of pathological conditions and the generated oxidatively modified lipids influence membrane properties and functions, including lipid-protein interactions and cellular signaling. Brewster angle microscopy demonstrated oxidatively truncated phosphatidylcholines to promote phase separation in monolayers of 1-palmitoyl-2-oleoyl-sn-glycerol-3 phosphocholine (POPC), sphingomyelin (SM) and cholesterol (Chol). More specifically, 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PazePC), was found to increase the miscibility transition pressure of the SM/Chol-phase. Lateral diffusion of lipids is influenced by a variety of membrane properties, thus making it a sensitive parameter to observe the coexistence of different lipid phases, for instance. The dependence on lipid lateral packing of the lateral diffusion of fluorophore-containing phospholipid analogs was investigated in Langmuir monolayers composed of POPC, SM, and Chol and additionally containing oxidatively truncated phosphatidylcholines, using fluorescence correlation spectroscopy (FCS). To our knowledge, these are the first FCS results on miscibility transition in ternary lipid monolayers, confirming previous results obtained using Brewster angle microscopy on such lipid monolayers. Wide-field fluorescence microscopy was additionally employed to verify the transition, i.e. the loss and reformation of SM/Chol domains. PMID- 25450342 TI - Hydrogel-assisted functional reconstitution of human P-glycoprotein (ABCB1) in giant liposomes. AB - This paper describes the formation of giant proteoliposomes containing P glycoprotein (P-gp) from a solution of small proteoliposomes that had been deposited and partially dried on a film of agarose. This preparation method generated a significant fraction of giant proteoliposomes that were free of internalized vesicles, making it possible to determine the accessible liposome volume. Measuring the intensity of the fluorescent substrate rhodamine 123 (Rho123) inside and outside these giant proteoliposomes determined the concentration of transported substrates of P-gp. Fitting a kinetic model to the fluorescence data revealed the rate of passive diffusion as well as active transport by reconstituted P-gp in the membrane. This approach determined estimates for the membrane permeability coefficient (Ps) of passive diffusion and rate constants of active transport (kT) by P-gp as a result of different experimental conditions. The Ps value for Rho123 was larger in membranes containing P-gp under all assay conditions than in membranes without P-gp indicating increased leakiness in the presence of reconstituted transmembrane proteins. For P-gp liposomes, the kT value was significantly higher in the presence of ATP than in its absence or in the presence of ATP and the competitive inhibitor verapamil. This difference in kT values verified that P-gp was functionally active after reconstitution and quantified the rate of active transport. Lastly, patch clamp experiments on giant proteoliposomes showed ion channel activity consistent with a chloride ion channel protein that co-purified with P-gp. Together, these results demonstrate several advantages of using giant rather than small proteoliposomes to characterize transport properties of transport proteins and ion channels. PMID- 25450343 TI - Lipid rafts, KCa/ClCa/Ca2+ channel complexes and EGFR signaling: Novel targets to reduce tumor development by lipids? AB - Membrane lipid rafts are distinct plasma membrane nanodomains that are enriched with cholesterol, sphingolipids and gangliosides, with occasional presence of saturated fatty acids and phospholipids containing saturated acyl chains. It is well known that they organize receptors (such as Epithelial Growth Factor Receptor), ion channels and their downstream acting molecules to regulate intracellular signaling pathways. Among them are Ca2+ signaling pathways, which are modified in tumor cells and inhibited upon membrane raft disruption. In addition to protein components, lipids from rafts also contribute to the organization and function of Ca2+ signaling microdomains. This article aims to focus on the lipid raft KCa/ClCa/Ca2+ channel complexes that regulate Ca2+ and EGFR signaling in cancer cells, and discusses the potential modification of these complexes by lipids as a novel therapeutic approach in tumor development. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25450345 TI - Native lysozyme and dry-heated lysozyme interactions with membrane lipid monolayers: lateral reorganization of LPS monolayer, model of the Escherichia coli outer membrane. AB - Lysozyme is mainly described active against Gram-positive bacteria, but is also efficient against some Gram-negative species. Especially, it was recently demonstrated that lysozyme disrupts Escherichia coli membranes. Moreover, dry heating changes the physicochemical properties of the protein and increases the membrane activity of lysozyme. In order to elucidate the mode of insertion of lysozyme into the bacterial membrane, the interaction between lysozyme and a LPS monolayer mimicking the E. coli outer membrane has been investigated by tensiometry, ellipsometry, Brewster angle microscopy and atomic force microscopy. It was thus established that lysozyme has a high affinity for the LPS monolayer, and is able to insert into the latter as long as polysaccharide moieties are present, causing reorganization of the LPS monolayer. Dry-heating increases the lysozyme affinity for the LPS monolayer and its insertion capacity; the resulting reorganization of the LPS monolayer is different and more drastic than with the native protein. PMID- 25450346 TI - Surface behavior of peptides from E1 GBV-C protein: Interaction with anionic model membranes and importance in HIV-1 FP inhibition. AB - The interaction between a peptide sequence from GB virus C E1 protein (E1P8) and its structural analogs (E1P8-12), (E1P8-13), and (E1P8-21) with anionic lipid membranes (POPG vesicles and POPG, DPPG or DPPC/DPPG (2:1) monolayers) and their association with HIV-1 fusion peptide (HIV-1 FP) inhibition at the membrane level were studied using biophysical methods. All peptides showed surface activity but leakage experiments in vesicles as well as insertion kinetics in monolayers and lipid/peptide miscibility indicated a low level of interaction: neither E1P8 nor its analogs induced the release of vesicular content and the exclusion pressure values (pie) were clearly lower than the biological membrane pressure (24-30 mN m(-1)) and the HIV-1 FP (35 mN m(-1)). Miscibility was elucidated in terms of the additivity rule and excess free energy of mixing (GE). E1P8, E1P8-12 and E1P8-21 (but not E1P8-13) induced expansion of the POPG monolayer. The mixing process is not thermodynamically favored as the positive GE values indicate. To determine how E1 peptides interfere in the action of HIV-1 FP at the membrane level, mixed monolayers of HIV-1 FP/E1 peptides (2:1) and POPG were obtained. E1P8 and its derivative E1P8-21 showed the greatest HIV-1 FP inhibition. The LC-LE phase lipid behavior was morphologically examined via fluorescence microscopy (FM) and atomic force microscopy (AFM). Images revealed that the E1 peptides modify HIV-1 FP lipid interaction. This fact may be attributed to a peptide/peptide interaction as indicated by AFM results. Finally, hemolysis assay demonstrated that E1 peptides inhibit HIV-1 FP activity. PMID- 25450347 TI - Docosahexaenoic and arachidonic acid peroxidation: It's a within molecule cascade. AB - Peroxidation is a well-known natural phenomenon associated with both health and disease. We compared the peroxidation kinetics of phosphatidylcholine (PC) molecules with different fatty acid compositions (i.e. 18:0, 18:1n-9, 18:2n-6, 20:4n-6 and 22:6n-3 at the sn-2 and 16:0 at sn-1 position) either as molecules free in solution or formed into liposomes. Fatty acid levels, oxygen consumption plus lipid hydroperoxide and malondialdehyde production were measured from the same incubations, at the same time during maximal elicitable peroxidation. PCs with highly peroxidizable fatty acids (i.e. 20:4n-6 and 22:6n-3) in the same incubation were found to be either fully peroxidized or intact. Rates of peroxidation of PCs with multiple bisallylic groups (i.e. 20:4n-6 and 22:6n-3) peroxidized at 2-3 times the rate per bisallylic bond than the same phospholipid with 18:2n-6. The results suggest that propagation of peroxidation (H-atom transfer) is firstly an intramolecular process that is several-fold faster than intermolecular peroxidation. PCs in solution peroxidized twice as fast as those in liposomes suggesting that only half of the phospholipids in liposomes were available to peroxidize i.e. the outer leaflet. Experiments on liposomes suggest that even after heavy peroxidation of the outer leaflet the inner leaflet is unaffected, indicating how cells may protect themselves from external peroxidation and maintain control over internal peroxidation. Intramolecular peroxidation may produce highly concentrated, localized sites of peroxidation product that together with internal control of peroxidation of the inner leaflet of membranes provide new insights into how cells control peroxidation at the membrane level. PMID- 25450348 TI - Experimental determination and computational interpretation of biophysical properties of lipid bilayers enriched by cholesteryl hemisuccinate. AB - Cholesteryl hemisuccinate (CHS) is one of the cholesterol-mimicking detergents not observed in nature. It is, however, widely used in protein crystallography, in biochemical studies of proteins, and in pharmacology. Here, we performed an extensive experimental and theoretical study on the behavior of CHS in lipid membranes rich in unsaturated phospholipids. We found that the deprotonated form of CHS (that is the predominant form under physiological conditions) does not mimic cholesterol very well. The protonated form of CHS does better in this regard, but also its ability to mimic the physical effects of cholesterol on lipid membranes is limited. Overall, although ordering and condensing effects characteristic to cholesterol are present in systems containing any form of CHS, their strength is appreciably weaker compared to cholesterol. Based on the considerable amount of experimental and atomistic simulation data, we conclude that these differences originate from the fact that the ester group of CHS does not anchor it in an optimal position at the water-membrane interface. The implications of these findings for considerations of protein-cholesterol interactions are briefly discussed. PMID- 25450349 TI - Membrane activity of the pentaene macrolide didehydroroflamycoin in model lipid bilayers. AB - Didehydroroflamycoin (DDHR), a recently isolated member of the polyene macrolide family, was shown to have antibacterial and antifungal activity. However, its mechanism of action has not been investigated. Antibiotics from this family are amphiphilic; thus, they have membrane activity, their biological action is localized in the membrane, and the membrane composition and physical properties facilitate the recognition of a particular compound by the target organism. In this work, we use model lipid membranes comprised of giant unilamellar vesicles (GUVs) for a systematic study of the action of DDHR. In parallel, experiments are conducted using filipin III and amphotericin B, other members of the family, and the behavior observed for DDHR is described in the context of that of these two heavily studied compounds. The study shows that DDHR disrupts membranes via two different mechanisms and that the involvement of these mechanisms depends on the presence of cholesterol. The leakage assays performed in GUVs and the conductance measurements using black lipid membranes (BLM) reveal that the pores that develop in the absence of cholesterol are transient and their size is dependent on the DDHR concentration. In contrast, cholesterol promotes the formation of more defined structures that are temporally stable. PMID- 25450350 TI - Phospholipases a2 from Viperidae snakes: Differences in membranotropic activity between enzymatically active toxin and its inactive isoforms. AB - We describe the interaction of various phospholipases A2 (PLA2) from snake venoms of the family Viperidae (Macrovipera lebetina obtusa, Vipera ursinii renardi, Bothrops asper) with giant unilamellar vesicles (GUVs) composed of natural brain phospholipids mixture, visualized through fluorescence microscopy. The membrane fluorescent probes 8-anilino-1-naphthalenesulfonicacid (ANS), LAUDRAN and PRODAN were used to assess the state of the membrane and specifically mark the lipid packing and membrane fluidity. Our results have shown that the three PLA2s which contain either of aspartic acid, serine, or lysine residues at position 49 in the catalytic center, have different effects on the vesicles. The PLA2 with aspartic acid at this position causes the oval deformation of the vesicles, while serine and lysine-containing enzymes lead to an appreciable increase of fluorescence intensity in the vesicles membrane, wherein the shape and dimensions of GUVs have not changed, but in this case GUV aggregation occurs. LAURDAN and PRODAN detect the extent of water penetration into the bilayer surface. We calculated generalized polarization function (GP), showing that for all cases (D49 PLA2, S49 PLA2 and K49 PLA2) both LAUDRAN and PRODAN GP values decrease. A higher LAURDAN GP is indicative of low water penetration in the lipid bilayer in case of K49 PLA2 compared with D49 PLA2, whereas the PRODAN mainly gives information when lipid is in liquid crystalline phase. PMID- 25450351 TI - Studies of the interactions of ursane-type bioactive terpenes with the model of Escherichia coli inner membrane-Langmuir monolayer approach. AB - Pentacyclic triterpenes (PT), ursolic acid (Urs), and alpha-amyrin (AMalf) are natural products exhibiting broad spectrum of antibacterial activity. These compounds are membrane-active and can disorder bacterial membranes when incorporated; however, the exact mechanism of their membrane activity is unknown. In our studies, we applied Langmuir monolayer technique supported by Brewster angle microscopy to model the interactions of the selected PT with the lipid matrix of E. coli inner membrane. As the model membrane, we applied mixtures (75/25 mole/.mole %) of the representative Escherichia coli phosphatidylethanolamine (POPE), with the cardiolipin (ECCL) or phosphatidylglycerol (ECPG) extracted from the E. coli inner membrane. On the basis of the recorded isotherms, we performed thermodynamic analysis and calculated free energy of mixing DeltaGexc. It turned out that the phospholipids forming the inner membrane of E. coli are ideally miscible, whereas in binary systems composed of PT and POPE, negative deviations from ideality indicating attractive interactions between the investigated PT and POPE molecules were observed. On the other hand, in ternary systems composed of PT, POPE and one of the E. coli anionic phospholipids large positive changes in DeltaGexc were observed. Thus, both PT exhibit disorganizing effect on the model E. coli membrane. It was also proved that at low terpene proportion, AMalf can be more active than Urs. However, at higher proportion Urs incorporation can lead to the disintegration of cardiolipin-rich domains present in bacterial membrane. PMID- 25450352 TI - Involvement of palmitate/Ca2+(Sr2+)-induced pore in the cycling of ions across the mitochondrial membrane. AB - The palmitate/Ca2+-induced (Pal/Ca2+) pore, which is formed due to the unique feature of long-chain saturated fatty acids to bind Ca2+ with high affinity, has been shown to play an important role in the physiology of mitochondria. The present study demonstrates that the efflux of Ca2+ from rat liver mitochondria induced by ruthenium red, an inhibitor of the energy-dependent Ca2+ influx, seems to be partly due to the opening of Pal/Ca2+ pores. Exogenous Pal stimulates the efflux. Measurements of pH showed that the Ca2+-induced alkalization of the mitochondrial matrix increased in the presence of Pal. The influx of Ca2+ (Sr2+) also induced an outflow of K+ followed by the reuptake of the ion by mitochondria. The outflow was not affected by a K+/H+ exchange blocker, and the reuptake was prevented by an ATP-dependent K+ channel inhibitor. It was also shown that the addition of Sr2+ to mitochondria under hypotonic conditions was accompanied by reversible cyclic changes in the membrane potential, the concentrations of Sr2+ and K+ and the respiratory rate. The cyclic changes were effectively suppressed by the inhibitors of Ca2+-dependent phospholipase A2, and a new Sr2+ cycle could only be initiated after the previous cycle was finished, indicating a refractory period in the mitochondrial sensitivity to Sr2+. All of the Ca2+- and Sr2+-induced effects were observed in the presence of cyclosporin A. This paper discusses a possible role of Pal/Ca2+ pores in the maintenance of cell ion homeostasis. PMID- 25450353 TI - Membrane sorting via the extracellular matrix. AB - We consider the coupling between a membrane and the extracellular matrix. Computer simulations demonstrate that the latter coupling is able to sort lipids. It is assumed that membranes are elastic manifolds, and that this manifold is disrupted by the extracellular matrix. For a solid-supported membrane with an actin network on top, regions of positive curvature are induced below the actin fibers. A similar mechanism is conceivable by assuming that the proteins which connect the cytoskeleton to the membrane induce local membrane curvature. The regions of non-zero curvature exist irrespective of any phase transition the lipids themselves may undergo. For lipids that prefer certain curvature, the extracellular matrix thus provides a spatial template for the resulting lateral domain structure of the membrane. PMID- 25450354 TI - Cofilin-1 is involved in regulation of actin reorganization during influenza A virus assembly and budding. AB - Influenza A virus (IAV) assembly and budding on host cell surface plasma membrane requires actin cytoskeleton reorganization. The underlying molecular mechanism involving actin reorganization remains unclarified. In this study, we found that the natural antiviral compound petagalloyl glucose (PGG) inhibits F-actin reorganization in the host cell membrane during the late stage of IAV infection, which are associated with the suppression of total cofilin-1 level and its phosphorylation. Knock-down of cofilin-1 reduces viral yields. These findings provide the first evidence that cofilin-1 plays an important role in regulating actin reorganization during IAV assembly and budding. PMID- 25450355 TI - High-resolution crystal structure reveals a HEPN domain at the C-terminal region of S. cerevisiae RNA endonuclease Swt1. AB - Swt1 is an RNA endonuclease that plays an important role in quality control of nuclear messenger ribonucleoprotein particles (mRNPs) in eukaryotes; however, its structural details remain to be elucidated. Here, we report the crystal structure of the C-terminal (CT) domain of Swt1 from Saccharomyces cerevisiae, which shares common characteristics of higher eukaryotes and prokaryotes nucleotide binding (HEPN) domain superfamily. To study in detail the full-length protein structure, we analyzed the low-resolution architecture of Swt1 in solution using small angle X-ray scattering (SAXS) method. Both the CT domain and middle domain exhibited a good fit upon superimposing onto the molecular envelope of Swt1. Our study provides the necessary structural information for detailed analysis of the functional role of Swt1, and its importance in the process of nuclear mRNP surveillance. PMID- 25450356 TI - MicroRNA-383 inhibits anchorage-independent growth and induces cell cycle arrest of glioma cells by targeting CCND1. AB - In recent years, microRNAs (miRNAs) have been proved to be closely related to the tumorigenesis and progression. An increasing number of researches have shown that microRNAs function as oncogenes or tumor suppressor genes in human malignant tumors. This study aims to explore the effects of microRNA-383 (miR-383) on malignant biological function of human gliomas. We detected the expression of miR 383 in glioma tissues and normal brain tissues by quantitative real-time PCR. Anchorage-independent growth assays, and flow cytometry were used to evaluate the functions of miR-383 that involves in cell growth and cell cycle. Western blotting assay was used to examine protein expression levels of Cyclin D1 (CCND1), a cell cycle-associated oncogene which has a predicted binding site of miR-383 within its 3'-untranslated region (3'-UTR), and luciferase activity assay was used to evaluate the 3'-UTR activity of CCND1. In this study, we found that miR-383 expression level was lower in gliomas than normal brain tissues. Overexpression of miR-383 in U251 and U87 cells showed a significant inhibitory effect on cell growth, which accompanied with cell cycle G0/G1 arrest as well as downregulation of CCND1 expression. Moreover, CCND1 was verified to be one of the direct targets of miR-383. In summary, this study suggested that miR-383 plays the role of tumor suppressor by targeting CCND1 in glioma cells, and may be useful for developing a new therapeutic strategy for gliomas. PMID- 25450357 TI - Screening of a synthetic peptide combinatorial library to identify inhibitors of the appressorium formation in Magnaporthe oryzae. AB - The rice blast disease caused by Magnaporthe oryzae is one of the most devastating diseases of cultivated rice. One of the most important stages in the infective cycle of M. oryzae is the formation of the dome-shaped structure called appressorium. The purpose of the present study was to identify novel peptides to control the rice blast disease by blocking the appressorium formation through screening of a synthetic peptide combinatorial library. As result of the screening, a set of 29 putative bioactive peptides were identified, synthesized and assayed in comparison with the previously identified peptide PAF104. The peptides MgAPI24, MgAPI40 and MgAPI47 showed improved inhibitory activity on the M. oryzae appressorium formation. Our data show that these peptides have a differential effect on two developmental structures: appressoria and appressorium like structures. Antimicrobial assays against M. oryzae and other non-target microorganisms showed a weak or no toxicity of these peptides, demonstrating their specific activity blocking the appressorium formation. Therefore, the outcome of this research would be useful in the development of novel target oriented peptides to use in plant protection. PMID- 25450358 TI - Canola (Brassica napus L.) NAC103 transcription factor gene is a novel player inducing reactive oxygen species accumulation and cell death in plants. AB - NAC transcription factors are plant-specific and play important roles in many processes including plant development, response to biotic and abiotic stresses and hormone signaling. So far, only a few NAC genes have been identified to mediate cell death. In this study, we identified a novel NAC gene from canola (Brassica napus L.), BnaNAC103 which induces reactive oxygen species (ROS) accumulation and cell death in Nicotianabenthamiana leaves. We found that BnaNAC103 responded to multiple signalings, including cold, salicylic acid (SA) and a fungal pathogen Sclerotinia sclerotiorum. BnaNAC103 is located in the nucleus. Expression of full-length BnaNAC103, but not either the N-terminal NAC domain or C-terminal regulatory domain, was identified to induce hypersensitive response (HR)-like cell death when expressed in N. benthamiana. The cell death triggered by BnaNAC103 is preceded by accumulation of ROS, with diaminobenzidine (DAB) staining supporting this. Moreover, quantification of ion leakage and malondialdehyde (MDA) of leaf discs indicates significant cell membrane breakage and lipid peroxidation induced by BnaNAC103 expression. Taken together, our work has identified a novel NAC transcription factor gene modulating ROS level and cell death in plants. PMID- 25450359 TI - The hsp70 inhibitor VER155008 induces paraptosis requiring de novo protein synthesis in anaplastic thyroid carcinoma cells. AB - In this study, we evaluated the effect of the hsp70 inhibitor VER155008 on survival of anaplastic thyroid carcinoma (ATC) cells. In ATC cells, VER155008 increased the percentages of dead cells and vacuolated cells. VER155008 did not lead to the cleavage of caspase-3 protein regardless of pretreatment with z-VAD fmk. VER155008 increased LC3-II protein levels but the protein levels were not changed by autophagy inhibitors. VER155008 caused the dilatation of endoplasmic reticulum (ER), and the increased mRNA levels of Bip and CHOP, suggesting paraptosis. VER155008-induced paraptosis was attenuated by pretreatment with cycloheximide. In conclusion, VER155008 induces paraptosis characterized by cytoplasmic vacuolation, independence of caspase, dilatation of ER and induction of ER stress markers in ATC cells. Moreover, VER155008-induced paraptosis requires de novo protein synthesis in ATC cells. PMID- 25450360 TI - Jasmonic acid enhancement of anthocyanin accumulation is dependent on phytochrome A signaling pathway under far-red light in Arabidopsis. AB - Anthocyanins are critical for plants. It is shown that the expression of genes encoding the key enzymes such as dihydroflavonol 4-reductase (DFR), UDP-Glc: flavonoid 3-O-glucosyltransferase (UF3GT), and leucoanthocyanidin dioxygenase (LDOX) in anthocyanin biosynthesis pathway is regulated by MYB75, a R2R3 MYB transcription factor. The production of anthocyanin is known to be promoted by jasmonic acid (JA) in light but not in darkness. The photoreceptors cryptochrome 1 (CRY1), phytochrome B (phyB), and phytochrome A (phyA) are also shown to mediate light promotion of anthocyanin accumulation, respectively, whereas their downstream factor COP1, a master negative regulator of photomorphogensis, represses anthocyanin accumulation. However, whether JA coordinates with photoreceptors in the regulation of anthocyanin accumulation is unknown. Here, we show that under far-red light, JA promotes anthocyanin accumulation in a phyA signaling pathway-dependent manner. The phyA mutant is hyposensitive to jasmonic acid analog methyl jasmonic acid (MeJA) under far-red light. The dominant mutant of MYB75, pap1-D, accumulates significantly higher levels of anthocyanin than wild type under far-red light, whereas knockdown of MYBs (MYB75, MYB90, MYB113, and MYB114) through RNAi significantly reduces MeJA promotion of anthocyanin accumulation. The phyA pap1-D double mutant shows reduced responsiveness to MeJA, similar to phyA mutant under far-red light. In darkness, a mutant allele of cop1, cop1-4, shows enhanced responsiveness to MeJA, but pap1-D mutant is barely responsive to MeJA. Upon MeJA application, the cop1-4 pap1-D double mutant accumulates considerably higher levels of anthocyanin than cop1-4 in darkness. Protein studies indicate that MYB75 protein is stabilized by white light and far red light. Further gene expression studies suggest that MeJA promotes the expression of DFR, UF3GT, and LDOX genes in a phyA- and MYB75-dependent manner under far-red light. Our findings suggest that JA promotion of anthocyanin accumulation under far-red light is dependent on phyA signaling pathway, consisting of phyA, COP1, and MYB75. PMID- 25450361 TI - Non-coding RNAs and heme oxygenase-1 in vaccinia virus infection. AB - Small nuclear RNAs (snRNAs) are <200 nucleotide non-coding uridylate-rich RNAs. Although the functions of many snRNAs remain undetermined, a population of snRNAs is produced during the early phase of infection of cells by vaccinia virus. In the present study, we demonstrate a direct correlation between expression of the cytoprotective enzyme heme oxygenase-1 (HO-1), suppression of selective snRNA expression, and inhibition of vaccinia virus infection of macrophages. Hemin induced HO-1 expression, completely reversed virus-induced host snRNA expression, and suppressed vaccinia virus infection. This involvement of specific virus induced snRNAs and associated gene clusters suggests a novel HO-1-dependent host defense pathway in poxvirus infection. PMID- 25450362 TI - Novel frame-shift mutation in Slc5a2 encoding SGLT2 in a strain of senescence accelerated mouse SAMP10. AB - The senescence-accelerated mouse prone10 (SAMP10) strain, a model of aging, exhibits cognitive impairments and cerebral atrophy. We noticed that SAMP10/TaSlc mice, a SAMP10 substrain, have developed persistent glucosuria over the past few years. In the present study, we characterized SAMP10/TaSlc mice and further identified a spontaneous mutation in the Slc5a2 gene encoding sodium-glucose co transporter (SGLT) 2. The mean concentration of urine glucose was high in SAMP10/TaSlc mice and increased further with advancing age, whereas other strains of senescence-accelerated mice, including SAMP1/SkuSlc, SAMP6/TaSlc and SAMP8/TaSlc or normal aging control SAMR1/TaSlc mice, exhibited no detectable glucose in urine. SAMP10/TaSlc mice consumed increasing amounts of food and water compared to SAMR1/TaSlc mice, suggesting the compensation of polyuria and the loss of glucose. Oral glucose tolerance tests showed decreased glucose reabsorption in the kidney of SAMP10/TaSlc mice. In addition, blood glucose levels decreased in an age-dependent fashion. The kidney was innately larger than that of control mice with no histological alterations. We examined the expression levels of glucose transporters in the kidney. Among SGLT1, SGLT2, glucose transporter (GLUT) 1 and GLUT2, we found a significant decrease only in the level of SGLT2. DNA sequencing of SGLT2 in SAMP10/TaSlc mice revealed a single nucleotide deletion of guanine at 1236, which resulted in a frameshift mutation that produced a truncated protein. We designate this strain as SAMP10/TaSlc Slc5a2(slc) (SAMP10-DeltaSglt2). Recently, SGLT2 inhibitors have been demonstrated to be effective for the treatment of patients with type 2 diabetes (T2D). SAMP10-DeltaSglt2 mice may serve as a unique preclinical model to study the link between aging-related neurodegenerative disorders and T2D. PMID- 25450363 TI - Naringenin suppresses macrophage infiltration into adipose tissue in an early phase of high-fat diet-induced obesity. AB - Obese adipose tissue is characterized by increased macrophage infiltration, which results in chronic inflammation in adipose tissue and leads to obesity-related diseases such as type 2 diabetes mellitus and atherosclerosis. The regulation of macrophage infiltration into adipose tissue is an important strategy for preventing and treating obesity-related diseases. In this study, we report that naringenin, a citrus flavonoid, suppressed macrophage infiltration into adipose tissue induced by short-term (14 days) feeding of a high-fat diet in mice; although naringenin did not show any differences in high-fat diet-induced changes of serum biochemical parameters in this short administration period. Naringenin suppressed monocyte chemoattractant protein-1 (MCP-1) in adipose tissue, and this effect was mediated in part through inhibition of c-Jun NH2-terminal kinase pathway. Naringenin also inhibited MCP-1 expression in adipocytes, macrophages, and a co-culture of adipocytes and macrophages. Our results suggest a mechanism by which daily consumption of naringenin may exhibit preventive effects on obesity-related diseases. PMID- 25450364 TI - Effect of 5-aminolevulinic acid on erythropoiesis: a preclinical in vitro characterization for the treatment of congenital sideroblastic anemia. AB - Congenital sideroblastic anemia (CSA) is a hereditary disorder characterized by microcytic anemia and bone marrow sideroblasts. The most common form of CSA is attributed to mutations in the X-linked gene 5-aminolevulinic acid synthase 2 (ALAS2). ALAS2 is a mitochondrial enzyme, which utilizes glycine and succinyl-CoA to form 5-aminolevulinic acid (ALA), a crucial precursor in heme synthesis. Therefore, ALA supplementation could be an effective therapeutic strategy to restore heme synthesis in CSA caused by ALAS2 defects. In a preclinical study, we examined the effects of ALA in human erythroid cells, including K562 cells and human induced pluripotent stem cell-derived erythroid progenitor (HiDEP) cells. ALA treatment resulted in significant dose-dependent accumulation of heme in the K562 cell line. Concomitantly, the treatment substantially induced erythroid differentiation as assessed using benzidine staining. Quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis confirmed significant upregulation of heme-regulated genes, such as the globin genes [hemoglobin alpha (HBA) and hemoglobin gamma (HBG)] and the heme oxygenase 1 (HMOX1) gene, in K562 cells. Next, to investigate the mechanism by which ALA is transported into erythroid cells, quantitative RT-PCR analysis was performed on previously identified ALA transporters, including solute carrier family 15 (oligopeptide transporter), member (SLC15A) 1, SLC15A2, solute carrier family 36 (proton/amino acid symporter), member (SLC36A1), and solute carrier family 6 (neurotransmitter transporter), member 13 (SLC6A13). Our analysis revealed that SLC36A1 was abundantly expressed in erythroid cells. Thus, gamma-aminobutyric acid (GABA) was added to K562 cells to competitively inhibit SLC36A1-mediated transport. GABA treatment significantly impeded the ALA-mediated increase in the number of hemoglobinized cells as well as the induction of HBG, HBA, and HMOX1. Finally, small-interfering RNA-mediated knockdown of ALAS2 in HiDEP cells considerably decreased the expression of HBA, HBG, and HMOX1, and these expression levels were rescued with ALA treatment. In summary, ALA appears to be transported into erythroid cells mainly by SLC36A1 and is utilized to generate heme. ALA may represent a novel therapeutic option for CSA treatment, particularly for cases harboring ALAS2 mutations. PMID- 25450365 TI - MiR-132 prohibits proliferation, invasion, migration, and metastasis in breast cancer by targeting HN1. AB - Accumulating evidence indicates that miRNAs play critical roles in tumorigenesis and cancer progression. This study aims to investigate the role and the underlying mechanism of miR-132 in breast cancer. Here, we report that miR-132 is significantly down-regulated in breast cancer tissues and cancer cell lines. Additional study identifies HN1 as a novel direct target of miR-132. MiR-132 down regulates HN1 expression by binding to the 3' UTR of HN1 transcript, thereby, suppressing multiple oncogenic traits such as cancer cell proliferation, invasion, migration and metastasis in vivo and in vitro. Overexpression of HN1 restores miR-132-suppressed malignancy. Importantly, higher HN1 expression is significantly associated with worse overall survival of breast cancer patients. Taken together, our data demonstrate a critical role of miR-132 in prohibiting cell proliferation, invasion, migration and metastasis in breast cancer through direct suppression of HN1, supporting the potential utility of miR-132 as a novel therapeutic strategy against breast cancer. PMID- 25450366 TI - The protective effects of Donepezil (DP) against cartilage matrix destruction induced by TNF-alpha. AB - The extracellular matrix apparatuses containing collagen and proteoglycan (aggrecan) are important factors for maintaining the integrity of cartilage. Collagen type II, the main component of total cartilage, is mainly degraded by matrix metalloproteinase13 (MMP-13), which is an important molecule responsible for joint damage in Osteoarthritis (OA). Donepezil (DP), a potent and selective acetylcholinesterase inhibitor, is a medication approved by the US Food and Drug Administration and used in the alleviation of dementia in Alzheimer's disease (AD). In this study, we found that DP treatment prevented the degradation of collagen type II induced by TNF-alpha. Mechanistically, DP treatment leads to the inhibition of the transcriptional activity of interferon response factor-1 (IRF 1), thereby prevents the induction of MMP-13. These findings suggest the potential therapeutic effects of DP in OA. PMID- 25450367 TI - Injectable cell scaffold restores impaired cell-based therapeutic angiogenesis in diabetic mice with hindlimb ischemia. AB - The clinical success of cell-based therapeutic angiogenesis has been limited in diabetic patients with critical limb ischemia. We previously reported that an injectable cell scaffold (ICS), which is a nano-scaled hydroxyapatite (HAp) coated polymer microsphere, enhances therapeutic angiogenesis. Subsequently, we developed a modified ICS for clinical use, measuring 50 MUm in diameter using poly(l-lactide-co-epsilon-caprolactone) as a biodegradable polymer, which achieved appropriately accelerated absorption in vivo. The aim of the present study was to evaluate the effectiveness of this practical ICS in diabetic hindlimb ischemia. Bone-marrow mononuclear cells (BMNCs) were intramuscularly injected, without or with a practical ICS, into the ischemic hindlimbs of mice (BMNCs or ICS+BMNCs group, respectively). Kaplan-Meier analysis demonstrated that the beneficial effects of BMNC transplantation for limb salvage after ischemic surgery were almost entirely abrogated in streptozotocin-induced diabetic mice. In contrast, injection of ICS+BMNCs revealed significant limb salvage in diabetic mice to a similar extent as in non-diabetic mice. The number of apoptotic transplanted BMNCs was 1.8-fold higher in diabetic mice 10 days after transplantation compared to non-diabetic mice, while that in the ICS+BMNCs group was markedly lower (8.3% of that in the BMNCs group) even in diabetic mice. The proangiogenic factors VEGF and FGF2, also known as antiapoptotic factors, mostly co-localized with transplanted GFP-positive BMNCs that were closely aggregated around the ICS in ischemic tissue. In conclusion, the practical ICS significantly augmented cell-based therapeutic angiogenesis even in diabetic animals, through local accumulation of proangiogenic factors and antiapoptotic effects in transplanted cells. PMID- 25450368 TI - Temporary upregulation of anti-inflammatory cytokine IL-13 expression in the brains of CD14 deficient mice in the early stage of prion infection. AB - CD14 deficient (CD14(-/-)) mice survived longer than wild-type (WT) C57BL/6J mice when inoculated with prions intracerebrally, accompanied by increased expression of anti-inflammatory cytokine IL-10 by microglia in the early stage of infection. To assess the immune regulatory effects of CD14 in detail, we compared the gene expression of pro- and anti-inflammatory cytokines in the brains of WT and CD14( /-) mice infected with the Chandler strain. Gene expression of the anti inflammatory cytokine IL-13 in prion-infected CD14(-/-) mice was temporarily upregulated at 75dpi, whereas IL-13 gene expression was not upregulated in prion infected WT mice. Immunofluorescence staining showed that IL-13 was mainly expressed in neurons of the thalamus at 75dpi. These results suggest that CD14 can suppress IL-13 expression in neurons during the early stage of prion infection. PMID- 25450369 TI - Passive smoking reduces and vitamin C increases exercise-induced oxidative stress: does this make passive smoking an anti-oxidant and vitamin C a pro oxidant stimulus? AB - The current interpretative framework states that, for a certain experimental treatment (usually a chemical substance) to be classified as "anti-oxidant", it must possess the property of reducing (or even nullifying) exercise-induced oxidative stress. The aim of the study was to compare side by side, in the same experimental setup, redox biomarkers responses to an identical acute eccentric exercise session, before and after chronic passive smoking (considered a pro oxidant stimulus) or vitamin C supplementation (considered an anti-oxidant stimulus). Twenty men were randomly assigned into either passive smoking or vitamin C group. All participants performed two acute eccentric exercise sessions, one before and one after either exposure to passive smoking or vitamin C supplementation for 12 days. Vitamin C, oxidant biomarkers (F2-isoprostanes and protein carbonyls) and the non-enzymatic antioxidant (glutathione) were measured, before and after passive smoking, vitamin C supplementation or exercise. It was found that chronic exposure to passive smoking increased the level of F2 isoprostanes and decreased the level of glutathione at rest, resulting in minimal increase or absence of oxidative stress after exercise. Conversely, chronic supplementation with vitamin C decreased the level of F2-isoprostanes and increased the level of glutathione at rest, resulting in marked exercise-induced oxidative stress. Contrary to the current scientific consensus, our results show that, when a pro-oxidant stimulus is chronically delivered, it is more likely that oxidative stress induced by subsequent exercise is decreased and not increased. Reversely, it is more likely to find greater exercise-induced oxidative stress after previous exposure to an anti-oxidant stimulus. We believe that the proposed framework will be a useful tool to reach more pragmatic explanations of redox biology phenomena. PMID- 25450370 TI - Disruption of TGF-beta signaling in smooth muscle cell prevents elastase-induced abdominal aortic aneurysm. AB - Transforming growth factor-beta (TGF-beta) signaling has been significantly implicated in the pathogenesis of aneurysm, prominently the initiation and progression of abdominal aortic aneurysm (AAA). Vascular smooth muscle cell (SMC) is the principal resident cell in aortic wall and is essential for its structure and function. However, the role of TGF-beta pathway in SMC for the formation of AAA remains unknown. Therefore, the goal of the present study was to investigate the effect of TGF-beta pathway in SMC for AAA pathogenesis, by using a genetical smooth muscle-specific (SM-specific) TGF-beta type II receptor (Tgfbr2) disruption animal model. Mice deficient in the expression of Tgfbr2 (MyhCre.Tgfbr2(f/f) and MyhCre.Tgfbr2(WT/f)) and their corresponding wild-type background mice (MyhCre.Tgfbr2(WT/WT)) underwent AAA induction by infrarenal peri adventitial application of elastase. Fourteen days after elastase treatment, the aortas were analyzed and indicated that disruption of 1 or 2 alleles of Tgfbr2 in SMC provided markedly step-wise protection from AAA formation. And elastin degradation, medial SMC loss, macrophage infiltration, and matrix metalloproteinases (MMP) expression were all significantly reduced in Tgfbr2 deletion mice. Our study demonstrated, for the first time, that the TGF-beta signaling pathway in SMC plays a critical role in AAA and disruption can prevent the aneurysm formation. PMID- 25450371 TI - A PAUF-neutralizing antibody targets both carcinoma and endothelial cells to impede pancreatic tumor progression and metastasis. AB - Pancreatic adenocarcinoma up-regulated factor (PAUF) is expressed in pancreatic ductal adenocarcinoma (PDAC) and plays an important role in tumor progression and metastasis. Here we evaluate the anti-tumor efficacy of a human monoclonal antibody against PAUF, PMAb83, to provide a therapeutic intervention to treat the disease. PMAb83 reduced tumor growth and distant metastasis in orthotopically xenografted mice of human PDAC cells. PMAb83 treatment retarded proliferation along with weakened aggressiveness traits of the carcinoma cells. AKT/beta catenin signaling played a role in the carcinoma cell proliferation and the treated xenograft tumors exhibited reduced levels of beta-catenin and cyclin D1. Moreover PMAb83 abrogated the PAUF-induced angiogenic responses of endothelial cells, reducing the density of CD31(+) vessels in the treated tumors. In combination with gemcitabine, PMAb83 conferred enhanced survival of xenografted mice by about twofold compared to gemcitabine alone. Taken together, our findings show that PMAb83 treatment decreases the aggressiveness of carcinoma cells and suppresses tumor vascularization, which culminates in mitigated tumor growth and metastasis with improved survival in PDAC mouse models. PMID- 25450372 TI - Characterization of a T-superfamily conotoxin TxVC from Conus textile that selectively targets neuronal nAChR subtypes. AB - T-superfamily conotoxins have a typical cysteine pattern of "CC-CC", and are known to mainly target calcium or sodium ion channels. Recently, we screened the targets of a series of T-superfamily conotoxins and found that a new T superfamily conotoxin TxVC (KPCCSIHDNSCCGL-NH2) from the venom of Conus textile. It selectively targeted the neuronal nicotinic acetylcholine receptor (nAChR) subtypes alpha4beta2 and alpha3beta2, with IC50 values of 343.4 and 1047.2nM, respectively, but did not exhibit obvious pharmacological effects on voltage gated potassium, sodium or calcium channel in DRG cells, the BK channels expressed in HEK293 cells, or the Kv channels in LbetaT2 cells. The changes in the inhibitory activities of its Ala mutants, the NMR structure, and molecular simulation results based on other conotoxins targeting nAChR alpha4beta2, all demonstrated that the residues Ile(6) and Leu(14) were the main hydrophobic pharmacophores. To our best knowledge, this is the first T-superfamily conotoxin that inhibits neuronal nAChRs and possesses high binding affinity to alpha4beta2. This finding will expand the knowledge of the targets of T-superfamily conotoxins and the motif information could help the design of new nAChR inhibitors. PMID- 25450373 TI - Overexpression of SAMD9 suppresses tumorigenesis and progression during non small cell lung cancer. AB - The Sterile Alpha Motif Domain-containing 9 (SAMD9) gene has been recently emphasized during the discovery that it is expressed at a lower level in aggressive fibromatosis and some cases of breast and colon cancer, however, the underlying mechanisms are poorly understood. Here, we found that SAMD9 is down regulated in human non-small cell lung cancer (NSCLC). Furthermore, knockdown of SAMD9 expression is increased the invasion, migration and proliferation in H1299 cells in vitro and overexpression of SAMD9 suppressed proliferation and invasion in A549 cells. Finally, depletion of SAMD9 increases tumor formation in vivo. Our results may provide a strategy for blocking NSCLC tumorigenesis and progression. PMID- 25450374 TI - Deletion of sterol O-acyltransferase 2 (SOAT2) function in mice deficient in lysosomal acid lipase (LAL) dramatically reduces esterified cholesterol sequestration in the small intestine and liver. AB - Sterol O-acyltransferase 2 (SOAT2), also known as ACAT2, is the major cholesterol esterifying enzyme in the liver and small intestine (SI). Esterified cholesterol (EC) carried in certain classes of plasma lipoproteins is hydrolyzed by lysosomal acid lipase (LAL) when they are cleared from the circulation. Loss-of-function mutations in LIPA, the gene that encodes LAL, result in Wolman disease (WD) or cholesteryl ester storage disease (CESD). Hepatomegaly and a massive increase in tissue EC levels are hallmark features of both disorders. While these conditions can be corrected with enzyme replacement therapy, the question arose as to what effect the loss of SOAT2 function might have on tissue EC sequestration in LAL deficient mice. When weaned at 21 days, Lal(-)(/)(-):Soat2(+)(/)(+) mice had a whole liver cholesterol content (mg/organ) of 24.7 mg vs 1.9mg in Lal(+/+):Soat2(+/+) littermates, with almost all the excess sterol being esterified. Over the next 31 days, liver cholesterol content in the Lal(-)(/)( ):Soat2(+)(/)(+) mice increased to 145 +/- 2 mg but to only 29 +/- 2 mg in their Lal(-)(/)(-):Soat2(-)(/)(-) littermates. The level of EC accumulation in the SI of the Lal(-)(/)(-):Soat2(-)(/)(-) mice was also much less than in their Lal( )(/)(-):Soat2(+)(/)(+) littermates. In addition, there was a >70% reduction in plasma transaminase activities in the Lal(-)(/)(-):Soat2(-)(/)(-) mice. These studies illustrate how the severity of disease in a mouse model for CESD can be substantially ameliorated by elimination of SOAT2 function. PMID- 25450375 TI - Ubiquitin E3 ligase dSmurf is essential for Wts protein turnover and Hippo signaling. AB - The Hippo pathway has been implicated in controlling organ size and tumorigenesis and the underlying molecular mechanisms have attracted intensive attentions. In this work, we identified dSmurf as a new regulator of Wts, a core component of the Hippo pathway, in Drosophila. Our data revealed that Wts and dSmurf colocalize to cytoplasm and physically form an immunoprecipitated complex in S2 cells. Sufficient knock-down of dSmurf increases the protein abundance of Wts and thus increases phosphorylation level at S168 of Yki, the key downstream target of Wts in the Hippo pathway. Genetic epistasis assays showed that halving dosage of dSmurf dominantly enhances the phenotype caused by overexpression of Wts and restrains Yki activity in Drosophila eyes. Our works defines a novel role of dSmurf in animal development through modulating Wts turnover and thereby Hippo signal transduction, implying that targeting dSmurf may be a promising therapeutic strategy to manipulate the Hippo pathway in pathological conditions. PMID- 25450376 TI - Nuclear lactate dehydrogenase modulates histone modification in human hepatocytes. AB - It is becoming increasingly apparent that the nucleus harbors metabolic enzymes that affect genetic transforming events. Here, we describe a nuclear isoform of lactate dehydrogenase (nLDH) and its ability to orchestrate histone deacetylation by controlling the availability of nicotinamide adenine dinucleotide (NAD(+)), a key ingredient of the sirtuin-1 (SIRT1) deacetylase system. There was an increase in the expression of nLDH concomitant with the presence of hydrogen peroxide (H2O2) in the culture medium. Under oxidative stress, the NAD(+) generated by nLDH resulted in the enhanced deacetylation of histones compared to the control hepatocytes despite no discernable change in the levels of SIRT1. There appeared to be an intimate association between nLDH and SIRT1 as these two enzymes co immunoprecipitated. The ability of nLDH to regulate epigenetic modifications by manipulating NAD(+) reveals an intricate link between metabolism and the processing of genetic information. PMID- 25450377 TI - Secretory phospholipase A2 activity in blood serum: the challenge to sense. AB - Excess levels of secretory phospholipase A2 (sPLA2) is known to contribute to several inflammatory diseases including vascular inflammation correlating with coronary events in coronary artery disease. Thus a method to monitor sPLA2 activity in blood serum is urgently needed. Such method is still a challenge since existing fluorescent probes do not allow to monitor sPLA2 activity directly in blood serum. Here we analyze and overcome barriers in sPLA2 sensing methodology and report a fluorescent probe and a kinetic model of its hydrolysis by sPLA2. New probe is designed with a fluorophore and a quencher not interfering binding to the enzyme. At the same time phospholipid matrix bearing the probe promotes efficient initial quenching of the fluorophore. Kinetic model of probe hydrolysis takes into account signal change due to the side processes. The probe and the kinetic model applied together prove the concept that the activity of sPLA can be measured directly in blood serum. PMID- 25450378 TI - miRNA-directed regulation of VEGF in tilapia under hypoxia condition. AB - The Nile tilapia represents an excellent model for hypoxia tolerance. Vascular endothelial growth factor (VEGF) plays a key role in physiological blood vessel formation and pathological angiogenesis under hypoxia conditions. Tight regulation of VEGF level is necessary for hypoxia adaptation in tilapia. MicroRNAs (miRNAs) function as important regulators of gene expression at the post-transcriptional level, which are usually involved in stress responses. We reasoned that VEGF level could be regulated by miRNAs. Through bioinformatics analysis, we identified a putative miR-204 binding site in the VEGF mRNA. We found that hypoxia leads to a marked up-regulation in VEGF level, but a decrease in miR-204 level. miR-204 directly regulates VEGF expression by targeting its 3' UTR, and inhibition of miR-204 substantially increases VEGF level in vivo. Moreover, we found that miR-204 loss of function could affect blood O2-carrying capacity, anaerobic metabolism, and antioxidant enzyme activity. Taken together, miR-204 is an endogenous regulator of VEGF expression, which participates in a regulatory circuit that allows rapid gene program transitions upon hypoxia stress. PMID- 25450380 TI - NDP52 associates with phosphorylated tau in brains of an Alzheimer disease mouse model. AB - We previously showed that NDP52 (also known as calcoco2) plays a role as an autophagic receptor for phosphorylated tau facilitating its clearance via autophagy. Here, we examined the expression and association of NDP52 with autophagy-regulated gene (ATG) proteins including LC3, as well as phosphorylated tau and amyloid-beta (Abeta) in brains of an AD mouse model. NDP52 was expressed not only in neurons, but also in microglia and astrocytes. NDP52 co-localized with ATGs and phosphorylated tau as expected since it functions as an autophagy receptor for phosphorylated tau in brain. Compared to wild-type mice, the number of autophagic vesicles (AVs) containing NDP52 in both cortex and hippocampal regions was significantly greater in AD model mice. Moreover, the protein levels of NDP52 and phosphorylated tau together with LC3-II were also significantly increased in AD model mice, reflecting autophagy impairment in the AD mouse model. By contrast, a significant change in p62/SQSTM1 level was not observed in this AD mouse model. NDP52 was also associated with intracellular Abeta, but not with the extracellular Abeta of amyloid plaques. We conclude that NDP52 is a key autophagy receptor for phosphorylated tau in brain. Further our data provide clear evidence for autophagy impairment in brains of AD mouse model, and thus strategies that result in enhancement of autophagic flux in AD are likely to be beneficial. PMID- 25450379 TI - Type I interferon-mediated immune response against influenza A virus is attenuated in the absence of p53. AB - Influenza A virus (IAV) infection induces secretion of type I interferon (IFN) and activation of p53, which play essential roles in the host defense against tumor development and viral infection. In this study, we knocked down p53 expression by RNA interference. The expression levels of IFN-stimulated genes (ISGs) including IFN regulatory factor (IRF) 5, IRF9, ISG15, ISG20, guanylate binding protein 1, retinoic acid-inducible gene-I and 2'-5'-oligoadenylate synthetase 1 were significantly attenuated in response to IAV infection and IFN alpha stimulation in p53-knockdown cells. This attenuated expression of ISGs was associated with enhanced replication of IAV. Pretreatment of p53-knockdown cells with IFN-alpha failed to inhibit IAV replication, indicating impaired antiviral activity. These findings indicate that p53 plays an essential role in the enhancement of the type I IFN-mediated immune response against IAV infection. PMID- 25450381 TI - Proteomics of dedifferentiation of SK-N-BE2 neuroblastoma cells. AB - Neuroblastoma develops through processes which include cellular dedifferentiation. Ability of tumors to form spheroids is one of the manifestations of dedifferentiation and carcinogenic transformation. To study mechanisms of dedifferentiation of neuroblastoma cells, we generated spheroids and performed a proteomics study to compare the spheroids with parental SK-N-BE2 cells. We observed that dedifferentiation induced extensive changes in the proteome profiles of the cells, which affected more than 30% of detected cellular proteins. Using mass spectrometry, we identified 239 proteins affected by dedifferentiation into spheroids as compared to the parental cells. These proteins represented such regulatory processes as transcription, cell cycle regulation, apoptosis, cell adhesion, metabolism, intracellular transport, stress response, and angiogenesis. A number of potent regulators of stemness, differentiation and cancer were detected as subnetworks formed by the identified proteins. Our validation tissue microarray study of 30 neuroblastoma cases confirmed that two of the identified proteins, DISC1 and DNA-PKcs, had their expression increased in advanced malignancies. Thus, our report unveiled extensive changes of the cellular proteome upon dedifferentiation of neuroblastoma cells, indicated top subnetworks and clusters of molecular mechanisms involved in dedifferentiation, and provided candidate biomarkers for clinical studies. PMID- 25450382 TI - U6 is not a suitable endogenous control for the quantification of circulating microRNAs. AB - Recently, microRNAs have been detected in serum and plasma, and circulating microRNA (miRNA) profiles have now been associated with many diseases such as cancers and heart disease, as well as altered physiological states. Because of their stability and disease resistance, circulation miRNAs appear to be an ideal material for biomarkers of diseases and physiological states in blood. However, the lack of a suitable internal reference gene (internal reference miRNA) has hampered research and application of circulating miRNAs. Currently, U6 and miR-16 are the most common endogenous controls in the research of miRNAs in tissues and cells. We performed microarray-based serum miRNA profiling on the serum of 20 nasopharyngeal carcinoma patients and 20 controls to detect the expressions of U6 and miRNAs. Profiling was followed by real-time quantitative Polymerase Chain Reaction (qPCR) in 80 patients (20 each with gastric cancer, nasopharyngeal carcinoma, colorectal cancer, and breast cancer) and 30 non-cancerous controls. qPCR was also performed to detect miRNAs in serum with repeated freezing and thawing. The results of microarray showed that with the exception of U6, Ct values of miR-16, miR-24, miR-142-3p, miR-19b and miR-192 in serum samples of nasopharyngeal carcinoma were greater than control samples. The results of 110 cases showed large fluctuations in U6 expression. The difference between the greatest and the least levels of expression was 3.29 for delta Ct values, and 1.23 for miR-16. The expressions of U6, miR-16 and miR-24 in serum subjected to different freeze-thaw cycles showed that U6 expression gradually decreased after 1, 2, and 4 cycles of freezing and thawing, while the expression of miR-16 and miR-24 remained relatively stable. Collectively, our results suggested that U6 is unsuitable as an internal reference gene in the research of circulating miRNAs. PMID- 25450383 TI - REDD1 attenuates cardiac hypertrophy via enhancing autophagy. AB - Cardiac hypertrophy is a major risk factor of cardiovascular morbidity and mortality. Autophagy is established to be involved in regulating cardiac hypertrophy. REDD1, a stress-responsive protein, is proved to contribute in autophagy induction. However, the role of REDD1 in cardiac hypertrophy remains unknown. Our study demonstrated that REDD1 knockdown by RNAi exacerbated phenylephrine (PE)-induced cardiac hypertrophy, manifested by increased hypertrophic markers such as ANP and cell surface area. In addition, we discovered that ERK1/2 signaling pathway was involved in the effect of REDD1 on hypertrophy. Moreover, our study showed that REDD1 knockdown impaired autophagy in hypertrophied cardiomyocytes. mTOR, a signaling molecule governing autophagy induction, was activated by the knockdown of REDD1 under PE stress. Importantly, the pro-hypertrophic effect of REDD1 knockdown was significantly reversed by the autophagy enhancer rapamycin. Taken together, we firstly prove that REDD1 is essential for inhibiting cardiac hypertrophy by enhancing autophagy. PMID- 25450384 TI - Overexpressed KDM5B is associated with the progression of glioma and promotes glioma cell growth via downregulating p21. AB - Epigenetic alterations such as aberrant expression of histone-modifying enzymes have been implicated in tumorigenesis. Upregulation of lysine (K)-specific demethylase 5B (KDM5B) has been reported in a variety of malignant tumors. However, the impact of KDM5B in glioma remains unclear. The objective of this study was to investigate the expression and prognostic value of KDM5B in glioma. In clinical glioma samples, we found that KDM5B expression was significantly upregulated in cancer lesions compared with normal brain tissues. Kaplan-Meier analysis showed that patients with glioma and higher KDM5B expression tend to have shorter overall survival time. By silencing or overexpressing KDM5B in glioma cells, we found that KDM5B could promote cell growth both in vitro and in vivo. Moreover, we demonstrated that KDM5B promoted glioma proliferation partly via regulation of the expression of p21. Our study provided evidence that KDM5B functions as a novel tumor oncogene in glioma and may be a potential therapeutic target for glioma management. PMID- 25450385 TI - Copine1 C2 domains have a critical calcium-independent role in the neuronal differentiation of hippocampal progenitor HiB5 cells. AB - Copine1 (CPNE1) has tandem C2 domains and an A domain and is known as a calcium dependent membrane-binding protein that regulates signal transduction and membrane trafficking. We previously demonstrated that CPNE1 directly induces neuronal differentiation via Akt phosphorylation in the hippocampal progenitor cell line, HiB5. To determine which region of CPNE1 is related to HiB5 cell neurite outgrowth, we constructed several mutants. Our results show that over expression of each C2 domain of CPNE1 increased neurite outgrowth and expression of the neuronal marker protein neurofilament (NF). Even though protein localization of the calcium binding-deficient mutant of CPNE1 was not affected by ionomycin, this mutant increased neurite outgrowth and NF expression in HiB5 cells. Furthermore, Akt phosphorylation was increased by over-expression of the calcium binding-deficient CPNE1 mutant. These results suggest that neither cellular calcium levels nor the localization of CPNE1 affect its function in neuronal differentiation. Collectively, our findings indicating that the C2 domains of CPNE1 play a calcium-independent role in regulating the neuronal differentiation of HiB5 cells. PMID- 25450386 TI - Evaluation of hypothalamic murine and human melanocortin 3 receptor transcript structure. AB - The melanocortin 3 receptor (MC3R) is involved in regulation of energy homeostasis. However, its transcript structure is not well understood. We therefore studied initiation and termination sites for hypothalamic murine Mc3r and human MC3R transcripts. Rapid Amplification of cDNA Ends (RACE) was performed for the 5' and 3' ends of murine and human hypothalamic RNA. 5' RACE experiments using hypothalamic murine RNA indicated mouse hypothalamus expresses two major Mc3r transcription start sites: one with a 5' UTR approximately 368 bases in length and another previously unknown transcript with a 5' UTR approximately 440 bases in length. 5' RACE experiments using human hypothalamic RNA identified a 5' UTR beginning 533 bases upstream of the start codon with a 248 base splice. 3' RACE experiments using hypothalamic murine RNA indicated the 3' UTR terminates approximately 1286 bases after the translational stop codon, with a previously unknown 787 base splice between consensus splice donor and acceptor sites. 3' RACE experiments using human MC3R transcript indicated the 3' UTR terminates approximately 115-160 bases after the translational stop codon. These data provide insight into melanocortin 3 receptor transcript structure. PMID- 25450387 TI - The contribution of tumor and host tissue factor expression to oncogene-driven gliomagenesis. AB - Glioblastoma multiforme (GBM) is an aggressive form of glial brain tumors, associated with angiogenesis, thrombosis, and upregulation of tissue factor (TF), the key cellular trigger of coagulation and signaling. Since TF is upregulated by oncogenic mutations occurring in different subsets of human brain tumors we investigated whether TF contributes to tumourigenesis driven by oncogenic activation of EGFR (EGFRvIII) and RAS pathways in the brain. Here we show that TF expression correlates with poor prognosis in glioma, but not in GBM. In situ, the TF protein expression is heterogeneously expressed in adult and pediatric gliomas. GBM cells harboring EGFRvIII (U373vIII) grow aggressively as xenografts in SCID mice and their progression is delayed by administration of monoclonal antibodies blocking coagulant (CNTO 859) and signaling (10H10) effects of TF in vivo. Mice in which TF gene is disrupted in the neuroectodermal lineage exhibit delayed progression of spontaneous brain tumors driven by oncogenic N-ras and SV40 large T antigen (SV40LT) expressed under the control of sleeping beauty transposase. Reduced host TF levels in low-TF/SCID hypomorphic mice mitigated growth of glioma subcutaneously but not in the brain. Thus, we suggest that tumor associated TF may serve as therapeutic target in the context of oncogene-driven disease progression in a subset of glioma. PMID- 25450388 TI - Amino acid substitutions away from the RNase H catalytic site increase the thermal stability of Moloney murine leukemia virus reverse transcriptase through RNase H inactivation. AB - We have previously used site-directed mutagenesis to introduce basic residues (i.e., Arg; Lys) in the nucleic acid binding cleft of the Moloney murine leukemia virus reverse transcriptase (MMLV RT) in order to increase its template-primer (T/P) binding affinity. Three stabilizing mutations (i.e., E286R, E302K, and L435R) were identified (Yasukawa et al., 2010). Now, we studied the mechanism by which those mutations increase the thermal stability of the RT. The three single mutants (E286R, E302K, and L435R), an RNase H-deficient MMLV RT (carrying the RNase H-inactivating mutation D524A), a quadruple mutant (E286R/E302K/L435R/D524A, designated as MM4) and the wild-type enzyme (WT) were produced in Escherichia coli. All RTs exhibited similar dissociation constants (Kd) for heteropolymeric DNA/DNA (2.9-6.5 nM) and RNA/DNA complexes (1.2-2.9 nM). Unlike the WT, mutant enzymes (E286R, E302K, L435R, D524A, and MM4) were devoid of RNase H activity, and were not able to degrade RNA in RNA/DNA complexes. These results suggest that the mutations, E286R, E302K, and L435R increase the thermostability of MMLV RT not by increasing its affinity for T/P but by abolishing its RNase H activity. PMID- 25450389 TI - Suspension of thymic emigration promotes the maintenance of antigen-specific memory T cells and the recall responses. AB - Thymic involution is evolutionarily conserved and occurs early in life. However, the physiological significance remains elusive of this seemingly detrimental process. The present study investigated the potential impact of altered thymic output on T cell memory using ovalbumin (OVA) expressed by Listeria monocytogenes as a model antigen. Suspension of thymic emigration by thymectomy was shown to lead to a marked increase in the frequency and total number of OVA-specific memory T cells. In contrast, oversupply of thymic emigrants through thymic grafting caused a significant decrease of such cells. When rechallenged with L. monocytogenes expressing OVA, the thymectomized mice mounted a more potent recall response as evidenced by the enlarged population of OVA-specific tetramer+ cells and the accelerated clearance of the bacteria. Notably, the memory-enhancing effect of thymectomy was abrogated following weekly adoptive transfer of naive T cells. Together, data from the present study indicate that reduced thymic output favors the maintenance of the memory T cell pool. PMID- 25450390 TI - Role of pigment epithelium-derived factor in the involution of hemangioma: autocrine growth inhibition of hemangioma-derived endothelial cells. AB - Hemangioma is a benign tumor derived from abnormal blood vessel growth. Unlike other vascular tumor counterparts, a hemangioma is known to proliferate during its early stage but it is followed by a stage of involution where regression of the tumor occurs. The critical onset leading to the involution of hemangioma is currently not well understood. This study focused on the molecular identities of the involution of hemangioma. We demonstrated that a soluble factor released from the involuting phase of hemangioma-derived endothelial cells (HemECs) and identified pigment epithelium-derived factor (PEDF) as an anti-angiogenic factor that was associated with the growth inhibition of the involuting HemECs. The growth inhibition of the involuting HemECs was reversed by suppression of PEDF in the involuting HemECs. Furthermore, we found that PEDF was more up-regulated in the involuting phase of hemangioma tissues than in the proliferating or the involuted. Taken together, we propose that PEDF accelerates the involution of hemangioma by growth inhibition of HemECs in an autocrine manner. The regulatory mechanism of PEDF expression could be a potential therapeutic target to treat hemangiomas. PMID- 25450391 TI - Mutant PrPCJD prevails over wild-type PrPCJD in the brain of V210I and R208H genetic Creutzfeldt-Jakob disease patients. AB - Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder characterized by the deposition of the pathological conformer (PrP(CJD)) of the host encoded cellular prion protein (PrP(C)). In genetic CJD associated with V210I or R208H PrP substitutions, the pathogenic role of mutant residues is still poorly understood. To understand how V210I or R208H PrP mutations facilitate the development of the disease, we determined by mass spectrometry the quantitative ratio of mutant/wild-type PrP(CJD) allotypes in brains from affected subjects. We found that the mutant PrP(CJD) allotypes moderately exceeds of 2- or 3-fold the amount of the wild-type counterpart suggesting that these mutations mainly exert their pathogenic effect on the onset of the pathogenic cascade. Different mechanisms can be hypothesized to explain the pathogenic role of mutant residues: V210I and R208H substitutions can increase the concentration of PrP(C) and the probability to form insoluble aggregates, or they may facilitate the formation of pathological intermediates, or, alternatively, they may increase the affinity for ligands that are involved in the initial phases of PrP(CJD) formation and aggregation. Whatever the mechanism, the enrichment found for the mutated PrP(CJD) species indicates that these altered structures are more prone, with respect to the non-mutated ones, to be captured in the polymerization process either at the onset or during the development of the disease. PMID- 25450392 TI - Hemin as a generic and potent protein misfolding inhibitor. AB - Protein misfolding causes serious biological malfunction, resulting in diseases including Alzheimer's disease, Parkinson's disease and cataract. Molecules which inhibit protein misfolding are a promising avenue to explore as therapeutics for the treatment of these diseases. In the present study, thioflavin T fluorescence and transmission electron microscopy experiments demonstrated that hemin prevents amyloid fibril formation of kappa-casein, amyloid beta peptide and alpha synuclein by blocking beta-sheet structure assembly which is essential in fibril aggregation. Further, inhibition of fibril formation by hemin significantly reduces the cytotoxicity caused by fibrillar amyloid beta peptide in vitro. Interestingly, hemin degrades partially formed amyloid fibrils and prevents further aggregation to mature fibrils. Light scattering assay results revealed that hemin also prevents protein amorphous aggregation of alcohol dehydrogenase, catalase and gammas-crystallin. In summary, hemin is a potent agent which generically stabilises proteins against aggregation, and has potential as a key molecule for the development of therapeutics for protein misfolding diseases. PMID- 25450393 TI - Effect of indomethacin and lactoferrin on human tenocyte proliferation and collagen formation in vitro. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in patients with injuries and inflammation of tendon and ligament, and as post-surgical analgesics. The aim of this study is to investigate the effect of indomethacin, a classic NSAID and its combinational effect with an anabolic agent of skeletal tissue, lactoferrin, on the proliferation and collagen formation of human tenocytes in vitro. A factorial experimental design was employed to study the dose-dependent effect of the combination of indomethacin and lactoferrin. The results showed that indomethacin at high concentration (100 MUM) inhibited human tenocyte proliferation in culture medium with 1-10% fetal bovine serum (FBS) in vitro. Also, high dose of indomethacin inhibited the collagen formation of human tenocytes in 1% FBS culture medium. Lactoferrin at 50-100 MUg/ml promoted human tenocyte survival in serum-free culture medium and enhanced proliferation and collagen synthesis of human tenocytes in 1% FBS culture medium. When 50-100 MUg/ml lactoferrin was used in combination with 100-200 MUM indomethacin, it partially rescued the inhibitory effects of indomethacin on human tenocyte proliferation, viability and collagen formation. To our knowledge, it is the first evidence that lactoferrin is anabolic to human tenocytes in vitro and reverses potential inhibitory effects of NSAIDs on human tenocytes. PMID- 25450395 TI - Silibinin activates AMP-activated protein kinase to protect neuronal cells from oxygen and glucose deprivation-re-oxygenation. AB - In this study, we explored the cytoprotective potential of silibinin against oxygen-glucose deprivation (OGD)-induced neuronal cell damages, and studied underling mechanisms. In vitro model of ischemic stroke was created by keeping neuronal cells (SH-SY5Y cells and primary mouse cortical neurons) in an OGD condition followed by re-oxygenation. Pre-treatment of silibinin significantly inhibited OGD/re-oxygenation-induced necrosis and apoptosis of neuronal cells. OGD/re-oxygenation-induced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) reduction were also inhibited by silibinin. At the molecular level, silibinin treatment in SH-SY5Y cells and primary cortical neurons led to significant AMP-activated protein kinase (AMPK) signaling activation, detected by phosphorylations of AMPKalpha1, its upstream kinase liver kinase B1 (LKB1) and the downstream target acetyl-CoA Carboxylase (ACC). Pharmacological inhibition or genetic depletion of AMPK alleviated the neuroprotective ability of silibinin against OGD/re-oxygenation. Further, ROS scavenging ability by silibinin was abolished with AMPK inhibition or silencing. While A-769662, the AMPK activator, mimicked silibinin actions and suppressed ROS production and neuronal cell death following OGD/re-oxygenation. Together, these results show that silibinin-mediated neuroprotection requires activation of AMPK signaling. PMID- 25450394 TI - Mechanisms of Rose Bengal inhibition on SecA ATPase and ion channel activities. AB - SecA is an essential protein possessing ATPase activity in bacterial protein translocation for which Rose Bengal (RB) is the first reported sub-micromolar inhibitor in ATPase activity and protein translocation. Here, we examined the mechanisms of inhibition on various forms of SecA ATPase by conventional enzymatic assays, and by monitoring the SecA-dependent channel activity in the semi-physiological system in cells. We build on the previous observation that SecA with liposomes form active protein-conducting channels in the oocytes. Such ion channel activity is enhanced by purified Escherichia coli SecYEG-SecDF.YajC liposome complexes. Inhibition by RB could be monitored, providing correlation of in vitro activity and intact cell functionality. In this work, we found the intrinsic SecA ATPase is inhibited by RB competitively at low ATP concentration, and non-competitively at high ATP concentrations while the translocation ATPase with precursors and SecYEG is inhibited non-competitively by RB. The Inhibition by RB on SecA channel activity in the oocytes with exogenous ATP-Mg(2+), mimicking translocation ATPase activity, is also non-competitive. The non competitive inhibition on channel activity has also been observed with SecA from other bacteria which otherwise would be difficult to examine without the cognate precursors and membranes. PMID- 25450396 TI - Telmisartan, a possible PPAR-delta agonist, reduces TNF-alpha-stimulated VEGF-C production by inhibiting the p38MAPK/HSP27 pathway in human proximal renal tubular cells. AB - Vascular endothelial growth factor-C (VEGF-C) is a main inducer of inflammation associated lymphangiogenesis in various inflammatory disorders including chronic progressive kidney diseases, for which angiotensin II receptor type 1 blockers (ARBs) are widely used as the main treatment. Although proximal renal tubular cells may affect the formation of lymphatic vessels in the interstitial area by producing VEGF-C, the molecular mechanisms of VEGF-C production and its manipulation by ARB have not yet been examined in human proximal renal tubular epithelial cells (HPTECs). In the present study, TNF-alpha dose-dependently induced the production of VEGF-C in HPTECs. The TNF-alpha-induced production of VEGF-C was mediated by the phosphorylation of p38MAPK and HSP27, but not by that of ERK or NFkB. Telmisartan, an ARB that can activate the peroxisome proliferator activated receptor (PPAR), served as a PPAR-delta activator and reduced the TNF alpha-stimulated production of VEGF-C. This reduction was partially attributed to a PPAR-delta-dependent decrease in p38MAPK phosphorylation. Our results indicate that TNF-alpha induced the production of VEGF-C in HPTECs by activating p38MAPK/HSP27, and this was partially inhibited by telmisartan in a PPAR-delta dependent manner. These results provide a novel insight into inflammation associated lymphangiogenesis. PMID- 25450397 TI - Hypoxia-inducible factor-1alpha regulates autophagy to activate hepatic stellate cells. AB - The role of autophagy in Hif-1alpha modulated activation of hepatic stellate cells was illustrated in current work. Autophagy markers were determined in livers of Schistosoma japonicum infected mice and hypoxia or LPS treated human hepatic stellate cell, LX-2 cells. The action of Hif-1 to autophagy was defined as increase of autophagy markers was significantly suppressed in Hif-1alpha siRNA transfected cells upon hypoxia or LPS stimulation. The function of autophagy in activation of LX-2 cells was assessed as increase of activation markers was blocked using autophagy inhibitors under hypoxia and LPS stimulation. Conclusively, Hif-1alpha regulates activation of hepatic stellate cell by modulating autophagy. PMID- 25450399 TI - Interaction between S100P and the anti-allergy drug cromolyn. AB - The S100P protein has been known to mediate cell proliferation by binding the receptor for advanced glycation end products (RAGE) to activate signaling pathways, such as the extracellular regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) pathways. S100P/RAGE signaling is involved in a variety of diseases, such as cancer, metastasis, and diabetes. Cromolyn is an anti-allergy drug that binds S100P to block the interaction between S100P and RAGE. In the present study, we characterized the properties of the binding between cromolyn and calcium-bound S100P using various biophysical techniques. The binding affinity for S100P and cromolyn was measured to be in the millimolar range by fluorescence spectroscopy. NMR-HSQC titration experiments and HADDOCK modeling was employed to determine the spatial structure of the proposed heterotetramer model of the S100P-cromolyn complex. Additional MD simulation results revealed the important properties in the complex stability and conformational flexibility of the S100P-cromolyn complex. This proposed model has provided an understanding of the molecular level interactions of S100P-cromolyn complex. PMID- 25450400 TI - Repression of LXRalpha by a novel member of additional sex comb-like family, ASXL3. AB - Among the members of the additional sex comb-like (ASXL) family, ASXL3 remains unexplored. Here, we showed that ASXL3 interacts with HP1alpha and LSD1, leading to transcriptional repression. We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXRalpha and TRbeta, which were repressed by ASXL3 overexpression. The ligand-dependent interactions of ASXL3 with LXRalpha and TRbeta were demonstrated by the GST pull-down and immunoprecipitation analyses. We confirmed that ASXL3 suppresses the expression of LXRalpha target genes through its recruitment to the LXR-response elements. Finally, we observed that lipid accumulation in Hep3B cells is downregulated upon ASXL3 overexpression but upregulated upon ASXL3 depletion. Overall, our data suggest that ASXL3 is another corepressor of LXRalpha, promoting to the regulation of lipid homeostasis. PMID- 25450398 TI - Intracellular modifiers of integrin alpha 6p production in aggressive prostate and breast cancer cell lines. AB - Cancer metastasis is a multi-step process in which tumor cells gain the ability to invade beyond the primary tumor and colonize distant sites. The mechanisms regulating the metastatic process confer changes to cell adhesion receptors including the integrin family of receptors. Our group previously discovered that the alpha6 integrin (ITGA6/CD49f) is post translationally modified by urokinase plasminogen activator (uPA) and its receptor, urokinase plasminogen activator receptor (uPAR), to form the variant ITGA6p. This variant of ITGA6 is a cleaved form of the receptor that lacks the ligand-binding domain. Although it is established that the uPA/uPAR axis drives ITGA6 cleavage, the mechanisms regulating cleavage have not been defined. Intracellular integrin dependent "inside-out" signaling is a major regulator of integrin function and the uPA/uPAR axis. We hypothesized that intracellular signaling molecules play a role in formation of ITGA6p to promote cell migration during cancer metastasis. In order to test our hypothesis, DU145 and PC3B1 prostate cancer and MDA-MB-231 breast cancer cell lines were treated with small interfering RNA targeting actin and the intracellular signaling regulators focal adhesion kinase (FAK), integrin linked kinase (ILK), and paxillin. The results demonstrated that inhibition of actin, FAK, and ILK expression resulted in significantly increased uPAR expression and ITGA6p production. Inhibition of actin increased ITGA6p, although inhibition of paxillin did not affect ITGA6p formation. Taken together, these results suggest that FAK and ILK dependent "inside-out" signaling, and actin dynamics regulate extracellular production of ITGA6p and the aggressive phenotype. PMID- 25450401 TI - RNA aptamer-conjugated liposome as an efficient anticancer drug delivery vehicle targeting cancer cells in vivo. AB - To minimize the systemic toxicity prevalent to chemotherapeutics, we designed a novel anticancer drug-encapsulating liposome conjugated with an RNA aptamer specific to the prostate specific membrane antigen (PSMA), which is expressed on the surface of prostate cancer cells. The RNA aptamer-conjugated liposome, termed an aptamosome, was prepared by the post-insertion method, in which RNA aptamer conjugated micelles were inserted into a liposome. These nanosized (90-100 nm) aptamer-conjugated liposomes specifically bind to LNCaP prostate epithelial cells that express PSMA and thus cause the nanoparticles to have significantly enhanced in vitro cellular binding and uptake as compared with nontargeted nanoparticles that lack the PSMA aptamer. Aptamosomes encapsulated with the anticancer drug doxorubicin (Dox) were significantly more toxic to the targeted LNCaP cells than to nontargeted cancer cells. Dox-encapsulating aptamosomes administered to LNCaP xenograft nude mice were selectively retained in tumor tissue. We also demonstrated in vivo anticancer efficacy of the Dox-encapsulating PSMA aptamosomes on tumor size regression in LNCaP xenograft mice. We suggest that the encapsulation of toxic chemicals with aptamer-conjugated liposomes will enable the use of these bioconjugates in clinical practice with fewer side effects. PMID- 25450403 TI - Gold nanoparticle-DNA aptamer composites as a universal carrier for in vivo delivery of biologically functional proteins. AB - Although the delivery of biologically functional protein(s) into mammalian cells could be of tremendous value to biomedical research, the development of such technology has been hindered by the lack of a safe and effective delivery method. Here, we present a simple, efficient, and versatile gold nanoparticle-DNA aptamer conjugate (AuNP-Apt)-based system, with nanoblock-like properties, that allows any recombinant protein to be loaded without additional modifications and delivered into mammalian living systems. AuNP-Apt-based protein delivery system was able to deliver various proteins into variety of cell types in vitro without showing cytotoxicity. This AuNP-Apt system was also effective for the local and systemic targeted delivery of proteins in vivo. A local injection of the AuNP-Apt loaded with the apoptosis-inducing BIM protein efficiently inhibited the growth of xenograft tumors in mice. Furthermore, an intravenous injection of AuNP-Apt loaded with both epidermal growth factor (EGF) and BIM resulted in the targeted delivery of BIM into a xenograft tumor derived from EGF receptor-overexpressing cancer cells with no detectable systemic toxicity. Our findings show that this system can serve as an innovative platform for the development of protein-based biomedical applications. PMID- 25450402 TI - Mechanistic studies of an autonomously pulsing hydrogel/enzyme system for rhythmic hormone delivery. AB - Numerous hormones are known to be endogenously secreted in a pulsatile manner. In particular, gonadotropin replacing hormone (GnRH) is released in rhythmic pulses, and disruption of this rhythm is associated with pathologies of reproduction and sexual development. In an effort to develop an implantable, rhythmic delivery system, a scheme has been demonstrated involving a negative feedback instability between a pH-sensitive membrane and enzymes that convert endogenous glucose to hydrogen ion. A bench prototype system based on this scheme was previously shown to produce near rhythmic oscillations in internal pH and in GnRH delivery over a period of one week. In the present work, a systematic study of conditions permitting such oscillations is presented, along with a study of factors causing period of oscillations to increase with time and ultimately cease. Membrane composition, glucose concentration, and surface area of marble (CaCO3), which is incorporated as a reactant, were found to affect the capacity of the system to oscillate, and the pH range over which oscillations occur. Accumulation of gluconate- and Ca2+ in the system over time correlated with lengthening of oscillation period, and possibly with cessation of oscillations. Enzyme degradation may also be a factor. These studies provide the groundwork for future improvements in device design. PMID- 25450406 TI - Arthritogenic T cells in autoimmune arthritis. AB - Autoimmune diseases, including arthritis, often result from an imbalance between regulatory T (Treg) cells and IL-17-producing (Th17) cells. Dozens of studies in mice and humans have shed light on the pathological significance of T cells in RA. Since Th17 cells play an important role in the exacerbation of inflammation and bone destruction in joints, it has been an important issue how arthritic Th17 cells arise. Th17 cells are generated in the local inflammatory milieu via cytokines produced by macrophages or synovial fibroblasts, while it is reported that Th17 cells are generated in the gut in the presence of specific commensal bacteria. A recent report showed a pathogenic Th17 cell subset with a distinct pattern of gene expression and a potent osteoclastogenic ability are converted from Foxp3(+) T cells in arthritic joints. Since Foxp3(+) Treg cells contain T cells which recognize self-antigens, the fate of plastic Foxp3(+) T cells can be a critical determinant of autoimmunity or self-tolerance. Further analysis on the molecular basis and antigen-specificity of arthritogenic Th17 cell subsets will be helpful to establish novel therapeutic approaches and clarify how self tolerance breaks down in autoimmune arthritis. PMID- 25450404 TI - Enhanced antitumor and anti-metastasis efficiency via combined treatment with CXCR4 antagonist and liposomal doxorubicin. AB - Metastasis is the main cause of cancer treatment failure and death. However, current therapies are designed to impair carcinoma metastasis mainly by impairing initial dissemination events. CXCR4 is a G-protein coupled receptor that exclusively binds its ligand CXCL12, which can stimulate cells to metastasize to distant sites. As the antagonist of chemokine receptor CXCR4, Peptide S exhibited anti-metastasis effect. In order to enhance treatment efficiency through destroying primary tumors and inhibiting their metastases, we combined PEGylated doxorubicin-loaded liposomes (DOX-Lip) with anti-metastasis Peptide S for tumor therapy for the first time. DOX-Lip exhibited similar cytotoxic activity compared to free DOX in vitro, and Peptide S showed no toxic effect on cell viability. However, the Peptide S sensitized CXCR4-positive B16F10 melanoma cells to DOX-Lip (5 MUM) when cocultured with stromal cells (50.18+/-0.29% of viable cells in the absence of Peptide S vs 33.70+/-3.99% of viable cells in the presence of Peptide S). Both Peptide S and DOX-Lip inhibited the adhesion of B16F10 cells to stromal cells. We further confirmed that the inhibition of phosphorylated Akt (pAkt) by Peptide S played a key role due to the fact that activation of pAkt by DOX-Lip promoted resistance to chemotherapy. Migration and invasion assays showed that DOX-Lip enhanced anti-metastasis effect of Peptide S in vitro because of the cytotoxicity of doxorubicin. In vivo studies also showed that the combined treatment with DOX-Lip and Peptide S not only retarded primary tumor growth, but also reduced lung metastasis. Both the DOX-Lip and DOX-Lip+Peptide S exhibited even more outstanding tumor inhibition effect (with tumor growth inhibition rates of 32.1% and 37.9% respectively). In conclusion, our combined treatment with CXCR4 antagonist and liposomal doxorubicin was proved to be promising for antitumor and anti-metastasis therapy. PMID- 25450405 TI - Material-mediated proangiogenic factor release pattern modulates quality of regenerated blood vessels. AB - Hydrogels designed to sustainably release bioactive molecules are extensively used to enhance tissue repair and regenerative therapies. Along this line, numerous efforts are made to control the molecular release rate and amount. In contrast, few efforts are made to control the molecular release pattern, and, subsequently, modulate the spatial organization of newly forming tissues, including blood vessels. Therefore, using a hydrogel printed to release vascular endothelial growth factor (VEGF) into a pre-defined pattern, this study demonstrates that spatial distribution of VEGF is important in guiding growth direction of new blood vessels, and also in retaining the structural integrity of pre-existing vasculature. Guided by a computational model, we fabricated a patch composed of micro-sized VEGF-releasing poly(ethylene glycol) diacrylate (PEGDA) hydrogel cylinders using an ink-jet printer. Interestingly, hydrogel printed with computationally optimized spacing created anisotropically aligned vasculature exclusively when the printed gel pattern was placed parallel to pre-existing blood vessels. In contrast, vascular sprouting from placing the printed gel pattern perpendicular to pre-existing vessels resulted in deformation and structural disintegration of the original vasculature. We envision that this study will be useful to better understand angiogenesis-modulated neovascularization and further improve the treatment quality for various wounds and tissue defects. PMID- 25450407 TI - Novel radiographic measurement algorithm demonstrating a link between obesity and lateral skull base attenuation. AB - OBJECTIVES: (1) To describe a validated algorithm for measuring tegmen thickness on computed tomography scans. (2) To compare the tegmen thickness in 3 groups: patients with spontaneous cerebrospinal fluid (CSF) leaks, obese controls, and nonobese controls. STUDY DESIGN: Retrospective review. SETTING: Patients with spontaneous CSF otorrhea often have highly attenuated tegmen plates. This is associated with obesity and/or idiopathic intracranial hypertension (IIH). No evidence exists, however, that objectively links obesity and/or IIH with skull base attenuation. SUBJECTS AND METHODS: This was a retrospective review from 2004 to the present. Patients with spontaneous CSF otorrhea and matched obese (body mass index [BMI] >30 kg/m(2)) and nonobese (BMI <30 kg/m(2)) controls were selected. Tegmen thickness was measured radiographically. Interrater validity was assessed. RESULTS: Ninety-eight patients were measured: 37 in the CSF group (BMI, 36.6 kg/m(2)), 30 in the obese group (BMI, 34.6 kg/m(2)), and 31 in the nonobese group (BMI, 24.2 kg/m(2)). The CSF group had a significantly thinner tegmen compared to both the obese control (P < .01) and nonobese control (P = .0004) groups. Obese controls had a thinner tegmen than nonobese controls (P < .00001). A significant inverse correlation was detected between skull base thickness and BMI. Signs/symptoms of IIH were most commonly found in the CSF group. Good to very good strength of agreement was detected for measures between raters. CONCLUSION: This is the first study to (1) quantify lateral skull base thickness and (2) significantly correlate obesity with lateral skull base attenuation. Patients who are obese with spontaneous CSF leaks have greater attenuation of their skull base than matched obese controls. This finding supports theories that an additional process, possibly congenital, has a pathoetiological role in skull base dehiscence. PMID- 25450408 TI - Novel porous oral patches for patients with mild obstructive sleep apnea and mouth breathing: a pilot study. AB - OBJECTIVES: Habitual open-mouth breathing (OMB) during sleep can cause snoring and obstructive sleep apnea (OSA). This study used a porous oral patch (POP) to treat patients with mild OSA and OMB during sleep. The subjective and objective outcomes were evaluated. STUDY DESIGN: Prospective study. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Patients with >=5 events hourly but <15 hourly on the apnea-hypopnea index (AHI) were enrolled. All patients slept with their mouths closed by using the POP, which is a porous skin pad consisting of 3 layers: silicone sheet, polyurethane foam, and polyurethane film. Before treatment and during treatment, subjective outcomes were assessed using the Epworth Sleepiness Scale (ESS) and visual analog scale (VAS) of snoring. Objective outcomes were assessed using polysomnography and cephalometry. RESULTS: Thirty patients were enrolled in this study. All patients slept with their mouths closed while using a POP. The ESS and VAS of snoring scores were 8.1 +/- 1.5 and 7.5 +/- 2.0 before the POP, respectively, in contrast to 5.2 +/- 1.6 and 2.4 +/- 1.4 while using a POP, respectively (P < .05). The median AHI score was significantly decreased by using a POP from 12.0 per hour before treatment to 7.8 per hour during treatment (P < .01). The snoring intensity and median snoring index were 49.1 +/- 10.8 dB and 146.7 per hour before the POP, respectively, which decreased to 41.1 +/- 7.8 dB and 40.0 per hour while using a POP, respectively (P < .01). Cephalometry revealed that the retropalatal space and retrolingual space were 7.4 +/- 1.6 mm and 6.8 +/- 2.5 mm before the POP, respectively, compared with 8.6 +/- 1.2 mm and 10.2 +/- 1.8 mm during treatment, respectively (P < .01). CONCLUSION: The POP is a useful device to treat patients with mild OSA and habitual OMB. PMID- 25450409 TI - Diode laser for the treatment of telangiectasias following hemangioma involution. AB - OBJECTIVE: Infantile hemangiomas are well known for their rapid growth during the first 6 to 9 months of life, followed by a spontaneous but slow involution. The standard of care is to treat these lesions at an early age with propranolol to expedite the involution process; however, surgery still remains an active component in the management. Medical treatment with propranolol or natural involution will often result in residual telangiectasias. We evaluated the efficacy of using a diode laser as a treatment for telangiectasias following cervicofacial infantile hemangioma involution. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care hospital and practice specializing in the care of vascular anomalies. SUBJECTS AND METHODS: Twenty patients, aged 4 months to 11 years (average 2.69 years), underwent treatment with a 532-nm diode laser to treat the residual telangiectasias following hemangioma involution. All procedures were performed in the operating room. To assess the efficacy, we independently evaluated pre- and posttreatment digital photographs and ranked them on a 0- to 4-point scale (0 = no change and 4 = complete response). Adverse reactions were also recorded. RESULTS: The telangiectasias showed considerable improvement following treatment. In more than half of the patients treated, the affected area demonstrated a complete response. No adverse reactions were noted. CONCLUSION: A 532-nm diode laser effectively treats the remaining telangiectasias following hemangioma involution. Whether used independently or in conjunction with other treatment modalities, the diode laser should be part of the surgical armamentarium when treating infantile hemangiomas. PMID- 25450410 TI - Readability assessment of online tracheostomy care resources. AB - OBJECTIVE: To assess the readability of online tracheostomy care resources. STUDY DESIGN: Cross-sectional study. SETTING: Academic center. SUBJECTS AND METHODS: A Google search was performed for "tracheostomy care" in January 2014. The top 50 results were categorized into major versus minor websites and patient-oriented versus professional-oriented resources. These websites were evaluated with the following readability tools: Flesch Reading Ease Score (FRES), Flesch-Kincaid Grade Level (FKGL), Simple Measure of Gobbledygook (SMOG), and Gunning Frequency of Gobbledygook (GFOG). RESULTS: Readability scores for the websites were FRES 57.21 +/- 16.71 (possible range = 0-100), FKGL 8.33 +/- 2.84 (possible range = 3 12), SMOG 11.25 +/- 2.49 (possible range = 3-19), and GFOG 11.43 +/- 4.07 (possible range = 3-19). There was no significant difference in all 4 readability scores between major (n = 41) and minor (n = 9) websites. Professional-oriented websites (n = 19) had the following readability scores: FRES 40.77 +/- 11.69, FKGL 10.93 +/- 2.48, SMOG 13.29 +/- 2.32, and GFOG 14.91 +/- 3.98. Patient oriented websites (n = 31) had the following readability scores: FRES 67.29 +/- 9.91, FKGL 6.73 +/- 1.61, SMOG 10.01 +/- 1.64, and GFOG 9.30 +/- 2.27. Professional-oriented websites had more difficult readability scores than patient oriented websites for FRES (P < .00), FKGL (P < .00), SMOG (P < .00), and GFOG (P < .00). CONCLUSION: Online tracheostomy care resources were written at a level more difficult than the recommended fourth- to sixth-grade level for written health information. There was no significant difference in readability between major and minor websites. Professional-oriented websites were more difficult to read than patient-oriented websites. PMID- 25450411 TI - Simulating the nasal cycle with computational fluid dynamics. AB - OBJECTIVES: (1) To develop a method to account for the confounding effect of the nasal cycle when comparing preoperative and postoperative objective measures of nasal patency. (2) To illustrate this method by reporting objective measures derived from computational fluid dynamics (CFD) models spanning the full range of mucosal engorgement associated with the nasal cycle in 2 subjects. STUDY DESIGN: Retrospective. SETTING: Academic tertiary medical center. SUBJECTS AND METHODS: A cohort of 24 patients with nasal airway obstruction was reviewed to select the 2 patients with the greatest reciprocal change in mucosal engorgement between preoperative and postoperative computed tomography (CT) scans. Three-dimensional anatomic models were created based on the preoperative and postoperative CT scans. Nasal cycling models were also created by gradually changing the thickness of the inferior turbinate, middle turbinate, and septal swell body. Moreover, CFD was used to simulate airflow and to calculate nasal resistance and the average heat flux. RESULTS: Before accounting for the nasal cycle, patient A appeared to have a paradoxical worsening nasal obstruction in the right cavity postoperatively. After accounting for the nasal cycle, patient A had small improvements in objective measures postoperatively. The magnitude of the surgical effect also differed in patient B after accounting for the nasal cycle. CONCLUSION: By simulating the nasal cycle and comparing models in similar congestive states, surgical changes in nasal patency can be distinguished from physiological changes associated with the nasal cycle. This ability can lead to more precise comparisons of preoperative and postoperative objective measures and potentially more accurate virtual surgery planning. PMID- 25450413 TI - Ocular findings in patients with alopecia areata: role of ultra-wide-field retinal imaging. AB - Alopecia areata is understood as an autoimmune disease T cell-mediated mainly involving hair follicles in humans. It is a multifactorial aetiologic disease characterised by non-scarring alopecia and asymptomatic areas, affecting approximately 2 % of dermatology patients. Recent studies suggest that the pathogenesis of AA plays an important role in the association of certain HLA groups, neuroendocrine parameters and immunogenic factors. During 3 months (March to May 2013) at Hospital Clinic de Barcelona, 22 patients with severe alopecia areata underwent ophthalmic examination to determine whether there were ocular findings in the following parameters: Best-corrected visual acuity on decimal Snellen optotype, anterior segment slit-lamp examination and photograph, intraocular pressure measurement and dilated fundoscopy. Ultra-wide-field retinal imaging with or without red-free photograph was carried out with the Optomap 200 Tx (Optos, DunFermline, UK). Forty-four eyes of 22 patients were analysed [15 females (68.2 %)]. The mean age was 38.9 (SD 13.7) and mean time of evolution was 19.9 years (SD 16.3). Alopecia areata clinical patterns were multifocal [n = 10 (45.5 %)], universalis [n = 7 (31.8 %)], totalis [n = 3 (13.6 %)] and focal [n = 2 (9.1 %)]. Best-corrected visual acuity was 1.0 in almost all patients, but only three eyes (6.8 %) had vision of 0.7. Ocular findings were as follows: madarosis [n = 7 partial loss of eyelashes (31.85 %) and n = 4 total loss (18.2 %)], lens changes [n = 4 (18.2 %)], cataract [n = 3 (13.65 %)]. Ultra-wide fundus photography examination showed peripheral drusen [n = 17 eyes (38.6 %)], white without-pressure changes [n = 8 eyes (18.22 %)] and peripheral retinal degenerations [n = 3 eyes (6.81 %)]. Ocular findings in patients with alopecia areata are reported and discussed by dermatologic and ophthalmic evaluation. PMID- 25450412 TI - A population-based study on the association between statin use and sudden sensorineural hearing loss. AB - OBJECTIVES: No study has reported the relationship between statin use and sudden sensorineural hearing loss (SSNHL). In this study, we examined the association between statin use and SSNHL using a population-based dataset. STUDY DESIGN: A case-control study. SETTING: Taiwan. SUBJECTS AND METHODS: The study sample was selected from the Taiwan Longitudinal Health Insurance Database. We identified 1263 subjects aged >=40 years with SSNHL and 6315 sex-, age-, hypertension-, and coronary heart disease-matched controls. We used conditional logistic regression to compute the odds ratio (OR) for having been a previous statin user between cases and controls. Furthermore, we performed conditional logistic regression to explore the relationship of regular and irregular statin users with SSNHL. RESULTS: There was a significant difference in the prevalence of statin use between cases and controls (27.2% vs 21.3%, respectively; P < .001). The OR of statin use before the index date for cases was 1.36 (95% confidence interval [CI], 1.18-1.57) compared to controls after taking gender, age group, hypertension, coronary heart disease, diabetes, renal disease, and hyperlipidemia into consideration. Furthermore, compared to controls, the adjusted ORs of regular and irregular statin use for cases were 1.30 (95% CI, 1.11-1.52) and 1.49 (95% CI, 1.11-1.93), respectively, compared to controls. CONCLUSION: This study found that SSNHL was significantly associated with previous statin use. PMID- 25450414 TI - Novel Platinum(II) compounds modulate insulin-degrading enzyme activity and induce cell death in neuroblastoma cells. AB - The properties of three novel Platinum(II) compounds toward the insulin-degrading enzyme (IDE) enzymatic activity have been investigated under physiological conditions. The rationale of this study resides on previous observations that these compounds, specifically designed and synthesized by some of us, induce apoptosis in various cancer cell lines, whereas IDE has been proposed as a putative oncogene involved in neuroblastoma onset and progression. Two of these compounds, namely [PtCl(O,O'-acac)(DMSO)] and [Pt(O,O'-acac)(gamma-acac)(DMS)], display a modulatory behavior, wherefore activation or inhibition of IDE activity occurs over different concentration ranges (suggesting the existence of two binding sites on the enzyme). On the other hand, [Pt(O,O'-acac)(gamma acac)(DMSO)] shows a typical competitive inhibitory pattern, characterized by a meaningful affinity constant (K i = 0.95 +/- 0.21 MUM). Although all three compounds induce cell death in neuroblastoma SHSY5Y cells at concentrations exceeding 2 MUM, the two modulators facilitate cells' proliferation at concentrations <= 1.5 MUM, whereas the competitive inhibitor [Pt(O,O'-acac)(gamma acac)(DMSO)] only shows a pro-apoptotic activity at all investigated concentrations. These features render the [Pt(O,O'-acac)(gamma-acac)(DMSO)] a promising "lead compound" for the synthesis of IDE-specific inhibitors (not characterized yet) with therapeutic potentiality. PMID- 25450415 TI - Pharmacokinetics of the dual melatonin receptor agonist tasimelteon in subjects with hepatic or renal impairment. AB - Tasimelteon is a circadian regulator that resets the master clock in the suprachiasmatic nuclei of the hypothalamus by binding to both melatonin MT1 and MT2 receptors making it a dual melatonin receptor agonist. Tasimelteon has been approved by the United States Food and Drug Administration for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24). Two prospective, single-center, open label studies evaluated the pharmacokinetics of tasimelteon and its main metabolites after a single 20 mg dose administered to subjects with mild or moderate hepatic impairment or severe renal impairment, including subjects on dialysis compared to healthy controls. In subjects with mild or moderate hepatic impairment, exposure to tasimelteon after a single 20 mg dose, as measured by area under the plasma concentration-time curve to infinity, was increased by approximately 2-fold. There was no apparent relationship between tasimelteon clearance and renal function. No safety concerns were apparent in either study. Based on these results, the changes in the pharmacokinetics of tasimelteon due to mild or moderate hepatic or severe renal impairment are not considered clinically relevant, and no dose adjustment is necessary in these patients. PMID- 25450416 TI - High speed and adaptable error correction for megabit/s rate quantum key distribution. AB - Quantum Key Distribution is moving from its theoretical foundation of unconditional security to rapidly approaching real world installations. A significant part of this move is the orders of magnitude increases in the rate at which secure key bits are distributed. However, these advances have mostly been confined to the physical hardware stage of QKD, with software post-processing often being unable to support the high raw bit rates. In a complete implementation this leads to a bottleneck limiting the final secure key rate of the system unnecessarily. Here we report details of equally high rate error correction which is further adaptable to maximise the secure key rate under a range of different operating conditions. The error correction is implemented both in CPU and GPU using a bi-directional LDPC approach and can provide 90-94% of the ideal secure key rate over all fibre distances from 0-80 km. PMID- 25450417 TI - Clinical and structural outcomes after arthroscopic repair of full-thickness rotator cuff tears with and without platelet-rich product supplementation: a meta analysis and meta-regression. AB - PURPOSE: The purpose of this study was to perform a systematic review, meta analysis, and meta-regression of all Level I and Level II studies comparing the clinical or structural outcomes, or both, after rotator cuff repair with and without platelet-rich product (PRP) supplementation. METHODS: A literature search of the PubMed and EMBASE databases was performed to identify all Level I or II studies comparing the clinical or structural outcomes, or both, after arthroscopic repair of full-thickness rotator cuff tears with (PRP+ group) and without (PRP- group) PRP supplementation. Data included outcome scores (American Shoulder and Elbow Surgeons [ASES], University of California Los Angeles [UCLA], Constant, Simple Shoulder Test [SST] and visual analog scale [VAS] scores) and retears diagnosed with imaging studies. Meta-analyses compared preoperative, postoperative, and gain in outcome scores and relative risk ratios for retears. Meta-regression compared the effect of PRP treatment on outcome scores and retear rates according to 6 covariates. Minimum effect sizes that were detectable with 80% power were also calculated for each study. RESULTS: Eleven studies were included in this review and a maximum of 8 studies were used for meta-analyses according to data availability. There were no statistically significant differences between the PRP+ and PRP- groups for overall outcome scores or retear rates (P > .05). Overall gain in the Constant score was decreased when liquid PRP was injected over the tendon surface compared with PRP application at the tendon bone interface (-6.88 points v +0.78 points, respectively; P = .046); however, this difference did not reach the previously reported minimum clinically important difference (MCID) for Constant scores. When the initial tear size was greater than 3 cm in anterior-posterior length, the PRP+ group exhibited decreased retear rates after double-row repairs when compared with the PRP- group (25.9% v 57.1%, respectively; P = .046). Sensitivity power analyses revealed that most included studies were only powered to detect large differences in outcome scores between groups. CONCLUSIONS: There were no statistically significant differences in overall gain in outcome scores or retear rates between treatment groups. Gain in Constant scores was significantly increased when PRPs were applied at the tendon-bone interface when compared with application over the top of the repaired tendon. Retear rates were significantly decreased when PRPs were used for the treatment of tears greater than 3 cm in anterior-posterior length using a double-row technique. Most of the included studies were only powered to detect large differences in outcome scores between treatment groups. In addition, an increased risk for selection, performance, and attrition biases was found. LEVEL OF EVIDENCE: Level II, meta-analysis of Level I and Level II studies. PMID- 25450418 TI - Results of isolated lateral retinacular reconstruction for iatrogenic medial patellar instability. AB - PURPOSE: The aim of this study was to assess the outcomes of an isolated lateral retinaculum reconstruction for iatrogenic medial patellar instability (IMPI) in patients with continued pain after failed lateral retinacular release (LRR), including associated psychometric analysis. METHODS: Pain was assessed using the visual analog scale (VAS) and disability was determined with the Lysholm scale. Psychological variables such as anxiety, depression, catastrophizing, and fear-of movement beliefs were studied by using self-administered psychometric questionnaires. RESULTS: All 17 patients (13 women and 4 men) in this retrospective study had undergone LRR previously for anterior knee pain or lateral patellar instability. Four patients had undergone LRR plus proximal (Insall) realignment, and one had undergone LRR plus a medial tibial tubercle transfer. After their procedures, all had disabling symptoms. All patients underwent reconstructive surgery for IMPI. At a minimum follow-up of 2 years (range, 2 to 8 years), the mean preoperative VAS score was 7.6 (range, 5 to 9) and improved to 1.9 (range, 0 to 8) at the time of final follow-up (P < .001). The mean preoperative Lysholm score was 36.4 (range, 20 to 55), and the knee was described as bad (<65 points) in all cases. Postoperatively, it improved to 86.1 (range, 70 to 94) at final follow-up (P < .001). Before surgery, 4 patients (24%) had the clinical criteria for depression, 10 (59%) had anxiety, 7 (41%) had "catastrophizing" ideas concerning pain, and all (100%) had kinesiophobia (fear of movement). After surgery, none of the patients had depression or anxiety, none had catastrophizing ideation, and only 53% had kinesiophobia. CONCLUSIONS: Reconstruction of the deep transverse layer of the lateral retinaculum (LR) using a central strip of the iliotibial band for IMPI in patients with continued pain after failed LRR can successfully treat these severely disabled patients. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25450419 TI - L-Cysteine and L-AP4 microinjections in the rat caudal ventrolateral medulla decrease arterial blood pressure. AB - The thiol amino acid L-cysteine increases arterial blood pressure (ABP) when injected into the cerebrospinal fluid space in conscious rats, indicating a pressor response to centrally acting L-cysteine. A prior synaptic membrane binding assay suggests that L-cysteine has a strong affinity for the L-2-amino-4 phosphonobutyric acid (L-AP4) binding site. The central action of L-cysteine may be vial-AP4 sensitive receptors. The present study investigated cardiovascular responses to L-cysteine and L-ap4 microinjected into the autonomic area of the caudal ventrolateral medulla (CVLM) where inhibitory neurons regulate ABP via pre sympathetic vasomotor neurons. Both the injection of L-cysteine and L-AP4 in the CVLM sites identified with L-glutamate produced the same depressor and bradycardic responses in urethane-anesthetized rats. Neither a prior antagonist microinjection of MK801 for the N-methyl-D-aspartate (NMDA) receptor nor CNQX for the non-NMDA receptor attenuated the responses to L-cysteine, but the combination of the two receptor blocking with an additional prior injection abolished the response. In contrast, either receptor blockade alone abolished the response to L AP4, indicating distinct mechanisms between responses to L-cysteine and L-AP4 in the CVLM. The results indicate that the CVLM is a central active site for L cysteine's cardiovascular response. Central L-cysteine's action could be independent of the L-AP4 sensitive receptors. Cardiovascular regulation may involve endogenous L-cysteine in the CVLM. Further multidisciplinary examinations are required to elaborate on L-cysteine's functional roles in the CVLM. PMID- 25450421 TI - Strain-dependent effects of transforming growth factor-beta1 and 2 during mouse secondary palate development. AB - Cleft palate is a common birth defect affecting 1 in 700 births. Transforming growth factor-betas (TGF-betas) are important signaling molecules, and their functions in murine palate development have received great attention. TGF-beta3 is expressed exclusively in palatal epithelial cells and mediates epithelial fusion, whereas the importance of TGF-beta1 and 2 in palate have not yet been demonstrated in vivo, since inactivation of Tgf-beta1 or Tgf-beta2 genes in mice did not reveal significant palate defects. We hypothesized that TGF-beta1 and TGF beta2 can compensate each other during palate formation. To test this, we generated Tgf-beta1 and Tgf-beta2 compound mutant mice and found that approximately 40% of [Tgf-beta1(+/-); Tgf-beta2(-/-)] compound mutant embryos display cleft palate on C57 background. In addition, 26% of Tgf-beta2(-/-) embryos on 129 background, but not in C57 or Black Swiss, displayed cleft palate. TGF-beta1 and 2 functions are required for murine palate development in strain dependent manner. PMID- 25450420 TI - Alcohol intake stimulates epithelial proliferation in an authentic model of the human breast. AB - The voluntary consumption of alcohol by humans is a modifiable lifestyle factor that has been consistently linked to a woman's risk of developing breast cancer. We have used an animal model that closely recapitulates breast development in humans to study the effect of alcohol intake on breast growth and morphology. Pubertal female pigs were fed alcohol for 4-5 weeks at 19-21% of total caloric intake, which led to average blood alcohol concentrations of 115-130mg/dL. Alongside increased liver mass, alcohol intake promoted the formation of distended ductules within lobular units in association with increased epithelial proliferation. Alcohol consumption also increased phosphorylation of the transcription factor STAT5 in the mammary epithelium, but did not lead to any evidence of precocious lactogenesis. In conclusion, feeding alcohol to female pigs having a similar physiology and mammary gland morphology to humans during a reproductive state equivalent to human adolescence leads to increased mammary gland proliferation and development of atypical lobular structures. These changes may phenocopy how alcohol intake increases the risk for developing breast cancer in humans. PMID- 25450422 TI - Use of ondansetron during pregnancy and congenital malformations in the infant. AB - The study investigates teratogenic risks with ondansetron (Zofran((r))). Data from the Swedish Medical Birth Register combined with the Swedish Register of Prescribed Drugs were used to identify 1349 infants born of women who had taken ondansetron in early pregnancy, 1998-2012. Presence of congenital malformations in the offspring was identified with three national health registers. In a Mantel Haenszel analysis adjustment was made for year of delivery, maternal age, parity, smoking in early pregnancy and pre-pregnancy body mass index. Risks were expressed as odds or risk ratios with 95% confidence intervals. No statistically significantly increased risk for a major malformation was found. The risks for a cardiovascular defect and notably a cardiac septum defect were increased and statistically significant (OR=1.62, 95% CI 1.04-2.14, and RR 2.05, 95% CI 1.19 3.28, respective). The teratogenic risk with ondansetron is low but an increased risk for a cardiac septum defect is likely. PMID- 25450423 TI - Ovarian dysfunction, obesity and pituitary tumors in female mice following neonatal exposure to low-dose diethylstilbestrol. AB - In a previous study, we found that early life exposure to low-dose diethylstilbestrol (DES) induced early onset of spontaneous abnormalities in estrus cycle and shortened survival in female Sprague-Dawley rats. In order to confirm the repeatability of the previous study, neonates of C57BL/6J mice were orally administered DES at doses of 0.005, 0.05, 0.5 and 5 MUg/kg/day, and the aging of their reproductive function was observed. As a result, delayed toxicity on ovarian function was found in females treated with 0.5 MUg/kg/day of DES. Concomitantly, the females in the 0.05 MUg/kg/day of DES, or greater, groups, had increased body weights and, in the 0.5 MUg/kg/day of DES, or greater, groups, had developed pituitary tumors, which were causal factors in their accelerated mortality. Thus, we found that early life exposure to low-dose DES induced early onset of spontaneous abnormalities in estrus cycle not only in female rats but also in female mice. PMID- 25450424 TI - Filling dynamics of the Brindley's glands in the blood-sucking bug Triatoma infestans (Hemiptera: Reduviidae). AB - The filling dynamics of exocrine defensive glands is an important component of the defensive capacity of an insect in its natural environment. We studied the filling state and reloading rate of the Brindley's glands in the haematophagous Chagas disease vector Triatoma infestans (Hemiptera: Reduviidae). Quantitative analyses of isobutyric acid, the main secretion component, were carried out with glands dissected from adults under different scenarios of development, number of discharging events and feeding conditions. The alarm-pheromone function of the gland secretion was also assessed in bioassays with conspecific nymphs. Although pharate adults have their glands completely developed, these were not full until imaginal ecdysis. If kept undisturbed, the adults maintained a constant gland load, and discharged about 75% of the gland contents upon one disturbance event. While the glands can be discharged several times, full replenishing was not complete after one week, unless the insect had access to food. The escape behavior of nymphs in bioassays correlated with the chemical analyses, with nymphs showing significant avoidance only toward gland discharges from undisturbed or disturbed/fed adults. The results are discussed in reference to the feeding frequency and gregarious behavior of T. infestans under natural conditions, which suggest a relevant role of the filling dynamics of the Brindley's glands in the intraspecific communication of the insect. PMID- 25450425 TI - Response profile of pheromone receptor neurons in male Grapholita molesta (Lepidoptera: Tortricidae). AB - The response profile of olfactory receptor neurons (ORNs) of male Grapholita molesta (Busck) to the three female sex pheromone components [(Z)-8-dodecenyl acetate (Z8-12:Ac), (E)-8-dodecenyl acetate (E8-12:Ac), and (Z)-8-dodecenyl alcohol (Z8-12:OH)] was tested with single sensillum electrophysiology. Sensilla trichodea housed normally one, but sometimes two or three ORNs with distinct action potential amplitudes. One third of the sensilla contacted contained ORNs that were unresponsive to any of the pheromone components tested. The remaining sensilla contained one ORN that responded either to the major pheromone component, Z8-12:Ac ("Z-cells", 63.7% of sensilla), or to its isomer E8-12:Ac ("E cells", 7.4% of sensilla). 31% of Z- and E-sensilla had 1 or 2 additional cells, but these did not respond to pheromone. None of the 176 sensilla contacted hosted ORNs that responded to Z8-12:OH. The proportion of Z- and E-cells on the antennae (100:11.6, respectively) is similar to the proportion of these compounds in the blend (100:6, respectively). The response of Z-cells was very specific, whereas E cells also responded to the Z isomer, albeit with lower sensitivity. PMID- 25450426 TI - Phenoloxidase and its zymogen are required for the larval-pupal transition in Bactrocera dorsalis (Diptera: Tephritidae). AB - Phenoloxidases (POs) play a key role in melanin production, are involved in invertebrate immune mechanisms, and are considered important enzymes in the insect development process. In the present study, we report the developmental stage and tissue-specific expression patterns of BdPPO1 and PO activity from Bactrocera dorsalis. The results showed that the activity of PO and its zymogen expression were closely related to the development of B. dorsalis during the larval-pupal transition, particularly in the integument. Additionally, biochemical characterization showed that PO from different developmental stages and tissues all had maximum activity at pH 7.5 and 37 degrees C. After feeding a metal ion-containing artificial diet, the activity of PO and expression of BdPPO1 were significantly increased, indicating that PO was a metalloprotein and it could be activated by Zn2+, Mg2+, Ca2+, and Cu2+. The functional analysis showed that the expression of BdPPO1 could be regulated by 20-hydroxyecdysone (20E) after injection. Furthermore, injection of the double-stranded RNA of BdPPO1 into the 3rd instar larvae significantly reduced mRNA levels after 24 h and 48 h, and resulted in a lower pupation rate and abnormal phenotype. These results expand the understanding of the important role of PO and its zymogen in the growth of B. dorsalis. PMID- 25450427 TI - Role of Phote-HrTH (Phormia terraenovae hypertrehalosemic hormone) in modulating the supercontractile muscles of the crop of adult Phormia regina Meigen. AB - Phote-HrTH (Phormia terraenovae hypertrehalosemic hormone) has been demonstrated in the Diptera to be involved in flight metabolism, reproduction, and diapause. Each of these events needs the hormone's action and requirement for carbohydrates is the common denominator. In Diptera, carbohydrates are taken up during feeding by action of the cibarial pump and are then stored in the crop. Using adult Phormia regina, both a bioassay and electrophysiological recordings show that Phote-HrTH slows down or inhibits the crop lobe muscles (P5) and, at the same time, stimulates the muscles of the pump 4 (P4) involved in pushing fluids out of the crop and up into the midgut for digestion. The EC50 for P4 was in the nanomolar range while the IC50 for P5 was 1.4-75.1 pM. The effect of Phote-HrTH on P4/5 suggests that the peptide is important in coordinating the two pumps, which are involved in moving carbohydrates up into the midgut for digestion. The adult crop organ is an essential storage organ for carbohydrates and now should be considered an important structure capable of delivering nutrients to the midgut for digestion. PMID- 25450428 TI - Transcriptome analysis of the salivary glands of Nephotettix cincticeps (Uhler). AB - The green rice leafhopper (GRH), Nephotettix cincticeps, is one of the most important pests of rice in temperate Asian countries. GRH, a vascular feeder, secretes watery and gelling saliva in the process of feeding on phloem and xylem sap. It is known that GRH saliva contains several bioactive proteins, including enzymes such as laccase and beta-glucosidase. In this study, we performed transcriptome analysis of salivary glands of GRH using Illumina paired-end sequencing. Of 51,788 assembled contigs, 16,017 (30.9%) showed significant similarity to known proteins in the NCBI nr database, while 34,978 (67.5%) could not be annotated by similarity search, Pfam, or gene ontology (GO). Contigs (905) with predicted signal peptides and no putative transmembrane domains are suggested to represent secreted protein coding genes. Among the 76 most highly expressed putative secretory protein contigs, 68 transcripts were found to be salivary gland-specific or at least -dominant, but not expressed in stomach or Malpighian tubules. However, 45 of the 68 transcripts were unknown proteins. These findings suggest that most of the GRH transcripts encoding secreted proteins expressed in salivary glands are species and/or tissue specific. Our results provide a fundamental list of genes involved in GRH-Poaceae host plant interactions including successful feeding and plant pathogen transmission. PMID- 25450430 TI - [Is digitalis currently useful for heart failure treatment?]. PMID- 25450429 TI - [Inhaled iloprost, a selective pulmonary vasodilator. Clinical evidence from its use in perioperative pulmonary hypertension cardiovascular surgery]. AB - Inhaled iloprost is one of the most recent drugs from prostanoids group's in the treatment of pulmonary arterial hypertension. His place in pulmonary hypertension seen in the perioperative cardiovascular surgery has not been defined. In this review we analyze pulmonary hypertension group's susceptibles of cardiac surgery and its importance, besides the current clinical evidence from drug use in this context. PMID- 25450431 TI - Effects of presenting risk information in different formats to cardiologists. A Latin American survey. AB - OBJECTIVE: Previous publications demonstrated that the presentation of treatment benefits in terms of relative risk reduction (RRR) rather than in terms of absolute risk reduction (ARR) or number of patients to treat (NNT) might favor the perception of outcome effectiveness. The objective was to perform a cognitive evaluation to assess how the manner in which risks and benefits of screening methods and treatments are presented can affect medical care decision-taking in a sample of cardiologists. METHODS: Four-hundred and six Latin American cardiologists answered a questionnaire reporting the results of clinical trials presented as RRR, ARR or NNT, associated or not to biased graphs. RESULTS: Cardiologists' decision-taking was different when comparing treatment benefits presented as RRR (62.2%) vs. ARR (40.4%) (p=0.000000), and as RRR vs. NNT (44.4%) (p=0.000000). However, their decision-taking was similar when information was presented as NNT or ARR (p=0.073). The inclusion of biased graphs was misinterpreted as an actual data difference (RRR: 61.6% vs. ARR: 14.0%, p=0.000000). CONCLUSIONS: This study demonstrated that Latin American cardiologists could misinterpret statistical data when information of clinical trials is presented in terms of RRR. We emphasize the need to enhance cardiologists' training in quantitative techniques, to improve medical care decision-making. PMID- 25450432 TI - [Ultrasound of gallbladder and bile duct]. AB - The cystic nature of the gallbladder and bile duct when dilated, and the advantages of ultrasound as a quick, reproducible, convenient, cheap and low risk technique, with a high sensitivity and specificity, make it the most eligible technique in biliary pathology studies. Ultrasound has become a valuable tool for doctors studying biliary pathology and its complications, from abnormal liver function results, right upper quadrant pain, or jaundice, to cholelithiasis, cholecystitis, or suspicion of biliary tumors. PMID- 25450433 TI - [Morel-Lavallee seroma: Presentation of a case]. PMID- 25450434 TI - [Non-traumatic acute groin pain in emergency departments: Hip arthritis in a young patient]. PMID- 25450436 TI - [Hyperhomocysteinemia in a multiple drug addicted patient held in a penitentiary center]. PMID- 25450435 TI - [Primary splenic cyst]. PMID- 25450437 TI - [Ecthyma]. PMID- 25450439 TI - Healthcare system supports for young adult patients with pediatric onset chronic conditions: a qualitative study. AB - Over 90% of children with chronic conditions survive into adulthood necessitating primary care teams to care for adults with pediatric-onset chronic conditions. This study explores practice supports and barriers to care for this population via qualitative techniques. Using in depth interviews with twenty-two healthcare providers practice supports identified include: formalizing intake processes, interoperable electronic medical records, and leveraging care coordination. Barriers identified included: definition of the medical team, lack of appropriate medical records, time and administrative burden, lack of training, and financial constraints. Themes may be utilized to design interventions and improve care coordination for patients with pediatric-onset chronic conditions. PMID- 25450438 TI - [Spanish interdisciplinary committee for cardiovascular disease prevention and the spanish society of cardiology position statement on dyslipidemia management. Differences between the European and american guidelines]. AB - The publication of the 2013 American College of Cardiology/American Heart Association guidelines on the treatment of high blood cholesterol has had a strong impact due to the paradigm shift in its recommendations. The Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention and the Spanish Society of Cardiology reviewed this guideline and compared it with current European guidelines on cardiovascular prevention and dyslipidemia management. The most striking aspect of the American guideline is the elimination of the low density lipoprotein cholesterol treat-to-target strategy and the adoption of a risk reduction strategy in 4 major statin benefit groups. In patients with established cardiovascular disease, both guidelines recommend a similar therapeutic strategy (high-dose potent statins). However, in primary prevention, the application of the American guidelines would substantially increase the number of persons, particularly older people, receiving statin therapy. The elimination of the cholesterol treat-to-target strategy, so strongly rooted in the scientific community, could have a negative impact on clinical practice, create a certain amount of confusion and uncertainty among professionals, and decrease follow-up and patient adherence. Thus, this article reaffirms the recommendations of the European guidelines. Although both guidelines have positive aspects, doubt remains regarding the concerns outlined above. In addition to using risk charts based on the native population, the messages of the European guideline are more appropriate to the Spanish setting and avoid the possible risk of overtreatment with statins in primary prevention. PMID- 25450440 TI - Striving to live a normal life: a review of children and young people's experience of feeling different when living with a long term condition. AB - This paper presents a review of findings from qualitative studies on children's experience of feeling different when living with the long term conditions; diabetes, epilepsy and asthma. Following electronic database and hand searches of reference lists of identified papers, eighteen studies were selected for inclusion in the review. These studies revealed three common themes; participation in everyday life-restrictions and adjustments; treatment regimens constraining and enabling; and communication-disclosure, stigma and support. Across these themes it was evident that children felt different physically and socially and they grappled constantly with balancing the dilemma of feeling and acting normal or feeling, being and revealing difference. PMID- 25450442 TI - Individualizing hospital care for children and young people with learning disabilities: it's the little things that make the difference. AB - This ethnographic study sought parent, patient and staff views about the needs of children and young people with learning disability and their families during hospitalization. Reported here are data from 27 staff. The need for individualized care was identified, based on gaining appropriate experience and training, identifying the population, focussing on the "little things", creating a safe, familiar environment and accessing and using appropriate resources. Parents played a central role in staff's delivery of individualized care. A lack of staff experience, knowledge and communication about learning disability can mean they rely on parent's input rather than forming a true partnership with them. PMID- 25450441 TI - What impact do hospital and unit-based rules have upon patient and family centered care in the pediatric intensive care unit? AB - Patient and family-centered care (PFCC) is the foundation for pediatric healthcare. The existence of hospital rules can, however, impact the extent to which PFCC is delivered. This qualitative, grounded theory study identified the existence of explicit and implicit rules in a pediatric intensive care unit, all of which negatively affected the family's ability to receive care that was attentive to their needs. The rules also placed the registered nurse in the challenging position of serving as rule enforcer and facilitator of PFCC. Further work is needed to explore how to adapt the hospital environment to better meet families' needs. PMID- 25450443 TI - Parental use of online physician rating sites. PMID- 25450444 TI - Become the PPUPET Master: Mastering Pressure Ulcer Risk Assessment With the Pediatric Pressure Ulcer Prediction and Evaluation Tool (PPUPET). AB - Hospital acquired pressure ulcers (HAPU) are serious, debilitating, and preventable complications in all inpatient populations. Despite evidence of the development of pressure ulcers in the pediatric population, minimal research has been done. Based on observations gathered during quarterly HAPU audits, bedside nursing staff recognized trends in pressure ulcer locations that were not captured using current pressure ulcer risk assessment tools. Together, bedside nurses and nursing leadership created and conducted multiple research studies to investigate the validity and reliability of the Pediatric Pressure Ulcer Prediction and Evaluation Tool (PPUPET). PMID- 25450445 TI - An on-the-job mindfulness-based intervention for pediatric ICU nurses: a pilot. AB - The feasibility of a 5-minute mindfulness meditation for PICU nurses before each work-shift to investigate change in nursing stress, burnout, self-compassion, mindfulness, and job satisfaction was explored. Thirty-eight nurses completed measures (Nursing Stress Scale, Maslach Burnout Inventory, Mindfulness Attention Awareness Scale and Self-Compassion Scale) at baseline, post-intervention and 1 month after. The intervention was found to be feasible for nurses on the PICU. A repeated measures ANOVA revealed significant decreases in stress from baseline to post intervention and maintained 1 month following the intervention. Findings may inform future interventions that support on-the-job self-care and stress reduction within a critical care setting. PMID- 25450448 TI - Phospholipase A2 regulation of lipid droplet formation. AB - The classical regard of lipid droplets as mere static energy-storage organelles has evolved dramatically. Nowadays these organelles are known to participate in key processes of cell homeostasis, and their abnormal regulation is linked to several disorders including metabolic diseases (diabetes, obesity, atherosclerosis or hepatic steatosis), inflammatory responses in leukocytes, cancer development and neurodegenerative diseases. Hence, the importance of unraveling the cell mechanisms controlling lipid droplet biosynthesis, homeostasis and degradation seems evident Phospholipase A2s, a family of enzymes whose common feature is to hydrolyze the fatty acid present at the sn-2 position of phospholipids, play pivotal roles in cell signaling and inflammation. These enzymes have recently emerged as key regulators of lipid droplet homeostasis, regulating their formation at different levels. This review summarizes recent results on the roles that various phospholipase A2 forms play in the regulation of lipid droplet biogenesis under different conditions. These roles expand the already wide range of functions that these enzymes play in cell physiology and pathophysiology. PMID- 25450446 TI - Identifying factors related to family management during the coping process of families with childhood chronic conditions: a multi-site study. AB - This study was designed to determine the key predictors for each aspect of family management of families with children who have chronic conditions in China. The participants included 399 caregivers whose children have chronic illnesses. We used the following instruments: Child Behavior Checklist; Feetham Family Functioning Survey; and Family Management Measures. The final modes of the hierarchical regression explained 29-48% of the variance in aspects of family management. More family support should be provided for those with low family income, children with renal and genetic disorders and rheumatic diseases and those living in rural areas. Child and family functioning affects family management. PMID- 25450447 TI - n-3 fatty acids effectively improve the reference memory-related learning ability associated with increased brain docosahexaenoic acid-derived docosanoids in aged rats. AB - We investigated whether a highly purified eicosapentaenoic acid (EPA) and a concentrated n-3 fatty acid formulation (prescription TAK-085) containing EPA and docosahexaenoic acid (DHA) ethyl ester could improve the learning ability of aged rats and whether this specific outcome had any relation with the brain levels of EPA-derived eicosanoids and DHA-derived docosanoids. The rats were tested for reference memory errors (RMEs) and working memory errors (WMEs) in an eight-arm radial maze. Fatty acid compositions were analyzed by GC, whereas brain eicosanoid/docosanoids were measured by LC-ESI-MS-MS-based analysis. The levels of lipid peroxides (LPOs) were measured by thiobarbituric acid reactive substances. The administration of TAK-085 at 300 mg.kg-1day-1 for 17 weeks reduced the number of RMEs in aged rats compared with that in the control rats. Both TAK-085 and EPA administration increased plasma EPA and DHA levels in aged rats, with concurrent increases in DHA and decreases in arachidonic acid in the corticohippocampal brain tissues. TAK-085 administration significantly increased the formation of EPA-derived 5-HETE and DHA-derived 7-, 10-, and 17-HDoHE, PD1, RvD1, and RvD2. ARA-derived PGE2, PGD2, and PGF2alpha significantly decreased in TAK-085-treated rats. DHA-derived mediators demonstrated a significantly negative correlation with the number of RMEs, whereas EPA-derived mediators did not exhibit any relationship. Furthermore, compared with the control rats, the levels of LPO in the plasma, cerebral cortex, and hippocampus were significantly reduced in TAK-085-treated rats. The findings of the present study suggest that long-term EPA+DHA administration may be a possible preventative strategy against age related cognitive decline. PMID- 25450449 TI - Constructing a synthetic metabolic pathway in Escherichia coli to produce the enantiomerically pure (R, R)-2,3-butanediol. AB - Enantiomerically pure (R, R)-2,3-butanediol has unique applications due to its special chiral group and spatial configuration. Currently, its chemical production route has many limitations. In addition, no native microorganisms can accumulate (R, R)-2,3-butanediol with an enantio-purity over 99%. Herein, we constructed a synthetic metabolic pathway for enantiomerically pure (R, R)-2,3 butanediol biosynthesis in Escherichia coli. The fermentation results suggested that introduction of the synthetic metabolic pathway redistributed the carbon fluxes to the neutral (R, R)-2,3-butanediol, and thus protected the strain against the acetic acid inhibition. Additionally, it showed that the traditionally used isopropyl beta-D-thiogalactoside (IPTG) induction displayed negative effect on (R, R)-2,3-butanediol biosynthesis in the recombinant E. coli, which was probably due to the protein burden. With no IPTG addition, the (R, R) 2,3-butanediol concentration reached 115 g/L by fed-batch culturing of the recombinant E. coli, with an enantio-purity over 99%, which is suitable for the pilot-scale production. PMID- 25450450 TI - Unconditional and conditional incentives differentially improved general practitioners' participation in an online survey: randomized controlled trial. AB - OBJECTIVES: To compare the impact of unconditional and conditional financial incentives on response rates among Australian general practitioners invited by mail to participate in an online survey about cancer care and to investigate possible differential response bias between incentive groups. STUDY DESIGN AND SETTING: Australian general practitioners were randomly allocated to unconditional incentive (book voucher mailed with letter of invitation), conditional incentive (book voucher mailed on completion of the online survey), or control (no incentive). Nonresponders were asked to complete a small subset of questions from the online survey. RESULTS: Among 3,334 eligible general practitioners, significantly higher response rates were achieved in the unconditional group (167 of 1,101, 15%) compared with the conditional group (118 of 1,111, 11%) (P = 0.0014), and both were significantly higher than the control group (74 of 1,122, 7%; both P < 0.001). Although more positive opinions about cancer care were expressed by online responders compared with nonresponders, there was no evidence that the magnitude of difference varied by the incentive group. The incremental cost for each additional 1% increase above the control group response rate was substantially higher for the unconditional incentive group compared with the conditional incentive group. CONCLUSION: Both unconditional and conditional financial incentives significantly increased response with no evidence of differential response bias. Although unconditional incentives had the largest effect, the conditional approach was more cost effective. PMID- 25450451 TI - Comparison of noninferiority margins reported in protocols and publications showed incomplete and inconsistent reporting. AB - OBJECTIVES: To compare noninferiority margins defined in study protocols and trial registry records with margins reported in subsequent publications. STUDY DESIGN AND SETTING: Comparison of protocols of noninferiority trials submitted 2001 to 2005 to ethics committees in Switzerland and The Netherlands with corresponding publications and registry records. We searched MEDLINE via PubMed, the Cochrane Controlled Trials Register (Cochrane Library issue 01/2012), and Google Scholar in September 2013 to identify published reports, and the International Clinical Trials Registry Platform of the World Health Organization in March 2013 to identify registry records. Two readers recorded the noninferiority margin and other data using a standardized data-abstraction form. RESULTS: The margin was identical in study protocol and publication in 43 (80%) of 54 pairs of study protocols and articles. In the remaining pairs, reporting was inconsistent (five pairs, 9%), or the noninferiority margin was either not reported in the publication (five pairs, 9%) or not defined in the study protocol (one pair). The confidence interval or the exact P-value required to judge whether the result was compatible with noninferior, inferior, or superior efficacy was reported in 43 (80%) publications. Complete and consistent reporting of both noninferiority margin and confidence interval (or exact P-value) was present in 39 (72%) protocol-publication pairs. Twenty-nine trials (54%) were registered in trial registries, but only one registry record included the noninferiority margin. CONCLUSION: The reporting of noninferiority margins was incomplete and inconsistent with study protocols in a substantial proportion of published trials, and margins were rarely reported in trial registries. PMID- 25450452 TI - Citations alone were enough to predict favorable conclusions in reviews of neuraminidase inhibitors. AB - OBJECTIVES: To examine the use of supervised machine learning to identify biases in evidence selection and determine if citation information can predict favorable conclusions in reviews about neuraminidase inhibitors. STUDY DESIGN AND SETTING: Reviews of neuraminidase inhibitors published during January 2005 to May 2013 were identified by searching PubMed. In a blinded evaluation, the reviews were classified as favorable if investigators agreed that they supported the use of neuraminidase inhibitors for prophylaxis or treatment of influenza. Reference lists were used to identify all unique citations to primary articles. Three classification methods were tested for their ability to predict favorable conclusions using only citation information. RESULTS: Citations to 4,574 articles were identified in 152 reviews of neuraminidase inhibitors, and 93 (61%) of these reviews were graded as favorable. Primary articles describing drug resistance were among the citations that were underrepresented in favorable reviews. The most accurate classifier predicted favorable conclusions with 96.2% accuracy, using citations to only 24 of 4,574 articles. CONCLUSION: Favorable conclusions in reviews about neuraminidase inhibitors can be predicted using only information about the articles they cite. The approach highlights how evidence exclusion shapes conclusions in reviews and provides a method to evaluate citation practices in a corpus of reviews. PMID- 25450453 TI - Does manipulating the speed of visual flow in virtual reality change distance estimation while walking in Parkinson's disease? AB - Although dopaminergic replacement therapy is believed to improve sensory processing in PD, while delayed perceptual speed is thought to be caused by a predominantly cholinergic deficit, it is unclear whether sensory-perceptual deficits are a result of corrupt sensory processing, or a delay in updating perceived feedback during movement. The current study aimed to examine these two hypotheses by manipulating visual flow speed and dopaminergic medication to examine which influenced distance estimation in PD. Fourteen PD and sixteen HC participants were instructed to estimate the distance of a remembered target by walking to the position the target formerly occupied. This task was completed in virtual reality in order to manipulate the visual flow (VF) speed in real time. Three conditions were carried out: (1) BASELINE: VF speed was equal to participants' real-time movement speed; (2) SLOW: VF speed was reduced by 50 %; (2) FAST: VF speed was increased by 30 %. Individuals with PD performed the experiment in their ON and OFF state. PD demonstrated significantly greater judgement error during BASELINE and FAST conditions compared to HC, although PD did not improve their judgement error during the SLOW condition. Additionally, PD had greater variable error during baseline compared to HC; however, during the SLOW conditions, PD had significantly less variable error compared to baseline and similar variable error to HC participants. Overall, dopaminergic medication did not significantly influence judgement error. Therefore, these results suggest that corrupt processing of sensory information is the main contributor to sensory perceptual deficits during movement in PD rather than delayed updating of sensory feedback. PMID- 25450454 TI - Recombinant goldfish thrombopoietin up-regulates expression of genes involved in thrombocyte development and synergizes with kit ligand A to promote progenitor cell proliferation and colony formation. AB - Thrombopoietin (TPO) is the principal regulator of thrombopoiesis and promotes the proliferation, differentiation and maturation of megakaryocytic progenitor cells in mammals. In this study we report on the molecular and functional characterization of goldfish TPO. Quantitative expression analysis of goldfish tpo revealed the highest mRNA levels in heart, followed by spleen, liver, brain, intestine and kidney tissues. Significant decrease of tpo and c-mpl expressions in goldfish primary kidney macrophage (PKM) cultures, as progenitor to macrophage development progressed, indicates that TPO is not involved in monopoiesis. Recombinant goldfish TPO (rgTPO) alone did not induce significant proliferation of progenitor cells, but TPO in cooperation with recombinant goldfish kit ligand A (rgKITLA) supported proliferation of progenitor cells in a dose-dependent manner. In response to rgTPO or a combination of rgTPO and rgKITLA, the mRNA levels of thrombopoietic markers cd41 and c-mpl as well as thrombo/erythropoietic transcription factors gata1 and lmo2 in sorted progenitor cells were up regulated, while the mRNA levels of granulopoietic markers (cebpalpha and gcsfr) and the lymphoid transcription factor gata3 were down-regulated. Furthermore, rgTPO and rgKITLA synergistically stimulated thrombocytic colony-formation. Our results demonstrate that goldfish TPO has similar functions to mammalian TPO as a regulator of thrombopoiesis, and suggests a highly conserved molecular mechanism of thrombocyte development throughout evolution of vertebrates. PMID- 25450455 TI - Extracellular matrix considerations for scar-free repair and regeneration: insights from regenerative diversity among vertebrates. AB - The extracellular matrix (ECM) is an essential feature of development, tissue homeostasis and recovery from injury. How the ECM responds dynamically to cellular and soluble components to support the faithful repair of damaged tissues in some animals but leads to the formation of acellular fibrotic scar tissue in others has important clinical implications. Studies in highly regenerative organisms such as the zebrafish and the salamander have revealed a specialist formulation of ECM components that support repair and regeneration, while avoiding scar tissue formation. By comparing a range of different contexts that feature scar-less healing and full regeneration vs. scarring through fibrotic repair, regenerative therapies that incorporate ECM components could be significantly enhanced to improve both regenerative potential and functional outcomes. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation. PMID- 25450456 TI - Harnessing the potential of lung stem cells for regenerative medicine. AB - In response to recurrent exposure to environmental insults such as allergens, pollution, irritants, smoke and viral/bacterial infection, the epithelium of the lung is continually damaged. Homeostasis of the lung requires a balance between immune regulation and promotion of tissue regeneration, which requires the co ordinated proliferation and differentiation of stem and progenitor cells. In this review we reflect on the current understanding of lung epithelial stem and progenitor cells and advocate a model hierarchy in which self-renewing multipotent lung epithelial stem cells give rise to lineage restricted progenitor cells that repopulate airway and alveolar epithelial cell lineages during homeostasis and repair. We also discuss the role of mesenchymal progenitor cells in maintaining the structural integrity of the lung and propose a model in which mesenchymal cells act as the quintessential architects of lung regeneration by providing molecular signals, such as FGF-10, to regulate the fate and specificity of epithelial stem and progenitor cells. Moreover, we discuss the current status and future prospects for translating lung stem cell therapies to the clinic to replace, repair, or regenerate diseased lung tissue. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation. PMID- 25450457 TI - Glioma cell-derived placental growth factor induces regulatory B cells. AB - Tumor specific immune regulatory cells play an important role in the pathogenesis of glioma. The mechanisms have not been fully understood yet. It is suggested that placenta growth factor (PlGF) is involved in the generation of immune regulatory cells. This study aims to investigate the role of glioma cell-derived PlGF in the generation of regulatory B cells (Breg). Glioma cells were isolated from surgically removed glioma tissue. Cytokines were measured by enzyme-linked immunosorbent assay, quantitative real time RT-PCR and Western blotting. Immune suppressor functions of Bregs were assessed by T cell proliferation assay. The results showed that glioma cells expressed PlGF, which was increased after a non specific activation. Naive B cells captured the PlGF to differentiate into transforming growth factor-beta positive Bregs. The Bregs were activated upon exposure to protein extracts of glioma tissue to suppress the CD8(+) T cell proliferation and the release of perforin and granzyme B. We conclude that glioma cell-released PlGF can induce Bregs to suppress CD8(+) T cell activities. PMID- 25450458 TI - A splice variant of the human phosphohistidine phosphatase 1 (PHPT1) is degraded by the proteasome. AB - Regulation of protein activity by phosphorylation is central in many cellular processes. Phosphorylation of serine, threonine and tyrosine residues is well documented and studied. In addition, other amino acids, like histidine can be phosphorylated, but neither the mechanism nor the function of this modification is well understood. Nevertheless, there is a 14 kDa enzyme with phosphohistidine phosphatase activity, named PHPT1, found in most animals, but not in bacteria, plant or fungi. There are a few splice variant transcripts formed from the human PHPT1 locus and some of them are predicted to form variant proteins, but studies of these proteins are lacking. In order to get insight into the possible function of the variant transcripts encoded at the PHPT1 locus, ectopic expression of PHPT1 transcript variant 6, predicted to be degraded by the non-sense mediated mRNA decay pathway, in HeLa cells was undertaken. In HeLa cells the splice variant protein was degraded by the proteasome, unlike the wild type protein. Using an in silico modeling approach the variant C-terminal end of the proteins were predicted to form different secondary structures that might explain the different properties of the two proteins. The specific degradation of the PHPT1 splice variant indicates that at least for the PHPT1 protein, the quality control and the self-guarding of the cellular system works at two levels, first at the RNA level, aberrant transcripts are degraded by the non-sense mediated mRNA decay pathway, and the small amount of proteins that are formed will be degraded by the proteasome. PMID- 25450459 TI - Crosstalk between HSF1 and HSF2 during the heat shock response in mouse testes. AB - Heat Shock Factor 1 (HSF1) is the primary transcription factor responsible for the response to cellular stress, while HSF2 becomes activated during development and differentiation, including spermatogenesis. Although both factors are indispensable for proper spermatogenesis, activation of HSF1 by heat shock initiates apoptosis of spermatogenic cells leading to infertility of males. To characterize mechanisms assisting such heat induced apoptosis we studied how HSF1 and HSF2 cooperate during the heat shock response. For this purpose we used chromatin immunoprecipitation and the proximity ligation approaches. We looked for co-occupation of binding sites by HSF1 and HSF2 in untreated (32 degrees C) or heat shocked (at 38 degrees C or 43 degrees C) spermatocytes, which are cells the most sensitive to hyperthermia. At the physiological temperature or after mild hyperthermia at 38 degrees C, the sharing of binding sites for both HSFs was observed mainly in promoters of Hsp genes and other stress-related genes. Strong hyperthermia at 43 degrees C resulted in an increased binding of HSF1 and releasing of HSF2, hence co-occupation of promoter regions was not detected any more. The close proximity of HSF1 and HSF2 (and/or existence of HSF1/HSF2 complexes) was frequent at the physiological temperature. Temperature elevation resulted in a decreased number of such complexes and they were barely detected after strong hyperthermia at 43 degrees C. We have concluded that at the physiological temperature HSF1 and HSF2 cooperate in spermatogenic cells. However, temperature elevation causes remodeling of chromatin binding and interactions between HSFs are disrupted. This potentially affects the regulation of stress response and contributes to the heat sensitivity of these cells. PMID- 25450460 TI - The second-sphere residue T263 is important for the function and catalytic activity of PTP1B via interaction with the WPD-loop. AB - Protein tyrosine phosphatases have diverse substrate specificities and intrinsic activities that lay the foundations for the fine-tuning of a phosphorylation network to precisely regulate cellular signal transduction. All classical PTPs share common catalytic mechanisms, and the important catalytic residues in the first sphere of their active sites have been well characterized. However, little attention has been paid to the second-sphere residues that are potentially important in defining the intrinsic activity and substrate specificity of PTPs. Here, we find that a conserved second-sphere residue, Thr263, located in the surface Q-loop is important for both the function and activity of PTPs. Using PTP1B as a study model, we found that mutations of Thr263 impaired the negative regulation role of PTP1B in insulin signaling. A detailed mechanistic study utilizing steady-state kinetics, Bronsted analysis and pH dependence in the presence of pNPP or phosphopeptide substrates revealed that Thr263 is required for the stabilization of the leaving group during catalysis. Further crystallographic studies and structural comparison revealed that Thr263 regulates the general acid function through modulation of the WPD-loop by the T263:F182/Y/H interaction pair, which is conserved in 26 out of 32 classical PTPs. In addition, the hydrophobic interaction between Thr263 and Arg1159 of the insulin receptor contributes to the substrate specificity of PTP1B. Taken together, our findings demonstrate the general role of the second-sphere residue Thr263 in PTP catalysis. Our findings suggest that the second sphere residues of PTP active site may play important roles in PTP-mediated function in both normal and diseased states. PMID- 25450461 TI - The AQP-3 water channel and the ClC-3 chloride channel coordinate the hypotonicity-induced swelling volume in nasopharyngeal carcinoma cells. AB - Cell volume regulation is a fundamental activity to maintain cell survival, and aquaporins and chloride channels play important roles in this process. However, the interactions between these channels are far from clear. In this study, the interactions between AQP-3 and ClC-3 were investigated in CNE-1 and CNE-2Z nasopharyngeal carcinoma cells, which are well and poorly differentiated, respectively. The correlation coefficient of AQP-3 and ClC-3 protein phylogenetic trees was 0.319. In CNE-1 cells, there are overlapping distributions of AQP-3 and ClC-3, mainly in the plasma membrane. This was confirmed by the co immunoprecipitation of AQP-3 and ClC-3, showing that they could be interlinked and form complexes. AQP-3 over-expression had no significant effects on swelling induced Cl(-) currents (ICl,swell); however, ICl,swell could be inhibited by aquaporin blockers, anti-AQP-3 antibodies and AQP-3-siRNAs. In addition, the AQP 3 expression was decreased by down-regulation of ClC-3 expression, indicating that ClC-3 can modulate the expression of AQP-3 proteins. The effects of aquaporin blockers, anti-AQP-3 antibodies and AQP-3 over-expression on ICl,swell in CNE-2Z cells were consistent with those in CNE-1 cells. In conclusion, AQP-3 and ClC-3 are functionally-related integral membrane channel proteins, and their interactions are involved in cell volume regulation in CNE-1 and CNE-2Z cells. The opening of ClC-3 transports Cl(-) across the cell membrane and then drives the efflux of water through AQP-3 channels and ion channels; AQP-3 may interact with ClC-3 in order to regulate the effluxes of chloride and water. PMID- 25450462 TI - Power frequency magnetic fields induced reactive oxygen species-related autophagy in mouse embryonic fibroblasts. AB - Power frequency magnetic fields (PFMF) have been reported to affect several cellular functions, such as cell proliferation and apoptosis. In this study, we investigated the effects of PFMF on mouse embryonic fibroblasts (MEF) autophagy. After cells were exposed to 50 Hz PFMF at 2 mT for 0.5 h, 2 h, 6 h, 12 h, and 24 h, we observed a significant increase in autophagic markers at 6 h, including (i) higher microtubule-associated protein 1 light chain 3-II (LC3-II), (ii) the increased formation of GFP-LC3 puncta, and (iii) increased numbers of autophagic vacuoles under transmission electron microscope. Moreover, we provide convincing evidence using chloroquine (CQ) that the increase of autophagic markers was the result of enhanced autophagic flux and not the suppression of lysosomal function. In a search for molecular mechanisms underlying PFMF-mediated autophagy, we observe that the autophagic process involved reactive oxygen species (ROS) and was independent of the mammalian target of rapamycin (mTOR) signaling pathway. PMID- 25450463 TI - S100A6 expression in keratinocytes and its impact on epidermal differentiation. AB - S100A6 is a calcium binding protein expressed in many types of epithelia including epidermis. S100A6 is a binding partner of a number of proteins engaged in cytoskeletal organization, cell cycle control, stress response or apoptosis. So far the effect of its overexpression or knock-down on cell physiology has been studied only at the cellular level. Here, we used an in vitro model of differentiating epidermis to study the role of S100A6 at the tissue level and in the context of tissue differentiation. First of all we have shown that S100A6 mRNA level diminished several fold during primary keratinocyte differentiation and investigated the epigenetic and transcriptional mechanisms involved in this tight expression control. Using bisulfite treatment, luciferase assay and chromatin immunoprecipitation we found that changes in S100A6 expression were DNA methylation independent but could be orchestrated by epidermal specific factors: the DeltaNp63 transcription factor and retinoic acid. To investigate if the drop down in S100A6 expression is indeed critical for keratinocyte differentiation we developed HaCaT cells with stable S100A6 knock-down or overexpression and tested them in 2- and 3-dimensional (organotypic) culture conditions. S100A6 overexpressing cells exhibited accelerated proliferation, enhanced adhesion properties and suppressed loricrin expression - features typical for undifferentiated keratinocytes. In organotypic culture these cells formed thicker epidermis with more Ki67 positive cells, keratin 10 expression spatially limited to the uppermost cell layers and non-detectable loricrin expression. Together, results obtained in both culture models proved that increased S100A6 content in keratinocytes dramatically changed the pace and extent of epidermal differentiation. PMID- 25450464 TI - Transient receptor potential vanilloid 1 is expressed in human cytotrophoblasts: induction of cell apoptosis and impairment of syncytialization. AB - The normal development of placenta relies essentially on a balanced proliferation, differentiation and apoptosis of cytotrophoblasts. These processes are tightly regulated by several hormones, cytokines, lipids and other molecules and anomalies in these events are associated with gestational complications. The cation channel transient receptor potential vanilloid 1 (TRPV1) is expressed in several organs and tissues and it participates in cellular events like nociception, inflammation and cell death. However, the expression and importance of this receptor in human placenta still remains unknown. In this work, we found that TRPV1 is expressed in human cytotrophoblasts and syncytiotrophoblasts. Furthermore, the TRPV1 agonists capsaicin and anandamide decreased cytotrophoblast viability and induced morphological alterations, such as chromatin condensation and fragmentation, which suggest the occurrence of apoptosis. Also, both TRPV1 agonists induced a loss of mitochondrial membrane potential and an increase of caspase 3/7 activity and production of reactive species of oxygen and nitrogen. Furthermore, capsaicin (10 MUM) impaired the spontaneous in vitro differentiation of cytotrophoblasts into syncytiotrophoblasts by triggering TRPV1, as observed by the decrease in placental alkaline phosphatase activity and in human chorionic gonadotropin secretion. On the other hand, anandamide decreased placental alkaline phosphatase activity via a TRPV1-independent mechanism but did not influence the secretion of human chorionic gonadotropin. In conclusion, we showed that TRPV1 is expressed in human cytotrophoblasts and syncytiotrophoblasts and also reported the involvement of this receptor in cytotrophoblast apoptosis and differentiation. PMID- 25450465 TI - WASP-1, a canonical Wnt signaling potentiator, rescues hippocampal synaptic impairments induced by Abeta oligomers. AB - Amyloid-beta (Abeta) oligomers are a key factor in Alzheimer's disease (AD) associated synaptic dysfunction. Abeta oligomers block the induction of hippocampal long-term potentiation (LTP) in rodents. The activation of Wnt signaling prevents Abeta oligomer-induced neurotoxic effects. The compound WASP-1 (Wnt-activating small molecule potentiator-1), has been described as a synergist of the ligand Wnt-3a, enhancing the activation of Wnt/beta-catenin signaling. Herein, we report that WASP-1 administration successfully rescued Abeta-induced synaptic impairments both in vitro and in vivo. The activation of canonical Wnt/beta-catenin signaling by WASP-1 increased synaptic transmission and rescued hippocampal LTP impairments induced by Abeta oligomers. Additionally, intra hippocampal administration of WASP-1 to the double transgenic APPswe/PS1dE9 mouse model of AD prevented synaptic protein loss and reduced tau phosphorylation levels. Moreover, we found that WASP-1 blocked Abeta aggregation in vitro and reduced pathological tau phosphorylation in vivo. These results indicate that targeting canonical Wnt signaling with WASP-1 could have value for treating AD. PMID- 25450466 TI - Behavioural deficits in transgenic mice expressing human truncated (1-120 amino acid) alpha-synuclein. AB - Accumulation and aggregation of alpha-synuclein in cortical and hippocampal areas is a pathological sign for dementia with Lewy bodies (DLB) and Parkinson's disease with dementia. However the mechanisms of alpha-synuclein triggered cellular dysfunction leading to the development of memory impairment is not clear. We have created a mouse model of DLB, where aggregation-prone human truncated (120 amino acid) alpha-synuclein is expressed in forebrain areas under the calcium/calmodulin-dependent protein kinase II alpha (CamKII-alpha) promoter. We have observed the presence of the transgenic protein in target forebrain areas, with small granular cytoplasmic accumulation of aggregated alpha synuclein. This was associated with a progressive deficit in cortical-hippocampal memory tests including the Barnes maze and novel object recognition. This data suggests that low levels of aggregation prone alpha-synuclein are sufficient to induce memory deficits in mice and that forebrain regions associated with cognitive function may have an increased sensitivity to the truncated toxic form of alpha-synuclein. PMID- 25450467 TI - Chemotherapy-induced peripheral neurotoxicity in immune-deficient mice: new useful ready-to-use animal models. AB - Cisplatin, paclitaxel and bortezomib are effective chemotherapy drugs in cancer treatment. However, they share severe peripheral neurotoxicity (PN) as one of their major dose-limiting side effects, often impairing cancer patients' quality of life and sometimes being permanent. Even if preclinical oncology is largely based on the use of immune-deficient mice, rodent models used to study the chemotherapy-induced PN are available only in immune-competent animals. In this study we characterized for the first time the PN induced by these chemotherapies through neurophysiological, behavioral, morphological and morphometric studies in athymic nude mice, a commonly employed strain in the preclinical oncology. The animals, divided into four groups, were chronically treated with cisplatin, paclitaxel or bortezomib once or twice a week for 4 or 6 weeks or were left untreated. These schedules were tolerated, neurotoxic and in the range of antineoplastic effectiveness. Despite similarities, differences in the features of PN were evident if compared with immune-competent models under comparable regimens of treatment. The results of this study may provide a basis for future combined analysis of antineoplastic and neurotoxic effects of chemotherapy in the same animals. PMID- 25450468 TI - Repetitive mild traumatic brain injury with impact acceleration in the mouse: Multifocal axonopathy, neuroinflammation, and neurodegeneration in the visual system. AB - Repetitive mild traumatic brain injury (mTBI) is implicated in chronic neurological illness. The development of animal models of repetitive mTBI in mice is essential for exploring mechanisms of these chronic diseases, including genetic vulnerability by using transgenic backgrounds. In this study, the rat model of impact acceleration (IA) was redesigned for the mouse cranium and used in two clinically relevant repetitive mTBI paradigms. We first determined, by using increments of weight dropped from 1m that the 40g weight was most representative of mTBI and was not associated with fractures, brain contusions, anoxic-ischemic injury, mortality, or significant neurological impairments. Quantitative evaluation of traumatic axonal injury (TAI) in the optic nerve/tract, cerebellum and corpus callosum confirmed that weight increase produced a graded injury. We next evaluated two novel repetitive mTBI paradigms (1 time per day or 3 times per day at days 0, 1, 3, and 7) and compared the resulting TAI, neuronal cell death, and neuroinflammation to single hit mTBI at sub-acute (7days) and chronic time points (10weeks) post-injury. Both single and repetitive mTBI caused TAI in the optic nerve/tract, cerebellum, corticospinal tract, lateral lemniscus and corpus callosum. Reactive microglia with phagocytic phenotypes were present at injury sites. Severity of axonal injury corresponded to impact load and frequency in the optic nerve/tract and cerebellum. Both single and repeat injury protocols were associated with retinal ganglion cell loss and optic nerve degeneration; these outcomes correlated with impact load and number/frequency. No phosphorylated tau immunoreactivity was detected in the brains of animals subjected to repetitive mTBI. Our findings establish a new model of repetitive mTBI model featured by TAI in discrete CNS tracts, especially the visual system and cerebellum. Injury in retina and optic nerve provides a sensitive measure of severity of mTBI, thus enabling further studies on mechanisms and experimental therapeutics. Our model can also be useful in exploring mechanisms of chronic neurological disease caused by repetitive mTBI in wild-type and transgenic mice. PMID- 25450469 TI - Acquired and genetic channelopathies: in vivo assessment of axonal excitability. AB - Neuronal or axonal ion channel function can be impaired or altered in a number of disorders, such as acquired (autoantibody-mediated, toxic, and metabolic) and genetic channelopathies, and even neurodegenerative (motor neuron disease) or inflammatory diseases (multiple sclerosis, immune-mediated neuropathies). When specific channels are affected, axonal/neuronal excitability primarily alters according to original function of the corresponding channels. Separately, in the 1990s, axonal excitability testing was developed to assess ion channel function, membrane potential, and passive membrane properties non-invasively in human subjects. Using this technique, numerous papers on altered axonal excitability in a variety of disorders have been published since 2000. In a recent issue of Experimental Neurology, Park et al. demonstrated changes in peripheral axonal excitability in limbic encephalitis and acquired neuromyotonia with anti-voltage gated potassium channel antibodies. Unexpectedly, the results were not consistent with those caused by simple potassium channel blockade, suggesting that multiple other factors contribute to altered axonal excitability. In contrast it was reported that patients with episodic ataxia type 1 (genetic channelopathy with mutation of Kv1.1 channel gene) show prominent excitability changes exactly compatible with fast potassium channel blockade. This commentary aims to highlight findings of this study in a broader context, and provides possible explanations for the discrepancy of patterns of axonal excitability changes in acquired and genetic potassium channelopathies. PMID- 25450470 TI - Tolerability and pharmacokinetics of two formulations of megestrol acetate under fed conditions in healthy volunteers. AB - PURPOSE: Megestrol acetate oral suspension is an appetite stimulant indicated for cachexia. It is available in a conventional formulation and as a nanocrystal dispersion. The aim of this study was to compare the tolerability and pharmacokinetics of these formulations under fed conditions in healthy Korean volunteers. METHODS: This was a randomized, single-dose, 3-treatment, 3-period, 6 sequence, crossover study in healthy Korean volunteers. In each period, participants received single oral doses of conventional formulation 800 mg/20 mL (reference), nanocrystal dispersion 650 mg/5.2 mL (test 1), and nanocrystal dispersion 675 mg/5.4 mL (test 2) after a high-calorie, high-fat meal. The periods were separated by a washout period of 14 days. Serial blood samples were collected up to 120 hours after dosing. The plasma concentrations of megestrol acetate were determined with a validated LC-MS/MS method. Pharmacokinetic parameters were obtained by noncompartmental analysis. Tolerability was assessed by physical examinations, vital signs, clinical laboratory test results, and electrocardiograms. FINDINGS: Thirty-eight healthy volunteers completed the study. The geometric mean ratios of the AUC(last) and C(max) for test 1/reference were 0.88 (90% CI, 0.84-0.92) and 1.07 (90% CI, 0.99-1.15), respectively. The geometric mean ratios of the AUC(last) and C(max) for test 2/reference were 0.88 (90% CI, 0.84-0.93) and1.03 (90% CI, 0.96-1.10), respectively. All formulations were well tolerated. IMPLICATIONS: The pharmacokinetic characteristics and tolerability of the 2 megestrol acetate formulations are similar in fed volunteers and suggest no relevant difference in tolerability. ClinicalTrials.gov identifier: NCT01342055. PMID- 25450471 TI - Selective COX-2 inhibitors suppress prostacyclin. PMID- 25450472 TI - Antidepressant agents in short bowel syndrome. AB - PURPOSE: This study aimed to determine whether short small intestine modifies antidepressant concentrations. METHODS: The Css values and concentration-dose ratios (CDRs) of citalopram or escitalopram, administered orally or intravenously, were determined in patients with short bowel syndrome. FINDINGS: Eight patients (6 males and 2 females) were included in the study. High CDRs were obtained in orally treated patients with >180 cm of small bowel and in those with >80 cm of small bowel and 50% of colon. Three patients had low Css values, including 1 patient who received intravenous treatment. IMPLICATIONS: The variability of drug absorption and metabolism makes prescribing SSRIs challenging in these patients. PMID- 25450474 TI - A review of sucroferric oxyhydroxide for the treatment of hyperphosphatemia in patients receiving dialysis. AB - PURPOSE: Sucroferric oxyhydroxide is the newest phosphate binder to receive US Food and Drug Administration approval for patients on dialysis. The purpose of this review is to critically evaluate the studies that have been conducted with this medication and determine where it may fit in the clinician's overall treatment plan for hyperphosphatemia in patients with chronic kidney disease. METHODS: Literature searches were performed in the PubMed database and www.ClinicalTrials.gov using the search terms sucroferric oxyhydroxide, and PA21 phosphate binder. Limits were set to include only clinical trials performed in human subjects. FINDINGS: Four completed clinical trials and 3 ongoing studies were identified. Completed clinical trials included Phase I, Phase II, and Phase III studies that all demonstrated the ability of sucroferric oxyhydroxide to lower serum phosphorus concentrations. One study compared sucroferric oxyhydroxide with sevelamer and reported no statistically significant difference in serum phosphorus-lowering ability. The ongoing trials are evaluating sucroferric oxyhydroxide for long term use, in peritoneal dialysis patients, and compared with calcium-based phosphate binders. IMPLICATIONS: Sucroferric oxyhydroxide is an effective phosphate binder for chronic kidney disease patients receiving hemodialysis and may offer an advantage in terms of pill burden. Gastrointestinal side effects are similar to those of current phosphate binders. Advantages of other phosphate binders (ie, the lipid- and uric acid-lowering abilities of sevelamer) may outweigh the pill burden benefits of sucroferric oxyhydroxide. PMID- 25450473 TI - Management of newer medications for attention-deficit/hyperactivity disorder in commercial health plans. AB - PURPOSE: In the United States, many individuals with attention deficit/hyperactivity disorder (ADHD) pay for their medications using private health insurance coverage. As in other drug classes, private insurers are actively seeking to influence use and costs, particularly for newer and costlier medications. The approaches that insurers use may have important effects on patients' access to medications. This article examines approaches (eg, copayments, prior authorization, and step therapy) that commercial health plans are using to manage newer medications used to treat ADHD and changes in approaches since 2003. METHODS: Data are from a nationally representative survey of commercial health plans in 60 market areas regarding alcohol, drug abuse, and mental health services in 2010. Responses were obtained from 389 plans (89% response rate), reporting on 925 insurance products. For each of 6 branded ADHD medications, respondents were asked whether the plan covered the medication and, if so, on what copayment tier each medication was placed and whether it was subject to prior authorization or step therapy. Measures of management approach were constructed for each medication and for the group of medications. Bivariate and multivariate analyses were used to test for association of the management approach with various health plan characteristics. FINDINGS: There was considerable variation across these 6 medications in how tightly they were managed by health plans, with newer medications being subject to more stringent management. The proportion of insurance products relying solely on copayment tiering to manage new ADHD medications appears to have decreased since 2003. Less than half of insurance products (43%) managed these 6 medications solely by use of tier 3 or 4 placement, and most of the remainder (48%) used other restrictions (with or without tier 3 or 4 placement). The average insurance product restricted access to at least 3 of the 6 brand-only medications examined, whether through copayment tier placement or other approaches. More ADHD medications were left unrestricted in health maintenance organization products than in preferred provider organization ones, products with internal or hybrid-internal contracts for behavioral health, those not contracting with pharmacy benefits managers, and those with for-profit ownership. IMPLICATIONS: Many plans have supplemented copayment tiering with other approaches, such as prior authorization and step therapy, to influence use and decrease costs. It may be that plans have found copayments to be less effective in redirecting use in this medication class. The effect on clinical outcomes was not examined in this study but should be prioritized using other data sources. PMID- 25450476 TI - Neurotoxicity with antimicrobials in the elderly: a review. AB - PURPOSE: Mild adverse drug reactions typically associated with antimicrobials are familiar to most clinicians. However, rare phenomena, such as neurotoxicity, are often unpredictable and potentially unexpected. The toxic effects of antimicrobials on the central nervous system are often underreported and the mechanism(s) may be mixed or obscure. Geriatric patients are at increased risk for adverse drug reactions given physiologic alterations affecting pharmacokinetic processes. A dearth of information exists regarding neurotoxic presentations precipitated by antimicrobial use in the geriatric population. The purpose of this review is to present the available literature on neurotoxic effects of antimicrobials in geriatric patients, with an emphasis on manifestations of psychosis or delirium, or both. METHODS: A comprehensive literature search of the PubMed, Medline via Ovid, and Embase databases was conducted from 1966 to 2014. It included systematic reviews, randomized controlled trials, observational studies, case series, and case reports that involved neurologic effects, specifically delirium and psychosis associated with antimicrobial use. FINDINGS: Various antimicrobial classes are implicated with neurotoxicity. The classes with the most reported cases include fluoroquinolones, macrolides, sulfonamides, nitrofurans, and beta-lactams. A higher risk of developing various symptoms of neurotoxicity was found in the elderly with use of piperacillin and tazobactam, cephalosporins, carbapenems, aminoglycosides, trimethoprim and sulfamethoxazole, nitrofurantoin, linezolid, and possibly the fluoroquinolones. Potential mechanisms of neurotoxicity differ between the agents. The etiology of neurotoxicity with some agents is not fully elucidated. Incidence may increase with reported risk factors, renal dysfunction, or drug interactions. IMPLICATIONS: Awareness of antimicrobials causing or contributing to neurotoxic events may enhance clinical decisions in diagnosis and management when such incidents occur. PMID- 25450475 TI - New approaches for managing preeclampsia: clues from clinical and basic research. AB - PURPOSE: One of the most common, and most vexing, obstetric complications is preeclampsia-a major cause of maternal and perinatal morbidity. Hallmarked by new onset hypertension and a myriad of other symptoms, the underlying cause of the disorder remains obscure despite intensive research into its etiology. Although the initiating events are not clear, one common finding in preeclamptic patients is failure to remodel the maternal arteries that supply the placenta, with resulting hypoxia/ischemia. Intensive research over the past 2 decades has identified several categories of molecular dysfunction resulting from placental hypoxia, which, when released into the maternal circulation, are involved in the spectrum of symptoms seen in these patients-in particular, angiogenic imbalance and the activation of innate and adaptive immune responses. Despite these new insights, little in the way of new treatments for the management of these patients has been advanced into clinical practice. Indeed, few therapeutic options exist for the obstetrician treating a case of preeclampsia. Pharmacologic management is typically seizure prophylaxis, and, in severe cases, antihypertensive agents for controlling worsening hypertension. Ultimately, the induction of labor is indicated, making preeclampsia a leading cause of premature birth. Here, the molecular mechanisms linking placental ischemia to the maternal symptoms of preeclampsia are reviewed, and several areas of recent research suggesting new potential therapeutic approaches to the management of preeclampsia are identified. PMID- 25450477 TI - Modelling drug degradation in a spray dried polymer dispersion using a modified Arrhenius equation. AB - The Pharmaceutical industry is increasingly utilizing amorphous technologies to overcome solubility challenges. A common approach is the use of drug in polymer dispersions to prevent recrystallization of the amorphous drug. Understanding the factors affecting chemical and physical degradation of the drug within these complex systems, e.g., temperature and relative humidity, is an important step in the selection of a lead formulation, and development of appropriate packaging/storage control strategies. The Arrhenius equation has been used as the basis of a number of models to predict the chemical stability of formulated product. In this work, we investigate the increase in chemical degradation seen for one particular spray dried dispersion formulation using hydroxypropyl methylcellulose acetate succinate (HPMC-AS). Samples, prepared using polymers with different substitution levels, were placed on storage for 6 months under a range of different temperature and relative humidity conditions and the degradant level monitored using high-performance liquid chromatography (HPLC). While the data clearly illustrates the impact of temperature and relative humidity on the degradant levels detected, it also highlighted that these terms do not account for all the variability in the data. An extension of the Arrhenius equation to include a term for the polymer chemistry, specifically the degree of succinoyl substitution on the polymer backbone, was shown to improve the fit of the model to the data. PMID- 25450478 TI - Zerumbone increases oxidative stress in a thiol-dependent ROS-independent manner to increase DNA damage and sensitize colorectal cancer cells to radiation. AB - Locally advanced rectal cancers are treated with neoadjuvant chemoradiation therapy followed by surgery. In a minority (~20%) of patients, no tumor is present at the time of surgery; these patients with a complete pathologic response (pathCR) to neoadjuvant therapy have better treatment outcomes. Unfortunately, the inherent radioresistance of colorectal cancer (CRC) cells dictates that the majority of patients do not achieve a pathCR. Efforts to improve these odds have fueled the search for novel, relatively less-toxic radiosensitizers with distinct molecular mechanism(s) and broad-spectrum anticancer activities. Here, we use zerumbone, a sesquiterpene from the edible ginger (Zingiber zerumbet Smith), to enhance radiosensitivity of CRC cells. Short exposure to zerumbone (7 h) profoundly sensitized CRC cells, independent of their p53 or k-RAS status. Zerumbone enhanced radiation-induced cell cycle arrest (G2/M), increased radiation-induced apoptosis, but induced little apoptosis by itself. Zerumbone significantly enhanced radiation-induced DNA damage, as evident by delayed resolution of post-irradiation nuclear gammaH2AX foci, whereas zerumbone treatment alone did not induce gammaH2AX foci formation. Zerumbone pretreatment inhibited radiation-induced nuclear expression of DNA repair proteins ataxia-telangiectasia mutated (ATM) and DNA-PKcs. Interestingly, zerumbone-mediated radiosensitization did not involve reactive oxygen species (ROS), but was mediated through depletion of cellular glutathione (GSH). Ability of only thiol-based antioxidants to abrogate zerumbone-mediated radiosensitization further corroborated this hypothesis. The alpha,beta unsaturated carbonyl group in zerumbone was found to be essential for its bioactivity as zerumbone analog alpha-Humulene that lacks this functional group, could neither radiosensitize CRC cells, nor deplete cellular GSH. Our studies elucidate novel mechanism(s) of zerumbone's ability to enhance CRC radiosensitivity. PMID- 25450481 TI - Early recognition of lung cancer by integrin targeted imaging in K-ras mouse model. AB - Non-small cell lung cancer is characterized by slow progression and high heterogeneity of tumors. Integrins play an important role in lung cancer development and metastasis and were suggested as a tumor marker; however their role in anticancer therapy remains controversial. In this work, we demonstrate the potential of integrin-targeted imaging to recognize early lesions in transgenic mouse model of lung cancer based on spontaneous introduction of mutated human gene bearing K-ras mutation. We conducted ex vivo and fluorescence molecular tomography-X-ray computed tomography (FMT-XCT) in vivo imaging and analysis for specific targeting of early lung lesions and tumors in rodent preclinical model for lung cancer. The lesions and tumors were characterized by histology, immunofluorescence and immunohistochemistry using a panel of cancer markers. Ex vivo, the integrin-targeted fluorescent signal significantly differed between wild type lung tissue and K-ras pulmonary lesions (PL) at all ages studied. The panel of immunofluorescence experiments demonstrated that PL, which only partially show cancer cell features were detected by alphavbeta3-integrin targeted imaging. Human patient material analysis confirmed the specificity of target localization in different lung cancer types. Most importantly, small tumors in the lungs of 4-week-old animals could be noninvasively detected in vivo on the fluorescence channel of FMT-XCT. Our findings demonstrated alphavbeta3 integrin targeted fluorescent imaging to specifically detect premalignant pleural lesions in K-ras mice. Integrin targeted imaging may find application areas in preclinical research and clinical practice, such as early lung cancer diagnostics, intraoperative assistance or therapy monitoring. PMID- 25450479 TI - Sulforaphane, a cancer chemopreventive agent, induces pathways associated with membrane biosynthesis in response to tissue damage by aflatoxin B1. AB - Aflatoxin B1 (AFB1) is one of the major risk factors for liver cancer globally. A recent study showed that sulforaphane (SF), a potent inducer of phase II enzymes that occurs naturally in widely consumed vegetables, effectively induces hepatic glutathione S-transferases (GSTs) and reduces levels of hepatic AFB1-DNA adducts in AFB1-exposed Sprague Dawley rats. The present study characterized the effects of SF pre-treatment on global gene expression in the livers of similarly treated male rats. Combined treatment with AFB1 and SF caused reprogramming of a network of genes involved in signal transduction and transcription. Changes in gene regulation were observable 4h after AFB1 administration in SF-pretreated animals and may reflect regeneration of cells in the wake of AFB1-induced hepatotoxicity. At 24h after AFB1 administration, significant induction of genes that play roles in cellular lipid metabolism and acetyl-CoA biosynthesis was detected in SF pretreated AFB1-dosed rats. Induction of this group of genes may indicate a metabolic shift toward glycolysis and fatty acid synthesis to generate and maintain pools of intermediate molecules required for tissue repair, cell growth and compensatory hepatic cell proliferation. Collectively, gene expression data from this study provide insights into molecular mechanisms underlying the protective effects of SF against AFB1 hepatotoxicity and hepatocarcinogenicity, in addition to the chemopreventive activity of this compound as a GST inducer. PMID- 25450482 TI - Physiotherapy management of acute exacerbations of chronic obstructive pulmonary disease. AB - [Holland AE (2014) Physiotherapy management of acute exacerbations of chronic obstructive pulmonary disease.Journal of Physiotherapy60: 181-188]. PMID- 25450480 TI - Jaridonin-induced G2/M phase arrest in human esophageal cancer cells is caused by reactive oxygen species-dependent Cdc2-tyr15 phosphorylation via ATM-Chk1/2 Cdc25C pathway. AB - Jaridonin, a novel diterpenoid from Isodon rubescens, has been shown previously to inhibit proliferation of esophageal squamous cancer cells (ESCC) through G2/M phase cell cycle arrest. However, the involved mechanism is not fully understood. In this study, we found that the cell cycle arrest by Jaridonin was associated with the increased expression of phosphorylation of ATM at Ser1981 and Cdc2 at Tyr15. Jaridonin also resulted in enhanced phosphorylation of Cdc25C via the activation of checkpoint kinases Chk1 and Chk2, as well as in increased phospho H2A.X (Ser139), which is known to be phosphorylated by ATM in response to DNA damage. Furthermore, Jaridonin-mediated alterations in cell cycle arrest were significantly attenuated in the presence of NAC, implicating the involvement of ROS in Jaridonin's effects. On the other hand, addition of ATM inhibitors reversed Jaridonin-related activation of ATM and Chk1/2 as well as phosphorylation of Cdc25C, Cdc2 and H2A.X and G2/M phase arrest. In conclusion, these findings identified that Jaridonin-induced cell cycle arrest in human esophageal cancer cells is associated with ROS-mediated activation of ATM-Chk1/2 Cdc25C pathway. PMID- 25450483 TI - Educators and students prefer traditional clinical education to a peer-assisted learning model, despite similar student performance outcomes: a randomised trial. AB - QUESTION: What is the efficacy and acceptability of a peer-assisted learning model compared with a traditional model for paired students in physiotherapy clinical education? DESIGN: Prospective, assessor-blinded, randomised crossover trial. PARTICIPANTS: Twenty-four physiotherapy students in the third year of a 4 year undergraduate degree. INTERVENTION: Participants each completed 5 weeks of clinical placement, utilising a peer-assisted learning model (a standardised series of learning activities undertaken by student pairs and educators to facilitate peer interaction using guided strategies) and a traditional model (usual clinical supervision and learning activities led by clinical educators supervising pairs of students). OUTCOME MEASURES: The primary outcome measure was student performance, rated on the Assessment of Physiotherapy Practice by a blinded assessor, the supervising clinical educator and by the student in self assessment. Secondary outcome measures were satisfaction with the teaching and learning experience measured via survey, and statistics on services delivered. RESULTS: There were no significant between-group differences in Assessment of Physiotherapy Practice scores as rated by the blinded assessor (p=0.43), the supervising clinical educator (p=0.94) or the students (p=0.99). In peer-assisted learning, clinical educators had an extra 6 minutes/day available for non-student related quality activities (95% CI 1 to 10) and students received an additional 0.33 entries/day of written feedback from their educator (95% CI 0.06 to 0.61). Clinical educator satisfaction and student satisfaction were higher with the traditional model. CONCLUSION: The peer-assisted learning model trialled in the present study produced similar student performance outcomes when compared with a traditional approach. Peer-assisted learning provided some benefits to educator workload and student feedback, but both educators and students were more satisfied with the traditional model. TRIAL REGISTRATION: ACTRN12610000859088. [Sevenhuysen S, Skinner EH, Farlie MK, Raitman L, Nickson W, Keating JL, Maloney S, Molloy E, Haines TP (2014) Educators and students prefer traditional clinical education to a peer-assisted learning model, despite similar student performance outcomes: a randomised trial.Journal of Physiotherapy60: 209-216]. PMID- 25450484 TI - Predictors of non-use of prostheses by people with lower limb amputation after discharge from rehabilitation: development and validation of clinical prediction rules. AB - QUESTIONS: Can rules be developed to predict the risk of non-use of prostheses by people with lower limb amputation following discharge from rehabilitation? Are these clinical prediction rules valid? DESIGN: Retrospective and prospective cohort study designs. PARTICIPANTS: Consecutive tertiary rehabilitation patients: 135 retrospective (103 males, mean age = 56 years, SD 15) and 66 prospective (58 males, mean age = 54 years, SD 16). METHOD: Medical records were audited for potential predictor variables. Retrospective participants were interviewed at a median of 1.9 years after discharge (IQR 1.4 to 2.5) and prospective participants at a median of 1.3 years (IQR 1.1 to 1.4). RESULTS: Clinical prediction rules were identified at 4, 8 and 12 months after discharge, and validated. Amputation levels above transtibial and mobility-aid use were common predictors for all three time frames. At 4 months, if four out of five predictor variables were present (LR+ = 43.9, 95% CI 2.73 to 999+), the probability of non-use increased from 12 to 86% (p<0.001). At 8 months, if all three predictor variables were present (LR+ = 33.9, 95% CI 2.1 to 999+), the probability of non-use increased from 15 to 86% (p<0.001). At 12 months, if two out of three predictor variables were present (LR+=2.8, 95% CI 0.9 to 6.6), the probability of non-use increased from 17 to 36% (p<0.031). CONCLUSIONS: These validated clinical prediction rules have implications for rehabilitation and service model development. [Roffman CE, Buchanan J, Allison GT (2014) Predictors of non-use of prostheses by people with lower limb amputation after discharge from rehabilitation: development and validation of clinical prediction rules.Journal of Physiotherapy60: 224-231]. PMID- 25450485 TI - Cross-talk between redox regulation and the ubiquitin-proteasome system in mammalian cell differentiation. AB - BACKGROUND: Embryogenesis and stem cell differentiation are complex and orchestrated signaling processes. Reactive oxygen species (ROS) act as essential signal transducers in cellular differentiation, as has been shown through recent discoveries. On the other hand, the ubiquitin-proteasome system (UPS) has long been known to play an important role in all cellular regulated processes, including differentiation. SCOPE OF REVIEW: In the present review, we focus on findings that highlight the interplay between redox signaling and the UPS regarding cell differentiation. Through systems biology analyses, we highlight major routes during cardiomyocyte differentiation based on redox signaling and UPS modulation. MAJOR CONCLUSION: Oxygen availability and redox signaling are fundamental regulators of cell fate upon differentiation. The UPS plays an important role in the maintenance of pluripotency and the triggering of differentiation. GENERAL SIGNIFICANCE: Cellular differentiation has been a matter of intense investigation mainly because of its potential therapeutic applications. Understanding regulatory mechanisms underlying cell differentiation is an important issue. Correspondingly, the role of UPS and regulation of redox processes have been emerged as essential factors to control the fate of cells upon differentiation. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. PMID- 25450486 TI - Redox regulation of cytoskeletal dynamics during differentiation and de differentiation. AB - BACKGROUND: The cytoskeleton, unlike the bony vertebrate skeleton or the exoskeleton of invertebrates, is a highly dynamic meshwork of protein filaments that spans through the cytosol of eukaryotic cells. Especially actin filaments and microtubuli do not only provide structure and points of attachments, but they also shape cells, they are the basis for intracellular transport and distribution, all types of cell movement, and--through specific junctions and points of adhesion--join cells together to form tissues, organs, and organisms. SCOPE OF REVIEW: The fine tuned regulation of cytoskeletal dynamics is thus indispensible for cell differentiation and all developmental processes. Here, we discussed redox signalling mechanisms that control this dynamic remodeling. Foremost, we emphasised recent discoveries that demonstrated reversible thiol and methionyl switches in the regulation of actin dynamics. MAJOR CONCLUSIONS: Thiol and methionyl switches play an essential role in the regulation of cytoskeletal dynamics. GENERAL SIGNIFICANCE: The dynamic remodeling of the cytoskeleton is controlled by various redox switches. These mechanisms are indispensible during development and organogenesis and might contribute to numerous pathological conditions. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. PMID- 25450487 TI - Hydrophobic drug concentration affects the acoustic susceptibility of liposomes. AB - The purpose of this study was to investigate the effect of encapsulated hydrophobic drug concentration on ultrasound-mediated leakage from liposomes. Studies have shown that membrane modifications affect the acoustic susceptibility of liposomes, likely because of changes in membrane packing. An advantage of liposome as drug carrier is its ability to encapsulate drugs of different chemistries. However, incorporation of hydrophobic molecules into the bilayer may cause changes in membrane packing, thereby affecting the release kinetics. Liposomes containing calcein and varying concentrations of papaverine, a hydrophobic drug, were exposed to 20 kHz, 2.2 Wcm(-2) ultrasound. Papaverine concentration was observed to affect calcein leakage although the effects varied widely based on liposome phase. For example, incorporation of 0.5mg/mL papaverine into Ld liposomes increased the leakage of hydrophilic encapsulants by 3* within the first minute (p=0.004) whereas the same amount of papaverine increased leakage by only 1.5* (p<0.0001). Papaverine was also encapsulated into echogenic liposomes and its concentration did not significantly affect calcein release rates, suggesting that burst release from echogenic liposomes is predictable regardless of encapsulants chemistry and concentration. PMID- 25450488 TI - Human cancer: is it linked to dysfunctional lipid metabolism? AB - BACKGROUND: Lipid metabolism dysfunction leading to excess fat deposits (obesity) may cause tumor (cancer) development. Both obesity and cancer are the epicenter of important medical issues. Lipid metabolism and cell death/proliferation are controlled by biochemical and molecular pathways involving many proteins, and organelles; alteration in these pathways leads to fat accumulation or tumor growth. Mammalian Kruppel-like factors, KLFs play key roles in both lipid metabolism and tumor development. SCOPE OF REVIEW: Substantial epidemiological and clinical studies have established strong association of obesity with a number of human cancers. However, we need more experimental verification to determine the exact role of this metabolic alteration in the context of tumor development. A clear understanding of molecules, pathways and the mechanisms involved in lipid metabolism and cell death/proliferation will have important implications in pathogenesis, and prevention of these diseases. MAJOR CONCLUSION: The regulatory role of KLFs, in both cell death/proliferation and lipid metabolism suggests a common regulation of both processes. This provides an excellent model for delivering a precise understanding of the mechanisms linking altered expression of KLFs to obesity and tumor development. GENERAL SIGNIFICANCE: Currently, mouse and rats are the models of choice for investigating disease mechanisms and pharmacological therapies but a genetic model is needed for a thorough examination of KLF function in vivo during the development of an organism. The worm Caenorhabditis elegans is an ideal model to study the connectivity between lipid metabolism and cell death/proliferation. PMID- 25450490 TI - Providing personal informal care to older European adults: should we care about the caregivers' health? AB - OBJECTIVE: In Europe, the demand for informal care is high and will increase because of the ageing population. Although caregiving is intended to contribute to the care recipient's health, its effects on the health of older European caregivers are not yet clear. This study explores the association between providing informal personal care and the caregivers' health. METHOD: Data were used from the longitudinal cohort (2004/2005-2010/2011) of the Survey of Health, Ageing and Retirement in Europe (SHARE) (n=7858). Generalized estimating equations were used to explore the longitudinal association of informal care and the caregiver's health using poor self-rated health (less than good), poor mental health (EURO-D score for depression >=4), and poor physical health (>=2 health complaints). RESULTS: Providing informal personal care was significantly associated with poor mental health (OR=1.23, 95% CI=1.04-1.47) and poor physical health (OR=1.18, 95% CI=1.01-1.38), after adjusting for various socio-demographic and health-related factors. No statistical significant association was found for self-rated health in the adjusted models. CONCLUSION: Providing informal personal care may negatively influence the caregiver's mental and physical health. More awareness of the beneficial and detrimental effects of caregiving among policy makers is needed to make well-informed decisions concerning the growth of care demands in the ageing population. PMID- 25450491 TI - The Active Living Research 2014 Conference: "niche to norm". PMID- 25450492 TI - Communities Creating Healthy Environments: improving access to healthy foods and safe places to play in communities of color. PMID- 25450489 TI - Pathogenesis associated with a restrictive cardiomyopathy mutant in cardiac troponin T is due to reduced protein stability and greatly increased myofilament Ca2+ sensitivity. AB - BACKGROUND: Dilated and hypertrophic cardiomyopathy mutations in troponin can blunt effects of protein kinase A (PKA) phosphorylation of cardiac troponin I (cTnI), decreasing myofilament Ca2+-sensitivity; however this effect has never been tested for restrictive cardiomyopathy (RCM) mutants. This study explores whether an RCM cardiac troponin T mutant (cTnT-DeltaE96) interferes with convergent PKA regulation and if TnT instability contributes to greatly enhanced Ca2+-sensitivity in skinned fibers. METHODS: Force of contraction in skinned cardiac porcine fiber and spectroscopic studies were performed. RESULTS: A decrease of -0.26 and -0.25 pCa units in Ca2+-sensitivity of contraction after PKA incubation was observed for skinned fibers incorporated with WT or cTnT DeltaE96, respectively. To further assess whether cTnT-DeltaE96 interferes solely with transmission of cTnI phosphorylation effects, skinned fibers were reconstituted with PKA pseudo-phosphorylated cTnI (cTnI-SS/DD.cTnC). Fibers displaced with cTnT-WT, reconstituted with cTnI-SS/DD.cTnC decreased Ca2+ sensitivity of force (pCa50=5.61) compared to control cTnI-WT.cTnC (pCa50=5.75), similarly affecting cTnT-DeltaE96 (pCa50=6.03) compared to control ?cTnI-WT.cTnC (pCa50=6.14). Fluorescence studies measuring cTnC(IAANS) Ca2+-affinity changes due to cTnT-DeltaE96 indicated that higher complexity (thin filament) better recapitulates skinned fiber Ca2+ sensitive changes. Circular dichroism revealed reduced alpha-helicity and earlier thermal unfolding for cTnT-DeltaE96 compared to WT. CONCLUSIONS: Although ineffective in decreasing myofilament Ca2+ sensitivity to normal levels, cTnT-DeltaE96 does not interfere with PKA cTnI phosphorylation mediated effects; 2) cTnT-DeltaE96 requires actin to increase cTnC Ca2+-affinity; and 3) deletion of E96 reduces cTnT stability, likely disrupting crucial thin filament interactions. GENERAL SIGNIFICANCE: The pathological effect of cTnT-DeltaE96 is largely manifested by dramatic myofilament Ca2+-sensitization which still persists even after PKA phosphorylation mediated Ca2+-desensitization. PMID- 25450493 TI - Promoting physical activity in Out-of-School-Time programs: we built the bridge- can we walk over it? AB - This commentary describes physical activity standards for Out-of-School Time programs and argues that their widespread adoption presents important opportunities for research on their implementation and impact. PMID- 25450494 TI - Changes in U.S. Preventive Services Task Force recommendations: effect on mammography screening in Olmsted County, MN 2004-2013. AB - OBJECTIVE: We assessed changes in adherence to screening mammography recommendations with the introduction of the new U.S. Preventive Services Task Force (USPSTF) recommendations in 2009. METHODS: Using the Rochester Epidemiology Project data linkage system, we examined mammography screening from 2004 to 2013 in 31,377 women 40years of age and older residing in Olmsted County, MN before and after the 2009 change in recommendations. Chi-square was used to compare screening rates before and after changes in recommendations overall, by age group, and by baseline adherence. RESULTS: Among women 40 years and older, declines in screening were observed: 69% of the population was adherent in 2004 2005, 61% in 2006-2009 and 53% in 2010-2013. Absolute decreases in screening were observed from pre- to post-change for those ages 40-49 (4%), 50-74 (9%), and those 75+ (19%, all p<0.0001). Relative declines in screening rates were observed among women aged 70-74 years who were non-adherent at baseline and among women who were adherent at baseline, overall, and in each age group (all p<.001). CONCLUSIONS: Declines in screening, both absolute and relative, were most pronounced among women who were adherent at baseline. Research is needed to assess factors that influence screening in the context of evolving recommendations. PMID- 25450496 TI - The relationship between utilitarian walking, utilitarian cycling, and body mass index in a population based cohort study of adults: comparing random intercepts and fixed effects models. AB - OBJECTIVE: To examine associations between utilitarian walking, utilitarian cycling, leisure time physical activity and body mass index (BMI). METHODS: Participants from the National Population Health Survey (NPHS) of Statistics Canada were interviewed by telephone every two years from 1994 to 2010. Analysis includes data from 6894 living participants aged 18-64years. Fixed effects and random intercepts models examined the association between BMI, utilitarian walking, and utilitarian cycling, controlling for behavioral and sociodemographic factors. RESULTS: The final adjusted fixed effects models showed no significant relationship between utilitarian walking and BMI. In the unbalanced sample utilitarian cycling for 1 to 5h per week (b=-0.15, 95% CI: -0.28 to -0.02), and more than 5h per week (b=-0.22, 95% CI: -0.44 to 0.00) was significantly associated with BMI over time. In the fully balanced sample utilitarian cycling for 1 to 5h per week (b=-0.12, 95% CI: -0.27 to 0.03), more than 5h per week (b= 0.16, 95% CI: -0.45 to 0.13) was not significantly associated with BMI over time. CONCLUSION: The results suggest that utilitarian walking is not related to BMI. The relationship between utilitarian cycling and BMI is less clear. PMID- 25450495 TI - Cultural relevance in medication adherence interventions with underrepresented adults: systematic review and meta-analysis of outcomes. AB - OBJECTIVE: This meta-analysis systematically compiles intervention research designed to increase medication adherence among underrepresented adults. METHOD: Comprehensive searching located published and unpublished studies with medication adherence behavior outcomes. Studies were included if samples were adults living in North America who had any of the following backgrounds or identities: African American, Native American, Latino, Latino American, Asian, Asian American, Pacific Islander, Native Alaskan, or Native Hawaiian. Random-effect analyses synthesized data to calculate effect sizes as a standardized mean difference and variability measures. Exploratory moderator analyses examined the association between specific efforts to increase the cultural relevance of medication adherence studies and behavior outcomes. RESULTS: Data were synthesized across 5559 subjects in 55 eligible samples. Interventions significantly improved medication adherence behavior of treatment subjects compared to control subjects (standardized mean difference=0.211). Primary studies infrequently reported strategies to enhance cultural relevance. Exploratory moderator analyses found no evidence that associated cultural relevance strategies with better medication adherence outcomes. CONCLUSION: The modest magnitude of improvements in medication adherence behavior documents the need for further research with clear testing of cultural relevance features. PMID- 25450497 TI - Development of a report card on healthy food environments and nutrition for children in Canada. AB - OBJECTIVE: The purpose of the Report Card on Healthy Food Environments and Nutrition for Children is to assess how current environments and policies in Canada support or create barriers to improving children's dietary behaviours and body weights. METHOD: In 2014 we reviewed the literature to identify indicators of the quality of children's food environments and related policies. Scoring systems used to monitor and report on progress on a variety of public health activities were consulted during development of a grading scheme. The Report Card was revised following reviews by an Expert Advisory Committee. RESULTS: The Report Card assigns a grade to policies and actions (42 indicators and benchmarks) within 4 micro-environments (physical, communication, economic, social) and within the political macro-environment. Grade-level scores of A through F are assigned that reflect achievement of, supports for, and monitoring of indicator-specific benchmarks. A Canadian Report Card will be released annually starting in 2015. CONCLUSION: The Report Card is a novel tool to monitor the state of children's food environments and supportive policies, inform stakeholders of the state of these environments and policies, engage society in a national discussion, and outline a policy-relevant research agenda for further study. PMID- 25450498 TI - Commentary: disparities in tobacco use by sexual orientation amongst high school students. PMID- 25450499 TI - Untangling taxonomic confusion and diversification patterns of the Streak breasted Scimitar Babblers (Timaliidae: Pomatorhinus ruficollis complex) in southern Asia. AB - Biodiversity patterns in Asia are poorly understood due to inferences drawn from incorrect taxonomy and limited survey effort. The Streak-breasted Scimitar Babblers (Pomatorhinus ruficollis complex) have a wide distribution across southern Asia and exhibit a high degree of plumage variability within and among populations. Continued use of traditional subspecies designations over revised species-limits based on plumage and DNA sequence data furthers confusion in this group and obscures complex biogeographic patterns. In this study, we combined previously published DNA sequences with newly sampled populations to produce a comprehensive dataset for the ruficollis complex. Phylogenetic analysis of these data confirms that traditional subspecies based on plumage alone are paraphyletic and therefore not good descriptors of evolutionary history. With increased sampling, our study supported previous delimitations of phylogenetic species as distinct units, refined the range limits of two taxa - P. reconditus (throughout central China) and P. nigrostellatus (Hainan, Guangxi, N Vietnam), showed two additional clades that may be distinct species, and uncovered a 'suture' zone where populations of multiple species occur in the same localities. Diversification within the ruficollis complex indicates a clade of Sino-Himalayan and SE Asian species sister to a clade distributed in central and southern China species. The 'suture' zone where different ruficollis species are in contact coincides with the meeting of these four major geographic areas in a highly geomorphologically complex region. PMID- 25450501 TI - Simultaneous determination of 14 constituents of Radix polygoni multiflori from different geographical areas by liquid chromatography-tandem mass spectrometry. AB - Radix polygoni multiflori (RPM) has antioxidative, anti-aging, liver-protective and antihuman cytomegalovirus activity. It has been proved to be hepatotoxic. Considering multiple ingredients to control RPM quality is essential. The aim of this study was to establish a simple, rapid method using resolution liquid chromatography coupled with a triple quadruple mass spectrometry to identify and quantify the major bioactive constituents in RPM. The method was applied to analyze 14 marker batches from manufacturers from the same province. The ultrasonic extracts of all samples were determined by LC-MS/MS, and assessed by hierarchical cluster analysis. The proposed method was applied to analyze 21 batches of samples with acceptable linearity (R(2) , 0.9930-0.9998), precision (relative standard deviation, RSD, 0.45-4.73%) repeatability (RSD, 1.14-9.41%), stability (RSD, 1.29-12.88%) and recovery (RSD, 1.80-12.15%) of the 14 compounds. Furthermore, the hierarchical cluster analysis was applied to classify 21 samples on the basis of characteristics of the 14 compound markers. The developed method was demonstrated to be simple, sensitive and reproducible, and has significant importance and comprehensive evaluation for quality control of RPM and related preparations. Hierarchical cluster analysis clearly indicated that the RPM from the same province was similar, whereas samples of RPM from different provinces were significantly different. PMID- 25450502 TI - Site-specific structural characterization of O-glycosylation and identification of phosphorylation sites of recombinant osteopontin. AB - Osteopontin (OPN) plays a key role in multiple physiological and pathological processes such as cytokine production, mineralization, inflammation, immune responses, and tumorigenesis. Post-translational modifications (PTMs) of OPN significantly affect its structure and biological properties; however, site specific characterization of O-glycosylation in human OPN has not been reported. In this work, we profiled the overall glycan pattern of human recombinant OPN using a lectin array and completed detailed structural analysis of O glycopeptides by mass spectrometry (MS). We detected 28 O-glycopeptides from 7 O glycosylation regions of human OPN, occupied by highly heterogeneous O-glycans. These O-glycans carried, in part, functionally relevant epitopes such as T antigens (Galbeta1-3GalNAcalpha1-), sialyl-Tn antigens, sialyl-T antigens, and sialyl-Le(x/a) antigens [Neualpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc/Neualpha2 3Galbeta1-3(Fucalpha1-4)GlcNAc]. MS(3) spectra of the generated O-glycopeptides showed cleavages of the peptide backbone and provided essential information on the peptide sequence. Furthermore, 26 phosphorylation sites were identified by reverse-phase liquid chromatography-tandem mass spectrometry (RPLC-MS/MS), including a novel one (Y209). We provide a detailed, site-specific structural characterization of O-glycosylation and identify the phosphorylation sites of OPN. These data lay the foundation for further research into the role of oligosaccharides and phosphorylation of recombinant human OPN. This article is part of a Special Issue entitled: Medical Proteomics. PMID- 25450503 TI - Denaturation of alpha-lactalbumin and myoglobin by the anionic biosurfactant rhamnolipid. AB - Glycolipid biosurfactants (GBS) are promising environmentally friendly alternatives to chemical surfactants. Surfactants interact with proteins in many applications, often leading to significant changes in protein properties. Given GBS' marked difference in structure compared to traditional chemical surfactants, it is of interest to investigate their impact on protein structure and stability. Here we combine spectroscopic and calorimetric studies to analyze the interactions between the anionic GBS rhamnolipid (RL) and two model proteins alpha-lactalbumin in the Ca(2+)-free apo-form (alphaLA) and myoglobin (Mb), whose interactions with traditional surfactants are well known. RL denatures alphaLA at sub-cmc concentrations (0.1-1mM) while Mb is only denatured above the cmc, i.e. in the presence of RL micelles. Denaturation leads to increased alpha-helicity, similar to the effect of SDS. The proteins bind approximately the same amount of RL by weight as SDS. However, RL employs a denaturation mechanism which combines features from non-ionic surfactants (very slow unfolding kinetics and few unfolding steps) with those of SDS (unfolding below the cmc in the case of alphaLA and the ability to unfold stable proteins in the case of Mb). We ascribe these features to RL's weakly acidic carboxylic head group and complex hydrophobic tail, which lead to a low cmc and low protein affinity. These features restrict the concentration range where RL monomers can bind and denature proteins while still allowing micelles to bind and denature to a significant extent. PMID- 25450500 TI - Adjustment of sensitisation and challenge protocols restores functional and inflammatory responses to ovalbumin in guinea-pigs. AB - INTRODUCTION: Inhalation of antigen in atopic asthma induces early (EAR) and late asthmatic responses (LARs), inflammatory cell infiltration and airways hyperresponsiveness (AHR). Previously, we have established a protocol of sensitisation and subsequent ovalbumin (Ova) inhalation challenge in guinea-pigs which induced these 4 features (Smith & Broadley, 2007). However, the responses of guinea-pigs to Ova challenge have recently declined, producing no LAR or AHR and diminished EAR and cells. By making cumulative modifications to the protocol, we sought to restore these features. METHODS: Guinea-pigs were sensitised with Ova (i.p. 100 or 150 MUg) on days 1 and 5 or days 1, 4 and 7 and challenged with nebulised Ova (100 or 300 MUg/ml, 1h) on day 15. Airway function was measured in conscious guinea-pigs by whole-body plethysmography to record specific airway conductance (sGaw). Airway responsiveness to aerosolized histamine (0.3mM) was determined before and 24h after Ova challenge. Bronchoalveolar lavage was performed for total and differential inflammatory cell counts. Lung sections were stained for counting of eosinophils. RESULTS: Lack of AHR and LAR with the original protocol was confirmed. Increasing the Ova challenge concentration from 100 to 300 MUg/ml restored AHR and eosinophils and increased the peak of the EAR. Increasing the number of sensitisation injections from 2 to 3 did not alter the responses. Increasing the Ova sensitisation concentration from 100 to 150 MUg significantly increased total cells, particularly eosinophils. A LAR was revealed and lymphocytes and eosinophils increased when either the Al(OH)3 concentration was increased or the duration between the final sensitisation injection and Ova challenge was extended from 15 to 21 days. DISCUSSION: This study has shown that declining allergic responses to Ova in guinea-pigs could be restored by increasing the sensitisation and challenge conditions. It has also demonstrated an important dissociation between EAR, LAR, AHR and inflammation. PMID- 25450504 TI - Crystal structure of HlyU, the hemolysin gene transcription activator, from Vibrio cholerae N16961 and functional implications. AB - HlyU in Vibrio cholerae is known to be the transcriptional activator of the hemolysin gene, HlyA and possibly a regulator of other virulence factors influencing growth, colonization and pathogenicity of this infective agent. Here we report the crystal structure of HlyU from V. cholerae N16961 (HlyU_Vc) at 1.8A. The protein, with five alpha-helices and three beta-strands in the topology of alpha1-alpha2-beta1-alpha3-alpha4-beta2-beta3-alpha5, forms a homodimer. Helices alpha3-alpha4 and a beta sheet form the winged helix-turn-helix (wHTH) DNA-binding motif common to the transcription regulators of the SmtB/ArsR family. In spite of an overall fold similar to SmtB/ArsR family, it lacks any metal binding site seen in SmtB. A comparison of the dimeric interfaces showed that the one in SmtB is much larger and have salt bridges that can be disrupted to accommodate metal ions. A model of HlyU-DNA complex suggests bending of the DNA. Cys38 in the structure was found to be modified as sulfenic acid; the oxidized form was not seen in another structure solved under reducing condition. Although devoid of any metal binding site, the presence of a Cys residue exhibiting oxidation-reduction suggests the possibility of the existence of a redox switch in transcription regulation. A structure-based phylogenetic analysis of wHTH proteins revealed the segregation of metal and non-metal binding proteins as well as those in the latter group that are under redox control. PMID- 25450505 TI - Alpha B- and betaA3-crystallins containing d-aspartic acids exist in a monomeric state. AB - Crystallin stability and subunit-subunit interaction are essential for eye lens transparency. There are three types of crystallins in lens, designated as alpha-, beta-, and gamma-crystallins. Alpha-crystallin is a hetero-polymer of about 800kDa, consisting of 35-40 subunits of two different alphaA- and alphaB subunits, each of 20kDa. The beta/gamma-crystallin superfamily comprises oligomeric beta-crystallin (2-6 subunits) and monomeric gamma-crystallin. Since lens proteins have very long half-lives, they undergo numerous post-translational modifications including racemization, isomerization, deamidation, oxidation, glycation, and truncation, which may decrease crystallin solubility and ultimately cause cataract formation. Racemization and isomerization of aspartyl (Asp) residues have been detected only in polymeric alpha- and oligomeric beta crystallin, while the situation in monomeric gamma-crystallin has not been studied. Here, we investigated the racemization and isomerization of Asp in the gamma-crystallin fraction of elderly donors. The results show that Asp residues of gammaS-, gammaD- and gammaC-crystallins were not racemized and isomerized. However, strikingly, we found that a portion of alphaB-crystallin and betaA3 crystallin moved to the lower molecular weight fraction which is the same size of gamma-crystallin. In those fractions, Asp-96 of alphaB-crystallin and Asp-37 of betaA3-crystallin were highly inverted, which do not occur in the native lens higher molecular weight fraction. Our results indicate the possibility that the inversion of Asp residues may induce dissociation of alphaB- and betaA3 crystallins from the polymeric and oligomeric states. This is the first report that stereoinversion of amino acids disturbs lens protein assembly in aged human lens. PMID- 25450506 TI - Kinetic analysis of PCNA clamp binding and release in the clamp loading reaction catalyzed by Saccharomyces cerevisiae replication factor C. AB - DNA polymerases require a sliding clamp to achieve processive DNA synthesis. The toroidal clamps are loaded onto DNA by clamp loaders, members of the AAA+family of ATPases. These enzymes utilize the energy of ATP binding and hydrolysis to perform a variety of cellular functions. In this study, a clamp loader-clamp binding assay was developed to measure the rates of ATP-dependent clamp binding and ATP-hydrolysis-dependent clamp release for the Saccharomyces cerevisiae clamp loader (RFC) and clamp (PCNA). Pre-steady-state kinetics of PCNA binding showed that although ATP binding to RFC increases affinity for PCNA, ATP binding rates and ATP-dependent conformational changes in RFC are fast relative to PCNA binding rates. Interestingly, RFC binds PCNA faster than the Escherichia coli gamma complex clamp loader binds the beta-clamp. In the process of loading clamps on DNA, RFC maintains contact with PCNA while PCNA closes, as the observed rate of PCNA closing is faster than the rate of PCNA release, precluding the possibility of an open clamp dissociating from DNA. Rates of clamp closing and release are not dependent on the rate of the DNA binding step and are also slower than reported rates of ATP hydrolysis, showing that these rates reflect unique intramolecular reaction steps in the clamp loading pathway. PMID- 25450508 TI - Contribution of in utero drug exposure when interpreting hair results in young children. AB - Hair specimen is necessary to complement blood and/or urine analyses as it permits differentiation of a single exposure from chronic use of a drug by segmentation of the hair for a stated growth period. Moreover, due to a frequent long delay between event and police declaration, hair can be the only solution for lack of corroborative evidence of a committed crime. With the exception of lower amount of biological material in children versus adults, there is no specific analytical problem when processing samples from children. The issue is the interpretation of the findings, with respect to the different pharmacological parameters. In some very young children, the interpretation can be complicated by potential in utero exposure. Twenty-four cases from daily practice have been reviewed. Children were less than 1 year old, hair was always longer than 4 cm and the corresponding mothers admitted having used drugs during pregnancy. Drugs involved include methadone, tramadol, diphenhydramine, diazepam, cannabis, heroin, amitriptyline and bromazepam. Analyses were achieved by hyphenated chromatographic validated procedures after hair decontamination and segmentation. The concentrations measured in the hair of children were lower than those observed in subjects using therapeutically (or illegally) these drugs. In that sense, the frequency of exposures appears as un-frequent (low level of exposure), with marked decrease in the more recent period. However, the parents denied any administration in all cases and there was no reason to suspect re-exposure after delivery and no clinical problem during the period between delivery and hair collection during regular visits to the physician was noticed. The pattern of drug distribution was similar in all these cases, low concentrations in the proximal segments and highest concentration in the distal segment (last segment). When considering the concentration in the distal segment as the 100% of the response (highest concentration), after analysis of 4 segments (irrespective of the length of the segment but longer than 1cm), it was observed the following pattern: proximal segment, 5-35% of the response; segment 2, 15-50% of the response; segment 3, 25-60% of the response; and distal segment, 100% of the response. It is proposed to consider 100% in utero contribution to the final interpretation when the ratio concentration of the proximal segment to the concentration of the distal segment is lower than 0.5. This can be applied only when the child is under 1 year old and the hair shaft length is at least 4 cm (to achieve suitable segmentation). It is important, when using this cut-off to have at least 3 or 4 segments to be able to observe the variation in drug concentrations, whatever the length of each segment (>1cm). PMID- 25450507 TI - Functional and dysfunctional conformers of human neuroserpin characterized by optical spectroscopies and Molecular Dynamics. AB - Neuroserpin (NS) is a serine protease inhibitor (SERPIN) involved in different neurological pathologies, including the Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB), related to the aberrant polymerization of NS mutants. Here we present an in vitro and in silico characterization of native neuroserpin and its dysfunctional conformation isoforms: the proteolytically cleaved conformer, the inactive latent conformer, and the polymeric species. Based on circular dichroism and fluorescence spectroscopy, we present an experimental validation of the latent model and highlight the main structural features of the different conformers. In particular, emission spectra of aromatic residues yield distinct conformational fingerprints, that provide a novel and simple spectroscopic tool for selecting serpin conformers in vitro. Based on the structural relationship between cleaved and latent serpins, we propose a structural model for latent NS, for which an experimental crystallographic structure is lacking. Molecular Dynamics simulations suggest that NS conformational stability and flexibility arise from a spatial distribution of intramolecular salt-bridges and hydrogen bonds. PMID- 25450510 TI - Positive identification by X-rays bone trabeculae comparison. AB - Positive (certain, absolute) identification of human remains needs a scientific comparison between ante mortem and post-mortem biologic features, as fingerprint, odontological, radiological or DNA comparisons. X-rays comparison has been extensively used, usually comparing some peculiarities such as outlines of the bones, degenerative evolution or pathological conditions. Trabeculae comparisons are sparsely underlined in the forensic literature. We report on a case of decomposed body where fingerprint, DNA and odontological comparisons were not possible. After dissecting the leg and preparing the bones, comparison of ante mortem and postmortem trabeculae led to a positive identification. It was observed that tens of radiolucencies and radiodensities drawn by the trabeculae were useful for comparison, within a very small part of bone. In the case reported here the positive identity could have been assessed only by the comparison of the first metatarsal. The statement of positive identification needs scientific criteria that will be discussed in this article. PMID- 25450509 TI - Fatal anoxia due to rachacha consumption: Two cases reported. AB - Deaths due to ingesting rachacha, which is a homemade paste obtained by decocting poppy heads, are very rare. No fatalities have been recorded in scientific publications. This product is not considered to be very dangerous by its users. We are reporting the first deaths (a 30-year-old man and a 28-year-old woman), after ingesting rachacha balls and alcohol consumption during an evening with a friend. Signs compatible with acute anoxia were observed during autopsy. Toxicological analyses highlighted the presence of morphine and codeine in the blood, urine and bile, with an absence of 6-acetylmorphine. Concomitant consumption of alcohol certainly played a role in the occurrence of death. The black paste found at the scene was identified as rachacha. The mean of consumption (orally) was confirmed by the presence of morphine and codeine in the gastric contents of both victims. The analysis of hair samples was performed to reveal the substance consumption history. Therefore, a possibility of contamination by sweat and/or putrefactive liquids in the post-mortem period must be considered for the interpretation of the results. These two cases show that taking rachacha can be dangerous, especially when combined with the consumption of substances which could potentiate respiratory depression induced by morphine. PMID- 25450511 TI - Bone-patch type secondary projectiles: A report on two shots fired at point-blank range using hollow point bullets. AB - The number of head wounds due to firearms remains low in France because these cases are primarily linked to suicide (or attempted suicide) and, to a lesser extent, to attacks or hunting accidents [1]. Characterized by the impact of a projectile, which in most cases is made of metal, at high levels of kinetic energy, such acts generally result in severe trans-cerebral lesions with significant levels of morbidity/mortality [2]. Seldom are cases reported in the literature that give a detailed study of intracranial foreign bodies made of bone in such situations [3]. Here we report on the case of two suicides resulting from a transcranial gunshot wounds caused by weapons and ammunition issued by the French police force. Each case helped distinguish a characteristic bone fragment, in the form of a "patch", equivalent in size to the caliber of the bullet. PMID- 25450512 TI - Bipolar disorders in the new DSM-5 and ICD-11 classifications. AB - The DSM-5 and ICD-11 classifications, the latter still under development, are aimed at harmonizing the diagnoses of mental disorders. A critical review is presented in the issues that can converge or separate both classifications regarding bipolar disorders, and those conditions-included in depressive disorders-with special relevance for bipolar (e.g. major depressive episode). The main novelties include the incorporation of dimensional parameters to assess the symptoms, as well as the sub-threshold states in the bipolar spectrum, the consideration of new course specifiers such as the mixed symptoms, the elimination of mixed episodes, and a more restrictive threshold for the diagnosis of hypo/mania. The most noticeable points of convergence are the inclusion of bipolar II disorder in ICD-11 and the additional requirement of an increase in activity, besides mood elation or irritability, for the diagnosis of hypo/mania in both classifications. The main differences are, most likely keeping the mixed depression and anxiety disorder diagnostic category, maintaining bereavement as exclusion criterion for the depressive episode, and maintaining the mixed episode diagnosis in bipolar disorder in the forthcoming ICD-11. CONCLUSION: Since DSM-5 has already been published, changes in the draft of ICD-11, or ongoing changes in DSM-5.1 will be necessary to improve the harmonization of psychiatric diagnoses. PMID- 25450513 TI - A new concept for obtaining SnO2 fiber-in-tube nanostructures with superior electrochemical properties. AB - Tin oxide (SnO2 ) nanotubes with a fiber-in-tube structure have been prepared by electrospinning and the mechanism of their formation has been investigated. Tin oxide-carbon composite nanofibers with a filled structure were formed as an intermediate product, which were then transformed into SnO2 nanotubes with a fiber-in-tube structure during heat treatment at 500 degrees C. Nanofibers with a diameter of 85 nm were found to be located inside hollow nanotubes with an outer diameter of 260 nm. The prepared SnO2 nanotubes had well-developed mesopores. The discharge capacities of the SnO2 nanotubes at the 2nd and 300th cycles at a current density of 1 A g(-1) were measured as 720 and 640 mA h g(-1), respectively, and the corresponding capacity retention measured from the 2nd cycle was 88 %. The discharge capacities of the SnO2 nanotubes at incrementally increased current densities of 0.5, 1.5, 3, and 5 A g(-1) were 774, 711, 652, and 591 mA h g(-1), respectively. The SnO2 nanotubes with a fiber-in-tube structure showed superior cycling and rate performances compared to those of SnO2 nanopowder. The unique structure of the SnO2 nanotubes with a fiber@void@tube configuration improves their electrochemical properties by reducing the diffusion length of the lithium ions, and also imparts greater stability during electrochemical cycling. PMID- 25450515 TI - Achievement of early complete donor chimerism in CD25+-activated leukocytes is a strong predictor of the development of graft-versus-host-disease after stem cell transplantation. AB - Chimerism dynamics in bone marrow, peripheral blood (PB), and T lymphocytes (TL) has been associated with the development of various complications after allogeneic stem-cell transplantation (allo-SCT). In the present study, the usefulness of chimerism monitoring in CD25(+)-activated leukocytes (AL), together with that in bone marrow, PB, and TL, for the anticipation of complications after allo-SCT, has been analyzed in 68 patients. In AL, we observed a slower dynamics toward complete chimerism (CC) than in PB (p = 0.042), while no significant differences were found between TL and PB (p = 0.12). Complete chimerism achievement in AL at day +30 has shown to be an independent risk factor for the development of grade II-IV acute graft-versus-host disease (aGvHD; hazard ratio [95% confidence interval]: 11.9 [1.5-91.7]; p = 0.017). Moreover, among patients achieving CC in TL and AL at different time-points after SCT (n = 17/68), the incidence of grade II-IV aGvHD was significantly higher in patients who achieved CC earlier in AL (5/5) than in those who achieved CC earlier in TL (1/11; p = 0.001). Therefore, achievement of early complete donor chimerism in CD25(+) AL is a strong predictor for the development of aGvHD. Prospective analysis of chimerism in AL could improve the post-SCT management of immunosuppressive therapy in transplanted patients. PMID- 25450516 TI - Forensic investigation of a chromium(VI) groundwater plume in Thiva, Greece. AB - A forensic investigation was conducted with the aim of decoupling the contribution of geogenic and anthropogenic Cr(VI) sources in the wider area of Thiva. Groundwater and topsoil samples were collected from two Cr(VI) groundwater plumes of 160 MUg/L and 75 MUg/L. A series of evidence support the view that the origin of Cr(VI) detected in groundwater is mainly geogenic. These are: (a) the presence of Cr in topsoil of the wider area, (b) the moderate Cr(VI) groundwater concentrations, (c) the high Ni levels within the Cr(VI) plumes, (d) the predominance of Mn(IV), which is a prerequisite for Cr(III) oxidation to Cr(VI), and (e) the absence of co-contaminants. The present study also revealed that, although both Cr(VI) plumes are clearly of geogenic origin, the plume with the elevated Cr(VI) values, in the north of Thiva town, exhibits also an anthropogenic component, which can potentially be attributed to the alkaline environment associated with the old uncontrolled landfill of Thiva and the industrial cluster located in this area. PMID- 25450514 TI - Variegated clonality and rapid emergence of new molecular lesions in xenografts of acute lymphoblastic leukemia are associated with drug resistance. AB - The use of genome-wide copy-number analysis and massive parallel sequencing has revolutionized the understanding of the clonal architecture of pediatric acute lymphoblastic leukemia (ALL) by demonstrating that this disease is composed of highly variable clonal ancestries following the rules of Darwinian selection. The current study aimed to analyze the molecular composition of childhood ALL biopsies and patient-derived xenografts with particular emphasis on mechanisms associated with acquired chemoresistance. Genomic DNA from seven primary pediatric ALL patient samples, 29 serially passaged xenografts, and six in vivo selected chemoresistant xenografts were analyzed with 250K single-nucleotide polymorphism arrays. Copy-number analysis of non-drug-selected xenografts confirmed a highly variable molecular pattern of variegated subclones. Whereas primary patient samples from initial diagnosis displayed a mean of 5.7 copy number alterations per sample, serially passaged xenografts contained a mean of 8.2 and chemoresistant xenografts a mean of 10.5 copy-number alterations per sample, respectively. Resistance to cytarabine was explained by a new homozygous deletion of the DCK gene, whereas methotrexate resistance was associated with monoallelic deletion of FPGS and mutation of the remaining allele. This study demonstrates that selecting for chemoresistance in xenografted human ALL cells can reveal novel mechanisms associated with drug resistance. PMID- 25450517 TI - A child's view: social and physical environmental features differentially predict parent and child perceived neighborhood safety. AB - Parent and child perceived neighborhood safety predicts child health outcomes such as sleep quality, asthma, physical activity, and psychological distress. Although previous studies identify environmental predictors of parent perceived safety, little is known about predictors of child perceived safety. This study aims to identify the social and physical environmental neighborhood features that predict child and parent perceived neighborhood safety and, simultaneously, to assess the association between child and parent perceptions. Data were from the QUebec Adipose and Lifestyle InvesTigation in Youth (QUALITY) cohort, an ongoing study of Caucasian children (aged 8-10 years) with a parental history of obesity, and their biological parents from Quebec, Canada. Measures of social and physical neighborhood features were collected using a spatial data infrastructure and in person audits. Structural equation modeling was used to test direct and indirect associations between neighborhood features, child and parent perceived safety. Results suggest that among children (N = 494), trees and lighting were positively associated with perceived neighborhood safety, whereas a high proportion of visible minorities was associated with poorer perceived safety. Parents' perceptions of safety were more strongly tied to indicators of disorder and a lack of community involvement, and to traffic. Child perceived safety was partly explained by parent perceived safety, suggesting moderate concordance between perceptions. Although associated with each other, parent and child perceived safety seemed to be determined by distinct environmental features. Though this study focused on determinants of child and parent perceived safety, future research investigating the impact of neighborhood safety on child health should consider both child and parent perspectives. PMID- 25450518 TI - Hepatitis C surveillance among youth and young adults in New York City, 2009 2013. AB - Increases in prescription opioid misuse, injection drug use, and hepatitis C infections have been reported among youth and young adults in the USA, particularly in rural and suburban areas. To better understand these trends in New York City and to characterize demographics and risk factors among a population who, by virtue of their age, are more likely to be recently infected with hepatitis C, we analyzed routine hepatitis C surveillance data from 2009 to 2013 and investigated a sample of persons 30 and younger newly reported with hepatitis C in 2013. Between 2009 and 2013, 4811 persons 30 and younger were newly reported to the New York City Department of Health and Mental Hygiene with hepatitis C. There were high rates of hepatitis C among persons 30 and younger in several neighborhoods that did not have high rates of hepatitis C among older people. Among 402 hepatitis C cases 30 and younger investigated in 2013, the largest proportion (44 %) were white, non-Hispanic, and the most commonly reported risk factor for hepatitis C was injection drug use, mostly heroin. Hepatitis C prevention and harm reduction efforts in NYC focused on young people should target these populations, and surveillance for hepatitis C among young people should be a priority in urban as well as rural and suburban settings. PMID- 25450520 TI - Mnks, eIF4E phosphorylation and cancer. AB - The MAP kinase signal-integrating kinases or MAP kinase-interacting protein kinases (Mnks) are activated by signaling through the oncogenic MAP kinase (ERK) pathway. The best-known Mnk substrate is eukaryotic initiation factor eIF4E, the protein which binds the 5'-cap structure of eukaryotic mRNAs and helps to recruit ribosomes to them. eIF4E is a well-established proto-oncogene, whose expression or activation is associated with transformation and tumorigenesis. Mnks phosphorylate eIF4E at a single site. Increasing evidence implicates the Mnks and/or phosphorylation of eIF4E in cell transformation, tumorigenesis or tumor progression, in a growing range of settings. Mnks and/or the phosphorylation of eIF4E have been suggested to regulate the expression of proteins involved in cell cycle progression, cell survival and cell motility. Further work is needed to extend our understanding of the impact of the Mnks on gene expression, explore the biochemical mechanisms involved and evaluate the utility of targeting the Mnks in cancer therapy. This article is part of a Special Issue entitled: Translation and Cancer. PMID- 25450519 TI - Somatic mutations of amino acid metabolism-related genes in gastric and colorectal cancers and their regional heterogeneity--a short report. AB - BACKGROUND: Metabolic reprogramming is an emerging topic in cancer research. However, genetic alterations in genes encoding enzymes involved in amino acid metabolism are largely unknown. The aim of this study was to explore whether genes known to be involved in amino acid metabolism are mutated in gastric cancer (GC) and/or colorectal cancer (CRC). METHODS: Through a public database search, we found that a number of genes known to be involved in amino acid metabolism, i.e., AGXT, ALDH2, APIP, MTR, DNMT1, ASH1L, ASPA, CAD, DDC, GCDH, DLD, LAP3, MCEE and MUT, harbor mononucleotide repeats that may serve as mutation targets in cancers exhibiting microsatellite instability (MSI). We assessed these genes for the presence of the mutations in 79 GCs and 124 CRCs using single-strand conformation polymorphism (SSCP) and direct sequencing analyses. RESULTS: Using SSCP in conjunction with DNA sequencing we detected frameshift mutations in AGXT (17 cases), ALDH2 (3 cases), APIP (4 cases), MTR (5 cases), DNMT1 (1 case), ASH1L (1 case), ASPA (2 cases), CAD (2 cases), DDC (1 case), GCDH (3 cases), DLD (1 case), LAP3 (1 case), MCEE (5 cases) and MUT (1 case). These mutations were exclusively detected in MSI-high (MSI-H), and not in MSI-low or MSI-stable (MSI L/MSS) cases. In addition, we analyzed 16 CRCs for the presence of intra-tumor heterogeneity (ITH) and found that two CRCs harbored regional ITH for GCDH frameshift mutations. CONCLUSIONS: Our data indicate that genes known to be involved in amino acid metabolism recurrently acquire somatic mutations in MSH-H GCs and MSH-H CRCs and that, in addition, mutation ITH does occur in at least some of these tumors. Together, these data suggest that metabolic reprogramming may play a role in the etiology of MSI-H GCs and CRCs. Our data also suggest that ultra-regional mutation analysis is required for a more comprehensive evaluation of the mutation status in these tumors. PMID- 25450521 TI - The role of eIF3 and its individual subunits in cancer. AB - Specific individual subunits of eIF3 are elevated or reduced in numerous human tumors, and their ectopic overexpression in immortal cells can result in malignant transformation. The structure and assembly of eIF3 and its role in promoting mRNA and methionyl-tRNAi binding to the ribosome during the initiation phase of protein synthesis are described. Methods employed to detect altered levels of eIF3 subunits in cancers are critically evaluated in order to conclude rigorously that such subunits may cause malignant transformation. Strong evidence is presented that the individual overexpression of eIF3 subunits 3a, 3b, 3c, 3h, 3i and 3m may cause malignant transformation, whereas underexpression of subunits 3e and 3f may cause a similar outcome. Possible mechanisms to explain the malignant phenotypes are examined. The involvement of eIF3 in cancer reinforces the view that translational control plays an important role in the regulation of cell proliferation, and provides new targets for the development of therapeutic agents. This article is part of a Special Issue entitled: Translation and Cancer. PMID- 25450522 TI - Genome-wide identification of hypoxia-inducible factor-1 and -2 binding sites in hypoxic human macrophages alternatively activated by IL-10. AB - Macrophages (MPhi) often accumulate in hypoxic areas, where they significantly influence disease progression. Anti-inflammatory cytokines, such as IL-10, generate alternatively activated macrophages that support tumor growth. To understand how alternative activation affects the transcriptional profile of hypoxic macrophages, we globally mapped binding sites of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha in primary human monocyte-derived macrophages prestimulated with IL-10. 713 HIF-1 and 795 HIF-2 binding sites were identified under hypoxia. Pretreatment with IL-10 altered the binding pattern, with 120 new HIF-1 and 188 new HIF-2 binding sites emerging. HIF-1 binding was most prominent in promoters, while HIF-2 binding was more abundant in enhancer regions. Comparison of ChIP-seq data obtained in other cells revealed a highly cell type specific binding of HIF. In MPhi HIF binding occurred preferentially in already active enhancers or promoters. To assess the roles of HIF on gene expression, primary human macrophages were treated with siRNA against HIF-1alpha or HIF 2alpha, followed by genome-wide gene expression analysis. Comparing mRNA expression to the HIF binding profile revealed a significant enrichment of hypoxia-inducible genes previously identified by ChIP-seq. Analysis of gene expression under hypoxia alone and hypoxia/IL-10 showed the enhanced induction of a set of genes including PLOD2 and SLC2A3, while another group including KDM3A and ADM remained unaffected or was reduced by IL-10. Taken together IL-10 influences the DNA binding pattern of HIF and the level of gene induction. PMID- 25450523 TI - Expression of citrate carrier gene is activated by ER stress effectors XBP1 and ATF6alpha, binding to an UPRE in its promoter. AB - The Unfolded Protein Response (UPR) is an intracellular signaling pathway which is activated when unfolded or misfolded proteins accumulate in the Endoplasmic Reticulum (ER), a condition commonly referred to as ER stress. It has been shown that lipid biosynthesis is increased in ER-stressed cells. The N(epsilon)-lysine acetylation of ER-resident proteins, including chaperones and enzymes involved in the post-translational protein modification and folding, occurs upon UPR activation. In both ER proteins acetylation and lipid synthesis, acetyl-CoA is the donor of acetyl group and it is transported from the cytosol into the ER. The cytosolic pool of acetyl-CoA is mainly derived from the activity of mitochondrial citrate carrier (CiC). Here, we have demonstrated that expression of CiC is activated in human HepG2 and rat BRL-3A cells during tunicamycin-induced ER stress. This occurs through the involvement of an ER stress responsive region identified within the human and rat CiC proximal promoter. A functional Unfolded Protein Response Element (UPRE) confers responsiveness to the promoter activation by UPR transducers ATF6alpha and XBP1. Overall, our data demonstrate that CiC expression is activated during ER stress through the binding of ATF6alpha and XBP1 to an UPRE element located in the proximal promoter of Cic gene. The role of ER stress-mediated induction of CiC expression has been discussed. PMID- 25450525 TI - Variations in the neonatal environment modulate adult behavioral and brain responses to palatable food withdrawal in adult female rats. AB - BACKGROUND/OBJECTIVES: Early handling alters adult behavioral responses to palatable food and to its withdrawal following a period of chronic exposure. However, the central mechanisms involved in this phenomenon are not known. Since neonatal handling has persistent effects on stress and anxiety responses, we hypothesized that its involvement in the aforementioned association may be associated with differential neuroadaptations in the amygdala during withdrawal periods. METHODS: Litters were randomized into two groups: handled (H, removed from their dam for 10min per day from the first to the tenth postnatal day and placed in an incubator at 32 degrees C) and non-handled (NH). Experiment 1: on PNDs 80-100, females were assigned to receive palatable food+rat chow for 15 or 30 days, and these two groups were compared in terms of palatable food preference, body weight and abdominal fat deposition. In Experiment 2, H and NH rats were exposed to a chronic diet of palatable food+rat chow for 15 days, followed by (a) no withdrawal, (b) 24h withdrawal from palatable food (receiving only rat chow) or (c) 7-day withdrawal from palatable food (receiving only rat chow). Body weight, 10-min rebound palatable food intake, abdominal fat deposition, serum corticosterone as well as TH and pCREB levels in the amygdala were then compared between groups. RESULTS: Experiment 1-chronic exposure to palatable food induces comparable metabolic effects after 15 and 30 days. Experiment 2-neonatal handling is associated with a peculiar response to palatable food withdrawal following chronic exposure for 15 days. Rats exposed to early handling ingested less of this food after a 24h withdrawal period, and displayed increased amygdala TH and pCREB levels. CONCLUSIONS: Variations in the neonatal environment affect both behavioral responses and amygdala neuroadaptation to acute withdrawal from a palatable diet. These findings contribute to the comprehension of the mechanisms that link early life events and altered feeding behavior and related morbidities such as obesity in adulthood. PMID- 25450524 TI - Assessment of in-utero venlafaxine induced, ROS-mediated, apoptotic neurodegeneration in fetal neocortex and neurobehavioral sequelae in rat offspring. AB - Venlafaxine (VEN), a serotonin and noradrenaline reuptake inhibitor is being used as a drug of choice for treating clinical depression even during pregnancy. It is an important therapeutic option in the treatment of perinatal depression, but the effects of VEN on fetus and the newborn are uncertain. Therefore, present study was undertaken to investigate the safety of in-utero exposure to VEN in terms of developmental neurotoxicity and neurodegenerative potential by using prenatal rat model. The selected doses of VEN (25, 40 and 50mg/kg) were administered to pregnant rats from GD 5 to 19 through oral gavage. The fetal brains were dissected and processed for histopathological measurements of neocortical thickness that showed significant reduction. Considering vulnerability of immature brain to free radical injury, VEN exposed neocortices were tested for reactive oxygen species (ROS) levels which were significantly increased. As ROS play important role in the initiation of apoptotic mechanisms, we explored for in situ detection of apoptosis by confocal microscopy that showed enhanced apoptosis including chromatin condensation which was further reconfirmed by electron microscopy. Substantially increased levels of pro-apoptotic protein Bax and decreased levels of anti-apoptotic protein Bcl2 as shown by western blotting also supported the increased neuro-apoptotic degeneration. For further correlation of these findings, prenatally VEN exposed young-adult rat offspring were assessed for open field exploratory behavior that showed increased anxiety-like and stereotypic responses indicating disturbed neurobehavioral pattern. The study concludes that prenatal VEN exposure may primarily enhance ROS generation that plays a key role in regulating release of proapoptotic factors from mitochondria and thereby enhancing apoptotic neurodegeneration that affect proliferation, migration and differentiation of cells, resulting in neuronal deficits manifested as long term neurobehavioral impairments. PMID- 25450526 TI - Cerebellum neurotransmission during postnatal development: [Pt(O,O'-acac)(gamma acac)(DMS)] vs cisplatin and neurotoxicity. AB - Several chemotherapeutic drugs are known to cause neurotoxicity. Platinum-based agents in use or in clinical trials display neurotoxic potential accompanied by neurological complications; recent studies have identified a large number of behavioural issues in paediatric oncology patients. To understand the toxicity of platinum drugs at the molecular and cellular levels, this study compares the possible cytotoxic effects of an older platinum compound, cisplatin and a new platinum compound, [Pt(O,O'-acac)(gamma-acac)(DMS)], on the CNS of postnatally developing rats, which is much more vulnerable to injury than the CNS of adult rats. Since several drugs interact with neurotransmitters during neuronal maturation, we performed immunostainings with antibodies raised against markers of glutamate and GABA, the major neurotransmitters in the cerebellum. After a single injection of cisplatin at postnatal day 10 (PD10), the labelling of Purkinje cells with the neurotransmitter markers evidenced alterations between PD11 and PD30, i.e. atrophy of the dendrite tree, changes in the distribution of synaptic contacts of parallel and climbing fibres, delay in the elimination of transient synapses on cell soma and severely impaired pinceau formation at the axon hillock. After treatment with [Pt(O,O'-acac)(gamma-acac)(DMS)], the sole relevant change concerned the timing of climbing fibres elimination; the transient synapses disappearance on the Purkinje cell soma was delayed in some cells; instead, the growth of Purkinje cell dendrite tree was normal as was the formation of inhibitory synaptic contacts on these neurons. These findings add new evidence not only on the lower neurotoxicity of [Pt(O,O'-acac)(gamma acac)(DMS)] vs cisplatin but also on the involvement of neurotransmitters and relative synaptic connections in the maturation of central nerve tissue. PMID- 25450527 TI - Increased expression of Hes5 protein in Notch signaling pathway in the hippocampus of mice offspring of dams fed a high-fat diet during pregnancy and suckling. AB - Maternal high-fat diet (HFD) impairs hippocampal development of offspring promoting decreased proliferation of neural progenitors, in neuronal differentiation, in dendritic spine density and synaptic plasticity reducing neurogenic capacity. Notch signaling pathway participates in molecular mechanisms of the neurogenesis. The activation of Notch signaling leads to the upregulation of Hes5, which inhibits the proliferation and differentiation of neural progenitors. This study aimed to investigate the Notch/Hes pathway activation in the hippocampus of the offspring of dams fed an HFD. Female Swiss mice were fed a control diet (CD) and an HFD from pre-mating until suckling. The bodyweight and mass of adipose tissue in the mothers and pups were also measured. The mRNA and protein expression of Notch1, Hes5, Mash1, and Delta1 in the hippocampus was assessed by RT-PCR and western blotting, respectively. Dams fed the HFD and their pups had an increased bodyweight and amount of adipose tissue. Furthermore, the offspring of mothers fed the HFD exhibited an increased Hes5 expression in the hippocampus compared with CD offspring. In addition, HFD offspring also expressed increased amounts of Notch1 and Hes5 mRNA, whereas Mash1 expression was decreased. However, the expression of Delta1 did not change significantly. We propose that the overexpression of Hes5, a Notch effector, downregulates the expression of the proneural gene Mash1 in the offspring of obese mothers, delaying cellular differentiation. These results provide further evidence that an offspring's hippocampus is molecularly susceptible to maternal HFD and suggest that Notch1 signaling in this brain region is important for neuronal differentiation. PMID- 25450528 TI - Evaluation of spontaneous dense array gamma oscillatory activity and minor physical anomalies as a composite neurodevelopmental endophenotype in schizophrenia. AB - OBJECTIVE: Minor physical anomalies (MPAs) and gamma oscillatory activity have been proposed as associated endophenotypes in schizophrenia. Combining these endophenotypes to create a composite endophenotype may help identify those at risk for schizophrenia better. The present study aims to investigate MPAs and gamma oscillatory activity in schizophrenia patients, their unaffected first degree relatives and healthy controls and appreciate whether they can be used together as a composite endophenotype. METHODS: This was a cross sectional family study conducted at a tertiary care mental health setup. Ninety participants including schizophrenia patients, their first degree relatives and controls (thirty each) were assessed for MPAs on the Extended Waldrop Scale. All participants underwent an awake, resting 192-channel EEG recording. Spectral power and coherence in 30-100Hz gamma bands were estimated using Welch's averaged periodogram method. One-way ANOVA, chi square test were used for comparing socio demographic-clinical variables. MANOVA supplemented by one-way ANOVAs (post hoc Tukey HSD) were done for comparison of spectral measures. Pearson's correlation, step-by-step linear discriminant functional and intra-familial correlation analysis were subsequently performed. RESULTS: An endophenotype pattern of finding was found for MPAs in the craniofacial region, the total number of MPAs, spectral power in right temporal region on all bands and in the right parietal region in 50-70Hz and 70-100Hz gamma bands. The three groups were most accurately classified when MPA total score, right temporal 30-50Hz gamma power and right occipital 'intra hemispheric' 50-70Hz gamma coherence were considered together than when considered independently. Significant intra familial correlation was seen for MPA total score and right temporal gamma 30-50Hz power. CONCLUSION: Composite evaluation of two developmentally linked markers i.e. MPAs and gamma spectral measures may prove useful in categorizing schizophrenia and identifying at-risk individuals. PMID- 25450529 TI - Immediate and long-term effects of psychological stress during adolescence in cardiovascular function: comparison of homotypic vs heterotypic stress regimens. AB - Adolescence has been proposed as an ontogenic period of vulnerability to stress. Nevertheless, the impact of stressful events during adolescence in cardiovascular activity is poorly understood. Therefore, the purpose of this study was to investigate the immediate and long-lasting effects of exposure to stressful events during adolescence in cardiovascular function of rats. To this end, we compared the impact of 10-days exposure to two chronic stress protocols: the repeated restraint stress (RRS, homotypic) and chronic variable stress (CVS, heterotypic). Independent groups of animals were tested 24h (immediate) or three weeks (long-lasting) following completion of stress period. Exposure to CVS, but not RRS, during adolescence increased basal HR values without affecting arterial pressure, which was followed by augmented power of oscillatory component at low frequency (sympathetic-related) of the pulse interval (PI). RRS enhanced variance of the PI with an increase in the power of both low and high (parasympathetic related) frequency components. RRS also increased the baroreflex gain. Neither RRS nor CVS affected systolic arterial pressure variability. The RRS-evoked changes in PI variability were long-lasting and persisted into adulthood while all alterations evoked by the CVS were reversed in adulthood. These findings indicate a stress type-specific influence in immediate and long-term effects of stress during adolescence in cardiovascular function. While immediate changes in cardiovascular function were mainly observed following CVS, long-lasting autonomic consequences in adulthood were observed only in animals exposed to RRS during adolescence. PMID- 25450530 TI - The Personal Impact of Epilepsy Scale (PIES). AB - OBJECTIVE: The impact of epilepsy is manifest by effects related to seizures and side effects of therapy and comorbidities such as depression. This report describes the development of a brief patient-reported outcome (PRO) instrument, the Personal Impact of Epilepsy Scale (PIES), to measure the influence of epilepsy overall and in each of these domains. METHODS: Instrument development followed standard procedures and an FDA Guidance. People with epilepsy were surveyed with open-ended questions to derive major themes of their concerns, resulting in 4 key areas: seizures, side effects, comorbidities, and overall quality of life (QOL). A preliminary set of 152 questions was based on these themes and completed by 50 patients, age 42.7 (range: 21-71) years, concurrent with comparator instruments, including the NH Seizure Severity Scale (NHSSS), the Liverpool Adverse Events Profile (LAEP), the Quality of Life in Epilepsy (QOLIE 31) scale, the Beck Depression Inventory, and the Epilepsy Foundation Depression: A Checklist. A multiple regression model indicated which PIES measures were associated with scores from the comparator instruments. Questions in each of the domains were selected for correlations and nonduplication. Test-retest consistency at a 3-day interval was completed by 38 subjects and a final set of questions constructed. RESULTS: The final question set comprised 25 items: 9 about characteristics of seizures, 7 about medication side effects, 8 about comorbidities, and 1 about overall quality of life. All items had 5 response choices (0-4), with higher scores reflecting more negative status. A total of 46 subjects completed the 25 questions. Cronbach's alpha was 0.87, indicating good internal consistency. Each of the three domains correlated well with the overall QOL item. The questions pertaining to seizures correlated with the NHSSS, the side effect questions with the LAEP, and the comorbidity questions with the QOLIE 31. CONCLUSION: The PIES provides a simple, brief PRO measure as a profile of overall impact of seizures, medication side effects, comorbidities, and overall QOL for people with epilepsy. Further study will explore sensitivity to change quantification of the minimal clinically significant change. PMID- 25450531 TI - Comments on Reuber et al. Psychogenic nonepileptic seizures: review and update. Epilepsy & behavior 2003;4:205-216. PMID- 25450534 TI - Boosting - an unusual yet attractive optimiser. AB - This editorial is part of a For-Discussion-Section of Methods of Information in Medicine about the papers "The Evolution of Boosting Algorithms - From Machine Learning to Statistical Modelling" and "Extending Statistical Boosting - An Overview of Recent Methodological Developments", written by Andreas Mayr and co authors. It preludes two discussed reviews on developments and applications of boosting in biomedical research. The two review papers, written by Andreas Mayr, Harald Binder, Olaf Gefeller, and Matthias Schmid, give an overview on recently published methods that utilise gradient or likelihood-based boosting for fitting models in the life sciences. The reviews are followed by invited comments by experts in both boosting theory and applications. PMID- 25450536 TI - Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and risk of venous thromboembolism: a meta-analysis. AB - INTRODUCTION: The plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism was considered to be associated with risk of venous thromboembolism (VTE), while evidence remains inadequate. To provide a more accurate estimation of this relationship, we performed an updated meta-analysis of all eligible studies. MATERIALS AND METHODS: A systematical search was performed in PubMed, EMBASE, Wanfang, China National Knowledge Infrastructure (CNKI) and Cqvip databases to identify relevant studies published before March 6(th) 2014. The odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using the fixed/random effects model using Review Manager 5.1 and STATA 12.0. RESULTS: A total of 34 studies with 3561 cases and 5693 controls were analyzed. Overall, significant association between the PAI-1 4G/5G variant and VTE risk in total population (dominant model: OR=1.32, 95%CI: 1.13-1.54) was observed. And this variant was also related to the deep vein thrombosis risk (dominant model: OR=1.60, 95%CI: 1.24-2.06, P=0.0003). In the subgroup analyses on ethnicity, significant results were obtained in both Asians (dominant model: OR=2.08, 95%CI: 1.29-3.35, P=0.003) and Caucasians (dominant model: OR=1.31, 95%CI: 1.10-1.56, P=0.003). However, no significant association was found in patients with provoked VTE. In terms of subgroup analyses on co-existence of other thrombotic risk factors, the PAI-1 4G/5G polymorphism was significantly associated with VTE risk in patients with factor V Leiden mutation (dominant model: OR=1.72, 95%CI: 1.17-2.53), but not in patients with cancer or surgery. CONCLUSION: Our findings demonstrate the role of PAI-1 4G/5G polymorphism being a risk candidate locus for VTE susceptibility, especially in patients with other genetic thrombophilic disorders. PMID- 25450535 TI - A case series of LMWH use in pregnancy: should trough anti-Xa levels guide dosing? AB - INTRODUCTION: Pregnancy is a thrombogenic state, increasing the risk for venous thromboembolism (VTE), and the risk of valve thrombosis amongst women with mechanical heart valves (MHV). While low molecular weight heparins (LMWH) are generally dosed based on weight (i.e., enoxaparin 1 mg/kg every 12 hours), data in pregnant women have shown that weight-based dosing does not consistently achieve target anti-Xa levels. In women with MHV, our practice includes titrating LMWH doses to target both trough and peak anti-Xa levels, while for those with VTE peak anti-Xa levels guide dosing. MATERIALS/METHODS: This retrospective case series included pregnant women requiring LMWH treatment doses with at least 3 peak (+/-trough) anti-Xa levels. Our primary objective was to describe the actual LMWH dose required to achieve targeted anti-Xa levels relative to weight-based dosing in patients with MHV. Secondarily, we compared the same for VTE patients; compared actual dosing between those with MHV and VTE; and examined maternal and fetal outcomes. RESULTS/CONCLUSION: Women with MHV (N=4) required greater than weight-based dosing of enoxaparin (1.35 mg/kg Q12H) to achieve targeted anti-Xa levels. Importantly, achieving target peak anti-Xa levels did not always ensure maintenance of minimum trough levels. VTE patients (N=12) did not require more enoxaparin (0.96 mg/kg Q12H) than weight based dosing. MHV patients received more enoxaparin compared to VTE patients (P<0.001). No bleeding or clotting complications were associated with LMWH administration. In pregnant women with MHV at high risk of thromboembolism, LMWH dosing guided by trough and peak anti Xa levels should be considered. PMID- 25450537 TI - Theta-burst stimulation: a new form of TMS treatment for depression? AB - Major depressive disorder (MDD) is a common debilitating condition where only one third of patients achieve remission after the first antidepressant treatment. Inadequate efficacy and adverse effects of current treatment strategies call for more effective and tolerable treatment options. Transcranial magnetic stimulation (TMS) is a noninvasive approach to manipulate brain activity and alter cortical excitability. There has been more than 15 years of research on the use of repetitive form of TMS (rTMS) for the treatment of patients with depression, which has shown it to be an effective antidepressant treatment. Even though rTMS treatment has shown efficacy in treating depression, there is a high degree of interindividual variability in response. A newer form of rTMS protocol, known as theta-burst stimulation (TBS), has been shown to produce similar if not greater effects on brain activity than standard rTMS. TBS protocols have a major advantage over standard rTMS approaches in their reduced administration duration. Conventional rTMS procedures last between 20 and 45 min, as compared to TBS paradigms that require 1 to 3 min of stimulation. Recently, a small number of studies have suggested that TBS has similar or better efficacy in treating depression compared to rTMS. Optimization, identification of response predictors, and clarification of neurobiological mechanisms of TBS is required if it is to be further developed as a less time intensive, safe, and effective treatment for MDD. PMID- 25450538 TI - Optimizing parameters on alignment of PCL/PGA nanofibrous scaffold: An artificial neural networks approach. AB - This paper proposes an artificial neural networks approach to finding the effects of electrospinning parameters on alignment of poly(E-caprolactone)/poly(glycolic acid) blend nanofibers. Four electrospinning parameters, namely total polymer concentration, working distance, drum speed and applied voltage were considered as input and the standard deviation of the angles of nanofibers, introducing fibers alignments, as the output of the model. The results demonstrated that drum speed and applied voltage are two critical factors influencing nanofibers alignment, however their effect are entirely interdependent. Their effects also are not independent of other electrospinning parameters. In obtaining aligned electrospun nanofibers, the concentration and working distance can also be effective. In vitro cell culture study on random and aligned nanofibers showed directional growth of cells on aligned fibers. PMID- 25450539 TI - Purification, characterization, and molecular cloning of an extracellular chitinase from Bacillus licheniformis stain LHH100 isolated from wastewater samples in Algeria. AB - An extracellular chitinase (ChiA-65) was produced and purified from a newly isolated Bacillus licheniformis LHH100. Pure protein was obtained after heat treatment and ammonium sulphate precipitation followed by Sephacryl S-200 chromatography. Based on matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/MS) analysis, the purified enzyme is a monomer with a molecular mass of 65,195.13 Da. The sequence of the 27 N-terminal residues of the mature ChiA-65 showed high homology with family-18 chitinases. Optimal activity was achieved at pH 4 and 75 degrees C. Among the inhibitors and metals tested, p-chloromercuribenzoic acid, N-ethylmaleimide, Hg(2+), and Hg(+) completely inhibited enzyme activity. Chitinase activity was high on colloidal chitin, glycol chitin, glycol chitosane, chitotriose, and chitooligosaccharide. Chitinase activity towards synthetic substrates in the order of p-NP-(GlcNAc)n (n = 2-4) was p-NP-(GlcNAc)2 > p-NP-(GlcNAc)4 > p-NP-(GlcNAc)3. Our results suggest that ChiA-65 preferentially hydrolyzed the second glycosidic link from the non reducing end of (GlcNAc)n. ChiA-65 obeyed Michaelis-Menten kinetics, the Km and kcat values being 0.385 mg, colloidal chitin/ml and 5000 s(-1), respectively. The chiA-65 gene encoding ChiA-65 was cloned in Escherichia coli and its sequence was determined. Above all, ChiA-65 exhibited remarkable biochemical properties suggesting that this enzyme is suitable for bioconversion of chitin waste. PMID- 25450540 TI - Preparation of chitosan nanofibers from completely deacetylated chitosan powder by a downsizing process. AB - Chitosan nanofibers were easily prepared from fully deacetylated chitosan dry powder using a high-pressure waterjet system. From SEM observation, after 10 cycles of treatment, most of the chitosan had been reduced to homogeneous nanofibers measuring tens of nanometers. On the other hand, further mechanical treatment did not show a significant change. Relative crystallinity of chitosan nanofibers gradually decreased as the number of passes increased since high pressure waterjet treatment damaged the crystalline region of chitosan nanofibers. The transmittance of the chitosan nanofiber slurry increased steeply, as the number of passes increased, indicating that the chitosan fibers were disintegrated effectively. Viscosity of chitosan nanofiber slurry also showed that the chitosan disintegrated well into nanofibers up to 10 passes. Above 10 passes, disintegration efficiency was saturated. The molecular weights of the nanofibers steeply decreased due to the depolymerization of chitosan by mechanical disintegration. The Young's modulus and tensile strength of chitosan nanofiber sheets were improved as the number of treatments increased, but further treatments deteriorated the tensile strength. PMID- 25450541 TI - Study on immobilization of yeast alcohol dehydrogenase on nanocrystalline Ni-Co ferrites as magnetic support. AB - The covalent binding of yeast alcohol dehydrogenase (YADH) enzyme complex in a series of magnetic crystalline Ni-Co nanoferrites, synthesized via sol-gel auto combustion technique was investigated. The structural analysis, morphology and magnetic properties of Ni-Co nanoferrites were determined by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), vibrating-sample magnetometer (VSM), high resolution transmission electron microscopy (HRTEM) and Fourier transform infrared spectroscopy (FTIR). The comparative analysis of the HRTEM micrographs of bare magnetic nanoferrite particles and particles immobilized with enzyme revealed an uniform distribution of the particles in both the cases without undergoing change in the size which was found to be in the range 20-30 nm. The binding of YADH to Ni-Co nanoferrites and the possible binding mechanism have been suggested by comparing the FTIR results. The binding properties of the immobilized YADH enzyme were also studied by kinetic parameters, optimum operational pH, temperature, thermal stability and reusability. The immobilized YADH exhibits enhanced thermal stability as compared to the free enzyme over a wide range of temperature and pH, and showed good durability after recovery by magnetic separation for repeated use. PMID- 25450542 TI - Foliar application of beta-D-glucan nanoparticles to control rhizome rot disease of turmeric. AB - The soilborne Oomycete Pythium aphanidermatum is the causal agent of rhizome rot disease, one of the most serious threats to turmeric crops. At present, effective fungicides are not available. Researches on nanoparticles in a number of crops have evidenced the positive changes in gene expression indicating their potential use in crop improvement. Hence, experiments were carried out to determine the effect of beta-D-glucan nanoparticles (nanobiopolymer) in protection of turmeric plants against rot disease by the way of products that reinforce plant's own defense mechanism. Foliar spray of beta-D-glucan nanoparticles (0.1%, w/v) elicited marked increase in the activity of defense enzymes such as peroxidases (E.C.1.11.1.7), polyphenol oxidases (E.C.1.14.18.1), protease inhibitors (E.C.3.4.21.1) and beta-1,3-glucanases (E.C.3.2.1.39) at various age levels. Constitutive and induced isoforms of these enzymes were investigated during this time-course study. beta-D-glucan nanoparticles (GNPs) significantly reduced the rot incidence offering 77% protection. Increased activities of defense enzymes in GNPs-applied turmeric plants may play a role in restricting the development of disease symptoms. These results demonstrated that GNPs could be used as an effective resistance activator in turmeric for control of rhizome rot disease. PMID- 25450543 TI - Acquired immunogenicity of calf thymus DNA and LDL modified by D-ribose: a comparative study. AB - Glycation of biologically important macromolecules leads to the establishment of advanced glycation end products (AGEs) having significant role in the pathophysiology of various diseases. d-Ribose, is a highly reactive pentose sugar resulting in the rapid formation of AGEs. Formation of d-ribose derived glycated DNA and LDL has been previously demonstrated; however no comparative, extensive studies have been performed to assess the immunogenicity of d-ribose glycated calf thymus DNA (CT-DNA) and LDL. In the present study, the results showed that animals immunized with d-ribose modified CT-DNA and LDL induced antibodies as detected by direct binding and competition ELISA. The modified CT-DNA and LDL were found to be highly immunogenic, eliciting high titer immunogen-specific antibodies, while the native forms of DNA was almost non-immunogenic. The induced antibodies from modified CT-DNA and LDL exhibited wide range of heterogeneity in recognizing various nucleic acid conformers, DNA bases and amino acids. Furthermore, Serum antibodies from diabetes and diabetes atherosclerosis patients were screened for their binding to native CT-DNA, LDL and glycated CT-DNA, LDL. Glycated CT-DNA showed almost equivalent binding to both diabetes and diabetic atherosclerosis group while high recognition was observed when glycated LDL was used as an antigen. PMID- 25450544 TI - Isolation, characterization and investigation of Cordia dichotoma fruit polysaccharide as a herbal excipient. AB - The objective of the present research work was to isolate, purify and characterize Cordia dichotoma gum and investigate its disintegration property in oral tablets. The isolated gum was tested for physicochemical characteristics such as solubility, pH (1% w/w in water), swelling index, loss on drying, ash value, bulk and tapped density, Carr's index, Hausner's ratio and angle of repose. The Orodispersible tablets of valsartan were prepared by direct compression method and evaluated for average weight (mg), drug content (%), thickness (mm), hardness (kg/cm(2)), friability (%), wetting time (sec), water absorption ratio (%) and disintegration time (sec). FTIR studies revealed that there was no interaction between drug, gum and other excipients used in the study. The F4 batch with disintegration time 26.34 +/- 0.78 s and in vitro release 99.64 +/- 0.43% was selected as optimized formulation. This formulation was compared with conventional marketed formulation and was found superior. Batch F4 was subjected to stability studies for three months and was tested for its disintegration time, drug contents and dissolution behaviour. Batch F4 was found stable for three months at accelerated temperature. PMID- 25450545 TI - MicroRNA delivery with osmotic polysorbitol-based transporter suppresses breast cancer cell proliferation. AB - MicroRNAs (miRNA) are short oligonucleotides of endogenous origin involved in post-transcriptional regulation and are altered in disease, making them potential therapeutic targets. miRNA replacement is necessary in cells with downregulated miRNAs levels in response to disease. miRNA 145 is a novel tumor suppressor gene involved in cell suppression, invasion and migration of cancer cells; it is downregulated in most cancers. Delivery of therapeutic miRNA using nanoparticles enhances the chances of successful delivery and expression of genes at the target site. We evaluated polysorbitol-mediated transporter (PSMT) in the cellular delivery of miRNA 145. The polysorbitol backbone possesses osmotic properties and leads to enhanced cellular uptake. PSMT delivers genes into cells by a caveolae mediated endocytic pathway. Caveolae expression is usually altered in transformed cancer cells. Physicochemical characterization, and the transfection efficiency and transgene expression capability of PSMT/reporter plasmid DNA nanoparticles, were determined. GFP-tagged miRNA 145 delivery with PSMT was confirmed by confocal microscopy and Western blotting. The functional effects of miRNA 145 delivered with PSMT were analyzed by confocal microscopy, as well as in apoptosis, proliferation and wound healing assays. Finally, the expression of an miRNA 145 target protein, c-myc, was determined by Western blotting after intracellular delivery of PSMT/miRNA 145 nanoparticle (NP). PMID- 25450546 TI - Corrosion mitigation of N-(2-hydroxy-3-trimethyl ammonium)propyl chitosan chloride as inhibitor on mild steel. AB - The biopolymer N-(2-hydroxy-3-trimethyl ammonium)propyl chitosan chloride (HTACC) was synthesised and its influence as a novel corrosion inhibitor on mild steel in 1M HCl was studied using gravimetric and electrochemical experiments. The compound obtained was characterised using FTIR and NMR studies. The inhibition efficiency increased with the increase in concentration and reached a maximum of 98.9% at 500 ppm concentration. Polarisation studies revealed that HTACC acts both as anodic and cathodic inhibitor. Electrochemical impedance studies confirmed that the inhibition is through adsorption on the metal surface. The extent of inhibition exhibits a negative trend with increase in temperature. Langmuir isotherm provides the best description on the adsorption nature of the inhibitor. SEM analysis indicated the presence of protective film formed by the inhibitor on the metal surface. PMID- 25450547 TI - Effect of water-soluble chitosan in combination with glutathione on the quality of pen shell adductor muscles. AB - In this study, the effects of the water-soluble chitosan (WSC) in combination with glutathione on preservation of pen shell adductor muscles (PSAM) during frozen storage were investigated. The PSAM samples were soaked in the solution containing 0.1% WSC in combination with 0.1% glutathione (treatment group) or in water (control group), and then they were stored under frozen conditions for 10 months, during which the samples were taken periodically and their total viable count, pH, total volatile basic nitrogen, and overall acceptability score were evaluated. Compared with the control group, treatment of WSC in combination with glutathione resulted in slower bacterial growth, lower pH increasing, lower total volatile basic nitrogen, and higher overall acceptability score of PSAM during frozen storage. The results show that treatment with WSC in combination with glutathione could prolong the shelf life of PSAM for up to 10 months. PMID- 25450548 TI - Gellan gum-g-N-vinyl-2-pyrrolidone: synthesis, swelling, metal ion uptake and flocculation behavior. AB - The synthesis of graft copolymer (gellan gum-g-N-vinyl-2-pyrrolidone) is carried out in nitrogen atmosphere using potassium bromate and silver as redox system. The reaction conditions for maximum grafting have been optimized by varying the reaction variables, including the concentration of N-vinyl-2-pyrrolidone (12.0 * 10(--2) to 28 * 10(--2) mol dm(-3)), potassium bromate (6 * 10(-3) to 22 * 10(-3) mol dm(-3)), silver (2.4 * 10(-3)to 5.6 * 10(-3) mol dm(-3)), sulphuric acid (2.0 * 10(-3) to 10 * 10(-3) mol dm(-3)), gellan gum (0.6-1.4 g dm(-3)) along with time duration (60 to 180 min) and temperature (30-50 degrees C).Water swelling capacity, metal ion sorption and flocculation studies of synthesized graft copolymer have been performed with respect to the parent polymer. The graft copolymer has been characterized by FTIR spectroscopy and thermogravimetric analysis. PMID- 25450549 TI - Kinetic models for the release of the anticancer drug doxorubicin from biodegradable polylactide/metal oxide-based hybrids. AB - For decades, studies on drug-release kinetics have been an important topic in the field of drug delivery because they provide important insights into the mechanism of drug release from carriers. In this work, polylactide (PLA), doxorubicin (DOX), and metal oxide (MO) (titanium dioxide, magnetic iron oxide, and zinc oxide) spheres were synthesised using the solvent-evaporation technique and were tested for sustained drug release. The efficacy of a dosage system is determined by its ability to deliver the drug at a sustained rate, afford an increased plasma half-life, a minimum exposure of toxic drugs to healthy cells and a high drug pay load. Mathematical models were used to elucidate the release mechanism of the drug from the spheres. The release fitted a zero-order model with a correlation coefficient in the range of 0.9878-0.9891 and the release mechanism followed an anomalous release, meaning drug release was afforded through both diffusion and the dissolution of PLA. Therefore, PLA/DOX/MO released the same amount of drug per unit time. Consequently, the potential for PLA use as a carrier was ascertained. PMID- 25450550 TI - Chitosan-based nanoparticles for tumor-targeted drug delivery. AB - Nanoparticles (NPs) have immense potential as drug-delivery carriers for cancer therapy due to their unique physicochemical properties. These particles can improve the pharmacological and therapeutic properties of the anti-cancer drugs by controlling release rates and targeted delivery process, which eliminate the limitations of conventional anti-cancer treatment methods. In recent years, chitosan-based NPs are emerging as one of the most promising delivery vehicles for cancer chemotherapy and diagnosis due to their unique characteristics such as biodegradability, biocompatibility, remarkable cell membrane penetrability, high drug-carrying capacities, pH-dependent therapeutic unloading, ability to have a multi-functionality and prolonged circulating time. This article reviews the recent developments on the preparation, properties and tumor-targeted drug delivery applications of NPs based on chitosan and its derivatives. PMID- 25450551 TI - Response surface optimization of ultrasound assisted extraction of pectin from pomegranate peel. AB - Ultrasound assisted extraction of pectin from waste pomegranate peel was investigated and optimized using Box-Behnken response surface design coupled with numerical optimization technique. The individual and interactive effect of process variables (solid-liquid ratio, pH, extraction time and temperature) on the pectin yield was studied. The experimental data obtained were analyzed by Pareto analysis of variance (ANOVA) and second-order polynomial models were developed using multiple regression analysis. The models developed from the experimental design were predictive and good fit with the experimental data with high coefficient of determination (R(2)) value. The optimal extraction condition was found to be 1:17.52 g/ml of solid-liquid ratio, 1.27 of pH, 28.31 min of extraction time and 61.90 degrees C of extraction temperature respectively. Under the optimal conditions, experimental yield was very close to the predicted values. PMID- 25450552 TI - Injectable and photocross-linkable gels based on gellan gum methacrylate: a new tool for biomedical application. AB - In this work, a natural polysaccharide gellan gum (GG) has been modified with methacrylic groups (GG-MA) and combined with polyethylene glycol dimethacrylate (PEG-DMA) in order to create novel injectable hydrogels that can be easily delivered through a needle and photocross-linked in the injection site. A novel synthetic procedure for methacrylation of GG has been proposed to better control its derivatization. Different degrees of functionalization have been achieved and their effects on the solubility and mechanical properties of GG-MA were investigated. A good balance in terms of hydrophilicity and elasticity of the corresponding hydrogels was identified, although not suitable enough as injectable material for the treatment of damaged soft tissues. For this reason, several concentrations and different molecular weights of PEG-DMA were investigated to modulate the composition of GG-MA hydrogels and overcome their extreme fragility. Swelling abilities of the hydrogels in different media were studied as a key parameter able to affect the release profile of loaded therapeutic agents. Model molecules having different spherical hindrance (sulindac and vitamin B12) were then chosen to study how the hydrogels were able to modulate their diffusion profiles over time. Finally, the hydrogel's safety was evaluated trough an MTT cytotoxicity test on human fibroblasts. PMID- 25450553 TI - Hyaluronic acid/chitosan nanoparticles for delivery of curcuminoid and its in vitro evaluation in glioma cells. AB - The aim of this work was to evaluate the potential of polyelectrolyte complex nanoparticles (PENPs) based on hyaluronic acid/chitosan (HA/CS) as carriers for water-insoluble curcuminoid (CUR) and explore in vitro performance against brain glioma cells. PENPs were observed to be affected by the order of addition, mass ratios and initial concentrations of the HA/CS, pH and ionic strength. PENPs remained stable over a temperature range of 5--55(C. CUR was successfully encapsulated into the PENPs. CUR-PENPs showed spherical shape with a mean diameter of 207 nm and positive charge of 25.37 mV. High encapsulation efficiency (89.9%) and drug loading (6.5%) was achieved. Drug release studies revealed initial burst release of drug from the PENPs up to 4h followed by sustained release pattern. DSC thermograms and XRD patterns showed that CUR was encapsulated inside the PENPs in a molecular or amorphous state. Compared with CUR-solution, CUR-PENPs showed stronger dose dependent cytotoxicity against C6 glioma cells and higher performance in uptake efficiency in C6 cells. Cellular uptake of CUR-PENPs was found to be governed by multi-mechanism in C6 cells, involving active endocytosis, macropinocytosis, clathrin-, caveolae-, and CD44 mediated endocytosis. In conclusion, CUR-PENPs might be a promising carrier for therapy of brain gliomas. PMID- 25450554 TI - Effect of media milling on lipid-lowering and antioxidant activities of chitosan. AB - The effect of media milling on lipid-lowering and antioxidant activities of chitosan was studied in rats fed high-fat diets. Results showed that media-milled chitosan was more effective than chitosan in reducing body weight gain and liver fat accumulation of rats. Compared with chitosan, the reducing effects of media milled chitosan on serum triacylglycerol (TG), total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) were increased by 10.1, 7.5 and 10.2%, and liver TG and TC-reducing effects were increased by 16.2 and 14.6%, respectively. Rats fed media-milled chitosan showed decreased levels of free fatty acid (FFA) and thiobarbituric acid-reactive substances (TBARS) and increased superoxide dismutase (SOD) activity. The cholesterol and fat in feces of rats fed media-milled chitosan were higher than those of rats fed chitosan. These results suggested media milling enhanced the lipid-lowering and antioxidant activities of chitosan, and the reason might be partly due to its effect on strengthening the ability of chitosan in promoting fecal lipid excretions. PMID- 25450555 TI - Synthesis and antibacterial of carboxymethyl starch-grafted poly(vinyl imidazole) against some plant pathogens. AB - Poly(N-vinyl imidazole) (PVI) has been grafted onto carboxymethyl starch (CMS) in aqueous solution using potassium persulfate (KPS) as initiator. Reaction parameters that affect grafting efficiency and percentage grafting such as monomer and initiator concentration, the reaction temperature and time were investigated. The grafted products were characterized by FTIR, thermal analysis, SEM photograph and elemental analysis. The antibacterial effects of the carboxymethyl starch-grafted-poly(N-vinylimidazole) (CMS-g-PVI) was examined against two plant pathogens Gram negative bacteria: Xanthomonas perforanss and Xanthomonas oryzae. Generally, upon application of the CMS-g-PVI to the bacterial cells; the mortality rate increased from 45.71 to 59.37% for Xanthomonas perforans and X. oryzae, respectively. While the MIC for most of both bacterial strains were recorded at concentration of 60 MUg/mL. The results indicate that CMS-g-PVI has bactericidal properties and can be used for seed treatment to control xanthomonads associated with bacterial leaf spot (BLS). PMID- 25450556 TI - Statistical optimization of aqueous extraction of pectin from waste durian rinds. AB - The objectives of this present study was to investigate and optimize the aqueous extraction conditions such as solid-liquid (SL) ratio (1:5-1:15 g/ml), pH (2-3), extraction time (20-60 min) and extraction temperature (75-95 degrees C) on maximum extraction of pectin from durian rinds using four factors, three levels Box-Behnken response design. The experimental data obtained were fitted to a second-order polynomial equation using multiple regression analysis and analyzed by analysis of variance (ANOVA). The optimum extraction condition was found to be as follows: SL ratio of 1:10 g/ml, pH of 2.8, extraction time of 43 min and extraction temperature of 86 degrees C respectively. Under the optimal conditions, the experimental pectin yield (9.1%) was well correlated with predicted yield (9.3%). PMID- 25450557 TI - A model for membrane potential and intracellular ion distribution. AB - Most cells carry a negative electric charge. It produces a potential difference across the membrane, which regulates voltage-sensitive ion transport and ATP synthesis in mitochondria. The negative charge comes partly from an excess of negative ions in the cell interior (Donnan potential) and partly from ionized groups on the membrane (surface potential). In this work we propose some important modifications to the existing theory of membrane potential. First, we calculate the concentration profile of intracellular positive ions and derive a simple equation to assess the submembrane depletion of positive ions that gives rise to the Donnan potential. The extent of depletion varies with potential, which may provide a regulatory mechanism for ion pumps and channels. Next we consider the surface component of the potential and note that the standard Gouy Chapman theory has been developed for planar membranes, whereas real cell membranes have a closed geometry. In this case, charges on the membrane surface are not expected to generate fields extending into the cell interior. This fact calls for reinterpretation of some theoretical points as well as experimental data. In particular, the experimentally demonstrated electrostatic attraction between cationic proteins and the negative membrane must now be explained without invoking intracellular fields, and we suggest a new mechanism that can account for this interaction. PMID- 25450559 TI - Breast cancer: Breast-conserving surgery and radiation therapy and comparison of radiotherapy techniques. PMID- 25450558 TI - Network of long-range concerted chemical shift displacements upon ligand binding to human angiogenin. AB - Molecular recognition models of both induced fit and conformational selection rely on coupled networks of flexible residues and/or structural rearrangements to promote protein function. While the atomic details of these motional events still remain elusive, members of the pancreatic ribonuclease superfamily were previously shown to depend on subtle conformational heterogeneity for optimal catalytic function. Human angiogenin, a structural homologue of bovine pancreatic RNase A, induces blood vessel formation and relies on a weak yet functionally mandatory ribonucleolytic activity to promote neovascularization. Here, we use the NMR chemical shift projection analysis (CHESPA) to clarify the mechanism of ligand binding in human angiogenin, further providing information on long-range intramolecular residue networks potentially involved in the function of this enzyme. We identify two main clusters of residue networks displaying correlated linear chemical shift trajectories upon binding of substrate fragments to the purine- and pyrimidine-specific subsites of the catalytic cleft. A large correlated residue network clusters in the region corresponding to the V1 domain, a site generally associated with the angiogenic response and structural stability of the enzyme. Another correlated network (residues 40-42) negatively affects the catalytic activity but also increases the angiogenic activity. (15) N-CPMG relaxation dispersion experiments could not reveal the existence of millisecond timescale conformational exchange in this enzyme, a lack of flexibility supported by the very low-binding affinities and catalytic activity of angiogenin. Altogether, the current report potentially highlights the existence of long-range dynamic reorganization of the structure upon distinct subsite binding events in human angiogenin. PMID- 25450560 TI - A novel granulocyte-specific alpha integrin is essential for cellular immunity in the silkworm Bombyx mori. AB - Haemocytes play crucial roles in immune responses and survival in insects. Specific cell markers have proven effective in clarifying the function and haematopoiesis of haemocytes. The silkworm Bombyx mori is a good model for studying insect haemocytes; however, little is known about haemocyte-specific markers or their functions in silkworm. In this study, we identified the alpha subunit of integrin, BmintegrinalphaPS3, as being specifically and highly expressed in silkworm haemocytes. Immunofluorescence analysis validated the specificity of BmintegrinalphaPS3 in larval granulocytes. Further analyses indicated that haemocytes dispersed from haematopoietic organs (HPOs) into the circulating haemolymph could differentiate into granulocytes. In addition, the processes of encapsulation and phagocytosis were controlled by larval granulocytes. Our work demonstrated that BmintegrinalphaPS3 could be used as a specific marker for granulocytes and could be applied to future molecular cell biology studies. PMID- 25450561 TI - Ecdysis behaviors and circadian rhythm of ecdysis in the stick insect, Carausius morosus. AB - Successful ecdysis in insects depends on proper timing and sequential activation of an elaborate series of motor programs driven by a relatively conserved network of neuropeptides. The behaviors must be activated at the appropriate times to ensure successful loosening and shedding of the old cuticle, and can be influenced by environmental cues in the form of immediate sensory feedback and by circadian rhythms. We assessed the behaviors, components of the neural network and the circadian basis of ecdysis in the stick insect, Carausius morosus. C. morosus showed many of the characteristic pre-ecdysis and ecdysis behaviors previously described in crickets and locusts. Ecdysis was described in three phases, namely the (i) preparatory or pre-ecdysis phase, (ii) the ecdysial phase, and (iii) the post-ecdysis or exuvial phase. The frequencies of push-ups and sways during the preparatory phase were quantified as well as durations of all the phases. The regulation of ecdysis appeared to act via elevation of cGMP, as described in many other insects, although eclosion hormone-like immunoreactivity was not noted using a lepidopteran antiserum. Finally, C. morosus showed a circadian rhythm to the onset of ecdysis, with ecdysis occurring just prior to or at lights on. Ecdysis could be induced precociously with mechanical stimulation. PMID- 25450562 TI - Antioxidant supplementation can reduce the survival costs of excess amino acid intake in honeybees. AB - Over-consuming amino acids is associated with reduced survival in many species, including honeybees. The mechanisms responsible for this are unclear but one possibility is that excessive intake of amino acids increases oxidative damage. If this is the case, antioxidant supplementation may help reduce the survival costs of high amino acid intake. We tested this hypothesis in African honeybees (Apis mellifera scutellata) using the major antioxidant in green tea, epigallocatechin-3-gallate (EGCG). We first determined the dose-range of EGCG that improved survival of caged honeybees fed sucrose solution. We then provided bees with eight diets that differed in their ratio of essential amino acids (EAA) to carbohydrate (C) (0:1, 1:250, 1:100, 1:75, 1:50, 1:25, 1:10, 1:5 EAA:C) and also in their EGCG dose (0.0 or 0.4 mM). We found that bees fed sucrose only solution survived better than bees fed EAA diets. Despite this, bees preferred a diet that contained intermediate ratios of EAA:C (ca. 1:25), which may represent the high demands for nitrogen of developing nurse bees. EGCG supplementation improved honeybee survival but only at an intermediate dose (0.3-0.5 mM) and in bees fed low EAA diets (1:250, 1:100 EAA:C). That EGCG counteracted the lifespan reducing effects of eating low EAA diets suggests that oxidative damage may be involved in the association between EAAs and lifespan in honeybees. However, that EGCG had no effect on survival in bees fed high EAA diets suggests that there are other physiological costs of over-consuming EAAs in honeybees. PMID- 25450563 TI - When mothers anticipate: effects of the prediapause stage on embryo development time and of maternal photoperiod on eggs of a temperate and a tropical strains of Aedes albopictus (Diptera: Culicidae). AB - BACKGROUND: The diapause of Aedes albopictus is maternally induced by photoperiod and initiates at the pharate larvae stage in eggs. This pre-diapause results in enhanced survival eggs during the winter. This study aims to disentangle the effects of photoperiod and diapause on embryonic developmental time and egg size in A. albopictus. A temperate strain capable to perform diapause and a tropical strain unable of diapause were reared at 21 degrees C with long-(LD) and short day (SD) lengths. Four distinct traits were studied on embryos and eggs were measured at the end of embryogenesis. RESULTS: The chronologies of embryo development for both strains were influenced by maternal photoperiod, especially in the temperate strain in which the development of SD eggs took longer than LD eggs. The delay increased gradually in the temperate strain, and reached up to 38 h at the end of embryogenesis. The kinetics of embryogenesis differed among the temperate and the tropical strains, each one of the 4 studied traits showing differences. For example the serosal cuticle was secreted precociously in the tropical strain. Egg width and volume are influenced by the maternal photoperiod and the strain*photoperiod interaction. For both strains, larger eggs were laid by female reared under SD when compared to LD. CONCLUSIONS: The influence of several maternal effects was demonstrated in this study. The diapause process modifies greatly the length of embryogenesis in the temperate strain, whereas the maternal photoperiod has a direct influence on egg size and embryogenesis regardless of the strain considered. These findings provide useful data on chronology of embryonic development for integrative biology studies of egg pre diapause stages. PMID- 25450564 TI - Involvement of plasma membrane Ca2+ channels, IP3 receptors, and ryanodine receptors in the generation of spontaneous rhythmic contractions of the cricket lateral oviduct. AB - In the present study, the isolated cricket (Gryllus bimaculatus) lateral oviduct exhibited spontaneous rhythmic contractions (SRCs) with a frequency of 0.29+/ 0.009 Hz (n=43) and an amplitude of 14.6+/-1.25 mg (n=29). SRCs completely disappeared following removal of extracellular Ca2+ using a solution containing 5mM EGTA. Application of the non-specific Ca2+ channel blockers Co2+, Ni2+, and Cd2+ also decreased both the frequency and amplitude of SRCs in dose-dependent manners, suggesting that Ca2+ entry through plasma membrane Ca2+ channels is essential for the generation of SRCs. Application of ryanodine (30 MUM), which depletes intracellular Ca2+ by locking ryanodine receptor (RyR)-Ca2+ channels in an open state, gradually reduced the frequency and amplitude of SRCs. A RyR antagonist, tetracaine, reduced both the frequency and amplitude of SRCs, whereas a RyR activator, caffeine, increased the frequency of SRCs with a subsequent increase in basal tonus, indicating that RyRs are essential for generating SRCs. To further investigate the involvement of phospholipase C (PLC) and inositol 1,4,5-trisphosphate receptors (IP3Rs) in SRCs, we examined the effect of a PLC inhibitor, U73122, and an IP3R antagonist, 2-aminoethoxydiphenyl borate (2-APB), on SRCs. Separately, U73122 (10 MUM) and 2-APB (30-50 MUM) both significantly reduced the amplitude of SRCs with little effect on their frequency, further indicating that the PLC/IP3R signaling pathway is fundamental to the modulation of the amplitude of SRCs. A hypotonic-induced increase in the frequency and amplitude of SRCs and a hypertonic-induced decrease in the frequency and amplitude of SRCs indicated that mechanical stretch of the lateral oviduct is involved in the generation of SRCs. The sarcoplasmic reticulum Ca2+-pump ATPase inhibitors thapsigargin and cyclopiazonic acid impaired or suppressed the relaxation phase of SRCs. Taken together, the present results indicate that Ca2+ influx through plasma membrane Ca2+ channels and Ca2+ release from RyRs play an essential role in pacing SRCs and that Ca2+ release from IP3Rs may play a role in modulating the amplitude of SRCs, probably via activation of PLC. PMID- 25450565 TI - A putative Delta1-pyrroline-5-carboxylate synthetase involved in the biosynthesis of proline and arginine in Leptinotarsa decemlineata. AB - Delta 1-pyrroline-5-carboxylate synthetase (P5CS) catalyzes the conversion of glutamate (Glu) to Glu semialdehyde (GSA). GSA spontaneously cyclizes to form P5C. P5C is then reduced to proline (Pro) or is converted to ornithine, the intermediate for arginine (Arg) biosynthesis. In the present study, a full-length Ldp5cs complementary DNA was cloned from the Colorado potato beetle Leptinotarsa decemlineata, a notorious insect defoliator of potato in most potato-growing regions of the world. Ldp5cs encodes a 792-amino-acid protein which shares high identity to homologues from other insect species. Quantitative reverse transcription polymerase chain reaction revealed that Ldp5cs was ubiquitously expressed in the eggs, first to fourth-instar larvae, wandering larvae, pupae and sexually mature adults. In the adults, Ldp5cs mRNA levels were higher in the fat body, foregut, midgut and hindgut, moderate in the ventral ganglion, lower in the thorax muscles, epidermis and Malpighian tubules. Two double-stranded RNAs (dsRNAs) (dsLdp5cs1 and dsLdp5cs2) targeting Ldp5cs were constructed and bacterially expressed. Ingestion during 3 consecutive days of dsLdp5cs1 or dsLdp5cs2 successfully silenced Ldp5cs, significantly reduced the contents of Pro and Arg in the hemolymph, decreased flight speed and shortened flight distance of the resulting adults. Furthermore, knocking down Ldp5cs significantly increased adult mortality. Thus, our results suggest that identified Ldp5cs encodes a functional P5CS enzyme that is involved in the biosynthesis of Pro and Arg in L. decemlineata. PMID- 25450566 TI - Straightforward multi-object video tracking for quantification of mosquito flight activity. AB - Mosquito flight activity has been studied using a variety of different methodologies, and largely concentrates on female mosquito activity as vectors of disease. Video recording using standard commercially available hardware has limited accuracy for the measurement of flight activity due to the lack of depth perception in two-dimensional images, but multi-camera observation for three dimensional trajectory reconstructions remain challenging and inaccessible to the majority of researchers. Here, in silico simulations were used to quantify the limitations of two-dimensional flight observation. We observed that, under the simulated conditions, two dimensional observation of flight was more than 90% accurate for the determination of population flight speeds and thus that two dimensional imaging can be used to provide accurate estimates of mosquito population flight speeds, and to measure flight activity over long periods of time. We optimized single camera video imaging to study male Aedes albopictus mosquitoes over a 30 h time period, and tested two different multi-object tracking algorithms for their efficiency in flight tracking. A. Albopictus males were observed to be most active at the start of the day period (06h00-08h00) with the longest period of activity in the evening (15h00-18h00) and that a single mosquito will fly more than 600 m over the course of 24 h. No activity was observed during the night period (18h00-06h00). Simplistic tracking methodologies, executable on standard computational hardware, are sufficient to produce reliable data when video imaging is optimized under laboratory conditions. As this methodology does not require overly-expensive equipment, complex calibration of equipment or extensive knowledge of computer programming, the technology should be accessible to the majority of computer-literate researchers. PMID- 25450567 TI - Genomic analysis of the interaction between pesticide exposure and nutrition in honey bees (Apis mellifera). AB - Populations of pollinators are in decline worldwide. These declines are best documented in honey bees and are due to a combination of stressors. In particular, pesticides have been linked to decreased longevity and performance in honey bees; however, the molecular and physiological pathways mediating sensitivity and resistance to pesticides are not well characterized. We explored the impact of coumaphos and fluvalinate, the two most abundant and frequently detected pesticides in the hive, on genome-wide gene expression patterns of honey bee workers. We found significant changes in 1118 transcripts, including genes involved in detoxification, behavioral maturation, immunity, and nutrition. Since behavioral maturation is regulated by juvenile hormone III (JH), we examined effects of these miticides on hormone titers; while JH titers were unaffected, titers of methyl farnesoate (MF), the precursor to JH, were decreased. We further explored the association between nutrition- and pesticide-regulated gene expression patterns and demonstrated that bees fed a pollen-based diet exhibit reduced sensitivity to a third pesticide, chlorpyrifos. Finally, we demonstrated that expression levels of several of the putative pesticide detoxification genes identified in our study and previous studies are also upregulated in response to pollen feeding, suggesting that these pesticides and components in pollen modulate similar molecular response pathways. Our results demonstrate that pesticide exposure can substantially impact expression of genes involved in several core physiological pathways in honey bee workers. Additionally, there is substantial overlap in responses to pesticides and pollen-containing diets at the transcriptional level, and subsequent analyses demonstrated that pollen-based diets reduce workers' pesticide sensitivity. Thus, providing honey bees and other pollinators with high quality nutrition may improve resistance to pesticides. PMID- 25450568 TI - Effects of the administration of 2,3-butanedione monoxime during conventional cardiopulmonary resuscitation on ischaemic contracture and resuscitability in a pig model of out-of-hospital cardiac arrest. AB - AIM OF THE STUDY: Ischaemic contracture compromises the haemodynamic effectiveness of cardiopulmonary resuscitation and resuscitability. 2,3 Butanedione monoxime (BDM) reduced ischaemic contracture by inhibiting actin myosin crossbridge formation in an isolated heart model. We investigated the effects of BDM on ischaemic contracture and resuscitation outcomes in a pig model of out-of-hospital cardiac arrest (OHCA). METHODS: After 15min of untreated ventricular fibrillation, followed by 8min of basic life support, 16 pigs were randomised to receive either 2mlkg(-1) of BDM solution (25gl(-1)) or 2mlkg(-1) of saline during advanced cardiac life support (ACLS). RESULTS: During the ACLS, the control group showed an increase in left ventricular (LV) wall thickness from 10.0mm (10.0-10.8) to 13.0mm (13.0-13.0) and a decrease in LV chamber area from 8.13cm(2) (7.59-9.29) to 7.47cm(2) (5.84-8.43). In contrast, the BDM group showed a decrease in the LV wall thickness from 10mm (9.0-10.8) to 8.5mm (7.0-9.8) and an increase in the LV chamber area from 9.86cm(2) (7.22-12.39) to 12.15 cm(2) (8.02-14.40). Mixed model analyses of the LV wall thickness and LV chamber area revealed significant group effects and group-time interactions. Spontaneous circulation was restored in four (50%) animals in the control group and in eight (100%) animals in the BDM group (p=0.077). All the resuscitated animals survived during an intensive care period of 4h. CONCLUSION: BDM administered during cardiopulmonary resuscitation reversed ischaemic contracture in a pig model of OHCA. PMID- 25450569 TI - Point of care ultrasound for orotracheal tube placement assessment in out-of hospital setting. AB - AIM OF THE STUDY: The percentage of unrecognised orotracheal tube displacement in an out-of-hospital setting has been reported to be between 4.8% and 25%. The aim of our study was to assess the sensitivity and specificity of Point-of-Care UltraSound (POCUS) for confirming the proper tube position after an urgent orotracheal intubation in an out-of-hospital setting and the time needed for POCUS. METHODS: Our single-centred prospective study included all patients who needed out-of-hospital orotracheal intubation. After the intubation, bilateral chest auscultation and assessment of bilateral lung sliding and diaphragm excursion within POCUS were done. Spectrographic quantitative capnography was used as the reference standard to confirm a proper tube position. RESULTS: We enrolled 124 patients. For auscultation, sensitivity and negative predicted value were 100%, specificity was 90% and positive predicted value 30% (95% confidence interval). Sensitivity, specificity, positive predicted value, and negative predicted value for POCUS alone and for a combination of auscultation and POCUS were 100% (95% confidence interval). In three patients, we detected endobronchial tube displacement with auscultation and POCUS. Capnography failed to detect displacement in all three cases. The median time needed for POCUS was 30s. CONCLUSION: Results of our study support POCUS as an accurate and reliable method for confirming the proper orotracheal tube placement in trachea and it is feasible for out-of-hospital setting implementation. POCUS also seems to be time saving method but to make definitive conclusion more studies should be done. PMID- 25450570 TI - Correlation between initial serum levels of lactate after return of spontaneous circulation and survival and neurological outcomes in patients who undergo therapeutic hypothermia after cardiac arrest. AB - OBJECTIVES: We analysed the relationship between serum levels of lactate within 1h of return of spontaneous circulation (ROSC) and survival and neurological outcomes in patients who underwent therapeutic hypothermia (TH). METHODS: This was a multi-centre retrospective and observational study that examined data from the first Korean Hypothermia Network (KORHN) registry from 2007 to 2012. The inclusion criteria were out-of-hospital cardiac arrest (OHCA) and examination of serum levels of lactate within 1h after ROSC, taken from KORHN registry data. The primary endpoint was survival outcome at hospital discharge, and the secondary endpoint was poor neurological outcome (Cerebral Performance Category, CPC, 3-5) at hospital discharge. Initial lactate levels and other variables collected within 1h of ROSC were analysed via multivariable logistic regression. RESULTS: Data from 930 cardiac arrest patients who underwent TH were collected from the KORHN registry. In a total of 443 patients, serum levels of lactate were examined within 1h of ROSC. In-hospital mortality was 289/443 (65.24%), and 347/443 (78.33%) of the patients had CPCs of 3-5 upon hospital discharge. The odds ratios of lactate levels for CPC and in-hospital mortality were 1.072 (95% confidence interval (CI) 1.026-1.121) and 1.087 (95% CI=1.031-1.147), respectively, based on multivariate ordinal logistic regression analyses. CONCLUSION: High levels of lactate in serum measured within 1h of ROSC are associated with hospital mortality and high CPC scores in cardiac arrest patients treated with TH. PMID- 25450571 TI - The different faces of ventricular fibrillation. PMID- 25450572 TI - Cardiopulmonary resuscitation duty cycle in out-of-hospital cardiac arrest. AB - BACKGROUND: Duty cycle is the portion of time spent in compression relative to total time of the compression-decompression cycle. Guidelines recommend a 50% duty cycle based largely on animal investigation. We undertook a descriptive evaluation of duty cycle in human resuscitation, and whether duty cycle correlates with other CPR measures. METHODS: We calculated the duty cycle, compression depth, and compression rate during EMS resuscitation of 164 patients with out-of-hospital ventricular fibrillation cardiac arrest. We captured force recordings from a chest accelerometer to measure ten-second CPR epochs that preceded rhythm analysis. Duty cycle was calculated using two methods. Effective compression time (ECT) is the time from beginning to end of compression divided by total period for that compression-decompression cycle. Area duty cycle (ADC) is the ratio of area under the force curve divided by total area of one compression-decompression cycle. We evaluated the compression depth and compression rate according to duty cycle quartiles. RESULTS: There were 369 ten second epochs among 164 patients. The median duty cycle was 38.8% (SD=5.5%) using ECT and 32.2% (SD=4.3%) using ADC. A relatively shorter compression phase (lower duty cycle) was associated with greater compression depth (test for trend <0.05 for ECT and ADC) and slower compression rate (test for trend <0.05 for ADC). Sixty-one of 164 patients (37%) survived to hospital discharge. CONCLUSIONS: Duty cycle was below the 50% recommended guideline, and was associated with compression depth and rate. These findings provider rationale to incorporate duty cycle into research aimed at understanding optimal CPR metrics. PMID- 25450573 TI - Potential association of bystander-patient relationship with bystander response and patient survival in daytime out-of-hospital cardiac arrest. AB - AIM: To investigate whether the bystander-patient relationship affects bystander response to out-of-hospital cardiac arrest (OHCA) and patient outcomes depending on the time of day. METHODS: This population-based observational study in Japan involving 139,265 bystander-witnessed OHCAs (90,426 family members, 10,479 friends/colleagues, and 38,360 others) without prehospital physician involvement was conducted from 2005 to 2009. Factors associated with better bystander response [early emergency call and bystander cardiopulmonary resuscitation (BCPR)] and 1-month neurologically favourable survival were assessed. RESULTS: The rates of dispatcher-assisted CPR during daytime (7:00-18:59) and nighttime (19:00-6:59) were highest in family members (45.6% and 46.1%, respectively, for family members; 28.7% and 29.2%, respectively, for friends/colleagues; and 28.1% and 25.3%, respectively, for others). However, the BCPR rates were lowest in family members (35.5% and 37.8%, respectively, for family members; 43.7% and 37.8%, respectively, for friends/colleagues; and 59.3% and 50.0%, respectively, for others). Large delays (>= 5 min) in placing emergency calls and initiating BCPR were most frequent in family members. The overall survival rate was lowest (2.7%) for family members and highest (9.1%) for friends/colleagues during daytime. Logistic regression analysis revealed that the effect of bystander relationship on survival was significant only during daytime [adjusted odds ratios (95% CI) for survival from daytime OHCAs with family as reference were 1.51 (1.36-1.68) for friends/colleagues and 1.23 (1.13-1.34) for others]. CONCLUSIONS: Family members are least likely to perform BCPR and OHCAs witnessed by family members are least likely to survive during daytime. Different strategies are required for family-witnessed OHCAs. PMID- 25450574 TI - Orexin administration to mice that underwent chronic stress produces bimodal effects on emotion-related behaviors. AB - Orexin plays diverse roles in regulating behaviors, such as sleep and wake, reward processing, arousal, and stress and anxiety. The orexin system may accomplish these multiple tasks through its complex innervations throughout the brain. The emerging evidence indicates a role of orexin in emotional behaviors; however, most of the previous studies have investigated the function of orexin in naive animals. Here, we examined a functional role of orexin in mice that had been exposed to repeated stress. Chronic social defeat stress produced differential social interaction behaviors in mice (susceptible versus resilient) and these two groups of mice displayed different levels of prepro-orexin in the hypothalamus. Exogenously added orexin A to the brain induced an antidepressant like effect in only the susceptible mice but not in the resilient mice. In contrast, orexin A and orexin B infused together produced an anxiogenic effect in only the resilient mice and not in the susceptible mice. Furthermore, we found that the antidepressant-like effect of orexin A is mediated by the bed nucleus of the stria terminalis (BNST) after exposure to chronic restraint stress. These findings reveal a bimodal effect of the orexin system in regulating emotional behavior that depends on stress susceptibility. PMID- 25450575 TI - Prior regular exercise reverses the decreased effects of sleep deprivation on brain-derived neurotrophic factor levels in the hippocampus of ovariectomized female rats. AB - Previous studies indicated that brain-derived neurotrophic factor (BDNF) is the main candidate to mediate the beneficial effects of exercise on cognitive function in sleep deprived male rats. In addition, our previous findings demonstrate that female rats are more vulnerable to the deleterious effects of sleep deprivation on cognitive performance and synaptic plasticity. Therefore, the current study was designed to investigate the effects of treadmill exercise and/or sleep deprivation (SD) on the levels of BDNF mRNA and protein in the hippocampus of female rats. Intact and ovariectomized (OVX) female Wistar rats were used in the present experiment. The exercise protocol was four weeks treadmill running and sleep deprivation was accomplished using the multiple platform method. Quantitative reverse transcriptase-polymerase chain reaction (RT PCR) and immunoblot analysis were used to evaluate the level of BDNF mRNA and protein in the rat hippocampus respectively. Our results showed that protein and mRNA expression of BDNF was significantly (p<0.05) decreased after 72 h SD in OVX rats in compared with other groups. Furthermore, sleep deprived OVX rats under exercise conditions had a significant (p<0.05) up-regulation of the BDNF protein and mRNA in the hippocampus. These findings suggest that regular exercise can exert a protective effect against hippocampus-related functions and impairments induced by sleep deprivation probably by inducing BDNF expression. PMID- 25450576 TI - Insulin-like growth factor-1 inhibits colonic smooth muscle cell apoptosis in diabetic rats with colonic dysmotility. AB - Cellular apoptosis and colonic dysmotility are involved in diabetes mellitus (DM) complications. Insulin-like growth factor-1 (IGF-1) is known to affect apoptosis and proliferation. Here, we demonstrated that the treatment of 1500 ng/kg IGF-1 partly recovers the decrease of the muscle thickness, body weight and gastrointestinal transit rate in DM rats. The gastrointestinal transit rate is positively correlated with the IGF-I level, but negatively correlated with the level of colonic cellular apoptosis. The DM-induced colonic apoptosis is also attenuated by the IGF-1 stimulation. Moreover, IGF-1 inhibits the apoptosis of the isolated colonic SMCs in vitro via the activation of PI3K/Akt and ERK1/2 signaling pathways. Taken together, our data indicated that IGF-1 inhibits the DM induced colonic SMC apoptosis and might be involved in the alleviation of colonic dysmotility in diabetic rats. PMID- 25450577 TI - Portrait of the PI3K/AKT pathway in colorectal cancer. AB - PI3K/AKT signaling leads to reduced apoptosis, stimulates cell growth and increases proliferation. Under normal conditions, PI3K/AKT activation is tightly controlled and dependent on both extracellular growth signals and the availability of amino acids and glucose. Genetic aberrations leading to PI3K/AKT hyper-activation are observed at considerable frequency in all major nodes in most tumors. In colorectal cancer the most commonly observed pathway changes are IGF2 overexpression, PIK3CA mutations and PTEN mutations and deletions. Combined, these alterations are found in about 40% of large bowel tumors. In addition, but not mutually exclusive to these, KRAS mutations are observed at a similar frequency. There are however additional, less frequent and more poorly understood events that may also push the PI3K/AKT pathway into overdrive and thus promote malignant growth. Here we discuss aberrations of components at the genetic, epigenetic, transcriptional, post-transcriptional, translational and post translational level where perturbations may drive excessive PI3K/AKT signaling. Integrating multiple molecular levels will advance our understanding of this cancer critical circuit and more importantly, improve our ability to pharmacologically target the pathway in view of clonal development, tumor heterogeneity and drug resistance mechanisms. In this review, we revisit the PI3K/AKT pathway cancer susceptibility syndromes, summarize the known aberrations at the different regulatory levels and the prognostic and predictive values of these alterations in colorectal cancer. PMID- 25450579 TI - PINK1 signalling in cancer biology. AB - PTEN-induced kinase 1 (PINK1) was identified initially in cancer cells as a gene up-regulated by overexpression of the major tumor suppressor, PTEN. Loss-of function mutations in PINK1 were discovered subsequently to cause autosomal recessive Parkinson's disease. Substantial work during the past decade has revealed that PINK1 regulates several primary cellular processes of significance in cancer cell biology, including cell survival, stress resistance, mitochondrial homeostasis and the cell cycle. Mechanistically, PINK1 has been shown to interact on a number of levels with the pivotal oncogenic PI3-kinase/Akt/mTOR signalling axis and to control critical mitochondrial and metabolic functions that regulate cancer survival, growth, stress resistance and the cell cycle. A cytoprotective and chemoresistant function for PINK1 has been highlighted by some studies, supporting PINK1 as a target in cancer therapeutics. This article reviews the function of PINK1 in cancer cell biology, with an emphasis on the mechanisms by which PINK1 interacts with PI3-kinase/Akt signalling, mitochondrial homeostasis, and the potential context-dependent pro- and anti-tumorigenic functions of PINK1. PMID- 25450581 TI - Molecular mechanisms associated with nosocomial carbapenem-resistant Acinetobacter baumannii in Mexico. AB - BACKGROUND AND AIMS: Acinetobacter baumannii is an emerging pathogen worldwide that is most commonly associated with nosocomial infections and multi-drug resistance. In the present study we determined the mechanisms of carbapenem resistance and clonal diversity of A. baumannii nosocomial isolates in Hospital Civil de Guadalajara, Mexico. METHODS: A total of 303 clinical isolates of A. baumannii identified during a period expanding from 2004-2011 were analyzed for carbapenem resistance using several microbiological and molecular methods. Clonal relatedness of these isolates was determined using pulsed-field gel electrophoresis. RESULTS: Of the 303 isolates, 84% were resistant to meropenem, 71.3% to imipenem and 78.3% the resistant isolates were positive for metallo-beta lactamases as determined by the phenotypic assay. In addition, 49.6% of carbapenem-intermediate or -resistant isolates carried the blaOXA-72 gene and 1.2% carried the blaVIM-1 gene. Efflux pump phenotype was responsible for reduced susceptibility to meropenem in 14.5% and to imipenem in 31.6% of the resistant isolates, respectively in the presence of the efflux pump inhibitor, carbonyl cyanide 3-chlorophenylhydrazone. Strains representing different carbapenem resistant patterns exhibited reduced expression of 22, 29, 33, and 43 kDa OMPs. Among the bacterial collection studied, 48 different clones were identified, two of which were predominant and persistently transmitted. CONCLUSIONS: Carbapenemase production in combination with efflux pump expression, reduction in OMPs expression and the cross-transmission of clones appear to be major contributors to the high frequency of carbapenem-resistance observed in A. baumannii. To our knowledge, this is the first study to define the molecular mechanisms associated with carbapenem-resistance in A. baumannii in Mexico. PMID- 25450582 TI - Bisphosphonates may protect against bone loss in postmenopausal women with early breast cancer receiving adjuvant aromatase inhibitor therapy: results from a meta analysis. AB - BACKGROUND AND AIMS: The efficacy of bisphosphonates (BPs) in treating bone loss associated with cancer therapies has been demonstrated in completed studies and ongoing clinical trials. The aim of this study was to investigate the evidence for BP use in treatment of bone loss in postmenopausal, early breast cancer (EBC) patients scheduled to receive aromatase inhibitors (AI). METHODS: A comprehensive search for relative articles published until December 2013 was performed. The outcomes included the percentage and absolute change in lumbar spine (LS) and total hip (TH) bone mineral density (BMD). Before pooled meta-analysis, the studies were evaluated for publication bias and heterogeneity. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated. We also performed subgroup and sensitivity analyses. RESULTS: A total of 11 trials contributed to the analysis. BP was shown to be efficacious in increasing BMD at the LS and TH. WMD in BMD absolute change was 0.21 g/cm(2) (95% CI, 0.13-0.28) at the LS and 0.27 g/cm(2) (95% CI, 0.02-0.12) at the TH. WMD in BMD percentage change was 5.42 (95% CI, 4.37-6.48) at the LS and 3.03 (95% CI, 2.01-4.01) at the TH. Subgroup analysis revealed that age difference, interventional duration, types of interventions and BP types were associated with variable effects on BMD at the LS and TH. CONCLUSIONS: BPs may protect against bone loss in postmenopausal women with EBC receiving adjuvant AI treatment. PMID- 25450585 TI - Preeclampsia is associated with lower production of vascular endothelial growth factor by peripheral blood mononuclear cells. AB - BACKGROUND: Recent studies show that vascular endothelial growth factor (VEGF) downregulation is implicated in preeclampsia (PE) pathophysiology. This study assessed the relationship between PE and VEGF levels produced by peripheral blood mononuclear cells (PBMCs) and their serum levels. METHODS: A cross-sectional design was performed in 36 patients who had hypertensive disorders during pregnancy. We also used a longitudinal design with 12 pregnant women with risk factors for PE development and/or abnormal uterine arteries by Doppler study. VEGF and soluble fms-like tyrosine kinase-1 (sFlt-1) levels were measured for all patients in both designs. RESULTS: sFlt-1 serum was higher in preeclamptic patients (n = 26), whereas VEGF produced by stimulated PBMCs was lower than in healthy pregnant women and VEGF levels produced by stimulated PBMCs were even lower (p <0.003) in severe PE (n = 16). The receiver-operating characteristic curve analysis allowed establishing a cut-off value to identify patients with PE. VEGF production by PBMCs was 339.87 pg/mL. In addition, a robust linear regression model was performed to adjust the variance in VEGF levels. The patients' age decreased VEGF levels and was adjusted by weeks of gestation (WG) in our model. In the longitudinal study, 7/12 patients developed PE. VEGF produced by PBMCs cells was significantly lower in PE at 24-26 WG. CONCLUSIONS: VEGF production by PBMCs is inhibited during PE, creating a downregulation of the microenvironment; this deficiency may contribute to the pathogenesis of disease. PMID- 25450584 TI - The role of signaling pathways in cervical cancer and molecular therapeutic targets. AB - Cervical cancer is a public health issue in developing countries. Although the Pap smear and colposcopy remain the major strategies for detection, most cases are diagnosed in the late stages. Therefore, a major concern has been to develop early diagnostic approaches and more effective treatments. Molecular pathways that participate in cervical malignant transformation have emerged as promising directed therapeutic targets. In this review, we explore some of the major pathways implicated in cervical cancer development, including RAF/MEK/ERK, phosphatidylinositol-3 kinase (PI3K/AKT), Wnt/b-catenin, apoptosis and coupled membrane receptor signaling. We focus on the role of these pathways in cervical carcinogenesis, their alterations and the consequences of these abnormalities. In addition, the most recent preclinical and clinical data on the rationally designed target-based agents that are currently being tested against elements of these pathways are reviewed. PMID- 25450583 TI - Oral coenzyme Q10 supplementation in patients with nonalcoholic fatty liver disease: effects on serum vaspin, chemerin, pentraxin 3, insulin resistance and oxidative stress. AB - BACKGROUNDS AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury. Chronic exposure to oxidative stress leads to depletion of liver antioxidants and abnormal cytokine production; antioxidant therapy is one of the main therapeutic lines in NAFLD. In the current study we aimed to investigate the effect of coenzyme Q10 (coQ10) therapy on several adipocytokines and insulin resistance in patients with NAFLD. METHODS: In the current randomized double-blind placebo controlled trial 44 NAFLD patients were enrolled. After randomization into two groups, 22 patients received 100 mg/day coQ10 capsules and 22 patients received placebo daily for 4 weeks. BMI and WHR were calculated for patients at the beginning and end of the study and blood samples were obtained from the patients to measure serum concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), fasting serum glucose (FSG), insulin resistance (IR), vaspin, chemerin, pentraxin 3 (PTX3) and markers of oxidative stress including total antioxidant capacity (TAC) and malondialdehyde (MDA). RESULTS: After 4 weeks of coQ10 supplementation, waist circumference (WC) and serum AST and TAC concentrations significantly decreased in intervention group (p <0.05) but no significant changes occurred in placebo treated group. In stepwise multivariate linear regression model, change in serum FSG was a significant predictor of changes in serum vaspin, chemerin and pentraxin 3 (p <0.001). CONCLUSIONS: The present study showed a potential for coQ10 therapy in improving several anthropometric and biochemical variables in NAFLD. Longer studies with higher doses of coQ10 are required to further evaluate this potential benefit. PMID- 25450586 TI - 50th anniversary of the Declaration of Helsinki: the double standard was introduced. AB - The Declaration of Helsinki (DoH), adopted by the World Medical Association (WMA), is one of the most influential international documents in research ethics, is turning 50 in 2014. Its regular updates, seven versions (1975, 1983, 1989, 1996, 2000, 2008, 2013) and two notes of clarification (2002, 2004), characterize it as a 'live' document. The seventh version of the DoH was amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013. The new version was reorganized and restructured, with paragraphs subdivided and regrouped. However, the DoH remains controversial and some ethical issues are still uncovered. The major problem was the insertion of the phrase 'less effective than the best proven' on placebo paragraph in order to allow double standard in medical research in low-resource countries. The DoH is a 'live' document, which will continually have to deal with new topics and challenges. Health equity needs to be a priority, and with that, a single ethical standard for medical research. PMID- 25450587 TI - Early disturbed placental ischemia and hypoxia creates immune alteration and vascular disorder causing preeclampsia. AB - Preterm preeclampsia (PE) remains a leading cause of maternal death and perinatal morbidity. The pathophysiological process that underlies PE has been proposed to occur in two episodes, the first is a reduced placental perfusion and then the maternal clinical syndrome. Placental ischemia/hypoxia is believed to result in the release of a variety of placental factors such as cytokines including TNF alpha and interleukin 6, activated circulating immune cells and autoantibodies that have profound effects on blood flow and arterial pressure regulation. PE is also associated with decreased formation of vasodilators such as nitric oxide and prostacyclin. It is accompanied by widespread maternal vascular dysfunction and a chronic inflammatory response. Additionally, anti-angiogenic peptides are released, inhibiting vascular remodeling essential for increased blood flow to the growing uteroplacental unit. Although these factors accompany the clinical syndrome of PE, it is suggested that they are secondary to the maternal decrease in placental blood flow. Experimental evidence has demonstrated the importance of these soluble factors to increase blood pressure and stimulate the production of such anti-angiogenic factors, thereby eliciting a vicious cycle existing within the maternal vasculature as well as within the placental unit. These alterations in vascular function not only lead to hypertension but to multi-organ dysfunction. The quantitative importance of the various endothelial and humoral factors that mediate vascular dysfunction and hypertension during PE remains to be elucidated. PMID- 25450588 TI - Adjuvant radiation therapy for breast cancer in patients with schizophrenia. AB - BACKGROUND: Schizophrenia affects approximately 1% of subjects in all populations studied thus far. We sought to evaluate how patients with schizophrenia who are later diagnosed with breast cancer fare when adjuvant radiation therapy (ART) is clinically indicated. METHODS: We searched patient treatment file, the national inpatient computer database of the Department of Veterans Affairs, to identify patients with schizophrenia who subsequently developed breast cancer. RESULTS: Forty patients had schizophrenia, who later developed breast cancer and were candidates for ART, according to well-established guidelines. Of the 40 patients who were considered candidates for ART, we found data about the decision to offer ART in 35; only 22 (63%) were offered ART and 5 of those 22 (23%) refused it. CONCLUSIONS: Patients with schizophrenia and breast cancer often do not understand the nature of their illnesses well. They often do not comply with recommended standard therapies such as ART. Treatment strategies that rely on ART are likely to be met with noncompliance. Breast-preserving treatment plans may be impractical. Initial radical surgery without ART may be preferable. PMID- 25450580 TI - mTOR signaling in tumorigenesis. AB - mTOR (the mechanistic target of rapamycin) is an atypical serine/threonine kinase involved in regulating major cellular functions including growth and proliferation. Deregulation of the mTOR signaling pathway is one of the most commonly observed pathological alterations in human cancers. To this end, oncogenic activation of the mTOR signaling pathway contributes to cancer cell growth, proliferation and survival, highlighting the potential for targeting the oncogenic mTOR pathway members as an effective anti-cancer strategy. In order to do so, a thorough understanding of the physiological roles of key mTOR signaling pathway components and upstream regulators would guide future targeted therapies. Thus, in this review, we summarize available genetic mouse models for mTORC1 and mTORC2 components, as well as characterized mTOR upstream regulators and downstream targets, and assign a potential oncogenic or tumor suppressive role for each evaluated molecule. Together, our work will not only facilitate the current understanding of mTOR biology and possible future research directions, but more importantly, provide a molecular basis for targeted therapies aiming at key oncogenic members along the mTOR signaling pathway. PMID- 25450578 TI - Regulation of cancer metastasis by cell-free miRNAs. AB - MicroRNAs (miRNAs) are integral molecules in the regulation of numerous physiological cellular processes that have emerged as critical players in cancer initiation and metastatic progression, both by promoting and suppressing metastasis. Recently, cell-free miRNAs shed from cancer cells into circulation have been reported in cancer patients, raising hope for development of novel biomarkers that can be routinely measured in easily accessible samples. In fact, establishing miRNA expression in the circulation likely has advantages over determination in primary tumor tissue, further augmenting the potential applications of miRNA detection in oncological practice. In addition, secretion of miRNAs impacting distant cell signaling or promoting the formation of a niche that sustains a distant tumor microenvironment allows for new treatment approaches to thwart cancer progression. PMID- 25450589 TI - Surgical ethics and the challenge of surgical innovation. AB - Surgical ethics as a specific discipline is relatively new to many. Surgical ethics focuses on the ethical issues that are particularly important to the care of surgical patients. Informed consent for surgical procedures, the level of responsibility that surgeons feel for their patients' outcomes, and the management of surgical innovation are specific issues that are important in surgical ethics and are different from other areas of medicine. The future of surgical progress is dependent on surgical innovation, yet the nature of surgical innovation raises specific concerns that challenge the professionalism of surgeons. These concerns will be considered in the following pages. PMID- 25450590 TI - Honokiol affects melanoma cell growth by targeting the AMP-activated protein kinase signaling pathway. AB - BACKGROUND: Malignant melanoma is an aggressive form of skin cancer with limited effective therapeutic options. Melanoma research concentrates on maximizing the effect on cancer cells with minimal toxicity to normal cells. AMP-activated protein kinase (AMPK) is an important regulator of cellular energy homeostasis and has been shown to control tumor progression regulating the cell cycle, protein synthesis, and cell growth and/or survival. Honokiol (HNK) is a biphenolic compound derived from Magnolia officinalis, a plant that has been used in traditional Chinese and Japanese medicine for the treatment of various pathological conditions. Recent studies have shown that HNK has antitumor activity with relatively low toxicity. In this study, we demonstrated that the growth inhibitory effects of HNK on melanoma and melanoma cancer stem cells were mediated through the activation of AMPK and hence AMPK signaling in melanoma cells. METHODS: We determined the effects of HNK treatment on various melanoma cell lines. HNK-induced cell growth inhibitory effects were determined using hexosaminidase assay. Protein expression studies were done by immunoblotting. Primary spheroid assay was used to assess stemness by growing single suspension cells in ultralow attachment plates. RESULTS: HNK is highly effective in inhibiting melanoma cells by attenuating protein kinase B/mammalian target of rapamycin and AMPK signaling. HNK showed significant inhibition of the spheroid forming capacity of melanoma cells and, hence, stemness. HNK significantly decreased the number and size of melanospheres in a dose-dependent manner. Western blot analyses showed enhanced phosphorylation of AMPK in melanoma cells. Furthermore, HNK decreased the cellular adenosine triphosphate pool in a dose dependent manner with maximum effects observed at 48 hours. CONCLUSIONS: The results suggest that HNK can target melanoma cells and mark them for cell death through AMPK signaling. Further studies are warranted for developing HNK as an effective chemopreventive/therapeutic agent in melanoma. PMID- 25450591 TI - Geographic maldistribution of general surgery PGYI residents: another US surgical desert. AB - BACKGROUND: Practicing general surgeons are unevenly distributed across the country. This study evaluates the geographic distribution of categorical, general surgery (GS) PGYI positions per capita. METHODS: Data were obtained from the 2012 National Resident Matching Program match and the 2010 US Census. RESULTS: The mean for GS PGYI positions per 10(6) population was 3.85 +/- .61; 27 states fell below this value. The 7 American College of Surgeons (ACS) regions ranged from a low of 1.4 +/- .50 (Intermountain) to a high of 9.89 +/- 4.41 (Northeast). The mean (2.18 +/- .34) for the 19 state membership of the Southwestern Surgical Congress was below the mean for the country. CONCLUSIONS: There is a maldistribution of GS PGYI positions compared with state and regional populations, particularly in rural areas. This mirrors the maldistribution of practicing general surgeons across the United States. Additional GS residences and resident positions are urgently needed to correct this "Surgical Desert" of graduate surgical education. PMID- 25450592 TI - Structural insights into enzymatic activity and substrate specificity determination by a single amino acid in nitrilase from Syechocystis sp. PCC6803. AB - Nitrilases are enzymes widely expressed in prokaryotes and eukaryotes that utilize a Cys-Glu-Lys catalytic triad to hydrolyze non-peptide carbon-nitrogen bonds. Nitrilase from Syechocystis sp. Strain PCC6803 (Nit6803) shows hydrolysis activity towards a broad substrate spectrum, ranging from mononitriles to dinitriles and from aromatic nitriles to aliphatic nitriles. Yet, the structural principle of the substrate specificity of this nitrilase is still unknown. We report the crystal structure of Nit6803 at 3.1 A resolution and propose a structural mechanism of substrate selection. Our mutagenesis data exhibited that the aromaticity of the amino acid at position 146 of Nit6803 is absolutely required for its nitrilase activity towards any substrates tested. Moreover, molecular docking and dynamic simulation analysis indicated that the distance between the sulfhydryl group of the catalytic cysteine residue and the cyano carbon of the substrate plays a crucial role in determining the nitrilase catalytic activity of Nit6803 and its mutants towards different nitrile substrates. PMID- 25450593 TI - Crystal structure of the VapBC-15 complex from Mycobacterium tuberculosis reveals a two-metal ion dependent PIN-domain ribonuclease and a variable mode of toxin antitoxin assembly. AB - Although PIN (PilT N-terminal)-domain proteins are known to have ribonuclease activity, their specific mechanism of action remains unknown. VapCs form a family of ribonucleases that possess a PIN-domain assembly and are known as toxins. The activities of VapCs are impaired by VapB antitoxins. Here we present the crystal structure of the VapBC-15 toxin-antitoxin complex from Mycobacterium tuberculosis determined to 2.1A resolution. The VapB-15 and VapC-15 components assemble into one heterotetramer (VapB2C2) and two heterotrimers (VapBC2) in each asymmetric unit of the crystal. The active site of VapC-15 toxin consists of a cluster of acidic amino acid residues and two divalent metal ions, forming a well organised ribonuclease active site. The distribution of the catalytic-site residues of the VapC-15 toxin is similar to that of T4 RNase H and of Methanococcus jannaschii FEN-1, providing strong evidence that these three proteins share a similar mechanism of activity. The presence of both VapB2C2 and VapBC2 emphasizes the fact that the same antitoxin can bind the toxin in 1:1 and 1:2 ratios. The crystal structure determination of the VapBC-15 complex reveals for the first time a PIN-domain ribonuclease protein that shows two metal ions at the active site and a variable mode of toxin-antitoxin assembly. The structure further shows that VapB-15 antitoxin binds to the same groove meant for the binding of putative substrate (RNA), resulting in the inhibition of VapC-15's toxicity. PMID- 25450594 TI - Separation of replication and transcription domains in nucleoli. AB - In mammalian cells, active ribosomal genes produce the 18S, 5.8S and 28S RNAs of ribosomal particles. Transcription levels of these genes are very high throughout interphase, and the cell needs a special strategy to avoid collision of the DNA polymerase and RNA polymerase machineries. To investigate this problem, we measured the correlation of various replication and transcription signals in the nucleoli of HeLa, HT-1080 and NIH 3T3 cells using a specially devised software for analysis of confocal images. Additionally, to follow the relationship between nucleolar replication and transcription in living cells, we produced a stable cell line expressing GFP-RPA43 (subunit of RNA polymerase I, pol I) and RFP-PCNA (the sliding clamp protein) based on human fibrosarcoma HT-1080 cells. We found that replication and transcription signals are more efficiently separated in nucleoli than in the nucleoplasm. In the course of S phase, separation of PCNA and pol I signals gradually increased. During the same period, separation of pol I and incorporated Cy5-dUTP signals decreased. Analysis of single molecule localization microscopy (SMLM) images indicated that transcriptionally active FC/DFC units (i.e. fibrillar centers with adjacent dense fibrillar components) did not incorporate DNA nucleotides. Taken together, our data show that replication of the ribosomal genes is spatially separated from their transcription, and FC/DFC units may provide a structural basis for that separation. PMID- 25450595 TI - Crystal structure of the essential Mycobacterium tuberculosis phosphopantetheinyl transferase PptT, solved as a fusion protein with maltose binding protein. AB - Phosphopantetheinyl transferases (PPTases) are key enzymes in the assembly-line production of complex molecules such as fatty acids, polyketides and polypeptides, where they activate acyl or peptidyl carrier proteins, transferring a 4'-phosphopantetheinyl moiety from coenzyme A (CoA) to a reactive serine residue on the carrier protein. The human pathogen Mycobacterium tuberculosis encodes two PPTases, both essential and therefore attractive drug targets. We report the structure of the type-II PPTase PptT, obtained from crystals of a fusion protein with maltose binding protein. The structure, at 1.75A resolution (R=0.156, Rfree=0.191), reveals an alpha/beta fold broadly similar to other type II PPTases, but with differences in peripheral structural elements. A bound CoA is clearly defined with its pantetheinyl arm tucked into a hydrophobic pocket. Interactions involving the CoA diphosphate, bound Mg(2+) and three active site acidic side chains suggest a plausible pathway for proton transfer during catalysis. PMID- 25450597 TI - Alpha 7 nicotinic acetylcholine receptor agonist GTS-21 mitigates isoflurane induced cognitive impairment in aged rats. AB - BACKGROUND: Postoperative cognitive dysfunction is increasingly recognized as an important clinical syndrome. Inhalation anesthetics are commonly used during surgery, and it has been proposed that inhalation anesthetics impair cognitive function. However, there are few clinical interventions and treatments available to prevent this disorder. GTS-21, a selective agonist of alpha 7 nicotinic acetylcholine receptor, has been indicated to exert neuroprotective effects in the experimental animal models of neurodegenerative diseases. Therefore, we hypothesized that pretreatment with GTS-21 attenuates isoflurane-induced cognitive decline in aged rats. METHODS: In the present study, 20-mo-old rats were administered GTS-21 or an equal volume of saline by intraperitoneal injection 30 min before exposure to isoflurane. Then the rats were exposed to 1.3% isoflurane for 4 h. Spatial learning and memory of the rats were assessed at 2 wk after isoflurane exposure. The expression levels of interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in the hippocampus and cerebral cortex were determined by enzyme-linked immunosorbent assay. Simultaneously, neuronal apoptosis in the hippocampus was also observed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and Nissl staining. RESULTS: We found that exposure to isoflurane induces learning and memory deficits of old rats. IL-1beta in the hippocampus was increased at 4 h after isoflurane exposure. Isoflurane also increased neuroapoptosis in the hippocampus and decreased neuronal density in the CA1 region. And GTS-21 pretreatment effectively alleviated these changes. CONCLUSIONS: The study demonstrated that pretreatment with alpha7 nicotinic acetylcholine receptor agonist GTS-21 attenuates isoflurane-induced learning and memory impairment in aged rats. PMID- 25450596 TI - Program Capacity to Eliminate Outcome Disparities in Addiction Health Services. AB - We evaluated program capacity factors associated with client outcomes in publicly funded substance abuse treatment organizations in one of the most populous and diverse regions of the United States. Using multilevel cross-sectional analyses of program data (n = 97) merged with client data from 2010 to 2011 for adults (n = 8,599), we examined the relationships between program capacity (leadership, readiness for change, and Medi-Cal payment acceptance) and client wait time and treatment duration. Acceptance of Medi-Cal was associated with shorter wait times, whereas organizational readiness for change was positively related to treatment duration. Staff attributes were negatively related to treatment duration. Overall, compared to low program capacity, high program capacity was negatively associated with wait time and positively related to treatment duration. In conclusion, program capacity, an organizational indicator of performance, plays a significant role in access to and duration of treatment. Implications for health care reform implementation in relation to expansion of public health insurance and capacity building to promote health equities are discussed. PMID- 25450598 TI - Siglec-10 is associated with survival and natural killer cell dysfunction in hepatocellular carcinoma. AB - BACKGROUND: The interaction between Siglec-10 and its ligand, CD24, selectively represses tissue damage-caused immune responses. However, the nature of Siglec-10 and CD24 in human hepatocellular carcinoma (HCC) is still poorly defined. Hereon, the expression, function, and regulation of CD24 and Siglec-10 in HCC were investigated in the present study. METHODS: Flow cytometry was performed to examine the expression of Siglec-10 in HCC tissues and adjacent non-tumor tissues of HCC patients. To further determine whether Siglec-10 expression is associated with the clinical characteristics and survival, conventional immunohistochemistry was performed in 96 HCC patients. Additionally, the role of Siglec-10 in the regulation of natural killer (NK) cell dysfunction was evaluated. Finally, CD24 expression in HCC was also assessed. RESULTS: Siglec-10 was expressed most on NK cells in HCC (40.7 +/- 4.5%). Compared with surrounding non-tumor tissues, tumor tissues had higher Siglec-10 expression (31.0 +/- 1.7% versus 40.7 +/- 4.5%, n = 10, P < 0.05), and the expression was negatively associated with patient survival. Siglec-10(+)CD56(+) NK cells exhibited reduced effector function, as shown by decreased granules and cytokine expressions compared with Siglec-10( )CD56(+) NK cells. Moreover, the number of CD24(+)CD45(-) cells in HCC tissues was higher than that in adjacent non-tumor tissues (9.4 +/- 0.9% versus 3.1 +/- 0.9%, n = 15, P < 0.05). CONCLUSIONS: These findings suggest that Siglec-10 is associated with decreased survival and impaired NK cell function in human HCC. This process may function via the CD24-Siglec-10 interaction, which may represent a therapeutic target in HCC patients. PMID- 25450599 TI - Risk factors for postoperative fatigue after gastrointestinal surgery. AB - BACKGROUND: Postoperative fatigue (POF) is an important complication that is commonly observed postoperatively and is also one of the most serious obstacles to postoperative convalescence. However, the risk factors for POF have not been fully addressed, and there is no effective method to predict POF. The aim of the present study was to investigate the risk factors for POF and to explore prediction of the degree of POF. METHODS: A prospective observational study was conducted of patients undergoing elective gastrointestinal surgery. Fatigue score, grip strength, length of postoperative hospital stay (LOS), as well as preoperative and intraoperative factors were collected. chi(2) was used to compare categorical variables, and multivariate logistic regression analysis was used to further analyze correlation between POF and preoperative and intraoperative factors. RESULTS: A total of 155 patients were included in our analysis without loss in follow-up. Multivariate logistic regression analysis after adjustment for factors with severe POF in univariate analysis including preoperative fatigue, plasma albumin and hemoglobin level, and cardiopulmonary function demonstrated that old age, gastrectomy, and a nutritional risk screening 2002 score >= 3 were associated with a higher relative risk of severe POF. Moreover, laparoscopic-assisted surgery was associated with lower relative risk of severe POF. CONCLUSIONS: Old age, nutritional risk screening 2002 score >= 3 and gastrectomy were risk factors for POF in patients undergoing elective gastrointestinal surgery. POF was reduced in laparoscopic-assisted surgery. Consideration of these factors could be important for the prevention and treatment of POF. PMID- 25450600 TI - Trauma system development in low- and middle-income countries: a review. AB - BACKGROUND: Trauma systems in resource-rich countries have decreased mortality for trauma patients through centralizing resources and standardizing treatment. Rapid industrialization and urbanization have increased the demand for formalized emergency medical services and trauma services (EMS and TS) in low- and middle income countries (LMICs). This systematic review examines initiatives to develop EMS and TS systems in LMICs to inform the development of comprehensive prehospital care systems in resource-poor settings. MATERIALS AND METHODS: EMS and TS system development publications were identified using MEDLINE, PubMed, and Scopus databases. Articles addressing subspecialty skill sets, public policy, or physicians were excluded. Two independent reviewers assessed titles, abstracts, and full texts in a hierarchical manner. RESULTS: A total of 12 publications met inclusion criteria, and 10 unique LMIC EMS and TS programs were identified. Common initiatives included the integration of existing EMS and TS services and provision of standardized training and formalized certification processes for prehospital care providers, as well as the construction of a conceptual framework for system development through the public health model. CONCLUSIONS: There is no single model of EMS and TS systems, and successful programs are heterogeneous across regions. Successful EMS and TS systems share common characteristics. A predevelopment needs assessment is critical in identifying existing EMS and TS resources as a foundation for further development. Implementation requires coordination of preexisting resources with cost-effective initiatives that involve local stakeholders. High-impact priority areas are identified to focus improvements. Financial stresses and mismatching of resources in LMICs are common and are more commonly encountered when implementing a high-income model EMS and TS in an LMIC. Preimplementation and postimplementation evaluations can determine the efficacy of initiatives to strengthen EMS and TS systems. PMID- 25450601 TI - Evaluation of the validity of medical students' self-assessments of proficiency in clinical simulations. AB - BACKGROUND: The accuracy of self-assessments has not been well supported in the literature. This study was undertaken to examine the validity of medical students' ratings of their proficiency during encounters with simulated patients and simulation devices. METHODS: Confidential self-assessments for 10 skills were collected from 195 students during a formal clinical skills assessment related to 3 cases at the end of a surgery clerkship. The cases required students to gather data from simulated patients and perform procedures such as rectal examinations, nasogastric tube insertions, and suturing on bench simulation models. The patients were trained to assess student performance. RESULTS: There were significant differences between student self-assessments and simulated patient scores for general clinical skills as opposed to procedural skills. Students' mean self-assessments in the data gathering and interpersonal skills were 2-6 % points higher than ratings of their proficiency by simulated patients. However, self-assessments on procedures were 5-8 points lower than patient ratings. The median correlation between self-assessments and patient ratings for general clinical skills such as data gathering and interpersonal skills was 0.08 (not significant), whereas the median correlation between student and patient ratings in procedures was 0.22 (P < 0.01). CONCLUSIONS: Third-year medical students' self assessments for specific procedures are more valid than self-assessments of general clinical skills. Students are less confident in their procedural skills compared with general clinical skills. Although self-assessments should not be used as the sole measure of performance in clinical simulations, self-assessments for specific procedures can provide supplemental information on proficiency. PMID- 25450602 TI - A new mutation in the COL4A3 gene responsible for autosomal dominant Alport syndrome, which only generates hearing loss in some carriers. AB - Bilateral sensorineural hearing loss is a characteristic feature of Alport syndrome, which is always linked to renal manifestations so they have a parallel evolution and prognosis, and deafness helps to identify the renal disease. We report a family that suffers an autosomal dominant Alport syndrome caused by a previously undescribed mutation in the COL4A3 gene, in which several members have hearing impairment as the only clinical manifestation, suggesting that in this family deafness can occur independent of renal disease. This mutation is also present in a patient with anterior lenticonus, an observation only found in families with recessive and sex-linked Alport disease. PMID- 25450603 TI - Mutations in patients with osteogenesis imperfecta from consanguineous Indian families. AB - Osteogenesis imperfecta (OI) is a spectrum of genetic disorders with decreased bone density and bone fragility. Most of the cases of OI are inherited in autosomal dominant fashion with mutations in COL1A1 or COL1A2 genes. Over last few years, twelve genes for autosomal recessive OI have been identified. In this study we have evaluated seven patients with OI from consanguineous Indian families. Homozygosity mapping using SNP microarray was done and selected candidate genes were sequenced. Candidate genes were identified in four out of seven patients studied. Four mutations, namely; a homozygous non-sense (p.Q178*) and a deletion (p.F277del) mutations in SERPINF1 gene, a missense mutation (p.M101K) in PPIB gene and a nonsense mutation (p.E45*) in CRTAP gene were identified. In three patients for whom the regions of homozygosity did not reveal any known autosomal recessive OI genes, exome sequencing was performed and we identified a known missense mutation (p.G1012S) in COL1A2 gene in one of the patients. As WNT1 gene was not properly covered in exome sequencing in one patient, the gene was sequenced and a homozygous in-frame deletion of four amino acids (p.Phe176_Leu179del) was identified. In one of the three cases the exome sequencing did not reveal a mutation in any known OI genes, suggesting the possibility of mutations in an unidentified gene. The phenotypes of all the cases are described. This work proves the power of homozygosity mapping followed by candidate gene sequencing approach for clinical application in consanguineous families. PMID- 25450604 TI - Microduplication of chromosome Xq25 encompassing STAG2 gene in a boy with intellectual disability. AB - Whole-genome microarray analysis is proven to be useful in the identification of submicroscopic copy number imbalances in families with intellectual disabilities. The first case of Xq25 duplication was identified using genome-wide array comparative genomic hybridization (array-CGH) in a 24-year-old patient with a syndromic intellectual disability. We report a 4-year-old boy with a de novo 591 kb duplication at Xq25. The duplication was first detected by a CytoScan HD array platform (Affymetrix, USA) and was confirmed by real-time quantitative PCR (qPCR) of the STAG2 gene, and by fluorescence in situ hybridization (FISH). The patient had clinical features partially consistent with published cases, including an intellectual disability and speech delay. The identification of this additional patient and a detailed analysis of duplications identified in other patient cohorts and absent in normal individuals support the existence of a rare pathological microduplication at Xq25 that encompasses STAG2. PMID- 25450605 TI - Clinical practice guidelines for the diagnosis and management of acute otitis media (AOM) in children in Japan - 2013 update. AB - OBJECTIVE: To (1) indicate methods of diagnosis and testing for childhood (<15 years) acute otitis media (AOM) and (2) recommend methods of treatment in accordance with the evidence-based consensus reached by the Subcommittee of Clinical Practice Guideline for Diagnosis and Management of AOM in Children (Subcommittee of Clinical Practice Guideline), in light of the causative bacteria and their drug sensitivity of AOM in Japan. METHODS: We investigated the most recently detected bacteria causing childhood AOM in Japan as well as antibacterial sensitivity and the worldwide distinct progress of vaccination, produced Clinical Questions concerning the diagnosis, testing methods, and treatment of AOM, searched literature published during 2000-2004, and issued the 2006 Guidelines. In the 2009 and 2013 Guidelines, we performed the same investigation with the addition of literature, which were not included in the 2006 Guidelines and published during 2005-2008 and during 2009-2012, respectively. RESULTS: We categorized AOM as mild, moderate, or severe on the basis of tympanic membrane findings and clinical symptoms, and presented recommended treatment for each degree of severity. CONCLUSION: Accurate assessment of tympanic membrane findings is important for judging the degree of severity and selecting a method of treatment. Some of new antimicrobial agents and pneumococcal vaccination are recommended as new treatment options. PMID- 25450606 TI - EUS-guided choledochoduodenostomy with a lumen-apposing metal stent before duodenal stent placement for malignant biliary and duodenal obstruction. PMID- 25450607 TI - Use of narrow-band imaging with magnification to predict depth of invasion of early esophageal squamous cell cancer and to guide endoscopic therapy. PMID- 25450609 TI - Mitochondrial calcium and the regulation of metabolism in the heart. AB - Consumption of adenosine triphosphate (ATP) by the heart can change dramatically as the energetic demands increase from a period of rest to strenuous activity. Mitochondrial ATP production is central to this metabolic response since the heart relies largely on oxidative phosphorylation as its source of intracellular ATP. Significant evidence has been acquired indicating that Ca(2+) plays a critical role in regulating ATP production by the mitochondria. Here the evidence that the Ca(2+) concentration in the mitochondrial matrix ([Ca(2+)]m) plays a pivotal role in regulating ATP production by the mitochondria is critically reviewed and aspects of this process that are under current active investigation are highlighted. Importantly, current quantitative information on the bidirectional Ca(2+) movement across the inner mitochondrial membrane (IMM) is examined in two parts. First, we review how Ca(2+) influx into the mitochondrial matrix depends on the mitochondrial Ca(2+) channel (i.e., the mitochondrial calcium uniporter or MCU). This discussion includes how the MCU open probability (PO) depends on the cytosolic Ca(2+) concentration ([Ca(2+)]i) and on the mitochondrial membrane potential (DeltaPsim). Second, we discuss how steady-state [Ca(2+)]m is determined by the dynamic balance between this MCU-based Ca(2+) influx and mitochondrial Na(+)/Ca(2+) exchanger (NCLX) based Ca(2+) efflux. These steady-state [Ca(2+)]m levels are suggested to regulate the metabolic energy supply due to Ca(2+)-dependent regulation of mitochondrial enzymes of the tricarboxylic acid cycle (TCA), the proteins of the electron transport chain (ETC), and the F1F0 ATP synthase itself. We conclude by discussing the roles played by [Ca(2+)]m in influencing mitochondrial responses under pathological conditions. This article is part of a Special Issue entitled "Mitochondria: From BasicMitochondrial Biology to Cardiovascular Disease." PMID- 25450608 TI - Further evaluation of [11C]MP-10 as a radiotracer for phosphodiesterase 10A: PET imaging study in rhesus monkeys and brain tissue metabolite analysis. AB - [(11)C]MP-10 is a potent and specific PET tracer previously shown to be suitable for imaging the phosphodiesterase 10A (PDE10A) in baboons with reversible kinetics and high specific binding. However, another report indicated that [(11)C]MP-10 displayed seemingly irreversible kinetics in rhesus monkeys, potentially due to the presence of a radiolabeled metabolite capable of penetrating the blood-brain-barrier (BBB) into the brain. This study was designed to address the discrepancies between the species by re-evaluating [(11)C]MP-10 in vivo in rhesus monkey with baseline scans to assess tissue uptake kinetics and self-blocking scans with unlabeled MP-10 to determine binding specificity. Ex vivo studies with one rhesus monkey and 4 Sprague-Dawley rats were also performed to investigate the presence of radiolabeled metabolites in the brain. Our results indicated that [(11)C]MP-10 displayed reversible uptake kinetics in rhesus monkeys, albeit slower than in baboons. Administration of unlabeled MP-10 reduced the binding of [(11)C]MP-10 in a dose-dependent manner in all brain regions including the cerebellum. Consequently, the cerebellum appeared not to be a suitable reference tissue in rhesus monkeys. Regional volume of distribution (VT) was mostly reliably derived with the multilinear analysis (MA1) method. In ex vivo studies in the monkey and rats only negligible amount of radiometabolites was seen in the brain of either species. In summary, results from the present study strongly support the suitability of [(11)C]MP-10 as a radiotracer for PET imaging and quantification of PDE10A in nonhuman primates. PMID- 25450610 TI - MicroRNA-specific regulatory mechanisms in atherosclerosis. AB - During the past decade, the crucial role of microRNAs (miRs) controlling tissue homeostasis and disease in the cardiovascular system has become widely recognized. By controlling the expression levels of their targets, several miRs have been shown to modulate the function of endothelial cells, vascular smooth muscle cells, and macrophages, thereby regulating the development and progression of atherosclerosis. For instance, miR-155 can exacerbate early stages of atherosclerosis by increasing the inflammatory activation and disturbing efficient lipid handling in macrophages. Conversely, miRs can exert atheroprotective roles, as has been established for the complementary miR-126 strand pair, which forms a dual system sustaining the endothelial proliferative reserve and promoting endothelial regeneration to counteract atherogenic effects of disturbed flow and hyperlipidemia. Under some conditions, miRs are released from cells and are transported by microvesicles, ribonucleoprotein complexes, and lipoproteins, being remarkably stable in circulation. Conferred by such delivery modules, miRs can regulate target mRNAs in recipient cells, representing a new tool for cell-cell communication in the context of atherosclerotic disease. Here, we will discuss novel aspects of miR-mediated regulatory mechanisms, namely the regulation by competing RNA targets, miRNA tandems, or complementary miR strand pairs, as well as their potential diagnostic and therapeutic value in atherosclerosis. This article is part of a Special Issue entitled 'Non-coding RNAs'. PMID- 25450611 TI - Impaired cytosolic NADH shuttling and elevated UCP3 contribute to inefficient citric acid cycle flux support of postischemic cardiac work in diabetic hearts. AB - Diabetic hearts are subject to more extensive ischemia/reperfusion (ISC/REP) damage. This study examined the efficiency of citric acid cycle (CAC) flux and the transfer of cytosolic reducing equivalents into the mitochondria for oxidative support of cardiac work following ISC/REP in hearts of c57bl/6 (NORM) and type 2 diabetic, db/db mouse hearts. Flux through the CAC and malate aspartate shuttle (MA) were monitored via dynamic (13)C NMR of isolated hearts perfused with (13)C palmitate+glucose. MA flux was lower in db/db than NORM. Oxoglutarate malate carrier (OMC) was elevated in the db/db heart, suggesting a compensatory response to low NADHc. Baseline CAC flux per unit work (rate pressure-product, RPP) was similar between NORM and db/db, but ISC/REP reduced the efficiency of CAC flux/RPP by 20% in db/db. ISC/REP also increased UCP3 transcription, indicating potential for greater uncoupling. Therefore, ISC/REP induces inefficient carbon utilization through the CAC in hearts of diabetic mice due to the combined inefficiencies in NADHc transfer per OMC content and increased uncoupling via UCP3. Ischemia and reperfusion exacerbated pre-existing mitochondrial defects and metabolic limitations in the cytosol of diabetic hearts. These limitations and defects render diabetic hearts more susceptible to inefficient carbon fuel utilization for oxidative energy metabolism. PMID- 25450612 TI - Interleukin-19 increases angiogenesis in ischemic hind limbs by direct effects on both endothelial cells and macrophage polarization. AB - Hypoxia in ischemic limbs typically initiates angiogenic and inflammatory factors to promote angiogenesis in attempt to restore perfusion. There is a gap in our knowledge concerning the role of anti-inflammatory interleukins in angiogenesis, macrophage polarization, and endothelial cell activation. Interleukin-19 is a unique anti-inflammatory Th2 cytokine that promotes angiogenic effects in cultured endothelial cells (EC); the purpose of this study was to characterize a role for IL-19 in restoration of blood flow in hind-limb ischemia, and define potential mechanisms. Hind limb ischemia was induced by femoral artery ligation, and perfusion quantitated using Laser Doppler Perfusion Imaging (LDPI). Wild type mice which received i.p. injections of rIL-19 (10ng/g/day) showed significantly increased levels of perfusion compared to PBS controls. LDPI values were significantly decreased in IL-19(-/-) mice when compared to wild type mice. IL 19(-/-) mice injected with rIL-19 had significantly increased LDPI compared with PBS control mice. Significantly increased capillary density was quantitated in rIL-19 treated mice, and significantly less capillary density in IL-19(-/-) mice. Multiple cell types participate in IL-19 induced angiogenesis. IL-19 treatment of human microvascular EC induced expression of angiogenic cytokines. M2 macrophage marker and VEGF-A expression were significantly increased in macrophage and the spleen from rIL-19 injected mice, and M1 marker expression was significantly increased in the spleen from IL-19(-/-) compared with controls. Plasma VEGF-A levels are higher in rIL-19 injected mice. IL-19 decreased the expression of anti angiogenic IL-12 in the spleen and macrophage. This study is the first to implicate IL-19 as a novel pro-angiogenic interleukin and suggests therapeutic potential for this cytokine. PMID- 25450613 TI - T-tubule disruption promotes calcium alternans in failing ventricular myocytes: mechanistic insights from computational modeling. AB - In heart failure (HF), T-tubule (TT) disruption contributes to dyssynchronous calcium (Ca) release and impaired contraction, but its role in arrhythmogenesis remains unclear. In this study, we investigate the effects of TT disruption and other HF remodeling factors on Ca alternans in ventricular myocytes using computer modeling. A ventricular myocyte model with detailed spatiotemporal Ca cycling modeled by a coupled Ca release unit (CRU) network was used, in which the L-type Ca channels and the ryanodine receptor (RyR) channels were simulated by random Markov transitions. TT disruption, which removes the L-type Ca channels from the associated CRUs, results in "orphaned" RyR clusters and thus provides increased opportunity for spark-induced Ca sparks to occur. This effect combined with other HF remodeling factors promoted alternans by two distinct mechanisms: 1) for normal sarco-endoplasmic reticulum Ca ATPase (SERCA) activity, alternans was caused by both CRU refractoriness and coupling. The increased opportunity for spark-induced sparks by TT disruption combined with the enhanced CRU coupling by Ca elevation in the presence or absence of increased RyR leakiness facilitated spark synchronization on alternate beats to promote Ca alternans; 2) for down regulated SERCA, alternans was caused by the sarcoplasmic reticulum (SR) Ca load dependent mechanism, independent of CRU refractoriness. TT disruption and increased RyR leakiness shifted and steepened the SR Ca release-load relationship, which combines with down-regulated SERCA to promote Ca alternans. In conclusion, the mechanisms of Ca alternans for normal and down-regulated SERCA are different, and TT disruption promotes Ca alternans by both mechanisms, which may contribute to alternans at different stages of HF. PMID- 25450614 TI - Early opening of sarcolemmal ATP-sensitive potassium channels is not a key step in PKC-mediated cardioprotection. AB - ATP-sensitive potassium (KATP) channels are abundantly expressed in the myocardium. Although a definitive role for the channel remains elusive they have been implicated in the phenomenon of cardioprotection, but the precise mechanism is unclear. We set out to test the hypothesis that the channel protects by opening early during ischemia to shorten action potential duration and reduce electrical excitability thus sparing intracellular ATP. This could reduce reperfusion injury by improving calcium homeostasis. Using a combination of contractile function analysis, calcium fluorescence imaging and patch clamp electrophysiology in cardiomyocytes isolated from adult male Wistar rats, we demonstrated that the opening of sarcolemmal KATP channels was markedly delayed after cardioprotective treatments: ischemic preconditioning, adenosine and PMA. This was due to the preservation of intracellular ATP for longer during simulated ischemia therefore maintaining sarcolemmal KATP channels in the closed state for longer. As the simulated ischemia progressed, KATP channels opened to cause contractile, calcium transient and action potential failure; however there was no indication of any channel activity early during simulated ischemia to impart an energy sparing hyperpolarization or action potential shortening. We present compelling evidence to demonstrate that an early opening of sarcolemmal KATP channels during simulated ischemia is not part of the protective mechanism imparted by ischemic preconditioning or other PKC-dependent cardioprotective stimuli. On the contrary, channel opening was actually delayed. We conclude that sarcolemmal KATP channel opening is a consequence of ATP depletion, not a primary mechanism of ATP preservation in these cells. PMID- 25450616 TI - Exercise makes the difference: deconstructing physiological hypertrophy in swine. PMID- 25450615 TI - Redox regulation of cardiomyocyte cell cycling via an ERK1/2 and c-Myc-dependent activation of cyclin D2 transcription. AB - Adult mammalian cardiomyocytes have a very limited capacity to proliferate, and consequently the loss of cells after cardiac stress promotes heart failure. Recent evidence suggests that administration of hydrogen peroxide (H2O2), can regulate redox-dependent signalling pathway(s) to promote cardiomyocyte proliferation in vitro, but the potential relevance of such a pathway in vivo has not been tested. We have generated a transgenic (Tg) mouse model in which the H2O2-generating enzyme, NADPH oxidase 4 (Nox4), is overexpressed within the postnatal cardiomyocytes, and observed that the hearts of 1-3week old Tg mice pups are larger in comparison to wild type (Wt) littermate controls. We demonstrate that the cardiomyocytes of Tg mouse pups have increased cell cycling capacity in vivo as determined by incorporation of 5-bromo-2'-deoxyuridine. Further, microarray analyses of the transcriptome of these Tg mouse hearts suggested that the expression of cyclin D2 is significantly increased. We investigated the molecular mechanisms which underlie this more proliferative phenotype in isolated neonatal rat cardiomyocytes (NRCs) in vitro, and demonstrate that Nox4 overexpression mediates an H2O2-dependent activation of the ERK1/2 signalling pathway, which in turn phosphorylates and activates the transcription factor c-myc. This results in a significant increase in cyclin D2 expression, which we show to be mediated, at least in part, by cis-acting c-myc binding sites within the proximal cyclin D2 promoter. Overexpression of Nox4 in NRCs results in an increase in their proliferative capacity that is ablated by the silencing of cyclin D2. We further demonstrate activation of the ERK1/2 signalling pathway, increased phosphorylation of c-myc and significantly increased expression of cyclin D2 protein in the Nox4 Tg hearts. We suggest that this pathway acts to maintain the proliferative capacity of cardiomyocytes in Nox4 Tg pups in vivo and so delays their exit from the cell cycle after birth. PMID- 25450618 TI - Thermodynamic parameters for binding of some halogenated inhibitors of human protein kinase CK2. AB - The interaction of human CK2alpha with a series of tetrabromobenzotriazole (TBBt) and tetrabromobenzimidazole (TBBz) analogs, in which one of the bromine atoms proximal to the triazole/imidazole ring is replaced by a methyl group, was studied by biochemical (IC50) and biophysical methods (thermal stability of protein-ligand complex monitored by DSC and fluorescence). Two newly synthesized tri-bromo derivatives display inhibitory activity comparable to that of the reference compounds, TBBt and TBBz, respectively. DSC analysis of the stability of protein-ligand complexes shows that the heat of ligand binding (Hbind) is driven by intermolecular electrostatic interactions involving the triazole/imidazole ring, as indicated by a strong correlation between Hbind and ligand pKa. Screening, based on fluorescence-monitored thermal unfolding of protein-ligand complexes, gave comparable results, clearly identifying ligands that most strongly bind to the protein. Overall results, additionally supported by molecular modeling, confirm that a balance of hydrophobic and electrostatic interactions contribute predominantly, relative to possible intermolecular halogen bonding, in binding of the ligands to the CK2alpha ATP-binding site. PMID- 25450617 TI - Increased myocardial stiffness due to cardiac titin isoform switching in a mouse model of volume overload limits eccentric remodeling. AB - We investigated the cellular and molecular mechanisms of diastolic dysfunction in pure volume overload induced by aortocaval fistula (ACF) surgery in the mouse. Four weeks of volume overload resulted in significant biventricular hypertrophy; protein expression analysis in left ventricular (LV) tissue showed a marked decrease in titin's N2BA/N2B ratio with no change in phosphorylation of titin's spring region. Titin-based passive tensions were significantly increased; a result of the decreased N2BA/N2B ratio. Conscious echocardiography in ACF mice revealed eccentric remodeling and pressure volume analysis revealed systolic dysfunction: reductions in ejection fraction (EF), +dP/dt, and the slope of the end-systolic pressure volume relationships (ESPVR). ACF mice also had diastolic dysfunction: increased LV end-diastolic pressure and reduced relaxation rates. Additionally, a decrease in the slope of the end diastolic pressure volume relationship (EDPVR) was found. However, correcting for altered geometry of the LV normalized the change in EDPVR and revealed, in line with our skinned muscle data, increased myocardial stiffness in vivo. ACF mice also had increased expression of the signaling proteins FHL-1, FHL-2, and CARP that bind to titin's spring region suggesting that titin stiffening is important to the volume overload phenotype. To test this we investigated the effect of volume overload in the RBM20 heterozygous (HET) mouse model, which exhibits reduced titin stiffness. It was found that LV hypertrophy was attenuated and that LV eccentricity was exacerbated. We propose that pure volume overload induces an increase in titin stiffness that is beneficial and limits eccentric remodeling. PMID- 25450619 TI - RIPK3 regulates p62-LC3 complex formation via the caspase-8-dependent cleavage of p62. AB - RIPK3 is a key molecule for necroptosis, initially characterized by necrotic cell death morphology and the activation of autophagy. Cell death and autophagic signaling are believed to tightly regulate each other. However, the associated recruitment of signaling proteins remains poorly understood. p62/sequestosome-1 is a selective autophagy substrate and a selective receptor for ubiquitinated proteins. In this study, we illustrated that both mouse and human RIPK3 mediate p62 cleavage and that RIPK3 interacts with p62, resulting in complex formation. In addition, RIPK3-dependent p62 cleavage is restricted by the inhibition of caspases, especially caspase-8. Moreover, overexpression of A20, a ubiquitin editing enzyme and an inhibitor of caspase-8 activity, inhibits RIPK3-dependent p62 cleavage. To further investigate the potential role of RIPK3 in selective autophagy, we analyzed p62-LC3 complex formation, revealing that RIPK3 prevents the localization of LC3 and ubiquitinated proteins to the p62 complex. In addition, RIPK3-dependent p62-LC3 complex disruption is regulated by caspase inhibition. Taken together, these results demonstrated that RIPK3 interacts with p62 and regulates p62-LC3 complex formation. These findings suggested that RIPK3 serves as a negative regulator of selective autophagy and provides new insights into the mechanism by which RIPK3 regulates autophagic signaling. PMID- 25450620 TI - Assessment of DNA synthesis in Islet-1+ cells in the adult murine heart. AB - RATIONALE: Islet-1 positive (Islet-1(+)) cardiac progenitor cells give rise to the right ventricle, atria and outflow tract during murine cardiac development. In the adult heart Islet-1 expression is limited to parasympathetic neurons, few cardiomyocytes, smooth muscle cells, within the proximal aorta and pulmonary artery and sinoatrial node cells. Its role in these cells is unknown. Here we tested the hypothesis that Islet-1(+) cells retain proliferative activity and may therefore play a role in regenerating specialized regions in the heart. METHODS AND RESULTS: DNA synthesis was analyzed by the incorporation of tritiated thymidine ((3)H-thymidine) in Isl-1-nLacZ mice, a transgenic model with an insertion of a nuclear beta-galactosidase in the Islet-1 locus. Mice received daily injections of (3)H-thymidine for 5 days. DNA synthesis was visualized throughout the heart by dipping autoradiography of cryosections. Colocalization of an nLacZ-signal and silver grains would indicate DNA synthesis in Islet-1(+) cells. Whereas Islet(-) non-myocyte nuclei were regularly marked by accumulation of silver grains, colocalization with nLacZ-signals was not detected in >25,000 cells analyzed. CONCLUSIONS: Islet-1(+) cells are quiescent in the adult heart, suggesting that, under normal conditions, even pacemaking cells do not proliferate at higher rates than normal cardiac myocytes. PMID- 25450621 TI - Disrupted cell cycle arrest and reduced proliferation in corneal fibroblasts from GCD2 patients: a potential role for altered autophagy flux. AB - This study investigates the role of impaired proliferation, altered cell cycle arrest, and defective autophagy flux of corneal fibroblasts in granular corneal dystrophy type 2 (GCD2) pathogenesis. The proliferation rates of homozygous (HO) GCD2 corneal fibroblasts at 72 h, 96 h, and 120 h were significantly lower (1.102 +/- 0.027, 1.397 +/- 0.039, and 1.527 +/- 0.056, respectively) than those observed for the wild-type (WT) controls (1.441+/-0.029, 1.758 +/- 0.043, and 2.003 +/- 0.046, respectively). Flow cytometry indicated a decreased G1 cell cycle progression and the accumulation of cells in the S and G2/M phases in GCD2 cells. These accumulations were associated with decreased levels of Cyclin A1, B1, and E1, and increased expression of p16 and p27. p21 and p53 expression was also significantly lower in GCD2 cells compared to the WT. Interestingly, treatment with the autophagy flux inhibitor, bafilomycin A1, resulted in similarly decreased Cyclin A1, B1, D1, and p53 expression in WT fibroblasts. Furthermore, similar findings, including a decrease in Cyclin A1, B1, and D1 and an increase in p16 and p27 expression were observed in autophagy-related 7 (Atg7; known to be essential for autophagy) gene knockout cells. These data provide new insight concerning the role of autophagy in cell cycle arrest and cellular proliferation, uncovering a number of novel therapeutic possibilities for GCD2 treatment. PMID- 25450622 TI - Analysis of actual healthcare costs of early versus interval cholecystectomy in acute cholecystitis. AB - BACKGROUND: Healthcare cost modeling have favored early (ELC) over interval laparoscopic cholecystectomy (ILC) for acute cholecystitis (AC). However, actual costs of treatment have never been studied. The aim of the present study was to compare actual hospital costs involved in ELC and ILC in patients with AC. METHODS: Retrospective study of patients who underwent laparoscopic cholecystectomy for AC was conducted. Demographic, clinical, operative data and costs were extracted and analyzed. RESULTS: Between 2011 and 2013, 201 had laparoscopic surgery for AC at Tan Tock Seng Hospital, Singapore. One hundred and thirty-four (67%) patients underwent ELC (<=7 days of presentation, within index admission). Median total length of stay (LOS) was 4.6 and 6.8 days for ELC and ILC groups, respectively (P = 0.006). Patients who had ELC also had significantly lesser total number of admissions (P < 0.001). The median (IQR) total inpatient costs were ?4.4 * 10(3) (3.6-5.6) and ?5.5 * 10(3) (4.0-7.5) for ELC and ILC patients, respectively (P < 0.007). Costs associated with investigations were significantly higher in the ILC group (P = 0.039), of which serological costs made most difference (P < 0.005). The ward costs were also significantly higher in the ILC group. CONCLUSION: The cost differences reflect the significantly increased total LOS, and repeat presentations associated with ILC. Therefore, ELC should be the preferred management strategy for AC. PMID- 25450623 TI - Effective use of heterologous hosts for characterization of biosynthetic enzymes allows production of natural products and promotes new natural product discovery. AB - In the past few years, there has been impressive progress in elucidating the mechanism of biosynthesis of various natural products accomplished through the use of genetic, molecular biological and biochemical techniques. Here, we present a comprehensive overview of the current results from our studies on fungal natural product biosynthetic enzymes, including nonribosomal peptide synthetase and polyketide synthase-nonribosomal peptide synthetase hybrid synthetase, as well as auxiliary enzymes, such as methyltransferases and oxygenases. Specifically, biosynthesis of the following compounds is described in detail: (i) Sch210972, potentially involving a Diels-Alder reaction that may be catalyzed by CghA, a functionally unknown protein identified by targeted gene disruption in the wild type fungus; (ii) chaetoglobosin A, formed via multi-step oxidations catalyzed by three redox enzymes, one flavin-containing monooxygenase and two cytochrome P450 oxygenases as characterized by in vivo biotransformation of relevant intermediates in our engineered Saccharomyces cerevisiae; (iii) (-) ditryptophenaline, formed by a cytochrome P450, revealing the dimerization mechanism for the biosynthesis of diketopiperazine alkaloids; (iv) pseurotins, whose variations in the C- and O-methylations and the degree of oxidation are introduced combinatorially by multiple redox enzymes; and (v) spirotryprostatins, whose spiro-carbon moiety is formed by a flavin-containing monooxygenase or a cytochrome P450 as determined by heterologous de novo production of the biosynthetic intermediates and final products in Aspergillus niger. We close our discussion by summarizing some of the key techniques that have facilitated the discovery of new natural products, production of their analogs and identification of biosynthetic mechanisms in our study. PMID- 25450624 TI - Design and synthesis of novel quinazoline derivatives and their evaluation as PI3Ks inhibitors. AB - The aim of this work was to synthesize 4-acetamido-, 4-amino- and 4-oxo-6 substituted aminoquinazolines and to evaluate them as phosphoinositide 3-kinases (PI3Ks) inhibitors. The respective chemotype was designed based on combining the structural features of two previously reported scaffolds acting as potent PI3Kgamma inhibitors, which are quinazoline derivatives and amino-heterocyclic derivatives. In vitro enzymatic assay at 10 uM against all the eight human PI3K isoforms showed that an unsubstituted benzamide group at position 6 and an acetyl group at N(4) gave the best inhibitory activity on PI3Kgamma. Interestingly, compounds 5a and 5e showed a significant, inhibitory effect on Class II PI3K C2gamma. This is of high value since there are very few inhibitors for this isoform reported in the literature. PMID- 25450625 TI - Formulation and in vitro characterization of a novel solid lipid-based drug delivery system. AB - The liquid self-emulsifying drug delivery system (L-SEDDS), commonly used to deliver effective but poorly water-soluble oleanolic acid (OA), has many limitations such as high manufacturing costs, few choices of dosage forms, risk of leakage from hard gelatin capsules, low stability, limited portability, incompatibility with capsule materials, and relatively restricted storage conditions. Thus the main purpose of our study was to develop a promising solid lipid-based drug delivery system (S-SEDDS) for OA. The S-SEDDS, prepared from wet granulation with an optimized L-SEDDS formulation and mannitol, was characterized by particle size analysis, scanning electron microscopy, differential scanning calorimetry, and X-ray powder diffraction. Finally, the solubility of the OA loaded S-SEDDS was compared with that of OA powder in the dissolution assay. Our new S-SEDDS for OA was developed from the optimum L-SEDDS with ethyl oleate (oil phase), Labrasol (surfactant), and Transcutol P (cosurfactant) at a volume ratio of 15:71:14 with 1.5% w/v OA and mannitol. The dissolution of OA was improved by 60% compared with that of the pure OA powder. All the problems associated with the L-SEDDS were resolved. The methodologies we developed for OA delivery could also be utilized for the delivery of other drugs with the S-SEDDS. PMID- 25450626 TI - Lyotropic behavior of a mono-tailed glycolipid assembly during solidification and melting of electrolyte/ice eutectic systems. AB - The properties of low molecular weight glycolipids at subzero temperatures have been paid much attention due to their great potential for applications in cryopreservation. In this study, the ability of glycolipids to maintain their lyotropic properties was investigated by analyzing the aggregation behavior of octyl-beta-D-glucoside (beta-OGlu) during solidification and melting of electrolyte/ice eutectic mixtures using a simultaneous X-ray diffraction differential scanning calorimetry measurement and cryomicroscopic observation. During the freezing process, eutectic formation increased the concentration of the beta-OGlu micelle solution in the unfrozen phase, leading to ordering of the molecular assembly. The molecular assembly exhibited a reversible phase transformation between liquid crystalline phases (e.g., lamellar (Lalpha) and hexagonal (H) phases) and an isotropic micelle solution (I), depending on the degree of eutectic formation, which was regulated by temperature. Because the coexistence of electrolyte/ice eutectic often induces the dehydration of lipids, the persistence of lyotropic properties under such arid conditions demonstrates an attractive performance of glycolipids for use in low temperature applications, such as the cryopreservation of poorly water-soluble drugs or proteins. PMID- 25450627 TI - Design, synthesis and biological evaluation of nitro oxide donating N hydroxycinnamamide derivatives as histone deacetylase inhibitors. AB - Novel nitro oxide (NO)-donating N-hydroxycinnamamide derivatives 12a-j were designed and synthesized by coupling the carboxyl group of N-hydroxycinnamamides with phenylsulfonylfuroxan through various diols or alkylol amines, and their in vitro biological activities were evaluated. It was discovered that most of target compounds showed good histone deacetylases (HDACs) inhibition and anti-tumor activities, particularly for 12j, which had great HDACs inhibitory activities (IC50s=0.15-0.26 uM) and antiproliferative effects (IC50s=3.21-7.12 uM) comparable to suberoylanilide hydroxamic acid (SAHA) (IC50s=0.16-1.41 uM for HDACs, IC50s=3.15-7.45 uM for cancer cell inhibition). Furthermore, compound 12j with strong antitumor activities produced high levels of NO (up to 8.0 uM of nitrites/nitrates) in colon cancer cells, and its antiproliferative activity was nearly half-diminished by hemoglobin (10 uM), an NO scavenger. These results suggest that the strong antiproliferative activity of 12j could be attributed to the additive effects of high levels of NO production and inhibition of HDAC in the cancer cells. PMID- 25450628 TI - A rare type of sesquiterpene and beta-santalol derivatives from Santalum album and their cytotoxic activities. AB - A rare type of sesquiterpene with a spiro bicyclic system (1) and seven new (2-8) and four known (9-12) beta-santalol derivatives were isolated from the heartwood of Santalum album (Santalaceae). The structures of these new compounds were determined by analysis of extensive spectroscopic data. The isolated compounds and derivatives were evaluated for their cytotoxic activity against HL-60 human promyelocytic leukemia cells, A549 human lung adenocarcinoma cells, HSC-2 and HSC 4 human oral squamous cell carcinoma cell lines, and TIG-3 normal human diploid fibroblasts. cis-beta-Santalol (9) and beta-santaldiol (10) induced apoptotic cell death in HL-60 cells. PMID- 25450629 TI - Synthesis and in vivo evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors. AB - A novel class of phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability in mouse liver microsomes were designed and synthesized starting from 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3 yl]phenoxy}methyl)quinoline (MP-10). Replacement of the phenoxymethyl part of MP 10 with an oxymethyl phenyl unit led to the identification of 2-[4-({[1-methyl-4 (pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (14), which showed moderate PDE10A inhibitory activity with improved metabolic stability in mouse and human liver microsomes over MP-10. Compound 14 showed high concentrations in plasma and brain after intraperitoneal administration and dose-dependently attenuated the hyperlocomotion induced by phencyclidine in mice, and oral administration of 14 (0.1, 0.3 mg/kg) also improved visual-recognition memory impairment in mice. PMID- 25450630 TI - Prediction of color changes using the time-temperature superposition principle in liquid formulations. AB - This study reports the results of applying the time-temperature superposition principle (TTSP) to the prediction of color changes in liquid formulations. A sample solution consisting of L-tryptophan and glucose was used as the model liquid formulation for the Maillard reaction. After accelerated aging treatment at elevated temperatures, the Commission Internationale de l'Eclairage (CIE) LAB color parameters (a*, b*, L*, and E*ab) of the sample solution were measured using a spectrophotometer. The TTSP was then applied to a kinetic analysis of the color changes. The calculated values of the apparent activation energy of a*, b*, L*, and DeltaE*ab were 105.2, 109.8, 91.6, and 103.7 kJ/mol, respectively. The predicted values of the color parameters at 40 degrees C were calculated using Arrhenius plots for each of the color parameters. A comparison of the relationships between the experimental and predicted values of each color parameter revealed the coefficients of determination for a*, b*, L*, and DeltaE*ab to be 0.961, 0.979, 0.960, and 0.979, respectively. All the R(2) values were sufficiently high, and these results suggested that the prediction was highly reliable. Kinetic analysis using the TTSP was successfully applied to calculating the apparent activation energy and to predicting the color changes at any temperature or duration. PMID- 25450631 TI - Molecular docking and panicolytic effect of 8-prenylnaringenin in the elevated T maze. AB - The purpose of this study was to investigate the effects of the chronic administration of a racemic mixture of 8-prenylnaringenin (8-PN) on rats submitted to the elevated T-maze (ETM) model of generalized anxiety and panic disorders. The selective serotonin (SERT) reuptake inhibitor fluoxetine was used as a positive control. Rat locomotion was assessed in a circular arena following each drug treatment. The administration of racemic 8-PN for 21 d in rats increased one-way escape latencies from the ETM open arm, indicating a panicolytic effect. To evaluate the interactions of 8-PN with monoamine transporters, a docking study was performed for both the R and S configurations of 8-PN towards SERT, norepinephrine (NET) and dopamine transporters (DAT). The application of the docking protocol showed that (R)-8-PN provides greater affinity to all transporters than does the S enantiomer. This result suggests that enantiomer (R)-8-PN is the active form in the in vivo test of the racemic mixture. PMID- 25450632 TI - Benzofuran-morpholinomethyl-pyrazoline hybrids as a new class of vasorelaxant agents: synthesis and quantitative structure-activity relationship study. AB - The benzofuran-morpholinomethyl-pyrazoline hybrids 4a-e, 5a-e and 6a-j were synthesized via reaction of alpha,beta-unsaturated carbonyl compounds 3a-e with hydrazine hydrate, semicarbazide or thiosemicarbazide. Applying the Mannich reaction to 5-(5-aryl-4,5-dihydro-1H-pyrazol-3-yl)-4-methoxybenzofuran-6-ols 7a-e with morpholine hydrochloride and paraformaldehyde afforded positional isomeric 7 morpholinomethyl derivatives 4a-e and N-morpholinomethyl derivatives 8a-e. All the synthesized compounds showed significant vasodilatation properties in isolated thoracic aortic rings of rats precontracted using the standard norepinephrine hydrochloride technique. Compounds 3d, 3e, 5a-c, 6b, 6c, 6f, 6h and 6i exhibited activity (IC50 0.3185-0.4577 mM) superior to that of prazocin (IC50 0.487 mM), while 5d, 6j and 8c showed comparable activity (IC50 0.4789 0.4951 mM). The quantitative structure-activity relationship study revealed a correlation between the observed vasorelaxant activities of the newly synthesized compounds and their different physicochemical parameters, especially solubility, in addition to structure connectivity and energetic quantities calculated from stored three dimensional (3D) conformations. Absorption, distribution, metabolism and elimination (ADME) evaluation showed good agreement with the biological results obtained. PMID- 25450633 TI - Bitterness evaluation of acidic pharmaceutical substances (NSAIDs) using a taste sensor. AB - The objective of this study was to evaluate an improved bitterness sensor which has been developed to allow the precise and sensitive prediction of the bitterness of acidic bitter pharmaceutical active ingredients, using as examples nine non-steroidal anti-inflammatory drugs (NSAIDs). The bitterness of the nine NSAIDs was measured using a multichannel taste-sensing system incorporating a bitterness sensor, C00, which has a membrane surface with high hydrophobicity, and was developed to allow an enhanced hydrophobic interaction with acidic bitter substances. The sourness intensities of the nine NSAIDs were also determined in gustatory sensation testing and by a taste sensor using a sourness-sensitive membrane, CA0. The 'Change in membrane Potential caused by Adsorption' (CPA) of sodium diclofenac and etodolac were also determined in the presence of increasing concentrations of tartaric acid using membrane C00. Multiple regression analysis performed on the data on bitterness intensity obtained using the taste sensor and in gustatory sensation testing showed that CPA values from C00 could be used to predict the bitterness of the NSAIDs. The derived equation was y = -0.0413 * CPA + 0.3164, where y represents the predicted bitterness intensity. There were concentration-dependent changes in the bitterness intensities of diclofenac sodium and etodolac without any change in their sourness intensities. For diclofenac sodium and etodolac, there was a good correlation between predicted and actual bitterness intensities in the presence of increasing concentrations of tartaric acid. The taste sensor may be useful for predicting the bitterness intensity of acidic bitter pharmaceutical active ingredients such as NSAIDs. PMID- 25450634 TI - Synthesis, antibacterial, antioxidant activity and QSAR studies of novel 2 arylidenehydrazinyl-4-arylthiazole analogues. AB - A novel series of 2-arylidenehydrazinyl-4-arylthiazole analogues (3a-p) was designed and synthesized in excellent yields using a rapid, simple, efficient methodology. Sixteen novel compounds were screened for in vitro antimicrobial activities against eleven bacteria, namely, Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, Bacillus subtilis, Klebsiella pneumonia, Citrobacter freundii, Cronobacter sakazakii, Salmonella enteritidis, Escherichia coli, Yersinia pestis, and Pseudomonas aeruginosa. All 16 compounds showed significant anti-bacterial activities against both Gram-positive and Gram negative bacteria. In particular, compound 3g showed potent inhibition of E. coli and K. pneumonia, compound 3i inhibited E. faecalis, compound 3n S. tythi and E. faecalis, and compound 3c E. coli and C. sakazakii. In fact, our results indicate that most of the compounds synthesized exhibit strong antibacterial activity. The qualitative structure-antibacterial activity relationships (QSAR) were studied using the physicochemical and quantum-chemical parameters of the ab initio Hartree-Fock model at the RHF/6-31G level of theory. A good qualitative correlation between predicted physicochemical parameters (log P and polar surface area (PSA)) and antibacterial activity has been found. The synthesized compounds were also evaluated for antioxidant activity. Compounds 3j, 3a and 3i exhibited the greatest antioxidant activity, with IC50 values of 0.66, 0.81, and 1.08 uM, respectively, which were comparable to that of ascorbic acid (IC50 0.87 uM). The promising antibacterial and antioxidant activities of some of these synthesized 2 arylidenehydrazinyl-4-arylthiazole derivatives, together with the results of quantum-chemical studies, could be helpful for the development of drugs to combat diseases caused by microorganisms and oxidative stress. PMID- 25450635 TI - Study of T helper 1 and T helper 2 responses in pemphigus vulgaris patients receiving interferon alpha 2a injections in addition to a standard protocol therapy: a randomized controlled trial. AB - T helper (Th)1 insufficiency was recently found to be related to the pathogenesis of pemphigus vulgaris (PV). Decreased Th1 response was particularly noticed in the early stages of PV. Therefore, administration of interferon alpha in the early stages of aggressive PV may lead to rapid control of the acute stage of the disease. Our aim was to evaluate the role of interferon alpha in the treatment of PV. 30 patients with acute severe PV (>60 % affection) and 30 age and sex-matched healthy subjects were included in this RCT. Patients were randomly divided into two groups (A and B). Group B patients received interferon retard (one subcutaneous injection/week for 4 weeks) in addition to our protocol for the treatment of PV (systemic pulse corticosteroids/cyclophosphamide in combination with sulphasalazine and pentoxifylline) that was administered to all the included patients. IFN-gamma and IL-4 were estimated by ELISA before treatment, after 4 weeks and at the end of the study duration (12 weeks). Clinical assessment was done by PAAS on a biweekly basis. All PV patients showed significantly (P < 0.001) elevated levels of IL-4 and significantly (P < 0.001) depressed mean concentration of IFN-gamma as compared with healthy controls. Twelve weeks after therapy both groups showed significant improvement in their mean PAAS being more evident and more rapid in group B. IFN-gamma was elevated significantly and IL-4 was dropped significantly in group B patients in comparison to group A (P < 0.001). As a conclusion, interferon therapy in severe PV could achieve a more prompt and better clinical response. PMID- 25450636 TI - Genome sequence of type strain Paenibacillus polymyxa DSM 365, a highly efficient producer of optically active (R,R)-2,3-butanediol. AB - Paenibacillus polymyxa DSM 365, an efficient producer of (R,R)-2,3-butanediol, is known to show the highest production titer and productivity reported to date. Here, the first draft genome sequence of this promising strain may provide the genetic basis for further insights into the molecular mechanisms underlying the production of (R,R)-2,3-butanediol with high optical purity and at a high titer. It will also facilitate the design of rational strategies for further strain improvements, as well as construction of artificial biosynthetic pathways through synthetic biology for asymmetric synthesis of chiral 2,3-butanediol or acetoin in common microbial hosts. PMID- 25450637 TI - Reprint of "Inhibition of biofilm formation by Camelid single-domainantibodies against the flagellum of Pseudomonas aeruginosa". AB - Pseudomonas aeruginosa is a leading cause of hospital-acquired infections in patients with compromised host defense mechanisms, including burn wound victims. In addition to its intrinsic resistance against most antibiotics, P. aeruginosa has the ability to form biofilms adhering to biotic or abiotic surfaces. These factors make treatment of P. aeruginosa infections complicated and demand new therapies and drugs. The flagellum of P. aeruginosa plays an important role in cell-cell and cell-surface interactions during the first stage of biofilm formation. In this study, we describe the selection of monoclonal anti-flagellin single-domain antibodies (VHHs) derived from the Camelid heavy-chain antibody repertoire of a llama immunized with P. aeruginosa antigens. The anti-flagellin VHHs could be produced efficiently in Saccharomyces cerevisiae, and surface plasmon resonance experiments demonstrated that they have apparent affinities in the nanomolar range. Functional screens showed that the anti-flagellin VHHs are capable of inhibiting P. aeruginosa from swimming and that they prevent biofilm formation in an in vitro assay. These data open doors for the development of novel methods for the prevention of P. aeruginosa-related infections. PMID- 25450638 TI - Endothelial cell high-enrichment from endovascular biopsy sample by laser capture microdissection and fluorescence activated cell sorting. AB - BACKGROUND AND PURPOSE: Endovascular sampling and characterization from patients can provide very useful information about the pathogenesis of different vascular diseases, but it has been limited by the lack of an effective method of endothelial cell (EC) enrichment. We optimized the EC yield and enrichment from conventional guide wires by laser capture microdissection (LCM) and fluorescence activated cell sorting (FACS) technique, and addressed the feasibility of using these enriched ECs for downstream gene expression detection. METHODS: Iliac artery endovascular samples from 10 patients undergoing routine catheter angiography were collected using conventional 0.038 in. J-shape guide wires. Each of these samples was equally divided into two parts, which were respectively used for EC enrichment by immunocytochemistry-coupled LCM or multiple color FACS. After RNA extraction and reverse transcription, the amplified cDNA was used for quantitative polymerase chain reaction (qPCR). RESULTS: Fixed ECs, with positive CD31 or vWF fluorescent signal and endothelial like nucleus, were successfully separated by LCM and live single ECs were sorted on FACS by a seven color staining panel. EC yields by LCM and FACS were 51 +/- 22 and 149 +/- 56 respectively (P < 0.001). The minimum number of fixed ECs from ICC-coupled LCM for acceptable qPCR results of endothelial marker genes was 30, while acceptable qPCR results as enriched by FACS were attainable from a single live EC. CONCLUSION: Both LCM and FACS can be used to enrich ECs from conventional guide wires and the enriched ECs can be used for downstream gene expression detection. FACS generated a higher EC yield and the sorted live ECs may be used for single cell gene expression detection. PMID- 25450639 TI - L-Arabinose (pyranose and furanose rings)-branched poly (vinylalcohol): enzymatic synthesis of the sugar esters followed by free radical polymerization. AB - Herein this study reports the successful synthesis of a new poly(vinyl alcohol) (PVA), containing L-arabinose (L-arabinopyranose and arabinofuranose isomers) branched in only two steps: (1) production of polymerizable monomers of L arabinose isomers (pyranose and furanose forms) through enzymatic synthesis using alkaline protease from Bacillus subtilis as catalyst and two substrates: L arabinose and Divinyl Adipate (DVA) in N,N-dimethylformamide (DMF); (2) radical polymerization of the monomers, using an initiator system consisting of potassium persulfate and hydrogen peroxide in water. The transesterification of DVA with L arabinose was monitored via qualitative analysis by TLC, confirming the formation of the vinyl sugar ester. The acylation occurred on the two different cyclic conformations of the L-arabinose which coexist in equilibrium: (alpha/beta) arabinofuranose and (alpha/beta) arabinopyranose. The acylation positions and the chemical structure of the 5-O-vinyl adipoyl L-arabinofuranose and 4-O-vinyl adipolyl L-arabinopyranose formed were determined by 13C NMR. The surface activity of the L-arabinose esters mixture (monomers) was compared with a commercial product based on phenol formaldehyde polyoxyalkylene polyamine, largely used as surfactant in many industries. FTIR spectroscopy of the sugar ester monomers and the respective polymer were compared revealing the disappearance of the vinyl group in the polymer spectrum. The polymer number average molar mass (Mn) and the weight-average molar mass (Mw) were determined by gel permeation chromatography (GPC) presenting the following results: 2.9 * 10(4) Da and 7.2 * 10(4) Da, respectively, and polydispersity (Mw/Mn) equal to 2.48. PMID- 25450640 TI - Enhanced lipid accumulation in the yeast Yarrowia lipolytica by over-expression of ATP:citrate lyase from Mus musculus. AB - Yarrowia lipolytica can accumulate large amounts of storage lipids and has considerable potential for the production of polyunsaturated fatty acids and other lipids for biofuels. When the nitrogen source is exhausted in the medium, the key intermediate, citrate, is converted to acetyl-CoA by ATP:citrate lyase (ACL) for lipid accumulation. However, in this yeast most of the citrate is also secreted into the culture medium. To increase the endogenous substrate (acetyl CoA) level for lipid biosynthesis, the acl gene from Mus musculus was over expressed in Y. lipolytica with mono-copy integration vector pINA1312sp and multi copy integration vector pINA1292sp. This increased the lipid content from 7.3% to between 11% and 23% (w/w) of the cell dry weight. Cell growth was only slightly affected. Multi-copy integration transformants had higher lipid contents than mono-copy integration transformants; the lipid content of the transformants was consistent with the copy number of acl gene integrated. Over-expression of ACL had no significant effect on fatty acid profile of the yeast. These results suggested that ACL is an important acetyl-CoA producer and plays a vital role in lipid accumulation in oleaginous yeast Y. lipolytica. PMID- 25450641 TI - Switching an anti-IgG binding site between archaeal extremophilic proteins results in Affitins with enhanced pH stability. AB - As a useful reagent for biotechnological applications, a scaffold protein needs to be as stable as possible to ensure longer lifetimes. We have developed archaeal extremophilic proteins from the "7 kDa DNA-binding" family as scaffolds to derive affinity proteins (Affitins). In this study, we evaluated a rational structure/sequence-guided approach to stabilize an Affitin derived from Sac7d by transferring its human IgG binding site onto the framework of the more thermally stable Sso7d homolog. The chimera obtained was functional, well expressed in Escherichia coli, but less thermally stable than the original Affitin (T(m) = 74.2 degrees C vs. T(m) = 80.4 degrees C). Two single mutations described as thermally stabilizing wild type Sso7d were introduced into chimeras. Only the double mutation nearly restored thermal stability (T(m) = 76.9 degrees C). Interestingly, the chimera and its double mutant were stable from pH 0 up to at least pH 13. Our results show that it is possible to increase further the stability of Affitins toward alkaline conditions (+2 pH units) while conserving their advantageous properties. As Affitins are based on a growing family of homologs from archaeal extremophiles, we conclude that this approach offers new potential for their improvement, which will be useful in demanding biotechnological applications. PMID- 25450642 TI - Process development of periplasmatically produced single chain fragment variable against epidermal growth factor receptor in Escherichia coli. AB - Prokaryotic production systems have been widely used to manufacture recombinant therapeutic proteins. Economically, the prokaryotic production - especially of small therapeutic molecules - is advantageous compared to eukaryotic production strategies. However, due to the potential endotoxin and host cell protein contamination, the requirements for the purification process are disproportionately higher and therefore more expensive and elaborate to circumvent. For this reason, the goal of this work was to develop and establish a rapid, simple, inexpensive and 'up-scalable' production and purification process, using the therapeutic relevant protein anti-EGFR scFv hu225 as model molecule. Configuring high cell density cultivation of Escherichia coli - using the rha-BAD expression system as production platform - a specific product concentration up to 20 mgscFv/gCDW was obtained. By combining freeze-and-thaw, osmotic shock and pH induced host cell protein precipitation, almost 70% of the product was extracted from the biomass. In a novel approach a mixed mode chromatography was implemented as a capturing and desalting step, which allowed the direct application of further ion exchange chromatography steps for purification up to pharmaceutical grade. Thereby, 50% of the produced scFv could be purified within 10 h while maintaining the biological activity. PMID- 25450643 TI - Outlining microbial community dynamics during temperature drop and subsequent recovery period in anaerobic co-digestion systems. AB - To improve the stability of anaerobic reactors, more knowledge is required about how the different communities react against operating perturbations and which specific ones respond better. The objective of this work was to monitor the changes in microbial community structure of an anaerobic digester during a temperature drop by applying different complementary molecular techniques. Temperature decrease led to an increase of Bacteroidales order, Porphyromonadaceae family and Bacteroides genus and a decrease in Syntrophomonas and Clostridium genera. Once the temperature was restored, the reactor recovered the steady state performance without requiring any modification in operational conditions or in the microbiome. During the recovery period, Sedimentibacter genus and Porphyromonadaceae family played an important role in the degradation of the accumulated volatile fatty acids. The hydrogenotrophic methanogens appeared to be the keystone archaeal population at low temperatures as well as in the recovery period. This study stands out that the understanding of microbial community dynamics during temperature drop could be utilized to develop strategies for the mitigation of temperature change consequences and speed up the recovery of stable reactor performance. PMID- 25450644 TI - Influence of biofilm thickness on nitrous oxide (N2O) emissions from denitrifying fluidized bed bioreactors (DFBBRs). AB - Nitrous oxide (N2O) is a significant anthropogenic greenhouse gas emitted from biological nutrient removal (BNR) processes. This study tries to get a deeper insight into N2O emissions from denitrifying fluidized bed bioreactors (DFBBRs) and its relationship to the biofilm thickness, diffusivity, and reaction rates. The DFBBR was operated at two different organic and nitrogen loading rates of 5.9 7 kg COD/(m3 d) and 1.2-2 kg N/(m3 d), respectively. Results showed that the N2O conversion rate from the DFBBR at a biofilm thickness of 680 MUm was 0.53% of the total influent nitrogen loading while at the limited COD and a biofilm thickness of 230 MUm, the N2O conversion rate increased by 196-1.57% of the influent nitrogen loading concomitant with a sevenfold increase in liquid nitrite concentration. Comparing the N2O emissions at different biofilm thickness showed that the N2O emission decreased exponentially with biofilm thickness due to the retention of slow growth denitrifiers and the limited diffusivity of N2O. PMID- 25450645 TI - The role of circulating adiponectin in prostate cancer: a meta-analysis. AB - PURPOSE: Emerging evidence suggests that adiponectin may play a protective role in tumor progression and prognosis. However, available evidence in prostate cancer is conflicting. Therefore, we carried out a meta-analysis to evaluate the role of circulating adiponectin and prostate cancer. METHODS AND RESULTS: An extensive search was performed on Google, PubMed, Elsevier Science and Springer from the date of the inception of those services to December 2013. Eleven studies with 2,504 patients and 3,565 controls concerning this association were included in our analysis. Standard mean difference (SMD) with 95% confidence intervals (95% CIs) was used to estimate this association. The pooled analysis showed that circulating adiponectin concentrations were lower in patients with prostate cancer than controls, with a pooled SMD of -0.893 MUg/mL (95% CI, -1.345 to 0.440, p=0.000). Dose-response relationships between concentrations of adiponectin and risk of prostate cancer were evaluated. We found that decreased concentrations of adiponectin were associated with a significantly greater risk of prostate cancer (p for nonlinearity = 0.043). CONCLUSIONS: The results of our analysis indicated that concentration of adiponectin in cancer patients was significantly lower than in controls. Thus, adiponectin may serve as a potential biomarker for early diagnosis of this disease. We also found that decreased concentration of adiponectin was associated with a significantly greater risk of prostate cancer. However, more studies in future, especially larger, prospective studies, are needed to confirm this association with underlying biological mechanisms. PMID- 25450646 TI - Serological tumor markers of hepatocellular carcinoma: a meta-analysis. AB - BACKGROUND: The clinical value of serum alpha-fetoprotein (AFP) to detect hepatocellular carcinoma (HCC) has been questioned due to its low sensitivity and specificity. Other than AFP, several new serum biomarkers including glypican-3 (GPC3), des-gamma-carboxy prothrombin (DCP), alpha-L-fucosidase enzyme (AFU) and vascular endothelial growth factor (VEGF) have been identified as useful HCC markers. MATERIAL AND METHODS: A systematic search on PubMed, Web of Science and others was performed. Twenty-six case-control studies on HCC-related biomarkers published from 2000 to 2014 were included in this analysis. Data on sensitivity and specificity of tests were extracted and analyzed using the Meta-DiSc 1.4 statistical program. Fixed or random-effects models were used depending on the absence or presence of significant heterogeneity. Summary receiver operating characteristic (sROC) curves were obtained to evaluate the accuracy of the studied markers. RESULTS: The areas under the sROC curve of AFP, GPC3, DCP, AFU, VEGF and the combination of each of the last 4 markers with AFP were 0.869, 0.928, 0.832, 0.851, 0.834, 0.964, 0.972, 0.873 and 0.948, respectively. A combination of AFP+GPC3, AFP+DCP or AFP+VEGF was superior to AFP alone in detecting HCC. The area under the sROC curve of GPC3 alone was significantly higher than that of AFP, whereas the areas of DCP, AFU and VEGF were comparable to that of AFP. CONCLUSIONS: GPC3, DCP, AFU and VEGF are suitable markers for HCC, and their determination with AFP may prove to be useful in the diagnosis and screening of HCC. PMID- 25450647 TI - Relationship between NOB1 expression and prognosis of resected non-small cell lung cancer. AB - BACKGROUND: The aim of this study was to investigate the relationship between Nin one binding (NOB1) protein expression and prognosis for resected non-small cell lung cancer (NSCLC). METHODS: A prospective cohort of 70 consecutive patients with resected NSCLC was studied in 2009. Immunohistochemistry was used in the detection of NOB1 protein expression. Prognosis outcomes included overall survival (OS) and progression-free survival (PFS). The log-rank test and Cox hazard model were used to estimate the relationship between NOB1 expression and prognosis. RESULTS: In the 70 NSCLC tissue specimens, 14 (20%) stained -, 24 (34%) stained +, 21 (30%) stained ++ and 11 (16%) stained +++. The NOB1 high expression rate was 16%. NOB1 expression was significantly different between TMN stage (p=0.024) and lymph node metastasis (p=0.001), as well as histopathological grades (p=0.037). Median OS was 43 months (95% confidence interval [95% CI], 35 51 months), and median PFS was 37 months (95% CI, 25-49 months). OS and PFS were related to TMN stage and lymph node metastasis, as well as NOB1 expression (p<0.05). After adjustment for TMN stage and lymph node metastasis, the hazard ratio (HR) for high NOB1 expression was 1.7 (95% CI, 1.1-3.0, p=0.027) for OS, and 1.8 (95% CI, 1.3-3.7, p=0.031) for PFS. CONCLUSIONS: Our results suggest that enhanced expression of NOB1 is related to poor overall survival and progression free survival in patients with resected NSCLC. PMID- 25450649 TI - FBXW7 mutation analysis and its correlation with clinicopathological features and prognosis in colorectal cancer patients. AB - PURPOSE: This study aimed to determine the prognostic value of mutations in the tumor suppressor gene FBXW7 for clinical outcomes in colorectal cancer (CRC). METHODS: Between January 2000 and December 2009, FBXW7 mutations in tumor tissues from 1,519 CRC patients at Taipei Veterans General Hospital were assessed using a MassArray system. We compared the clinicopathological variables and prognosis between the wild-type and mutant tumor tissue groups. RESULTS: FBXW7 mutations were present in 114/1,519 CRC patients (7.5%). In stage I/II CRC patients, mutant FBXW7 was more common than wild-type FBXW7 (62.3% vs. 50.8%). CRC patients with FBXW7 mutations did not differ significantly in their 5-year overall survival (OS). Stage I/II CRC patients with FBXW7 mutations had lower OS, but this difference was not significant (71.6% vs. 78.2%). Among FBXW7 tumors, S582L was the most frequent mutation type (19.3%), followed by R465H (16.6%), R505C (14.9%) and R479Q (14.9%). Subgroup analysis of FBXW7 mutants showed that R465H/R465C/R479Q had better 5-year OS than other mutant types (76.9% vs. 56.0%; p=0.012). CONCLUSIONS: There was no strong association between patient prognosis and FBXW7 mutations in our large-scale study. PMID- 25450650 TI - Prognostic effect of high pretreatment neutrophil to lymphocyte ratio on survival of patients with gastric adenocarcinoma in China. AB - BACKGROUND: A high neutrophil to lymphocyte ratio (NLR) is a strong predictor of poor survival in patients with colorectal, breast, pancreatic and lung cancers, while the prognostic value of NLR in gastric cancer is still controversial. The aim of our study was to determine the prognostic value of pretreatment NLR in a Chinese population of patients with gastric adenocarcinoma. METHODS: Our retrospective study used an unselected cohort of gastric adenocarcinoma patients treated in the Cancer Center of Sun Yat-sen University between January 2001 and December 2008. We used the data from 341 healthy individuals as controls to understand the difference of NLR between the gastric cancer patients and normal individuals. A total of 706 patients had a complete blood count (CBC) record prior to treatment. Cox regression analysis was used to evaluate the prognostic value of NLR. RESULTS: Gastric adenocarcinoma patients had a significantly higher NLR as well as neutrophilic granulocyte and lower lymphocyte counts compared with healthy individuals. By combining the nearby groups of NLR whose survival had no significant difference, we got a cutoff value for NLR of 3. Patients with a high NLR had a significantly lower survival rate than patients with a low NLR. On multivariate analysis, after adjusting for tumor stage and other clinicopathologic factors, high NLR turned out to be an independent risk factor for poor survival (p=0.016). CONCLUSIONS: Gastric cancer patients had a significantly higher incidence rate of high NLR compared with healthy individuals. High pretreatment NLR in gastric cancer was an independent prognostic factor. PMID- 25450648 TI - Correlation between LDH levels and response to sorafenib in HCC patients: an analysis of the ITA.LI.CA database. AB - BACKGROUND: Lactate dehydrogenase (LDH) is a predictor of clinical outcome in hepatocellular carcinoma (HCC) patients. However, its predictive role in the clinical outcomes of sorafenib treatment has been poorly documented. The correlation between LDH levels and clinical outcomes in HCC patients treated with sorafenib and included in the nationwide Italian database ITA.LI.CA was investigated here. PATIENTS AND METHODS: The ITA.LI.CA database contains data for 5,136 HCC patients. All patients treated with sorafenib treatment and with available LDH values were considered. Overall survival (OS) and time to progression (TTP) were compared in patients with LDH levels above and below a defined threshold, determined through an ROC analysis. An explorative analysis investigated the relationship between the variation of LDH levels during treatment and response to sorafenib. RESULTS: Baseline LDH levels were available for 97 patients. The most accurate cutoff value for LDH concentration was 297 U/L. Patients with LDH values above (n=45) and below (n=52) this threshold showed equal OS (12.0 months) and TTP (4.0 months) values. Data on LDH levels during sorafenib treatment were reported for 10 patients. LDH values decreased in 3 patients (mean difference = -219 U/L) who also reported a prolonged OS and TTP versus those with unmodified/increased LDH (OS: NE (not evaluated) vs. 8.0 months, p=0.0083; TTP: 19.0 vs. 3.0 months, p=0.008). CONCLUSIONS: The clinical benefits of sorafenib do not seem to be influenced by baseline LDH. According to the results of an explorative analysis, however, a decreased LDH concentration during sorafenib might be associated with improved clinical outcomes. PMID- 25450651 TI - Night eating and loss of control over eating in bariatric surgery candidates. AB - The goal was to examine the relationship between loss of control over eating (LOCE) and other variables, including eating pathology, in bariatric candidates. Two hundred and twenty-six participants completed measures of depressive symptoms, eating pathology, health-related quality of life (HRQOL), and alcohol use. Participants were divided into those who did (n = 123) and did not (n = 103) report subjective LOCE. Participants with LOCE had significantly higher levels of night eating, depressive symptoms, and eating disorder psychopathology and lower mental HRQOL. There were no observed differences in alcohol use, dietary restraint, or physical HRQOL. This study highlights eating and mental health related correlates of LOCE, providing evidence that it is associated with increased psychological burden in bariatric candidates. This is one of the first studies to report the relationship between LOCE and night eating in this group and future research could elaborate on these variables to determine their importance in long-term weight loss. PMID- 25450652 TI - Determination of lymphocyte subset reference ranges in peripheral blood of healthy adults by a dual-platform flow cytometry method. AB - Flow cytometry has emerged as a useful screening approach to evaluate whether specific cell populations are present or absent. Previous studies have shown different reference ranges in several countries. The aim of this study was to determine reference ranges of lymphocyte subsets in peripheral blood by flow cytometric method in Brazilian adults. In this study, relative and absolute reference ranges of lymphocyte subsets were: CD3+: 51.3-83.5%, 718-2494cells/MUl; CD4+: 24.4-54.2%, 456-1492cells/MUl; CD8+: 12.8-40.2%, 272-1144cells/MUl; CD4+CD8+: double-positive 0.01-3.6%, 2-88cells/MUl; TCR gammadelta: 1.0-15.9%, 19 345cells/MUl; CD3+CD4-CD8-: 1.2-13.3%, 28-292cells/MUl; TCR alphabeta+: 44.3 77.0%, 855-2384cells/MUl; CD4/CD8 ratio: 0.68-3.61; CD19+: 6.3-20.8%, 112 622cells/MUl; mature NK cells: 3.1-27.4%, 70-745cells/MUl; immature NK cells: 0.08-1.1%, 1-23cells/MUl; total NK cells: 3.7-28.5%, 82-760cells/MUl; and NKT cells: 0.9-21.4%, 18-488cells/MUl. Comparison with other studies showed differences among some of them. This suggests that there are differences among lymphocyte subsets in the worldwide population and also it is important to determine reference ranges in different populations in order to better assess and monitor patients. PMID- 25450653 TI - Outcome of decompression with and without fusion in spinal stenosis with degenerative spondylolisthesis in relation to preoperative pain pattern: a register study of 1,624 patients. AB - BACKGROUND CONTEXT: Patients with spinal stenosis with concomitant degenerative spondylolisthesis (DS) and predominant back pain (PBP) have been shown to have inferior outcome after surgery. Studies comparing outcome according to preoperative pain predominance and treatment received are lacking. PURPOSE: The purpose was to study if adding spinal fusion to the decompression in DS affects outcome in patients with PBP (back pain [BP] Visual Analog Scale [VAS] more than or equal to leg pain [LP] VAS) compared with predominant leg pain (PLP) (BP VAS less than LP VAS). PATIENT SAMPLE: The Swedish Spine Register was used and included 1,624 patients operated for DS at the L4-L5 level. OUTCOME MEASURES: Self-reported measures were used, including a VAS for BP and LP, the EuroQol-5D (EQ-5D), and the physical and mental component summaries of the Short-Form 36 to estimate health-related quality of life and the Oswestry disability index (ODI) to estimate function. METHODS: Inclusion criterion was single-level DS operated on with either decompression only (D) or decompression and instrumented posterolateral fusion (DF). Based on preoperative LP and BP scores, the patients were assigned to one of the two groups: LP predominance or BP predominance. The patients completed the outcome protocol at 1- and 2-year follow-ups. Statistical analysis was performed using linear regression adjusting for multiple potential confounders. RESULTS: In the adjusted outcome at the 1-year follow-up, patients with PLP reported a 7.9-mm more improvement on the VAS for BP with fusion, compared with D (95% confidence interval [CI], 0.7-15.2), p=.03. Despite more change in the fused group, the reported BP levels remained similar in the D versus decompressed and fused at the 1-year follow-up (28 vs. 24, p=.77). The patients with PBP benefited from adding fusion in terms of BP 7.1 (95% CI, 0.3 13.9, p=.04), LP 8.8 (2-15.7, p=.01), the ODI 5.7 (1.6-9.9, p=.006), and the EQ 5D 0.09 (1.7-0.02, p=.02) at the 1-year follow-up as the DF group reported greater change in the outcome compared with the D group. At the 2-year follow-up, no significant differences were found between D and decompressed and fused in either the LP or the PBP groups. CONCLUSIONS: Patients with PBP operated with DF report better outcomes in terms of pain, function, and health-related quality of life than patients with D. Although these differences are significant on a group level, they may fail to reach minimal clinical significant difference. Patients with PLP report significantly more improvement in terms of BP with DF compared with D, but because of baseline differences in preoperative BP, these improvements may not be explained by the added fusion per se. At the 2-year follow-up, no significant differences were observed between the D and DF patients in either the PBP or PLP groups, but greater loss to follow-up in the DF groups could potentially bias these findings. PMID- 25450654 TI - Exclusively epidural spinal metameric arteriovenous shunts: case report and literature review. AB - BACKGROUND CONTEXT: Spinal arteriovenous metameric syndrome (SAMS) is a subgroup of spinal arteriovenous malformations (AVMs). Most SAMS cases have intra- and extradural AVMs and suffer from hematomyelia, subarachnoid hemorrhage, or venous congestive myelopathy. PURPOSE: To present a rare case of SAMS in which spinal AVMs were exclusively epidural. We reviewed previous literature and evaluated the feasibility of a treatment strategy using endovascular interventions, followed by surgical obliteration. STUDY DESIGN: A case report and literature review of SAMS. METHODS: We report a case of a 15-year-old boy suffering from SAMS in which epidural venous ectasia because of extradural AVMs caused spinal cord compression. RESULTS: The patient was successfully treated with multiple sessions of transarterial embolization followed by open surgery. After the treatment, his neurologic deficits resolved. Postoperative angiography confirmed complete obliteration of extradural AVMs. CONCLUSIONS: Although exclusively epidural spinal AVM is an uncommon type of SAMS, combined endovascular and surgical interventions can be an effective treatment for AVMs to achieve better radiologic outcomes and complete resolution of patient symptoms. PMID- 25450657 TI - Spontaneous atlantoaxial rotatory dislocation in a patient with ankylosing spondylitis. PMID- 25450655 TI - The effect of kyphotic deformity because of vertebral fracture: a finite element analysis of a 10 degrees and 20 degrees wedge-shaped vertebral fracture model. AB - BACKGROUND CONTEXT: Kyphotic deformity associated with vertebral fracture is believed to be a significant risk factor for additional vertebral fractures. However, previously published research is limited. PURPOSE: The purpose of this study was to estimate the biomechanical stresses that kyphotic deformity, with an initial vertebral fracture, place on adjacent vertebrae using three-dimensional finite element (FE) of the spine, head, and ribs. STUDY DESIGN: This study is based on the basic science. METHODS: Total Human Model for Safety, a three dimensional FE model of the human body, was used and adjusted to represent an elderly osteoporotic woman. The 12th thoracic vertebra (T12), which is a frequent site of osteoporotic vertebral fractures, was transformed to a wedge shape at 0 degrees , 10 degrees , and 20 degrees to create a normal model, a 10 degrees kyphosis model, and a 20 degrees kyphosis model. Additionally, compensated postures were created for the 10 degrees and 20 degrees kyphosis models. Thus, five models were created: (A) a normal model, (B) a 10 degrees kyphosis model, (C) a 20 degrees kyphosis model, (D) a 10 degrees kyphosis model with compensated posture, and (E) a 20 degrees kyphosis model with compensated posture. Compressive principal stresses (CPSs) on T1-L5 in each model were calculated. RESULTS: The highest CPS value was 7.78 MPa placed on the anterior part of the T10 vertebra in the 20 degrees kyphosis model. In the 20 degrees kyphosis model, the higher CPS values showed bimodal peaks at T6 and T7 in the midthoracic spine and at T10 and T11 in the two superior adjacent vertebrae. The maximum CPS values in the A, B, C, D, and E models at T10 were 3.12, 6.74, 7.78, 6.61, and 5.78 MPa. At T11, they were 1.70, 4.41, 6.45, 4.07, and 4.79 MPa. CONCLUSIONS: The existence of an initial vertebral fracture at T12 caused an increase in stress on adjacent vertebrae. Higher CPS values showed bimodal peaks in midthoracic vertebrae and in two superior adjacent vertebrae when T12 was transformed to a wedge shape in the 20 degrees kyphosis model. PMID- 25450656 TI - Is kyphoplasty better than vertebroplasty at restoring form and function after severe vertebral wedge fractures? AB - BACKGROUND CONTEXT: The vertebral augmentation procedures, vertebroplasty and kyphoplasty, can relieve pain and facilitate mobilization of patients with osteoporotic vertebral fractures. Kyphoplasty also aims to restore vertebral body height before cement injection and so may be advantageous for more severe fractures. PURPOSE: The purpose of this study was to compare the ability of vertebroplasty and kyphoplasty to restore vertebral height, shape, and mechanical function after severe vertebral wedge fractures. STUDY DESIGN/SETTING: This is a biomechanical and radiographic study using human cadaveric spines. METHODS: Seventeen pairs of thoracolumbar "motion segments" from cadavers aged 70-98 years were injured, in a two-stage process involving flexion and compression, to create severe anterior wedge fractures. One of each pair underwent vertebroplasty and the other kyphoplasty. Specimens were then compressed at 1 kN for 1 hour to allow consolidation. Radiographs were taken before and after injury, after treatment, and after consolidation. At these same time points, motion segment compressive stiffness was assessed, and intervertebral disc "stress profiles" were obtained to characterize the distribution of compressive stress on the vertebral body and neural arch. RESULTS: On average, injury reduced anterior vertebral body height by 34%, increased its anterior wedge angle from 5.0 degrees to 11.4 degrees , reduced intradiscal (nucleus) pressure and motion segment stiffness by 96% and 44%, respectively, and increased neural arch load bearing by 57%. Kyphoplasty caused 97% of the anterior height loss to be regained immediately, although this reduced to 79% after consolidation. Equivalent gains after vertebroplasty were significantly lower: 59% and 47%, respectively (p<.001). Kyphoplasty reduced vertebral wedging more than vertebroplasty (p<.02). Intradiscal pressure, neural arch load bearing, and motion segment compressive stiffness were restored significantly toward prefracture values after both augmentation procedures, even after consolidation, but these mechanical effects were similar for kyphoplasty and vertebroplasty. CONCLUSIONS: After severe vertebral wedge fractures, vertebroplasty and kyphoplasty were equally effective in restoring mechanical function. However, kyphoplasty was better able to restore vertebral height and reverse wedge deformity. PMID- 25450658 TI - Incidence, impact, and risk factors of adverse events in thoracic and lumbar spine fractures: an ambispective cohort analysis of 390 patients. AB - BACKGROUND CONTEXT: Adverse events (AEs) in thoracic and lumbar spine fractures are common, but little is known about the type of AEs that are specific to this population. Furthermore, very little is known about the incidence and clinical impact of these AEs on patients in the presence of traumatic spinal cord injury and whether they are treated operatively or nonoperatively. PURPOSE: The purpose of this study was to determine primarily the incidence of AEs in patients with thoracic or lumbar spine fractures treated both operatively and nonoperatively and their impact on length of stay (LOS) and secondarily the difference in the incidence of AEs in both neurologically intact and compromised patients. STUDY DESIGN/SETTING: This is an ambispective cohort study at a quaternary referral center. PATIENT SAMPLE: Patients admitted at our institution with thoracic or lumbar fractures from January 2009 to December 2013 were identified. Patients with full Spine Adverse Events Severity System (SAVES) data were included. OUTCOME MEASURES: Number and type of AEs collected from SAVES were assessed. Impact of AE on acute LOS was also determined. METHODS: Data on intraoperative, preoperative, and postoperative AEs were prospectively collected using the SAVES data collection. Logistic regression was used to model the likelihood of experiencing at least one AE based on the patient characteristics. The impact of the total number of AEs experienced by a patient and that of each of the most common AEs on LOS was determined using Poisson regression. RESULTS: Three hundred and ninety patients were included in the final analysis. Two hundred and seventy six patients (70.8%) were treated operatively. One hundred and forty patients (36%) experienced neurologic deficit as a result of their initial injury. Adverse events occurred 56% of the time in the operatively treated patients and only 13% of the time in the nonoperative group. The presence of neurologic deficit increased the risk of AEs especially in high thoracic (T1-T6) trauma increasing the odds of having an AE by 12.1 (p<.0001). The most common AEs were urinary tract infections (19.7%), neuropathic pain (12.3%), pneumonias (11.8%), delirium (10.5%), and ileus (6.2%). Length of hospital stay increased significantly with pneumonia (p<.0001) and delirium (p=.0001). CONCLUSIONS: The presence of neurologic injury and the need for operative fixation of thoracic or lumbar injuries lead to a greater risk of AEs. Only pneumonia and delirium consistently increase LOS. PMID- 25450660 TI - Somatic mitochondrial DNA mutations do not increase neuronal vulnerability to MPTP in young POLG mutator mice. AB - Mitochondrial DNA (mtDNA) mutations are hypothesized to play a pathogenic role in aging and age-related neurodegenerative diseases such as Parkinson's disease (PD). In support of this, high levels of somatic mtDNA mutations in "POLG mutator" mice carrying a proofreading-deficient form of mtDNA polymerase a (Polg(D257A)) lead to a premature aging phenotype. However, the relevance of this finding to the normal aging process has been questioned as the number of mutations is greater even in young POLG mutator mice, which shows no overt phenotype, than levels achieved during normal aging in mice. Vulnerability of dopaminergic neurons to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) increases with age, and we hypothesized that this may result in part from the accumulation with age of somatic mtDNA mutations. If correct, then levels of mutations in young (2-3 month old) POLG mutator mice should be sufficient to increase vulnerability to MPTP. In contrast, we find that susceptibility to MPTP in both heterozygous and homozygous POLG mutator mice at this young age is not different from that of wild type littermate controls as measured by levels of tyrosine hydroxylase positive (TH+) striatal terminals, striatal dopamine and its metabolites, a marker of oxidative damage, or stereological counts of TH+ and total substantia nigra neurons. These unexpected results do not support the hypothesis that somatic mtDNA mutations contribute to the age-related vulnerability of dopaminergic neurons to MPTP. It remains possible that somatic mtDNA mutations influence vulnerability to other stressors, or require additional time for the deleterious consequences to manifest. Furthermore, the impact of the higher levels of mutations present at older ages in these mice was not assessed in our study, although a prior study also failed to detect an increase in vulnerability to MPTP in older mice. With these caveats, the current data do not provide evidence for a role of somatic mtDNA mutations in determining the vulnerability to MPTP. PMID- 25450659 TI - Comparison of a novel oxysterol molecule and rhBMP2 fusion rates in a rabbit posterolateral lumbar spine model. AB - BACKGROUND CONTEXT: The nonunion rate after lumbar spinal fusion is as high as 25%. Recombinant human bone morphogenetic protein 2 (rhBMP2) has been used as a biological adjunct to promote bony fusion. However, recently there have been concerns about BMP2. Oxysterol 133 (Oxy133) has been shown to promote excellent fusion rates in rodent lumbar spine models and offers a potential alternative to rhBMP2. PURPOSE: The purpose of this study was to compare the fusion rate of rhBMP2 and Oxy133 in a randomized controlled trial using a posterolateral lumbar rabbit spinal fusion model. STUDY DESIGN: This was a randomized control animal study. METHODS: Twenty-four male adult white New Zealand rabbits (3-3.5 kg) underwent bilateral posterolateral lumbar spinal fusion at L4-L5. Rabbits were divided into four groups: control (A), 30-MUg rhBMP2 (B), 20-mg Oxy133 (C), and 60-mg Oxy133 (D). At 4 weeks, fusion was evaluated by fluoroscopy, and at 8 weeks, the rabbits were sacrificed and fusion was evaluated radiographically, by manual palpation, and with microcomputed tomography. RESULTS: Fusion rates by radiographic analysis at 8 weeks were Group A, 40.0%; Group B, 91.7%; Group C, 91.7%; and Group D, 100%. Evaluation of fusion masses by manual palpation of excised spines after sacrifice showed the following fusion rates: Group A, 0%; Group B, 83.3%; Group C, 83.3%; and Group D, 90%. Microcomputed tomography scanning confirmed these findings. CONCLUSIONS: These findings in a rabbit model demonstrate that both 20- and 60-mg Oxy133 doses promote fusion that is equivalent to fusion induced by 30-MUg rhBMP2 and significantly greater than the control group. The present findings confirm that Oxy133 is a promising candidate for therapeutic development as an alternative to rhBMP2 to promote spinal fusion. PMID- 25450661 TI - Occupational pesticide exposure in early pregnancy associated with sex-specific neurobehavioral deficits in the children at school age. AB - Prenatal exposure to pesticides may affect neurodevelopment, while the impact of modern pesticides is unclear. From 1997-2001, women working in greenhouse horticultures were recruited at the beginning of their pregnancy. Based on detailed interview of the women and their employers, those categorized as occupationally exposed to pesticides were moved to unexposed work functions or went on paid leave, while women without any exposure were considered unexposed controls. Of the resulting birth cohort of 203 children, 133 (65%) were examined at age 6 to 11 years together with 44 newly recruited children of same age whose mothers were not occupationally exposed to pesticides in pregnancy. All children underwent a standardized examination including a battery of neurodevelopmental tests. Maternal occupational pesticide exposure in early pregnancy was associated with prolonged brainstem auditory evoked potential latencies in the children as a whole and with impaired neuropsychological function in girls, while no effect was apparent in boys. In girls, language and motor speed functions were significantly inversely associated with prenatal exposure, and a non-significant tendency toward decreased function was also seen for other neuropsychological outcomes. A structural equation model that combined all these test results showed an overall impaired neuropsychological function in girls prenatally exposed to pesticides. Thus, our findings suggest an adverse effect of maternal occupational pesticide exposure on their children's neurodevelopment, despite the fact that the exposures occurred solely during early pregnancy and under well regulated working conditions, where special measures to protect pregnant women were applied. PMID- 25450662 TI - Effects of adolescent treatment with nicotine, harmane, or norharmane in male Sprague-Dawley rats. AB - The initiation of tobacco use occurs most often in adolescence and may be especially detrimental as the adolescent brain is undergoing substantial development. In addition to nicotine, there are over 9000 other compounds present in tobacco products, including the beta-carbolines harmane and norharmane. The present study aimed to determine the long-term effects of adolescent exposure to nicotine (NIC), harmane (HAR), or norharmane (NOR) on locomotor activity, learning and memory, anxiety-like behavior, motor coordination, and monoamine/metabolite concentrations in the striatum and nucleus accumbens of male Sprague-Dawley rats. Beginning on postnatal day (PND) 27 and continuing through PND 55, subjects received twice daily intraperitoneal injections of 1ml/kg saline (CON), 0.5mg NIC/kg, 0.5mg HAR/kg, or 0.5mg NOR/kg. Body weight, food, and water intake were measured daily (PNDs 27-96). Locomotor activity was assessed on PND 40 or 41, PND 55, and PNDs 81 and 82. Other behaviors (anxiety-like behavior, motor coordination, and spatial learning and memory) were assessed at least 25 days after drug exposure ended (PNDs 80-91). On PND 97, subjects were decapitated and the striatum and nucleus accumbens were dissected and frozen for analysis. NIC treatment significantly decreased food intake, but did not alter locomotor activity during or after treatment. HAR and NOR treatment, however, caused significant open field hypoactivity. Motor coordination, water maze performance, and concentrations of monoamines and metabolites in the striatum and nucleus accumbens were unaltered by any drug treatment. These results indicate a long lasting effect on activity levels from adolescent HAR or NOR treatment; however, there were few long-lasting NIC effects. Given the paucity of data describing effects of HAR or NOR exposure, these data should encourage additional studies of these tobacco constituents as well as constituent combination studies. PMID- 25450664 TI - Microencapsulation of indocyanine green for potential applications in image guided drug delivery. AB - We present a novel process to encapsulate indocyanine green (ICG) in liposomal droplets at high concentration for potential applications in image-guided drug delivery. The microencapsulation process follows two consecutive steps of droplet formation by liquid-driven coaxial flow focusing (LDCFF) and solvent removal by oil phase dewetting. These biocompatible lipid vesicles may have important applications in drug delivery and fluorescence imaging. PMID- 25450666 TI - Genetic and morphometric diversity of the goldcrest (Regulus regulus) populations in the Azores. AB - We studied the genetic diversity and phylogeography of the goldcrest Regulus regulus from the archipelago of the Azores (North Atlantic Ocean) based on sequences of two mitochondrial genes (cytochrome b and the NADH dehydrogenase subunit 2) and one nuclear gene in the Z-chromosome (intron 9 of the aconitase 1) from 69 individuals, and 41 birds from the Canary Islands and continental Europe for outgroup comparison. To understand the level of concordance between the genetic data and possible morphometric variability, 197 adult living birds from the seven Azorean islands where the species breeds were analysed in terms of eight morphometric characters. Our results are in accordance with previous studies, indicating a recent expansion of goldcrests throughout the archipelago and a low divergence in relation to continental Europe. Within the Azores, there is evidence of historical and/or recent gene flow among the island's populations, revealing a lack of current genetic structure within the archipelago. Only goldcrests from Flores Island seem to be genetically distinct and showed significantly larger body mass and tarsus length than birds on the other islands. PMID- 25450663 TI - Prenatal immune challenge in rats: effects of polyinosinic-polycytidylic acid on spatial learning, prepulse inhibition, conditioned fear, and responses to MK-801 and amphetamine. AB - Prenatal maternal immune activation increases risk for schizophrenia and/or autism. Previous data suggest that maternal weight change in response to the immune activator polyinosinic-polycytidylic (Poly IC) in rats influences the severity of effect in the offspring as does the exposure period. We treated gravid Sprague-Dawley rats from E14 to 18 with 8mg/kg/day Poly IC or saline. The Poly IC group was divided into those that gained the least weight or lost (Poly IC (L)) and those that gained the most (Poly IC (H)) weight. There were no effects of Poly IC on anxiety (elevated zero-maze, open-field, object burying), or Morris water maze cued learning or working memory or Cincinnati water maze egocentric learning. The Poly IC (H) group males had decreased acoustic startle whereas Poly IC (L) females had reduced startle and increased PPI. Poly IC offspring showed exaggerated hyperactivity in response to amphetamine (primarily in the Poly IC (H) group) and attenuated hyperactivity in response to MK-801 challenge (primarily in the Poly IC (L) group). Poly IC (L) males showed reduced cued conditioned freezing; both sexes showed less time in the dark in a light dark test, and the Poly IC groups showed impaired Morris water maze hidden platform acquisition and probe performance. The data demonstrate that offspring from the most affected dams were more affected than those from less reactive dams indicating that degree of maternal immune activation predicts severity of effects on offspring behavior. PMID- 25450665 TI - Current directions and future perspectives from the third Nematostella research conference. AB - The third Nematostella vectensis Research Conference took place in December 2013 in Eilat, Israel, as a satellite to the 8th International Conference on Coelenterate Biology. The starlet sea anemone, N. vectensis, has emerged as a powerful cnidarian model, in large part due to the extensive genomic and transcriptomic resources and molecular approaches that are becoming available for Nematostella, which were the focus of several presentations. In addition, research was presented highlighting the broader utility of this species for studies of development, circadian rhythms, signal transduction, and gene environment interactions. PMID- 25450667 TI - Myricetin inhibits advanced glycation end product (AGE)-induced migration of retinal pericytes through phosphorylation of ERK1/2, FAK-1, and paxillin in vitro and in vivo. AB - Advanced glycation end products (AGE) have been implicated in the development of diabetic retinopathy. Characterization of the early stages of diabetic retinopathy is retinal pericytes loss, which is the result of pericytes migration. In this study, we investigated the pathological mechanisms of AGE on the migration of retinal pericytes and confirmed the inhibitory effect of myricetin on migration in vitro and in vivo. Migration assays of bovine retinal pericytes (BRP) were induced using AGE-BSA and phosphorylation of Src, ERK1/2, focal adhesion kinase (FAK-1) and paxillin were determined using immunoblot analysis. Sprague-Dawley rats (6 weeks old) were injected intravitreally with AGE BSA and morphological and immunohistochemical analysis of p-FAK-1 and p-paxillin were performed in the rat retina. Immunoblot analysis and siRNA transfection were used to study the molecular mechanism of myricetin on BRP migration. AGE-BSA increased BRP migration in a dose-dependent manner via receptor for AGEs (RAGE) dependent activation of the Src kinase-ERK1/2 pathway. AGE-BSA-induced migration was inhibited by an ERK1/2 specific inhibitor (PD98059), but not by p38 and Jun N terminal kinase inhibitors. AGE-BSA increased FAK-1 and paxillin phosphorylation in a dose- and time-dependent manner. These increases were attenuated by PD98059 and ERK1/2 siRNA. Phosphorylation of FAK-1 and paxillin was increased in response to AGE-BSA-induced migration of rat retinal pericytes. Myricetin strongly inhibited ERK1/2 phosphorylation and significantly suppressed pericytes migration in AGE-BSA-injected rats. Our results demonstrate that AGE-BSA participated in the pathophysiology of retinal pericytes migration likely through the RAGE-Src ERK1/2-FAK-1-paxillin signaling pathway. Furthermore, myricetin suppressed phosphorylation of ERK 1/2-FAK-1-paxillin and inhibited pericytes migration. PMID- 25450668 TI - Identification of a novel partial agonist of liver X receptor alpha (LXRalpha) via screening. AB - Liver X receptor alpha (LXRalpha) plays an important role in the cholesterol metabolism process, and LXRalpha activation can reduce atherosclerosis. In the present study, using an LXRalpha-GAL4 luciferase reporter screening, we discovered IMB-170, a structural analog of quinazolinone, which showed potent LXRalpha agonistic activity. IMB-170 significantly activated LXRalpha, with an EC50 value of 0.27MUM. Interestingly, IMB-170 not only increased the expression of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1), which are related to the reverse cholesterol transport (RCT) process, but also influenced the expression levels of other genes involved in the cholesterol metabolism pathway in many cell lines. Moreover, IMB-170 significantly reduced cellular lipid accumulation and increased cholesterol efflux from RAW264.7 and THP-1 macrophages. Interestingly, compared with TO901317, IMB-170 only slightly increased protein expression levels of lipogenesis-related genes in HepG2 cells, indicating that IMB-170 may have a lower lipogenesis side effect in vivo. These results suggest that IMB-170 showed the selective agonistic activity for LXRalpha. Moreover, compared with full LXR-agonists, IMB-170 possesses a differential ability to recruit coregulators. This suggests that IMB-170 has distinct interactions with the active sites in the LXRalpha ligand-binding domain. In summary, IMB-170 is a novel partial LXRalpha agonist without the classical lipogenesis side effects, which could be used as a potential anti atherosclerotic leading compound in the future. PMID- 25450669 TI - Combretastatin (CA)-4 and its novel analogue CA-432 impair T-cell migration through the Rho/ROCK signalling pathway. AB - The capacity of T-lymphocytes to migrate and localise in tissues is important in their protective function against infectious agents, however, the ability of these cells to infiltrate the tumour microenvironment is a major contributing factor in the development of cancer. T-cell migration requires ligand (ICAM 1)/integrin (LFA-1) interaction, activating intracellular signalling pathways which result in a distinct polarised morphology, with an actin-rich lamellipodium and microtubule (MT)-rich uropod. Combretastatin (CA)-4 is a MT-destabilising agent that possesses potent anti-tumour properties. In this study, the effect of CA-4 and its novel analogue CA-432 on human T-cell migration was assessed. Cellular pretreatment with either of CA compounds inhibited the migration and chemotaxis of the T-cell line HuT-78 and primary peripheral blood lymphocyte (PBL) T-cells. This migration-inhibitory effect of CA compounds was due to the disruption of the MT network of T-cells through tubulin depolymerisation, reduced tubulin acetylation and decreased MT stability. In addition, both CA compounds induced the RhoA/RhoA associated kinase (ROCK) signalling pathway, leading to the phosphorylation of myosin light chain (MLC). Furthermore, the siRNA-mediated depletion of GEF-H1, a MT-associated nucleotide exchange factor that activates RhoA upon release from MTs, in T-cells prevented CA-induced phosphorylation of MLC and attenuated the formation of actin-rich membrane protrusions and cell contractility. These results suggest an important role for a GEF-H1/RhoA/ROCK/MLC signalling axis in mediating CA-induced contractility of T-cells. Therapeutic agents that target cytoskeletal proteins and are effective in inhibiting cell migration may open new avenues in the treatment of cancer and metastasis. PMID- 25450670 TI - Human ATP-Binding Cassette transporters ABCB1 and ABCG2 confer resistance to CUDC 101, a multi-acting inhibitor of histone deacetylase, epidermal growth factor receptor and human epidermal growth factor receptor 2. AB - CUDC-101 is the first small-molecule inhibitor designed to simultaneously inhibit epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2) and histone deacetylase (HDAC) in cancer cells. Recently, in its first in human phase I study, CUDC-101 showed promising single agent activity against advanced solid tumors and favorable pharmacodynamic profile. However, the risk of developing drug resistance to CUDC-101 can still present a significant therapeutic challenge to clinicians in the future. One of the most common mechanisms of developing multidrug resistance (MDR) in cancer is associated with the overexpression of ATP-binding cassette (ABC) drug transporters ABCB1 and ABCG2. Together, they are able to reduce the efficacy and modify the pharmacological properties of anti-cancer agents, including many small molecule tyrosine kinase inhibitors (TKIs). Here, we have investigated the impact of ABCB1 and ABCG2 on the efficacy of CUDC-101 in human cancer cells. We revealed that although CUDC-101 has potent antiproliferative and proapoptotic activities against most cancer cell lines, the overexpression of ABCB1 or ABCG2 in cancer cells significantly reduced the activity of CUDC-101 against HDAC, EGFR and HER2, as well as its cytotoxicity and proapoptotic activity. Moreover, we showed that CUDC-101 modulated the function of both transporters without affecting the protein expression of either ABCB1 or ABCG2. More importantly, our study provides support for the rationale of combining CUDC-101 with modulators of ABC drug transporters to improve drug efficacy and overcome multidrug resistance associated with the overexpression of ABCB1 and ABCG2. PMID- 25450671 TI - Procyanidin B2 inhibits NLRP3 inflammasome activation in human vascular endothelial cells. AB - Procyanidins are the flavanols from polyphenols commonly found in fruits and red wine. Recent studies have shown that procyanidins possess potential anti inflammatory activities. However, underlying mechanisms remain to be understood. Inflammasomes are multi-protein complexes composed of pro-caspase and pattern recognition receptors (PRRs) such as NOD-like receptor family, pyrin domain containing 3 (NLRP3). Since aberrant activation of NLRP3 inflammasome is implicated in the pathogeneses of pro-inflammatory diseases such as diabetes, atherosclerosis and arthritis, we aimed to investigate whether procyanidin B2 (PCB2), the most widely distributed natural procyanidins, inhibits the activation of NLRP3 inflammasome in endothelial cells (ECs). We found that, in human umbilical vein ECs (HUVECs), PCB2 significantly suppressed the activation of NLRP3 inflammasome and inhibited subsequent caspase-1 activation and interleukin (IL)-1beta secretion in response to lipopolysaccharides (LPS). PCB2 negatively regulated the gene expression of NLRP3. In addition, PCB2 attenuated LPS-induced production of reactive oxygen species (ROS) and the transcriptional activity of activator protein-1 (AP-1). In conclusion, we demonstrated for the first time that procyanidin B2 inhibits NLRP3 inflammasome activation via suppression of AP 1 pathway in ECs. These results suggest a new mechanism by which natural flavoids such as procyanidins exert their vascular protective effects. PMID- 25450673 TI - Phosphatidic acid inhibits ceramide 1-phosphate-stimulated macrophage migration. AB - Ceramide 1-phosphate (C1P) was recently demonstrated to potently induce cell migration. This action could only be observed when C1P was applied exogenously to cells in culture, and was inhibited by pertussis toxin. However, the mechanisms involved in this process are poorly understood. In this work, we found that phosphatidic acid (PA), which is structurally related to C1P, displaced radiolabeled C1P from its membrane-binding site and inhibited C1P-stimulated macrophage migration. This effect was independent of the saturated fatty acid chain length or the presence of a double bond in each of the fatty acyl chains of PA. Treatment of RAW264.7 macrophages with exogenous phospholipase D (PLD), an enzyme that produces PA from membrane phospholipids, also inhibited C1P stimulated cell migration. Likewise, PA or exogenous PLD inhibited C1P-stimulated extracellularly regulated kinases (ERK) 1 and 2 phosphorylation, leading to inhibition of cell migration. However, PA did not inhibit C1P-stimulated Akt phosphorylation. It is concluded that PA is a physiological regulator of C1P stimulated macrophage migration. These actions of PA may have important implications in the control of pathophysiological functions that are regulated by C1P, including inflammation and various cellular processes associated with cell migration such as organogenesis or tumor metastasis. PMID- 25450674 TI - Cytohesin 2/ARF6 regulates preadipocyte migration through the activation of ERK1/2. AB - Preadipocyte migration is vital for the development of adipose tissue, which plays a crucial role in lipid metabolism. ADP-ribosylation factor 6 (ARF6) small GTPase, which regulates membrane trafficking, is activated by GTP-exchange factors (GEFs) such as cytohesin 2. Cytohesin 2 and ARF6 have previously been implicated in the regulation of 3T3-L1 preadipocyte migration. We investigated here the molecular mechanism underlying the cytohesin 2 and ARF6 mediated regulation of preadipocyte migration. Preadipocyte migration and the activation of ARF6 and ERK1/2 were studied by using a number of approaches, including pharmacological inhibitors, siRNA and the inhibitory peptides. The siRNA mediated down regulation of ARF6 and cytohesin 2 expression confirmed the requirement of both for migration of preadipocytes. Phosphatidylinositol 3-kinase (PI3K) and PI 4,5-bisphosphate (PIP2) have also found to be essential for the cytohesin 2/ARF6 induced preadipocyte migration. Pharmacological inhibition of the activation of ARF6, ERK1/2 or dynamin led to significant reduction in migration of 3T3-L1 preadipocytes. Furthermore, our study revealed the activation of ARF6 and ERK1/2 during migration of preadipocytes. In the migrating preadipocytes, ARF6 activation was inhibited with SecinH3 (cytohesin inhibitor) and LY294002 (PI3K inhibitor) whereas the ERK1/2 phosphorylation was inhibited with SecinH3, LY294002, PBP10 (a PIP2 sequester peptide) and PD98059 (MAPKK inhibitor). However, dynosore (dynamin inhibitor) had inhibited neither ARF6 activation nor ERK1/2 phosphorylation during preadipocyte migration. These results together suggest that cytohesin 2 activates ARF6 in a PI3K dependent manner and then the active ARF6 causes phosphorylation of ERK1/2 during preadipocyte migration. PMID- 25450672 TI - Antagonism of human formyl peptide receptor 1 (FPR1) by chromones and related isoflavones. AB - Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) expressed on a variety of cell types. Because FPRs play an important role in the regulation of inflammatory reactions implicated in disease pathogenesis, FPR antagonists may represent novel therapeutics for modulating innate immunity. Previously, 4H chromones were reported to be potent and competitive FPR1 antagonists. In the present studies, 96 additional chromone analogs, including related synthetic and natural isoflavones were evaluated for FPR1 antagonist activity. We identified a number of novel competitive FPR1 antagonists that inhibited fMLF-induced intracellular Ca2+ mobilization in FPR1-HL60 cells and effectively competed with WKYMVm-FITC for binding to FPR1 in FPR1-HL60 and FPR1-RBL cells. Compound 10 (6 hexyl-2-methyl-3-(1-methyl-1H-benzimidazol-2-yl)-4-oxo-4H-chromen-7-yl acetate) was found to be the most potent FPR1-specific antagonist, with binding affinity Ki~100 nM. These chromones inhibited Ca2+ flux and chemotaxis in human neutrophils with nanomolar-micromolar IC50 values. In addition, the most potent novel FPR1 antagonists inhibited fMLF-induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in FPR1-RBL cells. These antagonists were specific for FPR1 and did not inhibit WKYMVM/WKYMVm-induced intracellular Ca2+ mobilization in FPR2-HL60 cells, FPR3-HL60 cells, RBL cells transfected with murine Fpr1, or interleukin 8-induced Ca2+ flux in human neutrophils and RBL cells transfected with CXC chemokine receptor 1 (CXCR1). Moreover, pharmacophore modeling showed that the active chromones had a significantly higher degree of similarity with the pharmacophore template as compared to inactive analogs. Thus, the chromone/isoflavone scaffold represents a relevant backbone for development of novel FPR1 antagonists. PMID- 25450676 TI - A comparison of the metabolism of midazolam in C57BL/6J and hepatic reductase null (HRN) mice. AB - The hepatic cytochrome P450 reductase null (HRN) mouse, which has no functional hepatic Cyp P450s, may represent a useful model for examining extra-hepatic P450 related oxidative metabolism. Here the pharmacokinetics and metabolic fate of midazolam, a drug known to undergo such extra-hepatic metabolism, have been investigated in the HRN mouse and compared with a phenotypically normal strain (C57BL/6J). In addition, the effects of co-administration of the pan-P450 inhibitor 1'-aminobenzotriazole (ABT) on the metabolic profile have been compared in both strains. Significant pharmacokinetic differences for midazolam were observed between the two strains of mice with the HRN mice showing lower circulating concentrations of 1'-hydroxymidazolam but higher concentrations of 1' hydroxymidazolam-O-glucuronide. A significant increase in midazolam exposure was seen upon ABT exposure for both strains of mice, but no differences in the area under the concentration time curves (AUC) for the monitored metabolites were observed. Although oxidative metabolism of midazolam was not abolished, significant decreases in 1'-hydroxymidazolam formation ratios were observed for both strains of mice exposed to ABT. Metabolite profiling of blood and bile showed a number of qualitative and quantitative differences between HRN and normal mice. These differences in midazolam metabolism between the two strains of mice clearly demonstrate the role that liver P450 enzymes play in the murine metabolism of midazolam. The fate of the compound in the HRN mice shows the importance of extrahepatic metabolism and also showed that these mice appear to be more capable of forming circulating phase II glucuronides than the normal strain. PMID- 25450677 TI - Tetrahydropalmatine promotes myoblast differentiation through activation of p38MAPK and MyoD. AB - Myoblast differentiation is fundamental to the development and regeneration of skeletal muscle after injury or disease. MyoD family transcription factors play a key role to promote myoblast differentiation. In a screen for MyoD activators, we identified tetrahydropalmatine (THP), a natural compound isolated from Corydalis turtschaninovii. The treatment of C2C12 myoblasts with THP enhanced the level of MyoD, Myogenin and myosin heavy chain (MHC) proteins and the formation of larger multinucleated myotubes, compared to the control treatment. The THP treatment dramatically enhanced the activities of p38MAPK and Akt, the key promyogenic kinases which activate MyoD. The enhanced myoblast differentiation by THP treatment can be blocked by inhibition of p38MAPK or Akt by SB203580 or LY294002, respectively. In addition, THP treatment restored myotube formation of Cdo depleted C2C12 cells through activation of p38MAPK. Moreover, THP enhanced the efficiency of trans-differentiation of 10T1/2 fibroblasts into myoblasts mediated by MyoD. These results indicate that THP has a promyogenic effect by upregulation of p38MAPK and Akt resulting in enhanced MyoD activation. Our findings suggest that THP has a potential as a therapeutic candidate to prevent fibrosis and improve muscle regeneration and repair. PMID- 25450675 TI - Identification of CYP3A7 for glyburide metabolism in human fetal livers. AB - Glyburide is commonly prescribed for the treatment of gestational diabetes mellitus; however, fetal exposure to glyburide is not well understood and may have short- and long-term consequences for the health of the child. Glyburide can cross the placenta; fetal concentrations at term are nearly comparable to maternal levels. Whether or not glyburide is metabolized in the fetus and by what mechanisms has yet to be determined. In this study, we determined the kinetic parameters for glyburide depletion by CYP3A isoenzymes; characterized glyburide metabolism by human fetal liver tissues collected during the first or early second trimester of pregnancy; and identified the major enzyme responsible for glyburide metabolism in human fetal livers. CYP3A4 had the highest metabolic capacity towards glyburide, followed by CYP3A7 and CYP3A5 (Clint,u=37.1, 13.0, and 8.7ml/min/nmol P450, respectively). M5 was the predominant metabolite generated by CYP3A7 and human fetal liver microsomes (HFLMs) with approximately 96% relative abundance. M5 was also the dominant metabolite generated by CYP3A4, CYP3A5, and adult liver microsomes; however, M1-M4 were also present, with up to 15% relative abundance. CYP3A7 protein levels in HFLMs were highly correlated with glyburide Clint, 16alpha-OH DHEA formation, and 4'-OH midazolam formation. Likewise, glyburide Clint was highly correlated with 16alpha-OH DHEA formation. Fetal demographics as well as CYP3A5 and CYP3A7 genotype did not alter CYP3A7 protein levels or glyburide Clint. These results indicate that human fetal livers metabolize glyburide predominantly to M5 and that CYP3A7 is the major enzyme responsible for glyburide metabolism in human fetal livers. PMID- 25450678 TI - c-Cbl regulates alphaPix-mediated cell migration and invasion. AB - c-Cbl, a RING-type ubiquitin E3 ligase, down-regulates receptor tyrosine kinases, including EGF receptor, and inhibits cell proliferation. Moreover, c-Cbl mutations are frequently found in patients with myeloid neoplasm. Therefore, c Cbl is known as a tumor suppressor. alphaPix is expressed only in highly proliferative and mobile cells, including immune cells, and up-regulated in certain invasive tumors, such as glioblastoma multiforme. Here, we showed that c Cbl serves as an ubiquitin E3 ligase for proteasome-mediated degradation of alphaPix, but not betaPix. Remarkably, the rat C6 and human A172 glioma cells were unable to express c-Cbl, which leads to a dramatic accumulation of alphaPix. Depletion of alphaPix by shRNA markedly reduced the ability of the glioma cells to migrate and invade, whereas complementation of shRNA-insensitive alphaPix promoted it. These results indicate that c-Cbl negatively regulates alphaPix mediated cell migration and invasion and the lack of c-Cbl in the C6 and A172 glioma cells is responsible for their malignant behavior. PMID- 25450679 TI - Osteocytes up-regulate the terminal differentiation of pre-osteoblasts via gap junctions. AB - We examined cell-to-cell interaction between pre-osteoblasts and osteocytes using MC3T3-E1 and MLO-Y4, respectively. First, GFP expressing MC3T3-E1 (E1-GFP) cells were generated to isolate the cells from co-culture with MLO-Y4. No changes were observed in the expression of osteogenic transcription factors Runx2, Osterix, Dlx5 and Msx2, but expression of alkaline phosphatase (ALP) and bone sialoprotein (BSP) in E1-GFP co-cultured with MLO-Y4 was 300-400-fold greater than that in mono-cultured E1-GFP. In addition, mineralized nodule formation was drastically increased in co-cultured E1-GFP cells compared to mono-cultured cells. Patch clamp assay showed the presence of gap junctions between E1-GFP and MLO-Y4. Furthermore, when the gap junction inhibitor carbenoxolone (CBX) was added to the culture, increased expression of ALP and BSP in E1-GFP co-cultured with MLO-Y4 was suppressed. These results suggest that gap junction detected between pre osteoblasts and osteocytes plays an important role on the terminal differentiation of pre-osteoblasts. PMID- 25450680 TI - Co-culture of endothelial cells and patterned smooth muscle cells on titanium: construction with high density of endothelial cells and low density of smooth muscle cells. AB - Endothelialization has been considered a promising method to improve the biocompatibility of vascular implanted biomaterials. However, little is known about the anti-coagulation, anti-inflammatory, anti-atherosclerosis and anti shedding property of the attached endothelial cells (ECs) and the relationship with their bio-environment and material-environment, which are both important evaluations to the cardiovascular biomaterials designed for tissue engineering applications and in vivo implantation. In this in vitro study, a novel co-culture model was built, where vascular smooth muscle cells (SMCs) were cultured on the hyaluronic acid (HA) micro-strip patterned titanium (Ti) surface on a low density to biomimetic the EC pericyte environment. Subsequently, the EC number and its functional factor, including nitric oxide (NO), prostacyclin (PGI2), tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), and the inflammatory induced factor, endothelial leukocyte adhesion molecule-1 (E-selectin) were quantified, respectively. The anti-shedding property was also assessed by the blood flow shear stress (BFSS) acting. The results showed that the novel co culture model possessed better EC coverage, functional factor release and anti shedding functions than the control. PMID- 25450681 TI - Familial dysautonomia (FD) patients have reduced levels of the modified wobble nucleoside mcm(5)s(2)U in tRNA. AB - Familial dysautonomia (FD) is a recessive neurodegenerative genetic disease. FD is caused by a mutation in the IKBKAP gene resulting in a splicing defect and reduced levels of full length IKAP protein. IKAP homologues can be found in all eukaryotes and are part of a conserved six subunit protein complex, Elongator complex. Inactivation of any Elongator subunit gene in multicellular organisms cause a wide range of phenotypes, suggesting that Elongator has a pivotal role in several cellular processes. In yeast, there is convincing evidence that the main role of Elongator complex is in formation of modified wobble uridine nucleosides in tRNA and that their absence will influence translational efficiency. To date, no study has explored the possibility that FD patients display defects in formation of modified wobble uridine nucleosides as a consequence of reduced IKAP levels. In this study, we show that brain tissue and fibroblast cell lines from FD patients have reduced levels of the wobble uridine nucleoside 5 methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U). Our findings indicate that FD could be caused by inefficient translation due to lower levels of wobble uridine nucleosides. PMID- 25450682 TI - The growth factor-like adipokine tartrate-resistant acid phosphatase 5a interacts with the rod G3 domain of adipocyte-produced nidogen-2. AB - The adipokine tartrate resistant acid phosphatase (TRAP) 5a isoform exerts a growth factor-effect on pre-adipocytes. This study aimed to identify potential TRAP 5a interacting proteins in pre-adipocytes using pull down assays in combination with mass spectrometry. Nidogen-2, a protein shown to be expressed intracellularly and for secretion by pre-adipocytes, was shown to interact, through its globular G3 domain, with TRAP 5a in vitro. In vivo, TRAP 5a interacted with nidogen-2 in cultured 3T3-L1 mouse pre-adipocytes, as well as with transforming growth factor-beta (TGF-beta) interacting protein (TRIP-1), which is a protein that has previously been suggested to interact with TRAP in bone. In addition, TRAP 5a and nidogen-2 co-localized in adipose tissue cells in situ. These results indicate that TRAP 5a interacts with nidogen-2 and TRIP-1 in pre-adipocytic cells. PMID- 25450683 TI - Anti-interferon-alpha neutralizing antibody induced telaprevir resistance under the interferon-alpha plus telaprevir treatment in vitro. AB - Although the development of anti-interferon (IFN)-alpha neutralizing antibodies (NAbs) is likely to be a common clinical problem for patients with various diseases treated with IFN, anti-IFN-alpha NAb has been exceptionally considered to have no clinical significance in the treatment of chronic hepatitis C with pegylated IFN-alpha (Peg-IFN-alpha). However, we recently clarified that the presence of NAb was associated with a non-response to the Peg-IFN plus ribavirin (RBV) therapy. In this study, we used the HCV-replicon system with genotype 1b, and investigated the role of anti-IFN-alpha NAb in the response to telaprevir (TVR)-containing new antiviral therapy for hepatitis C virus (HCV). Anti-IFN alpha NAb-positive sera specifically inhibited the anti-HCV effects of IFN-alpha, without any effect on the activity of IFN-beta in vitro. The NAb-positive sera also inhibited the IFN-alpha-dependent induction of interferon-stimulated genes, MxA and OAS-1, in a dose-dependent manner. Although TVR monotherapy decreased the HCV-RNA in vitro, the HCV-RNA was increased again with the development of TVR resistant mutations. When IFN-alpha was administrated with TVR, the replication of HCV was continuously suppressed for more than a month. However, in the presence of anti-IFN-alpha NAb-positive sera, even when IFN-alpha was combined with TVR, the levels of HCV-RNA exhibited a time-course similar to that with TVR monotherapy, and HCV with TVR-resistant mutations emerged. In conclusion, our findings suggest that the presence of IFN-alpha NAb decreases the antiviral effects of IFN-alpha and may be related to the development of TVR-resistant mutated viruses. PMID- 25450684 TI - The cytosolic splicing variant of NELL2 inhibits PKCbeta1 in glial cells. AB - NELL2 is an abundant glycoprotein containing EGF-like domain in the neural tissues where it has multiple physiological functions by interacting with protein kinase C (PKC). There are two different splicing variant forms of NELL2 identified so far. One is secreted NELL2 (sNELL2) which is a neuron-specific variant and the other is cytosolic NELL2 (cNELL2) which is non-secreted splicing variant of NELL2. Although cNELL2 structure was well characterized, the expression pattern or the cellular function of cNELL2 is not fully determined. In this study, we found that cNELL2 specifically interacts with PKCbeta isotypes and inhibits PKCbeta1 through direct binding to the N-terminal pseudosubstrate domain of PKCbeta1. Here, we also demonstrate that cNELL2 is predominantly expressed and has inhibitory effects on the PKC downstream signaling pathways in astrocytes thereby establishing cNELL2 as an endogenous inhibitor of PKCbeta1 in glia. PMID- 25450685 TI - RETRACTED: Inhibition of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor and the author. We have been contacted by the corresponding author Yong Yang and by Houston Methodist Research Institute, who after investigation has concluded that the data of another researcher had been copied without authorization. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. PMID- 25450686 TI - Overexpression of Late Embryogenesis Abundant 14 enhances Arabidopsis salt stress tolerance. AB - Late embryogenesis abundant (LEA) proteins are implicated in various abiotic stresses in higher plants. In this study, we identified a LEA protein from Arabidopsis thaliana, AtLEA14, which was ubiquitously expressed in different tissues and remarkably induced with increased duration of salt treatment. Subcellular distribution analysis demonstrated that AtLEA14 was mainly localized in the cytoplasm. Transgenic Arabidopsis and yeast overexpressing AtLEA14 all exhibited enhanced tolerance to high salinity. The transcripts of salt stress responsive marker genes (COR15a, KIN1, RD29B and ERD10) were overactivated in AtLEA14 overexpressing lines compared with those in wild type plants under normal or salt stress conditions. In vivo and in vitro analysis showed that AtLEA14 could effectively stabilize AtPP2-B11, an important E3 ligase. These results suggested that AtLEA14 had important protective functions under salt stress conditions in Arabidopsis. PMID- 25450687 TI - Atypical nuclear localization of VIP receptors in glioma cell lines and patients. AB - An increasing number of G protein-coupled receptors, like receptors for vasoactive intestinal peptide (VIP), are found in cell nucleus. As VIP receptors are involved in the regulation of glioma cell proliferation and migration, we investigated the expression and the nuclear localization of the VIP receptors VPAC1 and VPAC2 in this cancer. First, by applying Western blot and immunofluorescence detection in three human glioblastoma (GBM) cell lines, we observed a strong nuclear staining for the VPAC1 receptor and a weak nuclear VPAC2 receptor staining. Second, immunohistochemical staining of VPAC1 and VPAC2 on tissue microarrays (TMA) showed that the two receptors were expressed in normal brain and glioma tissues. Expression in the non-nuclear compartment of the two receptors significantly increased with the grade of the tumors. Analysis of nuclear staining revealed a significant increase of VPAC1 staining with glioma grade, with up to 50% of GBM displaying strong VPAC1 nuclear staining, whereas nuclear VPAC2 staining remained marginal. The increase in VPAC receptor expression with glioma grades and the enhanced nuclear localization of the VPAC1 receptors in GBM might be of importance for glioma progression. PMID- 25450688 TI - Fatty acid binding protein 3 as a potential mediator for diabetic nephropathy in eNOS deficient mouse. AB - In human diabetic nephropathy, glomerular injury was found to comprise lipid droplets, suggesting that abnormal lipid metabolism might take place in the development of diabetic glomerular injury. However, its precise mechanism remains unclear. Fatty acid binding protein (FABP) is currently considered as a key molecule for lipid metabolism. Since diabetic eNOS knockout (KO) mouse is considered to be a good model for human diabetic nephropathy, we here investigated whether FABP could mediate glomerular injury in this model. We found that glomerular injuries were associated with inflammatory processes, such as macrophage infiltration and MCP-1 induction. Microarray assay with isolated glomeruli revealed that among 10 isoforms in FABP family, FABP3 mRNA was most highly expressed in diabetic eNOSKO mice compared to non-diabetic eNOSKO mice. FABP3 protein was found to be located in the mesangial cells. Overexpression of FABP3 resulted in a greater response to palmitate, a satulated FA, to induce MCP 1 in the rat mesangial cells. In turn, the heart, a major organ for FABP3 protein in normal condition, failed to alter its expression level under diabetic condition in either wild type or eNOSKO mice. In conclusion, FABP3 is induced in the mesangial cells and likely a mediator to induce MCP-1 in the diabetic nephropathy. PMID- 25450689 TI - Retinoids induce integrin-independent lymphocyte adhesion through RAR-alpha nuclear receptor activity. AB - Oxidative metabolites of vitamin A, in particular all-trans-retinoic acid (atRA), have emerged as key factors in immunity by specifying the localization of immune cells to the gut. Although it is appreciated that isomers of retinoic acid activate the retinoic acid receptor (RAR) and retinoid X receptor (RXR) family of nuclear receptors to elicit cellular changes, the molecular details of retinoic acid action remain poorly defined in immune processes. Here we employ a battery of agonists and antagonists to delineate the specific nuclear receptors utilized by retinoids to evoke lymphocyte cell adhesion to ADAM (adisintegrin and metalloprotease) protein family members. We report that RAR agonism is sufficient to promote immune cell adhesion in both immortal and primary immune cells. Interestingly, adhesion occurs independent of integrin function, and mutant studies demonstrate that atRA-induced adhesion to ADAM members required a distinct binding interface(s) as compared to integrin recognition. Anti inflammatory corticosteroids as well as 1,25-(OH)2D3, a vitamin D metabolite that prompts immune cell trafficking to the skin, potently inhibited the observed adhesion. Finally, our data establish that induced adhesion was specifically attributable to the RAR-alpha receptor isotype. The current study provides novel molecular resolution as to which nuclear receptors transduce retinoid exposure into immune cell adhesion. PMID- 25450690 TI - Kinesin-1 translocation: Surprising differences between bovine brain and MCF7 derived microtubules. AB - While there have been many single-molecule studies of kinesin-1, most have been done along microtubules purified from bovine or porcine brain, and relatively little is known about how variations in tubulin might alter motor function. Of particular interest is transport along microtubules polymerized from tubulin purified from MCF7 breast cancer cells, both because these cells are a heavily studied model system to help understand breast cancer, and also because the microtubules are already established to have interesting polymerization/stability differences from bovine tubulin, suggesting that perhaps transport along them is also different. Thus, we carried out paired experiments to allow direct comparison of in vitro kinesin-1 translocation along microtubules polymerized from either human breast cancer cells (MCF7) or microtubules from bovine brain. We found surprising differences: on MCF7 microtubules, kinesin-1's processivity is significantly reduced, although its velocity is only slightly altered. PMID- 25450691 TI - TRPM7 is required for ovarian cancer cell growth, migration and invasion. AB - Our previous study demonstrated that the melastatin-related transient receptor potential channel 7 (TRPM7) was highly expressed in ovarian carcinomas and its overexpression was significantly associated with poor prognosis in ovarian cancer patients. However, the function of TRPM7 in ovarian cancer is mostly unknown. In this study, we examined the roles of TRPM7 in ovarian cancer cell proliferation, migration and invasion. We found that short hairpin RNA interference-mediated silence of TRPM7 significantly inhibited cell proliferation, colony formation, migration and invasion in multiple ovarian cancer cell lines. Mechanistic investigation revealed that silence of TRPM7 decreased phosphorylation levels of Akt, Src and p38 and increased filamentous actin and focal adhesion number in ovarian cancer cells. Thus, our results suggest that TRPM7 is required for proliferation, migration and invasion of ovarian cancer cells through regulating multiple signaling transduction pathways and the formation of focal adhesions. PMID- 25450692 TI - The novel gene pFAM134B positively regulates fat deposition in the subcutaneous fat of Sus scrofa. AB - In this study, we analyzed the global gene expression profiles in the subcutaneous fat (SAT) of Jinhua pigs and Landrace pigs at 90d. Several genes were significantly highly expressed in Jinhua pigs, including genes encoding the rate limiting enzymes in the TCA cycle, fatty acid activation, fatty acid synthesis and triglyceride synthesis. We identified a novel gene tagged by the EST sequences as public No. BF702245.1, which was named porcine FAM134B (pFAM134B) and the pFAM134B mRNA levels of SAT was significantly higher in Jinhua pigs than that in Landrace pigs at 90d (P<0.01). Then the effects of pFAM134B on lipid accumulation were investigated by using RNAi and gene overexpression in the subcutaneous adipocytes. The results showed that pFAM134B played a significant positive role in regulating lipid deposition by increasing the mRNA levels of PPARgamma, lipogenic genes fatty acid synthetase (FAS) and acetyl-CoA carboxylase (ACC) (P<0.01) and reducing the mRNA levels of adipose triglyceride lipase (ATGL) and lipase, hormone-sensitive (HSL) (P<0.01). This study implied that pFAM134B might be a positive factor in lipid deposition, providing insight into the control of fat accumulation and lipid-related disorders. PMID- 25450694 TI - Inhibition of Axl improves the targeted therapy against ALK-mutated neuroblastoma. AB - Neuroblastoma (NB) patients harboring mutated ALK can be expected to potentially benefit from targeted therapy based on ALK tyrosine kinase inhibitor (TKI), such as crizotinib and ceritinib. However, the effect of the treatment varies with different individuals, although with the same genic changes. Axl receptor tyrosine kinase is expressed in a variety of human cancers, but little data are reported in NB, particularly in which carrying mutated ALK. In this study, we focus on the roles of Axl in ALK-mutated NB for investigating rational therapeutic strategy. We found that Axl is expressed in ALK-positive NB tissues and cell lines, and could be effectively activated by its ligand GAS6. Ligand dependent Axl activation obviously rescued crizotinib-mediated suppression of cell proliferation in ALK-mutated NB cells. Genetic inhibition of Axl with specific small interfering RNA markedly increased the sensitivity of cells to ALK TKIs. Furthermore, a small-molecule inhibitor of Axl significantly enhanced ALK targeted therapy, as an increased frequency of apoptosis was observed in NB cells co-expressing ALK and Axl. Taken together, our results demonstrated that activation of Axl could lead to insensitivity to ALK inhibitors, and dual inhibition of ALK and Axl might be a potential therapeutic strategy against ALK mutated NB. PMID- 25450695 TI - EGF stimulates Mg(2+) influx in mammary epithelial cells. AB - Magnesium is well established as a fundamental factor that regulates cell proliferation. However, the molecular mechanisms linking mitogenic signals, extracellular magnesium availability and intracellular effectors are still largely unknown. In the present study we sought to determine whether EGF regulates magnesium homeostasis in normal HC11 mammary epithelial cells. To this end, we measured Mg(2+) and Ca(2+) fluxes by confocal imaging in live cells loaded with specific fluorescent ion indicators (Mag-Fluo-4 and Fluo-4, respectively). EGF stimulation induces a rapid and sustained increase in intracellular Mg(2+), concomitantly with a rise in intracellular calcium. The increase in intracellular Mg(2+) derives from an influx from the extracellular compartment, and does not depend on Ca(2+). On the contrary, the increase in intracellular Ca(2+) derives from intracellular stores, and is impaired in the absence of extracellular magnesium. Inhibition of the EGF receptor tyrosine kinase by Tyrphostin AG1478 markedly inhibits EGF-induced Mg(2+) and Ca(2+) signals. These findings demonstrate that not only does Mg(2+) influx represent an important step in the physiological response of epithelial cells to EGF, but unexpectedly the EGF-induced Mg(2+) influx is essential for the Ca(2+) signal to occur. PMID- 25450693 TI - The RLIP76 N-terminus binds ARNO to regulate PI 3-kinase, Arf6 and Rac signaling, cell spreading and migration. AB - RLIP76 is a multifunctional protein involved in tumor growth and angiogenesis, and a promising therapeutic target in many cancers. RLIP76 harbors docking sites for many proteins, and we have found that it interacts with ARNO, a guanine nucleotide exchange factor for Arf6, and that RLIP76 regulates activation of Rac1 via Arf6, and regulates cell spreading and migration in an ARNO and Arf6 dependent manner. Here we show that ARNO interacts with the RLIP76 N-terminal domain, and this domain was required for RLIP76-dependent cell spreading and migration. We identified two sites in the RLIP76 N-terminus with differential effects on ARNO binding and downstream signaling: Ser29/Ser30 and Ser62. Ser29/30 mutation to Alanine inhibited ARNO interaction and was sufficient to block RLIP76 dependent cell spreading and migration, as well as RLIP76-dependent Arf6 activation. In contrast, RLIP76(S62A) interacted with ARNO and supported Arf6 activation. However, both sets of mutations blocked Rac1 activation. RLIP76 mediated Rac and Arf6 activation required PI3K activity. S29/30A mutations inhibited RLIP76-dependent PI3K activation, but S62A mutation did not. Together these results show that ARNO interaction with the RLIP76 N-terminus regulates cell spreading and motility via PI3K and Arf6, independent of RLIP76 control of Rac. PMID- 25450696 TI - Curcumin inhibits oral squamous cell carcinoma SCC-9 cells proliferation by regulating miR-9 expression. AB - Curcumin, a phytochemical derived from the rhizome of Curcuma longa, has shown anticancer effects against a variety of tumors. In the present study, we investigated the effects of curcumin on the miR-9 expression in oral squamous cell carcinoma (OSCC) and explored the potential relationships between miR-9 and Wnt/beta-catenin pathway in curcumin-mediated OSCC inhibition in vitro. As the results shown, the expression levels of miR-9 were significantly lower in clinical OSCC specimens than those in the adjacent non-tumor tissues. Furthermore, our results indicated that curcumin inhibited OSCC cells (SCC-9 cells) proliferation through up-regulating miR-9 expression, and suppressing Wnt/beta-catenin signaling by increasing the expression levels of the GSK-3beta, phosphorylated GSK-3beta and beta-catenin, and decreasing the cyclin D1 level. Additionally, the up-regulation of miR-9 by curcumin in SCC-9 cells was significantly inhibited by delivering anti-miR-9 but not control oligonucleotides. Downregulation of miR-9 by anti-miR-9 not only attenuated the growth-suppressive effects of curcumin on SCC-9 cells, but also re-activated Wnt/beta-catenin signaling that was inhibited by curcumin. Therefore, our findings would provide a new insight into the use of curcumin against OSCC in future. PMID- 25450697 TI - The BIR and BIR-like domains of Bombyx mori nucleopolyhedrovirus IAP2 protein are required for efficient viral propagation. AB - The baculovirus Bombyx mori nucleopolyhedrovirus (BmNPV) possesses two genes, iap1 and iap2, which encode inhibitor of apoptosis (IAP) proteins. We previously showed that although both genes are dispensable for viral propagation, iap2 is required for efficient viral propagation in cultured cells. BmNPV IAP2 contains three putative functional domains: a baculovirus IAP repeat (BIR), a BIR-like (BIRL) domain, and a RING finger domain. To identify the domain affecting viral growth, we generated a series of BmNPV bacmids expressing iap2 derivatives lacking one or two domains, or possessing a single amino acid substitution to abolish IAP2 ubiquitin ligase activity. We examined their properties in both cultured cells and B. mori larvae. We found that either the BIR or BIRL domain of IAP2 plays an important role in BmNPV infection, and that the RING finger domain, which is required for ubiquitin ligase activity, does not greatly contribute to BmNPV propagation. This is the first study to identify functional domains of the baculovirus IAP2 protein. PMID- 25450698 TI - Biochemical and structural characterization of an endoplasmic reticulum-localized late embryogenesis abundant (LEA) protein from the liverwort Marchantia polymorpha. AB - Late embryogenesis abundant (LEA) proteins, which accumulate to high levels in seeds during late maturation, are associated with desiccation tolerance. A member of the LEA protein family was found in cultured cells of the liverwort Marchantia polymorpha; preculture treatment of these cells with 0.5M sucrose medium led to their acquisition of desiccation tolerance. We characterized this preculture induced LEA protein, designated as MpLEA1. MpLEA1 is predominantly hydrophilic with a few hydrophobic residues that may represent its putative signal peptide. The protein also contains a putative endoplasmic reticulum (ER) retention sequence, HEEL, at the C-terminus. Microscopic observations indicated that GFP fused MpLEA1 was mainly localized in the ER. The recombinant protein MpLEA1 is intrinsically disordered in solution. On drying, MpLEA1 shifted predominantly toward alpha-helices from random coils. Such changes in conformation are a typical feature of the group 3 LEA proteins. Recombinant MpLEA1 prevented the aggregation of alpha-casein during desiccation-rehydration events, suggesting that MpLEA1 exerts anti-aggregation activity against desiccation-sensitive proteins by functioning as a "molecular shield". Moreover, the anti-aggregation activity of MpLEA1 was ten times greater than that of BSA or insect LEA proteins, which are known to prevent aggregation on drying. Here, we show that an ER localized LEA protein, MpLEA1, possesses biochemical and structural features specific to group 3 LEA proteins. PMID- 25450699 TI - Development of a sensitive screening method for selecting monoclonal antibodies to be internalized by cells. AB - Antibody-drug conjugates (ADCs), drugs developed by conjugation of an anticancer agent to a monoclonal antibody (mAb), have lately attracted attention in cancer therapy because ADCs can directly bind cancer cells and kill them. Although mAbs for ADCs must be internalized by the target cells, few methods are available for screening mAbs for their ability to be internalized by cells. We have developed a recombinant protein, termed DT3C, which consists of diphtheria toxin (DT) lacking the receptor-binding domain but containing the C1, C2, and C3 domains of Streptococcus protein G (3C). When a mAb-DT3C conjugate, which functions in vitro like an ADC, reduces the viability of cancer cells, the mAb being tested must have been internalized by the target cells. DT3C can thus be a tool to identify efficiently and easily mAbs that can be internalized by cells, thereby enhancing the development of promising ADCs. PMID- 25450701 TI - Angiotensin II induces mitochondrial oxidative stress and mtDNA damage in osteoblasts by inhibiting SIRT1-FoxO3a-MnSOD pathway. AB - Previous report showed that angiotensin II accelerates osteoporosis, and recent clinical studies suggest that several antihypertensive drugs, especially angiotensin-converting enzyme inhibitors, reduced bone fractures. However, the underling mechanism by which angiotensin II induces bone dysfunction is largely unknown. Here in this study, we show that angiotensin II induces mitochondrial oxidative stress and mitochondrial DNA (mtDNA) damage. We find that the protein and RNA levels of mitochondrial catalase and manganese superoxide dismutase (MnSOD) are decreased in osteoblasts in the presence of angiotensin II. Further, we show that angiotensin II inhibits the protein level of SIRT1, but not SIRT3, which results in the hyperacetylation of the forkhead box O3a (FoxO3a) and inhibition of the expression of catalase and MnSOD. Finally, we show that SRT3025 (Sirt1 activator) and Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP, a MnSOD mimetics) can markedly reduce mitochondrial oxidative stress and mtDNA damage. In summary, we identify a novel SIRT1-FoxO3a-MnSOD axis in angiotensin II induced mitochondrial oxidative stress and mtDNA damage in osteoblasts. PMID- 25450700 TI - Violacein inhibits matrix metalloproteinase mediated CXCR4 expression: potential anti-tumor effect in cancer invasion and metastasis. AB - Matrix metalloproteinases (MMP-2 and -9) play an important role in the tumor metastasis through cleavage of proinflammatory cytokines. Violacein a small molecule produced by Chromobacterium violaceum and has been implicated with anti cancer effects. In this study we investigated the molecular basis of violacein mediated downregulation of CXCL12/CXCR4, chemokine-receptor ligand interaction. Zymography analysis demonstrated that violacein significantly inhibited the cytokine (TNFalpha and TGFbeta) mediated MMP-2 activation in MCF-7 breast cancer cell line. MMP-2 plays a critical role in the secretion of inflammatory chemokine, CXCL12, involved in cell migration and cancer metastasis. ELISA analysis demonstrated that violacein inhibited the secretion of CXCL12 from the activated MCF-7 cells. Further, we show that MMP-2/-9 act synergistically at two distinct steps towards the membrane expression of the tumor metastasis chemokine receptor, CXCR4. Violacein efficiently downregulated the CXCR4 membrane expression through MMP-9 inhibition. Taken together, these studies demonstrate a unique anti-tumor mechanism of action of violacein through reduction of CXCL12/CXCR4 interaction. These studies could offer a novel venue for violacein in cancer therapy. PMID- 25450702 TI - An extract from medical leech improve the function of endothelial cells in vitro and attenuates atherosclerosis in ApoE null mice by reducing macrophages in the lesions. AB - AIM: Medicinal leech has been widely used as a traditional Chinese medicine in cardiovascular diseases. However, its pharmaceutical effect is not fully revealed. The goal of this study was to determine whether a leech extract has the effect of anti-atherosclerosis in ApoE -/- mice and the mechanism of this effect. METHODS AND RESULTS: In vivo experiments: ApoE -/- mice fed on high-cholesterol diet were separated into 5 groups. Control group was administrated with normal water; leech extract of low dose treatment group was given a leech extract of 0.02 g/kg/d; leech extract of medium dose treatment group was given a leech extract of 0.1 g/kg/d; leech extract of high dose treatment group was given a leech extract of 0.5 g/kg/d; simvastatin group was given simvastatin of 10 mg/kg/d. Leech extract significantly reduced atherosclerotic lesions in aortic root compared with control group. And the number of macrophage in or around the atherosclerosis plaque is significantly reduced in the leech extract groups compared with control group. In vitro experiments: human endothelial cell line, EA.hy926, was induced with TNF-alpha to perform endothelial dysfunction. Control group: EA.hy926 cells with no special treatment; TNF-alpha group: EA.hy926 cells were induced by 10 ng/ml TNF-alpha for 6 h; leech extract only group: EA.hy926 cells were treated with 200 mg/ml leech extract only; leech extract and TNF-alpha group: 200 mg/ml leech extract was applied before TNF-alpha induction. Protein and mRNA level were detected in each group, leech extract can decrease the expression of intercellular adhesion factor (ICAM-1) and monocyte chemotactic protein (MCP-1) compared with TNF-alpha group. Furthermore, it showed less adhesion and migration of THP-1 cells to EA.hy926 cells in the adhesion assay and transwell assay. The NF-kappaB translation to nucleus was blocked by leech extract in the NF-kappaB translocation assay. CONCLUSIONS: Leech extract could obviously attenuate the area of atherosclerosis lesion in ApoE -/- mice. And this effect is dose dependent. The effect is mainly a result of reduced invasion of monocyte in artery walls by blocking NF-kappaB translocation. PMID- 25450703 TI - Leptin confers protection against TNF-alpha-induced apoptosis in rat cardiomyocytes. AB - Leptin, an important adipose-derived hormone, is recognized as a crucial protein in energy homeostasis. Recent studies indicated that leptin is associated with cardiac pathophysiology, however, the role and mechanisms of leptin in cardiomyocytes apoptosis are poorly understood. Here we investigated whether leptin exerted protective effect on cardiomyocytes exposed to tumor necrosis factor-alpha (TNF-alpha) and the possible mechanisms. Neonatal rat cardiomyocytes were subjected to TNF-alpha in the presence or absence of leptin. By FITC/Annexin V flow cytometry and Western blot, we noticed that TNF-alpha increased Annexin V binding and cleaved caspase-3/PARP, which were attenuated by leptin pretreatment. Moreover, leptin protected cardiomyocytes against mitochondrial apoptosis by inhibiting cytochrome C elevation and Bcl-2 decreasing. TNF-alpha-induced P38 MAPK and NF-kappaB activation were abolished by leptin addition, and the P38 and NF-kappaB inhibitor, SB203580 and Bay117082, also mitigated the apoptotic effect of TNF-alpha, indicating that their activation might be responsible for the apoptosis in TNF-alpha-treated cardiomyocytes. Therefore, leptin conferred anti apoptotic effect in cardiomyocytes exposed to TNF-alpha possibly by inhibiting TNF-alpha-activated P38 MAPK and NF-kappaB pathways. PMID- 25450704 TI - High fat diet promotes achievement of peak bone mass in young rats. AB - The relationship between obesity and bone is complex. Epidemiological studies demonstrate positive as well as negative correlation between obesity and bone health. In the present study, we investigated the impact of high fat diet-induced obesity on peak bone mass. After 9 months of feeding young rats with high fat diet, we observed obesity phenotype in rats with increased body weight, fat mass, serum triglycerides and cholesterol. There were significant increases in serum total alkaline phosphatase, bone mineral density and bone mineral content. By micro-computed tomography (MU-CT), we observed a trend of better trabecular bones with respect to their microarchitecture and geometry. This indicated that high fat diet helps in achieving peak bone mass and microstructure at younger age. We subsequently shifted rats from high fat diet to normal diet for 6 months and evaluated bone/obesity parameters. It was observed that after shifting rats from high fat diet to normal diet, fat mass, serum triglycerides and cholesterol were significantly decreased. Interestingly, the gain in bone mineral density, bone mineral content and trabecular bone parameters by HFD was retained even after body weight and obesity were normalized. These results suggest that fat rich diet during growth could accelerate achievement of peak bone mass that is sustainable even after withdrawal of high fat diet. PMID- 25450705 TI - NAFLD incidence and remission: only a matter of weight gain and weight loss? PMID- 25450707 TI - Decreased cardiovascular and extrahepatic cancer-related mortality in treated patients with mild HFE hemochromatosis. AB - BACKGROUND & AIMS: Mortality studies in patients with hemochromatosis give conflicting results especially with respect to extrahepatic causes of death. Our objective was to assess mortality and causes of death in a cohort of patients homozygous for the C282Y mutation in the HFE gene, diagnosed since the availability of HFE testing. METHODS: We studied 1085 C282Y homozygotes, consecutively diagnosed from 1996 to 2009, and treated according to current recommendations. Mortality and causes of death were obtained from death certificates and compared to those of the general population. Standardized mortality ratios (SMRs) were used to assess specific causes of death and the Cox model was used to identify prognostic factors for death. RESULTS: Patients were followed for 8.3+/-3.9 years. Overall the SMR was the same as in the general population (0.94 CI: 0.71-1.22). Patients with serum ferritin?2000 MUg/L had increased liver-related deaths (SMR: 23.9 CI: 13.9-38.2), especially due to hepatic cancer (SMR: 49.1 CI: 24.5-87.9). Patients with serum ferritin between normal and 1000 MUg/L had a lower mortality than the general population (SMR: 0.27 CI: 0.1-0.5), due to a decreased mortality, related to reduced cardiovascular events and extrahepatic cancers in the absence of increased liver related mortality. Age, diabetes, alcohol consumption, and hepatic fibrosis were independent prognostic factors of death. CONCLUSIONS: In treated HFE hemochromatosis, only patients with serum ferritin higher than 2000 MUg/L have an increased mortality, mainly related to liver diseases. Those with mild iron burden have a decreased overall mortality in relation to reduced cardiovascular and extrahepatic cancer-related events. These results support a beneficial effect of early and sustained management of patients with iron excess, even when mild. PMID- 25450708 TI - Interaction between infection and hepatic encephalopathy. PMID- 25450706 TI - Survival benefit of liver resection for patients with hepatocellular carcinoma across different Barcelona Clinic Liver Cancer stages: a multicentre study. AB - BACKGROUND & AIMS: The role of hepatic resection for hepatocellular carcinoma (HCC) in different Barcelona Clinic Liver Cancer (BCLC) stages is controversial. We aimed at measuring the survival benefit of resection vs. non-surgical therapies in each BCLC stage. METHODS: Using the ITA.LI.CA database, we identified 2090 BCLC A, B, and C HCC patients observed between 2000 and 2012: 550 underwent resection, 1046 loco-regional therapy (LRT), and 494 best supportive care (BSC). A multivariate log-logistic model was chosen to predict median survival (MS) after resection vs. MS after LRT or BSC. The results were expressed as net survival benefit of resection: (MS resection-MS LRT)/MS BSC. RESULTS: After stratifying for BCLC stage, the median net survival benefit of resection over LRT was: BCLC 0=62% (40%, 82%), A=45% (13%, 65%), B=46% (9%, 76%), C=-16% ( 55%, 33%). Model for end-stage liver disease (MELD) score>9, Child B class, and performance status (PST)=2 were the main risk factors for liver resection. 1181 Child A patients (57%) with MELD?9 and PST<2 had always a large positive net survival benefit of resection over LRT, independently of BCLC stage: BCLC 0=64% (44%, 85%), A=59% (45%, 74%), B=71% (52%, 90%), C=56% (36%, 78%). Among the 909 (43%) patients with at least one risk factor (MELD>9 or PST=2 or Child B class), resection did not prove any survival benefit over LRT. CONCLUSIONS: Resection could result in survival benefit over LRT for HCC patients regardless of their BCLC stage, provided that liver dysfunction (Child B or MELD>9) and PST>1 are absent. PMID- 25450709 TI - Two-year treatment outcome of chronic hepatitis B infection treated with besifovir vs. entecavir: results from a multicentre study. AB - BACKGROUND & AIMS: We aimed to compare the viral suppression, safety and rate of drug resistance between besifovir (a new acyclic nucleotide analogue) and entecavir. METHODS: Treatment-naive chronic hepatitis B patients receiving besifovir 90 mg (n=31), 150 mg (n=28) and entecavir 0.5 mg (n=30) were monitored for liver biochemistry, viral serology, HBV DNA levels, development of drug resistance mutations, and adverse events throughout 96 weeks of treatment. RESULTS: The mean decline of HBV DNA levels from baseline to week 96 were 5.29, 5.15, and 5.67 logs IU/ml for patients receiving besifovir 90 mg, 150 mg and entecavir 0.5 mg, respectively (p>0.05). Undetectable HBV DNA (<20 IU/ml) were achieved in 80.7%, 78.6%, and 80%; ALT normalization in 90.3%, 78.6%, and 93.3%; and loss of HBeAg in 20%, 21.4%, and 22.2% of patients respectively (all p>0.05). One patient receiving besifovir 90 mg had a virological breakthrough due to drug non-compliance. No patient developed drug resistance mutations. Ten patients had serious adverse events, which were not related to the study medications. The most common side effect related to besifovir was carnitine depletion. Carnitine supplements were prescribed to 83.9% and 100% of patients, who had low carnitine level for any one time during follow-up, receiving besifovir 90 mg and 150 mg respectively. No patient had increased creatinine>0.5 mg/dl from baseline. CONCLUSIONS: Besifovir had the same antiviral property as compared to entecavir over 96 weeks of treatment for chronic hepatitis B patients. Besifovir was well tolerated and also had a good clinical safety profile. PMID- 25450710 TI - Microsteatosis may not interact with macrosteatosis in living donor liver transplantation. AB - BACKGROUND & AIMS: The insignificance of pure microsteatosis (MiS) was reported in living donor liver transplantation (LDLT). However, since steatosis is mostly found in a mixed form of microsteatosis (MiS) and macrosteatosis (MaS), we aimed to determine the importance of MiS mixed with MaS in LDLT. METHODS: Donor matching and recipient matching were independently performed with unfixed matching ratios. In donor matching, 51 donors with high (?30%) MiS mixed with MaS (H-MiS) were matched with 160 donors with low (?10%) MiS mixed with MaS (L-MiS), based on MaS degree, remnant liver volume, and others. In recipient matching, 50 recipients who received H-MiS grafts were matched with 176 recipients who received L-MiS grafts, based on MaS degree, graft volume, MELD score, and others. RESULTS: The median MiS degree was 10% (range 0%-10%) vs. 35% (range 30%-80%) in L-MiS livers vs. H-MiS livers after both matching. L-MiS and H-MiS donors were not significantly different regarding postoperative biochemical liver function (e.g. peak AST 232 vs. 246 IU/L, p=0.931). L-MiS and H-MiS recipients were not significantly different regarding 2-week graft regeneration (51% for both) and 5 year survival (HR 0.87, 95% CI 0.43-1.76, p=0.699). Post-transplant donor/recipient complication rates were not significantly different, either. CONCLUSIONS: There were no evidences of a significant impact of MiS mixed with MaS on post-LDLT outcomes. The results suggest less importance of MiS, and further indicate that there is no interaction between MiS and MaS. Thus, the risk of steatosis may be determined by the relative composition of MiS and MaS, rather than the total quantitative degree. PMID- 25450711 TI - Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. AB - BACKGROUND & AIMS: The roles of alternatively activated (M2) macrophages on pro tumour phenotypes have been well documented in many cancers except hepatocellular carcinoma (HCC). Considering their close relationship with chronic tissue injuries as well as enhanced tumour invasiveness and growth, we aimed to investigate the direct effects of M2 macrophages on HCC. METHODS: M2 macrophages in 95 HCC clinical specimens were quantified using immunohistochemistry and quantitative PCR. The pro-tumour functions and the underlying molecular mechanisms of M2 macrophages in HCC were investigated in vivo and in an in vitro co-culture system. RESULTS: In the clinical study, high M2-specific CD163 (hazard ratio=2.693; p=0.043) and scavenger receptor A (hazard ratio=3.563; p=0.044) levels indicated poor prognosis and correlated with increased tumour nodules and venous infiltration in HCC patients. In an orthotopic model, the liver tumour volume was increased 3.26-fold (1.27 cm3+/-0.36) after M2 macrophage injection compared with the control (0.39 cm3+/-0.05) (p=0.032). An increased rate of lung metastasis was also found in the treatment group. In vitro, co-cultivation with M2 macrophages elevated the number of HCC cells (MHCC97L) and migration events by 1.3-fold and 3.2-fold, respectively (p<0.05). Strongly induced by MHCC97L, M2 macrophage-derived CCL22 was proven to enhance tumour migration capacities and correlate with venous infiltration in HCC patients. Increased epithelial mesenchymal transition (EMT) via Snail activation in MHCC97L was found to be promoted by M2 macrophages and CCL22. CONCLUSIONS: M2 macrophages contribute to poor prognosis in HCC and promote tumour invasiveness through CCL22-induced EMT. PMID- 25450712 TI - Microencapsulated human mesenchymal stem cells decrease liver fibrosis in mice. AB - BACKGROUND & AIMS: Mesenchymal stem cell (MSC) transplantation was shown to be effective for the treatment of liver fibrosis, but the mechanisms of action are not yet fully understood. We transplanted encapsulated human MSCs in two mouse models of liver fibrosis to determine the mechanisms behind the protective effect. METHODS: Human bone marrow-derived MSCs were microencapsulated in novel alginate-polyethylene glycol microspheres. In vitro, we analyzed the effect of MSC-conditioned medium on the activation of hepatic stellate cells and the viability, proliferation, cytokine secretion, and differentiation capacity of encapsulated MSCs. The level of fibrosis induced by bile duct ligation (BDL) or carbon tetrachloride (CCl4) was assessed after intraperitoneal transplantation of encapsulated MSCs, encapsulated human fibroblasts, and empty microspheres. RESULTS: MSC-conditioned medium inhibited hepatic stellate cell activation and release of MSC secreted anti-apoptotic (IL-6, IGFBP-2) and anti-inflammatory (IL 1Ra) cytokines. Viability, proliferation, and cytokine secretion of microencapsulated MSCs were similar to those of non-encapsulated MSCs. Within the microspheres, MSCs maintained their capacity to differentiate into adipocytes, chondrocytes, and osteocytes. 23% (5/22) of the MSC clones were able to produce anti-inflammatory IL-1Ra in vitro. Microencapsulated MSCs significantly delayed the development of BDL- and CCl4-induced liver fibrosis. Fibroblasts had an intermediate effect against CCl4-induced fibrosis. Mice transplanted with encapsulated MSCs showed lower mRNA levels of collagen type I, whereas levels of matrix metalloproteinase 9 were significantly higher. Human IL-1Ra was detected in the serum of 36% (4/11) of the mice transplanted with microencapsulated MSCs. CONCLUSIONS: MSC-derived soluble molecules are responsible for an anti-fibrotic effect in experimental liver fibrosis. PMID- 25450713 TI - Immunomodulatory and antioxidant function of albumin stabilises the endothelium and improves survival in a rodent model of chronic liver failure. AB - BACKGROUND & AIMS: Liver failure is characterized by endothelial dysfunction, which results in hemodynamic disturbances leading to renal failure. Albumin infusion improves hemodynamics and prevents renal dysfunction in advance liver failure. These effects are only partly explained by the oncotic properties of albumin. This study was designed to test the hypothesis that albumin exerts its beneficial effects by stabilising endothelial function. METHODS: In vivo: systemic hemodynamics, renal function, markers of endothelial dysfunction (ADMA) and inflammation were studied in analbuminaemic and Sprague-Dawley rats, 6-weeks after sham/bile duct ligation surgery. In vitro: human umbilical vein endothelial cells were stimulated with LPS with or without albumin. We studied protein expression and gene expression of adhesion molecules, intracellular reactive oxygen species, and cell stress markers. RESULTS: Compared to controls, analbuminaemic rats had significantly greater hemodynamic deterioration after bile duct ligation, resulting in worse renal function and shorter survival. This was associated with significantly greater plasma renin activity, worse endothelial function, and disturbed inflammatory response. In vitro studies showed that albumin was actively taken up by endothelial cells. Incubation of albumin pre-treated endothelial cells with LPS was associated with significantly less activation compared with untreated cells, decreased intracellular reactive oxygen species, and markers of cell stress. CONCLUSIONS: These results show, for the first time, that absence of albumin is characterised by worse systemic hemodynamics, renal function and higher mortality in a rodent model of chronic liver failure and illustrates the important non-oncotic properties of albumin in protecting against endothelial dysfunction. PMID- 25450714 TI - Outcome and management of HCV/HIV coinfection pre- and post-liver transplantation. A 2015 update. AB - Liver transplantation is increasingly performed in selected HIV-infected patients in most developed countries, with excellent results reported in patients with liver diseases unrelated to HCV. In contrast, survival in HCV/HIV-coinfected liver recipients is poorer than in HCV-monoinfected patients, due to more aggressive recurrence of HCV and consequent graft loss and death. Results from American, French, and Spanish cohort studies showed a 5-year survival rate of only 50-55%. Therefore, it is debated whether liver transplantation should be offered to HCV/HIV-coinfected patients. Studies have shown that the variables more consistently associated with poor outcome are: (1) the use of old or HCV positive donors, (2) dual liver-kidney transplantation, (3) recipients with very low body mass index and (4) less site experience. However, the most effective factor influencing transplantation outcome is the successful treatment of HCV recurrence with anti-HCV. Survival is 80% in patients whose HCV infection resolves. Unfortunately, the rates of sustained virological response with pegylated-interferon plus ribavirin in coinfected recipients are low, particularly for genotype 1 (only 10%). Here we present a non-systematic review of the literature based on our own experience in different liver transplant scenarios. This review covers selection criteria in HIV-infected patients, pre- and post-LT management, donor selection, anti-HCV treatment, drug interactions with antiretrovirals and anti-HCV direct antiviral agents, hepatocellular carcinoma, and liver retransplantation. Recommendations are rated. Finally, we explain how the introduction of new effective and more tolerable direct antiviral agents may improve significantly the outcome of HCV/HIV-coinfected liver recipients. PMID- 25450715 TI - Dysregulated miR-124 and miR-200 expression contribute to cholangiocyte proliferation in the cholestatic liver by targeting IL-6/STAT3 signalling. AB - BACKGROUND & AIMS: Cholestatic liver disease is associated with dysregulated expression of microRNAs (miRNAs). However, it remains unknown whether miRNAs are involved in the cholestasis-induced proliferation of cholangiocytes. In this study, we tested the hypothesis that miRNAs modulate cholangiocyte proliferation through effects on the IL-6 pathway, a known regulator of cholangiocyte proliferation. METHODS: Expression of IL-6, Foxa2, and phosphorylated signal transducer activator of transcription 3 (STAT3) was investigated in patients with biliary atresia (BA) and in rats subjected to bile duct ligation (BDL). miRNA expression was determined in BA patients and BDL rats, with miRNA array and quantitative real-time PCR. Biological functions of miRNAs were studied using immunoblot, immunohistochemical and proliferation assays. Luciferase reporter assays and Western blots were performed to identify miRNA targets. RESULTS: Hepatic interleukin-6 (IL-6) expression was significantly elevated in BA patients and BDL rats, while the expression of miR-124 was dramatically decreased in comparison to controls. Moreover, mRNA levels of STAT3 and IL-6 receptor (IL-6R) were inversely correlated with those of miR-124. Ectopic expression of miR-124 inhibited IL-6-mediated cholangiocyte proliferation in vitro and cholangiocyte hyperplasia in vivo, through a mechanism involving direct targeting of the 3' untranslated region of STAT3 and IL-6R. We further demonstrated that miR-200 family members were significantly upregulated in cholestasis and inhibited FOXA2 expression in cholangiocytes, which further enhanced the expression of IL-6. CONCLUSIONS: Our findings suggest that downregulation of miR-124 and upregulation of miR-200 collaboratively promote bile duct proliferation through the IL-6/STAT3 pathway. PMID- 25450718 TI - Bioinformatics and database resources in hepatology. AB - Lately, advances in high-throughput technologies in biomedical research have led to a dramatic increase in the accessibility of molecular insights at multiple biological levels in hepatology. Much of this information is available in publications, but an increasing number of large-scale analyses are currently being stored in databases. Scopes of these databases are very divergent and may range from large, general databases collecting information on almost every known disease, to very specialized databases covering only a specific liver disease or aspect of hepatology. Over recent years, these bioinformatics data repositories have rapidly evolved into an essential aid for molecular hepatology. However, although publicly available through the internet, many of these databases are only known to a few experts. To facilitate access to these resources, the publicly available databases supporting research on liver diseases are summarized in this review. PMID- 25450717 TI - Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection. AB - BACKGROUND & AIMS: Tenofovir alafenamide, a phosphonate prodrug of tenofovir with greater plasma stability than tenofovir disoproxil fumarate, provides efficient delivery of active drug to hepatocytes at reduced systemic tenofovir exposures. METHODS: Non-cirrhotic, treatment-naive subjects with chronic hepatitis B were randomized (1:1:1:1:1) to receive tenofovir alafenamide 8, 25, 40, or 120 mg, or tenofovir disoproxil fumarate 300 mg for 28 days and assessed for safety, antiviral response, and pharmacokinetics, followed-up by off-treatment for 4 weeks. RESULTS: 51 subjects were randomized and all completed study treatment. Groups were generally well matched (67% male, 57% Asian, 53% HBeAg-negative, mean HBV DNA approximately 6.0 log10 IU/ml) with HBV genotypes reflective of the population. No subject experienced an adverse event that was serious or severe (grade 3/4). Across the tenofovir alafenamide groups, similar mean changes in serum HBV DNA were found at Week 4 (-2.81, -2.55, -2.19, and -2.76 log10 IU/ml for the 8, 25, 40, and 120 mg groups, respectively) which were also comparable to the control (-2.68 log10 IU/ml for tenofovir disoproxil fumarate 300 mg). Kinetics of viral decline were also similar among groups. Tenofovir alafenamide pharmacokinetics were linear and proportional to the dose; doses?25 mg were associated with ?92% reductions in mean tenofovir area under the curve relative to tenofovir disoproxil fumarate 300 mg. CONCLUSIONS: Tenofovir alafenamide was safe and well tolerated; declines in HBV DNA were similar to tenofovir disoproxil fumarate at all doses evaluated. Tenofovir alafenamide 25 mg has been selected for further hepatitis B clinical development. PMID- 25450716 TI - Recipient T cell TIM-3 and hepatocyte galectin-9 signalling protects mouse liver transplants against ischemia-reperfusion injury. AB - BACKGROUND & AIMS: By binding to T cell immunoglobulin mucin-3 (TIM-3) on activated Th1 cells, galectin-9 (Gal-9) negatively regulates Th1-type alloimmunity. Although T cells contribute to hepatic ischemia-reperfusion injury (IRI), it is unknown whether negative T cell-dependent TIM-3 co-stimulation may rescue IR-stressed orthotopic liver transplants from innate immunity-driven inflammation. METHODS: We used wild type (WT) and TIM-3 transgenic (Tg) mice (C57BL/6) as liver donors and recipients in a clinically-relevant model of hepatic cold storage (20 h at 4 degrees C in UW solution) and syngeneic orthotopic liver transplantation (OLT). RESULTS: Orthotopic liver transplants in WT or TIM-3Tg->TIM-3Tg groups were resistant against IR-stress, evidenced by preserved hepatocellular function (serum ALT levels) and liver architecture (Suzuki's score). In contrast, orthotopic liver transplants in WT or TIM-3Tg->WT groups were susceptible to IRI. TIM-3 induction in circulating CD4+ T cells of the recipient: (1) depressed T-bet/IFN-gamma, while amplifying GATA3 and IL-4/IL 10 expression in orthotopic liver transplants; (2) promoted T cell exhaustion (PD 1, LAG-3) phenotype; and (3) depressed neutrophil and macrophage infiltration/function in orthotopic liver transplants. In parallel studies, we documented for the first time that Gal-9, a natural TIM-3 ligand, was produced primarily by and released from IR-stressed hepatocytes, both in vivo and in vitro. Moreover, exogenous recombinant Gal-9 (rGal-9) potentiated liver resistance against IRI by depressing T cell activation and promoting apoptosis of CD4+ T cells. CONCLUSIONS: Harnessing TIM-3/Gal-9 signalling at the T cell hepatocyte interface facilitates homeostasis in IR-stressed orthotopic liver transplants. Enhancing anti-oxidant hepatocyte Gal-9 potentiates liver IR resistance. Negative regulation by recipient TIM-3+CD4+ cells provides evidence for cytoprotective functions of a discrete T cell subset, which should be spared when applying T cell-targeted immunosuppression in transplant recipients. PMID- 25450719 TI - Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine. AB - BACKGROUND & AIMS: Mice exposed to the hepatocellular carcinogen diethylnitrosamine at 2 weeks of age have a high risk of developing primary liver tumors later in life. Previous studies have demonstrated that diethylnitrosamine treated mice have increased tumor burden when fed an obesigenic "Western" diet rich in lard fat and sugar. However, the role of dietary fats vs. sugars in the promotion of liver cancer is poorly understood. The aim of this study was to determine how altering dietary fats vs. sugars affects tumor burden in the diethylnitrosamine model. METHODS: C57BL/6N mice were treated with diethylnitrosamine at 2 weeks of age and, from 6 to 32 weeks of age, fed one of five diets that differed in fat and sugar content, including normal chow, ketogenic, and Western diets. RESULTS: Mice fed sugar-rich diets had the greatest tumor burden irrespective of dietary fat content. In contrast, mice fed a high fat low-sugar diet had the least tumor burden despite obesity and glucose intolerance. When evaluated as independent variables, tumor burden was positively correlated with hepatic fat accumulation, postprandial insulin, and liver IL-6, and inversely correlated with serum adiponectin. In contrast, tumor burden did not correlate with adiposity, fasting insulin, or glucose intolerance. Furthermore, mice fed high sugar diets had lower liver expression of p21 and cleaved caspase-3 compared to mice fed low sugar diets. CONCLUSIONS: These data indicate that dietary sugar intake contributes to liver tumor burden independent of excess adiposity or insulin resistance in mice treated with diethylnitrosamine. PMID- 25450720 TI - Neuromuscular and neuropsychological assessments in survivors of acute respiratory distress syndrome: exploratory comparisons with an at-risk cohort. AB - BACKGROUND: Long-term studies of survivors of acute respiratory distress syndrome (ARDS) have reported neuromuscular, quality of life, and neuropsychological impairments. This study aims to determine if development of ARDS was associated with neuromuscular weakness and depression at 6-month following hospital discharge in a population-based cohort of patients at high risk for ARDS. METHODS: A validated lung injury prediction model prospectively identified adult patients at increased risk for ARDS admitted to Mayo Clinic between October 2008 and July 2011. Instruments for functional impairment [Overall Neuropathy Limitations Scale (ONLS)] and the presence of depressive symptoms (the Yale Single Question) were administered at baseline and at 6 months. RESULTS: Of 107 patients enrolled in the study, 98 (92 %) underwent baseline assessment. Of these, 83 (85 %) were admitted to intensive care, 41 (42 %) developed ARDS, and 67 (68 %) completed assessment at 6 months. Patients with ARDS had longer intensive care and hospital length of stay (7.9 vs. 3.1 days, p = 0.005 and 19.5 vs. 10.6 days, p = 0.004, respectively). There was no difference in reported functional impairment at 6 months from baseline in the ARDS group compared to the non-ARDS group-mean ONLS Total Score 2.95 versus 2.07 p = 0.09 and 3.0 versus 2.1 p = 027, respectively. There was also no difference in the prevalence of depression at 6 months between the ARDS and non-ARDS group (21.9 vs. 30.7 % p = 0.41). CONCLUSIONS: In this single-center population-based cohort study, survivors of ARDS in the community had similar reported functional impairment and depression prevalence compared to an at-risk cohort that did not develop ARDS. PMID- 25450721 TI - Indomethacin for control of ICP. AB - Our goal was to perform a systematic review of the literature on the use of indomethacin and its effects on intracranial pressure (ICP) in patients with neurological illness. All articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library, the International Clinical Trials Registry Platform (inception to July 2014), reference lists of relevant articles, and gray literature were searched. Two reviewers independently identified all manuscripts utilizing the following inclusion and exclusion criteria. INCLUSION CRITERIA: Humans, prospective studies (five or more patients), documented ICP response to indomethacin, and English. EXCLUSION CRITERIA: non-English, retrospective studies, no documentation of ICP response to indomethacin, and animal studies. A two-tier filter of references was conducted. First, we screened manuscripts by title and abstract. Second, those references passing the first filter were pulled, and the full manuscript was checked to see if it matched the criteria for inclusion. Two reviewers independently extracted data including population characteristics and treatment characteristics. The strength of evidence was adjudicated using both the Oxford and GRADE methodology. Our search strategy produced a total of 208 citations. Twelve original articles, 10 manuscripts, and 2 meeting proceeding, were considered for the review with all utilizing indomethacin, while documenting ICP in neurological patients. All studies were prospective. Across all studies, there were a total of 177 patients studied, with 152 receiving indomethacin and 25 serving as controls in a variety of heterogeneous studies. All but one study documented a decrease in ICP with indomethacin administration, with both bolus and continuous infusions. No significant complications were described. There currently exists Oxford level 2b, GRADE C evidence to support that indomethacin reduces ICP in the severe TBI population. Similar conclusions in other populations cannot be made at this time. Comments on its impact, on patient outcome, and side effects cannot be made given the available data. At this time, indomethacin for ICP control remains experimental and further prospective study is warranted. PMID- 25450722 TI - Six years ahead: a longitudinal analysis regarding course and predictive value of the Strengths and Difficulties Questionnaire (SDQ) in children and adolescents. AB - BACKGROUND: Scientifically sound and valid information concerning course and prediction of mental health problems in children and adolescents in the general population is scarce, although needed for public mental health issues and daily clinical practice. OBJECTIVES: The psychopathological profiles of children and adolescents were analysed using the parent version of the Strengths and Difficulties Questionnaire (SDQ-P) in a longitudinal setting, also investigating the predictive value of the SDQ-scores. METHODS: SDQ's total psychopathological difficulties, emotional symptoms and hyperactivity-inattention scores of n = 630 children and adolescents (age 6-18;11 years) were examined along four assessment measurement points (T0-T3) over 6 years, using data from the BELLA study. According to the English normative data, the participants were categorized as "normal", "borderline" or "abnormal" based on their SDQ-scores. Groups remaining within categories were descriptively determined by means of frequency analysis, a subsequent graphical evaluation displayed the transitions from T0 to T3 concerning the different categorical classifications. Finally, ordered probit regression was used to examine whether age, gender, socio-economic status (SES) and baseline impact-score (IS) correspond to the SDQ-predicted classification. RESULTS: As expected, low SES and high SDQ-IS were associated with significantly increased scores on all examined SDQ-scales. Regarding the long-term aspect of SDQ-scores it could be shown that most children and adolescents remained "normal" over a measurement period of 6 years, while only a small number of children and adolescents steadily remained "abnormal" or newly developed mental health problems, respectively. For example, on the "hyperactivity-inattention"-scale, only 1 % of the children and adolescents changed from "normal" to "abnormal" (T0 T3), whereas on the "emotional symptoms"-scale, 7 % changed from "normal" to "abnormal" (T0-T3). In general, the SDQ-category "borderline" and specifically the subscale "emotional symptoms" change in both directions. Abnormal SDQ-scores at baseline, SES, gender and IS were related to the prediction of the SDQ-sores at T3. CONCLUSION: An SDQ-screening of children and adolescents may help for early detection, prediction and treatment planning. Also, these results may contribute to a better understanding of the course of mental health problems in childhood and concurrently may allow a better psychoeducation and prevention. PMID- 25450723 TI - Efficacy of albendazole against Taenia multiceps larvae in experimentally infected goats. AB - A controlled trial was conducted to evaluate the efficacy of three therapeutics regimes of albendazole (ABZ) against Taenia multiceps larvae in experimental infected goats. Forty-nine goats experimentally infected with 3000 T. multiceps eggs were selected and randomly divided into treatment or control groups. Treatment with 10mg/kg for 3 days for group 1 (G1), 10mg/kg for group 2 (G2) and 20mg/kg/day for group 3 (G3) was applied 2 months after infection; group 4 (G4) served as a control group. A treatment with doses of 10mg/kg/day for 3 days on group 5 (G5) and group 6 (G6) was used as control, 5 months after the infection. The efficacy of ABZ was assessed as percentage of non-viable cysts which were determined by morphologic characteristics, movement and methyl blue staining technique. The efficacy of ABZ against 2 months old cysts was significantly different from the control and were 90.3% (28/31), 72.7% (8/11) and 73.9% (14/19) for G1, G2 and G3, respectively. No differences were observed in cyst viability between treated and control groups for 5-month old cysts. The results in this study indicate that ABZ is effective in goats against 2-month-old cysts of T. multiceps larva located in tissues outside the brain. PMID- 25450724 TI - Quantitative PCR detection of Theileria equi using laboratory workflows to detect asymptomatic persistently infected horses. AB - Equine piroplasmosis is the most important tick-borne disease of horses. Regulations on movement of horses into disease-free countries are in place to preserve international trade. Introduction of infectious disease, such as equine piroplasmosis, into non-endemic countries remains a substantial risk owing to the wide-spread distribution of vectors. Identification and restriction of movement of Theileria equi persistently infected horses is an integral part of control strategies, because persistently infected horses with low parasitaemia are an important reservoir. We used real-time PCR for diagnosis of T. equi DNA in clinically healthy horses in an equine piroplasmosis endemic area. The sensitivity was assessed using a synthetic plasmid DNA and a laboratory workflow was developed to maximise detection of persistently infected horses. The detection limit was 10 rDNA copies of the plasmid DNA. Assuming that each red blood cell contains a single T. equi genome the detection limit corresponded to 2.5 T. equi/MUl of total blood and parasitaemia as low as 2-3.8 * 10(-5)%. A laboratory workflow was developed and assessed on samples from Saudi Arabia. The laboratory workflow focused on samples returning no or single positive result in duplicate PCR. In total, we obtained 42% (59/141; 95% confidence interval: 33.85 50.15) T. equi positive samples, 26% (37/141) negative for T. equi samples. The remaining 45 samples were judged as suspect with no definitive diagnosis made. The Saudi Arabia's T. equi small subunit ribosomal DNA (SSU rDNA) sequencing (n=16) demonstrated A clade (n=15) as the dominant T. equi clade. Clade B was sequenced in a single case. We present an approach for diagnostic workflow to detect T. equi in clinically healthy but persistently infected horses. Results from Saudi Arabia confirm that T. equi is widespread in the Middle East region. High proportion of horses with low parasitaemia calls for caution with results based on a single blood sample. Understating of the fluctuation of the parasitaema in persistently infected horses in endemic areas is needed to establish the required sample numbers for reliable detection of T. equi. PMID- 25450725 TI - Human pharmacokinetic profiling of the dipeptidyl peptidase-IV inhibitor teneligliptin using physiologically based pharmacokinetic modeling. AB - Teneligliptin is a type 2 diabetes drug that has an inhibitory effect on dipeptidyl peptidase-4. The aim of this study was to establish a physiologically based pharmacokinetic (PBPK) model to elucidate in detail the pharmacokinetics of teneligliptin. A PBPK model of teneligliptin was developed using the population based Simcyp simulator incorporating the results of in vitro and in vivo studies. Model validation was conducted by comparison of simulated teneligliptin plasma concentrations with those from clinical trials. Using the PBPK model, predicted drug-drug interactions with concomitant medication were examined. The robustness of the PBPK model was demonstrated by the accurate simulation of clinically measured plasma concentrations of teneligliptin after oral administration in different ethnic groups, in subjects belonging to different age groups and in patients with kidney or liver impairment; none of these factors were incorporated during model development. The fraction absorbed and intestinal availability of teneligliptin predicted by the model were 0.62 and 0.99, respectively. The predicted ratios of areas under the time-concentration curves (AUCs) in patients with moderate and severe renal impairment who were concomitantly administered ketoconazole, a potent inhibitor of P450 3A4, were, respectively, 2.1- and 2.2 fold those in healthy adults who were given teneligliptin alone. A robust PBPK model reflecting the pharmacokinetic properties of teneligliptin was constructed. The final optimized PBPK model enabled us to elucidate in detail the factors affecting the pharmacokinetics of teneligliptin and to predict changes in exposure in drug-drug interactions or in specific populations. PMID- 25450726 TI - Hierarchical macro-meso-microporous ZSM-5 zeolite hollow fibers with highly efficient catalytic cracking capability. AB - Zeolite fibers have attracted growing interest for a range of new applications because of their structural particularity while maintaining the intrinsic performances of the building blocks of zeolites. The fabrication of uniform zeolite fibers with tunable hierarchical porosity and further exploration of their catalytic potential are of great importance. Here, we present a versatile and facile method for the fabrication of hierarchical ZSM-5 zeolite fibers with macro-meso-microporosity by coaxial electrospinning. Due to the synergistic integration of the suitable acidity and the hierarchical porosity, high yield of propylene and excellent anti-coking stability were demonstrated on the as prepared ZSM-5 hollow fibers in the catalytic cracking reaction of iso-butane. This work may also provide good model catalysts with uniform wall thickness and tunable porosity for studying a series of important catalytic reactions. PMID- 25450727 TI - [DRESS in intensive care unit: a challenging diagnosis and treatment]. AB - Drug reaction with eosinophilia ans systemic symptoms (DRESS) is a severe medication-induced adverse reaction, which can threaten patient's life. Clinical symptoms and organ failures present wide variability. Furthermore, the latency period is long, so that diagnosis could be a real challenge in the intensive care unit. We report the case of a woman developing a DRESS after neurosurgery complicated by a nosocomial infection. PMID- 25450728 TI - [Development of a tool for withholding and withdrawing life-sustaining treatment in the emergency room]. AB - OBJECTIVES: Active treatment withholding and withdrawing decisions in the emergency room (ER) must be taken collegially according to ethical and juridical statements. Specific tools can support this process and our main goal was to create and validate such a tool. METHOD: We created a first version of a tool to help for treatment withholding and withdrawing decisions inspired by similar documents from literature. Every item of this tool was then assessed by a group of experts (ER physicians and nurses) using the Delphi method to reach a consensus. RESULTS: Thirty-four experts from eleven ER (academic, regional centre) were included and participate to the first round and twenty-seven to the second round. From the eighty-two-item tool, sixty-five items reach a consensus during these two rounds and were kept to constitute the final version of the tool. CONCLUSION: We have been able to create a tool to help for treatment withholding and withdrawing decisions adapted to the guidelines for end of life patient's management in the ER. This tool has been validated using a Delphi method by a group of experts from different centres. This multicentre validation will help for the diffusion and use of this tool in the different ER of the Rhone Alpes region. PMID- 25450729 TI - [Efficacy and safety of tranexamic acid administration for the prevention and/or the treatment of post-partum haemorrhage: a systematic review with meta analysis]. AB - OBJECTIVE(S): Assess the efficacy and safety of tranexamic acid administration for the prevention and/or the treatment of postpartum haemorrhage. STUDY DESIGN: Systematic review with meta-analysis. MATERIAL AND METHODS: Systematic review of the literature with the aim of identifying prospective, randomised, controlled trials that assessed the effect of tranexamic acid on peripartum blood loss and transfusion requirement in three clinical contexts: (i) prevention of post-partum haemorrhage in case of elective caesarean section, (ii) prevention of post-partum haemorrhage in case of vaginal delivery, (iii) treatment of post-partum haemorrhage. RESULTS: Prophylactic administration of tranexamic acid reduced blood loss (mean difference for intraoperative blood loss: -177.9mL, IC 95%: 189.51 to -166.35, total blood loss: -183.94, IC 95%: -198.29 to -169.60), and the incidence of severe post-partum haemorrhage (OR: 0.49, IC 95%: 0.33 to 0.74). None of the published trials assessed the effect of tranexamic acid on blood products administration or transfusion requirement. Only one study assessed and reported the efficacy of tranexamic acid when administered as a treatment for postpartum haemorrhage. A significant reduction in blood loss was reported within 30 minutes after randomisation (P=0.03) and confirmed after 6 hours (median: 170mL (58-323) vs 221mL (110-543), P=0.04). None of the included studies adequately studied the incidence of side effects after tranexamic acid administration. CONCLUSION: Although tranexamic acid administration seemed to significantly reduce blood loss and the incidence of severe post-partum haemorrhage, further prospective trials are needed to confirm the efficacy and safety of tranexamic administration in the treatment of postpartum haemorrhage. Those studies should assess the pharmacokinetic profile and the safety of this drug in pregnant women. PMID- 25450730 TI - [Infusion of vasoactive drugs at low flow rate: effects of the syringe switch and syringe volume (experimental study)]. AB - OBJECTIVE: The flow rate of intravenous administration of vasoactive agents should be steady in order to prevent changes in hemodynamics. In the newborns, because the flow rate is often lower than 1mL/h, it is difficult to switch of the syringe. The aim of our study was to compare the variations of concentration of active substance delivered after a manual or an automatic switch off the syringe with three different volumes (10mL, 20mL and 50mL). MATERIALS AND METHODS: Glucose solution (10g/L) was used to simulate the administered substance. Saline was administered in "Y" simultaneously with the glucose solution through a catheter. The infused substance was collected at the tip of the catheter. The glucose concentration was measured at 15min-interval for 3hours. RESULTS: The manual switch of the syringe was associated with a significant alteration of the flow rate, lasting more than 15min. In contrast, the automatic switch of syringes was associated with no change of the flow rate, especially with small-volume syringes (10mL). CONCLUSION: In newborns, in order to prevent the change in flow rate of drugs after a switch of syringes, our results suggest the use of syringe pump with built-in automatic switch and small-volume syringes. PMID- 25450731 TI - [Preoperative psychological experience and beliefs in adult patients scheduled for surgery at the University Hospital of Parakou in Benin]. AB - OBJECTIVE: To study the preoperative psychological experience and beliefs in adult patients scheduled for surgery at the University Hospital of Parakou. PATIENTS AND METHODS: A descriptive and analytical study with prospective data collection conducted over three months (June 1st to August 30, 2012) and involved 75 patients. RESULTS: Of the 108 patients scheduled for surgery, 75 patients (69.44%) had been chosen. The average age was 44.11+/-16.24 years with a male predominance (56%). Fifty-five patients (73.3%) were anxious and 32 patients (46.7%) were afraid of dying. Forty-five patients (60%) had not received any information about the procedure they should undergo and 60 patients (80%) were not informed of the possible complications of surgery. Fifty-eight patients (77.3%) were aware of the anesthetic technique and 5.2% of patients were aware of the possible complications of anesthesia. In 56 patients (74.7%), the disease was of natural origin, in 18.6% of cases there was an enchantment and 5 patients (6.7%) the disease is due to a deity. In the context of spiritual care, 15 patients (20%) had consulted a marabout, 11 patients (14.7%) a healer and 10 patients (13.3) a fetish. CONCLUSION: The preoperative period induces a significant burden of anxiety among patients and their families. In Benin, the announcement of surgery is an opportunity for confrontation of the patient to an obsession with death which he manages to escape despite the countless sacrifices of traditional conjuring. PMID- 25450732 TI - [A post-intubation tracheal rupture in intensive care unit]. AB - INTRODUCTION: Tracheal rupture is one of the most serious post-intubation complication. However, it is widely underestimated. CLINICAL CASE: An 86-year-old patient with a history of pancreas adenocarcinoma treated with gemcitabin was admitted in intensive care unit for an acute respiratory failure with no identified etiology. The worsening of her respiratory status required invasive mechanical ventilation. One laryngoscopy, performed by a trained operator, found a Cormack 1. Intubation was realized without stylet and the cuff inflated with a syringe. Hemodynamic instability, impaired gas exchange and an extensive subcutaneous emphysema occurred immediately. A CT-scan showed a supracarinal tracheal rupture. COMMENT: The etiological analysis of this case identifies several causes of pars membranosa fragility, such as female sex, age greater than 50 years and the short stature. The emergency intubation and the cuff inflated by a syringe were the risk factors of tracheal rupture in this patient. CONCLUSION: Special care should be paid to this complication, early diagnosis has probably a prognostic value. Training operators in the use of stylets and monitoring cuff pressure are required. PMID- 25450733 TI - [Patient treated with sub-mental intubation for maxillofacial trauma]. AB - Maxillo-facial traumas are frequent and most often occur in young patients. Naso tracheal or orotracheal intubation may be contraindicated in case of combined occlusal fracture and nasal or ethmoido-nasal fracture. This study was carried out a clinical case of a patient treated at the Lille University Hospital for a maxillofacial trauma associating fracture of nose and maxilla. The purpose was to assess the reliability of submental intubation as an alternative to tracheotomy. Submental intubation is a reliable single and safe technique allowing an one stage surgical treatment in case of complex association of fractures without using tracheotomy. Its use should be implemented on a larger scale. PMID- 25450734 TI - [Fatal Panton-Valentine leukocidine-associated Staphylococcus aureus necrotizing pneumonia]. AB - Panton-Valentine leukocidin-producing Staphylococcus aureus necrotizing pneumonia is an unusual cause of community-acquired pneumonia associated with a high fatality rate. The specificities of its presentation must be known by the critical care doctor, in order to quickly make the diagnosis and start the right antibiotics and discuss adjunctive therapy with intravenous immunoglobin. Moreover, the management of close contacts (household and healthcare workers) of patient with such a pneumonia is not well-known. The present case report underlines the clinical presentation of this pneumonia, the specificities of its treatment, and specifies the management of close contacts. PMID- 25450735 TI - [Systemic thrombolysis with tenecteplase for massive pulmonary embolism after a recent cesarean]. PMID- 25450736 TI - [Injectable hemostatic sponges XStatTM: revolution or gadget?]. PMID- 25450737 TI - Infectivity and virulence of Nosema ceranae and Nosema apis in commercially available North American honey bees. AB - Nosema ceranae infection is ubiquitous in western honey bees, Apis mellifera, in the United States and the pathogen has apparently replaced Nosema apis in colonies nationwide. Displacement of N. apis suggests that N. ceranae has competitive advantages but N. ceranae was significantly less infective and less virulent than N. apis in commercially available lineages of honey bees in studies conducted in Illinois and Texas. At 5 days post eclosion, the most susceptible age of adult bees tested, the mean ID50 for N. apis was 359 spores compared to 3217 N. ceranae spores, a nearly 9-fold difference. Infectivity of N. ceranae was also lower than N. apis for 24-h and 14-day worker bees. N. ceranae was less infective than reported in studies using European strains of honey bees, while N. apis infectivity, tested in the same cohort of honey bees, corresponded to results reported globally from 1972 to 2010. Mortality of worker bees was similar for both pathogens at a dosage of 50 spores and was not different from the uninfected controls, but was significantly higher for N. apis than N. ceranae at dosages ?500 spores. Our results provide comparisons for evaluating research using different ages of bees and pathogen dosages and clarify some controversies. In addition, comparisons among studies suggest that the mixed lineages of US honey bees may be less susceptible to N. ceranae infections than are European bees or that the US isolates of the pathogen are less infective and less virulent than European isolates. PMID- 25450738 TI - Within-host competition among the honey bees pathogens Nosema ceranae and Deformed wing virus is asymmetric and to the disadvantage of the virus. AB - Two pathogens co-infecting a common host can either interact positively (facilitation), negatively (competition) or act independently. A correlative study has suggested that two pathogens of the honey bee, Nosema ceranae and Deformed wing virus (DWV), interact negatively within a host (Costa et al., 2011). To test this hypothesis, we sequentially co-infected honey bees with these pathogens in a reciprocally crossed experimental design. Prior establishment in the host ventriculus by N. ceranae inhibited DWV while prior infection by DWV did not impact N. ceranae, highlighting an asymmetry in the competitive interaction between these emerging pathogens. PMID- 25450739 TI - Enhancement of the Musca domestica hytrosavirus infection with orally delivered reducing agents. AB - House flies (Musca domestica L.) throughout the world are infected with the salivary gland hypertrophy virus MdSGHV (Hytrosaviridae). Although the primary route of infection is thought to be via ingestion, flies that are old enough to feed normally are resistant to infection per os, suggesting that the peritrophic matrix (PM) is a barrier to virus transmission. Histological examination of the peritrophic matrix of healthy flies revealed a multilaminate structure produced by midgut cells located near the proventriculus. SEM revealed the PM to form a confluent sheet surrounding the food bolus with pores/openings less than 10nm in diameter. TEM revealed the PM to be multilayered, varying in width from 350 to 900 nm, and generally thinner in male than in female flies. When flies were fed on the reducing agents dithiothetriol (DTT) or tris (2-caboxyethyl)phosphine hydrochloride (TCEP) for 48 h before per os exposure to the virus, infection rates increased 10- to 20-fold compared with flies that did not receive the reducing agent treatments. PM's from flies treated with DTT and TCEP displayed varying degrees of disruption, particularly in the outer layer, and lacked the electron-dense inner layer facing the ectoperitrophic space. Both drugs were somewhat toxic to the flies, resulting in>40% mortality at doses greater than 10mM (DTT) or 5 mM (TCEP). DTT increased male fly susceptibility (55.1% infected) more than that of females (7.8%), whereas TCEP increased susceptibility of females (42.9%) more than that of males (26.2%). The cause for the sex differences in response to oral exposure the reducing agents is unclear. Exposing flies to food treated with virus and the reducing agents at the same time, rather than pretreating flies with the drugs, had no effect on susceptibility to the virus. Presumably, the reducing agent disrupted the enveloped virus and acted as a viricidal agent. In summary, it is proposed that the reducing agents influence integrity of the PM barrier and increase the susceptibility of flies to infection by MdSGHV. PMID- 25450740 TI - Regional variation in composition and antimicrobial activity of US propolis against Paenibacillus larvae and Ascosphaera apis. AB - Propolis is a substance derived from antimicrobial plant resins that honey bees use in the construction of their nests. Propolis use in the hive is an important component of honey bee social immunity and confers a number of positive physiological benefits to bees. The benefits that bees derive from resins are mostly due to their antimicrobial properties, but it is unknown how the diversity of antimicrobial activities among resins might impact bee health. In our previous work, we found that resins from different North American Populus spp. differed in their ability to inhibit in vitro growth of the bee bacterial pathogen Paenibacillus larvae. The goal of our current work was to characterize the antimicrobial activity of propolis from 12 climatically diverse regions across the US against the bee pathogens P. larvae and Ascosphaera apis and compare the metabolite profiles among those samples using LC-MS-based metabolomic methods. Samples differed greatly in their ability to inhibit both bacterial and fungal growth in vitro, but propolis from Nevada, Texas, and California displayed high activity against both pathogens. Interestingly, propolis from Georgia, New York, Louisiana, and Minnesota were active against A. apis, but not very active against P. larvae. Metabolomic analysis of regional propolis samples revealed that each sample was compositionally distinct, and LC-FTMS profiles from each sample contained a unique number of shared and exclusive peaks. Propolis from Aspen, CO, Tuscon, AZ, and Raleigh, NC, contained relatively large numbers of exclusive peaks, which may indicate that these samples originated from relatively unique botanical sources. This is the first study to characterize how the diversity of bee preferred resinous plants in the US may affect bee health, and could guide future studies on the therapeutic potential of propolis for bees. PMID- 25450741 TI - Comprehensive summary--Predict-IV: A systems toxicology approach to improve pharmaceutical drug safety testing. AB - This special issue of Toxicology in Vitro is dedicated to disseminating the results of the EU-funded collaborative project "Profiling the toxicity of new drugs: a non animal-based approach integrating toxicodynamics and biokinetics" (Predict-IV; Grant 202222). The project's overall aim was to develop strategies to improve the assessment of drug safety in the early stage of development and late discovery phase, by an intelligent combination of non animal-based test systems, cell biology, mechanistic toxicology and in silico modeling, in a rapid and cost effective manner. This overview introduces the scope and overall achievements of Predict-IV. PMID- 25450742 TI - Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. AB - Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of solid tumours. The major dose-limiting factor is nephrotoxicity, in particular in the proximal tubule. Here, we use an integrated omics approach, including transcriptomics, proteomics and metabolomics coupled to biokinetics to identify cell stress response pathways induced by cisplatin. The human renal proximal tubular cell line RPTEC/TERT1 was treated with sub-cytotoxic concentrations of cisplatin (0.5 and 2 MUM) in a daily repeat dose treating regime for up to 14 days. Biokinetic analysis showed that cisplatin was taken up from the basolateral compartment, transported to the apical compartment, and accumulated in cells over time. This is in line with basolateral uptake of cisplatin via organic cation transporter 2 and bioactivation via gamma-glutamyl transpeptidase located on the apical side of proximal tubular cells. Cisplatin affected several pathways including, p53 signalling, Nrf2 mediated oxidative stress response, mitochondrial processes, mTOR and AMPK signalling. In addition, we identified novel pathways changed by cisplatin, including eIF2 signalling, actin nucleation via the ARP/WASP complex and regulation of cell polarization. In conclusion, using an integrated omic approach together with biokinetics we have identified both novel and established mechanisms of cisplatin toxicity. PMID- 25450743 TI - Application of RPTEC/TERT1 cells for investigation of repeat dose nephrotoxicity: A transcriptomic study. AB - The kidney is a major target organ for toxicity. Incidence of chronic kidney disease (CKD) is increasing at an alarming rate due to factors such as increasing population age and increased prevalence of heart disease and diabetes. There is a major effort ongoing to develop superior predictive models of renal injury and early renal biomarkers that can predict onset of CKD. In the EU FP7 funded project, Predict-IV, we investigated the human renal proximal tubule cells line, RPTEC/TERT1 for their applicability to long term nephrotoxic mechanistic studies. To this end, we used a tiered strategy to optimise dosing regimes for 9 nephrotoxins. Our final testing protocol utilised differentiated RPTEC/TERT1 cells cultured on filter inserts treated with compounds at both the apical and basolateral side, at concentrations not exceeding IC10, for 14 days in a 24 h repeat application. Transepithelial electrical resistance and supernatant lactate were measured over the duration of the experiments and genome wide transcriptomic profiles were assayed at day 1, 3 and 14. The effect of hypoxia was investigated for a subset of compounds. The transcriptomic data were analysed to investigate compound-specific effects, global responses and mechanistically informative signatures. In addition, several potential clinically useful renal injury biomarkers were identified. PMID- 25450744 TI - Identification of pathway-based toxicity in the BALB/c 3T3 cell model. AB - The particulate matter represents one of the most complex environmental mixtures, whose effects on human health and environment vary according to particles characteristics and source of emissions. The present study describes an integrated approach, including in vitro tests and toxicogenomics, to highlight the effects of air particulate matter on toxicological relevant endpoints. Air samples (PM2.5) were collected in summer and winter at different sites, representative of different levels of air pollution. Samples organic extracts were tested in the BALB/c 3T3 CTA at a dose range 1-12m(3). The effect of the exposure to the samples at a dose of 8m(3) on the whole-genome transcriptomic profile was also assessed. All the collected samples induced dose-related toxic effects in the exposed cells. The modulated gene pathways confirmed that toxicity was related to sampling season and sampling site. The analysis of the KEGG's pathways showed modulation of several gene networks related to oxidative stress and inflammation. Even if the samples did not induce cell transformation in the treated cells, gene pathways related to the onset of cancer were modulated as a consequence of the exposure. This integrated approach could provide valuable information for predicting toxic risks in humans exposed to air pollution. PMID- 25450745 TI - "The future of in vitro toxicology". AB - In 1959 Russell and Burch stated that "Mammalian tissue cultures have become one of the most important replacement techniques". Although they would likely be disappointed at the slow progress towards the 3Rs, I am sure they would be amazed and excited about the advances made. For example, omic technologies now provide an unbiased holistic view of cellular events and help the development of new mechanistic biomarker sets. New techniques to immortalise cells, such as telomerase overexpression, allow us to create human cell lines without introducing viral oncogenes and thereby provide a source of cells with normal phenotypes. In addition, the truly ground-breaking discovery of inducible pluripotent stem cells allows the possibility of generating target tissues from any individual. There has also been great advances in material science and bio engineering, creating exciting new microfluidic devices which are well placed for the development of in vitro multi-organ systems. All of these advances have allowed us to better understand the mechanisms of how cells deal with chemical induced cellular perturbations. Utilising this knowledge and these tools, together with biokinetics we can create strategies that will be useful for regulatory purposes. Only in such an integrated interdisciplinary way will we ensure that human in vitro systems become critical toxicological tools, eventually replacing animal models altogether. PMID- 25450746 TI - Adaptation of a dynamic in vitro model with real-time determination of butyrylcholinesterase activity in the presence of cyclosarin and an oxime. AB - The well-established dynamic in vitro model for the real-time determination of acetylcholinesterase activity was modified for use of human butyrylcholinesterase (BChE) activity. Human plasma as BChE source was layered on a syringe filter and the enzyme reactor was continuously perfused with phosphate buffer, butyrylthiocholine and Ellman's reagent at pH 7.4 and 37 C which resulted in a stable BChE activity for up to 240 min. Then, the model was applied for investigating the suitability of human BChE in combination with an oxime (HLo 7) to serve as a 'pseudo-catalytic' scavenger of the organophosphorus nerve agent cyclosarin. The application of different perfusion protocols demonstrated the ability of BChE-oxime combinations to prevent BChE from irreversible inhibition by cyclosarin even at toxicologically relevant concentrations. In the end, this model seems to be suitable for the investigation of human plasma BChE as an endogenous, 'pseudo-catalytic' scavenger of a variety of nerve agents. PMID- 25450747 TI - Consequences of Mrp2 deficiency for diclofenac toxicity in the rat intestine ex vivo. AB - The non-steroidal anti-inflammatory drug diclofenac (DCF) has a high prevalence of intestinal side effects in humans and rats. It has been reported that Mrp2 transporter deficient rats (Mrp2) are more resistant to DCF induced intestinal toxicity. This was explained in vivo by impaired Mrp2-dependent biliary transport of DCF-acylglucuronide (DAG), leading to decreased intestinal exposure to DAG and DCF. However, it is not known to what extent adaptive changes in the Mrp2 intestine itself influence its sensitivity to DCF toxicity without the influence of liver metabolites. To investigate this, DCF toxicity and disposition were studied ex vivo by precision-cut intestinal slices and Ussing chamber using intestines from wild type(WT) and Mrp2 rats. The results show that adaptive changes due to Mrp2 deficiency concerning Mrp2, Mrp3 and BCRP gene expression, GSH content and DAG formation were different between liver and intestine. Furthermore, Mrp2 intestine was intrinsically more resistant to DCF toxicity than its WT counterpart ex vivo. This can at least partly be explained by a reduced DCF uptake by the Mrp2 intestine, but isnot related to the other adaptive changes in the intestine. The extrapolation of this data to humans with MRP2 deficiency is uncertain due to species differences in activity and regulation of transporters. PMID- 25450748 TI - Development of an in vitro model for studying the penetration of chemicals through compromised skin. AB - The conventional safety approach that includes dermal absorption of pharmaceutical or consumer products uses models that are based on intact skin. However, when products are intended for application to skin with a less effective barrier, such as in new-born infants, or in cases where the skin is mildly damaged or diseased, there are instances where absorption through compromised skin is also important. A tape stripping procedure was investigated using dermatomed pig skin to assess if an in vitro model could replicate the typical changes in barrier function observed in humans with compromised skin. The relationship between Trans-Epidermal Water Loss (TEWL), Electrical Resistance (ER) and Tritiated Water Flux(TWF), markers of skin barrier function in OECD 428 studies was investigated. There was a step-wise reduction in ER from normal (control) skin following 5, 10, 15 or 20 tape strips. This was mirrored by increases in both TWF and TEWL. An in vitro experimental protocol using 5 tape strips, ER and dermatomed pig skin provided a rapid, robust and reproducible approach equivalent to the 3-4-fold increases in TEWL observed clinically in compromised skin. PMID- 25450749 TI - Global insights into the Chinese hamster and CHO cell transcriptomes. AB - Transcriptomics is increasingly being used on Chinese hamster ovary (CHO) cells to unveil physiological insights related to their performance during production processes. The rich transcriptome data can be exploited to provide impetus for systems investigation such as modeling the central carbon metabolism or glycosylation pathways, or even building genome-scale models. To harness the power of transcriptome assays, we assembled and annotated a set of RNA-Seq data from multiple CHO cell lines and Chinese hamster tissues, and constructed a DNA microarray. The identity of genes involved in major functional pathways and their transcript levels generated in this study will serve as a reference for future studies employing kinetic models. In particular, the data on glycolysis and glycosylation pathways indicate that the variability of gene expression level among different cell lines and tissues may contribute to their differences in metabolism and glycosylation patterns. Thereby, these insights can potentially lead to opportunities for cell engineering. This repertoire of transcriptome data also enables the identification of potential sequence variants in cell lines and allows tracing of cell lineages. Overall the study is an illustration of the potential benefit of RNA-Seq that is yet to be exploited. PMID- 25450750 TI - [Presence and role of trace elements in urinary calculi]. AB - AIM: To assess the possible nature and role of trace elements in the pathogenesis of urinary stones. MATERIAL AND METHOD: A series of 76 calculi from the East Algerian region has been investigated through Fourier transform infrared spectroscopy for chemical analysis and X-ray fluorescence for detecting trace elements. RESULTS: Among the detected trace elements, Zn, Sr, Pb, Cu, Rb and Se, only the first three had significant values. Overall, the calcium components, namely calcium oxalate and calcium phosphate, were the most loaded by these elements contrary to organic components such as uric acid and cystine, which had low contents. CONCLUSION: The correlation of contents of Zn and Sr with the stone components (carbapatite, weddellite and whewellite) suggests an adsorption of these trace elements in the case of calcium stones rather than a catalytic process. LEVEL OF EVIDENCE: 3. PMID- 25450752 TI - [Treatment of pseudoaneurysm following partial nephrectomy]. AB - BACKGROUND: Partial nephrectomy (PN) has become the gold standard for the treatment of small tumors confined to the kidney. As result, the number of PN procedures increased during the last years. Subsequently, we have more often to deal with the complications of this surgery. Among these, pseudoaneurysms are rare but potentially life-threatening due to a risk of bleeding. Therefore, pseudoaneurysms have to be treated according to a relevant strategy. METHODS: We performed a literature review of the cases of pseudoaneurysm after PN was reported as well as a focus on the different treatment strategies and their outcomes. RESULTS: The incidence of pseudoaneurysm is low, ranging from 0.5% to 4%. Radio-embolization represents the gold standard treatment, used in 98% of the cases reported in the literature, allowing high success rate and rare morbidity. However, in some selected cases, surveillance could be an alternative. PMID- 25450751 TI - [Ischemia is not an independent predictive factor of chronic renal failure after partial nephrectomy in a solitary kidney in patients without pre-operative renal insufficiency]. AB - OBJECTIVE: To assess the influence of vascular clamping and ischemia time on long term post-operative renal function following partial nephrectomy (PN) for cancer in a solitary kidney. PATIENTS AND METHODS: This is a retrospective study including 259 patients managed by PN between 1979 and 2010 in 13 centers. Clamping use, technique choice (pedicular or parenchymal clamping), ischemia time, and peri-operative data were collected. Pre-operative and last follow-up glomerular filtration rates were compared. A multivariate analysis using a Cox model was performed to assess the impact of ischemia on post-operative chronic renal failure risk. RESULTS: Mean tumor size was 4.0+/-2.3cm and mean pre operative glomerular filtration rate was 60.8+/-18.9mL/min. One hundred and six patients were managed with warm ischemia (40.9%) and 53 patients with cold ischemia (20.5%). Thirty patients (11.6%) have had a chronic kidney disease. In multivariate analysis, neither vascular clamping (P=0.44) nor warm ischemia time (P=0.1) were associated with a pejorative evolution of renal function. Pre operative glomerular filtration rate (P<0.0001) and blood loss volume (P=0.02) were significant independent predictive factors of long-term renal failure. CONCLUSION: Renal function following PN in a solitary kidney seems to depend on non-reversible factors such as pre-operative glomerular filtration rate. Our findings minimize the role of vascular clamping and ischemia time, which were not significantly associated with chronic renal failure risk in our study. LEVEL OF EVIDENCE: 5. PMID- 25450753 TI - [Urodynamic profile of voiding disorders persisting after treatment of posterior urethral valve]. AB - PURPOSE: Posterior urethral valves (PUV) are the most common cause of bladder outlet obstruction in infancy that impairs renal and bladder function. MATERIAL AND METHODS: We realize a retrospective study and examined 35 boys with urinary disorders post-treatment of PUV, seen at the urodynamic consultation. RESULTS: The mean age: 7.56 years, urinary problems are dominated by recurrent urinary tract infections and urinary leakage, morphological assessment is marked by the constant expansion of the urinary tract and bladder, 18 children have end-stage renal disease of which 8 are candidates for transplantation. About urodynamic, the uroflowmetry with measure of post-void urine residue: dysuria with significant residual urine in 14 children; for cystometry, 20 children with bladder hyperactivity, 9 bladders are hypotonic hypoactive with high capacity, 6 explorations are normal. CONCLUSION: Urodynamic explorations are all interest when voiding symptoms persist after endoscopic section valves and despite a good radiological result. PMID- 25450754 TI - [Evaluation of urine postvoid residuals in post-partum period: a prospective and descriptive clinical study]. AB - INTRODUCTION: Few studies have evaluated urine postvoid residuals (PVRs) and their risk factors during the post-partum (PP) period. The aim of this prospective study was to screen postvoid residuals in a cohort of patients in PP, and to identify the risk factors. MATERIALS AND METHODS: For three months, patients in PP were given an evaluation of their PVR (ultrasounds method) after a spontaneous urination. Clinical data as regards delivery were collected. RESULTS: One hundred and sixty-eight patients were included. Among them, 61% had a urine volume at the first urination over 500 mL, and 52% presented with a pathological PVR (PVR over 150 mL for a urine volume over 150 mL). The median PVR was 153.50 mL. The median volume of the first spontaneous urination was 400 mL. Among patients with a pathological PVR, the total duration of the labor and the duration of its second phase were significantly longer (P=0.003 and P<0.05, respectively), and the volume of the first urination was higher. Indwelling catheterization during the delivery decreased the volume of the first spontaneous urination (volume over 500 mL in 28% vs 72% of patients, P=0.017) but was not associated with a decreased PVR in non-pathological deliveries. Instrumental deliveries were associated with higher PVRs than caesarean or physiological deliveries (244 mL, 180 mL et 156 mL; P=0.033). A bacteriuria was not significantly associated with PVR (54% vs 49%, P>0.05). CONCLUSION: We were able to identify risk factors for PVR in the PP, such as the duration of labor, instrumental delivery and elevated volume of the first urination after delivery. PMID- 25450755 TI - [Evaluation of the electromyography activity of pelvic floor muscle during postural exercises using the Wii Fit Plus(c). Analysis and perspectives in rehabilitation]. AB - INTRODUCTION: The aim of this work was to evaluate the effect of postural awareness by using the Wii Fit Plus(c) on the quality of the baseline (automatic) activity of the pelvic floor muscles (PFM) measured by intravaginal surface electromyography (sEMG). METHODS: Four healthy continent female subjects, all able to perform a voluntary contraction, undertook 2 sets of 3 various exercises offered by the software Wii Fit Plus(c) using the Wii balance board(c) (WBB): one set without any visual control and the second set with postural control and sEMG visual feedback. Simultaneously, we recorded the sEMG activity of the PFM. RESULTS: Mean baseline activity of PFM in standing position at start was 2.87 mV, at submaximal voluntary contraction the sEMG activity raised at a mean of 14.43 mV (7.87-21.89). In the first set of exercises on the WBB without any visual feedback, the automatic activity of the PFM increased from 2.87 mV to 8.75 mV (7.96-9.59). In the second set, with visual postural and sEMG control, mean baseline sEMG activity even raised at 11.39 mV (10.17-11.58). CONCLUSION: Among women able of a voluntary contraction of PFM, visualisation of posture with the help of the WBB and of sEMG activity of the PFM during static and dynamic Wii Fit Plus(c) activities, may improve the automatic activation of the PFMs. LEVEL OF EVIDENCE: 4. PMID- 25450756 TI - Comparison of functional outcomes with purely laparoscopic sacrocolpopexy and robot-assisted sacrocolpopexy in obese women. AB - OBJECTIVE: To compare the functional outcomes and complication rates following laparoscopic sacrocolpopexy (LS) with those occurring in robot-assisted laparoscopic sacrocolpopexy (RALSCP) in obese women. PATIENTS AND METHODS: A comparative retrospective multicentre study was made, involving 39 obese women (BMI>=30 kg/m2) who underwent LS, and 17 obese women who underwent RASCLP. The operative parameters (length of operation, associated procedures, complication rate and length of hospitalization) and the objective and subjective results were evaluated at 12 months follow-up. RESULTS: The median (IQR) BMI was 30.5 kg/m2 (30-32) in the LS group vs 31.6 kg/m2 (30-34) in the RALSCP group (P=0.402). The anatomical results were comparable in both groups (LS vs RALSCP): post-operative stage of prolapse (POP-Q-ICS): stage 0-1: 34/39 (88%) vs 16/17 (94.1%), P=0.7; stage 2: 4/39 (10%) vs 0/17 (0%), P=0.7; stage 3-4: 1/39 (2%) vs 1/17 (5.9%), P=0.7. The complication rate was similar in both groups (LS vs RALSCP): bladder injury 2.5% (1/39) vs 0% (0/17), P=0.6, laparoconversion 5.1% (2/39) vs 5.9% (1/17), P=0.5. The overall reoperation rate was (LS vs RALSCP): 18% (7/39) vs 5.9% (1/17), P=0.4. CONCLUSION: Laparoscopic sacrocolpopexy and robot-assisted laparoscopic sacrocolpopexy have equal results in obese women. The complication rates and outcomes appear to be similar in both groups of obese women. LEVEL OF EVIDENCE: 3. PMID- 25450757 TI - [Study of the sensitivity of renal ultrasonography as an indirect means of assessing renal function in patients with neurogenic bladder, from a cohort of 103 patients]. AB - OBJECTIVES: The assessment of renal function is essential to follow up the patients with neurogenic bladder. The objective of this study was to determine if renal ultrasonography would both evaluate the morphology of the urinary tract and renal function. METHOD: In a retrospective study, all patients followed for neurogenic bladder were included, regardless of their neurological disease. Renal function was estimated by creatinine clearance (Cl24 h), the reference test in neurological patients, the glomerular filtration rate by the MDRD simplified (MDRDs) and CKD-EPI creatinine formula, and we identified renal abnormalities detected on ultrasonography. RESULTS: One hundred and three patients were included (57 men-36 women), mean age 51+/-13 years. Fifty-nine patients had multiple sclerosis, 23 spinal cord injury. Depending on the method used (Cl24h, MDRDs, CKD-EPI creatinine) respectively 54, 49 and 39 patients had abnormal renal function; eleven patients had abnormal findings on renal ultrasonography. The sensitivity of ultrasonography as an indirect indicator of renal function depending on the method used (Cl24h, MDRDs, CKD-EPI creatinine) was equal respectively to 14%, 8% and 10%. CONCLUSION: Renal ultrasonography, which is essential to follow up the neurogenic bladder, is not enough sensitive to detect abnormal renal function and should continue to be associated with an evaluation of renal function, which is suitable for neurological patients. LEVEL OF EVIDENCE: 4. PMID- 25450758 TI - [Postcoital rectovaginal injury in a young healthy woman following consensual sexual intercourse]. PMID- 25450760 TI - Difference of Gaussians revolved along elliptical paths for ultrasound fetal head segmentation. AB - We present a fully automatic method to segment the skull from 2-D ultrasound images of the fetal head and to compute the standard biometric measurements derived from the segmented images. The method is based on the minimization of a novel cost function. The cost function is formulated assuming that the fetal skull has an approximately elliptical shape in the image and that pixel values within the skull are on average higher than in surrounding tissues. The main idea is to construct a template image of the fetal skull parametrized by the ellipse parameters and the calvarial thickness. The cost function evaluates the match between the template image and the observed ultrasound image. The optimum solution that minimizes the cost is found by using a global multiscale, multistart Nelder-Mead algorithm. The method was qualitatively and quantitatively evaluated using 90 ultrasound images from a recent segmentation grand challenge. These images have been manually analyzed by three independent experts. The segmentation accuracy of the automatic method was similar to the inter-expert segmentation variability. The automatically derived biometric measurements were as accurate as the manual measurements. Moreover, the segmentation accuracy of the presented method was superior to the accuracy of the other automatic methods that have previously been evaluated using the same data. PMID- 25450759 TI - Segmentation of heterogeneous or small FDG PET positive tissue based on a 3D locally adaptive random walk algorithm. AB - A segmentation algorithm based on the random walk (RW) method, called 3D-LARW, has been developed to delineate small tumors or tumors with a heterogeneous distribution of FDG on PET images. Based on the original algorithm of RW [1], we propose an improved approach using new parameters depending on the Euclidean distance between two adjacent voxels instead of a fixed one and integrating probability densities of labels into the system of linear equations used in the RW. These improvements were evaluated and compared with the original RW method, a thresholding with a fixed value (40% of the maximum in the lesion), an adaptive thresholding algorithm on uniform spheres filled with FDG and FLAB method, on simulated heterogeneous spheres and on clinical data (14 patients). On these three different data, 3D-LARW has shown better segmentation results than the original RW algorithm and the three other methods. As expected, these improvements are more pronounced for the segmentation of small or tumors having heterogeneous FDG uptake. PMID- 25450761 TI - Abiotic partitioning of clothianidin under simulated rice field conditions. AB - BACKGROUND: Clothianidin is registered for pre- and post-flood application in Californian rice fields for control of the rice seed midge, Cricotopus sylvestris, and the rice water weevil, Lissorhoptrus oryzophilus. The objective was to characterize air-water and soil-water partitioning of clothianidin under simulated Californian rice field conditions. RESULTS: Clothianidin was confirmed to be non-volatile (from water) via the gas purge method, as no loss from the aqueous phase was observed at 22 and 37 degrees C; an upper-limit KH value was calculated at 2.9 * 10(-11) Pa m(3) mol(-1) (20 degrees C). Soil-water partitioning was determined by the batch equilibrium method using four soils collected from rice fields in the Sacramento Valley, and sorption affinity (Kd ), sorbent capacity, desorption and organic-carbon-normalized distribution (Koc ) were determined. Values for pH, cation exchange capacity and organic matter content ranged from 4.5 to 6.6, from 5.9 to 37.9 and from 1.25 to 1.97% respectively. The log Koc values (22 and 37 degrees C) ranged from 2.6 to 2.7, while sorption capacity was low at 22 degrees C and decreased further at 37 degrees C. Hysteresis was observed in soils at both temperatures, suggesting that bound residues do not readily desorb. CONCLUSIONS: Soil-water and air-water partitioning will not significantly reduce offsite transport of clothianidin from flooded rice fields via drainage. PMID- 25450762 TI - Tgfbi deficiency leads to a reduction in skeletal size and degradation of the bone matrix. AB - Transforming growth factor-beta-induced gene product-h3 (TGFBI/BIGH3) is an extracellular matrix protein expressed in a wide variety of tissues. TGFBI binds to type I, II, and IV collagens, as well as to biglycan and decorin and plays important roles in cell-to-cell, cell-to-collagen, and cell-to-matrix interactions. Furthermore, TGFBI is involved in cell growth and migration, tumorigenesis, wound healing, and apoptosis. To investigate whether TGFBI is involved in the maintenance of skeletal tissues, Tgfbi knockout mice were generated by crossing male and female Tgfbi heterozygous mice. Skeletal preparation showed that the skeletal size in Tgfbi knockout mice was smaller than in wild-type and heterozygous mice. However, chondrocytic cell alignment in the growth plates, bone mineral density, and bone forming rates were similar in Tgfbi knockout, wild-type, and heterozygous mice. Alterations in skeletal tissue arrangements in Tgfbi knockout mice were estimated from safranin O staining, trichrome staining, and immunohistochemistry for type II and X collagen, and matrix metalloproteinase 13 (MMP13). Cartilage matrix degradation was observed in the articular cartilage of Tgfbi knockout mice. Although the detection of type II collagen in the articular cartilage was lower in Tgfbi knockout mice than wild type mice, the detection of MMP13 was markedly higher, indicating that Tgfbi deficiency is associated with the degradation of cartilage matrix. These results suggest that TGFBI plays an important role in maintaining skeletal tissues and the cartilage matrix in mice. PMID- 25450763 TI - Small longitudinal study of serum anticholinergic activity and cognitive change in community-dwelling older adults. AB - OBJECTIVE: The discriminative ability of serum anticholinergic activity (SAA) to differentiate between older individuals with stable versus deteriorating cognition remains undetermined. We examined the relationship between SAA changes, the presence or absence of a mild neurocognitive disorder, age and anticholinergic medication over a one-year time period. METHODS: SAA at baseline and one-year follow-up was measured for 121 older adults without dementia. Participants were classified at both timepoints as being cognitively intact or meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a mild neurocognitive disorder. Medications were assessed according to the Anticholinergic Cognitive Burden (ACB) scale. RESULTS: SAA changes did not discriminate between individuals whose cognition remained stable versus those with improvement or decline (H[3]=0.725, p=0.867). SAA change did not vary between age groups, and could not reliably differentiate between individuals on ACB medication or not. CONCLUSION: While SAA does not appear to be a valid biomarker for cognitive decline, longitudinal studies with a larger sample size and longer duration are required to confirm this finding. PMID- 25450764 TI - A simplified system for generating recombinant E3-deleted canine adenovirus-2. AB - Canine adenovirus type 2 (CAV-2) has been used extensively as a vector for studying gene therapy and vaccine applications. We describe a simple strategy for generating a replication-competent recombinant CAV-2 using a backbone vector and a shuttle vector. The backbone plasmid containing the full-length CAV-2 genome was constructed by homologous recombination in Escherichia coli strain BJ5183. The shuttle plasmid, which has a deletion of 1478 bp in the nonessential E3 viral genome region, was generated by subcloning a fusion fragment containing the flanking sequences of the CAV-2 E3 region and expression cassette sequences from pcDNA3.1(+) into modified pUC18. To determine system effectiveness, a gene for enhanced green fluorescent protein (EGFP) was inserted into the shuttle plasmid and cloned into the backbone plasmid using two unique NruI and SalI sites. Transfection of Madin-Darby canine kidney (MDCK) cells with the recombinant adenovirus genome containing the EGFP expression cassette resulted in infectious viral particles. This strategy provides a solid foundation for developing candidate vaccines using CAV-2 as a delivery vector. PMID- 25450765 TI - Accumulation of single-stranded DNA in Escherichia coli carrying the colicin plasmid pColE3-CA38. AB - We sequenced the complete 7118 bp circular plasmid pColE3-CA38 (pColE3) from Escherichia coli, located the previously identified colicin components together with two new ORFs that have homology to mobilization and transfer proteins, and found that pColE3 is highly similar to a plasmid present in enterohemorrhagic E. coli O111. We also found that unusual aspects of the plasmid include the inability to be completely digested with restriction endonucleases and asymmetric Phred DNA sequencing quality scores, with significantly lower scores in the forward direction relative to the colicin and immunity proteins consistent with plus (+) strand DNA. Comparing the A260 with picogreen double-stranded DNA (dsDNA) fluorescence and oligreen single-stranded DNA (ssDNA) fluorescence as well as metachromatic staining by acridine orange, we found that the undigested pColE3 DNA stains preferentially as ssDNA and that it coexists with dsDNA. We also identified ssDNA in pColE5 and pColE9 but not in pColE1. Colicin plasmids producing ssDNA may represent a new subclass of rolling-circle replication plasmids and add to the known similarities between colicins and filamentous phage. PMID- 25450766 TI - Structural basis of receptor sulfotyrosine recognition by a CC chemokine: the N terminal region of CCR3 bound to CCL11/eotaxin-1. AB - Trafficking of leukocytes in immune surveillance and inflammatory responses is activated by chemokines engaging their receptors. Sulfation of tyrosine residues in peptides derived from the eosinophil chemokine receptor CCR3 dramatically enhances binding to cognate chemokines. We report the structural basis of this recognition and affinity enhancement. We describe the structure of a CC chemokine (CCL11/eotaxin-1) bound to a fragment of a chemokine receptor: residues 8-23 of CCR3, including two sulfotyrosine residues. We also show that intact CCR3 is sulfated and sulfation enhances receptor activity. The CCR3 sulfotyrosine residues form hydrophobic, salt bridge and cation-p interactions with residues that are highly conserved in CC chemokines. However, the orientation of the chemokine relative to the receptor N terminus differs substantially from those observed for two CXC chemokines, suggesting that initial binding of the receptor sulfotyrosine residues guides subsequent steps in receptor activation, thereby influencing the receptor conformational changes and signaling. PMID- 25450767 TI - Structural basis for selective recognition of endogenous and microbial polysaccharides by macrophage receptor SIGN-R1. AB - SIGN-R1 is a principal receptor for microbial polysaccharides uptake and is responsible for C3 fixation via an unusual complement activation pathway on splenic marginal zone macrophages. In these macrophages, SIGN-R1 is also involved in anti-inflammatory activity of intravenous immunoglobulin by direct interaction with sialylated Fcs. The high-resolution crystal structures of SIGN-R1 carbohydrate recognition domain and its complexes with dextran sulfate or sialic acid, and of the sialylated Fc antibody provide insights into SIGN-R1's selective recognition of a-2,6-sialylated glycoproteins. Unexpectedly, an additional binding site has been found in the SIGNR1 carbohydrate recognition domain, structurally separate from the calcium-dependent carbohydrate-binding site. This secondary binding site could bind repetitive molecular patterns, as observed in microbial polysaccharides, in a calcium-independent manner. These two binding sites may allow SIGNR1 to simultaneously bind both immune glycoproteins and microbial polysaccharide components, accommodating SIGN-R1's ability to relate the recognition of microbes to the activation of the classical complement pathway. PMID- 25450768 TI - Structure of the microtubule-binding domain of flagellar dynein. AB - Flagellar dyneins are essential microtubule motors in eukaryotes, as they drive the beating motions of cilia and flagella. Unlike myosin and kinesin motors, the track binding mechanism of dyneins and the regulation between the strong and weak binding states remain obscure. Here we report the solution structure of the microtubule-binding domain of flagellar dynein-c/DHC9 (dynein-c MTBD). The structure reveals a similar overall helix-rich fold to that of the MTBD of cytoplasmic dynein (cytoplasmic MTBD), but dynein-c MTBD has an additional flap, consisting of an antiparallel b sheet. The flap is positively charged and highly flexible. Despite the structural similarity to cytoplasmic MTBD, dynein-c MTBD shows only a small change in the microtubule- binding affinity depending on the registry change of coiled coil-sliding, whereby lacks the apparent strong binding state. The surface charge distribution of dynein-c MTBD also differs from that of cytoplasmic MTBD, which suggests a difference in the microtubule-binding mechanism. PMID- 25450769 TI - Modified T4 Lysozyme Fusion Proteins Facilitate G Protein-Coupled Receptor Crystallogenesis. AB - G protein-coupled receptors (GPCRs) mediate the majority of cellular responses to hormones and neurotransmitters. Most GPCR crystal structures have been obtained using a fusion protein strategy where the flexible third intracellular loop is replaced by T4 lysozyme (T4L). However, wild-type T4L may not be ideally suited for all GPCRs because of its size and the inherent flexibility between the N- and C-terminal subdomains. Here we report two modified T4L variants, designed to address flexibility and size, that can be used to optimize crystal quality or promote alternative packing interactions. These variants were tested on the M3 muscarinic receptor (M3). The original M3-T4L fusion protein produced twinned crystals that yielded a 3.4 A structure from a 70 crystal data set. We replaced T4L with the modified T4L variants. Both T4L variants yielded M3 muscarinic receptor crystals with alternate lattices that were not twinned, including one that was solved at 2.8 A resolution. PMID- 25450770 TI - Molecular perspectives on solid-state phase transformation and chemical reactivity of drugs: metoclopramide as an example. AB - Here, I provide an overview of the solid-state characteristics, phase transformations and chemical reactions of metoclopramide hydrochloride monohydrate (MCP HCl H2O). Three unique techniques, including thermoanalytical methods, one-step simultaneous differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) microspectroscopy, and hot-stage microscopic (HSM) imaging, have been applied to study the solid-state phase transitions of MCP HCl H2O in continuous dehydration, amorphization and recrystallization processes. I also review the effects of grinding or heating on ion-exchange reactions, milling, compression or colyophilization on Maillard reactions, and gamma-ray irradiation or electron beams on radiolysis in the solid state. I also report the exposure of MCP HCl H2O in solution to light, irradiation, oxidants or pi-acceptors. This review will serve as a useful keynote for the evolving realm of solid-state chemistry research. PMID- 25450771 TI - Peptide therapeutics: current status and future directions. AB - Peptides are recognized for being highly selective and efficacious and, at the same time, relatively safe and well tolerated. Consequently, there is an increased interest in peptides in pharmaceutical research and development (R&D), and approximately 140 peptide therapeutics are currently being evaluated in clinical trials. Given that the low-hanging fruits in the form of obvious peptide targets have already been picked, it has now become necessary to explore new routes beyond traditional peptide design. Examples of such approaches are multifunctional and cell penetrating peptides, as well as peptide drug conjugates. Here, we discuss the current status, strengths, and weaknesses of peptides as medicines and the emerging new opportunities in peptide drug design and development. PMID- 25450772 TI - Farnesyltransferase and geranylgeranyltransferase I: structures, mechanism, inhibitors and molecular modeling. AB - Farnesyltransferase (FTase) and geranylgeranyltransferase type I (GGTase-I) have crucial roles in the post-translational modifications of Ras proteins and, therefore, they are promising therapeutic targets for the treatment of various Ras-induced cancers and several other kinds of diseases. In this review, we provide an overview of the structures and biological functions of FTase and GGTase-I. Then, we summarize the typical inhibitors of FTase and GGTase-I, and highlight the drug candidates in clinical trials. In addition, we survey some recent advances in computer-aided drug design (CADD) and molecular modeling studies of FTase and GGTase-I. PMID- 25450773 TI - The Jordanian Mid Jordan Valley is a classic focus of Leishmania major as revealed by RFLP of 56 isolates and 173 ITS-1-PCR-positive clinical samples. AB - The identity of the causative species of cutaneous leishmaniasis (CL) in the endemic Jordanian Mid Jordan Valley (JMidJV) was investigated using the polymerase chain reaction (PCR) amplifying the ribosomal internal transcribed spacer 1 (ITS-1) followed by the restriction fragment length polymorphism (RFLP). The geographical distribution of CL and the usefulness of ITS1 PCR in diagnosis of suspected CL in the study area were also addressed. Over the period from 2004 to 2009, 56 clinical isolates of Leishmania promastigotes and 185 lesion scrapings spotted on filter papers were obtained from suspected CL patients living in the JMidJV, which is divided into northern and southern districts. The majority (67.1%) of patients occurred in the populated eastern part of the southern district. Of the 185 suspected CL patients, 173 (93.5%) were confirmed positive using PCR. Leishmanial DNA was detected in 27 (90%) of 30 patients having clinically atypical lesions of CL and in 60 (92%) of 65 smear- and culture negative cases having typical lesions of CL. The parasites in all of the 56 isolates and the 173 PCR-positive scrapings were classified as Leishmania major. In conclusion, PCR is useful in diagnosis of CL especially when smear and culture are negative. It is also recommended as a differential diagnostic tool of atypical lesions when CL is endemic. The identification of L. major as the causative species in such a considerable number of CL cases, representative of all mini foci of CL in the study area, shows that the JMidJV is a classic focus of L. major. PMID- 25450774 TI - Molecular characterization of Cyclophilin (TcCyP19) in Trypanosoma cruzi populations susceptible and resistant to benznidazole. AB - Cyclophilin (CyP), a peptidyl-prolyl cis/trans isomerase, is a key molecule with diverse biological functions that include roles in molecular chaperoning, stress response, immune modulation, and signal transduction. In this respect, CyP could serve as a potential drug target in disease-causing parasites. Previous studies employing proteomics techniques have shown that the TcCyP19 isoform was more abundant in a benznidazole (BZ)-resistant Trypanosoma cruzi population than in its susceptible counterpart. In this study, TcCyP19 has been characterized in BZ susceptible and BZ-resistant T. cruzi populations. Phylogenetic analysis revealed a clear dichotomy between Cyphophilin A (CyPA) sequences from trypanosomatids and mammals. Sequencing analysis revealed that the amino acid sequences of TcCyP19 were identical among the T. cruzi samples analyzed. Southern blot analysis showed that TcCyP19 is a single-copy gene, located in chromosomal bands varying in size from 0.68 to 2.2 Mb, depending on the strain of T. cruzi. Northern blot and qPCR indicated that the levels of TcCyP19 mRNA were twofold higher in drug-resistant T. cruzi populations than in their drug-susceptible counterparts. Similarly, as determined by two-dimensional gel electrophoresis immunoblot, the expression of TcCyP19 protein was increased to the same degree in BZ-resistant T. cruzi populations. No differences in TcCyP19 mRNA and protein expression levels were observed between the susceptible and the naturally resistant T. cruzi strains analyzed. Taken together, these data indicate that cyclophilin TcCyP19 expression is up-regulated at both transcriptional and translational levels in T. cruzi populations that were in vitro-induced and in vivo-selected for resistance to BZ. PMID- 25450775 TI - Plasmodium spp.: an experimental study on vertebrate host susceptibility to avian malaria. AB - The interest in experimental studies on avian malaria caused by Plasmodium species has increased recently due to the need of direct information about host parasite interactions. Numerous important issues (host susceptibility, development of infection, the resistance and tolerance to avian malaria) can be answered using experimental infections. However, specificity of genetically different lineages of malaria parasites and their isolates is largely unknown. This study reviews recent experimental studies and offers additional data about susceptibility of birds to several widespread cytochrome b (cyt b) lineages of Plasmodium species belonging to four subgenera. We exposed two domesticated avian hosts (canaries Serinus canaria and ducklings Anas platyrhynchos) and also 16 species of common wild European birds to malaria infections by intramuscular injection of infected blood and then tested them by microscopic examination and PCR-based methods. Our study confirms former field and experimental observations about low specificity and wide host-range of Plasmodium relictum (lineages SGS1 and GRW11) and P. circumflexum (lineage TURDUS1) belonging to the subgenera Haemamoeba and Giovannolaia, respectively. However, the specificity of different lineages and isolates of the same parasite lineage differed between species of exposed hosts. Several tested Novyella lineages were species specific, with a few cases of successful development in experimentally exposed birds. The majority of reported cases of mortality and high parasitaemia were observed during parasite co-infections. Canaries were susceptible mainly for the species of Haemamoeba and Giovannolaia, but were refractory to the majority of Novyella isolates. Ducklings were susceptible to three malaria infections (SGS1, TURDUS1 and COLL4), but parasitaemia was light (<0.01%) and transient in all exposed birds. This study provides novel information about susceptibility of avian hosts to a wide array of malaria parasite lineages, outlining directions for future experimental research on various aspects of biology and epidemiology of avian malaria. PMID- 25450777 TI - An overview of evidence-based program registers (EBPRs) for behavioral health. AB - Evaluations of behavioral health interventions have identified many that are potentially effective. However, clinicians and other decision makers typically lack the time and ability to effectively search and synthesize the relevant research literature. In response to this opportunity, and to increasing policy and funding pressures for the use of evidence-based practices, a number of "what works" websites have emerged to assist decision makers in selecting interventions with the highest probability of benefit. However, these registers as a whole are not well understood. This article, which represents phase one of a concurrent mixed methods study, presents a review of the scopes, structures, dissemination strategies, uses, and challenges faced by evidence-based registers in the behavioral health disciplines. The major findings of this study show that in general, registers of evidence-based practices are able, to a degree, to identify the most effective practices meet this need to a degree. However, much needs to be done to improve the ability of the registers to fully realize their purpose. PMID- 25450778 TI - Comparing rating paradigms for evidence-based program registers in behavioral health: evidentiary criteria and implications for assessing programs. AB - Decision makers need timely and credible information about the effectiveness of behavioral health interventions. Online evidence-based program registers (EBPRs) have been developed to address this need. However, the methods by which these registers determine programs and practices as being "evidence-based" has not been investigated in detail. This paper examines the evidentiary criteria EBPRs use to rate programs and the implications for how different registers rate the same programs. Although the registers tend to employ a standard Campbellian hierarchy of evidence to assess evaluation results, there is also considerable disagreement among the registers about what constitutes an adequate research design and sufficient data for designating a program as evidence-based. Additionally, differences exist in how registers report findings of "no effect," which may deprive users of important information. Of all programs on the 15 registers that rate individual programs, 79% appear on only one register. Among a random sample of 100 programs rated by more than one register, 42% were inconsistently rated by the multiple registers to some degree. PMID- 25450776 TI - Suppression of Ov-grn-1 encoding granulin of Opisthorchis viverrini inhibits proliferation of biliary epithelial cells. AB - Multistep processes likely underlie cholangiocarcinogenesis induced by chronic infection with the fish-borne liver fluke, Opisthorchis viverrini. One process appears to be cellular proliferation of the host bile duct epithelia driven by excretory-secretory (ES) products of this pathogen. Specifically, the secreted growth factor Ov-GRN-1, a liver fluke granulin, is a prominent component of ES and a known driver of hyper-proliferation of cultured human and mouse cells in vitro. We show potent hyper-proliferation of human cholangiocytes induced by low nanomolar levels of recombinant Ov-GRN-1 and similar growth produced by low microgram concentrations of ES products and soluble lysates of the adult worm. To further explore the influence of Ov-GRN-1 on the flukes and the host cells, expression of Ov-grn-1 was repressed using RNA interference. Expression of Ov-grn 1 was suppressed by 95% by day 3 and by ~100% by day 7. Co-culture of Ov-grn-1 suppressed flukes with human cholangiocyte (H-69) or human cholangiocarcinoma (KKU-M214) cell lines retarded cell hyper-proliferation by 25% and 92%, respectively. Intriguingly, flukes in which expression of Ov-grn-1 was repressed were less viable in culture, suggesting that Ov-GRN-1 is an essential growth factor for survival of the adult stage of O. viverrini, at least in vitro. To summarize, specific knock down of Ov-grn-1 reduced in vitro survival and capacity of ES products to drive host cell proliferation. These findings may help to contribute to a deeper understanding of liver fluke induced cholangiocarcinogenesis. PMID- 25450779 TI - Health, wellness and the allure of spices in the Middle Ages. AB - ETHNOPHARMOCOLOGICAL RELEVANCE: During the European Middle Ages aromatic products imported from Asia and Africa were credited with both preventive and curative medical properties. In addition spices provided an image of wellness and as they were expensive and had many uses in cuisine and fragrance, they functioned as prestige consumer goods. MATERIALS AND METHODS: This is an effort to look historically at a social and cultural phenomenon for the period roughly A.D. 1200 1500. Sources of information about the demand for and uses of spices include lists of materia medica, medical treatises, cookbooks, religious writings, descriptions of banquets and court ceremonial and literary works showing what might be called aspirational lifestyles. RESULTS: It is important to focus on the demand side of the spice trade rather than simply assuming a consistent demand and looking only at the supply (prices, routes, for example). CONCLUSIONS: The demand for spices must be understood in terms of their attributed medical and wellness powers, but these in turn are related to the mysterious Eastern origins of spices that enhanced their image as elite consumer products and their association with spiritual as well as medical healing. PMID- 25450780 TI - Analysis of 19 STR loci reveals genetic characteristic of eastern Chinese Han population. PMID- 25450781 TI - IPV--bridging the juridical gap between scratches and DNA detection under fingernails of cohabitating partners. AB - Intimate partner violence (IPV) is a global health issue with lifetime prevalences of physical and sexual violence against women of 12-71% in various populations. Due to its clandestine nature third party eye witnesses are scarce and prosecution of these cases has to rely on medical examination results, e.g. injury patterns of the victim and the perpetrator. Medicolegal assessment of DNA of the male partner found in fingernail specimen of the female partner after an assault is difficult since cohabitating couples are known to carry DNA of the respective partner in 17% of examined couples. In this study, male and total DNA content in fingernail specimen of 34 couples was analyzed after vigorous scratching of the male partners flank. Scratching and non-scratching fingers showed a highly significant difference in absolute and relative male DNA content allowing for the differentiation of DNA transfer caused by normal cohabitation and scratching during an assault. PMID- 25450782 TI - Efficient computations with the likelihood ratio distribution. AB - What is the probability that the likelihood ratio exceeds a threshold t, if a specified hypothesis is true? This question is asked, for instance, when performing power calculations for kinship testing, when computing true and false positive rates for familial searching and when computing the power of discrimination of a complex mixture. Answering this question is not straightforward, since there is are a huge number of possible genotypic combinations to consider. Different solutions are found in the literature. Several authors estimate the threshold exceedance probability using simulation. Corradi and Ricciardi [1] propose a discrete approximation to the likelihood ratio distribution which yields a lower and upper bound on the probability. Nothnagel et al. [2] use the normal distribution as an approximation to the likelihood ratio distribution. Dorum et al. [3] introduce an algorithm that can be used for exact computation, but this algorithm is computationally intensive, unless the threshold t is very large. We present three new approaches to the problem. Firstly, we show how importance sampling can be used to make the simulation approach significantly more efficient. Importance sampling is a statistical technique that turns out to work well in the current context. Secondly, we present a novel algorithm for computing exceedance probabilities. The algorithm is exact, fast and can handle relatively large problems. Thirdly, we introduce an approach that combines the novel algorithm with the discrete approximation of Corradi and Ricciardi. This last approach can be applied to very large problems and yields a lower and upper bound on the exceedance probability. The use of the different approaches is illustrated with examples from forensic genetics, such as kinship testing, familial searching and mixture interpretation. The algorithms are implemented in an R-package called DNAprofiles, which is freely available from CRAN. PMID- 25450783 TI - A series of recommended tests when validating probabilistic DNA profile interpretation software. AB - There has been a recent push from many jurisdictions for the standardisation of forensic DNA interpretation methods. Current research is moving from threshold based interpretation strategies towards continuous interpretation strategies. However laboratory uptake of software employing probabilistic models is slow. Some of this reluctance could be due to the perceived intimidating calculations to replicate the software answers and the lack of formal internal validation requirements for interpretation software. In this paper we describe a set of experiments which may be used to internally validate in part probabilistic interpretation software. These experiments included both single source and mixed profiles calculated with and without dropout and drop-in and studies to determine the reproducibility of the software with replicate analyses. We do this by way of example using three software packages: STRmixTM, LRmix, and Lab Retriever. We outline and demonstrate the profile examples where the expected answer may be calculated and provide all calculations. PMID- 25450784 TI - Second-generation sequencing of forensic STRs using the Ion TorrentTM HID STR 10 plex and the Ion PGMTM. AB - Second-generation sequencing (SGS) using Roche/454 and Illumina platforms has proved capable of sequencing the majority of the key forensic genetic STR systems. Given that Roche has announced that the 454 platforms will no longer be supported from 2015, focus should now be shifted to competing SGS platforms, such as the MiSeq (Illumina) and the Ion Personal Genome Machine (Ion PGMTM; Thermo Fisher). There are currently several challenges faced with amplicon-based SGS STR typing in forensic genetics, including current lengths of amplicons for CE-typing and lack of uniform data analysis between laboratories. Thermo Fisher has designed a human identification (HID) short tandem repeat (STR) 10-plex panel including amelogenin, CSF1PO, D16S539, D3S1358, D5S818, D7S820, D8S1179, TH01, TPOX and vWA, where the primers have been designed specifically for the purpose of SGS and the data analysis is supported by Ion TorrentTM software. Hence, the combination of the STR 10-plex and the Ion PGMTM represents the first fully integrated SGS STR typing solution from PCR to data analysis. In this study, four experiments were performed to evaluate the alpha-version of the STR 10-plex: (1) typing of control samples; (2) analysis of sensitivity; (3) typing of mixtures; and (4) typing of biological crime case samples. Full profiles and concordant results between replicate SGS runs and CE-typing were observed for all control samples. Full profiles were seen with DNA input down to 50 pg, with the exception of a single locus drop-out in one of the 100 pg dilutions. Mixtures were easily deconvoluted down to 20:1, although alleles from the minor contributor had to be identified manually as some signals were not called by the Ion TorrentTM software. Interestingly, full profiles were obtained for all biological samples from real crime and identification cases, in which only partial profiles were obtained with PCR-CE assays. In conclusion, the Ion TorrentTM HID STR 10-plex panel offers an all-in-one solution from amplification of STRs and amelogenin, and sequencing to data analysis. PMID- 25450786 TI - A more straightforward derivation of the LR for a database search. AB - Matching DNA profiles of an accused person and a crime scene trace are one of the most common forms of forensic evidence. A number of years ago the so-called 'DNA controversy' was concerned with how to quantify the value of such evidence. Given its importance, the lack of understanding of such a basic issue was quite surprising and concerning. Deriving the equation for the likelihood ratio of a DNA database match in a much more direct and simple way is the topic of this paper. As it is much easier to follow it is hoped that this derivation will contribute to the understanding. PMID- 25450785 TI - Full mtGenome reference data: development and characterization of 588 forensic quality haplotypes representing three U.S. populations. AB - Though investigations into the use of massively parallel sequencing technologies for the generation of complete mitochondrial genome (mtGenome) profiles from difficult forensic specimens are well underway in multiple laboratories, the high quality population reference data necessary to support full mtGenome typing in the forensic context are lacking. To address this deficiency, we have developed 588 complete mtGenome haplotypes, spanning three U.S. population groups (African American, Caucasian and Hispanic) from anonymized, randomly-sampled specimens. Data production utilized an 8-amplicon, 135 sequencing reaction Sanger-based protocol, performed in semi-automated fashion on robotic instrumentation. Data review followed an intensive multi-step strategy that included a minimum of three independent reviews of the raw data at two laboratories; repeat screenings of all insertions, deletions, heteroplasmies, transversions and any additional private mutations; and a check for phylogenetic feasibility. For all three populations, nearly complete resolution of the haplotypes was achieved with full mtGenome sequences: 90.3-98.8% of haplotypes were unique per population, an improvement of 7.7-29.2% over control region sequencing alone, and zero haplotypes overlapped between populations. Inferred maternal biogeographic ancestry frequencies for each population and heteroplasmy rates in the control region were generally consistent with published datasets. In the coding region, nearly 90% of individuals exhibited length heteroplasmy in the 12418-12425 adenine homopolymer; and despite a relatively high rate of point heteroplasmy (23.8% of individuals across the entire molecule), coding region point heteroplasmies shared by more than one individual were notably absent, and transversion-type heteroplasmies were extremely rare. The ratio of nonsynonymous to synonymous changes among point heteroplasmies in the protein-coding genes (1:1.3) and average pathogenicity scores in comparison to data reported for complete substitutions in previous studies seem to provide some additional support for the role of purifying selection in the evolution of the human mtGenome. Overall, these thoroughly vetted full mtGenome population reference data can serve as a standard against which the quality and features of future mtGenome datasets (especially those developed via massively parallel sequencing) may be evaluated, and will provide a solid foundation for the generation of complete mtGenome haplotype frequency estimates for forensic applications. PMID- 25450787 TI - Examination of DNA methylation status of the ELOVL2 marker may be useful for human age prediction in forensic science. AB - Age estimation in forensic investigations may complement the prediction of externally visible characteristics and the inference of biogeographical ancestry, thus allowing a better description of an unknown individual. Multiple CpG sites that show linear correlation between age and degree of DNA methylation have been identified in the human genome, providing a selection of candidates for age prediction. In this study, we optimized an assay based on bisulfite conversion and pyrosequencing of 7 CpG sites located in the ELOVL2 gene. Examination of 303 blood samples collected from individuals aged 2-75 years allowed selection of the most informative site, explaining 83% of variation in age. The final linear regression model included two CpG sites in ELOVL2 and enabled age prediction with R(2)=0.859, prediction error=6.85 and mean absolute deviation MAD=5.03. Examination of a testing set of 124 blood samples (MAD=5.75) showed that 68.5% of samples were correctly predicted, assuming that chronological and predicted ages matched +/- 7 years. It was found that the ELOVL2 methylation status in bloodstains had not changed significantly after 4 weeks of storage in room temperature conditions. Analysis of 45 bloodstains deposited on tissue paper after 5, 10 and 15 years of storage in room conditions indicated that although a gradual decrease of positive PCR results was observed, the general age prediction success rate remained similar and equaled 60-78%. The obtained results show that the ELOVL2 locus provides a very good source of information about human chronological age based on analysis of blood, including bloodstains, and it may constitute a powerful and reliable predictor in future forensic age estimation models. PMID- 25450788 TI - Sequence-based definition of eight short tandem repeat loci located within the HLA-region in an Austrian population. AB - Sequenced allelic ladders are a prerequisite for reliable genotyping of short tandem repeat (STR) polymorphisms and consistent results across instrument platforms. For eight STR-loci located on the short arm of chromosome 6 (6p21.3), a sequenced based nomenclature was established according to international recommendations. Publicly available reference DNA samples were sequenced enabling interested laboratories to construct their own allelic ladders. Three tetrameric (D6S2691, D6S2678, DQIV), one trimeric (D6S2906) and four dimeric repeat loci (D6S2972, D6S2792, D6S2789, D6S273) were investigated. Apart from the very complex sequence structure at the DQIV locus, three loci showed a compound and four loci a simple repeat pattern. In the flanking regions of some loci additional single nucleotide and insertion/deletion polymorphisms occurred as well as sequence polymorphisms within the repeat region of alleles with the same length. In an Austrian Caucasoid population sample (n=293) between eight and 22 alleles were found. No significant deviation from Hardy-Weinberg expectations was observed, the power of discrimination ranged from 0.826 to 0.978. The loci cover the HLA-coding region from HLA-A to HLA-DQB1 and can be used for a better definition of HLA haplotypes for population and disease association studies, recombination point mapping, haematopoietic stem cell transplantation as well as for identity and relationship testing. PMID- 25450789 TI - Analysis of 36 Y-STR marker units including a concordance study among 2085 Dutch males. AB - The genotypes of 36 Y-chromosomal short tandem repeat (Y-STR) marker units were analysed in a Dutch population sample of 2085 males. Profiling results were compared for several partially overlapping kits, i.e. PowerPlex Y, Yfiler, PowerPlex Y23, and two in-house designed multiplexes with rapidly mutating Y STRs. Nineteen Y-STR marker units, of which two are rapidly mutating, reside in at least two of these multiplexes, and for these markers concordance testing was performed. Two samples showed discordant genotyping results and the probable causative base change was revealed by Sanger sequencing. In addition, we encountered concordant, but aberrant genotyping results including one allele with low peak height and several null alleles. For 12 samples, this involved a null allele in two adjacent loci suggesting a large and recurrent deletion as the samples represent three distinct haplogroups. For each marker unit, the allele counts and frequencies are presented, as are the haplotype counts and haplotype diversities for several combinations of markers. PMID- 25450790 TI - STRait Razor v2.0: the improved STR Allele Identification Tool--Razor. AB - STRait Razor (the STR Allele Identification Tool - Razor) was developed as a bioinformatic software tool to detect short tandem repeat (STR) alleles in massively parallel sequencing (MPS) raw data. The method of detection used by STRait Razor allows it to make reliable allele calls for all STR types in a manner that is similar to that of capillary electrophoresis. STRait Razor v2.0 incorporates several new features and improvements upon the original software, such as a larger default locus configuration file that increases the number of detectable loci (now including X-chromosome STRs and Amelogenin), an enhanced custom locus list generator, a novel output sorting method that highlights unique sequences for intra-repeat variation detection, and a genotyping tool that emulates traditional electropherogram data. Users also now have the option to choose whether the program detects autosomal, X-chromosome, Y-chromosome, or all STRs. Concordance testing was performed, and allele calls produced by STRait Razor v2.0 were completely consistent with those made by the original software. PMID- 25450791 TI - The variability in likelihood ratios due to different mechanisms. AB - Recently there has been a drive towards standardisation of forensic DNA interpretation methods resulting in the uptake of probabilistic interpretation software. Some of these software solutions utilise Markov chain Monte Carlo techniques (MCMC). They will not produce an identical answer after repeat interpretations of the same evidence profile because of the Monte Carlo aspect. This is a new source of variability within the forensic DNA analysis process. In this paper we explore the size of the MCMC variability within the interpretation software STRmixTM compared to other sources of variability in forensic DNA profiling including PCR, capillary electrophoresis load and injection, and the makeup of allele frequency databases. The MCMC variability within STRmixTM was shown to be the smallest source of variability in this process. PMID- 25450792 TI - Gene and haplotype diversity of 23 Y-chromosomal short tandem repeat loci in the central Thai population. PMID- 25450793 TI - FACS separation of non-compromised forensically relevant biological mixtures. AB - Although focusing attention on the statistical analysis of complex mixture profiles is important, the forensic science community will also benefit from directing research to improving the reduction of the incidence of mixtures before DNA extraction. This preliminary study analysed the use of fluorescence assisted cell sorting (FACS) for separation of cellular mixtures before DNA extraction, specifically mixtures of relatively fresh blood and saliva from two donors, prepared in 14 different mixture ratios. Improvements in the number of detectable alleles from the targeted cell type and overall profile quality were seen when compared to the results from unseparated samples. STRmix calculations revealed increases in likelihood ratios after separation, demonstrating the potential for higher probative values to be obtained from forensically relevant mixtures after subjecting them to FACS than from unsorted samples. PMID- 25450795 TI - Minimizing inhibition of PCR-STR typing using digital agarose droplet microfluidics. AB - The presence of PCR inhibitors in forensic and other biological samples reduces the amplification efficiency, sometimes resulting in complete PCR failure. Here we demonstrate a high-performance digital agarose droplet microfluidics technique for single-cell and single-molecule forensic short tandem repeat (STR) typing of samples contaminated with high concentrations of PCR inhibitors. In our multifaceted strategy, the mitigation of inhibitory effects is achieved by the efficient removal of inhibitors from the porous agarose microgel droplets carrying the DNA template through washing and by the significant dilution of targets and remaining inhibitors to the stochastic limit within the ultralow nL volume droplet reactors. Compared to conventional tube-based bulk PCR, our technique shows enhanced (20 *, 10 *, and 16 *) tolerance of urea, tannic acid, and humic acid, respectively, in STR typing of GM09948 human lymphoid cells. STR profiling of single cells is not affected by small soluble molecules like urea and tannic acid because of their effective elimination from the agarose droplets; however, higher molecular weight humic acid still partially inhibits single-cell PCR when the concentration is higher than 200 ng/MUL. Nevertheless, the full STR profile of 9948 male genomic DNA contaminated with 500 ng/MUL humic acid was generated by pooling and amplifying beads carrying single-molecule 9948 DNA PCR products in a single secondary reaction. This superior performance suggests that our digital agarose droplet microfluidics technology is a promising approach for analyzing low-abundance DNA targets in the presence of inhibitors. PMID- 25450794 TI - Genetic identification of Cannabis sativa using chloroplast trnL-F gene. PMID- 25450796 TI - The multiethnic ancestry of Bolivians as revealed by the analysis of Y-chromosome markers. AB - We have analyzed the specific male genetic component of 226 Bolivians recruited in five different regions ("departments"), La Paz, Cochabamba, Pando, Beni, and Santa Cruz. To evaluate the effect of geography on the distribution of genetic variability, the samples were also grouped into three main eco-geographical regions, namely, Andean, Sub-Andean, and Llanos. All the individuals were genotyped for 17 Y-STR and 32 Y-SNP markers. The average Y-chromosome Native American component in Bolivians is 28%, and it is mainly represented by haplogroup Q1a3a, while the average Y-chromosome European ancestry is 65%, and it is mainly represented by haplogroup R1b1-P25. The data indicate that there exists significant population sub-division in the country in terms of continental ancestry. Thus, the partition of ancestries in Llanos, Sub-Andean, and Andean regions is as follows (respectively): (i) Native American ancestry: 47%, 7%, and 19%, (ii) European ancestry: 46%, 86%, and 75%, and (iii) African ancestry: 7%, 7%, and 6%. The population sub-structure in the country is also well mirrored when inferred from an AMOVA analysis, indicating that among-population variance in the country reaches 9.74-11.15%. This suggests the convenience of using regional datasets for forensic applications in Bolivia, instead of using a global and single country database. By comparing the Y-chromosome patterns with those previously reported on the same individuals on autosomal SNPs and mitochondrial DNA (mtDNA), it becomes clear that Bolivians show a strong gender-bias. PMID- 25450797 TI - AmgRS-mediated envelope stress-inducible expression of the mexXY multidrug efflux operon of Pseudomonas aeruginosa. AB - AmgRS is an envelope stress-responsive two-component system and aminoglycoside resistance determinant in Pseudomonas aeruginosa that is proposed to protect cells from membrane damage caused by aminoglycoside-generated mistranslated polypeptides. Consistent with this, a DeltaamgR strain showed increased aminoglycoside-promoted membrane damage, damage that was largely absent in AmgRS activated amgS-mutant strains. Intriguingly, one such mutation, V121G, while providing for enhanced resistance to aminoglycosides, rendered P. aeruginosa susceptible to several ribosome-targeting nonaminoglycoside antimicrobials that are inducers and presumed substrates of the MexXY-OprM multidrug efflux system. Surprisingly, the amgSV 121G mutation increased mexXY expression threefold, suggesting that export of these nonaminoglycosides was compromised in the amgSV 121G mutant. Nonetheless, a link was established between AmgRS activation and mexXY expression and this was confirmed in studies showing that aminoglycoside promoted mexXY expression is dependent on AmgRS. While nonaminoglycosides also induced mexXY expression, this was not AmgRS-dependent, consistent with these agents not generating mistranslated polypeptides and not activating AmgRS. The aminoglycoside inducibility of mexXY was abrogated in a mutant lacking the AmgRS target genes htpX and PA5528, encoding a presumed cytoplasmic membrane-associated protease and a membrane protein of unknown function, respectively. Thus, aminoglycoside induction of mexXY is a response to membrane damage and activation of the AmgRS two-component system. PMID- 25450799 TI - Clinico-epidemiology of stings and envenoming of Hottentotta tamulus (Scorpiones: Buthidae), the Indian red scorpion from Jaffna Peninsula in northern Sri Lanka. AB - In recent years, stings of a lethal scorpion species were recorded from Jaffna Peninsula in the northern dry zone of Sri Lanka. This species was identified as Hottentotta tamulus (Scorpiones: Buthidae) which is the Indian red scorpion commonly found in Maharashtra, India. The Teaching Hospital, Jaffna recorded 84 H. tamulus stings over a year in 2012 and of them, 23 cases provided offending scorpions (proven cases). Three localities in Jaffna were recorded as hotspots of scorpion stings namely Palali, Achchuvali and Karainagar. Of the proven cases, 13 (57%) and 10 (43%) were males and females respectively and had a mean age of 30 years (SD +/- 20 years). Among them, 5 (22%) were children below 12 years. In 13 (57%) patients stings occurred inside their houses including two children (40%). Six (26%) stings occurred at night when the victims were in sleep. Median time taken to arrive at the hospital from the time of stinging was 58 min (range 8-550 min). Signs of over activation of autonomic nervous system predominated the clinical picture-tachycardia in 14 (61%), high blood pressure in 11 (48%), excessive sweating in 9 (39%), excessive salivation in 5 (22%), hypotension in 4 (17%) and piloerection in 3 (13%). Children showed higher predilection to develop tachycardia - 4 (80%) and excessive salivation - 3 (60%). Priapism was not observed and 17 (74%) patients have developed intense pain at the site of sting. The commonest ECG change was tachycardia (73%) and occasional T wave inversion. Prazosin as a treatment was given to 22 (96%) patients. All patients made recovery and 13 (57%) patients left the hospital within two days. In future, there is a potential risk of spreading this species to elsewhere in the country and may disturb the ecological balance. PMID- 25450800 TI - PPAR-gamma activation by Tityus serrulatus venom regulates lipid body formation and lipid mediator production. AB - Tityus serrulatus venom (TsV) consists of numerous peptides with different physiological and pharmacological activities. Studies have shown that scorpion venom increases pro-inflammatory cytokine production, contributing to immunological imbalance, multiple organ dysfunction, and patient death. We have previously demonstrated that TsV is a venom-associated molecular pattern (VAMP) recognized by TLRs inducing intense inflammatory reaction through the production of pro-inflammatory cytokines and arachidonic acid-derived lipid mediators prostaglandin (PG)E2 and leukotriene (LT)B4. Lipid bodies (LBs) are potential sites for eicosanoid production by inflammatory cells. Moreover, recent studies have shown that the peroxisome proliferator-activated receptor gamma (PPAR-gamma) is implicated in LB formation and acts as an important modulator of lipid metabolism during inflammation. In this study, we used murine macrophages to evaluate whether the LB formation induced by TsV after TLR recognition correlates with lipid mediator generation by macrophages and if it occurs through PPAR-gamma activation. We demonstrate that TsV acts through TLR2 and TLR4 stimulation and PPAR-gamma activation to induce LB formation and generation of PGE2 and LTB4. Our data also show that PPAR-gamma negatively regulates the pro-inflammatory NF kappaB transcription factor. Based on these results, we suggest that during envenomation, LBs constitute functional organelles for lipid mediator production through signaling pathways that depend on cell surface and nuclear receptors. These findings point to the inflammatory mechanisms that might also be triggered during human envenomation by TsV. PMID- 25450798 TI - Inhibition of pancreatic tumoral cells by snake venom disintegrins. AB - Pancreatic cancer often has a poor prognosis, even when diagnosed early. Pancreatic cancer typically spreads rapidly and is rarely detected in its early stages, which is a major reason it is a leading cause of cancer death. Signs and symptoms may not appear until pancreatic cancer is quite advanced, and complete surgical removal is not possible. Furthermore, pancreatic cancer responds poorly to most chemotherapeutic agents. The importance of integrins in several cell types that affect tumor progression has made them an appealing target for cancer therapy. Some of the proteins found in the snake venom present a great potential as anti-tumor agents. In this study, we summarize the activity of two integrins antagonist, recombinant disintegrins mojastin 1 and viridistatin 2, on human pancreatic carcinoma cell line (BXPC-3). Both recombinant disintegrins inhibited some essential aspects of the metastasis process such as proliferation, adhesion, migration, and survival through apoptosis, making these proteins prominent candidates for the development of drugs for the treatment of pancreatic cancer. PMID- 25450801 TI - Biliary excretion of tetrodotoxin in the cultured pufferfish Takifugu rubripes juvenile after intramuscular administration. AB - Marine pufferfish of the family Tetraodontidae accumulate a considerable amount of tetrodotoxin (TTX), mainly in the liver and ovary. The detailed distribution of TTX in pufferfish body tissues, however, remains poorly understood. Here we investigated the tissue distribution and biliary excretion of TTX in cultured pufferfish Takifugu rubripes juveniles (6-month-old, 81.5 +/- 2.0 g body weight) for 24 h after intramuscular administration of 0.25 MUg TTX/g body weight into the caudal muscle. The blood TTX concentration was 0.53 +/- 0.15 MUg/mL at 1 h, and gradually decreased to 0.05 +/- 0.01 MUg/mL at 24 h after administration (p < 0.05). The TTX concentration in the liver declined from 1.59 +/- 0.10 MUg/g at 1 h to 0.48 +/- 0.21 MUg/g at 24 h (p < 0.05). In contrast, the TTX concentration in the skin increased from 0.27 +/- 0.04 MUg/g at 1 h to 0.48 +/- 0.08 MUg/g at 24 h (p < 0.05). The concentration of TTX in the bile remarkably increased from 0.08 +/- 0.03 MUg/mL at 1 h to 0.39 +/- 0.05 MUg/mL at 8 h (p < 0.05) and remained at almost the same level at 24 h. These findings indicate that TTX was excreted from the liver into the gallbladder bile in the pufferfish T. rubripes juveniles. PMID- 25450802 TI - HPV16 E5 expression induces switching from FGFR2b to FGFR2c and epithelial mesenchymal transition. AB - The E5 oncoprotein of the human papillomavirus type 16 (HPV16 E5) deregulates epithelial homeostasis through the modulation of receptor tyrosine kinases and their signaling. Accordingly, the fibroblast growth factor receptor 2b (FGFR2b/KGFR), epithelial splicing transcript variant of the FGFR2, is down modulated by the viral protein expression, leading to impairment of keratinocyte differentiation. Here, we report that, in cell models of transfected human keratinocytes as well as in cervical epithelial cells containing episomal HPV16, the down-regulation of FGFR2b induced by 16E5 is associated with the aberrant expression of the mesenchymal FGFR2c isoform as a consequence of splicing switch: in fact, quantitative RT-PCR analysis showed that this molecular event is transcriptionally regulated by the epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) and is able to produce effects synergistic with those caused by TGFbeta treatment. Immunofluorescence analysis revealed that this altered FGFR2 splicing leads to changes in the specificity for the ligands FGFs and in the cellular response, triggering epithelial-mesenchymal transition (EMT). Through 16E5 or FGFR2 silencing as well as inhibition of FGFR2 activity we demonstrated the direct role of the viral protein in the receptor isoform switching and EMT, suggesting that these early molecular events during HPV infection might represent additional mechanisms driving cervical transformation and tumor progression. PMID- 25450803 TI - Community-acquired meticillin-resistant Staphylococcus aureus strain USA300 resists staphylococcal protein A modulation by antibiotics and antimicrobial peptides. AB - Community-acquired meticillin-resistant Staphylococcus aureus (CA-MRSA) causes severe diseases through virulence factors such as staphylococcal protein A (SpA), which favours immune evasion. We have previously shown that antimicrobial peptides (AMPs) and antibiotics decrease SpA expression in CA-MRSA strains. Here we examined the effects of antibiotics and AMPs, alone and in combination, on SpA expression in various CA-MRSA strains. Six S. aureus isolates corresponding to the major worldwide CA-MRSA clones (ST8-USA300, ST80 and ST30) were selected. Strains were cultured to exponential growth phase and were subsequently incubated with antibiotics (tigecycline, linezolid, clindamycin and vancomycin) at 0.25* MIC or with AMPs [human neutrophil peptide (HNP)-1-3] at the LD50, alone and in combination. After 6h, cultures were assessed for spa mRNA by RT-PCR, whilst SpA protein was measured by specific ELISA after 18h. When used alone, antibiotics (clindamycin, linezolid and tigecycline) or HNPs significantly reduced both SpA production and mRNA levels in ST30 and ST80 strains. When used in combination, HNPs and clindamycin, linezolid or tigecycline synergistically reduced SpA production (6-100-fold) and spa mRNA levels (4-20-fold) in ST80 and ST30 strains. In contrast, for USA300 strains, among all antibiotics, clindamycin alone reduced SpA production (3.5-fold), whereas with combined treatments including HNPs, only a slight reduction in SpA production (1.7-2.2-fold) was observed. In conclusion, antibiotics and AMPs do not modulate SpA expression in USA300, unlike in other CA MRSA clones. This observation suggests that the virulence and successful spread of USA300 strains is associated with a specific regulatory network. PMID- 25450804 TI - Impact of poor compliance with levofloxacin and moxifloxacin on respiratory tract infection antimicrobial efficacy: a pharmacokinetic/pharmacodynamic simulation study. AB - The purpose of this report was to assess the impact of poor compliance on the efficacy of levofloxacin (LFX) and moxifloxacin (MOX), two fluoroquinolones with different pharmacokinetic (PK) and pharmacodynamic (PD) properties, in respiratory infections. The fAUC0-24h and fAUC0-24h/MIC90 ratio, a PK/PD index predictive of bacterial eradication, were extracted from previously described population PK models for LFX and MOX. The MIC90 was according to EUCAST. Monte Carlo simulations were used with LFX 500 mg every 24h (q24 h) or every 12h (q12h), LFX 750 mg q24 h and MOX 400mg q24 h in non-compliance scenarios to derive the proportion of patients achieving target ratios of fAUC0-24h/MIC90>33.8 for Streptococcus pneumoniae and >100 for Haemophilus influenzae and Moraxella catarrhalis (PTA>90%). In non-adherent dosing scenarios, LFX 500 mg q24 h was not able to reach the PK/PD index guaranteeing clinical efficacy. With LFX 500 mg q12 h or 750 mg q24 h, this probability was maintained although patients can take the dose with delays of up to 12h and 11h, respectively, for the three bacterial types. With MOX 400mg q24 h, the probability of achieving this PK/PD index is maintained with delay in dosing up to 16h. In conclusion, LFX 500 mg q24 h is the least robust treatment against S. pneumoniae, H. influenzae and M. catarrhalis in a non-adherence situation. A good choice is LFX 500 mg q12h, but in order to favour patient adherence, LFX 750 mg q24 h or MOX 400mg q24h appears as more appropriate. PMID- 25450805 TI - Dissemination of a clone carrying a fosA3-harbouring plasmid mediates high fosfomycin resistance rate of KPC-producing Klebsiella pneumoniae in China. AB - Fosfomycin has been proposed as an adjunct to other active agents for treating KPC-producing Klebsiella pneumoniae infections. This study aimed to investigate the prevalence of fosfomycin resistance and plasmid-mediated resistance determinants among KPC-producing K. pneumoniae isolates from clinical samples in China. In total, 278 KPC-producing and 80 extended-spectrum beta-lactamase (ESBL) producing (non-KPC-producing) clinical K. pneumoniae isolates were collected in 12 hospitals from 2010 to 2013. Fosfomycin susceptibility testing was carried out using the agar dilution method. Phylogenetic clonal patterns were revealed by pulsed-field gel electrophoresis (PFGE). Isolates were screened for plasmid mediated fosfomycin resistance genes (fosA, fosA3 and fosC2) by PCR amplification. A plasmid was completely sequenced by next-generation sequencing. The fosfomycin resistance rate in KPC-producers (60.8%; 169/278) was significantly higher than in ESBL-producers (12.5%; 10/80). In addition, 94 KPC producing isolates were positive for fosA3 and most of them were clonally related. A 23939-bp plasmid (pFOS18) co-harbouring fosA3 and bla(KPC-2) was completely sequenced, revealing that the fosA3 gene was flanked by two copies of IS26; however, bla(KPC-2) was located on a Tn3-Tn4401 integration structure. Although the fosA3 and blaKPC-2 genes are located on different transposon systems, they are able to spread together worldwide through plasmid transfer. Dissemination of the clone carrying the fosA3-harbouring plasmid mediates the high fosfomycin resistance rate of KPC-producing K. pneumoniae in China. Fosfomycin as an alternative option for treating infections caused by KPC producing K. pneumoniae should not be recommended in hospitals in which fosfomycin-resistant clonal dissemination is emerging. PMID- 25450806 TI - The mechanosensitive channel of small conductance (MscS) functions as a Jack-in the box. AB - Phenotypical analysis of the lipid interacting residues in the closed state of the mechanosensitive channel of small conductance (MscS) from Escherichia coli (E. coli) has previously shown that these residues are critical for channel function. In the closed state, mutation of individual hydrophobic lipid lining residues to alanine, thus reducing the hydrophobicity, resulted in phenotypic changes that were observable using in vivo assays. Here, in an analogous set of experiments, we identify eleven residues in the first transmembrane domain of the open state of MscS that interact with the lipid bilayer. Each of these residues was mutated to alanine and leucine to modulate their hydrophobic interaction with the lipid tail-groups in the open state. The effects of these changes on channel function were analyzed using in vivo bacterial assays and patch clamp electrophysiology. Mutant channels were found to be functionally indistinguishable from wildtype MscS. Thus, mutation of open-state lipid interacting residues does not differentially stabilize or destabilize the open, closed, intermediate, or transition states of MscS. Based on these results and other data from the literature, we propose a new gating paradigm for MscS where MscS acts as a "Jack-In-The-Box" with the intrinsic bilayer lateral pressure holding the channel in the closed state. In this model, upon application of extrinsic tension the channel springs into the open state due to relief of the intrinsic lipid bilayer pressure. PMID- 25450807 TI - Real-time examination of aminoglycoside activity towards bacterial mimetic membranes using Quartz Crystal Microbalance with Dissipation monitoring (QCM-D). AB - The rapid increase in multi-drug resistant bacteria has resulted in previously discontinued treatments being revisited. Aminoglycosides are effective "old" antibacterial agents that fall within this category. Despite extensive usage and understanding of their intracellular targets, there is limited mechanistic knowledge regarding how aminoglycosides penetrate bacterial membranes. Thus, the activity of two well-known aminoglycosides, kanamycin A and neomycin B, towards a bacterial mimetic membrane (DMPC:DMPG (4:1)) was examined using a Quartz Crystal Microbalance with Dissipation monitoring (QCM-D). The macroscopic effect of increasing the aminoglycoside concentration showed that kanamycin A exerts a threshold response, switching from binding to the membrane to disruption of the surface. Neomycin B, however, disrupted the membrane at all concentrations examined. At concentrations above the threshold value observed for kanamycin A, both aminoglycosides revealed similar mechanistic details. That is, they both inserted into the bacterial mimetic lipid bilayer, prior to disruption via loss of materials, presumably aminoglycoside-membrane composites. Depth profile analysis of this membrane interaction was achieved using the overtones of the quartz crystal sensor. The measured data is consistent with a two-stage process in which insertion of the aminoglycoside precedes the 'detergent-like' removal of membranes from the sensor. The results of this study contribute to the insight required for aminoglycosides to be reconsidered as active antimicrobial agents/co agents by providing details of activity at the bacterial membrane. Kanamycin and neomycin still offer potential as antimicrobial therapeutics for the future and the QCM-D method illustrates great promise for screening new antibacterial or antiviral drug candidates. PMID- 25450809 TI - Interferon-gamma induces a tryptophan-selective amino acid transporter in human colonic epithelial cells and mouse dendritic cells. AB - IDO1, which encodes the immunosuppressive and tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase-1 (IDO1), is a target for interferon-gamma (IFN gamma). IDO1-mediated tryptophan catabolism in dendritic cells and macrophages arrests T cell proliferation, thereby providing a molecular basis for the immunosuppressive function of IDO1. Whether the entry of tryptophan into IDO1 expressing cells is also regulated by IFN-gamma is not known. Here we used a human colonic epithelial cell line (CCD841) and a mouse dendritic cell line (DC2.4) to test the hypothesis that IFN-gamma, which induces IDO1, also induces a tryptophan transporter to promote substrate availability to IDO1. Upon treatment with IFN-gamma, there was a marked increase in IDO1 mRNA and a concomitant increase in tryptophan uptake in both cell lines. The induced uptake system was selective for tryptophan and saturable with a Michaelis constant of 36+/-3 MUM in CCD841 cells and 0.5+/-0.1 MUM in DC2.4 cells. The induction by IFN-gamma and the tryptophan-selectivity of the induced transport system were demonstrable even in the presence of physiologic concentrations of all other amino acids. Since kynurenine, the catabolic end product of IDO1, is a signaling molecule as an agonist for the aryl hydrocarbon receptor (AhR), we examined if AhR signaling induces the tryptophan-selective transporter. Treatment of the cells with kynurenine and other AhR agonists increased tryptophan uptake. The present studies demonstrate that IFN-gamma coordinately induces IDO1 and a tryptophan selective transporter to maximize tryptophan depletion in IDO1-expressing cells and that the process involves a positive feedback mechanism via kynurenine-AhR signaling. PMID- 25450808 TI - The p10 FAST protein fusion peptide functions as a cystine noose to induce cholesterol-dependent liposome fusion without liposome tubulation. AB - The reovirus p10 fusion-associated small transmembrane (FAST) proteins are the smallest known membrane fusion proteins, and evolved specifically to mediate cell cell, rather than virus-cell, membrane fusion. The 36-40-residue ectodomains of avian reovirus (ARV) and Nelson Bay reovirus (NBV) p10 contain an essential intramolecular disulfide bond required for both cell-cell fusion and lipid mixing between liposomes. To more clearly define the functional, biochemical and biophysical features of this novel fusion peptide, synthetic peptides representing the p10 ectodomains of ARV and NBV were analyzed by solution-state NMR spectroscopy, circular dichroism spectroscopy, fluorescence spectroscopy based hydrophobicity analysis, and liposome binding and fusion assays. Results indicate that disulfide bond formation promotes exposure of hydrophobic residues, as indicated by bis-ANS binding and time-dependent peptide aggregation under aqueous conditions, implying the disulfide bond creates a small, geometrically constrained, cystine noose. Noose formation is required for peptide partitioning into liposome membranes and liposome lipid mixing, and electron microscopy revealed that liposome-liposome fusion occurs in the absence of liposome tubulation. In addition, p10 fusion peptide activity, but not membrane partitioning, is dependent on membrane cholesterol. PMID- 25450811 TI - A thermodynamic signature of lipid segregation in biomembranes induced by a short peptide derived from glycoprotein gp36 of feline immunodeficiency virus. AB - The interactions between proteins/peptides and lipid bilayers are fundamental in a variety of key biological processes, and among these, the membrane fusion process operated by viral glycoproteins is one of the most important, being a fundamental step of the infectious event. In the case of the feline immunodeficiency virus (FIV), a small region of the membrane proximal external region (MPER) of the glycoprotein gp36 has been demonstrated to be necessary for the infection to occur, being able to destabilize the membranes to be fused. In this study, we report a physicochemical characterization of the interaction process between an eight-residue peptide, named C8, modeled on that gp36 region and some biological membrane models (liposomes) by using calorimetric and spectroscopic measurements. CD studies have shown that the peptide conformation changes upon binding to the liposomes. Interestingly, the peptide folds from a disordered structure (in the absence of liposomes) to a more ordered structure with a low but significant helix content. Isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC) results show that C8 binds with high affinity the lipid bilayers and induces a significant perturbation/reorganization of the lipid membrane structure. The type and the extent of such membrane reorganization depend on the membrane composition. These findings provide interesting insights into the role of this short peptide fragment in the mechanism of virus-cell fusion, demonstrating its ability to induce lipid segregation in biomembranes. PMID- 25450812 TI - Type 2 diabetes mellitus: Role of melatonin and oxidative stress. AB - Type 2 diabetes mellitus caused by transfer of susceptible immortal gene from parent to progeny in individuals prone, and/or in contribution of factors such as obesity and physical inactivity results in chronic extracellular hyperglycemia due to insulin resistance or impaired glucose tolerance. Hyperglycemia leads to increased production of superoxide radical in mitochondrial electron transport chain, consequently, inhibit glyceraldehyde-3-phosphate dehydrogenase activity, increase the flux of substrates that direct the expression of genes responsible for activation of polyol, hexosamine, advanced glycation end products and protein kinase-C pathways enzymes. Simultaneously, these pathways add-up free radicals in the body, hamper cell redox state, alter genes of insulin sensitivity and are responsible for the diabetic complications like retinopathy, atherosclerosis, cardiovascular diseases, nephropathy and neuropathy. Experimental evidence suggests that the indoleamine hormone melatonin is capable of influencing in development of diabetic complications by neutralizing the unnecessary production of ROS, protection of beta cells, as they possess low antioxidant potential and normalize redox state in the cell. However, studies reported the beneficial effects of pharmacological supplementation of melatonin in humans but it has not been extensively studied in a multicountric, multicentric which should include all ethnic population. PMID- 25450810 TI - The use of SMALPs as a novel membrane protein scaffold for structure study by negative stain electron microscopy. AB - Despite the great progress recently made in resolving their structures, investigation of the structural biology of membrane proteins still presents major challenges. Even with new technical advances such as lipidic cubic phase crystallisation, obtaining well-ordered crystals remains a significant hurdle in membrane protein X-ray crystallographic studies. As an alternative, electron microscopy has been shown to be capable of resolving >3.5A resolution detail in membrane proteins of modest (~300 kDa) size, without the need for crystals. However, the conventional use of detergents for either approach presents several issues, including the possible effects on structure of removing the proteins from their natural membrane environment. As an alternative, it has recently been demonstrated that membrane proteins can be effectively isolated, in the absence of detergents, using a styrene maleic acid co-polymer (SMA). This approach yields SMA lipid particles (SMALPs) in which the membrane proteins are surrounded by a small disk of lipid bilayer encircled by polymer. Here we use the Escherichia coli secondary transporter AcrB as a model membrane protein to demonstrate how a SMALP scaffold can be used to visualise membrane proteins, embedded in a near native lipid environment, by negative stain electron microscopy, yielding structures at a modest resolution in a short (days) timeframe. Moreover, we show that AcrB within a SMALP scaffold is significantly more active than the equivalent DDM stabilised form. The advantages of SMALP scaffolds within electron microscopy are discussed and we conclude that they may prove to be an important tool in studying membrane protein structure and function. PMID- 25450813 TI - Influence of macrolides, nutritional support and respiratory therapies in diabetes and normal glucose tolerance in cystic fibrosis. A retrospective analysis of a cohort of adult and younger patients. AB - AIM: The development of cystic fibrosis related diabetes is associated with increased morbidity and mortality, worse nutritional status and lung function decline. It is known that patients with cystic fibrosis have a chronic inflammation status and that beta pancreatic cells are very sensitive to oxidative stress. So these inflammatory mediators could contribute to the onset of progressive pancreatic fibrosis and, hence, to impair glucose metabolism. So, it could be hypothesized that the treatment with macrolides would protect and preserve beta-cell function by decreasing pro-inflammatory cytokines and free oxidative radicals. METHODS: We retrospectively analyzed a cohort of 64 patients affected of cystic fibrosis, older than 14 years, by using the first pathological 2-h oral glucose tolerance test; peripheral insulin resistance was calculated using the homeostasis model assessment for insulin resistance (HOMA - IR) and pancreatic beta-cell function was estimated according to Wareham. The influence of macrolides, microbiological colonization, nutritional support and related clinical parameters were analyzed. RESULTS: Comparing CFRD without FPG and NGT, and after adjustment for microbial colonization, the significance of the use of macrolides was lost (p=0.1), as a risk or protective factor for any of the studied groups. Non-significative associations were found in the use of macrolides, inhaled corticosteroids and nutritional support therapies within the different disorders of carbohydrate metabolism. CONCLUSIONS: The anti inflammatory and immunomodulating effect of macrolides did not seem to affect the beta cell function or insulin resistance in patients with cystic fibrosis. The use of inhaled corticosteroids or nutritional supplements have not any influence in the carbohydrate metabolism. Further prospective studies are needed to analyze a potential protective role of macrolides in the development of carbohydrate metabolism alterations in cystic fibrosis. PMID- 25450814 TI - Clinical characteristics and complications of patients with type 2 diabetes attending an urban hospital in Bangladesh. AB - AIMS: To investigate the clinical features of patients with type 2 diabetes on oral medication and determine the complications and risk factors in these patients. METHODS: A cross-sectional was conducted among 515 patients with type 2 diabetes at the outpatient clinics of Bangladesh Institute of Health Science (BIHS) hospital from September to December 2013. We collected data on socio economic characteristics, clinical status, risk factors, complications, anthropometric measurements and blood tests. Univariate and multivariate logistic regression was performed to identify risk factors associated with diabetes complications. RESULTS: The mean(+/-SD) age of the participants was 50.0(+/-10.1) years and 15.3% were less than 40 years. The mean HbA1c was 8.3(+/-2.1). Only 28.7% of the participants achieved targets for HbA1c. The overall prevalence of hypertension, obesity and dyslipidemia was 57.5%, 62.6% and 72.7%, respectively. Eye problems were the most common complication (68.9%) followed by chronic kidney diseases (21.3%) and cardiovascular diseases (11.8%). There were significant associations between the complications and age, duration of diabetes and duration of hypertension. In the multivariate analysis adjusting for other confounding variables, only systolic blood pressure was found to be significantly associated with complications [OR 0.809, 95% CI 0.666-0.981 (p-value 0.031)]. CONCLUSION: Results of the study confirm that even under best clinical settings a great majority Bangladeshi adults with type 2 diabetes have uncontrolled diabetes and a high prevalence of risk factors that might contribute to early development of complications. Early screening of high risk groups and proper management of diabetes is recommended to avoid early complications. PMID- 25450815 TI - Association between insulin resistance and risk of complications in children and adolescents with type 1 diabetes. AB - BACKGROUND: It has been hypothesized that insulin resistance may be involved in the development of type 1 diabetes complications and early diagnosis would be important for their prevention. Our aim was to study insulin resistance in our population of children with type 1 diabetes and to identify associated early risk factors for micro- and macrovascular complications. METHODS: A descriptive, cross sectional study was conducted including 150 children with type 1 diabetes. Anthropometric, bioelectric impedance, carotid Doppler ultrasonography, electromyography, and conduction velocity studies were performed. Baseline plasma glucose, lipid profile, uric acid, plasma thyrotropin, glycosylated hemoglobin A1C, and microalbuminuria were assessed. More insulin-resistant patients were defined as those having an estimated glucose disposal rate (eGDR) value below the first quartile. RESULTS: Clinically manifest microvascular complications were not found in any of the patients. More insulin-resistant patients had a greater sub scapular fold thickness, a higher incidence of obesity (12% vs. 1.7% p 0.007), higher fructosamine levels (496 vs. 403 p<0.00019, and a higher incidence of altered lipid metabolism (70% vs. 39% p 0.0007). CONCLUSION: In the subgroup of patients with lower eGDR there were more children with lipid disorders, obesity, and worse diabetic control, which, if not corrected, may lead to development of micro- and macrovascular complications. PMID- 25450816 TI - Possible resting metabolic rate modification by the circulating RBP4 in obese subjects. AB - AIM: Adipose tissue derived retinol-binding protein 4 (RBP-4), known as one of the most important adipokins, has a link with insulin resistance and metabolic syndrome in obesity. The purpose of this study was to investigate the possible correlation between fasting serum RBP4 and resting metabolic rate (RMR) as a predictor of weight gain, body composition and insulin resistance in obese and non-obese subjects. MATERIALS AND METHODS: In this case-control study, 73 obese and 90 non-obese participants were assessed following an overnight fasting for RMR by means of indirect calorimetry. Body composition was measured using body composition analyzer. Serum RBP4 levels were quantified by ELISA method. RESULTS: Circulating RBP4 level correlated positively with log insulin (r=0.278, p=0.04) in obese subjects. There were no significant correlation between RBP4 and body composition in obese subjects except fat free mass (r=0.42, p=0.001). We found reduced RMR/kg in higher RBP4 concentration, moreover, a negative correlation was found between RBP4 and RMR/kg (r=-0.35, p=0.01) in obese group. Based on ROC analysis and RMR/kg cut-off value (=20 kcal/24 h/kg) for predicting the risk of obesity, 83.3% of participants with RMR/kg<20 kcal/24 h/kg had high RBP4 concentration, however in subjects with RMR/kg>=20 kcal/24 h/kg this percentage was 16.7 (p=0.01). CONCLUSION: Our findings demonstrated that RBP4 concentration had relation with RMR which was different among obese and non-obese groups. These results may suggest the possible role of RBP4 in alteration of metabolic rate through insulin or other metabolic effects. PMID- 25450817 TI - Diabetic retinopathy--biomolecules and multiple pathophysiology. AB - One of the major complications in patients with diabetes is diabetic retinopathy (DR), a leading cause of blindness worldwide. It causes visual impairment and finally blindness, a result of long-term accumulated damage to the small blood vessels in the retina. It takes several years before any clinical symptoms of retinopathy appear in diabetic patients. Consequently, glycemic control, blood pressure and lipid-lowering therapy have all shown benefits in reducing the incidence and progression of DR. A number of hyperglycemia-induced metabolic stresses have been implicated in the pathophysiology of DR. The microvasculature of the retina responds to hyperglycemia through a number of biochemical changes, including the activation of protein kinase C (PKC), increased advanced glycation end-products (AGEs) formation, polyol pathway and oxidative stress. There is an accumulating body of evidence indicating that inflammation and neurodegeneration play an important role in the pathogenesis of DR. PMID- 25450818 TI - Comparative effects of metformin and pioglitazone on fetuin-A and osteoprotegerin concentrations in patients with newly diagnosed diabetes: A randomized clinical trial. AB - AIMS: Fetuin-A is a circulating glycoprotein capable of inhibiting insulin signaling both in vivo and in vitro and is positively associated with insulin resistance. Osteoprotegerin (OPG) acts as a regulatory molecule with increased levels in the early stages of diabetes and atherosclerosis, and is also associated with insulin resistance. We investigated the effects of pioglitazone and metformin as representative insulin-sensitizing therapies on fetuin-A and OPG levels. MATERIALS AND METHODS: In a randomized clinical trial setting (NCT02027103), 88 patients with newly diagnosed type 2 diabetes were randomly assigned to pioglitazone (30 mg/day, n=46) or metformin (1000 mg/day, n=42) for 12 weeks. Various anthropometric and metabolic parameters, fetuin-A, OPG, highly sensitive C-reactive protein (hsCRP), and homeostasis model assessment of insulin resistance (HOMA-IR) were measured at baseline and after three months. RESULTS: The reduction in fasting plasma glucose and haemoglobin A1c levels was comparable in the two arms. Pioglitazone resulted in a significant reduction in both fetuin A and OPG in men, but only fetuin-A in women. Metformin was only effective in lowering OPG levels in women. When compared, both medications were equally effective with regard to fetuin-A and OPG reduction in women (p=0.413 and 0.359, respectively). In men, pioglitazone more effectively decreased fetuin-A levels in both uni- (p=0.011) and multivariate models (p=0.015) and OPG levels in only uni- (p=0.023) but not the multivariate model (p=0.547). CONCLUSIONS: Metformin and pioglitazone differentially affect fetuin-A and osteoprotegrin levels in diabetic women and men. The level of change may not necessarily be associated with the amelioration of insulin resistance. PMID- 25450819 TI - PPAR gamma gene--a review. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) has been the focus of intense research because ligands for this receptor have emerged as potent insulin sensitizers used in the treatment of type 2 diabetes. There have been described three PPAR isotypes alpha, delta and gamma which have an integrated role in controlling the expression of genes playing key roles in the storage and mobilization of lipids, in glucose metabolism, in morphogenesis and inflammatory response. Recent advances include the discovery of novel genes that are regulated by PPARgamma, which helps to explain how activation of this adipocyte predominant transcription factor regulates glucose and lipid homeostasis. Increased levels of circulating free fatty acids and lipid accumulation in non-adipose tissue have been implicated in the development of insulin resistance. This situation is improved by PPARgamma ligands, which promotes fatty acid storage in fat deposits and regulates the expression of adipocyte-secreted hormones that impacts on glucose homeostasis. So the net result of the pleiotropic effects of PPARgamma ligands is improvement of insulin sensitivity. This review highlights the roles that PPAR gamma play in the regulation of gene expression of multiple diseases including obesity, diabetes and cancer and highlights the gene isolation transformation role. Further studies are needed for the transformation of PPAR gamma gene in plants and evaluate in animals for the treatment of type 2 diabetes. PMID- 25450820 TI - Burden of diabetes mellitus attributable to demographic levels in Qatar: an emerging public health problem. AB - BACKGROUND: Diabetes is one of the main contributors to ill health and premature mortality worldwide and its prevalence has been rising during the last decades. AIM: The aim of the present study was to quantify the burden of disease in terms of deaths and loss of healthy life years (DALYs) attributed to diabetes by its demographic levels in the State of Qatar. MATERIALS AND METHODS: The methods were largely based on the established Global Burden of Disease methodology and use the burden of disease in terms of disability adjusted life years (DALYs) and the years lost due to disability (YLD) as the outcome measure. We calculated years lost due to disability (YLD) and years life lost (YLL) attributable to diabetes. The study was conducted during the period from June 2013 to January 2014. RESULTS: The study findings revealed that disability adjusted life years (DALYs) has been increasing across the years and reached to 4.35 in 2011 from 2.58 in 2007. DALYs for men was remarkably higher than women during the period (2007 2011). Diabetes mellitus was the 6th leading cause of disease burden in Qatar (3.8%). The YLD showed a sharp increase in men (2.52 in 2011 from 1.34 in 2007) and women (1.05 in 2011 from 0.33 in 2007) during the year 2011. YLL portion of women enlarged considerably in 2011 (0.10) compared to 2010 (0.04). YLL for men and women was fluctuating across the years with a decrease in 2011 (18%) from 2007 (35%). Men and women in the age group 30-44 years had the highest peak across the years. CONCLUSION: The study findings revealed that diabetes disease burden was considerably high in Qatar, particularly in the working age group. DALYs has been increasing across the years. PMID- 25450821 TI - Comparison of Ramadan-specific education level in patients with diabetes seen at a Primary and a Tertiary care center of Karachi-Pakistan. AB - AIMS: To compare Ramadan-specific education level in fasting patients with diabetes at a Primary and a Tertiary care center. METHODOLOGY: An observational study was conducted in the Outpatient departments of a Primary care center and a Tertiary care center in Karachi-Pakistan. Recruitment of patients started at the end of Ramadan 2011 and continued till three months after Ramadan 2011. All patients with diabetes who observed fast during the month of Ramadan 2011 were included in the study. In Primary care center, patients were attended by physicians only, while at Tertiary care center patients were seen by physicians, diabetes educator and dietician. For data collection, standardized questionnaire based interview was conducted on one to one basis by trained healthcare professionals. Same questionnaire was used at both the centers. RESULTS: A total of 392 and 199 patients with diabetes recruited at Primary and Tertiary care centers, respectively. Ramadan-specific diabetes education received by 213 (55%) and 123 (61.80%) patients with diabetes at Primary and Tertiary care centers, respectively. Compared to Primary care center, patients at Tertiary care centers were more aware about components of Ramadan-specific diabetes education such as signs and symptoms of hypoglycemia and hyperglycemia, dose of medicines/insulin during Ramadan fasting, dose of medicines/insulin when not fasting, self monitoring of blood glucose, dietary modifications, physical activity, adequate nutrition and adequate hydration during Ramadan (p<0.05). CONCLUSION: It was observed that Ramadan-specific education level of patients at Tertiary care center was significantly better compared to patients at Primary care center. PMID- 25450822 TI - Circulatory adipocytokines and lipid profile variations in type-2 diabetic subjects: desirable side-effects of antidiabetic drugs. AB - AIM: Inspite of availability of a variety of drugs to treat type 2 diabetes, little is known about their effects on other systems. Normalization of glucose metabolism by these drugs may consequently affect the secretory function in adipocytes. Secretory adipocytokines like adiponectin and leptin are emerging as novel therapeutic targets for type 2 diabetes mellitus (T2DM). The present study was undertaken to analyze the effects of commonly used Oral Hypoglycemic Agents (OHAs) alone, or in combination with other drugs and/or insulin on circulatory adiponectin and leptin levels, lipid profile, and blood pressure in diabetic subjects. METHODS: The study was undertaken at IRSHA and Bharati Vidyapeeth Medical College and Hospital, MS, India. Clinically diagnosed T2DM subjects and age, gender matched healthy controls were recruited. Fasting blood was collected from each subject and the blood samples were analyzed for circulatory adipocytokines and lipid parameters using commercial kits. RESULTS: Serum adiponectin levels were significantly increased while leptin significantly decreased in diabetic men (p<0.05) and women (p<0.001) on OHA, as compared to healthy controls. Triglyceride levels significantly decreased (p<0.05) in diabetic men, however, they remained unchanged in women despite same drug treatment. Serum HDL and LDL levels (p<0.001) were significantly lower in diabetic women as compared to healthy women. Systolic (p<0.05) and diastolic (p<0.001) blood pressure was significantly high in diabetic men but remained unchanged in women. CONCLUSIONS: Frequently used OHAs significantly improve circulatory levels of adipocytokines. Selecting best treatment option for each patient is a key, and 2012 European Association for the Study of Diabetes (EASD) and ADA guidelines recommend diabetes treatment to be individualized depending on various socioeconomic and lifestyle factors. We recommend regular analysis of circulatory adipocytokines in T2DM patients to help clinicians select the best treatment option to normalize levels of these important therapeutic targets. PMID- 25450823 TI - Relationship between cardio-ankle vascular index and components of metabolic syndrome in combination with sex and age. AB - OBJECTIVE: The relationship between cardio-ankle vascular index (CAVI) and components of metabolic syndrome (MetS), in addition to age and sex as confounders was explored to verify the characteristics of CAVI. METHODS: A cross sectional study was conducted for 144 subjects (108 males and 36 females), aged 31-86 years, who were inhabitants undergoing intensive health checkups. Multiple logistic regression analysis was performed to analyze the association. RESULTS: MetS was present in 36 of 108 males (33%) and 13 of 36 females (36%). Significant association between CAVI>=9 and male subjects or age was recognized. Although five metabolic components did not show any significant association with CAVI>=9, there was a trend of positive association between CAVI and BMI<25 (p=0.060), high blood pressure (p=0.074) or hypertriglyceridemia (p=0.088). CONCLUSION: Male and age were significantly associated with CAVI>=9. Further study is needed to verify the association between CAVI>=9 and MetS components. PMID- 25450824 TI - "Diabetes and gum disease: the diabolic duo". AB - BACKGROUND: Diabetes and periodontitis have long been linked in the dental literature but have never been substantiated. Periodontitis is an oral infection affecting the tooth-supporting tissues. Although the etiology for this condition is bacterial plaque, the host immune response may also mediate destruction of the periodontal tissues. Diabetes mellitus is intricately related to the development, progression and severity of periodontitis. The literature is abundant with studies depicting this association. DISCUSSION: Diabetes mellitus (DM) is a complex disease with varying degrees of systemic and oral complications. The periodontium is also a target for diabetic damage. In recent years, a link between periodontitis and diabetes mellitus has been postulated. The present review highlights the relationship between diabetes mellitus and periodontitis. The potential mechanisms involved in the development of periodontitis in diabetic patients, influence of periodontitis on diabetes and the role of TNF-alpha, a prime inflammatory mediator linking both of them have been discussed. CONCLUSION: Diabetes clearly increases the risk of periodontal diseases, and biologically plausible mechanisms have been demonstrated in abundance. Less clear is the impact of periodontal diseases on glycemic control of diabetes and the mechanisms through which this occurs. It is possible that periodontal diseases may serve as initiators or propagators of insulin resistance in a way similar to obesity, thereby aggravating glycemic control. PMID- 25450826 TI - Signal persistence and amplification in cancer development and possible, related opportunities for novel therapies. AB - Research in cancer biology has been largely driven by experimental approaches whereby discreet inputs are used to assess discreet outputs, for example, gene knockouts to assess cancer occurrence. However, cancer hallmarks are only rarely, if ever, exclusively dependent on discreet regulatory processes. Rather, cancer related regulatory factors affect multiple cancer hallmarks. Thus, novel approaches and paradigms are needed for further advances. Signal pathway persistence and amplification, rather than signal pathway activation resulting from an on/off switch, represent emerging paradigms for cancer research, closely related to developmental regulatory paradigms. In this review, we address both mechanisms and effects of signal pathway persistence and amplification in cancer settings; and address the possibility that hyper-activation of pro-proliferative signal pathways in certain cancer settings could be exploited for therapy. PMID- 25450825 TI - Neuroendocrine differentiation in prostate cancer: novel morphological insights and future therapeutic perspectives. AB - Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that commonly arises in later stages of castration resistant prostate cancer (CRPC) The detection of NEPC has clinical implications as these patients are often treated with platinum chemotherapy rather than with androgen receptor targeted therapies. The poor molecular characterization of NEPC accounts in part for the lack of disease specific therapeutics. Several mechanisms are involved in NE differentiation, including inflammation and autophagy, and may actually represent future therapeutic targets for advanced NEPC patients. Furthermore, a growing body of evidence suggests a potential role of circulating tumor cells in the early diagnosis and treatment of NEPC. Here we summarize the recent findings on NEPC pathogenesis and we discuss the ongoing clinical trials and future perspectives for the treatment of NEPC patients. PMID- 25450828 TI - Chemical characterization and surface properties of a new bioemulsifier produced by Pedobacter sp. strain MCC-Z. AB - A novel biopolymer was described in the form of an extracellular polysaccharide (EPS) by Pedobacter sp. strain MCC-Z, a member of a bacterial genus not previously described as an emulsifier producer. The new biomolecule was extracted, purified and characterized, and its surface and emulsifying properties were evaluated. The purified bioemulsifier, named Pdb-Z, showed high emulsifying activity (E24% = 64%) and reduced the surface tension of water up to 41 mN/m with a critical micelle concentration value of 2.6 mg/mL. The chemical characterization of Pdb-Z was performed using (1)H NMR, FT-IR, HPLC/MS/MS and GC/MS. Pdb-Z was found to contain 67% of carbohydrates, consisting mainly of galactose and minor quantities of talose, 30% of lipids, being pentadecanoic acid the major lipidic constituent, and 3% of proteins. The bioemulsifier was a glycolipids-protein complex with an estimated molecular mass of 10(6)Da. Furthermore, Pdb-Z emulsified pure aliphatic and aromatic hydrocarbons as well as diesel more efficiently than commercial synthetic surfactants, used for comparison. Our results suggest Pdb-Z has interesting properties for applications in remediation of hydrocarbon-contaminated environments and bioremediation processes. PMID- 25450827 TI - Effect of peach gum polysaccharides on quality changes of white shrimp. AB - Peach gum polysaccharides (PGPs) have both antibacterial and antioxidant activities. In this study, the retardation effect of the PGPs on the quality changes of white shrimp (Penaeus vannamei) during refrigerated storage was investigated. Shrimp samples were untreated with different concentrations of the PGPs solution and then they were stored under refrigerated conditions for 10 days. During refrigerated storage, shrimp samples were taken periodically and their total viable count, pH value, total volatile basic nitrogen, and overall acceptability score were evaluated. Compared to the control, treatment of the PGPs solution effectively retarded bacterial growth and pH changes, reduced total volatile basic nitrogen, and increased overall acceptability score of white shrimp (P. vannamei) during refrigerated storage. The results indicate that treatment of PGPs could be a promising means to preserve white shrimp (P. vannamei). PMID- 25450829 TI - The effect of glycerol and 2-propanol on the molecular aggregation of collagen in solution. AB - The molecular aggregation of collagen solution (Col) in the presence of glycerol (Col-G) and 2-propanol (Col-P) was investigated. The transition temperature (Tm) of collagen, determined by ultra-sensitive differential scanning calorimetry, increased proportionally to the concentration of glycerol about 0.929 degrees C per 1M, while Tm decreased proportionally to the concentration of 2-propanol about 1.638 degrees C per 1M. The fluorescence spectra of collagen in solutions were detected by two-dimensional technique on the perturbation of the concentration of glycerol and 2-propanol and showed different results in Col-G and Col-P. The size of collagen aggregates in solutions was observed by dynamic light scattering. Compared with the aggregate size in Col, collagen aggregates became smaller in the presence of glycerol, whereas it grew larger in the presence of 2-propanol. Furthermore, the different extent of aggregation in Col, Col-G and Col-P influenced the self-assembly of collagen molecules under physiological conditions, and there were differences in the resulted fibril structures of Col, Col-G and Col-P after fibrillogenesis as determined by scanning electron microscopy. These results indicated that glycerol inhibited the collagen aggregates while 2-propanol promoted them in solution. PMID- 25450830 TI - Two-step purification procedure for recombinant human asialoerythropoietin expressed in transgenic plants. AB - Asialoerythropoietin (asialo-EPO) is a desialylated form of human glycoprotein hormone erythropoietin (EPO), which has been reported to be neuro-, cardio-, and renoprotective in animal models of organ injuries. Since the current method of production of asialo-EPO from mammalian cell-made recombinant human EPO (rhuEPO(M)) by enzymatic desialylation is not commercially viable, we and others used plant-based expression systems to produce recombinant human asialo-EPO (asialo-rhuEPO(P)). Despite achieving high expression levels in plants, its purification from plant extracts has remained a greater challenge, which has prevented studying its tissue-protective effects and translating it into clinical practice. In this study, a procedure was developed to purify asialo-rhuEPO(P) from transgenic tobacco leaf tissues in two steps: ion-exchange chromatography based on its high pI (8.75) to separate it from acidic plant proteins, and immunoaffinity chromatography to obtain pure asialo-rhuEPO(P). Using this process, up to 31% of the asialo-rhuEPO(P) could be recovered to near homogeneity from plant extracts. This work demonstrates that asialo-rhuEPO(P) expressed in tobacco plants could be purified in high yield and purity using minimal steps, which might be suitable for scale-up. Furthermore, the ion-exchange chromatography step together with the use of protein-specific antibody column could be used to purify a wide variety of basic recombinant proteins from transgenic leaf tissues. PMID- 25450831 TI - Improving the activity and stability of actinidin by immobilization on gold nanorods. AB - Immobilization of actinidin was carried out by ionic exchange and hydrophobic interactions on gold nanorods synthesized via sequential seed-mediated growth method. The optimum temperature of actinidin increased from 40 to 60 degrees C and its optimum pH was shifted from 7 to 8.5 upon immobilization. The kinetic parameters, K(m) and k(cat), were found to be 12.5 MUM and 29.2 s(-1) for free and 15.92 MUM and 20.74 s(-1) for immobilized actinidin, respectively. Immobilization process caused significant enhancement of shelf-life stability and resistance against the inhibitory effects of various bivalent metal ions with respect to actinidin. Enzymes show higher functionality than the free form when incubated for long time (1h) at 80 degrees C and at extreme pH values (3 and 12). The reasons of this enhanced stability of immobilized actinidin are discussed. PMID- 25450832 TI - Nanoparticle and polysaccharide conjugate: a potential candidate vaccine to improve immunological stimuli. AB - Active polysaccharides isolated from various fungal sources have been implicated to stimulate immune response against various pathogens as well as self anomalies such as cancer. Therefore, the nuanced approach presented in our work was to blend polysaccharides derived from Pleurotus ostreatus with biocompatible ferrite nanoparticles and thereafter investigate the enhanced immune functionality of the polysaccharide-nanoparticle composite. A Schiff base reductive amination reaction occurred between the aldehyde group of the polysaccharide and the amine group of the nanoparticles in the presence of a strong reducing agent such as sodium cyanoborohydride to form a stable amide bond between the two conjugating molecules. The multifaceted conjugate was characterized by physiochemical techniques such as electron microscopy, FTIR, VSM and DLS measurements. This particulate form of the polysaccharide showed a marked escalation in the production of free radicals such as reactive oxygen and nitrogen species in murine macrophages as compared to the soluble form. Animal based experiments demonstrated a reduction in tumor volume and augmentation in the proliferation of splenocytes in particulate or conjugated polysaccharide treated mice. Furthermore, molecular signaling studies showed a high upregulation in p-p38 and p-MEK molecules in particulate polysaccharide treated RAW264.7 cells suggesting a cellular downstream mechanistic regulation behind the immunostimulative response. PMID- 25450833 TI - Conformational variability of goat beta-lactoglobulin: crystallographic and thermodynamic studies. AB - Goat beta-lactoglobulin (GLG), lipocalin protein sharing high sequence similarity to bovine beta-lactoglobulin (BLG), has been structurally and thermodynamically characterized. Two crystal forms of GLG have been obtained, trigonal (P3121) and orthorhombic (P21212), with unique molecular packing, not observed previously for BLG. In the trigonal structure, GLG molecules have EF-loop in closed conformation while in the orthorhombic structure, for the first time, symmetric and asymmetric dimers of beta-lactoglobulin are observed simultaneously. It indicates that the opening or closing EF-loop does not occur in both subunits at the same time but might be sequential and cooperative. Comparison of GLG and BLG structures revealed presence of various conformers of EF and GH. ITC studies showed that at pH 7.5 GLG binds sodium dodecyl sulfate with Gibbs energy similar to BLG, however, with different contribution from enthalpic and entropic component. At pH 7.5 GLG forms dimers with dimerization constant Ka = 34.28 * 10(3) M(-1), significantly higher than observed for BLG. Similar mechanism of conformational changes and ligand binding indicates that GLG and BLG may play analogous biological role. PMID- 25450834 TI - A new method for polyhydroxyalkanoate (PHA) accumulating bacteria selection under physical selective pressure. AB - An aerobic dynamic discharge (ADD) process involving physical selective pressure to favor the accumulation of polyhydroxyalkanoates (PHAs) accumulating bacteria in microbial mixed cultures (MMCs) is proposed and evaluated in this study. Sequencing batch reactor PHA production in the ADD mode was compared to the conventional aerobic dynamic feeding (ADF) mode. Results showed that the cultures selected under the ADD mode showed a better PHA producing potential than ADF mode cultures in terms of both maximum PHA content and selection time, explained by altered physical selective pressure. The maximum PHA content of 74.16 (+/- 0.03)% and PHA yield of 0.72 (+/- 0.07) C mol PHA/C mol Ac were achieved after 30 days of the ADD operation, which were much higher than those obtained under the same organic loading rate in the ADF operation. The ADD mode is a promising method for quick selection of a strong-PHA accumulating culture. PMID- 25450835 TI - Safety evaluation of chitosan and chitosan acid salts from Panurilus argus lobster. AB - Chitosan is a natural polymer with excellent properties such as biocompatibility, biodegradability, non-toxicity and adsorptive abilities. We obtained chitosan derived from Panurilus argus lobster shell and its lactate and acetate salts to introduce in pharmaceutical industry. We examined the single and repeated dose toxicity of chitosan and its lactate and acetate salts. Single oral doses of 2000 mg/kg were well tolerated for all three materials. In the repeat dose tests, animals treated with chitosan only show a slight erythrocytes increase. Variations in erythrocyte and leukocyte count and some biochemical parameters were observed in animals treated with chitosan acid salts. One g/kg orally was found to be the subacute NOAEL for chitosan due to the hematological findings observed were not considered adverse. Chitosans obtained from Panurilus argus lobster shell have low toxicity and may be safe in rats because it did not cause any lethality or changes in the general behavior in both the single and repeated dose toxicity studies. PMID- 25450836 TI - Green synthesis of silver nanoparticles and their application to cotton fabrics. AB - Herein we present a green synthesis of silver nanoparticles (AgNPs) under the reducing action of sugar and the stabilizing action of polyethylene glycol (PEG). Factors affecting the synthesis notably molecular weight of PEG and concentrations of both sugar and silver nitrate were examined for the sake of optimization. Thus obtained AgNPs were characterized, by ultraviolet-visible (UV vis) spectra for estimation of AgNPs formation and, Transmission electron microscopy (TEM) for determination of size and shape. AgNPs were applied with 1,2,3,4-butane tetracarboxylic acid (BTCA) and sodium hypophosphite (SHP) as a catalyst to cotton fabric. Application was performed according to the conventional pad-dry-cure technique. The treated fabrics were evaluated via monitoring morphological changes of the fibers using scanning electron microscopy (SEM), tensile strength and crease recovery angles in addition to bioassay of antimicrobial activity of the treated fabrics. Research output disclosed that PEG having molecular weight 2000 is the best among the other PEG used. PMID- 25450837 TI - Epsilon-poly-L-lysine guided improving pulmonary delivery of supramolecular self assembled insulin nanospheres. AB - This work presents new spherical nanoparticles that are fabricated from supramolecular self-assembly of therapeutic proteins for inhalation treatment. The formation involved self-assembly of insulin into nanospheres (INS) by a novel thermal induced phase separation method. Surface functional modification of INS with E-poly-L-lysine (EPL), a homopolymerized cationic peptide, was followed to form a core-shell structure (INS@EPL). Both INS and INS@EPL were characterized as spherical particles with mean diameter size of 150-250 nm. The process of transient thermal treatment did not change their biological potency retention significantly. FTIR and CD characterizations indicated that their secondary structures and biological potencies were not changed significantly after self assembly. The in vivo investigation after pulmonary administration, including lung deposition, alveoli distribution, pharmacological effects and serum pharmacokinetics were investigated. Compared to that of INS, intratracheal administration of INS@EPL offered a pronounced and prolonged lung distribution, as well as pharmacological effects which were indicated by the 23.4% vs 11.7% of relative bioavailability. Accordingly, the work described here demonstrates the possibility of spherical supramolecular self-assembly of therapeutic proteins in nano-scale for pulmonary delivery application. PMID- 25450838 TI - Characterization of an anesthetized dog model of transient cardiac ischemia and rapid pacing: a pilot study for preclinical assessment of the potential for proarrhythmic risk of novel drug candidates. AB - INTRODUCTION: Preclinical proarrhythmic risk assessment of drug candidates is focused predominantly on arrhythmias arising from repolarization abnormalities. However, drug-induced cardiac conduction slowing is associated with significant risk of life-threatening ventricular arrhythmias, particularly in a setting of cardiac ischemia. Therefore, we optimized and characterized an anesthetized dog model to evaluate the potential proarrhythmic risk of drug candidates in ischemic heart disease patients. METHODS: Anesthetized dogs were instrumented with atrial and ventricular epicardial electrodes for pacing and measurement of conduction times, and a balloon occluder and flow probe placed around the left anterior descending coronary artery (LAD) distal to the first branch. Conduction times, ECG intervals and incidence of arrhythmias were assessed serially at the end of each dose infusion (flecainide: 0.32, 0.63, 1.25, 2.5 and 5mg/kg, i.v.; dofetilide:1.25, 2.5, 5, 10 and 20 MUg/kg, i.v.; or vehicle; n=6/group) both during normal flow (with and without rapid pacing) and during 5-min LAD occlusion (with and without rapid pacing). Compound X, a development candidate with mild conduction slowing activity, was also evaluated. RESULTS: Flecainide produced pronounced, dose-dependent slowing of conduction that was exacerbated during ischemia and rapid pacing. In addition, ventricular tachycardia (VT) and fibrillation (VF) occurred in 4 of 6 dogs (3 VF @ 0.63 mg/kg; 1VT @ 2.5mg/kg). In contrast, no animals in the vehicle group developed arrhythmias. Dofetilide, a potent IKr blocker that does not slow conduction, prolonged QT interval but did not cause further conduction slowing during ischemia with or without pacing and there were no arrhythmias. Compound X, like flecainide, produced marked conduction slowing and arrhythmias (VT, VF) during ischemia and pacing. DISCUSSION: This model may be useful to more accurately define shifts in safety margins in a setting of ischemia and increased cardiac demand for drugs that slow conduction. PMID- 25450839 TI - Optimization of a flow cytometric assay to evaluate the human neutrophil ability to phagocytose immune complexes via Fcgamma and complement receptors. AB - INTRODUCTION: This study aims to optimize some experimental conditions of a flow cytometric assay to examine the human neutrophil ability to phagocytose immune complexes (ICs) via Fcgamma and complement receptors (FcgammaR and CR, respectively). The parameters assessed were: number of cells, concentration of ICs, reaction time, pH and concentration of the Trypan Blue quenching solution. METHODS: Neutrophils were isolated from peripheral blood of healthy volunteers. Precipitated ICs composed of IgG and fluorescein isothiocyanate (FITC)-labeled ovalbumin, opsonized or not with serum complement, were used to trigger the neutrophil phagocytosis via FcgammaR, CR, and FcgammaR+CR. Fluorescence of the internalized ICs was measured by flow cytometry, after quenching the extracellular fluorescence with Trypan Blue. RESULTS: The optimal experimental conditions established for the phagocytosis assay were: 1 * 10(6) cells mL(-1) and 40 MUg mL(-1) FITC-labeled ICs, incubated for 30 min, at 37 degrees C, in 0.5 mL of reaction volume. Trypan Blue solution at 1.25 mg mL(-1) pH4.4 was the best fluorescence quencher of FITC-labeled ICs attached to the outer surface of neutrophils. DISCUSSION: The selected experimental conditions were viable to evaluate IC phagocytosis by neutrophils; they are also suitable to compare the efficiency of IC phagocytosis mediated by FcgammaR and CR classes of membrane receptors, alone or in combination. This method finds application in studies of (i) the receptor-specific phagocytic function of normal and pathogenic neutrophils as well as (ii) the impact of drugs and therapies on this essential effector function of neutrophils. PMID- 25450840 TI - Hepatosplenic T-cell lymphoma: A case series. AB - Hepatosplenic T-cell lymphoma (HSTCL) is a rare type of Non-Hodgkin Lymphoma (NHL), grouped under the mature or peripheral T-cell lymphomas. It is characterised by extranodal infiltration and proliferation of malignant T-cells within the sinusoids of the liver, sinuses and red pulp of the spleen, and the bone marrow. The tumour cells express CD2 and CD3, but are CD4, CD5 and CD8 negative and express a clonally restricted gamma-delta (or less commonly alpha beta) T-cell receptor. The disease has an aggressive clinical course associated with a poor prognosis. We highlight and report three patients from South Africa with HSTCL, all of whom had hepatosplenomegaly and cytopaenias, and despite being HIV seronegative and immunocompetent, had a poor outcome, with a mean survival of 7.5 months in the two evaluable patients. This rare entity has not previously been reported from South Africa and as yet needs to be adequately characterised in a population where lymphoma is the most common haematological malignancy in adults, and where approximately two thirds of the adult lymphoma population are HIV seropositive. PMID- 25450841 TI - Increasing proteome coverage for gel-based human tear proteome maps: towards a more comprehensive profiling. AB - In situations where the molecular mechanism of many ocular disorders is unknown, owing to the difficulties associated with sampling from ocular tissues, human tear film can be a promising medium in ophthalmic research. The present study demonstrates an in-depth gel-based proteome optimization survey to approach more appropriate and efficient systems in various situations such as normal and dry eye syndromes. Therefore, systematic and statistical evaluations were performed on different preparation methods, including acetone, acetone-methanol, chloroform methanol-water, trichloroacetic acid (TCA)-acetone, tri-n-butylphosphate-acetone methanol precipitations and ammonium sulfate fractionation at three different percentages of saturations (50, 70 and 90%). Methods were compared quantitatively on both one- and two-dimensional patterns. Some important parameters such as total protein recovery yield, densitometric analysis of some protein contaminants, banding patterns and total spot numbers along with statistical models for proper clustering were considered. Findings revealed noticeable impacts of preparation methods on all aspects of gel-based separations as well as recovery yield (ranging from 5.29 +/- 0.96 to 22.56 +/- 1.77 ug/mm) and banding and pattern resolution. In addition to all these, the most important point is that the total protein spot number on the final two-dimensional patterns (varied from 528.00 +/- 19.00 to 657.00 +/- 21.52 for different methods) were also noticeably increased in comparison with previously published reports (maximum of 250 spots), which is essential for a more comprehensive analysis. Increasing the proteome coverage in the present study is supposed to originate from improved solubility and effective rehydration during the sample application and isoelectric focusing (IEF) procedure along with proper sample preparation. PMID- 25450842 TI - Utility of T2 mapping and dGEMRIC for evaluation of cartilage repair after allograft chondrocyte implantation in a rabbit model. AB - OBJECTIVE: To investigate the effectiveness of quantitative Magnetic resonance imaging (MRI) for evaluating the quality of cartilage repair over time following allograft chondrocyte implantation using a three-dimensional scaffold for osteochondral lesions. DESIGN: Thirty knees from 15 rabbits were analyzed. An osteochondral defect (diameter, 4 mm; depth, 1 mm) was created on the patellar groove of the femur in both legs. The defects were filled with a chondrocyte seeded scaffold in the right knee and an empty scaffold in the left knee. Five rabbits each were euthanized at 4, 8, and 12 weeks and their knees were examined via macroscopic inspection, histological and biochemical analysis, and quantitative MRI (T2 mapping and dGEMRIC) to assess the state of tissue repair following allograft chondrocyte implantation with a three-dimensional scaffold for osteochondral lesions. RESULTS: Comparatively good regenerative cartilage was observed both macroscopically and histologically. In both chondrocyte-seeded and control knees, the T2 values of repair tissues were highest at 4 weeks and showed a tendency to decrease with time. DeltaR1 values of dGEMRIC also tended to decrease with time in both groups, and the mean DeltaR1 was significantly lower in the CS-scaffold group than in the control group at all time points. DeltaR1 = 1/r (R1post - R1pre), where r is the relaxivity of Gd-DTPA(2-), R1 = 1/T1 (longitudinal relaxation time). CONCLUSION: T2 mapping and dGEMRIC were both effective for evaluating tissue repair after allograft chondrocyte implantation. DeltaR1 values of dGEMRIC represented good correlation with histologically and biochemically even at early stages after the implantation. PMID- 25450843 TI - Changes of knee joint and ankle joint orientations after high tibial osteotomy. AB - OBJECTIVE: We sought to determine (1) whether change in the tibial plateau inclination (TPI) after high tibial osteotomy (HTO) is different from change in the knee joint line orientation (KJLO) relative to the ground; (2) whether, in varus knee OA patients before and after HTO, these radiographic measures are different from those in normal control; and (3) whether the postoperative values of the TPI and KJLO relative to the ground are associated with short term clinical outcome scores after HTO. DESIGN: Fifty patients who underwent HTO and 75 normal controls were assessed with four radiographic measures. We compared the measures before HTO with those after HTO and with those of the normal controls, then examined associations between the postoperative radiographic measures and clinical outcome scores 1-year after HTO. RESULTS: After HTO, TPI increased 9.0 degrees , whereas KJLO relative to the ground only increased 4.1 degrees , with a compensatory change of the ankle joint line orientation. However, the postoperative KJLO relative to the ground in the HTO group was significantly different from that of the normal controls (mean difference, 4.9 degrees ; P < 0.001). In the multiple regression analyses, the postoperative radiographic measures were not associated with outcome clinical scores 1 year after HTO. CONCLUSION: After HTO the relative KJLO changed significantly less than did the anatomical geometry of the proximal tibia. Although the KJLO after the HTO was still significantly different from that of normal knees, its value did not adversely affect clinical outcome scores 1 year after HTO. PMID- 25450844 TI - The rate of hypo-osmotic challenge influences regulatory volume decrease (RVD) and mechanical properties of articular chondrocytes. AB - OBJECTIVES: Osteoarthritis (OA) is associated with a gradual reduction in the interstitial osmotic pressure within articular cartilage. The aim of this study was to compare the effects of sudden and gradual hypo-osmotic challenge on chondrocyte morphology and biomechanics. METHODS: Bovine articular chondrocytes were exposed to a reduction in extracellular osmolality from 327 to 153 mOsmol/kg applied either suddenly (<5 s) or gradually (over 180 min). Temporal changes in cell diameter and the existence of regulatory volume decrease (RVD) were quantified along with changes in cortical actin and chromatin condensation. The cellular viscoelastic mechanical properties were determined by micropipette aspiration. RESULTS: In response to a sudden hypo-osmotic stress, 66% of chondrocytes exhibited an increase in diameter followed by RVD, whilst 25% showed no RVD. By contrast, cells exposed to gradual hypo-osmotic stress exhibited reduced cell swelling without subsequent RVD. There was an increase in the equilibrium modulus for cells exposed to sudden hypo-osmotic stress. However, gradual hypo-osmotic challenge had no effect on cell mechanical properties. This cell stiffening response to sudden hypo-osmotic challenge was abolished when actin organization was disrupted with cytochalasin D or RVD inhibited with REV5901. Both sudden and gradual hypo-osmotic challenge reduced cortical F-actin distribution and caused chromatin decondensation. CONCLUSIONS: Sudden hypo osmotic challenge increases chondrocyte mechanics by activation of RVD and interaction with the actin cytoskeleton. Moreover, the rate of hypo-osmotic challenge is shown to have a profound effect on chondrocyte morphology and biomechanics. This important phenomenon needs to be considered when studying the response of chondrocytes to pathological hypo-osmotic stress. PMID- 25450845 TI - Paper validates previous registry unicompartmental knee analyses. PMID- 25450849 TI - Response to Letter to the editor: 'Paper validates previous registry unicompartmental knee analyses'. PMID- 25450848 TI - Association between body mass index and risk of total knee replacement, the Singapore Chinese Health Study. AB - PURPOSE: Data on the association between body mass index (BMI) and risk of knee osteoarthritis (KOA) are sparse for Asian populations who are leaner than Western populations. We evaluated the association between BMI and risk of total knee replacement (TKR) due to severe KOA among Chinese in Singapore. METHODS: We used data from the Singapore Chinese Health Study (SCHS), a population-based prospective cohort of 63,257 Chinese men and women, aged 45-74 years at enrollment from 1993 to 1998. Information on height, weight, diet and lifestyle factors were obtained via in-person interviews. TKR cases for severe KOA were identified via linkage with the nationwide hospital discharge database through 2011. Cox regression and weighted least squares regression were used in the analysis. RESULTS: The mean BMI among cohort participants was 23.1 kg/m(2), and more than two-thirds had BMI below 25 kg/m(2). A total of 1649 had TKR attributable to severe KOA. Risk of TKR increased in a strong dose-dependent manner with increasing BMI throughout the 15-32 kg/m(2) range and became less clear at BMI >32 kg/m(2). In the BMI range 16-27 kg/m(2), there was a 27% increase in TKR risk for each unit increase in BMI (P for trend < 0.001). Compared to BMI 19-20 kg/m(2), the risk estimates of TKR were all statistically significant with increasing unit of BMI >=21 kg/m(2). Results were similar for men and women. CONCLUSION: Our results provided evidence for a constant mechanical mechanism underlying BMI and KOA initiation and/or progression. PMID- 25450847 TI - Effects of total and regional fat loss on plasma CRP and IL-6 in overweight and obese, older adults with knee osteoarthritis. AB - OBJECTIVE: To describe associations between total and regional body fat mass loss and reduction of systemic levels of inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6)) in obese, older adults with osteoarthritis (OA), undergoing intentional weight loss. DESIGN: Data come from a single-blind, 18-month, randomized controlled trial in adults (age: 65.6 +/- 6.2; Body mass index (BMI): 33.6 +/- 3.7) with knee OA. Participants were randomized to diet-induced weight loss plus exercise (D + E; n = 150), diet-induced weight loss-only (D; n = 149), or exercise-only (E; n = 151). Total body and region-specific (abdomen and thigh) fat mass were measured at baseline and 18 months. High-sensitivity CRP and IL-6 were measured at baseline, six and 18 months. Intervention effects were assessed using mixed models and associations between inflammation and adiposity were compared using logistic and mixed linear regression models. RESULTS: Intentional total body fat mass reduction was associated with significant reductions in log adjusted CRP (beta = 0.06 (95% CI = 0.04, 0.08) mg/L) and IL-6 (beta = 0.02 (95% CI = 0.01, 0.04) pg/mL). Loss of abdominal fat volume was also associated with reduced inflammation, independent of total body fat mass; although models containing measures of total adiposity yielded the best fit. The odds of achieving clinically desirable levels of CRP (<3.0 mg/L) and IL-6 (<2.5 pg/mL) were 3.8 (95% CI = 1.6, 8.9) and 2.2 (95% CI = 1.1, 4.6), respectively, with 5% total weight and fat mass loss. CONCLUSIONS: Achievement of clinically desirable levels of CRP and IL-6 more than double with intentional 5% loss of total body weight and fat mass. Global, rather than regional, measures of adiposity are better predictors of change in inflammatory burden. CLINICAL TRIAL REGISTRATION NUMBER: NCT00381290. PMID- 25450850 TI - Cartilage thickness at the posterior medial femoral condyle is increased in femorotibial knee osteoarthritis: a cross-sectional CT arthrography study (Part 2). AB - OBJECTIVE: To evaluate the thickness of cartilage at the posterior aspect of the medial and lateral condyle in Osteoarthritis (OA) knees compared to non-OA knees using computed tomography arthrography (CTA). DESIGN: 535 consecutive knee CTAs (mean patient age = 48.7 +/- 16.0; 286 males), were retrospectively analyzed. Knees were radiographically classified into OA or non-OA knees according to a modified Kellgren/Lawrence (K/L) grading scheme. Cartilage thickness at the posterior aspect of the medial and lateral femoral condyles was measured on sagittal reformations, and compared between matched OA and non-OA knees in the whole sample population and in subgroups defined by gender and age. RESULTS: The cartilage of the posterior aspect of medial condyle was statistically significantly thicker in OA knees (2.43 mm (95% confidence interval (CI) = 2.36, 2.51)) compared to non-OA knees (2.13 mm (95%CI = 2.02, 2.17)) in the entire sample population (P < 0.001), as well as for all subgroups of patients over 40 years old (all P <= 0.01), except for females above 60 years old (P = 0.07). Increase in cartilage thickness at the posterior aspect of the medial condyle was associated with increasing K/L grade in the entire sample population, as well as for males and females separately (regression coefficient = 0.10-0.12, all P < 0.001). For the lateral condyle, there was no statistically significant association between cartilage thickness and OA (either presence of OA or K/L grade). CONCLUSIONS: Cartilage thickness at the non-weight-bearing posterior aspect of the medial condyle, but not of the lateral condyle, was increased in OA knees compared to non-OA knees. Furthermore, cartilage thickness at the posterior aspect of the medial condyle increased with increasing K/L grade. PMID- 25450846 TI - Cell-based articular cartilage repair: the link between development and regeneration. AB - Clinical efforts to repair damaged articular cartilage (AC) currently face major obstacles due to limited intrinsic repair capacity of the tissue and unsuccessful biological interventions. This highlights a need for better therapeutic strategies. This review summarizes the recent advances in the field of cell-based AC repair. In both animals and humans, AC defects that penetrate into the subchondral bone marrow are mainly filled with fibrocartilaginous tissue through the differentiation of bone marrow mesenchymal stem cells (MSCs), followed by degeneration of repaired cartilage and osteoarthritis (OA). Cell therapy and tissue engineering techniques using culture-expanded chondrocytes, bone marrow MSCs, or pluripotent stem cells with chondroinductive growth factors may generate cartilaginous tissue in AC defects but do not form hyaline cartilage-based articular surface because repair cells often lose chondrogenic activity or result in chondrocyte hypertrophy. The new evidence that AC and synovium develop from the same pool of precursors with similar gene profiles and that synovium-derived chondrocytes have stable chondrogenic activity has promoted use of synovium as a new cell source for AC repair. The recent finding that NFAT1 and NFAT2 transcription factors (TFs) inhibit chondrocyte hypertrophy and maintain metabolic balance in AC is a significant advance in the field of AC repair. The use of synovial MSCs and discovery of upstream transcriptional regulators that help maintain the AC phenotype have opened new avenues to improve the outcome of AC regeneration. PMID- 25450851 TI - Anatomical distribution of areas of preserved cartilage in advanced femorotibial osteoarthritis using CT arthrography (Part 1). AB - OBJECTIVE: To determine subregions of normal and abnormal cartilage in advanced stages of femorotibial osteoarthritis (OA) by mapping the entire femorotibial joint in a cohort of pre-total knee replacement (TKR) OA knees. DESIGN: We defined an areal subdivision of the femorotibial articular cartilage surface on CT arthrography (CTA), allowing the division of the femorotibial articular surface into multiple (up to n = 204 per knee) subregions and the comparison of the same areas between different knees. Two readers independently classified each cartilage area as normal, abnormal or non-assessable in 41 consecutive pre-TKR OA knees. RESULTS: A total of 6447 cartilage areas (from 41 knees) were considered assessable by both readers. The average proportion of preserved cartilage was lower in the medial femorotibial joint than in the lateral femorotibial joint for both readers (32.0/69.8% and 33.9/68.5% (medial/lateral) for reader 1 and 2 respectively, all P < 0.001). High frequencies of normal cartilage were observed at the posterior aspect of the medial condyle (up to 89%), and the anterior aspect of the lateral femorotibial compartment (up to 100%). The posterior aspect of the medial condyle was the area that most frequently exhibited preserved cartilage in the medial femorotibial joint, contrasting with the high frequency of cartilage lesions in the rest of that compartment. CONCLUSIONS: Cartilage at the posterior aspect of the medial condyle, and at the anterior aspect of the lateral femorotibial compartment, may be frequently preserved in advanced grades of OA. PMID- 25450853 TI - Knee extensor muscle weakness is a risk factor for development of knee osteoarthritis. A systematic review and meta-analysis. AB - The objective of this study was to perform a systematic review and meta-analysis on the association between knee extensor muscle weakness and the risk of developing knee osteoarthritis. A systematic review and meta-analysis was conducted with literature searches in Medline, SPORTDiscus, EMBASE, CINAHL, and AMED. Eligible studies had to include participants with no radiographic or symptomatic knee osteoarthritis at baseline; have a follow-up time of a minimum of 2 years, and include a measure of knee extensor muscle strength. Hierarchies for extracting data on knee osteoarthritis and knee extensor muscle strength were defined prior to data extraction. Meta-analysis was applied on the basis of the odds ratios (ORs) of developing symptomatic knee osteoarthritis or radiographic knee osteoarthritis in subjects with knee extensor muscle weakness. ORs for knee osteoarthritis and 95% confidence intervals (CI) were estimated and combined using a random effects model. Twelve studies were eligible for inclusion in the meta-analysis after the initial searches. Five cohort studies with a follow-up time between 2.5 and 14 years, and a total number of 5707 participants (3553 males and 2154 females), were finally included. The meta-analysis showed an overall increased risk of developing symptomatic knee osteoarthritis in participants with knee extensor muscle weakness (OR 1.65 95% CI 1.23, 2.21; I(2) = 50.5%). This systematic review and meta-analysis showed that knee extensor muscle weakness was associated with an increased risk of developing knee osteoarthritis in both men and women. PMID- 25450852 TI - Demographic and clinical factors associated with radiographic severity of first metatarsophalangeal joint osteoarthritis: cross-sectional findings from the Clinical Assessment Study of the Foot. AB - OBJECTIVE: To explore demographic and clinical factors associated with radiographic severity of first metatarsophalangeal joint osteoarthritis (OA) (First MTPJ OA). DESIGN: Adults aged >=50 years registered with four general practices were mailed a Health Survey. Responders reporting foot pain within the last 12 months were invited to undergo a clinical assessment and weight-bearing dorso-plantar and lateral radiographs of both feet. Radiographic first MTPJ OA in the most severely affected foot was graded into four categories using a validated atlas. Differences in selected demographic and clinical factors were explored across the four radiographic severity subgroups using analysis of variance (ANOVA) and ordinal regression. RESULTS: Clinical and radiographic data were available from 517 participants, categorised as having no (n = 105), mild (n = 228), moderate (n = 122) or severe (n = 62) first MTPJ OA. Increased radiographic severity was associated with older age and lower educational attainment. After adjusting for age, increased radiographic first MTPJ OA severity was significantly associated with an increased prevalence of dorsal hallux and first MTPJ pain, hallux valgus, first interphalangeal joint (IPJ) hyperextension, keratotic lesions on the dorsal aspect of the hallux and first MTPJ, decreased first MTPJ dorsiflexion, ankle/subtalar joint eversion and ankle joint dorsiflexion range of motion, and a trend towards a more pronated foot posture. CONCLUSIONS: This cross-sectional study has identified several dose-response associations between radiographic severity of first MTPJ OA and a range of demographic and clinical factors. These findings highlight the progressive nature of first MTPJ OA and provide insights into the spectrum of presentation of the condition in clinical practice. PMID- 25450854 TI - Loss of Frzb and Sfrp1 differentially affects joint homeostasis in instability induced osteoarthritis. AB - OBJECTIVE: To investigate the specific role of Frizzled-related protein (FRZB) and Secreted frizzled-related protein 1 (SFRP1) in the onset and progression of Osteoarthritis (OA) using Frzb(-/-) and Sfrp1(-/-) mice in the destabilization of medial meniscus model (DMM), a slowly progressing model of OA. Secreted frizzled related proteins (SFRPs) were identified as secreted Wingless-type (Wnt) antagonists. The Wnt signaling cascade is a major regulator in cartilage development, homeostasis and degeneration. METHODS: The DMM model was surgically induced in eight-week-old male C57/Bl6 Frzb(-/-), Sfrp1(-/-) or wild-type mice by transection of the medial meniscotibial ligament. Cartilage damage in the femoral and tibial articular surfaces was calculated following the Osteoarthritis Research Society International (OARSI) histopathology initiative guidelines. Histomorphometry was used to evaluate the subchondral bone plate thickness. RESULTS: OA severity scores were significantly higher in the tibia of Frzb(-/-) mice as compared to littermates, whereas no interaction was seen between genotype and intervention in Sfrp1(-/-) mice. Moreover, the DMM model resulted in significantly greater subchondral bone changes compared to sham but was not different between Frzb(-/-) mice and littermates. In contrast, the subchondral bone properties in Sfrp1(-/-) mice were significantly different from littermates. CONCLUSION: Using the DMM model, we demonstrated that FRZB and SFRP1 differentially modulate joint homeostasis in two distinct compartments of the joint. These data highlight the fine-tuning of Wnt signaling in joint homeostasis and disease, show differential regulation of the cascade in cartilage and subchondral bone, and provide further evidence for a role of endogenous Wnt modulators as key players in OA. PMID- 25450856 TI - A case of atypical teratoid/rhabdoid tumor in the internal auditory canal. AB - OBJECTIVE: The case of a thirteen-year-old woman showing an atypical teratoid/rhabdoid tumor (AT/RT) primarily occurred in the internal auditory canal was presented. RESULTS: There was a delay in diagnosing AT/RT because of the first histological diagnosis of benign neurofibroma. If we had changed the surgical approach to one which was middle cranial fossa-based or translabyrinthine in the second or third operation, we might have reached an earlier final diagnosis. Although we faced a dilemma about whether to sacrifice facial nerve function for dissection of the tumor, we should have considered the possibility of malignancy at an earlier stage. CONCLUSION: This is a case report of AT/RT in the internal auditory canal presenting with progressive hearing loss as the initial symptom. Although no previous reports of AT/RT primarily occurring in the internal auditory canal are existent, this rare form of the disease should be considered in future evaluations as a differential diagnosis for internal auditory canal tumor. PMID- 25450855 TI - Effects of insulin-like growth factor-1 and dexamethasone on cytokine-challenged cartilage: relevance to post-traumatic osteoarthritis. AB - OBJECTIVE: Interleukin-1 is one of the inflammatory cytokines elevated after traumatic joint injury that plays a critical role in mediating cartilage tissue degradation, suppressing matrix biosynthesis, and inducing chondrocyte apoptosis, events associated with progression to post-traumatic osteoarthritis (PTOA). We studied the combined use of insulin-like growth factor-1 (IGF-1) and dexamethasone (Dex) to block these multiple degradative effects of cytokine challenge to articular cartilage. METHODS: Young bovine and adult human articular cartilage explants were treated with IL-1alpha in the presence or absence of IGF 1, Dex, or their combination. Loss of sulfated glycosaminoglycans (sGAG) and collagen were evaluated by the DMMB and hydroxyproline assays, respectively. Matrix biosynthesis was measured via radiolabel incorporation, chondrocyte gene expression by qRT-PCR, and cell viability by fluorescence staining. RESULTS: In young bovine cartilage, the combination of IGF-1 and Dex significantly inhibited the loss of sGAG and collagen, rescued the suppression of matrix biosynthesis, and inhibited the loss of chondrocyte viability caused by IL-1alpha treatment. In adult human cartilage, only IGF-1 rescued matrix biosynthesis and only Dex inhibited sGAG loss and improved cell viability. Thus, the combination of IGF-1 + Dex together showed combined beneficial effects in human cartilage. CONCLUSIONS: Our findings suggest that the combination of IGF-1 and Dex has greater beneficial effects than either molecule alone in preventing cytokine-mediated cartilage degradation in adult human and young bovine cartilage. Our results support the use of such a combined approach as a potential treatment relevant to early cartilage degradative changes associated with joint injury. PMID- 25450858 TI - Chemically and electrochemically triggered assembly of viologen radicals: towards multiaddressable molecular switches. AB - We have established that bipyridinium radicals can be reversibly pi-dimerized under the combined effects of chemical (proton transfer) and electrochemical (electron transfer) stimuli. Our investigations also led to the discovery that a bis-pyridinyl appended calixarene intermediate is involved in a fully reversible redox-triggered sigma-dimerization process. The structure of the most stable intramolecular sigma-dimer was provided by computational chemistry and its complete conversion into a noncovalent pi-dimer could be triggered chemically by addition of protons, leading to the formation of protonated cation radicals. Theoretical data collected with the N-methylated and N-protonated pi-dimers also support the existence of multivariant orientations in pi-bonded dimers of viologen cation-radicals. PMID- 25450857 TI - Vibrio cholerae T3SS effector VopE modulates mitochondrial dynamics and innate immune signaling by targeting Miro GTPases. AB - The cellular surveillance-activated detoxification and defenses (cSADD) theory postulates the presence of host surveillance mechanisms that monitor the integrity of common cellular processes and components targeted by pathogen effectors. Being organelles essential for multiple cellular processes, including innate immune responses, mitochondria represent an attractive target for pathogens. We describe a Vibrio cholerae Type 3 secretion system effector VopE that localizes to mitochondria during infection and acts as a specific GTPase activating protein to interfere with the function of mitochondrial Rho GTPases Miro1 and Miro2. Miro GTPases modulate mitochondrial dynamics and interfering with this functionality effectively blocks innate immune responses that presumably require mitochondria as signaling platforms. Our data indicate that interference with mitochondrial dynamics may be an unappreciated strategy that pathogens use to block host innate immune responses that would otherwise control these bacterial infections. VopE might represent a bacterial effector that targets the cSADD surveillance response. PMID- 25450859 TI - Current approaches to the pharmacological management of Cushing's disease. AB - If treatment of Cushing's disease (CD) by surgery is not successful, medical therapy is often required. Long-term use of metyrapone is limited by hirsutism and hypertension and escape because of increased ACTH levels. Although ketoconazole can normalize cortisol levels in 50%, liver toxicity limits its use. Mitotane, an adrenolytic agent, has had minimal use for benign disease. Etomidate is useful when rapid reduction in cortisol levels is needed. Cabergoline can normalize cortisol levels in CD in about one-third of patients and is well tolerated. Pasireotide can normalize cortisol levels in CD in about 25% but causes worsening of glucose tolerance in most patients. Mifepristone, a blocker of cortisol receptors, improves clinical aspects of CD in most patients but cortisol and ACTH measurements do not reflect clinical activity and adrenal insufficiency, hypokalemia, and endometrial hyperplasia can occur. Combinations of drugs can be tried in patients resistant to monotherapy. PMID- 25450861 TI - NFkappaB affects estrogen receptor expression and activity in breast cancer through multiple mechanisms. AB - Estrogen receptor (ER) and NFkappaB are two widely expressed, pleiotropic transcription factors that have been shown to interact and affect one another's activity. While the ability of ER to repress NFkappaB activity has been extensively studied and is thought to underlie the anti-inflammatory activity of estrogens, how NFkappaB signaling affects ER activity is less clear. This is a particularly important question in breast cancer since activation of NFkappaB in ER positive tumors is associated with failure of endocrine and chemotherapies. In this review, we provide an update on the multiple mechanisms by which NFkappaB can influence ER activity, including down-regulation of ER expression, enhanced ER recruitment to DNA, and increased transcriptional activity of both liganded and unliganded ER. Additionally, a novel example of NFkappaB potentiation of ER dependent gene repression is reviewed. Together, these mechanisms can alter response to endocrine therapies and may underlie the poor outcome for women with ER positive tumors that have active NFkappaB signaling. PMID- 25450860 TI - Phthalate esters affect maturation and function of primate testis tissue ectopically grafted in mice. AB - Di-n-Butyl (DBP) and Di-(2-EthylHexyl) (DEHP) phthalates can leach from daily-use products resulting in environmental exposure. In male rodents, phthalate exposure results in reproductive effects. To evaluate effects on the immature primate testis, testis fragments from 6-month-old rhesus macaques were grafted subcutaneously to immune-deficient mice, which were exposed to 0, 10, or 500 mg/kg of DBP or DEHP for 14 weeks or 28 weeks (DBP only). DBP exposure reduced the expression of key steroidogenic genes, indicating that Leydig cell function was compromised. Exposure to 500 mg/kg impaired tubule formation and germ cell differentiation and reduced numbers of spermatogonia. Exposure to 10 mg/kg did not affect development, but reduced Sertoli cell number and resulted in increased expression of inhibin B. Exposure to DEHP for 14 week also affected steroidogenic genes expression. Therefore, long-term exposure to phthalate esters affected development and function of the primate testis in a time and dosage dependent manner. PMID- 25450862 TI - [D-Lys3]-GHRP-6 exhibits pro-autophagic effects on skeletal muscle. AB - [D-Lys3]-GHRP-6 is regarded as a highly selective growth-hormone secretagogue receptor (GHSR) antagonist and has been widely used to investigate the dependency of GHSR-1a signalling mediated by acylated ghrelin. However, [D-Lys3]-GHRP-6 has been reported to influence other cellular processes which are unrelated to GHSR 1a. This study aimed to examine the effects of [D-Lys3]-GHRP-6 on autophagic and apoptotic cellular signalling in skeletal muscle. [D-Lys3]-GHRP-6 enhanced the autophagic signalling demonstrated by the increases in protein abundances of beclin-1 and LC3 II-to-LC3 1 ratio in both normal muscle and doxorubicin-injured muscle. [D-Lys3]-GHRP-6 reduced the activation of muscle apoptosis induced by doxorubicin. No histological abnormalities were observed in the [D-Lys3]-GHRP-6 treated muscle. Intriguingly, the doxorubicin-induced increase in centronucleated muscle fibres was not observed in muscle treated with [D-Lys3]-GHRP-6, suggesting the myoprotective effects of [D-Lys3]-GHRP-6 against doxorubicin injury. The [D Lys3]-GHRP-6-induced activation of autophagy was found to be abolished by the co treatment of CXCR4 antagonist, suggesting that the pro-autophagic effects of [D Lys3]-GHRP-6 might be mediated through CXCR4. In conclusion, [D-Lys3]-GHRP-6 exhibits pro-autophagic effects on skeletal muscle under both normal and doxorubicin-injured conditions. PMID- 25450863 TI - Alpha-lipoic acid attenuates cardiac hypertrophy via inhibition of C/EBPbeta activation. AB - Alpha-lipoic acid (ALA), a naturally occurring compound, exerts powerful protective effects in numerous cardiovascular disease models. However, the pharmacological property of ALA on cardiac hypertrophy has not been well investigated. The present study was carried out to determine whether ALA exerts a direct anti-hypertrophic effect in cultured cardiomyocytes and whether it modifies the hypertrophic process in vivo. Furthermore, we determined the potential underlying mechanisms for these actions. Treatment of cardiomyocytes with phenylephrine (PE) for 24 h produced a marked hypertrophic effect as evidenced by significantly increased in ANF and BNP mRNA levels, as well as cell surface area. These effects were attenuated by ALA in a concentration-dependent manner with a complete inhibition of hypertrophy at a concentration of 100 ug/mL. PE-induced cardiomyocyte hypertrophy was associated with increased mRNA and protein levels of C/EBPbeta, which were inhibited by pretreatment with ALA. However, when cardiomyocytes were co-transfected with C/EBPbeta, ALA failed to inhibit hypertrophic responses. Upregulation of C/EBPbeta expression was also evident in rats subjected to 4 weeks of coronary artery ligation (CAL). However, rats treated with ALA demonstrated markedly reduced hemodynamic and hypertrophic responses, which were accompanied by attenuation of upregulation of C/EBPbeta. Taken together, our results revealed a robust anti-hypertrophic and anti remodeling effect of ALA, which is mediated by inhibition of C/EBPbeta activation. PMID- 25450864 TI - Anabolic steroids activate calcineurin-NFAT signaling and thereby increase myotube size and reduce denervation atrophy. AB - Anabolic androgens have been shown to reduce muscle loss due to immobilization, paralysis and many other medical conditions, but the molecular basis for these actions is poorly understood. We have recently demonstrated that nandrolone, a synthetic androgen, slows muscle atrophy after nerve transection associated with down-regulation of regulator of calcineurin 2 (RCAN2), a calcineurin inhibitor, suggesting a possible role of calcineurin-NFAT signaling. To test this possibility, rat gastrocnemius muscle was analyzed at 56 days after denervation. In denervated muscle, calcineurin activity declined and NFATc4 was excluded from the nucleus and these effects were reversed by nandrolone. Similarly, nandrolone increased calcineurin activity and nuclear NFATc4 levels in cultured L6 myotubes. Nandrolone also induced cell hypertrophy that was blocked by cyclosporin A or overexpression of RCAN2. Finally protection against denervation atrophy by nandrolone in rats was blocked by cyclosporin A. These results demonstrate for the first time that nandrolone activates calcineurin-NFAT signaling, and that such signaling is important in nandrolone-induced cell hypertrophy and protection against paralysis-induced muscle atrophy. PMID- 25450865 TI - A clerodane diterpene inhibit adipogenesis by cell cycle arrest and ameliorate obesity in C57BL/6 mice. AB - A clerodane diterpene, 16alpha-Hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (compound 1) isolated from Polyalthia longifolia had previously been reported as a new structural class of HMG-CoA reductase inhibitor apart from statins. Statins are known to be anti-adipogenic in nature. The distant structural similarity between compound 1 and lovastatin (polyketide class of compound) prompted us to investigate effects of diterpene compound 1 on adipogenesis and thereby obesity. High content microscopy proved diterpene compound 1 exhibits better anti adipogenic activity and less toxicity in differentiating adipocytes. Moreover, it reduced expression levels of PPARgamma, C/EBPalpha and GLUT4 during differentiation in a time and concentration dependent manner. Diterpene compound 1 during early differentiation reduced MDI induced-Akt/mTOR phosphorylation and expression of cell cycle proteins, and thereby halted mitotic clonal expansion, the decisive factor in early adipogenesis. Further, its anti-adipogenic activity was validated in murine mesenchymal cell-line C3H10T1/2 and human mesenchymal stem cell models of adipogenic differentiation. When compound 1 was administered along with HFD, for another 8 weeks in 2 month HFD fed overweight mice (with BMI > 30 and impaired glucose tolerance), it attenuated weight gain and epididymal fat accumulation. It improved body glucose tolerance, reduced HFD induced increase in total cholesterol and leptin/adiponectin ratio. All these effects were comparable with standard anti-obesity drug Orlistat with added edge of potently decreasing circulating triglyceride levels comparable with normal chow fed group. Histological analysis shows that compound 1 inhibit adipocyte hypertrophy and decreased steatosis in hepatocytes. Both in vivo and in vitro results demonstrate a potential value of compound 1 as a novel anti-adipogenic and anti-obesity agent. PMID- 25450867 TI - Comparison between clinical and radiological evaluation before and after medical therapy in patients with Crohn's disease: new prospective roles of CT enterography. AB - PURPOSE: In recent years, CT enterography (CTE) has emerged as an important methodology to study patients with Crohn's disease (CD). The aim of this study was to evaluate the correlation between clinical response to therapy and CTE findings in CD patients. MATERIALS AND METHODS: Forty-five patients with proven CD underwent CTE before and after medical therapy. In CTE we evaluated bowel thickness, longitudinal extension of parietal thickening, presence of target signs and extraintestinal signs. The clinical response to therapy was judged based on clinical global assessment and classified as improved, worsened or stable disease. Radiological judgement was compared to clinical judgement. The Cohen kappa test, t test or Anova analysis and chi (2) test were used for comparisons. RESULTS: Among 45 enrolled patients, 21 (47 %) improved clinically, five (11 %) worsened, 19 (42 %) remained stable. Clinical improvement was significantly correlated to reduced intestinal thickness, reduced longitudinal extension of the disease, increased diameter of pathological bowel and reduced target signs (p < 0.05). Worsening conditions were significantly correlated to increased longitudinal extent, increased parietal thickness and reduced lumen diameter (p < 0.05). CT judgement was in agreement with physician's clinical assessment in 34 patients (76 %), showing improved disease in 16/21 patients (76 %), stable disease in 14/19 patients (74 %) and worsening in 4/5 patients (80 %). No agreement was observed in 11 (24 %) patients. CONCLUSIONS: CT enterography provide specific and measurable parameters in evaluating the response to therapy in CD patients. PMID- 25450866 TI - The influence of motor expertise on the brain activity of motor task performance: A meta-analysis of functional magnetic resonance imaging studies. AB - Previous research has investigated the influence of long-term motor training on the brain activity of motor processes, but the findings are inconsistent. To clarify how acquiring motor expertise induces cortical reorganization during motor task performance, the current study conducted a quantitative meta-analysis on 26 functional magnetic resonance imaging (fMRI) studies that investigate motor task performance in people with long-term motor training experience (e.g., athletes, musicians, and dancers) and control participants. Meta-analysis of the brain activation in motor experts and novices showed similar effects in the bilateral frontal and parietal regions. The meta-analysis on the contrast between motor experts and novices indicated that experts showed stronger effects in the left inferior parietal lobule (BA 40) than did novices in motor execution and prediction tasks. In motor observation tasks, experts showed stronger effects in the left inferior frontal gyrus (BA 9) and left precentral gyrus (BA 6) than novices. On the contrary, novices had stronger effects in the right motor areas and basal ganglia as compared with motor experts. These results indicate that motor experts have effect increases in brain areas involved in action planning and action comprehension, and suggest that intensive motor training might elaborate the motor representation related to the task performance. PMID- 25450868 TI - Left spermatic vein retrograde sclerosis: comparison between sclerosant agent injection through a diagnostic catheter versus through an occluding balloon catheter. AB - PURPOSE: The aim of this study was to compare the technical success between left spermatic vein (LSV) scleroembolisation achieved with the injection of sclerosant through a diagnostic catheter and through an occluding balloon (OB), in the treatment of male varicocele. MATERIALS AND METHODS: From January 2012 to September 2013, we prospectively enrolled 100 patients with left varicocele and an indication for LSV scleroembolisation related to symptoms or spermiogram anomalies; patients were randomised to two groups (we wrote a list of 100 lines assigned casually with A or B and each patient was consecutively allocated to group A or B on the basis of this list). Patients in group A underwent injection of the sclerosing agent through an angiographic diagnostic catheter (free catheter technique) and patients in group B through an OB catheter (OB technique). In cases of incomplete occlusion of the LSV, the procedure was completed with coils. Total occlusion of the LSV at post-treatment phlebography during a Valsalva manoeuvre before any coil embolisation was considered a technical success. The rate of complications was also evaluated. The Fischer's test was used for statistical analysis. RESULTS: We evaluated a total of 90 patients because five patients for each group were not included in the statistical analysis owing to technical problems or complications. In group A we had a technical success of 75.6 versus 93.4 % in group B, and the difference was statistically significant (P = 0.003); in particular, we had to complete the embolisation with insertion of coils in 11 cases (24.4 %) in group A, and in three cases in group B (6.6 %). In group A, LSV rupture occurred in four cases (8 %) so the procedure was completed by sclerosant injection through the OB located distally to the lesion. These patients were not considered for evaluation. In another case, a high flow shunt towards the inferior vena cava was detected, so the patient underwent OB injection to stop the flow to the shunt, and was not included for statistical evaluation. In group B, vein rupture with contrast leakage was noted in six cases (12 %); nonetheless, all the procedures were completed because the OB was positioned distally to the vessel tear, obviating any retrograde leakage of sclerosant. In group B, in five cases (10 %), we were unable to advance the OB though the LSV ostium so the procedures were completed with the diagnostic catheter and not considered for statistical evaluation. CONCLUSION: On the basis of our data, the embolisation of the LSV obtained by injecting the sclerosant through an OB rather than through a diagnostic catheter seems to be more effective in achieving total vein embolisation, as well as allowing a controlled injection of sclerosant even in cases of vein rupture. PMID- 25450870 TI - Validation of the immunochromatographic strip for alpha-thalassemia screening: a multicenter study. AB - alpha(0)-Thalassemia occurs from a deletion of 2 linked alpha-globin genes and interaction of these defective genes leads to hemoglobin (Hb) Bart's hydrops fetalis, the most severe and lethal thalassemia syndrome. Identification of alpha(0)-thalassemia carriers is thus essential for the prevention and control program. An immunochromatographic (IC) strip test was developed for rapid screening of alpha(0)-thalassemia by testing for Hb Bart's in the blood samples using a specific monoclonal antibody against Hb Bart's. To evaluate its sensitivity and specificity, the IC strip test was assessed in a cohort with various thalassemia genotypes from 4 different laboratories in Thailand and Australia. The result showed 97% sensitivity in alpha-thalassemia carriers with 2 alpha-globin genes deletion and Hb H disease. This is, in particular, the useful rapid screening test for regions where beta-thalassemia and homozygous Hb E are also common. Similar hematologic and Hb data make it impossible to address the concomitant inheritance of alpha(0)-thalassemia in these samples without polymerase chain reaction (PCR)-based techniques, leading to misdiagnosis of the risk of having Hb Bart's hydrops fetalis. However, alpha-globin genotyping should be carried out in samples with positive IC strip as positive reactivity was also observed in homozygous alpha(+)-thalassemia carriers who have 2 trans alpha globin gene deletions. These results indicate that in combination with red blood cell indices, the IC strip test could rule out mass populations for further alpha(0)-thalassemia detection by PCR-based analysis. The Alpha Thal IC strip also has the potential to replace testing for Hb H inclusion bodies, as it appears to be more sensitive, specific, and less labor intensive. PMID- 25450869 TI - Emergency radiology. AB - US has a relevant role in the initial assessment of non-traumatic emergencies of the abdomen, sometimes being conclusive and some other times for selecting the patients for further imaging with CT. Injection of a contrast medium may give to the radiologist additional information to that obtained at baseline US and Doppler examination, since real-time, contrast-enhanced US (CEUS) may allow observing findings in the abdomen not recognizable at baseline US or even at color Doppler imaging. Extravascular use of microbubbles may also be useful in clinical practice to rapidly solve a number of unclear aspects. CEUS has a number of distinct advantages in acute patients, including its quickness, low invasiveness, and its possible bedside use. The information based on contrast enhancement is useful for initial diagnosis, therapeutic decision making, and follow-up of the critically ill patients. The purpose of this review is to illustrate the possibilities and limitations of abdominal CEUS in the acute setting, with special emphasis on the detection and characterization of acute inflammatory processes, infarcts, and hemorrhages. PMID- 25450871 TI - Comparative effectiveness of first-line platinum-based chemotherapy regimens for advanced lung squamous cell carcinoma. AB - BACKGROUND: Platinum-based chemotherapy is the standard first-line therapy for patients with advanced lung squamous cell carcinoma (SCC). We compared the effectiveness of first-line chemotherapy regimens. METHODS: We searched the database of the Taiwan Cancer Registry for patients with newly diagnosed advanced lung SCC from 2004 to 2007. Medication prescription data were retrieved from the database of National Health Insurance, Taiwan. We identified patients who received standard first-line platinum-based chemotherapy, which was defined as chemotherapy with a platinum (P) compound (cisplatin or carboplatin) in addition to 1 of the 4 chemotherapy agents, including gemcitabine (G), docetaxel (D), paclitaxel (T), and vinorelbine (V). Deaths were identified by searching the National Death Registry. Overall survival (OS) was compared between patients who underwent different therapies. RESULTS: In total, 2790 patients were identified; 983 patients (35.2%) received standard first-line chemotherapy with P and G (58.1%), D (14.5%), T (11.6%), or V (15.8%). Older patients (age >= 70 years) were less likely to receive P + D than P + G, P + T, or P + V (P = .018). Patients who received P + G, P + D, P + T, or P + V had similar OS (median, 8.9, 7.9, 9.5, and 8.2 months; P = .816). In multivariate analyses adjusting for age, sex, and stage, the first-line chemotherapy regimen was not a predictor for OS. With P + G as the reference group, the adjusted hazard ratios of P + D, P + T, and P + V were 1.03, 0.90, and 1.02, respectively (P = .710). CONCLUSIONS: In patients with advanced lung SCC, various regimens did not have a significant effect on survival outcomes. PMID- 25450872 TI - Outcomes by tumor histology and KRAS mutation status after lung stereotactic body radiation therapy for early-stage non-small-cell lung cancer. AB - BACKGROUND: We analyzed outcomes after lung stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung-carcinoma (NSCLC) by histology and KRAS genotype. PATIENTS AND METHODS: We included 75 patients with 79 peripheral tumors treated with SBRT (18 Gy * 3 or 10 to 12 Gy * 5) at our institution from 2009 to 2012. Genotyping for KRAS mutations was performed in 10 patients. Outcomes were analyzed by the Kaplan-Meier method/Cox regression, or cumulative incidence method/Fine-Gray analysis. RESULTS: The median patient age was 74 (range, 46 to 93) years, and Eastern Cooperative Oncology Group performance status was 0 to 1 in 63%. Tumor histology included adenocarcinoma (44%), squamous cell carcinoma (25%), and NSCLC (18%). Most tumors were T1a (54%). Seven patients had KRAS mutant tumors (9%). With a median follow-up of 18.8 months among survivors, the 1 year estimate of overall survival was 88%, cancer-specific survival (CSS) 92%, primary tumor control 94%, and freedom from recurrence (FFR) 67%. In patients with KRAS-mutant tumors, there was a significantly lower tumor control (67% vs. 96%; P = .04), FFR (48% vs. 69%; P = .03), and CSS (75% vs. 93%; P = .05). On multivariable analysis, histology was not associated with outcomes, but KRAS mutation (hazard ratio, 10.3; 95% confidence interval, 2.3-45.6; P = .0022) was associated with decreased CSS after adjusting for age. CONCLUSION: In this SBRT series, histology was not associated with outcomes, but KRAS mutation was associated with lower FFR on univariable analysis and decreased CSS on multivariable analysis. Because of the small sample size, these hypothesis generating results need to be studied in larger data sets. PMID- 25450873 TI - Incidental receipt of cardiac medications and survival outcomes among patients with stage III non-small-cell lung cancer after definitive radiotherapy. AB - BACKGROUND: Preclinical and epidemiologic studies suggest that receipt of some cardiac medications such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers, or aspirin may have antiproliferative effects in several types of cancer. The aim of this study was to estimate survival outcomes in patients receiving incidental cardiac medications during treatment for lung cancer, and to compare outcomes with those patients not receiving these medications. PATIENTS AND METHODS: We retrospectively reviewed 673 patients who had received definitive radiotherapy for stage III non-small-cell lung cancer (NSCLC). Cox proportional hazard models were used to assess associations between receipt of ACEIs, ARBs, beta-blockers, or aspirin and locoregional progression-free survival (LRPFS), distant metastasis free survival (DMFS), disease-free survival (DFS), and overall survival (OS). RESULTS: Multivariate analyses showed that ACEI receipt was associated with poorer LRPFS but had no effect on DMFS, DFS, or OS. Aspirin receipt was associated only with improved DMFS, and beta-blocker receipt was associated with improved DMFS, DFS, and OS. CONCLUSION: Incidental receipt of ACEIs was associated with a higher prevalence of local failure, whereas receipt of either beta-blockers or aspirin had protective effects on survival outcomes in this large group of patients with lung cancer. This finding warrants further clinical and preclinical exploration, as it may have important implications for treating patients with lung cancer who are also receiving cardiac medications. PMID- 25450874 TI - Prospective assessment of pemetrexed or pemetrexed plus platinum in combination with gefitinib or erlotinib in patients with acquired resistance to gefitinib or erlotinib: a phase II exploratory and preliminary study. AB - PURPOSE: To evaluate the efficacy and safety of alternating gefitinib and erlotinib, tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), with chemotherapy in non-small-cell lung cancer (NSCLC) patients with acquired TKI resistance. METHODS: Forty-two patients with lung cancer that responded to TKIs for as least 6 months before developing TKI resistance were enrolled and received sequential pemetrexed or pemetrexed plus platinum followed by gefitinib or erlotinib. Chemotherapy was intravenously administered on day 1, and patients were provided oral EGFR-TKIs between days 6 and 21. The treatment was repeated every 3 weeks for 2 to 4 cycles. At the end of the specified treatment regimen, patients continued to receive EGFR-TKIs for maintenance until disease progression or unacceptable toxicity. The primary end point was the disease control rate. Secondary end points included overall remission rate, median progression-free survival, and survival rate. RESULTS: The disease control rate was 78.6%, the overall remission rate was 23.8%, and survival rate was 73.8%. Progression-free survival was 8 months, and median survival time was 11 months. The treatment protocol was generally well tolerated. Treatment interruption was required in 2 patients. Grade 3/4 hematologic toxicities included neutropenia (23.8%), leukopenia (16.7%), anemia (4.8%), and thrombocytopenia (4.8%). Common grade 3 nonhematologic toxicities included nausea (7.1%), vomiting (9.5%), anorexia (11.9%), rash (7.1%), fatigue (9.5%), infection (16.7%), and oral mucositis (2.4%). No toxicity-related deaths occurred. CONCLUSIONS: For patients with acquired TKI resistance, pemetrexed or pemetrexed plus platinum administration followed by gefitinib or erlotinib was well tolerated and associated with a fair response. PMID- 25450875 TI - Clinical likelihood of sporadic primary EGFR T790M mutation in EGFR-mutant lung cancer. AB - BACKGROUND: It has been reported that the presence of pretreatment EGFR T790M mutation may reduce the efficacy to EGFR tyrosine kinase inhibitors (TKI) in EGFR mutant lung cancer. However, clinicopathologic features related to the likelihood of T790M mutation before treatment remains unknown. PATIENTS AND METHODS: DNA from 124 pretreatment tissue samples from patients with advanced non-small-cell lung cancer carrying sensitive EGFR mutations was genotyped for EGFR T790M mutation with mass spectrometry. We compared the characteristics of 24 T790M patients and 100 patients with no or a low-level T790M mutation. RESULTS: There were no differences in age, sex, histology, or initial stage between T790M and non/low T790M groups. However, there were significantly more never-smokers in the T790M group (P = .017). Brain metastasis was also more common in the T790M group (P = .036). The response rates to platinum, taxane, gemcitabine, and pemetrexed did not differ between the 2 groups. In the T790M group, the response rates were not significantly different among the 4 cytotoxic drugs (P = .809). The median time to progression during EGFR-TKI therapy was shorter in the T790M group than in the non/low T790M group (4.1 vs. 11.5 months, respectively; P < .001). The median overall survival from the start of first-line treatment of advanced disease was similar in both groups (31.5 vs. 36.0 months, respectively; P = .310). CONCLUSION: The clinical features of EGFR T790M-mutant lung cancer were similar to those of sensitive EGFR-mutant lung cancer, except for the overrepresentation of never-smokers and brain metastasis. PMID- 25450876 TI - Radical-intent hypofractionated radiotherapy for locally advanced non-small-cell lung cancer: a systematic review of the literature. AB - PURPOSE: To identify survival and toxicity characteristics associated with radical-intent hypofractionated radiotherapy for the treatment of stage III non small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Relevant studies were identified from a systematic PubMed search of articles published between January 1990 and January 2014. All studies were peer reviewed and included both retrospective and prospective studies of NSCLC patients being treated with radical hypofractionated radiotherapy. Data on overall survival (OS) and toxicity were extracted from each of the studies where available. RESULTS: Of 685 studies initially identified by the search, a total of 33 studies were found to be relevant and were included in this systematic review. The number of fractions ranged from 15 to 35, the dose per fraction ranged from 2.3 to 3.5 Gy, and the delivered dose ranged from 45.0 to 85.5 Gy. Fifteen of the studies included concurrent chemotherapy, while 18 did not. OS was found to be associated with tumor biological effective dose, with the Pearson correlation coefficient ranging from 0.34 to 0.48. For both concurrent and nonconcurrent chemoradiotherapy acute pulmonary, late esophageal and late pulmonary incidences of toxicity ranged from 1.2% to 12.2%, but had 95% confidence intervals that included zero. The greatest incidence of toxicity was acute esophageal toxicity at 14.9% (95% confidence interval, 0.7%, 29.1%). CONCLUSIONS: There is a moderate linear relationship between biological effective dose and OS, and greater acute esophageal toxicity with concurrent chemotherapy. Improving outcomes in stage III NSCLC may involve some form of hypofractionation in the context of systemic concurrent therapy. PMID- 25450877 TI - Standard treatment option in stage III non-small-cell lung cancer: case against trimodal therapy and consolidation drug therapy. AB - Prospective randomized trials and meta-analyses established concurrent radiochemotherapy (RT-CHT) as standard treatment approach in patients with inoperable, locally advanced (stage IIIA and B) non-small-cell lung cancer (NSCLC). In patients with either clinically (c) or pathologically (p) staged disease (stage IIIA), including those with pN2 disease, trimodal therapy was also frequently practiced in the past and is currently still advocated by large cooperative groups and organizations. Similarly, consolidation CHT provided after concurrent RT-CHT was suggested to be feasible and effective in inoperable stage III NSCLC. Contrasting these practices and suggestions, there is no evidence that trimodal therapy in stage IIIA (clinically or pathologically staged) or consolidation CHT in inoperable stage III NSCLC plays any role in its treatment. In both cases, evidence clearly demonstrates that concurrent RT-CHT is of similar efficacy and less toxic, and it should be considered a standard treatment option for all patients with stage III NSCLC. PMID- 25450878 TI - Long-term lung cancer survivors have permanently decreased quality of life after surgery. AB - BACKGROUND: Retrospective evaluation of the long-term health-related quality of life (HRQoL) among survivors after non-small-cell lung cancer (NSCLC) surgery. PATIENTS AND METHODS: A total of 586 patients underwent surgery for NSCLC in Helsinki University Central Hospital between January 2000 and June 2009. Two validated quality-of-life questionnaires, the 15D and the EORTC QLQ-C30 with its lung cancer-specific module, QLQ-LC13, were sent to the 276 patients alive in June 2011. Response rate was 83.3%. Results of the 15D were compared with those of an age- and gender-standardized general population. RESULTS: Median follow-up was 5 years. Compared with a general population, our patients had a significantly lower 15D total score, representing their total HRQoL and scores for dimensions of mobility, breathing, usual activities, depression, distress, and vitality. The patients, however, scored significantly higher on vision, hearing, and mental function. CONCLUSIONS: NSCLC survivors may suffer postoperatively from permanently reduced long-term HRQoL compared to an age- and gender-matched general population. This is essential patient information as more patients are surviving longer. PMID- 25450880 TI - Direct reductive coupling of secondary amides: chemoselective formation of vicinal diamines and vicinal amino alcohols. AB - We report the first one-pot reductive homocoupling reaction of secondary amides and cross-coupling reaction of secondary amides with ketones to give secondary vicinal diamines and amino alcohols. This method relies on the direct generation of alpha-amino carbon radicals from secondary amides by activation with trifluoromethanesulfonic anhydride, partial reduction with triethylsilane and samarium diiodide-mediated single-electron transfer. The reactions were run under mild conditions and tolerated several functional groups. PMID- 25450879 TI - Italian multicenter phase III randomized study of cisplatin-etoposide with or without bevacizumab as first-line treatment in extensive stage small cell lung cancer: treatment rationale and protocol design of the GOIRC-AIFA FARM6PMFJM trial. AB - BACKGROUND: Neoangiogenesis is particularly abundant in small-cell lung cancer (SCLC) and is associated with poor prognosis. As a result of the promising nature of phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line chemotherapy with cisplatin etoposide for treatment of extensive disease SCLC. We present the treatment rationale and study design of GOIRC trial (FARM6PMFJM study), a multicenter randomized phase III study, supported by AIFA (Agenzia Italiana del Farmaco). PATIENTS AND METHODS: Patients are randomized to receive either cisplatin 25 mg/m(2) and etoposide 100 mg/m(2) intravenously on days 1 to 3 (control arm) or the same chemotherapy combined with bevacizumab 7.5 mg/kg intravenously on day 1 (experimental arm). Treatment is repeated every 3 weeks and for a maximum of 6 courses. Patients randomized to the experimental arm in the absence of disease progression after 6 cycles continue bevacizumab alone until progression or for a maximum of 18 courses. Tumor assessment is done every 3 cycles. Major eligibility criteria are: age >= 18 years; histologically or cytologically documented extensive disease SCLC; Eastern Cooperative Oncology Group performance status <= 2; adequate hematological, hepatic and renal functions; no history of grade 2 or higher hemoptysis; and no evidence of tumor cavitation. The primary end point of this study is overall survival. Secondary end points include response rate, time to progression, and toxicity. CONCLUSION: An interim futility analysis was performed by an Independent Data Monitoring Committee in September 2013 and the trial obtained approval to continue. As of July 31, 2014, 171 patients of 206 planned have been randomized. PMID- 25450881 TI - Glucose-6-phosphate dehydrogenase is required for extracellular polysaccharide production, cell motility and the full virulence of Xanthomonas oryzae pv. oryzicola. AB - Glucose-6-phosphate dehydrogenase (Zwf) catalyzes conversion of glucose 6 phosphate into gluconate 6-phosphate for Entner-Doudoroff (ED) and pentose phosphate pathways in living organisms. However, it is unclear whether the Zwf coding gene is involved in pathogenesis of phytopathogenic bacterium. In this report, we found that deletion mutation in zwf of Xanthomonas oryzae pv. oryzicola (Xoc), led the pathogen unable to effectively utilize glucose, sucrose, fructose, mannose and galactose for growth. The transcript level of zwf was strongly induced by glucose, sucrose, fructose, mannose and galactose than that by the NY medium (non sugar). The deletion mutagenesis in zwf also altered the transcript level of key genes, such as rpfF, rpfG and clp, in diffusible signal factor (DSF)-signaling network. In addition, the deletion mutation in zwf impaired bacterial virulence and growth capability in rice leaves, reduced bacterial cell motility and extracellular polysaccharide (EPS) production. The lost properties mentioned above in the zwf deletion mutant were completely restored to the wild-type level by the presence of zwf in trans. All these results suggest that zwf is required for the full virulence of Xoc in rice leaves by involving carbohydrate metabolisms that impact bacterial DSF-signaling network. PMID- 25450883 TI - A conserved region from biofilm associated protein as a biomarker for detection of Acinetobacter baumannii. AB - Acinetobacter baumannii is the leading cause of nosocominal infection within the family Moraxellaceae. Due to multiple antibiotic resistances of the bacteria, the treatment is very difficult, hence specific and economical test for early diagnosis of infection is needed. Development of such a test requires targeting specific cell surface antigens. Bacterial ability of biofilm formation grants major contribution in antimicrobial resistance and other environmental stresses such as nutrient limitation and dehydration. Biofilm associated protein (Bap), a specific cell surface protein, is directly involved in A. baumannii biofilm formation. The goal of this study is diagnosis of A. baumannii infection exploiting specific target from Bap. A selected subunit of Bap was cloned, expressed and purified. Mice were divided into three groups. Group one was immunized with recombinant Bap subunit, mice in group two were infected with A. baumannii (positive control) and mice in groups three served as negative control. Immunization with Bap subunit resulted in high antibody titers. Animals in control group that received same amount of adjuvant and PBS showed no Bap specific antibodies. Sensitivity and specificity of the antibodies raised were determined by ELISA and Western blotting. Recombinant Bap subunit was tested by ELISA using sera obtained from A. baumannii infected patients and healthy individuals. This conserved and immunodominant region of Bap could serve as an appropriate target for diagnosis A. baumannii infection. PMID- 25450882 TI - Efficacy of cefepime, ertapenem and norfloxacin against leptospirosis and for the clearance of pathogens in a hamster model. AB - Animals and humans with severe leptospirosis may require empirical treatment. Although many antibiotics are active against multiple leptospira serovars in vitro, their efficacy in vivo is limited. We evaluated the efficacy of cefepime (daily dose: 2, 5, 10, and 20 mg/kg), ertapenem (daily dose: 2.5, 5, and 10 mg/kg) and norfloxacin (daily dose: 20, 40, and 80 mg/kg) for the treatment of leptospirosis and the ability to clear leptospira in target organs (liver, kidney, lung, heart, and spleen) in a lethal hamster model using Leptospira interrogans serovar Autumnalis. The histopathology of infected kidney, lung and liver was also evaluated using hematoxylin and eosin stain (H&E stain). All untreated animals, serving as a negative control, died with leptospira existing in the target organs between the 5th and 7th day after infection. All of the treated groups displayed improved survival compared to the untreated group and demonstrated a dose-dependent decrease in the presence of leptospira in the target organs. Cefepime showed survival benefit comparable to the standard treatment, doxycycline. We conclude that all of the antibiotics tested in vivo produce a statistically significant survival advantage, alleviate tissue injury and decrease the abundance of leptospira in target organs. PMID- 25450884 TI - The role of pgaC in Klebsiella pneumoniae virulence and biofilm formation. AB - BACKGROUND: Klebsiella pneumoniae has emerged as one of the major pathogens for community-acquired and nosocomial infections. A four-gene locus that had a high degree similarity with Escherichia coli pgaABCD and Yersinia pestis hmsHFRS was identified in K. pneumoniae genomes. The pgaABCD in E. coli encodes the envelope spanning Pga machinery for the synthesis and secretion of poly-beta-linked N acetylglucosamine (PNAG). In a limited number of phylogenetically diverse bacteria, PNAG was demonstrated to mediate biofilm formation and had a role in the host-bacteria interactions. The presence of conserved pgaABCD locus among various K. pneumoniae strains suggested a putative requirement of PNAG for this bacterium. RESULTS: In this study, an in-frame deletion of pgaC was generated in K. pneumoniae CG43 and named DeltapgaC. The loss of pgaC affected the production of PNAG and attenuated the enhancement of in vitro biofilm formation upon the addition of bile salts mixture. In mouse models, DeltapgaC exhibited a weakened ability to colonize the intestine, to disseminate extraintestinally, and to induce a systemic infection when compared to K. pneumoniae CG43. CONCLUSIONS: Our study demonstrated that pgaC participated in the bile salts induced biofilm formation and was required for K. pneumoniae virulence in vivo. PMID- 25450886 TI - Adaptation and growth kinetics study of an Indian isolate of virulent duck enteritis virus in Vero cells. AB - Duck virus enteritis, also known as duck plague, is a viral infection of ducks caused by duck enteritis virus (DEV). The control of the disease is mainly done by vaccination with chicken embryo adapted live virus that is known to be poorly immunogenic and elicits only partial protection. Further, the embryo propagated vaccine virus pose a threat of harboring other infectious agents. Seeing these limitations, the present study reports for the first time regarding propagation and adaptation of a virulent Indian isolate of duck enteritis virus in Vero cell line. In this study isolation of an outbreak virus from Kerala state was done in chicken embryo fibroblast cell culture (CEF). Then adapted the DEV isolate in the Vero cell line. The characteristic cytopathic effects (CPE) of clumping and fusion of Vero cells were observed starting from the 7th passage onwards. The presence of the virus and its multiplication in Vero cells was confirmed by detection of viral specific DNA and antigen by using polymerase chain reaction (PCR) and indirect immuno fluorescent assay (IIFA), respectively. PCR detection of DEV using self designed primers for US4 (gD) and UL30 (DNA Polymerase) gene has been reported for the in the present study. The kinetics of DEV in Vero cells revealed a maximum infectivity titer of 10(5.6) TCID 50/ml after 48hr of viral infection. Compared to chicken embryo adapted DVE vaccine virus, the Vero cell culture system is free from other infectious agents. So it will be a good candidate for cultivation and propagation of duck enteritis virus vaccine strain. Further research studies are suggested to explore the feasibility of utilizing this Vero cell culture adapted DEV isolate for developing an attenuated vaccine virus against duck virus enteritis. PMID- 25450885 TI - Immunomodulatory effects of Taishan Pinus massoniana pollen polysaccharide and propolis on immunosuppressed chickens. AB - Co-infection of reticuloendotheliosis virus (REV) and avian leukosis virus subgroup J (ALV-J), which can cause suppressed immunity and vaccination failure, frequently occurs in chicken flocks in China. Taishan Pinus massoniana pollen polysaccharide (TPPPS) and propolis (PP) have been proven to possess immune modulatory effects and improve the immune effects of vaccines. This study aimed to investigate the immune modulatory ability of TPPPS and PP on chickens co infected with immunosuppressive viruses. Prior to the study, chickens were artificially established as REV and ALV-J co-infection models. Four randomly assigned groups of these immunosuppressed chickens were successively administered with TPPPS, PP, mixture of TPPPS and PP (TPPPS-PP), or phosphate-buffered saline (PBS) for three days. At nine days old, the four immunosuppressed groups, as well as one normal group, were inoculated with the attenuated Newcastle disease (ND) vaccine. During the monitoring period, the indices of immune organ weight, lymphocyte transformation rates, CD4(+) and CD8(+) T-lymphocyte counts in peripheral blood, IL-2 and IFN-gamma secretions, serum antibody titers of ND vaccine, and viral loads in spleens were determined. The results showed that chickens administered with TPPPS, PP, or TPPPS-PP could significantly enhance the levels of the above immune parameters compared to chickens in the PBS group. We observed the strongest immunity in the TPPPS-PP group, which indicates that the combination of TPPPS and PP versus TPPPS or PP alone, could generate better effects on improving the immune system effectiveness of immunosuppressed chickens. PMID- 25450887 TI - Characterization of cellular immune response and innate immune signaling in human and nonhuman primate primary mononuclear cells exposed to Burkholderia mallei. AB - Burkholderia pseudomallei infection causes melioidosis and is often characterized by severe sepsis. Although rare in humans, Burkholderia mallei has caused infections in laboratory workers, and the early innate cellular response to B. mallei in human and nonhuman primates has not been characterized. In this study, we examined the primary cellular immune response to B. mallei in PBMC cultures of non-human primates (NHPs), Chlorocebus aethiops (African Green Monkeys), Macaca fascicularis (Cynomolgus macaque), and Macaca mulatta (Rhesus macaque) and humans. Our results demonstrated that B. mallei elicited strong primary pro inflammatory cytokines (IFN-gamma, TNF-alpha, IL-1beta, and IL-6) equivalent to the levels of B. pseudomallei in primary PBMC cultures of NHPs and humans. When we examined IL-1beta and other cytokine responses by comparison to Escherichia coli LPS, African Green Monkeys appears to be most responsive to B. mallei than Cynomolgus or Rhesus. Characterization of the immune signaling mechanism for cellular response was conducted by using a ligand induced cell-based reporter assay, and our results demonstrated that MyD88 mediated signaling contributed to the B. mallei and B. pseudomallei induced pro-inflammatory responses. Notably, the induced reporter activity with B. mallei, B. pseudomallei, or purified LPS from these pathogens was inhibited and cytokine production was attenuated by a MyD88 inhibitor. Together, these results show that in the scenario of severe hyper-inflammatory responses to B. mallei infection, MyD88 targeted therapeutic intervention may be a successful strategy for therapy. PMID- 25450889 TI - Plasmodium and mononuclear phagocytes. AB - Plasmodium, the causative agent of malaria, initially multiplies inside liver cells and then in successive cycles inside erythrocytes, causing the symptoms of the disease. In this review, we discuss interactions between the extracellular and intracellular forms of the Plasmodium parasite and innate immune cells in the mammalian host, with a special emphasis on mononuclear phagocytes. We overview here what is known about the innate immune cells that interact with parasites, mechanisms used by the parasite to evade them, and the protective or detrimental contribution of these interactions on parasite progression through its life cycle and pathology in the host. PMID- 25450890 TI - Social influences on eating. An introduction to the special issue. PMID- 25450888 TI - Analysis of microvasculature phenotype and endothelial activation markers in skin lesions of lacaziosis (Lobomycosis). AB - Jorge Lobo's disease is a rare mycosis characterized by chronic inflammation, which causes skin lesions in the absence of visceral dissemination. The disease occurs mainly in hot and humid climates and most cases have been registered in the Brazilian Amazon region. This study investigated possible microvascular alterations in skin lesions caused by infection with Lacazia loboi which may interfere with the clinical progression of the disease. Immunohistochemistry was used to evaluate the density of blood and lymphatic vessels, as well as expression of the cell adhesion molecules ICAM-1, VCAM-1 and E-selectin. The results showed a reduced number of blood (62.66 +/- 20.30 vessels/mm(2)) and lymphatic vessels (3.55 +/- 5.84 vessels/mm(2)) in Jorge Lobo's disease when compared to control skin (169.66 +/- 66.38 blood vessels/mm(2) and 8 +/- 2.17 lymphatic vessels/mm(2)). There were a larger number of vessels expressing ICAM-1 (27.58 +/- 15.32 vessels/mm(2)) and VCAM-1 (7.55 +/- 6.2 vessels/mm(2)). No difference was observed in the expression of E-selectin (4.66 +/- 11 vessels/mm(2)). Taken together, the results indicate changes in the local microvasculature which may interfere with the development of an efficient cell mediated immune response and may explain restriction of the fungus to the site of injury. PMID- 25450891 TI - Using the theory of planned behaviour to measure motivation for recovery in anorexia nervosa. AB - Anorexia nervosa (AN) is a difficult to treat mental illness associated with low motivation for change. Despite criticisms of the transtheoretical stages of change model, both generally and in the eating disorders (EDs), this remains the only model to have been applied to the understanding of motivation to recover from AN. The aim of this pilot study was to determine whether the theory of planned behaviour (TPB) would provide a good fit for understanding and predicting motivation to recover from AN. Two studies were conducted - in the first study eight women who had recovered from chronic AN were interviewed about their experiences of recovery. The interview data were subsequently used to inform the development of a purpose-designed questionnaire to measure the components of the TPB in relation to recovery. In the second study, the resultant measure was administered to 67 females with a current diagnosis of AN, along with measures of eating disorder psychopathology, psychological symptoms, and an existing measure of motivation to recover (based on the transtheoretical model). Data from the interview study confirmed that the TPB is an appropriate model for understanding the factors that influence motivation to recover from AN. The results of the questionnaire study indicated that the pre-intention variables of the TPB accounted for large proportions of variance in the intention to recover (72%), and more specifically the intention to eat normally and gain weight (51%). Perceived behavioural control was the strongest predictor of intention to recover, while attitudes were more important in the prediction of the intention to eat normally/gain weight. The positive results suggest that the TPB is an appropriate model for understanding and predicting motivation in AN. Implications for theory and practice are discussed. PMID- 25450892 TI - Nutritional responses to acute training sessions in young elite rugby players. AB - BACKGROUND: Acute exercise has been shown to induce nutritional adaptations in obese and lean inactive youth but it remains unclear whether youth with a high level of physical activity experience such exercise-induced energy intake and appetite modifications. METHODS: 14 (15- to 16-year-old) male elite rugby players completed sessions on three separate occasions: (1) a control session (CON); (2) an exercise session (EX) and; (3) a rugby session (RUGBY). The energy induced by the rugby and exercise sessions was matched (Polar Team2 pro technology), and participants' energy intake, food preferences (ad libitum buffet meals) and appetite feelings (Visual Analogue Scales) were assessed throughout the experimental days. RESULTS: The energy intake during lunch and snack time was not different between conditions. Dinner time energy intake was significantly increased after RUBGY compared to CON with respectively 969 +/- 145 kcal and 777 +/- 183 kcal (p < 0.05). The energy intake at dinner time was significantly increased during EX (1185 +/- 199 kcal) compared to both CON (p < 0.001) and RUGBY (p < 0.01). None of the appetite feelings investigated were modified between sessions. CONCLUSION: Adolescent elite rugby players regulate their energy intake differently depending on the nature of their training; independently of the energy expended. This demonstrates the need for energetic and nutritional education to optimize their physical fitness and performance. PMID- 25450893 TI - Illusionary delusions. Willingness to exercise self-control can mask effects of glucose on self-control performance in experimental paradigms that use identical self-control tasks. AB - The purpose of the present article is to highlight limitations of Lange and Eggert's methodology of using identical self-control tasks in testing effects of glucose on depletion of self-control resources and self-control performance. We suggest that when participants engage in two identical self-control tasks, cognitions developed during initial act of self-control may mask the effects of glucose on self-control performance by undermining willingness to exert effort during the second act of self-control. As a consequence, glucose may increase ability to exercise self-control but participants may not want to capitalize on this "ability advantage" because they are unwilling to exercise self-control. The present article concludes that researchers who test the glucose hypothesis in the context of a depletion paradigm should employ dissimilar acts of self-control and ensure that depleted participants are sufficiently motivated to exercise self control. PMID- 25450894 TI - If ego depletion cannot be studied using identical tasks, it is not ego depletion. AB - The hypothesis that human self-control capacities are fueled by glucose has been challenged on multiple grounds. A recent study by Lange and Eggert adds to this criticism by presenting two powerful but unsuccessful attempts to replicate the effect of sugar drinks on ego depletion. The dual-task paradigms employed in these experiments have been criticized for involving identical self-control tasks, a methodology that has been argued to reduce participants' willingness to exert self-control. The present article addresses this criticism by demonstrating that there is no indication to believe that the study of glucose effects on ego depletion should be restricted to paradigms using dissimilar acts of self control. Failures to observe such effects in paradigms involving identical tasks pose a serious problem to the proposal that self-control exhaustion might be reversed by rinsing or ingesting glucose. In combination with analyses of statistical credibility, the experiments by Lange and Eggert suggest that the influence of sugar on ego depletion has been systematically overestimated. PMID- 25450895 TI - Unsuccessful attempts to replicate effects of self control operations and glucose on ego-depletion pose an interesting research question that demands explanation. AB - The hypothesis that sugar-containing drinks counteract depletion of self-control or ego resources is elegant and provocative because it entails that the origins of ego-energy and self-control operations can be traced to a physiological substrate. However, this hypothesis has not withstood scientific scrutiny. Lange and Eggert presented two unsuccessful attempts to replicate effects of glucose on ego-depletion. Chatzisarantis and Hagger argued that inconsistent findings may be due to experimental designs that expose participants to similar acts of self control. This methodology may not provide a rigorous test of the counteracting effects of glucose on ego-depletion because it does not control for factors (i.e., motivation) that interfere with glucose effects. In this article, we address Lange's comments and explore the possibility that findings reported by Lange and Eggert's and Hagger and Chatzisarantis' studies are consistent. In addition, we discuss a factor that researchers may wish to take into consideration when designing experiments that aim to test effects of glucose, or glucose rinsing, on ego-depletion. This factor is related to ego-depleting value of self-control tasks. PMID- 25450896 TI - Does maternal history of eating disorders predict mothers' feeding practices and preschoolers' emotional eating? AB - We aimed to examine whether a maternal history of eating disorders predicted mothers' feeding practices and preschoolers' emotional eating patterns. Data were available from 4851 mothers and their children, who participated in a Dutch population-based cohort study (the Generation R Study). Maternal history of lifetime eating disorders was assessed during pregnancy using a self-report questionnaire. Mothers filled out the Child Feeding Questionnaire and the Child Eating Behaviour Questionnaire when children were four years old. Linear regression analyses were performed, adjusting for potential confounders. Of all mothers, 8.6% had a history of an eating disorder (2.5% anorexia nervosa (AN); 3.9% bulimia nervosa (BN); 2.2% both AN and BN). Compared to mothers without a history of eating disorders, mothers with a history of eating disorders, in particular AN, used less pressuring feeding strategies (standardized B = -0.30; 95% CI: -0.49, -0.11). Children of mothers with a history of AN had relatively high levels of emotional overeating (standardized B = 0.19; 95% CI: 0.00, 0.39). Maternal history of BN was not related to mothers' feeding practices or children's emotional eating. Overall, the levels of emotional overeating among children of mothers with a history of eating disorders are noteworthy, particularly considering the young age (4 years) of participating children. This finding may reflect an effect of maternal eating disorders on the development of disordered eating patterns, but could also be subject to mothers' perception. PMID- 25450897 TI - Can't wait to lose weight? Characterizing temporal discounting parameters for weight-loss. AB - Obesity is often related to steeper temporal discounting, that is, higher decision impulsivity for immediate rewards over delayed rewards. However, previous studies have measured temporal discounting parameters through monetary rewards. The aim of this study was to develop a temporal discounting measure based on weight-loss rewards, which may help to understand decision-making mechanisms more closely related to body weight regulation. After having their heights and weights measured, healthy young adults completed the Monetary Choice Questionnaire (MCQ), and an adapted version of the MCQ, with weight-loss as a reward. Participants also completed self-reports that measure obesity-related cognitive variables. For 42 participants who expressed a desire to lose weight, weight-loss rewards were discounted over time and had a positive correlation with temporal discounting for monetary rewards. Higher temporal discounting for weight loss rewards (i.e., preference for immediate weight loss) showed correlations with beliefs that obesity is under obese persons' control and largely due to lack of willpower, while temporal discounting parameters for monetary rewards did not. Taken together, our weight loss temporal discounting measure demonstrated both convergent and divergent validity, which can be utilized for future obesity research and interventions. PMID- 25450898 TI - Nutrition practices of nurseries in England. Comparison with national guidelines. AB - Recent national guidelines call for improved nutrition within early years settings. The aim of this cross-sectional study was to describe foods and beverages served in nurseries, assess provider behaviors related to feeding, and compare these practices to national guidelines. We administered a mailed survey to a random sample of nurseries across England, stratifying by tertile of deprivation. A total of 851 nurseries returned the survey (54.3% response rate). We fitted separate multivariate logistic regression models to estimate the association of deprivation with each of the 13 food and beverage guidelines and the seven provider behavior guidelines. We also conducted a joint F-test for any deprivation effect, to evaluate the effect of the guidelines combined. After adjusting for confounders, we observed differences in the frequency of nurseries that reported serving healthier foods across the tertiles of deprivation (p = 0.02 for joint F test). These adjusted results were driven mainly by nurseries in more deprived areas serving more whole grains (OR 1.57 (95% CI 1.00, 2.46)) and legumes, pulses, and lentils (1.40 (1.01, 2.14)). We also observed differences in the frequency of nurseries reporting more provider behaviors consistent with national guidelines across the tertiles of deprivation (p = 0.01 for joint F test). Nurseries in more deprived areas were more likely to dilute juice with water (2.35 (1.48, 3.73)), allow children to select their own portions (1.09 (1.06, 1.58)), and sit with children during meals (1.84 (1.07, 3.15)). While nurseries in the most deprived areas reported serving more healthy foods, a large percentage were still not meeting national guidelines. Policy and intervention efforts may increase compliance with national guidelines in nurseries in more deprived areas, and across England. PMID- 25450899 TI - Mating strategy, disgust, and food neophobia. AB - Food neophobia and disgust are commonly thought to be linked, but this hypothesis is typically implicitly assumed rather than directly tested. Evidence for the connection has been based on conceptually and empirically unsound measures of disgust, unpublished research, and indirect findings. This study (N = 283) provides the first direct evidence of a relationship between trait-level food neophobia and trait-level pathogen disgust. Unexpectedly, we also found that food neophobia varies as a function of sexual disgust and is linked to mating strategy. Using an evolutionary framework, we propose a novel hypothesis that may account for these previously undiscovered findings: the food neophilia as mating display hypothesis. Our discussion centers on future research directions for discriminatively testing this novel hypothesis. PMID- 25450901 TI - Expression of visfatin in alloxan-induced diabetic rat testis. AB - Diabetes mellitus is a potential epidemic all over the world and causes dysfunction of reproductive activity. Visfatin, one of the adipokines, is present in various tissues including the testis. Our hypothesis was the level of testicular visfatin is affected in diabetic condition. The aim of the present study was to investigate the expression and localization of visfatin in the diabetic rat testis. No similar studies have been performed in diabetic rat testis with reference to visfatin. Overnight fasted adult male Wistar rats were made diabetic by the administration of alloxan (150 mg/kg i.p., in 0.9% saline). Blood glucose levels were tested on five days after alloxan treatment, rats with high blood glucose levels (>250 mg/dL) were considered as diabetic. Immunolocalization and Western blotting analysis of visfatin were performed. Correlation of visfatin expression was made in relation to body weight, testis weight, glucose concentration and serum testosterone level. Expression of visfatin was observed in Leydig cells, spermatocytes and sperm in control as well as in the diabetic group. Mild immunostaining of visfatin was observed in affected seminiferous tubules of alloxan-induced diabetic rat testis. Western blot analysis showed decreased expression of testicular visfatin in diabetic rats. The expression of visfatin showed a positive correlation with serum testosterone levels, body and testis weight, while a negative correlation was observed with blood glucose levels. This study showed involvement of visfatin in diabetic associated impairment of testicular activity. PMID- 25450900 TI - Understanding eating in the absence of hunger among young children: a systematic review of existing studies. AB - BACKGROUND: Eating in the Absence of Hunger (EAH), or consuming highly palatable foods when satiated, is one behavioral pathway that may lead to childhood obesity. EAH is an objective, laboratory-based measure. A more comprehensive understanding of potential determinants of EAH could inform childhood obesity programs outside of a laboratory setting. OBJECTIVE: Systematic review of EAH experiments to identify individual, familial, and societal-level correlates of EAH among children 12 years of age or younger. DESIGN: 1487 studies were retrieved from five electronic databases (Medline [PubMed], Web of Science, Cochrane Library, CINAHL, PsycINFO). Eligible studies were those that measured EAH as initially operationalized in a laboratory setting enrolling children <=12 years or reporting age-specific results for children <=12 years. Only articles written in English were included. RESULTS: 12 cross-sectional, six prospective, and one behavioral-intervention studies were included in the review. EAH was observable among boys and girls; absolute levels of EAH increased with age; and maternal feeding styles were associated with EAH among girls. The most consistent evidence supported increased levels of EAH among overweight and obese versus normal weight children, both cross-sectionally and prospectively. Two studies supported a genetic component to EAH. CONCLUSIONS: Studies enrolling independent samples support a positive association between weight status and EAH among children; studies addressing causality are needed. Other various individual, genetic, and familiar characteristics were associated with EAH, yet studies among more heterogeneous sample populations are needed to confirm findings. Studies addressing societal-level factors related to EAH were absent. PMID- 25450902 TI - Combination of Pitavastatin and melatonin shows partial antineoplastic effects in a rat breast carcinoma model. AB - Our previous results indicated significant tumor-suppressive effects of different statins in rat mammary carcinogenesis. The purpose of this experiment was to examine the chemopreventive effects of Pitavastatin alone and in combination with the pineal hormone melatonin in the model of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female Sprague-Dawley rats. Pitavastatin was administered dietary (10mg/kg) and melatonin in an aqueous solution (20MUg/ml). Chemoprevention began 7 days prior to carcinogen administration and subsequently continued for 15 weeks until autopsy. At autopsy, mammary tumors were removed and prepared for histopathological and immunohistochemical analysis. Compared to controls, Pitavastatin alone reduced average tumor volume by 58% and lengthened latency by 8 days; on the other hand, the drug increased tumor frequency by 23%. Combined administration of Pitavastatin with melatonin decreased tumor frequency by 23%, tumor volume by 44% and lengthened tumor latency by 5.5 days compared to control animals. The analysis of carcinoma cells showed significant increase in caspase-3 expression in both treated groups and a tendency of increased caspase-7 expression after Pitavastatin treatment alone. Significant expression decrease of Ki67 was found in carcinoma cells from both treated groups. Compared to control carcinoma cells, Pitavastatin alone increased VEGF expression by 41%, however melatonin totally reversed its undesirable effect. Pitavastatin combined with melatonin significantly increased femur compact bone thickness in animals. Pitavastatin alone decreased plasma triglycerides and total cholesterol levels, however it significantly increased levels of glucose. In summary, our results show a partial antineoplastic effect of Pitavastatin combined with melatonin in the rat mammary gland carcinoma model. PMID- 25450903 TI - The efficacy of low-level laser therapy for shoulder tendinopathy: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND AND PURPOSE: Low-level laser therapy (LLLT) is proposed as a treatment for tendinopathies. This is the first systematic review focusing solely on LLLT treatment effects in shoulder tendinopathy. METHODS: A systematic review with meta-analysis and primary outcome measures pain relief on 100-mm visual analogue scale (VAS) and relative risk for global improvement. Two independent assessors rated the included studies according to the PEDro scale. Intervention quality assessments were performed of LLLT dosage and treatment procedures according to World Association for Laser Therapy guidelines. The included trials were sub grouped by intervention quality and use of other physiotherapy interventions. RESULTS: Seventeen randomized controlled trials (RCTs) met the inclusion criteria, and 13 RCTs were of high and 4 RCTs of moderate methodological quality. Significant and clinically important pain relief was found with weighted mean differences (WMD) over placebo, for LLLT as monotherapy at 20.41 mm (95% CI: 12.38 to 28.44) and as adjunct to exercise therapy at 16.00 mm (95% CI: 11.88 to 20.12). The WMD when LLLT was used in a multimodal physiotherapy treatment regime reached statistical significance over placebo at 12.80 (95% CI: 1.67-23.94) mm pain reduction on VAS. Relative risks for global improvement were statistically significant at 1.96 (95% CI: 1.25-3.08) and 1.51 (95% CI: 1.12-2.03), for laser as monotherapy or adjunctive in a physiotherapy regime, respectively. Secondary outcome measures of shoulder function were only significantly in favour of LLLT when used as monotherapy. Trials performed with inadequate laser doses were ineffective across all outcome measures. CONCLUSION: This review shows that optimal LLLT can offer clinically relevant pain relief and initiate a more rapid course of improvement, both alone and in combination with physiotherapy interventions. Our findings challenge the conclusions in previous multimodal shoulder reviews of physiotherapy and their lack of intervention quality assessments. PMID- 25450904 TI - LGP2 plays extensive roles in modulating innate immune responses in Ctenopharyngodon idella kidney (CIK) cells. AB - LGP2 (laboratory of genetics and physiology 2), RIG-I (retinoic acid inducible gene-I) and MDA5 (melanoma differentiation associated gene 5) constitute the RLR (RIG-I-like receptor) family. LGP2 plays a pivotal role in modulating signaling of RIG-I and MDA5 in innate immune responses. In this study, three representative overexpression vectors were constructed and transfected into C. idella kidney (CIK) cell line to research functional characterizations of CiLGP2 (C. idella LGP2). CiLGP2 overexpression led to the induction of CiRIG-I transcripts. After GCRV challenge, CiLGP2 enhanced CiMDA5 and CiIPS-1 to reinforce the immune response, however, impaired the expression of CiRIG-I. Meanwhile, antiviral activity assays showed that overexpression of CiLGP2 or its domains could inhibit GCRV replication and protect cells from death. Besides, CiLGP2 lingeringly induced CiRIG-I mRNA expression and inhibited CiMDA5 transcripts post poly(I:C) simulation. As a result, CiLGP2 suppressed the RLR-mediated signaling pathway against poly(I:C). Furthermore, CiLGP2 played active roles in RLR signaling response to bacterial PAMPs (LPS and PGN) stimulation. CiLGP2 altered the expression pattern of CiIPS-1 after LPS treatment, while it significantly enhanced the RLR signaling pathway against PGN stimulation. These results collectively suggested that CiLGP2 played a strikingly broad regulation in RLR mediated innate immune responses in C. idella, responding to not only the dsRNA virus or synthetic dsRNA but also bacterial PAMPs, which contribute to the understanding of C. idella LGP2 and RLR signaling pathways. In addition, these results lay a foundation for the further functional mechanism research of LGP2 in fishes. PMID- 25450906 TI - Acute cold stress improved the transcription of pro-inflammatory cytokines of Chinese soft-shelled turtle against Aeromonas hydrophila. AB - Chinese soft-shelled turtle, Pelodiscus sinensis, is widely cultured in East and Southeast Asian countries. It frequently encounters the stress of abrupt temperature changes, which leads to mass death in most cases. However, the mechanism underlying the stress-elicited death remains unknown. We have suspected that the stress impaired the immune function of Chinese soft-shelled turtle, which could result in the mass death, as we noticed that there was a clinical syndrome of infection in dead turtles. To test our hypothesis, we first performed bioinformatic annotation of several pro-inflammatory molecules (IL-1beta, TNFalpha, IL-6, IL-12beta) of Chinese soft-shelled turtle. Then, we treated the turtles in six groups, injected with Aeromonas hydrophila before acute cold stress (25 degrees C) and controls, after acute cold stress (15 degrees C) and controls as well as after the temperature was restored to 25 degrees C and controls, respectively. Subsequently, real-time PCR for several pro-inflammatory cytokines (IL-1beta, TNFalpha, IL-6, IL-12beta, IL-8 and IFNgamma) was performed to assess the turtle immune function in spleen and intestine, 24 hours after the injection. We found that the mRNA expression levels of the immune molecules were all enhanced after acute cold stress. This change disappeared when the temperature was restored back to 25 degrees C. Our results suggest that abrupt temperature drop did not suppress the immune function of Chinese soft-shelled turtle in response to germ challenge after abrupt temperature drop. In contrast, it may even increase the expression of various cytokines at least, within a short time after acute cold stress. PMID- 25450905 TI - Identification and characterization of a cathepsin D homologue from lampreys (Lampetra japonica). AB - Cathepsin D (EC 3.4.23.5) is a lysosomal aspartic proteinase of the pepsin superfamily which participates in various digestive processes within the cell. In the present study, the full length cDNA of a novel cathepsin D homologue was cloned from the buccal glands of lampreys (Lampetra japonica) for the first time, including a 124-bp 5' terminal untranslated region (5'-UTR), a 1194-bp open reading frame encoding 397 amino acids, and a 472-bp 3'-UTR. Lamprey cathepsin D is composed of a signal peptide (Met 1-Ala 20), a propeptide domain (Leu 21-Ala 48) and a mature domain (Glu 76-Val 397), and has a conserved bilobal structure. Cathepsin D was widely distributed in the buccal glands, immune bodies, hearts, intestines, kidneys, livers, and gills of lampreys. After challenging with Escherichia coli or Staphylococcus aureus, the expression level of lamprey cathepsin D in the buccal gland was 8.5-fold or 6.5-fold higher than that in the PBS group. In addition, lamprey cathepsin D stimulated with Escherichia coli was also up-regulated in the hearts, kidneys, and intestines. As for the Staphylococcus aureus challenged group, the expression level of lamprey cathepsin D was found increased in the intestines. The above results revealed that lamprey cathepsin D may play key roles in immune response to exogenous pathogen and could serve as a potential antibacterial agent in the near future. In addition, lamprey cathepsin D was subcloned into pcDNA 3.1 vector and expressed in the human embryonic kidney 293 cells. The recombinant lamprey cathepsin D could degrade hemoglobin, fibrinogen, and serum albumin which are the major components in the blood, suggested that lamprey cathepsin D may also act as a digestive enzyme during the adaptation to a blood-feeding lifestyle. PMID- 25450907 TI - Diversity of animal immune receptors and the origins of recognition complexity in the deuterostomes. AB - Invertebrate animals are characterized by extraordinary diversity in terms of body plan, life history and life span. The past impression that invertebrate immune responses are controlled by relatively simple innate systems is increasingly contradicted by genomic analyses that reveal significant evolutionary novelty and complexity. One accessible measure of this complexity is the multiplicity of genes encoding homologs of pattern recognition receptors. These multigene families vary significantly in size, and their sequence character suggests that they vary in function. At the same time, certain aspects of downstream signaling appear to be conserved. Here, we analyze five major classes of immune recognition receptors from newly available animal genome sequences. These include the Toll-like receptors (TLR), Nod-like receptors (NLR), SRCR domain scavenger receptors, peptidoglycan recognition proteins (PGRP), and Gram negative binding proteins (GNBP). We discuss innate immune complexity in the invertebrate deuterostomes, which was first recognized in sea urchins, within the wider context of emerging genomic information across animal phyla. PMID- 25450909 TI - Polybrominated diphenyl ethers (PBDEs) in the indoor dust in China: levels, spatial distribution and human exposure. AB - Indoor environment is an important source of human exposure to several toxicants, such as brominated flame retardants. Indoor dust samples were collected in winter season in 2010, which covered 23 provinces across China, for the analysis of polybrominated diphenyl ethers (PBDEs). Concentrations of PBDEs (Sigma14PBDEs) ranged from 8.92 to 37,500 ng/g, with the mean of 3520 ng/g. BDE-209 was the most dominate congener, followed by BDE-183, BDE-47 and BDE-99. PBDE concentrations and the longitude were significantly correlated (p<0.05), which was consistent with the status of social-economic development and human activities. The results of exposure to PBDEs through dust ingestion and dermal absorption indicated that the toddlers had the highest exposure dose, with the median value of 6.0 ng/kg bw/day. According to the hazard quotients, health risk of PBDEs via dust ingestion in China is currently acceptable. Monte Carlo simulation was implemented to quantify the uncertainty and sensitivity of exposure models for determining the most influential variables. The results suggested that more specific and accurate parameters should be used for dust ingestion and dermal absorption exposure models in future. PMID- 25450908 TI - The DNA fibers of shrimp hemocyte extracellular traps are essential for the clearance of Escherichia coli. AB - Extracellular traps (ETs) are a part of the vertebrate immune response that was only recently discovered. These structures are formed in response to pathogenic invasion and they act to kill the invader. Vertebrate ETs are composed of chromosomal DNA, histone proteins and other antimicrobial cytoplasmic proteins. Pathogenic stimulation was also recently shown to trigger a similar ET response in shrimp hemocytes, and in the present study, we evaluate the role of the DNA fibers in the bactericidal properties of these invertebrate ETs. When the formation of shrimp ETs was disrupted by DNase I, the ETs anti-bacterial activity was also reduced, indicating that the DNA fibers are important for ET-mediated bacterial clearance. We also found that at high bacterial densities, shrimp ETs were a more effective anti-bacterial response than phagocytosis. PMID- 25450910 TI - Refinement of biodegradation tests methodologies and the proposed utility of new microbial ecology techniques. AB - Society's reliance upon chemicals over the last few decades has led to their increased production, application and release into the environment. Determination of chemical persistence is crucial for risk assessment and management of chemicals. Current established OECD biodegradation guidelines enable testing of chemicals under laboratory conditions but with an incomplete consideration of factors that can impact on chemical persistence in the environment. The suite of OECD biodegradation tests do not characterise microbial inoculum and often provide little insight into pathways of degradation. The present review considers limitations with the current OECD biodegradation tests and highlights novel scientific approaches to chemical fate studies. We demonstrate how the incorporation of molecular microbial ecology methods (i.e., 'omics') may improve the underlying mechanistic understanding of biodegradation processes, and enable better extrapolation of data from laboratory based test systems to the relevant environment, which would potentially improve chemical risk assessment and decision making. We outline future challenges for relevant stakeholders to modernise OECD biodegradation tests and put the 'bio' back into biodegradation. PMID- 25450911 TI - Environmental effects on the gills and blood of Oreochromis niloticus exposed to rivers of Bahia, Brazil. AB - Through the integration of chemical, biochemical and morphological analyses, this study investigated the effects of multiple pollutants on environmental biomarkers, such as gill histopathological changes and hematological and biochemical parameters, in Oreochromis niloticus exposed to four sites in the Jacuipe and Subae rivers over seven days. Sediment analyses identified Sapelba as the most contaminated site, followed by Oliveira de Campinhos, Santo Amaro and Jacuipe. Water analyses revealed aluminum, iron and manganese at all sites. Aluminum and other metal were also detected in the gills of fishes. Fish exposed to the Sapelba site exhibited significant necrosis formation, as well as higher hematological parameters and trend to increase of cortisol levels. However, filament epithelium proliferation was higher at the Oliveira de Campinhos and Santo Amaro sites, at which the lowest levels of the hematological variables were observed. Multivariate analysis grouped some gill histopathological changes together, such as epithelial detachment with edema and lamellar epithelial proliferation with the lamellar fusion of adjacent filaments, revealing relationships among them. Positive associations were identified between sediment contamination and necrosis and cortisol, while water contamination was related with filament epithelium proliferation, aneurism, lamellar fusion and several hematological parameters. Furthermore, relationships between blood parameters and gill histopathological changes demonstrated a joint physiological response that may have resulted from environmental variables such as dissolved oxygen. The results exhibited the direct influence of xenobiotics on these biomarkers but also highlighted the need to consider the complexity of environmental factors to optimize the adoption of these environmental predictive tools. PMID- 25450912 TI - Biochemical and behavioral responses of the Amazonian fish Colossoma macropomum to crude oil: the effect of oil layer on water surface. AB - The largest Brazilian terrestrial province of petroleum mining is located at the margins of Urucu River, Amazonas. Mined crude oil is transported along 400 km across Solimoes River to be refined in Manaus. Thus, the main goal of this study was to evaluate the effects of crude oil exposure on biochemical, physiological and behavioral parameters of juveniles of the Amazonian fish tambaqui (Colossoma macropomum). The toxicity of water-soluble and insoluble oil fractions and the influence of a layer formed by the oil on the water surface from low and high concentrations of crude oil were analyzed. The results showed a strong physical effect of oil at the water surface and a significant effect on fish behavior. Swimming time and response to alarm substance decreased when fish was exposed for just one day to water insoluble fraction, and remain lower after 30 days of exposure, compared to control. Chronic exposure to water insoluble fraction of the inert oil also affected these two parameters. Critical swimming velocity decreased in fish exposed to both crude and inert oil water insoluble fraction. These reductions are possibly related to a decrease in aerobic capacity. Only exposure to high concentrations of petroleum water-soluble fractions induced transient alterations of the analyzed parameters. The exposure of fish to low and high concentrations of water insoluble fraction of Urucu oil caused a reduction of responses to alarm substance, spontaneous swimming activity and swimming capacity (Ucrit), decreased activity of acetylcholinesterase, and increased activity of alkaline phosphatase. Severe hypertrophy of lamellar epithelium and extensive lamellar fusion of the gills were also observed. Overall, these results show significant behavioral and physiological changes caused by the oil layer on the water surface, which means that toxicity of petroleum produced by its chemical components is, in fact, in this fish species, enhanced by the presence of an oil phase as a physical barrier. PMID- 25450913 TI - Partitioning of PAHs in pore water from mangrove wetlands in Shantou, China. AB - To investigate the trend of selected polycyclic aromatic hydrocarbons (PAHs) partitioning, fifteen pore water samples collected from the sediments of three mangrove wetlands were analyzed, and the partition coefficients and the partition model for the PAHs were determined by the correlation between K(oc) and octanol water partition coefficient (K(ow)). The results revealed that the mean Kp values in inner mangrove wetlands were between 143 and 1031 L /Kg; the particulate organic carbon (POC) could strongly adsorb low-ring PAHs; the PAHs partitioning was on a obvious trend transported to particle phase. We suggest that the classic equilibrium model of organic carbon normalized (K(p)=K(oc)f(oc)) may be used to predict the trend of the selected PAHs partitioning. PMID- 25450914 TI - Toxic effects of heavy metal terbium ion on the composition and functions of cell membrane in horseradish roots. AB - The environmental safety of rare earth elements (REEs), especially the toxic effect of REEs on plants, has attracted increasing attention. However, the cellular mechanism of this toxic effect remains largely unknown. Here, the toxic effects of heavy REE terbium ion [Tb(III)] on the cell membrane of horseradish roots were investigated by using electron microscope autoradiography (EMARG) and histochemical methods. The results indicated that Tb(III) was distributed in the extracellular and intracellular spaces of the roots after horseradish was treated with Tb(III). Moreover, the percentage contents of the unsaturated fatty acids in the membrane lipids, the current of the outward K(+) channel and the average diameter of membrane proteins in the roots of horseradish treated with Tb(III) were decreased; on the contrary, the percentage contents of the saturated fatty acids and malondialdehyde in the roots of horseradish treated with Tb(III) were increased. Furthermore, the contents of intracellular N, P, Mg and Fe in the roots of horseradish treated with Tb(III) were decreased, while the contents of intracellular K and Ca in the roots of horseradish treated with Tb(III) were increased. Finally, the effects of Tb(III) on horseradish roots were increased with increasing concentration or duration of Tb(III) treatment. In conclusion, after horseradish was treated with Tb(III), Tb(III) could enter the cells of horseradish roots and lead to the toxic effects on horseradish, which caused the oxidation of the unsaturated fatty acids in the membrane lipids, the changes in the membrane proteins (including the outward K(+) channel), the decrease in the membrane fluidity, and then the inhibition of the intracellular/extracellular-ion exchange in horseradish roots. PMID- 25450915 TI - Effects of copper on induction of thiol-compounds and antioxidant enzymes by the fruiting body of Oudemansiella radicata. AB - Oudemansiella radicata has been found to have ability to tolerate and accumulate heavy metals. In this study, to know about the metal tolerance and detoxification strategy of O. radicata, the tolerance responses in both cap and stipe of the fruiting body, including the copper content, the changes of thiol compounds production and antioxidant enzymes activities, caused by various copper stress (150-600 mg kg(-1)) during 2-6 days were investigated. Results showed that Cu content in the fruiting bodies increased with the increasing Cu concentrations and growing time, which was higher in cap than that in stipe. For thiols contents, the maximum level was in the sample at 300 mg kg(-1) Cu after 2 d both in cap and stipe, in accordance with superoxide dismutase (SOD) and glutathione reductase (GR) activities. Guaicol peroxidase (POD) activities reached maximum at 150 mg kg(-1) Cu after 4 d and 6 d, respectively in cap and stipe, while the maximum of catalase (CAT) activities was recorded at 300 and 600 mg kg(-1) Cu after 4 d in the cap and stipe, respectively. As a whole, low concentration of Cu stimulated the production of thiols and activated the antioxidant enzymes activities in the fruiting body of O. radicata after 2/4 d, while high-level Cu decreased the thiols production and enzymes activities after 4/6 d. Furthermore, the cap was more sensitive than the stipe to Cu exposure. Different indicators showed different responses to copper accumulation and the different fruiting part (cap and stipe) of O. radicata had ability to response the oxidative stress caused by Cu. Considering the metal accumulation and its own detoxification with short growing time, mushroom might have the potential to be used as bio accumulator to deal with Cu exposure in the Cu-contaminated farmland soil. PMID- 25450916 TI - The combinational effects between sulfonamides and metals on nematode Caenorhabditis elegans. AB - As emerging pollutants, antibiotic sulfonamides are continuously emitted into the environment and encounter those already-existing contaminants, e.g., heavy metals, which may cause toxicity interactions in polluted habitats. So far, the sulfonamide mixture effects and the combinational effects between sulfonamides and metals have been seldom studied. In this study, lifespan, lethality (24 and 120 h), locomotion behavior and growth (96 h) of Caenorhabditis elegans were measured after exposure to mixtures containing sulfonamides (sulfadiazine, sulfapyridine, sulfamethoxazole and sulfamethazine as representatives) and/or metals (cadmium, copper, lead and zinc as representatives) at environmental concentrations. Results showed that sulfonamides did not cause acute (24 h) lethality at chosen concentrations, but they decreased the lifespan in a concentration dependent fashion. Moreover, sulfonamide mixtures caused synergisms at higher concentrations but antagonisms at lower concentrations on the subacute (120 h) lethal effects. The toxicity interactions of sulfonamide mixtures were addition action on body bending frequency, and antagonism on reversal movement and body length. In sulfonamide and metal mixtures, the toxicity interactions were different in acute and subacute lethal results, indicating the influence of the exposure time. According to the comparison among effects of mixtures containing sulfonamides and/or metals, subacute lethality of sulfonamides was enhanced by metals based on the synergistic mixture effects, while their inhibitions on the growth and behavior were weakened by metals based on the antagonistic mixture effects. Our findings highlighted studies on combinational effects between emerging and common contaminants for more accurate environmental risk evaluation, and also urged further mechanism studies. PMID- 25450917 TI - Phytoremediation of lead using corn in contaminated agricultural land-an in situ study and benefit assessment. AB - Phytoremediation is an environmentally friendly and economically feasible remediation technology for mitigating soil contamination in agricultural lands. However, phytoremediation can be a slow process, and for highly contaminated soils this approach would require hundreds to thousands of years to meet soil environmental quality standards. Such a long period of phytoremediation is relatively unfeasible without economic revenue from crop production. This study involves growth of corn in plots of lead-contaminated agricultural land with Pb concentrations of about 6000 mg/kg. Our results showed that Bright Jean No. 7 corn was highly tolerant to lead, as evidenced by minimal effects on its growth and biomass production. Annually, each hectare of corn could produce up to 93.4 tons of dry matter and removed up to 7.2 kg of lead. The corn biomass grown on such contaminated fields could be used as a bioenergy fuel, and each hectare of corn biomass could produce 1545 GJ of thermal energy every year, which is equivalent to the heat from combustion of 57 tons of hard coal. The lead content in the corn kernel was less than the EU standard limit for animal consumption. Each hectare could produce approximately 25 tons of corn grains for animal feed per year, and the remaining parts of the plant could be used as the bioenergy fuel to generate heat energy equivalent to 40 tons of hard coal. PMID- 25450918 TI - Biochemical responses in the gills of Meretrix meretrix after exposure to treated municipal effluent. AB - The biochemical effects in marine bivalves exposed to increasing concentrations of treated municipal effluent (TME), as discharged into receiving marine waters, are investigated. The effluent was collected from a municipal sewage treatment plant (STP) in Qingdao (China). Meretrix meretrix were exposed to effluent volume ratio (EVR, ratio of effluent volume accounted for tailwater seawater mixture) 0%, 1%, 5%, 10%, and 20% (v/v) TME for 15 days and the following biochemical responses in gills were measured: (1) the activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione (GSH) content, and lipid peroxidation levels of malondialdehyde (MDA), as oxidative stress biomarkers; (2) the activity of 7-ethoxyresorufin O deethylase (EROD) and gluthathione S-transferase (GST), as phase I and phase II conjugation enzymes, respectively; (3) acetylcholinesterase (AChE), as a biomarker of neurotoxicity, and (4) metallothioneins (MTs), as proteins strongly induced by heavy metals. Most of the biochemical indices present high and significant variation frequency (above 50%). There is enhancement in the antioxidant enzymes, EROD, GST, AChE, and MTs, as well as consumption of GSH. The current experimental results suggest that effluent with concentrations less than 20% (v/v) do not cause lipid peroxidation damage. This implies that the activated defense is sufficient to protect the bivalves' gill tissues from cytotoxicity produced by the effluent. Furthermore, GSH, GPx, MTs, and GR are suitable, and sufficiently sensitive, biomarkers to indicate the pollution levels in marine environments receiving such effluent. PMID- 25450919 TI - Integrated micro-biochemical approach for phytoremediation of cadmium and zinc contaminated soils. AB - The integrated potential of oilcake manure (OM), elemental sulphur (S(0)), Glomus fasciculatum and Pseudomonas putida by growing Helianthus annuus L for phytoremediation of cadmium and zinc contaminated soils was investigated under pot experiment. The integrated treatment (2.5 g kg(-1) OM, 0.8 g kg(-1) S(0) and co-inoculation with G. fasciculatum and P. putida promoted the dry biomass of the plant. The treatment was feasible for enhanced cadmium accumulation up to 6.56 and 5.25 mg kg(-1) and zinc accumulation up to 45.46 and 32.56 mg kg(-1) in root and shoot, respectively, which caused maximum remediation efficiency (0.73 percent and 0.25 percent) and bioaccumulation factor (2.39 and 0.83) for Cd and Zn, respectively showing feasible uptake (in mg kg(-1) dry biomass) of Cd (5.55) and Zn (35.51) at the contaminated site. Thus, authors conclude to integrate oilcake manure, S(0) and microbial co-inoculation for enhanced clean-up of cadmium and zinc-contaminated soils. PMID- 25450920 TI - Antimicrobial effects of short chained imidazolium-based ionic liquids-influence of anion chaotropicity. AB - Ionic liquids (ILs), a new solvent class composed solely of ions, have already found their way into numerous chemical and biochemical applications. Due to their unique properties and wide application range, research utilizing this new technology for biotechnological applications is steadily increasing. However, progress is hampered by lack of toxicological data, especially concerning IL anions and their general underlying toxicity mechanisms. The present study investigated for the first time the influence of the chaotropicity of the anion for nine imidazole based ILs on their antimicrobial behavior. The results indicate that for ILs with small cations ([C(n)mim](+) with n=2 and 4), the chaotropicity of the anion is a major factor regarding antimicrobial behavior, while for [C6mim](+) based ILs a surfactant-like behavior was identified that explains their high toxicity. It could also be shown that with increasing anion chaotropicity the surfactant-like behavior of the cation is strengthened. Identification of chaotropicity as an underlying mode of antimicrobial action of ILs presents a new point of adjustment for future design with regard to their toxicological behavior. PMID- 25450921 TI - Effect of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) on sexual behaviors and reproductive function in male zebrafish (Danio rerio). AB - BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are ubiquitous in various environmental matrices and organisms and pose a threat to reproductive systems of organisms. However, few studies have explored the effects of PBDEs on sexual and reproductive behaviors in animals. Here we evaluated the effect of BDE-47 exposure on sexual and reproductive behaviors in zebrafish (Danio rerio). METHODS: We used a charge-coupled device camera to evaluate 3 standard male zebrafish sexual behaviors-chasing, female association and induced female spawning-and assessed effects on reproductive success in female zebrafish that mated with exposed males. RESULTS: After 21-day BDE-47 exposure, the frequency and total time of males associating with females was dose-dependently decreased. With the highest BDE-47 exposure, 1000 ug/L, the frequency of inducing spawning was decreased. Sexual behaviors and spawning outcome were closely associated in both control and exposure groups. Logistic regression analysis revealed BDE-47 exposure and total time of female association as the main factors contributing to induced female spawning behaviors, which affected final egg production. Multiple stepwise regression analysis suggested that female association and induced spawning by males were associated with egg production. Meanwhile, fecundity was lower for BDE-47-treated groups than controls, with only a significant difference with the highest dose. BDE-47 exposure at 100 and 1000 ug/L in males decreased fertilization rate, but BDE47 had no effect on hatching rate. CONCLUSIONS: Exposure to BDE-47 may affect sexual behavior and reproductive output in zebrafish. PMID- 25450923 TI - The defense potential of glutathione-ascorbate dependent detoxification pathway to sulfur dioxide exposure in Tagetes erecta. AB - Sulfur dioxide (SO2) exposure is associated with increased risk of various damages to plants. However, little is known about the defense response in ornamental plants. In this study, an artificial fumigation protocol was carried out to study the defense potential of the glutathione (GSH)-ascorbate (AsA) dependent detoxification pathway to SO2 exposure in Tagetes erecta. The results show that when the plants were exposed to different doses of SO2 (0, 15, 30, 50 or 80 mg m(-3)) for different times (6, 12, 18, 24 or 33 h), SO2 induced oxidative stress was confirmed by the increased hydrogen peroxide (H2O2), malondialdehyde (MDA) and relative conductivity of membrane (RC) in a dose dependent manner for different exposure times. However, the increased levels for H2O2, MDA and RC were not significant vis-a-vis the control when SO2 doses and exposure times were lower than 15 mg m(-3)/33 h, 30 mg m(-3)/24 h or 50 mg m( 3)/12 h (p>0.05). The results could be explained by the increases in the content of reduced form of glutathione (GSH), total glutathione (TGSH), ascorbate (AsA), ratio of GSH/GSSG (oxidized form of glutathione), activities of ascorbate peroxidase (APX), glutathione peroxidase (GPX), glutathione reductase (GR) and glutathione S-transferases (GST). On the other hand, exposure to higher doses of SO2 and longer exposure times, the values of the GSH-AsA dependent antioxidative indices decreased significantly (p<0.01), manifested by increased levels of H2O2. Furthermore, the levels of H2O2, MDA and RC varied little when SO2 doses and exposure times reached a 'critical' value (50 mg m(-3)/24 h). The defense ability of T. erecta to SO2 reached nearly extremity. To summarize, the response of T. erecta to elevated SO2 was related to higher H2O2 levels. GSH-AsA dependent detoxification pathway played an important role in against SO2-induced toxicity, although the defense response could not sufficiently alleviate oxidative damage when SO2 doses and exposure times reached critical value. PMID- 25450922 TI - Preparation of a polyclonal antibody against goldfish (Carassius auratus) vitellogenin and its application to detect the estrogenic effects of monocrotophos pesticide. AB - Goldfish (Carassius auratus) represents a good model to detect the estrogenic effects of chemicals, and vitellogenin (Vtg) is a vital indicator of estrogenic activity. The heterologous anti-carp Vtg antibody has previously been used for goldfish Vtg detection. Here, we report the preparation of an anti-goldfish Vtg antibody to improve the sensitivity and specificity of goldfish Vtg immunoassays. Vtg was purified from the plasma of 17beta-estradiol (E2)-induced goldfish by gel filtration followed by anion-exchange chromatography. It was characterized as a phospholipoglycoprotein with an apparent molecular weight of ~460 kDa and separated into three major polypeptides corresponding to ~130, ~106, and ~81 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). A polyclonal antibody against goldfish Vtg was raised in rabbits and found to be specific for goldfish Vtg through immunoelectrophoresis and Western blot. A sensitive sandwich enzyme-linked immunosorbent assay (ELISA) was developed for the quantification of plasma Vtg, with a detection limit of 3.6 ng/mL and a detection range from 7.8 to 250 ng/mL. The intra- and inter-assay coefficients of variations were 2.4-6.8% and 6.7-10.8%, respectively. Additionally, we qualitatively and quantitatively detected the induction of Vtg in male fish exposed to 0.01, 0.01, and 1.00 mg/L monocrotophos pesticide by Western blot and ELISA. The homologous sandwich ELISA based on the anti-goldfish Vtg antibody could provide a valuable tool for the study of estrogenic effects of exogenous chemicals on goldfish. PMID- 25450924 TI - A comparative study of biodegradability of a carcinogenic aromatic amine (4,4' diaminodiphenylmethane) with OECD 301 test methods. AB - 4,4'-Diaminodiphenylmethane (MDA) is a widely used compound in industries. Studies on the biodegradability of MDA are necessary for environmental hazard identification and risk assessment. Previous studies have suggested that MDA was not readily biodegradable. In the present study, three batches of biodegradation tests (OECD 301A, B, D and F tests) were performed on MDA in June, August and December of 2012. MDA was found to be readily biodegradable and produced colored intermediates in the 301A, B and F test systems. MDA biodegradation measurements were consistent among the three batches of tests. Differences in the extent of biodegradation determined in different methods originated from different test conditions and assessment endpoints. The 301D test has stringent test conditions and is usually performed on chemicals that are toxic to microorganisms, so the test results obtained from 301D tests are less meaningful for evaluating the biodegradability of MDA. The low MDA biodegradation measurements in the 301B tests compared to the 301A and F tests were due to the assessment method, which did not account for MDA incorporation into biomass in its calculation of CO2 formation rate. The differences in the biodegradation rates, as measured by the different OECD 301 test systems, could also be related to the structure and properties of the chemical. For test substances that can be assessed by all OECD 301 test methods, the highest biodegradation values may be obtained from the 301A and F test methods. This study provides new information to assess the environmental fate in the risk assessment of MDA. PMID- 25450925 TI - Ecotoxicological effects of carbofuran and oxidised multiwalled carbon nanotubes on the freshwater fish Nile tilapia: nanotubes enhance pesticide ecotoxicity. AB - The interactions of carbon nanotubes with pesticides, such as carbofuran, classical contaminants (e.g., pesticides, polyaromatic hydrocarbons, heavy metals, and dyes) and emerging contaminants, including endocrine disruptors, are critical components of the environmental risks of this important class of carbon based nanomaterials. In this work, we studied the modulation of acute carbofuran toxicity to the freshwater fish Nile tilapia (Oreochromis niloticus) by nitric acid treated multiwalled carbon nanotubes, termed HNO3-MWCNT. Nitric acid oxidation is a common chemical method employed for the purification, functionalisation and aqueous dispersion of carbon nanotubes. HNO3-MWCNT were not toxic to Nile tilapia at concentrations ranging from 0.1 to 3.0 mg/L for exposure times of up to 96 h. After 24, 48, 72 and 96 h, the LC50 values of carbofuran were 4.0, 3.2, 3.0 and 2.4 mg/mL, respectively. To evaluate the influence of carbofuran-nanotube interactions on ecotoxicity, we exposed the Nile tilapia to different concentrations of carbofuran mixed together with a non-toxic concentration of HNO3-MWCNT (1.0 mg/L). After 24, 48, 72, and 96 h of exposure, the LC50 values of carbofuran plus nanotubes were 3.7, 1.6, 0.7 and 0.5 mg/L, respectively. These results demonstrate that HNO3-MWCNT potentiate the acute toxicity of carbofuran, leading to a more than five-fold increase in the LC50 values. Furthermore, the exposure of Nile tilapia to carbofuran plus nanotubes led to decreases in both oxygen consumption and swimming capacity compared to the control. These findings indicate that carbon nanotubes could act as pesticide carriers affecting fish survival, metabolism and behaviour. PMID- 25450927 TI - Antagonistic activity of dietary allicin against deltamethrin-induced oxidative damage in freshwater Nile tilapia; Oreochromis niloticus. AB - Allicin, the main biologically active component of garlic clove extracts, has been evaluated for its' efficacy in preventing deltamethrin-induced oxidative damage in Nile tilapia; Oreochromis niloticus. Fish were fed on 2 different doses of 0.5 g and 1 g of allicin/kg diet for 28 days. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), cholesterol, urea, uric acid, creatinine, total protein, albumin and globulin were estimated. Moreover, the level of malonaldehyde (MDA) was analyzed as a lipid peroxidation marker. In addition, reduced glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) were analyzed as antioxidant biomarkers in liver, kidney and gills. Results show that deltamethrin subacute intoxication (1.46 ug/L for 28 days) increased serum AST, ALT, ALP, cholesterol, urea, uric acid, creatinine and tissue MDA. At the same time, serum total protein and albumin as well as tissue level of GSH, GSH-Px, SOD and CAT were reduced. Allicin supplemented diets enhanced all the altered serum biochemical parameters as well as tissues' lipid peroxidation and antioxidant biomarkers in a dose dependent manner. The results suggest that feeding allicin can ameliorate deltamethrin-induced oxidative stress and might have some therapeutic properties to protect Nile tilapia on subacute deltamethrin toxicity. PMID- 25450926 TI - Cellular responses and biodegradation of amoxicillin in Microcystis aeruginosa at different nitrogen levels. AB - The influence of nitrogen on the interactions between amoxicillin and Microcystis aeruginosa was investigated using a 7-day exposure test. Growth of M. aeruginosa was not significantly (p>0.05) affected by amoxicillin at the lowest nitrogen level of 0.05 mg L(-1), stimulated by 500 ng L(-1) of amoxicillin at a moderate nitrogen level of 0.5 mg L(-1) and enhanced by 200-500 ng L(-1) of amoxicillin at the highest nitrogen level of 5 mg L(-1). The generation of reactive oxygen species (ROS) and the synthesis of glutathione S-transferases (GST) and glutathione (GSH) were more sensitive to amoxicillin and were stimulated at all nitrogen levels. At the lowest nitrogen level of 0.05 mg L(-1), superoxide dismutase and peroxidase were not effective at eliminating amoxicillin-induced ROS, resulting in the highest malondialdehyde content in M. aeruginosa. The biodegradation of 18.5-30.5% of amoxicillin by M. aeruginosa was coupled to increasing GST activity and GSH content. Elevated nitrogen concentrations significantly enhanced (p<0.05) the stimulation effect of amoxicillin on the growth of M. aeruginosa, the antioxidant responses to amoxicillin and the biodegradation of amoxicillin in M. aeruginosa. The nitrogen-dependent hormesis effect of the coexisting amoxicillin contaminant on the M. aeruginosa bloom should be fully considered during the control of M. aeruginosa bloom. PMID- 25450928 TI - Combined effect of temperature and copper pollution on soil bacterial community: climate change and regional variation aspects. AB - The aim of this study was to assess the combined effects of temperature and copper (Cu) contamination in the structure of soil bacterial community. For this, contaminated or spiked and control soils from two different geographic origins (PT-Portugal and DK-Denmark) were used. The DK soil was from a historically contaminated study field, representing a long-term exposure to Cu while the PT soil was from a clean site and freshly spiked with Cu. Soil bacterial communities were exposed in mesocosms during 84 days to 3 different temperatures based on values typically found in each geographic region and temperature conditions that simulated a warming scenario. Obtained results indicate that Cu stress alters the structure of bacterial community and that this effect is, to some extent, temperature-dependent. Effects on bacterial diversity for both soils were also observed. Differences in the DK and PT communities' response were apparent, with the community from the historically contaminated soil being more resilient to temperature fluctuations. This study presents evidence to support the hypothesis that temperature alters the effect of metals on soils. Further, our results suggest that the definition of soils quality criteria must be based on studies performed under temperatures selected for the specific geographic region. Studies taking into account temperature changes are needed to model and predict risks, this is important to e.g. future adjustments of the maximum permissible levels for soil metal contamination. PMID- 25450929 TI - Human health risks from metals and metalloid via consumption of food animals near gold mines in Tarkwa, Ghana: estimation of the daily intakes and target hazard quotients (THQs). AB - Heavy metal and metalloid contamination in food resulting from mining is of major concern due to the potential risk involved. Food consumption is the most likely route of human exposure to metals. This study was therefore to assess metals in different organs and different animal species near gold mines used for human consumption (free-range chicken, goat and sheep) in Tarkwa, Ghana, and to estimate the daily intake and health risk. The concentrations of Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Cd, and Pb were measured with an inductively coupled plasma-mass spectrometer and Hg analysis was done using the mercury analyzer. Principal component analysis of the results showed a clear separation between chicken, grouped on one side, and the ruminants clustered on another side in both offal and muscle. Interestingly, As, Cd, Hg, Mn and Pb made one cluster in the offal of chicken. Chicken muscle also showed similar distribution with As, Hg and Pb clustered together. The daily intake of metals (MUg/kg body weight/day) were in the following ranges; As [0.002 (kidneys of goat and sheep)-0.19 (chicken gizzard)], Cd [0.003 (chicken muscle)-0.55 (chicken liver)], Hg [0.002 (goat muscle)-0.29 (chicken liver)], Pb [0.01 (muscles and kidneys of goat and sheep) 0.96 (chicken gizzard)] and Mn [0.13 (goat kidney)-8.92 (sheep liver)]. From the results, daily intakes of As, Cd, Hg, Pb and Mn in these food animals were low compared to the provisional tolerable daily intake guidelines. The THQs although less than one, indicated that contributions of chicken gizzard and liver to toxic metal exposure in adults and especially children could be significant. PMID- 25450930 TI - Toxic assessment of the leachates of paddy soils and river sediments from e-waste dismantling sites to microalga, Pseudokirchneriella subcapitata. AB - The potential adverse effects of e-waste recycling activity on environment are getting increasing concern. In this work, a model alga, Pseudokirchneriella subcapitata, was employed to assess the toxic effects of the leachates of paddy soils and river sediments collected from e-waste dismantling sites. Chemical analysis of the paddy soils and river sediments and their leachates were carried out and the growth rate, chlorophyll a fluorescence and anti-oxidative systems of the alga were measured. Results showed that two leachates decreased the amount of PSII active reaction centers and affected photosynthesis performance, interfered with chlorophyll synthesis and inhibited algal growth. Some chemical pollutants in the sediments and soils such as polybrominated diphenyl ethers (PBDEs) and metals derived from e-waste recycling activity may impose oxidative stress on algae and affect the activity of anti-oxidative enzymes such as GST, SOD, CAT and APX. The leachates of both river sediments and paddy soils are potentially toxic to the primary producers, P. subcapitata and the leachate from sediments was more deleterious than that from soils. PMID- 25450931 TI - Can washing-pretreatment eliminate the health risk of municipal solid waste incineration fly ash reuse? AB - Although the reuse of washing-pretreated MSWI fly ash bas been a hot topic, the associated risk is still an issue of great concern. The present study investigated the influence of washing-pretreatment on the total contents and bioaccessibility of heavy metals in MSWI fly ash. Furthermore, the study incorporated bioaccessibility adjustment into probabilistic risk assessment, to quantify the health risk from multi-pathway exposure to the concerned chemicals as a result of reusing washed MSWI fly ash. The results revealed that both water washing and acid-washing process have resulted in the concentrated heavy metal content, and have reduced the bioaccessibility of heavy metals. Besides, the acid washing process increased the cancer risk in most cases, while the effect of water-washing process was uncertain. However, both water-washing and acid-washing pretreatment could decrease the hazard index based on bioaccesilbility. Despite the uncertainties accompanying these procedures, the results indicated that, in this application scenario, only water-washing or acid-washing process cannot reduce the actual risk from all samples to acceptable level, especially for cancer risk. PMID- 25450932 TI - Water quality monitoring using abnormal tail-beat frequency of crucian carp. AB - Fish are rapidly becoming favored as convenient sentinels for behavioral assays of toxic chemical exposure. Tail-beat frequency (TBF) of fish is highly correlated with swimming speed, which has been used to detect toxicants. Here we examined the effect on TBF of exposure to two chemicals, and evaluated the ability of this novel behavioral parameter to accurately monitor water quality. To further refine our approach, the Wall-hitting rate (WHR) was used to characterize behavioral avoidance after exposure. Overall, exposure to test chemicals at different levels induced significant increase in both behavioral parameters of the red crucian carp during 1-h exposure periods. Furthermore, the TBF achieved better performance as an indicator when it was calculated in cases where the fish hit the tank wall. Collectively, this study demonstrates the capacity of the TBF of fish to assess water quality in a reliable manner. PMID- 25450934 TI - Assessing the impacts of dimethoate on rotifers' reproduction through the pre exposure history. AB - Organism usually undergoes an exposure of environmental pollution after a maternal exposure before birth. Traditional toxicological studies often initiated with rotifer neonates derived from the unexposed mothers while ignoring the pre exposure (maternal exposure). The present study assessed the effect of dimethoate on the reproduction of the rotifer Brachionus calyciflorus, considering how the pre-exposure occurred in the parental generation influenced the subsequent impact. The F0 generation rotifers were exposed to the pesticide at five concentrations until the first F1 generation rotifers were reproduced. The neonates (F1 generation) were then exposed to the pesticide at the corresponding concentrations. The offspring reproduction, the time begins to reproduce, the duration of the reproductive period and the lifespan of the F1 generation rotifers were evaluated. Our results indicated that dimethoate influenced the maturation and reproduction of the rotifers. The highest concentration (1.8 mg L( 1)) of dimethoate caused an inhibition in the offspring reproduction, shortened the life span and reduced the duration of the reproductive period. In addition, of particular interest in our study was that reproduction is also accelerated by the lowest concentration (0.2 mg L(-1)). However, the pre-exposure had a significant effect on the subsequent impact. The dimethoate pre-exposure increased the impacts when the F1 generation rotifers were exposed to the substance, even at the same concentrations as in pre-exposure. It suggests that the maternal exposure history before birth is also important and has the long lasting consequence from one generation to another. PMID- 25450933 TI - Evaluation of the utility of six measures for algal (Microcystis aeruginosa, Planktothrix agardhii and Pseudokirchneriella subcapitata) viability. AB - Standard algal toxicity tests are used to discern responses of algae to a variety of exposures including pesticides, personal care products and complex mixtures such as runoff and effluents. There are concerns regarding the accuracy, precision and utility of algal viability measures used as endpoints in algal toxicity test protocols. To definitively evaluate six algal viability measures, algae were heat-treated to produce known live:dead cell ratios. Cultures of two prokaryotic algae (Microcystis aeruginosa and Planktothrix agardhii) and a eukaryotic alga (Pseudokirchneriella subcapitata) were boiled for five minutes and mixed after cooling with untreated cultures to produce suspensions of 0%, 25%, 50%, 75% and 100% live algal cells. Optical microscopy was used to assess the viability of algae on a cell-by-cell basis by measuring cell density, uptake of a vital stain (neutral red) and exclusion of a mortal stain (erythrosin b). Aggregate measures of algal cell viability included chlorophyll a concentrations, pheophytin a concentrations and respiration (measured as 2-(p-iodophenyl)-3-(p nitrophenyl)-5-phenyl tetrazolium formazan absorbance (INT)). Cell densities, erythrosin b stained cells and chlorophyll a concentrations correlated with viable M. aeruginosa, P. agardhii and P. subcapitata cells (R(2)=0.97-0.78, 0.98 0.85 and 0.99-0.97 respectively). Pheophytin a concentrations and neutral red stained cells did not correlate with viable algae (R(2)=0.41-0.01 and 0.15-0.03 respectively). For INT formazan absorbance, 50%, 75% and 100% viable algae had greater variances and did not strongly correlate (R(2)=0.75-0.54). This result was likely confounded by respiration associated with resident bacteria. Three of the six methods provided accurate and precise information regarding the viability of both prokaryotic and eukaryotic algae. These methods also have a relatively low initial expense and can be used widely. PMID- 25450935 TI - Effects of glyphosate on juvenile rainbow trout (Oncorhynchus mykiss): transcriptional and enzymatic analyses of antioxidant defence system, histopathological liver damage and swimming performance. AB - This study aims to determine the effect of glyphosate on the transcriptional and enzymatic activity of antioxidant metabolism enzymes of juvenile rainbow trout with short term (6, 12, 24, 48 and 96 h) and long term (21 days) exposures followed by a recovery treatment. This study also aims to determine the effects of glyphosate exposure on liver tissue damage and swimming performance due to short term (2.5, 5 and 10 mg/L) and long term (2.5 and 5 mg/L) exposures. Following pesticide administration, ten fish, each as a sample, were caught at 6th, 12th, 24th, 48th and 96th -h for the short term, and at 21st day for the long term exposure study. GPx activity was found to be significantly induced 12 h after the exposure to 2.5 mg/L of glyphosate as compared with the control group. A similar degree of induction was also observed for CAT activity but not for SOD. For long term exposure, except for the GPx activity after exposure to 5 mg/L of glyphosate, the activities of all other enzymes remained on a par with the control group. It was also observed that the levels of gene expression of these enzymes were not comparable with each other. It is assumed that these differences might result from the effect of glyphosate before translation and the possible reasons for this scenario are also discussed. The results of swimming performance are found to be consistent with responses of the antioxidant system, and they are attributed to the energy metabolism. The data are also supported with liver histopathology analysis. PMID- 25450936 TI - The physiological responses of the Caspian kutum (Rutilus frisii kutum) fry to the static magnetic fields with different intensities during acute and subacute exposures. AB - In recent years, the application of new technologies producing magnetic fields has widely increased in the aquatic environment. In this study, the effects of variable static magnetic fields on metabolic and immune parameters of the Caspian kutum fry were investigated. The Caspian kutum fry (n=220, body weight 1.78+/ 0.11 g) was exposed to static magnetic fields with different intensities (2.5, 5.0, 7.5 mT) induced by electrical power supply during acute (one week) and subacute (3 weeks) periods. The results showed an increment in the quantity of ALT and AST enzymes (metabolic parameters) with increasing magnetic fields intensities in subacute and acute exposures (p<0.05). The lysozyme level, an immune parameter, showed a significant decrease, especially at intensities higher than 2.5 mT during subacute and acute exposures (p<0.05). It seems that low intensity static magnetic fields can effect on the metabolism and immunity of the Caspian kutum fry as valuable commercial species. PMID- 25450937 TI - Cytogenetic index and functional genome alterations in Chironomus piger Strenzke (Diptera, Chironomidae) in the assessment of sediment pollution: a case study of Bulgarian and UK rivers. AB - The genotoxicity of trace metals in the sediments from a number of polluted sites on UK and Bulgarian rivers to Chironomus piger was assessed by an examination of genome instability as demonstrated by structural and functional changes to the salivary glands chromosomes. Based on the metal assays, the sediments were characterized to range from 'extremely' to 'strongly contaminated'. The cytogenetic index calculated on the basis of somatic structural chromosome alterations in the polytene chromosomes indicates a high level of pollution (0.07 0.06 in Bulgarian and 0.10-0.13 in UK stations). Exposure of C. piger to contaminated sediments resulted in a high level of chromosome damage as indicated by a somatic index of between 1.96 and 4.0. The transcription mechanism of the Balbiani rings and nucleolar organizer was damaged as their activity was either partially or completely suppressed. We have demonstrated that the C. piger genome is a sensitive sublethal indicator of sediment contamination, and is a highly suitable candidate for ecotoxicological monitoring of running waters. PMID- 25450939 TI - Circannual rhythms of acetylcholinesterase (AChE) activity in the freshwater fish Cnesterodon decemmaculatus. AB - The use of biomarkers as a tool to assess responses of organisms exposed to pollutants in toxicity bioassays, as well as in aquatic environmental risk assessment protocols, requires the understanding of the natural fluctuation of the particular biomarker. The aim of this study was to characterize the intrinsic variations of acetylcholinesterase (AChE) activity in tissues of a native freshwater teleost fish to be used as biomarker in toxicity tests, taking into account both seasonal influence and fish size. Specific AChE activity was measured by the method of Ellman et al. (1961) in homogenates of fish anterior section finding a seasonal variability. The highest activity was observed in summer, decreasing significantly below 40% in winter. The annual AChE activity cycle in the anterior section was fitted to a sinusoidal function with a period of 11.2 months. Moreover, an inverse relationship between enzymatic activity and the animal size was established. The results showed that both the fish length and seasonal variability affect AChE activity. AChE activity in fish posterior section showed a similar trend to that in the anterior section, while seasonal variations of the activity in midsection were observed but differences were not statistically significant. In addition, no relationship between AChE and total tissue protein was established in the anterior and posterior sections suggesting that the circannual rhythms observed are AChE-specific responses. Results highlight the importance of considering both the fish size and season variations to reach valid conclusions when AChE activity is employed as neurotoxicity biomarker. PMID- 25450938 TI - Combined action of estrogen receptor agonists and antagonists in two-hybrid recombinant yeast in vitro. AB - Estrogen receptor (ER) antagonistic chemicals in aquatic environments are believed to influence the binding of both endogenous and exogenous estrogens to ERs in aquatic organisms. Although the combined effects of estrogenic compounds have attracted much scientific concern, little work has been done on the influence of such antiestrogens on the biological effects of estrogens. This study focused on how the presence of different amounts of antagonists affects the results of ER agonist activity tests. To achieve this, three questions were stated and answered in sequence. A two-hybrid recombinant yeast assay mediated by ER was adopted, providing a single mode of action and single target of action for this study. Mixtures created by an ER agonist and three antagonists following the fixed-ratio principle were assessed. The concentration of 17beta-estradiol causing maximum induction was set as the fixed dose of estrogen in the antagonist activity test (question 1). When the two classes of chemicals coexisted, antiestrogens, which as a whole behaved according to the concentration addition model (question 2), decreased the response of estrogen and compressed the concentration-response curves along the y-axis in the agonist activity test (question 3). This may cause the estradiol equivalent to be underestimated and potentially mask the action of estrogenic effects in toxicity evaluation of environmental samples. PMID- 25450940 TI - Toxicity of mixtures of lambda-cyhalothrin, imidacloprid and cadmium on the earthworm Eisenia fetida by combination index (CI)-isobologram method. AB - Contaminants in the environment do not appear singly and usually occur as mixtures. We applied the combination index (CI)-isobologram method which allows computerized quantitation of synergism, additive effect and antagonism to determine the nature of toxicological interactions of two pesticides lambda cyhalothrin, imidacloprid, and heavy metal cadmium towards earthworm Eisenia fetida. In an artificial soil test, lambda-cyhalothrin and Cd combination was slightly synergistic at low effect levels which turned into a slight antagonism above f(a) values of 0.6, while the binary mixtures containing imidacloprid exhibited antagonism. The presence of imidacloprid in the ternary mixture also resulted in an antagonistic effect to the earthworms. This behavior became more antagonistic in the ternary mixture in filter paper tests. PMID- 25450941 TI - Macrocyclic-, polycyclic-, and nitro musks in cosmetics, household commodities and indoor dusts collected from Japan: implications for their human exposure. AB - This paper reported the occurrence and concentrations of macrocyclic-, polycyclic and nitro musks in cosmetics and household commodities collected from Japan. The high concentrations and detection frequencies of Musk T, habanolide, and exaltolides were found in commercial products, suggesting their large amounts of production and usage in Japan. Polycyclic musks, HHCB and OTNE, also showed high concentrations in cosmetics and products. The estimated dairy intakes of Musk T and HHCB by the dermal exposure to commercial products were 7.8 and 7.9 MUg/kg/day in human, respectively, and perfume and body lotion are dominant exposure sources. We also analyzed synthetic musks in house dusts. Polycyclic musks, HHCB and OTNE, showed high concentrations in samples, but macrocyclic musks were detected only in a few samples, although these types of musks were highly detected in commercial products. This is probably due to easy-degradation of macrocyclic musks in indoor environment. The dairy intakes of HHCB by dust ingestions were 0.22 ng/kg/day in human, which were approximately five orders of magnitudes lower than those of dermal absorption from commercial household commodities. PMID- 25450942 TI - Parent and halogenated polycyclic aromatic hydrocarbons in farmed cockroaches and implications for human exposure. AB - Medicinal insects have been widely used to cure human diseases for ages. Nevertheless, knowledge about the toxic chemicals accumulated in medicinal insects and their effects on human health was insufficient. In the present study, sixteen priority polycyclic aromatic hydrocarbons (PAHs) and nine halogenated PAHs (HPAHs) were determined in farmed medicinal cockroaches to address this issue. Total concentrations of PAHs in young nymphs, old nymphs, and adults ranged from 162 to 1025, 252 to 967, and 267 to 1168 ng/g, respectively. Levels of the sum of HPAHs varied from 0.84 to 9.17, 1.86 to 5.21, and 1.01 to 8.60 ng/g for young nymphs, old nymphs, and adults, respectively. The daily intake and excess cancer risk of PAHs and HPAHs were calculated for people who take cockroach-related drugs. Our results indicated that females and children have slightly higher exposure levels from the perspectives of gender and age, respectively. The estimated excess cancer risk of PAHs and HPAHs were both lower than the priority risk level (10(-4)), indicating a low potential carcinogenic risk with the medicinal cockroach consumption. PMID- 25450943 TI - Effects of silver nanoparticle properties, media pH and dissolved organic matter on toxicity to Daphnia magna. AB - Studies assessing the acute and chronic toxicity of silver nanoparticle (nAg) materials rarely consider potential implications of environmental variables. In order to increase our understanding in this respect, we investigated the acute and chronic effects of various nAg materials on Daphnia magna. Thereby, different nanoparticle size classes with a citrate coating (20-, ~30-, 60- as well as 100 nm nAg) and one size class without any coating (140 nm) were tested, considering at the same time two pH levels (6.5 and 8.0) as well as the absence or presence of dissolved organic matter (DOM; <0.1 or 8.0 mg total organic carbon/L). Results display a reduced toxicity of nAg in media with higher pH and the presence of DOM as well as increasing initial particle size, if similarly coated. This suggests that the associated fraction of Ag species <2 nm (including Ag(+)) is driving the nAg toxicity. This hypothesis is supported by normalizing the 48-h EC50-values to Ag species <2 nm, which displays comparable toxicity estimates for the majority of the nAg materials assessed. It may therefore be concluded that a combination of both the particle characteristics, i.e. its initial size and surface coating, and environmental factors trigger the toxicity of ion-releasing nanoparticles. PMID- 25450945 TI - Sub-lethal effects of RoundupTM on tadpole anti-predator responses. AB - RoundupTM is a commonly used pesticide applied to agriculture and forest habitats. These areas are generally ideal for amphibians due to the presence of small, ephemeral water bodies. While RoundupTM has been shown to have lethal effects on many species of amphibians, effects on behaviour and sensory perception have yet to be considered. Here, we exposed wood frog tadpoles to a sub-lethal concentration of RoundupTM and showed that the ability of tadpoles to respond to injured conspecific cues, an important source of information regarding local predation risk, was impaired. Subsequent experiments revealed that impaired responses likely result from a chemical reaction between the RoundupTM and the cues and that tadpoles chronically exposed to RoundupTM had reduced basal movement rates compared with unexposed tadpoles. Our data demonstrate that environmentally-relevant concentrations of RoundupTM can drastically alter movement and anti-predator responses of tadpoles, with potential negative consequences for the population. PMID- 25450944 TI - Excess copper induced proteomic changes in the marine brown algae Sargassum fusiforme. AB - Copper (Cu) is an essential micronutrient for algal growth and development; however, it is also generally considered to be one of the most toxic metals when present at higher levels. Seaweeds are often exposed to low concentrations of metals, including Cu, for long time periods. In cases of ocean outfall, they may even be abruptly exposed to high levels of metals. The physiological processes that are active under Cu stress are largely unknown. In this study, the brown macroalga Sargassum fusiforme was cultured in fresh seawater at final Cu concentrations of 0, 4, 8, 24 and 47 MUM. The Cu(2+) concentration and chlorophyll autofluorescence were measured to establish the toxic effects of Cu on this economically important seaweed. The accumulation of Cu by S. fusiforme was also dependent upon the external Cu concentration. Algal growth displayed a general decline with increasing media Cu concentrations, indicating that S. fusiforme was able to tolerate Cu stress at low concentrations, while it was negatively impacted at high concentrations. The term "acute stress" was employed to indicate exposure to high Cu concentrations for 1 day in this study. On the other hand, "chronic stress" was defined as exposure to lower sub-lethal Cu concentrations for 7 days. Proteins were extracted from control and Cu-treated S. fusiforme samples and separated by two-dimensional gel electrophoresis. Distinct patterns of protein expression in the acute and chronic stress conditions were observed. Proteins related to energy metabolism and photosynthesis were reduced significantly, whereas those related to carbohydrate metabolism, protein destination, RNA degradation and signaling regulation were induced in S. fusiforme in response to acute copper stress. Energy metabolism-related proteins were significantly induced by chronic Cu stress. Proteins from other functional groups, such as those related to membranes and transport, were present in minor quantities. These results suggest that S. fusiforme is sensitive to excess Cu, regardless of the presence of acute or chronic stress. We discuss the possible function of these identified proteins, taking into consideration the information available from other plant models. PMID- 25450946 TI - The role of elevated ozone on growth, yield and seed quality amongst six cultivars of mung bean. AB - Tropospheric ozone (O3) can be deleterious to plants by decreasing crop yield and quality. Present study was conducted on six cultivars of mung bean (HUM-1, HUM-2, HUM-6, HUM-23, HUM-24 and HUM-26) grown under ambient O3 (NFC) and elevated O3 levels (ambient+10 ppb; NFC+) in open top chambers (OTCs) for two consecutive years. Ozone monitoring data showed high mean ambient concentration of O3 at the experimental site, which was above the threshold value of 40 ppb. Ozone exposure induced symptoms of foliar injury and also depicted accumulation of reactive oxygen species (ROS) which led to increased membrane damage vis-a-vis solute leakage. Root/shoot allometric coefficient (k), yield and seed quality showed negative response to O3. Differential response of mung bean cultivars against elevated O3 was assessed by comparing the levels of antioxidants, metabolites, growth, total biomass and yield. Cultivar HUM-1 showed maximum sensitivity towards O3 as compared to other cultivars. Findings of present study emphasized the possibility of selection of suitable O3 resistant cultivars for the areas experiencing high concentrations of O3. PMID- 25450947 TI - Lipoprotein internalisation induced by oncogenic AMPK activation is essential to maintain glioblastoma cell growth. AB - AIM OF THE STUDY: Metabolic adaptations are essential during tumour growth to maintain the high proliferation levels exhibited by cancer cells. In this study, we examined the transformations that occurred in the lipid metabolism in astrocytic tumours, and the possible role of the fuel-sensing enzyme AMPK. Metabolic targets might help design new and effective drugs for cancer. METHODS: To accomplish this objective, we studied both mice and human astrocytic tumours. We first used a mouse model of astrocytoma driven by oncogenic H-RasV12 and/or with PTEN deletion based on the common constitutive activation of the Raf/MEK/ERK and PI3K/AKT cascades in human astrocytomas. We then confirmed the results in human glioblastoma cell lines and in glioblastoma tissue samples from patients. RESULTS: We show that the high levels of activated AMPK, observed in astrocytic tumours, increase extracellular lipid internalisation and reduce energy expenditure by inhibiting 'de novo' fatty acid (FA) synthesis, which allows tumour cells to obtain building blocks and energy to be able to create new organelles and new cells. CONCLUSIONS: Our findings demonstrate that AMPK plays a crucial role in glioblastoma cell growth and suggest that blocking lipoprotein receptors could potentially be used as a plausible therapeutic approach for these and other type of tumours with high levels of AMPK. PMID- 25450948 TI - Non-target progression--the fine line between objectivity and subjectivity. PMID- 25450950 TI - Action control processes in autism spectrum disorder--insights from a neurobiological and neuroanatomical perspective. AB - Autism spectrum disorders (ASDs) encompass a range of syndromes that are characterized by social interaction impairments, verbal and nonverbal communication difficulties, and stereotypic or repetitive behaviours. Although there has been considerable progress in understanding the mechanisms underlying the changes in the 'social' and 'communicative' aspects of ASD, the neurofunctional architecture of repetitive and stereotypic behaviours, as well as other cognitive domains related to response and action control, remain poorly understood. Based on the findings of neurobiological and neuroanatomical alterations in ASD and the functional neuroanatomy and neurobiology of different action control functions, we emphasize that changes in action control processes, including response inhibition, conflict and response monitoring, task switching, dual-tasking, motor timing, and error monitoring, are important facets of ASD. These processes must be examined further to understand the executive control deficits in ASD that are related to stereotypic or repetitive behaviours as a major facet of ASD. The review shows that not all domains of action control are strongly affected in ASD. Several factors seem to determine the consistency with which alterations in cognitive control are reported. These factors relate to the relevance of neurobiological changes in ASD for the cognitive domains examined and in how far action control relies upon the adjustment of prior experience. Future directions and hypotheses are outlined that may guide basic and clinical research on action control in ASD. PMID- 25450951 TI - Review of the genus Endoreticulatus (Microsporidia, Encephalitozoonidae) with description of a new species isolated from the grasshopper Poecilimon thoracicus (Orthoptera: Tettigoniidae) and transfer of Microsporidium itiiti Malone to the genus. AB - The historic genus Pleistophora (Plistophora) is a highly polyphyletic clade with invertebrate Microsporidia reassigned to several new genera since the 1980s. Two genera, Endoreticulatus and Cystosporogenes, clearly separate into distinct but closely related clades based on small subunit ribosomal RNA analysis but are included in different families that are each polyphyletic. A microsporidium with morphology resembling the Endoreticulatus/Cystosporogenes clade was isolated from the grasshopper Poecilimon thoracicus from a site in Northwest Bulgaria. It produced intense infections in the digestive tract of the host but no behavioral changes were noted in infected individuals. Prevalence of the microsporidium increased over the active feeding season yearly. Mature spores were oval and measured 2.58+/-0.21 MUm*1.34+/-0.24 MUm, with 16 to approximately 32 spores in a parasitophorous vacuole. The spores were uninucleate and polar filament coils numbered 8-9 situated in a single row. The spore polaroplast consisted of an anterior lamellar section and a posterior vesicular section, and the posterior vacuole was reduced. Analyses of a 1221 bp partial SSU-rRNA sequence indicated that the isolate is more closely related to the Endoreticulatus clade than to Cystosporogenes, but shows earlier phylogenetic separation from species infecting Lepidoptera and represents a new species, Endoreticulatus poecilimonae. To compare sequences of Endoreticulatus spp. from Lepidoptera to those infecting other insect orders, an isolate, Microsporidium itiitiMalone (1985), described from the Argentine stem weevil, Listronotus bonariensis, was sequenced. Like the grasshopper isolate, the weevil isolate is closely related but basal to the lepidopteran Endoreticulatus clade. The original description combined with the new sequence data confirms species status and permits transfer of the isolate from Microsporidium, a genus erected for microsporidian species of uncertain taxonomic status, to Endoreticulatus. PMID- 25450952 TI - A pilot metabolic profiling study in hepatopancreas of Litopenaeus vannamei with white spot syndrome virus based on 1H NMR spectroscopy. AB - White spot syndrome virus, which was a pathogen first found in 1992, had emerged globally affecting shrimp populations in aquaculture. Here, we comprehensively analyzed the metabolic changes of hepatopancreas from Litopenaeus vannamei which were infected with white spot syndrome virus by (1)H nuclear magnetic resonance (NMR). Through the NOESYPR1D spectrum combined with multi-variate pattern recognition analysis, including principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) models, significantly metabolic changes were observed in WSSV-infected groups compared with the control groups. In the first 48 h, alpha-glucose and beta-glucose were higher in the WSSV infected group. Meanwhile, acetate, lactate, N-acetyl glycoprotein signals, lysine, tyrosine and lipid were significantly decreased in the WSSV-infected group. These results suggest that WSSV caused absorption inhibition of amino acids and disturbed protein metabolism as well as cell metabolism in favor of its replication. Our findings could also contribute to further understanding of disease mechanisms. PMID- 25450953 TI - Inflammation is genetically implicated in Parkinson's disease. AB - Inflammation has long been associated with the pathogenesis of Parkinson's disease (PD) but the extent to which it is a cause or consequence is sill debated. Over the past decade a number of genes have been implicated in PD. Relatively rare missense mutations in genes such as LRRK2, Parkin, SNCA and PINK1 are causative for familial PD whereas more common variation in genes, including LRRK2, SNCA and GBA, comprise risk factors for sporadic PD. Determining how the function of these genes and the proteins they encode are altered in PD has become a priority, as results will likely provide much needed insights into contributing causes. Accumulating evidence indicates that many of these genes function in pathways that regulate aspects of immunity, particularly inflammation, suggesting close associations between PD and immune homeostasis. PMID- 25450955 TI - CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid. AB - Activation of microglia associated with neuroinflammation and loss of phagocytic activity is considered to play a prominent role in the pathogenesis of Alzheimer's disease (AD). CHF5074 (CSP-1103) has been shown to improve cognition and reduce brain inflammation in patients with mild cognitive impairment (MCI). CHF5074 was also found to reverse impairments in recognition memory and improve hippocampal long-term potentiation when administered to plaque-free Tg2576 mice (5-month-old) for 4 weeks. Though, no investigation has focused on the consequence of CHF5074 treatment on microglia polarization yet. In this study we evaluated the effect of CHF5074 administration (375 ppm in the diet) to 5-month old Tg2576 mice on the expression of pro-inflammatory (M1) genes, Interleukin 1 beta (IL-1beta), Tumor Necrosis Factor alpha (TNFalpha) and inducible Nitric Oxide Synthase (iNOS), and anti-inflammatory/phagocytic (M2) markers Mannose Receptor type C 1 (MRC1/CD206), Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Chitinase 3-like 3 (Ym1). No changes of pro-inflammatory gene transcription but a reduced expression of MRC1/CD206, TREM2 and Ym1 were detected in the hippocampus of young Tg2576 mice receiving normal diet, when compared to wild-type littermates. CHF5074 did not affect the pro-inflammatory transcription but significantly increased the expression of MRC1/CD206 and Ym1. CHF5074 effects appeared to be hippocampus-specific, as the M2 transcripts were only slightly modified in the cerebral cortex. In primary cultures of mouse astrocyte microglia, CHF5074 totally suppressed the expression of TNF-alpha, IL-1beta and iNOS induced by 10 MUM beta-amyloid1-42 (Abeta42). Moreover, CHF5074 significantly increased the expression of anti-inflammatory/phagocytic markers MRC1/CD206 and TREM2, reduced by the Abeta42 application alone. The effect of CHF5074 was not reproduced by ibuprofen (3 MUM or 500 MUM) or R-flurbiprofen (3 MUM or 100 MUM), as both compounds limited the pro-inflammatory gene expression but did not modify the anti-inflammatory/phagocytic transcription. These data show that CHF5074 specifically drives the expression of microglia M2 markers either in young Tg2576 hippocampus or in primary astrocyte-microglia cultures, suggesting its potential therapeutic efficacy as microglial modulator in the early phase of AD. PMID- 25450956 TI - Gender differences in association between serotonin transporter gene polymorphism and resting-state EEG activity. AB - Human brain oscillations represent important features of information processing and are highly heritable. Gender has been observed to affect association between the 5-HTTLPR (serotonin-transporter-linked polymorphic region) polymorphism and various endophenotypes. This study aimed to investigate the effects of 5-HTTLPR on the spontaneous electroencephalography (EEG) activity in healthy male and female subjects. DNA samples extracted from buccal swabs and resting EEG recorded at 60 standard leads were collected from 210 (101 men and 109 women) volunteers. Spectral EEG power estimates and cortical sources of EEG activity were investigated. It was shown that effects of 5-HTTLPR polymorphism on electrical activity of the brain vary as a function of gender. Women with the S/L genotype had greater global EEG power compared to men with the same genotype. In men, current source density was markedly different among genotype groups in only alpha 2 and alpha 3 frequency ranges: S/S allele carriers had higher current source density estimates in the left inferior parietal lobule in comparison with the L/L group. In women, genotype difference in global power asymmetry was found in the central-temporal region. Contrasting L/L and S/L genotype carriers also yielded significant effects in the right hemisphere inferior parietal lobule and the right postcentral gyrus with L/L genotype carriers showing lower current source density estimates than S/L genotype carriers in all but gamma bands. So, in women, the effects of 5-HTTLPR polymorphism were associated with modulation of the EEG activity in a wide range of EEG frequencies. The significance of the results lies in the demonstration of gene by sex interaction with resting EEG that has implications for understanding sex-related differences in affective states, emotion and cognition. PMID- 25450954 TI - Caveolin expression changes in the neurovascular unit after juvenile traumatic brain injury: signs of blood-brain barrier healing? AB - Traumatic brain injury (TBI) is one of the major causes of death and disability in pediatrics, and results in a complex cascade of events including the disruption of the blood-brain barrier (BBB). A controlled-cortical impact on post natal 17-day-old rats induced BBB disruption by IgG extravasation from 1 to 3 days after injury and returned to normal at day 7. In parallel, we characterized the expression of three caveolin isoforms, caveolin 1 (cav-1), caveolin 2 (cav-2) and caveolin 3 (cav-3). While cav-1 and cav-2 are expressed on endothelial cells, both cav-1 and cav-3 were found to be present on reactive astrocytes, in vivo and in vitro. Following TBI, cav-1 expression was increased in blood vessels at 1 and 7 days in the perilesional cortex. An increase of vascular cav-2 expression was observed 7 days after TBI. In contrast, astrocytic cav-3 expression decreased 3 and 7 days after TBI. Activation of endothelial nitric oxide synthase (eNOS) (via its phosphorylation) was detected 1 day after TBI and phospho-eNOS was detected both in association with blood vessels and with astrocytes. The molecular changes involving caveolins occurring in endothelial cells following juvenile-TBI might participate, independently of eNOS activation, to a mechanism of BBB repair while, they might subserve other undefined roles in astrocytes. PMID- 25450949 TI - Epigenetic programming of hypoxic-ischemic encephalopathy in response to fetal hypoxia. AB - Hypoxia is a major stress to the fetal development and may result in irreversible injury in the developing brain, increased risk of central nervous system (CNS) malformations in the neonatal brain and long-term neurological complications in offspring. Current evidence indicates that epigenetic mechanisms may contribute to the development of hypoxic/ischemic-sensitive phenotype in the developing brain in response to fetal stress. However, the causative cellular and molecular mechanisms remain elusive. In the present review, we summarize the recent findings of epigenetic mechanisms in the development of the brain and their roles in fetal hypoxia-induced brain developmental malformations. Specifically, we focus on DNA methylation and active demethylation, histone modifications and microRNAs in the regulation of neuronal and vascular developmental plasticity, which may play a role in fetal stress-induced epigenetic programming of hypoxic/ischemic-sensitive phenotype in the developing brain. PMID- 25450958 TI - Comparative analysis of developmentally regulated expressions of Gadd45a, Gadd45b, and Gadd45g in the mouse and marmoset cerebral cortex. AB - The cerebral cortex is an indispensable region that is involved in higher cognitive function in the mammalian brain, and is particularly evolved in the primate brain. It has been demonstrated that cortical areas are formed by both innate and activity-dependent mechanisms. However, it remains unknown what molecular changes induce cortical expansion and complexity during primate evolution. Active DNA methylation/demethylation is one of the epigenetic mechanisms that can modify gene expression via the methylation/demethylation of promoter regions. Three growth arrest and DNA damage-inducible small nuclear proteins, Gadd45 alpha, beta, and gamma, have been identified as regulators of methylation status. To understand the involvement of epigenetic factors in primate cortical evolution, we started by analyzing expression of these demethylation genes in the developing common marmoset (Callithrix jacchus) and mouse (Mus musculus) brain. In the marmoset brain, we found that cortical expression levels of Gadd45 alpha and gamma were reduced during development, whereas there was high expression of Gadd45 beta in some areas of the adult brain, including the prefrontal, temporal, posterior parietal and insula cortices, which are particularly expanded in greater primates and humans. Compared to the marmoset brain, there were no clear regional differences and constant or reduced Gadd45 expression was seen between juvenile and adult mouse brain. Double staining with a neuronal marker revealed that most Gadd45 expressing cells were NeuN-positive neurons. Thus, these results suggest the possibility that differential Gadd45 expression affects neurons, contributing cortical evolution and diversity. PMID- 25450957 TI - Region-specific role for GluN2B-containing NMDA receptors in injury to Purkinje cells and CA1 neurons following global cerebral ischemia. AB - Motor deficits are present in cardiac arrest survivors and injury to cerebellar Purkinje cells (PCs) likely contribute to impairments in motor coordination and post-hypoxic myoclonus. N-Methyl-D-aspartic acid (NMDA) receptor-mediated excitotoxicity is a well-established mechanism of cell death in several brain regions, but the role of NMDA receptors in PC injury remains understudied. Emerging data in cortical and hippocampal neurons indicate that the GluN2A containing NMDA receptors signal to improve cell survival and GluN2B-containing receptors contribute to neuronal injury. This study compared neuronal injury in the hippocampal CA1 region to that in PCs and investigated the role of NMDA receptors in PC injury in our mouse model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Analysis of cell density demonstrated a 24% loss of PCs within 24 h after 8 min CA/CPR and injury stabilized to 33% by 7 days. The subunit promiscuous NMDA receptor antagonist MK-801 protected both CA1 neurons and PCs from ischemic injury following CA/CPR, demonstrating a role for NMDA receptor activation in injury to both brain regions. In contrast, the GluN2B antagonist, Co 101244, had no effect on PC loss while protecting against injury in the CA1 region. These data indicate that ischemic injury to cerebellar PCs progresses via different cell death mechanisms compared to hippocampal CA1 neurons. PMID- 25450959 TI - An elevated level of circulating galanin promotes developmental expression of myelin basic protein in the mouse brain. AB - Myelinogenesis is a scheduled process that is regulated by the intrinsic properties of the cell and extracellular signals. Galanin (GAL) is a bioactive neuropeptide that is widely distributed throughout the nervous system. Chronic increase in circulating GAL levels protects the demyelination processes. Furthermore, GAL is synthesized in myelin-producing glial cells, such as oligodendrocytes and its expression level is at its highest between postnatal days 10 and 40. In the present study, we use our GAL transgenic mouse model to examine the effects of GAL on postnatal myelinogenesis in the CNS. Although we observed no difference in the proliferation of oligodendrocyte precursor cells, we found that GAL has a strong pro-myelinating effect. The transgenic mice at postnatal day 10 appeared to undergo myelinogenesis at an accelerated rate, as demonstrated by the increase in myelin basic protein (MBP) synthesis. The immunohistochemical results are consistent with our preliminary findings that suggest that GAL is a regulator of myelination and may be one of the myelination promoters. This finding is especially important for studies focusing on endogenous molecules for treating myelin-related diseases, such as multiple sclerosis and other leukodystrophies. PMID- 25450961 TI - Developmental increase in hyperpolarization-activated current regulates intrinsic firing properties in rat vestibular ganglion cells. AB - The primary vestibular neurons convey afferent information from hair cells in the inner ear to the vestibular nuclei and the cerebellum. The intrinsic firing properties of vestibular ganglion cells (VGCs) are heterogeneous to sustained membrane depolarization, and undergo marked developmental changes from phasic to tonic types during the early postnatal period. Previous studies have shown that low-voltage-activated potassium channels, Kv1 and Kv7, play a critical role in determining the firing pattern of VGCs. In the present study, we explored the developmental changes in the properties of hyperpolarization-activated current (Ih) in rat VGCs and the role played by Ih in determining the firing properties of VGCs. Tonic firing VGCs showed a larger current density of Ih as compared to phasic firing VGCs, and tonic firing VGCs became phasic firing in the presence of ZD7288, an Ih channel blocker, indicating that Ih contributes to control the firing pattern of VGCs. The amplitude of Ih increased and the activation kinetics of Ih became faster during the developmental period. Analysis of developmental changes in the expression of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels revealed that expression of HCN1 protein and its mRNA increased during the developmental period, whereas expression of HCN2-4 protein and its mRNA did not change. Our results suggest that HCN1 channels as well as Kv1 channels are critical in determining the firing pattern of rat VGCs and that developmental up-regulation of HCN1 transforms VGCs from phasic to tonic firing phenotypes. PMID- 25450960 TI - Plasticity of glomeruli and olfactory-mediated behavior in zebrafish following detergent lesioning of the olfactory epithelium. AB - The zebrafish olfactory system is a valuable model for examining neural regeneration after damage due to the remarkable plasticity of this sensory system and of fish species. We applied detergent to the olfactory organ and examined the effects on both morphology and function of the olfactory system in adult zebrafish. Olfactory organs were treated once with Triton X-100 unilaterally to study glomerular innervation patterns or bilaterally to study odor detection. Fish were allowed to recover for 4-10 days and were compared to untreated control fish. Axonal projections were analyzed using whole mount immunocytochemistry with anti-keyhole limpet hemocyanin, a marker of olfactory axons in teleosts. Chemical lesioning of the olfactory organ with a single dose of Triton X-100 had profound effects on glomerular distribution in the olfactory bulb at 4 days after treatment, with the most significant effects in the medial region of the bulb. Glomeruli had returned by 7 days post-treatment. Analysis of the ability of the fish to detect cocktails of amino acids or bile salts consisted of counting the number of turns the fish made before and after odorant delivery. Control fish turned more after exposure to both odorants. Fish tested 4 and 7 days after chemical lesioning made more turns in response to amino acids but did not respond to bile salts. At 10 days post-lesion, these fish had regained the ability to detect bile salts. Thus, the changes seen in bulbar innervation patterns correlated to odorant-mediated behavior. We show that the adult zebrafish brain has the capacity to recover rapidly from detergent damage of the olfactory epithelium, with both glomerular distribution and odorant-mediated behavior returning in 10 days. PMID- 25450962 TI - Distinct digit kinematics by professional and amateur pianists. AB - Many everyday tasks such as typing, grasping, and object manipulation require coordination of dynamic movement across multiple joints and digits. Playing a musical instrument is also one such task where the precise movement of multiple digits is transformed into specific sounds defined by the instrument. Through extensive practice musicians are able to produce precisely controlled movements to interact with the instrument and produce specific sequences of sounds. The present study aimed to determine what aspects of these dynamic movement patterns differ between pianists who have achieved professional status compared to amateur pianists that have also trained extensively. Common patterns of movement for each digit strike were observed for both professional and amateur pianists that were sequence specific, i.e. influenced by the digit performing the preceding strike. However, group differences were found in multi-digit movement patterns for sequences involving the ring or little finger. In some sequences, amateur subjects tended to work against the innate connectivity between digits while professionals allowed slight movement at non-striking digits (covariation) which was a more economical strategy. In other sequences professionals used more individuated finger movements for performance. Thus the present study provided evidence in favor of enhancement of both movement covariation and individuation across fingers in more skilled musicians, depending on fingering and movement sequence. PMID- 25450963 TI - Mouse models of sepsis elicit spontaneous action potential discharge and enhance intracellular Ca2+ signaling in postganglionic sympathetic neurons. AB - Sepsis is a severe systemic inflammatory disorder that rapidly activates the sympathetic nervous system to enhance catecholamine secretion from postganglionic sympathetic neurons and adrenal chromaffin cells. Although an increase in preganglionic drive to postganglionic sympathetic tissues has been known to contribute to this response for quite some time, only recently was it determined that sepsis also has direct effects on adrenal chromaffin cell Ca2+ signaling and epinephrine release. In the present study, we characterized the direct effects of sepsis on postganglionic sympathetic neuron function. Using the endotoxemia model of sepsis in mice, we found that almost a quarter of postganglionic neurons acquired the ability to fire spontaneous action potentials, which was absent in cells from control mice. Spontaneously firing neurons possessed significantly lower rheobases and fired a greater number of action potentials at twice the rheobase compared to neurons from control mice. Sepsis did not significantly affect voltage-gated Ca2+ currents. However, global Ca2+ signaling was enhanced in postganglionic neurons isolated from 1 to 24 h endotoxemic mice. A similar increase in the amplitude of high-K+-stimulated Ca2+ transients was observed during the cecal ligation and puncture model of sepsis. The enhanced excitability and Ca2+ signaling produced during sepsis likely amplify the effect of increased preganglionic drive on norepinephrine release from postganglionic neurons. This is important, as sympathetic neurons are integral to the anti-inflammatory autonomic reflex that is activated during sepsis. PMID- 25450964 TI - Dopamine midbrain neurons in health and Parkinson's disease: emerging roles of voltage-gated calcium channels and ATP-sensitive potassium channels. AB - Dopamine (DA) releasing midbrain neurons are essential for multiple brain functions, such as voluntary movement, working memory, emotion and cognition. DA midbrain neurons within the substantia nigra (SN) and the ventral tegmental area (VTA) exhibit a variety of distinct axonal projections and cellular properties, and are differentially affected in diseases like schizophrenia, attention deficit hyperactivity disorder, and Parkinson's disease (PD). Apart from having diverse functions in health and disease states, DA midbrain neurons display distinct electrical activity patterns, crucial for DA release. These activity patterns are generated and modulated by specific sets of ion channels. Recently, two ion channels have been identified, not only contributing to these activity patterns and to functional properties of DA midbrain neurons, but also seem to render SN DA neurons particularly vulnerable to degeneration in PD and its animal models: L type calcium channels (LTCCs) and ATP-sensitive potassium channels (K-ATPs). In this review, we focus on the emerging physiological and pathophysiological roles of these two ion channels (and their complex interplay with other ion channels), particularly in highly vulnerable SN DA neurons, as selective degeneration of these neurons causes the major motor symptoms of PD. PMID- 25450965 TI - The direct, not V1-mediated, functional influence between the thalamus and middle temporal complex in the human brain is modulated by the speed of visual motion. AB - The main visual pathway that conveys motion information to the middle temporal complex (hMT+) originates from the primary visual cortex (V1), which, in turn, receives spatial and temporal features of the perceived stimuli from the lateral geniculate nucleus (LGN). In addition, visual motion information reaches hMT+ directly from the thalamus, bypassing the V1, through a direct pathway. We aimed at elucidating whether this direct route between LGN and hMT+ represents a 'fast lane' reserved to high-speed motion, as proposed previously, or it is merely involved in processing motion information irrespective of speeds. We evaluated functional magnetic resonance imaging (fMRI) responses elicited by moving visual stimuli and applied connectivity analyses to investigate the effect of motion speed on the causal influence between LGN and hMT+, independent of V1, using the Conditional Granger Causality (CGC) in the presence of slow and fast visual stimuli. Our results showed that at least part of the visual motion information from LGN reaches hMT+, bypassing V1, in response to both slow and fast motion speeds of the perceived stimuli. We also investigated whether motion speeds have different effects on the connections between LGN and functional subdivisions within hMT+: direct connections between LGN and MT-proper carry mainly slow motion information, while connections between LGN and MST carry mainly fast motion information. The existence of a parallel pathway that connects the LGN directly to hMT+ in response to both slow and fast speeds may explain why MT and MST can still respond in the presence of V1 lesions. PMID- 25450966 TI - Administration of nicotinic receptor antagonists during the period of memory consolidation affects passive avoidance learning and modulates synaptic efficiency in the CA1 region in vivo. AB - We examined whether a non-selective antagonist of nAChRs mecamylamine and selective antagonists of alpha4beta2-containing nAChRs dihydro-beta-erythroidine (DHbetaE) and alpha7-containing nAChRs methyllycaconitine (MLA) affect learning performance and synaptic efficiency in the CA1 area of the hippocampus of freely moving rats during the memory consolidation period. Adult male Wistar rats received mecamylamine (0.5 mg/kg), DHbetaE (1 mg/kg), MLA (2 mg/kg) or saline immediately after training in a passive avoidance task. Memory retention was examined 24 h after the training. The changes in the latency of the first entry into a dark compartment of a test chamber were chosen as a criterion of learning. The ability of nAChRs antagonists to induce changes in the basal level of focal potentials (fEPSP, field excitatory postsynaptic potential) was estimated before training (baseline), 90 min after the training (consolidation period) and 24 h after the training (retention period). We found that in untrained rats mecamylamine, DHbetaE and MLA diminished the amplitude of fEPSP within the first 90 min after the injection; similar effect was observed in DHbetaE- and MLA treated trained animals. These suppressive effects of DHbetaE and MLA were associated with memory loss. In contrast, mecamylamine, when applied to trained animals, tended to increase latency to enter the dark chamber and did not influence fEPSP during first 90 min after injection. Thus, the nAChRs antagonists with different selectivity induced different changes in fEPSP and behavior which suggests that nAChRs with different subunit composition are diversely involved in memory consolidation. PMID- 25450967 TI - Spinally projecting preproglucagon axons preferentially innervate sympathetic preganglionic neurons. AB - Glucagon-like peptide-1 (GLP-1) affects central autonomic neurons, including those controlling the cardiovascular system, thermogenesis, and energy balance. Preproglucagon (PPG) neurons, located mainly in the nucleus tractus solitarius (NTS) and medullary reticular formation, produce GLP-1. In transgenic mice expressing glucagon promoter-driven yellow fluorescent protein (YFP), these brainstem PPG neurons project to many central autonomic regions where GLP-1 receptors are expressed. The spinal cord also contains GLP-1 receptor mRNA but the distribution of spinal PPG axons is unknown. Here, we used two-color immunoperoxidase labeling to examine PPG innervation of spinal segments T1-S4 in YFP-PPG mice. Immunoreactivity for YFP identified spinal PPG axons and perikarya. We classified spinal neurons receiving PPG input by immunoreactivity for choline acetyltransferase (ChAT), nitric oxide synthase (NOS) and/or Fluorogold (FG) retrogradely transported from the peritoneal cavity. FG microinjected at T9 defined cell bodies that supplied spinal PPG innervation. The deep dorsal horn of lower lumbar cord contained YFP-immunoreactive neurons. Non-varicose, YFP immunoreactive axons were prominent in the lateral funiculus, ventral white commissure and around the ventral median fissure. In T1-L2, varicose, YFP containing axons closely apposed many ChAT-immunoreactive sympathetic preganglionic neurons (SPN) in the intermediolateral cell column (IML) and dorsal lamina X. In the sacral parasympathetic nucleus, about 10% of ChAT-immunoreactive preganglionic neurons received YFP appositions, as did occasional ChAT-positive motor neurons throughout the rostrocaudal extent of the ventral horn. YFP appositions also occurred on NOS-immunoreactive spinal interneurons and on spinal YFP-immunoreactive neurons. Injecting FG at T9 retrogradely labeled many YFP-PPG cell bodies in the medulla but none of the spinal YFP-immunoreactive neurons. These results show that brainstem PPG neurons innervate spinal autonomic and somatic motor neurons. The distributions of spinal PPG axons and spinal GLP-1 receptors correlate well. SPN receive the densest PPG innervation. Brainstem PPG neurons could directly modulate sympathetic outflow through their spinal inputs to SPN or interneurons. PMID- 25450969 TI - Plasma membrane reorganization: A glycolipid gateway for microbes. AB - Ligand-receptor interactions, which represent the core for cell signaling and internalization processes are largely affected by the spatial configuration of host cell receptors. There is a growing piece of evidence that receptors are not homogeneously distributed within the plasma membrane, but are rather pre clustered in nanodomains, or clusters are formed upon ligand binding. Pathogens have evolved many strategies to evade the host immune system and to ensure their survival by hijacking plasma membrane receptors that are most often associated with lipid rafts. In this review, we discuss the early stage molecular and physiological events that occur following ligand binding to host cell glycolipids. The ability of various biological ligands (e.g. toxins, lectins, viruses or bacteria) that bind to glycolipids to induce their own uptake into mammalian cells by creating negative membrane curvature and membrane invaginations is explored. We highlight recent trends in understanding nanoscale plasma membrane (re-)organization and present the benefits of using synthetic membrane systems. This article is part of a Special Issue entitled: Nanoscale membrane organisation and signalling. PMID- 25450968 TI - H9c2 and HL-1 cells demonstrate distinct features of energy metabolism, mitochondrial function and sensitivity to hypoxia-reoxygenation. AB - Dysfunction of cardiac energy metabolism plays a critical role in many cardiac diseases, including heart failure, myocardial infarction and ischemia-reperfusion injury and organ transplantation. The characteristics of these diseases can be elucidated in vivo, though animal-free in vitro experiments, with primary adult or neonatal cardiomyocytes, the rat ventricular H9c2 cell line or the mouse atrial HL-1 cells, providing intriguing experimental alternatives. Currently, it is not clear how H9c2 and HL-1 cells mimic the responses of primary cardiomyocytes to hypoxia and oxidative stress. In the present study, we show that H9c2 cells are more similar to primary cardiomyocytes than HL-1 cells with regard to energy metabolism patterns, such as cellular ATP levels, bioenergetics, metabolism, function and morphology of mitochondria. In contrast to HL-1, H9c2 cells possess beta-tubulin II, a mitochondrial isoform of tubulin that plays an important role in mitochondrial function and regulation. We demonstrate that H9c2 cells are significantly more sensitive to hypoxia-reoxygenation injury in terms of loss of cell viability and mitochondrial respiration, whereas HL-1 cells were more resistant to hypoxia as evidenced by their relative stability. In comparison to HL-1 cells, H9c2 cells exhibit a higher phosphorylation (activation) state of AMP-activated protein kinase, but lower peroxisome proliferator-activated receptor gamma coactivator 1-alpha levels, suggesting that each cell type is characterized by distinct regulation of mitochondrial biogenesis. Our results provide evidence that H9c2 cardiomyoblasts are more energetically similar to primary cardiomyocytes than are atrial HL-1 cells. H9c2 cells can be successfully used as an in vitro model to simulate cardiac ischemia-reperfusion injury. PMID- 25450970 TI - Role of the focal adhesion protein TRIM15 in colon cancer development. AB - The tripartite motif containing (TRIM) proteins are a large family of proteins that have been implicated in many biological processes including cell differentiation, apoptosis, transcriptional regulation, and signaling pathways. Here, we show that TRIM15 co-localized to focal adhesions through homo dimerization and significantly suppressed cell migration. Domain mapping analysis indicated that B-box2 and PRY domains were essential for TRIM15 localization to focal adhesions and inhibition of cell migration. Our protein-protein interaction screen of TRIM15 with the integrin adhesome identified several TRIM15 interacting proteins including coronin 1B, cortactin, filamin binding LIM protein1, and vasodilator-stimulated phosphoprotein, which are involved in actin cytoskeleton dynamics. TRIM15 expression was tissue-restricted and downregulated in colon cancer. Level of TRIM15 expression was associated with colon cancer cell migration, as well as both in vitro and in vivo tumor growth. These data provide novel insights into the role of TRIM15 as an additional component of the integrin adhesome, regulating cell migration, and suggest that TRIM15 may function as a tumor suppressor of colon cancer. PMID- 25450971 TI - Imatinib restores VASP activity and its interaction with Zyxin in BCR-ABL leukemic cells. AB - Vasodilator-stimulated phosphoprotein (VASP) and Zyxin are interacting proteins involved in cellular adhesion and motility. PKA phosphorylates VASP at serine 157, regulating VASP cellular functions. VASP interacts with ABL and is a substrate of the BCR-ABL oncoprotein. The presence of BCR-ABL protein drives oncogenesis in patients with chronic myeloid leukemia (CML) due to a constitutive activation of tyrosine kinase activity. However, the function of VASP and Zyxin in BCR-ABL pathway and the role of VASP in CML cells remain unknown. In vitro experiments using K562 cells showed the involvement of VASP in BCR-ABL signaling. VASP and Zyxin inhibition decreased the expression of anti-apoptotic proteins, BCL2 and BCL-XL. Imatinib induced an increase in phosphorylation at Ser157 of VASP and decreased VASP and BCR-ABL interaction. VASP did not interact with Zyxin in K562 cells; however, after Imatinib treatment, this interaction was restored. Corroborating our data, we demonstrated the absence of phosphorylation at Ser157 in VASP in the bone marrow of CML patients, in contrast to healthy donors. Phosphorylation of VASP on Ser157 was restored in Imatinib responsive patients though not in the resistant patients. Therefore, we herein identified a possible role of VASP in CML pathogenesis, through the regulation of BCR-ABL effector proteins or the absence of phosphorylation at Ser157 in VASP. PMID- 25450972 TI - Mitochondria in peroxisome-deficient hepatocytes exhibit impaired respiration, depleted DNA, and PGC-1alpha independent proliferation. AB - The tight interrelationship between peroxisomes and mitochondria is illustrated by their cooperation in lipid metabolism, antiviral innate immunity and shared use of proteins executing organellar fission. In addition, we previously reported that disruption of peroxisome biogenesis in hepatocytes severely impacts on mitochondrial integrity, primarily damaging the inner membrane. Here we investigated the molecular impairments of the dysfunctional mitochondria in hepatocyte selective Pex5 knockout mice. First, by using blue native electrophoresis and in-gel activity stainings we showed that the respiratory complexes were differentially affected with reduction of complexes I and III and incomplete assembly of complex V, whereas complexes II and IV were normally active. This resulted in impaired oxygen consumption in cultured Pex5(-/-) hepatocytes. Second, mitochondrial DNA was depleted causing an imbalance in the expression of mitochondrial- and nuclear-encoded subunits of the respiratory chain complexes. Third, mitochondrial membranes showed increased permeability and fluidity despite reduced content of the polyunsaturated fatty acid docosahexaenoic acid. Fourth, the affected mitochondria in peroxisome deficient hepatocytes displayed increased oxidative stress. Acute deletion of PEX5 in vivo using adeno-Cre virus phenocopied these effects, indicating that mitochondrial perturbations closely follow the loss of functional peroxisomes in time. Likely to compensate for the functional impairments, the volume of the mitochondrial compartment was increased several folds. This was not driven by PGC-1alpha but mediated by activation of PPARalpha, possibly through c-myc overexpression. In conclusion, loss of peroxisomal metabolism in hepatocytes perturbs the mitochondrial inner membrane, depletes mitochondrial DNA and causes mitochondrial biogenesis independent of PGC-1alpha. PMID- 25450973 TI - Human placental eXpanded (PLX) mesenchymal-like adherent stromal cells confer neuroprotection to nerve growth factor (NGF)-differentiated PC12 cells exposed to ischemia by secretion of IL-6 and VEGF. AB - Mesenchymal stem cells are potent candidates in stroke therapy due to their ability to secrete protective anti-inflammatory cytokines and growth factors. We investigated the neuroprotective effects of human placental mesenchymal-like adherent stromal cells (PLX) using an established ischemic model of nerve growth factor (NGF)-differentiated pheochromocytoma PC12 cells exposed to oxygen and glucose deprivation (OGD) followed by reperfusion. Under optimal conditions, 2 * 105 PLX cells, added in a trans-well system, conferred 30-60% neuroprotection to PC12 cells subjected to ischemic insult. PC12 cell death, measured by LDH release, was reduced by PLX cells or by conditioned medium derived from PLX cells exposed to ischemia, suggesting the active release of factorial components. Since neuroprotection is a prominent function of the cytokine IL-6 and the angiogenic factor VEGF165, we measured their secretion using selective ELISA of the cells under ischemic or normoxic conditions. IL-6 and VEGF165 secretion by co-culture of PC12 and PLX cells was significantly higher under ischemic compared to normoxic conditions. Exogenous supplementation of 10 ng/ml each of IL-6 and VEGF165 to insulted PC12 cells conferred neuroprotection, reminiscent of the neuroprotective effect of PLX cells or their conditioned medium. Growth factors as well as co-culture conditioned medium effects were reduced by 70% and 20% upon pretreatment with 240 ng/ml Semaxanib (anti VEGF165) and/or 400 ng/ml neutralizing anti IL-6 antibody, respectively. Therefore, PLX-induced neuroprotection in ischemic PC12 cells may be partially explained by IL-6 and VEGF165 secretion. These findings may also account for the therapeutic effects seen in clinical trials after treatment with these cells. PMID- 25450975 TI - Downregulation of diacylglycerol kinase zeta enhances activation of cytokine induced NF-kappaB signaling pathway. AB - The transcription factor NF-kappaB family serves as a key component of many pathophysiological events such as innate and adaptive immune response, inflammation, apoptosis, and oncogenesis. Various cell signals trigger activation of the regulatory mechanisms of NF-kappaB, resulting in its nuclear translocation and transcriptional initiation. The diacylglycerol kinase (DGK) family, a lipid second messenger-metabolizing enzyme in phosphoinositide signaling, is shown to regulate widely various cellular processes. Results of recent studies suggest that one family member, DGKzeta, is closely involved in immune and inflammatory responses. Nevertheless, little is known about the regulatory mechanism of DGKzeta on NF-kappaB pathway in cytokine-induced inflammatory signaling. This study shows that siRNA-mediated DGKzeta knockdown in HeLa cells facilitates degradation of IkappaB, followed by nuclear translocation of NF-kappaB p65 subunit. In addition, DGKzeta-deficient MEFs show upregulation of p65 subunit phosphorylation at Serine 468 and 536 and its interaction with CBP transcriptional coactivator upon TNF-alpha stimulation. These modifications of p65 subunit might engender enhanced NF-kappaB transcriptional reporter assay of DGKzeta knockdown cells. These findings provide further insight into the regulatory mechanisms of cytokine-induced NF-kappaB activation. PMID- 25450974 TI - The nanoscale organization of the B lymphocyte membrane. AB - The fluid mosaic model of Singer and Nicolson correctly predicted that the plasma membrane (PM) forms a lipid bi-layer containing many integral trans-membrane proteins. This model also suggested that most of these proteins were randomly dispersed and freely diffusing moieties. Initially, this view of a dynamic and rather unorganized membrane was supported by early observations of the cell surfaces using the light microscope. However, recent studies on the PM below the diffraction limit of visible light (~250nm) revealed that, at nanoscale dimensions, membranes are highly organized and compartmentalized structures. Lymphocytes are particularly useful to study this nanoscale membrane organization because they grow as single cells and are not permanently engaged in cell:cell contacts within a tissue that can influence membrane organization. In this review, we describe the methods that can be used to better study the protein:protein interaction and nanoscale organization of lymphocyte membrane proteins, with a focus on the B cell antigen receptor (BCR). Furthermore, we discuss the factors that may generate and maintain these membrane structures. PMID- 25450976 TI - Endothelial Nlrp3 inflammasome activation associated with lysosomal destabilization during coronary arteritis. AB - Inflammasomes play a critical role in the development of vascular diseases. However, the molecular mechanisms activating the inflammasome in endothelial cells and the relevance of this inflammasome activation is far from clear. Here, we investigated the mechanisms by which an Nlrp3 inflammasome is activated to result in endothelial dysfunction during coronary arteritis by Lactobacillus casei (L. casei) cell wall fragments (LCWE) in a mouse model for Kawasaki disease. Endothelial dysfunction associated with increased vascular cell adhesion protein 1 (VCAM-1) expression and endothelial-leukocyte adhesion was observed during coronary arteritis in mice treated with LCWE. Accompanied with these changes, the inflammasome activation was also shown in coronary arterial endothelium, which was characterized by a marked increase in caspase-1 activity and IL-1beta production. In cultured endothelial cells, LCWE induced Nlrp3 inflammasome formation, caspase-1 activation and IL-1beta production, which were blocked by Nlrp3 gene silencing or lysosome membrane stabilizing agents such as colchicine, dexamethasone, and ceramide. However, a potassium channel blocker glibenclamide or an oxygen free radical scavenger N-acetyl-l-cysteine had no effects on LCWE-induced inflammasome activation. LCWE also increased endothelial cell lysosomal membrane permeability and triggered lysosomal cathepsin B release into cytosol. Silencing cathepsin B blocked LCWE-induced Nlrp3 inflammasome formation and activation in endothelial cells. In vivo, treatment of mice with cathepsin B inhibitor also abolished LCWE-induced inflammasome activation in coronary arterial endothelium. It is concluded that LCWE enhanced lysosomal membrane permeabilization and consequent release of lysosomal cathepsin B, resulting in activation of the endothelial Nlrp3 inflammasome, which may contribute to the development of coronary arteritis. PMID- 25450977 TI - Calcium signaling in taste cells. AB - The sense of taste is a common ability shared by all organisms and is used to detect nutrients as well as potentially harmful compounds. Thus taste is critical to survival. Despite its importance, surprisingly little is known about the mechanisms generating and regulating responses to taste stimuli. All taste responses depend on calcium signals to generate appropriate responses which are relayed to the brain. Some taste cells have conventional synapses and rely on calcium influx through voltage-gated calcium channels. Other taste cells lack these synapses and depend on calcium release to formulate an output signal through a hemichannel. Beyond establishing these characteristics, few studies have focused on understanding how these calcium signals are formed. We identified multiple calcium clearance mechanisms that regulate calcium levels in taste cells as well as a calcium influx that contributes to maintaining appropriate calcium homeostasis in these cells. Multiple factors regulate the evoked taste signals with varying roles in different cell populations. Clearly, calcium signaling is a dynamic process in taste cells and is more complex than has previously been appreciated. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID- 25450986 TI - What does it mean to be a 'picky eater'? A qualitative study of food related identities and practices. AB - Picky eaters are defined as those who consume an inadequate variety of food through rejection of a substantial amount of food stuffs that are both familiar and unfamiliar. Picky eating is a relatively recent theoretical concept and while there is increasing concern within public health over the lack of diversity in some children's diets, adult picky eaters remain an under researched group. This paper reports on the findings of a qualitative study on the routine food choices and practices of 26 families in Sandwell, West Midlands, UK. Photo elicitation and go-along interview data collection methods were used to capture habitual food related behaviours and served to describe the practices of nine individuals who self identified or were described as picky eaters. A thematic analysis revealed that those with the food related identity of picky eater had very restricted diets and experienced strong emotional and physical reactions to certain foods. For some this could be a distressing and alienating experience that hindered their ability to engage in episodes of social eating. Further research is needed to illuminate the specific practices of adult picky eaters, how this impacts on their lives, and how possible interventions might seek to address the challenges they face. PMID- 25450978 TI - Fe-S proteins that regulate gene expression. AB - Iron-sulfur (Fe-S) cluster containing proteins that regulate gene expression are present in most organisms. The innate chemistry of their Fe-S cofactors makes these regulatory proteins ideal for sensing environmental signals, such as gases (e.g. O2 and NO), levels of Fe and Fe-S clusters, reactive oxygen species, and redox cycling compounds, to subsequently mediate an adaptive response. Here we review the recent findings that have provided invaluable insight into the mechanism and function of these highly significant Fe-S regulatory proteins. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. PMID- 25450988 TI - [Personalized medicine]. PMID- 25450979 TI - CD138-negative myeloma cells regulate mechanical properties of bone marrow stromal cells through SDF-1/CXCR4/AKT signaling pathway. AB - As the second most prevalent hematologic malignancy, multiple myeloma (MM) remains incurable and relapses due to intrinsic or acquired drug resistance. Therefore, new therapeutic strategies that target molecular mechanisms responsible for drug resistance are attractive. Interactions of tumor cells with their surrounding microenvironment impact tumor initiation, progression and metastasis, as well as patient prognosis. This cross-talk is bidirectional. Tumor cells can also attract or activate tumor-associated stromal cells by releasing cytokines to facilitate their growth, invasion and metastasis. The effect of myeloma cells on bone marrow stromal cells (BMSCs) has not been well studied. In our study, we found that higher stiffness of BMSCs was not a unique characteristic of BMSCs from MM patients (M-BMSCs). BMSCs from MGUS (monoclonal gammopathy of undetermined significance) patients were also stiffer than the BMSCs from healthy volunteers (N-BMSCs). The stiffness of M-BMSCs was enhanced when cocultured with myeloma cells. In contrast, no changes were seen in myeloma cell-primed MGUS- and N-BMSCs. Interestingly, our data indicated that CD138- myeloma cells, but not CD138+ cells, regulated M-BMSC stiffness. SDF-1 was highly expressed in the CD138- myeloma subpopulation compared with that in CD138+ cells. Inhibition of SDF-1 using AMD3100 or knocking-down CXCR4 in M-BMSCs blocked CD138 myeloma cells-induced increase in M-BMSC stiffness, suggesting a crucial role of SDF-1/CXCR4. AKT inhibition attenuated SDF-1-induced increases in M-BMSC stiffness. These findings demonstrate, for the first time, CD138- myeloma cell directed cross-talk with BMSCs and reveal that CD138- myeloma cells regulate M BMSC stiffness through SDF-1/CXCR4/AKT signaling. PMID- 25450987 TI - Validation of an iPad visual analogue rating system for assessing appetite and satiety. AB - The study aimed to validate appetite ratings made on a new electronic device, the Apple iPad Mini, against an existing but now obsolete electronic device (Hewlett Packard iPAQ). Healthy volunteers (9 men and 9 women) rated their appetite before and 0, 30, 60, 90 and 120 minutes after consuming both a low energy (LE: 77 kcal) and high energy (HE: 274 kcal) beverage at breakfast on 2 non-consecutive days in counter-balanced order. Rated hunger, desire to eat and how much participants could consume was significantly lower after HE than LE on both devices, although there was better overall differentiation between HE and LE for ratings on iPad. Rated satiation and fullness, and a composite measure combining all five ratings, was significantly higher after HE than LE on both devices. There was also evidence that differences between conditions were more significant when analysed at each time point than using an overall area under the curve (AUC) measure. Overall, these data confirm that appetite ratings made using iPad are at least as sensitive as those on iPAQ, and offer a new platform for researchers to collect appetite data. PMID- 25450981 TI - The inhibition of aromatase alters the mechanical and rheological properties of non-small-cell lung cancer cell lines affecting cell migration. AB - Tumor invasion and metastasis are key aspects of non-small cell lung cancer (NSCLC). During migration, cells undergo mechanical alterations. The mechanical phenotype of breast cancer cells is correlated with aromatase gene expression. We have previously shown that targeting aromatase is a promising strategy for NSCLC. The aim of this study was to examine morphological and mechanical changes of NSCLC cells, upon treatment with aromatase inhibitor and correlate their ability to migrate and invade. In vitro experiments were performed using H23 and A549 NSCLC cell lines and exemestane was used for aromatase inhibition. We demonstrated that exemestane reduced H23 cell migration and invasion and caused changes in cell morphology including increased vacuolar structures and greater pleomorphism. In addition, exemestane changed the distribution of alpha-tubulin in H23 and A549 cells in a way that might destabilize microtubules polymerization. These effects were associated with increased cell viscosity and decreased elastic shear modulus. Although exemestane caused similar effects in A549 cells regarding viscosity and elastic shear modulus, it did not affect A549 cell migration and caused an increase in invasion. The increased invasion was in line with vimentin perinuclear localization. Our data show that the treatment of NSCLC cells with an aromatase inhibitor not only affects cell migration and invasion but also alters the mechanical properties of the cells. It suggests that the different origin of cancer cells is associated with different morphological characteristics and mechanical behavior. PMID- 25450980 TI - Tangled web of interactions among proteins involved in iron-sulfur cluster assembly as unraveled by NMR, SAXS, chemical crosslinking, and functional studies. AB - Proteins containing iron-sulfur (Fe-S) clusters arose early in evolution and are essential to life. Organisms have evolved machinery consisting of specialized proteins that operate together to assemble Fe-S clusters efficiently so as to minimize cellular exposure to their toxic constituents: iron and sulfide ions. To date, the best studied system is the iron-sulfur cluster (isc) operon of Escherichia coli, and the eight ISC proteins it encodes. Our investigations over the past five years have identified two functional conformational states for the scaffold protein (IscU) and have shown that the other ISC proteins that interact with IscU prefer to bind one conformational state or the other. From analyses of the NMR spectroscopy-derived network of interactions of ISC proteins, small-angle X-ray scattering (SAXS) data, chemical crosslinking experiments, and functional assays, we have constructed working models for Fe-S cluster assembly and delivery. Future work is needed to validate and refine what has been learned about the E. coli system and to extend these findings to the homologous Fe-S cluster biosynthetic machinery of yeast and human mitochondria. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. PMID- 25450989 TI - [Ectopic connection of the left coronary artery with the contralateral sinus with or without intramural pathway: how and why differentiating them?]. AB - Among the wide spectrum of congenital abnormalities of coronary arteries, a left coronary artery connected with the contralateral sinus is considered as an anatomical high-risk while associated with a proximal preaortic course. The ectopic connection may be associated with or without intramural pathway regarding the aortic wall. An intramural pathway is a characteristic to be considered because it is able to be involved in myocardial ischemia-related adverse events of which the sudden death. Therefore, making an identification of an intramural pathway is essential for the ectopic connections of the left coronary artery associated with a preaortic course. PMID- 25450990 TI - [ST segment elevation myocardial infarction in a young patient: special physiopathology and unusual management]. AB - We report the case of a 24-year-old patient admitted for anterior ST segment elevation myocardial complicated by ventricular fibrillation and revealing thrombotic sub occlusion of the left anterior descending coronary artery. Revascularization is achieved by manual thrombectomy and use of Glycoprotein GPIIbIIIa inhibitors and permits to restore TIMI 3 flow. Given the large thrombotic burden, the patient is initially treated medically (optimal anti thrombotic therapy without stenting) and benefits from angiographic control 48 hours later with imaging by Optical Coherence Tomography (OCT). It shows a reduction of thrombus burden and lack of significant underlying organic lesion (no organic stenosis or plaque rupture). In view of these data, it was decided to continue medical treatment alone without stenting. OCT imaging at 6 months shows atheroma without stenosis, thrombus or plaque rupture. This young patient remains asymptomatic and recovered normal left ventricular function with a 2-year follow up. PMID- 25450991 TI - [Transcatheter aortic valve implantation]. AB - As the French population is aging, a growing number of elderly patients with symptomatic severe aortic stenosis are going to require therapeutic management. Approximately 30 to 40 % of these patients do not undergo surgical treatment and a high proportion is considered to be at high risk for surgery. The transluminal aortic valve implantation technique has been increasingly used over the past few years, thus providing a solution to a major therapeutic issue in our industrialized countries. Thanks to major randomized studies such as the PARTNER US trial, this treatment has been approved for high-risk patients. Expertise and new devices are now opening the way to intermediate risk population. PMID- 25450992 TI - [Atherosclerotic renal artery stenosis]. AB - Atherosclerotic renal artery stenosis can cause ischaemic nephropathy and arterial hypertension. Renal artery stenosis (RAS) continues to be a problem for clinicians, with no clear consensus on how to investigate and assess the clinical significance of stenotic lesions and manage the findings. RAS caused by fibromuscular dysplasia is probably commoner than previously appreciated, should be actively looked for in younger hypertensive patients and can be managed successfully with angioplasty. Atheromatous RAS is associated with increased incidence of cardiovascular events and increased cardiovascular mortality, and is likely to be seen with increasing frequency. Many patients with RAS may be managed effectively with medical therapy for several years without endovascular stenting, as demonstrated by randomized, prospective trials including the cardiovascular outcomes in Renal Atherosclerotic Lesions (CORAL) trial, the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial. These trials share the limitation of excluding subsets of patients with high-risk clinical presentations, including episodic pulmonary edema and rapidly progressing renal failure and hypertension. Blood pressure control and medication adjustment may become more difficult with declining renal function and may prevent the use of angiotensin receptor blocker and angiotensin-converting enzyme inhibitors. The objective of this review is to evaluate the current management of RAS for cardiologists in the context of recent randomized clinical trials. There is now interest in looking more closely at patient selection for intervention, with focus on intervening only in patients with the highest-risk presentations such as flash pulmonary edema, rapidly declining renal function and severe resistant hypertension. PMID- 25450993 TI - [Muscle retraining or aerobic endurance training? What will improve the aerobic capacity of patients with coronary disease in the only 4 weeks?]. AB - OBJECTIVE: The aim of this study was to compare the effects of 4 weeks of CT and AT, which training impulse (total external workload and perceived exertion), are similar on power associated at VO2 peak (pVO2 peak) and cardiorespiratory responses of patient with CAD. METHOD: Eighteen male with CAD (62 +/- 7 years, 175 +/- 2 cm, 84 +/- 16 kg, fraction of ejection = 0.49 +/- 0.16) performed 4 weeks of CT (n = 9) or AT (n = 9). pVO2 peak, maximal and first ventilatory threshold values of oxygen uptake (VO2 peak, VO2-vt) and heart rate (HRmax, HR vt) were measured before and after training session. Total training impulse (exercise rehabilitation and other paramedical actions) were evaluated and harmonized between AT and CT according to Foster et al. formula (1996) RESULTS: No significant difference were found in training impulse between AT and CT (3650 +/- 220 vs 3497 +/- 190 U, P = NS). VO2 pic increased after AT (16.9 +/- 4.4 vs 18.9 +/- 4.9 mL O2/min/kg, P < 0.05) and remained unchanged after CT (17.7 +/- 7.8 vs 17.8 +/- 7.2, P = NS). Four weeks of training induced significant increase in pVO2 peak, VO2-vt and FC-vt, expressed in absolute or relative value (P < 0,05), without any difference between AT and CT modalities (P = NS). CONCLUSIONS: Improving pVO2 pic following an exercise training does not necessarily preclude an improvement in coronary VO2 pic. pVO2 peak was not improved with the same cardiorespiratory adaptations between AT and CT. Thus, there seems important to measure gas exchanges of subject with CAD during the incremental test and identify the respective part of muscular and cardiorespiratory functions in exercise exhaustion. PMID- 25450994 TI - [Platypnea-orthodeoxia revealed by recurrent syncope episodes]. AB - Platypnea-orthodeoxia is a rare clinical condition which must be examined as a differential diagnosis for any bout of faintness occurring during standing or dyspnea that is exacerbated by standing. This syndrome is often associated with a patent foramen ovale. Its physiopathology is not univocal and the association of many anatomical criteria seems to be mandatory. Contrast echocardiography confirms diagnosis and closure of the patent foramen ovale during interventional catheterization and is currently the therapeutic method of choice. After closure of the foramen ovale, clinical improvement is spectacular and durable. PMID- 25450995 TI - [Longitudinal stent deformation during bifurcation lesion treatment]. AB - Longitudinal stent deformation is defined as a compression of stent length after its implantation. It's a rare complication but dangerous seen with several stents. We reported a case of longitudinal stent deformation during bifurcation lesion treatment with a Promus Element((r)) and we perform a short review of this complication. PMID- 25450996 TI - [Renal denervation by trans-radial access for resistant hypertension]. AB - Renal denervation which consists in the ablation of the sympathetic fibers located in the adventitia of renal arteries is a therapeutic strategy allowing improved arterial hypertension control in patients who do not respond to medical treatment. This technique is currently performed using the femoral approach in the majority of cases. The diameter and the length of the ablation catheters limit their use via the radial route. The most frequent peri-procedural complications are vascular problems. We report here two cases of renal denervation via the trans-humeral and trans-radial routes respectively. PMID- 25450997 TI - [Diagnosis and treatment of spastic angina revealed by cardiac arrest]. AB - The prevalence of vasospastic angina is said to be low in Europe, but maybe because of a lack of diagnosis in the daily practice. However, coronary spasm is a common cause of cardiac arrest, especially among patients free of cardiac illness, and it should be systematically investigated after an unexplained cardiac arrest. Intracoronary spasm provocation test exposes patients to a lower risk compared to the risk of spontaneous spastic angina. Accurate modalities and diagnostic criteria have to be clarified for European population. Avoiding external causes of coronary spasm (such as cigarette smoking or more generally consuming coronary spasm inducing drugs) and prescribing antispastic medicine (first of all calcium channel blockers) are the basis of vasospastic angina treatment. However, recurrent coronary spasms have been reported despite an appropriate treatment and implantable automatic defibrillator has been implanted after case discussion when the onset of illness was cardiac arrest. We report the case of a patient recovering from cardiac arrest who had a positive spasm coronary provocation test, and was treated with calcium channel blockers and had been an automatic defibrillator implanted, with a coronary spasm provocation test performed afterward still contentious. While discussing this case, we are making a literature review of the diagnosis and treatment of spastic angina revealed by cardiac arrest. PMID- 25450998 TI - In vitro immunocompetence of two compounds isolated from Polygala tenuifolia and development of resistance against grass carp reovirus (GCRV) and Dactylogyrus intermedius in respective host. AB - The present study was undertaken to isolate some compounds from methanol extract of Polygala tenuifolia and evaluate their immunostimulatory properties and antiviral activity using grass carp Ctenopharyngodon idella kidney (CIK) cells and GCRV. By applying insecticidal bioassay-guided, chromatography techniques and successive recrystallization, two purified compounds were obtained. The changes of expression of selected immune genes (Mx1, IL-1beta, TNFalpha, MyD88 and IgM) in C. idella kidney cell lines were evaluated after exposure to these isolated compounds. The results showed that compound 1 and 2 up-regulated to varying degrees of Mx1, IL-1beta, TNFalpha, and MyD88 in C. idella kidney cells. WST-8 kit assay verified the two compounds has no toxic effects on CIK cell, and furthermore, have in vitro antivirus activity. Especially, that there is keeping 79% cell viability when exposure to compound 2 (100 mg L(-1)). According to in vivo insecticidal assays against Dactylogyrus intermedius, compound 2 exhibited higher efficacy than compound 1, which was found to be 87.2% effective at the concentrations of 5 mg L(-1) and safe to goldfish (Carassius auratus). Besides, the purified compounds were identified by spectral data as: (1) 1,5-Anhydro-D glucitol and (2) 3,4,5-trimethoxy cinnamic acid. Overall, the results indicate that bath administration of these compounds modulates the immune related genes in C. idella kidney cells and to some extent, eliminate the virus and parasitic infections. PMID- 25450999 TI - Identification and characterisation of TLR18-21 genes in Atlantic salmon (Salmo salar). AB - Teleost fish possess many types of toll-like receptor (TLR) some of which exist in other vertebrate groups and some that do not (ie so-called "fish-specific" TLRs). In this study, we identified in Atlantic salmon (Salmo salar) whole-genome shotgun (WGS) contigs seven TLRs that are not found in mammals, including six types of fish-specific TLRs (one TLR18, one TLR19, and four TLR20 members (two of which are putative soluble forms (s)) and one TLR21. Phylogenetic analysis revealed that teleost TLR19-21 are closely related with murine TLR11-TLR13, whilst teleost TLR18 groups with mammalian TLR1, 2, 6 and 10. A typical TLR protein domain structure was found in all these TLRs with the exception of TLR20b(s) and TLR20c(s). TLR-GFP expression plasmids transfected into SHK-1 cells showed that salmon TLR19, TLR20a and TLR20d were preferentially localised to the intracellular compartment. Real time PCR analysis suggested that salmon TLR19 TLR21 are mainly expressed in immune related organs, such as spleen, head kidney and gills, while TLR18 transcripts are more abundant in muscle. In vitro stimulation of primary head kidney cells with type I IFN, IFNgamma and IL-1beta had no impact on TLR expression. Infectious salmon anaemia virus (ISAV) infection, in vivo, down-regulated TLR20a, TLR20b(s), TLR20d and TLR21 in infected salmon kidney tissue. In contrast, up-regulation of TLR19 and TLR20a expression was found in posterior kidney in rainbow trout with clinical proliferative kidney disease (PKD). PMID- 25451000 TI - Effects of dietary fructooligosaccharide levels and feeding modes on growth, immune responses, antioxidant capability and disease resistance of blunt snout bream (Megalobrama amblycephala). AB - This study aimed to determine the effects of fructooligosaccharide (FOS) levels and its feeding modes on growth, immune response, antioxidant capability and disease resistance of blunt snout bream (Megalobrama amblycephala). Fish (12.5 +/ 0.5 g) were subjected to three FOS levels (0, 0.4% and 0.8%) and two feeding modes (supplementing FOS continuously and supplementing FOS two days interval 5 days) according to a 3 * 2 factorial design. At the end of 8-week feeding trial, fish were challenged by Aeromonas hydrophila with concentration of 1 * 10(5) CFU mL(-1) and mortality was recorded for the next 96 h. Fish fed 0.4% FOS continuously (D2) and fish fed the basal diet for 5 days followed by 0.8% FOS for 2 days (D5) showed admirable growth performance. The highest plasma lysozyme, acid phosphatase and myeloperoxidase activities as well as complement component 3, total protein and immunoglobulin M (IgM) levels were all observed in fish fed D5. They were significantly higher (P < 0.05) than those of the control group and/or fish fed 0.8% FOS continuously, but exhibited no statistical difference (P > 0.05) with that of fish fed D2. A similar trend was also observed in antioxidant capability as well as the expression of Leap-I and Leap-II. Mortality showed an opposite trend with the immune response with the lowest rate observed in fish fed D5. The results indicated that diet supplementing FOS in appropriate levels and feeding modes could improve the growth, immune response and antioxidant capability of fish, as might consequently lead to enhanced disease resistance. It can be speculated that the basal diet for 5 days followed by 0.8% FOS for 2 days was most suitable for blunt snout bream. PMID- 25451001 TI - In vitro and in vivo evaluation of lactic acid bacteria of aquatic origin as probiotics for turbot (Scophthalmus maximus L.) farming. AB - Turbot (Scophthalmus maximus L.) is an important commercial marine flatfish. Its production may be affected by bacterial diseases that cause severe economical losses, mainly tenacibaculosis and vibriosis, provoked by Tenacibaculum maritimum and Vibrio splendidus, respectively. An alternative or complementary strategy to chemotherapy and vaccination for the control of these diseases is the use of probiotics. In this work, we report the in vitro and in vivo potential of eight lactic acid bacteria (LAB), previously isolated from fish, seafood and fish products intended for human consumption, as turbot probiotics. Seven out of the eight LAB exerted direct antimicrobial activity against, at least, four strains of T. maritimum and V. splendidus. All LAB survived in seawater at 18 degrees C for 7 days, and withstood exposure to pH 3.0 and 10% (v/v) turbot bile; however, they differed in cell surface hydrophobicity (8.2-21.7%) and in their ability to adhere to turbot skin (1.2-21.7%) and intestinal (0.7-2.1%) mucus. Most of the tested strains inhibited the binding of turbot pathogens to the mucus. Leuconostoc mesenteroides subsp. cremoris SMM69 and Weissella cibaria P71 were selected based on their strong antimicrobial activity against T. maritimum and V. splendidus, good probiotic properties, and different adhesion ability to skin mucus and capacity to inhibit the adhesion of turbot pathogens to mucus. These two LAB strains were harmless when administered by bath to turbot larvae and juveniles; moreover, real-time PCR on the transcription levels of the immunity related genes encoding IL-1beta, TNF-alpha, lysozyme, C3, MHC-Ialpha and MHC IIalpha in five organs (head-kidney, spleen, liver, intestine and skin) revealed the ability of these LAB to stimulate their expression in turbot juveniles, especially the non-specific immunity associated genes in mucosal tissues. Based on our results, Lc. cremoris SMM69 and W. cibaria P71 may be considered as suitable probiotic candidates for turbot farming. PMID- 25451002 TI - Changes in the interbranchial lymphoid tissue of Atlantic salmon (Salmo salar) affected by amoebic gill disease. AB - The interbranchial lymphoid tissue (ILT) was recently described in the gills of salmonids. This study examined changes in the ILT during a parasitic infection in marine environment, using amoebic gill disease (AGD) as a model. Atlantic salmon (Salmo salar) experimentally infected with Neoparamoeba perurans were sampled at 0, 3, 7, 14 and 28 days post challenge. Transversal sections of three areas of the gills (dorsal, medial and ventral) were histologically assessed for morphological and cellular changes. AGD induced morphological changes and a cellular response in the ILT of affected fish. These changes included a significant increase in the ILT surface area in fish 28 days after AGD challenge, compared to control fish at the same time point. The length of the ILT increased significantly 28 days post exposure in the dorsal area of the gill arch in the fish affected by AGD. The lymphocyte density of the ILT increased after AGD challenge, peaking at 7 days post exposure; however, by 28 days post exposure, a reduction of lymphocyte density to values close to pre-infection levels was observed. PCNA immunostaining revealed that epithelial hyperplasia was the most likely factor contributing to the ILT enlargement in the affected fish. PMID- 25451003 TI - Effect of dietary isoleucine on the immunity, antioxidant status, tight junctions and microflora in the intestine of juvenile Jian carp (Cyprinus carpio var. Jian). AB - This study was conducted to investigate the effects of dietary isoleucine (Ile) on the immune response, antioxidant status, tight junctions, and microbial population in the intestine of juvenile Jian carp (Cyprinus carpio var. Jian). A total of 1200 juvenile Jian carp with average initial weight 6.9 +/- 0.03 g were fed semi-purified isonitrogenous diets containing 4.2 (unsupplemented control group), 7.0, 9.5, 11.9, 13.9 and 16.9 g Ile kg(-1) diet for 60 days. Results indicated that Ile supplementation decreased malondialdehyde (MDA) and protein carbonyl content, and the amounts of Escherichia coli and Aeromonas in the intestine (P < 0.05), and increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR), glutathione content and the amounts of Lactobacillus and Bacillus in the intestine (P < 0.05). Furthermore, real time polymerase chain reaction revealed that relative mRNA expression of copper/zinc superoxide dismutase (Cu-ZnSOD), manganese superoxide dismutase (MnSOD), CAT, NF-E2-related factor 2 (Nrf2), p38 mitogen-activated protein kinases (p38MAPK) in the intestine were increased with increasing of dietary Ile up to a certain point (P < 0.05). Conversely, the relative mRNA expression of occludin, claudin-3, claudin-7, TNF-alpha, IL-10, Kelch-like-ECH- associated protein 1 (Keap1), extracellular signal-regulated kinase 1 (ERK1) in the intestine showed a downward trend (P < 0.05). In conclusion, dietary Ile improves intestinal immune function, antioxidant capacity and microbial population, and regulates gene expression of antioxidant enzyme, tight junctions, Nrf2, Keap1, p38 and ERK1 in the intestine of Jian carp. PMID- 25451004 TI - Poststroke depression and its multifactorial nature: results from a prospective longitudinal study. AB - OBJECTIVE: Poststroke depression (PSD) is commonly observed in stroke patients and has a negative impact on functional outcome and quality of life. Therefore, a prospective, longitudinal epidemiological study was conducted aiming to determine prevalence and risk factors for PSD at 1, 3, 6, 12 and 18 months poststroke. METHODS: A total of 222 patients were included in the study and 201 patients entered data analysis. Demographic data, vascular risk factors, stroke characteristics, functional and neurocognitive outcome measures and psychosocial factors were considered as potential risk factors for PSD. Clinically significant signs and symptoms of PSD were quantified by means of the Cornell Scale for Depression (CSD) and the Montgomery and Asberg Depression Rating Scale (MADRS). RESULTS: PSD was present at 1, 3, 6, 12 and 18 months poststroke in 24.5%, 27.1%, 28.3%, 19.8% and 26.3% of the patients respectively. Univariate regression analyses revealed that PSD was significantly associated with stroke severity, physical disability, cognitive impairment and stroke outcome during the 18 months time frame of the study. Reduced social activities and the presence of apraxia were consistently associated with PSD whereas aphasia was only significantly associated in the first 6 months after stroke. Patients with relational problems had a 3 times greater risk of becoming depressed at 18 months poststroke than patients without relational problems (OR=3.09; 95% CI=1.31-7.26). CONCLUSIONS: Risk factors for PSD seem variable indicating the need for clinicians to consider the dynamic and multifactorial nature of PSD emphasizing the importance of a rigorous and long-term monitoring and support of stroke patients and their caregivers. PMID- 25451005 TI - MiRNA profiles in cerebrospinal fluid from patients with central hypersomnias. AB - MicroRNAs (miRNAs) are involved in the pathogenesis of many human diseases, including some neurological disorders. Recently, we have reported dysregulated miRNAs in plasma from patients with central hypersomnias including type 1 and type 2 narcolepsy, and idiopathic hypersomnia. This study addressed whether miRNA levels are altered in the cerebrospinal fluid (CSF) of patients with central hypersomnias. We conducted high-throughput analyses of miRNAs in CSF from patients using quantitative real-time polymerase chain reaction panels. We identified 13, 9, and 11 miRNAs with a more than two-fold change in concentration in CSF from patients with type 1 and type 2 narcolepsy and idiopathic hypersomnia, respectively, compared with matched healthy controls. Most miRNAs differed in more than one of the sleep disorders. However, all miRNAs were detected at low levels in CSF and varied between individuals. None of them showed significant differences in concentrations between groups after correcting for multiple testing, and none could be validated in an independent cohort. Nevertheless, approximately 60% of the most abundant miRNAs in the profile reported here have previously been identified in the CSF of healthy individuals, showing consistency with previous miRNA profiles found in CSF. In conclusion, we were not able to demonstrate distinct levels or patterns of miRNAs in CSF from central hypersomnia patients. PMID- 25451007 TI - Death effecter domain for the assembly of death-inducing signaling complex. AB - Death-inducing signaling complex (DISC) is a platform for the activation of initiator caspase in extrinsic apoptosis. Assembly of DISC is accomplished by two different types of homotypic interaction: one is between death domains (DDs) of a death receptor and FADD, and the other is between death effecter domains (DEDs) of FADD, procaspase-8/-10 and cFLIP. Recent biochemical investigations on the stoichiometry of DISC have revealed that single-DED-containing FADD exists in DISC in a substantially lower abundance than the sum of tandem-DEDs-containing components that are procaspase-8 and cFLIP. In addition, the homology models of the tandem DEDs in procaspase-8 and cFLIP show that two different interaction faces, H1-H4 face and H2-H5 face, are exposed for possible inter-molecular DED DED interactions. These recent findings led to a proposal of the DED chain model for the interactions between FADD, procaspase-8 and cFLIP in DISC. This emerging view provides new insights on the topology of DED-DED network in DISC and furthermore on how procaspase-8 and cFLIP cluster for dimerization and proteolytic activation. PMID- 25451006 TI - Analysis among cognitive profiles and gray matter volume in newly diagnosed Parkinson's disease with mild cognitive impairment. AB - PURPOSE: To analyze the characteristics of neuropsychological profiles and gray matter volume in de novo, drug-naive Parkinson's disease with mild cognitive impairment (PD-MCI). METHODS: Fifty-two newly diagnosed PD patients were assessed with neuropsychological testing, and PD-MCI was defined in patients with at least one or more abnormal cognitive test domains. PD with normal cognition (PD-NC) did not meet the criteria for PD-MCI or PD with dementia. Brain MRI scans was acquired from the patients and healthy controls (HC). The imaging processing and analysis of the gray matter (GM) volume were performed platform to determine the difference between PD-MCI and PD-NC. RESULTS: There were no differences of motor subscores between PD-MCI and PD-NC. The clinical dementia rating, global deterioration scale, and verbal memory were significantly worse in PD-MCI than in PD-NC. GM volume loss was observed in the right hippocampus, right cuneus, and right precuneus in PD-NC compared to in the HC. PD-MCI had significantly decreased GM volume in the bilateral temporal and frontal areas compared with that of the HC. The GM volume was significantly decreased in the right temporal pole, left precuneus, medial frontal and posterior cingulated gyrus in PD-MCI compared with PD-NC. CONCLUSIONS: Clinical dementia ratings and global deterioration scales could differentiate PD-MCI from PD-NC. Verbal memory impairment is characterized as a cognitive deficit of de novo PD-MCI and is associated with the posterior cortical area. PMID- 25451008 TI - Structural basis of cell apoptosis and necrosis in TNFR signaling. AB - The tumor necrosis factor receptors (TNFRs) play essential roles in innate and adaptive immunity. Depending on conditions, TNFR induces multiple cell fates including cell survival, cell apoptosis, and cell programmed necrosis. Here, we review recent progress in structural studies of the TNFR signaling pathway. The structural basis for the high order signal complexes, including the DISC, ripoptosome, necrosome, and RIP3/MLKL complex, may provide novel insights for understanding the biophysical principles of cell signaling cascades. PMID- 25451009 TI - Structure and function of Toll/interleukin-1 receptor/resistance protein (TIR) domains. AB - The Toll/interleukin-1 receptor/resistance protein (TIR) domain is a protein protein interaction domain consisting of 125-200 residues, widely distributed in animals, plants and bacteria but absent from fungi, archea and viruses. In plants and animals, these domains are found in proteins with functions in innate immune pathways, while in bacteria, some TIR domain-containing proteins interfere with the innate immune pathways in the host. TIR domains function as protein scaffolds, mostly involving self-association and homotypic interactions with other TIR domains. In the last 15 years, the three-dimensional structures of TIR domains from several mammalian, plant and bacterial proteins have been reported. These structures, jointly with functional data including the identification of interacting proteins, have started to provide insight into the molecular basis of the assembly of animal and plant immune signaling complexes, and for host immunosuppression by bacterial pathogens. This review focuses on the current knowledge of the structures of the TIR domains and how the structure relates to function. PMID- 25451011 TI - Neuroprotective effects of three different sizes nanochelating based nano complexes in MPP(+) induced neurotoxicity. AB - Parkinson's disease (PD) is the world's second most common dementia, which the drugs available for its treatment have not had effects beyond slowing the disease process. Recently nanotechnology has induced the chance for designing and manufacturing new medicines for neurodegenerative disease. It is demonstrated that by tuning the size of a nanoparticle, the physiological effect of the nanoparticle can be controlled. Using novel nanochelating technology, three nano complexes: Pas (150 nm), Paf (100 nm) and Pac (40 nm) were designed and in the present study their neuroprotective effects were evaluated in PC12 cells treated with 1-methyl-4-phenyl-pyridine ion (MPP (+)). PC12 cells were pre-treated with the Pas, Paf or Pac nano complexes, then they were subjected to 10 MUM MPP (+). Subsequently, cell viability, intracellular free Calcium and reactive oxygen species (ROS) levels, mitochondrial membrane potential, catalase (CAT) and superoxide dismutase (SOD) activity, Glutathione (GSH) and malondialdehyde (MDA) levels and Caspase 3 expression were evaluated. All three nano complexes, especially Pac, were able to increase cell viability, SOD and CAT activity, decreased Caspase 3 expression and prevented the generation of ROS and the loss of mitochondrial membrane potential caused by MPP(+). Pre-treatment with Pac and Paf nano complexes lead to a decrease of intracellular free Calcium, but Pas nano complex could not decrease it. Only Pac nano complex decreased MDA levels and other nano complexes could not change this parameter compared to MPP(+) treated cells. Hence according to the results, all nanochelating based nano complexes induced neuroprotective effects in an experimental model of PD, but the smallest nano complex, Pac, showed the best results. PMID- 25451012 TI - A feature analysis of lower solubility proteins in three eukaryotic systems. AB - Because misfolded and damaged proteins can form potentially harmful aggregates, all living organisms have evolved a wide variety of quality control mechanisms. However, the timely clearance of aggregation-prone species may not always be achieved, potentially leading to the accumulation of low solubility proteins. At the same time, promiscuity, which can be a driving force for aggregation, is also important to the functionality of certain proteins which have a large number of interaction partners. Considerable efforts have been made towards characterizing why some proteins appear to be more aggregation-prone than others. In this study, we analyze the features of proteins which precipitate following centrifugation in unstressed yeast cells, human SH-SY5Y cells and mouse brain tissue. By normalizing for protein abundance, we devised an approach whereby lower solubility proteins are reliably identified. Our findings indicate that these tend to be longer, low abundance proteins, which contain fewer hydrophobic amino acids. Furthermore, low solubility proteins also contain more low complexity and disordered regions. Overall, we observed an increase in features that link low solubility proteins to functional aggregates. Our results indicate that lower solubility proteins from three biologically distinct model systems share several common traits, shedding light on potentially universal solubility determinants. BIOLOGICAL SIGNIFICANCE: We set up a novel approach to identify lower solubility proteins in unstressed cells by comparing precipitated proteins with those that remain soluble after centrifugation. By analyzing three eukaryotic model systems in parallel, we were able to identify traits which cross the species barrier, as well as species-specific characteristics. Notably, our analyses revealed a number of primary and secondary structural features that set apart lower solubility proteins, a number of which connected them to a greater potential for promiscuity. This article is part of a Special Issue entitled: Protein dynamics in health and disease. Guest Editors: Pierre Thibault and Anne-Claude Gingras. PMID- 25451010 TI - An updated view on the structure and function of PYRIN domains. AB - The PYRIN domain (PYD) is a protein-protein interaction domain, which belongs to the death domain fold (DDF) superfamily. It is best known for its signaling function in innate immune responses and particularly in the assembly of inflammasomes, which are large protein complexes that allow the induced proximity mediated activation of caspase-1 and subsequently the release of pro-inflammatory cytokines. The molecular mechanism of inflammasome assembly was only recently elucidated and specifically requires PYD oligomerization. Here we discuss the recent advances in our understanding of PYD signaling and its regulation by PYD only proteins. PMID- 25451013 TI - Identification of anti-metastatic drug and natural compound targets in isogenic colorectal cancer cells. AB - Therapeutic strategies for cancer treatment often remain challenging due to the cumulative risk derived from metastasis, which has been described as an aggressive state of cancer cell proliferation often resulting in failure of clinical therapy. In the current study, anti-metastatic properties of three chemotherapeutic drugs and three compounds from natural sources were investigated by comparative proteomic analysis. Proteomic profile comparison of the isogenic primary and metastatic colon cancer cell lines SW480 and SW620 identified two potential metastasis related molecular targets: fatty acid synthase and histone H4. To demonstrate their biological roles in cancer metastasis, the expression of these target genes was suppressed by siRNA transfection. Subsequent cell migration assays demonstrated reduced migratory effects. SW620 cells were treated with six anti-cancerous components. Through comprehensive proteomic analysis, three of the tested compounds, oxaliplatin, ginsenoside 20(S)-Rg3 and curcumin, were revealed to have a suppressive effect on FASN and histone H4 expression. SW620 cells treated with these drugs showed significantly reduced migratory activity, which suggests that drug-induced targeted suppression of these genes may affect cell migration. The validity of the proteomic datasets was verified by knowledgebase pathway analysis and immunoblotting assays. The anti-metastatic components revealed by the current proteomic analysis represent promising chemotherapeutic candidates for the treatment of colorectal adenocarcinoma. BIOLOGICAL SIGNIFICANCE: The current study demonstrates anti-metastatic activity of chemotherapeutics and natural components by the suppression of target molecules, fatty acid synthase and histone H4 identified by a comparative proteomic analysis employing the isogenic primary and metastatic colon cancer cell lines, SW480 and SW620. Three tested drugs, namely, oxaliplatin, ginsenoside 20(S)-Rg3 and curcumin were revealed to possess suppressive effects on fatty acid synthase and histone H4 and reduce metastasis as determined by cell migration assay. Data were confirmed by the correlation between spectral counts from proteomic data and Western blot analysis, which were in good agreement with immunohistochemistry. PMID- 25451014 TI - NanoUPLC/MS(E) proteomic analysis reveals modulation on left ventricle proteome from hypertensive rats after exercise training. AB - NanoUPLC/MS(E) was used to verify the effects of 8weeks of low (SHR-LIT=4) and high (SHR-HIT=4) intensity training over the left ventricle proteome of hypertensive rats (SHR-C=4). Training enhanced the aerobic capacity and reduced the systolic blood pressure in all exercised rats. NanoUPLC/MS(E) identified 250 proteins, with 233 in common to all groups and 16 exclusive to SHR-C, 2 to SHR LIT, and 2 to the SHR-HIT. Cardiac hypertrophy related proteins appeared only in SHR-C. The SHR-LIT enhanced the abundance of 30 proteins and diminished 6, while SHR-HIT enhanced the abundance of 39 proteins and reduced other 7. The levels of metabolic (beta and gamma-enolase, adenine phosphoribosultransferase, and cytochrome b-c1), myofibril (myosin light chain 4, tropomyosin alpha and beta chain), and transporter proteins (hemoglobin, serum albumin, and hemopexin) were increased by both intensities. Transcription regulator and histone variants were enhanced by SHR-LIT and SHR-HIT respectively. SHR-LIT reduced the concentration of myosin binding protein C, while desmin and membrane voltage dependent anion selective channel protein-3 were reduced only by SHR-HIT. In addition, polyubiquitin B and C, and transcription regulators decreased in both intensities. Exercise also increased the concentration of anti-oxidant proteins, peroxiredozin-6 and glutathione peroxidase-1. BIOLOGICAL SIGNIFICANCE: Pathologic left ventricle hypertrophy if one of the major outcomes of hypertension being a strong predictor of heart failure. Among the various risk factors for cardiovascular disorders, arterial hypertension is responsible for the highest rates of mortality worldwide. In this way, this present study contribute to the understanding of the molecular mechanisms involved in the attenuation of hypertension and the regression of pathological cardiac hypertrophy induced by exercise training. PMID- 25451015 TI - Absolute quantification of Corynebacterium glutamicum glycolytic and anaplerotic enzymes by QconCAT. AB - The soil bacterium Corynebacterium glutamicum is one of the best-studied production hosts for industrial biotechnology, and it is primarily used for the large-scale production of essential amino acids, such as l-lysine. For rational strain development, detailed knowledge of intracellular protein concentration is crucial to determine metabolic capacities and limitations. We developed a QconCAT approach for the accurate absolute quantification of key enzymes of C. glutamicum glycolysis and anaplerosis. Following well-defined batch cultivations, 10 metabolic enzymes were quantified, accounting for approximately 6% of the total cell dry weight. Copy numbers per cell ranged from 36,700+/-3500 for phosphofructokinase (PFK) to 507,700+/-40,300 for enolase (ENO), which is considerably lower than the corresponding data obtained from Saccharomyces cerevisiae. Moreover, accurate measurement of the biovolume permitted an estimation of molar concentrations of intracellular enzyme catalysts ranging from 7.6+/-1.9MUM (PFK) to 105.2+/-28.6MUM (ENO). Finally, model-assisted data evaluation demonstrates that our method provides an important cornerstone toward a more detailed mechanistic understanding of C. glutamicum metabolism. BIOLOGICAL SIGNIFICANCE: Determination of absolute protein amounts using quantitative concatemers (QconCAT's) has already been successfully demonstrated for various species including human, animal and yeast. Interestingly, application of the QconCAT methodology for the determination of cytoplasmic enzyme concentrations in a prokaryote has not been described so far. This study is concerned with a novel targeted approach for the absolute quantification of 10 key enzymes from the central carbon metabolism of the industrially important organism Corynebacterium glutamicum. We demonstrate a method that enables complete cell lysis of this robust soil bacterium, thus allowing for accurate quantification of cytoplasmic enzymes. By linking measured enzyme amounts with respective biovolume data, intracellular enzyme concentrations were estimated, which are of special importance for any systems biology approach studying C. glutamicum's metabolism at the mechanistic level. To our knowledge this is the first report of applying the QconCAT methodology for determining intracellular enzyme concentrations in a prokaryote. PMID- 25451018 TI - Papilledema from craniosynostosis in pycnodysostosis. PMID- 25451016 TI - Ozone inhalation leads to a dose-dependent increase of cytogenetic damage in human lymphocytes. AB - Ozone is an important constituent of ambient air pollution and represents a major public health concern. Oxidative injury due to ozone inhalation causes the generation of reactive oxygen species and can be genotoxic. To determine whether ozone exposure causes genetic damage in peripheral blood lymphocytes, we used a well-validated cytokinesis-block micronucleus Cytome assay. Frequencies of micronuclei (MN) and nucleoplasmic bridges (NB) were used as indicators of cytogenetic damage. Samples were obtained from 22 non-smoking healthy subjects immediately before and 24-hr after controlled 4-hr exposures to filtered air, 100 ppb, and 200 ppb ozone while exercising in a repeated-measure study design. Inhalation of ozone at different exposure levels was associated with a significant dose-dependent increase in MN frequency (P < 0.0001) and in the number of cells with more than one MN per cell (P < .0005). Inhalation of ozone also caused an increase in the number of apoptotic cells (P = 0.002). Airway neutrophilia was associated with an increase in MN frequency (P = 0.033) independent of the direct effects of ozone exposure (P < 0.0001). We also observed significant increases in both MN and NB frequencies after exercise in filtered air, suggesting that physical activity is also an important inducer of oxidative stress. These results corroborate our previous findings that cytogenetic damage is associated with ozone exposure, and show that damage is dose-dependent. Further study of ozone-induced cytogenetic damage in airway epithelial cells could provide evidence for the role of oxidative injury in lung carcinogenesis, and help to address the potential public health implications of exposures to oxidant environments. PMID- 25451017 TI - A randomized double-blind placebo-controlled clinical trial of adjuvant buspirone for irritability in autism. AB - BACKGROUND: The brain serotonin level is decreased in individuals with autism. Buspirone is a 5-HT(1A) receptor agonist with antiaggressive effects increasing prosocial behaviors. METHODS: We conducted an 8-week randomized double-blind placebo-controlled clinical trial. Participants included 40 outpatient children and adolescents with autism. The patients took buspirone plus risperidone or risperidone plus placebo during 8 weeks. The patients were assessed at baseline, week 4, and week 8 using the Aberrant Behavior Checklist-Community Rating Scale. RESULTS: Eighteen patients in the placebo group and 16 patients in the buspirone group completed this trial. The mean dose of buspirone was 6.7 (SD 2.7) mg/day. Irritability subscale score significantly decreased during this trial in both groups (buspirone group: declined from 25.7 [SD 5.7] to 16.3 [SD 8.5]; placebo group: declined from 24.7 [SD 7.6] to 18.2 [SD 7.7]). The Cohen d effect size was .45. Thirteen (81.2%) of 16 patients in the buspirone group and 7 (38.9%) of 18 patients in the placebo group showed a >=30% decline in irritability score. The relative risk for treatment was 2.1. There were no serious adverse effects. The most common adverse effects in the buspirone group were increased appetite, drowsiness, and fatigue. CONCLUSION: This clinical trial supports that low dose buspirone plus risperidone is more effective than risperidone plus placebo for treating irritability in individuals with autism. PMID- 25451019 TI - Transverse myelitis in measles. PMID- 25451020 TI - [Proper use of apixaban: an outline for clinical practice]. AB - Apixaban is a direct inhibitor of coagulation factor Xa. Superior efficacy over aspirin and antivitamin K has been shown in the prevention of stroke and systemic embolism during non-valvular atrial fibrillation with a more favorable safety profile, even though the risk of hemorrhage cannot be ignored, considering its mechanism of action. The recommended dose is 5mg twice daily which can be reduced to 2.5mg depending on the individual risk. Apixaban is also indicated for the treatment of venous thromboembolism but reimbursement has not yet been accepted in France for this indication. As with all direct oral anticoagulants, no routine biological monitoring is required, nevertheless their use may have an impact on all coagulation tests, eventually hampering interpretation. In particular clinical circumstances where a measure of anticoagulant efficacy is deemed necessary, specific assay of anti-Xa activity is appropriate, the result being expressed as concentration of the anticoagulant used. It is therefore necessary to state the name of the medicine for which the assay is requested. With these new anticoagulants, management of hemorrhagic events can be more difficult due to the lack of a specific antidote. Pro-hemostatic substances have exhibited efficacy in animal models but results are still insufficiently documented in clinical practice. Local or locoregional hemostasis measurements, when possible, are an essential factor in the treatment of hemorrhagic events. PMID- 25451021 TI - [Is there a place for the ultrasound in the diagnosis and follow up of Takayasu's arteritis?]. PMID- 25451022 TI - [French Society of Vascular Medicine good medical practice guidelines on safety and environment in vascular medicine: Treatment of varicose veins]. AB - These guidelines proposed by the French Society of Vascular Medicine define the optimal environment for vascular medicine practice: outpatient clinic; equipment, layout and maintenance of the care center; infection risk prevention (hand hygiene, individual protective measures, exposure to blood, ultrasound apparatus, etc.); common interventions and techniques (liquid and foam sclerotherapy, endovenous thermal treatments). These guidelines do not include phlebectomy and use of ultrasound contrast agents. PMID- 25451023 TI - Comparative Proteome Profiling during Cardiac Hypertrophy and Myocardial Infarction Reveals Altered Glucose Oxidation by Differential Activation of Pyruvate Dehydrogenase E1 Component Subunit beta. AB - Cardiac hypertrophy and myocardial infarction (MI) are two etiologically different disease forms with varied pathological characteristics. However, the precise molecular mechanisms and specific causal proteins associated with these diseases are obscure to date. In this study, a comparative cardiac proteome profiling was performed in Wistar rat models for diseased and control (sham) groups using two-dimensional difference gel electrophoresis followed by matrix assisted laser desorption/ionization tandem time-of-flight mass spectrometry. Proteins were identified using Protein PilotTM software (version 4.0) and were subjected to stringent statistical analysis. Alteration of key proteins was validated by Western blot analysis. The differentially expressed protein sets identified in this study were associated with different functional groups, involving various metabolic pathways, stress responses, cytoskeletal organization, apoptotic signaling and other miscellaneous functions. It was further deciphered that altered energy metabolism during hypertrophy in comparison to MI may be predominantly attributed to induced glucose oxidation level, via reduced phosphorylation of pyruvate dehydrogenase E1 component subunit beta (PDHE1-B) protein during hypertrophy. This study reports for the first time the global changes in rat cardiac proteome during two etiologically different cardiac diseases and identifies key signaling regulators modulating ontogeny of these two diseases culminating in heart failure. This study also pointed toward differential activation of PDHE1-B that accounts for upregulation of glucose oxidation during hypertrophy. Downstream analysis of altered proteome and the associated modulators would enhance our present knowledge regarding altered pathophysiology of these two etiologically different cardiac disease forms. PMID- 25451024 TI - Light-induced helix movements in channelrhodopsin-2. AB - Channelrhodopsin-2 (ChR2) is a cation-selective light-gated channel from Chlamydomonas reinhardtii (Nagel G, Szellas T, Huhn W, Kateriya S, Adeishvili N, Berthold P, et al. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc Natl Acad Sci USA 2003;100:13940-5), which has become a powerful tool in optogenetics. Two-dimensional crystals of the slow photocycling C128T ChR2 mutant were exposed to 473 nm light and rapidly frozen to trap the open state. Projection difference maps at 6A resolution show the location, extent and direction of light-induced conformational changes in ChR2 during the transition from the closed state to the ion-conducting open state. Difference peaks indicate that transmembrane helices (TMHs) TMH2, TMH6 and TMH7 reorient or rearrange during the photocycle. No major differences were found near TMH3 and TMH4 at the dimer interface. While conformational changes in TMH6 and TMH7 are known from other microbial-type rhodopsins, our results indicate that TMH2 has a key role in light-induced channel opening and closing in ChR2. PMID- 25451025 TI - Determinants of the rate of mRNA translocation in bacterial protein synthesis. AB - Studying the kinetics of translocation of mRNA and tRNAs on the translating ribosome is technically difficult since the rate-limiting steps involve large conformational changes without covalent bond formation or disruption. Here, we have developed a unique assay system for precise estimation of the full translocation cycle time at any position in any type of open reading frame (ORF). Using a buffer system optimized for high accuracy of tRNA selection together with high concentration of elongation factor G, we obtained in vivo compatible translocation rates. We found that translocation was comparatively slow early in the ORF and faster further downstream of the initiation codon. The maximal translocation rate decreased from the in vivo compatible value of 30 s(-1) at 1 mM free Mg2+ concentration to the detrimentally low value of 1 s(-1) at 6 mM free Mg2+ concentration. Thus, high and in vivo compatible accuracy of codon translation, as well as high and in vivo compatible translocation rate, required a remarkably low Mg2+ concentration. Finally, we found that the rate of translocation deep inside an ORF was not significantly affected upon variation of the standard free energy of interaction between a 6-nt upstream Shine-Dalgarno (SD)-like sequence and the anti-SD sequence of 16S rRNA in a range of 0-6 kcal/mol. Based on these experiments, we discuss the optimal choice of Mg2+ concentration for maximal fitness of the living cell by taking its effects on the accuracy of translation, the peptide bond formation rate and the translocation rate into account. PMID- 25451026 TI - Assembly of Abeta proceeds via monomeric nuclei. AB - Aggregation of amyloid-beta (Abeta) peptides is fundamental to Alzheimer's disease. It has now been shown that nucleated proliferation of Abeta fibrils utilizes a secondary mechanism with existing fibrils catalyzing the formation of new ones. Here it is shown that the data for Abeta40 and Abeta42 require that the nuclei be monomeric; that is, an initial, unfavorable conformational change is rate limiting for the processes that appear to be nucleation. Following the conformational change, the assembly process is "downhill" despite clear lag times and significant concentration dependence. The similarity to polyglutamine nucleation suggests that monomeric nuclei may be widespread in amyloid formation. PMID- 25451028 TI - Model for the architecture of claudin-based paracellular ion channels through tight junctions. AB - Claudins are main cell-cell adhesion molecules of tight junctions (TJs) between cells in epithelial sheets that form tight barriers that separate the apical from the basolateral space but also contain paracellular channels that regulate the flow of ions and solutes in between these intercellular spaces. Recently, the first crystal structure of a claudin was determined, that of claudin-15, which indicated the parts of the large extracellular domains that likely form the pore lining surfaces of the paracellular channels. However, the crystal structure did not show how claudin molecules are arranged in the cell membrane to form the backbone of TJ strands and to mediate interactions between adjacent cells, information that is essential to understand how the paracellular channels in TJs function. Here, we propose that TJ strands consist of claudin protomers that assemble into antiparallel double rows. This model is based on cysteine crosslinking experiments that show claudin-15 to dimerize face to face through interactions between the edges of the extracellular beta-sheets. Strands observed by freeze-fracture electron microscopy of TJs also show that their width is consistent with the dimensions of a claudin dimer. Furthermore, we propose that extracellular variable regions are responsible for head-to-head interactions of TJ strands in adjoining cells, thus resulting in the formation of paracellular channels. Our model of the TJ architecture provides a basis to discuss structural mechanisms underlying the selective ion permeability and barrier properties of TJs. PMID- 25451027 TI - Potent and specific peptide inhibitors of human pro-survival protein Bcl-xL. AB - The Bcl-2 family of proteins plays a critical role regulating apoptosis, and pro survival Bcl-2 family members are important therapeutic targets due to their overexpression in different cancers. Pro-apoptotic Bcl-2 homology 3 (BH3)-only proteins antagonize pro-survival Bcl-2 protein functions by binding directly to them, and a sub-class of BH3-only proteins termed sensitizers can initiate apoptosis via this mechanism in response to diverse signals. The five pro survival proteins Bcl-xL, Mcl-1, Bcl-2, Bcl-w and Bfl-1 differ in their binding preferences, with Bcl-xL, Bcl-2 and Bcl-w sharing similar interaction profiles for many natural sensitizers and small molecules. Peptides that bind selectively to just one or a subset of family members have shown utility in assays that diagnose apoptotic blockades in cancer cells and as reagents for dissecting apoptotic mechanism. Combining computational design, combinatorial library screening and rational mutagenesis, we designed a series of BH3 sensitizer peptides that bind Bcl-xL with sub-nanomolar affinity and selectivity up to 1000 fold over each of the four competing pro-survival proteins. We demonstrate the efficacy of our designed BH3 peptides in assays that differentiate between cancer cells that are dependent on different pro-survival proteins. PMID- 25451030 TI - Mia40 combines thiol oxidase and disulfide isomerase activity to efficiently catalyze oxidative folding in mitochondria. AB - Mia40 (a mitochondrial import and assembly protein) catalyzes disulfide bond formation in proteins in the mitochondrial intermembrane space. By using Cox17 (a mitochondrial copper-binding protein) as a natural substrate, we discovered that, in the presence of Mia40, the formation of native disulfides is strongly favored. The catalytic mechanism of Mia40 involves a functional interplay between the chaperone site and the catalytic disulfide. Mia40 forms a specific native disulfide in Cox17 much more rapidly than other disulfides, in particular, non native ones, which originates from the recently described high affinity for hydrophobic regions near target cysteines and the long lifetime of the mixed disulfide. In addition to its thiol oxidase function, Mia40 is active also as a disulfide reductase and isomerase. We found that species with inadvertently formed incorrect disulfides are rebound by Mia40 and reshuffled, revealing a proofreading mechanism that is steered by the conformational folding of the substrate protein. PMID- 25451029 TI - The high-risk HPV16 E7 oncoprotein mediates interaction between the transcriptional coactivator CBP and the retinoblastoma protein pRb. AB - The oncoprotein E7 from human papillomavirus (HPV) strains that confer high cancer risk mediates cell transformation by deregulating host cellular processes and activating viral gene expression through recruitment of cellular proteins such as the retinoblastoma protein (pRb) and the cyclic-AMP response element binding binding protein (CBP) and its paralog p300. Here we show that the intrinsically disordered N-terminal region of E7 from high-risk HPV16 binds the TAZ2 domain of CBP with greater affinity than E7 from low-risk HPV6b. HPV E7 and the tumor suppressor p53 compete for binding to TAZ2. The TAZ2 binding site in E7 overlaps the LxCxE motif that is crucial for interaction with pRb. While TAZ2 and pRb compete for binding to a monomeric E7 polypeptide, the full-length E7 dimer mediates an interaction between TAZ2 and pRb by promoting formation of a ternary complex. Cell-based assays show that expression of full-length HPV16 E7 promotes increased pRb acetylation and that this response depends both on the presence of CBP/p300 and on the ability of E7 to form a dimer. These observations suggest a model for the oncogenic effect of high-risk HPV16 E7. The disordered region of one E7 molecule in the homodimer interacts with the pocket domain of pRb, while the same region of the other E7 molecule binds the TAZ2 domain of CBP/p300. Through its ability to dimerize, E7 recruits CBP/p300 and pRb into a ternary complex, bringing the histone acetyltransferase domain of CBP/p300 into proximity to pRb and promoting acetylation, leading to disruption of cell cycle control. PMID- 25451031 TI - Conformation-dependent epitopes recognized by prion protein antibodies probed using mutational scanning and deep sequencing. AB - Prion diseases are caused by a structural rearrangement of the cellular prion protein, PrP(C), into a disease-associated conformation, PrP(Sc), which may be distinguished from one another using conformation-specific antibodies. We used mutational scanning by cell-surface display to screen 1341 PrP single point mutants for attenuated interaction with four anti-PrP antibodies, including several with conformational specificity. Single-molecule real-time gene sequencing was used to quantify enrichment of mutants, returning 26,000 high quality full-length reads for each screened population on average. Relative enrichment of mutants correlated to the magnitude of the change in binding affinity. Mutations that diminished binding of the antibody ICSM18 represented the core of contact residues in the published crystal structure of its complex. A similarly located binding site was identified for D18, comprising discontinuous residues in helix 1 of PrP, brought into close proximity to one another only when the alpha helix is intact. The specificity of these antibodies for the normal form of PrP likely arises from loss of this conformational feature after conversion to the disease-associated form. Intriguingly, 6H4 binding was found to depend on interaction with the same residues, among others, suggesting that its ability to recognize both forms of PrP depends on a structural rearrangement of the antigen. The application of mutational scanning and deep sequencing provides residue-level resolution of positions in the protein-protein interaction interface that are critical for binding, as well as a quantitative measure of the impact of mutations on binding affinity. PMID- 25451033 TI - Traceless splicing enabled by substrate-induced activation of the Nostoc punctiforme Npu DnaE intein after mutation of a catalytic cysteine to serine. AB - Inteins self-catalytically cleave out of precursor proteins while ligating the surrounding extein fragments with a native peptide bond. Much attention has been lavished on these molecular marvels with the hope of understanding and harnessing their chemistry for novel biochemical transformations including coupling peptides from synthetic or biological origins and controlling protein function. Despite an abundance of powerful applications, the use of inteins is still hampered by limitations in our understanding of their specificity (defined as flanking sequences that permit splicing) and the challenge of inserting inteins into target proteins. We examined the frequently used Nostoc punctiforme Npu DnaE intein after the C-extein cysteine nucleophile (Cys+1) was mutated to serine or threonine. Previous studies demonstrated reduced rates and/or splicing yields with the Npu DnaE intein after mutation of Cys+1 to Ser+1. In this study, genetic selection identified extein sequences with Ser+1 that enabled the Npu DnaE intein to splice with only a 5-fold reduction in rate compared to the wild-type Cys+1 intein and without mutation of the intein itself to activate Ser+1 as a nucleophile. Three different proteins spliced efficiently after insertion of the intein flanked by the selected sequences. We then used this selected specificity to achieve traceless splicing in a targeted enzyme at a location predicted by primary sequence similarity to only the selected C-extein sequence. This study highlights the latent catalytic potential of the Npu DnaE intein to splice with an alternative nucleophile and enables broader intein utility by increasing insertion site choices. PMID- 25451035 TI - Bicistronic mRNAs to enhance membrane protein overexpression. AB - Functional overexpression of membrane proteins is essential for their structural and functional characterization. However, functional overexpression is often difficult to achieve, and frequently either no expression or expression as misfolded aggregates is observed. We present an approach for improving the functional overexpression of membrane proteins in Escherichia coli using transcriptional fusions. The method involves the use of a small additional RNA sequence upstream to the RNA sequence of the target membrane protein and results in the production of a bicistronic mRNA. In contrast to the common approach of translational fusions to enhance protein expression, transcriptional fusions do not require protease treatment and subsequent removal of the fusion protein. Using this strategy, we observed improvements in the quantity and/or the quality of the produced material for several membrane proteins to levels compatible with structural studies. Our analysis revealed that translation of the upstream RNA sequence was not essential for increased expression. Rather, the sequence itself had a large impact on protein yields, suggesting that alternative folding of the transcript was responsible for the observed effect. PMID- 25451034 TI - Crosstalk between signaling pathways provided by single and multiple protein phosphorylation sites. AB - Cellular fate depends on the spatiotemporal separation and integration of signaling processes that can be provided by phosphorylation events. In this study, we identify the crucial points in signaling crosstalk that can be triggered by discrete phosphorylation events on a single target protein. We integrated the data on individual human phosphosites with the evidence on their corresponding kinases, the functional consequences of phosphorylation on activity of the target protein and corresponding pathways. Our results show that there is a substantial fraction of phosphosites that can play critical roles in crosstalk between alternative and redundant pathways and regulatory outcome of phosphorylation can be linked to a type of phosphorylated residue. These regulatory phosphosites can serve as hubs in the signal flow and their functional roles are directly connected to their specific properties. Namely, phosphosites with similar regulatory functions are phosphorylated by the same kinases and participate in regulation of similar biochemical pathways. Such sites are more likely to cluster in sequence and space unlike sites with antagonistic outcomes of their phosphorylation on a target protein. In addition, we found that in silico phosphorylation of sites with similar functional consequences has comparable outcomes on a target protein stability. An important role of phosphorylation sites in biological crosstalk is evident from the analysis of their evolutionary conservation. PMID- 25451032 TI - Orientation of myosin binding protein C in the cardiac muscle sarcomere determined by domain-specific immuno-EM. AB - Myosin binding protein C is a thick filament protein of vertebrate striated muscle. The cardiac isoform [cardiac myosin binding protein C (cMyBP-C)] is essential for normal cardiac function, and mutations in cMyBP-C cause cardiac muscle disease. The rod-shaped molecule is composed primarily of 11 immunoglobulin- or fibronectin-like domains and is located at nine sites, 43nm apart, in each half of the A-band. To understand how cMyBP-C functions, it is important to know its structural organization in the sarcomere, as this will affect its ability to interact with other sarcomeric proteins. Several models, in which cMyBP-C wraps around, extends radially from, or runs axially along the thick filament, have been proposed. Our goal was to define cMyBP-C orientation by determining the relative axial positions of different cMyBP-C domains. Immuno electron microscopy was performed using mouse cardiac myofibrils labeled with antibodies specific to the N- and C-terminal domains and to the middle of cMyBP C. Antibodies to all regions of the molecule, except the C-terminus, labeled at the same nine axial positions in each half A-band, consistent with a circumferential and/or radial rather than an axial orientation of the bulk of the molecule. The C-terminal antibody stripes were slightly displaced axially, demonstrating an axial orientation of the C-terminal three domains, with the C terminus closer to the M-line. These results, combined with previous studies, suggest that the C-terminal domains of cMyBP-C run along the thick filament surface, while the N-terminus extends toward neighboring thin filaments. This organization provides a structural framework for understanding cMyBP-C's modulation of cardiac muscle contraction. PMID- 25451036 TI - Landscape of intertwined associations in multi-domain homo-oligomeric proteins. AB - This study charts the landscape of multi-domain protein structures that form intertwined homodimers by exchanging structural domains between subunits. A representative dataset of such homodimers was derived from the Protein Data Bank, and their structural and topological properties were compared to those of a representative set of non-intertwined homodimers. Most of the intertwined dimers form closed assemblies with head-to-tail arrangements, where the subunit interface involves contacts between dissimilar domains. In contrast, the non intertwined dimers form preferentially head-to-head arrangements, where the subunit interface involves contacts between identical domains. Most of these contacts engage only one structural domain from each subunit, leaving the remaining domains free to form other associations. Remarkably, we find that multi domain proteins closely related to the intertwined homodimers are significantly more likely than relatives of the non-intertwined versions to adopt alternative intramolecular domain arrangements. In ~40% of the intertwined dimers, the plasticity in domain arrangements among relatives affords maintenance of the head to-head or head-to-tail topology and conservation of the corresponding subunit interface. This property seems to be exploited in several systems to regulate DNA binding. In ~58%, however, intramolecular domain re-arrangements are associated with changes in oligomeric states and poorly conserved interfaces among relatives. This time, the corresponding structural plasticity appears to be exploited by evolution to modulate function by switching between active and inactive states of the protein. Surprisingly, in total, only three systems were found to undergo the classical monomer to intertwined dimer conversion associated with three-dimensional domain swapping. PMID- 25451038 TI - A dietary phytochemical blend prevents liver damage associated with adipose tissue mobilization in ovariectomized rats. AB - OBJECTIVE: Menopausal reduction in estrogen causes increased adipose accumulation, leading many to turn to dietary supplements to prevent and treat such changes. Enhanced adipose mobilization stimulated by some supplements can increase the risk of non-alcoholic fatty liver disease (NAFLD). Cytoprotective and anti-obesity compounds may prevent the lipotoxicity associated with mobilization. METHODS: A phytochemical blend was tested in aged, ovariectomized rats. Rats were given the AIN-93M basal diet or a diet containing varying doses of phytochemicals with 2.4 IU/g vitamin D [diet 1: 1000 mg/kg genistein (G); diet 2: 500 mg/kg (G), 200 mg/kg resveratrol (R), and 1000 mg/kg quercetin (Q); diet 3: 1000 mg/kg (G), 400 mg/kg (R), and 2000 mg/kg (Q)]. RESULTS: Serum free fatty acids and hepatic triglycerides were elevated with diets 2 and 3. Despite this increase, the phytochemical blends did not increase apoptotic, cell repair, or remodeling gene expression. The highest phytochemical dose prevented increases in serum alanine aminotransferase. CONCLUSIONS: Adverse hepatic effects secondary to ovariectomy were mitigated through the inclusion of a dietary phytochemical blend in aged ovariectomized rats. The use of such compounds may not only help with weight management and disease risk in menopausal women, but may also prevent the lipotoxicity in NAFLD. PMID- 25451037 TI - A general computational approach for repeat protein design. AB - Repeat proteins have considerable potential for use as modular binding reagents or biomaterials in biomedical and nanotechnology applications. Here we describe a general computational method for building idealized repeats that integrates available family sequences and structural information with Rosetta de novo protein design calculations. Idealized designs from six different repeat families were generated and experimentally characterized; 80% of the proteins were expressed and soluble and more than 40% were folded and monomeric with high thermal stability. Crystal structures determined for members of three families are within 1A root-mean-square deviation to the design models. The method provides a general approach for fast and reliable generation of stable modular repeat protein scaffolds. PMID- 25451039 TI - Development and evaluation of a novel TPGS-mediated paclitaxel-loaded PLGA-mPEG nanoparticle for the treatment of ovarian cancer. AB - One of the major obstacles to successful paclitaxel (PTX) chemotherapy is toxic side effects, which are often due to the conventional surfactants used, such as Cremophor EL. PTX is characterized by its hydrophobicity and insolubility, which limit its application in ovarian cancer therapy. The aim of this study was to develop Cremophor EL-free PTX-loaded methoxy poly(ethylene glycol)-block-(lactic co-glycolic acid) copolymers (PLGA-mPEG) nanoparticles (NPs) using d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) as a novel emulsifier. The ability of nanoparticles loaded with paclitaxel (NP-PTX) to inhibit tumor growth was assessed in vitro and in vivo. The acute toxicity of NP-PTX was also evaluated in vivo. We found that paclitaxel was efficiently encapsulated into PLGA-mPEG NPs with a low concentration of TPGS as the emulsifier. The synthesized NP-PTX demonstrated the desired diameter of 80 nm as characterized by transmission electron microscopy. The NP-PTX also exhibited a sustained release of loaded PTX over 4 d with the same chemotherapeutic efficiency and reduced side effects. NP-PTX-treated cells showed slightly lower cytotoxic responses compared with those treated with free PTX at the same concentration. In vivo studies confirmed that NP-PTX significantly enhanced the median lethal dose of paclitaxel by 10-fold, and a similar effect on the inhibition of tumor growth was achieved in nude mice. PMID- 25451041 TI - The hybrid model of attentional control: New insights into hemispheric asymmetries inferred from TMS research. AB - Several competing theories on the mechanisms underlying attentional control have emerged over the years that, despite their substantial differences, all emphasize the importance of hemispheric asymmetries. Transcranial magnetic stimulation (TMS) has proven particularly successful in teasing them apart by selective perturbation of the dorsal and ventral fronto-parietal network. We here critically review the TMS literature and show that hemispheric asymmetries within the dorsal attention network differ between parietal and frontal cortex. Specifically, posterior parietal cortex seems to be characterized by a contralateral bias of each hemisphere and competition between them. In contrast, the right frontal eye field seems to be involved in shifting attention toward both hemifields, whereas left frontal eye field is only involved on shifting attention toward the contralateral hemifield. In the light of presented evidence, we propose to revise the functional-anatomical model originally proposed by Corbetta and Shulman (2011, 2002) and introduce a hybrid model of hemispheric asymmetries in attentional control. PMID- 25451040 TI - Ion antiport accelerates photosynthetic acclimation in fluctuating light environments. AB - Many photosynthetic organisms globally, including crops, forests and algae, must grow in environments where the availability of light energy fluctuates dramatically. How photosynthesis maintains high efficiency despite such fluctuations in its energy source remains poorly understood. Here we show that Arabidopsis thaliana K(+) efflux antiporter (KEA3) is critical for high photosynthetic efficiency under fluctuating light. On a shift from dark to low light, or high to low light, kea3 mutants show prolonged dissipation of absorbed light energy as heat. KEA3 localizes to the thylakoid membrane, and allows proton efflux from the thylakoid lumen by proton/potassium antiport. KEA3's activity accelerates the downregulation of pH-dependent energy dissipation after transitions to low light, leading to faster recovery of high photosystem II quantum efficiency and increased CO2 assimilation. Our results reveal a mechanism that increases the efficiency of photosynthesis under fluctuating light. PMID- 25451042 TI - Semantic memory: Which side are you on? AB - We present two patients in whom the combination of lesion site and cognitive performance was uniquely informative about the organisation and functional anatomy of semantic memory. One had had a single lobar stroke with an unusual distribution, largely destroying the whole of the left temporal lobe ventral to the superior temporal sulcus. The other patient had had herpes simplex encephalitis with destruction that was confined to the left cerebral hemisphere. The lesion again mainly encompassed the left temporal lobe, but also extended to the left inferior frontal gyrus. Cognitive outcomes in the two patients were compared with each other and with published results from patients with semantic dementia. This is because, whereas the majority of semantic dementia patients present with more prominent atrophy of the left rostroventral temporal lobe, they invariably have a degree of atrophy in the mirror region on the right that progresses. Semantic dementia therefore provides no clear evidence about the specific role of the left rostroventral temporal lobe. The two patients showed a highly consistent cognitive profile. Their deficits were also similar in many respects to that observed in patients with mild-moderate semantic dementia, including severe anomia that was not resolved by phonological cues and impairment on non-verbal as well as verbal semantic tasks. Certain key features of the semantic dementia profile, however-including sensitivity to the familiarity and typicality of the stimulus materials-appeared only in tasks requiring verbal output in these two patients with unilateral left temporal lesions. Results in these cases provide some of the first definitive evidence regarding the specific functions of the left anterior temporal lobe. PMID- 25451043 TI - Between-session intra-individual variability in sustained, selective, and integrational non-linguistic attention in aphasia. AB - A number of studies have identified impairments in one or more types/aspects of attention processing in patients with aphasia (PWA) relative to healthy controls; person-to-person variability in performance on attention tasks within the PWA group has also been noted. Studies using non-linguistic stimuli have found evidence that attention is impaired in this population even in the absence of language processing demands. An underlying impairment in non-linguistic, or domain-general, attention processing could have implications for the ability of PWA to attend during therapy sessions, which in turn could impact long-term treatment outcomes. With this in mind, this study aimed to systematically examine the effect of task complexity on reaction time (RT) during a non-linguistic attention task, in both PWA and controls. Additional goals were to assess the effect of task complexity on between-session intra-individual variability (BS IIV) in RT and to examine inter-individual differences in BS-IIV. Eighteen PWA and five age-matched neurologically healthy controls each completed a novel computerized non-linguistic attention task measuring five types of attention on each of four different non-consecutive days. A significant effect of task complexity on both RT and BS-IIV in RT was found for the PWA group, whereas the control group showed a significant effect of task complexity on RT but not on BS IIV in RT. Finally, in addition to these group-level findings, it was noted that different patients exhibited different patterns of BS-IIV, indicating the existence of inter-individual variability in BS-IIV within the PWA group. Results may have implications for session-to-session fluctuations in attention during language testing and therapy for PWA. PMID- 25451044 TI - Mechanism of reduced vancomycin susceptibility conferred by walK mutation in community-acquired methicillin-resistant Staphylococcus aureus strain MW2. AB - Point mutations with unclear molecular mechanisms are often associated with vancomycin resistance in Staphylococcus aureus. Here, we observed that the walK (G223D) mutation caused decreased expression of genes associated with cell wall metabolism, decreased autolytic activity, thickened cell walls, and reduced vancomycin susceptibility. A phosphorylation assay showed that WalK (G223D) exhibited reduced autophosphorylation, which led to reduced phosphorylation of WalR. An electrophoretic mobility shift assay indicated that WalK (G223D) phosphorylated WalR had a reduced capacity to bind to the atlA promoter. PMID- 25451045 TI - Evolution of Staphylococcus aureus under vancomycin selective pressure: the role of the small-colony variant phenotype. AB - Staphylococcus aureus small-colony variants (SCVs) often persist despite antibiotic therapy. Against a 10(8)-CFU/ml methicillin-resistant S. aureus (MRSA) (strain COL) population of which 0%, 1%, 10%, 50%, or 100% was an isogenic hemB knockout (Ia48) subpopulation displaying the SCV phenotype, vancomycin achieved maximal reductions of 4.99, 5.39, 4.50, 3.28, and 1.66 log10 CFU/ml over 48 h. Vancomycin at >=16 mg/liter shifted a population from 50% SCV cells at 0 h to 100% SCV cells at 48 h, which was well characterized by a Hill-type model (R2>0.90). PMID- 25451046 TI - Molecular mechanisms of fluconazole resistance in Candida parapsilosis isolates from a U.S. surveillance system. AB - Candida parapsilosis is the second or third most common cause of candidemia in many countries. The Infectious Diseases Society of America recommends fluconazole as the primary therapy for C. parapsilosis candidemia. Although the rate of fluconazole resistance among C. parapsilosis isolates is low in most U.S. institutions, the resistance rate can be as high as 7.5%. This study was designed to assess the mechanisms of fluconazole resistance in 706 incident bloodstream isolates from U.S. hospitals. We sequenced the ERG11 and MRR1 genes of 122 C. parapsilosis isolates with resistant (30 isolates; 4.2%), susceptible dose dependent (37 isolates; 5.2%), and susceptible (55 isolates) fluconazole MIC values and used real-time PCR of RNA from 17 isolates to investigate the regulation of MDR1. By comparing these isolates to fully fluconazole-susceptible isolates, we detected at least two mechanisms of fluconazole resistance: an amino acid substitution in the 14-alpha-demethylase gene ERG11 and overexpression of the efflux pump MDR1, possibly due to point mutations in the MRR1 transcription factor that regulates MDR1. The ERG11 single nucleotide polymorphism (SNP) was found in 57% of the fluconazole-resistant isolates and in no susceptible isolates. The MRR1 SNPs were more difficult to characterize, as not all resulted in overexpression of MDR1 and not all MDR1 overexpression was associated with an SNP in MRR1. Further work to characterize the MRR1 SNPs and search for overexpression of other efflux pumps is needed. PMID- 25451047 TI - Identification of capsular types in carbapenem-resistant Klebsiella pneumoniae strains by wzc sequencing and implications for capsule depolymerase treatment. AB - Klebsiella pneumoniae is an important human pathogen associated with a variety of diseases, and the prevalence of multidrug-resistant K. pneumoniae (MDRKP) is rapidly increasing. Here we determined the capsular types of 85 carbapenem resistant K. pneumoniae (CRKP) strains by wzc sequencing and investigated the presence of carbapenemases and integrons among CRKP strains. Ten CRKP strains (12%) were positive for carbapenemase (imipenemase, 6/85 strains; K. pneumoniae carbapenemase, 3/85 strains; Verona integron-encoded metallo-beta-lactamase, 1/85 strains). Capsular type K64 accounted for 32 CRKP strains (38%), followed by K62 (13%), K24 (8%), KN2 (7%), and K28 (6%). Sequence types (STs) were determined by multilocus sequence typing (MLST), and the results indicated that ST11, which accounted for 47% of these CRKP strains (40/85 strains), was the major ST. We further isolated a K64-specific capsule depolymerase (K64dep), which could enhance serum and neutrophil killing in vitro and increase survival rates for K64 K. pneumoniae-inoculated mice. The toxicity study demonstrated that mice treated with K64dep showed normal biochemical parameters and no significant histopathological changes of liver, kidney, and spleen, indicating that enzyme treatment did not cause toxicity in mice. Therefore, the findings of capsular type clustering among CRKP strains and effective treatment with capsule depolymerase for MDRKP infections are important for capsule-based vaccine development and therapy. PMID- 25451048 TI - Macrolide-resistant Mycoplasma pneumoniae in adults in Zhejiang, China. AB - Mycoplasma pneumoniae is a major pathogen causing community-acquired pneumoniae (CAP), which is generally treated with macrolides. In recent years, however, although macrolide-resistant M. pneumoniae has been reported frequently, particularly in China, very little is known about the prevalence of macrolide resistant M. pneumoniae infection in adults. In this study, we survey the macrolide-resistant M. pneumoniae in adults in Zhejiang province and characterize the mechanisms of resistance to macrolide. Six hundred fifty throat swab samples were collected from adult patients with CAP from January 2012 to August 2014. These samples were assayed by nested PCR and then cultivated for M. pneumoniae. All isolates were sequenced to determine the mutation in domain V of the 23S rRNA gene. The activities of 10 antibiotics against macrolide-resistant M. pneumoniae isolates were also investigated in vitro. Moreover, restriction fragment length polymorphism (RFLP) analysis of the amplified P1 gene was used to type 50 resistant strains. One hundred percent (71/71) of M. pneumoniae strains isolated from adults with CAP were resistant to erythromycin (MIC=128 to >256 MUg/ml), clarithromycin (MIC=128 to >256 MUg/ml), and azithromycin (MIC=32 to >64 MUg/ml). Furthermore, all macrolide-resistant M. pneumoniae strains identified had an A2063G mutation in domain V of the 23S rRNA gene. Forty-six resistant strains (92.0%) were classified into type I strain on the basis of P1 gene PCR-RFLP analysis. According to these findings, it is suggested that macrolide-resistant M. pneumoniae infection is very prevalence among adults in Zhejiang province. Thus, there is necessary to perform the epidemiological monitoring of macrolide resistant M. pneumoniae in the future. PMID- 25451049 TI - Susceptibility profiles of amphotericin B and posaconazole against clinically relevant mucorales species under hypoxic conditions. AB - The effect of hypoxic conditions on the in vitro efficacy of amphotericin B and posaconazole against Mucorales was evaluated by defining MICs with Etest and broth microdilution and identifying minimal fungicidal concentrations (MFCs). With Etest, oxygen-dependent changes were detected, while the MIC and the MFC determined with broth microdilution remained unaltered with reduced oxygen levels. The observed differences depended on the method used. PMID- 25451050 TI - In vitro resistance studies with bacteria that exhibit low mutation frequencies: prediction of "antimutant" linezolid concentrations using a mixed inoculum containing both susceptible and resistant Staphylococcus aureus. AB - Bacterial resistance studies using in vitro dynamic models are highly dependent on the starting inoculum that might or might not contain spontaneously resistant mutants (RMs). To delineate concentration-resistance relationships with linezolid exposed Staphylococcus aureus, a mixed inoculum containing both susceptible cells and RMs was used. An RM selected after the 9th passage of the parent strain (MIC, 2 MUg/ml) on antibiotic-containing media (RM9; MIC, 8 MUg/ml) was chosen for the pharmacodynamic studies, because the mutant prevention concentration (MPC) of linezolid against the parent strain in the presence of RM9 at 10(2) (but not at 10(4)) CFU/ml did not differ from the MPC value determined in the absence of the RMs. Five-day treatments with twice-daily linezolid doses were simulated at concentrations either between the MIC and MPC or above the MPC. S. aureus RMs (resistant to 2* and 4*MIC but not 8* and 16*MIC) were enriched at ratios of the 24-h area under the concentration-time curve (AUC24) to the MIC that provide linezolid concentrations between the MIC and MPC for 100% (AUC24/MIC, 60 h) and 86% (AUC24/MIC, 120 h) of the dosing interval. No such enrichment occurred when linezolid concentrations were above the MIC and below the MPC for a shorter time (37% of the dosing interval; AUC24/MIC, 240 h) or when concentrations were consistently above the MPC (AUC24/MIC, 480 h). These findings obtained using linezolid-susceptible staphylococci supplemented with RMs support the mutant selection window hypothesis. This method provides an option to delineate antibiotic concentration-resistance relationships with bacteria that exhibit low mutation frequencies. PMID- 25451051 TI - Pharmacokinetics and safety of voriconazole intravenous-to-oral switch regimens in immunocompromised Japanese pediatric patients. AB - The aim of this study was to investigate the pharmacokinetics, safety, and tolerability of voriconazole following intravenous-to-oral switch regimens used with immunocompromised Japanese pediatric subjects (age 2 to <15 years) at high risk for systemic fungal infection. Twenty-one patients received intravenous-to oral switch regimens based on a recent population pharmacokinetic modeling; they were given 9 mg/kg of body weight followed by 8 mg/kg of intravenous (i.v.) voriconazole every 12 h (q12h), and 9 mg/kg (maximum, 350 mg) of oral voriconazole q12h (for patients age 2 to <12 or 12 to <15 years and <50 kg) or 6 mg/kg followed by 4 mg/kg of i.v. voriconazole q12h and 200 mg of oral voriconazole q12h (for patients age 12 to <15 years and >=50 kg). The steady state area under the curve over the 12-h dosing interval (AUC0-12,ss) was calculated using the noncompartmental method and compared with the predicted exposures in Western pediatric subjects based on the abovementioned modeling. The geometric mean (coefficient of variation) AUC0-12,ss values for the intravenous and oral regimens were 51.1 MUg . h/ml (68%) and 45.8 MUg.h/ml (90%), respectively; there was a high correlation between AUC0-12,ss and trough concentration. Although the average exposures were higher in the Japanese patients than those in the Western pediatric subjects, the overall voriconazole exposures were comparable between these two groups due to large interindividual variability. The exposures in the 2 cytochrome P450 2C19 poor metabolizers were among the highest. Voriconazole was well tolerated. The most common treatment related adverse events were photophobia and abnormal hepatic function. These recommended doses derived from the modeling appear to be appropriate for Japanese pediatric patients, showing no additional safety risks compared to those with adult patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01383993.). PMID- 25451052 TI - Broad coverage of genetically diverse strains of Clostridium difficile by actoxumab and bezlotoxumab predicted by in vitro neutralization and epitope modeling. AB - Clostridium difficile infections (CDIs) are the leading cause of hospital acquired infectious diarrhea and primarily involve two exotoxins, TcdA and TcdB. Actoxumab and bezlotoxumab are human monoclonal antibodies that neutralize the cytotoxic/cytopathic effects of TcdA and TcdB, respectively. In a phase II clinical study, the actoxumab-bezlotoxumab combination reduced the rate of CDI recurrence in patients who were also treated with standard-of-care antibiotics. However, it is not known whether the antibody combination will be effective against a broad range of C. difficile strains. As a first step toward addressing this, we tested the ability of actoxumab and bezlotoxumab to neutralize the activities of toxins from a number of clinically relevant and geographically diverse strains of C. difficile. Neutralization potencies, as measured in a cell growth/survival assay with purified toxins from various C. difficile strains, correlated well with antibody/toxin binding affinities. Actoxumab and bezlotoxumab neutralized toxins from culture supernatants of all clinical isolates tested, including multiple isolates of the BI/NAP1/027 and BK/NAP7/078 strains, at antibody concentrations well below plasma levels observed in humans. We compared the bezlotoxumab epitopes in the TcdB receptor binding domain across known TcdB sequences and found that key substitutions within the bezlotoxumab epitopes correlated with the relative differences in potencies of bezlotoxumab against TcdB of some strains, including ribotypes 027 and 078. Combined with in vitro neutralization data, epitope modeling will enhance our ability to predict the coverage of new and emerging strains by actoxumab-bezlotoxumab in the clinic. PMID- 25451053 TI - In vitro and in vivo antiviral activity and resistance profile of the hepatitis C virus NS3/4A protease inhibitor ABT-450. AB - The development of direct-acting antiviral agents is a promising therapeutic advance in the treatment of hepatitis C virus (HCV) infection. However, rapid emergence of drug resistance can limit efficacy and lead to cross-resistance among members of the same drug class. ABT-450 is an efficacious inhibitor of HCV NS3/4A protease, with 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively. In vitro, the most common amino acid variants selected by ABT-450 in genotype 1 were located in NS3 at positions 155, 156, and 168, with the D168Y variant conferring the highest level of resistance to ABT-450 in both genotype 1a and 1b replicons (219- and 337-fold, respectively). In a 3-day monotherapy study with HCV genotype 1-infected patients, ABT-450 was coadministered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. A mean maximum HCV RNA decline of 4.02 log10 was observed at the end of the 3-day dosing period across all doses. The most common variants selected in these patients were R155K and D168V in genotype 1a and D168V in genotype 1b. However, selection of resistant variants was significantly reduced at the highest ABT-450 dose compared to lower doses. These findings were informative for the subsequent evaluation of ABT-450 in combination with additional drug classes in clinical trials in HCV-infected patients. (Study M11 602 is registered at ClinicalTrials.gov under registration no. NCT01074008.). PMID- 25451054 TI - The novel arylamidine T-2307 maintains in vitro and in vivo activity against echinocandin-resistant Candida albicans. AB - We evaluated the in vitro and in vivo activities of the investigational arylamidine T-2307 against echinocandin-resistant Candida albicans. T-2307 demonstrated potent in vitro activity, and daily subcutaneous doses between 0.75 and 6 mg/kg of body weight significantly improved survival and reduced fungal burden compared to placebo control and caspofungin (10 mg/kg/day) in mice with invasive candidiasis caused by an echinocandin-resistant strain. Thus, T-2307 may have potential use in the treatment of echinocandin-resistant C. albicans infections. PMID- 25451055 TI - In vitro and in vivo antiviral activity and resistance profile of ombitasvir, an inhibitor of hepatitis C virus NS5A. AB - Ombitasvir (ABT-267) is a hepatitis C virus (HCV) NS5A inhibitor with picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC50s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a. Ombitasvir retained these levels of potency against a panel of 69 genotype 1 to 6 chimeric replicons containing the NS5A gene derived from HCV-infected patients, despite the existence of natural sequence diversity within NS5A. In vitro resistance selection identified variants that conferred resistance to ombitasvir in the HCV NS5A gene at amino acid positions 28, 30, 31, 58, and 93 in genotypes 1 to 6. Ombitasvir was evaluated in vivo in a 3-day monotherapy study in 12 HCV genotype 1-infected patients at 5, 25, 50, or 200 mg dosed once daily. All patients in the study were HCV genotype 1a infected and were without preexisting resistant variants at baseline as determined by clonal sequencing. Decreases in HCV RNA up to 3.1 log10 IU/ml were observed. Resistance-associated variants at position 28, 30, or 93 in NS5A were detected in patient samples 48 hours after the first dose. Clonal sequencing analysis indicated that wild-type virus was largely suppressed by ombitasvir during 3-day monotherapy, and at doses higher than 5 mg, resistant variant M28V was also suppressed. Ombitasvir was well tolerated at all doses, and there were no serious or severe adverse events. These data support clinical development of ombitasvir in combination with inhibitors targeting HCV NS3/4A protease (ABT-450 with ritonavir) and HCV NS5B polymerase (ABT-333, dasabuvir) for the treatment of chronic HCV genotype 1 infection. (Study M12-116 is registered at ClinicalTrials.gov under registration no. NCT01181427.). PMID- 25451056 TI - Analysis of Neisseria gonorrhoeae azithromycin susceptibility in the United States by the Gonococcal Isolate Surveillance Project, 2005 to 2013. AB - Azithromycin, administered with ceftriaxone, is recommended by the CDC for the treatment of gonorrhea. Many experts have expressed concern about the ease with which Neisseria gonorrhoeae can acquire macrolide resistance. We sought to describe gonococcal azithromycin susceptibility in the United States and to determine whether azithromycin susceptibility has changed over time. We analyzed data from 2005 to 2013 from the Gonococcal Isolate Surveillance Project, a CDC supported sentinel surveillance network that monitors gonococcal antimicrobial susceptibility. A total of 44,144 N. gonorrhoeae isolates were tested for azithromycin susceptibility by agar dilution methods. The overall azithromycin MIC50 was 0.25 MUg/ml, and the MIC90 was 0.5 MUg/ml. There were no overall temporal trends in geometric means. Isolates from men who had sex with men had significantly higher geometric mean MICs than isolates from men who had sex exclusively with women. The overall prevalence of reduced azithromycin susceptibility (MIC, >=2 MUg/ml) was 0.4% and varied by year from 0.3% (2006 and 2009) to 0.6% (2013). We did not find a clear temporal trend in gonococcal azithromycin MICs in the United States, and the prevalence of reduced azithromycin susceptibility remains low. These findings support the continued use of azithromycin in a combination therapy regimen for gonorrhea. PMID- 25451057 TI - Unexpected challenges in treating multidrug-resistant Gram-negative bacteria: resistance to ceftazidime-avibactam in archived isolates of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a notoriously difficult-to-treat pathogen that is a common cause of severe nosocomial infections. Investigating a collection of beta lactam-resistant P. aeruginosa clinical isolates from a decade ago, we uncovered resistance to ceftazidime-avibactam, a novel beta-lactam/beta-lactamase inhibitor combination. The isolates were systematically analyzed through a variety of genetic, biochemical, genomic, and microbiological methods to understand how resistance manifests to a unique drug combination that is not yet clinically released. We discovered that avibactam was able to inactivate different AmpC beta lactamase enzymes and that blaPDC regulatory elements and penicillin-binding protein differences did not contribute in a major way to resistance. By using carefully selected combinations of antimicrobial agents, we deduced that the greatest barrier to ceftazidime-avibactam is membrane permeability and drug efflux. To overcome the constellation of resistance determinants, we show that a combination of antimicrobial agents (ceftazidime/avibactam/fosfomycin) targeting multiple cell wall synthetic pathways can restore susceptibility. In P. aeruginosa, efflux, as a general mechanism of resistance, may pose the greatest challenge to future antibiotic development. Our unexpected findings create concern that even the development of antimicrobial agents targeted for the treatment of multidrug-resistant bacteria may encounter clinically important resistance. Antibiotic therapy in the future must consider these factors. PMID- 25451059 TI - Synergistic effect of nitazoxanide with neuraminidase inhibitors against influenza A viruses in vitro. AB - The emergence of drug-resistant influenza A virus (IAV) strains represents a serious threat to global human health and underscores the need for novel approaches to anti-influenza chemotherapy. Combination therapy with drugs affecting different IAV targets represents an attractive option for influenza treatment. We have previously shown that the thiazolide anti-infective nitazoxanide (NTZ) inhibits H1N1 IAV replication by selectively blocking viral hemagglutinin maturation. Herein we investigate the anti-influenza activity of NTZ against a wide range of human and avian IAVs (H1N1, H3N2, H5N9, H7N1), including amantadine-resistant and oseltamivir-resistant strains, in vitro. We also investigate whether therapy with NTZ in combination with the neuraminidase inhibitors oseltamivir and zanamivir exerts synergistic, additive, or antagonistic antiviral effects against influenza viruses. NTZ was effective against all IAVs tested, with 50% inhibitory concentrations (IC50s) ranging from 0.9 to 3.2 MUM, and selectivity indexes (SIs) ranging from >50 to >160, depending on the strain and the multiplicity of infection (MOI). Combination therapy studies were performed in cell culture-based assays using A/Puerto Rico/8/1934 (H1N1), A/WSN/1933 (H1N1), or avian A/chicken/Italy/9097/1997 (H5N9) IAVs; dose effect analysis and synergism/antagonism quantification were performed using isobologram analysis according to the Chou-Talalay method. Combination index (CI) analysis indicated that NTZ and oseltamivir combination treatment was synergistic against A/Puerto Rico/8/1934 (H1N1) and A/WSN/1933 (H1N1) IAVs, with CI values ranging between 0.39 and 0.63, independently of the MOI used. Similar results were obtained when NTZ was administered in combination with zanamivir (CI=0.3 to 0.48). NTZ-oseltamivir combination treatment was synergistic also against the avian A/chicken/Italy/9097/1997 (H5N9) IAV (CI=0.18 to 0.31). Taken together, the results suggest that regimens that combine neuraminidase inhibitors and nitazoxanide exert synergistic anti-influenza effects. PMID- 25451060 TI - Mechanism of action for respiratory syncytial virus inhibitor RSV604. AB - Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in young children and other high-risk populations. RSV nucleoprotein (N) is essential for virus assembly and replication as part of the viral ribonucleoprotein (RNP) complex. RSV604 was a putative N inhibitor in phase 2 clinical trials whose molecular mechanism of action (MoA) was not well understood. This study investigated the cell line-dependent potency of RSV604 and demonstrated its direct binding to the N protein in vitro, providing the first evidence of direct target engagement for this class of inhibitors reported to date. The affinity of RSV604 N binding was not affected by RSV604 resistance mutations in the N protein. RSV604 engaged in two different MoAs in HeLa cells, inhibiting both RSV RNA synthesis and the infectivity of released virus. The lack of inhibition of viral RNA synthesis in some cell lines explained the cell-type dependent potency of the inhibitor. RSV604 did not inhibit viral RNA synthesis in the RSV subgenomic replicon cells or in the cell-free RNP assay, suggesting that it might act prior to viral replication complex formation. RSV604 did not alter N protein localization in the infected cells. Taken together, these results provide new insights leading to an understanding of the MoAs of RSV604 and other similar N inhibitors. PMID- 25451061 TI - Decidualisation of ovarian endometriomas in pregnancy: a management dilemma. A case report and review of the literature. AB - INTRODUCTION: Increased progesterone levels during pregnancy may cause decidualisation of endometriomas mimicking malignancies on radiology and causing management dilemmas. CASE: An ovarian cyst was detected in a 33-year-old woman at her routine 12-week gestation ultrasound scan. By 18 weeks, the unilocular mass was increasing in size with features suggestive of early ovarian malignancy. The cyst was monitored throughout pregnancy and caesarean section at 38 weeks delivered a healthy male. Histology confirmed a decidualised endometrioma and benign dermoid cyst with no evidence of malignancy. LITERATURE REVIEW: The evidence for decidualised ovarian endometriomas in pregnancy was explored; 14 papers were identified, which reported 26 cases, excluding our index case. Of the 27 cases, 19 (70%) were managed surgically, 4 of which were delayed till caesarean section with concomitant cyst excision; 8 cases were managed conservatively through serial monitoring of the cyst, which spontaneously regressed following delivery. CONCLUSION: Surgical management of the cyst provides histological diagnosis but may introduce risks to mother and fetus; a conservative approach may cause anxiety but limits interventions. Elective caesarean section following monitoring throughout pregnancy may bridge the gap between surgical and purely conservative approaches if appropriate. Limited available evidence makes a definitive decision regarding management difficult. Decidualisation should be considered as a differential for suspicious ovarian lesions in pregnancy. PMID- 25451058 TI - Hydroxylated tropolones inhibit hepatitis B virus replication by blocking viral ribonuclease H activity. AB - Hepatitis B virus (HBV) remains a major human pathogen despite the development of both antiviral drugs and a vaccine, in part because the current therapies do not suppress HBV replication far enough to eradicate the virus. Here, we screened 51 troponoid compounds for their ability to suppress HBV RNaseH activity and HBV replication based on the activities of alpha-hydroxytropolones against HIV RNaseH, with the goal of determining whether the tropolone pharmacophore may be a promising scaffold for anti-HBV drug development. Thirteen compounds inhibited HBV RNaseH, with the best 50% inhibitory concentration (IC50) being 2.3 MUM. Similar inhibition patterns were observed against HBV genotype D and C RNaseHs, implying limited genotype specificity. Six of 10 compounds tested against HBV replication in culture suppressed replication via blocking of viral RNaseH activity, with the best 50% effective concentration (EC50) being 0.34 MUM. Eighteen compounds inhibited recombinant human RNaseH1, and moderate cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC50]=25 to 79 MUM). Therapeutic indexes ranged from 3.8 to 94. Efficient inhibition required an intact alpha-hydroxytropolone moiety plus one or more short appendages on the tropolone ring, but a wide variety of constituents were permissible. These data indicate that troponoids and specifically alpha-hydroxytropolones are promising lead candidates for development as anti-HBV drugs, providing that toxicity can be minimized. Potential anti-RNaseH drugs are envisioned to be employed in combination with the existing nucleos(t)ide analogs to suppress HBV replication far enough to block genomic maintenance, with the goal of eradicating infection. PMID- 25451062 TI - The avian coronavirus spike protein. AB - Avian coronaviruses of the genus Gammacoronavirus are represented by infectious bronchitis virus (IBV), the coronavirus of chicken. IBV causes a highly contagious disease affecting the respiratory tract and, depending on the strain, other tissues including the reproductive and urogenital tract. The control of IBV in the field is hampered by the many different strains circulating worldwide and the limited protection across strains due to serotype diversity. This diversity is believed to be due to the amino acid variation in the S1 domain of the major viral attachment protein spike. In the last years, much effort has been undertaken to address the role of the avian coronavirus spike protein in the various steps of the virus' live cycle. Various models have successfully been developed to elucidate the contribution of the spike in binding of the virus to cells, entry of cell culture cells and organ explants, and the in vivo tropism and pathogenesis. This review will give an overview of the literature on avian coronavirus spike proteins with particular focus on our recent studies on binding of recombinant soluble spike protein to chicken tissues. With this, we aim to summarize the current understanding on the avian coronavirus spike's contribution to host and tissue predilections, pathogenesis, as well as its role in therapeutic and protective interventions. PMID- 25451063 TI - A structural view of coronavirus-receptor interactions. AB - In the coronavirus (CoV), the envelope spike (S) glycoprotein is responsible for CoV cell entry and host-to-host transmission. The S is a multifunctional glycoprotein that mediates both attachment of CoV particles to cell surface receptor molecules as well as membrane penetration by fusion. Receptor-binding domains (RBD) have been identified in the S of diverse CoV; they usually contain antigenic determinants targeted by antibodies that neutralize CoV infections. To penetrate host cells, the CoV can use various cell surface molecules, although they preferentially bind to ectoenzymes. Several crystal structures have determined the folding of CoV RBD and the mode by which they recognize cell entry receptors. Here we review the CoV-receptor complex structures reported to date, and highlight the distinct receptor recognition modes, common features, and key determinants of the binding specificity. Structural studies have established the basis for understanding receptor recognition diversity in CoV, its evolution and the adaptation of this virus family to different hosts. CoV responsible for recent outbreaks have extraordinary potential for cross-species transmission; their RBD bear large platforms specialized in recognition of receptors from different species, which facilitates host-to-host circulation and adaptation to man. PMID- 25451065 TI - Insights into RNA synthesis, capping, and proofreading mechanisms of SARS coronavirus. AB - The successive emergence of highly pathogenic coronaviruses (CoVs) such as the Severe Acute Respiratory Syndrome (SARS-CoV) in 2003 and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in 2012 has stimulated a number of studies on the molecular biology. This research has provided significant new insight into functions and activities of the replication/transcription multi protein complex. The latter directs both continuous and discontinuous RNA synthesis to replicate and transcribe the large coronavirus genome made of a single-stranded, positive-sense RNA of ~30 kb. In this review, we summarize our current understanding of SARS-CoV enzymes involved in RNA biochemistry, such as the in vitro characterization of a highly active and processive RNA polymerase complex which can associate with methyltransferase and 3'-5' exoribonuclease activities involved in RNA capping, and RNA proofreading, respectively. The recent discoveries reveal fascinating RNA-synthesizing machinery, highlighting the unique position of coronaviruses in the RNA virus world. PMID- 25451064 TI - Viral capsid assembly as a model for protein aggregation diseases: Active processes catalyzed by cellular assembly machines comprising novel drug targets. AB - Viruses can be conceptualized as self-replicating multiprotein assemblies, containing coding nucleic acids. Viruses have evolved to exploit host cellular components including enzymes to ensure their replicative life cycle. New findings indicate that also viral capsid proteins recruit host factors to accelerate their assembly. These assembly machines are RNA-containing multiprotein complexes whose composition is governed by allosteric sites. In the event of viral infection, the assembly machines are recruited to support the virus over the host and are modified to achieve that goal. Stress granules and processing bodies may represent collections of such assembly machines, readily visible by microscopy but biochemically labile and difficult to isolate by fractionation. We hypothesize that the assembly of protein multimers such as encountered in neurodegenerative or other protein conformational diseases, is also catalyzed by assembly machines. In the case of viral infection, the assembly machines have been modified by the virus to meet the virus' need for rapid capsid assembly rather than host homeostasis. In the case of the neurodegenerative diseases, it is the monomers and/or low n oligomers of the so-called aggregated proteins that are substrates of assembly machines. Examples for substrates are amyloid beta peptide (Abeta) and tau in Alzheimer's disease, alpha-synuclein in Parkinson's disease, prions in the prion diseases, Disrupted-in-schizophrenia 1 (DISC1) in subsets of chronic mental illnesses, and others. A likely continuum between virus capsid assembly and cell-to-cell transmissibility of aggregated proteins is remarkable. Protein aggregation diseases may represent dysfunction and dysregulation of these assembly machines analogous to the aberrations induced by viral infection in which cellular homeostasis is pathologically reprogrammed. In this view, as for viral infection, reset of assembly machines to normal homeostasis should be the goal of protein aggregation therapeutics. A key basis for the commonality between viral and neurodegenerative disease aggregation is a broader definition of assembly as more than just simple aggregation, particularly suited for the crowded cytoplasm. The assembly machines are collections of proteins that catalytically accelerate an assembly reaction that would occur spontaneously but too slowly to be relevant in vivo. Being an enzyme complex with a functional allosteric site, appropriated for a non-physiological purpose (e.g. viral infection or conformational disease), these assembly machines present a superior pharmacological target because inhibition of their active site will amplify an effect on their substrate reaction. Here, we present this hypothesis based on recent proof-of-principle studies against Abeta assembly relevant in Alzheimer's disease. PMID- 25451066 TI - Middle East respiratory syndrome coronavirus (MERS-CoV) entry inhibitors targeting spike protein. AB - The recent outbreak of Middle East respiratory syndrome (MERS) coronavirus (MERS CoV) infection has led to more than 800 laboratory-confirmed MERS cases with a high case fatality rate (~35%), posing a serious threat to global public health and calling for the development of effective and safe therapeutic and prophylactic strategies to treat and prevent MERS-CoV infection. Here we discuss the most recent studies on the structure of the MERS-CoV spike protein and its role in virus binding and entry, and the development of MERS-CoV entry/fusion inhibitors targeting the S1 subunit, particularly the receptor-binding domain (RBD), and the S2 subunit, especially the HR1 region, of the MERS-CoV spike protein. We then look ahead to future applications of these viral entry/fusion inhibitors, either alone or in combination with specific and nonspecific MERS-CoV replication inhibitors, for the treatment and prevention of MERS-CoV infection. PMID- 25451067 TI - Construction of an infectious molecular clone of Japanese encephalitis virus genotype V and its derivative subgenomic replicon capable of expressing a foreign gene. AB - Japanese encephalitis virus (JEV) genotype V was originally isolated in Malaysia in 1952 and has long been restricted to the area. In 2009, sudden emergence of the genotype V in China and Korea was reported, suggesting expansion of its geographical distribution. Although studies on the genotype V are becoming more important, they have been limited partly due to lack of its infectious molecular clone. In this study, a plasmid carrying cDNA corresponding to the entire genome of JEV Muar strain, which belongs to genotype V, in the downstream of T7 promoter was constructed. Electroporation of viral RNA transcribed by T7 RNA polymerase (T7RNAP) in vitro from the plasmid led to production of progeny viruses both in mammalian and mosquito cells. Also, transfection of the infectious clone plasmid into mammalian cells expressing T7RNAP transiently or stably was demonstrated to generate infectious progenies. When the viral structural protein genes were partially deleted from the full-length cDNA, the subgenomic RNA transcribed in vitro from the modified plasmid was shown to replicate itself in mammalian cells as a replicon. The replicon carrying the firefly luciferase gene in place of the deleted structural protein genes was also shown to efficiently replicate itself and express luciferase in mammalian cells. Compared with the replicon derived from JEV genotype III (Nakayama strain), the genotype V-derived replicon appeared to be more tolerant to introduction of a foreign gene. The infectious clone and the replicons constructed in this study may serve as useful tools for characterizing JEV genotype V. PMID- 25451068 TI - Galectin-9 ameliorates respiratory syncytial virus-induced pulmonary immunopathology through regulating the balance between Th17 and regulatory T cells. AB - Respiratory syncytial virus (RSV) infections are characterized by lung inflammation, mucus hypersecretion, and hyperresponsiveness. CD4+ T cells play a pivotal role in the development of RSV-induced lung pathology. Thus targeting the activation of CD4+ T cell subsets and enhancing regulatory functions of CD4+ T cells could be an effectively therapeutic approach. In the present study, we showed that RSV-induced lung inflammation can be suppressed by lectin family member Galectin-9 (Gal-9), which is identified as a T-cell immunoglobulin- and mucindomain-containing molecule-3 (Tim-3) ligand (L) and the Gal-9/Tim-3 interaction acts as a specific inhibitor of T helper(Th)1 and Th17 immune responses. Tim-3 expression was up-regulated in RSV-infected mice compared to non infected controls. Therefore, we constructed a recombinant adenoviral (rAAV) 9 Gal-9 adenoviral plasmid, and administered it intranasally into RSV-infected mice for five times at every other day until day 8 post-infection. We found that Gal-9 administration significantly decreased viral load, inhibited mucus production, and diminished severity of lung pathology which were all induced by RSV infection. Complicated mechanisms were involved in these inhibitory effects, including inhibition of Th17 cell production, induction of regulatory cell expansion, as well as alteration of CD8 T-cell apoptosis. Our findings suggest that regulating the function of the Gal-9/Tim-3 pathway will be an effective and safe approach to treat RSV infection in lungs. PMID- 25451069 TI - Porcine reproductive and respiratory syndrome virus replication and quasispecies evolution in pigs that lack adaptive immunity. AB - The replication of porcine reproductive and respiratory syndrome virus (PRRSV) was studied in a line of pigs possessing a severe combined immunodeficiency (SCID). Real-time RT-PCR revealed a unique course of infection for the SCID group. During the course of infection, viremia was initially significantly lower than normal littermates, but by 21 days was significantly elevated. Deep sequencing of the viral structural genes at days 11 and 21 identified seven amino acid substitutions in both normal and SCID pigs. The most significant change was a W99R substitution in GP2, which was present in the inoculum at a frequency of 35%, but eventually disappeared from all pigs regardless of immune status. Therefore, amino acid substitutions that appear during acute infection are likely the result of the adaptation of the virus to replication in pigs and not immune selection. PMID- 25451070 TI - Abnormal anatomy of inferior orbital fissure and herniation of buccal fat pad. AB - The anatomy of the inferior orbital fissure has been well studied, and its reported dimensions vary little. It is encountered during exploration of the orbital floor and when possible is not disturbed. We describe a case of herniation of buccal fat through the inferior orbital fissure that was found during exploration and repair of the orbital floor. PMID- 25451071 TI - Bilateral parotid gland metastases from carcinoma of the breast that presented 25 years after initial treatment. AB - We report a case of a 76-year-old woman with metastases to both parotid glands almost 25 years after mastectomy and chemotherapy for primary carcinoma of the breast. Immunohistochemical staining is invaluable in establishing the origin of metastatic deposits, in this case, expression of oestrogen receptors in a previously resected adenocarcinoma of the breast. The information can be used to target treatment accurately in selected cases of advanced malignancy. PMID- 25451072 TI - Sialendoscopy-assisted treatment of trauma to Stensen's duct: technical note. PMID- 25451073 TI - Effect of tube drainage compared with conventional suturing on postoperative discomfort after extraction of impacted mandibular third molars. AB - The aim of this prospective randomised study was to assess the effects of tube drainage on postoperative discomfort after the extraction of impacted mandibular third molars. We studied 40 patients (11 men and 29 women) 18 years or older (mean (SD) 21 (3), range 18-29) who required extraction of mandibular third molars. We used a randomised crossover design by which if a drain was inserted on one side, then the other side was managed without a drain on a later occasion. Pain, swelling, and mouth opening were evaluated after 48 h and 7 days postoperatively in both groups. Facial swelling (p=0.001), pain p=0.001), and trismus (p=0.001) were significantly less common in the drained group compared with those not drained. We conclude that the use a tube drain is of benefit in minimising postoperative swelling, pain, and trismus after extraction of mandibular third molars. PMID- 25451074 TI - Exploring Work-Related Causal Attributions of Common Mental Disorders. AB - PURPOSE: Common mental disorders (CMDs) are major causes of sickness absence and disability. Prevention requires knowledge of how individuals perceive causal mechanisms, and in this study we sought to examine work-related factors as causal attribution of CMDs. METHODS: A trial sample of n = 1,193, recruited because they struggled with work participation due to CMDs, answered an open-ended questionnaire item about what they believed were the most important causes of their CMDs. The population included participants at risk of sickness absence, and participants with reduced work participation due to sickness absence, disability or unemployment. We used thematic content analysis and categorized responses from 487 participants who reported work-related factors as causal attributions of their CMDs. Gender differences in work-related causal attributions were also examined. RESULTS: The participants attributed their CMDs to the following work related factors; work stress, leadership, reduced work participation, job dissatisfaction, work conflict, social work environment, job insecurity and change, workplace bullying, and physical strain. Women tended to attribute CMDs to social factors at work. CONCLUSION: Findings from this study suggest several work-related risk factors for CMDs. Both factors at the workplace, and reduced work participation, were perceived by study participants as contributing causes of CMDs. Thus, there is a need to promote work participation whilst at the same time targeting aversive workplace factors. Further, our findings indicate that work-related factors may affect women and men differently. This illustrates that the association between work participation and CMDs is complex, and needs to be explored further. PMID- 25451075 TI - A screen of the NIH Clinical Collection small molecule library identifies potential anti-coronavirus drugs. AB - With the recent emergence of Middle East Respiratory Syndrome coronavirus in humans and the outbreak of devastating porcine epidemic diarrhea coronavirus in swine, therapeutic intervention is urgently needed. However, anti-coronavirus drugs currently are not available. In an effort to assist rapid development of anti-coronavirus drugs, here we screened the NIH Clinical Collection in cell culture using a luciferase reporter-expressing recombinant murine coronavirus. Of the 727 compounds screened, 84 were found to have a significant anti-coronavirus effect. Further experiments revealed that 51 compounds blocked virus entry while 19 others inhibited viral replication. Additional validation studies with the top 3 inhibitors (hexachlorophene, nitazoxanide and homoharringtonine) demonstrated robust anti-coronavirus activities (a reduction of 6 to 8log10 in virus titer) with an IC50 ranging from 11nM to 1.2MUM. Furthermore, homoharringtonine and hexachlorophene exhibited broad antiviral activity against diverse species of human and animal coronaviruses. Since the NIH Clinical Collection consists of compounds that have already been through clinical trials, these small molecule inhibitors have a great potential for rapid development as anti-coronavirus drugs. PMID- 25451076 TI - Antioxidant and oxidative stress related responses in the Mediterranean land snail Cantareus apertus exposed to the carbamate pesticide Carbaryl. AB - The aim of the present work was to study the alterations of the antioxidant defenses and the overall susceptibility to oxidative stress of the terrestrial snail Cantareus apertus exposed to the carbamate pesticide Carbaryl at a low environmentally realistic concentration. The animals were exposed to Lactuca sativa soaked for 1h in 1MUM Carbaryl. The temporal dynamics of the responses was assessed by measurements at 3, 7 and 14days of exposure. C. apertus exposed to Carbaryl activates a number of enzymatic antioxidant responses, represented by the early induction of catalase, glutathione peroxidase, glutathione reductase, followed by a delayed induction of superoxide dismutase. Concomitantly, a derangement of the total oxyradical scavenging of the tissues was observed, suggesting an overall impairment of the tissue capability to neutralize ROS probably resulting from the overall negative balance between enzymatic antioxidant defense capability and oxidative stress intensity. This negative balance exposed the animals to the risk of oxidative stress damages including genotoxic damage. Compared to acetylcholinesterase inhibition, the antioxidant responses developed to Carbaryl exposure at the low concentration utilized showed a greater percentage variation in exposed organisms. The results pointed out the high sensitivity of the antioxidant and oxidative stress related responses to Carbaryl exposure at an environmental realistic concentration, demonstrating their usefulness in environmental monitoring and risk assessment. The study highlights also the usefulness of the terrestrial snail C. apertus as potential bioindicator species for assessing the risk of pesticide environmental contamination. PMID- 25451077 TI - The influence of salinity and copper exposure on copper accumulation and physiological impairment in the sea anemone, Exaiptasia pallida. AB - Copper is a common pollutant in many aquatic environments, particularly those surrounding densely populated areas with substantial anthropogenic inputs. These same areas may also experience changes in salinity due to freshwater discharge and tidal influence. Biota that inhabit near-shore coastal environments may be susceptible to both stressors. Although copper is a noted concern in marine environments, effects of copper and varying salinity on symbiotic cnidarians are only scarcely studied. The sea anemone, Exaiptasia pallida, was used to investigate effects of copper on physiological impairment (i.e. activities of anti-oxidant enzymes) at two different salinities (20 and 25ppt). E. pallida was exposed to a control and three elevated copper concentrations for up to 21d, and copper accumulation and activity of the enzymes: catalase, glutathione reductase, glutathione peroxidase, and carbonic anhydrase were measured in the anemones. Photosynthetic parameters in E. pallida's symbiotic dinoflagellate algae were also quantified. Over the course of the exposure, E. pallida accumulated copper in a concentration-dependent manner. Higher tissue copper concentrations were observed in anemones exposed to the lower salinity water (20ppt), and physiological impairment was observed as a consequence of both increased copper exposure and decreased salinity; however, changes in salinity caused a greater response than copper exposure, at the levels tested. In general, antioxidant enzyme activity increased as a consequence of decreased salinity and/or increased copper exposure. These results clearly demonstrated the influence of two local stressors, at environmentally realistic concentrations, on a sensitive cnidarian, and highlight the importance of characterizing combined exposure scenarios. PMID- 25451078 TI - MiR-133 modulates TGF-beta1-induced bladder smooth muscle cell hypertrophic and fibrotic response: implication for a role of microRNA in bladder wall remodeling caused by bladder outlet obstruction. AB - Bladder outlet obstruction (BOO) evokes urinary bladder wall remodeling significantly, including the phenotype shift of bladder smooth muscle cells (BSMCs) where transforming growth factor-beta1 (TGF-beta1) plays a pivotal role given the emerging function of modulating cellular phenotype. miR-133 plays a role in cardiac and muscle remodeling, however, little is known about its roles in TGF-beta1-induced BSMC hypertrophic and fibrotic response. Here, we verified BOO induced bladder wall remodeling and TGF-beta1 expression mainly located in bladder endothelium. Furthermore, we uncovered miR-133a/b expression profile in BOO rats, and then explored its regulated effects on BSMCs' phenotypic shift. Our study found that miR-133 became down-regulated during rat bladder remodeling. Next, we sought to examine whether the expression of miR-133 was down-regulated in primary BSMCs in response to TGF-beta1 stimulation and whether forced overexpression of miR-133 could regulate profibrotic TGF-beta signaling. We found that stimulation of BSMCs with exogenous TGF-beta1 of increasing concentrations resulted in a dose-dependent decrease of miR-133a/b levels and transfection with miR-133 mimics attenuated TGF-beta1-induced alpha-smooth muscle actin, extracellular matrix subtypes and fibrotic growth factor expression, whereas it upregulated high molecular weight caldesmon expression compared with the negative control. Also, downregulation of p-Smad3, not p-Smad2 by miR-133 was detected. Additionally, miR-133 overexpression suppressed TGF-beta1-induced BSMC hypertrophy and proliferation through influencing cell cycle distribution. Bioinformatics analyses predicted that connective tissue growth factor (CTGF) was the potential target of miR-133, and then binding to the 3'-untranslated region of CTGF was validated by luciferase reporter assay. These results reveal a novel regulator for miR-133 to modulate TGF-beta1-induced BSMC phenotypic changes by targeting CTGF through the TGF-beta-Smad3 signaling pathway. A novel antifibrotic functional role for miR-133 is presented which may represent a potential target for diagnostic and therapeutic strategies in bladder fibrosis. PMID- 25451079 TI - Regulation of prostate stromal fibroblasts by the PIM1 protein kinase. AB - The PIM1 oncogene is over-expressed in human prostate cancer epithelial cells. Importantly, we observe that in human hyperplastic and cancerous prostate glands PIM1 is also markedly elevated in prostate fibroblasts, suggesting an important role for this kinase in epithelial/stromal crosstalk. The ability of PIM1 to regulate the biologic activity of stromal cells is demonstrated by the observation that expression of PIM1 kinase in human prostate fibroblasts increases the level and secretion of the extracellular matrix molecule, collagen 1A1 (COL1A1), the pro-inflammatory chemokine CCL5, and the platelet-derived growth factor receptors (PDGFR). PIM1 is found to regulate the transcription of CCL5. In co-cultivation assays where PIM1 over-expressing fibroblasts are grown with BPH1 prostate epithelial cells, PIM1 activity markedly enhances the ability of these fibroblasts to differentiate into myofibroblasts and express known markers of cancer-associated fibroblasts (CAFs). This differentiation can be reversed by the addition of small molecule PIM kinase inhibitors. Western blots demonstrate that PIM1 expression in prostate fibroblasts stimulates the phosphorylation of molecules that regulate 5'Cap driven protein translation, including 4EBP1 and eIF4B. Consistent with the hypothesis that the kinase controls translation of specific mRNAs in prostate fibroblasts, we demonstrate that PIM1 expression markedly increases the level of COL1A1 and PDGFRbeta mRNA bound to polysomes. Together these results point on PIM1 as a novel factor in regulation of the phenotype and differentiation of fibroblasts in prostate cancer by controlling both the transcription and translation of specific mRNAs. PMID- 25451080 TI - The Dictyostelium MAPK ERK1 is phosphorylated in a secondary response to early developmental signaling. AB - Previous reports have suggested that the two mitogen-activated protein kinases (MAPKs) in Dictyostelium discoideum, ERK1 and ERK2, can be directly activated in response to external cAMP even though these MAPKs play different roles in the developmental life cycle. To better characterize MAPK regulation, the levels of phosphorylated MAPKs were analyzed in response to external signals. Only ERK2 was rapidly phosphorylated in response to the chemoattractants, cAMP and folate. In contrast, the phosphorylation of ERK1 occurred as a secondary or indirect response to these stimuli and this phosphorylation was enhanced by cell-cell interactions, suggesting that other external signals can activate ERK1. The phosphorylation of ERK1 or ERK2 did not require the function of the other MAPK in these responses. Folate stimulation of a chimeric population of erk1- and galpha4 cells revealed that the phosphorylation of ERK1 could be mediated through an intercellular signal other than folate. Loss of ERK1 function suppressed the developmental delay and the deficiency in anterior cell localization associated with galpha5- mutants suggesting that ERK1 function can be down regulated through Galpha5 subunit-mediated signaling. However, no major changes in the phosphorylation of ERK1 were observed in galpha5- cells suggesting that the Galpha5 subunit signaling pathway does not regulate the phosphorylation of ERK1. These findings suggest that the activation of ERK1 occurs as a secondary response to chemoattractants and that other cell-cell signaling mechanisms contribute to this activation. Galpha5 subunit signaling can down regulate ERK1 function to promote prestalk cell development but not through major changes to the level of phosphorylated ERK1. PMID- 25451081 TI - Disordered signaling governing ferroportin transcription favors breast cancer growth. AB - Iron is a necessary chemical element needed by all organisms. Iron metabolism is finely tuned in mammals, and the hepcidin-ferroportin (FPN) axis is the central signaling in governing systemic iron homeostasis. Deregulation of this signaling would lead to iron disorders and likely other diseases including cancers. Reduced FPN was previously found to correlate with poor prognosis in breast cancer patients. Nonetheless, the biological effects of abnormal FPN expression in tumor cells remain largely unexplored, and the mechanisms underlying misregulated expression of FPN in cancers keep elusive. In the current study, we scrutinized the effects of abnormal FPN on tumor growth and the molecular mechanisms of diminished tumor FPN. Downregulation of FPN significantly promoted breast cancer growth, whereas FPN upregulation impeded tumor growth. We demonstrated that the transcription factors Nrf2 (nuclear factor erythroid 2-like 2) and MZF-1 (myeloid zinc finger-1) synergistically transactivated FPN expression in breast cancer cells. Moreover, CpG island methylation at the FPN promoter was the reason of attenuated FPN expression. Downregulation of Nrf2 and MZF-1 and hypermethylation of the FPN promoter were concurrently associated with decreased FPN concentration in breast tumors. Taken together, our study highlighted the contribution of disordered iron metabolism to breast cancer growth, and also signified an oncogenic effect of misregulated ferroportin in breast cancers. This work represents a promising starting point to the possibility of restraining breast cancer through targeting FPN or its upstream regulatory factors. PMID- 25451082 TI - Regulation of phagocytosis and cytokine secretion by store-operated calcium entry in primary isolated murine microglia. AB - Microglia are immune effector cells in the central nervous system that participate in tissue repair, inflammatory responses, and neuronal degeneration. The most important signaling factor in the differentiation of immune-active cells after stimulation is the sustained high calcium concentration in the cytosol, which is called store-operated calcium entry (SOCE). Recently, the molecular identity of the store-operated channel (SOC) has revealed that Orai1, Orai2, Orai3, Stim1, and Stim2 constitute the most of SOC. In this study, we demonstrate that Orai1- and Stim1-mediated SOC regulated the phagocytic activity and cytokine release of primary isolated murine microglia. RT-PCR analysis revealed that primary cultured microglia from neonatal ICR mouse brains had Orai1, Orai2, Orai3, and Stim1. To elucidate the role of SOCE in the immune functions of microglia, pharmacological inhibitors or knockdown with Orai1 or Stim1 siRNA was applied, and UDP-induced phagocytic activity and LPS-induced cytokine secretion activity were compared. The pharmacological inhibition and siRNA effect was verified by measuring thapsigargin (TG)-, ATP-, or UDP-activated SOCE Ca2+ influx and proper siRNA-mediated knockdown was verified by western blot analysis. UDP induced phagocytic activity was inhibited by pharmacological inhibitors of SOCE, such as SKF96365 or 2-APB, and knockdown of Orai1 and Stim1. Cytokine secretion of TNF-alpha and IL-6 by LPS treatment was also inhibited by SKF96365 and knockdown of Orai1 and Stim1. Meanwhile, LPS stimulation-induced NF-kappaB activation was not altered, but NFAT1 activity was attenuated with Stim1 knockdown. These results indicate that SOCE, which was composed of Orais and Stim1, regulates UDP-induced phagocytosis and LPS-stimulated cytokine secretion in microglia. PMID- 25451083 TI - Elemental characterisation of the medical plant Alchemilla velebitica. AB - Alchemilla, commonly called "lady's mantle", is a genus of herbaceous perennial plants belonging to the family Rosaceae. The species Alchemilla velebitica is found only in Southern Europe, like in the Croatian National Park Northern Velebit. Its benefits, such as a astringent and emmenagogue activity as well as wound healing are correlated to the organic compounds found in the plant, but also certain trace elements are known to reduce skin lesions, such as zinc, selenium, copper, manganese, silicon and lithium. Thus the objective of the present study was the elemental characterization of leaves, blossoms and roots of A. velebitica. After acidic microwave assisted digestion the concentrations of selected essential and trace elements were determined by inductively coupled plasma--atomic emission spectrometry and inductively coupled plasma--mass spectrometry. Other minor elements, such as Al, B, Cu, Fe, Mn, Sr and Zn are also found in leaves, blossoms and roots with contents in MUg/kg range. The preparation of decoctions and the extraction yields of the elements of interest are calculated. PMID- 25451084 TI - The 10th Nordic Symposium on Trace Elements in Human Health and Disease. Foreword. PMID- 25451086 TI - Questions of age differences in interference control: When and how, not if? AB - Declines in the control of attention and working memory are often considered a core feature of cognitive aging. In particular, the idea that older adults are differentially vulnerable to interference from irrelevant information has played an important but sometimes controversial role in guiding research. However, age differences in performance on measures of interference control are sometimes surprisingly small, and in some cases (e.g., mind-wandering and sustained attention), older adults perform better than young adults. Are age differences in interference control more myth than reality? We consider the evidence in light of neurocognitive frameworks that acknowledge the sometimes complex interactions between age-related declines and compensation. When operations can be performed within the focus of attention, age differences in interference control may be more easily detected in neural measures than behavioral ones, whereas behavioral differences are more likely to occur in tasks that require retrieval of information into the focus. Our analysis suggests that age differences in interference control have multiple sources, but also offer multiple opportunities for compensation and intervention. This article is part of a Special Issue entitled SI: Memory & Aging. PMID- 25451085 TI - Baincalein alleviates early brain injury after experimental subarachnoid hemorrhage in rats: possible involvement of TLR4/NF-kappaB-mediated inflammatory pathway. AB - Early brain injury (EBI) following subarachnoid hemorrhage (SAH) largely contributes to unfavorable outcomes. Hence, effective therapeutic strategies targeting on EBI have recently become a major goal in the treatment of SAH patients. Baicalein is a flavonoid that has been shown to offer neuroprotection in kinds of brain injury models. This study investigated the effects of baicalein on EBI in rats following SAH. SAH was inducted in male Sprauge-Dawley rats by injection of fresh non-heparinized arterial blood into the prechiasmatic cistern. Baicalein (30 or 100 mg/kg) or vehicle were administrated 30 min after injury. Neurological deficit, brain edema, blood-brain barrier (BBB) permeability and neural cell apoptosis were assessed. To explore the further mechanisms, the change of toll-like receptor 4 (TLR4) and nuclear factor-kappaB (NF-kappaB) signaling pathway and the levels of apoptosis associated proteins were also examined. Our study showed that treatment with baicalein (30 mg/kg) significantly improved neurological function at 24h after SAH and reduced brain edema at both 24h and 72 h after SAH. Baicalein also significantly reduced neural cell death, BBB permeability. These changes were associated with the remarkable reductions of TLR4 expression, IkappaB-alpha degradation, NF-kappaB translocation to nucleus, as well as the expressions of matrix metalloproteinase-9, tight junctions protein, interleukin-1beta and tumor necrosis factor- alpha. These findings suggest that baicalein may ameliorate EBI after SAH potentially via inhibition of inflammation-related pathway. PMID- 25451088 TI - Propofol prevents neuronal mtDNA deletion and cerebral damage due to ischemia/reperfusion injury in rats. AB - Propofol is a commonly used intravenous anesthetic that has been demonstrated to be neuroprotective against cerebral ischemia-reperfusion (I/R) injury. It remains unclear whether this protective effect has any relationship with the prevention of neuronal mitochondrial deoxyribonucleic acid (mtDNA) deletion. In this study, 81 Wistar rats were randomly divided into three groups (n = 27 each): sham (S group), ischemia/reperfusion (I/R group), or propofol (P group). Cerebral ischemia was induced by clamping the bilateral common carotid arteries for 10 min. A polymerase chain reaction (PCR) was conducted to determine mtDNA deletion. The mitochondrial membrane potential (MMP) changes were detected via microplate reader. The neuronal ultrastructure was visualized via electron microscope. MMP significantly decreased after I/R (P<0.05 compared with the S group). Severe damage to the ultrastructure of neuronal mitochondria was observed in cerebral I/R injury. When propofol (1.0mg/kg/min) was administered intravenously for 1h prior to the induction of I/R, the neuronal structure and MMP were well preserved, and mtDNA deletion was reduced after ischemia/reperfusion injury compared with the I/R group (P<0.05). These data suggested that propofol prevented mtDNA deletion and preserved a normal structure and MMP, which are important for normal mitochondrial function and increase neuronal resistance to I/R injury. PMID- 25451087 TI - Region-specific effects of isoflurane anesthesia on Fos immunoreactivity in response to intravenous cocaine challenge in rats with a history of repeated cocaine administration. AB - We have previously shown that acute intravenous (i.v.) administration of cocaine increases Fos immunoreactivity in rats under isoflurane anesthesia. Given that Fos expression is a marker of neural activation, the results suggested that isoflurane is appropriate for imaging cocaine effects under anesthesia. However, most imaging research in this area utilizes subjects with a history of repeated cocaine exposure and this drug history may interact with anesthetic use differently from acute cocaine exposure. Thus, this study further examined Fos expression under isoflurane in rats with a history of repeated i.v. cocaine administration. Rats received daily injections of either saline or cocaine (2mg/kg, i.v.) across 7 consecutive days, followed by 5 days of no drug exposure. On the test day, rats were either nonanesthetized or anesthetized under isoflurane and were given an acute challenge of cocaine (2mg/kg, i.v.). Additional saline-exposed controls received a saline challenge. Ninety min after the drug challenge, the rats were perfused under isoflurane anesthesia and their brains were processed for Fos protein immunohistochemistry. We found that challenge injections of cocaine following a regimen of repeated cocaine exposure resulted in Fos expression in the prefrontal cortex and striatum roughly equivalent to that found in rats who had received the cocaine challenge after a history of vehicle injections. Additionally, isoflurane anesthesia resulted in a heterogeneous attenuation of cocaine-induced Fos expression, with the most robust effect in the orbital cortex but no effect in the nucleus accumbens core (NAcC). These results indicate that cocaine-induced Fos is preserved in the NAcC under isoflurane, suggesting that isoflurane can be used in imaging studies involving cocaine effects in this region. PMID- 25451089 TI - Regulation of hippocampal synaptic plasticity by BDNF. AB - The neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a major regulator of activity-dependent plasticity at excitatory synapses in the mammalian central nervous system. In particular, much attention has been given to the role of the neurotrophin in the regulation of hippocampal long-term potentiation (LTP), a sustained enhancement of excitatory synaptic strength believed to underlie learning and memory processes. In this review we summarize the evidence pointing to a role for BDNF in generating functional and structural changes at synapses required for both early- and late phases of LTP in the hippocampus. The available information regarding the pre- and/or postsynaptic release of BDNF and action of the neurotrophin during LTP will be also reviewed. Finally, we discuss the effects of BDNF on the synaptic proteome, either by acting on the protein synthesis machinery and/or by regulating protein degradation by calpains and possibly by the ubiquitin-proteasome system (UPS). This fine-tuned control of the synaptic proteome rather than a simple upregulation of the protein synthesis may play a key role in BDNF-mediated synaptic potentiation. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25451090 TI - Astrocytic phospholipase A2 contributes to neuronal glutamate toxicity. AB - The role of astrocytes in glutamate toxicity has been controversial. Here, we show that astrocytes in neuron-astrocyte co-cultures increased neuronal sensitivity to chronic glutamate exposure but not to acute exposure. Enhanced neuronal toxicity by chronic exposure was dependent on astrocyte cell numbers. A reduced generation of extracellular H2O2 induced by glutamate was observed in co cultures. Further, neuronal glutamate toxicity was not suppressed by NADPH oxidase (Nox) inhibitors, catalase or Nox4 knockdown in co-cultures, whereas these compounds effectively reduced the toxicity in pure neuron cultures. Instead, the intracellular scavenger of reactive oxygen species, N-acetylcysteine (NAC), reduced neuronal cytotoxicity in co-cultures, whereas catalase worked in pure neuron cultures. Lipoxygenase (LOX) inhibitors attenuated neuronal glutamate toxicity in co-cultures but not in pure neuron cultures. Neuronal 5-LOX activity was increased only in co-cultures, whereas 12-LOX activity was increased in both types of cultures. The cyclooxygenase (COX) inhibitors, indomethacin and NS-398, and the phospholipase A2 (PLA2) inhibitors, LY311727 and MAFP, more effectively reduced neuronal glutamate toxicity in co-cultures than in pure neuron cultures. However, in co-cultures, pre-treating neurons and astrocytes with the same inhibitors generated opposite results. COX inhibitors suppressed neuronal glutamate toxicity in pre-treated neurons rather than astrocytes, whereas PLA2 inhibitors reduced the toxicity in pre-treated astrocytes rather than neurons. Gene-specific knockdown of PLA2 confirmed these results. Knockdown of cPLA2alpha and/or sPLA2-V in astrocytes rather than in neurons more effectively reduced glutamate toxicity in co-cultures. These findings suggest that astrocytic PLA2 activity increases neuronal sensitivity to chronic glutamate exposure in neuron astrocyte co-cultures. PMID- 25451091 TI - Analysis of G-protein-activated inward rectifying K(+) (GIRK) channel currents upon GABAB receptor activation in rat supraoptic neurons. AB - While magnocellular neurons in the supraoptic nucleus (SON) possess rich Gi/o mediated mechanisms, molecular and cellular properties of G-protein-activated inwardly rectifying K(+) (GIRK) channels have been controversial. Here, properties of GIRK channels are examined by RT-PCR and whole-cell patch-clamp techniques in rat SON neurons. Patch clamp experiments showed that the selective GABAB agonist, baclofen, enhanced currents in a high K(+) condition. The baclofen enhanced currents exhibited evident inward rectification and were blocked by the selective GABAB antagonist, CGP55845A, the IRK channel blocker, Ba(2+), and the selective GIRK channel blocker, tertiapin, indicating that baclofen activates GIRK channels via GABAB receptors. The GIRK currents were abolished by N ethylmaleimide pretreatment, and prolonged by GTPgammaS inclusion in the patch pipette, suggesting that Gi/o proteins are involved. RT-PCR analysis revealed mRNAs for all four GIRK 1-4 channels and for both GABABR1 and GABABR2 receptors in rat SON. However, the concentration-dependency of the baclofen-induced activation of GIRK currents had an EC50 of 110 uM, which is about 100 times higher than that of baclofen-induced inhibition of voltage-dependent Ca(2+) channels. Moreover, baclofen caused no significant changes in the membrane potential and the firing rate. These results suggest that although GIRK channels can be activated by GABAB receptors via the Gi/o pathway, this occurs at high agonist concentrations, and thus may not be a physiological mechanism regulating the function of SON neurons. This property that the membrane potential receives little influence from GIRK currents seems to be uncommon for CNS neurons possessing rich Gi/o-coupled receptors, and could be a special feature of rat SON neurons. PMID- 25451093 TI - White matter integrity and cognition in mild traumatic brain injury following motor vehicle accident. AB - The aim of this study is to explore the white matter structure integrity in patients with mild traumatic brain injury (mTBI) using diffusion tensor imaging (DTI), and to analyze the relationship between the white matter structure integrity and cognitive impairment of patients with mTBI. Twenty-five patients with mTBI and 25 healthy control subjects were studied with conventional MR imaging and diffusion tensor imaging. Fractional anisotropy (FA) and mean diffusivity (MD) maps of patients with mTBI were calculated and compared, with these control maps using tract-based spatial statistics (TBSS). Significantly lower fractional anisotropy was found in patients in the uncinate fasciculus, superior longitudinal fasciculus, inferior longitudinal fasciculus, and internal capsule. Mean diffusivity was significantly elevated in the body of corpus callosum, uncinate fasciculus, superior longitudinal fasciculus, and internal capsule in the mTBI group compared with the control group (P<0.05). The mTBI group showed a significant negative correlation between the elevated mean diffusivity of the uncinate fasciculus and the working memory index (WMI) (R(2)=0.51, P<0.05), and the internal capsule of MD values was significantly negatively related to processing speed index (PSI) (R(2)=0.45, P<0.05). There was a positive correlation between the FA value of the uncinate fasciculus and Mini Mental State Examination (MMSE) in the mTBI patient group (R(2)=0.36, P<0.05). TBSS analysis of DTI suggests that patients with mTBI have focal axonal injury, and the pathophysiology is significantly related to the MMSE and IQ of mTBI patients. Diffusion tensor imaging can be a powerful technique for in vivo detection of mTBI, and can help in the diagnosis of patients with mTBI. PMID- 25451092 TI - Glutamate, GABA, and glutamine are synchronously upregulated in the mouse lateral septum during the postpartum period. AB - Dramatic structural and functional remodeling occurs in the postpartum brain for the establishment of maternal care, which is essential for the growth and development of young offspring. Glutamate and GABA signaling are critically important in modulating multiple behavioral performances. Large scale signaling changes occur in the postpartum brain, but it is still not clear to what extent the neurotransmitters glutamate and GABA change and whether the ratio of glutamate/GABA remains balanced. In this study, we examined the glutamate/GABA glutamine cycle in the lateral septum (LS) of postpartum female mice. In postpartum females (relative to virgins), tissue levels of glutamate and GABA were elevated in LS and increased mRNA was found for the respective enzymes producing glutamate and GABA, glutaminase (Gls) and glutamate decarboxylase 1 and 2 (Gad1 and Gad2). The common precursor, glutamine, was elevated as was the enzyme that produces it, glutamate-ammonia ligase (Glul). Additionally, glutamate, GABA, and glutamine were positively correlated and the glutamate/GABA ratio was almost identical in the postpartum and virgin females. Collectively, these findings indicate that glutamate and GABA signaling are increased and that the ratio of glutamate/GABA is well balanced in the maternal LS. The postpartum brain may provide a useful model system for understanding how glutamate and GABA are linked despite large signaling changes. Given that some mental health disorders, including depression and schizophrenia display dysregulated glutamate/GABA ratio, and there is increased vulnerability to mental disorders in mothers, it is possible that these postpartum disorders emerge when glutamate and GABA changes are not properly coordinated. PMID- 25451094 TI - Contribution of alpha4beta2 nAChR in nicotine-induced intracellular calcium response and excitability of MSDB neurons. AB - The neurons of medial septal diagonal band of broca (MSDB) project to hippocampus and play an important role in MSDB-hippocampal synaptic transmission, plasticity and network oscillation. Nicotinic acetylcholine receptor (nAChR) subunits, alpha4beta2 and alpha7 nAChRs, are expressed in MSDB neurons and permeable to calcium ions, which may modulate the function of MSDB neurons. The aims of this study are to determine the roles of selective nAChR activation on the calcium responses and membrane currents in MSDB neurons. Our results showed that nicotine increased calcium responses in the majority of MSDB neurons, pre-treatment of MSDB slices with a alpha4beta2 nAChR antagonist, DhbetaE but not a alpha7 nAChR antagonist, MLA prevented nicotine-induced calcium responses. The whole cell patch clamp recordings showed that nicotine-induced inward current and acetylcholine (ACh) induced-firing activity can be largely reduced or prevented by DhbetaE in MSDB neurons. Surprisingly, post-treatment of alpha4beta2 or alpha7 nAChR antagonists failed to block nicotine's role, they increased calcium responses instead. Application of calcium chelator EGTA reduced calcium responses in all neurons tested. These results suggest that there was a subtype specific modulation of nAChRs on calcium signaling and membrane currents in MSDB neurons and nAChR antagonists were also able to induce calcium responses involving a distinct mechanism. PMID- 25451095 TI - Carvacrol presynaptically enhances spontaneous excitatory transmission and produces outward current in adult rat spinal substantia gelatinosa neurons. AB - Carvacrol, which is abundantly contained in oregano essential oils, has various pharmacological actions including antinociception. Although the oral administration of carvacrol results in antinociception, cellular mechanisms for this action have not been examined yet. We investigated the action of carvacrol on glutamatergic spontaneous excitatory transmission in substantia gelatinosa neurons which play a pivotal role in regulating nociceptive transmission from the periphery by using the patch-clamp technique in adult rat spinal cord slices. Carvacrol superfused for 2 min produced either spontaneous excitatory postsynaptic current frequency increase or outward current at -70 mV, or both of them in many of the neurons tested. The frequency increase and outward current had the EC(50) values of 0.69 mM and 0.55 mM, respectively. The former action was inhibited by a selective TRPA1 antagonist HC-030031 but not a selective TRPV1 antagonist capsazepine, while the latter action was unaffected by their antagonists. The current-voltage relationship for the outward current indicated an involvement in the current of a change in the membrane permeability of K(+) and its outward rectification. The outward current was inhibited in 10 mM-K((+) 0but not K(+)-channel blockers [tetraethylammonium and Ba(2+)]-containing and 11.0 mM-Cl- Krebs solution. These results indicate that carvacrol increases the spontaneous release of l-glutamate from nerve terminals by activating TRPA1 but not TRPV1 channels and produces membrane hyperpolarization, which is possibly mediated by tetraethylammonium- and Ba(2+)-insensitive K(+) channels, in substantia gelatinosa neurons. It is suggested that the hyperpolarizing effect of carvacrol could contribute to its antinociceptive action. PMID- 25451096 TI - Environmental enrichment enhances autophagy signaling in the rat hippocampus. AB - The findings that antidepressive treatments increase hippocampal neurotrophins have led researchers to emphasize the importance of neurogenesis, formation of new dendrites, and survival of neurons in the brain. However, it is difficult to maintain neural plasticity just by enriching the environment to facilitate formation of new networks. Neural plasticity also requires a degradation process that clears off unnecessary and undesirable components. We have recently reported an increase in autophagy signaling (wherein the cell digests components of itself) that has the potential of enhancing neuronal and synaptic plasticity after multiple sessions of electroconvulsive seizure treatment. The present study revealed an increase in autophagy signaling in the rat hippocampus following 2 weeks of environmental enrichment (EE), a procedure known to elicit antidepressive and anxiolytic behavioral changes in various animal paradigms. Western blot analysis showed an increase in hippocampal expression of microtubule associated protein light chain 3-II (LC3-II), which is lipidated from LC3-I, in rats in the EE group. The effectiveness of the 2-week EE housing condition was validated by anxiolytic effects observed in the elevated plus maze test, enhanced habituation in the open field test, and elevation of hippocampal brain-derived neurotrophic factor expression. In addition, we showed that the EE housing condition ameliorated numbing/avoidance behaviors, but not hypervigilant behaviors, in an animal model of post-traumatic stress disorder (PTSD). This is the first report to show that EE can increase autophagy signaling and improve numbing/avoidance behaviors in an animal model of PTSD. PMID- 25451098 TI - Protective effects of blueberry- and strawberry diets on neuronal stress following exposure to (56)Fe particles. AB - Particles of high energy and charge (HZE particles), which are abundant outside the magnetic field of the Earth, have been shown to disrupt the functioning of neuronal communication in critical regions of the brain. Previous studies with HZE particles, have shown that irradiation produces enhanced indices of oxidative stress and inflammation as well as altered neuronal function that are similar to those seen in aging. Feeding animals antioxidant-rich berry diets, specifically blueberries and strawberries, countered the deleterious effects of irradiation by reducing oxidative stress and inflammation, thereby improving neuronal signaling. In the current study, we examined the effects of exposure to (56)Fe particles in critical regions of brain involved in cognitive function, both 36h and 30 days post irradiation. We also studied the effects of antioxidant-rich berry diets, specifically a 2% blueberry or strawberry diet, fed for 8 weeks prior to radiation as well as 30 days post irradiation. (56)Fe exposure caused significant differential, neurochemical changes in critical regions of the brain, such as hippocampus, striatum, frontal cortex, and cerebellum, through increased inflammation, and increased oxidative stress protein markers. (56)Fe exposure altered the autophagy markers, and antioxidant-rich berry diets significantly reduced the accumulation of p62 in hippocampus, a scaffold protein that co localizes with ubiquitinated protein at the 30 days post irradiation time-point. Exposure to (56)Fe particles increased the accumulation of disease-related proteins such as PHF-tau in the hippocampus of animals fed the control diet, but not in the irradiated animals fed the blueberry diet. These results indicate the potential protective effects of antioxidant-rich berry diets on neuronal functioning following exposure to HZE particles. PMID- 25451097 TI - p38 MAP kinase mediates transforming-growth factor-beta1-induced upregulation of matrix metalloproteinase-9 but not -2 in human brain pericytes. AB - Pericytes are vascular mural cells embedded within the basal lamina of blood micro-vessels. Within the neurovascular unit, pericytes play important roles in regulating neurovascular homeostasis by secreting soluble factors, such as matrix metalloproteinases (MMPs). However, little is known about the regulatory signaling pathways in brain pericytes. Here we show that transforming growth factor-beta1 (TGF-beta1) induces MMP-9 upregulation in pericytes via p38 mitogen activated protein (MAP) kinase signaling. Cultured human brain vascular pericytes were used in this study. When the brain pericytes were treated with purified human TGF-beta1 (0.1-10ng/mL for 24h), the levels of MMP-2 and MMP-9 in culture media were significantly increased in a concentration dependent manner as measured by gelatin zymography. WST assay confirmed that TGF-beta1 did not affect cell survival of the brain pericytes. A TGF-beta-receptor inhibitor SB431542 (0.5 5MUM) decreased the TGF-beta1-induced upregulation of MMP-2 and MMP-9. To assess the underlying intracellular mechanisms, we focused on p38 MAP kinase signaling, which is one of the major downstream kinases for TGF-beta1. A well-validated p38 MAP kinase inhibitor SB203580 (0.5-5MUM) cancelled the effect of TGF-beta1 in upregulation of MMP-9 but not MMP-2. Western blotting confirmed that TGF-beta1 treatment increased the level of p38 MAP kinase phosphorylation in pericytes, and again, the TGF-beta-receptor inhibitor SB431542 (0.5-5MUM) blocked the TGF-beta1 induced phosphorylation of p38 MAP kinase. Both TGF-beta1 and MMP-9 are major neurovascular mediators, and therefore, our current finding may suggest a novel mechanism for how pericytes regulate neurovascular homeostasis. PMID- 25451099 TI - The persisting effects of electroconvulsive stimulation on the hippocampal proteome. AB - Electroconvulsive therapy (ECT) is the most acutely effective treatment available for severe depression. However, its mechanism of action is not fully understood. Elucidating the protein changes induced in the brain by ECT will enhance our understanding of this antidepressant therapy. Electroconvulsive stimulation (ECS), the animal analogue of ECT, was administered to rats to determine the proteomic changes induced in the hippocampus, a region of the brain implicated in the biology of depression and its treatment. Two-dimensional difference in gel electrophoresis (2D-DiGE) and liquid chromatography tandem mass spectrometry (LC MS/MS) methods were applied to identify differentially expressed proteins following acute (*1 treatment), chronic (*10 treatments) or chronic(+4 weeks) (*10 treatments plus 4 weeks later) ECS. Administration of acute, chronic and chronic(+4 weeks) ECS induced significant changes in multiple DiGE gel protein spots. Interestingly, the largest number of differentially expressed protein spots was identified following chronic(+4 weeks) ECS. Following protein identification by LC-MS/MS, gene ontology analysis primarily implicated proteins with cytoskeletal and metabolism-related roles in the action of ECS. Immunoblotting confirmed the changes in abundance of the cytoskeletal protein actin following chronic(+4 weeks) ECS. Overall, chronic(+4 weeks) ECS was particularly effective at inducing longer-lasting changes in the abundance of hippocampal proteins with cytoskeletal and metabolism roles. These results suggest a role for persisting cytoskeletal-related neuroplastic changes in the action of ECS and may be informative as to the antidepressant mechanisms of ECT in patients with depression. PMID- 25451100 TI - Suppression of acute seizures by theta burst electrical stimulation of the hippocampal commissure using a closed-loop system. AB - This study investigated the effects of electrical stimulation with theta burst stimulation (eTBS) on seizure suppression. Optimal parameters of eTBS were determined through open-loop stimulation experiments and then implemented in a close-loop seizure control system. For the experiments, 4-aminopyridine (4-AP) was injected into the right hippocampus of Sprague-Dawley rats to induce an acute seizure. eTBS was applied on the ventral hippocampal commissure and the effects of eTBS with different combinations of burst frequency and number of pulses per burst were analyzed in terms of seizure suppression. A closed-loop seizure control system was then implemented based on optimal eTBS parameters. The efficiency of the closed-loop eTBS was evaluated and compared to that of high frequency stimulation. The results show that eTBS induced global suppression in the hippocampus and this was sustained even after the application of eTBS. The optimal parameter of eTBS in the open-loop stimulation experiments was a burst frequency at 100Hz with nine pulses in a burst. The eTBS integrated with the on off control law yielded less actions and cumulative delivered charge, but induced longer after-effects of seizure suppression compared to continuous high frequency stimulation (cHFS). To conclude, eTBS has suppressive effects on 4-AP induced seizure. A closed-loop eTBS system provides a more effective way of suppressing seizure and requires less effort compared to cHFS. eTBS may be a novel stimulation protocol for effective seizure control. PMID- 25451101 TI - A chronic disease dietary consultation system using OWL-based ontologies and semantic rules. AB - Chronic diseases patients often require constant dietary control that involves complicated interaction among factors such as the illness stage, the patient's physical condition, the patient's activity level, the amount of food intake, and key nutrient restrictions. This study aims to integrate multiple knowledge sources for problem solving modeling and knowledge-based system (KBS) development. A chronic kidney disease dietary consultation system is constructed by using Web Ontology Language (OWL) and Semantic Web Rule Language (SWRL) to demonstrate how a KBS approach can achieve sound problem solving modeling and effective knowledge inference. For system evaluation, information from 84 case patients is used to evaluate the performance of the system in recommending appropriate food serving amounts from different food groups for balanced key nutrient ingestion. The results show that, excluding interference factors, the OWL-based KBS can achieve accurate problem solving reasoning while maintaining knowledge base shareability and extensibility. PMID- 25451102 TI - Secondary use of electronic health records for building cohort studies through top-down information extraction. AB - Controlled clinical trials are usually supported with an in-front data aggregation system, which supports the storage of relevant information according to the trial context within a highly structured environment. In contrast to the documentation of clinical trials, daily routine documentation has many characteristics that influence data quality. One such characteristic is the use of non-standardized text, which is an indispensable part of information representation in clinical information systems. Based on a cohort study we highlight challenges for mining electronic health records targeting free text entry fields within semi-structured data sources. Our prototypical information extraction system achieved an F-measure of 0.91 (precision=0.90, recall=0.93) for the training set and an F-measure of 0.90 (precision=0.89, recall=0.92) for the test set. We analyze the obtained results in detail and highlight challenges and future directions for the secondary use of routine data in general. PMID- 25451103 TI - Portable automatic text classification for adverse drug reaction detection via multi-corpus training. AB - OBJECTIVE: Automatic detection of adverse drug reaction (ADR) mentions from text has recently received significant interest in pharmacovigilance research. Current research focuses on various sources of text-based information, including social media-where enormous amounts of user posted data is available, which have the potential for use in pharmacovigilance if collected and filtered accurately. The aims of this study are: (i) to explore natural language processing (NLP) approaches for generating useful features from text, and utilizing them in optimized machine learning algorithms for automatic classification of ADR assertive text segments; (ii) to present two data sets that we prepared for the task of ADR detection from user posted internet data; and (iii) to investigate if combining training data from distinct corpora can improve automatic classification accuracies. METHODS: One of our three data sets contains annotated sentences from clinical reports, and the two other data sets, built in-house, consist of annotated posts from social media. Our text classification approach relies on generating a large set of features, representing semantic properties (e.g., sentiment, polarity, and topic), from short text nuggets. Importantly, using our expanded feature sets, we combine training data from different corpora in attempts to boost classification accuracies. RESULTS: Our feature-rich classification approach performs significantly better than previously published approaches with ADR class F-scores of 0.812 (previously reported best: 0.770), 0.538 and 0.678 for the three data sets. Combining training data from multiple compatible corpora further improves the ADR F-scores for the in-house data sets to 0.597 (improvement of 5.9 units) and 0.704 (improvement of 2.6 units) respectively. CONCLUSIONS: Our research results indicate that using advanced NLP techniques for generating information rich features from text can significantly improve classification accuracies over existing benchmarks. Our experiments illustrate the benefits of incorporating various semantic features such as topics, concepts, sentiments, and polarities. Finally, we show that integration of information from compatible corpora can significantly improve classification performance. This form of multi-corpus training may be particularly useful in cases where data sets are heavily imbalanced (e.g., social media data), and may reduce the time and costs associated with the annotation of data in the future. PMID- 25451105 TI - Molecular pathways: exploiting tumor-specific molecular defects in DNA repair pathways for precision cancer therapy. AB - Disabling mutations in genome maintenance and DNA repair pathways are frequently observed in cancer. These DNA repair defects represent genetic aberrations that are specific to cancer cells and not present in healthy tissues. It is thought that these molecular defects produce a "mutator phenotype," which allows incipient cancer cells to accumulate additional cancer-promoting mutations. In recent years, our molecular understanding of DNA double-strand break (DSB) repair mechanisms has led to the development of targeted therapeutic approaches to selectively eradicate cancer cells that display defects in homologous recombination-mediated DNA DSB repair. These regimens for the treatment of homologous recombination-defective tumors predominantly aim at pharmacologically repressing the activity of PARP1, which is crucial for base excision repair, or to inhibit the nonhomologous end joining kinase DNA-PKcs (DNA-dependent protein kinase, catalytic subunit). Normal tissue can bypass PARP1- or DNA-PKcs inhibitor induced genotoxic lesions via homologous recombination-mediated DNA DSB repair. In contrast, homologous recombination-defective cancer cells are unable to properly repair DNA DSBs, in the presence of PARP1 or DNA-PKcs inhibitors, ultimately leading to apoptotic cancer cell death. PMID- 25451107 TI - Thomas C. Hall, MD, FACP: in memoriam. PMID- 25451109 TI - Differential effects of corticosterone on the colocalization of reelin and neuronal nitric oxide synthase in the adult hippocampus in wild type and heterozygous reeler mice. AB - Repeated corticosterone (CORT) treatment induces a deficit in dentate gyrus subgranular zone reelin-positive cells, in maturation of newborn neurons, and results in a consistent depressive-like behavior. However, the molecular mechanisms underlying these processes are not known in detail. The purpose of the present study was to characterize the effect of three weeks of 20mg/kg CORT injections in the number of reelin and neuronal nitric oxide synthase (nNOS), as well as their colocalization, in hippocampal regions in wild type (WTM) and heterozygous reeler mice (HRM). ANOVA analysis shows a CORT*genotype interaction in the density of reelin+ cells co-localizing nNOS in the dentate subgranular zone and stratum-lacunosum moleculare, and in the density of nNOS+ cells in the hilus. There is a main effect of CORT in the density of both reelin+ and nNOS+ cells in the dentate subgranular zone and hilus, and in reelin+ cells in the molecular layer and CA3 stratum radiatum; and a main effect of genotype on the co localization of both markers in the dentate subgranular zone, and in the density of reelin+ cell sin the stratum lacunosum moleculare. These alterations suggest a possible interconnection between reelin and nNOS expression that is altered by repeated CORT treatment. PMID- 25451106 TI - Safety and preliminary evidence of biologic efficacy of a mammaglobin-a DNA vaccine in patients with stable metastatic breast cancer. AB - PURPOSE: Mammaglobin-A (MAM-A) is overexpressed in 40% to 80% of primary breast cancers. We initiated a phase I clinical trial of a MAM-A DNA vaccine to evaluate its safety and biologic efficacy. EXPERIMENTAL DESIGN: Patients with breast cancer with stable metastatic disease were eligible for enrollment. Safety was monitored with clinical and laboratory assessments. The CD8 T-cell response was measured by ELISPOT, flow cytometry, and cytotoxicity assays. Progression-free survival (PFS) was described using the Kaplan-Meier product limit estimator. RESULTS: Fourteen subjects have been treated with the MAM-A DNA vaccine and no significant adverse events have been observed. Eight of 14 subjects were HLA A2(+), and the CD8 T-cell response to vaccination was studied in detail. Flow cytometry demonstrated a significant increase in the frequency of MAM-A-specific CD8 T cells after vaccination (0.9% +/- 0.5% vs. 3.8% +/- 1.2%; P < 0.001), and ELISPOT analysis demonstrated an increase in the number of MAM-A-specific IFNgamma-secreting T cells (41 +/- 32 vs. 215 +/- 67 spm; P < 0.001). Although this study was not powered to evaluate progression-free survival (PFS), preliminary evidence suggests that subjects treated with the MAM-A DNA vaccine had improved PFS compared with subjects who met all eligibility criteria, were enrolled in the trial, but were not vaccinated because of HLA phenotype. CONCLUSION: The MAM-A DNA vaccine is safe, capable of eliciting MAM-A-specific CD8 T-cell responses, and preliminary evidence suggests improved PFS. Additional studies are required to define the potential of the MAM-A DNA vaccine for breast cancer prevention and/or therapy. PMID- 25451112 TI - Modulation of functional connectivity following visual adaptation: homeostasis in V1. AB - Sensory neurons exhibit remarkable adaptability in acquiring new optimal selectivity to unfamiliar features when a new stimulus becomes prevalent in the environment. In conventionally prepared adult anesthetized cats, we used visual adaptation to change the preferred orientation selectivity in V1 neurons. Cortical circuits are dominated by complex and intricate connections between neurons. Cross-correlation of cellular spike-trains discloses the putative functional connection between two neurons. We sought to investigate changes in these links following a 12 min uninterrupted application of a specific, usually non-preferred, orientation. We report that visual adaptation, mimicking training, modulates the magnitude of crosscorrelograms suggesting that the strength of inter-neuronal relationships is modified. While individual cell-pairs exhibit changes in their response correlation strength, the average correlation of the recorded cell cluster remains unchanged. Hence, visual adaptation induces plastic changes that impact the connectivity between neurons. PMID- 25451110 TI - Short-lived diabetes in the young-adult ZDF rat does not exacerbate neuronal Ca(2+) biomarkers of aging. AB - Results from clinical studies provide evidence that cognitive changes relatively late in life may be traced to antecedent conditions including diabetes, obesity, a sedentary lifestyle, and an atherogenic diet. As such, several traits of Type 2 diabetes (T2DM) could be considered pathogenic factors of aging, contributing to age-dependent cognitive decline and our susceptibility to Alzheimer's disease. It appears that both the duration of metabolic condition and the age of the individual, together can contribute to the potential impact on peripheral as well as brain health. Because of robust evidence that in animal models of aging, Ca(2+) dysregulation alters neuronal health, synaptic plasticity, and learning and memory processes, we tested the hypothesis that peripheral metabolic dysregulation could exacerbate Ca(2+) dysfunction in hippocampal CA1 neurons. Using intracellular/ extracellular electrophysiological and Ca(2+) imaging techniques, we show that Ca(2+)levels at rest or during synaptic stimulation, the Ca(2+)-dependent afterhyperpolarization, baseline field potentials, and short term synaptic plasticity were not significantly altered in young-adult male Zucker diabetic fatty rats compare to their lean counterparts. Our observations suggest that early phases of T2DM characterized by high levels of glucose and insulin may be too transient to alter hippocampal CA1 physiology in this animal model of diabetes. These results are supported by clinical data showing that longer T2DM duration can have greater negative impact on cognitive functions. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25451111 TI - Head direction is coded more strongly than movement direction in a population of entorhinal neurons. AB - The spatial firing pattern of entorhinal grid cells may be important for navigation. Many different computational models of grid cell firing use path integration based on movement direction and the associated movement speed to drive grid cells. However, the response of neurons to movement direction has rarely been tested, in contrast to multiple studies showing responses of neurons to head direction. Here, we analyzed the difference between head direction and movement direction during rat movement and analyzed cells recorded from entorhinal cortex for their tuning to movement direction. During foraging behavior, movement direction differs significantly from head direction. The analysis of neuron responses shows that only 5 out of 758 medial entorhinal cells show significant coding for both movement direction and head direction when evaluating periods of rat behavior with speeds above 10 cm/s and +/-30 degrees angular difference between movement and head direction. None of the cells coded movement direction alone. In contrast, 21 cells in this population coded only head direction during behavioral epochs with these constraints, indicating much stronger coding of head direction in this population. This suggests that the movement direction signal required by most grid cell models may arise from other brain structures than the medial entorhinal cortex. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25451113 TI - Norepinephrine transporter knock-out alters expression of the genes connected with antidepressant drugs action. AB - Norepinephrine transporter knock-out mice (NET-KO) exhibit depression-resistant phenotypes. They manifest significantly shorter immobility times in both the forced swim test and the tail suspension test. Moreover, biochemical studies have revealed the up-regulation of other monoamine transporters (dopamine and serotonin) in the brains of NET-KO mice, similar to the phenomenon observed after the chronic pharmacological blockade of norepinephrine transporter by desipramine in wild-type (WT) animals. NET-KO mice are also resistant to stress, as we demonstrated previously by measuring plasma corticosterone concentration. In the present study, we used a microdissection technique to separate target brain regions and the TaqMan Low Density Array approach to test the expression of a group of genes in the NET-KO mice compared with WT animals. A group of genes with altered expression were identified in four brain structures (frontal and cingulate cortices, dentate gyrus of hippocampus and basal-lateral amygdala) of NET-KO mice compared with WT mice. These genes are known to be altered by antidepressant drugs administration. The most interesting gene is Crh-bp, which modulates the activity of corticotrophin--releasing hormone (CRH) and several CRH family members. Generally, genetic disturbances within noradrenergic neurons result in biological changes, such as in signal transduction and intercellular communication, and may be linked to changes in noradrenaline levels in the brains of NET-KO mice. PMID- 25451114 TI - Characterisation of multiple regulatory domains spanning the major transcriptional start site of the FUS gene, a candidate gene for motor neurone disease. AB - Fused-In-Sarcoma (FUS) is a candidate gene for neurological disorders including motor neurone disease and Parkinson's disease in addition to various types of cancer. Recently it has been reported that over expression of FUS causes motor neurone disease in mouse models hence mutations leading to changes in gene expression may contribute to the development of neurodegenerative disease. Genome evolutionary conservation was used to predict important cis-acting DNA regulators of the FUS gene promoter that direct transcription. The putative regulators identified were analysed in reporter gene assays in cells and in chick embryos. Our analysis indicated in addition to regulatory domains 5' of the transcriptional start site an important regulatory domain resides in intron 1 of the gene itself. This intronic domain functioned both in cell lines and in vivo in the neural tube of the chick embryo including developing motor neurones. Our data suggest the interaction of multiple domains including intronic domains are involved in expression of FUS. A better understanding of the regulation of expression of FUS may give insight into how its stimulus inducible expression may be associated with neurological disorders. PMID- 25451115 TI - Iron administration prevents BDNF decrease and depressive-like behavior following chronic stress. AB - Pro-inflammatory cytokines play important roles in responses to stresses and affect iron metabolism. Iron is essential for survival of hippocampus neurons and plays a role in depression. Noting the close causal effect relation between stress and depression, in this experimental study we investigated the influence of iron on stress-induced depression. Rats were exposed to chronic mild stress and were treated with three different iron doses (9, 12, and 20mg/kg) three times a week for four weeks with an iron chelator in the first and third week. Serum interleukin-6 (enzyme-linked immune sorbent assay), hippocampus iron content (atomic absorption spectrometry), brain-derived neurotrophic factor (BDNF) gene expression (real-time polymerase chain reaction), CA1 pyramidal cell count (Nissl method) and a behavioral test (forced swimming test) were evaluated. In both the stressed and stressed plus iron groups, hippocampus cell counts were lower than in the control group (non-stressed). The use of deferiprone in the stressed groups markedly prevented neuronal loss. In stressed rats, the iron content of the hippocampus was higher than in the control group (P<0.001). Moreover, in the stressed group with moderate iron administration (12 mg/kg), there was a significant elevation of BDNF expression (P<0.05) and decreased immobility behavior time (P<0.05). These results indicate that high doses of iron in stressful situations augment neuronal degeneration and loss, possibly by iron accumulation. Deferiprone as an iron chelator could reverse this effect. During chronic mild stress, cerebrospinal fluid possibly reduces the iron content and may result in reduction of monoamines being involved in mood regulation. Iron administration in a moderate dose can increase these neurotransmitters and BDNF expression. PMID- 25451118 TI - DSCAM and DSCAML1 regulate the radial migration and callosal projection in developing cerebral cortex. AB - Down syndrome cell adhesion molecule (Dscam) is essential for self-avoidance and tiling of dendritic development in sensory neurons in Drosophila. Recent studies also show that DSCAM together with its closely related protein DSCAML1 functions in dendritic self-avoidance of a certain types of interneuron in mammalian retina. However, the functions of these DSCAMs in developing mammalian cerebral cortex are not well understood. Here we reduced the expression of DSCAM or DSCAML1 in mouse cortical neurons by RNA interference both in vitro and in vivo. We found that knockdown of DSCAM or DSCAML1 increases the complexity of proximal dendritic branching, and impedes the axon growth in cultured neurons. In vivo knockdown experiments showed that both DSCAM and DSCAML1 contribute to normal radial migration and callosal projection during the postnatal development. Our results indicate an important role of DSCAM and DSCAML1 in the development of cortical neural network. PMID- 25451119 TI - Electrophysiological brain dynamics during the esthetic judgment of human bodies and faces. AB - This experiment investigated how the esthetic judgment of human body and face modulates cognitive and affective processes. We hypothesized that judgments on ugliness and beauty would elicit separable event-related brain potentials (ERP) patterns, depending on the esthetic value of body and faces in both genders. In a pretest session, participants evaluated images in a range from very ugly to very beautiful, what generated three sets of beautiful, ugly and neutral faces and bodies. In the recording session, they performed a task consisting in a beautiful neutral-ugly judgment. Cognitive and affective effects were observed on a differential pattern of ERP components (P200, P300 and LPC). Main findings revealed a P200 amplitude increase to ugly images, probably the result of a negativity bias in attentional processes. A P300 increase was found mostly to beautiful images, particularly to female bodies, consistent with the salience of these stimuli, particularly for stimulus categorization. LPC appeared significantly larger to both ugly and beautiful images, probably reflecting later, decision processes linked to keeping information in working memory. This finding was especially remarkable for ugly male faces. Our findings are discussed on the ground of evolutionary and adaptive value of esthetics in person evaluation. This article is part of a Special Issue entitled Hold Item. PMID- 25451117 TI - 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine inhibit TNF-alpha and CXCL10 production from activated primary murine microglia via A2A receptors. AB - BACKGROUND: Some cells, tissues and organs release 2',3'-cAMP (a positional isomer of 3',5'-cAMP) and convert extracellular 2',3'-cAMP to 2'-AMP plus 3'-AMP and convert these AMPs to adenosine (called the extracellular 2',3'-cAMP adenosine pathway). Recent studies show that microglia have an extracellular 2',3'-cAMP-adenosine pathway. The goal of the present study was to investigate whether the extracellular 2',3'-cAMP-adenosine pathway could have functional consequences on the production of cytokines/chemokines by activated microglia. METHODS: Experiments were conducted in cultures of primary murine microglia. In the first experiment, the effect of 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine on LPS-induced TNF-alpha and CXCL10 production was determined. In the next experiment, the first protocol was replicated but with the addition of 1,3 dipropyl-8-p-sulfophenylxanthine (DPSPX) (0.1 MUM; antagonist of adenosine receptors). The last experiment compared the ability of 2-chloro-N(6) cyclopentyladenosine (CCPA) (10 MUM; selective A1 agonist), 5'-N-ethylcarboxamide adenosine (NECA) (10 MUM; agonist for all adenosine receptor subtypes) and CGS21680 (10 MUM; selective A2A agonist) to inhibit LPS-induced TNF-alpha and CXCL10 production. RESULTS: (1) 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine similarly inhibited LPS-induced TNF-alpha and CXCL10 production; (2) DPSPX nearly eliminated the inhibitory effects of 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine on LPS-induced TNF-alpha and CXCL10 production; (3) CCPA did not affect LPS-induced TNF-alpha and CXCL10; (4) NECA and CGS21680 similarly inhibited LPS-induced TNF alpha and CXCL10 production. CONCLUSIONS: 2',3'-cAMP and its metabolites (3'-AMP, 2'-AMP and adenosine) inhibit LPS-induced TNF-alpha and CXCL10 production via A2A receptor activation. Adenosine and its precursors, via A2A receptors, likely suppress TNF-alpha and CXCL10 production by activated microglia in brain diseases. PMID- 25451120 TI - Mitochondrial energy metabolism and apoptosis regulation in glioblastoma. AB - Glioblastoma is the most aggressive form of gliomas and is associated with short survival. Recent advancements in molecular genetics resulted in the identification of glioma genomic, epigenomic and transcriptomic hallmarks, and multidimensional data allowed clustering of glioblastomas into molecular subtypes. Parallel with these developments, much scientific attention has been attracted by the exploration of two functional processes linked to mitochondrial regulation. One of these processes involves genomic and mitochondrial gene mutations, mitochondrial protein expression modifications and altered metabolic regulation that define glioblastoma. The second mitochondrially-centered process involves complex molecular interactions and pathways that influence the extrinsic or the intrinsic mechanisms of apoptosis regulation and may underlie the uncontrolled spreading, recurrence and drug resistance of glioblastoma. While the available data are not yet comprehensive, these two complex processes represent important aspects of tumor cell biology, which may provide complementary opportunities for therapeutic manipulations of this highly resistant tumor type. PMID- 25451116 TI - Brain-derived neurotrophic factor and addiction: Pathological versus therapeutic effects on drug seeking. AB - Many abused drugs lead to changes in endogenous brain-derived neurotrophic factor (BDNF) expression in neural circuits responsible for addictive behaviors. BDNF is a known molecular mediator of memory consolidation processes, evident at both behavioral and neurophysiological levels. Specific neural circuits are responsible for storing and executing drug-procuring motor programs, whereas other neural circuits are responsible for the active suppression of these "seeking" systems. These seeking-circuits are established as associations are formed between drug-associated cues and the conditioned responses they elicit. Such conditioned responses (e.g. drug seeking) can be diminished either through a passive weakening of seeking- circuits or an active suppression of those circuits through extinction. Extinction learning occurs when the association between cues and drug are violated, for example, by cue exposure without the drug present. Cue exposure therapy has been proposed as a therapeutic avenue for the treatment of addictions. Here we explore the role of BDNF in extinction circuits, compared to seeking-circuits that "incubate" over prolonged withdrawal periods. We begin by discussing the role of BDNF in extinction memory for fear and cocaine-seeking behaviors, where extinction circuits overlap in infralimbic prefrontal cortex (PFC). We highlight the ability of estrogen to promote BDNF-like effects in hippocampal-prefrontal circuits and consider the role of sex differences in extinction and incubation of drug-seeking behaviors. Finally, we examine how opiates and alcohol "break the mold" in terms of BDNF function in extinction circuits. PMID- 25451121 TI - Neuroprotection by JM-1232(-) against oxygen-glucose deprivation-induced injury in rat hippocampal slice culture. AB - JM-1232(-) (JM) is a novel isoindoline derivative with sedative and hypnotic activities that are mediated by binding to the benzodiazepine site of the Gamma aminobutyric acid type A (GABAA) receptor. Although the neuroprotective effects of other GABAA receptor agonists are well known, there is no published report regarding JM. Thus, we examined the effects of JM on neurons exposed to oxygen glucose deprivation (OGD) using rat hippocampal slice cultures. Hippocampal slices were assigned to either control or JM-administered groups. To assess the neuroprotective effects of JM from necrotic changes, we measured the fluorescence of propidium iodide and compared the cell mortality 24h following OGD between the control and JM-administered groups. We also verified that the effects of JM were mediated by GABAA receptors by adding flumazenil, a benzodiazepine receptor antagonist, in the same experimental settings. JM, at concentrations of 250 and 500 uM, significantly reduced cell mortality in pyramidal neurons after OGD; however, flumazenil did not inhibit this effect. To analyze more immediate effects of JM, we next measured the fluorescence of Oregon Green 488 BAPTA-1 during the OGD and re-oxygenation periods, and evaluated changes in intracellular Ca(2+) in single CA1 pyramidal neurons. JM reduced the elevation of intracellular Ca(2+) concentration during OGD, and this effect was antagonized by flumazenil. These findings indicate that JM suppressed the elevation of intracellular Ca(2+) concentration during OGD through GABAA receptors, but its neuroprotective effects from necrotic changes also involve other unknown mechanisms. PMID- 25451122 TI - Maternal caffeine exposure alters neuromotor development and hippocampus acetylcholinesterase activity in rat offspring. AB - The objective of this study was to evaluate the effects of maternal caffeine intake on the neuromotor development of rat offspring and on acetylcholine degradation and acetylcholinesterase (AChE) expression in the hippocampus of 14 day-old infant rats. Rat dams were treated with caffeine (0.3g/L) throughout gestation and lactation until the pups were 14 days old. The pups were divided into three groups: (1) control, (2) caffeine, and (3) washout caffeine. The washout group received a caffeine solution until the seventh postnatal day (P7). Righting reflex (RR) and negative geotaxis (NG) were assessed to evaluate postural parameters as an index of neuromotor reflexes. An open-field (OF) test was conducted to assess locomotor and exploratory activities as well as anxiety like behaviors. Caffeine treatment increased both RR and NG latency times. In the OF test, the caffeine group had fewer outer crossings and reduced locomotion compared to control, while the washout group showed increased inner crossings in relation to the other groups and fewer rearings only in comparison to the control group. We found decreased AChE activity in the caffeine group compared to the other groups, with no alteration in AChE transcriptional regulation. Chronic maternal exposure to caffeine promotes important alterations in neuromotor development. These results highlight the ability of maternal caffeine intake to interfere with cholinergic neurotransmission during brain development. PMID- 25451123 TI - Dual role of Src kinase in governing neuronal survival. AB - BACKGROUND: Src-family kinases (SFKs) are involved in neuronal survival and their aberrant regulation contributes to neuronal death. However, how they control neuronal survival and death remains unclear. OBJECTIVE: To define the effect of inhibition of Src activity and expression on neuronal survival. RESULTS: In agreement with our previous findings, we demonstrated that Src was cleaved by calpain to form a 52-kDa truncated fragment in neurons undergoing excitotoxic cell death, and expression of the recombinant truncated Src fragment induced neuronal death. The data confirm that the neurotoxic signaling pathways are intact in the neurons we used for our study. To define the functional role of neuronal SFKs, we treated these neurons with SFK inhibitors and discovered that the treatment induced cell death, suggesting that the catalytic activity of one or more of the neuronal SFKs is critical to neuronal survival. Using small hairpin RNAs that suppress Src expression, we demonstrated that Src is indispensable to neuronal survival. Additionally, we found that neuronal death induced by expression of the neurotoxic truncated Src mutant, treatment of SFK inhibitors or knock-down of Src expression caused inhibition of the neuroprotective protein kinases Erk1/2, or Akt. CONCLUSIONS: Src is critical to both neuronal survival and death. Intact Src sustains neuronal survival. However, in the excitotoxic condition, calpain cleavage of Src generates a neurotoxic truncated Src fragment. Both intact Src and the neurotoxic truncated Src fragment exert their biological actions by controlling the activities of neuroprotective protein kinases. PMID- 25451124 TI - Orexin receptor activity in the basal forebrain alters performance on an olfactory discrimination task. AB - Cholinergic innervation of the prefrontal cortex is critical for various forms of cognition, although the efferent modulators contributing to acetylcholine (ACh) release are not well understood. The main source of cortical ACh, the basal forebrain, receives projections from lateral and perifornical hypothalamic neurons releasing the peptides orexin (orexin A; OxA, and orexin B; OxB), of which OxA is hypothesized to play a role in various cognitive functions. We sought to assess one such function known to be susceptible to basal forebrain cholinergic manipulation, olfactory discrimination acquisition, and reversal learning, in rats following intra-basal forebrain infusion of OxA or the orexin 1 receptor (OxR1) antagonist SB-334867. OxA administration facilitated, while OxR1 antagonism impaired performance on both the acquisition and reversal portions of the task. These data suggest that orexin acting in the basal forebrain may be important for cortical-dependant executive functions, possibly through the stimulation of cortical ACh release. PMID- 25451125 TI - Reduced late positivity in younger adults, but not older adults, during short term repetition. AB - Although word repetition was generally associated with enhanced amplitude of late positive complex (LPC), it seemed to yield attenuated LPC when words were repeated over short enough lags. However, this issue and its corresponding age effects have not been examined directly. For this purpose, EEG was recorded when young and elderly participants were required to make animacy decision during an incidental word repetition paradigm with words repeated after one, six, or nine intervening words. The results revealed that with one intervening word lag LPC decreased for nonliving words which supposed to be related to higher semantic activation levels reflected by larger N400, unchanged for living words associated with lower semantic incongruity activation levels, and increased in relatively longer lags (with six or nine intervening words) in the young group. Whereas, enhanced LPC was observed in the elderly in all conditions. Furthermore, significant age-related LPC repetition differences were revealed only with one intervening word lag for nonliving words. The results suggested that (1) how LPC changes after repetition is influenced by the initial incongruity activation levels of items and their thereafter maintenance in short-term memory; (2) the age-related differences result from the declining of short-term memory maintenance rather than from initial lower incongruity activations among elderly adults. PMID- 25451126 TI - An ERP investigation of orthographic priming with superset primes. AB - Prime stimuli formed by inserting unrelated letters in a given target word (called "superset" primes) provide a means to modify the relative positions of the letters shared by prime and target. Here we examined the time-course of superset priming effects in an ERP study using the sandwich-priming paradigm. We compared the effects of superset primes formed by the insertion of unrelated letters (e.g., maurkdet-MARKET), or by the insertion of hyphens (e.g., ma-rk-et MARKET), with identity priming (e.g., market-MARKET), all measured relative to unrelated control primes. Behavioral data revealed significantly greater priming in the hyphen-insert condition compared with the letter-insert condition. In the ERP signal, letter-insert priming emerged later than hyphen-insert priming and produced a reversed priming effect in the N400 time-window compared with the more typical N400 priming effects seen for both hyphen-insert priming and identity priming. The different pattern of priming effects seen for letter-insert primes and hyphen-insert primes suggests that compared with identity priming, letter superset priming reflects the joint influence of: (1) a disruption in letter position information, and (2) an inhibitory influence of mismatching letters. PMID- 25451128 TI - Pharmacological inactivation of the prelimbic cortex emulates compulsive reward seeking in rats. AB - Drug addiction is a chronic, relapsing brain disorder characterized by compulsive drug use. Contemporary addiction theories state that loss of control over drug use is mediated by a combination of several processes, including a transition from goal-directed to habitual forms of drug seeking and taking, and a breakdown of the prefrontally-mediated cognitive control over drug intake. In recent years, substantial progress has been made in the modelling of loss of control over drug use in animal models, but the neural substrates of compulsive drug use remain largely unknown. On the basis of their involvement in goal-directed behaviour, value-based decision making, impulse control and drug seeking behaviour, we identified the prelimbic cortex (PrL) and orbitofrontal cortex (OFC) as candidate regions to be involved in compulsive drug seeking. Using a conditioned suppression model, we have previously shown that prolonged cocaine self administration reduces the ability of a conditioned aversive stimulus to reduce drug seeking, which may reflect the unflagging pursuit of drugs in human addicts. Therefore, we tested the hypothesis that dysfunction of the PrL and OFC underlies loss of control over drug seeking behaviour, apparent as reduced conditioned suppression. Pharmacological inactivation of the PrL, using the GABA receptor agonists baclofen and muscimol, reduced conditioned suppression of cocaine and sucrose seeking in animals with limited self-administration experience. Inactivation of the OFC did not influence conditioned suppression, however. These data indicate that reduced neural activity in the PrL promotes persistent seeking behaviour, which may underlie compulsive aspects of drug use in addiction. PMID- 25451129 TI - Minocycline-induced attenuation of iron overload and brain injury after experimental germinal matrix hemorrhage. AB - Germinal matrix hemorrhage (GMH) is the most important adverse neurologic event during the newborn period. Evidence has shown that neonates with GMH and hydrocephalus have more severe damage compared to those with GMH alone. Our preliminary study demonstrated the role of iron in hydrocephalus and brain damage in adult rats following intraventricular hemorrhage. Therefore, the aim of the current study was to investigate iron accumulation and iron-handling proteins in a rat model of GMH and whether minocycline reduces iron overload after GMH and iron-induced brain injury in vivo. This study was divided into two parts. In the first part, rats received either a needle insertion or an intracerebral injection of 0.3 U of clostridial collagenase VII-S. Brain iron and brain iron handling proteins (heme oxygenase-1 and ferritin) were measured. In the second part, rats with a GMH were treated with minocycline or vehicle. Brain edema, brain cell death, hydrocephalus, iron-handling proteins and long-term motor function were examined. The result showed iron accumulation and upregulation of iron-handling proteins after GMH. Minocycline treatment significantly reduced GMH-induced brain edema, hydrocephalus and brain damage. Minocycline also suppressed upregulation of ferritin after GMH. In conclusion, the current study found that iron plays a role in brain injury following GMH and that minocycline reduces iron overload after GMH and iron-induced brain injury. PMID- 25451127 TI - Chronic methamphetamine abuse and corticostriatal deficits revealed by neuroimaging. AB - Despite aggressive efforts to contain it, methamphetamine use disorder continues to be major public health problem; and with generic behavioral therapies still the mainstay of treatment for methamphetamine abuse, rates of attrition and relapse remain high. This review summarizes the findings of structural, molecular, and functional neuroimaging studies of methamphetamine abusers, focusing on cortical and striatal abnormalities and their potential contributions to cognitive and behavioral phenotypes that can serve to promote compulsive drug use. These studies indicate that individuals with a history of chronic methamphetamine abuse often display several signs of corticostriatal dysfunction, including abnormal gray- and white-matter integrity, monoamine neurotransmitter system deficiencies, neuroinflammation, poor neuronal integrity, and aberrant patterns of brain connectivity and function, both when engaged in cognitive tasks and at rest. More importantly, many of these neural abnormalities were found to be linked with certain addiction-related phenotypes that may influence treatment response (e.g., poor self-control, cognitive inflexibility, maladaptive decision making), raising the possibility that they may represent novel therapeutic targets. PMID- 25451130 TI - In vitro discrimination of the role of LRP1 at the BBB cellular level: focus on brain capillary endothelial cells and brain pericytes. AB - Several studies have demonstrated that the blood-brain barrier (BBB) (dynamic cellular complex composed by brain capillary endothelial cells (BCECs) and surrounded by astrocytic end feet and pericytes) regulates the exchanges of amyloid beta (Abeta) peptide between the blood and the brain. Deregulation of these exchanges seems to be a key trigger for the brain accumulation of Abeta peptide observed in Alzheimer's disease (AD). Whereas the involvement of receptor for advanced glycation end-products in Abeta peptide transcytosis has been demonstrated in our laboratory, low-density lipoprotein receptor's role at the cellular level needs to be clarified. For this, we used an in vitro BBB model that consists of a co-culture of bovine BCECs and rat glial cells. This model has already been used to characterize low-density lipoprotein receptor-related peptide (LRP)'s involvement in the transcytosis of molecules such as tPA and angiopep-2. Our results suggest that Abeta peptide efflux across the BCEC monolayer involves a transcellular transport. However, the experiments with RAP discard an involvement of LRP family members at BCECs level. In contrast, our results show a strong transcriptional expression of LRP1 in pericytes and suggest its implication in Abeta endocytosis. Moreover, the observations of pericytes contraction and local downregulation of LRP1 in response to Abeta treatment opens up perspectives for studying this cell type with respect to Abeta peptide metabolism and AD. PMID- 25451132 TI - Neurotrophic factors for spinal cord repair: Which, where, how and when to apply, and for what period of time? AB - A variety of neurotrophic factors have been used in attempts to improve morphological and behavioural outcomes after experimental spinal cord injury (SCI). Here we review many of these factors, their cellular targets, and their therapeutic impact on spinal cord repair in different, primarily rodent, models of SCI. A majority of studies report favourable outcomes but results are by no means consistent, thus a major aim of this review is to consider how best to apply neurotrophic factors after SCI to optimize their therapeutic potential. In addition to which factors are chosen, many variables need be considered when delivering trophic support, including where and when to apply a given factor or factors, how such factors are administered, at what dose, and for how long. Overall, the majority of studies have applied neurotrophic support in or close to the spinal cord lesion site, in the acute or sub-acute phase (0-14 days post injury). Far fewer chronic SCI studies have been undertaken. In addition, comparatively fewer studies have administered neurotrophic factors directly to the cell bodies of injured neurons; yet in other instructive rodent models of CNS injury, for example optic nerve crush or transection, therapies are targeted directly at the injured neurons themselves, the retinal ganglion cells. The mode of delivery of neurotrophic factors is also an important variable, whether delivered by acute injection of recombinant proteins, sub-acute or chronic delivery using osmotic minipumps, cell-mediated delivery, delivery using polymer release vehicles or supporting bridges of some sort, or the use of gene therapy to modify neurons, glial cells or precursor/stem cells. Neurotrophic factors are often used in combination with cell or tissue grafts and/or other pharmacotherapeutic agents. Finally, the dose and time-course of delivery of trophic support should ideally be tailored to suit specific biological requirements, whether they relate to neuronal survival, axonal sparing/sprouting, or the long-distance regeneration of axons ending in a different mode of growth associated with terminal arborization and renewed synaptogenesis. This article is part of a Special Issue entitled SI: Spinal cord injury. PMID- 25451133 TI - Maternal stress, nutrition and physical activity: Impact on immune function, CNS development and psychopathology. AB - Evidence suggests that maternal and fetal immune dysfunction may impact fetal brain development and could play a role in neurodevelopmental disorders, although the definitive pathophysiological mechanisms are still not completely understood. Stress, malnutrition and physical inactivity are three maternal behavioral lifestyle factors that can influence immune and central nervous system (CNS) functions in both the mother and fetus, and may therefore, increase risk for neurodevelopmental/psychiatric disorders. First, we will briefly review some aspects of maternal-fetal immune system interactions and development of immune tolerance. Second, we will discuss the bidirectional communication between the immune system and CNS and the pathways by which immune dysfunction could contribute to neurodevelopmental disorders. Third, we will discuss the effects of prenatal stress and malnutrition (over and undernutrition) on perinatal programming of the CNS and immune system, and how this might influence neurodevelopment. Finally, we will discuss the beneficial impact of physical fitness during pregnancy on the maternal-fetal unit and infant and how regular physical activity and exercise can be an effective buffer against stress- and inflammatory-related disorders. Although regular physical activity has been shown to promote neuroplasticity and an anti-inflammatory state in the adult, there is a paucity of studies evaluating its impact on CNS and immune function during pregnancy. Implementing stress reduction, proper nutrition and ample physical activity during pregnancy and the childbearing period may be an efficient strategy to counteract the impact of maternal stress and malnutrition/obesity on the developing fetus. Such behavioral interventions could have an impact on early development of the CNS and immune system and contribute to the prevention of neurodevelopmental and psychiatric disorders. Further research is needed to elucidate this relationship and the underlying mechanisms of protection. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease. PMID- 25451134 TI - Cell based advanced therapeutic medicinal products for bone repair: Keep it simple? AB - The development of cell based advanced therapeutic medicinal products (ATMPs) for bone repair has been expected to revolutionize the health care system for the clinical treatment of bone defects. Despite this great promise, the clinical outcomes of the few cell based ATMPs that have been translated into clinical treatments have been far from impressive. In part, the clinical outcomes have been hampered because of the simplicity of the first wave of products. In response the field has set-out and amassed a plethora of complexities to alleviate the simplicity induced limitations. Many of these potential second wave products have remained "stuck" in the development pipeline. This is due to a number of reasons including the lack of a regulatory framework that has been evolving in the last years and the shortage of enabling technologies for industrial manufacturing to deal with these novel complexities. In this review, we reflect on the current ATMPs and give special attention to novel approaches that are able to provide complexity to ATMPs in a straightforward manner. Moreover, we discuss the potential tools able to produce or predict 'goldilocks' ATMPs, which are neither too simple nor too complex. PMID- 25451131 TI - Leveraging biomedical informatics for assessing plasticity and repair in primate spinal cord injury. AB - Recent preclinical advances highlight the therapeutic potential of treatments aimed at boosting regeneration and plasticity of spinal circuitry damaged by spinal cord injury (SCI). With several promising candidates being considered for translation into clinical trials, the SCI community has called for a non-human primate model as a crucial validation step to test efficacy and validity of these therapies prior to human testing. The present paper reviews the previous and ongoing efforts of the California Spinal Cord Consortium (CSCC), a multidisciplinary team of experts from 5 University of California medical and research centers, to develop this crucial translational SCI model. We focus on the growing volumes of high resolution data collected by the CSCC, and our efforts to develop a biomedical informatics framework aimed at leveraging multidimensional data to monitor plasticity and repair targeting recovery of hand and arm function. Although the main focus of many researchers is the restoration of voluntary motor control, we also describe our ongoing efforts to add assessments of sensory function, including pain, vital signs during surgery, and recovery of bladder and bowel function. By pooling our multidimensional data resources and building a unified database infrastructure for this clinically relevant translational model of SCI, we are now in a unique position to test promising therapeutic strategies' efficacy on the entire syndrome of SCI. We review analyses highlighting the intersection between motor, sensory, autonomic and pathological contributions to the overall restoration of function. This article is part of a Special Issue entitled SI: Spinal cord injury. PMID- 25451135 TI - Mesenchymal stromal cells for sphincter regeneration. AB - Stress urinary incontinence (SUI), defined as the involuntary loss of considerable amounts of urine during increased abdominal pressure (exertion, effort, sneezing, coughing, etc.), is a severe problem to the individuals affected and a significant medical, social and economic challenge. SUI is associated with pelvic floor debility, absence of detrusor contraction, or a loss of control over the sphincter muscle apparatus. The pathology includes an increasing loss of muscle cells, replacement of muscular tissue with fibrous tissue, and general aging associated processes of the sphincter complex. When current therapies fail to cure or improve SUI, application of regeneration competent cells may be an alternative therapeutic option. Here we discuss different aspects of the biology of mesenchymal stromal cells, which are relevant to their clinical applications and for regenerating the sphincter complex. However, there are reports in favor of and against cell-based therapies. We therefore summarize the potential and the risks of cell-based therapies for the treatment of SUI. PMID- 25451136 TI - Formulation and stabilization of recombinant protein based virus-like particle vaccines. AB - Vaccine formulation development has traditionally focused on improving antigen storage stability and compatibility with conventional adjuvants. More recently, it has also provided an opportunity to modify the interaction and presentation of an antigen/adjuvant to the immune system to better stimulate the desired immune responses for maximal efficacy. In the last decade, there has been a paradigm shift in vaccine antigen and formulation design involving an improved physical understanding of antigens and a better understanding of the immune system. In addition, the discovery of novel adjuvants and delivery systems promises to further improve the design of new, more effective vaccines. Here we describe some of the fundamental aspects of formulation design applicable to virus-like particle based vaccine antigens (VLPs). Case studies are presented for commercially approved VLP vaccines as well as some investigational VLP vaccine candidates. An emphasis is placed on the biophysical analysis of vaccines to facilitate formulation and stabilization of these particulate antigens. PMID- 25451137 TI - Inhaled formulations and pulmonary drug delivery systems for respiratory infections. AB - Respiratory infections represent a major global health problem. They are often treated by parenteral administrations of antimicrobials. Unfortunately, systemic therapies of high-dose antimicrobials can lead to severe adverse effects and this calls for a need to develop inhaled formulations that enable targeted drug delivery to the airways with minimal systemic drug exposure. Recent technological advances facilitate the development of inhaled anti-microbial therapies. The newer mesh nebulisers have achieved minimal drug residue, higher aerosolisation efficiencies and rapid administration compared to traditional jet nebulisers. Novel particle engineering and intelligent device design also make dry powder inhalers appealing for the delivery of high-dose antibiotics. In view of the fact that no new antibiotic entities against multi-drug resistant bacteria have come close to commercialisation, advanced formulation strategies are in high demand for combating respiratory 'super bugs'. PMID- 25451138 TI - Delivery systems for the treatment of degenerated intervertebral discs. AB - The intervertebral disc (IVD) is the most avascular and acellular tissue in the body and therefore prone to degeneration. During IVD degeneration, the balance between anabolic and catabolic processes in the disc is deregulated, amongst others leading to alteration of extracellular matrix production, abnormal enzyme activities and production of pro-inflammatory substances like cytokines. The established treatment strategy for IVD degeneration consists of physiotherapy, pain medication by drug therapy and if necessary surgery. This approach, however, has shown limited success. Alternative strategies to increase and prolong the effects of bioactive agents and to reverse the process of IVD degeneration include the use of delivery systems for drugs, proteins, cells and genes. In view of the specific anatomy and physiology of the IVD and depending on the strategy of the therapy, different delivery systems have been developed which are reviewed in this article. PMID- 25451139 TI - CNS involvement in pancreatic adenocarcinoma: a report of eight cases from the Johns Hopkins Hospital and review of literature. AB - PURPOSE: CNS metastasis of pancreatic cancer is extremely rare, although systemic metastasis is very common. We present eight such cases with various forms of nervous system involvement. METHODS: Data was gathered from chart review of 800 patients with pancreatic cancer treated between 2004 and 2012 of which eight patients are described with CNS metastases. RESULTS: The median age of patients was 61.5 years and the median time to develop CNS metastasis was 29 months. Interestingly, two patients had no other sites of metastasis. The treatment modalities tried included resection followed by radiation, resection alone, or whole brain radiation. PMID- 25451140 TI - Interaction between nickel and cobalt toxicity in Enchytraeus crypticus is due to competitive uptake. AB - Uptake and toxicity of Ni-Co mixtures in Enchytraeus crypticus were determined after 4 d, 7 d, 10 d, and 14 d exposure. Generally, body concentrations of Ni and Co increased with increasing exposure concentrations. Ni body concentration was significantly reduced in the presence of Co, whereas Ni only marginally affected Co uptake. When expressed as free ion activities, individual toxicity of Ni and Co increased with time, with median lethal concentrations (LC50) decreasing from 78.3 MUM and 511 MUM at 4 d to 40.4 MUM and 393 MUM at 14 d, respectively. When expressed as body concentrations, LC50BodyNi remained constant with time whereas LC50BodyCo increased during the first 7 d but remained stable afterwards. As identified by the MIXTOX model, interactions between Ni and Co were mainly antagonistic when based on free ion activities, however, no interaction was observed when based on body concentrations. A process-based model, incorporating exposure time to analyze the mechanisms underlying the dynamic mixture toxicity confirmed the differences in toxicokinetics of the 2 metals. The author's findings suggest that body concentrations, which incorporate bioaccumulation processes, are time-independent and can act as a more constant indicator of metal toxicity. The observed antagonism was mainly caused by competition between Co and Ni for binding sites and subsequent inhibition of Ni uptake. This competitive interaction occurred at the uptake level (toxicokinetics), but not at the target level (toxicodynamics). PMID- 25451141 TI - Quantum chemical investigation of the primary thermal pyrolysis reactions of the sodium carboxylate group in a brown coal model. AB - The primary pyrolysis mechanisms of the sodium carboxylate group in sodium benzoate-used as a model compound of brown coal-were studied by performing quantum chemical computations using B3LYP and the CBS method. Various possible reaction pathways involving reactions such as unimolecular and bimolecular decarboxylation and decarbonylation, crosslinking, and radical attack in the brown coal matrix were explored. Without the participation of reactive radicals, unimolecular decarboxylation to release CO2 was calculated to be the most energetically favorable primary reaction pathway at the B3LYP/6-311+G (d, p) level of theory, and was also found to be more energetically favorable than decarboxylation of an carboxylic acid group. When CBS-QBS results were included, crosslinking between the sodium carboxylate group and the carboxylic acid and the decarboxylation of the sodium carboxylate group (catalyzed by the phenolic hydroxyl group) were found to be possible; this pathway competes with unimolecular decarboxylation of the sodium carboxylate group. Provided that H and CH3 radicals are present in the brown coal matrix and can access the sodium carboxylate group, accelerated pyrolysis of the sodium carboxylate group becomes feasible, leading to the release of an Na atom or an NaCO2 radical at the B3LYP/6 311+G (d, p) or CBS-QB3 level of theory, respectively. PMID- 25451142 TI - The structure, stability, and electronic properties of ultra-thin BC2N nanotubes: a first-principles study. AB - Rapid developments of the silicon electronics industry have close to the physical limits and nanotube materials are the ideal materials to replace silicon for the preparation of next generation electronic devices. Boron-carbon-nitrogen nanotubes (BCNNT) can be formed by joining carbon nanotube (CNT) and boron nitride nanotube (BNNT) segments, and BC2N nanotubes have been widely and deeply studied. Here, we employed first-principles calculations based on density function theory (DFT) to study the structure, stability, and electronic properties of ultra thin (4 A diameter) BC2N nanotubes. Our results showed that the cross sections of BC2N nanotubes can transform from round to oval when CNT and BNNT segments are parallel to the tube axis. It results when the curvature of BNNT segments become larger than CNT segments. Further, we found the stability of BC2N nanotubes is sensitive to the number of B-N bonds, and the phase segregation of BNNT and CNT segments is energetically favored. We also obtained that all (3,3) BC2N nanotubes are semiconductor, whereas (5,0) BC2N nanotubes are conductor when CNT and BNNT segments are perpendicular to the tube axis; and semiconductor when CNT and BNNT segments are parallel to the tube axis. These electronic properties are abnormal when compared to the relative big ones. PMID- 25451143 TI - Structure, vibrational, and optical properties of platinum cluster: a density functional theory approach. AB - Using density functional theory, stability, chemical, and optical properties of small platinum clusters, Ptn (n = 2 to 10) have been investigated. An attempt has been made to establish a correlation between stability and chemical reactivity parameters. The calculated geometries are in agreement with the available experimental and theoretical results. The atom addition energy change (DeltaE1) and stability function (DeltaE2) reveal that Pt7 is more stable than its neighboring clusters. Very good agreement of the calculated electron affinity with the available experimental results has been observed. The polarizability of the Ptn clusters depends almost linearly on the number of atoms. A correlation between the static polarizability and ionization potential is found, paving a way to calculate polarizabilty of larger clusters from their ionization potential. The calculated vibrational frequencies are compared with available experimental and theoretical results and good agreement between them has been established. In general, the prominent peak of molar absorption coefficient is shifting toward the lower energy side when cluster size grows. Our DOS calculation suggests that d orbital is primarily responsible for HOMO position and s orbital is responsible for LUMO position. PMID- 25451144 TI - Response to: Health related quality of life in burn patients - a review of the literature. PMID- 25451145 TI - A prospective observational study investigating all children presenting to a specialty paediatric burns centre. AB - AIM AND METHOD: The aim of this study was to describe the mechanism of injury and outcome of all children who presented to The Stuart Pegg Paediatric Burns Centre (SPPBC) with a burn injury in the year 2013. A detailed proforma was completed prospectively at time of presentation to hospital. RESULTS: During the one year period, 758 children with a median age of 2 years 3 months presented with a burn injury. Overall, 12.7% of patients (n=96) were initially treated as inpatients. Similarities existed between in and outpatients. Over half the children admitted had a scald injury (53.1%). Whilst slightly higher than the outpatient scald rate of 43.1% there was no statistical significant difference. However, there was a significant difference between inpatients and outpatients with respect to other mechanisms of injury. Contact burns were under represented in inpatients (27.1%) compared to outpatients (44.5%), p<0.05. In contrast, flame burns were over represented in inpatients, 11.5% compared to outpatients, 2.9% (p<0.05). CONCLUSION: Paediatric burns are a common cause of childhood injury. The majority of children present with small to medium sized partial thickness injuries and are managed as outpatients. In order to understand the true impact of paediatric burn injury and to develop appropriate targeted injury prevention campaigns, data repositories must include detailed information regarding outpatient paediatric burns. PMID- 25451147 TI - Efficacy of aquacel Ag dressing in the treatment of deep burns in children. PMID- 25451146 TI - Feasibility study of an active wound dressing based on hollow fiber membranes in a porcine wound model. AB - INVESTIGATION: A novel active wound dressing (AWD) concept based on a microporous hollow fiber membrane network was investigated in an animal model. It provides a local solution-perfused environment for regenerative cell nutrition, wound irrigation, debris removal, electrolyte balancing, pH regulation, and topical antibiosis. The device is capable of supplying soluble factors, as tested experimentally for the recombinant human growth and differentiation factor-5 (rhGDF-5). METHODS: Following in vitro studies for rhGDF-5 using primary human keratinocytes and dermal fibroblasts, we employed a porcine partial thickness wound model with five distinct wounds on each back of n=8 pigs. Four wound groups were perfused differently over 9 days and compared with a negative control wound without perfusion: (1) 1% trehalose solution, pH 5.5; (2) rhGDF-5 (150 ng/ml) in 1% trehalose solution, pH 5.5; (3) nutrition solution; and (4) rhGDF-5 (150 ng/ml) in nutrition solution with 1% trehalose, pH 5.5. RESULTS: Promoted wound healing was observed within group 1 and more pronounced within group 2. Groups 3 and 4, with nutrition solution, showed significant adverse effects on wound healing (p<0.05). CONCLUSIONS: The investigated AWD concept appears to be an interesting therapeutic tool to study further wound healing support. Additionally, topical application of rhGDF-5 could be promising. PMID- 25451148 TI - Alteration of biomechanical properties of burned skin. AB - BACKGROUND: The prevalence of burns in the general population is high. Despite new research findings, skin burns and its resulting tissue damage are still not entirely understood. In particular, little is known about the depth-dependent alteration of skin biomechanical properties of these wounds. METHODS: Thirty-six burn wounds with six different depths were generated on the abdomen of six Gottingen minipigs. The alteration of skin biomechanical properties was evaluated objectively after 15 and 360 min using a Cutometer device. Biopsies for histological evaluation were taken and the depth of burn was correlated with biomechanical properties. RESULTS: Firmness of skin (R0), overall elasticity (R8) and calculated elasticity (Ue) demonstrated a continuous decrease with an increasing depth of burn 15 min after wound generation. Gross elasticity (R2), net elasticity (R5) and amount of elasticity of the whole curve (R7), however, showed an increase of values with increasing depth of injury. A further decrease of elasticity was demonstrated 360 min after wound generation. CONCLUSION: The alteration of skin biomechanical properties is a function of damaged tissue structures. The presented results demonstrate a depth-dependent decrease of principal elastic parameters with an increasing depth of burn and the results indicate progressive tissue damage over the time. PMID- 25451149 TI - Our experiences on the reconstruction of lateral scalp burn alopecia with tissue expanders. AB - INTRODUCTION: Cicatricial alopecia is a form of hair loss that causes both cosmetic and psychological concerns. Although tissue expanders are the common approach to reconstruction, no algorithm exists in the literature for this process. In this study, it was aimed to create an algorithm for the reconstruction of lateral scalp alopecias with the goal to achieve better and standardized results. MATERIALS AND METHODS: Lateral scalp alopecias were divided into three groups: total lateral alopecia (type I), temporal and sideburn alopecia (type II), and sideburn alopecia (type III). Tissue expanders were placed at the parieto-occipital area in type I defects, parietal area in type II defects, and the temporal region in type III defects. Tissue expanders were used to create flaps that were advanced with 60 degrees rotation, 90 degrees rotation, and no rotation for type I, II, and III defects, respectively. RESULTS: Fifteen patients were treated with this algorithm. Using this simple approach, we achieved natural, standardized aesthetic results for each patient, all of whom were satisfied with the final results. CONCLUSION: Although the number of case were limited, the ideal and standardized cosmetic results could be obtained by this approach. PMID- 25451150 TI - WITHDRAWN: Enhanced Detection and Phenotypic and Karyotypic in Situ Characterization of Circulating Tumor Cells. AB - Available online October 16, 2014 This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25451152 TI - Mechanisms of aberrant organization of growth plates in conditional transgenic mouse model of spondyloepiphyseal dysplasia associated with the R992C substitution in collagen II. AB - Mutations in collagen II, a main structural protein of cartilage, are associated with various forms of spondyloepiphyseal dysplasia (SED), whose main features include aberrations of linear growth. Here, we analyzed the pathomechanisms responsible for growth alterations in transgenic mice with conditional expression of the R992C collagen II mutation. Specifically, we studied the alterations of the growth plates of mutant mice in which chondrocytes lacked their typical columnar arrangement. Our studies demonstrated that chondrocytes expressing the thermolabile R992C mutant collagen II molecules endured endoplasmic reticulum stress, had atypical polarization, and had reduced proliferation. Moreover, we demonstrated aberrant organization and morphology of primary cilia. Analyses of the extracellular collagenous deposits in mice expressing the R992C mutant collagen II molecules indicated their poor formation and distribution. By contrast, transgenic mice expressing wild-type collagen II and mice in which the expression of the transgene encoding the R992C collagen II was switched off were characterized by normal growth, and the morphology of their growth plates was correct. Our study with the use of a conditional mouse SED model not only indicates a direct relation between the observed aberration of skeletal tissues and the presence of mutant collagen II, but also identifies cellular and matrix elements of the pathomechanism of SED. PMID- 25451151 TI - Novel roles for caspase-8 in IL-1beta and inflammasome regulation. AB - Caspase-8 is an initiator and apical activator caspase that plays a central role in apoptosis. Caspase-8-deficient mice are embryonic lethal, which makes study of caspase-8 in primary immune cells difficult. Recent advances have rescued caspase 8-deficient mice by crossing them to mice deficient in receptor-interacting serine-threonine kinase 3 (RIPK3). These genetic tools have made it possible to study the role of caspase-8 in vivo and in primary immune cells. Several recent studies have identified novel roles for caspase-8 in modulating IL-1beta and inflammation, showing that caspase-8 directly regulates IL-1beta independent of inflammasomes or indirectly through the regulation of inflammasomes, depending on the stimulus or stimuli that initiate the signaling cascade. Here, we address recent findings on caspase-8 and its role in modulating IL-1beta and inflammation. PMID- 25451154 TI - Bone marrow mesenchymal stem cells provide an antibiotic-protective niche for persistent viable Mycobacterium tuberculosis that survive antibiotic treatment. AB - During tuberculosis (TB), some Mycobacterium tuberculosis bacilli persist in the presence of an active immunity and antibiotics that are used to treat the disease. Herein, by using the Cornell model of TB persistence, we further explored our recent finding that suggested that M. tuberculosis can escape therapy by residing in the bone marrow (BM) mesenchymal stem cells. We initially showed that M. tuberculosis rapidly disseminates to the mouse BM after aerosol exposure and maintained a stable burden for at least 220 days. In contrast, in the lungs, the M. tuberculosis burden peaked at 28 days and subsequently declined approximately 10-fold. More important, treatment of the mice with the antibiotics rifampicin and isoniazid, as expected, resulted in effective clearance of M. tuberculosis from the lungs and spleen. In contrast, M. tuberculosis persisted, albeit at low numbers, in the BM of antibiotic-treated mice. Moreover, most viable M. tuberculosis was recovered from the bone marrow CD271(+)CD45(-) enriched cell fraction, and only few viable bacteria could be isolated from the CD271(-)CD45(+) cell fraction. These results clearly show that BM mesenchymal stem cells provide an antibiotic-protective niche for M. tuberculosis and suggest that unraveling the mechanisms underlying this phenomenon will enhance our understanding of M. tuberculosis persistence in treated TB patients. PMID- 25451155 TI - Antiphospholipid antibodies promote tissue factor-dependent angiogenic switch and tumor progression. AB - Progression to an angiogenic state is a critical event in tumor development, yet few patient characteristics have been identified that can be mechanistically linked to this transition. Antiphospholipid autoantibodies (aPLs) are prevalent in many human cancers and can elicit proangiogenic expression in several cell types, but their role in tumor biology is unknown. Herein, we observed that the elevation of circulating aPLs among breast cancer patients is specifically associated with invasive-stage tumors. By using multiple in vivo models of breast cancer, we demonstrated that aPL-positive IgG from patients with autoimmune disease rapidly accelerates tumor angiogenesis and consequent tumor progression, particularly in slow-growing avascular tumors. The action of aPLs was local to the tumor site and elicited leukocytic infiltration and tumor invasion. Tumor cells treated with aPL-positive IgG expressed multiple proangiogenic genes, including vascular endothelial growth factor, tissue factor (TF), and colony stimulating factor 1. Knockdown and neutralization studies demonstrated that the effects of aPLs on tumor angiogenesis and growth were dependent on tumor cell derived TF. Tumor-derived TF was essential for the development of pericyte coverage of tumor microvessels and aPL-induced tumor cell expression of chemokine ligand 2, a mediator of pericyte recruitment. These findings identify antiphospholipid autoantibodies as a potential patient-specific host factor promoting the transition of indolent tumors to an angiogenic malignant state through a TF-mediated pathogenic mechanism. PMID- 25451153 TI - Multiple requirements of the focal dermal hypoplasia gene porcupine during ocular morphogenesis. AB - Wnt glycoproteins control key processes during development and disease by activating various downstream pathways. Wnt secretion requires post-translational modification mediated by the O-acyltransferase encoded by the Drosophila porcupine homolog gene (PORCN). In humans, PORCN mutations cause focal dermal hypoplasia (FDH, or Goltz syndrome), an X-linked dominant multisystem birth defect that is frequently accompanied by ocular abnormalities such as coloboma, microphthalmia, or even anophthalmia. Although genetic ablation of Porcn in mouse has provided insight into the etiology of defects caused by ectomesodermal dysplasia in FDH, the requirement for Porcn and the actual Wnt ligands during eye development have been unknown. In this study, Porcn hemizygosity occasionally caused ocular defects reminiscent of FDH. Conditional inactivation of Porcn in periocular mesenchyme led to defects in mid- and hindbrain and in craniofacial development, but was insufficient to cause ocular abnormalities. However, a combination of conditional Porcn depletion in optic vesicle neuroectoderm, lens, and neural crest-derived periocular mesenchyme induced severe eye abnormalities with high penetrance. In particular, we observed coloboma, transdifferentiation of the dorsal and ventral retinal pigment epithelium, defective optic cup periphery, and closure defects of the eyelid, as well as defective corneal morphogenesis. Thus, Porcn is required in both extraocular and neuroectodermal tissues to regulate distinct Wnt-dependent processes during morphogenesis of the posterior and anterior segments of the eye. PMID- 25451156 TI - Glycogen synthase kinase 3alpha deficiency attenuates atherosclerosis and hepatic steatosis in high fat diet-fed low density lipoprotein receptor-deficient mice. AB - Studies have implicated signaling through glycogen synthase kinase (GSK) 3alpha/beta in the activation of pro-atherogenic pathways and the accelerated development of atherosclerosis. By using a mouse model, we examined the role of GSK3alpha in the development and progression of accelerated atherosclerosis. We crossed Gsk3a/GSK3alpha-knockout mice with low-density lipoprotein receptor (Ldlr) knockout mice. Five-week-old Ldlr(-/-);Gsk3a(+/+), Ldlr(-/-);Gsk3a(+/-), and Ldlr(-/-);Gsk3a(-/-) mice were fed a chow diet or a high-fat diet for 10 weeks and then sacrificed. GSK3alpha deficiency had no detectible effect on any measured parameters in chow-fed mice. High-fat-diet fed Ldlr(-/-) mice that were deficient for GSK3alpha had significantly less hepatic lipid accumulation and smaller atherosclerotic lesions (60% smaller in Ldlr(-/-);Gsk3a(+/-) mice, 80% smaller in Ldlr(-/-);Gsk3a(-/-) mice; P < 0.05), compared with Ldlr(-/ );Gsk3a(+/+) controls. GSK3alpha deficiency was associated with a significant increase in plasma IL-10 concentration and IL-10 expression in isolated macrophages. A twofold to threefold enhancement in endoplasmic reticulum stress induced IL-10 expression was observed in Thp-1-derived macrophages that were pretreated with the GSK3alpha/beta inhibitor CT99021. Together, these results suggest that GSK3alpha plays a pro-atherogenic role, possibly by mediating the effects of endoplasmic reticulum stress in the activation of pro-atherogenic pathways. PMID- 25451157 TI - In vitro metabolism of an estrogen-related receptor gamma modulator, GSK5182, by human liver microsomes and recombinant cytochrome P450s. AB - GSK5182 (4-[(Z)-1-[4-(2-dimethylaminoethyloxy)phenyl]-hydroxy-2-phenylpent-1 enyl]phenol) is a specific inverse agonist for estrogen-related receptor gamma, a member of the orphan nuclear receptor family that has important functions in development and homeostasis. This study was performed to elucidate the metabolites of GSK5182 and to characterize the enzymes involved in its metabolism. Incubation of human liver microsomes with GSK5182 in the presence of NADPH resulted in the formation of three metabolites, M1, M2 and M3. M1 and M3 were identified as N-desmethyl-GSK5182 and GSK5182 N-oxide, respectively, on the basis of liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. M2 was suggested to be hydroxy-GSK5182 through interpretation of its MS/MS fragmentation pattern. In addition, the specific cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) isoforms responsible for GSK5182 oxidation to the three metabolites were identified using a combination of correlation analysis, chemical inhibition in human liver microsomes and metabolism by expressed recombinant P450 and FMO isoforms. GSK5182 N-demethylation and hydroxylation is mainly mediated by CYP3A4, whereas FMO1 and FMO3 contribute to the formation of GSK5182 N-oxide from GSK5182. The present data will be useful for understanding the pharmacokinetics and drug interactions of GSK5182 in vivo. PMID- 25451158 TI - Primary immunodeficiencies in the Netherlands: national patient data demonstrate the increased risk of malignancy. AB - PURPOSE: To analyze the data of the national registry of all Dutch primary immune deficiency (PID) patients, according to the European Society for Immunodeficiencies (ESID) definitions. RESULTS: In the Netherlands, 745 patients had been registered between 2009 and 2012. An overall prevalence of 4.0 per 100,000 inhabitants was calculated. The most prevalent PID was 'predominantly antibody disorder (PAD)' (60.4%). In total, 118 transplantations were reported, mostly hematopoietic stem cell transplantations (HSCT). Almost 10% of the PID patients suffered from a malignancy, in particular 'lymphoma' and 'skin cancer'. Compared to the general Dutch population, the relative risk of developing any malignancy was 2.3-fold increased, with a >10-fold increase for some solid tumors (thymus, endocrine organs) and hematological disease (lymphoma, leukemia), varying per disease category. CONCLUSIONS: The incidence rate and characteristics of PID in the Netherlands are similar to those in other European countries. Compared to the general population, PID patients carry an increased risk to develop a malignancy. PMID- 25451159 TI - BCG-induced trained immunity in NK cells: Role for non-specific protection to infection. AB - Adaptive features of innate immunity, also termed 'trained immunity', have recently been shown to characterize monocytes of BCG vaccinated healthy volunteers. Trained immunity leads to increased cytokine production in response to non-related pathogens via epigenetic reprogramming of monocytes. Recently, memory-like properties were also observed in NK cells during viral infections, but it is unknown if memory properties of NK cells contribute to trained immunity due to BCG vaccination. BCG vaccination of healthy volunteers increased proinflammatory cytokine production following ex vivo stimulation of NK cells with mycobacteria and other unrelated pathogens up until at least three months after vaccination. In addition, in a murine model of disseminated candidiasis, BCG vaccination led to an increased survival in SCID mice, which was partially dependent on NK cells. These findings suggest that NK cells may contribute to the non-specific (heterologous) beneficial effects of BCG vaccination. PMID- 25451160 TI - A novel homozygous Fas ligand mutation leads to early protein truncation, abrogation of death receptor and reverse signaling and a severe form of the autoimmune lymphoproliferative syndrome. AB - We report a novel type of mutation in the death ligand FasL that was associated with a severe phenotype of the autoimmune lymphoproliferative syndrome in two patients. A frameshift mutation in the intracellular domain led to complete loss of FasL expression. Cell death signaling via its receptor and reverse signaling via its intracellular domain were completely abrogated. In vitro lymphocyte proliferation induced by weak T cell receptor stimulation could be blocked and cell death was induced by engagement of FasL in T cells derived from healthy individuals and a heterozygous carrier, but not in FasL-deficient patient derived cells. Expression of genes implicated in lymphocyte proliferation and activation (CCND1, NFATc1, NF-kappaB1) was increased in FasL-deficient T cells and could not be downregulated by FasL engagement as in healthy cells. Our data thus suggest, that deficiency in FasL reverse signaling may contribute to the clinical lymphoproliferative phenotype of ALPS. PMID- 25451161 TI - A chimeric human-mouse model of Sjogren's syndrome. AB - Despite recent advances in the understanding of Sjogren's Syndrome (SjS), the pathogenic mechanisms remain elusive and an ideal model for early drug discovery is not yet available. To establish a humanized mouse model of SjS, peripheral blood mononuclear cells (PBMCs) from healthy volunteers or patients with SjS were transferred into immunodeficient NOD-scid IL-2rgamma(null) mouse recipients to produce chimeric mice. While no difference was observed in the distribution of cells, chimeric mice transferred with PBMCs from SjS patients produced enhanced cytokine levels, most significantly IFN-gamma and IL-10. Histological examination revealed enhanced inflammatory responses in the lacrimal and salivary glands of SjS chimeras, as measured by digital image analysis and blinded histopathological scoring. Infiltrates were primarily CD4+, with minimal detection of CD8+ T-cells and B-cells. These results demonstrate a novel chimeric mouse model of human SjS that provides a unique in vivo environment to test experimental therapeutics and investigate T-cell disease pathology. PMID- 25451162 TI - The DNA methylation signature of human TCRalphabeta+CD4-CD8- double negative T cells reveals CG demethylation and a unique epigenetic architecture permissive to a broad stimulatory immune response. AB - T cell receptor (TCR) alphabeta+CD4-CD8- double negative T cells represent a rare T cell subset implicated in the pathogenesis of several autoimmune diseases. We investigated the DNA methylation signature of double negative T cells to gain insight into the epigenetic architecture of peripheral blood primary human double negative T cells compared to autologous CD4+ and CD8+ T cells. We identified 2984 CG sites across the genome with unique loss of DNA methylation in double negative T cells, and showed significant reduction in mRNA expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B. DNA methylation was increased in CD8A/CD8B and CD4 consistent with epigenetic repression of both the CD8 and CD4 genetic loci in double negative T cells. We show a consistent increase in non-CG methylation in double negative T cells, a finding suggestive of pluripotency. Network analyses indicate a strong relationship between double negative T cells and functions related to cell-cell interaction, cell adhesion, and cell activation pathways. Our data also suggest a robust pro-inflammatory epigenetic signature in double negative T cells, consistent with a transcriptional permissiveness in key inflammatory cytokines including IFNgamma, IL-17F, IL-12B, IL-5, IL-18, TNFSF11 (RANKL), and TNFSF13B (BLYS or BAFF). These findings highlight an epigenetic basis for a role of double negative T cells in autoimmunity. PMID- 25451163 TI - Controlling spin-dependent tunneling by bandgap tuning in epitaxial rocksalt MgZnO films. AB - Widespread application of magnetic tunnel junctions (MTJs) for information storage has so far been limited by the complicated interplay between tunnel magnetoresistance (TMR) ratio and the product of resistance and junction area (RA). An intricate connection exists between TMR ratio, RA value and the bandgap and crystal structure of the barrier, a connection that must be unravelled to optimise device performance and enable further applications to be developed. Here, we demonstrate a novel method to tailor the bandgap of an ultrathin, epitaxial Zn-doped MgO tunnel barrier with rocksalt structure. This structure is attractive due to its good Delta1 spin filtering effect, and we show that MTJs based on tunable MgZnO barriers allow effective balancing of TMR ratio and RA value. In this way spin-dependent transport properties can be controlled, a key challenge for the development of spintronic devices. PMID- 25451164 TI - miRNA expression patterns in chemoresistant breast cancer tissues. AB - BACKGROUND/AIMS: Breast cancer chemoresistance is a major obstacle to the successful treatment of patients. miRNAs perform critical roles in biological processes, including tumorigenesis and chemoresistance. However, little clinical data are available regarding the relationship between miRNA expression patterns and breast cancer chemoresistance. METHODS: We created a doxorubicin-resistant MCF-7 (MCF-/Adr) cell line using a pulse-selection method; then verified the resistance of the MCF-7/Adr cell line to doxorubicin by using the methyl thiazolyl tetrazolium (MTT) assay, terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining, and Intracellular doxorubicin accumulation assay. Then, we performed qRT-PCR to detect the expression patterns of 14 selected miRNAs (which are related to breast cancer resistance) in both cell lines. Subsequently, we performed a bioinformatics analysis, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, to determine the putative functions of 13 differentially expressed miRNA-targeted genes. Finally, we tested the expression levels of these 13 miRNAs in 10 chemotherapy non-responder breast cancer tissues and 29 responder tissues. All statistical analyses were performed by a two-tailed Student's t test, and a P value less than 0.05 was considered statistically significant. RESULTS: The results of the MTT assay showed that the MCF-7/Adr cell line was significantly more resistant to doxorubicin compared to the MCF-7 cells The results of the TUNEL assay indicated that doxorubicin induced an increase in the number apoptotic cells in the MCF-7 group. Additionally, the accumulation of doxorubicin was higher in MCF-7 cells compared to MCF-7/Adr cells, which was consistent with the MTT and TUNEL results. The qRT-PCR results demonstrated that compared to the parental MCF-7 cell line, miR-200a, miR-141, miR-200c, miR-31, miR-429, and miR-196b were over-expressed, and let-7e, miR-576-3p, miR-125b-1, miR-370, miR-145, miR-765, and miR-760 were significantly down-regulated in MCF 7/Adr cells. The GO analysis results revealed that the predicted target genes of these 14 miRNAs primarily regulated protein binding, zinc ion binding, DNA binding, and transcription factor activity. The KEGG data demonstrated that these target genes are mainly involved in the MAPK signaling pathway, regulation of the actin cytoskeleton, cytokine-cytokine receptor interaction, and other signaling pathways. Compared to the breast cancer tissues from chemotherapy responders, 10 miRNAs were identified to be dysregulated in the chemoresistant breast cancer tissues. Three of these miRNAs were up-regulated (miR-141, miR-200c, and miR-31), and 7 were down-regulated (let-7e, miR-576-3p, miR-125b-1, miR-370, miR-145, miR 765, and miR-760). CONCLUSION: In this study, we identified 10 dysregulated miRNAs in both breast cancer cells and chemoresistant tissues, which might be biomarkers for the prognosis of breast cancer chemoresistance. Our study contributes to a comprehensive understanding of prognostic biomarkers during clinical treatment, and we hypothesize that the miRNA signatures of drug resistant carcinoma tissues could be useful for developing new strategies for targeted therapies in patients with chemoresistant breast cancer. PMID- 25451165 TI - Newly approved integrase inhibitors for clinical treatment of AIDS. AB - The current therapy for the human immunodeficiency virus (HIV) infection is a combination of anti-HIV drugs targeting multiple steps of virus replication. The drugs for the acquired immunodeficiency syndrome (AIDS) treatment include reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, co-receptor inhibitor and the newly added integrase inhibitors. Raltegravir, elvitegravir and dolutegravir are the three Food and Drug Administration (FDA) approved integrase strand transfer inhibitors for clinical treatment of HIV infection. The addition of these integrase inhibitors benefits a lot to HIV infected patients. Although it is only seven years from the first integrase inhibitor, which was approved by FDA to now, multiple drug resistant HIV strains have emerged in clinical treatment. Most of the drug resistant virus strains are against raltegravir. Some are cross-resistant to elvitegravir. Dolutegravir is effective for suppression of the current drug resistant viruses. A number of clinical trials have been performed on the three integrase inhibitors. In this study, the application of the three integrase inhibitors in clinical treatment and the findings of drug resistance to integrase inhibitors are summarized. PMID- 25451166 TI - Smoothened activates breast cancer stem-like cell and promotes tumorigenesis and metastasis of breast cancer. AB - Smoothened (Smo) is a G protein-coupled receptor protein encoded by the Smo gene of the hedgehog signalling pathway, which is thought to play an important role in maintaining organ patterning, cell differentiation and self-renewal. The possible role of Smo in the process of tumorigenesis and metastasis of breast cancer still remains unclear. The present experiments were to investigate the effect of Smo on activating breast cancer stem-like CD44(+)CD24(-) cells and the tumorigenesis and metastasis of breast cancer. By injected CD44(+)CD24(-) cells (1*10(4)) into the cleared fat pad of NOD/SCID mice, it was observed that CD44(+)CD24(-) cells possess higher tumor-initiating capacity and metastasis properties than equal numbers of non-CD44(+)CD24(-) cells. The mRNA and protein expressions of Smo in CD44(+)CD24(-) cells were higher than those in non-CD44(+)CD24(-) cells, indicating that Smo may play a role in maintaining breast cancer stem cell features. qRT-PCR results revealed that expressions of STAT3, Bcl-2 and cyclinD1 mRNA in MCF-7 cells were decreased after transfected by Smo siRNA. In addition, the expressions of MMP-2 and MMP-9 were downregulated in MCF-7 cells after Smo expression was inhibited. Smo inhibition may be a possible therapeutic target that potentially suppresses breast tumor formation and development. PMID- 25451167 TI - The mitochondrial calcium uniporter: mice can live and die without it. AB - Calcium is of critical importance to mitochondrial and cell function, and calcium signaling is highly localized in the cell. When stimulated, mitochondria are capable of rapidly taking up calcium, affecting both matrix energetics within mitochondria and shaping the amplitude and frequency of cytosolic calcium "waves". During pathological conditions a large increase in mitochondrial calcium levels is thought to activate the mitochondrial permeability transition pore, resulting in cell death. The protein responsible for mitochondrial calcium uptake, the mitochondrial calcium uniporter (MCU), was identified in 2011 and its molecular elucidation has stimulated and invigorated research in this area. MCU knockout mice have been created, a variety of other regulators have been identified, and a disease phenotype in humans has been attributed to the loss of a uniporter regulator. In the three years since its molecular elucidation, further research into the MCU has revealed a complex uniporter, and raised many questions about its physiologic and pathologic cell roles. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease". PMID- 25451169 TI - TNF-alpha-mediated adhesion of monocytes to endothelial cells-The role of ephrinA1. AB - The ligand ephrin A1 is more often discussed to play a role in the development of the atherosclerotic plaque and in this context especially in the monocyte adhesion to endothelial cells. As tumor necrosis factor-alpha (TNF-alpha) is known to induce monocyte adhesion to endothelium and ephrin A1 expression, the present study focuses on the involvement of ephrin A1 in TNF-alpha-mediated monocyte adhesion. The analysis of different members of the Eph/ephrin system in TNF-alpha-treated human umbilical vein endothelial cells (HUVEC) revealed that especially ephrinA1 was found to be highly regulated by TNF-alpha compared to other members of the Eph family. This effect is also present in arterial endothelial cells from the umbilical artery and from the coronary artery. This regulation is dependent on NFkappaB-activation as shown by the expression of a constitutive-active IkappaB-mutant. By using siRNA-mediated silencing and adenoviral overexpression of ephrinA1 in HUVEC, the involvement of ephrinA1 in the TNF-alpha triggered monocyte adhesion to endothelial cells could be demonstrated. In addition, these results could be verified by quantitative adhesion measurement using atomic force microscopy-based single-cell force spectroscopy and under flow conditions. Furthermore, this effect is mediated via the EphA4 receptor. EphrinA1 does not influence the mRNA or protein expression of the adhesion receptors VCAM-1 and ICAM-1 in endothelial cells. However, the surface presentation of these adhesion receptors is modulated in an ephrinA1 dependent manner. In conclusion, these data demonstrate that ephrinA1 plays an important role in the TNF-alpha-mediated adhesion of monocytes to endothelial cells, which might be of great importance in the context of atherosclerosis. PMID- 25451168 TI - Mitochondrial protein turnover: methods to measure turnover rates on a large scale. AB - Mitochondrial proteins carry out diverse cellular functions including ATP synthesis, ion homeostasis, cell death signaling, and fatty acid metabolism and biogenesis. Compromised mitochondrial quality control is implicated in various human disorders including cardiac diseases. Recently it has emerged that mitochondrial protein turnover can serve as an informative cellular parameter to characterize mitochondrial quality and uncover disease mechanisms. The turnover rate of a mitochondrial protein reflects its homeostasis and dynamics under the quality control systems acting on mitochondria at a particular cell state. This review article summarizes some recent advances and outstanding challenges for measuring the turnover rates of mitochondrial proteins in health and disease. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease". PMID- 25451171 TI - Dual loss of PI3Kalpha and PI3Kgamma signaling leads to an age-dependent cardiomyopathy. AB - Phosphatidylinositide 3-kinase (PI3K) signaling plays a critical role in maintaining normal cardiac structure and function. PI3Kalpha and PI3Kgamma are the dominant cardiac isoforms and have both adaptive and maladaptive roles in heart disease. Broad spectrum PI3K inhibitors are emerging as potential new chemotherapeutic agents which may have deleterious long-term effects on the heart. We created a double mutant (PI3KDM) model by crossing p110gamma(-/-) (PI3KgammaKO) with cardiac-specific PI3KalphaDN mice and studied cardiac structure and function at 1-year of age. Pressure-volume loop analysis and echocardiographic assessment showed PI3KDM mice developed marked impairment in systolic function while the wildtype, PI3KalphaDN, and PI3KgammaKO mice maintained normal systolic and diastolic function at 1-year of age. The PI3KDM hearts displayed increased expression of disease markers, increased myocardial fibrosis and matrix metalloproteinase (MMP) activity, depolymerization of intracellular F-actin, loss of phospho(threonine-308)-Akt, and normalization of phospho-Erk1/2 signaling. Dual loss of PI3Kalpha and PI3Kgamma isoforms results in an age-dependent cardiomyopathy implying that long-term exposure to pan-PI3K inhibitors may lead to severe cardiotoxicity. PMID- 25451170 TI - Mitochondria-targeted ROS scavenger improves post-ischemic recovery of cardiac function and attenuates mitochondrial abnormalities in aged rats. AB - Mitochondria-generated reactive oxygen species (ROS) play a crucial role in the pathogenesis of aging and age-associated diseases. In this study, we evaluated the effects of XJB-5-131 (XJB), a mitochondria-targeted ROS and electron scavenger, on cardiac resistance to ischemia-reperfusion (IR)-induced oxidative stress in aged rats. Male adult (5-month old, n=17) and aged (29-month old, n=19) Fischer Brown Norway (F344/BN) rats were randomly assigned to the following groups: adult (A), adult+XJB (AX), aged (O), and aged+XJB (OX). XJB was administered 3 times per week (3mg/kg body weight, IP) for four weeks. At the end of the treatment period, cardiac function was continuously monitored in excised hearts using the Langendorff technique for 30 min, followed by 20 min of global ischemia, and 60-min reperfusion. XJB improved post-ischemic recovery of aged hearts, as evidenced by greater left ventricular developed-pressures and rate pressure products than the untreated, aged-matched group. The state 3 respiration rates at complexes I, II and IV of mitochondria isolated from XJB-treated aged hearts were 57% (P<0.05), 25% (P<0.05) and 28% (P<0.05), respectively, higher than controls. Ca(2+)-induced swelling, an indicator of permeability transition pore opening, was reduced in the mitochondria of XJB-treated aged rats. In addition, XJB significantly attenuated the H2O2-induced depolarization of the mitochondrial inner membrane as well as the total and mitochondrial ROS levels in cultured cardiomyocytes. This study underlines the importance of mitochondrial ROS in aging-induced cardiac dysfunction and suggests that targeting mitochondrial ROS may be an effective therapeutic approach to protect the aged heart against IR injury. PMID- 25451172 TI - Exchanging cardiac phenotype: Is AKT-mediated NHE1 inhibition a permissive switch in physiological hypertrophy? PMID- 25451173 TI - Ca2+ Sparks and Ca2+ waves are the subcellular events underlying Ca2+ overload during ischemia and reperfusion in perfused intact hearts. AB - Abnormal intracellular Ca(2+) cycling plays a key role in cardiac dysfunction, particularly during the setting of ischemia/reperfusion (I/R). During ischemia, there is an increase in cytosolic and sarcoplasmic reticulum (SR) Ca(2+). At the onset of reperfusion, there is a transient and abrupt increase in cytosolic Ca(2++), which occurs timely associated with reperfusion arrhythmias. However, little is known about the subcellular dynamics of Ca(2+) increase during I/R, and a possible role of the SR as a mechanism underlying this increase has been previously overlooked. The aim of the present work is to test two main hypotheses: (1) An increase diastolic Ca(2+) sparks frequency (cspf) constitutes a mayor substrate for the ischemia-induced diastolic Ca(2+) increase; (2) an increase in cytosolic Ca(2+) pro-arrhythmogenic events (Ca(2+) waves), mediates the abrupt diastolic Ca(2+) rise at the onset of reperfusion. We used confocal microscopy on mouse intact hearts loaded with Fluo-4. Hearts were submitted to global I/R (12/30 min) to assess epicardial Ca(2+) sparks in the whole heart. Intact heart sparks were faster than in isolated myocytes whereas cspf was not different. During ischemia, cspf significantly increased relative to preischemia (2.07+/-0.33 vs. 1.13+/-0.20 sp/s/100 MUm, n=29/34, 7 hearts). Reperfusion significantly changed Ca(2+) sparks kinetics, by prolonging Ca(2+) sparks rise time and decreased cspf. However, it significantly increased Ca(2+) wave frequency relative to ischemia (0.71+/-0.14 vs. 0.38+/-0.06 w/s/100 MUm, n=32/33, 7 hearts). The results show for the first time the assessment of intact perfused heart Ca(2+) sparks and provides direct evidence of increased Ca(2+) sparks in ischemia that transform into Ca(2+) waves during reperfusion. These waves may constitute a main trigger for reperfusion arrhythmias. PMID- 25451174 TI - The immediate effect of HCM causing actin mutants E99K and A230V on actin-Tm myosin interaction in thin-filament reconstituted myocardium. AB - Human cardiac actin mutants E99K and A230V were expressed with baculovirus/insect cells and used to reconstitute the thin-filament of bovine cardiac (BVC) muscle fibers, together with tropomyosin (Tm) and troponin (Tn) purified from bovine ventricles. Effects of [Ca(2+)], [ATP], and [phosphate] on tension and its transients were studied at 25 degrees C. In the absence of Tm/Tn, both mutants significantly decreased the tension of actin filament reconstituted fibers (WT: 0.75+/-0.06 T0, E99K: 0.58+/-0.04 T0, A230V: 0.58+/-0.03 T0), where T0 is active tension of native fibers (T0=26.9+/-1.1kPa, N=41), indicating diminished actin myosin interactions. However, in the presence of Tm and Tn, WT, E99K, and A230V recovered tension (0.85+/-0.06 T0, 0.89+/-0.06 T0, and 0.85+/-0.05 T0, respectively), demonstrating the compensatory effect of Tm/Tn. Ca(2+) sensitivity (pCa50) increased (5.59+/-0.02, 5.80+/-0.03, 5.77+/-0.03, respectively) and cooperativity (nH) decreased (2.6+/-0.3, 1.87+/-0.21, 1.60+/-0.11, respectively). The kinetic constants of the cross-bridge cycle were deduced using sinusoidal analysis. E99K did not show any significant changes in any of the kinetic constants compared to those of WT. A230V caused a decrease in K1 (ATP association constant), k2 and k-2 (rate constants of the cross-bridge detachment step). The cross-bridge distribution was similar among WT, E99K, and A230V. In conclusion, our experiments demonstrate that the first step of HCM pathogenesis with E99K is increased pCa50 and decreased nH, which result in larger tension during partial activation to cause a diastolic problem. The effect on nH is more severe with A230V. In addition, A230V has a problem of decreased cross-bridge kinetics, which affects the normal functions of the cross-bridge cycle and may contribute to the first step of the HCM pathogenesis. PMID- 25451176 TI - Identification of novel hypomorphic and null mutations in Klf1 derived from a genetic screen for modifiers of alpha-globin transgene variegation. AB - Position-effect variegation of transgene expression is sensitive to the chromatin state. We previously reported a forward genetic screen in mice carrying a variegated alpha-globin GFP transgene to find novel genes encoding epigenetic regulators. We named the phenovariant strains "Mommes" for modifiers of murine metastable epialleles. Here we report positional cloning of mutations in two Momme strains which result in suppression of variegation. Both strains harbour point mutations in the erythroid transcription factor, Klf1. One (D11) generates a stop codon in the zinc finger domain and a homozygous null phenotype. The other (D45) generates an amino acid transversion (H350R) within a conserved linker between zinc fingers two and three. Homozygous MommeD45 mice have chronic microcytic anaemia which models the phenotype in a recently described family. This is the first genetic evidence that the linkers between the zinc fingers of transcription factors have a function beyond that of a simple spacer. PMID- 25451177 TI - Characterization of TATA-containing genes and TATA-less genes in S. cerevisiae by network topologies and biological properties. AB - The TATA box is the core sequence of the promoter and the binding site of many transcription factors. Based on the presence or absence of TATA box, genes can be defined as TATA-containing or TATA-less genes. Many important stress-response functions and highly variable expression patterns are found to be correlated with the TATA box. However, until now, the relationships and differences between TATA containing and TATA-less genes remain unclear. In this study, based on the transcriptional profiling of the Saccharomyces cerevisiae genome, the perturbation sensitivity (PS) network is constructed. The topological and biological properties are used to investigate differences between TATA-containing and TATA-less genes. Significant differences are found in all topological properties and most of the biological properties. Notably, the TF number, determined mathematically by the number of transcription factors regulating a gene, demonstrates the highest discrimination between TATA-containing and TATA less genes when all properties are estimated by the F-score. PMID- 25451175 TI - Genome-wide transcriptome analysis of human epidermal melanocytes. AB - Because human epidermal melanocytes (HEMs) provide critical protection against skin cancer, sunburn, and photoaging, a genome-wide perspective of gene expression in these cells is vital to understanding human skin physiology. In this study we performed high throughput sequencing of HEMs to obtain a complete data set of transcript sizes, abundances, and splicing. As expected, we found that melanocyte specific genes that function in pigmentation were among the highest expressed genes. We analyzed receptor, ion channel and transcription factor gene families to get a better understanding of the cell signaling pathways used by melanocytes. We also performed a comparative transcriptomic analysis of lightly versus darkly pigmented HEMs and found 16 genes differentially expressed in the two pigmentation phenotypes; of those, only one putative melanosomal transporter (SLC45A2) has known function in pigmentation. In addition, we found 166 transcript isoforms expressed exclusively in one pigmentation phenotype, 17 of which are genes involved in signal transduction. Our melanocyte transcriptome study provides a comprehensive view and may help identify novel pigmentation genes and potential pharmacological targets. PMID- 25451178 TI - Transcriptional and structural plasticity of tyrosine hydroxylase expressing neurons in both striatum and nucleus accumbens following dopaminergic denervation. AB - Mice that express green fluorescent protein (GFP) under the control of tyrosine hydroxylase (TH) gene promoter were used to visualize transcriptional as well as structural regulation of TH cells following prolonged dopaminergic denervation. A unilateral lesion of the medial forebrain bundle was induced by 6 hydroxydopamine. In the unlesioned contralateral striatum and nucleus accumbens surprisingly high numbers of resident GFP-positive neurons (about 2653 and 422 per striatum and accumbens, respectively) were observed while only much lower TH positive neurons (about 214 and 102 per striatum and accumbens, respectively) were detectable. In the lesioned hemisphere the number of GFP neurons was slightly increased already at day 4 by 16% and more at day 40 by 47% while the number of TH-immunoreactive neurons was dramatically increased by 848% at day 4 and by 1139% at day 40 over the control side. Additionally and particularly pronounced in the nucleus accumbens, GFP-positive neurons demonstrated increased sprouting of their projections over time, stronger than observed by TH immunostaining. The load in TH protein may be essentially determined by post transcriptional suppression/degradation while GFP may rather reflect the gross transcriptional activity. Thus, permanent dopaminergic pathway injury induces both transcriptional as well as structural plasticity of TH expressing neurons in striatal and accumbal target areas of ventral midbrain dopaminergic neurons. PMID- 25451180 TI - Primary skin closure after damage control laparotomy (Br J Surg 2015: 102: 67 75). PMID- 25451179 TI - Learning from the QUEST multicentre feasibility randomization trials in breast reconstruction after mastectomy. AB - BACKGROUND: Breast reconstruction aims to improve health-related quality of life after mastectomy. However, evidence guiding patients and surgeons in shared decision-making concerning the optimal type or timing of surgery is lacking. METHODS: QUEST comprised two parallel feasibility phase III randomized multicentre trials to assess the impact of the type and timing of latissimus dorsi breast reconstruction on health-related quality of life when postmastectomy radiotherapy is unlikely (QUEST A) or highly probable (QUEST B). The primary endpoint for the feasibility phase was the proportion of women who accepted randomization, and it would be considered feasible if patient acceptability rates exceeded 25 per cent of women approached. A companion QUEST Perspectives Study (QPS) of patients (both accepting and declining trial participation) and healthcare professionals assessed trial acceptability. RESULTS: The QUEST trials opened in 15 UK centres. After 18 months of recruitment, 17 patients were randomized to QUEST A and eight to QUEST B, with overall acceptance rates of 19 per cent (17 of 88) and 22 per cent (8 of 36) respectively. The QPS recruited 56 patients and 51 healthcare professionals. Patient preference was the predominant reason for declining trial entry, given by 47 (53 per cent) of the 88 patients approached for QUEST A and 22 (61 per cent) of the 36 approached for QUEST B. Both trials closed to recruitment in December 2012, acknowledging the challenges of achieving satisfactory patient accrual. CONCLUSION: Despite extensive efforts to overcome recruitment barriers, it was not feasible to reach timely recruitment targets within a feasibility study. Patient preferences for breast reconstruction types and timings were common, rendering patients unwilling to enter the trial. PMID- 25451181 TI - Liver resection in patients with eight or more colorectal liver metastases. AB - BACKGROUND: Patients with large numbers of colorectal liver metastases (CRLMs) are potential candidates for resection, but the benefit from surgery is unclear. METHODS: Patients undergoing resection for CRLMs between 1998 and 2012 in two high-volume liver surgery centres were categorized according to the number of CRLMs: between one and seven (group 1) and eight or more (group 2). Overall (OS) and recurrence-free (RFS) survival were compared between the groups. Multivariable analysis was performed to identify adverse prognostic factors. RESULTS: A total of 849 patients were analysed: 743 in group 1 and 106 in group 2. The perioperative mortality rate (90 days) was 0.4 per cent (all group 1). Median follow-up was 37.4 months. Group 1 had higher 5-year OS (44.2 versus 20.1 per cent; P < 0.001) and RFS (28.7 versus 13.6 per cent; P < 0.001) rates. OS and RFS in group 2 were similar for patients with eight to ten, 11-15 or more than 15 metastases (48, 40 and 18 patients respectively). In group 2, multivariable analysis identified three preoperative adverse prognostic factors: extrahepatic disease (P = 0.010), no response to chemotherapy (P = 0.023) and primary rectal cancer (P = 0.039). Patients with two or more risk factors had very poor outcomes (median OS and RFS 16.9 and 2.5 months; 5-year OS zero); patients in group 2 with no risk factors had similar survival to those in group 1 (5-year OS rate 44 versus 44.2 per cent). CONCLUSION: Liver resection is safe in selected patients with eight or more metastases, and offers reasonable 5-year survival independent of the number of metastases. However, eight or more metastases combined with at least two adverse prognostic factors is associated with very poor survival, and surgery may not be beneficial. PMID- 25451182 TI - Survival after pelvic exenteration for T4 rectal cancer. AB - BACKGROUND: The purpose of this study was to analyse retrospectively the pooled results after pelvic exenteration for locally advanced T4 rectal cancer. Historically, patients with T4 rectal cancers requiring pelvic exenteration have been offered only palliative surgery or no operation. METHODS: The basic treatment principle was preoperative (chemo)radiotherapy, radical surgery and, in some patients, adjuvant chemotherapy. Risk factors for local recurrence, distant metastases and overall survival were studied in univariable and multivariable analyses. RESULTS: Ninety-five patients with T4 rectal cancer who underwent pelvic exenteration in two tertiary referral centres up to 2013 were studied. Clear margins (R0) were achieved in 87 per cent of patients. Adjuvant chemotherapy was administered in 33 per cent, independent of the resection margin, lymph node status and postoperative T category. The 5-year local recurrence rate was 17 per cent, with a distant metastasis rate of 16 per cent and overall survival rate of 62 per cent. In multivariable analysis the only factor associated with death was omission of adjuvant chemotherapy (P = 0.016). The effect of adjuvant chemotherapy was more pronounced in the elderly: patients aged over 70 years who had chemotherapy had a 5-year overall survival rate of 80 per cent, compared with 39 per cent of elderly patients who did not receive chemotherapy (P = 0.019). CONCLUSION: Pelvic exenteration led to an R0 resection rate of 87 per cent for T4 rectal cancer, giving good local control and overall survival comparable to population-based colorectal cancer survival rates. Adjuvant chemotherapy may improve overall survival further, even in the elderly. PMID- 25451185 TI - Detrimental effect of high volume fluid administration in acute pancreatitis - a retrospective analysis of 391 patients. AB - BACKGROUND: Early fluid resuscitation is recommended for the therapy of acute pancreatitis in order to prevent complications. There are, however, no convincing data supporting this approach. METHODS: We reviewed 391 consecutive cases of confirmed acute pancreatitis. Admitting physicians had been advised to administer an aggressive fluid resuscitation in the early phase of disease, if possible. We tested whether disease severity according to the revised Atlanta Classification, local complications, and maximum C-reactive protein levels were predictable by the initial volume therapy in logistic and linear regression models, respectively. We also determined which parameters on admission encouraged a more aggressive fluid resuscitation. RESULTS: The recorded fluid administered within the first 24 h was 5300 [3760; 7100] ml (median [1st; 3rd quartile]). More aggressive volume therapy was associated with disease severity and a higher rate of local complications. There was a linear relationship between administered volume and the maximum C-reactive protein. The amount of administered fluid was significantly attributed to age, hematocrit, and white blood cell count on admission. When adjusted for these parameters the impact of administered volume on outcome was still present but attenuated. CONCLUSIONS: We found detrimental effects of fluid therapy on major outcome parameters throughout the whole range of administered volume. More volume was administered in younger patients and in patients with evidence of hemoconcentration and inflammation. The adverse effects of volume therapy persisted after elimination of these parameters. Caution should therefore be advised with regards to volume therapy in patients with acute pancreatitis. PMID- 25451187 TI - Active and passive exposure to tobacco smoke in relation to insulin sensitivity and pancreatic beta-cell function in Japanese subjects. AB - AIM: Several studies have suggested that cigarette-smoking affects insulin sensitivity in Western populations. The present study evaluated glucose tolerance, pancreatic beta-cell function and insulin sensitivity in relation to active and passive smoking among the Japanese. METHODS: A total of 411 men and 586 women were recruited into a community-based cross-sectional study in Gifu, Japan. Diabetes, impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) were screened for by a 75g oral glucose tolerance test. HOMA and insulinogenic (DeltaI0-30/DeltaG0-30) indexes were used to estimate insulin secretion and sensitivity. To assess the possible association of self-reported smoking status and parameters of glucose metabolism, logistic regression was applied after adjusting for potential confounders. RESULTS: Currently smoking women were more likely to have diabetes, IGT or IFG compared with never-smoking women (OR: 2.26, 95% CI: 1.05-4.84). Heavy-smoking men (>=25 cigarettes/day) were likely to be in the lowest tertile group of DeltaI0-30/DeltaG0-30 compared with never-smoking men (OR: 2.64, 95% CI: 1.05-6.68, Ptrend=0.04). The number of cigarettes/day was borderline significantly associated with diabetes in men. Also with borderline significance, never-smoking women with smoking husbands were more likely to have diabetes, IGT or IFG (OR: 1.62, 95% CI: 1.00-2.62) and significantly more likely to have lower HOMA-beta (OR: 2.17, 95% CI: 1.36-3.48) than those without smoking husbands. CONCLUSION: The greater the number of cigarettes smoked per day appears to be associated with diabetes among men whereas, among women, both active and passive smoking appear to be associated with diabetic states, including IGT and IFG. An association between smoking status and insulin secretion is also suggested, whereas no significant association was observed with HOMA-IR in this Japanese subjects, suggesting that the influence of smoking on glucose metabolism may differ among races. PMID- 25451188 TI - Malignant insulinoma may arise during the course of type 1 diabetes mellitus: A case report. PMID- 25451189 TI - Use of insulin in type 2 diabetes: what we learned from recent clinical trials on the benefits of early insulin initiation. AB - The majority of people with type 2 diabetes mellitus (T2DM) require insulin therapy to maintain HbA(1c) levels < 7% during the first decade of diagnosis. Large prospective trials investigating the cardiovascular (CV) benefits of intensive glycaemic control have produced inconsistent results; however, meta analyses have suggested that intensive glycaemic control provides both micro- and macrovascular benefits. The ORIGIN study investigated the impact of basal insulin glargine therapy targeting <= 5.3 mmol/L for fasting plasma glucose compared with standard care on CV outcomes in people with pre- or early diabetes, and demonstrated a neutral effect on CV outcomes with long-term use of insulin glargine early in the course of diabetes, with a low rate of severe hypoglycaemia and modest weight gain. The EARLY, GLORY and EASIE studies also demonstrated that insulin use earlier in the treatment pathway led to improved glycaemic control, reduced weight gain and fewer hypoglycaemic episodes than when insulin was added later in the course of disease. The beneficial effect of early transient intensive insulin therapy (TIIT) at diagnosis has been demonstrated in a number of trials; it rapidly limits the damage caused by gluco- and lipotoxicity, improving residual beta-cell function and potentially slowing disease progression. The evidence suggests that people newly diagnosed with T2DM and HbA(1c) > 9% should be given early TIIT to achieve normoglycaemia within weeks, after which standard care should then be adopted. Insulin use earlier in the treatment pathway should be considered, as it reduces the risk of hypoglycaemia as well as allows beta-cell rest, which can help preserve beta-cell function. PMID- 25451186 TI - Comparison of PEGylated FGF-21 with insulin glargine for long-lasting hypoglycaemic effect in db/db mice. AB - AIM: This study investigated the long-acting antidiabetic efficacy of PEGylated fibroblast growth factor (FGF)-21 in type 2 diabetic db/db mice. METHODS: PEGylated FGF-21 was prepared by modifying the N-terminus of human FGF-21 (hFGF 21) using mPEG-ALD. To compare the long-lasting hypoglycaemic effects of PEGylated FGF-21 and insulin glargine in diabetic db/db mice, their pharmacological efficacy was evaluated by changes in blood glucose levels, body weight, insulin levels, glycosylated haemoglobin levels, lipid profile and liver function parameters, and by oral glucose tolerance tests (OGTTs). RESULTS: Both PEGylated FGF-21 and insulin glargine decreased plasma glucose in db/db mice. However, compared with insulin glargine treatment, PEGylated FGF-21 therapy had more significant effects in lowering blood glucose and glycosylated haemoglobin levels, improving lipid profile and liver function parameters, alleviating insulin resistance and reducing the glucose area under the curve in OGTTs. CONCLUSION: Our results suggest that PEGylated FGF-21 is an ideal candidate as a long-acting antidiabetes drug, and holds significant promise as an effective therapeutic agent in the treatment of type 2 diabetes patients. PMID- 25451190 TI - Association between metabolically unhealthy overweight/obesity and chronic kidney disease: the role of inflammation. AB - AIM: Our study explored the association between subtypes of increased fat mass (with or without associated metabolic alterations) and the presence of chronic kidney disease (CKD). METHODS: In this cross-sectional survey in China, body mass index (BMI) was used to assess fat mass. Metabolically healthy was defined as no insulin resistance or any metabolic syndrome components except abdominal obesity. We also used two previous definitions of metabolically healthy. Multiple logistic regression models were used. Normal weight with metabolic health was designated the reference group. Three other subgroups included normal weight with metabolic unhealthiness, overweight/obesity with metabolic health and overweight/obesity with metabolic unhealthiness. RESULTS: Of the 2324 subjects, 11.77% overweight/obese subjects were metabolically healthy. Compared with normal-weight subjects who were metabolically healthy, overweight/obese subjects who were metabolically healthy did not have an increased risk of CKD (OR: 0.79, 95% CI: 0.29-2.14; P = 0.64), whereas overweight/obese subjects who were metabolically unhealthy had a significantly higher risk of CKD (OR: 2.47, 95% CI: 1.5-3.95; P < 0.001). Normal-weight subjects who were metabolically unhealthy also had a higher risk of CKD, but the P value was of borderline significance. On further adjusting for C-reactive protein (CRP) levels, ORs were much attenuated, but did not alter the associations observed. Using two other definitions of metabolically healthy resulted in similar results. CONCLUSION: Metabolically unhealthy overweight/obesity, but not metabolically healthy overweight/obesity, is associated with an increased risk of CKD. Inflammation might mediate at least part of the association between metabolic changes and CKD prevalence. PMID- 25451191 TI - Switching from insulin glargine to insulin degludec reduced HbA1c, daily insulin doses and anti-insulin antibody in anti-insulin antibody-positive subjects with type 1 diabetes. PMID- 25451192 TI - Target-independent ephrina/EphA-mediated axon-axon repulsion as a novel element in retinocollicular mapping. AB - EphrinAs and EphAs play critical roles during topographic map formation in the retinocollicular projection; however, their complex expression patterns in both the retina and superior colliculus (SC) have made it difficult to uncover their precise mechanisms of action. We demonstrate here that growth cones of temporal axons collapse when contacting nasal axons in vitro, and removing ephrinAs from axonal membranes by PI-PLC treatment abolishes this response. In conditional knockout mice, temporal axons display no major targeting defects when ephrinA5 is removed only from the SC, but substantial mapping defects were observed when ephrinA5 expression was removed from both the SC and from the retina, with temporal axons invading the target areas of nasal axons. Together, these data indicate that ephrinA5 drives repellent interactions between temporal and nasal axons within the SC, and demonstrates for the first time that target-independent mechanisms play an essential role in retinocollicular map formation in vivo. PMID- 25451193 TI - A TRPV channel in Drosophila motor neurons regulates presynaptic resting Ca2+ levels, synapse growth, and synaptic transmission. AB - Presynaptic resting Ca(2+) influences synaptic vesicle (SV) release probability. Here, we report that a TRPV channel, Inactive (Iav), maintains presynaptic resting [Ca(2+)] by promoting Ca(2+) release from the endoplasmic reticulum in Drosophila motor neurons, and is required for both synapse development and neurotransmission. We find that Iav activates the Ca(2+)/calmodulin-dependent protein phosphatase calcineurin, which is essential for presynaptic microtubule stabilization at the neuromuscular junction. Thus, loss of Iav induces destabilization of presynaptic microtubules, resulting in diminished synaptic growth. Interestingly, expression of human TRPV1 in Iav-deficient motor neurons rescues these defects. We also show that the absence of Iav causes lower SV release probability and diminished synaptic transmission, whereas Iav overexpression elevates these synaptic parameters. Together, our findings indicate that Iav acts as a key regulator of synaptic development and function by influencing presynaptic resting [Ca(2+)]. PMID- 25451194 TI - PKA-GluA1 coupling via AKAP5 controls AMPA receptor phosphorylation and cell surface targeting during bidirectional homeostatic plasticity. AB - Bidirectional synaptic plasticity occurs locally at individual synapses during long-term potentiation (LTP) or long-term depression (LTD), or globally during homeostatic scaling. LTP, LTD, and homeostatic scaling alter synaptic strength through changes in postsynaptic AMPA-type glutamate receptors (AMPARs), suggesting the existence of overlapping molecular mechanisms. Phosphorylation controls AMPAR trafficking during LTP/LTD. We addressed the role of AMPAR phosphorylation during homeostatic scaling. We observed bidirectional changes of the levels of phosphorylated GluA1 S845 during scaling, resulting from a loss of protein kinase A (PKA) from synapses during scaling down and enhanced activity of PKA in synapses during scaling up. Increased phosphorylation of S845 drove scaling up, while a knockin mutation of S845, or knockdown of the scaffold AKAP5, blocked scaling up. Finally, we show that AMPARs scale differentially based on their phosphorylation status at S845. These results show that rearrangement in PKA signaling controls AMPAR phosphorylation and surface targeting during homeostatic plasticity. PMID- 25451195 TI - Independent, reciprocal neuromodulatory control of sweet and bitter taste sensitivity during starvation in Drosophila. AB - An organism's behavioral decisions often depend upon the relative strength of appetitive and aversive sensory stimuli, the relative sensitivity to which can be modified by internal states like hunger. However, whether sensitivity to such opposing influences is modulated in a unidirectional or bidirectional manner is not clear. Starved flies exhibit increased sugar and decreased bitter sensitivity. It is widely believed that only sugar sensitivity changes, and that this masks bitter sensitivity. Here we use gene- and circuit-level manipulations to show that sweet and bitter sensitivity are independently and reciprocally regulated by starvation in Drosophila. We identify orthogonal neuromodulatory cascades that oppositely control peripheral taste sensitivity for each modality. Moreover, these pathways are recruited at increasing hunger levels, such that low risk changes (higher sugar sensitivity) precede high-risk changes (lower sensitivity to potentially toxic resources). In this way, state-intensity dependent, reciprocal regulation of appetitive and aversive peripheral gustatory sensitivity permits flexible, adaptive feeding decisions. PMID- 25451196 TI - Maintenance of GABAergic activity by neuregulin 1-ErbB4 in amygdala for fear memory. AB - Inhibitory neurotransmission in amygdala is important for fear learning and memory. However, mechanisms that control the inhibitory activity in amygdala are not well understood. We provide evidence that neuregulin 1 (NRG1) and its receptor ErbB4 tyrosine kinase are critical for maintaining GABAergic activity in amygdala. Neutralizing endogenous NRG1, inhibition, or genetic ablation of ErbB4, which was expressed in a majority of palvalbumin (PV)+ neurons in amygdala, reduced GABAergic transmission and inhibited tone-cued fear conditioning. Specific ablation of ErbB4 in PV+ neurons reduced eIPSC/eEPSC ratios and impaired fear conditioning. Notably, expression of ErbB4 in amygdala was sufficient to diminish synaptic dysfunction and fear conditioning deficits in PV-ErbB4-/- mice. These observations indicated that NRG1 signaling maintains high GABAergic activity in amygdala and, thus, regulates fear memory. Considering that both NRG1 and ErbB4 are susceptibility genes of schizophrenia, our study sheds light on potential pathophysiological mechanisms of this disorder. PMID- 25451197 TI - Savoring the past: positive memories evoke value representations in the striatum. AB - Reminders of happy memories can bring back pleasant feelings tied to the original experience, suggesting an intrinsic value in reminiscing about the positive past. However, the neural circuitry underlying the rewarding aspects of autobiographical memory is poorly understood. Using fMRI, we observed enhanced activity during the recall of positive relative to neutral autobiographical memories in corticostriatal circuits that also responded to monetary reward. Enhanced activity in the striatum and medial prefrontal cortex was associated with increases in positive emotion during recall, and striatal engagement further correlated with individual measures of resiliency. Striatal response to the recall of positive memories was greater in individuals whose mood improved after the task. Notably, participants were willing to sacrifice a more tangible reward, money, in order to reminisce about positive past experiences. Our findings suggest that recalling positive autobiographical memories is intrinsically valuable, which may be adaptive for regulating positive emotion and promoting better well-being. PMID- 25451199 TI - Visuo-vestibular contributions to anxiety and fear. AB - The interactive roles of the visual and vestibular systems allow for postural control within boundaries of perceived safety. In specific circumstances, visual vestibular and postural interactions act as a cue that trigger fear, similarly to what occurs in motion sickness. Unusual patterns of visuo-vestibular interaction that emerge without warning can elicit fear, which can then become associated to a certain stimuli or situation, creating a CS-US association, (i.e., phobia), or can emerge without warning but also without becoming associated to a particular concomitant event (i.e., panic). Depending on the individual sensitivity to visuo vestibular unusual patterns and its impact in postural control, individuals will be more or less vulnerable to develop these disorders. As such, the mechanism we here propose is also sufficient to explain the lack of certain fears albeit exposure. Following this rationale, a new subcategory of anxiety disorders, named visuo-vestibular fears can be considered. This model brings important implications for developmental and evolutionary psychological science, and invites to place visuo-vestibular fears in a particular subtype or specification within the DSM-5 diagnostic criteria. PMID- 25451200 TI - Beyond sexual selection: The evolution of sex differences from brain to behavior. PMID- 25451198 TI - Conformational dynamics of shaker-type Kv1.1 ion channel in open, closed, and two mutated states. AB - The dynamic properties of shaker-type Kv1.1 ion channel in its open, closed, & two mutated (E325D & V408A) states embedded in DPPC membrane have been investigated using all-atom force field-based MD simulation. Here, we represent the detailed channel stability, gating environment of charge-carrying residues, salt bridge interaction among the voltage-sensing domains (VSDs), movement of S4 helix, and ion conduction of pore. At positive potential, the S4 helix undergoes lateral fluctuations in accordance with their gating motions found in every model. During transition from closed to active state conformation, charged residues of S4 move "up" across the membrane with an average tilt angle difference of 24 degrees , which is more consistent with the paddle model of channel gating. The E325D mutation at C-terminal end of S4-S5 helical linker leads the channel to a rapid activated state by pushing the gating charge residues upward beside the VSDs resulting in more prominent tilt of S4. Similarly in V408A mutant model, disruption of hydrophobic gate at S6 C-terminal end takes place, which causes the violation of channel-active conformation by bringing the C-terminal end of S4 to its corresponding resting state. The ion permeation is observed only in open-state conformation. PMID- 25451201 TI - A systematic review of fatigue in patients with traumatic brain injury: the course, predictors and consequences. AB - BACKGROUND: Fatigue is common after traumatic brain injury (TBI). Its risk factors, natural history and consequences are uncertain. Best-evidence synthesis was used to address the gaps. METHODS: Five databases were searched for relevant peer-reviewed studies. Of the 33 articles appraised, 22 longitudinal studies were selected. Results were reported separately based on their timing of baseline assessment. RESULTS: All studies document changes in fatigue frequency and severity with time, irrespective of setting or TBI severity. There is limited evidence for certain clinical and psychosocial variables as predictors of fatigue severity at follow-up. Early fatigue severity predicted persistent post concussive symptoms and Glasgow outcome score at follow-up. CONCLUSIONS: Fatigue is present before and immediately following injury, and can persist long term. The variation in findings supports the idea of fatigue in TBI as a nonhomogeneous entity, with different factors influencing the course of new onset or chronic fatigue. To decrease the heterogeneity, we emphasize the need for agreement on a core set of relevant fatigue predictors, definitions and outcome criteria. PROSPERO registry number: CRD42013004262. PMID- 25451202 TI - Fluoroquinolone-mediated Achilles rupture: a case report and review of the literature. AB - Fluoroquinolone use for the treatment of bacterial infections is a common practice for foot and ankle surgeons because of its rather broad-spectrum coverage against common pathogens, good tissue penetration, and high bioavailability. An associated risk of tendinopathy has been reported in published studies, although tendon rupture has been much less frequent. In addition, tendinopathy has been more commonly reported with earlier generations of fluoroquinolones. We present a case of levofloxacin-mediated Achilles rupture that was complicated by the presence of an infected hematoma and abscess and subsequent long-term postoperative follow-up data, with a review of the literature. PMID- 25451203 TI - Avulsion Fracture of the Calcaneus Treated With a Soft Anchor Bridge and Lag Screw Technique: A Report of Two Cases. AB - The displaced extra-articular avulsion fracture of the calcaneus has been classified as a Bohler type 1c calcaneal fracture, and most cases will require surgical repair. In the present report, we describe 2 patients in whom we performed the soft anchor bridge technique using single loaded suture anchors with lag screws for the repair of Bohler type 1c avulsion fractures of the calcaneus. In one of these patients, clinically relevant osteoporosis complicated the injury. In both cases, bone union was achieved, and by 1.5 months after surgery satisfactory recovery was observed. To our knowledge, the soft anchor bridge technique was first used for the treatment of rotator cuff tears, and the greatest merit of this technique is the ability to generate vertical compression force to the pulled out rotator cuff through the use of knotting sutures. In recent years, the soft anchor bridge technique using 4 suture anchors has also been used for fractures of the greater tuberosity of the humerus, an injury that poses operative difficulties similar to those encountered with an avulsion fracture of the calcaneus owing to the traction force of the rotator cuff and relative weakness of adjacent bone. The outcomes of our patients suggest that the soft anchor bridge technique combined with adjunct lag screws is useful in the fixation of avulsion fractures of the calcaneus. In addition, the result in the elderly patient indicates the possibility of using this technique for patients with osteoporosis. PMID- 25451204 TI - Intercuneiform and Lisfranc Fracture-Dislocation Due to Seizure: A Case Report. AB - Cuneiform dislocation associated with Lisfranc injury is a very rare injury. Dislocation over the midfoot due to a seizure has not been previously reported in published studies. A 35-year-old female presented with an intercuneiform dislocation and Lisfranc fracture-dislocation after a generalized seizure. Immediate close reduction of the dorsally dislocated cuneiforms was performed, followed by definitive treatment to restore the foot arches. A proposed underlying pathophysiology of dislocation due to seizure in terms of the biomechanics is discussed. The purpose of our report was to present the unusual etiology of this form of cuneiform dislocation and Lisfranc joint complex injury. PMID- 25451205 TI - Mineral density and penetration strength of the subchondral bone plate of the talar dome: high correlation and specific distribution patterns. AB - The subchondral bone plate plays an important role in stabilizing the osteochondral joint unit and in the pathomechanism of osteochondral lesions and osteoarthritis. The objective of the present study was to measure the mineral density distribution and subchondral bone plate penetration strength of the talar dome joint facet to display and compare the specific distribution patterns. Ten cadaver specimens were used for computed tomography (CT) scans, from which densitograms were derived using CT-osteoabsorptiometry, and for mechanical indentation testing from which the penetration strength was obtained. Our results showed 2 different distribution patterns for mineral density and penetration strength. Of the 10 specimens, 6 (60%) showed bicentric maxima (anteromedially and anterolaterally), and 4 (40%) showed a monocentric maximum (either anteromedially or anterolaterally). A highly significant correlation (p < .0001) for both methods confirmed that the mineral density relied on local load characteristics. In conclusion, the biomechanical properties of the subchondral bone plate of the talar dome joint facet showed specific distribution patterns. CT-osteoabsorptiometry is a reliable method to display the mineral density distribution noninvasively. We recommend CT-osteoabsorptiometry for noninvasive analysis of the biomechanical properties of the subchondral bone plate in osteochondral joint reconstruction and the prevention and treatment of osteoarthritis and osteochondral lesions. PMID- 25451207 TI - Extra Ossification Center at the Tip of the Medial Malleolus Suspected as Fracture: A Clinical Clue. AB - The appearance of displaced bone inferior (distal) to the medial malleolus, present on radiographs in an adolescent patient, can be confused with a fracture, when, in fact, it is the radiographic appearance of a secondary center of ossification. Foot and ankle surgeons should be aware of extra ossification centers and accessory bones, including one at the tip of the medial malleolus, to avoid misdiagnosis and overtreatment. In the present report, I describe the case of a 9-year-old male with bilateral extra ossification centers at the tip of each medial malleolus. PMID- 25451206 TI - Osteomyelitis after TightRope((r)) fixation of the ankle syndesmosis: a case report and review of the literature. AB - Fixation of ankle syndesmosis injuries using the Ankle TightRope((r)) has been gaining popularity. It has been shown to produce good results, facilitate early weightbearing, reduce the need for implant removal, and allow an earlier return to work and, possibly, a more anatomic syndesmotic reduction compared with screw fixation. However, its usage has been associated with complications such as soft tissue irritation, infection and wound breakdown, suture-button subsidence, and pathologic fracture from the screw tract. We describe a case of chronic osteomyelitis and suture-button migration associated with TightRope((r)) fixation and a limited contact-dynamic compression plate for ankle syndesmosis disruption and lateral malleolus fracture. PMID- 25451208 TI - Modified lapidus arthrodesis with crossed screw fixation: early weightbearing in 136 patients. AB - Modified Lapidus arthrodesis is a versatile and powerful procedure for correcting the hallux valgus deformity typically associated with significant metatarsus primus varus or increased first ray mobility. Traditionally, patients have remained non-weightbearing until the arthrodesis has consolidated. More recently, numerous studies have evaluated the outcomes of early postoperative weightbearing using a variety of fixation constructs. The present retrospective cohort study evaluated 136 consecutive patients who had undergone modified Lapidus arthrodesis for hallux valgus deformity with conventional, crossed, solid core, screw fixation, were enrolled in an early weightbearing protocol, and were followed for 12 months. All the patients were partial weightbearing in a protective boot a mean of 12.2 (SD +/- 4.36) days after surgery, with full weightbearing at 34.4 (SD +/- 11.89) days. Union was achieved in 133 patients (97.8%). Of the 3 (2.2%) patients with nonunion, 2 (1.5%) remained asymptomatic. The mean time to radiographic union was 65 (SD +/- 37.24) days. Significant improvement was seen in the first intermetatarsal angle and hallux abductus angle after surgery (p < .0001). Deformity correction was not compromised by early weightbearing and was well maintained over time. These results support early weightbearing with traditional crossed screw fixation for modified Lapidus arthrodesis with outcomes and complication rates comparable to those previously published. PMID- 25451209 TI - Negative pressure wound therapy in the management of late deep infections after open reconstruction of achilles tendon rupture. AB - Infection is a major complication after open reconstruction of Achilles tendon ruptures. We report on the use of vacuum-assisted closure (VAC) therapy in the treatment of late deep infections after open Achilles tendon reconstruction. Six patients (5 males [83.33%], 1 female [16.67%]; mean age, 52.8 [range 37 to 66] years) were been treated using an identical protocol. Surgical management consisted of debridement, lavage, and necrectomy of infected tendon parts. The VAC therapy was used for local wound preconditioning and infection management. A continuous negative pressure of 125 mm Hg was applied on each wound. For final wound closure, a split-thickness skin graft was performed. The skin graft healing process was also supported by VAC therapy during the first 5 days. The VAC dressings were changed a mean average of 3 (range 1 to 4) times until split thickness skin grafting could be performed. The mean total duration of the VAC therapy was 13.6 +/- 5.9 days. The mean hospital stay was 31.2 +/- 15.9 days. No complications with regard to bleeding, seroma, or hematoma formation beneath the skin graft were observed. At a mean follow-up duration of 29.9 (range 4 to 65) months, no re-infection or infection persistence was observed. The VAC device seems to be a valuable tool in the treatment of infected tendons. The generalization of these conclusions should await the results of future studies with larger patient series. PMID- 25451210 TI - Pneumococcal meningitis: epidemiological profile pre- and post-introduction of the pneumococcal 10-valent conjugate vaccine. AB - OBJECTIVES: To evaluate the possible effects of the introduction of the pneumococcal conjugate 10-valent vaccine schedule in the state of Parana on pneumococcal meningitis cases and to assess the distribution of serotypes among cases. METHOD: Cross-sectional study with retrospective data collection of cases of pneumococcal meningitis in the state of Parana reported to Sistema de Informacao de Agravos de Notificacao (SINAN), from 1998 to 2011. A total of 1,339 cases of pneumococcal meningitis were analyzed; 1,205 cases from the pre-vaccine period (1998-2009) were compared to 134 cases from the post-vaccine period (2010 2011). Descriptive and comparative statistical analyses (chi-squared test and prevalence ratio) were performed using JMP 5.1.2 statistical software (JMP Statistical Discovery, North Carolina, USA) and EPI INFO 6 (Centers for Disease Control and Prevention, Georgia, EUA). RESULTS: There was a significant reduction in the mean rates of incidence and mortality in the general population. The analysis of cases in the pre- and post-vaccination periods in the age groups covered by vaccination (younger than 2 years) showed significant reductions in incidence rates (6.01 cases/100,000 to 2.49 cases/100,000 individuals) and mortality (1.85 cases/100,000 population to 0.47 cases/100,000 population), while the mean lethality rate did not change significantly. There was a significant reduction in cases whose serotypes are included in the vaccine (80.7% to 53.3%). CONCLUSION: Even after a short time of use, the 10-valent pneumococcal conjugate vaccine has already had a significant impact in reducing the incidence and mortality of meningitis cases among infants, as well as the reduction of cases whose serotypes are included in the vaccine. PMID- 25451211 TI - Systematic review: hereditary thrombophilia associated to pediatric strokes and cerebral palsy. AB - OBJECTIVES: This review aimed to organize and consolidate the latest knowledge about mutations and genetic polymorphisms related to hereditary thrombophilia and their potential association with pediatric stroke and cerebral palsy (CP). SOURCES: Scientific articles published from 1993 to 2013, written in Portuguese, English, French, and Spanish, were selected and reviewed. The publications were searched in electronic databases, and also in the collections of local libraries. The terms "hereditary thrombophilia", "polymorphisms", "mutation", "pediatric strokes", and "cerebral palsy" were used for the research. SUMMARY OF THE FINDINGS: The search in databases and in the bibliographic references retrieved 75 articles for inclusion in this review. Studies that investigated hereditary thrombophilias and their associations to CP and arterial and venous pediatric stroke presented contradictory results. The meta-analysis and case-control studies that showed positive results for this association described only slightly increased relative risks and sometimes had questionable conclusions. The association of two or more hereditary thrombophilias, or the association between thrombophilia and other specific clinical risk factors, suggest a higher risk of CP and pediatric stroke than isolated hereditary thrombophilia. CONCLUSIONS: Larger, multicenter studies should be developed in order to elucidate the role of mutations leading to hereditary thrombophilia and the development of CP and pediatric stroke. The complex and multifactorial etiology of CP and stroke makes this an arduous and difficult task; however, the benefits generated by these studies are immeasurable. PMID- 25451212 TI - Characterization of the binding properties of T-773 as a PET radioligand for phosphodiesterase 10A. AB - INTRODUCTION: Phosphodiesterase 10A (PDE10A) is a dual-substrate PDE that hydrolyzes both cAMP and cGMP and is selectively expressed in striatal medium spiny neurons. Recent studies have suggested that PDE10A inhibition is a novel approach for the treatment of disorders such as schizophrenia and Huntington's disease. A positron emission tomography (PET) occupancy study can provide useful information for the development of PDE10A inhibitors. We discovered T-773 as a candidate PET radioligand for PDE10A and investigated its properties by in vitro autoradiography and a PET study in a monkey. METHODS: Profiling of T-773 as a PET radioligand for PDE10A was conducted by in vitro enzyme inhibitory assay, in vitro autoradiography, and PET study in a monkey. RESULTS: T-773 showed a high binding affinity and selectivity for human recombinant PDE10A2 in vitro; the IC50 value in an enzyme inhibitory assay was 0.77nmol/L, and selectivity over other PDEs was more than 2500-fold. In autoradiography studies using mouse, rat, monkey, or human brain sections, radiolabeled T-773 selectively accumulated in the striatum. This selective accumulation was not observed in the brain sections of Pde10a-KO mice. The binding of [(3)H]T-773 to PDE10A in rat brain sections was competitively inhibited by MP-10, a selective PDE10A inhibitor. In rat brain sections, [(3)H]T-773 bound to a single high affinity site of PDE10A with Kd values of 12.2+/-2.2 and 4.7+/-1.2nmol/L in the caudate-putamen and nucleus accumbens, respectively. In a monkey PET study, [(11)C]T-773 showed good brain penetration and striatum-selective accumulation. CONCLUSION: These results suggest that [(11)C]T-773 is a potential PET radioligand for PDE10A. PMID- 25451213 TI - Preclinical evaluation of [(18)F]PK-209, a new PET ligand for imaging the ion channel site of NMDA receptors. AB - INTRODUCTION: The present study was designed to assess whether [(18)F]PK-209 (3 (2-chloro-5-(methylthio)phenyl)-1-(3-([(18)F]fluoromethoxy)phenyl)-1 methylguanidine) is a suitable ligand for imaging the ion-channel site of N methyl-D-aspartate receptors (NMDArs) using positron emission tomography (PET). METHODS: Dynamic PET scans were acquired from male rhesus monkeys over 120min, at baseline and after the acute administration of dizocilpine (MK-801, 0.3mg/kg; n=3/condition). Continuous and discrete arterial blood samples were manually obtained, to generate metabolite-corrected input functions. Parametric volume-of distribution (VT) images were obtained using Logan analysis. The selectivity profile of PK-209 was assessed in vitro, on a broad screen of 79 targets. RESULTS: PK-209 was at least 50-fold more selective for NMDArs over all other targets examined. At baseline, prolonged retention of radioactivity was observed in NMDAr-rich cortical regions relative to the cerebellum. Pretreatment with MK 801 reduced the VT of [(18)F]PK-209 compared with baseline in two of three subjects. The rate of radioligand metabolism was high, both at baseline and after MK-801 administration. CONCLUSIONS: PK-209 targets the intrachannel site with high selectivity. Imaging of the NMDAr is feasible with [(18)F]PK-209, despite its fast metabolism. Further in vivo evaluation in humans is warranted. PMID- 25451214 TI - The feasibility of imaging myocardial ischemic/reperfusion injury using (99m)Tc labeled duramycin in a porcine model. AB - When pathologically externalized, phosphatidylethanolamine (PE) is a potential surrogate marker for detecting tissue injuries. (99m)Tc-labeled duramycin is a peptide-based imaging agent that binds PE with high affinity and specificity. The goal of the current study was to investigate the clearance kinetics of (99m)Tc labeled duramycin in a large animal model (normal pigs) and to assess its uptake in the heart using a pig model of myocardial ischemia-reperfusion injury. METHODS: The clearance and distribution of intravenously injected (99m)Tc duramycin were characterized in sham-operated animals (n=5). In a closed chest model of myocardial ischemia, coronary occlusion was induced by balloon angioplasty (n=9). (99m)Tc-duramycin (10-15mCi) was injected intravenously at 1hour after reperfusion. SPECT/CT was acquired at 1 and 3hours after injection. Cardiac tissues were analyzed for changes associated with acute cellular injuries. Autoradiography and gamma counting were used to determine radioactivity uptake. For the remaining animals, (99m)Tc-tetrafosamin scan was performed on the second day to identify the infarct site. RESULTS: Intravenously injected (99m)Tc duramycin cleared from circulation predominantly via the renal/urinary tract with an alpha-phase half-life of 3.6+/-0.3minutes and beta-phase half-life of 179.9+/ 64.7minutes. In control animals, the ratios between normal heart and lung were 1.76+/-0.21, 1.66+/-0.22, 1.50+/-0.20 and 1.75+/-0.31 at 0.5, 1, 2 and 3hours post-injection, respectively. The ratios between normal heart and liver were 0.88+/-0.13, 0.80+/-0.13, 0.82+/-0.19 and 0.88+/-0.14. In vivo visualization of focal radioactivity uptake in the ischemic heart was attainable as early as 30min post-injection. The in vivo ischemic-to-normal uptake ratios were 3.57+/-0.74 and 3.69+/-0.91 at 1 and 3hours post-injection, respectively. Ischemic-to-lung ratios were 4.89+/-0.85 and 4.93+/-0.57; and ischemic-to-liver ratios were 2.05+/-0.30 to 3.23+/-0.78. The size of (99m)Tc-duramycin positive myocardium was qualitatively larger than the infarct size delineated by the perfusion defect in (99m)Tc-tetrafosmin uptake. This was consistent with findings from tissue analysis and autoradiography. CONCLUSION: (99m)Tc-duramycin was demonstrated, in a large animal model, to have suitable clearance and biodistribution profiles for imaging. The agent has an avid target uptake and a fast background clearance. It is appropriate for imaging myocardial injury induced by ischemia/reperfusion. PMID- 25451216 TI - N-[(11)C]-methyl-hydroxyfasudil is a potential biomarker of cardiac hypertrophy. AB - INTRODUCTION: Pathologic cardiac hypertrophy is one of the leading causes of sudden death from cardiac disease and involves a complex network of bio-signaling mechanisms. To date, the clinical detection and pathologic progression of hypertrophy remains elusive. Here we tested whether imaging Rho kinase activity would serve an accurate proxy for detecting hypertrophy. Specifically, we examine the use of the N-[(11)C]-methylated derivative of hydroxyfasudil, a Rho kinase inhibitor, as a biomarker for accurate identification of cardiomyocyte hypertrophy. METHODS: Both transformed and primary neonatal cardiomyocytes were treated with isoproterenol to induce beta-adrenergic receptor stimulation and hypertrophy. Phenotypic hypertrophy was verified using cytochemical evaluation of cell and nuclear size. Western blot and activity assays were used to detect ERK 1/2 mTOR and Rho kinase activation. N-[(11)C]-methyl-hydroxyfasudil binding was verified using in vitro binding assays with isoproterenol stimulated cells. RESULTS: Isoproterenol induced a rapid and distinct activation of ERK 1/2, mTOR and Rho kinase with negligible cytotoxicity. Subsequent expansion in cell and nuclear size that is typically associated with hypertrophy was also observed. Enhanced retention of N-[(11)C]-methyl-hydroxyfasudil observed after ISO-induced Rho kinase activation in hypertrophic cells was prevented by pre-treatment with unlabeled hydroxyfasudil. CONCLUSIONS: N-[(11)C]-methyl-hydroxyfasudil is able to measure increased Rho kinase activity via specific binding in hypertrophied cardiomyocytes and demonstrates the potential for molecular imaging of altered Rho kinase activity in diseases such as cardiac hypertrophy. PMID- 25451217 TI - Phylogeny and evolution of apicoplasts and apicomplexan parasites. AB - The phylum Apicomplexa includes many parasitic genera of medical and veterinary importance including Plasmodium (causative agent of malaria), Toxoplasma (toxoplasmosis), and Babesia (babesiosis). Most of the apicomplexan parasites possess a unique, essential organelle, the apicoplast, which is a plastid without photosynthetic ability. Although the apicoplast is considered to have evolved through secondary endosymbiosis of a red alga into the common ancestral cell of apicomplexans, its evolutionary history has been under debate until recently. The apicoplast has a genome around 30-40 kb in length. Repertoire and arrangement of the apicoplast genome-encoded genes differ among apicomplexan genera, although within the genus Plasmodium these are almost conserved. Genes in the apicoplast genome may be useful markers for Plasmodium phylogeny, because these are single copy (except for the inverted repeat region) and may have more phylogenetic signal than the mitochondrial genome that have been most commonly used for Plasmodium phylogeny. This review describes recent studies concerning the evolutionary origin of the apicoplast, presents evolutionary comparison of the primary structures of apicoplast genomes from apicomplexan parasites, and summarizes recent findings of malaria phylogeny based on apicoplast genome encoded genes. PMID- 25451215 TI - The pharmacokinetics of Zr-89 labeled liposomes over extended periods in a murine tumor model. AB - (89)Zr (t1/2=78.4h), a positron-emitting metal, has been exploited for PET studies of antibodies because of its relatively long decay time and facile labeling procedures. Here, we used (89)Zr to evaluate the pharmacokinetics of long-circulating liposomes over 168h (1week). We first developed a liposomal labeling method using p-isothiocyanatobenzyl-desferrioxamine (df-Bz-NCS) and df PEG1k-DSPE. Df-Bz-NCS was conjugated to 1mol% amino- and amino-PEG2k-DSPE, where the 1mol% df-PEG1k-DSPE was incorporated when the liposomes were formulated. Incubation of (89)Zr with df, df-PEG1k, and df-PEG2k liposomes for one hour resulted in greater than 68% decay-corrected yield. The loss of the (89)Zr label from liposomes after incubation in 50% human serum for 48h ranged from ~1 to 3% across the three formulations. Tail vein administration of the three liposomal formulations in NDL tumor-bearing mice showed that the (89)Zr label at the end of the PEG2k brush was retained in the tumor, liver, spleen and whole body for a longer time interval than (89)Zr labels located under the PEG2k brush. The blood clearance rate of all three liposomal formulations was similar. Overall, the results indicate that the location of the (89)Zr label altered the clearance rate of intracellularly-trapped radioactivity and that df-PEG1k-DSPE provides a stable chelation site for liposomal or lipid-based particle studies over extended periods of time. PMID- 25451218 TI - Instar growth and molt increments in Lepeophtheirus salmonis (Copepoda: Caligidae) chalimus larvae. AB - The salmon louse (Lepeophtheirus salmonis) is an ectoparasitic copepod causing severe problems to the fish farming industry and to wild salmonids. Morphologically, all stages in the life cycle of L. salmonis have been described in detail based on successive samples from host populations. However, the rate of development differs between males and females as well as between individuals. It has therefore been difficult to observe development within stages, and this has led to a longstanding misinterpretation of the number of chalimus stages. Here samples of chalimi obtained for 12 consecutive days were observed daily in incubators. Chalimus 1 was able to molt in incubators only when fully grown and close to molting, whereas chalimus 2 was able to molt at about 60% of total instar growth. Total length instar growth was about 35% in both chalimus 1 and chalimus 2 and about equal among males and females; the cephalothorax increased by about 12% and the posterior body by about 80%. Instar growth was probably the main factor that led to the former belief that L. salmonis had four chalimus stages. Relative total length increase at molting was at the same order of magnitude as instar growth, but total length of females increased significantly more than that of males at molting. Consequently, a sexual size dimorphism was established upon molting to chalimus 2 and males were about 10% smaller than females. While growth by molting was mainly caused by cephalothorax increase, instar growth was mainly due to increase of the posterior body. The cephalothorax/total length ratio decreased from beginning to end of the instar phase suggesting that it may be used as an instar age marker. Male and female chalimus 2 can almost uniquely be identified by cephalothorax length. Chalimus 1 lasted between 5 and 6 days for males and between 6 and 7 days for females at 10 degrees C. Chalimus 2 males lasted between 6 and 7 days and females between 7 and 8 days. PMID- 25451219 TI - What did we learn from "isolated subcutaneous hydatid cysts" about the transmission ways of Echinococcus granulosus? PMID- 25451220 TI - What we learnt from "isolated subcutaneous hydatid cysts" about the transmission ways of Echinococcus? PMID- 25451221 TI - Epigenetic regulation of the NR4A orphan nuclear receptor NOR1 by histone acetylation. AB - The nuclear receptor NOR1 is an immediate-early response gene implicated in the transcriptional control of proliferation. Since the expression level of NOR1 is rapidly induced through cAMP response element binding (CREB) protein-dependent promoter activation, we investigated the contribution of histone acetylation to this transient induction. We demonstrate that NOR1 transcription is induced by histone deacetylase (HDAC) inhibition and by depletion of HDAC1 and HDAC3. HDAC inhibition activated the NOR1 promoter, increased histone acetylation and augmented the recruitment of phosphorylated CREB to the promoter. Furthermore, HDAC inhibition increased Ser133 phosphorylation of CREB and augmented NOR1 protein stability. These data outline previously unrecognized mechanisms of NOR1 regulation and illustrate a key role for histone acetylation in the rapid induction of NOR1. PMID- 25451222 TI - Hypoxia reduces MAX expression in endothelial cells by unproductive splicing. AB - The MYC-MAX-MXD network is involved in the regulation of cell differentiation and proliferation. Hypoxia affects the expression levels of several members of this network, but changes specific to MAX expression have so far not been shown. We found that in endothelial cells, hypoxia induces alternative splicing of MAX, thereby increasing the expression of two MAX isoforms that differ from the wild type in their 3' end. Isoform C is degraded by nonsense-mediated decay and isoform E encodes a highly unstable protein. The instability of isoform E is conferred by 36 isoform-specific amino acids, which have the capacity to destabilize heterologous proteins. Both splicing events are therefore unproductive and serve the purpose to downregulate the wild type protein. PMID- 25451223 TI - GBF/Gea mutant with a single substitution sustains fungal growth in the absence of BIG/Sec7. AB - Golgi Arf1-guanine nucleotide exchange factors (GEFs) belong to two subfamilies: GBF/Gea and BIG/Sec7. Both are conserved across eukaryotes, but the physiological role of each is not well understood. Aspergillus nidulans has a single member of the early Golgi GBF/Gea-subfamily, geaA, and the late Golgi BIG/Sec7-subfamily, hypB. Both geaA and hypB are essential. hypB5 conditionally blocks secretion. We sought extragenic hypB5 suppressors and obtained geaA1. geaA1 results in Tyr1022Cys within a conserved GBF/Gea-specific S(Y/W/F)(L/I) motif in GeaA. This mutation alters GeaA localization. Remarkably, geaA1 suppresses hypBDelta, indicating that a single mutant Golgi Arf1-GEF suffices for growth. PMID- 25451224 TI - miR-25 alleviates polyQ-mediated cytotoxicity by silencing ATXN3. AB - MicroRNAs (miRNAs) have been reported to play significant roles in the pathogenesis of various polyQ diseases. This study aims to investigate the regulation of ATXN3 gene expression by miRNA. We found that miR-25 reduced both wild-type and polyQ-expanded mutant ataxin-3 protein levels by interacting with the 3'UTR of ATXN3 mRNA. miR-25 also increased cell viability, decreased early apoptosis, and downregulated the accumulation of mutant ataxin-3 protein aggregates in SCA3/MJD cells. These novel results shed light on the potential role of miR-25 in the pathogenesis of SCA3/MJD, and provide a possible therapeutic intervention for this disorder. PMID- 25451225 TI - Glutamine synthetase desensitizes differentiated adipocytes to proinflammatory stimuli by raising intracellular glutamine levels. AB - The role of glutamine synthetase (GS) during adipocyte differentiation is unclear. Here, we assess the impact of GS on the adipocytic response to a proinflammatory challenge at different differentiation stages. GS expression at the late stages of differentiation desensitized mature adipocytes to bacterial lipopolysaccharide (LPS) by increasing intracellular glutamine levels. Furthermore, LPS-activated mature adipocytes were unable to produce inflammatory mediators; LPS sensitivity was rescued following GS inhibition and the associated drop in intracellular glutamine levels. The ability of adipocytes to differentially respond to LPS during differentiation negatively correlates to GS expression and intracellular glutamine levels. Hence, modulation of intracellular glutamine levels by GS expression represents an endogenous mechanism through which mature adipocytes control the inflammatory response. PMID- 25451226 TI - Identification of the WNT1 residues required for palmitoylation by Porcupine. AB - The post-translational palmitoylation of WNT morphogens is critical for proper signaling during embryogenesis and adult homeostasis. The addition of palmitoyl groups to WNT proteins is catalyzed by Porcupine (PORCN). However, the Wnt amino acid residues required for recognition and palmitoylation by PORCN have not been fully characterized. We show that WNT1 residues 214-234 are sufficient for PORCN dependent palmitoylation of Ser224. Substitution of Ser224 with Thr, but not Cys, is tolerated in palmitoylation and biological assays. Our data highlight the importance of palmitoylation for WNT1 activity and establish PORCN as an O-acyl transferase for WNT1. PMID- 25451228 TI - PACAP inhibits tumor growth and interferes with clusterin in cervical carcinomas. AB - Secretory clusterin (sCLU), an anti-apoptotic protein, is overexpressed in many tumors and enhances tumorigenesis and chemo-resistance. However, the regulation mechanism controlling the sCLU maturation process or activity remains undetermined. In this study, we found PACAP as a negative regulator of CLU. Overexpression of the PACAP gene in cervical cancer cell lines lacking PACAP expression significantly inhibited cell growth and induced apoptosis. We further demonstrated that interaction of PACAP with CLU significantly downregulated CLU expression and secretion, inhibited the Akt-Raf-ERK pathway, and suppressed the growth of human tumor xenografts in nude mice. This novel inhibitory function of PACAP may be applicable for developing novel molecular therapies for tumors with increased sCLU expression. PMID- 25451227 TI - Crystal structures of sialyltransferase from Photobacterium damselae. AB - Sialyltransferase structures fall into either GT-A or GT-B glycosyltransferase fold. Some sialyltransferases from the Photobacterium genus have been shown to contain an additional N-terminal immunoglobulin (Ig)-like domain. Photobacterium damselae alpha2-6-sialyltransferase has been used efficiently in enzymatic and chemoenzymatic synthesis of alpha2-6-linked sialosides. Here we report three crystal structures of this enzyme. Two structures with and without a donor substrate analog CMP-3F(a)Neu5Ac contain an immunoglobulin (Ig)-like domain and adopt the GT-B sialyltransferase fold. The binary structure reveals a non productive pre-Michaelis complex, which are caused by crystal lattice contacts that prevent the large conformational changes. The third structure lacks the Ig domain. Comparison of the three structures reveals small inherent flexibility between the two Rossmann-like domains of the GT-B fold. PMID- 25451229 TI - RPA-1 from Leishmania amazonensis (LaRPA-1) structurally differs from other eukaryote RPA-1 and interacts with telomeric DNA via its N-terminal OB-fold domain. AB - Replication protein A-1 (RPA-1) is a single-stranded DNA-binding protein involved in DNA metabolism. We previously demonstrated the interaction between LaRPA-1 and telomeric DNA. Here, we expressed and purified truncated mutants of LaRPA-1 and used circular dichroism measurements and molecular dynamics simulations to demonstrate that the tertiary structure of LaRPA-1 differs from human and yeast RPA-1. LaRPA-1 interacts with telomeric ssDNA via its N-terminal OB-fold domain, whereas RPA from higher eukaryotes show different binding modes to ssDNA. Our results show that LaRPA-1 is evolutionary distinct from other RPA-1 proteins and can potentially be used for targeting trypanosomatid telomeres. PMID- 25451230 TI - An improved capping unit for stabilizing the ends of associated beta-strands. AB - Understanding protein beta structures has been hindered by the challenge of designing small, well-folded beta-sheet systems. A beta-capping motif was previously designed to help solve this problem, but not without limitations, as the termini of this beta-cap were not fully available for chain extension. Combining Coulombic side chain attractions with a Trp/Trp edge-to-face interaction we produced a new capping motif that provided greater beta-sheet stability. This stability was maintained even in systems lacking a turn locus with a high propensity for chain direction reversal. The Coulombic cap was shown to improve beta-sheet stability in a number of difficult systems, hence providing an additional tool for protein structure and folding studies. PMID- 25451231 TI - Crystal structure of the rigor-like human non-muscle myosin-2 motor domain. AB - We determined the crystal structure of the motor domain of human non-muscle myosin 2B (NM-2B) in a nucleotide-free state and at a resolution of 2.8 A. The structure shows the motor domain with an open active site and the large cleft that divides the 50 kDa domain in a closed state. Compared to other rigor-like myosin motor domain structures, our structure shows subtle but significant conformational changes in regions important for actin binding and mechanochemical coupling. Moreover, our crystal structure helps to rationalize the impact of myosin, heavy chain 9 (MYH9)-related disease mutations Arg709Cys and Arg709His on the kinetic and functional properties of NM-2B and of the closely related non muscle myosin 2A (NM-2A). PMID- 25451232 TI - miR-96 promotes osteogenic differentiation by suppressing HBEGF-EGFR signaling in osteoblastic cells. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs with important roles in various biological and pathological processes, including osteoblast differentiation. Here, we identified miR-96 as a positive regulator of osteogenic differentiation in a mouse osteoblastic cell line (MC3T3-E1) and in mouse bone marrow-derived mesenchymal stem cells. Moreover, we found that miR-96 down regulates post-transcriptional expression of heparin-binding EGF-like growth factor (HB-EGF) by specifically binding to the 3'untranslated region of HB-EGF mRNA. Furthermore, in MC3T3-E1 cells, miR-96-induced HB-EGF down-regulation suppressed the phosphorylation of epidermal growth factor receptor (EGFR) and of extracellular signal-regulated kinase 1 (ERK1) and AKT, which both lie downstream of EGFR activation. Taken together, miR-96 promotes osteogenic differentiation by inhibiting HB-EGF and by blocking the HB-EGF-EGFR signaling pathway in osteoblastic cells. PMID- 25451233 TI - CXCL14 is no direct modulator of CXCR4. AB - C-X-C motif chemokine 12/C-X-C chemokine receptor type 4 (CXCL12/CXCR4) signaling is involved in ontogenesis, hematopoiesis, immune function and cancer. Recently, the orphan chemokine CXCL14 was reported to inhibit CXCL12-induced chemotaxis - probably by allosteric modulation of CXCR4. We thus examined the effects of CXCL14 on CXCR4 regulation and function using CXCR4-transfected human embryonic kidney (HEK293) cells and Jurkat T cells. CXCL14 did not affect dose-response profiles of CXCL12-induced CXCR4 phosphorylation, G protein-mediated calcium mobilization, dynamic mass redistribution, kinetics of extracellular signal regulated kinase 1 (ERK1) and ERK2 phosphorylation or CXCR4 internalization. Hence, essential CXCL12-operated functions of CXCR4 are insensitive to CXCL14, suggesting that interactions of CXCL12 and CXCL14 pathways depend on a yet to be identified CXCL14 receptor. PMID- 25451234 TI - A novel packing arrangement of AcrB in the lipid bilayer membrane. AB - The central component AcrB of the Escherichia coli drug efflux complex AcrA-AcrB TolC has been extensively investigated by X-ray crystallography of detergent protein 3-D crystals. In these crystals, AcrB packs as trimers - the functional unit. We visualized the AcrB-AcrB interaction in its native environment by examining E. coli lipid reconstituted 2-D crystals, which were overwhelmingly formed by asymmetric trimers stabilized by strongly-interacting monomers from adjacent trimers. Most interestingly, we observed lattices formed by an arrangement of AcrB monomers distinct from that in traditional trimers. This hitherto unobserved packing, might play a role in the biogenesis of trimeric AcrB. PMID- 25451235 TI - An engineered dimeric fragment of hepatocyte growth factor is a potent c-MET agonist. AB - Hepatocyte growth factor (HGF), through activation of the c-MET receptor, mediates biological processes critical for tissue regeneration; however, its clinical application is limited by protein instability and poor recombinant expression. We previously engineered an HGF fragment (eNK1) that possesses increased stability and expression yield and developed a c-MET agonist by coupling eNK1 through an introduced cysteine residue. Here, we further characterize this eNK1 dimer and show it elicits significantly greater c-MET activation, cell migration, and proliferation than the eNK1 monomer. The efficacy of the eNK1 dimer was similar to HGF, suggesting its promise as a c-MET agonist. PMID- 25451237 TI - Increased alcohol consumption in urocortin 3 knockout mice is unaffected by chronic inflammatory pain. AB - AIMS: Stress neurocircuitry may modulate the relationship between alcohol drinking and chronic pain. The corticotropin-releasing factor (CRF) system is crucial for regulation of stress responses. The current study aimed to elucidate the role of the endogenous CRF ligand Urocortin 3 (Ucn3) in the relationship between alcohol drinking behavior and chronic pain using a genetic approach. METHODS: Ucn3 (KO) and wildtype (WT) littermates were subjected to a 24-h access drinking procedure prior to and following induction of chronic inflammatory pain. RESULTS: Ucn3 KO mice displayed significantly increased ethanol intake and preference compared with WT across the time course. There were no long-term effects of chronic pain on alcohol drinking behavior, regardless of genotype, nor any evidence for alcohol-induced analgesia. CONCLUSION: The increased drinking in Ucn3 KO supports a role for this peptide in alcohol-related behavior. These data suggest the necessity for more research exploring the relationship between alcohol drinking, chronic pain and the CRF system in rodent models. PMID- 25451239 TI - Temporal dynamics of different cases of bi-stable figure-ground perception. AB - Segmentation of a visual scene in "figure" and "ground" is essential for perception of the three-dimensional layout of a scene. In cases of bi-stable perception, two distinct figure-ground interpretations alternate over time. We were interested in the temporal dynamics of these alternations, in particular when the same image is presented repeatedly, with short blank periods in-between. Surprisingly, we found that the intermittent presentation of Rubin's classical "face-or-vase" figure, which is frequently taken as a standard case of bi-stable figure-ground perception, often evoked perceptual switches during the short presentations and stabilization was not prominent. Interestingly, bi-stable perception of Kanizsa's anomalous transparency figure did strongly stabilize across blanks. We also found stabilization for the Necker cube, which we used for comparison. The degree of stabilization (and the lack of it) varied across stimuli and across individuals. Our results indicate, against common expectation, that the stabilization phenomenon cannot be generally evoked by intermittent presentation. We argue that top-down feedback factors such as familiarity, semantics, expectation, and perceptual bias contribute to the complex processes underlying the temporal dynamics of bi-stable figure-ground perception. PMID- 25451238 TI - Nurse practitioner knowledge, use, and referral of complementary/alternative therapies. AB - PURPOSE: The study aims are to (a) describe nurse practitioners' (NPs') belief in effectiveness, knowledge, referral, and use of complementary/alternative therapies (C/ATs), (b) explore the initiation of C/AT dialogue between NPs and their patients, and (c) examine the relationships between demographic variables and NP C/AT knowledge, beliefs, use, referrals. DATA SOURCES: A mixed-method cross-sectional online survey of licensed NPs (N = 2874) from a Midwestern state was analyzed using descriptive statistics, thematic analysis, and content analysis. CONCLUSIONS: NPs (n = 410) report the most knowledge about prayer (40%) and mind-body practices (32%). Many NPs (84%) report using vitamins for personal use and 85% refer their patients for massage/bodywork. Most (95%) believe NPs should have knowledge of the most common C/AT and 81% believe C/AT have a legitimate use in allopathic medicine. NPs' knowledge, belief, use, and referral of C/AT are significantly correlated. NPs initiate C/AT dialogue with their patients 54% of the time. Factors that impact the NP and patient C/AT dialogue include patient/family openness, nature of the health problem, NP C/AT knowledge, time, and accessibility. IMPLICATIONS FOR PRACTICE: Centralized C/AT sources could help expedite C/AT referrals. Implementing workplace C/AT clinics could help build knowledge, referral, personal use, and acceptance of C/AT. PMID- 25451236 TI - Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging related susceptibility to lung fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder with unknown cause and no effective treatment. The incidence of and mortality from IPF increase with age, suggesting that advanced age is a major risk factor for IPF. The mechanism underlying the increased susceptibility of the elderly to IPF, however, is unknown. In this study, we show for the first time that the protein level of plasminogen activator inhibitor 1 (PAI-1), a protease inhibitor which plays an essential role in the control of fibrinolysis, was significantly increased with age in mouse lung homogenate and lung fibroblasts. Upon bleomycin challenge, old mice experienced augmented PAI-1 induction and lung fibrosis as compared to young mice. Most interestingly, we show that fewer (myo)fibroblasts underwent apoptosis and more (myo)fibroblasts with increased level of PAI-1 accumulated in the lung of old than in young mice after bleomycin challenge. In vitro studies further demonstrate that fibroblasts isolated from lungs of old mice were resistant to H2O2 and tumor necrosis factor alpha-induced apoptosis and had augmented fibrotic responses to TGF-beta1, compared to fibroblasts isolated from young mice. Inhibition of PAI-1 activity with a PAI-1 inhibitor, on the other hand, eliminated the aging-related apoptosis resistance and TGF-beta1 sensitivity in isolated fibroblasts. Moreover, we show that knocking down PAI-1 in human lung fibroblasts with PAI-1 siRNA significantly increased their sensitivity to apoptosis and inhibited their responses to TGF-beta1. Together, the results suggest that increased PAI-1 expression may underlie the aging-related sensitivity to lung fibrosis in part by protecting fibroblasts from apoptosis. PMID- 25451240 TI - Dissecting perception and memory-driven imagery by boosting GABA-ergic neurotransmission. AB - Flanking lateral masks enhance or weaken the detection of a low-contrast visual target. This effect depends on the target-to-mask distance. An improvement of stimulus detection can also be observed when participants imagine (i.e., retrieve from memory) the previously presented masks. In this double-blind, placebo controlled study, we show that the gamma-aminobutyric acid-A (GABAA) receptor agonist alprazolam disrupts perceptual but not imagery enhancement of contrast detection in individuals with generalized anxiety and adjustment disorder. The weakened target detection at short target-to-mask distances became more pronounced after the administration of the GABA-agonist in both perception and imagery conditions. Healthy control participants did not differ from individuals with generalized anxiety and adjustment disorder receiving placebo. These results indicate that perception and imagery can be dissociated by boosting GABA-ergic neurotransmission. Further studies are warranted to investigate this effect in healthy individuals. PMID- 25451241 TI - Goal-oriented gaze strategies afforded by object interaction. AB - Task influence has long been known to play a major role in the way our eyes scan a scene. Yet most studies focus either on visual search or on sequences of active tasks in complex real world scenarios. Few studies have contrasted the distribution of eye fixations during viewing and grasping objects. Here we address how attention is deployed when different actions are planned on objects, in contrast to when the same objects are categorized. In this respect, we are particularly interested in the role every fixation plays in the unfolding dynamics of action control. We conducted an eye-tracking experiment in which participants were shown images of real-world objects. Subjects were either to assign the displayed objects to one of two classes (categorization task), to mimic lifting (lifting task), or to mimic opening the object (opening task). Results suggest that even on simplified, two dimensional displays the eyes reveal the participant's intentions in an anticipatory fashion. For the active tasks, already the second saccade after stimulus onset was directed towards the central region between the two locations where the thumb and the rest of the fingers would be placed. An analysis of saliency at fixation locations showed that fixations in active tasks have higher correspondence with salient features than fixations in the passive task. We suggest that attention flexibly coordinates visual selection for information retrieval and motor planning, working as a gateway between three components, linking the task (action), the object (target), and the effector (hand) in an effective way. PMID- 25451242 TI - Temporal summation of global form signals in dynamic Glass patterns. AB - The ability to perceive complex objects in the environment requires that the visual system integrate local form information into global shapes. Glass patterns (GPs) are stimuli that are commonly used to study this integration process. GPs consist of randomly positioned dot-pairs oriented in a coherent way to create a global form. When multiple GPs are presented sequentially, observers report a percept of illusory coherent motion and have lower detection thresholds relative to a single presentation GPs. The percept of illusory motion has been attributed to the visual system interpreting the dot-pairs in GPs as motion streaks. However, it remains unclear why dynamic GPs are detected at lower thresholds than static GPs. Two main differences exist between static and dynamic GPs: (a) dynamic GPs contain multiple presentations of global form signals compared to a single presentation in static GPs and (b) dynamic GPs have a greater temporal frequency than static GPs. Here we investigated which of these two factors contributed to the heightened sensitivities for dynamic GPs. We systematically varied the number of unique GPs and the rate at which each unique frame is presented (i.e., temporal frequency). The results show that, within the range of temporal frequency used, the primary influence on detection thresholds was the number of unique frames. These results suggest that the improved detection sensitivities can be driven by a mechanism of temporal summation of global form. PMID- 25451243 TI - Perceived object stability depends on shape and material properties. AB - Humans can detect whether an unstable object will fall or right itself, suggesting that the visual system can extract an object's center of mass (COM) and relate this to its base of support. While the COM can be approximated by its shape, this assumes uniform density. We created images of computer-generated goblets made of different materials to assess whether the visual system estimates an object's COM from both shape and material properties. The images were either uniformly dense (e.g., glass, gold, etc.) or made of composite materials (e.g., glass and gold) and positioned upright or upside-down near a table ledge. We compared each goblet's critical angle (CA), the angle at which each goblet is equally likely to fall or right itself, to the perceived CA in a two-alternative forced-choice paradigm. Participants also rank-ordered 20 materials by density on a questionnaire. The results show that observers accurately estimate the CA for all goblets and are sensitive to subtle changes of an object's COM with change in shape and composite material properties. Importantly, rated density - as measured from the questionnaire - and true material density were positively correlated, suggesting that humans might maintain a representation of relative material density with which to assess object stability. We conclude that the brain is able to assess an object's behavior in a gravitational environment by forming a reliable assessment of an object's COM from both its geometric shape and material properties. PMID- 25451244 TI - Effects of contrast, spatial frequency, and stimulus duration on reaction time in rats. AB - Early visual processing in rats is mediated by several pre-cortical pathways as well as multiple retinal ganglion cell types that vary in response characteristics. Discrete processing is thereby optimized for select ranges of stimulus parameters. In order to explore variation in response characteristics at a perceptual level, visual detection in rats was measured across a range of contrasts, spatial frequencies, and durations. Rats responded to the onset of Gabor patches. Onset time occurred after a random delay, and reaction time (RT) frequency distribution served to index target visibility. It was found that lower spatial frequency produced shorter RTs, as well as increased RT equivalent of contrast gain. Brief stimulus presentation reduced target visibility, slowed RTs, and reduced contrast gain at higher spatial frequencies. However, brief stimuli shortened RTs at low contrasts and low spatial frequencies, suggesting transient stimuli are more efficiently processed under these conditions. Collectively, perceptual characteristics appear to reflect distinctions in neural responses at early stages of processing. The RT characteristics found here may thereby reflect the contribution of multiple channels, and suggest a progressive shift in relative involvement across parameter levels. PMID- 25451245 TI - Are attentional resources a mediator for sex differences in memory? AB - The divided attention paradigm was used to investigate sex differences in encoding and retrieval processes of memory. Participants performed a memory and reaction time (RT) task under full attention and two divided attention conditions, that is, at encoding and retrieval. Results revealed that females recalled significantly more words than males under the full attention and divided attention at encoding conditions. Results further showed that secondary task costs were larger for males than females during divided attention at retrieval. Furthermore, regardless of sex, recall was best under full attention and worst under divided attention at encoding conditions. In relation to the RT task, RTs were shorter under full attention and longer under the divided attention at retrieval condition. Overall, these results show that females recall more words than males possibly due to a more severe effect of reduced attention during encoding than retrieval for males. The current findings thus suggest that a reduction in attentional resources may mediate sex-related decreases in word recall. PMID- 25451246 TI - Developing cognitive-emotional training exercises as interventions for mood and anxiety disorders. AB - There is an urgent need for more effective treatments for mood and anxiety disorders. As our understanding of the cognitive and affective neuroscience underlying psychiatric disorders expands, so do opportunities to develop novel interventions that capitalize on the capacity for brain plasticity. Cognitive training is one such strategy. This paper provides the background and rationale for developing cognitive-emotional training exercises as an intervention strategy, and proposes guidelines for the development and evaluation of cognitive training interventions with a specific focus on major depressive disorder as an example. PMID- 25451247 TI - Cell cycle transcription factor E2F2 mediates non-stress temperature response of AtHSP70-4 in Arabidopsis. AB - AtHSP70 expression exhibits both stress and non-stress temperature response, however, the molecular mechanisms underlying these temperature signaling pathways remain elusive. Here we performed truncation and deletion assay to investigate the cis-elements within the promoter region of AtHSP70-4 (AT3G12580). And found the region between -1000 and -1100 bp from the translation initiation site (TIS) was indispensable for the non-stress temperature response of AtHSP70. Further deletion assay of several candidate motifs within this region suggested that one 'GCGCCAAA' sequence played the critical role. This motif was found as the reverse DNA-binding motif of cell cycle transcription factor E2F family. EMSA assay verified one number of Arabidopsis E2F family-E2F2 could bind to AtHSP70-4 promoter via this motif. These results indicated the temperature regulated expression of AtHSP70-4 may be mediated by cell cycle transcription factors and participate in plant acclimations to non-stress temperature changes. PMID- 25451248 TI - CD47 does not mediate amyloid-beta(1-42) protofibril-stimulated microglial cytokine release. AB - Neuroinflammation triggered by accumulation of amyloid-beta protein (Abeta) is a significant component of the Alzheimer's disease (AD) brain. Senile plaques composed of Abeta attract and activate microglia cells resulting in cytokine secretion and a proinflammatory environment. The mechanism by which Abeta activates microglia is complex and involves numerous cellular components. One receptor potentially involved in Abeta recognition and the ensuing microglia proinflammatory response is CD47. Since there is significant interest in soluble aggregated Abeta species, we sought to determine if CD47 plays a key role in microglia cytokine release stimulated by soluble Abeta(1-42) protofibrils. Pretreatment of primary murine microglia with the CD47 antagonist peptide 4N1K significantly and potently inhibited both tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta) secretion stimulated by Abeta(1-42) protofibrils. 4N1K displayed toxicity to the microglia but only at concentrations much higher than the observed inhibition. Surprisingly, 4N1K also potently inhibited TNFalpha secretion triggered by lipopolysaccharide which is not known to signal through CD47. Treatment of the microglia with a neutralizing anti-CD47 antibody failed to block the Abeta protofibril response even though comparable samples were completely inhibited by 4N1K. Finally, Abeta(1-42) protofibrils stimulated similar levels of secreted TNFalpha production in both wild-type and CD47(-/-) microglia and 4N1K still potently inhibited the Abeta protofibril response even in the CD47(-/-) microglia. The overall findings demonstrated that the microglial proinflammatory response to Abeta(1-42) protofibril is not dependent on CD47 and that 4N1K exhibits CD47-independent inhibitory activity. PMID- 25451249 TI - Disruption of TGF-beta signaling in smooth muscle cell prevents flow-induced vascular remodeling. AB - Transforming growth factor-beta (TGF-beta) signaling has been prominently implicated in the pathogenesis of vascular remodeling, especially the initiation and progression of flow-induced vascular remodeling. Smooth muscle cells (SMCs) are the principal resident cells in arterial wall and are critical for arterial remodeling. However, the role of TGF-beta signaling in SMC for flow-induced vascular remodeling remains unknown. Therefore, the goal of our study was to determine the effect of TGF-beta pathway in SMC for vascular remodeling, by using a genetical smooth muscle-specific (SM-specific) TGF-beta type II receptor (Tgfbr2) deletion mice model. Mice deficient in the expression of Tgfbr2 (MyhCre.Tgfbr2(f/f)) and their corresponding wild-type background mice (MyhCre.Tgfbr2(WT/WT)) underwent partial ligation of left common carotid artery for 1, 2, or 4 weeks. Then the carotid arteries were harvested and indicated that the disruption of Tgfbr2 in SMC provided prominent inhibition of vascular remodeling. And the thickening of carotid media, proliferation of SMC, infiltration of macrophage, and expression of matrix metalloproteinase (MMP) were all significantly attenuated in Tgfbr2 disruption mice. Our study demonstrated, for the first time, that the TGF-beta signaling in SMC plays an essential role in flow-induced vascular remodeling and disruption can prevent this process. PMID- 25451250 TI - A proximity based general method for identification of ligand and receptor interactions in living cells. AB - Autocrine based selections from intracellular combinatorial antibody and peptide libraries have proven to be a powerful method for selection of agonists and identification of new therapeutic targets. However, success requires a case-by case construction of a robust selection system which is a process that can be time consuming and expensive. Here we report a general system that takes advantage of the chemical rate acceleration caused by approximation of a membrane tethered ligand and its receptor. The system uses an artificial signal transduction and is, thus, agnostic to the endogenous signal transduction of the receptor-ligand system. This method allows analysis of receptor-ligand interactions and selection of molecules from large libraries that interact with receptors when they are in their natural milieu. PMID- 25451251 TI - Transplantation of mature adipocyte-derived dedifferentiated fat cells promotes locomotor functional recovery by remyelination and glial scar reduction after spinal cord injury in mice. AB - Mature adipocyte-derived dedifferentiated fat cells (DFAT) have a potential to be useful as new cell-source for cell-based therapy for spinal cord injury (SCI), but the mechanisms remain unclear. The objective of this study was to examine whether DFAT-induced functional recovery is achieved through remyelination and/or glial scar reduction in a mice model of SCI. To accomplish this we subjected adult female mice (n=22) to SCI. On the 8th day post-injury locomotor tests were performed, and the mice were randomly divided into two groups (control and DFAT). The DFAT group received stereotaxic injection of DFAT, while the controls received DMEM medium. Functional tests were conducted at repeated intervals, until the 36th day, and immunohistochemistry or staining was performed on the spinal cord sections. DFAT transplantation significantly improved locomotor function of their hindlimbs, and promoted remyelination and glial scar reduction, when compared to the controls. There were significant and positive correlations between promotion of remyelination or/and reduction of glial scar, and recovery of locomotor function. Furthermore, transplanted DFAT expressed markers for neuron, astrocyte, and oligodendrocyte, along with neurotrophic factors, within the injured spinal cord. In conclusion, DFAT-induced functional recovery in mice after SCI is probably mediated by both cell-autonomous and cell-non-autonomous effects on remyelination of the injured spinal cord. PMID- 25451252 TI - Optimization protein productivity of human interleukin-2 through codon usage, gene copy number and intracellular tRNA concentration in CHO cells. AB - Transfer RNA (tRNA) abundance is one of the critical factors for the enhancement of protein productivity in prokaryotic and eukaryotic hosts. Gene copy number of tRNA and tRNA codon usage bias are generally used to match tRNA abundance of protein-expressing hosts and to optimize the codons of recombinant proteins. Because sufficient concentration of intracellular tRNA and optimized codons of recombinant proteins enhanced translation efficiency, we hypothesized that sufficient supplement of host's tRNA improved protein productivity in mammalian cells. First, the small tRNA sequencing results of CHO-K1 cells showed moderate positive correlation with gene copy number and codon usage bias. Modification of human interleukin-2 (IL-2) through codons with high gene copy number and high codon usage bias (IL-2 HH, modified on Leu, Thr, Glu) significantly increased protein productivity in CHO-K1 cells. In contrast, modification through codons with relatively high gene copy number and low codon usage bias (IL-2 HL, modified on Ala, Thr, Val), or relatively low gene copy number and low codon usage bias (IL-2 LH, modified on Ala, Thr, Val) did not increase IL-2 productivity significantly. Furthermore, supplement of the alanine tRNA or threonine tRNA increased IL-2 productivity of IL-2 HL. In summary, we revealed a potential strategy to enhance productivity of recombinant proteins, which may be applied in production of protein drug or design of DNA vaccine. PMID- 25451253 TI - Megakaryocytes are essential for HSC quiescence through the production of thrombopoietin. AB - Tissue homeostasis demands regulatory feedback, suggesting that hematopoietic stem cell (HSC) activity is controlled in part by HSC progeny. Yet, cell extrinsic HSC regulation has been well characterized only in niche cells of non hematopoietic origin. Here we identify feedback regulation of HSCs by megakaryocytes (Mks), which are mature hematopoietic cells, through production of thrombopoietin (Thpo), a cytokine pertinent for HSC maintenance. Induced ablation of Mk cell population in mice perturbed quiescent HSCs in bone marrow (BM). The ablation of Mks resulted in decreased intra-BM Thpo concentration presumably due to Thpo production by Mks. Thpo administration Mk ablated mice restored HSC functions. Overall, our study establishes Mk as an essential cellular component of the HSC niche and delineates cytokine-oriented regulation of HSCs by their own progeny. PMID- 25451254 TI - Apolipoprotein A-I expression suppresses COX-2 expression by reducing reactive oxygen species in hepatocytes. AB - Abnormal lipid metabolism may contribute to the increase of reactive oxygen species (ROS) and inflammation in the pathogenesis of non-alcoholic steatohepatitis (NASH). Apolipoprotein A-I (apoA-I) accepts cellular cholesterol and phospholipids transported by ATP-binding cassette transporter A1 to generate nascent high density lipoprotein particles. Previous studies revealed that the overexpression of ABCA1 or apoA-I alleviated hepatic lipid levels by modifying lipid transport. Here, we examined the effect of apoA-I overexpression on ROS and genes involved in inflammation in both BEL-7402 hepatocytes and mice. Human apoA I was overexpressed by transfection in BEL-7402 hepatocytes and by an adenoviral vector in C57BL/6J mice fed a methionine choline-deficient diet. The overexpression of apoA-I in both models resulted in decreased ROS and lipid peroxidation levels, as well as a reduced MAPK phosphorylation and decreased expression levels of c-Fos and COX-2. These results suggest that apoA-I overexpression can reduce steatosis by decreasing ROS levels and suppressing COX 2-induced inflammation in hepatocytes. MAPK and c-Fos are involved in this regulatory process. PMID- 25451255 TI - The single N-glycan deletion mutant of soluble ErbB3 protein attenuates heregulin beta1-induced tumor progression by blocking of the HIF-1 and Nrf2 pathway. AB - It has been well documented that activation of the ErbB3-PI3K-Akt pathway is implicated in tumor survival and progression. We previously demonstrated that the single N-glycan deletion mutant of soluble ErbB3 protein (sErbB3 N418Q) attenuates heregulin beta1-induced ErbB3 signaling. The active PI3K-Akt pathway augments the nuclear accumulation of hypoxia inducible factor (HIF)-1alpha, which activates the transcription of many target genes and drives cancer progression. In this study, we focused on the effects of sErbB3 N418Q mutant on nuclear accumulation of HIF-1alpha. Pretreatment with the sErbB3 N418Q mutant suppressed heregulin beta1-induced HIF-1alpha activation in MCF7 cells. Similar results were also obtained in other breast cancer cell lines, T47D and BT474. Interestingly, these suppressive effects were not observed with the sErbB3 wild type. In addition, pretreatment with the sErbB3 N418Q mutant suppressed the cell migration of MCF7 cells induced by heregulin beta1. Furthermore, incubation with heregulin beta1 also induced the nuclear accumulation of Nrf2, and this effect was also reduced by the sErbB3 N418Q mutant, but not the sErbB3 wild type. These findings indicated that the sErbB3 N418Q mutant suppressed malignant formation of cancer cells by blocking of the HIF-1alpha and Nrf2 pathways. PMID- 25451256 TI - Fibulin-3 negatively regulates ALDH1 via c-MET suppression and increases gamma radiation-induced sensitivity in some pancreatic cancer cell lines. AB - Fibulin-3 (FBLN-3) has been postulated to be either a tumor suppressor or promoter depending on the cell type, and hypermethylation of the FBLN-3 promoter is often associated with human disease, especially cancer. We report that the promoter region of the FBLN-3 was significantly methylated (>95%) in some pancreatic cancer cell lines and thus FBLN-3 was poorly expressed in pancreatic cancer cell lines such as AsPC-1 and MiaPaCa-2. FBLN-3 overexpression significantly down-regulated the cellular level of c-MET and inhibited hepatocyte growth factor-induced c-MET activation, which were closely associated with gamma radiation resistance of cancer cells. Moreover, we also showed that c-MET suppression or inactivation decreased the cellular level of ALDH1 isozymes (ALDH1A1 or ALDH1A3), which serve as cancer stem cell markers, and subsequently induced inhibition of cell growth in pancreatic cancer cells. Therefore, forced overexpression of FBLN-3 sensitized cells to cytotoxic agents such as gamma radiation and strongly inhibited the stemness and epithelial to mesenchymal transition (EMT) property of pancreatic cancer cells. On the other hand, if FBLN3 was suppressed in FBLN-3-expressing BxPC3 cells, the results were opposite. This study provides the first demonstration that the FBLN-3/c-MET/ALDH1 axis in pancreatic cancer cells partially modulates stemness and EMT as well as sensitization of cells to the detrimental effects of gamma-radiation. PMID- 25451257 TI - Enhanced Nox1 expression and oxidative stress resistance in c-kit-positive hematopoietic stem/progenitor cells. AB - Although stem cells are generally thought to be resistant to oxidative stress, the fact and in detail molecular mechanism are still to be clearly identified. We herein tried to understand the overall characterization of redox regulatory signaling in hematopoietic stem cells. We purified c-kit-positive hematopoietic stem/progenitor cells from the bone marrow of healthy mice, and then evaluated their redox regulatory property. Compared to the c-kit-negative matured mononuclear cells, c-kit-positive stem/progenitor cells showed lower basic levels of intracellular reactive oxygen species, faster clearance of the accumulated intracellular reactive oxygen species, and higher resistant to oxidative stress. An overall view on the gene expression profile associated with redox regulation showed to be widely differed between cell types. We confirmed that the c-kit positive stem/progenitor cells expressed significantly higher of Nox1 and catalase, but less of lactoperoxidase than these matured mononuclear cells. Our data suggests that stem cells keep specific redox regulatory property for defensing against oxidative stress. PMID- 25451258 TI - Brain derived neurotrophic factor is involved in the regulation of glycogen synthase kinase 3beta (GSK3beta) signalling. AB - Glycogen synthase kinase 3beta (GSK3beta) is involved in several biochemical processes in neurons regulating cellular survival, gene expression, cell fate determination, metabolism and proliferation. GSK3beta activity is inhibited through the phosphorylation of its Ser-9 residue. In this study we sought to investigate the role of BDNF/TrkB signalling in the modulation of GSK3beta activity. BDNF/TrkB signalling regulates the GSK3beta activity both in vivo in the retinal tissue as well as in the neuronal cells under culture conditions. We report here for the first time that BDNF can also regulate GSK3beta activity independent of its effects through the TrkB receptor signalling. Knockdown of BDNF lead to a decline in GSK3beta phosphorylation without having a detectable effect on the TrkB activity or its downstream effectors Akt and Erk1/2. Treatment with TrkB receptor agonist had a stimulating effect on the GSK3beta phosphorylation, but the effect was significantly less pronounced in the cells in which BDNF was knocked down. The use of TrkB receptor antagonist similarly, manifested itself in the form of downregulation of GSK3beta phosphorylation, but a combined TrkB inhibition and BDNF knockdown exhibited a much stronger negative effect. In vivo, we observed reduced levels of GSK3beta phosphorylation in the retinal tissues of the BDNF(+/-) animals implicating critical role of BDNF in the regulation of the GSK3beta activity. Concluding, BDNF/TrkB axis strongly regulates the GSK3beta activity and BDNF also exhibits GSK3beta regulatory effect independent of its actions through the TrkB receptor signalling. PMID- 25451259 TI - Identification and characterization of novel NuMA isoforms. AB - The large nuclear mitotic apparatus (NuMA) has been investigated for over 30years with functions related to the formation and maintenance of mitotic spindle poles during mitosis. However, the existence and functions of NuMA isoforms generated by alternative splicing remains unclear. In the present work, we show that at least seven NuMA isoforms (categorized into long, middle and short groups) generated by alternative splicing from a common NuMA mRNA precursor were discovered in HeLa cells and these isoforms differ mainly at the carboxyl terminus and the coiled-coil domains. Two "hotspot" exons with molecular mass of 3366-nt and 42-nt tend to be spliced during alternative splicing in long and middle groups. Furthermore, full-length coding sequences of long and middle NuMA obtained by using fusion PCR were constructed into GFP-tagged vector to illustrate their cellular localization. Long NuMA mainly localized in the nucleus with absence from nucleoli during interphase and translocated to the spindle poles in mitosis. Middle NuMA displayed the similar cell cycle-dependent distribution pattern as long NuMA. However, expression of NuMA short isoforms revealed a distinct subcellular localization. Short NuMA were present in the cytosol during the whole cycle, without colocalization with mitotic apparatus. These results have allowed us tentatively to explore a new research direction for NuMA's various functions. PMID- 25451260 TI - Role of Flightless-I (Drosophila) homolog in the transcription activation of type I collagen gene mediated by transforming growth factor beta. AB - Flightless-I (Drosophila) homolog (FLII) is a nuclear receptor coactivator that is known to interact with other transcriptional regulators such as the SWI/SNF complex, an ATP-dependent chromatin-remodeling complex, at the promoter or enhancer region of estrogen receptor (ER)-alpha target genes. However, little is known about the role of FLII during transcription initiation in the transforming growth factor beta (TGFbeta)/SMAD-dependent signaling pathway. Here, we demonstrate that FLII functions as a coactivator in the expression of type I collagen gene induced by TGFbeta in A549 cells. FLII activates the reporter gene driven by COL1A2 promoter in a dose-dependent manner. Co-expression of GRIP1, CARM1, or p300 did not show any synergistic activation of transcription. Furthermore, the level of COL1A2 expression correlated with the endogenous level of FLII mRNA level. Depletion of FLII resulted in a reduction of TGFbeta-induced expression of COL1A2 gene. In contrast, over-expression of FLII caused an increase in the endogenous expression of COL1A2. We also showed that FLII is associated with Brahma-related gene 1 (BRG1) as well as SMAD in A549 cells. Notably, the recruitment of BRG1 to the COL1A2 promoter region was decreased in FLII-depleted A549 cells, suggesting that FLII is required for TGFbeta-induced chromatin remodeling, which is carried out by the SWI/SNF complex. Furthermore, formaldehyde-assisted isolation of regulatory elements (FAIRE)-quantitative polymerase chain reaction (qPCR) experiments revealed that depletion of FLII caused a reduction in chromatin accessibility at the COL1A2 promoter. These results suggest that FLII plays a critical role in TGFbeta/SMAD-mediated transcription of the COL1A2 gene through its role in recruiting the SWI/SNF complex to facilitate chromatin accessibility. PMID- 25451261 TI - Angiotensin II upregulates Kv1.5 expression through ROS-dependent transforming growth factor-beta1 and extracellular signal-regulated kinase 1/2 signalings in neonatal rat atrial myocytes. AB - Kv1.5 potassium channel represents a promising target for atrial fibrillation (AF) therapy. During AF, the renin-angiotensin system is markedly activated. Recent evidence indicates that angiotensin II (Ang II) can upregulate Kv1.5 channel, but the mechanism remains unknown. In this study, we report that Ang II mediated transforming growth factor-beta1 (TGF-beta1)/Smad2/3 and extracellular signal-regulated kinase (ERK) 1/2 signalings are involved in atrial Kv1.5 expression. In neonatal rat atrial myocytes, quantitative PCR and Western blotting revealed that Ang II upregulated TGF-beta1, synapse-associated protein 97 (SAP97) and Kv1.5 expression in a time- and concentration-dependent manner. The Ang II-induced upregulation of Kv1.5, SAP97 and phosphorylated Smad2/3 (P Smad2/3) were reversed by the Ang II type 1 (AT1) receptor antagonist losartan, an anti-TGF-beta1 antibody and the ERK 1/2 inhibitor PD98059 but not by the AT2 receptor antagonist PD123319. mRNA knockdown of either Smad2 or Smad3 blocked Ang II-induced expression of Kv1.5 and SAP97. These data suggest that AT1 receptor/TGF-beta1/P-Smad2/3 and ERK 1/2 signalings are involved in Ang II induced Kv1.5 and SAP97 expression. Flow cytometry and Western blotting revealed that losartan and the anti-TGF-beta1 antibody diminished Ang II-induced reactive oxygen species (ROS) generation and that the antioxidants diphenyleneiodonium and N-acetyl cysteine inhibited Ang II-induced expression of P-Smad2/3, phosphorylated ERK (P-ERK) 1/2, Kv1.5, SAP97, suggesting that ROS participate in Kv1.5 and SAP97 regulation by modulating Ang II-induced P-Smad2/3 and P-ERK 1/2 expression. In conclusion, we demonstrate that ROS-dependent Ang II/AT1 receptor/TGF-beta1/P-Smad2/3 and Ang II/ERK 1/2 signalings are involved in atrial Kv1.5 and SAP97 expression. Antioxidants would be beneficial for AF treatment through inhibiting atrial Kv1.5 expression. PMID- 25451262 TI - beta-Lapachone attenuates mitochondrial dysfunction in MELAS cybrid cells. AB - Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disease caused by mutations in the mitochondrial genome. This study investigated the efficacy of beta-lapachone (beta-lap), a natural quinone compound, in rescuing mitochondrial dysfunction in MELAS cybrid cells. beta-Lap significantly restored energy production and mitochondrial membrane potential as well as normalized the elevated ROS level in MELAS cybrid cells. Additionally, beta-lap reduced lactic acidosis and restored glucose uptake in the MELAS cybrid cells. Finally, beta-lap activated Sirt1 by increasing the intracellular NAD(+)/NADH ratio, which was accompanied by increased mtDNA content. Two other quinone compounds (idebenone and CoQ10) that have rescued mitochondrial dysfunction in previous studies of MELAS cybrid cells had a minimal effect in the current study. Taken together, these results demonstrated that beta lap may provide a novel therapeutic modality for the treatment of MELAS. PMID- 25451263 TI - Targeting miR-21 sensitizes Ph+ ALL Sup-b15 cells to imatinib-induced apoptosis through upregulation of PTEN. AB - Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) cells are insensitive to BCR-ABL tyrosine kinase inhibitor imatinib, the underlying mechanisms remain largely unknown. Here, we showed that imatinib treatment induced significant upregulation of miR-21 and downregulation of PTEN in Ph+ ALL cell line Sup-b15. Transient inhibition of miR-21 resulted in increased apoptosis, PTEN upregulation and AKT dephosphorylation, whereas ectopic overexpression of miR-21 further conferred imatinib resistance. Furthermore, knockdown of PTEN protected the cells from imatinib-induced apoptosis achieved by inhibition of miR-21. Additionally, PI3K inhibitors also notably enhanced the effects of imatinib on Sup-b15 cells and primary Ph+ ALL cells similar to miR-21 inhibitor. Therefore, miR-21 contributes to imatinib resistance in Ph+ ALL cells and antagonizing miR-21 demonstrates therapeutic potential by sensitizing the malignancy to imatinib therapy. PMID- 25451264 TI - Regulation of the subcellular shuttling of Sgo1 between centromeres and chromosome arms by Aurora B-mediated phosphorylation. AB - A minor fraction of cohesin complexes at chromosome arms is not removed by the prophase pathway, and maintained until metaphase and enriched at centromeres. Sgo1 localizes to chromosome arms from prophase to metaphase, and is indispensable for removing cohesin complexes from chromosome arms. However, it has not been established how the chromosome arm localization of Sgo1 leads to the establishment of cohesion on chromosomes. Here, we report that Aurora B kinase interacts with and phosphorylates Sgo1 in vitro and in vivo. Furthermore, the phosphorylation of Sgol by Aurora B kinase regulated the distribution of Sgo1 between centromeres and chromosome arms, and the expression of Aurora B kinase dead mutants of Sgo1 caused mislocalization from centromeres to chromosome arms. These results suggest Aurora B kinase directly regulates the subcellular distribution of Sgo1 to facilitate the accurate separation of mitotic chromosomes. PMID- 25451265 TI - Association of malectin with ribophorin I is crucial for attenuation of misfolded glycoprotein secretion. AB - We previously demonstrated that malectin associates with ribophorin I, which is a subunit of oligosaccharyltransferase in the endoplasmic reticulum (ER). When malectin and ribophorin I are overexpressed in the ER, secretion of an alpha1 antitrypsin (AT) variant whose folding is defective, termed null Hong Kong (AT(NHK)), is decreased. To confirm whether the interaction between malectin and ribophorin I is involved in the decreased secretion of misfolded glycoproteins, we constructed an expression vector encoding truncated malectin, which could not associate with ribophorin I and had an Lys-Asp-Glu-Leu ER-retention sequence at its C-terminus. Expression of wild-type malectin abrogated AT(NHK) secretion, whereas expression of truncated malectin did not affect AT(NHK) secretion. Both wild-type and truncated malectin bound to AT(NHK), and the level of AT(NHK) was similar in cells expressing wild-type malectin and those expressing truncated malectin. Furthermore, we previously showed that decreased secretion of misfolded AT(NHK) by malectin overexpression is restored by treatment with a proteasome inhibitor. These results clearly demonstrate that the association of malectin with ribophorin I is required to capture misfolded glycoproteins and direct them to the degradation pathway. PMID- 25451266 TI - Activation of cytosolic Slingshot-1 phosphatase by gelsolin-generated soluble actin filaments. AB - Slingshot-1 (SSH1) is a protein phosphatase that dephosphorylates and activates cofilin, an actin-severing and -disassembling protein. SSH1 is bound to and activated by F-actin, but not G-actin. SSH1 is accumulated in the F-actin-rich lamellipodium but is also diffusely distributed in the cytoplasm. It remains unknown whether SSH1 is activated by soluble (low-level polymerized) actin filaments in the cytoplasm. In this study, we show that SSH1 binds to gelsolin via actin filaments in the cytosolic fraction. Gelsolin promoted solubilization of actin filaments and SSH1 in cell-free assays and in cultured cells. SSH1 was activated by gelsolin-generated soluble actin filaments. Furthermore, gelsolin enhanced cofilin dephosphorylation in neuregulin-stimulated cells. Our results suggest that cytosolic SSH1 forms a complex with gelsolin via soluble actin filaments and is activated by gelsolin-generated soluble actin filaments and that gelsolin promotes stimulus-induced cofilin dephosphorylation through increasing soluble actin filaments, which support SSH1 activation in the cytoplasm. PMID- 25451267 TI - Short N-terminal region of UDP-galactose transporter (SLC35A2) is crucial for galactosylation of N-glycans. AB - UDP-galactose transporter (UGT) and UDP-N-acetylglucosamine transporter (NGT) form heterologous complexes in the Golgi apparatus (GA) membrane. We aimed to identify UGT region responsible for galactosylation of N-glycans. Chimeric proteins composed of human UGT and either NGT or CMP-sialic acid transporter (CST) localized to the GA, and all but UGT/CST chimera corrected galactosylation defect in UGT-deficient cell lines, although at different efficiency. Importantly, short N-terminal region composed of 35 N-terminal amino-acid residues of UGT was crucial for galactosylation of N-glycans. The remaining molecule must be derived from NGT not CST, confirming that the role played by UGT and NGT is coupled. PMID- 25451268 TI - Fluorescent labelling of intestinal epithelial cells reveals independent long lived intestinal stem cells in a crypt. AB - BACKGROUND AND AIMS: The dynamics of intestinal stem cells are crucial for regulation of intestinal function and maintenance. Although crypt stem cells have been identified in the intestine by genetic marking methods, identification of plural crypt stem cells has not yet been achieved as they are visualised in the same colour. METHODS: Intestinal organoids were transferred into Matrigel(r) mixed with lentivirus encoding mCherry. The dynamics of mCherry-positive cells was analysed using time-lapse imaging, and the localisation of mCherry-positive cells was analysed using 3D immunofluorescence. RESULTS: We established an original method for the introduction of a transgene into an organoid generated from mouse small intestine that resulted in continuous fluorescence of the mCherry protein in a portion of organoid cells. Three-dimensional analysis using confocal microscopy showed a single mCherry-positive cell in an organoid crypt that had been cultured for >1year, which suggested the presence of long-lived mCherry-positive and -negative stem cells in the same crypt. Moreover, a single mCherry-positive stem cell in a crypt gave rise to both crypt base columnar cells and transit amplifying cells. Each mCherry-positive and -negative cell contributed to the generation of organoids. CONCLUSIONS: The use of our original lentiviral transgene system to mark individual organoid crypt stem cells showed that long-lived plural crypt stem cells might independently serve as intestinal epithelial cells, resulting in the formation of a completely functional villus. PMID- 25451270 TI - MicroRNA-26a modulates transforming growth factor beta-1-induced proliferation in human fetal lung fibroblasts. AB - MicroRNA-26a is a newly discovered microRNA that has a strong anti-tumorigenic capacity and is capable of suppressing cell proliferation and activating tumor specific apoptosis. However, whether miR-26a can inhibit the over-growth of lung fibroblasts remains unclear. The relationship between miR-26a and lung fibrosis was explored in the current study. We first investigated the effect of miR-26a on the proliferative activity of human lung fibroblasts with or without TGF-beta1 treatment. We found that the inhibition of endogenous miR-26a promoted proliferation and restoration of mature miR-26a inhibited the proliferation of human lung fibroblasts. We also examined that miR-26a can block the G1/S phase transition via directly targeting 3'-UTR of CCND2, degrading mRNA and decreasing protein expression of Cyclin D2. Furthermore, we showed that miR-26a mediated a TGF-beta 2-TGF-beta 1 feedback loop and inhibited TGF-beta R I activation. In addition, the overexpression of miR-26a also significantly suppressed the TGF beta 1-interacting-CTGF-collagen fibrotic pathway. In summary, our studies indicated an essential role of miR-26a in the anti-fibrotic mechanism in TGF beta1-induced proliferation in human lung fibroblasts, by directly targeting Cyclin D2, regulating TGF-beta R I as well as TGF-beta 2, and suggested the therapeutic potential of miR-26a in ameliorating lung fibrosis. PMID- 25451269 TI - Effect of mitochondrial tRNA(Lys) mutation on the clinical and biochemical characteristics of Chinese essential hypertensive subjects. AB - Mitochondrial dysfunction has been potentially implicated in both human and experimental hypertension. We performed the mutational analysis of tRNA(Lys) gene by PCR amplification and subsequent sequence analysis of the PCR fragments from 990 Chinese essential hypertensive subjects. We also made a comparative analysis of the collected data of the essential hypertension subjects who carried tRNA(Lys) mutation and those who did not carry the mutation using the methods of 1:1 case-control study. We totally found 7 mutation sites in 10 subjects. The onset ages of the individuals carrying the mutation were earlier than those who did not bear them. The level of blood urea nitrogen in hypertension subjects who carried tRNA(Lys) mutation was higher than the hypertension subjects who did not carried tRNA(Lys) mutation, while the serum potassium was significantly lower. The level of platelet count in hypertension subjects who carried tRNA(Lys) mutation was lower. The level of ventricular septal thickness in hypertension subjects who carried tRNA(Lys) mutation was higher and the level of left ventricular end diastolic diameter in hypertension subjects was significantly lower. Mitochondrial tRNA(Lys) mutations might result in the change of their structure and function, and then damaged the blood metabolism, the balance of the blood electrolyte, the steady-state of the blood cells and the heart structure and function, which were involved in the progress of the essential hypertension. Part of the essential hypertension patients clinically presented the characters of maternal inheritance, which might be associated with the tRNA(Lys) mutation. PMID- 25451271 TI - p53 negatively regulates Pin1 expression under ER stress. AB - Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a major role in the development of many diseases. A previous study indicated that the apoptotic regulator p53 is significantly increased in response to ER stress and participates in ER stress-induced apoptosis. However, the regulators of p53 expression during ER stress are still not fully understood. Here, we investigated whether p53 contributes to the impairment of Pin1 signaling under ER stress. We found that treatment with thapsigargin, a stimulator of p53 expression and an inducer of ER stress, decreased Pin1 expression in HCT116 cells. Also, we identified functional p53 response elements (p53REs) in the Pin1 promoter. Overexpression of p53 significantly decreased Pin1 expression in HCT116 cells while abolition of p53 gene expression induced Pin1 expression. Pin1 expression was significantly increased by treatment with the p53 inhibitor pifithrin-alpha or down-regulation of p53 expression. Taken together, ER stress decreased Pin1 expression through p53 activation, and this mechanism may be associated with ER stress-induced cell death. These data reported here support the importance of Pin1 as a potential target molecule mediating tumor development. PMID- 25451272 TI - Inherent lipid metabolic dysfunction in glycogen storage disease IIIa. AB - We studied two patients from a nonconsanguineous family with life-long abnormal liver function, hepatomegaly and abnormal fatty acid profiles. Abnormal liver function, hypoglycemia and muscle weakness are observed in various genetic diseases, including medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and glycogen storage diseases. The proband showed increased free fatty acids, mainly C8 and C10, resembling fatty acid oxidation disorder. However, no mutation was found in ACADM and ACADL gene. Sequencing of theamylo-alpha-1, 6-glucosidase, 4 alpha-glucanotransferase (AGL) gene showed that both patients were compound heterozygotes for c.118C > T (p.Gln40X) and c.753_756 del CAGA (p.Asp251Glufsx29), whereas their parents were each heterozygous for one of these mutations. The AGL protein was undetectable in EBV-B cells from the two patients. Transcriptome analysis demonstrated a significant different pattern of gene expression in both of patients' cells, including genes involving in the PPAR signaling pathway, fatty acid biosynthesis, lipid synthesis and visceral fat deposition and metabolic syndrome. This unique gene expression pattern is probably due to the absence of AGL, which potentially accounts for the observed clinical phenotypes of hyperlipidemia and hepatocyte steatosis in glycogen storage disease type IIIa. PMID- 25451273 TI - Surveying genetic variants and molecular phylogeny of cerebral cavernous malformation gene, CCM3/PDCD10. AB - The three cerebral cavernous malformations (CCMs) genes namely CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 have been identified for which mutations cause cerebral cavernous malformations. However, the protein products of these genes involved in forming CCM signaling, are still poorly understood imposing an urgent need to understand these genes and their signaling processes in details. So far involvement of CCM3/PDCD10 in the cavernous angioma has been characterized from biochemical and biophysical analyses. However, there is no comprehensive study illustrating the phylogenetic history and comprehensive genetic variants of CCM3/PDCD10. Herein, we explored the phylogenetic history and genetic variants of CCM3/PDCD10 gene. Synteny analyses revealed that CCM3/PDCD10 gene shared same genomic loci from Drosophila to human and the gene structure of CCM3/PDCD10 is conserved from human to Branchiostoma floridae for about 500 MYs with some changes in sea urchin and in insects. The conserved CCM3/PDCD10 is characterized by presence of indels in the N-terminal dimerization domain. We identified 951 CCM3/PDCD10 variants by analysis of 1092 human genomes with top three variation classes belongs to 84% SNPs, 6.9% insertions and 6.2% deletions. We identified 22 missense mutations in the human CCM3/PDCD10 protein and out of which three mutations are deleterious. We also identified four stop-codon gaining mutations at the positions E34*, E68*, E97* and E140*, respectively. This study is the first comprehensive analysis of the CCM3/PDCD10 gene based on phylogenetic origin and genetic variants. This study corroborates that the evolution of CCM proteins with tubular organization evolvements by endothelial cells. PMID- 25451274 TI - Genetic portrait of Lisboa immigrant population from Angola with mitochondrial DNA. AB - Portugal has been considered a country of emigrants, nevertheless in the past decades the number of immigrants has grown throughout all the country. This migratory flux has contributed to a raise of heterogeneity at multiple levels. According to statistical data, at the end of 2012 the total number of Angolan immigrants in Portugal equalled about 20,000 individuals. A territorial predominance has been found for the metropolitan region of Lisboa. Angola is a country located in the Atlantic coast of Africa. The presence of Bantu people and the colonisation by Portuguese people on Angolan territory are considered to be the major modulators of the genetic patterns in Angola. Mitochondrial DNA is known for its features that enable an approach to the study of human origin and evolution, as well to the different migration pathways of populations. This genetic marker can also contribute to ascertaining the identity of individuals in forensic cases. The main aim of this study was to determine the genetic structure of the Angolan immigrant population living in Lisboa. Therefore, a total of 173 individuals, inhabitants in Lisboa, nonrelated and with Angolan ancestry were studied. Total control region of mitochondrial DNA was amplified from position 16,024 to position 576 using two pairs of primers - L15997/H016 and L16555/H639. The majority of the identified haplotypes belong to mtDNA lineages known to be specific of the sub-Saharan region. Our results show that this immigrant population inhabitant in Lisboa presents a genetic profile that is characteristic of African populations. This study also demonstrates the genetic diversity that this immigrant population introduces in Lisboa. This does not contradict the historical data concerning colonization of Angola, since this was made mainly by male European individuals, who did not contribute with their maternal information of mtDNA. Lisboa immigrant population from Angola can be accessed via EMPOP dataset with accession number EMPOP662. PMID- 25451275 TI - Differences in prefrontal cortex GABA/glutamate ratio after acute restraint stress in rats are associated with specific behavioral and neurobiological patterns. AB - In patients suffering from stress-related pathologies and depression, frontal cortex GABA and glutamate contents are reported to decrease and increase, respectively. This suggests that the GABA and/or glutamate content may participate in pathological phenotype expression. Whether differences in frontal cortex GABA and glutamate contents would be associated with specific behavioral and neurobiological patterns remains unclear, especially in the event of exposure to moderate stress. We hypothesized that an increase in prefrontal cortex GABA/glutamate ratio would be associated with a blunted prefrontal cortex activation, an enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activation and changes in behavior. Rats being restrained for 1-h were then tested in an open-field test in order to assess their behavior while under stress, and were sacrificed immediately afterward. The GABA/glutamate ratio was assessed by (1)H high-resolution magic angle spinning magnetic resonance spectroscopy ((1)H-HRMAS-MRS). The neurobiological response was evaluated through prefrontal cortex mRNA expression and plasma corticosterone levels. The stressed rats were distributed into two subgroups according to their high (H-G/g) or low (L-G/g) GABA/glutamate ratio. Compared to the L-G/g rats, the H-G/g rats exhibited a decrease in c-fos, Arc, Npas4, Nr4a2 mRNA expression suggesting blunted prefrontal cortex activation. They also showed a more pronounced stress with an enhanced rise in corticosterone, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), creatine kinase (CK) and lactate dehydrogenase (LDH) levels, as well as behavioral disturbances with decreased locomotion speed. These changes were independent from prefrontal cortex energetic status as mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) pathway activities were similar in both subpopulations. The differences in GABA/glutamate ratio in the frontal cortex observed in the stressed animals may participate in shaping individual differences in psychophysiological reactions. PMID- 25451277 TI - Localization of aquaporin 1 water channel in the Schmidt-Lanterman incisures and the paranodal regions of the rat sciatic nerve. AB - Aquaporin 1 (AQP1) is a member of a family of small, integral membrane water transporting proteins, which facilitate water movement across cell membranes in response to osmotic gradients. Several papers have studied the expression and function of the AQPs in the central nervous system. However, little is known about the AQPs in the peripheral nervous system (PNS). In the PNS, AQP1, AQP2 and AQP4 have been reported in both peripheral neurons and glial cells. In this work we studied the expression and localization of AQP1 in the rat sciatic nerve. We found that from the four AQPs we studied (AQP1, AQP2, AQP4 and AQP9) only AQP1 is expressed in the nerve by reverse transcription polymerase chain reaction (RT PCR). AQP1 is also observed at the protein level by Western blot analysis. We also studied the localization of AQP1 in the sciatic nerve by immunohistochemistry. The results show that AQP1 is present in both myelinating and non-myelinating Schwann cells. In myelin internodes AQP1 is enriched in the Schmidt-Lanterman incisures and in some internodes it is also present in the abaxonal membrane. At the nodes of Ranvier, AQP1 co-localizes with actin in the paranodal regions of the nerve. Therefore, AQP1 might play an important role in myelin homeostasis maintaining the thermodynamic equilibrium across the plasma membrane in myelinated axons during electrical activity. Also the expression of AQP1 in non-myelinating Schwann cells supports the involvement of AQP1 in pain perception. PMID- 25451278 TI - Neurotransmitter receptor density changes in Pitx3ak mice--a model relevant to Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by alterations of nigrostriatal dopaminergic neurotransmission. Compared to the wealth of data on the impairment of the dopamine system, relatively limited evidence is available concerning the role of major non dopaminergic neurotransmitter systems in PD. Therefore, we comprehensively investigated the density and distribution of neurotransmitter receptors for glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine in brains of homozygous aphakia mice being characterized by mutations affecting the Pitx3 gene. This genetic model exhibits crucial hallmarks of PD on the neuropathological, symptomatic and pharmacological level. Quantitative receptor autoradiography was used to characterize 19 different receptor binding sites in eleven brain regions in order to understand receptor changes on a systemic level. We demonstrated striking differential changes of neurotransmitter receptor densities for numerous receptor types and brain regions, respectively. Most prominent, a strong up-regulation of GABA receptors and associated benzodiazepine binding sites in different brain regions and concomitant down-regulations of striatal nicotinic acetylcholine and serotonergic receptor densities were found. Furthermore, the densities of glutamatergic kainate, muscarinic acetylcholine, adrenergic alpha1 and dopaminergic D2/D3 receptors were differentially altered. These results present novel insights into the expression of neurotransmitter receptors in Pitx3(ak) mice supporting findings on PD pathology in patients and indicating on the possible underlying mechanisms. The data suggest Pitx3(ak) mice as an appropriate new model to investigate the role of neurotransmitter receptors in PD. Our study highlights the relevance of non-dopaminergic systems in PD and for the understanding of its molecular pathology. PMID- 25451276 TI - Heterotypic gap junctions at glutamatergic mixed synapses are abundant in goldfish brain. AB - Gap junctions provide for direct intercellular electrical and metabolic coupling. The abundance of gap junctions at "large myelinated club ending (LMCE)" synapses on Mauthner cells (M-cells) of the teleost brain provided a convenient model to correlate anatomical and physiological properties of electrical synapses. There, presynaptic action potentials were found to evoke short-latency electrical "pre potentials" immediately preceding their accompanying glutamate-induced depolarizations, making these the first unambiguously identified "mixed" (i.e., chemical plus electrical) synapses in the vertebrate CNS. We recently showed that gap junctions at these synapses exhibit asymmetric electrical resistance (i.e., electrical rectification), which we correlated with total molecular asymmetry of connexin composition in their apposing gap junction hemiplaques, with connexin35 (Cx35) restricted to axon terminal hemiplaques and connexin34.7 (Cx34.7) restricted to apposing M-cell plasma membranes. We now show that similarly heterotypic neuronal gap junctions are abundant throughout goldfish brain, with labeling exclusively for Cx35 in presynaptic hemiplaques and exclusively for Cx34.7 in postsynaptic hemiplaques. Moreover, the vast majority of these asymmetric gap junctions occur at glutamatergic axon terminals. The widespread distribution of heterotypic gap junctions at glutamatergic mixed synapses throughout goldfish brain and spinal cord implies that pre- vs. postsynaptic asymmetry at electrical synapses evolved early in the chordate lineage. We propose that the advantages of the molecular and functional asymmetry of connexins at electrical synapses that are so prominently expressed in the teleost CNS are unlikely to have been abandoned in higher vertebrates. However, to create asymmetric coupling in mammals, where most gap junctions are composed of connexin36 (Cx36) on both sides, would require some other mechanism, such as differential phosphorylation of connexins on opposite sides of the same gap junction or on asymmetric differences in the complement of their scaffolding and regulatory proteins. PMID- 25451279 TI - Mitogen and stress-activated kinases 1/2 regulate ischemia-induced hippocampal progenitor cell proliferation and neurogenesis. AB - Pathophysiological conditions such as cerebral ischemia trigger the production of new neurons from the neurogenic niche within the subgranular zone (SGZ) of the dentate gyrus. The functional significance of ischemia-induced neurogenesis is believed to be the regeneration of lost cells, thus contributing to post-ischemia recovery. However, the cell signaling mechanisms by which this process is regulated are still under investigation. Here, we investigated the role of mitogen and stress-activated protein kinases (MSK1/2) in the regulation of progenitor cell proliferation and neurogenesis after cerebral ischemia. Using the endothelin-1 model of ischemia, wild-type (WT) and MSK1(-/-)/MSK2(-/-) (MSK dKO) mice were injected with BrdU and sacrificed 2 days, 4 weeks, or 6 weeks later for the analysis of progenitor cell proliferation, neurogenesis, and neuronal morphology, respectively. We report a decrease in SGZ progenitor cell proliferation in MSK dKO mice compared to WT mice. Moreover, MSK dKO mice exhibited reduced neurogenesis and a delayed maturation of ischemia-induced newborn neurons. Further, structural analysis of neuronal arborization revealed reduced branching complexity in MSK dKO compared to WT mice. Taken together, this dataset suggests that MSK1/2 plays a significant role in the regulation of ischemia-induced progenitor cell proliferation and neurogenesis. Ultimately, revealing the cell signaling mechanisms that promote neuronal recovery will lead to novel pharmacological approaches for the treatment of neurodegenerative diseases such as cerebral ischemia. PMID- 25451282 TI - Effect of pain chronification and chronic pain on an endogenous pain modulation circuit in rats. AB - We tested the hypothesis that chronic pain development (pain chronification) and ongoing chronic pain (chronic pain) reduce the activity and induce plastic changes in an endogenous analgesia circuit, the ascending nociceptive control. An important mechanism mediating this form of endogenous analgesia, referred to as capsaicin-induced analgesia, is its dependence on nucleus accumbens MU-opioid receptor mechanisms. Therefore, we also investigated whether pain chronification and chronic pain alter the requirement for nucleus accumbens MU-opioid receptor mechanisms in capsaicin-induced analgesia. We used an animal model of pain chronification in which daily subcutaneous prostaglandin E2 (PGE2) injections into the rat's hind paw for 14 days, referred to as the induction period of persistent hyperalgesia, induce a long-lasting state of nociceptor sensitization referred to as the maintenance period of persistent hyperalgesia, that lasts for at least 30 days following the cessation of the PGE2 treatment. The nociceptor hypersensitivity was measured by the shortening of the time interval for the animal to respond to a mechanical stimulation of the hind paw. We found a significant reduction in the duration of capsaicin-induced analgesia during the induction and maintenance period of persistent mechanical hyperalgesia. Intra accumbens injection of the MU-opioid receptor selective antagonist Cys(2),Tyr(3),Orn(5),Pen(7)amide (CTOP) 10 min before the subcutaneous injection of capsaicin into the rat's fore paw blocked capsaicin-induced analgesia. Taken together, these findings indicate that pain chronification and chronic pain reduce the duration of capsaicin-induced analgesia, without affecting its dependence on nucleus accumbens MU-opioid receptor mechanisms. The attenuation of endogenous analgesia during pain chronification and chronic pain suggests that endogenous pain circuits play an important role in the development and maintenance of chronic pain. PMID- 25451280 TI - Central or peripheral delivery of an adenosine A1 receptor agonist improves mechanical allodynia in a mouse model of painful diabetic neuropathy. AB - Diabetic peripheral neuropathy is a common complication of diabetes mellitus, and a significant proportion of individuals suffer debilitating pain that significantly affects their quality of life. Unfortunately, symptomatic treatment options have limited efficacy, and often carry significant risk of systemic adverse effects. Activation of the adenosine A1 receptor (A1R) by the analgesic small molecule adenosine has been shown to have antinociceptive benefits in models of inflammatory and neuropathic pain. The current study used a mouse model of painful diabetic neuropathy to determine the effect of diabetes on endogenous adenosine production, and if central or peripheral delivery of adenosine receptor agonists could alleviate signs of mechanical allodynia in diabetic mice. Diabetes was induced using streptozocin in male A/J mice. Mechanical withdrawal thresholds were measured weekly to characterize neuropathy phenotype. Hydrolysis of AMP into adenosine by ectonucleotidases was determined in the dorsal root ganglia (DRG) and spinal cord at 8 weeks post-induction of diabetes. AMP, adenosine and the specific A1R agonist, N(6)-cyclopentyladenosine (CPA), were administered both centrally (intrathecal) and peripherally (intraplantar) to determine the effect of activation of adenosine receptors on mechanical allodynia in diabetic mice. Eight weeks post-induction, diabetic mice displayed significantly decreased hydrolysis of extracellular AMP in the DRG; at this same time, diabetic mice displayed significantly decreased mechanical withdrawal thresholds compared to nondiabetic controls. Central delivery AMP, adenosine and CPA significantly improved mechanical withdrawal thresholds in diabetic mice. Surprisingly, peripheral delivery of CPA also improved mechanical allodynia in diabetic mice. This study provides new evidence that diabetes significantly affects endogenous AMP hydrolysis, suggesting that altered adenosine production could contribute to the development of painful diabetic neuropathy. Moreover, central and peripheral activation of A1R significantly improved mechanical sensitivity, warranting further investigation into this important antinociceptive pathway as a novel therapeutic option for the treatment of painful diabetic neuropathy. PMID- 25451281 TI - Hydrogen peroxide administered into the rat spinal cord at the level elevated by contusion spinal cord injury oxidizes proteins, DNA and membrane phospholipids, and induces cell death: attenuation by a metalloporphyrin. AB - We previously demonstrated that hydrogen peroxide concentration ([H2O2]) significantly increases after spinal cord injury (SCI). The present study explored (1) whether SCI-elevated [H2O2] is sufficient to induce oxidation and cell death, (2) if apoptosis is a pathway of H2O2-induced cell death, and (3) whether H2O2-induced oxidation and cell death could be reversed by treatment with the catalytic antioxidant Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP). H2O2 was perfused through a microcannula into the uninjured rat spinal cord to mimic the conditions induced by SCI. Protein and DNA oxidation, membrane phospholipids peroxidation (MLP), cell death and apoptosis were characterized by histochemical and immunohistochemical staining with antibodies against markers of oxidation and apoptosis. Stained cells were quantified in sections of H2O2-, or artificial cerebrospinal fluid (ACSF)-exposed with vehicle-, or MnTBAP-treated groups. Compared with ACSF-exposed animals, SCI-elevated [H2O2] significantly increased intracellular protein and DNA oxidation by threefold and MLP by eightfold in neurons, respectively. H2O2-elevated extracellular malondialdehyde was measured by microdialysis sampling. We demonstrated that SCI-elevated [H2O2] significantly increased extracellular malondialdehyde above pre-injury levels. H2O2 also significantly increased cell loss and the numbers of terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate-(dUTP) biotin nick end labeling (TUNEL)-positive and active caspase-3-positive neurons by 2.3-, 2.8-, and 5.6-fold compared to ACSF controls, respectively. Our results directly and unequivocally demonstrate that SCI-elevated [H2O2] contributes to post-SCI MLP, protein, and DNA oxidation to induce cell death. Therefore, we conclude that (1) the role of H2O2 in secondary SCI is pro-oxidation and pro-cell death, (2) apoptosis is a pathway for SCI-elevated [H2O2] to induce cell death, (3) caspase activation is a mechanism of H2O2-induced apoptosis after SCI, and (4) MnTBAP treatment significantly decreased H2O2-induced oxidation, cell loss, and apoptosis to the levels of ACSF controls, further supporting MnTBAP's ability to scavenge H2O2 by in vivo evidence. PMID- 25451283 TI - Anoxia-induced changes in optimal substrate for peripheral nerve. AB - Hyperglycemia accentuates the injury produced by anoxia both in the central and peripheral nervous system. To understand whether this is a consequence of changes in metabolic pathways produced by anoxia, the effect of the metabolic substrate used by the rat peripheral nerve on the nerve action potential (NAP) was studied in the presence and absence of anoxia. In the continuously oxygenated state, the NAP was well preserved with glucose, lactate, as well as with high concentrations of sorbitol and fructose but not beta-hydroxybutyrate, acetate or galactose. With intermittent anoxia, the pattern of substrate effects on the NAP changed markedly so that low concentrations of fructose became able to support neurophysiologic activity but not high concentrations of glucose. These alterations occurred gradually with repeated episodes of anoxia as reflected by the progressive increase in the time needed for the NAP to disappear during anoxia when using glucose as substrate. This "preconditioning" effect was not seen with other substrates and an opposite effect was seen with lactate. In fact, the rate at which the NAP disappeared during anoxia was not simply related to degree of recovery after anoxia. These are distinct phenomena. For example, the NAP persisted longest during anoxia in the setting of hyperglycemia but this was the state in which the anoxic damage was most severe. Correlating the results with existing literature on the metabolic functions of Schwann cells and axons generates testable hypotheses for the mechanism of hyperglycemic damage during anoxia and lead to discussions of the role for a metabolic shuttle between Schwann cells and axons as well as a potential important role of glycogen. PMID- 25451284 TI - Homocysteine-induced attenuation of vascular endothelium-dependent hyperalgesia in the rat. AB - We have recently demonstrated a role of the vascular endothelium in peripheral pain mechanism by disrupting endothelial cell function using intravascular administration of octoxynol-9, a non-selective membrane active agent. As an independent test of the role of endothelial cells in pain mechanisms, we evaluated the effect of homocysteine, an agent that damages endothelial cell function. Mechanical stimulus-induced enhancement of endothelin-1 hyperalgesia in the gastrocnemius muscle of the rat was first prevented then enhanced by intravenous administration of homocysteine, but was only inhibited by its precursor, methionine. Both homocysteine and methionine significantly attenuated mechanical hyperalgesia in two models of ergonomic muscle pain, induced by exposure to vibration, and by eccentric exercise, and cutaneous mechanical hyperalgesia in an ischemia-reperfusion injury model of Complex Regional Pain Syndrome type I, all previously shown responsive to octoxynol-9. This study provides independent support for a role of the endothelial cell in pain syndromes thought to have a vascular basis, and suggests that substances that are endothelial cell toxins can enhance vascular pain. PMID- 25451285 TI - Associations of endogenous 17-beta-estradiol with theta amplitude and performance in semantic categorization in young women. AB - In semantic categorization processes, individuals form a relation between perceived or imagined objects and knowledge about these objects. In the present semantic categorization study, we correlated endogenous 17-beta-estradiol levels (E2) with performance as well as amplitude of theta oscillations in young women (age 23.1+/-3.4 years). The semantic categorization task consisted of nouns representing either living or non-living items. Each item was characterized either by many or by few features. We identified parameters associated or not associated with menstrual cycle phases. Irrespective of the menstrual cycle phase, women (1) responded faster to living items as well as to nouns characterized by many features compared to non-living items and items characterized by few features, (2) showed higher accuracy to non-living items and items having many features, and (3) showed negative correlation between response time (RT) and theta amplitude. RT, accuracy and post-stimulus theta amplitude were not statistically significantly different among early follicular, late follicular or luteal women. In early follicular but not in late follicular or luteal women, we observed (1) a positive correlation between E2 and latency in RT, (2) a negative correlation between E2 and accuracy, and (3) a negative correlation between E2 and post-stimulus theta amplitude. A mosaic of menstrual cycle phase-dependent and -independent associations may indicate that a similar performance in each menstrual cycle phase is related to different modulation of synaptic activity by hormones. PMID- 25451286 TI - Lesions of the laterodorsal tegmental nucleus alter the cholinergic innervation and neuropeptide Y expression in the medial prefrontal cortex and nucleus accumbens. AB - The effects of the ibotenic acid infused into the area of the laterodorsal tegmental nucleus (LDT) of rats on the expression of cortical and accumbal neuropeptides were assessed. The effects of this manipulation were determined in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) by estimating the numerical density of varicosities immunoreactive for vesicular acetylcholine transporter and the total number of NAc neurons immunoreactive for choline acetyltransferase (ChAT) and neuropeptide Y (NPY) as well as the total number of mPFC neurons immunoreactive for NPY and vasoactive intestinal polypeptide (VIP). In LDT-lesioned rats, the density of the cholinergic varicosities was reduced in the ventral divisions of the mPFC and in all divisions of the NAc. In addition, in these rats, the total number of NPY-immunoreactive neurons was reduced in all subregions of the mPFC and in the NAc. Conversely, the total number of VIP immunoreactive neurons in the mPFC and of ChAT-immunoreactive neurons in the NAc did not differ between LDT- and sham-lesioned rats. These data provide the first direct evidence for a relationship between selective damage of LDT cholinergic neurons and decreased expression of NPY in the mPFC and NAc. They also reveal that different types of cortical and accumbal interneurons respond differently to the cholinergic denervation induced by LDT lesions. PMID- 25451288 TI - Effect of actual long-term spaceflight on BDNF, TrkB, p75, BAX and BCL-XL genes expression in mouse brain regions. AB - Mice of C57BL/6J strain were exposed to 1-month spaceflight on Russian biosatellite Bion-M1 to determine the effect of long-term actual spaceflight on the expression of genes involved in the processes of neurogenesis and apoptosis. Specifically, we focused on the genes encoding proapoptotic factor BAX, antiapoptotic factor BCL-XL, brain-derived neurotrophic factor (BDNF) and BDNF receptors TrkB and p75. Spaceflight reduced the expression of the antiapoptotic BCL-XL gene in the striatum and hypothalamus, but increased it in the hippocampus. To estimate environmental stress contribution into spaceflight effects we analyzed spaceflight-responsive genes in mice housed for 1 month on Earth in the same shuttle cabins that were used for spaceflight, and in mice of the laboratory control group. It was shown that 1-month shuttle cabin housing decreased BCL-XL gene expression in the striatum but failed to alter BCL-XL mRNA levels in the hippocampus or hypothalamus. Spaceflight failed to alter the expression of the proapoptotic BAX gene in all investigated brain structures, although the insignificant increase of the BAX mRNA level in the hippocampus of spaceflight mice was found. At the same time, shuttle cabin housing produced insignificant decrease in BAX gene expression in the hippocampus. In contrast to the BCL-XL gene, genes encoding BAX, BDNF as well as TrkB and p75 receptors did not respond to 30-day spaceflight. Thus, long-term spaceflight (1) did not affect the expression of genes encoding BDNF as well as TrkB and p75 receptors, (2) produced dysregulation in genetic control of the neuronal apoptosis, (3) implicated BCL-XL as the risk factor for spaceflight-induced behavioral abnormalities. PMID- 25451287 TI - Connexin26 (GJB2) deficiency reduces active cochlear amplification leading to late-onset hearing loss. AB - Connexin26 (Cx26, GJB2) mutations account for >50% of nonsyndromic hearing loss. The deafness is not always congenital. A large group of these patients (~30%) demonstrate a late-onset hearing loss, starting in childhood. They have normal hearing early in life and are therefore good candidates for applying protective and therapeutic interventions. However, the underlying deafness mechanism is unclear. In this study, we used a time-controlled, inducible gene knockout technique to knockout Cx26 expression in the cochlea after birth. We found that deletion of Cx26 after postnatal day 5 (P5) in mice could lead to late-onset hearing loss. Similar to clinical observations, the mice demonstrated progressive, mild to moderate hearing loss. The hearing loss initiated at high frequencies and then extended to the middle- and low-frequency range. The cochlea showed normal development and had no apparent hair cell loss. However, distortion product otoacoustic emission (DPOAE) was reduced. The reduction was also progressive and large at high-frequencies. Consistent with DPOAE reduction, we found that outer hair cell electromotility-associated nonlinear capacitance was shifted to the right and the slope of voltage dependence was reduced. The endocochlear potential was reduced in Cx26 conditional knockout (cKO) mice but the reduction was not associated with progressive hearing loss. These data suggest that Cx26 deficiency may impair active cochlear amplification leading to late-onset hearing loss. Our study also helps develop newer protective and therapeutic interventions to this common nonsyndromic hearing loss. PMID- 25451289 TI - Amygdalar neuronal activity mediates the cardiovascular responses evoked from the dorsolateral periaqueductal gray in conscious rats. AB - There is ample evidence that both lateral/dorsolateral periaqueductal gray (l/dlPAG) and basolateral amygdala (BLA) are essential for the regulation of the autonomic responses evoked during innate reactions to threatening stimuli. However, it is not well established to what extent the BLA regulates the upstream functional connection from the l/dlPAG. Here we evaluated the role of the BLA and its glutamatergic receptors in the cardiovascular responses induced by l/dlPAG stimulation in rats. We examined the influence of acute inhibition of the BLA, unilaterally, by injecting muscimol on the cardiovascular responses evoked by the injection of N-methyl D-aspartate (NMDA) into the l/dlPAG. We also evaluated the role of BLA ionotropic glutamate receptors in these responses by injecting antagonists of NMDA and AMPA/kainate receptor subtypes into the BLA. Our results show that the microinjection of NMDA in the BLA increased the mean arterial pressure (MAP) and heart rate (HR). Injection of NMDA into the l/dlPAG caused similar increases in these variables, which was prevented by the prior injection of muscimol, a GABAA agonist, into the BLA. Moreover, injection of glutamatergic antagonists (2-amino-5-phosphonopentanoate (AP5) and 6-cyano-7-nitroquinoxaline 2,3-dione (CNQX)) into the BLA reduced the increase in MAP and HR induced by l/dlPAG activation. Finally, the inhibition of the central amygdala neurons failed to reduce the cardiovascular changes induced by l/dlPAG activation. These results indicate that physiological responses elicited by l/dlPAG activation require the neuronal activity in the BLA. This ascending excitatory pathway from the l/dlPAG to the BLA might ensure the expression of the autonomic component of the defense reaction. PMID- 25451290 TI - KATP-channels play a minor role in the protective hypoxic shut-down of cerebellar activity in eider ducks (Somateria mollissima). AB - Eider duck (Somateria mollissima) cerebellar neurons are highly tolerant toward hypoxia in vitro, which in part is due to a hypoxia-induced depression of their spontaneous activity. We have studied whether this response involves ATP sensitive potassium (KATP) channels, which are known to be involved in the hypoxic/ischemic defense of mammalian neural and muscular tissues, by causing hyperpolarization and reduced ATP demand. Extracellular recordings in the Purkinje layer of isolated normoxic eider duck cerebellar slices showed that their spontaneous neuronal activity decreased significantly compared to in control slices when the KATP channel opener diazoxide (600 MUM) was added (F1,70=92.781, p<0.001). Adding the KATP channel blocker tolbutamide (400 MUM) 5 min prior to diazoxide completely abolished its effect (F1,55=39.639, p<0.001), strongly suggesting that these drugs have a similar mode of action in this avian species as in mammals. The spontaneous activity of slices treated with tolbutamide in combined hypoxia/chemical anoxia (95% N2-5% CO2 and 2 mM NaCN) was not significantly different from that of control slices (F1,203=0.071, p=0.791). Recovery from hypoxia/anoxia was, however, slightly but significantly weaker in tolbutamide-treated slices than in control slices (F1,137=15.539, p<0.001). We conclude that KATP channels are present in eider duck cerebellar neurons and are activated in hypoxia/anoxia, but that they do not play a key role in the protective shut-down response to hypoxia/anoxia. PMID- 25451291 TI - TGF-beta1 is critical for Wallerian degeneration after rat sciatic nerve injury. AB - Wallerian degeneration (WD) is a process of axonal degeneration distal to the injury site followed by a robust regenerative response. It involves degeneration and regeneration which can be directly induced by nerve injury and activated by transcription factors. Although WD has been studied extensively, the precise mechanisms of transcription factors regulating WD are still elusive. In this study, we reported the effect of transforming growth factor-beta1 (TGF-beta1) on WD after rat sciatic nerve injury. The data showed that TGF-beta1 may express in injured rat sciatic nerve and cultured Schwann cells (SCs). Knock down of TGF beta1 expressions resulted in the reduction of SC proliferation and apoptosis, up regulation of cytokines and Smad2, 4. Enhanced expression of TGF-beta1 could promote SC proliferation and apoptosis, down regulation of cytokines and Smad2, 4. Altered expressions of TGF-beta1 may affect Smad and AKT but not c-Jun and extracellular regulated protein kinase (ERK) pathways. Our results revealed the role of TGF-beta1 on WD and provided the basis for the molecular mechanisms of TGF-beta1-regulated nerve degeneration and/or regeneration. PMID- 25451293 TI - Targeting thioredoxin-1 with siRNA exacerbates oxidative stress injury after cerebral ischemia/reperfusion in rats. AB - Reactive oxygen species and their detrimental effects on the brain after transient ischemia/reperfusion (I/R) have been implicated in the pathogenesis of ischemic reperfusion injury. Thioredoxin-1 (Trx-1) is an endogenous antioxidant protein that has neuroprotective effects. We hypothesized that Trx-1 plays a crucial role in regulating cerebral I/R injury. To be able to test this, 190 Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (tMCAO) with Trx-1 siRNA (small interference RNA) injected 24 h prior to ischemia. At 24 h after tMCAO, we measured neurological deficits, infarct volume, and brain water content, and found that neurological dysfunction, brain infarct size, and brain edema were worse in the Trx-1 siRNA group than in the control group. Oxidative stress was evaluated by measuring superoxide dismutase activity and malondialdehyde level. The levels of Trx-1 and its cofactor, peroxiredoxin (Prdx), were significantly decreased after Trx-1 down-regulated. However, there is no significant difference in the Prdx mRNA level after administration of Trx-1 siRNA. In contrast, Prdx-SO3 protein levels were significantly increased in the Trx-1 siRNA group. We also investigated the specific role of nuclear factor erythroid 2-related factor 2 (Nrf2) in Trx-1 induction by knocking down Nrf2. Nrf2 siRNA injection decreased Trx-1 mRNA and protein expression. Our results suggest that the exacerbation of brain damage was associated with enhanced cerebral peroxidation in brain tissues. Moreover, these results revealed that Trx 1, which is more likely regulated by Nrf2, exerts a neuroprotective role probably through maintaining the reduction activity of Prdx1-4. PMID- 25451294 TI - PUMA is invovled in ischemia/reperfusion-induced apoptosis of mouse cerebral astrocytes. AB - PUMA (p53-upregulated modulator of apoptosis), a BH3-only member of the Bcl-2 protein family, is required for p53-dependent and p53-independent forms of apoptosis. PUMA has been invovled in the onset and progress of several diseases, including cancer, acquired immunodeficiency syndrome, and ischemic brain disease. Although many studies have shown that ischemia and reperfusion (I/R) can induce the apoptosis of astrocytes, the role of PUMA in I/R-mediated apoptosis of cerebral astrocyte apoptosis remains unclear. To mimic in vivo I/R conditions, primary mouse cerebral astrocytes were incubated in a combinational cultural condition of oxygen, glucose, and serum deprivation (OSGD) for 1 h followed by reperfusion (OSGD/R). Cell death determination assays and cell viability assays indicated that OSGD and OSGD/R induce the apoptosis of primary cerebral astrocytes. The expression of PUMA was significantly elevated in primary cerebral astrocytes during OSGD/R. Moreover, targeted down-regulation of PUMA by siRNA transfection significantly decreased the OSGD/R-induced apoptosis of primary cerebral astrocytes. We also found that OSGD and OSGD/R triggered the release of cytochrome c in astrocytes, indicating the dependence on a mitochondrial apoptotic pathway. Reactive oxygen species (ROS) was extremely generated during OSGD and OSGD/R, and the elimination of ROS by treated with N-acetyl-L-cysteine (NAC) remarkably inhibited the expression of PUMA and the apoptosis of primary cerebral astrocytes. The activation of Caspase 3 and Caspase 9 was extremely elevated in primary cerebral astrocytes during OSGD. In addition, we found that knockdown of PUMA led to the depressed expression of Bax, cleaved caspase-9 and caspase-3 during OSGD/R. These results indicate that PUMA is invovled in the apoptosis of cerebral astrocytes upon I/R injury. PMID- 25451292 TI - Early-life exposure to the SSRI paroxetine exacerbates depression-like behavior in anxiety/depression-prone rats. AB - Selective serotonin reuptake inhibitor (SSRI) antidepressants are the mainstay treatment for the 10-20% of pregnant and postpartum women who suffer major depression, but the effects of SSRIs on their children's developing brain and later emotional health are poorly understood. SSRI use during pregnancy can elicit antidepressant withdrawal in newborns and increase toddlers' anxiety and social avoidance. In rodents, perinatal SSRI exposure increases adult depression- and anxiety-like behavior, although certain individuals are more vulnerable to these effects than others. Our study establishes a rodent model of individual differences in susceptibility to perinatal SSRI exposure, utilizing selectively bred Low Responder (bLR) and High Responder (bHR) rats that were previously bred for high versus low behavioral response to novelty. Pregnant bHR/bLR females were chronically treated with the SSRI paroxetine (10 mg/kg/day p.o.) to examine its effects on offspring's emotional behavior and gene expression in the developing brain. Paroxetine treatment had minimal effect on bHR/bLR dams' pregnancy outcomes or maternal behavior. We found that bLR offspring, naturally prone to an inhibited/anxious temperament, were susceptible to behavioral abnormalities associated with perinatal SSRI exposure (which exacerbated their Forced Swim Test immobility), while high risk-taking bHR offspring were resistant. Microarray studies revealed robust perinatal SSRI-induced gene expression changes in the developing bLR hippocampus and amygdala (postnatal days 7-21), including transcripts involved in neurogenesis, synaptic vesicle components, and energy metabolism. These results highlight the bLR/bHR model as a useful tool to explore the neurobiology of individual differences in susceptibility to perinatal SSRI exposure. PMID- 25451296 TI - Evidence for the contribution of adult neurogenesis and hippocampal cell death in experimental cerebral malaria cognitive outcome. AB - Cognitive dysfunction is a major sign of cerebral malaria (CM). However, the underlying mechanisms of CM cognitive outcome remain poorly understood. A body of evidence suggests that adult neurogenesis may play a role in learning and memory processes. It has also been reported that these phenomena can be regulated by the immune system. We hypothesized that memory dysfunction in CM results from hippocampal neurogenesis impairment mediated by the deregulated immune response during the acute phase of CM. C57Bl/6 mice were infected with Plasmodium berghei ANKA (PbA) strain, using a standardized inoculation of 10(6) parasitized erythrocytes. Long-term working memory was evaluated using the novel object recognition test. The mRNA expression of brain-derived neurotrophic factor (BDNF), tropomyosin-receptor-kinase (TRK-B) and nerve growth factor (NGF) in the frontal cortex and hippocampus was estimated by real-time polymerase chain reaction (PCR). The protein levels of cytokine interleukin-2 (IL-2), IL-4, IL-6, IL-10, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and CCL11 and neurotrophins BDNF and NGF were determined using a cytometric bead array (CBA) kit or enzyme-linked immunosorbent assay. Cell viability in the hippocampus was analyzed by Confocal Microscopy. Neurogenesis in the dentate gyrus was determined through quantification of doublecortin (DCX) positive cells. PbA-infected mice presented working memory impairment on day 5 post-infection. At this same time point, CM mice exhibited a decrease in DCX-positive cells in the dentate gyrus in parallel with increased cell death and elevated inflammatory cytokines (IL-6, TNF-alpha, IFN-gamma and CCL11) in the hippocampus and frontal cortex. A significant reduction of BDNF mRNA expression was also found. IL-6 and TNF-alpha correlated negatively with BDNF and NGF levels in the hippocampus of CM mice. In summary, we provide further evidence that neuroinflammation following PbA-infection influences neurotrophin expression, impairs adult hippocampal neurogenesis and increases hippocampal cell death in association with memory impairment following CM course. The current study identified potential mediators of memory impairment in CM. PMID- 25451295 TI - Greater ethanol inhibition of presynaptic dopamine release in C57BL/6J than DBA/2J mice: Role of nicotinic acetylcholine receptors. AB - The mesolimbic dopamine system, originating in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc), has been heavily implicated in the reinforcing effects of ethanol. Recent slice voltammetry studies have shown that ethanol inhibits dopamine release selectively during high-frequency activity that elicits phasic dopamine release shown to be important for learning and reinforcement. Presently, we examined ethanol inhibition of electrically evoked NAc dopamine in two mouse strains with divergent dopamine responses to ethanol, C57BL/6 (C57) and DBA/2J (DBA) mice. Previous electrophysiology and microdialysis studies have demonstrated greater ethanol-induced VTA dopaminergic firing and NAc dopamine elevations in DBA compared to C57 mice. Additionally, DBA mice have greater ethanol responses in dopamine-related behaviors, including hyperlocomotion and conditioned place preference. Currently, we demonstrate greater sensitivity of ethanol inhibition of NAc dopamine signaling in C57 compared to DBA mice. The reduced sensitivity to ethanol inhibition in DBA mice may contribute to the overall greater ethanol-induced dopamine signaling and related behaviors observed in this strain. NAc cholinergic activity is known to potently modulate terminal dopamine release. Additionally, ethanol is known to interact with multiple aspects of nicotinic acetylcholine receptor activity. Therefore, we examined ethanol-mediated inhibition of dopamine release at two ethanol concentrations (80 and 160 mM) during bath application of the non selective nicotinic receptor antagonist mecamylamine, as well as compounds selective for the beta2-(dihydro-beta-erythroidine hydrobromide; DhbetaE) and alpha6-(alpha-conotoxin MII [H9A; L15A]) subunit-containing receptors. Mecamylamine and DhbetaE decreased dopamine release and reduced ethanol's inhibitory effects on dopamine in both DBA and C57 mice. Further, alpha-conotoxin also reduced the dopamine release and the dopamine-inhibiting effects of ethanol at the 80 mM, but not 160 mM, concentration. These data suggest that ethanol is acting in part through nicotinic acetylcholine receptors, or downstream effectors, to reduce dopamine release during high-frequency activity. PMID- 25451297 TI - Lithium chloride stimulates PLP and MBP expression in oligodendrocytes via Wnt/beta-catenin and Akt/CREB pathways. AB - Deciphering the molecular pathways involved in myelin gene expression is a major point of interest to better understand re/myelination processes. In this study, we investigated the role of Lithium Chloride (LiCl), a drug largely used for the treatment of neurological disorders, on the two major central myelin gene expression (PLP and MBP) in mouse oligodendrocytes. We show that LiCl enhances the expression of both PLP and MBP, by increasing mRNA amount and promoter activities. We investigated whether Wnt/beta-catenin and/or Akt/CREB pathways are modulated by LiCl to regulate myelin gene expression. We showed that beta-catenin is required both for PLP and MBP basal promoter activities and for LiCl-induced myelin gene stimulation. Furthermore, while CREB functionality does not influence PLP expression, MBP promoter activity depends on Akt/CREB activation. Finally, we show that LiCl can stimulate oligodendrocyte morphological maturation, and promote remyelination after lysolecithin-induced demyelination of organotypic cerebellar slice cultures. Our data provide mechanistic evidences that Akt/CREB together with beta-catenin participate in the transcriptional control of PLP and MBP exerted by LiCl. Therefore, the use of LiCl to balance between beta-catenin and CREB effectors could be considered as an efficient remyelinating strategy. PMID- 25451299 TI - Porcine interferon-induced protein with tetratricopeptide repeats 3, poIFIT3, inhibits swine influenza virus replication and potentiates IFN-beta production. AB - Porcine interferon-induced protein with tetratricopeptide repeats 3 (poIFIT3) is one of the genes most abundantly induced by IFN-alpha/beta and swine influenza virus (SIV). However, little information is available about the role of poIFIT3 in host defense among pigs. In this study, we detected the upregulation of poIFIT3 in porcine alveolar macrophages (PAM) infected with SIV and subsequently cloned poIFIT3 from poly(I:C)-treated PAM cells. The overexpression of poIFIT3 can efficiently suppress the replication of SIV, whereas knockdown of poIFIT3 increases SIV replication. Further experiments on the functional domains showed that the C-terminal of poIFIT3 plays the main role in the antiviral activity of poIFIT3. Moreover, poIFIT3 can significantly enhance poly(I:C)-induced IFN-beta promoter activity through both IRF3- and NF-kappaB-mediated signaling pathways. poIFIT3 potentiates IFN-beta production by targeting MAVS, which was further verified by co-immunoprecipitation. This study suggests that poIFIT3 plays a significant role in the clearance of SIV in pigs and potentiates IFN-beta production. PMID- 25451298 TI - Medial prefrontal cortex serotonergic and GABAergic mechanisms modulate the expression of contextual fear: intratelencephalic pathways and differential involvement of cortical subregions. AB - Several lines of evidence indicate that the dorsal hippocampus (dH) and medial prefrontal cortex (mPFC) regulate contextual fear conditioning. The prelimbic (PrL), infralimbic (IL) and the anterior cingulate cortex (ACC) subregions of the mPFC likely play distinct roles in the expression of fear. Moreover, studies have highlighted the role of serotonin (5-hydroxytryptamine, 5-HT)- and gamma aminobutyric acid (GABA)-mediated mechanisms in the modulation of innate fear in the mPFC. The present study characterized dH-mPFC pathways and investigated the role of serotonergic and GABAergic mechanisms of the PrL, IL and ACC-area 1 (Cg1) in the elaboration of contextual fear conditioning using fear-potentiated startle (FPS) and freezing behavior in Rattus norvegicus. The results of neurotracing with microinjections of biotinylated dextran amine into the dH revealed a neural link of the dH with the PrL and ACC. Intra-PrL injections of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and the GABAA receptor-selective agonist muscimol reduced contextual FPS and freezing responses. Intra-Cg1 injections of muscimol but not 8-OH-DPAT decreased FPS and freezing responses. However, neither intra-IL injections of a 5-HT1A agonist nor of a GABAA agonist affected these defensive responses. Labeled neuronal fibers from the dH reached the superficial layers of the PrL cortex and spread to the inner layers of PrL and Cg1 cortices, supporting the pharmacological findings. The present results confirmed the involvement of PrL and Cg1 in the expression of FPS and freezing responses to aversive conditions. In addition, PrL serotoninergic mechanisms play a key role in contextual fear conditioning. This study suggests that PrL, IL and Cg1 distinctively contribute to the modulation of contextual fear conditioning. PMID- 25451300 TI - Characterization of two novel ADP ribosylation factors from giant freshwater prawn Macrobrachium rosenbergii and their responses to WSSV challenge. AB - ADP-ribosylation factors (Arfs) are small GTP-binding proteins that have an essential function in intracellular trafficking and organelle structure. To date, little information is available on the Arfs in the economically important giant freshwater prawn Macrobrachium rosenbergii and their relationship to viral infection. Here we identified two Arf genes from M. rosenbergii (MrArf1 and MrArf2) for the first time. Phylogenetic analysis showed that MrArf1, together with MjArf1 from shrimp Marsupenaeus japonicus belonged to Class I Arfs. By contrast, MrArf2 didn't not match any of the Arfs classes of I/II/III, although it could be clustered with an Arf protein from M. japonicas called MjArfn, which may represent an analog of the Arf. MrArf1 was ubiquitously expressed in all the examined tissues, with the highest transcription level in the hepatopancreas, whereas MrArf2 was only highly expressed in the hepatopancreas and exhibited very low levels in the heart, stomach, gills and intestine. The expression level of MrArf1 in the gills was down-regulated post 24 h WSSV challenge, and reached the maximal level at 48 h. MrArf1 in the hepatopancreas went up from 24 to 48 h WSSV challenge. MrArf2 transcript in the gill also went down at 24 h and then was upregulated at 48 h WSSV challenge. MrArf2 increased significantly in the hepatopancreas 24 h after infection and then went down at 48 h WSSV challenge. RNAi results showed that knockdown of MrArf1 or MrArf2 could inhibit the expression of the envelope protein gene vp28 of the WSSV. So, it could be speculated that MrArf1 and MrArf2 might play important roles in the innate immune system against WSSV infection. PMID- 25451301 TI - Lectin-like molecules in transcriptome of Littorina littorea hemocytes. AB - The common periwinkle Littorina littorea was introduced in the list of models for comparative immunobiology as a representative of phylogenetically important taxon Caenogastropoda. Using Illumina sequencing technology, we de novo assembled the transcriptome of Littorina littorea hemocytes from 182 million mRNA-Seq pair-end 100 bp reads into a total of 15,526 contigs clustered in 4472 unigenes. The transcriptome profile was analyzed for presence of carbohydrate-binding molecules in a variety of architectural contexts. Hemocytes' repertoire of lectin-like proteins bearing conserved carbohydrate-recognition domains (CRDs) is highly diversified, including 11 of 15 lectin families earlier described in animals, as well as the novel members of lectin family found for the first time in mollusc species. The new molluscan lineage-specific domain combinations were confirmed by cloning and sequencing, including the fuco-lectin related molecules (FLReMs) composed of N-terminal region with no sequence homology to any known protein, a middle Fucolectin Tachylectin-4 Pentaxrin (FTP) domain, and a C-terminal epidermal growth factor (EGF) repeat region. The repertoire of lectin-like molecules is discussed in terms of their potential participation in the receptor phase of immune response. In total, immune-associated functions may be attributed to 70 transcripts belonging to 6 lectin families. These lectin-like genes show low overlap between species of invertebrates, suggesting relatively rapid evolution of immune-associated genes in the group. The repertoire provides valuable candidates for further characterization of the gene functions in mollusc immunity. PMID- 25451304 TI - Simultaneous quantification of leukotrienes and hydroxyeicosatetraenoic acids in cell culture medium using liquid chromatography/tandem mass spectrometry. AB - Leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) are important bioactive lipid mediators that participate in various pathophysiological processes. To advance understanding of the mechanisms that regulate these mediators in physiological and pathological processes, an analytical method using liquid chromatography/tandem mass spectrometry for the simultaneous quantification of LTB4, LTC4, LTD4, LTE4, 5-HETE, 8-HETE, 12-HETE and 15-HETE in cell culture media was developed. A SupelTM-Select HLB solid-phase extraction cartridge was used for sample preparation. The compounds were separated on a C18 column using gradient elution with acetonitrile-water-formic acid (20:80:0.1, v/v/v) and acetonitrile-formic acid (100:0.1, v/v). The calibration curves of LTB4, LTD4, LTE4 and HETEs were linear in the range of 0.025-10 ng/mL, and the calibration curve of LTC4 was linear in the range of 0.25-10 ng/mL. Validation assessment showed that the method was highly reliable with good accuracy and precision. The stability of LTs and HETEs was also investigated. Using the developed method, we measured LTs and HETEs in the culture supernatant of the human mast cell line HMC-1. The present method could facilitate investigations of the mechanisms that regulate the production, release and signaling of LTs and HETEs. PMID- 25451302 TI - A family of variable immunoglobulin and lectin domain containing molecules in the snail Biomphalaria glabrata. AB - Technical limitations have hindered comprehensive studies of highly variable immune response molecules that are thought to have evolved due to pathogen mediated selection such as fibrinogen-related proteins (FREPs) from Biomphalaria glabrata. FREPs combine upstream immunoglobulin superfamily (IgSF) domains with a C-terminal fibrinogen-related domain (FreD) and participate in reactions against trematode parasites. From RNAseq data we assembled a de novo reference transcriptome of B. glabrata to investigate the diversity of FREP transcripts. This study increased over two fold the number of bonafide FREP subfamilies and revealed important sequence diversity within FREP12 subfamily. We also report the discovery of related molecules that feature one or two IgSF domains associated with different C-terminal lectin domains, named C-type lectin-related proteins (CREPs) and Galectin-related protein (GREP). Together, the highly similar FREPs, CREPs and GREP were designated VIgL (Variable Immunoglobulin and Lectin domain containing molecules). PMID- 25451303 TI - CT imaging for evaluation of calcium crystal deposition in the knee: initial experience from the Multicenter Osteoarthritis (MOST) study. AB - OBJECTIVE: Role of intra-articular calcium crystals in osteoarthritis (OA) is unclear. Imaging modalities used to date for its evaluation have limitations in their ability to fully characterize intra-articular crystal deposition. Since Computed Tomography (CT) imaging provides excellent visualization of bones and calcified tissue, in this pilot project we evaluated the utility of CT scan in describing intra-articular calcium crystal deposition in the knees. METHOD: We included 12 subjects with and four subjects without radiographic chondrocalcinosis in the most recent visit from the Multicenter Osteoarthritis (MOST) study, which is a longitudinal cohort of community-dwelling older adults with or at risk for knee OA. All subjects underwent CT scans of bilateral knees. Each knee was divided into 25 subregions and each subregion was read for presence of calcium crystals by a musculoskeletal radiologist. To assess reliability, readings were repeated 4 weeks later. RESULTS: CT images permitted visualization of 25 subregions with calcification within and around the tibio-femoral and patello-femoral joints in all 24 knees with radiographic chondrocalcinosis. Intra articular calcification was seen universally including meniscal cartilage (most common site involved in 21/24 knees), hyaline cartilage, cruciate ligaments, medial collateral ligament and joint capsule. Readings showed good agreement for specific tissues involved with calcium deposition (kappa: 0.70, 95% CI 0.62 0.80). CONCLUSION: We found CT scan to be a useful and reliable tool for describing calcium crystal deposition in the knee and therefore potentially for studying role of calcium crystals in OA. We also confirmed that "chondrocalcinosis" is a misnomer because calcification is present ubiquitously. PMID- 25451305 TI - Thermoreversible hydrogels based on triblock copolymers of poly(ethylene glycol) and carboxyl functionalized poly(epsilon-caprolactone): The effect of carboxyl group substitution on the transition temperature and biocompatibility in plasma. AB - In this study we report on the development, characterization and plasma protein interaction of novel thermoresponsive in situ hydrogels based on triblock copolymers of poly(ethylene glycol) (PEG) and poly(alpha-carboxyl-co-benzyl carboxylate)-epsilon-caprolactone (PCBCL) having two different degrees of carboxyl group substitution on the PCBCL block. Block copolymers were synthesized through ring-opening polymerization of alpha-benzyl carboxylate-epsilon caprolactone by dihydroxy PEG, leading to the production of poly(alpha-benzyl carboxylate-epsilon-caprolactone)-PEG-poly(alpha-benzyl carboxylate-epsilon caprolactone) (PBCL-PEG-PBCL). This was followed by partial debenzylation of PBCL blocks under controlled conditions, leading to the preparation of PCBCL-PEG-PCBCL triblock copolymers with 30 and 54mol.% carboxyl group substitution. Prepared PCBCL-PEG-PCBCL block copolymers have been shown to have a concentration dependent sol to gel transition as a result of an increase in temperature above ~29 degrees C, as evidenced by the inverse flow method, differential scanning calorimetry and dynamic mechanical analysis. The sol-gel transition temperature/concentration and dynamic mechanical properties of the gel were found to be dependent on the level of carboxyl group substitution. Both hydrogels (30 and 54mol.% carboxyl group substitution) showed similar amounts of protein adsorption but striking differences in the profiles of the adsorbed proteome. Additionally, the two systems showed similarities in their clot formation kinetics but substantial differences in clot endpoints. The results show great promise for the above-mentioned thermoreversible in situ hydrogels as biocompatible materials for biomedical applications. PMID- 25451308 TI - Acute infusion of brain-derived neurotrophic factor in the insular cortex promotes conditioned taste aversion extinction. AB - Brain-derived neurotrophic factor (BDNF) has emerged as one of the most potent molecular mediators not only for synaptic plasticity, but also for the behavioral organism-environment interactions. Our previous studies in the insular cortex (IC), a neocortical region that has been related with acquisition and retention of conditioned taste aversion (CTA), have demonstrated that intracortical microinfusion of BDNF induces a lasting potentiation of synaptic efficacy in the basolateral amygdaloid nucleus (Bla)-IC projection and enhances the retention of CTA memory of adult rats in vivo. The aim of the present study was to analyze whether acute BDNF-infusion in the IC modifies the extinction of CTA. Accordingly, animals were trained in the CTA task and received bilateral IC microinfusions of BDNF before extinction training. Our results showed that taste aversion was significantly reduced in BDNF rats from the first extinction trial. Additionally, we found that the effect of BDNF on taste aversion did not require extinction training. Finally we showed that the BDNF effect does not degrade the original taste aversion memory trace. These results emphasize that BDNF activity underlies memory extinction in neocortical areas and support the idea that BDNF is a key regulator and mediator of long-term synaptic modifications. PMID- 25451306 TI - Dopamine depletion in either the dorsomedial or dorsolateral striatum impairs egocentric Cincinnati water maze performance while sparing allocentric Morris water maze learning. AB - Both egocentric route-based learning and spatial learning, as assessed by the Cincinnati water maze (CWM) and Morris water maze (MWM), respectively, are impaired following an 80% dopamine (DA) loss in the neostriatum after 6 hydroxydopamine (6-OHDA) administration in rats. The dorsolateral striatum (DLS) and the dorsomedial striatum (DMS) are implicated in different navigational learning types, namely the DLS is implicated in egocentric learning while the DMS is implicated in spatial learning. This experiment tested whether selective DA loss through 6-OHDA lesions in the DMS or DLS would impair one or both types of navigation. Both DLS and DMS DA loss significantly impaired route-based CWM learning, without affecting spatial or cued MWM performance. DLS 6-OHDA lesions produced a 75% DA loss in this region, with no changes in other monoamine levels in the DLS or DMS. DMS 6-OHDA lesions produced a 62% DA loss in this region, without affecting other monoamine levels in the DMS or DLS. The results indicate a role for DA in DLS and DMS regions in route-based egocentric but not spatial learning and memory. Spatial learning deficits may require more pervasive monoamine reductions within each region before deficits are exhibited. This is the first study to implicate DLS and DMS DA in route-based egocentric navigation. PMID- 25451309 TI - Treadmill exercise alters histone acetylation differently in rats exposed or not exposed to aversive learning context. AB - Epigenetic modifications have been linked to memory formation after learning context exposure and to exercise effects on memory performance. The aim of this study was to investigate the effect of treadmill exercise (20 min/day during 2 weeks) on H3K14 acetylation and H3S10 phosphorylation levels in the hippocampi of 3-month-old Wistar rats exposed and not exposed to aversive learning context. Male Wistar rats aged 2-3 months were assigned to non-exercised (sedentary) and exercised (running daily for 20 min for 2 weeks) groups. Single-trial step-down inhibitory avoidance (IA) conditioning was employed as an aversive memory model. Epigenetic parameters were determined 30 min after the IA test. A decrease in the H3K14 acetylation in the hippocampus 24 h after IA training (30 min after test session) was observed. Exercise reversed the IA effect, and no effect was observed in the non-IA exposed group. Our data support the hypothesis that modulation of H3K14 acetylation levels in the hippocampus might be related, at least in part, to exercise effects on aversive memory. PMID- 25451307 TI - An increase in insulin is important for the acquisition conditioned taste aversion in Lymnaea. AB - Conditioned taste aversion (CTA) in Lymnaea is brought about by pairing a sucrose solution (the conditioned stimulus, CS) with an electric shock (the unconditioned stimulus, US). Following repeated CS-US pairings, CTA occurs and it is consolidated into long-term memory (LTM). The best CTA is achieved, if snails are food-deprived for 1 day before training commences. With a longer period of food deprivation (5 days), learning and memory formation does not occur. It has been hypothesized that the levels of insulin in the central nervous system (CNS) are very important for CTA to occur. To test his hypothesis, we injected insulin directly into 5-day food-deprived snails. The injection of insulin, as expected, resulted in a decrease in hemolymph glucose concentration. Consistent with our hypothesis with insulin injection, learning and memory formation of CTA occurred. That is, the 'insulin spike' is more important than an increase in hemolymph glucose concentration for CTA-LTM. If we injected an insulin receptor antibody into the snails before the insulin injection, learning was formed but memory formation was not, which is consistent with our previous study. Therefore, a rise in the insulin concentration (i.e., insulin spike) in the CNS is considered to be a key determining factor in the process of CTA-LTM. PMID- 25451310 TI - Chronic high-frequency repetitive transcranial magnetic stimulation improves age related cognitive impairment in parallel with alterations in neuronal excitability and the voltage-dependent Ca2+ current in female mice. AB - Chronic high-frequency repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method to increase the excitability of neurons, and it induces long term effects that can improve symptoms related to neurodegenerative diseases, including cognitive ability. The present study was undertaken to identify the mechanism by which rTMS improves cognitive impairments in mice. The novel object recognition test in vivo was used to evaluate the cognitive function of the mice. Whole-cell patch-clamp recordings were used to evaluate the neuronal excitability, including the resting membrane potential, the number of action potentials induced by depolarized current, after-hyperpolarization, and the voltage-dependent Ca(2+) current in hippocampal slices. We found that the aged mice showed impairments in cognitive function, and high-frequency (25Hz) rTMS for 14 consecutive-days ameliorated the impairments. Whole-cell patch-clamp recordings showed that, compared to matured mice, the hippocampal CA1 pyramidal neurons of aged mice showed significantly hyperpolarized resting membrane potential, significantly decreased numbers of action potentials after injection of depolarizing current, and significantly increased after-hyperpolarization after an action potential. The exposure to high-frequency rTMS significantly improved the above deficits in the neuronal excitability in the aged rTMS mice. Consistent with the above changes, the exposure to high-frequency rTMS also significantly decreased the voltage-dependent Ca(2+) current of the neurons compared with the aged sham mice. These data suggested that the rTMS could improve the age-related cognitive impairment in parallel with regulating the neuronal excitability and modifying the voltage-dependent Ca(2+) channels. PMID- 25451311 TI - Statistical learning of music- and language-like sequences and tolerance for spectral shifts. AB - In our previous study (Daikoku, Yatomi, & Yumoto, 2014), we demonstrated that the N1m response could be a marker for the statistical learning process of pitch sequence, in which each tone was ordered by a Markov stochastic model. The aim of the present study was to investigate how the statistical learning of music- and language-like auditory sequences is reflected in the N1m responses based on the assumption that both language and music share domain generality. By using vowel sounds generated by a formant synthesizer, we devised music- and language-like auditory sequences in which higher-ordered transitional rules were embedded according to a Markov stochastic model by controlling fundamental (F0) and/or formant frequencies (F1-F2). In each sequence, F0 and/or F1-F2 were spectrally shifted in the last one-third of the tone sequence. Neuromagnetic responses to the tone sequences were recorded from 14 right-handed normal volunteers. In the music- and language-like sequences with pitch change, the N1m responses to the tones that appeared with higher transitional probability were significantly decreased compared with the responses to the tones that appeared with lower transitional probability within the first two-thirds of each sequence. Moreover, the amplitude difference was even retained within the last one-third of the sequence after the spectral shifts. However, in the language-like sequence without pitch change, no significant difference could be detected. The pitch change may facilitate the statistical learning in language and music. Statistically acquired knowledge may be appropriated to process altered auditory sequences with spectral shifts. The relative processing of spectral sequences may be a domain-general auditory mechanism that is innate to humans. PMID- 25451312 TI - Early life inflammatory pain induces long-lasting deficits in hippocampal dependent spatial memory in male and female rats. AB - The present experiment tested the hypothesis that neonatal injury disrupts adult hippocampal functioning and that normal aging or chronic stress during adulthood, which are known to have a negative impact on hippocampal function, exacerbate these effects. Male and female Sprague-Dawley rats were given an intraplantar injection of the inflammatory agent carrageenan (1%) on the day of birth and their memory was tested in the hippocampal-dependent spatial water maze in adulthood and again in middle age. We found that neonatal injury impaired hippocampal-dependent memory in adulthood, that the effects of injury on memory were more pronounced in middle-aged male rats, and that chronic stress accelerated the onset of these memory deficits. Neonatal injury also decreased glucocorticoid receptor mRNA in the dorsal CA1 area of middle-aged rats, a brain region critical for spatial memory. Morphine administration at the time of injury completely reversed injury-induced memory deficits, but neonatal morphine treatments in the absence of injury produced significant memory impairments in adulthood. Collectively, these findings are consistent with our hypothesis that neonatal injury produces long-lasting disruption in adult hippocampal functioning. PMID- 25451313 TI - Investigation of basic cognitive predictors of reading and spelling abilities in Tunisian third-grade primary school children. AB - BACKGROUND: This study investigated first the main cognitive abilities; phonological processing, visual cognition, automatization and receptive vocabulary in predicting reading and spelling abilities in Arabic. Second, we compared good/poor readers and spellers to detect the characteristics of cognitive predictors which contribute to identifying reading and spelling difficulties in Arabic speaking children. METHODS: A sample of 116 Tunisian third grade children was tested on their abilities to read and spell, phonological processing, visual cognition, automatization and receptive vocabulary. RESULTS: For reading, phonological processing and automatization uniquely predicted Arabic word reading and paragraph reading abilities. Automatization uniquely predicted Arabic non-word reading ability. For spelling, phonological processing was a unique predictor for Arabic word spelling ability. Furthermore, poor readers had significantly lower scores on the phonological processing test and slower reading times on the automatization test as compared with good readers. Additionally, poor spellers showed lower scores on the phonological processing test as compared with good spellers. Visual cognitive processing and receptive vocabulary were not significant cognitive predictors of Arabic reading and spelling abilities for Tunisian third grade children in this study. CONCLUSIONS: Our results are consistent with previous studies in alphabetic orthographies and demonstrate that phonological processing and automatization are the best cognitive predictors in detecting early literacy problems. We suggest including phonological processing and automatization tasks in screening tests and in intervention programs may help Tunisian children with poor literacy skills overcome reading and spelling difficulties in Arabic. PMID- 25451314 TI - Infantile tauopathies: Hemimegalencephaly; tuberous sclerosis complex; focal cortical dysplasia 2; ganglioglioma. AB - Tau is a normal microtubule-associated protein; mutations to phosphorylated or acetylated forms are neurotoxic. In many dementias of adult life tauopathies cause neuronal degeneration. Four developmental disorders of the fetal and infant brain are presented, each of which exhibits up-regulation of tau. Microtubules are cytoskeletal structures that provide the strands of mitotic spindles and specify cellular polarity, growth, lineage, differentiation, migration and axonal transport of molecules. Phosphorylated tau is abnormal in immature as in mature neurons. Several malformations are demonstrated in which upregulated tau may be important in pathogenesis. All produce highly epileptogenic cortical foci. The prototype infantile tauopathy is (1) hemimegalencephaly (HME); normal tau is degraded by a mutant AKT3 or AKT1 gene as the aetiology of focal somatic mosaicism in the periventricular neuroepithelium. HME may be isolated or associated with neurocutaneous syndromes, particularly epidermal naevus syndromes, also due to somatic mutations. Other tauopathies of early life include: (2) tuberous sclerosis complex; (3) focal cortical dysplasia type 2b (FCD2b); and (4) ganglioglioma, a tumor with dysplastic neurons and neoplastic glial cells. Pathological tau in these infantile cases alters cellular growth and architecture, synaptic function and tissue organization, but does not cause neuronal loss. All infantile tauopathies are defined neuropathologically as a tetrad of (1) dysmorphic and megalocytic neurons; (2) activation of the mTOR signaling pathway; (3) post-zygotic somatic mosaicism; and (4) upregulation of phosphorylated tau. HME and FCD2b may be the same disorder with different timing of the somatic mutation in the mitotic cycles of the neuroepithelium. HME and FCD2b may be the same disorder with different timing of the somatic mutation in the mitotic cycles of the neuroepithelium. Tauopathies must be considered in infantile neurological disease and no longer restricted to adult dementias. The mTOR inhibitor everolimus, already demonstrated to be effective in TSC, also may be a potential treatment in other infantile tauopathies. PMID- 25451315 TI - Tris-heteroleptic ruthenium-dipyrrinate chromophores in a dye-sensitized solar cell. AB - Two novel tris-heteroleptic Ru-dipyrrinates were prepared and tested as sensitizers in the dye-sensitized solar cell (DSSC). Under AM 1.5 sunlight, DSSCs employing these dyes achieved power conversion efficiencies (PCEs) of 3.4 and 2.2 %, substantially exceeding the value achieved previously with a bis-heteroleptic dye (0.75 %). As shown by electrochemical measurements and DFT calculations, the improved PCEs stem from the synthetically tuned electronic structure, which affords more negative excited state redox potentials and favorable electron injection into the TiO2 conduction band. Electron injection was quantified by nanosecond transient absorption spectroscopy, which revealed that the highest injection yield is achieved with the dye that acts as the strongest photoreductant. PMID- 25451316 TI - A novel serum microRNA panel to discriminate benign from malignant ovarian disease. AB - Ovarian cancer is the seventh most common cancer in women and the most frequent cause of gynaecological malignancy-related mortality in women. Currently, no standardized reliable screening test exists. MicroRNA profiling has allowed the identification of signatures associated with diagnosis, prognosis and response to treatment of human tumours. The aim of this study was to determine if a microRNA signature could distinguish between malignant and benign ovarian disease. A training set of 5 serous ovarian carcinomas and 5 benign serous cystadenomas were selected for the initial experiments. The validation set included 20 serous ovarian carcinomas and 20 benign serous cystadenomas. The serum/plasma focus microRNA Exiqon panel was used for the training set. For the validation set a pick and mix Exiqon panel, which focuses on microRNAs of interest was used. A panel of 4 microRNAs (let-7i-5p, miR-122, miR-152-5p and miR-25-3p) was significantly down regulated in cancer patients. These microRNAs target WNT signalling, AKT/mTOR and TLR-4/MyD88, which have previously been found to play a role in ovarian carcinogenesis and chemoresistance. let-7i-5p, miR-122, miR-152 5p and miR-25-3p could act as diagnostic biomarkers in ovarian cancer. PMID- 25451319 TI - The emerging roles of microRNAs in cancer metabolism. AB - The major goal of cancer therapy is to destroy cancer cells without harming normal cells. However, because cancer cells have incredible heterogeneity and adaptability, it is difficult to target them therapeutically. Metabolic reprogramming has emerged as a common feature of cancer. Ever since microRNAs (miRNAs) have been found to influence metabolism, researchers have been trying to address the connection between cancer cells and specific miRNAs. Many of the well known miRNAs relate to crucial genes that can impact metabolic pathways, both negatively and positively. With a better understanding of how different pathways are affected, the roles of miRNAs will be more transparent, which could lead to the discovery of new ideas about the concept of tumorigenesis and other cancer related topics. PMID- 25451318 TI - Big genes are big mutagen targets: a connection to cancerous, spherical cells? AB - We determined the most commonly mutated genes in five cancer genome atlas (TCGA) datasets. Many of these genes were extraordinarily large, as are many cancer fusion gene partners. And many of these genes had cytoskeletal related functions. We further determined that these genes were distributed into high and low frequency mutation groups largely according to overall rate of gene-occurrence in the high and low mutation frequency groups, as was also the case with common metastasis and tumor suppressor genes. Oncoproteins were selectively mutated in the low mutation frequency groups in colon and lung datasets. Thus, genes that have very large coding regions and may impact the cytoskeleton are more commonly mutated than are common metastasis and tumor suppressor genes in both high and low frequency mutation groups. These analyses raise questions related to cell shape: (i) Are cancer cells often spherical because cytoskeletal-related proteins are large mutagen targets? (ii) Is drug-resistance facilitated by relatively common mutant proteins that lead to round cells, with altered cell physiology or reduced surface to volume ratios that could reduce intra-cellular drug concentrations? PMID- 25451317 TI - LPA-mediated migration of ovarian cancer cells involves translocalization of Galphai2 to invadopodia and association with Src and beta-pix. AB - Lysophosphatidic acid (LPA) plays a critical role in the migration and invasion of ovarian cancer cells. However, the downstream spatiotemporal signaling events involving specific G protein(s) underlying this process are largely unknown. In this report, we demonstrate that LPA signaling causes the translocation of Galphai2 into the invadopodia leading to its interaction with the tyrosine kinase Src and the Rac/CDC42-specific guanine nucleotide exchange factor, beta-pix. Our results establish that Galphai2 activates Rac1 through a p130Cas-dependent pathway in ovarian cancer cells. Moreover, our report reveals that knockdown of Galphai2 leads to loss of beta-pix and active-Rac association in the invadopodia. We also show that knockdown of Galphai2 leads to the complete loss of translocation to p130Cas to focal adhesions. Finally, when Galphai2 is knocked down, this led to the total distribution of Src being shifted primarily from invadopodia and the leading edge of the cells to the perinuclear region, suggesting that Src is inactive in the absence of Galphai2. Overall, our report provides tantalizing evidence that Galphai2 is a critical signaling component of a large signaling complex in the invadopodia that if disrupted could serve as an excellent target for therapy in ovarian and potentially other cancers. PMID- 25451320 TI - Ultrasound texture-based CAD system for detecting neuromuscular diseases. AB - PURPOSE: Diagnosis of neuromuscular diseases in ultrasonography is a challenging task since experts are often unable to discriminate between healthy and pathological cases. A computer-aided diagnosis (CAD) system for skeletal muscle ultrasonography was developed and tested for myositis detection in ultrasound images of biceps brachii. METHODS: Several types of features were extracted from rectangular and polygonal image regions-of-interest (ROIs), including first-order statistics, wavelet-based features, and Haralick's features. Features were chosen that are sensitive to the change in contrast and structure for pathological ultrasound images of neuromuscular diseases. The number of features was reduced by applying different sequential feature selection strategies followed by a supervised principal component analysis. For classification, two linear approaches were investigated: Fisher's classifier and the linear support vector machine (SVM) as well as the nonlinear [Formula: see text]-nearest neighbor approach. The CAD system was benchmarked on datasets of 18 subjects, seven of which were healthy, while 11 were affected by myositis. Three expert radiologists provided pre-classification and testing interpretations. RESULTS: Leave-one-out cross-validation on the training data revealed that the linear SVM was best suited for discriminating healthy and pathological muscle tissue, achieving 85/87 % accuracy, 90 % sensitivity, and 83/85 % specificity, depending on the radiologist. CONCLUSION: A muscle ultrasonography CAD system was developed, allowing a classification of an ultrasound image by one-click positioning of rectangular ROIs with minimal user effort. The applicability of the system was demonstrated with the challenging example of myositis detection, showing highly accurate results that were robust to imprecise user input. PMID- 25451321 TI - The effects of beta-2 adrenergic agonist and antagonist on human bone metabolism: a randomized controlled trial. AB - PURPOSE: Genetic knockout or pharmacological inhibition of the beta-2 adrenergic receptor (B2AR) increased bone mass, whereas stimulation decreased bone mass in rodents. In humans, observational studies support sympathetic nervous system regulation of bone metabolism, but intervention studies are lacking. We aimed to determine the effects of a selective beta-2 adrenergic agonist and non-selective antagonist on human bone metabolism. METHODS: 32 healthy postmenopausal women were included in a randomized controlled trial conducted in the Academic Medical Center Amsterdam. Participants were randomized to receive treatment with 17-beta estradiol 2mg/day; 17-beta estradiol 2mg/day and terbutaline 5mg/day (selective B2AR agonist); propranolol 80mg/day (non-selective B-AR antagonist); or no treatment during 12weeks. Main outcome measure was the change in serum concentrations of procollagen type I N propeptide (P1NP) and C-terminal crosslinking telopeptides of collagen type I (CTx) as markers of bone formation and resorption after 12weeks compared between the treatment groups. Data were analyzed with mixed model analysis. RESULTS: 17-beta estradiol decreased bone turnover compared to control (P1NP p<0.001, CTx p=0.003), but terbutaline combined with 17-beta estradiol failed to increase bone turnover compared to 17 beta estradiol alone (P1NP p=0.135, CTx p=0.406). Propranolol did not affect bone turnover compared to control (P1NP p=0.709, CTx p=0.981). CONCLUSION: Selective beta-2 adrenergic agonists and non-selective beta-antagonists do not affect human bone turnover although we cannot exclude small changes below the detection limit of this study. PMID- 25451324 TI - Walking, obesity and urban design in Chinese neighborhoods. AB - OBJECTIVE: We examined the connections (1) between the design of the built environment and walking, (2) between the design of the built environment and obesity, and (3) between walking and obesity and income in urban settings in China. METHODS: Six neighborhoods with different built environment characteristics, located in the Chinese cities of Shanghai and Hangzhou, were studied. Data on walking and other physical activity and obesity levels from 1070 residents were collected through a street intercept survey conducted in 2013. Built environment features of 527 street segments were documented using the Irvine-Minnesota Inventory-China (IMI-C) environmental audit. Data were analyzed using the State of PlaceTM Index. RESULTS: Walking rates, household income and Body Mass Index (BMI) were related; neighborhoods with a higher State of PlaceTM Index were associated with higher rates of walking. CONCLUSION: This study began to establish an evidence base for the association of built environment features with walking in the context of Chinese urban design. Findings confirmed that the associations between "walkable" built environment features and walking established in existing research in other countries, also held true in the case of Chinese neighborhoods. PMID- 25451325 TI - Afterschool shared use of public school facilities for physical activity in North Carolina. AB - OBJECTIVE: To determine the status and common characteristics of shared use in public schools in North Carolina. METHOD: All public school principals (N=2,359) in North Carolina were invited to participate in an online survey (February - May, 2013) designed to provide baseline information about the extent and nature of shared use of school facilities. RESULTS: Responses (n=1182, 50.1%) indicated that most schools share their facilities (88.9%). Formal agreements were more common when schools shared gyms and outdoor athletic fields. Informal agreements were most common with playgrounds and track facilities. Schools with more low income or Black students were less likely to share facilities. For schools that did not share use of their facilities the most frequent reason was no outside groups had ever asked. CONCLUSION: Schools may be more accommodating to shared use partnerships. Community organizations seeking to use indoor school facilities or athletic fields should be prepared to complete a formal written agreement. Preconceived notions that schools are unwilling to share their facilities may be preventing community organizations from initiating shared use inquiries. Schools located in the middle tier of economic distress and schools with a greater concentration of Black students were less likely to share their facilities. PMID- 25451322 TI - Twelve months of voluntary heavy alcohol consumption in male rhesus macaques suppresses intracortical bone remodeling. AB - Chronic heavy alcohol consumption is a risk factor for cortical bone fractures in males. The increase in fracture risk may be due, in part, to reduced bone quality. Intracortical (osteonal) bone remodeling is the principle mechanism for maintaining cortical bone quality. However, it is not clear how alcohol abuse impacts intracortical bone remodeling. This study investigated the effects of long-duration heavy alcohol consumption on intracortical bone remodeling in a non human primate model. Following a 4-month induction period, male rhesus macaques (Macaca mulatta, n=21) were allowed to voluntarily self-administer water or alcohol (4% ethanol w/v) for 22h/d, 7 d/wk for 12months. Control monkeys (n=13) received water and an isocaloric maltose-dextrin solution. Tetracycline hydrochloride was administered orally 17 and 3days prior to sacrifice for determination of active mineralization sites. Animals in the alcohol group consumed 2.7+/-0.2g alcohol/kg/d (mean+/-SE) during the 12months of self administration, resulting in a mean daily blood alcohol concentration of 77+/ 9mg/dl from samples taken at 7h after the start of a daily session. However, blood alcohol concentration varied widely from day to day, with peak levels exceeding 250mg/dl, modeling a binge-drinking pattern of alcohol consumption. The skeletal response to alcohol was determined by densitometry, microcomputed tomography and histomorphometry. Significant differences in tibial bone mineral content, bone mineral density, and cortical bone architecture (cross-sectional volume, cortical volume, marrow volume, cortical thickness, and polar moment of inertia) in the tibial diaphysis were not detected with treatment. However, cortical porosity was lower (1.8+/-0.5 % versus 0.6+/-0.1 %, p=0.021) and labeled osteon density was lower (0.41+/-0.2/mm(2)versus 0.04+/-0.01/mm(2), p<0.003) in alcohol-consuming monkeys compared to controls, indicating a reduced rate of intracortical bone remodeling. In concordance, plasma CTx was lower (2.5+/ 0.3ng/ml versus 1.7+/-0.1ng/ml, p=0.028) in the alcohol group. These results suggest that chronic heavy alcohol consumption may negatively impact bone health, in part, by suppressing intracortical bone remodeling. PMID- 25451326 TI - Disparities in park availability, features, and characteristics by social determinants of health within a U.S.-Mexico border urban area. AB - OBJECTIVE: To examine disparities in park availability, features, and characteristics by income and the percentage of foreign-born population within a predominately-Hispanic border community. METHODS: This study occurred in 2010 2011 in El Paso, Texas. All census tracts (n=112) were categorized as low, medium, or high income and percent foreign-born. The number of parks intersecting each tract was determined using ArcGIS and park features (facilities, amenities) and characteristics (aesthetic features, park and neighborhood quality/safety concerns) were assessed via park audits (n=144). Analysis of variance and Kruskal Wallis tests examined differences across income and percent foreign-born tertiles for all park measures. RESULTS: The medium income tertile had more parks than the high tertile, and more park facilities than the low or high tertiles, but no differences in park amenities were observed across income groups. As well, none of park availability, facilities, or amenities differed across percent foreign born tertiles. Finally, parks in the high income tertile had significant fewer park and neighborhood quality/safety concerns and parks in the high percent foreign-born tertile had significantly greater park and neighborhood quality/safety concerns. CONCLUSION: Identifying disparities in park availability, features, and characteristics can aid policymakers and citizens in improving the contribution of parks to community health for all. PMID- 25451323 TI - Ten-year incident osteoporosis-related fractures in the population-based Canadian Multicentre Osteoporosis Study - comparing site and age-specific risks in women and men. AB - BACKGROUND: Population-based incident fracture data aid fracture prevention and therapy decisions. Our purpose was to describe 10-year site-specific cumulative fracture incidence by sex, age at baseline, and degree of trauma with/without consideration of competing mortality in the Canadian Multicentre Osteoporosis Study adult cohort. METHODS: Incident fractures and mortality were identified by annual postal questionnaires to the participant or proxy respondent. Date, site and circumstance of fracture were gathered from structured interviews and medical records. Fracture analyses were stratified by sex and age at baseline and used both Kaplan-Meier and competing mortality methods. RESULTS: The baseline (1995 97) cohort included 6314 women and 2789 men (aged 25-84 years; mean+/-SD 62+/-12 and 59+/-14, respectively), with 4322 (68%) women and 1732 (62%) men followed to year-10. At least one incident fracture occurred for 930 women (14%) and 247 men (9%). Competing mortality exceeded fracture risk for men aged 65+years at baseline. Age was a strong predictor of incident fractures especially fragility fractures, with higher age gradients for women vs. men. Major osteoporotic fracture (MOF) (hip, clinical spine, forearm, humerus) accounted for 41-74% of fracture risk by sex/age strata; in women all MOF sites showed age-related increases but in men only hip was clearly age-related. The most common fractures were the forearm for women and the ribs for men. Hip fracture incidence was the highest for the 75-84 year baseline age-group with no significant difference between women 7.0% (95% CI 5.3, 8.9) and men 7.0% (95% CI 4.4, 10.3). INTERPRETATION: There are sex differences in the predominant sites and age gradients of fracture. In older men, competing mortality exceeds cumulative fracture risk. PMID- 25451327 TI - HPV vaccine acceptability in Africa: a systematic review. AB - OBJECTIVE: The objective of this study was to provide a systematic review of peer reviewed literature on the factors associated with HPV vaccine acceptability among adults in African countries. METHODS: A systematic search was conducted across five electronic databases: EMBASE, PsychINFO, CINAHL, Global Health and Ovid MEDLINE, to identify studies related to HPV vaccination acceptability in African countries (August 2013). The Health Belief Model was used to guide data abstraction and synthesis. RESULTS: Fourteen unique studies representing ten sub Saharan African countries were identified, with more than half published within the last two years. Acceptability of the HPV vaccine for daughters was high (range 59-100%); however, vaccine-related awareness and knowledge were low. Perceived barriers including accessibility and cost concerns were important for acceptance, as were cues to action from healthcare providers and governments. CONCLUSIONS: This review suggests that acceptability of the HPV vaccine in countries in this region will be high. Broad knowledge gaps were highlighted regarding HPV and cervical cancer and these should be addressed. Education on the vaccine's effectiveness and reducing perceived barriers to vaccination would also be useful. Public endorsement by governments and healthcare providers will likely also increase acceptance. PMID- 25451328 TI - Probing the role of amino acids in oxime-mediated reactivation of nerve agent inhibited human acetylcholinesterase. AB - In this study, we employed site-directed mutagenesis to understand the role of amino acids in the gorge in oxime-induced reactivation of nerve agent-inhibited human (Hu) acetylcholinesterase (AChE). The organophosphorus (OP) nerve agents studied included GA (tabun), GB (sarin), GF (cyclosarin), VX, and VR. The kinetics of reactivation were examined using both the mono-pyridinium oxime 2-PAM and bis-pyridinium oximes MMB4, HI-6, and HLo-7. The second-order reactivation rate constants were used to compare reactivation of nerve agent-inhibited wild type (WT) and mutant enzymes. Residues including Y72, Y124 and W286 were found to play important roles in reactivation by bis-pyridinium, but not by mono pyridinium oximes. Residue Y124 also was found to play a key role in reactivation by HI-6 and HLo-7, while E202 was important for reactivation by all oximes. Residue substitutions of F295 by Leu and Y337 by Ala showed enhanced reactivation by bis-pyridinium oximes MMB4, HI-6, and HLo-7, possibly by providing more accessibility of the OP moiety associated at the active-site serine to the oxime. These results are similar to those observed previously with bovine AChE and demonstrate that there is significant similarity between human and bovine AChEs with regard to oxime reactivation. PMID- 25451329 TI - Development of a CCK1R-membrane nanoparticle as a fish-out tool for bioactive peptides. AB - The cholecystokinin receptor type 1 (CCK1R) is a G protein-coupled receptor (GPCR) that is involved in several biological processes including the regulation of the secretion of digestive enzymes. The peptide hormone cholecystokinin (CCK) binds to CCK1R, which is an important pharmacological target for several diseases, including obesity. Interestingly, nutritional dietary peptides also appear to activate CCK1R, and may play a role in CCK1R signaling in the gut. In this study, a novel technique to screen for CCK1R ligands based on affinity selection is described. Functional expressed CCK1R is reconstituted into membrane nanoparticles called NABBs (nanoscale apo-lipoprotein bound bilayers). NABBs are native-like bilayer membrane systems for incorporation of GPCRs. CCK1R-NABBs were characterized using a fluorescently labeled CCK analog and can be used as a cutting-edge technology to screen for CCK1R ligands using affinity-selection mass spectrometry. PMID- 25451330 TI - The effect of neuropeptide Y on brown-like adipocyte's differentiation and activation. AB - Despite its wide distribution in the central nervous system, the presence of Neuropeptide Y (NPY) in peripheral tissues has been detected. White adipose tissue (WAT) is a new site of NPY synthesis and secretion. The development of brown-like adipocytes in WAT is controlled by hypothalamic NPY neurons through interaction with sympathetic nervous system (SNS). However, whether peripheral NPY has a direct effect on induction of the Uncoupling protein1 (UCP1)-positive adipocytes is unknown. We have used adipocytes derived from C3H10T1/2 stem cells as a model of brown-like adipocyte, and investigated the role of NPY in their differentiation and activation. In general, NPY had no effect on brown adipogenesis of C3H10T1/2 stem cell, but suppressed db-cAMP activation of brown like adipocytes, which was due to blunting brown fat-relevant gene expression and mitochondrial function. NPY showed suppression in a receptor-dependent manner, inhibition of endogenous cAMP production and cAMP-PKA-dependent pathways p38 MAPK and CREB phosphorylation were involved in the downstream mechanisms. A novel role of NPY in the peripheral is presented, which may help decrease energy expenditure in WAT of obese subjects. PMID- 25451331 TI - Visinin-like peptide 1 in adrenal gland of the rat. Gene expression and its hormonal control. AB - VSNL1 encodes the calcium-sensor protein visinin-like 1 and was identified previously as an upregulated gene in a sample set of aldosterone-producing adenomas. Recently, by means of microarray studies we demonstrated high expression of Vsnl1 gene in rat adrenal zona glomerulosa (ZG). Only scanty data are available on the role of this gene in adrenal function as well as on regulation of its expression by factors affecting adrenal cortex structure and function. Therefore we performed relevant studies aimed at clarifying some of the above issues. By Affymetrix((r)) Rat Gene 1.1 ST Array Strip, QPCR and immunohistochemistry we demonstrated that expression levels of Vsnl1 in the rat adrenal ZG are notably higher than in the fasciculata/reticularis zone. In QPCR assay this difference was approximately 10 times higher. Expression of this gene in the rat adrenal gland or adrenocortical cells was acutely down regulated by ACTH, while chronic administration of corticotrophin or dexamethasone did not change Vsnl1 mRNA levels. In enucleation-induced adrenocortical regeneration expression levels of both Vsnl1 and Cyp11b2 were notably lowered and positively correlated. Despite these findings, the physiological significance of adrenal Vsnl1 remains unclear, and requires further investigation. PMID- 25451332 TI - Angiotensin IV stimulates high atrial stretch-induced ANP secretion via insulin regulated aminopeptidase. AB - Angiotensin IV (Ang IV) is formed by aminopeptidase N (APN) from angiotensin III (Ang III) by removing the first N-terminal amino acid. Previously, we reported that angiotensin II (Ang II) inhibits atrial natriuretic peptide (ANP) secretion via angiotensin II type 1 receptor (AT1R). In contrast, angiotensin-(1-7) [Ang-(1 7)] and Ang III stimulate ANP secretion via Mas receptor (Mas R) and angiotensin II type 2 receptor (AT2R), respectively. However, it is not known whether there is any relationship between Ang IV and ANP secretion. Therefore, the aim of the present study was to determine the effect of Ang IV on ANP secretion and to find its downstream signaling pathway using in isolated perfused beating atria. Ang IV (0.1, 1 and 10MUM) stimulated high atrial stretch-induced ANP secretion and ANP concentration in a dose-dependent manner. The augmented effect of Ang IV (1MUM) on high atrial stretch-induced ANP secretion and concentration was attenuated by pretreatment with insulin-regulated aminopeptidase (IRAP) antagonist but not by AT1R or AT2R antagonist. Pretreatment with inhibitors of downstream signaling pathway including phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) and mammalian target of rapamycin (mTOR) blocked Ang IV-induced ANP secretion and concentration. Therefore, these results suggest that Ang IV stimulates ANP secretion and concentration via IRAP and PI3K-Akt-mTOR pathway. PMID- 25451333 TI - Effects of cyclotides against cutaneous infections caused by Staphylococcus aureus. AB - The main bacterium associated with skin infection is Staphylococcus aureus, occurring especially in infections acquired via surgical wounds, commonly leading to lethal hospital-acquired infections, emphasizing the importance of identifying new antimicrobial compounds. Among them, cyclotides have gained interest due to their high stability and multifunctional properties. Here, cycloviolacin 2 (CyO2) and kalata B2 (KB2) were evaluated to determinate their anti-staphylococcal activities using a subcutaneous infection model. Anti-staphylococcal activities of 50mM for KB2 and 25mM for CyO2 were detected with no cytotoxic activities against RAW 264.7 monocytes. In the in vivo assays, both cyclotides reduced bacterial load and CyO2 demonstrated an increase in the phagocytosis index, suggesting that the CyO2 in vivo anti-staphylococcal activity may be associated with phagocytic activity, additionally to direct anti-pathogenic activity. PMID- 25451335 TI - Pheromonotropic and melanotropic PK/PBAN receptors: differential ligand-receptor interactions. AB - The aim of the present study was to further characterize the PK/PBAN receptors and their interaction with various PK/PBAN peptides in order to get a better understanding of their ubiquitous and multifunctional nature. Two cloned receptors stably expressed in Spodoptera frugiperda (Sf9) cells were used in this study: a Heliothis peltigera pheromone gland receptor (Hep-PK/PBAN-R) (which stimulates sex pheromone biosynthesis) and Spodoptera littoralis larval receptor (Spl-PK/PBAN-R) (which mediates cuticular melanization in moth larvae) and their ability to respond to several native PK/PBAN peptides: beta-subesophageal neuropeptide (beta-SGNP), myotropin (MT) and Leucophaea maderae pyrokinin (LPK), as well as linear and cyclic analogs was tested by monitoring their ability to stimulate Ca(2+) release. The receptors exhibited a differential response to beta SGNP, which activated the Hep-PK/PBAN-R but not the Spl-PK/PBAN-R - a response opposite to that previously demonstrated with diapause hormone (DH). MT was somewhat more active on Spl-PK/PBAN-R than on Hep-PK/PBAN-R. LPK elicited similar positive responses in both receptors (like that with PBAN). A differential response toward both receptors was also noticed with the PBAN-derived backbone cyclic (BBC) conformationally constrained peptide BBC-5. The peptides BBC-7 and BBC-8 activated both receptors. The results correlate between two PK/PBAN mediated function (cuticular melanization and sex pheromone biosynthesis) and the peptides that activate them and thus advance our understanding of the mode of action of the PK/PBAN family, and might help in exploring novel high-affinity receptor-specific antagonists that could serve as a basis for development of new families of insect-control agents. PMID- 25451336 TI - Effects of 12 Weeks of Supervised Exercise After Endovascular Treatment: A Randomized Clinical Trial. AB - BACKGROUND AND PURPOSE: This study aimed to assess the effects of supervised exercise training (SET) after percutaneous transluminal angioplasty (PTA) compared with PTA alone on physical function, limb hemodynamics and health related quality of life in patients with intermittent claudication. METHODS: Fifty patients who all underwent PTA for intermittent claudication were included in the study. Both groups received usual post-operative care. In addition, the intervention group performed two sessions of hospital-based SET and one home based exercise session per week for 12 weeks after PTA. The control group did not receive any additional follow-up regarding exercise. The primary outcome was the result of a standardized 6-minute walk test. Secondary outcomes were the treadmill maximum walking distance, treadmill pain-free walking distance, ankle brachial index, pulse volume recording on the leg and ultrasound scanning. Health related quality of life was measured using the Short Form 36 and the Claudication Scale. RESULTS: All measures, except for the Short Form 36 domain of mental health, showed statistically significant positive changes from baseline to 3 months for both groups (p < 0.05). At 3 months, there was a trend towards better results for the intervention group compared with the control group. The median improvement from baseline to 3 months for the 6-minute walk test was 66 m for the intervention group and 45 m for the control group. For maximum walking distance, the median improvement was 251 m for the intervention group and 93 m for the control group. DISCUSSION: Supervised exercise training after endovascular treatment for patients with intermittent claudication led to greater positive changes after 3 months in the intervention group compared with the control group. The present study's trends of better results with SET after PTA add to the emerging existing evidence, which should encourage physiotherapy practice to offer SET for this patient group. PMID- 25451337 TI - Age-adjusted D-dimer cutoff for reducing CT pulmonary angiography tests in elderly patients with suspected pulmonary embolism: improvement or restoration back to normal? PMID- 25451334 TI - Selective agonists of somatostatin receptor subtype 1 or 2 injected peripherally induce antihyperalgesic effect in two models of visceral hypersensitivity in mice. AB - Somatostatin interacts with five G-protein-coupled receptor (sst1-5). Octreotide, a stable sst2?3>=5 agonist, exerts a visceral anti-hyperalgesic effect in experimental and clinical studies. Little is known on the receptor subtypes involved. We investigated the influence of the stable sst1-5 agonist, ODT8-SST and selective receptor subtype peptide agonists (3 or 10MUg/mouse) injected intraperitoneally (ip) on visceral hypersensitivity in mice induced by repeated noxious colorectal distensions (four sets of three CRD, each at 55mmHg) or corticotropin-releasing factor receptor 1 agonist, cortagine given between two sets of graded CRD (15, 30, 45, and 60mmHg, three times each pressure). The mean visceromotor response (VMR) was assessed using a non-invasive manometry method and values were expressed as percentage of the VMR to the 1st set of CRD baseline or to the 60mmHg CRD, respectively. ODT8-SST (10MUg) and the sst2 agonist, S-346 011 (3 and 10MUg) prevented mechanically induced visceral hypersensitivity in the three sets of CRD, the sst1 agonist (10MUg) blocked only the 2nd set and showed a trend at 3MUg while the sst4 agonist had no effect. The selective sst2 antagonist, S-406-028 blocked the sst2 agonist but not the sst1 agonist effect. The sst1 agonist (3 and 10MUg) prevented cortagine-induced hypersensitivity to CRD at each pressure while the sst2 agonist at 10MUg reduced it. These data indicate that in addition to sst2, the sst1 agonist may provide a novel promising target to alleviate visceral hypersensitivity induced by mechanoreceptor sensitization and more prominently, stress-related visceral nociceptive sensitization. PMID- 25451338 TI - Robotic lobectomy and the principles of technology diffusion. PMID- 25451339 TI - Overweight and obesity are risk factors for COPD misdiagnosis and overtreatment. PMID- 25451340 TI - Improving the management of children with bronchiolitis: the updated American Academy of Pediatrics Clinical Practice Guideline. PMID- 25451341 TI - POINT: should patients receiving statins prior to ICU admission be continued on statin therapy? Yes. PMID- 25451342 TI - COUNTERPOINT: should patients receiving statins prior to ICU admission be continued on statin therapy? No. PMID- 25451343 TI - Rebuttal from Drs Flannery and Kruger. PMID- 25451344 TI - Rebuttal from Drs Mermis and Simpson. PMID- 25451345 TI - Did we finally slay the evil dragon of cigarette smoking in the late 20th century?: unfortunately, the answer is no - the dragon is still alive and well in the 21st century and living in the third world. Shame on us! AB - If cigarettes were introduced as a new consumer product today, it is unlikely they would receive government regulatory approval. Cigarettes have proven biologic toxicities (carcinogenesis, atherogenesis, teratogenesis) and well established causal links to human disease. Things were very different in 1913 when the R. J. Reynolds Tobacco Company introduced the first modern cigarette, the iconic Camel. By the early 1950s, definitive scientific reports linked cigarettes and human disease, but it was more than a half century later (2006) that cigarette manufacturers were found guilty by a federal court of deceptive product marketing regarding the health hazards of tobacco use. In the United States, cigarette smoking remains a major but slowly declining problem. But in developing countries, cigarette use is expanding tremendously. In global terms, the epidemic of smoking-caused disease is projected to increase rapidly in coming decades, not decline. Society may have begun to slowly win the smoking battle in the developed world, but we are resoundingly losing the global war on smoking. All is not lost! There is some good news! The 2003 Framework Convention on Tobacco Control, supported strongly by the American College of Chest Physicians, is the first global public health treaty of the new millennium. Many developed societies have begun planning to rid their countries of cigarettes in what is called the Endgame Strategy, and now is the time for the international medical community to help change tobacco policy to a worldwide endgame approach to rid all humanity of smoking-related diseases. PMID- 25451346 TI - Characterization of patients with borderline pulmonary arterial pressure. AB - BACKGROUND: Resting mean pulmonary artery pressure (mPAP) values between 20 and 25 mm Hg are above normal but do not fulfill the criteria for pulmonary hypertension (PH). The clinical relevance of such borderline hemodynamics is a matter of discussion. METHODS: We focused on patients who underwent right-sided heart catheterization during rest and exercise for symptoms indicative of PH or due to underlying disease associated with an increased risk for pulmonary arterial hypertension and characterized the patients according to their resting mPAP. Patients with manifest PH (mPAP >= 25 mm Hg) were excluded. RESULTS: We included 141 patients, 32 of whom presented with borderline hemodynamics (20 < mPAP < 25 mm Hg). Borderline patients were older (65.8 +/- 12.5 years vs 57.3 +/- 12.5 years, P = .001) and more often had cardiac comorbidities (53% vs 15%, P < .001) or decreased lung function (47% vs 16%, P < .001) as compared with patients with resting mPAP < 21 mm Hg. After correction for age, borderline patients had significantly increased pulmonary vascular resistance (2.7 +/- 0.7 Wood units vs 1.8 +/- 0.8 Wood units, P < .001) and mPAP/cardiac output (CO) and transpulmonary gradient/CO slopes (both P < .001) as well as lower peak oxygen uptake (16.9 +/- 4.6 mL/min/kg vs 20.9 +/- 4.7 mL/min/kg, P = .009) and 6-min walk distance (383 +/- 120 m vs 448 +/- 92 m, P = .001). During follow-up (4.4 +/- 1.4 years), the mortality rate of borderline patients vs patients with resting mPAP < 21 mm Hg was 19% vs 4%. CONCLUSIONS: In patients undergoing right-sided heart catheterization with exclusion of manifest PH, borderline elevation of pulmonary arterial pressure is associated with cardiac and pulmonary comorbidities, decreased exercise capacity, and a poor prognosis. PMID- 25451347 TI - One-year safety and efficacy study of arformoterol tartrate in patients with moderate to severe COPD. AB - BACKGROUND: Arformoterol tartrate (arformoterol, 15 MUg bid) is a nebulized long acting beta2-agonist approved for maintenance treatment of COPD. METHODS: This was a multicenter, double-blind, randomized, placebo-controlled study. Patients (aged >= 40 years with baseline FEV1 <= 65% predicted, FEV1 > 0.50 L, FEV1/FVC <= 70%, and >= 15 pack-year smoking history) received arformoterol (n = 420) or placebo (n = 421) for 1 year. The primary assessment was time from randomization to respiratory death or first COPD exacerbation-related hospitalization. RESULTS: Among 841 patients randomized, 103 had >= 1 primary event (9.5% vs 15.0%, for arformoterol vs placebo, respectively). Patients who discontinued treatment for any reason (39.3% vs 49.9%, for arformoterol vs placebo, respectively) were followed for up to 1 year postrandomization to assess for primary events. Fewer patients receiving arformoterol than placebo experienced COPD exacerbation related hospitalizations (9.0% vs 14.3%, respectively). Twelve patients (2.9%) receiving arformoterol and 10 patients (2.4%) receiving placebo died during the study. Risk for first respiratory serious adverse event was 50% lower with arformoterol than placebo (P = .003). Numerically more patients on arformoterol (13; 3.1%) than placebo (10; 2.4%) experienced cardiac serious adverse events; however, time-to-first cardiac serious adverse event was not significantly different. Improvements in trough FEV1 and FVC were greater with arformoterol (least-squares mean change from baseline vs placebo: 0.051 L, P = .030 and 0.075 L, P = .018, respectively). Significant improvements in quality of life (overall St. George's Hospital Respiratory Questionnaire and Clinical COPD Questionnaire) were observed with arformoterol vs placebo (P < .05). CONCLUSIONS: Arformoterol demonstrated an approximately 40% lower risk of respiratory death or COPD exacerbation-related hospitalization over 1 year vs placebo. Arformoterol was well-tolerated and improved lung function vs placebo. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00909779; URL: www.clinicaltrials.gov. PMID- 25451348 TI - Heterogeneity of specific gas volume changes: a new tool to plan lung volume reduction in COPD. AB - OBJECTIVE: The aim of this work was to investigate if regional differences of specific gas volume (SVg) in the different regions (lobes and bronchopulmonary segments) in healthy volunteers and patients with severe emphysema can be used as a tool for planning lung volume reduction (LVR) in emphysema. METHODS: CT scans of 10 healthy subjects and 10 subjects with severe COPD were obtained at end inspiration (total lung capacity [TLC]) and end-expiration (residual volume [RV]). For each subject, DeltaSVg (DeltaSVg = SVg,TLC - SVg,RV, where SVg,TLC and SVg,RV are specific gas volume at TLC and RV, respectively) vs DeltaV (DeltaV = V,TLC-V,RV, where V,TLC and V,RV are lung volume at TLC and RV, respectively) was plotted for the entire lung, each lobe, and all bronchopulmonary segments. For each subject, a heterogeneity index (HI) was defined to quantify the range of variability of DeltaSVg/DeltaV in all bronchopulmonary regions. RESULTS: In patients with COPD, SVg,TLC and SVg,RV were significantly higher and DeltaSVg variations lower than in healthy subjects (P < .001). In COPD, DeltaSVg/DeltaV slopes were lower in upper lobes than in lower lobes. In healthy subjects, the entire lung, lobes, and bronchopulmonary segments all showed similar DeltaSVg/DeltaV slopes, whereas in COPD a high variance was found. As a consequence, HI was significantly higher in subjects with COPD than in healthy subjects (0.80 +/- 0.34 vs 0.15 +/- 0.10, respectively; P < .001). CONCLUSIONS: SVg variations within the lung are highly homogeneous in healthy subjects. Regions with low DeltaSVg/DeltaV (ie, more pronounced gas trapping) should be considered as target areas for LVR. Regions with negative values of DeltaSVg/DeltaV identify where collateral ventilation is present. HI is helpful to assess the patient in the different stages of disease and the effect of different LVR treatments. PMID- 25451349 TI - End-of-life expenditure in the ICU and perceived quality of dying. AB - OBJECTIVE: Although end-of-life care in the ICU accounts for a large proportion of health-care costs, few studies have examined the association between costs and satisfaction with care. The objective of this study was to investigate the association of ICU costs with family- and nurse-assessed quality of dying and family satisfaction. METHODS: This was an observational study surveying families and nurses for patients who died in the ICU or within 30 h of transfer from the ICU. A total of 607 patients from two Seattle hospitals were included in the study. Survey data were linked with administrative records to obtain ICU and hospital costs. Regression analyses assessed the association between costs and outcomes assessing satisfaction with care: nurse- and family-assessed Quality of Death and Dying (QODD-1) and Family Satisfaction in the ICU (FS-ICU). RESULTS: For family-reported outcomes, patient insurance status was an important modifier of results. For underinsured patients, higher daily ICU costs were significantly associated with higher FS-ICU and QODD-1 (P < .01 and P = .01, respectively); this association was absent for privately insured or Medicare patients (P = .50 and P = .85, QODD-1 and FS-ICU, respectively). However, higher nurse-assessed QODD-1 was significantly associated with lower average daily ICU cost and total hospital cost (P < .01 and P = .05, respectively). CONCLUSIONS: Family-rated satisfaction with care and quality of dying varied depending on insurance status, with underinsured families rating satisfaction with care and quality of dying higher when average daily ICU costs were higher. However, patients with higher costs were assessed by nurses as having a poorer quality of dying. These findings highlight important differences between family and clinician perspectives and the important role of insurance status. PMID- 25451351 TI - Personalized therapy for lung cancer. AB - The past decade has seen an enormous advancement in the therapy for lung cancer, predominantly seen in adenocarcinoma, ranging from the introduction of histology based drugs to the discovery of targetable mutations. These events have led to a personalized therapeutic approach with the delivery of drugs that target specific oncogenic pathways active in a given tumor with the intent of acquiring the best response rate. The discovery of sensitizing mutation in the epidermal growth factor receptor gene as the basis for clinical response to tyrosine kinase inhibitors led to a systematic search for other molecular targets in lung cancer. Currently, there are several molecular alterations that can be targeted by experimental drugs. These new discoveries would not be possible without a parallel technological evolution in diagnostic molecular pathology. Next generation sequencing (NGS) is a technology that allows for the evaluation of multiple molecular alterations in the same sample using a small amount of tissue. Selective evaluation of targeted cancer genes, instead of whole-genome evaluation, is the approach that is best suited to enter clinical practice. This technology allows for the detection of most molecular alteration with a single test, thus saving tissue for future discoveries. The use of NGS is expected to increase and gain importance in clinical and experimental approaches, since it can be used as a diagnostic tool as well as for new discoveries. The technique may also help us elucidate the interplay of several genes and their alteration in the mechanism of drug response and resistance. PMID- 25451352 TI - Clinical approach and management for selected fungal infections in pulmonary and critical care patients. AB - Fungal lung infections are widely encountered and present both diagnostic and therapeutic challenges. The increasing prevalence of fungal infections is correlated with increasing numbers of immunocompromised patients, enhanced awareness of these infections, and improved methodologies for diagnosis. Fortunately, additional antifungal agents are available to combat these important infections. This review covers the clinical approach to fungal lung infections encountered in pulmonary and critical care practice. PMID- 25451350 TI - Automated surveillance for ventilator-associated events. AB - BACKGROUND: The US Centers for Disease Control and Prevention has implemented a new, multitiered definition for ventilator-associated events (VAEs) to replace their former definition of ventilator-associated pneumonia (VAP). We hypothesized that the new definition could be implemented in an automated, efficient, and reliable manner using the electronic health record and that the new definition would identify different patients than those identified under the previous definition. METHODS: We conducted a retrospective cohort analysis using an automated algorithm to analyze all patients admitted to the ICU at a single urban, tertiary-care hospital from 2008 to 2013. RESULTS: We identified 26,466 consecutive admissions to the ICU, 10,998 (42%) of whom were mechanically ventilated and 675 (3%) of whom were identified as having any VAE. Any VAE was associated with an adjusted increased risk of death (OR, 1.91; 95% CI, 1.53-2.37; P < .0001). The automated algorithm was reliable (sensitivity of 93.5%, 95% CI, 77.2%-98.8%; specificity of 100%, 95% CI, 98.8%-100% vs a human abstractor). Comparison of patients with a VAE and with the former VAP definition yielded little agreement (kappa = 0.06). CONCLUSIONS: A fully automated method of identifying VAEs is efficient and reliable within a single institution. Although VAEs are strongly associated with worse patient outcomes, additional research is required to evaluate whether and which interventions can successfully prevent VAEs. PMID- 25451353 TI - Medical futility: a new look at an old problem. AB - Efforts to answer the question of whether or when physicians may unilaterally refuse to provide treatments they deem medically futile, but that are nonetheless demanded by patients or their surrogates, have been characterized as intractable failures. We propose a new look at this old problem and suggest reframing the debate in terms of the implicit social contract, in healthy democracies, between the medical profession and the society it serves. This ever-evolving contract is predicated upon providing patients with beneficial and desired medical care within the constraints of scarce resources and the characteristics of our health care system. The contract ranges over a continuum of decisions, from those that do not need an explicit negotiated agreement with the patient or surrogate, to those that do. Between these two poles lies a contentious gray area, where the rights and obligations of patients and physicians are being shaped continuously by the many forces that are at play in a democratic society, including professional guidelines, social advocacy, legislation, and litigation. We provide examples of how this gray area has been and is negotiated around rights to refuse and demand a variety of life-sustaining treatments, and anticipate conflicts likely to arise in the future. Reframing the futility debate in this way reveals that the issue is not a story of intractable failure, but rather, a successful narrative about how democracies balance the legitimate perspectives of patients and physicians against a backdrop of societal constraints and values. PMID- 25451354 TI - Where there is smoke...there is sleep apnea: exploring the relationship between smoking and sleep apnea. AB - Smoking and OSA are widely prevalent and are associated with significant morbidity and mortality. It has been hypothesized that each of these conditions adversely affects the other, leading to increased comorbidity while altering the efficacy of existing therapies. However, while the association between smoking and OSA is plausible, the evidence is less than conclusive. Cigarette smoking may increase the severity of OSA through alterations in sleep architecture, upper airway neuromuscular function, arousal mechanisms, and upper airway inflammation. Conversely, some evidence links untreated OSA with smoking addiction. Smoking cessation should improve OSA, but the evidence to support this is also limited. This article reviews the current evidence linking both conditions and the efficacy of various treatments. Limitations of the current evidence and areas in need of future investigation are also addressed. PMID- 25451355 TI - Swallowing dysfunction after critical illness. AB - Critical care practitioners must frequently make decisions about their patients' ability to swallow food, liquids, and pills. These decisions can be particularly difficult given the incompletely defined epidemiology, diagnostic criteria, and prognostic features of swallowing disorders in critically ill patients. Furthermore, the consequences of improper decisions-namely, aspiration, malnutrition, hunger, and thirst-can be devastating to patients and their families. This review outlines the problem of swallowing dysfunction in critically ill patients and then addresses the most clinically relevant questions that critical care practitioners face today. First, we review the epidemiology of swallowing dysfunction in critically ill patients. Next, we describe the different diagnostic tests for swallowing dysfunction and describe a general approach to the initial assessment for swallowing disorders. Finally, we explore the existing treatments for swallowing dysfunction. Given the burden of swallowing dysfunction in patients recovering from critical illness, enabling critical care practitioners to manage these disorders, while stimulating new investigation into their pathophysiology, diagnosis, and management, will enhance our care of critically ill patients. PMID- 25451360 TI - Talc pleurodesis through indwelling pleural catheters for malignant pleural effusions: retrospective case series of a novel clinical pathway. AB - Malignant pleural effusions cause significant morbidity, but there is no gold standard minimally invasive treatment. A new therapeutic approach combines talc pleurodesis and indwelling pleural catheters (IPCs) to enable outpatient management. This case series summarizes the safety and efficacy data of all patients (24) with a symptomatic malignant pleural effusion who underwent talc pleurodeses via IPCs between December 2010 and July 2013. Successful pleurodesis was achieved in 22 procedures (92%). There was one empyema, one hydropneumothorax, one recurrent effusion, and two minor complications: one drain site wound infection and one complaint of chest pain. Twenty-two procedures (92%) were performed in the outpatient setting. This report confirms the safety and efficacy of administering talc slurry through IPCs in an outpatient setting. Studies in a larger cohort are necessary to define the role of this novel approach in the treatment algorithm of patients with this condition. PMID- 25451359 TI - A case of hypercalcemia secondary to hot tub lung. AB - Hypersensitivity pneumonitis (HP) is a diffuse granulomatous lung disease resulting from inhalation of an antigen to which an individual has been previously sensitized. Hot tub lung is an increasingly common form of HP associated with inhalation of water aerosols containing Mycobacterium avium complex organisms that contaminate hot tub water. Granulomatous lung disorders, most classically sarcoidosis, have been associated with unregulated 1-alpha hydroxylase expression by macrophages present in the granulomas, causing conversion of 25-OH-vitamin D to the active form of vitamin D, 1,25(OH)2 vitamin D, and, thus, hypercalcemia. To our knowledge, this is the first confirmed case of hypercalcemia secondary to elevated 1,25(OH)2 vitamin D levels associated with HP. PMID- 25451361 TI - A woman in her 70s presented to the ED complaining of worsening shortness of breath. PMID- 25451362 TI - A 40-year-old woman with multiple pulmonary nodules. Pulmonary hyalinizing granuloma. AB - A 40-year-old woman (a nonsmoker) with history of idiopathic thrombocytopenic purpura and a platelet count > 90,000 cells/MUL without specific medication was referred to pulmonary clinic for evaluation of multiple pulmonary nodules. The patient presented to an outside hospital with fatigue, lack of energy, and dyspnea on exertion for 2 years. She denied fever, cough, chest pain, or weight loss. An initial chest radiograph showed bilateral multiple pulmonary nodules. A chest CT scan revealed multiple nodular lesions, varying in size, in all lobes of both lungs. There was no mediastinal lymphadenopathy or pleural effusion. There was no significant hypermetabolic activity on a subsequent fluorodeoxyglucose PET scan/CT scan, and there had been no significant change. She underwent CT scan guided percutaneous transthoracic biopsy and bronchoscopy with transbronchial biopsies, all of which were inconclusive. An open lung biopsy was considered. PMID- 25451363 TI - A 44-year-old woman with excessive sleepiness. Opioid-induced central sleep apnea. PMID- 25451364 TI - Increasing pulmonary infiltrates in a 72-year-old woman with metastatic breast cancer. PMID- 25451365 TI - Secondary Outcomes and Peto OR in Meta-analysis. PMID- 25451366 TI - Response. PMID- 25451367 TI - Acute coronary syndrome after nasal spray of oxymetazoline. PMID- 25451368 TI - Dual-time point whole-body 18F-fluorodeoxyglucose PET/CT imaging in undiagnosed mediastinal lymphadenopathy: a prospective study of 117 patients with sarcoidosis and TB. PMID- 25451369 TI - Linear endobronchial ultrasound learning curve: hard to predict. PMID- 25451370 TI - A survey of Japanese thoracic oncologists' perception of diagnostic and treatment strategies for EGFR mutant or EML4-ALK fusion non-small cell lung cancer. PMID- 25451371 TI - Repeated polysomnograms after antiinflammatory therapy of mild pediatric OSA. PMID- 25451372 TI - Response. PMID- 25451373 TI - National trends in lung volume reduction surgery in the United States: 2000 to 2010. PMID- 25451374 TI - Interpreting lung ultrasound B-lines in acute respiratory failure. PMID- 25451375 TI - Response. PMID- 25451377 TI - How to assess alveolar nitric oxide: a quest of the grail? PMID- 25451376 TI - Long-term assessment of quality of life in primary ciliary dyskinesia: time for new tools? PMID- 25451379 TI - Comprehensive clinical evidence for pulmonary embolism diagnosis and workup: response. PMID- 25451378 TI - The prognostic value of plasma heart-type fatty acid-binding protein in acute pulmonary embolism. PMID- 25451380 TI - Effects of aging on the neuromagnetic mismatch detection to speech sounds. AB - The ability to discriminate speech sounds is crucial for higher language functions in humans. However, it remains unclear whether physiological aging affects the functional integrity of pre-attentive phonological discrimination. The neuromagnetic cortical responses during automatic change detection of speech sounds (/ba/versus/da/) were recorded in 24 young and 21 aged male adults. We used minimum norm estimate of source reconstruction to characterize the spatiotemporal dynamics of magnetic mismatch responses (MMNm). Distributed activations to phonetic changes were identified in the temporal, frontal and parietal regions. Compared to younger participants, elderly volunteers exhibited a significant reduction of cortical responses to phonetic-MMNm, except for the left orbitofrontal cortex and anterior inferior temporal gyrus. However, among the identified regions of interest, we did not observe significant between-group differences in the hemispheric asymmetry of phonetic-MMNm. Conclusively, our results suggest an altered phonetic processing at the perceptual level during physiological aging. PMID- 25451382 TI - Changes in attention to an emotional task after sleep deprivation: neurophysiological and behavioral findings. AB - While sleep loss is shown to have widespread effects on cognitive processes, little is known about the impact of sleep loss on emotion processes. In order to expand on previous behavioral and physiological findings on how sleep loss influences emotion processing, we administered positive, negative, and neutral affective visual stimuli to individuals after one night of sleep deprivation while simultaneously acquiring EEG event related potential (ERP) data and recording affective behavioral responses. We compared these responses to a baseline testing session. We specifically looked at the late positive potential (LPP) component of the visual ERP as an established sensitive measure of attention to emotionally-charged visual stimuli. Our results show that after sleep deprivation, the LPP no longer discriminates between emotional and non emotional pictures; after sleep deprivation the LPP amplitude was of similar amplitude for neutral, positive, and negative pictures. This effect was driven by an increase in the LPP to neutral pictures. Our behavioral measures show that, relative to baseline testing, emotional pictures are rated as less emotional following sleep deprivation with a concomitant reduction in emotional picture induced anxiety. We did not observe any change in cortisol concentrations after sleep deprivation before or after emotional picture exposure, suggesting that the observed changes in emotion processing are independent of potential stress effects of sleep deprivation. Combined, our findings suggest that sleep loss interferes with proper allocation of attention resources during an emotional task. PMID- 25451381 TI - Knowing your own heart: distinguishing interoceptive accuracy from interoceptive awareness. AB - Interoception refers to the sensing of internal bodily changes. Interoception interacts with cognition and emotion, making measurement of individual differences in interoceptive ability broadly relevant to neuropsychology. However, inconsistency in how interoception is defined and quantified led to a three-dimensional model. Here, we provide empirical support for dissociation between dimensions of: (1) interoceptive accuracy (performance on objective behavioural tests of heartbeat detection), (2) interoceptive sensibility (self evaluated assessment of subjective interoception, gauged using interviews/questionnaires) and (3) interoceptive awareness (metacognitive awareness of interoceptive accuracy, e.g. confidence-accuracy correspondence). In a normative sample (N=80), all three dimensions were distinct and dissociable. Interoceptive accuracy was only partly predicted by interoceptive awareness and interoceptive sensibility. Significant correspondence between dimensions emerged only within the sub-group of individuals with greatest interoceptive accuracy. These findings set the context for defining how the relative balance of accuracy, sensibility and awareness dimensions explain cognitive, emotional and clinical associations of interoceptive ability. PMID- 25451384 TI - Sense of impending doom: inhibitory activity in waiting blood donors who subsequently experience vasovagal symptoms. AB - This study examined autonomic and hemodynamic processes associated with the development of naturally occurring vasovagal responses. Data from a study assessing the physiological correlates of an intervention to reduce vasovagal responses in blood donors were examined (Ditto et al., 2009). Ninety-eight participants were assigned randomly to groups that either practiced applied tension or not. Dependent variables included ratings of vasovagal symptoms, heart rate, blood pressure, and other parameters derived from ambulatory impedance cardiography. Participants who subsequently experienced vasovagal symptoms had a lower ratio between low and high frequency components (LF/HF HRV) of heart rate variability (HRV) before blood donation, suggesting lower sympathetic nervous system activity. They also showed sharper decreases in total peripheral resistance and lower respiration rates. The results suggest that vasovagal reactions that begin during anticipation of a medical procedure may be characterized by an inhibitory process from the outset and do not support the belief that reactions follow a diphasic pattern. PMID- 25451383 TI - Harsh discipline and behavior problems: the moderating effects of cortisol and alpha-amylase. AB - Numerous studies link harsh discipline to adjustment problems in youth, yet not all individuals exposed to harsh discipline develop behavior problems. Contemporary theory suggests that this relationship could be moderated by individual differences in environmentally sensitive biological systems. This study investigated whether the interaction between hypothalamic-pituitary-adrenal (HPA) activity and autonomic nervous system (ANS) arousal moderated the link between harsh discipline and behavior problems. Three saliva samples were collected on a single day from 425 inner city youth (50% male, age 11-12 years, 80% African American) and were later assayed for cortisol (HPA) and alpha-amylase (ANS). Problem behavior was assessed by self- and parent-report using the Child Behavior Checklist. Youth also reported the level of harsh discipline that they experienced. Harsh discipline was positively associated with externalizing and internalizing problems only when there were asymmetrical profiles of HPA activity and ANS arousal. This pattern was evident for boys but not girls. Findings are discussed in relation to prevailing theories suggesting that biological susceptibility translates adversity into risk for behavior problems. PMID- 25451385 TI - Degradation of cardiac myosin light chain kinase by matrix metalloproteinase-2 contributes to myocardial contractile dysfunction during ischemia/reperfusion. AB - Although ischemia/reperfusion (I/R)-induced myocardial contractile dysfunction is associated with a prominent decrease in myofilament Ca(2+) sensitivity, the underlying mechanisms have not yet been fully clarified. Phosphorylation of ventricular myosin light chain 2 (MLC-2v) facilitates actin-myosin interactions and enhances contractility, however, its level and regulation by cardiac MLC kinase (cMLCK) and cMLC phosphatase (cMLCP) in I/R hearts are debatable. In this study, the levels and/or effects of MLC-2v phosphorylation, cMLCK, cMLCP, and proteases during I/R were determined. Global myocardial I/R-suppressed cardiac performance in isolated rat hearts was concomitant with decreases of MLC-2v phosphorylation, myofibrillar Ca(2+)-stimulated ATPase activity, and cMLCK content, but not cMLCP proteins. Consistently, simulated I/R in isolated cardiomyocytes inhibited cell shortening, Ca(2+) transients, MLC-2v phosphorylation, and myofilament sensitivity to Ca(2+). These observations were reversed by cMLCK overexpression, while the specific cMLCK knockdown by short hairpin RNA (shRNA) had the opposite effect. Moreover, the inhibition of matrix metalloproteinase-2 (MMP-2, a zinc-dependent endopeptidase) reversed IR-decreased cMLCK, MLC-2v phosphorylation, myofibrillar Ca(2+)-stimulated ATPase activity, myocardial contractile function, and myofilament sensitivity to Ca(2+), while the inhibition or knockdown of cMLCK by ML-9 or specific shRNA abolished MMP-2 inhibition-induced cardioprotection. Finally, the co-localization in cardiomyocytes and interaction in vivo of MMP-2 and cMLCK were observed. Purified recombinant rat cMLCK was concentration- and time-dependently degraded by rat MMP 2 in vitro, and this was prevented by the inhibition of MMP-2. These findings reveal that the I/R-activated MMP-2 leads to the degradation of cMLCK, resulting in a reduction of MLC-2v phosphorylation, and myofibrillar Ca(2+)-stimulated ATPase activity, which subsequently suppresses myocardial contractile function through a decrease of myofilament Ca(2+) sensitivity. PMID- 25451387 TI - Gene reprogramming in exercise-induced cardiac hypertrophy in swine: A transcriptional genomics approach. AB - Cardiac hypertrophy of the left ventricle (LV) in response to dynamic exercise training (EX) is a beneficial adaptation to increased workload, and is thought to result from genetic reprogramming. We aimed to determine which transcription factors (TFs) are involved in this genetic reprogramming of the LV in swine induced by exercise-training. Swine underwent 3-6 weeks of dynamic EX, resulting in a 16% increase of LV weight/body weight ratio compared to sedentary animals (P=0.03). Hemodynamic analysis showed an increased stroke volume index (stroke volume/body weight +35%; P=0.02). Microarray-analysis of LV tissue identified 339 upregulated and 408 downregulated genes (false discovery rate<0.05). Of the human homologues of the differentially expressed genes, promoter regions were searched for TF consensus binding sites (TFBSs). For upregulated and downregulated genes, 17 and 24 TFBSs were overrepresented by >1.5-fold (P<0.01), respectively. In DNA binding assays, using LV nuclear protein extracts and protein/DNA array, signal intensity changes >2-fold were observed for 23 TF-specific DNA probes. Matching results in TFBS and protein/DNA array analyses were obtained for transcription factors YY1 (Yin Yang 1), PAX6 (paired box 6) and GR (glucocorticoid receptor). Notably, PAX6 and GR show lower signals in TFBS and protein/DNA array analyses upon exercise-training, whereas we previously showed higher signals for these factors in the remodeled LV of swine post-myocardial infarction (MI). In conclusion, we have identified transcription factors that may drive the genetic reprogramming underlying exercise-training induced LV hypertrophy in swine. PAX6 and GR are among the transcription factors that are oppositely regulated in LV hypertrophy after exercise-training and MI. These proteins may be at the base of the differences between pathological and physiological hypertrophy. PMID- 25451386 TI - Phospholamban interactome in cardiac contractility and survival: A new vision of an old friend. AB - Depressed sarcoplasmic reticulum (SR) calcium cycling, reflecting impaired SR Ca transport and Ca-release, is a key and universal characteristic of human and experimental heart failure. These SR processes are regulated by multimeric protein complexes, including protein kinases and phosphatases as well as their anchoring and regulatory subunits that fine-tune Ca-handling in specific SR sub compartments. SR Ca-transport is mediated by the SR Ca-ATPase (SERCA2a) and its regulatory phosphoprotein, phospholamban (PLN). Dephosphorylated PLN is an inhibitor of SERCA2a and phosphorylation by protein kinase A (PKA) or calcium calmodulin-dependent protein kinases (CAMKII) relieves these inhibitory effects. Recent studies identified additional regulatory proteins, associated with PLN, that control SR Ca-transport. These include the inhibitor-1 (I-1) of protein phosphatase 1 (PP1), the small heat shock protein 20 (Hsp20) and the HS-1 associated protein X-1 (HAX1). In addition, the intra-luminal histidine-rich calcium binding protein (HRC) has been shown to interact with both SERCA2a and triadin. Notably, there is physical and direct interaction between these protein players, mediating a fine-cross talk between SR Ca-uptake, storage and release. Importantly, regulation of SR Ca-cycling by the PLN/SERCA interactome does not only impact cardiomyocyte contractility, but also survival and remodeling. Indeed, naturally occurring variants in these Ca-cycling genes modulate their activity and interactions with other protein partners, resulting in depressed contractility and accelerated remodeling. These genetic variants may serve as potential prognostic or diagnostic markers in cardiac pathophysiology. PMID- 25451388 TI - Elevated amygdala activity during reappraisal anticipation predicts anxiety in avoidant personality disorder. AB - BACKGROUND: Avoidant personality disorder is characterized by pervasive anxiety, fear of criticism, disapproval, and rejection, particularly in anticipation of exposure to social situations. An important but underexplored question concerns whether anxiety in avoidant patients is associated with an impaired ability to engage emotion regulatory strategies in anticipation of and during appraisal of negative social stimuli. METHODS: We examined the use of an adaptive emotion regulation strategy, cognitive reappraisal, in avoidant patients. In addition to assessing individual differences in state and trait anxiety levels, self-reported affect as well as measures of neural activity were compared between 17 avoidant patients and 21 healthy control participants both in anticipation of and during performance of a reappraisal task. RESULTS: Avoidant patients showed greater state and trait-related anxiety relative to healthy participants. In addition, relative to healthy participants, avoidant patients showed pronounced amygdala hyper-reactivity during reappraisal anticipation, and this hyper-reactivity effect was positively associated with increasing self-reported anxiety levels. LIMITATIONS: Our finding of exaggerated amygdala activity during reappraisal anticipation could reflect anxiety about the impending need to reappraise, anxiety about the certainty of an upcoming negative image, or anxiety relating to anticipated scrutiny of task responses by the experimenters. While we believe that all of these possibilities are consistent with the phenomenology of avoidant personality disorder, future research may clarify this ambiguity. CONCLUSIONS: These results suggest that amygdala reactivity in anticipation of receiving negative social information may represent a key component of the neural mechanisms underlying the heightened anxiety present in avoidant patients. PMID- 25451390 TI - Association of depression & health related quality of life with body composition in children and youth with obesity. AB - BACKGROUND: There is an increasing recognition of the relationship between mental illness and obesity in the pediatric population. Our objective was to explore the individual, biological and family determinants of depressive symptoms and HRQOL in youth with obesity in a clinical setting. METHODS: We studied 244 youth aged 8 17 years at the time of entry to a weight management program. Depressive symptoms were evaluated using the Center for Epidemiological Studies Depression Scale for Children questionnaire, with a score of >=15 or antidepressant use indicating depression. HRQOL was examined using the PedsQL4.0. We considered the influence of age, sex, health history, anthropometry, body fat, family health and socioeconomic status (SES) on depression and HRQOL. RESULTS: Depression was common in this population (36.4%). In multivariate analysis, the extent of obesity (body fat) predicted both depression (OR 1.1 (1.0-1.2); p=0.05) and low HRQOL scores (beta -0.63 (p<0.001)). Family SES was an important predictor of depression but not of HRQOL. In contrast to population-based studies, sex, age, pubertal status and family history of depression did not predict depressive symptoms. LIMITATIONS: As this study included children and adolescents seeking obesity treatment, results may not be generalizable to the general population of obese youth. CONCLUSIONS: Depression and low HRQOL are common in youth entering weight management programs. Extent of obesity predicted depressive symptoms and low HRQOL. Predictors of depression in this population differ from non-obese populations studied. It is important to consider these characteristics to assist clinicians in identifying these children. PMID- 25451389 TI - A systematic review of relations between resting-state functional-MRI and treatment response in major depressive disorder. AB - BACKGROUND: Resting-state functional magnetic resonance imaging (fMRI) is a promising predictor of treatment response in major depressive disorder (MDD). METHODS: A search for papers published in English was conducted using PubMed with the following words: depression, treatment, resting-state, connectivity, and fMRI. Findings from 21 studies of relations between resting-state fMRI and treatment response in MDD are presented, and common findings and themes are discussed. RESULTS: The use of resting-state fMRI in research on MDD treatment response has yielded a number of consistent findings that provide a basis for understanding the potential mechanisms of action of antidepressant treatment response. These included (1) associations between response to antidepressant medications and increased functional connectivity between frontal and limbic brain regions, possibly resulting in greater inhibitory control over neural circuits that process emotions; (2) connectivity of visual recognition circuits in studies that compared treatment resistant and treatment sensitive patients; (3) response to TMS was consistently predicted by subcallosal cortex connectivity; and (4) hyperconnectivity of the default mode network and hypoconnectivity of the cognitive control network differentiated treatment resistant from treatment-sensitive MDD patients. LIMITATIONS: There was also considerable variability between studies with respect to study designs and analytic strategies that made direct comparisons across all studies difficult. CONCLUSIONS: Continued standardization of study designs and analytic strategies as well as aggregation of larger datasets will allow the field to better elucidate the potential mechanisms of action of treatment response in patients with MDD to ultimately generate algorithms to predict which patients will respond to which antidepressant treatments. PMID- 25451391 TI - Generalized anxiety in community-dwelling elderly: Prevalence and clinical characteristics. AB - BACKGROUND: Generalized anxiety disorder (GAD) is a chronic and disabling disorder with a low rate of full remission. As it is commonly assumed that cases in the elderly principally represent the continuing chronic course of early onset illness, there has been little research into the clinical characteristics, including comorbid psychiatric and physical conditions, which may be specific to older people. METHODS: Lifetime GAD and psychiatric comorbidity were diagnosed in 1974 community-dwelling elderly people aged 65 or over using a standardized psychiatric examination, the MINI, based on DSM-IV criteria. Multivariate regression analyses were adjusted for socio-demographic, lifestyle, biological, and clinical variables, as well as adverse life events. RESULTS: The lifetime prevalence of GAD was 11% (95% CI=9.6-12.4%) of whom 24.6% reported a late onset with a first episode after 50 years of age. The 6-month current prevalence was 4.6% (95% CI=3.7-5.5%). Most of the prevalent cases were recurrent but only 36.3% were receiving treatment. Fourteen percent were comorbid with major depression and 34% with phobia but their associated factors differed. The factors associated with pure GAD were being female, having cognitive impairment, lower body mass index, reporting low affective support during childhood, taking a high number of somatic medications independently of other mental health factors, e.g. psychotropic medication use, major depression, and phobia. LIMITATIONS: The study is limited by cross-sectional design. CONCLUSIONS: Our data indicate that GAD prevalence is high in elderly people with a late-life onset of GAD in 25% of cases. GAD in the elderly is not just a severity marker of depression and is clinically distinct from phobia, the other major anxiety disorder of the elderly. PMID- 25451392 TI - A comparison of schizophrenia, schizoaffective disorder, and bipolar disorder: Results from the Second Australian national psychosis survey. AB - INTRODUCTION: It remains uncertain whether schizoaffective disorder (SAD) is a discrete diagnostic entity, is a variant of either a psychotic mood disorder such as bipolar disorder (BDP) or schizophrenia (SCZ), or exists on a spectral continuum between these disorders. The present study examined whether SCZ, SAD, and BDP differed qualitatively on demographic and clinical variables based on a large Australian dataset. METHODS: This study examined data from the Australian Survey of High Impact Psychosis (SHIP), in which 1469 of the 1825 participants in who had an ICD-10 diagnosis of SCZ (n=857), SAD (n=293), and BDP (n=319) were assessed across a broad range of variables. RESULTS: When compared to patients with SCZ, those with SAD reported more current delusional and thought disorder symptoms, a greater number of lifetime depression, mania, and positive symptoms, and fewer negative symptoms. Relative to the BPD group, the SAD group were younger, endorsed more current positive, delusional, and thought disorder symptoms, fewer lifetime mania symptoms, more lifetime psychotic, hallucination, and delusional symptoms, and recorded lower premorbid IQ scores. Compared to patients with BPD, those with SCZ were significantly younger, endorsed more current psychotic and hallucination symptoms, fewer lifetime depression and mania symptoms, more lifetime psychotic, hallucination, and delusional symptoms, reported more negative symptoms and had lower premorbid IQ and psychosocial functioning scores. LIMITATIONS: Validated psychometric measures of psychotic or mood symptoms were not used. CONCLUSION: This pattern of results is consistent with the conceptualisation of a spectrum of disorders, ranging from BDP at one end, to SAD in the middle, and SCZ at the other end. PMID- 25451394 TI - Analysis of telomere attrition in bipolar disorder. AB - BACKGROUND: Telomeres can be considered a marker of biological aging. Studies have suggested that telomere shortening may be associated with aging related diseases and also psychiatric disorders. OBJECTIVES: Investigate whether bipolar disorder (BD) and its clinical specificities are associated with telomere shortening. METHODS: Eighty-five BD patients and 95 healthy controls were paired for age, sex and educational level. Volunteers were submitted to a psychiatric interview and clinical evaluation. Patients and controls were compared as a whole sample and within specific telomere range (short and long telomeres). Intrapatients group comparison involved type of BD and comorbidities. A Real Time Quantitative PCR was performed in order to verify leukocytes telomere length. RESULTS: Bipolar disorder patients presented shorter telomeres when compared to controls (p<0.001). However, there was no significant difference in telomere length between different BD subtypes. When two groups of patients (long and short telomeres) were compared, only panic disorder showed an association with telomere categories (chi(2)=6.91; p=0.009; OR=4.27). LIMITATIONS: It was not possible to collect information about time since diagnosis, which limited conclusions regarding BD chronicity and telomere length. Furthermore, medication interference upon telomere length was not controlled. CONCLUSIONS: Results suggest that BD is associated with reduced telomere length. Also, panic comorbidity may represent an additive risk factor. Understanding aspects that contribute to determination of telomere size in bipolar patients allows us to understand what the impact on telomeres size is, which is a health vulnerability marker. PMID- 25451393 TI - Social communication deficits: Specific associations with Social Anxiety Disorder. AB - BACKGROUND: Social communication deficits are prevalent amongst children with anxiety disorders; however whether they are over-represented specifically among children with Social Anxiety Disorder has not been examined. This study set out to examine social communication deficits among children with Social Anxiety Disorder in comparison to children with other forms of anxiety disorder. METHODS: Parents of 404 children with a diagnosed anxiety disorder completed the Social Communication Questionnaire (SCQ; Rutter, M., Bailey, A., Lord, C., 2003. The Social Communication Questionnaire - Manual. Western Psychological Services, Los Angeles, CA). Children with a diagnosis of Social Anxiety Disorder (n=262) and anxious children without Social Anxiety Disorder (n=142) were compared on SCQ total and subscale scores and the frequency of participants scoring above clinical cut-offs. RESULTS: Children with Social Anxiety Disorder scored significantly higher than anxious children without Social Anxiety Disorder on the SCQ total (t(352)=4.85, p<.001, d=.55, r=.27), Reciprocal Social Interaction (t(351)=4.73, p<.001, d=.55, r=.27), communication (t(344)=3.62, p<.001, d=.43, r=.21) and repetitive, restrictive and stereotyped behaviors subscales (t(353)=3.15, p=.002, d=.37, r=.18). Furthermore, children with Social Anxiety Disorder were three times more likely to score above clinical cut-offs. LIMITATIONS: The participants were a relatively affluent group of predominantly non-minority status. The social communication difficulties measure relied on parental report which could be influenced by extraneous factors. CONCLUSIONS: Treatments for Social Anxiety Disorder may benefit from a specific focus on developing social communication skills. Future research using objective assessments of underlying social communication skills is required. PMID- 25451395 TI - Two-year follow-up of treated adolescents with early-onset bipolar disorder: Changes in neurocognition. AB - BACKGROUND: Few studies have analyzed the course of neurocognition in treated children and adolescents with early-onset bipolar disorder (EOBD) and shown improvements in attention, working memory, and verbal memory after treatment. The aim of this study was to determine the progress over two years in neuropsychological performance of a sample of medicated adolescents with EOBD compared to healthy controls (HC). METHODS: Twenty adolescents, diagnosed in clinical setting as DSM-IV bipolar disorder, treated for two years, euthymic, and 20 gender and age-matched HC were assessed at two moments in reasoning, verbal and visual memory, working memory, speed, visual-motor skills and executive function. Multivariate analyses of variance was carried out to analyze the differences between groups over time, and to monitor the influence of psychotic symptoms and type of mood-stabilizer. RESULTS: The entire sample improved on verbal and visual memory tests (verbal recall p<0.01; visual recall p<0.001). Moreover, patients improved more than controls in verbal reasoning (p<0.01), working memory (p<0.01), processing speed (p<0.01) and visual-motor skills (p<0.001). Psychotic symptoms and treatment with lithium were associated with poorer development in executive control tasks. LIMITATIONS: Sample size was small and groups were re-evaluated in slight different follow-up periods. Doses of antipsychotics drugs over time were not controlled. CONCLUSIONS: Processing speed and visual-motor skills in the EOBD group normalized during follow-up. Executive functioning, working memory, and verbal and visual memory remained impaired in patients versus controls. The knowledge of cognitive deficits due to normal course of illness or to drug effects allows better therapeutic strategies. PMID- 25451396 TI - Atherogenic index of plasma and atherogenic coefficient are increased in major depression and bipolar disorder, especially when comorbid with tobacco use disorder. AB - BACKGROUND: There is a robust comorbidity between mood disorders and cardiovascular disorder (CVD). The atherogenic index of plasma (AIP) and the atherogenic coefficient (AC) are important atherogenic indexes. The aims of this study were to delineate whether AIP and AC are increased in mood disorders especially when comorbid with tobacco use disorder (TUD). METHODS: In this case control study we included 134 patients with mood disorders, bipolar disorder and unipolar depression (cases), and 197 individuals without mood disorder (controls) divided into those with and without TUD (defined as never-smokers). Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLc) and low-density lipoprotein cholesterol (LDLc) were measured. AIP and AC were computed as log (TG/HDLc) and non-HDLc/HDLc, respectively. RESULTS: The AIP and AC indexes were significantly increased in patients with mood disorders versus controls, both in depression and bipolar disorder. Patients with mood disorder without TUD and patients with TUD without mood disorder showed higher AIP and AC values than never-smokers while those with comorbid mood disorders and TUD showed significantly higher AIP and AC levels than all other individuals. A large part of the variance in the AIC (26.4%) and AC (20.4%) was explained by mood disorders, TUD, male gender and body mass index. CONCLUSIONS: The findings suggest that lipid abnormalities leading to an increased atherogenic potential are involved in the pathophysiology of mood disorders (depression and bipolar disorder) and especially comorbid mood disorder and TUD. The comorbidity between mood disorders and CVD may be partly explained increased through AIP and AC indexes, impacting increments in atherogenic potential. PMID- 25451397 TI - Molecular signatures of mood stabilisers highlight the role of the transcription factor REST/NRSF. AB - BACKGROUND: The purpose of this study was to address the affects of mood modifying drugs on the transcriptome, in a tissue culture model, using qPCR arrays as a cost effective approach to identifying regulatory networks and pathways that might coordinate the cell response to a specific drug. METHODS: We addressed the gene expression profile of 90 plus genes associated with human mood disorders using the StellARrayTM qPCR gene expression system in the human derived SH-SY5Y neuroblastoma cell line. RESULTS: Global Pattern Recognition (GPR) analysis identified a total of 9 genes (DRD3(*), FOS(?), JUN(*), GAD1(*?), NRG1(*), PAFAH1B3(*), PER3(*), RELN(*) and RGS4(*)) to be significantly regulated in response to cellular challenge with the mood stabilisers sodium valproate ((*)) and lithium ((?)). Modulation of FOS and JUN highlights the importance of the activator protein 1 (AP-1) transcription factor pathway in the cell response. Enrichment analysis of transcriptional networks relating to this gene set also identified the transcription factor neuron restrictive silencing factor (NRSF) and the oestrogen receptor as an important regulatory mechanism. LIMITATIONS: Cell line models offer a window of what might happen in vivo but have the benefit of being human derived and homogenous with regard to cell type. CONCLUSIONS: This data highlights transcription factor pathways, acting synergistically or separately, in the modulation of specific neuronal gene networks in response to mood stabilising drugs. This model can be utilised in the comparison of the action of multiple drug regimes or for initial screening purposes to inform optimal drug design. PMID- 25451398 TI - Association of brain-derived neurotrophic factor DNA methylation and reduced white matter integrity in the anterior corona radiata in major depression. AB - Considerable evidence suggests a crucial role for the epigenetic regulation of brain-derived neurotrophic factor (BDNF) in the pathophysiology of major depressive disorder (MDD). However, the relationship between BDNF DNA methylation and white matter (WM) integrity in MDD has not yet been investigated. In the current study, we examined the association between the DNA methylation status of the BDNF promoter region and WM integrity in MDD. Sixty patients with MDD and 53 healthy controls underwent T1-weighted structural magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), to assess their WM integrity. BDNF DNA methylation at 4 CpG sites of the promoter region was also measured. As compared to healthy controls, the MDD group demonstrated reduced fractional anisotropy (FA) in the bilateral anterior and posterior corona radiata (ACR and PCR), genu of the corpus callosum, and the bilateral posterior thalamic radiations. We observed a significant inverse correlation between the DNA methylation of the BDNF promoter region and the FA of the right ACR in MDD patients. Our findings demonstrate a relationship between methylation of the BDNF promoter region and the integrity of the ACR, a key structural component of the emotional and cognitive control network involved in the pathophysiology of MDD. This correlation suggests that BDNF DNA methylation may contribute to structural WM changes in MDD patients. PMID- 25451399 TI - Bioprofiling of platelets in medicated patients with depression. AB - BACKGROUND: Changes in platelet bioactivity and aggregation are of interest when studying patients with depression as this could help to explain the statistically observed association of depression and chronic somatic, especially cardiovascular disease. This link could potentially be mediated through serotonergic signaling or immunological changes. METHODS: 38 medicated patients with major depressive disorder (MDD) and 30 mentally healthy controls, both without a diagnosis of cardiovascular disease, were included in this naturalistic study. Demographic and psychometric data were obtained. Platelet aggregability was measured by PFA-100 and bioactive compounds and serotonin levels were quantified in platelet sonicate. RESULTS: The comparison of patients with controls revealed no changes in platelet aggregability, but significant differences in platelet content of several bioactive compounds. In a second analysis, patients were grouped according to the receptors and transporters influenced by their medication and again compared to controls. A significant effect of MDD was found for platelet content of serotonin, CD40L, interleukin-1beta, and platelet factor-4, independent of medication. These markers can thus be classified as sensitive to MDD. The effect of medication on platelet parameters was also evaluated. Platelet content of matrix metalloproteinase-2 and beta-thromboglobulin was normalized in MDD patients by medication acting on the serotonin transporter. LIMITATIONS: Owing to the naturalistic study design, patients were on a variety of different medications and combination therapies. This was accounted for by a novel analysis method. CONCLUSION: Platelet serotonin levels and content of immunomodulatory compounds are significantly altered in patients with MDD, even if treatment effects are taken into account. PMID- 25451402 TI - Influence of GNB3 C825T polymorphism on the efficacy of antidepressants in the treatment of major depressive disorder: A meta-analysis. AB - OBJECTIVE: We performed the present meta-analysis in order to evaluate the influence of a common polymorphism (C825T, rs5443 C>T) in the GNB3 gene on the efficacy of antidepressants in the treatment of major depressive disorder (MDD). METHOD: A relevant literature was searched using the PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CBM and CNKI databases without any language restrictions. STATA Version 12.0 software (Stata Corporation, College Station, Texas USA) was used for this meta-analysis. Odds ratio (OR) and its corresponding 95% confidence interval (95% CI) were calculated. RESULTS: Our findings suggested that the GNB3 C825T polymorphism was significantly correlated with a higher response rate to antidepressants in MDD patients under the allele and dominant models. Furthermore, we found significant associations between GNB3 C825T polymorphisms and antidepressant-induced remission in MDD patients. Ethnicity-stratified analysis indicated that GNB3 C825T polymorphisms may be strongly related to the efficacy of antidepressants in the treatment of MDD among Asians, but not in Caucasians (all P>0.05). CONCLUSION: Our findings provide empirical evidence that GNB3 C825T polymorphisms may be correlated with the efficacy of antidepressants in the treatment of MDD, especially among Asians patients. PMID- 25451401 TI - Depression is not a consistent syndrome: An investigation of unique symptom patterns in the STAR*D study. AB - BACKGROUND: The DSM-5 encompasses a wide range of symptoms for Major Depressive Disorder (MDD). Symptoms are commonly added up to sum-scores, and thresholds differentiate between healthy and depressed individuals. The underlying assumption is that all patients diagnosed with MDD have a similar condition, and that sum-scores accurately reflect the severity of this condition. To test this assumption, we examined the number of DSM-5 depression symptom patterns in the "Sequenced Treatment Alternatives to Relieve Depression" (STAR*D) study. METHODS: We investigated the number of unique symptom profiles reported by 3703 depressed outpatients at the beginning of the first treatment stage of STAR*D. RESULTS: Overall, we identified 1030 unique symptom profiles. Of these profiles, 864 profiles (83.9%) were endorsed by five or fewer subjects, and 501 profiles (48.6%) were endorsed by only one individual. The most common symptom profile exhibited a frequency of only 1.8%. Controlling for overall depression severity did not reduce the amount of observed heterogeneity. LIMITATIONS: Symptoms were dichotomized to construct symptom profiles. Many subjects enrolled in STAR*D reported medical conditions for which prescribed medications may have affected symptom presentation. CONCLUSIONS: The substantial symptom variation among individuals who all qualify for one diagnosis calls into question the status of MDD as a specific consistent syndrome and offers a potential explanation for the difficulty in documenting treatment efficacy. We suggest that the analysis of individual symptoms, their patterns, and their causal associations will provide insights that could not be discovered in studies relying on only sum-scores. PMID- 25451400 TI - The relationship between somatic and cognitive-affective depression symptoms and error-related ERPs. AB - BACKGROUND: The symptoms that contribute to the clinical diagnosis of depression likely emerge from, or are related to, underlying cognitive deficits. To understand this relationship further, we examined the relationship between self reported somatic and cognitive-affective Beck'sDepression Inventory-II (BDI-II) symptoms and aspects of cognitive control reflected in error event-related potential (ERP) responses. METHODS: Task and assessment data were analyzed within 51 individuals. The group contained a broad distribution of depressive symptoms, as assessed by BDI-II scores. ERPs were collected following error responses within a go/no-go task. Individual error ERP amplitudes were estimated by conducting group independent component analysis (ICA) on the electroencephalographic (EEG) time series and analyzing the individual reconstructed source epochs. Source error amplitudes were correlated with the subset of BDI-II scores representing somatic and cognitive-affective symptoms. RESULTS: We demonstrate a negative relationship between somatic depression symptoms (i.e. fatigue or loss of energy) (after regressing out cognitive affective scores, age and IQ) and the central-parietal ERP response that peaks at 359 ms. The peak amplitudes within this ERP response were not significantly related to cognitive-affective symptom severity (after regressing out the somatic symptom scores, age, and IQ). LIMITATIONS: These findings were obtained within a population of female adults from a maximum-security correctional facility. Thus, additional research is required to verify that they generalize to the broad population. CONCLUSIONS: These results suggest that individuals with greater somatic depression symptoms demonstrate a reduced awareness of behavioral errors, and help clarify the relationship between clinical measures of self-reported depression symptoms and cognitive control. PMID- 25451404 TI - Everyday functioning of male adolescents who later died by suicide: Results of a pilot case-control study using mixed-method analysis. AB - OBJECTIVE: Previous research has shown a link between difficulties in everyday functioning and suicidality in adolescence. The majority of research in this field focuses on suicidal ideation and attempts, rather than on completed suicide. The main goal of this study is to better characterize everyday functioning among young men who later completed suicide. Based on previous literature, we hypothesized that the functioning of adolescents who died by suicide would be poor, compared to controls. METHODS: The current study is a record-driven study, which examined summaries of screening interviews performed by the Israeli Defense Forces (IDF) of 20 male adolescents who later completed suicide, compared with 20 matched living controls. The current study is a pilot stage of a larger project. The study used unique data, collected as part of the IDF pre-induction process, in the months or years before the tragic outcome. The data were extracted by two psychologists, blinded to the participants' suicide or non-suicide outcome, using mixed-method technique, combining qualitative and quantitative analysis. RESULTS: The main findings indicated that, in comparison with controls, male adolescents who later died by suicide were described as having more interpersonal difficulties, were more likely to be involved in violent behavior, had more difficulties in dealing with problems in everyday functioning and had an avoidant conflict resolution style. CONCLUSIONS: Functional difficulties are apparent in a wide range of behavioral domains in adolescents who later complete suicide. These findings indicate a need for interventions that might assist young persons, and it is possible that such assistance might reduce the likelihood of suicide. However, because suicide is a rare outcome and these behavioral traits are common in adolescence, the presence of such traits might not be useful in identifying people at risk of suicide. PMID- 25451403 TI - Transcultural adaption and validation of the Spanish version of the Bipolar Depression Rating Scale (BDRS-S). AB - BACKGROUND: The Bipolar Depression Rating Scale (BDRS) arguably better captures symptoms in bipolar depression especially depressive mixed states than traditional unipolar depression rating scales. The psychometric properties of the Spanish adapted version, BDRS-S, are reported. METHODS: The BDRS was translated into Spanish by two independent psychiatrists fluent in English and Spanish. After its back-translation into English, the BDRS-S was administered to 69 DSMI IV bipolar I and II patients who were recruited from two Spanish psychiatric hospitals. The Hamilton Depression Rating Scale (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS) were concurrently administered. 42 patients were reviewed via video by four psychiatrists blind to the psychopathological status of those patients. In order to assess the BDRS-S intra-rater or test-retest validity, 22 subjects were assessed by the same investigator performing two evaluations within five days. RESULTS: The BDRS-S had a good internal consistency (Cronbach's alpha=0.870). We observed strong correlations between the BDRS-S and the HDRS (r=0.874) and MADRS (r=0.854) and also between the mixed symptom cluster score of the BDRS-S and the YMRS (r=0.803). Exploratory factor analysis revealed a three factor solution: psychological depressive symptoms cluster, somatic depressive symptoms cluster and mixed symptoms cluster. LIMITATIONS: A relatively small sample size for a 20 item scale. CONCLUSIONS: The BDRS-S provides solid psychometric performance and in particular captures depressive or mixed symptoms in Spanish bipolar patients. PMID- 25451406 TI - A Dutch version of the Overall Anxiety Severity and Impairment Scale (OASIS): Psychometric properties and validation. AB - BACKGROUND: The Overall Anxiety Severity and Impairment Scale (OASIS) is a 5-item self-report measure that can be used to assess the impact of any anxiety disorder or multiple anxiety disorders. Prior US investigations have shown the OASIS to be a reliable and valid measure. To date the OASIS has not been validated for use in a Dutch sample of anxiety disordered patients. METHODS: The present study assessed the psychometric properties of a Dutch version of the OASIS in a clinical sample of anxiety patients. Latent structure, internal consistency, convergent and discriminant validity, and cutoff score analyses were conducted. Results were compared to those obtained from a clinical sample of patients with psychiatric diagnoses other than anxiety disorders. RESULTS: Principal component analysis supported a unidimensional structure. The five OASIS items loaded strongly on a single factor (eigenvalue=3.682, loadings=.80-.89) which accounted for 73.65% of the variance, and had a high degree of internal consistency (Cronbach's alpha=91). OASIS scores demonstrated robust correlations with other measures of anxiety, neuroticism and general distress. Correlations with unrelated constructs were weak. Mean score (8.46) and cutoff score of the Dutch sample of anxiety patients were lower than scores previously found in American samples. A cutoff score of 5 correctly classified 82.5% of this sample as having an anxiety disorder diagnosis or not. An improvement of 4 points is indicative of a clinically significant change. LIMITATIONS: This study mainly relied on self report measures in order to assess validity. Other types of measures should be used in future studies. CONCLUSIONS: The Dutch version of the OASIS showed good reliability and validity. Its brevity and sound psychometric properties make it a good instrument for screening and assessment purposes in the field of anxiety disorders. PMID- 25451405 TI - Prevalence of post-traumatic stress disorder and depression in two groups of children one year after the January 2010 earthquake in Haiti. AB - BACKGROUND: More than 500 studies were conducted in Haiti following the January 12 of 2010 earthquake, yet few of them assessed mental health of the population. To our knowledge, none targeted the effectiveness of various methods used to treat survivors, whether adults or children METHOD: Our study aimed to assess one year after the disaster, the effect of a specific psycho-social support offered to relocated children in Port-au-Prince compared with a control group. RESULTS: The two groups were homogeneous in the intensity of the peritraumatic distress they experienced. We were unable to show a significant difference between both in the average scores for PTSD, nor for depression, nor in three out of the four sub scales of the Child Behavior Check-List. In case children, 68% and 40.9%, respectively, and 50% and 20.5% of the control group, reported severe levels of the symptoms of PTSD and depression. These surprising results can be explained by the absence of equivalence in the two groups from a socio-demographic point of view and because subjects were not randomly selected in the recruitment process. CONCLUSION: This study has not made it possible to indicate the effectiveness of a specific psycho-social support offered to children in the aftermath of the disaster. On the other hand, the sample illustrates the high prevalence (more than 50% for PTSD) of severe post-traumatic stress in this group of school-age children, one year after the earthquake. These results indicate that serious attention should be paid to the mental health aspects in reconstruction program for the country. PMID- 25451407 TI - Trajectories of posttraumatic stress symptoms (PTSS) after major war among Palestinian children: Trauma, family- and child-related predictors. AB - OBJECTIVE: Research shows great individual variation in changes in posttraumatic stress symptoms (PTSSs) after major traumas of terrorist attacks, military combat, and natural disasters. Earlier studies have identified specific mental health trajectories both in children and adults. This study aimed, first, to identify potential PTSS-related trajectories by using latent class growth analyses among children in a three-wave assessment after the 2008/2009 War on Gaza, Palestine. Second, it analyzed how family- and child related factors (e.g., attachment relations, posttraumatic cognitions (PTCs), guilt, and emotion regulation) associate with the trajectory class membership. METHODS: The sample consisted of 240 Palestinian children (49.4% girls and 50.6% boys) of 10-13 years of age (M=11.29, SD=0.68), who completed PTSS (CRIES) assessments at 3 (T1), 5 (T2), and 11 (T3) months after the war. Children reported their personal exposure to war trauma, attachment style, cognitive trauma processing, and emotion regulation, and their parents reported family war trauma exposure and attachment style. RESULTS: Results revealed a three-trajectory solution, a majority of children belonging to the Recovery trajectory (n=183), and a minority belonged either to Resistant trajectory (n=29) or to Increasing symptoms trajectory (n=28). Low levels of negative posttraumatic cognitive appraisals, feelings of guilt and emotion regulation were characteristic of children in the Resistant trajectory as compared to Increasing symptoms trajectory. Father's attachment security was further associated with the Resistant trajectory membership. Children's attachment avoidance and high parental trauma were typical to children in Recovery trajectory (as compared to the Increasing symptoms trajectory). PMID- 25451408 TI - Does temperature or sunshine mediate the effect of latitude on affective temperaments? A study of 5 regions in Japan. AB - BACKGROUND: Previously, we compared the hyperthymic scores of residents in Sapporo, Koshigaya, and Oita (which are located at latitudes of 43 degrees N, 36 degrees N, and 33 degrees N in Japan, respectively) using the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire version (TEMPS-A). We found that residents who lived at lower latitudes had higher hyperthymic temperament scores; however, the mechanism of the effect of latitude on hyperthymic temperament remained unclear. The current study examined the mediators of the latitude effect in additional regions with different annual temperatures and amounts of ambient sunshine. METHODS: The Japanese archipelago stretches over 4000 km from north to south and has four large islands: Hokkaido, Honshu, Shikoku, and Kyushu. In addition to the TEMPS-A previously reported data collected at Sapporo (latitude 43 degrees N), Koshigaya (36 degrees N), and Oita (33 degrees N), we collected the TEMPS-A data of 189 and 106 residents from Takaoka (36 degrees N) and Obihiro (42 degrees N), respectively. Taken together, these five regions have different patterns (i.e., highs and lows) of annual ambient total sunshine (hours) and mean temperature ( degrees C). The effect of latitude, sunshine, and temperature on affective temperaments was analyzed for five Japanese regions. RESULTS: Multiple regression analyses revealed that latitude predicted significant variance in hyperthymic temperament. Ambient temperature, but not sunshine, significantly affected hyperthymic temperament. LIMITATIONS: The light exposure that residents actually received was not measured. The number of regions studied was limited. The findings might not generalize to residents across Japan or other countries. CONCLUSIONS: The present findings suggest that latitude affects hyperthymic temperament, and ambient temperature might mediate this effect. PMID- 25451409 TI - Maintaining factors of posttraumatic stress symptoms following childbirth: A population-based, two-year follow-up study. AB - BACKGROUND: Previous research has established a number of risk factors that are associated with the onset of PTSD following childbirth. However, little is known about factors that maintain PTSD symptoms. METHODS: This study is part of the Akershus Birth Cohort. Questionnaire data from pregnancy week 17, 8 weeks postpartum and 2 years postpartum were used. 1473 women completed all these three questionnaires and were included in the analyses. Post-traumatic stress symptoms were measured with the Impact of Event Scale. Potential maintaining factors were personality, sleep, support and life events. The factors that were significantly correlated with post-traumatic stress symptoms were entered into regression analyses. Mediation analyses were run to test whether significant predictors would serve as mediator of post-traumatic stress symptoms at 8 weeks postpartum to post-traumatic stress symptoms at 2 years postpartum. RESULTS: We found several low to moderate associations between maintaining factors and PTSD symptoms two years postpartum. Adjusting for the starting point - PTSD symptoms 8 weeks postpartum - only insomnia remained significantly associated. Further, insomnia mediated a small portion of the effect of PTSD symptoms 8 weeks postpartum to PTSD symptoms 2 years postpartum. LIMITATIONS: Limitations of the study include a relative homogeneous sample, modest effect sizes, low internal consistency of some of the measures and the challenge to distinguish insomnia from PTSD symptoms. CONCLUSIONS: Treatment of postpartum PTSD might benefit from addressing insomnia if present. Alleviating insomnia may itself reduce daytime symptoms of PTSD and it may also increase the efficacy of primary PTSD treatments. PMID- 25451410 TI - Differences in prescribing patterns for anxiety and depression between General Internal Medicine and Family Medicine. AB - INTRODUCTION: Depression and anxiety are routinely managed by physicians in Family Medicine (FM) or General Internal Medicine (GIM). Because FM requires more behavioral health training than GIM, we sought to determine if prescribing patterns for patients with anxiety, depression, or both differed between FM vs. GIM providers. METHODS: In a cross-sectional design, patient data and provider type were obtained from 2008 to 2013 electronic medical record patient data registry (n=27,225 (FM=10,994, GIM=16,231)) Prescription orders were modeled for specific benzodiazepines and antidepressants and by drug class. Covariates included gender, age, race, marital status and comorbidity index. Separate logistic regression models were computed, before and after adjusting for covariates, to estimate the odds of FM vs. GIM providers prescribing benzodiazepine or antidepressant medication to patients with anxiety, depression, and both disorders. RESULTS: After adjusting for covariates, patients with anxiety alone, depression alone, and both had significantly greater odds of receiving an antidepressant (OR=2.08;95%CI:1.46-2.96, OR=2.13;95%CI:1.48-3.06, and OR=2.26;95%CI:1.09-4.66, respectively) if treated by FM vs. GIM. Benzodiazepine prescription did not differ by physician type. LIMITATIONS: It is not known if results will generalize to other regions of the United States. CONCLUSIONS: Patients with anxiety, depression, and both seen by FM providers, as compared to GIM providers, are more likely to receive antidepressant medications. Further investigation into the determinants of these differences is warranted. Under-treatment in GIM may result in less advantageous outcomes. PMID- 25451411 TI - Dentate gyrus volume and memory performance in major depressive disorder. AB - BACKGROUND: Magnetic resonance imaging (MRI) has shown lower hippocampal volume in major depressive disorder (MDD). Patients with MDD have consistently demonstrated worse performance than healthy controls a number of memory tests. Memory functions within the hippocampus in healthy younger subjects appear to be linked to cornu ammonis (CA1-3) and dentate gyrus (DG) subfields. Therefore, the main goal of the present study was to investigate whether memory deficits in MDD patients are related to reduction in hippocampal subfields volumes, particularly DG and CA 1-3. METHODS: 15 MDD patients meeting DSM-IV criteria for MDD with moderate or severe episodes were recruited, together with 15 healthy controls. We used T2-weighted 2D Fast Spin Echo (FSE) and T1-weighted 3D MPRAGE sequences at 4.7 T to compare hippocampal subfield volumes at 0.09 MUl voxel volume. Participants were administered the Wechsler Memory Scale. RESULTS: MDD patients underperformed in several episodic visual memory tasks, as well as in visual working memory, compared to healthy controls. Global hippocampal volumes were similar between groups; however, MDD patients showed significantly reduced DG volumes within the hippocampal body. Duration of depression correlated with MDD patients' total volumes in the hippocampal body and CA1-3 and DG subfields within it. LIMITATIONS: Our study sample was relatively small and the majority of patients were on antidepressant treatment. CONCLUSIONS: Our findings suggest that DG volumes in particular may be worthy of further study to further elucidate their precise role in MDD, both by itself as well as in relation to memory. PMID- 25451412 TI - Predicting suicide in older adults - a community-based cohort study in Taipei City, Taiwan. AB - BACKGROUND: Older adults worldwide are at a greater risk of suicide than other age groups. There is a scarcity of prospective studies exploring risk factors for suicide in older people and their discriminative ability to identify future suicide. METHODS: We examined a prospective cohort of senior Taipei City residents between 2005 and 2009 (N=101,764). Cox proportional hazards regression analysis was used to determine significant risk factors and to construct a predictive score. The accuracy of the derived score in the prediction was tested by Receiver Operating Characteristic analysis. RESULTS: Male sex (Hazard Ratio [HR]=3.41, p<0.001), lower education (HR=3.31, p<0.001) and lower income (HR=2.52, p=0.01) were associated with an increased risk of suicide, as well as depressed mood (HR=1.44, p=0.02; per unit increase in a 4-point scale) and insomnia (HR=1.30, p=0.03; per unit increase in a 4-point scale). The derived prediction score yielded a sensitivity of 0.63 a specificity of 0.73 and an area under curve of 0.73. Removing depressed mood from the prediction model did not significantly alter suicide predictability (P=0.11). LIMITATIONS: The dataset examined did not contain information regarding to important risk factors such as substance misuse and prescribed medications and the measures of mental health were relatively limited. CONCLUSION: Prediction of suicide based on factors recorded in a routine health screen of elderly people was unsatisfactory; the strongest predictors were factors that cannot be easily altered. Further understanding of how the socioeconomic condition of seniors contributes to suicide may provide valuable insights for intervention targeting this growing population-at-risk. PMID- 25451413 TI - Bipolar disorder incidence between children and adolescents: A brief communication. AB - BACKGROUND: Bipolar affective disorder is one of most injurious psychiatric diseases, not, rarely leading patient for suicide, and its prevalence keeps increasing worldwide, notably on low and, middle-income countries. For children living in northeast Brazil, extreme social conditions constitute, an environment of special vulnerability. OBJECTIVE: Here we show that bipolar disorder incidence, between children and adolescents in this Brazilian region increased 34.2% from 2005 to 2014 and, in, the same area and age group, deaths provoked by self-caused injuries also became progressively, greater. RESULTS: According to DATASUS, the Brazilian national databank for public health, information, in the last five years, we observed an increase of Bipolar Disorder incidence rates under, 19 year-old of about 34.2% in the northeast region of Brazil, while the increase for Brazilian general, population was 12.4%. If considered only patients under 10, this number is even greater, of 47.2%. Content of Table 2 shows this disproportion, while comparing the advance of bipolar disorder, morbidity indices nationwide and worldwide. CONCLUSION: Children living in Brazil's northeast, region are in a condition of extreme social disadvantage, what can be determinant for the recent and, sequential increase of bipolar disorder prevalence and the mortality in this age-group due to suicide, one of possible reflections of untreated mood disorders. For protecting these children is important to, identify the factors which prevent these illnesses and promote resilience for these young people. PMID- 25451414 TI - Association between core-assigned melancholia and the melancholia subscale of the HAM-D. AB - BACKGROUND: Clinical observation and research data suggest that major depression (MD) is a heterogeneous disorder, possibly representing a group of different clinical entities. The identification of more homogeneous subtypes of depression could enhance research and enable development of more specific treatments. A melancholic subtype of MD, defined by the presence of observable psychomotor disturbance (PMD), is proposed to be more homogeneous and associated with biological determinants. The aim of this study was to investigate the homogeneity of this melancholic subtype in terms of symptoms by searching for an association between melancholia and a unidimensional subscale of the Hamilton Depression Rating Scale (HAM-D) proposed to have biological validity (HAM-D6). METHODS: A cross-sectional assessment of 385 outpatients presenting with a unipolar major depressive episode was carried out to evaluate depressive symptoms using the HAM D and melancholic or nonmelancholic subtype, according to the CORE measure of PMD. RESULTS: Melancholic patients exhibited more severe depressive symptoms, mainly associated with the HAM-D6. The items of this melancholia subscale represent 42.3% of the total HAM-D and were responsible for 59.4% of between group differences. Correlation analysis showed similar results. LIMITATIONS: Most patients received previous treatment, and some were not at the nadir of the episode when assessed. This could have lowered the CORE measure sensibility. CONCLUSION: Melancholic depression, as assigned by the CORE measure, represents a more severe and homogeneous subtype of MD. This observation may allow identification of proper biomarkers and development of more specific treatments. PMID- 25451415 TI - The utilization of unified protocols in behavioral cognitive therapy in transdiagnostic group subjects: A clinical trial. AB - BACKGROUND: The practicing of protocols based on behavioral cognitive therapy (CBT) have been frequently used in the last decades and adapted to better manage the necessities of patients and providers. OBJECTIVES: The goal is to build a treatment that is evidence-based - for that reason the unified protocol for multiple emotional disorders (transdiagnostics) have been utilized to simplify treatment - without losing scientific traits. The main goal of this study is to evaluate the unified protocol in groups of patients with depression and anxiety disorders. MATERIALS AND METHODS: In a pool of 48 subjects, divided in two groups, one was submitted to 12 intervention sessions of the unified protocol while the other was solely given medication. MINI, BAI and BDI were the instruments used at the beginning and at the end of treatment. RESULTS: The results were highly significant (p<0.001) in as much as with the improvement of anxiety and depressive disorders as it was in the group which was treated with the unified protocol compared with the group which was only given medication LIMITATIONS: Limitations of this study were the number of sample participants and the non-randomization of subjects in both groups. CONCLUSION: Group therapy has not been largely implemented though it is deemed very useful for treatments when the unified protocol is used in transdiagnostic patients. Not only does it allow for emotional stabilizing and socialization but it also enables subjects with an altruistic feeling amongst themselves. PMID- 25451416 TI - EEG power, cordance and coherence differences between unipolar and bipolar depression. AB - INTRODUCTION: Understanding the biological underpinnings of unipolar (UD) and bipolar depression (BD) is vital for avoiding inappropriate treatment through the misdiagnosis of bipolar patients in their first depressive episode. One plausible way to distinguish between UD and BD is to compare EEG brain dynamics to identify potential neurophysiological biomarkers. Here we aimed to test group differences in EEG power, cordance and coherence values between UD and BD. METHODS: Twenty five bipolar and 56 unipolar depression patients were recruited. Sociodemographic and clinical variables were collected in addition to resting state EEG. Data was analyzed with multivariate and repeated analyses of variance where parametric assumptions were met. RESULTS: Accordingly, we did not find any differences in the EEG absolute power and frontal asymmetry indexes between UD and BD. Regarding cordance, significant group differences were observed in the right theta cordance values (p=0.031). Regarding coherence, BD patients (as compared to UD) exhibited greater central-temporal theta (p=0.003), and parietal-temporal alpha (p=0.007) and theta (p=0.001) coherence. Lastly, less alpha coherence in BD was present at right frontal-central (p=0.007) and central inter-hemispheric (p=0.019) regions. CONCLUSIONS: Our results demonstrate that EEG cordance and coherence values have potential to discriminate between UD and BD. The loss of temporal synchronization in the frontal interhemispheric and right sided frontolimbic neuronal networks may be a unique feature that distinguishes between BD and UD. PMID- 25451417 TI - Could the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) be used in depressed schizophrenia patients? AB - BACKGROUND: Developing accurate and time-efficient tools to measure depressive symptoms in schizophrenia is important for research and clinical practice. This study tested the psychometric properties of the Chinese version of the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR) in depressed schizophrenia patients. METHODS: This study included 337 clinically stable patients with schizophrenia. The severity of depressive symptoms was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), QIDS-SR at baseline and 2 weeks later. Negative symptoms and extrapyramidal symptoms were measured with the negative symptom score of Brief Psychiatric Rating Scale (BPRS) and the Simpson Angus Scale of Extrapyramidal Symptoms (SAS), respectively. RESULTS: Internal consistency (Cronbach's alpha) was 0.73 and 0.67 for QIDS-SR at the baseline and endpoint, respectively. The intra-class correlation coefficient (ICC) for test retest reliability over the two weeks was 0.77. Two domains (involvement and energy) at baseline and one domain (energy) at endpoint had the highest item total correlations. The QIDS-SR total score was significantly correlated with the MADRS total score at baseline (r=0.44, p<0.01). Weak correlations of the QIDS-SR score with the scores of the BPRS negative (r=0.18) and the SAS (r=0.05) indicate good discriminant validity. The QIDS-SR showed unidimensional measurement properties in exploratory factor analysis at both baseline. The main limitation of the study is that only clinically stable schizophrenia patients were included. CONCLUSIONS: The QIDS-SR has acceptable psychometric properties in stable schizophrenia patients and may be useful in both research and clinical practice. PMID- 25451418 TI - Dissociation, shame, complex PTSD, child maltreatment and intimate relationship self-concept in dissociative disorder, chronic PTSD and mixed psychiatric groups. AB - BACKGROUND: Whilst a growing body of research has examined dissociation and other psychiatric symptoms in severe dissociative disorders (DDs), there has been no systematic examination of shame and sense of self in relationships in DDs. Chronic child abuse often associated with severe DDs, like dissociative identity disorder, is likely to heighten shame and relationship concerns. This study investigated complex posttraumatic stress disorder (PTSD), borderline and Schneiderian symptoms, dissociation, shame, child abuse, and various markers of self in relationships (e.g., relationship esteem, relationship depression, fear of relationships). METHODS: Participants were assessed via clinical interview with psychometrically sound questionnaires. They fell into three diagnostic groups, dissociative disorder (n=39; primarily dissociative identity disorder), chronic PTSD (Chr-PTSD; n=13) or mixed psychiatric presentations (MP; n=21; primarily mood and anxiety disorders). All participants had a history of child abuse and/or neglect, and the groups did not differ on age and gender. RESULTS: The DD group was higher on nearly all measured variables than the MP group, and had more severe dissociative, borderline and Schneiderian symptoms than the Chr PTSD sample. Shame and complex PTSD symptoms fell marginally short of predicting reductions in relationship esteem, pathological dissociative symptoms predicted increased relationship depression, and complex PTSD symptoms predicted fear of relationships. LIMITATIONS: The representativeness of the samples was unknown. CONCLUSION: Severe psychiatric symptoms differentiate DDs from chronic PTSD, while dissociation and shame have a meaningful impact on specific markers of relationship functioning in psychiatric patients with a history of child abuse and neglect. PMID- 25451419 TI - Predictors for initiation of pharmacological prophylaxis in patients with newly diagnosed bipolar disorder--A nationwide cohort study. AB - BACKGROUND: Treatment guidelines state that all patients with bipolar disorder should use pharmacological prophylaxis; however the actual use of prophylactic drugs after bipolar disorder diagnosis is unknown. Our aim was to assess the use of, and predictors for, pharmacoprophylaxis in newly diagnosed bipolar disorder patients. METHODS: Data from three Swedish nationwide registers were obtained. We identified patients aged 18-75 with a first time diagnosis of bipolar disorder between 2006 and 2012 (n=31,770) and reviewed subsequent mood-stabilizer and antipsychotic prescription fills. In multivariable Cox regression models, we studied demographic and illness related factors as predictors of prescription fills after diagnosis. RESULTS: In total, 72.2% (95% confidence interval [CI] 71.7-72.7%) of the patients filled a prescription of a prophylactic drug within 3 months after diagnosis. Pharmacological prophylaxis was mainly associated with a longer duration of hospitalization at bipolar disorder diagnosis (adjusted hazard ratio [AHR] 2.18; CI 2.02-2.35 for a hospitalization of >=28 days compared to <7 days) and previous use of any mood-stabilizer or antipsychotic (inpatients: AHR 1.24; CI 1.17-1.31 and outpatients: AHR 1.78; CI 1.73-1.84). LIMITATIONS: We had no information on drug prescriptions that were never filled. CONCLUSIONS: The proportion of newly diagnosed bipolar disorder patients without pharmacological prophylaxis is substantial. Patients who are naive to mood-stabilizers and antipsychotics and are hospitalized for a brief period at diagnosis are the ones least likely to initiate pharmacoprophylaxis, suggesting that this group deserves attention in order to improve the long term prognosis. PMID- 25451420 TI - The association between cannabis use and mood disorders: A longitudinal study. AB - BACKGROUND: The association between cannabis use and mood disorders is well documented, yet evidence regarding causality is conflicting. This study explored the association between cannabis use, major depressive disorder (MDD) and bipolar disorder (BPD) in a 3-year prospective study. METHODS: Data was drawn from waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). MDD and BPD were controlled at baseline and defined as meeting full criteria in the 12 months prior to the follow-up. Initiation of cannabis use was defined as any cannabis used by former lifetime abstainers in the time period between baseline and follow-up. RESULTS: Cannabis use was not significantly associated with increased incidence of MDD (Adjusted Odds Ratio (AOR) for daily use=0.58(0.22-1.51)). Weekly to almost daily cannabis use was associated with increased incidence of BPD ((AOR for weekly to daily use=2.47(1.03-5.92)); daily use was not (AOR=0.52(0.17-1.55)). Baseline MDD was associated with initiation of cannabis use (AOR=1.72(1.1-2.69)). A crude association between baseline BPD and incidence of cannabis use was not maintained in adjusted models (AOR=0.61(0.36 1.04)). LIMITATIONS: Lack of information regarding frequency of cannabis use at follow-up and limitations regarding generalization of the results. CONCLUSIONS: Our findings do not support a longitudinal association between cannabis use and incidence of MDD. Results regarding the association between cannabis use and incidence of BPD are conflicting and require further investigation. Baseline MDD, but not BPD, may be associated with future initiation of cannabis use. This may have implications for clinical, social and legislative aspects of cannabis use. PMID- 25451421 TI - The influence of inflammatory cytokines in physiopathology of suicidal behavior. AB - BACKGROUND: Based on the urgent need for reliable biomarkers in relation to suicide risk both for more accurate prediction as well as for new therapeutic opportunities, several researchers have been studied evidences of the potential participation of inflammatory processes in the brain, in particular cytokines, in suicide. The purpose of this review was to analyze the associations between inflammation markers and suicide. METHODS: To achieve this goal, a systematic review of literature was conducted via electronic database Scopus using the Medical Subject Headings (MeSH) terms: "cytokines", "suicide" and "inflammation". Through this search it was found 54 articles. After analyzing them 15 met the eligibility criteria and were included in the final sample. RESULTS: One of the most mentioned inflammatory markers was Interferon-alpha (IFN-alpha), a pro inflammatory cytokine which has been shown to increase serum concentrations of pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-a (TNF- alpha) and IFN-Upsilon, which are factors increased suicide victims and attempters. In this line, IL-6 is not only found to be elevated in the cerebrospinal fluid of suicide attempters, even its levels in the peripheral blood have been proposed as a biological suicide marker. Another study stated that increased levels of IL-4 and IL-13 transcription in the orbitofrontal cortex of suicides suggest that these cytokines may affect neurobehavioral processes relevant to suicide. LIMITATIONS: A lack of studies and great amount of cross sectional studies. CONCLUSION: Inflammation may play an important role in the pathophysiology of suicide, especially, levels of some specific inflammatory cytokines. PMID- 25451422 TI - Listening to the heart: A meta-analysis of cognitive behavior therapy impact on the heart rate of patients with anxiety disorders. AB - INTRODUCTION: The future of psychotherapy relies on the dialog with the basic science, being the identification of psychotherapeutifc biomarkers of efficacy a core necessity. Heart rate (HR) is one of the most studied psychophysiological parameters in anxiety disorders. METHODS: To investigate the impact of cognitive behavior therapy (CBT) on the HR of patients with anxiety disorders, we conducted a meta-analysis and systematic review. Electronic searches were conducted in the ISI/Web of Knowledge, PsychINFO and PubMed/MEDLINE for studies which evaluated HR at least once before and after CBT. Keywords related to anxiety disorders, HR and CBT were used in the search. RESULTS: 474 studies, of which 47 were selected for the systematic review and 8 for the meta-analysis, were identified. The results provide evidence that CBT significantly decreases the HR of posttraumatic stress disorder patients. In social phobia, obsessive-compulsive disorder and acute stress disorder, the results point in the same direction, although it is still early to attribute the decrease in HR to CBT. In specific phobias, traditional exposure therapy showed greater effect size than exposure with distractors or without psycho-education. LIMITATIONS: Most of the randomized trials have not been conducted in accordance with rigorous methodological quality criteria. CONCLUSIONS: Standardization in the methods used and in treatment protocols, as well as investigations in groups of patients with low physiological reactivity, are necessary in order to reach better conclusions. Notwithstanding these limitations, HR is beginning to emerge as a potential biomarker of efficacy in anxiety disorders. PMID- 25451424 TI - The Affective and Emotional Composite Temperament Scale (AFECTS): Psychometric properties of the Spanish version in a community sample from Mexico City and comparison between remitted psychiatric patients. AB - INTRODUCTION: AFECTS is a novel psychometric instrument that provides an integrated framework based on affective temperamental traits and their trait dimensions. It has the potential to be used in clinical and research fields to study psychopathology and mental health. It is now necessary to field-test this instrument with diverse populations and psychopathological entities. OBJECTIVE: The primary aim was to test the construct validity and the internal consistency of the Spanish Version of the AFECTS instrument on Mexican subjects. AFECTS characteristics were then compared between general population and stable psychiatric patients. METHODS: A cross-sectional design involving 350 subjects from the general population in Mexico City and 91 stable patients with a bipolar disorder (BPD, n=20), major depressive disorder (MDD, n=35), or with a schizophrenia (n=36) diagnosis. RESULTS: A six-factor structure in trait dimensions, explaining 61.4% of the variance, with a Cronbach's alpha of 0.93 was found. Euthymic (23%) and hyperthymic (12%) affective temperaments were the most frequent, while dysphoric (3%) and apathetic (3%) were the least. Trait dimension differences were found in Volition, Sensitivity, and the Instability Index between the groups, particularly those with a bipolar disorder. LIMITATIONS: Use of a self report instrument, and a small sample not representative of the Mexican population or patients with psychiatric conditions. CONCLUSIONS: The Spanish Version of the AFECTS instrument has adequate psychometric properties. This version of AFECTS will allow the use of this instrument among Spanish speaking populations and contribute to the continued research efforts on integrative models such as AFECT. PMID- 25451423 TI - Clinical, cognitive, and functional connectivity correlations of resting-state intrinsic brain activity alterations in unmedicated depression. AB - The pervasive and persistent nature of depressive symptoms has made resting-state functional magnetic resonance imaging (rs-fMRI) an appropriate approach for understanding the underlying mechanisms of major depressive disorder. The majority of rs-fMRI research has focused on depression-related alterations in the interregional coordination of brain baseline low frequency oscillations (LFOs). However, alteration of the regional amplitude of LFOs in depression, particularly its clinical, cognitive and network implications, has not been examined comprehensively yet. rs-fMRI amplitudes of low-frequency fluctuation (ALFF/fALFF) mediated by two LFO bands of 0.01-0.08 Hz (LF-ALFF/fALFF) and 0.1-0.25 Hz (HF ALFF/fALFF) were measured in unmedicated subjects with major depressive disorder (n=20) and a healthy control group (n=25). A novel method of "ALFF-based functional connectivity" analysis was developed to test regional/network interaction abnormalities in depression. Our results revealed abnormal alterations in ALFF for both lower and higher frequency bands of LFOs in regions that participate in affective networks, corticostriatal circuits and motor/somatosensory networks. A strong positive correlation was detected between depressive symptom severity and fALFF in the anterior cingulate cortex. Functional connectivity of the thalamus and postcentral area with altered ALFF were found to be decreased with other interacting regions of their involved networks. Major depressive disorder relates to the alterations of regional properties of intrinsic neural activity with meaningful clinical and cognitive correlations. This study also proposes an integrating regional/network dysfunction in MDD. PMID- 25451425 TI - The prevalence and illness characteristics of DSM-5-defined "mixed feature specifier" in adults with major depressive disorder and bipolar disorder: Results from the International Mood Disorders Collaborative Project. AB - BACKGROUND: A substantial proportion of individuals with mood disorders present with sub-syndromal hypo/manic features. The objective of this analysis was to evaluate the prevalence and illness characteristics of the Diagnostic and Statistical Manual Version-5 (DSM-5) - defined mixed features specifier (MFS) in adults with major depressive disorder (MDD) and bipolar disorder (BD). METHOD: Data from participants who met criteria for a current mood episode as part of MDD (n=506) or BD (BD-I: n=216, BD-II: n=130) were included in this post-hoc analysis. All participants were enrolled in the International Mood Disorders Collaborative Project (IMDCP): a collaborative research platform at the Mood Disorders Psychopharmacology Unit, University of Toronto and the Cleveland Clinic, Cleveland, Ohio. Mixed features specifier was operationalized as a score >= 1 on 3 or more select items on the Young Mania Rating Scale (YMRS) or >= 1 on 3 select items of the Montgomery Asberg Depression Rating Scale (MADRS) or Hamilton Depression Rating Scale (HAMD-17) during an index major depressive episode (MDE) or hypo/manic episode, respectively. RESULTS: A total of 26.0% (n=149), 34.0% (n=65), and 33.8% (n=49) of individuals met criteria for MFS during an index MDE as part of MDD, BD-I and BD-II, respectively. Mixed features specifier during a hypo/manic episode was identified in 20.4% (n=52) and 5.1% (n=8) in BD-I and BD-II participants, respectively. Individuals with MDE-MFS as part of BD or MDD exhibited a more severe depressive phenotype (p=0.0002 and p<0.0002, respectively) and reported a higher rate of alcohol/substance use disorder in the context of BD but not MDD (p=0.002). Individuals with MFS were more likely to have co-existing heart disease suggestive of a distinct pattern of comorbidity and neurobiology. LIMITATIONS: Data were post-hoc and obtained from individuals utilizing a university-based mood disorder centre which may affect generalizability. CONCLUSIONS: Diagnostic and Statistical Manual Version-5 defined MFS is common during an MDE as part of MDD and BD. The presence of MFS identifies a subgroup of individuals with greater illness complexity and possibly a higher rate of cardiovascular comorbidity. The results herein underscore the common occurrence of MFS in adults with either BD or MDD. Moreover, the results of our analysis indicate that adults with mood disorders and MFS have distinct clinical characteristics and comorbidity patterns. PMID- 25451427 TI - Factors affecting recruitment into depression trials: Systematic review, meta synthesis and conceptual framework. AB - BACKGROUND: Depression is common and clinical trials are crucial for evaluating treatments. Difficulties in recruiting participants into depression trials are well-documented, yet no study has examined the factors affecting recruitment. This review aims to identify the factors affecting recruitment into depression trials and to develop a conceptual framework through systematic assessment of published qualitative research. METHODS: Systematic review and meta-synthesis of published qualitative studies. Meta-synthesis involves a synthesis of themes across a number of qualitative studies to produce findings that are "greater than the sum of the parts". ASSIA, CINAHL, Embase, Medline and PsychInfo were searched up to April 2013. Reference lists of included studies, key publications and relevant reviews were also searched. Quality appraisal adopted the "prompts for appraising qualitative research". RESULTS: 7977 citations were identified, and 15 studies were included. Findings indicate that the decision to enter a depression trial is made by patients and gatekeepers based on the patient's health state at the time of being approached to participate; on their attitude towards the research and trial interventions; and on the extent to which patients become engaged with the trial. Our conceptual framework highlights that the decision to participate by both the patient and the gatekeeper involves a judgement between risk and reward. LIMITATIONS: Only English language publications were included in this review. CONCLUSIONS: Findings from this review have implications for the design of interventions to improve recruitment into depression trials. Such interventions may aim to diminish the perceived risks and increase the perceived rewards of participation. PMID- 25451426 TI - The Influence of genetic factors on peripartum depression: A systematic review. AB - BACKGROUND: This systematic review aimed to explore the potential influence of genetic factors on the symptoms of peripartum depression and to critically analyze the methodologies employed by the examined studies. METHODS: A systematic review of the literature indexed prior to July 2014 identified 200 articles. After applying the inclusion and exclusion criteria, 39 papers were included. RESULTS: The papers predominantly featured a molecular genetic approach (n=35), and the majority examined polymorphisms (n=27). Most studies used samples of Caucasians living in high income countries. The results suggest that the influence of genetic factors become more consistent when methodological variations among the studies are considered. Environmental stressors are also important variables that influence the relationship between genetic factors and peripartum depressive states. In addition, differences in the influence of genetic factors were observed depending upon the precise time point during pregnancy or the postpartum period that was examined in the studies. The late stages of pregnancy and the early postpartum period were times of greater genetic vulnerability. LIMITATIONS: This study was limited by the small number of papers reviewed and by the lack of information regarding whether the effects of genetics on peripartum depression are specific to certain ethnicities and/or stressors. CONCLUSIONS: Genetic studies of perinatal depression reinforce a pathophysiological role of the hormonal changes inherent in the childbirth period. However, the distinction between depressive episodes that begin during pregnancy from those that begin during the postpartum period can still be useful to improve our understanding of the physiopathology of depressive disorders. PMID- 25451428 TI - Efficacy of psychoeducational family intervention for bipolar I disorder: A controlled, multicentric, real-world study. AB - BACKGROUND: This study assessed the efficacy of the Falloon model of psychoeducational family intervention (PFI), originally developed for schizophrenia management and adapted to bipolar I disorder. The efficacy of the intervention was evaluated in terms of improvement of patients' social functioning and reduction of family burden. METHODS: This was a multicentre, real world, controlled, outpatient trial carried out in 11 randomly recruited Italian mental health centres. Enroled patients and key-relatives were consecutively allocated either to receive PFI and Treatment As Usual (TAU) or to a waiting list receiving TAU alone. The efficacy of the intervention was evaluated in terms of improvement in patients' social functioning (primary outcome) and reduction of family burden (secondary outcome). RESULTS: Of the 137 recruited families, 70 were allocated to the experimental group and 67 to the control group. At the end of the intervention, significant improvements in patients' social functioning and in relatives' burden were found in the treated group compared to TAU. This effect of the intervention remained also after controlling for several confounding patient's socio-demographic and clinical factors. The experimental intervention had an impact also on other outcome measures, such as patients' clinical status and personal burden. LIMITATIONS: Lack of an active control group. CONCLUSIONS: The results of this study clearly show that the psychoeducational family intervention according to the Falloon model is effective in improving the social outcome of patients with bipolar I disorder. PMID- 25451429 TI - Can manic switches be predicted in pediatric major depression? A systematic literature review. AB - BACKGROUND: The rate of switching from major depression to bipolar disorder is high in children. Predicting who is at risk for switching poses unique challenges and is of high clinical relevance. Our aim was to examine the existing scientific literature elucidating if certain clinical correlates predict ultimate bipolar switches in children initially presenting with a depressive episode. METHODS: We conducted a systematic literature search of studies assessing the risk factors for bipolar switching in youth. In all, seven studies fit our a priori criteria and were thus included in our qualitative review. RESULTS: Together, these papers found that manic switches in pediatric depression can be predicted by several risk factors, including positive family history of mood disorders, emotional and behavioral dysregulation, subthreshold mania, and psychosis. LIMITATIONS: We identified only seven prospective informative studies for our review. The majority of subjects included in these studies were referred and Caucasian. Thus, the results may not generalize to other community samples and other ethnicities. CONCLUSIONS: These findings can help alert clinicians of the risk of manic switches. PMID- 25451431 TI - The effect of aphasia upon personality traits, depression and anxiety among stroke patients. AB - BACKGROUND: Post-stroke patients with aphasia have higher levels of psychological distress. We aimed to find the relation between post-stroke aphasia and depression, anxiety and personality traits. METHODS: One month after stroke, 61 consecutive patients with stroke were included in this study. Thirty post-stroke patients with aphasia and 31 patients without aphasia. We used the following scales a clinical-friendly: Aphasic test, Eysenck Personality Questionnaire, Hamilton anxiety and Beck Depression Inventory. RESULTS: Depression and anxiety were more prominent among patients with aphasia than stroke without aphasia. Psychosis was more prominent among post-stroke patients with aphasia. LIMITATIONS: Our results may not exclusively exclude pre-morbid personality traits. CONCLUSIONS: Our study highlights the growing need to develop community rehabilitation services in the developing world, which address both physical and psychological morbidity. PMID- 25451432 TI - An adaptationist perspective on the etiology of depression. AB - Major depressive disorder (MDD) presents with a variety of symptoms and responds to a wide range of treatment interventions. Diagnostic criteria collapse multiple syndromes with distinct etiologies into the same disorder. MDD is typically understood as a malfunction of neurotransmission or brain circuitry regulating mood, pleasure and reward, or executive function. However, research from an evolutionary perspective suggests that the "normal" functioning of adaptations may also generate symptoms meeting diagnostic criteria. Functioning adaptations may be an underappreciated etiological pathway to MDD. Many adaptive functions for depressive symptoms have been suggested: biasing cognition to avoid losses, conserving energy, disengaging from unobtainable goals, signaling submission, soliciting resources, and promoting analytical thinking. We review the potential role of these adaptive functions and how they can lead to specific clusters of depressive symptoms. Understanding MDD from such a perspective reduces the heterogeneity of cases and may help to select the best intervention for each patient. We discuss the implications of different adaptive and maladaptive etiological pathways for the use of antidepressants and various modes of psychotherapy. In particular, instances of MDD caused by functioning adaptations may benefit most from treatments that support the adaptive function, or that target the precipitating causal stressor. We conclude that an evolutionary approach to the study of MDD may be one of the more promising approaches to reduce its heterogeneity and to better match patients and treatment. PMID- 25451433 TI - Maternal anxiety and neural responses to infant faces. AB - BACKGROUND: Women may be especially vulnerable to anxiety during the postpartum period and early infancy. However, little is known regarding the potential impact of maternal anxiety on the neural processing of infant-relevant information. METHODS: In this ERP study, 47 recent mothers viewed neutral and distressed infant faces, concurrent with EEG collection. We examined the N170 as a perceptual marker of face processing and the late positive potential (LPP) as an index of engagement with stimulus processing. Mothers also completed the Spielberger State-Trait Anxiety Inventory. RESULTS: While the N170 was unaffected by infant affect and anxiety levels, the LPP was greater in amplitude for distressed vs. neutral faces. Moreover, the degree of LPP amplitude elicited by neutral infant faces was positively correlated with state anxiety. There were no associations between anxiety and the LPP elicited by distressed infant faces. LIMITATIONS: We employed self-report measures of state and trait anxiety symptomatology and including diagnostic classification of anxiety disorders will be important in future research. CONCLUSIONS: These results indicate that recent mothers with higher levels of state anxiety may be more engaged with processing neutral infant cues. PMID- 25451430 TI - Shank3 as a potential biomarker of antidepressant response to ketamine and its neural correlates in bipolar depression. AB - BACKGROUND: Shank3, a post-synaptic density protein involved in N-methyl-d aspartate (NMDA) receptor tethering and dendritic spine rearrangement, is implicated in the pathophysiology of bipolar disorder. We hypothesized that elevated baseline plasma Shank3 levels might predict antidepressant response to the NMDA receptor antagonist ketamine. METHODS: Twenty-nine subjects with bipolar depression received a double-blind, randomized, subanesthetic dose (.5 mg/kg) ketamine infusion. Of the patients for whom Shank3 levels were collected, 15 completed baseline 3-Tesla MRI and 17 completed post-ketamine [(18)F]-FDG PET. RESULTS: Higher baseline Shank3 levels predicted antidepressant response at Days 1 (r=-.39, p=.047), 2 (r=-.45, p=.02), and 3 (r=-.42, p=.03) and were associated with larger average (r=.58, p=.02) and right amygdala volume (r=.65, p=.009). Greater baseline Shank3 also predicted increased glucose metabolism in the hippocampus (r=.51, p=.04) and amygdala (r=.58, p=.02). LIMITATIONS: Limitations include the small sample size, inability to assess the source of peripheral Shank3, and the lack of a placebo group for baseline Shank3 levels and comparative structural/functional neuroimaging. CONCLUSIONS: Shank3 is a potential biomarker of antidepressant response to ketamine that correlates with baseline amygdala volume and increased glucose metabolism in the amygdala and hippocampus. PMID- 25451435 TI - Screening for bipolar spectrum disorders: A comprehensive meta-analysis of accuracy studies. AB - BACKGROUND: Bipolar spectrum disorders are frequently under-recognized and/or misdiagnosed in various settings. Several influential publications recommend the routine screening of bipolar disorder. A systematic review and meta-analysis of accuracy studies for the bipolar spectrum diagnostic scale (BSDS), the hypomania checklist (HCL-32) and the mood disorder questionnaire (MDQ) were performed. METHODS: The Pubmed, EMBASE, Cochrane, PsycINFO and SCOPUS databases were searched. Studies were included if the accuracy properties of the screening measures were determined against a DSM or ICD-10 structured diagnostic interview. The QUADAS-2 tool was used to rate bias. RESULTS: Fifty three original studies met inclusion criteria (N=21,542). At recommended cutoffs, summary sensitivities were 81%, 66% and 69%, while specificities were 67%, 79% and 86% for the HCL-32, MDQ, and BSDS in psychiatric services, respectively. The HCL-32 was more accurate than the MDQ for the detection of type II bipolar disorder in mental health care centers (P=0.018). At a cutoff of 7, the MDQ had a summary sensitivity of 43% and a summary specificity of 95% for detection of bipolar disorder in primary care or general population settings. LIMITATIONS: Most studies were performed in mental health care settings. Several included studies had a high risk of bias. CONCLUSIONS: Although accuracy properties of the three screening instruments did not consistently differ in mental health care services, the HCL-32 was more accurate than the MDQ for the detection of type II BD. More studies in other settings (for example, in primary care) are necessary. PMID- 25451436 TI - STin2 VNTR polymorphism is associated with comorbid tobacco use and mood disorders. AB - BACKGROUND: There is a significant comorbidity between mood disorders and tobacco use disorder (TUD), which may be related to both genetic and environmental factors. Gene variants of the 5-HT transporter, such as STin2 VNTR (a variable number of tandem repeats in the functional serotonin transporter intron 2) may be associated with mood disorders and TUD. AIMS: This study aimed to delineate the association between the STin2 genetic polymorphism and comorbid TUD and mood disorders, including depression or bipolar disorder. METHODS: We examined the STin2 VNTR polymorphism in never-smokers (n=113); patients with mood disorders without TUD (n=62); patients with TUD without mood disorders (n=90); and patients with both disorders (n=95). RESULTS: We found a significant association between the STin2 genetic polymorphism and the above diagnostic groups whereby the STin2.12 allele shows a positive association with comorbid TUD and mood disorders (Odds ratio=3.07, 95% CI=1.41-6.68), while the STin2.10/10 homozygous genotype shows a negative association (Odds ratio=0.34, 95% CI=0.16-0.74). Adjusting for years of education, age, gender, marital status and ethnicity did not change these results, but showed that TUD was associated with lower education levels and less stable relationships, whereas mood disorders were related to female gender. A family history of TUD was significantly associated with TUD in subjects without mood disorders only. CONCLUSIONS: The STin2.12 allele is positively and the STin2.10/10 genotype is negatively associated with comorbid TUD and mood disorders, depression or bipolar depression, suggesting that biological endophenotypes, e.g. disorders in serotonin metabolism, may in part underpin this comorbidity. PMID- 25451437 TI - Different patterns of manic/hypomanic symptoms in depression: A pilot modification of the hypomania checklist-32 to assess mixed depression. AB - BACKGROUND: There are no self-report scales that assess manic/hypomanic symptoms in patients with depression. The aim of this study was to explore the use of a modified screening instrument for bipolar disorder to assess current manic/hypomanic symptoms in patients with a depressive episode. METHODS: The study sample consisted of 188 patients with Structured Clinical Interview for DSM IV-TR disorders (SCID) confirmed bipolar or major depressive disorder. We modified the Hypomania Checklist-32 (mHCL-32) to assess current instead of lifetime symptoms. An Exploratory Factor Analysis (EFA) was conducted to identify clusters of mHCL-32 items that were endorsed concurrently. A Latent Class Analysis (LCA) was carried out to identify groups of patients with similar mHCL 32 item endorsement patterns. RESULTS: The EFA identified 3 factors: factor #1 ("elation-disinhibition-increased goal directed activity"), factor #2 ("risk taking-impulsivity-substance use") and factor #3 (distractibility-irritability). The LCA yielded 3 classes (2 showing manic/hypomanic features). While class #1 patients endorsed more items related to disinhibition and racing thoughts, class #2 patients recognized more items associated with irritability and substance use. LIMITATIONS: Lack of an adequate gold standard measure of mixed depression to compare to, the cross-sectional design and the lack of a validation sample. CONCLUSIONS: The mHCL-32 scale allowed a comprehensive and convergent delineation of hypomanic/manic symptoms in depression. Further validation of these findings is needed. PMID- 25451438 TI - The relationship between burnout and depressive symptoms in patients with depressive disorders. AB - BACKGROUND: Burnout - physical or psychological fatigue in the personal, work and client-related work domains - appears to share numerous overlapping characteristics with major depressive episodes. However, whether burnout and depression are in fact separate conditions is still ambiguous. Our aim was to examine burnout in a clinically depressed patient sample. METHODS: Outpatients with a DSM-IV depressive episode (major depressive episode and dysthymic disorder) completed the Copenhagen Burnout Inventory (CBI) and the Quick Inventory for Depressive Symptomatology, Self-Rated (QIDS-SR). The relationship between CBI-defined burnout and depressive symptoms was examined using correlation and hierarchical multiple regression analyses. RESULTS: Depressed patients had high rates of CBI-defined burnout as well as significant correlations between burnout scores and overall depression severity scores. Individual depressive symptoms were significantly higher between patients with and without burnout, and significantly correlated with burnout scores, with the exception of guilt/worthlessness. Multiple regression analysis identified changes in sleep and fatigue as significant predictors of burnout. LIMITATIONS: The main limitations of the study were the sample size, the broad definition of depression, and the cross-sectional design. CONCLUSIONS: The high burnout scores and correlations between burnout and depression severity observed in this study highlight the importance of understanding burnout in depressed patients. Despite the significant overlap between burnout and depression, the relationship between these two concepts still requires further clarification. PMID- 25451439 TI - Peripheral markers of oxidative stress and antioxidative defense in euthymia of bipolar disorder--Gender and obesity effects. AB - INTRODUCTION: Oxidative and nitrosative stress are implicated in the pathogenesis of uni- and bipolar disorder. Herein we primarily sought to characterize markers of oxidative/nitrosative stress during euthymia in adults with bipolar disorder (BD). Oxidative markers were further evaluated in this BD sample in synopsis with excess overweight or obesity and/or comorbid metabolic syndrome (MetS). METHODS: Peripheral markers of oxidative stress [i.e. thiobarbituric acid reactive substance, (TBARS), malondialdehyde (MDA), and carbonyl proteins] and antioxidant markers [e.g. total antioxidative capacity (TAC), superoxide dismutase (SOD), glutathione S-transferase (GST)] were obtained in a cohort of euthymic adults with BD (N=113) and compared to healthy controls (CG) (N=78). Additionally, anthropometric measures included the body mass index (BMI) [kg/m(2)], waist and hip circumference [cm], waist-to-hip-ratio (WHR), waist to height ratio (WtHR) as well as the IDF-defined MetS. RESULTS: The major finding was a significantly decreased TAC in BD compared to the CG (p<0.01; BD: M 1.18, SD 0.47; CG: M 1.39, SD 0.49). MDA was significantly and TBARS by trend higher in the CG compared to the euthymic bipolar test persons (MDA: p<0.01, BD: M 0.70, SD 0.18; CG: M 0.81, SD 0.25; TBARS: p<0.1, BD: M 0.78, SD 0.28; CG: M 0.76, SD 0.30). The antioxidative enzyme GST was significantly elevated in both patients and controls (BD: M 298.24, SD 133.02; CG: M 307.27 SD 118.18). Subgroup analysis revealed that the CG with concurrent MetS and obesity had significantly elevated TAC when compared to CG without concurrent MetS (p<0.05, no MetS: M 1.33, SD 0.50; MetS: M 1.67, SD 0.32), as well as persons with BD with or without current MetS (no MetS: M 1.18, SD 0.44; MetS: M 1.15, SD 0.49). Significant correlations between GST and anthropometric variables were found in male study participants. Multivariate analysis indicated a significant gender effect concerning TBARS values in all patients and CG (p<0.01, females: M 0.73, SD 0.29; males: M 0.83, SD 0.28). CONCLUSION: Euthymic bipolar adults exhibit peripheral evidence of a disturbed biosignature of oxidative stress and antioxidative defense. Male test persons showed significantly higher peripheral markers of oxidative stress than women- female sex may exert protective effects. Furthermore, the biosignature of oxidative stress obtained herein was more pronounced in males with concurrent metabolic disorders. Our results further extend knowledge by introducing the moderating influence of gender and obesity on oxidative stress and BD. PMID- 25451434 TI - Elucidating the transdiagnostic dimensional structure of trauma-related psychopathology: Findings from VA cooperative study 504 - risperidone treatment for military service related chronic post traumatic stress disorder. AB - BACKGROUND: Three of the most common trauma-related mental disorders posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD)-are highly comorbid and share common transdiagnostic symptom dimensions of threat (i.e., fear) and loss (i.e., dysphoria) symptomatology. However, empirical evaluation of the dimensional structure of component aspects of these disorders is lacking. METHODS: Using structured clinical interview data from U.S. military veterans with chronic military-related PTSD, we evaluated the transdiagnostic dimensional structure of PTSD, MDD, and GAD symptoms. We then examined the relationship between the best fitting transdiagnostic model of these symptoms, and measures of physical and mental functioning, and life satisfaction and well-being. RESULTS: Exploratory factor analysis revealed that a 3-factor transdiagnostic model comprised of loss (i.e., dysphoria), threat (i.e., anxious arousal, re-experiencing, and avoidance symptoms), and somatic anxiety (i.e., physiological manifestations of anxiety) symptoms provided the best representation of trauma-related PTSD, MDD, and GAD symptoms. Somatic anxiety symptoms were independently associated with physical functioning, while loss symptoms were independently associated with mental functioning and life satisfaction and well-being. LIMITATIONS: Evaluation of study aims in a relatively homogeneous sample of veterans with chronic, military related PTSD. CONCLUSIONS: Results of this study suggest that a 3-factor transdiagnostic model best characterizes the dimensional structure of PTSD, MDD, and GAD symptoms in military veterans with chronic military-related PTSD. This model evidenced external validity in demonstrating differential associations with measures of physical and mental functioning, and life satisfaction and well being. Results provide support for emerging contemporary models of psychopathology, which emphasize transdiagnostic and dimensional conceptualizations of mental disorders. Such models may have utility in understanding the functional status of trauma survivors. PMID- 25451440 TI - Psychometric properties of the Affective Lability Scale (54 and 18-item version) in patients with bipolar disorder, first-degree relatives, and healthy controls. AB - INTRODUCTION: The aim of this study was to investigate the psychometric properties of the original 54 item version (ALS-54) and the short 18 item version (ALS-18) of the Affective Lability Scale (ALS) in patients with bipolar disorders, their first-degree relatives and healthy controls. Internal Consistency and Confirmatory Factor Analysis were performed, comparing clinical and non-clinical group comparisons on ALS scores. METHODS: A total of 993 participants (patients with bipolar disorders [n=422], first-degree relatives [n=201] and controls [n=370]) were recruited from France and Norway. Diagnosis and clinical characteristics were assessed using the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I), or the Diagnostic Interview for Genetic Studies (DIGS). Affective lability was measured using the ALS-54 and ALS 18. RESULTS: Both ALS-54 and ALS-18 showed high internal consistency, but the subdimensions of both versions were highly inter-correlated. From confirmatory factor analysis both versions revealed acceptable to good model fit. Patients had significantly higher ALS scores compared to controls, with affected first-degree relatives presenting intermediate scores. CONCLUSION: Both the original ALS-54 version and the short ALS-18 version showed good psychometric properties. They also discriminated between patients with a bipolar disorder (high ALS), first degree relatives (intermediate ALS), and healthy controls (low ALS). A high correlation between ALS items for both versions was observed. Our study supports reducing the scale from 54 to 18 items. PMID- 25451441 TI - Poor sleep predicts symptoms of depression and disability retirement due to depression. AB - BACKGROUND: Disturbed sleep is associated with mood disorders. Both depression and insomnia may increase the risk of disability retirement. The longitudinal links among insomnia, depression and work incapacity are poorly known. METHODS: We examined association of self-reported sleep quality with incident symptoms of depression and disability retirement due to depressive disorders in a longitudinal population-based sample of twins (n=12,063 individuals). These adults were categorized by their sleep quality in 1975 and 1981, excluding individuals with depressed mood in 1975/1981. The outcomes were the Beck Depression Inventory (BDItot) and its subscale Negative Attitudes Towards Self (BDINATS) in 1990 as dichotomized measures, and the incidence of disability retirement due to depressive disorder during 1991-2004. RESULTS: Onset of poor sleep between 1975 and 1981 predicted incident depression (BDItot OR=4.5, 95% CI: 2.7-7.4, BDINATS OR=2.0, 95% CI: 1.4-2.7), while persistent poor sleep showed somewhat weaker effects (BDItot; OR=2.5, 95% CI: 1.0-6.0, BDINATS OR=1.9, 95% CI: 1.1-3.3). Among those with few recent stressful life events, onset of poor sleep predicted strongly depression (BDINATS OR=9.5, 95% CI: 3.7-24.2). Likewise onset of poor sleep by 1981 increased the risk of disability retirement due to depression (OR=2.9, 95% CI: 1.8-4.9) with a similar risk among those with persistent poor sleep (OR=2.7, 95% CI: 1.3-5.7). LIMITATIONS: Lack of baseline diagnostic interviews; sleep quality based on self-report. CONCLUSIONS: Poor sleep is of importance in etiology of depression and disability retirement due to depression. This emphasizes the importance of early detection and treatment of sleep disturbances. PMID- 25451443 TI - The association of affective temperaments with smoking initiation and maintenance in adult primary care patients. AB - BACKGROUND: Smoking behaviour and its course is influenced by personality factors. Affective temperaments could allow a more specific framework of the role trait affectivity plays in this seriously harmful health-behaviour. The aim of our study was to investigate if such an association exists in an ageing population with a special emphasis on gender differences. METHODS: 459 primary care patients completed the TEMPS-A, Beck Depression Inventory (BDI) and Hamilton Anxiety Rating Scale (HAM-A). Subjects were characterized according to their smoking behaviour as current, former or never smokers. Univariate analysis ANOVA and logistic regression were performed to analyse differences in the three smoking subgroups to predict smoking initiation and maintenance. RESULTS: Current smokers were younger and less educated than former or never smokers. Males were more likely to try tobacco during their lifetime and were more successful in cessation. Depressive, cyclothymic and irritable temperament scores showed significant differences between the three smoking subgroups. Irritable temperament was a predictor of smoking initiation in females whereas depressive temperament predicted smoking maintenance in males with a small, opposite effect of HAM-A scores independent of age, education, lifetime depression and BDI scores. Whereas smoking initiation was exclusively predicted by a higher BDI score in males, smoking maintenance was predicted by younger age and lower education in females. LIMITATIONS: The cross-sectional nature of the study design may lead to selective survival bias and hinder drawing causal relationships. CONCLUSIONS: Affective temperaments contribute to smoking initiation and maintenance independently of age, education, and depression. The significant contribution of depressive temperament in males and irritable temperament in females may highlight the role of gender-discordant temperaments in vulnerable subgroups. PMID- 25451444 TI - Serum triglycerides, but not cholesterol or leptin, are decreased in suicide attempters with mood disorders. AB - BACKGROUND: Many peripheral biomarkers, including low cholesterol and its fractions, have been examined to identify suicidal behavior. Herein, we assessed serum lipid profile and some proteins putatively associated with suicidal behavior in subjects with mood disorder (bipolar disorder or major depressive disorder) with a recent suicide attempt and with no lifetime history of suicide attempts. METHODS: Fifty subjects had presented an episode of attempted suicide during the last 15 days, and 36 subjects had no history of any suicide attempt. We measured total cholesterol, HDL, LDL and triglycerides as well as serum leptin, brain-derived neurotrophic factor (BDNF), S100B and C-reactive protein (CRP). RESULTS: Individuals that had attempted suicide presented decreased body mass index (BMI) and waist circumference. After adjusting for these confounders, we found that triglycerides were decreased in attempted suicide subjects. We found no differences among total cholesterol, LDL, and HDL or leptin, S100B, CRP and BDNF. LIMITATIONS: This is a cross-sectional study, and we cannot therefore assess whether a decrease in triglycerides caused a mood episode with suicidal ideation that led to a suicide attempt or if the presence of a mood episode originated a loss of appetite and consequent loss of weight, therefore decreasing triglyceride levels. CONCLUSIONS: These results do not support the hypothesis that lower levels of cholesterol are associated with suicidal behavior in a mood disorder sample. However, our data support the idea that adiposity is differentiated in these patients (reduced BMI, waist circumference and serum triglycerides), which could lead to an altered communication between the adipose tissue and brain. PMID- 25451442 TI - Depression, anxiety and stress among pregnant migraineurs in a pacific-northwest cohort. AB - BACKGROUND: The co-occurrence of migraine and unipolar psychiatric disorders has been well documented in non-pregnant populations, however little is known in pregnant populations. METHODS: A cohort of 1321 women was interviewed during the first trimester of pregnancy. At the time of interview lifetime migraine status was ascertained using International Classification of Headache Disorders diagnostic criteria (ICHD-II). Information regarding unipolar depression, anxiety and stress during pregnancy was collected using the Patient Health Questionnaire Depression Module-9 (PHQ-9), and the Depression Anxiety Stress Scales 21-item Short Form (DASS-21). Multivariable logistic regression procedures were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of migraine and mood disorders during pregnancy. RESULTS: Approximately 28.2% (N=372) were classified as having a lifetime history of migraine; among migraineurs 122 were classified as migraineurs with aura and 250 as migraineurs without aura. Compared with non-migraineurs, migraineurs were associated with 1.60-fold increased odds of depression as measured by a PHQ-9 score >=10 (AOR=1.60; 95% CI: 1.12-2.31). Overall, migraine with aura was more strongly associated with depression than was migraine without aura. Migraineurs, as compared with non-migraineurs, also had higher odds of mood disorders as measured by the DASS-21. CONCLUSIONS: The comorbidity of mood and migraine disorders in pregnant populations supports the need for integrated mental and physical clinical evaluation, increased vigilance, and treatment of patients with such disorders. PMID- 25451445 TI - Unidirectionally affected causal connectivity of cortico-limbic-cerebellar circuit by structural deficits in drug-naive major depressive disorder. AB - BACKGROUND: Structural deficits and resting-state functional connectivity (FC) alterations in the cortico-limbic-cerebellar circuit have been implicated in the neurobiology of major depressive disorder (MDD). This study was conducted to examine the causal connectivity biased by structural deficits in MDD patients. METHODS: Resting-state functional magnetic resonance imaging data were acquired from 44 drug-naive MDD patients and 44 healthy controls. Granger causality analysis (GCA) was used to analyze the functional data. RESULTS: We previously observed two brain regions, the left angular gyrus (AG) and the right inferior temporal gyrus (ITG), with reduced gray matter volume (GMV), which were selected as seeds. Compared with healthy controls, the patients showed inhibitory effect from the left AG to the left superior temporal gyrus (STG) and the left inferior frontal gyrus (IFG, opercular part), and from the right ITG to bilateral cerebellum 6. In contrast, the right ITG exhibited excitatory effect to the right insula. However, no abnormal feedback effect was observed in patients. There was no significant correlation between abnormal causal effect and clinical variables, such as HRSD scores, illness duration, and episode number. CONCLUSIONS: Brain regions within the cortico-limbic-cerebellar circuit showed unidirectionally affected causal connectivities driven by structural deficits in MDD. The findings suggest that the causal topology of the cortico-limbic-cerebellar circuit may be disrupted unidirectionally by structural deficits in MDD. PMID- 25451446 TI - Diagnostic stability in pediatric bipolar disorder. AB - BACKGROUND: The diagnostic stability of pediatric bipolar disorder has not been investigated previously. The aim was to investigate the diagnostic stability of the ICD-10 diagnosis of pediatric mania/bipolar disorder. METHODS: All patients below 19 years of age who got a diagnosis of mania/bipolar disorder at least once in a period from 1994 to 2012 at psychiatric inpatient or outpatient contact in Denmark were identified in a nationwide register. RESULTS: Totally, 354 children and adolescents got a diagnosis of mania/bipolar disorder at least once; a minority, 144 patients (40.7%) got the diagnosis at the first contact whereas the remaining patients (210; 59.3%) got the diagnosis at later contacts before age 19. For the latter patients, the median time elapsed from first treatment contact with the psychiatric service system to the first diagnosis with a manic episode/bipolar disorder was nearly 1 year and for 25% of those patients it took more than 21/2 years before the diagnosis was made. The most prevalent other diagnoses than bipolar disorder at first contact were depressive disorder (21.4%), acute and transient psychotic disorders or other non-organic psychosis (19.2%), reaction to stress or adjustment disorder (14.8%) and behavioral and emotional disorders with onset during childhood or adolescents (10.9%). Prevalence rates of schizophrenia, personality disorders, anxiety disorder or hyperkinetic disorders (ADHD) were low. LIMITATIONS: Data concern patients who get contact to hospital psychiatry only. CONCLUSIONS: Clinicians should be more observant on manic symptoms in children and adolescents who at first glance present with transient psychosis, reaction to stress/adjustment disorder or with behavioral and emotional disorders with onset during childhood or adolescents (F90-98) and follow these patients more closely over time identifying putable hypomanic and manic symptoms as early as possible. PMID- 25451448 TI - Emotion regulation as a mediator in the relationship between attachment and depressive symptomatology: A systematic review. AB - BACKGROUND: Attachment theory has been conceptualised as an emotion regulation theory. Research attributes the occurrence of depressive symptoms to a dysfunction of emotion regulation. Anxious attachment and avoidant attachment, which are two dimensions of insecure attachment, are hypothesised to lead to the development of hyperactivating and deactivating emotion regulation strategies. METHODS: This systematic review examines the literature on the role of emotion regulation and its relationship with attachment and depressive symptomatology. Furthermore, we examined evidence for hyperactivating and deactivating strategies. RESULTS: Nineteen papers were identified. Adolescent studies demonstrated associations of varying strength and found unreliable and contradictory results for emotion regulation as a mediator. Conversely, adult studies provided strong evidence for emotion regulation as a mediator. The hypothesis that hyperactivating strategies mediate anxious attachment and depressive symptoms was consistently supported. Mixed evidence was provided for deactivating strategies as mediators to avoidant attachment and depressive symptomatology. LIMITATIONS: Limitations of methodology and quality of studies are identified with particular attention drawn to problems with conceptual singularity and multicollinearity. CONCLUSIONS: Despite mixed variable findings, this review indicates that emotion regulation is a mediator between attachment and depression. Hyperactivating strategies, in particular, have been consistently noted as mediators for anxious attachment and depressive symptomatology, whereas evidence for deactivating strategies as mediators between avoidant attachment and depressive symptoms has been mixed. Future research should test the mediators of attachment and symptoms and examine theoretically grounded models of psychopathology, such as metacognitive and cognitive models using clinical samples. PMID- 25451447 TI - Soft drink consumption is associated with depressive symptoms among adults in China. AB - BACKGROUND: Research evidence supports a positive link between soft drinks and depressive symptoms. However, data thus far are only from Caucasian populations. We investigated whether high levels of consumption of soft drinks were associated with the depressive symptoms among adults in China. METHODS: A cross-sectional survey was conducted with 3667 adults in Tianjin, China. Dietary intake was assessed using a valid self-administered food frequency questionnaire, and depressive symptoms were assessed with the Zung Self-Rating Depression Scale (SDS), cut-off point of 40, 45 or 50 indicating elevated depressive symptoms. RESULTS: The prevalence of elevated depressive symptoms was 7.6% (SDS >=50). After adjustments for potentially confounding factors, the odds ratios (95% confidence interval) of having elevated depressive symptoms by increasing levels of soft drink consumption were 1.00, 1.43 (1.01, 2.01) and 2.00 (1.15, 3.37) (p for trend <0.01). Similar relations were observed when SDS >=40 or 45 were used as a definition of depressive symptoms. LIMITATION: This is a cross-sectional study, causal relation remains unknown. CONCLUSION: Our results suggested that high consumption of soft drinks was significantly related to a higher prevalence of depressive symptoms among adults in China. This is the first large cross sectional study addressing this topic in an Asia population. PMID- 25451449 TI - Auditory selective attention in adolescents with major depression: An event related potential study. AB - BACKGROUND: Major depression (MD) is associated with deficits in selective attention. Previous studies in adults with MD using event-related potentials (ERPs) reported abnormalities in the neurophysiological correlates of auditory selective attention. However, it is yet unclear whether these findings can be generalized to MD in adolescence. Thus, the aim of the present ERP study was to explore the neural mechanisms of auditory selective attention in adolescents with MD. METHODS: 24 male and female unmedicated adolescents with MD and 21 control subjects were included in the study. ERPs were collected during an auditory oddball paradigm. RESULTS: Depressive adolescents tended to show a longer N100 latency to target and non-target tones. Moreover, MD subjects showed a prolonged latency of the P200 component to targets. Across groups, longer P200 latency was associated with a decreased tendency of disinhibited behavior as assessed by a behavioral questionnaire. LIMITATIONS: To be able to draw more precise conclusions about differences between the neural bases of selective attention in adolescents vs. adults with MD, future studies should include both age groups and apply the same experimental setting across all subjects. CONCLUSIONS: The study provides strong support for abnormalities in the neurophysiolgical bases of selective attention in adolecents with MD at early stages of auditory information processing. Absent group differences in later ERP components reflecting voluntary attentional processes stand in contrast to results reported in adults with MD and may suggest that adolescents with MD possess mechanisms to compensate for abnormalities in the early stages of selective attention. PMID- 25451451 TI - Diagnostic accuracy and adequacy of treatment of depressive and anxiety disorders: A comparison of primary care and specialized care patients. AB - BACKGROUND: Clinical diagnosis of depressive and anxiety disorders has poor sensitivity, and treatment is often not guideline-concordant. This longitudinal study aims to compare diagnostic validity and treatment adequacy in primary care (PC) and specialized care (SC), to assess associated risk factors, and to evaluate their impact on clinical outcome at one-month and three-month follow ups. METHODS: Two hundred twelve patients with depressive and anxious symptoms were recruited from 3 PC and 1 SC centers in Barcelona, Spain. Sensitivity and specificity were calculated comparing medical records' diagnoses with a reference (MINI interview). Adequate treatment was defined according to clinical guidelines. Logistic regression was used to estimate associations with risk factors. Impact on outcome was assessed with MANOVA models. RESULTS: Valid diagnosis of depression was more frequent in patients attending SC. Sensitivity for depression was 0.75 in SC and 0.49 in PC (adjusted OR=17.34, 95% CI=4.73 63.61). Detection of anxious comorbidity in depressed patients was low (50%) in SC. Treatment adequacy of depressive disorders was higher in SC than in PC (94.4% vs. 80.6%, adjusted OR=8.11, 95% CI=1.39-47.34). Depression severity was associated with valid diagnosis. LIMITATIONS: Only four disorders (major depression, dysthymia, panic disorder and generalized anxiety disorder) were evaluated with the MINI interview in a convenience clinical sample. Treatment dosage was unavailable. CONCLUSIONS: Our results suggest that GPs need tools to improve detection of depression and its severity. Psychiatrists should enhance recognition of anxious comorbidity. Evaluation of the impact on outcome deserves further research. PMID- 25451453 TI - Dihydromyricetin ameliorates the oxidative stress response induced by methylglyoxal via the AMPK/GLUT4 signaling pathway in PC12 cells. AB - Dihydromyricetin (DMY), the major bioactive flavonoid ingredient extracted from the leaves of Ampelopsis grossedentata (Hand.-Mazz) W.T. Wang, displays multiple pharmacological activities, including oxidation resistance, antitumor properties and free radical scavenging capacities. However, the role of DMY in methylglyoxal (MG)-induced diabetes-associated cognitive decline and its underlying molecular mechanisms are unclear. The aim of the present study was to evaluate the effects of DMY on oxidative stress and glucose transport activity in a MG-induced PC12 cell line and to explore the related mechanisms. The effects of DMY on cell survival and apoptosis were examined, and the dysregulation of intracellular Ca(2+) was determined. Oxidative stress was evaluated by monitoring ROS production and the glutathione to glutathione disulfide ratio. The effects of DMY on glucose metabolism were investigated using a fluorescently labeled deoxyglucose analog and by measuring ATP and lactate production. Western blot analysis was performed to examine the protein levels of glyoxalase I (Glo-1), glucose transporter 4 (GLUT4), AMP-activated protein kinase (AMPKalpha) and phosphorylated AMPKalpha (p-AMPKalpha). The results revealed that DMY suppressed cellular oxidative stress in PC12 cells and balanced glucose metabolism. Additionally, DMY reduced GLUT4 translocation dysfunction and increased Glo-1 and p-AMPKalpha expression. We found that DMY protected PC12 cells against MG-induced apoptosis and glycometabolic disorders, at least in part by restraining the hyperactivation of p-AMPK activity and normalizing the translocation of GLUT4 from the intracellular compartment, resulting in a balance in glucose uptake. This result indicates that DMY may serve as a novel and effective candidate agent to treat diabetic encephalopathy by reducing the toxicity of MG. PMID- 25451452 TI - Association of COMT and TPH-2 genes with DSM-5 based PTSD symptoms. AB - BACKGROUND: Dopaminergic and serotonergic systems have been implicated in PTSD. The present study evaluated the association of four catechol-O-methyltransferase (COMT) gene loci, and the joint effect of COMT and tryptophan hydroxylase 2 (TPH2) genes on PTSD symptoms. METHODS: Subjects included 200 Caucasian Armenian adults exposed to the 1988 Spitak earthquake from 12 multigenerational (3-5 generations) families. Instruments used included the UCLA PTSD Reaction Index based on DSM-5 criteria, and the Beck Depression Inventory. RESULTS: The adjusted heritabilitiy of vulnerability to DSM-5 based PTSD symptoms was 0.60 (p<10(-4)). There was a significant association of the COMT allele rs4633C with total PTSD (p<0.03), and D category (p<0.04) (negative alterations in cognitions and mood) severity scores, but not with C category (avoidance) scores. There was no genetic correlation between C and D category severity scores. COMT allele rs4633C and the TPH-2 allele rs11178997T together accounted for 7% of the variance in PTSD severity scores (p<0.001). None of the COMT alleles were associated with depression. LIMITATIONS: The ratings of earthquake exposure and prior trauma may have been subject to recall bias. The findings may not be generalizable to other ethnic/racial populations. CONCLUSION: COMT allele rs4633C may be causally related and/or is in linkage disequilibrium with gene(s) that are causally related to PTSD symptoms. Carriers of these COMT and the TPH-2 alleles may be at increased risk for PTSD. The findings provide biological support for dividing DSM IV category C symptoms into DSM-5 categories C and D. PMID- 25451454 TI - Anisomycin administered in the olfactory bulb and dorsal hippocampus impaired social recognition memory consolidation in different time-points. AB - To identify an individual as familiar, rodents form a specific type of memory named social recognition memory. The olfactory bulb (OB) is an important structure for social recognition memory, while the hippocampus recruitment is still controversial. The present study was designed to elucidate the OB and the dorsal hippocampus contribution to the consolidation of social memory. For that purpose, we tested the effect of anisomycin (ANI), which one of the effects is the inhibition of protein synthesis, on the consolidation of social recognition memory. Swiss adult mice with cannulae implanted into the CA1 region of the dorsal hippocampus or into the OB were exposed to a juvenile during 5 min (training session; TR), and once again 1.5 h or 24 h later to test social short term memory (S-STM) or social long-term memory (S-LTM), respectively. To study S LTM consolidation, mice received intra-OB or intra-CA1 infusion of saline or ANI immediately, 3, 6 or 18 h after TR. ANI impaired S-LTM consolidation in the OB, when administered immediately or 6h after TR. In the dorsal hippocampus, ANI was amnesic only if administered 3 h after TR. Furthermore, the infusion of ANI in either OB or CA1, immediately after training, did not affect S-STM. Moreover, ANI administered into the OB did not alter the animal's performance in the buried food-finding task. Altogether, our results suggest the consolidation of S-LTM requires both OB and hippocampus participation, although in different time points. This study may help shedding light on the specific roles of the OB and dorsal hippocampus in social recognition memory. PMID- 25451455 TI - Molecular pathways of mitochondrial dysfunctions: possible cause of cell death in anesthesia-induced developmental neurotoxicity. AB - The effect of anesthesia on the developing brain has attracted more attention and arguments. This review summarizes various studies on developmental neurotoxicity induced by anesthesia, particularly focuses on the function of the mitochondrial dysfunction. Experimental results present evidence that general anesthesia can cause mitochondrial dysfunction via complex pathways, including oxidative stress, electron transport chain dysfunction, mitochondrial dynamics, calcium homeostasis, and mitochondrion-dependent apoptotic pathway. Hence, the molecular processes of mitochondrial dysfunction should be understood to develop novel therapeutic strategies that can prevent anesthesia-induced neurotoxicity and provide neuroprotection against developmental central nervous system. PMID- 25451456 TI - Automated counting of bacterial colonies by image analysis. AB - Research on microorganisms often involves culturing as a means to determine the survival and proliferation of bacteria. The number of colonies in a culture is counted to calculate the concentration of bacteria in the original broth; however, manual counting can be time-consuming and imprecise. To save time and prevent inconsistencies, this study proposes a fully automated counting system using image processing methods. To accurately estimate the number of viable bacteria in a known volume of suspension, colonies distributing over the whole surface area of a plate, including the central and rim areas of a Petri dish are taken into account. The performance of the proposed system is compared with verified manual counts, as well as with two freely available counting software programs. Comparisons show that the proposed system is an effective method with excellent accuracy with mean value of absolute percentage error of 3.37%. A user friendly graphical user interface is also developed and freely available for download, providing researchers in biomedicine with a more convenient instrument for the enumeration of bacterial colonies. PMID- 25451458 TI - Construction of an efficient RNAi system in the cellulolytic fungus Trichoderma reesei. AB - An improved RNA interference method was developed in Trichoderma reesei, using convergent dual promoters for efficient and high-throughput RNA silencing. This new vector allowed for the silencing of the eGFP gene and target genes to occur simultaneously, significantly facilitating the rapid screening of the transformants using eGFP as a reporter. PMID- 25451457 TI - Identification of whole pathogenic cells by monoclonal antibodies generated against a specific peptide from an immunogenic cell wall protein. AB - We selected the immunogenic cell wall beta-(1,3)-glucosyltransferase Bgl2p from Candida albicans as a target protein for the production of antibodies. We identified a unique peptide sequence in the protein and generated monoclonal anti C. albicans Bgl2p antibodies, which bound in particular to whole C. albicans cells. PMID- 25451450 TI - Genome wide association study identifies variants in NBEA associated with migraine in bipolar disorder. AB - BACKGROUND: Migraine is a common comorbidity among individuals with bipolar disorder, but the underlying mechanisms for this co-occurrence are poorly understood. The aim of this study was to investigate the genetic background of bipolar patients with and without migraine. METHODS: We performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS). RESULTS: We identified one genome-wide significant association between migraine in bipolar disorder patients and rs1160720, an intronic single nucleotide polymorphism (SNP) in the NBEA gene (P=2.97 * 10(-8), OR: 1.82, 95% CI: 1.47-2.25), although this was not replicated in a smaller sample of 289 migraine cases. LIMITATIONS: Our study is based on self-reported migraine. CONCLUSIONS: NBEA encodes neurobeachin, a scaffolding protein primarily expressed in the brain and involved in trafficking of vesicles containing neurotransmitter receptors. This locus has not previously been implicated in migraine per se. We found no evidence of association in data from the GWAS migraine meta-analysis consortium (n=118,710 participants) suggesting that the association might be specific to migraine co-morbid with bipolar disorder. PMID- 25451459 TI - Development of a replicative plasmid for gene expression in Mycoplasma bovis. AB - Mycoplasma bovis (M. bovis) is a pathogen related to a variety of disease syndromes that result in significant economic losses in the cattle industry. Here, a stable replicative plasmid system is developed for use in M. bovis, utilizing an origin of replication (oriC) region. Additionally, the heterologous protein beta-galactosidase and a FLAG tag-fused endogenous protein were successfully expressed by this plasmid system. These findings provide evidence that this oriC-based vector is applicable for the study of M. bovis. PMID- 25451460 TI - A novel universal DNA labeling and amplification system for rapid microarray based detection of 117 antibiotic resistance genes in Gram-positive bacteria. AB - A rapid and simple DNA labeling system has been developed for disposable microarrays and has been validated for the detection of 117 antibiotic resistance genes abundant in Gram-positive bacteria. The DNA was fragmented and amplified using phi-29 polymerase and random primers with linkers. Labeling and further amplification were then performed by classic PCR amplification using biotinylated primers specific for the linkers. The microarray developed by Perreten et al. (Perreten, V., Vorlet-Fawer, L., Slickers, P., Ehricht, R., Kuhnert, P., Frey, J., 2005. Microarray-based detection of 90 antibiotic resistance genes of gram positive bacteria. J.Clin.Microbiol. 43, 2291-2302.) was improved by additional oligonucleotides. A total of 244 oligonucleotides (26 to 37 nucleotide length and with similar melting temperatures) were spotted on the microarray, including genes conferring resistance to clinically important antibiotic classes like beta lactams, macrolides, aminoglycosides, glycopeptides and tetracyclines. Each antibiotic resistance gene is represented by at least 2 oligonucleotides designed from consensus sequences of gene families. The specificity of the oligonucleotides and the quality of the amplification and labeling were verified by analysis of a collection of 65 strains belonging to 24 species. Association between genotype and phenotype was verified for 6 antibiotics using 77 Staphylococcus strains belonging to different species and revealed 95% test specificity and a 93% predictive value of a positive test. The DNA labeling and amplification is independent of the species and of the target genes and could be used for different types of microarrays. This system has also the advantage to detect several genes within one bacterium at once, like in Staphylococcus aureus strain BM3318, in which up to 15 genes were detected. This new microarray-based detection system offers a large potential for applications in clinical diagnostic, basic research, food safety and surveillance programs for antimicrobial resistance. PMID- 25451461 TI - Evaluation of a simple phenotypic method for the detection of carbapenemase producing Enterobacteriaceae. AB - We investigated the performance of a phenotypic test, the Carbapenemase Detection Set (MAST-CDS), for the identification of carbapenemase-producing Enterobacteriaceae. Our results indicated that MAST-CDS is rapid, easily performed, simple to interpret, and highly sensitive for the identification of carbapenemase producers, particularly imipenemase producers. PMID- 25451462 TI - I-SceI-mediated scarless gene modification via allelic exchange in Clostridium. AB - Although gene disruption in Clostridium spp. with the TargeTron technology is much more effective than single-crossover integration, it cannot achieve gene modification via allelic exchange. Here, we developed a targeted, nonpolar, scarless gene modification system based on the I-SceI endonuclease. First, a replicative plasmid containing homology arms on either side of the target sequence and I-SceI recognition sites was integrated into the Clostridium chromosome, resulting in single-crossover integrants containing a mutant allele. Second, the cells were transformed with plasmids containing the synthetic gene (sceC) encoding the I-SceI enzyme, resulting in double-stranded breaks at the I SceI recognition sites, which stimulated homologous recombination and yielded double-crossover mutants. Application of the method was demonstrated by deleting two genes (adc and glcG) from C. acetobutylicum ATCC 824 and one gene (adc) from C. beijerinckii NCIMB 8052, and by introducing point mutations into xylR of C. beijerinckii NCIMB 8052. The double-crossover mutants displayed similar fermentation phenotypes to those constructed with the TargeTron technology. PMID- 25451463 TI - Branched terthiophenes in organic electronics: from small molecules to polymers. AB - A zoo of chemical structures is accessible when the branched unit 2,2':3',2" terthiophene (3T) is included both in structurally well-defined small molecules and polymer-like architectures. The first part of this review article highlights literature on all-thiophene based branched oligomers including dendrimers as well as combinations of 3T-units with functional moieties for light-harvesting systems. Motivated by the perfectly branched macromolecular dendrimers both electropolymerization as well as chemical approaches are presented as methods for the preparation of branched polythiophenes with different branching densities. Structure-function relationships between the molecular architecture and optical and electronic properties are discussed throughout the article. PMID- 25451464 TI - The temporomandibular joint of California sea lions (Zalophus californianus): part 1 - characterisation in health and disease. AB - OBJECTIVES: This study aimed to characterise the histologic, biomechanical and biochemical properties of the temporomandibular joint (TMJ) of California sea lions. In addition, we sought to identify structure-function relationships and to characterise TMJ lesions found in this species. DESIGN: Temporomandibular joints from fresh cadaver heads (n=14) of California sea lions acquired from strandings were examined macroscopically and microscopically. The specimens were also evaluated for their mechanical and biochemical properties. Furthermore, if TMJ arthritic changes were present, joint characteristics were described and compared to healthy joints. RESULTS: Five male and 9 female specimens demonstrated macroscopically normal fibrocartilaginous articular surfaces and fibrous discs in the TMJ. Out of the 9 female specimens, 4 specimens had TMJ lesions were seen either in the articular surface or the disc. Histologically, these pathologic specimens demonstrated subchondral bone defects, cartilage irregularities and inflammatory cell infiltrates. The normal TMJ discs did not exhibit significant direction dependence in tensile stiffness or strength in the rostrocaudal direction compared with the mediolateral direction among normal discs or discs from affected joints. The TMJ discs were not found to be anisotropic in tensile properties. This feature was further supported by randomly oriented collagen fibres as seen by electron microscopy. Furthermore, no significant differences were detected in biochemical composition of the discs dependent upon population. CONCLUSION: The TMJ and its disc of the California sea lion exhibit similarities but also differences compared to other mammals with regards to structure-function relationships. A fibrous TMJ disc rich in collagen with minimal glycosaminoglycan content was characterised, and random fibre organisation was associated with isotropic mechanical properties in the central region of the disc. PMID- 25451465 TI - The temporomandibular joint of California sea lions (Zalophus californianus): part 2-osteoarthritic changes. AB - OBJECTIVES: Following comprehensive characterization of the temporomandibular joint (TMJ) of the California sea lion, as well demonstrating that TMJ osteoarthritis (OA) occurs in this species, the objective of this part of the investigation was to describe the macroscopic osteologic findings associated with TMJ-OA in a large museum collection of skull specimens. DESIGN: Museum skull specimens (n=497) of California sea lions were examined macroscopically according to defined criteria for the presence, severity, location and characteristics of TMJ-OA. The specimens, acquired from strandings, varied in age from young adults to mature adults. RESULTS: Overall 63.5% of the specimens had findings consistent with TMJ-OA. Of these, 56.2% were from females 43.8% were from males. Moreover, 71.2% specimens were from mature adults and 28.8% from young adults. However, there was no significant association between age and sex with the presence or severity of TMJ-OA. The most prominent TMJ-OA changes were the presence of subchondral bone defects and abnormal porosity. The majority of the OA present at the mandibular head affected the entire articular surface. In contrast, the OA present on the mandibular fossa of the temporal bone was located primarily on the medial aspect (P<0.001). CONCLUSION: The incidence of TMJ-OA in California sea lions is high and varies in severity. Although the significance of the high incidence of this disease in the California sea lion remains elusive, the occurrence and severity of TMJ-OA detected in this study may play an important role in the species' morbidity and mortality. PMID- 25451467 TI - Progesterone and 17beta-estradiol regulate expression of nesfatin-1/NUCB2 in mouse pituitary gland. AB - Nesfatin-1 was first shown to be involved in the control of appetite and energy metabolism in the hypothalamus. Many recent reports have shown nesfatin-1 expression in various tissues including the pituitary gland, but its expression and regulation mechanisms in the pituitary gland are unclear. Therefore, first, we investigated the mRNA and protein expression of nesfatin-1 in the pituitary using qRT-PCR and Western blotting, respectively. Expression of NUCB2 mRNA and nesfatin-1 protein was higher in the pituitary gland than in other organs, and nesfatin-1 protein was localized in many cells in the anterior pituitary gland. Next, we investigated whether NUCB2 mRNA expression in the pituitary gland was regulated by sex steroid hormones secreted by the ovary. Mice were ovariectomized and injected with progesterone (P4) and 17beta-estradiol (E2). The expression of NUCB2 in the pituitary gland was dramatically decreased after ovariectomy and increased with injection of P4 and E2, respectively. The in vitro experiment to elucidate the direct effect of P4 and E2 on NUCB2 mRNA expression showed NUCB2 mRNA expression was significantly increased with E2 and decreased with P4 alone and P4 plus E2 in cultured pituitary tissue. The present study demonstrated that nesfatin-1/NUCB2 was highly expressed in the mouse pituitary and was regulated by P4 and E2. These data suggest that reproductive-endocrine regulation through hypothalamus-pituitary-ovary axis may contribute to nesfatin-1/NUCB2 expression in the pituitary gland. PMID- 25451466 TI - The effect of exogenous oxytocin on streptozotocin (STZ)-induced diabetic adult rat testes. AB - Oxytocin (OXY) plays a crucial role in reproduction. The aim of this study is to investigate the therapeutic and protective effects of oxytocin treatment on streptozotocin (STZ) induced diabetes in testicular tissue. The rats were randomly divided into four experimental groups: (I) Control Group, (II) STZ induced Diabetic Group (STZ Group), (III) STZ induced Diabetic Group with Pre Oxytocin treatment (Pre-OXY Group) and (IV) STZ induced Diabetic Group with Post Oxytocin treatment (Post-OXY Group); each group contains six animals. The rats whose blood glucose levels were more than 200mg/dl were included to the experiment. At the end of the 4th week, testes tissue samples were taken to be processed for light microscopy and transmission electron microscopy. Malondialdehyde (MDA), Glutathione (GSH) and Advanced Oxidation Protein Products (AOPP) levels were determined biochemically in blood samples. Testicular tissue samples stained with Hematoxylin and Eosin (H&E) and Periodic acid-Schiff (PAS) reaction were evaluated under light microscope. The histopathological damage score of testicular tissue, which was significantly increased in STZ group, was decreased by oxytocin treatment. According to biochemical data, MDA and AOPP levels have been increased in the blood of STZ Group compared to the Control Group whereas they decreased significantly in Oxytocin-treated Groups compared to STZ Group. GSH levels were significantly decreased in the blood of STZ Group and increased in the blood of Oxytocin-treated Groups compared to STZ Group. In conclusion, oxytocin has a potential protective effect on the testes tissue of STZ-induced diabetic rats. PMID- 25451468 TI - Blood-brain transfer and antinociception of linear and cyclic N-methyl-guanidine and thiourea-enkephalins. AB - Enkephalins are active in regulation of nociception in the body and are key in development of new synthetic peptide analogs that target centrally located opioid receptors. In this study, we investigated the in vivo blood-brain barrier (BBB) penetration behavior and antinociceptive activity of two cyclic enkephalin analogs with a thiourea (CycS) or a N-methyl-guanidine bridge (CycNMe), and their linear counterparts (LinS and LinNMe) in mice, as well as their in vitro metabolic stability. (125)I-LinS had the highest blood-brain clearance (K1=3.46MUL/gmin), followed by (125)I-LinNMe, (125)I-CycNMe, and (125)I-CycS (K1=1.64, 0.31, and 0.11MUL/gmin, respectively). Also, these peptides had a high metabolic stability (t1/2>1h) in mouse serum and brain homogenate, and half inhibition constant (Ki) values in the nanomolar range with predominantly MU opioid receptor selectivity. The positively charged NMe-enkephalins showed a higher antinociceptive activity (LinNMe: 298% and CycNMe: 205%), expressed as molar-dose normalized area under the curve (AUC) relative to morphine, than the neutral S-enkephalins (CycS: 122% and LinS: 130%). PMID- 25451470 TI - Self-feeding MUSE: a robust method for high resolution diffusion imaging using interleaved EPI. AB - Single-shot echo planar imaging (EPI) with parallel imaging techniques has been well established as the most popular method for clinical diffusion imaging, due to its fast acquisition and motion insensitivity. However, this approach is limited by the relatively low spatial resolution and image distortion. Interleaved EPI is able to break the limitations but the phase variations among different shots must be considered for artifact suppression. The introduction of multiplexed sensitivity-encoding (MUSE) can address the phase issue using sensitivity encoding (SENSE) for self-navigation of each interleave. However, MUSE has suboptimal results when the number of shots is high. To achieve higher spatial resolution and lower geometric distortion, we introduce two new schemes into the MUSE framework: 1) a self-feeding mechanism is adopted by using prior information regularized SENSE in order to obtain reliable phase estimation; and 2) retrospective motion detection and data rejection strategies are performed to exclude unusable data corrupted by severe pulsatile motions. The proposed method is named self-feeding MUSE (SF-MUSE). Experiments on healthy volunteers demonstrate that this new SF-MUSE approach provides more accurate motion-induced phase estimation and fewer artifacts caused by data corruption when compared with the original MUSE method. SF-MUSE is a robust method for high resolution diffusion imaging and suitable for practical applications with reasonable scan time. PMID- 25451471 TI - Pharyngeal electrical stimulation can modulate swallowing in cortical processing and behavior - magnetoencephalographic evidence. AB - BACKGROUND: The act of swallowing is a complex neuromuscular function that is processed in a distributed network involving cortical, subcortical and brainstem structures. Difficulty in swallowing arises from a variety of neurologic diseases for which therapeutic options are currently limited. Pharyngeal electrical stimulation (PES) is a novel intervention designed to promote plastic changes in the pharyngeal motor cortex to aid dysphagia rehabilitation. In the present study we evaluate the effect of PES on cortical swallowing network activity and associated changes in swallowing performance. METHODS: In a randomized, crossover study design 10min of real (0.2-ms pulses, 5Hz, 280V, stimulation intensity at 75% of maximum tolerated threshold) or sham PES were delivered to 14 healthy volunteers in two separate sessions. Stimulation was delivered via a pair of bipolar ring electrodes mounted on an intraluminal catheter positioned in the pharynx. Before and after each intervention swallowing capacity (ml/s) was tested using a 150ml-water swallowing stress test. Event-related desynchronization (ERD) of cortical oscillatory activity during volitional swallowing was recorded applying whole-head magnetoencephalography before, immediately after and 45min past the intervention. RESULTS: A prominent reduction of ERD in sensorimotor brain areas occurred in the alpha and beta frequency ranges immediately after real PES but not after sham stimulation (p<0.05) and had faded after 45min. Volume per swallow and swallowing capacity significantly increased following real stimulation only. CONCLUSION: Attenuation of ERD following PES reflects stimulation-induced increased swallowing processing efficiency, which is associated with subtle changes in swallowing function in healthy subjects. Our data contribute evidence that swallowing network organization and behavior can effectively be modulated by PES. PMID- 25451472 TI - The minimum spanning tree: an unbiased method for brain network analysis. AB - The brain is increasingly studied with graph theoretical approaches, which can be used to characterize network topology. However, studies on brain networks have reported contradictory findings, and do not easily converge to a clear concept of the structural and functional network organization of the brain. It has recently been suggested that the minimum spanning tree (MST) may help to increase comparability between studies. The MST is an acyclic sub-network that connects all nodes and may solve several methodological limitations of previous work, such as sensitivity to alterations in connection strength (for weighted networks) or link density (for unweighted networks), which may occur concomitantly with alterations in network topology under empirical conditions. If analysis of MSTs avoids these methodological limitations, understanding the relationship between MST characteristics and conventional network measures is crucial for interpreting MST brain network studies. Here, we firstly demonstrated that the MST is insensitive to alterations in connection strength or link density. We then explored the behavior of MST and conventional network-characteristics for simulated regular and scale-free networks that were gradually rewired to random networks. Surprisingly, although most connections are discarded during construction of the MST, MST characteristics were equally sensitive to alterations in network topology as the conventional graph theoretical measures. The MST characteristics diameter and leaf fraction were very strongly related to changes in the characteristic path length when the network changed from a regular to a random configuration. Similarly, MST degree, diameter, and leaf fraction were very strongly related to the degree of scale-free networks that were rewired to random networks. Analysis of the MST is especially suitable for the comparison of brain networks, as it avoids methodological biases. Even though the MST does not utilize all the connections in the network, it still provides a, mathematically defined and unbiased, sub-network with characteristics that can provide similar information about network topology as conventional graph measures. PMID- 25451469 TI - Automated segmentation of multifocal basal ganglia T2*-weighted MRI hypointensities. AB - Multifocal basal ganglia T2*-weighted (T2*w) hypointensities, which are believed to arise mainly from vascular mineralization, were recently proposed as a novel MRI biomarker for small vessel disease and ageing. These T2*w hypointensities are typically segmented semi-automatically, which is time consuming, associated with a high intra-rater variability and low inter-rater agreement. To address these limitations, we developed a fully automated, unsupervised segmentation method for basal ganglia T2*w hypointensities. This method requires conventional, co registered T2*w and T1-weighted (T1w) volumes, as well as region-of-interest (ROI) masks for the basal ganglia and adjacent internal capsule generated automatically from T1w MRI. The basal ganglia T2*w hypointensities were then segmented with thresholds derived with an adaptive outlier detection method from respective bivariate T2*w/T1w intensity distributions in each ROI. Artefacts were reduced by filtering connected components in the initial masks based on their standardised T2*w intensity variance. The segmentation method was validated using a custom-built phantom containing mineral deposit models, i.e. gel beads doped with 3 different contrast agents in 7 different concentrations, as well as with MRI data from 98 community-dwelling older subjects in their seventies with a wide range of basal ganglia T2*w hypointensities. The method produced basal ganglia T2*w hypointensity masks that were in substantial volumetric and spatial agreement with those generated by an experienced rater (Jaccard index = 0.62 +/- 0.40). These promising results suggest that this method may have use in automatic segmentation of basal ganglia T2*w hypointensities in studies of small vessel disease and ageing. PMID- 25451473 TI - A stochastic model for EEG microstate sequence analysis. AB - The analysis of spontaneous resting state neuronal activity is assumed to give insight into the brain function. One noninvasive technique to study resting state activity is electroencephalography (EEG) with a subsequent microstate analysis. This technique reduces the recorded EEG signal to a sequence of prototypical topographical maps, which is hypothesized to capture important spatio-temporal properties of the signal. In a statistical EEG microstate analysis of healthy subjects in wakefulness and three stages of sleep, we observed a simple structure in the microstate transition matrix. It can be described with a first order Markov chain in which the transition probability from the current state (i.e., map) to a different map does not depend on the current map. The resulting transition matrix shows a high agreement with the observed transition matrix, requiring only about 2% of mass transport (1/2 L1-distance). In the second part, we introduce an extended framework in which the simple Markov chain is used to make inferences on a potential underlying time continuous process. This process cannot be directly observed and is therefore usually estimated from discrete sampling points of the EEG signal given by the local maxima of the global field power. Therefore, we propose a simple stochastic model called sampled marked intervals (SMI) model that relates the observed sequence of microstates to an assumed underlying process of background intervals and thus, complements approaches that focus on the analysis of observable microstate sequences. PMID- 25451474 TI - Creating external reminders for delayed intentions: dissociable influence on "task-positive" and "task-negative" brain networks. AB - Studies of prospective memory and other paradigms requiring participants to remember delayed intentions typically reveal a distinction between lateral and medial rostral prefrontal cortex, whereby the experimental condition yields increased signal in the former region and decreased signal in the latter. These regions comprise nodes of larger "task-positive" and "task-negative" networks that often show opposite patterns of signal change in response to diverse cognitive demands. However, it is not clear to what extent activity in these networks is A) inverse but equivalent, or B) functionally dissociable. In order to address this question, participants performed an "intention-offloading" task while undergoing fMRI. On each trial they remembered a delayed intention, which they had the opportunity to fulfill after a brief filled delay. In one condition they were required to set an external reminder of this intention, while in the other they acted without any external memory aid. Results indicated a clear functional dissociation between the two networks. Compared with a control task with no delayed intention, there was a highly significant reduction in task negative deactivation when participants used an external memory aid. However, there was no reduction in task-positive activation. These results are consistent with previous evidence that medial rostral prefrontal cortex plays a prominent role in representing the content of delayed intentions, accompanied by a reduction in BOLD signal and potentially increased theta-band oscillatory activity. This role is no longer required once an external reminder has been created. By contrast, lateral rostral prefrontal cortex may play a content-free role, unaffected by the offloading of content into the external environment. PMID- 25451476 TI - Non-invasive single-trial EEG detection of evoked human neocortical population spikes. AB - QUESTION: Human high-frequency (>400 Hz) components of somatosensory evoked potentials (hf-SEPs), which can be recorded non-invasively at the scalp, are generated by cortical population spikes, as inferred from microelectrode recordings in non-human primates. It is a critical limitation to broader neurophysiological study of hf-SEPs in that hundreds of responses have to be averaged to detect hf-SEPs reliably. Here, we establish a framework for detecting human hf-SEPs non-invasively in single trials. METHODS: Spatio-temporal features were extracted from band-pass filtered (400-900 Hz) hf-SEPs by bilinear Common Spatio-Temporal Patterns (bCSTP) and then classified by a weighted Extreme Learning Machine (w-ELM). The effect of varying signal-to-noise ratio (SNR), number of trials, and degree of w-ELM re-weighting was characterized using surrogate data. For practical demonstration of the algorithm, median nerve hf SEPs were recorded inside a shielded room in four subjects, spanning the hf-SEP signal-to-noise ratio characteristic for a larger population, utilizing a custom built 29-channel low-noise EEG amplifier. RESULTS: Using surrogate data, the SNR proved to be pivotal to detect hf-SEPs in single trials efficiently, with the trade-off between sensitivity and specificity of the algorithm being obtained by the w-ELM re-weighting parameter. In practice, human hf-SEPs were detected non invasively in single trials with a sensitivity of up to 99% and a specificity of up to 97% in two subjects, even without any recourse to knowledge of stimulus timing. Matching with the results of the surrogate data analysis, these rates dropped to 62-79% sensitivity and 18-31% specificity in two subjects with lower SNR. CONCLUSIONS: Otherwise buried in background noise, human high-frequency EEG components can be extracted from low-noise recordings. Specifically, refined supervised filter optimization and classification enables the reliable detection of single-trial hf-SEPs, representing non-invasive correlates of cortical population spikes. SIGNIFICANCE: While low-frequency EEG reflects summed postsynaptic potentials, and thereby neuronal input, we suggest that high frequency EEG (>400 Hz) can provide non-invasive access to the unaveraged output of neuronal computation, i.e., single-trial population spike activity evoked in the responsive neuronal ensemble. PMID- 25451475 TI - Calibrating the BOLD response without administering gases: comparison of hypercapnia calibration with calibration using an asymmetric spin echo. AB - The calibrated BOLD (blood oxygen level dependent) technique was developed to quantify the BOLD signal in terms of changes in oxygen metabolism. In order to achieve this a calibration experiment must be performed, which typically requires a hypercapnic gas mixture to be administered to the participant. However, an emerging technique seeks to perform this calibration without administering gases using a refocussing based calibration. Whilst hypercapnia calibration seeks to emulate the physical removal of deoxyhaemoglobin from the blood, the aim of refocussing based calibration is to refocus the dephasing effect of deoxyhaemoglobin on the MR signal using a spin echo. However, it is not possible to refocus all of the effects that contribute to the BOLD signal and a scale factor is required to estimate the BOLD scaling parameter M. In this study the feasibility of a refocussing based calibration was investigated. The scale factor relating the refocussing calibration to M was predicted by simulations to be approximately linear and empirically measured to be 0.88+/-0.36 for the visual cortex and 0.93+/-0.32 for a grey matter region of interest (mean+/-standard deviation). Refocussing based calibration is a promising approach for greatly simplifying the calibrated BOLD methodology by eliminating the need for the subject to breathe special gas mixtures, and potentially provides the basis for a wider implementation of quantitative functional MRI. PMID- 25451477 TI - Memory function and hippocampal volumes in preterm born very-low-birth-weight (VLBW) young adults. AB - The hippocampi are regarded as core structures for learning and memory functions, which is important for daily functioning and educational achievements. Previous studies have linked reduction in hippocampal volume to working memory problems in very low birth weight (VLBW; <= 1500 g) children and reduced general cognitive ability in VLBW adolescents. However, the relationship between memory function and hippocampal volume has not been described in VLBW subjects reaching adulthood. The aim of the study was to investigate memory function and hippocampal volume in VLBW young adults, both in relation to perinatal risk factors and compared to term born controls, and to look for structure-function relationships. Using Wechsler Memory Scale-III and MRI, we included 42 non disabled VLBW and 61 control individuals at age 19-20 years, and related our findings to perinatal risk factors in the VLBW-group. The VLBW young adults achieved lower scores on several subtests of the Wechsler Memory Scale-III, resulting in lower results in the immediate memory indices (visual and auditory), the working memory index, and in the visual delayed and general memory delayed indices, but not in the auditory delayed and auditory recognition delayed indices. The VLBW group had smaller absolute and relative hippocampal volumes than the controls. In the VLBW group inferior memory function, especially for the working memory index, was related to smaller hippocampal volume, and both correlated with lower birth weight and more days in the neonatal intensive care unit (NICU). Our results may indicate a structural-functional relationship in the VLBW group due to aberrant hippocampal development and functioning after preterm birth. PMID- 25451478 TI - Duration of early adversity and structural brain development in post institutionalized adolescents. AB - For children reared in institutions for orphaned or abandoned children, multiple aspects of the early environment deviate from species-typical experiences, which may lead to alterations in neurobehavioral development. Although the effects of early deprivation and early life stress have been studied extensively in animal models, less is known about implications for human brain development. This structural neuroimaging study examined the long-term neural correlates of early adverse rearing environments in a large sample of 12-14 year old children (N = 110) who were internationally adopted from institutional care as young children (median age at adoption = 12 months) relative to a same age, comparison group reared with their biological families in the United States. History of institutional rearing was associated with broad changes in cortical volume even after controlling for variability in head size. Results suggested that prefrontal cortex was especially susceptible to early adversity, with significant reductions in volume (driven primarily by differences in surface area rather than cortical thickness) in post-institutionalized youth. Hippocampal volumes showed an association with duration of institutional care, with later-adopted children showing the smallest volumes relative to non-adopted controls. Larger amygdala volumes were not detected in this sample of post-institutionalized children. These data suggest that this temporally discrete period of early deprivation is associated with persisting alterations in brain morphology even years after exposure. Furthermore, these alterations are not completely ameliorated by subsequent environmental enrichment by early adolescence. PMID- 25451479 TI - Frequency-dependent functional neuromodulatory effects on the motor network by ventral lateral thalamic deep brain stimulation in swine. AB - Thalamic deep brain stimulation (DBS) is an FDA-approved neurosurgical treatment for medication-refractory essential tremor. Its therapeutic benefit is highly dependent upon stimulation frequency and voltage parameters. We investigated these stimulation parameter-dependent effects on neural network activation by performing functional magnetic resonance imaging (fMRI) during DBS of the ventral lateral (VL) thalamus and comparing the blood oxygenation level-dependent (BOLD) signals induced by multiple stimulation parameter combinations in a within subject study of swine. Low (10 Hz) and high (130 Hz) frequency stimulation was applied at 3, 5, and 7 V in the VL thalamus of normal swine (n = 5). We found that stimulation frequency and voltage combinations differentially modulated the brain network activity in the sensorimotor cortex, the basal ganglia, and the cerebellum in a parameter-dependent manner. Notably, in the motor cortex, high frequency stimulation generated a negative BOLD response, while low frequency stimulation increased the positive BOLD response. These frequency-dependent differential effects suggest that the VL thalamus is an exemplary target for investigating functional network connectivity associated with therapeutic DBS. PMID- 25451480 TI - A voxel-wise encoding model for early visual areas decodes mental images of remembered scenes. AB - Recent multi-voxel pattern classification (MVPC) studies have shown that in early visual cortex patterns of brain activity generated during mental imagery are similar to patterns of activity generated during perception. This finding implies that low-level visual features (e.g., space, spatial frequency, and orientation) are encoded during mental imagery. However, the specific hypothesis that low level visual features are encoded during mental imagery is difficult to directly test using MVPC. The difficulty is especially acute when considering the representation of complex, multi-object scenes that can evoke multiple sources of variation that are distinct from low-level visual features. Therefore, we used a voxel-wise modeling and decoding approach to directly test the hypothesis that low-level visual features are encoded in activity generated during mental imagery of complex scenes. Using fMRI measurements of cortical activity evoked by viewing photographs, we constructed voxel-wise encoding models of tuning to low-level visual features. We also measured activity as subjects imagined previously memorized works of art. We then used the encoding models to determine if putative low-level visual features encoded in this activity could pick out the imagined artwork from among thousands of other randomly selected images. We show that mental images can be accurately identified in this way; moreover, mental image identification accuracy depends upon the degree of tuning to low-level visual features in the voxels selected for decoding. These results directly confirm the hypothesis that low-level visual features are encoded during mental imagery of complex scenes. Our work also points to novel forms of brain-machine interaction: we provide a proof-of-concept demonstration of an internet image search guided by mental imagery. PMID- 25451481 TI - Improved image registration by sparse patch-based deformation estimation. AB - Despite intensive efforts for decades, deformable image registration is still a challenging problem due to the potential large anatomical differences across individual images, which limits the registration performance. Fortunately, this issue could be alleviated if a good initial deformation can be provided for the two images under registration, which are often termed as the moving subject and the fixed template, respectively. In this work, we present a novel patch-based initial deformation prediction framework for improving the performance of existing registration algorithms. Our main idea is to estimate the initial deformation between subject and template in a patch-wise fashion by using the sparse representation technique. We argue that two image patches should follow the same deformation toward the template image if their patch-wise appearance patterns are similar. To this end, our framework consists of two stages, i.e., the training stage and the application stage. In the training stage, we register all training images to the pre-selected template, such that the deformation of each training image with respect to the template is known. In the application stage, we apply the following four steps to efficiently calculate the initial deformation field for the new test subject: (1) We pick a small number of key points in the distinctive regions of the test subject; (2) for each key point, we extract a local patch and form a coupled appearance-deformation dictionary from training images where each dictionary atom consists of the image intensity patch as well as their respective local deformations; (3) a small set of training image patches in the coupled dictionary are selected to represent the image patch of each subject key point by sparse representation. Then, we can predict the initial deformation for each subject key point by propagating the pre-estimated deformations on the selected training patches with the same sparse representation coefficients; and (4) we employ thin-plate splines (TPS) to interpolate a dense initial deformation field by considering all key points as the control points. Thus, the conventional image registration problem becomes much easier in the sense that we only need to compute the remaining small deformation for completing the registration of the subject to the template. Experimental results on both simulated and real data show that the registration performance can be significantly improved after integrating our patch-based deformation prediction framework into the existing registration algorithms. PMID- 25451483 TI - Pulmonary rehabilitation during induction chemoradiotherapy for lung cancer improves pulmonary function. AB - OBJECTIVE: Chemoradiotherapy for non-small cell lung cancer can impair pulmonary function, particularly when it is followed by surgery. This study aimed to document the changes in respiratory function as a result of a perioperative intensive pulmonary rehabilitation program in patients with non-small cell lung cancer who underwent induction chemoradiotherapy. METHODS: A total of 82 consecutive patients underwent pulmonary resection after undergoing induction chemoradiotherapy. A pulmonary rehabilitation program was started at the same time as the induction chemoradiotherapy. Standard respiratory function tests were performed before and after induction chemoradiotherapy. Treatment-related mortality and the incidence of postoperative respiratory complications were investigated. The Wilcoxon signed-rank test was used to analyze the differences in spirometric changes. RESULTS: All patients underwent a pulmonary rehabilitation program for an average of 10 weeks. Significant increases were observed in forced vital capacity (+6.4%, P = .0096) and forced expiratory volume in 1 second (+10.4%, P < .0001). Diffusing capacity of the lung for carbon monoxide decreased (-14.0%, P < .0001). Patients with respiratory impairment (forced vital capacity <80% predicted or forced expiratory volume in 1 second/forced vital capacity <70%) showed significant improvements in forced vital capacity (+13.9%, P = .0025) and forced expiratory volume in 1 second (+22.5%, P < .0001). Significant increases were observed in forced vital capacity (+7.0%, P = .0042) and forced expiratory volume in 1 second (+10.8%, P = .0001) in patients with a smoking history. There was no mortality, and postoperative respiratory morbidity was 6.1%. CONCLUSIONS: A pulmonary rehabilitation program for patients with non-small cell lung cancer undergoing induction chemoradiotherapy seems to improve respiratory function. It is particularly recommended for smokers and patients with respiratory impairment. PMID- 25451482 TI - STAT6 silencing up-regulates cholesterol synthesis via miR-197/FOXJ2 axis and induces ER stress-mediated apoptosis in lung cancer cells. AB - MiRNAs and transcription factors have emerged as important regulators for gene expression and are known to regulate various biological processes, including cell proliferation, differentiation and apoptosis. Previously, using genome-wide expression profiling studies, we have shown an inverse relationship of STAT6 and cholesterol biosynthesis and also identified FOXJ2 binding sites in the upstream region of 3 key genes (HMGCR, HMGCS1 and IDI1) of the cholesterol synthesis pathway. Our previous study also provided clues toward the anti-apoptotic role played by STAT6. For better understanding of the cellular response and underlying signaling pathways activated by STAT6 silencing, we examined the changes in miRNome profile after the siRNA-mediated silencing of STAT6 gene in NCI-H460 cells using LNA-based miRNA microarray. Our analysis showed significant downregulation of miRNAs, let-7b and miR-197, out of which miR-197 was predicted to target FOXJ2. We here show that miR-197 not only negatively regulates FOXJ2 expression through direct binding to its respective binding site in its 3'UTR but also alters total cholesterol levels by regulating genes associated with cholesterol biosynthesis pathway. We further demonstrated that STAT6 silencing elicited ER stress-mediated apoptosis in NCI-H460 cells through C/EBP homologous protein (CHOP) induction, alteration of BH3 only proteins expression and ROS production. The apoptosis induced by STAT6 downregulation was partially reversed by NAC, the ROS scavenger. Based on the above findings, we suggest that ER stress plays a major role in STAT6-induced apoptosis. PMID- 25451484 TI - Aborted episode of sudden death due to delayed heart block after transcatheter aortic valve insertion. PMID- 25451485 TI - Contemporaneous comparison of the Yasui and Norwood procedures at a single institution. AB - OBJECTIVE: It is recognized that there are numerous anatomic variants that result in hypoplastic left heart physiology. One such variant includes critical aortic stenosis or atresia, a hypoplastic aortic arch, and a reasonably well-developed left ventricle due to the presence of a ventricular septal defect. These patients are candidates for 1 of 3 surgical options: (1) a Norwood procedure followed by a single-ventricle pathway; (2) a Norwood procedure followed by a Rastelli procedure (2-stage Yasui); or (3) a single-stage Yasui procedure. Because 2 of the 3 options include a Norwood procedure as the initial step, the purpose of this study was to evaluate the contemporaneous results of the Yasui and Norwood procedures at a single institution. METHODS: This was a retrospective review of patients who underwent a Yasui or Norwood procedure at Lucile Packard Children's Hospital between 2004 and 2013. Eighteen patients underwent a Yasui, of whom 15 had a single-stage procedure and 3 had a 2-stage procedure. During this time frame, 113 patients underwent a Norwood procedure. Kaplan-Meier survival curves and freedom from reoperation were compared for the 2 procedures. RESULTS: The operative mortality (using the Society of Thoracic Surgeons definition) for the single-stage Yasui was 6.7% compared with 16% for the Norwood procedure (P < .05); survival was 85% versus 62% at 1 year, 85% versus 60% at 3 years, and 85% versus 58% at 5 years, respectively (log-rank P = .06). The average interval to first reoperation was 13.5 +/- 3 months versus 4.5 +/- 1 months for the Yasui and Norwood procedures, respectively (P < .001). CONCLUSIONS: The Yasui procedure had a significantly lower operative mortality compared with the Norwood procedure. Early and midterm survival was also higher in the Yasui group versus the Norwood followed by a single ventricle pathway. These results indicate that the Yasui procedure has significant midterm benefits compared with the Norwood procedure and should be pursued when the anatomy is amenable for this approach. PMID- 25451486 TI - Minimal access rapid deployment aortic valve replacement: initial single-center experience and 12-month outcomes. AB - OBJECTIVES: A single-center observational study was initialized to evaluate the feasibility of rapid deployment aortic valve replacement using the Edwards Intuity valve system (Edwards Lifesciences Corp, Irvine, Calif) in a minimally invasive setting. A total of 60 implantations have been performed at the Ruhr University Hospital Bergmannsheil using a minimal access technique. We present the first short-term and 12-month clinical and hemodynamic results. METHODS: Aortic valve replacement using a partial sternotomy was performed in all patients. Patients' mean age was 75.5 (+/-6.2) years. The mean logistic European System for Cardiac Operative Risk Evaluation was 8.4 +/- 4.2, and 39% (n = 23) of patients were female. A clinical follow-up for echocardiographic assessment was performed after 12 months. RESULTS: The 30-day mortality rate was 1.7% (n = 1). The mean postoperative transprosthetic gradient was 11.7 (+/-4.3) mm Hg. The mean effective orifice area was 1.8 (+/-0.3) cm(2). One case of higher-grade regurgitation (aortic insufficiency >+1) occurred. The late mortality rate was 5.1% (3/59). After 12 months, the mean transprosthetic gradient was 10.3 (+/-3.8) mm Hg. The mean effective orifice area of 1.8 (+/-0.3) cm(2) remained unchanged. The mean implantation time was 9 (+/-3) minutes. The mean crossclamp time was 26 (+/-7) minutes. The average bypass time was 56 (+/-16) minutes. CONCLUSIONS: Reproducible short crossclamp and bypass times were achieved in a minimally invasive setting. The valve shows good hemodynamic performance comparable to other sutureless or rapid deployment valves. Nevertheless, future follow-up investigation has to be awaited to gain more data concerning durability and safety issues. PMID- 25451488 TI - Optimizing hepatic flow distribution with the Fontan Y-graft: lessons from computational simulations. PMID- 25451489 TI - "RESCUE me": Sweet music for patients with aortic transection. PMID- 25451487 TI - Implication of right ventricular dysfunction on long-term outcome in patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting with or without surgical ventricular reconstruction. AB - OBJECTIVE: Whether right ventricular dysfunction affects clinical outcome after coronary artery bypass grafting with or without surgical ventricular reconstruction is still unknown. The aim of the study was to assess the impact of right ventricular dysfunction on clinical outcome in patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting with or without surgical ventricular reconstruction. METHODS: Of 1000 patients in the Surgical Treatment for Ischemic Heart Failure with coronary artery disease, left ventricular ejection fraction 35% or less, and anterior dysfunction, who were randomized to undergo coronary artery bypass grafting or coronary artery bypass grafting + surgical ventricular reconstruction, baseline right ventricular function could be assessed by echocardiography in 866 patients. Patients were followed for a median of 48 months. All-cause mortality or cardiovascular hospitalization was the primary end point, and all-cause mortality alone was a secondary end point. RESULTS: Right ventricular dysfunction was mild in 102 patients (12%) and moderate or severe in 78 patients (9%). Moderate to severe right ventricular dysfunction was associated with a larger left ventricle, lower ejection fraction, more severe mitral regurgitation, higher filling pressure, and higher pulmonary artery systolic pressure (all P < .0001) compared with normal or mildly reduced right ventricular function. A significant interaction between right ventricular dysfunction and treatment allocation was observed. Patients with moderate or severe right ventricular dysfunction who received coronary artery bypass grafting + surgical ventricular reconstruction had significantly worse outcomes compared with patients who received coronary artery bypass grafting alone on both the primary (hazard ratio, 1.86; confidence interval, 1.06 3.26; P = .028) and the secondary (hazard ratio, 3.37; confidence interval, 1.36 8.37; P = .005) end points. After adjusting for all other prognostic clinical factors, the interaction remained significant with respect to all-cause mortality (P = .022). CONCLUSIONS: Adding surgical ventricular reconstruction to coronary artery bypass grafting may worsen long-term survival in patients with ischemic cardiomyopathy with moderate to severe right ventricular dysfunction, which reflects advanced left ventricular remodeling. PMID- 25451490 TI - Don't touch that aorta! PMID- 25451491 TI - Can patients with interstitial lung disease safely undergo pulmonary resection? PMID- 25451492 TI - Hybrid palliation for hypoplastic left heart syndrome: where do we stand now? PMID- 25451493 TI - Open thoracoabdominal aneurysm repair in octogenarians: is the enemy of good, perfect? PMID- 25451494 TI - Feel isolated? Bridging communication between host myocardium and skeletal myoblast grafts. PMID- 25451495 TI - "The times they are a-changin'". PMID- 25451496 TI - Fraser B. Gurd (1883-1948). PMID- 25451497 TI - Lung cancer survivors need lung cancer screening. PMID- 25451498 TI - Current status of cerebral protection for aortic arch surgery. PMID- 25451499 TI - Timing is even more important than we thought! The effect of gestational age versus body weight on outcomes of neonatal heart surgery. PMID- 25451500 TI - Palliative and corrective surgery in low-weight infants is associated with an increased mortality risk: how can we do better? PMID- 25451501 TI - Intraoperative pleural lavage cytology: more evidence on its prognostic and staging values. PMID- 25451502 TI - Surgical ventricular restoration, myocardial viability, and your mother's fine China. PMID- 25451503 TI - Is a 1% isolated coronary artery bypass grafting mortality really a valid goal? PMID- 25451504 TI - To cool or not to cool? PMID- 25451505 TI - Low-gradient severe aortic stenosis also benefits from aortic valve replacement. PMID- 25451506 TI - Belt and suspenders: can we keep them in the drawer? PMID- 25451507 TI - Endovascular repair for blunt thoracic aortic injury: a safe and durable procedure. PMID- 25451508 TI - To stent or stent-graft? It depends. PMID- 25451509 TI - Right here waiting...? PMID- 25451510 TI - A comparative analysis of behaviors and sexual affiliation networks among men who have sex with men in Hong Kong. AB - In Hong Kong, men who have sex with men (MSM) account for a significant proportion of HIV infections. While perceived as a hidden population, they constitute a distinct social network shaped by their differential use of unique channels for sex partnership. To characterize their pattern of connectivity and association with high-risk sexual behaviors, 311 MSM were recruited via saunas and the internet to participate in a questionnaire survey. Internet recruits were younger, and many (31/43) were solely reliant on the internet to seek sex partners, while visiting a similar number of venues as the sauna recruits (p = 0.98). Internet users generally had a high frequency of unprotected anal intercourse (UAI). MSM who had visited only a single venue reported more UAI with their regular partners (adjusted OR 6.86, 1.88-24.96) and sought fewer casual partners than those frequenting multiple venues (adjusted OR 0.33, 0.19-0.60). This study provides evidence for the heterogeneity of the sexual affiliation networks of MSM in Hong Kong. High HIV risk of UAI could be offset by fewer casual partners in certain venues, the implications of which would need to be explored in longitudinal studies. Methodologically, internet sampling was very efficient in identifying sex networking venues, while internet recruits gave a high retention rate for updating profiles. However, sampling at high centrality saunas did not necessarily identify the MSM-affiliating venues in the networks efficiently. The sampling strategy of MSM survey should therefore be objective driven, which may differ for health message dissemination and social marketing, versus HIV surveillance or risk assessment. PMID- 25451511 TI - Genetic determinants and dynamics of permanent teeth emergence in Northwest Indian twins: a chronogenetic study. AB - The understanding of the role of genetic factors in phenotypic variation in the emergence of secondary teeth in humans remains is incomplete. Dental emergence data based on a mixed longitudinal study were collected on 111 twin pairs from an urban population of Chandigarh. The observations over time on a single individual varied from one to nine, thus giving a total of 595 entities. Female twins manifested emergence priority over males. The differences between zygosities in mean emergence ages were significant for only 6 of 16 (37%) instances. Magnitude of variations seen between twins and singletons in their mean emergence timings and duration of the hiatus between two dental phases of emergence were of the order observed among different samples from the same population/ethnic group. Heritability estimates for the specified number of the teeth emerged showed age variations. These estimates were highest in the first two age groups (from 5 to 7 years), when the first molars and incisors emerged. Maxilla-mandible differences were seen for tooth emergence timings and sequence patterns. Heritability for tooth emergence timings was higher in maxilla than in mandible. Multifactorial model of inheritance was the best fit model to explain variations observed in dental emergence timings and dental sequence pattern polymorphisms and there were significant genetic components of variation for both of these. There were sex differences in heritability; females had higher estimates than males. Genetic factors accounted for about 60% of the total phenotypic variation in the length of hiatus interval between two active stages of permanent teeth emergence. PMID- 25451512 TI - Anthropometric variables, lifestyle and sports in school-age children: comparison between the cities of Bologna and Crotone. AB - Weight disorders are rapidly increasing in childhood. In Italy a strong geographic North-South gradient of overweight and obesity has been reported. The purpose of this study is to examine anthropometric variables, physical activity and lifestyles in school-age children in the cities of Bologna and Crotone. The sample consists of 963 children attending primary schools, aged 6-10 years. Height, weight, triceps, and subscapular skinfolds were measured for each child; body mass index (BMI) and percentage of fat mass were calculated. Physical activity was determined through an interview with each child. Another questionnaire was submitted to parents, in order to obtain information on sleep duration, means of transport and type of physical activity. In the city of Bologna, the mean values of anthropometric variables were: height (boys - 1,335 mm, girls - 1,332 mm), BMI (boys - 17.8 kg/m(2), girls - 17.3 kg/m(2)), and the proportion of overweight and obese individuals was: boys - 20.6%, girls - 12.7%. In Crotone the mean values were: height (boys - 1,275 mm, girls - 1,265 mm), BMI (boys - 19.4 kg/m(2), girls - 19.3 kg/m(2)), and the proportion of overweight and obese individuals was: boys - 46.7%, girls - 49.0%. The results have demonstrated significant correlations of lifestyle and physical activity with children's weight status. In Crotone there is a larger variation of weight disorders with higher percentages of overweight children than in Bologna. The children in Crotone are engaged in sedentary activities for a significantly longer time than children in Bologna, who are more physically active. The data show a strong North South gradient concerning not only distribution of weight status, but also lifestyles especially including participation in sports and sedentary behavior. Our study also provides meaningful suggestions how to define lifestyles in order to achieve an optimal health status during growth. PMID- 25451513 TI - Secular changes of pelvis in Croatian perinatal women. AB - The goal of the study was to examine secular changes of pelvic size in parturient women over the 25-year period from 1985 to 2009. Data were collected from randomly selected patients' medical records of 2414 parturient women from four time periods (1985-1986, 1992-1994, 2000-2002, and 2007-2009). Three different pelvic measurements were collected: distantia spinarum, distantia cristarum, and distantia trochanterica. Regression analyses were conducted in order to test predictors of pelvic dimensions. The multivariate analysis of covariance (MANCOVA) was used to test changes in pelvic dimensions over time, with body mass index (BMI) as a covariate. The average size of distantia spinarum, distantia cristarum, and distantia trochanterica was 249.3mm (SD=13.7), 277.9 mm (SD=15.6), and 318.3mm (SD=19.6), respectively. Pelvic dimensions were all positively related to woman's height and pre-pregnancy weight. After controlling for the BMI, there were significant changes in pelvic dimensions over the 25-year period and it was shown that distantia spinarum, cristarum, and trochanterica all increased (F [3,2408]=16.4, p<0.01), especially from the 1992-1994 period to the present. To conclude, parallel with secular changes of weight and height in parturient women, changes in bones are also evident. The size of pelvis in parturient women had significantly enlarged over the 25-year period. PMID- 25451514 TI - Association between ABO blood group and osteoporosis among postmenopausal women of North India. AB - The present study is an attempt to examine possible associations between ABO blood groups and the risk of osteoporosis among postmenopausal women of North India. This cross-sectional study involved 250 postmenopausal women from North India, ranging in age from 45 to 80 years. Four anthropometric measurements (height, weight, waist circumference and hip circumference), blood sample (ABO status and haemoglobin concentration) and grip strength (dominant as well as non dominant hand) of all the participants were taken. Bone mineral density (BMD) was evaluated by using dual energy X-ray absorptiometry (DXA) at lumbar spine (L1-L4) and proximal femur. Analysis of data revealed that at lumbar spine (L1-L4) osteoporosis was more prevalent among individuals with blood group A (31.58%), followed by those with blood group B (29.67%), AB (28.57%) and then blood group O (15%), whereas for proximal femur individuals with blood group AB (21.43%) showed the highest prevalence of osteoporosis followed by a decreasing trend from blood group A (17.54%) to B (12.08%) and then O (5%). Total prevalence of osteoporosis was 26.4% in lumbar spine and 13.2% in proximal femur, indicating that lumbar spine had an elevated risk for osteoporosis among postmenopausal women. All the anthropometric variables, haemoglobin concentration as well as grip strength of individuals with blood group O demonstrated non-significant differences with non O blood group except for weight and body mass index, where differences were statistically significant. Women with blood group O exhibited significantly higher bone mineral density for lumbar spine (0.90 g/cm(2) vs. 0.85 g/cm(2), p<0.05) and proximal femur (0.87 g/cm(2) vs. 0.79 g/cm(2), p<0.05) as compared to those with non-O blood group, thereby suggesting an increasing risk of osteoporosis among individuals with non-O blood group. PMID- 25451516 TI - Games of corruption: how to suppress illegal logging. AB - Corruption is one of the most serious obstacles for ecosystem management and biodiversity conservation. In particular, more than half of the loss of forested area in many tropical countries is due to illegal logging, with corruption implicated in a lack of enforcement. Here we study an evolutionary game model to analyze the illegal harvesting of forest trees, coupled with the corruption of rule enforcers. We consider several types of harvesters, who may or may not be committed towards supporting an enforcer service, and who may cooperate (log legally) or defect (log illegally). We also consider two types of rule enforcers, honest and corrupt: while honest enforcers fulfill their function, corrupt enforcers accept bribes from defecting harvesters and refrain from fining them. We report three key findings. First, in the absence of strategy exploration, the harvester-enforcer dynamics are bistable: one continuum of equilibria consists of defecting harvesters and a low fraction of honest enforcers, while another consists of cooperating harvesters and a high fraction of honest enforcers. Both continua attract nearby strategy mixtures. Second, even a small rate of strategy exploration removes this bistability, rendering one of the outcomes globally stable. It is the relative rate of exploration among enforcers that then determines whether most harvesters cooperate or defect and most enforcers are honest or corrupt, respectively. This suggests that the education of enforcers, causing their more frequent trialing of honest conduct, can be a potent means of curbing corruption. Third, if information on corrupt enforcers is available, and players react opportunistically to it, the domain of attraction of cooperative outcomes widens considerably. We conclude by discussing policy implications of our results. PMID- 25451515 TI - Genotoxicity of synthetic amorphous silica nanoparticles in rats following short term exposure. Part 2: intratracheal instillation and intravenous injection. AB - Synthetic amorphous silica nanomaterials (SAS) are extensively used in food and tire industries. In many industrial processes, SAS may become aerosolized and lead to occupational exposure of workers through inhalation in particular. However, little is known about the in vivo genotoxicity of these particulate materials. To gain insight into the toxicological properties of four SAS (NM-200, NM-201, NM-202, and NM-203), rats are treated with three consecutive intratracheal instillations of 3, 6, or 12 mg/kg of SAS at 48, 24, and 3 hrs prior to tissue collection (cumulative doses of 9, 18, and 36 mg/kg). Deoxyribonucleic acid (DNA) damage was assessed using erythrocyte micronucleus test and the standard and Fpg-modified comet assays on cells from bronchoalveolar lavage fluid (BALF), lung, blood, spleen, liver, bone marrow, and kidney. Although all of the SAS caused increased dose-dependent changes in lung inflammation as demonstrated by BALF neutrophilia, they did not induce any significant DNA damage. As the amount of SAS reaching the blood stream and subsequently the internal organs is probably to be low following intratracheal instillation, an additional experiment was performed with NM-203. Rats received three consecutive intravenous injections of 5, 10, or 20 mg/kg of SAS at 48, 24, and 3 hrs prior to tissue collection. Despite the hepatotoxicity, thrombocytopenia, and even animal death induced by this nanomaterial, no significant increase in DNA damage or micronucleus frequency was observed in SAS exposed animals. It was concluded that under experimental conditions, SAS induced obvious toxic effects but did cause any genotoxicity following intratracheal instillation and intravenous injection. PMID- 25451517 TI - Comparison between mathematical models of intermittent androgen suppression for prostate cancer. AB - Mathematical modelling is essential for personalizing intermittent androgen suppression, which was proposed to delay the relapse of prostate cancer by stopping and resuming the hormone therapy repeatedly than adopting the conventional continuous androgen suppression, or normal hormonal therapy. Although there are several mathematical models for intermittent androgen suppression, the performances of these mathematical models have not been compared sufficiently. In this paper, we compare the Hirata-Bruchovsky-Aihara model with the Portz-Kuang-Nagy model, two recently proposed models for intermittent androgen suppression. We fitted these mathematical models to the actual data of 17 patients and examined the dynamical behavior and prediction accuracy of these models. Although we found no significant difference between these models in terms of prediction accuracy, the Portz-Kuang-Nagy model could not reproduce the relapse under the simulation condition assuming the continuous androgen suppression. Thus, the results suggest that the Hirata-Bruchovsky-Aihara model is more useful than the Portz-Kuang-Nagy model when we attempt to compare the therapeutic efficiencies of intermittent suppression and continuous androgen suppression. PMID- 25451518 TI - The size of the character state space affects the occurrence and detection of homoplasy: modelling the probability of incompatibility for unordered phylogenetic characters. AB - This study models the probability of incompatibility versus compatibility for binary or unordered multistate phylogenetic characters, by treating the allocation of taxa to character states as a classical occupancy problem in probability. It is shown that, under this model, the number of character states has a non-linear effect on the probability of character incompatibility, which is also affected by the number of taxa. Effects on homoplasy from the number of character states are further explored using evolutionary computer simulations. The results indicate that the character state space affects both the known levels of homoplasy (recorded during simulated evolution) and those inferred from parsimony analysis of the resulting character data, with particular relevance for morphological phylogenetic analyses which generally use the parsimony method. When the evolvable state space is large (more potential states per character) there is a reduction in the known occurrence of homoplasy (as reported previously). However, this is not always reflected in the levels of homoplasy detected in a parsimony analysis, because higher numbers of states per character can lead to an increase in the probability of character incompatibility (as well as the maximum homoplasy measurable with some indices). As a result, inferred trends in homoplasy can differ markedly from the underlying trend (that recorded during evolutionary simulation). In such cases, inferred homoplasy can be entirely misleading with regard to tree quality (with higher levels of homoplasy inferred for better quality trees). When rates of evolution are low, commonly used indices such as the number of extra steps (H) and the consistency index (CI) provide relatively good measures of homoplasy. However, at higher rates, estimates may be improved by using the retention index (RI), and particularly by accounting for homoplasy measured among randomised character data using the homoplasy excess ratio (HER). PMID- 25451519 TI - Initiation of atrial fibrillation by interaction of pacemakers with geometrical constraints. AB - Atrial fibrillation (AF) is the most common arrhythmia of the heart in industrialized countries. Its generation and the transitory behavior of paroxysmal AF are still not well understood. In this work we examine the interaction of two activation sources via an isthmus as possible cause for the initiation of fibrillation episodes. For this study, the electrophysiological model of Bueno-Orovio, Cherry and Fenton is adapted to atrial electrophysiology, both for physiological and electrophysiologically remodeled conditions due to AF. We show that the interaction of the pacemakers, combined with the geometrical constraints of the isthmus, can produce fibrillatory-type irregularities, which we quantify by the loss of spatial phase coherence in the transmembrane voltage. Transitions to irregular behavior occur when the frequencies of the pacemakers exceed certain thresholds, suggesting that AF episodes are initiated by frequency changes of the activating sources (sinus node, ectopic focus). PMID- 25451520 TI - Sensitivity of chemical reaction networks: a structural approach. 1. Examples and the carbon metabolic network. AB - In biological cells, chemical reaction pathways lead to complex network systems like metabolic networks. One experimental approach to the dynamics of such systems examines their "sensitivity": each enzyme mediating a reaction in the system is increased/decreased or knocked out separately, and the responses in the concentrations of chemicals or their fluxes are observed. In this study, we present a mathematical method, named structural sensitivity analysis, to determine the sensitivity of reaction systems from information on the network alone. We investigate how the sensitivity responses of chemicals in a reaction network depend on the structure of the network, and on the position of the perturbed reaction in the network. We establish and prove some general rules which relate the sensitivity response to the structure of the underlying network. We describe a hierarchical pattern in the flux response which is governed by branchings in the network. We apply our method to several hypothetical and real life chemical reaction networks, including the metabolic network of the Escherichia coli TCA cycle. PMID- 25451521 TI - Evolution of dispersal distance: maternal investment leads to bimodal dispersal kernels. AB - Since dispersal research has mainly focused on the evolutionary dynamics of dispersal rates, it remains unclear what shape evolutionarily stable dispersal kernels have. Yet, detailed knowledge about dispersal kernels, quantifying the statistical distribution of dispersal distances, is of pivotal importance for understanding biogeographic diversity, predicting species invasions, and explaining range shifts. We therefore examine the evolution of dispersal kernels in an individual-based model of a population of sessile organisms, such as trees or corals. Specifically, we analyze the influence of three potentially important factors on the shape of dispersal kernels: distance-dependent competition, distance-dependent dispersal costs, and maternal investment reducing an offspring's dispersal costs through a trade-off with maternal fecundity. We find that without maternal investment, competition and dispersal costs lead to unimodal kernels, with increasing dispersal costs reducing the kernel's width and tail weight. Unexpectedly, maternal investment inverts this effect: kernels become bimodal at high dispersal costs. This increases a kernel's width and tail weight, and thus the fraction of long-distance dispersers, at the expense of simultaneously increasing the fraction of non-dispersers. We demonstrate the qualitative robustness of our results against variations in the tested parameter combinations. PMID- 25451522 TI - Mathematical modeling of aortic valve dynamics during systole. AB - We have derived a mathematical model describing aortic valve dynamics and blood flow during systole. The model presents a realistic coupling between aortic valve dynamics, sinus vortex local pressure, and variations in the systemic vascular resistance. The coupling is introduced by using Hill's classical semi-spherical vortex model and an aortic pressure-area compliance constitutive relationship. The effects of introducing aortic sinus eddy vortices and variable systemic vascular resistance on overall valve opening-closing dynamics, left ventricular pressure, aortic pressure, blood flow rate, and aortic orifice area are examined. In addition, the strength of the sinus vortex is coupled explicitly to the valve opening angle, and implicitly to the aortic orifice area in order to predict how vortex strength varies during the four descriptive phases of aortic valve motion (fast-opening, fully-opening, slow-closing, and fast-closing). Our results compare favorably with experimental observations and the model reproduces well known phenomena corresponding to aortic valve function such as the dicrotic notch and retrograde flow at end systole. By invoking a more complete set of physical phenomena, this new model will enable representation of pathophysiological conditions such as aortic valve stenosis or insufficiency, making it possible to predict their integrated effects on cardiac load and systemic hemodynamics. PMID- 25451523 TI - Algorithmically generated rodent hepatic vascular trees in arbitrary detail. AB - Physiologically realistic geometric models of the vasculature in the liver are indispensable for modelling hepatic blood flow, the main connection between the liver and the organism. Current in vivo imaging techniques do not provide sufficiently detailed vascular trees for many simulation applications, so it is necessary to use algorithmic refinement methods. The method of Constrained Constructive Optimization (CCO) (Schreiner et al., 2006) is well suited for this purpose. Its results after calibration have been previously compared to experimentally acquired human vascular trees (Schwen and Preusser, 2012). The goal of this paper is to extend this calibration to the case of rodents (mice and rats), the most commonly used animal models in liver research. Based on in vivo and ex vivo micro-CT scans of rodent livers and their vasculature, we performed an analysis of various geometric features of the vascular trees. Starting from pruned versions of the original vascular trees, we applied the CCO procedure and compared these algorithmic results to the original vascular trees using a suitable similarity measure. The calibration of the postprocessing improved the algorithmic results compared to those obtained using standard CCO. In terms of angular features, the average similarity increased from 0.27 to 0.61, improving the total similarity from 0.28 to 0.40. Finally, we applied the calibrated algorithm to refine measured vascular trees to the (higher) level of detail desired for specific applications. Having successfully adapted the CCO algorithm to the rodent model organism, the resulting individual-specific refined hepatic vascular trees can now be used for advanced modeling involving, e.g., detailed blood flow simulations. PMID- 25451524 TI - On high heels and short muscles: a multiscale model for sarcomere loss in the gastrocnemius muscle. AB - High heels are a major source of chronic lower limb pain. Yet, more than one third of all women compromise health for looks and wear high heels on a daily basis. Changing from flat footwear to high heels induces chronic muscle shortening associated with discomfort, fatigue, reduced shock absorption, and increased injury risk. However, the long-term effects of high-heeled footwear on the musculoskeletal kinematics of the lower extremities remain poorly understood. Here we create a multiscale computational model for chronic muscle adaptation to characterize the acute and chronic effects of global muscle shortening on local sarcomere lengths. We perform a case study of a healthy female subject and show that raising the heel by 13cm shortens the gastrocnemius muscle by 5% while the Achilles tendon remains virtually unaffected. Our computational simulation indicates that muscle shortening displays significant regional variations with extreme values of 22% in the central gastrocnemius. Our model suggests that the muscle gradually adjusts to its new functional length by a chronic loss of sarcomeres in series. Sarcomere loss varies significantly across the muscle with an average loss of 9%, virtually no loss at the proximal and distal ends, and a maximum loss of 39% in the central region. These changes reposition the remaining sarcomeres back into their optimal operating regime. Computational modeling of chronic muscle shortening provides a valuable tool to shape our understanding of the underlying mechanisms of muscle adaptation. Our study could open new avenues in orthopedic surgery and enhance treatment for patients with muscle contracture caused by other conditions than high heel wear such as paralysis, muscular atrophy, and muscular dystrophy. PMID- 25451526 TI - Dynamical analysis on a chronic hepatitis C virus infection model with immune response. AB - A mathematical model for HCV infection is established, in which the effect of dendritic cells (DC) and cytotoxic T lymphocytes (CTL) on HCV infection is considered. The basic reproduction numbers of chronic HCV infection and immune control are found. The obtained results show that the infection dies out finally as the basic reproduction number of HCV infection is less than unity, and the infection becomes chronic as it is greater than unity. In the presence of chronic infection, the existence of immune control equilibrium is discussed completely, which illustrates that the backward bifurcation may occur under certain conditions, and that the two quantities, the sizes of the activated DC and the removed CTL during their average life-terms, play a critical role in controlling chronic HCV infection and immune response. The occurrence of backward bifurcation implies that there may be bistability for the model, i.e., the outcome of infection depends on the initial situation. By choosing the activated rate of non activated DC or the cross-representation rate of activated DC as bifurcation number, Hopf bifurcation for certain condition shows the existence of periodic solution of the model. Again, numerical simulations suggest the dynamical complexity of the model including the instability of immune control equilibrium and the existence of stable periodic solution. PMID- 25451525 TI - Application of stochastic phenomenological modelling to cell-to-cell and beat-to beat electrophysiological variability in cardiac tissue. AB - Variability in the action potential of isolated myocytes and tissue samples is observed in experimental studies. Variability is manifested as both differences in the action potential (AP) morphology between cells (extrinsic variability), and also 'intrinsic' or beat-to-beat variability of repolarization (BVR) in the AP duration of each cell. We studied the relative contributions of experimentally recorded intrinsic and extrinsic variability to dispersion of repolarization in tissue. We developed four cell-specific parameterizations of a phenomenological stochastic differential equation AP model exhibiting intrinsic variability using APs recorded from isolated guinea pig ventricular myocytes exhibiting BVR. We performed simulations in tissue using the four different model parameterizations in the presence and the absence of both intrinsic and extrinsic variability. We altered the coupling of the tissue to determine how inter-cellular coupling affected the dispersion of the AP duration in tissue. Both intrinsic and extrinsic variability were gradually revealed by reduction of tissue coupling. However, the recorded extrinsic variability between individual myocytes produced a greater degree of dispersion in repolarization in tissue than the intrinsic variability of each myocyte. PMID- 25451527 TI - Demographic stochasticity alters the outcome of exploitation competition. AB - Temporal variability in resource density is one of the mechanisms that facilitate coexistence between competitors. This study examines whether demographic stochasticity as a source of resource fluctuation can facilitate coexistence. The dynamics of a deterministic model (without demographic stochasticity) and a stochastic individual-based model (with demographic stochasticity) are compared. The deterministic model is an exploitation competition module consisting of two consumer species and one resource. The Gillespie algorithm is used to simulate demographic stochasticity in the corresponding individual-based model. The parameters of the models are chosen to represent cases where the deterministic model shows competitive exclusion according to the R(*) rule and exhibits only stable equilibrium dynamics based on any combinations of the species. The analysis of the individual-based model shows that demographic stochasticity induces persistent population cycles between a consumer and the resource (i.e., when one of the consumers is absent), and this resource fluctuation allows the two consumers to coexist. Coexistence becomes possible through emerging tradeoffs that allow an inferior species (predicted by the deterministic model) to become competitively dominant (e.g., deviation of the R(*) rule). These tradeoffs are useful for interpreting apparently contradicting empirical observations. PMID- 25451529 TI - Network impact on persistence in a finite population dynamic diffusion model: application to an emergent seed exchange network. AB - Dynamic extinction colonisation models (also called contact processes) are widely studied in epidemiology and in metapopulation theory. Contacts are usually assumed to be possible only through a network of connected patches. This network accounts for a spatial landscape or a social organization of interactions. Thanks to social network literature, heterogeneous networks of contacts can be considered. A major issue is to assess the influence of the network in the dynamic model. Most work with this common purpose uses deterministic models or an approximation of a stochastic Extinction-Colonisation model (sEC) which are relevant only for large networks. When working with a limited size network, the induced stochasticity is essential and has to be taken into account in the conclusions. Here, a rigorous framework is proposed for limited size networks and the limitations of the deterministic approximation are exhibited. This framework allows exact computations when the number of patches is small. Otherwise, simulations are used and enhanced by adapted simulation techniques when necessary. A sensitivity analysis was conducted to compare four main topologies of networks in contrasting settings to determine the role of the network. A challenging case was studied in this context: seed exchange of crop species in the Reseau Semences Paysannes (RSP), an emergent French farmers' organisation. A stochastic Extinction-Colonisation model was used to characterize the consequences of substantial changes in terms of RSP's social organization on the ability of the system to maintain crop varieties. PMID- 25451528 TI - Computational modelling of amino acid exchange and facilitated transport in placental membrane vesicles. AB - Placental amino acid transport is required for fetal development and impaired transport has been associated with poor fetal growth. It is well known that placental amino acid transport is mediated by a broad array of specific membrane transporters with overlapping substrate specificity. However, it is not fully understood how these transporters function, both individually and as an integrated system. We propose that mathematical modelling could help in further elucidating the underlying mechanisms of how these transporters mediate placental amino acid transport. The aim of this work is to model the sodium independent transport of serine, which has been assumed to follow an obligatory exchange mechanism. However, previous amino acid uptake experiments in human placental microvillous plasma membrane vesicles have persistently produced results that are seemingly incompatible with such a mechanism; i.e. transport has been observed under zero-trans conditions, in the absence of internal substrates inside the vesicles to drive exchange. This observation raises two alternative hypotheses; (i) either exchange is not fully obligatory, or (ii) exchange is indeed obligatory, but an unforeseen initial concentration of amino acid substrate is present within the vesicle which could drive exchange. To investigate these possibilities, a mathematical model for tracer uptake was developed based on carrier mediated transport, which can represent either facilitated diffusion or obligatory exchange (also referred to as uniport and antiport mechanisms, respectively). In vitro measurements of serine uptake by placental microvillous membrane vesicles were carried out and the model applied to interpret the results based on the measured apparent Michaelis-Menten parameters Km and Vmax. In addition, based on model predictions, a new time series experiment was implemented to distinguish the hypothesised transporter mechanisms. Analysis of the results indicated the presence of a facilitated transport component, while based on the model no evidence for substantial levels of endogenous amino acids within the vesicle was found. PMID- 25451530 TI - Modelling of FDG metabolism in liver voxels. AB - Kinetic analysis is a tool used to glean additional information from positron emission tomography (PET) data by exploiting the dynamics of tissue metabolism. The standard irreversible and reversible two compartment models used in kinetic analysis were initially developed to analyse brain PET data. The application of kinetic analysis to PET of the liver presents the opportunity to move beyond the generic standard models and develop physiologically informed pharmacokinetic models that incorporate structural and functional features in particular to the liver. In this paper, we develop a new compartment model, called the tubes model, which is informed by the liver's sinusoidal architecture, high fractional blood volume, high perfusion rate, and large hepatocyte surface area facing the space of Disse. The tubes model distributes tracer between the blood and intracellular compartments in more physiologically faithful proportions than the standard model, producing parametric images with improved contrast between healthy and neoplastic tissue. PMID- 25451531 TI - Joint fitting reveals hidden interactions in tumor growth. AB - Tumor growth is often the result of the simultaneous development of two or more cancer cell populations. Crucial to the system evolution are the interactions between these populations. To obtain information about these interactions we apply the recently developed vector universality (VUN) formalism to various instances of competition between tumor populations. The formalism allows us (a) to quantify the growth mechanisms of a HeLa cell colony, describing the phenotype switching responsible for its fast expansion, (b) to reliably reconstruct the evolution of the necrotic and viable fractions in both in vitro and in vivo tumors using data for the time dependences of the total masses alone, and (c) to show how the shedding of cells leading to subspheroid formation is beneficial to both the spheroid and subspheroid populations, suggesting that shedding is a strong positive influence on cancer dissemination. PMID- 25451532 TI - A model for global diversity in response to temperature change over geological time scales, with reference to planktic organisms. AB - There are strong propositions in the literature that abiotic factors override biotic drivers of diversity on time scales of the fossil record. In order to study the interaction of biotic and abiotic forces on long term changes, we devise a spatio-temporal discrete-time Markov process model of macroevolution featuring population formation, speciation, migration and extinction, where populations are free to migrate. In our model, the extinction probability of these populations is controlled by latitudinally and temporally varying environment (temperature) and competition. Although our model is general enough to be applicable to disparate taxa, we explicitly address planktic organisms, which are assumed to disperse freely without barriers over the Earth's oceans. While rapid and drastic environmental changes tend to eliminate many species, generalists preferentially survive and hence leave generalist descendants. In other words, environmental fluctuations result in generalist descendants which are resilient to future environmental changes. Periods of stable or slow environmental changes lead to more specialist species and higher population numbers. Simulating Cenozoic diversity dynamics with both competition and the environmental component of our model produces diversity curves that reflect current empirical knowledge, which cannot be obtained with just one component. Our model predicts that the average temperature optimum at which planktic species thrive best has declined over the Neogene, following the trend of global average temperatures. PMID- 25451533 TI - Dynamic optimization of metabolic networks coupled with gene expression. AB - The regulation of metabolic activity by tuning enzyme expression levels is crucial to sustain cellular growth in changing environments. Metabolic networks are often studied at steady state using constraint-based models and optimization techniques. However, metabolic adaptations driven by changes in gene expression cannot be analyzed by steady state models, as these do not account for temporal changes in biomass composition. Here we present a dynamic optimization framework that integrates the metabolic network with the dynamics of biomass production and composition. An approximation by a timescale separation leads to a coupled model of quasi-steady state constraints on the metabolic reactions, and differential equations for the substrate concentrations and biomass composition. We propose a dynamic optimization approach to determine reaction fluxes for this model, explicitly taking into account enzyme production costs and enzymatic capacity. In contrast to the established dynamic flux balance analysis, our approach allows predicting dynamic changes in both the metabolic fluxes and the biomass composition during metabolic adaptations. Discretization of the optimization problems leads to a linear program that can be efficiently solved. We applied our algorithm in two case studies: a minimal nutrient uptake network, and an abstraction of core metabolic processes in bacteria. In the minimal model, we show that the optimized uptake rates reproduce the empirical Monod growth for bacterial cultures. For the network of core metabolic processes, the dynamic optimization algorithm predicted commonly observed metabolic adaptations, such as a diauxic switch with a preference ranking for different nutrients, re utilization of waste products after depletion of the original substrate, and metabolic adaptation to an impending nutrient depletion. These examples illustrate how dynamic adaptations of enzyme expression can be predicted solely from an optimization principle. PMID- 25451534 TI - Population structure and the rate of evolution. AB - The way population size, population structure (with migration), and spatially dependent selection (where there is no globally optimal allele), combine to affect the substitution rate is poorly understood. Here, we consider a two patch model where mutant alleles are beneficial in one patch and deleterious in the other patch. We assume that the spatial average of selection on mutant alleles is zero. We take each patch to maintain a finite number of N adults each generation, hence random genetic drift can independently occur in each patch. We show that the principal way the population size, N, when large, affects the substitution rate, Rinfinity, is through its dependence on two composite parameters. These are the scaled migration rate M (? population size * migration rate), and the scaled selection intensity S (?population size * beneficial effect of a mutant). Any relation between S and M that arises for ecological/evolutionary reasons can strongly influence the way the substitution rate, Rinfinity, depends on the population size, N. In the simplest situation, both M and S are proportional to N, and this is shown to lead to Rinfinity increasing with N when S is not large. The behaviour, that Rinfinity increases with N, is not inevitable; a more complex relation between S and M can lead to the opposite or other behaviours. In particular, let us assume that dM/dN is positive, as would occur if the migration rate were constant, S is not large, and S depends on M (i.e., S=S(M)). We then find that if S(M) satisfies S(M)>((1+M)/1+2M)S(0) then the substitution rate, Rinfinity, increases with N, but if S(M)<((1+M)/1+2M)S(0) then Rinfinity decreases with N. PMID- 25451535 TI - Potential role of hCG in apoptosis of human luteinized granulosa cells. AB - The corpus luteum (CL) forms after ovulation and acts as a temporary endocrine gland that produces progesterone (P4), a hormone that is essential for implantation and maintenance of pregnancy in mammals. In pregnant women, human chorionic gonadotropin (hCG) secreted by the conceptus prevents luteolysis. hCG also increases the survival of cultured human luteinized granulosa cells (hLGCs). To clarify the maintenance mechanism of the human CL, we investigated the effects of hCG and P4 receptor antagonists, onapristone (OP) and RU486, on the viability of hLGCs. With the patients' consent, hLGCs were isolated from follicular aspirates for in vitro fertilization. The cells were cultured with hCG (0.1, 1, 10, 100 IU/ml), OP (10, 25, 50, 100 MUM), RU486 (100 MUM), P4 (1, 10, 25, 50 MUM) or some combination of the four for 24 h. Cell viability was significantly increased by hCG (100 IU/ml) and significantly decreased by OP (100 MUM) compared with the control. Cells treated with hCG and OP together were significantly less viable than the control and OP-treated cells. The combined treatment also significantly increased CASP3 activity and cleaved CASP3 protein expression. Furthermore, P4 addition reversed the reduction in cell viability caused by the combination of hCG and OP treatment. The overall findings suggest that hCG cooperates with P4 to increase survival of hLGCs and to induce apoptosis when P4 action supported by hCG is attenuated in the human CL. PMID- 25451537 TI - The effect of intermittent dosing of Nicotiana glauca on teratogenesis in goats. AB - Sustained inhibition of fetal movement in livestock species, induced by several poisonous plants, can result in numerous skeletal-contracture malformations. Lupines are responsible for a condition in cattle referred to as "crooked calf syndrome" that occurs when pregnant cattle graze teratogenic lupines. Similar malformations are also seen in animals poisoned by Conium maculatum (coniine) and Nicotiana glauca (anabasine). A proposed management strategy to limit these types of birth defects includes utilizing an intermittent grazing schedule to allow short durations of grazing lupine-infested areas interrupted by movement to a lupine-free pasture. The objective of this study was to use a goat model to determine if an intermittent schedule of five continuous days on treatment followed by two days off treatment would be sufficient to decrease, or prevent, the incidence of anabasine-induced malformations. The data from this study suggest that, for N. glauca in goats, the intermittent grazing program of five days exposure with two days of non-exposure is insufficient to prevent significant skeletal malformations from occurring. However, this study did demonstrate an inverse relationship between the amount of serum anabasine in the dam and the extent of fetal movement. PMID- 25451536 TI - Deficiency in Nrf2 transcription factor decreases adipose tissue mass and hepatic lipid accumulation in leptin-deficient mice. AB - OBJECTIVE: To evaluate whether Nrf2 deficiency impacts insulin resistance and lipid accumulation in liver and white adipose tissue. METHODS: Lep(ob/ob) mice (OB) with targeted Nrf2 deletion (OB-Nrf2KO) were generated. Pathogenesis of obesity and type 2 diabetes was measured in C57BL/6J, Nrf2KO, OB, and OB-Nrf2KO mice. Hepatic lipid content, lipid clearance, and very low-density lipoprotein (VLDL) secretion were determined between OB and OB-Nrf2KO mice. RESULTS: OB Nrf2KO mice exhibited decreased white adipose tissue mass and decreased adipogenic and lipogenic gene expression compared with OB mice. Nrf2 deficiency prolonged hyperglycemia in response to glucose challenge, which was paralleled by reduced insulin-stimulated Akt phosphorylation. In OB mice, Nrf2 deficiency decreased hepatic lipid accumulation, decreased peroxisome proliferator-activated receptor gamma expression and nicotinamide adenine dinucleotide phosphate (NADPH) content, and enhanced VLDL secretion. However, this observation was opposite in lean mice. Additionally, OB-Nrf2KO mice exhibited increased plasma triglyceride content, decreased HDL-cholesterol content, and enhanced apolipoprotein B expression, suggesting Nrf2 deficiency caused dyslipidemia in these mice. CONCLUSIONS: Nrf2 deficiency in Lep(ob/ob) mice reduced white adipose tissue mass and prevented hepatic lipid accumulation but induced insulin resistance and dyslipidemia. This study indicates a dual role of Nrf2 during metabolic dysregulation-increasing lipid accumulation in liver and white adipose tissue but preventing lipid accumulation in obese mice. PMID- 25451538 TI - Proteomic investigation of Sri Lankan hump-nosed pit viper (Hypnale hypnale) venom. AB - The hump-nosed pit viper, Hypanle hypnale, contributes to snakebite mortality and morbidity in Sri Lanka. Studies showed that the venom is hemotoxic and nephrotoxic, with some biochemical and antigenic properties similar to the venom of Calloselasma rhodostoma (Malayan pit viper). To further characterize the complexity composition of the venom, we investigated the proteome of a pooled venom sample from >10 Sri Lankan H. hypnale with reverse-phase high performance liquid chromatography (rp-HPLC), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and peptide sequencing (tandem mass-spectrometry and/or N-terminal sequencing). The findings ascertained that two phospholipase A2 subtypes (E6-PLA2, W6-PLA2) dominate the toxin composition by 40.1%, followed by snake venom metalloproteases (36.9%), l-amino acid oxidase (11.9%), C-type lectins (5.5%), serine proteases (3.3%) and others (2.3%). The presence of the major toxins correlates with the venom's major pathogenic effects, indicating these to be the principal target toxins for antivenom neutralization. This study supports the previous finding of PLA2 dominance in the venom but diverges from the view that H. hypnale venom has low expression of large enzymatic toxins. The knowledge of the composition and abundance of toxins is essential to elucidate the pathophysiology of H. hypnale envenomation and to optimize antivenom formulation in the future. PMID- 25451539 TI - Alternariol-induced cytotoxicity in Caco-2 cells. Protective effect of the phenolic fraction from virgin olive oil. AB - The extra virgin olive oil (EVOO) has been associated to antioxidant effects. The mycotoxin alternariol (AOH) can contaminate olives. The aims of this work were to determine the cytotoxic effects and reactive oxygen species (ROS) produced by AOH, tyrosol and oleuropein (two polyphenols of olive oil) and a real EVOO extract in Caco-2 cells. The MTT assay and the ROS production by the H2-DCFDA probe were used. Results demonstrated that AOH reduces cellular proliferation depending on concentration, whereas tyrosol and oleuropein did not (12.5-100 MUM). The combination of AOH + oleuropein (50 MUM) increased cell proliferation (24%) whereas, AOH + tyrosol decreased (47%) it. Besides, AOH increased ROS generation depending on time and concentration. Oleuropein + AOH decreased ROS production. However, 25 MUM of tyrosol increased 1.2-fold the ROS production. Respect to the EVOO extract, cytoprotective effect (151%) was evidenced, even with the combination EVOO extract + AOH (15%-55% respect to cells exposed to AOH alone). ROS generation was significantly reduced compared to ROS generation produced by 25 MUM of AOH alone. The phenolic antioxidant of EVOO decreases cytotoxicity and ROS production in Caco-2 cells exposed to AOH. Thus, polyphenols of EVOO could contribute to diminish the toxicological risk that mycotoxins can produce to humans. PMID- 25451540 TI - Tuning charge-discharge induced unit cell breathing in layer-structured cathode materials for lithium-ion batteries. AB - For LiMO2 (M=Co, Ni, Mn) cathode materials, lattice parameters, a(b), contract during charge. Here we report such changes in opposite directions for lithium molybdenum trioxide (Li2MoO3). A 'unit cell breathing' mechanism is proposed based on crystal and electronic structural changes of transition metal oxides during charge-discharge. Metal-metal bonding is used to explain such 'abnormal' behaviour and a generalized hypothesis is developed. The expansion of the metal metal bond becomes the controlling factor for a(b) evolution during charge, in contrast to the shrinking metal-oxygen bond as controlling factor in 'normal' materials. The cation mixing caused by migration of molybdenum ions at higher oxidation state provides the benefits of reducing the c expansion range in the early stage of charging and suppressing the structure collapse at high voltage charge. These results may open a new strategy for designing layered cathode materials for high energy density lithium-ion batteries. PMID- 25451541 TI - Does mean platelet volume really increase in sudden sensorial hearing loss? PMID- 25451542 TI - Chondrosarcoma of the nasal septum. AB - Chondrosarcomas are non-epithelial malignant, slow growing tumors that usually involve pelvis, ribs, and long bones of extremities, scapula and sternum. Median age at diagnosis for head and neck chondrosarcomas is in the fourth decade. The etiopathogenesis of chondrosarcomas remains unknown. Treatment of choice is surgical, with adjuvant therapy having a limited role. In fact, radiation therapy and chemotherapy are reserved for residual or recurrent disease and palliation. As for surgery, several surgical procedures have been described. Recently, endoscopic surgery has allowed for the successful and less invasive treatment of inverting papillomas and even nasopharyngeal angiofibromas, lesions previously requiring extended external approaches. The aim of this paper was to present a case of nasal septal chondrosarcoma that was successfully treated with endoscopic surgery and radiation adjuvant therapy. PMID- 25451543 TI - Biodegradable capsules as non-viral vectors for in vitro delivery of PEI/siRNA polyplexes for efficient gene silencing. AB - The efficiency of siRNA delivery is demonstrated to be improved by encapsulating the siRNA within a non-viral carrier based on layer-by-layer assembly of oppositely charged biodegradable and biocompatible polyelectrolytes. In comparison to other non-viral delivery vehicles such as polycation-based complexes, a smaller amount of siRNA was necessary to produce in vitro gene silencing as early as 20-30 h after incubation. Colloidal carriers based on assembled biodegradable polyelectrolytes offer several advantages, such as efficient intracellular delivery after endocytosis followed by release to the cytosol, as well as protection of the siRNA, which is crucial for its therapeutic activity. PMID- 25451544 TI - Macromolecular (pro)drugs with concurrent direct activity against the hepatitis C virus and inflammation. AB - Macromolecular prodrugs (MPs) are a powerful tool to alleviate side-effects and improve the efficacy of the broad-spectrum antiviral agent ribavirin. In this work, we sought an understanding of what makes an optimal formulation within the macromolecular parameter space--nature of the polymer carrier, average molar mass, drug loading, or a good combination thereof. A panel of MPs based on biocompatible synthetic vinylic and (meth)acrylic polymers was tested in an anti inflammatory assay with relevance to alleviating inflammation in the liver during hepatitis C infection. Pristine polymer carriers proved to have a pronounced anti inflammatory activity, a notion which may prove significant in developing MPs for antiviral and anticancer treatments. With conjugated ribavirin, MPs revealed enhanced activity but also higher toxicity. Therapeutic windows and therapeutic indices were determined and discussed to reveal the most potent formulation and those with optimized safety. Polymers were also tested as inhibitors of replication of the hepatitis C viral RNA using a subgenomic viral replicon system. For the first time, negatively charged polymers are revealed to have an intracellular activity against hepatitis C virus replication. Concerted activity of the polymer and ribavirin afforded MPs which significantly increased the therapeutic index of ribavirin-based treatment. Taken together, the systematic investigation of the macromolecular space identified lead candidates with high efficacy and concurrent direct activity against the hepatitis C virus and inflammation. PMID- 25451545 TI - Fate of inhaled monoclonal antibodies after the deposition of aerosolized particles in the respiratory system. AB - Monoclonal antibodies (mAbs) are usually delivered systemically, but only a small proportion of the drug reaches the lung after intravenous injection. The inhalation route is an attractive alternative for the local delivery of mAbs to treat lung diseases, potentially improving tissue concentration and exposure to the drug while limiting passage into the bloodstream and adverse effects. Several studies have shown that the delivery of mAbs or mAb-derived biopharmaceuticals via the airways is feasible and efficient, but little is known about the fate of inhaled mAbs after the deposition of aerosolized particles in the respiratory system. We used cetuximab, an anti-EGFR antibody, as our study model and showed that, after its delivery via the airways, this mAb accumulated rapidly in normal and cancerous tissues in the lung, at concentrations twice those achieved after intravenous delivery, for early time points. The spatial distribution of cetuximab within the tumor was heterogeneous, as reported after i.v. injection. Pharmacokinetic (PK) analyses were carried out in both mice and macaques and showed aerosolized cetuximab bioavailability to be lower and elimination times shorter in macaques than in mice. Using transgenic mice, we showed that FcRn, a key receptor involved in mAb distribution and PK, was likely to make a greater contribution to cetuximab recycling than to the transcytosis of this mAb in the airways. Our results indicate that the inhalation route is potentially useful for the treatment of both acute and chronic lung diseases, to boost and ensure the sustained accumulation of mAbs within the lungs, while limiting their passage into the bloodstream. PMID- 25451547 TI - Support needs of breast-feeding women: views of Australian midwives and health nurses. AB - OBJECTIVE: to explore the views of midwives and maternal-child health nurses regarding factors that influence breast feeding initiation and continuation, focusing on how support for women could be improved to increase breast feeding duration. DESIGN: a focus group study. SETTING: hospital or domiciliary (home visiting) midwives and community-based maternal and child health (MCH) nurses in one region of Victoria, Australia. METHODS: twelve MCH nurses and five midwives who provided supportive services to women in the immediate postnatal period attended one of three audio-recorded focus groups. Thematic findings were identified. FINDINGS: four key themes were: 'Guiding women over breast-feeding hurdles', 'Timing, and time to care'; 'Continuity of women's care' and 'Imparting professional knowledge'. Given the a pattern of hospital discharge of mother and infant on day one or day two after birth, participants thought the timing of immediate postnatal breast-feeding support was critical to enable women to initiate and continue breast feeding. Community-based MCH nurses reported time gaps in uptake of new mother referrals and time-pressured face-to-face consultations. Both groups perceived barriers to continuity of women's care. CONCLUSIONS: health services subscribe to the Baby Friendly Health Initiative and government policies which support breast feeding, however providers described time pressures and a lack of continuity of women's care, including during transition from hospital to community services. IMPLICATIONS FOR PRACTICE: there is a need to examine administration of service delivery and how domiciliary and community nurses can collaborate to establish and maintain supportive relationships with breast feeding women. PMID- 25451546 TI - An ethnographic study of communication challenges in maternity care for immigrant women in rural Alberta. AB - BACKGROUND: many immigrant and ethno-cultural groups in Canada face substantial barriers to accessing health care including language barriers. The negative consequences of miscommunication in health care settings are well documented although there has been little research on communication barriers facing immigrant women seeking maternity care in Canada. This study identified the nature of communication difficulties in maternity services from the perspectives of immigrant women, health care providers and social service providers in a small city in southern Alberta, Canada. METHODS: a focused ethnography was undertaken incorporating interviews with 31 participants recruited using purposive and snowball sampling. A community liaison and several gatekeepers within the community assisted with recruitment and interpretation where needed (n=1). All interviews were recorded and audio files were transcribed verbatim by a professional transcriptionist. The data was analysed drawing upon principles expounded by Roper and Shapira (2000) for the analysis of ethnographic data, because of (1) the relevance to ethnographic data, (2) the clarity and transparency of the approach, (3) the systematic approach to analysis, and (4) the compatibility of the approach with computer-assisted qualitative analysis software programs such as Atlas.ti (ATLAS.ti Scientific Software Development GmbH, Germany). This process included (1) coding for descriptive labels, (2) sorting for patterns, (3) identification of outliers, (4) generation of themes, (5) generalising to generate constructs and theories, and (6) memoing including researcher reflections. FINDINGS: four main themes were identified including verbal communication, unshared meaning, non-verbal communication to build relationships, and trauma, culture and open communication. Communication difficulties extended beyond matters of language competency to those encompassing non-verbal communication and its relation to shared meaning as well as the interplay of underlying pre-migration history and cultural factors which affect open communication, accessible health care and perhaps also maternal outcomes. CONCLUSION: this study provided insights regarding maternity health care communication. Communication challenges may be experienced by all parties, yet the onus remains for health care providers and for those within health care management and professional bodies to ensure that providers are equipped with the skills necessary to facilitate culturally appropriate care. PMID- 25451548 TI - Exploring midwifery students' views and experiences of caseload midwifery: A cross-sectional survey conducted in Victoria, Australia. AB - OBJECTIVES: in Australia, models of maternity care that offer women continuity of care with a known midwife have been promoted. Little is known about the intentions of the future midwifery workforce to work in such models. This study aimed to explore midwifery students' views and experiences of caseload midwifery and their work intentions in relation to the caseload model following graduation. DESIGN: cross-sectional survey. SETTING: Victoria, Australia. PARTICIPANTS: 129 midwifery students representing all midwifery course pathways (Post Graduate Diploma, Bachelor of Midwifery, Bachelor of Nursing/Bachelor of Midwifery) in Victoria. FINDINGS: midwifery students from all course pathways considered that continuity of care is important to women and indicated that exposure to continuity models during their course was very positive. Two-thirds of the students (67%) considered that the continuity experiences made them want to work in a caseload model; only 5% reported that their experiences had discouraged them from continuity of care work in the future. Most wanted a period of consolidation to gain experience as a midwife prior to commencing in the caseload model. Perceived barriers to caseload work were being on-call, and challenges in regard to work/life balance and family commitments. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: midwifery students in this study were very positive about caseload midwifery and most would consider working in caseload after a period of consolidation. Continuity of care experiences during students' midwifery education programmes appeared to provide students with insight and understanding of continuity of care for both women and midwives. Further research should explore what factors influence students' future midwifery work, whether or not their plans are fulfilled, and whether or not the caseload midwifery workforce can be sustained. PMID- 25451549 TI - The evidence base regarding the experiences of and attitudes to preimplantation genetic diagnosis in prospective parents. AB - BAACKGROUND: Preimplantation genetic diagnosis was developed as an alternative to prenatal diagnosis for couples with a family history of genetic disease. After in vitro fertilization, the embryos can be analysed to ensure that only healthy embryos are transferred to the uterus. Past studies have suggested that couples who wish to avoid having a child with an inherited genetic condition look favourably on preimplantation genetic diagnosis as it prevents the need for termination of pregnancy following prenatal diagnosis of an affected fetus. However, it is important to understand the experiences of couples who have used or consider using this technique. METHODS: To ascertain the current evidence base on this topic, we conducted a mixed methods systematic review. Four databases were searched for relevant peer-reviewed papers published between 2000 and 2013. Of 453 papers, nine satisfied the inclusion criteria and were assessed for quality. Results of nine papers were analysed and synthesised using a narrative approach. FINDINGS: Three main themes emerged: (1) motivating factors; (2) emotional labour; (3) choices and uncertainty. The review has identified an emotional and difficult journey for couples pursuing preimplantation genetic diagnosis. While use of the technique gives hope to families who wish to prevent transmission of a genetic disease this is not without hard decision-making and periods of uncertainty. Lack of information was perceived as a barrier to access this reproductive option. IMPLICATIONS FOR PRACTICE: Recommendations include: training and education in genetics for midwives who are the first point of contact for pregnant women; clinics to use a decision-making tool to emphasise the uncertainty involved in PGD and improved communication and psychological support to couples. PMID- 25451550 TI - Enhancing optical forces on fluorescent up-converting nanoparticles by surface charge tailoring. AB - 3D remote control of multifunctional fluorescent up-converting nanoparticles (UCNPs) using optical forces is being required for a great variety of applications including single-particle spectroscopy, single-particle intracellular sensing, controlled and selective light-activated drug delivery and light control at the nanoscale. Most of these potential applications find a serious limitation in the reduced value of optical forces (tens of fN) acting on these nanoparticles, due to their reduced dimensions (typically around 10 nm). In this work, this limitation is faced and it is demonstrated that the magnitude of optical forces acting on UCNPs can be enhanced by more than one order of magnitude by a controlled modification of the particle/medium interface. In particular, substitution of cationic species at the surface by other species with higher mobility could lead to UCNPs trapping with constants comparable to those of spherical metallic nanoparticles. PMID- 25451551 TI - 3alpha-diol administration decreases hippocampal PKA (II) mRNA expression and impairs Morris water maze performance in adult male rats. AB - The effect of testosterone and its metabolites on learning and memory has been the subject of many studies. This study used the Morris water maze task to investigate the effect of intra-hippocampal injection of 3alpha-diol (one of the metabolites of testosterone) on acquisition stage of spatial memory in adult male rats. During the experiment we observed that 3alpha-diol, significantly impaired Morris water maze performance in treated rat's compared with controls. Because signaling event mediated by protein kinase A (PKA) especially PKA (II) are critical for many neuronal functions such as learning and memory, the hippocampus was analyzed for mRNA expression of PKA (II) using TaqMan real time RT-PCR. The results indicated that the transcription levels of PKA (II) were significantly decreased in animals treated with 3alpha-diol compared with controls. Thus, the findings suggest that administration of 3alpha-diol in hippocampus of adult male rats impairs memory function, possibly via down-regulation of PKA. PMID- 25451553 TI - The role of orthographic neighborhood size effects in Chinese word recognition. AB - Previous studies about the orthographic neighborhood size (NS) in Chinese have overlooked the morphological processing, and the co-variation between the character frequency and the the NS. The present study manipulated the word frequency and the NS simultaneously, with the leading character frequency controlled, to explore their influences on word lexical decision (Experiment 1) and naming (Experiment 2). The results showed a robust effect that words with a larger NS produced shorter reaction time than those with a smaller NS, irrespective of the word frequency and the tasks. This facilitative effect may occur due to a semantic network formed by neighbor words, resulting in the semantic activation to accelerate the word recognition. Moreover, the comparison of the effect sizes of word frequency between the two tasks showed that lexical decision responses demonstrated a larger word frequency effect, indicating that the sub-word processing was involved in the multi-character word recognition. PMID- 25451554 TI - Reactivity of aldehydes at the air-water interface. Insights from molecular dynamics simulations and ab initio calculations. AB - Understanding the influence of solute-solvent interactions on chemical reactivity has been a subject of intense research in the last few decades. Theoretical studies have focused on bulk solvation phenomena and a variety of models and methods have been developed that are now widely used by both theoreticians and experimentalists. Much less attention has been paid, however, to processes that occur at liquid interfaces despite the important role such interfaces play in chemistry and biology. In this study, we have carried out sequential molecular dynamics simulations and quantum mechanical calculations to analyse the influence of the air-water interface on the reactivity of formaldehyde, acetaldehyde and benzaldehyde, three simple aldehydes of atmospheric interest. The calculated free energy profiles exhibit a minimum at the interface, where the average reactivity indices may display large solvation effects. The study emphasizes the role of solvation dynamics, which are responsible for large fluctuations of some molecular properties. We also show that the photolysis rate constant of benzaldehyde in the range 290-308 nm increases by one order of magnitude at the surface of a water droplet, from 2.7 * 10(-5) s(-1) in the gas phase to 2.8 * 10( 4) s(-1) at the air-water interface, and we discuss the potential impact of this result on the chemistry of the troposphere. Experimental data in this domain are still scarce and computer simulations like those presented in this work may provide some insights that can be useful to design new experiments. PMID- 25451552 TI - Decreased dopamine receptor 1 activity and impaired motor-skill transfer in Dyt1 DeltaGAG heterozygous knock-in mice. AB - DYT1 dystonia is a movement disorder caused by a trinucleotide deletion (DeltaGAG) in DYT1 (TOR1A), corresponding to a glutamic acid loss in the C terminal region of torsinA. Functional alterations in the basal ganglia circuits have been reported in both DYT1 dystonia patients and rodent models. Dyt1 DeltaGAG heterozygous knock-in (KI) mice exhibit motor deficits and decreased striatal dopamine receptor 2 (D2R) binding activity, suggesting a malfunction of the indirect pathway. However, the role of the direct pathway in pathogenesis of dystonia is not yet clear. Here, we report that Dyt1 KI mice exhibit significantly decreased striatal dopamine receptor 1 (D1R) binding activity and D1R protein levels, suggesting the alteration of the direct pathway. The decreased D1R may be caused by translational or post-translational processes since Dyt1 KI mice had normal levels of striatal D1R mRNA and a normal number of striatal neurons expressing D1R. Levels of striatal ionotropic glutamate receptor subunits, dopamine transporter, acetylcholine muscarinic M4 receptor and adenosine A2A receptor were not altered suggesting a specificity of affected polytopic membrane-associated proteins. Contribution of the direct pathway to motor-skill learning has been suggested in another pharmacological rat model injected with a D1R antagonist. In the present study, we developed a novel motor skill transfer test for mice and found deficits in Dyt1 KI mice. Further characterization of both the direct and the indirect pathways in Dyt1 KI mice will aid the development of novel therapeutic drugs. PMID- 25451555 TI - Echinococcus granulosus antigen B: a Hydrophobic Ligand Binding Protein at the host-parasite interface. AB - Lipids are mainly solubilized by various families of lipid binding proteins which participate in their transport between tissues as well as cell compartments. Among these families, Hydrophobic Ligand Binding Proteins (HLBPs) deserve special consideration since they comprise intracellular and extracellular members, are able to bind a variety of fatty acids, retinoids and some sterols, and are present exclusively in cestodes. Since these parasites have lost catabolic and biosynthetic pathways for fatty acids and cholesterol, HLBPs are likely relevant for lipid uptake and transportation between parasite and host cells. Echinococcus granulosus antigen B (EgAgB) is a lipoprotein belonging to the HLBP family, which is very abundant in the larval stage of this parasite. Herein, we review the literature on EgAgB composition, structural organization and biological properties, and propose an integrated scenario in which this parasite HLBP contributes to adaptation to mammalian hosts by meeting both metabolic and immunomodulatory parasite demands. PMID- 25451556 TI - Dietary n-3/long-chain n-3 polyunsaturated fatty acids for prevention of sporadic colorectal tumors: a randomized controlled trial in polypectomized participants. AB - To address preventive effects of n-3 PUFAs/LC n-3 PUFAs on CRTs, a randomized controlled trial was conducted. One-hundred four experimental group participants were advised to increase intake of n-3 PUFAs, including fish/shell fish, fish oil supplements and perilla oils, and to decrease consumption of n-6 PUFAs and fats/oils as a whole for 24 months. One-hundred one control group participants were only cautioned to reduce consumption of fats/oils as a whole. Random allocation was satisfactorily attained, and participants sufficiently complied with our regimen. Intakes, plasma concentrations, and compositions of the RBC and sigmoid colon membranes of n-3 PUFAs, LC n-3 PUFAs, EPA and DHA increased, and the ratios of n-6 PUFAs/n-3 PUFAs and AA/LC n-3 PUFAs decreased without any adverse response. Twenty-four months after the intervention, the multivariate adjusted hazard ratio (95% confidence intervals) was estimated to be 0.805 (0.536 1.209) with a signal towards the reduced CRT incidence. PMID- 25451557 TI - A method for long term stabilisation of long chain polyunsaturated fatty acids in dried blood spots and its clinical application. AB - Conventional assays of omega-3 long chain polyunsaturated fatty acid (n-3 LCPUFA) status in humans involve venous blood collection and expensive, multi-step processes that limit their usefulness as screening tools. This study aimed to develop a capillary dried blood spot (DBS) system capable of protecting n-3 LCPUFA from oxidation for up to 2 months at room temperature (20-25 degrees C). We demonstrated that a DBS system comprising both an antioxidant and chelating agent on silica-gel coated paper prevented any significant change in the n-3 LCPUFA profile after 2 months. Our DBS assay was then tested in fifty subjects, and this demonstrated the presence of strong and significant correlations between the results obtained from the DBS system and those obtained from conventional measures for all fatty acids, in particular the n-3 LCPUFA EPA and DHA (r>0.96, P<0.0001). This study therefore validates our DBS system as a reliable method for the assessment of n-3 LCPUFA status in humans. PMID- 25451558 TI - Partial replacement of dietary linoleic acid with long chain n-3 polyunsaturated fatty acids protects against dextran sulfate sodium-induced colitis in rats. AB - Imbalances in the dietary n-6 and n-3 polyunsaturated fatty acids have been implicated in the increased prevalence of inflammatory bowel disease. This study investigated the effects of substitution of linoleic acid with long chain n-3 polyunsaturated fatty acids and hence decreasing n-6:n-3 fatty acid ratio on inflammatory response in dextran sulfate sodium induced colitis. Male weanling Sprague Dawley rats were fed diets with n-6:n-3 fatty acid in the ratios of 215,50,10 or 5 for 3 months and colitis was induced by administration of dextran sulfate sodium in drinking water during last 11 days. Decreasing the dietary n 6:n-3 fatty acid ratio to 10 and 5 significantly attenuated the severity of colitis as evidenced by improvements in clinical symptoms, reversal of shortening of colon length, reduced severity of anemia, preservation of colonic architecture as well as reduced colonic mucosal myeloperoxidase activity. This protection was associated with suppression of colonic mucosal proinflammatory mediators such as TNFalpha, IL-1beta and nitric oxide. These findings suggest that long chain n-3 polyunsaturated fatty acids at a level of 3.0 g/kg diet (n-6:n-3 ratio of 10) prevents dextran sulfate sodium induced colitis by suppressing the proinflammatory mediators. PMID- 25451559 TI - Surgical management of vascular access related aneurysms to salvage dialysis access: case report and a systematic review of the literature. AB - PURPOSE: We retrospectively evaluated the surgical outcome of revising vascular access related aneurysms (VARAs) to salvage dialysis access. METHODS: Twenty-six consecutive hemodialysis patients (mean age 67.6 years, range: 32-89 years) who presented with true or false VARA and underwent surgery between January 2006 and February 2011 were enrolled in this study, and comprised 11 women and 15 men. Aneurysms were true in 21 patients and false in five; native arteriovenous fistulas (AVFs) were reported in 23, including one infected native pseudoaneurysm, and arteriovenous prosthetic grafts (AVGs) in three. The mean aneurysm diameter was 29.8 +/- 8.0 mm, ranging from 18 to 50 mm. Indications of surgical intervention were local pain, rapid enlargement of the aneurysm, and AVF failure due to stenosis. Surgical revision was performed by resection of VARA and concomitant creation of a new proximal arteriovenous anastomosis in 18 patients. RESULTS: Two aneurysms were ruptured by blunt dissection; however, bleeding did not occur due to prior clamping of the inflow artery without hemodynamic compromise. VARA plication was performed in one case in which severe calcified VARA could not be incised. No significant complications were reported, except for delayed wound healing in three patients and minor peripheral neuropathy in five. The postoperative course was uneventful without hospital mortality in all patients with VARA. CONCLUSIONS: Aggressive surgical management of VARAs is likely to become an acceptable procedure to salvage dialysis access and consistently maintain AVF or AVG function. PMID- 25451560 TI - The changing epidemiology of inflammatory bowel disease: identifying new high risk populations. PMID- 25451561 TI - Neurocognitive function among middle-aged and older Hispanic/Latinos: results from the Hispanic Community Health Study/Study of Latinos. AB - We sought to examine and describe neurocognitive function among middle-aged and older Hispanic/Latino Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants. We analyzed baseline cross-sectional data from the middle-aged and older (ages 45-74 years old) participants (n = 9,063) to calculate neurocognitive function scores and their correlates. Older age and higher depressive symptoms scores were associated with lower average neurocognitive performance, whereas greater educational attainment and household income were associated with higher neurocognitive performance. Hispanic/Latino heritage groups significantly varied in neurocognitive performances. Some neurocognitive differences between Hispanics/Latinos were maintained after controlling for language preference, education, household income, and depressive symptoms. We found notable differences in neurocognitive scores between Hispanic/Latino heritage groups that were not fully explained by the cultural and socioeconomic correlates examined in this study. Further investigations into plausible biological and environmental factors contributing to the Hispanic/Latino heritage group differences in neurocognitive found in the HCHS/SOL are warranted. PMID- 25451562 TI - Tumor necrosis factor-related apoptosis-inducing ligand in vascular inflammation and atherosclerosis: a protector or culprit? AB - In addition to inducing tumor cell apoptosis, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows broad biological functions both in vitro and in vivo. TRAIL gene deletion enhanced atherogenesis in hyperlipidemic mice, supporting that endogenous TRAIL has protective actions in maintaining blood vessel homeostasis and repressing atherosclerosis. The mechanisms of this beneficial effect are not understood. It remains to be determined whether the athero-protective action of TRAIL is via direct impacts on residential vascular cells or indirectly by modulating systemic immune functions. However, in vitro experiments indicate that excessive TRAIL may stimulate endothelial cell apoptosis, smooth muscle proliferation and migration, and inflammatory responses. Moreover, TRAIL can stimulate lipid uptake and foam cell formation in cultured macrophages. Here we provide a critical review on the potential relationships between TRAIL and atherosclerosis. We propose that increased TRAIL production may also have potential detrimental effects on vascular inflammation and atherosclerosis. Further in vivo experiments are warranted to elucidate the effects of exogenous TRAIL on atherogenesis. PMID- 25451563 TI - Safety and efficacy of fibrate-statin combination therapy compared to fibrate monotherapy in patients with dyslipidemia: a meta-analysis. AB - BACKGROUND: Dyslipidemia is a major risk factor for the development of cardiovascular disease. Treatment with fibrate, statins, or other lipid-lowering drugs prevents primary or recurrent cardiovascular events. However, all lipid lowering drugs have side effects, which may become more severe if combination therapy is prescribed. METHODS: We performed a meta-analysis of published data to compare the safety and efficacy of fibrates alone, compared to fibrate-statin combinations, in patients with dyslipidemia. Six articles were assessed in terms of the efficacy of therapy and nine from the viewpoint of therapeutic safety. RESULTS: In terms of efficacy, fibrate-statin combinations afforded significantly greater reductions in the levels of total cholesterol (SE=-2.248; 95% CI 1.986 2.510), LDL cholesterol (SE=-2.274; 95% CI 2.015-2.533), and triglycerides (SE= 0.465; 95% CI 0.272-0.658) compared to fibrate alone. In terms of safety, treatment with fibrate alone was associated with a significant decrease in the number of kidney-related adverse events (RR=-0.547; 95% CI 0.368-0.812), compared to treatment with fibrate-statin combinations. CONCLUSION: We suggest that treatment with a fibrate-statin combination affords clinical benefits that are superior to treatment with fibrate alone, but increases the risk of side effects (particularly renal). Therapy should thus be carefully monitored. PMID- 25451565 TI - Angiotensin type 1 and type 2 receptors during ontogeny: cardiovascular and renal effects. AB - The renin-angiotensin system (RAS) is a major component of cardiovascular and renal homeostasis, maintaining blood pressure and water and electrolyte balance in health and disease. Whilst knowledge regarding the RAS in adult organisms has substantially increased over the last three decades, physiological effects and levels of functioning of the system during the perinatal period are poorly understood. It has been shown, however, that the RAS is subject to remarkable developmental changes that involve all system components, including the main active biologic peptide, angiotensin II (Ang II) and the receptors through which these effects are mediated, type 1 receptors (AT1Rs) and type 2 receptors (AT2Rs). The pattern of developmental changes suggests a relevant physiological role for the RAS in the critical cardio-renal adaptations to life after birth. In adulthood, the majority of the physiological functions of Ang II are mediated by activation of AT1Rs, whilst the roles for AT2Rs are less clear. Although the integrity of the AT1R signalling pathway is a pre-requisite for normal renal development, the physiological effects mediated by A1TRs during ontogeny are not well characterized. Much less is known regarding the roles that AT2Rs may play in regulating cardio-renal homeostasis in the newborn, despite the fact that the RAS appears to be a major player in fetal programming of disease. This article reviews current knowledge regarding the temporal and spatial expression pattern of ATRs during ontogeny, the cardiovascular and renal effects mediated by the ATRs early in life, as well as the clinical relevance for ATRs in the newborn period. PMID- 25451564 TI - Antiplatelet action of indirubin-3'-monoxime through suppression of glycoprotein VI-mediated signal transduction: a possible role for ERK signaling in platelets. AB - We investigated the antiplatelet activity of indirubin-3'-monoxime (I3O) and the underlying mechanisms. In a rat carotid artery injury model, oral administration (20 mg/kg/day) of I3O for 3 days significantly prolonged occlusion time, and ADP- and collagen-induced platelet aggregation. In washed platelets in vitro, I3O potently inhibited collagen-induced platelet aggregation by suppressing phospholipase Cgamma2 (PLCgamma2) phosphorylation, subsequently blocking diacylglycerol and arachidonic acid (AA) formation, P-selectin secretion and the production of thromboxane B2. Platelet aggregation induced by phorbol-12 myristate 13-acetate, a protein kinase C (PKC) activator, was inhibited by I3O. Both I3O and U0126, an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor, markedly reduced collagen-induced phosphorylation of ERK1/2 and p47, resulting in the blockade of cyclooxygenase (COX)-mediated AA metabolite production in AA-treated platelets. I3O suppressed phosphorylation of JNK, p38, GSK-3beta, and AKT. I3O inhibited glycoprotein VI (GPVI), as a collagen receptor, by suppressing the phosphorylation of tyrosine kinase Syk of GPVI and the phosphorylation of PLCgamma2 and ERK1/2 stimulated by convulxin, as a specific stimulator. Our results indicate that an antiplatelet effect of I3O is due to the suppression of GPVI-mediated signaling pathways. In collagen-stimulated platelets, ERK1/2 phosphorylation is adenylyl cyclase-dependent and leads to the modulation of PKC-p47 signaling and COX-1-mediated AA-metabolic pathways. PMID- 25451567 TI - Quaternary ammonium salt containing soybean oil: an efficient nanosize gene delivery carrier for halophile green microalgal transformation. AB - Dunaliella salina, a halophile green microalga, is considered a robust photobioreactor and a remarkable cost beneficial system for the production of therapeutic recombinant proteins. In this study, with low overall cost, a proper cationic lipid was synthesized from renewable soybean oil as an efficient gene delivery carrier for D. salina cells to create appropriate protein-producing transformed cell lines. To obtain an effective carrier, quaternary ammonium salt containing soybean oil (QASSO) was synthesized through the ring opening reaction of the epoxy groups of epoxidized soybean oil with diethylamine. QASSO was characterized using nuclear magnetic resonance and Fourier-transform infrared instruments. QASSO was used to prepare nanolipoplex construct using plasmid DNA molecules containing green fluorescent protein (GFP) as reporter gene. These nanolipoplexes (QASSO-pGFP, N/P=3) and QASSO had diameter of 63.62 and 110.63 nm, and zeta potential of -68.89 and 48.25 mV at pH 7.0, respectively. Results indicated the GFP gene expression and cytoplasmic accumulation of GFP protein in the transformants after incubation under desirable conditions for 48 h and 1 week. The transformation efficiency was quantitatively assayed by flow cytometry, which yielded transformations of 58.87% and 48.34% for QASSO and 38.32% and a negligible percentage for Polyfect(r) after 48 h and 1 week incubation, respectively. PMID- 25451566 TI - Aldose reductase inhibition alleviates hyperglycemic effects on human retinal pigment epithelial cells. AB - Chronic hyperglycemia is an important risk factor involved in the onset and progression of diabetic retinopathy (DR). Among other effectors, aldose reductase (AR) has been linked to the pathogenesis of this degenerative disease. The purpose of this study was to investigate whether the novel AR inhibitor, beta glucogallin (BGG), can offer protection against various hyperglycemia-induced abnormalities in human adult retinal pigment epithelial (ARPE-19) cells. AR is an enzyme that contributes to cellular stress by production of reactive oxygen species (ROS) under high glucose conditions. A marked decrease in cell viability (from 100% to 78%) following long-term exposure (4 days) of RPE cells to high glucose (HG) was largely prevented by siRNA-mediated knockdown of AR gene expression (from 79% to 97%) or inhibition using sorbinil (from 66% to 86%). In HG, BGG decreased sorbitol accumulation (44%), ROS production (27%) as well as ER stress (22%). Additionally, we demonstrated that BGG prevented loss of mitochondrial membrane potential (MMP) under HG exposure. We also showed that AR inhibitor pretreatment reduced retinal microglia-induced apoptosis in APRE-19 cells. These results suggest that BGG may be useful as a therapeutic agent against retinal degeneration in the diabetic eye by preventing RPE cell death. PMID- 25451568 TI - Polyoxometalates as antitumor agents: Bioactivity of a new polyoxometalate with copper on a human osteosarcoma model. AB - Polyoxometalates (POMs) are early transition metal oxygen anion clusters. They display interesting biological effects mainly related to their antiviral and antitumor properties. On the other hand, copper compounds also show different biological and pharmacological effects in cell culture and in animal models. We report herein for the first time, a detailed study of the mechanisms of action of a copper(II) compound of the group of HPOMs with the formula K7Na3[Cu4(H2O)2(PW9034)2]20H2O (PW9Cu), in a model of human osteosarcoma derived cell line, MG-63. The compound inhibited selectively the viability of the osteosarcoma cells in the range of 25-100MUM (p<0.01). Besides, we have clearly shown a more deleterious action of PW9Cu on tumor osteoblasts than in normal cells. Cytotoxicity studies also showed deleterious effects for PW9Cu. The increment of reactive oxygen species (ROS) and the decrease of the GSH/GSSG ratio were involved in the antiproliferative effects of PW9Cu. Moreover, the compound caused cell cycle arrest in G2 phase, triggering apoptosis as determined by flow cytometry. As a whole, these results showed the main mechanisms of the deleterious effects of PW9Cu in the osteosarcoma cell line MG-63, demonstrating that this compound is a promissory agent for cancer treatments. PMID- 25451569 TI - Blueberry anthocyanins-enriched extracts attenuate the cyclophosphamide-induced lung toxicity. AB - The influence of blueberry anthocyanins-enriched extracts (BAE) on cyclophosphamide (CTX)-induced lung damage was investigated. BAE (20 and 80mg/kg/d) were orally dosed to rats 7d both before and after CTX administration (100mg/kg, intraperitoneal injection, single dose). The results showed CTX treatment induced obvious pathological pulmonary injury with raised injury score and lung/body weight ratio. In CTX group, the activity of lysosomal proteases, lung permeability and the number of neutrophil infiltrates all elevated. On the other hand, claudin-4 and zonula occluden-1 protein levels decreased. And also changes of oxidative stress and inflammatory cytokines parameters together with nuclear factor-kappaB activation were shown. Improvement of all above-mentioned physiological and biochemical parameters was exhibited in BAE groups, with a dose dependent manner. In conclusion, BAE attenuate the CTX-induced lung toxicity, antioxidant and anti-inflammatory characteristics are involved in the protective mechanism of BAE. PMID- 25451570 TI - Evaluation of enzyme inhibition kinetics in drug-drug interactions. AB - Inhibition of CYP enzymes is thought to be the most common cause of drug-drug and/or herb-drug interactions. To characterize the inhibition of CYP enzymes activities by chemicals, enzyme inhibition kinetic experiments are usually carried out. The purpose of this letter is to call attention to evaluate the enzyme inhibition kinetics in drug-drug interactions. PMID- 25451571 TI - Effect of functionalized and non-functionalized nanodiamond on the morphology and activities of antioxidant enzymes of lung epithelial cells (A549). AB - The development of nanotechnology opens up new ways for biomedical applications of unmodified and modified diamond nanoparticles which are one of the most popular nanomaterials used in biology, biotechnology, medicine, cosmetics and engineering. They have been applied as diagnostic and therapeutic agents because they can be targeted to and localized in cells causing apoptosis and necrosis. The problem of biocompatibility of nanodiamonds at higher concentrations is thus of primary importance. The first step in the modification of DNPs is usually the introduction of hydrogen groups, which can bind other functional groups. The basic method to introduce -OH groups onto nanoparticles is the Fenton reaction. The aim of this study was to compare the effect of unmodified nanodiamond particles and nanoparticles modified by introduction of -OH groups and etoposide onto their surface reaction on human non-small lung cancer cells. A549 cells were incubated with 2-100MUg/ml nanopowders and at 0.6-24MUg/ml etoposide in the DMEM medium. We observed a decrease of cells viability and generation of reactive oxygen/ nitrogen species in the cells after incubation, estimated by oxidation of H2DCF-DA and DAF-FM-DA. Modified detonation nanoparticles affected also the cellular content of glutathione and activities of main antioxidant enzymes (glutathione peroxidase, glutathione reductase, glutathione S-transferase, superoxide dismutase and catalase). The results of TEM microscopy show changes in cell morphology. These data demonstrate that modified nanoparticles induce oxidative stress in the target cells. PMID- 25451572 TI - The role of the efflux carriers Abcg2 and Abcc2 for the hepatobiliary elimination of benzo[a]pyrene and its metabolites in mice. AB - The ATP-binding cassette transporters Breast Cancer Resistance Protein (Abcg2) and Multidrug Resistance-associated Protein 2 (Abcc2) play an important role for the hepatobiliary elimination of drugs and toxins as well as their metabolites. Previous in vitro transport studies showed that both transporters are involved in the active efflux of phase II metabolites of carcinogenic benzo[a]pyrene (BP), however the role of these carriers in hepatobiliary elimination in vivo is still unknown. In the present study, Abcg2(-/-) and Abcc2(-/-) knockout mice were used to elucidate the role of Abcg2 and Abcc2 for the hepatobiliary excretion of BP and its metabolites. After intravenous application of [(3)H]BP the hepatobiliary excretion was significantly reduced in these mice: whereas wild type mice excreted on average 25.4% of the applied dose into the bile over 90min, Abcg2(-/ ) knockout mice only excreted 10.7% and Abcc2(-/-) knockout mice 8.6%. As a consequence, [(3)H]BP concentrations were in general higher in the plasma and in most of the organs of the Abcg2 and Abcc2 knockout mice. Both transporters may have a protective function for BP-induced carcinogenesis in humans, due to its crucial importance for the hepatobiliary elimination of BP via bile. Subjects with reduced ABCG2 or ABCC2 expression might have higher oral bioavailability for BP due to a reduced excretion and so might be more susceptible to BP-induced carcinogenesis. PMID- 25451573 TI - Fatty acids binding to human serum albumin: Changes of reactivity and glycation level of Cysteine-34 free thiol group with methylglyoxal. AB - Fatty acids (FAs) binding to human serum albumin (HSA) could lead to the changes of Cys-34 thiol group accessibility and reactivity, i.e. its scavenger capacity and antioxidant property. The influence of saturated, mono and poly unsaturated, and fish oil FAs binding to HSA on the carbonylation level and the reactivity of HSA-SH and HSA modified with methylglyoxal (MG-HSA-SH) was investigated. Changes of thiol group reactivity were followed by determination of pseudo first order rate constant (k') for thiols reaction with 5,5'-dithiobis(2-nitrobenzoic acid). HSA changes were monitored using native PAG electrophoresis and fluorescence spectroscopy. For FA/HSA molar ratios screening, qTLC and GC were used. FAs increase thiol group carbonylation levels from 8% to 20%. The k' values obtained for FAs-free HSA-SH and FAs-free MG-HSA-SH are almost equal (7.5*10(-3) and 7.7*10(-3)s(-1), resp.). Binding of all FAs amplify the reactivity (k' values from 14.6*10(-3) to 26.0*10(-3)s(-1)) of HSA-SH group for 2-3.5times in the order: palmitic, docosahexaenoic, fish oil extract, stearic, oleic, myristic and eicosapentaenoic acid, due to HSA conformational changes. FAs-bound MG-HSA-SH samples follow that pattern, but their k' values (from 9.8*10(-3) to 14.3*10( 3)s(-1)) were lower compared to unmodified HSA due to additional conformation changes of HSA molecules during carbonylation. Carbonylation level and reactivity of Cys34 thiol group of unmodified and carbonylated HSA depend on type of FAs bound to HSA, which implies the possibility for modulation of -SH reactivity (scavenger capacity and antioxidant property) by FAs as a supplement. PMID- 25451574 TI - Sauchinone attenuates liver fibrosis and hepatic stellate cell activation through TGF-beta/Smad signaling pathway. AB - Hepatic stellate cells (HSCs) are key mediators of fibrogenesis, and the regulation of their activation is now viewed as an attractive target for the treatment of liver fibrosis. Here, the authors investigated the ability of sauchinone, an active lignan found in Saururus chinensis, to regulate the activation of HSCs, to prevent liver fibrosis, and to inhibit oxidative stress in vivo and in vitro. Blood biochemistry and histopathology were assessed in CCl4 induced mouse model of liver fibrosis to investigate the effects of sauchinone. In addition, transforming growth factor-beta1 (TGF-beta1)-activated LX-2 cells (a human HSC line) were used to investigate the in vitro effects of sauchinone. Sauchinone significantly inhibited liver fibrosis, as indicated by decreases in regions of hepatic degeneration, inflammatory cell infiltration, and the intensity of alpha-smooth muscle actin staining in mice. Sauchinone blocked the TGF-beta1-induced phosphorylation of Smad 2/3 and the transcript levels of plasminogen activator inhibitor-1 and matrix metalloproteinase-2 as well as autophagy in HSCs. Furthermore, sauchinone inhibited oxidative stress, as assessed by stainings of 4-hydroxynonenal and nitrotyrosine: these events may have a role in its inhibitory effects on HSCs activation. Sauchinone attenuated CCl4-induced liver fibrosis and TGF-beta1-induced HSCs activation, which might be, at least in part, mediated by suppressing autophagy and oxidative stress in HSCs. PMID- 25451575 TI - Anti-inflammatory effects of 7-hydroxyl-1-methylindole-3-acetonitrile, a synthetic arvelexin derivative, on the macrophages through destabilizing mPGES-1 mRNA and suppressing NF-kappaB activation. AB - We previously demonstrated that 7-hydroxyl-1-methylindole-3-acetonitrile (7 HMIA), a synthesized analog of arvelexin, showed the strong inhibitory effects on LPS-induced NO and PGE2 production in macrophages. In this study, we focused on elucidating the anti-inflammatory properties of 7-HMIA and the mechanisms involved using in vitro and in vivo experimental models. In LPS-induced RAW 264.7 macrophages, 7-HMIA significantly inhibited the release of proinflammatory mediators such as prostaglandin E2 (PGE2), nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6). We also found that 7-HMIA suppressed PGE2 production not by inhibiting cyclooxygenase-2 (COX-2) expression or activity, but rather by suppressing the mRNA stability of microsomal prostaglandin E synthase (mPGES-1). Furthermore, 7-HMIA mediated attenuation of inducible NO synthase (iNOS), TNF-alpha, and IL-6 was closely associated with suppression of transcriptional activities of nuclear factor-kappa B (NF-kappaB), by decreasing p65 nuclear translocation and Akt phosphorylation. Animal studies revealed that 7-HMIA potently suppressed the carrageenan-induced paw edema and myeloperoxidase (MPO) activity in paw tissues. Taken together, our data indicated that the molecular basis for the anti-inflammatory properties of 7-HMIA involved the inhibition of mRNA stability of mPGES-1 and PI3K/Akt-mediated NF-kappaB pathways. PMID- 25451576 TI - Demethylation of neferine in human liver microsomes and formation of quinone methide metabolites mediated by CYP3A4 accentuates its cytotoxicity. AB - Neferine is a bisbenzylisoquinoline alkaloid isolated from the seed embryos of Nelumbonucifera Gaertn (Lotus) with various potent pharmacological effects. Recently, neferine has attracted attention for its anti-tumor activities. Our study explored its metabolism and cytotoxicity mechanism. Approaches using chemical inhibitors and recombinant human enzymes to characterize the involved enzymes and kinetic studies indicated that the demethylation of neferine by cytochrome P450 (CYP) 2D6 and CYP3A4 fitted a biphasic kinetic profile. Glutathione (GSH) was used as a trapping agent to identify reactive metabolites of neferine, and four novel GSH conjugates were detected with [M+H](+) ions at m/z 902.4, 916.2, 916.1, and 930.4. Based on its structure containing para methylene phenol and results from a product ion scan, GSH tends to conjugate with C9' after undergoing oxidative metabolism to form the binding site predominated by CYP3A4. Furthermore, the addition of recombinant human GSTA1, GSTT1, and GSTP1 had little effect on the production of the GSH conjugates. In a 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide assay, combined with the GSH modulators l-buthionine sulfoximine or N-acetyl-l-cysteine, neferine treatment of MDCK-hCYP3A4 and HepG2 cells revealed that CYP3A4 expression and cellular GSH content could cause an EC50 shift. Metabolic activation mediated by CYP3A4 and GSH depletion significantly enhanced neferine-induced cytotoxicity. PMID- 25451578 TI - Social norms and their influence on eating behaviours. AB - Social norms are implicit codes of conduct that provide a guide to appropriate action. There is ample evidence that social norms about eating have a powerful effect on both food choice and amounts consumed. This review explores the reasons why people follow social eating norms and the factors that moderate norm following. It is proposed that eating norms are followed because they provide information about safe foods and facilitate food sharing. Norms are a powerful influence on behaviour because following (or not following) norms is associated with social judgements. Norm following is more likely when there is uncertainty about what constitutes correct behaviour and when there is greater shared identity with the norm referent group. Social norms may affect food choice and intake by altering self-perceptions and/or by altering the sensory/hedonic evaluation of foods. The same neural systems that mediate the rewarding effects of food itself are likely to reinforce the following of eating norms. PMID- 25451577 TI - Neuroprotective effects of macranthoin G from Eucommia ulmoides against hydrogen peroxide-induced apoptosis in PC12 cells via inhibiting NF-kappaB activation. AB - Oxidative stress-mediated cellular injury has been considered as a major cause of neurodegenerative diseases including Alzheimer and Parkinson diseases. The scavenging of reactive oxygen species (ROS) mediated by antioxidants may be a potential strategy for retarding the disease's progression. Macranthoin G (MCG), isolated from Eucommia ulmoides, is a derivative from chlorogenic acid methyl ester and caffeic acid. This study is aimed to investigate the protective role of MCG against the cytotoxicity induced by hydrogen peroxide (H2O2) and to elucidate potential protective mechanisms in rat pheochromocytoma (PC12) cells. The results showed that the treatment of PC12 cells with MCG prior to H2O2 exposure effectively increased the cell viability, and stabilized the mitochondria membrane potential (MMP); furthermore, it enhanced the antioxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) and the levels of intracellular glutathione (GSH); it also decreased the malondialdehyde (MDA) content, intracellular ROS, caspase-3 activation, as well as cell apoptosis. In addition, the MCG treatment minimized the cell injury by H2O2 via down-regulation of the NF-kappaB pathway as well as activation of phosphorylation of IkappaBalpha, p38, and the extracellular signal regulated kinase (ERK). These results showed that that MCG is promising as a potential therapeutic agent for neurodegenerative diseases induced by oxidative damage and should be encouraged for further research. PMID- 25451579 TI - Maternal employment, acculturation, and time spent in food-related behaviors among Hispanic mothers in the United States. Evidence from the American Time Use Survey. AB - Employment is a major factor underlying im/migration patterns. Unfortunately, lower diet quality and higher rates of obesity appear to be unintended consequences of moving to the US. Changes in food preparation practices may be a factor underlying dietary acculturation. The relationships between employment, acculturation, and food-related time use in Hispanic families have received relatively little attention. We used cross-sectional data collected from Hispanic mothers (ages 18-65) with at least one child <13 years old participating in the 2003-2011 American Time Use Survey (n = 3622) to estimate the relationship between employment, acculturation (US-born vs. im/migrant), and time spent in food preparation and family dinner. Regression models were estimated separately for the employed and the non-working and were adjusted for Hispanic origin group, socio-demographic and household characteristics. Working an eight-hour day was associated with spending 38 fewer minutes in food preparation (-38.0 +/- SE 4.8, p < 001). Although being US-born was associated with spending fewer minutes in food preparation, this relationship varied by origin group. Acculturation did not appear to modify the relationship between hours worked and time spent in food preparation or family dinner. Mothers who worked late hours spent less time eating the evening meal with their families (-9.8 +/- SE 1.3). Although an eight hour workday was associated with a significant reduction in food preparation time, an unexpected result is that, for working mothers, additional time spent in paid work is not associated with the duration of family dinner later that day. PMID- 25451580 TI - Association between Australian-Indian mothers' controlling feeding practices and children's appetite traits. AB - This cross-sectional study examined the association between controlling feeding practices and children's appetite traits. The secondary aim studied the relationship between controlling feeding practices and two proxy indicators of diet quality. Participants were 203 Australian-Indian mothers with children aged 1-5 years. Controlling feeding practices (pressure to eat, restriction, monitoring) and children's appetite traits (food approach traits: food responsiveness, enjoyment of food, desire to drink, emotional overeating; food avoidance traits: satiety responsiveness, slowness in eating, fussiness and emotional undereating) were measured using self-reported, previously validated scales/questionnaires. Children's daily frequency of consumption of core and non core foods was estimated using a 49-item list of foods eaten (yes/no) in the previous 24 hours as an indicator of diet quality. Higher pressure to eat was associated with higher scores for satiety responsiveness, slowness in eating, fussiness and lower score for enjoyment of food. Higher restriction was related to higher scores for food responsiveness and emotional overeating. Higher monitoring was inversely associated with fussiness, slowness in eating, food responsiveness and emotional overeating and positively associated with enjoyment of food. Pressure to eat and monitoring were related to lower number of core and non-core foods consumed in the previous 24 hours, respectively. All associations remained significant after adjusting for maternal and child covariates (n = 152 due to missing data). In conclusion, pressure to eat was associated with higher food avoidance traits and lower consumption of core foods. Restrictive feeding practices were associated with higher food approach traits. In contrast, monitoring practices were related to lower food avoidance and food approach traits and lower non-core food consumption. PMID- 25451581 TI - Mealtime duration in problem and non-problem eaters. AB - Young children commonly encounter difficulties at mealtimes, which are important to address early to avoid the maintenance of problematic eating behaviour. Amongst these are drawn-out meals, which some research has associated with more mealtime problems. However, research on meal duration, and therefore guidelines for appropriate meal length, is lacking. This research aimed to compare the meal duration of problem-eaters and controls, and to examine changes to meal length amongst problem-eaters following a parenting intervention. The mealtimes of 96 problem-eaters and 105 controls were examined via parent-report and in-home observations; meal length was also compared amongst problem-eaters who had received intervention and a waitlist control. Meal duration was similar across groups, though problem-eaters engaged in more aversive behaviour and less eating than controls. Observed eating and mealtime behaviour altered following intervention but not duration. Parents who reported meal length as a specific concern had longer meals and reported less successful feeding than those who did not. These results suggest that what is happening during the meal may better distinguish problem-eaters than duration alone. PMID- 25451582 TI - The role of attentional bias in the effect of food advertising on actual food intake among children. AB - This study examined the potential moderating role of attentional bias (i.e., gaze duration, number of fixations, latency of initial fixation) in the effect of advergames promoting energy-dense snacks on children's snack intake. A randomized between-subject design was conducted with 92 children who played an advergame that promoted either energy-dense snacks or nonfood products. Eye movements and reaction times to food and nonfood cues were recorded to assess attentional bias during playtime using eye-tracking methods. Children could eat freely after playing the game. The results showed that playing an advergame containing food cues increased total intake. Furthermore, children with a higher gaze duration for the food cues ate more of the advertised snacks. In addition, children with a faster latency of initial fixation to the food cues ate more in total and ate more of the advertised snacks. The number of fixations on the food cues did not increase actual snack intake. Food advertisements are designed to grab attention, and this study shows that the extent to which a child's attention is directed to a food cue increases the effect of the advertisement. PMID- 25451583 TI - The effects of a single bout of aerobic or resistance exercise on food reward. AB - It is unknown whether an acute bout of calorie-matched aerobic and resistance exercise alters food reward in a similar manner. Thus, we examined the effects of isocaloric resistance and aerobic exercise sessions on acute food reward. Sixteen men and women (age: 21.9 +/- 2.6 years; BMI: 22.8 +/- 1.8 kg/m(2)) participated in three randomized crossover sessions: aerobic exercise, resistance exercise, and sedentary control. The target exercise energy expenditure was matched at 4 kcal/kg of body weight, and performed at 70% of VO2peak or 12 repetition-maximum (equivalent to 70% of 1 repetition-maximum). A validated computer task assessed the wanting and liking for visual food cues following exercise, and following an ad libitum lunch. Decreases in the relative preference for high vs. low fat foods were noted following exercise compared to the control session, and this was independent of modality (aerobic: P = 0.04; resistance: P = 0.03). Furthermore, the explicit liking for high vs. low fat foods was lower following resistance exercise compared to the control session (P = 0.04). However, these changes in food reward were not correlated with changes in energy intake (EI) between sessions. Exercise, independent of modality, led to decreases in the relative preference for high fat relative to low fat foods. Additionally, decreases in the hedonic "liking" of high fat foods following resistance, but not aerobic, exercise may imply that modality does influence acute food hedonic responses. However, these decreases in food hedonics were not related to lower EI, thus suggesting that a dissociation may exist between food hedonics and actual EI. PMID- 25451585 TI - The evolving content of meals in Great Britain. Results of a survey in 2012 in comparison with the 1950s. AB - This paper examines food eaten at meals in Great Britain. It presents findings about contemporary meal content, reflecting on the relationship between meal content and occasion, and makes comparison with an earlier study. Drawing on an online survey (N = 2784), conducted in September 2012, it describes the food consumed at daily eating events in terms of content, volume and complexity, common components and combinations, and sequence. Socio-demographic and economic differences are examined. Conceptual tools for analysing the association between food content and meal occasions are refined. The paper first explores the regularity of meal patterns. This is followed by description of the contours of the three principal daily eating events, with a brief section on snacks. The paper interprets distinctive features of current patterns by way of comparison with a similar study of eating habits in the 1950s. Findings reveal morning and midday eating events as simple and homogeneous in content, particularly on weekdays, with respondents breakfasting on cereal or toast, and lunching on sandwiches. Evening meals are more complex, structured and varied in content. Common patterns and systematic differentiation can be discerned, particularly across age cohort. Significant historical change can also be observed in relation to meal content and, to a lesser extent, meal pattern. PMID- 25451584 TI - Why don't poor men eat fruit? Socioeconomic differences in motivations for fruit consumption. AB - BACKGROUND: Those of lower socioeconomic status (SES) tend to have less healthy diets than those of higher SES. This study aimed to assess whether differences in motivations for particular foods might contribute to socioeconomic differences in consumption. METHODS: Participants (n = 732) rated their frequency of consumption and explicit liking of fruit, cake and cheese. They reported eating motivations (e.g., health, hunger, price) and related attributes of the investigated foods (healthiness, expected satiety, value for money). Participants were randomly assigned to an implicit liking task (Single Category Implicit Association Task) for one food category. Analyses were conducted separately for different SES measures (income, education, occupational group). RESULTS: Lower SES and male participants reported eating less fruit, but no SES differences were found for cheese or cake. Analyses therefore focused on fruit. In implicit liking analyses, results (for income and education) reflected patterning in consumption, with lower SES and male participants liking fruit less. In explicit liking analyses, no differences were found by SES. Higher SES participants (all indicators) were more likely to report health and weight control and less likely report price as motivators of food choices. For perceptions of fruit, no SES-based differences were found in healthiness whilst significant interactions (but not main effects) were found (for income and education) for expected satiety and value for money. Neither liking nor perceptions of fruit were found to mediate the relationship between SES and frequency of fruit consumption. CONCLUSIONS: There is evidence for social patterning in food motivation, but differences are modified by the choice of implicit or explicit measures. Further work should clarify the extent to which these motivations may be contributing to the social and gender patterning in diet. PMID- 25451587 TI - Nrf2-mediated adaptive response to methyl glyoxal in HepG2 cells involves the induction of AKR7A2. AB - Methyl glyoxal (MG), a highly reactive dicarbonyl metabolite, causes a range of changes within the cell. It forms adducts with DNA and protein and contributes to the progression of several diseases as well as causing hepatic damage. In this study, we have used human hepatoma (HepG2) cells as a model to investigate the induction of protective enzymes in response to MG exposure. We have shown that treating HepG2 cells with sub-lethal concentrations of MG increases the level of NADPH:quinone oxidoreductase (NQO1) mRNA by 4.5-fold, AKR1C3 mRNA by 14-fold and AKR7A2 mRNA by 4-fold. Levels of AKR7A2 protein are increased by 2.1- and 1.8 fold following 9h and 24h exposure of cells to 50 MUM MG. The role of AKR7A2 in protecting HepG2 cells against MG toxicity was further investigated using specific siRNAs against AKR7A2 and Nrf2. Knockdown of AKR7A2 in HepG2 shows that AKR7A2 is responsible for up to 50% of the protection against MG toxicity in HepG2 cells. We have also shown that MG was able to induce the translocation of the transcription factor Nrf2 to the nucleus. HepG2 cells in which Nrf2 had been knocked down exhibited decreased NQO1 and AKR7A2 mRNA levels compared to control cells. In conclusion, these findings indicate that protective enzymes are significantly up-regulated in response to low concentrations of MG in HepG2 cells and that AKR7A2 contributes to protection against MG-induced toxicity. Nrf2 is critical in mediating MG induced expression of protective genes. PMID- 25451586 TI - Evolutionary origins of retinoid active short-chain dehydrogenases/reductases of SDR16C family. AB - Vertebrate enzymes that belong to the 16C family of short-chain dehydrogenases/reductases (SDR16C) were shown to play an essential role in the control of retinoic acid (RA) levels during development. To trace the evolution of enzymatic function of SDR16C family, and to examine the origins of the pathway for RA biosynthesis from vitamin A, we identified putative SDR16C enzymes through the extensive search of available genome sequencing data in a subset of species representing major metazoan phyla. The phylogenetic analysis revealed that enzymes from protostome, non-chordate deuterostome and invertebrate chordate species are found in three clades of SDR16C family containing retinoid active enzymes, which are retinol dehydrogenase 10 (RDH10), retinol dehydrogenases E2 (RDHE2) and RDHE2-similar, and dehydrogenase reductase (SDR family) member 3 (DHRS3). For the initial functional analysis, we cloned RDH10- and RDHE2-related enzymes from the early developmental stages of a non-chordate deuterostome, green sea urchin Lytechinus variegatus, and an invertebrate chordate, sea squirt Ciona intestinalis. In situ hybridization revealed that these proteins are expressed in a pattern relevant to development, while assays performed on proteins expressed in mammalian cell culture showed that they possess retinol-oxidizing activity as their vertebrate homologs. The existence of invertebrate homologs of DHRS3 was inferred from the analysis of phylogeny and cofactor-binding residues characteristic of preference for NADP(H). The presence of invertebrate homologs in the DHRS3 group of SDR16C is interesting in light of the complex mutually activating interaction, which we have recently described for human RDH10 and DHRS3 enzymes. Further functional analysis of these homologs will establish whether this interaction evolved to control retinoid homeostasis only in vertebrates, or is also conserved in pre-vertebrates. PMID- 25451588 TI - Molecular and biochemical characterisation of human short-chain dehydrogenase/reductase member 3 (DHRS3). AB - Dehydrogenase/reductase (SDR family) member 3 (DHRS3), also known as retinal short-chain dehydrogenase/reductase (retSDR1) is a member of SDR16C family. This family is thought to be NADP(H) dependent and to have multiple substrates; however, to date, only all-trans-retinal has been identified as a DHRS3 substrate. The reductive reaction catalysed by DHRS3 seems to be physiological, and recent studies proved the importance of DHRS3 for maintaining suitable retinoic acid levels during embryonic development in vivo. Although it seems that DHRS3 is an important protein, knowledge of the protein and its properties is quite limited, with the majority of information being more than 15 years old. This study aimed to generate a more comprehensive characterisation of the DHRS3 protein. Recombinant enzyme was prepared and demonstrated to be a microsomal, integral-membrane protein with the C-terminus oriented towards the cytosol, consistent with its preference of NADPH as a cofactor. It was determined that DHRS3 also participates in the metabolism of other endogenous compounds, such as androstenedione, estrone, and DL-glyceraldehyde, and in the biotransformation of xenobiotics (e.g., NNK and acetohexamide) in addition to all-trans-retinal. Purified and reconstituted enzyme was prepared for the first time and will be used for further studies. Expression of DHRS3 was shown at the level of both mRNA and protein in the human liver, testis and small intestine. This new information could open other areas of DHRS3 protein research. PMID- 25451589 TI - Alcohol dehydrogenase, SDR and MDR structural stages, present update and altered era. AB - It is now about half a century since molecular research on alcohol dehydrogenase (ADH), short-chain dehydrogenase/reductase (SDR) and medium-chain dehydrogenase/reductase (MDR) started. During this time, at least four stages of research can be distinguished, which led to many ADH, SDR and MDR structures from which their origins could be traced. An introductory summary of these stages is given, followed by a current update on the now known structures, including the present pattern of mammalian MDR-ADH enzymes into six classes and their evolutionary relationships. In spite of the wide spread in evolutionary changes from the "constant" class III to the more "variable" other classes, the change in class V (only confirmed as a transcript in humans) and class VI (absent in humans) are also restricted. Such spread in variability is visible also in other dehydrogenases, but not always so restricted in other co-evolving proteins we have studied. Finally, the shift in era of present ADH research is highlighted, as well as levels of likely future continuation. PMID- 25451591 TI - Resiniferatoxin induces death of bladder cancer cells associated with mitochondrial dysfunction and reduces tumor growth in a xenograft mouse model. AB - Bladder cancer (BC) is the fifth most common non-cutaneous malignancy and the most common form of BC in Western countries is transitional cell carcinoma. Resiniferatoxin (RTX) has found therapeutic usefulness for the treatment of bladder dysfunction but no data are available on its use as chemotherapeutic agent. The aim of this work is to evaluate the use of RTX as new anti-cancer drug in BC therapy. The effects of RTX on cell viability and cell death were evaluated on T24 and 5637 BC cell lines by MTT assay, cell cycle analysis, Annexin-V/PI staining and agarose gel electrophoresis of DNA. Mitochondrial depolarization and ROS production were assessed by flow cytometry. ADP/ATP ratio was measured by bioluminescence and caspase 3 cleavage by Western blot. For in vivo experiments, athymic nude mice, xenografted with T24 cells, received subcutaneous administrations of RTX. Tumor volumes were measured and immunohistochemistry was performed on tumor sections. Our data demonstrated that RTX influences cell cycle and induces necrotic cell death of BC cells by altering mitochondrial function, leading to depolarization, increase in ADP/ATP ratio and ROS production. Moreover, RTX is able to reduce tumor growth in a xenograft mouse model. Overall, we demonstrated that RTX induces necrotic cell death of BC cells and reduces tumor growth in a xenograft mouse model of BC, suggesting RTX as a new potential anti-cancer drug in BC chemotherapy. PMID- 25451590 TI - Shikonin, a constituent of Lithospermum erythrorhizon exhibits anti-allergic effects by suppressing orphan nuclear receptor Nr4a family gene expression as a new prototype of calcineurin inhibitors in mast cells. AB - Over the last few decades, food allergy (FA) has become a common disease in infants in advanced countries. However, anti-allergic medicines available in the market have no effect on FA, and consequently effective drug therapies for FA are not yet available. We have already demonstrated that mucosal mast cells play an essential role in the development of FA in a murine model. Thus, we screened many constituents from medicinal herbs for the ability to inhibit rat basophilic leukemia-2H3 mast-like cell degranulation, and found that shikonin, a naphthoquinone dye from Lithospermum erythrorhizon, exhibited the most potent inhibitory effect among them. Furthermore, shikonin extremely inhibited the IgE/antigen-induced and calcium ionophore-induced upregulation of tumor necrosis factor (TNF)-alpha mRNA expression in mucosal-type bone marrow-derived mast cells (mBMMCs). Global gene expression analysis confirmed by real-time PCR revealed that shikonin drastically inhibited the IgE/antigen-induced and calcium ionophore induced upregulation of mRNA expression of the nuclear orphan receptor 4a family (Nr4a1, Nr4a2 and Nr4a3) in mBMMCs, and knockdown of Nr4a1 or Nr4a2 suppressed the IgE/antigen-induced upregulation of TNF-alpha mRNA expression. Computational docking simulation of a small molecule for a target protein is a useful technique to elucidate the molecular mechanisms underlying the effects of drugs. Therefore, the simulation revealed that the predicted binding sites of shikonin to immunophilins (cyclophilin A and FK506 binding protein (FKBP) 12) were almost the same as the binding sites of immunosuppressants (cyclosporin A and FK506) to immunophilins. Indeed, shikonin inhibited the calcineurin activity to a similar extent as cyclosporin A that markedly suppressed the IgE/antigen-enhanced mRNA expression of TNF-alpha and the Nr4a family in mBMMCs. These findings suggest that shikonin suppresses mucosal mast cell activation by reducing Nr4a family gene expression through the inhibition of calcineurin activity. Therefore, shikonin has therapeutic potential for the treatment of allergic diseases as a new calcineurin inhibitor. PMID- 25451592 TI - Evaluation of anticandidal and antioxidant activities of phenolic compounds from Pyrostegia venusta (Ker Gawl.) Miers. AB - We have investigated the in vitro anticandidal and antioxidant activities of phenolic compounds from Pyrostegia venusta flower extracts. We used the HPLC technique to purify the flavonoid (quercetin-3-O-alpha-l-rhamnopyranosyl-(1->6) beta-d-galactopyranoside) and two phenylpropanoid glycosides (verbascoside and isoverbascoside); we evaluated the antimicrobial activity of the extracts against Candida strains (Candidaalbicans; Candidakrusei ATCC 6258; and the clinical isolate strains of Candida sp. C. albicans, C. krusei, Candidatropicalis, Candidaparapsilosis, and Candidaguilhermondii). The P. venusta flower extracts displayed antimicrobial and antioxidant activities. The semi-purified fraction of the P. venusta flower extract and the phenylpropanoid glycoside verbascoside exhibited activity similar to that of amphotericin B, which denoted that they are potentially applicable as natural antioxidant and anticandidal agents in the pharmaceutical industries. PMID- 25451593 TI - (E)-3-(3,4-dihydroxy-2-methoxyphenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one, a novel licochalcone B derivative compound, suppresses lipopolysaccharide stimulated inflammatory reactions in RAW264.7 cells and endotoxin shock in mice. AB - Activated macrophages mediate inflammation, as they release nitric oxide and pro inflammatory cytokines in various inflammatory diseases. Suppressing macrophage activation may alleviate inflammatory processes. Here, we report that (E)-3-(3,4 dihydroxy-2-methoxyphenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one (DDP), a novel licochalcone B derivative compound, inhibits inflammatory reactions in macrophages and protects mice from endotoxin shock. In vitro experiments showed that DDP suppressed the generation of nitric oxide and pro-inflammatory cytokines by suppressing the activation of nuclear factor-kappaB and activator protein-1 and simultaneously inhibited its upstream inflammatory signaling cascades in lipopolysaccharide in RAW264.7 cells. In an animal model, DDP protected BALB/c mice from lipopolysaccharide-induced endotoxin shock, possibly through inhibition of the production of inflammatory cytokines. DDP inhibited the production of inflammatory mediators and may be a potential target for treatment of various inflammatory diseases. PMID- 25451594 TI - Gastroprotective effects of goniothalamin against ethanol and indomethacin induced gastric lesions in rats: Role of prostaglandins, nitric oxide and sulfhydryl compounds. AB - Goniothalamin (GTN), a styryl-lactone, is a secondary metabolite naturally found in its enantiomeric form (R) in plants of the genus Goniothalamus (Annonaceae). The antiproliferative activity against human tumor cell lines reported in several studies suggest that the alpha,beta-unsaturated delta-lactone moiety emerges as a key Michael acceptor for cysteine residues or other nucleophilic biological molecules. Our group reported on the in vivo activity of (R)- and (S)-GTN as well as its racemic form (rac-GTN) in both Ehrlich solid tumor and carrageenan-induced paw edema in mice, without side effects in the effective doses. Despite the rich body of data on the in vitro GTN biological activity, much less is known about its in vivo pharmacological action. Herein we describe the gastroprotective activity of rac-GTN on chemical-induced gastric ulcers models in rats. GTN has a potent gastroprotective effect on ethanol-induced ulcers (effective dose50=18mg/kg) and this activity is dependent on sulfhydryl compounds and prostaglandins generation, but independent of nitric oxide (NO), gastric secretion and mucus production. We hypothesize that goniothalamin may act as a mild irritant, inducing the production of sulfhydryl compounds and prostaglandins, in a process known as adaptive cytoprotection. This hypothesis is supported by the fact that Michael acceptors are the most potent inducers of antioxidant response (as activation of Nrf2 pathway) through generation of mild oxidative stress and that gastroprotective activity of goniothalamin is inhibited after pre-treatment with NEM (N-ethylmaleimide) and NSAID (non-steroidal anti inflammatory drugs), highlighting the importance of sulfhydryl compounds and prostaglandins on GTN activity. PMID- 25451595 TI - Chloroacetic acid triggers apoptosis in neuronal cells via a reactive oxygen species-induced endoplasmic reticulum stress signaling pathway. AB - Chloroacetic acid (CA), a chlorinated analog of acetic acid and an environmental toxin that is more toxic than acetic, dichloroacetic, or trichloroacetic acids, is widely used in chemical industries. Furthermore, CA has been found to be the major disinfection by-products (DBPs) of drinking water. CA has been reported to be highly corrosive and to induce severe tissue injuries (including nervous system) that lead to death in mammals. However, the effects and underlying mechanisms of CA-induced neurotoxicity remain unknown. In the present study, we found that CA (0.5-2.0 mM) significantly increased LDH release, decreased the number of viable cells (cytotoxicity) and induced apoptotic events (including: increases in the numbers of apoptotic cells, the membrane externalization of phosphatidylserine (PS), and caspase-3/-7 activity) in Neuro-2a cells. CA (1.5 mM; the approximate to LD50) also triggered ER stress, which was identified by monitoring several key molecules that are involved in the unfolded protein responses (including the increase in the expressions of p-PERK, p-IRE-1, p eIF2alpha, ATF-4, ATF-6, CHOP, XBP-1, GRP 78, GRP 94, and caspase-12) and calpain activity. Transfection of GRP 78- and GRP 94-specific si-RNA effectively abrogated CA-induced cytotoxicity, caspase-3/-7 and caspase-12 activity, and GRP 78 and GRP 94 expression in Neuro-2a cells. Additionally, pretreatment with 2.5 mM N-acetylcysteine (NAC; a glutathione (GSH) precursor) dramatically suppressed the increase in lipid peroxidation, cytotoxicity, apoptotic events, calpain and caspase-12 activity, and ER stress-related molecules in CA-exposed cells. Taken together, these results suggest that the higher concentration of CA exerts its cytotoxic effects in neuronal cells by triggering apoptosis via a ROS-induced ER stress signaling pathway. PMID- 25451596 TI - Diacylglycerol kinase (DGK) inhibitor II (R59949) could suppress retinal neovascularization and protect retinal astrocytes in an oxygen-induced retinopathy model. AB - Hypoxia-inducible factors (HIF) play a fundamental role in retinal neovascularization (NV) induced by low oxygen tension. In the presence of oxygen, the HIF-alpha subunit becomes hydroxylated at specific prolyl residues by prolyl hydroxylases (PHD), which triggers HIF-alpha for degradation. In our present study, we examined the effect of R59949, the diacylglycerol kinase (DGK) inhibitor II, on the retinal NV and its potential mechanism in an oxygen-induced retinopathy (OIR) model. OIR model was induced by exposure of hyperoxia (75 % oxygen) to C57BL/6J mice from postnatal day 7 (P7) to P12 and then returned to room air. By intraperitoneal injection once a day (10 MUg/g/day) from P12 to P17, R59949 not only effectively prevented pathologic NV but also preserved the astrocyte morphology. Furthermore, the expression of PHD-2 was upregulated and HIF-1alpha and vascular endothelial growth factor (VEGF) were downregulated in the retina of OIR mice following R59949 treatment. These findings suggested a potential possibility that R59949 suppressed retinal neovascular pathophysiology via PHD2/HIF-1alpha/VEGF pathway. PMID- 25451598 TI - Crystal structure of the Csm3-Csm4 subcomplex in the type III-A CRISPR-Cas interference complex. AB - Clustered, regularly interspaced, short palindromic repeat (CRISPR) loci play a pivotal role in the prokaryotic host defense system against invading genetic materials. The CRISPR loci are transcribed to produce CRISPR RNAs (crRNAs), which form interference complexes with CRISPR-associated (Cas) proteins to target the invading nucleic acid for degradation. The interference complex of the type III-A CRISPR-Cas system is composed of five Cas proteins (Csm1-Csm5) and a crRNA, and targets invading DNA. Here, we show that the Csm1, Csm3, and Csm4 proteins from Methanocaldococcus jannaschii form a stable subcomplex. We also report the crystal structure of the M. jannaschii Csm3-Csm4 subcomplex at 3.1A resolution. The complex structure revealed the presence of a basic concave surface around their interface, suggesting the RNA and/or DNA binding ability of the complex. A gel retardation analysis showed that the Csm3-Csm4 complex binds single-stranded RNA in a non-sequence-specific manner. Csm4 structurally resembles Cmr3, a component of the type III-B CRISPR-Cas interference complex. Based on bioinformatics, we constructed a model structure of the Csm1-Csm4-Csm3 ternary complex, which provides insights into its role in the Csm interference complex. PMID- 25451597 TI - Interplay between E. coli DnaK, ClpB and GrpE during protein disaggregation. AB - The DnaK/Hsp70 chaperone system and ClpB/Hsp104 collaboratively disaggregate protein aggregates and reactivate inactive proteins. The teamwork is specific: Escherichia coli DnaK interacts with E. coli ClpB and yeast Hsp70, Ssa1, interacts with yeast Hsp104. This interaction is between the middle domains of hexameric ClpB/Hsp104 and the DnaK/Hsp70 nucleotide-binding domain (NBD). To identify the site on E. coli DnaK that interacts with ClpB, we substituted amino acid residues throughout the DnaK NBD. We found that several variants with substitutions in subdomains IB and IIB of the DnaK NBD were defective in ClpB interaction in vivo in a bacterial two-hybrid assay and in vitro in a fluorescence anisotropy assay. The DnaK subdomain IIB mutants were also defective in the ability to disaggregate protein aggregates with ClpB, DnaJ and GrpE, although they retained some ability to reactivate proteins with DnaJ and GrpE in the absence of ClpB. We observed that GrpE, which also interacts with subdomains IB and IIB, inhibited the interaction between ClpB and DnaK in vitro, suggesting competition between ClpB and GrpE for binding DnaK. Computational modeling of the DnaK-ClpB hexamer complex indicated that one DnaK monomer contacts two adjacent ClpB protomers simultaneously. The model and the experiments support a common and mutually exclusive GrpE and ClpB interaction region on DnaK. Additionally, homologous substitutions in subdomains IB and IIB of Ssa1 caused defects in collaboration between Ssa1 and Hsp104. Altogether, these results provide insight into the molecular mechanism of collaboration between the DnaK/Hsp70 system and ClpB/Hsp104 for protein disaggregation. PMID- 25451600 TI - One more piece down to solve the III-A CRISPR puzzle. PMID- 25451599 TI - Computational design of selective peptides to discriminate between similar PDZ domains in an oncogenic pathway. AB - Reagents that target protein-protein interactions to rewire signaling are of great relevance in biological research. Computational protein design may offer a means of creating such reagents on demand, but methods for encoding targeting selectivity are sorely needed. This is especially challenging when targeting interactions with ubiquitous recognition modules--for example, PDZ domains, which bind C-terminal sequences of partner proteins. Here we consider the problem of designing selective PDZ inhibitor peptides in the context of an oncogenic signaling pathway, in which two PDZ domains (NHERF-2 PDZ2-N2P2 and MAGI-3 PDZ6 M3P6) compete for a receptor C-terminus to differentially modulate oncogenic activities. Because N2P2 has been shown to increase tumorigenicity and M3P6 to decreases it, we sought to design peptides that inhibit N2P2 without affecting M3P6. We developed a structure-based computational design framework that models peptide flexibility in binding yet is efficient enough to rapidly analyze tradeoffs between affinity and selectivity. Designed peptides showed low micromolar inhibition constants for N2P2 and no detectable M3P6 binding. Peptides designed for reverse discrimination bound M3P6 tighter than N2P2, further testing our technology. Experimental and computational analysis of selectivity determinants revealed significant indirect energetic coupling in the binding site. Successful discrimination between N2P2 and M3P6, despite their overlapping binding preferences, is highly encouraging for computational approaches to selective PDZ targeting, especially because design relied on a homology model of M3P6. Still, we demonstrate specific deficiencies of structural modeling that must be addressed to enable truly robust design. The presented framework is general and can be applied in many scenarios to engineer selective targeting. PMID- 25451602 TI - Short aggregation-prone peptide detectives: finding proteins and truths about aggregation. PMID- 25451601 TI - Transport of L-glutamine, L-alanine, L-arginine and L-histidine by the neuron specific Slc38a8 (SNAT8) in CNS. AB - Glutamine transporters are important for regulating levels of glutamate and GABA in the brain. To date, six members of the SLC38 family (SNATs) have been characterized and functionally subdivided them into System A (SNAT1, SNAT2 and SNAT4) and System N (SNAT3, SNAT5 and SNAT7). Here we present the first functional characterization of SLC38A8, one of the previous orphan transporters from the family, and we suggest that the encoded protein should be named SNAT8 to adhere with the SNAT nomenclature. We show that SLC38A8 has preference for transporting L-glutamine, L-alanine, L-arginine, L-histidine and L-aspartate using a Na+-dependent transport mechanism and that the functional characteristics of SNAT8 have highest similarity to the known System A transporters. We also provide a comprehensive central nervous system expression profile in mouse brain for the Slc38a8 gene and the SNAT8 protein. We show that Slc38a8 (SNAT8) is expressed in all neurons, both excitatory and inhibitory, in mouse brain using in situ hybridization and immunohistochemistry. Furthermore, proximity ligation assay shows highly similar subcellular expression of SNAT7 and SNAT8. In conclusion, the neuronal SLC38A8 has a broad amino acid transport profile and is the first identified neuronal System A transporter. This suggests a key role of SNAT8 in the glutamine/glutamate (GABA) cycle in the brain. PMID- 25451603 TI - How proteins knot their ties. PMID- 25451604 TI - INO80-C and SWR-C: guardians of the genome. AB - The double membrane of the eukaryotic nucleus surrounds the genome, constraining it to a nuclear sphere. Proteins, RNA protein particles and artificial chromosome rings diffuse rapidly and freely throughout the nucleoplasm, while chromosomal loci show subdiffusive movement with varying degrees of constraint. In situ biochemical approaches and live imaging studies have revealed the existence of nuclear subcompartments that are enriched for specific chromatin states and/or enzymatic activities. This sequestration is thought to enhance the formation of heterochromatin, particularly when factors of limited abundance are involved. Implicit in the concept of compartmentation is the idea that chromatin is able to move from one compartment to another. Indeed, in budding yeast, gene activation, repression and the presence of persistent DNA double-strand breaks each has been shown to provoke subnuclear relocalization of chromatin. In some cases, movement has been linked to the action of ATP-dependent chromatin remodeling complexes, more specifically to the Snf2-related ATPase-containing complexes, SWR-C and INO80-C. Here we examine how these multi-subunit remodelers contribute to chromatin-based processes linked to the DNA damage response. We review recent evidence that supports a role for yeast SWR-C and INO80-C in determining the subnuclear position of damaged domains and finally, we recap the multiple ways in which these remodelers contribute to genomic integrity. PMID- 25451605 TI - Differential damage and repair responses of pubococcygeus and bulbospongiosus muscles in multiparous rabbits. AB - AIM: To determine the extent of damage and regeneration associated with multiparity on the pubococcygeus and bulbospongiosus muscles. METHODS: Age matched virgin nulliparous and multiparous rabbits that were killed at days 3 and 20 after the fourth delivery were used to harvest pubococcygeus and bulbospongiosus muscles. The activity of the lysosomal enzyme beta-glucuronidase was used as a muscle damage indicator. The number of immunoreactive myofiber associated nuclei anti-Pax7, -MyoD, and -myogenin, as well as the anti-desmin immunoreactive area were measured in muscle sections to estimate some regenerative stages. Significant differences were considered at a P <= 0.05. RESULTS: The beta-glucuronidase activity was increased at postpartum day 20 in the pubococcygeus muscle. This variable was unaltered in the bulbospongiosus muscles of multiparas regardless of the postpartum day on which this was measured. The number of immunoreactive nuclei anti-Pax7 in the pubococcygeus muscle was similar between nulliparas and multiparas, whilst those of anti-MyoD and anti-myogenin were increased at postpartum days 3 and 20. The same was true for these latter three markers evaluated in the bulbospongiosus muscles, supporting an ongoing regeneration. The desmin-positive percentage of muscle area per field was increased at postpartum day 20 in the pubococcygeus muscle, whilst such an increment was seen at postpartum days 3 and 20 in the bulbospongiosus muscles. CONCLUSIONS: Damage and regeneration of the pubococcygeus and bulbospongiosus muscles are differently influenced by multiparity in rabbits. This could rely on the anatomical location, metabolism, myofiber composition, and muscle exertion during pregnancy and/or the delivery of each muscle. PMID- 25451606 TI - Management of choroidal metastases. AB - BACKGROUND: Choroidal metastases (CM) are the most common malignant intraocular lesion observed in up to 4-12% of necropsy series of patients with solid cancer. The spectrum of presentations varies from prevalent CM in disseminated cancer to isolated CM. CM are responsible for visual deterioration. Depending on the primary cancer, estimated life expectancy, overall cancer presentation and ocular symptoms, the management of CM varies widely. We address the multidisciplinary management of CM and technical aspects of radiotherapy. MATERIAL AND METHODS: A systematic review of literature was performed from 1974 to 2014. RESULTS: Choroidal metastases occur preferentially in breast and lung carcinomas but are reported in all cancer types. The standard treatment remains external beam radiotherapy, applying 30Gy in 10 fractions or 40Gy in 20 fractions. The reported complete response and improved visual acuity rates are 80% and 57% to 89%, respectively. Some chemotherapy or new targeted therapy regimens yield promising CM response rates. DISCUSSION: Radiation therapy consistently shows rapid symptom alleviation, yield excellent local control and functional outcomes. However, there are only few reports on late toxicities after 6months given the unfavorable prognostic of CM patients. Selected patients may live more than two years, underlying the need to better assess mean and long term outcomes. Some authors have favored exclusive systemic strategies with omission of irradiation. The current literature suffers from the scarcity of prospective trials. Duration of tumor response following systemic therapy is rarely reported but appears less favorable as compared to radiotherapy. Systemic treatments may be proposed for pauci-symptomatic CM in a polymetastatic context while radiation therapy remains necessary in symptomatic CM either upfront or as an alternating treatment. Focalized radiation like brachytherapy and proton therapy may be proposed for isolated CM with long disease-free interval between primary and CM, as these techniques have the potential to yield better tumor and functional outcomes in patients with long life expectancy. PMID- 25451607 TI - An HLA-G(*)14bp insertion/deletion polymorphism associates with the development of autistic spectrum disorders. AB - HLA-G expressed by the trophoblast ligates KIR molecules expressed by maternal NK cells at the uterine fetal/maternal interface: this interaction is involved in generating immune tolerance during pregnancy. A 14-bp insertion in the HLA-G 3' UTR associates with significantly reduced levels of both HLA-G mRNA and soluble HLA-G, thus hampering the efficacy of HLA-G-mediated immune tolerance during pregnancy. Because prenatal immune activation is suggested to play an important role in the onset of autistic spectrum disorders (ASD) we performed an in-depth evaluation of HLA-G polymorphisms in a well-characterized cohort of Italian families of ASD children. Results showed that frequency of both homozygous 14bp+/14bp+ genotype and 14bp+ allele was significantly higher in ASD children and their mothers compared to controls (p<0.05 in all cases); analysis of the frequency of transmission of the 14bp+ allele from parents to ASD children and their non-ASD siblings showed that the 14bp+ allele was more frequently transmitted (T) to ASD children, whereas it was preferentially not transmitted (NT) to the non-ASD siblings (overall discrepancy: p=0.02; OR: 2.6, 95% CI: 1.1 6.4). Results herein suggest that HLA-G polymorphisms are associated with ASD development, possibly as a consequence of prenatal immune activation. These data infer that the immune alterations seen in ASD are associated with the maternal fetal interaction alone, and reinforce the observation that different genetic backgrounds characterize ASD children and their non-ASD siblings. PMID- 25451608 TI - Negative affectivity predicts decreased pain tolerance during low-grade inflammation in healthy women. AB - INTRODUCTION: Experimental animal studies provided evidence for a synergistic effect of immunological and psychological stressors on subsequent sickness behaviours. Up to now, little corroborating evidence for such synergy exists for humans, in whom it may provide a mechanism leading to the expression of functional somatic symptoms. The aim of the present study was to determine an interaction between stress(-vulnerability) and an immunological activation on experimental pain sensitivity, i.e., pressure pain threshold and tolerance in healthy humans. METHODS: In healthy female participants (n=25, mean age 22.3 years), negative affectivity (NA) and experienced stress were assessed by questionnaire before receiving a Salmonella typhi vaccine or saline control in a randomized blinded cross-over design. Pressure pain threshold was assessed at the lower back and calves and pain tolerance was assessed at the thumbnail, before and six hours after each injection. RESULTS: Vaccination induced leukocytosis (+100%) and increased serum IL-6 (+670%). NA predicted decreased pain tolerance after vaccination (beta=-.57, p=.007), but not after placebo (beta=.25, p=.26). Post-hoc analyses also demonstrated an association with administration order. DISCUSSION: NA moderated the effects of inflammation on pain tolerance. This finding is consistent with a synergistic model whereby inflammation may lower the threshold for pain reporting in individuals with increased vulnerability for somatic symptom reporting. PMID- 25451609 TI - Elevated levels of IL-6 and IL-18 in manic and hypomanic states in rapid cycling bipolar disorder patients. AB - Inflammatory system dysregulation may be involved in the pathophysiology of bipolar disorder with peripheral cytokine levels varying between affective states; however, the evidence is based primarily on case-control studies and limited by methodological issues. The objectives of the present study were to assess alterations of peripheral cytokine levels between affective states in rapid cycling bipolar disorder patients and to compare these with levels in healthy control subjects. In a longitudinal design, repeated measurements of plasma levels of IL-6, IL-10, IL-18, IL-1beta and TNF-alpha were obtained in affective states of varying polarity during 6-12 months in 37 rapid cycling bipolar disorder patients and compared with repeated measurements in 40 age- and gender matched healthy control subjects, using rigorous laboratory-, clinical- and statistical methodology. Adjusting for demographical, clinical- and lifestyle factors, levels of IL-6 (p<0.05) and IL-18 (p<0.005) were significantly elevated in rapid cycling bipolar disorder patients in a manic/hypomanic state, compared with a depressed and a euthymic state. Compared with healthy control subjects, unadjusted levels of IL-6 (p<0.05) and IL-18 (p<0.05) were elevated in manic/hypomanic bipolar disorder patients. Levels of IL-10 and IL-1beta were undetectable in the majority of samples; high TNF-alpha assay variability was found. The results support a role for altered peripheral immune response signaling in rapid cycling bipolar disorder and suggest that IL-6 and IL-18 could be markers of manic episodes. PMID- 25451611 TI - Effect of long-term sleep restriction and subsequent recovery sleep on the diurnal rhythms of white blood cell subpopulations. AB - While acute modifications of sleep duration induces a wide array of immune function alterations, less is known of how longer periods with insufficient sleep affect immune functions and how they return to normal once recovery sleep is obtained. The purpose of the present study was to investigate the effects of five days of restricted sleep and a subsequent 7-day period of sleep recovery on white blood cell (WBC) subpopulation count and diurnal rhythms. Nine healthy males participated in a sleep protocol consisting of two baseline days (8h of sleep/night), five nights with restricted sleep (4h of sleep/night) and seven days of recovery sleep (8h of sleep/night). During nine of these days, blood was drawn hourly during night-time end every third hour during daytime, and differential WBC count was analyzed. Gradual increase across the days of sleep restriction was observed for total WBC (p<.001), monocytes (p<.001), neutrophils (p<.001) and lymphocytes (p<.05). Subsequent recovery sleep resulted in a gradual decrease in monocytes (p<.001) and lymphocytes (p=.001), but not in neutrophils that remained elevated over baseline level at the end of the 7-day recovery period. These effects were associated with altered diurnal rhythms of total WBC and neutrophils, restricted sleep being associated with higher levels during the night and at awakening, resulting in a flattening of the rhythm. The diurnal alterations were reversed when recovery sleep was allowed, although the amplitude of total WBC, neutrophils and monocytes was increased at the end of the recovery period in comparison to baseline. Altogether, these data show that long-term sleep restriction leads to a gradual increase of circulating WBC subpopulations and alterations of the respective diurnal rhythms. Although some of the effects caused by five days of restricted sleep were restored within the first days of recovery, some parameters were not back to baseline even after a period of seven recovery days. PMID- 25451610 TI - Feeding the beast: can microglia in the senescent brain be regulated by diet? AB - Microglial cells, resident macrophages in the central nervous system (CNS), are relatively quiescent but can respond to signals from the peripheral immune system and induce neuroinflammation. In aging, microglia tend to transition to the M1 pro-inflammatory state and become hypersensitive to messages emerging from immune to-brain signaling pathways. Thus, whereas in younger individuals where microglia respond to signals from the peripheral immune system and induce a well-controlled neuroinflammatory response that is adaptive (e.g., when well controlled, fever and sickness behavior facilitate recovery from infection), in older individuals with an infection, microglia overreact and produce excessive levels of inflammatory cytokines causing behavioral pathology including cognitive dysfunction. Importantly, recent studies indicate a number of naturally occurring bioactive compounds present in certain foods have anti-inflammatory properties and are capable of mitigating brain microglial cells. These include, e.g., flavonoid and non-flavonoid compounds in fruits and vegetables, and n-3 polyunsaturated fatty acids (PUFA) in oily fish. Thus, dietary bioactives have potential to restore the population of microglial cells in the senescent brain to a more quiescent state. The pragmatic concept to constrain microglia through dietary intervention is significant because neuroinflammation and cognitive deficits are co-morbid factors in many chronic inflammatory diseases. Controlling microglial cell reactivity has important consequences for preserving adult neurogenesis, neuronal structure and function, and cognition. PMID- 25451612 TI - Systemic lipopolysaccharide administration impairs retrieval of context-object discrimination, but not spatial, memory: Evidence for selective disruption of specific hippocampus-dependent memory functions during acute neuroinflammation. AB - Neuroinflammation is implicated in impairments in neuronal function and cognition that arise with aging, trauma, and/or disease. Therefore, understanding the underlying basis of the effect of immune system activation on neural function could lead to therapies for treating cognitive decline. Although neuroinflammation is widely thought to preferentially impair hippocampus dependent memory, data on the effects of cytokines on cognition are mixed. One possible explanation for these inconsistent results is that cytokines may disrupt specific neural processes underlying some forms of memory but not others. In an earlier study, we tested the effect of systemic administration of bacterial lipopolysaccharide (LPS) on retrieval of hippocampus-dependent context memory and neural circuit function in CA3 and CA1 (Czerniawski and Guzowski, 2014). Paralleling impairment in context discrimination memory, we observed changes in neural circuit function consistent with disrupted pattern separation function. In the current study we tested the hypothesis that acute neuroinflammation selectively disrupts memory retrieval in tasks requiring hippocampal pattern separation processes. Male Sprague-Dawley rats given LPS systemically prior to testing exhibited intact performance in tasks that do not require hippocampal pattern separation processes: novel object recognition and spatial memory in the water maze. By contrast, memory retrieval in a task thought to require hippocampal pattern separation, context-object discrimination, was strongly impaired in LPS-treated rats in the absence of any gross effects on exploratory activity or motivation. These data show that LPS administration does not impair memory retrieval in all hippocampus-dependent tasks, and support the hypothesis that acute neuroinflammation impairs context discrimination memory via disruption of pattern separation processes in hippocampus. PMID- 25451613 TI - Sleep loss activates cellular inflammation and signal transducer and activator of transcription (STAT) family proteins in humans. AB - Sleep disturbance and short sleep duration are associated with inflammation and related disorders including cardiovascular disease, arthritis, diabetes mellitus, and certain cancers. This study was undertaken to test the effects of experimental sleep loss on spontaneous cellular inflammation and activation of signal transducer and activator of transcription (STAT) family proteins, which together promote an inflammatory microenvironment. In 24 healthy adults (16 females; 8 males), spontaneous production of IL-6 and TNF-alpha in monocytes and spontaneous intranuclear expression of activated STAT1, STAT3, and STAT5 in peripheral blood mononuclear cells (PBMC), monocyte-, and lymphocyte populations were measured in the morning after uninterrupted baseline sleep, partial sleep deprivation (PSD, sleep period from 3a.m. to 7a.m.), and recovery sleep. Relative to baseline, spontaneous monocytic expression of IL-6 and TNF-alpha was significantly greater after PSD (P<0.02) and after recovery sleep (P<0.01). Relative to baseline, spontaneous monocytic expression of activated STAT1 and STAT5 was significantly greater after recovery sleep (P<0.007 and P<0.02, respectively) but not STAT3 (P=0.09). No changes in STAT1, STAT3, or STAT5 were found in lymphocyte populations. Sleep loss induces activation of spontaneous cellular innate immunity and of STAT family proteins, which together map the dynamics of sleep loss on the molecular signaling pathways that regulate inflammatory and other immune responses. Treatments that target short sleep duration have the potential to constrain inflammation and reduce the risk for inflammatory disorders and some cancers in humans. PMID- 25451615 TI - Increased cerebrospinal fluid interleukin-8 in bipolar disorder patients associated with lithium and antipsychotic treatment. AB - Inflammation has been linked to the pathophysiology of bipolar disorder based on studies of inflammation markers, such as cytokine concentrations, in plasma and serum samples from cases and controls. However, peripheral measurements of cytokines do not readily translate to immunological activity in the brain. The aim of the present study was to study brain immune and inflammatory activity. To this end, we analyzed cytokines in cerebrospinal fluid from 121 euthymic bipolar disorder patients and 71 age and sex matched control subjects. Concentrations of 11 different cytokines were determined using immunoassays. Cerebrospinal fluid IL 8 concentrations were significantly higher in patients as compared to controls. The other cytokines measured were only detectable in part of the sample. IL-8 concentrations were positively associated to lithium- and antipsychotic treatment. The findings might reflect immune aberrations in bipolar disorder, or be due to the effects of medication. PMID- 25451614 TI - Differential activation of immune factors in neurons and glia contribute to individual differences in resilience/vulnerability to sleep disruption. AB - Individuals frequently find themselves confronted with a variety of challenges that threaten their wellbeing. While some individuals face these challenges efficiently and thrive (resilient) others are unable to cope and may suffer persistent consequences (vulnerable). Resilience/vulnerability to sleep disruption may contribute to the vulnerability of individuals exposed to challenging conditions. With that in mind we exploited individual differences in a fly's ability to form short-term memory (STM) following 3 different types of sleep disruption to identify the underlying genes. Our analysis showed that in each category of flies examined, there are individuals that form STM in the face of sleep loss (resilient) while other individuals show dramatic declines in cognitive behavior (vulnerable). Molecular genetic studies revealed that Antimicrobial Peptides, factors important for innate immunity, were candidates for conferring resilience/vulnerability to sleep deprivation. Specifically, Metchnikowin (Mtk), drosocin (dro) and Attacin (Att) transcript levels seemed to be differentially increased by sleep deprivation in glia (Mtk), neurons (dro) or primarily in the head fat body (Att). Follow-up genetic studies confirmed that expressing Mtk in glia but not neurons, and expressing dro in neurons but not glia, disrupted memory while modulating sleep in opposite directions. These data indicate that various factors within glia or neurons can contribute to individual differences in resilience/vulnerability to sleep deprivation. PMID- 25451616 TI - A century of pavlovian experiments forming a circuit from the elucidation of neural reflexes to pharmaceuticals and electroceuticals to treat diseases. PMID- 25451617 TI - A long-term follow-up of a randomized controlled trial of mother-infant psychoanalytic treatment: outcomes on the children. AB - A randomized controlled trial (RCT) compared two groups of mother-infant dyads in a Stockholm sample. One had received mother-infant psychoanalytic treatment (MIP group) and the other Child Health Center care (CHCC group). Effects were found on mother-reported depression and expert-rated mother-infant relationship qualities and maternal sensitivity. When the children were 41/2 years old, they were followed up with assessments of attachment representations, socioemotional development, and global functioning. They also were divided into two types according to individual characteristics and psychological well-being: the "OK" and the "Troubled" children. Of 80 dyads in the mother-infant RCT, data were gathered from 66 cases approximately 31/2 years after treatment. The children in the MIP group had better results on global functioning. There were more OK children in the MIP group and more Troubled children in the CHCC group. No other between-group differences were found. A relatively brief mother-infant psychotherapy seemed to help the children function better and be less troubled 31/2 years after therapy. PMID- 25451618 TI - The effect of resveratrol on the recurrent attacks of gouty arthritis. AB - Gouty arthritis is characterized by inflammation induced by monosodium urate (MSU) crystal deposition, which is resulted by an increase of serum urate concentration. The management of gout, especially the recurrent acute attacks of chronic gouty arthritis, is still a problem to be resolved. In this study, we aimed to develop the preventive and therapeutic effect of resveratrol on gouty arthritis. MSU was used to induce gouty arthritis in the foot pad of C57BL/6 mice. Yeast polysaccharide and potassium oxonate were used to induce hyperuricemia in Kunming mice. Resveratrol was intraperitoneal injected to the mice in the treatment group. The pad inflammation and the level of serum uric acid were investigated to estimate the effect of resveratrol in gouty arthritis. Hyperuricemia was significantly detected in the mice treated with yeast polysaccharide and potassium oxonate, and gouty arthritis was successfully induced with MSU in mice. We further identified that resveratrol inhibited pad swelling and pad 99mTc uptake in gouty mice. Moreover, serum uric acid level was also decreased by resveratrol in hyperuricemia mice. This study highlighted that resveratrol might be applied to prevent the recurrent acute attack of gouty arthritis because of its inhibition of articular inflammation and down-regulation of serum uric acid. PMID- 25451619 TI - Increased cortical responses to forepaw stimuli immediately after peripheral deafferentation of hindpaw inputs. AB - Both central and peripheral injuries of the nervous system induce dramatic reorganization of the primary somatosensory cortex. We recently showed that spinal cord injuries at thoracic level in anesthetized rats can immediately increase the responses evoked in the forepaw cortex by forepaw stimuli (above the level of the lesion), suggesting that the immediate cortical reorganization after deafferentation can extend across cortical representations of different paws. Here we show that a complete deafferentation of inputs from the hindpaw induced by injury or pharmacological block of the peripheral nerves in anesthetized rats also increases the responses evoked in the forepaw cortex by forepaw stimuli. This increase of cortical responses after peripheral deafferentation is not associated with gross alterations in the state of cortical spontaneous activity. The results of the present study, together with our previous works on spinal cord injury, suggest that the forepaw somatosensory cortex is critically involved in the reorganization that starts immediately after central or peripheral deafferentation of hindpaw inputs. PMID- 25451620 TI - The associations between preexisting mental disorders and subsequent onset of chronic headaches: a worldwide epidemiologic perspective. AB - Although there is a significant association between preexisting depression and later onset of chronic headache, the extent to which other preexisting mental disorders are associated with subsequent onset of headache in the general population is not known. Also unknown is the extent to which these associations vary by gender or by life course. We report global data from the WHO's World Mental Health surveys (n = 52,095), in which, by means of the Composite International Diagnostic Interview-3.0, 16 mental disorders from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were retrospectively assessed in terms of lifetime prevalence and age of onset. Frequent or severe headaches were assessed using self-reports. After adjustment for covariates, survival models showed a moderate but consistent association between preexisting mood (odds ratios [ORs] = 1.3-1.4), anxiety (ORs = 1.2-1.7), and impulse-control disorders (ORs = 1.7-1.9) and the subsequent onset of headache. We also found a dose-response relationship between the number of preexisting mental disorders and subsequent headache onset (OR ranging from 1.9 for 1 preexisting mental disorder to 3.4 for >=5 preexisting mental disorders). Our findings suggest a consistent and pervasive relationship between a wide range of preexisting mental disorders and the subsequent onset of headaches. This highlights the importance of assessing a broad range of mental disorders, not just depression, as specific risk factors for the subsequent onset of frequent or severe headaches. PERSPECTIVE: This study shows that there is a temporal association between a broad range of preexisting mental disorders and the subsequent onset of severe or frequent headaches in general population samples across the world. PMID- 25451621 TI - Data interpretation in analgesic clinical trials with statistically nonsignificant primary analyses: an ACTTION systematic review. AB - Peer-reviewed publications of randomized clinical trials (RCTs) are the primary means of disseminating research findings. "Spin" in RCT publications is misrepresentation of statistically nonsignificant research findings to suggest treatment benefit. Spin can influence the way readers interpret clinical trials and use the information to make decisions about treatments and medical policies. The objective of this study was to determine the frequency with which 4 types of spin were used in publications of analgesic RCTs with nonsignificant primary analyses in 6 major pain journals. In the 76 articles included in our sample, 28% of the abstracts and 29% of the main texts emphasized secondary analyses with P values <.05; 22% of abstracts and 29% of texts emphasized treatment benefit based on nonsignificant primary results; 14% of abstracts and 18% of texts emphasized within-group improvements over time, rather than primary between-group comparisons; and 13% of abstracts and 10% of texts interpreted a nonsignificant difference between groups in a superiority study as comparable effectiveness. When considering the article conclusion sections, 21% did not mention the nonsignificant primary result, 22% were presented with no uncertainty or qualification, 30% did not acknowledge that future research was required, and 8% recommended the intervention for clinical use. PERSPECTIVE: This article identifies relatively frequent "spin" in analgesic RCTs. These findings highlight a need for authors, reviewers, and editors to be more cognizant of how analgesic RCT results are presented and attempt to minimize spin in future clinical trial publications. PMID- 25451622 TI - Subgrouping for patients with low back pain: a multidimensional approach incorporating cluster analysis and the STarT Back Screening Tool. AB - Early screening for psychological distress has been suggested to improve patient management for individuals experiencing low back pain. This study compared 2 approaches to psychological screening (ie, multidimensional and unidimensional) so that preliminary recommendations on which approach may be appropriate for use in clinical settings other than primary care could be provided. Specifically, this study investigated aspects of the STarT Back Screening Tool (SBT): 1) discriminant validity by evaluating its relationship with unidimensional psychological measures and 2) construct validity by evaluating how SBT risk categories compared to empirically derived subgroups using unidimensional psychological and disability measures. Patients (N = 146) receiving physical therapy for LBP were administered the SBT and a battery of unidimensional psychological measures at initial evaluation. Clinical measures consisted of pain intensity and self-reported disability. Several SBT risk-dependent relationships (ie, SBT low < medium < high risk) were identified for unidimensional psychological measure scores, with depressive symptom scores associated with the strongest influence on SBT risk categorization. Empirically derived subgroups indicated that there was no evidence of distinctive patterns among psychological or disability measures other than high or low profiles; therefore, 2 groups may provide a clearer representation of the level of pain-associated psychological distress, maladaptive coping, and disability in this setting compared with 3 groups as suggested when using the SBT in primary care settings. PERSPECTIVE: This study suggests that the SBT can replace administering several unidimensional psychological measures as a first-line screening measure for psychological distress. However, clinicians need to be aware of the potential for misclassification with SBT results when compared to unidimensional measures. This study also suggests that a modified SBT risk stratification scheme based on empirically derived subgroups could potentially assist in identifying elevated levels of pain-associated psychological distress, maladaptive coping, and disability in practice settings outside of primary care. Patients identified with elevated levels of pain-associated distress and maladaptive coping may be indicated for additional assessment using construct-specific questionnaires. PMID- 25451624 TI - Motor cortical activity during motor tasks is normal in patients with complex regional pain syndrome. AB - Motor dysfunction in complex regional pain syndrome (CRPS) is often considered a functional movement disorder. Earlier studies in patients with functional movement disorders found evidence of cortical inhibition during explicit but not implicit motor tasks, suggesting active inhibition from other brain areas. In this study, we explored whether active inhibition occurs in CRPS patients. We compared patients with CRPS with 2 control groups: healthy controls matched for age and sex, and patients whose hand was immobilized to treat a scaphoid fracture. We used transcranial magnetic stimulation to measure corticospinal excitability at rest and during motor imagery (explicit motor task) and motor observation (implicit motor task). Motor corticospinal excitation measured at rest and during implicit and explicit motor tasks was similar for CRPS patients and healthy controls. Patients with an immobilized hand showed an absence of motor cortical excitation of the corresponding hemisphere during motor imagery of tasks involving the immobilized hand, but not during motor observation. The normal motor cortical processing during motor imagery and motor observation found in the corresponding hemisphere of CPRS patients suggests that the nature of motor dysfunction in this condition differs from that described in literature for patients with functional paresis or under circumstances of limb immobilization. PERSPECTIVE: This study shows that the nature of motor dysfunction in CRPS patients differs from that encountered in patients with functional paresis or under circumstances of limb immobilization. This information is important for patients and pain clinicians and could help prevent implementation of therapeutic strategies based on incorrect assumptions. PMID- 25451623 TI - A developmental analysis of the factorial validity of the parent-report version of the Adult Responses to Children's Symptoms in children versus adolescents with chronic pain or pain-related chronic illness. AB - The widely used Adult Responses to Children's Symptoms measures parental responses to child symptom complaints among youth aged 7 to 18 years with recurrent/chronic pain. Given developmental differences between children and adolescents and the impact of developmental stage on parenting, the factorial validity of the parent-report version of the Adult Responses to Children's Symptoms with a pain-specific stem was examined separately in 743 parents of 281 children (7-11 years) and 462 adolescents (12-18 years) with chronic pain or pain related chronic illness. Factor structures of the Adult Responses to Children's Symptoms beyond the original 3-factor model were also examined. Exploratory factor analysis with oblique rotation was conducted on a randomly chosen half of the sample of children and adolescents as well as the 2 groups combined to assess underlying factor structure. Confirmatory factor analysis was conducted on the other randomly chosen half of the sample to cross-validate factor structure revealed by exploratory factor analyses and compare it to other model variants. Poor loading and high cross-loading items were removed. A 4-factor model (Protect, Minimize, Monitor, and Distract) for children and the combined (child and adolescent) sample and a 5-factor model (Protect, Minimize, Monitor, Distract, and Solicitousness) for adolescents was superior to the 3-factor model proposed in previous literature. Future research should examine the validity of derived subscales and developmental differences in their relationships with parent and child functioning. PERSPECTIVE: This article examined developmental differences in the structure of a widely used measure of caregiver responses to chronic pain or pain-related chronic illness in youth. Results suggest that revised structures that differ across developmental groups can be used with youth with a range of clinical pain-related conditions. PMID- 25451625 TI - Plasma membrane mechanisms in a preclinical rat model of chronic pain. AB - We have recently shown that the prolongation of prostaglandin E2 hyperalgesia in a preclinical model of chronic pain-hyperalgesic priming-is mediated by release of cyclic adenosine monophosphate from isolectin B4-positive nociceptors and its metabolism by ectonucleotidases to produce adenosine. The adenosine, in turn, acts in an autocrine mechanism at an A1 adenosine receptor whose downstream signaling mechanisms in the nociceptor are altered to produce nociceptor sensitization. We previously showed that antisense against an extracellular matrix molecule, versican, which defines the population of nociceptors involved in hyperalgesic priming, eliminated the prolongation of prostaglandin E2 hyperalgesia. To further evaluate the mechanisms at the interface between the extracellular matrix and the nociceptor's plasma membrane involved in hyperalgesia prolongation, we interrupted a plasma membrane molecule involved in versican signaling, integrin beta1, with an antisense oligodeoxynucleotide. Integrin beta1 antisense eliminated mechanical hyperalgesia induced by an adenosine A1 receptor agonist, cyclopentyladenosine, in the primed rat. We also disrupted a molecular complex of signaling molecules that contains integrin beta1, lipid rafts, with methyl-beta-cyclodextrin, which attenuated the prolongation without affecting the acute phase of prostaglandin E2 hyperalgesia, while having no effect on cyclopentyladenosine hyperalgesia. Our findings help to define the plasma membrane mechanisms involved in a preclinical model of chronic pain. PERSPECTIVE: The present study contributes to a further understanding of mechanisms involved in the organization of messengers at the plasma membrane that participate in the transition from acute to chronic pain. PMID- 25451628 TI - Transcranial magnetic stimulation reveals cortical hyperexcitability in episodic cluster headache. AB - Evidence shows involvement of the cerebral cortex in the pathophysiology of cluster headache (CH). Here we investigated cortical excitability in episodic CH patients by using transcranial magnetic stimulation. In 25 patients with episodic CH and 13 healthy subjects we evaluated the motor cortical response to single pulse (ie, motor threshold, input-output curves, cortical silent period) and paired-pulse (ie, intracortical facilitation, short intracortical inhibition) transcranial magnetic stimulation in both hemispheres. Thirteen patients were evaluated outside bout and the remaining 12 patients inside bout. Our results showed increased slope of the input-output curves after stimulation of both hemispheres in patients outside bout and in the hemisphere contralateral to the headache side in patients inside bout. Increased intracortical facilitation was observed in the hemisphere ipsilateral to the headache side in patients evaluated both outside and inside bout; reduced short intracortical inhibition was observed in patients inside bout ipsilateral to the side of pain. In conclusion, we provide evidence of increased cortical excitability in episodic CH both outside and inside bout, especially in the hemisphere ipsilateral to the side of headache attacks. Our results suggest that an abnormal regulation of cortical excitability could be involved in the pathophysiology of CH. PERSPECTIVES: We investigated cortical excitability in episodic cluster headache by using transcranial magnetic stimulation, providing evidence of cortical hyperexcitability in patients both inside and outside bout. We suggest that an abnormal state of cortical excitability could be involved in the pathophysiology of the disease. PMID- 25451627 TI - Effectiveness of jyoti meditation for patients with chronic neck pain and psychological distress--a randomized controlled clinical trial. AB - Chronic neck pain is a common medical complaint partly mediated by psychosocial distress and having a high socioeconomic impact. There is preliminary evidence that stress reduction by meditation might be beneficial in chronic pain syndromes. We aimed to evaluate the effectiveness of an 8-week meditation program (jyoti meditation) in patients with chronic neck pain by means of a randomized clinical trial. Eighty-nine patients (aged 49.7 +/- 10.5 years, 73 female) with chronic neck pain who scored >40 mm on a 100-mm visual analog scale and had concomitant increased perceived stress were randomized to an 8-week meditation program (jyoti meditation) with weekly 90-minute classes (n = 45) or to a home based exercise program (n = 44) with a wait list offer for meditation. Both groups were instructed to practice at home. Outcomes were assessed at baseline and after 8 weeks. Primary outcome measure was change of mean pain at rest (visual analog scale score) from baseline to week 8. Secondary outcomes included pain at motion, functional disability, pain-related bothersomeness, perceived stress, quality of life, and psychological outcomes. Patients had neck pain for a mean of 11 years. Eighteen patients in the meditation group and 16 patients in the exercise group were lost to follow-up. Meditation training significantly reduced pain when compared to the exercise group after 8 weeks (reduction of 45.5 +/- 23.3 mm to 21.6 +/- 17.2 mm in the meditation group, and 43.8 +/- 22.0 mm to 37.7 +/- 21.5 mm in the exercise group; mean difference: 13.2 mm [95% confidence interval: 2.1, 24.4; P = .02]). Pain-related bothersomeness decreased more in the meditation group (group difference 11.0 mm [95% confidence interval: 1.0, 21.0; P = .03]). No significant treatment effects were found for pain at motion, psychological scores, and quality of life, although the meditation group showed nonsignificant greater improvements compared to the exercise group. In conclusion, meditation may support chronic pain patients in pain reduction and pain coping. Further well-designed studies including more active control comparisons and longer-term follow-up are warranted. PERSPECTIVE: This article presents the results of a randomized controlled trial on the clinical effects of an 8-week meditation program or self-care exercise in patients with chronic neck pain. Meditation reduced pain at rest but not disability and might be a useful treatment option for pain management of chronic neck pain. PMID- 25451626 TI - Peripheral group I metabotropic glutamate receptor activation leads to muscle mechanical hyperalgesia through TRPV1 phosphorylation in the rat. AB - Elevated glutamate levels within injured muscle play important roles in muscle pain and hyperalgesia. In this study, we hypothesized that protein kinase C (PKC) dependent TRPV1 phosphorylation contributes to the muscle mechanical hyperalgesia following activation of Group I metabotropic glutamate receptors (mGlu1/5). Mechanical hyperalgesia induced by (R,S)-3,5-dihydroxyphenylglycine (DHPG), an mGlu1/5 agonist, in the masseter muscle was attenuated by AMG9810, a specific TRPV1 antagonist. AMG9810 also suppressed mechanical hyperalgesia evoked by pharmacologic activation of PKC. DHPG-induced mechanical hyperalgesia was suppressed by pretreatment with a decoy peptide that disrupted interactions between TRPV1 and A-kinase-anchoring protein (AKAP), which facilitates phosphorylation of TRPV1. In dissociated trigeminal ganglia, DHPG upregulated serine phosphorylation of TRPV1 (S800), during which DHPG-induced mechanical hyperalgesia was prominent. The TRPV1 phosphorylation at S800 was suppressed by a PKC inhibitor. Electrophysiologic measurements in trigeminal ganglion neurons demonstrated that TRPV1 sensitivity was enhanced by pretreatment with DHPG, and this was prevented by a PKC inhibitor, but not by a protein kinase A inhibitor. These results suggest that mGlu1/5 activation in masseter afferents invokes phosphorylation of TRPV1 serine residues including S800, and that phosphorylation induced sensitization of TRPV1 is involved in masseter mechanical hyperalgesia. These data support a role of TRPV1 as an integrator of glutamate receptor signaling in muscle nociceptors. PERSPECTIVE: This article demonstrates that activation of mGlu1/5 leads to phosphorylation of a specific TRPV1 residue via PKC and AKAP150 in trigeminal sensory neurons and that functional interactions between glutamate receptors and TRPV1 mediate mechanical hyperalgesia in the muscle tissue. PMID- 25451629 TI - Lyme disease: a rigorous review of diagnostic criteria and treatment. AB - Lyme disease was originally identified in Lyme, Connecticut, based upon an unusual cluster of what appeared to be patients with juvenile rheumatoid arthritis. It was subsequently identified as a new clinical entity originally called Lyme arthritis based on the observation that arthritis was a major clinical feature. However, Lyme arthritis is now called Lyme disease based upon the understanding that the clinical features include not only arthritis, but also potential cardiac, dermatologic and neurologic findings. Lyme disease typically begins with an erythematous rash called erythema migrans (EM). Approximately 4-8% of patients develop cardiac, 11% develop neurologic and 45-60% of patients manifest arthritis. The disease is transmitted following exposure to a tick bite containing a spirochete in a genetically susceptible host. There is considerable data on spirochetes, including Borrelia burgdorferi (Bb), the original bacteria identified in this disease. Lyme disease, if an organism had not been identified, would be considered as a classic autoimmune disease and indeed the effector mechanisms are similar to many human diseases manifest as loss of tolerance. The clinical diagnosis is highly likely based upon appropriate serology and clinical manifestations. However, the serologic features are often misinterpreted and may have false positives if confirmatory laboratory testing is not performed. Antibiotics are routinely and typically used to treat patients with Lyme disease, but there is no evidence that prolonged or recurrent treatment with antibiotics change the natural history of Lyme disease. Although there are animal models of Lyme disease, there is no system that faithfully recapitulates the human disease. Further research on the effector mechanisms that lead to pathology in some individuals should be further explored to develop more specific therapy. PMID- 25451630 TI - Refinement treatment of nasal bone fracture: A 6-year study of 329 patients. AB - BACKGROUND: The reliability of X-ray radiography for diagnosing nasal bone fractures (NBFs) remains controversial. Recent studies show that, for determining the orientation and location of the displaced/depressed fracture, nasal sonography is as accurate as facial computed tomography. This retrospective study compared conductor-assisted nasal sonography (CANS) to conventional diagnostic tools and reported subjective patient satisfaction and discomfort after closed reduction combined with tube technique. METHODS: This retrospective study reports the results of 329 refinement treatments for nasal bone fracture (including 199 men and 130 women) performed from 2005 to 2011. All patients were assessed with CANS and completed a survey immediately prior to removing the packing. Questionnaires were adapted from the nasal obstruction symptom evaluation (NOSE) scale. RESULTS: The study found that CANS has a 97.2% rate of accuracy in diagnosing NBF. The visual analog scale scores of nasal obstruction, nasal congestion, sleep disturbance, trouble breathing, and inability to move air through the nose were analyzed. The experimental group scores were significantly different from the control group for all scores (p < 0.001). CONCLUSION: Compared to conventional methods, CANS is more accurate for detecting NBF. We recommend its use as an alternative tool for diagnosing a nasal fracture. Because the tube technique balances pressure between the nasopharynx and middle ear during swallowing, patient comfort is enhanced. Application of these modifications can improve accuracy in diagnosing NBF and can improve the quality of NBF treatment. PMID- 25451631 TI - Short- and long-term results of harmonic scalpel hemorrhoidectomy versus stapler hemorrhoidopexy in treatment of hemorrhoidal disease. AB - PURPOSE: In this prospective randomized study, our aim is to compare the short- and long-term results of harmonic scalpel hemorrhoidectomy (HSH) and stapler hemorrhoidopexy (SH) methods in the surgical treatment of Grade III and Grade IV hemorrhoidal disease. METHODS: Ninety-nine consecutive patients diagnosed with Grade III or Grade IV internal hemorrhoidal disease were included in the study. Patients were randomized to HSH (n = 48) or SH (n = 51) treatments. Data on patient demographic and clinical characteristics, operative details, postoperative pain score on a visual analog scale, additional analgesic requirement, postoperative short- and long-term complications, and recurrence of hemorrhoidal disease were also recorded. Patients were regularly followed for a total period of 24 (6-36) months. RESULTS: The patient demographic and clinical characteristics were similar in the two groups. The operative time was significantly shorter in the HSH group compared with the SH group. Overall pain scores were not significantly different between the groups, although severe pain was significantly more common in the HSH group. Recurrence was significantly lower in the HSH group compared with the SH group. CONCLUSION: HSH and SH are both safe and effective methods for surgical treatment of Grade III and Grade IV hemorrhoidal disease. In our study, the HSH method was determined to be safer, easier, and faster to perform, and associated with fewer long-term recurrences than the SH method. PMID- 25451632 TI - Laparoscopic adrenalectomy for adrenal tumors: a 21-year single-institution experience. AB - OBJECTIVE: We have performed laparoscopic adrenalectomy including retroperitoneoscopic adrenalectomy via a single large port (RASLP) and conventional laparoscopic adrenalectomy (CLA) for adrenal tumors since 1992, and report our experience to date. METHODS: The study population consisted of 134 patients who underwent laparoscopic adrenalectomy from 1992 to 2012. Fifty-eight patients (18 aldosterone-producing adenomas, 13 adenomas with Cushing's syndrome, 1 adenoma with preclinical Cushing's syndrome, and 26 nonfunctioning tumors) were treated using RASLP, and 76 patients (33 aldosterone-producing adenomas, 17 adenomas with Cushing's syndrome, 6 adenomas with preclinical Cushing's syndrome, 17 pheochromocytomas, and 3 nonfunctioning tumors) were treated using CLA. Complications were graded according to the modified Clavien system. RESULTS: The majority of RASLPs were performed during the 1990s, whereas all patients underwent CLA after 2000. The mean operation times (166 vs. 205 minutes, p < 0.01) and intraoperative estimated blood loss (85 vs. 247 mL, p < 0.01) were significantly lower in the CLA group. Conversion to open surgery was required in three patients (5%) in the RASLP group and five patients (7%) in the CLA group (p = 0.73). Postoperative complications were grade 1 in three patients and grades 4 and 5 in one patient each in the RASLP group, whereas grade 2 in one patient was observed in the CLA group (p = 0.085). CONCLUSION: Although this study included biases such as different eras and indications, CLA resulted in decreased operative times, blood loss, and postoperative complications compared with RASLP. CLA has so far become our preferred procedure for patients with adrenal tumor in our experience. PMID- 25451633 TI - Bioconcentration of TNT and RDX in coastal marine biota. AB - The bioconcentration factor (BCF) was measured for 2,4,6-trinitrotoluene (TNT) and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in seven different marine species of varying trophic levels. Time series and concentration gradient treatments were used for water column and tissue concentrations of TNT, RDX, and their environmentally important derivatives 2-amino-4,6-dintrotoluene (2-ADNT) and 4-amino-2,6-dinitrotoluene (4-ADNT). BCF values ranged from 0.0031 to 484.5 mL g(-1) for TNT and 0.023 to 54.83 mL g(-1) for RDX. The use of log K ow value as an indicator was evaluated by adding marine data from this study to previously published data. For the munitions in this study, log K ow value was a good indicator in the marine environment. The initial uptake and elimination rates of TNT and RDX for Fucus vesiculosus were 1.79 and 0.24 h(-1) for TNT and 0.50 and 0.0035 h(-1) for RDX respectively. Biotransformation was observed in all biota for both TNT and RDX. Biotransformation of TNT favored 4-ADNT over 2-ADNT at ratios of 2:1 for F. vesiculosus and 3:1 for Mytilus edulis. Although RDX derivatives were measureable, the ratios of RDX derivatives were variable with no detectable trend. Previous approaches for measuring BCF in freshwater systems compare favorably with these experiments with marine biota, yet significant gaps on the ultimate fate of munitions within the biota exist that may be overcome with the use stable isotope-labeled munitions substrates. PMID- 25451634 TI - [Key messages in nail disease]. AB - Nail diseases are varied, and their diagnosis is often difficult. Misdiagnosis can result in failure to recognize a severe disease in urgent need of treatment and in the prescription of treatments that are inappropriate, long, ineffective, and expensive. Acute paronychia must be managed rapidly, treated with antiseptics several times a day, and closely monitored. Nail lichen must be recognized early and treated rapidly and appropriately to prevent permanent scarring. All chronic pain (to shocks or cold) of the tip of a finger or toe should suggest a glomus tumor. Any unexplained persistent single-finger onychopathy should in principle cause the physician to suspect a tumor, carcinoma, or melanoma and to order a histologic examination. An onychopathy must not be treated as an onychomycosis without diagnostic certainty. Repeated microtraumas of the toenails cause injuries that absolutely must be differentiated from onychomycosis. In growth of the big toenail can often be avoided by appropriate cutting of the nails, leaving in place the lateral parts of the nail plate. PMID- 25451635 TI - [Management of COPD exacerbations: from primary care to hospitalization]. AB - The Societe de pneumologie de langue francaise defines acute exacerbation of chronic obstructive pulmonary disease (AE COPD) as an increase in daily respiratory symptoms, basically duration >= 48h or need for treatment adjustment. Etiology of EA COPD are mainly infectious, viral (rhinovirus, influenzae or parainfluenzae virus, coronavirus, adenovirus and respiratory syncytial virus) or bacterial (Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis). Pollutant exposure can also lead to AE COPD, such as NO2, SO2, ozone or particulates (PM10 and PM2.5). In 30% the etiology remains unknown. Differential diagnoses of AE COPD include infectious pneumonia, pneumothorax, acute heart failure and pulmonary embolism. Presences of signs of severity impose hospitalization: signs of respiratory distress, shock, acute confusion but also fragile patients, insufficient home support or absence of response to initial treatment. AE COPD treatments consist on increase in bronchodilators, chest physiotherapy, and antibiotics if sputum is frankly purulent. Systemic corticosteroids should not be systematic. Recommended dose is 0.5 mg/kg on short course (5-7 days). During hospitalization, oxygen supplementation and thromboprophylaxis could be prescribed. The main interest in non-invasive ventilation is persistent hypercapnia despite optimal medical management. During ambulatory management or hospitalization, clinical assessment at 48-72 h is mandatory. PMID- 25451636 TI - [COPD: beyond the respiratory system]. AB - COPD is a respiratory disease associated with multiple extrapulmonary comorbidities: cardiovascular diseases, osteoporosis, depression and psychological disorders are the most prevalent. Comorbidities, especially ischemic heart disease, represent a major cause of morbidity and mortality in COPD patients. The putative link between COPD and comorbidities could be the low grade systemic inflammation, which is common in COPD. The presence of multiple comorbidities has a strong impact on the management of COPD patients. PMID- 25451637 TI - [Exercise-induced vocal cord dysfunction in asthma: a new diagnostic method]. AB - OBJECTIVE: Vocal cord dysfunction (VCD) is an under-recognized cause of dyspnea and is difficult to diagnose. The symptoms caused by exercise-induced VCD (IEVCD) often falsely suggest asthma, but there is sometimes a real association between the two diseases. The objective of this study was to evaluate a new, simple method for analyzing vocal cord behavior in the diagnosis of IEVCD, and to clarify the prevalence of IEVCD in an uncontrolled asthma population with unexplained exertional dyspnea. METHODS: This single-center study was conducted prospectively between April 2012 and March 2013. The main inclusion criterion was uncontrolled asthma with unexplained dyspnea. The assessment included cardiopulmonary exercise testing and supraglottal laryngoscopy during exercise with measurement of the vocal cord-opening angle (VCOA). Data from 15 asthmatic patients were compared with those from 10 non-asthmatic dyspneic patients (controls) to define specific criteria for the endoscopic diagnosis of IEVCD. RESULTS: Endoscopy during bicycle exercising was well tolerated. Normal value of inspiratory VCOA (itVCOA) was>49 degrees . Values for the itVCOA were lower for asthmatics than for controls when exercising at 50% maximal power (52.8 degrees +/-13.3 degrees and 64.5 degrees +/-8.3 degrees , respectively). Four of the 15 asthmatics (26%) demonstrated IEVCD characterized with itVCOApeak of less than 49 degrees . CONCLUSION: Measurement of VCOA represents a new, simple method for obtaining objective data in the exploration of VCD. The prevalence of IEVCD in uncontrolled asthmatic patients is important (26% in our small sample). IEVCD is probably an under-diagnosed aggravating factor in asthma, and its diagnosis and management could avoid the therapeutic climbing in asthma. This method of analysis may help to accurately and objectively assess vocal cord dysfunction. PMID- 25451638 TI - Cutaneous HPV and skin cancer. AB - Papillomaviruses (HPVs) are small non-enveloped icosahedral viruses that infect the keratinocytes of skin and mucosa. The cutaneous HPV types are represented mainly by the beta and gamma genera, which are widely present in the skin of normal individuals. More than 40 beta-HPV types and 50 gamma-HPV types have been isolated, and these numbers are continuously growing. The main cause of non melanoma skin cancer is exposure to ultraviolet radiation (UVR). However, cutaneous HPVs that belong to the beta genus may act as a co-carcinogen with UVR. The association between beta-HPVs and skin cancer was first reported in patients with epidermodysplasia verruciformis (EV), who frequently develop cutaneous squamous cell carcinoma (SCC) on sun-exposed areas. Isolation of HPVs from the lesions suggested that HPVs might act as a co-carcinogen with UVR in EV patients. Beta-HPVs may also play a role in cutaneous SCC in immunocompromised non-EV and in immunocompetent individuals. Several studies have reported an association of viral DNA and/or antibodies to beta HPV types with SCC. Interestingly, HPV prevalence and viral load decrease during skin carcinogenesis, being significantly higher in actinic keratosis than in SCC, suggesting that the virus may play a role in the early stages of tumour development (the "hit-and-run" hypothesis). Concordantly, in vivo and in vitro studies have shown that E6 and E7 from certain cutaneous HPV types display transforming activities, further confirming their potential role in carcinogenesis. PMID- 25451640 TI - Limb ischemic preconditioning protects against contrast-induced acute kidney injury in rats via phosphorylation of GSK-3beta. AB - Contrast-induced acute kidney injury (CI-AKI) resulting from the use of intravascular iodinated contrast media for diagnostic and interventional cardiovascular procedures is associated with substantial morbidity and mortality. Despite preventative measures intended to mitigate the risk of CI-AKI, there remains a need for a novel and effective therapeutic approach. Limb ischemic preconditioning (LIPC), where short-term ischemia/reperfusion is applied to an arm prior to administration of the contrast agent, has been shown in several trials to preserve renal function in patients at high risk for CI-AKI. However, the underlying mechanism by which this procedure provides renoprotection against contrast media insults is not known. Here, we explored the molecular mechanism(s) of LIPC-induced protection of the kidneys from CI-AKI, particularly the role of phosphorylated glycogen synthase kinase-3beta (GSK-3beta). We used a novel CI-AKI model consisting of 5/6 nephrectomized (NE) rats at 6 weeks after the ablative surgery. LIPC- or sham-treated rats were administered iohexol (10 ml/kg, 3.5 gI) via the tail vein. The results showed that LIPC protected the kidneys against iohexol-induced injury. This protective effect was accompanied by the attenuation of renal dysfunction, tubular damage, apoptosis, mitochondrial swelling, oxidative stress, and inflammation. Furthermore, LIPC-induced renoprotection was blocked via treatment with inhibitors of PI3K (wortmannin or LY294002), but not ERK (U0126 or PD98059). LIPC also increased the protein expression levels of phospho-Akt, phospho-GSK-3beta, and nuclear Nrf2, and decreased the levels of nuclear NF-kappaB. A specific GSK-3beta inhibitor (SB216763) mimicked this effect of LIPC, by inhibiting the opening of the mitochondrial permeability transition pore and reducing the levels of oxidative stress and inflammation via activation of Nrf2 and suppression of NF-kappaB. The above results demonstrate that LIPC induces protection against CI-AKI, making this procedure a promising strategy for preventing CI-AKI. In particular, this renoprotective effect involves the phosphorylation of GSK-3beta. PMID- 25451641 TI - Skin resistance to oxidative stress induced by resveratrol: from Nrf2 activation to GSH biosynthesis. AB - Skin is particularly exposed to oxidative stress, either from environmental insults such as sunlight or pollution or as a consequence of specific impairments in antioxidant status resulting from pathologies or aging. Traditionally, antioxidant products are exogenously provided to neutralize pro-oxidant species. However, another approach based on stimulation of endogenous antioxidant defense pathways is more original. Resveratrol (RSV) was reported to display such a behavior in various tissues, but data about the mechanisms of action in skin are scarce. We show here that, in primary culture of normal human keratinocytes (NHKs) or in full-thickness reconstructed human skin, RSV activated the Nrf2 pathway at nontoxic doses, from 20 uM up to 100uM. Among the Nrf2 downstream genes, glutamylcysteinyl ligase and glutathione peroxidase-2 were induced at the mRNA and protein levels. In parallel, a significant increase in glutathione content, assessed by LC/MS analysis, was observed in both models. Nrf2 gene silencing experiments performed in NHKs confirmed that Nrf2 was involved in RSV induced modulation of cellular antioxidant status, in part by increasing cellular glutathione content. Finally, improvement of endogenous defenses induced in RSV pretreated reconstructed skin ensured protection against the toxic oxidative effects of cumene hydroperoxide (CHP). In fact after RSV pretreatment, in response to CHP stress, glutathione content did not decrease as in unprotected samples. Cellular alterations at the dermal-epidermal junction were clearly prevented. Together, these complementary experiments demonstrated the beneficial effects of RSV on skin, beyond its direct antioxidant properties, by upregulation of a cutaneous endogenous antioxidant pathway. PMID- 25451639 TI - Regulation of iNOS function and cellular redox state by macrophage Gch1 reveals specific requirements for tetrahydrobiopterin in NRF2 activation. AB - Inducible nitric oxide synthase (iNOS) is a key enzyme in the macrophage inflammatory response, which is the source of nitric oxide (NO) that is potently induced in response to proinflammatory stimuli. However, the specific role of NO production, as distinct from iNOS induction, in macrophage inflammatory responses remains unproven. We have generated a novel mouse model with conditional deletion of Gch1, encoding GTP cyclohydrolase 1 (GTPCH), an essential enzyme in the biosynthesis of tetrahydrobiopterin (BH4) that is a required cofactor for iNOS NO production. Mice with a floxed Gch1 allele (Gch1(fl/fl)) were crossed with Tie2cre transgenic mice, causing Gch1 deletion in leukocytes (Gch1(fl/fl)Tie2cre). Macrophages from Gch1(fl/fl)Tie2cre mice lacked GTPCH protein and de novo biopterin biosynthesis. When activated with LPS and IFNgamma, macrophages from Gch1(fl/fl)Tie2cre mice induced iNOS protein in a manner indistinguishable from wild-type controls, but produced no detectable NO, as judged by L-citrulline production, EPR spin trapping of NO, and by nitrite accumulation. Incubation of Gch1(fl/fl)Tie2cre macrophages with dihydroethidium revealed significantly increased production of superoxide in the presence of iNOS expression, and an iNOS-independent, BH4-dependent increase in other ROS species. Normal BH4 levels, nitric oxide production, and cellular redox state were restored by sepiapterin, a precursor of BH4 production by the salvage pathway, demonstrating that the effects of BH4 deficiency were reversible. Gch1(fl/fl)Tie2cre macrophages showed only minor alterations in cytokine production and normal cell migration, and minimal changes in basal gene expression. However, gene expression analysis after iNOS induction identified 78 genes that were altered between wild-type and Gch1(fl/fl)Tie2cre macrophages. Pathway analysis identified decreased NRF2 activation, with reduced induction of archetypal NRF2 genes (gclm, prdx1, gsta3, nqo1, and catalase) in BH4-deficient Gch1(fl/fl)Tie2cre macrophages. These findings identify BH4-dependent iNOS regulation and NO generation as specific requirements for NRF2-dependent responses in macrophage inflammatory activation. PMID- 25451642 TI - Antimicrobial photodynamic inactivation with decacationic functionalized fullerenes: oxygen-independent photokilling in presence of azide and new mechanistic insights. AB - Functionalized fullerenes are gaining wide interest for mediating photodynamic therapy (PDT) of diseases such as cancers and infections. We recently reported the synthesis of two new decacationic fullerene monoadducts: C60[>M(C3N6(+)C3)2] (I(-))10(LC14) and its derivative with a light-harvesting antenna conjugated as a C60[>CPAF-(MN6(+)C3)2]-(I(-))10 nanostructure (LC15). We studied the ability of these compounds to mediate PDT of human cancer cells in vitro when excited by UVA light or by white light. Here we report the synthesis of a new fullerene derivative C60[>M(C3N6(+)C3)2][>M(C3N6C3)2]-(I(-))10 (LC16 derived from LC14), as a malonate bisadduct containing a covalently bound decatertiary amine arm. We investigated the relative abilities of the three compounds to generate singlet oxygen ((1)O2), hydroxyl radicals (HO.), and hydrogen peroxide (H2O2) after excitation by UVA or by white light. We used three different classes of pathogenic microbial cells (Gram-positive bacterium, methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative bacterium Escherichia coli, and fungal yeast Candida albicans). LC15 was the most powerful broad spectrum antimicrobial fullerenyl photosensitizer (FPS) followed by LC16, and LC14 was least powerful. Killing depended on both fullerene monoadduct concentration and light fluence. UVA was five times more effective than white light for killing, but not for generation of ROS and relative absorption was greater in white spectral region. Bacterial killing was not much inhibited by addition of azide anions and in some cases was potentiated. In the absence of oxygen, microbial photokilling was highly potentiated (up to 5 logs) by the addition of azide anions. We conclude that molecular functional addends that encourage a type I electron-transfer mechanism increase the ability of photoactivated fullerene monoadducts to kill microbial cells. Oxygen-independent photokilling is possible with fullerene monoadducts in the presence of azide anions, probably mediated by azidyl radicals. UVA excitation may kill bacteria partly by an electron-transfer mechanism directly into bacteria as well as by ROS. PMID- 25451643 TI - Inhibition of Fe(2+)- and Fe(3+)- induced hydroxyl radical production by the iron chelating drug deferiprone. AB - Deferiprone (L1) is an effective iron-chelating drug that is widely used for the treatment of iron-overload diseases. It is known that in aqueous solutions Fe(2+) and Fe(3+) ions can produce hydroxyl radicals via Fenton and photo-Fenton reactions. Although previous studies with Fe(2+) have reported ferroxidase activity by L1 followed by the formation of Fe(3+) chelate complexes and potential inhibition of Fenton reaction, no detailed data are available on the molecular antioxidant mechanisms involved. Similarly, in vitro studies have also shown that L1-Fe(3+) complexes exhibit intense absorption bands up to 800nm and might be potential sources of phototoxicity. In this study we have applied an EPR spin trapping technique to answer two questions: (1) does L1 inhibit the Fenton reaction catalyzed by Fe(2+) and Fe(3+) ions and (2) does UV-Vis irradiation of the L1-Fe(3+) complex result in the formation of reactive oxygen species. PBN and TMIO spin traps were used for detection of oxygen free radicals, and TEMP was used to trap singlet oxygen if it was formed via energy transfer from L1 in the triplet excited state. It was demonstrated that irradiation of Fe(3+) aqua complexes by UV and visible light in the presence of spin traps results in the appearance of an EPR signal of the OH spin adduct (TMIO-OH, a(N)=14.15G, a(H)=16.25G; PBN-OH, a(N)=16.0G, a(H)=2.7G). The presence of L1 completely inhibited the OH radical production. The mechanism of OH spin adduct formation was confirmed by the detection of methyl radicals in the presence of dimethyl sulfoxide. No formation of singlet oxygen was detected under irradiation of L1 or its iron complexes. Furthermore, the interaction of L1 with Fe(2+) ions completely inhibited hydroxyl radical production in the presence of hydrogen peroxide. These findings confirm an antioxidant targeting potential of L1 in diseases related to oxidative damage. PMID- 25451644 TI - Generator-specific targets of mitochondrial reactive oxygen species. AB - To understand the role of reactive oxygen species (ROS) in oxidative stress and redox signaling it is necessary to link their site of generation to the oxidative modification of specific targets. Here we have studied the selective modification of protein thiols by mitochondrial ROS that have been implicated as deleterious agents in a number of degenerative diseases and in the process of biological aging, but also as important players in cellular signal transduction. We hypothesized that this bipartite role might be based on different generator sites for "signaling" and "damaging" ROS and a directed release into different mitochondrial compartments. Because two main mitochondrial ROS generators, complex I (NADH:ubiquinone oxidoreductase) and complex III (ubiquinol:cytochrome c oxidoreductase; cytochrome bc1 complex), are known to predominantly release superoxide and the derived hydrogen peroxide (H2O2) into the mitochondrial matrix and the intermembrane space, respectively, we investigated whether these ROS generators selectively oxidize specific protein thiols. We used redox fluorescence difference gel electrophoresis analysis to identify redox-sensitive targets in the mitochondrial proteome of intact rat heart mitochondria. We observed that the modified target proteins were distinctly different when complex I or complex III was employed as the source of ROS. These proteins are potential targets involved in mitochondrial redox signaling and may serve as biomarkers to study the generator-dependent dual role of mitochondrial ROS in redox signaling and oxidative stress. PMID- 25451646 TI - CLL2-1, a chemical derivative of orchid 1,4-phenanthrenequinones, inhibits human platelet aggregation through thiol modification of calcium-diacylglycerol guanine nucleotide exchange factor-I (CalDAG-GEFI). AB - CalDAG-GEFI is a guanine nucleotide exchange factor, which actives small GTPase Rap1 and plays an important role in platelet aggregation. Our previous study has shown that CalDAG-GEFI contains redox-sensitive thiols, and its function can be inhibited by thiol modification. In the present study, the effect of CLL2-1, a 1,4-phenanthrenequinone, on CalDAG-GEFI and platelet functions was investigated. In human platelets, CLL2-1 prevented platelet aggregation caused by various stimulators. Flow cytometric analysis revealed that CLL2-1 inhibited GPIIb/IIIa activation and P-selectin secretion. Moreover, CLL2-1 prevented Rap1 activation caused by thrombin, the Ca(2+) ionophore A23187, and the diacylglycerol mimetic phorbol 12-myristate 13-acetate, while only slightly inhibited thrombin-induced increases in [Ca(2+)]i and did not inhibit protein kinase C activation. Western blots after reducing SDS-PAGE showed that treatment of either platelets or platelet lysates with CLL2-1 led to a decrease of monomeric CalDAG-GEFI and appearance of cross-linked oligomers of CalDAG-GEFI, and these effects were inhibited by pretreatment of platelets or lysates with thiol reducing agents prior to the addition of CLL2-1, indicating thiol modification of CalDAG-GEFI by CLL2-1. Furthermore, the thiol reducing agents also prevented the inhibitory effect of CLL2-1 on Rap1 activation, GPIIb/IIIa activation, and platelet aggregation. In CalDAG-GEFI-overexpressing human embryonic kidney 293T cells, CLL2-1 also inhibited CalDAG-GEFI-mediated Rap1 activation. Taken together, our results suggest that the antiplatelet effect of CLL2-1 is due to, at least in part, inhibition of CalDAG-GEFI-mediated Rap1 activation, and provide the basis for development of novel antiplatelet drugs. PMID- 25451647 TI - Competency-based education, feedback, and humility. PMID- 25451645 TI - Mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide. AB - The thioredoxin system, which consists of a family of proteins, including thioredoxin (Trx), peroxiredoxin (Prx), and thioredoxin reductase (TrxR), plays a critical role in the defense against oxidative stress by removing harmful hydrogen peroxide (H2O2). Specifically, Trx donates electrons to Prx to remove H2O2 and then TrxR maintains the reduced Trx concentration with NADPH as the cofactor. Despite a great deal of kinetic information gathered on the removal of H2O2 by the Trx system from various sources/species, a mechanistic understanding of the associated enzymes is still not available. We address this issue by developing a thermodynamically consistent mathematical model of the Trx system which entails mechanistic details and provides quantitative insights into the kinetics of the TrxR and Prx enzymes. Consistent with experimental studies, the model analyses of the available data show that both enzymes operate by a ping pong mechanism. The proposed mechanism for TrxR, which incorporates substrate inhibition by NADPH and intermediate protonation states, well describes the available data and accurately predicts the bell-shaped behavior of the effect of pH on the TrxR activity. Most importantly, the model also predicts the inhibitory effects of the reaction products (NADP(+) and Trx(SH)2) on the TrxR activity for which suitable experimental data are not available. The model analyses of the available data on the kinetics of Prx from mammalian sources reveal that Prx operates at very low H2O2 concentrations compared to their human parasite counterparts. Furthermore, the model is able to predict the dynamic overoxidation of Prx at high H2O2 concentrations, consistent with the available data. The integrated Prx-TrxR model simulations well describe the NADPH and H2O2 degradation dynamics and also show that the coupling of TrxR- and Prx-dependent reduction of H2O2 allowed ultrasensitive changes in the Trx concentration in response to changes in the TrxR concentration at high Prx concentrations. Thus, the model of this sort is very useful for integration into computational H2O2 degradation models to identify its role in physiological and pathophysiological functions. PMID- 25451648 TI - Apparently asymptomatic patients with serologic markers of celiac disease and gluten-free diet. PMID- 25451649 TI - Dietary saturated lipids in alcoholic liver disease: new microbiota-targeting bullets? PMID- 25451650 TI - Molecular subtyping of colorectal cancer: time to explore both intertumoral and intratumoral heterogeneity to evaluate patient outcome. PMID- 25451651 TI - Sofosbuvir treatment in the pre and post liver transplantation phase: the sooner, the better. PMID- 25451653 TI - Reply: To PMID 24941021. PMID- 25451654 TI - Reply: To PMID 24837306. PMID- 25451655 TI - Reply: To PMID 24818764. PMID- 25451656 TI - Innate cytokines dictate the fate of acute intestinal inflammation. PMID- 25451657 TI - The TM6SF2 variants, novel genetic predictors for nonalcoholic steatohepatitis. PMID- 25451658 TI - Surgery or endoscopy first for suspected bile duct stone? PMID- 25451659 TI - Reply: To PMID 25451658. PMID- 25451660 TI - Central pain processing in irritable bowel syndrome is modulated by mood: a mechanism for the beneficial effects of antidepressants? PMID- 25451661 TI - Reasons for caution before screening for celiac disease. PMID- 25451662 TI - Liver biopsy for the selection of patients with nonalcoholic steatohepatitis for clinical trials. PMID- 25451663 TI - Ribosomopathy association with colorectal cancer. PMID- 25451664 TI - The Holy Grail, or only half way there? PMID- 25451665 TI - Perceived complexity of various liver resections: results of a survey of experts with development of a complexity score and classification. AB - BACKGROUND: Liver resections have classically been distinguished as "minor" or "major" based on the number of segments removed. However, it is clear that the number of segments alone does not convey the complexity of a resection. To date, no study has formally assessed the complexity of various anatomic liver resections. STUDY DESIGN: A 4-question survey was administered to 135 expert liver surgeons in 14 countries. The first 3 questions related to the country in which the surgeon was practicing and the surgeon's experience. In the fourth question, the experts were asked to rate the difficulty of various open, anatomic liver resections on a scale of 1 to 10. RESULTS: Sixty-six of 135 (48.9%) surgeons responded to the survey. Twelve procedures were rated. The lowest mean score of 1.37-indicating least difficulty-was given to peripheral wedge resection. Left trisectionectomy with caudate resection was deemed most difficult, with a score of 8.28. The mean scores for the 2 procedures perceived as least difficult-peripheral wedge resection and left lateral sectionectomy-were lower than the mean scores of all the rest of the procedures at a highly statistically significant level (p < 0.0001). The 4 procedures with the highest scores shared the common attribute that they involved the right intersectional plane. CONCLUSIONS: These data represent the first quantitative assessment of the perceived difficulty of a variety of liver resections. The complexity scores generated allow for separation of liver resections into 3 categories of complexity (low complexity, medium complexity, and high complexity) on a quantitative basis. PMID- 25451667 TI - Focal herniation of cerebral parenchyma into transverse sinus. PMID- 25451666 TI - Perfusion assessment in laparoscopic left-sided/anterior resection (PILLAR II): a multi-institutional study. AB - BACKGROUND: Our primary objective was to demonstrate the utility and feasibility of the intraoperative assessment of colon and rectal perfusion using fluorescence angiography (FA) during left-sided colectomy and anterior resection. Anastomotic leak (AL) after colorectal resection increases morbidity, mortality, and, in cancer cases, recurrence rates. Inadequate perfusion may contribute to AL. The PINPOINT Endoscopic Fluorescence Imaging System allows for intraoperative assessment of anastomotic perfusion. STUDY DESIGN: This is a prospective, multicenter, open-label, clinical trial that assessed the feasibility and utility of FA for intraoperative perfusion assessment during left-sided colectomy and anterior resection at 11 centers in the United States. RESULTS: A total of 147 patients were enrolled, of whom 139 were eligible for analysis. Diverticulitis (44%), rectal cancer (25%), and colon cancer (21%) were the most prevalent indications for surgery. The mean level of anastomosis was 10 +/- 4 cm from the anal verge. Splenic-flexure mobilization was performed in 81% and high ligation of the inferior mesenteric artery in 61.9% of patients. There was a 99% success rate for FA, and FA changed surgical plans in 11 (8%) patients, with the majority of changes occurring at the time of transection of the proximal margin (7%). Overall morbidity rates were 17%. The anastomotic leak rate was 1.4% (n = 2). There were no anastomotic leaks in the 11 patients who had a change in surgical plan based on intraoperative perfusion assessment with FA. CONCLUSIONS: PINPOINT is a safe and feasible tool for intraoperative assessment of tissue perfusion during colorectal resection. There were no anastomotic leaks in patients in whom the anastomosis was revised based on inadequate perfusion with FA. PMID- 25451668 TI - Comparison of susceptibility-weighted and perfusion-weighted magnetic resonance imaging in the detection of penumbra in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: To investigate detection of ischemic penumbra in stroke patients with acute cerebral infarction by susceptibility-weighted imaging (SWI) in comparison with perfusion-weighted imaging (PWI). MATERIALS AND METHODS: This study included 18 stroke patients with acute infarction who underwent diffusion weighted imaging (DWI), SWI, PWI, and magnetic resonance angiography (MRA) within 3 days after symptom onset. The Alberta Stroke Program Early CT Score (ASPECTS) was used to evaluate lesions on DWI, SWI, and PWI. DWI-SWI and DWI-PWI mismatches were calculated. RESULTS: The DWI-SWI mismatch was not significantly different from the DWI-mean transit time (MTT) mismatch (P=0.163) in evaluating ischemic penumbra. The susceptibility vessel sign (SVS) in SWI occurred in 11 (61%) of 18 patients with cerebral infarction. Stenosis or occlusion of the affected vessels was identified by MRA in 10 (91%) of the 11 SVS-positive patients. The SVS on SWI was significantly associated with the occurrence of damaged vessels or the presence of thrombus in the affected vessels (P=0.047). CONCLUSIONS: DWI-SWI mismatch is a good marker for evaluating ischemic penumbra in stroke patients with cerebral infarction. SWI can detect thrombus in the affected vessels, and may be useful for guiding intra-arterial thrombolytic therapy. PMID- 25451669 TI - Interest of local intra-arterial fibrinolysis in acute central retinal artery occlusion: Clinical experience in 16 patients. AB - OBJECTIVE: Central retinal artery occlusion (CRAO) is a rare disease with poor visual prognosis. We evaluated clinical effectiveness of in situ fibrinolysis with original angiographic scores describing the aspect of carotid siphon, proximal ophthalmic artery, and choroid blush. METHODS: Retrospective study of 16 consecutive cases of CRAO between 2007 and 2013. Fourteen underwent in situ fibrinolysis, two were excluded due to pre-occlusive internal carotid stenosis on pre-procedural diagnostic angio-CT. Fibrinolysis was performed with rt-PA (average injected dose: 35 mg), with an average onset delay of 8hours (4-17h). We reported angiographic scores pre- and post-fibrinolysis, visual acuity (VA) before and after treatment, and VA improvement evaluated by ophthalmologist 6 to 12 months after thrombolysis. RESULTS: Six patients (43%) recovered post fibrinolysis VA significally improved, superior or equal to 1/10 (1/10 to 8/10). An irregular carotid siphon (2 cases) appeared as a predictive factor of failure. Fibrinolysis procedure led to a significant improvement of angiographic permeability of proximal ophthalmic artery (P=0.0498), but this result was not accompanied by any VA improvement. The aspect of choroid blush showed no correlation with the management of thrombolysis. CONCLUSION: In situ fibrinolysis was more effective than medical treatments or natural evolution of CRAO (VA improvement was respectively 40% and 20%). However, the benefit/risk ratio must be discussed, and an angio-CT of supra-aortic trunks could be systematically performed before thrombolysis, to assess the potential VA recovery compared with complications such as ischemic stroke. PMID- 25451670 TI - MR screening of candidates for thrombolysis: How to identify stroke mimics? AB - Stroke mimics account for up to a third of suspected strokes. The main causes are epileptic deficit, migraine aura, hypoglycemia, and functional disorders. Accurate recognition of stroke mimics is important for adequate identification of candidates for thrombolysis. This decreases the number of unnecessary treatments and invasive vascular investigations. Correctly identifying the cause of symptoms also avoids delaying proper care. Therefore, this pictorial review focuses on what the radiologist should know about the most common MRI patterns of stroke mimics in the first hours after onset of symptoms. The issues linked to the accurate diagnosis of stroke mimics in the management of candidates for thrombolysis will be discussed. PMID- 25451671 TI - [Intraprostatic calcifications as natural fiducial markers in image-guided radiotherapy for prostate cancer]. AB - PURPOSE: To establish whether intraprostatic calcifications can serve as natural fiducials for image-guided radiotherapy (IGRT), replacing the implantation of intraprostatic fiducial markers. PATIENTS AND METHODS: Patients with prostate cancer, having intraprostatic calcifications visible on CT scan were selected and underwent intensity-modulated radiotherapy/3D conformal radiotherapy with IGRT in the department of radiotherapy of Henri-Mondor Hospital. All cone-beam computed tomographies (CBCT) were repositioned on intraprostatic calcifications. For each acquired image, displacements of intraprostatic calcifications were calculated with reference to position on planning CT in three directions: lateral, longitudinal and vertical. RESULTS: Between 2011 and 2013, nine patients had 183 CBCT. For each image, three displacements and space coordinates were calculated using a single reference (intraprostatic calcification). Mean lateral, longitudinal and vertical movements were 0.26+/-5.7 mm, -1+/-4.6 mm and 0.42+/ 3.5 mm, respectively. CONCLUSION: Studies exploring prostatic movements with fiducial markers as reference and ours with natural fiducials yield similar results. Our data confirm previous studies that have suggested that intraprostatic calcifications can be used as natural fiducials with potential reduction of iatrogenic risks and costs associated with the implantation of fiducial markers. PMID- 25451672 TI - Intensity-modulated whole pelvic radiotherapy provides effective dosimetric outcomes for cervical cancer treatment with lower toxicities. AB - PURPOSE: To compare the efficacy of intensity-modulated radiotherapy, three dimensional conformal radiotherapy, and conventional radiotherapy for cervical cancer treatment. MATERIALS AND METHODS: Whole pelvis intensity-modulated radiotherapy, three-dimensional conformal radiotherapy, and conventional radiotherapy plans were designed for 16 patients with stage IIB cervical cancer, each using the prescribed dose of 50.4 Gy/28 fractions. Dose-volume histograms of the target volume and organs at risk were evaluated. RESULTS: Compared to the 3D conformal and conventional radiotherapy plans, the intensity-modulated radiotherapy plan demonstrated superior conformal treatment. The mean planning target volume dose of all three plans reached the target effective therapeutic dose. The planning target volume dose of the intensity-modulated radiotherapy plan was significantly higher than that of either the three-dimensional conformal radiotherapy or conventional radiotherapy plan (P<0.05). When more than 30 Gy was administered in intensity-modulated radiotherapy, organs at risk including the small intestine, rectum, bladder, and bone marrow received a significantly reduced volume of radiation. In comparison of the average planning target volume doses, significant volume reductions in irradiation of organs at risk were obtained with full bladders. CONCLUSIONS: An intensity-modulated radiotherapy plan with appropriate margins encompassing the primary tumour and potential microscopic pelvic disease reduces the dose to organs at risk without compromising target coverage. Intensity-modulated radiotherapy is an appropriate definitive treatment for patients with cervical cancer. PMID- 25451673 TI - [Radiotherapy of a glioma in a pregnant woman: evaluation of the foetal dose in conformational 3D or intensity-modulated]. AB - The purpose was to assess three treatments planning techniques including one in intensity-modulated radiation therapy (IMRT) for cerebral irradiation of pregnant woman, in order to limit the dose delivered to the foetus. The treatment provided was 60 Gy to the planning target volume. Estimated foetal dose was measured using an anthropomorphic phantom, on the upper and middle part of the uterus. The first plan consisted in four beams in conformational technique delivered from a Varian accelerator with a 120 leaves collimator, the second one used non-coplanar fields and the third one assessed IMRT. With the conformational technique, the dose at the upper part of the uterus was 8.3 mGy and 6.3 mGy at the middle part. The dose delivered to the foetus was higher with the non-coplanar fields. In IMRT, the dose at the upper part of the uterus was 23.8 mGy and 14.3 mGy at the middle part. The three plans used 6 MV X-rays. Because of the use of leaves and non coplanar fields, IMRT does not seem to be the optimal technique for the treatment of pregnant woman. However, the dose delivered to the foetus remains low and below the dose of 100 mGy recommended by the International Commission of Radiological Protection. It seems possible to consider the use of this technique for a better sparing of organs at risk for the mother. PMID- 25451675 TI - Fiducial marker implantation in prostate radiation therapy: complication rates and technique. AB - PURPOSE: This study aims to report the complication rate from the transrectal ultrasound-guided implantation of gold seed markers in prostate radiotherapy, as well as describing the technique used. MATERIALS AND METHODS: Between May 2010 and December 2012, 169 patients with localized prostate cancer had an intraprostatic fiducial marker implantation under transrectal ultrasound guidance. The procedure included prophylactic antibiotic therapy, fleet enema, implantation performed by trained radiation oncologists at our center prior to image-guided radiotherapy. Toxicity occurring between implantation and subsequent radiotherapy start date was assessed. The following parameters were analyzed via medical chart review: antibiotic therapy, anticoagulant interruption, bleeding, pain, prostate volume, number of markers implanted, post-implantation complications and delay before starting radiotherapy. RESULTS: Of the 169 men, 119 (70.4%) underwent insertion of 4 fiducial markers and the other 50 (29.6%) had 3. The procedure was well-tolerated. There was no interruption of the implantation with regards to pain or hemorrhage. No grade 3 or 4 complications were observed. Seed migration rate was 0.32%, for the migration of 2 markers on 626 implanted. Mean prostate volume was 38 cm(3) (range: 10-150 cm(3)). Two patients (1.18%) developed a urinary tract infection following the procedure: prostate volume of 25 and 65 cm(3), four gold seed markers implanted, urinary tract infection resistant to prophylactic antibiotherapy, and treated with antibiotics specific to their infection as determined on urine culture. CONCLUSION: Transrectal fiducial marker implantation for image-guided radiotherapy in prostate cancer is a well-tolerated procedure without major associated complications. PMID- 25451674 TI - [Non-targeted effects (bystander, abscopal) of external beam radiation therapy: an overview for the clinician]. AB - Radiotherapy is advocated in the treatment of cancer of over 50 % of patients. It has long been considered as a focal treatment only. However, the observation of effects, such as fatigue and lymphopenia, suggests that systemic effects may also occur. The description of bystander and abscopal effects suggests that irradiated cells may exert an action on nearby or distant unirradiated cells, respectively. A third type of effect that involves feedback interactions between irradiated cells was more recently described (cohort effect). This new field of radiation therapy is yet poorly understood and the definitions suffer from a lack of reproducibility in part due to the variety of experimental models. The bystander effect might induce genomic instability in non-irradiated cells and is thus extensively studied for a potential risk of radiation-induced cancer. From a therapeutic perspective, reproducing an abscopal effect by using a synergy between ionizing radiation and immunomodulatory agents to elicit or boost anticancer immune responses is an interesting area of research. Many applications are being developed in particular in the field of hypofractionated stereotactic irradiation of metastatic disease. PMID- 25451676 TI - [Primary central nervous lymphoma: what is the role for radiotherapy?]. AB - Primary central nervous system lymphoma is a rare extranodal form of non-Hodgkin lymphoma with an aggressive course and unsatisfactory outcome. Historically, whole-brain radiotherapy was the sole treatment for patients with primary central nervous system lymphoma, with high response rates but typically, this did not result in long-lasting remissions. The addition of high-dose methotrexate-based chemotherapy regimens to whole-brain radiotherapy has significantly improved patients' outcome, but has resulted in a higher incidence of late neurotoxicity, particularly in elderly patients. To date, the role of consolidation radiotherapy is controversial, and some investigators have developed alternative strategies aiming at avoiding immediate irradiation or using a reduced radiotherapy dose to the whole-brain with promising results. PMID- 25451677 TI - Edwin Grant Conklin (1863-1952) and the great divide: creation versus evolution. PMID- 25451678 TI - Protein folding in the cell, from atom to organism. PMID- 25451680 TI - The role of the concentration scale in the definition of transfer free energies. AB - The Gibbs free energy of transferring a solute at infinite dilution between two solvents quantifies differences in solute-solvent interactions - if the transfer takes place at constant molarity of the solute. Yet, many calculation formulae and measuring instructions that are commonly used to quantify solute-solvent interactions correspond to transfer processes in which not the molarity of the solute but its concentration measured in another concentration scale is constant. Here, we demonstrate that in this case, not only the change in solute-solvent interactions is quantified but also the entropic effect of a volume change during the transfer. Consequently, the "phenomenon" which is known as "concentration scale dependence" of transfer free energies is simply explained by a volume entropy effect. Our explanations are of high importance for the study of cosolvent effects on protein stability. PMID- 25451679 TI - AEBP2 as a transcriptional activator and its role in cell migration. AB - Aebp2 encodes an evolutionarily conserved zinc finger protein that has not been well studied so far, yet recent studies indicated that this gene is closely associated with the Polycomb Repressive Complex 2 (PRC2). Thus, the current study characterized the basic aspects of this gene, including alternative promoters and protein isoforms. According to the results, Aebp2 is controlled through three alternative promoters, deriving three different transcripts encoding the embryonic (32 kDa) and somatic (52 kDa) forms. Chromatin Immuno-Precipitation (ChIP) experiments revealed that AEBP2 binds to its own promoter as well as the promoters of Jarid2 and Snai2. While the embryonic form acts as a transcriptional repressor for Snai2, the somatic form functions as a transcriptional activator for Jarid2, Aebp2 and Snai2. Cell migration assays also demonstrated that the Aebp2 somatic form has an enhancing activity in cell migration. This is consistent with the functional association of Aebp2 with migratory neural crest cells. These results suggest that the two protein isoforms of AEBP2 may have opposite functions for the PcG target genes, and may play significant roles in cell migration during development. PMID- 25451681 TI - Effects of two stabilizing substitutions, D137L and G126R, in the middle part of alpha-tropomyosin on the domain structure of its molecule. AB - We applied differential scanning calorimetry (DSC) to investigate the effects of substitutions D137L and G126R (i.e. replacement of conserved non-canonical residues Asp137 and Gly126 by canonical ones) in the middle part of tropomyosin (Tm), as well as the combined one, D137L/G126R, on the thermal unfolding of Tm. Special approaches (e.g. combination of DSC with measurements of temperature dependences of pyrene excimer fluorescence) were applied to assign separate thermal transitions (calorimetric domains) on the DSC profiles to the certain parts of Tm molecule. The results show that substitutions D137L and G126R (and, especially, the combined one, D137L/G126R) may stabilize not only the middle region of Tm, but also the other parts of its molecule including N- and C terminal parts. These results suggest that the stabilization of the Tm middle part can be transmitted along the coiled-coil length displaying long-range effects. PMID- 25451682 TI - The interdigitated gel phase in mixtures of cationic and zwitterionic phospholipids. AB - To examine the phase behavior of mixtures of zwitterionic and cationic lipids we used three derivatives of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). All three lipids are uniquely capable of spontaneously forming the interdigitated gel phase (LbetaI) under typical hydration conditions. The P-O-ethyl derivative, 1,2 dipalmitoyl-sn-glycero-3-ethylphosphocholine (EDPPC), was chosen as the cationic lipid. For the zwitterionic lipids, we use the ether-linked 1,2-di-O-hexadecyl-sn glycero-3-phosphocholine, (DHPC) and the fluorine substituted 1-palmitoyl-2-(16 fluoropalmitoyl)-sn-glycero-3-phosphocholine (F-DPPC). Differential scanning calorimetry (DSC) and fluorescence spectroscopy were used to analyze the lipid mixtures. The F-DPPC/EDPPC mixtures are interdigitated at all lipid ratios below the main transition temperature (Tm). In addition, EDPPC stabilizes the interdigitated gel phase of DHPC until the ripple gel phase (Pbeta') is eliminated and only the LbetaI to liquid crystalline phase (Lalpha) main transition remains. These results demonstrate that mixtures of cationic and zwitterionic lipids can be compatible with the interdigitated phase. PMID- 25451683 TI - Miltefosine and BODIPY-labeled alkylphosphocholine with leishmanicidal activity: Aggregation properties and interaction with model membranes. AB - Miltefosine (hexadecylphosphocholine, MT) afforded successful oral treatment against human visceral and cutaneous leishmaniasis. Knowledge of MT aggregation in aqueous solutions and of its interaction with lipid membranes is important to understand pharmacokinetics, bioavailability and antiparasitic effects. Methods based on surface tension and fluorescence spectroscopy gave the value of 50MUM for critical micelle concentration (CMC) in buffered water solution, and the value is influenced by salt content. Interaction between MT and lipid vesicles was monitored by fluorescence and the drug promotes only minor changes in the surface of the vesicles. At MT concentration below CMC, modifications in probe fluorescence are due to disordering effects promoted by the drug in the bilayer. Above the CMC, MT promoted large modifications in the vesicles as a whole, resulting in mixed aggregates containing lipids, drug and probe. Effects are less evident above thermal phase transition when the bilayer is in less ordered state. PMID- 25451684 TI - The potency-insolubility conundrum in pharmaceuticals: Mechanism and solution for hepatitis C protease inhibitors. AB - As compounds are optimized for greater potency during pharmaceutical discovery, their aqueous solubility often decreases, making them less viable as orally administered drugs. To investigate whether potency and insolubility share a common origin, we examined the structural and thermodynamic properties of telaprevir, a sparingly soluble inhibitor of hepatitis C virus protease. Comparison of the hydrogen bond motifs in crystalline telaprevir with those present in the protease-telaprevir complex revealed striking similarities. Additionally, the thermodynamics of telaprevir dissolution closely resembles those of protein-ligand dissociation. Together, these findings point to a common origin of potency and insolubility rooted in particular amide-amide hydrogen bond patterns. The insolubility of telaprevir is shown by computational analysis to be caused by interactions in the crystal, not unfavorable hydrophobic hydration. Accordingly, competing out the particular amide-amide hydrogen bond motifs in crystalline telaprevir with 4-hydroxybenzoic acid yielded a co-crystalline solid with excellent aqueous dissolution and oral absorption. The analysis suggests a generalizable approach for identifying drug candidate compounds that either can or cannot be rendered orally bioavailable by alteration of their crystalline solid phases, in an approach that provides a pragmatic way to attain substantial enhancements in the success rate of drug discovery and development. PMID- 25451685 TI - Training pouched rats to find people. AB - Giant African pouched rats equipped with video cameras may be a tenable option for locating living humans trapped under debris from collapsed structures. In the present study, 5 pouched rats were trained to contact human targets in a simulated collapsed building and to return to the release point after hearing a signal to do so. During test sessions, each rat located human targets more often than it located similar-sized inanimate targets on which it had not previously been trained and spent more time within 1 m of the human target than within 1 m of the other targets. Overall, the rats found humans, plastic bags containing clothes, and plastic bags without clothes on 83%, 37%, and 11% of trials, respectively. These findings suggest that using pouched rats to search for survivors in collapsed structures merits further attention. PMID- 25451686 TI - Identification of new P-glycoprotein inhibitors derived from cardiotonic steroids. AB - P-glycoprotein (ABCB1, MDR1) is capable of extruding chemotherapeutics outside the cell and its overexpression in certain cancer cells may cause failure of chemotherapy. Many attempts were carried out to identify potent inhibitors of this transporter and numerous compounds were shown to exert inhibitory effects in vitro, but so far none were able to make their way to the clinic due to serious complications. Natural compounds represent a great source of therapeutics, which are believed to be safe and effective. Therefore, we have screened a large library of naturally occurring cardiotonic steroids and their derivatives using high throughput flow cytometry. We were able to identify six compounds capable of modulating P-glycoprotein activity. By using P-glycoprotein ATPase assays, molecular docking in silico studies and resazurin reduction assays, the outcome of this high throughput screening platform has been validated. These novel compounds may serve as candidates to reverse doxorubicin resistance in leukemia cells. PMID- 25451687 TI - Sex-dependent regulation of hepatic CYP3A by growth hormone: Roles of HNF6, C/EBPalpha, and RXRalpha. AB - Sex-based differences in the pharmacological profiles of many drugs are due in part to the female-predominant expression of CYP3A4, which is the most important CYP isoform responsible for drug metabolism. Transcription factors trigger the sexually dimorphic expression of drug-metabolizing enzymes in response to sex dependent growth hormone (GH) secretion. We investigated the roles of HNF6, C/EBPalpha, and RXRalpha in the regulation of human female-predominant CYP3A4, mouse female-specific CYP3A41, and rat male-specific CYP3A2 expression by GH secretion patterns using HepG2 cells, growth hormone receptor (GHR) knockout mice as well as rat models of orchiectomy and hypophysectomy. The constitutive expression of HNF6 and RXRalpha was GH-dependent, and GHR deficiency decreased HNF6/C/EBPalpha complex levels and increased HNF6/RXRalpha complex levels. Feminine GH secretion induced the binding of HNF6 and C/EBPalpha to the CYP3A4 and Cyp3a41 promoters and HNF6/C/EBPalpha complex levels was more efficiently compared with masculine pattern. Additionally, a greater inhibition of the binding of RXRalpha to the CYP3A4 and Cyp3a41 promoters and HNF6/RXRalpha complex levels was observed by feminine GH secretion, but less inhibition was observed by masculine pattern. The binding of HNF6, C/EBPalpha, and RXRalpha to the CYP3A2 promoter was not directly regulated by androgens. RXRalpha completely abolished the synergistic activation of the CYP3A4, Cyp3a41, and CYP3A2 promoters by HNF6 and C/EBPalpha. The results demonstrate that sex-dependent GH secretion patterns affect the expressions and interactions of HNF6, C/EBPalpha, and RXRalpha as well as their binding to CYP3A genes. RXRalpha mediates the sex-dependent influence of GH on CYP3A expression as an important signalling molecule. PMID- 25451688 TI - Oncogenic c-Myc and prothymosin-alpha protect hepatocellular carcinoma cells against sorafenib-induced apoptosis. AB - Prothymosin alpha (PTMA) is overexpressed in various human tumors, including hepatocellular carcinoma (HCC). The significance of PTMA overexpression and its underlying mechanism remain unclear. We show here that silencing PTMA sensitizes HCC cells to the kinase inhibitor sorafenib. In contrast, ectopic expression of PTMA induces cell resistance to the drug. While inhibitors targeting JNK, ERK or PI3K reduce PTMA expression, only ERK activation is suppressed by sorafenib. In addition, inhibition of ERK produces a dramatic decrease in both endogenous PTMA level and promoter activation. Ectopic expression of active MKK1/2 considerably induces PTMA expression. We also identify a sorafenib-responsive segment lying 1000-1500-bp upstream of the PTMA transcription start site and observe that it is controlled by c-Myc and ERK. Mutation in the PTMA promoter at the predicted c-Myc binding site and silencing of c-Myc both abrogate sorafenib's effect on PTMA transcription. We also find that silencing PTMA potentiates Bax translocation to mitochondria in response to sorafenib and this is associated with increased cytochrome c release from mitochondria and enhanced caspase-9 activation. These results indicate that PTMA is positively regulated by the oncoprotein c-Myc and protects HCC cells against sorafenib-induced cell death, thus identifying PTMA as a new target for chemotherapy against HCC. PMID- 25451689 TI - Ceramide synthases CerS4 and CerS5 are upregulated by 17beta-estradiol and GPER1 via AP-1 in human breast cancer cells. AB - Ceramide synthases (CerS) are important enzymes of the sphingolipid pathway, responsible for the production of ceramides with distinct chain lengths. In human breast cancer tissue, we detected a significant increase in CerS4 and CerS6 mRNA in estrogen receptor positive (ER+) cancer tissue. To clarify the molecular mechanism of this upregulation, we cloned CerS2, -4, -5 and CerS6 promoter and 3' UTR fragments into luciferase reporter gene plasmids and determined luciferase activity in MCF-7 (ERalpha/beta) and MDA-MB-231 (ERbeta) cells after 17beta estradiol treatment. Only the activities of CerS4 and CerS5 promoter Luc constructs, as well as CerS2- and CerS5-3'-UTR Luc constructs increased after estradiol treatment in MCF-7 cells, and this could be inhibited by the anti estrogen fulvestrant. Co-transfection with the G protein-coupled estrogen receptor 1 (GPER1) also enhanced CerS2, CerS4 and CerS6 promoter activity whereas CerS5 promoter activity was inhibited in both cell lines. Promoter deletion and mutation constructs from CerS4 and CerS5 promoters revealed that estradiol and GPER1 mediate their effects on both promoters by activating AP-1, most likely through dimerization of c-Jun and c-Fos. At least we could show, that cell proliferation induced by estradiol could be blocked by co-treatment with Fumonisin B1, indicating that upregulation of CerS in breast cancer cells by estrogen is important for cell proliferation and possibly tumor development. In conclusion, our data highlight transcriptional and posttranscriptional mechanisms regulating CerS expression in human cells which provide the basis for further studies investigating the regulation of CerS expression and ceramide synthesis after diverse stimuli in physiological and pathophysiological processess. PMID- 25451690 TI - Hepatic protein tyrosine phosphatase 1B (PTP1B) deficiency protects against obesity-induced endothelial dysfunction. AB - Growing evidence suggests that hepatic-insulin resistance is sufficient to promote progression to cardiovascular disease. We have shown previously that liver-specific protein-tyrosine-phosphatase 1B (PTP1B) deficiency improves hepatic-insulin sensitivity and whole-body glucose homeostasis. The aim of this study was to investigate the impact of liver-specific PTP1B-deficiency (L-PTP1B-/ ) on cardiac and peripheral vascular function, with special emphasis on endothelial function in the context of high-fat diet (HFD)-induced obesity. L PTP1B-/- mice exhibited an improved glucose and lipid homeostasis and increased insulin sensitivity, without changes in body weight. HFD-feeding increased systolic blood pressure (BP) in both L-PTP1B-/- and control littermates; however, this was significantly lower in L-PTP1B-/- mice. HFD-feeding increased diastolic BP in control mice only, whilst the L-PTP1B-/- mice were completely protected. The analysis of the function of the left ventricle (LV) revealed that HFD-feeding decreased LV fractional shortening in control animals, which was not observed in L-PTP1B-/- mice. Importantly, HFD feeding significantly impaired endothelium dependent vasorelaxation in response to acetylcholine in aortas from control mice, whilst L-PTP1B-/- mice were fully protected. This was associated with alterations in eNOS phosphorylation. Selective inhibition of COX-2, using NS-398, decreased the contractile response in response to serotonin (5-HT) only in vessels from control mice. HFD-fed control mice released enhanced levels of prostaglandin E, a vasoconstrictor metabolite; whilst both chow- and HFD-fed L PTP1B-/- mice released higher levels of prostacylin, a vasorelaxant metabolite. Our data indicate that hepatic-PTP1B inhibition protects against HFD-induced endothelial dysfunction, underscoring the potential of peripheral PTP1B inhibitors in reduction of obesity-associated cardiovascular risk in addition to its anti-diabetic effects. PMID- 25451691 TI - Regulation of vascular tone in rabbit ophthalmic artery: cross talk of endogenous and exogenous gas mediators. AB - Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulphide (H2S) modulate vascular tone. In view of their therapeutic potential for ocular diseases, we examined the effect of exogenous CO and H2S on tone of isolated rabbit ophthalmic artery and their interaction with endogenous and exogenous NO. Ophthalmic artery segments mounted on a wire myograph were challenged with cumulative concentrations of phenylephrine (PE) in the presence or absence of NG-nitro-L arginine (LNNA) to inhibit production of NO, the CO-releasing molecules CORMs or the H2S-donor GYY4137. The maximal vasoconstriction elicited by PE reached 20-30% of that induced by KCl but was dramatically increased by incubation with LNNA. GYY4137 significantly raised PE-mediated vasoconstriction, but it did not change the response to PE in the presence of LNNA or the relaxation to sodium nitroprusside (SNP). CORMs concentration-dependently inhibited PE-induced constriction, an effect that was synergistic with endogenous NO (reduced by LNNA), but insensitive to blockade of guanylyl cyclase by 1H [1,2,4]oxadiazolo[4,3,-alpha]quinoxalin-1-one (ODQ). In vascular tissues cyclic GMP (cGMP) levels seemed reduced by GYY4137 (not significantly), but were not changed by CORM. These data indicate that CO is able per se to relax isolated ophthalmic artery and to synergize with NO, while H2S counteracts the effect of endogenous NO. CO does not stimulate cGMP production in our system, while H2S may reduce cGMP production stimulated by endogenous NO. These findings provide new insights into the complexities of gas interactions in the control of ophthalmic vascular tone, highlighting potential pharmacological targets for ocular diseases. PMID- 25451692 TI - Dual-specificity phosphatase 6 predicts the sensitivity of progestin therapy for atypical endometrial hyperplasia. AB - OBJECTIVE: We previously found that Dual-specificity phosphatase 6 (Dusp6) over expression enhanced the growth-promoting effect of estrogen in endometrial adenocarcinoma cells. The aim of this study was to explore the correlation of Dusp6 expression with progestin sensitivity in atypical endometrial hyperplasia (AEH) and earlier endometrial carcinomas (EC). METHODS: Using immunohistochemistry study, we analyzed the expression of Dusp6 protein in AEH. RESULTS: We found that progestin treatment was effective in 89% of AEH and 50% of EC. Before treatment, Dusp6 expression was significantly higher in progestin sensitive AEH groups compared with progestin-resistant groups. After treatment, Dusp6 expression was significantly upregulated in progestin-sensitive groups, but not in progestin-resistant groups. Moreover, a high-dose of Dusp6 transfection significantly enhanced progestin-induced growth-inhibition in Ishikawa cells. CONCLUSIONS: Dusp6 could be a predicting marker for deciding the effectiveness of progestin therapy in AEH. PMID- 25451694 TI - Risk of cancer among women with polycystic ovary syndrome: a Danish cohort study. AB - OBJECTIVE: To assess the association between polycystic ovary syndrome (PCOS) and cancer, especially of the endometrium, breast and ovary. METHODS: The Danish National Patient Register was used to identify 12,070 in- and outpatients in whom PCOS was diagnosed when they were aged 9-49 years during 1977-2012. Using the Danish Cancer Registry, we followed the cohort through 2012 and compared the women's cancer incidence with that of the general Danish female population by means of standardized incidence ratios (SIRs). RESULTS: Cancer was diagnosed in 279 women with PCOS (SIR = 1.19; 95% CI = 1.06-1.34). We found an almost fourfold increased risk for endometrial cancer (numbers observed (N) = 16, SIR = 3.9; 95% CI = 2.2-6.3), the large majority of cases being type 1 (N = 14, SIR = 4.7; 95% CI = 2.6-7.9). We found no association between PCOS and breast (N = 59, SIR = 1.1; 95% CI = 0.8-1.4) or ovarian cancer (N = 10, SIR = 1.8; 95% CI = 0.8-3.2); however, significantly increased risks were found for kidney, colon and brain cancers. CONCLUSION: The results of this large cohort study support those of case control studies showing that women with PCOS are at increased risk for endometrial cancer, whereas their risks for breast and ovarian cancer are similar to those of women in the general population. Our finding that women with PCOS also are at increased risk for cancers of the kidney, colon and brain requires further study. PMID- 25451693 TI - Perioperative blood transfusion in gynecologic oncology surgery: analysis of the National Surgical Quality Improvement Program Database. AB - OBJECTIVE: To use a large-scale multi-institutional dataset to quantify the prevalence of packed red blood cell transfusions and examine the associations between transfusion and perioperative outcomes in gynecologic cancer surgery. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) participant use file was queried for all gynecologic cancer cases between 2010 and 2012. Demographic, preoperative and intraoperative variables were compared between transfusion and non-transfusion groups using chi-squared, Fisher's exact and Wilcoxon rank-sum tests. The primary endpoint was 30-day composite morbidity. Secondary endpoints included composite surgical site infections, mortality and length of stay. RESULTS: A total of 8519 patients were analyzed, and 13.8% received a packed red blood cell transfusion. In the multivariate analysis, after adjusting for key clinical and perioperative factors, including preoperative anemia and case magnitude, transfusion was associated with higher composite morbidity (OR = 1.85, 95% CI 1.5-2.24), surgical site infections (OR 1.80, 95% CI 1.39-2.35), mortality (OR 3.38, 95% CI 1.80 6.36) and length of hospital stay (3.02 days v. 7.17 days, P < 0.001). CONCLUSIONS: Blood transfusions are associated with increased surgical wound infections, composite morbidity and mortality. Based on our analysis of the NSQIP database, transfusion practices in gynecologic cancer should be scrutinized. Examination of institutional practices and creation of transfusion guidelines for gynecologic malignancies could potentially result in better utilization of blood bank resources and clinical outcomes among patients. PMID- 25451697 TI - Optogenetic control of astrocytes: is it possible to treat astrocyte-related epilepsy? AB - Epilepsy is a neurological disorder that affects around 1% of the population worldwide. The two main therapies, pharmacology and the electrical stimulation, both have some shortcomings. For instance, pharmacological therapy is frequently accompanied by side effects, and current anticonvulsive drugs fail to be effective to around a third of patients. These patients could suffer astrocyte related epilepsy, as increasing evidence indicates that dysfunctions of astrocytes can result in epilepsy. However, epilepsy drugs that affect astrocytes are not available currently. Although electrical stimulation has benefited many patients, the electrode stimulates unselective neurons or circuits. All these need to develop new strategies for improving the life of the patients. As channelrhodopsins (ChRs) were discovered, a novel method referred to as "optogenetics" was developed. It has advantages over electrical stimulation of being less-invasiveness and allowing spatiotemporally stimulation. Recently, a number of experiments have explored the treatments for epilepsy with optogenetic control of neurons. Here, we discuss the possibility that an optogenetic approach could be used to control the release of gliotransmitters and improve astrocyte function such as glutamate and K(+) uptake, and thereby offer a potential strategy to investigate and treat astrocyte-related epilepsy. PMID- 25451696 TI - Desvenlafaxine reduces apoptosis in amygdala after myocardial infarction. AB - This study was designed to determine if desvenlafaxine (DV), a serotonin norepinephrine reuptake inhibitor, can attenuate apoptosis observed in the limbic system after myocardial infarction (MI). MI was induced in rats by occlusion of the left descending artery for 40 min followed by reperfusion. Another group of sham (control) rats was similarly manipulated, but without occlusion. Half of the full cohort received DV (3 mg/kg/day intraperitoneal), starting 5 min after the onset of reperfusion; the other half received the vehicle (0.5 ml of 0.9% saline). Rats were sacrificed after 3 days for biochemical analyses and MI size measurements. Infarct size was significantly smaller in DV- compared to vehicle treated rats. At 3 days post-MI, caspase-3 and -8 activities and terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-positive cells were decreased in the amygdala of DV-treated rats compared to MI-vehicle controls. No difference was observed between the sham groups. The data indicates that DV given immediately after an acute MI event can reduce MI size and apoptosis in amygdala when measured three days post-MI. PMID- 25451695 TI - Significance of lymph node ratio in defining risk category in node-positive early stage cervical cancer. AB - OBJECTIVE: The ratio of positive to negative lymph nodes, or lymph node ratio (LNR), is an important prognostic factor in several solid tumors. The objective of this study was to determine if LNR can be used to define a high-risk category of patients with node-positive early stage cervical cancer. METHODS: We performed a retrospective review of patients diagnosed with node-positive stage I or II cervical cancer who underwent radical hysterectomy and pelvic +/- para-aortic lymphadenectomy at MD Anderson from January 1990 to December 2011. Univariate and multivariate analyses were used to identify prognostic factors for progression free (PFS) and overall survival (OS). RESULTS: Ninety-five patients met the inclusion criteria and were included in the analysis. Median total nodes removed were 19 (range 1-58), and median number of positive nodes was 1 (range 1-12). Fifty-eight patients (61%) received radiation with concurrent cisplatin and 27 patients (28%) received radiotherapy alone. Twenty-one (22%) patients recurred. On multivariate analysis, a LNR > 6.6% was associated with a worse PFS (HR = 2.97, 95% CI 1.26-7.02, p = 0.01), and a LNR > 7.6% with a worse OS (HR = 3.96, 95% CI 1.31-11.98, p = 0.01). On multivariate analysis, positive margins were associated with worse PFS (p = 0.001) and OS (p = 0.002), and adjuvant radiotherapy (p = 0.01) with improved OS. CONCLUSIONS: LNR appears to be a useful tool to identify patients with worse prognosis in node-positive early stage cervical cancer. LNR may be used in addition to pathologic risk factors to tailor adjuvant treatment in this population. PMID- 25451698 TI - Distinctive hippocampal and amygdalar cytoarchitectural changes underlie specific patterns of behavioral disruption following stress exposure in an animal model of PTSD. AB - Alterations in cytoarchitecture and molecular signaling have been observed in adaptive and maladaptive responses to stress and presumably underlie the physiological and behavioral changes observed. The relationship between behavioral responses to stress exposure and changes in cytoarchitecture of subregions of the hippocampus and amygdala was investigated in an animal model of PTSD. Behaviors in elevated plus-maze and acoustic startle response tests were assessed in rats 7 days after exposure to predator scent stress. Brains were harvested 24h later. Neurons from CA1, CA3, and dentate gyrus subregions and basolateral amygdala were reconstructed and subjected to Sholl analysis and spine density estimation. Glucocorticoid receptor, brain-derived neurotrophic factor, phospho-NR1-Ser-889, phospho-GluR1-Ser-845, phospho-calcium/calmodulin dependent protein kinase II-Thy-286, post-synaptic density protein 95 and phospho-CREB-Ser 133 were evaluated in the hippocampus. Data were analyzed by retrospective classification of individual rats into three behavioral response groups. The extent and distribution of changes in the morphology of hippocampal and amygdalar dendrites was significantly associated with stress-induced behavioral response classification. Extreme (PTSD-like) behavioral disruption was associated with extensive neuronal retraction in the hippocampus and proliferation in the amygdala. Neither structure displayed such changes in minimal behavioral responders. Partial behavioral response was associated with identical changes in the hippocampus only. Patterns of change in requisite molecular signaling genes and endophenotypic markers corresponded to the structural and behavioral responses. The extent and distribution of changes in the cytoarchitecture of hippocampal and amygdalar subregions is directly related to the pattern of behavioral response of the individual to stress exposure. PMID- 25451699 TI - Dermatoglyphics in relation to brain volumes in twins concordant and discordant for bipolar disorder. AB - Palmar and finger dermatoglyphics are formed between the 10th and the 17th weeks of gestation and their morphology can be influenced by genetic or environmental factors, interfering with normal intrauterine development. As both the skin and the brain develop from the same embryonal ectoderm, dermatoglyphic alterations may be informative for early abnormal neurodevelopmental processes in the brain. We investigated whether dermatoglyphic alterations are related to structural brain abnormalities in bipolar disorder and to what extent they are of a genetic and of an environmental origin. Dermatoglyphics and volumetric data from structural MRI were obtained in 53 twin pairs concordant or discordant for bipolar disorder and 51 healthy matched control twin pairs. Structural equation modeling was used. Bipolar disorder was significantly positively associated with palmar a-b ridge count (ABRC), indicating higher ABRC in bipolar patients (rph=.17 (CI .04-.30)). Common genes appear to be involved because the genetic correlation with ABRC was significant (rph-A=.21 (CI .05-.36). Irrespective of disease, ABRC showed a genetically mediated association with brain volume, indicated by a significant genetic correlation rph-A of respectively -.36 (CI .52 to -.22) for total brain, -.34 (CI -.51 to -.16) total cortical volume, -.27 (CI -.43 to -.08) cortical gray matter and -.23 (CI -.41 to -.04) cortical white matter. In conclusion, a genetically determined abnormal development of the foetal ectoderm between the 10th and 15th week of gestation appears related to smaller brain volumes in (subjects at risk for) bipolar disorder. PMID- 25451700 TI - Disruption of the ErbB signaling in adolescence increases striatal dopamine levels and affects learning and hedonic-like behavior in the adult mouse. AB - The ErbB signaling pathway has been genetically and functionally implicated in schizophrenia. Numerous findings support the dysregulation of Neuregulin (NRG) and epidermal growth factor (EGF) signaling in schizophrenia. However, it is unclear whether alterations of these pathways in the adult brain or during development are involved in the pathophysiology of schizophrenia. Herein we characterized the behavioral profile and molecular changes resulting from pharmacologically blocking the ErbB signaling pathway during a critical period in the development of decision making, planning, judgments, emotions, social cognition and cognitive skills, namely adolescence. We demonstrate that chronic administration of the pan-ErbB kinase inhibitor JNJ-28871063 (JNJ) to adolescent mice elevated striatal dopamine levels and reduced preference for sucrose without affecting locomotor activity and exploratory behavior. In adulthood, adolescent JNJ-treated mice continue to consume less sucrose and needed significantly more correct-response trials to reach the learning criterion during the discrimination phase of the T-maze reversal learning task than their saline-injected controls. In addition, JNJ mice exhibited deficit in reference memory but not in working memory as measured in the radial arm maze. Inhibition of the pathway during adolescence did not affect exploratory behavior and locomotor activity in the open field, social interaction, social memory, and reversal learning in adult mice. Our data suggest that alteration of ErbB signaling during adolescence resulted in changes in the dopaminergic systems that emerge in pathological learning and hedonic behavior in adulthood, and pinpoints the possible role of the pathway in the development of cognitive skills and motivated behavior. PMID- 25451701 TI - Construction of a tetracycline inducible expression vector and characterization of its use in Vibrio cholerae. AB - We report the construction of a tetracycline inducible expression vector that allows regulated gene expression in the enteric pathogen Vibrio cholerae. The expression vector, named pXB300, contains the tetracycline regulatory elements from Tn10, a multiple cloning site downstream of the tetA promoter and operator sequences, a ColE1 origin of replication, a beta-lactamase resistance gene for positive selection, and the hok/sok addiction system for selection in the absence of antibiotic. The function of the tetracycline expression system was demonstrated by cloning lacZ under control of the tetA promoter and quantifying beta-galactosidase expression in Escherichia coli and V. cholerae. The utility for pXB300 was documented by complementation of V. cholerae virulence mutants during growth under virulence inducing conditions. The results showed that pXB300 allowed high-level expression of recombinant genes with linear induction in response to the exogenous concentration of the inducer anhydrotetracycline. We further show that pXB300 was reliably maintained in V. cholerae during growth in the absence of antibiotic selection. PMID- 25451702 TI - ST2 pathogenetic profile in ambulatory heart failure patients. AB - BACKGROUND: Soluble ST2 is involved in multiple pathogenic pathways, including cardiac strain, inflammation, and myocardial necrosis with remodeling. The relative weight of ST2 and the point at which its prognostic value in heart failure (HF) is affected by different degrees of myocardial strain, inflammation, necrosis, and remodeling is unknown. METHODS AND RESULTS: We examined whether soluble ST2 levels improves HF risk stratification relative to other biomarkers representative of multiple pathogenic pathways-N-terminal pro-B-type natriuretic peptide (NT-proBNP; strain), high-sensitivity C-reactive protein (hsCRP; inflammation), and galectin-3 and high-sensitivity troponin T (hsTnT; necrosis and remodeling)-in 1,015 patients with mean left ventricular ejection fraction (LVEF) 33.5%. Mean follow-up was 4.2 +/- 2.1 years. The correlation with soluble ST2 was highest with NT-proBNP (r = 0.32; P < .001) and lowest with galectin-3 (r = 0.15; P < .001). ST2 levels increased with increasing concentrations of the other biomarkers (P < .001 in all cases). During follow-up, 467 patients died. Soluble ST2 remained an independent prognosticator of risk at every tertile of each biomarker. This was observed even after adjusting for clinical parameters. CONCLUSIONS: Soluble ST2 may be regarded as a 3-in-1 prognosis biomarker in HF. ST2 provides valuable long-term risk stratification information in HF beyond that reported by other biomarkers of stretch, inflammation, necrosis, and remodeling. PMID- 25451703 TI - Plasma ultrasensitive cardiac troponin during long-term follow-up of heart transplant recipients. AB - BACKGROUND: Plasma troponin is a risk factor for cardiac events in various populations. We evaluated the determinants and predictive value of plasma cardiac troponin I (cTnI) during the long-term follow-up of heart transplantation. METHODS AND RESULTS: We prospectively measured cTnI in 100 heart transplant recipients, 13.0 +/- 6.0 years after transplantation, during a routine visit including echocardiography and laboratory measurements. The patients were followed for 21.3 +/- 4.9 months after this troponin measurement. cTnI >=0.006 MUg/L (detection threshold) was found in 37 of these 100 patients. Plasma troponin significantly increased with the presence and severity of coronary lesions detected by means of coronary angiography and was significantly associated with age, left ventricular mass, history of post-transplantation heart failure, body mass index, and plasma creatinine. Of 37 patients with cTnI >=0.006 MUg/L, 13 had a cardiac event during follow-up compared with 2 of 63 patients with cTnI <0.006 MUg/L (P < .0001). The relation between cTnI and cardiac events remained significant in multivariate analysis. CONCLUSIONS: cTnI is frequently detectable during long-term follow-up after heart transplantation and is associated with chronic graft rejection and renal failure. A detectable cTnI may help identify heart transplant recipients at high risk of cardiac events. PMID- 25451704 TI - Novel extracellular matrix biomarkers as predictors of adverse outcome in chronic heart failure: association between biglycan and response to statin therapy in the CORONA trial. AB - BACKGROUND: The extracellular matrix (ECM) plays an important role in left ventricular remodeling and progression of heart failure (HF). Biglycan and mimecan are ECM proteins that are abundantly expressed in cardiac tissue but have not been evaluated as prognostic markers in HF. We investigated their interaction with statin treatment and association with adverse outcome in chronic HF. METHODS AND RESULTS: The association between serum levels of biglycan and mimecan and the primary end point (cardiovascular [CV] death, nonfatal myocardial infarction, nonfatal stroke), all-cause mortality, CV death, the composite of all-cause mortality/hospitalization for worsening of HF, and the coronary end point was evaluated in 1,390 patients >60 years of age with ischemic systolic HF in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) population, randomly assigned to 10 mg rosuvastatin or placebo. Serum biglycan and mimecan added no prognostic information beyond conventional risk factors, including N-terminal pro B-type natriuretic peptide. However, statin treatment improved all outcomes except CV death in patients with low biglycan levels (ie, lower tertile), even after full multivariable adjustment. CONCLUSIONS: Although circulating levels of mimecan and biglycan were of limited predictive value in patients with chronic HF, circulating biglycan could be a useful marker for targeting statin therapy in patients with HF. PMID- 25451705 TI - Prognostic impact of central sleep apnea in patients with heart failure. AB - BACKGROUND: Central sleep apnea (CSA) is common in patients with heart failure (HF). Earlier studies investigating the influence of CSA on mortality in HF patients, however, have yielded contradictory results. METHODS AND RESULTS: In a prospective study involving 267 patients with left ventricular (LV) ejection fractions <=50%, we performed polysomnography and compared heart transplant-free survival rates between patients with no or mild CSA (apnea-hypopnea index [AHI] <=15/h) and those with moderate CSA (AHI 15.1-30/h) or severe CSA (AHI >30/h). During 43 +/- 18 months' mean follow-up, 67 patients (25%) died and 4 patients (1%) underwent heart transplantation. Multivariate Cox analysis identified age, male sex, chronic kidney disease, and decreased LV ejection fraction, but not moderate CSA or severe CSA, as predictors of transplant-free survival. CONCLUSIONS: In patients with stable HF, moderate CSA as well as severe CSA do not appear to predict transplant-free survival independently from confounding factors. PMID- 25451706 TI - Heart rate-dependent left ventricular diastolic function in patients with and without heart failure. AB - BACKGROUND: Chronic heart rate (HR) reduction in the treatment of heart failure (HF) with systolic dysfunction is beneficial, but the immediate mechanical advantages or disadvantages of altering HR are incompletely understood. We examined the effects of increasing HR on early and late diastole in humans with and without HF. METHODS AND RESULTS: We studied force-interval relationships of the left ventricle (LV) in 11 HF patients and 14 control subjects. HR was controlled by right atrial pacing, and LV pressure was recorded by a micromanometer-tipped catheter. The time constant of isovolumic relaxation (tau) was calculated, and simultaneous sonographic images were analyzed for LV volumes. The end-diastolic pressure-volume relationship (EDPVR) was analyzed with the use of a single-beat method. Tau was shortened in response to increasing HR in both groups; the slope of this relationship was steeper in HF than in control subjects. The predicted volume at a theoretic pressure of 0 mm Hg (V30) increased at higher HRs compared with baseline, shifting the predicted EDPVR compliance curve to the right in HF patients but not in control subjects. CONCLUSIONS: In HF, changes in HR affect early relaxation and diastolic compliance to a greater extent than in control subjects. Our study reinforces current recommendations for HR-lowering drug treatment in HF. PMID- 25451707 TI - Reply:. PMID- 25451708 TI - Pediatric versus adult cardiomyopathy and heart failure-related hospitalizations: a value-based analysis. AB - BACKGROUND: Value-based health care is a proposed driver for reimbursement under the Affordable Care Act, with value broadly defined as outcomes divided by cost. Data on value-based health care in pediatric heart failure are scarce. METHODS AND RESULTS: A retrospective analysis of the Healthcare Cost and Utilization Project Kids' Inpatient Database and Nationwide Inpatient Sample was performed for pediatric and adult cardiomyopathy and heart failure-related hospitalizations. The study included 5,689 pediatric and 473,416 adult hospitalizations. Pediatric cardiomyopathy and heart failure hospitalizations were significantly longer than adult hospitalizations (mean +/- SE 16.2 +/- 0.7 days vs 6.8 +/- 0.1 days; P < .001). Overall mortality was greater for pediatric hospitalizations (7.7% vs 5.6%; P < .001), although it decreased over time for both pediatric and adult hospitalizations. Charges were greater for pediatric hospitalizations, both overall ($116,483 +/- $5,735 vs $40,662 +/- $1,419; P < .001) and for all years evaluated. CONCLUSIONS: In a value-based model, pediatric cardiomyopathy and heart failure-related hospitalizations are associated with worse outcomes and greater charges than adult hospitalizations. More research is needed to understand the cost effectiveness of pediatric heart failure treatment and to reduce the burden on the health care system. PMID- 25451710 TI - Dobutamine stress echocardiography, diastolic function, and myocardial performance index in patients with history of takotsubo syndrome. PMID- 25451709 TI - Association of antidiabetic medications targeting the glucagon-like peptide 1 pathway and heart failure events in patients with diabetes. AB - BACKGROUND: Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors (GLP-1 agents) may be protective in heart failure (HF). We set out to determine whether GLP-1 agent use is associated with HF risk in diabetics. METHODS AND RESULTS: In this retrospective cohort study of members of a large health system, we identified >19,000 adult diabetics from January 1, 2000, to July 1, 2012. GLP-1 agent users were matched 1:2 to control subjects with the use of propensity matching based on age, race, sex, coronary disease, HF, diabetes duration, and number of antidiabetic medications. The association of GLP-1 agents with time to HF hospitalization was tested with multivariable Cox regression. All cause hospitalization and mortality were secondary end points. We identified 1,426 users of GLP-1 agents and 2,798 control subjects. Both were similar except for angiotensin-converting enzyme inhibitors/angiotensin receptor blocker use, number of antidiabetic medications, and age. There were 199 hospitalizations, of which 128 were for HF, and 114 deaths. GLP-1 agents were associated with reduced risk of HF hospitalization (adjusted hazard ratio [aHR] 0.51, 95% confidence interval [CI] 0.34-0.77; P = .002), all-cause hospitalization (aHR 0.54, 95% CI 0.38-0.74; P = .001), and death (aHR 0.31, 95% CI 0.18-0.53; P = .001). CONCLUSIONS: GLP-1 agents may reduce the risk of HF events in diabetics. PMID- 25451711 TI - Co-regulation of pluripotency and genetic integrity at the genomic level. AB - The Disposable Soma Theory holds that genetic integrity will be maintained at more pristine levels in germ cells than in somatic cells because of the unique role germ cells play in perpetuating the species. We tested the hypothesis that the same concept applies to pluripotent cells compared to differentiated cells. Analyses of transcriptome and cistrome databases, along with canonical pathway analysis and chromatin immunoprecipitation confirmed differential expression of DNA repair and cell death genes in embryonic stem cells and induced pluripotent stem cells relative to fibroblasts, and predicted extensive direct and indirect interactions between the pluripotency and genetic integrity gene networks in pluripotent cells. These data suggest that enhanced maintenance of genetic integrity is fundamentally linked to the epigenetic state of pluripotency at the genomic level. In addition, these findings demonstrate how a small number of key pluripotency factors can regulate large numbers of downstream genes in a pathway specific manner. PMID- 25451712 TI - DICER1 mutations in a patient with an ovarian Sertoli-Leydig tumor, well differentiated fetal adenocarcinoma of the lung, and familial multinodular goiter. AB - DICER1 syndrome, a recently described tumor-predisposition syndrome, often involves multiple organs and is characterized by pleuropulmonary blastoma (PPB), cystic nephroma, ovarian Sertoli-Leydig tumors, familial multinodular goiter, etc. Germline DICER1 mutations have been identified in individuals with a variety of malignant conditions. However, in a review of the reported DICER1 syndrome cases that feature an unusual array of neoplastic and hyperplastic phenotypes, no mentions are made of these patients also presenting well-differentiated fetal adenocarcinoma of the lung. Here, we present a 16-year-old Chinese adolescent suffering from an ovarian Sertoli-Leydig cell tumor,well-differentiated fetal adenocarcinoma of the lung, and familial multinodular goiter with a nonsense mutation (c.3540C > A; p.Tyr1180*) in exon 21 of DICER1. This report presents the first case in which the clinical features of DICER1 syndrome appear in combination with well-differentiated fetal adenocarcinoma of the lung. We hypothesize that this case may suggest that well-differentiated fetal adenocarcinoma of the lung falls within the wide spectrum of manifestations of the DICER1 syndrome. Remarkably, this mutation is reported in a patient from The International PPB Registry. PMID- 25451713 TI - Heterozygous deletion of CHL1 gene: detailed array-CGH and clinical characterization of a new case and review of the literature. AB - CHL1 gene maps at 3p26.3 and encodes a cell adhesion molecule of the immunoglobulin superfamily highly expressed in the brain. CHL1 regulates neuronal migration and neurite overgrowth in the developing brain, while in mature neurons it accumulates in the axonal membrane and regulates synapse function via the clathrin-dependent pathways. To our knowledge, to date only three familial cases presenting heterozygous deletion of chromosome 3 at band p26.3, including only the CHL1 gene, have been reported. All the patients presented cognitive impairment characterized by learning and language difficulties. Here, we describe a six-year-old boy in which array-CGH analysis disclosed a terminal 3p26.3 deletion. The deletion was transmitted from his normal mother and included only the CHL1 gene. Our patient presented microcephaly, short stature, mild mental retardation, learning and language delay, and strabismus. In our study we compare the phenotypic and molecular cytogenetic features of CHL1 gene deletion cases. Verbal function developmental delay seems to be a common key finding. The concomitance of the genetic and phenotypic alterations could be a good evidence of a new emerging syndrome associated with the deletion of CHL1 gene alone, although the identification of new cases is required. PMID- 25451714 TI - 16p11.2 de novo microdeletion encompassing SRCAP gene in a patient with speech impairment, global developmental delay and behavioural problems. AB - We describe a patient with speech impairment, global developmental delay, behavioural problems and a 186 kb de novo microdeletion on 16p11.2. There are four OMIM Phenotypes entries partially overlapping with the deleted region and related to recurrent microdeletions/microduplications in 16p11.2. A detailed review of published data shows that microdeletions/microduplications' boundaries do not include genes that are deleted in the case here reported. The deletion encompasses 9 RefSeq genes and includes SRCAP (Snf2-related CREBBP activator protein, OMIM*611421), a disease causing gene. Recently, truncating mutations in the SRCAP gene have been shown to cause Floating-Harbor syndrome (FHS, OMIM#136140), a rare disorder characterized by peculiar facial features, short stature with delayed osseous maturation and speech impairment. The patient reported here shows few subtle phenotypic features resembling that of FHS, but she does not have sufficient signs and symptoms for the clinical diagnosis and a clinical classification based on facial gestalt is not possible. This is the first report of a 16p11.2 deletion completely removing one copy of SRCAP, suggesting that haploinsufficiency of this gene could be associated to speech impairment, global developmental delay, behavioural problems and few subtle phenotypic features resembling FHS. However, further evidence for the putative causative role of SRCAP isolated deletion is needed. PMID- 25451716 TI - MLST typing of antimicrobial-resistant Propionibacterium acnes isolates from patients with moderate to severe acne vulgaris. AB - Molecular typing data on antimicrobial-resistant Propionibacterium strains are limited in the literature. We examined antimicrobial resistance profiles and the underlying resistance mechanisms in Propionibacterium spp. isolates recovered from patients with moderate to severe acne vulgaris in Greece. The clonallity of the resistant Propionibacterium acnes isolates was also investigated. Propionibacterium spp. isolates were detected using Tryptone-Yeast Extract Glucose (TYG) agar plates supplemented with 4% furazolidone. Erythromycin, clindamycin, vancomycin, penicillin, co-trimoxazole, doxycycline, minocycline and ciprofloxacin MICs were determined using the gradient strip method. Erythromycin, clindamycin and tetracycline mechanisms of resistance were determined using PCR and sequencing of the domain V of 23S rRNA and 16S rRNA, as well as the presence of the ermX gene. Typing was performed using the multi locus sequence typing (MLST) methodology. Seventy nine isolates from 76 patients were collected. Twenty three isolates (29.1%) exhibited resistance to erythromycin and clindamycin, while two additional isolates (2.5%) were resistant only to erythromycin. Resistance to tetracycline was not detected. The underlying molecular mechanisms were point mutations A2059G and A2058G. MLST typing of the P. acnes resistant isolates revealed that lineage type IA1 (ST-1, 3 and 52) prevailed (12/18; 66.7%), whilst lineage type IA2 (ST-2 and 22) accounted for five more isolates (27.8%). Susceptible isolates were more evenly distributed between ST types. Propionibacterium spp. from moderate to severe acne vulgaris in Greece are frequently resistant to erythromycin/clindamycin but not to tetracyclines, mainly due to the point mutations A2059G and A2058G. P. acnes resistant isolates were more clonally related than susceptible ones and belonged to a limited number of MLST types. PMID- 25451715 TI - Influence of E. coli-induced prostatic inflammation on expression of androgen responsive genes and transforming growth factor beta 1 cascade genes in rats. AB - BACKGROUND: Prostatic inflammation is reportedly associated with the development of prostatic hyperplasia. We investigated the effects of prostatic inflammation on expression levels of androgen-responsive genes and growth factors in the rat prostate. METHODS: Prostatic inflammation was induced by Escherichia coli (strain 1677) injection (0.2 ml of 1 * 10(8) CFU/ml) into the prostatic urethra of male Sprague-Dawley rats, and ventral lobes of the prostate were harvested on day 84. Rats were given 10 mg/kg celecoxib during the last month in the COX-2 inhibitor treated group. Histopathology and multiplex enzyme-linked immunosorbent assay (ELISA) for inflammation-related proteins were performed. Glandular epithelial cells and stromal regions were separately isolated using laser-capture microdissection (LCM). Real-time RT-PCR was performed to examine mRNA levels of androgen-responsive genes in the epithelium and tumor growth factor-beta1 (TGF beta1) cascade genes in the stroma. RESULTS: Hematoxylin and eosin staining showed that mild inflammation was distributed diffusely throughout the prostate. Polymorphonuclear cells infiltrated the slightly edematous stroma, but no morphological changes were observed in the epithelium. Immunohistochemically, expression of androgen receptor and TGF-beta1 in addition to IL-6 and cyclooxigenase-2 (COX-2) were enhanced in the E. coli inoculated rats. All of these factors were suppressed in the celecoxib-treated rats. Upregulation of IL 1alpha, IL-1beta, IL-6, and RANTES in the E. coli-inoculated rats was normalized by celecoxib treatment. Significant upregulation of androgen receptor and androgen-responsive genes such as Eaf2, ELL2, FKBP5, calreticulin, and ornithine decarboxylase was observed in the LCM-dissected epithelium. Also TGF-beta1 and its downstream cascade genes such as Hic-5, collagen 1, and fibronectin were upregulated significantly in the LCM-dissected stroma. The COX-2 inhibitor treatment suppressed upregulation of these genes. CONCLUSIONS: Prostatic inflammation changed the expression of androgen-responsive genes in the epithelium and TGF-beta1 cascade genes in the stroma. Activation of TGF-beta1 cascade genes in the inflamed stroma, as well as altered androgen-responsive gene expression in the epithelium, might be involved in the development of BPH. Prostate 75:381-389, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25451717 TI - General surgery residents' perception of robot-assisted procedures during surgical training. AB - INTRODUCTION: With the continued expansion of robotically assisted procedures, general surgery residents continue to receive more exposure to this new technology as part of their training. There are currently no guidelines or standardized training requirements for robot-assisted procedures during general surgical residency. The aim of this study was to assess the effect of this new technology on general surgery training from the residents' perspective. METHODS: An anonymous, national, web-based survey was conducted on residents enrolled in general surgery training in 2013. The survey was sent to 240 Accreditation Council for Graduate Medical Education-approved general surgery training programs. RESULTS: Overall, 64% of the responding residents were men and had an average age of 29 years. Half of the responses were from postgraduate year 1 (PGY1) and PGY2 residents, and the remainder was from the PGY3 level and above. Overall, 50% of the responses were from university training programs, 32% from university-affiliated programs, and 18% from community-based programs. More than 96% of residents noted the availability of the surgical robot system at their training institution. Overall, 63% of residents indicated that they had participated in robotic surgical cases. Most responded that they had assisted in 10 or fewer robotic cases with the most frequent activities being assisting with robotic trocar placement and docking and undocking the robot. Only 18% reported experience with operating the robotic console. More senior residents (PGY3 and above) were involved in robotic cases compared with junior residents (78% vs 48%, p < 0.001). Overall, 60% of residents indicated that they received no prior education or training before their first robotic case. Approximately 64% of residents reported that formal training in robotic surgery was important in residency training and 46% of residents indicated that robotic-assisted cases interfered with resident learning. Only 11% felt that robotic-assisted cases would replace conventional laparoscopic surgery in the future. CONCLUSIONS: This study illustrates that although the most residents have a robot at their institution and have participated in robotic surgery cases, very few residents received formal training before participating in a robotic case. PMID- 25451718 TI - Hospital mortality following trauma: an analysis of a hospital-based injury surveillance registry in sub-Saharan Africa. AB - IMPORTANCE: Injuries are a significant cause of death and disability, particularly in low- and middle-income countries. Health care systems in resource poor countries lack personnel and are ill equipped to treat severely injured patients; therefore, many injury-related deaths occur after hospital admission. OBJECTIVES: This study evaluates the mortality for hospitalized trauma patients at a tertiary care hospital in Malawi. DESIGN: This study is a retrospective analysis of prospectively collected trauma surveillance data. We performed univariate and bivariate analyses to describe the population and logistic regression analysis to identify predictors of mortality. SETTING: Tertiary care hospital in sub-Saharan Africa. PARTICIPANT: Patients with traumatic injuries admitted to Kamuzu Central Hospital between January 2010 and December 2012. MAIN OUTCOME MEASURES: Predictors of in-hospital mortality. RESULTS: The study population consisted of 7559 patients, with an average age of 27 years (+/-18 years) and a male predominance of 76%. Road traffic injuries, falls, and assaults were the most common causes of injury. The overall mortality was 4.2%. After adjusting for age, sex, type and mechanism of injury, and shock index, head/spine injuries had the highest odds of mortality, with an odds ratio of 5.80 (2.71 12.40). CONCLUSION AND RELEVANCE: The burden of injuries in sub-Saharan Africa remains high. At this institution, road traffic injuries are the leading cause of injury and injury-related death. The most significant predictor of in-hospital mortality is the presence of head or spinal injury. These findings may be mitigated by a comprehensive injury-prevention effort targeting drivers and other road users and by increased attention and resources dedicated to the treatment of patients with head and/or spine injuries in the hospital setting. PMID- 25451720 TI - The first 3-connected SrSi2 -type 3D chiral framework constructed from {Ni6 PW9 } building units. AB - A novel 3-connected SrSi2 -type 3D chiral framework constructed from hexa-Ni(II) cluster-substituted polyoxometalate (POM) units [Ni(enMe)2 ]3 [WO4 ]3 [Ni6 (enMe)3 (OH)3 PW9 O34 ]2 ?9H2 O (1) (enMe=1,2-diaminopropane) has been made from a hydrothermal synthetic method. This POM represents the first 3D framework based on {Ni6 PW9 } units and {WO4 } connectors. PMID- 25451719 TI - The call, the save, and the threat: understanding expert help-seeking behavior during nonroutine operative scenarios. AB - OBJECTIVE: Asking for help in the operating room occurs within a surgical culture that has traditionally valued independence, decisiveness, and confidence. A tension exists between these deeply ingrained character traits and the new culture of team-based practice that emphasizes maximizing patient safety. The objective of this study is to explore surgeon-to-surgeon help-seeking behaviors during complex and unanticipated operative scenarios. STUDY DESIGN: Semistructured interviews were conducted with a purposeful sample of 14 consultant surgeons from multiple specialties. We used constructivist grounded theory to explore help-seeking experiences. Analysis occurred alongside and informed data collection. Themes were identified iteratively using constant comparisons. SETTING: The setting included 3 separate hospital sites in a Canadian academic health sciences center. PARTICIPANTS: A total of 14 consultant surgeons from 3 separate departments and 7 divisions were included. RESULTS: We developed the "Call-Save-Threat" framework to conceptualize the help-seeking phenomenon. Respondents highlighted both explicit and tacit reasons for calling for help; the former included technical assistance and help with decision making, and the latter included the need for moral support, "saving face," and "political cover." "The Save" included the provision of enhanced technical expertise, a broader intraoperative perspective, emotional support, and a learning experience. "The Threat" included potential downsides to calling, which may result in near term or delayed negative consequences. These included giving up autonomy as primary surgeon, threats to a surgeon's image as a competent practitioner, and a failure to progress with respect to independent judgment and surgical abilities. CONCLUSIONS: Our "Call-Save-Threat" framework suggests that surgeons recurrently negotiate when and how to seek help in the interests of patient safety, while attending to the traditional cultural values of autonomy and decisive action. This has important implications for surgical postgraduate education and also throughout a surgeon's career trajectory. PMID- 25451721 TI - The effects of lobeline on depression-like behavior and hippocampal cell proliferation following chronic stress in mice. AB - We have reported that brain nicotinic acetylcholine receptor (nAChR) ligand lobeline has antidepressant-like effects in mice. The present study examined the effects of lobeline on chronic unpredictable stress (CUS)-induced depression-like behavior, deficits in brain-derived neurotrophic factor (BDNF) expression and cell proliferation in the hippocampus. Adult C57BL/6J mice were exposed to CUS for 6 weeks. Lobeline (1 or 4 mg/kg, s.c.) or saline was administered once daily during the last 14 days of CUS. CUS-exposed mice showed increased immobility time in the FST compared to control. Pretreatment with lobeline (1 mg/kg) significantly reduced immobility time in the CUS-exposed mice. Twenty-four hour following lobeline or saline treatment, BDNF expression or cell proliferation was measured in the hippocampus using Western blotting and bromodeoxyuridine immunohistochemistry, respectively. Lobeline (1 mg/kg) treatment prevented CUS induced reduction in BDNF expression and cell proliferation in the hippocampus. Overall, our findings suggest that antidepressant-like effects of lobeline could involve nAChR mediated signaling, BDNF expression, and/or hippocampal cell proliferation. PMID- 25451722 TI - Retinal neurodegeneration on optical coherence tomography and cerebral atrophy. AB - Neurodegeneration in dementia is mainly evaluated by assessing cerebral atrophy, while retinal neurodegeneration can be quantified in vivo using optical coherence tomography (OCT). We examined the association of retinal nerve fibre layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thinning with global and regional cerebral atrophy on magnetic resonance imaging (MRI). Malay participants aged 60-80 years from the Epidemiology of Dementia in Singapore Study underwent comprehensive examinations, including 3-Tesla cranial MRI. RNFL and GC-IPL thicknesses were obtained from spectral domain-OCT; and cerebral grey and white matter volumes were obtained from MRI scans using a validated segmentation tool. Linear regression models were constructed with adjustment for age and sex; and additionally for vascular risk factors and MRI markers including intracranial volume. 164 participants without glaucoma with gradable quality MRI and OCT scans were included for analysis. GC-IPL thinning was associated with reduction in total brain volume in the occipital (mean change in GC-IPL per standard deviation (SD) decrease in occipital lobe volume: -1.77 MUm, 95% confidence interval (CI) 6.55 to 0.01 MUm) and temporal lobes (mean change in GC-IPL per SD decrease in temporal lobe volume: -3.45 MUm, 95%CI -5.40 to -1.49 MUm) in multivariate adjusted models. In particular, GC-IPL thinning was primarily associated with grey matter volume, whereas no association was found with white matter changes. Retinal neuronal damage, as reflected by GC-IPL thinning, was independently associated with grey matter loss in the occipital and temporal lobes, suggesting that retinal OCT may provide insights for assessing neurodegeneration in the brain. PMID- 25451723 TI - Antiallodynic effect through spinal endothelin-B receptor antagonism in rat models of complex regional pain syndrome. AB - Complex regional pain syndrome (CRPS) is a very complicated chronic pain disorder that has been classified into two types (I and II). Endothelin (ET) receptors are involved in pain conditions at the spinal level. We investigated the role of spinal ET receptors in CRPS. Chronic post-ischemia pain (CPIP) was induced in male Sprague-Dawley rats as a model for CRPS-I by placing a tourniquet (O-ring) at the ankle joint for 3h, and removing it to allow reperfusion. Ligation of L5 and L6 spinal nerves to induce neuropathic pain was performed as a model for CRPS II. After O-ring application and spinal nerve ligation, the paw withdrawal threshold was significantly decreased at injured sites. Intrathecal administration of the selective ET-B receptor antagonist BQ 788 dose-dependently increased the withdrawal threshold in both CRPS-I and CRPS-II. In contrast, ET-A receptor antagonist BQ 123 did not affect the withdrawal threshold in either CRPS type. The ET-1 levels of plasma and spinal cord increased in both CRPS types. Intrathecal BQ 788 decreased the spinal ET-1 level. These results suggest that ET 1 is involved in the development of mechanical allodynia in CRPS. Furthermore, the ET-B receptor appears to be involved in spinal cord-related CRPS. PMID- 25451724 TI - Serotonin transporter polymorphisms predict response inhibition in healthy volunteers. AB - Serotoninergic transmission is reliably implicated in inhibitory control processes. The aim of this study was to test the hypothesis if serotonin transporter polymorphisms mediate inhibitory control in healthy people. 141 healthy subjects, carefully screened for previous and current psychopathology, were genotyped for the 5-HTTLPR and rs25531 polymorphisms. Inhibitory control was ascertained with the Stop Signal Task (SST) from the Cambridge Neuropsychological Test Automated Battery (CANTAB). The triallelic gene model, reclassified and presented in a biallelic functional model, revealed a dose-dependent gene effect on SST performance with Individuals carrying the low expressive allele had inferior inhibitory control compared to high expressive carriers. This directly implicates serotonin transporter polymorphisms (5-HTTLPR plus rs25531) in response inhibition in healthy subjects. PMID- 25451725 TI - LGR5/GPR49 is implicated in motor neuron specification in nervous system. AB - The biological roles of stem cell marker LGR5, the receptor for the Wnt-agonistic R-spondins, for nervous system are poorly known. Bioinformatics analysis in normal human brain tissues revealed that LGR5 is closely related with neuron development and functions. Interestingly, LGR5 and its ligands R-spondins (RSPO2 and RSPO3) are specifically highly expressed in projection motor neurons in the spinal cord, brain stem and cerebral. Inhibition of Notch activity in neural stem cells (NSCs) increased the percentage of neuronal cells and promoted LGR5 expression, while activation of Notch signal decreased neuronal cells and inhibited the LGR5 expression. Furthermore, knockdown of LGR5 inhibited the expression of neuronal markers MAP2, NeuN, GAP43, SYP and CHRM3, and also reduced the expression of genes that program the identity of motor neurons, including Isl1, Lhx3, PHOX2A, TBX20 and NEUROG2. Our data demonstrated that LGR5 is highly expressed in motor neurons in nervous system and is involved in their development by regulating transcription factors that program motor neuron identity. PMID- 25451726 TI - Inborn stress reactivity shapes adult behavioral consequences of early-life maternal separation stress. AB - Early-life experience strongly impacts neurodevelopment and stress susceptibility in adulthood. Maternal separation (MS), an established model of early-life adversity, has been shown to negatively impact behavioral and endocrine responses to stress in adulthood. However, the impact of MS in rats with heightened inborn stress susceptibility has not been fully explored. To address this issue we conducted MS in Wistar-Kyoto (WKY) rats, an animal model of comorbid depression and anxiety, and Wistar rats, which share a similar genetic background with WKYs. WKY and Wistar pups experienced either 180-min daily MS or 15-min separation (neonatal handling) during the first two postnatal weeks, and were tested for depressive- and anxiety- like behaviors in adulthood. Exposure to early-life MS in WKY rats decreased anxiety- and depressive- like behaviors, leading to increased exploration on the open field test (OFT), enhanced social interaction, and diminished immobility on the forced swim test. MS had an opposite effect in Wistar offspring, leading to enhanced anxiety-like behaviors, such as reduced OFT exploration and decreased social interaction. These findings are consistent with the match/mismatch theory of disease and the predictive adaptive response, which suggests that early life stress exposure can confer adaptive value in later life within certain individuals. Our data supports this theory, showing that early life MS has positive and perhaps adaptive effects within stress-vulnerable WKY offspring. Future studies will be required to elucidate the neurobiological underpinnings of contrasting behavioral effects of MS on WKY vs. Wistar offspring. PMID- 25451727 TI - GABA-mediated modulation of ATP-induced intracellular calcium responses in nodose ganglion neurons of the rat. AB - We examined ATP-induced intracellular Ca(2+) ([Ca(2+)]i) responses in the neurons and satellite cells from one of the viscerosensory ganglia, the nodose ganglion (NG), as well as the GABA-mediated modulation of ATP-induced neuronal [Ca(2+)]i responses using intracellular calcium imaging. In neurons with satellite cells, ATP induced [Ca(2+)]i increases in both the neurons and satellite cells. The P2X receptor agonist, alpha,beta-meATP, induced [Ca(2+)]i increases in neurons and this response was inhibited by the P2X receptor antagonist, PPADS. On the other hand, the P2Y receptor agonist, ADP, induced [Ca(2+)]i increases in satellite cells, and this response was inhibited by the P2Y receptor antagonist, MRS2179. RT-PCR detected the expression of P2X2, P2X3, P2Y1, and P2Y2 receptor mRNAs in NG extracts. Immunohistochemistry revealed that NG neurons and satellite cells were immunoreactive to P2X2 and P2X3, and P2Y1 and P2Y2 receptors, respectively. In isolated neurons, the ATP-evoked [Ca(2+)]i increase was inhibited by GABA. However, in neurons with satellite cells, the GABAA receptor antagonist, bicuculline, enhanced the ATP-induced [Ca(2+)]i increase in neurons. These results suggest that viscerosensory neuronal excitability may be modulated by GABA from satellite cells in NG. PMID- 25451728 TI - Neurogenesis of the spiral ganglion cells in the cochlea requires the transcriptional cofactor TIS21. AB - The molecular mechanisms controlling the proliferation and differentiation of spiral ganglion cells (SGCs) in the inner ear are still largely unknown. TIS21 is a transcriptional cofactor that shows antiproliferative, antiapoptotic, and prodifferentiative effects on neural progenitor cells. To investigate the function of TIS21 during SGC development, we analyzed SGC neurogenesis from embryonic day 13.5 (E13.5) to postnatal day 4 (P4) in Tis21-GFP knock-in mice, in which the protein-encoding exon of the Tis21 gene was replaced by EGFP. Through E13.5 to P4, we found fewer SGCs in homozygous Tis21-GFP knock-in mice than in wild-type mice. Our results suggest that TIS21 is required for development of SGCs. Deleting Tis21 may affect progenitor cells or neuroblasts at the beginning of cochlear-vestibular ganglion formation and would consequently lead to a decrease in the number of SGCs. PMID- 25451729 TI - Behavioral inflexibility and motor dedifferentiation in persons with Parkinson's disease: bilateral coordination deficits during a unimanual reaching task. AB - We evaluated kinematics of people with Parkinson's disease (PD) and age-matched controls during cued and uncued reaching movements. Maximum hand velocity, its variability and shoulder-to-shoulder coupling, quantified by phase locking value (PLV), were compared between PD (n=14) and Control (n=4). The PD group achieved significantly lower maximum hand velocities during the reaching movement in comparison to the Control group (p=0.05), whereas the Control group exhibited significantly greater variability (i.e., larger SDs) of maximum hand velocities across the blocks than the PD group (p=0.01). Persons with PD exhibited higher PLVs than the healthy elderly individuals when performing reaching movements with their dominant side (p=0.05), while the PLVs did not differ between groups when the movements were performed with their non-dominant hand. The present study suggests that persons with PD have a reduced ability to: (1) modulate maximum reaching velocity; and (2) alter coordination across the shoulders to different reaching actions. In persons with PD, the velocity-oriented (dominant) limb becomes slowed and less flexible, to the point that its movement dynamics are effectively similar to that of the position-oriented (non-dominant) limb. PMID- 25451730 TI - Perforations of the esophagus and stomach: what should I do? AB - INTRODUCTION: Esophageal and gastroduodenal perforations are relatively uncommon; however, they both can be potentially life-threatening. Esophageal perforations most commonly occur due to iatrogenic injury, forceful retching (Boerhaave's syndrome), malignancy, foreign body ingestion, or caustic injury. Gastroduodenal perforations are most commonly due to peptic ulcer disease or malignancy. Pain and signs of sepsis are the most common presenting symptoms and signs. METHODS: Determining the extent of critical illness and addressing hemodynamics and sepsis are the first priorities. Identifying the location and size of the perforation as well as extent of contamination is the next priorities. Although surgical intervention has been the mainstay of treatment, newer approaches have led to a heterogeneity of approaches. CONCLUSION: For esophageal perforation, observation, endoscopic, radiological, and surgical approaches may be appropriate. For gastroduodenal perforation, surgical approach is still the most appropriate, although a concomitant acid-reducing operation is usually not necessary. Despite these advances, mortality for both perforations can still be high. Sound judgment is necessary for optimal results. PMID- 25451731 TI - Letter in response to "Perioperative blood transfusion is associated with decreased survival in patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma: a multi-institutional study". PMID- 25451732 TI - Reply to the letter to the editor regarding manuscript entitled: "Perioperative blood transfusion is associated with decreased survival in patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma: a multi-institutional study". PMID- 25451733 TI - Quantifying the burden of complications following total pancreatectomy using the postoperative morbidity index: a multi-institutional perspective. AB - BACKGROUND: While contemporary studies demonstrate decreasing complication rates following total pancreatectomy (TP), none have quantified the impact of post-TP complications. The Postoperative Morbidity Index (PMI)-a quantitative measure of postoperative morbidity-combines ACS-NSQIP complication data with severity weighting derived from Modified Accordion Grading System. We establish the PMI for TP in a multi-institutional cohort. METHODS: Nine institutions contributed ACS-NSQIP data for 64 TPs (2005-2011). Each complication was assigned an Accordion severity weight ranging from 0.110 (grade 1/mild) to 1.00 (grade 6/death). PMI equals the sum of complication severity weights ("Total Burden") divided by total number of patients. RESULTS: Overall, 29 patients (45.3 %) suffered 55 ACS-NSQIP complications; 15 (23.4 %) had >1 complication. Thirteen patients (20.3 %) were readmitted and one death (1.6 %) occurred within 30 days. Non-risk adjusted PMI was 0.151, while PMI for complication-bearing cases rose to 0.333. Bleeding/Transfusion and Sepsis were the most common complications. Discordance between frequency and burden of complications was observed. While grades 4-6 comprised only 18.5 % of complications, they contributed 37.1 % to the series' total burden. CONCLUSION: This multi-institutional series is the first to quantify the complication burden following TP using the rigor of ACS-NSQIP. A PMI of 0.151 indicates that, collectively, patients undergoing TP have an average burden of complications in the mild to moderate severity range, although complication-bearing patients have a considerable reduction in health utility. PMID- 25451734 TI - Intraoperative surgical margin re-resection for colorectal liver metastasis: is it worth the effort? AB - OBJECTIVE: This study was conducted to evaluate recurrence and survival among patients who underwent intraoperative margin re-resection for colorectal cancer liver metastases (CRLM). BACKGROUND: Among patients who receive intraoperative margin re-resection, the relation between final margin status, pattern of recurrence, and survival is largely unknown. METHODS: Three hundred thirty-two patients who underwent hepatic resection for CRLM between 2000 and 2013 were identified. Demographics, operative data, pathologic margin status, site of recurrence, and long-term survival data were collected and analyzed. Patients were stratified in three groups based on their margin status: R0, R1, and R1 -> R0. RESULTS: R0 resections were achieved in 247 (74.4%) patients, 61 (18.4%) patients had an R1 resection, whereas 24 (7.2%) had an R1 -> R0. Median survival for patients undergoing R0 resections was 50.2 (95% confidence interval (CI) 49.2 66.2) months versus 63.0 (95% CI 50.3-70.5) months for patients undergoing R1 resections versus 49.2 (95% CI 29.9-NA) months for patients undergoing intraoperative margin re-resection (P > 0.05). Differences in recurrence rate and pattern were not significant between the three groups (P > 0.05). CONCLUSION: In the era of modern systemic chemotherapy, it seems that the impact of margin status on outcomes may be minimal compared to that of patient and tumor factors. In this scenario, margin re-resection to achieve R0 status does not improve long term outcomes. PMID- 25451735 TI - Risk factors for 30-day readmissions after hepatectomy: analysis of 2444 patients from the ACS-NSQIP database. AB - AIMS: The aim of this study was to identify risk factors associated with unplanned readmissions after hepatectomies. METHODS: Patients who underwent hepatectomies between January and December of 2011 were identified using the ACS NSQIP database. A multivariate logistic regression analysis was performed to determine predictors of unplanned readmissions related to the procedure within 30 days. RESULTS: Unplanned readmissions occurred in 10.5 % of all patients who received a hepatectomy. On multivariate analysis, transfusion within 72 h after surgery (odds ratio [OR] 1.74, p < 0.001), complexity of procedure (extended, OR 1.84, p = 0.004; right hepatectomy, OR 1.66, p = 0.003), and longer operative time (>median 320 min, OR 2.43, p < 0.001) were independent perioperative predictors of unplanned readmissions. Independent preoperative risk factors included elevated alkaline phosphatase (OR 1.45, p = 0.017), bleeding disorders (OR 1.72, p = 0.051), and lower albumin levels (OR 1.30, p = 0.036). CONCLUSION: Transfusion, complexity of procedure, and duration of operation were the strongest predictors of unplanned readmissions after liver resection. PMID- 25451736 TI - Hydrogen bond distinction and activation upon catalytic etherification of hydroxyl compounds. AB - An excellent linear correlation between ln delta (OH chemical shift) and 1/T (temperature) is discovered for the first time for hydroxyl compounds. The derived slope (A) provides information as an index not only for distinguishing different types of H-bonds, but also for predicting their reactivities. This finding can be extended to other H-bond-containing molecules. PMID- 25451737 TI - Ultrastructural studies of some character of Diptera (Muscidae) of forensically importance. AB - Insects are important in the decomposition of cadavers. In the field of forensic entomology, the taxonomic identification is essential to proceed to any procedure. The use of these insects in medico criminal investigation is the object of forensic entomological studies; the flies are generally attracted to cadavers and one of the most important contributions is to estimate the postmortem interval. The scanning electron microscopy, which allows rapid and accurate identification of character could be used to help identify different species of forensics flies, has been highlighted as it allows better visualization of the external morphology of immature and some adults. The aim of this study was to describe the katepisternals in females of Morellia humeralis and Biopyrellia bipuncta; the ommatidia of the compounds eyes of the male of B. bipuncta; the antennae of females of Ophyra aenescens and Ophyra albuquerquei and the ocellar triangle of the last two species and O. chalcogaster examined by scanning electron microscopy to help increase the anatomical database on flies for forensic importance. The katepisternals of M. humeralis and B. bipuncta were densely covered by different groups of sensilla. The surface of the ocellar region of O. aenescens was not covered by sensilla, but in O. albuquerquei and O. chalcogaster were densely covered by different types of sensilla. The coeloconic sensilla were only found in the flagellum of O. albuquerquei. PMID- 25451738 TI - Genome-wide transcriptional profiling of chronic cutaneous lupus erythematosus (CCLE) peripheral blood identifies systemic alterations relevant to the skin manifestation. AB - Major gaps remain regarding pathogenetic mechanisms underlying clinical heterogeneity in lupus erythematosus (LE). As systemic changes are likely to underlie skin specific manifestation, we analyzed global gene expression in peripheral blood of a small cohort of chronic cutaneous LE (CCLE) patients and healthy individuals. Unbiased hierarchical clustering distinguished patients from controls revealing a "disease" based signature. Functional annotation of the differentially expressed genes (DEGs) highlight enrichment of interferon related immune response and apoptosis signatures, along with other key pathways. There is a 26% overlap of the blood and lesional skin transcriptional profile from a previous analysis by our group. We identified four transcriptional "hot spots" at chromosomal regions harboring statistically increased numbers of DEGs which offer prioritized potential loci for downstream fine mapping studies in the search for CCLE specific susceptibility loci. Additionally, we uncover evidence to support both shared and distinct mechanisms for cutaneous and systemic manifestations of lupus. PMID- 25451739 TI - The effects of telomere shortening on cancer cells: a network model of proteomic and microRNA analysis. AB - Previously, we have shown that shortening of telomeres by telomerase inhibition sensitized cancer cells to cisplatinum, slowed their migration, increased DNA damage and impaired DNA repair. The mechanism behind these effects is not fully characterized. Its clarification could facilitate novel therapeutics development and may obviate the time consuming process of telomere shortening achieved by telomerase inhibition. Here we aimed to decipher the microRNA and proteomic profiling of cancer cells with shortened telomeres and identify the key mediators in telomere shortening-induced damage to those cells. Of 870 identified proteins, 98 were differentially expressed in shortened-telomere cells. 47 microRNAs were differentially expressed in these cells; some are implicated in growth arrest or act as oncogene repressors. The obtained data was used for a network construction, which provided us with nodal candidates that may mediate the shortened-telomere dependent features. These proteins' expression was experimentally validated, supporting their potential central role in this system. PMID- 25451740 TI - Statistical power for identifying nucleotide markers associated with quantitative traits in genome-wide association analysis using a mixed model. AB - Use of mixed models is in the spotlight as an emerging method for genome-wide association studies (GWASs). This study investigated the statistical power for identifying nucleotide variants associated with quantitative traits using the mixed model methodology. Quantitative traits were simulated through design of heritability, the number of causal variants (NCV), the number of polygenic variants, and genetic variance ratio of causal to polygenic variants (VRCTP). Statistical power estimates were influenced not only by individual factors of heritability, NCV, and VRCTP, but also by their interactions (P < 0.05). As the genetic variance ratio decreased, the difference in power between heritabilities of 0.3 and 0.5 increased with the use of 20 causal variants, but decreased when there were 100 causal variants (P < 0.05). The power empirically estimated from the simulation study would be applicable to the design of GWAS for quantitative traits with known genetic parameters by predicting the degree of false negative associations. PMID- 25451741 TI - Adaptive evolution at immune system genes and deep pregnancy implantation in primates. AB - A major evolutionary change in the lineage ancestral to humans, chimpanzee and gorilla (HCG) has been the embedding of the embryo into maternal tissue. Thus, the first layer of cells (trophoblast) to differentiate after fertilization must adapt to invade the uterus. Such event would likely leave signatures of positive selection at genes with roles in embryo implantation. Here, 163 pregnancy implantation genes are tested for evidence of adaptive diversification in the ancestral lineage to HCG. Two immune system genes, HLA-E and KIR2DL4 showed evidence of positive selection. Some of the positive selected sites involve amino acid substitution with predicted damaging effects on protein function, thus highlighting the possibility of antagonistic pleiotropic effects. Selection at a gene coding for a receptor expressed in uterine cells (KIR) that interacts with trophoblast human leukocyte antigen (HLA) genes suggests a main role for immunological adaptations in embryo deep invasion of the maternal endometrium. PMID- 25451742 TI - Transcriptomics expression analysis to unveil the molecular mechanisms underlying the cocoa polyphenol treatment in diet-induced obesity rats. AB - Cocoa polyphenol (CP), due to their biological actions, may be supplementary treatments for adipose tissue-fat gain. However, the molecular mechanism of CPs is still ambiguous. This study investigated the hypothesis that CP treatment modulates expressing of lipid metabolism genes in mesenteric white adipose tissue (MES-WAT). Sprague-Dawley (SD) rats were fed a low-fat (LF) or high-fat (HF) diet for 12 weeks. Thereafter, HFD rats (n = 10/group) were treated at a dose of 600 mg/kg bw/day CPs (HFD + CPs) for 4 weeks. DNA microarray analysis resulted in 753 genes of the 13,008 genes expressed. Bioinformatics tools showed CP treatment significantly decreased gene expression levels for lipogenic enzymes, while increased the mRNA levels responsible for lipolysis enzymes. CP administration differentially regulates gene expression involved in lipid metabolism in MES-WAT. These data unveil a new insight into the molecular mechanisms underlying the pharmacological effect of CPs on obesity biomarkers in obese rats. PMID- 25451743 TI - A GCC-box motif in the promoter of nudix hydrolase 7 (AtNUDT7) gene plays a role in ozone response of Arabidopsis ecotypes. AB - Arabidopsis nudix hydrolase 7 (AtNudt7) plays an important role in regulating redox homeostasis during stress/defense signaling and seed germination. The early responsiveness of AtNudt7 provides a useful marker especially during oxidative cell death in plants. Nuclear run-on assays demonstrate that AtNudt7 is transcriptionally regulated. AtNUDT7 promoter-GUS transgenic plants show rapid inducibility in response to ozone and pathogens. A 16-bp insertion containing a GCC-box motif was identified in the promoter of a Ws-2 ecotype and was absent in Col-0. The 16-bp sequence was identified in 5% of the Arabidopsis ecotypes used in the 1001 genome sequencing project. The kinetics of expression of Ethylene Response Factor 1 (ERF1), a GCC-box binding factor is in synchrony with expression of AtNudt7 in response to ozone stress. ERF1 protein binds to the GCC box motif in the AtNUDT7 promoter. In silico analysis of erf1 mutant and overexpressor lines supports a role for this protein in regulating AtNUDT7 expression. PMID- 25451744 TI - A 454 sequencing approach to dipteran mitochondrial genome research. AB - The availability of complete mitochondrial genome (mtgenome) data for Diptera, one of the largest metazoan orders, in public databases is limited. The advent of high throughput sequencing technology provides the potential to generate mtgenomes for many species affordably and quickly. However, these technologies need to be validated for dipterans as the members of this clade play important economic and research roles. Illumina and 454 sequencing platforms are widely used in genomic research involving non-model organisms. The Illumina platform has already been utilized for generating mitochondrial genomes without using conventional long range PCR for insects whereas the power of 454 sequencing for generating mitochondrial genome drafts without PCR has not yet been validated for insects. Thus, this study examines the utility of 454 sequencing approach for dipteran mtgenomic research. We generated complete or nearly complete mitochondrial genomes for Cochliomyia hominivorax, Haematobia irritans, Phormia regina and Sarcophaga crassipalpis using a 454 sequencing approach. Comparisons between newly obtained and existing assemblies for C. hominivorax and H. irritans revealed no major discrepancies and verified the utility of 454 sequencing for dipteran mitochondrial genomes. We also report the complete mitochondrial sequences for two forensically important flies, P. regina and S. crassipalpis, which could be used to provide useful information to legal personnel. Comparative analyses revealed that dipterans follow similar codon usage and nucleotide biases that could be due to mutational and selection pressures. This study illustrates the utility of 454 sequencing to obtain complete mitochondrial genomes for dipterans without the aid of conventional molecular techniques such as PCR and cloning and validates this method of mtgenome sequencing in arthropods. PMID- 25451745 TI - Fabrication and evaluation of celecoxib microparticle surface modified by hydrophilic cellulose and surfactant. AB - This study was undertaken to improve the solubility and dissolution of a poorly water-soluble drug, celecoxib, by surface modification with a hydrophilic polymer and a surfactant by using a spray-drying technique. Based on the preliminary solubility tests, hydroxypropylmethyl cellulose (HPMC) and D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) were selected as the polymer and the surfactant, respectively. A novel surface-modified celecoxib microparticle was successfully fabricated using a spray-drying process with water, HPMC, and TPGS, and without the use of an organic solvent. The physicochemical properties of the surface-modified celecoxib microparticle were characterized using scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), a particle size analyzer, and contact angle determination. The formulation with drug/HPMC/TPGS at the weight ratio of 1:0.5:1.5 was determined to be the most effective composition in the preparation of the surface-modified celecoxib microparticle, based on the results of wettability, solubility, and dissolution studies. We found that the surface modification of microparticles with HPMC and TPGS can be an effective formulation strategy for new dosage forms of poorly water-soluble active pharmaceutical ingredients (APIs) to provide higher solubility and dissolution. PMID- 25451746 TI - In vitro anticancer activity of fucoidan from Turbinaria conoides against A549 cell lines. AB - The present study was conducted to evaluate the anticancer activity of fucoidan isolated from brown seaweed Turbinaria conoides. Extracted fucoidan contained 53 +/- 0.69% of fucose and 38 +/- 0.42% of sulphate, respectively. Functional groups and structural characteristics of the fucoidan were analyzed by FT-IR and NMR. In vitro anticancer effect was studied on A549 cell line. Fucoidan inhibited the growth of cancer cells in a dose-dependent manner and potent anticancer activities were 24.9-73.5% in the concentrations of 31.25-500 MUg/ml. The CTC50 value against the cancer cell was found to be 45 MUg/ml and the CTC50 value of normal Vero cell line is 325 MUg/ml. This study suggests that the fucoidan from T. conoides could be significantly improved if the active component is further purified and tested for further investigation in various cancer cell lines. PMID- 25451747 TI - Separation, preliminary characterization, and moisture-preserving activity of polysaccharides from Ulva fasciata. AB - Sulfated polysaccharide (UFP(31)) extracted from the marine algae Ulva fasciata (UFP) was a heteropolysaccharide, and consisted of rhamnose, xylose, and glucose in a ratio of 1:0.46:0.27 with a (1 -> 4)-linked glycosyl backbone. The rheology of UFP(31) solution has been investigated by steady shear and small amplitude oscillatory experiments. The effects of concentration, temperature, and time were systematically investigated. Steady-shear rheological measurement in a range of shear rate (1-1000 s(-1)) exhibited that UFP(31) has a Newtonian behavior in diluted solutions (1.0%, 3.0%, and 5.0%, w/v), dilatant flow behavior at higher concentrations (7.0% and 9.0%, w/v). Specifically, UFP(31) solution (7%, w/v) exhibited antithixotropic behavior. In small amplitude oscillatory experiments, both the storage modulus (G') and the loss modulus (G") of UFP(31) solution (7%, w/v) increased with frequency swept but G' increased more quickly. As a consequence, G' tends to overcome G" at 2.7 Hz. The capability of moisture absorption and moisture-retention of the polysaccharide was also respectively examined gravimetrically in comparison with those of glycerol. It revealed that UFP(31) exhibited a higher ability both in the moisture-absorption and moisture retention test throughout the entire experiment. These results clearly establish the possibility that UFP(31) could be employed as a new material of nature moisturizer. PMID- 25451748 TI - Protective effects of Acanthopanax polysaccharides on cerebral ischemia reperfusion injury and its mechanisms. AB - A kind of Acanthopanax polysaccharides extracted from the root of Acanthioanax senticosus was named CASPs. The protective effect of CASPs on the cerebral ischemia-reperfusion injury was observed and the underlying mechanism was explored. Wistar male rats were randomly divided into six groups, namely, sham operated group, model group, nimodipine group (15 mg/kg/day) and CASPs groups (50, 100 and 200 mg/kg/day). The suture method was used to embolize the middle cerebral artery to establish a rat cerebral ischemia-reperfusion injury model. On day 15 before the surgery, the intragastric administration of agents started once daily. The results confirmed that the CASPs could improve the symptoms of rats with the cerebral ischemia-reperfusion injury, and reduce the brain infarct volume and brain water content. In addition, CASPs could elevate SOD and GSH-Px activities and IL-10 levels, and reduce MDA, IL-1beta and TNF-alpha levels in the brain tissue of rats with the cerebral ischemia-reperfusion injury. The results indicate that CASPs can play a certain protective role in the cerebral ischemia reperfusion injury, and the protective effect may be related to the improvement of CASPs on the antioxidant capacity of brain tissue and the inhibition of overproduction of inflammatory cytokines. PMID- 25451749 TI - Polysaccharides produced by Enterobacter cloacae induce apoptosis in cervical cancer cells. AB - The effects and possible mechanism of polysaccharides produced by Enterobacter cloacae (EPS) on cervical cancer cells (Hela and SiHa) were investigated in vitro in the current study. The results showed that supplementation of EPS inhibited the proliferation of HeLa and SiHa cells in a concentration- and time-dependent manner. In addition, the EPS also induced the apoptosis of the cervical cancer cells by changing the nuclear morphology and decreasing the mitochondrial membrane potential. Furthermore, the EPS-induced apoptosis was associated with the regulation of Bcl-2 family protein expression. In particular, the pro apoptotic protein Bak-1 was increased and anti-apoptotic protein Bcl-2 was decreased with the increasing concentration at certain range of EPS. These results indicated that EPS might induce the apoptosis of cervical cancer cells through an intrinsic apoptotic pathway, and EPS may act as potent antitumor agents. PMID- 25451750 TI - Binding of actin to thioglycolic acid modified superparamagnetic nanoparticles for antibody conjugation. AB - Thioglycolic acid modified superparamagnetic iron oxide nanoparticles (TG-APTS SPION) were synthesized by using (3-aminopropyl) triethoxysilane (APTS) and thioglycolic acid (TG). Actin was immobilized on the nanoparticle surfaces. Binding amount of the actin (Act) on TG-APTS-SPIONs was determined by using a calibration curve equation that was drawn using fluorescence spectra at 280 and 342 nm of excitation and emission wavelengths. Anti-Actin (anti-Act) was interacted with the actin immobilized TG-APTS-SPIONs as primary antibody. Horse radish peroxidase (HRP) was also interacted with antibody conjugated nanoparticles as secondary antibody. The binding capacity of primary and secondary antibodies was also estimated by fluorescence spectroscopy. Scanning electron microscopy (SEM), Infrared spectroscopy (FTIR) and energy dispersive X ray (EDX) analysis were also clarified binding of the protein and antibodies to the nanoparticles' surfaces. Western blot analysis was also done for actin conjunction with anti Act antibody to confirm binding of the antibody to the protein. PMID- 25451751 TI - Use of aiiA gene amplification for AHL-lactonase production from endophytic bacterium Enterobacter species. AB - AHL-lactonase has gained renewed interest due to biotechnological applications such as antiquorum sensing, antibiofilm strategies, biofouling, etc. In our study, the production of AHL-lactonase from endophytic bacteria Enterobacter aerogenes VT66 was optimized by response surface methodology (RSM) using central composite design (CCD) for four different cultural conditions. The relative activity of AHL-lactonase was correlated with amplification of aiiA homologous gene amplification with respect to cultural conditions. Statistical analysis by ANOVA of the quadratic regression model showed that the RSM model constructed is highly significant, as indicated by F-test with a low probability value (p(model) < 0.0001) and high regression coefficient (0.9997) as well as lower coefficient of variation (1.86%) indicate that suitability of variable parameters. The quadratic regression model of AHL-lactonase production in terms of relative activity was built and the optimal cultural conditions for maximum enzyme production were determined as 32.5 degrees C temperature, pH 7.0, 350 MUM of substrate concentration and 33 h of incubation time. The enhanced AHL-lactonase yielded 1.33 fold increases in relative activity and it positively correlated with the amplification of aiiA gene. PMID- 25451752 TI - Characterization and evaluation of smart starch from Kyllinga nemoralis. AB - Starch from Kyllinga nemoralis (KNSS) rhizomes was investigated for its morphological, chemical and functional properties in order to utilize its potential as a pharmaceutical adjuvant. Rhizomes of K. nemoralis yielded an appreciable amount of starch that is 19.77% (w/w). Amylose content was measured as of 28.66%. The shapes of starch granules were mostly round, disc like, flat and the size varied from 3.93 to 9.45 MUm. Further polysaccharide nature of KNSS was confirmed by FTIR spectra. The solubility and swelling power was found to be increased with the increase in the temperature. Micromeritic properties of the isolated starch showed unique feasibility of KNSS being used as a pharmaceutical excipient. The TGA data revealed that KNSS is thermally stable with less bound water. In vitro release study confirmed that KNSS in pH 6.8 slows down the release of the drug smartly compared to pH 1.2, due its ability to respond to the external pH-stimuli. Release profile proved that KNSS could find an application as a smart polymer for its stimuli-responsive and bio-related applications such as drug delivery. PMID- 25451754 TI - Application of D-optimal design to extract the pectin from lime bagasse using microwave green irradiation. AB - The main objective of the present study is to extract the pectin from lime bagasse under various extraction conditions such as microwave power, extraction time, temperature, pH and mass of the sample. RSM coupled with D-optimal experimental design was used to optimize and investigate the extraction conditions on the pectin yield. Second order polynomial equation was developed and its adequacy was analyzed by analysis of variance (ANOVA). The optimal extraction was found to be as follows; microwave power of 400 W, extraction time of 500 s, temperature of 30 degrees C, pH of 1 and mass of the sample of 6g. Under these optimal scheme, 7.8 g/100g of pectin was extracted. Molecular weight of the pectin polymer and the distribution of the pectin compounds were determined by gel filtration chromatography. PMID- 25451753 TI - Immobilization of proteases on chitosan for the development of films with anti biofilm properties. AB - Bacterial resistance due to biofilm formation-particularly Staphylococci biofilms is associated with multiple problems in medical settings where biofilms can colonize medical indwelling devices and cause nosocomial infections. It was against this backdrop that we explored the anti-biofilm activities of a set of proteases against biofilm formation by Staphylococcus aureus, Listeria monocytogenes and Pseudomonas aeruginosa. The selected screened enzymes were immobilized on chitosan to obtain films with anti-biofilm activities. Immobilization efficiency was about 94% for protease from Bacillus licheniformis and reached up to 96% for Neutrase. In vitro assays performed in brain heart infusion (BHI) broth using the Biofilm Ring Test highlighted that immobilized enzymes were efficient against biofilms of Staphylococci cultures, especially protease from B. licheniformis and Neutrase from Bacillus amyloliquefaciens. PMID- 25451755 TI - Structural characterization and bioactivities of sulfated polysaccharide from Monostroma oxyspermum. AB - Sulfated polysaccharide was isolated from Monostroma oxyspermum through hot water extraction, anion-exchange and gel permeation column chromatography. The sulfated polysaccharide contained 92% of carbohydrate, 0% of protein, 7.8% of uronic acid, 22% of ash and 33% of moisture respectively. The elemental composition was analyzed using CHNS/O analyzer. The molecular weight of sulfated polysaccharide determined through PAGE was found to be as 55 kDa. Monosaccharides analysis revealed that sulfated polysaccharide was composed of rhamnose, fructose, galactose, xylose, and glucose. The structural features of sulfated polysaccharide were analyzed by NMR spectroscopy. Further the sulfated polysaccharide showed total antioxidant and DPPH free radical scavenging activity were as 66.29% at 250 MUg/ml and 66.83% at 160 MUg/ml respectively. The sulfated polysaccharide also showed ABTS scavenging ability and reducing power were as 83.88% at 125 MUg/ml and 15.81% at 400 MUg/ml respectively. The anticoagulant activity was determined for human plasma with respect to Activated Partial Thromboplastin Time (APTT) and Prothrombin Time (PT) was 20.09 IU and 1.79 IU at 25 MUg/ml respectively. These results indicated that the sulfated polysaccharide from M. oxyspermum had potent antioxidant and anticoagulant activities. PMID- 25451756 TI - Modulatory effect of Decalepis hamiltonii on ethanol-induced toxicity in transgenic Drosophila model of Parkinson's disease. AB - Overexpression of human alpha-synuclein gene in Drosophila can reduce lifespan, and we have performed lifespan assay for A30P and A53Talpha-synuclein transgenic and control (elav-GAL4, UAS-A30P, UAS-A53T) flies. Our results showed reduced lifespan of transgenic flies compared to controls. We have also investigated behavioral responses, levels of reactive oxygen species (ROS) and lipid peroxidation (LPO) and activities of catalase (CAT) and superoxide dismutase (SOD) in a combined genetic-toxin model (Ethanol-A30P or A53Talpha-synuclein models) and controls. Our results showed that sedation time (ST50) of A30P or A53Talpha-synuclein PD model flies was significantly lower while recovery time (RC50) of them was remarkably higher compared to control flies. The levels of oxidative markers (ROS and LPO) were significantly higher and the activities of CAT and SOD were lower in transgenic flies that underwent ethanol exposure compared to control. Based on our earlier studies on antioxidant properties of isolated and characterized molecules from Decalepis hamiltonii (Dh) root extract, its protective effect in this combined toxicity model has been investigated. Surprisingly, Dh treatment increased ST50 and decreased RC50 values of transgenic flies. Moreover, we showed that Dh pre-treatment could decrease the levels of ROS and LPO and increase the activities of CAT and SOD in the ethanol-alpha-synuclein model. This is the first report on protective effects of natural antioxidants in A30P or A53Talpha-synuclein PD model flies against oxidative stress induced by ethanol. PMID- 25451757 TI - Protective effects of anthocyanins against amyloid beta-induced neurotoxicity in vivo and in vitro. AB - Alzheimer's disease (AD) is one of the most common neurodegenerative disorders in recent world, characterized by increased production of amyloid beta in the nervous system with an ultimate effect of apoptotic neurodegeneration. This study was aimed to investigate the neuroprotective effect of black soybean anthocyanins in a neurodegenerative model of amyloid beta 1-42 (Abeta1-42). Abeta1-42 was treated to HT22 cell lines or adult male rats via intra-cerebro-ventricular injection to induce neurotoxicity in these experimental models. Anthocyanins were treated 0.2 mg/kg in case of cell lines or 4 mg/kg intragastrically to adult rats to protect against Abeta-induced neurodegeneration. Assay for cell viability, mitochondrial membrane potential (Psim), intracellular free Ca(2+) and apoptotic cells (fluoro-jade B and TUNEL) were performed in vitro while western blot analyses were performed to the hippocampal proteins of adult rats. Our results showed that Abeta1-42 treatment reduced cell viability, disturbed the Psim and Ca(2+) homeostasis in and out of the cell, and increased neuronal apoptosis. Treatment with anthocyanins for 12 hr retained the cell viability, normalized Psim and Ca(2+) level, and decreased the neuronal cell death. In accordance, anthocyanins reversed Abeta-induced effect on protein expression of mitochondrial apoptotic pathway (Bax, cytochrome C, caspase-9 and caspase-3) and major Alzheimer's markers i.e. Abeta, APP, P-tau and BACE-1. Overall, our results showed that anthocyanins are potential candidates to treat neurodegenerative disorders like AD. PMID- 25451758 TI - Hormonal regulation of c-KIT receptor and its ligand: implications for human infertility? AB - The c-KIT, a tyrosine kinase receptor, and its ligand the stem cell factor (SCF) play an important role in the production of male and female gametes. The interaction of SCF with c-KIT is required for germ cell survival and growth, and abnormalities in the activity of the SCF/c-KIT system have been associated with human infertility. Recently, it was demonstrated that gonadotropic and sex steroid hormones, among others, regulate the expression of SCF and c-KIT in testicular and ovarian cells. Therefore, the hormonal (de)regulation of SCF/c-KIT system in the testis and ovary may be a cause underpinning infertility. In the present review, we will discuss the effects of hormones modulating the expression levels of SCF and c-KIT in the human gonads. In addition, the implications of hormonal regulation of SCF/c-KIT system for germ cell development and fertility will be highlighted. PMID- 25451759 TI - Feedback Received While Practicing Everyday Activities During Rehabilitation After Stroke: An Observational Study. AB - BACKGROUND AND PURPOSE: The provision of feedback is important for effective skill learning. The purpose of this study was to examine the nature of feedback provided during the practice of everyday activities (such as standing up, walking, and reaching and grasping objects) during stroke rehabilitation, both when the therapist was present and when the patient was practicing alone. METHOD: DESIGN: A cross-sectional observational study of the feedback received during rehabilitation by people who had had a stroke was conducted. Forty unique patient therapist dyads were observed during 30 minutes of actual practice of everyday activities with data collected through behavioural mapping. The following was recorded: the activity practiced, whether the therapist was present, whether feedback was provided verbally or by equipment, and the content of feedback. PARTICIPANTS: A sample of all therapists providing rehabilitation within one Australian health service and their patients who had had a stroke. MEASURES: Quantity, frequency, mode (verbal or equipment) and content (information feedback, motivational statements, unrelated or none) of feedback during the practice of everyday activities were determined. RESULTS: For 68% of the time that patients were practicing activities, they received >=1 occasion of feedback/minute. When the therapist was present, the frequency of motivational statements was more than four times greater, at 1.32 (SD 0.6) occasions/minute, than information feedback. For 25% of the time, the therapist was not present, and no feedback was provided. CONCLUSION: Given the importance of specific content for learning, therapists could replace some motivational statements with information feedback. When practicing alone, information feedback could be provided by commercially available biofeedback or customized equipment. PMID- 25451760 TI - Effect of drift, selection and recombination on the equilibrium frequency of deleterious mutations. AB - We study the stationary state of a population evolving under the action of random genetic drift, selection and recombination in which both deleterious and reverse beneficial mutations can occur. We find that the equilibrium fraction of deleterious mutations decreases as the population size is increased. We calculate exactly the steady state frequency in a nonrecombining population when population size is infinite and for a neutral finite population, and obtain bounds on the fraction of deleterious mutations. We also find that for small and very large populations, the number of deleterious mutations depends weakly on recombination, but for moderately large populations, recombination alleviates the effect of deleterious mutations. An analytical argument shows that recombination decreases disadvantageous mutations appreciably when beneficial mutations are rare as is the case in adapting microbial populations, whereas it has a moderate effect on codon bias where the mutation rates between the preferred and unpreferred codons are comparable. PMID- 25451761 TI - Folding of SAM-II riboswitch explored by replica-exchange molecular dynamics simulation. AB - Riboswitches are cis-acting RNA fragments that function via a conformational transition mechanism when a specific target molecule binds to its binding pocket, representing an inviting new class of biomolecular target for the development of antibiotics. To understand the folding mechanism of SAM-II riboswitch, occurring predominantly in proteobacteria, a 100ns replica-exchange molecular dynamics simulation in explicit solvent is performed. Our results show that this RNA pseudoknot has multiple folding pathways, and various intermediate structures. The resultant riboswitch conformational transition map is well consistent with the recent fluorescence measurement, which confirms the dynamical properties of this pseudoknot. Moreover, a novel transition pathway is predicted. The global folding dynamics is mainly coupled with the helix rather than the loop region. The potential folding pathways of the riboswitch presented here should lead to a deeper understanding of the folding mechanism of the riboswitch, as well as the conformational change of RNA pseudoknot. PMID- 25451762 TI - Biological complexity and adaptability of simple mammalian olfactory memory systems. AB - Chemosensory systems play vital roles in the lives of most mammals, including the detection and identification of predators, as well as sex and reproductive status and the identification of individual conspecifics. All of these capabilities require a process of recognition involving a combination of innate (kairomonal/pheromonal) and learned responses. Across very different phylogenies, the mechanisms for pheromonal and odour learning have much in common. They are frequently associated with plasticity of GABA-ergic feedback at the initial level of processing the chemosensory information, which enhances its pattern separation capability. Association of odourant features into an odour object primarily involves anterior piriform cortex for non-social odours. However, the medial amygdala appears to be involved in both the recognition of social odours and their association with chemosensory information sensed by the vomeronasal system. Unusually not only the sensory neurons themselves, but also the GABA-ergic interneurons in the olfactory bulb are continually being replaced, with implications for the induction and maintenance of learned chemosensory responses. PMID- 25451764 TI - Can sleep apnea cause Alzheimer's disease? AB - Both obstructive sleep apnea (OSA) and Alzheimer's disease (AD) are increasing health concerns. The objective of this study is to review systematically the effects of OSA on the development of AD. The search was conducted in PubMed and Cochrane CENTRAL, and followed by a manual search of references of published studies. Cross-sectional, cohorts, and randomized clinical trials were reviewed. Besides clinical studies, we also discuss neuroimaging data, experimental animal evidence, and molecular mechanisms. Although a causal relationship between OSA and AD is not yet established, OSA induces neurodegenerative changes as a result of two major contributing processes: sleep fragmentation and intermittent hypoxia. As such, inflammation and cellular stress are sufficient to impair cell cell interactions, synaptic function, and neural circuitry, leading to a decline of cognitive behavior. Sustained OSA could promote cognitive dysfunction, overlapping with that in AD and other neurodegenerative diseases. Early treatment by positive airway pressure and other current standards of care should have a positive impact to alleviate structural and functional deterioration. With better understanding of the cellular and neurophysiological mechanisms by which OSA contributes to AD, we may identify novel molecular targets for intervention. PMID- 25451765 TI - Person recognition and the brain: merging evidence from patients and healthy individuals. AB - Recognizing other persons is a key skill in social interaction, whether it is with our family at home or with our colleagues at work. Due to brain lesions such as stroke, or neurodegenerative disease, or due to psychiatric conditions, abilities in recognizing even personally familiar persons can be impaired. The underlying causes in the human brain have not yet been well understood. Here, we provide a comprehensive overview of studies reporting locations of brain damage in patients impaired in person-identity recognition, and relate the results to a quantitative meta-analysis based on functional imaging studies investigating person-identity recognition in healthy individuals. We identify modality-specific brain areas involved in recognition from different person characteristics, and potential multimodal hubs for person processing in the anterior temporal, frontal, and parietal lobes and posterior cingulate. Our combined review is built on cognitive and neuroscientific models of face- and voice-identity recognition and revises them within the multimodal context of person-identity recognition. These results provide a novel framework for future research in person-identity recognition both in the clinical as well as basic neurosciences. PMID- 25451763 TI - The nonspecific thalamus: A place in a wedding bed for making memories last? AB - We summarize anatomical, electrophysiological and behavioral evidence that the rostral intralaminar (ILN) and the reuniens and rhomboid (ReRh) nuclei that belong to the nonspecific thalamus, might be part of a hippocampo-cortico thalamic network underlying consolidation of enduring declarative(-like) memories at systems level. The first part of this review describes the anatomical and functional organization of these thalamic nuclei. The second part presents the theoretical models supporting the active systems-level consolidation, a process that relies upon sleep specific field-potential oscillations occurring during both slow-wave sleep (SWS) and rapid eye movement (REM) sleep. The last part presents data in the rat showing that the lesion of the rostral ILN or of the ReRh specifically hinders the formation of remote spatial memories without affecting task acquisition or retrieval of a recent memory. These results showing a critical role of the ILN and ReRh nuclei in the transformation of a recent memory into a remote one are discussed in the context of their control of cortical arousal (ARAS) and of thalamo-cortico-thalamic synchronization. PMID- 25451766 TI - [Triage: prioritization of injured after a major accident or mass casualty incident]. AB - The present work deals primarily with the triage of injured victims after a mass casualty incident by emergency physicians. Triage is central for successful execution at the scene of a major accident. It ensures that the chaos is left at the scene of the accident and does not reach the hospitals. The enormous psychological burden for triage physicians is reflected and the delegation of activities to lay persons is critically examined. The work reflects the long-term experience of the authors. PMID- 25451767 TI - [Early parenteral or enteral nutrition in intensive care patients. Results of the CALORIES Trial]. PMID- 25451768 TI - Structural analysis of in silico mutant experiments of human inner-kinetochore structure. AB - Large multi-molecular complexes like the kinetochore are lacking of suitable methods to determine their spatial structure. Here, we use and evaluate a novel modeling approach that combines rule-bases reaction network models with spatial molecular geometries. In particular, we introduce a method that allows to study in silico the influence of single interactions (e.g. bonds) on the spatial organization of large multi-molecular complexes and apply this method to an extended model of the human inner-kinetochore. Our computational analysis method encompasses determination of bond frequency, geometrical distances, statistical moments, and inter-dependencies between bonds using mutual information. For the analysis we have extend our previously reported human inner-kinetochore model by adding 13 new protein interactions and three protein geometry details. The model is validated by comparing the results of in silico with reported in vitro single protein deletion experiments. Our studies revealed that most simulations mimic the in vitro behavior of the kinetochore complex as expected. To identify the most important bonds in this model, we have created 39 mutants in silico by selectively disabling single protein interactions. In a total of 11,800 simulation runs we have compared the resulting structures to the wild-type. In particular, this allowed us to identify the interaction Cenp-W-H3 and Cenp-S-Cenp X as having the strongest influence on the inner-kinetochore's structure. We conclude that our approach can become a useful tool for the in silico dynamical study of large, multi-molecular complexes. PMID- 25451769 TI - Fluctuation driven fixation of cooperative behavior. AB - Cooperative behaviors are defined as the production of common goods benefitting all members of the community at the producer's cost. They could seem to be in contradiction with natural selection, as non-cooperators have an increased fitness compared to cooperators. Understanding the emergence of cooperation has necessitated the development of concepts and models (inclusive fitness, multilevel selection, etc.) attributing deterministic advantages to this behavior. In contrast to these models, we show here that cooperative behaviors can emerge by taking into account only the stochastic nature of evolutionary dynamics: when cooperative behaviors increase the population size, they also increase the genetic drift against non-cooperators. Using the Wright-Fisher models of population genetics, we compute exactly this increased genetic drift and its consequences on the fixation probability of both types of individuals. This computation leads to a simple criterion: cooperative behavior dominates when the relative increase in population size caused by cooperators is higher than the selection pressure against them. This is a purely stochastic effect with no deterministic interpretation. PMID- 25451770 TI - CytoNCA: a cytoscape plugin for centrality analysis and evaluation of protein interaction networks. AB - BACKGROUND AND SCOPE: Nowadays, centrality analysis has become a principal method for identifying essential proteins in biological networks. Here we present CytoNCA, a Cytoscape plugin integrating calculation, evaluation and visualization analysis for multiple centrality measures. IMPLEMENTATION AND PERFORMANCE: (i) CytoNCA supports eight different centrality measures and each can be applied to both weighted and unweighted biological networks. (ii) It allows users to upload biological information of both nodes and edges in the network, to integrate biological data with topological data to detect specific nodes. (iii) CytoNCA offers multiple potent visualization analysis modules, which generate various forms of output such as graph, table, and chart, and analyze associations among all measures. (iv) It can be utilized to quantitatively assess the calculation results, and evaluate the accuracy by statistical measures. (v) Besides current eight centrality measures, the biological characters from other sources could also be analyzed and assessed by CytoNCA. This makes CytoNCA an excellent tool for calculating centrality, evaluating and visualizing biological networks. AVAILABILITY: http://apps.cytoscape.org/apps/cytonca. PMID- 25451771 TI - Pyrolysis of activated sludge: energy analysis and its technical feasibility. AB - A comprehensive study on the potential of pyrolysis of activated sludge to generate substances that can be used to produce energy was evaluated for its technical and environmental viability. The products of the process viz., pyrolysis gas, pyrolysis oil and char can readily be used by the major energy consumers viz., electricity and transportation. Based on the results obtained it is estimated that a 1 ton capacity process for pyrolysis of activated sludge can serve the electrical needs of a maximum of 239, 95 and 47 Indian houses per day, considering lower middle class, middle class and upper middle class, respectively. In addition the process would also produce the daily methane (CNG) requirement of 128 public transport buses. The process was determined to be technically feasible at low and medium temperatures for both, pyrolysis gas and electrical energy. The gas generated could be utilized as fuel directly while the oil generated would require pretreatment before its potential application. The process is potentially sustainable when commercialized and can self-sustain in continuous mode of operation in biorefinery context. PMID- 25451772 TI - Factors governing dissolution process of lignocellulosic biomass in ionic liquid: current status, overview and challenges. AB - The utilisation of non-feed lignocellulosic biomass as a source of renewable bio energy and synthesis of fine chemical products is necessary for the sustainable development. The methods for the dissolution of lignocellulosic biomass in conventional solvents are complex and tedious due to the complex chemical ultra structure of biomass. In view of this, recent developments for the use of ionic liquid solvent (IL) has received great attention, as ILs can solubilise such complex biomass and thus provides industrial scale-up potential. In this review, we have discussed the state-of-art for the dissolution of lignocellulosic material in representative ILs. Furthermore, various process parameters and their influence for biomass dissolution were reviewed. In addition to this, overview of challenges and opportunities related to this interesting area is presented. PMID- 25451773 TI - Effects of mechanical treatment of digestate after anaerobic digestion on the degree of degradation. AB - The aim of this study was to increase the biogas production from different substrates by applying a mechanical treatment only to the non-degraded digestate after the fermentation process in order to feed it back into the process. To evaluate this approach, digestates were grounded with a ball mill for four different treatment time periods (0, 2, 5, 10 min) and then the effects on the particle size, volatile organic substances, methane yield and degradation kinetic were measured. A decrease of volatile fatty acids based on this treatment was not detected. The mechanical treatment caused in maximum to a triplication of the methane yield and to a quadruplicating of the daily methane production. PMID- 25451774 TI - Influence of different substrates on the performance of a two-stage high pressure anaerobic digestion system. AB - The two-stage autogenerative high-pressure digestion technique is a novel and promising approach for the production of gaseous fuels or upgraded biogas. This new technique is described in the patent DE 10 2011 015415 A1 and integrates biogas production, its upgrading and pressure boosting in one process. Anaerobic digestion under elevated pressure conditions leads to decreasing pH-values in the digestate due to the augmented formation of carboxylic acid. Model calculations carried out to evaluate the two-stage design showed that the pH-value in the pressurized anaerobic filter has a major influence on the methane content of the biogas produced. Within this study, the influence of the nitrogen content as one of the most important buffering substances on the performance of the system has been tested. The results show that higher NH4 contents lead to higher pH-values in the digester and as a consequence to higher methane contents. PMID- 25451775 TI - Fed-batch cultivation of Desmodesmus sp. in anaerobic digestion wastewater for improved nutrient removal and biodiesel production. AB - Desmodesmus sp. was used in anaerobically digested wastewater (ADW) for nutrients removal and the biodiesel production was measured and compared using fed-batch cultivation was investigated and compared with batch cultivation. The Desmodesmus sp. was able to remove 236.143, 268.238 and 6.427 mg/L of TN, NH4-N and PO4-P respectively after 40 d of fed-batch cultivation, while in batch cultivation the quantities of TN, NH4-N and PO4-P removed were 33.331, 37.227 and 1.323 mg/L. Biomass production of Desmodesmus sp. was also enhanced in fed-batch cultivation, when ADW loading was carried out every 2 days; the biomass concentration peaked at 1.039 g/L, which was three times higher than that obtained in batch cultivation (0.385 g/L). The highest lipid production (261.8 mg/L) was also recorded in fed-batch cultivation as compared to batch cultivation (83.3 mg/L). Fed-batch cultivation of Desmodesmus sp. could provide effective control of nutrients limitation and/or ammonia inhibition on microalgae cultivation. PMID- 25451776 TI - From microalgae oil to produce novel structured triacylglycerols enriched with unsaturated fatty acids. AB - Novel structured triacylglycerols (STAGs) enriched with unsaturated fatty acids (UFAs) and low palmitic acid (PA) content were firstly synthesized from Schizochytrium sp. oil and oleic acid (OA) via solvent-free acidolysis catalyzed by Lipozyme RM IM. The results indicated that, the PA content decreased from 24.49% to 6.95%, while the UFAs content increased from 70.20% to 90.9% at the sn 1,3 positions in the STAGs under the optimal condition (i.e., lipase load of 7%, molar ratio of microalgae oil TAGs to OA of 1:3, and temperature of 65 degrees C). The lipase Lipozyme RM IM could be reused 16 times without significant loss of activity. The improved plastic and storage ranges of STAGs are useful for infant formula formulations, by which a possible method is blending of this product and 1,3-dioleoyl-2-palmitoylglycerol enriched fats and minor lipids based on the corresponding chemical compositions of human milk fat. PMID- 25451777 TI - Enhancement of bio-oil production via pyrolysis of wood biomass by pretreatment with H2SO4. AB - In this work, a Japanese cedar wood sample was treated during the first step at ambient temperature and atmospheric pressure using several concentrations of sulfuric acid (H2SO4) in a stirred flask. During this pretreatment C-O bonds of cellulose, hemicellulose, and lignin were cleaved. The second step involved the pyrolysis of the pretreated wood sample at 550 degrees C in a quartz glass tube reactor. A maximum oil yield of 46.8 wt% with the minimum char yield of 10.1 wt% was obtained by the treatment with 3 M H2SO4, whereas untreated wood samples resulted in a 30.1 wt% yield of oil. The main components in the oils were levoglucosan and tar. These results suggest that moderate acid pretreatment produced shorter chain units of cellulose, hemicellulose, and lignin, thereby facilitating the conversion into oil by pyrolysis. The results of thermogravimetry-mass spectroscopy supported the presence of shorter chain units in the pretreated wood samples. PMID- 25451778 TI - Impact of carbon and nitrogen feeding strategy on high production of biomass and docosahexaenoic acid (DHA) by Schizochytrium sp. LU310. AB - A new isolated Schizochytrium sp. LU310 from the mangrove forest of Wenzhou, China, was found as a high producing microalga of docosahexaenoic acid (DHA). In this study, the significant improvements for DHA fermentation by the batch mode in the baffled flasks (i.e. higher oxygen supply) were achieved. By applied the nitrogen-feeding strategy in 1000 mL baffled flasks, the biomass, DHA concentration and DHA productivity were increased by 110.4%, 117.9% and 110.4%, respectively. Moreover, DHA concentration of 21.06 g/L was obtained by feeding 15 g/L of glucose intermittently, which was an increase of 41.25% over that of the batch mode. Finally, an innovative strategy was carried out by intermittent feeding carbon and simultaneously feeding nitrogen. The maximum DHA concentration and DHA productivity in the fed-batch cultivation reached to 24.74 g/L and 241.5 mg/L/h, respectively. PMID- 25451779 TI - Characterization of activated carbon prepared from chlorella-based algal residue. AB - The chlorella-based microalgal residue (AR) was tested as a novel precursor for preparing activated carbons. A combined carbonization-activation process with flowing N2 and CO2 gases was used to prepare the carbon materials at the activation temperatures of 800-1000 degrees C and the residence times of 0-30 min in this work. The elemental contents, pore properties and scanning electron microscopy (SEM) observations of the resulting activated carbons have been performed. The results showed that activation temperature may be the most important parameter for determining their pore properties. The maximal Brunauer Emmett-Teller (BET) surface area and total pore volume of the resulting activated carbon, which was produced at the activation temperature of 950 degrees C with the residence time of 30 min, were 840 m(2)/g and 0.46 cm(3)/g, respectively. More interestingly, the resulting activated carbons have significant nitrogen contents of 3.6-9.6 wt%, which make them lower carbon contents (i.e., 54.6-68.4 wt%) than those of commercial activated carbons. PMID- 25451780 TI - Hydrothermal liquefaction of biomass: developments from batch to continuous process. AB - This review describes the recent results in hydrothermal liquefaction (HTL) of biomass in continuous-flow processing systems. Although much has been published about batch reactor tests of biomass HTL, there is only limited information yet available on continuous-flow tests, which can provide a more reasonable basis for process design and scale-up for commercialization. High-moisture biomass feedstocks are the most likely to be used in HTL. These materials are described and results of their processing are discussed. Engineered systems for HTL are described; however, they are of limited size and do not yet approach a demonstration scale of operation. With the results available, process models have been developed, and mass and energy balances determined. From these models, process costs have been calculated and provide some optimism as to the commercial likelihood of the technology. PMID- 25451781 TI - Algaculture integration in conventional wastewater treatment plants: anaerobic digestion comparison of primary and secondary sludge with microalgae biomass. AB - This study evaluated the feasibility of using microalgae biomass as feedstock for anaerobic digestion together with other biomasses (primary and secondary sludge) normally generated in WWTP. Raw microalgae biomass anaerobic biodegradability (33%) was higher than that of secondary sludge (23%). Thermal pretreatment enhanced 62% and 16% methane yield for Chlorellavulgaris and secondary sludge, respectively. When both substrates were codigested, methane yields remained low. On the other hand, primary sludge supported the highest anaerobic biodegradability (97%) and when combined with thermally pretreated C. vulgaris, methane yields were higher (13-17%) than the ones expected theoretically. Despite the high protein content of those substrates and the high nitrogen mineralization, no ammonia inhibition was detected. Thereby, this study showed that algae biomass is a potential cosubstrate for biogas production together with municipal wastewater sludge. PMID- 25451783 TI - Selectivity of aggregation-determining interactions. AB - Protein aggregation is sequence specific, favoring self-assembly over cross seeding with non-homologous sequences. Still, as the majority of proteins in a proteome are aggregation prone, the high level of homogeneity of protein inclusions in vivo both during recombinant overexpression and in disease remains surprising. To investigate the selectivity of protein aggregation in a proteomic context, we here compared the selectivity of aggregation-determined interactions with antibody binding. To that purpose, we synthesized biotin-labeled peptides, corresponding to aggregation-determining sequences of the bacterial protein beta galactosidase and two human disease biomarkers: C-reactive protein and prostate specific antigen. We analyzed the selectivity of their interactions in Escherichia coli lysate, human serum and human seminal plasma, respectively, using a Western blot-like approach in which the aggregating peptides replace the conventional antibody. We observed specific peptide accumulation in the same bands detected by antibody staining. Combined spectroscopic and mutagenic studies confirmed accumulation resulted from binding of the peptide on the identical sequence of the immobilized target protein. Further, we analyzed the sequence redundancy of aggregating sequences and found that about 90% of them are unique within their proteome. As a result, the combined specificity and low sequence redundancy of aggregating sequences therefore contribute to the observed homogeneity of protein aggregation in vivo. This suggests that these intrinsic proteomic properties naturally compartmentalize aggregation events in sequence space. In the event of physiological stress, this might benefit the ability of cells to respond to proteostatic stress by allowing chaperones to focus on specific aggregation events rather than having to face systemic proteostatic failure. PMID- 25451782 TI - An ancient autoproteolytic domain found in GAIN, ZU5 and Nucleoporin98. AB - A large family of G protein-coupled receptors (GPCRs) involved in cell adhesion has a characteristic autoproteolysis motif of HLT/S known as the GPCR proteolysis site (GPS). GPS is also shared by polycystic kidney disease proteins and it precedes the first transmembrane segment in both families. Recent structural studies have elucidated the GPS to be part of a larger domain named GPCR autoproteolysis inducing (GAIN) domain. Here we demonstrate the remote homology relationships of GAIN domain to ZU5 domain and Nucleoporin98 (Nup98) C-terminal domain by structural and sequence analysis. Sequence homology searches were performed to extend ZU5-like domains to bacteria and archaea, as well as new eukaryotic families. We found that the consecutive ZU5-UPA-death domain domain organization is commonly used in human cytoplasmic proteins with ZU5 domains, including CARD8 (caspase recruitment domain-containing protein 8) and NLRP1 (NACHT, LRR and PYD domain-containing protein 1) from the FIIND (Function to Find) family. Another divergent family of extracellular ZU5-like domains was identified in cartilage intermediate layer proteins and FAM171 proteins. Current diverse families of GAIN domain subdomain B, ZU5 and Nup98 C-terminal domain likely evolved from an ancient autoproteolytic domain with an HFS motif. The autoproteolytic site was kept intact in Nup98, p53-induced protein with a death domain and UNC5C-like, deteriorated in many ZU5 domains and changed in GAIN and FIIND. Deletion of the strand after the cleavage site was observed in zonula occluden-1 and some Nup98 homologs. These findings link several autoproteolytic domains, extend our understanding of GAIN domain origination in adhesion GPCRs and provide insights into the evolution of an ancient autoproteolytic domain. PMID- 25451785 TI - The CamSol method of rational design of protein mutants with enhanced solubility. AB - Protein solubility is often an essential requirement in biotechnological and biomedical applications. Great advances in understanding the principles that determine this specific property of proteins have been made during the past decade, in particular concerning the physicochemical characteristics of their constituent amino acids. By exploiting these advances, we present the CamSol method for the rational design of protein variants with enhanced solubility. The method works by performing a rapid computational screening of tens of thousand of mutations to identify those with the greatest impact on the solubility of the target protein while maintaining its native state and biological activity. The application to a single-domain antibody that targets the Alzheimer's Abeta peptide demonstrates that the method predicts with great accuracy solubility changes upon mutation, thus offering a cost-effective strategy to help the production of soluble proteins for academic and industrial purposes. PMID- 25451784 TI - Lysophospholipid-containing membranes modulate the fibril formation of the repeat domain of a human functional amyloid, pmel17. AB - Pmel17 is an important protein for pigmentation in human skin and eyes. Proteolytic fragments from Pmel17 form fibrils upon which melanin is deposited in melanosomes. The repeat domain (RPT) derived from Pmel17 only forms fibrils under acidic melanosomal conditions. Here, we examined the effects of lipids on RPT aggregation to explore whether intramelanosomal vesicles can facilitate fibrillogenesis. Using transmission electron microscopy, circular dichroism, and fluorescence spectroscopy, we monitored fibril formation at the ultrastructural, secondary conformational, and local levels, respectively. Phospholipid vesicles and lysophospholipid (lysolipid) micelles were employed as membrane mimics. The surfactant-like lysolipids are particularly pertinent due to their high content in melanosomal membranes. Interestingly, RPT aggregation kinetics were influenced only by lysolipid-containing phospholipid vesicles. While both vesicles containing either anionic lysophosphatidylglycerol (LPG) or zwitterionic lysophosphatidylcholine (LPC) stimulate aggregation, LPG exerted a greater effect on reducing the apparent nucleation time. A detailed comparison showed distinct behaviors of LPG versus LPC monomers and micelles plausibly originating from their headgroup hydrogen bonding capabilities. Acceleration and retardation of aggregation were observed for LPG monomers and micelles, respectively. Because a specific interaction between LPG and RPT was identified by intrinsic W423 fluorescence and induced alpha-helical structure, it is inferred that binding of LPG near the C-terminal amyloid core initiates intermolecular association, whereas stabilization of alpha-helical conformation inhibits beta-sheet formation. Contrastingly, LPC promotes RPT aggregation at both submicellar and micellar concentrations via non-specific binding with undetectable secondary structural change. Our findings suggest that protein-lysolipid interactions within melanosomes may regulate amyloid formation in vivo. PMID- 25451787 TI - Effects of heat acclimation on time perception. AB - Cognitive performance is impaired during prolonged exercise in hot environment compared to temperate conditions. These effects are related to both peripheral markers of heats stress and alterations in CNS functioning. Repeated-exposure to heat stress results in physiological adaptations, and therefore improvement in exercise capacity and cognitive functioning are observed. The objective of the current study was to clarify the factors contributing to time perception under heat stress and examine the effect of heat acclimation. 20 young healthy male subjects completed three exercise tests on a treadmill: H1 (at 60% VO(2)peak until exhaustion at 42 degrees C), N (at 22 degrees C; duration equal to H1) and H2 (walk until exhaustion at 42 degrees C) following a 10-day heat acclimation program. Core temperature (T(C)) and heart rate (HR), ratings of perceived fatigue and exertion were obtained continuously during the exercise, and blood samples of hormones were taken before, during and after the exercise test for estimating the prolactin, growth hormone and cortisol response to acute exercise heat stress. Interval production task was performed before, during and after the exercise test. Lower rate of rise in core temperature, heart rate, hormone response and subjective ratings indicated that the subjects had successfully acclimated. Before heat acclimation, significant distortions in produced intervals occurred after 60 minutes of exercise relative to pre-trial coefficients, indicating speeded temporal processing. However, this effect was absent after in acclimated subjects. Blood prolactin concentration predicted temporal performance in both conditions. Heat acclimation slows down the increase in physiological measures, and improvement in temporal processing is also evident. The results are explained within the internal clock model in terms of the pacemaker-accumulator functioning. PMID- 25451786 TI - TMEM16 proteins: unknown structure and confusing functions. AB - The TMEM16 family of membrane proteins, also known as anoctamins, plays key roles in a variety of physiological functions that range from ion transport to phospholipid scrambling and to regulating other ion channels. The first two family members to be functionally characterized, TMEM16A (ANO1) and TMEM16B (ANO2), form Ca(2+)-activated Cl(-) channels and are important for transepithelial ion transport, olfaction, phototransduction, smooth muscle contraction, nociception, cell proliferation and control of neuronal excitability. The roles of other family members, such as TMEM16C (ANO3), TMEM16D (ANO4), TMEM16F (ANO6), TMEM16G (ANO7) and TMEM16J (ANO9), remain poorly understood and controversial. These homologues were reported to be phospholipid scramblases, ion channels, to have both functions or to be regulatory subunits of other channels. Mutations in TMEM16F cause Scott syndrome, a bleeding disorder caused by impaired Ca(2+)-dependent externalization of phosphatidylserine in activated platelets, suggesting that this homologue might be a scramblase. However, overexpression of TMEM16F has also been associated with a remarkable number of different ion channel types, raising the possibility that this protein might be involved in both ion and lipid transports. The recent identification of an ancestral TMEM16 homologue with intrinsic channel and scramblase activities supports this hypothesis. Thus, the TMEM16 family might have diverged in two or three different subclasses, channels, scramblases and dual-function channel/scramblases. The structural bases and functional implication of such a functional diversity within a single protein family remain to be elucidated and the links between TMEM16 functions and human physiology and pathologies need to be investigated. PMID- 25451789 TI - Meniscal root tears: a classification system based on tear morphology. AB - BACKGROUND: Meniscal root tears present in many forms and can have profound consequences on the health of knee articular cartilage. While the biomechanics, natural history, and treatment of root tears have been increasingly investigated, the spectrum of meniscal root tear patterns observed during arthroscopic examination has yet to be defined and categorized. PURPOSE: To establish a classification system for meniscal root tears by reporting the morphology of meniscal root tears from a consecutive series of arthroscopic surgeries. It was hypothesized that meniscal root tears could be grouped into types by distinct tear patterns and that recognition of tear pattern would affect treatment choice. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: All patients who underwent arthroscopic surgery from April 2010 to May 2014 by a single orthopaedic surgeon were included. After arthroscopic examination, data regarding the integrity of the meniscal roots were prospectively recorded in a data registry. Tear morphology and treatment received were subsequently extracted by 2 independent reviewers from operative notes and arthroscopic surgical photos. RESULTS: A total of 71 meniscal root tears in 67 patients were grouped into tear types with similar tear morphologies. Meniscal root tear patterns were categorized into partial stable root tears (type 1; n = 5); complete radial tears within 9 mm of the bony root attachment (type 2; n = 48), further subclassified into types 2A, 2B, and 2C, located 0 to <3 mm, 3 to <6 mm, and 6 to 9 mm from the root attachment, respectively; bucket-handle tears with a complete root detachment (type 3; n = 4); complex oblique tears with complete root detachments extending into the root attachment (type 4; n = 7); and bony avulsion fractures of the root attachments (type 5; n = 7). CONCLUSION: This study demonstrated that it was possible to establish a concise classification system to group patients with meniscal root tears by tear morphology. Treatments received varied across tear types. PMID- 25451788 TI - Fear load: The psychophysiological over-expression of fear as an intermediate phenotype associated with trauma reactions. AB - Psychophysiological measures of fear expression provide observable intermediate phenotypes of fear-related symptoms. Research Domain Criteria (RDoC) advocate using neurobiological intermediate phenotypes that provide dimensional correlates of psychopathology. Negative Valence Systems in the RDoC matrix include the construct of acute threat, which can be measured on a physiological level using potentiation of the acoustic startle reflex assessed via electromyography recordings of the orbicularis oculi muscle. Impairments in extinction of fear potentiated startle due to high levels of fear (termed fear load) during the early phases of extinction have been observed in posttraumatic stress disorder (PTSD). The goals of the current work were to examine dimensional associations between fear-related symptoms of PTSD and fear load variables to test their validity as an intermediate phenotype. We examined extinction of fear-potentiated startle in a cohort (n=269) of individuals with a broad range of civilian trauma exposure (range 0-13 traumatic events per person, mean=3.5). Based on previously reported findings, we hypothesized that fear load would be significantly associated with intrusion and fear memories of an index traumatic event. The results indicated that early extinction was correlated with intrusive thoughts (p=0.0007) and intense physiological reactions to trauma reminders (p=0.036). Degree of adult or childhood trauma exposure, and depression severity were not associated with fear load. After controlling for age, sex, race, income, level of prior trauma, and level of fear conditioning, fear load during extinction was still significantly predictive of intrusive thoughts (p=0.004). The significance of these findings is that they support dimensional associations with symptom severity rather than diagnostic category and, as such, fear load may emerge as a transdiagnostic intermediate phenotype expressed across fear-related disorders (e.g., specific phobia, social phobia). PMID- 25451790 TI - Anterior Cruciate Ligament and Knee Injury Prevention Programs for Soccer Players: A Systematic Review and Meta-analysis. AB - BACKGROUND: Soccer has one of the highest incidences of anterior cruciate ligament (ACL) injuries for both males and females. Several injury prevention programs have been developed to address this concern. However, an analysis of the pooled effect has yet to be elicited. PURPOSE: To conduct a systematic review and meta-analysis of ACL and knee injury prevention programs for soccer players, assess the heterogeneity among the studies, and evaluate the reported effectiveness of the prevention programs. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A systematic search of the literature was conducted on PubMed (Medline), Embase, CINAHL, and Central-Cochrane Database. Studies were limited to randomized controlled trials (RCTs) of injury prevention programs specific to the knee and/or ACL in soccer players. The Cochrane Q test and I (2) index were independently used to assess heterogeneity among the studies. The pooled risk difference, assessing knee and/or ACL injury rates between intervention and control groups, was calculated by random-effects models with use of the DerSimonian-Laird method. Publication bias was assessed with a funnel plot and Egger weighted regression technique. RESULTS: Nine studies met the inclusion criteria as RCTs. A total of 11,562 athletes were included, of whom 7889 were analyzed for ACL-specific injuries. Moderate heterogeneity was found among studies of knee injury prevention (P = .041); however, there was insignificant variation found among studies of ACL injury prevention programs (P = .222). For studies of knee injury prevention programs, the risk ratio was 0.74 (95% CI, 0.55 0.89), and a significant reduction in risk of knee injury was found in the prevention group (P = .039). For studies of ACL injury prevention programs, the risk ratio was 0.66 (95% CI, 0.33-1.32), and a nonsignificant reduction in risk of ACL injury was found in the prevention group (P = .238). No evidence of publication bias was found among studies of either knee or ACL injury prevention programs. CONCLUSION: This systematic review and meta-analysis of ACL and knee injury prevention program studies found a statistically significant reduction in injury risk for knee injuries but did not find a statistically significant reduction of ACL injuries. PMID- 25451791 TI - Cost-effectiveness analysis of the diagnosis of meniscus tears. AB - BACKGROUND: Diagnostic imaging represents the fastest growing segment of costs in the US health system. This study investigated the cost-effectiveness of alternative diagnostic approaches to meniscus tears of the knee, a highly prevalent disease that traditionally relies on MRI as part of the diagnostic strategy. PURPOSE: To identify the most efficient strategy for the diagnosis of meniscus tears. STUDY DESIGN: Economic and decision analysis; Level of evidence, 1. METHODS: A simple-decision model run as a cost-utility analysis was constructed to assess the value added by MRI in various combinations with patient history and physical examination (H&P). The model examined traumatic and degenerative tears in 2 distinct settings: primary care and orthopaedic sports medicine clinic. Strategies were compared using the incremental cost effectiveness ratio (ICER). RESULTS: In both practice settings, H&P alone was widely preferred for degenerative meniscus tears. Performing MRI to confirm a positive H&P was preferred for traumatic tears in both practice settings, with a willingness to pay of less than US$50,000 per quality-adjusted life-year. Performing an MRI for all patients was not preferred in any reasonable clinical scenario. The prevalence of a meniscus tear in a clinician's patient population was influential. For traumatic tears, MRI to confirm a positive H&P was preferred when prevalence was less than 46.7%, with H&P preferred above that. For degenerative tears, H&P was preferred until the prevalence reaches 74.2%, and then MRI to confirm a negative was the preferred strategy. In both settings, MRI to confirm positive physical examination led to more than a 10-fold lower rate of unnecessary surgeries than did any other strategy, while MRI to confirm negative physical examination led to a 2.08 and 2.26 higher rate than H&P alone in primary care and orthopaedic clinics, respectively. CONCLUSION: For all practitioners, H&P is the preferred strategy for the suspected degenerative meniscus tear. An MRI to confirm a positive H&P is preferred for traumatic tears for all practitioners. Consideration should be given to implementing alternative diagnostic strategies as well as enhancing provider education in physical examination skills to improve the reliability of H&P as a diagnostic test. CLINICAL RELEVANCE: Alternative diagnostic strategies that do not include the use of MRI may result in decreased health care costs without harm to the patient and could possibly reduce unnecessary procedures. PMID- 25451792 TI - Isoporous block copolymer membranes. AB - The developments in membranes based on tailored block copolymers are reported with an emphasis on isoporous membranes. These membranes can be prepared in different geometries, namely flat sheets and hollow fibers. They display narrow pore size distributions due to their formation by self-assembly. The preparation of these membranes and possibilities to further functionalize such membranes will be discussed. Different ways to control the pore size will be addressed, and the potential of block copolymer blends to fabricate membranes with tailored pore sizes will be shown. PMID- 25451793 TI - Studies on cytotoxic pregnane sapogenins from Cynanchum wilfordii. AB - To investigate their cytotoxicity, seventeen C21-steroidal pregnane sapogenins 1 17 were isolated from the hydrolytic extracts of the roots of Cynanchum wilfordii. Among them, sapogenins 1-7 are new compounds, whose structures were determined by extensive analysis of spectroscopic data and X-ray crystallographic analysis. Especially, sapogenins with salicyl or vanilloyl group, and a new aberrant pregnane skeleton with ether linkage between C-12 and C-20 were found for the first time. Compound 1 revealed significant cytotoxicities on HL-60 (IC50 6.72MUM) and MCF-7 (IC50 2.89MUM), and compounds 14 and 15 also revealed strong inhibitory activities against K-562 (IC50 6.72MUM) or MCF-7 (IC50 2.49MUM), respectively. PMID- 25451794 TI - Stimulation effect of wide type CFTR chloride channel by the naturally occurring flavonoid tangeretin. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride channel expressed in the apical membrane of serous epithelial cells. Both deficiency and overactivation of CFTR may cause fluid and salt secretion related diseases. In the present study, we identified tangeretin from Pericarpium Citri Reticulatae Viride as a CFTR activator using high-throughput screening based on FRT cell-based fluorescence assay. The activation effect of tangeretin on CFTR chloride channel and the possible underlying mechanisms were investigated. Fluorescence quenching tests showed that tangeretin dose- and time dependently activated CFTR chloride channel, the activity had rapid and reversible characteristics and the activation effect could be completely reversed by the CFTR specific blocker CFTRinh-172. Primary mechanism studies indicated that the activation effect of tangeretin on CFTR chloride channel was FSK dependent as well as had additional effect with FSK and IBMX suggesting that tangeretin activates CFTR by direct interacting with the protein. Ex-vivo tests revealed that tangeretin could accelerate the speed of the submucosal gland fluid secretion. Short-circuit current measurement demonstrated that tangeretin activated rat colonic mucosa chloride current. Thus, CFTR Cl(-) channel is a molecular target of natural compound tangeretin. Tangeretin may have potential use for the treatment of CFTR-related diseases like cystic fibrosis, bronchiectasis and habitual constipation. PMID- 25451795 TI - Neolignan inhibitors of antigen-induced degranulation in RBL-2H3 cells from the needles of Pinus thunbergii. AB - The ethanolic extract of the needles of Pinus thunbergii was found to suppress antigen mediated degranulation of rat basophilic leukemia (RBL-2H3) cells. A new neolignan glycoside, named pinusthunbergiside A (1), as well as six known neolignan glycosides (2-7) were isolated from the ethanolic extract using bioassay-guided fractionation. Their structures were elucidated by a combination of 1D and 2D NMR, HRESI-MS, and circular dichroism (CD) data. Compounds 2-7 were found for the first time in this plant. The inhibitory effects of isolated constituents on the release of beta-hexosaminidase from RBL-2H3 cells were examined, and compounds 2, 3, 5, and 6 were found to show the inhibitory activity with IC50 values ranging between 52.3 and 75.3 MUM. PMID- 25451796 TI - Bioactive metabolites of Schisanlactone E transformed by Cunninghamella blakesleana AS 3.970. AB - Schisanlactone E (SE) is a major triterpene obtained from the plants of genus Kadsura. The aim of this research was to investigate the transformed metabolites of SE by fungi and evaluate the bioactivities of these products. After screening 10 strains of filamentous fungi, Cunninghamella blakesleana AS 3.970 was chosen as a potent organism to be used for the biotransformation of SE. 13 metabolites were obtained and determined to be new compounds through the use of spectroscopic data, including UV, 1D-, 2D-NMR, and HR-ESIMS. Furthermore, in an in vitro bioassay, metabolites 7 and 9 showed moderate inhibitory effects on the nitric oxide production in LPS-induced macrophages with IC50 values of 16.73, 5.91 MUM, respectively; 9 could inhibit the proliferation of acetaldehyde-induced HSC-T6 cells, with the IC50 value of 21.4 MUM. Preliminary findings on the structure activity relationships for these metabolites were also discussed. PMID- 25451798 TI - Di-O-demethylcurcumin protects SK-N-SH cells against mitochondrial and endoplasmic reticulum-mediated apoptotic cell death induced by Abeta25-35. AB - Alzheimer's disease (AD) is a neurodegenerative and progressive disorder. The hallmark of pathological AD is amyloid plaque which is the accumulation of amyloid beta (Abeta) in extracellular neuronal cells and neurofibrillary tangles (NFT) in neuronal cells, which lead to neurotoxicity via reactive oxygen species (ROS) generation related apoptosis. Loss of synapses and synaptic damage are the best correlates of cognitive decline in AD. Neuronal cell death is the main cause of brain dysfunction and cognitive impairment. Abeta activates neuronal death via endoplasmic reticulum (ER) stress and mitochondria apoptosis pathway. This study investigated the underlying mechanisms and effects of di-O-demethylcurcumin in preventing Abeta-induced apoptosis. Pretreatment with di-O-demethylcurcumin for 2 h, which was followed by Abeta25-35 (10 uM) in human neuroblastoma SK-N-SH cells improved cell viability by using MTS assay and decreased neuronal cell apoptosis. Pretreatment with di-O-demethylcurcumin attenuated the number of nuclear condensations and number of apoptotic cells in Abeta25-35-induced group in a concentration-dependent manner by using transmission electron microscope (TEM) and flow cytometry, respectively. Di-O-demethylcurcumin also increased the ratio of Bcl-XL/Bax protein, and reduced intracellular ROS level, cytochrome c protein expression, cleaved caspase-9 protein expression, and cleaved caspase-3 protein expression. Additionally, di-O-demethylcurcumin treatment also reduced the expression of ER stress protein markers, including protein kinase RNA like endoplasmic reticulum kinase (PERK) phosphorylation, eukaryotic translation initiation factor 2 alpha (eIF2alpha) phosphorylation, inositol-requiring enzyme 1 (IRE1) phosphorylation, X-box-binding protein-1 (XBP-1), activating transcription factor (ATF6), C/EBP homologous protein (CHOP), and cleaved caspase 12 protein. CHOP and cleaved caspase-12 protein are the key mediators of apoptosis. Our data suggest that di-O-demethylcurcumin is a candidate protectant against neuronal death through its suppression of the apoptosis mediated by mitochondrial death and ER stress pathway. PMID- 25451797 TI - Astroglial NMDA receptors inhibit expression of Kir4.1 channels in glutamate overexposed astrocytes in vitro and in the brain of rats with acute liver failure. AB - Astroglial inward rectifying Kir4.1 potassium channels are fundamental for the maintenance of ion and water homeostasis in the central nervous system (CNS). Down-regulation of Kir4.1 expression is observed in CNS disorders associated with excessive extracellular glutamate (Glu) accumulation, including hepatic encephalopathy related to acute liver failure (ALF). Here we demonstrate that prolonged (3 days) treatment of cultured rat cortical astrocytes with 2 mM Glu or 100 uM NMDA decreases the expression of Kir4.1 mRNA and protein. Inhibition by Glu of Kir4.1 mRNA expression was reversed by NMDA receptor antagonists MK-801 and AP-5 (each at 50 uM), and by a non-transportable inhibitor of Glu uptake TBOA (100 uM). MK-801 reversed the inhibitory effect of Glu on Kir4.1 protein expression. In contrast, transcription of Kir4.1 channels was not affected by: (i) a transportable Glu uptake inhibitor PDC (100 uM); (ii) by group I mGluR antagonist MTEP (100 uM); (iii) by antagonists of oxidative-nitrosative stress (ONS) in astrocytes, including the neuroprotective amino acid taurine (Tau; 10 mM), the NADPH oxidase inhibitor apocyanine (APO; 300 uM), the nitric oxide synthase inhibitor, L-NNA (100 uM), and a membrane permeable glutathione precursor, glutathione-diethyl ester (GEE; 3 mM). Down-regulation of Kir4.1 transcription in rats with ALF was attenuated by intraperitoneal administration of a competitive NMDA receptor antagonist memantine, but not by histidine, which reverses ONS associated with ALF. Collectively, the results indicate that over activation of astroglial NMDA receptors, aided by as yet undefined effects of Glu entry to astrocytes, is a primary cause of the reduction of Kir4.1 expression in CNS disorders associated with increased exposure to Glu. PMID- 25451799 TI - ALS-related misfolded protein management in motor neurons and muscle cells. AB - Amyotrophic Lateral Sclerosis (ALS) is the most common form of adult-onset motor neuron disease. It is now considered a multi-factorial and multi-systemic disorder in which alterations of the crosstalk between neuronal and non-neuronal cell types might influence the course of the disease. In this review, we will provide evidence that dysfunctions of affected muscle cells are not only a marginal consequence of denervation associated to motor neurons loss, but a direct consequence of cell muscle toxicity of mutant SOD1. In muscle, the misfolded state of mutant SOD1 protein, unlike in motor neurons, does not appear to have direct effects on protein aggregation and mitochondrial functionality. Muscle cells are, in fact, more capable than motor neurons to handle misfolded proteins, suggesting that mutant SOD1 toxicity in muscle is not mediated by classical mechanisms of intracellular misfolded proteins accumulation. Several recent works indicate that a higher activation of molecular chaperones and degradative systems is present in muscle cells, which for this reason are possibly able to better manage misfolded mutant SOD1. However, several alterations in gene expression and regenerative potential of skeletal muscles have also been reported as a consequence of the expression of mutant SOD1 in muscle. Whether these changes in muscle cells are causative of ALS or a consequence of motor neuron alterations is not yet clear, but their elucidation is very important, since the understanding of the mechanisms involved in mutant SOD1 toxicity in muscle may facilitate the design of treatments directed toward this specific tissue to treat ALS or at least to delay disease progression. PMID- 25451800 TI - Phylogenetic relationships of Mesoamerican spider monkeys (Ateles geoffroyi): Molecular evidence suggests the need for a revised taxonomy. AB - Mesoamerican spider monkeys (Ateles geoffroyi sensu lato) are widely distributed from Mexico to northern Colombia. This group of primates includes many allopatric forms with morphologically distinct pelage color and patterning, but its taxonomy and phylogenetic history are poorly understood. We explored the genetic relationships among the different forms of Mesoamerican spider monkeys using mtDNA sequence data, and we offer a new hypothesis for the evolutionary history of the group. We collected up to ~800 bp of DNA sequence data from hypervariable region 1 (HV1) of the control region, or D-loop, of the mitochondrion for multiple putative subspecies of Ateles geoffroyi sensu lato. Both maximum likelihood and Bayesian reconstructions, using Ateles paniscus as an outgroup, showed that (1) A. fusciceps and A. geoffroyi form two different monophyletic groups and (2) currently recognized subspecies of A. geoffroyi are not monophyletic. Within A. geoffroyi, our phylogenetic analysis revealed little concordance between any of the classifications proposed for this taxon and their phylogenetic relationships, therefore a new classification is needed for this group. Several possible clades with recent divergence times (1.7-0.8 Ma) were identified within Ateles geoffroyi sensu lato. Some previously recognized taxa were not separated by our data (e.g., A. g. vellerosus and A. g. yucatanensis), while one distinct clade had never been described as a different evolutionary unit based on pelage or geography (Ateles geoffroyi ssp. indet. from El Salvador). Based on well-supported phylogenetic relationships, our results challenge previous taxonomic arrangements for Mesoamerican spider monkeys. We suggest a revised arrangement based on our data and call for a thorough taxonomic revision of this group. PMID- 25451801 TI - Revisiting the phylogenetic relationships, biogeography, and taxonomy of spider monkeys (genus Ateles) in light of new molecular data. AB - Spider monkeys (Ateles) are one of the most endangered groups of primates in the Neotropics. The genus is widely distributed from Mexico to the north of Bolivia and includes many morphologically distinct forms in terms of pelage color and patterning. The taxonomy, phylogenetic relationships, and biogeographic history of the genus have been subject to much debate, making scientific communication difficult and creating challenges for conservation actions. We extracted DNA from samples of all currently recognized species of spider monkeys collected from across the geographic range of the genus, sequenced ~3.5 kilobases of coding sequence from the mitochondrial genome, and used this large dataset to (a) infer the phylogenetic relationships among the different forms of spider monkeys, (b) evaluate whether currently recognized species of spider monkeys form reciprocally monophyletic groups that are concordant with contemporary classifications, and (c) estimate divergence dates among the different lineages of Ateles. We found that all proposed species of spider monkeys for which we have samples from multiple localities indeed appear to form monophyletic groups. However, in contrast to previous studies, several of our analyses robustly inferred Ateles marginatus from northeast Brazil as the sister taxon to all other spider monkeys. A Bayesian dating analysis suggests that the most recent common ancestor of extant Ateles dates to ~6.7 Ma, in the late Miocene, and most species-level splits within the genus took place in the late Pliocene, suggesting that the modern diversity in spider monkeys cannot be explained principally by isolation and divergence of populations in forest refugia during the Pleistocene. Based on our new phylogenetic inference and dating analysis, we propose a revised biogeographic scenario for the evolution of this genus. PMID- 25451802 TI - Morphology and mitochondrial phylogenetics reveal that the Amazon River separates two eastern squirrel monkey species: Saimiri sciureus and S. collinsi. AB - Saimiri has a complicated taxonomic history, and there is continuing disagreement about the number of valid taxa. Despite these controversies, one point of consensus among morphologists has been that the eastern Amazonian populations of squirrel monkeys form a single terminal taxon, Saimiri sciureus sciureus (Linnaeus, 1758). This group is distributed to both the north and south of the middle to lower Amazon River and in the Marajo Archipelago. However, a recent molecular study by Lavergne and colleagues suggested that the Saimiri sciureus complex (comprised of S. s. sciureus sensu lato, S. s. albigena, S. s. macrodon, and S. s. cassiquiarensis) was paraphyletic. The discordance between morphological and molecular studies prompted us to conduct a new multidisciplinary analysis, employing a combination of morphological, morphometric, and molecular markers. Our results suggest the currently recognized taxon S. s. sciureus contains two distinct species, recognized by the Phylogenetic Species Concept: Saimiri sciureus (Linnaeus, 1758) and Saimiri collinsi Osgood, 1916. East Amazonian squirrel monkeys north of the Amazon have a gray crown (S. sciureus), and south of the Amazon, the crown is yellow (S. collinsi). Morphometric measurements also clearly distinguish between the two species, with the most important contributing factors including width across upper canines for both sexes. For males, the mean zygomatic breadth was significantly wider in S. sciureus compared to S. collinsi, and for females, the width across the upper molars was wider in S. sciureus compared to S. collinsi. Mitochondrial phylogenetic analyses support this separation of the eastern Amazonian squirrel monkeys into two distinct taxa, recovering one clade (S. sciureus) distributed to the north of the Amazon River, from the Negro River and Branco River to the Guiana coast and the Brazilian state of Amapa, and another clade (S. collinsi) south of the Amazon River, from the region of the Tapajos River to the state of Maranhao, as well as within the Marajo Archipelago. The revalidation of the species S. collinsi was corroborated by all of the methods in the study, as the clades recovered in our molecular study are congruent with the pattern of morphological variation. We confirm both the paraphyly of the Saimiri sciureus complex and the paraphyly of the subspecies S. s. sciureus as defined in the current literature. PMID- 25451803 TI - Special issue: Comparative biogeography of Neotropical primates. AB - New research presented in this special issue of Molecular Phylogenetics and Evolution on the "Phylogeny and Biogeography of Neotropical Primates" greatly improves our understanding of the evolutionary history of the New World monkeys and provides insights into the multiple platyrrhine radiations, diversifications, extinctions, and recolonizations that have taken place over time and over space in the Neotropics. Here, we synthesize genetic and biogeographic research from the past several years to construct an overarching hypothesis for platyrrhine evolution. We also highlight continuing controversies in Neotropical primate biogeography, such as whether the location of origin of platyrrhines was Africa or Asia; whether Patagonian fossil primates are stem or crown platyrrhines; and whether cis- and trans-Andean Neotropical primates were subject to vicariance through Andes mountain building, or instead diversified through isolation in mountain valleys after skirting around the Andes on the northwestern coast of South America. We also consider the role of the Amazon River and its major tributaries in shaping platyrrhine biodiversity, and how and when primates from the Amazon reached the Atlantic Forest. A key focus is on primate colonizations and extirpations in Central America, the Andes, and the seasonally dry tropical forests and savannas (such as the Llanos, Caatinga, and Cerrado habitats), all ecosystems that have been understudied up until now for primates. We suggest that most primates currently inhabiting drier open habitats are relatively recent arrivals, having expanded from rainforest habitats in the Pleistocene. We point to the Pitheciidae as the taxonomic group most in need of further phylogenetic and biogeographic research. Additionally, genomic studies on the Platyrrhini are deeply needed and are expected to bring new surprises and insights to the field of Neotropical primate biogeography. PMID- 25451804 TI - Molecular phylogenetics of tribe Eudemeae (Brassicaceae) and implications for its morphology and distribution. AB - Tribe Eudemeae comprises a morphologically heterogeneous group of genera distributed along the Andes of South America from Colombia southward into southern Chile and Argentina. The tribe currently includes seven genera: Aschersoniodoxa, Brayopsis, Dactylocardamum, Delpinophytum, Eudema, Onuris, and Xerodraba, and exhibits a wide morphological diversification in growth habit, inflorescences, and fruits. However, little is known about the phylogenetic relationships and evolution of the tribe. We present here a molecular phylogeny of representative sampling of all genera, utilizing sequence data from the nuclear ribosomal ITS region and chloroplast regions trnL-F, trnH-psbA, and rps16. Additionally, climatic niches of the tribe and its main lineages, along with the evolution of diagnostic morphological characters, were studied. All analyses confirmed the monophyly of Eudemeae, with the exception of Delpinophytum that was included with genera of the lineage I of Brassicaceae. Eudemeae is divided into two main lineages differentiated by their geographical distribution and climatic niche: the primarily north-central Andean lineage included Aschersoniodoxa, Brayopsis, Dactylocardamum, and Eudema, and the Patagonian and southern Andean lineage included Onuris and Xerodraba. Finally, ancestral-state reconstructions in the tribe generally reveal multiple and independent gains or losses of diagnostic morphological characters, such as growth form, inflorescence reduction, and fruit type. Relevant taxonomic implications stemming from the results are also discussed. PMID- 25451805 TI - Scorched mussels (BIVALVIA: MYTILIDAE: BRACHIDONTINAE) from the temperate coasts of South America: phylogenetic relationships, trans-Pacific connections and the footprints of Quaternary glaciations. AB - This study addresses aspects of the phylogeny and phylogeography of scorched mussels (BIVALVIA: MYTILIDAE: BRACHIDONTINAE) from southern South America (Argentina and Chile), as well as their ecophylogenetic implications. Relationships were inferred from sequences of two nuclear (28S and 18S) and one mitochondrial (COI) genes, using Bayesian and maximum likelihood analyses. Our results indicate that the monophyletic BRACHIDONTINAE include three well supported clades: [i] Brachidontes Swainson (=Hormomya Morch), [ii] Ischadium Jukes-Browne+Geukensia van de Poel, and [iii] Austromytilus Laseron+Mytilisepta Habe (usually considered a member of the SEPTIFERINAE)+Perumytilus Olsson. Species of clade [iii] are distributed along the temperate coasts of the Pacific Ocean. Available evidence supports divergence between Austromytilus (Australia) and Perumytilus (South American) following the breakup of Australian, Antarctic and South American shelves. Four brachidontins occur in southern South America: Brachidontes rodriguezii (d'Orbigny), B. granulatus (Hanley), and two genetically distinct clades of Perumytilus. The latter are confined to the Chile-Peru (North Clade) and Magellanic (South Clade) Biogeographic Provinces, respectively warm- and cold-temperate. The South Clade is the only brachidontin restricted to cold temperate waters. Biogeographic considerations and the fossil record prompted the hypothesis that the South Clade originated from the North Clade by incipient peripatric differentiation, followed by isolation during the Quaternary glaciations, genetic differentiation in the non-glaciated coasts of eastern Patagonia, back-expansion over southern Chile following post-LGM de-glaciation, and development of a secondary contact zone between the two clades in south central Chile. Evidence of upper Pleistocene expansion of the South Clade parallels similar results on other organisms that have colonized coastal ecosystems from eastern Patagonia since the LGM, apparently occupying free ecological space. We emphasize that the assembly of communities cannot be explained solely in terms of environmental drivers, as history also matters. PMID- 25451806 TI - Phylogenetic relationships of Amazonian anole lizards (Dactyloa): taxonomic implications, new insights about phenotypic evolution and the timing of diversification. AB - The ecology and evolution of Caribbean anoles are well described, yet little is known about mainland anole species. Lack of phylogenetic information limits our knowledge about species boundaries, morphological evolution, and the biogeography of anoles in South America. To help fill this gap, we provide an updated molecular phylogeny of the Dactyloa (Dactyloidae), with emphasis on the punctata species group. By sampling understudied Amazonian taxa, we (i) assess the phylogenetic placement of the 'odd anole', D. dissimilis; (ii) infer the relationships of the proboscis-bearing D. phyllorhina, testing the hypothesis of independent nasal appendage evolution within the anole radiation; and (iii) examine genetic and dewlap color variation in D. punctata and D. philopunctata. Combining multiple nuclear loci with a review of the fossil record, we also (iv) estimate divergence times within the pleurodont iguanian clade of lizards, including Amazonian representatives of Dactyloa and Norops (Dactyloidae) and of Polychrus (Polychrotidae). We recover the five Dactyloa clades previously referred to as the aequatorialis, heteroderma, latifrons, punctata and roquet species groups, as well as a sixth clade composed of D. dissimilis and the non Amazonian D. neblinina and D. calimae. We find D. phyllorhina to be nested within the punctata group, suggesting independent evolution of the anole proboscis. We consistently recover D. philopunctata nested within D. punctata, and report limited genetic divergence between distinct dewlap phenotypes. The most recent common ancestor of Dactyloa, Anolis and Norops dates back to the Eocene. Most Amazonian taxa within both Dactyloa and Norops diverged in the Miocene, but some diversification events were as old as the late Eocene and late Oligocene. Amazonian Polychrus diverged in the Pliocene. Our findings have broad implications for anole biogeography, disputing recent suggestions that modern dactyloid genera were present in the Caribbean region during the Cretaceous. PMID- 25451807 TI - Discovery of unusual anatomical and continuous characters in the evolutionary history of Conostegia (Miconieae: Melastomataceae). AB - Conostegia has been traditionally defined to consist of 42 species in the tribe Miconieae. Recent phylogenetic studies have cast doubt on the monophyly of the genus and highlighted the need for a phylogenetic study focused on Conostegia. The purpose of this study was to test the monophyly of Conostegia and address relationships in the genus. We addressed the evolutionary history of Conostegia using DNA sequences from six loci. Difficulty in finding discrete characters that support clades prompted an anatomical survey of leaves and flowers as well as the exploratory use of some continuous characters. We coded as many species as possible for fifteen characters. Lastly, field work was conducted to document floral traits at anthesis due to the poor quality of preservation of flowers on herbarium specimens. Conostegia was found to be paraphyletic and composed of three main clades. The historically important characters of a calyptrate calyx and pleiostemony were found to have evolved more than once inside the Conostegia clade. Several other characters were found to support the clades we identified. The most unusual characters were mucilage inside the ovary which is here reported in the Melastomataceae for the first time, a stele inside the style which is mostly restricted to one clade of Conostegia and known only in this clade of the Melastomataceae, and herkogamy which has been lost in two clades within Conostegia. A combination of molecular phylogenetic analyses and broad morphological surveys allowed the better understanding of the evolutionary history in a clade of mostly cloud forest Neotropical trees. The need to include anatomical studies and tackle continuous characters is here demonstrated. PMID- 25451808 TI - Indications and results of direct cerebral revascularization in the modern era. AB - BACKGROUND: There has been a progressive decrease in the indications for cerebral revascularization during the past 30 years, particularly with the advance of endovascular techniques. Our objective was to define indications for and evaluate outcomes of patients treated with bypass surgery in the modern endovascular era. METHODS: We retrospectively reviewed the charts of all patients who underwent direct cerebral revascularization procedures between January 2006 and March 2013. RESULTS: In total, 121 patients underwent 131 direct microsurgical revascularization procedures. The indications for bypass surgery were moyamoya angiopathy (40 patients, 47 bypasses), complex aneurysms (54 patients, 56 bypasses), and occlusive vascular disease (27 patients, 28 bypasses). Revascularization resulted in improvement of symptoms in 77.5% of patients with moyamoya angiopathy (mean clinical follow-up 18.8 months) and 55.5% of patients with occlusive vascular disease (mean clinical follow-up 10.4 months). Among the aneurysm patients treated with revascularization, 81.5% had a favorable outcome (Glasgow Outcome Scale score 4-5) at long-term follow-up (mean clinical followup 18.5 months). CONCLUSIONS: Although microvascular cerebral revascularization is no longer performed as commonly as in the past, it remains an essential part of the skill set required to treat select vascular pathologies. Complex aneurysms are the single largest indication for direct bypass procedures. Moyamoya disease is by far the largest indication if indirect bypass procedures are included in the analysis. In experienced hands, the morbidity and mortality of patients undergoing cerebral revascularization procedures are low and long-term outcomes generally excellent. PMID- 25451809 TI - Physician protect thyself. PMID- 25451810 TI - Further classification to gain much more clarification: an evolving scheme of the internal carotid artery as seen from the endoscopic endonasal perspective. PMID- 25451811 TI - The endoscopic technique for removal of intraparenchymal lesions: a smooth passage in between brain fascicles. PMID- 25451812 TI - Paradigm shift: the endoscopic carotid. PMID- 25451813 TI - The enemy of good is perfect. PMID- 25451814 TI - Serotonin stimulates secretion of exosomes from microglia cells. AB - Microglia are resident immune cells in the brain and exert important functions in the regulation of inflammatory processes during infection or cellular damage. Upon activation, microglia undergo complex morphological and functional transitions, including increased motility, phagocytosis and cytokine secretion. Recent findings indicate that exosomes, small vesicles that derive from fusion of multivesicular bodies with the plasma membrane, are involved in secretion of certain cytokines. The presence of specific receptors on the surface of microglia suggests communication with neurons by neurotransmitters. Here, we demonstrate expression of serotonin receptors, including 5-HT2a,b and 5-HT4 in microglial cells and their functional involvement in the modulation of exosome release by serotonin. Our data demonstrate the involvement of cAMP and Ca(2+) dependent signaling pathways in the regulation of exosome secretion. Co-culture of microglia with embryonic stem cell-derived serotonergic neurons further demonstrated functional signaling between neurons and microglia. Together, these data provide evidence for neurotransmitter-dependent signaling pathways in microglial cells that regulate exosome release. PMID- 25451816 TI - Nonlinear predictive control for Hammerstein-Wiener systems. AB - This paper discusses a nonlinear Model Predictive Control (MPC) algorithm for multiple-input multiple-output dynamic systems represented by cascade Hammerstein Wiener models. The block-oriented Hammerstein-Wiener model, which consists of a linear dynamic block embedded between two nonlinear steady-state blocks, may be successfully used to describe numerous processes. A direct application of such a model for prediction in MPC results in a nonlinear optimisation problem which must be solved at each sampling instant on-line. To reduce the computational burden, a linear approximation of the predicted system trajectory linearised along the future control scenario is successively found on-line and used for prediction. Thanks to linearisation, the presented algorithm needs only quadratic optimisation, time-consuming and difficult on-line nonlinear optimisation is not necessary. In contrast to some control approaches for cascade models, the presented algorithm does not need inverse of the steady-state blocks of the model. For two benchmark systems, it is demonstrated that the algorithm gives control accuracy very similar to that obtained in the MPC approach with nonlinear optimisation while performance of linear MPC and MPC with simplified linearisation is much worse. PMID- 25451815 TI - Vertebral fractures on routine chest computed tomography: relation with arterial calcifications and future cardiovascular events. AB - Osteoporosis and cardiovascular disease often coexist. Vertebral fractures incidentally imaged in the course of routine care might be able to contribute to the prediction of cardiovascular events. Following a case-cohort design, 5,679 patients undergoing chest CT were followed for a median duration of 4.4 years. Cases were defined as patients who subsequently developed a cardiovascular event (n = 493). The presence and severity of vertebral fractures, as well as aortic, coronary and valvular calcifications on CT were investigated. Cases were more likely to be male (69 vs 60 %) and older (66 vs 61 years old). Prevalent vertebral fractures conferred an elevated risk of cardiovascular events after adjustment for age and gender [hazard ratio (HR) of 1.28, 95 % confidence interval (CI) 1.07 to 1.54]. This effect remained moderate after correction for cardiovascular calcifications (HR 1.20, CI 0.99-1.44). However, in terms of discrimination, vertebral fractures did not have substantial incremental prognostic value after correction (C-index was 0.683 vs 0.682 for models with and without vertebral fractures respectively). Prevalent vertebral fractures on routine clinical chest CT are related to future cardiovascular events but do not have additional prognostic value to models that already include age, gender and cardiovascular calcifications. PMID- 25451817 TI - Sliding mode based trajectory linearization control for hypersonic reentry vehicle via extended disturbance observer. AB - This paper proposes a novel hybrid control framework by combing observer-based sliding mode control (SMC) with trajectory linearization control (TLC) for hypersonic reentry vehicle (HRV) attitude tracking problem. First, fewer control consumption is achieved using nonlinear tracking differentiator (TD) in the attitude loop. Second, a novel SMC that employs extended disturbance observer (EDO) to counteract the effect of uncertainties using a new sliding surface which includes the estimation error is integrated to address the tracking error stabilization issues in the attitude and angular rate loop, respectively. In addition, new results associated with EDO are examined in terms of dynamic response and noise-tolerant performance, as well as estimation accuracy. The key feature of the proposed compound control approach is that chattering free tracking performance with high accuracy can be ensured for HRV in the presence of multiple uncertainties under control constraints. Based on finite time convergence stability theory, the stability of the resulting closed-loop system is well established. Also, comparisons and extensive simulation results are presented to demonstrate the effectiveness of the control strategy. PMID- 25451818 TI - Estimation of intra-operative brain shift based on constrained Kalman filter. AB - In this study, the problem of estimation of brain shift is addressed by which the accuracy of neuronavigation systems can be improved. To this end, the actual brain shift is considered as a Gaussian random vector with a known mean and an unknown covariance. Then, brain surface imaging is employed together with solutions of linear elastic model and the best estimation is found using constrained Kalman filter (CKF). Moreover, a recursive method (RCKF) is presented, the computational cost of which in the operating room is significantly lower than CKF, because it is not required to compute inverse of any large matrix. Finally, the theory is verified by the simulation results, which show the superiority of the proposed method as compared to one existing method. PMID- 25451819 TI - Soft sensor for real-time cement fineness estimation. AB - This paper describes the design and implementation of soft sensors to estimate cement fineness. Soft sensors are mathematical models that use available data to provide real-time information on process variables when the information, for whatever reason, is not available by direct measurement. In this application, soft sensors are used to provide information on process variable normally provided by off-line laboratory tests performed at large time intervals. Cement fineness is one of the crucial parameters that define the quality of produced cement. Providing real-time information on cement fineness using soft sensors can overcome limitations and problems that originate from a lack of information between two laboratory tests. The model inputs were selected from candidate process variables using an information theoretic approach. Models based on multi layer perceptrons were developed, and their ability to estimate cement fineness of laboratory samples was analyzed. Models that had the best performance, and capacity to adopt changes in the cement grinding circuit were selected to implement soft sensors. Soft sensors were tested using data from a continuous cement production to demonstrate their use in real-time fineness estimation. Their performance was highly satisfactory, and the sensors proved to be capable of providing valuable information on cement grinding circuit performance. After successful off-line tests, soft sensors were implemented and installed in the control room of a cement factory. Results on the site confirm results obtained by tests conducted during soft sensor development. PMID- 25451821 TI - [Monitoring the functional capacity of patients with rheumatoid arthritis for three years]. AB - OBJECTIVE: To quantify modification of functional capacity in a three year period in a group of patients with rheumatoid arthritis (RA) using HAQ and EPM-ROM inventories. METHODS: Forty patients with RA on methotrexate (MTX) as disease modifying anti rheumatic drug (DMARD) were followed for up to three years. The functional status was assessed at the beginning and end of the period by HAQ and EPM-ROM. RESULTS: Thirty two patients were retrieved, with initial HAQ score of 1.14+/-0.49 (mean+/-SD) and EPM-ROM score of 5.8+/-2.75. After an average period of three years, the HAQ score was 1.13+/-0.49 and EPM-ROM score, 6.81+/-3.66. In the subgroup of seven patients submitted to orthopedic surgery, HAQ score decreased from 0.84+/-0.72 to 1.64+/-0.56 and the EPM-ROM score, from 5.8+/-1.80 to 8.3+/-0.74. In the subgroup of non-operated patients, HAQ score varied from of 1.2+/-0.45 to 1.07+/-0.70 and EPM-ROM score, from 5.7+/-3.06 to 6.4+/-3.90. CONCLUSION: In a group of RA patients in use of only MTX as DMARD, there was little change on HAQ score and EPM-ROM scores over the average period of three years. Worsening functional capacity was observed in the group of operated patients in comparison to the not operated ones. This fact alerts us to the need for use of broader therapeutic regimens availability of musculoskeletal surgeries in a timely manner in patients with RA. PMID- 25451822 TI - EDCs DataBank: 3D-Structure database of endocrine disrupting chemicals. AB - Endocrine disrupting chemicals (EDCs) are a group of compounds that affect the endocrine system, frequently found in everyday products and epidemiologically associated with several diseases. The purpose of this work was to develop EDCs DataBank, the only database of EDCs with three-dimensional structures. This database was built on MySQL using the EU list of potential endocrine disruptors and TEDX list. It contains the three-dimensional structures available on PubChem, as well as a wide variety of information from different databases and text mining tools, useful for almost any kind of research regarding EDCs. The web platform was developed employing HTML, CSS and PHP languages, with dynamic contents in a graphic environment, facilitating information analysis. Currently EDCs DataBank has 615 molecules, including pesticides, natural and industrial products, cosmetics, drugs and food additives, among other low molecular weight xenobiotics. Therefore, this database can be used to study the toxicological effects of these molecules, or to develop pharmaceuticals targeting hormone receptors, through docking studies, high-throughput virtual screening and ligand protein interaction analysis. EDCs DataBank is totally user-friendly and the 3D structures of the molecules can be downloaded in several formats. This database is freely available at http://edcs.unicartagena.edu.co. PMID- 25451823 TI - Carbon black nanoparticle exposure during middle and late fetal development induces immune activation in male offspring mice. AB - Increasing exposure to nanoparticles (NPs) has raised concerns regarding their health and safety profiles in humans and animals, especially in developing organisms, which may display increased sensitivity to NP toxicity. The present study examined the effects of gestational exposure to carbon black NP (CB-NP) on the development of the offspring immune system. Pregnant mice were exposed to CB NP (95MUg/kg body weight) by intranasal instillation on gestational days 9 and 15. The thymus and spleen were collected from their offspring mice on postnatal day (PND) 1, 3 and 5. Thymocyte and splenocyte phenotypes were examined by determining the expression of cell-surface molecules using flow cytometry. Gene expression in the thymus and spleen was examined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Prenatal exposure to CB-NP increased total thymocytes and their immunophenotypes (CD4(-)CD8(-) and CD4(+)CD8(+) cells). It also induced an increase in total lymphocytes, and CD4( )CD8(-), particularly CD3(-)B220(-)cells, at PND 5 in the spleen of newborn male offspring, reflecting the stimulation of immature splenocytes. Furthermore, mRNA expression of genes related to the induction of peripheral tolerance (i.e. thymic Traf6) was upregulated. These data suggest that respiratory exposure to CB-NP during middle and late gestation may have allergic or inflammatory effects in male offspring, and may provide initial information on the potential developmental immunotoxicity of nanoparticles. PMID- 25451824 TI - Detection of significant prostate cancer with magnetic resonance targeted biopsies--should transrectal ultrasound-magnetic resonance imaging fusion guided biopsies alone be a standard of care? AB - PURPOSE: Magnetic resonance imaging-transrectal ultrasound fusion targeted prostate biopsies were suggested to detect significant cancer with more accuracy than systematic biopsies. In this study we evaluate the pathological characteristics of multiparametric magnetic resonance imaging detected and undetected tumor foci on radical prostatectomy specimens. MATERIALS AND METHODS: We selected 125 consecutive patients treated with radical prostatectomy for clinically localized prostate cancer diagnosed on magnetic resonance imaging transrectal ultrasound targeted biopsy and/or systematic biopsy. On multiparametric magnetic resonance imaging each suspicious area was graded according to the PI-RADS score. On radical prostatectomy specimen, tumor foci with a Gleason score greater than 3+3 and/or tumor volume greater than 0.5 ml were considered significant. A correlation analysis between multiparametric magnetic resonance imaging and pathological findings was performed. RESULTS: Pathological analysis of radical prostatectomy specimens detected 230 tumor foci. Of these, 137 were considered significant (Gleason score greater than 3+3 in 112) and were observed in 111 (89%) glands. A total of 95 individual tumor foci, including 14 significant foci, were missed with multiparametric magnetic resonance imaging. All of them were located in glands where another focus was detected with multiparametric magnetic resonance imaging. An additional 9 individual tumor foci, including 7 significant, were detected on multiparametric magnetic resonance imaging but missed with targeted biopsy, resulting in 5 (4%) significant cancers undetected with magnetic resonance imaging-transrectal ultrasound fusion targeted biopsy. The magnetic resonance imaging target largest diameter was associated with high volume (greater than 0.5 cc) foci detection, while PI-RADS score and cancer involvement on targeted biopsy were associated with significant foci detection. CONCLUSIONS: In these series of men with suspicious prostate multiparametric magnetic resonance imaging findings, magnetic resonance imaging-transrectal ultrasound fusion guided targeted biopsy alone strategy would have resulted in the under detection of only 4% significant cancers. PMID- 25451825 TI - Renal cell carcinoma in children, adolescents and young adults: a National Cancer Database study. AB - PURPOSE: We compared the presentation and outcomes of patients younger than 21 years with renal cell carcinoma and determined risk factors associated with mortality. MATERIALS AND METHODS: We searched the National Cancer Database for patients diagnosed with renal cell carcinoma between 1998 and 2011. We evaluated patients younger than 30 years with renal cell carcinoma, including clear cell, chromophobe, papillary and not otherwise specified subcategories. We used logistic regression to compare presenting cancer, demographics and treatment variables in patients 0 to 15 years, 15 to 21 years and 21 to 30 years old. Cox regression analysis was used to determine risk factors for mortality in patients younger than 21. RESULTS: Of 3,658 patients younger than 30 years included in the study 161 were younger than 15 and 337 were 15 to 21 years old. A higher proportion of younger patients had renal cell carcinoma not otherwise specified and papillary histology compared to those 21 to 30 years (p < 0.001). Younger patients presented with higher stage (p < 0.0001), higher grade (p < 0.0001) and larger tumors (p < 0.0001) than those 21 to 30 years. A higher percentage of younger patients underwent lymph node dissection (p < 0.0001) or chemotherapy as first-line treatment (p < 0.0001) compared to those 21 to 30 years. Cox regression analysis demonstrated that stage 4 presentation, government insurance status, nonchromophobic pathology results and not undergoing surgery as first line treatment were independently associated with increased mortality in patients younger than 21 years. CONCLUSIONS: Children and adolescents with renal cell carcinoma present with more advanced disease than those 21 to 30 years old. In patients younger than 21 years mortality was associated with the nonchromophobe histological subtype, stage 4 disease, government insurance and not undergoing surgery as first-line therapy. PMID- 25451826 TI - The mutational spectrum of WT1 in male infertility. AB - PURPOSE: We evaluated the impact of WT1 mutations in isolated severe spermatogenic impairment in a population of European ancestry. WT1 was first identified as the gene responsible for Wilms tumor. It was later associated with a plethora of clinical phenotypes often accompanied by urogenital defects and male infertility. The recent finding of WT1 missense mutations in Chinese azoospermic males without major gonadal malformations broadened the phenotypic spectrum of WT1 defects and motivated this study. MATERIALS AND METHODS: We analyzed the WT1 coding region in a cohort of 194 Portuguese patients with nonobstructive azoospermia and in 188 with severe oligozoospermia with increased depth for the exons encoding the regulatory region of the protein. We also analyzed a group of 31 infertile males with a clinical history of unilateral or bilateral cryptorchidism and 1 patient with anorchia. RESULTS: We found 2 WT1 missense substitutions at higher frequency in patients than in controls. 1) A novel variant in exon 1 (p.Pro130Leu) that disrupted a mammalian specific polyproline stretch in the self-association domain was more frequent in azoospermia cases (0.27% vs 0.13%, p = 0.549). 2) A rare variant in a conserved residue in close proximity to the first zinc finger (pCys350Arg) was more frequent in severe oligozoospermia cases (0.80% vs 0.13%, p = 0.113). CONCLUSIONS: Results suggest a role for rare WT1 damaging variants in severe spermatogenic failure in populations of European ancestry. Large multicenter studies are needed to fully assess the contribution of WT1 genetic alterations to male infertility in the absence of other disease phenotypes. PMID- 25451827 TI - Serum inhibin B values in boys with unilateral vanished testis or unilateral cryptorchidism. AB - PURPOSE: Boys with cryptorchidism have overall increased gonadotropin and decreased serum inhibin B levels compared to normal. Serum inhibin B levels, produced by Sertoli cells, may reflect the state of germinative epithelium in cryptorchid testes. We evaluated whether serum inhibin B levels differed between boys with unilateral vanished testis and those with unilateral cryptorchidism. MATERIALS AND METHODS: Blood samples from 297 boys 1.5 to 5 years old were included, of whom 222 had unilateral cryptorchidism, 29 had unilateral vanished testis and 46 had undergone unilateral orchiopexy 1 year previously. Serum inhibin B levels were measured using a commercially available ELISA kit and were compared to normal range. RESULTS: Serum inhibin B levels in boys with unilateral vanished testis were not different from those with unilateral cryptorchidism. Serum inhibin B values were above the normal median in 43% of boys previously operated on for unilateral cryptorchidism, compared to 17% at surgery (p = 0.0003). The percentage of patients with inhibin B levels below normal range was 14% in those with unilateral vanished testis, 23% in those with unilateral cryptorchidism and 11% in those who had undergone orchiopexy 1 year previously for unilateral cryptorchidism. The percentage of boys with inhibin B levels above normal median was 24% in those with unilateral vanished testis, 17% in those with unilateral cryptorchidism and 43% in those who had undergone orchiopexy. However, in boys with a vanished testis the frequency of serum inhibin B above normal median was only 5% before age 1.5 years, after which the rate was 67% (p = 0.0022). CONCLUSIONS: Our findings may reflect the development of contralateral testicular hypertrophy in boys with unilateral vanished testis. The initial low inhibin B values may be explained by impaired total number of Sertoli cells. Serum inhibin B values also indicated that in 6-month to 5-year-old boys with cryptorchidism orchiopexy was beneficial for the germinative epithelium. PMID- 25451828 TI - Long-term caloric restriction in rats may prevent age related impairment of in vitro bladder function. AB - PURPOSE: Bladder function is often impaired with aging. In other organs caloric restriction has had a prophylactic effect on the biological changes associated with aging. We tested the hypothesis that long-term caloric restriction can prevent age related impaired bladder function in the rat. MATERIALS AND METHODS: Fisher 344 male rats were divided into 3 groups, including 16 young rats at age 6 months with free access to normal food, 15 old rats at age 25 to 28 months with free access to normal food and 16 old rats at age 25 to 28 months fed with normal food 3 days per week since age 6 weeks (caloric restriction). We performed frequency volume measurements, in vitro organ bath functional studies using full thickness longitudinal detrusor strips, evaluation of muscarinic and purinergic receptor mRNA expression, and histological examination with Masson trichrome staining of bladder tissue. RESULTS: Frequency volume changes did not significantly differ among the 3 groups. The old group fed normal food showed weaker contractile responses to carbachol and electrical field stimulation (especially in the cholinergic component), lower M3 receptor mRNA expression and higher collagen deposition compared to the young group. These age related bladder changes were milder in the old group with caloric restriction than in the old group fed normal food. CONCLUSIONS: This study suggests that in the rat long-term caloric restriction has a preventive effect against age related functional and morphological bladder changes. These changes include impaired detrusor contractility that may be related to decreased expression of M3 receptors and to bladder wall fibrosis. PMID- 25451829 TI - Influence of age on incident diabetes and cardiovascular disease in prostate cancer survivors receiving androgen deprivation therapy. AB - PURPOSE: Observational data suggest that androgen deprivation therapy increases the risk of diabetes and cardiovascular disease. Using data from the population based PCOS we evaluated whether age at diagnosis and comorbidity impact the association of androgen deprivation therapy with incident diabetes and cardiovascular disease. MATERIALS AND METHODS: We identified men with nonmetastatic prostate cancer diagnosed from 1994 to 1995 who were followed through 2009 to 2010. We used multivariable logistic regression models to assess the relationship of androgen deprivation therapy exposure (2 or fewer years, greater than 2 years or none) with incident diabetes and cardiovascular disease, adjusting for age at diagnosis, race, stage and comorbidity. RESULTS: Of 3,526 eligible study participants 2,985 without diabetes and 3,112 without cardiovascular disease comprised the cohorts at risk. Androgen deprivation therapy was not associated with an increased risk of diabetes or cardiovascular disease in men diagnosed with prostate cancer before age 70 years. Prolonged androgen deprivation therapy and increasing age at diagnosis in older men was associated with an increased risk of diabetes (at age 76 years OR 2.1, 95% CI 1.0 4.4) and cardiovascular disease (at age 74 years OR 1.9, 95% CI 1.0-3.5). Men with comorbidities were at greater risk for diabetes (OR 4.3, 95% CI 2.3-7.9) and cardiovascular disease (OR 8.1, 95% CI 4.3-15.5) than men without comorbidities. CONCLUSIONS: Prolonged androgen deprivation therapy exposure increases the risk of cardiovascular disease and diabetes in men diagnosed with prostate cancer who are older than approximately 75 years, especially those with other comorbidities. Older men who receive prolonged androgen deprivation therapy should be closely monitored for diabetes and cardiovascular disease. PMID- 25451830 TI - Multi-institutional validation of the predictive value of Ki-67 in patients with high grade urothelial carcinoma of the upper urinary tract. AB - PURPOSE: We validate the independent predictive value of Ki-67 in patients with high grade upper tract urothelial carcinoma. MATERIALS AND METHODS: A total of 475 patients from the international Upper Tract Urothelial Carcinoma Collaboration who underwent extirpative surgery for high grade upper tract urothelial carcinoma were included in this study. Immunohistochemical staining for Ki-67 was performed on tissue microarray formed from this patient cohort. Ki 67 expression was assessed in a semiquantitative fashion and considered over expressed at a cutoff of 20%. Multivariate analyses were performed to assess independent predictors of oncologic outcomes and Harrell's C indices were calculated for predictive models. RESULTS: The median age of the cohort was 69.7 years and 55.2% of patients were male. Ki-67 was over expressed in 25.9% of patients. Ki-67 over expression was significantly associated with ureteral tumor location, higher pT-stage, lymphovascular invasion, sessile tumor architecture, tumor necrosis, concomitant carcinoma in situ and regional lymph node metastases. On Kaplan-Meier analyses over expressed Ki-67 was associated with worse recurrence-free survival (HR 12.6, p <0.001) and cancer specific survival (HR 15.8, p <0.001). On multivariate analysis Ki-67 was an independent predictor of recurrence-free survival (HR 1.6, 95% CI 1.07-2.30, p=0.021) and cancer specific survival (HR 1.9, 95% CI 1.29-2.90, p=0.001). Ki-67 improved Harrell's C index from 0.66 to 0.70 (p <0.0001) for recurrence-free survival as well as cancer specific survival in our preoperative model, and from 0.81 to 0.82 (p=0.0018) for recurrence-free survival and 0.81 to 0.83 (p=0.005) for cancer specific survival in our postoperative model. CONCLUSIONS: Ki-67 was validated as an independent predictor of recurrence-free survival and cancer specific survival in patients treated with extirpative surgery for high grade upper tract urothelial carcinoma in a large, multi-institutional cohort. PMID- 25451831 TI - Clinical practice guidelines on prostate cancer: a critical appraisal. AB - PURPOSE: Clinical practice guidelines are increasingly being used by leading organizations to promote high quality evidence-based patient care. However, the methodological quality of clinical practice guidelines developed by different organizations varies considerably. We assessed published clinical practice guidelines on the treatment of localized prostate cancer to evaluate the rigor, applicability and transparency of their recommendations. MATERIALS AND METHODS: We searched for English based clinical practice guidelines on treatment of localized prostate cancer from leading organizations in the 15-year period from 1999 to 2014. Clinical practice guidelines limited to early detection, screening, staging and/or diagnosis of prostate cancer were excluded from analysis. Four independent reviewers used the validated AGREE II instrument to assess the quality of clinical practice guidelines in 6 domains, including 1) scope and purpose, 2) stakeholder involvement, 3) rigor of development, 4) clarity of presentation, 5) applicability and 6) editorial independence. RESULTS: A total of 13 clinical practice guidelines met inclusion criteria. Overall the highest median scores were in the AGREE II domains of clarity of presentation, editorial independence, and scope and purpose. The lowest median score was for applicability (28.1%). Although the median score of editorial independence was high (85.4%), variability was also substantial (IQR 12.5-100). NICE and AUA clinical practice guidelines consistently scored well in most domains. CONCLUSIONS: Clinical practice guidelines from different organizations on treatment of localized prostate cancer are of variable quality and fall short of current standards in certain areas, especially in applicability and stakeholder involvement. Improvements in these key domains can enhance the impact and implementation of clinical practice guidelines. PMID- 25451832 TI - Impact of real-time elastography on magnetic resonance imaging/ultrasound fusion guided biopsy in patients with prior negative prostate biopsies. AB - PURPOSE: The fusion of multiparametric resonance imaging and ultrasound has been proven capable of detecting prostate cancer in different biopsy settings. The addition of real-time elastography promises to increase the precision of the outcome of targeted biopsies. We investigated whether real-time elastography improves magnetic resonance imaging/transrectal ultrasound fusion targeted biopsy in patients after previous negative biopsies. MATERIALS AND METHODS: Prospectively 121 men underwent 3T magnetic resonance imaging. Using magnetic resonance imaging/real-time elastography fusion every suspicious lesion was characterized according to its tissue density and sampled by 2 fusion guided targeted biopsies. Additionally, all patients underwent 12-core systematic biopsy. The detection rate of clinically significant and insignificant cancers was compared between targeted und systematic biopsies. The accuracy to predict high grade prostate cancer was evaluated for with the PI-RADS scoring system and compared to the magnetic resonance imaging/real-time elastography fusion score. RESULTS: Overall prostate cancer was detected in 52 patients (43%). Targeted fusion guided biopsy revealed prostate cancer in 32 men (26.4%) and systematic biopsy in 46 (38%). The proportion of clinically significant cancers was higher for targeted biopsy (90.6%) compared to systematic biopsy (73.9%). The detection rate per core was higher for targeted biopsies (14.7%) compared to systematic biopsies (6.5%, p <0.001). The prediction of biopsy result according to magnetic resonance imaging/real-time elastography fusion was better (AUC 0.86) than magnetic resonance imaging alone (AUC 0.79). Sensitivity and specificity for magnetic resonance imaging/real-time elastography fusion was 77.8% and 77.3% vs 74.1% and 62.9% for magnetic resonance imaging. CONCLUSIONS: Magnetic resonance imaging/transrectal ultrasound fusion enhances the likelihood of detecting clinically significant cancers in a repeat biopsy setting. Adding real-time elastography to magnetic resonance imaging supports the characterization of cancer suspicious lesions. PMID- 25451833 TI - Understanding hospital readmission intensity after radical cystectomy. AB - PURPOSE: Hospital readmissions after radical cystectomy vary with respect to intensity in terms of impact on patients and health care systems. Therefore, we conducted a population based study to examine factors associated with increasing readmission intensity after radical cystectomy for bladder cancer. MATERIALS AND METHODS: Using SEER (Surveillance, Epidemiology, and End Results)-Medicare data we identified 1,782 patients who underwent radical cystectomy from 2003 to 2009. We defined readmission intensity in terms of length of stay (days) divided into quartiles of less than 3 (lowest), 3 to 4, 5 to 7 and more than 7 (highest). We used logistic regression to examine factors associated with readmission intensity. RESULTS: More than half of the patients with the highest intensity readmissions were readmitted within the first week and 77% were readmitted within 2 weeks of discharge. Patients with the highest intensity readmissions were similar in age, gender, race, socioeconomic status, pathological stage, comorbidity, neoadjuvant chemotherapy use and urinary diversion type compared to patients with the lowest intensity readmissions. After multivariable adjustment, complications during the index cystectomy admission (p <0.001), readmission week (p=0.04), and the interaction between index length of stay and discharge to a skilled nursing facility (p=0.04) were associated with the highest readmission intensity. CONCLUSIONS: Readmission intensity differs widely after discharge following radical cystectomy. As postoperative efforts to minimize the readmission burden increase, a better understanding of the factors that contribute to the highest intensity readmissions will help direct limited resources (eg telephone calls, office visits) toward high yield areas. PMID- 25451834 TI - The effect of concomitant carcinoma in situ on neoadjuvant chemotherapy for urothelial cell carcinoma of the bladder: inferior pathological outcomes but no effect on survival. AB - PURPOSE: It is generally believed that carcinoma in situ is refractory to chemotherapy but specific data are lacking to validate this. We evaluated the effect of concomitant clinical carcinoma in situ on cancer specific outcomes after neoadjuvant chemotherapy for muscle invasive bladder cancer. MATERIALS AND METHODS: We performed an institutional review board approved, multi institutional, retrospective review of the records of patients treated with neoadjuvant chemotherapy followed by radical cystectomy for muscle invasive bladder cancer from 2008 to 2012. Pretreatment clinical variables were collected and patients were stratified by the presence of clinical carcinoma in situ on precystectomy transurethral bladder tumor resection specimens. Pathological outcomes, including the complete response rate (pT0N0Mx) after neoadjuvant chemotherapy, were compared between the 2 groups. Recurrence-free, cancer specific and overall survival was analyzed. RESULTS: Of 189 patients who met study criteria 56 (29.6%) had concomitant carcinoma in situ. The condition was associated with a significant decrease in the pathological complete response rate (10.7% vs 26.3%, p = 0.02). This difference was significant on univariate and multivariable analysis (OR 0.34, 95% CI 0.13-0.85, p = 0.02 and OR 0.31, 95% CI 0.12-0.81, p = 0.02, respectively). Despite the decreased complete response rate clinical carcinoma in situ was not associated with a difference in recurrence free, cancer specific or overall survival. Additionally, when down-staging to pathological carcinoma in situ only disease was considered a complete response, there was no significant change in recurrence-free, cancer specific or overall survival. CONCLUSIONS: Concomitant carcinoma in situ is associated with a decrease in the complete response rate but this does not appear to impact the survival outcome. PMID- 25451835 TI - Is hyperuricemia a risk factor for arteriosclerosis? Uric acid and arteriosclerosis in apolipoprotein e-deficient mice. AB - Although hyperlipidemia, high blood pressure, and diabetes increase the risk of arteriosclerosis, it is not clear whether hyperuricemia increases the risk of arteriosclerosis or not. We examined the effects of uric acid and curative drugs for hyperuricemia on atherosclerosis-susceptible C57BL/6J apolipoprotein E deficient (apoE(-/-)) mice. Male apoE(-/-) mice (age: 6 weeks) were fed a normal diet (normal diet group) or a uric acid-enriched diet. Mice fed the uric acid enriched diet were divided into three groups and administered a drinking vehicle (high uric acid diet group), allopurinol (20 mg.kg(-1).d(-1)), or benzbromarone (20 mg.kg(-1).d(-1)) for 10 weeks. Serum uric acid concentrations were higher in the high uric acid diet group than in the normal diet group, and concentrations in the allopurinol and benzbromarone groups were lower than in the high uric acid diet group. Serum total cholesterol and triglyceride levels were lower in the allopurinol group than in the high uric acid diet group. Oxidative stress was lower in the benzbromarone group than in the high uric acid diet group. Atherosclerotic lesion areas were smaller in the allopurinol and benzbromarone groups than in the high uric acid diet group. Thus, hyperuricemia may not be an independent risk factor for arteriosclerosis; however, the administration of allopurinol and benzbromarone prevented the development of atherosclerosis in apoE(-/-) mice fed a uric acid-enriched diet. The anti-atherosclerotic effect was in part due to lower total cholesterol and oxidative stress in the serum. Other possible mechanisms underlying this effect should be investigated. PMID- 25451836 TI - Lipopolysaccharide reciprocally alters the stromal cell-regulated positive and negative balance between myelopoiesis and B lymphopoiesis in C57BL/6 mice. AB - Hematopoiesis in the bone marrow (BM) and spleen is controlled by stromal cells. Inflammation promotes myelopoiesis and simultaneously suppresses B lymphopoiesis. However, the role of the reciprocal regulation of myelopoiesis and B lymphopoiesis by stromal cells during inflammation is not fully understood. We investigated inflammation-induced alteration of hematopoietic regulation in lipopolysaccharide (LPS)-treated mice. C57BL/6 female mice were intravenously injected with a single, 5-ug dose of LPS, which induced a rapid decrease in the number of granulocyte-macrophage progenitors (colony-forming unit granulocyte macrophage; CFU-GM) and B cell progenitors (CFU-preB) in BM. The CFU-GM count rapidly recovered, whereas the recovery of CFU-preB was delayed. LPS induced a marked increase in the number of CFU-GM but not in the number of CFU-preB in spleen. After LPS treatment, gene expression levels of positive regulators of myelopoiesis such as granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in BM and spleen were markedly upregulated whereas levels of positive regulators for B lymphopoiesis such as stromal cell-derived factor (SDF)-1, stem cell factor (SCF), and IL-7 remained unchanged. Meanwhile, the negative regulator of B lymphopoiesis tumor necrosis factor (TNF)-alpha was markedly up-regulated. The number of CFU-GM in S-phase in BM increased after LPS treatment, whereas the number of CFU-preB in S-phase decreased. These results suggest that LPS-activated stromal cells induce positive-dominant regulation of myelopoiesis and negative dominant regulation of B lymphopoiesis, which facilitates emergency myelopoiesis during inflammation by suppressing B lymphopoiesis, thereby contributing to the host defense against infection. PMID- 25451837 TI - Doxycycline hyclate protects lipopolysaccharide-induced endothelial barrier dysfunction by inhibiting the activation of p38 mitogen-activated protein kinase. AB - Doxycycline hyclate (DOX-h) attenuates inflammatory conditions independent of its antimicrobial effect. This study aimed to observe the effects of DOX-h on lipopolysaccharide (LPS)-induced endothelial barrier dysfunction. The endothelial monolayer permeability of human umbilical vein endothelial cells (HUVECs) was monitored by transendothelial electrical resistance (TEER). The phosphorylation of mitogen-activated protein kinases (MAPKs) and the arrangement of F-actin were detected. The results showed that both pretreatment and simultaneous treatment with DOX-h markedly attenuated the LPS-induced reduction in TEER and the disorganization of F-actin on HUVECs in a dose- and time-dependent manner. LPS mediated the phosphorylation of all three MAPKs (p38, extracellular signal regulated kinase (ERK)1/2, and c-Jun N-terminal kinase (JNK)), but DOX-h was only able to inhibit the LPS-induced phosphorylation of p38 and JNK. The data further suggested that DOX-h alleviated LPS-evoked TEER reduction and F-actin redistribution by inhibiting the phosphorylation of p38 and its downstream target, heat shock protein (HSP)27. Thus, DOX-h attenuates LPS-induced endothelial barrier dysfunction via inhibition of the p38 MAPK-HSP27-F-actin pathway. PMID- 25451838 TI - Protective effects of ginsenoside Rg1 on astrocytes and cerebral ischemic reperfusion mice. AB - Ginsenoside Rg1 (Rg1), one of the active ingredients in Panax ginseng, has been known to regulate many cellular processes. The purpose of this study was to investigate the protective effects of Rg1 on apoptosis in mouse cultured astrocytes in vitro and a mouse model of cerebral ischemia and reperfusion in vivo. The cell apoptosis was measured by fluorescence microplate reader and xCELLigence system and the Ca(2+) overload was recorded by confocal microscopy. The mitochondrial membrane potential and reactive oxygen species (ROS) were determined by flow cytometry. BALB/c mice were subjected to transient middle cerebral artery occlusion (MCAO) and randomly divided into four groups: Sham (sham-operated +0.9% saline), MCAO (MCAO+0.9% saline), Rg1-L (MCAO+Rg1 20 mg/kg) and Rg1-H (MCAO+Rg1 40 mg/kg). Neurological deficit scores, brain water content and infarct volume were evaluated at 24 h after reperfusion. The results showed that Rg1 significantly attenuated H2O2-induced apoptosis in astrocytes. Rg1 efficiently inhibited intracellular Ca(2+) overload, loss of mitochondrial membrane potential, and ROS production in astrocytes. In vivo study, it was also observed that Rg1 markedly reduced the neurological deficit scores, brain edema, and infarct volume in the model mice. These results suggest that Rg1 possesses significant neuroprotective effects, which might be related to the prevention of astrocytes from apoptosis. PMID- 25451839 TI - Alteration of a human intestinal microbiota under extreme life environment in the Antarctica. AB - The human intestinal microbiota (HIM) settles from birth and continues to change phenotype by some factors (e.g. host's diet) throughout life. However, the effect of extreme life environment on human HIM composition is not well known. To understand HIM fluctuation under extreme life environment in humans, fecal samples were collected from six Japanese men on a long Antarctic expedition. They explored Antarctica for 3 months and collected their fecal samples at once monthly intervals. Using terminal restriction fragment length polymorphism (T RFLP) and real time polymerase chain reaction (PCR) analysis, the composition of HIM in six subjects was investigated. Three subjects presented restoration of HIM after the expedition compared versus before and during the expedition. Two thirds samples collected during the expedition belonged to the same cluster in dendrogram. However, all through the expedition, T-RFLP patterns showed interindividual variability. Especially, Bifidobacterium spp. showed a tendency to decrease during and restore after the expedition. A reduction of Bifidobacterium spp. was observed in five subjects the first 1 month of the expedition. Bacteroides thetaiotaomicron, which is thought to proliferate during emotional stress, significantly decreased in one subject, indicating that other factors in addition to emotional stress may affect the composition of HIM in this study. These findings could be helpful to understand the effect of extreme life environment on HIM. PMID- 25451840 TI - Co-localization of TRPV2 and insulin-like growth factor-I receptor in olfactory neurons in adult and fetal mouse. AB - TRPV2, a member of the transient receptor potential family, has been isolated as a capsaicin-receptor homolog and is thought to respond to noxious heat. Here we show that TRPV2 mRNA is predominantly expressed in the subpopulation of olfactory sensory neurons (OSNs). We carried out histochemical analyses of TRPV2 and insulin-like growth factor-I receptor (IGF-IR) using in situ hybridization and immunofluorescence in the adult olfactory system. In olfactory mucosa, intensive TRPV2 immunostaining was observed at the olfactory axon bundles but not at the soma. TRPV2-positive labeling was preferentially found in the olfactory nerve layer in the olfactory bulb (OB). Furthermore, we demonstrated that a positive signal for IGF-IR mRNA was detected in OSNs expressing TRPV2 mRNA. In embryonic stages, TRPV2 immunoreactivity was observed on axon bundles of developing OSNs in the nasal region starting from 12.5 d of gestation and through fetal development. Observations in this study suggest that TRPV2 coupled with IGF-IR localizes to growing olfactory axons in the OSNs. PMID- 25451841 TI - Camphor induces cold and warm sensations with increases in skin and muscle blood flow in human. AB - Application of camphor to the skin has been empirically thought to improve blood circulation. However, camphor's effects on blood circulation to the skin and on thermal sensation have not been well elucidated. In this study, we examined its effects on the quality of sensation as well as on skin and muscle blood flow in human. Nine adults (average age 37+/-9.4 years) participated in the study. Petroleum jelly containing 5%, 10%, 20% camphor, or 2% menthol was separately applied to the skin on the medial side of one forearm of each subject. Just after the application, camphor at each concentration induced a cold sensation in a dose dependent manner. Within 10 min, each subject reported that the cold sensation had faded, after which it was replaced by a warm sensation. As reported previously, a cold sensation was induced by application of 2% menthol, but the subjects did not adapt to that sensation. In addition, menthol did not induce a warm sensation at all. Application of menthol has been shown to increase blood flow in the skin. Finally, we measured blood flow in skin and muscle after the application of camphor or menthol. Application of camphor or menthol separately induced increases in local blood flow in the skin and muscle. The present results indicate that camphor induces both cold and warm sensations and improves blood circulation. PMID- 25451842 TI - Comparative study of the sensitivities of cancer cells to doxorubicin, and relationships between the effect of the drug-efflux pump P-gp. AB - Multi-drug resistance (MDR) of cancers to chemotherapy including doxorubicin (DOX) is mediated by several factors. To design an effective therapy for the treatment of chemotherapy-resistant cancers, it is essential to explore the elements responsible for mediating MDR. However, exploring these factors in detail in a wide range of tumor types is challenging as several critical analytical steps are involved. Here, we demonstrated the way of exploring the factors mediating MDR in the tumor types without performing the analysis at the molecular level of cells. The sensitivities of 15 different types of cancer cells to DOX were evaluated, and the role of P-glycoprotein (P-gp), one of the major efflux-pumps, was explored. A correlation curve was developed between the intracellular amounts of DOX and the sensitivities of cells, and, based on this correlation, the cells were classified in response to the involvement of P-gp that mediates MDR. P-gp plays an active role in mediating MDR of cancer cells where a correlation between the sensitivities of cells and the accumulated DOX exists. In contrast, in cells that show a resistance to DOX but whose sensitivities are independent of the amount of accumulated drug, it was reasonably presumed that mechanisms other than P-gp are likely to be involved in mediating MDR. Based on the correlation between the availability of a drug and cell sensitivity, it would be reasonable to explore the factors governing cancer MDR, which is essential in designing an effective therapeutic approach for treating chemotherapy-resistant cancers using chemotherapeutic drugs. PMID- 25451843 TI - Iejimalide C is a potent V-ATPase inhibitor, and induces actin disorganization. AB - Iejimalides (IEJLs) A-D are 24-membered macrolides isolated from a tunicate Eudistoma cf. rigida, and exhibit potent cytotoxicity in vitro and antitumor activity in vivo. We previously reported that the molecular target of IEJL-A and B was the vacuolar-type H(+)-ATPases (V-ATPases). However IEJL-C and -D, which are sulfonylated IEJL-A and -B, respectively, show more potent antitumor activity, and their molecular targets remain to be discovered. Here, we report that IEJL-C is also a potent V-ATPase inhibitor by binding in a site similar to the bafilomycin-binding site. Two-hour treatment with IEJL-C resulted in the complete disappearance of acidic organelles in HeLa cells. Interestingly, after 24-h treatment, small actin aggregates were observed instead of actin fibers. The same actin reorganization was also observed in cells treated with another V ATPase inhibitor, bafilomycin A1. Because IEJLs did not inhibit actin polymerization in vitro, these results suggest that the primary target of IEJL-C, as well as IEJL-A and -B, is V-ATPase, and actin reorganizations are probably caused by the disruption of pH homeostasis via V-ATPase inhibition. PMID- 25451844 TI - Astrocytes, but not neurons, exhibit constitutive activation of P2X7 receptors in mouse acute cortical slices under non-stimulated resting conditions. AB - We previously demonstrated that the P2X7 receptor (P2X7R), a purinergic receptor, expressed by mouse cultured cortical astrocytes is constitutively activated without any exogenous stimulus, differing from the case of neurons. It is well known that astrocytic morphology differs between in vitro and in vivo situations, implying different functionalities. Brain acute slices are widely accepted as an in vitro experimental system that reflects in vivo cell conditions better than in vitro cell culture ones. We examined whether astrocytic P2X7Rs exhibited constitutive activation in mouse cortical slices. In acute cortical slices, P2X7R immunoreactivity was detected in both glial fibrillary acidic protein immunopositive astrocytes and microtubule-associated protein 2-immunopositive neurons. Astrocytic, but not neuronal, spontaneous uptake of propidium iodide, an indicator of P2X7R channel/pore activity, was inhibited by representative antagonists of P2X7R, but they had no effect on the uptake by astrocytes in membrane-permeabilized fixed slices. These findings indicate that astrocytes, but not neurons, in acute cortical slices exhibit constitutive activation of P2X7Rs under non-stimulated resting conditions as in the case of cell culture systems. PMID- 25451845 TI - Genotoxicity of rice bran oil extracted by supercritical CO2 extraction. AB - Rice bran oil extracted by supercritical CO2 extraction (RB-SCE) reportedly exhibits pharmacological activities such as antioxidant and in vivo hair growth inducing effects. Such activities raise the possibility of the development of novel hair growth-inducing agents using RB-SCE. The aim of this study was to investigate the potential genotoxic effects of RB-SCE in three short-term mutagenicity assays (bacterial reverse mutation assay, in vitro mammalian chromosomal aberration test, and in vivo micronucleus assay). RB-SCE showed no genotoxicity in the bacterial reverse mutation assay up to 5000 mg/plate and in the in vivo micronucleus test up to 600 mg/kg body weight. However, at 120 ug/mL with S9 mix and 200 ug/mL without S9 mix RB-SCE showed significantly different genotoxicity than the negative control in the in vitro chromosome aberration test. The induction of chromosomal aberrations under the present conditions may have no biological significance. We have herein demonstrated that RB-SCE can be regarded as a non-genotoxic material based on the available in vivo and in vitro results. PMID- 25451846 TI - Synthesis and evaluation of curcumin-related compounds containing inden-2-one for their effects on human cancer cells. AB - Indanones are very useful molecules as starting building blocks for the synthesis of biologically active compounds. A series of novel curcumin-related compounds containing indan-2-one were synthesized and screened for anticancer activities. The structures were confirmed by spectral data (IR, NMR, and Mass). Inhibitory effects of these compounds on the growth of prostate cancer PC-3 cells, pancreatic cancer BxPC-3 cells, colon cancer HT-29 cells, lung cancer H1299 cells and non-tumorigenic human prostate epithelial RWPE-1 cells were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC50 for compound IND-4 was lower than 1 uM in the four cancer cell lines. The present study indicates that IND-4 may have useful effects on human cancer cells. PMID- 25451847 TI - Apoptosis occurs during early development of the bursa of Fabricius in chicken embryos. AB - The bursa of Fabricius (BF) is a unique primary lymphoid organ, and among vertebrates is unique to birds. Despite its importance to the immune systems of various avian species, little is known of the molecular mechanisms underlying early BF development. In the present study, we demonstrated that apoptosis occurs during early development of the bursa of Fabricius in chicken embryos. Initial histological analyses of BF morphogenesis in chicken embryos led to the hypothesis that formation of the bursal lumen correlates with fusion of vacuoles, which appear in the cloacal epithelial bud. Using terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) analysis and immunostaining with an anti-cleaved (activated) caspase-3 antibody, we detected multiple apoptotic cells around these vacuoles. In further experiments, treatments with a caspase inhibitor caused abnormal bursal lumen in vivo. The present data indicate that apoptosis may play important roles in BF morphogenesis in chickens. PMID- 25451848 TI - Treatment of newborn mice with inhibitors of vascular endothelial growth factor receptor tyrosine kinase induces abnormal retinal vascular patterning. AB - We have previously reported that treatment of newborn mice with KRN633, a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, delayed retinal vascularization leading to abnormal retinal vascular growth and patterns. To determine whether similar abnormalities are observed in newborn mice treated with other VEGF receptor tyrosine kinase inhibitors, we administered axitinib to mice on the day of birth and on the following day. When compared with control pups, a significant delay in retinal vascularization was observed in pups treated with axitinib (5 mg/kg). Axitinib-treated pups had a very dense capillary network on postnatal day (P) 6 and fewer central arteries and veins on P8 and P12. Central veins, but not arteries, were significantly enlarged on P8. These abnormalities were similar to those observed in KRN633-treated pups and probably represent a common phenotype induced by short-term treatment with VEGF receptor inhibitors in newborn mice. Therefore, mice treated postnatally with VEGFR inhibitors could serve as an animal model for studying the mechanisms of retinal vascular formation and patterning. PMID- 25451849 TI - Comparison of the effects of azole antifungal agents on the anticoagulant activity of warfarin. AB - The package insert of the antithrombotic agent warfarin warns users of its interaction with azole antifungals. However, information on the frequency or degree of these interactions is limited. In particular, the time to onset of azole-mediated prothrombin time prolongation, expressed as the international normalized ratio (INR), is poorly characterized. Therefore, we retrospectively examined the INR in 29 patients administered warfarin with fluconazole (FLCZ), voriconazole (VRCZ), or itraconazole (ITCZ). INRs in 18 patients taking FLCZ and in 5 patients taking VRCZ significantly increased from 1.40 to 2.94 and from 1.95 to 2.89, respectively. The warfarin sensitivity index (WSI), calculated as INR/daily warfarin dose, also significantly increased from 1.06 to 1.89 with FLCZ and showed an upward trend from 1.13 to 2.23 with VRCZ. ITCZ had no influence on the INR or WSI in 6 patients. The INRs observed when warfarin was coadministered with azoles (Y) correlated significantly with those observed in the absence of azoles (X): FLCZ, Y=4.94X-3.96, r(2)=0.80; VRCZ, Y=2.13X-1.27, r(2)=0.93. Moreover, in all 8 patients with closely monitored INRs, the WSI increased within 1 week of FLCZ or VRCZ coadministration. In conclusion, FLCZ and VRCZ augmented the anticoagulant activity of warfarin. The INR should be closely monitored within 1 week of initiating FLCZ or VRCZ coadministration with warfarin, especially in patients with high INRs. PMID- 25451850 TI - The role of obesity duration on the association between obesity and risk of physical disability. AB - OBJECTIVE: To relate measured obesity duration in mid-life with subsequent incidence of physical disability over and above body mass index (BMI) attained. METHODS: Framingham Offspring Study is a longitudinal study that began in 1971. Examination 5 (1991-1995; "baseline") and disability onset ascertained from examinations 6-8 (2008) were used. About 2,095 disability-free participants aged 45-65 years at baseline were included. Obesity (BMI >= 30 kg/m(2) ) duration was calculated between examination 1 and examination 5. Cox regression was used to analyze time to disability. RESULTS: 204 participants developed disability (incidence rate=7.9 per 1,000 person-years). Obesity duration ranged from 0 to 22 years (mean of 2.0 years overall, 8.3 years for those with baseline obesity). Obesity duration increased risk of new disability (hazard ratio [HR] 1.07 per year of obesity; 95% confidence interval [CI] 1.05-1.09). This association was attenuated on further adjustment for baseline BMI (HR 1.03; 95% CI 1.00-1.06). CONCLUSIONS: Being obese for longer during mid-life increases the risk of later life disability over and above attained BMI. These results support the need for prevention of weight gain in young adults to avoid an increasing burden of physical disability in later life. PMID- 25451852 TI - Relevance of corpus callosum splenium versus middle cerebellar peduncle hyperintensity for FXTAS diagnosis in clinical practice. AB - Fragile X-associated tremor ataxia syndrome (FXTAS) is caused by FMR1 premutation. The features include ataxia, action tremor and middle cerebellar peduncle (MCP) hyperintensity, the latter being the only major radiological criterion in the diagnosis of definite FXTAS until very recently. The importance of corpus callosum splenium (CCS) hyperintensity was recently reported and this sign is now considered as an additional major radiological diagnostic criterion in the diagnosis of FXTAS. However, little is known about its relevance for the diagnosis of FXTAS in clinical practice. We report a practical justification of the relevance of CCS hyperintensity in parallel with MCP hyperintensity for the diagnosis of FXTAS. Clinical and radiological study of 22 FMR1 premutation carriers with neurological signs that may be encountered in FXTAS compared to series of patients with essential tremor, multiple system atrophy of cerebellar type, Parkinson's disease, Alzheimer's disease and stroke. Among the 22 patients with FMR1 premutation [17 men, 5 women; mean age, 63 +/- 7.5 (46-84)], 14 were diagnosed with definite FXTAS with the initial criteria. Considering CCS hyperintensity as a new major radiological criterion permitted the diagnosis of definite FXTAS in 3 additional patients. Overall CCS proved as frequent as MCP hyperintensity (64 versus 64 %), while 23 % of patients had CCS but not MCP hyperintensity, 14 % of patients had CCS hyperintensity but neither MCP, nor brainstem hyperintensity. In contrast with CCS hyperintensity, MCP hyperintensity proved less frequent in women than in men. CCS and MCP hyperintensity were more frequent in FXTAS than in the other neurodegenerative disorders. The combination of CCS and MCP hyperintensity was specific of FXTAS. We confirmed the relevance of CCS hyperintensity in FXTAS and we clarified its interest compared to MCP hyperintensity. Our results support the inclusion of CCS hyperintensity in the diagnostic criteria as a new major radiological criterion. PMID- 25451853 TI - Pompe disease presenting as an isolated generalized dilative arteriopathy with repeated brain and kidney infarcts. PMID- 25451851 TI - Intravenous thrombolysis or endovascular therapy for acute ischemic stroke associated with cervical internal carotid artery occlusion: the ICARO-3 study. AB - The aim of the ICARO-3 study was to evaluate whether intra-arterial treatment, compared to intravenous thrombolysis, increases the rate of favourable functional outcome at 3 months in acute ischemic stroke and extracranial ICA occlusion. ICARO-3 was a non-randomized therapeutic trial that performed a non-blind assessment of outcomes using retrospective data collected prospectively from 37 centres in 7 countries. Patients treated with endovascular treatment within 6 h from stroke onset (cases) were matched with patients treated with intravenous thrombolysis within 4.5 h from symptom onset (controls). Patients receiving either intravenous or endovascular therapy were included among the cases. The efficacy outcome was disability at 90 days assessed by the modified Rankin Scale (mRS), dichotomized as favourable (score of 0-2) or unfavourable (score of 3-6). Safety outcomes were death and any intracranial bleeding. Included in the analysis were 324 cases and 324 controls: 105 cases (32.4 %) had a favourable outcome as compared with 89 controls (27.4 %) [adjusted odds ratio (OR) 1.25, 95 % confidence interval (CI) 0.88-1.79, p = 0.1]. In the adjusted analysis, treatment with intra-arterial procedures was significantly associated with a reduction of mortality (OR 0.61, 95 % CI 0.40-0.93, p = 0.022). The rates of patients with severe disability or death (mRS 5-6) were similar in cases and controls (30.5 versus 32.4 %, p = 0.67). For the ordinal analysis, adjusted for age, sex, NIHSS, presence of diabetes mellitus and atrial fibrillation, the common odds ratio was 1.15 (95 % IC 0.86-1.54), p = 0.33. There were more cases of intracranial bleeding (37.0 versus 17.3 %, p = 0.0001) in the intra-arterial procedure group than in the intravenous group. After the exclusion of the 135 cases treated with the combination of I.V. thrombolysis and I.A. procedures, 67/189 of those treated with I.A. procedures (35.3 %) had a favourable outcome, compared to 89/324 of those treated with I.V. thrombolysis (27.4 %) (adjusted OR 1.75, 95 % CI 1.00-3.03, p = 0.05). Endovascular treatment of patients with acute ICA occlusion did not result in a better functional outcome than treatment with intravenous thrombolysis, but was associated with a higher rate of intracranial bleeding. Overall mortality was significantly reduced in patients treated with endovascular treatment but the rates of patients with severe disability or death were similar. When excluding all patients treated with the combination of I.V. thrombolysis and I.A. procedures, a potential benefit of I.A. treatment alone compared to I.V. thrombolysis was observed. PMID- 25451854 TI - Clinical characteristics related to worsening of motor function assessed by the Unified Parkinson's Disease Rating Scale in the elderly population. AB - There is evidence that nigrostriatal pathology may at least partly underlie mild Parkinsonian signs. We evaluated whether an increase in the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) could be predicted by the presence of risk and prodromal markers for neurodegenerative diseases in elderly individuals without those diseases. Therefore, we analyzed the UPDRS-III score and various risk and prodromal markers known to antecede neurodegenerative diseases in a population-based cohort comprising 807 individuals free of neurodegenerative diseases at baseline. After 5 years, eight persons (1.0 %) were diagnosed with Parkinson's Disease (PD). Of those, seven (87.5 %) had motor worsening >=3 points on the UPDRS-III from baseline to follow-up, one had two points increase. Of the 788 people without PD, 568 (72.1 %) showed no increase in the UPDRS-III scale, 220 (27.9 %) had >=1 point increase and out of these 104 (13.2 %) had an increase of >=3 points in the UPDRS-III score after 5 years. We identified an age >60 years (relative risk, RR = 1.7; confidence interval, CI 1.3-2.1) and the occurrence of >=2 risk factors (RR = 1.5; CI 1.2-1.9) as possible predictors of motor progression. After 5 years, individuals with an increase in the UPDRS-III score had more often a one-sided reduced arm swing (p < 0.001) and identified less odors in the Sniffin' sticks test (p < 0.041) than persons with stable motor performance. Our data support the assumption that progression of Parkinsonian signs assessed by the UPDRS-III parallels the development of prodromal markers for neurodegenerative diseases in the elderly population. PMID- 25451855 TI - Characterization of sleep disorders in patients with E200K familial Creutzfeldt Jakob disease. AB - The largest cluster of E200K familial Creutzfeldt-Jakob disease (fCJD) which occurs is in Jews of Libyan origin in Israel. Insomnia is a very common early complaint in those patients and may even be the presenting symptom. The aim of this study was to assess and characterize sleep pathology in E200K fCJD patients. To do so, sleep studies of 10 consecutive fCJD patients were compared with those of 39 age and gender-matched controls. All patients presented pathological sleep characterized by fragmentation of sleep, loss of sleep spindles and reduced REM sleep amount. Respiration was characterized by irregular rhythm, periodic breathing, apneas and hypopneas, either central or obstructive. EMG recordings revealed repeated movements in sleep, with loss of REM atonia. Comparing to controls, a significant decrease of total sleep time, sleep efficacy and slow wave sleep as well as a significant increase in the number of awakenings, apnea hypopnea index and mixed and central apneas were evident in CJD patients. Comparison of two sequential sleep studies in one patient revealed a 40 % reduction of the total sleep time, a 40 % reduction in sleep efficacy and a 40 fold increase of the number of arousals in the second study. A significant correlation was found between the disease severity, as reflected by the CJD Neurological Scale and Periodic leg movement index. These definite and characteristic sleep pathologies in patients with fCJD associated with the E200K mutation may serve as a new diagnostic tool in the disease. PMID- 25451856 TI - A nairovirus isolated from African bats causes haemorrhagic gastroenteritis and severe hepatic disease in mice. AB - Bats can carry important zoonotic pathogens. Here we use a combination of next generation sequencing and classical virus isolation methods to identify novel nairoviruses from bats captured from a cave in Zambia. This nairovirus infection is highly prevalent among giant leaf-nosed bats, Hipposideros gigas (detected in samples from 16 individuals out of 38). Whole-genome analysis of three viral isolates (11SB17, 11SB19 and 11SB23) reveals a typical bunyavirus tri-segmented genome. The strains form a single phylogenetic clade that is divergent from other known nairoviruses, and are hereafter designated as Leopards Hill virus (LPHV). When i.p. injected into mice, the 11SB17 strain causes only slight body weight loss, whereas 11SB23 produces acute and lethal disease closely resembling that observed with Crimean-Congo Haemorrhagic Fever virus in humans. We believe that our LPHV mouse model will be useful for research on the pathogenesis of nairoviral haemorrhagic disease. PMID- 25451857 TI - Tissue engineered buccal mucosa for urethroplasty: progress and future directions. AB - PURPOSE: Autologous buccal mucosa is commonly utilized in the surgical treatment of urethral strictures. Extensive strictures require a larger quantity of tissue, which may lead to donor site morbidity. This review assesses progress in producing tissue engineered buccal mucosa as an alternative graft material. RESULTS: Few clinical studies have introduced cells onto biological or synthetic scaffolds and implanted resulting constructs in patients. The available studies show that buccal mucosa cells on acellular human dermis or on collagen matrix lead to good acute stage tissue integration. Urothelial cells on a synthetic substrate also perform well. However while some patients do well many years post grafting, others develop stricture recurrence. Acellular biomaterials used to treat long urethral defects in animals commonly lead to fibrosis. CONCLUSIONS: Tissue engineered buccal mucosa shows promise as a substitute for native tissue. The fibrosis which occurs months post-implantation may reflect the underlying disease process recurring in these patients. PMID- 25451859 TI - Changes in muscle activity in typically developing children walking with unilaterally induced equinus. AB - BACKGROUND: Distinguishing changes in lower limb muscle activation during gait caused by abnormal motor control or adaptations to the presence of a fixed equinus remains a challenge. The objective of this study was to determine a threshold degree of equinus at which changes in muscle activity occur and to characterize adaptive patterns of muscle activity in typically developing children walking with unilateral induced equinus. METHODS: Ten typically developing children were included. A customized orthosis was fitted to the right ankle. Five conditions of dorsiflexion limitation were evaluated: 10 degrees dorsiflexion, 0 degrees , 10 degrees , 20 degrees of plantar flexion and maximum plantar flexion. Muscle activity of the rectus femoris, vastus lateralis, hamstring, tibialis anterior and soleus muscles of both limbs was recorded. FINDINGS: Significant changes in muscle activation and co-activation occurred from 10 degrees of plantar flexion in the orthosis limb and from maximum plantar flexion in the contralateral limb. Soleus activation occurred prematurely in terminal swing and increased with the degree of equinus. Tibialis anterior activation was increased during initial and midswing and was decreased during terminal swing. From the -20 degrees condition, hamstring activation was increased during the loading response. Vastus lateralis and rectus femoris activation was increased during stance phase. Similar changes in tibialis anterior and soleus activation occurred on the contralateral side. Changes in co activation occurred in the soleus/tibialis anterior muscle pair in both limbs. INTERPRETATION: This study provides indications regarding changes in muscle activity during simulation of equinus gait which should be helpful for therapeutic decision making. PMID- 25451860 TI - Lumbar kinematic variability during gait in chronic low back pain and associations with pain, disability and isolated lumbar extension strength. AB - BACKGROUND: Chronic low back pain is a multifactorial condition with many dysfunctions including gait variability. The lumbar spine and its musculature are involved during gait and in chronic low back pain the lumbar extensors are often deconditioned. It was therefore of interest to examine relationships between lumbar kinematic variability during gait, with pain, disability and isolated lumbar extension strength in participants with chronic low back pain. METHODS: Twenty four participants with chronic low back pain were assessed for lumbar kinematics during gait, isolated lumbar extension strength, pain, and disability. Angular displacement and kinematic waveform pattern and offset variability were examined. FINDINGS: Angular displacement and kinematic waveform pattern and offset variability differed across movement planes; displacement was highest and similar in frontal and transverse planes, and pattern variability and offset variability higher in the sagittal plane compared to frontal and transverse planes which were similar. Spearman's correlations showed significant correlations between transverse plane pattern variability and isolated lumbar extension strength (r=-.411) and disability (r=.401). However, pain was not correlated with pattern variability in any plane. The r(2) values suggested 80.5% to 86.3% of variance was accounted for by other variables. INTERPRETATION: Considering the lumbar extensors role in gait, the relationship between both isolated lumbar extension strength and disability with transverse plane pattern variability suggests that gait variability may result in consequence of lumbar extensor deconditioning or disability accompanying chronic low back pain. However, further study should examine the temporality of these relationships and other variables might account for the unexplained variance. PMID- 25451858 TI - Stem cells as drug delivery methods: application of stem cell secretome for regeneration. AB - Mesenchymal stem cells (MSCs) are a unique cell population defined by their ability to indefinitely self-renew, differentiate into multiple cell lineages, and form clonal cell populations. It was originally thought that this ability for broad plasticity defined the therapeutic potential of MSCs. However, an expanding body of recent literature has brought growing awareness to the remarkable array of bioactive molecules produced by stem cells. This protein milieu or "secretome" comprises a diverse host of cytokines, chemokines, angiogenic factors, and growth factors. The autocrine/paracrine role of these molecules is being increasingly recognized as key to the regulation of many physiological processes including directing endogenous and progenitor cells to sites of injury as well as mediating apoptosis, scarring, and tissue revascularization. In fact, the immunomodulatory and paracrine role of these molecules may predominantly account for the therapeutic effects of MSCs given that many in vitro and in vivo studies have demonstrated limited stem cell engraftment at the site of injury. While the study of such a vast protein array remains challenging, technological advances in the field of proteomics have greatly facilitated our ability to analyze and characterize the stem cell secretome. Thus, stem cells can be considered as tunable pharmacological storehouses useful for combinatorial drug manufacture and delivery. As a cell-free option for regenerative medicine therapies, stem cell secretome has shown great potential in a variety of clinical applications including the restoration of function in cardiovascular, neurodegenerative, oncologic, and genitourinary pathologies. PMID- 25451862 TI - Persistence of long term isokinetic strength deficits in subjects with lateral ankle sprain as measured with a protocol including maximal preloading. AB - BACKGROUND: The assessment of muscle function is a cornerstone in the management of subjects who have sustained a lateral ankle sprain. The ankle range of motion being relatively small, the use of preloading allows to measure maximal strength throughout the whole amplitude and therefore to better characterize ankle muscles weaknesses. This study aimed to assess muscle strength of the injured and uninjured ankles in subjects with a lateral ankle sprain, to document the timeline of strength recovery, and to determine the influence of sprain grade on strength loss. METHODS: Maximal torque of the periarticular muscles of the ankle in a concentric mode using a protocol with maximal preloading was tested in 32 male soldiers at 8 weeks and 6 months post-injury. FINDINGS: The evertor muscles of the injured ankles were weaker than the uninjured ones at 8 weeks and 6 months post-injury (P<0.0001, effect size=0.31-0.42). Muscle weaknesses also persisted in the plantarflexors of the injured ankles at 8 weeks (P=0.0014, effect size=0.52-0.58) while at 6 months, only the subjects with a grade II sprain displayed such weaknesses (P<0.0001, effect size 0.27-0.31). The strength of the invertor and dorsiflexor muscles did not differ between sides. INTERPRETATION: The use of an isokinetic protocol with preloading demonstrates significant but small strength deficits in the evertor and plantarflexor muscles. These impairments may contribute to the high incidence of recurrence of lateral ankle sprain in very active individuals. PMID- 25451861 TI - Re-evaluating the functional implications of the Q-angle and its relationship to in-vivo patellofemoral kinematics. AB - BACKGROUND: The Q-angle is widely used clinically to evaluate individuals with anterior knee pain. Recent studies have questioned the utility of this measure and have suggested that a large Q-angle may not be associated with lateral patellofemoral translation, as often assumed. The objective of this study was to determine: 1) how accurately the Q-angle represents the line-of-action of the quadriceps and 2) if adding active quadriceps contraction or a bent knee position to the measurement of the Q-angle improves its reliability, accuracy, and association with patellofemoral kinematics. METHODS: The study included individuals diagnosed with chronic idiopathic patellofemoral pain and control subjects (n=43 and n=30 knees). Three measures of the clinical Q-angle (straight- and bent-knee with relaxed quadriceps and straight-knee with maximum isometric quadriceps contraction) were obtained with a goniometer and compared to a fourth MR-based measure of Q-angle. Patellofemoral kinematics were derived from dynamic cine-phase contrast images, acquired while subjects extended/flexed their knee from approximately 0 degrees and 45 degrees . FINDINGS: The Q-angle did not represent the line-of-action of the quadriceps. The average difference between each clinical and the MR-based Q-angle ranged from 5 degrees to 8 degrees . These differences varied greatly across subjects (range: -28.5 degrees to 3.9(o)). Adding an active quadriceps contraction or a bent knee position, did not improve the reliability of the Q-angle. An increased Q-angle correlated to medial patellar displacement and tilt (r=0.38-0.54, P<0.001) in the cohort with anterior knee pain. INTERPRETATION: Clinicians are cautioned against using the Q-angle to infer patellofemoral kinematics. PMID- 25451864 TI - Discrepancies in perceptions of close relationships of young adolescents: a risk for psychopathology? AB - Discrepancies between children and partners (e.g., parents, friends, peers) in reports of social functioning and self-other relationships are common in clinical practice and in research. However, it is not clear whether children's biased perceptions of self-other relationships, relative to the reports of partners, are predominantly a reflection of underlying psychological dysfunctions or whether these biased perceptions present a risk factor for subsequent problematic development. This longitudinal study therefore examined the effects of adolescent mother disagreement and adolescent-best friend disagreement in perceptions of close (dyadic) relationships on the development of psychopathology in early adolescence. The sample included 497 thirteen year-old adolescents of Dutch Caucasian backgrounds (57 % boys; 41 % at high risk for externalizing problems), their mothers, and self-nominated best friends. The participants completed reports of positive dyadic relationship quality (warmth) in Grade 7. Discrepancy scores were based on difference scores between the adolescents' versus the partners' reports. Both absolute disagreement and direction of disagreement (i.e., over- or underestimation relative to the relationship partner) were examined. Self-reported symptoms of depression and mother-reported aggression were assessed in Grade 7, 8, and 9. Absolute disagreement in perceptions of warmth between adolescents and best friends was significantly related to higher baseline levels of aggression. No significant effects of discrepancy scores on growth curves of symptoms of depression and aggression were found. The results may suggest that it is more important for adolescents to develop positive perceptions of close relationships than to agree with partners on the quality of the relationship. PMID- 25451865 TI - UV-visible and (1)H-(15)N NMR spectroscopic studies of colorimetric thiosemicarbazide anion sensors. AB - Four model thiosemicarbazide anion chemosensors containing three N-H bonds, substituted with phenyl and/or 4-nitrophenyl units, were synthesised and studied for their anion binding abilities with hydroxide, fluoride, acetate, dihydrogen phosphate and chloride. The anion binding properties were studied in DMSO and 9 : 1 DMSO-H2O by UV-visible absorption and (1)H/(13)C/(15)N NMR spectroscopic techniques and corroborated with DFT studies. Significant changes were observed in the UV-visible absorption spectra with all anions, except for chloride, accompanied by dramatic colour changes visible to the naked eye. These changes were determined to be due to the deprotonation of the central N-H proton and not due to hydrogen bonding based on (1)H/(15)N NMR titration studies with acetate in DMSO-d6-0.5% water. Direct evidence for deprotonation was confirmed by the disappearance of the central thiourea proton and the formation of acetic acid. DFT and charge distribution calculations suggest that for all four compounds the central N-H proton is the most acidic. Hence, the anion chemosensors operate by a deprotonation mechanism of the central N-H proton rather than by hydrogen bonding as is often reported. PMID- 25451863 TI - Subcellular compartmentalization in protoplasts from Artemisia annua cell cultures: engineering attempts using a modified SNARE protein. AB - Plants are ideal bioreactors for the production of macromolecules but transport mechanisms are not fully understood and cannot be easily manipulated. Several attempts to overproduce recombinant proteins or secondary metabolites failed. Because of an independent regulation of the storage compartment, the product may be rapidly degraded or cause self-intoxication. The case of the anti-malarial compound artemisinin produced by Artemisia annua plants is emblematic. The accumulation of artemisinin naturally occurs in the apoplast of glandular trichomes probably involving autophagy and unconventional secretion thus its production by undifferentiated tissues such as cell suspension cultures can be challenging. Here we characterize the subcellular compartmentalization of several known fluorescent markers in protoplasts derived from Artemisia suspension cultures and explore the possibility to modify compartmentalization using a modified SNARE protein as molecular tool to be used in future biotechnological applications. We focused on the observation of the vacuolar organization in vivo and the truncated form of AtSYP51, 51H3, was used to induce a compartment generated by the contribution of membrane from endocytosis and from endoplasmic reticulum to vacuole trafficking. The artificial compartment crossing exocytosis and endocytosis may trap artemisinin stabilizing it until extraction; indeed, it is able to increase total enzymatic activity of a vacuolar marker (RGUSChi), probably increasing its stability. Exploring the 51H3-induced compartment we gained new insights on the function of the SNARE SYP51, recently shown to be an interfering-SNARE, and new hints to engineer eukaryote endomembranes for future biotechnological applications. PMID- 25451866 TI - Monitoring IgA multiple myeloma: immunoglobulin heavy/light chain assays. AB - BACKGROUND: The use of electrophoresis to monitor monoclonal immunoglobulins migrating in the beta fraction may be difficult because of their comigration with transferrin and complement proteins. METHODS: Immunoassays specific for IgGkappa, IgGlambda, IgAkappa, IgAlambda, IgMkappa, and IgMlambda heavy/light chain (HLC) were validated for use in the clinical laboratory. We assessed sample stability, inter- and intraassay variability, linearity, accuracy, and reference intervals for all 6 assays. We tested accuracy by verifying that the sum of the concentrations for the HLC-pairs accounted for the total immunoglobulins in each of 129 healthy sera, and that the HLC-pair ratios (rHLCs) were outside the reference interval in 97% of 518 diagnostic multiple myeloma (MM) samples. RESULTS: We assessed diagnostic samples and posttreatment sera in 32 IgG and 30 IgA patients for HLC concentrations, rHLC, and total immunoglobulins and compared these nephelometry results with serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE). In sample sets from patients with IgG MM, the sensitivity of SPEP was almost the same as for rHLC, and no additional advantage was conferred by running HLC assays. In pre- and posttreatment samples from patients with IgA MM, the SPEP, rHLC, and IFE identified clonality in 28%, 56%, and 61%, respectively. In addition, when M-spikes were quantifiable, the concentration of the involved HLC was linearly related to that of the SPEP M spike, with a slope near 1. CONCLUSIONS: The use of IgA HLC assays for monitoring beta-migrating IgA monoclonal proteins can substitute for the combination of SPEP, IFE, and total IgA quantification. PMID- 25451867 TI - Hot cells, raise your hands. PMID- 25451869 TI - DNA/RNA preparation for molecular detection. AB - BACKGROUND: Effective upstream preparation of nucleic acid (NA) is important for molecular techniques that detect unique DNA or RNA sequences. The isolated NA should be extracted efficiently and purified away from inhibitors of a downstream molecular assay. CONTENT: Many NA sample preparation techniques and commercial kits are available. Techniques for cell lysis and isolation or purification of NA were discovered in early NA characterization studies, evolved in the 20th century with molecular techniques, and still serve as the foundation for current methods. Advances in solid phase extraction methods with nonhazardous chemicals and automated systems have changed the way NA is prepared. Factors to consider when selecting NA preparation methods for molecular detection include lysis (from sources as diverse as human cells, viruses, bacterial spores, or protozoan oocysts), DNA vs RNA, sample background, appropriate preparation chemicals, and required detection limits. Methods are also selected on the basis of requirements for a particular application, such as sample volume or removal of inhibitors. Sometimes tradeoffs are made. SUMMARY: Good automated and manual methods are available to effectively prepare NA for molecular detection in under an hour. Numerous systems are available for various applications, including techniques that are flexible for multiple sample types, are capable of processing large batches, can be performed in <10 min, or that can yield high-purity NA. When methods are selected using the most applicable combination of lysis isolation efficiency and concentration, NA preparation can be very effective, even for molecular detection of multiple targets from the same sample. PMID- 25451868 TI - Comparison of cardiac troponins I and T measured with high-sensitivity methods for evaluation of prognosis in atrial fibrillation: an ARISTOTLE substudy. AB - BACKGROUND: Although cardiac troponin is associated with outcomes in atrial fibrillation (AF), the complementary prognostic information provided by cardiac troponin I (cTnI) and cTnT is unknown. This study investigated the distribution, determinants, and prognostic value of cTnI and cTnT concentrations in patients with AF. METHODS: Samples were collected. At the time of randomization, we analyzed cTnI and cTnT concentrations of 14806 AF patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial using high-sensitivity assays. Correlations (Spearman), determinants (multivariable linear regression), and outcomes (adjusted Cox models and c-statistics) were investigated. RESULTS: Concentrations of cTnI and cTnT were correlated (r = 0.70) and measurable in most participants [cTnI 98.5% (median 5.4 ng/L, >=99th percentile in 9.2%) and cTnT 93.5% (median 10.9 ng/L, >=99th percentile in 34.4%)]. Renal impairment was the most important factor affecting the concentrations of both troponins. cTnI increase was more associated with heart failure, vascular disease, and persistent/permanent AF, and cTnT with age, male sex, and diabetes. Over a median 1.9 years of follow-up, patients with both troponins above the median had significantly higher risk for stroke/systemic embolism [hazard ratio (HR) 1.72 (95% CI 1.31-2.27)], cardiac death [3.14 (2.35 4.20)], and myocardial infarction [2.99 (1.78-5.03)] than those with both troponins below median (all P < 0.005). Intermediate risks were observed when only 1 troponin was above the median. When combined with clinical information, each marker provided similar prognostication and had comparable c-index. CONCLUSIONS: cTnI and cTnT concentrations are moderately correlated and measurable in plasma of most AF patients. The risk of stroke and cardiovascular events is highest when both troponins are above median concentrations. Each troponin provides comparable prognostic information when combined with clinical risk factors. ClinicalTrials.gov/NCT00412984. PMID- 25451870 TI - Bioinformatics for clinical next generation sequencing. AB - BACKGROUND: Next generation sequencing (NGS)-based assays continue to redefine the field of genetic testing. Owing to the complexity of the data, bioinformatics has become a necessary component in any laboratory implementing a clinical NGS test. CONTENT: The computational components of an NGS-based work flow can be conceptualized as primary, secondary, and tertiary analytics. Each of these components addresses a necessary step in the transformation of raw data into clinically actionable knowledge. Understanding the basic concepts of these analysis steps is important in assessing and addressing the informatics needs of a molecular diagnostics laboratory. Equally critical is a familiarity with the regulatory requirements addressing the bioinformatics analyses. These and other topics are covered in this review article. SUMMARY: Bioinformatics has become an important component in clinical laboratories generating, analyzing, maintaining, and interpreting data from molecular genetics testing. Given the rapid adoption of NGS-based clinical testing, service providers must develop informatics work flows that adhere to the rigor of clinical laboratory standards, yet are flexible to changes as the chemistry and software for analyzing sequencing data mature. PMID- 25451871 TI - Molecular cloning of precursors for TEP-1 and TEP-2: The GGNG peptide-related peptides of a prosobranch gastropod, Thais clavigera. AB - TEP (Thais excitatory peptide)-1 and TEP-2 are molluscan counterparts of annelidan GGNG-peptides, identified in a neogastropod, Thais clavigera (Morishita et al., 2006). We have cloned two cDNAs encoding TEP-1 and TEP-2 precursor protein, respectively, by the standard molecular cloning techniques. Predicted TEP-1 precursor protein consists of 161 amino acids, while predicted TEP-2 precursor protein has 118 amino acids. Only a single copy of TEP was found on the respective precursor. The semi-quantitative RT-PCR showed that expression of TEP 1 was high in sub-esophageal, pleural, pedal and visceral ganglia, while it was low in supra-esophageal ganglion. By contrast, expression level of TEP-2 was high in pedal and visceral ganglia. In situ hybridization visualized different subsets of TEP-1 and TEP-2 expressing neurons in Thais ganglia. For example, supra esophageal ganglion contained many TEP-2 expressing neuron, but not TEP-1 expressing ones. These results suggest that expression of TEP-1 and TEP-2 is differently regulated in the Thais ganglia. PMID- 25451873 TI - [Urologist 2.0: how to lead the change]. AB - Modern urology started about 150 years ago in France, with a strong contribution made by other European countries including Italy. The figure of the modern urologist is linked to a technological evolution but also to the contribution made by great men who have played a crucial role in the evolution of the surgical technique and in the clinical approach to the discipline. An analysis of the evolution of the surgical technique of radical prostatectomy can be paradigmatic in describing the development and, above all, the direction of the hyper specialization concerning the urologic discipline. To this kind of centrifugal fragmentation is associated a fragmentation at the scientific level which can be defined as centripetal, with a multiplicity of national societies that ultimately complicate the management of the urology discipline. This pathway, made up of divisions and hyper-specializations, contrasts with another less travelled one, which foresees a drastic revision of the figure of the urologist and of the urological discipline in its totality. One which places the patient at the center of the scene, and not only his pathology. Urology cannot become the mere execution of surgical acts, and the objective of our National Residency Programmes should not be solely to form the "perfect surgeon", but to produce a complete specialist able to manage prevention and a correct diagnosis and to guarantee a therapeutic approach including the uro-andrological follow-up of the patient. It is necessary that both basic research and translational research become an integral part of the formative baggage of the young urologist. PMID- 25451872 TI - Synthesis of analogs of peptides from Buthus martensii scorpion venom with potential antibiotic activity. AB - Five analogs of a natural peptide (BmKn1) found in the venom of scorpion Buthus martensii Karsh have been synthesized and tested to compare their antimicrobial and hemolytic activity with the wild type. Circular dichroism spectra show that these peptides form an alpha helix structure and its amino acid positions predict an amphipathic nature. Results show that increasing hydrophobicity by substituting successively positions 5 and 9 of the sequence (on the hydrophobic side of the helix) with alanine, valine and leucine enhances antimicrobial activity and hemolysis. When changes are done on positions 7 and 10 (on the hydrophilic side) by introducing more positive charges with addition of lysine, both activities also increase. However, when negative charges are introduced instead (with glutamic acids), antimicrobial activity is observed but hemolysis is reduced to zero under the concentrations studied. Although strong inhibitory activity begins at low concentrations (10MUg/mL), some peptides level off inhibition and no change is observed as concentrations are increased. PMID- 25451874 TI - [Pain in urology: pathophysiological aspects of pain and chronicity.] AB - Chronic pain has been traditionally defined by pain duration, but this approach has limited empirical support and does not account for chronic pain multidimensionality. Defining chronic pain solely by duration is based on the view that acute pain signals potential tissue damage, whereas chronic pain results from central sensitization in which pain is sustained after nociceptive inputs have diminished. Chronic urological pain is a prevalent condition, which can represent a major challenge to health care providers due to its complex aetiology and poor response to therapy. In most cases, clear signs of on-going tissue trauma, inflammation or infection are not present. Despite this, more underhanded pathophysiological mechanisms, affecting the urinary system or other pelvic organ systems (musculoskeletal, neurologic, urologic, gynaecologic) and some psychological aspects may be present. In this article, some pathophysiological aspects of visceral pain are discussed; the definition of 'chronic pain', the mechanism of action of drugs used in the treatment of pain and the rationale for association therapy are also reviewed. PMID- 25451875 TI - [Urinary tract infections.] AB - Urinary tract infections (UTI) are amongst the most frequent bacterial infections and therefore are responsible for a significant fraction of antibiotic use, thus carrying a relevant social and economic burden. UTI may present as benign, uncomplicated cystitis or severe, life-threatening urosepsis. Due to the heterogeneity of UTI the European Section of Infections in Urology (ESIU) has introduced a phenotypical classification, based upon the clinical presentation, the risk factors and the antibiotic susceptibility of the causative pathogens. Presence of risk factors is a key point and could change dramatically the course of UTI. In scenario of uroseptic patients, early diagnosis and therapy are mandatory and a successful decompression of the obstructed urinary tract is predictor of survival. The multidisciplinary approach and a timely microbiological characterization are critical in this context. PMID- 25451876 TI - [Adequacy of antimicrobial therapy in urinary tract infections (UTI).] AB - Urinary tract infections are one of the most common reasons for antimicrobial prescriptions, however urine cultures are often unavailable and the choice of antibiotics is therefore empiric. The ideal antimicrobial agent must have specific pharmacokinetic and pharmacodynamic characteristics and an adequate spectrum of activity in order to obtain the potential eradication of the pathogen from the site of infection, minimizing the risk of recurrences and ensuring the best safety profile. There are several factors to be considered in the therapy choice: the type of infection, the increasing presence of extended-spectrum beta lactamase (ESBL) producing bacteria showing resistance to most antibiotics and the problem of the bacterial internalization, that is a frequent cause of treatment failure and early recurrences. Prulifloxacin is a recent oral fluoroquinolone antibiotic approved in several European countries for the treatment of lower urinary tract infections and shows some interesting advantages in comparison with other antibiotics. PMID- 25451877 TI - [Medico-legal notes in urology] AB - In recent years, claims for damages for medical liability have significantly increased. This implies that urologists need to know at least some basic concepts and updates regarding Forensic Medicine. Hence it is mandatory that, beyond the requirements of the law, every physician is covered by insurance liability for medical professionals. With the aim to protect and help the urologist in response to a claim for damages, the Italian Society of Urology has established and activated a "urological first aid", which any member can turn to in a moment of need. In the case of an accident, urologists can contact the "urological first aid" otherwise they can send a letter within 3 days to his/her insurance company, which will analyze the complaint and prepare a brief statement of defence and choose a civil lawyer specializing in medical professional liability. In this paper we will deal with some concepts of forensic medicine, distinguishing between public-liability and penal setting. PMID- 25451878 TI - Isolation and characterization of cancer stem cells in renal cell carcinoma. AB - Recently, several studies have investigated the presence of cancer stem cells in kidney cancer, performed characterization, and compared their profile with the normal stem cell counterparts. CD133, alone or in combination with other molecular markers, has been used to isolate normal and cancer stem cells from different sources, including renal carcinoma; however, it is still a matter of debate whether CD133+ cells really represent the main tumorigenic population within the heterogeneous pool of cancer cells that characterize this tumor. In this review, we summarize and discuss the current findings related to cancer stem cells isolation in renal cell carcinoma, focusing on controversies about their origin and the identification of a specific marker. PMID- 25451879 TI - Bilateral metachronous adrenal metastases of operated renal cell carcinoma. AB - BACKGROUND: The adrenal glands are among the target metastatic organs due to the potential of systemic metastasis from renal cell carcinoma (RCC). The number of cases with bilateral metachronous metastases from RCC is about twenty. PATIENTS AND METHODS: A sixty-one-year-old man presented for routine checks due to an operated left renal tumor (clear cell carcinoma, PT2N0M0, Fuhrman grade III). The patient underwent 18FDG-PET/CT in order to re-stage the disease upon observation of bilateral adrenal masses on ultrasound and CT. A bilateral metachronous metastasis was found, whose SUVmax was 6.7 x 50 x 38 x 20 cm on the left adrenal gland, and another metastasis whose SUVmax was 5.5 40 x 29 x 20 on the right adrenal gland. RESULTS: The patient underwent a CT-guided biopsy and diagnosis of adrenal metastasis was made by pathological and immunohistochemical examination. The laparoscopic treatment was performed. CONCLUSIONS: There is no standard approach for the treatment of these patients in the literature. But metastasectomy is the most realistic part of the treatment. Making definitive diagnosis with biopsy, following hormonal examination and treatment with minimally invasive adrenal sparing surgical procedure containing frozen-section are strongly recommended. Cancer specific survival significantly increases with metastasectomy. PMID- 25451881 TI - Cystic presentation of a renal medullary carcinoma in a young woman. AB - Renal medullary carcinoma (RMC) is a rare tumor, originating in the epithelial papillary cells, that primarily affects young black men with sickle cell trait. We report the case of a 29-year-old Caucasian woman, who at ultrasound showed a cystic mass at the right kidney, with a vascular pattern at the level of the cystic wall. A CT-guided biopsy of the lesion was performed, revealing the presence of unspecified tumor cells. A total nephrectomy was then performed. Microscopically, a tumor resulting from the epithelial papillary cells was observed; several areas of lymphoplasmacytic infiltrates were seen at the junction between the normal kidney tissue and the tumor, and a renal medullary carcinoma was diagnosed. Six months later, the patient developed multiple pulmonary metastases and started chemotherapy with Carboplatin, Paclitaxel and Gemcitabine. The patient died after 27 months of follow-up.RMC is a tumor that usually occurs in young black men, at an average age of 25 years with extremes of 11 and 39 years. Sickle-cell disease or sickle-cell trait is often present. The longest documented survival (until now) for RMC was 16 months. The best treatment is surgery with enlarged nephrectomy. There are still no appropriate chemotherapy protocols. PMID- 25451882 TI - Nosocomial urinary tract infections: A review. AB - Nosocomial urinary tract infections are a common complication in healthcare systems worldwide. A review of the literature was performed in June 2014 using the Medical Literature Analysis and Retrieval System Online (MEDLINE) database, through either PubMed or Ovid as a search engine, to identify publications regarding nosocomial urinary tract infections (NUTIs) definition, epidemiology, etiology and treatment.According to current definitions, more than 30% of nosocomial infections are urinary tract infections (UTIs). A UTI is defined 'nosocomial' (NUTI) when it is acquired in any healthcare institution or, more generally, when it is related to patient management. The origin of nosocomial bacteria is endogenous (the patient's flora) in two thirds of the cases. Patients with indwelling urinary catheters, those undergoing urological surgery and manipulations, long-stay elderly male patients and patients with debilitating diseases are at high risk of developing NUTIs. All bacterial NUTIs should be treated, whether the patient is harboring a urinary catheter or not. The length of treatment depends on the infection site. There is abundance of important guidance which should be considered to reduce the risk of NUTIs (hand disinfection with instant hand sanitizer, wearing non-sterile gloves permanently, isolation of infected or colonized catheterized patients). Patients with asymptomatic bacteriuria can generally be treated initially with catheter removal or catheter exchange, and do not necessarily need antimicrobial therapy. Symptomatic patients should receive antibiotic therapy. Resistance of urinary pathogens to common antibiotics is currently a topic of concern. PMID- 25451883 TI - Does the emptier have no clothes? Diabetes, gastric emptying, and the syndrome of gastroparesis. PMID- 25451884 TI - Ambulatory monitoring for gastroesophageal reflux disease: where do we stand? PMID- 25451885 TI - Myths and mysteries about staging hepatic fibrosis by fibroscan. PMID- 25451886 TI - Catheter ablation of tachycardia arising from the pulmonary venous atrium after surgical repair of congenital heart disease. AB - BACKGROUND: Tachycardia arising from the pulmonary venous atrium (PVA) has not been adequately characterized in the setting of surgically repaired congenital heart disease (CHD). OBJECTIVE: The purpose of this study was to determine the mechanisms, approach, and outcomes of catheter ablation of PVA tachycardia after CHD repair. METHODS: The adult CHD procedural database was searched for consecutive ablation procedures over a 4-year period. Procedural characteristics of the population with tachycardia arising from the PVA were compared to those without PVA tachycardia. Groups were classified as (1) biventricular CHD, (2) single ventricle, or (3) d-transposition of the great arteries (DTGA)-baffle. RESULTS: Complete 3-dimensional mapping was possible for 113 of 124 sustained tachycardias during 81 procedures. Of these, 31 (19%) arose from the PVA, including 11 (15%) tachycardias in biventricular CHD, 8 (31%) in single ventricle, and 12 (80%) in DTGA-baffle procedures. Intra-atrial reentrant tachycardia was less frequently observed in the PVA vs the systemic venous atrium (SVA) (P = .012). Independent predictors of PVA tachycardia were absence of biventricular CHD (odds ratio 0.19, confidence interval 0.05-0.64, P = .010) and ipsilateral atrial surgery (odds ratio 15.7, confidence interval 4.8-59.9, P <.001). PVA procedure duration was greater than SVA-only procedures (median 5.3 hours vs 4.0 hours, P = .012), but acute success was similar (87% vs 82%, respectively, P = NS). CONCLUSION: PVA tachycardia is not unusual after surgical repair of CHD. Predictors include ipsilateral atrial surgery and absence of biventricular CHD. Such procedures involve increased complexity and unique tachycardia substrates but appear equally amenable to catheter ablation. PMID- 25451887 TI - Laparoscopic guided epicardial access. PMID- 25451889 TI - Risk factors for development and progression of nonproliferative retinopathy in normoalbuminuric patients with type 1 diabetes. AB - BACKGROUND: The aim of this study was to evaluate risk factors for development and progression of nonproliferative retinopathy (NPR) in normoalbuminuric patients with type 1 diabetes mellitus (T1DM). METHODS: A total of 223 T1DM with normal renal function and normoalbuminuria were included in this study and followed for 48 months. Photodocumented retinopathy status was made according to the EURODIAB protocol. Urinary albumin excretion rate (UAE) was measured from at least two 24-h urine samples. Possible risk factors for development or progression of NPR were examined in backward stepwise Cox's multiple regression analysis. RESULTS: The majority of patients (70%) had no retinopathy while 67 (30%) had NPR at baseline. Patients with NPR were older, had longer duration of diabetes, higher systolic blood pressure, BMI, resting heart rate, UAE and lower estimated glomerular filtration rate (p <= 0.04 for all). After 48 months 24 patients (10.7%) developed NPR or progressed to proliferative retinopathy. Systolic blood pressure (HR 1.03, CI 1.01-1.05, p=0.02), UAE (HR 1.14, CI 1.07 1.21, p<0.001), and resting heart rate (HR 1.05, CI 1.01-1.09, p=0.006) were significantly associated with development or progression of NPR. CONCLUSIONS: Our results suggest that retinopathy is present and may progress in T1DM even when coexisting renal disease is excluded. Normoalbuminuric T1DM requires close monitoring for the early detection of retinopathy, especially if they have a higher UAE, systolic blood pressure and resting heart rate. PMID- 25451888 TI - Comprehensive phenotyping of regulatory T cells after liver transplantation. AB - Regulatory T cells (Tregs) play an important role in controlling alloreactivity after solid organ transplantation, but they may also impair antiviral immunity. We hypothesized that the Treg frequency and the Treg phenotype are altered in hepatitis C virus (HCV)-infected recipients of liver transplantation (LT) with possible prognostic implications. Tregs from 141 individuals, including healthy individuals, LT recipients with or without persistent HCV infections, and nontransplant patients with chronic HCV, were studied. A comprehensive phenotypic analysis was performed with multicolor flow cytometry, which included standard Treg markers [CD4(+), CD25(hi), CD127(-), and FoxP3(+) in addition to HLA DR, CCR7, CD45RA, CD62L, CD49d, CD39, ICOS and LAP-TGFbeta stainings. Healthy individuals and LT patients displayed similar Treg frequencies and largely comparable Treg phenotypes, which were stable over time after transplantation. In contrast, Tregs with a CD45RA(-) CCR7(-) effector phenotype were enriched in LT recipients with chronic HCV versus HCV-negative transplant patients. HCV infection, rather than LT, altered the expression of functional markers on Tregs. A principal component analysis revealed distinct Treg phenotypes in HCV-infected LT recipients with rejection and patients with recurrent graft HCV. In conclusion, Treg phenotypes are altered in HCV-infected LT patients. An investigation of Tregs may possibly help to distinguish recurrent HCV from graft rejection. Further functional studies are needed to define the role of Tregs in determining the balance between antiviral and allogenic immunity. PMID- 25451890 TI - Effects of miglitol, sitagliptin, and initial combination therapy with both on plasma incretin responses to a mixed meal and visceral fat in over-weight Japanese patients with type 2 diabetes. "the MASTER randomized, controlled trial". AB - AIM: To assess changes in circulating incretin levels and body fat compositions with initial combination therapy with alpha-glucosidase inhibitor and dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes (T2D). METHODS: In this multicenter open-label 24-week trial, Japanese over-weight (BMI >= 25 kg/m(2)) patients with T2D not taking medication or taking metformin and/or sulfonylurea were randomly assigned to receive either 50mg of miglitol three times a day (M, n=14), 50mg of sitagliptin once a day (S, n=14), or a combination of both (M+S, n=13). Changes in plasma incretin levels during a meal tolerance test (MTT) and body fat composition with impedance method were evaluated. RESULTS: During MTT, postprandial plasma glucose levels decreased more after M+S than after M or S, and postprandial serum insulin levels decreased significantly after M and M+S whereas they increased after S. After M, active gastric inhibitory polypeptide (aGIP) decreased significantly at 30 min despite a significant increase at 120 min. After S, aGIP levels increased significantly throughout the MTT. After M+S, aGIP increased significantly at 0 and 120 min despite of significant decrease at 30 min. M+S further enhanced postprandial active glucagon-like peptide-1 levels during MTT than S did. Total body fat mass decreased significantly after M and M+S. Visceral fat mass decreased significantly only after M+S. Serum adiponectin increased significantly only after M+S. CONCLUSIONS: In over-weight patients with T2D, M+S may have a beneficial effect on adiposity with relation to these different effects on two incretins. PMID- 25451891 TI - Mortality of patients with type 2 diabetes in Taiwan: a 10-year nationwide follow up study. AB - AIMS: This study aims to investigate the distribution of underlying-causes-of death (UCOD) among deceased patients with type 2 diabetes mellitus (DM) in Taiwan and assess the influence of socio-demographic characteristics on mortality in type 2 DM patients. METHODS: A cohort study on patients who sought medical care for type 2 DM from 2000 to 2008 was conducted on 65,599 type 2 DM patients retrieved from the 1-million beneficiaries randomly selected from Taiwan's National Health Insurance Database. The study cohort was then linked to Taiwan's Mortality Registry to ascertain the patients who died between 2000 and 2009. We examined the distribution of UCOD in the deceased subjects. The hazard ratios of mortality in relation to socio-demographic characteristics were estimated from Cox proportional hazard model. RESULTS: The leading causes of death in type 2 DM included neoplasm (22.68%), cardiovascular diseases (21.46%), and endocrine diseases (20.78%). Male gender and older ages were associated with significantly increased risk of mortality. In addition, lower urbanization and greater co morbidity score were also significantly associated with an increased risk of mortality with a dose-gradient pattern. CONCLUSIONS: Neoplasm accounts for the largest portion (22.68%) of deaths in type 2 DM patients closely followed by with cardiovascular diseases (21.46%). An increased risk of mortality in type 2 DM patients in lower urbanized areas may reflect poor diabetes care in these areas. PMID- 25451893 TI - Type 2 diabetes care in North Karelia Finland: do area-level socio-economic factors affect processes and outcomes? AB - AIMS: This research assessed the impact of area-level socio-economic factors on the prevalence and outcomes of type 2 diabetes in North Karelia, Finland. METHODS: All type 2 diabetes patients (n=10,204) were analyzed from the regional electronic patient database during the years 2011 and 2012. The patient's individual laboratory data was used to assess whether hemoglobin A1c (HbA1c) was measured and whether the recommended level of HbA1c <7% (<53 mmol/l) was achieved. The variables describing socio-economic characteristics of postal code areas were retrieved from the database of Statistics Finland. Linear and logistic regression analyses were used to determine associations. RESULTS: HbA1c had been measured in 83% of patients. Over 70% of those with HbA1c measured reached the recommended level of HbA1c. The worse the area-level socio-economic status, the more probably HbA1c was not measured. Achieving the recommended HbA1c level was associated with being female and having a better area-level socio-economic status. The age-adjusted prevalence of type 2 diabetes was not linearly dependent on the socio-economic circumstances of the postal code areas. CONCLUSIONS: This study shows that socio-economic factors at the small area-level are associated with treatment outcomes. The information from the regional electronic patient database linked with area-level socio-economic information could be effectively utilized to improve diabetes care. PMID- 25451892 TI - Effect of maternal use of flaxseed oil during pregnancy and lactation on glucose metabolism and pancreas histomorphometry of male offspring from diabetic rats. AB - AIM: Investigate if the maternal use of flaxseed oil prevents pancreatic alterations in the offspring of diabetic mothers. METHODS: Diabetes was induced in female wistar rats (n=12) by a high-fat diet and low-dose of streptozotocin. After the confirmation of the diabetes (glucose >300 mg/dL), rats were mated and once pregnancy was confirmed, they were allocated into three groups (n=6): high fat group (HFG); flaxseed oil group (FOG); and control group (CG) (nondiabetic rats). At weaning, male offspring (n=12/group) received a standard chow diet. The animals were euthanized in two phases: at 100 and at 180 days, (n=6/group). The pancreas was collected for histomorphometric and immunohistochemistry analysis. RESULTS: HFG showed hypertrophy of pancreatic islets at 100 and at 180 days (p<0.0001), while the FOG offspring had islets with smaller diameters compared to HFG at both phases of sacrifice (p<0.0001). HFG had a lower percentage of small islets when compared to CG and FOG, which had a higher percentage when compared to HFG (p=0.0053) at 100 days. At 180 days HFG showed higher percentage of larger islets (p=0.00137) and lower percentage of smaller islets (p=0.00112), when compared to FOG. HFG showed lower islet insulin immunodensity at 100 days (p<0.0001) and 180 days (p<0.0001), whereas FOG was similar to CG (p<0.0001) at 100 days and higher at 180 days (p<0.0001). CONCLUSIONS: Flaxseed oil reduced the damage caused by maternal hyperglycemia, promoting normal pancreas histomorphometry and beta cell mass. PMID- 25451894 TI - Efficacy of shock wave therapy on chronic diabetic foot ulcer: a single-blinded randomized controlled clinical trial. AB - OBJECTIVE: This study was conducted to evaluate the efficacy of extracorporeal shock wave therapy (ESWT) on the healing rate, wound surface area and wound bed preparation in chronic diabetic foot ulcers (DFU). METHODS: Thirty eight patients with 45 chronic DFU were randomly assigned into; the ESWT-group (19 patients/24 ulcers) and the control-group (19 patients/21 ulcers). Blinded therapist measured wound surface area (WSA), the percentage of reduction in the WSA, rate of healing and wound bed preparation at baseline, after the end of the interventions (W8), and at 20-week follow-up (W20). The ESWT group received shock wave therapy twice per week for a total of eight treatments. Each ulcer was received ESWT at a frequency of 100 pulse/cm(2), and energy flux density of 0.11mJ/cm(2). All patients received standardized wound care consisting of debridement, blood glucose control agents, and footwear modification for pressure reduction. RESULTS: The overall clinical results showed completely healed ulcers in 33.3% and 54% in ESWT-groups and 14.28% and 28.5% in the control group after intervention (W8), and at follow-up (W20) respectively. The average healing time was significantly lower (64.5 +/- 8.06 days vs 81.17 +/- 4.35 days, p<0.05) in the ESWT-group compared with the control group. CONCLUSION: ESWT-treated ulcers had a significant reduction in wound size and median time required for ulcer healing, with no adverse reactions. So, the ESWT is advocated as an adjunctive therapy in chronic diabetic wound. PMID- 25451895 TI - Uncontrolled diabetes mellitus: prevalence and risk factors among people with type 2 diabetes mellitus in an Urban District of Karachi, Pakistan. AB - AIMS: This study aimed to explore the prevalence of, and factors associated with, uncontrolled diabetes mellitus (UDM) in a community setting in Pakistan. METHODOLOGY: A single-center, cross-sectional study, conducted in a community based specialized care center (SCC) for diabetes in District Central Karachi, in 2003, registered 452 type 2 DM participants, tested for HbA1c and interviewed face-to-face for other information. Logistic regression analysis was conducted to identify factors associated with UDM. RESULTS: Prevalence of UDM among diabetes patients was found to be 38.9% (95% CI: 34.4-43.4%). Multivariable logistic regression model analysis indicated that age <50 years (OR: 1.9; 95% CI: 1.2 2.9), being diagnosed in a hospital (vs. a clinic) (OR: 1.8; 95% CI: 1.1-2.8), diabetes information from a doctor or nurse only (vs. multiple sources) (OR: 1.8; 95% CI: 1.2-2.9), higher monthly treatment cost (OR: 1.3; 95% CI: 1.1-1.6; for every extra 500 PKR), and higher consumption of tea (OR: 1.5; 95% CI: 1.0-2.2; for every 2 extra cups) were independently associated with UDM. CONCLUSION: The prevalence of UDM was approximately 39% among persons with type 2 diabetes visiting a community based SCC for diabetes. Modifiable risk factors such as sources of diabetes information and black tea consumption can be considered as potential targets of interventions in Karachi. PMID- 25451896 TI - Diabetes and cancer mortality: a multifaceted association. AB - In a large cohort of subjects with diabetes cancer mortality increased by 30%, possibly due to lower survival, reverse causality, and an etiologic role of diabetes in cancer. A two-fold increased mortality from liver and pancreatic cancer was confirmed in both genders irrespective of follow-up period or disease duration. PMID- 25451899 TI - Gender differences and time trends in incidence and prevalence of type 2 diabetes in Sweden--a model explaining the diabetes epidemic worldwide today? AB - Gender differences in type 2 diabetes in Sweden were studied based on a literature search. The male predominance in 1940s (male/female ratio 1.2-1.4 in the ages 10-55 years) increased over time especially in the age 45-64 years with a male/female ratio up to 2. PMID- 25451898 TI - Validation of the Spanish version of the Problem Areas in Diabetes (PAID-SP) Scale. AB - This study aimed to assess the psychometric properties of the Spanish version of the Problem Areas in Diabetes (PAID-SP) Scale. Data were collected from patients with type 1 and type 2 diabetes. The findings suggested that the PAID-SP is a reliable and valid measure of diabetes-specific emotional problems. PMID- 25451900 TI - Decreased A20 mRNA and protein expression in peripheral blood mononuclear cells in patients with type 2 diabetes and latent autoimmune diabetes in adults. AB - AIMS: A20 is a negative regulator of nuclear factor kappa B activation and the central gatekeeper in inflammation and immunity. While its role in type 1 diabetes has been widely studied, its expression level in immune cells from type 2 diabetes (T2D) and latent autoimmune diabetes in adult (LADA) patients remains unclear. This study aimed to clarify whether the expression of A20 is altered in patients with T2D or LADA. METHODS: Quantitative real-time polymerase chain reaction and western blotting were utilized to determine the expression of A20 mRNA and protein respectively in peripheral blood mononuclear cells (PBMCs) from patients with T2D (n=36) or LADA (n=17) and sex- and age-matched healthy controls (n=34). RESULTS: The mRNA and protein expression of A20 in PBMCs from T2D and LADA patients was significantly decreased compared with healthy controls (P<0.05). Furthermore, A20 mRNA and protein expression was significantly lower in newly diagnosed T2D patients (<=1 year since diagnosis) than in patients with a long T2D duration (>1 year since diagnosis) (P<0.05). CONCLUSIONS: Our results suggest that decreased expression of A20 in PBMCs may be involved in the pathogenesis of diabetes, and targeting A20 may offer a potential therapeutic tool in the treatment of diabetes. PMID- 25451901 TI - Association between post-dinner dietary intakes and nocturnal hypoglycemic risk in adult patients with type 1 diabetes. AB - AIMS: To describe (i) current bedtime nutritional practices and (ii) the association between post-dinner dietary intake and the occurrence of non-severe nocturnal hypoglycemia (NH) in real-life conditions among adult patients with type 1 diabetes using insulin analogs. METHODS: One hundred adults (median [interquartile range]: age 46.4 [36.0-55.8] years, HbA1c 7.9 [7.3-8.6] % (63 [56 70] mmol/mol)) using multiple daily injections (n=67) or insulin pump (n=33) wore a blinded continuous glucose monitoring system and completed a food diary for 72 h. RESULTS: NH occurred on 28% of 282 nights analyzed. (i) Patients reported post dinner dietary intakes on 63% of the evenings. They injected rapid-acting insulin boluses on 64 occasions (23% of 282 evenings). These insulin boluses were mostly injected with (n=37) dietary intakes. (ii) Post-dinner dietary intake was not associated with NH occurrence in univariate analyses. In multivariate analyses, the injection of rapid-acting insulin modulated the association between post dinner dietary intake and NH: with insulin, post-dinner carbohydrate intake was positively associated with NH (odds ratio (OR): 1.16 [95% confidence interval, CI: 1.04-1.29] per 5g increase, p=0.008); without insulin, post-dinner protein intake was inversely associated with NH occurrence (OR [95% CI]: 0.88 [0.78-1.00] per 2g increase, p=0.048). CONCLUSIONS: NH remains frequent in adults with type 1 diabetes. There is a complex relationship between post-dinner dietary intake and NH occurrence, including the significant role of nutrient content and rapid acting insulin injection that requires further investigation. PMID- 25451902 TI - Subsequent ischemic events associated with lower extremity amputations in patients with type 2 diabetes: a population-based cohort study. AB - AIMS: To explore the risk of subsequent ischemic events in type 2 diabetes mellitus (DM) patients who had lower extremity amputations (LEAs) were compared with DM patients without LEAs. METHODS: A population-based cohort study was conducted utilizing the data of 2011 patients with newly diagnosed DM with and without LEAs sourced from the Longitudinal Health Insurance Database 2000 (LHID 2000) of the Taiwan National Health Insurance (NHI) program between 1996 and 2008. MAIN OUTCOME MEASURES: Relative risks (RRs), hazard ratios (HRs), and disease-free rates for various ischemic events. RESULTS: In contrast with the comparison group, subjects with LEAs were more likely to reside in less urbanized areas, be white collar workers, and have higher DM-related costs (p<0.05). Subjects with LEAs also had significantly higher risks of developing ischemic diseases, except intestinal ischemia. In the multivariate Cox proportional hazards regression model analysis, the HR of end-stage renal disease (ESRD) was highest (HR=3.91, 95% CI=2.38-6.42), followed by embolism and thrombosis (HR=3.47, 95% CI=2.12-5.67), other peripheral vascular diseases (HR=3.11, 95% CI=2.11-4.57), atherosclerosis (HR=2.64, 95% CI=1.60-4.35), retinopathy (HR=2.24, 95% CI=1.79-2.80), cerebral ischemia (HR=1.61, 95% CI=1.25-2.06), and coronary artery disease (HR=1.44, 95% CI=1.18-1.74). CONCLUSIONS: DM patients with LEAs had significantly higher risks for subsequent ischemic events, particularly among men. The greatest risk detected among DM patients with LEA's was for end-stage renal disease. Disease free survival rates also indicated that the course of generalized DM ischemia proceeded despite treatment. PMID- 25451903 TI - Quality of life in Danish children and adolescents with type 1 diabetes treated with continuous subcutaneous insulin infusion or multiple daily injections. AB - AIMS: The aims of the study were to compare health-related quality of life (HRQoL) in a National Danish population of children and adolescents with type 1 diabetes (T1D) treated with either continuous subcutaneous insulin injection (CSII) or multiple daily insulin injections (MDI), and to investigate whether HRQoL assessments were influenced by treatment duration. METHODS: Participants were recruited through the Danish Registry for Diabetes in Childhood and Adolescence. A total of 700 children and adolescents (360 girls), 8-17 years, were included. Of these, 295 were treated with CSII (160 for more than one year) and 405 with MDI (238 for more than one year). Participants and their parents completed the Pediatric Quality of Life Inventory Diabetes and Generic Module. HbA1c was analyzed centrally. RESULTS: Parents reported children and adolescents on CSII for more than one year to have less diabetes-related symptoms and worry, less problems in communicating diabetes, and better generic functioning compared with those on MDI. Children and adolescents on CSII for more than one year reported less diabetes-related symptoms, but more treatment problems, and better generic functioning in all subscales except social functioning compared with those on MDI for more than one year. Comparing those on CSII and MDI for less than one year, no differences in HRQoL ratings were found, apart from better rating of treatment barriers in the MDI group. CONCLUSIONS: This Danish national study on HRQoL in children and adolescents on CSII or MDI showed better HRQoL in children and adolescents on long time CSII, particularly concerning generic HRQoL. PMID- 25451897 TI - Perceptions and experiences of using automated bolus advisors amongst people with type 1 diabetes: a longitudinal qualitative investigation. AB - AIMS: We explored people's reasons for, and experiences of, using bolus advisors to determine insulin doses; and, their likes/dislikes of this technology. SUBJECTS AND METHODS: 42 people with type 1 diabetes who had received instruction in use of bolus advisors during a structured education course were interviewed post-course and 6 months later. Data were analysed thematically. RESULTS: Participants who considered themselves to have poor mathematical skills highlighted a gratitude for, and heavy reliance on, advisors. Others liked and chose to use advisors because they saved time and effort calculating doses and/or had a data storage facility. Follow-up interviews highlighted that, by virtue of no longer calculating their doses, participants could become deskilled and increasingly dependent on advisors. Some forgot what their mealtime ratios were; others reported a misperception that, because they were pre-programmed during courses, these parameters never needed changing. Use of data storage facilities could hinder effective review of blood glucose data and some participants reported an adverse impact on glycaemic control. DISCUSSION: While participants liked and perceived benefits to using advisors, there may be unintended consequences to giving people access to this technology. To promote effective use, on-going input and education from trained health professionals may be necessary. PMID- 25451905 TI - Portugal meets Eurodiale: better late than never. AB - Understanding the quality of diabetic foot care delivery is essential. The Eurodiale consortium addressed subjects' characteristics, diabetic foot ulcer prognostic predictors and clinical outcomes, in 10 European countries. We analyzed the results of a specialized Portuguese diabetic foot clinic at the light of the ones from Eurodiale. PMID- 25451904 TI - Effect of neighborhood factors on diabetes self-care behaviors in adults with type 2 diabetes. AB - OBJECTIVE: The objective of this study was to identify latent variables for neighborhood factors and diabetes self-care and examine the effect of neighborhood factors on diabetes self-care in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: 615 subjects were recruited from an academic medical center and a Veterans affairs medical center in the southeastern United States. Validated scales were used to assess neighborhood factors and diabetes-related self-care. Confirmatory factor analysis (CFA) was used to determine the latent constructs. Structural equation modeling (SEM) was then used to assess the relationship between neighborhood factors and diabetes self-care. RESULTS: Based on a theoretical framework, CFA yielded four latent variables for neighborhood factors (neighborhood violence, access to healthy food, social support, and neighborhood esthetics) and one latent variable diabetes self-care (including diet, exercise, foot care, blood sugar testing and medication adherence). SEM showed that social support (r=0.28, p<0.001) and access to healthy foods (r= 0.16, p=0.003) were significantly associated with self-care behaviors, while neighborhood violence (r=-0.06, p<0.001) and esthetics (r=-0.07, p=0.278) were not chi(2) (180, N=611)=192, p=0.26, RMSEA=0.01, CFI=0.999). In the final trimmed model, social support (r=0.31, p<0.001) and access to healthy foods (r=-0.20, p<0.001) remained significantly associated with self-care behaviors chi(2) (76, N=611)=60, p=0.91, RMSEA=0.00, CFI=1.0). CONCLUSION: This study developed latent factors for neighborhood characteristics and diabetes self-care and found that social support and access to healthy foods were significantly associated with diabetes self-care and should be considered as targets for future interventions. PMID- 25451906 TI - Increase in body mass index during pregnancy and risk of gestational diabetes. AB - We recorded gestational weight gain (GWG) and change in body mass index (BMI) at 28 weeks gestation in 343 vs. 339 women with and without gestational diabetes (GDM). GDM was associated with a greater increment in BMI, but not with increased GWG in kilograms. PMID- 25451907 TI - Sustained weight loss one year after group telephone intervention: 3-year results from the SHINE study. AB - A telephone delivered translation of the DPP weight loss program, delivered by trained primary care staff over 2 years, resulted in significant weight loss for patients with metabolic syndrome. Participants in groups (conference calls) continued to lose weight a full year after the program ended, while those called individually regained. PMID- 25451908 TI - Understanding geographical inequities in diabetes: multilevel evidence from 114,755 adults in Sydney, Australia. AB - Multilevel analysis revealed the odds of having diabetes varied geographically by 42% among 114,755 persons. Approximately 9% of this variation was attributable to behavioural risk factors, 41% due to health status and obesity, 26% due to socioeconomic circumstances and 13% to country of birth. Contextual risk factors warrant future investigation. PMID- 25451909 TI - Pharmacist managed diabetes and cardiovascular risk reduction clinic in kidney transplant recipients: bridging the gap in care transition. AB - The purpose was to assess the feasibility of a care transition intervention for kidney transplant recipients (KTRs) with diabetes. Results document improved quality indicators and reduced resource utilization. These findings imply that a care transition intervention for KTRs with diabetes is feasible and associated with improved patient outcomes. PMID- 25451910 TI - Investigation of a lifestyle change strategy for high-risk women with a history of gestational diabetes. AB - Fifty-nine women with recent gestational diabetes participated in a randomized controlled trial to assess the feasibility and efficacy of a pragmatic diabetes risk reduction intervention. Intervention participants achieved improvements in energy, total and saturated fats, and carbohydrate intake, but no change in physical activity. Recruitment was challenging and below expectations. PMID- 25451911 TI - Glycaemic control is harder to achieve than blood pressure or lipid control in Irish adults with type 1 diabetes. AB - We sought to determine the attainment of targets for glycaemic control and vascular risk reduction in an Irish cohort of T1DM adults. Of 797 patients (53% male, mean age 40.3 +/- 14.8 years, HbA1c 8.5 +/- 1.6% (69.6 +/- 17.8 mmol mol( 1))), 15%, 68% and 62% achieved targets for HbA1c, blood pressure and LDL cholesterol, respectively. PMID- 25451912 TI - Ethnic specific differences in survival of patients with type 2 diabetes: analysis of data collected from an Australian multi-ethnic cohort over a 25 year period. AB - AIMS: To examine the survival of patients with type 2 diabetes from 7 ethnic groups, living in the shared environment of an Australian city. METHODS: Hazard ratio of death (HR) after diagnosis of diabetes was compared between Anglo-Celtic (n=5433), Indigenous Australian (n=439), Pacific Islander (n=354), Mediterranean (n=3138), Arabic (n=768), Indian (n=702) and Chinese (n=1632) patients who live in metropolitan Sydney. Mortality was ascertained by data-linkage with the Australian National Death Index. The modulating effects of glycaemic control, diabetes/vascular complications and risk factors, year of diabetes diagnosis and duration of diabetes on ethnic differences were analysed by Cox regression. Socio economic status and competence in English were also examined. RESULTS: There were significant differences in survival between the ethnic groups; the Indigenous Australians had the highest HR for death (2.3, 95% CI 1.7-3.0) and the Chinese the lowest (0.4, 95% CI 0.4-0.5). The survival of the Anglo-Celtics (HR 1) was surprisingly poorer than for Indian (0.6, 95% CI 0.5-0.8), Arab (0.7, 95% CI 0.6 0.8) and Mediterranean groups (0.8, 95% CI 0.7-0.9). Prevalence of smoking and albuminuria were strongly associated with HR. The better survival of Chinese and Arab and the worse survival of Indigenous Australians remained after adjustment of risk factors. Need for an interpreter was a favourable risk factor for survival. CONCLUSIONS: Ethnicity is a significant determinant of survival in type 2 diabetes and this is substantially but not completely mediated by smoking and vascular risk factors. The favourable impact associated with less competence in English may represent a Healthy-migrant effect. PMID- 25451913 TI - A systematic review and meta-analysis of exercise interventions in adults with type 1 diabetes. AB - AIMS: Conflicting evidence exists regarding the benefits of physical activity for long-term blood glucose control in adults with type 1 diabetes (T1D). The object of this systematic review was to determine the effects of physical activity on long-term blood glucose control in T1D adults. METHODS: PubMed/Medline, Embase, CENTRAL, SPORTdiscus, Global Health and ICTRP were searched up to October 2013 for randomized trials of aerobic or resistance exercise training in T1D adults. Exercises had to be performed at least twice weekly for a minimum of two months. The primary outcome was glycated hemoglobin (HbA1c). Secondary outcomes included cardiorespiratory fitness and insulin dose. RESULTS: Six randomized trials were identified (323 adults); sample sizes ranged from n=6 to n=148 participants receiving the intervention. Five trials had an unknown risk of bias; one trial was deemed to be at high risk of bias. Exercise frequency varied from twice weekly to daily, with intensities (50-90% VO2peak), and session durations (20-120 min) varying widely. Four trials reported HbA1c, which decreased with exercise training (mean difference [MD] -0.78% (-9 mmol/mol), 95% CI -1.14 (-13 mmol/mol) to -0.41 (-5 mmol/mol); p<0.0001; I(2) 0%) compared with controls. Exercise training improved cardiorespiratory fitness by 3.45 ml/kg/min (95% CI 0.59 to 6.31, p=0.02, I(2) 0%) compared with controls. One trial reported an effect on insulin dose (MD -0.4U/kg, 95% CI -0.53 to -0.27, p<0.00001) compared to controls. CONCLUSION: There are currently insufficient well-designed studies to ascertain the true effect of exercise training on HbA1c in individuals with T1D, but current results are promising. PMID- 25451914 TI - Relationship between olfactory dysfunction and cognitive impairment in elderly patients with type 2 diabetes mellitus. AB - AIMS: Recent clinical studies identified the relation between olfactory dysfunction and cognitive impairment in the elderly without type 2 diabetes mellitus. The aim of the present study was to define the relation between olfactory function and cognition in elderly patients with type 2 diabetes mellitus. METHODS: The study participants comprised 250 elderly (age, 68-77, median 72) Japanese outpatient with type 2 diabetes mellitus free of clinically evident cognitive impairment. Olfactory and cognitive functions were evaluated by the Open Essence (OE) test and Mini-mental State Examination (MMSE), respectively. RESULTS: Based on the MMSE score, 62.0%, 24.4%, and 13.6% of the participants were considered to have no impairment, possible cognitive impairment and probable dementia, respectively. The OE test score of the probable dementia group was significantly lower than other groups. Furthermore, age and serum uric acid were significantly higher in the probable dementia group than other groups. Simple correlation analysis showed positive correlation between the MMSE score and diastolic blood pressure, education, OE test score, total cholesterol, LDL cholesterol, folic acid, and negative correlation with age, HbA1c, aspartate aminotransferase, serum adiponectin and urinary albumin excretion. Multivariate regression analysis showed that OE test score correlated significantly and independently with MMSE score (standardized coefficients beta=0.542, R(2)=0.478, P<0.01), in addition to education level, HbA1c and serum adiponectin. CONCLUSIONS: The results suggested the association of olfactory dysfunction with cognitive impairment in elderly patients with type 2 diabetes mellitus. PMID- 25451915 TI - Protection effect of [Gly14]-Humanin from apoptosis induced by high glucose in human umbilical vein endothelial cells. AB - AIMS: Humanin (HN) is known for its anti-apoptotic functions in neuronal cells. In this study, we sought to investigate the protective effect of [Gly14]-Humanin (HNG) in high glucose (HG)-induced apoptosis of human umbilical vein endothelial cells (HUVECs). METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to examine cell viability, DNA chromatin morphology was assessed using Hoechst 33342 staining, and the generation of intracellular reactive oxygen species (ROS) was assessed using the fluorescent probe dichlorofluorescein diacetate (DCFH-DA). The expression of poly ADP-ribose polymerase (PARP), the pro-apoptotic protein bax and the anti-apoptotic protein bcl-2 were examined using western blot analysis. The mRNA level of bax and bcl-2 were detected by quantitative Real-Time PCR. RESULTS: Compared with treatment with HG 72h, pretreatment with HNG for 3h significantly increased cell viability (P<0.001), reduced nuclear fluorescence of HUVECs (P<0.05), the levels of cleaved PARP (P<0.05), ROS formation (P<0.05) and the ratio of bax/bcl-2 (P<0.05) compared with treatment with HG for 72h. Quantitative Real-Time PCR showed that mRNA level of bax reduced (P<0.05) and mRNA level of bcl-2 increased (P<0.05) after pretreatment with HNG. CONCLUSIONS: Our results imply that HNG can protect HUVECs from apoptosis induced by HG through the bax/bcl-2 pathway. PMID- 25451917 TI - Structural advantage of sugar beet alpha-glucosidase to stabilize the Michaelis complex with long-chain substrate. AB - The alpha-glucosidase from sugar beet (SBG) is an exo-type glycosidase. The enzyme has a pocket-shaped active site, but efficiently hydrolyzes longer maltooligosaccharides and soluble starch due to lower Km and higher kcat/Km for such substrates. To obtain structural insights into the mechanism governing its unique substrate specificity, a series of acarviosyl-maltooligosaccharides was employed for steady-state kinetic and structural analyses. The acarviosyl maltooligosaccharides have a longer maltooligosaccharide moiety compared with the maltose moiety of acarbose, which is known to be the transition state analog of alpha-glycosidases. The clear correlation obtained between log Ki of the acarviosyl-maltooligosaccharides and log(Km/kcat) for hydrolysis of maltooligosaccharides suggests that the acarviosyl-maltooligosaccharides are transition state mimics. The crystal structure of the enzyme bound with acarviosyl-maltohexaose reveals that substrate binding at a distance from the active site is maintained largely by van der Waals interactions, with the four glucose residues at the reducing terminus of acarviosyl-maltohexaose retaining a left-handed single-helical conformation, as also observed in cycloamyloses and single helical V-amyloses. The kinetic behavior and structural features suggest that the subsite structure suitable for the stable conformation of amylose lowers the Km for long-chain substrates, which in turn is responsible for higher specificity of the longer substrates. PMID- 25451916 TI - Choline kinase beta mutant mice exhibit reduced phosphocholine, elevated osteoclast activity, and low bone mass. AB - The maintenance of bone homeostasis requires tight coupling between bone-forming osteoblasts and bone-resorbing osteoclasts. However, the precise molecular mechanism(s) underlying the differentiation and activities of these specialized cells are still largely unknown. Here, we identify choline kinase beta (CHKB), a kinase involved in the biosynthesis of phosphatidylcholine, as a novel regulator of bone homeostasis. Choline kinase beta mutant mice (flp/flp) exhibit a systemic low bone mass phenotype. Consistently, osteoclast numbers and activity are elevated in flp/flp mice. Interestingly, osteoclasts derived from flp/flp mice exhibit reduced sensitivity to excessive levels of extracellular calcium, which could account for the increased bone resorption. Conversely, supplementation of cytidine 5'-diphosphocholine in vivo and in vitro, a regimen that bypasses CHKB deficiency, restores osteoclast numbers to physiological levels. Finally, we demonstrate that, in addition to modulating osteoclast formation and function, loss of CHKB corresponds with a reduction in bone formation by osteoblasts. Taken together, these data posit CHKB as a new modulator of bone homeostasis. PMID- 25451918 TI - Topoisomerase II regulates the maintenance of DNA methylation. AB - The maintenance of DNA methylation in nascent DNA is a critical event for numerous biological processes. Following DNA replication, DNMT1 is the key enzyme that strictly copies the methylation pattern from the parental strand to the nascent DNA. However, the mechanism underlying this highly specific event is not thoroughly understood. In this study, we identified topoisomerase IIalpha (TopoIIalpha) as a novel regulator of the maintenance DNA methylation. UHRF1, a protein important for global DNA methylation, interacts with TopoIIalpha and regulates its localization to hemimethylated DNA. TopoIIalpha decatenates the hemimethylated DNA following replication, which might facilitate the methylation of the nascent strand by DNMT1. Inhibiting this activity impairs DNA methylation at multiple genomic loci. We have uncovered a novel mechanism during the maintenance of DNA methylation. PMID- 25451920 TI - The novel small leucine-rich protein chondroadherin-like (CHADL) is expressed in cartilage and modulates chondrocyte differentiation. AB - The constitution and biophysical properties of extracellular matrices can dramatically influence cellular phenotype during development, homeostasis, or pathogenesis. These effects can be signaled through a differentially regulated assembly of collagen fibrils, orchestrated by a family of collagen-associated small leucine-rich proteins (SLRPs). In this report, we describe the tissue specific expression and function of a previously uncharacterized SLRP, chondroadherin-like (CHADL). We developed antibodies against CHADL and, by immunohistochemistry, detected CHADL expression mainly in skeletal tissues, particularly in fetal cartilage and in the pericellular space of adult chondrocytes. In situ hybridizations and immunoblots on tissue lysates confirmed this tissue-specific expression pattern. Recombinant CHADL bound collagen in cell culture and inhibited in vitro collagen fibrillogenesis. After Chadl shRNA knockdown, chondrogenic ATDC5 cells increased their differentiation, indicated by increased transcript levels of Sox9, Ihh, Col2a1, and Col10a1. The knockdown increased collagen II and aggrecan deposition in the cell layers. Microarray analysis of the knockdown samples suggested collagen receptor-related changes, although other upstream effects could not be excluded. Together, our data indicate that the novel SLRP CHADL is expressed in cartilaginous tissues, influences collagen fibrillogenesis, and modulates chondrocyte differentiation. CHADL appears to have a negative regulatory role, possibly ensuring the formation of a stable extracellular matrix. PMID- 25451919 TI - Human liver cytochrome P450 3A4 ubiquitination: molecular recognition by UBC7 gp78 autocrine motility factor receptor and UbcH5a-CHIP-Hsc70-Hsp40 E2-E3 ubiquitin ligase complexes. AB - CYP3A4 is an abundant and catalytically dominant human liver endoplasmic reticulum-anchored cytochrome P450 enzyme engaged in the biotransformation of endo- and xenobiotics, including >50% of clinically relevant drugs. Alterations of CYP3A4 protein turnover can influence clinically relevant drug metabolism and bioavailability and drug-drug interactions. This CYP3A4 turnover involves endoplasmic reticulum-associated degradation via the ubiquitin (Ub)-dependent 26 S proteasomal system that relies on two highly complementary E2 Ub-conjugating-E3 Ub-ligase (UBC7-gp78 and UbcH5a-C terminus of Hsc70-interacting protein (CHIP) Hsc70-Hsp40) complexes, as well as protein kinases (PK) A and C. We have documented that CYP3A4 Ser/Thr phosphorylation (Ser(P)/Thr(P)) by PKA and/or PKC accelerates/enhances its Lys ubiquitination by either of these E2-E3 systems. Intriguingly, CYP3A4 Ser(P)/Thr(P) and ubiquitinated Lys residues reside within the cytosol-accessible surface loop and/or conformationally assembled acidic Asp/Glu clusters, leading us to propose that such post-translational Ser/Thr protein phosphorylation primes CYP3A4 for ubiquitination. Herein, this possibility was examined through various complementary approaches, including site directed mutagenesis, chemical cross-linking, peptide mapping, and LC-MS/MS analyses. Our findings reveal that such CYP3A4 Asp/Glu/Ser(P)/Thr(P) surface clusters are indeed important for its intermolecular electrostatic interactions with each of these E2-E3 subcomponents. By imparting additional negative charge to these Asp/Glu clusters, such Ser/Thr phosphorylation would generate P450 phosphodegrons for molecular recognition by the E2-E3 complexes, thereby controlling the timing of CYP3A4 ubiquitination and endoplasmic reticulum associated degradation. Although the importance of phosphodegrons in the CHIP targeting of its substrates is known, to our knowledge this is the first example of phosphodegron involvement in gp78-substrate recruitment, an important step in CYP3A4 proteasomal degradation. PMID- 25451921 TI - The tumor suppressor pVHL down-regulates never-in-mitosis A-related kinase 8 via hypoxia-inducible factors to maintain cilia in human renal cancer cells. AB - NEK8 (never in mitosis gene A (NIMA)-related kinase 8) is involved in cytoskeleton, cilia, and DNA damage response/repair. Abnormal expression and/or dysfunction of NEK8 are related to cancer development and progression. However, the mechanisms that regulate NEK8 are not well declared. We demonstrated here that pVHL may be involved in regulating NEK8. We found that CAK-I cells with wild type vhl expressed a lower level of NEK8 than the cells loss of vhl, such as 786 O, 769-P, and A-498 cells. Moreover, pVHL overexpression down-regulated the NEK8 protein in 786-O cells, whereas pVHL knockdown up-regulated NEK8 in CAK-I cells. In addition, we found that the positive hypoxia response elements (HREs) are located in the promoter of the nek8 sequence and hypoxia could induce nek8 expression in different cell types. Consistent with this, down-regulation of hypoxia-inducible factors alpha (HIF-1alpha or HIF-2alpha) by isoform-specific siRNA reduced the ability of hypoxia inducing nek8 expression. In vivo, NEK8 and HIF-1alpha expression were increased in kidneys of rats subjected to an experimental hypoxia model of ischemia and reperfusion. Furthermore, NEK8 siRNA transfection significantly blocked pVHL-knockdown-induced cilia disassembling, through impairing the pVHL-knockdown-up-regulated NEK8 expression. These results support that nek8 may be a novel hypoxia-inducible gene. In conclusion, our findings show that nek8 may be a new HIF target gene and pVHL can down-regulate NEK8 via HIFs to maintain the primary cilia structure in human renal cancer cells. PMID- 25451922 TI - BRCA1-associated protein 1 (BAP1) deubiquitinase antagonizes the ubiquitin mediated activation of FoxK2 target genes. AB - BRCA1-associated protein 1 (BAP1), which is frequently mutated in cancer, functions as a deubiquitinase (DUB) for histone H2A. Although BAP1 interacts with a transcriptional regulator, HCF-1, and transcription factors FoxK1 and FoxK2, how BAP1 controls gene expression remains unclear. This study investigates the importance of BAP1 DUB activity and the interactions with FoxK2 and HCF-1 in the regulation of FoxK2 target genes. We show that FoxK2 recruits BAP1 to the target genes through the forkhead-associated domain, which interacts with Thr(P)-493 on BAP1. BAP1, in turn, recruits HCF-1, thereby forming a ternary complex in which BAP1 bridges FoxK2 and HCF-1. BAP1 represses FoxK2 target genes, and this effect requires BAP1 DUB activity but not interaction with HCF-1. Importantly, BAP1 depletion causes up-regulation of FoxK2 target genes only in the presence of the Ring1B-Bmi1 complex, an E3 ubiquitin ligase for histone H2A, indicating an antagonizing role of BAP1 against Ring1B-Bmi1. Our findings suggest that BAP1 deficiency causes increased expression of target genes in a Ring1B-Bmi1-dependent manner. PMID- 25451923 TI - Structural model of the cytosolic domain of the plant ethylene receptor 1 (ETR1). AB - Ethylene initiates important aspects of plant growth and development through disulfide-linked receptor dimers located in the endoplasmic reticulum. The receptors feature a small transmembrane, ethylene binding domain followed by a large cytosolic domain, which serves as a scaffold for the assembly of large molecular weight complexes of different ethylene receptors and other cellular participants of the ethylene signaling pathway. Here we report the crystallographic structures of the ethylene receptor 1 (ETR1) catalytic ATP binding and the ethylene response sensor 1 dimerization histidine phosphotransfer (DHp) domains and the solution structure of the entire cytosolic domain of ETR1, all from Arabidopsis thaliana. The isolated dimeric ethylene response sensor 1 DHp domain is asymmetric, the result of different helical bending angles close to the conserved His residue. The structures of the catalytic ATP-binding, DHp, and receiver domains of ethylene receptors and of a homologous, but dissimilar, GAF domain were refined against experimental small angle x-ray scattering data, leading to a structural model of the entire cytosolic domain of the ethylene receptor 1. The model illustrates that the cytosolic domain is shaped like a dumbbell and that the receiver domain is flexible and assumes a position different from those observed in prokaryotic histidine kinases. Furthermore the cytosolic domain of ETR1 plays a key role, interacting with all other receptors and several participants of the ethylene signaling pathway. Our model, therefore, provides the first step toward a detailed understanding of the molecular mechanics of this important signal transduction process in plants. PMID- 25451924 TI - miR-638 regulates differentiation and proliferation in leukemic cells by targeting cyclin-dependent kinase 2. AB - MicroRNAs have been extensively studied as regulators of hematopoiesis and leukemogenesis. We identified miR-638 as a novel regulator in myeloid differentiation and proliferation of leukemic cells. We found that miR-638 was developmentally up-regulated in cells of myeloid but not lymphoid lineage. Furthermore, significant miR-638 down-regulation was observed in primary acute myeloid leukemia (AML) blasts, whereas miR-638 expression was dramatically up regulated in primary AML blasts and leukemic cell lines undergoing forced myeloid differentiation. These observations suggest that miR-638 might play a role in myeloid differentiation, and its dysregulation may contribute to leukemogenesis. Indeed, ectopic expression of miR-638 promoted phorbol 12-myristate 13-acetate- or all-trans-retinoic acid-induced differentiation of leukemic cell lines and primary AML blasts, whereas miR-638 inhibition caused an opposite phenotype. Consistently, miR-638 overexpression induced G1 cell cycle arrest and reduced colony formation in soft agar. Cyclin-dependent kinase 2 (CDK2) was found to be a target gene of miR-638. CDK2 inhibition phenotypically mimicked the overexpression of miR-638. Moreover, forced expression of CDK2 restored the proliferation and the colony-forming ability inhibited by miR-638. Our data suggest that miR-638 regulates proliferation and myeloid differentiation by targeting CDK2 and may serve as a novel target for leukemia therapy or marker for AML diagnosis and prognosis. PMID- 25451927 TI - Fusidic acid targets elongation factor G in several stages of translocation on the bacterial ribosome. AB - The antibiotic fusidic acid (FA) targets elongation factor G (EF-G) and inhibits ribosomal peptide elongation and ribosome recycling, but deeper mechanistic aspects of FA action have remained unknown. Using quench flow and stopped flow experiments in a biochemical system for protein synthesis and taking advantage of separate time scales for inhibited (10 s) and uninhibited (100 ms) elongation cycles, a detailed kinetic model of FA action was obtained. FA targets EF-G at an early stage in the translocation process (I), which proceeds unhindered by the presence of the drug to a later stage (II), where the ribosome stalls. Stalling may also occur at a third stage of translocation (III), just before release of EF G from the post-translocation ribosome. We show that FA is a strong elongation inhibitor (K50% ~ 1 MUm), discuss the identity of the FA targeted states, and place existing cryo-EM and crystal structures in their functional context. PMID- 25451926 TI - Vitamin A deficiency causes hyperglycemia and loss of pancreatic beta-cell mass. AB - We show that vitamin A (all-trans-retinol) (VA) is required both for the maintenance of pancreatic beta-cell and alpha-cell mass and for glucose stimulated insulin secretion in adult mice. Dietary VA deprivation (VAD) causes greatly decreased pancreatic VA levels, hyperglycemia, and reduced insulin secretion. Adult mice fed VAD diets display remodeling of the endocrine pancreas, marked beta-cell apoptosis, shifts to smaller islet size distributions, decreased beta-cell mass, increased alpha-cell mass, and hyperglucagonemia. Importantly, although we induced VAD in the entire animal, the pancreatic beta-cells are exquisitely sensitive to VAD-associated apoptosis compared with other cell types in other organs. VAD causes major reductions in levels of the VA intracellular binding protein Crbp1 and the retinoic acid-metabolizing enzyme Cyp26a1 specifically in larger islets, suggesting the use of these proteins as biomarkers for early endocrine mass abnormalities. In the VAD mice, the reductions in pancreatic islet sizes and the associated aberrant endocrine functions, which show similarities to the phenotype in advanced type 2 diabetes, result from reductions in pancreatic VA signaling. Reintroduction of dietary VA to VAD mice restores pancreatic VA levels, glycemic control, normal islet size distributions, beta-cell to alpha-cell ratios, endocrine hormone profiles, and RARbeta2 and RARgamma2 transcript levels. Restoration of beta-cell mass by reintroducing VA to VAD mice does not involve increased beta-cell proliferation or neogenesis. Pharmacologic modulation of pancreatic VA signaling should be explored for the preservation and/or restoration of pancreatic beta-cell mass and function in individuals with diabetes mellitus. PMID- 25451929 TI - Flies without trehalose. AB - Living organisms adapt to environmental changes through metabolic homeostasis. Sugars are used primarily for the metabolic production of ATP energy and carbon sources. Trehalose is a nonreducing disaccharide that is present in many organisms. In insects, the principal hemolymph sugar is trehalose instead of glucose. As in mammals, hemolymph sugar levels in Drosophila are regulated by the action of endocrine hormones. Therefore, the mobilization of trehalose to glucose is thought to be critical for metabolic homeostasis. However, the physiological role of trehalose as a hemolymph sugar during insect development remains largely unclear. Here, we demonstrate that mutants of the trehalose-synthesizing enzyme Tps1 failed to produce trehalose as expected but survived into the late pupal period and died before eclosion. Larvae without trehalose grew normally, with a slight reduction in body size, under normal food conditions. However, these larvae were extremely sensitive to starvation, possibly due to a local defect in the central nervous system. Furthermore, Tps1 mutant larvae failed to grow on a low-sugar diet and exhibited severe growth defects on a low-protein diet. These diet-dependent phenotypes of Tps1 mutants demonstrate the critical role of trehalose during development in Drosophila and reveal how animals adapt to changes in nutrient availability. PMID- 25451925 TI - Characterization of a Drosophila ortholog of the Cdc7 kinase: a role for Cdc7 in endoreplication independent of Chiffon. AB - Cdc7 is a serine-threonine kinase that phosphorylates components of the pre replication complex during DNA replication initiation. Cdc7 is highly conserved, and Cdc7 orthologs have been characterized in organisms ranging from yeast to humans. Cdc7 is activated specifically during late G1/S phase by binding to its regulatory subunit, Dbf4. Drosophila melanogaster contains a Dbf4 ortholog, Chiffon, which is essential for chorion amplification in Drosophila egg chambers. However, no Drosophila ortholog of Cdc7 has yet been characterized. Here, we report the functional and biochemical characterization of a Drosophila ortholog of Cdc7. Co-expression of Drosophila Cdc7 and Chiffon is able to complement a growth defect in yeast containing a temperature-sensitive Cdc7 mutant. Cdc7 and Chiffon physically interact and can be co-purified from insect cells. Cdc7 phosphorylates the known Cdc7 substrates Mcm2 and histone H3 in vitro, and Cdc7 kinase activity is stimulated by Chiffon and inhibited by the Cdc7-specific inhibitor XL413. Drosophila egg chamber follicle cells deficient for Cdc7 have a defect in two types of DNA replication, endoreplication and chorion gene amplification. However, follicle cells deficient for Chiffon have a defect in chorion gene amplification but still undergo endocycling. Our results show that Cdc7 interacts with Chiffon to form a functional Dbf4-dependent kinase complex and that Cdc7 is necessary for DNA replication in Drosophila egg chamber follicle cells. Additionally, we show that Chiffon is a member of an expanding subset of DNA replication initiation factors that are not strictly required for endoreplication in Drosophila. PMID- 25451928 TI - Significantly enhanced heme retention ability of myoglobin engineered to mimic the third covalent linkage by nonaxial histidine to heme (vinyl) in synechocystis hemoglobin. AB - Heme proteins, which reversibly bind oxygen and display a particular fold originally identified in myoglobin (Mb), characterize the "hemoglobin (Hb) superfamily." The long known and widely investigated Hb superfamily, however, has been enriched by the discovery and investigation of new classes and members. Truncated Hbs typify such novel classes and exhibit a distinct two-on-two alpha helical fold. The truncated Hb from the freshwater cyanobacterium Synechocystis exhibits hexacoordinate heme chemistry and bears an unusual covalent bond between the nonaxial His(117) and a heme porphyrin 2-vinyl atom, which remains tightly associated with the globin unlike any other. It seems to be the most stable Hb known to date, and His(117) is the dominant force holding the heme. Mutations of amino acid residues in the vicinity did not influence this covalent linkage. Introduction of a nonaxial His into sperm whale Mb at the topologically equivalent position and in close proximity to vinyl group significantly increased the heme stability of this prototype globin. Reversed phase chromatography, electrospray ionization-MS, and MALDI-TOF analyses confirmed the presence of covalent linkage in Mb I107H. The Mb mutant with the engineered covalent linkage was stable to denaturants and exhibited ligand binding and auto-oxidation rates similar to the wild type protein. This indeed is a novel finding and provides a new perspective to the evolution of Hbs. The successful attempt at engineering heme stability holds promise for the production of stable Hb-based blood substitute. PMID- 25451930 TI - Interhelical interaction and receptor phosphorylation regulate the activation kinetics of different human beta1-adrenoceptor variants. AB - G protein-coupled receptors represent the largest class of drug targets, but genetic variation within G protein-coupled receptors leads to variable drug responses and, thereby, compromises their therapeutic application. One of the most intensely studied examples is a hyperfunctional variant of the human beta1 adrenoceptor that carries an arginine at position 389 in helix 8 (Arg-389-ADRB1). However, the mechanism underlying the higher efficacy of the Arg-389 variant remained unclear to date. Despite its hyperfunctionality, we found the Arg-389 variant of ADRB1 to be hyperphosphorylated upon continuous stimulation with norepinephrine compared with the Gly-389 variant. Using ADRB1 sensors to monitor activation kinetics by fluorescence resonance energy transfer, Arg-389-ADRB1 exerted faster activation speed and arrestin recruitment than the Gly-389 variant. Both activation speed and arrestin recruitment depended on phosphorylation of the receptor, as shown by knockdown of G protein-coupled receptor kinases and phosphorylation-deficient ADRB1 mutants. Structural modeling of the human beta1-adrenoceptor suggested interaction of the side chain of Arg 389 with opposing amino acid residues in helix 1. Site-directed mutagenesis of Lys-85 and Thr-86 in helix 1 revealed that this interaction indeed determined ADRB1 activation kinetics. Taken together, these findings indicate that differences in interhelical interaction regulate the different activation speed and efficacy of ADRB1 variants. PMID- 25451931 TI - Substrate-induced changes in domain interaction of vacuolar H+-pyrophosphatase. AB - Single molecule atomic force microscopy (smAFM) was employed to unfold transmembrane domain interactions of a unique vacuolar H(+)-pyrophosphatase (EC 3.6.1.1) from Vigna radiata. H(+)-Pyrophosphatase is a membrane-embedded homodimeric protein containing a single type of polypeptide and links PPi hydrolysis to proton translocation. Each subunit consists of 16 transmembrane domains with both ends facing the lumen side. In this investigation, H(+) pyrophosphatase was reconstituted into the lipid bilayer in the same orientation for efficient fishing out of the membrane by smAFM. The reconstituted H(+) pyrophosphatase in the lipid bilayer showed an authentically dimeric structure, and the size of each monomer was ~4 nm in length, ~2 nm in width, and ~1 nm in protrusion height. Upon extracting the H(+)-pyrophosphatase out of the membrane, force-distance curves containing 10 peaks were obtained and assigned to distinct domains. In the presence of pyrophosphate, phosphate, and imidodiphosphate, the numbers of interaction curves were altered to 7, 8, and 10, respectively, concomitantly with significant modification in force strength. The substrate binding residues were further replaced to verify these domain changes upon substrate binding. A working model is accordingly proposed to show the interactions between transmembrane domains of H(+)-pyrophosphatase in the presence and absence of substrate and its analog. PMID- 25451932 TI - Distinct roles of N-glycosylation at different sites of corin in cell membrane targeting and ectodomain shedding. AB - Corin is a membrane-bound protease essential for activating natriuretic peptides and regulating blood pressure. Human corin has 19 predicted N-glycosylation sites in its extracellular domains. It has been shown that N-glycans are required for corin cell surface expression and zymogen activation. It remains unknown, however, how N-glycans at different sites may regulate corin biosynthesis and processing. In this study, we examined corin mutants, in which each of the 19 predicted N-glycosylation sites was mutated individually. By Western analysis of corin proteins in cell lysate and conditioned medium from transfected HEK293 cells and HL-1 cardiomyocytes, we found that N-glycosylation at Asn-80 inhibited corin shedding in the juxtamembrane domain. Similarly, N-glycosylation at Asn-231 protected corin from autocleavage in the frizzled-1 domain. Moreover, N glycosylation at Asn-697 in the scavenger receptor domain and at Asn-1022 in the protease domain is important for corin cell surface targeting and zymogen activation. We also found that the location of the N-glycosylation site in the protease domain was not critical. N-Glycosylation at Asn-1022 may be switched to different sites to promote corin zymogen activation. Together, our results show that N-glycans at different sites may play distinct roles in regulating the cell membrane targeting, zymogen activation, and ectodomain shedding of corin. PMID- 25451933 TI - Aip1 promotes actin filament severing by cofilin and regulates constriction of the cytokinetic contractile ring. AB - Aip1 (actin interacting protein 1) is ubiquitous in eukaryotic organisms, where it cooperates with cofilin to disassemble actin filaments, but neither its mechanism of action nor its biological functions have been clear. We purified both fission yeast and human Aip1 and investigated their biochemical activities with or without cofilin. Both types of Aip1 bind actin filaments with micromolar affinities and weakly nucleate actin polymerization. Aip1 increases up to 12-fold the rate that high concentrations of yeast or human cofilin sever actin filaments, most likely by competing with cofilin for binding to the side of actin filaments, reducing the occupancy of the filaments by cofilin to a range favorable for severing. Aip1 does not cap the barbed ends of filaments severed by cofilin. Fission yeast lacking Aip1 are viable and assemble cytokinetic contractile rings normally, but rings in these Deltaaip1 cells accumulate 30% less myosin II. Further, these mutant cells initiate the ingression of cleavage furrows earlier than normal, shortening the stage of cytokinetic ring maturation by 50%. The Deltaaip1 mutation has negative genetic interactions with deletion mutations of both capping protein subunits and cofilin mutations with severing defects, but no genetic interaction with deletion of coronin. PMID- 25451935 TI - Organelle-specific subunit interactions of the vertebrate two-pore channel family. AB - The organellar targeting of two-pore channels (TPCs) and their capacity to associate as homo- and heterodimers may be critical to endolysosomal signaling. A more detailed understanding of the functional association of vertebrate TPC1-3 is therefore necessary. We report here that when stably expressed in HEK293 cells, human (h) TPC1 and chicken (c) TPC3 were specifically targeted to different subpopulations of endosomes, hTPC2 was specifically targeted to lysosomes, and rabbit (r) TPC3 was specifically targeted to both endosomes and lysosomes. Intracellular dialysis of NAADP evoked a Ca(2+) transient in HEK293 cells that stably overexpressed hTPC1, hTPC2, and rTPC3, but not in cells that stably expressed cTPC3. The Ca(2+) transients induced in cells that overexpressed endosome-targeted hTPC1 were abolished upon depletion of acidic Ca(2+) stores by bafilomycin A1, but remained unaffected following depletion of endoplasmic reticulum stores by thapsigargin. In contrast, Ca(2+) transients induced via lysosome-targeted hTPC2 and endolysosome-targeted rTPC3 were abolished by bafilomycin A1 and markedly attenuated by thapsigargin. NAADP induced marked Ca(2+) transients in HEK293 cells that stably coexpressed hTPC2 with hTPC1 or cTPC3, but failed to evoke any such response in cells that coexpressed interacting hTPC2 and rTPC3 subunits. We therefore conclude that 1) all three TPC subtypes may support Ca(2+) signaling from their designate acidic stores, and 2) lysosome-targeted (but not endosome-targeted) TPCs support coupling to the endoplasmic reticulum. PMID- 25451934 TI - A dimer interface mutation in glyceraldehyde-3-phosphate dehydrogenase regulates its binding to AU-rich RNA. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an enzyme best known for its role in glycolysis. However, extra-glycolytic functions of GAPDH have been described, including regulation of protein expression via RNA binding. GAPDH binds to numerous adenine-uridine rich elements (AREs) from various mRNA 3' untranslated regions in vitro and in vivo despite its lack of a canonical RNA binding motif. How GAPDH binds to these AREs is still unknown. Here we discovered that GAPDH binds with high affinity to the core ARE from tumor necrosis factor alpha mRNA via a two-step binding mechanism. We demonstrate that a mutation at the GAPDH dimer interface impairs formation of the second RNA-GAPDH complex and leads to changes in the RNA structure. We investigated the effect of this interfacial mutation on GAPDH oligomerization by crystallography, small-angle x ray scattering, nano-electrospray ionization native mass spectrometry, and hydrogen-deuterium exchange mass spectrometry. We show that the mutation does not significantly affect GAPDH tetramerization as previously proposed. Instead, the mutation promotes short-range and long-range dynamic changes in regions located at the dimer and tetramer interface and in the NAD(+) binding site. These dynamic changes are localized along the P axis of the GAPDH tetramer, suggesting that this region is important for RNA binding. Based on our results, we propose a model for sequential GAPDH binding to RNA via residues located at the dimer and tetramer interfaces. PMID- 25451937 TI - Internal dynamics of dynactin CAP-Gly is regulated by microtubules and plus end tracking protein EB1. AB - CAP-Gly domain of dynactin, a microtubule-associated activator of dynein motor, participates in multiple cellular processes, and its point mutations are associated with neurodegenerative diseases. Recently, we have demonstrated that conformational plasticity is an intrinsic property of CAP-Gly. To understand its origin, we addressed internal dynamics of CAP-Gly assembled on polymeric microtubules, bound to end-binding protein EB1 and free, by magic angle spinning NMR and molecular dynamics simulations. The analysis of residue-specific dynamics of CAP-Gly on time scales spanning nano- through milliseconds reveals its unusually high mobility, both free and assembled on polymeric microtubules. On the contrary, CAP-Gly bound to EB1 is significantly more rigid. Molecular dynamics simulations indicate that these motions are strongly temperature dependent, and loop regions are surprisingly mobile. These findings establish the connection between conformational plasticity and internal dynamics in CAP-Gly, which is essential for the biological functions of CAP-Gly and its ability to bind to polymeric microtubules and multiple binding partners. In this work, we establish an approach, for the first time, to probe atomic resolution dynamic profiles of a microtubule-associated protein assembled on polymeric microtubules. More broadly, the methodology established here can be applied for atomic resolution analysis of dynamics in other microtubule-associated protein assemblies, including but not limited to dynactin, dynein, and kinesin motors assembled on microtubules. PMID- 25451936 TI - Conformational selection and equilibrium governs the ability of retinals to bind opsin. AB - Despite extensive study, how retinal enters and exits the visual G protein coupled receptor rhodopsin remains unclear. One clue may lie in two openings between transmembrane helix 1 (TM1) and TM7 and between TM5 and TM6 in the active receptor structure. Recently, retinal has been proposed to enter the inactive apoprotein opsin (ops) through these holes when the receptor transiently adopts the active opsin conformation (ops*). Here, we directly test this "transient activation" hypothesis using a fluorescence-based approach to measure rates of retinal binding to samples containing differing relative fractions of ops and ops*. In contrast to what the transient activation hypothesis model would predict, we found that binding for the inverse agonist, 11-cis-retinal (11CR), slowed when the sample contained more ops* (produced using M257Y, a constitutively activating mutation). Interestingly, the increased presence of ops* allowed for binding of the agonist, all-trans-retinal (ATR), whereas WT opsin showed no binding. Shifting the conformational equilibrium toward even more ops* using a G protein peptide mimic (either free in solution or fused to the receptor) accelerated the rate of ATR binding and slowed 11CR binding. An arrestin peptide mimic showed little effect on 11CR binding; however, it stabilized opsin . ATR complexes. The TM5/TM6 hole is apparently not involved in this conformational selection. Increasing its size by mutagenesis did not enable ATR binding but instead slowed 11CR binding, suggesting that it may play a role in trapping 11CR. In summary, our results indicate that conformational selection dictates stable retinal binding, which we propose involves ATR and 11CR binding to different states, the latter a previously unidentified, open-but-inactive conformation. PMID- 25451938 TI - Extracellular signal-regulated kinase mediates expression of arginase II but not inducible nitric-oxide synthase in lipopolysaccharide-stimulated macrophages. AB - The mitogen-activated protein kinases (MAPK) have been shown to participate in iNOS induction following lipopolysaccharide (LPS) stimulation, while the role of MAPKs in the regulation of arginase remains unclear. We hypothesized that different MAPK family members are involved in iNOS and arginase expression following LPS stimulation. LPS-stimulated RAW 264.7 cells exhibited increased protein and mRNA levels for iNOS, arginase I, and arginase II; although the induction of arginase II was more robust than that for arginase I. A p38 inhibitor completely prevented iNOS expression while it only attenuated arginase II induction. In contrast, a MEK1/2 inhibitor (ERK pathway) completely abolished arginase II expression while actually enhancing iNOS induction in LPS-stimulated cells. Arginase II promoter activity was increased by ~4-fold following LPS stimulation, which was prevented by the ERK pathway inhibitor. Arginase II promoter activity was unaffected by a p38 inhibitor or JNK pathway interference. Transfection with a construct expressing a constitutively active RAS mutant increased LPS-induced arginase II promoter activity, while transfection with a vector expressing a dominant negative ERK2 mutant or a vector expressing MKP-3 inhibited the arginase II promoter activity. LPS-stimulated nitric oxide (NO) production was increased following siRNA-mediated knockdown of arginase II and decreased when arginase II was overexpressed. Our results demonstrate that while both the ERK and p38 pathways regulate arginase II induction in LPS-stimulated macrophages, iNOS induction by LPS is dependent on p38 activation. These results suggest that differential inhibition of the MAPK pathway may be a potential therapeutic strategy to regulate macrophage phenotype. PMID- 25451939 TI - Negative regulation of melanoma differentiation-associated gene 5 (MDA5) dependent antiviral innate immune responses by Arf-like protein 5B. AB - RIG-I-like receptors (RLRs), including retinoic acid-inducible gene-I (RIG-I) and MDA5, constitute a family of cytoplasmic RNA helicases that senses viral RNA and mounts antiviral innate immunity by producing type I interferons and inflammatory cytokines. Despite their essential roles in antiviral host defense, RLR signaling is negatively regulated to protect the host from excessive inflammation and autoimmunity. Here, we identified ADP-ribosylation factor-like protein 5B (Arl5B), an Arl family small GTPase, as a regulator of RLR signaling through MDA5 but not RIG-I. Overexpression of Arl5B repressed interferon beta promoter activation by MDA5 but not RIG-I, and its knockdown enhanced MDA5-mediated responses. Furthermore, Arl5B-deficient mouse embryonic fibroblast cells exhibited increased type I interferon expression in response to MDA5 agonists such as poly(I:C) and encephalomyocarditis virus. Arl5B-mediated negative regulation of MDA5 signaling does not require its GTP binding ability but requires Arl5B binding to the C-terminal domain of MDA5, which prevents interaction between MDA5 and poly(I:C). Our results, therefore, suggest that Arl5B is a negative regulator for MDA5. PMID- 25451940 TI - Liver kinase B1 suppresses lipopolysaccharide-induced nuclear factor kappaB (NF kappaB) activation in macrophages. AB - Liver kinase B1 (LKB1), a serine/threonine kinase, is a tumor suppressor and metabolic regulator. Recent data suggest that LKB1 is essential in regulating homeostasis of hematopoietic cells and immune responses. However, its role in macrophages and innate immune system remains unclear. Here we report that macrophage LKB1 inhibits pro-inflammatory signaling in response to LPS. LPS induced pro-inflammatory cytokines and pro-inflammatory enzymes were monitored in bone marrow-derived macrophages isolated from myeloid cell-specific LKB1 knock out mice and their wild type littermate control mice. LPS induced higher levels of pro-inflammatory cytokines and pro-inflammatory enzymes in bone marrow-derived macrophages from LKB1 KO than those from wild type mice. Consistently, LPS induced higher levels of NF-kappaB activation in LKB1-deficient macrophages than those in wild type. Further, LPS stimulation significantly increased LKB1 phosphorylation at serine 428, which promoted its binding to IkappaB kinasebeta (IKKbeta), resulting in the inhibition of NF-kappaB. Finally, LPS injection caused higher levels of cytokine release and more severe tissue injury in the lung tissues of LKB1 KO mice than in those of control mice. We conclude that LKB1 inhibits LPS-induced NF-kappaB activation in macrophages. PMID- 25451941 TI - Specific inhibition of histone deacetylase 8 reduces gene expression and production of proinflammatory cytokines in vitro and in vivo. AB - ITF2357 (generic givinostat) is an orally active, hydroxamic-containing histone deacetylase (HDAC) inhibitor with broad anti-inflammatory properties, which has been used to treat children with systemic juvenile idiopathic arthritis. ITF2357 inhibits both Class I and II HDACs and reduces caspase-1 activity in human peripheral blood mononuclear cells and the secretion of IL-1beta and other cytokines at 25-100 nm; at concentrations >200 nm, ITF2357 is toxic in vitro. ITF3056, an analog of ITF2357, inhibits only HDAC8 (IC50 of 285 nm). Here we compared the production of IL-1beta, IL-1alpha, TNFalpha, and IL-6 by ITF2357 with that of ITF3056 in peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS), heat-killed Candida albicans, or anti-CD3/anti-CD28 antibodies. ITF3056 reduced LPS-induced cytokines from 100 to 1000 nm; at 1000 nm, the secretion of IL-1beta was reduced by 76%, secretion of TNFalpha was reduced by 88%, and secretion of IL-6 was reduced by 61%. The intracellular levels of IL-1alpha were 30% lower. There was no evidence of cell toxicity at ITF3056 concentrations of 100-1000 nm. Gene expression of TNFalpha was markedly reduced (80%), whereas IL-6 gene expression was 40% lower. Although anti-CD3/28 and Candida stimulation of IL-1beta and TNFalpha was modestly reduced, IFNgamma production was 75% lower. Mechanistically, ITF3056 reduced the secretion of processed IL-1beta independent of inhibition of caspase-1 activity; however, synthesis of the IL-1beta precursor was reduced by 40% without significant decrease in IL-1beta mRNA levels. In mice, ITF3056 reduced LPS-induced serum TNFalpha by 85% and reduced IL-1beta by 88%. These data suggest that specific inhibition of HDAC8 results in reduced inflammation without cell toxicity. PMID- 25451942 TI - Functional consequences of glucagon-like peptide-1 receptor cross-talk and trafficking. AB - The signaling capacity of seven-transmembrane/G-protein-coupled receptors (7TM/GPCRs) can be regulated through ligand-mediated receptor trafficking. Classically, the recycling of internalized receptors is associated with resensitization, whereas receptor degradation terminates signaling. We have shown previously that the incretin glucagon-like peptide-1 receptor (GLP-1R) internalizes fast and is primarily resensitized through recycling back to the cell surface. GLP-1R is expressed in pancreatic islets together with the closely related glucose-dependent insulinotropic polypeptide (GIPR) and glucagon (GCGR) receptors. The interaction and cross-talk between coexpressed receptors is a wide phenomenon of the 7TM/GPCR superfamily. Numerous reports show functional consequences for signaling and trafficking of the involved receptors. On the basis of the high structural similarity and tissue coexpression, we here investigated the potential cross-talk between GLP-1R and GIPR or GCGR in both trafficking and signaling pathways. Using a real-time time-resolved FRET-based internalization assay, we show that GLP-1R, GIPR, and GCGR internalize with differential properties. Remarkably, upon coexpression of the internalizing GLP 1R and the non-internalizing GIPR, GLP-1-mediated GLP-1R internalization was impaired in a GIPR concentration-dependent manner. As a functional consequence of such impaired internalization capability, GLP-1-mediated GLP-1R signaling was abrogated. A similar compromised signaling was found when GLP-1R internalization was abrogated by a dominant-negative version of dynamin (dynamin-1 K44E), which provides a mechanistic link between GLP-1R trafficking and signaling. This study highlights the importance of receptor internalization for full functionality of GLP-1R. Moreover, cross-talk between the two incretin receptors GLP-1R and GIPR is shown to alter receptor trafficking with functional consequences for GLP-1R signaling. PMID- 25451945 TI - Multiple biomarker strategies for risk stratification in heart failure. AB - Biomarkers of cardiovascular diseases are indispensable tools for diagnosis and prognosis, and the use of biomarkers is now considered standard-of-care. New markers continue to be developed, but few prove to be substantially better than established markers. Heart failure (HF) risk stratification may be refined by the use of biomarkers for different pathobiological processes that established mortality risk factors do not directly reflect. Biomarkers that are currently available can provide information about at least seven pathobiological processes operative in HF, help to identify the specific processes involved in individual patients, and aid in constructing management plans. However, the additional prognostic information gained by any biomarker over a clinical risk model plus other biomarkers needs to be determined with adequate statistical tools. A major problem in selecting a biomarker profile is the proportional increase in economic burden; thus, the addition of any biomarker to a profile should be justified by adequate discrimination, calibration, reclassification, and likelihood analyses. This review assesses the value of multimarker strategies in both acutely decompensated (ADHF) and chronic HF. Most data on biomarkers have been derived from patient cohorts with chronic HF. However, risk prediction in patients admitted with ADHF remains a challenge. ADHF is not a single disease, it presents in various manners and different etiologies may underlie ADHF, which are reflected by different biomarkers. The optimal panel of markers, the change in these markers over time, and how these changes might help guide therapeutic interventions remain to be defined. PMID- 25451944 TI - Genome annotation by shotgun inactivation of a native gene in hemizygous cells: application to BRCA2 with implication of hypomorphic variants. AB - The greatest interpretive challenge of modern medicine may be to functionally annotate the vast variation of human genomes. Demonstrating a proposed approach, we created a library of BRCA2 exon 27 shotgun-mutant plasmids including solitary and multiplex mutations to generate human knockin clones using homologous recombination. This 55-mutation, 13-clone syngeneic variance library (SyVaL) comprised severely affected clones having early-stop nonsense mutations, functionally hypomorphic clones having multiple missense mutations emphasizing the potential to identify and assess hypomorphic mutations in novel proteomic and epidemiologic studies, and neutral clones having multiple missense mutations. Efficient coverage of nonessential amino acids was provided by mutation multiplexing. Severe mutations were distinguished from hypomorphic or neutral changes by chemosensitivity assays (hypersensitivity to mitomycin C and acetaldehyde), by analysis of RAD51 focus formation, and by mitotic multipolarity. A multiplex unbiased approach of generating all-human SyVaLs in medically important genes, with random mutations in native genes, would provide databases of variants that could be functionally annotated without concerns arising from exogenous cDNA constructs or interspecies interactions, as a basis for subsequent proteomic domain mapping or clinical calibration if desired. Such gene-irrelevant approaches could be scaled up for multiple genes of clinical interest, providing distributable cellular libraries linked to public-shared functional databases. PMID- 25451943 TI - Transcriptional regulation of adipocyte differentiation: a central role for CCAAT/enhancer-binding protein (C/EBP) beta. AB - A detailed understanding of the processes controlling adipogenesis is instrumental in the fight against the obesity epidemic. Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) beta plays an essential role. During 3T3-L1 adipocyte differentiation, C/EBPbeta is induced early to transactivate the expression of C/EBPalpha and peroxisome proliferator-activated receptor gamma (PPARgamma), two master transcription factors for terminal adipocyte differentiation. Studies in recent years have revealed many new target genes of C/EBPbeta, implicating its participation in many other processes during adipogenesis, such as mitotic clonal expansion, epigenetic regulation, unfolded protein response, and autophagy. Moreover, the function of C/EBPbeta is highly regulated by post-translational modifications, which are crucial for the proper activation of the adipogenic program. Advances toward elucidation of the function and roles of the post-translational modification of C/EBPbeta during adipogenesis will greatly improve our understanding of the molecular mechanisms governing adipogenesis. PMID- 25451946 TI - Atypical/malignant urothelial cells in routine urinary sediment: worth knowing and reporting. AB - BACKGROUND: Urinary cytology (Ucytol), which is performed in pathology laboratories on fixed and stained samples, represents the gold standard for the identification of atypical/malignant urothelial cells (A/MUC) due to urothelial carcinoma. In this paper we describe three patients in whom A/MUC, due to a bladder carcinoma, were identified with conventional urine sediment (Used) examination on unfixed and unstained samples. METHODS: Included are urine samples prepared with conventional and standardized techniques as currently used in general clinical laboratories. Samples were examined with phase contrast microscopy. A/MUC were identified according to the criteria currently used for Ucytol. RESULTS: A/MUC (i.e., cells with unusual and pleomorphic size and shape, increased nuclear/cytoplasmic ratio, increased number of nuclei, irregular nuclear borders and irregular chromatin patterns, either isolated or in clusters) were identified in the urine of three patients, all of whom were found to have bladder carcinoma by cystoscopy. CONCLUSIONS: At variance with the common and widespread view, A/MUC can also be identified with conventional Used examination, even though Ucytol still represents the gold standard method. PMID- 25451947 TI - Serum free 1,25-dihydroxy-vitamin D is more closely associated with fibroblast growth factor 23 than other vitamin D forms in chronic dialysis patients. AB - BACKGROUND: Mineral bone disorder (MBD) is prevalent among chronic dialysis patients. However, relationship between different forms of vitamin D and fibroblast growth factor 23 (FGF-23) remains unclear in this population. METHODS: A multicenter hemodialysis cohort was assembled. We evaluated 25-OH-D and 1,25 (OH)2-D, vitamin D-binding protein, and FGF-23, in this cohort. Multiple regression analyses were performed to investigate the relationship and stewardship between different vitamin D forms and FGF-23 concentrations. RESULTS: Chronic dialysis patients presented significantly higher FGF-23 concentrations. 25-OH-D concentrations of <20 ng/ml (deficiency), 20-30 ng/ml (insufficiency), and >=30 ng/ml (sufficiency) were associated with progressively lower FGF-23 concentrations (p<0.01). Serum FGF-23 concentrations were significantly correlated with total (p=0.02), free (p<0.01) and bioavailable (p<0.01) 25-OH-D and total (p=0.04), free (p=0.02), and bioavailable (p=0.03) 1,25-(OH)2-D concentrations. With all 25-OH-D and 1,25-(OH)2-D forms in the regression model, we found that free 1,25-(OH)2-D outweighed all other vitamin D forms regarding its association with FGF-23 (p=0.03). CONCLUSION: The relationship between FGF-23 and vitamin D is stronger using free forms of 25-OH-D and 1,25-(OH)2-D. Subsequent studies aiming at MBD should consider including free 25-OH-D and 1,25 (OH)2-D in the analysis. PMID- 25451948 TI - Clinical applicability of reticulated platelets. AB - BACKGROUND: Reticulated platelets (RPs), immature platelets newly released from the bone marrow into the circulation, have a high content of ribonucleic acid and are larger and more active in thrombus formation. OBJECTIVE: This review compiles articles that evaluated RP in order to establish their clinical significance. DISCUSSION: RPs increase when platelet production rises and decrease when production falls. As such, the measurement of circulating RPs allows the assessment of thrombocytopenia, i.e., bone marrow production or peripheral destruction. CONCLUSION: RPs are a promising laboratory tool for evaluation of idiopathic thrombocytopenia (differentiating hypoproduction from accelerated platelet destruction), chemotherapy and after stem cell transplantation (predicting platelet recovery) and thrombocytosis (estimating platelet turnover). Additional randomized and well controlled clinical studies are required to clearly establish the significance of circulating RPs in other clinical conditions. PMID- 25451949 TI - Implications of reverse cholesterol transport: recent studies. AB - INTRODUCTION: There is a strong epidemiological relationship between high density lipoproteins and atherosclerotic coronary vascular disease (ASCVD). The process of reverse cholesterol transport (RCT) has been hypothesized to help explain this relationship. The corollary that raising HDL should reduce ASCVD is also drawn from this relationship. In recent years, the metabolism of HDL has become better understood. A hypothetical process for explaining RCT has been superimposed on the currently understood HDL metabolic pathways. METHODS: Outline of HDL metabolism and the superimposed RCT process. Literature review of studies of persons with genetic defects, HDL cholesterol raising clinical trials, Mendelian randomization studies and treatments with molecules that mimic HDL. CONCLUSIONS: Mutation studies of ABCA1, LCAT and SR-B1 genes in humans showed expected variations in HDLC but little association with ASCVD and there was no significant association between HDLC and ASCVD in Mendelian randomization studies. Elevations in HDLC due to treatment with niacin and cholesteryl ester transport protein inhibitors in randomized trials raised HDLC but did not significantly reduce risk of ASCVD. Treatment with molecules that mimic HDL did not seem to reduce ASCVD. Thus, recent evidence does not seem to support RCT as currently proposed. This hypothesis seems to need substantial revision. PMID- 25451950 TI - Molecular and clinical delineation of 12 patients with glycogen storage disease type III in Western Turkey. AB - BACKGROUND: Glycogen storage disease type III (GSD III; MIM #232400) is an autosomal recessive inherited disorder characterized by fasting hypoglycemia, growth retardation, hepatomegaly, progressive myopathy, and cardiomyopathy. GSD III is caused by deficiency in the glycogen debranching enzyme (gene symbol: AGL). Molecular analyses of AGL have indicated heterogeneity depending on ethnic groups. In Turkey we reported 13 different AGL mutations from GSD III patients in the Eastern region; however, the full spectrum of AGL mutations in Turkish population remains unclear. Here we investigated 12 GSD III patients mostly from Western Turkey. METHODS: The full coding exons, their relevant exon-intron boundaries, and the 5'- and 3'-flanking regions of the patients' AGL were sequenced. AGL haplotypes were determined. Splicing mutations were characterized by RNA transcript analysis. RESULTS: Twelve different mutations were identified: 7 novel AGL mutations [69-base pair deletion (c.1056_1082+42del69), 21-base par deletion (c.3940_3949+11del21), two small duplications (c.364_365dupCT and c.1497_1500dupAGAG), and 3 splicing mutations (c.1736-11A>G, c.3259+1G>A and c.3588+2T>G)], along with 5 known mutations (c.1019delA, c.958+1G>A, c.4161+5G>A, p.R864X and p.R1218X). Transcripts of splicing mutations (c.1736-11A>G, c.3588+2T>G and c.4161+5G>A) were shown to cause aberrant splicing. AGL haplotype analyses suggested that c.1019delA and c.958+1G>A are founder mutations in Turkish patients, while p.R864X is a recurrent mutation. CONCLUSIONS: Our study broadens the spectrum of AGL mutations and demonstrates that mutations in Western Turkey are different from those in the Eastern region. PMID- 25451951 TI - Catastrophic hemophagocytic lymphohistiocytosis in a young man with nephrotic syndrome. AB - BACKGROUND: In its early stage, necrotizing fasciitis mimics a milder cutaneous infection, such as cellulitis, and is an uncommon but potentially fatal complication of nephrotic syndrome. It may trigger an uncontrolled and catastrophic immune response, such as hemophagocytic lymphohistiocytosis (HLH). CASE REPORT: A 19-y-old man presented with steroid-resistant nephrotic syndrome and rapidly progressing Escherichia coli monomicrobial necrotizing fasciitis with bacteremia. The conditions developed one day after steroid therapy, leading to multiple organ dysfunction syndrome. A provisional diagnosis of HLH was promptly made, based upon the patient's fever, unremitting shock, marked pancytopenia, hyperferritinemia, hypofibrinogenemia, and the typical histiocytic hemophagocytosis in pleural effusion. Despite aggressive medical treatment and organ support, the patient died 8 days after transfer to our intensive care unit. Final bone marrow examination confirmed the diagnosis of HLH. CONCLUSIONS: Although nephrotic syndrome associated with E. coli infection is common, this is the first reported case of E. coli monomicrobial necrotizing fasciitis with bacteremia resulting in HLH in a patient with nephrotic syndrome. PMID- 25451952 TI - Elevated levels of preoperative circulating CD44+ lymphocytes and neutrophils predict poor survival for non-small cell lung cancer patients. AB - BACKGROUND: Certain circulating cells have been shown to predict the clinical outcome of several cancers. The objective of this study was to identify clinical, hematological and immunological predictors of prognosis in non-small cell lung cancer (NSCLC) patients. METHODS: A retrospective study on a prevalent cohort of 225 NSCLC patients hospitalized at the Zhejiang Province Cancer Hospital (ZPCH) was conducted from August 1, 2006 to April 15, 2008. Circulating lymphocytes were measured by flow cytometry. WBC count and classification in peripheral blood were measured with a Coulter counter. We calculated the proportion of patients surviving after first hospital admission and hazard ratios (HR) using the Cox proportional hazards model. RESULTS: Elevated levels of preoperative circulating CD44(+) lymphocytes, WBCs and neutrophils indicated low cumulative survival. Clinical stage (HR: 2.292; 95% confidence interval (CI): 1.34-3.91, P=0.002), neutrophils (HR: 1.877; 95% CI: 1.34-2.62, P<0.001) and CD44(+) lymphocytes (HR: 1.018; 95% CI: 1.00-1.03, P=0.002) are independent predictors of survival in NSCLC patients, respectively. Elevated levels of CD44(+) lymphocytes and neutrophils correlated with distant metastasis and prognosis in NSCLC patients with stage III/IV, respectively. CONCLUSIONS: CD44(+) lymphocytes along with neutrophils could serve as an independent prognostic marker for NSCLC patients. PMID- 25451953 TI - False deletion of the D15S986 maternal allele in a suspected case of Angelman syndrome. AB - BACKGROUND: Angelman syndrome (AS) is a neurological disorder caused by genetic defects of the chromosome region 15q11-q13; some 70-80% of cases are due to deletions of the maternal allele, as the paternal copy is imprinted. DESIGN AND METHODS: A maternal deletion at D15S986 was reported in a suspected case of AS; this marker is located in intron 2 of the ATP10C gene, which has been implicated in the development of AS. A segment of ~830bp, including this marker and the primers used in routine genetic test, was cloned and sequenced. RESULTS: A single nucleotide deletion (named ATP10C*c.760+3808delA, GenBank accession number HQ856823) was detected in the middle of the forward primer, leading to allele dropout. A large European population sample (N=363) was typed, and the detected variant was characterized as a novel polymorphism, with allele frequencies of 0.882 (TAT allele) and 0.118 (T-T allele). CONCLUSIONS: An alternative primer set was developed, for which the segregation pattern of D15S986 in the proband extended family was normal. It can replace the currently used set. PMID- 25451954 TI - Current aspects in hemoglobin A1c detection: a review. AB - Type 2 diabetes mellitus (T2DM) is a pressing health issue that threatens global health and the productivity of populations worldwide. Despite its long-recognized role in diabetes management, glycated hemoglobin (HbA1c) only received WHO endorsement as a T2DM diagnostic tool in 2011. Although conventional plasma specific tests have long been utilized to diagnose T2DM, the public should be informed that plasma-specific tests are not markedly better than HbA1c tests, particularly in terms of variability and convenience for diagnosing diabetes. In the midst of the debates associated with establishing HbA1c as the preeminent diabetes diagnostic tool, unceasing efforts to standardize HbA1c tests have played an integral part in achieving more efficient communication from laboratory to clinical practice and thus better diabetes care. This review discusses the current status of HbA1c tests in the diagnosis, prevention, treatment and management of T2DM across the globe, focusing on increasing the recognition of glycated hemoglobin variants with effective utilization of different HbA1c methods, updating the current status of HbA1c standardization programs, tapping into the potential of POC analyzers to establish a cost-effective HbA1c test for diabetes care, and inspiring the advancement of HbA1c biosensors for future clinical usage. PMID- 25451955 TI - Validation of a lipoprotein(a) particle concentration assay by quantitative lipoprotein immunofixation electrophoresis. AB - BACKGROUND: Low-density lipoprotein (LDL) particle (P, or molar) concentration has been shown to be a more sensitive marker of cardiovascular disease (CVD) risk than LDL cholesterol. Although elevated circulating lipoprotein(a) [Lp(a)] cholesterol and mass have been associated with CV risk, no practicable method exists to measure Lp(a)-P. We have developed a method of determining Lp(a)-P suitable for routine clinical use. METHODS: Lipoprotein immunofixation electrophoresis (Lipo-IFE) involves rigidly controlled electrophoretic separation of serum lipoproteins, probing with polyclonal apolipoprotein B antibodies, then visualization after staining with a nonspecific protein stain (Acid Violet). Lipo IFE was compared to the Lp(a) mass assay for 1086 randomly selected patient samples, and for 254 samples stratified by apo(a) isoform size. RESULTS: The Lipo IFE method was shown to be precise (CV <10% above the 50 nmol/l limit of quantitation) and linear across a 16-fold range. Lipo-IFE compared well with the mass-based Lp(a) assay (r=0.95), but was not affected by variations in apo(a) isoform size. With a throughput of 100 samples in 90 min, the assay is suitable for use in the clinical laboratory. CONCLUSIONS: The Lipo-IFE method will allow Lp(a)-P to be readily tested as a CVD risk factor in large-scale clinical trials. PMID- 25451956 TI - Real-time PCR detection chemistry. AB - Real-time PCR is the method of choice in many laboratories for diagnostic and food applications. This technology merges the polymerase chain reaction chemistry with the use of fluorescent reporter molecules in order to monitor the production of amplification products during each cycle of the PCR reaction. Thus, the combination of excellent sensitivity and specificity, reproducible data, low contamination risk and reduced hand-on time, which make it a post-PCR analysis unnecessary, has made real-time PCR technology an appealing alternative to conventional PCR. The present paper attempts to provide a rigorous overview of fluorescent-based methods for nucleic acid analysis in real-time PCR described in the literature so far. Herein, different real-time PCR chemistries have been classified into two main groups; the first group comprises double-stranded DNA intercalating molecules, such as SYBR Green I and EvaGreen, whereas the second includes fluorophore-labeled oligonucleotides. The latter, in turn, has been divided into three subgroups according to the type of fluorescent molecules used in the PCR reaction: (i) primer-probes (Scorpions, Amplifluor, LUX, Cyclicons, Angler); (ii) probes; hydrolysis (TaqMan, MGB-TaqMan, Snake assay) and hybridization (Hybprobe or FRET, Molecular Beacons, HyBeacon, MGB-Pleiades, MGB Eclipse, ResonSense, Yin-Yang or displacing); and (iii) analogues of nucleic acids (PNA, LNA, ZNA, non-natural bases: Plexor primer, Tiny-Molecular Beacon). In addition, structures, mechanisms of action, advantages and applications of such real-time PCR probes and analogues are depicted in this review. PMID- 25451957 TI - Australia, the forgotten continent, hitting above its weight in research. PMID- 25451958 TI - A 2014 snapshot audit of the role of urodynamics in the UK for benign prostatic enlargement surgery. PMID- 25451959 TI - Mathematical modeling of tuberculosis data of China. AB - This paper concentrates on the tuberculosis data of China from January 2005 to December 2012. We set up a mathematical model to fit those data with the goodness of fit and obtain the optimal parameter values of the model. By the Chi-square test of the statistical inference, the optimal parameter values of the model are reasonable. We get the effective reproductive number of the disease for each year, and also investigate the preventive measures to control the tuberculosis. PMID- 25451960 TI - In silico aided thoughts on mitochondrial vitamin C transport. AB - The huge demand of mitochondria as the quantitatively most important sources of ROS in the majority of heterotrophic cells for vitamin C is indisputable. The reduced form of the vitamin, l-ascorbic acid, is imported by an active mechanism requiring two sodium-dependent vitamin C transporters (SVCT1 and SVCT2). The oxidized form, dehydroascorbate is taken up by different members of the GLUT family. Because of the controversial experimental results the picture on mitochondrial vitamin C transport became quite obscure by the spring of 2014. Thus in silico prediction tools were applied in aid of the support of in vitro and in vivo results. The role of GLUT1 as a mitochondrial dehydroascorbate transporter could be reinforced by in silico predictions however the mitochondrial presence of GLUT10 is not likely since this transport protein got far the lowest mitochondrial localization scores. Furthermore the possible roles of GLUT9 and 11 in mitochondrial vitamin C transport can be proposed leastwise on the base of their computational localization analysis. In good concordance with the newest experimental observations on SVCT2 the mitochondrial presence of this transporter could also be supported by the computational prediction tools. PMID- 25451961 TI - Modeling of sensing potency of cytoskeletal systems decorated with metabolic enzymes. AB - The highly dynamic cytoskeleton interacts with enzymes and other proteins that are involved in metabolic or signaling pathways. These interactions can influence the structural and functional characteristics of the partners at the microscopic level of individual proteins and polymers. In this work the functional consequences of such interactions have been studied at the macroscopic level in order to evaluate the integrative and regulatory roles of the metabolic pathways associated with the microtubule cytoskeleton. Here we present mathematical models of the interactions between a hypothetical metabolic pathway and microtubule assembly, and explore for the first time the functional consequences of these interactions in distinct situations. The models include kinetic constants of the individual steps and testable, relevant parameters which allow the quantification of the coupled processes at the microscopic and macroscopic levels. For example our kinetic model for the self-assembly of microtubules reproduces the alteration of the time-dependent turbidity caused by pyruvate kinase binding. Our data reveal the power of a mechanistic description of a filamentous system to explain how cells sense the state of metabolic and other pathways. PMID- 25451962 TI - Fisheries-induced disruptive selection. AB - Commercial harvesting is recognized to induce adaptive responses of life-history traits in fish populations, in particular by shifting the age and size at maturation through directional selection. In addition to such evolution of a target stock, the corresponding fishery itself may adapt, in terms of fishing policy, technological progress, fleet dynamics, and adaptive harvest. The aim of this study is to assess how the interplay between natural and artificial selection, in the simplest setting in which a fishery and a target stock coevolve, can lead to disruptive selection, which in turn may cause trait diversification. To this end, we build an eco-evolutionary model for a size structured population, in which both the stock's maturation schedule and the fishery's harvest rate are adaptive, while fishing may be subject to a selective policy based on fish size and/or maturity stage. Using numerical bifurcation analysis, we study how the potential for disruptive selection changes with fishing policy, fishing mortality, harvest specialization, life-history tradeoffs associated with early maturation, and other demographic and environmental parameters. We report the following findings. First, fisheries-induced disruptive selection is readily caused by commonly used fishing policies, and occurs even for policies that are not specific for fish size or maturity, provided that the harvest is sufficiently adaptive and large individuals are targeted intensively. Second, disruptive selection is more likely in stocks in which the selective pressure for early maturation is naturally strong, provided life-history tradeoffs are sufficiently consequential. Third, when a fish stock is overexploited, fisheries targeting only large individuals might slightly increase sustainable yield by causing trait diversification (even though the resultant yield always remains lower than the maximum sustainable yield that could be obtained under low fishing mortality, without causing disruptive selection). We discuss the broader implications of our results and highlight how these can be taken into account for designing evolutionarily informed fisheries-management regimes. PMID- 25451963 TI - The role of the biarticular hamstrings and gastrocnemius muscles in closed chain lower limb extension. AB - The role of the biarticular muscles is a topic that has received considerable attention however their function is not well understood. In this paper, we argue that an analysis that is based upon considering the effect of the biarticular muscles on the segments that they span (rather than their effect on joint rotations) can be illuminating. We demonstrate that this understanding is predicated on a consideration of the relative sizes of the moment arms of a biarticular muscle about the two joints that it crosses. The weight of the previous literature suggests that the moment arms of both the biarticular hamstrings and gastrocnemius are smaller at the knee than at the hip or ankle, (respectively). This in turn leads to the conclusion that both biarticular hamstrings and gastrocnemius are extensors of the lower limb. We show that the existence of these biarticular structures lends a degree of flexibility to the motor control strategies available for lower limb extension. In particular, the role of the gastrocnemius and biarticular hamstrings in permitting a large involvement of the quadriceps musculature in closed chain lower limb extension may be more important than is typically portrayed. Finally, the analysis presented in this paper demonstrates the importance of considering the effects of muscles on the body as a whole, not just on the joints they span. PMID- 25451964 TI - A model for the development of Aedes (Stegomyia) aegypti as a function of the available food. AB - We discuss the preimaginal development of the mosquito Aedes aegypti from the point of view of the statistics of developmental times and the final body-size of the pupae and adults. We begin the discussion studying existing models in relation to published data for the mosquito. The data suggest a developmental process that is described by exponentially distributed random times. The existing data show as well that the idea of cohorts emerging synchronously is verified only in optimal situations created at the laboratory but it is not verified in field experiments. We propose a model in which immature individuals progress in successive stages, all of them with exponentially distributed times, according to two different rates (one food-dependent and the other food-independent). This phenomenological model, coupled with a general model for growing, can explain the existing observations and new results produced in this work. The emerging picture is that the development of the larvae proceeds through a sequence of steps. Some of the steps depend on the available food. While food is in abundance, all steps can be thought as having equal duration, but when food is scarce, those steps that depend on food take considerably longer times. For insufficient levels of food, increase in larval mortality sets in. As a consequence of the smaller rates, the average pupation time increases and the cohort disperses in time. Dispersion, as measured by standard deviation, becomes a quadratic function of the average time indicating that cohort dispersion responds to the same causes than delays in pupation and adult emergence. During the whole developmental process the larva grows monotonically, initially at an exponential rate but later at decreasing rates, approaching a final body-size. Growth is stopped by maturation when it is already slow. As a consequence of this process, there is a slight bias favoring small individuals: Small individuals are born before larger individuals, although the tendency is very weak. PMID- 25451965 TI - The strains of Rhizorhapis and related genera isolated from lettuce roots that were used to develop specific primers for Rhizorhapis suberifaciens. PMID- 25451966 TI - Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases. AB - Cardiovascular disease is the leading cause of death worldwide. Despite advancements in diagnosis and treatment of cardiovascular disease, the incidence of cardiovascular disease is still rising. Therefore, new lines of medications are needed to treat the growing population of patients with cardiovascular disease. Although the majority of the existing pharmacotherapies for cardiovascular disease are synthesized molecules, natural compounds, such as resveratrol, are also being tested. Resveratrol is a non-flavonoid polyphenolic compound, which has several biological effects. Preclinical studies have provided convincing evidence that resveratrol has beneficial effects in animal models of hypertension, atherosclerosis, stroke, ischemic heart disease, arrhythmia, chemotherapy-induced cardiotoxicity, diabetic cardiomyopathy, and heart failure. Although not fully delineated, some of the beneficial cardiovascular effects of resveratrol are mediated through activation of silent information regulator 1 (SIRT1), AMP-activated protein kinase (AMPK), and endogenous anti-oxidant enzymes. In addition to these pathways, the anti-inflammatory, anti-platelet, insulin-sensitizing, and lipid-lowering properties of resveratrol contribute to its beneficial cardiovascular effects. Despite the promise of resveratrol as a treatment for numerous cardiovascular diseases, the clinical studies for resveratrol are still limited. In addition, several conflicting results from trials have been reported, which demonstrates the challenges that face the translation of the exciting preclinical findings to humans. Herein, we will review much of the preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular disease and provide information about the physiological and molecular signaling mechanisms involved. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes. PMID- 25451968 TI - Neuroprotective effect of purple rice extract and its constituent against amyloid beta-induced neuronal cell death in SK-N-SH cells. AB - This study evaluated the protective effects of purple rice (Oryza sativa L.) extract (PRE) and its major constituent, cyanidin, and their underlying mechanisms against Abeta 25-35-induced neuronal cell death in SK-N-SH cells. Abeta 25-35-induced neuronal toxicity is characterized by decrease in cell viability, the release of lactate dehydrogenase (LDH), decrease superoxide dismutase (SOD) activity, increase in reactive oxygen species (ROS) production, morphological alteration, and activation of mitochondrial death pathway. Pretreatment with PRE and cyanidin significantly attenuated Abeta 25-35-induced loss of cell viability, apoptosis, and increase in ROS and RNS production in a dose-dependent manner. In addition, PRE and cyanidin also helped to bring about the downregulation of the expression of Bax, cytochrome c, cleavage caspase-9, and cleavage caspase-3 proteins, and the upregulation of the Bcl-XL protein in cascade. Therefore, it is evident that PRE and its major constituent, cyanidin, were successful in protecting from the cytotoxic effect of Abeta 25-35 through attenuation ROS and RNS production and modulation of mitochondrial death pathway in SK-N-SH cells. This result suggests that PRE and its major constituent, cyanidin, might be beneficial as potential therapeutic agents in preventing neurodegenerative diseases. PMID- 25451969 TI - Platelet hyperactivity, neurobehavioral symptoms and depression among Indian women chronically exposed to low level of arsenic. AB - The prevalence of neurobehavioral symptoms (NBS) and depression has been investigated in premenopausal rural women of West Bengal, India enrolled from arsenic (As) endemic (groundwater As 11-50 MUg/L; n = 342) and control areas (As level <= 10 MUg/L; n = 312). The subjective symptoms questionnaire and Beck's 21 point depression inventory-II were used for the detection of NBS and depression, respectively. Platelet P-selectin expression was measured by flow cytometry, plasma neurotransmitter activity with high performance liquid chromatography and groundwater As level by atomic absorption spectroscopy. The As level in groundwater was 2.72 +/- 1.18 MUg/L in control and 28.3 +/- 13.51 MUg/L in endemic areas (p < 0.0001). Women residing in endemic areas demonstrated a higher prevalence of depressive symptoms (39.8 vs. 19.9%, p < 0.001) and anxiety (43.3 vs. 18.0% in control, p < 0.001), fatigue (68.4 vs. 23.4%, p < 0.0001), reduced sense of taste (15.8 vs. 4.5%, p<0.0001) and smell (14.9 vs. 5.8%, p < 0.001); burning sensation (36.8 vs. 5.4%, p < 0.0001) and tingling or numbness in the extremities (25.1 vs. 5.1%, p < 0.0001); and transient loss of memory (69.9 vs. 28.2%, p < 0.001). As-exposed women had 1.6-times more plasma epinephrine and norepinephrine (p < 0.05), 1.8-times higher level plasma serotonin with 28.9% lower intraplatelet serotonin (p < 0.05 for both), but their plasma dopamine level was not significantly different (p>0.05) from that of controls. Moreover, women from endemic areas had 2.3-times more P-selectin-expressing platelets in their circulation (p < 0.001). After controlling the potential confounders, chronic low level As (11-50 MUg/L) exposure showed a positive association with the prevalence of neurobehavioral symptoms and depression among Indian women in their child-bearing age. PMID- 25451967 TI - Neuroprotective role of prostaglandin PGE2 EP2 receptor in hemin-mediated toxicity. AB - Heme (Fe(2+) protoporphyrin IX) and hemin (Fe(3+)), the prosthetic group of hemoprotein, are cytotoxic due to their ability to contribute to the production of reactive oxygen species, increased intracellular calcium levels, and stimulate glutamate-mediated excitotoxicity. Previous work by our group showed that blockade of the prostaglandin E2 (PGE2)-EP1 receptor reduced hemin-induced cytotoxicity in primary cortical neuronal cultures. However, the role of the prostaglandin E2 (PGE2)-EP2 receptor in hemin neurotoxicity remains unclear. Activation of the EP2 receptor in neurons results in increased cyclic AMP (cAMP) and protein kinase A signaling; therefore, we hypothesized that the activation of the EP2 receptor decreases hemin neurotoxicity. Using postnatal primary cortical neurons cultured from wildtype-control (WT) and EP2(-/-) mice, we investigated the role of the EP2 receptor in hemin neurotoxicity by monitoring cell survival with the Calcein-AM live-cell and lactate dehydrogenase assays. MitoTracker staining was also performed to determine how mitochondria were affected by hemin. Hemin neurotoxicity in EP2(-/-) neurons was 37.2 +/- 17.0% greater compared to WT neurons. Of interest, cotreatment with the EP2 receptor agonist, butaprost (1 and 10 MUM), significantly attenuated hemin neurotoxicity by 55.7 +/- 21.1% and 60.1 +/- 14.8%, respectively. To further investigate signaling mechanisms related to EP2 receptor mediating cytoprotection, neurons were cotreated with hemin and activators/inhibitors of both the cAMP-protein kinase A/exchange protein directly activated by cAMP (Epac) pathways. Forskolin, a cAMP activator, and 8-pCPT-cAMP, an Epac activator, both attenuated hemin neurotoxicity by 78.8 +/- 22.2% and 58.4 +/- 9.8%, respectively, as measured using the lactate dehydrogenase assay. Together, the results reveal that activation of the EP2 receptor is protective against hemin neurotoxicity in vitro and these findings suggest that neuroprotection occurs through the cAMP-Epac pathway in neuronal cultures. Therefore, activation of the EP2 receptor could be used to minimize neuronal damage following exposure to supraphysiological levels of hemin. PMID- 25451970 TI - Changes in rat urinary porphyrin profiles predict the magnitude of the neurotoxic effects induced by a mixture of lead, arsenic and manganese. AB - The neurotoxic metals lead (Pb), arsenic (As) and manganese (Mn) are ubiquitous contaminants occurring as mixtures in environmental settings. The three metals may interfere with enzymes of the heme bioshyntetic pathway, leading to excessive porphyrin accumulation, which per se may trigger neurotoxicity. Given the multi mechanisms associated with metal toxicity, we posited that a single biomarker is unlikely to predict neurotoxicity that is induced by a mixture of metals. Our objective was to evaluate the ability of a combination of urinary porphyrins to predict the magnitude of motor activity impairment induced by a mixture of Pb/As/Mn. Five groups of Wistar rats were treated for 8 days with Pb (5mg/kg), As (60 mg/L) or Mn (10mg/kg), and the 3-metal mixture (same doses as the single metals) along with a control group. Motor activity was evaluated after the administration of the last dose and 24-hour (h) urine was also collected after the treatments. Porphyrin profiles were determined both in the urine and brain. Rats treated with the metal-mixture showed a significant decrease in motor parameters compared with controls and the single metal-treated groups. Both brain and urinary porphyrin levels, when combined and analyzed by multiple linear regressions, were predictable of motor activity (p<0.05). The magnitude of change in urinary porphyrin profiles was consistent with the greatest impairments in motor activity as determined by receiver operating characteristic (ROC) curves, with a sensitivity of 88% and a specificity of 96%. Our work strongly suggests that the use of a linear combination of urinary prophyrin levels accurately predicts the magnitude of motor impairments in rats that is induced by a mixture of Pb, As and Mn. PMID- 25451971 TI - S100beta in heavy metal-related child attention-deficit hyperactivity disorder in an informal e-waste recycling area. AB - Exposure to lead even at low levels correlates with attention deficit/hyperactivity disorder (ADHD). However, lead-contaminated environments are often contaminated with other heavy metals that could exacerbate lead-induced ADHD. We conducted this study to evaluate the relationship between multiple heavy metals and child behaviors, and the involvement of S100 calcium-binding protein beta (S100beta) expression in child ADHD in Guiyu, an internationally-known e waste contaminated recycling town. Two hundred and forty kindergarten children, 3 to 7-years of age, who lived in Guiyu, were recruited for this study. Child behavioral assessment was derived from parent and teacher ratings. Serum S100beta was assayed by an enzyme-linked immunosorbent assay (ELISA). Lead (Pb), cadmium (Cd) and manganese (Mn) levels in whole blood were measured using graphite furnace atomic absorption spectrometry (GFAAS). The prevalence of children with ADHD symptoms in Guiyu was 18.6%, with the percentage of children suspected to have behavior problems being 46.2% or 46.5%, based on the Rutter parents' or teachers' scale scores, respectively. Child blood levels of Pb, Cd, and Mn correlated with certain behavioral abnormalities, such as conduct problems and antisocial behavior. Serum S100beta levels were associated with heavy metal levels in blood, and certain behavioral abnormalities. These findings suggest that exposure to various environmental heavy metals in Guiyu might result in child behavior disorders. Results also indicate that S100beta may provide information for laboratory evaluation of neurotoxicity. PMID- 25451973 TI - Immunological cross-reactivity between four distant parvalbumins-Impact on allergen detection and diagnostics. AB - Fish are the largest and most diverse group of vertebrates. Fish are also a part of the eight food groups that cause the majority of IgE mediated food reactions. Detection tools for fish allergens are however limited due to the great diversity of fish species, despite fish allergy and its major allergen parvalbumin being well documented. The most commonly studied fish are frequently consumed in North America and Europe. However, much less is known about fish allergens in the Australasian region although fish is widely consumed in this region. A comprehensive phylogenetic analysis was performed of known parvalbumin amino acid sequences to determine possible candidate antigens for new cross-reactive antibodies to be used to detect most fish parvalbumins. Polyclonal rabbit antibodies were raised against parvalbumins from frequently consumed barramundi (Lates calcarifer), basa (Pangasius bocourti), pilchard (Sardinops sagax) and Atlantic salmon (Salmo salar). These were evaluated for cross-reactivity against a panel of 45 fish extracts (raw, heated and canned fish). Anti-barramundi parvalbumin proved to be the most cross-reactive antibody, detecting 87.5% of the 40 species analyzed, followed by anti-pilchard and anti-basa antibody. In contrast the anti-salmon antibody was very specific and only reacted to salmonidae and a few other fish. All analyzed fish species, except mahi mahi, swordfish, yellowfin tuna and all 5 canned fish had parvalbumin detected in raw extracts. However antibody reactivity to many fish was heat liable or susceptible to denaturation, demonstrating that some parvalbumins have most likely conformational epitopes, which lose antibody reactivity after heat treatment. We have demonstrated the generation of highly cross-reactive anti-parvalbumin antibodies that could be used for the detection of allergenic fish parvalbumin in contaminated food products. This cross-reactivity study thus shows processing of fish, especially canning, can have on impact on antibody recognition by ELISA, possibly similar to IgE-binding in vivo. PMID- 25451972 TI - Self-pMHCII complexes are variably expressed in the thymus and periphery independent of mRNA expression but dependent on the activation state of the APCs. AB - Self-peptide MHCII ligands are critical for selection of CD4+ T cells in the thymus, and maintenance in the periphery. To date, no investigation as to the exact thymic and peripheral expression of a naturally occurring positive selecting self-peptide MHCII (self-pMHCII) complex has taken place. We have generated a sensitive T cell hybridoma to functionally detect the endogenous presentation of a confirmed positive selecting self-pMHCII complex for a CD4+ transgenic T cell. Using this tool to survey and quantify the expression selecting of self-pMHCII, we have shown unequivocal proof that a known CD4+ selecting ligand can be presented on both positive and negative selecting thymic APCs. We also show that peripheral presentation of this same selecting ligand is affected by the activation state of the APCs. Furthermore, discrepancies between the gene expression and self-pMHCII complex presentation of this bona fide selecting ligand suggest that functional detection self-ligand complexes will be required to establish a complete view of the naturally presented endogenous self pMHC landscape. PMID- 25451974 TI - IgE recognition of chimeric isoforms of the honeybee (Apis mellifera) venom allergen Api m 10 evaluated by protein array technology. AB - Api m 10 has recently been established as novel major allergen that is recognized by more than 60% of honeybee venom (HBV) allergic patients. Previous studies suggest Api m 10 protein heterogeneity which may have implications for diagnosis and immunotherapy of HBV allergy. In the present study, RT-PCR revealed the expression of at least nine additional Api m 10 transcript isoforms by the venom glands. Two distinct mechanisms are responsible for the generation of these isoforms: while the previously known variant 2 is produced by an alternative splicing event, novel identified isoforms are intragenic chimeric transcripts. To the best of our knowledge, this is the first report of the identification of chimeric transcripts generated by the honeybee. By a retrospective proteomic analysis we found evidence for the presence of several of these isoforms in the venom proteome. Additionally, we analyzed IgE reactivity to different isoforms by protein array technology using sera from HBV allergic patients, which revealed that IgE recognition of Api m 10 is both isoform- and patient-specific. While it was previously demonstrated that the majority of HBV allergic patients display IgE reactivity to variant 2, our study also shows that some patients lacking IgE antibodies for variant 2 display IgE reactivity to two of the novel identified Api m 10 variants, i.e. variants 3 and 4. PMID- 25451975 TI - Highly reduced binding to high and low affinity mouse Fc gamma receptors by L234A/L235A and N297A Fc mutations engineered into mouse IgG2a. AB - The effects of the Fc silencing mutations such as leucine (L) to alanine (A) substitution at the position 234 and 235 (LALA) and the alanine (A) to asparagine (N) substitution at position 297 (N297A) are well investigated for human IgG. However, the effects of the same two silencing Fc mutations in a mouse IgG backbone are not yet well investigated in respect to binding to mouse Fc gamma receptors (FcgammaRs), complement and subsequent effector functions. By using a mouse IgG2a tool antibody directed against mouse OX40L, we demonstrate a strongly reduced binding of the two Fc mutants to high and low affinity recombinant and cell expressed mouse FcgammaRs, when compared to the mouse IgG2a with the wild type (wt) backbone. Reduced FcgammaR binding by the two investigated Fc mutants could further be confirmed on primary mouse macrophages expressing their native FcgammaRs. In addition, we reveal that the LALA and N297A mutations in the mIgG2a also slightly reduced binding to C1q of human origin. Thus, here we provide experimental evidence that the two investigated Fc mutations in the mouse IgG backbone lead to similar "silencing" properties as previously demonstrated for the human IgG and thus represent a useful method to alter effector functions in tool antibodies to be used in mouse models. PMID- 25451976 TI - Cellular energy sensors: AMPK and beyond. PMID- 25451977 TI - Oxytocin activates NF-kappaB-mediated inflammatory pathways in human gestational tissues. AB - Human labour, both at term and preterm, is preceded by NF-kappaB-mediated inflammatory activation within the uterus, leading to myometrial activation, fetal membrane remodelling and cervical ripening. The stimuli triggering inflammatory activation in normal human parturition are not fully understood. We show that the neurohypophyseal peptide, oxytocin (OT), activates NF-kappaB and stimulates downstream inflammatory pathways in human gestational tissues. OT stimulation (1 pM-100 nM) specifically via its receptor (OTR) in human myometrial and amnion primary cells led to MAPK and NF-kappaB activation within 15 min and maximal p65-subunit nuclear translocation within 30 min. Both in human myometrium and amnion, OT-induced activation of the canonical NF-kappaB pathway upregulated key inflammatory labour-associated genes including IL-8, CCL5, IL-6 and COX-2. IKKbeta inhibition (TPCA1; 10 uM) suppressed OT-induced NF-kappaB-p65 phosphorylation, whereas p65-siRNA knockdown reduced basal and OT-induced COX-2 levels in myometrium and amnion. In both gestational tissues, MEK1/2 (U0126; 10 uM) or p38 inhibition (SB203580; 10 uM) suppressed OT-induced COX-2 expression, but OT-induced p65-phosphorylation was only inhibited in amnion, suggesting OT activation of NF-kappaB in amnion is MAPK-dependent. Our data provide new insight into the OT/OTR system in human parturition and suggest that its therapeutic modulation could be a strategy for regulating both contractile and inflammatory pathways in the clinical context of term/preterm labour. PMID- 25451978 TI - In vitro differentiation between oxytocin- and vasopressin-secreting magnocellular neurons requires more than one experimental criterion. AB - The phenotypic differentiation between oxytocin (OT)- and vasopressin (VP) secreting magnocellular neurosecretory cells (MNCs) from the supraoptic nucleus is relevant to understanding how several physiological and pharmacological challenges affect their electrical activity. Although the firing patterns of OT and VP neurons, both in vivo and in vitro, may appear different from each other, much is assumed about their characteristics. These assumptions make it practically impossible to obtain a confident phenotypic differentiation based exclusively on the firing patterns. The presence of a sustained outward rectifying potassium current (SOR) and/or an inward rectifying hyperpolarization activated current (IR), which are presumably present in OT neurons and absent in VP neurons, has been used to distinguish between the two types of MNCs in the past. In this study, we aimed to analyze the accuracy of the phenotypic discrimination of MNCs based on the presence of rectifying currents using comparisons with the molecular phenotype of the cells, as determined by single cell RT-qPCR and immunohistochemistry. Our results demonstrated that the phenotypes classified according to the electrophysiological protocol in brain slices do not match their molecular counterparts because vasopressinergic and intermediate neurons also exhibit both outward and inward rectifying currents. In addition, we also show that MNCs can change the relative proportion of each cell phenotype when the system is challenged by chronic hypertonicity (70% water restriction for 7 days). We conclude that for in vitro preparations, the combination of mRNA detection and immunohistochemistry seems to be preferable when trying to characterize a single MNC phenotype. PMID- 25451980 TI - Unraveling the estrogen receptor (er) genes in Atlantic salmon (Salmo salar) reveals expression differences between the two adult life stages but little impact from polychlorinated biphenyl (PCB) load. AB - Estrogen receptors (ers) not only are activated by hormones but also interact with many human-derived environmental contaminants. Here, we present evidence for four expressed er genes in Atlantic salmon cDNA - two more ers (eralpha2 and erbeta2) than previously published. To determine if er gene expression differs between two adult life-stages we sampled 20 adult salmon from the feeding phase in the Baltic Sea and during migration in the River Morrum, Sweden. Results show that all four er genes are present in the investigated tissues, except for eralpha2 not appearing in the spleen. Overall, a profile analysis reveals the eralpha1 gene to be the most highly expressed er gene in both female and male Baltic Sea salmon tissues, and also in female River Morrum salmon. In contrast, this gene has the lowest gene expression level of the four er genes in male salmon from the River Morrum. The eralpha2 gene is expressed at the lowest levels in both female/male Baltic Sea salmon and in female River Morrum salmon. Statistical analyses indicate a significant and complex interaction where both sex and adult life stage can impact er gene expression. Regression analyses did not demonstrate any significant relationship between polychlorinated biphenyl (PCB) body burden and er gene expression level, suggesting that accumulated pollutants from the Baltic Sea may be deactivated inside the salmon's lipid tissues and have limited impact on er activity. This study is the first comprehensive analysis of four er gene expression levels in two wild salmon populations from two different adult life stages where information about PCB load is also available. PMID- 25451979 TI - Estrogen mediated epithelial proliferation in the uterus is directed by stromal Fgf10 and Bmp8a. AB - To define endometrial stromal-derived paracrine mediators that participate in estradiol-17beta (E2)-induced epithelial proliferation, microarray analysis of gene expression was carried out in mouse uterine epithelial-stromal co-culture systems under the condition of E2 or vehicle (control). Our results demonstrated gene alteration by E2: in epithelial cells, we found up-regulation of 119 genes and down-regulation of 28 genes, while in stroma cells we found up-regulation of 144 genes and down-regulation of 184 genes. A functional enrichment analysis of the upregulated epithelial genes implicated them for proliferation, while upregulated stromal genes were associated with extracellular functions. Quantitative RT-PCR and in situ hybridization results confirmed differential gene expression in both cell cultures and ovariectomized uteri after the above treatments. Based on our identification of stromal secretory factors, we found evidence that suppression by siRNA specifically for Bmp8a and/or Fgf10 in the stromal layer caused significant inhibition of proliferation by E2 in the co culture system, suggesting Bmp8a and Fgf10 act as paracrine mediators during E2 dependent control of uterine proliferation. The localization of receptors and receptor activation signaling in epithelial cells in both the co-culture system and uteri was consistent with their involvement in ligand-receptor signaling. Interestingly, loss of Bmp8a or Fgf10 also caused abrogation of E2-regulated epithelial receptor signaling in co-culture systems, suggesting that stroma derived Fgf10 and Bmp8a are responsible for epithelial communication. Overall, stromal Fgf10 and Bmp8a serve as potential paracrine factors for E2-dependent regulation of epithelial proliferation in the uterus. PMID- 25451981 TI - Regulation of transcriptional activation function of rat estrogen receptor alpha (ERalpha) by novel C-terminal splice inserts. AB - Estrogen receptor alpha (ERalpha) mediates estrogen diverse actions on tissues. ERalpha gene has eight constitutively expressing exons and is known to have multiple isoforms generated by alternative initiation of transcription and splicing events including exon skipping. We have discovered two novel exons inserted between exon 5 and 6 of rat ERalpha that can add independently or in tandem 18 and 14 amino acids to the estrogen binding/activator function 2 domain of the receptor. Their transcript expression is three to six fold higher in heart compared to brain, aorta, liver, ovary and uterus. In heart, the new variants increased ~2 fold with animal growth from prenatal to adulthood, and had a minor increment in aged animals (28 months). Inclusion of these exons yields a receptor with practically no binding capacity for estrogen and reduced dimerization. The new variants show nuclear localization but are less efficient in binding to estrogen responsive elements (EREs) and failed to transcriptionally activate promoters containing EREs (mSlo, KCNE2). Thus, the new variants can regulate the wild-type receptor function and may contribute to the regulatory action of estrogen, especially in the maturing heart where they are more abundant. PMID- 25451982 TI - Metabolic syndrome-associated sperm alterations in an experimental rabbit model: relation with metabolic profile, testis and epididymis gene expression and effect of tamoxifen treatment. AB - The influence of metabolic syndrome (MetS) on sperm quality and function is debated. Using a well-established high fat diet (HFD) rabbit model resembling human MetS, including development of hypogonadism, we demonstrate that HFD decreased sperm motility, morphology and acrosome reaction in response to progesterone and increased sperm cholesterol content. All the above parameters were associated with most MetS features, its severity and plasma testosterone (T) at univariate analysis. After T adjustment, sperm morphology and motility retained a significant association, respectively, with mean arterial pressure and circulating cholesterol levels. MetS modified the expression of inflammatory and tissue remodelling genes in the testis and of aquaporins in the epididymis. In a multivariate analysis, sperm morphology resulted associated with testis expression of fibronectin and collagen type 1 genes, whereas motility with epididymis aquaporin 1 gene. Administration of tamoxifen, used in the treatment of idiopathic male infertility, to HFD rabbits partially restored motility, but further decreased morphology and increased spontaneous acrosome reaction, without restoring responsiveness to progesterone. Overall our results indicate that development of MetS produces detrimental effects on sperm quality and functionality by inducing metabolic disorders leading to alterations in testis and epididymis functions and evidence a role of hypertension as a new determinant of abnormal sperm morphology, in line with a previous human study from our group. PMID- 25451983 TI - Emission turn-on and solubility turn-off in conjugated polymers: one- and two photon-induced removal of fluorescence-quenching solubilizing groups. AB - The synthesis of highly efficient two-photon uncaging groups and their potential use in functional conjugated polymers for post-polymerization modification are reported. Careful structural design of the employed nitrophenethyl caging groups allows to efficiently induce bond scission by a two-photon process through a combination of exceptionally high two-photon absorption cross-sections and high reaction quantum yields. Furthermore, pi-conjugated polyfluorenes are functionalized with these photocleavable side groups and it is possible to alter their emission properties and solubility behavior by simple light irradiation. Cleavage of side groups leads to a turn-on of the fluorescence while solubility of the pi-conjugated materials is drastically reduced. PMID- 25451984 TI - The suprachiasmatic nuclei as a seasonal clock. AB - In mammals, the suprachiasmatic nucleus (SCN) contains a central clock that synchronizes daily (i.e., 24-h) rhythms in physiology and behavior. SCN neurons are cell-autonomous oscillators that act synchronously to produce a coherent circadian rhythm. In addition, the SCN helps regulate seasonal rhythmicity. Photic information is perceived by the SCN and transmitted to the pineal gland, where it regulates melatonin production. Within the SCN, adaptations to changing photoperiod are reflected in changes in neurotransmitters and clock gene expression, resulting in waveform changes in rhythmic electrical activity, a major output of the SCN. Efferent pathways regulate the seasonal timing of breeding and hibernation. In humans, seasonal physiology and behavioral rhythms are also present, and the human SCN has seasonally rhythmic neurotransmitter levels and morphology. In summary, the SCN perceives and encodes changes in day length and drives seasonal changes in downstream pathways and structures in order to adapt to the changing seasons. PMID- 25451986 TI - Capsule commentary on Unroe et al., hospice use among nursing home and non nursing home patients. PMID- 25451985 TI - Effect of chorioamnionitis on regulatory T cells in moderate/late preterm neonates. AB - Regulatory T-cells (Treg) have a protective role for the control of immune activation and tissue damage. The effects of chorioamnionitis (chorio) on Treg in moderate/late preterm newborns are not known. We hypothesized that infants exposed to chorio would have decreased Treg frequency and/or function. We isolated mononuclear cells from adult peripheral blood and cord blood from term and moderate/late preterm infants who were classified for severity of chorio exposure. Mononuclear cells were analyzed by flow cytometry for Treg frequency and phenotype. Treg suppression of activation of conventional T-cells (Tcon) was also quantified. Treg frequencies were similar in all groups of neonates, but lower than that found in adults. Newborn Treg had a naive phenotype, with decreased levels of CD45RO, HLA-DR, CD39 and TIGIT compared to adult Treg and chorio did not affect the phenotype. Treg from preterm newborns exposed to severe chorio had higher expression of Ki67 compared to the other groups. Treg from preterm newborns were less suppressive than Treg from adults or term, and the level of suppression was reduced with severe chorio. Relative to term, Treg frequency and phenotype were not affected by prematurity and chorio but their functionality was decreased. Lower Treg activity may contribute to inflammation in newborns that is often associated with chorioamnionitis. PMID- 25451987 TI - Association of early post-discharge follow-up by a primary care physician and 30 day rehospitalization among older adults. AB - BACKGROUND: Rehospitalizations within 30 days of discharge are responsible for a large portion of healthcare spending. One approach to preventing rehospitalizations is early follow-up, usually defined as an office visit with a primary care physician within 7 days of discharge--an approach that is being incentivized by health plans. However, evidence regarding its effectiveness is limited. OBJECTIVE: We aimed to determine whether an office visit with a primary care physician within 7 days after discharge is associated with 30-day rehospitalization. DESIGN: This was an observational study set within a randomized trial. PARTICIPANTS: The study included patients age 65 and older receiving care from a multi-specialty group practice and discharged from hospital to home between 26 August 2010 and 25 August 2011. To control for confounding, we identified characteristics of patients and hospital stays that are predictive of rehospitalization, and also developed high-dimensional propensity scores. Analyses used Cox proportional hazards models and took into account varying amounts of opportunity time for office visits. MAIN MEASURES: We looked at 30-day rehospitalizations at any hospital. KEY RESULTS: Of 3,661 patients discharged to home during the study year, 707 (19.3%) were rehospitalized within 30 days. Patients receiving an office visit within 7 days numbered 1,808 (49.4%), and of these, 1,000 (27.3%) were with a primary care physician. In models predicting rehospitalization, stratified on deciles of propensity score and controlling for additional confounders, the hazard ratios associated with office visits with a primary care physician within 7 days were 0.98 (95% CI 0.80, 1.21); for visits with any physician, the hazard ratio was HR 1.04, (95% CI 0.87, 1.25). CONCLUSIONS: We found no protective effect for office visits within 7 days. Such visits may need to be specifically focused on a range of issues related to the specific reasons why patients are rehospitalized. It is likely that outpatient visits will need to be set within comprehensive transition programs. PMID- 25451988 TI - Aspirin for primary prevention: what's a clinician to do? PMID- 25451989 TI - Using a single item to measure burnout in primary care staff: a psychometric evaluation. AB - BACKGROUND: Burnout affects nearly half of all U.S. nurses and physicians, and has been linked to poor outcomes such as worse patient safety. The most common measure of burnout is the well-validated Maslach Burnout Inventory (MBI). However, the MBI is proprietary and carries licensing fees, posing challenges to routine or repeated assessment. OBJECTIVE: To compare a non-proprietary, single item burnout measure to a single item from the MBI Emotional Exhaustion (MBI:EE) subscale that has been validated as a standalone burnout measure. DESIGN: Cross sectional online survey. PARTICIPANTS: A sample of primary care providers (PCPs), registered nurses, clinical associates (e.g., licensed practical nurses (LPNs), medical technicians), and administrative clerks in the Veterans Health Administration surveyed in 2012. MAIN METHODS: We compared a validated one-item version of the MBI:EE and a non-proprietary single-item burnout measure used in the Physician Work Life Study. We calculated kappa statistics, sensitivity and specificity, positive predictive (PPV) and negative predictive values (NPV), and area under the receiver operator curve (AUC). We conducted analyses stratified by occupation to determine the stability of the correlation between the two measures. KEY RESULTS: We analyzed responses from 5,404 participants, including 1,769 providers and 1,380 registered nurses. The prevalence of burnout was 36.7% as measured on the single MBI:EE item and 38.5% as measured on the non proprietary single-item measure. Relative to the MBI:EE, the non-proprietary single-item measure had a correlation of 0.79, sensitivity of 83.2%, specificity of 87.4%, and AUC of 0.93 (se = 0.004). Results were similar when stratified by respondent occupation. CONCLUSIONS: A non-proprietary single-item measure served as a reliable substitute for the MBI:EE across occupations. Because it is non proprietary and easy to interpret, it has logistical advantages over the one-item MBI. PMID- 25451990 TI - Impact of a randomized controlled educational trial to improve physician practice behaviors around screening for inherited breast cancer. AB - BACKGROUND: Many primary care physicians (PCPs) are ill-equipped to provide screening and counseling for inherited breast cancer. OBJECTIVE: To evaluate the outcomes of an interactive web-based genetics curriculum versus text curriculum for primary care physicians. DESIGN: Randomized two-group design. PARTICIPANTS: 121 California and Pennsylvania community physicians. INTERVENTION: Web-based interactive genetics curriculum, evaluated against a control group of physicians who studied genetics review articles. After education, physicians interacted with an announced standardized patient (SP) at risk for inherited breast cancer. MAIN MEASURES: Transcripts of visit discussions were coded for presence or absence of 69 topics relevant to inherited breast cancer. KEY RESULTS: Across all physicians, history-taking, discussions of test result implications, and exploration of ethical and legal issues were incomplete. Approximately half of physicians offered a genetic counseling referral (54.6%), and fewer (43.8%) recommended testing. Intervention physicians were more likely than controls to explore genetic counseling benefits (78.3% versus 60.7%, P = 0.048), encourage genetic counseling before testing (38.3% versus 21.3%, P = 0.048), ask about a family history of prostate cancer (25.0% versus 6.6%, P = 0.006), and report that a positive result indicated an increased risk of prostate cancer for male relatives (20.0% versus 1.6%, P = 0.001). Intervention-group physicians were less likely than controls to ask about Ashkenazi heritage (13.3% versus 34.4%, P = 0.01) or to reply that they would get tested when asked, "What would you do?" (33.3% versus 54.1%, P = 0.03). CONCLUSIONS: Physicians infrequently performed key counseling behaviors, and this was true regardless of whether they had completed the web-based interactive training or read clinical reviews. PMID- 25451991 TI - Predicting and communicating risk of clinical deterioration: an observational cohort study of internal medicine residents. AB - BACKGROUND: Despite its importance, little is known about internal medicine (IM) residents' ability to assess and communicate a patient's overnight risk during the resident-to-resident handoff. OBJECTIVE: To evaluate IM residents' ability to identify patients at risk for clinical deterioration using the Patient Acuity Rating (PAR) tool (scored on a 1-7 symmetric scale; 1="Extremely unlikely", 7="Extremely likely"), and to measure how well IM residents conveyed a patient's potential for clinical deterioration during day-to-night handoff. DESIGN AND PARTICIPANTS: Observational cohort study of 46 postgraduate year 1 (PGY-1) and 32 postgraduate year 3 (PGY-3) internal medicine residents rotating on one of four general medicine services from October 2013 through January 2014. MAIN MEASURES: Primary outcomes were (1) level of agreement between resident handoff giver and receiver regarding patients' clinical risk and (2) accuracy of resident-assigned PAR score in predicting a patient's risk of clinical deterioration over the subsequent 24 hours. KEY RESULTS: Analysis of PGY-1 giver-receiver handoff agreement revealed an intraclass correlation coefficient (ICC) (95 % CI) of 0.51 (0.45-0.56), while PGY-3 giver-receiver agreement yielded an ICC (95 % CI) of 0.42 (0.36-0.47). Based on 865 ratings of 378 patients, PGY-1 handoff giver PAR scores of 5 and 6+ were significantly associated with increased odds of clinical deterioration within 24 hours (aOR = 6.5 and 12.4; P = 0.03 and 0.005, respectively). For the 1,170 PAR ratings of 438 patients assigned by PGY-3 handoff givers, PAR scores of 4, 5, and 6+ were significantly associated with increased odds of an event within 24 hours (aORs = 6.0, 9.6, and 18.1; P = 0.03, 0.01, and 0.0008, respectively). CONCLUSIONS: The PAR is a useful tool to quantify IM residents' judgment of patient stability, and may be particularly valuable during resident handoff, given that the level of agreement between giver and receiver regarding patient risk is only fair. PMID- 25451993 TI - Capsule commentary on O'Malley et al., overcoming challenges to teamwork in patient-centered medical homes: a qualitative study. PMID- 25451994 TI - Musical interlude. PMID- 25451992 TI - Gender, race, and variation in the evaluation of microscopic hematuria among Medicare beneficiaries. AB - BACKGROUND: Female gender and black race are associated with delayed diagnosis and inferior survival in patients with bladder cancer. OBJECTIVE: We aimed to determine the association between gender, race, and evaluation of microscopic hematuria (an early sign of bladder cancer). DESIGN AND PARTICIPANTS: This was a cohort study using a 5 % random sample of fee-for-service Medicare beneficiaries diagnosed with incident hematuria (International Classification of Diseases, Ninth Revision [ICD-9] code 599.7x) between January 2009 and June 2010 in a primary care setting. Beneficiaries with pre-existing explanatory diagnoses or genitourinary procedures were excluded. MAIN MEASURES: The main endpoint was completeness of the hematuria evaluation in the 180 days after diagnosis. Evaluations were categorized as complete, incomplete, or absent based on receipt of relevant diagnostic procedures and imaging studies. KEY RESULTS: In all, 9,211 beneficiaries met the study criteria. Hematuria evaluations were complete in 14 %, incomplete in 21 %, and absent in 65 % of subjects. Compared to males, females were less likely to have a procedure (26 vs. 12 %), imaging (41 vs. 30 %), and a complete evaluation (22 vs. 10 %) (p < 0.001 for each comparison). Receipt of a complete evaluation did not differ by race. Controlling for baseline characteristics, a complete evaluation was less likely in white women (OR, 0.40 [95 % CI, 0.35-0.46]) and black women (OR, 0.46 [95 % CI, 0.29-0.70]) compared to white men; no difference was found between black and white men. CONCLUSIONS: Women are less likely than men to undergo a complete and timely hematuria evaluation, a finding likely relevant to women's more advanced stage at bladder cancer diagnosis. System-level process improvement between providers of urologic and primary care in the evaluation of hematuria may benefit women harboring malignancy. PMID- 25451996 TI - Diets and the heart. So many to choose from, but which work? PMID- 25451995 TI - Antecedents and consequences of fear of childbirth in nulliparous and parous women. AB - The study aimed to explore the differences in the role of specific personal and interpersonal risk factors in predicting fear of childbirth (FOC) and to examine whether FOC predicts postnatal maternal adaptation in nulliparous and parous women. A prospective correlational design with two time periods (pre- and postnatal) was carried out with 158 women, 85 nulliparous and 73 parous. Women at Week 32 of gestation completed a demographic questionnaire, the Wijma Delivery Expectancy Questionnaire (K.Wijma, B. Wijma, & M. Zar, 1998), the State-Trait Anxiety Inventory (C.D. Spielberger, R.L. Gorsuch, & R.E. Lushene, 1970), the Symptom Checklist-90-Revised (L.R. Derogatis, 1983), the Dyadic Adjustment Scale (G.B. Spanier, 1976), and the Reciprocal Attachment Questionnaire (M. West, A. Sheldon, & L. Reiffer, 1987). Three months after delivery, the women completed the Edinburgh Postnatal Depression Scale (J.L. Cox, J.M. Holden, & R. Sagovsky, 1987) and the Parenting Stress Index-Short Form (R. Abidin, 1986). Pearson's correlations and a series of multiple regressions were conducted. The results indicated that in the prenatal period, higher state anxiety, beta = .35, p < .001, lower dyadic adjustment, beta = -.26, p = .03, and higher insecurity in attachment relationships, beta = .39, p < .001, predicted FOC in first-time mothers only. In the postnatal period, FOC predicted postnatal maternal risk for depression, beta = .39, p = .02, and parenting stress, beta = .42, p = .02, for nulliparous women only. The specific antecedents and consequences of FOC in nulliparous and parous women should be taken into consideration when developing specific interventions. PMID- 25451997 TI - Pentacycloundecylamines and conjugates thereof as chemosensitizers and reversed chloroquine agents. AB - The control of malaria has been complicated by increased resistance of the malaria parasite to existing antimalarials such as chloroquine (CQ). Herein, we report the ability of NGP1-01, the prototype pentacycloundecylamine (PCU), to reverse CQ resistance (>50%) and act as a chemosensitizer. Based on this finding we set out to synthesize a small series of novel agents comprising of a PCU moiety as the reversal agent conjugated to a CQ-like aminoquinoline (AM) molecule and evaluate the potential of these PCU-AM derivatives as reversed CQ agents. PCU AM derivatives 1-3 showed anti-plasmodial IC50 values in the ranges of 3.74-17.6 nM and 27.6-253.5 nM against CQ-sensitive (D10) and CQ-resistant strains (Dd2) of Plasmodium falciparum, respectively. Compound 1 presented with the best antiplasmodial activity at low nM concentrations against both strains and was found to be 5 fold more active against the resistant strain than CQ. Compound 1 can be considered as a lead compound to develop reversed CQ agents with improved pharmacodynamic and pharmacokinetic properties. PMID- 25451998 TI - 2-Butyl-4-chloroimidazole based substituted piperazine-thiosemicarbazone hybrids as potent inhibitors of Mycobacterium tuberculosis. AB - Here a series of 2-butyl-4-chloroimidazole based substituted piperazine thiosemicarbazone hybrids were designed by combining three different pharmacophoric fragments in single molecular architecture. 2-Butyl-4-chloro-1-(3 (4-substituted)piperazin-1-yl)propyl)-1H-imidazole-5-carbaldehydes (4a-p) prepared by reacting carboxaldehyde 2 with N-alkyl piperazines 3a-p which were condensed with thiosemicarbazine to give desired compounds 5a-p in very good yields. Among all sixteen compounds screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB), two compounds (E)-2-((2 butyl-4-chloro-1-(3-(4-(o-tolyl) piperazin-1-yl)propyl)-1H-imidazol-5 yl)methylene)hydrazinecarbothioamide 5e and (E)-2-((2-butyl-4-chloro-1-(3-(4-(2 methoxyphenyl)piperazin-1-yl)propyl)-1H-imidazol-5-yl)methylene) hydrazine carbothioamide 5f were found to be the most potent antitubercular agents (MIC: 3.13 MUg/mL) with low toxicity profile. PMID- 25451999 TI - Amine-linked diquercitols as new alpha-glucosidase inhibitors. AB - Two new diastereomeric amine-linked diquercitols 7 and 8 were synthesized by reductive amination of ketoquercitol 4 and epimeric aminoquercitols 3 and 6. The ketone and amines were successfully prepared, without the formation of byproducts, from naturally available (+)-proto-quercitol (1). The amine-linked diquercitols showed inhibitory effect against alpha-glucosidases with more pronounced potency than their original aminoquercitol monomers. PMID- 25452000 TI - Tritium-labeled (E,E)-2,5-bis(4'-hydroxy-3'-carboxystyryl)benzene as a probe for beta-amyloid fibrils. AB - Accumulation of Abeta in the brains of Alzheimer disease (AD) patients reflects an imbalance between Abeta production and clearance from their brains. Alternative cleavage of amyloid precursor protein (APP) by processing proteases generates soluble APP fragments including the neurotoxic amyloid Abeta40 and Abeta42 peptides that assemble into fibrils and form plaques. Plaque-buildup occurs over an extended time-frame, and the early detection and modulation of plaque formation are areas of active research. Radiolabeled probes for the detection of amyloid plaques and fibrils in living subjects are important for noninvasive evaluation of AD diagnosis, progression, and differentiation of AD from other neurodegenerative diseases and age-related cognitive decline. Tritium labeled (E,E)-1-[(3)H]-2,5-bis(4'-hydroxy-3'-carbomethoxystyryl)benzene possesses an improved level of chemical stability relative to a previously reported radioiodinated analog for radiometric quantification of Abeta plaque and tau pathology in brain tissue and in vitro studies with synthetic Abeta and tau fibrils. PMID- 25452001 TI - Synthesis and SAR of thieno[3,2-b]pyridinyl urea derivatives as urotensin-II receptor antagonists. AB - The preparation and SAR profile of thieno[3,2-b]pyridinyl urea derivatives as novel and potent urotensin-II receptor antagonists are described. An activity optimization study, probing the effects of substituents on thieno[3,2-b]pyridinyl core and benzyl group of the piperidinyl moiety, led to the identification of p fluorobenzyl substituted thieno[3,2-b]pyridinyl urea 6n as a highly potent UT antagonist with an IC50 value of 13nM. Although 6n displays good metabolic stability and low hERG binding activity, it has an unacceptable oral bioavailability. PMID- 25452002 TI - A simple and widely applicable hit validation strategy for protein-protein interaction inhibitors based on a quantitative ligand displacement assay. AB - Identification of inhibitors for protein-protein interactions (PPIs) from high throughput screening (HTS) is challenging due to the weak affinity of primary hits. We present a hit validation strategy of PPI inhibitors using quantitative ligand displacement assay. From an HTS for Bcl-xL/Mcl-1 inhibitors, we obtained a hit candidate, I1, which potentially forms a reactive Michael acceptor, I2, inhibiting Bcl-xL/Mcl-1 through covalent modification. We confirmed rapid reversible and competitive binding of I1 with a probe peptide, suggesting non covalent binding. The advantages of our approach over biophysical assays include; simplicity, higher throughput, low protein consumption and universal application to PPIs including insoluble membrane proteins. PMID- 25452003 TI - DeltaF508-CFTR correctors: synthesis and evaluation of thiazole-tethered imidazolones, oxazoles, oxadiazoles, and thiadiazoles. AB - The most common mutation causing cystic fibrosis (CF) is deletion of phenylalanine residue 508 in the cystic fibrosis transmembrane regulator conductance (CFTR) protein. Small molecules that are able to correct the misfolding of defective DeltaF508-CFTR have considerable promise for therapy. Reported here are the design, preparation, and evaluation of five more hydrophilic bisazole analogs of previously identified bithiazole CF corrector 1. Interestingly, bisazole DeltaF508-CFTR corrector activity was not increased by incorporation of more H-bond acceptors (O or N), but correlated best with the overall bisazole molecular geometry. The structure activity data, together with molecular modeling, suggested that active bisazole correctors adopt a U-shaped conformation, and that corrector activity depends on the molecule's ability to access this molecular geometry. PMID- 25452004 TI - Compliance with a massive transfusion protocol (MTP) impacts patient outcome. AB - BACKGROUND: About 5% of civilian trauma requires massive transfusion. Protocolized resuscitation with blood products to achieve high plasma:RBC ratio has been advocated to improve survival. Our objectives were to measure compliance to our institutional MTP, to identify quality assurance activities that could improve protocol compliance and to determine if protocol compliance was related to patient outcome. METHODS: The investigators determined 13 compliance criteria based upon our institutional protocol. We measured compliance in 72 consecutive MTP activations between January 2010 and September 2011 at a Level I trauma centre. Data elements were retrospectively retrieved from blood bank, trauma registry and clinical records. Patients were stratified into three groups based on compliance level, and mortality differences were compared. RESULTS: Average compliance for the cohort (n=72) was 66%. The most common cause of non-compliance was failure to send a complete haemorrhage panel from the trauma bay (96%). Failure to monitoring blood work every 30min occurred in 89% of cases. Delay in activation and deactivation occurred in 50% and 50% respectively. Non-compliance to protocol-based administration of blood products happened in 47%. The cohort was stratified into three groups based on compliance, A: <60%, B: 60-80% and C: >80% (low, moderate and high compliance groups). There was no statistical significance with regard to median age, median ISS, ED SBP, ED GCS and AIS of the head/spine, chest and abdomen. The mortality rates in each group were 62%, 50% and 10% in the low, moderate and high compliance groups respectively. Mortality differences were compared using adjusted logistic regression. The OR for mortality between Groups A and B=1.1 [95% CI 0.258-4.687 (P=0.899)] while the OR for mortality between Groups C and B=0.02 [95% CI <0.001-0.855 (P=0.041)]. CONCLUSIONS: Measures should be directed towards provider and system factors to improve compliance. In this study, there was an association between survival and higher level of compliance. PMID- 25452005 TI - 3-D titanium mesh reconstruction of defective skull after frontal craniectomy in traumatic brain injury. AB - INTRODUCTION: Decompressive craniectomy (DC) is a treatment strategy used to reduce intracranial pressure in patients with traumatic brain injuries. However, this procedure has a number of shortcomings, such as excessive sinking of the skin flap, which can lead to cerebral compromise and negatively affect the appearance of the patient. The reconstruction of skull defects has been proposed as a means to overcome these disadvantages. Few previous studies have reported the reconstruction of frontal skull defects using titanium mesh. The aim of this study was to provide a comprehensive review of aesthetic and surgical outcomes associated with this procedure and to list the complications encountered during the repair of frontal skull defects using three-dimensional (3-D) titanium mesh. METHODS: A retrospective review was conducted using records from seven adult patients (32-60 years of age) who received titanium mesh implants at a university hospital in Taiwan between January 2011 and June 2012. Aesthetic outcomes, the function of cranial nerves V and VII, and complications (hardware extrusions, meningitis, osteomyelitis, brain abscess, and pneumocephalus) were evaluated. RESULTS: An algorithm capable of accounting for bifrontal skull defects and median bone ridges was developed to improve computer-assisted design/manufacturing (CAD/CAM) of one-piece 3-D titanium mesh implants, thereby making it possible to repair bifrontal skull defects in a single operation. Following this procedure, aesthetic and functional outcomes were excellent and the implants in all patients appeared stable. However, extended healing times in two of the patients resulted in subclinical infections, which were resolved by administering antibiotics over a period of 2 weeks. No patients suffered trigeminal or facial dysfunction. CONCLUSIONS: Our findings support the use of 3 D titanium mesh in frontal skull reconstruction. Few complications were encountered, the contours of the forehead were faithfully rendered, and the cosmetic appearance of patients was excellent. For patients with bifrontal skull defects, the use of one-piece implants in a single operation provides numerous advantages over conventional staged surgeries. This application helps to reduce operating time, which is particularly beneficial for elderly patients and those requiring bifrontal cranioplasties. PMID- 25452006 TI - Rising stars: modulation of brain functions by astroglial type-1 cannabinoid receptors. AB - The type-1-cannabinoid (CB1 ) receptor is amongst the most widely expressed G protein-coupled receptors in the brain. In few decades, CB1 receptors have been shown to regulate a large array of functions from brain cell development and survival to complex cognitive processes. Understanding the cellular mechanisms underlying these functions of CB1 is complex due to the heterogeneity of the brain cell types on which the receptor is expressed. Although the large majority of CB1 receptors act on neurons, early studies pointed to a direct control of CB1 receptors over astroglial functions including brain energy supply and neuroprotection. In line with the growing concept of the tripartite synapse highlighting astrocytes as direct players in synaptic plasticity, astroglial CB1 receptor signaling recently emerged as the mediator of several forms of synaptic plasticity associated to important cognitive functions. Here, we shortly review the current knowledge on CB1 receptor-mediated astroglial functions. This functional spectrum is large and most of the mechanisms by which CB1 receptors control astrocytes, as well as their consequences in vivo, are still unknown, requiring innovative approaches to improve this new cannabinoid research field. PMID- 25452007 TI - Analyzing Movements Development and Evaluation of the Body Awareness Scale Movement Quality (BAS MQ). AB - BACKGROUND AND PURPOSE: Limitations in everyday movements, physical activities are/or pain are the main reasons for seeking help from a physiotherapist. The purpose of this study was to investigate the psychometric properties of the Body Awareness Scale Movement Quality (BAS MQ) focusing on factor structure, validity and reliability and to explore whether BAS MQ could discriminate between healthy individuals and patients. BAS MQ assesses both limitations and resources concerning functional ability and quality of movements. METHODS: The total sample in the study (n = 172) consisted of individuals with hip osteoarthritis (OA) (n = 132), individuals with psychiatric disorders (n = 33) and healthy individuals (n = 7). A factor analysis of the BAS MQ was performed for the total group. Inter rater reliability was tested in a group of individuals with hip OA (n = 24). Concurrent validity was tested in a group of individuals with hip OA (n = 89). The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), the 6-Minute Walk Test (6MWT) and the Hip Osteoarthritis Outcome Score (HOOS) were chosen in the validation process. RESULTS: The factor analysis revealed three factors that together explained 60.8% of the total variance of BAS MQ. The inter-rater reliability was considered good or very good with a kappa value of 0.61. Significant correlations between BAS MQ and SF-36, HOOS and 6MWT in the subjects with hip OA confirmed the validity. The BAS MQ was able to discriminate between healthy individuals and individuals with physical and psychiatric limitations. CONCLUSION: Results of the study revealed that BAS MQ has a satisfactory factor structure. The inter-rater reliability and validity were acceptable in a group of individuals with hip OA. BAS MQ could be a useful assessment tool for physiotherapists when evaluating the quality of everyday movements in different patient groups. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25452008 TI - Why do seals have cones? Behavioural evidence for colour-blindness in harbour seals. AB - All seals and cetaceans have lost at least one of two ancestral cone classes and should therefore be colour-blind. Nevertheless, earlier studies showed that these marine mammals can discriminate colours and a colour vision mechanism has been proposed which contrasts signals from cones and rods. However, these earlier studies underestimated the brightness discrimination abilities of these animals, so that they could have discriminated colours using brightness only. Using a psychophysical discrimination experiment, we showed that a harbour seal can solve a colour discrimination task by means of brightness discrimination alone. Performing a series of experiments in which two harbour seals had to discriminate the brightness of colours, we also found strong evidence for purely scotopic (rod based) vision at light levels that lead to mesopic (rod-cone-based) vision in other mammals. This finding speaks against rod-cone-based colour vision in harbour seals. To test for colour-blindness, we used a cognitive approach involving a harbour seal trained to use a concept of same and different. We tested this seal with pairs of isoluminant stimuli that were either same or different in colour. If the seal had perceived colour, it would have responded to colour differences between stimuli. However, the seal responded with "same", providing strong evidence for colour-blindness. PMID- 25452010 TI - Neck muscle vibration can improve sensorimotor function in patients with neck pain. AB - BACKGROUND CONTEXT: People with neck pain display a diminished joint position sense and disturbed postural control, which is thought to be a result of impaired somatosensory afferent activity and/or integration. Afferent processing can be artificially manipulated by vibration and was shown to reduce motor performance in healthy subjects. However, the effect of vibration on sensorimotor function in neck pain patients is scarcely investigated. PURPOSE: To assess the effect of neck muscle vibration on joint position sense and postural control in neck pain subjects and healthy controls. STUDY DESIGN: Case control study. PATIENT SAMPLE: Thirteen neck pain patients and 10 healthy controls participated in the present study. OUTCOME MEASUREMENTS: Cervical joint position sense and dynamic and static postural stability. METHODS: Short-term, targeted neck muscle vibration with 100 Hz was applied after baseline measurement. RESULTS: Vibration had opposite effects in patients and healthy subjects. Patients showed improved joint position sense (p<.01) and reduced dynamic postural sway (p<.05) after vibration, whereas vibration resulted in reduced joint position sense acuity (p<.05) and a nonsignificant increase in postural sway in healthy controls. CONCLUSIONS: This is the first study showing an improved motor performance after neck muscle vibration in patients with neck pain. Thus, vibration may be used to counteract sensorimotor impairment of the cervical spine. Potential underlying mechanisms are discussed. PMID- 25452009 TI - Bipolar/rod-shaped microglia are proliferating microglia with distinct M1/M2 phenotypes. AB - Microglia are generally considered the resident immune cells in the central nervous system (CNS) that regulate the primary events of neuroinflammatory responses. Microglia also play key roles in repair and neurodegeneration of the CNS after injury. Recent studies showed that trains of bipolar/rod-shaped microglia align end-to-end along the CNS injury site during the initial recovery phase. However, the cellular characteristics of bipolar/rod-shaped microglia remain largely unknown. Here, we established a highly reproducible in vitro culture model system to enrich and characterize bipolar/rod-shaped microglia by simply generating multiple scratches on a poly-d-lysine/laminin-coated culture dish. Trains of bipolar/rod-shaped microglia formed and aligned along the scratches in a manner that morphologically resembled microglial trains observed in injured brain. These bipolar/rod-shaped microglia were highly proliferative and expressed various M1/M2 markers. Further analysis revealed that these bipolar/rod-shaped microglia quickly transformed into amoeboid microglia within 30 minutes of lipopolysaccharide treatment, leading to the upregulation of pro inflammatory cytokine gene expression and the activation of Jak/Stat. In summary, our culture system provides a model to further characterize this highly dynamic cell type. We suggest that bipolar/rod-shaped microglia are crucial for repairing the damaged CNS and that the molecular mechanisms underlying their morphological changes may serve as therapeutic biomarkers. PMID- 25452011 TI - Treatment of dystrophic scoliosis in neurofibromatosis Type 1 with one-stage posterior pedicle screw technique. AB - BACKGROUND CONTEXT: Corrective surgery for dystrophic scoliosis in neurofibromatosis Type 1 (NF-1) is challenging. There are various surgical methods, all with unsatisfactory outcomes. PURPOSE: The purpose of the study was to evaluate the clinical outcomes of the treatment of dystrophic scoliosis in NF 1 with one-stage posterior pedicle screw approach. STUDY DESIGN: This is a retrospective clinical study. PATIENT SAMPLE: Sixteen patients with dystrophic scoliosis in NF-1 underwent one-stage posterior surgery with pedicle screw system. OUTCOME MEASUREMENT: We used preoperative and postoperative whole-spine radiographs to determine coronal and sagittal Cobb angles (curve correction); distance between apex vertebra and central sacral vertical line (DAC), pelvic obliquity, and shoulder tilt (coronal balance improvement); and sagittal vertical axis and pelvic tilt angle (sagittal balance improvement). We assessed the fusion rate using fusion segment computed tomography scan. METHODS: Patients underwent surgery with or without osteotomy according to spinal flexibility. Fusion segment selection method of fusion segments selection which mean fusing from one or two levels proximal to upper end vertebra to one or two levels distal to the lower end vertebra (EV+1 or 2) or stable vertebrae fusion. There were no study-specific conflict of interest-associated biases. RESULTS: The average follow-up time was 40.9 months. Mean scoliosis and kyphosis improved from 83.2 degrees to 27.6 degrees and 58.5 degrees to 26.8 degrees , respectively; at the last follow-up, it was 30.4 degrees and 27.4 degrees , respectively. Mean DAC, pelvic obliquity, and shoulder tilt improved from 53.0 to 23.9, 8.1 to 4.9, and 9.8 to 7.5 mm, respectively. Sagittal vertical axis and pelvic tilt angle improved from -5.8 to 1.6 mm and 17.9 degrees to -5.8 degrees , respectively. During follow-up, mean coronal and sagittal correction losses were 2.8 degrees and 0.7 degrees , respectively. Two EV+1 or 2 patients had decompensation. No pseudoarthrosis was identified. CONCLUSIONS: The one-stage posterior pedicle screw approach is safe and effective in the treatment of dystrophic scoliosis in NF-1. Posterior vertebral column resection is recommended if flexibility is less than 35%. Stable vertebrae fusing is recommended. PMID- 25452012 TI - The spinal stenosis pedometer and nutrition lifestyle intervention (SSPANLI): development and pilot. AB - BACKGROUND CONTEXT: Owing to mobility limitations, people with lumbar spinal stenosis (LSS) are at risk for diseases of inactivity, including obesity. Therefore, weight management in LSS is critical. Body mass index is the strongest predictor of function in LSS, suggesting that weight loss may promote physical activity and provide a unique treatment option. We propose a lifestyle modification approach of physical activity and nutrition education, delivered through an e-health platform. PURPOSE: The purpose of this study was to develop and pilot an e-health intervention aimed at increasing physical activity and decreasing fat mass in people with LSS. STUDY DESIGN: The study design was based on intervention development and pilot. PATIENT SAMPLE: Ten overweight or obese individuals with LSS were confirmed clinically and on imaging. OUTCOME MEASURES: Self-reported measures were food record, Short-Form 36 (SF-36), pain scales, Swiss Spinal Stenosis Symptom and Physical Function Scales, Oswestry Disability Index (ODI), Pain Catastrophizing Questionnaire, Tampa Scale for Kinesiophobia, Center for Epidemiologic Studies(Depression) Scale, Behavioral Regular in Exercise Questionnaire, and Regulation for Eating Behavior Scale and physiologic measures were dual-energy X-ray absorptiometry (DXA), blood draw, 7-day accelerometry, self-paced walking test, and balance test. METHODS: The e-health platform was developed. INTERVENTION: during Week 1, participants received a pedometer and a personalized consultation with a dietitian and an exercise physiologist. For 12 weeks, participants logged on to the e-health Web site to access personal step goals, nutrition education videos, and a discussion board. Follow-up occurred at Week 13. RESULTS: Nine participants had a mean age of 67.5+/-6.7 years (60% women). Significant improvements were observed for fat mass (DXA), trunk fat mass, symptom severity (Swiss Symptom Scale), energy intake, maximum continuous activity (accelerometry), and mental health (SF-36) (p<.05). Nonsignificant improvements were observed for waist circumference, pain, ODI, and obesity biomarkers. Seventy percent lost weight, 50% increased walking capacity, and 60% increased quality of life. The mean increase in steps was 15%. CONCLUSIONS: The spinal stenosis pedometer and nutrition lifestyle intervention was shown to be feasible, attractive to participants, and effective in this small sample. This intervention provides people with LSS the opportunity to participate in their own health management, potentially improving access to care. Efficacy is currently being assessed in a randomized trial. PMID- 25452013 TI - Clinician proficiency in delivering manual treatment for neck pain within specified force ranges. AB - BACKGROUND CONTEXT: Neck pain is a common musculoskeletal complaint responsive to manual therapies. Doctors of chiropractic commonly use manual cervical distraction, a mobilization procedure, to treat neck pain patients. However, it is unknown if clinicians can consistently apply standardized cervical traction forces, a critical step toward identifying an optimal therapeutic dose. PURPOSE: To assess clinicians' proficiency in delivering manually applied traction forces within specified ranges to neck pain patients. STUDY DESIGN: An observational study nested within a randomized clinical trial. SAMPLE: Two research clinicians provided study interventions to 48 participants with neck pain. OUTCOME MEASURES: Clinician proficiency in delivering cervical traction forces within three specified ranges (low force, less than 20 N; medium force, 21-50 N; and high force 51-100 N). METHODS: Participants were randomly allocated to three force based treatment groups. Participants received five manual cervical distraction treatments over 2 weeks while lying prone on a treatment table instrumented with force sensors. Two clinicians delivered manual traction forces according to treatment groups. Clinicians treated participants first without real-time visual feedback displaying traction force and then with visual feedback. Peak traction force data were extracted and descriptively analyzed. RESULTS: Clinicians delivered manual cervical distraction treatments within the prescribed traction force ranges 75% of the time without visual feedback and 97% of the time with visual feedback. CONCLUSIONS: This study demonstrates that doctors of chiropractic can successfully deliver prescribed traction forces while treating neck pain patients, enabling the capability to conduct force-based dose response clinical studies. PMID- 25452014 TI - Paraganglioma of the cauda equina region. AB - BACKGROUND CONTEXT: Cauda equina paragangliomas (CEPs) are rare neuroendocrine tumors. The difficulty in differential diagnosis with other tumors of this region may be misleading for surgical planning and prognostic expectations. PURPOSE: To report on a rare case of CEP and review the most current information regarding the diagnosis, treatment options, and outcomes. STUDY DESIGN: Case report and literature review. PATIENT SAMPLE: One patient affected by CEP. METHODS: We report on a 33-year-old woman with a 2-month history of worsening low back pain, aggravated by sitting, bending, and coughing. Neurological examination revealed normal power and muscular tone, no sensory or sphincter abnormality, and normal reflex. Magnetic resonance imaging of the lumbar spine demonstrated an intradural extramedullary lesion at L3, with homogeneous contrast enhancement and hypointense punctate foci. The patient underwent an L3 laminectomy and tumor removal. Relevant articles covering CEPs from 1970 to the present were reviewed. RESULTS: The histopathological examinations described paraganglioma features. The postoperative course was uneventful, and all the symptoms resolved, with no tumor recurrence after 3 years' follow-up. CONCLUSIONS: Cauda equina paragangliomas are rare, benign, and slow-growing tumors. Except for its secreting tumor characteristics, preoperative CEP diagnosis is very difficult. Magnetic resonance imaging is important and may suggest specific radiological features for these tumors; however, these are only relative, and it is rare that diagnosis is made before surgery. Diagnosis is established by histological examination and electron microscopy, and immunohistochemical techniques must be used to achieve a correct diagnosis. Cauda equina paragangliomas are well-encapsulated tumors that may be cured by surgery alone, whereas radiotherapy is reserved for incompletely resected tumors. Overall, prolonged postoperative observation is mandatory because of the slow tumor evolution and the possibility of tumor relapse even up to 30 years after surgery. PMID- 25452015 TI - Evaluation of topical application and systemic administration of rosuvastatin in preventing epidural fibrosis in rats. AB - BACKGROUND CONTEXT: Epidural fibrosis is a major challenge in spine surgery, with some patients having recurrent symptoms secondary to excessive formation of scar tissue resulting in neurologic compression. One of the most important factors initiating the epidural fibrosis is assumed to be the transforming growth factor 1beta (TGF-1beta). Rosuvastatin (ROS) has shown to demonstrate preventive effects over fibrosis via inhibiting the TGF-1beta. PURPOSE: We hypothesized that ROS might have preventive effects over epidural fibrosis through the inhibition of TGF-1beta pathways. STUDY DESIGN: Experimental animal study. METHODS: Forty-eight adult male Wistar Albino rats were equally and randomly divided into four groups (laminectomy, spongostan, topical ROS, and systemic ROS). Laminectomy was performed at the L3 level in all rats. Four weeks later, the extent of epidural fibrosis was assessed both macroscopically and histopathologically. RESULTS: Our data revealed that topical application and systemic administration of ROS both were effective in reducing epidural fibrosis formation. Furthermore, the systemic administration of ROS yielded better results than topical application. CONCLUSIONS: Both topical application and systemic administration of ROS show meaningful preventive effects over epidural fibrosis through multiple mechanisms. The results of our study provide the first experimental evidence of the preventive effects of ROS over epidural fibrosis. PMID- 25452016 TI - Diagnostic value of oblique magnetic resonance images for evaluating cervical foraminal stenosis. AB - BACKGROUND CONTEXT: The benefits of oblique magnetic resonance imaging (MRI) reformations to assess cervical neural foramina have been reported previously in clinical and cadaveric studies. But there is a paucity of literature investigating intra- and interobserver variabilities for assessing cervical foraminal stenosis using oblique MRI views. PURPOSE: To determine the value of oblique MRI views compared with axial and sagittal views for assessing foraminal stenosis of the cervical spine using intra- and interobserver variabilities. STUDY DESIGN: A retrospective study. PATIENT SAMPLE: Twenty-six patients were included. OUTCOME MEASURES: Two independent reviewers blindly identified the presence of foraminal stenosis as definite or indeterminate on the sagittal, axial, and oblique views. The assessments using the different views were compared using an independent t test. Intra- and interobserver variabilities were assessed using Kappa analysis. METHODS: We evaluated the cervical spine MRIs of patients with varying degrees of foraminal stenosis. The mean age of the patients was 60.8 years (range 50-86 years). Male to female ratio was 16:10. The oblique images were obtained by reformatting the scans perpendicular to the long axis of the right and left neural foramina, respectively. RESULTS: The oblique or axial views had significantly greater confidence rates for determining the presence of foraminal stenosis than the sagittal views (92.3%, 88.1% vs. 58.0%, respectively, p=.000). The oblique view had significantly better intraobserver agreement than the sagittal and axial images. Both the axial and oblique views had significantly better interobserver agreement than the sagittal images. CONCLUSIONS: Oblique MRI views of the cervical spine significantly reduce the degree of intra- and interobserver variabilities and increase observer confidence in the assessment of foraminal stenosis. Our results suggest that routine use of oblique cervical MRI views might be useful for evaluating cervical foraminal stenosis. PMID- 25452017 TI - Effects of low back pain stabilization or movement system impairment treatments on voluntary postural adjustments: a randomized controlled trial. AB - BACKGROUND: People with low back pain (LBP) exhibit impaired anticipatory postural adjustments (APAs). OBJECTIVE: To evaluate whether current motor retraining treatments address LBP-associated changes in movement coordination during tasks that do and do not require APAs. DESIGN: Prospectively registered randomized controlled trial with a blinded assessor. SETTING: Outcome evaluations occurred in a university laboratory; treatments were carried out in outpatient physical therapy clinics. PATIENTS: Fifteen subjects without LBP and 33 subjects with chronic, recurrent, and nonspecific LBP. INTERVENTION: Twelve subjects with LBP received stabilization treatment, 21 received movement system impairment based treatment, for more than 6 weekly 1-hour sessions plus home exercises. MEASUREMENTS: Pre- and post-treatment, surface electromyography (EMG) was recorded bilaterally from trunk and leg muscles during unsupported and supported leg-lifting tasks, which did and did not require an APA, respectively. Vertical reaction forces under the contralateral leg were recorded to characterize the APA. Oswestry disability scores and numeric pain ratings were also recorded. RESULTS: Persons with LBP demonstrated an impaired APA compared with persons without LBP, characterized by increased premovement contralateral force application and increased postmovement trunk EMG amplitude, regardless of the task. After treatments, both groups similarly improved in disability and function; however, APA characteristics did not change (ie, force application or EMG amplitude) in either task. LIMITATIONS: Treating clinicians were not blinded to treatment allocation, only short-term outcomes were assessed, and main effects of treatment do not rule out nonspecific effects of time or repeated exposure. CONCLUSIONS: Movement impairments in persons with LBP are not limited to tasks requiring an APA. Stabilization and movement system impairment-based treatments for LBP do not ameliorate and may exacerbate APA impairments (ie, excessive force application and increased post-movement trunk muscle activation). PMID- 25452018 TI - Interspinous process devices versus standard conventional surgical decompression for lumbar spinal stenosis: cost-utility analysis. AB - BACKGROUND CONTEXT: In the 1980s, a new implant was developed to treat patients with intermittent neurogenic claudication caused by lumbar spinal stenosis (LSS). This implant is now widely used. PURPOSE: The objective of this study is to determine whether a favorable cost-effectiveness for interspinous process devices (IPDs) compared with conventional bony decompression is attained. STUDY DESIGN/SETTING: Cost-utility analysis was performed alongside a double-blind randomized controlled trial. Five neurosurgical centers (including one academic and four secondary level care centers) included participants for this study. PATIENT SAMPLE: One hundred fifty-nine patients with LSS were treated with the implantation of IPD and with bony decompression. Eighty participants received an IPD, and seventy-nine participants underwent spinal bony decompression. OUTCOME MEASURES: Outcome measures were quality-adjusted life-years (QALYs) and societal costs in the first year (estimated per quarter), estimated from patient-reported utilities (US and The Netherlands EuroQol 5D [EQ-5D] and EuroQol visual analog scale) and diaries on costs (health-care costs, patient costs, and productivity costs). METHODS: All analyses followed the intention-to-treat principle. Given the statistical uncertainty of differences between costs and QALYs, cost effectiveness acceptability curves graph the probability that a strategy is cost effective, as a function of willingness to pay. Paradigm Spine funded this trial but did not have any part in data analysis or the design and preparation of this article. RESULTS: According to the EQ-5D, the valuation of quality of life after IPD and decompression was not different. Mean utilities during all four quarters were, not significantly, less favorable after IPD according to the EQ-5D with a decrease in QALYs according to the US EQ-5D of 0.024 (95% confidence interval, 0.031 to 0.079). From a health-care perspective, the costs of IPD treatment were higher (difference ?3,030 per patient, 95% confidence interval, ?561-?5,498). This significant difference is mainly because of additional cost of implants of ?2,350 apiece. From a societal perspective, a nonsignificant difference of ?2,762 (95% confidence interval, -?1,572 to ?7,095) in favor of conventional bony decompression was found. CONCLUSIONS: Implantation of IPD as indirect decompressing device is highly unlikely to be cost effective compared with bony decompression for patients with intermittent neurogenic claudication caused by LSS. TRIAL REGISTRATION: Dutch Trial Register Number: NTR1307. PMID- 25452019 TI - Pertussis may be the cause of prolonged cough in adolescents and adults in the interepidemic period. AB - OBJECTIVE: This study was aimed to evaluate the prevalence of pertussis in adolescents and adults with cough lasting more than 14 days and less than 30 days. METHODS: This is a prospective observational study in interepidemic period of pertusis. Ten public health outpatient clinics in the city of Recife, Brazil, were randomly selected for the study. The study population consisted of individuals aged 10 years and over with cough that had lasted between 14 and 30 days. Nasopharyngeal swabs were collected for culture and PCR in order to identify Bordetella pertussis. We adopted the Centers for Disease Control and Prevention in the US (CDC) definition of cases of pertussis. RESULTS: A total of 192 individuals were identified as suspected cases. Their mean age was 40.7 years. Pertussis was confirmed in 10 of the 192 suspected cases, with an estimated prevalence of 5.21% (95% confidence interval 2.03-8.38). All cases met the clinical case definition for pertussis; one suspect had both culture and PCR positive. PCR confirmed 100% of the cases, 7/10 by PCR and 3/10 by epidemiological linkage with a case confirmed by PCR. CONCLUSION: During an interepidemic period, 1 in 20 cases of prolonged cough had pertussis, suggesting this is an important cause of prolonged cough in adolescents and adults. PMID- 25452021 TI - Sexual neurosteroids and synaptic plasticity in the hippocampus. AB - Sexual neurosteroids (SN), namely 17beta-estradiol (E2) and 5alpha dehydrotestosterone (DHT), are synthesized in the hippocampus, where they induce circuit modifications by changing the number of excitatory spine synapses in a paracrine and sex-specific manner. The mechanisms of this sex-specific synapse turnover, which are likely to affect cognitive functions, are poorly understood. We found that hippocampal neurons synthesize estradiol, which maintains LTP and synapses in females but not in males. In females, inhibition of estradiol synthesis results in impairment of LTP and synapse loss. These effects were not seen in males. The essential role of local estrogen on the stability and maintenance of connectivity in the hippocampus is consistent with age-related cognitive decline in women after menopause. In male animals the regulation of synaptic stability and plasticity by locally synthesized sexual steroids remains to be clarified. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25452020 TI - Effects of prefrontal cortex and hippocampal NMDA NR1-subunit deletion on complex cognitive and social behaviors. AB - Glutamate N-methyl-D-aspartate receptors (NMDARs) in the medial prefrontal cortex (mPFC) and hippocampus may play an integral role in complex cognitive and social deficits associated with a number of psychiatric illnesses including autism, mood disorders, and schizophrenia. We used localized infusions of adeno-associated virus Cre-recombinase in adult, targeted knock-in mice with loxP sites flanking exons 11-22 of the NR1 gene to investigate the effects of chronic NMDAR dysfunction in the mPFC and CA3 hippocampus on cognitive and social behavior. A 5 choice serial reaction time task (5-CSRTT) was used to monitor aspects of cognitive function that included attention and response inhibition. Social behavior was assessed using Crowley's sociability and preference for social novelty protocol. Chronic NMDAR dysfunction localized to the anterior cingulate/prelimbic mPFC or dorsal CA3 hippocampus differentially affected the response inhibition and social interaction. mPFC NR1-deletion increased perseverative responding in the 5-CSRTT and enhanced preference for social novelty, whereas CA3 NR1-deletion increased premature responding in the 5-CSRTT and decreased social approach behavior. These findings suggest that mPFC and CA3 NMDARs play selective roles in regulating compulsive and impulsive behavior, respectively. Furthermore, these findings are consistent with emerging evidence that these behaviors are mediated by distinct, albeit overlapping, neural circuits. Our data also suggest that NMDARs in these regions uniquely contribute to the expression of normal social behavior. In this case, mPFC and CA3 NMDARs appear to inhibit and facilitate aspects of social interaction, respectively. The latter dissociation raises the possibility that distinct circuits contribute to the expression of social intrusiveness and impoverished social interaction. PMID- 25452023 TI - Administration of human platelet-rich plasma reduces infarction volume and improves motor function in adult rats with focal ischemic stroke. AB - Platelet-rich plasma (PRP) is a milieu of bioactive factors, including platelet derived growth factor, transforming growth factor beta, among many others. Despite accumulating evidence on PRP's safety and efficacy for treating musculoskeletal injuries, limited studies have been performed using PRP in brain disorders. This study aimed to explore the potential benefits of administration of human PRP lysate after ischemic stroke in rats. An ischemic stroke model was generated by occlusion of the right middle cerebral artery, then 90 min later, stroke rats were randomly assigned to receive local infusion to the ischemic area of human PRP lysate, human albumin solution (HSA), saline or no treatment at all. An additional group of stroke rats received systemic infusion of human PRP lysate to further assess the therapeutic effects of this treatment. Results showed that while local infusion of HSA or saline, and systemic administration of human PRP lysate, compared to no treatment significantly reduced infarct volume (37.4%, 40.1%, and 39.9% vs 49.7%) and neurological deficit score (2.2, 2.6, and 2.8 vs 3.7), the greatest neuroprotection (31.0% infarct volume and 1.6 neurological deficit score) was found in stroke animals that received local intra-arterial infusion of human PRP lysate (p's<0.05). In conclusion, administration of human PRP attenuates brain injury after focal ischemia. Our results suggest PRP should be investigated further as a potential point-of-care biomaterial following stroke. PMID- 25452022 TI - Theta-burst LTP. AB - This review covers the spatial and temporal rules governing induction of hippocampal long-term potentiation (LTP) by theta-burst stimulation. Induction of LTP in field CA1 by high frequency stimulation bursts that resemble the burst discharges (complex-spikes) of hippocampal pyramidal neurons involves a multiple step mechanism. A single burst is insufficient for LTP induction because it evokes both excitatory and inhibitory currents that partially cancel and limit postsynaptic depolarization. Bursts repeated at the frequency (~5 Hz) of the endogenous theta rhythm induce maximal LTP, primarily because this frequency disables feed-forward inhibition and allows sufficient postsynaptic depolarization to activate voltage-sensitive NMDA receptors. The disinhibitory process, referred to as "priming", involves presynaptic GABA autoreceptors that inhibit GABA release. Activation of NMDA receptors allows a calcium flux into dendritic spines that serves as the proximal trigger for LTP. We include new data showing that theta-burst stimulation is more efficient than other forms of stimulation for LTP induction. In addition, we demonstrate that associative interactions between synapses activated during theta-bursts are limited to major dendritic domains since such interactions occur within apical or basal dendritic trees but not between them. We review evidence that recordings of electrophysiological responses during theta burst stimulation can help to determine if experimental manipulations that affect LTP do so by affecting events antecedent to the induction process, such as NMDA receptor activation, or downstream signaling cascades that result from postsynaptic calcium fluxes. Finally, we argue that theta-burst LTP represents a minimal model for stable, non decremental LTP that is more sensitive to a variety of experimental manipulations than is LTP induced by other stimulation paradigms. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25452024 TI - Effects of ethanol exposure and withdrawal on dendritic morphology and spine density in the nucleus accumbens core and shell. AB - Exposure to drugs of abuse can result in profound structural modifications on neurons in circuits involved in addiction that may contribute to drug dependence, withdrawal and related processes. Structural alterations on medium spiny neurons (MSNs) of the nucleus accumbens (NAc) have been observed following exposure to and withdrawal from a variety of drugs; however, relatively little is known about the effects of alcohol exposure and withdrawal on structural alterations of NAc MSNs. In the present study male rats were chronically exposed to vaporized ethanol for 10 days and underwent 1 or 7 days of withdrawal after which the brains were processed for Golgi-Cox staining and analysis of dendritic length, branching and spine density. MSNs of the NAc shell and core underwent different patterns of changes following ethanol exposure and withdrawal. At 1 day of withdrawal there were modest reductions in the dendritic length and branching of MSNs in both the core and the shell compared to control animals exposed only to air. At 7 days of withdrawal the length and branching of shell MSNs was reduced, whereas the length and branching of core MSNs were increased relative to the shell. The density of mature spines was increased in the core at 1 day of withdrawal, whereas the density of less mature spines was increased in both regions at 7 days of withdrawal. Collectively, these observations indicate that MSNs of the NAc core and shell undergo distinct patterns of structural modifications following ethanol exposure and withdrawal suggesting that modifications in dendritic structure in these regions may contribute differentially to ethanol withdrawal. PMID- 25452026 TI - Lithium prevents parkinsonian behavioral and striatal phenotypes in an aged parkin mutant transgenic mouse model. AB - Lithium has long been used as a treatment for the psychiatric disease bipolar disorder. However, previous studies suggest that lithium provides neuroprotective effects in neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease. The exact mechanism by which lithium exerts these effects still remains unclear. In the present study, we evaluated the effects of low-dose lithium treatment in an aged mouse model expressing a parkin mutation within dopaminergic neurons. We found that low-dose lithium treatment prevented motor impairment as demonstrated by the open field test, pole test, and rearing behavior. Furthermore, lithium prevented dopaminergic striatal degeneration in parkin animals. We also found that parkin-induced striatal astrogliosis and microglial activation were prevented by lithium treatment. Our results further corroborate the use of this parkin mutant transgenic mouse line as a model for PD for testing novel therapeutics. The findings of the present study also provide further validation that lithium could be re-purposed as a therapy for PD and suggest that anti-inflammatory effects may contribute to its neuroprotective mechanisms. PMID- 25452027 TI - Dynamic expression of 11beta-hydroxylase during testicular development, recrudescence and after hCG induction, in vivo and in vitro in catfish, Clarias batrachus. AB - Cytochrome P450 11beta-hydroxylase (11beta-h), is involved in the production of 11-hydroxytestosterone, an immediate precursor for 11-ketotestosterone (11-KT), a potent androgen in teleosts. To understand the role of 11beta-h in gonadal development, maturation, function and recrudescence in an annually reproducing teleost, the present study was conducted using Clarias batrachus. Four forms of 11beta-h cDNA, regular type (2.253 kb), variant 1 (1.290 kb), variant 2 (1.223 kb) and variant 3 (1.978 kb) were identified from the testis of catfish which expressed ubiquitously with high levels in testis. 11beta-h transcripts were detected as early as 0 days post hatch further, stage- and sex-dependent increase in the 11beta-h transcripts were seen during gonadal differentiation/development. In addition, high expression of 11beta-h (regular type) in pre-spawning phase was detected. Corroboratively, levels of 11-KT in serum and testicular tissue was high during pre-spawning and spawning phases, which might facilitate initiation and normal progression of spermatogenesis. The expression of 11beta-h was high after human chorionic gonadotropin induction in vivo (all forms), and in vitro (regular type). Immunohistochemical and immunofluorescence localization showed the presence of 11beta-h in Sertoli and interstitial/Leydig cells of the testis. These results suggest that 11beta-h is involved in late stages of testicular development, together with the regulation of seasonal reproductive cycle in catfish. PMID- 25452028 TI - Kisspeptin drives germ cell progression in the anuran amphibian Pelophylax esculentus: a study carried out in ex vivo testes. AB - Kisspeptin, via Gpr54 receptor, regulates puberty onset in most vertebrates. Thus, the direct involvement of kisspeptin activity in testis physiology was investigated in the anuran amphibian, Pelophylax esculentus. In this vertebrate gpr54 mRNA has been localized in both interstitial compartment and spermatogonia (SPG), whereas SPG proliferation requires the cooperation between estradiol and testicular Gonadotropin releasing hormone (Gnrh). In the pre-reproductive period, dose response curve to assess the effects of Kisspeptin-10 (Kp-10) was carried out in vitro (dose range: 10(-9)-10(-6)M; incubation times: 1 and 4h); proliferative activity and germ cell progression were evaluated by expression analysis of proliferating cell nuclear antigen (pcna), estrogen receptor beta (erbeta), Gnrh system (gnrh1, gnrh2, gnrhr1, r2, r3) and by the count of empty, mitotic and meiotic tubules. All selected markers were up regulated at 4h Kp-10 incubation. Histological analysis also proved the increase of mitotic activity and the progression of spermatogenesis. Besides Kp-10 modulation of testicular Gnrh system, in vitro treatment with 17beta-estradiol (10(-6)M) +/- the antagonist ICI182-780 (10(-5)M) revealed gnrh2 and gnrhr3 estrogen dependent expression. In the reproductive period, testes were incubated for 1 and 4h with Kp-10 (10(-7)M) or Kp-10 (10(-7)M)+kisspeptin antagonist [Kp-234 (10(-6)M)]. Results obtained in the pre-reproductive period were confirmed and Kp-234 completely counteracted Kp-10 effects. In conclusion, Kp-10 modulated the expression of pcna, erbeta, gnrhs and gnrhrs, inducing the progression of the spermatogenesis. PMID- 25452029 TI - Novel genes and hormonal regulation for gonadal development during embryogenesis in chickens. AB - Asymmetrical gonadal morphogenesis is well known in female chickens in contrast to males where both gonads develop symmetrically. However, only a few genes have been reported to determine differential morphology between female and male gonads in chicken and their mechanisms of action are unclear. Therefore, we focused on three genes (TOM1L1, TTR, and ZEB1) that are related to cellular proliferation and embryonic development based on previous study indicating up- or down regulated transcripts in the asymmetric female gonads between embryonic day 6 (E6) and E9 by microarray analyses. To define the validity of the gene expression pattern discovered, q-PCR and in situ hybridization analyses were performed. In the left female gonad between E6 and E9 the expression of TOM1L1, TTR and ZEB1 increased at E9. On the other hand, TOM1L1 and TTR increased significantly in both male gonads between E6 and E9. In addition, recombinant FSH and LH stimulated proliferation of gonadal cells and influenced expression of selected genes in chickens. This suggests that hormonal regulation is involved in growth and development in the embryonic gonad of chickens. Collectively, the results show differential gene expression between the left and right gonads in chicken embryos and that of is regulated by gonadotropin. These results provide novel insights into candidate genes regulating gonad development and differentiation. PMID- 25452030 TI - Use of salivary cortisol to evaluate the influence of rides in dromedary camels. AB - Animals in captivity and in the wild face numerous challenges, including the risk of enduring acute or chronic stress. In captivity, facilities attempt to alleviate the risk of chronic stress by providing environmental enrichment, shown to minimize behavioral disorders and stress in several species. One potential form of enrichment in zoos is training animals to provide rides for guests, however, the effect of this activity on the welfare of individual animals has never been examined. We validated the use of saliva for assessing stress in dromedary camels (Camelus dromedarius), an animal commonly used for rides. We then measured variation in salivary cortisol in four male camels while providing rides of differing frequency for guests at the Toronto Zoo. The camels were sampled during the ride season (June to September) using four treatments: (1) in their pasture, (2) at the ride area when not performing rides, (3) while providing a low number of rides (n=50/day) and (4) while providing a high number of rides (n=150/day). Furthermore, samples were taken before and after the ride season for comparison. There was a significant difference between the post-ride season treatment and the three treatments involving guest presence during the ride season (ride area, low rides, high rides). In general, cortisol concentrations were lower during the ride season and higher during the non-ride season. Based on the metrics we used, performing rides is not a stressful experience for these dromedary camels and suggests that rides may be a form of enrichment. PMID- 25452025 TI - Use of biomarkers in ALS drug development and clinical trials. AB - The past decade has seen a dramatic increase in the discovery of candidate biomarkers for ALS. These biomarkers typically can either differentiate ALS from control subjects or predict disease course (slow versus fast progression). At the same time, late-stage clinical trials for ALS have failed to generate improved drug treatments for ALS patients. Incorporation of biomarkers into the ALS drug development pipeline and the use of biologic and/or imaging biomarkers in early- and late-stage ALS clinical trials have been absent and only recently pursued in early-phase clinical trials. Further clinical research studies are needed to validate biomarkers for disease progression and develop biomarkers that can help determine that a drug has reached its target within the central nervous system. In this review we summarize recent progress in biomarkers across ALS model systems and patient population, and highlight continued research directions for biomarkers that stratify the patient population to enrich for patients that may best respond to a drug candidate, monitor disease progression and track drug responses in clinical trials. It is crucial that we further develop and validate ALS biomarkers and incorporate these biomarkers into the ALS drug development process. This article is part of a Special Issue entitled ALS complex pathogenesis. PMID- 25452033 TI - Allogeneic hematopoietic cell transplantation for acute myeloid leukemia. AB - Allogeneic stem cell transplantation is an increasingly important treatment option in the management of adult acute myeloid leukemia (AML). The major causes of treatment failure remain disease relapse and treatment toxicity. In this review, Dr Vyas presents an overview of important recent data defining molecular factors associated with treatment failure in AML. He also identifies the emerging importance of leukemia stem cell biology in determining both response to therapy and relapse risk in AML. Dr Appelbaum discusses advances in the design and delivery of both myeloablative and reduced-intensity conditioning regimens, highlighting novel strategies with the potential to improve outcome. Dr Craddock discusses the development of both novel conditioning regimens and post transplantation strategies aimed at reducing the risk of disease relapse. PMID- 25452031 TI - B cells in chronic graft-versus-host disease. AB - Chronic graft-versus-host disease (cGVHD) continues to be a common complication of allogeneic hematopoietic stem cell transplantation. Unlike acute graft-versus host disease, which is mediated almost entirely by donor T cells, the immune pathology of cGVHD is more complex and donor B cells have also been found to play an important role. Recent studies from several laboratories have enhanced our understanding of how donor B cells contribute to this clinical syndrome and this has led to new therapeutic opportunities. Here, Dr Sarantopoulos reviews some of the important mechanisms responsible for persistent B cell activation and loss of B cell tolerance in patients with cGVHD. Dr Blazar describes recent studies in preclinical models that have identified novel B cell-directed agents that may be effective for prevention or treatment of cGVHD. Some B cell-directed therapies have already been tested in patients with cGVHD and Dr Cutler reviews the results of these studies documenting the potential efficacy of this approach. Supported by mechanistic studies in patients and preclinical models, new B cell-directed therapies for cGVHD will now be evaluated in clinical trials. PMID- 25452032 TI - Allogeneic hematopoietic cell transplantation outcomes in acute myeloid leukemia: similar outcomes regardless of donor type. AB - The use of alternative donor transplants is increasing as the transplantation eligible population ages and sibling donors are less available. We evaluated the impact of donor source on transplantation outcomes for adults with acute myeloid leukemia undergoing myeloablative (MA) or reduced-intensity conditioning (RIC) transplantation. Between January 2000 and December 2010, 414 consecutive adult patients with acute myeloid leukemia in remission received MA or RIC allogeneic transplantation from either a matched related donor (n = 187), unrelated donor (n = 76), or umbilical cord blood donor (n = 151) at the University of Minnesota or Hopital St. Louis in Paris. We noted similar 6-year overall survival across donor types: matched related donor, 47% (95% confidence interval [CI], 39% to 54%); umbilical cord blood, 36% (95% CI, 28% to 44%); matched unrelated donor, 54% (95% CI, 40% to 66%); and mismatched unrelated donor, 51% (95% CI, 28% to 70%) (P < .11). Survival differed based on conditioning intensity and age, with 6-year survival of 57% (95% CI, 47% to 65%), 39% (95% CI, 28% to 49%), 23% (95% CI, 6% to 47%), 47% (95% CI, 36% to 57%), and 28% (95% CI, 17% to 41%) for MA age 18 to 39, MA age 40+, or RIC ages 18 to 39, 40 to 56, and 57 to 74, respectively (P < .01). Relapse was increased with RIC and lowest in younger patients receiving MA conditioning (hazard ratio, 1.0 versus 2.5 or above for all RIC age cohorts), P < .01. Transplantation-related mortality was similar across donor types. In summary, our data support the use of alternative donors as a graft source with MA or RIC for patients with acute myeloid leukemia when a sibling donor is unavailable. PMID- 25452034 TI - Predonation health-related quality of life scores predict time to recovery in hematopoietic stem cell donors. AB - The physical reactions to hematopoietic stem cell donation have been extensively studied, but less is known about factors that predict poorer donation experiences. The aim of this prospective study was to examine demographic and health-related quality of life (HRQOL) factors that might be associated with recovery and side effects. We also described the changes in HRQOL during the donation process. In total, 275 peripheral blood stem cell (PBSC) and 37 bone marrow (BM) consecutive donors completed the SF-36 questionnaire predonation and 4 weeks, and 3 months postdonation. Predonation HRQOL markers were the strongest predictors of time to recovery. Poorer predonation physical health was associated with longer recovery (P = .017) and certain side effects in PBSC donors. Poorer predonation mental health was associated with longer recovery in BM donors (P = .03) and pain after PBSC donation (P = .003). Physical HRQOL scores declined significantly from predonation to 4 weeks postdonation. This was shown both for PBSC and BM donors (P < .001 and P = .009, respectively), but the decline was much greater for BM donors. There was a return to predonation HRQOL values 3 months after donation in both groups with values well above the mean of the general population (P < .001). PMID- 25452035 TI - Recent advances in cytomegalovirus: an update on pharmacologic and cellular therapies. AB - The 2015 Tandem American Society for Blood and Marrow Transplantation/Center for International Blood and Marrow Transplant Meetings provide an opportunity to review the current status and future perspectives on therapy for cytomegalovirus (CMV) infection in the setting of hematopoietic stem cell transplantation (HSCT). After many years during which we have seen few tangible advances in terms of new antiviral drugs, we are now experiencing an exciting period of late-stage drug development, characterized by a series of phase III trials incorporating a variety of novel agents. These trials have the potential to shift our current standard therapeutic strategies, which generally involve pre-emptive therapy based on sensitive molecular surveillance, towards the prophylactic approaches we see more generally with other herpes viruses such as herpes simplex and varicella zoster. This comes at a time when the promise of extensive preclinical research has been translated into encouraging clinical responses with several cellular immunotherapy strategies, which have also been moved towards definitive late stage clinical trials. How these approaches will be integrated with the new wave of antiviral drugs remains open to conjecture. Although most of the focus of these cellular immunotherapy studies has been on adaptive immunity, and in particular T cells, an increasing awareness of the possible role of other cellular subsets in controlling CMV infection has developed. In particular, the role of natural killer (NK) cells is being revisited, along with that of gammadelta T cells. Depletion of NK cells in mice results in higher titers of murine CMV in tissues and increased mortality, whereas NK cell deficiency in humans has been linked to severe CMV disease. We will review recent progress in these areas. PMID- 25452036 TI - Q-fever patients suffer from impaired health status long after the acute phase of the illness: results from a 24-month cohort study. AB - OBJECTIVES: During the largest Q-fever outbreak ever reported, a cohort study was established to assess the health status of Q-fever patients over a 24-month period and to identify factors associated with health status. METHODS: Laboratory confirmed Q-fever patients participated at six time points after onset of illness. Scores on twelve subdomains from two health status instruments were calculated for each time point to determine progression and compare to reference groups. RESULTS: The study included 336 Q-fever patients. There is a significant linear improvement over time in nine of the twelve health status subdomains. For example, the proportion of patients with severe fatigue improved from 73.0% at three months to 60.0% at twelve months and 37.0% at twenty-four months, but this was still high compared to a healthy reference group (2.5%). For the three most severely affected subdomains -'Fatigue', 'General Quality of Life' and 'Role Physical'- the baseline characteristics significantly associated with a long-term reduced health status were being female, being a young adult and having pre existing health problems. CONCLUSIONS: Despite a significant linear improvement over time in nine of the twelve health status subdomains, more than one out of three patients still suffered from a reduced health status at 24 months. PMID- 25452038 TI - A multilevel approach to assessing temporal change of CD4 recovery following HAART initiation in a cohort of Chinese HIV positive patients. PMID- 25452037 TI - Delayed reconstitution of B cell immunity to pneumococcus in HIV-infected Malawian children on antiretroviral therapy. AB - OBJECTIVE: Despite CD4(+) count restoration and viral load suppression with antiretroviral therapy (ART), HIV-infected children remain at increased risk of life-threatening infections including invasive pneumococcal disease (IPD). We therefore investigated whether persistent susceptibility to IPD following ART is associated with incomplete recovery of B-cell function. METHODS: 41 HIV-infected Malawian children commencing ART were followed-up for a 1 year period during which time blood samples were collected at 0, 3, 6 and 12 months for comprehensive immunophenotyping and pneumomococcal-specific Memory B-cell Enzyme Linked Immunospot assays. In addition, nasopharyngeal swab samples were cultured to determine pneumococcal carriage rates. RESULTS: Normalization of major lymphocyte subsets such as CD4(+) percentages was evident following 3 months of ART. The proportions of mature naive B cells (CD19(+) CD10(-) CD27(-) CD21(hi)) and resting memory B cells (CD19(+) CD27(+) CD21(hi)) increased and apoptosis prone mature activated B cells (CD19(+) CD21(lo) CD10(-)) decreased markedly by 12 months. However, in the context of high nasopharyngeal pneumococcal carriage rates (83%), restoration of pneumococcal protein antigen-specific B-cell memory was more delayed. CONCLUSIONS: These data show that, in chronically HIV-infected children receiving ART, improvement in B-cell memory profiles and function is slower than CD4(+) T-cells. This supports early initiation of ART and informs research into optimal timing of immunization with pneumococcal vaccines. PMID- 25452039 TI - Missed diagnosis of Clostridium difficile infection; a prospective evaluation of unselected stool samples. AB - BACKGROUND: Clostridium difficile infection (CDI) is the leading cause of hospital-acquired diarrhoea in developed countries, however a high proportion of CDI episodes go undiagnosed, either because physicians do not request identification of toxigenic C. difficile or microbiologists do not perform the appropriate tests. OBJECTIVE: To investigate the clinical characteristics of patients with CDI within a non-selected population and to determine risk factors for clinical underdiagnosis. METHODS: We conducted a prospective study in which systematic testing for toxigenic C. difficile on all diarrhoeic stool samples was performed regardless of the clinician's request. Patients aged >2 years positive for toxigenic C. difficile and diarrhoea were enrolled (Jan-June 2013) and monitored at least 2 months after their last episode. RESULTS: We identified 204 cases of CDI, of which three-quarters were healthcare-associated. Most cases were mild to moderate (83.8%), the recurrence rate was 16.2%, and CDI-related mortality was low (2.5%). A significant proportion (12.7%) of CDI cases would have been missed owing to lack of clinical suspicion. Community-acquired cases and young age were risk factors for clinical underdiagnosis. CONCLUSION: Our data support the introduction of a systematic search for toxigenic C. difficile in all diarrhoeic stools from inpatients and outpatients older than 2 years. PMID- 25452040 TI - Adjunctive biomarkers for improving diagnosis of tuberculosis and monitoring therapeutic effects. AB - OBJECTIVES: To identify host biomarkers associated with latent tuberculosis infection (LTBI), active tuberculosis (TB), and nontuberculous mycobacteria (NTM) diseases to improve diagnosis and effective anti-TB treatment. METHODS: Active TB and NTM patients at diagnosis, recent TB contacts, and normal healthy subjects were recruited. Tuberculin skin tests, QuantiFERON-TB Gold In-Tube tests, and multiplex bead arrays with 17 analytes were performed. TB patients were re evaluated after 2 and 6 months of treatment. RESULTS: Mycobacterium tuberculosis (M. tb) antigen-specific IFN-gamma, IL-2, and CXCL10 responses were significantly higher in active TB and LTBI compared with controls (P < 0.01). Only serum VEGF levels varied between the active TB and LTBI groups (AUC = 0.7576, P < 0.001). Active TB and NTM diseases were differentiated by serum IL-2, IL-9, IL-13, IL-17, TNF-alpha and sCD40L levels (P < 0.05). Increased sCD40L and decreased M. tb antigen-specific IFN-gamma levels correlated with sputum clearance of M. tb after 2 months of treatment (P < 0.001). CONCLUSIONS: Serum IL-2, IL-9, IL-13, IL-17, TNF-alpha, sCD40L and VEGF-A levels may be adjunctive biomarkers for differential diagnosis of active TB, LTBI, and NTM disease. Assessment of serum sCD40L and M. tb antigen-specific IFN-gamma, TNF-alpha, and IL-2 levels could help predict successful anti-TB treatment in conjunction with M. tb clearance. PMID- 25452041 TI - Specific mutations in the C-terminus domain of HBV surface antigen significantly correlate with low level of serum HBV-DNA in patients with chronic HBV infection. AB - BACKGROUND: To define HBsAg-mutations correlated with different serum HBV-DNA levels in HBV chronically-infected drug-naive patients. METHODS: This study included 187 patients stratified into the following ranges of serum HBV-DNA:12 2000 IU/ml, 2000-100,000 IU/ml, and >100,000 IU/ml. HBsAg-mutations were associated with HBV-DNA levels by applying a Bayesian-Partitional-Model and Fisher-exact test. Mutant and wild-type HBV genotype-D genomes were expressed in Huh7 cells and HBsAg-production was determined in cell-supernatants at 3 days post-transfection. RESULTS: Specific HBsAg-mutations (M197T,-S204N-Y206C/H-F220L) were significantly correlated with serum HBV-DNA <2000 IU/ml (posterior probability>90%, P < 0.05). The presence of Y206C/H and/or F220L was also associated with lower median (IQR) HBsAg-levels and lower median (IQR) transaminases (for HBsAg:250[115-840] IU/ml for Y206C/H and/or F220L versus 4300[640-11,838] IU/ml for wild-type, P = 0.023; for ALT:28[21-40] IU/ml versus 53[34-90] IU/ml, P < 0.001). These mutations were localized in the HBsAg C terminus, known to be involved in virion and/or HBsAg secretion. The co occurrence of Y206C + F220L was found significant by cluster-analysis, (P = 0.02). In addition, in an in-vitro model Y206C + F220L determined a 2.8-3.3 fold reduction of HBsAg-amount released in supernatants compared to single mutants and wt (Y206C + F220L = 5,679 IU/ml; Y206H = 16,305 IU/ml; F220L = 18,368 IU/ml; Y206C = 18,680 IU/ml; wt = 14,280 IU/ml, P < 0.05). CONCLUSIONS: Specific HBsAg mutations (compartmentalized in the HBsAg C-terminus) correlated with low-serum HBV-DNA and HBsAg-levels. These findings can be important to understand mechanisms underlying low HBV replicative potential including the inactive carrier state. PMID- 25452042 TI - High hepatitis E virus seroprevalence with absence of chronic infection in HIV infected patients. AB - BACKGROUND & AIMS: The seroprevalence of the hepatitis E virus (HEV) and its chronicity rate in the HIV-infected population has not been well established. As a result, the magnitude of this emerging disease in this population cannot be established. METHODS: Prospective study that included HIV-infected patients followed up between September 2012 and May 2013. All included patients were tested for anti-HEV IgG/IgM. In patients with confirmed anti-HEV IgG/IgM positivity, RT-PCR was performed. In patients where HEV RNA was amplified, a second RT-PCR assay was performed 6 months later to identify transient or chronic HEV infections. RESULTS: Eight hundred and ninety-four HIV-infected patients were enrolled in the study. Of these patients, 399 (44.6%) were monoinfected with HIV; 462 (51.6%) were co-infected with HIV/HCV; 12 (1.3%) were co-infected with HIV/HBV; and 21 (2.3%) were co-infected with HIV/HCV/HBV. In 88 patients, anti HEV IgG/IgM was detected (seroprevalence: 9.8% [95% CI: 8.02%-11.9%]). In five patients (0.5%; 95% CI: 0.2%-1.2%), HEV RNA was detected; 5.7% (95% CI: 2.1% 12.1%) of the patients were anti-HEV IgG/IgM positive. None of these patients showed detectable HEV RNA six months later. CONCLUSION: HEV infection is frequent in HIV-infected patients but developing a chronic HEV infection may be considered an uncommon liver disease in this population. PMID- 25452044 TI - Pneumococcal meningitis-associated pyogenic ventriculitis. PMID- 25452043 TI - Differences in serum microRNA profiles in hepatitis B and C virus infection. AB - OBJECTIVES: Patients infected with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) are at greater risk of cirrhosis and hepatocellular carcinoma. The objective of this study was to identify virus-specific serum microRNA profiles associated with liver function and disease progression. Microarray analysis of serum microRNAs was performed using the Toray 3D array system in 22 healthy subjects, 42 HBV patients, and 30 HCV patients. Selected microRNAs were then validated by qRT-PCR in 186 HBV patients, 107 HCV patients, and 22 healthy subjects. RESULTS: Microarray analysis showed up-regulation of a number of microRNAs in serum of both HBV and HCV patients. In qRT-PCR analysis, miR-122, miR-99a, miR-125b, miR-720, miR-22, and miR-1275 were up-regulated both in HBV patients relative to healthy subjects, and all except miR-1275 were up-regulated in HBeAg-positive patients relative to HBeAg-negative patients. Specific microRNAs were independently associated with different aspects of HBV infection. MiR-122 was independently associated with HBV DNA level, whereas miR-125b was independently associated with levels of HBV DNA, HBsAg, and HBeAg. MiR-22 and miR 1275 were independently associated with serum gamma-glutamyl transpeptidase levels. CONCLUSIONS: Serum microRNA levels reflect differences in the etiology and stage of viral hepatitis. PMID- 25452045 TI - Expanded blood borne virus testing in a tuberculosis clinic. A cost and yield analysis. AB - OBJECTIVES: Testing for HIV is a standard of care for people with active tuberculosis (TB). People investigated for TB in the UK often originate from areas with a high prevalence of HIV and other blood borne viruses (BBV). However, assessment for these infections is patchy. We determined the yield and costs of different testing strategies for BBV in a UK TB clinic. METHODS: Since 2009, it has been routine to test all TB clinic attendees. Demographic, clinical and virological data were retrospectively extracted from patient notes and hospital databases. RESULTS: Over 3 years, 1036 people were assessed in the TB service. 410 had a final diagnosis of active TB. HIV testing of the latter population diagnosed 27 new HIV cases at a cost of L3017. When BBV testing was offered to all clinic attendees, a further 6 (total 33) new HIV, 5 Hepatitis B (HBV) and 2 Hepatitis C (HCV) diagnoses were made at a total cost of L22,170. CONCLUSIONS: We have identified previously undiagnosed HIV, HBV and HCV in a TB clinic population. Our data suggest that despite increasing upfront expense, the associated yield argues strongly for BBV testing to be offered to all patients being investigated for possible TB, irrespective of their final diagnosis. PMID- 25452046 TI - Improving adherence to hysterosalpingography after hysteroscopic sterilization using an electronic reminder. AB - STUDY OBJECTIVE: The US package labeling of the Essure system (Bayer Healthcare, Whippany, NJ) requires hysterosalpingography (HSG) as a confirmatory test after hysteroscopic sterilization to ensure proper placement and tubal occlusion. Previous studies have shown that implementation of a protocol to track patients after Essure procedures can improve HSG adherence. The primary objective of this study was to investigate whether implementation of an electronic reminder for the office staff increases post-Essure HSG adherence. DESIGN: Retrospective cohort study of patients who underwent the Essure procedure between January 2005 and January 2012 (Canadian Task Force classification II-3). SETTING: University affiliated hospital. PATIENTS: Two hundred eleven patients underwent the Essure procedure during the study period. INTERVENTIONS: Implementation of an electronic reminder for the office staff. MEASUREMENTS AND MAIN RESULTS: One hundred thirty seven (64.9%) patients underwent the procedure before implementation of the electronic reminder, and 74 (35.1%) patients underwent the procedure after implementation. Although the odds of post-Essure HSG adherence increased in the overall (odds ratio [OR] = 1.7; 95% confidence interval [CI], .9-3.2) and faculty practice (OR = 2.1; 95% CI, .2-18.6) patient population, these results were not statistically significant. In contrast, the odds of post-Essure HSG adherence increased by almost 3-fold (OR = 2.9; 95% CI, 1.4-6.3) in the resident clinic patient population (p = .003). CONCLUSION: Implementation of an electronic reminder increases post-Essure HSG adherence in the resident clinic patient population. PMID- 25452047 TI - Molecular cloning and expression analysis of the Ajuba gene of grass carp (Ctenopharyngodon idella) involved in cellular response to viral infection. AB - Ajuba belongs to the LIM domain proteins, which are involved in the assembly of the extracellular matrix and, along with associated proteins, regulate target genes that connect the extracellular matrix and the cytoskeleton. In the present study, we characterized the entire cDNA sequence of the Ajuba gene from grass carp (gcAjuba). The gcAjuba cDNA contained an open reading frame (ORF) of 2121 bp encoding a polypeptide of 706 amino acids with an estimated molecular mass of 75.966 kDa and three LIM domains in the C-terminal. The transcriptional level of gcAjuba was significantly up-regulated following the stimulation of virus in vitro. Sub-cellular location of gcAjuba and GCRV-JX01 NS26 proteins did not overlap in the cytoplasm and no direct interaction between gcAjuba and the protein NS26 was detected by co-immunoprecipitation (CO-IP) test in grass carp kidney cells. Based on these results, the gcAjuba is determined to be an immediately inducible gene responding to viral infection and in vivo association of gcAjuba with NS26 could not be confirmed, which has been suggested by yeast two-hybrid assay in previous report. PMID- 25452048 TI - Association between metabolic deteriorations and prior gestational diabetes according to weight status. AB - OBJECTIVE: The aim of the present study is to investigate the effect of prior gestational diabetes mellitus (GDM) on glucose and insulin homeostasis according to weight status. METHODS: The analysis included 299 women, 216 with [GDM(+)] and 83 without prior GDM [GDM(-)]. The mean time between pregnancy and testing was 3.9 years. Glucose values were obtained from a 2-h 75 g oral glucose tolerance test (OGTT). Body composition was measured by dual-energy X-ray. RESULTS: In women with normal BMI, fasting glucose, 2-h post-OGTT glucose, and HbA1 were higher for GDM(+) (P<0.05). Normal-weight women with GDM(+) presented lower HOMA IS, insulin secretion, and insulinogenic index (P<0.05) compared to GDM(-). Body fat and android fat mass were higher, gynoid fat mass was similar, and lean body mass was decreased in GDM(+) vs. GDM(-) with normal weight (P<0.05). A greater proportion of GDM(+) with overweight/obesity had prediabetes (72.1%) or type 2 diabetes (T2D) (21.7%) vs. GDM(-) and overweight/obesity (17.1 and 2.4%) or GDM(+) and normal weight (60.5 and 14.0%). CONCLUSIONS: A combination of GDM and overweight/obesity is associated with T2D-related metabolic deteriorations. Nevertheless, normal-weight women with GDM(+) had increased android fat and greater metabolic complications, suggesting that women with prior GDM should benefit from lifestyle intervention, regardless of their weight status. PMID- 25452049 TI - Predictors of non-use of illicit heroin in opioid injection maintenance treatment of long-term heroin dependence. AB - AIMS: To investigate baseline and concurrent predictors of non-use of illicit heroin among participants randomized to injectable opioids in the North American Opiate Medication Initiative (NAOMI) clinical trial. METHODS: NAOMI was an open label randomized controlled trial comparing the effectiveness of injectable diacetylmorphine and hydromorphone for long-term opioid-dependency. Outcomes were assessed at baseline and during treatment (3, 6, 9, 12months). Days of non-use of illicit heroin in the prior month at each follow-up visit were divided into three categories: Non-use; Low use (1 to 7days) and High use (8days or more). Tested covariates were: Sociodemographics, Health, Treatment, Drug use and illegal activities. Mixed-effect proportional odds models with random intercept for longitudinal ordinal outcomes were used to assess the predictors of the non-use of illicit heroin. RESULTS: 139 participants were included in the present analysis. At each follow-up visit, those with non-use of illicit heroin represented 47.5% to 54.0% of the sample. Fewer days of cocaine use (p=0.074), fewer days engaged in illegal activities at baseline (p<0.01) and at each visit (p<0.01), less money spent on drugs (p<0.001), days with injection opioid or oral methadone treatment (p<0.001) and total mg of injectable opioids taken (p<0.001), independently predicted lower use of illicit heroin. CONCLUSIONS: The independent effect of several concurrent factors besides the injection of opioid dose suggests benefits from the clinic that go beyond the provision of the medication alone. Thus, this supervised model of care presents an opportunity to maximize the beneficial impact of medical and psychosocial components of the treatment on improving outcomes associated with non-use of illicit heroin. PMID- 25452050 TI - Self-affirmation theory and cigarette smoking warning images. AB - INTRODUCTION: The present study examined self-affirmation theory, cigarette smoking, and health-related images depicting adverse effects of smoking. Previous research examining self-affirmation and negative health-related images has shown that individuals who engage in a self-affirmation activity are more receptive to messages when compared to those who do not affirm. We were interested in examining the extent to which self-affirmation would reduce defensive responding to negative health images related to cigarette smoking. METHODS: Participants included 203 daily smokers who were undergraduate students at a large southern university. Participants completed a battery of questionnaires and were then randomly assigned to one of four conditions (non-smoking image control, smoking image control, low affirmation, and high affirmation). Analyses evaluated the effectiveness of affirmation condition as it related to defensive responding. RESULTS: Results indicated that both affirmation conditions were effective in reducing defensive responding for those at greatest risk (heavier smokers) and those more resistant to health benefits associated with quitting. CONCLUSIONS: Findings are discussed in terms of potential public health implications as well as the role defensive responding plays in the evaluation and processing of negative health messages. PMID- 25452052 TI - Hospitalized smokers' expectancies for electronic cigarettes versus tobacco cigarettes. AB - INTRODUCTION: The objectives of the current study were to compare hospitalized smokers' expectancies for electronic cigarettes (e-cigarettes) against their expectancies for tobacco cigarettes and evaluate relationships between e cigarette expectancies and intention to use e-cigarettes. METHODS: Analysis of baseline data from a one-year longitudinal observational study. The setting was a tertiary care academic center hospital in the Southeastern U.S. Participants were 958 hospitalized tobacco cigarette smokers. A questionnaire of e-cigarette expectancies based on the Brief Smoking Consequences Questionnaire-Adult (BSCQ-A) was developed and administered along with the original, tobacco-specific, BSCQ-A. Intention to use e-cigarettes was assessed with a single 10-point Likert scale item. RESULTS: Participants reported significantly weaker expectancies for e cigarettes relative to tobacco cigarettes on all 10 BSCQ-A scales. Participants held sizably weaker expectancies that e-cigarettes pose health risks (p<.001, Cohen's d=-2.07), relieve negative affect (p<.001, Cohen's d=-1.01), satisfy the desire for nicotine (p<.001, Cohen's d=-.83), and taste pleasant (p<.001, Cohen's d=-.73). Among the strongest predictors of intention to use e-cigarettes were greater expectancies that e-cigarettes taste pleasant (p<.001, adjusted beta=.34), relieve negative affect (p<.001, adjusted beta=.32), and satisfy the desire for nicotine (p<.001, adjusted beta=.31). CONCLUSIONS: Hospitalized tobacco smokers expect fewer negative and positive outcomes from e-cigarettes versus tobacco cigarettes. This suggests that e-cigarettes might be viable though imperfect substitutes for tobacco cigarettes. PMID- 25452051 TI - Understanding the service needs of assault-injured, drug-using youth presenting for care in an urban Emergency Department. AB - BACKGROUND: Violence is a leading cause of injury among youth 15-24years and is frequently associated with drug use. To inform optimal violence interventions, it is critical to understand the baseline characteristics and intent to retaliate of drug-using, assault-injured (AI) youth in the Emergency Department (ED) setting, where care for violent injury commonly occurs. METHODS: At an urban ED, AI youth ages 14-24 endorsing any past six-month substance use (n=350), and a proportionally-sampled substance-using comparison group (CG) presenting for non assault-related care (n=250), were recruited and completed a baseline assessment (82% participation). Medical chart review was also conducted. Conditional logistic regression was performed to examine correlates associated with AI. RESULTS: Over half (57%) of all youth met the criteria for drug and/or alcohol use disorder, with only 9% receiving prior treatment. Among the AI group, 1 in 4 intended to retaliate, of which 49% had firearm access. From bivariate analyses, AI youth had poorer mental health, greater substance use, and were more likely to report prior ED visits for assault or psychiatric evaluation. Based on multivariable modeling, AI youth had greater odds of being on probation/parole (AOR=2.26; CI=1.28, 3.90) and having PTSD (AOR=1.88; CI=1.01, 3.50) than the CG. CONCLUSIONS: AI youth may have unmet needs for substance use and mental health treatment, including PTSD. These characteristics along with the risk of retaliation, increased ED service utilization, low utilization of other health care venues, and firearm access highlight the need for interventions that initiate at the time of ED visit. PMID- 25452053 TI - Frequency of drinking games participation and alcohol-related problems in a multiethnic sample of college students: do gender and ethnicity matter? AB - INTRODUCTION: A drinking game (DG) is a high-risk, social drinking activity that consists of certain rules (i.e., when to drink and how much to consume) designed to promote inebriation and that requires each player to perform a cognitive and/or motor task (Zamboanga et al., 2013). Research suggests that non-White or female students who play DGs are at an increased risk of experiencing alcohol related problems. Thus, this study examined whether the associations between DG participation and alcohol-related problems were similar for men and women and across ethnic groups. METHOD: College students (N=7409; 73% women; 64% White, 8% Black, 14% Hispanic, 14% Asian) from 30 U.S. colleges/universities completed self report questionnaires. RESULTS: Controlling for age, site, Greek membership (i.e., membership in a fraternity or sorority), and typical alcohol consumption, results indicated that the association between DG participation and alcohol related problems was stronger for men compared to women. With respect to ethnicity, the association between these variables was stronger among Black women than Black men. CONCLUSIONS: Findings from this large-scale study highlight the need to closely investigate how gender and ethnicity moderate the associations between DG participation and alcohol-related problems. College intervention efforts designed to address high-risk drinking behaviors such as DG participation might consider paying close attention to ethnic minority populations, perhaps particularly Black women. PMID- 25452054 TI - Randomized trial of a secondhand smoke exposure reduction intervention among hospital-based pregnant women. AB - OBJECTIVE: This study sought to assess the effectiveness of a secondhand tobacco smoke (SHS) prevention program based on an expanded Health Belief Model (HBM) incorporating self-efficacy among pregnant women in a hospital setting in Taiwan. METHODOLOGY: This study utilized a two-group longitudinal randomized controlled trial design. Participants in the intervention group (n=50) enrolled in a SHS prevention program based on the HBM, while participants in the comparison group (n=50) received standard government-mandated counseling care. Both groups were given questionnaires as a pre-test, two weeks into the intervention, and one month following the conclusion of the intervention. The questionnaire and intervention were developed based on the understanding gained through a series of in-depth interviews and a focus-group conducted among pregnant women. Exhaled carbon monoxide was also measured and used as a proxy for SHS exposure. RESULTS: Intervention group scores were all significantly higher than comparison group scores (p<0.001), indicating a significant increase in knowledge, HBM scores, cues to action, self-efficacy, preventative behaviors, and a significant decrease in smoking exposure. These differences remained significant at the one-month follow-up assessment (p<0.001). CONCLUSIONS: These results should encourage health professionals to educate pregnant women regarding the harms of SHS while both empowering and equipping them with the tools to confront their family members and effectively reduce their SHS exposure while promoting smoke-free social norms. PMID- 25452056 TI - Blood alcohol concentration is negatively associated with gambling money won on the Iowa gambling task in naturalistic settings after controlling for trait impulsivity and alcohol tolerance. AB - INTRODUCTION: Acute alcohol intoxication has been found to increase perseverative errors on the Wisconsin Card Sorting Test, a well known neuropsychological index of prefrontal cortical functioning, in both laboratory and naturalistic settings. METHOD: The present study examined the relationship between levels of alcohol consumption at campus drinking venues and performance of the Iowa Gambling Task (IGT), another neuropsychological test designed to assess prefrontal cortex dysfunction, after controlling for potential confounding variables including habitual alcohol intake (as a proxy for alcohol tolerance), trait impulsivity, and everyday executive functioning. RESULTS: The 49 participants of both genders aged 18 to 30years were recruited at the relevant venues and showed a broad range of blood alcohol concentrations (BACs) from virtually zero (.002%) to .19%. After controlling for demographic variables, habitual use of alcohol and illicit drugs, and frontal lobe related behavioural traits including impulsivity and disinhibition, BAC negatively predicted gambling money won on the last two trial blocks of the IGT. CONCLUSIONS: Trait impulsivity and habitual alcohol use were also significant predictors. Results are discussed in terms of acute effects of alcohol on brain systems and the behavioural consequences of such effects on decision making. PMID- 25452055 TI - Depression and nicotine dependence from adolescence to young adulthood. AB - INTRODUCTION: Despite the highly replicated relationship between depression and nicotine dependence, little is known about this association across both time and levels of lifetime smoking exposure. In the present study, we evaluate if symptoms of depression are associated with emerging nicotine dependence after accounting for smoking exposure and whether this relationship varies from adolescence to young adulthood and across increasing levels of smoking. PATIENTS AND METHODS: The sample was drawn from the Social and Emotional Contexts of Adolescent Smoking Patterns Study which measured smoking, nicotine dependence and depression over 6 assessment waves spanning 6years. Analyses were based on repeated assessment of 941 participants reporting any smoking 30days prior to individual assessment waves. Mixed-effects regression models were estimated to examine potential time and smoking exposure varying effects in the association between depression and nicotine dependence. RESULTS: Inter-individual differences in mean levels of depression and within subject changes in depression from adolescence to young adulthood were each significantly associated with nicotine dependence symptoms over and above lifetime smoking exposure. This association was consistent across both time and increasing levels of lifetime smoking. DISCUSSION: Depression is a consistent risk factor for nicotine dependence over and above exposure to cigarettes and this association can be demonstrated from the earliest experiences with smoking in adolescents through the establishment of more regular smoking patterns across the transition to young adulthood. CONCLUSION: Depression remains a prominent risk factor for nicotine dependence, and youth with depression symptoms represent an important subgroup in need of targeted smoking intervention. PMID- 25452057 TI - Alcohol mixed with energy drinks are robustly associated with patterns of problematic alcohol consumption among young adult college students. AB - BACKGROUND: Young adults are a population at great risk for problematic health behaviors. Alcohol mixed with energy drink (AmED) consumption is a relatively popular health risk behavior among young adults. AmED consumption continues to illustrate negative outcomes in the research literature, having been linked with other substance use, high-risk sexual behavior, and sexual victimization. Limited research to date has examined associations between AmED consumption and patterns of alcohol dependence. METHODS: Undergraduate college students (n=757) filled out an online survey which assessed their drinking habits in the past week and month, including their consumption of AmED beverages, personality characteristics, substance use, and problematic alcohol consumption via the Alcohol Use Disorders Identification Test (AUDIT). RESULTS: A minority of participants reported AmED consumption in both the past month (11.6%) and past week (9.7%). Compared to their alcohol-only drinking counterparts, AmED consumers scored significantly higher on measures of impulsivity, and lower on anxiety sensitivity when compared to their alcohol-only drinking counterparts. In multivariate analyses, AmED consumption was robustly associated with patterns of alcohol dependence (AUDIT score>=8) among young adult college students, while controlling for energy drink use, alcohol use, personality factors, substance use, and demographic variables. CONCLUSIONS: AmED consumption in the past month is robustly associated with problematic alcohol consumption. The present study describes harmful outcomes associated with AmED consumption, and extends the literature on the combined effects of alcohol and energy drinks on young adult risk behaviors. Further research needs to address causal mechanisms for the AmED and problematic alcohol consumption relation. PMID- 25452058 TI - Prevalence and correlates of electronic-cigarette use in young adults: findings from three studies over five years. AB - BACKGROUND: We aimed to examine prevalence and correlates of past-month electronic cigarette ("e-cigarette") use and use of e-cigarettes to aid a cessation attempt in three samples of young adult smokers recruited online in 2009-2010 (Study 1), 2010-2011 (Study 2), and 2013 (Study 3). METHODS: Participants were young adults aged 18 to 25 who smoked at least one cigarette in the previous month (Study 1, N=1987 and Study 2, N=570) or smoked 3 or more days each week and used Facebook 4 or more days per week (Study 3, N=79). We examined both past-month e-cigarette use and ever use of e-cigarettes to quit conventional cigarettes. RESULTS: Prevalence of past-month use of e-cigarettes was higher in each subsequent study: Study 1 (6%), Study 2 (19%), and Study 3 (41%). In multivariate analyses, significant correlates of past-month e-cigarette use were identified for Study 1 (male sex OR=2.1, p=.03; past-year quit attempt OR=1.6, p=.03) and Study 2 (male sex, OR=1.7, p=.03; younger age OR=0.88, p=.05), but not Study 3. In multivariate analyses, significant correlates of ever use of e cigarette to quit conventional cigarettes were identified for Study 1 (education, OR=1.2, p=.02; smoking within 30min of waking, OR=2.8, p=.02; past year quit attempt OR=4.1, p=.02), and Study 3 (desire to quit smoking, OR=1.3, p=.02), but not Study 2. CONCLUSIONS: E-cigarette use is increasingly common among young adults, particularly men. E-cigarette use for quitting conventional cigarettes appears more common among those more nicotine dependent and interested in quitting. PMID- 25452059 TI - The effect of combination oral contraceptives on smoking-related symptomatology during short-term smoking abstinence. AB - Although an estimated 25% of premenopausal smokers report using oral contraceptives (OC), little is known about how OC use may influence smoking cessation. The purpose of this study was to examine the difference in smoking related symptomatology during acute smoking abstinence between women on a standardized combination OC (Tri-Sprintec(TM)) compared to women not on OCs (no OC). Participants were women aged 18-40 who smoked >=5 cigarettes/day and reported regular menstrual cycles. Using a controlled cross-over design, participants completed two six-day testing weeks: Low Progesterone Week (LPW; Follicular (F) phase in no-OC or 1st week of pills in OC) and High Progesterone Week (HPW; Luteal (L) phase in no-OC or 3rd week of pills in OC). Each testing week included daily assessment of symptomatology and biochemical confirmation of smoking status. During smoking abstinence, the OC group (n=14) reported significantly lower levels of positive affect (21.56+/-7.12 vs. 24.57+/-6.46; beta=3.63, p=0.0323) than the no-OC group (n=28). Further significant interactions between group and testing week were observed as follows: Smoking satisfaction was higher during LPW in the OC group (LPW: 4.29+/-1.30 vs. HPW: 4.10+/-1.37) but higher during HPW in the no-OC group (LPW: 3.91+/-1.30 vs. HPW: 4.23+/-1.30; beta=-0.5499, p<0.0001). Similar interactions were noted in negative affect and psychological reward of smoking. These results suggest that women on OCs may have different patterns of smoking-related symptomatology during short term smoking abstinence as compared to women not on OCs. Additional work is needed to examine how this may affect smoking cessation efforts. PMID- 25452061 TI - A field investigation of the effects of drinking consequences on young adults' readiness to change. AB - In the research on readiness to change (RTC) one's drinking, there has been little assessment of the influence of positive drinking consequences or other potential moderating variables. To address these limitations, we examined how young adults' RTC their alcohol consumption shortly following a drinking episode was associated with self-reported drinking consequences, as well as any potential moderating effects of gender and Breath Alcohol Concentration (BrAC). In street interviews outside bars, 238 young adults were administered questionnaires about their drinking, including a measure examining participants' current readiness to reduce their alcohol consumption. Within 72h of their drinking episode, 67 participants (36 males; entire sample Mage=20.90years, Range=18-26years) completed an online survey, once again measuring RTC as well as positive and negative drinking consequences. Consistent with our hypothesis, positive drinking consequences were negatively associated with participants' changes in RTC. Additionally, a three-way interaction of gender*BrAC*positive drinking consequences on RTC showed that females with low BrACs reported higher RTC scores when they had endorsed fewer positive drinking consequences. Interestingly, negative drinking consequences alone did not impact individuals' RTC. Because positive drinking consequences were a significantly better predictor of RTC than were negative drinking consequences, researchers are advised to examine both types of consequences in future studies. Finally, effective alcohol education programs for those who have never consumed alcohol as well as social drinkers should include consideration of the experience of positive outcomes. PMID- 25452063 TI - Social strain, couple dynamics and gender differences in gambling problems: evidence from Chinese married couples. AB - Knowledge of the influence of couple dynamics on gender differences in gambling behavior remains meager. Building on general strain theory from the sociology of deviance and stress crossover theory from social psychology, we argue that the strain encountered by one partner in a social setting may affect his or her spouse. For instance, the wife of a man under more social strain may experience more strain in turn and thus be at a higher risk of developing disordered gambling than the wife of a man under less social strain. Using community survey data of 1620 Chinese married couples, we performed multilevel dyad analyses to address social strain and couple dynamics, in addition to their roles as predictors of gambling behavior in both spouses. This was a community survey of Hong Kong and therefore was not representative of China. Based on the DSM-IV screen, the rates of probable problem gambling and pathological gambling among male partners (12.8% vs. 2.5%) were twice those among female partners (5.2% vs. 0.3%). We also found that the social strain experienced by a male partner significantly predicted both his and his wife's likelihood of developing gambling problems. Although a female partner's exposure to social strain was a significant correlate of her gambling problem, it had no significant association with her husband's gambling behavior. These results suggest that the cross-spouse transference of social strain may be a gendered process. PMID- 25452060 TI - Drowning the pain: intimate partner violence and drinking to cope prospectively predict problem drinking. AB - INTRODUCTION: The present study examined the longitudinal association among drinking problems, drinking to cope, and degree of intimate partner violence (IPV). Two competing models were tested; the first model posited that drinking to cope leads to greater drinking problems and this subsequently leads to more violence in the relationship (an intoxication-violence model). The second model speculated that violence in the relationship leads to drinking to cope, which in turn leads to greater drinking problems (a self-medication model). METHODS: Eight hundred and eighteen undergraduate students at a large north-western university participated in the study over a two year period, completing assessments of IPV, alcohol related problems and drinking to cope at five time points over a two year period as part of a larger social norms intervention study. RESULTS: Analyses examined two competing models; analyses indicated that there was support for the self-mediation model, whereby people who have experienced violence have more drinking problems later, and this association is temporally mediated by drinking to cope. DISCUSSION: The current results are discussed in light of past research on the self-medication model. PMID- 25452062 TI - Social predictors of cessation treatment use among smokers with serious mental illness. AB - OBJECTIVE: Social factors play an important role in quitting smoking in the general population, but relatively little is known about social influences on smoking cessation efforts among individuals with serious mental illness who suffer disproportionately high rates of smoking. This study examined social factors as predictors of using smoking cessation treatment among adults with serious mental illness. METHODS: We conducted a secondary analysis of data from a randomized study comparing two versions of a motivational decision support system for smoking cessation treatment including 124 smokers with schizophrenia or severe mood disorders. Hierarchical logistic regression with blocked entry of theoretically linked predictor variables was used to model two types of social influences (explicit and implicit) as predictors of using cessation group therapy or smoking cessation medication. RESULTS: Approximately 31% of participants initiated smoking cessation treatment during the 2-month follow-up. Hierarchical logistic regression analyses revealed that over and above demographic and personal factors, implicit social influences (others' approval of treatment) significantly predicted use of smoking cessation medication, while explicit social influences (smoking with others) significantly predicted use of cessation group therapy. CONCLUSIONS: For people with serious mental illness, social factors appear to influence use of smoking cessation treatment above and beyond personal factors and may be specific to the type of treatment. These data support the need to further explore the role of social factors as potential leverage points for engagement in smoking cessation treatments in this population. PMID- 25452065 TI - Using multiple methods to examine gender differences in alcohol involvement and marital interactions in alcoholic probands. AB - BACKGROUND: This study examined gender differences in alcohol involvement and marital interactions among probands with a past 1-year alcohol use disorder (AUD). METHODS: Adults with alcohol dependence (37 males and 17 females) and their spouses were recruited from a local substance abuse treatment center and from the local community. Couples completed a series of self-report measures and a 15-min videotaped marital interaction task that was coded for negative and positive behaviors and sequential interactions. Couples also separately called in to an interactive voice response (IVR) system every night for 14 consecutive nights and reported on their spouse's negative and positive marital behaviors. RESULTS: Compared to male probands, female probands reported a) more negative marital interactions in the previous month; b) higher levels of negative reciprocity and a lower positive-to-negative ratio in the marital interaction task; and c) more daily and nightly marital conflict over the 14-day diary period. Negative marital behaviors in the evening by female spouses were associated with higher odds of intoxication among male probands on the following day. In contrast, a) negative marital behaviors by male spouses were cross sectionally associated with higher odds of intoxication among female probands within the same day; and b) positive marital behaviors by male spouses during the day were associated with lower odds of intoxication among female probands that night. CONCLUSIONS: Marital conflict, assessed via multiple methods over multiple time scales, appears to be more frequent among female compared to male alcoholics. Marital conflict predicts daily intoxication among male and female probands. PMID- 25452064 TI - Longitudinal family effects on substance use among an at-risk adolescent sample. AB - OBJECTIVE: Adult and peer factors may influence whether adolescents use alcohol and other drugs (AOD). This longitudinal study examined the direct effects of adult monitoring, perceived adult AOD use, and cultural values on adolescent AOD use. METHODS: Participants were 193 at-risk adolescents referred to a California diversion program called Teen Court for a first-time AOD offense. We assessed youth reports of past 30day AOD use (any alcohol use, heavy drinking, marijuana use), demographics, changes in parental monitoring and family values (from baseline to follow-up 180days later), as well as family structure and perceived adult substance use at follow-up. RESULTS: Adolescents who reported that a significant adult in their life used marijuana were more likely to have increased days of drinking, heavy drinking, and marijuana use at follow-up. Higher levels of familism (importance the teen places on their family's needs over their own needs) and being in a nuclear family served as protective factors for future alcohol use. Additionally, poor family management was associated with increased alcohol use and heavy drinking. CONCLUSION: Findings highlight how family management and perceptions of adult marijuana use influence subsequent adolescent AOD use, and how an increase in familism over time is associated with a decrease in adolescent drinking. Tailoring interventions, by including the teen's family and/or providing support to adults who use AOD may be crucial for improving interventions for adolescent AOD use. PMID- 25452066 TI - Prevalence and determinants of gambling disorder among older adults: a systematic review. AB - AIMS: This paper aims to systematically review studies on the prevalence of gambling disorder among older adults aged 60years and above and to summarize the evidence on the determinants, risk factors as well as the comorbidities associated with it. METHODS: A systematic search was conducted for peer-reviewed, journal articles between 1st January 1995 and 1st May 2013. Only original studies which were published in English, included participants older than 60years of age and provided prevalence figures specifically among them, and where participants were assessed to have a gambling disorder by a validated instrument in non treatment seeking/non-clinical setting were included. RESULTS: 25 eligible studies were identified from the literature. The prevalence of lifetime gambling disorder ranged from 0.01% to 10.6% across studies. Prevalence of gambling disorder is higher among the younger age groups (of older adults) and among males as compared to females. Those with gambling disorder were more likely to be single or divorced/separated. Findings indicate that older adults may gamble more in an effort to ameliorate negative emotional states; they may have limited access to other exciting activities or they may be unable to participate in activities that they were previously able to and they might attempt to fill this gap with gambling. CONCLUSIONS: Gambling disorder among older adults is a significant problem. Fixed incomes and limited prospects of future earnings make them an extremely vulnerable group. There is an urgent need to understand the phenomenon of gambling disorder in older adults. PMID- 25452068 TI - Changes in gender and racial/ethnic disparities in rates of cigarette use, regular heavy episodic drinking, and marijuana use: ages 14 to 32. AB - BACKGROUND: The purpose of this study is to investigate disparities in substance use behaviors across gender and race/ethnicity as a flexible function of age from mid-adolescence through young adulthood. METHODS: Using data from the National Longitudinal Study of Adolescent Health, the time-varying effect model (TVEM) was used to examine gender and racial/ethnic differences in the prevalence of cigarette use, regular heavy episodic drinking (HED), and marijuana use as a smooth function of developmental age. RESULTS: Prevalence of cigarette use, regular HED, and marijuana use was higher for males than females overall, although gender differences varied with age. With regard to race, prevalence of each substance was higher for White than Hispanic or Black individuals; these differences increased considerably from ages 16 to 20, particularly for cigarette use. Differences in cigarette use by race/ethnicity were found across age, but were largest at age 18, when cigarette use peaks for White individuals, but continues to climb throughout the 20s among Hispanic and Black individuals. CONCLUSIONS: These results suggest that substance use, particularly for certain population subgroups, increases past early adolescence. Disparities in substance use behaviors fluctuate considerably throughout adolescence and young adulthood, suggesting that targeted intervention programs are more critical at particular ages. These findings also demonstrate that TVEM can advance our understanding of health risk behaviors and their correlates across developmental time. PMID- 25452067 TI - Smoking history, and not depression, is related to deficits in detection of happy and sad faces. AB - INTRODUCTION: Previous research has demonstrated that chronic cigarette smoking and major depressive disorder (MDD) are each associated with cognitive decrements. Further, these conditions co-occur commonly, though mechanisms in the comorbid condition are poorly understood. There may be distinct, additive, or overlapping factors underlying comorbid cigarette smoking and MDD. The present study investigated the impact of smoking and MDD on executive function and emotion processing. METHODS: Participants (N=198) were grouped by diagnostic category (MDD and healthy controls, HC) and smoking status (ever-smokers, ES and never-smokers, NS). Participants completed the Facial Emotion Perception Test (FEPT), a measure of emotional processing, and the parametric Go/No-go task (PGNG), a measure of executive function. RESULTS: FEPT performance was analyzed using ANCOVA with accuracy and reaction time as separate dependent variables. Repeated measures MANCOVA was conducted for PGNG with performance measure and task level as dependent variables. Analyses for each task included diagnostic and smoking group as independent variables, and gender was controlled for. Results for FEPT reveal that lower overall accuracy was found for ES relative to NS, though MDD did not differ from HC. Post-hoc analyses revealed that ES were poorer at identifying happy and sad, but not fearful or angry, faces. For PGNG, poorer performance was observed in MDD relative to HC in response time to Go targets, but there were no differences for ES and NS. Interaction of diagnosis and smoking group was not observed for performance on either task. CONCLUSIONS: The results of this study provide preliminary evidence for distinctive cognitive decrements in smokers and individuals with depression. PMID- 25452069 TI - Efficacy of automated telephone continuing care following outpatient therapy for alcohol dependence. AB - BACKGROUND: Relapse rates following cognitive behavioral therapy (CBT) for alcohol dependence are high. Continuing care programs can prolong therapeutic effects but are underutilized. Thus, there is need to explore options having greater accessibility. METHODS: This randomized controlled trial tested the efficacy of a novel, fully automated continuing care program, Alcohol Therapeutic Interactive Voice Response (ATIVR). ATIVR enables daily monitoring of alcohol consumption and associated variables, offers targeted feedback, and facilitates use of coping skills. Upon completing 12weeks of group CBT for alcohol dependence, participants were randomly assigned to either four months of ATIVR (n=81) or usual care (n=77). Drinking behavior was assessed pre- and post-CBT, then at 2weeks, 2months, 4months, and 12months post-randomization. RESULTS: Drinking days per week increased over time for the control group but not the intervention group. There were no significant differences between groups on the other alcohol-related outcome measures. Comparisons on the subset of participants abstinent at the end of CBT (n=72) showed higher rates of continuous abstinence in the experimental group. Effect sizes for the other outcome variables were moderate but not significant in this subgroup. CONCLUSIONS: For continuing care, ATIVR shows some promise as a tool that may help clients maintain gains achieved during outpatient treatment. However, ATIVR may not be adequate for clients who have not achieved treatment goals at the time of discharge. PMID- 25452070 TI - Alcohol use among reserve-dwelling adult First Nation members: use, problems, and intention to change drinking behavior. AB - INTRODUCTION: Although alcohol use was not part of traditional First Nation (FN) life, alcohol misuse currently poses a significant public health problem. There is a dearth of research efforts to understand both alcohol misuse and efforts to resolve these problems. The primary aims of this study were to 1) present descriptive data on alcohol use in FN adults living on one reserve in Eastern Canada; and 2) explore correlates of help seeking intentions and past behaviors. METHODS: We administered questionnaires to 211 FN people (96 men; 113 women; 2 unknown). RESULTS: Nearly two-thirds of our sample were current drinkers (N=150). Of those, 29% endorsed they needed help with their drinking, and half reported that they would probably try to cut down or stop drinking in the next year. Multiple regression analyses suggested that drinking was positively associated with a greater perceived need for help with drinking (beta=.40, p=<.001). Lower scores on a measure of cultural identity (i.e., stronger FN identity) was associated with a greater perceived need for help with drinking (beta=-.18, p=.04). Greater endorsement of past year attempts to stop drinking (beta=.33, p<.001) and higher alcohol reduction expectancies (beta=.43, p<.00) were positively associated and lower scores on cultural identity (i.e., stronger FN identity) (beta=-.19, p=.03) was associated with trying to cut down or stop drinking in the next year. CONCLUSIONS: Future research should explore the nature of cultural identity as a protective factor. PMID- 25452072 TI - Ultra-violet indoor tanning addiction: a reinforcer pathology interpretation. AB - Ultra-violet indoor tanning (UVIT) is a pervasive issue that is increasing at record rates, despite obvious and well-publicized links to skin cancer. Recent studies on UVIT have found that frequent users face difficulty quitting and report symptomatology similar to substance-related disorders, causing the medical field to begin classifying excessive UVIT use as an addicting behavior. Despite calls for research, relatively little behavioral research has been aimed at determining the psychology of UVIT. This mini-review reinterprets the existing dermatology literature in light of the reinforcer pathology model of addiction. The relevancy of this model, in conjunction with the similarities between UVIT addiction and other substance-related addiction, suggests that behavioral economic research on UVIT is overdue. This mini-review concludes with directions for future research in this area. PMID- 25452071 TI - Tobacco use trajectories among a large cohort of treated smokers with posttraumatic stress disorder. AB - INTRODUCTION: This study identified distinct tobacco use trajectories across 18months in 943 veteran smokers with posttraumatic stress disorder (PTSD) in order to describe quit and relapse patterns, examine associations between trajectory groups on baseline characteristics and cessation service utilization, and explore group differences in mental health outcomes. METHODS: Veterans who participated in a multisite, randomized trial of integrated smoking cessation care were grouped using k-means clustering based on reported daily tobacco use between baseline and 18months. Four trajectory clusters were identified: no reduction (62%), temporary reduction (11%), late sustained reduction (9%) and early sustained reduction (18%). RESULTS: Median quit times in the early, late, temporary, and no reduction groups were 451, 141.5, 97, and 2days, respectively. Compared to the early reduction group, the temporary reduction group exhibited higher baseline depression (p<0.01) and anxiety (p<0.01), but did not differ in treatment received, with both groups attending significantly more cessation visits (p<0.001) and more likely to receive recommended pharmacotherapy (p<0.001) than the no reduction group between baseline and 6months. The early reduction group exhibited lower depression relative to the no reduction (p<0.01) and temporary reduction (p<0.01) groups across all assessments between baseline and 18months. Differences were not observed between groups in depressive or PTSD symptom change over time between baseline and 18months. CONCLUSIONS: Tobacco use trajectories among treated smokers with PTSD vary distinctly. Characteristics of identified subgroups may lead to targeted interventions among smokers with PTSD and potentially other psychiatric disorders. PMID- 25452073 TI - Violence and non-violence-related injuries and alcohol in women from developed and developing countries: a multi-site emergency room study. AB - This study sought to analyze the association between alcohol consumption and the occurrence of injuries in women attending the emergency room (ER) from developing and developed countries. The sample consisted of ER data from women in 15 countries that were collected as part of two multi-site studies using similar methodologies: the Emergency Room Collaborative Alcohol Analysis Project (ERCAAP), and World Health Organization Collaborative Study on Alcohol and Injuries (WHO Study). Women ranged in age from 18 to 98years. Those from developed countries had higher levels of education (43% completed high-school) than women from developing countries (37%). Over half of the women from developing countries reported they had not consumed alcohol in the last 12months (abstentious), while 2% reported drinking every day. In addition, current drinking women from developing countries reported more binge drinking episodes (33% reported 5 to 11 drinks and 15% reported 12 or more drinks on an occasion) compared to those from developed countries (28% and 11%, respectively). Violence related injury was more prevalent in developing countries (18%) compared to developed countries (9%). An association between injury and the frequency of alcohol consumption in the last 12months was observed in both developing and developed countries. Although women from developing countries who suffered violence-related injuries were more likely to demonstrate alcohol abstinence or have lower rates of daily alcohol consumption, these women drank in a more dangerous way, and violence-related injuries were more likely to occur in these women than in those living in developed countries. PMID- 25452075 TI - Further investigation of the Monty Hall Dilemma in pigeons and rats. AB - In the Monty Hall Dilemma (MHD), three doors are presented with a prize behind one and participants are instructed to choose a door. One of the unchosen doors not containing the prize is revealed, following which the participant can choose to stay with their chosen door or switch to the other one. The optimal strategy is to switch. Herbranson and Schroeder (2010) found that humans performed poorly on this task, whereas pigeons learned to switch readily. We found that pigeons performed only slightly better than humans and that pigeons stayed nearly exclusively when staying and switching were reinforced equally and when staying was the optimal strategy (Stagner et al., 2013b). In Experiment 1 of the present research, rats were trained under these same conditions to observe if possible differences in foraging strategy would influence performance on this task. In Experiment 2, pigeons were trained in an analogous procedure to better compare the two species. We found that both species were sensitive to the overall probability of reinforcement, as both switched significantly more often than subjects that were reinforced equally for staying and switching or reinforced more often for staying. Overall, the two species performed very similarly within the parameters of the current procedure. "This article is part of a Special Issue entitled: Tribute to Tom Zentall." PMID- 25452074 TI - Development and psychometric properties of the Social Smoking Situations (S(3)) Scale: an enhanced measure of social exposure to smoking during adolescence. AB - Common questions of exposure to smoking, such as number of parents, siblings, or friends who smoke, fail to capture the contexts in which the exposure occurs. This study developed the Social Smoking Situations (S(3)) Scale to more precisely measure contextual exposure to smoking during adolescence. Informed by the cue reactivity literature and using informal focus groups, items of contextual exposure to smoking were generated for three categories of smokers: parents, siblings, and peers. Participants (N=761; Mage=15.6, SD=1.3; 61.4% female) were recruited as part of the AdoQuest Study in Montreal, QC. Principal components analysis was used to identify the component structure of the parent, sibling, and peer versions of the S(3) Scale. S(3) scores were computed subsequently to test their association with smoking behavior and smoking expectancies. Further, S(3) scores were compared with common questions (i.e., number of smokers) via univariate modeling to determine which would generate larger estimates of effect size when predicting smoking behavior and smoking expectancies. Overall, S(3) scores generated larger estimates than common questions; this finding was consistent across the parent (ORavg: 2.59 vs. 1.36), sibling (ORavg: 3.44 vs. 1.59), and peer (ORavg: 3.89 vs. 1.38) versions. The S(3) Scale is a new psychometrically sound instrument that may provide a more robust measurement of social exposure to smoking during adolescence. Importantly, it has the potential to strengthen prevention programming and intervention efforts aimed at adolescents, as it could depict a more precise portrait of the individual and contextual sources of social exposure to smoking. PMID- 25452076 TI - The interaction between working and reference spatial memories in rats on a radial maze. AB - The interaction of reference and working memory was studied in rats on an eight arm radial maze. Each trial involved a two-phase procedure in which a rat was forced to enter four arms on the maze in a study phase and then was allowed to choose among all eight arms in a test phase given 5-s later, with choice of only the previously unvisited arms rewarded. For each rat, two arms on the maze were designated as reference memory arms because they were never entered in the study phase and were always rewarded in the test phase. The other two arms never entered in the study phase and rewarded in the test phase were working memory arms and varied randomly from trial to trial. In Experiment 1, rats showed acquisition of equivalent preference for entering the reference and working memory arms in their first four choices of the test phase. Subsequent tests carried out in Experiment 2 compared performance at 5-s, 1-h, and 24-h retention intervals when reference memory and working memory were congruent and incongruent. Higher accuracy for choice of reference memory arms than working memory arms appeared at the 1-h and 24-h retention intervals on congruent tests but not on incongruent tests. A process dissociation procedure analysis indicated that working memory but not reference memory declined over the 24-h retention interval. The interaction of working and reference memory was shown by superior choice of reference memory arms on congruent tests than on incongruent tests at 1 h and 24-h retention intervals but not at the 5-s retention interval. These findings suggest that working and reference memory are independent systems that can facilitate and compete with one another. This article is part of a Special Issue entitled: Tribute to Tom Zentall. PMID- 25452077 TI - Wild, free-living rufous hummingbirds do not use geometric cues in a spatial task. AB - In the laboratory, many species orient themselves using the geometric properties of an enclosure or array and geometric information is often preferred over visual cues. Whether animals use geometric cues when relocating rewarded locations in the wild, however, has rarely been investigated. We presented free-living rufous hummingbirds with a rectangular array of four artificial flowers to investigate learning of rewarded locations using geometric cues. In one treatment, we rewarded two of four flowers at diagonally opposite corners. In a second treatment, we provided a visual cue to the rewarded flower by connecting the flowers with "walls" consisting of four dowels (three white, one blue) laid on the ground connecting each of the flowers. Neither treatment elicited classical geometry results; instead, hummingbirds typically chose one particular flower over all others. When we exchanged that flower with another, hummingbirds tended to visit the original flower. These results suggest that (1) hummingbirds did not use geometric cues, but instead may have used a visually derived cue on the flowers themselves, and (2) using geometric cues may have been more difficult than using visual characteristics. Although hummingbirds typically prefer spatial over visual information, we hypothesize that they will not use geometric cues over stable visual features but that they make use of small, flower-specific visual cues. Such cues may play a more important role in foraging decisions than previously thought. PMID- 25452078 TI - Skylarks trade size and energy content in weed seeds to maximize total ingested lipid biomass. AB - The trade-off between forage quality and quantity has been particularly studied in herbivore organisms, but much less for seed eating animals, in particular seed eating birds which constitute the bulk of wintering passerines in European farmlands. The skylark is one of the commonest farmland birds in winter, mainly feeding on seeds. We focus on weed seeds for conservation and management purposes. Weed seeds form the bulk of the diet of skylarks during winter period, and although this is still a matter for discussion, weed seed predation by granivorous has been suggested as an alternative to herbicides used to regulate weed populations in arable crops. Our objectives were to identify whether weed seed traits govern foraging decisions of skylarks, and to characterize key seed traits with respect to size, which is related to searching and handling time, and lipid content, which is essential for migratory birds. We combined a single-offer experiment and a multiple-offer one to test for feeding preferences of the birds by estimating seed intake on weed seed species differing in their seed size and seed lipid content. Our results showed (1) a selective preference for smaller seeds above a threshold of seed size or seed size difference in the pair and, (2) a significant effect of seed lipid biomass suggesting a trade-off between foraging for smaller seeds and selecting seeds rich in lipids. Skylarks foraging decision thus seems to be mainly based on seed size, that is presumably a 'proxy' for weed seed energy content. However, there are clearly many possible combinations of morphological and physiological traits that must play crucial role in the plant-bird interaction such as toxic compound or seed coat. PMID- 25452079 TI - Equating context conditioning in Pavlovian incubation of US signal value. AB - The present study replicated the finding by Goddard (2013), that when a single food pellet unconditioned stimulus (US) signaled the delivery of three additional pellets, responding after the single US was significantly greater on a delayed, compared to an early, test. Importantly, the present study equated context conditioning by delivering the identical number of food pellets in both conditioning and testing and showed that responding was significantly reduced in control subjects that had received unpaired single food-triple food presentations. Implications for theories of conditioning are considered. PMID- 25452080 TI - Emotional contagion: dogs and humans show a similar physiological response to human infant crying. AB - Humans respond to an infant crying with an increase in cortisol level and heightened alertness, a response interpreted as emotional contagion, a primitive form of empathy. Previous results are mixed when examining whether dogs might respond similarly to human distress. We examined whether domestic dogs, which have a long history of affiliation with humans, show signs of emotional contagion, testing canine (n=75) and human (n=74) responses to one of three auditory stimuli: a human infant crying, a human infant babbling, and computer generated "white noise", with the latter two stimuli acting as controls. Cortisol levels in both humans and dogs increased significantly from baseline only after listening to crying. In addition, dogs showed a unique behavioral response to crying, combining submissiveness with alertness. These findings suggest that dogs experience emotional contagion in response to human infant crying and provide the first clear evidence of a primitive form of cross-species empathy. PMID- 25452081 TI - Levodopa-induced dyskinesias are associated with transient down-regulation of cAMP and cGMP in the caudate-putamen of hemiparkinsonian rats: reduced synthesis or increased catabolism? AB - Second messenger cAMP and cGMP represent a key step in the action of dopamine that modulates directly or indirectly their synthesis. We aimed to verify whether levodopa-induced dyskinesias are associated with changes of the time course of levodopa/dopamine stimulated cAMP and cGMP levels, and/or with changes of their catabolism by phosphodiesterase activity in rats with experimental hemiparkinsonism. Microdialysis and tissue homogenates of the striatal tissues demonstrated that extracellular and intracellular cAMP/cGMP levels were lower in dyskinetic animals during the increasing phase of dyskinesias compared to eukinetic animals, but cAMP/cGMP levels increased in dyskinetic animals during the phase of decreasing and extinction of dyskinesias. Dyskinesias and the abnormal lowering of striatal cGMP and cAMP after levodopa were prevented by pretreatment with the multipotent drug amantadine, outlining the inverse relationship of cAMP/cGMP to dyskinesias. Moreover, dyskinetic animals showed higher striatal hydrolyzing cGMP-phosphodiesterase but not hydrolyzing cAMP phosphodiesterase activity, suggesting that low cGMP but not cAMP levels could be due to increased catabolism. However, expressions of isozyme phosphodiesterase-1B and -10A highly and specifically located in the basal ganglia were not changed after levodopa in dyskinetic and eukinetic animals: accordingly, selective inhibitors of phosphodiesterase-1B and -10A were ineffective on levodopa dyskinesias. Therefore, the isozyme(s) expressing higher cGMP-phosphodiesterase activity in the striatum of dyskinetic animal should be determined. These observations suggest that dopamine-mediated processes of synthesis and/or degradation of cAMP/cGMP could be acutely impaired in levodopa dyskinesias, opening new ways to understanding physiopathology and treatment. PMID- 25452082 TI - Small-molecule inhibitors at the PSD-95/nNOS interface attenuate MPP+-induced neuronal injury through Sirt3 mediated inhibition of mitochondrial dysfunction. AB - Post-synaptic density protein 95 (PSD-95) links neuronal nitric oxide synthase (nNOS) with the N-methyl-D-aspartic acid (NMDA) receptor in the central nervous system, and this molecular complex has been implicated in regulating neuronal excitability in several neurological disorders. Here, small-molecule inhibitors of the PSD-95/nNOS interaction, IC87201 and ZL006 were tested for neuroprotective effects in an in vitro Parkinson's disease (PD) model. We now report that IC87201 and ZL006 reduced MPP(+)-induced neuronal injury and apoptotic cell death in a dose-dependent manner in cultured cortical neurons. These protective effects were associated with suppressed mitochondrial dysfunction, as evidenced by decreased reactive oxygen species (ROS) generation, cytochrome c release, mitochondrial membrane potential (MMP) collapse, and the preserved mitochondrial complex I activity and ATP synthesis. IC87201 and ZL006 also preserved intracellular homeostasis through mitigating mitochondrial Ca(2+) uptake and promoting mitochondrial Ca(2+) buffering capacity. Moreover, treatment with IC87201 and ZL006 significantly increased the expression of Sirt3 after MPP(+) exposure, and knockdown of Sirt3 using specific targeted small interfere RNA (siRNA) partially nullified the protective effects induced by these two inhibitors. These data strongly support the hypothesis that targeting the PSD-95/nNOS interaction produces neuroprotective effects and may represent a novel class of therapeutics for PD as well as other neurological diseases where detrimental NMDA receptor signaling plays a major role. PMID- 25452083 TI - Adverse events after treatment of patients with acute limb ischemia. AB - BACKGROUND: To assess the outcome and the occurrence and consequences of adverse events (AEs) after treatment of acute limb ischemia (ALI). METHODS: Retrospective analysis on intra-arterial thrombolysis (group I) and thromboembolectomy (group II). Outcome measures were primary patency and limb salvage rates. AEs and consequences were registered during admission and 30 days after discharge. RESULTS: A total of 238 procedures were included (group I, 173 vs. group II, 65). The primary patency (P = 0.144) and limb salvage rates (P = 0.166) were not significantly different between both groups. A total of 195 AEs were registered. Most AEs were procedure related and resulted in surgical reintervention (77% vs. 76%). Some AEs resulted in irreversible physical damage (15% vs. 25%) and death (6% vs. 12%). CONCLUSIONS: Both, intra-arterial thrombolysis and thromboembolectomies are adequate therapies; however, they result in a wide variety of AEs resulting in serious morbidity and even death. PMID- 25452084 TI - Cryptococcal aortitis presenting as a symptomatic abdominal aortic aneurysm. AB - We report a case of cryptococcal aortitis in a 59-year-old man presenting as a symptomatic suprarenal abdominal aortic aneurysm (AAA). The patient underwent repair of his aneurysm using a rifampin-soaked graft with omental wrapping. Intraoperative Gram stains showed yeast organisms, the cultures eventually grew Cryptococcus neoformans with results available 43 days postoperatively. He was started on antifungal therapy intraoperatively and will be on lifelong antifungal treatment. Our case is the first report of cryptoccocal aortitis presenting as a symptomatic AAA; the diagnosis of a true mycotic aneurysm was made intraoperatively. PMID- 25452085 TI - Time course of the dependence of associative memory retrieval on the entorhinal cortex. AB - As the gateway between the hippocampal system and the neocortex, the entorhinal cortex (EC) is hypothesized to be the hub in which the transformation of recent memory to remote memory is processed. We explored the role of the EC on the retrieval of recent and remote associative fear memory. A within-subject approach was adopted to compare the freezing rates of rats in EC intact and EC inactivated conditions following trace fear conditioning. The EC was inactivated by infusing an AMPA antagonist. The fear conditioning used a combined visual and auditory conditioned stimulus with a foot shock. On week 1 following the conditioning, the rats in the EC intact condition exhibited a freezing rate of 92.4+/-9.5% in response to the light stimulus compared with a 6.3+/-7.9% freezing rate in the EC inactivated condition. The freezing rates were 87.0+/-17.8% and 4.7+/-6.5% on week 2 in the EC intact and inactivated conditions, respectively. These results indicate that the EC participates in the retrieval of associative memory. Extinction of the fear memory was observed in the EC intact condition, as the mean freezing rate decreased to 62.7+/-23.0% on week 4 and 41.2+/-26.4% on week 5. However, the freezing rate increased to 26.8+/-14.2% on week 4 and 22.3+/ 14.4% on week 5 in the EC inactivated condition. The normalized dependence of fear memory retrieval on the EC was 93.2+/-8.3% on week 1, and significantly decreased on weeks 4 and 5. In summary, the retrieval of associative memory depends on the EC, but this dependence decreases over time. PMID- 25452086 TI - Dopamine D1/D5 receptors in the dorsal hippocampus are required for the acquisition and expression of a single trial cocaine-associated memory. AB - The role of the hippocampus in memory supporting associative learning between contexts and unconditioned stimuli is well documented. Hippocampal dopamine neurotransmission modulates synaptic plasticity and memory processing of fear motivated and spatial learning tasks. Much less is known about the involvement of the hippocampus and its D1/D5 dopamine receptors in the acquisition, consolidation and expression of memories for drug-associated experiences, more particularly, in the processing of single pairing cocaine conditioned place preference (CPP) training. To determine the temporal dynamics of cocaine CPP memory formation, we trained rats in a one-pairing CPP paradigm and tested them at different time intervals after conditioning. The cocaine-associated memory lasted 24 h but not 72 h. Then, we bilaterally infused the dorsal hippocampus with the GABA A receptor agonist muscimol or the D1/D5 dopamine receptor antagonist SCH 23390 at different stages to evaluate the mechanisms involved in the acquisition, consolidation or expression of cocaine CPP memory. Blockade of D1/D5 dopamine receptors at the moment of training impaired the acquisition of cocaine CPP memories, without having any effect when administered immediately or 12 h after training. The expression of cocaine CPP memory was also affected by the administration of SCH 23390 at the moment of the test. Conversely, muscimol impaired the consolidation of cocaine CPP memory only when administered 12 h post conditioning. These findings suggests that dopaminergic inputs to the dorsal hippocampus are required for the acquisition and expression of one trial cocaine associated memory while neural activity of this structure is required for the late consolidation of these types of memories. PMID- 25452088 TI - [Arthroscopy of the wrist and hand]. PMID- 25452087 TI - The external-internal loop of interference: two types of attention and their influence on the learning abilities of mice. AB - Attention is a component of the working memory system, and is responsible for protecting task-relevant information from interference. Cognitive performance (particularly outside of the laboratory) is often plagued by interference, and the source of this interference, either external or internal, might influence the expression of individual differences in attentional ability. By definition, external attention (also described as "selective attention") protects working memory against sensorial distractors of all kinds, while internal attention (also called "inhibition") protects working memory against emotional impulses, irrelevant information from memory, and automatically-generated responses. At present, it is unclear if these two types of attention are expressed independently in non-human animals, and how they might differentially impact performance on other cognitive processes, such as learning. By using a diverse battery of four attention tests (with varying levels of internal and external sources of interference), here we aimed both to explore this issue, and to obtain a robust and general (less task-specific) measure of attention in mice. Exploratory factor analyses revealed two factors (external and internal attention) that in total, accounted for 73% of the variance in attentional performance. Confirmatory factor analyses found an excellent fit with the data of the model of attention that assumed an external and internal distinction (with a resulting correlation of 0.43). In contrast, a model of attention that assumed one source of variance (i.e., "general attention") exhibited a poor fit with the data. Regarding the relationship between attention and learning, higher resistance against external sources of interference promoted better new learning, but tended to impair performance when cognitive flexibility was required, such as during the reversal of a previously instantiated response. The present results suggest that there can be (at least) two types of attention that contribute to the common variance in attentional performance in mice, and that external and internal attentions might have opposing influences on the rate at which animals learn. PMID- 25452089 TI - [Standard wrist arthroscopy: technique and documentation]. AB - OBJECTIVE: Minimally invasive approach to the wrist in order to diagnose and treat different wrist pathologies. INDICATIONS: Diagnosis of unclear chronic pain syndromes, cartilage status, intra-articular ligament structures as well as post traumatic and inflammatory conditions of the wrist. Treatment of ulnar impaction syndrome, dorsal ganglia and also in fracture treatment and various different wrist interventions. CONTRAINDICATIONS: Soft tissue infections around the wrist, severe scarring may impede access to the joint. SURGICAL TECHNIQUE: Supine position with the forearm upright and in neutral position, the elbow flexed by 90 degrees , axial traction of 3-4 kg. Superficial stab incision, blunt preparation through joint capsule, insertion of optic through 3-4 portal and probe through 4 5 portal, and radial and ulnar midcarpal portals, respectively. Either sodium chloride, CO2 or air is used as arthroscopy medium. Diagnostic round with standardized examination of all parts of the joint. Standardized written and high quality photo and/or video documentation to facilitate understandability of the findings. POSTOPERATIVE MANAGEMENT: Forearm cast for 1 week, limited load for 2 more weeks, then load is increased to normal. PMID- 25452090 TI - [Arthroscopy of the distal radioulnar joint]. AB - OBJECTIVE: Insertion of a small joint arthroscope into the proximal and distal parts of the distal radioulnar joint (DRUJ) allows visualization of the proximal pouch of the DRUJ, the joint surfaces of the sigmoid notch and the ulnar head, the convexity of the ulnar head and the proximal ulnar-sided surface of the triangular fibrocartilage complex (TFCC). INDICATIONS: Evaluation of joint pathologies in ulnar-sided wrist pain, especially in cases without diagnostic findings in standard X-rays and MRI, suspected cartilage lesions without osteochondral changes (signs of osteoarthritis), undefined swelling of the DRUJ in suspected synovitis, removal of loose bodies and arthroscopical synovialectomy, suspected lesions of the deep part of the TFCC, respectively foveal avulsions, wear or superficial tears of the proximal TFCC and arthroscopic assisted ulnar shortening. CONTRAINDICATIONS: Significant changes of the local topographical anatomy, extensive scar formation, ulna plus variance, local infection or open wounds, affected sensibility in the area of the dorsal branch of the ulnar nerve, fractures of the sigmoid notch or the ulnar head, capsular tears causing effusion of irrigation fluid. SURGICAL TECHNIQUE: In vertical extension of the wrist, two portals are created on the dorsal side of the DRUJ between the extensor digiti minimi and extensor carpi ulnaris tendons. Partial visualization of the ulnar head, the sigmoid notch, the proximal pouch of the DRUJ, and the proximal surface of the TFCC. POSTOPERATIVE MANAGEMENT: Following isolated diagnostic arthroscopies immobilization of the wrist in a semicircular ulnar-sided cast for 1 week. No extensive load to the wrist for 4 weeks. RESULTS: Still rarely performed procedure for diagnosis and therapy of ulnar-sided wrist pain. Technically demanding with a flat learning curve and anatomy-related obstacles. A complete view of the joint is not always accessible. Rare complications are injuries of the extensor digiti minimi tendon as well as contusion or sectioning of the transverse branch of the dorsal branch of the ulnar nerve. In distinct cases this procedure offers valuable additional information about the distal radioulnar joint. PMID- 25452091 TI - [Trapeziometacarpal arthroscopy]. AB - OBJECTIVE: Trapeziometacarpal arthroscopy improves diagnostic and therapeutic options in pathologies of the carpometacarpal (CMC) I joint. INDICATIONS: Pathologic conditions of the CMC I joint which are not sufficiently diagnosed by X-rays or MRI. CONTRAINDICATIONS: Pathologic conditions of the CMC I joint in which trapeziometacarpal arthroscopy is not expected to make a contribution to diagnosis or therapy. SURGICAL TECHNIQUE: Trapeziometacarpal arthroscopy using a 1.9 mm arthroscope after instillation of physiological solution. POSTOPERATIVE MANAGEMENT: Thumb cast sparing the interphalangeal joint for 1 week, then functional therapy. RESULTS: Trapeziometacarpal arthroscopy improves diagnosis of CMC I pathologies and gives new therapeutic options, a field which is still rapidly expanding. PMID- 25452092 TI - [Metacarpophalangeal joint arthroscopy]. AB - OBJECTIVE: Pain reduction in the affected metacarpophalangeal joint (MP joint) by synovectomy, loose body extraction and resection of intraarticular scars. INDICATIONS: Synovitis in rheumatoid arthritis (RA) not responding to antirheumatic treatment, primary and secondary degenerative arthritis, osteochondral lesions, loose bodies, foreign bodies, capsular contracture, septic arthritis, posttraumatic arthralgia (old collateral ligament injury), intraarticular fractures. CONTRAINDICATIONS: Established biomechanical changes in RA such as ulnar deviation and palmar subluxation with extensor tendon luxation of the MP joint. Advanced radiologic changes in degenerative arthritis. Joint instability in posttraumatic conditions. Fresh skin lesion near portals. SURGICAL TECHNIQUE: Longitudinal traction of the affected finger in a Chinese finger trap. The joint is filled with Ringer solution. Placement of a radial and ulnar dorsal portal at joint space level, through the extensor hood, at the dorsal border of the collateral ligaments. Diagnostic arthroscopy. In case of insufficient visibility (i.e., bulky synovitis in RA) "blind" shaving in the dorsal recess at first. Completion of synovectomy under sight. If necessary additional ablation of synovial tissue by a radiofrequency (RF) electrosurgical system. Use of arthroscope (1.9 mm) with a 30 degrees angle of vision and shaver (aggressive cutter; 2.0 mm). Low-suction drain, soft padded dressing. POSTOPERATIVE MANAGEMENT: Immediate postoperative mobilization for the full range of finger movement. RESULTS: In 106 MP joint arthroscopies from 2009-2011, very high patient satisfaction was achieved. Best results were obtained in RA, even in advanced radiologic changes (Larsen stages 1-3). Only in Larsen stage 4 results were rated lower. In early stages of degenerative arthritis (Kellgren-Lawrence 0 2), patient satisfaction was also very high, however decreased rapidly with increasing degree of radiologic changes. The results in posttraumatic cases are promising. PMID- 25452094 TI - [Improvements in the V-tek(r) system]. PMID- 25452093 TI - [Arthroscopic treatment of tibial plateau fractures]. AB - OBJECTIVE: The aim of arthroscopically assisted treatment of tibial plateau fractures is to achieve minimally invasive reduction and internal fixation of the joint fracture of the tibial plateau. Using the arthroscopic procedure, both the approach morbidity and the control of the articular reduction can be optimized. INDICATIONS: Displaced tibia plateau fractures of AO type A1 and B1/2/3 or Tscherne P2. CONTRAINDICATIONS: Strongly displaced tibial plateau fractures, which require an open surgical approach and stabilization with plate fixation (e.g., AO type C fractures or Moore type 5 fractures); 2nd and 3rd degree open fractures. Danger of compartment syndrome. SURGICAL TECHNIQUE: Planning of the surgical approach and confirmation of the indication by CT imaging. Diagnostic arthroscopy of the knee joint with treatment of associated injuries and confirming the indications for arthroscopically assisted reduction. Under arthroscopic control, insertion of an ACL tibial aiming device. In the central portion of the dislocated fracture fragment, a 2.4 mm K-wire is placed with the help of the aiming device. Opening of the outer cortex using a cannulated drill (9-11 mm diameter), introduction of a cannulated plunger below the fracture resulting in reduction of the fracture and compression of the cancellous bone below the fracture. Simultaneously the reduction is controlled by arthroscopy. Finally, the fracture is fixed using minimally invasive screw fixation (3.5-7.3 mm cancellous screws with washers) or by plate osteosynthesis (e.g., support plate). The metaphyseal defect can optionally be filled with bone substitute material. POSTOPERATIVE MANAGEMENT: Rehabilitation is dependent on the extent of the fracture. In arthroscopically treated fractures, partial weight bearing of 20 kg over a period of 6-12 weeks is usually necessary. PMID- 25452095 TI - Enhancing effects of salt formation on catalytic activity and enantioselectivity for asymmetric hydrogenation of isoquinolinium salts by dinuclear halide-bridged iridium complexes bearing chiral diphosphine ligands. AB - Asymmetric hydrogenation of 1- and 3-substituted and 1,3-disubstituted isoquinolinium chlorides using triply halide-bridged dinuclear iridium complexes [{Ir(H)(diphosphine)}2 (MU-Cl)3 ]Cl has been achieved by the strategy of HCl salt formation of isoquinolines to afford the corresponding chiral 1,2,3,4 tetrahydroisoquinolines (THIQs) in high yields and with excellent enantioselectivities after simple basic work-up. The effects of salt formation have been investigated by time-course experiments, which revealed that the generation of isoquinolinium chlorides clearly prevented formation of the catalytically inactive dinuclear trihydride complex, which was readily generated in the catalytic reduction of salt-free isoquinoline substrates. Based on mechanistic investigations, including by (1) H and (31) P{(1) H} NMR studies and the isolation and characterization of several intermediates, the function of the chloride anion of the isoquinolinium chlorides has been elucidated, allowing us to propose a new outer-sphere mechanism involving coordination of the chloride anion of the substrates to an iridium dihydride species along with a hydrogen bond between the chloride ligand and the N-H proton of the substrate salt. PMID- 25452096 TI - Assessment of early renal allograft dysfunction with blood oxygenation level dependent MRI and diffusion-weighted imaging. AB - PURPOSE: To investigate blood oxygenation level-dependent (BOLD) MRI and diffusion-weighted imaging (DWI) at 3 T for assessment of early renal allograft dysfunction. MATERIALS AND METHODS: 34 patients with a renal allograft (early dysfunction, 24; normal, 10) were prospectively enrolled. BOLD MRI and DWI were performed at 3 T. R2* and apparent diffusion coefficient (ADC) values were measured in cortex and medulla of the allografts. Correlation between R2* or ADC values and estimated glomerular filtration rate (eGFR) was investigated. R2* or ADC values were compared among acute rejection (AR), acute tubular necrosis (ATN) and normal function. RESULTS: In all renal allografts, cortical or medullary R2* and ADC values were moderately correlated with eGFR (P < 0.05). Early dysfunction group showed lower R2* and ADC values than normal function group(P < 0.05). AR or ATN had lower R2* values than normal allografts (P < 0.05), and ARs had lower cortical ADC values than normal allografts (P < 0.05). No significant difference of R2* or ADC values was found between AR and ATN (P > 0.05). CONCLUSION: BOLD MRI and DWI at 3 T may demonstrate early functional state of renal allografts, but may be limited in characterizing a cause of early renal allograft dysfunction. Further studies are needed. PMID- 25452097 TI - Effect of listening to music and essential oil inhalation on patients undergoing screening CT colonography: a randomized controlled trial. AB - OBJECTIVE: To prospectively evaluate the effect of listening to music and inhaling aroma oil on patients undergoing screening computed tomography colonography. MATERIALS AND METHODS: Two hundred and twenty four participants were randomly allocated to one of the four groups including: (1) combined music and aroma, (2) music alone, (3) aroma alone, and (4)control. The visual analog scale for pain and a questionnaire were used for subjective outcomes. We also used a pre-test-post-test design to compare the differences in blood pressure and heart rate as objective outcomes. RESULTS: There were no statistical differences between the control group and other groups in the visual analog scale or changes in heart rate. Changes in blood pressure were similar. Participants reported good overall experiences. There were no differences in terms of overall satisfaction, pain rating, willingness to repeat the computed tomography colonography procedure in the future, or preference between colonoscopy and computed tomography colonography. More participants using music and/or aroma requested music and/or aroma during the next computed tomography colonography (P < 0.0001). CONCLUSION: Although audio and olfactory intervention had little effect on perceived pain or discomfort and vital signs, participants who listened to music and inhaled aroma during the computed tomography colonography preferred music and aroma during the next computed tomography colonography. PMID- 25452098 TI - Role of magnetic resonance spectroscopy for the differentiation of recurrent glioma from radiation necrosis: a systematic review and meta-analysis. AB - PURPOSE: Differentiating glioma recurrence from radiation necrosis remains a great challenge. We conducted a meta-analysis to evaluate the diagnostic quality of magnetic resonance spectroscopy (MRS) in differentiating glioma recurrence from radiation necrosis. METHODS: Studies about evaluation of MRS for the differential diagnosis of glioma recurrence from radiation necrosis were systematically searched in PubMed, Embase and Chinese Biomedical databases up to May 4, 2014. The data were extracted to perform heterogeneity test, threshold effect test and to calculate sensitivity (SEN), specificity (SPE) and areas under summary receiver operating characteristic curve (SROC). RESULTS: Eighteen articles comprising a total sample size of 455 patients (447 lesions) with suspected glioma recurrence after radiotherapy, met all inclusion and exclusion criteria, and were included in our meta-analysis. Quantitative synthesis of studies showed that the pooled SEN and SPE for Cho/Cr ratio were 0.83 (95% CI: 0.77, 0.89) and 0.83 (95% CI: 0.74, 0.90). The area under the curve (AUC) under the SROC was 0.9001. The pooled SEN and SPE for Cho/NAA ratio were 0.88 (95% CI: 0.81, 0.93) and 0.86 (95% CI: 0.76, 0.93). The AUC under the SROC was 0.9185. CONCLUSION: This meta-analysis shows that MRS alone has moderate diagnostic performance in differentiating glioma recurrence from radiation necrosis using metabolite ratios like Cho/Cr and Cho/NAA ratio. It is strongly recommended that MRS should combine other advanced imaging technologies to improve diagnostic accuracy. This article underlines the importance of implementing multimodal imaging trials and multicentre trials in the future. PMID- 25452099 TI - Vertically-expanded imidazo[1,2-a]pyridines and imidazo[1,5-a]pyridine via dehydrogenative coupling. AB - The anion-radical coupling of structurally diverse series of aromatic compounds possessing biaryl linkages led to seven fused, polycyclic heterocycles in reasonable yields. The yield of the key step (K, toluene, O2) depends on both electronic and steric factors. The whole strategy consists of just two steps starting from an unsubstituted imidazo[1,2-a]pyridine, giving target compounds in an overall yield of 4-34%. The same strategy also works for derivatives of imidazo[1,5-a]pyridine. A new process has been discovered for such vertically expanded imidazo[1,2-a]pyridines, consisting of a sequential Diels-Alder reaction followed by a retro-Diels-Alder reaction. The optical properties of the library of pi-expanded imidazo[1,2-a]pyridines were for the first time fully characterized, showing that fluorescence quantum yields are significantly lower than for the singly-linked compounds. PMID- 25452100 TI - Predicting cardiac and all-cause death in asymptomatic patients on hemodialysis - importance of training in interpretation of beta-methyl iodophenyl-pentadecanoic acid single-photon emission computed tomography (BMIPP SPECT) imaging. PMID- 25452101 TI - Impact of left ventricular diastolic dysfunction on outcome of catheter ablation for atrial fibrillation in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: The relationship between outcome of radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) and the severity of left ventricular (LV) diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM) remains unknown. METHODS AND RESULTS: Twenty-two HCM patients (12 female, aged 65 +/- 11 years) with paroxysmal (n=5; 23%) or persistent (n=17; 77%) AF were enrolled. LV diastolic function was evaluated according to the ratio of the mitral inflow early filling velocity to the velocity of the early medial mitral annular ascent (E/e') measured on pulsed wave and tissue Doppler assessments in all patients. Pulmonary vein isolation was performed in all patients. A second procedure was performed in 3 patients. During a follow-up of 21 +/- 12 months, sinus rhythm was maintained in 13 of 22 patients (59%). E/e' was significantly higher in the patients with AF recurrence than in those without (18 +/- 7 vs. 11 +/- 3; P<0.01). On Kaplan-Meier analysis the prevalence of AF recurrence was significantly higher in patients with E/e' >= 15 (n=6) than in those with E/e' <15 (n=16; P<0.01). On multivariate Cox regression analysis the only significant and independent predictor for AF recurrence was E/e' (hazard ratio, 1.16; 95% confidence interval: 1.01-1.37, P=0.03). CONCLUSIONS: LV diastolic dysfunction evaluated using E/e' was associated with difficulty of rhythm control after RFCA in patients with HCM and AF. PMID- 25452102 TI - Vascular response to bare metal stents in the superficial femoral artery as assessed on optical coherence tomography. PMID- 25452103 TI - Mechanical stretch and endothelial to mesenchymal transition - importance of integrin beta1. PMID- 25452104 TI - miR-206 modulates lipopolysaccharide-mediated inflammatory cytokine production in human astrocytes. AB - Astrocyte-derived inflammation is a common component of acute or chronic injury in the central nervous system. MicroRNAs (miRNAs) are small non-coding RNAs that play important regulatory roles in the inflammatory response. In this study, we found that miR-206 is induced upon stimulation with lipopolysaccharide. Overexpression of miR-206 in astrocytes led to increased expression of inflammatory cytokines (interleukin-6, interleukin-1beta, CCL5) upon exposure to lipopolysaccharide, whereas knockdown of miR-206 had completely opposite effects. We used a combination of bioinformatics and experimental techniques to demonstrate that NR4A2, which belongs to the nuclear receptor (NR) 4 family of orphan nuclear receptors, is a direct target of miR-206. Overexpression of miR 206 mimics decreased the activity of a luciferase reporter containing the NR4A2 3'-untranslated region and led to decreased NR4A2 mRNA and protein levels. In contrast, ectopic expression of an miR-206 inhibitor led to elevated NR4A2 expression. We also found that miR-206 modulated the lipopolysaccharide-induced proinflammatory response by targeting NR4A2 and activating nuclear factor-kappa B activity. Finally, we demonstrated that the transcription factor AP-1 plays a critical role in lipopolysaccharide-induced expression of miR-206 and that the extracellular signal-regulated kinase signaling pathway contributes to the regulation of miR-206 level in astrocytes. These data demonstrate that miR-206 positively regulates the lipopolysaccharide-induced inflammatory response in human astrocytes. PMID- 25452105 TI - MAPK-dependent phosphorylation modulates the activity of Suppressor of Hairless in Drosophila. AB - Cell differentiation strictly depends on the epidermal growth factor receptor (EGFR)- and Notch-signalling pathways, which are closely intertwined. Here we address the molecular cross talk at the level of Suppressor of Hairless [Su(H)]. The Drosophila transcription factor Su(H) mediates Notch signalling at the DNA level: in the presence of signalling input Su(H) assembles an activator complex on Notch target genes and a repressor complex in its absence. Su(H) contains a highly conserved mitogen activated protein kinase (MAPK) target sequence. Here we provide evidence that Su(H) is phosphorylated in response to MAPK activity. Mutation of the Su(H) MAPK-site modulated the Notch signalling output: whereas a phospho-deficient Su(H)(MAPK-ko) isoform provoked a stronger Notch signalling activity, a phospho-mimetic Su(H)(MAPK-ac) mutant resulted in its attenuation. In vivo assays in Drosophila cell culture as well as in flies support the idea that Su(H) phosphorylation affects the dynamics of repressor or activator complex formation or the transition from the one into the other complex. In summary, the phosphorylation of Su(H) attenuates Notch signalling in vivo in several developmental settings. Consequently, a decrease of EGFR signal causes an increase of Notch signalling intensity. Hence, the antagonistic relationship between EGFR- and Notch-signalling pathways may involve a direct modification of Su(H) by MAPK in several developmental contexts of fly development. The high sequence conservation of the MAPK target site in the mammalian Su(H) homologues supports the idea that EGFR signalling impacts on Notch activity in a similar way in humans as well. PMID- 25452106 TI - Modulation of TCR responsiveness by the Grb2-family adaptor, Gads. AB - T cell antigen receptor (TCR) signaling depends on three interacting adaptor proteins: SLP-76, Gads, and LAT. Their mechanisms of signaling have been extensively explored, with the aid of fortuitously isolated LAT- and SLP-76 deficient T cell lines, but no such tools were available for Gads, a Grb2-family adaptor that bridges the TCR-inducible interaction between SLP-76 and LAT. TALEN directed genome editing was applied to disrupt the first coding exon of human Gads in the Jurkat T cell line. Gads was dispensable for TCR-induced phosphorylation of SLP-76, but was a dose-dependent amplifier of TCR-induced CD69 expression. Gads conferred responsiveness to weak TCR stimuli, leading to PLC gamma1 phosphorylation and calcium flux. TALEN-derived, Gads-deficient T cell lines provide a uniquely tractable genetic platform for exploring its regulatory features, such as Gads phosphorylation at T262, which we observed by mass spectrometry. Upon mutation of this site, TCR responsiveness and sensitivity to weak TCR stimuli were increased. This study demonstrates the feasibility of TALEN based reverse genetics in Jurkat T cells, while enriching our understanding of Gads as a regulated modulator of TCR sensitivity. PMID- 25452109 TI - Synthetic studies toward penitrem E: enantiocontrolled construction of B-E rings. AB - Enantiocontrolled construction of B-E rings of penitrem E was accomplished from 4 iodoindole in 13 steps with an overall yield of 1.7%. Diastereoselective Tf2NH catalyzed (2+2)-cycloaddition between silyl enol ether and methyl acrylate furnished a tetracyclic product possessing the characteristic cyclobutane ring bearing a hydroxyl group. PMID- 25452107 TI - MiR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of ZO-1, occludin and claudin-5. AB - The purposes of this study were to investigate the possible molecular mechanisms of miR-18a regulating the permeability of blood-tumor barrier (BTB) via down regulated expression and distribution of runt-related transcription factor 1 (RUNX1). An in vitro BTB model was established with hCMEC/D3 cells and U87MG cells to obtain glioma vascular endothelial cells (GECs). The endogenous expressions of miR-18a and RUNX1 were converse in GECs. The overexpression of miR 18a significantly impaired the integrity and increased the permeability of BTB, which respectively were detected by TEER and HRP flux assays, accompanied by down regulated mRNA and protein expressions and distributions of ZO-1, occludin and claudin-5 in GECs. Dual-luciferase reporter assay was carried out and revealed RUNX1 is a target gene of miR-18a. Meanwhile, mRNA and protein expressions and distribution of RUNX1 were downregulated by miR-18a. Most important, miR-18a and RUNX1 could reversely regulate the permeability of BTB as well as the expressions and distributions of ZO-1, occludin and claudin-5. Finally, chromatin immunoprecipitation verified that RUNX1 interacted with "TGGGGT" DNA sequence in promoter region of ZO-1, occludin and claudin-5 respectively. Taken together, our present study indicated that miR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of tight junction related proteins ZO-1, occludin and claudin-5, which would attract more attention to miR-18a and RUNX1 as potential targets of drug delivery across BTB and provide novel strategies for glioma treatment. PMID- 25452110 TI - Nobiletin Inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and migration and attenuates neointimal hyperplasia in a rat carotid artery injury model. AB - Preclinical Research The abnormal migration and proliferation of vascular smooth muscle cells (VSMCs) plays a pivotal role in the development of neointimal hyperplasia after vascular injury. Nobiletin, a citrus bioflavonoid, exhibits anti-inflammatory and anti-oxidative activities. The present study evalutaed whether nobiletin could inhibit platelet-derived growth factor (PDGF)-BB- stimulated VSMC proliferation and migration and decrease neointimal hyperplasia in a rat carotid artery injury model. Cultured VSMCs from rat thoracic aortas were treated with nobiletin before being stimulated with 20 ng/ml PDGF-BB, and rats were subjected to carotid artery injury. Nobiletin inhibited PDGF-BB-induced VSMC proliferation and migration, attenuated reactive oxygen species (ROS) production and reduced phosphorylation of ERK1/2 and the expression of nuclear NF kappaB p65 in PDGF-BB-stimulated VSMCs. Nobiletin decreased the intima area and the ratio of neointima to media in balloon-injured rat carotid arteries. Serum levels of TNF-alpha and IL-6 in nobiletin-treated rats were decreased. These results indicated that nobiletin could be a potential protective agent for the prevention and treatment of restenosis after angioplasty. PMID- 25452111 TI - Demystifying "free will": the role of contextual information and evidence accumulation for predictive brain activity. AB - Novel multivariate pattern classification analyses have enabled the prediction of decision outcomes from brain activity prior to decision-makers' reported awareness. These findings are often discussed in relation to the philosophical concept of "free will". We argue that these studies demonstrate the role of unconscious processes in simple free choices, but they do not inform the philosophical debate. Moreover, these findings are difficult to relate to cognitive decision-making models, due to misleading assumptions about random choices. We review evidence suggesting that sequential-sampling models, which assume accumulation of evidence towards a decision threshold, can also be applied to free decisions. If external evidence is eliminated by the task instructions, decision-makers might use alternative, subtle contextual information as evidence, such as their choice history, that is not consciously monitored and usually concealed by the experimental design. We conclude that the investigation of neural activity patterns associated with free decisions should aim to investigate how decisions are jointly a function of internal and external contexts, rather than to resolve the philosophical "free will" debate. PMID- 25452112 TI - Complex associative memory processing and sleep: a systematic review and meta analysis of behavioural evidence and underlying EEG mechanisms. AB - The beneficial influence of sleep on memory consolidation is well established; however, the mechanisms by which sleep can dynamically consolidate new memories into existing networks for the continued environmental adaptation of the individual are unclear. The role of sleep in complex associative memory is an emerging field and the literature has not yet been systematically reviewed. Here, we systematically review the published literature on the role of sleep in complex associative memory processing to determine (i) if there is reasonable published evidence to support an active role for sleep facilitating complex associative processes such rule and gist extraction and false memory; (ii) to determine which sleep physiological events and states impact these processes, and to quantify the strength of these relationships through meta-analysis. Twenty-seven studies in healthy adults were identified which combined indicate a moderate effect of sleep in facilitating associative memory as tested behaviourally. Studies which have measured sleep physiology have reported mixed findings. Significant associations between sleep electrophysiology and outcome appear to be based largely on mode of acquisition. We interpret these findings as supporting reactivation based models of associative processing. PMID- 25452113 TI - The learning of fear extinction. AB - Recent work on the extinction of fear-motivated learning places emphasis on its putative circuitry and on its modulation. Extinction is the learned inhibition of retrieval of previously acquired responses. Fear extinction is used as a major component of exposure therapy in the treatment of fear memories such as those of the posttraumatic stress disorder (PTSD). It is initiated and maintained by interactions between the hippocampus, basolateral amygdala and ventromedial prefrontal cortex, which involve feedback regulation of the latter by the other two areas. Fear extinction depends on NMDA receptor activation. It is positively modulated by d-serine acting on the glycine site of NMDA receptors and blocked by AP5 (2-amino-5-phosphono propionate) in the three structures. In addition, histamine acting on H2 receptors and endocannabinoids acting on CB1 receptors in the three brain areas mentioned, and muscarinic cholinergic fibers from the medial septum to hippocampal CA1 positively modulate fear extinction. Importantly, fear extinction can be made state-dependent on circulating epinephrine, which may play a role in situations of stress. Exposure to a novel experience can strongly enhance the consolidation of fear extinction through a synaptic tagging and capture mechanism; this may be useful in the therapy of states caused by fear memory like PTSD. PMID- 25452115 TI - [Non-drug addictions]. PMID- 25452114 TI - Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. AB - One-third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within 6 months. Treatment options for these patients remain limited. Here we analyse 20 BRAF(V600)-mutant melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2(C125S), but not the synonymous MEK1(C121S) protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (for example, RAC1 and AKT3) that activate the MAPK and PI3K pathways and are thus predicted to diminish response to MAPK inhibitors. PMID- 25452116 TI - Use of serial assessment of disease severity and liver biopsy for indication for liver transplantation in pediatric Epstein-Barr virus-induced fulminant hepatic failure. AB - The decision to perform liver transplantation (LT) in patients with Epstein-Barr virus (EBV)-induced fulminant hepatic failure (FHF) relies on a precise assessment of laboratory and pathological findings. In this study, we analyzed clinical and laboratory data as well as the pathological features of the liver in order to evaluate the pathogenesis and the need for LT in 5 patients with EBV induced FHF. According to the King's College criteria, the Acute Liver Failure Early Dynamic (ALFED) model, and the Japanese criteria (from the Acute Liver Failure Study Group of Japan), only 1 patient was considered to be a candidate for LT. However, explanted liver tissues in 3 cases exhibited massive hepatocellular necrosis together with diffuse CD8-positive T cell infiltration in both the portal area and the sinusoid. EBV was detected in the liver, plasma, and peripheral blood mononuclear cells (PBMNCs). In 2 cases indicated to be at moderate risk by the ALFED model, liver biopsy showed CD8-positive and EBV encoded RNA signal-positive lymphocytic infiltration predominantly in the portal area, but massive hepatocellular necrosis was not observed. These patients were treated with immunosuppressants and etoposide under the diagnosis of EBV-induced hemophagocytic lymphohistiocytosis or systemic EBV-positive T cell lymphoproliferative disease of childhood. EBV DNA was detected at a high level in PBMNCs, although it was negative in plasma. On the basis of the pathological analysis of the explanted liver tissues, LT was proposed for the restoration of liver function and the removal of the EBV-infected lymphocytes concentrated in the liver. Detecting EBV DNA by a quantitative polymerase chain reaction in plasma and PBMNCs was informative. An accurate evaluation of the underlying pathogenesis is essential for developing a treatment strategy in patients with EBV-induced FHF. PMID- 25452118 TI - The development of mixed cryoglobulinemia in Capillaria hepatica-infected mice is associated with the capillaria antigen-induced selective proliferation of splenic B-1a cells in response to interleukin-5 stimulation. AB - Chronic infection by pathogens such as hepatitis C virus induces monoclonal or oligoclonal proliferation of B cells, which produce IgM rheumatoid factor, leading to the development of mixed cryoglobulinemia (MC). Antigen-driven lymphoproliferation is essential to the onset of MC; however, the underlying mechanism is largely unknown. Herein, we show that type II MC is induced by Capillaria hepatica infection through a mechanism in which splenic B-1a cells reacting to C. hepatica-specific antigen selectively proliferate, producing IgM rheumatoid factor under co-stimulation of the specific worm antigen and IL-5. In vitro assays using B-1a cells from infected mice showed that stimulation by C. hepatica soluble fraction promoted the proliferation of B-1a cells and the secretion of IgM, which reacted with the 75-kDa antigen in the soluble fraction. The severity of MC was correlated with the increase in serum IL-5 levels in the infected mice. Furthermore, i.p. injection of the soluble worm fraction caused MC without an inflammatory response in IL-5 transgenic mice, indicating that IL-5 is critical for the development of MC. These results indicate that the selective proliferation of IgM rheumatoid factor-secreting B-1a cells is induced by co stimulation by the specific pathogen antigen and IL-5 in the development of MC in C. hepatica-infected mice. PMID- 25452117 TI - Prostaglandin E2 receptor subtype 2 regulation of scavenger receptor CD36 modulates microglial Abeta42 phagocytosis. AB - Recent studies underline the potential relevance of microglial innate immune activation in Alzheimer disease. Primary mouse microglia that lack prostaglandin E2 receptor subtype 2 (EP2) show decreased innate immune-mediated neurotoxicity and increased amyloid beta (Abeta) peptide phagocytosis, features that were replicated in vivo. Here, we tested the hypothesis that scavenger receptor CD36 is an effector of EP2-regulated Abeta phagocytosis. CD36 expression was 143-fold greater in mouse primary microglia than in primary astrocytes. Three different means of suppressing EP2 signaling increased and an agonist of EP2 decreased CD36 expression in primary wild-type microglia. Activation of Toll-like receptor (TLR) 3, TLR4, and TLR7, but not TLR2 or TLR9, reduced primary microglial CD36 transcription and cell surface CD36 protein and reduced Abeta42 phagocytosis as well. At each step, the effects of innate immune activation on CD36 were reversed by at least 50% by an EP2 antagonist, and this partial rescue of microglia Abeta42 phagocytosis was largely mediated by CD36 activity. Finally, we showed in hippocampus of wild-type mice that innate immune activation suppressed CD36 expression by an EP2-dependent mechanism. Taken together with results of others that found brain clearance of Abeta peptides and behavioral improvements mediated by CD36 in mice, regulation of CD36-mediated Abeta phagocytosis by suppression of EP2 signaling may provide a new approach to suppressing some aspects of Alzheimer disease pathogenesis. PMID- 25452119 TI - Global deletion of Ankrd1 results in a wound-healing phenotype associated with dermal fibroblast dysfunction. AB - The expression of ankyrin repeat domain protein 1 (Ankrd1), a transcriptional cofactor and sarcomeric component, is strongly elevated by wounding and tissue injury. We developed a conditional Ankrd1(fl/fl) mouse, performed global deletion with Sox2-cre, and assessed the role of this protein in cutaneous wound healing. Although global deletion of Ankrd1 did not affect mouse viability or development, Ankrd1(-/-) mice had at least two significant wound-healing phenotypes: extensive necrosis of ischemic skin flaps, which was reversed by adenoviral expression of ANKRD1, and delayed excisional wound closure, which was characterized by decreased contraction and reduced granulation tissue thickness. Skin fibroblasts isolated from Ankrd1(-/-) mice did not spread or migrate on collagen- or fibronectin-coated surfaces as efficiently as fibroblasts isolated from Ankrd1(fl/fl) mice. More important, Ankrd1(-/-) fibroblasts failed to contract three-dimensional floating collagen gels. Reconstitution of ANKRD1 by adenoviral infection stimulated both collagen gel contraction and actin fiber organization. These in vitro data were consistent with in vivo wound closure studies, and suggest that ANKRD1 is important for the proper interaction of fibroblasts with a compliant collagenous matrix both in vitro and in vivo. PMID- 25452120 TI - The Patched 1 tumor-suppressor gene protects the mouse lens from spontaneous and radiation-induced cataract. AB - Age-related cataract is the most common cause of visual impairment. Moreover, traumatic cataracts form after injury to the eye, including radiation damage. We report herein that sonic hedgehog (Shh) signaling plays a key role in cataract development and in normal lens response to radiation injury. Mice heterozygous for Patched 1 (Ptch1), the Shh receptor and negative regulator of the pathway, develop spontaneous cataract and are highly susceptible to cataract induction by exposure to ionizing radiation in early postnatal age, when lens epithelial cells undergo rapid expansion in the lens epithelium. Neonatally irradiated and control Ptch1(+/-) mice were compared for markers of progenitors, Shh pathway activation, and epithelial-to-mesenchymal transition (EMT). Molecular analyses showed increased expression of the EMT-related transforming growth factor beta/Smad signaling pathway in the neonatally irradiated lens, and up-regulation of mesenchymal markers Zeb1 and Vim. We further show a link between proliferation and the stemness property of lens epithelial cells, controlled by Shh. Our results suggest that Shh and transforming growth factor beta signaling cooperate to promote Ptch1-associated cataract development by activating EMT, and that the Nanog marker of pluripotent cells may act as the primary transcription factor on which both signaling pathways converge after damage. These findings highlight a novel function of Shh signaling unrelated to cancer and provide a new animal model to investigate the molecular pathogenesis of cataract formation. PMID- 25452121 TI - The role of SIRT1 in cancer: the saga continues. AB - This Commentary highlights the article by Di Sante et al, which presents data supporting the status of SIRT1 as a tumor suppressor in prostate cancer. PMID- 25452123 TI - Editorial on EMC 2014 special issue. PMID- 25452122 TI - Open power morcellation versus contained power morcellation within an insufflated isolation bag: comparison of perioperative outcomes. AB - STUDY OBJECTIVE: To compare perioperative outcomes, particularly operative time, between uncontained and in-bag power morcellation of uterine tissue at the time of laparoscopic surgery. DESIGN: Canadian Task Force classification II-3. SETTING: Academic tertiary care hospitals. PATIENTS: Women undergoing laparoscopic hysterectomy or myomectomy who required morcellation of uterine tissue for specimen extraction. INTERVENTIONS: Outcomes among patients who had in bag power morcellation were compared with outcomes among patients who had traditional power morcellation. The technique for in-bag morcellation entails placing the specimen into a large containment bag within the abdomen, insufflating the bag within the peritoneal cavity, and then using a power morcellator to remove the specimen from inside the bag. MEASUREMENTS AND MAIN RESULTS: The cohort consisted of 85 consecutive patients who underwent surgery with morcellation of uterine tissue. Prospective data collected from 36 patients who underwent in-bag morcellation were compared with retrospective data collected from the immediately preceding 49 patients who had uncontained power morcellation. Baseline demographics were comparable between the 2 groups although women who underwent in-bag morcellation were on average older than the open morcellation group (mean age in years [standard deviation], 49.19 [1.12] vs 44.06 [8.93]; p = .01). The mean operating room time was longer in the in-bag morcellation group (mean time in minutes [standard deviation], 119.0 [55.91] vs 93.13 [44.90]; p = .02). The estimated blood loss, specimen weight, hospital length of stay, and perioperative complication rate did not vary between the 2 groups. Operative times did not vary significantly by surgeon. There were no cases of malignancy or isolation bag disruption. CONCLUSIONS: In-bag power morcellation, a tissue extraction technique developed to reduce the risk of tissue dissemination, results in perioperative outcomes comparable with the traditional laparoscopic approach. In this cohort, the mean operative time was prolonged by 26 minutes with in-bag morcellation but may potentially be reduced with further refinement of the technique. PMID- 25452124 TI - Effect of protons on the mechanical response of rat muscle nociceptive fibers and neurons in vitro. AB - Strong exercise makes muscle acidic, and painful. The stimulus that activates muscle nociceptors in such instance may be protons. Reportedly, however, not many afferents are excited by protons alone. We, therefore, posited that protons sensitize muscular nociceptors to mechanical stimuli. We examined effects of protons on mechanical sensitivity of muscle nociceptors by single-fiber recording from rat muscle-nerve preparations in vitro and by whole cell patch-clamp recording of mechanically activated (MA) currents from cultured rat dorsal root ganglion neurons. We recorded 38 Adelta- and C-fibers. Their response magnitude was increased by both pH 6.2 and pH 6.8; in addition the mechanical threshold was lowered by pH 6.2. Decrease in the threshold by pH6.2 was also observed in MA currents. Presently observed sensitization by protons could be involved in several types of ischemic muscle pain, and may also be involved in cardiovascular and respiratory controls during exercise. PMID- 25452125 TI - The neural bases for valuing social equality. AB - The neural basis of how humans value and pursue social equality has become a major topic in social neuroscience research. Although recent studies have identified a set of brain regions and possible mechanisms that are involved in the neural processing of equality of outcome between individuals, how the human brain processes equality of opportunity remains unknown. In this review article, first we describe the importance of the distinction between equality of outcome and equality of opportunity, which has been emphasized in philosophy and economics. Next, we discuss possible approaches for empirical characterization of human valuation of equality of opportunity vs. equality of outcome. Understanding how these two concepts are distinct and interact with each other may provide a better explanation of complex human behaviors concerning fairness and social equality. PMID- 25452126 TI - Partial dopaminergic denervation-induced impairment in stimulus discrimination acquisition in parkinsonian rats: a model for early Parkinson's disease. AB - Parkinson's disease (PD) produces progressive nigrostriatal dopamine (DA) denervation resulting in cognitive and motor impairment. However, it is unknown whether cognitive impairments, such as instrumental learning deficits, are associated with the early stage PD-induced mild DA denervation. The current study sought to model early PD-induced instrumental learning impairments by assessing the effects of low dose (5.5MUg), bilateral 6OHDA-induced striatal DA denervation on acquisition of instrumental stimulus discrimination in rats. 6OHDA (n=20) or sham (n=10) lesioned rats were tested for stimulus discrimination acquisition either 1 or 2 weeks post surgical lesion. Stimulus discrimination acquisition across 10 daily sessions was used to assess discriminative accuracy, or a probability measure of the shift toward reinforced responding under one stimulus condition (Sd) away from extinction, when reinforcement was withheld, under another (S(d) phase). Striatal DA denervation was assayed by tyrosine hydroxylase (TH) staining intensity. Results indicated that 6OHDA lesions produced significant loss of dorsal striatal TH staining intensity and marked impairment in discrimination acquisition, without inducing akinetic motor deficits. Rather 6OHDA-induced impairment was associated with perseveration during extinction (S(Delta) phase). These findings suggest that partial, bilateral striatal DA denervation produces instrumental learning deficits, prior to the onset of gross motor impairment, and suggest that the current model is useful for investigating mild nigrostriatal DA denervation associated with early stage clinical PD. PMID- 25452127 TI - Short-term efficacy of sacroiliac joint corticosteroid injection based on arthrographic contrast patterns. AB - OBJECTIVE: To determine the relationship between sacroiliac joint (SIJ) contrast dispersal patterns during SIJ corticosteroid injection and pain relief at 2 and 8 weeks after the procedure. The association between the number of positive provocative SIJ physical examination maneuvers (minimum of one in all patients undergoing SIJ injection) and the patient's response to the intervention was also assessed. DESIGN: Retrospective chart review. SETTING: Academic outpatient musculoskeletal practice. PATIENTS: Fifty-four subjects who underwent therapeutic SIJ corticosteroid injection were screened for inclusion; 49 subjects were included in the final analysis. METHODS: A retrospective review of electronic medical records identified patients who underwent SIJ corticosteroid injection. Fluoroscopic contrast flow patterns were categorized as type I (intra-articular injection with cephalad extension within the SIJ) or type II (intra-articular injection with poor cephalad extension). Self-reported numeric pain rating scale (NPRS) values at the time of injection and 2 and 8 weeks after the procedure were recorded. The number of positive provocative SIJ physical examination maneuvers at the time of the initial evaluation was also recorded. MAIN OUTCOME MEASURES: The primary outcome measure was the effect of contrast patterns (type I or type II) on change in NPRS values at 2 weeks and 8 weeks after the injection. The secondary outcome measure was the association between the number of positive provocative SIJ physical examination maneuvers and decrease in the level of pain after the procedure. RESULTS: At 2 weeks after the procedure, type I subjects demonstrated a significantly lower mean NPRS value compared with type II subjects (2.8 +/- 1.4 versus 3.8 +/- 1.6, respectively, P = .02). No statistically significant difference was observed at 8 weeks after the procedure. NPRS values were significantly reduced both at 2 weeks and 8 weeks, compared with baseline, in both subjects identified as having type I flow and those with type II flow (P < .0001 for all within-group comparisons). CONCLUSIONS: Fluoroscopically guided corticosteroid injections into the SIJ joint are effective in decreasing NPRS values in patients with SIJ-mediated pain. Delivery of corticosteroid to the superior portion of the SIJ leads to a greater reduction in pain at 2 weeks, but not at 8 weeks. Patients with at least one positive provocative maneuver should benefit from an intra-articular corticosteroid injection. PMID- 25452128 TI - A review of the clinical value of isolated lumbar extension resistance training for chronic low back pain. AB - OBJECTIVE: Chronic low back pain (CLBP) is prevalent, costly, and acknowledged as multifactorial in nature. However, deconditioning of the lumbar extensor musculature may be a common factor. Thus specific resistance exercise is often recommended. Many resistance exercises for the lumbar extensors exist, although recent evidence suggests that isolated lumbar extension (ILEX) resistance training may best for conditioning these muscles. Thus this review aimed to examine the use of ILEX resistance training in participants with CLBP to provide a best-evidence synthesis for practitioners and clinicians. LITERATURE SURVEY: Reference lists from previous reviews were searched in addition to SPORTDiscus, PubMed, and Google Scholar databases up to May 2014 using search terms including combinations and synonyms of "isolation," "lumbar extension," "lumbar exercise," "lumbar strength," "lumbar endurance," "lumbar spine," "low back exercise," "CLBP," "pain," and "disability." METHODOLOGY: A "snowballing"-style literature search was used that involved an emergent approach. Studies examining ILEX resistance training as an intervention in symptomatic CLBP populations reporting pain, disability, or global perceived outcomes (GPO) as outcomes were examined. Pain and disability were outcomes and were compared to consensus guidelines for minimal clinically important changes. Single case reports were excluded. SYNTHESIS: Results suggest that ILEX resistance training produces significant and meaningful improvements in perceived pain, disability, and GPOs, as part of a multiple intervention or stand-alone approach. A low frequency (once per week) yet high intensity of effort (to momentary muscular failure) approach using either full or limited range-of-motion ILEX resistance training appears to be sufficient and best for significant and meaningful outcomes. Limited comparative studies between ILEX resistance training and other specific exercise approaches exist; however, only limited evidence supports ILEX resistance training as being more effective. CONCLUSIONS: These findings highlight ILEX resistance training as effective for significant and meaningful improvements in perceived pain, disability, and GPOs for CLBP participants. Further research should elucidate comparisons between ILEX resistance training and other specific exercise approaches and should clarify whether lumbar extensor conditioning is the mechanism responsible for the improvements reported. PMID- 25452129 TI - BioID identifies novel c-MYC interacting partners in cultured cells and xenograft tumors. AB - The BioID proximity-based biotin labeling technique was recently developed for the characterization of protein-protein interaction networks [1]. To date, this method has been applied to a number of different polypeptides expressed in cultured cells. Here we report the adaptation of BioID to the identification of protein-protein interactions surrounding the c-MYC oncoprotein in human cells grown both under standard culture conditions and in mice as tumor xenografts. Notably, in vivo BioID yielded >100 high confidence MYC interacting proteins, including >30 known binding partners. Putative novel MYC interactors include components of the STAGA/KAT5 and SWI/SNF chromatin remodeling complexes, DNA repair and replication factors, general transcription and elongation factors, and transcriptional co-regulators such as the DNA helicase protein chromodomain 8 (CHD8). Providing additional confidence in these findings, ENCODE ChIP-seq datasets highlight significant coincident binding throughout the genome for the MYC interactors identified here, and we validate the previously unreported MYC CHD8 interaction using both a yeast two hybrid analysis and the proximity-based ligation assay. In sum, we demonstrate that BioID can be utilized to identify bona fide interacting partners for a chromatin-associated protein in vivo. This technique will allow for a much improved understanding of protein-protein interactions in a previously inaccessible biological setting. BIOLOGICAL SIGNIFICANCE: The c-MYC (MYC) oncogene is a transcription factor that plays important roles in cancer initiation and progression. MYC expression is deregulated in more than 50% of human cancers, but the role of this protein in normal cell biology and tumor progression is still not well understood, in part because identifying MYC-interacting proteins has been technically challenging: MYC-containing chromatin-associated complexes are difficult to isolate using traditional affinity purification methods, and the MYC protein is exceptionally labile, with a half-life of only ~30 min. Developing a new strategy to gain insight into MYC-containing protein complexes would thus mark a key advance in cancer research. The recently described BioID proximity-based labeling technique represents a promising new complementary approach for the characterization of protein-protein interactions (PPIs) in cultured cells. Here we report that BioID can also be used to characterize protein-protein interactions for a chromatin associated protein in tumor xenografts, and present a comprehensive, high confidence in vivo MYC interactome. This article is part of a Special Issue entitled: Protein dynamics in health and disease. Guest Editors: Pierre Thibault and Anne-Claude Gingras. PMID- 25452131 TI - Identification of novel post-translational modifications in linker histones from chicken erythrocytes. AB - Chicken erythrocyte nuclei were digested with micrococcal nuclease and fractionated by centrifugation in low-salt buffer into soluble and insoluble fractions. Post-translational modifications of the purified linker histones of both fractions were analyzed by LC-ESI-MS/MS. All six histone H1 subtypes (H1.01, H1.02, H1.03, H1.10, H1.1L and H1.1R) and histone H5 were identified. Mass spectrometry analysis enabled the identification of a wide range of PTMs, including N(alpha)-terminal acetylation, acetylation, formylation, phosphorylation and oxidation. A total of nine new modifications in chicken linker histones were mapped, most of them located in the N-terminal and globular domains. Relative quantification of the modified peptides showed that linker histone PTMs were differentially distributed among both chromatin fractions, suggesting their relevance in the regulation of chromatin structure. The analysis of our results combined with previously reported data for chicken and some mammalian species showed that most of the modified positions were conserved throughout evolution, highlighting their importance in specific linker histone functions and epigenetics. BIOLOGICAL SIGNIFICANCE: Post-translational modifications of linker histones could have a role in the regulation of gene expression through the modulation of chromatin higher-order structure and chromatin remodeling. Finding new PTMs in linker histones is the first step to elucidate their role in the histone code. In this manuscript we report nine new post-translational modifications of the linker histones from chicken erythrocytes, one in H5 and eight in the H1 subtypes. Chromatin fractionated by centrifugation in low-salt buffer resulted in two fractions with different contents and compositions of linker histones and enriched in specific core histone PTMs. Of particular interest is the fact that linker histone PTMs were differentially distributed in both chromatin fractions, suggesting specific functions. Future studies are needed to establish the interplay between PTMs of linker and core histones in order to fully understand chromatin regulation. A protein sequence alignment summarizing the PTMs found to date in chicken, mouse, rat and humans showed that, while many of the modified positions were conserved between these species, the type of modification often varied depending on the species or the cellular type. This finding suggests an important role for the PTMs in the regulation of linker histone functions. PMID- 25452132 TI - Analysis of epididymal sperm maturation by MALDI profiling and top-down mass spectrometry. AB - The fertilization ability of male gametes is achieved after their transit through the epididymis where important post-gonadal differentiation occurs in different cellular compartments. Most of these maturational modifications occur at the protein level. The epididymal sperm maturation process was investigated using the ICM-MS (Intact Cell MALDI-TOF MS) approach on boar spermatozoa isolated from four different epididymal regions (immature to mature stage). Differential and quantitative MALDI-TOF profiling for whole cells or sub-cellular fractions was combined with targeted top-down MS in order to identify endogenous biomolecules. Using this approach, 172m/z peaks ranging between 2 and 20kDa were found to be modified during maturation of sperm. Using top-down MS, 62m/z were identified corresponding to peptidoforms/proteoforms with post-translational modifications (MS data are available via ProteomeXchange with identifier PXD001303). Many of the endogenous peptides were characterized as N-, C-terminal sequences or internal fragments of proteins presenting specific cleavages, suggesting the presence of sequential protease activities in the spermatozoa. This is the first time that such proteolytic activities could be evidenced for various sperm proteins through quantification of their proteolytic products. ICM-MS/top-down MS thus proved to be a valid approach for peptidome/degradome studies and provided new contributions to understanding of the maturation process of the male gamete involved in the development of male fertility. BIOLOGICAL SIGNIFICANCE: This peptidomic study (i) characterized the peptidome of epididymal spermatozoa from boar (Sus scrofa); (ii) established characteristic molecular phenotypes distinguishing degrees of maturation of spermatozoa during epididymal transit, and (iii) revealed that protease activities were at the origin of numerous peptides from known and unknown proteins involved in sperm maturation and/or fertility processes. PMID- 25452130 TI - Quantitative proteomics of the yeast Hsp70/Hsp90 interactomes during DNA damage reveal chaperone-dependent regulation of ribonucleotide reductase. AB - The highly conserved molecular chaperones Hsp90 and Hsp70 are indispensible for folding and maturation of a significant fraction of the proteome, including many proteins involved in signal transduction and stress response. To examine the dynamics of chaperone-client interactions after DNA damage, we applied quantitative affinity-purification mass spectrometry (AP-MS) proteomics to characterize interactomes of the yeast Hsp70 isoform Ssa1 and Hsp90 isoform Hsp82 before and after exposure to methyl methanesulfonate. Of 256 proteins identified and quantified via (16)O(/18)O labeling and LC-MS/MS, 142 are novel Hsp70/90 interactors. Nearly all interactions remained unchanged or decreased after DNA damage, but 5 proteins increased interactions with Ssa1 and/or Hsp82, including the ribonucleotide reductase (RNR) subunit Rnr4. Inhibiting Hsp70 or 90 chaperone activity destabilized Rnr4 in yeast and its vertebrate homolog hRMM2 in breast cancer cells. In turn, pre-treatment of cancer cells with chaperone inhibitors sensitized cells to the RNR inhibitor gemcitabine, suggesting a novel chemotherapy strategy. All MS data have been deposited in the ProteomeXchange with identifier PXD001284. BIOLOGICAL SIGNIFICANCE: This study provides the dynamic interactome of the yeast Hsp70 and Hsp90 under DNA damage which suggest key roles for the chaperones in a variety of signaling cascades. Importantly, the cancer drug target ribonucleotide reductase was shown to be a client of Hsp70 and Hsp90 in both yeast and breast cancer cells. As such, this study highlights the potential of a novel cancer therapeutic strategy that exploits the synergy of chaperone and ribonucleotide reductase inhibitors. PMID- 25452133 TI - Snake venom serine proteinases specificity mapping by proteomic identification of cleavage sites. AB - Many snake venom toxins are serine proteases but their specific in vivo targets are mostly unknown. Various act on components of the coagulation cascade, and fibrinolytic and kallikrein-kinin systems to trigger various pathological effects observed in the envenomation. Despite showing high similarity in terms of primary structure snake venom serine proteinases (SVSPs) show exquisite specificity towards macromolecular substrates. Therefore, the characterization of their peptide bond specificity is important for understanding the active site preference associated with effective proteolysis as well as for the design of peptide substrates and inhibitors. Bothrops jararaca contains various SVSPs among which Bothrops protease A is a specific fibrinogenolytic agent and PA-BJ is a platelet-activating enzyme. In this study we used proteome derived peptide libraries in the Proteomic Identification of protease Cleavage Sites (PICS) approach to explore the peptide bond specificity of Bothrops protease A and PA-BJ in order to determine their individual peptide cleavage sequences. A total of 371 cleavage sites (208 for Bothrops protease A and 163 for PA-BJ) were detected and both proteinases displayed a clear preference for arginine at the P1 position. Moreover, the analysis of the specificity profiles of Bothrops protease A and PA BJ revealed subtle differences in the preferences along P6-P6', despite a common yet unusual preference for Pro at P2. Taken together, these results map the subsite specificity of both SVSPs and shed light in the functional differences between these proteinases. BIOLOGICAL SIGNIFICANCE: Proteolysis is key to various pathological effects observed upon envenomation by viperid snakes. The use of the Proteomic Identification of protease Cleavage Sites (PICS) approach for the easy mapping of proteinase subsite preferences at both the prime- and non-prime sides concurrently gives rise to a fresh understanding of the interaction of the snake venom serine proteinases with peptide and macromolecular substrates and indicates that their hydrolytic activity is influenced by the amino acid sequences adjacent to the scissile bond. PMID- 25452134 TI - Quantitative proteome analysis of Caenorhabditis elegans upon exposure to nematicidal Bacillus thuringiensis. AB - Caenorhabditis elegans can be infected by a plethora of pathogens, most of them are also pathogenic for humans. Consequently, the nematode has emerged as a powerful surrogate host to model microbial human infectious diseases in a non vertebrate, for the study of innate immunity and host-pathogen interactions. Signaling cascades are well investigated that face bacterial or fungal pathogens. We analyzed the downstream processes of these cascades, i.e. the differential expression of effector and regulatory molecules due to a microbial challenge with a pathogenic strain of the bacterium Bacillus thuringiensis (Bt) in comparison to a non-pathogenic Bt strain. The protein abundance profile of the nematode was studied by quantitative proteomics using iTRAQ labeling and 2D-LC-MS analysis. We developed (i) a novel method for the preparation of defined C. elegans samples; (ii) a pooling strategy for fractions in 2D-LC separation schemes; and (iii) an isobaric labeling scheme reducing the number of necessary LC-MS experiments. More than 3,600 proteins were quantified, 288 of which showed altered abundances, implicating protein classes such as lectins, lysozymes, and transthyretin-like proteins to be involved in the nematode innate immune defense. A number of gene products previously only identified by transcriptomic profiling could be verified at the protein level. Moreover, several other protein classes such as proteases, proteins related to autophagy and apoptosis, structural proteins, and proteins involved in chromatin organization were detected. The results provide an overview of the physiological response towards a pathogen at protein level in the important model organism C. elegans, giving insights into highly complex host pathogen interactions. BIOLOGICAL SIGNIFICANCE: This study identified system-wide effects of Bt intoxication on C. elegans at protein level, expanding the catalogue of immune effectors potentially acting towards the pathogen, and provide verification for numerous gene products implicated in previous transcriptomic studies. The data present evidence in support of both a general defense response as well as a specific reaction against the Bt toxin within the nematode. The described findings will also contribute to a deeper understanding of host-microbe interaction in other organisms, including humans, and may provide key information that touches far reaching aspects of coevolutionary processes. PMID- 25452135 TI - Discrimination of acidic and alkaline enzyme using Chou's pseudo amino acid composition in conjunction with probabilistic neural network model. AB - Enzyme catalysis is one of the most essential and striking processes among of all the complex processes that have evolved in living organisms. Enzymes are biological catalysts, which play a significant role in industrial applications as well as in medical areas, due to profound specificity, selectivity and catalytic efficiency. Refining catalytic efficiency of enzymes has become the most challenging job of enzyme engineering, into acidic and alkaline. Discrimination of acidic and alkaline enzymes through experimental approaches is difficult, sometimes impossible due to lack of established structures. Therefore, it is highly desirable to develop a computational model for discriminating acidic and alkaline enzymes from primary sequences. In this study, we have developed a robust, accurate and high throughput computational model using two discrete sample representation methods Pseudo amino acid composition (PseAAC) and split amino acid composition. Various classification algorithms including probabilistic neural network (PNN), K-nearest neighbor, decision tree, multi-layer perceptron and support vector machine are applied to predict acidic and alkaline with high accuracy. 10-fold cross validation test and several statistical measures namely, accuracy, F-measure, and area under ROC are used to evaluate the performance of the proposed model. The performance of the model is examined using two benchmark datasets to demonstrate the effectiveness of the model. The empirical results show that the performance of PNN in conjunction with PseAAC is quite promising compared to existing approaches in the literature so for. It has achieved 96.3% accuracy on dataset1 and 99.2% on dataset2. It is ascertained that the proposed model might be useful for basic research and drug related application areas. PMID- 25452136 TI - Oxygen as a critical determinant of bone fracture healing-a multiscale model. AB - A timely restoration of the ruptured blood vessel network in order to deliver oxygen and nutrients to the fracture zone is crucial for successful bone healing. Indeed, oxygen plays a key role in the aerobic metabolism of cells, in the activity of a myriad of enzymes as well as in the regulation of several (angiogenic) genes. In this paper, a previously developed model of bone fracture healing is further improved with a detailed description of the influence of oxygen on various cellular processes that occur during bone fracture healing. Oxygen ranges of the cell-specific oxygen-dependent processes were established based on the state-of-the art experimental knowledge through a rigorous literature study. The newly developed oxygen model is compared with previously published experimental and in silico results. An extensive sensitivity analysis was also performed on the newly introduced oxygen thresholds, indicating the robustness of the oxygen model. Finally, the oxygen model was applied to the challenging clinical case of a critical sized defect (3mm) where it predicted the formation of a fracture non-union. Further model analyses showed that the harsh hypoxic conditions in the central region of the callus resulted in cell death and disrupted bone healing thereby indicating the importance of a timely vascularization for the successful healing of a large bone defect. In conclusion, this work demonstrates that the oxygen model is a powerful tool to further unravel the complex spatiotemporal interplay of oxygen delivery, diffusion and consumption with the several healing steps, each occurring at distinct, optimal oxygen tensions during the bone repair process. PMID- 25452137 TI - Is trabecular bone permeability governed by molecular ordering-induced fluid viscosity gain? Arguments from re-evaluation of experimental data in the framework of homogenization theory. AB - It is generally agreed on that trabecular bone permeability, a physiologically important quantity, is governed by the material's (vascular or intertrabecular) porosity as well as by the viscosity of the pore-filling fluids. Still, there is less agreement on how these two key factors govern bone permeability. In order to shed more light onto this somewhat open issue, we here develop a random homogenization scheme for upscaling Poiseuille flow in the vascular porosity, up to Darcy-type permeability of the overall porous medium "trabecular bone". The underlying representative volume element of the macroscopic bone material contains two types of phases: a spherical, impermeable extracellular bone matrix phase interacts with interpenetrating cylindrical pore channel phases that are oriented in all different space directions. This type of interaction is modeled by means of a self-consistent homogenization scheme. While the permeability of the bone matrix equals to zero, the permeability of the pore phase is found through expressing the classical Hagen-Poiseuille law for laminar flow in the format of a "micro-Darcy law". The upscaling scheme contains pore size and porosity as geometrical input variables; however, they can be related to each other, based on well-known relations between porosity and specific bone surface. As two key results, validated through comprehensive experimental data, it appears (i) that the famous Kozeny-Carman constant (which relates bone permeability to the cube of the porosity, the square of the specific surface, as well as to the bone fluid viscosity) needs to be replaced by an again porosity-dependent rational function, and (ii) that the overall bone permeability is strongly affected by the pore fluid viscosity, which, in case of polarized fluids, is strongly increased due to the presence of electrically charged pore walls. PMID- 25452138 TI - Analysis of an epidemic model with awareness decay on regular random networks. AB - The existence of a die-out threshold (different from the classic disease-invasion one) defining a region of slow extinction of an epidemic has been proved elsewhere for susceptible-aware-infectious-susceptible models without awareness decay, through bifurcation analysis. By means of an equivalent mean-field model defined on regular random networks, we interpret the dynamics of the system in this region and prove that the existence of bifurcation for this second epidemic threshold crucially depends on the absence of awareness decay. We show that the continuum of equilibria that characterizes the slow die-out dynamics collapses into a unique equilibrium when a constant rate of awareness decay is assumed, no matter how small, and that the resulting bifurcation from the disease-free equilibrium is equivalent to that of standard epidemic models. We illustrate these findings with continuous-time stochastic simulations on regular random networks with different degrees. Finally, the behaviour of solutions with and without decay in awareness is compared around the second epidemic threshold for a small rate of awareness decay. PMID- 25452139 TI - The effect of fluticasone furoate/umeclidinium in adult patients with asthma: a randomized, dose-ranging study. AB - BACKGROUND: We evaluated the dose-response of umeclidinium (UMEC; a long-acting muscarinic antagonist) combined with fluticasone furoate (FF; an inhaled corticosteroid [ICS]) in patients with asthma. METHODS: In a double-blind, three period crossover study, 421 subjects (symptomatic on ICS), were randomized to a sequence of three of seven treatments: FF 100 mcg alone, FF 100 mcg combined with UMEC (15.6, 31.25, 62.5, 125, or 250 mcg), or vilanterol 25 mcg (a long-acting beta-agonist), inhaled once-daily for 14 days (12-14-day washout). Trough forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), and safety were assessed. RESULTS: Period baseline was a significant covariate, indicating a potential carryover effect between treatment periods. Across all treatment periods, trough FEV1 improved with FF/UMEC 125 and 250 versus FF (treatment difference 0.055 L [both doses]; p = 0.018). FF/UMEC increased morning (15.9-22.9 L/min) and evening (16.2-28.8 L/min) PEF versus FF. As intended assessments were confounded, post hoc Period 1 data analyses were performed, demonstrating significant increases in trough FEV1 with FF/UMEC 31.25, 62.5, and 250 versus FF. Trough FEV1 improvements with FF/UMEC were greater in subjects with fixed (0.095 0.304 L) versus non-fixed (-0.084 to 0.041 L) obstruction. The incidence of on treatment adverse events was 13-25% across groups. No treatment-related effects on laboratory parameters were reported. CONCLUSION: FF/UMEC may be a viable treatment for patients with asthma symptomatic on ICS; benefit may be most prominent in those with fixed obstruction. The carryover effect suggests future UMEC studies should use an alternative design. ClinicalTrials.gov: NCT01573624. PMID- 25452141 TI - The effects of mitochondrial complex I blockade on ATP and permeability in rat pulmonary microvascular endothelial cells in culture (PMVEC) are overcome by coenzyme Q1 (CoQ1). AB - In isolated rat lung perfused with a physiological saline solution (5.5mM glucose), complex I inhibitors decrease lung tissue ATP and increase endothelial permeability (Kf), effects that are overcome using an amphipathic quinone (CoQ1) [Free Radic. Biol. Med.65:1455-1463; 2013]. To address the microvascular endothelial contribution to these intact lung responses, rat pulmonary microvascular endothelial cells in culture (PMVEC) were treated with the complex I inhibitor rotenone and ATP levels and cell monolayer permeability (PS) were measured. There were no detectable effects on ATP or permeability in experimental medium that, like the lung perfusate, contained 5.5mM glucose. To unmask a potential mitochondrial contribution, the glucose concentration was lowered to 0.2mM. Under these conditions, rotenone decreased ATP from 18.4+/-1.6 (mean+/ SEM) to 4.6+/-0.8nmol/mg protein, depolarized the mitochondrial membrane potential (Deltapsim) from -129.0+/-3.7 (mean+/-SEM) to -92.8+/-5.5mV, and decreased O2 consumption from 2.0+/-0.1 (mean+/-SEM) to 0.3+/-0.1nmol/min/mg protein. Rotenone also increased PMVEC monolayer permeability (reported as PS in nl/min) to FITC-dextran (~40kDa) continually over a 6 h time course. When CoQ1 was present with rotenone, normal ATP (17.4+/-1.4nmol/mg protein), O2 consumption (1.5+/-0.1nmol/min/mg protein), Deltapsim (-125.2+/-3.3mV), and permeability (PS) were maintained. Protective effects of CoQ1 on rotenone-induced changes in ATP, O2 consumption rate, Deltapsim, and permeability were blocked by dicumarol or antimycin A, inhibitors of the quinone-mediated cytosol-mitochondria electron shuttle [Free Radic. Biol. Med.65:1455-1463; 2013]. Key rotenone effects without and with CoQ1 were qualitatively reproduced using the alternative complex I inhibitor, piericidin A. We conclude that, as in the intact lung, PMVEC ATP supply is linked to the permeability response to complex I inhibitors. In contrast to the intact lung, the association in PMVEC was revealed only after decreasing the glucose concentration in the experimental medium from 5.5 to 0.2mM. PMID- 25452140 TI - A primer on peroxiredoxin biochemistry. AB - Peroxiredoxins were not recognized as a family of enzymes until the 1990s but are now known to be the dominant peroxidases in most organisms. Here, the history and fundamental properties of peroxiredoxins are briefly reviewed, with a special focus on describing how an exquisitely tunable balance between fully folded and locally unfolded conformations plays a large role in peroxiredoxin catalytic properties. PMID- 25452142 TI - Exendin-4 protects adipose-derived mesenchymal stem cells from apoptosis induced by hydrogen peroxide through the PI3K/Akt-Sfrp2 pathways. AB - Adipose-derived mesenchymal stem cells (ADMSCs)-based therapy is a promising modality for the treatment of myocardial infarction in the future. However, the majority of transplanted cells are readily lost after transplantation because of hypoxia and oxidative stress. An efficient means to enhance the ability of ADMSCs to survive under pathologic conditions is required. In our study, we explored the effects of exendin-4 (Ex-4) on ADMSCs apoptosis in vitro induced by hydrogen peroxide, focusing in particular on mitochondrial apoptotic pathways and PI3K/Akt secreted frizzled-related protein 2 (Sfrp2) survival signaling. We demonstrated that ADMSCs subjected to H2O2 for 12h exhibited impaired mitochondrial function and higher apoptotic rate. However, Ex-4 (1-20 nM) preconditioning for 12h could protect ADMSCs against H2O2-mediated apoptosis in a dose-dependent manner. Furthermore, Ex-4 pretreatment upregulated the levels of superoxide dismutase and glutathione as well as downregulating the production of reactive oxygen species and malondialdehyde. Western blots revealed that increased antiapoptotic proteins Bcl-2 and c-IAP1/2 as well as decreased proapoptotic proteins Bax and cytochrome c appeared in ADMSCs with Ex-4 incubation, which inhibited the caspase-9-involved mitochondrial apoptosis pathways with evidence showing inactivation of caspase 9/3 and preservation of mitochondrial membrane potential. Furthermore, we illustrated that Ex-4 enhanced Akt phosphorylation, which increased the expression of Sfrp2. Notably, blockade of the PI3K/Akt pathway or knockdown of Sfrp2 with siRNA obviously abolished the protective effects of Ex-4 on mitochondrial function and ADMSCs apoptosis under H2O2. In summary, this study confirmed that H2O2 induced ADMSCs apoptosis through mitochondria-dependent cell death pathways, and Ex-4 preconditioning may reduce such apoptosis of ADMSCs through the PI3K/Akt-Sfrp2 pathways. PMID- 25452143 TI - APE1 promotes antioxidant capacity by regulating Nrf-2 function through a redox dependent mechanism. AB - APE1 is a multifunctional protein that has recently been implicated in protecting cells from oxidative stress. In the current study, we confirmed that APE1's effect on cellular antioxidant capacity is related to its redox activity through the use of an APE1 functional mutant, and we investigated the mechanism through which this multifunctional protein affects the function of the transcription factor Nrf-2 in regulating oxidative stress-induced genes. Using a pair of mutants for both the redox activity and the acetylation-regulated activity of APE1, in vitro assays showed that the redox activity of APE1 is crucial for its nuclear association with Nrf-2 and subsequent activation of Nrf-2's transcription of several downstream genes during oxidative challenge. Important oxidative stress genes are affected by APE1 redox activity, including Hmox1, Gstm1, and Txnrd1. In addition, utilizing human non-small-cell lung cancer sample tissue as well as a nude mouse xenograft model, we determined that APE1 expression levels are inversely correlated to oxidative stress in vivo. These findings indicated that interference with these crucial functions of APE1 shows promise in preventing resistance to certain radiotherapies and that further research is necessary to understand APE1's complex roles in regulating both the basal redox status and the oxidative stress state of the cellular environment. PMID- 25452144 TI - Basic mechanisms in endoplasmic reticulum stress and relation to cardiovascular diseases. AB - The folding process is an important step in protein synthesis for the functional shape or conformation of the protein. The endoplasmic reticulum (ER) is the main organelle for the correct folding procedure, which maintains the homeostasis of the organism. This process is normally well organized under unstressed conditions, whereas it may fail under oxidative and ER stress. The unfolded protein response (UPR) is a defense mechanism that removes the unfolded/misfolded proteins to prevent their accumulation, and two main degradation systems are involved in this defense, including the proteasome and autophagy. Cells decide which mechanism to use according to the type, severity, and duration of the stress. If the stress is too severe and in excess, the capacity of these degradation mechanisms, proteasomal degradation and autophagy, is not sufficient and the cell switches to apoptotic death. Because the accumulation of the improperly folded proteins leads to several diseases, it is important for the body to maintain this balance. Cardiovascular diseases are one of the important disorders related to failure of the UPR. Especially, protection mechanisms and the transition to apoptotic pathways have crucial roles in cardiac failure and should be highlighted in detailed studies to understand the mechanisms involved. This review is focused on the involvement of the proteasome, autophagy, and apoptosis in the UPR and the roles of these pathways in cardiovascular diseases. PMID- 25452145 TI - Reaction kinetics and targeting to cellular glutathione S-transferase of the glutathione peroxidase mimetic PhSeZnCl and its D,L-polylactide microparticle formulation. AB - Catalytic properties and cellular effects of the glutathione peroxidase (GPx) mimetic compound PhSeZnCl or its d,l-lactide polymer microencapsulation form (M PhSeZnCl) were investigated and compared with the prototypical Se-organic compounds ebselen and diselenide (PhSe)2. PhSeZnCl was confirmed to catalyze the ping-pong reaction of GPx with higher Vmax than ebselen and (PhSe)2, but the catalytic efficiency calculated for the cosubstrates glutathione (GSH) and H2O2, and particularly the high reactivity against thiols (lowest KM for GSH in the series of test molecules), suggested poor biological applicability of PhSeZnCl as a GPx mimetic. Cytotoxicity of PhSeZnCl was demonstrated in various cancer cell lines via increased reactive oxygen species (ROS) generation, depletion of intracellular thiols, and induction of apoptosis. Experiments carried out in GSH S-transferase P (GSTP)-overexpressing K562 human erythroleukemia cells and in GSTP1-1-knockout murine embryonic fibroblasts (MEFs) demonstrated that this cytosolic enzyme represents a preferential target of the redox disturbances produced by this Se-compound with a key role in controlling H2O2 generation and the perturbation of stress/survival kinase signaling. Microencapsulation was adopted as a strategy to control the thiol reactivity and oxidative stress effects of PhSeZnCl, then assessing applications alternative to anticancer. The uptake of this "depowered" GPx-mimetic formulation, which occurred through an endocytosis-like mechanism, resulted in a marked reduction of cytotoxicity. In MCF-7 cells transfected with different allelic variants of GSTP, M-PhSeZnCl lowered the burst of cellular ROS induced by the exposure to extracellular H2O2, and the extent of this effect changed between the GSTP variants. Microencapsulation is a straightforward strategy to mitigate the toxicity of thiol-reactive Se-organic drugs that enhanced the antioxidant and cellular protective effects of PhSeZnCl. A mechanistic linkage of these effects with the expression pattern and signaling properties of GSTP . This has overcome the GPx mimetic paradigm proposed for Se-organic drugs with a more pragmatic concept of GSTP signaling modulators. PMID- 25452147 TI - Global changes in DNA methylation in Alzheimer's disease peripheral blood mononuclear cells. AB - Changes in epigenetic marks may help explain the late onset of Alzheimer's disease (AD). In this study we measured genome-wide DNA methylation by luminometric methylation assay, a quantitative measurement of genome-wide DNA methylation, on DNA isolated from peripheral blood mononuclear cells of 37 subjects with late-onset AD (LOAD) and 44 healthy controls (CT). We found an increase in global DNA methylation in LOAD subjects compared to CT (p=0.0122), associated with worse cognitive performances (p=0.0002). DNA hypermethylation in LOAD group was paralleled by higher DNA methyltransferase 1 (DNMT1) gene expression and protein levels. When data were stratified on the basis of the APOE polymorphisms, higher DNA methylation levels were associated with the presence of APOE epsilon4 allele (p=0.0043) in the global population. Among the APOE epsilon3 carriers, a significant increase of DNA methylation was still observed in LOAD patients compared to healthy controls (p=0.05). Our data suggest global DNA methylation in peripheral samples as a useful marker for screening individuals at risk of developing AD. PMID- 25452148 TI - Comparison of Pandemrix and Arepanrix, two pH1N1 AS03-adjuvanted vaccines differentially associated with narcolepsy development. AB - Narcolepsy onset in children has been associated with the 2009 influenza A H1N1 pandemic and vaccination with Pandemrix. However it was not clearly observed with other adjuvanted pH1N1 vaccines such as Arepanrix or Focetria. Our aim was to characterize the differences between Pandemrix and Arepanrix that might explain the risk for narcolepsy after Pandemrix vaccination using 2D-DIGE and mass spectrometry (MS). We found that Pandemrix (2009 batch) and Arepanrix (2010 batch) showed 5 main viral proteins: hemagglutinin HA1 and HA2 subunits, neuraminidase NA, nucleoprotein NP, and matrix protein MA1 and non-viral proteins from the Gallus gallus growth matrix used in the manufacturing of the vaccines. Latticed patterns of HA1, HA2 and NA indicated charge and molecular weight heterogeneity, a phenomenon likely caused by glycosylation and sulfation. Overall, Pandemrix contained more NP and NA, while Arepanrix displayed a larger diversity of viral and chicken proteins, with the exception of five chicken proteins (PDCD6IP, TSPAN8, H-FABP, HSP and TUB proteins) that were relatively more abundant in Pandemrix. Glycosylation patterns were similar in both vaccines. A higher degree of deamidation and dioxidation was found in Pandemrix, probably reflecting differential degradation across batches. Interestingly, HA1 146N (residue 129N in the mature protein) displayed a 10-fold higher deamidation in Arepanrix versus Pandemrix. In recent vaccine strains and Focetria, 146N is mutated to D which is associated with increased production yields suggesting that 146N deamidation may have also occurred during the manufacturing of Arepanrix. The presence of 146N in large relative amounts in Pandemrix and the wild type virus and in lower relative quantities in Arepanrix or other H1N1 vaccines may have affected predisposition to narcolepsy. PMID- 25452146 TI - M1 muscarinic receptors modify oxidative stress response to acetaminophen-induced acute liver injury. AB - The role of muscarinic receptor subtypes in modulating acute liver injury is unknown. We detected M1 muscarinic receptor (M1R) expression in human and murine hepatocytes, and investigated the consequences of M1R deficiency on acute liver injury in vivo and inhibiting M1R activation on hepatocyte injury in vitro. Age matched wild-type (WT) and M1R-deficient (Chrm1(-/-)) male mice were injected intraperitoneally with 200mg/kg acetaminophen (APAP) and euthanized 0, 2, 4, 16, 24, and 36h later. Biochemical and histological parameters indicated that liver injury peaked within 16h after APAP treatment and resolved by 24h. Compared to WT, M1R-deficient mice had reduced intrahepatic hemorrhage and hepatocyte necrosis, reflected by an attenuated rise in serum alanine aminotransferase levels. Livers of M1R-deficient mice showed reduced hepatocyte DNA fragmentation and attenuated expression of injury cytokines (Il-1alpha, Il-1beta, Il-6, and Fasl). In all mice hepatic glutathione levels decreased after APAP injection, but they recovered more quickly in M1R-deficient mice. During the course of APAP induced liver injury in M1R-deficient compared to WT mice, hepatic Nrf-2, Gclc, and Nqo1 expressions increased and nitrotyrosine generation decreased. APAP metabolic pathways were not altered by M1R deficiency; expression of hepatic Cyp2e1, Cyp1a2, Cyp3a11, Cyp3a13, Car, and Pxr was similar in Chrm1(-/-) and WT mice. Finally, treatment of murine AML12 hepatocytes with a novel M1R antagonist, VU0255035, attenuated H2O2-induced oxidative stress, prevented GSH depletion, and enhanced viability. We conclude that M1R modify hepatocyte responses to oxidative stress and that targeting M1R has therapeutic potential for toxic liver injury. PMID- 25452150 TI - Polyunsaturated fatty acids (PUFAs) levels in patients with cardiovascular diseases (CVDs) with and without depression. AB - BACKGROUND: Cardiovascular diseases (CVDs) are commonly comorbid with depression and vice versa. Polyunsaturated fatty acids (PUFAs) have been suggested to mediate in CVDs and depression in cross-sectional and observational studies. With the patients of CVDs, we investigated the role of depression on the effect of PUFAs. METHODS: Forty-four patients with CVDs were recruited and assessed with Hamilton depression rating scale (HAMD). Patients' CVDs markers were measured by electrocardiogram and their red blood cell (RBC) samples were collected for PUFAs analyses. RESULTS: The data of 44 subjects were analyzed; where 10 participants (23%) with CVDs had moderate or severe depression, defined by a HAMD score more than 19 points. The moderate depression group had lower docosahexaenoic acid (DHA), omega-3 (N3) and omega-6(N6) to N3 (N6/N3) ratio than non-depression group (HAMD score less than 8), while no differences between the 2 groups in terms of corrected QT (QTc) intervals and high sensitivity C-reactive protein (hsCRP) levels. Furthermore, when we analyzed the data with an inclusion of a more heterogeneous depression group, where HAMD score is greater than or equal to 10 (mild depression group, N=24), the differences in PUFAs levels between the 2 groups disappear. Secondary analysis of the moderate depression group showed a positive correlation between DHA, N3 PUFAs, and N6/N3 ratio and total HAMD scores, a positive correlation between N3 PUFAs and QTc intervals in non depression group. CONCLUSION: Moderate depression group of patients with CVDs had lower levels of DHA, N3, and N6/N3 ratio than non-depression group, while both groups had no differences in QTc and hsCRP. On the other hand, the differences in PUFAs levels disappear in the mild depression group after inclusion of patients with CVDs with greater heterogeneity of depression. Hence, the role of N3 PUFAs is implicated in depression of patients with CVDs if the depression status is more strictly defined. PMID- 25452151 TI - Pectus excavatum with delayed diagnosis of implant tear on MRI apparently causing recurrent postoperative seromas: A case report. AB - Seroma formation is the most common early postoperative complication after pectus excavatum repair, but later seromas are rare. While many seromas eventually resorb or decrease in size after aspiration, our case demonstrates recurrent seroma formation as a late complication of pectus excavatum repair in a patient with an implant tear. Postoperative seromas can result in prolonged chest wall pain, large chest wall masses, and increased mass effect on the heart with potential risk for resultant right ventricular outflow obstruction. This case report illustrates a solid silicone implant tear. Though rare, early recognition may help to decrease the likelihood of recurrent postoperative seromas. PMID- 25452152 TI - Synthesis of ultrahigh-molecular-weight ethylene-1-hexene copolymers with high hexene content via living polymerization with fluorinated bis(phenoxy-imine) titanium(IV). AB - The fluorinated FI-Ti catalyst bis[N-(3-propylsalicylidene)-pentafluoroanilinato] titanium(IV) dichloride (PFI) combined with dried methylaluminoxane (dMAO) is investigated for ethylene/1-hexene copolymerization at 50 degrees C under atmospheric pressure. The reaction shows good livingness and has a high activity at high [H]/[E] molar ratios up to 14. Ultrahigh molecular weight (>1.4 * 10(6) g mol(-1) ) copolymers with high 1-hexene content (>25 mol%) are prepared. Kinetic parameters of the copolymerization with PFI are determined. The first-order Markov statistics applies and the product of the reactivity ratios r1 r2 is close to 1, giving random unit distributions. PMID- 25452149 TI - Endogenous circadian regulation of pro-inflammatory cytokines and chemokines in the presence of bacterial lipopolysaccharide in humans. AB - Various aspects of immune response exhibit 24-h variations suggesting that infection susceptibility and treatment efficacy may vary by time of day. Whether these 24-h variations are endogenous or evoked by changes in environmental or behavioral conditions is not known. We assessed the endogenous circadian control and environmental and behavioral influences on ex-vivo lipopolysaccharide stimulation of whole blood in thirteen healthy participants under 48h of baseline conditions with standard sleep-wake schedules and 40-50h of constant environmental and behavioral (constant routine; CR) conditions. Significant 24-h rhythms were observed under baseline conditions in Monocyte Chemotactic Protein, Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin 8 but not Tumor Necrosis Factor alpha whereas significant 24-h rhythms were observed in all four immune factors under CR conditions. The rhythm amplitudes, expressed as a percentage of mean, were comparable between immune factors and across conditions. In contrast, the acrophase time (time of the fitted peak) was different between immune factors, and included daytime and nighttime peaks and changes across behavioral conditions. These results suggest that the endogenous circadian system underpins the temporal organization of immune responses in humans with additional effects of external environmental and behavioral cycles. These findings have implications for understanding the adverse effects of recurrent circadian disruption and sleep curtailment on immune function. PMID- 25452153 TI - Advantages of a combined method of decalcification compared to EDTA. AB - Decalcification of mineralized tissues is an essential step during tissue processing in the routine histopathology. The time required for complete decalcification, and the effect of decalcifier on cellular and tissue morphology are important parameters which influence the selection of decalcifying agents. In this study, we compared a decalcifying solution (ETDA) composed of both acid and chelating agents to a classical and well-known decalcifying agent (EDTA). To this purpose, the optic density of bone radiographs, residual calcium analysis, bone sample weight, and histological and immunohistochemical analysis were performed. Our data suggest that, similarly to EDTA, the ETDA solution completely removes the calcium ions from the samples enabling easy sectioning. However, unlike the EDTA, this agent takes much less time. Furthermore, both agents showed comparable decalcification efficacy, and similarly, they did not produce cellular, tissue or antigenicity impairments. Therefore, ETDA may be a suitable option when it is necessary an association between a rapid and complete removal of calcium minerals, and a suitable preservation of structure and antigenicity of tissues. PMID- 25452154 TI - Physical activity and osteoarthritis - considerations at the population and clinical level. PMID- 25452156 TI - Metabolic triggered inflammation in osteoarthritis. AB - Osteoarthritis (OA) is a common chronic joint disorder with a multifactorial etiology including genetic and environmental factors. Metabolic triggered inflammation, induced by nutrient overload and metabolic surplus, consists of components such as obesity, pro-inflammatory cytokines and adipokines, abnormal metabolites, acute phase proteins, vitamin D deficiency, and deregulated microRNAs that may play a role in OA pathophysiology. Obesity-related metabolic factors, especially adipokines, contribute to OA development by inducing pro inflammatory cytokines and degradative enzymes, leading to cartilage matrix impairment and subchondral bone remodeling. Ectopic metabolite deposition and low grade systemic inflammation can contribute to a toxic internal environment that exacerbates OA. Complement components highly expressed in osteoarthritic joints have also been proposed as causative factors. Vitamin D deficiency has been associated with obesity and is implicated to be associated with cartilage loss in OA. Metabolic microRNAs may explain the inflammatory link between obesity and OA. Therapies targeting metabolic-triggered inflammation and its components are anticipated to have potential for the treatment of OA. PMID- 25452157 TI - The influence of long-term exposure and timing of physical activity on new joint pain and stiffness in mid-age women. AB - OBJECTIVE: To examine the influence of long-term exposure and timing of physical activity (PA) on new joint pain/stiffness in mid-age women. METHODS: Data were from 5105 participants (born 1946-51) in the Australian Longitudinal Study on Women's Health (ALSWH) who completed survey items on PA (1998, 2001 and 2004) and joint pain/stiffness (2007 and 2010). PA was categorized in five levels at each survey and summed into a cumulative PA score (CPA, range 0-12). Associations were analysed using logistic regression, with separate models for the cumulative model (using CPA), the sensitive periods model (i.e., PA measured at each survey in one regression model) and the critical periods model (i.e., separate regression models for PA at each survey). RESULTS: 951 (18.6%) participants reported new onset joint pain/stiffness. In the cumulative model, CPA was associated joint pain/stiffness when included as a continuous variable (adjusted odds ratio [OR] = 0.97, 95% confidence interval [CI] = 0.95-0.99), but not when included as a categorical variable. In both the sensitive periods and critical periods models, low to high levels of PA in 2001 and 2004 had stronger inverse associations with joint pain/stiffness than PA levels in 1998. The model fit was better for the sensitive periods than the cumulative or critical periods models. CONCLUSIONS: In mid-age women, PA between the ages 47 and 58 was associated with a lower risk of joint pain/stiffness 9 years later. Associations were stronger for PA in the last 6 years than for earlier PA. PMID- 25452155 TI - Passage-dependent relationship between mesenchymal stem cell mobilization and chondrogenic potential. AB - OBJECTIVE: Galvanotaxis, the migratory response of cells in response to electrical stimulation, has been implicated in development and wound healing. The use of mesenchymal stem cells (MSCs) from the synovium (synovium-derived stem cells, SDSCs) has been investigated for repair strategies. Expansion of SDSCs is necessary to achieve clinically relevant cell numbers; however, the effects of culture passage on their subsequent cartilaginous extracellular matrix production are not well understood. METHODS: Over four passages of SDSCs, we measured the expression of cell surface markers (CD31, CD34, CD49c, CD73) and assessed their migratory potential in response to applied direct current (DC) electric field. Cells from each passage were also used to form micropellets to assess the degree of cartilage-like tissue formation. RESULTS: Expression of CD31, CD34, and CD49c remained constant throughout cell expansion; CD73 showed a transient increase through the first two passages. Correspondingly, we observed that early passage SDSCs exhibit anodal migration when subjected to applied DC electric field strength of 6 V/cm. By passage 3, CD73 expression significantly decreased; these cells exhibited cell migration toward the cathode, as previously observed for terminally differentiated chondrocytes. Only late passage cells (P4) were capable of developing cartilage-like tissue in micropellet culture. CONCLUSIONS: Our results show cell priming protocols carried out for four passages selectively differentiate stem cells to behave like chondrocytes, both in their motility response to applied electric field and their production of cartilaginous tissue. PMID- 25452158 TI - Functional-structural degeneration in dorsal and ventral attention systems for Alzheimer's disease, amnestic mild cognitive impairment. AB - Growing evidence of attention related failures in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) has already been proposed by previous studies. However, previous studies lacked of systematic investigation on the functional and structural substrates for attention function for patients with AD and aMCI. In this work, we investigated the functional connectivity and gray matter density in dorsal and ventral attention networks (DAN, VAN) of normal participants (n = 15) and patients with aMCI (n = 12) and AD (n = 16) by applying group independent component analysis (ICA) and voxel-based morphometry (VBM) analysis. Using ICA, we extracted the functional patterns of DAN and VAN which are respectively responsible for the "top-down" attention process and "bottom-up" process. One-way analysis of variance (ANOVA) revealed significant group-differed functional connectivity in bilateral frontal eye fields (FEF) area and intraparietal sulcus (IPS) area, as well as posterior cingulate cortex and precuneus in the dorsal system. With regard to the ventral system, group-effects were significantly focused in right orbital superior/middle frontal gyrus, right inferior parietal lobule, angular gyrus, and supramarginal gyrus around the temporal-parietal junction area. Post hoc cluster-level comparisons revealed totally impaired functional substrates for both attentional networks for patients with AD, whereas selectively impaired attention systems for patients with aMCI with impaired functional patent of DAN but preserved functional pattern of VAN. Correspondingly, VBM analysis revealed gray matter loss in right ventral and dorsal frontal cortex was in the AD group, whereas preserved gray matter density was in aMCI, even a little extent of expansion of gray matter density in several participants. Using multivariate regression analysis we found discrepant couplings of functional-structural degenerations between both patient groups. Specifically, positive coupling of structural functional degeneration was found in right dorsal and ventral frontal cortex in the AD group, whereas inverse coupling in dorsal frontal cortex was found in the aMCI group. These findings suggested discrepant functional-structural degenerations in both attention systems between both patient groups, widening avenues to better understanding the attentional deficits in patients with aMCI and AD. PMID- 25452161 TI - The European Journal of Heart Failure from 2010 to 2015: a farewell and a move of the Editorial Team from Groningen to Brescia. PMID- 25452159 TI - Does an intervention to reduce maternal anxiety, depression and trauma also improve mothers' perceptions of their preterm infants' vulnerability? AB - To determine if an intervention to reduce maternal distress and address maternal perceptions of infants' vulnerability also reduces perceptions of vulnerability, 105 mothers of premature infants (25- to 34-weeks' gestational age; >600 g) with depression, anxiety, or trauma were randomized to a six- or nine-session intervention or a comparison condition. The outcome was changes in a measure of perception of infant vulnerability between 4 to 5 weeks' and 6 months' postdelivery, the Vulnerability Baby Scale (VBS; B. Forsyth, S. Horwitz, J. Leventhal, & J. Burger, 1996; N. Kerruish, K. Settle, P. Campbell-Stokes, & B. Taylor, 2005). High scores on the VBS were indicative of high levels of perceived infant vulnerability. The perceptions of infants' vulnerability showed significant declines, with no differences across groups or in rate of change. Mothers reporting prior trauma at entry to the study showed much lower perceptions of infants' vulnerability scores under the intervention, Cohen's d = 0.86, p = .01. Given that women with prior trauma are very likely to view their premature infants as vulnerable, this intervention may have important implications for subsequent parenting behaviors and child development. PMID- 25452162 TI - Acute heart failure: have we got it all wrong? PMID- 25452160 TI - Activation of 5-HT(2C) receptor promotes the expression of neprilysin in U251 human glioma cells. AB - Abeta accumulation, a hallmark of Alzheimer's disease, promotes the disease progress in multiple facets. Abeta is formed through amyloidogenic cleavage pathway of amyloid precursor protein (APP). Production of Abeta can be decreased via activation of 5-HT2C receptor, which enhances alternative APP non amyloidogenic cleavage. Besides, as one of the best characterized Abeta degrading enzymes, neprilysin (NEP) in AD progress has drawn more and more attention. We investigated whether there exists any connection between 5-HT2C receptor and NEP expression. The mRNA and protein expressions of NEP were increased after treatment of 5-HT2C receptor agonist RO-60-0175 in concentration- and time dependent manners, and NEP expression was decreased after treatment of 5-HT2C receptor antagonist SB242084 correspondingly. These results suggest that 5-HT2C receptor may inhibit the Abeta formation by promoting NEP expression. The underlying mechanism will be explored in follow-up study and may provide potential target for AD therapy. PMID- 25452163 TI - CaMKII confirms its promise in ischaemic heart disease. PMID- 25452164 TI - LVEF: long-standing monarch of systolic dysfunction, buckling under the strain? PMID- 25452165 TI - Breathlessness at rest is not the dominant presentation of patients admitted with heart failure. AB - AIMS: Many assume that most patients hospitalized with heart failure (HF) are short of breath at rest (SOBAR). The National HF Audit for England and Wales suggests that this assumption is false, which has profound implications for management METHODS AND RESULTS: A retrospective case-note review was carried out of patients hospitalized with HF to determine how many present with shortness of breath at rest or are comfortable at rest but breathless on slight exertion (CARBOSE). Vital signs were tracked for 24 h and mortality for 180 days. Of 311 patients, those who were SOBAR (42%) had higher median heart rate (HR) (100 vs. 85 b.p.m.; P < 0.001), systolic blood pressure (SBP) (141 vs. 122 mmHg; P < 0.001), and respiratory rate (RR) (24 vs. 18 breaths/min; P < 0.001) compared with those who were CARBOSE (56%). Vital signs changed little in those who were CARBOSE over the first 4-6 h, but SBP (141-128 mmHg; P < 0.001), HR (100-90 b.p.m.; P = 0.002), and RR (24-20 breaths/min; P < 0.001) fell in those who were SOBAR. At presentation, SBP was >125 mmHg in 73% of patients who were SOBAR and in 46% who were CARBOSE, dropping to 52% and 37%, respectively, by 4-6 h. Mortality amongst those who were SOBAR and those who were CARBOSE was, respectively, 19% and 34% (odds ratio 2.29; P = 0.005, 95% confidence interval 1.29-4.06). CONCLUSION: Many patients admitted with HF are CARBOSE. Shortness of breath at rest may be more alarming, but those who are CARBOSE have a worse prognosis, perhaps reflecting more severe right heart dysfunction. Clinical trials of hospitalized HF may inappropriately exclude patients if they focus on shortness of breath at rest rather than peripheral congestion. PMID- 25452167 TI - Pleiotropy of the de novo-originated gene MDF1. AB - MDF1 is a young de novo-originated gene from a non-coding sequence in baker's yeast, S. cerevisiae, which can suppress mating and promote vegetative growth. Our previous experiments successfully demonstrated how Mdf1p binds to the key mating pathway determinant MATalpha2 to suppress mating. However, how Mdf1p promotes growth and fulfills the crosstalk between the yeast mating and growth pathways are still open questions. Thus, the adaptive significance of this new de novo gene remains speculative. Here, we show that Mdf1p shortens the lag phase of S. cerevisiae by physically interacting with SNF1, the governing factor for nonfermentable carbon source utilization, and thereby confers a selective advantage on yeasts through the rapid consumption of glucose in the early generational stage in rich medium. Therefore, MDF1 functions in two important molecular pathways, mating and fermentation, and mediates the crosstalk between reproduction and vegetative growth. Together, our results provide a comprehensive example of how a de novo-originated gene organizes new regulatory circuits and thereby confers a selective advantage on S. cerevisiae to allow exquisite adaptation to the changing environment. PMID- 25452169 TI - Predicting outcomes from radiosurgery for intracranial arteriovenous malformations: effect of embolization, prior hemorrhage, and nidus anatomy. PMID- 25452166 TI - Macrophages in spinal cord injury: phenotypic and functional change from exposure to myelin debris. AB - Macrophage activation and persistent inflammation contribute to the pathological process of spinal cord injury (SCI). It was reported that M2 macrophages were induced at 3-7 days after SCI but M2 markers were reduced or eliminated after 1 week. By contrast, M1 macrophage response is rapidly induced and then maintained at injured spinal cord. However, factors that modulate macrophage phenotype and function are poorly understood. We developed a model to distinguish bone-marrow derived macrophages (BMDMs) from residential microglia and explored how BMDMs change their phenotype and functions in response to the lesion-related factors in injured spinal cord. Infiltrating BMDMs expressing higher Mac-2 and lower CX3CR1 migrate to the epicenter of injury, while microglia expressing lower Mac-2 but higher CX3CR1 distribute to the edges of lesion. Myelin debris at the lesion site switches BMDMs from M2 phenotype towards M1-like phenotype. Myelin debris activates ATP-binding cassette transporter A1 (ABCA1) for cholesterol efflux in response to myelin debris loading in vitro. However, this homeostatic mechanism in injured site is overwhelmed, leading to the development of foamy macrophages and lipid plaque in the lesion site. The persistence of these cells indicates a pro-inflammatory environment, associated with enhanced neurotoxicity and impaired wound healing. These foamy macrophages have poor capacity to phagocytose apoptotic neutrophils resulting in uningested neutrophils releasing their toxic contents and further tissue damage. In conclusion, these data demonstrate for the first time that myelin debris generated in injured spinal cord modulates macrophage activation. Lipid accumulation following macrophage phenotype switch contributes to SCI pathology. PMID- 25452168 TI - Altered expression of neurofilament 200 and amyloid-beta peptide (1-40) in a rat model of chronic cerebral hypoperfusion. AB - Chronic cerebral hypoperfusion (CCH) is damaging to white matter in the brain. So far few studies have investigated long-term axonal damage following CCH. The aim of this study was to investigate the involvement of neurofilament 200 (NF200) and amyloid-beta (1-40) [Abeta (1-40)] in the pathological mechanism for neuronal damage, and to quantify changes in their expression over time in a rat model of CCH. A rat model of CCH was established using partial bilateral ligation of the common carotid arteries. The extent of stenosis was verified by measuring the changes in cerebral blood flow after surgery. Histology was used to assess hippocampal neuronal pathology, and immunohistochemistry was used to quantify the expression of NF200 and Abeta (1-40) at 2, 4, and 12 weeks after surgery. The cerebral blood flow reduced to 33.89 +/- 5.48 % at 2 weeks, 36.83 +/- 4.63 % at 4 weeks and 51.44 +/- 4.90 % at 12 weeks. Immunofluorescence staining of neuronal perikarya sections revealed a marked decrease in the population of surviving pyramidal cells in the hippocampal CA1 region, a significant up-regulation in the expression of Abeta (1-40), and a significant reduction in the expression of NF200 following CCH surgery. Moreover, this trend was increasingly obvious over time. Our data demonstrate that CCH leads to axonal damage over time. We also confirmed that the expression of Abeta (1-40) and NF200 may be useful biomarkers of axonal damage following CCH. PMID- 25452170 TI - Foregut morphology and ontogeny of the mud crab Dyspanopeus sayi (Smith, 1869) (Decapoda, Brachyura, Panopeidae). AB - The morphology of the foregut of the Say's mud crab Dyspanopeus sayi was described in adults and larvae. The ossicle system was illustrated based on a staining method with Alizarin-Red. The gastric teeth and cardio-pyloric valve were dissected and examined using optical and scanning electron microscopy. In the adults, the morphology of ossicles and gastric teeth of D. sayi is very similar to the related species Rhithropanopeus harrisii. The foregut of first zoea (ZI) presented a functional cardio-pyloric valve while the filter press was lacking. The filter press was observed in the pyloric chamber from ZII. The most significant changes in morphology take place after metamorphosis from ZIV to megalopa, including the occurrence of the gastric mill. The organization and morphology of many megalopal foregut ossicles are recognizable in the adult phase, although the morphology of the gastric teeth differs from the morphology of adults. A correlation of gastric mill structures with food preferences and their contribution to the phylogeny are briefly discussed. PMID- 25452171 TI - Prognostic value of differential CCND1 expression in patients with resected gastric adenocarcinoma. AB - Cyclin D1 (CCND1) plays essential roles in cancer progression. In this study, CCND1 expression patterns in 211 cases of resected gastric adenocarcinoma (RGA) tissue were determined by immunohistochemistry, and the association between CCND1 expression levels and RGA prognosis was analyzed. RGA tissues displayed differential CCND1 expression (high expression, 52.1 %; n = 110, and low expression, 47.9 %; n = 101). CCND1 expression levels were related with median overall survival time (MST). MST in patients with high CCND1 expression was 43 months, whereas with low CCND1 expression it was 62 months (P = 0.013). When data were stratified by postoperative treatments and CCND1 expression levels, the MST for patients treated with fluoropyrimidine plus platinum (n = 140) was significantly longer than for those treated with fluoropyrimidine only (n = 71) in both high and low CCND1 expression groups (65.0 vs. 29.0 months, P = 0.041; and 74.5 vs. 33.0 months, P = 0.003, respectively). Cox multivariate analyses further confirmed that high CCND1 expression was related with poor prognosis in both treatment groups [hazard ratio (HR) 1.91, 95 % confidence interval (CI) 1.12 3.23; P = 0.017, and HR 2.14, 95 % CI 1.08-4.25; P = 0.029] and that fluoropyrimidine plus platinum was more effective than fluoropyrimidine only in high CCND1 (HR 0.47, 95 % CI 0.28-0.78; P = 0.004) and low CCND1 (HR 0.44; 95 % CI 0.23-0.82; P = 0.01) expression patients. Therefore, CCND1 may be used as a prognostic biomarker for patients with RGA. PMID- 25452173 TI - Texosome-anchored superantigen triggers apoptosis in original ovarian cancer cells. AB - Texosomes, nano-endosomal vesicles, are candidates for cancer immunotherapy due to their immunostimulating properties. We designed a new structure based on texosome and staphylococcal enterotoxin B (SEB) and assessed its cytotoxic impact on an ovarian cell line. Texosomes were isolated from tumor cells, and SEB was anchored onto by protein transfer method. MTT assay and Hoechst staining were used to identify the cytotoxic and apoptotic effects of this compound on treated cells with different concentrations of texosome-SEB (TEX-SEB). Moreover, the expression rate of bcl-2, bax, bak, bcl-xl and the activity of caspase-3 and caspase-9 were investigated. Treatments of the cells with 0.5, 2.5 and 10 MUg/100 MUl TEX-SEB were significantly cytotoxic within 24 h (p < 0.001). Hoechst staining revealed that all tested concentrations caused apoptosis after 24 h compared with the control cells (p < 0.001). Furthermore, it was found that treatment with all examined concentrations of TEX-SEB enhanced caspase-9 activity after 24 and 48 h, while caspase-3 activity was increased upon treatment with only 0.5 and 2.5 MUg/100 MUl of TEX-SEB after 24 h (p < 0.001). None of the concentrations of TEX-SEB affected the expression of the cancer-promoting genes. Our construct, the TEX-SEB, is a new model being able to create cytostatic properties on cancer cells. PMID- 25452172 TI - (-)-Epigallocatechin-3-gallate induces cancer cell apoptosis via acetylation of amyloid precursor protein. AB - Epigenetic modifications are involved in cancer pathogenesis, and HDACis are considered potential therapeutic agents. We and others have shown the inhibitory activity of EGCG on HDAC1. But little is known about the effect of EGCG as on epigenetic regulation in cancer. Here, we try to demonstrate that EGCG acts as an HDACi downregulated APP expression, which was pathophysiologically upregulated in cancers and exerts a key role in cancer cell growth. We used PC-12 cells, SK-N-SH cells and primary tumor tissues for our analysis. Male 4-week-old athymic nude mice were used for heterotopic tumor growth assay. We employed Western blotting analysis to detect Bcl-2, Bax, APP, caspase-3, caspase-7, HDAC1 and H4Ac. We used AnnexinV-FITC and TUNEL staining for apoptosis detection. Tumor tissues were examined by immunohistochemical staining. We demonstrated that EGCG suppresses the growth of xenografted adrenal pheochromocytoma. Flow cytometry analysis and TUNEL staining showed that EGCG induced the apoptosis. Treatment with EGCG resulted in decrease in Bcl-2 but increase in Bax and activated caspase-3 and caspase-7. HDAC inhibitor EGCG leaded to hyperacetylated histone H4 by immunofluorescence. EGCG decreased APP levels by immunofluorescence staining and Western blot analysis. Silencing specific to HDAC1 leaded to caspase-3 and caspase-7 activation and cleavage. Our results are the first to demonstrate a functional interaction between EGCG and APP in suppression tumor growth, and provide a new epigenetic effects of EGCG on antitumor. PMID- 25452174 TI - Morphological and biochemical alterations activated by antitumor clerodane diterpenes. AB - Casearia sylvestris Swartz (Salicaceae) is a plant commonly widespread in the Americas. It has oxygenated tricyclic bioactive clerodane diterpenes with antimicrobial, antiulcer, larvicidal, chemopreventive, anti-inflammatory, antioxidant and antiproliferative properties. Due to this requirement for the developing of new anticancer drugs, it was initially evaluated the cytotoxic activity of a fraction with Casearins (FC) and its clerodane diterpenes Casearin B (Cas B), D (Cas D), X (Cas X) and Caseargrewiin F (Cas F) isolated from C.sylvestris leaves against 7 tumor cell lines, Sarcoma 180 cells (S180) and on normal peripheral blood mononuclear cells (PBMC). All substances tested showed cytotoxic potential. Cas F and X were the most active compounds. Cell death analyzes with Cas F (0.5 and 1MUM) and Cas X (0.7 and 1.5MUM) using the HL-60 leukemia line as experimental model showed DNA synthesis and membrane integrity reduction, DNA fragmentation and mitochondrial depolarization, specially after 24h exposure, cell cycle arrest in G0/G1 phase caused by Cas X, activation of the initiator -8/-9 and effector -3/-7 caspases and phosphatidylserine externalization, all biochemical features of apoptosis corroborated by chromatinic condensation, karyorrhexis, cytoplasmic vacuolation and rarefaction and cellular shrinkage, morphological findings specially observed after 12 and 24h of incubation. Therefore, Cas X and F were the most functional molecules with more pronounced lethal and discriminating effects on tumor cells and antiproliferative action predominantly mediated by apoptosis, highlighting clerodane dipertenes as promising lead antineoplastic compounds. PMID- 25452175 TI - Free radicals, reactive oxygen species, oxidative stress and its classification. AB - Reactive oxygen species (ROS) initially considered as only damaging agents in living organisms further were found to play positive roles also. This paper describes ROS homeostasis, principles of their investigation and technical approaches to investigate ROS-related processes. Especial attention is paid to complications related to experimental documentation of these processes, their diversity, spatiotemporal distribution, relationships with physiological state of the organisms. Imbalance between ROS generation and elimination in favor of the first with certain consequences for cell physiology has been called "oxidative stress". Although almost 30years passed since the first definition of oxidative stress was introduced by Helmut Sies, to date we have no accepted classification of oxidative stress. In order to fill up this gape here classification of oxidative stress based on its intensity is proposed. Due to that oxidative stress may be classified as basal oxidative stress (BOS), low intensity oxidative stress (LOS), intermediate intensity oxidative stress (IOS), and high intensity oxidative stress (HOS). Another classification of potential interest may differentiate three categories such as mild oxidative stress (MOS), temperate oxidative stress (TOS), and finally severe (strong) oxidative stress (SOS). Perspective directions of investigations in the field include development of sophisticated classification of oxidative stresses, accurate identification of cellular ROS targets and their arranged responses to ROS influence, real in situ functions and operation of so-called "antioxidants", intracellular spatiotemporal distribution and effects of ROS, deciphering of molecular mechanisms responsible for cellular response to ROS attacks, and ROS involvement in realization of normal cellular functions in cellular homeostasis. PMID- 25452176 TI - Radiographic progression in rheumatoid arthritis: does it still happen and does it matter? PMID- 25452177 TI - Interpreting studies of diagnostic accuracy. PMID- 25452178 TI - Early aggressive therapy for patients with juvenile idiopathic arthritis: are we there yet? PMID- 25452179 TI - How do we classify rheumatoid arthritis in established disease--can we apply the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria? PMID- 25452180 TI - Unusual cause of limited elbow movement in a patient with psoriatic arthritis. PMID- 25452181 TI - Ankylosing spondylitis with bulbar syndrome and atlantoaxial synovitis. PMID- 25452182 TI - Destructive arthritis of the hand after diving. PMID- 25452183 TI - A particular case of pubic pain. PMID- 25452184 TI - Peter Lee, MD, FRCPC, FRACP, 1943-2014. PMID- 25452185 TI - Effects of TNF-alpha inhibitors on abdominal adiposity in patients with inflammatory rheumatic diseases. PMID- 25452186 TI - Dr. Hmamouchi, et al reply. PMID- 25452187 TI - Pregnancy outcome in idiopathic inflammatory myopathy patients in a multicenter study. PMID- 25452188 TI - Retinal vessels thrombosis as onset manifestation of systemic sclerosis: 3 clinical cases. PMID- 25452189 TI - Prolonged remission of marginal zone lymphoma in a patient with rheumatoid arthritis treated with anti-tumor necrosis factor agents. PMID- 25452192 TI - The analysis of microRNA-34 family expression in human cancer studies comparing cancer tissues with corresponding pericarcinous tissues. AB - Recently many studies have focused on the microRNA-34 (miR-34) family expression in various cancers; nevertheless, the controversial results of these studies still exist in identifying miR-34 members as new biomarkers of cancers. Therefore, we carried out this comprehensive meta-analysis of published studies that compared the miR-34 family expression profiles between cancer tissues and paired neighboring noncancerous tissues to systemically evaluate the findings globally and address the inconsistencies of pertinent literatures. The data included in this article were collected from Embase, PubMed and Web of Science up to December 2013. To overcome the difficulties that many raw data were unavailable and study methods were different, a vote-counting strategy was adopted to identify consistent markers in our analysis. Ultimately, a total of 23 cancers were reported in the 61 eligible studies, of which 46 studies provided fold-change value information. In the consistently reported cancer types, non small cell lung cancer (NSCLC), glioma and nasopharyngeal carcinoma (NPC) ranked at the top with down-regulated feature. Cervical neoplasm was consistently reported to be over-expressed in the panel of each member of miR-34s. Subgroup analysis of miR-34 family expression demonstrated that colorectal cancer (CRC), gastric cancer (GC), hepatocellular carcinoma (HCC) and prostate cancer (PCa) were most frequently reported with inconsistent regulations. Our meta-analysis showed that miR-34 family members could be expected to become potential diagnostic and prognostic biomarkers in some types of human cancers. Further well designed and larger sample studies are surely warranted to identify the role of the miR-34 family in the occurrence and development of tumors. PMID- 25452193 TI - Involvement of a putative allatostatin in regulation of juvenile hormone titer and the larval development in Leptinotarsa decemlineata (Say). AB - Juvenile hormone III (JH III) plays primary roles in regulation of metamorphosis, reproduction and diapause in Leptinotarsa decemlineata, a notorious defoliator of potato. The neurosecretory cell-borne substance(s) negatively affects the final two steps in JH biosynthesis, catalyzed respectively by an epoxidase CYP15A1 and a juvenile hormone acid methyltransferase (JHAMT). In a few insect species other than L. decemlineata, the inhibitory substance is allatostatin (AS) neuropeptide. In this study, two putative AS genes encoding LdAS-C and LdAS-B precursors were cloned. Both LdAS-C and LdAS-B were expressed in the egg, larvae, pupae and adults, and highly expressed in the brain and the gut. Dietary introduction of double-stranded RNAs (dsRNAs) targeting LdAS-C and LdAS-B successfully knocked down respective target genes. Ingestion during 3 and 6 consecutive days of dsLdAS C significantly increased the LdJHAMT mRNA levels by 3.8 and 9.9 fold respectively. In contrast, ingestion of dsLdAS-B only slightly increased the LdJHAMT expression level by 1.1 and 1.7 fold. Moreover, after one, two and three days' ingestion of dsLdAS-C, the relative JH levels in the hemolymph of treated larvae were 2.5, 4.2 and 1.9 fold higher than those in control beetles. Furthermore, ingestion of dsLdAS-C and dsLdAS-B significantly affected larval growth and delayed larval development. Thus, we provide a line of experimental evidence in L. decemlineata to support the concept that AS-C acts as an allatostatin and inhibit JH biosynthesis. PMID- 25452194 TI - Reconstruction and analysis of the genome-scale metabolic model of Lactobacillus casei LC2W. AB - Lactobacillus casei LC2W is a recently isolated probiotic lactic acid bacterial strain, which is widely used in the dairy and pharmaceutical industries and in clinical medicine. The first genome-scale metabolic model for L. casei, composed of 846 genes, 969 metabolic reactions, and 785 metabolites, was reconstructed using both manual genome annotation and an automatic SEED model. Then, the iJL846 model was validated by simulating cell growth on 15 reported carbon sources. The iJL846 model explored the metabolism of L. casei on a genome scale: (1) explanation of the genetic codes-metabolic functions of 342 genes were reannotated in this model; (2) characterization of the physiology-10 amino acids and 7 vitamins were identified to be essential nutrients for L. casei LC2W growth; (3) analyses of metabolic pathways-the transport and metabolism of the 17 essential nutrients and exopolysaccharide (EPS) biosynthesis-were performed; (4) exploration of metabolic capacity was conducted-for lactate, the importance of genes in its biosynthetic pathways was evaluated, and the requirements of amino acids were predicted for mixed acid fermentation; for flavor compounds, the effects of oxygen were analyzed, and three new knockout targets were selected for acetoin production; for EPS, 11 types of nutrients in the rich medium and important reactions in the biosynthetic pathway were identified that enhanced EPS production. In conclusion, the iJL846 model serves as a useful tool for understanding and engineering the metabolism of this probiotic strain. PMID- 25452195 TI - Phenolic content, physical and sensory properties of breads made with different types of barley wort. AB - BACKGROUND: Barley wort, an intermediate product of beer brewing, is rich in phenolic compounds. The aim of this work was to evaluate the possibility of increasing the antioxidant content of bread by replacing water with three types of wort: two of them withdrawn at the end of the mashing operation during the production of a Pilsner and a Double Malt Pilsner beer respectively; the other collected at an intermediate stage of mashing of the Pilsner beer. The chemical, physical and sensory properties of the wort-added breads were compared with those of a control bread. RESULTS: All three worts led to increased phenolic content, volume and specific volume of the breads and induced significant changes in 11 of 23 sensory descriptors. The highest phenolic contents were detected in breads made either with the Pilsner wort withdrawn at an intermediate stage of mashing or with the Double Malt Pilsner wort. The former also gave the highest increase in volume and specific volume but significantly reduced the scores for crunchiness, firmness and cohesiveness. The latter led to lower increases in volume and specific volume, but less significant changes in the sensory properties were associated with its use. CONCLUSION: Worts can be conveniently used to increase the antioxidant content of bread. However, different types of wort can modify to different extents the physical and sensory properties of the product. PMID- 25452197 TI - Renal denervation with a percutaneous bipolar radiofrequency balloon catheter in patients with resistant hypertension: 6-month results from the REDUCE-HTN clinical study. AB - AIMS: To evaluate the safety and efficacy of the balloon-based bipolar Vessix Renal Denervation System in treating patients with resistant hypertension. METHODS AND RESULTS: In this prospective, multicentre, single-arm study, 146 patients (age 58.6+/-10.5 years; 61% men) with office systolic blood pressure (BP) >=160 mmHg despite >=3 antihypertensive medications at maximally tolerated doses were treated with the Vessix System. Efficacy endpoints were reductions in office and 24-hour ambulatory systolic and diastolic BPs at six months. Acute and long-term safety, with a focus on the renal artery and estimated glomerular filtration rate (eGFR), were assessed. Baseline office and ambulatory BPs were 182.4+/-18.4/100.2+/-14.0 mmHg and 153.0+/-15.1/87.5+/-13.2 mmHg, respectively. No acute renal artery injury requiring intervention or serious periprocedural cardiovascular events occurred. At six months, office BP was reduced by 24.7+/ 22.1/10.3+/-12.7 mmHg (p<0.0001) and ambulatory BP was reduced by 8.4+/ 14.4/5.9+/-9.1 mmHg (N=69; p<0.0001). Twenty-six patients (18%) achieved an office systolic BP <140 mmHg. One patient had renal artery stenosis which required stenting. Mean eGFR remained stable. CONCLUSIONS: Renal artery denervation with the Vessix System reduced both office and ambulatory BP at six months in patients with resistant hypertension. Renal artery safety and renal function results are favourable. PMID- 25452196 TI - An exploratory analysis of Go/Nogo event-related potentials in major depression and depression following traumatic brain injury. AB - Rates of major depressive disorder (MDD) following traumatic brain injury (TBI) are estimated to be between 20% and 45%, a higher prevalence than that seen in the general population. These increased rates may be due to specific changes in brain function following TBI. Event related potentials (ERPs) are well suited for measuring the electrophysiological differences between groups in areas of cognitive processing impaired in both MDD and TBI, such as response inhibition. The current study presented an emotional Go/Nogo task (with schematic emotional faces as stimuli) to participants with TBI, participants with MDD, and participants with both TBI and MDD (TBI-MDD). Topographical distribution of activity and global field power comparisons were made across stimulus-locked epochs between these groups and healthy controls. The results indicated that ERPs were not altered by TBI alone. Both MDD and TBI-MDD groups showed similar alterations in topographical distribution and global field power in the N2 window, as well as late epoch alterations. The MDD and TBI-MDD groups showed significantly less fronto-central negativity during the N2 window in Nogo trials compared with the control group. The MDD and TBI-MDD groups also showed significantly less global field power in Nogo trials than Go trials during the N2 window while the control group showed the opposite pattern. The MDD and TBI-MDD groups showed no mood-congruent bias in behavioural or ERP measures. The results suggest that TBI-MDD displays similar electrophysiological changes to those found in the MDD group without TBI. PMID- 25452198 TI - Twelve-month results of the rapid renal sympathetic denervation for resistant hypertension using the OneShotTM ablation system (RAPID) study. AB - AIMS: Renal denervation has emerged as a treatment option for patients with drug resistant hypertension. This study was designed to assess the safety and effectiveness of the OneShota Renal Denervation System. METHODS AND RESULTS: RAPID is a prospective, multicentre, single-arm study which enrolled 50 patients at 11 clinical sites in Europe and New Zealand. Eligible patients had an office systolic blood pressure (SBP) >=160 mmHg and were on a stable regimen of >=3 antihypertensive medications including a diuretic. The primary safety endpoints were acute procedural safety at discharge and chronic procedural safety at six months. The primary effectiveness endpoint was the rate of office SBP reduction >=10 mmHg at six months compared to baseline. While not a predefined endpoint, change in 24-hour ambulatory BP was evaluated. The mean baseline office SBP and diastolic BP measurements were 181.6+/-20.8 and 95.5+/-15.5 mmHg, respectively. Patients were on a mean of 5.1 antihypertensive medications at baseline. The mean office BP decreased by -20/-8 mmHg (p<0.0001/p=0.0002), and -22/-8 mmHg (p<0.0001/p=0.0014), from baseline to six and 12 months, respectively. The 24 hour ABPM was also significantly reduced by -11/-6 mmHg at six months compared to baseline (p=0.0085/p=0.037). There were no serious adverse events (SAE) at discharge related to groin and vascular access complication or renal artery injury or SAE/adverse device effects at six months. CONCLUSIONS: The results of the RAPID study demonstrate safe delivery of RF energy by the OneShot Renal Denervation System for renal sympathetic denervation and sustained efficacy, as evidenced by a significant reduction in office and 24-hour ABPM for six months, which was sustained up to 12 months. ClinicalTrials.gov Identifier: NCT01520506. PMID- 25452199 TI - Protein and glucose metabolic responses to hyperinsulinemia, hyperglycemia, and hyperaminoacidemia in obese men. AB - OBJECTIVE: In insulin-resistant states, resistance of protein anabolism occurs concurrently with that of glucose, but can be compensated for by abundant amino acid (AA) provision. This effect and its mechanism were sought in obesity. METHODS: Pancreatic clamps were performed in 8 lean and 11 obese men, following 5 h postabsorptive, 3-h infusions of octreotide, basal glucagon, and growth hormone, with clamped postprandial-level insulin, glucose, and AA. Whole-body [1 (13) C]-leucine and [3-(3) H]-glucose kinetics, skeletal muscle protein ((2) H5 phenylalanine) fractional synthesis rates, and insulin signaling were determined. RESULTS: Clamp Delta insulin and Delta branched-chain AA did not differ; fasting glucagon and growth hormone were maintained. Glucose uptake was 20% less in obese concurrent with less Akt(Ser473) , but also less IRS-1(Ser636/639) phosphorylation. Stimulation of whole-body, myofibrillar, and sarcoplasmic protein synthesis was similar. Whole-body protein catabolism suppression tended to be less (P=0.06), resulting in lesser net balance (1.09 +/- 0.07 vs. 1.31 +/- 0.08 MUmol [kg FFM(-1) ] min(-1) , P=0.048). Increments in muscle S6K1(Thr389) phosphorylation were less in the obese, but 4E-BP1(Ser65) did not differ. CONCLUSIONS: Hyperaminoacidemia with hyperinsulinemia stimulated protein synthesis (possibly via nutrient signaling) normally in obesity, but suppression of proteolysis may be compromised. Whether long-term high protein intakes could compensate for the insulin resistance of protein anabolism remains to be determined. PMID- 25452200 TI - Copper-catalyzed difunctionalization of activated alkynes by radical oxidation tandem cyclization/dearomatization to synthesize 3-trifluoromethyl spiro[4.5]trienones. AB - A copper-catalyzed difunctionalizing trifluoromethylation of activated alkynes with the cheap reagent sodium trifluoromethanesulfinate (NaSO2CF3 or Langlois' reagent) has been developed incorporating a tandem cyclization/dearomatization process. This strategy affords a straightforward route to synthesis of 3 (trifluoromethyl)-spiro[4.5]trienones, and presents an example of difunctionalization of alkynes for simultaneous formation of two carbon-carbon single bonds and one carbon-oxygen double bond. PMID- 25452201 TI - Non-invasive computed fractional flow reserve from computed tomography (CT) for diagnosing coronary artery disease - Japanese results from NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps). AB - BACKGROUND: Recently, a non-invasive method using computational fluid dynamics to calculate vessel-specific fractional flow reserve (FFRCT) from routinely acquired coronary computed tomography angiography (CTA) was described. The Analysis of Coronary Blood Flow Using CT Angiography: Next Steps (NXT) trial, which was a prospective, multicenter trial including 254 patients with suspected coronary artery disease, noted high diagnostic performance of FFRCT compared with invasive FFR. The aim of this post-hoc analysis was to assess the diagnostic performance of non-invasive FFRCT vs. standard stenosis quantification on coronary CTA in the Japanese subset of the NXT trial. METHODS AND RESULTS: A total of 57 Japanese participants were included from Okayama University (n=36), Kyoto University (n=17), and Keio University (n=4) Hospitals. Per-patient diagnostic accuracy of FFRCT(74%; 95% confidence interval [CI]: 60-85%) was higher than for coronary CTA (47%; 95% CI: 34-61%, P<0.001) arising from improved specificity (63% vs. 27%, P<0.001). FFRCT correctly reclassified 53% of patients and 63% of vessels with coronary CTA false positives as true negatives. When patients with Agatston score >1,000 were excluded, per-patient accuracy of FFRCT was 83% with a high specificity of 76%, similar to the overall NXT trial findings. CONCLUSIONS: FFRCT has high diagnostic performance compared with invasive FFR in the Japanese subset of patients in the NXT trial. PMID- 25452202 TI - Immunosuppressive therapy in myocarditis. AB - Although there is general agreement on the favorable effect of immunosuppression in eosinophilic, granulomatous, giant-cell myocarditis and in lymphocytic myocarditis associated with connective tissue disorders and with rejection of a transplanted heart, its therapeutic role in lymphocytic inflammatory cardiomyopathy (ICM) is still debated. Previous retrospective studies reported a relevant clinical benefit in 90% of patients with virus-negative ICM and no response or cardiac impairment in 85% of those with virus-positive ICM following immunosuppression. Other studies identified cardiomyocyte HLA upregulation as an additional indicator of ICM susceptibility to immunosuppressive therapy. Recently in a single-center randomized prospective double-blind trial using a combination of prednisone and azathioprine in addition to supportive treatment in 85 virus negative ICM patients, a significant improvement in left ventricular (LV) ejection fraction and a significant reduction in LV dimensions in 88% of 43 treated patients compared with 42 patients receiving placebo who showed a cardiac impairment in 83% of cases (TIMIC study) was reported. These data confirm the efficacy of immunosuppression in virus-negative ICM. Lack of response in 12% of cases suggests the presence of unscreened viruses or mechanisms of damage and inflammation not susceptible to immunosuppression. Recovery of cardiac function in responders to immunosuppression was associated with inhibition of cardiomyocyte death, increased cell proliferation and with newly synthesized contractile material. PMID- 25452203 TI - New strategy for the treatment of myocarditis by cell-sheet technology. PMID- 25452204 TI - DryLab(r) optimised two-dimensional high performance liquid chromatography for differentiation of ephedrine and pseudoephedrine based methamphetamine samples. AB - In-silico optimised two-dimensional high performance liquid chromatographic (2D HPLC) separations of a model methamphetamine seizure sample are described, where an excellent match between simulated and real separations was observed. Targeted separation of model compounds was completed with significantly reduced method development time. This separation was completed in the heart-cutting mode of 2D HPLC where C18 columns were used in both dimensions taking advantage of the selectivity difference of methanol and acetonitrile as the mobile phases. This method development protocol is most significant when optimising the separation of chemically similar chemical compounds as it eliminates potentially hours of trial and error injections to identify the optimised experimental conditions. After only four screening injections the gradient profile for both 2D-HPLC dimensions could be optimised via simulations, ensuring the baseline resolution of diastereomers (ephedrine and pseudoephedrine) in 9.7 min. Depending on which diastereomer is present the potential synthetic pathway can be categorized. PMID- 25452205 TI - Cause and manner of death and phase of the blood alcohol curve. AB - In a large number of forensic autopsies (N = 28,184) the concentrations of ethanol in femoral blood and bladder urine were determined and the urine-to-blood concentration ratios of ethanol were calculated. Based on the differences in ethanol concentration between urine and blood, the deaths were classified as having occurred during the absorptive, the peak or the post-absorptive phase of the blood-alcohol curve. Most people died in the post-absorptive phase, N = 24,223 (86%), whereas 1538 individuals (5.5%) were still absorbing alcohol and 2423 (8.6%) were at or close to the peak BAC at time of death. Both blood-alcohol concentration (BAC) and urine-alcohol concentration (UAC) were significantly higher in the post-absorptive phase (p < 0.001). The proportions of people dying in the absorptive and peak phases increased with advancing age. The cause of death (CoD) and manner of death (MoD) according to death certificates were compared with phase of the blood-alcohol curve using a multinomial regression model with and without making adjustment for possible effects of age, gender and BAC. The relative risk (RR) and relative risk ratios (RRR) showed some associations between CoD and phase of the blood-alcohol curve. Undetermined MoD was significantly higher in the absorptive phase compared with the post absorptive phase (RRR = 2.12). Deaths related to esophagus, stomach and duodenum (RRR = 2.04) and alcoholic liver diseases (RRR = 1.85) were significantly higher at or close to peak phase compared to the post-absorptive phase. Road-traffic fatalities were more prevalent in the peak BAC phase (RRR = 1.33) and deaths by accidental falls were less in the absorptive phase (RRR = 0.58) compared with the post-absorptive phase. The phase of alcohol intoxication seems relevant to consider by forensic experts when alcohol-related deaths are investigated. PMID- 25452206 TI - Sparse sampling: theory, methods and an application in neuroscience. AB - The current methods used to convert analogue signals into discrete-time sequences have been deeply influenced by the classical Shannon-Whittaker-Kotelnikov sampling theorem. This approach restricts the class of signals that can be sampled and perfectly reconstructed to bandlimited signals. During the last few years, a new framework has emerged that overcomes these limitations and extends sampling theory to a broader class of signals named signals with finite rate of innovation (FRI). Instead of characterising a signal by its frequency content, FRI theory describes it in terms of the innovation parameters per unit of time. Bandlimited signals are thus a subset of this more general definition. In this paper, we provide an overview of this new framework and present the tools required to apply this theory in neuroscience. Specifically, we show how to monitor and infer the spiking activity of individual neurons from two-photon imaging of calcium signals. In this scenario, the problem is reduced to reconstructing a stream of decaying exponentials. PMID- 25452207 TI - Pearling and arching instabilities of a granular suspension on a super-absorbing surface. AB - We show that a granular suspension, composed of particles immersed in a liquid, can form pearls, hooks, and arches when deposited from a nozzle onto a translating substrate that acts as a liquid super-absorber. The removal of the liquid induces a rapid pinning of the contact line leading to mechanically stable structures that are held together by capillary adhesion with shapes that depend on the relative solidification rate. Pearls or hooks form depending on whether the suspension snaps off before or after coming into contact with the substrate. A cylindrical thread with a near circular cross-section and various undulatory structures forms if solidification occurs prior to snap-off. In particular, when the jet solidifies before coming into contact with the substrate, it folds periodically, resulting in arches with a span length determined by the deposition flux and the substrate speed. Period doubling and meandering are observed leading to further structures with vertical and horizontal ripples when the deposition flux is increased. PMID- 25452208 TI - Tool use for food acquisition in a wild mountain gorilla (Gorilla beringei beringei). AB - On May 14, 2013, a wild, human-habituated, juvenile female mountain gorilla (Gorilla beringei beringei) in Volcanoes National Park, Rwanda was observed utilizing a tool to acquire food. The young gorilla watched an adult male use his hand to collect ants from a hole in the ground, and then quickly withdrew his hand and move away from the hole, shaking his arm to presumably remove biting ants. The juvenile female engaged in similar behavior, withdrawing her hand covered in ants, and shaking her arm vigorously. She then selected a piece of wood approximately 20 cm long and 2 cm wide at one end, 1 cm wide at the other, and proceeded to insert the stick into the hole, withdraw the stick, and then lick ants off of the stick. In contrast to the sizeable body of literature on tool use in wild chimpanzees, this is the first report of tool use for food acquisition by a wild gorilla. PMID- 25452213 TI - A dihydroindolizino indole derivative selectively stabilizes G-quadruplex DNA and down-regulates c-MYC expression in human cancer cells. AB - BACKGROUND: Telomeric and NHE III1, a c-MYC promoter region is abundant in guanine content and readily form G-quadruplex structures. Small molecules that stabilize G-quadruplex DNA were shown to reduce oncoprotein expression, initiate apoptosis and they may function as anticancer molecules. METHODS: Electrospray ionization mass spectrometry, spectroscopy, isothermal titration calorimetry, Taq DNA polymerase stop assay, real time PCR and luciferase reporter assay. Cell migration assay to find out the effect of derivatives on normal as well as cancer cell proliferation. RESULTS: Among three different dihydroindolizino indole derivatives, 4-cyanophenyl group attached derivative has shown maximum affinity, selective interaction and higher stability towards G-quadruplex DNA over dsDNA. Further, as a potential G-quadruplex DNA stabilizer, 4-cyanophenyl linked dihydroindolizino indole derivative was found to be more efficient in inhibiting in vitro DNA synthesis, c-MYC expression and cancer cell proliferation among human cancer cells. CONCLUSION: The present study reveals that dihydroindolizino indole derivative having 4-cyanophenyl group has potential to stabilize G quadruplex DNA and exhibit anticancer activity. GENERAL SIGNIFICANCE: These studies are useful in the identification and synthesis of lead derivatives that will selectively stabilize G-quadruplex DNA and function as anticancer agents. PMID- 25452209 TI - Differential effects of binge methamphetamine injections on the mRNA expression of histone deacetylases (HDACs) in the rat striatum. AB - Methamphetamine use disorder is characterized by recurrent binge episodes. Humans addicted to methamphetamine experience various degrees of cognitive deficits and show evidence of neurodegenerative processes in the brain. Binge injections of METH to rodents also cause significant toxic changes in the brain. In addition, this pattern of METH injections can alter gene expression in the dorsal striatum. Gene expression is regulated, in part, by histone deacetylation. We thus tested the possibility that METH toxic doses might cause changes in the mRNA levels of histone deacetylases (HDACs). We found that METH did produce significant decreases in the mRNA expression of HDAC8, which is a class I HDAC. METH also decreased expression of HDAC6, HDAC9, and HDAC10 that are class II HDACs. The expression of the class IV HDAC, HDAC11, was also suppressed by METH. The expression of Sirt2, Sirt5, and Sirt6 that are members of class III HDACs was also downregulated by METH injections. Our findings implicate changes in HDAC expression may be an early indicator of impending METH-induced neurotoxicity in the striatum. This idea is consistent with the accumulated evidence that some HDACs are involved in neurodegenerative processes in the brain. PMID- 25452214 TI - Engineered chimeras reveal the structural basis of hexacoordination in globins: a case study of neuroglobin and myoglobin. AB - BACKGROUND: Myoglobin (Mb) and neuroglobin (Ngb) are representative members of pentacoordinated and bis-histidyl, hexacoordinated globins. In spite of their low sequence identity, they show surprisingly similar three-dimensional folds. The ability of Ngb to form a hexacoordinated bis-histidyl complex with the distal HisE7 has a strong impact on ligand affinity. The factors governing such different behaviors have not been completely understood yet, even though they are extremely relevant to establish structure-function relationships within the globin superfamily. METHODS: In this work we generated chimeric proteins by swapping a previously identified regulatory segment - the CD region - and evaluated comparatively the structural and functional properties of the resulting proteins by molecular dynamics simulations, and spectroscopic and kinetic investigations. RESULTS: Our results show that chimeric proteins display heme coordination properties displaced towards those expected for the corresponding CD region. In particular, in the absence of exogenous ligands, chimeric Mb is found as a partially hexacoordinated bis-histidyl species, whereas chimeric Ngb shows a lower equilibrium constant for forming a hexacoordinated bis-histidyl species. CONCLUSIONS: While these results confirm the regulatory role of the CD region for bis-histidyl hexacoordination, they also suggest that additional sources contribute to fine tune the equilibrium. General significance Globins constitute a ubiquitous group of heme proteins widely found in all kingdoms of life. These findings raise challenging questions regarding the structure-function relationships in these proteins, as bis-histidyl hexacoordination emerges as a novel regulatory mechanism of the physiological function of globins. PMID- 25452216 TI - Case series of infants presenting with end stage retinopathy of prematurity to two tertiary eye care facilities in Mexico: underlying reasons for late presentation. AB - To describe the characteristics of infants with bilateral Stage 4b or 5 ROP (i.e. with subtotal or total retinal detachment) who presented to eye departments in two major cities in Mexico, to identify reasons why they may have become blind in order to recommend how programs could be improved. A large case-series of infants with Stage 4b or 5 ROP in both eyes confirmed by ultrasound who attended the ROP Clinic, Hospital Civil de Guadalajara from September 2010 to November 2012, and the Department of Ophthalmology, Hospital Infantil de Mexico Federico Gomez from December 2011 to December 2012 were identified from the diagnostic databases of each hospital. Mothers of infants in Guadalajara had a telephone interview. 89/94 eligible infants were included in the study, 48 in Guadalajara and 41 in Mexico City. Cases came from 22 of the 32 states in Mexico. Half of the infants attending Guadalajara 24/48 (50 %) had been cared for in NICUs without ROP screening programs and were not examined. Among the 24 infants cared for in NICUs with ROP programs, 7/24 (29.1 %) mothers reported that their infant had not been examined while in the NICU, and a further 9/24 (37.5 %) were either not referred for screening after discharge or they did not attend. Two infants had failed laser treatment. Strategies and resources to prevent end stage ROP have not been firmly established in Mexico. There is an urgent need to expand the coverage and quality of ROP programs, to ensure that existing screening guidelines are better adhered to, and to improve communication with parents. PMID- 25452215 TI - Prenatal depression and adverse birth outcomes: an updated systematic review. AB - Complications related to preterm birth (PTB) and low birth weight (LBW) are leading causes of infant morbidity and mortality. Prenatal depression is a hypothesized psychosocial risk factor for both birth outcomes. The purpose of this systematic review was to examine evidence published between 1977 and 2013 on prenatal depression and risks of these primary adverse birth outcomes. A systematic search of the PUBMED and PsycINFO databases was conducted to identify studies testing the associations between prenatal depressive symptoms, or diagnoses of depression, and risk of PTB or LBW. We systematically selected 50 published reports on PTB and length of gestation, and 33 reports on LBW and BW. Results were reviewed by two independent reviewers and we evaluated the quality of the evidence with an established systematic review method, the Newcastle Ottawa Scale. We then undertook a narrative synthesis of the results following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Less than a quarter of 50 published reports found that prenatal depression was significantly associated with PTB or gestational age. In contrast, slightly more than half of the 33 reports found that prenatal depression was associated with LBW or BW. When weighing methodological features, we determined that the effects of prenatal depression on LBW are more consistent than effects on length of gestation or PTB. Although the evidence may not be strong enough to support routine depression screening for risk of adverse outcomes, screening to enable detection and timely treatment to reduce risk of postpartum depression is warranted. Further rigorous research on prenatal depression and adverse birth outcomes is needed. PMID- 25452217 TI - Adolescent relationship violence and acculturation among NYC Latinos. AB - Acculturation has been shown to positively and negatively affect Latino health. Little research investigates the overlap between acculturation and the different types of relationship violence among Latino youth and most research in this area predominantly involves Mexican-American samples. The current study examined associations between indices of acculturation (language use at home, chosen survey language, and nativity) and relationship physical violence and sexual coercion, both received and delivered, among predominantly Dominican and Puerto Rican adolescents from New York City. From 2006 to 2007, 1,454 adolescents aged 13-21 years in New York City completed an anonymous survey that included the Conflict in Adolescent Relationships Inventory which estimates experiences of physical violence and sexual coercion, both received and delivered, in the previous year. This analysis includes bivariate and multivariate methods to test the associations between language use at home, chosen survey language, and nativity with the different types of relationship violence. Among females, there is a significant association between language use at home and overall level of acculturation with delivering and receiving relationship physical violence; however, we did not find this association in delivering and receiving relationship sexual coercion. We found no association between acculturation and any type of relationship violence among males. Among Latina females, language spoken at home is an indicator of other protective factors of physical relationship violence. Future research in this area should explore the potential protective factors surrounding relationship violence among Latina females of various subgroups using comprehensive measures of acculturation, household composition and family engagement. PMID- 25452218 TI - Positive effect of IGF-1 injection on gastrocnemius of rat during distraction osteogenesis. AB - Distraction osteogenesis (DO) is used to form new bone between bone segments to lengthen the callus. Skeletal muscles frequently fail to adapt to distraction, which causes complications. Insulin-like growth factor-1 (IGF-1) has been implicated as a central regulator of muscle repair. We hypothesized that IGF-1 injection could reduce muscle complications in DO. A total of 102 Sprague-Dawley rats received DO or did not were randomly assigned into saline, IGF-1 and normal groups. On the day before the distraction, the rats in the IGF-1 group were injected with IGF-1. The gastrocnemius muscles of the rats were harvested at the 0, 1st, 4th, 7th, and 10th days of distraction. The weight of the muscles, cross sectional area (CSA) of the muscle fibers, collagen volume fraction (CVF), maximum limit load (MLL), maximum contraction forces, and gene expression of Akt, MyoD, myogenin, myostatin, and collagen I were analyzed. The results indicated that IGF-1 injection had increased the weights, CSA of the muscle fibers, MLL and force generation of the gastrocnemius. Also, Akt, MyoD, and myogenin were upregulated, and myostatin was downregulated in the IGF-1 group. Injection of IGF 1 could attenuate the gastrocnemius atrophy, prevent fibrosis, increase MLL, and regulate the related mRNA. PMID- 25452221 TI - Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. AB - BACKGROUND: Early enteral feeding practices are potentially modifiable risk factors for necrotising enterocolitis in very preterm or very low birth weight (VLBW) infants. Observational studies suggest that conservative feeding regimens, including slowly advancing enteral feed volumes, reduce the risk of necrotising enterocolitis. However, slow feed advancement may delay establishment of full enteral feeding and be associated with metabolic and infectious morbidities secondary to prolonged exposure to parenteral nutrition. OBJECTIVES: To determine the effect of slow rates of enteral feed advancement on the incidence of necrotising enterocolitis, mortality, and other morbidities in very preterm or VLBW infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group Specialised Register. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 8), MEDLINE, EMBASE, and CINAHL (to September 2014), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that assessed the effect of slow (up to 24 ml/kg per day) versus faster rates of advancement of enteral feed volumes upon the incidence of necrotising enterocolitis in very preterm or VLBW infants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias and undertook data extraction. We analysed the treatment effects in the individual trials and reported the risk ratio and risk difference for dichotomous data and mean difference for continuous data, with respective 95% confidence intervals. We used a fixed-effect model in meta-analyses and explored the potential causes of heterogeneity in sensitivity analyses. MAIN RESULTS: We identified six randomised controlled trials in which a total of 618 infants participated. Most participants were stable preterm infants of birth weight between 1000 g and 1500 g. Few participants were extremely preterm, extremely low birth weight, or growth restricted. The trials typically defined slow advancement as daily increments of 15 ml/kg to 20 ml/kg and faster advancement as 30 ml/kg to 35 ml/kg. Meta analyses did not detect statistically significant effects on the risk of necrotising enterocolitis (typical risk ratio (RR) 0.96, 95% confidence interval (CI) 0.55 to 1.70) or all-cause mortality (typical RR 1.57, 95% CI 0.92 to 2.70). Infants who had slow advancement took significantly longer to regain birth weight (reported median differences 2 to 6 days) and to establish full enteral feeding (1 to 5 days). AUTHORS' CONCLUSIONS: The available trial data suggest that advancing enteral feed volumes at daily increments of 30 ml/kg to 35 ml/kg does not increase the risk of necrotising enterocolitis in very preterm or VLBW infants. Advancing the volume of enteral feeds at slow rates resulted in several days delay in regaining birth weight and establishing full enteral feeds. The applicability of these findings to extremely preterm, extremely low birth weight, or growth-restricted infants is limited. Further randomised controlled trials in these populations may be warranted to resolve this uncertainty. PMID- 25452222 TI - Cognitive and Guided Mastery Therapies for Panic Disorder with Agoraphobia: 18 Year Long-Term Outcome and Predictors of Long-Term Change. AB - In this study, we wished to compare the long-term outcome of (medication-free) panic disorder with agoraphobia patients randomized to cognitive or guided mastery therapy. Thirty-one (67.4%) of 46 patients who had completed treatment were followed up about 18 years after end of treatment. In the combined sample and using intent-to-follow-up analyses, there were large within-group effect sizes of -1.79 and -1.63 on the primary interview-based and self-report outcome measures of avoidance of situations when alone, and 56.5% no longer had a panic disorder and/or agoraphobia diagnosis. No outcome differences between the two treatments emerged. Guided mastery was associated with greater beneficial changes in catastrophic beliefs and self-efficacy. For two of five outcome measures, more reduction in panic-related beliefs about physical and mental catastrophes from pre- to post-treatment predicted lower level of anxiety from post-treatment to 18 year follow-up when the effect of treatment changes in (a) self-efficacy and (b) anxiety was controlled. However, for one of the outcome measures, this effect attenuated with time. Copyright (c) 2014 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: The results suggest that the very-long-term outcome of both cognitive therapy and guided mastery therapy for agoraphobia is positive. The results support the role of catastrophic beliefs as mediator of change. The pattern of results suggests that learning processes other than catastrophic beliefs may be important for long-term outcome as well. PMID- 25452223 TI - Prospective fathers' adverse childhood experiences, pregnancy-related anxiety, and depression during pregnancy. AB - There is a growing knowledge of the predictors of depressive or anxious feelings during pregnancy among prospective fathers, and the present study investigates how paternal adverse childhood experiences relate to anxious and depressive feelings during pregnancy. Participants were recruited to "The Little in Norway Study (LIN-study)" (2010) at different well-baby clinics in Norway; 976 fathers consented to participate in the study, of which 881 had valid data for adverse childhood experiences. The study reports on the relationship between the Adverse Childhood Experience Scale (ACE Scale; R.F. Anda, A. Butchart, V.J. Felitti, & D.W. Brown, 2010) and depressive feelings, using the Edinburgh Postnatal Depression Scale (EPDS; M. Eberhard-Gran & K. Slinning, 2007), and pregnancy related anxiety, using the Pregancy-Related Anxiety Scale-Revised (PRAQ-R; A.C. Huizink, E.J. Mulder, D.M.P.G. Robles, & G.H. Visser, 2004). Data collection was comprised of five time points during pregnancy: Time 1 (T1; Weeks 8-34) and four follow-up time points; Time 2 (T2: Weeks 20-25), Time 3 (T3: Weeks 26-31), Time 4 (T4: Weeks 32-34), and Time 5 (T5: Week 36). Fathers' with higher ACE scores reported more pregnancy-related anxiety than did fathers with lower scores at all time points in pregnancy, except at T5 (36 weeks), while also reporting more depressive feelings during pregnancy. Health providers and community centers should pay more attention to fathers' mental health during pregnancy, as the whole family system needs to be considered during pregnancy to provide optimal healthcare. Adverse childhood experiences among fathers-to-be may increase depressive and anxious feelings during pregnancy. PMID- 25452219 TI - FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. AB - The purpose of these guidelines is to assist physicians in recommending, performing, interpreting and reporting the results of FDG PET/CT for oncological imaging of adult patients. PET is a quantitative imaging technique and therefore requires a common quality control (QC)/quality assurance (QA) procedure to maintain the accuracy and precision of quantitation. Repeatability and reproducibility are two essential requirements for any quantitative measurement and/or imaging biomarker. Repeatability relates to the uncertainty in obtaining the same result in the same patient when he or she is examined more than once on the same system. However, imaging biomarkers should also have adequate reproducibility, i.e. the ability to yield the same result in the same patient when that patient is examined on different systems and at different imaging sites. Adequate repeatability and reproducibility are essential for the clinical management of patients and the use of FDG PET/CT within multicentre trials. A common standardised imaging procedure will help promote the appropriate use of FDG PET/CT imaging and increase the value of publications and, therefore, their contribution to evidence-based medicine. Moreover, consistency in numerical values between platforms and institutes that acquire the data will potentially enhance the role of semiquantitative and quantitative image interpretation. Precision and accuracy are additionally important as FDG PET/CT is used to evaluate tumour response as well as for diagnosis, prognosis and staging. Therefore both the previous and these new guidelines specifically aim to achieve standardised uptake value harmonisation in multicentre settings. PMID- 25452224 TI - Renal arcuate vein microthrombi-associated AKI. AB - BACKGROUNDS AND OBJECTIVES: This report describes six patients with AKI stages 2 3 (median admission creatinine level, 2.75 mg/dl [range, 1.58-5.44 mg/dl]), hematuria (five with hemoproteinuria), and unremarkable imaging with an unusual and unexplained histologic diagnosis on renal biopsy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The patients were young adults who presented to two neighboring United Kingdom nephrology centers over a 40-month period (between July 2010 and November 2013). Four were male, and the median age was 22.5 years (range, 18-27 years). Their principal symptoms were flank pain or lower back pain. All had consumed alcohol in the days leading up to admission. RESULTS: Renal biopsy demonstrated microthrombi in the renal arcuate veins with a corresponding stereotypical, localized inflammatory infiltrate at the corticomedullary junction. All patients recovered to baseline renal function with supportive care (median, 17 days; range, 6-60 days), and none required RRT. To date, additional investigations have not revealed an underlying cause for these histopathologic changes. Investigations have included screening for thrombophilic tendencies, renal vein Doppler ultrasonographic studies, and testing for recreational drugs and alcohol (including liquid chromatography-mass spectrometry of urine) to look for so-called designer drugs. Inquiries to the United Kingdom National Poisons Information Centre have identified no other cases with similar presentation or histologic findings. CONCLUSIONS: Increased awareness and additional study of future cases may lead to a greater understanding of the underlying pathophysiologic mechanisms that caused AKI in these patients. PMID- 25452226 TI - Lignocellulose degradation by the isolate of Streptomyces griseorubens JSD-1. AB - Streptomyces griseorubens JSD-1 is an isolate that can utilize lignocellulose (straw) as its sole carbon source for growth, and these lignocellulolytic genes involved in this biotransformation are expected to be crucial. However, little is known about the genetic basis related to this process. To further investigate the lignocellulose-degrading mechanisms, genome sequencing was carried out using MiSeq platform. After obtaining its draft genome, the key lignocellulolytic genes such as multicopper oxidase, exo-1, 4-beta-glucanase, endo-1,4-beta-glucanase, and beta-xylosidase were identified and characterized. Multiple sequence alignments were performed to find out the identities of these analyzed proteins to those of their similar species. Signal peptide cleavage sites were predicted by SignalP 4.1 to reflect the cellular localization of their mature proteins. Besides, predicted 3D structures of these proteins were modeled by Phyre2, which showed to be highly identical to the templates in the PDB database. Finally, quantitative real-time PCR revealed that expression levels of all analyzed enzymes were significantly and generally up-regulated during the whole cultivation, indicating that they all contributed to the biodegradation. PMID- 25452225 TI - Adiposity patterns and the risk for ESRD in postmenopausal women. AB - BACKGROUND AND OBJECTIVES: Body mass index and waist circumference associate with adverse health outcomes, including CKD. Studies of the association of body mass index and ESRD have been inconsistent; these adiposity measures have not been previously assessed together for ESRD risk or among postmenopausal women. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: This was prospective cohort study of 20,117 postmenopausal women enrolled in the multiethnic cohort of the Women's Health Initiative. Body mass index and waist circumference were obtained at baseline, incident ESRD was obtained from the US Renal Data System, and all-cause death was obtained from surveillance data. A competing-risk framework was used to account for the effect of mortality before ESRD while adjusting for significant predictors and baseline kidney function. Associations of adiposity with mortality were also studied. RESULTS: Events included 212 patients with incident ESRD and 3104 deaths for a mean follow-up of 11.6 years. Increased waist circumference and body mass index were associated with 2.59- (95% confidence interval, 1.89 to 3.53) and 1.97-fold (95% confidence interval, 1.30 to 2.98) higher hazards of ESRD as well as 1.42- (95% confidence interval, 1.32 to 1.53) and 1.21-fold (95% confidence interval, 1.11 to 1.33) higher hazards of death, respectively, compared with the lower categories in adjusted analyses. The associations of waist circumference with ESRD varied by baseline renal function (P for interaction=0.01) and were significant only among women without baseline eGFR defined CKD (hazard ratio, 1.93; 95% confidence interval, 1.23 to 3.03). CONCLUSIONS: Central obesity was associated with an increased risk of ESRD in postmenopausal women, even among women with normal body mass index but not among women with reduced baseline kidney function, and an increased risk of death. Body mass index was associated with ESRD, and the association is likely mediated through hypertension and diabetes. PMID- 25452227 TI - Posttreatment with 11-Keto-beta-Boswellic Acid Ameliorates Cerebral Ischemia Reperfusion Injury: Nrf2/HO-1 Pathway as a Potential Mechanism. AB - Oxidative stress is well known to play a pivotal role in cerebral ischemia reperfusion injury. The nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway has been considered a potential target for neuroprotection in stroke. 11-Keto-beta-boswellic acid (KBA) is a triterpenoid compound from extracts of Boswellia serrata. The aim of the present study was to determine whether KBA, a novel Nrf2 activator, can protect against cerebral ischemic injury. Middle cerebral artery occlusion (MCAO) was operated on male Sprague-Dawley rats. KBA (25 mg/kg) applied 1 h after reperfusion significantly reduced infarct volumes and apoptotic cells as well as increased neurologic scores at 48 h after reperfusion. Meanwhile, posttreatment with KBA significantly decreased malondialdehyde (MDA) levels, restored the superoxide dismutase (SOD) activity, and increased the protein Nrf2 and HO-1 expression in brain tissues. In primary cultured astrocytes, KBA increased the Nrf2 and HO-1 expression, which provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. But knockdown of Nrf2 or HO-1 attenuated the protective effect of KBA. In conclusion, these findings provide evidence that the neuroprotection of KBA against oxidative stress-induced ischemic injury involves the Nrf2/HO-1 pathway. PMID- 25452228 TI - Validating GWAS-Identified Risk Loci for Alzheimer's Disease in Han Chinese Populations. AB - In recent years, genome-wide association studies (GWASs) have identified many novel susceptible genes/loci for Alzheimer's disease (AD). However, most of these studies were conducted in European and populations of European origin, and limited studies have been performed in Han Chinese. In this study, we genotyped 14 single-nucleotide polymorphisms (SNPs) in eight GWAS-reported AD risk genes in 1509 individuals comprising two independent Han Chinese case-control cohorts. Four SNPs (rs11234495, rs592297, rs676733, and rs3851179) in the PICALM gene were significantly associated with late-onset (LO)-AD in populations from Southwest China, whereas SNPs rs744373 (BIN1), rs9331942 (CLU), and rs670139 (MS4A4E) were linked to LO-AD in populations from East China. In the combined Han Chinese population, positive associations were observed between PICALM, CLU, MS4A4E genes, and LO-AD. The association between rs3851179 (PICALM), rs744373 (BIN1), and AD was further confirmed by meta-analysis of Asian populations. Our study verified the association between PICALM, BIN1, CLU, and MS4A4E variants and AD susceptibility in Han Chinese populations. We also discerned some regional differences concerning AD susceptibility SNPs. PMID- 25452230 TI - Using improved serial blood sampling method of mice to study pharmacokinetics and drug-drug interaction. AB - In pharmacokinetic evaluation of mice, using serial sampling methods rather than a terminal blood sampling method could reduce the number of animals needed and lead to more reliable data by excluding individual differences. In addition, using serial sampling methods can be valuable for evaluation of the drug-drug interaction (DDI) potential of drug candidates. In this study, we established an improved method for serially sampling the blood from one mouse by only one incision of the lateral tail vein, and investigated whether our method could be adapted to pharmacokinetic and DDI studies. After intravenous and oral administration of ibuprofen and fexofenadine (BCS class II and III), the plasma concentration and pharmacokinetic parameters were evaluated by our method and a terminal blood sampling method, with the result that both methods gave comparable results (ibuprofen: 63.8 +/- 4.0% and 64.4%, fexofenadine: 6.5 +/- 0.7% and 7.9%, respectively, in bioavailability). In addition, our method could be adapted to DDI study for cytochrome P450 and organic anion transporting polypeptide inhibition. These results demonstrate that our method can be useful for pharmacokinetic evaluation from the perspective of reliable data acquisition as well as easy handling and low stress to mice and improve the quality of pharmacokinetic and DDI studies. PMID- 25452232 TI - [Next stages of drug discovery and evolution for intractable diseases created by young pharmacologists]. PMID- 25452231 TI - Composition of fatty acids in virgin olive oils from cross breeding segregating populations by gas chromatography separation with flame ionization detection. AB - BACKGROUND: Recent technological advances to improve the quality of virgin olive oil (VOO) have been focused on olive breeding programs by selecting outstanding cultivars and target progenies. Fatty acid (FA) composition, with special emphasis on oleic acid (C18:1) and palmitic acid (C16:0), is one of the most critical quality factors to be evaluated in VOO. For this reason, the profile of FAs is frequently used as a decision tool in olive breeding programs. RESULTS: A method based on gas chromatography with flame ionization detection (GC-FID) was used to study the influence of genotype on the concentration of ten of the most important FAs in VOOs from target crosses Arbequina * Arbosana, Picual * Koroneiki and Sikitita * Arbosana and their corresponding genitors Arbequina, Arbosana, Koroneiki, Picual and Sikitita. For this purpose, a targeted approach was selected for determination of esterified FAs (EFAs) and non-esterified FAs (NEFAs) in a dual analysis by the same chromatographic method. A Pearson analysis revealed correlations between pairs of FAs, which allowed detecting metabolic connections through desaturation and elongation enzymes. An ANOVA test (with P < 0.01) led to identification of C16:0 EFA, C16:1 EFA and C18:1 EFA and also C16:1 NEFA and C18:0 NEFA as the FAs more influenced by cross breeding. Statistical analysis was carried out by unsupervised analysis using principal component analysis (PCA) and cluster analysis (CA) to look for variability sources. CONCLUSION: Crosses with a common genitor (Arbequina * Arbosana and Sikitita * Arbosana) were partially overlapped in the PCAs using the profile of FAs. The CA results revealed clear differences between Sikitita * Arbosana and Picual * Koroneiki crosses in the composition of the most significant FAs, while Arbequina * Arbosana was not properly discriminated from the other crosses. PMID- 25452229 TI - A long-term intensive lifestyle intervention and physical function: the look AHEAD Movement and Memory Study. AB - OBJECTIVE: To assess the long-term effects of an intensive lifestyle intervention on physical function using a randomized post-test design in the Look AHEAD trial. METHODS: Overweight and obese (BMI >= 25 kg m(-2)) middle-aged and older adults (aged 45-76 years at enrollment) with type 2 diabetes (n = 964) at four clinics in Look AHEAD, a trial evaluating an intensive lifestyle intervention (ILI) designed to achieve weight loss through caloric restriction and increased physical activity compared to diabetes support and education (DSE), underwent standardized assessments of performance-based physical function including an expanded short physical performance battery (SPPBexp ), 20-m and 400-m walk, and grip and knee extensor strength 8 years post-randomization, during the trial's weight maintenance phase. RESULTS: Eight years post-randomization, individuals randomized to ILI had better SPPBexp scores [adjusted mean (SE) difference: 0.055 (0.022), P = 0.01] and faster 20-m and 400-m walk speeds [0.032 (0.012) m s(-1) , P = 0.01, and 0.025 (0.011) m s(-1) , P = 0.02, respectively] compared to those randomized to DSE. Achieved weight loss greatly attenuated the group differences in physical function, and the intervention effect was no longer significant. CONCLUSIONS: An intensive lifestyle intervention has long-term benefits for mobility function in overweight and obese middle-aged and older individuals with type 2 diabetes. PMID- 25452234 TI - [Role of hydrogen sulfide, a gasotransmitter, in colonic pain and inflammation]. AB - Hydrogen sulfide (H2S), the third known gaseous transmitter following nitric oxide and carbon monoxide, is generated by multiple enzymes including cystathionine-gamma-lyase (CSE) in vivo. We previously demonstrated that H2S activates Cav3.2 T-type Ca(2+) channels expressed on sensory neurons, leading to hyperalgesia and facilitation of inflammation. Here, we describe the role of H2S in processing of colonic pain and inflammation. Intracolonic (i.col.) administration of NaHS, an H2S donor, to mice evoked colonic pain-like nociceptive behavior and referred hyperalgesia accompanied by phosphorylation of ERK in the superficial layers of spinal dorsal horn, a marker for excitation of nociceptive neurons. The pronociceptive effect of NaHS was abolished by inhibitors or knockdown of Cav3.2 and by an inhibitor of TRPA1, another target molecule of H2S. In rats with colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS), on the other hand, repeated i.col. administration of NaHS prevented colonic ulcer and inflammatory symptoms, which were inhibited by ablation of capsaicin-sensitive sensory neurons or T-type Ca(2+) channel inhibitor. NaHS, given i.col., caused phosphorylation of ERK in the spinal dorsal horn of rats with TNBS-induced colitis, but not of naive rats. In TNBS-treated rats, Cav3.2 was upregulated in the dorsal root ganglia, while CSE was downregulated in the colon. Taken together, these findings suggest that inhibitors of the CSE/H2S/Cav3.2 or TRPA1 pathways might be useful for the treatment of colonic pain diseases such as irritable bowel syndrome, while H2S donors or Cav3.2 activators might be useful for the treatment of inflammatory bowel disease including Crohn's disease. PMID- 25452233 TI - [Establishment of a novel therapeutic strategy for heart failure based on the mechanism underlying maintenance of redox homeostasis by reactive sulfur species]. AB - Cardiac redox homeostasis is precisely regulated by reactive oxygen species (ROS) or electrophilic molecules that are formed by ROS reacting with intracellular substrates, and their eliminating systems. We have focused on the role of nitric oxide (NO) generated from inducible NO synthase (iNOS) that is continuously upregulated from early stage of heart failure, and revealed that iNOS-derived NO acts as a protective factor in the early stage of heart failure, whereas it contributes to induction of cardiac early senescence in later stages. The switching mechanism of NO-mediated signaling includes formation of endogenous NO derived electrophilic byproducts such as 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), which selectively targets an oncogenic small GTPase H-Ras at Cys-184, leading to cardiac cell senescence via covalent modification (S guanylation) and activation of H-Ras. We also found that hydrogen sulfide-related reactive sulfur species (RSS) function as potent nucleophiles to eliminate electrophilic modification of H-Ras and suppress the onset of chronic heart failure after myocardial infarction. Our results strongly suggest a new concept of redox biology in which suppression of electrophilic irreversible modification of protein cysteine thiols by RSS may be a new therapeutic strategy of cardiovascular diseases. PMID- 25452235 TI - [The causative gene of Parkinsonism and its medical treatment strategy]. AB - Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The neurodegenerative condition of Parkinson's disease (PD) is the most common cause of parkinsonism. PD is classified as sporadic PD and familial PD. Whereas idiopathic PD is caused by a number of complex factors, familial PD is a result of mutations in PD-associated genes. Unraveling the mechanisms surrounding familial PD will offer pivotal clues in understanding etiology of not only familial PD but also sporadic PD. We have demonstrated neuroprotective effects with particular focus on DJ-1. On the other hand, idiopathic basal ganglia calcification, also known as Fahr disease (FD) is another condition characterized by parkinsonism. In 2012, solute carrier family 20A2 (SLC20A2) was identified as the causative gene for familial FD. Our analysis of patient samples revealed a novel mutation in SLC20A2. Type-III sodium dependent phosphate transporter 2 (PiT-2), the protein encoded by SLC20A2, plays an important role in phosphate homeostasis. However, PiT-2's role in the pathology of FD remains largely unclear. We have established induced pluripotent stem (iPS) cells from FD patients and are investigating their usefulness in drug development. Here, we present some of our latest research findings. PMID- 25452236 TI - [Regulation of osteoclastogenesis by osteocytes through growth differentiation factor-15]. AB - Osteocytes are the most abundant cells in bone. However, little attention has been paid to their role in bone remodeling. In this study, osteoclast differentiation was significantly enhanced by conditioned media derived from cultures of osteocytic MLO-Y4 cells that were cultured under hypoxic conditions. Using microarray analysis, we identified growth differentiation factor-15 (GDF15) as a pivotal factor secreted from osteocytes under hypoxia. Indeed, treatment with recombinant GDF15 markedly increased osteoclast differentiation in vitro. Further to investigate the importance of GDF15 in vivo, we used a hypoxic murine model that involved ligation of the right femoral artery. The volume of cancellous bone in the proximal tibia of the ligated limb was significantly reduced, together with a significant increase in osteoclast-related parameters. Addition of anti-GDF15 antibody prevented bone loss and osteoclastic activation in the tibiae of mice that had undergone femoral artery ligation. These results suggest that GDF15, which is secreted from osteocytes under hypoxia during bone remodeling, may be a positive regulator of osteoclastic differentiation. The in vivo usefulness of the anti-GDF15 antibody might provide insights for the development of novel therapeutics for bone disorders related to hypoxia or ischemic insults. PMID- 25452237 TI - [A new taxonomic system of the genus Murraya (Rutaceae) based on integration of morphology-based taxonomy and chemotaxonomy; and a philological survey on M. exotica in view of the relationship between Okinawa and China]. AB - This review concerns the taxonomic status of the genus Murraya in tribe Clausenae, subfamily Aurantioideae, family Rutaceae, and presents a new system integrating both morphology-based taxonomy and chemotaxonomy. This genus has been morphologically divided into the sects Murraya and Bergera. This dichotomy is justified by the noticeable difference of secondary metabolites with 3 prenylindoles in Murraya and carbazoles in Bergera. As for other metabolites of genus Murraya, coumarins are found in both sects, but differ clearly in types; 8 prenylcoumarins occur throughout the sect Murraya whereas geranylated furocoumarins are known from some species of the sect Bergera. As far as chemical properties are concerned, sect Bergera is much closer to genus Clausena than sect Murraya, suggesting the dichotomy of genus Murraya to be generic rather than sectional. 8-Prenylcoumarins characterizing sect Murraya play a decisive role in the distinction of M. exotica from M. paniculata that occurs most widely in subtropical and tropical Asia and is well known for morphologic as well as chemical diversity. Though the morphological difference between the two species is slight only in leaves and leaflets, the distinction is well substantiated by the following chemical feature: 7-OMe-8-prenylcoumarins occur in M. exotica whereas 5,7-di-OMe-8-prenylcoumarins in M. paniculata. Sect Murraya has a very close relation to genus Merrillia that is chemically characterized by similar types of 8-prenylcoumarins, and is also related to a certain extent to genus Micromelum. M. exotica is philologically surveyed in view of the delicate relationships between Okinawa, the only habitat of this plant in Japan, and China in order to clarify its historical background. PMID- 25452238 TI - [Synthesis of hypervalent organo-lambda(3)-bromanes and their reactions by using leaving group ability of lambda(3)-bromanyl group]. AB - Hypervalent organo-lambda(3)-iodanes have attracted great interest in organic synthesis; however, the chemistry of hypervalent organo-lambda(3)-bromanes remains largely unexplored, mainly because of synthetic difficulties. Iodobenzene is readily oxidized by common oxidants such as peracids under mild conditions, whereas bromobenzene is inert. Since the ionization potential of bromobenzene (8.98 eV) is higher than that of iodobenzene (8.69 eV), hypervalent-lambda(3) bromane would show much higher reactivity. We overcame this problem by using difluoro(aryl)-lambda(3)-bromane (Frohn's reagent), which serves as a pivotal progenitor of various lambda(3)-bromanes including imino-lambda(3)-bromane, cyclopent-1-enyl-lambda(3)-bromane, (E)-beta-alkylvinyl-lambda(3)-bromane, and diacetoxy-lambda(3)-bromane. These reagents possess highly unusual reactivity based on the enormously enhanced nucleofugality of the aryl-lambda(3)-bromanyl group. PMID- 25452239 TI - [Mechanism of spinal pain transmission and its regulation]. AB - Morphine has been widely used for the treatment of acute, chronic, and cancer pain and is considered the strongest analgesic in clinical care. Conversely, morphine-induced analgesia may be accompanied by several side effects. Animal studies have demonstrated that low doses of morphine administered intrathecally can produce reliable analgesia for thermal, mechanical, and chemical nociceptive stimulation. On the other hand, high doses of morphine administered intrathecally may induce spontaneous nociceptive responses such as scratching, biting, and licking in mice as well as agitation and vocalization in rats. In addition, similar nociceptive responses including hyperalgesia, allodynia, and myoclonus have been observed in humans following intrathecal or systemic administration of high-dose morphine. It has been suggested that the spontaneous nociceptive behaviors evoked by high-dose morphine may be mediated by a non-opioid mechanism that is not yet fully understood. This review describes the mechanisms of spontaneous nociceptive behaviors evoked by high-dose morphine focusing on the neurotransmitters/neuromodulators released from primary afferent fibers. PMID- 25452240 TI - [Efficient synthesis of multisubstituted aromatic compounds from phenol derivatives]. AB - Phenols are abundant in nature and diverse phenols are readily available commercially at low cost. Thus, phenols can be used as the raw materials for the synthesis of valuable multisubstituted aromatic compounds by the direct activation of phenolic hydroxyl groups (C-O bond activation), followed by substitutions with other substituents. Although the derivatization of phenolic hydroxyl groups to sulfonates, such as triflates, nonaflates, tosylates and mesylates, followed by the transition-metal-catalyzed coupling reactions has been extensively investigated for this purpose, the direct C-O bond activation of phenols for subsequent functional group transformation has been a long-standing challenge in modern organic synthesis. In this review, I have summarized my recent studies on the formal direct C-O bond activation of phenols using nonafluorobutanesulfonyl fluoride (NfF) for the synthesis of multisubstituted aromatics. I have focused on the dual use of NfF, a less expensive commercially available reagent, including the tentative formation of highly reactive nonaflates from phenols and the use of the liberated fluoride ion as a nucleophile to promote the reactions of nonaflates. The following four topics are discussed: 1) palladium-catalyzed coupling reactions of phenols, 2) novel preparation of benzynes from 2-silylphenols, 3) synthesis of fluorinated aromatic compounds via the formation of benzynes, and 4) Hiyama coupling of (tert butyldimethylsilyl)arenes activated by internal phenolic hydroxyl groups. PMID- 25452241 TI - [Development of artificial nucleic acids functionalized for damaged gene diagnosis, gene inhibition and delivery system]. AB - Artificial nucleic acids have recently been widely used with their properties optimized for various technologies such as the inhibition of gene expression (antisense/antigene strategies, RNA interference) and genetic diagnosis (single nucleotide polymorphism (SNP), damaged nucleobase). For practical application of nucleic acid therapeutics, establishment of an effective delivery system for oligonucleotides is also required because of their poor permeability into cells. Various useful delivery technologies including lipoplexes formed using cationic lipids and polyplexes made with cationic polymers have been developed; however, there is no crucial tool for oligonucleotide therapeutics at present. If technologies of functional nucleic acids and adequate delivery systems are cooperatively developed, the realization of nucleic acid therapeutics might be effectively accelerated. Based on this concept, we have been cooperatively developing these technologies based on organic synthetic chemistry during the past decade. This paper summarizes our recent results: 1) development of a specific fluorescent probe for 8-oxoguanine; 2) synthesis and evaluation of a prodrug-type small interfering RNA (siRNA) molecule; and 3) targeted intracellular delivery of oligonucleotides via conjugation with receptor-targeted ligands. PMID- 25452242 TI - [Investigation of the educational effectiveness of including small group discussion as part of a drug abuse prevention program for junior high school students]. AB - We evaluated the effectiveness of small group discussion (SGD) in association with a drug abuse prevention program for junior high school students. The students first received a lecture about drug abuse prevention, then participated in SGD. The discussion focused on how to take action when tempted to abuse drugs. We gave a questionnaire 3 times; before and after the lecture (before SGD), and after SGD. Seventy-seven students replied to these questionnaires. After the lecture, knowledge about drug abuse was improved and all students answered that they had never abused drugs. However, in answer to a different question, a few students noted that they might use drugs in some situations. We consider it necessary to give more consideration to this problem. After the lecture, 35.5% of the students felt that they had definitely acquired skills for drug abuse prevention, whereas after the SGD this was increased to 73.7%. In addition, more than 75% of the students answered that the SGD program was useful since the opinions of other students could be heard. These results suggest that more students acquired skills to prevent drug abuse by participation in SGD. Our findings showed that SGD was useful and that the students were able to more effectively understand important concepts related to drug abuse prevention. PMID- 25452243 TI - [A survey of self-medication practices and related factors in the general population: the Ohasama study]. AB - Encouraging self-medication is expected to reduce healthcare costs. To assess the current situation of self-medication practices in the general population, we conducted a questionnaire survey regarding the use of over-the-counter (OTC) medications or dietary supplements in 1008 participants (37% men; mean age, 64+/ 13 years) from Ohasama, a rural Japanese community. A total of 519 (52%) participants used OTC medications or dietary supplements, with common cold medication (36%) and supplements (28%) such as shark cartilage products representing the most common choices. Stepwise logistic regression showed female gender, a higher frequency of visits from a household medicine kit distributor, dyslipidemia, and lower home systolic blood pressure levels as predictors for the use of such materials (chi-square values: 25.3, 12.6, 7.0, and 4.6, respectively; all p<0.03). Stratifying the participants according to the use of antihypertensive treatment showed a negative association between systolic blood pressure and the use of OTC medications or supplements only in participants being treated for hypertension. These results suggest that although the adoption rate of self-medication in Japan can be increased in rural areas, it may remain lower in urban areas. The present study clarifies the factors associated with the use of OTC medications or dietary supplements and indicates that appropriate self medication practices might improve the control of hypertension, particularly in patients undergoing antihypertensive treatment. PMID- 25452244 TI - [Trial and evaluation of a remedial education program at Kobe Pharmaceutical University]. AB - Pharmaceutical education is suffering from the decentralization of students due to the establishment of new pharmaceutical universities, the shift to a six-year program from a four-year program in the colleges of pharmacy in 2006, and a decrease in the number of students. Combined, these have lead to academic failings, even at high-ranking universities. However, abundant knowledge and ability are necessary to pass the national examination for pharmacists. At Kobe Pharmaceutical University, a Basic Education Center for Pharmacy was instituted in 2006 for the purpose of supporting the scholastic abilities of students with various challenges, as well as for students in general. One approach at the Basic Education Center for Pharmacy, has been to offer supplementary lessons, and to provide additional opportunities for learning for the repeater. We offer supplementary lessons as an "Office Hours Class" and also use DVD-learning for remedial teaching. "Office Hours Class" is conducted in a question/answer format with a small number of students. In order to develop the DVD-learning system (pharmaceutical educational digital learning; PEDL), which promotes self learning, our supplementary lectures and "Office Hours Class" lectures are recorded and edited on DVD media. The learning effect of using these systems, as determined by regular examination, shows that these have been helpful. As a result, we concluded that these supplementary learning programs are useful as a learning method to help students acquire necessary knowledge as potential pharmaceutical professionals, and to increase student motivation. PMID- 25452245 TI - [Necessity of personalized initial loading dose calculation of teicoplanin by clinical pharmacist-examination of the utility of using systemic inflammatory response syndrome score-]. AB - When teicoplanin (TEIC) is injected at the maintenance dose, a long period is required for achievement of the target plasma trough concentration because of its long elimination half-life. An initial loading dose is necessary for rapid achievement of an effective plasma trough concentration. Thus, we proposed that it is necessary for a pharmacist determine the initial loading dose of TEIC to reach an effective plasma trough concentration rapidly after its administration to a patient. In the present study, we evaluated the effectiveness of initial loading dose determination by pharmacists and physicians by comparing the achievement rate of target plasma trough concentrations (>15 MUg/mL) and expression of adverse effects. Among 61 patients, 34 were treated according to an initial loading dose determined by a pharmacist (pharmacist intervention) and 27 were treated according to the treating physician's discretion (non-pharmacist intervention). The achievement rate of target concentrations was 91.2% (plasma trough concentration 23.3+/-5.3 MUg/mL) in the pharmacist intervention group and 25.9% (plasma trough concentration 14.0+/-5.9 MUg/mL) in the non-pharmacist intervention group. There was no difference in the incidence of adverse effects between the two groups. Also, we found that systemic inflammatory response syndrome (SIRS) may have a correlation with plasma trough concentrations of TEIC. We suggest that the SIRS score could become a means way of determining initial loading dose. These findings suggest that it is potentially effective for a pharmacist to determine this initial dose in order to rapidly achieve the target plasma trough concentration of TEIC. PMID- 25452246 TI - Dominance, access to females, and mating success among coresident male mantled howlers (Alouatta palliata) at La Pacifica, Costa Rica. AB - The priority-of-access (POA) model posits that high dominance rank increases male mating success by increasing access to fertile females. However, the relationship between rank, access to females, and subsequent mating success is variable in primates, and there are few studies representing Neotropical taxa. The purpose here was to test the parameters of the POA model in an asynchronously breeding Neotropical primate, Alouatta palliata, to contribute to our understanding of the relationship between dominance and reproductive strategies in platyrrhines. I collected data on adult males within two large, multimale-multifemale groups exhibiting clear dominance hierarchies at La Pacifica, Costa Rica. Females were classified as sexually receptive (SR) or potentially cycling (PC) based on behavioral and birth data. Access to mates was measured based on total time in proximity to SR/PC females, and mating success was measured based on copulation frequency. Results did not support the predictions of the POA model in that first ranked males maintained lower than expected time in proximity to SR females, did not consistently maintain the greatest proportion of time in proximity to PC females, obtained lower than expected copulation rates, and did not obtain the highest copulation rates compared to subordinates in either group. Deviations from the POA model were significantly affected by varying operational sex ratios only when considering the lower numbers of available SR females in one group. Alternative reproductive tactics by subordinate males such as tolerance by first ranked males appeared to be operating, allowing subordinates to obtain mating success when they would otherwise be unable to do so. The study also highlighted how factors such as operational sex ratio may limit the willingness or ability of dominant males to monopolize access to females, and can vary both within and between groups in a population. PMID- 25452247 TI - Plant communities on infertile soils are less sensitive to climate change. AB - BACKGROUND AND AIMS: Much evidence suggests that plant communities on infertile soils are relatively insensitive to increased water deficit caused by increasing temperature and/or decreasing precipitation. However, a multi-decadal study of community change in the western USA does not support this conclusion. This paper tests explanations related to macroclimatic differences, overstorey effects on microclimate, variation in soil texture and plant functional traits. METHODS: A re-analysis was undertaken of the changes in the multi-decadal study, which concerned forest understorey communities on infertile (serpentine) and fertile soils in an aridifying climate (southern Oregan) from 1949-1951 to 2007-2008. Macroclimatic variables, overstorey cover and soil texture were used as new covariates. As an alternative measure of climate-related change, the community mean value of specific leaf area was used, a functional trait measuring drought tolerance. We investigated whether these revised analyses supported the prediction of lesser sensitivity to climate change in understorey communities on infertile serpentine soils. KEY RESULTS: Overstorey cover, but not macroclimate or soil texture, was a significant covariate of community change over time. It strongly buffered understorey temperatures, was correlated with less change and averaged >50 % lower on serpentine soils, thereby counteracting the lower climate sensitivity of understorey herbs on these soils. Community mean specific leaf area showed the predicted pattern of less change over time in serpentine than non serpentine communities. CONCLUSIONS: Based on the current balance of evidence, plant communities on infertile serpentine soils are less sensitive to changes in the climatic water balance than communities on more fertile soils. However, this advantage may in some cases be lessened by their sparser overstorey cover. PMID- 25452248 TI - Immunolabelling of intervessel pits for polysaccharides and lignin helps in understanding their hydraulic properties in Populus tremula * alba. AB - BACKGROUND AND AIMS: The efficiency and safety functions of xylem hydraulics are strongly dependent on the pits that connect the xylem vessels. However, little is known about their biochemical composition and thus about their hydraulic properties. In this study, the distribution of the epitopes of different wall components (cellulose, hemicelluloses, pectins and lignins) was analysed in intervessel pits of hybrid poplar (Populus tremula * alba). METHODS: Immunogold labelling with transmission electron microscopy was carried out with a set of antibodies raised against different epitopes for each wall polysaccharide type and for lignins. Analyses were performed on both immature and mature vessels. The effect of sap ionic strength on xylem conductance was also tested. KEY RESULTS: In mature vessels, the pit membrane (PM) was composed of crystalline cellulose and lignins. None of the hemicellulose epitopes were found in the PM. Pectin epitopes in mature vessels were highly concentrated in the annulus, a restricted area of the PM, whereas they were initially found in the whole PM in immature vessels. The pit border also showed a specific labelling pattern, with higher cellulose labelling compared with the secondary wall of the vessel. Ion-mediated variation of 24 % was found for hydraulic conductance. CONCLUSIONS: Cellulose microfibrils, lignins and annulus-restricted pectins have different physicochemical properties (rigidity, hydrophobicity, porosity) that have different effects on the hydraulic functions of the PM, and these influence both the hydraulic efficiency and vulnerability to cavitation of the pits, including ion-mediated control of hydraulic conductance. Impregnation of the cellulose microfibrils of the PM with lignins, which have low wettability, may result in lower cavitation pressure for a given pore size and thus help to explain the vulnerability of this species to cavitation. PMID- 25452249 TI - Evaluation of the presence of arabinogalactan proteins and pectins during Quercus suber male gametogenesis. AB - BACKGROUND AND AIMS: Quercus suber (cork oak) is a dominant tree of the Fagaceae in forests of the south-west Iberian Peninsula. It is monoecious with a long progamic phase that provides a comprehensive system for comparative studies in development and sexual reproduction. In this study the distribution of arabinogalactan protein (AGPs) and pectin epitopes in anthers of Q. suber was assessed to map these hydroxyproline-rich glycoproteins and the galacturonate rich acidic polysaccharides during pollen development. Methods Immunolocalization in male flowers was performed with a set of monoclonal antibodies directed against the carbohydrate moiety that recognizes AGPs and pectins. To identify AGP genes involved in cork oak male flower development, a search was conducted for annotated AGP genes in the available transcriptome data of the Cork Oak EST Consortium database (www.corkoakdb.org). KEY RESULTS: Ubiquitous labelling in all cell types was obtained with anti-homogalacturan antibodies for methyl-esterified pectins. In contrast, the antibody that labelled non-methyl-esterified homogalacturans had a preferential presence in microsporocyte cells walls at the beginning of pollen development. Intense labelling was obtained with anti-AGP antibodies both in the tapetum and in the intine wall near the pollen apertures and later in the generative cell wall and vegetative cell. Evaluation of the putative AGPs highly expressed in the male gametophyte was achieved by quantitative RT-PCR analysis in male and female cork oak flowers. CONCLUSIONS: Four putative AGP genes were identified that are preferentially expressed in the male flower compared with the female flower. The putative Arabidopsis thaliana orthologues of these genes are associated with preferential expression in pollen, suggesting that the AGPs probably play a significant role in cork oak reproduction. PMID- 25452250 TI - Analysing growth and development of plants jointly using developmental growth stages. AB - BACKGROUND AND AIMS: Plant growth, the increase of organ dimensions over time, and development, the change in plant structure, are often studied as two separate processes. However, there is structural and functional evidence that these two processes are strongly related. The aim of this study was to investigate the co ordination between growth and development using mango trees, which have well defined developmental stages. METHODS: Developmental stages, determined in an expert way, and organ sizes, determined from objective measurements, were collected during the vegetative growth and flowering phases of two cultivars of mango, Mangifera indica. For a given cultivar and growth unit type (either vegetative or flowering), a multistage model based on absolute growth rate sequences deduced from the measurements was first built, and then growth stages deduced from the model were compared with developmental stages. KEY RESULTS: Strong matches were obtained between growth stages and developmental stages, leading to a consistent definition of integrative developmental growth stages. The growth stages highlighted growth asynchronisms between two topologically connected organs, namely the vegetative axis and its leaves. CONCLUSIONS: Integrative developmental growth stages emphasize that developmental stages are closely related to organ growth rates. The results are discussed in terms of the possible physiological processes underlying these stages, including plant hydraulics, biomechanics and carbohydrate partitioning. PMID- 25452251 TI - Macroevolutionary patterns of salt tolerance in angiosperms. AB - BACKGROUND: Halophytes are rare, with only 0.25% of angiosperm species able to complete their life cycle in saline conditions. This could be interpreted as evidence that salt tolerance is difficult to evolve. However, consideration of the phylogenetic distribution of halophytes paints a different picture: salt tolerance has evolved independently in many different lineages, and halophytes are widely distributed across angiosperm families. In this Viewpoint, I will consider what phylogenetic analysis of halophytes can tell us about the macroevolution of salt tolerance. HYPOTHESIS: Phylogenetic analyses of salt tolerance have shown contrasting patterns in different families. In some families, such as chenopods, salt tolerance evolved early in the lineage and has been retained in many lineages. But in other families, including grasses, there have been a surprisingly large number of independent origins of salt tolerance, most of which are relatively recent and result in only one or a few salt-tolerant species. This pattern of many recent origins implies either a high transition rate (salt tolerance is gained and lost often) or a high extinction rate (salt tolerant lineages do not tend to persist over macroevolutionary timescales). While salt tolerance can evolve in a wide range of genetic backgrounds, some lineages are more likely to produce halophytes than others. This may be due to enabling traits that act as stepping stones to developing salt tolerance. The ability to tolerate environmental salt may increase tolerance of other stresses or vice versa. CONCLUSIONS: Phylogenetic analyses suggest that enabling traits and cross-tolerances may make some lineages more likely to adapt to increasing salinization, a finding that may prove useful in assessing the probable impact of rapid environmental change on vegetation communities, and in selecting taxa to develop for use in landscape rehabilitation and agriculture. PMID- 25452252 TI - Evidence for phylogenetic correlation of plant-AMF assemblages? AB - BACKGROUND AND AIMS: Specificity in biotic interactions is mediated' by functional traits inducing shifts in the community species composition. Functional traits are often evolutionarily conserved, resulting in closely related species tending to interact with similar species. This tendency may initially shape the phylogenetic composition of coexisting guilds, but other intraguild ecological processes may either blur or promote the mirroring of the phylogenetic compositions between guilds. The roles of intra- and interguild interactions in shaping the phylogenetic community composition are largely unknown, beyond the mere selectivity in the interguild interactions. Plant facilitation is a phylogenetically structured species-specific process involving interactions not only between the same guild of plants, but also between plants and other guilds such as arbuscular mycorrhizal fungi (AMF). In this study it is hypothesized that reciprocal plant-AMF interactions will leave an interdependent phylogenetic signal in the community composition of both plants and AMF. METHODS: A correlation was used to test for a relationship between the phylogenetic composition of plant and AMF assemblages in a patchy xeric shrubland environment shaped by plant facilitation. In addition, a null model was used to test whether this correlation can be solely explained by selectivity in plant-AMF interactions. KEY RESULTS: A significant correlation was observed between the phylogenetic composition of plant and AMF assemblages. Plant phylogenetic composition in a patch was related to the predominance of plant species with high nursery quality that can influence the community assembly. AMF phylogenetic composition was related to the AMF phylogenetic diversity in each patch. CONCLUSIONS: This study shows that shifts in the phylogenetic composition of plants and AMF assemblages do not occur independently. It is suggested that besides selectivity in plant-AMF interactions, inter-related succession dynamics of plants and AMF within patches could be an ecological mechanism driving community assembly. Future lines of research might explore whether interlinked above- and below-ground dynamics could be occurring across multiple guilds simultaneously. PMID- 25452254 TI - Treatment of severely recalcitrant chronic spontaneous urticaria: a discussion of relevant issues. AB - Chronic spontaneous urticaria (CSU) is a common disorder with a prevalence of 1% that is characterized by recurrent wheals, angioedema, or both. CSU is self limited but in many patients symptoms recur for several years and can be refractory to standard therapies. In this review, we present an illustrative case of a female patient with CSU who, despite taking 15 antihistamines a day in addition to a number of second-line therapies, continued to be refractory to treatment. However, once we initiated subcutaneous treatment with omalizumab 300 mg every 4 weeks, she experienced rapid relief of her CSU symptoms. Through this case, we present a review of the relevant issues, including the efficacy of laboratory tests to identify the cause of a patient's CSU, the association between CSU and thyroid disease and its relevance to treatment options, the recommendation to increase antihistamine dose up to fourfold and possible adverse events associated with this treatment option. We also include a discussion of the use of second-line therapies as well as omalizumab in refractory CSU patients. PMID- 25452253 TI - Seed bank dynamics govern persistence of Brassica hybrids in crop and natural habitats. AB - BACKGROUND AND AIMS: Gene flow from crops to their wild relatives has the potential to alter population growth rates and demography of hybrid populations, especially when a new crop has been genetically modified (GM). This study introduces a comprehensive approach to assess this potential for altered population fitness, and uses a combination of demographic data in two habitat types and mathematical (matrix) models that include crop rotations and outcrossing between parental species. METHODS: Full life-cycle demographic rates, including seed bank survival, of non-GM Brassica rapa * B. napus F1 hybrids and their parent species were estimated from experiments in both agricultural and semi-natural habitats. Altered fitness potential was modelled using periodic matrices including crop rotations and outcrossing between parent species. KEY RESULTS: The demographic vital rates (i.e. for major stage transitions) of the hybrid population were intermediate between or lower than both parental species. The population growth rate (lambda) of hybrids indicated decreases in both habitat types, and in a semi-natural habitat hybrids became extinct at two sites. Elasticity analyses indicated that seed bank survival was the greatest contributor to lambda. In agricultural habitats, hybrid populations were projected to decline, but with persistence times up to 20 years. The seed bank survival rate was the main driver determining persistence. It was found that lambda of the hybrids was largely determined by parental seed bank survival and subsequent replenishment of the hybrid population through outcrossing of B. rapa with B. napus. CONCLUSIONS: Hybrid persistence was found to be highly dependent on the seed bank, suggesting that targeting hybrid seed survival could be an important management option in controlling hybrid persistence. For local risk mitigation, an increased focus on the wild parent is suggested. Management actions, such as control of B. rapa, could indirectly reduce hybrid populations by blocking hybrid replenishment. PMID- 25452257 TI - Segmental fat-free and fat mass measurements by bioelectrical impedance analysis in 2,224 healthy Spanish women aged 18-85 years. AB - OBJECTIVES: This study provides updated data on body composition in adult Spanish women. METHODS: We considered data, including height and weight, from a survey conducted on a total of 4,013 adult women between 2009 and 2010. A subgroup of 2,224 women completed a bioelectrical body impedance analysis of body composition using a Tanita Body Composition Analyzer (Model no. BF-418). RESULTS: Total fat mass (FM) gradually increased between 18 and 74 years of age and decreased thereafter. FM increased in both legs between 65 and 74 years of age (5.69 +/- 1.4 Kg and 5.66 +/- 1.4 Kg for right and left legs, respectively) and decreased thereafter. FM in the right arm increased until 44 years of age (1.22 +/- 2.6 Kg), decreased to 1.19 +/- 0.5 Kg between 45 and 54 years of age, and increased to 1.54 +/- 0.63 from 65 to 74 years of age. FM in the left arm increased constantly until it reached a peak of 1.63 +/- 0.6 Kg between 65 and 74 years of age and decreased thereafter. FM increased in the trunk throughout life (peaks at 13.27+/-3.8 Kg) until subjects reached between 65 and 74 years of age. Fat free mass increased until 44 years of age (42.42 +/- 4.17 Kg) and decreased thereafter. The prevalence of overweight/obesity significantly increased with age in the entire sample. CONCLUSIONS: Our results indicate that age-related increases in weight were at least partially due to increased adiposity. PMID- 25452258 TI - Low-level laser therapy attenuates LPS-induced rats mastitis by inhibiting polymorphonuclear neutrophil adhesion. AB - The aim of this study was to investigate the effects of low-level laser therapy (LLLT) on a rat model of lipopolysaccharide (LPS)-induced mastitis and its underlying molecular mechanisms. The rat model of mastitis was induced by inoculation of LPS through the canals of the mammary gland. The results showed that LPS-induced secretion of IL-1beta and IL-8 significantly decreased after LLLT (650 nm, 2.5 mW, 30 mW/cm(2)). LLLT also inhibited intercellular adhesion molecule-1 (ICAM-1) expression and attenuated the LPS-induced decrease of the expression of CD62L and increase of the expression of CD11b. Moreover, LLLT also suppressed LPS-induced polymorphonuclear neutrophils (PMNs) entering the alveoli of the mammary gland. The number of PMNs in the mammary alveolus and the myeloperoxidase (MPO) activity were decreased after LLLT. These results suggested that LLLT therapy is beneficial in decreasing the somatic cell count and improving milk nutritional quality in cows with an intramammary infection. PMID- 25452260 TI - An unusual presentation of femoral neck fracture in a young patient. AB - Femoral neck fractures in young patients can have unusual presentation making diagnosis and subsequent management more difficult. Early detection is essential to avoid complications; however, it is only achievable with a high index of suspicion. We present an unusual case of a 39-year-old office worker who presented with a 5-month history of spontaneous onset of hip pain. She had multiple clinic visits prior to the diagnosis of neck of femur fracture. Fracture displacement and delayed diagnosis had resulted in a non-union by the time of presentation. She was subsequently managed with a fixation using a dynamic hip screw along with subtrochanteric osteotomy. No underlying cause for the initial fracture was identified despite thorough investigation. Learning points for early detection and operative management are discussed. PMID- 25452256 TI - CCR5 receptor antagonists block metastasis to bone of v-Src oncogene-transformed metastatic prostate cancer cell lines. AB - Src family kinases (SFK) integrate signal transduction for multiple receptors, regulating cellular proliferation, invasion, and metastasis in human cancer. Although Src is rarely mutated in human prostate cancer, SFK activity is increased in the majority of human prostate cancers. To determine the molecular mechanisms governing prostate cancer bone metastasis, FVB murine prostate epithelium was transduced with oncogenic v-Src. The prostate cancer cell lines metastasized in FVB mice to brain and bone. Gene expression profiling of the tumors identified activation of a CCR5 signaling module when the prostate epithelial cell lines were grown in vivo versus tissue cultures. The whole body, bone, and brain metastatic prostate cancer burden was reduced by oral CCR5 antagonist. Clinical trials of CCR5 inhibitors may warrant consideration in patients with CCR5 activation in their tumors. PMID- 25452259 TI - Prognostic utility of apoptosis index, Ki-67 and survivin expression in dogs with nasal carcinoma treated with orthovoltage radiation therapy. AB - Apoptosis, Ki-67 and survivin expression have been reported as prognostic values in human cancer treated with radiation therapy. The aim of this study was to evaluate the correlation between the outcome of canine nasal carcinomas treated with radiation therapy and these cancer markers. The apoptotic index (AI) was evaluated with TUNEL assays, and an immunohistochemical evaluation was performed on Ki-67 and survivin in 33 biopsy samples taken before treatment. Median survival times were estimated using Kaplan-Meier curves and the log-rank method. The AI ranged from 0 to 0.7%, and the percentage of Ki-67-positive cells defined as the proliferative index (PI) ranged from 0.8 to 77% in all samples. Neither the AI nor the PI had a significant relationship with survival time (P=0.056 and 0.211). Survivin expression was detected in 84.9% of samples of canine nasal carcinoma. Dogs with high survivin expression were associated with poorer response to treatment and had shorter survival times (P=0.017 and 0.031). Advanced-stage tumors were also significantly associated with a high level of survivin (P=0.026). Overexpression of survivin was shown to be an unfavorable prognostic factor in dogs with nasal carcinomas treated with radiation therapy. PMID- 25452261 TI - Idiopathic internal mammary artery aneurysm. AB - Aneurysms of the internal mammary artery are extremely rare, and their presentation and treatment are variable. Since these aneurysms often tend to rupture and cause haemothorax and life-threatening conditions, the knowledge of secure treatment options is indispensable. We here report the case of an idiopathic internal mammary aneurysm in a 46-year-old man. Open surgical resection of the aneurysm was performed in this case without any complications. The postoperative course was uneventful and the patient was in a good physical condition without any vascular or neurological abnormalities during follow-up. PMID- 25452262 TI - Penile cancer in patient with a 'Bouglou' penile adornment. AB - Implantation of penile nodules under the foreskin aims at improving male and female sexual pleasures during intercourse. This case discusses the characteristics of the South American penile adornment 'Bouglou' as well as the risk factors for penile cancer in this region of Amazonia. This is a case report of a 48-year-old man whose penis presented a destructive gland/penile shaft lesion and three adornments in the penile shaft, reported as 'Bouglou'. The diagnosis of penile cancer was confirmed after total penectomy. This study is the first that suggests a possible association between squamous cell carcinoma and these penile adornments. PMID- 25452263 TI - Isolation and biological activity of a novel cadinane-type sesquiterpenoid from the essential oil of Alangium salviifolium. AB - The components of the essential oil from the roots of Alangium salviifolium were analyzed by capillary gas chromatography-mass spectrometry (GC-MS). Ninety compounds, representing 74.5% of the total oil, were identified; the main components of the oil were epi-alpha-cadinol, followed by trans-2 hydroxycalamenene, cadalene, and cadina-4,10(15)-dien-3-one. A further unknown component comprised 5.5% of the oil. Therefore, the essential oil was purified by flash column chromatography to isolate this component. Its structure was established using extensive spectroscopic data analyses, including NMR, HR-EI-MS, and IR. The results showed that this isolated compound was (-)-7, 8 dihydroxycalamenal, which is a novel cadinane-type sesquiterpenoid. This compound was tested for its antioxidant activity and inhibition of tyrosinase, and showed particularly strong inhibition effects. PMID- 25452264 TI - Chemical composition of the essential oil of Amorpha canescens Pursh. AB - The essential oils from inflorescences, leaves and fruits of Amorpha canescens Pursh were analysed by GC, GC-MS and (1)H-NMR spectroscopy. More than 100 compounds were identified. Germacrene D (43.6%) and germacrene D-4-ol (8.3%) were the main constituents in the fruit oil. The oil from inflorescences contained mainly beta-elemol (29.4%) and germacrene D (14.6%), whereas the leaf oil contained germacrene D (30.3%), germacrene D-4-ol (10.9%) and beta-elemol (10.1%). PMID- 25452265 TI - Lipase-catalyzed preparation of phospholipids containing n-3 polyunsaturated fatty acids from soy phospholipids. AB - To utilize n-3 polyunsaturated fatty acid (PUFA) for a wide range of applications, we prepared phospholipids (PLs) containing PUFAs as constituent fatty acids (PUFA-PLs) via commercially available lipase OF-mediated transacylation with PL from soy (Soy-PL) and ethyl ester of PUFA (PUFA-Et). In a preliminary study to evaluate PUFA-incorporation (wt%) on phosphatidylcholine (PC), we observed that dehydration of Soy-PL is critical. PUFA-incorporation in PLs increased with acyl ratio and time. Finally, maximum PUFA-incorporation (47.1 +/- 2.1 wt%) was obtained using the following reaction conditions: 2.0 mmol of Soy-PL, a PUFA-Et/Soy-PL acyl ratio of 7, 13 mL of hexane, 2.2 * 10(5) U of lipase OF, 500 rpm of agitation, a temperature of 37 degrees C, and 72 h of reaction time. The analysis of fatty acid composition at the sn-2 position of obtained PL revealed that PUFAs incorporated into Soy-PL localized to the sn-2 position of the PL molecule in spite of using lipase OF whose positional specificity is random for triacylglycerol. PMID- 25452266 TI - Lowering effect of firefly squid powder on triacylglycerol content and glucose-6 phosphate dehydrogenase activity in rat liver. AB - Effects of dietary firefly squid on serum and liver lipid levels were investigated. Male Wistar rats were fed a diet containing 5% freeze-dried firefly squid or Japanese flying squid for 2 weeks. There was no significant difference in the liver triacylglycerol level between the control and Japanese flying squid groups, but the rats fed the firefly squid diet had a significantly lower liver triacylglycerol content than those fed the control diet. No significant difference was observed in serum triacylglycerol levels between the control and firefly squid groups. The rats fed the firefly squid had a significantly lower activity of liver glucose-6-phosphate dehydrogenase compared to the rats fed the control diet. There was no significant difference in liver fatty acid synthetase activity among the three groups. Hepatic gene expression and lipogenic enzyme activity were investigated; a DNA microarray showed that the significantly enriched gene ontology category of down-regulated genes in the firefly squid group was "lipid metabolic process". The firefly squid group had lower mRNA level of glucose-6-phosphate dehydrogenase compared to the controls. These results suggest that an intake of firefly squid decreases hepatic triacylglycerol in rats, and the reduction of mRNA level and enzyme activity of glucose-6-phosphate dehydrogenase might be related to the mechanisms. PMID- 25452267 TI - Development of new mineral oil-based antifoams containing size-controlled hydrophobic silica particles for gloss paints. AB - Water-based architectural paints commonly contain either mineral oil-based or silicone-based antifoams. Mineral oil-based antifoams generally reduce the gloss of paint films; thus, silicone-based antifoams are mainly used in the field of architectural paints. The relationship between the antifoaming performance and the particle size of hydrophobic silica for mineral oil-based antifoams was investigated and a novel mineral oil-based antifoam that provided a glossy surface to the paint films equivalent to the surface obtained with silicone-based antifoams and with excellent antifoaming performance compared to silicone-based antifoams was developed. The novel mineral oil-based antifoam exhibits better performance than silicon-based antifoam, and thus the former is a perfect alternative to the latter for use in architectural paints. PMID- 25452268 TI - Physicochemical and structural properties of glycerin gel prepared using glycyrrhizic acid diethyl ester. AB - Glycyrrhizic acid diethyl ester (GZ-DE) was developed as a prodrug of glycyrrhizic acid (GZ), a hepatitis therapeutic drug. We fortuitously found that GZ-DE gels with glycerin selectively while searching for a safe solvent with which to dissolve GZ-DE. Based on this gelation, the aim of this study was to investigate the preparation of the gel and study the rheology, physicochemical and structural properties of the glycerin gel by differential scanning calorimeter (DSC), capillary electrophoresis (CEP), nuclear magnetic resonance (NMR), and small angle X-ray scattering (SAXS). The glycerin gel was prepared by the addition of at least 2.0% w/w GZ-DE. This gel did not flow at room temperature. After mixing glycerin and GZ-DE, a gel was formed after 2 days at 25 degrees C or 3 h at 60 degrees C. Glycerin gel containing 2.4% w/w GZ-DE provided the following results: 1) The glycerin gel exhibited creep at a constant stress of less than 10 Pa, but it is a fragile gel, showing Newtonian flow at 10 Pa stress. 2) Dynamic viscoelastic measurements showed that the elastic modulus (G') exceeds the viscous modulus (G''), indicating that glycerin gel has solid-like properties. 3) DSC showed a significant difference between the glass transition temperature of glycerin and glycerin gel. 4) CEP did not reveal a new compound in the glycerin gel. 5) NMR confirmed that glycerin gel is a physical gel. 6) SAXS measurements revealed that the glycerin gel has an oval-shaped basic frame (119 nm long and 65 nm wide). PMID- 25452269 TI - Curcumin ameliorates renal fibrosis by inhibiting local fibroblast proliferation and extracellular matrix deposition. AB - Renal fibrosis is mainly characterized by activation and proliferation of interstitial fibroblasts and by excessive synthesis and accumulation of extracellular matrix (ECM) components, including fibronectin (FN) and collagen. This study investigated the effects of curcumin on proliferation of renal interstitial fibroblasts and their underlying mechanisms in vivo and in vitro. ECM components were visualized by Sirius red and immunohistochemistry staining and quantified by western blot analysis in mice with unilateral ureteral obstruction (UUO). Duplex staining for proliferating cell nuclear antigen and alpha-smooth muscle actin (alpha-SMA), as well as MTT and flow cytometry assays, were performed to measure fibroblast proliferation. Protein expression of phosphorylated Smad2/3 (p-Smad2/3) and peroxisome proliferator-activated receptor gamma (PPAR-gamma) were assessed by western blotting. Curcumin treatment decreased the accumulation of type I collagen and FN in the kidney of animals with UUO. Activation of rat renal interstitial fibroblasts (NRK-49F) was induced by TGF-beta1. Curcumin treatment inhibited fibroblast proliferation and the cell cycle was arrested in the G1 phase. Curcumin treatment upregulated the expression of PPAR-gamma and downregulated the expression of p-Smad2/3. These results suggest that curcumin treatment ameliorates renal fibrosis by reducing fibroblast proliferation and ECM accumulation mediated by PPAR-gamma and Smad-dependent TGF beta1 signaling. PMID- 25452271 TI - Differential spatial and structural organization of the X chromosome underlies dosage compensation in C. elegans. AB - The adjustment of X-linked gene expression to the X chromosome copy number (dosage compensation [DC]) has been widely studied as a model of chromosome-wide gene regulation. In Caenorhabditis elegans, DC is achieved by twofold down regulation of gene expression from both Xs in hermaphrodites. We show that in males, the single X chromosome interacts with nuclear pore proteins, while in hermaphrodites, the DC complex (DCC) impairs this interaction and alters X localization. Our results put forward a structural model of DC in which X specific sequences locate the X chromosome in transcriptionally active domains in males, while the DCC prevents this in hermaphrodites. PMID- 25452272 TI - The evolution of thymic lymphomas in p53 knockout mice. AB - Germline deletion of the p53 gene in mice gives rise to spontaneous thymic (T cell) lymphomas. In this study, the p53 knockout mouse was employed as a model to study the mutational evolution of tumorigenesis. The clonality of the T-cell repertoire from p53 knockout and wild-type thymic cells was analyzed at various ages employing TCRbeta sequencing. These data demonstrate that p53 knockout thymic lymphomas arose in an oligoclonal fashion, with tumors evolving dominant clones over time. Exon sequencing of tumor DNA revealed that all of the independently derived oligoclonal mouse tumors had a deletion in the Pten gene prior to the formation of the TCRbeta rearrangement, produced early in development. This was followed in each independent clone of the thymic lymphoma by the amplification or overexpression of cyclin Ds and Cdk6. Alterations in the expression of Ikaros were common and blocked further development of CD-4/CD-8 T cells. While the frequency of point mutations in the genome of these lymphomas was one per megabase, there were a tremendous number of copy number variations producing the tumors' driver mutations. The initial inherited loss of p53 functions appeared to delineate an order of genetic alterations selected for during the evolution of these thymic lymphomas. PMID- 25452270 TI - So many pieces, one puzzle: cell type specification and visual circuitry in flies and mice. AB - The visual system is a powerful model for probing the development, connectivity, and function of neural circuits. Two genetically tractable species, mice and flies, are together providing a great deal of understanding of these processes. Current efforts focus on integrating knowledge gained from three cross-fostering fields of research: (1) understanding how the fates of different cell types are specified during development, (2) revealing the synaptic connections between identified cell types ("connectomics") by high-resolution three-dimensional circuit anatomy, and (3) causal testing of how identified circuit elements contribute to visual perception and behavior. Here we discuss representative examples from fly and mouse models to illustrate the ongoing success of this tripartite strategy, focusing on the ways it is enhancing our understanding of visual processing and other sensory systems. PMID- 25452273 TI - Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110alpha. AB - Increased PI 3-kinase (PI3K) signaling in pancreatic ductal adenocarcinoma (PDAC) correlates with poor prognosis, but the role of class I PI3K isoforms during its induction remains unclear. Using genetically engineered mice and pharmacological isoform-selective inhibitors, we found that the p110alpha PI3K isoform is a major signaling enzyme for PDAC development induced by a combination of genetic and nongenetic factors. Inactivation of this single isoform blocked the irreversible transition of exocrine acinar cells into pancreatic preneoplastic ductal lesions by oncogenic Kras and/or pancreatic injury. Hitting the other ubiquitous isoform, p110beta, did not prevent preneoplastic lesion initiation. p110alpha signaling through small GTPase Rho and actin cytoskeleton controls the reprogramming of acinar cells and regulates cell morphology in vivo and in vitro. Finally, p110alpha was necessary for pancreatic ductal cancers to arise from Kras-induced preneoplastic lesions by increasing epithelial cell proliferation in the context of mutated p53. Here we identify an in vivo context in which p110alpha cellular output differs depending on the epithelial transformation stage and demonstrate that the PI3K p110alpha is required for PDAC induced by oncogenic Kras, the key driver mutation of PDAC. These data are critical for a better understanding of the development of this lethal disease that is currently without efficient treatment. PMID- 25452274 TI - Production of systemically circulating Hedgehog by the intestine couples nutrition to growth and development. AB - In Drosophila larvae, growth and developmental timing are regulated by nutrition in a tightly coordinated fashion. The networks that couple these processes are far from understood. Here, we show that the intestine responds to nutrient availability by regulating production of a circulating lipoprotein-associated form of the signaling protein Hedgehog (Hh). Levels of circulating Hh tune the rates of growth and developmental timing in a coordinated fashion. Circulating Hh signals to the fat body to control larval growth. It regulates developmental timing by controlling ecdysteroid production in the prothoracic gland. Circulating Hh is especially important during starvation, when it is also required for mobilization of fat body triacylglycerol (TAG) stores. Thus, we demonstrate that Hh, previously known only for its local morphogenetic functions, also acts as a lipoprotein-associated endocrine hormone, coordinating the response of multiple tissues to nutrient availability. PMID- 25452275 TI - Structural basis of X chromosome DNA recognition by the MSL2 CXC domain during Drosophila dosage compensation. AB - The male-specific lethal dosage compensation complex (MSL-DCC) selectively assembles on the X chromosome in Drosophila males and activates gene transcription by twofold through histone acetylation. An MSL recognition element (MRE) sequence motif nucleates the initial MSL association, but how it is recognized remains unknown. Here, we identified the CXC domain of MSL2 specifically recognizing the MRE motif and determined its crystal structure bound to specific and nonspecific DNAs. The CXC domain primarily contacts one strand of DNA duplex and employs a single arginine to directly read out dinucleotide sequences from the minor groove. The arginine is flexible when bound to nonspecific sequences. The core region of the MRE motif harbors two binding sites on opposite strands that can cooperatively recruit a CXC dimer. Specific DNA binding mutants of MSL2 are impaired in MRE binding and X chromosome localization in vivo. Our results reveal multiple dynamic DNA-binding modes of the CXC domain that target the MSL-DCC to X chromosomes. PMID- 25452276 TI - Pre-mRNA splicing is facilitated by an optimal RNA polymerase II elongation rate. AB - Alternative splicing modulates expression of most human genes. The kinetic model of cotranscriptional splicing suggests that slow elongation expands and that fast elongation compresses the "window of opportunity" for recognition of upstream splice sites, thereby increasing or decreasing inclusion of alternative exons. We tested the model using RNA polymerase II mutants that change average elongation rates genome-wide. Slow and fast elongation affected constitutive and alternative splicing, frequently altering exon inclusion and intron retention in ways not predicted by the model. Cassette exons included by slow and excluded by fast elongation (type I) have weaker splice sites, shorter flanking introns, and distinct sequence motifs relative to "slow-excluded" and "fast-included" exons (type II). Many rate-sensitive exons are misspliced in tumors. Unexpectedly, slow and fast elongation often both increased or both decreased inclusion of a particular exon or retained intron. These results suggest that an optimal rate of transcriptional elongation is required for normal cotranscriptional pre-mRNA splicing. PMID- 25452278 TI - Use of an endogenous plasmid locus for stable in trans complementation in Borrelia burgdorferi. AB - Targeted mutagenesis and complementation are important tools for studying genes of unknown function in the Lyme disease spirochete Borrelia burgdorferi. A standard method of complementation is reintroduction of a wild-type copy of the targeted gene on a shuttle vector. However, shuttle vectors are present at higher copy numbers than B. burgdorferi plasmids and are potentially unstable in the absence of selection, thereby complicating analyses in the mouse-tick infectious cycle. B. burgdorferi has over 20 plasmids, with some, such as linear plasmid 25 (lp25), carrying genes required by the spirochete in vivo but relatively unstable during in vitro cultivation. We propose that complementation on an endogenous plasmid such as lp25 would overcome the copy number and in vivo stability issues of shuttle vectors. In addition, insertion of a selectable marker on lp25 could ensure its stable maintenance by spirochetes in culture. Here, we describe the construction of a multipurpose allelic-exchange vector containing a multiple cloning site and either of two selectable markers. This suicide vector directs insertion of the complementing gene into the bbe02 locus, a site on lp25 that was previously shown to be nonessential during both in vitro and in vivo growth. We demonstrate the functional utility of this strategy by restoring infectivity to an ospC mutant through complementation at this site on lp25 and stable maintenance of the ospC gene throughout mouse infection. We conclude that this represents a convenient and widely applicable method for stable gene complementation in B. burgdorferi. PMID- 25452279 TI - Passage of Wolbachia pipientis through mutant drosophila melanogaster induces phenotypic and genomic changes. AB - Wolbachia pipientis is a nearly ubiquitous, maternally transmitted bacterium that infects the germ line of insect hosts. Estimates are that Wolbachia infects 40 to 60% of insect species on the planet, making it one of the most prevalent infections on Earth. However, we know surprisingly little about the molecular mechanisms used by Wolbachia to infect its hosts. We passaged Wolbachia through normally restrictive Drosophila melanogaster hosts, bottlenecking Wolbachia through stochastic segregation while simultaneously selecting for mutants that could recolonize these previously restrictive hosts. Here, we show that Wolbachia alters its behavior when passaged through heterozygous mutant flies. After only three generations, Wolbachia was able to colonize the previously restrictive hosts at control titers. Additionally, the Wolbachia organisms passaged through heterozygous mutant D. melanogaster alter their pattern of tissue-specific Wsp protein production, suggesting a behavioral response to the host genotype. Using whole-genome resequencing, we identified the mutations accumulated by these lineages of Wolbachia and confirmed the existence and persistence of the mutations through clone library Sanger sequencing. Our results suggest that Wolbachia can quickly adapt to new host contexts, with genomic mutants arising after only two generations. PMID- 25452280 TI - The role of host phylogeny varies in shaping microbial diversity in the hindguts of lower termites. AB - The hindguts of lower termites and Cryptocercus cockroaches are home to a distinct community of archaea, bacteria, and protists (primarily parabasalids and some oxymonads). Within a host species, the composition of these hindgut communities appears relatively stable, but the evolutionary and ecological factors structuring community composition and stability are poorly understood, as are differential impacts of these factors on protists, bacteria, and archaea. We analyzed the microbial composition of parabasalids and bacteria in the hindguts of Cryptocercus punctulatus and 23 species spanning 4 families of lower termites by pyrosequencing variable regions of the small-subunit rRNA gene. Especially for the parabasalids, these data revealed undiscovered taxa and provided a phylogenetic basis for a more accurate understanding of diversity, diversification, and community composition. The composition of the parabasalid communities was found to be strongly structured by the phylogeny of their hosts, indicating the importance of historical effects, although exceptions were also identified. Particularly, spirotrichonymphids and trichonymphids likely were transferred between host lineages. In contrast, host phylogeny was not sufficient to explain the majority of bacterial community composition, but the compositions of the Bacteroidetes, Elusimicrobia, Tenericutes, Spirochaetes, and Synergistes were structured by host phylogeny perhaps due to their symbiotic associations with protists. All together, historical effects probably resulting from vertical inheritance have had a prominent role in structuring the hindgut communities, especially of the parabasalids, but dispersal and environmental acquisition have played a larger role in community composition than previously expected. PMID- 25452281 TI - High-resolution taxonomic profiling of the subgingival microbiome for biomarker discovery and periodontitis diagnosis. AB - The oral microbiome plays a key role for caries, periodontitis, and systemic diseases. A method for rapid, high-resolution, robust taxonomic profiling of subgingival bacterial communities for early detection of periodontitis biomarkers would therefore be a useful tool for individualized medicine. Here, we used Illumina sequencing of the V1-V2 and V5-V6 hypervariable regions of the 16S rRNA gene. A sample stratification pipeline was developed in a pilot study of 19 individuals, 9 of whom had been diagnosed with chronic periodontitis. Five hundred twenty-three operational taxonomic units (OTUs) were obtained from the V1 V2 region and 432 from the V5-V6 region. Key periodontal pathogens like Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia could be identified at the species level with both primer sets. Principal coordinate analysis identified two outliers that were consistently independent of the hypervariable region and method of DNA extraction used. The linear discriminant analysis (LDA) effect size algorithm (LEfSe) identified 80 OTU-level biomarkers of periodontitis and 17 of health. Health- and periodontitis-related clusters of OTUs were identified using a connectivity analysis, and the results confirmed previous studies with several thousands of samples. A machine learning algorithm was developed which was trained on all but one sample and then predicted the diagnosis of the left-out sample (jackknife method). Using a combination of the 10 best biomarkers, 15 of 17 samples were correctly diagnosed. Training the algorithm on time-resolved community profiles might provide a highly sensitive tool to detect the onset of periodontitis. PMID- 25452282 TI - Substrate-induced radical formation in 4-hydroxybutyryl coenzyme A dehydratase from Clostridium aminobutyricum. AB - 4-Hydroxybutyryl-coenzyme A (CoA) dehydratase (4HBD) from Clostridium aminobutyricum catalyzes the reversible dehydration of 4-hydroxybutyryl-CoA to crotonyl-CoA and the irreversible isomerization of vinylacetyl-CoA to crotonyl CoA. 4HBD is an oxygen-sensitive homotetrameric enzyme with one [4Fe-4S](2+) cluster and one flavin adenine dinucleotide (FAD) in each subunit. Upon the addition of crotonyl-CoA or the analogues butyryl-CoA, acetyl-CoA, and CoA, UV visible light and electron paramagnetic resonance (EPR) spectroscopy revealed an internal one-electron transfer to FAD and the [4Fe-4S](2+) cluster prior to hydration. We describe an active recombinant 4HBD and variants produced in Escherichia coli. The variants of the cluster ligands (H292C [histidine at position 292 is replaced by cysteine], H292E, C99A, C103A, and C299A) had no measurable dehydratase activity and were composed of monomers, dimers, and tetramers. Variants of other potential catalytic residues were composed only of tetramers and exhibited either no measurable (E257Q, E455Q, and Y296W) hydratase activity or <1% (Y296F and T190V) dehydratase activity. The E455Q variant but not the Y296F or E257Q variant displayed the same spectral changes as the wild-type enzyme after the addition of crotonyl-CoA but at a much lower rate. The results suggest that upon the addition of a substrate, Y296 is deprotonated by E455 and reduces FAD to FADH., aided by protonation from E257 via T190. In contrast to FADH., the tyrosyl radical could not be detected by EPR spectroscopy. FADH. appears to initiate the radical dehydration via an allylic ketyl radical that was proposed 19 years ago. The mode of radical generation in 4HBD is without precedent in anaerobic radical chemistry. It differs largely from that in enzymes, which use coenzyme B12, S-adenosylmethionine, ATP-driven electron transfer, or flavin-based electron bifurcation for this purpose. PMID- 25452283 TI - Identification of a wide range of motifs inhibitory to shiga toxin by affinity driven screening of customized divalent peptides synthesized on a membrane. AB - Shiga toxin (Stx), a major virulence factor of enterohemorrhagic Escherichia coli, binds to target cells through a multivalent interaction between its B subunit pentamer and the cell surface receptor globotriaosylceramide, resulting in a remarkable increase in its binding affinity. This phenomenon is referred to as the "clustering effect." Previously, we developed a multivalent peptide library that can exert the clustering effect and identified Stx neutralizers with tetravalent peptides by screening this library for high-affinity binding to the specific receptor-binding site of the B subunit. However, this technique yielded only a limited number of binding motifs, with some redundancy in amino acid selectivity. In this study, we established a novel technique to synthesize up to 384 divalent peptides whose structures were customized to exert the clustering effect on the B subunit on a single cellulose membrane. By targeting Stx1a, a major Stx subtype, the customized divalent peptides were screened to identify high-affinity binding motifs. The sequences of the peptides were designed based on information obtained from the multivalent peptide library technique. A total of 64 candidate motifs were successfully identified, and 11 of these were selected to synthesize tetravalent forms of the peptides. All of the synthesized tetravalent peptides bound to the B subunit with high affinities and effectively inhibited the cytotoxicity of Stx1a in Vero cells. Thus, the combination of the two techniques results in greatly improved efficiency in identifying biologically active neutralizers of Stx. PMID- 25452284 TI - Burkholderia cepacia complex Phage-Antibiotic Synergy (PAS): antibiotics stimulate lytic phage activity. AB - The Burkholderia cepacia complex (Bcc) is a group of at least 18 species of Gram negative opportunistic pathogens that can cause chronic lung infection in cystic fibrosis (CF) patients. Bcc organisms possess high levels of innate antimicrobial resistance, and alternative therapeutic strategies are urgently needed. One proposed alternative treatment is phage therapy, the therapeutic application of bacterial viruses (or bacteriophages). Recently, some phages have been observed to form larger plaques in the presence of sublethal concentrations of certain antibiotics; this effect has been termed phage-antibiotic synergy (PAS). Those reports suggest that some antibiotics stimulate increased production of phages under certain conditions. The aim of this study is to examine PAS in phages that infect Burkholderia cenocepacia strains C6433 and K56-2. Bcc phages KS12 and KS14 were tested for PAS, using 6 antibiotics representing 4 different drug classes. Of the antibiotics tested, the most pronounced effects were observed for meropenem, ciprofloxacin, and tetracycline. When grown with subinhibitory concentrations of these three antibiotics, cells developed a chain-like arrangement, an elongated morphology, and a clustered arrangement, respectively. When treated with progressively higher antibiotic concentrations, both the sizes of plaques and phage titers increased, up to a maximum. B. cenocepacia K56-2 infected Galleria mellonella larvae treated with phage KS12 and low-dose meropenem demonstrated increased survival over controls treated with KS12 or antibiotic alone. These results suggest that antibiotics can be combined with phages to stimulate increased phage production and/or activity and thus improve the efficacy of bacterial killing. PMID- 25452285 TI - The zeamine antibiotics affect the integrity of bacterial membranes. AB - The zeamines (zeamine, zeamine I, and zeamine II) constitute an unusual class of cationic polyamine-polyketide-nonribosomal peptide antibiotics produced by Serratia plymuthica RVH1. They exhibit potent bactericidal activity, killing a broad range of Gram-negative and Gram-positive bacteria, including multidrug resistant pathogens. Examination of their specific mode of action and molecular target revealed that the zeamines affect the integrity of cell membranes. The zeamines provoke rapid release of carboxyfluorescein from unilamellar vesicles with different phospholipid compositions, demonstrating that they can interact directly with the lipid bilayer in the absence of a specific target. DNA, RNA, fatty acid, and protein biosynthetic processes ceased simultaneously at subinhibitory levels of the antibiotics, presumably as a direct consequence of membrane disruption. The zeamine antibiotics also facilitated the uptake of small molecules, such as 1-N-phenylnaphtylamine, indicating their ability to permeabilize the Gram-negative outer membrane (OM). The valine-linked polyketide moiety present in zeamine and zeamine I was found to increase the efficiency of this process. In contrast, translocation of the large hydrophilic fluorescent peptidoglycan binding protein PBDKZ-GFP was not facilitated, suggesting that the zeamines cause subtle perturbation of the OM rather than drastic alterations or defined pore formation. At zeamine concentrations above those required for growth inhibition, membrane lysis occurred as indicated by time-lapse microscopy. Together, these findings show that the bactericidal activity of the zeamines derives from generalized membrane permeabilization, which likely is initiated by electrostatic interactions with negatively charged membrane components. PMID- 25452286 TI - Effect of proximity to a cattle feedlot on Escherichia coli O157:H7 contamination of leafy greens and evaluation of the potential for airborne transmission. AB - The impact of proximity to a beef cattle feedlot on Escherichia coli O157:H7 contamination of leafy greens was examined. In each of 2 years, leafy greens were planted in nine plots located 60, 120, and 180 m from a cattle feedlot (3 plots at each distance). Leafy greens (270) and feedlot manure samples (100) were collected six different times from June to September in each year. Both E. coli O157:H7 and total E. coli bacteria were recovered from leafy greens at all plot distances. E. coli O157:H7 was recovered from 3.5% of leafy green samples per plot at 60 m, which was higher (P < 0.05) than the 1.8% of positive samples per plot at 180 m, indicating a decrease in contamination as distance from the feedlot was increased. Although E. coli O157:H7 was not recovered from air samples at any distance, total E. coli was recovered from air samples at the feedlot edge and all plot distances, indicating that airborne transport of the pathogen can occur. Results suggest that risk for airborne transport of E. coli O157:H7 from cattle production is increased when cattle pen surfaces are very dry and when this situation is combined with cattle management or cattle behaviors that generate airborne dust. Current leafy green field distance guidelines of 120 m (400 feet) may not be adequate to limit the transmission of E. coli O157:H7 to produce crops planted near concentrated animal feeding operations. Additional research is needed to determine safe set-back distances between cattle feedlots and crop production that will reduce fresh produce contamination. PMID- 25452287 TI - Mycofumigation by the volatile organic compound-producing Fungus Muscodor albus induces bacterial cell death through DNA damage. AB - Muscodor albus belongs to a genus of endophytic fungi that inhibit and kill other fungi, bacteria, and insects through production of a complex mixture of volatile organic compounds (VOCs). This process of mycofumigation has found commercial application for control of human and plant pathogens, but the mechanism of the VOC toxicity is unknown. Here, the mode of action of these volatiles was investigated through a series of genetic screens and biochemical assays. A single gene knockout screen revealed high sensitivity for Escherichia coli lacking enzymes in the pathways of DNA repair, DNA metabolic process, and response to stress when exposed to the VOCs of M. albus. Furthermore, the sensitivity of knockouts involved in the repair of specific DNA alkyl adducts suggests that the VOCs may induce alkylation. Evidence of DNA damage suggests that these adducts lead to breaks during DNA replication or transcription if not properly repaired. Additional cytotoxicity profiling indicated that during VOC exposure, E. coli became filamentous and demonstrated an increase in cellular membrane fluidity. The volatile nature of the toxic compounds produced by M. albus and their broad range of inhibition make this fungus an attractive biological agent. Understanding the antimicrobial effects and the VOC mode of action will inform the utility and safety of potential mycofumigation applications for M. albus. PMID- 25452288 TI - Development of a matrix tool for the prediction of Vibrio species in oysters harvested from North Carolina. AB - The United States has federal regulations in place to reduce the risk of seafood related infection caused by the estuarine bacteria Vibrio vulnificus and Vibrio parahaemolyticus. However, data to support the development of regulations have been generated in a very few specific regions of the nation. More regionally specific data are needed to further understand the dynamics of human infection relating to shellfish-harvesting conditions in other areas. In this study, oysters and water were collected from four oyster harvest sites in North Carolina over an 11-month period. Samples were analyzed for the abundances of total Vibrio spp., V. vulnificus, and V. parahaemolyticus; environmental parameters, including salinity, water temperature, wind velocity, and precipitation, were also measured simultaneously. By utilizing these data, preliminary predictive management tools for estimating the abundance of V. vulnificus bacteria in shellfish were developed. This work highlights the need for further research to elucidate the full suite of factors that drive V. parahaemolyticus abundance. PMID- 25452289 TI - Discovery of two novel viruses expands the diversity of single-stranded DNA and single-stranded RNA viruses infecting a cosmopolitan marine diatom. AB - Recent studies have suggested that diatom viruses are an important factor affecting diatom population dynamics, which in turn are important in considering marine primary productivity. The marine planktonic diatom Chaetoceros tenuissimus Meunier is a cosmopolitan species and often causes blooms off the western coast of Japan. To date, two viruses, C. tenuissimus DNA virus (CtenDNAV) type I and CtenRNAV type I, have been identified that potentially affect C. tenuissimus population dynamics in the natural environment. In this study, we successfully isolated and characterized two additional novel viruses (CtenDNAV type II and CtenRNAV type II). This paper reports the basic characteristics of these new viruses isolated from surface water or sediment from the Hiroshima Bay, Japan. The physiological and morphological characteristics of the two new viruses were similar to those of the previously isolated viruses. However, the amino acid sequences of the structural proteins of CtenDNAV type II and CtenRNAV type II were clearly distinct from those of both type I viruses, with identity scores of 38.3% and 27.6%, respectively. Our results suggest that at least four genetically distinct viruses sharing the same diatom host are present in western Japan and affect the population dynamics of C. tenuissimus. Moreover, the result that CtenRNAV type II lysed multiple diatom species indicates that RNA viruses may affect various diatom populations in the natural environment. PMID- 25452290 TI - Inactivation of murine norovirus on a range of copper alloy surfaces is accompanied by loss of capsid integrity. AB - Norovirus is one of the most common causes of acute viral gastroenteritis. The virus is spread via the fecal-oral route, most commonly from infected food and water, but several outbreaks have originated from contamination of surfaces with infectious virus. In this study, a close surrogate of human norovirus causing gastrointestinal disease in mice, murine norovirus type 1 (MNV-1), retained infectivity for more than 2 weeks following contact with a range of surface materials, including Teflon (polytetrafluoroethylene [PTFE]), polyvinyl chloride (PVC), ceramic tiles, glass, silicone rubber, and stainless steel. Persistence was slightly prolonged on ceramic surfaces. A previous study in our laboratory observed that dry copper and copper alloy surfaces rapidly inactivated MNV-1 and destroyed the viral genome. In this new study, we have observed that a relatively small change in the percentage of copper, between 70 and 80% in copper nickels and 60 and 70% in brasses, had a significant influence on the ability of the alloy to inactivate norovirus. Nickel alone did not affect virus, but zinc did have some antiviral effect, which was synergistic with copper and resulted in an increased efficacy of brasses with lower percentages of copper. Electron microscopy of purified MNV-1 that had been exposed to copper and stainless steel surfaces suggested that a massive breakdown of the viral capsid had occurred on copper. In addition, MNV-1 that had been exposed to copper and treated with RNase demonstrated a reduction in viral gene copy number. This suggests that capsid integrity is compromised upon contact with copper, allowing copper ion access to the viral genome. PMID- 25452291 TI - CIP10 optimization for 4,4-methylene diphenyl diisocyanate aerosol sampling and field comparison with impinger method. AB - 4,4-methylene diphenyl diisocyanate (MDI) aerosol exposure evaluation in spray foam insulation application is known as being a challenge because the spray foam application actually involves a fast-curing process. Available techniques are either not user-friendly or are inaccurate or not validated for this application. To address these issues, a new approach using a CIP10M was developed to appropriately collect MDI aerosol in spray foam insulation while being suitable for personal sampling. The CIP10M is a commercially available personal aerosol sampler that has been validated for the collection of microbial spores into a liquid medium. Tributylphosphate with 1-(2-methoxyphenyl)piperazine (MOPIP) was introduced into the CIP10M to collect and stabilize the MDI aerosols. The limit of detection and limit of quantification of the method were 0.007 and 0.024 MUg ml(-1), respectively. The dynamic range was from 0.024 to 0.787 MUg ml(-1) (with R (2) >= 0.990), which corresponds to concentrations in the air from 0.04 to 1.3 ug m(-3), assuming 60 min of sampling at 10 l min(-1). The intraday and interday analytical precisions were <2% for all of the concentration levels tested, and the accuracy was within an appropriate range of 98 +/- 1%. No matrix effect was observed, and a total recovery of 99% was obtained. Parallel sampling was performed in a real MDI foam spraying environment with a CIP10M and impingers containing toluene/MOPIP (reference method). The results obtained show that the CIP10M provides levels of MDI monomer in the same range as the impingers, and higher levels of MDI oligomers. The negative bias observed for MDI monomer was between 2 and 26%, whereas the positive bias observed for MDI oligomers was between 76 and 113%, with both biases calculated with a confidence level of 95%. The CIP10M seems to be a promising approach for MDI aerosol exposure evaluation in spray foam applications. PMID- 25452292 TI - Protection efficacy of gloves against components of the solvent in a sprayed isocyanate coating utilizing a reciprocating permeation panel. AB - OBJECTIVES: Determine protection effectiveness of 5-mil natural rubber latex (0.13-mm), 5-mil nitrile rubber (0.13-mm), and 13-mil butyl rubber (0.33-mm) glove materials against solvents present in a commonly used automotive clear coat formulation using a novel permeation panel. The latex and nitrile gloves were the type commonly used by local autobody spray painters. METHODS: Glove materials were tested by spraying an automotive clear coat onto an automated reciprocating permeation panel (permeation panel II). Temperature, relative humidity, and spray conditions were controlled to optimize clear coat loading homogeneity as evaluated by gravimetric analysis. Solvent permeation was measured using charcoal cloth analyzed by the National Institute for Occupational Safety and Health 1501 method. RESULTS: Natural rubber latex allowed 3-5 times the permeation of solvents relative to nitrile rubber for all 10 solvents evaluated: ethyl benzene, 2-heptanone, 1-methoxy-2-propyl acetate, o-xylene, m-xylene, p-xylene, n-butyl acetate, methyl isobutyl ketone, petroleum distillates, and toluene. There is a distinct behavior in solvent permeation before and after the coating dry time. Solvent permeation increased steadily before coating dry time and remained fairly constant after coating dry time. Butyl was not permeated by any of the solvents under the conditions tested. CONCLUSIONS: Commonly used 5-mil thick (0.13-mm) latex and nitrile gloves were ineffective barriers to solvents found in a commonly used clear coat formulation. Conversely, 13-mil (0.33-mm) butyl gloves were found to be protective against all solvents in the clear coat formulation. PMID- 25452293 TI - Evaluation of exposure to airborne heavy metals at gun shooting ranges. AB - Aerosols formed during shooting events were studied with various techniques including the wide range size resolving sampling system Nano-ID((r)) Select, followed by inductively coupled plasma mass spectrometry chemical analysis, scanning electron microscopy, and fast mobility particle sizing. The total lead mass aerosol concentration ranged from 2.2 to 72 ug m(-3). It was shown that the mass concentration of the most toxic compound lead is much lower than the total mass concentration. The deposition fraction in various compartments of the respiratory system was calculated using the ICRP lung deposition model. It was found that the deposition fraction in the alveolar range varies by a factor >3 for the various aerosols collected, depending on the aerosol size distribution and total aerosol concentration, demonstrating the importance of size resolved sampling in health risk evaluation. The proportion of the total mass of airborne particles deposited in the respiratory tract varies from 34 to 70%, with a median of 55.9%, suggesting the health risk based upon total mass significantly overestimates the accumulated dose and therefore the health risk. A comparison between conventional and so called 'green' ammunition confirmed significant lowering of concentrations of lead and other toxic metals like antimony in the atmosphere of indoor shooting ranges using 'green' ammunition, although higher concentrations of manganese and boron were measured. These metals are likely to be the constituents of new types of primers. They occur predominantly in the size fraction <250 nm of aerosols. PMID- 25452294 TI - The challenges of human population ageing. AB - The 20th century saw an unprecedented increase in average human lifespan as well as a rapid decline in human fertility in many countries of the world. The accompanying worldwide change in demographics of human populations is linked to unanticipated and unprecedented economic, cultural, medical, social, public health and public policy challenges, whose full implications on a societal level are only just beginning to be fully appreciated. Some of these implications are discussed in this commentary, an outcome of Cultures of Health and Ageing, a conference co-sponsored by the University of Copenhagen (UCPH) and the Center for Healthy Ageing at UCPH, which took place on 20-21 June 2014 in Copenhagen, Denmark. Questions discussed here include the following: what is driving age structural change in human populations? how can we create 'age-friendly' societies and promote 'ageing-in-community'? what tools will effectively promote social engagement and prevent social detachment among older individuals? is there a risk that further extension of human lifespan would be a greater burden to the individual and to society than is warranted by the potential benefit of longer life? PMID- 25452296 TI - Elevated serum erythropoietin in a patient with polycythaemia vera presenting with Budd-Chiari syndrome. AB - Polycythaemia vera (PV) is a clonal disorder of bone marrow stem cells characterised by erythrocytosis. Diagnosis of PV requires exclusion of secondary causes of polycythaemia. It has been held that an elevated erythropoietin (Epo) level strongly indicates secondary erythrocytosis and excludes PV diagnosis, to the extent that the reduced serum Epo level is currently listed as a minor criterion in the WHO classification scheme for PV. However, patients with PV who co-present with Budd-Chiari syndrome have been documented with elevated serum Epo levels. For these patients, identification of the Janus kinase 2 (JAK2) V617F point mutation along with the transient nature of the Epo elevation provides certainty of PV diagnosis, as illustrated by the proband. In this case report, the patient's positive response to cytoreductive therapy (hydroxyurea 500 mg daily) and phlebotomy (750 mL over three phlebotomies) further supports validity of PV diagnosis with elevated Epo. The patient remains on rivaroxaban (Xarelto) for treatment of her portal vein thrombosis. PMID- 25452297 TI - Complete tamponade system for management of severe postpartum vaginal haemorrhage due to uterine atony. AB - A 30-year-old, 39 weeks pregnant, multiparous woman with single fetus, attended our obstetric clinic with complete cervical dilation in intractable mentum anterior presentation. The fetus was delivered by caesarean section with vertical uterine incision under general anaesthesia and lithotomy position. After surgery, examination of the vagina revealed multiple, serious tears with severe haemorrhage. Vaginal bleeding could not be controlled by sutures and concurrently uterine atony developed, which could not be controlled with medical treatment. Owing to intractable bleeding from uterus and vagina, a complete tamponade system was used. After the instillation of the uterine balloon with 500 mL and vaginal balloon with 300 mL liquid, the bleeding was controlled. The estimated blood loss was 3200 mL. The vaginal wound healed well during the postoperative 2 weeks. A complete tamponade system may be an effective treatment method for treatment of postpartum haemorrhage owing to vaginal lacerations and uterine atony. PMID- 25452298 TI - Empyema necessitatis due to Aspergillus fumigatus. AB - We present an extremely rare case of empyema necessitatis secondary to Aspergillus fumigatus infection. A 58-year-old woman presented to our hospital with a painful skin rash on the right thorax. Three fistulas communicating with the pleural space were found. Since she did not show a clinical improvement despite antituberculous and antibacterial treatment, we looked for other causes. Pleural fungus culture showed A. fumigatus and chest wall biopsy revealed numerous fungal hyphae. Treatment with necrotic tissue debridement and antifungal agents was successful. PMID- 25452299 TI - Fracture and migration into the coronary sinus of a totally implantable catheter introduced via the right internal jugular vein. AB - There has been an increase in the use of totally implantable devices. Catheter fractures are rare but known complications. This case report presents a rare migration site of the catheter fragment into the coronary sinus. The totally implantable catheter was introduced into the right internal jugular vein to deliver chemotherapy. Although it was an unusual site, the catheter fragment was removed without complications using loop-snare technique. PMID- 25452300 TI - Should Blood Pressure Targets After Lacunar Stroke Vary by Body Size? The SPS3 Trial. AB - BACKGROUND: It is unknown whether the physiological impact of a given blood pressure (BP) varies by body size. We explored interactions between higher vs. lower systolic BP (SBP) targets and anthropometric measures (body mass index (BMI), body surface area (BSA), height, weight) and recurrent stroke and death in the Secondary Prevention of Small Subcortical Strokes (SPS3) Trial. METHODS: Patients with recent magnetic resonance imaging-proven lacunar infarcts were randomized to 2 BP targets (130-149 mm Hg vs. <130) in a prospective, open-label, blinded end-point design. Time to outcome was evaluated with Cox proportional hazard models and compared between targets. We examined multiplicative interactions between each anthropometric measure and target and mean difference in achieved BP 1 year after randomization between BP groups by quartile. We also computed rates of recurrent stroke and death by quartiles of anthropometrics. RESULTS: Three thousand and twenty patients were followed over a mean of 3.7 (SD 2.0) years. Mean age was 63; 63% were male. Mean height was 167 (SD 11) cm, weight 81 (18) kg, BMI 29 (5.9) kg/m(2), and BSA 1.9 (0.25) m(2). Achieved BP at 1 year was comparable between quartiles for each anthropometric measurement. We found no consistent interactions between BP target and anthropometrics for either outcome, nor were there any significant associations between hazard of stroke or death when assessed by BMI, BSA, height, or weight. CONCLUSIONS: We found no interactions between BP target groups and quartiles of anthropometrics for rates of stroke and death in SPS3. There is no evidence at this time supporting body size-based modifications to current BP targets for secondary prevention after lacunar stroke. CLINICAL TRIALS REGISTRATION: Trial Number NCT00059306. PMID- 25452301 TI - Disruption of the ran system by cysteine oxidation of the nucleotide exchange factor RCC1. AB - Transport regulation by the Ran GTPase requires its nuclear localization and GTP loading by the chromatin-associated exchange factor RCC1. These reactions generate Ran protein and Ran nucleotide gradients between the nucleus and the cytoplasm. Cellular stress disrupts the Ran gradients, but the specific mechanisms underlying this disruption have not been elucidated. We used biochemical approaches to determine how oxidative stress disrupts the Ran system. RCC1 exchange activity was reduced by diamide-induced oxidative stress and restored with dithiothreitol. Using mass spectrometry, we found that multiple solvent-exposed cysteines in RCC1 are oxidized in cells treated with diamide. The cysteines oxidized in RCC1 included Cys93, which is solvent exposed and unique because it becomes buried upon contact with Ran. A Cys93Ser substitution dramatically reduced exchange activity through an effect on RCC1 binding to RanGDP. Diamide treatment reduced the size of the mobile fraction of RCC1-green fluorescent protein in cells and inhibited nuclear import in digitonin permeabilized cell assays. The Ran protein gradient was also disrupted by UV induced stress but without affecting RCC1 exchange activity. Our data suggest that stress can disrupt the Ran gradients through RCC1-dependent and RCC1 independent mechanisms, possibly dependent on the particular stress condition. PMID- 25452302 TI - Nedd8 regulates inflammasome-dependent caspase-1 activation. AB - Caspase-1 is activated by the inflammasome complex to process cytokines like interleukin-1beta (IL-1beta). Pro-caspase-1 consists of three domains, CARD, p20, and p10. Association of pro-caspase-1 with the inflammasome results in initiation of its autocatalytic activity, culminating in self-cleavage that generates catalytically active subunits (p10 and p20). In the current study, we show that Nedd8 is required for efficient self-cleavage of pro-caspase-1 to generate its catalytically active subunits. Nedd8 silencing or treating cells with the neddylation inhibitor MLN4924 led to diminished caspase-1 processing and reduced IL-1beta maturation following inflammasome activation. Coimmunoprecipitation and mass spectrometric analysis of 293 cells overexpressing pro-caspase-1 (and CARD) and Nedd8 suggested possible neddylation of caspase-1 CARD. Following inflammasome activation in primary macrophages, we observed colocalization of endogenous Nedd8 with caspase-1. Similarly, interaction of endogenous Nedd8 with caspase-1 CARD was detected in inflammasome-activated macrophages. Furthermore, enhanced autocatalytic activity of pro-caspase-1 was observed following Nedd8 overexpression in 293 cells, and such activity in inflammasome-activated macrophages was drastically diminished upon treatment of cells with MLN4924. Thus, our studies demonstrate a role of Nedd8 in regulating caspase-1 activation following inflammasome activation, presumably via augmenting autoprocessing/cleavage of pro-caspase-1 into its corresponding catalytically active subunits. PMID- 25452303 TI - CPEB regulation of TAK1 synthesis mediates cytokine production and the inflammatory immune response. AB - The cytoplasmic-element-binding (CPEB) protein is a sequence-specific RNA-binding protein that regulates cytoplasmic polyadenylation-induced translation. In mouse embryo fibroblasts (MEFs) lacking CPEB, many mRNAs encoding proteins involved in inflammation are misregulated. Correlated with this aberrant translation in MEFs, a macrophage cell line depleted of CPEB and treated with lipopolysaccharide (LPS) to stimulate the inflammatory immune response expresses high levels of interleukin-6 (IL-6), which is due to prolonged nuclear retention of NF-kappaB. Two proteins involved in NF-kappaB nuclear localization and IL-6 expression, IkappaBalpha and transforming growth factor beta-activated kinase 1 (TAK1), are present at excessively low and high steady-state levels, respectively, in LPS treated CPEB-depleted macrophages. However, only TAK1 has an altered synthesis rate that is CPEB dependent and CPEB/TAK1 double depletion alleviates high IL-6 production. Peritoneal macrophages isolated from CPEB knockout (KO) mice treated with LPS in vitro also have prolonged NF-kappaB nuclear retention and produce high IL-6 levels. LPS-injected CPEB KO mice secrete prodigious amounts of IL-6 and other proinflammatory cytokines and exhibit hypersensitivity to endotoxic shock; these effects are mitigated when the animals are also injected with (5Z)-7 oxozeaenol, a potent and specific inhibitor of TAK1. These data show that CPEB control of TAK1 mRNA translation mediates the inflammatory immune response. PMID- 25452304 TI - The calcineurin-NFAT axis controls allograft immunity in myeloid-derived suppressor cells through reprogramming T cell differentiation. AB - While cyclosporine (CsA) inhibits calcineurin and is highly effective in prolonging rejection for transplantation patients, the immunological mechanisms remain unknown. Herein, the role of calcineurin signaling was investigated in a mouse allogeneic skin transplantation model. The calcineurin inhibitor CsA significantly ameliorated allograft rejection. In CsA-treated allograft recipient mice, CD11b(+) Gr1(+) myeloid-derived suppressor cells (MDSCs) were functional suppressive immune modulators that resulted in fewer gamma interferon (IFN-gamma) producing CD8(+) T cells and CD4(+) T cells (T(H)1 T helper cells) and more interleukin 4 (IL-4)-producing CD4(+) T cells (T(H2)) and prolonged allogeneic skin graft survival. Importantly, the expression of NFATc1 is significantly diminished in the CsA-induced MDSCs. Blocking NFAT (nuclear factor of activated T cells) with VIVIT phenocopied the CsA effects in MDSCs and increased the suppressive activities and recruitment of CD11b(+) Gr1(+) MDSCs in allograft recipient mice. Mechanistically, CsA treatment enhanced the expression of indoleamine 2,3-dioxygenase (IDO) and the suppressive activities of MDSCs in allograft recipients. Inhibition of IDO nearly completely recovered the increased MDSC suppressive activities and the effects on T cell differentiation. The results of this study indicate that MDSCs are an essential component in controlling allograft survival following CsA or VIVIT treatment, validating the calcineurin-NFAT-IDO signaling axis as a potential therapeutic target in transplantation. PMID- 25452305 TI - Inactivation of tristetraprolin in chronic hypoxia provokes the expression of cathepsin B. AB - Macrophages play important roles in many diseases and are frequently found in hypoxic areas. A chronic hypoxic microenvironment alters global cellular protein expression, but molecular details remain poorly understood. Although hypoxia inducible factor (HIF) is an established transcription factor allowing adaption to acute hypoxia, responses to chronic hypoxia are more complex. Based on a two dimensional differential gel electrophoresis (2D-DIGE) approach, we aimed to identify proteins that are exclusively expressed under chronic but not acute hypoxia (1% O2). One of the identified proteins was cathepsin B (CTSB), and a knockdown of either HIF-1alpha or -2alpha in primary human macrophages pointed to an HIF-2alpha dependency. Although chromatin immunoprecipitation (ChIP) experiments confirmed HIF-2 binding to a CTSB enhancer in acute hypoxia, an increase of CTSB mRNA was evident only under chronic hypoxia. Along those lines, CTSB mRNA stability increased at 48 h but not at 8 h of hypoxia. However, RNA stability at 8 h of hypoxia was enhanced by a knockdown of tristetraprolin (TTP). Inactivation of TTP under prolonged hypoxia was facilitated by c-Jun N-terminal kinase (JNK), and inhibition of this kinase lowered CTSB mRNA levels and stability. We postulate a TTP-dependent mechanism to explain delayed expression of CTSB under chronic hypoxia. PMID- 25452307 TI - The EULAR Outcome Measures Library: an evolutional database of validated patient reported instruments. PMID- 25452306 TI - Shugoshins: tension-sensitive pericentromeric adaptors safeguarding chromosome segregation. AB - The shugoshin/Mei-S332 family are proteins that associate with the chromosomal region surrounding the centromere (the pericentromere) and that play multiple and distinct roles in ensuring the accuracy of chromosome segregation during both mitosis and meiosis. The underlying role of shugoshins appears to be to serve as pericentromeric adaptor proteins that recruit several different effectors to this region of the chromosome to regulate processes critical for chromosome segregation. Crucially, shugoshins undergo changes in their localization in response to the tension that is exerted on sister chromosomes by the forces of the spindle that will pull them apart. This has led to the idea that shugoshins provide a platform for activities required at the pericentromere only when sister chromosomes lack tension. Conversely, disassembly of the shugoshin pericentromeric platform may provide a signal that sister chromosomes are under tension. Here the functions and regulation of these important tension-sensitive pericentromeric proteins are discussed. PMID- 25452309 TI - Relationship between quantitative radiographic assessments of interstitial lung disease and physiological and clinical features of systemic sclerosis. AB - OBJECTIVES: Extent of systemic sclerosis (SSc)-related interstitial lung disease (ILD) assessed from thoracic high-resolution CT (HRCT) predicts disease course, mortality and treatment response. While quantitative HRCT analyses of extent of lung fibrosis (QLFib) or total interstitial lung disease (QILD) are more sensitive and reproducible than visual HRCT assessments of SSc-ILD, these analyses are not widely available. This study evaluates the relationship between clinical disease parameters and QLFib and QILD scores to identify potential surrogate measures of radiographic extent of ILD. METHODS: Using baseline data from the Scleroderma Lung Study I (SLS I; N=158), multivariate regression analyses were performed using the best subset selection method to identify one to five variable models that best correlated with QLFib and QILD scores in both whole lung (WL) and the zone of maximal involvement (ZM). These models were subsequently validated using baseline data from SLS II (N=142). Bivariate analyses of the radiographic and clinical variables were also performed using pooled data. SLS I and II did not include patients with clinically significant pulmonary hypertension (PH). RESULTS: Diffusing capacity for carbon monoxide (DLCO) was the single best predictor of both QLF and QILD in the WL and ZM in all of the best subset models. Adding other disease parameters to the models did not substantially improve model performance. Forced vital capacity (FVC) did not predict QLF or QILD scores in any of the models. CONCLUSIONS: In the absence of PH, DLCO provides the best overall estimate of HRCT-measured lung disease in patients from two large SSc cohorts. FVC, although commonly used, may not be the best surrogate measure of extent of SSc-ILD at any point in time. TRIAL REGISTRATION NUMBERS: SLS I: www.clinicaltrials.gov NCT 00000-4563; SLS II: www.clinicaltrials.gov NCT 00883129. PMID- 25452308 TI - Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast like synoviocyte activation by suppressing HDAC5 expression. AB - OBJECTIVES: Epigenetic modifications play an important role in the regulation of gene transcription and cellular function. Here, we examined if pro-inflammatory factors present in the inflamed joint of patients with rheumatoid arthritis (RA) could regulate histone deacetylase (HDAC) expression and function in fibroblast like synoviocytes (FLS). METHODS: Protein acetylation in synovial tissue was assessed by immunohistochemistry. The mRNA levels of HDAC family members and inflammatory mediators in the synovial tissue and the changes in HDAC expression in RA FLS were measured by quantitative (q) PCR. FLS were either transfected with HDAC5 siRNA or transduced with adenoviral vector encoding wild-type HDAC5 and the effects of HDAC5 manipulation were examined by qPCR arrays, ELISA and ELISA-based assays. RESULTS: Synovial class I HDAC expression was associated with local expression of tumour necrosis factor (TNF) and matrix metalloproteinase-1, while class IIa HDAC5 expression was inversely associated with parameters of disease activity (erythrocyte sedimentation rate, C-reactive protein, Disease Activity Score in 28 Joints). Interleukin (IL)-1beta or TNF stimulation selectively suppressed HDAC5 expression in RA FLS, which was sufficient and required for optimal IFNB, CXCL9, CXCL10 and CXCL11 induction by IL-1beta, associated with increased nuclear accumulation of the transcription factor, interferon regulatory factor 1(IRF1). CONCLUSIONS: Inflammatory cytokines suppress RA FLS HDAC5 expression, promoting nuclear localisation of IRF1 and transcription of a subset of type I interferon response genes. Our results identify HDAC5 as a novel inflammatory mediator in RA, and suggest that strategies rescuing HDAC5 expression in vivo, or the development of HDAC inhibitors not affecting HDAC5 activity, may have therapeutic applications in RA treatment. PMID- 25452311 TI - Provision of nitrogen as ammonium rather than nitrate increases silicon uptake in sugarcane. AB - Silicon (Si) is important in mitigating abiotic and biotic plant stresses, yet many agricultural soils, such as those of the rainfed production areas of the South African sugar industry, are deficient in plant-available Si, making Si supplementation necessary. However, Si uptake by sugarcane (Saccharum spp. hybrids) is limited even where silicate amendments improve soil Si status. Rhizosphere pH, which can affect Si uptake, can be manipulated using different N form fertilizers. We tested whether (i) fertilization with [Formula: see text] (rhizosphere acidification) increased Si uptake compared with [Formula: see text] (rhizosphere alkalinization); and (ii) uptake differed between an N-efficient, more acid-tolerant cultivar (N12) and an N-inefficient, less acid-tolerant cultivar (N14). Two pot trials with low-Si soil were fertilized with calcium silicate (Ca2SiO4) slag, plus N from ammonium sulphate [(NH4)2SO4], ammonium thiosulphate [(NH4)2S2O3] and calcium nitrate [Ca(NO3)2] (Trial 1) or N from (NH4)2S2O3 and Ca(NO3)2 only (Trial 2). Trial 2 included cultivars N12 and N14. Nitrate treatments significantly increased soil pH and soil Si compared with [Formula: see text] However, [Formula: see text] treatments significantly increased leaf and stalk Si content compared with [Formula: see text] reflected in a significant negative relationship between soil pH and leaf Si. Acid extracted soil Si was negatively related to leaf and stalk Si, likely due to adsorption of silicic acid to soil surfaces under higher pH of the [Formula: see text] treatment and its reduced availability for plant uptake. We conclude that [Formula: see text] increased Si uptake into leaf and stalk, and propose that reduced rhizosphere pH solubilized Si from Ca2SiO4 and increased silicic acid availability for plant uptake. By contrast, [Formula: see text] may have reduced Si uptake due to adsorption of Si to soil surfaces at higher pH. Our results indicate that ammoniacal fertilizers, such as (NH4)2SO4 and urea, have potential for promoting dissolution of applied Ca2SiO4 and subsequent uptake of Si by sugarcane. PMID- 25452310 TI - A comparison of safety profiles of tumour necrosis factor alpha inhibitors and rituximab therapy in patients with rheumatoid arthritis and chronic hepatitis C. PMID- 25452312 TI - N-linked (N-) glycoproteomics of urinary exosomes. [Corrected]. AB - Epithelial cells lining the urinary tract secrete urinary exosomes (40-100 nm) that can be targeted to specific cells modulating their functionality. One potential targeting mechanism is adhesion between vesicle surface glycoproteins and target cells. This makes the glycopeptide analysis of exosomes important. Exosomes reflect the physiological state of the parent cells; therefore, they are a good source of biomarkers for urological and other diseases. Moreover, the urine collection is easy and noninvasive and urinary exosomes give information about renal and systemic organ systems. Accordingly, multiple studies on proteomic characterization of urinary exosomes in health and disease have been published. However, no systematic analysis of their glycoproteomic profile has been carried out to date, whereas a conserved glycan signature has been found for exosomes from urine and other sources including T cell lines and human milk. Here, we have enriched and identified the N-glycopeptides from these vesicles. These enriched N-glycopeptides were solved for their peptide sequence, glycan composition, structure, and glycosylation site using collision-induced dissociation MS/MS (CID-tandem MS) data interpreted by a publicly available software GlycopeptideId. Released glycans from the same sample was also analyzed with MALDI-MS. We have identified the N-glycoproteome of urinary exosomes. In total 126 N-glycopeptides from 51 N-glycosylation sites belonging to 37 glycoproteins were found in our results. The peptide sequences of these N glycopeptides were identified unambiguously and their glycan composition (for 125 N-glycopeptides) and structures (for 87 N-glycopeptides) were proposed. A corresponding glycomic analysis with released N-glycans was also performed. We identified 66 unique nonmodified N-glycan compositions and in addition 13 sulfated/phosphorylated glycans were also found. This is the first systematic analysis of N-glycoproteome of urinary exosomes. PMID- 25452313 TI - N-glycomic profiling as a tool to separate rectal adenomas from carcinomas. AB - All human cells are covered by glycans, the carbohydrate units of glycoproteins, glycolipids, and proteoglycans. Most glycans are localized to cell surfaces and participate in events essential for cell viability and function. Glycosylation evolves during carcinogenesis, and therefore carcinoma-related glycan structures are potential cancer biomarkers. Colorectal cancer is one of the world's three most common cancers, and its incidence is rising. Novel biomarkers are essential to identify patients for targeted and individualized therapy. We compared the N glycan profiles of five rectal adenomas and 18 rectal carcinomas of different stages by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry. Paraffin-embedded tumor samples were deparaffinized, and glycans were enzymatically released and purified. We found differences in glycosylation between adenomas and carcinomas: monoantennary, sialylated, pauci-mannose, and small high-mannose N-glycan structures were more common in carcinomas than in adenomas. We also found differences between stage I-II and stage III carcinomas. Based on these findings, we selected two glycan structures: pauci-mannose and sialyl Lewis a, for immunohistochemical analysis of their tissue expression in 220 colorectal cancer patients. In colorectal cancer, poor prognosis correlated with elevated expression of sialyl Lewis a, and in advanced colorectal cancer, poor prognosis correlated with elevated expression of pauci-mannose. In conclusion, by mass spectrometry we found several carcinoma related glycans, and we demonstrate a method of transforming these results into immunohistochemistry, a readily applicable method to study biomarker expression in patient samples. PMID- 25452315 TI - Heated humidified high-flow nasal cannula therapy in children. AB - Heated humidified high-flow nasal cannula therapy (HHHFNC) was originally described as a mode of respiratory support in premature neonates and is now increasingly used in the management of acute respiratory failure in older infants and children. Heating and humidification of gas mixtures allow comfortable delivery of flow rates that match or exceed the patient's inspiratory flow rate. Emerging evidence from observational studies suggests that the use of HHHFNC therapy may be associated with reduced work of breathing, improved ventilation efficiency and a decreased need for intubation in children with respiratory insufficiency. There are several proposed mechanisms of action, and the potential for provision of unpredictable positive distending pressure has caused concern. Randomised controlled trial evidence comparing clinical outcomes with those achieved using other forms of respiratory support is, however, awaited. We review the proposed mechanisms of actions, indications, advantages and complications of HHHFNC therapy in children and describe our approach to its use in the paediatric ward environment. PMID- 25452316 TI - Privatizing funding for maternal, child health. PMID- 25452317 TI - The tobacco reliquary. PMID- 25452314 TI - A novel role for the Pol I transcription factor UBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes. AB - Mechanisms to coordinate programs of highly transcribed genes required for cellular homeostasis and growth are unclear. Upstream binding transcription factor (UBTF, also called UBF) is thought to function exclusively in RNA polymerase I (Pol I)-specific transcription of the ribosomal genes. Here, we report that the two isoforms of UBTF (UBTF1/2) are also enriched at highly expressed Pol II-transcribed genes throughout the mouse genome. Further analysis of UBTF1/2 DNA binding in immortalized human epithelial cells and their isogenically matched transformed counterparts reveals an additional repertoire of UBTF1/2-bound genes involved in the regulation of cell cycle checkpoints and DNA damage response. As proof of a functional role for UBTF1/2 in regulating Pol II transcription, we demonstrate that UBTF1/2 is required for recruiting Pol II to the highly transcribed histone gene clusters and for their optimal expression. Intriguingly, lack of UBTF1/2 does not affect chromatin marks or nucleosome density at histone genes. Instead, it results in increased accessibility of the histone promoters and transcribed regions to micrococcal nuclease, implicating UBTF1/2 in mediating DNA accessibility. Unexpectedly, UBTF2, which does not function in Pol I transcription, is sufficient to regulate histone gene expression in the absence of UBTF1. Moreover, depletion of UBTF1/2 and subsequent reduction in histone gene expression is associated with DNA damage and genomic instability independent of Pol I transcription. Thus, we have uncovered a novel role for UBTF1 and UBTF2 in maintaining genome stability through coordinating the expression of highly transcribed Pol I (UBTF1 activity) and Pol II genes (UBTF2 activity). PMID- 25452318 TI - Broken trust drives native health disparities. PMID- 25452319 TI - Is your hospital culturally safe? PMID- 25452320 TI - Venous thrombosis in inflammatory bowel disease. PMID- 25452321 TI - Free lunch is a good thing for children. PMID- 25452322 TI - A 62-year-old woman with syncope. PMID- 25452323 TI - 10 health stories that mattered: Nov. 22-28. PMID- 25452325 TI - Competency-based training for physicians: are we doing no harm? PMID- 25452324 TI - Congenital sucrase-isomaltase deficiency: identification of a common Inuit founder mutation. AB - BACKGROUND: Congenital sucrase-isomaltase deficiency is a rare hereditary cause of chronic diarrhea in children. People with this condition lack the intestinal brush-border enzyme required for digestion of di- and oligosaccharides, including sucrose and isomaltose, leading to malabsorption. Although the condition is known to be highly prevalent (about 5%-10%) in several Inuit populations, the genetic basis for this has not been described. We sought to identify a common mutation for congenital sucrase-isomaltase deficiency in the Inuit population. METHODS: We sequenced the sucrase-isomaltase gene, SI, in a single Inuit proband with congenital sucrase-isomaltase deficiency who had severe fermentative diarrhea and failure to thrive. We then genotyped a further 128 anonymized Inuit controls from a variety of locales in the Canadian Arctic to assess for a possible founder effect. RESULTS: In the proband, we identified a novel, homozygous frameshift mutation, c.273_274delAG (p.Gly92Leufs*8), predicted to result in complete absence of a functional protein product. This change was very common among the Inuit controls, with an observed allele frequency of 17.2% (95% confidence interval [CI] 12.6%-21.8%). The predicted Hardy-Weinberg prevalence of congenital sucrase-isomaltase deficiency in Inuit people, based on this single founder allele, is 3.0% (95% CI 1.4%-4.5%), which is comparable with previous estimates. INTERPRETATION: We found a common mutation, SI c.273_274delAG, to be responsible for the high prevalence of congenital sucrase-isomaltase deficiency among Inuit people. Targeted mutation testing for this allele should afford a simple and minimally invasive means of diagnosing this condition in Inuit patients with chronic diarrhea. PMID- 25452326 TI - Kinetics of human sperm acrosomal exocytosis. AB - The acrosome reaction is a unique event in the lifespan of sperm characterized by the exocytosis of the acrosomal content and the release of hybrid vesicles formed by patches of the outer acrosomal membrane and the plasma membrane. This unique regulated exocytosis is mediated by essentially the same membrane fusion machinery present in neuroendocrine cells. However, whereas secretion in neuroendocrine cells occurs in less than a second, the acrosome reaction is normally assessed after several minutes of incubation with inducers. In this report, we measured the kinetics of human sperm exocytosis triggered by two stimuli (calcium ionophore and progesterone) by using electron microscopy and three different approaches based on the incorporation of fluorescent Pisum sativum agglutinin into the acrosome upon opening of fusion pores connecting the extracellular medium with the acrosomal lumen. The results with the different methods are consistent with a slow kinetics (t1/2 = 14 min). We also manipulated the system to measure different steps of the process. We observed that cytosolic calcium increased with a relatively fast kinetics (t1/2 = 0.1 min). In contrast, the swelling of the acrosomal granule that precedes exocytosis was a slow process (t1/2 = 13 min). When swelling was completed, the fusion pore opening was fast (t1/2 = 0.2 min). The results indicate that acrosomal swelling is the slowest step and it determines the kinetics of the acrosome reaction. After the swelling is completed, the efflux of calcium from intracellular stores triggers fusion pores opening and the release of hybrid vesicles in seconds. PMID- 25452328 TI - The 2nd International Conference on Radiation and Dosimetry in Various Fields of Research (RAD 2014) and the 2nd East European Radon Symposium (SEERAS). Preface. PMID- 25452329 TI - Monte Carlo as a tool to evaluate the effect of different lung densities on radiotherapy dose distribution. AB - This study aims at evaluating the effects of different lung densities on dose distribution after irradiation at different field sizes, by comparing experimental measurements, GEANT4 Monte Carlo (MC) simulations and two TPS calculation algorithms on ad hoc phantoms. Irradiations were performed with a Varian Clinac 2100 C/D with a nominal energy of 6 MV. Dosimetric experimental measurements were obtained with radiochromic films. A model based on GEANT4 MC code was developed to simulate both the accelerator and the phantoms. Results of dose distribution show an acceptable agreement between MC simulations and experimental measurements, both in the tumour-equivalent region and in the normal tissue-equivalent ones. On the opposite, results vary among the TPS algorithms, especially in regions of lung-equivalent material at low density, but also at the interface between lung- and tumour-equivalent materials. PMID- 25452327 TI - Reversing translational suppression and induction of toxicity in pancreatic cancer cells using a chemoprevention gene therapy approach. AB - Pancreatic cancer is an aggressive disease with limited therapeutic options. Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), a potent antitumor cytokine, shows cancer-specific toxicity in a vast array of human cancers, inducing endoplasmic reticulum stress and apoptosis, toxic autophagy, an antitumor immune response, an antiangiogenic effect, and a significant "bystander" anticancer effect that leads to enhanced production of this cytokine through autocrine and paracrine loops. Unfortunately, mda-7/IL-24 application in pancreatic cancer has been restricted because of a "translational block" occurring after Ad.5-mda-7 gene delivery. Our previous research focused on developing approaches to overcome this block and increase the translation of the MDA-7/IL-24 protein, thereby promoting its subsequent toxic effects in pancreatic cancer cells. We demonstrated that inducing reactive oxygen species (ROS) after adenoviral infection of mda-7/IL-24 leads to greater translation into MDA-7/IL-24 protein and results in toxicity in pancreatic cancer cells. In this study we demonstrate that a novel chimeric serotype adenovirus, Ad.5/3-mda-7, displays greater efficacy in delivering mda-7/IL-24 compared with Ad.5-mda-7, although overall translation of the protein still remains low. We additionally show that d limonene, a dietary monoterpene known to induce ROS, is capable of overcoming the translational block when used in combination with adenoviral gene delivery. This novel combination results in increased polysome association of mda-7/IL-24 mRNA, activation of the preinitiation complex of the translational machinery in pancreatic cancer cells, and culminates in mda-7/IL-24-mediated toxicity. PMID- 25452330 TI - An efficient TOF-SIMS image analysis with spatial correlation and alternating non negativity-constrained least squares. AB - MOTIVATION: Advances in analytical instrumentation towards acquiring high resolution images of mass spectrometry constantly demand efficient approaches for data analysis. This is particularly true of time-of-flight secondary ion mass spectrometry imaging where recent advances enable acquisition of high-resolution data in multiple dimensions. In many applications, the distribution of different species from a sampled surface is spatially continuous in nature and a model that incorporates the spatial correlation across the surface would be preferable to estimations at discrete spatial locations. A key challenge here is the capability to analyse the high-resolution multidimensional data to extract relevant information reliably and efficiently. RESULTS: We propose a framework based on alternating non-negativity-constrained least squares which accounts for the spatial correlation across the sample surface. The proposed method also decouples the computational complexity of the estimation procedure from the image resolution, which significantly reduces the processing time. We evaluate the performance of the algorithm with biochemical image datasets generated from mixture of metabolites. PMID- 25452331 TI - Cost-effectiveness of transoral robotic surgery in the unknown primary: the problem of extended dominance. PMID- 25452332 TI - Cost-effectiveness of transoral robotic surgery in the unknown primary: corrigendum and response to comments. PMID- 25452336 TI - ARTD1-induced poly-ADP-ribose formation enhances PPARgamma ligand binding and co factor exchange. AB - PPARgamma-dependent gene expression during adipogenesis is facilitated by ADP ribosyltransferase D-type 1 (ARTD1; PARP1)-catalyzed poly-ADP-ribose (PAR) formation. Adipogenesis is accompanied by a dynamic modulation of the chromatin landscape at PPARgamma target genes by ligand-dependent co-factor exchange. However, how endogenous PPARgamma ligands, which have a low affinity for the receptor and are present at low levels in the cell, can induce sufficient co factor exchange is unknown. Moreover, the significance of PAR formation in PPARgamma-regulated adipose tissue function is also unknown. Here, we show that inhibition of PAR formation in mice on a high-fat diet reduces weight gain and cell size of adipocytes, as well as PPARgamma target gene expression in white adipose tissue. Mechanistically, topoisomerase II activity induces ARTD1 recruitment to PPARgamma target genes, and ARTD1 automodification enhances ligand binding to PPARgamma, thus promoting sufficient transcriptional co-factor exchange in adipocytes. Thus, ARTD1-mediated PAR formation during adipogenesis is necessary to adequately convey the low signal of endogenous PPARgamma ligand to effective gene expression. These results uncover a new regulatory mechanism of ARTD1-induced ADP-ribosylation and highlight its importance for nuclear factor regulated gene expression. PMID- 25452337 TI - Assessing the gene regulatory properties of Argonaute-bound small RNAs of diverse genomic origin. AB - High-throughput sequencing reveals an abundance of microRNA-sized fragments derived from larger non-coding RNAs. Roles for these small RNAs in gene silencing are suggested by their co-precipitation with Argonaute, the microRNA effector protein, though the extent to which they suppress gene expression endogenously remains unclear. To address this, we used luciferase reporters to determine the endogenous functionality of small RNAs from a diverse range of sources. We demonstrate small RNAs derived from snoRNAs have the capacity to act in a microRNA-like manner, though we note the vast majority of these are bound to Argonaute at levels below that required for detectable silencing activity. We show Argonaute exhibits a high degree of selectivity for the small RNAs with which it interacts and note that measuring Argonaute-associated levels is a better indicator of function than measuring total expression. Although binding to Argonaute at sufficient levels is necessary for demonstrating microRNA functionality in our reporter assay, this alone is not enough as some small RNAs derived from other non-coding RNAs (tRNAs, rRNAs, Y-RNAs) are associated with Argonaute at very high levels yet do not serve microRNA-like roles. PMID- 25452335 TI - Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5. AB - Two human demethylases, the fat mass and obesity-associated (FTO) enzyme and ALKBH5, oxidatively demethylate abundant N(6)-methyladenosine (m(6)A) residues in mRNA. Achieving a method for selective inhibition of FTO over ALKBH5 remains a challenge, however. Here, we have identified meclofenamic acid (MA) as a highly selective inhibitor of FTO. MA is a non-steroidal, anti-inflammatory drug that mechanistic studies indicate competes with FTO binding for the m(6)A-containing nucleic acid. The structure of FTO/MA has revealed much about the inhibitory function of FTO. Our newfound understanding, revealed herein, of the part of the nucleotide recognition lid (NRL) in FTO, for example, has helped elucidate the principles behind the selectivity of FTO over ALKBH5. Treatment of HeLa cells with the ethyl ester form of MA (MA2) has led to elevated levels of m(6)A modification in mRNA. Our collective results highlight the development of functional probes of the FTO enzyme that will (i) enable future biological studies and (ii) pave the way for the rational design of potent and specific inhibitors of FTO for use in medicine. PMID- 25452338 TI - Operator recognition by the ROK transcription factor family members, NagC and Mlc. AB - NagC and Mlc, paralogous members of the ROK family of proteins with almost identical helix-turn-helix DNA binding motifs, specifically regulate genes for transport and utilization of N-acetylglucosamine and glucose. We previously showed that two amino acids in a linker region outside the canonical helix-turn helix motif are responsible for Mlc site specificity. In this work we identify four amino acids in the linker, which are required for recognition of NagC targets. These amino acids allow Mlc and NagC to distinguish between a C/G and an A/T bp at positions +/-11 of the operators. One linker position, glycine in NagC and arginine in Mlc, corresponds to the major specificity determinant for the two proteins. In certain contexts it is possible to switch repression from Mlc-style to NagC-style, by interchanging this glycine and arginine. Secondary determinants are supplied by other linker positions or the helix-turn-helix motif. A wide genomic survey of unique ROK proteins shows that glycine- and arginine-rich sequences are present in the linkers of nearly all ROK family repressors. Conserved short sequence motifs, within the branches of the ROK evolutionary tree, suggest that these sequences could also be involved in operator recognition in other ROK family members. PMID- 25452340 TI - Systematic integration of RNA-Seq statistical algorithms for accurate detection of differential gene expression patterns. AB - RNA-Seq is gradually becoming the standard tool for transcriptomic expression studies in biological research. Although considerable progress has been recorded in the development of statistical algorithms for the detection of differentially expressed genes using RNA-Seq data, the list of detected genes can differ significantly between algorithms. We present a new method (PANDORA) that combines multiple algorithms toward a summarized result, more efficiently reflecting true experimental outcomes. This is achieved through the systematic combination of several analysis algorithms, by weighting their outcomes according to their performance with realistically simulated data sets generated from real data. Results supported by the analysis of both simulated and real data from different organisms as well as correlation with PolII occupancy demonstrate that PANDORA improves the detection of differential expression. It accomplishes this by optimizing the tradeoff between standard performance measurements, such as precision and sensitivity. PMID- 25452339 TI - Comparative genomic analysis of Helicobacter pylori from Malaysia identifies three distinct lineages suggestive of differential evolution. AB - The discordant prevalence of Helicobacter pylori and its related diseases, for a long time, fostered certain enigmatic situations observed in the countries of the southern world. Variation in H. pylori infection rates and disease outcomes among different populations in multi-ethnic Malaysia provides a unique opportunity to understand dynamics of host-pathogen interaction and genome evolution. In this study, we extensively analyzed and compared genomes of 27 Malaysian H. pylori isolates and identified three major phylogeographic lineages: hspEastAsia, hpEurope and hpSouthIndia. The analysis of the virulence genes within the core genome, however, revealed a comparable pathogenic potential of the strains. In addition, we identified four genes limited to strains of East-Asian lineage. Our analyses identified a few strain-specific genes encoding restriction modification systems and outlined 311 core genes possibly under differential evolutionary constraints, among the strains representing different ethnic groups. The cagA and vacA genes also showed variations in accordance with the host genetic background of the strains. Moreover, restriction modification genes were found to be significantly enriched in East-Asian strains. An understanding of these variations in the genome content would provide significant insights into various adaptive and host modulation strategies harnessed by H. pylori to effectively persist in a host-specific manner. PMID- 25452342 TI - Regulatory focus affects predictions of the future. AB - This research investigated how regulatory focus might influence trend-reversal predictions. We hypothesized that compared with promotion focus, prevention focus hinders sense of control, which in turn predicts more trend-reversal developments. Studies 1 and 3 revealed that participants expected trend-reversal developments to be more likely to occur when they focused on prevention than when they focused on promotion. Study 2 extended the findings by including a control condition, and revealed that participants expected trend-reversal developments to be more likely to occur in the prevention condition than in the promotion and control conditions. Studies 4 and 5 revealed that participants' chronic prevention focus predicted a low sense of control (Study 4), and that promotion focus predicted a high sense of control (Studies 4 and 5). Furthermore, participants with a high sense of control expected trend-reversal developments to be less likely to occur. Thus, the results provided converging evidence for the hypothesis. PMID- 25452343 TI - Ebola--lessons still to be learned. PMID- 25452341 TI - Flexibility and structural conservation in a c-KIT G-quadruplex. AB - A quadruplex sequence from the promoter region of the c-KIT gene forms a stable quadruplex, as characterized by crystallographic and NMR methods. Two new crystal structures are reported here, together with molecular dynamics simulation studies on these quadruplex crystal structures and an NMR structure. The new crystal structures, each in a distinct space group and lattice packing arrangement, together with the existing structures, demonstrate that the c-KIT quadruplex fold does not change with differing environments, suggesting that quadruplex topological dynamism is not a general phenomenon. The single and dinucleotide loops in these structures show a high degree of conformational flexibility within the three crystal forms and the NMR ensemble, with no evidence of clustering to particular conformers. This is in accord with the findings of high loop flexibility from the molecular dynamics studies. It is suggested that intramolecular quadruplexes can be grouped into two broad classes (i) those with at least one single-nucleotide loop, often showing singular topologies even though loops are highly flexible, and (ii) with all loops comprising at least two nucleotides, leading to topological dynamism. The loops can have more stable and less dynamic base-stacked secondary structures. PMID- 25452344 TI - Diabetes therapy and cancer risk. PMID- 25452345 TI - In reply. PMID- 25452346 TI - Sarcoidal infiltration of tattoos. PMID- 25452347 TI - When does an adult with headaches need central nervous system imaging? PMID- 25452348 TI - Q: Is antibiotic treatment indicated in a patient with a positive urine culture but no symptoms? PMID- 25452349 TI - A 41-year-old man with abdominal pain. PMID- 25452350 TI - Ebola virus: questions, answers, and more questions. AB - Ebola virus causes a hemorrhagic fever with a high case-fatality rate. Treatment remains supportive although a variety of specific treatments are still in the early stages of investigation. This report reviews the clinical virology of Ebola virus, the reported proposed treatments, and the current outbreak. PMID- 25452351 TI - Identifying statin-associated autoimmune necrotizing myopathy. AB - Statins up-regulate expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis and the major target of autoantibodies in statin-associated immune-mediated necrotizing myopathy. As muscle cells regenerate, they express high levels of HMGCR, which may sustain the immune response even after statin therapy is stopped. Awareness of this entity will help physicians who prescribe statins to take action to limit the associated morbidity. PMID- 25452352 TI - Updated guidelines on cardiovascular evaluation before noncardiac surgery: a view from the trenches. AB - In August 2014, the American College of Cardiology and American Heart Association updated their guidelines on cardiovascular evaluation and care before noncardiac surgery and simultaneously published a systematic review of perioperative use of beta-blockers. The update reinforces many previous recommendations and provides new evidence and expert opinion that is useful to the perioperative team. PMID- 25452353 TI - Perioperative medicine: combining the science and the art. PMID- 25452354 TI - Syncope: etiology and diagnostic approach. AB - There are three major types of syncope: neurally mediated (the most common), orthostatic hypotensive, and cardiac (the most worrisome). Several studies have shown a normal long-term survival rate in patients with syncope who have no structural heart disease, which is the most important predictor of death and ventricular arrhythmia. The workup of unexplained syncope depends on the presence or absence of heart disease: electrophysiologic study if the patient has heart disease, tilt-table testing in those without heart disease, and prolonged rhythm monitoring in both cases if syncope remains unexplained. PMID- 25452355 TI - Tilt-table testing. PMID- 25452356 TI - One step at a time. PMID- 25452357 TI - 'Big data' reporting guidelines: how to answer big questions, yet avoid big problems. AB - The extent and depth of routine health care data are growing at an ever increasing rate, forming huge repositories of information. These repositories can answer a vast array of questions. However, an understanding of the purpose of the dataset used and the quality of the data collected are paramount to determine the reliability of the result obtained. This Editorial describes the importance of adherence to sound methodological principles in the reporting and publication of research using 'big' data, with a suggested reporting framework for future Bone & Joint Journal submissions. PMID- 25452358 TI - The orthopaedic research scene and strategies to improve it. AB - Trauma and orthopaedics is the largest of the surgical specialties and yet attracts a disproportionately small fraction of available national and international funding for health research. With the burden of musculoskeletal disease increasing, high-quality research is required to improve the evidence base for orthopaedic practice. Using the current research landscape in the United Kingdom as an example, but also addressing the international perspective, we highlight the issues surrounding poor levels of research funding in trauma and orthopaedics and indicate avenues for improving the impact and success of surgical musculoskeletal research. PMID- 25452359 TI - The role of femoral neck anteversion in the development of osteoarthritis in dysplastic hips. AB - There have been several studies examining the association between the morphological characteristics seen in acetabular dysplasia and the incidence of the osteoarthritis (OA). However, most studies focus mainly on acetabular morphological analysis, and few studies have scrutinised the effect of femoral morphology. In this study we enrolled 36 patients with bilateral acetabular dysplasia and early or mid-stage OA in one hip and no OA in the contralateral hip. CT scans were performed from the iliac crest to 2 cm inferior to the tibial tuberosity, and the morphological characteristics of both acetabulum and femur were studied. In addition, 200 hips in 100 healthy volunteer Chinese adults formed a control group. The results showed that the dysplastic group with OA had a significantly larger femoral neck anteversion and a significantly shorter abductor lever arm than both the dysplastic group without OA and the controls. Femoral neck anteversion had a significant negative correlation with the length of the abductor lever arm and we conclude that it may contribute to the development of OA in dysplastic hips. PMID- 25452360 TI - Prevalence of a soft-tissue lesion after small head metal-on-metal total hip replacement: 13- to 19-year follow-up study. AB - We investigated the incidence of soft-tissue lesions after small head metal-on metal total hip replacement (MoM THR). Between December 1993 and May 1999, 149 patients (195 hips) underwent primary cementless MoM THR. During the follow-up period, three patients (five THRs) died and eight patients (14 THRs) were lost to follow-up. We requested that all patients undergo CT evaluation. After exclusion of five patients (six THRs) who had undergone a revision procedure, and 22 (28 THRs) who were unwilling to take part in this study, 111 patients (142 THRs) were evaluated. There were 63 men (88 THRs) and 48 women (54 THRs) with a mean age of 45.7 years (37 to 56) at the time of surgery. The mean follow-up was 15.4 years (13 to 19). A soft-tissue lesion was defined as an abnormal peri-prosthetic collection of fluid, solid lesion or asymmetrical soft-tissue mass. At final follow-up, soft-tissue lesions were found in relation to 28 THRs (19.7%), including 25 solid and three cystic lesions. They were found in 20 men and eight women; 26 lesions were asymptomatic and two were symptomatic. The mean maximal diameter of the soft-tissue lesion was 42.3 mm (17 to 135). The relatively high rate of soft-tissue lesions observed with small head MoM THR remains a concern. PMID- 25452361 TI - Predictors of time to revision and clinical outcomes following revision of metal on-metal hip replacements for adverse reaction to metal debris. AB - We undertook a retrospective cohort study to determine clinical outcomes following the revision of metal-on-metal (MoM) hip replacements for adverse reaction to metal debris (ARMD), and to identify predictors of time to revision and outcomes following revision. Between 1998 and 2012 a total of 64 MoM hips (mean age at revision of 57.8 years; 46 (72%) female; 46 (72%) hip resurfacings and 18 (28%) total hip replacements) were revised for ARMD at one specialist centre. At a mean follow-up of 4.5 years (1.0 to 14.6) from revision for ARMD there were 13 hips (20.3%) with post-operative complications and eight (12.5%) requiring re-revision. The Kaplan-Meier five-year survival rate for ARMD revision was 87.9% (95% confidence interval 78.9 to 98.0; 19 hips at risk). Excluding re revisions, the median absolute Oxford hip score (OHS) following ARMD revision using the percentage method (0% best outcome and 100% worst outcome) was 18.8% (interquartile range (IQR) 7.8% to 48.3%), which is equivalent to 39/48 (IQR 24.8/48 to 44.3/48) when using the modified OHS. Histopathological response did not affect time to revision for ARMD (p = 0.334) or the subsequent risk of re revision (p = 0.879). Similarly, the presence or absence of a contralateral MoM hip bearing did not affect time to revision for ARMD (p = 0.066) or the subsequent risk of re-revision (p = 0.178). Patients revised to MoM bearings had higher rates of re-revision (five of 16 MoM hips re-revised; p = 0.046), but those not requiring re-revision had good functional results (median absolute OHS 14.6% or 41.0/48). Short-term morbidity following revision for ARMD was comparable with previous reports. Caution should be exercised when choosing bearing surfaces for ARMD revisions. PMID- 25452362 TI - Adverse reaction to metal debris is more common in patients following MoM total hip replacement with a 36 mm femoral head than previously thought: results from a modern MoM follow-up programme. AB - We conducted a retrospective study to assess the prevalence of adverse reactions to metal debris (ARMD) in patients operated on at our institution with metal-on metal (MoM) total hip replacements with 36 mm heads using a Pinnacle acetabular shell. A total of 326 patients (150 males, 175 hips; 176 females, 203 hips) with a mean age of 62.7 years (28 to 85) and mean follow-up of 7.5 years (0.1 to 10.8) participating in our in-depth modern MoM follow-up programme were included in the study, which involved recording whole blood cobalt and chromium ion measurements, Oxford hip scores (OHS) and plain radiographs of the hip and targeted cross sectional imaging. Elevated blood metal ion levels (> 5 parts per billion) were seen in 32 (16.1%) of the 199 patients who underwent unilateral replacement. At 23 months after the start of our modern MoM follow-up programme, 29 new cases of ARMD had been revealed. Hence, the nine-year survival of this cohort declined from 96% (95% CI 95 to 98) with the old surveillance routine to 86% (95% CI 82 to 90) following the new protocol. Although ARMD may not be as common in 36 mm MoM THRs as in those with larger heads, these results support the Medicines and Healthcare Products Regulatory Agency guidelines on regular reviews and further investigations, and emphasise the need for specific a follow-up programme for patients with MoM THRs. PMID- 25452363 TI - Significant muscle damage after multiple revision total hip replacements through the direct lateral approach. AB - Intact abductors of the hip play a crucial role in preventing limping and are known to be damaged through the direct lateral approach. The extent of trauma to the abductors after revision total hip replacement (THR) is unknown. The aim of this prospective study was to compare the pre- and post-operative status of the gluteus medius muscle after revision THR. We prospectively compared changes in the muscle and limping in 30 patients who were awaiting aseptic revision THR and 15 patients undergoing primary THR. The direct lateral approach as described by Hardinge was used for all patients. MRI scans of the gluteus medius and functional analyses were recorded pre-operatively and six months post operatively. The overall mean fatty degeneration of the gluteus medius increased from 35.8% (1.1 to 98.8) pre-operatively to 41% (1.5 to 99.8) after multiple revision THRs (p = 0.03). There was a similar pattern after primary THR, but with considerably less muscle damage (p = 0.001), indicating progressive muscle damage. Despite an increased incidence of a positive Trendelenburg sign following revision surgery (p = 0.03) there was no relationship between the cumulative fatty degeneration in the gluteus medius and a positive Trendelenburg sign (p = 0.26). The changes associated with other surgical approaches to the hip warrant investigation. PMID- 25452364 TI - The shape of the distal femur: a geometrical study using MRI. AB - We scanned 25 left knees in healthy human subjects using MRI. Multiplanar reconstruction software was used to take measurements of the inferior and posterior facets of the femoral condyles and the trochlea. A 'basic circle' can be defined which, in the sagittal plane, fits the posterior and inferior facets of the lateral condyle, the posterior facet of the medial condyle and the floor of the groove of the trochlea. It also approximately fits both condyles in the coronal plane (inferior facets) and the axial plane (posterior facets). The circle fitting the inferior facet of the medial condyle in the sagittal plane was consistently 35% larger than the other circles and was termed the 'medial inferior circle'. There were strong correlations between the radii of the circles, the relative positions of the centres of the condyles, the width of the condyles, the total knee width and skeletal measurements including height. There was poor correlation between the radii of the circles and the position of the trochlea relative to the condyles. In summary, the condyles are approximately spherical except for the inferior facet medially, which has a larger radius in the sagittal plane. The size and position of the condyles are consistent and change with the size of the person. However, the position of the trochlea is variable even though its radius is similar to that of the condyles. This information has implications for understanding anterior knee pain and for the design of knee replacements. PMID- 25452365 TI - The usefulness of MRI and arthroscopy in the diagnosis and treatment of soft tissue injuries associated with split-depression fractures of the lateral tibial condyle. AB - The role of arthroscopy in the treatment of soft-tissue injuries associated with proximal tibial fractures remains debatable. Our hypothesis was that MRI over diagnoses clinically relevant associated soft-tissue injuries. This prospective study involved 50 consecutive patients who underwent surgical treatment for a split-depression fracture of the lateral tibial condyle (AO/OTA type B3.1). The mean age of patients was 50 years (23 to 86) and 27 (54%) were female. All patients had MRI and arthroscopy. Arthroscopy identified 12 tears of the lateral meniscus, including eight bucket-handle tears that were sutured and four that were resected, as well as six tears of the medial meniscus, of which five were resected. Lateral meniscal injuries were diagnosed on MRI in four of 12 patients, yielding an overall sensitivity of 33% (95% confidence interval (CI) 11 to 65). Specificity was 76% (95% CI 59 to 88), with nine tears diagnosed among 38 menisci that did not contain a tear. MRI identified medial meniscal injuries in four of six patients, yielding an overall sensitivity of 67% (95% CI 24 to 94). Specificity was 66% (95% CI 50 to 79), with 15 tears diagnosed in 44 menisci that did not contain tears. MRI appears to offer only a marginal benefit as the specificity and sensitivity for diagnosing meniscal injuries are poor in patients with a fracture. There were fewer arthroscopically-confirmed associated lesions than reported previously in MRI studies. PMID- 25452366 TI - The influence of diabetes mellitus on the post-operative outcome of elective primary total knee replacement: a systematic review and meta-analysis. AB - Total knee replacement (TKR) is an effective method of treating end-stage arthritis of the knee. It is not, however, a procedure without risk due to a number of factors, one of which is diabetes mellitus. The purpose of this study was to estimate the general prevalence of diabetes in patients about to undergo primary TKR and to determine whether diabetes mellitus adversely affects the outcome. We conducted a systematic review and meta-analysis according to the Meta analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. The Odds Ratio (OR) and mean difference (MD) were used to represent the estimate of risk of a specific outcome. Our results showed the prevalence of diabetes mellitus among patients undergoing TKR was 12.2%. Patients with diabetes mellitus had an increased risk of deep infection (OR = 1.61, 95% confidence interval (CI), 1.38 to 1.88), deep vein thrombosis (in Asia, OR = 2.57, 95% CI, 1.58 to 4.20), periprosthetic fracture (OR = 1.89, 95% CI, 1.04 to 3.45), aseptic loosening (OR = 9.36, 95% CI, 4.63 to 18.90), and a poorer Knee Society function subscore (MD = -5.86, 95% CI, -10.27 to -1.46). Surgeons should advise patients specifically about these increased risks when obtaining informed consent and be meticulous about their peri-operative care. PMID- 25452367 TI - Stepwise surgical correction of instability in flexion after total knee replacement. AB - Instability in flexion after total knee replacement (TKR) typically occurs as a result of mismatched flexion and extension gaps. The goals of this study were to identify factors leading to instability in flexion, the degree of correction, determined radiologically, required at revision surgery, and the subsequent clinical outcomes. Between 2000 and 2010, 60 TKRs in 60 patients underwent revision for instability in flexion associated with well-fixed components. There were 33 women (55%) and 27 men (45%); their mean age was 65 years (43 to 82). Radiological measurements and the Knee Society score (KSS) were used to assess outcome after revision surgery. The mean follow-up was 3.6 years (2 to 9.8). Decreased condylar offset (p < 0.001), distalisation of the joint line (p < 0.001) and increased posterior tibial slope (p < 0.001) contributed to instability in flexion and required correction at revision to regain stability. The combined mean correction of posterior condylar offset and joint line resection was 9.5 mm, and a mean of 5 degrees of posterior tibial slope was removed. At the most recent follow-up, there was a significant improvement in the mean KSS for the knee and function (both p < 0.001), no patient reported instability and no patient underwent further surgery for instability. The following step-wise approach is recommended: reduction of tibial slope, correction of malalignment, and improvement of condylar offset. Additional joint line elevation is needed if the above steps do not equalise the flexion and extension gaps. PMID- 25452368 TI - Re-admissions, re-operations and length of stay in hospital after aseptic revision knee replacement in Denmark: a two-year nationwide study. AB - We present detailed information about early morbidity after aseptic revision knee replacement from a nationwide study. All aseptic revision knee replacements undertaken between 1st October 2009 and 30th September 2011 were analysed using the Danish National Patient Registry with additional information from the Danish Knee Arthroplasty Registry. The 1218 revisions involving 1165 patients were subdivided into total revisions, large partial revisions, partial revisions and revisions of unicondylar replacements (UKR revisions). The mean age was 65.0 years (27 to 94) and the median length of hospital stay was four days (interquartile range: 3 to 5), with a 90 days re-admission rate of 9.9%, re operation rate of 3.5% and mortality rate of 0.2%. The age ranges of 51 to 55 years (p = 0.018), 76 to 80 years (p < 0.001) and >= 81 years (p < 0.001) were related to an increased risk of re-admission. The age ranges of 76 to 80 years (p = 0.018) and the large partial revision subgroup (p = 0.073) were related to an increased risk of re-operation. The ages from 76 to 80 years (p < 0.001), age >= 81 years (p < 0.001) and surgical time > 120 min (p < 0.001) were related to increased length of hospital stay, whereas the use of a tourniquet (p = 0.008) and surgery in a low volume centre (p = 0.013) were related to shorter length of stay. In conclusion, we found a similar incidence of early post-operative morbidity after aseptic knee revisions as has been reported after primary procedures. This suggests that a length of hospital stay <= four days and discharge home at that time is safe following aseptic knee revision surgery in Denmark. PMID- 25452369 TI - Increased risk of failure following revision total knee replacement in patients aged 55 years and younger. AB - The aims of this retrospective study were to compare the mid-term outcomes following revision total knee replacement (TKR) in 76 patients (81 knees) < 55 years of age with those of a matched group of primary TKRs based on age, BMI, gender and comorbid conditions. We report the activity levels, functional scores, rates of revision and complications. Compared with patients undergoing primary TKR, those undergoing revision TKR had less improvement in the mean Knee Society function scores (8.14 (-55 to +60) vs 23.3 points (-40 to +80), p < 0.001), a similar improvement in UCLA activity level (p = 0.52), and similar minor complication rates (16% vs 13%, p = 0.83) at a mean follow-up of 4.6 years (2 to 13.4). Further revision surgery was more common among revised TKRs (17% vs 5%, p = 0.02), with deep infection and instability being the most common reasons for failure. As many as one-third of patients aged < 55 years in the revision group had a complication or failure requiring further surgery. Young patients undergoing revision TKR should be counselled that they can expect somewhat less improvement and a higher risk of complications than occur after primary TKR. PMID- 25452370 TI - Return to theatre for elective hip and knee replacements: what is the relative importance of patient factors, surgeon and hospital? AB - The aim of this study was to define return to theatre (RTT) rates for elective hip and knee replacement (HR and KR), to describe the predictors and to show the variations in risk-adjusted rates by surgical team and hospital using national English hospital administrative data. We examined information on 260 206 HRs and 315 249 KRs undertaken between April 2007 and March 2012. The 90-day RTT rates were 2.1% for HR and 1.8% for KR. Male gender, obesity, diabetes and several other comorbidities were associated with higher odds for both index procedures. For HR, hip resurfacing had half the odds of cement fixation (OR = 0.58, 95% confidence intervals (CI) 0.47 to 0.71). For KR, unicondylar KR had half the odds of total replacement (OR = 0.49, 95% CI 0.42 to 0.56), and younger ages had higher odds (OR = 2.23, 95% CI 1.65 to 3.01) for ages < 40 years compared with ages 60 to 69 years). There were more funnel plot outliers at three standard deviations than would be expected if variation occurred on a random basis. Hierarchical modelling showed that three-quarters of the variation between surgeons for HR and over half the variation between surgeons for KR are not explained by the hospital they operated at or by available patient factors. We conclude that 90-day RTT rate may be a useful quality indicator for orthopaedics. PMID- 25452371 TI - Field testing the Unified Classification System for periprosthetic fractures of the femur, tibia and patella in association with knee replacement: an international collaboration. AB - The Unified Classification System (UCS) was introduced because of a growing need to have a standardised universal classification system of periprosthetic fractures. It combines and simplifies many existing classification systems, and can be applied to any fracture around any partial or total joint replacement occurring during or after operation. Our goal was to assess the inter- and intra observer reliability of the UCS in association with knee replacement when classifying fractures affecting one or more of the femur, tibia or patella. We used an international panel of ten orthopaedic surgeons with subspecialty fellowship training and expertise in adult hip and knee reconstruction ('experts') and ten residents of orthopaedic surgery in the last two years of training ('pre-experts'). They each received 15 radiographs for evaluation. After six weeks they evaluated the same radiographs again but in a different order. The reliability was assessed using the Kappa and weighted Kappa values. The Kappa values for inter-observer reliability for the experts and the pre-experts were 0.741 (95% confidence interval (CI) 0.707 to 0.774) and 0.765 (95% CI 0.733 to 0.797), respectively. The weighted Kappa values for intra-observer reliability for the experts and pre-experts were 0.898 (95% CI 0.846 to 0.950) and 0.878 (95% CI 0.815 to 0.942) respectively. The UCS has substantial inter-observer reliability and 'near perfect' intra-observer reliability when used for periprosthetic fractures in association with knee replacement in the hands of experienced and inexperienced users. PMID- 25452372 TI - The impact of diabetes on the short- to mid-term outcome of total ankle replacement. AB - We compared the clinical and radiographic results of total ankle replacement (TAR) performed in non-diabetic and diabetic patients. We identified 173 patients who underwent unilateral TAR between 2004 and 2011 with a minimum of two years' follow-up. There were 88 male (50.9%) and 85 female (49.1%) patients with a mean age of 66 years (sd 7.9, 43 to 84). There were 43 diabetic patients, including 25 with controlled diabetes and 18 with uncontrolled diabetes, and 130 non-diabetic patients. The clinical data which were analysed included the Ankle Osteoarthritis Scale (AOS) and the American Orthopaedic Foot and Ankle Society (AOFAS) scores, as well the incidence of peri-operative complications. The mean AOS and AOFAS scores were significantly better in the non-diabetic group (p = 0.018 and p = 0.038, respectively). In all, nine TARs (21%) in the diabetic group had clinical failure at a mean follow-up of five years (24 to 109), which was significantly higher than the rate of failure of 15 (11.6%) in the non-diabetic group (p = 0.004). The uncontrolled diabetic subgroup had a significantly poorer outcome than the non-diabetic group (p = 0.02), and a higher rate of delayed wound healing. The incidence of early-onset osteolysis was higher in the diabetic group than in the non-diabetic group (p = 0.02). These results suggest that diabetes mellitus, especially with poor glycaemic control, negatively affects the short- to mid-term outcome after TAR. PMID- 25452373 TI - Heterotopic ossification after surgery for distal humeral fractures. AB - We retrospectively reviewed 89 consecutive patients (45 men and 44 women) with a mean age at the time of injury of 58 years (18 to 97) who had undergone external fixation after sustaining a unilateral fracture of the distal humerus. Our objectives were to determine the incidence of heterotopic ossification (HO); identify risk factors associated with the development of HO; and characterise the location, severity and resultant functional impairment attributable to the presence of HO. HO was identified in 37 elbows (42%), mostly around the humerus and along the course of the medial collateral ligament. HO was hazy immature in five elbows (13.5%), mature discrete in 20 (54%), extensive mature in 10 (27%), and complete bone bridges were present in two elbows (5.5%). Mild functional impairment occurred in eight patients, moderate in 27 and severe in two. HO was associated with less extension (p = 0.032) and less overall flexion-to-extension movement (p = 0.022); the flexion-to-extension arc was < 100o in 21 elbows (57%) with HO compared with 18 elbows (35%) without HO (p = 0.03). HO was removed surgically in seven elbows. The development of HO was significantly associated with sustaining a head injury (p = 0.015), delayed internal fixation (p = 0.027), the method of fracture fixation (p = 0.039) and the use of bone graft or substitute (p = 0.02).HO continues to be a substantial complication after internal fixation for distal humerus fractures. PMID- 25452374 TI - Evaluation of the Instability Severity Index Score and the Western Ontario Shoulder Instability Index as predictors of failure following arthroscopic Bankart repair. AB - In this study we evaluated whether the Instability Severity Index Score (ISIS) and the Western Ontario Shoulder Instability Index (WOSI) could detect those patients at risk of failure following arthroscopic Bankart repair. Between April 2008 and June 2010, the ISIS and WOSI were recorded pre-operatively in 110 patients (87 male, 79%) with a mean age of 25.1 years (16 to 61) who underwent this procedure for recurrent anterior glenohumeral instability. A telephone interview was performed two-years post-operatively to determine whether patients had experienced a recurrent dislocation and whether they had returned to pre injury activity levels. In all, six (5%) patients had an ISIS > 6 points (0 to 9). Of 100 (91%) patients available two years post-operatively, six (6%) had a recurrent dislocation, and 28 (28%) did not return to pre-injury activity. No patient who dislocated had an ISIS > 6 (p = 1.0). There was no difference in the mean pre-operative WOSI in those who had a re-dislocation and those who did not (p = 0.99). The pre-operative WOSI was significantly lower (p = 0.02) in those who did not return to pre-injury activity, whereas the ISIS was not associated with return to pre-injury activity (p = 0.13). In conclusion, neither the pre operative ISIS nor WOSI predicted recurrent dislocation within two years of arthroscopic Bankart repair. Patients with a lower pre-operative WOSI were less likely to return to pre-injury activity. PMID- 25452375 TI - Patient-reported outcome and quality of life after total en bloc spondylectomy for a primary spinal tumour. AB - Total en bloc spondylectomy (TES) is the total resection of a vertebra containing a tumour. Many authors have investigated patient-reported outcomes after routine spinal surgery and surgery for tumours in general. However, this is the first report of patient-reported outcomes, including health-related quality of life (HRQoL) and satisfaction, after en bloc vertebral resection for a spinal tumour. Of the 54 patients who underwent TES for a primary tumour between 1993 and 2010, 19 died and four were lost to follow-up. In January 2012, a questionnaire was sent to the 31 surviving patients. This included the short form-36 to assess HRQoL and questions about the current condition of their disease, activities of daily living (ADL) and surgery. The response rate was high at 83.9% (26/31 patients). We found that most patients were satisfied and maintained good performance of their ADLs. The mental health status and social roles of the HRQoL scores were nearly equivalent to those of healthy individuals, regardless of the time since surgery. There was significant impairment of physical health in the early post-operative years, but this usually returned to normal approximately three years after surgery. PMID- 25452376 TI - Removal of the syndesmotic screw after the surgical treatment of a fracture of the ankle in adult patients does not affect one-year outcomes: a randomised controlled trial. AB - Our aim was to compare the one-year post-operative outcomes following retention or removal of syndesmotic screws in adult patients with a fracture of the ankle that was treated surgically. A total of 51 patients (35 males, 16 females), with a mean age of 33.5 years (16 to 62), undergoing fibular osteosynthesis and syndesmotic screw fixation, were randomly allocated to retention of the syndesmotic screw or removal at three months post-operatively. The two groups were comparable at baseline. One year post-operatively, there was no significant difference in the mean Olerud-Molander ankle score (82.4 retention vs 86.7 removal, p = 0.367), the mean American Orthopedic Foot and Ankle Society ankle hindfoot score (88.6 vs 90.1, p = 0.688), the mean American Academy of Orthopedic Surgeons foot and ankle score (96.3 vs 94.0, p = 0.250), the mean visual analogue pain score (1.0 vs 0.7, p = 0.237), the mean active dorsiflexion (10.2 degrees vs 13.0 degrees , p = 0.194) and plantar flexion (33.6 degrees vs 31.3 degrees , p = 0.503) of the ankle, or the mean radiological tibiofibular clear space (5.0 mm vs 5.3 mm, p = 0.276) between the two groups. A total of 19 patients (76%) in the retention group had a loose and/or broken screw one year post-operatively. We conclude that removal of a syndesmotic screw produces no significant functional, clinical or radiological benefit in adult patients who are treated surgically for a fracture of the ankle. PMID- 25452377 TI - Clinical outcome of pedestal cup endoprosthetic reconstruction after resection of a peri-acetabular tumour. AB - Peri-acetabular tumour resections and their subsequent reconstruction are among the most challenging procedures in orthopaedic oncology. Despite the fact that a number of different pelvic endoprostheses have been introduced, rates of complication remain high and long-term results are mostly lacking. In this retrospective study, we aimed to evaluate the outcome of reconstructing a peri acetabular defect with a pedestal cup endoprosthesis after a type 2 or type 2/3 internal hemipelvectomy. A total of 19 patients (11M:8F) with a mean age of 48 years (14 to 72) were included, most of whom had been treated for a primary bone tumour (n = 16) between 2003 and 2009. After a mean follow-up of 39 months (28 days to 8.7 years) seven patients had died. After a mean follow-up of 7.9 years (4.3 to 10.5), 12 patients were alive, of whom 11 were disease-free. Complications occurred in 15 patients. Three had recurrent dislocations and three experienced aseptic loosening. There were no mechanical failures. Infection occurred in nine patients, six of whom required removal of the prosthesis. Two patients underwent hindquarter amputation for local recurrence. The implant survival rate at five years was 50% for all reasons, and 61% for non-oncological reasons. The mean Musculoskeletal Tumor Society score at final follow-up was 49% (13 to 87). Based on these poor results, we advise caution if using the pedestal cup for reconstruction of a peri-acetabular tumour resection. PMID- 25452378 TI - John Fixsen (1934 to 2014). PMID- 25452381 TI - Contesting epistemic authority: Conspiracy theories on the boundaries of science. AB - Conspiracy theories are immensely popular today, yet in the social sciences they are often dismissed as "irrational," "bad science," or "religious belief." In this study, we take a cultural sociological approach and argue that this persistent disqualification is a form of "boundary work" that obscures rather than clarifies how and why conspiracy theorists challenge the epistemic authority of science. Based on a qualitative study of the Dutch conspiracy milieu, we distinguish three critiques that are motivated by encounters with scientific experts in everyday life: the alleged dogmatism of modern science, the intimate relation of scientific knowledge production with vested interests, and the exclusion of lay knowledge by scientific experts forming a global "power elite." Given their critique that resonates with social scientific understandings of science, it is concluded that conspiracy theorists compete with (social) scientists in complex battles for epistemic authority in a broader field of knowledge contestation. PMID- 25452382 TI - Letter to the editor: "fatty acids and placental transport: insight or in vitro artifact?". PMID- 25452383 TI - Reply to "Letter to the editor: 'fatty acids and placental transport: insight or in vitro artifact?'". PMID- 25452384 TI - Bromodomain and extraterminal domain inhibitors (BETi) for cancer therapy: chemical modulation of chromatin structure. AB - In cancer, epigenetic proteins are intensely studied targets for therapeutic drug discovery, showing great promise. These proteins include the chromatin-modifying enzymes that "write" and "erase" histone posttranslational modifications (PTM), and those that "read" these marks through binding modules. In an effort to find a compound that could disrupt the protein-protein interactions between a PTM and reader, JQ1 has proven to be a first-in-class, drug-like inhibitor of the "bromodomain and extraterminal domain" epigenetic readers (BETs), which recognize histone lysine acetylation marks. JQ1 has facilitated the mechanistic study and therapeutic application in cancer of this kind of epigenetic inhibition. By using this chemical probe, we have discovered that the bromodomain inhibitors (BETi) have compelling activity in preclinical models of multiple myeloma and acute myeloid leukemia. In particular, BETi down-regulates the MYC, IL-7R, and E2F transcriptional programs. We are continuously integrating the transcriptional consequences of BETi with changes in the epigenomic landscapes of cancer cells to elucidate the mechanisms underlying response to BETi using chemical and genetic perturbations. PMID- 25452386 TI - SOXC proteins amplify canonical WNT signaling to secure nonchondrocytic fates in skeletogenesis. AB - Canonical WNT signaling stabilizes beta-catenin to determine cell fate in many processes from development onwards. One of its main roles in skeletogenesis is to antagonize the chondrogenic transcription factor SOX9. We here identify the SOXC proteins as potent amplifiers of this pathway. The SOXC genes, i.e., Sox4, Sox11, and Sox12, are coexpressed in skeletogenic mesenchyme, including presumptive joints and perichondrium, but not in cartilage. Their inactivation in mouse embryo limb bud caused massive cartilage fusions, as joint and perichondrium cells underwent chondrogenesis. SOXC proteins govern these cells cell autonomously. They replace SOX9 in the adenomatous polyposis coli-Axin destruction complex and therein inhibit phosphorylation of beta-catenin by GSK3. This inhibition, a crucial, limiting step in canonical WNT signaling, thus becomes a constitutive event. The resulting SOXC/canonical WNT-mediated synergistic stabilization of beta-catenin contributes to efficient repression of Sox9 in presumptive joint and perichondrium cells and thereby ensures proper delineation and articulation of skeletal primordia. This synergy may determine cell fate in many processes besides skeletogenesis. PMID- 25452385 TI - Epigenetic regulation in plants. AB - The study of epigenetics in plants has a long and rich history, from initial descriptions of non-Mendelian gene behaviors to seminal discoveries of chromatin modifying proteins and RNAs that mediate gene silencing in most eukaryotes, including humans. Genetic screens in the model plant Arabidopsis have been particularly rewarding, identifying more than 130 epigenetic regulators thus far. The diversity of epigenetic pathways in plants is remarkable, presumably contributing to the phenotypic plasticity of plant postembryonic development and the ability to survive and reproduce in unpredictable environments. PMID- 25452387 TI - CDK5 is a major regulator of the tumor suppressor DLC1. AB - DLC1 is a tumor suppressor protein whose full activity depends on its presence at focal adhesions, its Rho-GTPase activating protein (Rho-GAP) function, and its ability to bind several ligands, including tensin and talin. However, the mechanisms that regulate and coordinate these activities remain poorly understood. Here we identify CDK5, a predominantly cytoplasmic serine/threonine kinase, as an important regulator of DLC1 functions. The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. In cancer, these anti-oncogenic effects of CDK5 can provide selective pressure for the down regulation of DLC1, which occurs frequently in tumors, and can contribute to the pro-oncogenic activity of CDK5 in lung adenocarcinoma. PMID- 25452388 TI - An Elmo-Dock complex locally controls Rho GTPases and actin remodeling during cadherin-mediated adhesion. AB - Cell-cell contact formation is a dynamic process requiring the coordination of cadherin-based cell-cell adhesion and integrin-based cell migration. A genome wide RNA interference screen for proteins required specifically for cadherin dependent cell-cell adhesion identified an Elmo-Dock complex. This was unexpected as Elmo-Dock complexes act downstream of integrin signaling as Rac guanine nucleotide exchange factors. In this paper, we show that Elmo2 recruits Dock1 to initial cell-cell contacts in Madin-Darby canine kidney cells. At cell-cell contacts, both Elmo2 and Dock1 are essential for the rapid recruitment and spreading of E-cadherin, actin reorganization, localized Rac and Rho GTPase activities, and the development of strong cell-cell adhesion. Upon completion of cell-cell adhesion, Elmo2 and Dock1 no longer localize to cell-cell contacts and are not required subsequently for the maintenance of cell-cell adhesion. These studies show that Elmo-Dock complexes are involved in both integrin- and cadherin based adhesions, which may help to coordinate the transition of cells from migration to strong cell-cell adhesion. PMID- 25452391 TI - No circulating human cytomegalovirus in 14 cases of glioblastoma. PMID- 25452390 TI - Glioma-derived versican promotes tumor expansion via glioma-associated microglial/macrophages Toll-like receptor 2 signaling. AB - BACKGROUND: Accumulation and infiltration of microglia/brain macrophages around and into glioma tissue promote tumor invasion and expansion. One tumor-promoting mechanism of microglia/brain macrophages is upregulation of membrane type 1 matrix metalloprotease (MT1-MMP), which promotes the degradation of extracellular matrix. MT1-MMP upregulation is induced by soluble factors released by glioma cells activating microglial Toll-like receptor 2 (TLR2). METHODS: Versican identified by proteomics was silenced in glioma cells by short interference RNA and short hairpin RNA approaches and studied in vitro and after injection into mouse brains or organotypic brain slices. RESULTS: The splice variants V0/V1 of the endogenous TLR2 ligand versican are highly expressed in mouse and human glioma tissue. Versican-silenced gliomas induced less MT1-MMP expression in microglia both in vitro and in vivo, which resulted in smaller tumors and longer survival rates as compared with controls. Recombinant versican V1 induced significantly higher levels of MT1-MMP in wild-type microglia compared with untreated and treated TLR2 knockout microglial cells. Using glioma-injected organotypic brain slices, we found that the impact of versican signaling on glioma growth depended on the presence of microglia. Moreover, we found that TLR2 expression is upregulated in glioma-associated microglia but not in astrocytes. Additionally, an established TLR2 neutralizing antibody reduced glioma-induced microglial MT1-MMP expression as well as glioma growth ex vivo. CONCLUSIONS: Our results show that versican released from glioma promotes tumor expansion through glioma-associated microglial/macrophage TLR2 signaling and subsequent expression of MT1-MMP. This signaling cascade might be a novel target for glioma therapies. PMID- 25452392 TI - Evidence of polyclonality in neurofibromatosis type 2-associated multilobulated vestibular schwannomas. AB - BACKGROUND: Neurofibromatosis type 2 (NF2) is a tumor syndrome that results from mutation of the NF2 tumor suppressor gene. The hallmark of NF2 is the presence of bilateral vestibular schwannoma (VS). Though NF2-associated and sporadic VS share identical histopathologic findings and cytogenetic alterations, NF2-associated VS often appears multilobulated, is less responsive to radiosurgery, and has worse surgical outcomes. Temporal bone autopsy specimens and MRI of the inner ear performed on NF2 patients suggest that multiple discrete tumors may be present within the labyrinth and cerebellopontine angle. METHODS: Treatment-naive ears in patients enrolled in a prospective NF2 natural history study (NIH#08-N-0044) were included for MRI analysis. T2-weighted and postcontrast T1-weighted MRIs were evaluated for the presence of multiple discrete tumors or a multilobulated mass. Peripheral blood (germline) and regional samples of tumor tissue were procured from consecutive patients enrolled in this study undergoing resection of a multilobulated VS (MVS). Histopathologic evaluation and genetic analysis (single nucleotide polymorphism array analysis, NF2 sequencing) were performed on each specimen. RESULTS: Over half of NF2 ears harbored either an MVS (60/139 ears) or multiple discrete masses (19/139 ears). For 4 successive MVSs, genetic analysis revealed an admixture of cell populations, each with its own somatic NF2 mutation or deletion. CONCLUSIONS: These findings suggest that the majority of NF2 associated VSs are polyclonal, such that the tumor mass represents a collision of multiple, distinct tumor clones. This explains the characteristic lobulated gross appearance of NF2-associated VS, and may also explain the substantially different treatment outcomes compared with sporadic VS. PMID- 25452393 TI - Factorial clinical trials: a new approach to phase II neuro-oncology studies. PMID- 25452394 TI - TERT promoter mutation designates biologically aggressive primary glioblastoma. PMID- 25452396 TI - Patient-reported outcome measures for patients with cerebral aneurysms acquired via social media: data from a large nationwide sample. AB - BACKGROUND: With greater survival rates, patient-reported outcome measures (PROMs) among survivors of ruptured cerebral aneurysm should be an increasing concern among neurointerventionalists. Prior studies were limited in scale and generalizability. Our study aims were to (1) evaluate the validity of cerebral aneurysm PROMs obtained from social media; (2) determine the persistence of PROMs over time; and (3) determine what PROMs still exist in those with no physical impairments. METHODS: By engaging national brain aneurysm support groups and using an online questionnaire modeled after the generic EQ-5D instrument, we asked respondents to classify their health in five dimensions including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression using a 3 point Likert scale. RESULTS: In 2 months we received 604 responses from 46 states in the USA. Our cohort of ruptured aneurysm respondents reported PROMs similar to previously published series. Over time, headache and anxiety improved while depression, level of exercise, and return to work remained unchanged. We found that memory worsened after 2 years. Among those without any physical impairment, rates of 20.6%, 14.9%, 12.6%, and 23% were seen for significant headaches, significant memory loss, significant depression, and sense of life being negatively affected, respectively. CONCLUSIONS: Despite this novel study design, we obtained results comparable to prior studies. These results suggest that many patients with ruptured cerebral aneurysms, regardless of whether they are >2 years after the event and/or free of physical impairment, struggle with a poor quality of life. The latency, scale, and low cost of this study design may accelerate future cerebral aneurysm PROM research. PMID- 25452397 TI - HPV infection status in cervical metaplastic carcinomas. PMID- 25452395 TI - Delayed contrast extravasation MRI: a new paradigm in neuro-oncology. AB - BACKGROUND: Conventional magnetic resonance imaging (MRI) is unable to differentiate tumor/nontumor enhancing tissues. We have applied delayed-contrast MRI for calculating high resolution treatment response assessment maps (TRAMs) clearly differentiating tumor/nontumor tissues in brain tumor patients. METHODS: One hundred and fifty patients with primary/metastatic tumors were recruited and scanned by delayed-contrast MRI and perfusion MRI. Of those, 47 patients underwent resection during their participation in the study. Region of interest/threshold analysis was performed on the TRAMs and on relative cerebral blood volume maps, and correlation with histology was studied. Relative cerebral blood volume was also assessed by the study neuroradiologist. RESULTS: Histological validation confirmed that regions of contrast agent clearance in the TRAMs >1 h post contrast injection represent active tumor, while regions of contrast accumulation represent nontumor tissues with 100% sensitivity and 92% positive predictive value to active tumor. Significant correlation was found between tumor burden in the TRAMs and histology in a subgroup of lesions resected en bloc (r(2) = 0.90, P < .0001). Relative cerebral blood volume yielded sensitivity/positive predictive values of 51%/96% and there was no correlation with tumor burden. The feasibility of applying the TRAMs for differentiating progression from treatment effects, depicting tumor within hemorrhages, and detecting residual tumor postsurgery is demonstrated. CONCLUSIONS: The TRAMs present a novel model-independent approach providing efficient separation between tumor/nontumor tissues by adding a short MRI scan >1 h post contrast injection. The methodology uses robust acquisition sequences, providing high resolution and easy to interpret maps with minimal sensitivity to susceptibility artifacts. The presented results provide histological validation of the TRAMs and demonstrate their potential contribution to the management of brain tumor patients. PMID- 25452398 TI - Serum free light chains in patients with HIV infection: their association with markers of disease severity and antiretroviral use. AB - AIM: Serum free light chain measurements are used to follow-up and manage patients with monoclonal gammopathies, and abnormal ratios are associated with risk of progression in certain diseases. B cell dysfunction is well described in HIV and patients are at risk of developing B cell lymphomas. This study investigated whether HIV is associated with abnormal free light chain levels and the impact of antiretroviral treatment (ART) on these. METHODS: kappa And lambda free light chain concentrations and ratios, serum albumin and immunoglobulin G (IgG) were measured in 366 HIV positive subjects and correlated with CD4+ counts, viral loads, IgG, albumin and ART use. RESULTS: 66% were women and most were black Africans (66%), 26% were of mixed ethnicity and 8% were Caucasian or of unknown or other race. 89% were on ART. kappa Free light chain values ranged from 5.59 to 357.0 mg/L (median 19.6 mg/L) and lambda free light chain values ranged from 9.28 to 286 mg/L (median 22.3 mg/L). Both correlated positively with viral load and IgG and negatively with CD4+ counts and albumin concentrations. The ratio only correlated with IgG concentrations. Patients on ART had significantly lower free light chain concentrations, but the ratio was not significantly affected. CONCLUSIONS: This study demonstrated that free light chain concentrations were significantly correlated with markers of HIV disease severity, suggesting ongoing B cell dysfunction despite ART use. Free light chain ratio was not significantly affected. PMID- 25452401 TI - Increased Age-Related Cardiac Dysfunction in Bradykinin B2 Receptor-Deficient Mice. AB - Experimental evidence indicates that the kinin peptide binds to bradykinin B2 receptor (B2R) to trigger various beneficial effects on the cardiovascular system. However, the effects and underlying mechanisms of B2R in cardiac aging remain unknown. A significant age-dependent decrease in B2R expression in the myocardium was observed in C57BL/6J mice. Echocardiographic measurements showed that aging caused a significant cardiac dysfunction in C57BL/6J mice, and importantly B2R deficiency augmented this dysfunction in aging mice. The deficiency of B2R expression in the aging heart repressed p53-pGC-1alpha-induced mitochondria renewal, increased reactive oxygen species production, and destroyed mitochondrial ultrastructure. Age-related decrease or lack of B2R increased oxidative stress, macrophage infiltration, and inflammatory cytokine expression and compromised antioxidant enzyme expression. Moreover, the inflammatory signals were mainly mediated by the activation of p38 MAPK, JNK, and subsequent translocation of nuclear factor-kappa B to the nucleus. In summary, our data provide evidence that B2R deficiency contributes to the aging-induced cardiac dysfunction, which is likely mediated by increased mitochondrial dysfunction, oxidative stress, and inflammation. This study indicates that preventing the loss of cardioprotective B2R expression may be a novel approach for the prevention and treatment of age-related cardiac dysfunction. PMID- 25452405 TI - Harnessing the therapeutic power of volunteering. PMID- 25452403 TI - Living Arrangements and Health of Older Adults in India. AB - OBJECTIVES: We investigate the association between the multigenerational household context and health of older adults in India, taking into account potential selection effects. METHODS: Using data from the India Human Development Survey (2004-05), a nationally representative multitopic data set, we employed a two-step analytical strategy--logistic regression followed by propensity score stratification method--to model the effect of contrasting living arrangement types on short-term illness. RESULTS: Overall, older adults living in multigenerational households have the lowest levels of short-term illness. Among them, those who live with their spouse, adult children, and young grandchildren experience the highest health gains. Health advantage diminishes when older adults live only with a spouse and adult children, and further diminishes when they live only with their spouse. Solitary living is associated with the highest likelihood of short-term morbidity. Good health is also shown to be associated with household wealth, gender, household size, and urban residence. DISCUSSION: Our study demonstrates that multigenerational households--the traditional and the most dominant form of living arrangement in India--have protective health benefits for older adults, while taking into account potential selection mechanisms. On Contrary to some epidemiological studies, we do not find any elevated risk of exposure to short-term illness, when older adults are living in households with young grandchildren. PMID- 25452402 TI - Telomerase Gene (hTERT) and Survival: Results From Two Swedish Cohorts of Older Adults. AB - Telomere length has been associated with longevity. As telomere length is partly determined by the human telomerase reverse transcriptase (hTERT), we investigated the association between an hTERT polymorphism located in its promoter region ((-) (1327)T/C) and longevity in two cohorts of older adults. Participants from the Kungsholmen project (KP; n = 1,205) and the Swedish National study of Aging and Care in Kungsholmen (SNAC-K; n = 2,764) were followed for an average period of 7.5 years. The main outcomes were hazard ratios (HR) of mortality and median age at death. In both cohorts, mortality was lower in female T/T carriers, aged 75+ years in KP (HR = 0.8, 95% CI: 0.5-0.9) and 78+ years in SNAC-K (HR = 0.6, 95% CI: 0.4-0.8) compared with female C/C carriers. T/T carriers died 1.8-3 years later than the C/C carriers. This effect was not present in men, neither in SNAC K women aged 60-72 years. The association was not modified by presence of cancer, cardiovascular diseases, number of chronic diseases, or markers of inflammation, and did not interact with APOE genotype or estrogen replacement therapy. The gender-specific increased survival in T/T carriers can be due to a synergistic effect between genetic background and the life-long exposure to endogenous estrogen. PMID- 25452406 TI - Enteral nutrition in the prevention and treatment of pressure ulcers in adult critical care patients. AB - Prevention and healing of pressure ulcers in critically ill patients can be especially challenging because of the patients' burden of illness and degree of physiological compromise. Providing adequate nutrition may help halt the development or worsening of pressure ulcers. Optimization of nutrition can be considered an essential ingredient in prevention and healing of pressure ulcers. Understanding malnutrition in critical care patients, the effect of nutrition on wound healing, and the application of evidence-based nutritional guidelines are important aspects for patients at high risk for pressure ulcers. Appropriate screenings for nutritional status and risk for pressure ulcers, early collaboration with a registered dietician, and administration of appropriate feeding formulations and micronutrient and macronutrient supplementation to promote wound healing are practical solutions to improve the nutritional status of critical care patients. Use of nutritional management and enteral feeding protocols may provide vital elements to augment nutrition and ultimately result in improved clinical outcomes. PMID- 25452408 TI - The Adam Williams initiative: collaborating with community resources to improve care for traumatic brain injury. AB - BACKGROUND: The Brain Trauma Foundation has developed treatment guidelines for the care of patients with acute traumatic brain injury. However, a method to provide broad acceptance and application of these guidelines has not been published. OBJECTIVE: To describe methods for the development, funding, and continued educational efforts of the Adam Williams Initiative; the experiences from the first 10 years may serve as a template for hospitals and nurses that seek to engage in long-term quality improvement collaborations with foundations and/or industry. METHODS: In 2004, the nonprofit Adam Williams Initiative was established with the goal of providing education and resources that would encourage hospitals across the United States to incorporate the Brain Trauma Foundation's guidelines into practice. RESULTS: Between 2004 and 2014, 37 hospitals have been funded by the Adam Williams Initiative and have had staff members participate in an immersion experience at Mission Hospital (Mission Viejo, California) during which team members received both didactic and hands-on education in the care of traumatic brain injury. CONCLUSIONS: Carefully cultivated relationships and relentless teamwork have contributed to successful implementation of the Brain Trauma Foundation's guidelines in US hospitals. PMID- 25452409 TI - Introduction to complementary, alternative, and traditional therapies. AB - The use of complementary, alternative, and traditional therapies is increasing in the United States, and patients and their families are bringing these practices into the acute care setting. Acute and critical care nurses are in a unique and trusted position to advocate for their patients and to promote safe incorporation of complementary, alternative, and traditional therapies into the plan of care. PMID- 25452410 TI - Quality improvement or research--deciding which road to take. AB - Critical care nurses are constantly challenged to provide safe, high-quality patient care at a low cost with increasingly scarce resources while implementing the latest evidence-based practices into their own clinical practice. This article is the first in a 4-part series to provide a practical quality improvement guide for critical care nurses interested in implementing system process or performance improvement projects within their own units. Part 1 is designed to answer the question "What method is better for measuring real-world patient outcomes-quality improvement or clinical research?" A broad overview of the differences between quality improvement and clinical research is provided. A newly published checklist to differentiate between attributes of each process is introduced, and readers can test their own knowledge between quality improvement and research with a quick quiz of studies recently published in Critical Care Nurse. PMID- 25452407 TI - Improving patients' readiness for coronary artery bypass graft surgery. AB - BACKGROUND: Preoperative interventions improve outcomes for patients after coronary artery bypass surgery (CABG). OBJECTIVE: To reduce mortality for patients undergoing urgent CABG. METHODS: Eight centers implemented preoperative aspirin and statin, preinduction heart rate less than 80/min, hematocrit greater than 30%, blood sugar less than 150 mg/dL (8.3 mmol/L), and delayed surgery at least 3 days after a myocardial infarction. Data were collected on the last 150 isolated, urgent CABGs at each center (n=1200). A "bundle" score of 0 to 100 was calculated for each patient to represent the percentage of interventions used. RESULTS: Scores ranged from 33 to 100. About 56% of patients had a perfect score. Crude mortality and composite rates were lower in patients with higher scores, but once adjusted for patient and disease characteristics, the difference in scores was not significant. Higher scores were associated with shorter intubation: 6.0 hours (score 100), 8.0 hours (score 80-99), 8.4 hours (score<80) (log-rank P<.001). Median length of stay was shorter for patients with higher scores: 5 days (score 100), 6 days (scores 80-99), and 6 days (scores <80) (log rank P<.001). CONCLUSION: Implementation of interventions to optimize patients' "readiness for surgery" is associated with shorter intubation times and shorter hospital stays after CABG. PMID- 25452411 TI - Becoming certified is wicked good. PMID- 25452412 TI - Sequential compression devices and clots. PMID- 25452414 TI - Dim down the lights: implementing quiet time in the coronary care unit. PMID- 25452416 TI - I am a critical care nurse. PMID- 25452418 TI - Mean of the typical decoding rates: a new translation efficiency index based on the analysis of ribosome profiling data. AB - Gene translation modeling and prediction is a fundamental problem that has numerous biomedical implementations. In this work we present a novel, user friendly tool/index for calculating the mean of the typical decoding rates that enables predicting translation elongation efficiency of protein coding genes for different tissue types, developmental stages, and experimental conditions. The suggested translation efficiency index is based on the analysis of the organism's ribosome profiling data. This index could be used for example to predict changes in translation elongation efficiency of lowly expressed genes that usually have relatively low and/or biased ribosomal densities and protein levels measurements, or can be used for example for predicting translation efficiency of new genetically engineered genes. We demonstrate the usability of this index via the analysis of six organisms in different tissues and developmental stages. Distributable cross platform application and guideline are available for download at: http://www.cs.tau.ac.il/~tamirtul/MTDR/MTDR_Install.html. PMID- 25452421 TI - Qualitative health research : one quarter of a century. PMID- 25452419 TI - Parallel profiling of fission yeast deletion mutants for proliferation and for lifespan during long-term quiescence. AB - Genetic factors underlying aging are remarkably conserved from yeast to human. The fission yeast Schizosaccharomyces pombe is an emerging genetic model to analyze cellular aging. Chronological lifespan (CLS) has been studied in stationary-phase yeast cells depleted for glucose, which only survive for a few days. Here, we analyzed CLS in quiescent S. pombe cells deprived of nitrogen, which arrest in a differentiated, G0-like state and survive for more than 2 months. We applied parallel mutant phenotyping by barcode sequencing (Bar-seq) to assay pooled haploid deletion mutants as they aged together during long-term quiescence. As expected, mutants with defects in autophagy or quiescence were under-represented or not detected. Lifespan scores could be calculated for 1199 mutants. We focus the discussion on the 48 most long-lived mutants, including both known aging genes in other model systems and genes not previously implicated in aging. Genes encoding membrane proteins were particularly prominent as pro aging factors. We independently verified the extended CLS in individual assays for 30 selected mutants, showing the efficacy of the screen. We also applied Bar seq to profile all pooled deletion mutants for proliferation under a standard growth condition. Unlike for stationary-phase cells, no inverse correlation between growth and CLS of quiescent cells was evident. These screens provide a rich resource for further studies, and they suggest that the quiescence model can provide unique, complementary insights into cellular aging. PMID- 25452420 TI - Identical substitutions in magnesium chelatase paralogs result in chlorophyll deficient soybean mutants. AB - The soybean [Glycine max (L.) Merr.] chlorophyll-deficient line MinnGold is a spontaneous mutant characterized by yellow foliage. Map-based cloning and transgenic complementation revealed that the mutant phenotype is caused by a nonsynonymous nucleotide substitution in the third exon of a Mg-chelatase subunit gene (ChlI1a) on chromosome 13. This gene was selected as a candidate for a different yellow foliage mutant, T219H (Y11y11), that had been previously mapped to chromosome 13. Although the phenotypes of MinnGold and T219H are clearly distinct, sequencing of ChlI1a in T219H identified a different nonsynonymous mutation in the third exon, only six base pairs from the MinnGold mutation. This information, along with previously published allelic tests, were used to identify and clone a third yellow foliage mutation, CD-5, which was previously mapped to chromosome 15. This mutation was identified in the ChlI1b gene, a paralog of ChlI1a. Sequencing of the ChlI1b allele in CD-5 identified a nonsynonymous substitution in the third exon that confers an identical amino acid change as the T219H substitution at ChlI1a. Protein sequence alignments of the two Mg-chelatase subunits indicated that the sites of amino acid modification in MinnGold, T219H, and CD-5 are highly conserved among photosynthetic species. These results suggest that amino acid alterations in this critical domain may create competitive inhibitory interactions between the mutant and wild-type ChlI1a and ChlI1b proteins. PMID- 25452422 TI - Feasibility of a mindfulness-based intervention to address youth issues in Vietnam. AB - Youth problems including risky sex, drug use, violence and mental health issues are on the rise in Vietnam. Mindfulness is proposed as one way to address unskillful responses to stress that give rise to these behavioral and psychosocial issues in Vietnam. This study explores the feasibility of a mindfulness program for adolescents and young adults in a central city in Vietnam. The mindfulness-based intervention was comprised 1-h daily session over 3 weeks that was conducted at two different sites, one with handicapped adolescents/young adults at the Vocational School for Handicapped and the other with at-risk youth at a semi-private high school. Forty-two Vietnamese youth participants and five Vietnamese teachers/facilitators who were trained in the mindfulness program provided personal reflections of their experiences. Analyses of the qualitative data suggest that mindfulness was enthusiastically received and accepted by both youth and teachers. There is strong indication that mindfulness is promising as a prevention strategy to help with stress and to build important life skills among Vietnamese youth. PMID- 25452424 TI - Immunology and skin in health and disease. AB - The skin is a complex organ that, in addition to providing a strong barrier against external insults, serves as an arena for a wide variety of inflammatory processes, including immunity against infections, tumor immunity, autoimmunity, and allergy. A variety of cells collaborate to mount functional immune responses, which are initiated by resident populations and evolve through the recruitment of additional cell populations to the skin. Inflammatory responses are quite diverse, resulting in a wide range of signs and symptoms that depend on the initiating signals, characteristics of the infiltrating cell populations, and cytokines that are produced (cytokines are secreted protein that allows for cell cell communication; usually refers to communication between immune-immune cells or stromal-immune cells). In this work, we will review the skin architecture and resident and recruited cell populations and discuss how these populations contribute to inflammation using human diseases and treatments when possible to illustrate their importance within a clinical context. PMID- 25452425 TI - Laparoscopic Surgery In The Treatment of Gastrointestinal Stromal Tumors. AB - BACKGROUND AND AIMS: Gastrointestinal stromal tumors are rare neoplasms of the gastrointestinal tract. These lesions are characterized by different levels of malignancy. Only radical surgery offers a chance of curing the disease. The aim of this study is to present the results of gastrointestinal stromal tumor treatment with minimally invasive surgery. MATERIAL AND METHODS: The study group included 27 patients operated laparoscopically on for gastrointestinal stromal tumor with laparoscopic surgery between September 2009 and December 2013. The most common location of the tumor was the stomach (21 patients, 77.8%) and the small intestine (4 patients, 14.8%). We analyzed early surgery results, the number and character of complications, lengths of hospital stays, histological types of the removed tumors, and long-term results of treatment. RESULTS: There was no need for conversion to open surgery in any patient from the study group. Post-surgery complications occurred in 2 patients (7.4%). The median duration of the hospital stay was 4.5 days; none of the patients had to be readmitted to the hospital in the first 30 days after the procedure. In 26 out of 27 patients, microscopic examination confirmed the radicality of the surgical procedure (R0 resection). The mean size of the removed lesions was 4.1 cm. Using the Joensuu malignancy classification model, it was established that in 6 (22.2%) patients gastrointestinal stromal tumor was characterized by a very low level of malignancy, in 11 patients (40.7%) a low level, in 4 (14.9%) a medium level, and in 6 (22.2%) a high level. The average duration of follow-up was 13 months. During the observation period, there was no recurrence of the disease. CONCLUSION: Minimally invasive surgery in the treatment of gastrointestinal stromal tumors is possible and allows for satisfactory results both in terms of the postoperative course and the oncological quality of the procedure. PMID- 25452423 TI - Epidermal polarity genes in health and disease. AB - The epidermis of the skin is a highly polarized, metabolic tissue with important innate immune functions. The polarity of the epidermis is, for example, reflected in controlled changes in cell shape that accompany differentiation, oriented cell division, and the planar orientation of hair follicles and cilia. The establishment and maintenance of polarity is organized by a diverse set of polarity proteins that include transmembrane adhesion proteins, cytoskeletal scaffold proteins, and kinases. Although polarity proteins have been extensively studied in cell culture and in vivo in simple epithelia of lower organisms, their role in mammalian tissue biology is only slowly evolving. This article will address the importance of polarizing processes and their molecular regulators in epidermal morphogenesis and homeostasis and discuss how alterations in polarity may contribute to skin disease. PMID- 25452426 TI - Effects of a combination of umeclidinium/vilanterol on exercise endurance in patients with chronic obstructive pulmonary disease: two randomized, double-blind clinical trials. AB - OBJECTIVE: Exercise intolerance is a hallmark of chronic obstructive pulmonary disease (COPD). METHODS: Patients with COPD were randomized in two multicentre, double-blind, incomplete block crossover studies. Patients received two of six treatments in sequence (12 weeks each): placebo, umeclidinium (UMEC)/vilanterol (VI) (125/25 mcg or 62.5/25 mcg), VI (25 mcg) or UMEC (62.5 mcg or 125 mcg). Exercise endurance time (EET) and trough forced expiratory volume in 1 second (FEV1) (Week 12) were co-primary endpoints. Safety was monitored throughout. RESULTS: Both studies showed similar 3-hour post-dose EET improvements from baseline for UMEC/VI (Week 12). Significant EET improvements were observed with both UMEC/VI doses versus placebo at Week 12 in Study 418 (UMEC/VI 125/25 mcg: 65.8 s; p = 0.005; UMEC/VI 62.5/25 mcg: 69.4 s; p = 0.003), but not in Study 417, where a placebo effect was evident. Post hoc integrated data analysis showed significant but smaller EET improvements for both UMEC/VI doses versus placebo at Week 12 (UMEC/VI 125/25 mcg: 47.5 s; p = 0.002; UMEC/VI 62.5/25 mcg: 43.7 s; p = 0.001). Both studies showed trough FEV1 improvements at Week 12 for both UMEC/VI doses. The incidence of adverse events was similar between treatment groups within each study. CONCLUSIONS: UMEC/VI improved lung function and EET. PMID- 25452427 TI - The CCC2000 Birth Cohort Study of Register-Based Family History of Mental Disorders and Psychotic Experiences in Offspring. AB - Psychotic experiences (PE) in individuals of the general population are hypothesized to mark the early expression of the pathology underlying psychosis. This notion of PE as an intermediate phenotype is based on the premise that PE share genetic liability with psychosis. We examined whether PE in childhood was predicted by a family history of mental disorder with psychosis rather than a family history of nonpsychotic mental disorder and whether this association differed by severity of PE. The study examined data on 1632 children from a general population birth cohort assessed at age 11-12 years by use of a semistructured interview covering 22 psychotic symptoms. The Danish national registers were linked to describe the complete family history of hospital-based psychiatric diagnoses. Uni- and multivariable logistic regressions were used to test whether a family history of any mental disorder with psychosis, or of nonpsychotic mental disorder, vs no diagnoses was associated with increased risk of PE in offspring (hierarchical exposure variable). The occurrence of PE in offspring was significantly associated with a history of psychosis among the first-degree relatives (adjusted relative risk [RR] = 3.29, 95% CI: 1.82-5.93). The risk increased for combined hallucinations and delusions (adjusted RR = 5.90, 95% CI: 2.64-13.16). A history of nonpsychotic mental disorders in first-degree relatives did not contribute to the risk of PE in offspring nor did any mental disorder among second-degree relatives. Our findings support the notion of PE as a vulnerability marker of transdiagnostic psychosis. The effect of psychosis in first-degree relatives may operate through shared genetic and environmental factors. PMID- 25452428 TI - SEPN1, an endoplasmic reticulum-localized selenoprotein linked to skeletal muscle pathology, counteracts hyperoxidation by means of redox-regulating SERCA2 pump activity. AB - Selenoprotein N (SEPN1) is a broadly expressed resident protein of the endoplasmic reticulum (ER) whose loss-of-function inexplicably leads to human muscle disease. We found that SEPN1 levels parallel those of endoplamic reticulum oxidoreductin 1 (ERO1), an ER protein thiol oxidase, and that SEPN1's redox activity defends the ER from ERO1-generated peroxides. Moreover, we have defined the redox-regulated interactome of SEPN1 and identified the ER calcium import SERCA2 pump as a redox-partner of SEPN1. SEPN1 enhances SERCA2 activity by reducing luminal cysteines that are hyperoxidized by ERO1-generated peroxides. Cells lacking SEPN1 are hypersensitive to ERO1 overexpression and conspicuously defective in ER calcium re-uptake. After being muscle-transduced with an adeno associated virus driving ERO1alpha, SEPN1 knockout mice unmasks a myopathy that resembles the dense core disease due to human mutations in SEPN1, whereas the combined attenuation of ERO1alpha and SEPN1 enhances cell fitness. These observations reveal the involvement of SEPN1 in ER redox and calcium homeostasis and that an ERO1 inhibitor, restoring redox-dependent calcium homeostasis, may ameliorate the myopathy of SEPN1 deficiency. PMID- 25452430 TI - ATRX promotes gene expression by facilitating transcriptional elongation through guanine-rich coding regions. AB - ATRX is a chromatin remodeling protein involved in deposition of the histone variant H3.3 at telomeres and pericentromeric heterochromatin. It also influences the expression level of specific genes; however, deposition of H3.3 at transcribed genes is currently thought to occur independently of ATRX. We focused on a set of genes, including the autism susceptibility gene Neuroligin 4 (Nlgn4), that exhibit decreased expression in ATRX-null cells to investigate the mechanisms used by ATRX to promote gene transcription. Overall TERRA levels, as well as DNA methylation and histone modifications at ATRX target genes are not altered and thus cannot explain transcriptional dysregulation. We found that ATRX does not associate with the promoter of these genes, but rather binds within regions of the gene body corresponding to high H3.3 occupancy. These intragenic regions consist of guanine-rich DNA sequences predicted to form non-B DNA structures called G-quadruplexes during transcriptional elongation. We demonstrate that ATRX deficiency corresponds to reduced H3.3 incorporation and stalling of RNA polymerase II at these G-rich intragenic sites. These findings suggest that ATRX promotes the incorporation of histone H3.3 at particular transcribed genes and facilitates transcriptional elongation through G-rich sequences. The inability to transcribe genes such as Nlgn4 could cause deficits in neuronal connectivity and cognition associated with ATRX mutations in humans. PMID- 25452429 TI - Ataxia is the major neuropathological finding in arylsulfatase G-deficient mice: similarities and dissimilarities to Sanfilippo disease (mucopolysaccharidosis type III). AB - Deficiency of arylsulfatase G (ARSG) leads to a lysosomal storage disease in mice resembling biochemical and pathological features of the mucopolysaccharidoses and particularly features of mucopolysaccharidosis type III (Sanfilippo syndrome). Here we show that Arsg KO mice share common neuropathological findings with other Sanfilippo syndrome models and patients, but they can be clearly distinguished by the limitation of most phenotypic alterations to the cerebellum, presenting with ataxia as the major neurological finding. We determined in detail the expression of ARSG in the central nervous system and observed highest expression in perivascular macrophages (which are characterized by abundant vacuolization in Arsg KO mice) and oligodendrocytes. To gain insight into possible mechanisms leading to ataxia, the pathology in older adult mice (>12 months) was investigated in detail. This study revealed massive loss of Purkinje cells and gliosis in the cerebellum, and secondary accumulation of glycolipids like GM2 and GM3 gangliosides and unesterified cholesterol in surviving Purkinje cells, as well as neurons of some other brain regions. The abundant presence of ubiquitin and p62-positive aggregates in degenerating Purkinje cells coupled with the absence of significant defects in macroautophagy is consistent with lysosomal membrane permeabilization playing a role in the pathogenesis of Arsg-deficient mice and presumably Sanfilippo disease in general. Our data delineating the phenotype of mucopolysaccharidosis IIIE in a mouse KO model should help in the identification of possible human cases of this disease. PMID- 25452431 TI - alpha-Synuclein modifies mutant huntingtin aggregation and neurotoxicity in Drosophila. AB - Protein misfolding and aggregation is a major hallmark of neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Until recently, the consensus was that each aggregation-prone protein was characteristic of each disorder [alpha-synuclein (alpha-syn)/PD, mutant huntingtin (Htt)/HD, Tau and amyloid beta peptide/AD]. However, growing evidence indicates that aggregation-prone proteins can actually co-aggregate and modify each other's behavior and toxicity, suggesting that this process may also contribute to the overlap in clinical symptoms across different diseases. Here, we show that alpha-syn and mutant Htt co-aggregate in vivo when co-expressed in Drosophila and produce a synergistic age-dependent increase in neurotoxicity associated to a decline in motor function and life span. Altogether, our results suggest that the co-existence of alpha-syn and Htt in the same neuronal cells worsens aggregation-related neuropathologies and accelerates disease progression. PMID- 25452433 TI - Histopathological and Immunohistochemical Characterization of Methyl Eugenol induced Nonneoplastic and Neoplastic Neuroendocrine Cell Lesions in Glandular Stomach of Rats. AB - Methyl eugenol induces neuroendocrine (NE) cell hyperplasia and tumors in F344/N rat stomach. Detailed histopathological and immunohistochemical (IHC) characterization of these tumors has not been previously reported. The objective of this study was to fill that data gap. Archived slides and paraffin blocks were retrieved from the National Toxicology Program Archives. NE hyperplasias and tumors were stained with chromogranin A, synaptophysin, amylase, gastrin, H(+)/K(+) adenosine triphosphatase (ATPase), pepsinogen, somatostatin, and cytokeratin 18 (CK18) antibodies. Many of the rats had gastric mucosal atrophy, due to loss of chief and parietal cells. The hyperplasias and tumors were confined to fundic stomach, and females were more affected than the males. Hyperplasia of NE cells was not observed in the pyloric region. Approximately one third of the females with malignant NE tumors had areas of pancreatic acinar differentiation. The rate of metastasis was 21%, with liver being the most common site of metastasis. Immunohistochemically, the hyperplasias and tumors stained consistently with chromogranin A and synaptophysin. Neoplastic cells were also positive for amylase and CK18 and negative for gastrin, somatostatin, H(+)/K(+) ATPase, and pepsinogen. Metastatic neoplasms histologically similar to the primary neoplasm stained positively for chromogranin A and synaptophysin. Based on the histopathological and IHC features, the neoplasms appear to arise from enterochromaffin-like cells. PMID- 25452432 TI - A defect in early myogenesis causes Otitis media in two mouse models of 22q11.2 Deletion Syndrome. AB - Otitis media (OM), the inflammation of the middle ear, is the most common disease and cause for surgery in infants worldwide. Chronic Otitis media with effusion (OME) often leads to conductive hearing loss and is a common feature of a number of craniofacial syndromes, such as 22q11.2 Deletion Syndrome (22q11.2DS). OM is more common in children because the more horizontal position of the Eustachian tube (ET) in infants limits or delays clearance of middle ear effusions. Some mouse models with OM have shown alterations in the morphology and angle of the ET. Here, we present a novel mechanism in which OM is caused not by a defect in the ET itself but in the muscles that control its function. Our results show that in two mouse models of 22q11.2DS (Df1/+ and Tbx1(+/-)) presenting with bi- or unilateral OME, the fourth pharyngeal arch-derived levator veli palatini muscles were hypoplastic, which was associated with an earlier altered pattern of MyoD expression. Importantly, in mice with unilateral OME, the side with the inflammation was associated with significantly smaller muscles than the contralateral unaffected ear. Functional tests examining ET patency confirmed a reduced clearing ability in the heterozygous mice. Our findings are also of clinical relevance as targeting hypoplastic muscles might present a novel preventative measure for reducing the high rates of OM in 22q11.2DS patients. PMID- 25452434 TI - A PDE-Based Regularization Algorithm Toward Reducing Speckle Tracking Noise: A Feasibility Study for Ultrasound Breast Elastography. AB - Obtaining accurate ultrasonically estimated displacements along both axial (parallel to the acoustic beam) and lateral (perpendicular to the beam) directions is an important task for various clinical elastography applications (e.g., modulus reconstruction and temperature imaging). In this study, a partial differential equation (PDE)-based regularization algorithm was proposed to enhance motion tracking accuracy. More specifically, the proposed PDE-based algorithm, utilizing two-dimensional (2D) displacement estimates from a conventional elastography system, attempted to iteratively reduce noise contained in the original displacement estimates by mathematical regularization. In this study, tissue incompressibility was the physical constraint used by the above mentioned mathematical regularization. This proposed algorithm was tested using computer-simulated data, a tissue-mimicking phantom, and in vivo breast lesion data. Computer simulation results demonstrated that the method significantly improved the accuracy of lateral tracking (e.g., a factor of 17 at 0.5% compression). From in vivo breast lesion data investigated, we have found that, as compared with the conventional method, higher quality axial and lateral strain images (e.g., at least 78% improvements among the estimated contrast-to-noise ratios of lateral strain images) were obtained. Our initial results demonstrated that this conceptually and computationally simple method could be useful for improving the image quality of ultrasound elastography with current clinical equipment as a post-processing tool. PMID- 25452435 TI - Age at menopause in women with type 1 diabetes mellitus: the OVADIA study. AB - STUDY QUESTION: Is type 1 diabetes a determinant of advanced ovarian ageing, resulting in an early age at natural menopause? SUMMARY ANSWER: No clear evidence was provided that type 1 diabetes is a determinant of accelerated ovarian ageing resulting in an early menopause. WHAT IS KNOWN ALREADY: The association between type 1 diabetes and early menopause has been examined previously with inconsistent results. STUDY DESIGN, SIZE, DURATION: A cross-sectional study was performed in 140 post-menopausal women with, and 5426 post-menopausal women without, diabetes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Both women with and without diabetes had experienced natural menopause. Study participants filled out a standardized questionnaire including report of their age at last menstrual period. Differences in menopausal age were analysed using linear regression analyses, with adjustment for possible confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Mean age at natural menopause was 49.8 +/- 4.7 years in women with type 1 diabetes and 49.8 +/- 4.1 in women without diabetes. Linear regression analyses showed that type 1 diabetes was not associated with an earlier menopause compared with the reference group without diabetes, after adjustment for age, smoking history and parity (difference in age at menopause between women with type 1 diabetes and reference group 0.34 years, 95% confidence interval -0.34, 1.01). LIMITATIONS, REASON FOR CAUTION: Age at menopause was self-reported and assessed retrospectively. We had no information regarding microvascular complications therefore a possible association between vascular health and menopausal age could not be investigated. WIDER IMPLICATIONS OF THE FINDINGS: It has been hypothesized that the possible mechanism behind an accelerated ovarian ageing process in type 1 diabetes is prolonged poor glycaemic control and subsequent effects on vascular health. The improved glycaemic control during the last decades may have prevented vascular damage from occurring to an extent that would affect organ function. Nevertheless, the present findings are reassuring for reproductive health prospects in women with type 1 diabetes. PMID- 25452436 TI - Targeting high mobility group box protein 1 ameliorates testicular inflammation in experimental autoimmune orchitis. AB - STUDY QUESTION: Does high mobility group box protein 1 (HMGB1) regulate inflammatory reactions in a rat model of experimental autoimmune orchitis (EAO)? SUMMARY ANSWER: HMGB1 appears to be involved in regulating inflammatory reactions in testes, as HMGB1 is translocated from testicular cells during the course of EAO and blocking its action by ethyl pyruvate (EP) reduces disease progression and spermatogenic damage. WHAT IS KNOWN ALREADY: Despite its immune privileged status, the human testis is prone to inflammatory lesions associated with male factor infertility. Accumulating evidence shows that HMGB1 plays an important role in onset and progression of autoimmune diseases. STUDY DESIGN, SIZE, DURATION: This is a cross sectional and longitudinal study involving Wistar male rats immunized with testicular homogenates to induce EAO 50 (EAO50; n = 10) and 80 (EAO80; n = 10) days after first immunization. Control adjuvant animals received saline instead of testicular homogenate (n = 16). Untreated animals (n = 10) were also studied. An interventional study was performed to block the action of HMGB1 starting 20 days after first immunization in EAO animals and respective controls (n = 17). Rats were treated i.p. with EP and the effect of EP treatment on testicular pathogenesis was evaluated 30 days later. Moreover, human testicular biopsies from infertile men with focal lymphocytic infiltrates (n = 7) and sections with intact spermatogenesis (n = 6) were probed with antibodies against HMGB1. PARTICIPANTS/MATERIALS, SETTING, METHODS: Testicular RNA and protein extracts from EAO animals, EAO animals treated with EP and relevant controls were used for analysis of cytokine expression by real-time RT-PCR and enzyme-linked immunosorbent assay. HMGB1 was co-localized on rat testicular cross sections with antibodies against testicular macrophages (TM), peritubular cells (PTC) and Sertoli cells (SC). Interaction of HMGB1 and its receptors (RAGE, TLR4) as well signaling pathways after HMGB1 stimulation were studied in isolated TM, PTC and SC by proximity ligation assay and western blot, respectively. Furthermore, HMGB1 immunofluorescence on human testicular biopsies was performed. MAIN RESULTS AND THE ROLE OF CHANCE: HMGB1 was translocated from the nuclei in EAO testes and testes of infertile men with impaired spermatogenesis and lymphocytic infiltrates. Elevated HMGB1 levels were observed during late phase of EAO. In testicular somatic cells HMGB1 receptors Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) were differentially expressed: HMGB1-TLR4 binding was predominant in TM, while HMGB1-RAGE interaction was prevalent in SC and PTC. In support, HMGB1 triggered extracellular signal regulated kinase (ERK)1/2 and cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) activation in SC and PTC, while TM responded to HMGB1 stimulation with p38 mitogen-activated protein kinase (MAPK) and p65 nuclear factor Kappa B (NF-KB) phosphorylation followed by increased tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) mRNA levels. In vivo treatment of EAO animals with EP 20 days after induction of disease revealed beneficial effects, as documented by reduced disease progression and spermatogenic damage, lower macrophage numbers, as well as decreased concentrations of HMGB1 and IL-6 in the testis compared with EAO controls. LIMITATIONS, REASONS FOR CAUTION: The ability of HMGB1 to bind to a wide range of receptors makes it difficult to prevent its action by blockade of a specific receptor; therefore we applied EP, a drug preventing HMGB1 release from cells. Due to its mode of action EP decreases also the secretion of some other pro inflammatory cytokines. Using isolated primary cells imposes limitations for cell transfection studies. As a compromise between purity and yield primary cells need to be isolated from animals of different age, which has to be considered when comparing their responses. WIDER IMPLICATIONS OF THE FINDINGS: HMGB1 could be a promising target in attenuating testicular damage caused by inflammatory reactions. PMID- 25452438 TI - The long and winding road. PMID- 25452437 TI - Randomized exercise trial of aromatase inhibitor-induced arthralgia in breast cancer survivors. AB - PURPOSE: Arthralgia occurs in up to 50% of breast cancer survivors treated with aromatase inhibitors (AIs) and is the most common reason for poor AI adherence. We conducted, in 121 breast cancer survivors receiving an AI and reporting arthralgia, a yearlong randomized trial of the impact of exercise versus usual care on arthralgia severity. PATIENTS AND METHODS: Eligibility criteria included receiving an AI for at least 6 months, reporting >= 3 of 10 for worst joint pain on the Brief Pain Inventory (BPI), and reporting < 90 minutes per week of aerobic exercise and no strength training. Participants were randomly assigned to exercise (150 minutes per week of aerobic exercise and supervised strength training twice per week) or usual care. The BPI, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index, and Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire were completed at baseline and at 3, 6, 9, and 12 months. Intervention effects were evaluated using mixed-model repeated measures analysis, with change at 12 months as the primary end point. RESULTS: Over 12 months, women randomly assigned to exercise (n = 61) attended 70% (+/- standard deviation [SD], 28%) of resistance training sessions and increased their exercise by 159 (+/- SD, 136) minutes per week. Worst joint pain scores decreased by 1.6 points (29%) at 12 months among women randomly assigned to exercise versus a 0.2 point increase (3%) among those receiving usual care (n = 60; P < .001). Pain severity and interference, as well as DASH and WOMAC pain scores, also decreased significantly at 12 months in women randomly assigned to exercise, compared with increases for those receiving usual care (all P < .001). CONCLUSION: Exercise led to improvement in AI-induced arthralgia in previously inactive breast cancer survivors. PMID- 25452439 TI - Revised risk classification for pediatric extracranial germ cell tumors based on 25 years of clinical trial data from the United Kingdom and United States. AB - PURPOSE: To risk stratify malignant extracranial pediatric germ cell tumors (GCTs). PATIENTS AND METHODS: Data from seven GCT trials conducted by the Children's Oncology Group (United States) or the Children's Cancer and Leukemia Group (United Kingdom) between 1985 and 2009 were merged to create a data set of patients with stage II to IV disease treated with platinum-based therapy. A parametric cure model was used to evaluate the prognostic importance of age, tumor site, stage, histology, tumor markers, and treatment regimen and estimate the percentage of patients who achieved long-term disease-free (LTDF) survival in each subgroup of the final model. Validation of the model was conducted using the bootstrap method. RESULTS: In multivariable analysis of 519 patients with GCTs, stage IV disease (P = .001), age >= 11 years (P < .001), and tumor site (P < .001) were significant predictors of worse LTDF survival. Elevated alpha fetoprotein (AFP) >= 10,000 ng/mL was associated with worse outcome, whereas pure yolk sac tumor (YST) was associated with better outcome, although neither met criteria for statistical significance. The analysis identified a group of patients age > 11 years with either stage III to IV extragonadal tumors or stage IV ovarian tumors with predicted LTDF survival < 70%. A bootstrap procedure showed retention of age, tumor site, and stage in > 94%, AFP in 12%, and YST in 27% of the replications. CONCLUSION: Clinical trial data from two large national pediatric clinical trial organizations have produced a new evidence-based risk stratification of malignant pediatric GCTs that identifies a poor-risk group warranting intensified therapy. PMID- 25452440 TI - High-dose chemotherapy for recurrent ovarian germ cell tumors. PMID- 25452442 TI - Effectiveness of neoadjuvant chemoradiotherapy for early-stage esophageal cancer. PMID- 25452443 TI - Reply to B. Gyawali et Al. PMID- 25452444 TI - Reply to P.S.N. van Rossum et al and J. Shapiro et al. PMID- 25452441 TI - Inherited mutations in 17 breast cancer susceptibility genes among a large triple negative breast cancer cohort unselected for family history of breast cancer. AB - PURPOSE: Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. PATIENTS AND METHODS: Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. RESULTS: Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations. CONCLUSION: Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives. PMID- 25452445 TI - Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node positive breast cancer: the SN FNAC study. AB - PURPOSE: An increasing proportion of patients (> 30%) with node-positive breast cancer will obtain an axillary pathologic complete response after neoadjuvant chemotherapy (NAC). If sentinel node (SN) biopsy (SNB) is accurate in this setting, completion node dissection (CND) morbidity could be avoided. PATIENTS AND METHODS: In the prospective multicentric SN FNAC study, patients with biopsy proven node-positive breast cancer (T0-3, N1-2) underwent both SNB and CND. Immunohistochemistry (IHC) use was mandatory, and SN metastases of any size, including isolated tumor cells (ypN0[i+], <= 0.2 mm), were considered positive. The optimal SNB identification rate (IR) >= 90% and false-negative rate (FNR) <= 10% were predetermined. RESULTS: From March 2009 to December 2012, 153 patients were accrued to the study. The SNB IR was 87.6% (127 of 145; 95% CI, 82.2% to 93.0%), and the FNR was 8.4% (seven of 83; 95% CI, 2.4% to 14.4%). If SN ypN0(i+)s had been considered negative, the FNR would have increased to 13.3% (11 of 83; 95% CI, 6.0% to 20.6%). There was no correlation between size of SN metastases and rate of positive non-SNs. Using this method, 30.3% of patients could potentially avoid CND. CONCLUSION: In biopsy-proven node-positive breast cancer after NAC, a low SNB FNR (8.4%) can be achieved with mandatory use of IHC. SN metastases of any size should be considered positive. The SNB IR was 87.6%, and in the presence of a technical failure, axillary node dissection should be performed. We recommend that SN evaluation with IHC be further evaluated before being included in future guidelines on the use of SNB after NAC in this setting. PMID- 25452448 TI - National Cancer Institute-supported clinical trials networks. PMID- 25452446 TI - Randomized, double-blind, placebo-controlled, multicenter phase II study of the efficacy and safety of apricoxib in combination with either docetaxel or pemetrexed in patients with biomarker-selected non-small-cell lung cancer. AB - PURPOSE: Overexpression of COX-2 correlates with advanced stage and worse outcomes in non-small-cell lung cancer (NSCLC), possibly as a result of elevated levels of COX-2-dependent prostaglandin E2 (PGE2). Exploratory analyses of studies that used COX-2 inhibitors have demonstrated potentially superior outcome in patients in whom the urinary metabolite of PGE2 (PGE-M) is suppressed. We hypothesized that patients with disease defined by PGE-M suppression would benefit from the addition of apricoxib to second-line docetaxel or pemetrexed. PATIENTS AND METHODS: Patients with NSCLC who had disease progression after one line of platinum-based therapy, performance status of 0 to 2, and normal organ function were potentially eligible. Only patients with a >= 50% decrease in urinary PGE-M after 5 days of treatment with apricoxib could enroll. Docetaxel 75 mg/m(2) or pemetrexed 500 mg/m(2) once every 21 days per the investigator was administered with apricoxib or placebo 400 mg once per day. The primary end point was progression-free survival (PFS). Exploratory analysis was performed regarding baseline urinary PGE-M and outcomes. RESULTS: In all, 101 patients completed screening, and 72 of the 80 who demonstrated >= 50% suppression were randomly assigned to apricoxib or placebo. Toxicity was similar between the arms. No improvement in PFS was seen with apricoxib versus placebo. The median PFS for the control arm was 97 days (95% CI, 52 to 193 days) versus 85 days (95% CI, 67 to 142 days) for the experimental arm (P = .91). CONCLUSION: Apricoxib did not improve PFS, despite biomarker-driven patient selection. PMID- 25452447 TI - Randomized placebo-controlled trial of cognitive behavioral therapy and armodafinil for insomnia after cancer treatment. AB - PURPOSE: Insomnia is a distressing and often persisting consequence of cancer. Although cognitive behavioral therapy for insomnia (CBT-I) is the treatment of choice in the general population, the use of CBT-I in patients with cancer is complicated, because it can result in transient but substantial increases in daytime sleepiness. In this study, we evaluated whether CBT-I, in combination with the wakefulness-promoting agent armodafinil (A), results in better insomnia treatment outcomes in cancer survivors than CBT-I alone. PATIENTS AND METHODS: We report on a randomized trial of 96 cancer survivors (mean age, 56 years; female, 87.5%; breast cancer, 68%). The primary analyses examined whether >= one of the 7 week intervention conditions (ie, CBT-I, A, or both), when compared with a placebo capsule (P) group, produced significantly greater clinical gains. Insomnia was assessed by the Insomnia Severity Index and sleep quality by the Pittsburgh Sleep Quality Inventory. All patients received sleep hygiene instructions. RESULTS: Analyses controlling for baseline differences showed that both the CBT-I plus A (P = .001) and CBT-I plus P (P = .010) groups had significantly greater reductions in insomnia severity postintervention than the P group, with effect sizes of 1.31 and 1.02, respectively. Similar improvements were seen for sleep quality. Gains on both measures persisted 3 months later. CBT I plus A was not significantly different from CBT-I plus P (P = .421), and A alone was not significantly different from P alone (P = .584). CONCLUSION: CBT-I results in significant and durable improvements in insomnia and sleep quality. A did not significantly improve the efficacy of CBT-I or independently affect insomnia or sleep quality. PMID- 25452449 TI - Neoadjuvant chemoradiotherapy for stage I and II esophageal cancer. PMID- 25452450 TI - Some questions on the randomized controlled trial of communication skills training for oncologists. PMID- 25452451 TI - Tumor markers in older patients with early breast cancer: why are we still doing useless tests? PMID- 25452453 TI - Clouds of oxygen: adolescents with cancer tell their story in music. PMID- 25452452 TI - Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. AB - PURPOSE: Nivolumab is a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody that restores T-cell immune activity. This phase II trial assessed the antitumor activity, dose-response relationship, and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Patients with clear-cell mRCC previously treated with agents targeting the vascular endothelial growth factor pathway were randomly assigned (blinded ratio of 1:1:1) to nivolumab 0.3, 2, or 10 mg/kg intravenously once every 3 weeks. The primary objective was to evaluate the dose-response relationship as measured by progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 168 patients were randomly assigned to the nivolumab 0.3- (n = 60), 2- (n = 54), and 10-mg/kg (n = 54) cohorts. One hundred eighteen patients (70%) had received more than one prior systemic regimen. Median PFS was 2.7, 4.0, and 4.2 months, respectively (P = .9). Respective ORRs were 20%, 22%, and 20%. Median OS was 18.2 months (80% CI, 16.2 to 24.0 months), 25.5 months (80% CI, 19.8 to 28.8 months), and 24.7 months (80% CI, 15.3 to 26.0 months), respectively. The most common treatment-related adverse event (AE) was fatigue (24%, 22%, and 35%, respectively). Nineteen patients (11%) experienced grade 3 to 4 treatment-related AEs. CONCLUSION: Nivolumab demonstrated antitumor activity with a manageable safety profile across the three doses studied in mRCC. No dose-response relationship was detected as measured by PFS. These efficacy and safety results in mRCC support study in the phase III setting. PMID- 25452454 TI - Science and society: Fifty years later--the 2014 presidential address. PMID- 25452455 TI - Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. AB - PURPOSE: To provide recommendations on prevention, screening, genetics, treatment, and management for people at risk for hereditary colorectal cancer (CRC) syndromes. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS: The Familial Risk Colorectal Cancer: European Society for Medical Oncology Clinical Practice Guideline published in 2013 on behalf of the European Society for Medical Oncology (ESMO) Guidelines Working Group in Annals of Oncology was reviewed for developmental rigor by methodologists, with content and recommendations reviewed by an ASCO endorsement panel. RESULTS: The ASCO endorsement panel determined that the recommendations of the ESMO guidelines are clear, thorough, and based on the most relevant scientific evidence. The ASCO panel endorsed the ESMO guidelines and added a few qualifying statements. RECOMMENDATIONS: Approximately 5% to 6% of patient cases of CRC are associated with germline mutations that confer an inherited predisposition for cancer. The possibility of a hereditary cancer syndrome should be assessed for every patient at the time of CRC diagnosis. A diagnosis of Lynch syndrome, familial adenomatous polyposis, or another genetic syndrome can influence clinical management for patients with CRC and their family members. Screening for hereditary cancer syndromes in patients with CRC should include review of personal and family histories and testing of tumors for DNA mismatch repair deficiency and/or microsatellite instability. Formal genetic evaluation is recommended for individuals who meet defined criteria. PMID- 25452457 TI - Neurogenic muscle hypertrophy. PMID- 25452456 TI - Disentangling interactions between atmospheric pollution and weather. PMID- 25452458 TI - rTMS in fibromyalgia: a randomized trial evaluating QoL and its brain metabolic substrate. PMID- 25452459 TI - Intensive care unit admission in multiple sclerosis: Increased incidence and increased mortality. PMID- 25452460 TI - Teaching neuroimages: eosinophilic infiltration and necrotizing vasculitis on nerve biopsy in Churg-Strauss syndrome. PMID- 25452461 TI - Issue @ a glance. PMID- 25452462 TI - 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. PMID- 25452463 TI - The molecular bases of delta/alphabeta T cell-mediated antigen recognition. AB - alphabeta and gammadelta T cells are disparate T cell lineages that can respond to distinct antigens (Ags) via the use of the alphabeta and gammadelta T cell Ag receptors (TCRs), respectively. Here we characterize a population of human T cells, which we term delta/alphabeta T cells, expressing TCRs comprised of a TCR delta variable gene (Vdelta1) fused to joining alpha and constant alpha domains, paired with an array of TCR-beta chains. We demonstrate that these cells, which represent ~50% of all Vdelta1(+) human T cells, can recognize peptide- and lipid based Ags presented by human leukocyte antigen (HLA) and CD1d, respectively. Similar to type I natural killer T (NKT) cells, CD1d-lipid Ag-reactive delta/alphabeta T cells recognized alpha-galactosylceramide (alpha-GalCer); however, their fine specificity for other lipid Ags presented by CD1d, such as alpha-glucosylceramide, was distinct from type I NKT cells. Thus, delta/alphabetaTCRs contribute new patterns of Ag specificity to the human immune system. Furthermore, we provide the molecular bases of how delta/alphabetaTCRs bind to their targets, with the Vdelta1-encoded region providing a major contribution to delta/alphabetaTCR binding. Our findings highlight how components from alphabeta and gammadeltaTCR gene loci can recombine to confer Ag specificity, thus expanding our understanding of T cell biology and TCR diversity. PMID- 25452465 TI - Measurements of plasma metanephrines by immunoassay vs liquid chromatography with tandem mass spectrometry for diagnosis of pheochromocytoma. AB - BACKGROUND: Reports conflict concerning measurements of plasma metanephrines (MNs) for diagnosis of pheochromocytomas/paragangliomas (PPGLs) by immunoassays compared with other methods. We aimed to compare the performance of a commercially available enzyme-linked immunoassay (EIA) kit with liquid chromatography-tandem mass spectrometric (LC-MS/MS) measurements of MNs to diagnose PPGLs. METHODS: In a substudy of a prospective, multicenter trial to study the biochemical profiles of monoamine-producing tumors, we included 341 patients (174 males and 167 females) with suspected PPGLs (median age 54 years), of whom 54 had confirmed PPGLs. Plasma MNs were measured by EIA and LC-MS/MS, each in a specialized laboratory. RESULTS: Plasma normetanephrine (NMN) and MN were measured 60 and 39% lower by EIA than by LC-MS/MS. Using upper cut-offs stipulated for the EIA, diagnostic sensitivity was only 74.1% at a specificity of 99.3%. In contrast, use of similar cut-offs for MN and overall lower age-adjusted cut-offs for NMN measured by LC-MS/MS returned a diagnostic sensitivity and specificity of 98.1 and 99.7%. Areas under receiver-operating characteristic curves, nevertheless, indicated comparable diagnostic performance of the EIA (0.993) and LC-MS/MS (0.985). Diagnostic sensitivity for the EIA increased to 96.2% with a minimal loss in specificity (95.1%) following use of cut-offs for the EIA adapted to correct for the negative bias. CONCLUSIONS: The EIA underestimates plasma MNs and diagnostic sensitivity is poor using commonly stipulated cut-offs, resulting in a high risk for missing patients with PPGLs. Correction of this shortcoming can be achieved by appropriately determined cut offs resulting in comparable diagnostic performance of EIA and LC-MS/MS assays. PMID- 25452466 TI - Management of endocrine disease: pituitary tumour apoplexy. AB - Pituitary tumour apoplexy (PA) is a rare clinical syndrome that occurs as a result of acute haemorrhage and/or infarction within a frequently undiagnosed pituitary tumour. The sudden enlargement of the pituitary mass undergoing PA is responsible for a wide range of acute symptoms/signs (severe headache, visual loss, diplopia, hypopituitarism, impaired consciousness) which, together with the radiological evidence of a pituitary lesion, establish the diagnosis. The optimal care of PA requires involvement of a multidisciplinary team including endocrinologist, neurosurgeon, neuroophthalmologist and the management strategy that depends on the clinical manifestations, as well as the presence of co morbidities. Prompt surgical decompression is initially indicated in cases with severe or progressive impairment of the visual acuity or the visual fields or with altered mental state and leads to visual and neurological recovery in most of the patients. The patients with mild, stable clinical picture (including those with isolated ocular palsies) can be managed conservatively (support of fluid and electrolyte balance and stress doses of steroids in most cases) with favourable visual and neurological outcome. Frequent reassessment is mandatory because the clinical course can be unpredictable; if progression of symptoms occurs, later elective surgery is indicated and is beneficial, especially in terms of visual outcome. The endocrinological outcome is less favourable, irrespective of the treatment option, with many patients remaining on long-term replacement therapy. Despite the above guidelines, clear proof of optimal outcomes in the form of randomised controlled trials is lacking. Regrowth of the pituitary tumour years after a PA episode is possible and patients require long-term surveillance. PMID- 25452464 TI - Bmi1 enhances skeletal muscle regeneration through MT1-mediated oxidative stress protection in a mouse model of dystrophinopathy. AB - The Polycomb group (PcG) protein Bmi1 is an essential epigenetic regulator of stem cell function during normal development and in adult organ systems. We show that mild up-regulation of Bmi1 expression in the adult stem cells of the skeletal muscle leads to a remarkable improvement of muscle function in a mouse model of Duchenne muscular dystrophy. The molecular mechanism underlying enhanced physiological function of Bmi1 depends on the injury context and it is mediated by metallothionein 1 (MT1)-driven modulation of resistance to oxidative stress in the satellite cell population. These results lay the basis for developing Bmi1 pharmacological activators, which either alone or in combination with MT1 agonists could be a powerful novel therapeutic approach to improve regeneration in muscle wasting conditions. PMID- 25452467 TI - Shift of the TSH reference range with improved iodine supply in Northeast Germany. AB - OBJECTIVE: Germany was iodine deficient until the mid-1990s when a nationwide iodine fortification program became effective. It is expected that after a longer period of sufficient iodine supply, median TSH values in the general population will shift to the right. Hence, the previous TSH reference range does not reflect the current TSH distribution in the general population of Germany. Thus, we aimed to establish a new reference range for serum TSH levels. DESIGN AND METHODS: We used data from the Study of Health in Pomerania TREND, a population-based study including 4420 individuals. The reference population consisted of 1596 individuals without diagnosed thyroid diseases or thyroid-related findings in ultrasound and serum analysis. Serum TSH levels were measured by an immunochemiluminescent procedure on a Siemens Dimension Vista. RESULTS: The overall reference range for TSH was 0.49 mIU/l (95% CI=0.44; 0.53)-3.29 mIU/l (95% CI=3.08; 3.50). The lower reference limit differed significantly by sex, whereas the upper reference limit showed no significant difference between males and females. Age was significantly associated with the 2.5th TSH percentile in males but not in females, whereas age was significantly associated in males and females for the 97.5th TSH percentile. CONCLUSIONS: We demonstrate a shift toward the right of the TSH reference range in comparison with data from the same study region 10 years earlier, which is likely due to the improved iodine supply of the study region. Our study indicates that TSH reference limits are dependent on past and current iodine supply of populations. PMID- 25452468 TI - Pulse wave velocity ratio: the new "gold standard" for measuring arterial stiffness. PMID- 25452469 TI - Soluble guanylate cyclase is required for systemic vasodilation but not positive inotropy induced by nitroxyl in the mouse. AB - Nitroxyl (HNO), the reduced and protonated form of nitric oxide (NO.), confers unique physiological effects including vasorelaxation and enhanced cardiac contractility. These features have spawned current pharmaceutical development of HNO donors as heart failure therapeutics. HNO interacts with selective redox sensitive cysteines to effect signaling but is also proposed to activate soluble guanylate cyclase (sGC) in vitro to induce vasodilation and potentially enhance contractility. Here, we tested whether sGC stimulation is required for these HNO effects in vivo and if HNO also modifies a redox-sensitive cysteine (C42) in protein kinase G-1alpha to control vasorelaxation. Intact mice and isolated arteries lacking the sGC-beta subunit (sGCKO, results in full sGC deficiency) or expressing solely a redox-dead C42S mutant protein kinase G-1alpha were exposed to the pure HNO donor, CXL-1020. CXL-1020 induced dose-dependent systemic vasodilation while increasing contractility in controls; however, vasodilator effects were absent in sGCKO mice whereas contractility response remained. The CXL-1020 dose reversing 50% of preconstricted force in aortic rings was ~400-fold greater in sGCKO than controls. Cyclic-GMP and cAMP levels were unaltered in myocardium exposed to CXL-1020, despite its inotropic-vasodilator activity. In protein kinase G-1alpha(C42S) mice, CXL-1020 induced identical vasorelaxation in vivo and in isolated aortic and mesenteric vessels as in littermate controls. In both groups, dilation was near fully blocked by pharmacologically inhibiting sGC. Thus, sGC and cGMP-dependent signaling are necessary and sufficient for HNO induced vasodilation in vivo but are not required for positive inotropic action. Redox modulation of protein kinase G-1alpha is not a mechanism for HNO-mediated vasodilation. PMID- 25452470 TI - Neurokinin 3 receptor and phosphocholine transferase: missing factors for pathogenesis of C-reactive protein in preeclampsia. AB - C-reactive protein (CRP), an innate immune mediator, is elevated in the circulation before symptoms in patients with preeclampsia, a severe hypertensive pregnancy disorder with high mortality and morbidity. However, the specific sources underlying increased CRP and the role of elevated CRP in preeclampsia are undefined. Here, we report that circulating CRP levels are significantly increased in a large cohort of normotensive pregnant individuals when compared with nulligravid women and is further increased in patients with preeclampsia. These findings led us to discover further that placental syncytiotrophoblasts are previously unrecognized cellular sources of CRP and underlie elevated CRP in normotensive pregnant women and the additional increase in patients with preeclampsia. Next, we demonstrated that injection of CRP induces preeclampsia features, including hypertension (157 mm Hg CRP treated versus 119 mm Hg control), proteinuria (35.0 mg/MUg CRP treated versus 14.1 mg/MUg control), kidney, and placental damage and increased levels of sFlt-1 in pregnant mice but not in nonpregnant mice. Our study implicates that phosphocholine transferase, a placental-specific enzyme post-translationally modifying neurokinin B, is essential for the pathogenic role of CRP in preeclampsia through activation of the neurokinin 3 receptor. Overall, our studies have provided significant new insight on the pathogenic role of CRP in preeclampsia and highlighted innovative therapeutic strategies. PMID- 25452471 TI - Augmented vascular smooth muscle cell stiffness and adhesion when hypertension is superimposed on aging. AB - Hypertension and aging are both recognized to increase aortic stiffness, but their interactions are not completely understood. Most previous studies have attributed increased aortic stiffness to changes in extracellular matrix proteins that alter the mechanical properties of the vascular wall. Alternatively, we hypothesized that a significant component of increased vascular stiffness in hypertension is due to changes in the mechanical and adhesive properties of vascular smooth muscle cells, and that aging would augment the contribution from vascular smooth muscle cells when compared with the extracellular matrix. Accordingly, we studied aortic stiffness in young (16-week-old) and old (64-week old) spontaneously hypertensive rats and Wistar-Kyoto wild-type controls. Systolic and pulse pressures were significantly increased in young spontaneously hypertensive rats when compared with young Wistar-Kyoto rats, and these continued to rise in old spontaneously hypertensive rats when compared with age-matched controls. Excised aortic ring segments exhibited significantly greater elastic moduli in both young and old spontaneously hypertensive rats versus Wistar-Kyoto rats. were isolated from the thoracic aorta, and stiffness and adhesion to fibronectin were measured by atomic force microscopy. Hypertension increased both vascular smooth muscle cell stiffness and vascular smooth muscle cell adhesion, and these increases were both augmented with aging. By contrast, hypertension did not affect histological measures of aortic collagen and elastin, which were predominantly changed by aging. These findings support the concept that stiffness and adhesive properties of vascular smooth muscle cells are novel mechanisms contributing to the increased aortic stiffness occurring with hypertension superimposed on aging. PMID- 25452472 TI - Maternal diet during gestation and lactation modifies the severity of salt induced hypertension and renal injury in Dahl salt-sensitive rats. AB - Environmental exposure of parents or early in life may affect disease development in adults. We found that hypertension and renal injury induced by a high-salt diet were substantially attenuated in Dahl SS/JrHsdMcwiCrl (SS/Crl) rats that had been maintained for many generations on the grain-based 5L2F diet compared with SS/JrHsdMcwi rats (SS/Mcw) maintained on the casein-based AIN-76A diet (mean arterial pressure, 116+/-9 versus 154+/-25 mm Hg; urinary albumin excretion, 23+/ 12 versus 170+/-80 mg/d). RNAseq analysis of the renal outer medulla identified 129 and 82 genes responding to a high-salt diet uniquely in SS/Mcw and SS/Crl rats, respectively, along with minor genetic differences between the SS substrains. The 129 genes responding to salt in the SS/Mcw strain included numerous genes with homologs associated with hypertension, cardiovascular disease, or renal disease in human. To narrow the critical window of exposure, we performed embryo-transfer experiments in which single-cell embryos from 1 colony (SS/Mcw or SS/Crl) were transferred to surrogate mothers from the other colony, with parents and surrogate mothers maintained on their respective original diet. All offspring were fed the AIN-76A diet after weaning. Salt-induced hypertension and renal injury were substantially exacerbated in rats developed from SS/Crl embryos transferred to SS/Mcw surrogate mothers. Conversely, salt-induced hypertension and renal injury were significantly attenuated in rats developed from SS/Mcw embryos transferred to SS/Crl surrogate mothers. Together, the data suggest that maternal diet during the gestational-lactational period has substantial effects on the development of salt-induced hypertension and renal injury in adult SS rats. PMID- 25452473 TI - Aortic-brachial stiffness mismatch and mortality in dialysis population. AB - We hypothesized that increased aortic stiffness (central elastic artery) combined with a decrease in brachial stiffness (peripheral muscular artery) leads to the reversal of the physiological stiffness gradient (ie, mismatch), promoting end organ damages through increased forward pressure wave transmission into the microcirculation. We, therefore, examined the effect of aortic-brachial stiffness mismatch on mortality in patients in need of dialysis. In a prospective observational study, aortic-brachial arterial stiffness mismatch (pulse wave velocity ratio) was assessed using carotid-femoral pulse wave velocity divided by carotid-radial pulse wave velocity in 310 adult patients on dialysis. After a median follow-up of 29 months, 146 (47%) deaths occurred. The hazard ratio (HR) for mortality related to PWV ratio in a Cox regression analysis was 1.43 (95% confidence interval [CI], 1.24-1.64; P<0.001 per 1 SD) and was still significant after adjustments for confounding factors, such as age, dialysis vintage, sex, cardiovascular disease, diabetes mellitus, smoking status, and weight (HR, 1.23; 95% CI: 1.02-1.49). The HRs for changes in 1 SD of augmentation index (HR, 1.35; 95% CI, 1.12-1.63), carotid-femoral pulse wave velocity (HR, 1.29; 95% CI, 1.11 1.50), and carotid-radial pulse wave velocity (HR, 0.80; 95% CI, 0.67-0.95) were statistically significant in univariate analysis, but were no longer statistically significant after adjustment for age. In conclusion, aortic brachial arterial stiffness mismatch was strongly and independently associated with increased mortality in this dialysis population. Further studies are required to confirm these finding in lower-risk groups. PMID- 25452474 TI - Salt-sensitive hypertension: food for thought. PMID- 25452475 TI - Glucagon-like peptide-1 and blood pressure in young and healthy adults from the general population. AB - Hypertension and diabetes mellitus are highly correlated, but the underlying mechanisms are only partly understood. Therefore, the aim of our study was to investigate the relationships between plasma levels of glucagon-like peptide-1, a key factor in the regulation of glucose homeostasis, and various blood pressure indices. Healthy adults aged 25 to 41 years were enrolled in a population-based study. Established cardiovascular disease, diabetes mellitus, or a body mass index >35 kg/m(2) were exclusion criteria. Fasting plasma glucagon-like peptide-1 levels as determined with a novel high-sensitive assay and ambulatory blood pressure data were available in 1479 participants not using antihypertensive treatment. Median age of our population was 38 years. Mean systolic and diastolic blood pressure across increasing glucagon-like peptide-1 quartiles were 120.6, 122.8, 123.2, and 124.9 mm Hg and 77.1, 78.7, 78.9, and 79.9 mm Hg, respectively. We found a linear relationship of glucagon-like peptide-1 with 24-hour ambulatory blood pressure after multivariable adjustment (beta per 1 log-unit increase 2.01; 95% confidence interval, 1.02-3.00; P<0.0001 for systolic and 1.22; 0.47-1.97; P=0.002 for diastolic blood pressure). In separate analyses, glucagon-like peptide-1 was significantly related to both awake (beta per 1 log-unit increase 2.05; 1.02-3.09; P=0.0001 for systolic and 1.15; 0.35-1.96; P=0.005 for diastolic blood pressure) and asleep blood pressure (beta per 1 log-unit increase 1.34; 0.26-2.42; P=0.01 for systolic and 1.05; 0.26-1.84; P=0.009 for diastolic blood pressure). In conclusion, plasma levels of glucagon-like peptide-1 are significantly associated with both systolic and diastolic blood pressure levels. PMID- 25452476 TI - C-reactive protein and its role in preeclampsia. PMID- 25452477 TI - Thanks! PMID- 25452478 TI - American Society of Plant Biologists: position statement on the education of young children about plants. PMID- 25452479 TI - Explain the brain: websites to help scientists teach neuroscience to the general public. PMID- 25452480 TI - Recent research in science teaching and learning. PMID- 25452481 TI - NEST 2014: views from the trainees-talking about what matters in efforts to diversify the STEM workforce. PMID- 25452482 TI - Using small-scale randomized controlled trials to evaluate the efficacy of new curricular materials. AB - How can researchers in K-12 contexts stay true to the principles of rigorous evaluation designs within the constraints of classroom settings and limited funding? This paper explores this question by presenting a small-scale randomized controlled trial (RCT) designed to test the efficacy of curricular supplemental materials on epigenetics. The researchers asked whether the curricular materials improved students' understanding of the content more than an alternative set of activities. The field test was conducted in a diverse public high school setting with 145 students who were randomly assigned to a treatment or comparison condition. Findings indicate that students in the treatment condition scored significantly higher on the posttest than did students in the comparison group (effect size: Cohen's d = 0.40). The paper discusses the strengths and limitations of the RCT, the contextual factors that influenced its enactment, and recommendations for others wishing to conduct small-scale rigorous evaluations in educational settings. Our intention is for this paper to serve as a case study for university science faculty members who wish to employ scientifically rigorous evaluations in K-12 settings while limiting the scope and budget of their work. PMID- 25452483 TI - Course-based undergraduate research experiences can make scientific research more inclusive. PMID- 25452485 TI - A campus-wide study of STEM courses: new perspectives on teaching practices and perceptions. AB - At the University of Maine, middle and high school science, technology, engineering, and mathematics (STEM) teachers observed 51 STEM courses across 13 different departments and collected information on the active-engagement nature of instruction. The results of these observations show that faculty members teaching STEM courses cannot simply be classified into two groups, traditional lecturers or instructors who teach in a highly interactive manner, but instead exhibit a continuum of instructional behaviors between these two classifications. In addition, the observation data reveal that student behavior differs greatly in classes with varied levels of lecture. Although faculty members who teach large enrollment courses are more likely to lecture, we also identified instructors of several large courses using interactive teaching methods. Observed faculty members were also asked to complete a survey about how often they use specific teaching practices, and we find that faculty members are generally self-aware of their own practices. Taken together, these findings provide comprehensive information about the range of STEM teaching practices at a campus-wide level and how such information can be used to design targeted professional development for faculty. PMID- 25452486 TI - Addressing health disparities in the undergraduate curriculum: an approach to develop a knowledgeable biomedical workforce. AB - Disparities in health and healthcare are a major concern in the United States and worldwide. Approaches to alleviate these disparities must be multifaceted and should include initiatives that touch upon the diverse areas that influence the healthcare system. Developing a strong biomedical workforce with an awareness of the issues concerning health disparities is crucial for addressing this issue. Establishing undergraduate health disparities courses that are accessible to undergraduate students in the life sciences is necessary to increase students' understanding and awareness of these issues and motivate them to address these disparities during their careers. The majority of universities do not include courses related to health disparities in their curricula, and only a few universities manage them from their life sciences departments. The figures are especially low for minority-serving institutions, which serve students from communities disproportionally affected by health disparities. Universities should consider several possible approaches to infuse their undergraduate curricula with health disparities courses or activities. Eliminating health disparities will require efforts from diverse stakeholders. Undergraduate institutions can play an important role in developing an aware biomedical workforce and helping to close the gap in health outcomes. PMID- 25452484 TI - A survey of scholarly literature describing the field of bioinformatics education and bioinformatics educational research. AB - Bioinformatics education can be broadly defined as the teaching and learning of the use of computer and information technology, along with mathematical and statistical analysis for gathering, storing, analyzing, interpreting, and integrating data to solve biological problems. The recent surge of genomics, proteomics, and structural biology in the potential advancement of research and development in complex biomedical systems has created a need for an educated workforce in bioinformatics. However, effectively integrating bioinformatics education through formal and informal educational settings has been a challenge due in part to its cross-disciplinary nature. In this article, we seek to provide an overview of the state of bioinformatics education. This article identifies: 1) current approaches of bioinformatics education at the undergraduate and graduate levels; 2) the most common concepts and skills being taught in bioinformatics education; 3) pedagogical approaches and methods of delivery for conveying bioinformatics concepts and skills; and 4) assessment results on the impact of these programs, approaches, and methods in students' attitudes or learning. Based on these findings, it is our goal to describe the landscape of scholarly work in this area and, as a result, identify opportunities and challenges in bioinformatics education. PMID- 25452487 TI - Undergraduates achieve learning gains in plant genetics through peer teaching of secondary students. AB - This study tests the hypothesis that undergraduates who peer teach genetics will have greater understanding of genetic and molecular biology concepts as a result of their teaching experiences. Undergraduates enrolled in a non-majors biology course participated in a service-learning program in which they led middle school (MS) or high school (HS) students through a case study curriculum to discover the cause of a green tomato variant. The curriculum explored plant reproduction and genetic principles, highlighting variation in heirloom tomato fruits to reinforce the concept of the genetic basis of phenotypic variation. HS students were taught additional activities related to mole-cular biology techniques not included in the MS curriculum. We measured undergraduates' learning outcomes using pre/postteaching content assessments and the course final exam. Undergraduates showed significant gains in understanding of topics related to the curriculum they taught, compared with other course content, on both types of assessments. Undergraduates who taught HS students scored higher on questions specific to the HS curriculum compared with undergraduates who taught MS students, despite identical lecture content, on both types of assessments. These results indicate the positive effect of service-learning peer-teaching experiences on undergraduates' content knowledge, even for non-science major students. PMID- 25452488 TI - High school students' learning and perceptions of phylogenetics of flowering plants. AB - Basic phylogenetics and associated "tree thinking" are often minimized or excluded in formal school curricula. Informal settings provide an opportunity to extend the K-12 school curriculum, introducing learners to new ideas, piquing interest in science, and fostering scientific literacy. Similarly, university researchers participating in science, technology, engineering, and mathematics (STEM) outreach activities increase awareness of college and career options and highlight interdisciplinary fields of science research and augment the science curriculum. To aid in this effort, we designed a 6-h module in which students utilized 12 flowering plant species to generate morphological and molecular phylogenies using biological techniques and bioinformatics tools. The phylogenetics module was implemented with 83 high school students during a weeklong university STEM immersion program and aimed to increase student understanding of phylogenetics and coevolution of plants and pollinators. Student response reflected positive engagement and learning gains as evidenced through content assessments, program evaluation surveys, and program artifacts. We present the results of the first year of implementation and discuss modifications for future use in our immersion programs as well as in multiple course settings at the high school and undergraduate levels. PMID- 25452489 TI - Student interpretations of phylogenetic trees in an introductory biology course. AB - Phylogenetic trees are widely used visual representations in the biological sciences and the most important visual representations in evolutionary biology. Therefore, phylogenetic trees have also become an important component of biology education. We sought to characterize reasoning used by introductory biology students in interpreting taxa relatedness on phylogenetic trees, to measure the prevalence of correct taxa-relatedness interpretations, and to determine how student reasoning and correctness change in response to instruction and over time. Counting synapomorphies and nodes between taxa were the most common forms of incorrect reasoning, which presents a pedagogical dilemma concerning labeled synapomorphies on phylogenetic trees. Students also independently generated an alternative form of correct reasoning using monophyletic groups, the use of which decreased in popularity over time. Approximately half of all students were able to correctly interpret taxa relatedness on phylogenetic trees, and many memorized correct reasoning without understanding its application. Broad initial instruction that allowed students to generate inferences on their own contributed very little to phylogenetic tree understanding, while targeted instruction on evolutionary relationships improved understanding to some extent. Phylogenetic trees, which can directly affect student understanding of evolution, appear to offer introductory biology instructors a formidable pedagogical challenge. PMID- 25452490 TI - Practice makes pretty good: assessment of primary literature reading abilities across multiple large-enrollment biology laboratory courses. AB - Primary literature is essential for scientific communication and is commonly utilized in undergraduate biology education. Despite this, there is often little time spent training our students how to critically analyze a paper. To address this, we introduced a primary literature module in multiple upper-division laboratory courses. In this module, instructors conduct classroom discussions that dissect a paper as researchers do. While previous work has identified classroom interventions that improve primary literature comprehension within a single course, our goal was to determine whether including a scientific paper module in our classes could produce long-term benefits. On the basis of performance in an assessment exam, we found that our module resulted in longitudinal gains, including increased comprehension and critical-thinking abilities in subsequent lab courses. These learning gains were specific to courses utilizing our module, as no longitudinal gains were seen in students who had taken other upper-division labs that lacked extensive primary literature discussion. In addition, we assessed whether performance on our assessment correlated with a variety of factors, including grade point average, course performance, research background, and self-reported confidence in understanding of the article. Furthermore, all of the study conclusions are independent of biology disciplines, as we observe similar trends within each course. PMID- 25452491 TI - Students who demonstrate strong talent and interest in STEM are initially attracted to STEM through extracurricular experiences. AB - What early experiences attract students to pursue an education and career in science, technology, engineering, and mathematics (STEM)? Does hands-on research influence them to persevere and complete a major course of academic study in STEM? We evaluated survey responses from 149 high school and undergraduate students who gained hands-on research experience in the 2007-2013 Aspiring Scientists Summer Internship Programs (ASSIP) at George Mason University. Participants demonstrated their strong interest in STEM by volunteering to participate in ASSIP and completing 300 h of summer research. The survey queried extracurricular experiences, classroom factors, and hands-on projects that first cultivated students' interest in the STEM fields, and separately evaluated experiences that sustained their interest in pursuing a STEM degree. The majority of students (65.5%, p < 0.0001) reported extracurricular encounters, such as the influence of a relative or family member and childhood experiences, as the most significant factors that initially ignited their interest in STEM, while hands-on lab work was stated as sustaining their interest in STEM (92.6%). Based on these findings collected from a cohort of students who demonstrated a strong talent and interest in STEM, community-based programs that create awareness about STEM for both children and their family members may be key components for igniting long term academic interest in STEM. PMID- 25452492 TI - The python project: a unique model for extending research opportunities to undergraduate students. AB - Undergraduate science education curricula are traditionally composed of didactic instruction with a small number of laboratory courses that provide introductory training in research techniques. Research on learning methodologies suggests this model is relatively ineffective, whereas participation in independent research projects promotes enhanced knowledge acquisition and improves retention of students in science. However, availability of faculty mentors and limited departmental budgets prevent the majority of students from participating in research. A need therefore exists for this important component in undergraduate education in both small and large university settings. A course was designed to provide students with the opportunity to engage in a research project in a classroom setting. Importantly, the course collaborates with a sponsor's laboratory, producing a symbiotic relationship between the classroom and the laboratory and an evolving course curriculum. Students conduct a novel gene expression study, with their collective data being relevant to the ongoing research project in the sponsor's lab. The success of this course was assessed based on the quality of the data produced by the students, student perception data, student learning gains, and on whether the course promoted interest in and preparation for careers in science. In this paper, we describe the strategies and outcomes of this course, which represents a model for efficiently providing research opportunities to undergraduates. PMID- 25452494 TI - A comprehensive faculty, staff, and student training program enhances student perceptions of a course-based research experience at a two-year institution. AB - Early research experiences must be made available to all undergraduate students, including those at 2-yr institutions who account for nearly half of America's college students. We report on barriers unique to 2-yr institutions that preclude the success of an early course-based undergraduate research experience (CURE). Using a randomized study design, we evaluated a CURE in equivalent introductory biology courses at a 4-yr institution and a 2-yr institution within the same geographic region. We found that these student populations developed dramatically different impressions of the experience. Students at the 4-yr institution enjoyed the CURE significantly more than the traditional labs. However, students at the 2 yr institution enjoyed the traditional labs significantly more, even though the CURE successfully produced targeted learning gains. On the basis of course evaluations, we enhanced instructor, student, and support staff training and reevaluated this CURE at a different campus of the same 2-yr institution. This time, the students reported that they enjoyed the research experience significantly more than the traditional labs. We conclude that early research experiences can succeed at 2-yr institutions, provided that a comprehensive implementation strategy targeting instructor, student, and support staff training is in place. PMID- 25452493 TI - A central support system can facilitate implementation and sustainability of a Classroom-based Undergraduate Research Experience (CURE) in Genomics. AB - In their 2012 report, the President's Council of Advisors on Science and Technology advocated "replacing standard science laboratory courses with discovery-based research courses"-a challenging proposition that presents practical and pedagogical difficulties. In this paper, we describe our collective experiences working with the Genomics Education Partnership, a nationwide faculty consortium that aims to provide undergraduates with a research experience in genomics through a scheduled course (a classroom-based undergraduate research experience, or CURE). We examine the common barriers encountered in implementing a CURE, program elements of most value to faculty, ways in which a shared core support system can help, and the incentives for and rewards of establishing a CURE on our diverse campuses. While some of the barriers and rewards are specific to a research project utilizing a genomics approach, other lessons learned should be broadly applicable. We find that a central system that supports a shared investigation can mitigate some shortfalls in campus infrastructure (such as time for new curriculum development, availability of IT services) and provides collegial support for change. Our findings should be useful for designing similar supportive programs to facilitate change in the way we teach science for undergraduates. PMID- 25452496 TI - Receptor guanylyl cyclase-G is a novel thermosensory protein activated by cool temperatures. AB - Transmembrane guanylyl cyclases (GCs), with activity regulated by peptide ligands and/or calcium-binding proteins, are essential for various physiological and sensory processes. The mode of activation of the GC subtype GC-G, which is expressed in neurons of the Grueneberg ganglion that respond to cool temperatures, has been elusive. In searching for appropriate stimuli to activate GC-G, we found that its enzymatic activity is directly stimulated by cool temperatures. In this context, it was observed that dimerization/oligomerization of GC-G, a process generally considered as critical for enzymatic activity of GCs, is strongly enhanced by coolness. Moreover, heterologous expression of GC-G in cultured cells rendered these cells responsive to coolness; thus, the protein might be a sensor for cool temperatures. This concept is supported by the observation of substantially reduced coolness-induced response of Grueneberg ganglion neurons and coolness-evoked ultrasonic vocalization in GC-G-deficient mouse pups. GC-G may be a novel thermosensory protein with functional implications for the Grueneberg ganglion, a sensory organ responding to cool temperatures. PMID- 25452497 TI - RNA polymerase II contributes to preventing transcription-mediated replication fork stalls. AB - Transcription is a major contributor to genome instability. A main cause of transcription-associated instability relies on the capacity of transcription to stall replication. However, we know little of the possible role, if any, of the RNA polymerase (RNAP) in this process. Here, we analyzed 4 specific yeast RNAPII mutants that show different phenotypes of genetic instability including hyper recombination, DNA damage sensitivity and/or a strong dependency on double-strand break repair functions for viability. Three specific alleles of the RNAPII core, rpb1-1, rpb1-S751F and rpb9?, cause a defect in replication fork progression, compensated for by additional origin firing, as the main action responsible for instability. The transcription elongation defects of rpb1-S751F and rpb9? plus our observation that rpb1-1 causes RNAPII retention on chromatin suggest that RNAPII could participate in facilitating fork progression upon a transcription replication encounter. Our results imply that the RNAPII or ancillary factors actively help prevent transcription-associated genome instability. PMID- 25452499 TI - Forelimb muscle architecture and myosin isoform composition in the groundhog (Marmota monax). AB - Scratch-digging mammals are commonly described as having large, powerful forelimb muscles for applying high force to excavate earth, yet studies quantifying the architectural properties of the musculature are largely unavailable. To further test hypotheses about traits that represent specializations for scratch-digging, we quantified muscle architectural properties and myosin expression in the forelimb of the groundhog (Marmota monax), a digger that constructs semi-complex burrows. Architectural properties measured were muscle moment arm, muscle mass (MM), belly length (ML), fascicle length (l(F)), pennation angle and physiological cross-sectional area (PCSA), and these metrics were used to estimate maximum isometric force, joint torque and power. Myosin heavy chain (MHC) isoform composition was determined in selected forelimb muscles by SDS-PAGE and densitometry analysis. Groundhogs have large limb retractors and elbow extensors that are capable of applying moderately high torque at the shoulder and elbow joints, respectively. Most of these muscles (e.g. latissimus dorsi and pectoralis superficialis) have high l(F)/ML ratios, indicating substantial shortening ability and moderate power. The unipennate triceps brachii long head has the largest PCSA and is capable of the highest joint torque at both the shoulder and elbow joints. The carpal and digital flexors show greater pennation and shorter fascicle lengths than the limb retractors and elbow extensors, resulting in higher PCSA/MM ratios and force production capacity. Moreover, the digital flexors have the capacity for both appreciable fascicle shortening and force production, indicating high muscle work potential. Overall, the forelimb musculature of the groundhog is capable of relatively low sustained force and power, and these properties are consistent with the findings of a predominant expression of the MHC-2A isoform. Aside from the apparent modifications to the digital flexors, the collective muscle properties observed are consistent with its behavioral classification as a less-specialized burrower and these may be more representative of traits common to numerous rodents with burrowing habits or mammals with some fossorial ability. PMID- 25452498 TI - BREX is a novel phage resistance system widespread in microbial genomes. AB - The perpetual arms race between bacteria and phage has resulted in the evolution of efficient resistance systems that protect bacteria from phage infection. Such systems, which include the CRISPR-Cas and restriction-modification systems, have proven to be invaluable in the biotechnology and dairy industries. Here, we report on a six-gene cassette in Bacillus cereus which, when integrated into the Bacillus subtilis genome, confers resistance to a broad range of phages, including both virulent and temperate ones. This cassette includes a putative Lon like protease, an alkaline phosphatase domain protein, a putative RNA-binding protein, a DNA methylase, an ATPase-domain protein, and a protein of unknown function. We denote this novel defense system BREX (Bacteriophage Exclusion) and show that it allows phage adsorption but blocks phage DNA replication. Furthermore, our results suggest that methylation on non-palindromic TAGGAG motifs in the bacterial genome guides self/non-self discrimination and is essential for the defensive function of the BREX system. However, unlike restriction-modification systems, phage DNA does not appear to be cleaved or degraded by BREX, suggesting a novel mechanism of defense. Pan genomic analysis revealed that BREX and BREX-like systems, including the distantly related Pgl system described in Streptomyces coelicolor, are widely distributed in ~10% of all sequenced microbial genomes and can be divided into six coherent subtypes in which the gene composition and order is conserved. Finally, we detected a phage family that evades the BREX defense, implying that anti-BREX mechanisms may have evolved in some phages as part of their arms race with bacteria. PMID- 25452501 TI - Nitric oxide production and sequestration in the sinus gland of the green shore crab Carcinus maenas. AB - Molting in decapod crustaceans is regulated by molt-inhibiting hormone (MIH), a neuropeptide produced in the X-organ (XO)/sinus gland (SG) complex of the eyestalk ganglia (ESG). Pulsatile release of MIH from the SG suppresses ecdysteroidogenesis by the molting gland or Y-organ (YO). The hypothesis is that nitric oxide (NO), a neuromodulator that controls neurotransmitter release at presynaptic membranes, depresses the frequency and/or amount of MIH pulses to induce molting. NO synthase (NOS) mRNA was present in Carcinus maenas ESG and other tissues and NOS protein was present in the SG. A copper based ligand (CuFL), which reacts with NO to form a highly fluorescent product (NO-FL), was used to image NO in the ESG and SG and quantify the effects of NO scavenger (cPTIO), NOS inhibitor (l-NAME), and sodium azide (NaN3) on NO production in the SG. Pre-incubation with cPTIO prior to CuFL loading decreased NO-FL fluorescence ~30%; including l-NAME had no additional effect. Incubating SG with l-NAME during pre-incubation and loading decreased NO-FL fluorescence ~40%, indicating that over half of the NO release was not directly dependent on NOS activity. Azide, which reacts with NO-binding metal groups in proteins, reduced NO-FL fluorescence to near background levels without extensive cell death. Spectral shift analysis showed that azide displaced NO from a soluble protein in SG extract. These data suggest that the SG contains NO-binding protein(s) that sequester NO and releases it over a prolonged period. This NO release may modulate neuropeptide secretion from the axon termini in the SG. PMID- 25452500 TI - Milk output and composition in mice divergently selected for basal metabolic rate. AB - From an evolutionary perspective, the high basal metabolic rate (BMR) of homeotherms is hypothesised to be a by-product of natural selection for effective parental care. We estimated daily milk output during two consecutive lactation bouts in mice divergently selected for high/low BMR and applied a cross-fostered design to control for potential differences in the between-line suckling abilities of nursed juveniles. Additionally, to remedy the potential limitation imposed by the ability of mother mice to dissipate excess heat, we exposed them to an ambient temperature of 17 degrees C during the most energetically demanding second week of lactation. We found that the mice selected for high BMR produced significantly more milk in a 24 h period in both reproductive bouts. The milk samples obtained from the high BMR females had lower protein concentration and did not differ with respect to fat. However, the concentration of the primary milk carbohydrate - lactose - was higher. Although all the above between-line differences were statistically significant, their magnitude was too small to unambiguously ascribe them as stemming from a positive genetic correlation between the physiological traits underlying BMR and lactation performance. Nevertheless, our study lends such support at least at the level of phenotypic variation. PMID- 25452502 TI - Nitric oxide modulates a swimmeret beating rhythm in the crayfish. AB - The modulatory effects of nitric oxide (NO) and cAMP on the rhythmic beating activity of the swimmeret motor neurones in the crayfish were examined. Swimmerets are paired appendages located on the ventral side of each abdominal segment that show rhythmic beating activity during forward swimming, postural righting behaviour and egg ventilation in gravid females. In isolated abdominal nerve cord preparations, swimmeret motor neurones are usually silent or show a continuous low-frequency spiking activity. Application of carbachol, a cholinergic agonist, elicited rhythmic bursts of motor neurone spikes. The co application of L-arginine, the substrate for NO synthesis with carbachol increased the burst frequency of the motor neurones. The co-application of the NO donor SNAP with carbachol also increased the burst frequency of the motor neurones. By contrast, co-application of a NOS inhibitor, L-NAME, with carbachol decreased beating frequency of the motor neurones. These results indicate that NO may act as a neuromodulator to facilitate swimmeret beating activity. The facilitatory effect of L-arginine was cancelled by co-application of the soluble guanylate cyclase (sGC) inhibitor ODQ suggesting that NO acts by activating sGC to promote the production of cGMP. Application of L-arginine alone or membrane permeable cGMP analogue 8-Br-cGMP alone did not elicit rhythmic activity of motor neurones, but co-application of 8-Br-cGMP with carbachol increased bursting frequency of the motor neurones. Furthermore, application of the membrane permeable cAMP analogue CPT-cAMP alone produced rhythmic bursting of swimmeret motor neurones, and the bursting frequency elicited by CPT-cAMP was increased by co-application with L-arginine. Co-application of the adenylate cyclase inhibitor SQ22536 ceased rhythmic bursts of motor neurone spikes elicited by carbachol. These results suggest that a cAMP system enables the rhythmic bursts of motor neurone spikes and that a NO-cGMP signaling pathway increases cAMP activity to facilitate swimmeret beating. PMID- 25452503 TI - Pigeons produce aerodynamic torques through changes in wing trajectory during low speed aerial turns. AB - The complexity of low speed maneuvering flight is apparent from the combination of two critical aspects of this behavior: high power and precise control. To understand how such control is achieved, we examined the underlying kinematics and resulting aerodynamic mechanisms of low speed turning flight in the pigeon (Columba livia). Three birds were trained to perform 90 deg level turns in a stereotypical fashion and detailed three-dimensional (3D) kinematics were recorded at high speeds. Applying the angular momentum principle, we used mechanical modeling based on time-varying 3D inertia properties of individual sections of the pigeon's body to separate angular accelerations of the torso based on aerodynamics from those based on inertial effects. Directly measured angular accelerations of the torso were predicted by aerodynamic torques, justifying inferences of aerodynamic torque generation based on inside wing versus outside wing kinematics. Surprisingly, contralateral asymmetries in wing speed did not appear to underlie the 90 deg aerial turns, nor did contralateral differences in wing area, angle of attack, wingbeat amplitude or timing. Instead, torso angular accelerations into the turn were associated with the outside wing sweeping more anteriorly compared with a more laterally directed inside wing. In addition to moving through a relatively more retracted path, the inside wing was also more strongly pronated about its long axis compared with the outside wing, offsetting any difference in aerodynamic angle of attack that might arise from the observed asymmetry in wing trajectories. Therefore, to generate roll and pitch torques into the turn, pigeons simply reorient their wing trajectories toward the desired flight direction. As a result, by acting above the center of mass, the net aerodynamic force produced by the wings is directed inward, generating the necessary torques for turning. PMID- 25452504 TI - Predator-driven intra-species variation in locomotion, metabolism and water velocity preference in pale chub (Zacco platypus) along a river. AB - Fish inhabit environments that vary greatly in terms of predation intensity, and these predation regimes are generally expected to be a major driver of divergent natural selection. To test whether there is predator-driven intra-species variation in the locomotion, metabolism and water velocity preference of pale chub (Zacco platypus) along a river, we measured unsteady and steady swimming and water velocity preference among fish collected from both high- and low-predation habitats in the Wujiang River. We also measured the routine metabolic rate (RMR), maximum metabolic rate (MMR) and cost of transport (COT) and calculated the optimal swimming speed (Uopt). The fish from the high-predation populations showed a shorter response latency, elevated routine metabolism, lower swimming efficiency at low swimming speed and lower water velocity preference compared with those from the low-predation populations. Neither of the kinematic parameters fast-start and critical swimming speed (Ucrit) showed a significant difference between the high- and low-predation populations. The fish from the high-predation populations may improve their predator avoidance capacity primarily through an elevated routine metabolism and shorter response latency to achieve advanced warning and escape, rather than an improved fast-start swimming speed or acceleration. Thus, the cost of this strategy is an elevated RMR, and no trade-off between unsteady and steady swimming performance was observed in the pale chub population under various predation stresses. It was interesting to find that the high-predation fish showed an unexpected lower velocity preference, which might represent a compromise between predation avoidance, foraging and energy saving. PMID- 25452505 TI - Migratory blackcaps tested in Emlen funnels can orient at 85 degrees but not at 88 degrees magnetic inclination. AB - Migratory birds are known to use the Earth's magnetic field as an orientation cue on their tremendous journeys between their breeding and overwintering grounds. The magnetic compass of migratory birds relies on the magnetic field's inclination, i.e. the angle between the magnetic field lines and the Earth's surface. As a consequence, vertical or horizontal field lines corresponding to 0 or 90 deg inclination should offer no utilizable information on where to find North or South. So far, very little is known about how small the deviations from horizontal or vertical inclination are that migratory birds can detect and use as a reference for their magnetic compass. Here, we asked: what is the steepest inclination angle at which a migratory bird, the Eurasian blackcap (Sylvia atricapilla), can still perform magnetic compass orientation in Emlen funnels? Our results show that blackcaps are able to orient in an Earth's strength magnetic field with inclination angles of 67 and 85 deg, but fail to orient in a field with 88 deg inclination. This suggests that the steepest inclination angle enabling magnetic compass orientation in migratory blackcaps tested in Emlen funnels lies between 85 and 88 deg. PMID- 25452507 TI - Future perfect. PMID- 25452508 TI - Antibiotic overuse: a key driver of antimicrobial resistance. PMID- 25452506 TI - Prioritization of skeletal muscle growth for emergence from hibernation. AB - Mammalian hibernators provide an extreme example of naturally occurring challenges to muscle homeostasis. The annual hibernation cycle is characterized by shifts between summer euthermy with tissue anabolism and accumulation of body fat reserves, and winter heterothermy with fasting and tissue catabolism. The circannual patterns of skeletal muscle remodelling must accommodate extended inactivity during winter torpor, the motor requirements of transient winter active periods, and sustained activity following spring emergence. Muscle volume in thirteen-lined ground squirrels (Ictidomys tridecemlineatus) calculated from MRI upper hindlimb images (n=6 squirrels, n=10 serial scans) declined from hibernation onset, reaching a nadir in early February. Paradoxically, mean muscle volume rose sharply after February despite ongoing hibernation, and continued total body mass decline until April. Correspondingly, the ratio of muscle volume to body mass was steady during winter atrophy (October-February) but increased (+70%) from February to May, which significantly outpaced changes in liver or kidney examined by the same method. Generally stable myocyte cross-sectional area and density indicated that muscle remodelling is well regulated in this hibernator, despite vastly altered seasonal fuel and activity levels. Body composition analysis by echo MRI showed lean tissue preservation throughout hibernation amid declining fat mass by the end of winter. Muscle protein synthesis was 66% depressed in early but not late winter compared with a summer fasted baseline, while no significant changes were observed in the heart, liver or intestine, providing evidence that could support a transition in skeletal muscle regulation between early and late winter, prior to spring emergence and re feeding. PMID- 25452509 TI - Audit: time to review the cycle. PMID- 25452511 TI - Virtually addicted: why general practice must now confront screen dependency. PMID- 25452510 TI - Child health indicators: from theoretical frameworks to practical reality? PMID- 25452512 TI - What's new in multiple sclerosis? PMID- 25452514 TI - The future NHS: time for another change? PMID- 25452515 TI - Delays in diagnosis of young females with symptomatic cervical cancer in England. PMID- 25452516 TI - Vision loss as a presenting symptom of type 2 diabetes mellitus. PMID- 25452517 TI - Non-contact infrared thermometers. PMID- 25452518 TI - Headaches in the absence of other signs do not require imaging by GPs. PMID- 25452519 TI - Family and friends test. PMID- 25452520 TI - Young carers. PMID- 25452521 TI - Should we celebrate outstanding achievement in general practice training? PMID- 25452522 TI - Research into practice: management of atrial fibrillation in general practice. PMID- 25452523 TI - Junior doctors and waterpipe tobacco smoking. PMID- 25452525 TI - The NHS Five Year Forward View: transforming care. PMID- 25452526 TI - GPs and the Ebola patient: working safely in primary care. PMID- 25452527 TI - Dangerous Ideas: resistant superbugs and the potential of the microbiome. PMID- 25452528 TI - Substance misuse, dementia, worklessness, and seaside towns. PMID- 25452529 TI - Philosophy of general practice: in the eye of the beholder. PMID- 25452530 TI - The 68th Edinburgh International Film Festival. PMID- 25452531 TI - An A-Z of medical philosophy: X is for Existentialism: Kierkegaard, Heidegger and Sartre. PMID- 25452534 TI - Gifts and gratitude. PMID- 25452535 TI - Can the outcome of primary care be measured by a Patient Reported Outcome Measure? PMID- 25452536 TI - Advance care planning: an unsuitable subject for QOF? PMID- 25452537 TI - Research into practice: understanding ethnic differences in healthcare usage and outcomes in general practice. PMID- 25452538 TI - Understanding quality improvement at scale in general practice: a qualitative evaluation of a COPD improvement programme. AB - BACKGROUND: A growing body of knowledge exists to guide efforts to improve the organisation and delivery of health care, most of which is based on work carried out in hospitals. It is uncertain how transferable this knowledge is to primary care. AIM: To understand the enablers and constraints to implementing a large scale quality improvement programme in general practice, designed to improve care for people with chronic obstructive pulmonary disease. DESIGN AND SETTING: A qualitative study of 189 general practices in a socioeconomically and ethnically mixed, urban area in east London, UK. METHOD: Twelve semi-structured interviews were conducted with people leading the programme and 17 in-depth interviews with those participating in it. Participants were local health system leaders, clinicians, and managers. A theoretical framework derived from evidence-based guidance for improvement programmes was used to interpret the findings. A complex improvement intervention took place with social and technical elements including training and mentorship, guidance, analytical tools, and data feedback. RESULTS: Practice staff wanted to participate in and learn from well-designed collaborative improvement projects. Nevertheless, there were limitations in the capacities and capabilities of the workforce to undertake systematic improvement, significant problems with access to and the quality of data, and tensions between the narrative-based generalist orientation of many primary care clinicians and the quantitative single-disease orientation that has characterised much of the quality improvement movement to date. CONCLUSION: Improvement guidance derived largely from hospital-based studies is, for the most part, applicable to improvement efforts in primary care settings, although large-scale change in general practice presents some particular challenges. These need to be better understood and addressed if improvement initiatives are to be effective. PMID- 25452539 TI - Primary care quality indicators for children: measuring quality in UK general practice. AB - BACKGROUND: Child health care is an important part of the UK general practice workload; in 2009 children aged <15 years accounted for 10.9% of consultations. However, only 1.2% of the UK's Quality and Outcomes Framework pay-for-performance incentive points relate specifically to children. AIM: To improve the quality of care provided for children and adolescents by defining a set of quality indicators that reflect evidence-based national guidelines and are feasible to audit using routine computerised clinical records. DESIGN AND SETTING: Multi-step consensus methodology in UK general practice. METHOD: Four-step development process: selection of priority issues (applying nominal group methodology), systematic review of National Institute for Health and Care Excellence (NICE) and Scottish Intercollegiate Guidelines Network (SIGN) clinical guidelines, translation of guideline recommendations into quality indicators, and assessment of their validity and implementation feasibility (applying consensus methodology used in selecting QOF indicators). RESULTS: Of the 296 national guidelines published, 48 were potentially relevant to children in primary care, but only 123 of 1863 recommendations (6.6%) met selection criteria for translation into 56 potential quality indicators. A further 13 potential indicators were articulated after review of existing quality indicators and standards. Assessment of the validity and feasibility of implementation of these 69 candidate indicators by a clinical expert group identified 35 with median scores 8 on a 9-point Likert scale. However, only seven of the 35 achieved a GRADE rating >1 (were based on more than expert opinion). CONCLUSION: Producing valid primary care quality indicators for children is feasible but difficult. These indicators require piloting before wide adoption but have the potential to raise the standard of primary care for all children. PMID- 25452540 TI - Relationship continuity: when and why do primary care patients think it is safer? AB - BACKGROUND: Doctor-patient continuity is popular with patients and practitioners, and is associated with better outcomes; however, changes in policy and practice organisation have diminished its scope. Although there has been some discussion of safety implications from professionals' perspective, patients' views remain largely unexplored. AIM: To explore patients' understanding of safety in primary care. DESIGN AND SETTING: An interview-based study with patients from general practices in the northwest of England. METHOD: Patients were recruited from five general practices through patient participation groups and posters in waiting rooms, with further participants recruited through snowballing techniques until no new themes emerged. In-depth interviews were digitally recorded and transcribed. Anonymised transcripts were coded and analysed inductively. Emergent themes were discussed by the team. RESULTS: For patients, relationship continuity was not simply a matter of service quality but an important safety concern that offered greater psychosocial security than consultations with unfamiliar GPs. Relationship continuity enabled the GP to become a repository of information; acquire specialist knowledge of a patient's condition; become familiar with the patient's consulting behaviour; provide holistic care; and foster the development of trust. Patients were also aware of the risks: a false sense of security and lack of a fresh perspective. Their desire for continuity varied with the nature of their concerns, psychological vulnerability, and perception of GPs' qualities and skills. No one supported a return to imposed continuity. CONCLUSION: Relationship continuity and choice of GP were important safety strategies, neither of which is adequately supported by recent policy changes. PMID- 25452542 TI - Decision making and referral from primary care for possible lung and colorectal cancer: a qualitative study of patients' experiences. AB - BACKGROUND: The challenge for GPs when assessing whether to refer a patient for cancer investigation is that many cancer symptoms are also caused by benign self limiting illness. UK National Institute for Health and Care Excellence (NICE) referral guidelines emphasise that the patient should be involved in the decision making process and be informed of the reasons for referral. Research to date, however, has not examined the extent to which these guidelines are borne out in practice. AIM: To assess the degree to which patients are involved in the decision to be referred for investigation for symptoms associated with cancer and their understanding of the referral. DESIGN AND SETTING: Qualitative interview study of patients referred to secondary care for symptoms suspicious of lung and colorectal cancer. Patients were recruited from two regions of England using maximum variation sampling. METHOD: Transcribed interviews were analysed thematically. RESULTS: The analysis was based on 34 patient interviews. Patients in both symptom pathways reported little involvement in the decision to be referred for investigation. This tended to be accompanied by a patient expectation for referral, however, to explain ongoing and un-resolving symptoms. It was also found that reasons for referral tended to be couched in non-specific terms rather than cancer investigation, even when the patient was on a cancer specific pathway. CONCLUSION: GPs should consider a more overt discussion with patients when referring them for further investigation of symptoms suspicious of cancer. This would align clinical practice with NICE guidelines and encourage more open discussion between GPs and primary care patients around cancer. PMID- 25452543 TI - Digital rectal examination in primary care is important for early detection of prostate cancer: a retrospective cohort analysis study. AB - BACKGROUND: Currently, there is no standardised screening for prostate cancer in Europe. Assessment of risk is opportunistically undertaken in consultation with the GP or urologist. Evaluation of the prostate gland consists of a prostate specific antigen (PSA) serum level and a digital rectal examination (DRE) of the gland. DRE is an essential part of the assessment that can independently predict prostate cancer in the setting of a normal PSA level. AIM: To evaluate the clinical usefulness of the DRE in general practice and urology clinics, and to ascertain its positive predictive value and sensitivity. DESIGN AND SETTING: A retrospective analysis study of a cohort of Irish men who underwent TRUS guided biopsy of the prostate in a single Irish tertiary referral centre, despite a normal PSA level. Patients were identified from a Rapid Access Prostate Clinic patient database. Pathological biopsy results were correlated with clinical DRE findings. METHOD: Patient demographics, PSA levels, and DRE findings from a prospectively established database and hospital data systems from May 2009 to October 2013 were analysed. RESULTS: Of 103 men referred over a 53-month period with a normal age-adjusted PSA level, 67% were referred on the basis of an abnormal DRE alone. Thirty-five per cent of males with a normal PSA had prostate cancer. DRE alone had a sensitivity and specificity of 81% and 40% respectively in diagnosing prostate cancer, with a positive predictive value of 42%. Seventy six per cent of these men had high-grade disease. CONCLUSION: DRE is a key part of the assessment for prostate cancer. It can independently identify patients at risk of prostate cancer, with a substantial proportion of these having clinically significant disease requiring treatment. This study reinforces the importance of DRE in the primary care setting in the assessment for prostate cancer. An abnormal DRE, even in the setting of a normal PSA level, necessitates referral. PMID- 25452541 TI - Referral interventions from primary to specialist care: a systematic review of international evidence. AB - BACKGROUND: Demand management defines any method used to monitor, direct, or regulate patient referrals. Strategies have been developed to manage the referral of patients to secondary care, with interventions that target primary care, specialist services, or infrastructure. AIM: To review the international evidence on interventions to manage referral from primary to specialist care. DESIGN AND SETTING: Systematic review. METHOD: Iterative, systematic searches of published and unpublished sources public health, health management, management, and grey literature databases from health care and other industries were undertaken to identify recent, relevant studies. A narrative synthesis of the data was completed to structure the evidence into groups of similar interventions. RESULTS: The searches generated 8327 unique results, of which 140 studies were included. Interventions were grouped into four intervention categories: GP education (n = 50); process change (n = 49); system change (n = 38); and patient focused (n = 3). It is clear that there is no 'magic bullet' to managing demand for secondary care services: although some groups of interventions may have greater potential for development, given the existing evidence that they can be effective in specific contexts. CONCLUSIONS: To tackle demand management of primary care services, the focus cannot be on primary care alone; a whole-systems approach is needed because the introduction of interventions in primary care is often just the starting point of the referral process. In addition, more research is needed to develop and evaluate interventions that acknowledge the role of the patient in the referral decision. PMID- 25452544 TI - Risk of breast cancer in symptomatic women in primary care: a case-control study using electronic records. AB - BACKGROUND: Breast cancer is the most common cancer in the UK. GPs are encouraged to refer all women whose symptoms may represent cancer, rather than selecting those at highest risk. AIM: To identify and quantify features of breast cancer in primary care. DESIGN AND SETTING: A UK case-control study using the Clinical Practice Research Database (CPRD). METHOD: Possible features of breast cancer were identified in the year before diagnosis, and odds ratios calculated using conditional logistic regression. Positive predictive values (PPVs) were estimated for consulting women. RESULTS: A total of 3994 women aged >=40 years with breast cancer between 2000 and 2009, and 16 873 age-, sex-, and practice-matched controls were studied. Median age at diagnosis was 63 years (interquartile range 55-74 years). Four features were significantly associated with breast cancer: breast lump (odds ratio [OR] 110; 95% confidence interval [CI] = I88 to 150), breast pain (OR = 4.2; 95% CI = 3.0 to 6.0), nipple retraction (OR = 26; 95% CI = 10 to 64), nipple discharge (OR = 19; 95% CI = 8.6 to 41): all P-values <0.01. In the year before diagnosis, 1762 (44%) of cases had a breast lump compared with 132 (0.8%) controls. The PPV of breast cancer with a breast lump was 4.8% in women aged 40-49 years, rising to 48% in women aged >70 years. PPVs were lower in women who also reported breast pain. CONCLUSION: Generally, the figures support current referral practice. However, the low likelihood of cancer for all the non lump symptoms means that the current guidance recommends investigation for possible cancer at a more liberal risk threshold than for other cancers. Although supported by patients, this may not meet current NHS criteria for cost-benefit. PMID- 25452546 TI - Should we use outcomes data to help manage general practice? PMID- 25452545 TI - Dying at home: a qualitative study of family carers' views of support provided by GPs community staff. AB - BACKGROUND: Dying at home is the preference of many patients with life-limiting illness. This is often not achieved and a key factor is the availability of willing and able family carers. AIM: To elicit family carers' views about the community support that made death at home possible. DESIGN AND SETTING: Qualitative study in East Devon, North Lancashire, and Cumbria. METHOD: Participants were bereaved family carers who had provided care at the end of life for patients dying at home. Semi-structured interviews were conducted 6-24 months after the death. RESULTS: Fifty-nine bereaved family carers were interviewed (54% response rate; 69% female). Two-thirds of the patients died from cancer with median time of home care being 5 months and for non-cancer patients the median time for home care was 30 months. An overarching theme was of continuity of care that divided into personal, organisational, and informational continuity. Large numbers and changes in care staff diluted personal continuity and failure of the GPs to visit was viewed negatively. Family carers had low expectations of informational continuity, finding information often did not transfer between secondary and primary care and other care agencies. Organisational continuity when present provided comfort and reassurance, and a sense of control. CONCLUSION: The requirement for continuity in delivering complex end-of-life care has long been acknowledged. Family carers in this study suggested that minimising the number of carers involved in care, increasing or ensuring personal continuity, and maximising the informational and organisational aspects of care could lead to a more positive experience. PMID- 25452547 TI - Optimising treatment of Bell's Palsy in primary care: the need for early appropriate referral. PMID- 25452548 TI - CD73-generated adenosine is critical for immune regulation during Toxoplasma gondii infection. AB - As an obligate intracellular pathogen, the apicomplexan parasite Toxoplasma gondii evades immune system-mediated clearance by undergoing stage differentiation to persist indefinitely in susceptible hosts. Previously, we found that mice deficient in the ectoenzyme CD73, which generates adenosine in the extracellular matrix, were resistant to chronic toxoplasmosis after oral infection with T. gondii. Resistance in CD73 knockout mice was due to a delay in parasite differentiation in the central nervous system (CNS). To further clarify the role of CD73 and extracellular adenosine in T. gondii pathogenesis, we infected wild-type (WT) and CD73(-/-) mice with T. gondii cysts systemically by the intraperitoneal (i.p.) route. In contrast to oral infection, i.p. infected CD73(-/-) mice were highly susceptible to immune-mediated pathology, with significantly increased infiltration of neutrophils and T cells into the peritoneal cavity. Administration of the broad-spectrum adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) protected CD73(-/-) mice against T. gondii-induced immunopathology, suggesting that the absence of CD73-generated adenosine led to the increased susceptibility in these mice. Peritoneal exudate cells from infected CD73(-/-) mice produced higher levels of the inflammatory mediators nitric oxide, tumor necrosis factor alpha (TNF-alpha), and interleukin 1beta (IL-1beta), without enhanced parasite killing or clearance. Bone marrow chimeras established that CD73 expression in both hematopoietic and nonhematopoietic compartments contributes to limiting T. gondii-induced immunopathology. In addition, mice deficient in the adenosine receptor A(2A) were more susceptible to immunopathology during intraperitoneal infection with T. gondii than WT mice. Thus, extracellular adenosine is a key immune regulator that limits collateral tissue damage due to an intracellular pathogen and promotes host survival. PMID- 25452550 TI - Immunization with the Entamoeba histolytica surface metalloprotease EhMSP-1 protects hamsters from amebic liver abscess. AB - Diarrhea and amebic liver abscesses due to invasive Entamoeba histolytica infections are an important cause of morbidity and mortality in the developing world. Entamoeba histolytica adherence and cell migration, two phenotypes linked to virulence, are both aberrant in trophozoites deficient in the metallosurface protease EhMSP-1, which is a homologue of the Leishmania vaccine candidate leishmanolysin (GP63). We examined the potential of EhMSP-1 for use as a vaccine antigen to protect against amebic liver abscesses. First, existing serum samples from South Africans naturally infected with E. histolytica were examined by enzyme-linked immunosorbent assay (ELISA) for the presence of EhMSP-1-specific IgG. Nine of 12 (75%) people with anti-E. histolytica IgG also had EhMSP-1 specific IgG antibodies. We next used a hamster model of amebic liver abscess to determine the effect of immunization with a mixture of four recombinant EhMSP-1 protein fragments. EhMSP-1 immunization stimulated a robust IgG antibody response. Furthermore, EhMSP-1 immunization of hamsters reduced development of severe amebic liver abscesses following intrahepatic injection of E. histolytica by a combined rate of 68% in two independent animal experiments. Purified IgG from immunized compared to control animals bound to the surface of E. histolytica trophozoites and accelerated amebic lysis via activation of the classical complement cascade. We concluded that EhMSP-1 is a promising antigen that warrants further study to determine its full potential as a target for therapy and/or prevention of invasive amebiasis. PMID- 25452551 TI - Recombinant protein truncation strategy for inducing bactericidal antibodies to the macrophage infectivity potentiator protein of Neisseria meningitidis and circumventing potential cross-reactivity with human FK506-binding proteins. AB - A recombinant macrophage infectivity potentiator (rMIP) protein of Neisseria meningitidis induces significant serum bactericidal antibody production in mice and is a candidate meningococcal vaccine antigen. However, bioinformatics analysis of MIP showed some amino acid sequence similarity to human FK506-binding proteins (FKBPs) in residues 166 to 252 located in the globular domain of the protein. To circumvent the potential concern over generating antibodies that could recognize human proteins, we immunized mice with recombinant truncated type I rMIP proteins that lacked the globular domain and the signal leader peptide (LP) signal sequence (amino acids 1 to 22) and contained the His purification tag at either the N or C terminus (C-term). The immunogenicity of truncated rMIP proteins was compared to that of full (i.e., full-length) rMIP proteins (containing the globular domain) with either an N- or C-terminal His tag and with or without the LP sequence. By comparing the functional murine antibody responses to these various constructs, we determined that C-term His truncated rMIP (-LP) delivered in liposomes induced high levels of antibodies that bound to the surface of wild-type but not Deltamip mutant meningococci and showed bactericidal activity against homologous type I MIP (median titers of 128 to 256) and heterologous type II and III (median titers of 256 to 512) strains, thereby providing at least 82% serogroup B strain coverage. In contrast, in constructs lacking the LP, placement of the His tag at the N terminus appeared to abrogate bactericidal activity. The strategy used in this study would obviate any potential concerns regarding the use of MIP antigens for inclusion in bacterial vaccines. PMID- 25452549 TI - Granzyme-mediated regulation of host defense in the liver in experimental Leishmania donovani infection. AB - In the livers of susceptible C57BL/6 (B6) mice infected with Leishmania donovani, CD8(+) T cell mechanisms are required for granuloma assembly, macrophage activation, intracellular parasite killing, and self-cure. Since gene expression of perforin and granzymes A and B (GzmA and GzmB), cytolytic proteins linked to CD8(+) cell effector function, was enhanced in infected liver tissue, B6 mice deficient in these granular proteins were used to gauge host defense roles. Neither perforin nor GzmA was required; however, mice deficient in GzmB (GzmB(-/ ), GzmB cluster(-/-), and GzmA*B cluster double knockout [DKO] mice) showed both delayed granuloma assembly and initially impaired control of parasite replication. Since these two defects in B6 mice were limited to early-stage infection, innately resistant 129/Sv mice were also tested. In this genetic setting, expression of both innate and subsequent T (Th1) cell-dependent acquired resistance, including the self-cure phenotype, was entirely derailed in GzmA*B cluster DKO mice. These results, in susceptible B6 mice for GzmB and in resistant 129/Sv mice for GzmA and/or the GzmB cluster, point to granzyme-mediated host defense regulation in the liver in experimental visceral leishmaniasis. PMID- 25452552 TI - Klebsiella pneumoniae translocates across the intestinal epithelium via Rho GTPase- and phosphatidylinositol 3-kinase/Akt-dependent cell invasion. AB - Klebsiella pneumoniae is an important pathogen that causes hospital-acquired septicemia and is associated with the recent emergence of community-acquired pyogenic liver abscess (PLA). Clinical typing suggests that K. pneumoniae infections originate from the gastrointestinal reservoir. However, the underlying mechanism remains unknown. Here, we have sought to determine how K. pneumoniae penetrates the intestinal barrier. We identified that bacteremia and PLA clinical isolates adhered to and invaded intestinal epithelial cells. Internalization of K. pneumoniae in three different human colonic cell lines was visualized by confocal microscopy and three-dimensional (3D) imaging. Using a Transwell system, we demonstrated that these K. pneumoniae isolates translocated across a polarized Caco-2 monolayer. No disruptions of transepithelial electrical resistance and altered distribution of tight junction protein ZO-1 or occludin were observed. Therefore, K. pneumoniae appeared to penetrate the intestinal epithelium via a transcellular pathway. Using specific inhibitors, we characterized the host signaling pathways involved. Inhibition by cytochalasin D and nocodazole suggested that actin and microtubule cytoskeleton were both important for K. pneumoniae invasion. A Rho inhibitor, ML141, LY294002, and an Akt1/2 inhibitor diminished K. pneumoniae invasion in a dose-dependent manner, indicating that Rho family GTPases and phosphatidylinositol 3-kinase (PI3K)/Akt signaling were required. By a mouse model of gastrointestinal colonization, in vivo invasion of K. pneumoniae into colonic epithelial cells was demonstrated. Our results present evidence to describe a possible mechanism of gastrointestinal translocation for K. pneumoniae. Cell invasion by manipulating host machinery provides a pathway for gut-colonized K. pneumoniae cells to penetrate the intestinal barrier and access extraintestinal locations to cause disease. PMID- 25452553 TI - THEMIS is required for pathogenesis of cerebral malaria and protection against pulmonary tuberculosis. AB - We identify an N-ethyl-N-nitrosourea (ENU)-induced I23N mutation in the THEMIS protein that causes protection against experimental cerebral malaria (ECM) caused by infection with Plasmodium berghei ANKA. Themis(I23N) homozygous mice show reduced CD4(+) and CD8(+) T lymphocyte numbers. ECM resistance in P. berghei ANKA infected Themis(I23N) mice is associated with decreased cerebral cellular infiltration, retention of blood-brain barrier integrity, and reduced proinflammatory cytokine production. THEMIS(I23N) protein expression is absent from mutant mice, concurrent with the decreased THEMIS(I23N) stability observed in vitro. Biochemical studies in vitro and functional complementation in vivo in Themis(I23N/+):Lck(-/+) doubly heterozygous mice demonstrate that functional coupling of THEMIS to LCK tyrosine kinase is required for ECM pathogenesis. Damping of proinflammatory responses in Themis(I23N) mice causes susceptibility to pulmonary tuberculosis. Thus, THEMIS is required for the development and ultimately the function of proinflammatory T cells. Themis(I23N) mice can be used to study the newly discovered association of THEMIS (6p22.33) with inflammatory bowel disease and multiple sclerosis. PMID- 25452555 TI - Use of human serum for human corneal endothelial cell culture. AB - BACKGROUND/AIMS: To study human corneal endothelial cells (HCECs) cultured in vitro with human serum (HS) supplemented media (HS-SM) compared with HCEC cultured in fetal bovine serum (FBS) supplemented media (FBS-SM). METHODS: One cornea from a donor aged 21 years and a pair of corneas from a 16 year-old donor were obtained from the eye bank and used to create two different cell populations. At the first passage, the cell populations were equally divided and seeded in two different wells containing FBS-SM or HS-SM. In subsequent passages, HS-SM was compared with FBS-SM by morphology, growth curves, immunohistochemistry and real-time reverse-transcriptase PCR for endothelial cell markers. RESULTS: No difference in morphology could be seen in P2, P5 or in any other passages for cells grown in the two media. By growth curves, cell counts were similar in FBS SM and HS-SM from days 1 to 5, with a trend towards higher cell counts in HS-SM at day 7. Cells grown in FBS-SM and HS-SM media showed similar expression of endothelial cell markers when assessed by immunohistochemistry and real-time reverse-transcriptase PCR. CONCLUSIONS: HS-SM was similar to FBS-SM for HCEC culture when assessed by cell morphology, proliferation and protein/gene expression. PMID- 25452556 TI - Impact of a new definition of acute kidney injury based on creatinine kinetics in cardiac surgery patients: a comparison with the RIFLE classification. AB - OBJECTIVES: Acute kidney injury (AKI) after cardiac surgery is associated with adverse patient outcome. A new definition and staging system for AKI based on creatinine kinetics (CKs) has been proposed recently. Their proponents hypothesize that early absolute increases in serum creatinine (sCr) after kidney injury are superior to percentage increases, especially in patients with chronic kidney disease (CKD). The aims of our study were to measure agreement between CK definition and the current consensus definition [risk, injury, failure, loss and end-stage renal disease (RIFLE) system], and to compare time to diagnosis and prognostic value between both systems. METHODS: Retrospective cohort study. Agreement on AKI diagnosis by both classifications, time to diagnosis and prognostic value of both systems were compared in cardiac surgeries performed during a 6-year period (2002-2007) in a single centre. RESULTS: We found substantial agreement between both classifications (0.67). More patients were diagnosed with AKI by the CK definition than by RIFLE criteria both globally (28.2 vs 13.9%) and in every category (16.5 vs 8.4% for CK-1 vs RIFLE-R; 8.4 vs 3.6% for CK-2 vs RIFLE-I and 3.2 vs 2.0% for CK-3 vs RIFLE-F). Time to diagnosis was shorter for the CK definition (1.8 vs 2.5 days). Prognostic value in terms of information about in-hospital death and need for renal replacement was comparable between classifications. CONCLUSIONS: In cardiac surgery, the CK definition and classification system showed substantial agreement with the current standard, was more sensitive than RIFLE and detected AKI earlier without loss of prognostic information. PMID- 25452559 TI - Advocacy for booster seat legislation in Florida: a lesson in politics and policy formation. AB - MVCs are a major contributor to child injury and death. Infant restraint seats and child booster seats have been shown to reduce the odds of severe injury or death when used correctly. While all states have mandated the use of these restraint systems, the age at which a child can be legally restrained using an adult seat belt varies from state to state. Efforts to strengthen Florida's weak child restraint laws have failed for more than a decade; in the 2014 legislative session, advocates succeeded in raising the state's age requirement from 3 years to 5 years. While many factors contributed to this year's success, some key elements included efficient communication of supporting data, a strong and broad advocacy network and the leveraging of election year political rivalries. Efforts to further strengthen the law will continue into future legislative sessions. PMID- 25452554 TI - B cells modulate systemic responses to Pneumocystis murina lung infection and protect on-demand hematopoiesis via T cell-independent innate mechanisms when type I interferon signaling is absent. AB - HIV infection results in a complex immunodeficiency due to loss of CD4(+) T cells, impaired type I interferon (IFN) responses, and B cell dysfunctions causing susceptibility to opportunistic infections such as Pneumocystis murina pneumonia and unexplained comorbidities, including bone marrow dysfunctions. Type I IFNs and B cells critically contribute to immunity to Pneumocystis lung infection. We recently also identified B cells as supporters of on-demand hematopoiesis following Pneumocystis infection that would otherwise be hampered due to systemic immune effects initiated in the context of a defective type I IFN system. While studying the role of type I IFNs in immunity to Pneumocystis infection, we discovered that mice lacking both lymphocytes and type I IFN receptor (IFrag(-/-)) developed progressive bone marrow failure following infection, while lymphocyte-competent type I IFN receptor-deficient mice (IFNAR( /-)) showed transient bone marrow depression and extramedullary hematopoiesis. Lymphocyte reconstitution of lymphocyte-deficient IFrag(-/-) mice pointed to B cells as a key player in bone marrow protection. Here we define how B cells protect on-demand hematopoiesis following Pneumocystis lung infection in our model. We demonstrate that adoptive transfer of B cells into IFrag(-/-) mice protects early hematopoietic progenitor activity during systemic responses to Pneumocystis infection, thus promoting replenishment of depleted bone marrow cells. This activity is independent of CD4(+) T cell help and B cell receptor specificity and does not require B cell migration to bone marrow. Furthermore, we show that B cells protect on-demand hematopoiesis in part by induction of interleukin-10 (IL-10)- and IL-27-mediated mechanisms. Thus, our data demonstrate an important immune modulatory role of B cells during Pneumocystis lung infection that complement the modulatory role of type I IFNs to prevent systemic complications. PMID- 25452560 TI - The dancing heart. AB - A woman with palliative breast cancer presents with dyspnoea and is noted to have an unusual electrocardiogram, with an alternating electrical axis observed. Subsequent echocardiogram demonstrates the classical findings of a large pericardial effusion causing 'electrical alternans' aptly illustrating why this rare phenomenon occurs. PMID- 25452561 TI - Splenic B cells from Hymenolepis diminuta-infected mice ameliorate colitis independent of T cells and via cooperation with macrophages. AB - Helminth parasites provoke multicellular immune responses in their hosts that can suppress concomitant disease. The gut lumen-dwelling tapeworm Hymenolepis diminuta, unlike other parasites assessed as helminth therapy, causes no host tissue damage while potently suppressing murine colitis. With the goal of harnessing the immunomodulatory capacity of infection with H. diminuta, we assessed the putative generation of anti-colitic regulatory B cells following H. diminuta infection. Splenic CD19(+) B cells isolated from mice infected 7 [HdBc(7(d))] and 14 d (but not 3 d) previously with H. diminuta and transferred to naive mice significantly reduced the severity of dinitrobenzene sulfonic acid (DNBS)-, oxazolone-, and dextran-sodium sulfate-induced colitis. Mechanistic studies with the DNBS model, revealed the anti-colitic HdBc(7(d)) was within the follicular B cell population and its phenotype was not dependent on IL-4 or IL 10. The HdBc(7(d)) were not characterized by increased expression of CD1d, CD5, CD23, or IL-10 production, but did spontaneously, and upon LPS plus anti-CD40 stimulation, produce more TGF-beta than CD19(+) B cells from controls. DNBS induced colitis in RAG1(-/-) mice was inhibited by administration of HdBc(7(d)), indicating a lack of a requirement for T and B cells in the recipient; however, depletion of macrophages in recipient mice abrogated the anti-colitic effect of HdBc(7(d)). Thus, in response to H. diminuta, a putatively unique splenic CD19(+) B cell with a functional immunoregulatory program is generated that promotes the suppression of colitis dominated by TH1, TH2, or TH1-plus-TH2 events, and may do so via the synthesis of TGF-beta and the generation of, or cooperation with, a regulatory macrophage. PMID- 25452563 TI - A CD46-like molecule functional in teleost fish represents an ancestral form of membrane-bound regulators of complement activation. AB - In the complement system, the regulators of complement activation (RCA) play crucial roles in controlling excessive complement activation and in protecting host cell from misdirected attack of complement. Several members of RCA family have been cloned from cyclostome and bony fish species and classified into soluble and membrane-bound type as in mammalian RCA factors. Complement regulatory functions have been described only for soluble RCA of lamprey and barred sand bass; however, little is known on the biological function of the membrane-bound RCA proteins in the lower vertebrates. In this study, a membrane bound RCA protein, designated teleost complement-regulatory membrane protein (Tecrem), was cloned and characterized for its complement-regulatory roles. Carp Tecrem, an ortholog of a zebrafish type 2 RCA, ZCR1, consists of four short consensus repeat modules, a serine/threonine/proline-rich domain, a transmembrane region, and a cytoplasmic domain, from the N terminus, as does mammalian CD46. Tecrem showed a ubiquitous mRNA expression in carp tissues, agreeing well with the putative regulatory role in complement activation. A recombinant Chinese hamster ovary cell line bearing carp Tecrem showed a significantly higher tolerance against lytic activity of carp complement and less deposition of C3-S, the major C3 isotypes acting on the target cell, than control Chinese hamster ovary (mock transfectant). Anti-Tecrem mAb enhanced the depositions of carp C3 and two C4 isotypes on autologous erythrocytes. Thus, the present findings provide the evidence of complement regulation by a membrane-bound group 2 RCA in bony fish, implying the host-cell protection is an evolutionarily conserved mechanism in regulation of the complement system. PMID- 25452562 TI - Ex vivo-expanded but not in vitro-induced human regulatory T cells are candidates for cell therapy in autoimmune diseases thanks to stable demethylation of the FOXP3 regulatory T cell-specific demethylated region. AB - Regulatory T cell (Treg) therapy is a promising approach for transplant rejection and severe autoimmunity. Unfortunately, clinically meaningful Treg numbers can be obtained only upon in vitro culture. Functional stability of human expanded (e)Tregs and induced (i)Tregs has not been thoroughly addressed for all proposed protocols, hindering clinical translation. We undertook a systematic comparison of eTregs and iTregs to recommend the most suitable for clinical implementation, and then tested their effectiveness and feasibility in rheumatoid arthritis (RA). Regardless of the treatment, iTregs acquired suppressive function and FOXP3 expression, but lost them upon secondary restimulation in the absence of differentiation factors, which mimics in vivo reactivation. In contrast, eTregs expanded in the presence of rapamycin (rapa) retained their regulatory properties and FOXP3 demethylation upon restimulation with no stabilizing agent. FOXP3 demethylation predicted Treg functional stability upon secondary TCR engagement. Rapa eTregs suppressed conventional T cell proliferation via both surface (CTLA 4) and secreted (IL-10, TGF-beta, and IL-35) mediators, similarly to ex vivo Tregs. Importantly, Treg expansion with rapa from RA patients produced functionally stable Tregs with yields comparable to healthy donors. Moreover, rapa eTregs from RA patients were resistant to suppression reversal by the proinflammatory cytokine TNF-alpha, and were more efficient in suppressing synovial conventional T cell proliferation compared with their ex vivo counterparts, suggesting that rapa improves both Treg function and stability. In conclusion, our data indicate Treg expansion with rapa as the protocol of choice for clinical application in rheumatological settings, with assessment of FOXP3 demethylation as a necessary quality control step. PMID- 25452564 TI - Crosstalk among IL-23 and DNAX activating protein of 12 kDa-dependent pathways promotes osteoclastogenesis. AB - IL-23 has been well studied in the context of T cell differentiation; however, its role in the differentiation of myeloid progenitors is less clear. In this paper, we describe a novel role of IL-23 in myeloid cell differentiation. Specifically, we have identified that in human PBMCs, IL-23 induces the expression of MDL-1, a PU.1 transcriptional target during myeloid differentiation, which orchestrates osteoclast differentiation through activation of DNAX activating protein of 12 kDa and its ITAMs. The molecular events that lead to the differentiation of human macrophages to terminally differentiated osteoclasts are dependent on spleen tyrosine kinase and phospholipase Cgamma2 phosphorylation for the induction of intracellular calcium flux and the subsequent activation of master regulator osteoclast transcription factor NFATc1. IL-23-elicited osteoclastogenesis is independent of the receptor activator of NF kappaB ligand pathway and uses a unique myeloid DNAX activating protein of 12 kDa associated lectin-1(+)/DNAX activating protein of 12 kDa(+) cell subset. Our data define a novel pathway that is used by IL-23 in myeloid cells and identify a major mechanism for the stimulation of osteoclastogenesis in inflammatory arthritis. PMID- 25452565 TI - Dysregulated miR-34a-SIRT1-acetyl p65 axis is a potential mediator of immune activation in the colon during chronic simian immunodeficiency virus infection of rhesus macaques. AB - Persistent gastrointestinal inflammation, a hallmark of progressive HIV/SIV infection, causes disruption of the gastrointestinal epithelial barrier, microbial translocation, and generalized immune activation/inflammation driving AIDS progression. Apart from protein regulators, recent studies strongly suggest critical roles for microRNAs (miRNAs) in regulating and managing certain aspects of the inflammatory process. To examine their immunoregulatory role, we profiled miRNA expression in the colon from 12 chronic SIV-infected and 4 control macaques. After applying multiple comparisons correction, 10 (3 upregulated and 7 downregulated) miRNAs showed differential expression. Most notably, miR-34a showed significant upregulation in both epithelial and lamina propria leukocyte (LPL) compartments. Intense gammaH2A.X expression in colonic epithelium and LPLs confirmed the contribution of DNA damage response in driving miR-34a upregulation. SIRT1 mRNA and protein decreased significantly in both colonic epithelium and LPLs. Luciferase reporter assays validated rhesus macaque SIRT1 as a direct miR-34a target. Decreased SIRT1 expression was associated with constitutively enhanced expression of the transcriptionally active form of the p65 (acetylated on lysine 310) subunit of NF-kappaB exclusively in the LPL compartment. The intensity and number of acetylated p65(+) cells was markedly elevated in LPLs of chronically SIV-infected macaques compared with uninfected controls and localized to increased numbers of IgA(+) and IgG(+) plasma cells. These findings provide new insights into the potential role of the miR-34a-SIRT1 p65 axis in causing hyperactivation of the intestinal B cell system. Our results point to a possible mechanism where the normal immunosuppressive function of SIRT1 is inhibited by elevated miR-34a expression resulting in constitutive activation of acetylated p65 (lysine 310). PMID- 25452567 TI - Differential Alterations of Auditory Gamma Oscillatory Responses Between Pre Onset High-Risk Individuals and First-Episode Schizophrenia. AB - Alterations in gamma-band auditory steady-state response (ASSR) are the most robust finding of abnormal neural oscillations in patients with first-episode (FES) and chronic schizophrenia. Gamma-band ASSRs may indicate GABAergic interneuron dysfunction. Nevertheless, it is unknown whether abnormal gamma-band ASSRs are present before the onset of psychosis. Subjects were 15 ultra-high-risk (UHR) individuals, 13 FES patients, and 21 healthy control (HC) subjects. We performed electroencephalogram recordings and measured ASSRs in each group as they were presented with click trains at 20, 30, and 40 Hz. We then conducted time-frequency analyses and calculated intertrial phase coherence and event related spectral perturbation. The time course of gamma-band ASSRs showed significantly different features among groups. Compared with the HC group, the UHR group was characterized by intact early-latency (0-100 ms) and reduced late latency (300-500 ms) ASSRs. In contrast, both early- and late-latency ASSRs were significantly reduced in the FES group. Gamma-band ASSRs were correlated with clinical symptoms and attentional functioning in FES (|rs| > 0.70). These results suggest differential alterations of gamma-band ASSRs between UHR and FES groups. The late-latency ASSR alteration may represent a biomarker for early detection of psychosis, while the early-latency ASSR abnormality may develop through the onset of psychosis. PMID- 25452566 TI - Antibody stabilization of peptide-MHC multimers reveals functional T cells bearing extremely low-affinity TCRs. AB - Fluorochrome-conjugated peptide-MHC (pMHC) multimers are commonly used in combination with flow cytometry for direct ex vivo visualization and characterization of Ag-specific T cells, but these reagents can fail to stain cells when TCR affinity and/or TCR cell-surface density are low. pMHC multimer staining of tumor-specific, autoimmune, or MHC class II-restricted T cells can be particularly challenging, as these T cells tend to express relatively low affinity TCRs. In this study, we attempted to improve staining using anti fluorochrome unconjugated primary Abs followed by secondary staining with anti-Ab fluorochrome-conjugated Abs to amplify fluorescence intensity. Unexpectedly, we found that the simple addition of an anti-fluorochrome unconjugated Ab during staining resulted in considerably improved fluorescence intensity with both pMHC tetramers and dextramers and with PE-, allophycocyanin-, or FITC-based reagents. Importantly, when combined with protein kinase inhibitor treatment, Ab stabilization allowed pMHC tetramer staining of T cells even when the cognate TCR pMHC affinity was extremely low (KD >1 mM) and produced the best results that we have observed to date. We find that this inexpensive addition to pMHC multimer staining protocols also allows improved recovery of cells that have recently been exposed to Ag, improvements in the recovery of self-specific T cells from PBMCs or whole-blood samples, and the use of less reagent during staining. In summary, Ab stabilization of pMHC multimers during T cell staining extends the range of TCR affinities that can be detected, yields considerably enhanced staining intensities, and is compatible with using reduced amounts of these expensive reagents. PMID- 25452568 TI - Neuronal Progenitor Maintenance Requires Lactate Metabolism and PEPCK-M-Directed Cataplerosis. AB - This study investigated the metabolic requirements for neuronal progenitor maintenance in vitro and in vivo by examining the metabolic adaptations that support neuronal progenitors and neural stem cells (NSCs) in their undifferentiated state. We demonstrate that neuronal progenitors are strictly dependent on lactate metabolism, while glucose induces their neuronal differentiation. Lactate signaling is not by itself capable of maintaining the progenitor phenotype. The consequences of lactate metabolism include increased mitochondrial and oxidative metabolism, with a strict reliance on cataplerosis through the mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) pathway to support anabolic functions, such as the production of extracellular matrix. In vivo, lactate maintains/induces populations of postnatal neuronal progenitors/NSCs in a PEPCK-M-dependent manner. Taken together, our data demonstrate that, lactate alone or together with other physical/biochemical cues maintain NSCs/progenitors with a metabolic signature that is classically found in tissues with high anabolic capacity. PMID- 25452569 TI - Neural Activation During Mental Rotation in Complete Androgen Insensitivity Syndrome: The Influence of Sex Hormones and Sex Chromosomes. AB - Sex hormones, androgens in particular, are hypothesized to play a key role in the sexual differentiation of the human brain. However, possible direct effects of the sex chromosomes, that is, XX or XY, have not been well studied in humans. Individuals with complete androgen insensitivity syndrome (CAIS), who have a 46,XY karyotype but a female phenotype due to a complete androgen resistance, enable us to study the separate effects of gonadal hormones versus sex chromosomes on neural sex differences. Therefore, in the present study, we compared 46,XY men (n = 30) and 46,XX women (n = 29) to 46,XY individuals with CAIS (n = 21) on a mental rotation task using functional magnetic resonance imaging. Previously reported sex differences in neural activation during mental rotation were replicated in the control groups, with control men showing more activation in the inferior parietal lobe than control women. Individuals with CAIS showed a female-like neural activation pattern in the parietal lobe, indicating feminization of the brain in CAIS. Furthermore, this first neuroimaging study in individuals with CAIS provides evidence that sex differences in regional brain function during mental rotation are most likely not directly driven by genetic sex, but rather reflect gonadal hormone exposure. PMID- 25452570 TI - Adenosine A1 Receptor Suppresses Tonic GABAA Receptor Currents in Hippocampal Pyramidal Cells and in a Defined Subpopulation of Interneurons. AB - Adenosine is an endogenous neuromodulator that decreases excitability of hippocampal circuits activating membrane-bound metabotropic A1 receptor (A1R). The presynaptic inhibitory action of adenosine A1R in glutamatergic synapses is well documented, but its influence on inhibitory GABAergic transmission is poorly known. We report that GABAA receptor (GABAAR)-mediated tonic, but not phasic, transmission is suppressed by A1R in hippocampal neurons. Adenosine A1R activation strongly inhibits GABAAR agonist (muscimol)-evoked currents in Cornu Ammonis 1 (CA1) pyramidal neurons and in a specific subpopulation of interneurons expressing axonal cannabinoid receptor type 1. In addition, A1R suppresses tonic GABAAR currents measured in the presence of elevated ambient GABA as well as in naive slices. The inhibition of GABAergic currents involves both protein kinase A (PKA) and protein kinase C (PKC) signaling pathways and decreases GABAAR delta subunit expression. On the contrary, no A1R-mediated modulation was detected in phasic inhibitory postsynaptic currents evoked either by afferent electrical stimulation or by spontaneous quantal release. The results show that A1R modulates extrasynaptic rather than synaptic GABAAR-mediated signaling, and that this modulation selectively occurs in hippocampal pyramidal neurons and in a specific subpopulation of inhibitory interneurons. We conclude that modulation of tonic GABAAR signaling by adenosine A1R in specific neuron types may regulate neuronal gain and excitability in the hippocampus. PMID- 25452571 TI - Probabilistic Maps of Visual Topography in Human Cortex. AB - The human visual system contains an array of topographically organized regions. Identifying these regions in individual subjects is a powerful approach to group level statistical analysis, but this is not always feasible. We addressed this limitation by generating probabilistic maps of visual topographic areas in 2 standardized spaces suitable for use with adult human brains. Using standard fMRI paradigms, we identified 25 topographic maps in a large population of individual subjects (N = 53) and transformed them into either a surface- or volume-based standardized space. Here, we provide a quantitative characterization of the inter subject variability within and across visual regions, including the likelihood that a given point would be classified as a part of any region (full probability map) and the most probable region for any given point (maximum probability map). By evaluating the topographic organization across the whole of visual cortex, we provide new information about the organization of individual visual field maps and large-scale biases in visual field coverage. Finally, we validate each atlas for use with independent subjects. Overall, the probabilistic atlases quantify the variability of topographic representations in human cortex and provide a useful reference for comparing data across studies that can be transformed into these standard spaces. PMID- 25452573 TI - The Faces in Radiological Images: Fusiform Face Area Supports Radiological Expertise. AB - The fusiform face area (FFA) has often been used as an example of a brain module that was developed through evolution to serve a specific purpose-face processing. Many believe, however, that FFA is responsible for holistic processing associated with any kind of expertise. The expertise view has been tested with various stimuli, with mixed results. One of the main stumbling blocks in the FFA controversy has been the fact that the stimuli used have been similar to faces. Here, we circumvent the problem by using radiological images, X-rays, which bear no resemblance to faces. We demonstrate that FFA can distinguish between X-rays and other stimuli by employing multivariate pattern analysis. The sensitivity to X-rays was significantly better in experienced radiologists than that in medical students with limited radiological experience. For the radiologists, it was also possible to use the patterns of FFA activations obtained on faces to differentiate X-ray stimuli from other stimuli. The overlap in the FFA activation is not based on visual similarity of faces and X-rays but rather on the processes necessary for expertise with both kinds of stimulus. Our results support the expertise view that FFA's main function is related to holistic processing. PMID- 25452572 TI - Ranbp1, Deleted in DiGeorge/22q11.2 Deletion Syndrome, is a Microcephaly Gene That Selectively Disrupts Layer 2/3 Cortical Projection Neuron Generation. AB - Ranbp1, a Ran GTPase-binding protein implicated in nuclear/cytoplasmic trafficking, is included within the DiGeorge/22q11.2 Deletion Syndrome (22q11.2 DS) critical region associated with behavioral impairments including autism and schizophrenia. Ranbp1 is highly expressed in the developing forebrain ventricular/subventricular zone but has no known obligate function during brain development. We assessed the role of Ranbp1 in a targeted mouse mutant. Ranbp1(-/ ) mice are not recovered live at birth, and over 60% of Ranbp1(-/-) embryos are exencephalic. Non-exencephalic Ranbp1(-/-) embryos are microcephalic, and proliferation of cortical progenitors is altered. At E10.5, radial progenitors divide more slowly in the Ranpb1(-/-) dorsal pallium. At E14.5, basal, but not apical/radial glial progenitors, are compromised in the cortex. In both E10.5 apical and E14.5 basal progenitors, M phase of the cell cycle appears selectively retarded by loss of Ranpb1 function. Ranbp1(-/-)-dependent proliferative deficits substantially diminish the frequency of layer 2/3, but not layer 5/6 cortical projection neurons. Ranbp1(-/-) cortical phenotypes parallel less severe alterations in LgDel mice that carry a deletion parallel to many (but not all) 22q11.2 DS patients. Thus, Ranbp1 emerges as a microcephaly gene within the 22q11.2 deleted region that may contribute to altered cortical precursor proliferation and neurogenesis associated with broader 22q11.2 deletion. PMID- 25452574 TI - Brain Network Connectivity During Language Comprehension: Interacting Linguistic and Perceptual Subsystems. AB - The dynamic neural processes underlying spoken language comprehension require the real-time integration of general perceptual and specialized linguistic information. We recorded combined electro- and magnetoencephalographic measurements of participants listening to spoken words varying in perceptual and linguistic complexity. Combinatorial linguistic complexity processing was consistently localized to left perisylvian cortices, whereas competition-based perceptual complexity triggered distributed activity over both hemispheres. Functional connectivity showed that linguistically complex words engaged a distributed network of oscillations in the gamma band (20-60 Hz), which only partially overlapped with the network supporting perceptual analysis. Both processes enhanced cross-talk between left temporal regions and bilateral pars orbitalis (BA47). The left-lateralized synchrony between temporal regions and pars opercularis (BA44) was specific to the linguistically complex words, suggesting a specific role of left frontotemporal cross-cortical interactions in morphosyntactic computations. Synchronizations in oscillatory dynamics reveal the transient coupling of functional networks that support specific computational processes in language comprehension. PMID- 25452575 TI - Causal Influence of Articulatory Motor Cortex on Comprehending Single Spoken Words: TMS Evidence. AB - Classic wisdom had been that motor and premotor cortex contribute to motor execution but not to higher cognition and language comprehension. In contrast, mounting evidence from neuroimaging, patient research, and transcranial magnetic stimulation (TMS) suggest sensorimotor interaction and, specifically, that the articulatory motor cortex is important for classifying meaningless speech sounds into phonemic categories. However, whether these findings speak to the comprehension issue is unclear, because language comprehension does not require explicit phonemic classification and previous results may therefore relate to factors alien to semantic understanding. We here used the standard psycholinguistic test of spoken word comprehension, the word-to-picture-matching task, and concordant TMS to articulatory motor cortex. TMS pulses were applied to primary motor cortex controlling either the lips or the tongue as subjects heard critical word stimuli starting with bilabial lip-related or alveolar tongue related stop consonants (e.g., "pool" or "tool"). A significant cross-over interaction showed that articulatory motor cortex stimulation delayed comprehension responses for phonologically incongruent words relative to congruous ones (i.e., lip area TMS delayed "tool" relative to "pool" responses). As local TMS to articulatory motor areas differentially delays the comprehension of phonologically incongruous spoken words, we conclude that motor systems can take a causal role in semantic comprehension and, hence, higher cognition. PMID- 25452576 TI - A Neural Mechanism for Nonconscious Activation of Conditioned Placebo and Nocebo Responses. AB - Fundamental aspects of human behavior operate outside of conscious awareness. Yet, theories of conditioned responses in humans, such as placebo and nocebo effects on pain, have a strong emphasis on conscious recognition of contextual cues that trigger the response. Here, we investigated the neural pathways involved in nonconscious activation of conditioned pain responses, using functional magnetic resonance imaging in healthy participants. Nonconscious compared with conscious activation of conditioned placebo analgesia was associated with increased activation of the orbitofrontal cortex, a structure with direct connections to affective brain regions and basic reward processing. During nonconscious nocebo, there was increased activation of the thalamus, amygdala, and hippocampus. In contrast to previous assumptions about conditioning in humans, our results show that conditioned pain responses can be elicited independently of conscious awareness and our results suggest a hierarchical activation of neural pathways for nonconscious and conscious conditioned responses. Demonstrating that the human brain has a nonconscious mechanism for responding to conditioned cues has major implications for the role of associative learning in behavioral medicine and psychiatry. Our results may also open up for novel approaches to translational animal-to-human research since human consciousness and animal cognition is an inherent paradox in all behavioral science. PMID- 25452577 TI - Cortical Tubers: Windows into Dysregulation of Epilepsy Risk and Synaptic Signaling Genes by MicroRNAs. AB - Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutations in the TSC1 and TSC2 genes. Over 80% of TSC patients are affected by epilepsy, but the molecular events contributing to seizures in TSC are not well understood. Recent reports have demonstrated that the brain is enriched with microRNA activity, and they are critical in neural development and function. However, little is known about the role of microRNAs in TSC. Here, we report the characterization of aberrant microRNA activity in cortical tubers resected from 5 TSC patients surgically treated for medically intractable epilepsy. By comparing epileptogenic tubers with adjacent nontuber tissue, we identified a set of 4 coordinately overexpressed microRNAs (miRs 23a, 34a, 34b*, 532-5p). We used quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomic profiling to investigate the combined effect of the 4 microRNAs on target proteins. The proportion of repressed proteins among the predicted targets was significantly greater than in the overall proteome and was highly enriched for proteins involved in synaptic signal transmission. Among the combinatorial targets were TSC1, coding for the protein hamartin, and several epilepsy risk genes. We found decreased levels of hamartin in epileptogenic tubers and confirmed targeting of the TSC1 3' UTR by miRs-23a and 34a. PMID- 25452579 TI - Functional Changes in the Language Network in Response to Increased Amyloid beta Deposition in Cognitively Intact Older Adults. AB - Word finding symptoms are frequent early in the course of Alzheimer's disease and relate principally to functional changes in left posterior temporal cortex. In cognitively intact older adults, we examined whether amyloid load affects the network for language and associative-semantic processing. Fifty-six community recruited subjects (52-74 years), stratified for apolipoprotein E and brain derived neurotrophic factor genotype, received a neurolinguistic assessment, (18)F-flutemetamol positron emission tomography, and a functional MRI of the associative-semantic system. The primary measure of amyloid load was the cerebral to-cerebellar gray matter standardized uptake value ratio in a composite cortical volume of interest (SUVR(comp)). The primary outcome analysis consisted of a whole-brain voxelwise linear regression between SUVR(comp) and fMRI response during associative-semantic versus visuoperceptual processing. Higher activity in one region, the posterior left middle temporal gyrus, correlated positively with increased amyloid load. The correlation remained significant when only the word conditions were contrasted but not for pictures. According to a stepwise linear regression analysis, offline naming reaction times correlated positively with SUVR(comp). A binary classification into amyloid-positive and amyloid-negative cases confirmed our findings. The left posterior temporal activity increase may reflect higher demands for semantic control in the presence of a higher amyloid burden. PMID- 25452580 TI - Heightened avidity for trisodium pyrophosphate in mice lacking Tas1r3. AB - Laboratory rats and mice prefer some concentrations of tri- and tetrasodium pyrophosphate (Na3HP2O7 and Na4P2O7) to water, but how they detect pyrophosphates is unknown. Here, we assessed whether T1R3 is involved. We found that relative to wild-type littermate controls, Tas1r3 knockout mice had stronger preferences for 5.6-56mM Na3HP2O7 in 2-bottle choice tests, and they licked more 17.8-56mM Na3HP2O7 in brief-access tests. We hypothesize that pyrophosphate taste in the intact mouse involves 2 receptors: T1R3 to produce a hedonically negative signal and an unknown G protein-coupled receptor to produce a hedonically positive signal; in Tas1r3 knockout mice, the hedonically negative signal produced by T1R3 is absent, leading to a heightened avidity for pyrophosphate. PMID- 25452578 TI - A Neural Marker for Social Bias Toward In-group Accents. AB - Accents provide information about the speaker's geographical, socio-economic, and ethnic background. Research in applied psychology and sociolinguistics suggests that we generally prefer our own accent to other varieties of our native language and attribute more positive traits to it. Despite the widespread influence of accents on social interactions, educational and work settings the neural underpinnings of this social bias toward our own accent and, what may drive this bias, are unexplored. We measured brain activity while participants from two different geographical backgrounds listened passively to 3 English accent types embedded in an adaptation design. Cerebral activity in several regions, including bilateral amygdalae, revealed a significant interaction between the participants' own accent and the accent they listened to: while repetition of own accents elicited an enhanced neural response, repetition of the other group's accent resulted in reduced responses classically associated with adaptation. Our findings suggest that increased social relevance of, or greater emotional sensitivity to in-group accents, may underlie the own-accent bias. Our results provide a neural marker for the bias associated with accents, and show, for the first time, that the neural response to speech is partly shaped by the geographical background of the listener. PMID- 25452581 TI - An Ultra-Trace Analysis Technique for SF6 Using Gas Chromatography with Negative Ion Chemical Ionization Mass Spectrometry. AB - Sulfur hexafluoride (SF6) is widely used as a tracer gas because of its detectability at low concentrations. This attribute of SF6 allows the quantification of both small-scale flows, such as leakage, and large-scale flows, such as atmospheric currents. SF6's high detection sensitivity also facilitates greater usage efficiency and lower operating cost for tracer deployments by reducing quantity requirements. The detectability of SF6 is produced by its high molecular electronegativity. This property provides a high potential for negative ion formation through electron capture thus naturally translating to selective detection using negative ion chemical ionization mass spectrometry (NCI-MS). This paper investigates the potential of using gas chromatography (GC) with NCI-MS for the detection of SF6. The experimental parameters for an ultra-trace SF6 detection method utilizing minimal customizations of the analytical instrument are detailed. A method for the detection of parts per trillion (ppt) level concentrations of SF6 for the purpose of underground ventilation tracer gas analysis was successfully developed in this study. The method utilized a Shimadzu gas chromatography with negative ion chemical ionization mass spectrometry system equipped with an Agilent J&W HP-porous layer open tubular column coated with an alumina oxide (Al2O3) S column. The method detection limit (MDL) analysis as defined by the Environmental Protection Agency of the tracer data showed the method MDL to be 5.2 ppt. PMID- 25452582 TI - Retraction: 'A subfamily of RNA-binding DEAD-box proteins acts as an estrogen receptor alpha coactivator through the N-terminal activation domain (AF-1) with an RNA coactivator, SRA'. PMID- 25452584 TI - Retraction: 'Ligand-induced transrepression by VDR through association of WSTF with acetylated histones'. PMID- 25452583 TI - Retraction: 'Transrepression by a liganded nuclear receptor via a bHLH activator through co-regulator switching'. PMID- 25452585 TI - Retraction: 'A cell cycle-dependent co-repressor mediates photoreceptor cell specific nuclear receptor function'. PMID- 25452589 TI - Progress in the health and nutrition of girls in the Asia-Pacific region. AB - Since its inception 3 decades ago the Asia-Pacific Academic Consortium for Public Health (APACPH) has emphasized improving the health of disadvantaged and minority groups. In 1990, APACPH held a conference in Kathmandu with the theme, "The Girl Child in Asia: A Neglected Majority." Over the past 3 decades, the mortality rates for all children, particularly girls, have improved in our region. PMID- 25452590 TI - Access to safe legal abortion in Malaysia: women's insights and health sector response. AB - Malaysia has an abortion law, which permits termination of pregnancy to save a woman's life and to preserve her physical and mental health (Penal Code Section 312, amended in 1989). However, lack of clear interpretation and understanding of the law results in women facing difficulties in accessing abortion information and services. Some health care providers were unaware of the legalities of abortion in Malaysia and influenced by their personal beliefs with regard to provision of abortion services. Accessibility to safer abortion techniques is also an issue. The development of the 2012 Guidelines on Termination of Pregnancy and Guidelines for Management of Sexual and Reproductive Health among Adolescents in Health Clinics by the Ministry of Health, Malaysia, is a step forward toward increasing women's accessibility to safe abortion services in Malaysia. This article provides an account of women's accessibility to abortion in Malaysia and the health sector response in addressing the barriers. PMID- 25452588 TI - Identification and characterization of novel factors that act in the nonsense mediated mRNA decay pathway in nematodes, flies and mammals. AB - Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that degrades mRNAs harboring premature termination codons (PTCs). We have conducted a genome wide RNAi screen in Caenorhabditis elegans that resulted in the identification of five novel NMD genes that are conserved throughout evolution. Two of their human homologs, GNL2 (ngp-1) and SEC13 (npp-20), are also required for NMD in human cells. We also show that the C. elegans gene noah-2, which is present in Drosophila melanogaster but absent in humans, is an NMD factor in fruit flies. Altogether, these data identify novel NMD factors that are conserved throughout evolution, highlighting the complexity of the NMD pathway and suggesting that yet uncovered novel factors may act to regulate this process. PMID- 25452586 TI - Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus specific neutralizing antibody response. AB - RNA-sensing toll-like receptors (TLRs) mediate innate immunity and regulate anti viral response. We show here that TLR3 regulates host immunity and the loss of TLR3 aggravates pathology in Chikungunya virus (CHIKV) infection. Susceptibility to CHIKV infection is markedly increased in human and mouse fibroblasts with defective TLR3 signaling. Up to 100-fold increase in CHIKV load was observed in Tlr3-/- mice, alongside increased virus dissemination and pro-inflammatory myeloid cells infiltration. Infection in bone marrow chimeric mice showed that TLR3-expressing hematopoietic cells are required for effective CHIKV clearance. CHIKV-specific antibodies from Tlr3-/- mice exhibited significantly lower in vitro neutralization capacity, due to altered virus-neutralizing epitope specificity. Finally, SNP genotyping analysis of CHIKF patients on TLR3 identified SNP rs6552950 to be associated with disease severity and CHIKV specific neutralizing antibody response. These results demonstrate a key role for TLR3-mediated antibody response to CHIKV infection, virus replication and pathology, providing a basis for future development of immunotherapeutics in vaccine development. PMID- 25452592 TI - Reduced rotavirus vaccine effectiveness among children born during the rotavirus season: a pooled analysis of 5 case-control studies from the Americas. AB - Using data from rotavirus vaccine effectiveness (VE) studies, we assessed whether rotavirus season modifies rotavirus VE in infants. In the first year of life, adjusted VE was 72% for children born during rotavirus season and 84% for children born in other months (P = .01). Seasonal factors may interfere with vaccine performance. PMID- 25452591 TI - High Atopobium vaginae and Gardnerella vaginalis vaginal loads are associated with preterm birth. AB - BACKGROUND: Bacterial vaginosis is a risk factor for preterm birth. The various conventional methods for its diagnosis are laborious and not easily reproducible. Molecular quantification methods have been reported recently, but the specific risk factors they might identify remain unclear. METHODS: A prospective multicenter national study included pregnant women at risk of preterm birth. A quantitative molecular tool using a specific real-time polymerase chain reaction assay and serial dilutions of a plasmid suspension quantified Atopobium vaginae, Gardnerella vaginalis, lactobacilli, Mycoplasma hominis, and the human albumin gene (for quality control). RESULTS: In 813 pregnancies, high vaginal loads of either or both of A. vaginae and G. vaginalis were associated with preterm birth (hazard ratio [HR], 3.9; 95% confidence interval {CI}, 1.1-14.1; P = .031). A high vaginal load of A. vaginae was significantly associated with shortened time to delivery and therefore pregnancy length. These times were, respectively, 152.2 and 188.2 days (HR, 5.6; 95% CI, 1.5-21.3; P < .001) before 22 weeks, 149.0 and 183.2 days (HR, 2.8; 95% CI, 1.1-8.2; P = .048) before 28 weeks, and 132.6 and 170.4 days (HR, 2.2; 95% CI, 1.1-4.6; P = .033) before 32 weeks. After multivariate analysis, A. vaginae levels >=10(8) copies/mL remained significantly associated with delivery before 22 weeks of gestation (adjusted HR, 4.7; 95% CI, .2-17.6; P = .014). CONCLUSIONS: High vaginal loads of A. vaginae and G. vaginalis are associated with late miscarriage and prematurity in high-risk pregnancies. A high vaginal load of A. vaginae (DNA level >=10(8) copies/mL) identifies a population at high risk of preterm birth. Further studies that both screen for and then treat A. vaginae are needed. CLINICAL TRIALS REGISTRATION: NCT00484653. PMID- 25452594 TI - Clinical presentation and risk factors for cytomegalovirus colitis in immunocompetent adult patients. AB - BACKGROUND: Cytomegalovirus (CMV) colitis is a common manifestation of CMV end organ disease, which has typically been described in immunocompromised hosts. Recently, it has been noted that this also occurs in immunocompetent patients. To gather relevant data about clinical presentation, prognosis, and risk factors for development of CMV colitis in immunocompetent hosts, we analyzed all cases that occurred during a 19-year period at our institution. METHODS: A case-control study was performed to identify risk factors for CMV colitis in immunocompetent hosts. Electronic medical records of individuals who were admitted and diagnosed with CMV colitis between January 1995 and February 2014 at a tertiary care university hospital were reviewed. Two non-CMV colitis patients who were age- and sex-matched were selected as controls for each case. RESULTS: A total of 51 patients with CMV colitis were included in this study along with 102 control patients. Certain conditions including renal disease on hemodialysis, neurologic disease, rheumatologic disease, intensive care unit admission, and exposure to antibiotics, antacids, steroids, or red blood cell (RBC) transfusions within 1 month of diagnosis of colitis were associated with CMV colitis on univariate analysis. Among these, steroid use and RBC transfusion within 1 month were identified as independent risk factors for developing CMV colitis on multivariate analysis. The 30-day mortality rate was 7.8% without any attributable mortality. CONCLUSIONS: Steroid use and RBC transfusion within 1 month of the diagnosis of colitis were independent risk factors for development of CMV colitis in immunocompetent hosts. PMID- 25452593 TI - Vaccines against malaria. AB - Despite global efforts to control malaria, the illness remains a significant public health threat. Currently, there is no licensed vaccine against malaria, but an efficacious vaccine would represent an important public health tool for successful malaria elimination. Malaria vaccine development continues to be hindered by a poor understanding of antimalarial immunity, a lack of an immune correlate of protection, and the genetic diversity of malaria parasites. Current vaccine development efforts largely target Plasmodium falciparum parasites in the pre-erythrocytic and erythrocytic stages, with some research on transmission blocking vaccines against asexual stages and vaccines against pregnancy associated malaria. The leading pre-erythrocytic vaccine candidate is RTS,S, and early results of ongoing Phase 3 testing show overall efficacy of 46% against clinical malaria. The next steps for malaria vaccine development will focus on the design of a product that is efficacious against the highly diverse strains of malaria and the identification of a correlate of protection against disease. PMID- 25452595 TI - Whole-genome sequencing and epidemiological analysis do not provide evidence for cross-transmission of mycobacterium abscessus in a cohort of pediatric cystic fibrosis patients. AB - BACKGROUND: Mycobacterium abscessus has emerged as a major pathogen in cystic fibrosis (CF) patients and has been associated with poor clinical outcomes, particularly following lung transplant. We investigated the acquisition of this bacterium in a cohort of pediatric CF patients. METHODS: Demographic and patient location data were used to uncover epidemiological links between patients with genetically related strains of M. abscessus that had been previously typed by variable-number tandem repeat profiling. Whole-genome sequencing was applied to 27 M. abscessus isolates from the 20 patients in this cohort to provide definitive data on the genetic relatedness of strains. RESULTS: Whole-genome sequencing data demonstrated that M. abscessus isolates from 16 patients were unrelated, differing by at least 34 single-nucleotide polymorphisms (SNPs) from any other isolate, suggesting that independent acquisition events have occurred. Only 2 clusters of very closely related (<25 SNPs) isolates from different patients were seen. The first cluster contained 8 isolates, differing by a maximum of 17 SNPs, from a sibling pair who had intense exposure to each other both inside and outside the hospital. The second cluster contained 3 isolates, differing by a maximum of 24 SNPs, from 2 individuals with no apparent epidemiological links. CONCLUSIONS: We have not demonstrated cross-transmission of M. abscessus within our hospital, except between 1 sibling pair. Alternative routes of acquisition of M. abscessus infection, in particular the environment, require further investigation. PMID- 25452598 TI - Can there be false hope in recovery? AB - Although hope is key to recovery, might the course of some people's mental illness be so severe that false promise is offered? This paper unpacks considerations and, after a critical analysis, concludes hope is still central to healing and personal well-being. PMID- 25452596 TI - Disseminated, persistent, and fatal infection due to the vaccine strain of varicella-zoster virus in an adult following stem cell transplantation. AB - Live attenuated varicella vaccine is recommended for healthy individuals who are susceptible to varicella. Although the vaccine is safe, effective, and used worldwide, serious adverse events have been reported, mainly in immunocompromised patients who subsequently recovered. Here, we describe the fatality of an immunocompromised patient who received the varicella vaccine. His medical history provides a cautionary lens through which to view the decision of when vaccination is appropriate. A middle-aged man with non-Hodgkin lymphoma received chemotherapy and a stem cell transplant. He was vaccinated 4 years post-transplantation, despite diagnosis of a new low-grade lymphoma confined to the lymph nodes. Within 3 months of vaccination, he developed recurrent rashes with fever, malaise, weakness, hepatitis, weight loss, and renal failure. The syndrome was eventually determined to be associated with persistent disseminated zoster caused by the vaccine virus. This case illustrates a circumstance when a live viral vaccine should not be used. PMID- 25452599 TI - Why are job stressors relevant for psychiatry? AB - Work-related mental health disorders are a major public health problem. Consequently, psychiatrists encounter many patients whose clinical state is profoundly affected by work conditions. Psychiatrists therefore, need training in occupational/stress medicine. This would help integrate health services for these patients, aimed at preservation of work fitness and mental health. PMID- 25452600 TI - Breast cancer screening in women with mental illness: comparative meta-analysis of mammography uptake. AB - BACKGROUND: There is a higher mortality rate due to cancer in people with mental illness and previous work suggests suboptimal medical care in this population. It remains unclear if this extends to breast cancer population screening. AIMS: To conduct a systematic review and meta-analysis to establish if women with a mental health condition are less likely to receive mammography screening compared with those without mental ill health. METHOD: Major electronic databases were searched from inception until February 2014. We calculated odds ratios (OR) with a random effects meta-analysis comparing mammography screening rates among women with and without a mental illness. Results were stratified according to primary diagnosis including any mental illness, mood disorders, depression, severe mental illness (SMI), distress and anxiety. RESULTS: We identified 24 publications reporting breast cancer screening practices in women with mental illness (n = 715,705). An additional 5 studies investigating screening for those with distress (n = 21,491) but no diagnosis of mental disorder were identified. The pooled meta-analysis showed significantly reduced rates of mammography screening in women with mental illness (OR = 0.71, 95% CI 0.66-0.77), mood disorders (OR = 0.83, 95% CI 0.76 0.90) and particularly SMI (OR = 0.54, 95% CI 0.45-0.65). No disparity was evident among women with distress alone. CONCLUSIONS: Rates of mammography screening are lower in women with mental illness, particularly women with SMI, and this is not explained by the presence of emotional distress. Disparities in medical care due to mental illness clearly extend into preventive population screening. PMID- 25452597 TI - Circulating atrial natriuretic peptide genetic association study identifies a novel gene cluster associated with stroke in whites. AB - BACKGROUND: The goal of this study was to identify genetic determinants of plasma N-terminal proatrial natriuretic peptide (NT-proANP) in the general community by performing a large-scale genetic association study and to assess its functional significance in in vitro cell studies and on disease susceptibility. METHODS AND RESULTS: Genotyping was performed across 16 000 genes in 893 randomly selected individuals, with replication in 891 subjects from the community. Plasma NT proANP1-98 concentrations were determined using a radioimmunoassay. Thirty-three genome-wide significant single-nucleotide polymorphisms were identified in the MTHFR-CLCN6-NPPA-NPPB locus and were all replicated. To assess the significance, in vitro functional genomic studies and clinical outcomes for carriers of a single-nucleotide polymorphism rs5063 (V32M) located in NPPA that represented the most significant variation in this genetic locus were assessed. The rs5063 variant allozyme in transfected HEK293 cells was decreased to 55+/-8% of wild type protein (P=0.01) as assessed by quantitative western blots. Carriers of rs5063 had lower NT-proANP levels (1427 versus 2291 pmol/L; P<0.001) and higher diastolic blood pressures (75 versus 73 mm Hg; P=0.009) and were at an increased risk of stroke when compared with wild-type subjects independent of age, sex, diabetes mellitus, hypertension, atrial fibrillation, and cholesterol levels (hazard ratio, 1.6; P=0.004). CONCLUSIONS: This is the first large-scale genetic association study of circulating NT-proANP levels performed with replication and functional assessment that identified genetic variants in the MTHFR-CLCN6-NPPA NPPB cluster to be significantly associated with NT-proANP levels. The clinical significance of this variation is related to lower NT-proANP levels, higher blood pressures, and an increased risk of stroke in the general community. PMID- 25452601 TI - Non-pharmacological interventions for agitation in dementia: systematic review of randomised controlled trials. AB - BACKGROUND: Agitation in dementia is common, persistent and distressing and can lead to care breakdown. Medication is often ineffective and harmful. AIMS: To systematically review randomised controlled trial evidence regarding non pharmacological interventions. Method We reviewed 33 studies fitting predetermined criteria, assessed their validity and calculated standardised effect sizes (SES). RESULTS: Person-centred care, communication skills training and adapted dementia care mapping decreased symptomatic and severe agitation in care homes immediately (SES range 0.3-1.8) and for up to 6 months afterwards (SES range 0.2-2.2). Activities and music therapy by protocol (SES range 0.5-0.6) decreased overall agitation and sensory intervention decreased clinically significant agitation immediately. Aromatherapy and light therapy did not demonstrate efficacy. CONCLUSIONS: There are evidence-based strategies for care homes. Future interventions should focus on consistent and long-term implementation through staff training. Further research is needed for people living in their own homes. PMID- 25452602 TI - Craddock and Mynors-Wallis's assault on thinking. PMID- 25452603 TI - Authors' reply. PMID- 25452604 TI - Concerns regarding an evaluation of MTFC-A for adolescents in English care. PMID- 25452606 TI - Are we reinforcing the anti-medical model? PMID- 25452605 TI - Authors' reply. PMID- 25452607 TI - Author's reply: To PMID 25252316. PMID- 25452608 TI - Electronic monitoring of forensic patients. PMID- 25452609 TI - Electronic monitoring of forensic patients. PMID- 25452610 TI - Authors' reply. PMID- 25452611 TI - Kaleidoscope. PMID- 25452612 TI - Specific exercise effects of preventive neuromuscular training intervention on anterior cruciate ligament injury risk reduction in young females: meta-analysis and subgroup analysis. AB - CONTEXT: Clinical trials have demonstrated that preventive neuromuscular training (PNMT) can be effective to reduce ACL injuries in young females. However, the magnitude of the overall effect of PNMT for ACL injury reduction has not reached consensus. In addition, the effects of individual exercises in PNMT that optimise ACL injury reduction are unknown. OBJECTIVE: The purpose of this project was to systematically review previously published clinical trials and evaluate types of exercises that best support ACL injury reduction in young females. DATA SOURCES: The key words 'knee', 'anterior cruciate ligament', 'ACL', 'prospective', 'neuromuscular', 'training', 'female', and 'prevention' were used for studies published from 1995 to May 2012 in PubMed and EBSCO host. STUDY SELECTION: Inclusion criteria for the current analysis were: (1) documented number of ACL injuries, (2) employed a PNMT intervention that aimed to reduce ACL injuries, (3) had a comparison group, (4) used a prospective controlled study design, (5) recruited female athletes and (6) recorded exercises implemented in the PNMT. DATA EXTRACTION: The number of ACL injuries and female athletes in each group (control and intervention) were extracted. In addition, exercises were categorised into four types and analysed for each investigation. DATA SYNTHESIS: A total of 14 clinical trials met the inclusion criteria. The subgroup analyses identified fewer ACL injuries in PNMT that focused on strengthening (OR 0.32, 95% CI 0.23 to 0.46, p=0.001), proximal control exercises (OR 0.33, 95% CI 0.23 to 0.47, p=0.001) and multiple exercise interventions (OR 0.32, CI 0.22 to 0.46, p=0.001). CONCLUSIONS: The current subgroup analyses indicate strengthening, proximal control exercises and multi exercise genres increased efficacy in PNMT intervention designed to reduce ACL injury in young female athletes. PMID- 25452613 TI - Cerebrovascular reactivity assessed by transcranial Doppler ultrasound in sport related concussion: a systematic review. AB - BACKGROUND: Traumatic brain injury influences regulation of cerebral blood flow in animal models and in human studies. We reviewed the use of transcranial Doppler ultrasound (US) to monitor cerebrovascular reactivity following sport related concussion. REVIEW METHOD: A narrative and systematic review of articles published in the English language, from December 1982 to October 2013. DATA SOURCES: Articles were retrieved via numerous databases using relevant key terms. Observational, cohort, correlational, cross-sectional and longitudinal studies were included. RESULTS: Three publications met the criteria for inclusion; these provided data from 42 athletes and 33 controls. All three studies reported reductions in cerebrovascular reactivity via transcranial Doppler US. CONCLUSIONS: These initial results support the use of cerebrovascular reactivity as a research tool for identifying altered neurophysiology and monitoring recovery in adult athletes. Larger cross-sectional, prospective and longitudinal studies are required to understand the sensitivity and prognostic value of cerebrovascular reactivity in sport-related concussion. PMID- 25452616 TI - Anatomy of a care quality commission inspection. PMID- 25452617 TI - Editorial: RSV: a new box of delights for an old enemy. PMID- 25452615 TI - BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma. AB - Follicular lymphoma (FL), an indolent neoplasm caused by a t(14;18) chromosomal translocation that juxtaposes the BCL2 gene and immunoglobulin locus, has a variable clinical course and frequently undergoes transformation to an aggressive lymphoma. Although BCL2 mutations have been previously described, their relationship to FL progression remains unclear. In this study, we evaluated the frequency and nature of BCL2 mutations in 2 independent cohorts of grade 1 and 2 FLs, along with the correlation between BCL2 mutations, transformation risk, and survival. The prevalence of BCL2 coding sequence mutations was 12% in FL at diagnosis and 53% at transformation (P < .0001). The presence of these BCL2 mutations at diagnosis correlated with an increased risk of transformation (hazard ratio 3.6; 95% CI, 2.0-6.2; P < .0001) and increased risk of death due to lymphoma (median survival of 9.5 years with BCL2 mutations vs 20.4 years without; P = .012). In a multivariate analysis, BCL2 mutations and high FL international prognostic index were independent risk factors for transformation and death due to lymphoma. Some mutant Bcl-2 proteins exhibited enhanced antiapoptotic capacity in vitro. Accordingly, BCL2 mutations can affect antiapoptotic Bcl-2 function, are associated with increased activation-induced cytidine deaminase expression, and correlate with increased risk of transformation and death due to lymphoma. PMID- 25452619 TI - Australia's proposal for copayments is set to fail amid confusion. PMID- 25452614 TI - Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell depleted stem cell transplantation. AB - Natural killer (NK) cells can enhance engraftment and mediate graft-versus leukemia following allogeneic hematopoietic stem cell transplantation (HSCT), but the potency of graft-versus-leukemia mediated by naturally reconstituting NK cells following HSCT is limited. Preclinical studies demonstrate that activation of NK cells using interleukin-15 (IL-15) plus 4-1BBL upregulates activating receptor expression and augments killing capacity. In an effort to amplify the beneficial effects of NK cells post-HSCT, we conducted a first-in-human trial of adoptive transfer of donor-derived IL-15/4-1BBL-activated NK cells (aNK-DLI) following HLA-matched, T-cell-depleted (1-2 * 10(4) T cells/kg) nonmyeloablative peripheral blood stem cell transplantation in children and young adults with ultra-high-risk solid tumors. aNK-DLI were CD3(+)-depleted, CD56(+)-selected lymphocytes, cultured for 9 to 11 days with recombinant human IL-15 plus 4 1BBL(+)IL-15Ralpha(+) artificial antigen-presenting cells. aNK-DLI demonstrated potent killing capacity and displayed high levels of activating receptor expression. Five of 9 transplant recipients experienced acute graft-versus-host disease (GVHD) following aNK-DLI, with grade 4 GVHD observed in 3 subjects. GVHD was more common in matched unrelated donor vs matched sibling donor recipients and was associated with higher donor CD3 chimerism. Given that the T-cell dose was below the threshold required for GVHD in this setting, we conclude that aNK DLI contributed to the acute GVHD observed, likely by augmenting underlying T cell alloreactivity. This trial was registered at www.clinicaltrials.gov as #NCT01287104. PMID- 25452618 TI - Editorial: activation, functions, and generation of immunological memory in gammadelta T lymphocytes: lessons from nonhuman primates. PMID- 25452620 TI - The winning of the Western. PMID- 25452623 TI - What I know I owe to patients. PMID- 25452622 TI - Retraction: 'Switching of chromatin-remodelling complexes for oestrogen receptor alpha'. PMID- 25452624 TI - Toy-related injuries among children treated in US Emergency Departments, 1990 2011. AB - This study investigates the epidemiology of injuries associated with toys among US children by analyzing data from the National Electronic Injury Surveillance System. During 1990-2011, an estimated 3278073 (95% confidence interval = 2762281 3793865) children <18 years old were treated in US emergency departments for toy related injuries, averaging 149003 cases annually. The annual injury rate per 10000 children increased significantly by 39.9% from 18.88 in 1990 to 26.42 in 2011. The number and rate of injuries peaked at age 2 years; 63.4% of patients were male; and 80.3% of injuries occurred at home. Ride-on toys accounted for 34.9% of injuries and 42.5% of hospital admissions. This study is the first to comprehensively investigate toy-related injuries among children using a nationally representative data set. The increasing number and rate of toy-related injuries to children, especially those associated with ride-on toys, underscore the need for increased efforts to prevent these injuries. PMID- 25452625 TI - Secondary prevention after acute myocardial infarction: drug adherence, treatment goals, and predictors of health lifestyle habits. The BLITZ-4 Registry. AB - BACKGROUND: To describe drug adherence and treatment goals, and to identify the independent predictors of smoking persistence and unsatisfactory lifestyle habits six months after an acute myocardial infarction (AMI). METHODS AND RESULTS: 11,706 patients with AMI (30% female, mean age 68 years) were enrolled in 163 large-volume coronary care units (CCUs). At six months, drug adherence was >=90%, while blood pressure (BP) <140/90 mmHg, low density lipoprotein (LDL) <100 mg/dl (in patients on statins), HbA1c <7% (in treated diabetics), and smoking persistence were observed in 74%, 76%, 45%, and 27% of patients, respectively. Inadequate fish intake decreased from 73% to 55%, inadequate intake of fruit and vegetables from 32% to 23%, and insufficient exercise in eligible patients from 74% to 59% (p < 0.0001). At multivariable analysis, a post-discharge cardiac visit and referral to cardiac rehabilitation at follow-up were independently associated with a lower risk of insufficient physical exercise (odds ratio (OR) 0.71 and 0.70, respectively) and persistent smoking (OR 0.68 and 0.60), whereas only referral to cardiac rehabilitation was associated with a lower risk of inadequate fish and fruit/vegetable intake (OR 0.70 and 0.65). CONCLUSIONS: Six months after an AMI, despite a high adherence to drug treatments, BP, LDL, and diabetic goals are inadequately achieved. Subjects with healthy lifestyles improved after discharge, but the rate of those with regular exercise habits and adequate fish intake could be further improved. Access to post-discharge cardiac visit and referral to cardiac rehabilitation were associated with better adherence to healthy lifestyles. Knowledge of the variables associated with specific lifestyle changes may help in tailoring secondary prevention programmes. PMID- 25452626 TI - Women's preferences for cardiac rehabilitation program model: a randomized controlled trial. AB - BACKGROUND: Although cardiac rehabilitation (CR) is effective, women often report programs do not meet their needs. Innovative models have been developed that may better suit women. The objectives of the study were to describe: (1) adherence to CR model allocation; (2) satisfaction by model attended; and (3) CR preferences. DESIGN AND METHODS: Tertiary objectives from a randomized controlled trial of female patients randomized to mixed-sex, women-only, or home-based CR were tested. Patients were recruited from six hospitals. Consenting participants were asked to complete a survey and undertook a CR intake assessment. Eligible patients were randomized. Participants were mailed a follow-up survey six months later. Adherence to model allocation was ascertained from CR charts. RESULTS: Overall 169 (18.6%) patients were randomized, of which 116 (68.6%) completed the post-test survey. Forty-five (26.6%) participants did not receive the allocated model, with those referred to home-based CR least likely to attend the allocated model (n = 25; 45.4%). Semi-structured interviews revealed participants also often switched from women-only to mixed-sex CR due to time conflicts. Satisfaction was high across all models (mean = 4.23 +/- 1.16/5; p = 0.85) but participants in the women-only program felt significantly more comfortable in their workout attire (p = 0.003) and perceived the environment as less competitive (p = 0.02). Patients equally preferred mixed-sex (n = 44, 41.9%) and women-only (n = 44, 41.9%) CR, over home-based (n = 17, 16.2%), with patients preferring the model they attended. CONCLUSION: Females were highly satisfied regardless of CR model attended but preferred supervised programs most. Patient preference and session timing should be considered in program model allocation decisions. PMID- 25452627 TI - Anchorage loss due to Herbst mechanics-preventable through miniscrews? AB - AIM: To assess if mandibular incisor proclination and protrusion during treatment with the Herbst/multibracket appliance can be prevented through simple screws (MIs) anchorage. MATERIAL AND METHODS: After a statistical power analysis, 12 Herbst patients with MIs (100% MIs survival) ligated to the Herbst/multibracket appliance to reinforce anchorage were investigated. A control group matched for gender and skeletal maturity treated without MIs anchorage was selected. Pre- and posttreatment cephalograms were analysed for overjet reduction, mandibular incisor proclination (IL/ML), protrusion (Ii-MLp) and intrusion (Ii-ML), as well as occlusal plane inclination (OP/ML) by a single-blinded examiner. RESULTS: No statistically significant differences between the two groups were found concerning overjet reduction, incisor protrusion- and intrusion or occlusal plane tilt. Although the MIs group generally showed less lower incisor proclination (4.8 degrees ) than the group without skeletal anchorage (6.5 degrees ), a large interindividual variation was observed. CONCLUSION: Interradicular MIs anchorage cannot prevent anchorage loss during Herbst treatment. For the individual patient, the amount of incisor proclination and protrusion remains unpredictable. PMID- 25452628 TI - Effect of self-ligating bracket type and vibration on frictional force and stick slip phenomenon in diverse tooth displacement conditions: an in vitro mechanical analysis. AB - OBJECTIVE: To evaluate the effects of self-ligating bracket (SLB) type and vibration on frictional force and stick-slip phenomenon (SSP) in diverse tooth displacement conditions when a levelling/alignment wire was drawn. MATERIALS AND METHODS: A total of 16 groups were tested (n = 10/group): Two types of SLBs [active SLB (ASLB, In-Ovation R) and passive SLB (PSLB, Damon Q)]; vibration (30 Hz and 0.25 N) and non-vibration conditions; and 4 types of displacement [2mm lingual displacement of the maxillary right lateral incisor (LD), 2mm gingival displacement of the maxillary right canine (GD), combination of LD and GD (LGD), and control]. After applying artificial saliva to the typodont system, 0.018 copper nickel-titanium archwire was drawn by Instron with a speed of 0.5mm/min for 5 minutes at 36.5 degrees C. After static/kinetic frictional forces (SFF/KFF), and frequency/amplitude of SSP were measured, statistical analysis was performed. RESULTS: ASLB exhibited higher SFF, KFF, and SSP amplitude (all P < 0.001) and lower SSF frequency (all P < 0.05) than PSLB in all displacement groups. Vibration decreased SFF, KFF, and SSP amplitude and increased SSP frequency in control and all displacement groups (all P < 0.001). ASLB exhibited lower SSP frequency than PSLB only under non-vibration condition (P < 0.05 in LD and GD, P < 0.01 in LGD). However, regardless of vibration conditions, ASLB demonstrated higher SSP amplitude than PSLB in all displacement groups (all P < 0.001 under non-vibration; all P < 0.01 under vibration). CONCLUSION: Even in tooth displacement conditions, vibration significantly reduced SFF, KFF, SSP amplitude, and increased SPP frequency in both PSLB and ASLB. However, in vivo studies would be needed to confirm the clinical significance. PMID- 25452629 TI - Five-year postretention outcomes of three retention methods--a randomized controlled trial. AB - OBJECTIVE: Comparison of three different retention strategies 5 years or more postretention. DESIGN, SETTING, AND PARTICIPANTS: Randomized, prospective, single centre controlled trial. Forty-nine patients (33 girls and 16 boys) were randomly assigned to one of three retention methods during 2 years by picking a ballot shortly before start of retention treatment. Inclusion criteria were no previous orthodontics, permanent dentition, normal skeletal sagittal, vertical, and transversal relationships, Class I dental relationship, space deficiencies, treatment plan with extractions of four premolars followed by fixed straight-wire appliance. Maxillary and mandibular Little's irregularity index (LII), intercanine and intermolar width, arch length, and overbite/overjet were recorded in a blinded manner, altogether 10 measurements on each patient. Significant differences in means within groups assessed by t-test and between groups by one way analysis of variance. INTERVENTIONS: Retention methods: removable vacuum formed retainer (VFR) covering the palate and the maxillary anterior teeth from canine-to-canine and bonded canine-to-canine retainer in the lower arch (group V CTC); maxillary VFR combined with stripping of the lower anterior teeth (group V S); and prefabricated positioner (group P). RESULTS: Maxillary mean LII ranged from 1.8 to 2.6mm, mean intercanine width 33.6-35.3mm with a significant difference between groups V-S and P, mean intermolar width 46.8-47.4mm and mean arch length 21.8-22.8mm. Mandibular mean LII ranged from 2.0 to 3.4mm with a significant difference between groups V-S and P, mean intercanine width from 25.4 to 26.6mm, mean intermolar width from 40.8 to 40.9mm and mean arch length from 16.9 to 17.3mm. Mean overbite ranged from 1.8 to 2.7mm and mean overjet from 3.7 to 4.1mm. LIMITATIONS: A single centre study could be less generalizable. CONCLUSIONS: The three retention methods disclosed equally favourable clinical results. TRIAL REGISTRATION: This trial was not registered. PROTOCOL: The protocol was not published before trial commencement. PMID- 25452630 TI - A farewell to dogmatic retention. AB - SummaryFine orthodontic treatment results are fine. Fine stable results are finer. But when is stability achieved? Many studies show that the decline from optimal alignment and occlusion is most rapid immediately after appliance removal and slows down after some three to five years. For stabilization, we need some form of retention. Many retention regiments have been proposed sometimes with almost missionary fervour. The following commentary is a rather personal, but yet objective evaluation to highlight the quality evidence that the article by Edman, Petren, Bondemark, and Lilja-Karlander presents which helps us clinicians to make informed decisions about orthodontic retention technique. It also underscores why the article is a masterpiece. PMID- 25452631 TI - In vitro debonding of orthodontic retainers analyzed with finite element analysis. AB - OBJECTIVE: The aim of this in vitro study was to determine the load and deflection at failure of different lingual retainers bonded with composite to enamel in a standardized three-point bending test. The results were rationalized with finite element analysis (FEA) models. MATERIALS AND METHODS: Four types of multistranded wires, Dead Soft Respond, Twisted ligature, Penta-One, Gold-plated Penta-One, and two glass fibre-reinforced composite retainers, Fibre 07 and Fibre 09, were bonded to enamel with composite and submitted to a three-point bending test. The load and deflection at failure and the mode of debonding were recorded. The stiffness of the wires was determined and all experimental data were used in FEA models to rationalize the observed values and mode of debonding. RESULTS: Significant higher load and deflection were found for the most flexible retainers Twisted ligature and Dead Soft Respond. All retainers failed between the wire and composite, which was confirmed by FEA showing the highest stress in the composite around the retainer. The FEA models showed that the amount of composite used for bonding the retainers should be 2-4mm. CONCLUSIONS: Based on the in vitro results, optimal bonding of lingual retainers can be achieved by flexible retainers, bonded with intrinsically strong composites. According to the FEA models the retainer should be bonded with 2-4mm composite, leaving the critical 'free-wire' length for the success of the retainer system. PMID- 25452632 TI - Geriatric and physically oriented rehabilitation improves the ability of independent living and physical rehabilitation reduces mortality: a randomised comparison of 538 patients. AB - OBJECTIVE: To examine effects of physical and geriatric rehabilitation on institutionalisation and mortality after hip fracture. DESIGN: Prospective randomised study. SETTING: Physically oriented (187 patients), geriatrically oriented (171 patients), and health centre hospital rehabilitation (180 patients, control group). SUBJECTS: A total of 538 consecutively, independently living patients with non-pathological hip fracture. MAIN MEASURES: Patients were evaluated on admission, at 4 and 12 months for social status, residential status, walking ability, use of walking aids, pain in the hip, activities of daily living (ADL) and mortality. RESULTS: Mortality was significantly lower at 4 and 12 months in physical rehabilitation (3.2%, 8.6%) than in geriatric rehabilitation group (9.6%, 18.7%, P=0.026, P=0.005, respectively) or control group (10.6%, 19.4%, P=0.006, P=0.004, respectively). At 4 months more patients in physical (84.4%) and geriatric rehabilitation group (78.0%) were able to live at home or sheltered housing than in control group (71.9%, P=0.0012 and P<0.001, respectively). No significant difference was found between physical rehabilitation and geriatric rehabilitation (P=0.278). Analysis of femoral neck and trochanteric fractures showed that significant difference was true only for femoral neck fractures (physical rehabilitation vs geriatric rehabilitation P=0.308, physical rehabilitation vs control group P<0,001 and geriatric rehabilitation vs control group P<0.001). Effects of intensified rehabilitations disappeared at 12 months. No impact on walking ability or ADL functions was observed. CONCLUSIONS: Physical rehabilitation reduced mortality. Physical and geriatric rehabilitation significantly improved the ability of independent living after 4 months especially among the femoral neck fracture patients but this effect could not be seen after 12 months. PMID- 25452633 TI - An augmented cognitive behavioural therapy for treating post-stroke depression: description of a treatment protocol. AB - AIM: Currently, no evidence-based treatment is available for mood problems after stroke. We present a new psychological intervention designed to reduce depressive complaints after stroke. METHOD OF PROTOCOL DEVELOPMENT: This intervention was based on cognitive behavioural therapy principles and was shown feasible in a pilot study. In order to meet the specific needs of stroke patients (concerning both sensori-motor, cognitive, and behavioural problems), we incorporated motivational interviewing, grief resolution, and psycho-education. We emphasised for each session to take into account the cognitive deficits of the patients (i.e. be concrete, accessible, structured, specific, and repeat information). Moreover, we augmented the psychologist-administered therapy with the contribution of an occupational or movement therapist aimed at facilitating patients' goal-setting and attainment. The intervention consisted of 12 one-hour sessions with a psychologist and three or four one-hour sessions with an occupational or movement therapist. Currently, the effectiveness of the intervention is evaluated in a randomised controlled trial. DISCUSSION: The proposed psychological treatment protocol is innovative, as it applies cognitive behavioural therapy in a stroke-specific manner; moreover, it supports goal attainment by incorporating occupational or movement therapy sessions. PMID- 25452634 TI - Early mobilization of patients who have had a hip or knee joint replacement reduces length of stay in hospital: a systematic review. AB - OBJECTIVE: To systematically review the effect of early mobilization after hip or knee joint replacement surgery on length of stay in an acute hospital. METHODS: Randomized controlled trials were selected from electronic databases based on inclusion criterion requiring an experimental group mobilizing (sitting out of bed/walking) earlier than a comparison group post joint replacement surgery of the hip or knee in an acute hospital. Clinically homogeneous data were analyzed with meta-analysis. RESULTS: Five randomized controlled trials (totaling 622 participants) were included for review. A meta-analysis of 5 trials found a reduced length of stay of 1.8 days (95% confidence interval 1.1 to 2.6) in favor of the experimental group. In 4 of the 5 trials the experimental group first sat out of bed within 24 hours post operatively. In 4 of the 5 trials the experimental group first walked within 48 hours post operatively. Individual trials reported benefits in range of motion, muscle strength and health-related quality of life in favor of the experimental group. There were no differences in discharge destinations, incidence of negative outcomes or adverse events attributable to early mobilization when compared to the comparison groups. CONCLUSION: Early mobilization post hip or knee joint replacement surgery can result in a reduced length of stay of about 1.8 days. Trials that reported these positive results showed that early mobilization can be achieved within 24 hours of operation. This positive gain was achieved without an increase in negative outcomes. PMID- 25452635 TI - A comparative study between total contact cast and pressure-relieving ankle foot orthosis in diabetic neuropathic foot ulcers. AB - Off-loading of the ulcer area is extremely important for the healing of plantar ulcers. Off-loading with total contact cast (TCC) may be superior to other off loading strategies studied so far, but practical limitations can dissuade clinicians from using this modality. This study was conducted to evaluate the efficacy of TCC compared with that of a pressure-relieving ankle foot orthosis (PRAFO) in healing of diabetic neuropathic foot ulcers and their effect on gait parameters. Thirty adult diabetic patients attending the foot clinic with neuropathic plantar ulcers irrespective of sex, age, duration and type of diabetes were randomly assigned to 1 of 2 off-loading modalities (TCC and PRAFO). Main outcome measures were ulcer healing after 4 weeks of randomization and effect of each of the modalities on various gait parameters. The percentage reduction of the ulcer surface area at 4 weeks from baseline was 75.75 +/- 9.25 with TCC and 34.72 +/- 13.07 with PRAFO, which was significantly different (P < .001). The results of this study however, showed that most of the gait parameters were better with PRAFO than with TCC. This study comprehensively evaluated the well known advantages and disadvantages of a removable (PRAFO) and a nonremovable device (TCC) in the treatment of diabetic neuropathic foot ulcer. Further studies are needed involving larger subjects and using 3D gait analysis to collect more accurate data on gait parameters and wound healing with different off-loading devices. PMID- 25452636 TI - The UGT1 locus is a determinant of prostate cancer recurrence after prostatectomy. AB - The prognostic significance of common deletions in uridine diphospho glucuronosyltransferase 2B (UGT2B) genes encoding sex steroid metabolic enzymes has been recently recognized in localized prostate cancer (PCa) after radical prostatectomy (RP). However, the role of germline variations at the UGT1 locus, encoding half of all human UGTs and primarily involved in estrogen metabolism, remains unexplored. We investigated whether variants of UGT1 are potential prognostic markers. We studied 526 Caucasian men who underwent RP for clinically localized PCa. Genotypes of patients for 34 haplotype-tagged single-nucleotide polymorphisms (htSNPs) and 11 additional SNPs across the UGT1 locus previously reported to mark common variants including functional polymorphisms were determined. The risk of biochemical recurrence (BCR) was estimated using adjusted Cox proportional hazards regression and Kaplan-Meier analysis. We further investigated whether variants are associated with plasma hormone levels by mass spectrometry. In multivariable models, seven htSNPs were found to be significantly associated with BCR. A greater risk was revealed for four UGT1 intronic variants with hazard ratios (HRs) of 1.59-1.88 (P<0.002) for htSNPs in UGT1A10, UGT1A9, and UGT1A6. Conversely, decreased BCR was associated with three htSNPs in introns of UGT1A10 and UGT1A9 (HR=0.56-058; P<=0.01). An unfavorable UGT1 haplotype comprising all risk alleles, with a frequency of 14%, had a HR of 1.68 (95% CI=1.13-2.50; P=0.011). Significant alteration in circulating androsterone levels was associated with this haplotype, consistent with changes in hormonal exposure. This study provides the first evidence, to our knowledge, that germline polymorphisms of UGT1 are potential predictors of recurrence of PCa after prostatectomy. PMID- 25452643 TI - Murky definitions, missing data prevent meaningful conclusions. PMID- 25452644 TI - Study on sleep location flawed, inconclusive. PMID- 25452645 TI - Risk factors and a true cause of SIDS. PMID- 25452647 TI - In reply to the letter from Dr Cutz. PMID- 25452646 TI - In reply to the letters from Smith et al and Bartick et al. PMID- 25452648 TI - Severe RSV disease in preterm infants born at 29 to 35 weeks' gestation in the United States. PMID- 25452649 TI - Re: technical report. PMID- 25452650 TI - Authors' responses in response to the letter from Ambrose. PMID- 25452651 TI - In response to the letter from Braden. PMID- 25452652 TI - Hazardous bedding in infants' sleep environment is still common and a cause for concern. PMID- 25452653 TI - Coparenting breastfeeding support and exclusive breastfeeding: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of a coparenting intervention on exclusive breastfeeding among primiparous mothers and fathers. METHODS: A randomized controlled trial was conducted in a large teaching hospital in Toronto, Canada. Couples were randomized to receive either usual care (n = 107) or a coparenting breastfeeding support intervention (n = 107). Follow-up of exclusive breastfeeding and diverse secondary outcomes was conducted at 6 and 12 weeks postpartum. RESULTS: Significantly more mothers in the intervention group than in the control group continued to breastfeed at 12 weeks postpartum (96.2% vs 87.6%, P = .02). Although proportionately more mothers in the intervention group were exclusively breastfeeding at 6 and 12 weeks, these differences were not significant. Fathers in the intervention group had a significantly greater increase in breastfeeding self-efficacy scores from baseline to 6 weeks postpartum compared with fathers in the control group (P = .03). In addition, significantly more mothers in the intervention group than in the control group reported that their partners provided them with breastfeeding help in the first 6 weeks (71% vs 52%, P = .02) and that they were satisfied with their partners' involvement with breastfeeding (89% vs 78.1%, P = .04). Mothers in the intervention group were also more satisfied with the breastfeeding information they received (81% vs 62.5%, P < .001). CONCLUSIONS: The significant improvements in breastfeeding duration, paternal breastfeeding self-efficacy, and maternal perceptions of paternal involvement and assistance with breastfeeding suggest that a coparenting intervention involving fathers warrants additional investigation. PMID- 25452655 TI - Should we tell parents when we've made an error? AB - One of the most difficult experiences for any doctor or nurse is when they realize that they have made a mistake that has harmed a patient. In the past, mistakes were seldom disclosed to patients. The prevailing ethos was one of professional silence, secrecy, and shame. That has begun to change. Many professional organizations in both medicine and health law recommend full disclosure of mistakes and apologies for the harm that is caused. An atmosphere of openness and honesty leads to a culture of quality and safety. In this Ethics Rounds, we analyze the complex emotional and ethical issues that arise when doctors recognize that an error has occurred. PMID- 25452654 TI - Trends in infant bedding use: National Infant Sleep Position study, 1993-2010. AB - BACKGROUND: Use of potentially hazardous bedding, as defined by the American Academy of Pediatrics (eg, pillows, quilts, comforters, loose bedding), is a modifiable risk factor for sudden infant death syndrome and unintentional sleep related suffocation. The proportion of US infants sleeping with these types of bedding is unknown. METHODS: To investigate the US prevalence of and trends in bedding use, we analyzed 1993-2010 data from the National Infant Sleep Position study. Infants reported as being usually placed to sleep with blankets, quilts, pillows, and other similar materials under or covering them in the last 2 weeks were classified as bedding users. Logistic regression was used to describe characteristics associated with bedding use. RESULTS: From 1993 to 2010, bedding use declined but remained a widespread practice (moving average of 85.9% in 1993 1995 to 54.7% in 2008-2010). Prevalence was highest for infants of teen-aged mothers (83.5%) and lowest for infants born at term (55.6%). Bedding use was also frequently reported among infants sleeping in adult beds, on their sides, and on a shared surface. The rate of decline in bedding use was markedly less from 2001 2010 compared with 1993-2000. For 2007 to 2010, the strongest predictors (adjusted odds ratio: >=1.5) of bedding use were young maternal age, non-white race and ethnicity, and not being college educated. CONCLUSIONS: Bedding use for infant sleep remains common despite recommendations against this practice. Understanding trends in bedding use is important for tailoring safe sleep interventions. PMID- 25452656 TI - Cesarean section and chronic immune disorders. AB - OBJECTIVES: Immune diseases such as asthma, allergy, inflammatory bowel disease, and type 1 diabetes have shown a parallel increase in prevalence during recent decades in westernized countries. The rate of cesarean delivery has also increased in this period and has been associated with the development of some of these diseases. METHODS: Mature children born by cesarean delivery were analyzed for risk of hospital contact for chronic immune diseases recorded in the Danish national registries in the 35-year period 1977-2012. Two million term children participated in the primary analysis. We studied childhood diseases with a suspected relation to a deviant immune-maturation and a debut at young age. The effect of cesarean delivery on childhood disease incidences were estimated by means of confounder-adjusted incidence rate ratios with 95% confidence intervals obtained in Poisson regression analyses. RESULTS: Children delivered by cesarean delivery had significantly increased risk of asthma, systemic connective tissue disorders, juvenile arthritis, inflammatory bowel disease, immune deficiencies, and leukemia. No associations were found between cesarean delivery and type 1 diabetes, psoriasis, or celiac disease. CONCLUSIONS: Cesarean delivery exemplifies a shared environmental risk factor in early life associating with several chronic immune diseases. Understanding commonalities in the underlying mechanisms behind chronic diseases may give novel insight into their origin and allow prevention. PMID- 25452657 TI - Categorizing weight loss in breastfed infants: a good first step. PMID- 25452658 TI - An approach to renal masses in pediatrics. AB - Renal masses in children may be discovered during routine clinical examination or incidentally during the course of diagnostic or therapeutic procedures for other causes. Renal cancers are rare in the pediatric population and include a spectrum of pathologies that may challenge the clinician in choosing the optimal treatment. Correct identification of the lesion may be difficult, and the appropriate surgical procedure is paramount for lesions suspected to be malignant. The purpose of this article is to provide a comprehensive overview regarding the spectrum of renal tumors in the pediatric population, both benign and malignant, and their surgical management. PMID- 25452659 TI - Borrelia burgdorferi (Lyme disease). PMID- 25452660 TI - Complementary and integrative methods in fibromyalgia. PMID- 25452663 TI - Tall stature. PMID- 25452661 TI - Respiratory syncytial virus infection and bronchiolitis. PMID- 25452662 TI - Index of suspicion. PMID- 25452665 TI - Visual diagnosis: 3-year-old boy with persistent right chest wheezing. PMID- 25452666 TI - Visual diagnosis: chest pain in a boy with duchenne muscular dystrophy and cardiomyopathy. PMID- 25452667 TI - Iron-binding E3 ligase mediates iron response in plants by targeting basic helix loop-helix transcription factors. AB - Iron uptake and metabolism are tightly regulated in both plants and animals. In Arabidopsis (Arabidopsis thaliana), BRUTUS (BTS), which contains three hemerythrin (HHE) domains and a Really Interesting New Gene (RING) domain, interacts with basic helix-loop-helix transcription factors that are capable of forming heterodimers with POPEYE (PYE), a positive regulator of the iron deficiency response. BTS has been shown to have E3 ligase capacity and to play a role in root growth, rhizosphere acidification, and iron reductase activity in response to iron deprivation. To further characterize the function of this protein, we examined the expression pattern of recombinant ProBTS::beta GLUCURONIDASE and found that it is expressed in developing embryos and other reproductive tissues, corresponding with its apparent role in reproductive growth and development. Our findings also indicate that the interactions between BTS and PYE-like (PYEL) basic helix-loop-helix transcription factors occur within the nucleus and are dependent on the presence of the RING domain. We provide evidence that BTS facilitates 26S proteasome-mediated degradation of PYEL proteins in the absence of iron. We also determined that, upon binding iron at the HHE domains, BTS is destabilized and that this destabilization relies on specific residues within the HHE domains. This study reveals an important and unique mechanism for plant iron homeostasis whereby an E3 ubiquitin ligase may posttranslationally control components of the transcriptional regulatory network involved in the iron deficiency response. PMID- 25452670 TI - The Challenges and innovative solutions to rural health dilemma. PMID- 25452668 TI - Provider Visits and Early Vascular Access Placement in Maintenance Hemodialysis. AB - Medicare reimbursement policy encourages frequent provider visits for patients with ESRD undergoing hemodialysis. We hypothesize that patients seen more frequently by their nephrologist or advanced practitioner within the first 90 days of hemodialysis are more likely to undergo surgery to create an arteriovenous (AV) fistula or place an AV graft. We selected 35,959 patients aged >=67 years starting hemodialysis in the United States from a national registry. We used multivariable regression to evaluate the associations between mean visit frequency and AV fistula creation or graft placement in the first 90 days of hemodialysis. We conducted an instrumental variable analysis to test the sensitivity of our findings to potential bias from unobserved characteristics. One additional visit per month in the first 90 days of hemodialysis was associated with a 21% increase in the odds of AV fistula creation or graft placement during that period (95% confidence interval, 19% to 24%), corresponding to an average 4.5% increase in absolute probability. An instrumental variable analysis demonstrated similar findings. Excluding visits in months when patients were hospitalized, one additional visit per month was associated with a 10% increase in odds of vascular access surgery (95% confidence interval, 8% to 13%). In conclusion, patients seen more frequently by care providers in the first 90 days of hemodialysis undergo earlier AV fistula creation or graft placement. Payment policies that encourage more frequent visits to patients at key clinical time points may yield more favorable health outcomes than policies that operate irrespective of patients' health status. PMID- 25452671 TI - Indian medical research: perception and paradox. PMID- 25452669 TI - The dark side of extracellular ATP in kidney diseases. AB - Intracellular ATP is the most vital source of cellular energy for biologic systems, whereas extracellular ATP is a multifaceted mediator of several cell functions via its interaction, in an autocrine or paracrine manner, with P2 purinergic receptors expressed on the cell surface. These ionotropic and metabotropic P2 purinergic receptors modulate a variety of physiologic events upon the maintenance of a highly sensitive "set point," the derangement of which may lead to the development of key pathogenic mechanisms during acute and chronic diseases. Growing evidence suggests that extracellular ATP signaling via P2 purinergic receptors may be involved in different renal pathologic conditions. For these reasons, investigators and pharmaceutical companies are actively exploring novel strategies to antagonize or block these receptors with the goal of reducing extracellular ATP production or accelerating extracellular ATP clearance. Targeting extracellular ATP signaling, particularly through the P2X7 receptor, has considerable translational potential, given that novel P2X7 receptor inhibitors are already available for clinical use (e.g., CE224,535, AZD9056, and GSK1482160). This review summarizes the current evidence regarding the involvement of extracellular ATP and its P2 purinergic receptor-mediated signaling in physiologic and pathologic processes in the kidney; potential therapeutic options targeting extracellular ATP purinergic receptors are analyzed as well. PMID- 25452672 TI - Brain-Derived Neurotrophic Factor in children with Autism Spectrum Disorder. AB - BACKGROUND: Autism Spectrum Disorder (ASD) is a complex neurobehavioral syndrome with no known biomarker so far for early detection. It has been challenging, both to classify typical autism and associate a suitable biomarker with clinical phenotype spectrum. Brain-derived neurotrophic factor (BDNF) has emerged as a key neurotrophin regulating synaptic plasticity, neuronal differentiation and survival. PURPOSE: Recently, BDNF depletion is reported in neurodegenerative as well as in psychiatric disorders, associated with severity of neurological dysfunction. Role of BDNF as a biomarker in ASD is gaining significance. Pre clinical results have linked BDNF depletion in autism and mental retardation, however, with conflicting findings. METHODS: In view of this, a preliminary study was carried out to measure serum BDNF levels in 48 children with ASD and mental retardation, and 29 age-matched controls. RESULTS: Serum BDNF levels were found significantly higher (p<0.001) in atypical autistic subjects (clinically milder phenotype) as compared to controls, but not in typical ASD cases (clinically severe phenotype). BDNF levels were significantly lower in females with typical/Rett Syndrome (p<0.05), but not in males with typical autism (p>0.1), as compared to controls. Lower BDNF levels indicate impairment in neuroprotective mechanism, while higher levels may imply a manifested protective response. CONCLUSION: Our study highlights the differential BDNF response based on the severity of neurobehavioral deficit, indicating a possible neuroprotective role of this molecule and supporting its exploration in targeted therapy in ASD. PMID- 25452673 TI - Glycine gated spiking inhibitory postsynaptic membrane at the synaptic cleft. AB - BACKGROUND: Enzyme modified field effect transistor (ENFET) may be used to represent the variable conductance of transmitter-gated ion channels in the postsynaptic region of the neuron. PURPOSE: The objective of this work is to develop a simple analog circuit model that can simulate the function of neurotransmitter glycine gated ion channels of postsynaptic membrane at the synaptic cleft. METHODS: In this paper, Glycine sensitive ENFET is incorporated into the Hodgkin-Huxley (H-H) circuit model of the postsynaptic membrane at the synaptic cleft. RESULTS: Simulation of the circuit model yields an output representing the membrane potential of the synaptic region. Simulation is performed in MATLAB environment for inhibitory action of synapses. CONCLUSION: This model can be used in neuro-bioengineering fields for simulation of binding activity and electrical activity of the postsynaptic region. PMID- 25452674 TI - Study of five novel non-synonymous polymorphisms in human brain-expressed genes in a Colombian sample. AB - BACKGROUND: Non-synonymous single nucleotide polymorphisms (nsSNPs) in brain expressed genes represent interesting candidates for genetic research in neuropsychiatric disorders. PURPOSE: To study novel nsSNPs in brain-expressed genes in a sample of Colombian subjects. METHODS: We applied an approach based on in silico mining of available genomic data to identify and select novel nsSNPs in brain-expressed genes. We developed novel genotyping assays, based in allele specific PCR methods, for these nsSNPs and genotyped them in 171 Colombian subjects. RESULTS: Five common nsSNPs (rs6855837; p.Leu395Ile, rs2305160; p.Thr394Ala, rs10503929; p.Met289Thr, rs2270641; p.Thr4Pro and rs3822659; p.Ser735Ala) were studied, located in the CLOCK, NPAS2, NRG1, SLC18A1 and WWC1 genes. We reported allele and genotype frequencies in a sample of South American healthy subjects. There is previous experimental evidence, arising from genome wide expression and association studies, for the involvement of these genes in several neuropsychiatric disorders and endophenotypes, such as schizophrenia, mood disorders or memory performance. CONCLUSIONS: Frequencies for these nsSNPSs in the Colombian samples varied in comparison to different HapMap populations. Future study of these nsSNPs in brain-expressed genes, a synaptogenomics approach, will be important for a better understanding of neuropsychiatric diseases and endophenotypes in different populations. PMID- 25452676 TI - IL-18 attenuates experimental choroidal neovascularization as a potential therapy for wet age-related macular degeneration. Sci Transl Med 6, 230ra44 (2014). PMID- 25452675 TI - Brain processes during the perception of sensory signals in men with high and low output alpha-frequencies. AB - BACKGROUND: Human functional capabilities largely depend upon genetic qualities of person's nervous system. The registration of the spontaneous electroencephalogram (EEG) is among the physiological technigues allowing making a direct estimation of specific features of the nervous system, in particular, the human brain activity. PURPOSE: The study is devoted to the investigation of brain processes in men with high and low levels of individual alpha-frequency determined in a quiescent state during the perception of sensory signals. METHODS: A test group consisting of 104 right-hand healthy men from the ages of 19 to 21 was divided into two groups according to the magnitude of their individual alpha- frequency (IAF) median - groups with high (n = 53, IA >= 10,04 Hz) and low (n = 51, IAF<=10,03 Hz) levels of IAF. The power and coherence of the electrical activity of the cerebral cortex as well as inter group differences were evaluated in a quiescent state and during the perception of sensory signals by Subjects. RESULTS: A localized power increase of the EEG alpha1-waves are registered in frontal areas, beta1, beta2- oscillations - in the anterior cortex, gamma- activity - around the scalp and its decrease is present in the posterior temporal, parietal and occipital cortex leads, especially in the alpha- and beta- frequency spectrum during the perception of sensory signals in men with a high IAF. The generalized depression of the theta-, alpha- and beta- activity of the cortex is fixed in individuals with a low IAF while the expression of gamma- waves is more local. The generalized increase of data in EEG coherence fluctuations throughout the frequency spectrum of the EEG in the cortex is set in all Subjects. The dextrocerebral preponderance is observable in posterior structures of the Subjects' right hemisphere. A localized decrease of the coherence concerning theta-, alpha1-, alpha3-, beta- and gamma- oscillations are traced in the frontal and anterior temporal areas of the left hemisphere. CONCLUSION: We are of the opinion that the establishment of such common factors in the studied groups is an important step towards the release of the clear prognostic criteria for the functionality of men in the sensory area according to the congenital features of brain function. PMID- 25452678 TI - ARVO 2014 Report. PMID- 25452677 TI - Ca(2+)- and CaMKII-mediated processes in early LTP. AB - Learning methods determine the degree of stimulation of engrams encoding information to be memorised. More enriching modes of learning allow more enduring long-term potentiation of the synapses associated with these memories. The additional activity causes a prolonged increase in [Ca2+] in the dendritic spine of the postsynaptic neuron. This allows Ca(2+)-mediated molecular pathways to bring about cytoskeletal remodeling, posttranslational modifications, and protein trafficking. These processes contribute to early long-term potentiation of the synapses, strengthening the memory they store and lead to improved performance on tests of memory recall. PMID- 25452679 TI - Beating the Odds: Intact Neuropsychological Functioning despite TLE. AB - Patients with Temporal lobe epilepsy (TLE) frequently display cognitive comorbidity and can have widespread network abnormalities, which might affect a variety of cognitive and intellectual functions. As a result, refractory TLE seems to be associated with slow but ongoing cognitive deterioration. The case is of a 32 year old, right handed male, engineering graduate, diagnosed with TLE- right mesial, 12 years ago. A number of head injuries were caused due to the seizure present, which includes a fall from height of 12 feet in childhood. The neuropsychological tests administered were Gesell's Drawing Test, Mini Mental State Examination, PGI Memory Scale, Battery of Performance Tests of Intelligence, Verbal Adult Intelligence Scale, Hamilton Rating Scale for Depression, Bender Visual Motor Gestalt Test and Dysfunction Analysis Questionnaire. No impairment found on orientation; average cognitive functioning; above average attention and concentration, verbal working memory, visual and verbal memory; average practical ability, abstract ability, average verbal intellectual ability; superior ability on comprehension and average performance ability. Mild to moderate impairment on perceptuo-motor functioning and an evidence of depression were present. Patient showed high dysfunction in personal, social, vocational and cognitive areas. The study highlights that even despite chronic epilepsy, with a series of head injuries due to the seizures; an individual can still have average neuropsychological abilities. Holistic neuropsychological rehabilitation along with Vocational Retraining would go a long way in the functional independence of the patient. Neuropsychologists have a significant role in the assessment, treatment, and rehabilitation of people with epilepsy. PMID- 25452680 TI - Adaptation of an HIV Medication Adherence Intervention for Adolescents and Young Adults. AB - Rising rates of human immunodeficiency virus (HIV) infection among adolescents and young adults underscore the importance of interventions for this population. While the morbidity and mortality of HIV has greatly decreased over the years, maintaining high rates of adherence is necessary to receive optimal medication effects. Few studies have developed interventions for adolescents and young adults and none have specifically been developed for sexual minority (lesbian, gay, and bisexual; LGB) youth. Guided by an evidence-based adult intervention and adolescent qualitative interviews, we developed a multicomponent, technology enhanced, customizable adherence intervention for adolescents and young adults for use in a clinical setting. The two cases presented in this paper illustrate the use of the five-session positive strategies to enhance problem solving (Positive STEPS) intervention, based on cognitive-behavioral techniques and motivational interviewing. We present a perinatally infected heterosexual woman and a behaviorally infected gay man to demonstrate the unique challenges faced by these youth and showcase how the intervention can be customized. Future directions include varying the number of intervention sessions based on mode of HIV infection and incorporating booster sessions. PMID- 25452681 TI - Evolutionary Analysis and Prediction of Peptide Vaccine Candidates for Foot-and Mouth-Disease Virus Types A and O in Bangladesh. AB - Foot-and-mouth disease (FMD), an endemic disease of cloven-hoofed animals, causes an annual economic loss of US$60-150 million in Bangladesh. There is no cross protection among the foot-and-mouth disease virus (FMDV) serotypes and vaccination escape mutation may happen. Peptide vaccine is a safer alternative. The aim of this study is to predict and map the B and T cell epitopes of VP1 proteins of FMDV serotypes O and A that were circulating in Bangladesh from 2011 to 2013. Using evolutionary and computational approach (BCPred, BepiPred, DiscoTope, ElliPro, and ProPred-I, IEDB analysis for MHC-I prediction), a total of 11 B and T cell epitopes were predicted. Also, the three-dimensional (3D) structure of VP1 protein showed that the predicted five epitopes residing on N- and C-termini can be considered as good vaccine candidates, and epitopes on the G H loop can serve as receptor recognition sites for vaccine design. The scores of predicted epitopes of one method were cross-checked with other one for potential epitope mining. Within the VP1 antigenic sites, significant evidence of positive selection was present indicating evolution of VP1 under high immune surveillance. PMID- 25452682 TI - In silico prediction of synthetic lethality by meta-analysis of genetic interactions, functions, and pathways in yeast and human cancer. AB - A major goal in cancer medicine is to find selective drugs with reduced side effect. A pair of genes is called synthetic lethality (SL) if mutations of both genes will kill a cell while mutation of either gene alone will not. Hence, a gene in SL interactions with a cancer-specific mutated gene will be a promising drug target with anti-cancer selectivity. Wet-lab screening approach is still so costly that even for yeast only a small fraction of gene pairs has been covered. Computational methods are therefore important for large-scale discovery of SL interactions. Most existing approaches focus on individual features or machine learning methods, which are prone to noise or overfitting. In this paper, we propose an approach named MetaSL for predicting yeast SL, which integrates 17 genomic and proteomic features and the outputs of 10 classification methods. MetaSL thus combines the strengths of existing methods and achieves the highest area under the Receiver Operating Characteristics (ROC) curve (AUC) of 87.1% among all competitors on yeast data. Moreover, through orthologous mapping from yeast to human genes, we then predicted several lists of candidate SL pairs in human cancer. Our method and predictions would thus shed light on mechanisms of SL and lead to discovery of novel anti-cancer drugs. In addition, all the experimental results can be downloaded from http://www.ntu.edu.sg/home/zhengjie/data/MetaSL. PMID- 25452683 TI - Conducting Retrospective Ontological Clinical Trials in ICD-9-CM in the Age of ICD-10-CM. AB - OBJECTIVE: To quantify the impact of International Classification of Disease 10th Revision Clinical Modification (ICD-10-CM) transition in cancer clinical trials by comparing coding accuracy and data discontinuity in backward ICD-10-CM to ICD 9-CM mapping via two tools, and to develop a standard ICD-9-CM and ICD-10-CM bridging methodology for retrospective analyses. BACKGROUND: While the transition to ICD-10-CM has been delayed until October 2015, its impact on cancer-related studies utilizing ICD-9-CM diagnoses has been inadequately explored. MATERIALS AND METHODS: Three high impact journals with broad national and international readerships were reviewed for cancer-related studies utilizing ICD-9-CM diagnoses codes in study design, methods, or results. Forward ICD-9-CM to ICD-10-CM mapping was performing using a translational methodology with the Motif web portal ICD-9 CM conversion tool. Backward mapping from ICD-10-CM to ICD-9-CM was performed using both Centers for Medicare and Medicaid Services (CMS) general equivalence mappings (GEMs) files and the Motif web portal tool. Generated ICD-9-CM codes were compared with the original ICD-9-CM codes to assess data accuracy and discontinuity. RESULTS: While both methods yielded additional ICD-9-CM codes, the CMS GEMs method provided incomplete coverage with 16 of the original ICD-9-CM codes missing, whereas the Motif web portal method provided complete coverage. Of these 16 codes, 12 ICD-9-CM codes were present in 2010 Illinois Medicaid data, and accounted for 0.52% of patient encounters and 0.35% of total Medicaid reimbursements. Extraneous ICD-9-CM codes from both methods (Centers for Medicare and Medicaid Services general equivalent mapping [CMS GEMs, n = 161; Motif web portal, n = 246]) in excess of original ICD-9-CM codes accounted for 2.1% and 2.3% of total patient encounters and 3.4% and 4.1% of total Medicaid reimbursements from the 2010 Illinois Medicare database. DISCUSSION: Longitudinal data analyses post-ICD-10-CM transition will require backward ICD-10-CM to ICD-9 CM coding, and data comparison for accuracy. Researchers must be aware that all methods for backward coding are not comparable in yielding original ICD-9-CM codes. CONCLUSIONS: The mandated delay is an opportunity for organizations to better understand areas of financial risk with regards to data management via backward coding. Our methodology is relevant for all healthcare-related coding data, and can be replicated by organizations as a strategy to mitigate financial risk. PMID- 25452684 TI - CORM: An R Package Implementing the Clustering of Regression Models Method for Gene Clustering. AB - We report a new R package implementing the clustering of regression models (CORM) method for clustering genes using gene expression data and provide data examples illustrating each clustering function in the package. The CORM package is freely available at CRAN from http://cran.r-project.org. PMID- 25452685 TI - TEGS-CN: A Statistical Method for Pathway Analysis of Genome-wide Copy Number Profile. AB - The effects of copy number alterations make up a significant part of the tumor genome profile, but pathway analyses of these alterations are still not well established. We proposed a novel method to analyze multiple copy numbers of genes within a pathway, termed Test for the Effect of a Gene Set with Copy Number data (TEGS-CN). TEGS-CN was adapted from TEGS, a method that we previously developed for gene expression data using a variance component score test. With additional development, we extend the method to analyze DNA copy number data, accounting for different sizes and thus various numbers of copy number probes in genes. The test statistic follows a mixture of X (2) distributions that can be obtained using permutation with scaled X (2) approximation. We conducted simulation studies to evaluate the size and the power of TEGS-CN and to compare its performance with TEGS. We analyzed a genome-wide copy number data from 264 patients of non-small cell lung cancer. With the Molecular Signatures Database (MSigDB) pathway database, the genome-wide copy number data can be classified into 1814 biological pathways or gene sets. We investigated associations of the copy number profile of the 1814 gene sets with pack-years of cigarette smoking. Our analysis revealed five pathways with significant P values after Bonferroni adjustment (<2.8 * 10( 5)), including the PTEN pathway (7.8 * 10(-7)), the gene set up-regulated under heat shock (3.6 * 10(-6)), the gene sets involved in the immune profile for rejection of kidney transplantation (9.2 * 10(-6)) and for transcriptional control of leukocytes (2.2 * 10(-5)), and the ganglioside biosynthesis pathway (2.7 * 10(-5)). In conclusion, we present a new method for pathway analyses of copy number data, and causal mechanisms of the five pathways require further study. PMID- 25452686 TI - Unsupervised outlier profile analysis. AB - In much of the analysis of high-throughput genomic data, "interesting" genes have been selected based on assessment of differential expression between two groups or generalizations thereof. Most of the literature focuses on changes in mean expression or the entire distribution. In this article, we explore the use of C(alpha) tests, which have been applied in other genomic data settings. Their use for the outlier expression problem, in particular with continuous data, is problematic but nevertheless motivates new statistics that give an unsupervised analog to previously developed outlier profile analysis approaches. Some simulation studies are used to evaluate the proposal. A bivariate extension is described that can accommodate data from two platforms on matched samples. The proposed methods are applied to data from a prostate cancer study. PMID- 25452687 TI - Mapping Splicing Quantitative Trait Loci in RNA-Seq. AB - BACKGROUND: One of the major mechanisms of generating mRNA diversity is alternative splicing, a regulated process that allows for the flexibility of producing functionally different proteins from the same genomic sequences. This process is often altered in cancer cells to produce aberrant proteins that drive the progression of cancer. A better understanding of the misregulation of alternative splicing will shed light on the development of novel targets for pharmacological interventions of cancer. METHODS: In this study, we evaluated three statistical methods, random effects meta-regression, beta regression, and generalized linear mixed effects model, for the analysis of splicing quantitative trait loci (sQTL) using RNA-Seq data. All the three methods use exon-inclusion levels estimated by the PennSeq algorithm, a statistical method that utilizes paired-end reads and accounts for non-uniform sequencing coverage. RESULTS: Using both simulated and real RNA-Seq datasets, we compared these three methods with GLiMMPS, a recently developed method for sQTL analysis. Our results indicate that the most reliable and powerful method was the random effects meta-regression approach, which identified sQTLs at low false discovery rates but higher power when compared to GLiMMPS. CONCLUSIONS: We have evaluated three statistical methods for the analysis of sQTLs in RNA-Seq. Results from our study will be instructive for researchers in selecting the appropriate statistical methods for sQTL analysis. PMID- 25452688 TI - Toolbox for mobile-element insertion detection on cancer genomes. AB - Mobile elements constitute greater than 45% of the human genome as a result of repeated insertion events during human genome evolution. Although most of mobile elements are fixed within the human population, some elements (including ALU, long interspersed elements (LINE) 1 (L1), and SVA) are still actively duplicating and may result in life-threatening human diseases such as cancer, motivating the need for accurate mobile-element insertion (MEI) detection tools. We developed a software package, TANGRAM, for MEI detection in next-generation sequencing data, currently serving as the primary MEI detection tool in the 1000 Genomes Project. TANGRAM takes advantage of valuable mapping information provided by our own MOSAIK mapper, and until recently required MOSAIK mappings as its input. In this study, we report a new feature that enables TANGRAM to be used on alignments generated by any mainstream short-read mapper, making it accessible for many genomic users. To demonstrate its utility for cancer genome analysis, we have applied TANGRAM to the TCGA (The Cancer Genome Atlas) mutation calling benchmark 4 dataset. TANGRAM is fast, accurate, easy to use, and open source on https://github.com/jiantao/Tangram. PMID- 25452689 TI - Type I error control for tree classification. AB - Binary tree classification has been useful for classifying the whole population based on the levels of outcome variable that is associated with chosen predictors. Often we start a classification with a large number of candidate predictors, and each predictor takes a number of different cutoff values. Because of these types of multiplicity, binary tree classification method is subject to severe type I error probability. Nonetheless, there have not been many publications to address this issue. In this paper, we propose a binary tree classification method to control the probability to accept a predictor below certain level, say 5%. PMID- 25452690 TI - A Bayesian Framework to Improve MicroRNA Target Prediction by Incorporating External Information. AB - MicroRNAs (miRNAs) are small regulatory RNAs that play key gene-regulatory roles in diverse biological processes, particularly in cancer development. Therefore, inferring miRNA targets is an essential step to fully understanding the functional properties of miRNA actions in regulating tumorigenesis. Bayesian linear regression modeling has been proposed for identifying the interactions between miRNAs and mRNAs on the basis of the integrated sequence information and matched miRNA and mRNA expression data; however, this approach does not use the full spectrum of available features of putative miRNA targets. In this study, we integrated four important sequence and structural features of miRNA targeting with paired miRNA and mRNA expression data to improve miRNA-target prediction in a Bayesian framework. We have applied this approach to a gene-expression study of liver cancer patients and examined the posterior probability of each miRNA-mRNA interaction being functional in the development of liver cancer. Our method achieved better performance, in terms of the number of true targets identified, than did other methods. PMID- 25452691 TI - A Study of Method Development, Validation, and Forced Degradation for Simultaneous Quantification of Paracetamol and Ibuprofen in Pharmaceutical Dosage Form by RP-HPLC Method. AB - A rapid and stability-indicating reversed phase high-performance liquid chromatography (RP-HPLC) method was developed for simultaneous quantification of paracetamol and ibuprofen in their combined dosage form especially to get some more advantages over other methods already developed for this combination. The method was validated according to United States Pharmacopeia (USP) guideline with respect to accuracy, precision, specificity, linearity, solution stability, robustness, sensitivity, and system suitability. Forced degradation study was validated according to International Conference on Harmonisation (ICH). For this, an isocratic condition of mobile phase comprising phosphate buffer (pH 6.8) and acetonitrile in a ratio of 65:35, v/v at a flow rate of 0.7 mL/minute over RP C18 (octadecylsilane (ODS), 150 * 4.6 mm, 5 MUm, Phenomenex Inc.) column at ambient temperature was maintained. The method showed excellent linear response with correlation coefficient (R (2)) values of 0.999 and 1.0 for paracetamol and ibuprofen respectively, which were within the limit of correlation coefficient (R (2) > 0.995). The percent recoveries for two drugs were found within the acceptance limit of (97.0-103.0%). Intra-and inter-day precision studies of the new method were less than the maximum allowable limit percentage of relative standard deviation (%RSD) <= 2.0. Forced degradation of the drug product was carried out as per the ICH guidelines with a view to establishing the stability indicating property of this method and providing useful information about the degradation pathways, degradation products, and how the quality of a drug substance and drug product changes with time under the influence of various stressing conditions. The degradation of ibuprofen was within the limit (5-20%, according to the guideline of ICH), while paracetamol showed <20% degradation in oxidation and basic condition. PMID- 25452692 TI - The Expression of Serum Antibodies Against Gonadotropin-releasing Hormone (GnRH1), Progonadoliberin-2, Luteinizing Hormone (LH), and Related Receptors in Patients with Gastrointestinal Dysfunction or Diabetes Mellitus. AB - Gonadotropin-releasing hormone (GnRH) 1 and 2 and luteinizing hormone (LH) receptors have been described in the gastrointestinal tract. We have previously demonstrated antibodies in serum against GnRH1 in patients with gastrointestinal dysfunction and diabetes mellitus, and antibodies against GnRH receptor, LH, and LH receptor in patients with infertility. The aim of this study was to search for the expression of serum antibodies against GnRH1 with an improved enzyme-linked immune sorbent assay (ELISA), and antibodies against progonadoliberin-2, GnRH2, GnRH receptor, LH, and LH receptor with newly developed ELISAs, in patients with gastrointestinal dysfunction or diabetes mellitus. Healthy blood donors served as controls. Medical records were scrutinized. Our conclusion was that IgM antibodies against GnRH1, progonadoliberin-2, and/or GnRH receptors were more prevalent in patients with functional gastrointestinal disorders, gastrointestinal dysmotility, and/or diabetes mellitus, whereas IgG antibodies against these peptides, and LH- and LH receptor antibodies, were expressed in the same magnitude as in controls. PMID- 25452693 TI - Withaferin A Inhibits STAT3 and Induces Tumor Cell Death in Neuroblastoma and Multiple Myeloma. AB - Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that has been implicated in many human cancers and has emerged as an ideal target for cancer therapy. Withaferin A (WFA) is a natural product with promising antiproliferative properties through its association with a number of molecular targets including STAT3. However, the effect of WFA in pediatric neuroblastoma (NB) and its interaction with STAT3 have not been reported. In this study, we found that WFA effectively induces dose-dependent cell death in high-risk and drug-resistant NB as well as multiple myeloma (MM) tumor cells, prevented interleukin-6 (IL-6)-mediated and persistently activated STAT3 phosphorylation at Y705, and blocked the transcriptional activity of STAT3. We further provide computational models that show that WFA binds STAT3 near the Y705 phospho-tyrosine residue of the STAT3 Src homology 2 (SH2) domain, suggesting that WFA prevents STAT3 dimer formation similar to BP-1-102, a well established STAT3 inhibitor. Our findings propose that the antitumor activity of WFA is mediated at least in part through inhibition of STAT3 and provide a rationale for further drug development and clinical use in NB and MM. PMID- 25452694 TI - Economic evidence on the health impacts of climate change in europe. AB - BACKGROUND: In responding to the health impacts of climate change, economic evidence and tools inform decision makers of the efficiency of alternative health policies and interventions. In a time when sweeping budget cuts are affecting all tiers of government, economic evidence on health protection from climate change spending enables comparison with other public spending. METHODS: The review included 53 countries of the World Health Organization (WHO) European Region. Literature was obtained using a Medline and Internet search of key terms in published reports and peer-reviewed literature, and from institutions working on health and climate change. Articles were included if they provided economic estimation of the health impacts of climate change or adaptation measures to protect health from climate change in the WHO European Region. Economic studies are classified under health impact cost, health adaptation cost, and health economic evaluation (comparing both costs and impacts). RESULTS: A total of 40 relevant studies from Europe were identified, covering the health damage or adaptation costs related to the health effects of climate change and response measures to climate-sensitive diseases. No economic evaluation studies were identified of response measures specific to the impacts of climate change. Existing studies vary in terms of the economic outcomes measured and the methods for evaluation of health benefits. The lack of robust health impact data underlying economic studies significantly affects the availability and precision of economic studies. CONCLUSIONS: Economic evidence in European countries on the costs of and response to climate-sensitive diseases is extremely limited and fragmented. Further studies are urgently needed that examine health impacts and the costs and efficiency of alternative responses to climate-sensitive health conditions, in particular extreme weather events (other than heat) and potential emerging diseases and other conditions threatening Europe. PMID- 25452696 TI - Temporal and Spatial Distribution of Tick-Borne Disease Cases among Humans and Canines in Illinois (2000-2009). AB - Four tick-borne diseases (TBDs), anaplasmosis, ehrlichiosis, Lyme disease (LD), and Rocky Mountain spotted fever (RMSF), are endemic in Illinois. The prevalence of human and canine cases of all four TBDs rose over the study period with significant differences in geographic distribution within the state. Among human cases, there were associations between cases of RMSF and LD and total forest cover, seasonal precipitation, average mean temperature, racial-ethnic groups, and gender. Estimated annual prevalence of three canine TBDs exceeded human TBD cases significantly in each region. There was concordance in the number of human and canine cases by county of residence, in annual prevalence trends, and in time of year at which they were diagnosed. To account for multiple environmental risk factors and to facilitate early diagnosis of cases, integrated surveillance systems must be developed and communication between veterinarians, physicians, and public health agencies must be improved. PMID- 25452697 TI - The lebanese society of cardiology: plans and perspectives, navigating against contrary winds and progressing against all odds. AB - Scientific societies in medicine theoretically aim to improve a medical field as a science; however, this role is expanding nowadays to seeking also the improved practice of a certain medical field. In this regard, the current Lebanese Society of Cardiology (2013-2015) has laid many plans and considered many perspectives. These concern mainly, but not exclusively, the increase of public awareness regarding prevention, investment in research, implementation of guidelines, support of continuous medical education, organization of cardiology symposia and congresses, and achievement of national registries regarding main cardiac conditions, as well as the society's main objective of decreasing the burden of cardiovascular diseases in Lebanon. Nonetheless, the implementation of such plans and perspectives is facing contrary winds related to a multifaceted phenomenon: the dominance of private medicine with a subsequent lack of teamwork, the dominance of private media, the social and political unrest in Lebanon, significant discrepancies in the scientific background of cardiologists, and the absence of a standardized national cardiology licensing exam. Importantly, the implementation of such plans and perspectives requires individual commitment, along with the cooperation of the Order of Physicians, the Syndicate of Hospitals in Lebanon (representing private hospitals) and the Ministry of Health. Moreover, industry must be more committed to medical scientific societies; the support of cardiology events organized without the auspices of the Lebanese Society of Cardiology is not encouraged because of the presence of significant conflict of interest. PMID- 25452695 TI - Generation of reactive oxygen species from silicon nanowires. AB - Processing and synthesis of purified nanomaterials of diverse composition, size, and properties is an evolving process. Studies have demonstrated that some nanomaterials have potential toxic effects and have led to toxicity research focusing on nanotoxicology. About two million workers will be employed in the field of nanotechnology over the next 10 years. The unknown effects of nanomaterials create a need for research and development of techniques to identify possible toxicity. Through a cooperative effort between National Institute for Occupational Safety and Health and IBM to address possible occupational exposures, silicon-based nanowires (SiNWs) were obtained for our study. These SiNWs are anisotropic filamentary crystals of silicon, synthesized by the vapor-liquid-solid method and used in bio-sensors, gas sensors, and field effect transistors. Reactive oxygen species (ROS) can be generated when organisms are exposed to a material causing cellular responses, such as lipid peroxidation, H2O2 production, and DNA damage. SiNWs were assessed using three different in vitro environments (H2O2, RAW 264.7 cells, and rat alveolar macrophages) for ROS generation and possible toxicity identification. We used electron spin resonance, analysis of lipid peroxidation, measurement of H2O2 production, and the comet assay to assess generation of ROS from SiNW and define possible mechanisms. Our results demonstrate that SiNWs do not appear to be significant generators of free radicals. PMID- 25452699 TI - Genetic Diversity and Allelic Frequency of Glutamate-Rich Protein (GLURP) in Plasmodium falciparum Isolates from Sub-Saharan Africa. AB - Glutamate-rich protein is a Plasmodium falciparum (Pf) antigen found in all stages of the parasite and has been reported to induce clinical immunity. The R0 and R2 regions have been found to exhibit a high degree of conservation, therefore serving as a good vaccine design material. We assayed the genetic diversity of Pf glurp genes in the R0 and R2 regions, as well as evaluated the role of seasonality on allelic frequency. A total of 402 genomic DNA samples, extracted from filter paper blood samples, were screened by nested polymerase chain reaction (PCR) analysis of Pf glurp R0 and R2 regions, in addition to fragment analysis of the polymorphic regions to identify allelic diversity of the parasite population. We found an extensive heterogeneity in the R2 region in general, and this heterogeneity is seasonally dependent, indicative of region plasticity. The R0 region displayed genetic conservation, as expected. We conclude that positive genotyping results with glurp R0 region should be seen as indicative of an active Pf infection, requiring adequate treatment. In addition, we advocate extending the possibility that an R0 region genotypic positivity could serve as diagnostic tool, thereby reducing cases of untreated or poorly treated infection, contributory to recrudescence or treatment failure. PMID- 25452698 TI - Evaluative profiling of arsenic sensing and regulatory systems in the human microbiome project genomes. AB - The influence of environmental chemicals including arsenic, a type 1 carcinogen, on the composition and function of the human-associated microbiota is of significance in human health and disease. We have developed a suite of bioinformatics and visual analytics methods to evaluate the availability (presence or absence) and abundance of functional annotations in a microbial genome for seven Pfam protein families: As(III)-responsive transcriptional repressor (ArsR), anion-transporting ATPase (ArsA), arsenical pump membrane protein (ArsB), arsenate reductase (ArsC), arsenical resistance operon transacting repressor (ArsD), water/glycerol transport protein (aquaporins), and universal stress protein (USP). These genes encode function for sensing and/or regulating arsenic content in the bacterial cell. The evaluative profiling strategy was applied to 3,274 genomes from which 62 genomes from 18 genera were identified to contain genes for the seven protein families. Our list included 12 genomes in the Human Microbiome Project (HMP) from the following genera: Citrobacter, Escherichia, Lactobacillus, Providencia, Rhodococcus, and Staphylococcus. Gene neighborhood analysis of the arsenic resistance operon in the genome of Bacteroides thetaiotaomicron VPI-5482, a human gut symbiont, revealed the adjacent arrangement of genes for arsenite binding/transfer (ArsD) and cytochrome c biosynthesis (DsbD_2). Visual analytics facilitated evaluation of protein annotations in 367 genomes in the phylum Bacteroidetes identified multiple genomes in which genes for ArsD and DsbD_2 were adjacently arranged. Cytochrome c, produced by a posttranslational process, consists of heme containing proteins important for cellular energy production and signaling. Further research is desired to elucidate arsenic resistance and arsenic-mediated cellular energy production in the Bacteroidetes. PMID- 25452700 TI - A standardized and reproducible urine preparation protocol for cancer biomarkers discovery. AB - A suitable and standardized protein purification technique is essential to maintain consistency and to allow data comparison between proteomic studies for urine biomarker discovery. Ultimately, efforts should be made to standardize urine preparation protocols. The aim of this study was to develop an optimal analytical protocol to achieve maximal protein yield and to ensure that this method was applicable to examine urine protein patterns that distinguish disease and disease-free states. In this pilot study, we compared seven different urine sample preparation methods to remove salts, and to precipitate and isolate urinary proteins. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE) profiles showed that the sequential preparation of urinary proteins by combining acetone and trichloroacetic acid (TCA) alongside high speed centrifugation (HSC) provided the best separation, and retained the most urinary proteins. Therefore, this approach is the preferred method for all further urine protein analysis. PMID- 25452701 TI - Transcatheter Aortic Valve Implantation (TAVI): Is it Time for This Intervention to be Applied in a Lower Risk Population? AB - Patients with severe aortic stenosis are sometimes not candidates for conventional open heart surgery because of severe deconditioning, excessive risk factors, and multiple comorbidities. Transcatheter aortic valve implantation (TAVI) is a relatively recent intervention, which was initially addressed to individuals with severe symptomatic aortic stenosis at substantial or prohibitive surgical risk. Despite the documented beneficial effects of this therapeutic intervention in certain carefully selected individuals, it has not yet been applied to lower risk patients. This is a review of the current literature and accumulated clinical data of this rapidly evolving invasive procedure in an attempt to resolve whether it can now be applied to a wider portion of patients with aortic stenosis. PMID- 25452702 TI - Cardiac sarcoidosis: clinical manifestations, imaging characteristics, and therapeutic approach. AB - Sarcoidosis is a multi-system disease pathologically characterized by the accumulation of T-lymphocytes and mononuclear phagocytes into the sine qua non pathologic structure of the noncaseating granuloma. Cardiac involvement remains a key source of morbidity and mortality in sarcoidosis. Definitive diagnosis of cardiac sarcoidosis, particularly early enough in the disease course to provide maximal therapeutic impact, has proven a particularly difficult challenge. However, major advancements in imaging techniques have been made in the last decade. Advancements in imaging modalities including echocardiography, nuclear spectroscopy, positron emission tomography, and magnetic resonance imaging all have improved our ability to diagnose cardiac sarcoidosis, and in many cases to provide a more accurate prognosis and thus targeted therapy. Likewise, therapy for cardiac sarcoidosis is beginning to advance past a "steroids-only" approach, as novel immunosuppressant agents provide effective steroid-sparing options. The following focused review will provide a brief discussion of the epidemiology and clinical presentation of cardiac sarcoidosis followed by a discussion of up-to date imaging modalities employed in its assessment and therapeutic approaches. PMID- 25452703 TI - Stroke awareness in luxemburg: deficit concerning symptoms and risk factors. AB - BACKGROUND: Awareness of stroke risk factors is important for stroke prevention. Knowledge of stroke symptoms and awareness regarding the necessity of seeking urgent stroke treatment are vital to provide rapid admission to a stroke unit. Data on this specific knowledge in Luxemburg are lacking. METHODS: We investigated 420 patients from the Department of Neurology and their relatives using a questionnaire. There were 44% men and 56% women; 25% were immigrants and 75% Luxemburgish nationals; 13% already had had a stroke or transient ischemic attack (TIA); and the mean age was 55 years ranging from 18 to 87 years. RESULTS: A total of 88% of participants knew that a stroke occurs in the head/brain. In all, 10% of participants did not know any symptom of a stroke. The most frequently quoted symptoms (>15%) were paralysis/weakness (36%), speech disorders (32%), cranial nerve deficit (16%), vertigo (15%), and visual disorders (15%). Sensory deficits were mentioned by only 4% of patients. Known risk factors (>15%) were smoking (40%), hypertension (32%), alcohol (32%), poor nutrition (28%), high cholesterol (26%), stress (23%), and lack of exercise (19%). Age (4%), diabetes (6%), carotid stenosis (2%), and heart disease (1%) were less frequently known. In all, 11% of participants did not know any risk factor of a stroke. A total of 89% of participants would correctly call the 112 (emergency phone number). The following groups were better informed: Luxemburgish nationals, younger people, and participants with higher education level. Stroke/TIA patients were better informed concerning stroke symptoms, but unfortunately not concerning how to react in the case of a stroke. There was no relevant gender difference. DISCUSSION: Although most of the participants knew what to do in the case of a stroke, they did not know the relevant stroke symptoms and risk factors. Future campaigns should therefore focus on risk factors and symptoms, and should address immigrants, elderly persons, less-educated persons, and patients who had already suffered a stroke/TIA. PMID- 25452705 TI - Acute iodine toxicity from a suspected oral methamphetamine ingestion. AB - BACKGROUND: Iodine is a naturally occurring element commercially available alone or in a multitude of products. Iodine crystals and iodine tincture are used in the production of methamphetamine. Although rarely fatal, iodine toxicity from oral ingestion can produce distressing gastrointestinal symptoms and systemic symptoms, such as hypotension and tachycardia, from subsequent hypovolemia. OBJECTIVE: The objective of this case report is to describe a case of iodine toxicity from suspected oral methamphetamine ingestion. CASE REPORT: A male in his early 20's presented with gastrointestinal symptoms, chills, fever, tachycardia, and tachypnea after orally ingesting a substance suspected to be methamphetamine. The patient had elevated levels of serum creatinine, liver function tests, and bands on arrival, which returned to within normal limits by day 4 of admission. Based on the patient's narrow anion gap, halogen levels were ordered on day 3 and indicated iodine toxicity. This is thought to be the first documented case of iodine toxicity secondary to suspected oral methamphetamine abuse. CONCLUSION: Considering that the incidence of methamphetamine abuse is expected to continue to rise, clinicians should be aware of potential iodine toxicity in a patient with a history of methamphetamine abuse. PMID- 25452704 TI - Atherosclerosis as a possible extrahepatic manifestation of chronic hepatitis C virus infection. AB - Chronic infection and associated inflammation may play a role in various unfavorable pathologic conditions, including atherosclerosis. Chronic hepatitis C virus (HCV) infection is thought to be associated with a higher prevalence of atherosclerotic vascular changes in the coronary artery, cerebrovascular artery, and carotid artery; however, little is known about the precise mechanisms by which HCV enhances atherogenic processes. Furthermore, some studies have found no association, or even an inverse association, between HCV infection and atherosclerotic vascular changes or cardiovascular events. Differences in data regarding the mode of association may be because of variations in sample size, target population, and study design. Nevertheless, physicians should be aware of cardiovascular disorders as a possible comorbidity - owing to their considerable consequences - among patients with chronic HCV infection. PMID- 25452706 TI - Switching from nitrate therapy to ranolazine in patients with coronary artery disease receiving phosphodiesterase type-5 inhibitors for erectile dysfunction. AB - Coronary artery disease (CAD) and erectile dysfunction (ED) frequently coexist. The introduction of phosphodiesterase type-5 (PDE-5) inhibitors has revolutionized medical management of organic ED; however, in patients with angina pectoris, a common symptom of CAD, coadministration of PDE-5 inhibitors and nitrates has been implicated in CAD-related deaths following sexual activity. The mechanism of action of PDE-5 inhibitors results in a potential cumulative drop in blood pressure (BP); thus, these agents are contraindicated in patients receiving nitrates. Beta-blockers and calcium channel antagonists are considered the mainstays of antianginal therapy, but may not be tolerated by all patients. Ranolazine is an antianginal agent that produces minimal reductions in heart rate and BP. Here we report three cases of men with CAD, chronic angina, and concomitant ED. We describe our treatment approach in these patients, using ranolazine as a potential substitute to nitrate therapy. PMID- 25452707 TI - Safety and tolerance evaluation of milk fat globule membrane-enriched infant formulas: a randomized controlled multicenter non-inferiority trial in healthy term infants. AB - OBJECTIVE: This multicenter non-inferiority study evaluated the safety of infant formulas enriched with bovine milk fat globule membrane (MFGM) fractions. METHODS: Healthy, full-term infants (n = 119) age <=14 days were randomized to standard infant formula (control), standard formula enriched with a lipid-rich MFGM fraction (MFGM-L), or standard formula enriched with a protein-rich MFGM fraction (MFGM-P). Primary outcome was mean weight gain per day from enrollment to age 4 months (non-inferiority margin: -3.0 g/day). Secondary (length, head circumference, tolerability, morbidity, adverse events) and exploratory (phospholipids, metabolic markers, immune markers) outcomes were also evaluated. RESULTS: Weight gain was non-inferior in the MFGM-L and MFGM-P groups compared with the control group. Among secondary and exploratory outcomes, few between group differences were observed. Formula tolerance rates were high (>94%) in all groups. Adverse event and morbidity rates were similar across groups except for a higher rate of eczema in the MFGM-P group (13.9% vs control [3.5%], MFGM-L [1.4%]). CONCLUSION: Both MFGM-enriched formulas met the primary safety endpoint of non-inferiority in weight gain and were generally well tolerated, although a higher rate of eczema was observed in the MFGM-P group. PMID- 25452708 TI - Individualized Treatment from Theory to Practice: The Private Case of Adding LH during GnRH Antagonist-based Stimulation Protocol. AB - The study evaluated the proportion of patients whose pituitary glands respond with a sharp decrease in luteinizing hormone (LH) levels when exposed to a conventional dose of 0.25 mg gonadotropin releasing hormone (GnRH) antagonist in a prospective, single-center, non-randomized, proof-of-concept study. Fifty women eligible for in vitro fertilization (IVF) received recFSH (Gonal-F) from day 2 or 3 of menstrual period. Basal estradiol, progesterone, and LH were measured on the same day and 4-5 days later-immediately before GnRH antagonist 0.25 mg administration, and 24 hours after its administration. Responders were defined as "normal" if 24 hours after the first GnRH antagonist injection, LH level was >=50% of the pre-injection level and as "over-suppressed" if it was <50% of the pre-injection level. Twelve patients (26% of the total) were "over-suppressed" with a mean LH level of 37% of the level 24 hours earlier. These patients also demonstrated a significant decrease in estradiol rise during the first 24 hours after initial antagonist administration. This effect was reversed for the rest of the stimulation period during which recLH (Luveris, 150 IU/day) was added to the "over-suppressed." If proven advantageous in terms of pregnancy rate, this approach to individualized treatment would be easy to implement. TRIAL REGISTRATION: ClinicalTrials. gov Identifier: NCT01936077. PMID- 25452709 TI - Choroid plexus in developmental and evolutionary perspective. AB - The blood-cerebrospinal fluid boundary is present at the level of epithelial cells of the choroid plexus. As one of the sources of the cerebrospinal fluid (CSF), the choroid plexus (CP) plays an important role during brain development and function. Its formation has been studied largely in mammalian species. Lately, progress in other model animals, in particular the zebrafish, has brought a deeper understanding of CP formation, due in part to the ability to observe CP development in vivo. At the same time, advances in comparative genomics began providing information, which opens a possibility to understand further the molecular mechanisms involved in evolution of the CP and the blood-cerebrospinal fluid boundary formation. Hence this review focuses on analysis of the CP from developmental and evolutionary perspectives. PMID- 25452711 TI - A functional model and simulation of spinal motor pools and intrafascicular recordings of motoneuron activity in peripheral nerve. AB - Decoding motor intent from recorded neural signals is essential for the development of effective neural-controlled prostheses. To facilitate the development of online decoding algorithms we have developed a software platform to simulate neural motor signals recorded with peripheral nerve electrodes, such as longitudinal intrafascicular electrodes (LIFEs). The simulator uses stored motor intent signals to drive a pool of simulated motoneurons with various spike shapes, recruitment characteristics, and firing frequencies. Each electrode records a weighted sum of a subset of simulated motoneuron activity patterns. As designed, the simulator facilitates development of a suite of test scenarios that would not be possible with actual data sets because, unlike with actual recordings, in the simulator the individual contributions to the simulated composite recordings are known and can be methodically varied across a set of simulation runs. In this manner, the simulation tool is suitable for iterative development of real-time decoding algorithms prior to definitive evaluation in amputee subjects with implanted electrodes. The simulation tool was used to produce data sets that demonstrate its ability to capture some features of neural recordings that pose challenges for decoding algorithms. PMID- 25452712 TI - Electrophysiological evidence for change detection in speech sound patterns by anesthetized rats. AB - Human infants are able to detect changes in grammatical rules in a speech sound stream. Here, we tested whether rats have a comparable ability by using an electrophysiological measure that has been shown to reflect higher order auditory cognition even before it becomes manifested in behavioral level. Urethane anesthetized rats were presented with a stream of sequences consisting of three pseudowords carried out at a fast pace. Frequently presented "standard" sequences had 16 variants which all had the same structure. They were occasionally replaced by acoustically novel "deviant" sequences of two different types: structurally consistent and inconsistent sequences. Two stimulus conditions were presented for separate animal groups. In one stimulus condition, the standard and the pattern obeying deviant sequences had an AAB structure, while the pattern-violating deviant sequences had an ABB structure. In the other stimulus condition, these assignments were reversed. During the stimulus presentation, local-field potentials were recorded from the dura, above the auditory cortex. Two temporally separate differential brain responses to the deviant sequences reflected the detection of the deviant speech sound sequences. The first response was elicited by both types of deviant sequences and reflected most probably their acoustical novelty. The second response was elicited specifically by the structurally inconsistent deviant sequences (pattern-violating deviant sequences), suggesting that rats were able to detect changes in the pattern of three-syllabic speech sound sequence (i.e., location of the reduplication of an element in the sequence). Since all the deviant sound sequences were constructed of novel items, our findings indicate that, similarly to the human brain, the rat brain has the ability to automatically generalize extracted structural information to new items. PMID- 25452710 TI - The Drosophila blood-brain barrier: development and function of a glial endothelium. AB - The efficacy of neuronal function requires a well-balanced extracellular ion homeostasis and a steady supply with nutrients and metabolites. Therefore, all organisms equipped with a complex nervous system developed a so-called blood brain barrier, protecting it from an uncontrolled entry of solutes, metabolites or pathogens. In higher vertebrates, this diffusion barrier is established by polarized endothelial cells that form extensive tight junctions, whereas in lower vertebrates and invertebrates the blood-brain barrier is exclusively formed by glial cells. Here, we review the development and function of the glial blood brain barrier of Drosophila melanogaster. In the Drosophila nervous system, at least seven morphologically distinct glial cell classes can be distinguished. Two of these glial classes form the blood-brain barrier. Perineurial glial cells participate in nutrient uptake and establish a first diffusion barrier. The subperineurial glial (SPG) cells form septate junctions, which block paracellular diffusion and thus seal the nervous system from the hemolymph. We summarize the molecular basis of septate junction formation and address the different transport systems expressed by the blood-brain barrier forming glial cells. PMID- 25452713 TI - Perinatal systemic gene delivery using adeno-associated viral vectors. AB - Neurodegenerative monogenic diseases often affect tissues and organs beyond the nervous system. An effective treatment would require a systemic approach. The intravenous administration of novel therapies is ideal but is hampered by the inability of such drugs to cross the blood-brain barrier (BBB) and precludes efficacy in the central nervous system. A number of these early lethal intractable diseases also present devastating irreversible pathology at birth or soon after. Therefore, any therapy would ideally be administered during the perinatal period to prevent, stop, or ameliorate disease progression. The concept of perinatal gene therapy has moved a step further toward being a feasible approach to treating such disorders. This has primarily been driven by the recent discoveries that particular serotypes of adeno-associated virus (AAV) gene delivery vectors have the ability to cross the BBB following intravenous administration. Furthermore, safety has been demonstrated after perinatal administration mice and non-human primates. This review focuses on the progress made in using AAV to achieve systemic transduction and what this means for developing perinatal gene therapy for early lethal neurodegenerative diseases. PMID- 25452714 TI - Elevated mRNA-levels of distinct mitochondrial and plasma membrane Ca(2+) transporters in individual hypoglossal motor neurons of endstage SOD1 transgenic mice. AB - Disturbances in Ca(2+) homeostasis and mitochondrial dysfunction have emerged as major pathogenic features in familial and sporadic forms of Amyotrophic Lateral Sclerosis (ALS), a fatal degenerative motor neuron disease. However, the distinct molecular ALS-pathology remains unclear. Recently, an activity-dependent Ca(2+) homeostasis deficit, selectively in highly vulnerable cholinergic motor neurons in the hypoglossal nucleus (hMNs) from a common ALS mouse model, the endstage superoxide dismutase SOD1(G93A) transgenic mouse, was described. This functional deficit was defined by a reduced hMN mitochondrial Ca(2+) uptake capacity and elevated Ca(2+) extrusion across the plasma membrane. To address the underlying molecular mechanisms, here we quantified mRNA-levels of respective potential mitochondrial and plasma membrane Ca(2+) transporters in individual, choline acetyltransferase (ChAT) positive hMNs from wildtype (WT) and endstage SOD1(G93A) mice, by combining UV laser microdissection with RT-qPCR techniques, and specific data normalization. As ChAT cDNA levels as well as cDNA and genomic DNA levels of the mitochondrially encoded NADH dehydrogenase ND1 were not different between hMNs from WT and endstage SOD1(G93A) mice, these genes were used to normalize hMN specific mRNA-levels of plasma membrane and mitochondrial Ca(2+) transporters, respectively. We detected about 2-fold higher levels of the mitochondrial Ca(2+) transporters MCU/MICU1, Letm1, and UCP2 in remaining hMNs from endstage SOD1(G93A) mice. These higher expression-levels of mitochondrial Ca(2+) transporters in individual hMNs were not associated with a respective increase in number of mitochondrial genomes, as evident from hMN specific ND1 DNA quantification. Normalized mRNA-levels for the plasma membrane Na(+)/Ca(2+) exchanger NCX1 were also about 2-fold higher in hMNs from SOD1(G93A) mice. Thus, pharmacological stimulation of Ca(2+) transporters in highly vulnerable hMNs might offer a neuroprotective strategy for ALS. PMID- 25452715 TI - Substitution of natural sensory input by artificial neurostimulation of an amputated trigeminal nerve does not prevent the degeneration of basal forebrain cholinergic circuits projecting to the somatosensory cortex. AB - Peripheral deafferentation downregulates acetylcholine (ACh) synthesis in sensory cortices. However, the responsible neural circuits and processes are not known. We irreversibly transected the rat infraorbital nerve and implanted neuroprosthetic microdevices for proximal stump stimulation, and assessed cytochrome-oxidase and choline- acetyl-transferase (ChAT) in somatosensory, auditory and visual cortices; estimated the number and density of ACh-neurons in the magnocellular basal nucleus (MBN); and localized down-regulated ACh-neurons in basal forebrain using retrograde labeling from deafferented cortices. Here we show that nerve transection, causes down regulation of MBN cholinergic neurons. Stimulation of the cut nerve reverses the metabolic decline but does not affect the decrease in cholinergic fibers in cortex or cholinergic neurons in basal forebrain. Artifical stimulation of the nerve also has no affect of ACh innervation of other cortices. Cortical ChAT depletion is due to loss of corticopetal MBN ChAT-expressing neurons. MBN ChAT downregulation is not due to a decrease of afferent activity or to a failure of trophic support. Basalocortical ACh circuits are sensory specific, ACh is provided to each sensory cortex "on demand" by dedicated circuits. Our data support the existence of a modality specific cortex-MBN-cortex circuit for cognitive information processing. PMID- 25452716 TI - Molecules and mechanisms that regulate multipolar migration in the intermediate zone. AB - Most neurons migrate with an elongated, "bipolar" morphology, extending a long leading process that explores the environment. However, when immature projection neurons enter the intermediate zone (IZ) of the neocortex they become "multipolar". Multipolar cells extend and retract cytoplasmic processes in different directions and move erratically-sideways, up and down. Multipolar cells extend axons while they are in the lower half of the IZ. Remarkably, the cells then resume radial migration: they reorient their centrosome and Golgi apparatus towards the pia, transform back to bipolar morphology, and commence locomotion along radial glia (RG) fibers. This reorientation implies the existence of directional signals in the IZ that are ignored during the multipolar stage but sensed after axonogenesis. In vivo genetic manipulation has implicated a variety of candidate directional signals, cell surface receptors, and signaling pathways, that may be involved in polarizing multipolar cells and stabilizing a pia directed leading process for radial migration. Other signals are implicated in starting multipolar migration and triggering axon outgrowth. Here we review the molecules and mechanisms that regulate multipolar migration, and also discuss how multipolar migration affects the orderly arrangement of neurons in layers and columns in the developing neocortex. PMID- 25452717 TI - Robust sequential working memory recall in heterogeneous cognitive networks. AB - Psychiatric disorders are often caused by partial heterogeneous disinhibition in cognitive networks, controlling sequential and spatial working memory (SWM). Such dynamic connectivity changes suggest that the normal relationship between the neuronal components within the network deteriorates. As a result, competitive network dynamics is qualitatively altered. This dynamics defines the robust recall of the sequential information from memory and, thus, the SWM capacity. To understand pathological and non-pathological bifurcations of the sequential memory dynamics, here we investigate the model of recurrent inhibitory-excitatory networks with heterogeneous inhibition. We consider the ensemble of units with all-to-all inhibitory connections, in which the connection strengths are monotonically distributed at some interval. Based on computer experiments and studying the Lyapunov exponents, we observed and analyzed the new phenomenon clustered sequential dynamics. The results are interpreted in the context of the winnerless competition principle. Accordingly, clustered sequential dynamics is represented in the phase space of the model by two weakly interacting quasi attractors. One of them is similar to the sequential heteroclinic chain-the regular image of SWM, while the other is a quasi-chaotic attractor. Coexistence of these quasi-attractors means that the recall of the normal information sequence is intermittently interrupted by episodes with chaotic dynamics. We indicate potential dynamic ways for augmenting damaged working memory and other cognitive functions. PMID- 25452720 TI - Habits as learning enhancers. PMID- 25452718 TI - Frontostriatal circuits and the development of bulimia nervosa. AB - Bulimia nervosa (BN) is characterized by both recurrent episodes of binge eating that are, in part, defined by a sense of loss of control and compensatory behaviors to avoid weight gain. Impulsive behaviors are also common in individuals with BN, indicating more pervasive difficulties in behavioral self regulation. Findings from functional and anatomical neuroimaging studies of individuals with BN suggest dysfunction in the dorsal frontostriatal circuits that support self-regulatory capacities and habit learning and in overlapping ventral circuits that support reward processing and reward-based learning. In this review, we describe the normal development of frontostriatal circuits and then present behavioral and neuroimaging data from adolescents and adults with BN. These data suggest that the abnormal maturation of frontostriatal circuits may contribute to the habitual binge-eating and purging behaviors of BN. Future longitudinal imaging studies will improve understanding of how these circuits contribute to the developmental trajectory of BN and will inform novel interventions that could target or prevent the impulsive and habit-like features of this disorder. PMID- 25452721 TI - Changes of right-hemispheric activation after constraint-induced, intensive language action therapy in chronic aphasia: fMRI evidence from auditory semantic processing. AB - The role of the two hemispheres in the neurorehabilitation of language is still under dispute. This study explored the changes in language-evoked brain activation over a 2-week treatment interval with intensive constraint induced aphasia therapy (CIAT), which is also called intensive language action therapy (ILAT). Functional magnetic resonance imaging (fMRI) was used to assess brain activation in perilesional left hemispheric and in homotopic right hemispheric areas during passive listening to high and low-ambiguity sentences and non-speech control stimuli in chronic non-fluent aphasia patients. All patients demonstrated significant clinical improvements of language functions after therapy. In an event-related fMRI experiment, a significant increase of BOLD signal was manifest in right inferior frontal and temporal areas. This activation increase was stronger for highly ambiguous sentences than for unambiguous ones. These results suggest that the known language improvements brought about by intensive constraint-induced language action therapy at least in part relies on circuits within the right-hemispheric homologs of left-perisylvian language areas, which are most strongly activated in the processing of semantically complex language. PMID- 25452719 TI - A review of brain circuitries involved in stuttering. AB - Stuttering has been the subject of much research, nevertheless its etiology remains incompletely understood. This article presents a critical review of the literature on stuttering, with particular reference to the role of the basal ganglia (BG). Neuroimaging and lesion studies of developmental and acquired stuttering, as well as pharmacological and genetic studies are discussed. Evidence of structural and functional changes in the BG in those who stutter indicates that this motor speech disorder is due, at least in part, to abnormal BG cues for the initiation and termination of articulatory movements. Studies discussed provide evidence of a dysfunctional hyperdopaminergic state of the thalamocortical pathways underlying speech motor control in stuttering. Evidence that stuttering can improve, worsen or recur following deep brain stimulation for other indications is presented in order to emphasize the role of BG in stuttering. Further research is needed to fully elucidate the pathophysiology of this speech disorder, which is associated with significant social isolation. PMID- 25452722 TI - The processing of facial identity and expression is interactive, but dependent on task and experience. AB - Facial identity and emotional expression are two important sources of information for daily social interaction. However the link between these two aspects of face processing has been the focus of an unresolved debate for the past three decades. Three views have been advocated: (1) separate and parallel processing of identity and emotional expression signals derived from faces; (2) asymmetric processing with the computation of emotion in faces depending on facial identity coding but not vice versa; and (3) integrated processing of facial identity and emotion. We present studies with healthy participants that primarily apply methods from mathematical psychology, formally testing the relations between the processing of facial identity and emotion. Specifically, we focused on the "Garner" paradigm, the composite face effect and the divided attention tasks. We further ask whether the architecture of face-related processes is fixed or flexible and whether (and how) it can be shaped by experience. We conclude that formal methods of testing the relations between processes show that the processing of facial identity and expressions interact, and hence are not fully independent. We further demonstrate that the architecture of the relations depends on experience; where experience leads to higher degree of inter-dependence in the processing of identity and expressions. We propose that this change occurs as integrative processes are more efficient than parallel. Finally, we argue that the dynamic aspects of face processing need to be incorporated into theories in this field. PMID- 25452723 TI - Motor unit firing rates during spasms in thenar muscles of spinal cord injured subjects. AB - Involuntary contractions of paralyzed muscles (spasms) commonly disrupt daily activities and rehabilitation after human spinal cord injury (SCI). Our aim was to examine the recruitment, firing rate modulation, and derecruitment of motor units that underlie spasms of thenar muscles after cervical SCI. Intramuscular electromyographic activity (EMG), surface EMG, and force were recorded during thenar muscle spasms that occurred spontaneously or that were triggered by movement of a shoulder or leg. Most spasms were submaximal (mean: 39%, SD: 33 of the force evoked by median nerve stimulation at 50 Hz) with strong relationships between EMG and force (R (2) > 0.69). Unit recruitment occurred over a wide force range (0.2-103% of 50 Hz force). Significant unit rate modulation occurred during spasms (frequency at 25% maximal force: 8.8 Hz, 3.3 SD; at maximal force: 16.1 Hz, 4.1 SD). Mean recruitment frequency (7.1 Hz, 3.2 SD) was significantly higher than derecruitment frequency (5.4 Hz, 2.4 SD). Coactive unit pairs that fired for more than 4 s showed high (R (2) > 0.7, n = 4) or low (R (2):0.3-0.7, n = 12) rate-rate correlations, and derecruitment reversals (21 pairs, 29%). Later recruited units had higher or lower maximal firing rates than lower threshold units. These discrepant data show that coactive motoneurons are drive both by common inputs and by synaptic inputs from different sources during muscle spasms. Further, thenar motoneurons can still fire at high rates in response to various peripheral inputs after SCI, supporting the idea that low maximal voluntary firing rates and forces in thenar muscles result from reduced descending drive. PMID- 25452724 TI - Glial cells, but not neurons, exhibit a controllable response to a localized inflammatory microenvironment in vitro. AB - The ability to design long-lasting intracortical implants hinges on understanding the factors leading to the loss of neuronal density and the formation of the glial scar. In this study, we modify a common in vitro mixed cortical culture model using lipopolysaccharide (LPS) to examine the responses of microglia, astrocytes, and neurons to microwire segments. We also use dip-coated polyethylene glycol (PEG), which we have previously shown can modulate impedance changes to neural microelectrodes, to control the cellular responses. We find that microglia, as expected, exhibit an elevated response to LPS-coated microwire for distances of up to 150 MUm, and that this elevated response can be mitigated by co-depositing PEG with LPS. Astrocytes exhibit a more complex, distance dependent response, whereas neurons do not appear to be affected by the type or magnitude of glial response within this in vitro model. The discrepancy between our in vitro responses and typically observed in vivo responses suggest the importance of using a systems approach to understand the responses of the various brain cell types in a chronic in vivo setting, as well as the necessity of studying the roles of cell types not native to the brain. Our results further indicate that the loss of neuronal density observed in vivo is not a necessary consequence of elevated glial activation. PMID- 25452725 TI - Alpha and beta EEG power reflects L-dopa acute administration in parkinsonian patients. AB - AIM: To evaluate the effect of an acute L-dopa administration on eye-closed resting state electroencephalographic (EEG) activity of cognitively preserved Parkinsonian patients. METHODS: We examined 24 right-handed patients diagnosed as uncomplicated probable Parkinson's disease (PD). Each patient underwent Unified Parkinson's Disease Rating Scale (UPDRS)-part-III evaluation before and 60 min after an oral load of L-dopa-methyl-ester/carbidopa 250/25 mg. Resting condition eyes-closed EEG data were recorded both pre- and post L-dopa load. Absolute EEG power values were calculated at each scalp derivation for Delta, Theta, Alpha and Beta frequency bands. UPDRS scores (both global and subscale scores) and EEG data (power values of different frequency bands for each scalp derivation) were submitted to a statistical analysis to compare Pre and Post L-Dopa conditions. Finally, a correlation analysis was carried out between EEG spectral content and UPDRS scores. RESULTS: Considering EEG power spectral analysis, no statistically significant differences arose on Delta and Theta bands after L-dopa intake. Conversely, Alpha and Beta rhythms significantly increased on centro-parietal scalp derivations, as a function of L-dopa administration. Correlation analysis indicated a significant negative correlation between Beta power increase on centro-parietal areas and UPDRS subscores (Rigidity of arms and Bradykinesia). A minor significant negative correlation was also found between Alpha band increase and resting tremor. CONCLUSIONS: Assuming that a significant change in EEG power spectrum after L-dopa intake may be related to dopaminergic mechanisms, our findings are consistent with the hypothesis that dopaminergic defective networks are implicated in cortical oscillatory abnormalities at rest in non-demented PD patients. PMID- 25452727 TI - Vision of the active limb impairs bimanual motor tracking in young and older adults. AB - Despite the intensive investigation of bimanual coordination, it remains unclear how directing vision toward either limb influences performance, and whether this influence is affected by age. To examine these questions, we assessed the performance of young and older adults on a bimanual tracking task in which they matched motor-driven movements of their right hand (passive limb) with their left hand (active limb) according to in-phase and anti-phase patterns. Performance in six visual conditions involving central vision, and/or peripheral vision of the active and/or passive limb was compared to performance in a no vision condition. Results indicated that directing central vision to the active limb consistently impaired performance, with higher impairment in older than young adults. Conversely, directing central vision to the passive limb improved performance in young adults, but less consistently in older adults. In conditions involving central vision of one limb and peripheral vision of the other limb, similar effects were found to those for conditions involving central vision of one limb only. Peripheral vision alone resulted in similar or impaired performance compared to the no vision (NV) condition. These results indicate that the locus of visual attention is critical for bimanual motor control in young and older adults, with older adults being either more impaired or less able to benefit from a given visual condition. PMID- 25452726 TI - Impulsive and compulsive behaviors in Parkinson's disease. AB - BACKGROUND: Impulsive and compulsive behaviors (ICBs) are a heterogeneous group of conditions that may be caused by long-term dopaminergic replacement therapy (DRT) of Parkinson's disease (PD). The spectrum of ICBs includes dopamine dysregulation syndrome (DDS), punding, and impulse control disorders (ICDs). CONTENTS: We made a detailed review regarding the epidemiology, pathology, clinical characteristics, risk factors, diagnosis as well as treatment of ICBs. RESULTS: The prevalence of ICBs in PD patients is approximately 3-4% for DDS, 0.34-4.2% for punding, and 6-14% for ICDs, with higher prevalence in Western populations than in Asian. Those who take high dose of levodopa are more prone to have DDS, whereas, ICDs are markedly associated with dopamine agonists. Different subtypes of ICBs share many risk factors such as male gender, higher levodopa equivalent daily dose, younger age at PD onset, history of alcoholism, impulsive, or novelty-seeking personality. The Questionnaire for Impulsive-Compulsive Disorder in Parkinson's Disease-Rating Scale seems to be a rather efficacious instrument to obtain relevant information from patients and caregivers. Treatment of ICBs is still a great challenge for clinicians. Readjustment of DRT remains the primary method. Atypical antipsychotics, antidepressants, amantadine, and psychosocial interventions are also prescribed in controlling episodes of psychosis caused by compulsive DRT, but attention should be drawn to balance ICBs symptoms and motor disorders. Moreover, deep brain stimulation of the subthalamic nucleus might be a potential method in controlling ICBs. CONCLUSION: The exact pathophysiological mechanisms of ICBs in PD remains poorly understood. Further researches are needed not only to study the pathogenesis, prevalence, features, and risk factors of ICBs, but to find efficacious therapy for patients with these devastating consequences. PMID- 25452728 TI - Adolescent cocaine exposure simplifies orbitofrontal cortical dendritic arbors. AB - Cocaine and amphetamine remodel dendritic spines within discrete cortico-limbic brain structures including the orbitofrontal cortex (oPFC). Whether dendrite structure is similarly affected, and whether pre-existing cellular characteristics influence behavioral vulnerabilities to drugs of abuse, remain unclear. Animal models provide an ideal venue to address these issues because neurobehavioral phenotypes can be defined both before, and following, drug exposure. We exposed mice to cocaine from postnatal days 31-35, corresponding to early adolescence, using a dosing protocol that causes impairments in an instrumental reversal task in adulthood. We then imaged and reconstructed excitatory neurons in deep-layer oPFC. Prior cocaine exposure shortened and simplified arbors, particularly in the basal region. Next, we imaged and reconstructed orbital neurons in a developmental-genetic model of cocaine vulnerability-the p190rhogap+/- mouse. p190RhoGAP is an actin cytoskeleton regulatory protein that stabilizes dendrites and dendritic spines, and p190rhogap+/- mice develop rapid and robust locomotor activation in response to cocaine. Despite this, oPFC dendritic arbors were intact in drug-naive p190rhogap+/- mice. Together, these findings provide evidence that adolescent cocaine exposure has long-term effects on dendrite structure in the oPFC, and they suggest that cocaine-induced modifications in dendrite structure may contribute to the behavioral effects of cocaine more so than pre-existing structural abnormalities in this cell population. PMID- 25452730 TI - Eicosapentaenoic acid attenuates cigarette smoke-induced lung inflammation by inhibiting ROS-sensitive inflammatory signaling. AB - Cigarette smoking causes chronic lung inflammation that is mainly regulated by redox-sensitive pathways. Our previous studies have demonstrated that cigarette smoke (CS) activates reactive oxygen species (ROS)-sensitive mitogen-activated protein kinases (MAPKs)/nuclear factor-kappaB (NF-kappaB) signaling resulting in induction of lung inflammation. Eicosapentaenoic acid (EPA), a major type of omega-3 polyunsaturated fatty acid, is present in significant amounts in marine based fish and fish oil. EPA has been shown to possess antioxidant and anti inflammatory properties in vitro and in vivo. However, whether EPA has similar beneficial effects against CS-induced lung inflammation remains unclear. Using a murine model, we show that subchronic CS exposure for 4 weeks caused pulmonary inflammatory infiltration (total cell count in bronchoalveolar lavage fluid (BALF), 11.0-fold increase), increased lung vascular permeability (protein level in BALF, 3.1-fold increase), elevated levels of chemokines (11.4-38.2-fold increase) and malondialdehyde (an oxidative stress biomarker; 2.0-fold increase) in the lungs, as well as lung inflammation; all of these CS-induced events were suppressed by daily supplementation with EPA. Using human bronchial epithelial cells, we further show that CS extract (CSE) sequentially activated NADPH oxidase (NADPH oxidase activity, 1.9-fold increase), increased intracellular levels of ROS (3.0-fold increase), activated both MAPKs and NF-kappaB, and induced interleukin-8 (IL-8; 8.2-fold increase); all these CSE-induced events were inhibited by pretreatment with EPA. Our findings suggest a novel role for EPA in alleviating the oxidative stress and lung inflammation induced by subchronic CS exposure in vivo and in suppressing the CSE-induced IL-8 in vitro via its antioxidant function and by inhibiting MAPKs/NF-kappaB signaling. PMID- 25452731 TI - Blue LEDs get the Nobel Prize while Red LEDs are poised to save lives. PMID- 25452732 TI - Decoding dynamic Ca(2+) signaling in the vascular endothelium. AB - Although acute and chronic vasoregulation is inherently driven by endothelial Ca(2+), control and targeting of Ca(2+)-dependent signals are poorly understood. Recent studies have revealed localized and dynamic endothelial Ca(2+) events comprising an intricate signaling network along the vascular intima. Discrete Ca(2+) transients emerging from both internal stores and plasmalemmal cation channels couple to specific membrane K(+) channels, promoting endothelial hyperpolarization and vasodilation. The spatiotemporal tuning of these signals, rather than global Ca(2+) elevation, appear to direct endothelial functions under physiologic conditions. In fact, altered patterns of dynamic Ca(2+) signaling may underlie essential endothelial dysfunction in a variety of cardiovascular diseases. Advances in imaging approaches and analyses in recent years have allowed for detailed detection, quantification, and evaluation of Ca(2+) dynamics in intact endothelium. Here, we discuss recent insights into these signals, including their sources of origination and their functional encoding. We also address key aspects of data acquisition and interpretation, including broad applications of automated high-content analysis. PMID- 25452733 TI - Temporal factors affecting somatosensory-auditory interactions in speech processing. AB - Speech perception is known to rely on both auditory and visual information. However, sound-specific somatosensory input has been shown also to influence speech perceptual processing (Ito et al., 2009). In the present study, we addressed further the relationship between somatosensory information and speech perceptual processing by addressing the hypothesis that the temporal relationship between orofacial movement and sound processing contributes to somatosensory auditory interaction in speech perception. We examined the changes in event related potentials (ERPs) in response to multisensory synchronous (simultaneous) and asynchronous (90 ms lag and lead) somatosensory and auditory stimulation compared to individual unisensory auditory and somatosensory stimulation alone. We used a robotic device to apply facial skin somatosensory deformations that were similar in timing and duration to those experienced in speech production. Following synchronous multisensory stimulation the amplitude of the ERP was reliably different from the two unisensory potentials. More importantly, the magnitude of the ERP difference varied as a function of the relative timing of the somatosensory-auditory stimulation. Event-related activity change due to stimulus timing was seen between 160 and 220 ms following somatosensory onset, mostly around the parietal area. The results demonstrate a dynamic modulation of somatosensory-auditory convergence and suggest the contribution of somatosensory information for speech processing process is dependent on the specific temporal order of sensory inputs in speech production. PMID- 25452734 TI - Auditory driving of the autonomic nervous system: Listening to theta-frequency binaural beats post-exercise increases parasympathetic activation and sympathetic withdrawal. AB - Binaural beats are an auditory illusion perceived when two or more pure tones of similar frequencies are presented dichotically through stereo headphones. Although this phenomenon is thought to facilitate state changes (e.g., relaxation), few empirical studies have reported on whether binaural beats produce changes in autonomic arousal. Therefore, the present study investigated the effects of binaural beating on autonomic dynamics [heart rate variability (HRV)] during post-exercise relaxation. Subjects (n = 21; 18-29 years old) participated in a double-blind, placebo-controlled study during which binaural beats and placebo were administered over two randomized and counterbalanced sessions (within-subjects repeated-measures design). At the onset of each visit, subjects exercised for 20-min; post-exercise, subjects listened to either binaural beats ('wide-band' theta-frequency binaural beats) or placebo (carrier tones) for 20-min while relaxing alone in a quiet, low-light environment. Dependent variables consisted of high-frequency (HF, reflecting parasympathetic activity), low-frequency (LF, reflecting sympathetic and parasympathetic activity), and LF/HF normalized powers, as well as self-reported relaxation. As compared to the placebo visit, the binaural-beat visit resulted in greater self reported relaxation, increased parasympathetic activation and increased sympathetic withdrawal. By the end of the 20-min relaxation period there were no observable differences in HRV between binaural-beat and placebo visits, although binaural-beat associated HRV significantly predicted subsequent reported relaxation. Findings suggest that listening to binaural beats may exert an acute influence on both LF and HF components of HRV and may increase subjective feelings of relaxation. PMID- 25452735 TI - Sequential modulation of distractor-interference produced by semantic generalization of stimulus features. AB - Sequential modulations of distractor-related interference (i.e., reduced congruency effect after incongruent as compared to congruent predecessor trials, a.k.a. Gratton effect) have been taken to reflect conflict-induced attentional focusing. To dismiss an alternative interpretation based on integration and retrieval of low-level features, it is important to exert experimental control of stimulus and response feature sequences. This has been achieved by considering only trials associated with complete feature changes. Furthermore, distractors from two different perceptual dimensions, such as stimulus location and shape, have been combined in the same experiment to investigate the question of specificity vs. generality of conflict adaptation. With this method feature sequence control can be exerted, in principle, without disregarding data from feature repetition trials. However, such control may be insufficient when the distractor dimensions overlap semantically. In two experiments we found evidence consistent with the assumption that semantic generalization of stimulus features, such as between a stimulus presented at a left-sided location and a stimulus shape pointing to the left, may yield a between-dimension Gratton effect. These findings raise doubts about inferring generalized attentional conflict adaptation when semantically related distractor dimensions are used. PMID- 25452736 TI - Magic in the machine: a computational magician's assistant. AB - A human magician blends science, psychology, and performance to create a magical effect. In this paper we explore what can be achieved when that human intelligence is replaced or assisted by machine intelligence. Magical effects are all in some form based on hidden mathematical, scientific, or psychological principles; often the parameters controlling these underpinning techniques are hard for a magician to blend to maximize the magical effect required. The complexity is often caused by interacting and often conflicting physical and psychological constraints that need to be optimally balanced. Normally this tuning is done by trial and error, combined with human intuitions. Here we focus on applying Artificial Intelligence methods to the creation and optimization of magic tricks exploiting mathematical principles. We use experimentally derived data about particular perceptual and cognitive features, combined with a model of the underlying mathematical process to provide a psychologically valid metric to allow optimization of magical impact. In the paper we introduce our optimization methodology and describe how it can be flexibly applied to a range of different types of mathematics based tricks. We also provide two case studies as exemplars of the methodology at work: a magical jigsaw, and a mind reading card trick effect. We evaluate each trick created through testing in laboratory and public performances, and further demonstrate the real world efficacy of our approach for professional performers through sales of the tricks in a reputable magic shop in London. PMID- 25452737 TI - Development and initial validation of the Cardiovascular Disease Acceptance and Action Questionnaire (CVD-AAQ) in an Italian sample of cardiac patients. AB - Psychological inflexibility refers to the attempt to decrease internal distress even when doing so is inconsistent with life values, and has been identified as a potential barrier to making and maintaining health behavior changes that are consistent with a heart-healthy lifestyle. Disease- and behavior-specific measures of psychological inflexibility have been developed and utilized in treatment research. However, no specific measure has been created for patients with heart disease. Thus, the CardioVascular Disease Acceptance and Action Questionnaire (CVD-AAQ) was developed. The present study is aimed to evaluate the psychometric properties of the CVD-AAQ and to explore its association with measures of psychological adjustment and cardiovascular risk factors in an Italian sample of 275 cardiac patients. Exploratory factor analysis showed a structural one-factor solution with satisfactory internal consistency and test retest reliability. The relation with other measures was in the expected direction with stronger correlations for the theoretically consistent variables, supporting convergent and divergent validity. CVD-AAQ scores were associated with general psychological inflexibility, anxiety and depression and inversely correlated with psychological well-being. Moreover, the results showed that CVD AAQ scores are associated with two relevant risk factors for cardiac patients, namely low adherence to medication and being overweight. In sum, results suggest that the CVD-AAQ is a reliable and valid measure of heart disease-specific psychological inflexibility with interesting clinical applications for secondary prevention care. PMID- 25452738 TI - Closing in on the constitution of consciousness. AB - The science of consciousness is a nascent and thriving field of research that is founded on identifying the minimally sufficient neural correlates of consciousness. However, I have argued that it is the neural constitution of consciousness that science seeks to understand and that there are no evident strategies for distinguishing the correlates and constitution of (phenomenal) consciousness. Here I review this correlation/constitution distinction problem and challenge the existing foundations of consciousness science. I present the main analyses from a longer paper in press on this issue, focusing on recording, inhibition, stimulation, and combined inhibition/stimulation strategies, including proposal of the Jenga analogy to illustrate why identifying the minimally sufficient neural correlates of consciousness should not be considered the ultimate target of consciousness science. Thereafter I suggest that while combined inhibition and stimulation strategies might identify some constitutive neural activities-indeed minimally sufficient constitutive neural activities-such strategies fail to identify the whole neural constitution of consciousness and thus the correlation/constitution distinction problem is not fully solved. Various clarifications, potential objections and related scientific and philosophical issues are also discussed and I conclude by proposing new foundational claims for consciousness science. PMID- 25452729 TI - Does the kappa opioid receptor system contribute to pain aversion? AB - The kappa opioid receptor (KOR) and the endogenous peptide-ligand dynorphin have received significant attention due the involvement in mediating a variety of behavioral and neurophysiological responses, including opposing the rewarding properties of drugs of abuse including opioids. Accumulating evidence indicates this system is involved in regulating states of motivation and emotion. Acute activation of the KOR produces an increase in motivational behavior to escape a threat, however, KOR activation associated with chronic stress leads to the expression of symptoms indicative of mood disorders. It is well accepted that KOR can produce analgesia and is engaged in chronic pain states including neuropathic pain. Spinal studies have revealed KOR-induced analgesia in reversing pain hypersensitivities associated with peripheral nerve injury. While systemic administration of KOR agonists attenuates nociceptive sensory transmission, this effect appears to be a stress-induced effect as anxiolytic agents, including delta opioid receptor agonists, mitigate KOR agonist-induced analgesia. Additionally, while the role of KOR and dynorphin in driving the dysphoric and aversive components of stress and drug withdrawal has been well characterized, how this system mediates the negative emotional states associated with chronic pain is relatively unexplored. This review provides evidence that dynorphin and the KOR system contribute to the negative affective component of pain and that this receptor system likely contributes to the high comorbidity of mood disorders associated with chronic neuropathic pain. PMID- 25452739 TI - Voluntary settlement and its consequences on predictors of happiness: the influence of initial cultural context. AB - Hokkaido-a northern island of Japan that was settled by ethnic Japanese during the late nineteenth century and the early twentieth century-may remain to be a hybrid of interdependent culture of the mainland Japan and independent culture associated with frontier settlement. We thus anticipated that contemporary Hokkaido residents would exhibit either independent or interdependent psychological profiles depending on the types of behaviors that were required in a given situation. As expected, happiness was associated with positive disengaging emotions (e.g., pride in the self)-an independent profile-in situations that required personal goal pursuit and interpersonal influence; however, happiness was associated with positive engaging emotions (e.g., feelings of closeness)-an interdependent profile-in situations that required interpersonal harmony and adjustment. In contrast, such situational dependency was not observed for either mainland Japanese or Americans. For mainland Japanese happiness was associated with positive engaging emotions whereas for Americans happiness was associated with positive disengaging emotions. PMID- 25452740 TI - Word encoding during sleep is suggested by correlations between word-evoked up states and post-sleep semantic priming. AB - To test whether humans can encode words during sleep we played everyday words to men while they were napping and assessed priming from sleep-played words following waking. Words were presented during non-rapid eye movement (NREM) sleep. Priming was assessed using a semantic and a perceptual priming test. These tests measured differences in the processing of words that had been or had not been played during sleep. Synonyms to sleep-played words were the targets in the semantic priming test that tapped the meaning of sleep-played words. All men responded to sleep-played words by producing up-states in their electroencephalogram. Up-states are NREM sleep-specific phases of briefly increased neuronal excitability. The word-evoked up-states might have promoted word processing during sleep. Yet, the mean performance in the priming tests administered following sleep was at chance level, which suggests that participants as a group failed to show priming following sleep. However, performance in the two priming tests was positively correlated to each other and to the magnitude of the word-evoked up-states. Hence, the larger a participant's word-evoked up-states, the larger his perceptual and semantic priming. Those participants who scored high on all variables must have encoded words during sleep. We conclude that some humans are able to encode words during sleep, but more research is needed to pin down the factors that modulate this ability. PMID- 25452741 TI - Communication in cancer care: psycho-social, interactional, and cultural issues. A general overview and the example of India. AB - Communication is a core aspect of psycho-oncology care. This article examines key psychosocial, cultural, and technological factors that affect this communication. Drawing from advances in clinical work and accumulating bodies of empirical evidence, the authors identify determining factors for high quality, efficient, and sensitive communication and support for those affected by cancer. Cancer care in India is highlighted as a salient example. Cultural factors affecting cancer communication in India include beliefs about health and illness, societal values, integration of spiritual care, family roles, and expectations concerning disclosure of cancer information, and rituals around death and dying. The rapidly emerging area of e-health significantly impacts cancer communication and support globally. In view of current globalization, understanding these multidimensional psychosocial, and cultural factors that shape communication are essential for providing comprehensive, appropriate, and sensitive cancer care. PMID- 25452742 TI - Global tractography with embedded anatomical priors for quantitative connectivity analysis. AB - Tractography algorithms provide us with the ability to non-invasively reconstruct fiber pathways in the white matter (WM) by exploiting the directional information described with diffusion magnetic resonance. These methods could be divided into two major classes, local and global. Local methods reconstruct each fiber tract iteratively by considering only directional information at the voxel level and its neighborhood. Global methods, on the other hand, reconstruct all the fiber tracts of the whole brain simultaneously by solving a global energy minimization problem. The latter have shown improvements compared to previous techniques but these algorithms still suffer from an important shortcoming that is crucial in the context of brain connectivity analyses. As no anatomical priors are usually considered during the reconstruction process, the recovered fiber tracts are not guaranteed to connect cortical regions and, as a matter of fact, most of them stop prematurely in the WM; this violates important properties of neural connections, which are known to originate in the gray matter (GM) and develop in the WM. Hence, this shortcoming poses serious limitations for the use of these techniques for the assessment of the structural connectivity between brain regions and, de facto, it can potentially bias any subsequent analysis. Moreover, the estimated tracts are not quantitative, every fiber contributes with the same weight toward the predicted diffusion signal. In this work, we propose a novel approach for global tractography that is specifically designed for connectivity analysis applications which: (i) explicitly enforces anatomical priors of the tracts in the optimization and (ii) considers the effective contribution of each of them, i.e., volume, to the acquired diffusion magnetic resonance imaging (MRI) image. We evaluated our approach on both a realistic diffusion MRI phantom and in vivo data, and also compared its performance to existing tractography algorithms. PMID- 25452743 TI - Positron Emission Tomography with [(18)F]FLT Revealed Sevoflurane-Induced Inhibition of Neural Progenitor Cell Expansion in vivo. AB - Neural progenitor cell expansion is critical for normal brain development and an appropriate response to injury. During the brain growth spurt, exposures to general anesthetics, which either block the N-methyl-d-aspartate receptor or enhance the gamma-aminobutyric acid receptor type A can disturb neuronal transduction. This effect can be detrimental to brain development. Until now, the effects of anesthetic exposure on neural progenitor cell expansion in vivo had seldom been reported. Here, minimally invasive micro positron emission tomography (microPET) coupled with 3'-deoxy-3' [(18)F] fluoro-l-thymidine ([(18)F]FLT) was utilized to assess the effects of sevoflurane exposure on neural progenitor cell proliferation. FLT, a thymidine analog, is taken up by proliferating cells and phosphorylated in the cytoplasm, leading to its intracellular trapping. Intracellular retention of [(18)F]FLT, thus, represents an observable in vivo marker of cell proliferation. Here, postnatal day 7 rats (n = 11/group) were exposed to 2.5% sevoflurane or room air for 9 h. For up to 2 weeks following the exposure, standard uptake values (SUVs) for [(18)F]-FLT in the hippocampal formation were significantly attenuated in the sevoflurane-exposed rats (p < 0.0001), suggesting decreased uptake and retention of [(18)F]FLT (decreased proliferation) in these regions. Four weeks following exposure, SUVs for [(18)F]FLT were comparable in the sevoflurane-exposed rats and in controls. Co administration of 7-nitroindazole (30 mg/kg, n = 5), a selective inhibitor of neuronal nitric oxide synthase, significantly attenuated the SUVs for [(18)F]FLT in both the air-exposed (p = 0.00006) and sevoflurane-exposed rats (p = 0.0427) in the first week following the exposure. These findings suggested that microPET in couple with [(18)F]FLT as cell proliferation marker could be used as a non invasive modality to monitor the sevoflurane-induced inhibition of neural progenitor cell proliferation in vivo. PMID- 25452744 TI - Local Application of Sodium Salicylate Enhances Auditory Responses in the Rat's Dorsal Cortex of the Inferior Colliculus. AB - Sodium salicylate (SS) is a widely used medication with side effects on hearing. In order to understand these side effects, we recorded sound-driven local-field potentials in a neural structure, the dorsal cortex of the inferior colliculus (ICd). Using a microiontophoretic technique, we applied SS at sites of recording and studied how auditory responses were affected by the drug. Furthermore, we studied how the responses were affected by combined local application of SS and an agonists/antagonist of the type-A or type-B gamma-aminobutyric acid receptor (GABAA or GABAB receptor). Results revealed that SS applied alone enhanced auditory responses in the ICd, indicating that the drug had local targets in the structure. Simultaneous application of the drug and a GABAergic receptor antagonist synergistically enhanced amplitudes of responses. The synergistic interaction between SS and a GABAA receptor antagonist had a relatively early start in reference to the onset of acoustic stimulation and the duration of this interaction was independent of sound intensity. The interaction between SS and a GABAB receptor antagonist had a relatively late start, and the duration of this interaction was dependent on sound intensity. Simultaneous application of the drug and a GABAergic receptor agonist produced an effect different from the sum of effects produced by the two drugs released individually. These differences between simultaneous and individual drug applications suggest that SS modified GABAergic inhibition in the ICd. Our results indicate that SS can affect sound driven activity in the ICd by modulating local GABAergic inhibition. PMID- 25452746 TI - Temperature dependent bacteriophages of a tropical bacterial pathogen. AB - There is an increasing awareness of the multiple ways that bacteriophages (phages) influence bacterial evolution, population dynamics, physiology, and pathogenicity. By studying a novel group of phages infecting a soil borne pathogen, we revealed a paradigm shifting observation that the phages switch their lifestyle according to temperature. We sampled soil from an endemic area of the serious tropical pathogen Burkholderia pseudomallei, and established that podoviruses infecting the pathogen are frequently present in soil, and many of them are naturally occurring variants of a common virus type. Experiments on one phage in the related model B. thailandensis demonstrated that temperature defines the outcome of phage-bacteria interactions. At higher temperatures (37 degrees C), the phage predominantly goes through a lytic cycle, but at lower temperatures (25 degrees C), the phage remains temperate. This is the first report of a naturally occurring phage that follows a lytic or temperate lifestyle according to temperature. These observations fundamentally alter the accepted views on the abundance, population biology and virulence of B. pseudomallei. Furthermore, when taken together with previous studies, our findings suggest that the phenomenon of temperature dependency in phages is widespread. Such phages are likely to have a profound effect on bacterial biology, and on our ability to culture and correctly enumerate viable bacteria. PMID- 25452747 TI - The R package otu2ot for implementing the entropy decomposition of nucleotide variation in sequence data. AB - Oligotyping is a novel, supervised computational method that classifies closely related sequences into "oligotypes" (OTs) based on subtle nucleotide variation (Eren et al., 2013). Its application to microbial datasets has helped reveal ecological patterns which are often hidden by the way sequence data are currently clustered to define operational taxonomic units (OTUs). Here, we implemented the OT entropy decomposition procedure and its unsupervised version, Minimal Entropy Decomposition (MED; Eren et al., 2014c), in the statistical programming language and environment, R. The aim of this implementation is to facilitate the integration of computational routines, interactive statistical analyses, and visualization into a single framework. In addition, two complementary approaches are implemented: (1) An analytical method (the broken stick model) is proposed to help identify OTs of low abundance that could be generated by chance alone and (2) a one-pass profiling (OP) method, to efficiently identify those OTUs whose subsequent oligotyping would be most promising to be undertaken. These enhancements are especially useful for large datasets, where a manual screening of entropy analysis results and the creation of a full set of OTs may not be feasible. The package and procedures are illustrated by several tutorials and examples. PMID- 25452745 TI - Novel approaches to identify protective malaria vaccine candidates. AB - Efforts to develop vaccines against malaria have been the focus of substantial research activities for decades. Several categories of candidate vaccines are currently being developed for protection against malaria, based on antigens corresponding to the pre-erythrocytic, blood stage, or sexual stages of the parasite. Long lasting sterile protection from Plasmodium falciparum sporozoite challenge has been observed in human following vaccination with whole parasite formulations, clearly demonstrating that a protective immune response targeting predominantly the pre-erythrocytic stages can develop against malaria. However, most of vaccine candidates currently being investigated, which are mostly subunits vaccines, have not been able to induce substantial (>50%) protection thus far. This is due to the fact that the antigens responsible for protection against the different parasite stages are still yet to be known and relevant correlates of protection have remained elusive. For a vaccine to be developed in a timely manner, novel approaches are required. In this article, we review the novel approaches that have been developed to identify the antigens for the development of an effective malaria vaccine. PMID- 25452748 TI - Insights into environmental controls on microbial communities in a continental serpentinite aquifer using a microcosm-based approach. AB - Geochemical reactions associated with serpentinization alter the composition of dissolved organic compounds in circulating fluids and potentially liberate mantle derived carbon and reducing power to support subsurface microbial communities. Previous studies have identified Betaproteobacteria from the order Burkholderiales and bacteria from the order Clostridiales as key components of the serpentinite-hosted microbiome, however there is limited knowledge of their metabolic capabilities or growth characteristics. In an effort to better characterize microbial communities, their metabolism, and factors limiting their activities, microcosm experiments were designed with fluids collected from several monitoring wells at the Coast Range Ophiolite Microbial Observatory (CROMO) in northern California during expeditions in March and August 2013. The incubations were initiated with a hydrogen atmosphere and a variety of carbon sources (carbon dioxide, methane, acetate, and formate), with and without the addition of nutrients and electron acceptors. Growth was monitored by direct microscopic counts; DNA yield and community composition was assessed at the end of the 3 month incubation. For the most part, results indicate that bacterial growth was favored by the addition of acetate and methane, and that the addition of nutrients and electron acceptors had no significant effect on microbial growth, suggesting no nutrient- or oxidant-limitation. However, the addition of sulfur amendments led to different community compositions. The dominant organisms at the end of the incubations were closely related to Dethiobacter sp. and to the family Comamonadaceae, which are also prominent in culture-independent gene sequencing surveys. These experiments provide one of first insights into the biogeochemical dynamics of the serpentinite subsurface environment and will facilitate experiments to trace microbial activities in serpentinizing ecosystems. PMID- 25452749 TI - Benthic protists and fungi of Mediterranean deep hypsersaline anoxic basin redoxcline sediments. AB - Some of the most extreme marine habitats known are the Mediterranean deep hypersaline anoxic basins (DHABs; water depth ~3500 m). Brines of DHABs are nearly saturated with salt, leading many to suspect they are uninhabitable for eukaryotes. While diverse bacterial and protistan communities are reported from some DHAB water-column haloclines and brines, the existence and activity of benthic DHAB protists have rarely been explored. Here, we report findings regarding protists and fungi recovered from sediments of three DHAB (Discovery, Urania, L' Atalante) haloclines, and compare these to communities from sediments underlying normoxic waters of typical Mediterranean salinity. Halocline sediments, where the redoxcline impinges the seafloor, were studied from all three DHABs. Microscopic cell counts suggested that halocline sediments supported denser protist populations than those in adjacent control sediments. Pyrosequencing analysis based on ribosomal RNA detected eukaryotic ribotypes in the halocline sediments from each of the three DHABs, most of which were fungi. Sequences affiliated with Ustilaginomycotina Basidiomycota were the most abundant eukaryotic signatures detected. Benthic communities in these DHABs appeared to differ, as expected, due to differing brine chemistries. Microscopy indicated that only a low proportion of protists appeared to bear associated putative symbionts. In a considerable number of cases, when prokaryotes were associated with a protist, DAPI staining did not reveal presence of any nuclei, suggesting that at least some protists were carcasses inhabited by prokaryotic scavengers. PMID- 25452750 TI - Laboratory investigation of high pressure survival in Shewanella oneidensis MR-1 into the gigapascal pressure range. AB - The survival of Shewanella oneidensis MR-1 at up to 1500 MPa was investigated by laboratory studies involving exposure to high pressure followed by evaluation of survivors as the number (N) of colony forming units (CFU) that could be cultured following recovery to ambient conditions. Exposing the wild type (WT) bacteria to 250 MPa resulted in only a minor (0.7 log N units) drop in survival compared with the initial concentration of 10(8) cells/ml. Raising the pressure to above 500 MPa caused a large reduction in the number of viable cells observed following recovery to ambient pressure. Additional pressure increase caused a further decrease in survivability, with approximately 10(2) CFU/ml recorded following exposure to 1000 MPa (1 GPa) and 1.5 GPa. Pressurizing samples from colonies resuscitated from survivors that had been previously exposed to high pressure resulted in substantially greater survivor counts. Experiments were carried out to examine potential interactions between pressure and temperature variables in determining bacterial survival. One generation of survivors previously exposed to 1 GPa was compared with WT samples to investigate survival between 37 and 8 degrees C. The results did not reveal any coupling between acquired high pressure resistance and temperature effects on growth. PMID- 25452751 TI - Nitrogen gas flushing can be bactericidal: the temperature-dependent destiny of Bacillus weihenstephanensis KBAB4 under a pure N2 atmosphere. AB - Gram-negative Pseudomonas and Gram-positive Bacillus are the most common spoilage bacteria in raw and pasteurized milk, respectively. In previous studies, nitrogen (N2) gas flushing treatments of raw and pasteurized milk at cold chain temperatures inhibited bacterial spoilage and highlighted different susceptibilities to the N2 treatment with the exclusion of certain bacterial types. Here, we investigated the effects of pure N2 gas flushing on representative strains of these genera grown in mono- or co-cultures at 15 and 25 degrees C. Bacillus weihenstephanensis, a frequent inhabitant of fluid dairy products, is represented by the genome-sequenced KBAB4 strain. Among Pseudomonas, P. tolaasii LMG 2342(T) and strain C1, a raw milk psychrotroph, were selected. The N2 gas flushing treatment revealed: (1) temperature-dependent responses; (2) inhibition of the growth of both pseudomonads; (3) emergence of small colony variants (SCVs) for B. weihenstephanensis strain KBAB4 at 15 degrees C induced by the N2 treatment or when grown in co-culture with Pseudomonas strains; (4) N2 gas flushing modulates (suppressed or stimulated) bacterial antagonistic reactions in co-cultures; (5) most importantly, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses revealed that at 25 degrees C the majority of the KBAB4 cells were killed by pure N2 gas flushing. This observation constitutes the first evidence that N2 gas flushing has bactericidal effects. PMID- 25452752 TI - Comparative gene expression of Wigglesworthia inhabiting non-infected and Trypanosoma brucei gambiense-infected Glossina palpalis gambiensis flies. AB - Tsetse flies (Glossina sp.) that transmit trypanosomes causing human (and animal) African trypanosomiasis (HAT and AAT, respectively) harbor symbiotic microorganisms, including the obligate primary symbiont Wigglesworthia glossinidia. A relationship between Wigglesworthia and tsetse fly infection by trypanosomes has been suggested, as removal of the symbiont results in a higher susceptibility to midgut infection in adult flies. To investigate this relationship and to decipher the role of W. glossinidia in the fly's susceptibility to trypanosome infection, we challenged flies with trypanosomes and subsequently analyzed and compared the transcriptomes of W. glossinidia from susceptible and refractory tsetse flies at three time points (3, 10, and 20 days). More than 200 W. glossinidia genes were found to be differentially expressed between susceptible and refractory flies. The high specificity of these differentially expressed genes makes it possible to distinguish Wigglesworthia inhabiting these two distinct groups of flies. Furthermore, gene expression patterns were observed to evolve during the infection time course, such that very few differentially expressed genes were found in common in Wigglesworthia from the 3-, 10- and 20-day post-feeding fly samples. The overall results clearly demonstrate that the taking up of trypanosomes by flies, regardless of whether flies proceed with the developmental program of Trypanosoma brucei gambiense, strongly alters gene expression in Wigglesworthia. These results therefore provide a novel framework for studies that aim to decrease or even abolish tsetse fly vector competence. PMID- 25452753 TI - Pyrosequencing reveals diverse fecal microbiota in Simmental calves during early development. AB - From birth to the time after weaning the gastrointestinal microbiota of calves must develop into a stable, autochthonous community accompanied by pivotal changes of anatomy and physiology of the gastrointestinal tract. The aim of this pilot study was to examine the fecal microbiota of six Simmental dairy calves to investigate time-dependent dynamics of the microbial community. Calves were followed up from birth until after weaning according to characteristic timepoints during physiological development of the gastrointestinal tract. Pyrosequencing of 16S rRNA gene amplicons from 35 samples yielded 253,528 reads clustering into 5410 operational taxonomic units based on 0.03 16S rRNA distance. Operational taxonomic units were assigned to 296 genera and 17 phyla with Bacteroidetes, Firmicutes, and Proteobacteria being most abundant. An age-dependent increasing diversity and species richness was observed. Highest similarities between fecal microbial communities were found around weaning compared with timepoints from birth to the middle of the milk feeding period. Principal coordinate analysis revealed a high variance particularly in samples taken at the middle of the milk feeding period (at the age of approximately 40 days) compared to earlier timepoints, confirming a unique individual development of the fecal microbiota of each calf. This study provides first deep insights into the composition of the fecal microbiota of Simmental dairy calves and might be a basis for future more detailed studies. PMID- 25452754 TI - IL-1 Receptor-Associated Kinase Signaling and Its Role in Inflammation, Cancer Progression, and Therapy Resistance. AB - Chronic inflammation has long been associated with the development of cancer. Among the various signaling pathways within cancer cells that can incite the expression of inflammatory molecules are those that activate IL-1 receptor associated kinases (IRAK). The IRAK family is comprised of four family members, IRAK-1, IRAK-2, IRAK-3 (also known as IRAK-M), and IRAK-4, which play important roles in both positively and negatively regulating the expression of inflammatory molecules. The wide array of inflammatory molecules that are expressed in response to IRAK signaling within the tumor microenvironment regulate the production of factors which promote tumor growth, metastasis, immune suppression, and chemotherapy resistance. Based on published reports we propose that dysregulated activation of the IRAK signaling pathway in cancer cells contributes to disease progression by creating a highly inflammatory tumor environment. In this article, we present both theoretical arguments and reference experimental data in support of this hypothesis. PMID- 25452757 TI - Autoimmuno-Anti-Tumor Immunity - Understanding the Immune Responses against "self" and "Altered-Self". PMID- 25452756 TI - Genetic Susceptibility to ANCA-Associated Vasculitis: State of the Art. AB - ANCA-associated vasculitis (AAV) is a group of disorders that is caused by inflammation affecting small blood vessels. Both arteries and veins are affected. AAV includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) renamed from Wegener's granulomatosis, and eosinophilic granulomatosis with polyangiitis (EGPA), renamed from Churg-Strauss syndrome. AAV is primarily due to leukocyte migration and resultant damage. Despite decades of research, the mechanisms behind AAV disease etiology are still not fully understood, although it is clear that genetic and environmental factors are involved. To improve the understanding of the disease, the genetic component has been extensively studied by candidate association studies and two genome-wide association studies. The majority of the identified genetic AAV risk factors are common variants. These have uncovered information that still needs further investigation to clarify its importance. In this review, we summarize and discuss the results of the genetic studies in AAV. We also present the novel approaches to identifying the causal variants in complex susceptibility loci and disease mechanisms. Finally, we discuss the limitations of current methods and the challenges that we still have to face in order to incorporate genomic and epigenomic data into clinical practice. PMID- 25452758 TI - Arginase in the vascular endothelium: friend or foe? PMID- 25452755 TI - Mast cell mediators: their differential release and the secretory pathways involved. AB - Mast cells (MC) are widely distributed throughout the body and are common at mucosal surfaces, a major host-environment interface. MC are functionally and phenotypically heterogeneous depending on the microenvironment in which they mature. Although MC have been classically viewed as effector cells of IgE mediated allergic diseases, they are also recognized as important in host defense, innate and acquired immunity, homeostatic responses, and immunoregulation. MC activation can induce release of pre-formed mediators such as histamine from their granules, as well as release of de novo synthesized lipid mediators, cytokines, and chemokines that play diverse roles, not only in allergic reactions but also in numerous physiological and pathophysiological responses. Indeed, MC release their mediators in a discriminating and chronological manner, depending upon the stimuli involved and their signaling cascades (e.g., IgE-mediated or Toll-like receptor-mediated). However, the precise mechanisms underlying differential mediator release in response to these stimuli are poorly known. This review summarizes our knowledge of MC mediators and will focus on what is known about the discriminatory release of these mediators dependent upon diverse stimuli, MC phenotypes, and species of origin, as well as on the intracellular synthesis, storage, and secretory processes involved. PMID- 25452759 TI - Transcriptional responses of Arabidopsis thaliana to chewing and sucking insect herbivores. AB - We tested the hypothesis that Arabidopsis can recognize and respond differentially to insect species at the transcriptional level using a genome wide microarray. Transcriptional reprogramming was characterized using co-expression analysis in damaged and undamaged leaves at two times in response to mechanical wounding and four insect species. In all, 2778 (10.6%) of annotated genes on the array were differentially expressed in at least one treatment. Responses differed mainly between aphid and caterpillar and sampling times. Responses to aphids and caterpillars shared only 10% of up-regulated and 8% of down-regulated genes. Responses to two caterpillars shared 21 and 12% of up- and down-regulated genes, whereas responses to the two aphids shared only 7 and 4% of up-regulated and down regulated genes. Overlap in genes expressed between 6 and 24 h was 3-15%, and depended on the insect species. Responses in attacked and unattacked leaves differed at 6 h but converged by 24 h. Genes responding to the insects are also responsive to many stressors and included primary metabolism. Aphids down regulated amino acid catabolism; caterpillars stimulated production of amino acids involved in glucosinolate synthesis. Co-expression analysis revealed 17 response networks. Transcription factors were a major portion of differentially expressed genes throughout and responsive genes shared most of the known or postulated binding sites. However, cis-element composition of genes down regulated by the aphid M. persicae was unique, as were those of genes down regulated by caterpillars. As many as 20 cis-elements were over-represented in one or more treatments, including some from well-characterized classes and others as yet uncharacterized. We suggest that transcriptional changes elicited by wounding and insects are heavily influenced by transcription factors and involve both enrichment of a common set of cis-elements and a unique enrichment of a few cis-elements in responding genes. PMID- 25452761 TI - Models to reconcile plant science and stochasticity. PMID- 25452760 TI - Ecological dynamics and complex interactions of Agrobacterium megaplasmids. AB - As with many pathogenic bacteria, agrobacterial plant pathogens carry most of their virulence functions on a horizontally transmissible genetic element. The tumor-inducing (Ti) plasmid encodes the majority of virulence functions for the crown gall agent Agrobacterium tumefaciens. This includes the vir genes which drive genetic transformation of host cells and the catabolic genes needed to utilize the opines produced by infected plants. The Ti plasmid also encodes, an opine-dependent quorum sensing system that tightly regulates Ti plasmid copy number and its conjugal transfer to other agrobacteria. Many natural agrobacteria are avirulent, lacking the Ti plasmid. The burden of harboring the Ti plasmid depends on the environmental context. Away from diseased hosts, plasmid costs are low but the benefit of the plasmid is also absent. Consequently, plasmidless genotypes are favored. On infected plants the costs of the Ti plasmid can be very high, but balanced by the opine benefits, locally favoring plasmid bearing cells. Cheating derivatives which do not incur virulence costs but can benefit from opines are favored on infected plants and in most other environments, and these are frequently isolated from nature. Many agrobacteria also harbor an At plasmid which can stably coexist with a Ti plasmid. At plasmid genes are less well characterized but in general facilitate metabolic activities in the rhizosphere and bulk soil, such as the ability to breakdown plant exudates. Examination of A. tumefaciens C58, revealed that harboring its At plasmid is much more costly than harboring it's Ti plasmid, but conversely the At plasmid is extremely difficult to cure. The interactions between these co-resident plasmids are complex, and depend on environmental context. However, the presence of a Ti plasmid appears to mitigate At plasmid costs, consistent with the high frequency with which they are found together. PMID- 25452762 TI - Fragile X mental retardation protein expression in Alzheimer's disease. AB - The FMR1 protein product, FMRP, is an mRNA binding protein associated with translational inhibition of target transcripts. One FMRP target is the amyloid precursor protein (APP) mRNA, and APP levels are elevated in Fmr1 KO mice. Given that elevated APP protein expression can elicit Alzheimer's disease (AD) in patients and model systems, we evaluated whether FMRP expression might be altered in Alzheimer's autopsy brain samples and mouse models compared to controls. In a double transgenic mouse model of AD (APP/PS1), we found no difference in FMRP expression in aged AD model mice compared to littermate controls. FMRP expression was also similar in AD and control patient frontal cortex and cerebellum samples. Fragile X-associated tremor/ataxia syndrome (FXTAS) is an age-related neurodegenerative disorder caused by expanded CGG repeats in the 5' untranslated region of the FMR1 gene. Patients experience cognitive impairment and dementia in addition to motor symptoms. In parallel studies, we measured FMRP expression in cortex and cerebellum from three FXTAS patients and found reduced expression compared to both controls and Alzheimer's patient brains, consistent with animal models. We also find increased APP levels in cerebellar, but not cortical, samples of FXTAS patients compared to controls. Taken together, these data suggest that a decrease in FMRP expression is unlikely to be a primary contributor to Alzheimer's disease pathogenesis. PMID- 25452764 TI - A novel mutation in TTC19 associated with isolated complex III deficiency, cerebellar hypoplasia, and bilateral basal ganglia lesions. AB - Isolated complex III (cIII) deficiency is a rare biochemical finding in mitochondrial disorders, mainly associated with mutations in mitochondrial DNA MTCYB gene, encoding cytochrome b, or in assembly factor genes (BCS1L, TTC19, UQCC2, and LYRM7), whereas mutations in nuclear genes encoding cIII structural subunits are extremely infrequent. We report here a patient, a 9 year old female born from first cousin related parents, with normal development till 18 months when she showed unsteady gait with frequent falling down, cognitive, and speech worsening. Her course deteriorated progressively. Brain MRI showed cerebellar vermis hypoplasia and bilateral lentiform nucleus high signal lesions. Now she is bed ridden with tetraparesis and severely impaired cognitive and language functions. Biochemical analysis revealed isolated cIII deficiency in muscle, and impaired respiration in fibroblasts. We identified a novel homozygous rearrangement in TTC19 (c.213_229dup), resulting in frameshift with creation of a premature termination codon (p.Gln77Argfs*30). Western blot analysis demonstrated the absence of TTC19 protein in patient's fibroblasts, while Blue-Native Gel Electrophoresis analysis revealed the presence of cIII-specific assembly intermediates. Mutations in TTC19 have been rarely associated with mitochondrial disease to date, being described in about ten patients with heterogeneous clinical presentations, ranging from early onset encephalomyopathy to adult forms with cerebellar ataxia. Contrariwise, the biochemical defect was a common hallmark in TTC19 mutant patients, confirming the importance of TTC19 in cIII assembly/stability. Therefore, we suggest extending the TTC19 mutational screening to all patients with cIII deficiency, independently from their phenotypes. PMID- 25452765 TI - Quantifying the impact of inter-site heterogeneity on the distribution of ChIP seq data. AB - Chromatin Immunoprecipitation followed by sequencing (ChIP-seq) is a valuable tool for epigenetic studies. Analysis of the data arising from ChIP-seq experiments often requires implicit or explicit statistical modeling of the read counts. The simple Poisson model is attractive, but does not provide a good fit to observed ChIP-seq data. Researchers therefore often either extend to a more general model (e.g., the Negative Binomial), and/or exclude regions of the genome that do not conform to the model. Since many modeling strategies employed for ChIP-seq data reduce to fitting a mixture of Poisson distributions, we explore the problem of inferring the optimal mixing distribution. We apply the Constrained Newton Method (CNM), which suggests the Negative Binomial - Negative Binomial (NB-NB) mixture model as a candidate for modeling ChIP-seq data. We illustrate fitting the NB-NB model with an accelerated EM algorithm on four data sets from three species. Zero-inflated models have been suggested as an approach to improve model fit for ChIP-seq data. We show that the NB-NB mixture model requires no zero-inflation and suggest that in some cases the need for zero inflation is driven by the model's inability to cope with both artifactual large read counts and the frequently observed very low read counts. We see that the CNM based approach is a useful diagnostic for the assessment of model fit and inference in ChIP-seq data and beyond. Use of the suggested NB-NB mixture model will be of value not only when calling peaks or otherwise modeling ChIP-seq data, but also when simulating data or constructing blacklists de novo. PMID- 25452763 TI - Can pharmacogenetics explain efficacy and safety of cisplatin pharmacotherapy? AB - Several recent pharmacogenetic studies have investigated the variability in both outcome and toxicity in cisplatin-based therapies. These studies have focused on the genetic variability of therapeutic targets that could affect cisplatin response and toxicity in diverse type of cancer including lung, gastric, ovarian, testicular, and esophageal cancer. In this review, we seek to update the reader in this area of investigation, focusing primarily on DNA reparation enzymes and cisplatin metabolism through Glutathione S-Transferases (GSTs). Current evidence indicates a potential application of pharmacogenetics in therapeutic schemes in which cisplatin is the cornerstone of these treatments. Therefore, a collaborative effort is required to study these molecular characteristics in order to generate a genetic panel with clinical utility. PMID- 25452766 TI - A HIF-1 network reveals characteristics of epithelial-mesenchymal transition in acute promyelocytic leukemia. AB - BACKGROUND: Acute promyelocytic leukemia (APL) is a sub-type of acute myeloid leukemia (AML) characterized by a block of myeloid differentiation at the promyelocytic stage and the predominant t(15:17) chromosomal translocation. We have previously determined that cells from APL patients show increased expression of genes regulated by hypoxia-inducible transcription factors (HIFs) compared to normal promyelocytes. HIFs regulate crucial aspects of solid tumor progression and are currently being implicated in leukemogenesis. METHODS: To investigate the contribution of hypoxia-related signaling in APL compared to other AML sub-types, we reverse engineered a transcriptional network from gene expression profiles of AML patients' samples, starting from a list of direct target genes of HIF-1. A HIF-1-dependent subnetwork of genes specifically dysregulated in APL was derived from the comparison between APL and other AMLs. RESULTS: Interestingly, this subnetwork shows a unique involvement of genes related to extracellular matrix interaction and cell migration, with decreased expression of genes involved in cell adhesion and increased expression of genes implicated in motility and invasion, thus unveiling the presence of characteristics of epithelial mesenchymal transition (EMT). We observed that the genes of this subnetwork, whose dysregulation shows a peculiar pattern across different AML sub-types, distinguish malignant from normal promyelocytes, thus ruling out dependence on a myeloid developmental stage. Also, expression of these genes is reversed upon treatment of APL-derived NB4 cells with all-trans retinoic acid and cell differentiation. CONCLUSIONS: Our data suggest that pathways related to EMT-like processes can be implicated also in hematological malignancies besides solid tumors, and can identify specific AML sub-types. PMID- 25452767 TI - Evaluating the relationship between amyloid-beta and alpha-synuclein phosphorylated at Ser129 in dementia with Lewy bodies and Parkinson's disease. AB - INTRODUCTION: Lewy body and Alzheimer-type pathologies often co-exist. Several studies suggest a synergistic relationship between amyloid-beta (Abeta) and alpha synuclein (alpha-syn) accumulation. We have explored the relationship between Abeta accumulation and the phosphorylation of alpha-syn at serine-129 (pSer129 alpha-syn), in post-mortem human brain tissue and in SH-SY5Y neuroblastoma cells transfected to overexpress human alpha-syn. METHODS: We measured levels of Abeta40, Abeta42, alpha-syn and pSer129 alpha-syn by sandwich enzyme-linked immunosorbent assay, in soluble and insoluble fractions of midfrontal, cingulate and parahippocampal cortex and thalamus, from cases of Parkinson's disease (PD) with (PDD; n = 12) and without dementia (PDND; n = 23), dementia with Lewy bodies (DLB; n = 10) and age-matched controls (n = 17). We also examined the relationship of these measurements to cognitive decline, as measured by time-to dementia and the mini-mental state examination (MMSE) score in the PD patients, and to Braak tangle stage. RESULTS: In most brain regions, the concentration of insoluble pSer129 alpha-syn correlated positively, and soluble pSer129 alpha-syn negatively, with the levels of soluble and insoluble Abeta. Insoluble pSer129 alpha-syn also correlated positively with Braak stage. In most regions, the levels of insoluble and soluble Abeta and the proportion of insoluble alpha-syn that was phosphorylated at Ser129 were significantly higher in the PD and DLB groups than the controls, and higher in the PDD and DLB groups than the PDND brains. In PD, the MMSE score correlated negatively with the level of insoluble pSer129 alpha-syn. Exposure of SH-SY5Y cells to aggregated Abeta42 significantly increased the proportion of alpha-syn that was phosphorylated at Ser129 (aggregated Abeta40 exposure had a smaller, non-significant effect). CONCLUSIONS: Together, these data show that the concentration of pSer129 alpha-syn in brain tissue homogenates is directly related to the level of Abeta and Braak tangle stage, and predicts cognitive status in Lewy body diseases. PMID- 25452769 TI - Status of vitamin D, antimicrobial peptide cathelicidin and T helper-associated cytokines in patients with diabetes mellitus and pulmonary tuberculosis. AB - Pulmonary tuberculosis (PTB) is a high burden infectious disease in China. The immune function is damaged in patients with diabetes mellitus (DM) who are easy to infect with Mycobacterium tuberculosis (Mtb). The growth of Mtb has been shown to be restrained following the administration of vitamin D and antimicrobial peptide cathelicidin (LL-37); however, the effect in patients with DM and PTB remains unclear. Vitamin D can regulate the immune system through Vitamin D receptors expressed in T helper (Th) cells. The aim of the present study was to analyze the status and correlations of vitamin D, LL-37 and Th-associated cytokines in patients with PTB or PTB with DM (DMPTB). Serum 25-hydroxyvitamin D3 [25(OH)D3] levels were measured by liquid chromatography-tandem mass spectrometry, while plasma LL-37 levels were analyzed using a solid-phase enzyme linked immunosorbent assay. Flow cytometry was used to analyze the levels of Th cytokines, including Th1-associated IFN-gamma, Th2-associated IL-4 and Th17 associated IL-17. The results revealed that patients with PTB and DMPTB were vitamin D deficient or had insufficient vitamin D levels. Furthermore, the levels of LL-37, IFN-gamma, IL-4 and IL-17 were higher in the PTB and DMPTB groups when compared with the normal controls. These results indicated that vitamin D supplementation is necessary for PTB and DMPTB patients. In addition, LL-37, IFN gamma and IL-17 may be diagnostic indexes that become elevated in the compensatory response caused by Mtb infection. Vitamin D can regulate the immune status in patients suffering from PTB. PMID- 25452768 TI - Mechanism of subclinical hypothyroidism accelerating endothelial dysfunction (Review). AB - The association between subclinical hypothyroidism (SH) and cardiovascular disease has received increasing attention in recent years. The predisposition of patients with SH to endothelial dysfunction, an early sign of atherosclerosis, has been observed. This predisposition may be partially explained by the factors also found in patients with SH, including changes in lipid profile, low grade chronic inflammation, oxidative stress and insulin resistance. The proportional risks of endothelial dysfunction to thyroid stimulating hormone (TSH) also indicate that the action of TSH on extra thyroidal-stimulating hormone receptor (TSHR) is a possible mechanism underlying the correlation, which has later been supported by the associated basic studies. L-thyroxine replacement therapy appears to improve the aforementioned aspects, whereas there remain certain controversies, particularly for the elderly. Thus, more study data are required to confirm the benefit of L-thyroxine treatment for patients with SH. PMID- 25452771 TI - Osteogenic ability of bone marrow stem cells intraoperatively enriched by a novel matrix. AB - Poly-L-lysine (PLL) is commonly used as an adhibiting agent due to its good viscosity, and demineralized bone matrix (DBM) is a common enriched matrix for selective cell retention technology. Therefore, the aim of this study was to use PLL to coat the surface and interspaces of DBM to form a novel type of enriched matrix [DBM coated with PLL (PLL-DBM)], in order to effectively improve the enrichment effects of bone marrow stem cells and enhance their osteogenic ability. Electron microscope scanning and the infrared spectrum were used to observe the structure of PLL-DBM and the optimal conditions for the combination of PLL and DBM. Enriching effects on bone marrow nucleated cells (NCs) and platelets (PLTs) were detected with an automated hematology analyzer. The osteogenesis of the following four groups was assessed with a grafting bone model in a goat spinal transverse process: IA, tissue engineered bone (TEB) fabricated following enrichment of bone marrow with PLL-DBM; IB, autogenous iliac bone; IIC, TEB fabricated following enrichment of bone marrow with DBM; IID, blank DBM. The goats were sacrificed in one batch at week 16 after the surgery and the fusion specimens were examined using X-ray and three-dimensional computed tomography (CT). In addition, the CT value was determined and the histology and biomechanics were analyzed in order to evaluate the osteogenic ability. The results showed that PLL and DBM combined well and that PLL-DBM exhibited a natural mesh pore structure. The fold enrichment of NCs and PLTs with PLL-DBM was significantly higher than that with DBM. The fusion effects of the IA and IB groups were similar and significantly enhanced compared with those of the IIC and IID groups. The results confirmed that PLL-DBM is an ideal enriched matrix for bone marrow stem cells, and TEB rapidly fabricated by PLL-DBM intraoperatively enriched bone marrow stem cells exhibits an improved osteogenic ability. PMID- 25452770 TI - Significance of human epidermal growth factor receptor 2 expression in colorectal cancer. AB - The aim of the present study was to evaluate the protein expression level of human epidermal growth factor receptor 2 (HER-2) using immunohistochemistry (IHC), and assess the association with clinicopathological parameters and the prognosis of patients with colorectal cancer (CRC). In addition, the current study observed the consistency between the levels of HER-2 protein expression determined by IHC and HER-2 gene amplification determined by fluorescence in situ hybridization (FISH) in the CRC samples. Overexpression of HER-2 and gene amplification were examined with semiquantitative standardized IHC in 878 formalin-fixed paraffin-embedded CRC samples, while 102 of these cases were analyzed with FISH. A total of 102 cases (11.6%), out of the 878 cases, were determined by IHC to overexpress HER-2. Of these, 25 cases were strongly positive (IHC3+), while 77 cases revealed moderate staining (IHC2+). HER-2 overexpression was more frequent in early-stage cases compared with advanced-stage cases of CRC (P<0.001). However, there was no association observed between HER-2 overexpression and clinicopathological parameters. FISH analysis revealed that 64% (16/25) of the IHC3+ cases had HER-2 gene amplification. By contrast, only 6.5% (5/77) of the IHC2+ cases, and none of the 20 randomly selected IHC0 or 1+ cases, demonstrated HER-2 gene amplification. Furthermore, no associations were observed between HER-2 overexpression or gene amplification with the survival time. Thus, the present study observed that HER-2 overexpression does not correlate with other clinicopathological data or the survival rate, with the exception of clinical stages. However, IHC3+ and 2+ cases should be further analyzed by FISH to assess the status of the HER-2 gene in CRC. Patients with HER 2 gene amplification may constitute as potential candidates for targeted therapy with trastuzumab. PMID- 25452773 TI - Antistress and antioxidant effects of virgin coconut oil in vivo. AB - Virgin coconut oil (VCO) has been consumed worldwide for various health-related reasons and some of its benefits have been scientifically evaluated. Medium-chain fatty acids were found to be a potential antidepressant functional food; however, this effect had not been evaluated in VCO, which is rich in polyphenols and medium-chain fatty acids. The aim of this study was to evaluate the antistress and antioxidant effects of VCO in vivo, using mice with stress-induced injury. The antistress effect of VCO (administered per os, at a dose of 10 ml/kg body weight) was evaluated using the forced swim test and chronic cold restraint stress models. VCO was able to reduce immobility time and restore oxidative stress in mice post-swim test. Furthermore, mice treated with VCO were found to exhibit higher levels of brain antioxidants, lower levels of brain 5 hydroxytryptamine and reduced weight of the adrenal glands. Consequently, the serum cholesterol, triglyceride, glucose and corticosterone levels were also lower in VCO-treated mice. These results suggest the potential value of VCO as an antistress functional oil. PMID- 25452772 TI - Effects of basic fibroblast growth factor and cyclin D1 on cigarette smoke induced pulmonary vascular remodeling in rats. AB - Cigarette smoking may contribute to pulmonary hypertension in chronic obstructive pulmonary disease by resulting in pulmonary vascular remodeling that involves pulmonary artery smooth muscle cell proliferation. This study investigated the effects of basic fibroblast growth factor (bFGF) and cyclin D1 on the pulmonary vascular remodeling in smoking-exposed rats. Twenty-four male Wistar rats were randomly divided into four groups. Three tobacco-exposed groups were exposed to the smoke produced by 20 cigarettes for 60 min, twice a day for two, four or eight weeks, and the control group were exposed to fresh air. The expression of bFGF and cyclin D1 in the pulmonary arterial smooth muscle cells were determined using immunohistochemistry. Quantitative polymerase chain reaction was conducted to determine the expression levels of bFGF and cyclin D1 mRNA. In addition, the expression of bFGF and cyclin D1 proteins was evaluated by western blotting. The expression of bFGF and cyclin D1 at the mRNA and protein levels was shown to increase with the duration of smoke exposure (P<0.05). The correlation analysis indicated the expression of bFGF and cyclin D1 was positively associated with the pulmonary vessel wall thickness. The expression of bFGF was positively associated with that of cyclin D1. Collectively, the data demonstrated that the upregulation of bFGF and cyclin D1 occurred in rats subjected to smoke exposure, which may be associated with the abnormal proliferation of the smooth muscle cells in the pulmonary arteries. PMID- 25452774 TI - Extracts of black bean peel and pomegranate peel ameliorate oxidative stress induced hyperglycemia in mice. AB - Oxidative stress has a central role in the progression of diabetes mellitus (DM), which can directly result in the injury of islet beta cells and consequent hyperglycemia. The aim of the present study was to evaluate the possible protective effects of black bean peel extract (BBPE), pomegranate peel extract (PPE) and a combination of the two (PPE + BBPE) on streptozotocin-induced DM mice. Oxidative stress was assessed by the levels of total antioxidative capability and glutathione in the serum. Fasting blood glucose and insulin levels, as well as the pancreas weight index and the histological changes in the pancreas, were also determined. The results showed that, after fours weeks of treatment with PPE, BBPE or PPE + BBPE, DM mice showed, to different degrees, a decrease in blood glucose, increases in insulin secretion and the pancreas weight index, and an increase in antioxidative activity. These changes were particularly evident in the DM mice subjected to the combined intervention strategy of PPE + BBPE. The histological findings indicated that the injury to the pancreatic islets in DM mice was also ameliorated following treatment. In conclusion, PPE and BBPE, particularly the combination of the two, have the ability to ameliorate hyperglycemia by inhibiting oxidative stress-induced pancreatic damage; this finding may be useful in the prevention and treatment of DM. PMID- 25452775 TI - Expression of serotonin receptors in human lower esophageal sphincter. AB - Serotonin (5-HT) is a neurotransmitter and vasoactive amine that is involved in the regulation of a large number of physiological functions. The wide variety of 5-HT-mediated functions is due to the existence of different classes of serotonergic receptors in the mammalian gastrointestinal tract and nervous system. The aim of this study was to explore the expression of multiple types of 5-HT receptor (5-HT1AR, 5-HT2AR, 5-HT3AR, 5-HT4R, 5-HT5AR, 5-HT6R and 5-HT7R) in sling and clasp fibers from the human lower esophageal sphincter (LES). Muscle strips of sling and clasp fibers from the LES were obtained from patients undergoing esophagogastrectomy, and circular muscle strips from the esophagus and stomach were used as controls. Reverse transcription-polymerase chain reaction (RT-PCR), quantitative PCR and western blotting were used to investigate the expression of the various 5-HT receptor types. Messenger RNA for all seven 5-HT receptor types was identified in the sling and clasp fibers of the LES. At the mRNA level, the expression levels were highest for 5-HT3AR and 5-HT4R, and lowest for 5-HT5AR, 5-HT6R and 5-HT7R. At the protein level, the expression levels were highest for 5-HT3AR and 5-HT4R, followed by 5-HT1AR and 5-HT2AR; 5-HT7R was also detected at a low level. The expression of 5-HT5AR and 5-HT6R proteins was not confirmed. The results indicate that a variety of 5-HT receptor types can be detected in the human LES and probably contribute to LES function. PMID- 25452776 TI - Solitary fibrous tumor of the spermatic cord: A case report and literature review. AB - A 31-year-old male patient with a six-year history of left inguinoscrotal swelling was admitted to the Second Xiangya Hospital (Changsha, China). The mass was not found to be associated with intraperitoneal pressure. Ultrasonography and computed tomography examinations demonstrated several solid, botryoidal masses involving the spermatic cord, with limited capacity of mobility. The demarcation between the masses and the left testicle was clear; thus, the masses were removed by a left spermatic cord tumor resection via a left inguinal approach, under epidural anesthesia. Positive staining of the tumor markers, CD34+, CD99+ and Bcl 2+, was confirmed by pathological examination following surgery, and a solitary fibrous tumor of the spermatic cord was diagnosed. No recurrence and metastasis were observed in the patient during the subsequent 25-month follow-up period. PMID- 25452777 TI - Evidence of timing effects on acupuncture: A functional magnetic resonance imaging study. AB - According to Traditional Chinese Medicine there is an optimum time to administer acupuncture at a particular acupoint. The present study used functional magnetic resonance imaging to investigate the timing effects of acupuncture at the Zusanli (ST36) acupoint. A total of 10 healthy volunteers and 10 post-stroke patients were recruited. The subjects received acupuncture stimulation at ST36 during two time periods: between 7:00 a.m. and 9:00 a.m. (the AM condition) and between 3:00 p.m. and 5:00 p.m. (the PM condition), seven days later. Blood oxygenation level dependent signals were captured while the patient was receiving the acupuncture stimulation. The results showed a stronger activation in the AM condition than in the PM condition in both healthy and stroke subjects. The significant regions in the healthy subjects included the prefrontal cortex, cingulum, thalamus and cerebellum; for the stroke patients, the significant regions were the cuneus, supplementary motor area and inferior parietal gyrus. Timing can therefore modulate brain activation patterns during acupuncture in healthy subjects and stroke patients; however, the modulation effect appears to differ between the two subject groups. Further studies are required to explore the timing effects of acupuncture at different acupoints in different populations. PMID- 25452778 TI - Association between calcitonin receptor AluI gene polymorphism and bone mineral density: A meta-analysis. AB - The association between calcitonin receptor (CTR) AluI gene polymorphism and bone mineral density (BMD) remains unclear. In order to elucidate this association, a meta-analysis was performed to provide a comprehensive assessment of the studies carried out to date. PubMed, the Cochrane Library, Web of Science and the China National Knowledge Infrastructure database were searched to identify eligible studies. The data were extracted independently by two authors using a standard form, the studies were meta-analyzed and disagreements were resolved through discussion. Fifteen eligible studies involving 3,093 females and 654 males were included for analysis. Overall, the male subjects with the CC genotype had non statistically different lumbar spine and femoral neck BMD compared to subjects with the CT/TT and CT genotypes. The BMD of female subjects with the CC genotype was similar to that of patients with the CT or CT/TT genotypes. In Chinese male subjects, those with the CC genotype had almost the same BMD as those with the CT and CT/TT genotypes. The results also demonstrated that Chinese female subjects with the CC genotype had similar BMD at the lumbar spine and femoral neck to subjects with the CT and CT/TT genotypes. Furthermore, Southern Chinese subjects with CC genotypes did not have a different BMD at the lumbar spine and femoral neck compared to patients with CT and CT/TT genotypes. Notably, Northern Chinese subjects with the CC genotype had a higher BMD at the lumbar spine compared to subjects with CT/TT genotypes and a lower BMD at the femoral neck compared to subjects with CT/TT genotypes. Among Northern Chinese females, those with CC genotypes also had a higher BMD at the lumbar spine compared to those with CT/TT genotypes, while no difference was observed in the BMD of the lumbar spine and femoral neck between patients with CC and CT genotypes. In Southern Chinese females, no significant difference was found in the BMD at the lumbar spine and femoral neck between those with CC and those with CT or CT/TT genotypes. In conclusion, the AluI gene polymorphism may have an association with BMD in Northern Chinese subjects and the CC genotype may have a protective effect on spine BMD; however, the CC genotype may be a risk factor for low femoral neck BMD in Northern Chinese subjects. Further studies are required to fully investigate the potential association between AluI gene polymorphism and BMD. PMID- 25452779 TI - Comparative serum proteome expression of the steroid-induced femoral head osteonecrosis in adults. AB - Steroid-induced osteonecrosis of the femoral head (SONFH) is a disabling, aseptic and ischemic disease that develops following steroid therapy. The pathogenesis of SONFH is unclear, so the early diagnosis and treatment for this disease is yet to be established. The purpose of the present study was to identify potential biomarkers for SONFH. The differential expression of serum proteins from patients with SONFH and healthy volunteers was analyzed by the proteomics method. The protein samples were labeled and subjected to isoelectric focusing and two dimensional gel electrophoresis. The resultant protein spots were matched and quantified by an imaging analysis system. The differentially-expressed protein spots were subjected to in-gel trypsin digestion followed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Significantly lower levels of complement component 3 (C3), C4, inter-alpha-trypsin inhibitor heavy chain H4 and alpha-2-macroglobulin were found in the serum of patients with SONFH. These proteins are reported to be actively involved in intravascular coagulation, apoptosis and reactive oxygen species imbalance, indicating that multiple pathological reactions occur in SONFH and these proteins may serve as potential biomarkers for the diagnosis of SONFH. PMID- 25452780 TI - Single administration of vildagliptin attenuates postprandial hypertriglyceridemia and endothelial dysfunction in normoglycemic individuals. AB - Postprandial hypertriglyceridemia impairs endothelial function and plays an important role in the development of atherosclerosis. The aim of the present study was to examine the postprandial effects of the dipeptidyl peptidase-4 inhibitor vildagliptin and the alpha-glucosidase inhibitor voglibose on endothelial dysfunction and lipid profiles following a single administration. A randomized cross-over trial using 11 normoglycemic individuals was performed. The postprandial effects of a single administration of vildagliptin (50 mg) or voglibose (0.3 mg) on endothelial function were analyzed using brachial artery flow-mediated dilation (FMD) and lipid profiles during fasting and 1.5 and 3 h after an oral cookie-loading test. Compared with voglibose, vildagliptin significantly suppressed postprandial endothelial dysfunction, (%FMD, -1.6+/-0.9 vildagliptin vs. -4.0+/-0.7 voglibose; P=0.01) and the postprandial incremental increase in the triglyceride level (28+/-18 vildagliptin vs. 51+/-26 mg/dl voglibose; P=0.01) 3 h after a cookie-loading test. In addition, vildagliptin significantly increased the levels of glucagon-like peptide-1 compared with voglibose 3 h after a loading cookie test (4.4+/-0.6 vs. 2.9+/-0.7 pmol/l, respectively; P=0.04). No significant differences in the levels of glucose, apolipoprotein B-48, glucagon or insulin were observed between vildagliptin and voglibose treatments. In conclusion, a single administration of vildagliptin attenuated postprandial endothelial dysfunction and postprandial hypertriglyceridemia, suggesting that vildagliptin may be a promising antiatherogenic agent. PMID- 25452781 TI - Ras-related C3 botulinum toxin substrate 1 activation is involved in the pathogenesis of diabetic retinopathy. AB - This study used a streptozotocin (STZ)-induced rat model of diabetes to investigate whether Ras-related C3 botulinum toxin substrate 1 (Rac1) was involved in the pathogenesis of diabetic retinopathy. The effects of Rac1 inhibition on vascular endothelial (VE)-cadherin and beta-catenin expression in high glucose-induced rat retinal endothelial cells (RRECs) were additionally examined. Rac1 activation in the retinas from STZ-induced diabetic rats and in high glucose-induced RRECs was measured by reverse transcription-quantitative polymerase chain reaction analysis, immunohistochemistry and western blot analysis. The expression levels of VE-cadherin and beta-catenin were also examined with or without Rac1 inhibition through small interfering (si)RNA transfection. STZ-induced diabetes was associated with an increase in the vascular permeability of the retina. Furthermore, Rac1 activation was increased in the retina of STZ-induced diabetic rats and in high glucose-induced RRECs compared with that in the controls. Immunohistochemistry showed that immunostaining of Rac1 was localized in the outer plexiform, inner nuclear, inner plexiform and ganglion cell layers and in the retinal microvasculature of rats. The expression of beta-catenin was increased in the retinas of the diabetic rats at four, eight and 12 weeks after the induction of diabetes compared with that in the controls. Additionally, Rac1 activation was required for the high glucose induced VE-cadherin expression decrease and for beta-catenin expression in high glucose-induced RRECs. Rac1 inhibition by Rac1-siRNA transfection effectively prevented hyperpermeability, beta-catenin expression and the VE-cadherin expression decrease in high glucose-induced RRECs. In conclusion, diabetes affects the expression of Rac1 in the retina. Rac1 may be involved in the diabetes-induced damage and/or alterations to the blood-retinal barrier through changes in VE-cadherin and beta-catenin expression. PMID- 25452782 TI - Changes of pathological and physiological indicators affecting drug metabolism in rats after acute exposure to high altitude. AB - High altitude environments cause the human body to undergo a series of pathological, physiological and biochemical changes, which have a certain effect on drug pharmacokinetics. The objective of the present study was to observe changes in factors affecting pharmacokinetics in rats following acute exposure to high altitude and return to low altitude. A total of 21 male Wistar rats were randomly assigned to three groups. The rats in group A were maintained at low altitude in Shanghai, 55 m above sea level; those in group B were acutely exposed to high altitude in Maqu, Gansu, 4,010 m above sea level; and those in group C were acutely exposed to high altitude and then returned to low altitude. Blood was collected from the orbit for the analysis of significant biochemical indicators and from the abdominal aorta for blood gas analysis. Brain, lung and kidney tissues were removed to observe pathological changes. In group B, the pH, buffer base (BB), base excess (BE), total carbon dioxide content (ctCO2), oxygen saturation of arterial blood (sO2), oxygen tension of arterial blood (pO2), serum sodium (Na+) concentration, lactate dehydrogenase (LDH) activity and total protein (TP) level were significantly reduced, and the carbon dioxide tension of arterial blood (pCO2), serum chloride (Cl-) concentration, serum total bilirubin (TBIL) level and alkaline phosphatase (ALP) activity were significantly increased compared with those in group A (P<0.05). In group C, the pH, BB, BE, sO2, pO2, hemoglobin (Hb) level, serum Na+ concentration, LDH activity and TP level were significantly reduced, and the pCO2, serum Cl- concentration, alanine transaminase activity, TBIL and urea levels were significantly increased (P<0.05) compared with those in group A. The Hb and ALP levels in group C were significantly lower than those in group B (P<0.05); and the TP, TBIL and urea levels in group C were significantly higher than those in group B (P<0.05). Pathological observation revealed that the alveolar wall was hyperemic, edematous and incrassate, the alveolar epithelium was hyperplastic and infiltrated with neutrophilic granulocytes and the alveolar septum was widened; brain neurons were edematous with enlarged perivascular spaces, and hippocampal neurons were metamorphic and karyopyknotic; and kidney mesangial cells were hyperplastic, both following acute exposure to high altitude and after returning to low altitude. In conclusion, blood gas indices, biochemical indicators and functions of the heart, liver, kidney were significantly changed, and marked pathological changes occurred in the brain, liver and kidney following acute exposure to high altitude and also after returning to low altitude. These changes are likely to seriously affect the pharmacokinetics of drugs. PMID- 25452783 TI - Inhibitory effects and mechanism of 5-fluorouracil combined with celecoxib on human gastric cancer xenografts in nude mice. AB - 5-Fluorouracil (5-Fu) is one of the most commonly used drugs to treat gastric cancer; however, drug-resistance in cancer cells reduces the efficacy of 5-Fu. Celecoxib may be able to reduce resistance to 5-Fu chemotherapy. The aim of the present study was to investigate the inhibitory effects of a combination of 5-Fu and celecoxib on implanted gastric cancer xenografts in nude mice and to elucidate the underlying mechanism. A tumor-bearing nude mice model was established. The mice were divided into blank control, 5-Fu, celecoxib and combination groups. The weight change and the tumor inhibition rate in each group were calculated. Immunocytochemistry, reverse transcription-polymerase chain reaction and western blotting methods were used to observe hypoxia-inducible factor-2alpha (HIF-2alpha), ATP-binding cassette transporter G2 (ABCG2) and octamer-binding transcription factor 4 (Oct-4) expression in the SGC7901 cells. Inhibition of the growth of the implanted gastric cancer was observed in the 5 Fu, celecoxib and combination groups. In the celecoxib and combination treatment groups, the mean tumor mass was significantly less than that in the control group (P<0.05), and the mean tumor mass in the combination treatment group was significantly less than that in the 5-Fu group (P<0.05). The tumor inhibition rates in the 5-Fu, celecoxib and combination groups were 26.36, 59.70 and 88.37%, respectively. The combination group exhibited the highest inhibition rate; the inhibition rates of the combination and celecoxib groups were significantly higher compared with the 5-Fu group (P<0.05). The expression levels of HIF-2, ABCG2 and Oct-4 mRNA and protein were high in the blank control group, and were further increased in the 5-Fu group. However, in the celecoxib and combination groups, the expression levels were lower compared with those in the control group. Significant differences were identified among the 5-Fu, celecoxib and combination groups (P<0.01). Celecoxib has antitumor effects in vivo. The mechanism may be associated with the reduced expression of cancer stem cell markers HIF-2alpha, Oct-4 and ABCG2. 5-Fu and celecoxib have a synergistic antitumor effect. The mechanism associated with the amelioration of resistance to chemotherapy in gastric cancer and the enhancement of the effect of chemotherapy may be via the reduction of the expression of HIF-2alpha, ABCG2, Oct-4 and other cancer stem cell markers in the tumor tissues. PMID- 25452784 TI - 99mTc-dextran lymphoscintigraphy can detect sentinel lymph node in breast cancer patients. AB - The aim of this study was to retrospectively determine the accuracy and feasibility of using 99mTc-dextran (DX) lymphoscintigraphy for the localization of sentinel lymph nodes (SLNs) in breast cancer patients. The relevant factors affecting lymphoscintigraphy were also investigated. In this study, 235 breast cancer patients underwent 99mTc-DX lymphoscintigraphic imaging and examination by a gamma-probe method in combination with blue dye staining to detect SLNs. The detection results were considered in combination with rapid frozen pathology results to determine whether SLN metastasis was positive or negative. SLNs were identified in 191 patients by gamma-probe detection among the 202 patients that tested positive by lymphoscintigraphic imaging, a coincidence rate of 94.6%. This suggested that lymph node metastasis had occurred and could be detected using lymphoscintigraphy. The axillary status of the breast cancer patients was also predicted using lymphoscintigraphy and the false-negative rate, sensitivity, specificity and positive predictive value were 13.3% (4/30), 90.7% (39/43), 23.4% (45/192) and 13.5% (21/155), respectively. The age of the patient, menstrual status, tumor location, tumor size, pathological type, preoperative biopsy and neoadjuvant chemotherapy were unrelated to the success of lymphoscintigraphy (P>0.05). 99mTc-DX lymphoscintigraphy is able to exactly determine the location of SLN in breast cancer patients, and can be used for guiding gamma-probe methods and sentinel lymph node biopsy. PMID- 25452785 TI - Long-term survival of a patient with lung cancer metastasis to the spine following surgical treatment combined with radiation and epithelial growth factor receptor inhibitor therapy: A case report. AB - The prognosis of patients with lung cancer metastasis to the spine is poor, and the choice of surgery is questionable based on the aggressiveness of the disease. The present study describes a case of a 56-year-old male with metastatic spinal cord compression. The patient underwent surgery for posterior decompression and internal fixation, in addition to receiving postoperative radiation and epidermal growth factor receptor (EGFR) inhibitor medication. After 24 months, positron emission tomography-computed tomography scan showed a reduction in the left upper lobe mass in the short axis and inactivation of the neoplasm in the left upper lobe and T9 vertebra. Based on these promising results, it is suggested that orthopedic oncologists consider the combination of radiation and EGFR inhibitor therapy with surgery for the treatment of lung cancer metastasis to the spine. PMID- 25452786 TI - Inhibition of vascular endothelial growth factor by small interfering RNA upregulates differentiation, maturation and function of dendritic cells. AB - This study aimed to investigate the effects of vascular endothelial growth factor (VEGF) secreted by MCF-7 breast cancer cells on the differentiation, maturation and function of dendritic cells (DCs). Small interfering RNAs (siRNAs) directed against the VEGF gene were designed and transfected into MCF-7 breast cancer cells at an optimal concentration (100 nmol/l) using cationic liposome transfection reagent, whereas the control group was transfected with only transfection reagent. Western blot analysis and ELISA were used to determine VEGF protein expression and VEGF concentration, respectively. Mononuclear cells were cultured with the culture supernatants from primary MCF-7 cells (control group) and siRNA-treated MCF-7 cells (siRNA group). The DC phenotypes, including CD1a, CD80, CD83, CD86 and HLA-DR, were evaluated by flow cytometry. The MTT assay was used to assess the cytotoxicity of DC-mediated tumor-specific cytotoxic T lymphocytes (CTLs) against MCF-7 cells in the two different culture supernatants. The VEGF-targeted constructed siRNA inhibited VEGF expression in MCF-7 cells. Cultivation with the culture supernatants from MCF-7 cells treated with siRNA affected DC morphology. DCs in the siRNA group exhibited a significantly higher expression of CD86, CD80, CD83 and HLA-DR compared to the cells in the control group, whereas the expression of CD1a in the siRNA group was significantly lower compared to that in the control group. The cytotoxic activity of CTLs mediated by DCs was significantly altered by siRNA transfection. These results indicated that VEGF may play a significant role in tumor development, progression and immunosuppression. PMID- 25452787 TI - Seasonal changes in gastric mucosal factors associated with peptic ulcer bleeding. AB - A close association has been established between climate and peptic ulcer bleeding (PUB). The incidence of PUB in cold climates is significantly higher than that in hot climates. In this study, gastric mucosal damage and its barrier function (through associated barrier factors) in extreme climate conditions were examined to investigate the pathogenesis of PUB in extreme cold climates. Gastric juice and biopsy specimens were collected from 176 patients with peptic ulcer. Conventional hematoxylin and eosin staining was used to exclude malignant ulcers. Helicobacter pylori infections were detected by modified Giemsa staining. pH values of the gastric juice samples were obtained on-site by precise pH dipstick readings. The protein expression levels of heat shock protein (HSP) 70, occludin, nitric oxide synthase (NOS), epidermal growth factor (EGF) and EGF receptor (EGFR) in the gastric mucosa were detected by immunohistochemistry. No significant differences were identified between the high and low bleeding risk groups in the rates of H. pylori infection and the pH values of the gastric juices in the extreme hot or cold climates. Furthermore, no statistically significant differences were identified in the protein expression levels of occludin, NOS, EGF and EGFR between the high and low bleeding risk groups. In the extreme cold climate, the expression of HSP70 and the mucus thickness of the gastric antrum in the high bleeding risk group were significantly lower than those in the low bleeding risk group. The protein expression levels of occludin, HSP70, NOS and EGFR in the extreme cold climate were significantly lower than those in the extreme hot climate, whereas the gastric acid secretion was significantly higher in the extreme cold climate than that in the extreme hot climate. In conclusion, low expression of HSP70 in the gastric mucosa and reduced gastric mucus thickness may play key roles in the mechanism of PUB in extreme cold climates. The significant decrease in barrier factors and increase in damage in extreme cold climates may be associated with the seasonal pattern of peptic ulcers. PMID- 25452788 TI - Adiponectin protects against paraquat-induced lung injury by attenuating oxidative/nitrative stress. AB - The specific mechanisms underlying paraquat (PQ)-induced lung injury remain unknown, which limits understanding of its cytotoxic potential. Although oxidative stress has been established as an important mechanism underlying PQ toxicity, multiple antioxidants have proven ineffective in attenuating the deleterious effects of PQ. Adiponectin, which shows anti-oxidative and antinitrative effects, may have the potential to reduce PQ-mediated injury. The present study determined the protective action of globular domain adiponectin (gAd) on PQ-induced lung injury, and attempted to elucidate the underlying mechanism or mechanisms of action. BALB/c mice were administered PQ, with and without 12 or 36 h of gAd pre-treatment. The pulmonary oxidative/nitrative status was assessed by measuring pulmonary O2*-, superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and 8-hydroxy-2-dydeoxy guanosine (8 OHdG) production, and blood 3-Nitrotyrosine (3-NT). At a dose of 20 mg/kg, PQ markedly increased O2*-, SOD, MDA, NO and 8-OHdG production 3 h post administration, but did not significantly increase 3-NT levels until 12 h. gAd inhibited these changes in a dose-dependent manner, via transient activation of MDA, followed by attenuation of MDA formation from 6 h onwards. Histological analysis demonstrated that gAd decreased interstitial edema and inflammatory cell infiltration. These results suggest that gAd protects against PQ-induced lung injury by mitigating oxidative/nitrative stress. Furthermore, gAd may be a potential therapeutic agent for PQ-induced lung injury, and further pharmacological studies are therefore warranted. PMID- 25452789 TI - Correlation between red blood cell transfusion volume and mortality in patients with massive blood transfusion: A large multicenter retrospective study. AB - This study aimed to explore the correlation between red blood cell (RBC) transfusion volume and patient mortality in massive blood transfusion. A multicenter retrospective study was carried out on 1,601 surgical inpatients who received massive blood transfusion in 20 large comprehensive hospitals in China. According to RBC transfusion volume and duration, the patients were divided into groups as follows: 0-4, 5-9, 10-14, 15-19, 20-24, 25-29, 30-39 and >=40 units within 24 or 72 h. Mortality in patients with different RBC transfusion volumes was analyzed. It was found that patient mortality increased with the increase in the volume of RBC transfusion when the total RBC transfusion volume was >=10 units within 24 or 72 h. Survival analysis revealed significant differences in mortality according to the RBC transfusion volume (chi2=72.857, P<0.001). Logistic regression analysis revealed that RBC transfusion volume is an independent risk factor [odds ratio (OR) = 0.52; confidence interval (CI): 0.43 0.64; P<0.01] for the mortality of patients undergoing a massive blood transfusion. When RBCs were transfused at a volume of 5-9 units within 24 and 72 h, the mortality rate was the lowest, at 3.7 and 2.3% respectively. It is concluded that during massive blood transfusion in surgical inpatients, there is a correlation between RBC transfusion volume within 24 or 72 h and the mortality of the patients. Patient mortality increases with the increase in the volume of RBC transfusion. RBC transfusion volume, the length of stay at hospital and intensive care unit stay constitute the independent risk factors for patient mortality. PMID- 25452790 TI - Tartrate-resistant acid phosphatase 5b is a marker of osteoclast number and volume in RAW 264.7 cells treated with receptor-activated nuclear kappaB ligand. AB - Tartrate-resistant acid phosphatase 5b (TRACP 5b) has been used as a biomarker of bone resorption and cancer metastasis. TRACP 5b has also been suggested to be a reliable marker of osteoclast number. In this study, the correlation of TRACP 5b level and osteoclast-like cell number was investigated in RAW 264.7 cells treated with receptor-activated nuclear factor kappaB ligand (RANKL). RAW 264.7 cells were cultured with alpha-MEM containing RANKL (40 ng/ml) for 3, 5 and 7 days. Osteoclast formation and TRACP 5b levels were determined by TRACP staining, scanning electron microscopy and enzyme-linked immunosorbent assay. The RAW 264.7 cells that were not exposed to RANKL did not secrete TRACP 5b. RANKL induced the RAW 264.7 cells to differentiate into osteoclasts and to secrete TRACP 5b. The TRACP 5b level in the RAW 264.7 cells treated with RANKL was significantly correlated with the number and volume of osteoclasts (r=0.95 and r=0.92, respectively; P<0.0001). TRACP 5b is a good marker of RANKL-induced osteoclast formation in RAW 264.7 cells. TRACP 5b analysis may be used as an alternative to osteoclast counting in vitro. PMID- 25452791 TI - Pulmonary MALT lymphoma: A case report and review of the literature. AB - Mucosa-associated lymphoid tissue (MALT) lymphoma is an extranodal low-grade B cell lymphoma. Pulmonary MALT lymphoma is considered to originate from bronchial MALT and is also referred to as bronchial-associated lymphoid tissue lymphoma. Pulmonary MALT lymphoma is a rare disease, but it is the most frequent subset of primary pulmonary lymphoma. The median age at diagnosis of pulmonary MALT lymphoma is 50-60 years, with only few patients aged <30 years. This is the case report of a 19-year-old patient with pulmonary MALT lymphoma presenting with a multiple pulmonary consolidation pattern on computed tomography scans, who underwent successful chemotherapeutic treatment with a chlorambucil-based regimen. PMID- 25452792 TI - Diagnosis of 65 cases of ampullary renal pelvis after postnatal follow-up of 1,167 newborn infants with prenatally suspected hydronephrosis. AB - The aim of the present study was to assess the morbidity of ampullary renal pelvis (ARP) and document its natural history in post-natal life. A total of 1,167 newborn infants with prenatally suspected hydronephrosis were retrospectively analyzed. Of these, 65 patients were diagnosed with ARP by computed tomography urography (CTU) and/or magnetic resonance urography (MRU). All cases were followed up with ultrasonogrophy at 1, 3, 6 and 12 months after birth, and one case was followed up for 5 years. Changes in the separation of the renal pelvis collection system were recorded. Children with ARP accounted for 5.57% of the total cases (65/1,167) followed-up. No lack of connection between the renal calyces and the renal pelvis was detected. The long-term follow-up revealed that the separation of the renal pelvis collection system did not tend to increase over time. In addition to imaging examinations, long-term follow-up observation is recommended for the accurate diagnosis of pediatric ARP, particularly for differentiation from hydronephrosis. PMID- 25452793 TI - An integrated microfluidic device for screening the effective concentration of locally applied tacrolimus for peripheral nerve regeneration. AB - The effectiveness of tacrolimus (FK506) for the promotion of nerve regeneration is known. However, at present, due to the fact that systemic application may lead to opportunistic infections and tumors, and that the treatment of peripheral nerve injury with systemic immunosuppression is not generally accepted, FK506 has not been widely used for the treatment of simple or peripheral nerve injury. In this study, a pyramid-shaped microfluidic device was designed and fabricated that was able to analyze the effective concentration of locally applied FK506. After testing the effectiveness of the microfluidic device by measuring the fluorescence intensity of fluorescein isothiocyanate-dextran, rat Schwann cells (SCs) were loaded into the device and cultured for 9 days in the presence of different concentrations of FK506. SC proliferation in the presence of FK506 was concentration-dependent between 0 and 2.5+/-0.003 ng/ml. The proliferation rate reached a maximum at 1.786+/-0.014 ng/ml, which was statistically significantly different from the proliferation rate at lower FK506 concentrations. There was no statistically significant difference in the proliferation rate between the 1.786 ng/ml group and groups of higher FK506 concentrations. Furthermore, the SCs in the microfluidic device and a 96-well plate continued to proliferate as the culture time increased. No statistically significant differences were identified between the microfluidic device and a 96-well plate with regard to the proliferation rates in each corresponding group. The results obtained in this study demonstrated that the microfluidic device can be used as an excellent platform for the study of drug concentration at the cellular level, and the effective FK506 concentration for local application is 1.786+/-0.014 ng/ml. PMID- 25452794 TI - Pulmonary tuberculosis with false-positive 18F-fluorodeoxyglucose positron emission tomography mimicking recurrent lung cancer: A case report. AB - Recurrent lung cancer is a common clinical condition. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is currently the predominant non-invasive imaging technique used for the detection of tumor recurrence. In the present study, the case of a 67-year-old male suspected to have postoperative recurrence of primary lung cancer was examined. Chest computed tomography (CT) scans identified a subpleural nodule grown within a short time period, along with the occurrence of multiple patchy shadows on the right lung. PET-CT scans revealed an increased FDG uptake in the surgical site, which exhibited features of a malignant disease. However, a video-assisted thoracoscopic biopsy provided the diagnosis of tuberculosis and guided further appropriate treatment. In conclusion, further evaluation is required in all patients with suspected metastatic and recurrent carcinoma. PMID- 25452795 TI - Efficacy of intravesical Bacillus Calmette-Guerin therapy against tumor immune escape in an orthotopic model of bladder cancer. AB - The aim of this study was to evaluate the antitumor immune response of the Bacillus Calmette-Guerin (BCG) in an orthotopic bladder cancer model. The murine bladder cancer cell line MBT-2 was transurethrally implanted in the bladder of syngeneic female C3H/He mice. The animals were randomly divided into three treatment groups: Phosphate-buffered saline (PBS), low-dose BCG and high-dose BCG. The analyses of luciferin-stained tumor images 28 days after each treatment showed significant tumor growth inhibition in the high-dose group in comparison with that in the low-dose- or PBS-treated groups. In addition, the percentage of myeloid-derived suppressor cells in the high-dose group was significantly suppressed in comparison with that in the PBS and low-dose agent treatment groups. These findings are notable in terms of the clinical evaluations of this therapy for patients with bladder cancer. The outcomes of this study also provide important implications regarding antitumor immune responses in human cancer. PMID- 25452796 TI - Identification of dysregulated miRNAs and their regulatory signature in glioma patients using the partial least squares method. AB - Using microarray data, the present study identified differentially expressed microRNAs (miRNAs) and evaluated their regulatory characteristics in high-grade glioma patients, with the aim to further the understanding into the underlying etiology of the condition. Previously, studies have generally implemented regression or variance analysis, which ignores various background biological factors. However, in the present study, analysis was performed with microarray data collected from the Gene Expression Omnibus database using a partial least squares-based method, which is more sensitive in handling microarray data. Among the six identified differentially expressed miRNAs, hsa-miR-21 and hsa-miR-612 have been previously reported to be associated with glioma. In addition, the remaining miRNAs, hsa-miR-4680, hsa-miR-1908, hsa-miR-4656 and hsa-miR-4467, may also contribute to glioma progression since they are all associated with the tumorigenesis of other types of cancer. Moreover, the expression levels of hsa miR-1908, hsa-miR-4656 and hsa-miR-4680 have been identified to significantly correlate with the survival rate. Enrichment analysis of the dysregulated target genes revealed that the selected miRNAs primarily affect biological processes in the nervous system and the protein phosphorylation process. Therefore, the results may offer a new understanding into the pathogenesis of high-grade glioma. PMID- 25452797 TI - Strontium coating by electrochemical deposition improves implant osseointegration in osteopenic models. AB - Osteopenia, a preclinical state of osteoporosis, restricts the application of adult orthodontic implant anchorage and tooth implantation. Strontium (Sr) is able to promote bone formation and inhibit bone absorption. The aim of the present study was to evaluate a new method for improving the success rate of dental implantation. In this study, an electrochemical deposition (ECD) method was used to prepare a Sr coating on a titanium implant. The coating composition was investigated by energy dispersive X-ray spectroscopy and X-ray diffraction, and the surface morphology of the coating was studied using scanning electron microscopy. A total of 24 Sprague-Dawley rats received bilateral ovariectomy (OVX) and an additional 12 rats underwent a sham surgery. All rats were then implanted in the bilateral tibiae with titanium mini-implants with or without a Sr coating. The results of histological examination and a fluorescence double labeling assay showed strong new bone formation with a wider zone between the double labels, a higher rate of bone mineralization and better osseointegration in the OVX rats that received Sr-coated implants compared with the OVX rats that received uncoated implants. The study indicates that Sr coatings are easily applied by an ECD method, and that Sr coatings have a promoting effect on implant osseointegration in animals with osteopenia. PMID- 25452798 TI - Effect of prazosin on diabetic nephropathy patients with positive alpha1 adrenergic receptor autoantibodies and refractory hypertension. AB - To investigate the effect of prazosin on patients with diabetic nephropathy (DN), alpha1-adrenergic receptor (alpha1-R) autoantibodies and refractory hypertension, a total of 126 patients with DN and hypertension were recruited. The patients were divided into a refractory hypertension group, (n=76) and a non-refractory hypertension group (n=50). The epitope of the second extracellular loop of the alpha1-R (192-218) was synthesized and an enzyme-linked immunosorbent assay (ELISA) was performed to detect serum autoantibodies. In the group with DN associated refractory hypertension, the positive rate of autoantibodies against the alpha1-R was 80.3% (n=61). The 61 patients who were positive for alpha1-R autoantibodies were randomly divided into a treatment group (n=31) and a control group (n=30). The patients were given drugs at the same dosage and administration, with the exception of prazosin, which was provided only to the patients in the treatment group [1 mg, three times a day (tid)] for a duration of six weeks. Subsequently, prazosin was added (1 mg, tid) to the therapeutic schedule of the patients in the control group and the alpha1-R autoantibody negative group for another six weeks. The analysis was carried out on an intention-to-treat basis. The prazosin treatment resulted in significant improvements in hypertension in the treatment group (P<0.05), while there was no marked improvement in the control group. The total effective rate of hypertension improvement was 90.3% in the treatment group, which was higher compared with that of the control group (33.3%). In conclusion, alpha1-R autoantibodies may play an important role in the pathogenesis of DN with refractory hypertension. Prazosin was demonstrated to be effective and safe in the treatment of DN with refractory hypertension. PMID- 25452799 TI - Correlation between ApoE gene polymorphisms and the occurrence of urolithiasis. AB - The aim of the present study was to investigate the correlation between apolipoprotein E (ApoE) gene polymorphisms and the occurrence of urolithiasis and dyslipidemia. A total of 180 Uyghur individuals, including 90 urolithiasis patients and 90 healthy controls, were enrolled in this study. The blood lipid profiles of the patients and controls were investigated and compared, and the composition of the urinary calculi was determined. The polymorphisms of the ApoE alleles were analyzed using polymerase chain reaction-restriction fragment length polymorphism analysis. Three common genotypes of the ApoE gene, E3/3, E3/4 and E4/4, were detected in the urolithiasis patients and control group. In the patient group, 28 patients with the E3/3 genotype (30.1%), 58 patients with the E3/4 genotype (64.4%) and four patients with the E4/4 genotype (4.5%) were identified. By contrast, in the control group, 52 patients with the E3/3 genotype (57.8%), 35 patients with the E3/4 genotype (38.9%) and three patients with the E4/4 genotype (3.3%) were identified. The frequency of the E3/4 genotype was found to be significantly higher in the patient group when compared with the control group (chi2=12.96; P<0.001). In addition, the frequency of the E4 allele was significantly higher in the patient group when compared with the control group (chi2= 6.61; P=0.025). In conclusion, the occurrence of urolithiasis was found to be associated with ApoE gene polymorphisms, and the E4 allele may be a potential susceptibility factor for urolithiasis. PMID- 25452800 TI - Effects of recombinant adeno-associated virus-mediated CD151 gene transfer on the expression of rat vascular endothelial growth factor in ischemic myocardium. AB - The aim of this study was to observe the effects of cluster of differentiation (CD) 151 on the expression of vascular endothelial growth factor (VEGF) in ischemic myocardium by the injection of a recombinant adeno-associated virus (rAAV) vector carrying the human CD151 gene. A rat acute myocardial infarction model was established, and rAAV-CD151 was injected into the ischemic myocardium. Four weeks later, the ischemic myocardium was removed in order to detect the expression of exogenous CD151 mRNA by reverse transcriptase polymerase chain reaction. In addition, the expression of CD151 and VEGF was detected by western blot analysis to evaluate the effect of CD151 overexpression on VEGF expression. Four weeks after injection of the vector, exogenous CD151 mRNA was expressed in the myocardial tissues of the CD151 group, whereas it was not detected in sham surgery, model control or rAAV-green fluorescent protein (GFP) gene-treated groups. The expression levels of CD151 protein were significantly higher in the CD151 group compared with those in the other three groups (P<0.05). The VEGF expression level in the CD151 group was higher compared with those in the control and GFP groups (P>0.05). These results indicate that rAAV-CD151 effectively transfects rat myocardial tissues, and may promote angiogenesis of the ischemic myocardium, improve left ventricular function and increase VEGF expression to improve ventricular function. PMID- 25452801 TI - Effect of kidney-reinforcing and marrow-beneficial traditional Chinese medicine intervened serum on the proliferation and osteogenic differentiation of bone marrow stromal cells. AB - The present study aimed to investigate the effect of kidney-reinforcing and marrow-beneficial traditional Chinese medicine (TCM)-intervened (KRMBTI)-serum on the proliferation and osteogenic differentiation of bone marrow stromal cells (BMSCs) in rats. Rat BMSCs were isolated and cultured in vitro with various concentrations of serum obtained from rats at different time-points following treatment with low, medium and high doses of KRMBT. The alkaline phosphatase (ALP) activity and proliferation of the BMCSs was assessed to determine the optimal serum sampling time-point and serum concentration. Transforming growth factor (TGF)-beta1 expression of the BMSCs was detected using enzyme-linked immunosorbent assay (ELISA), and hepcidin mRNA expression in the rat livers was detected using reverse transcription polymerase chain reaction. The proliferation of BMCSs treated with serum obtained l h after dosing was observed to be significantly higher than that for BMCSs treated with serum obtained at the four other time-points (P<0.05). Furthermore, the proliferation following treatment with 25% KRMBTI-serum was significantly higher than that for the other KRMBTI serum concentrations (P<0.01). For a 25% concentration of the serum collected at l h, the proliferation in the high- and low-dose KRMBTI-serum groups was significantly higher than that of the medium-dose and control groups (P<0.01) and no statistical significance was observed between the high- and low-dose groups. In the osteogenic differentiation process of the high-dose group, the ALP activity at every time-point was significantly higher than that of the low-dose group and the peak value of the former was achieved at concentrations between 20 and 30%. KRMBTI-serum was shown to promote the expression of TGF-beta1. Furthermore, hepcidin was observed to be expressed at significantly higher levels in the high-dose group than in the control group, and hepcidin expression was significantly higher after 10 weeks compared with that after five weeks. These findings suggest that KRMBTI-serum increases TGF-beta1 and hepcidin expression levels, which may be the mechanism underlying the promotion of osteogenic differentiation induced by KRMBTI-serum in BMSCs. PMID- 25452802 TI - A retrospective analysis of the clinicopathological characteristics of large cell carcinoma of the lung. AB - The aim of the present study was to analyze and summarize the clinicopathological characteristics of large-cell lung carcinoma (LCLC) of the lung, in order to improve the definite diagnosis rate of LCLC. Clinicopathological data of 174 patients with LCLC, confirmed pathologically, were retrospectively reviewed. The 174 cases of LCLC accounted for 5.7% of the total lung cancer cases during the corresponding time period at the Affiliated Cancer Hospital of Tianjin Medical University (Tianjin, China), among which there were 131 males and 43 females with an average age of 61.4 years. The postoperative pathological diagnosis of the 174 cases showed 80 cases of classic LCLC, 64 cases of large cell neuroendocrine carcinoma (LCNEC), six cases of combined LCNEC, 19 cases of basaloid carcinoma, three cases of clear cell carcinoma and two cases of lymphoepithelioma-like carcinoma. Of the total 174 LCLC cases, 96 patients exhibited lymph node metastasis. LCLC is a highly aggressive malignancy with a high tendency of invasion and metastasis, although the incidence rate is low. A definite diagnosis of LCLC primarily relies on the pathological diagnosis. Each subtype of LCLC has its own pathomorphological and immunohistochemical characteristics. PMID- 25452803 TI - Expression of human DNA mismatch-repair protein, hMSH2, in patients with oral lichen planus. AB - hMSH2 is one of the human DNA mismatch repair genes that plays an important role in reducing mutations and maintaining genomic stability. The aim of the present study was to detect the expression and significance of hMSH2 protein in patients with oral lichen planus (OLP). The expression levels of hMSH2 in the OLP group (n=51) and control group with normal oral mucosa (NM; n=40) were detected using an immunohistochemical method and subsequently assessed. The positive rate of hMSH2 expression in the OLP group was 52.94%, while the rate was 80% in the control group, exhibiting a statistically significant difference (chi2=7.1993; P<0.05). However, the expression of hMSH2 in the OLP tissues was not shown to significantly correlate with the patient gender, age and type of OLP (P>0.05). In conclusion, the protein expression levels of hMSH2 in the OLP tissues were significantly reduced as compared with that in the NM tissues, indicating that hMSH2 plays a role in the development of OLP. Therefore, hMSH2 may be used as a biomarker for evaluating the cancer risk of patients with OLP. PMID- 25452804 TI - 3-Tesla magnetic resonance imaging improves the prostate cancer detection rate in transrectral ultrasound-guided biopsy. AB - The detection rate of prostate cancer (PCa) using traditional biopsy guided by transrectal ultrasound (TRUS) is not satisfactory. The aim of this study was to determine the utility of 3-Tesla (3-T) magnetic resonance imaging (MRI) prior to TRUS-guided prostate biopsy and to investigate which subgroup of patients had the most evident improvement in PCa detection rate. A total of 420 patients underwent 3-T MRI examination prior to the first prostate biopsy and the positions of suspicious areas were recorded respectively. TRUS-guided biopsy regimes included systematic 12-core biopsy and targeted biopsy identified by MRI. Patients were divided into subgroups according to their serum prostate-specific antigen (PSA) levels, PSA density (PSAD), prostate volume, TRUS findings and digital rectal examination (DRE) findings. The ability of MRI to improve the cancer detection rate was evaluated. The biopsy positive rate of PCa was 41.2% (173/420), and 41 of the 173 (23.7%) patients were detected only by targeted biopsy in the MRI suspicious area. Compared with the systematic biopsy, the positive rate was significantly improved by the additional targeted biopsy (P=0.0033). The highest improvement of detection rate was observed in patients with a PSA level of 4-10 ng/ml, PSAD of 0.12-0.20 ng/ml2, prostate volume >50 ml, negative TRUS findings and negative DRE findings (P<0.05). Therefore, it is considered that 3-T MRI examination could improve the PCa detection rate on first biopsy, particularly in patients with a PSA level of 4-10 ng/ml, PSAD of 0.12-0.20 ng/ml2, prostate volume of >50 ml, negative TRUS findings and negative DRE findings. PMID- 25452806 TI - Serine/threonine kinase 15 gene polymorphism and risk of digestive system cancers: A meta-analysis. AB - Previous studies have reported an association between the two coding polymorphisms (91T>A and 169G>A) of the serine/threonine kinase 15 (STK15) gene and the risk of digestive system cancers; however, the results are inconsistent. In the present study, a meta-analysis was carried out to assess the association between the two STK15 polymorphisms and the risk of digestive system cancers. Relevant studies were identified using PubMed, Web of Science, China National Knowledge Infrastructure, WanFang and VIP databases up to February 18, 2014. The pooled odds ratio (OR) with a 95% confidence interval (CI) was calculated using the fixed or random effects model. A total of 15 case-control studies from 14 publications were included. Of these, 15 studies concerned the 91T>A polymorphism and included 7,619 cases and 7,196 controls and four studies concerned the 161G>A polymorphism and included 826 cases and 713 controls. A significantly increased risk of digestive system cancers was observed for the 91T>A polymorphism (recessive model: OR, 1.19; 95% CI, 1.07-1.31). In subgroup analysis by ethnicity, a significant association was detected in Asian populations (recessive model: OR, 1.21; 95% CI, 1.08-1.36) but not in Caucasian and mixed populations. Stratification by tumor type indicated that the 91T>A polymorphism was associated with an increased risk of esophageal and colorectal cancers under the recessive model (OR, 1.19; 95% CI, 1.03-1.38; and OR, 1.24; 95% CI, 1.04-1.46; respectively); however, no significant association was observed between the 169G>A polymorphism and the risk of digestive system cancers in any of the genetic models. Furthermore, in subgroup analysis by ethnicity, similar results were observed in the Asian and Caucasian populations. The present meta-analysis demonstrated that the STK15 gene 91T>A polymorphism, but not the 169G>A polymorphism, may be a risk factor for digestive system cancers, particularly for esophageal and colorectal cancers. PMID- 25452805 TI - Effect of epigallocatechin-3-gallate on proliferation and phenotype maintenance in rabbit articular chondrocytes in vitro. AB - In autologous chondrocyte implantation (ACI) to restore defective cartilage, limited cell numbers and dedifferentiation of chondrocytes are the major difficulties. An alternative is the use of growth factors, but their high cost and potential for tumorigenesis are major obstacles. To ensure successful ACI therapy, it is important to find an effective substitute pro-chondrogenic agent. Epigallocatechin-3-gallate (EGCG), one of the green tea catechins, has been widely investigated in studies of interleukin-1beta-induced chondrocytes. In the present study, the effects of EGCG on rabbit articular chondrocytes were investigated through the examination of cell proliferation, morphology, glycosaminoglycan synthesis and cartilage-specific gene expression. The results showed that EGCG could effectively promote chondrocyte growth and enhance the secretion and synthesis of the cartilage extracellular matrix by upregulating expression levels of aggrecan, collagen II and Sox9 genes. Expression of the collagen I gene was downregulated, which showed that EGCG effectively inhibited the dedifferentiation of chondrocytes. Hypertrophy, which may lead to chondrocyte ossification, was also undetectable in the EGCG groups. In conclusion, the recommended dose of EGCG was found to be in the range of 5 to 20 MUM, with the most marked response observed with 10 MUM. The present study may provide a basis for the development of a novel agent as a substitute for growth factors in the treatment of articular cartilage defects. PMID- 25452807 TI - Expression and significance of transforming growth factor-beta receptor type II and DPC4/Smad4 in non-small cell lung cancer. AB - The aim of the present study was to investigate the expression levels of transforming growth factor-beta (TGF-beta) receptor type II (TbetaRII) and DPC4/Smad4 in the TGF-beta signaling pathway and the importance of these expression levels in non-small cell lung cancer (NSCLC). The mRNA and protein expression levels of TbetaRII and DPC4/Smad4 were detected by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively, in NSCLC and control nonlesional lung tissues of 60 patients. The protein expression levels of DPC4/Smad4 were detected by immunohistochemistry in paraffin-embedded samples of NSCLC. In addition, the correlations among the expression levels of TbetaRII and DPC4/Smad4 and their association with the clinical and pathological features of NSCLC were analyzed. The expression levels of TbetaRII and DPC4/Smad4 in NSCLC tissues were significantly lower when compared with the control nonlesional lung tissues (P<0.05). In addition, the expression of TbetaRII and DPC4/Smad4 in poorly-differentiated NSCLC tissues was significantly lower compared with moderately- or well-differentiated NSCLC tissues (P<0.05). The expression levels of TbetaRII and DPC4/Smad4 were significantly lower in NSCLC tissues with metastatic lymph nodes compared with tissue without metastatic lymph nodes (P<0.05). Thus, the expression levels were demonstrated to significantly correlate with the clinical and pathological stages, and subsequently were shown to be associated with the occurrence and progression of NSCLC. In conclusion, TbetaRII and DPC4/Smad4 may play an important role in the tumorigenesis, differentiation and progression of NSCLC via the TGF-beta signaling pathway. PMID- 25452808 TI - Clinical diagnostic utility of CA 15-3 for the diagnosis of malignant pleural effusion: A meta-analysis. AB - Malignant pleural effusion (MPE) is one of the most common pleura-associated conditions observed in clinical practice. The development of MPE usually defines advanced cancer with a poor prognosis. Carbohydrate antigen 15-3 (CA 15-3), as an effective pleural fluid biomarker, has been an object of ongoing research in the detection of MPE. The aim of this meta-analysis was to establish the overall diagnostic accuracy of the measurement of pleural CA 15-3 for diagnosing MPE. The databases Medline (using PubMed as the search engine), Embase, Ovid, Web of Science and Cochrane database (up to December 2013) were searched to identify relevant studies. No lower date limit was applied. All literature published in English was reviewed. Sensitivity, specificity, likelihood ratio and diagnostic odds ratio (DOR) were pooled using a random-effect model. Summary receiver operating characteristic (SROC) curve analysis was conducted to evaluate the overall diagnostic value. The methodological quality was assessed in line with the Quality Assessment for Studies of Diagnostic Accuracy statement. Twenty-one studies with a total of 2,861 cases were included in present meta-analysis. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and DOR of CA 15-3 in the diagnosis of MPE were 0.58 [95% confidence interval (CI), 0.56-0.61], 0.91 (95% CI, 0.90-0.93), 8.93 (95% CI, 4.45-17.93), 0.46 (95% CI, 0.37-0.56) and 24.89 (95% CI, 10.39-59.63), respectively. In addition, the area under the curve (AUC) was 0.84. In conclusion, due to the significantly high specificity of pleural CA 15-3 in detecting MPE, it may play a pivotal role in screening to identify patients who may benefit from further invasive pathologic examination, particularly in those presenting clinical manifestations of MPE but with negative cytological findings of the pleural fluid. However, ruling out MPE by testing CA15-3 alone is not recommended due to its limited sensitivity, and it is recommended that the results of CA15-3 assays are interpreted in parallel with conventional test results and other clinical findings. PMID- 25452809 TI - Protease-activated receptor 2 agonist increases cell proliferation and invasion of human pancreatic cancer cells. AB - The aim of this study was to determine the expression of protease-activated receptor 2 (PAR-2) in the human pancreatic cancer cell line SW1990, and to evaluate its effect on cell proliferation and invasion. The expression of PAR-2 protein and mRNA in SW1990 cells was determined by immunocytochemistry and reverse transcription polymerase chain reaction (PCR), respectively. MTT and cell invasion and migration assays, as well as semi-quantitative PCR and zymography analysis, were additionally performed. PAR-2 mRNA was significantly upregulated in the cells treated with trypsin or the PAR-2 activating peptide Ser-Leu-Ile-Gly Lys-Val (SLIGKV) (P<0.01), but not in the Val-Lys-Gly-Ile-Leu-Ser group (P>0.05). Trypsin and SLIGKV significantly promoted SW1990 cell proliferation in a dose- and time-dependent manner (P<0.05). Compared with the control group, trypsin and SLIGKV significantly increased the mRNA expression (P<0.01) and gelatinolytic activity (P<0.01) of matrix metalloproteinase (MMP)-2. In conclusion, PAR-2 is expressed in SW1990 cells. PAR-2 activation may promote the invasion and migration of human pancreatic cancer cells by increasing MMP-2 expression. PMID- 25452810 TI - Evaluation of the promoter region polymorphism (5-HTTLPR) in the serotonin transporter gene in females with postpartum depression. AB - The aim of the present study was to investigate the association between polymorphism in the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) in the promoter region of the 5-HTT gene and the pathogenesis of postpartum depression (PPD). Blood samples were collected from 120 female patients with PPD and 140 age-matched normal controls. Polymerase chain reaction analysis was performed to detect the 5-HTTLPR polymorphism in these subjects, and the genotype and allele frequencies were compared between the two groups. The disease severity was evaluated using the Hamilton Depression Rating Scale (HAMD) score. The results showed that the frequency of the homozygous long/long (L/L) genotype was significantly lower in the PPD group than that in the control group; by contrast, the frequencies of the heterozygous long/short (L/S) and homozygous S/S genotypes were similar for the two groups, without significant differences. No significant differences were observed in the L and S allele frequencies between the two groups. Furthermore, compared with the L/S heterozygous and S/S homozygous genotypes, patients with PPD with the L/L homozygous genotype had a significantly lower HAMD score. The present results suggest that female patients with PPD carrying the homozygous L/L genotype may be less susceptible to depressive symptoms and that the L/L genotype may be associated with the reduced occurrence of PPD. These findings provide a theoretical basis for the clinical diagnosis and treatment of PPD. PMID- 25452811 TI - T lymphocyte subset imbalances in patients contribute to ankylosing spondylitis. AB - Ankylosing spondylitis is a chronic inflammatory rheumatic disease, which is characterized by inflammation of the spine and the sacroiliac joints. To date, the disease etiology remains unclear. In the present study, the correlation of T lymphocyte subset changes with the progression of ankylosing spondylitis was investigated. A total of 55 patients with ankylosing spondylitis (22 severe and 23 mild cases) and 20 healthy individuals were selected. Firstly, the punctured cells in the lesions and the serum were collected, and the lymphocytes and the peripheral blood mononuclear cells were prepared. Secondly, quantitative PCR, ELISA and flow cytometry analyses were carried out to detect the levels of a series of immunoglobulins, complements, helper T cells, cytotoxic T cells, regulatory cells and cytokines. The expression levels of alpha-globulin, gamma globulin, immunoglobulin (Ig)G, IgA, IgM, serum complement C3, and complement C4 were found to be significantly increased in ankylosing spondylitis patients. In addition, the percentage of Th1 and Th17 cells was found to be significantly higher in the ankylosing spondylitis groups (mild and severe) compared with the healthy individuals. As a result, the Th1/Th2 and Th17/Treg ratios were significantly higher in patients with ankylosing spondylitis. In addition, T lymphocyte subset ratio imbalances contributed to an increased expression of immune mediators, including interferon (IFN)-gamma and interleukin (IL)-17A. The mRNA and protein expression levels of IFN-gamma and IL-17A were found to be higher in the ankylosing spondylitis groups compared with the control group. The present study provided further evidence on the function and underlying mechanism of T lymphocyte subsets, which may be useful in the diagnosis and treatment of ankylosing spondylitis. PMID- 25452812 TI - Inhibitory effect of Puerariae radix flavones on platelet-derived growth factor BB-induced proliferation of vascular smooth muscle cells via PI3K and ERK pathways. AB - Abnormal proliferation of vascular smooth muscle cells (VSMCs) results in intimal thickening of the aorta, which may lead to arteriosclerosis. Therefore, VSMC antiproliferative agents may be efficient in the prevention and treatment of arteriosclerosis. Puerariae radix (PR) is the dried root of Pueraria lobata Ohwi or Pueraria thomsonii Benth. Flavones are the main components of PR and have been shown to have a protective effect on vascular disorders in traditional Chinese medicine treatments. However, the underlying molecular mechanism remains unclear. The aim of the present study was to explore the effect of PR flavone (PRF) on platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation. PDGF-BB (25 ng/ml) and different doses of PRF (10, 50, 100 and 200 ng/ml) were used to treat VSMCs. The results revealed that PRF notably inhibited the PDGF-BB-induced VSMC proliferation and induced a cell cycle arrest at growth 1 phase of the cell cycle. In addition, cell cycle-associated proteins, including cyclin D1, proliferating cell nuclear antigen and cyclin-dependent kinase 4, were found to be downregulated. Furthermore, PRF inhibited the PDGF-BB-stimulated downregulation of VSMC markers, including alpha-smooth muscle actin, desmin and smoothelin. PDGF-BB upregulated the phosphorylation levels of phosphatidylinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK), which are associated with cell proliferation; however, these were decreased following PRF treatment. These observations indicated that PRF had a suppressive effect on PDGF-BB-induced VSMC proliferation by inhibiting PI3K and ERK pathways. PMID- 25452813 TI - Computed tomography-guided cutting needle pleural biopsy: Accuracy and complications. AB - In cases of pleural lesion, tissue samples can be obtained through thoracoscopy or closed needle biopsy for histopathological analysis. Cutting needle biopsy is a relatively recent addition to these techniques. The aim of this study was to evaluate the diagnostic accuracy and safety of computed tomography-guided cutting needle pleural biopsy (CT-CNPB), as well as the associated complications, in patients with pleural lesion. This study was a retrospective analysis of 92 percutaneous CT-CNPBs on 90 patients between March 2008 and May 2013. For group comparisons, chi2 tests were used to detect the risk factors for diagnostic accuracy (false-negative rate). Of the 92 CT-CNPBs, malignant lesions were diagnosed in 55 cases (mesothelioma in 12, metastatic pleural disease in 36, synoviosarcoma in one, indeterminate-origin disease in one and false-negative lesion in five) and benign pleural disease was diagnosed in 37 cases (inflammation in 15, tuberculosis in 10, granuloma in three, solitary fibrous tumor in two, hematoma in one, fungus in one and indeterminate-origin disease in five). The sensitivity of diagnostic malignant lesion was 90.9%, and the specificity and positive and negative predictive values were 100, 100 and 88.1%, respectively. The overall diagnostic accuracy was 94.6%. A specific diagnosis was achieved in 89.1% of malignant lesions and 86.4% of benign lesions. Univariate analysis of the risk factors affecting accuracy (false-negative rate) did not reveal any significant differences (all P>0.05). The complication rates were 6.5% for pneumothorax, 8.7% for hemorrhage and 1.1% for hemothorax. In conclusion, CT CNPB is a safe and accurate diagnostic technique that can be recommended as the primary method of diagnosis in patients with pleural thickening or lesions observed by CT scan. PMID- 25452814 TI - Risk factors for clopidogrel resistance in patients with ischemic cerebral infarction and the correlation with ABCB1 gene rs1045642 polymorphism. AB - The aim of the present study was to examine clopidogrel resistance (CR) in patients with ischemic cerebral infarction and its potential association with a single nucleotide polymorphism (SNP; rs1045642) in the ABCB1 gene. Patients with ischemic cerebral infarction received clopidogrel (75 mg/day) for 7 days and were then subjected to a turbidimetric assay to determine platelet aggregation. Patients were then divided into a CR group and a clopidogrel-sensitive (CS) group. Demographic and clinical data between the two groups were compared. Multivariate logistic regression analysis was performed to determine independent risk factors of CR. PCR products were sequenced to assess ABCB1 rs1045642 SNP genotype and allele frequencies in each group. In total, 303 patients were enrolled in the study; this included 51 CR cases (16.83%) and 252 CS cases (83.17%). Several parameters, including hypertension, diabetes, calcium channel blocker (CCB), beta-receptor blocking agent and proton pump inhibitor use, and creatinine, fasting blood glucose, homocysteine (HCY), high-sensitivity C reactive protein (hs-CRP) and triglyceride levels were significantly higher in the CR group than in the CS group. Diabetes, hs-CRP-increased use of CCBs, and use of beta-blockers were found to be independent risk factors for CR. However, ABCB1 gene rs1045642 polymorphism was not found to be an independent risk factor for CR. In conclusion, CR in ischemic stroke patients is associated with several independent risk factors, including diabetes, hs-CRP-increased use of CCBs, and use of beta-blockers. However, ABCB1 gene rs1045642 polymorphism has no correlation with CR. PMID- 25452815 TI - Preventive effect of Lactobacillus fermentum Lee on activated carbon-induced constipation in mice. AB - The aim of this study was to investigate the effects of Lactobacillus fermentum Lee (LF-Lee) on activated carbon-induced constipation in ICR mice. ICR mice were orally administered lactic acid bacteria for nine days. Body weight, dietary and water intake, defecation status, gastrointestinal (GI) transit and defecation time, as well as levels of motilin (MTL), gastrin (Gas), endothelin (ET), somatostatin (SS), acetylcholinesterase (AChE), substance P (SP) and vasoactive intestinal peptide (VIP) in serum were measured to evaluate the preventive effects of LF-Lee on constipation. Bisacodyl, a laxative drug, was administered as a positive control. The time taken until the first defecation of a black stool for normal, control, bisacodyl- (100 mg/kg, oral administration), Lactobacillus bulgaricus (LB)-, LF-Lee low dose (L)- and LF-Lee high dose (H)-treated mice was 90, 218, 117, 180, 161 and 151 min, respectively. Following the consumption of LB, LF-Lee (L) or LF-Lee (H), or the oral administration of bisacodyl, the GI transit was reduced to 55.2, 65.8, 73.1 and 94.6%, respectively, of the transit in normal mice. The serum levels of MTL, Gas, ET, AChE, SP and VIP were significantly increased and those of SS were reduced in the mice treated with LF Lee compared with those in the untreated control mice (P<0.05). These results demonstrate that lactic acid bacteria have preventive effects on constipation in mice and that LF-Lee has superior functional activity. PMID- 25452817 TI - Welcome to the December 2014 Issue of the IJTMB. PMID- 25452818 TI - This Issue's Trigger Points Call for Discussion: Hypertonicity of the Quadratus Lumborum Muscle. PMID- 25452816 TI - Clinical significance of epigenetic silencing and re-expression of O6 methylguanine-DNA methyltransferase using epigenetic agents in laryngeal carcinoma. AB - The aim of the present study was to investigate the association between O6 methylguanine-DNA methyltransferase (MGMT) gene expression levels, and DNA methylation status and histone modifications in laryngeal squamous cell carcinoma (LSCC). Chromatin immunoprecipitation, methylation-specific polymerase chain reaction (PCR), and reverse transcription-quantitative PCR were performed to analyze histone modifications, DNA methylation status and mRNA expression levels in the promoter region of the MGMT gene in laryngeal carcinoma HEp-2 cells, as well as in 50 paired healthy and LSCC tissue samples. The present study demonstrated that treatment of HEp-2 cells with 5-aza-2'-deoxycytidine (Aza), a DNA methyltransferase inhibitor, significantly upregulated MGMT mRNA expression levels, reduced MGMT DNA methylation, reduced MGMT histone H3 lysine 9 (H3K9) di methylation, and increased MGMT histone H3 lysine 4 di-methylation without a significant change in H3K9 acetylation. Trichostatin A (TSA), a histone deacetylase inhibitor, marginally upregulated MGMT mRNA expression levels without affecting the DNA methylation status, or H3K9 or H3K4 di-methylation, however, TSA treatment caused a significant increase in H3K9 acetylation. Furthermore, Aza and TSA combination treatment produced a synergistic effect. In the LSCC samples, the rate of DNA methylation in the MGMT gene was 54%, compared with 24% in the healthy control group (P<0.05). Therefore, data from the present study indicates that MGMT may serve as a novel therapeutic target in the treatment of LSCC. PMID- 25452819 TI - Case report: the effects of massage therapy on a woman with thoracic outlet syndrome. AB - INTRODUCTION: Thoracic outlet syndrome (TOS) refers to a group of conditions resulting from compression of the neurovascular structures of the thoracic outlet. The parameters for physical therapy include myofascial release (MFR), neuromuscular therapy (NMT), muscle strengthening, and stretching. This case study examined the effects of neuromuscular therapy, massage, and other manual therapies on a 56-year-old female presenting with bilateral numbness over the forearms and hands on waking. Numbness occurred most days, progressing to "dead rubbery" forearms and hands once or twice a month. METHODS: The treatment plan was implemented over eight weeks and consisted of six, 50-minute bodywork sessions. Several nonbodywork strategies were also employed to address potential contributing factors to the TOS symptomology experienced by the client. Objective measurements included posture analysis (PA), range of movement (ROM), and Roos and Adson's tests. The Measure Your Own Medical Outcome Profile (MYMOP2), a client-generated measure of clinical outcome, was used to measure clinical change. RESULTS: MYMOP2 overall profile score results demonstrated an improvement of 2.25 from pretreatment to post-treatment measurement. Clinically meaningful change was measured by the individual and was indicative of substantial symptom improvement where a score change of over one was considered as meaningful. CONCLUSIONS: A course of massage was effective for numbness symptoms in an individual with TOS, and results lasted over a year without additional treatments. Further research is needed to fully understand the effects of massage for TOS symptoms. PMID- 25452820 TI - Negotiating consent: exploring ethical issues when therapeutic massage bodywork practitioners are trained in multiple therapies. AB - INTRODUCTION: Obtaining informed consent from competent patients is essential to the ethical delivery of health care, including therapeutic massage and bodywork (TMB). The informed consent process used by TMB practitioners has not been previously studied. Little information is available about the practice of informed consent in a treatment-focused environment that may involve multiple decision points, use of multiple TMB therapies, or both. METHODS: As part of a larger study on the process of providing TMB therapy, 19 practitioners were asked about obtaining informed consent during practice. Qualitative description was used to analyze discussions of the consent process generally, and about its application when practitioners use multiple TMB therapies. RESULTS: Two main consent approaches emerged, one based on a general consent early in the treatment process, and a second ongoing consent process undertaken throughout the course of treatment. Both processes are constrained by how engaged a patient wants to be, and the amount of information and time needed to develop a truly informed consent. CONCLUSIONS: An understanding-based consent process that accommodates an acknowledged information differential between the patient and practitioner, and that is guided by clearly delineated goals within a trust-based relationship, may be the most effective consent process under the conditions of real practice conditions. PMID- 25452821 TI - Zen shiatsu: a longitudinal case study measuring stress reduction in a child with autism spectrum disorder. AB - INTRODUCTION: Autism Spectrum Disorder (ASD) is a developmental disability that manifests as impairments in social interaction, communication, and behavior. OBJECTIVE: The objective of this study is to determine if Zen Shiatsu can reduce short- and long-term stress levels in a child with ASD. METHODS: This is a longitudinal case study of a seven-year-old male with a diagnosis of autism who was given 20-min Zen Shiatsu sessions weekly for six consecutive weeks. Using a five-point stress scale designed for children with autism, the client indicated his stress level before and after each session. In addition, the parent was given the PEDS QL 4.0 Young Child Questionnaire to determine the child's HRQoL (Health Related Quality of Life) prior to Zen Shiatsu treatment to establish a baseline. The parent completed the same questionnaire after six weeks of sessions to compare results. RESULTS: Based on the five-point pictorial stress scale, data collected before and after each Zen Shiatsu session indicated a decrease in stress levels after treatment. The PEDS QL 4.0 showed higher HRQoL scores in all domains, indicating that the child's overall quality of life improved within the six weeks of receiving Zen Shiatsu. CONCLUSIONS: Zen Shiatsu, a Japanese modality based on traditional Chinese medicine, provided meaningful and positive benefits for a child with autism. This case study offers preliminary evidence for the possibility of Zen Shiatsu providing a viable complementary therapy for alleviating stress in children with Autism Spectrum Disorder, thereby potentially improving the overall health-related quality of life. PMID- 25452822 TI - The future of medical care for older adults in Canada. PMID- 25452823 TI - Geriatric Psychiatry: What's in a Name, and Five Concerns about DSM-5. PMID- 25452824 TI - Emergency department utilization by older adults: a descriptive study. AB - BACKGROUND: Emergency Departments (EDs) are playing an increasingly important role in the care of older adults. Characterizing ED usage will facilitate the planning for care delivery more suited to the complex health needs of this population. METHODS: In this retrospective cross-sectional study, administrative and clinical data were extracted from four study sites. Visits for patients aged 65 years or older were characterized using standard descriptive statistics. RESULTS: We analyzed 34,454 ED visits by older adults, accounting for 21.8% of the total ED visits for our study time period. Overall, 74.2% of patient visits were triaged as urgent or emergent. Almost half (49.8%) of visits involved diagnostic imaging, 62.1% involved lab work, and 30.8% involved consultation with hospital services. The most common ED diagnoses were symptom- or injury-related (25.0%, 17.1%. respectively). Length of stay increased with age group (Mann Whitney U; p < .0001), as did the proportion of visits involving diagnostic testing and consultation (chi(2); p < .0001). Approximately 20% of older adults in our study population were admitted to hospital following their ED visit. CONCLUSIONS: Older adults have distinct patterns of ED use. ED resource use intensity increases with age. These patterns may be used to target future interventions involving alternative care for older adults. PMID- 25452825 TI - Exploring the Realities of Curriculum-by-Random-Opportunity: The Case of Geriatrics on the Internal Medicine Clerkship Rotation. AB - BACKGROUND: While major clerkship blocks may have objectives related to specialized areas such as geriatrics, gay and lesbian bisexual transgender health, and palliative care, there is concern that teaching activities may not attend sufficiently to these objectives. Rather, these objectives are assumed to be met "by random opportunity".((1)) This study explored the case of geriatric learning opportunities on internal medicine clinical teaching units, to better understand the affordances and limitations of curriculum by random opportunity. METHODS: Using audio-recordings of morning case review discussions of 13 patients > 65 years old and the Canadian geriatric core competencies for medical students, we conducted a content analysis of each case for potential geriatric and non geriatric learning opportunities. These learning opportunities were compared with attendings' case review teaching discussions. The 13 cases contained 40 geriatric related and 110 non-geriatric-related issues. While many of the geriatric issues (e.g., delirium, falls) were directly relevant to the presenting illness, attendings' teaching discussions focused almost exclusively on non-geriatric medical issues, such as management of diabetes and anemia, many of which were less directly relevant to the reason for presenting to hospital. RESULTS: The authors found that the general medicine rotation provides opportunities to acquire geriatric competencies. However, the rare uptake of opportunities in this study suggests that, in curriculum-by-random-opportunity, presence of an opportunity does not justify the assumption that learning objectives will be met. CONCLUSIONS: More studies are required to investigate whether these findings are transferrable to other vulnerable populations about which undergraduate students are expected to learn through curriculum by random opportunity. PMID- 25452826 TI - Making our health and care systems fit for an ageing population: considerations for Canada. AB - A report from the United Kingdom on making health and care systems fit for an ageing population proposes a range of interventions to make care better for older adults, especially those who are frail. Here, we discuss the proposed shift for the acute care hospital to other models of care. The key for these models of care requires a fundamental shift to care that addresses the full range of an individual's needs, rather than being based around single diseases. How this might apply in the Canadian context is considered. We emphasize strategies to keep people out of hospital but still receive needed care, make acute hospital care less hazardous, and improve the interface between acute and long-term care. PMID- 25452827 TI - Re: making health and care systems fit for and ageing population. Why we wrote it, who we wrote it for, and how relevant it might be to Canada. AB - In response to the commentary((1)) in this month's Canadian Geriatrics Journal by Andrew and Rockwood on the recent paper I co-wrote with King's Fund colleagues "Making Health and Care Systems Fit for an Ageing Population"((2))-I wanted to pen a very personal response, not least because of my visits to health systems in Ontario and Alberta and conversations with many Canadian colleagues that are fresh in my mind. The paper was certainly the most important and influential thing I have written, and was an attempt to weave all the elements of good practice in health care for older people into one overarching narrative. Whilst its biggest target audience is UK health services, I hope it has some relevance to Canada and might stimulate some constructive conversations. PMID- 25452828 TI - Sexual dysfunction in married women with Systemic Sclerosis. AB - INTRODUCTION: Sexuality is an often neglected area in patients with rheumatic disease. The aim of this study is to assess sexual functioning and quality of life in a group of married women with Systemic Sclerosis (SSc). METHODS: This is a horizontal study for descriptive and analytical purposes. Married women with SSc were interviewed about their sexual functioning and their quality of life. RESULTS: A total of ten patients who met the criteria have accepted to participate to the study. Their mean age was 52, 4+/- 8,2 years. Eight women thought that the disease had affected their sexual activity. All patients reported a decrease in the frequency of intercourse since the onset of their disease. Eight of the sample reported a diminished desire for a sexual relationship. The reasons were fatigue, altered body image and pain. The assessment of sexual functioning using the Female sexual function index (FSFI) showed a mean FSFI score at 14,2+/-7,8 with nine women scoring in the range associated with sexual dysfunction (SD) (<26). All the subscales were affected. Our patients reported a mean total score on WHOQOL-brief (World Health Quality of Life-Brief Version) of 60 out of 120 indicating a moderate altered quality of life. Depression has been identified as determinants of impaired sexual function. CONCLUSION: The prevalence of SD in women with SSc is high when a specific questionnaire is used to assess it. These results indicate that in daily practice, inquiring about sexuality and screening for depressive symptoms is indicated for every patient with SSc. PMID- 25452829 TI - [Post-traumatic fat embolism syndrome]. PMID- 25452830 TI - [Pelvic mass in a young girl: think of hematocolpos]. PMID- 25452831 TI - [Liver biopsy in Dakar: indications, complications and diagnostic contribution- about 70 cases]. PMID- 25452832 TI - [Rare cause of decrease in visual acuity in pregnancy]. PMID- 25452833 TI - Baseline demographic, clinical and immunological profiles of HIV-infected children at the Yaounde Gynaeco-Obstetric and Pediatric hospital, Cameroon. AB - INTRODUCTION: Approximately 2.5 million children below 15 years are infected with the HIV virus, with 90% in sub-Saharan Africa. The Yaounde Gynaeco-obstetric and Pediatric hospital has been a treatment center for HIV since 2006. The aim of this study was to analyze the baseline demographic, clinical and immunologic characteristics of the children with the HIV infection in this hospital. METHODS: It was a retrospective, cross- sectional and analytic study, carried out between January and April 2011 which included 61 HIV positive children aged 0-15 years. The socio-demographic, clinical and immunologic data were obtained from their medical records. RESULTS: Most (52.5%) of the children studied were above 60 months of age with a mean age of 71 months. Most (57.4%) were females. Mother-to child transmission was the principal mode of contamination in 88.5% of cases. More than half of their mothers (55.7%) did not receive antiretroviral prophylaxis during pregnancy and labor. Common clinical findings included prolonged fever (44.6%), malnutrition (37.6%), lymphadenopathy (34.4%), respiratory tract infections (34.4%) and diarrhea (24.5%). Diagnosis was confirmed by HIV serology for most of the patients (93.4%). Polymerase chain reaction served as method of diagnosis in only 6.6% of the cases. HIV 1 was the predominant viral type. More than half of the children (52.5%) were seen at an advanced stage of the disease. CONCLUSION: HIV screening during pregnancy and prevention of mother-to-child transmission should be reinforced in this context, and fathers of HIV-infected children should be encouraged to go for HIV testing. PMID- 25452835 TI - Post-traumatic cavernous hemangioma of the frontal cranial vault. PMID- 25452834 TI - Survival status of hiv positive adults on antiretroviral treatment in Debre Markos Referral Hospital, Northwest Ethiopia: retrospective cohort study. PMID- 25452836 TI - [Immunization coverage and factors associated with drop-out in children 12 to 23 months in Djoungolo-Cameroon Health District in 2012]. PMID- 25452837 TI - Caecal volvulus in an adolescent African male: a case report and brief review of the literature. AB - Caecal volvulus is an infrequent clinical condition caused by an axial twist of ascending colon, caecum and terminal ileum around the mesenteric pedicle. This article presents the case of a 16-year old African male from Kenya who presented to the emergency department with acute onset right sided lower abdominal pain diagnosed intra-operatively as caecal volvulus. The rare nature of the condition, the need for a high index of suspicion and surgical management are highlighted. PMID- 25075301 TI - Data publication consensus and controversies. AB - The movement to bring datasets into the scholarly record as first class research products (validated, preserved, cited, and credited) has been inching forward for some time, but now the pace is quickening. As data publication venues proliferate, significant debate continues over formats, processes, and terminology. Here, we present an overview of data publication initiatives underway and the current conversation, highlighting points of consensus and issues still in contention. Data publication implementations differ in a variety of factors, including the kind of documentation, the location of the documentation relative to the data, and how the data is validated. Publishers may present data as supplemental material to a journal article, with a descriptive "data paper," or independently. Complicating the situation, different initiatives and communities use the same terms to refer to distinct but overlapping concepts. For instance, the term published means that the data is publicly available and citable to virtually everyone, but it may or may not imply that the data has been peer-reviewed. In turn, what is meant by data peer review is far from defined; standards and processes encompass the full range employed in reviewing the literature, plus some novel variations. Basic data citation is a point of consensus, but the general agreement on the core elements of a dataset citation frays if the data is dynamic or part of a larger set. Even as data publication is being defined, some are looking past publication to other metaphors, notably "data as software," for solutions to the more stubborn problems. PMID- 25452838 TI - Different waves and directions of Neolithic migrations in the Armenian Highland. AB - BACKGROUND: The peopling of Europe and the nature of the Neolithic agricultural migration as a primary issue in the modern human colonization of the globe is still widely debated. At present, much uncertainty is associated with the reconstruction of the routes of migration for the first farmers from the Near East. In this context, hospitable climatic conditions and the key geographic position of the Armenian Highland suggest that it may have served as a conduit for several waves of expansion of the first agriculturalists from the Near East to Europe and the North Caucasus. RESULTS: Here, we assess Y-chromosomal distribution in six geographically distinct populations of Armenians that roughly represent the extent of historical Armenia. Using the general haplogroup structure and the specific lineages representing putative genetic markers of the Neolithic Revolution, haplogroups R1b1a2, J2, and G, we identify distinct patterns of genetic affinity between the populations of the Armenian Highland and the neighboring ones north and west from this area. CONCLUSIONS: Based on the results obtained, we suggest a new insight on the different routes and waves of Neolithic expansion of the first farmers through the Armenian Highland. We detected at least two principle migratory directions: (1) westward alongside the coastline of the Mediterranean Sea and (2) northward to the North Caucasus. PMID- 25452840 TI - Colonic motility in ulcerative colitis. AB - BACKGROUND: Inflammatory conditions affecting the gut may cause motility disturbances, and ulcerative colitis - one of the main disorders among the inflammatory bowel diseases - may display abnormal colonic motility. AIM: To review the abnormalities of the large bowel in ulcerative colitis, by considering the motility, laboratory (in vitro) and pathological studies dealing with this topic. METHODS: A comprehensive online search of Medline and the Science Citation Index was carried out. RESULTS: Patients with ulcerative colitis frequently display colonic motor abnormalities, including lack of contractility, an increase of propulsive contractile waves, an excessive production of nitric oxide, vasoactive intestinal polypeptide nerves, interleukin 1 beta, neurotensin, tachykinins levels and the weaker action of substance P, likely related to a neuromuscular dysfunction due to the inflammatory process. CONCLUSIONS: A better understanding of the pathophysiological grounds of altered colonic motility in ulcerative colitis may lead to a more in-depth knowledge of the accompanying symptoms and to better and more targeted therapeutic approaches. PMID- 25452841 TI - Assessing patient reported outcome measures: A practical guide for gastroenterologists. AB - Gastrointestinal illnesses cause physical, emotional and social impact on patients. Patient reported outcome measures (PROMs) are increasingly used in clinical decision-making, clinical research and approval of new therapies. In the last decade, there has been a rapid increase in the number of PROMs in gastroenterology and, therefore, the choice between which of these PROMs to use can be difficult. Not all PROM instruments currently used in research and clinical practice in gastroenterology have gone through a rigorous development methodology. New drugs and therapies will not have access to the market if the PROMs used in their clinical trials are not validated according to the guidelines of the international agencies. Therefore, it is important to know the required properties of PROMs when choosing or evaluating a drug or a clinical intervention. This paper reviews the current literature on how to assess the validity and reliability of PROMs. It summarises the required properties into a practical guide for gastroenterologists to use in assessing an instrument for use in clinical practice or research. PMID- 25452842 TI - Accuracy of liquid cytology in the diagnosis and monitoring of eosinophilic oesophagitis. AB - BACKGROUND: Oesophagoscopy with biopsy is considered the gold standard for diagnosing and monitoring eosinophilic oesophagitis (EoE). Therefore is important to discover less-invasive diagnostic methods. METHODS: Cytology specimens were obtained in patients with active EoE (AEoE) (>=15 eos/hpf) and EoE in remission (EoER) (<15 eos/hpf). The samples were assessed by two independent pathologists and were compared with biopsy samples. EoE cytology specimens were compared with specimens obtained from patients with GERD. RESULTS: Specimens of 36 patients (69.4% male, mean age 30.88 years) were included. AEoE (17, 47.2%), EoER (11, 30.5%) and GERD (22.2%). eos/hpf in cytology (AEoE 9.23 vs. EoER 1.54 vs. GERD 2, p = 0.01). Linear correlation between eos/hpf average biopsy and cytology eos/hpf: r = 0.57, p < 0.001. For diagnosis of EoE >=3 eos/hpf in cytology obtained a sensitivity of 70%, specificity 81%, PPV 86% and NPV 60% (AUC = 0.81, p = 0.01). For detection of AEoE, >=3 eos/hpf in LBC obtained a sensitivity of 70%, specificity 82%, PPV 81% and NPV 66% (AUC = 0.87, p = 0.001). CONCLUSIONS: LBC in oesophageal aspirate seems to be effective for the diagnosis and monitoring activity in EoE. These results support the usefulness of non-invasive methods for the diagnosis and monitoring of EoE. PMID- 25452843 TI - Sexual activity does not predispose to reflux episodes in patients with gastroesophageal reflux disease. AB - BACKGROUND: The role of sexual activity on gastroesophageal reflux disease (GERD) is an under-recognized concern of patients, and one rarely assessed by physicians. OBJECTIVE: The objective of this article is to determine the influence of sexual activity on the intraesophageal acid exposure and acid reflux events in GERD patients. METHODS: Twenty-one patients with the diagnosis of GERD were prospectively enrolled. Intraesophageal pH monitoring was recorded for 48 hours with a Bravo capsule. All patients were instructed to have sexual intercourse or abstain in a random order two hours after the same refluxogenic dinner within two consecutive nights. Patients were requested to have sex in the standard "missionary position" and women were warned to avoid abdominal compression. The patients completed a diary reporting the time of the sexual intercourse and GERD symptoms. The percentage of reflux time and acid reflux events were compared in two ways: within 30 and 60 minutes prior to and after sexual intercourse on the day of sexual intercourse and in the same time frame of the day without sexual intercourse. RESULTS: Fifteen of 21 GERD patients were analyzed. The percentage of reflux time and number of acid reflux events did not show a significant difference within the 30- and 60-minute periods prior to and after sexual intercourse on the day of sexual intercourse and on the day without sexual intercourse, as well. CONCLUSION: Sexual activity does not predispose to increased intraesophageal acid exposure and acid reflux events. Larger studies are needed to confirm our findings in patients who define reflux symptoms during sexual intercourse. PMID- 25452844 TI - Emergency single-balloon enteroscopy in overt obscure gastrointestinal bleeding: Efficacy and safety. AB - We aimed to evaluate the impact of emergency single-balloon enteroscopy (SBE) on the diagnosis and treatment for active overt obscure gastrointestinal bleeding (OGIB). METHODS: SBE procedures for OGIB were retrospectively reviewed and sub divided according to the bleeding types: active-overt and inactive-overt bleeding. The patient's history, laboratory results, endoscopic findings and therapeutic interventions were registered. Emergency SBE was defined as an endoscopy that was performed for active-overt OGIB, within 24 hours of clinical presentation. RESULTS: Between January 2010 and February 2013, 53 SBEs were performed in 43 patients with overt OGIB. Seventeen emergency SBEs were performed in 15 patients with active overt-OGIB procedures (group A), which diagnosed the bleeding source in 14: angiodysplasia (n = 5), ulcers/erosions (n = 3), bleeding tumors (gastrointestinal stromal tumor (GIST), n = 3; neuroendocrine tumor, n = 1), and erosioned polyps (n = 2). Endoscopic treatment was performed in nine patients, with one or multiple hemostatic therapies: argon plasma coagulation (n = 5), epinephrine submucosal injection (n = 5), hemostatic clips (n = 3), and polypectomy (n = 2). Twenty-eight patients with inactive bleeding (group B) were submitted to 36 elective SBEs, which successfully diagnosed 18 cases. The diagnostic yield in group A (93.3%) was significantly higher than in group B (64.3%)-Fisher's exact test, p = 0.038. CONCLUSION: This study revealed an important role of emergency SBE in the diagnosis of bleeding etiology in active overt OGIB. PMID- 25452845 TI - Endoscopic mucosal resection of large rectal adenomas in the era of centralization: Results of a multicenter collaboration. AB - BACKGROUND AND OBJECTIVE: Endoscopic mucosal resection (EMR) of large rectal adenomas is largely being centralized. We assessed the safety and effectiveness of EMR in the rectum in a collaboration of 15 Dutch hospitals. METHODS: Prospective, observational study of patients with rectal adenomas >3 cm, resected by piecemeal EMR. Endoscopic treatment of adenoma remnants at 3 months was considered part of the intervention strategy. Outcomes included recurrence after 6, 12 and 24 months and morbidity. RESULTS: Sixty-four patients (50% male, age 69 +/- 11, 96% ASA 1/2) presented with 65 adenomas (diameter 46 +/- 17 mm, distance ab ano 4.5 cm (IQR 1-8), 6% recurrent lesion). Sixty-two procedures (97%) were technically successful. Histopathology revealed invasive carcinoma in three patients (5%), who were excluded from effectiveness analyses. At 3 months' follow up, 10 patients showed adenoma remnants. Recurrence was diagnosed in 16 patients during follow-up (recurrence rate 25%). Fifteen of 64 patients (23%) experienced 17 postprocedural complications. CONCLUSION: In a multicenter collaboration, EMR was feasible in 97% of patients. Recurrence and postprocedural morbidity rates were 25% and 23%. Our results demonstrate the outcomes of EMR in the absence of tertiary referral centers. PMID- 25452846 TI - Are IBD patients more likely to have a prior diagnosis of irritable bowel syndrome? Report of a case-control study in the General Practice Research Database. AB - BACKGROUND: Inflammatory bowel disease (IBD) patients are sometimes first diagnosed with irritable bowel syndrome (IBS), which may be construed as a misdiagnosis. OBJECTIVE: The objective of this article is to determine if this occurs more than expected by chance. METHODS: We conducted a case-control study nested in the General Practice Research Database. We selected incident cases of IBD and up to 10 matched controls for each. We assessed the proportions with IBS recorded prior to the IBD diagnosis and variation by age, sex, and calendar time. We compared proportions affected in fixed time periods and conducted conditional logistic regression to derive odds ratios. RESULTS: The 20, 193 cases were three times as likely as controls to have a prior record of IBS. Fifteen per cent of IBD cases and 5% of controls had IBS coded before diagnosis with 11% having a code for IBS over one year before IBD (cf. 5% of controls) and 6% over five years earlier (cf. 3%). These figures roughly doubled if typical antispasmodic therapies were assumed to represent IBS diagnoses. CONCLUSION: If excess IBS diagnoses represent misdiagnoses of IBD, our results suggest that about 10% of IBD patients are misdiagnosed and in 3% of cases this may persist for five or more years. PMID- 25452847 TI - High prevalence of symptoms in a severely abused "non-patient" women population. AB - OBJECTIVE: The objective of this article is to assess the prevalence of somatic symptoms and of gastrointestinal (GI) syndromes in abused "non-patient" women and the association with the time of perpetration, type, and severity of abuse. METHODS: Sixty-seven women, 18-58 years, receiving shelter in anti-violence associations were invited to fill out an anonymous questionnaire with a medical and an abuse section. The severity of abuse was expressed as the 0-6 Abuse Severity Measure (ASM). The association between abuse characteristics and the number of symptoms, and GI syndromes was assessed by Poisson regression model. RESULTS: Most women suffered from childhood and adulthood sexual and physical abuse. They reported a mean of 5.1 GI symptoms (range 0-13; median 5; IQR 6) and of 1.3 extra-GI symptoms (range 0-6; median 1; IQR 2); 30% of women matched the Rome II Criteria for one, 36% for two, and 4.4% for three or more syndromes, respectively. Women with an ASM of 5-6, having suffered from both sexual and physical abuse, reported significantly (p = 0.02) more GI symptoms, but not extra GI ones (p = 0.07), and met criteria for more GI syndromes than women with an ASM <=4 and those reporting only one type of abuse. No association was found between the time of perpetration of the abuse and the number of GI and extra-GI symptoms. CONCLUSIONS: Symptoms in abused "non-patient" women mainly concern the abdomen and the GI tract. A history of severe, combined physical and sexual abuse is associated with a higher number of GI symptoms. PMID- 25452850 TI - Survey of digestive health across Europe: Final report. Part 1: The burden of gastrointestinal diseases and the organisation and delivery of gastroenterology services across Europe. PMID- 25452848 TI - Diagnostic accuracy of fecal immunochemical test in average- and familial-risk colorectal cancer screening. AB - BACKGROUND: There is little information about the fecal immunochemical test (FIT) in familial-risk colorectal cancer (CRC) screening. OBJECTIVES: The objective of this article is to investigate whether FIT diagnostic accuracy for advanced neoplasia (AN) differs between average and familial-risk (first-degree relative) patients. METHODS: A total of 1317 consecutive participants (595 familial) who collected one stool sample before performing a colonoscopy as a CRC screening test were included. FIT diagnostic accuracy for AN was evaluated with Chi-square test at a 20 ug hemoglobin/g of feces cut-off value. Finally, we determined which variables were independently related to AN. RESULTS: An AN was found in 151 (11.5%) patients. The overall accuracy was not statistically different between both cohorts for AN (88.4%, 91.7%; p = 0.051). At the cut-off stablished, differences in FIT sensitivity (31.1%, 40.6%; p = 0.2) or specificity (96.5%, 97.3%; p = 0.1) were not statistically significant. Finally, independent variables such as sex (male) (odds ratio (OR) 2.1, 95% confidence interval (CI) 1.4-3.1), age (50-65, >65 years) (OR 2.1, 95% CI 1.1-4.3; OR 2.7, 95% CI 1.2 6.1), previous colonoscopy (OR 0.4, 95% CI 0.2-0.9) and FIT >=20 ug/g feces (OR 17.7, 95% CI 10.8-29.1) were associated with AN diagnosis. CONCLUSIONS: FIT accuracy for AN detection is equivalent in average and familial-risk CRC screening cohorts. PMID- 25452849 TI - Whole-liver CT texture analysis in colorectal cancer: Does the presence of liver metastases affect the texture of the remaining liver? AB - BACKGROUND: Liver metastases limit survival in colorectal cancer. Earlier detection of (occult) metastatic disease may benefit treatment and survival. OBJECTIVE: The objective of this article is to evaluate the potential of whole liver CT texture analysis of apparently disease-free liver parenchyma for discriminating between colorectal cancer (CRC) patients with and without hepatic metastases. METHODS: The primary staging CT examinations of 29 CRC patients were retrospectively analysed. Patients were divided into three groups: patients without liver metastases (n = 15), with synchronous liver metastases (n = 10) and metachronous liver metastases within 18 months following primary staging (n = 4). Whole-liver texture analysis was performed by delineation of the apparently non diseased liver parenchyma (excluding metastases or other focal liver lesions) on portal phase images. Mean grey-level intensity (M), entropy (E) and uniformity (U) were derived with no filtration and different filter widths (0.5 = fine, 1.5 = medium, 2.5 = coarse). RESULTS: Mean E1.5 and E2.5 for the whole liver in patients with synchronous metastases were significantly higher compared with the non-metastatic patients (p = 0.02 and p = 0.01). Mean U1.5 and U2.5 were significantly lower in the synchronous metastases group compared with the non metastatic group (p = 0.04 and p = 0.02). Texture parameters for the metachronous metastases group were not significantly different from the non-metastatic group or synchronous metastases group (p > 0.05), although - similar to the synchronous metastases group - there was a subtle trend towards increased E1.5, E2.5 and decreased U1.5, U2.5 values. Areas under the ROC curve for the diagnosis of synchronous metastatic disease based on the texture parameters E1.5,2.5 and U1.5,2.5 ranged between 0.73 and 0.78. CONCLUSION: Texture analysis of the apparently non-diseased liver holds promise to differentiate between CRC patients with and without metastatic liver disease. Further research is required to determine whether these findings may be used to benefit the prediction of metachronous liver disease. PMID- 25452852 TI - BMJ Open Diabetes Research & Care. PMID- 25452851 TI - Association between long working hours and serum gamma-glutamyltransferase levels in female workers: data from the fifth Korean National Health and Nutrition Examination Survey (2010-2011). AB - OBJECTIVES: The present study investigated the association between long working hours and serum gamma-glutamyltransferase (GGT) levels, a factor influencing the incidence of cardiovascular disease. METHODS: Data from the fifth Korean National Health and Nutrition Examination Survey (2010-2011) were used to analyze 1,809 women. Subjects were divided into three groups based on the number of weekly working hours: <=29, 30-51, and >=52 hours per week. Complex samples logistic regression was performed after adjusting for general and occupational factors to determine the association between long working hours and high serum GGT levels. RESULTS: The prevalence of high serum GGT levels in groups with <=29, 30-51, and >=52 working hours per week was 22.0%, 16.9%, and 26.6%, respectively. Even after adjusting for general and occupational factors, those working 30-51 hours per week had the lowest prevalence of high serum GGT levels. Compared to those working 30-51 hours per week, the odds ratios (OR) of having high serum GGT levels in the groups with >=52 and <=29 working hours per week were 1.56 (95% confidence interval [CI], 1.10-2.23) and 1.53 (95% CI, 1.05-2.24), respectively. CONCLUSIONS: Long working hours were significantly associated with high serum GGT levels in Korean women. PMID- 25452853 TI - Comparative associations of diabetes risk factors with five measures of hyperglycemia. AB - OBJECTIVE: To compare the associations of diabetes mellitus risk factors with nontraditional markers of hyperglycemia (glycated albumin, fructosamine, 1,5 anhydroglucitol (1,5-AG)) to those observed with traditional markers (fasting glucose, hemoglobin A1c (HbA1c)). DESIGN: Cross-sectional study. SETTING: The community-based Atherosclerosis Risk in Communities (ARIC) Study cohort. PARTICIPANTS: A subsample of 1764 participants (309 with diagnosed diabetes and 1455 without diagnosed diabetes) from the ARIC Study who attended a clinic visit in 2005-2006. MAIN OUTCOME MEASURES: Elevated levels of glycated albumin, fructosamine, 1,5-AG, fasting glucose, and HbA1c in persons with and without a diagnosis of diabetes. RESULTS: The mean age of participants was 70 years (SD, 6), 43% were men, and 20% were African-American. Black race and family history of diabetes were generally positively associated with elevated levels of all biomarkers of hyperglycemia except 1,5-AG, which showed inverse but weaker associations with the risk factors examined. In general, patterns of risk factor associations observed for fasting glucose and HbA1c were similar to those observed for the nontraditional biomarkers of hyperglycemia but with one clear exception: body mass index (BMI). In persons without a diagnosis of diabetes, BMI was positively associated with fasting glucose and HbA1c, but the associations of BMI with glycated albumin and fructosamine were inverse, with high values of these markers at low levels of BMI. 1,5-AG, which is lowered in the setting of hyperglycemia, was positively associated with BMI. CONCLUSIONS: Traditional diabetes risk factors have similar associations with glycated albumin and fructosamine as those for fasting glucose and HbA1c, with the exception of BMI. Risk factor associations with 1,5-AG were mostly inverse. The inverse associations of BMI with glycated albumin and fructosamine, and positive associations with 1,5-AG, may reflect pathways independent of glucose metabolism and merit further examination. PMID- 25452854 TI - Effect of baseline HbA1c level on the development of diabetes by lifestyle intervention in primary healthcare settings: insights from subanalysis of the Japan Diabetes Prevention Program. AB - OBJECTIVES: To determine the effects of a lifestyle intervention on the development of type 2 diabetes mellitus (T2DM) among participants with impaired glucose tolerance (IGT), in particular in the subgroup with baseline glycated hemoglobin (HbA1c) levels >=5.7%, in primary healthcare settings. DESIGN: Randomized controlled trial. SETTING: 32 healthcare centers in Japan. PARTICIPANTS: Participants with IGT, aged 30-60 years, were randomly assigned to either an intensive lifestyle intervention group (ILG) or a usual care group (UCG). INTERVENTIONS: During the initial 6 months, participants in the ILG received four group sessions on healthy lifestyles by public health providers. An individual session was further conducted biannually during the 3 years. Participants in the UCG received usual care such as one group session on healthy lifestyles. OUTCOME MEASURES: The primary endpoint was the development of T2DM based on an oral glucose tolerance test. RESULTS: The mean follow-up period was 2.3 years. The annual incidence of T2DM were 2.7 and 5.1/100 person-years of follow-up in the ILG (n=145) and UCG (n=149), respectively. The cumulative incidence of T2DM was significantly lower in the ILG than in the UCG among participants with HbA1c levels >=5.7% (log-rank=3.52, p=0.06; Breslow=4.05, p=0.04; Tarone-Ware=3.79, p=0.05), while this was not found among participants with HbA1c levels <5.7%. CONCLUSIONS: Intensive lifestyle intervention in primary healthcare setting is effective in preventing the development of T2DM in IGT participants with HbA1c levels >=5.7%, relative to those with HbA1c levels <5.7%. TRIAL REGISTRATION NUMBER: UMIN000003136. PMID- 25452855 TI - Coronary artery disease in patients with atypical chest pain with and without diabetes mellitus assessed with coronary CT angiography. AB - INTRODUCTION: Coronary artery disease (CAD) in diabetes mellitus (DM) is often widespread when diagnosed. Non-invasive coronary calcium scoring and coronary CT angiography (CAC-score/CCTA) are accurate in the detection of CAD. This study compared CAD characteristics as identified by CCTA between patients with and without DM with atypical chest pain. METHODS: CAD was defined as CAC-score >0 and/or presence of coronary plaque. Several CAD characteristics (number of affected segments, obstructive (>50% stenosis) CAD and CAD distribution) were compared on a per patient and segment basis. Subanalysis of duration of DM (<5 or >5 years) and gender was performed. RESULTS: A total of 1148 patients (63.3% men, mean age 57.7+/-10.7), of whom 99 (8.6%) suffered from DM, were referred for CCTA. There was no difference in the prevalence of CAD between patients with and without DM (53.5% vs 50.9%, p=0.674). However patients with DM showed more affected coronary segments compared with patients without DM (2.5+/-3.4 vs 1.7+/ 2.4, p=0.003). Multivariate analysis indicated that DM was an independent predictor of obstructive CAD (OR 2.16, 95% CI 1.23 to 3.78), as were age, women, and Diamond-Forrester score. In our study, obstructive CAD was more prevalent in women than in men (DM 40.0% vs 14.1%, p=0.003; non-DM 16.8% vs 8.4%, p<0.001). Patients suffering from DM >5 years showed more distal plaques (11.2% vs 7.7%, p=0.030). CONCLUSIONS: Patients with atypical chest pain and DM showed more extensive CAD, as well as more obstructive CAD, particularly in women. Diabetes duration (>5 years) was not associated with more obstructive coronary disease or different plaque morphology, although more distal disease was present. PMID- 25452856 TI - Prevalence and risk factors for diabetic retinopathy in rural India. Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetic Study III (SN DREAMS III), report no 2. AB - OBJECTIVE: The study was aimed at estimating the prevalence of type 2 diabetes mellitus and diabetic retinopathy in a rural population of South India. DESIGN: A population-based cross-sectional study. PARTICIPANTS: 13 079 participants were enumerated. METHODS: A multistage cluster sampling method was used. All eligible participants underwent comprehensive eye examination. The fundi of all patients were photographed using 45 degrees , four-field stereoscopic digital photography, and an additional 30 degrees seven-field stereo digital pairs were taken for participants with diabetic retinopathy. The diagnosis of diabetic retinopathy was based on Klein's classification. MAIN OUTCOME MEASURES: Prevalence of diabetes mellitus and diabetic retinopathy and associated risk factors. RESULTS: The prevalence of diabetes in the rural Indian population was 10.4% (95% CI 10.39% to 10.42%); the prevalence of diabetic retinopathy, among patients with diabetes mellitus, was 10.3% (95% CI 8.53% to 11.97%). Statistically significant variables, on multivariate analysis, associated with increased risk of diabetic retinopathy were: gender (men at greater risk; OR 1.52; 95% CI 1.01 to 2.29), use of insulin (OR 3.59; 95% CI 1.41 to 9.14), longer duration of diabetes (15 years; OR 6.01; 95% CI 2.63 to 13.75), systolic hypertension (OR 2.14; 95% CI 1.20 to 3.82), and participants with poor glycemic control (OR 3.37; 95% CI 2.13 to 5.34). CONCLUSIONS: Nearly 1 of 10 individuals in rural South India, above the age of 40 years, showed evidence of type 2 diabetes mellitus. Likewise, among participants with diabetes, the prevalence of diabetic retinopathy was around 10%; the strongest predictor being the duration of diabetes. PMID- 25452857 TI - Association of TCF7L2 variation with single islet autoantibody expression in children with type 1 diabetes. AB - BACKGROUND: The transcription factor 7-like 2 (TCF7L2) gene has the strongest genetic association with type 2 diabetes. TCF7L2 also associates with latent autoimmune diabetes in adults, which often presents with a single islet autoantibody, but not with classical type 1 diabetes. METHODS: We aimed to test if TCF7L2 is associated with single islet autoantibody expression in pediatric type 1 diabetes. We studied 71 prospectively recruited children who had newly diagnosed type 1 diabetes and evidence of islet autoimmunity, that is, expressed >=1 islet autoantibody to insulin, glutamic acid decarboxylase 65, islet cell autoantigen 512, or zinc transporter 8. TCF7L2 rs7903146 alleles were identified. Data at diagnosis were cross-sectionally analyzed. RESULTS: We found that 21.1% of the children with autoimmune type 1 diabetes expressed a single islet autoantibody. The distribution of TCF7L2 rs7903146 genotypes in children with a single autoantibody (n=15) was 40% CC, 26.7% CT and 33.3% TT, compared with children with >=2 islet autoantibodies (50% CC, 42.9% CT and 7.1% TT, p=0.024). Furthermore, compared with children with >=2 autoantibodies, single-autoantibody children had characteristics reflecting milder autoimmune destruction of beta cells. Restricting to lean children (body mass index<85th centile; n=36), 45.5% of those expressing a single autoantibody were rs7903146 TT homozygotes, compared with 0% of those with >=2 autoantibodies (p<0.0001). CONCLUSION: These results suggest that, in children with only mild islet autoimmunity, mechanisms associated with TCF7L2 genetic variation contribute to diabetogenesis, and this contribution is larger in the absence of obesity. PMID- 25452858 TI - Adiponectin and IGFBP-1 in the development of gestational diabetes in obese mothers. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) is more common in pregnancies complicated by obesity and both diseases increase the risk for fetal overgrowth and long-term adverse health consequences for the mother and child. Previous studies have linked low maternal serum adiponectin to GDM in normal and overweight women. We hypothesized that lower adiponectin, in particular the high molecular-weight form, and insulin-like growth factor I (IGF-I) and its binding protein (IGFBP-1) are associated with GDM in pregnant obese Hispanic women. METHODS: 72 obese, predominantly Hispanic (92%), women were recruited at 24-28 weeks of gestation. Adiposity was assessed, fasting serum samples were collected, and glucose, insulin, triglyceride, cholesterol levels, adipokines, and hormones associated with obesity and insulin resistance were measured. 30 women had been recently diagnosed with GDM. RESULTS: Gestational weeks, body mass index, triceps skinfold thickness, mid-arm circumference, serum leptin, IGF-I, tumor necrosis factor alpha, and interleukin-6 did not differ in the two groups. Obese women with GDM had significantly higher fasting glucose, A1C, triglycerides, very-low density lipoprotein cholesterol and lower high-density lipoprotein cholesterol, adiponectin, and IGFBP-1 compared to obese women without GDM. Homeostasis model assessment of insulin resistance was positively correlated to IGF-I and negatively correlated to adiponectin. CONCLUSIONS: Obese pregnant women with recently diagnosed GDM had a significantly exacerbated metabolic profile, low serum adiponectin and IGFBP-1 levels at 24-28 weeks of gestation, as compared to women with obesity alone. Because low adiponectin is well established to cause insulin resistance and decreased IGFBP-1 indicates increased IGF-I bioavailability, we propose that these changes are mechanistically linked to the development of GDM in obese Hispanic women. PMID- 25452859 TI - Retinopathy and clinical outcomes in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia. AB - OBJECTIVE: Retinopathy is an established microvascular complication of type 2 diabetes mellitus (T2DM), but its independent relationship with macrovascular and other microvascular complications is less well defined across the spectrum of kidney disease in T2DM. We examined the prognostic value of retinopathy in assessing the risk of developing end-stage renal disease (ESRD), cardiovascular morbidity or death among patients in the Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT). DESIGN: TREAT enrolled 4038 patients with T2DM, chronic kidney disease (CKD) and moderate anemia. Patients were grouped by baseline history of retinopathy. Proportional hazards regression models were utilized to assess the association between retinopathy and subsequent ESRD, cardiovascular morbidity or death over an average of 2.4 years. RESULTS: Although younger, the 1895 (47%) patients with retinopathy had longer duration of diabetes, lower estimated glomerular filtration rate, more proteinuria, and more microvascular complications. In univariate analysis, retinopathy was associated with a higher rate of ESRD, but not with cardiovascular events or mortality. After adjustment, retinopathy was no longer statistically significant for the prediction of ESRD or any clinical endpoint. CONCLUSIONS: In a large cohort of patients with T2DM, CKD, and anemia, retinopathy was common but not independently associated with a higher risk of renal or cardiovascular morbidity or death. TRIAL REGISTRATION NUMBER: NCT00093015. PMID- 25452860 TI - Forecasting the burden of type 2 diabetes in Singapore using a demographic epidemiological model of Singapore. AB - OBJECTIVE: Singapore is a microcosm of Asia as a whole, and its rapidly ageing, increasingly sedentary population heralds the chronic health problems other Asian countries are starting to face and will likely face in the decades ahead. Forecasting the changing burden of chronic diseases such as type 2 diabetes in Singapore is vital to plan the resources needed and motivate preventive efforts. METHODS: This paper describes an individual-level simulation model that uses evidence synthesis from multiple data streams-national statistics, national health surveys, and four cohort studies, and known risk factors-aging, obesity, ethnicity, and genetics-to forecast the prevalence of type 2 diabetes in Singapore. This comprises submodels for mortality, fertility, migration, body mass index trajectories, genetics, and workforce participation, parameterized using Markov chain Monte Carlo methods, and permits forecasts by ethnicity and employment status. RESULTS: We forecast that the obesity prevalence will quadruple from 4.3% in 1990 to 15.9% in 2050, while the prevalence of type 2 diabetes (diagnosed and undiagnosed) among Singapore adults aged 18-69 will double from 7.3% in 1990 to 15% in 2050, that ethnic Indians and Malays will bear a disproportionate burden compared with the Chinese majority, and that the number of patients with diabetes in the workforce will grow markedly. CONCLUSIONS: If the recent rise in obesity prevalence continues, the lifetime risk of type 2 diabetes in Singapore will be one in two by 2050 with concomitant implications for greater healthcare expenditure, productivity losses, and the targeting of health promotion programmes. PMID- 25452861 TI - The effect of slow spaced eating on hunger and satiety in overweight and obese patients with type 2 diabetes mellitus. AB - BACKGROUND: Slow spaced eating is associated with improved satiety and gut hormone responses in normal-weight participants. This crossover study compared the effect of slow and rapid eating patterns on hunger, fullness, glucose, insulin, and the appetite-related gut hormones peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and ghrelin in overweight and obese participants with type 2 diabetes mellitus (T2DM). METHODS: 20 overweight and obese participants with T2DM on metformin were recruited. A test meal of 300 mL ice-cream was consumed in random order in two different sessions by each participant; meal duration was 5 or 30 min. Fullness and hunger as assessed by visual analog scales (VAS), and glucose, insulin, PYY, GLP-1, and ghrelin were measured at baseline and at 30 min intervals after meal termination for 3 h. RESULTS: Fullness VAS ratings were significantly higher at the 90', 120', 150', and 180' time points and hunger ratings were lower at 90', 150', and 180' for the 30 min meal. The area under the curve (AUC) for fullness was higher after the 30 min meal than after the 5 min meal (11 943.7+/-541.2 vs 10 901.0+/-568.8 mm min, p=0.003) whereas the hunger AUC was lower (4442.9+/-328 vs 4966.7+/-347.5 mm min, p=0.012). There were no differences in glucose, insulin, PYY, GLP-1, and ghrelin responses. CONCLUSIONS: Slow spaced eating increased fullness and decreased hunger ratings in overweight and obese participants with T2DM, without the improvement in gut hormone responses found in normal-weight participants. Slow spaced eating may be a useful prevention strategy, but might also help curb food intake in those already suffering from obesity and diabetes. PMID- 25452862 TI - Elevated 1 h postload plasma glucose levels identify adults with normal glucose tolerance but increased risk of non-alcoholic fatty liver disease. AB - OBJECTIVE: To determine the ability of the proposed diagnostic value of a 1-h OGTT glucose >=155mg/dL to identify individuals with non-alcoholic fatty liver disease (NAFLD) diagnosed by ultrasonography in a cohort of adult white individuals. DESIGN: The study group comprised 710 white individuals participating to the CATAnzaro MEtabolic RIsk factors (CATAMERI) Study, a cross sectional study assessing cardio-metabolic risk factors in individuals carrying at least one risk factor including dysglycemia, overweight/obesity, hypertension, dyslipidemia. a 75 g oral Oral Glucose Tolerance Test (OGTT) was performed with 0, 30, 60, 90 and 120 min sampling for plasma glucose and insulin measurements. Cardio-metabolic risk factors including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) were assessed in the whole cohort. RESULTS: Of the 710 participants examined, 295 had normal glucose tolerance (NGT) with 1-hour post-load plasma glucose <155 mg/dL (NGT 1h-low), 109 individuals had NGT 1h-high, 104 had isolated impaired fasting glucose (IFG), and 202 had impaired glucose tolerance (IGT). As compared with NGT 1h-low, NGT 1h high and IGT subjects exhibited significantly higher body mass index (BMI), triglycerides, high sensitivity C reactive protein, ALT, GGT, and hepatic insulin resistance (IR), assessed by the liver IR index, as well as lower high density lipoprotein, and insulin-like growth factor-1 (IGF-1) levels. In a logistic regression analysis adjusted for age, gender, and BMI, NGT 1h-high participants had a 1.5-fold increased risk of having NAFLD and an even increased risk was observed in subjects with IGT (1.8-fold), but not in the isolated IFG group (1.01 fold). CONCLUSIONS: These data suggest that the value of a 1-hour OGTT glucose >=155 mg/dL may be helpful to identify a subset of NGT individuals at risk for NAFLD. PMID- 25452863 TI - Statins impair glucose uptake in human cells. AB - OBJECTIVE: Considering the increasing number of clinical observations indicating hyperglycemic effects of statins, this study was designed to measure the influence of statins on the uptake of glucose analogs by human cells derived from liver, adipose tissue, and skeletal muscle. DESIGN: Flow cytometry and scintillation counting were used to measure the uptake of fluorescently labeled or tritiated glucose analogs by differentiated visceral preadipocytes, skeletal muscle cells, skeletal muscle myoblasts, and contact-inhibited human hepatocellular carcinoma cells. A bioinformatics approach was used to predict the structure of human glucose transporter 1 (GLUT1) and to identify the presence of putative cholesterol-binding (cholesterol recognition/interaction amino acid consensus (CRAC)) motifs within this transporter. Mutagenesis of CRAC motifs in SLC2A1 gene and limited proteolysis of membrane GLUT1 were used to determine the molecular effects of statins. RESULTS: Statins significantly inhibit the uptake of glucose analogs in all cell types. Similar effects are induced by methyl-beta cyclodextrin, which removes membrane cholesterol. Statin effects can be rescued by addition of mevalonic acid, or supplementation with exogenous cholesterol. Limited proteolysis of GLUT1 and mutagenesis of CRAC motifs revealed that statins induce conformational changes in GLUTs. CONCLUSIONS: Statins impair glucose uptake by cells involved in regulation of glucose homeostasis by inducing cholesterol-dependent conformational changes in GLUTs. This molecular mechanism might explain hyperglycemic effects of statins observed in clinical trials. PMID- 25452864 TI - Efficacy and safety of linagliptin in Hispanic/Latino patients with type 2 diabetes mellitus: a pooled analysis from six randomized placebo-controlled phase 3 trials. AB - OBJECTIVE: The number of individuals diagnosed with type 2 diabetes mellitus is expected to rise disproportionately in Hispanic/Latino populations. We therefore aimed to assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin specifically in Hispanic/Latino patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: Data from 745 patients who self-identified their ethnicity as Hispanic or Latino were pooled from six randomized, placebo controlled phase 3 trials. Participants received linagliptin (5 mg/day) or placebo as monotherapy, or in combination with other oral antidiabetes drugs for 18 or 24 weeks. RESULTS: The placebo-adjusted mean change (95% CI) in glycated hemoglobin from baseline (mean 8.2%) was -0.63% (-0.77 to -0.48; p<0.0001) at week 18, and -0.58% (-0.74 to -0.42; p<0.0001) at week 24. The placebo-adjusted mean change (95% CI) in fasting plasma glucose from baseline was -11.7 mg/dL ( 19.3 to -4.0; p=0.0028) at week 18 and -14.1 mg/dL (-22.0 to -6.3; p=0.0004) at week 24. Hypoglycemia incidence was 17.4% with linagliptin and 21% with placebo. In patients not receiving concomitant sulfonylurea, the hypoglycemia incidence was 10.1% with linagliptin and 19.4% with placebo. The overall incidence of adverse events (AEs), drug-related AEs, and serious AEs with linagliptin was similar to placebo (AEs 67.6% vs 68.9%; drug-related AEs 15.1% vs 18.7%; serious AEs 3.6% vs 3.0%). The mean body weight remained unchanged in both groups. CONCLUSIONS: In Hispanic/Latino patients with inadequately controlled type 2 diabetes mellitus, linagliptin provided clinically meaningful improvements in glycemic control without weight gain or increased risk of hypoglycemia. PMID- 25452865 TI - Obesity independently predicts responders to biphasic insulin 50/50 (Humalog Mix50 and Insuman Comb 50) following conversion from other insulin regimens: a retrospective cohort study. AB - AIMS: This study aims to examine the metabolic effects of intensification or initiation of insulin treatment with biphasic insulin 50/50, and determine the predictors of responders or non-responders to biphasic insulin 50/50. METHODS: A cohort of 2183 patients >=18 years with diabetes, newly treated with biphasic insulin 50/50 between January 2000 and May 2012, were sourced from UK General Practices via The Health Improvement Network (THIN) database. Baseline clinical parameters of 1267 patients with suboptimal glycated hemoglobin (HbA1c) >7.5% (>58 mmol/mol) who had received background insulin regimens for at least 6 months preceding biphasic insulin 50/50 were compared against 12-month outcome data. Responders were defined as those with HbA1c <7.5% (58 mmol/mol) and/or HbA1c reduction of >=1% (10.9 mmol/mol) at 12 months. Comparative analyses were carried out on subgroups of 237 patients initiating insulin therapy with biphasic insulin 50/50, and between users of the Humalog Mix50 (HM50) versus Insuman Comb 50 (IC50). Associations were examined using t tests and multivariate logistic regression techniques. RESULTS: The overall mean HbA1c reduction at 12 months as a result of intensification and initiation with biphasic insulin 50/50 was 0.5% (5.5 mmol/mol) and 1.6% (17.5 mmol/mol), respectively. Adjusted ORs show obesity (body mass index >30 kg/m(2)), treatment duration for >=9 months, and baseline HbA1c are independent determinants of responders. In addition, stratified for baseline HbA1c levels, HM50 was associated with better HbA1c outcome compared with IC50. CONCLUSIONS: biphasic insulin 50/50 is effective for achieving glycemic control in suboptimal HbA1c levels, especially among obese patients with insulin-treated diabetes. Stratified for baseline HbA1c, HM50 was associated with improved HbA1c outcome compared with IC50. PMID- 25452866 TI - Closing the loop overnight at home setting: psychosocial impact for adolescents with type 1 diabetes and their parents. AB - OBJECTIVE: To explore the experiences of adolescents with type 1 diabetes mellitus (T1DM) and their parents taking part in an overnight closed loop study at home, using qualitative and quantitative research methods. RESEARCH DESIGN AND METHODS: Adolescents aged 12-18 years on insulin pump therapy were recruited to a pilot closed loop study in the home setting. Following training on the use of a study insulin pump and continuous glucose monitoring (CGM), participants were randomized to receive either real-time CGM combined with overnight closed loop or real-time CGM alone followed by the alternative treatment for an additional 21 days with a 2-3-week washout period in between study arms. Semistructured interviews were performed to explore participants' perceptions of the impact of the closed loop technology. At study entry and again at the end of each 21-day crossover arm of the trial, participants completed the Diabetes Technology Questionnaire (DTQ) and Hypoglycemia Fear Survey (HFS; also completed by parents). RESULTS: 15 adolescents and 13 parents were interviewed. Key positive themes included reassurance/peace of mind, confidence, 'time off' from diabetes demands, safety, and improved diabetes control. Key negative themes included difficulties with calibration, alarms, and size of the devices. DTQ results reflected these findings. HFS scores were mixed. CONCLUSIONS: Closed loop insulin delivery represents cutting-edge technology in the treatment of T1DM. Results indicate that the psychological and physical benefits of the closed loop system outweighed the practical challenges reported. Further research from longitudinal studies is required to determine the long-term psychosocial benefit of the closed loop technology. PMID- 25452867 TI - Effect of vitamin D3 supplementation on glycated hemoglobin (HbA1c), fructosamine, serum lipids, and body mass index: a randomized, double-blinded, placebo-controlled trial among healthy immigrants living in Norway. AB - OBJECTIVE: Despite the suggested role of vitamin D in the prevention of diabetes and cardiovascular disease or its risk factors, the evidence is not consistent and there is a paucity of randomized controlled trials in this field. We aimed to investigate the effect of 16-week daily vitamin D3 supplementation on glycated hemoglobin (HbA1c), fructosamine, body mass index (BMI), and serum lipids. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Immigrant community centers in Oslo, Norway. PARTICIPANTS: 251 healthy adults aged 18-50 years with a non-Western immigrant background. All participants performed the baseline test and 215 (86%) returned to the follow-up test. INTERVENTION: 16 weeks of daily oral supplementation with either 10 MUg vitamin D3, 25 MUg vitamin D3, or placebo. MAIN OUTCOME MEASURES: Difference in absolute change during the 16-week intervention between the intervention groups combined (10 or 25 MUg of vitamin D3/day) and placebo, in HbA1c, fructosamine, serum lipids (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), and BMI. RESULTS: A total of 215 (86%) participants completed the study. Serum 25-hydroxyvitamin D increased from 29 nmol/L at baseline to 49 nmol/L after intervention, with little change in the placebo group. However, there was no difference in change of HbA1c between those receiving vitamin D3 compared with placebo (mean difference: 0.01% (95% CI -0.04 to 0.06, p=0.7)). Neither did the vitamin D3 supplementation have any effect on the other end points: fructosamine, serum lipids, and BMI. CONCLUSIONS: 16-week vitamin D3 supplementation to healthy immigrants from South Asia, the Middle East, or Africa and now living in Norway with low vitamin D status did not improve HbA1c, fructosamine, lipid profiles, or BMI. An updated meta-analysis of similar published trials showed that our results were generally consistent with those of other studies. TRIAL REGISTRATION NUMBER: NCT01263288. PMID- 25452868 TI - Association of fasting insulin and C peptide with diabetic retinopathy in Latinos with type 2 diabetes. AB - OBJECTIVE: Residual insulin secretion provides important protection against the development of diabetic retinopathy in type 1 diabetes. The data to support this in type 2 diabetes are unclear. We therefore tested in type 2 diabetes whether markers of residual beta-cell function are associated with the development of diabetic retinopathy, an important microvascular complication of diabetes. DESIGN: Prospective, cross-sectional, family-based study. PARTICIPANTS: 585 Latino type 2 diabetic participants, ascertained in families via a proband either with known diabetes duration of greater than 10 years and/or with diabetic retinopathy. OUTCOME MEASURES: CIRCULATING LEVELS OF FASTING INSULIN AND C PEPTIDE MEASURED AND CORRELATED TO DEGREE OF DIABETIC RETINOPATHY, ASSESSED BY DIGITAL FUNDUS PHOTOGRAPHY AND GRADED USING THE MODIFIED AIRLIE HOUSE CLASSIFICATION AND THE EARLY TREATMENT DIABETIC RETINOPATHY STUDY SCALE (RANGE: levels 10-85). RESULTS: Fasting plasma insulin (beta=-0.29; 95% CI -0.38 to 0.20; p<0.0001) and C peptide (beta=-0.21; 95% CI -0.30 to -0.13; p<0.0001) concentrations in these diabetic participants were significantly correlated with retinopathy and its degree of severity. This relationship remained significant after adjusting for potential covariates including age, gender, glycosylated hemoglobin, duration of diabetes, blood pressure, and renal function. CONCLUSIONS: These data suggest that residual endogenous insulin secretion is associated with the presence of diabetic retinopathy and its severity in Latinos with familial type 2 diabetes. It remains to be proven whether beta-cell targeted therapies, to maintain beta-cell mass and/or function in addition to glycemic control, will further the goal of preventing diabetic microvascular disease. PMID- 25452869 TI - Renal histological heterogeneity and functional progress in normoalbuminuric and microalbuminuric Japanese patients with type 2 diabetes. AB - BACKGROUND AND OBJECTIVES: Renal histological injury patterns in type 2 diabetes are heterogeneous. We compared renal histological injury patterns using renal biopsy findings with renal function and followed up renal functional changes in normoalbuminuric and microalbuminuric patients with type 2 diabetes to determine whether renal function progresses according to injury patterns. DESIGN SETTING PARTICIPANTS AND MEASUREMENTS: We examined 111 patients with type 2 diabetes with percutaneous renal biopsy (78 men, 52+/-11 years old, 59 normoalbuminuria, 52 microalbuminuria) and followed up 37 cases for 11 years. Light microscopy of tissues revealed renal injury patterns as: category I (CI), normal or near-normal structure; category II (CII), typical diabetic glomerulopathy; category III (CIII), atypical (disproportionately severe tubulointerstitial/vascular damage with no/mild glomerulopathy). RESULTS: There were 29 CI, 62 CII, and 20 CIII patients. CII patients had a higher frequency of chronic kidney disease (CKD) G3 4, while the injury pattern distribution was not different among the albuminuria stages. The mean glomerular volume and volume fraction of cortical interstitium were larger than those of controls. The arteriolar hyalinosis index was larger in CII and CIII, while the percent global glomerular sclerosis was larger in CKD G3 4 compared with CKD G1-2. Renal function at follow-up was decreased in CII and CIII compared with the baseline estimated glomerular filtration rate (eGFR), while the GFR decline rate was faster in CII. CONCLUSIONS: In normoalbuminuric and microalbuminuric patients with type 2 diabetes, loss of GFR could indicate typical diabetic glomerulosclerosis and a high frequency of global glomerular sclerosis. Urinary biomarkers identifying histological patterns of renal injury are necessary because GFR decline rates differed according to histological injury patterns. PMID- 25452870 TI - Objectively assessed physical activity, adiposity, and inflammatory markers in people with type 2 diabetes. AB - OBJECTIVE: Inflammatory processes may play an important role in the development of acute coronary syndromes in people with type 2 diabetes; thus, strategies to control inflammation are of clinical importance. We examined the cross-sectional association between objectively assessed physical activity and inflammatory markers in a sample of people with type 2 diabetes. METHODS: Participants were 71 men and 41 women (mean age=63.9+/-7 years), without a history of cardiovascular disease, drawn from primary care clinics. Physical activity was objectively measured using waist-worn accelerometers (Actigraph GT3X) during waking hours for seven consecutive days. RESULTS: We observed inverse associations between moderate-to-vigorous physical activity (per 10 min) with plasma interleukin-6 (B= 0.035, 95% CI -0.056 to -0.015), interleukin-1ra (B=-0.033, 95% CI -0.051 to 0.015), and monocyte chemotactic protein-1 (B=-0.011, 95% CI -0.021 to 0.000). These associations largely persisted in multivariable adjusted models, although body mass index considerably attenuated the effect estimate. CONCLUSIONS: These data demonstrate an inverse association between physical activity and inflammatory markers in people with type 2 diabetes. PMID- 25452871 TI - Dilated eye examination screening guideline compliance among patients with diabetes without a diabetic retinopathy diagnosis: the role of geographic access. AB - OBJECTIVE: To estimate the prevalence of, and factors associated with, dilated eye examination guideline compliance among patients with diabetes mellitus (DM), but without diabetic retinopathy. RESEARCH DESIGN AND METHODS: Utilizing the computerized billing records database, we identified patients with International Classification of Diseases (ICD)-9 diagnoses of DM, but without any ocular diagnoses. The available medical records of patients in 2007-2008 were reviewed for demographic and ocular information, including visits through 2010 (n=200). Patients were considered guideline compliant if they returned at least every 15 months for screening. Participant street addresses were assigned latitude and longitude coordinates to assess their neighborhood socioeconomic status (using the 2000 US census data), distance to the screening facility, and public transportation access. Patients not compliant, based on the medical record review, were contacted by phone or mail and asked to complete a follow-up survey to determine if screening took place at other locations. RESULTS: The overall screening compliance rate was 31%. Patient sociodemographic characteristics, insurance status, and neighborhood socioeconomic measures were not significantly associated with compliance. However, in separate multivariable logistic regression models, those living eight or more miles from the screening facility were significantly less likely to be compliant relative to those living within eight miles (OR=0.36 (95% CI 0.14 to 0.86)), while public transit access quality was positively associated with screening compliance (1.34 (1.07 to 1.68)). CONCLUSIONS: Less than one-third of patients returned for diabetic retinopathy screening at least every 15 months, with transportation challenges associated with noncompliance. Our results suggest that reducing transportation barriers or utilizing community-based screening strategies may improve compliance. PMID- 25452872 TI - Prevalence of dysglycemia in Calabar: a cross-sectional observational study among residents of Calabar, Nigeria. AB - OBJECTIVE: Population data on dysglycemia are scarce in West Africa. This study aimed to determine the pattern of dysglycemia in Calabar city in South East Nigeria. DESIGN: This was a cross-sectional observational study. METHODS: 1134 adults in Calabar were recruited. A multistage sampling method randomly selected 4 out of 22 wards, and 50 households from each ward. All adults within each household were recruited and an oral glucose tolerance test was performed. Dysglycemia was defined as any form of glucose intolerance, including: impaired fasting glucose (blood glucose level 110-125 mg/dL), impaired glucose tolerance (blood glucose level >=140 mg/dL 2 h after consuming 75 g of glucose), or diabetes mellitus (DM), as defined by fasting glucose level >=126 mg/dL, or a blood glucose level >=200 mg/dL, 2 h after a 75 g glucose load. RESULTS: Mean values of fasting plasma glucose were 95 mg/dL (95% CI 92.1 to 97.5) for men and 96 mg/dL (95% CI 93.2 to 98.6) for women. The overall prevalence of dysglycemia was 24%. The prevalence of impaired fasting glucose was 9%, the prevalence of impaired glucose tolerance 20%, and the prevalence of undiagnosed DM 7%. All values were a few percentage points higher for men than women. CONCLUSIONS: The prevalence of undiagnosed DM among residents of Calabar is similar to studies elsewhere in Nigeria but much higher than the previous national prevalence survey, with close to a quarter of the adults having dysglycemia and 7% having undiagnosed DM. This is a serious public health problem requiring a programme of mass education and case identification and management in all health facilities. TRIAL REGISTRATION NUMBER: CRS/MH/CR-HREC/020/Vol.8/43. PMID- 25452873 TI - Bubble formation occurs in insulin pumps in response to changes in ambient temperature and atmospheric pressure but not as a result of vibration. AB - INTRODUCTION: Bubble formation in insulin pump giving sets is a common problem. We studied change in temperature, change in atmospheric pressure, and vibration as potential mechanisms of bubble formation. METHODS: 5 Animas 2020 pumps with 2 mL cartridges and Inset II infusion systems, 5 Medtronic Paradigm pumps with 1.8 mL cartridge and Quickset and 3 Roche Accu-chek pumps with 3.15 mL cartridges were used. Temperature study: insulin pumps were exposed to a temperature change from 4 degrees C to 37 degrees C. Pressure study: insulin pumps were taken to an altitude of 300 m. Vibration study: insulin pumps were vigorously shaken. All were observed for bubble formation. RESULTS: Bubble formation was observed with changes in temperature and atmospheric pressure. Bubble formation did not occur with vibration. DISCUSSION: Changes in insulin temperature and atmospheric pressure are common and may result in bubble formation. Vibration may distribute bubbles but does not cause bubble formation. PMID- 25452874 TI - Performance of the Medtronic Sentrino continuous glucose management (CGM) system in the cardiac intensive care unit. AB - BACKGROUND: Maintaining glucose in the target range, while avoiding hypoglycemia, is challenging in critically ill patients. We investigated the performance and safety of Medtronic Sentrino, a newly developed continuous glucose management (CGM) system for critically ill adults. METHODS: This was a prospective, single center, single-arm, open-label study in adult patients with cardiac ICU admission. Sentrino subcutaneous glucose sensors were inserted into patients' thigh with planned study participation of 72 h. Sensor glucose results were displayed, and the system's alerts and alarms fully enabled. Reference blood glucose was collected from central venous catheter and analyzed with a blood gas analyzer. Treatment decisions were made independently of sensor glucose values, according to the existing standard of care. RESULTS: A total of 21 patients were enrolled; all successfully completed the study. Sensor glucose values were displayed 96% of the time, and 870 paired blood glucose-sensor glucose points were analyzed. Overall mean absolute relative difference (MARD) was 12.8% (95% CI 11.9% to 13.6%). No clinically significant differences in accuracy were seen within subgroups of hemodynamic status (MARD 12.3% and 13.1% for compromised vs stable hemodynamics). Consensus grid analysis showed >99% of sensor glucose values within A/B zones. No device or study-related adverse events were reported. 100% of clinicians found Sentrino easy to use after two patients. CONCLUSIONS: In our single-center experience, Sentrino CGM system demonstrated good accuracy and reliability, with no device-related adverse events in critically ill cardiac patients, and was easy to use and integrate in the cardiac ICU. TRIAL REGISTRATION NUMBER: NCT01763567. PMID- 25452875 TI - Serum alpha-hydroxybutyrate (alpha-HB) predicts elevated 1 h glucose levels and early-phase beta-cell dysfunction during OGTT. AB - OBJECTIVE: Serum alpha-hydroxybutyrate (alpha-HB) is elevated in insulin resistance and diabetes. We tested the hypothesis that the alpha-HB level predicts abnormal 1 h glucose levels and beta-cell dysfunction inferred from plasma insulin kinetics during a 75 g oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: This cross-sectional study included 217 patients at increased risk for diabetes. 75 g OGTTs were performed with multiple postload glucose and insulin measurements over a 30-120 min period. OGTT responses were analyzed by repeated measures analysis of variance (ANOVA). Multivariable logistic regression was used to predict 1 h glucose >=155 mg/dL with alpha-HB added to traditional risk factors. RESULTS: Mean+/-SD age was 51+/-15 years (44% male, 25% with impaired glucose tolerance). Fasting glucose and insulin levels, but not age or body mass index (BMI), were significantly higher in the second/third alpha-HB tertiles (>3.9 ug/mL) than in the first tertile. Patients in the second/third alpha-HB tertiles exhibited a higher glucose area under the receiver operating characteristics curve (AUC) and reduced initial slope of insulin response during OGTT. The AUC for predicting 1 h glucose >=155 mg/dL was 0.82 for a base model that included age, gender, BMI, fasting glucose, glycated hemoglobin (HbA1c), and insulin, and increased to 0.86 with alpha-HB added (p=0.015), with a net reclassification index of 52% (p<0.0001). CONCLUSIONS: Fasting serum alpha-HB levels predicted elevated 1 h glucose during OGTT, potentially due to impaired insulin secretion kinetics. This association persisted even in patients with an otherwise normal insulin-glucose homeostasis. Measuring serum alpha-HB could thus provide a rapid, inexpensive screening tool for detecting early subclinical hyperglycemia, beta-cell dysfunction, and increased risk for diabetes. PMID- 25452876 TI - Age at diagnosis predicts deterioration in glycaemic control among children and adolescents with type 1 diabetes. AB - BACKGROUND: Poor glycemic control early in the course of type 1 diabetes mellitus (T1DM) increases the risk for microvascular complications. However, predictors of deteriorating control after diagnosis have not been described, making it difficult to identify high-risk patients and proactively provide aggressive interventions. OBJECTIVE: We examined whether diagnostic age, gender, and race were associated with deteriorating glycemic control during the first 5 years after diagnosis. PARTICIPANTS: 2218 pediatric patients with T1DM. METHODS: We conducted a longitudinal cohort study of pediatric patients with T1DM from the Midwest USA, 1993-2009, evaluating within-patient glycated hemoglobin (HbA1c) trajectories constructed from all available HbA1c values within 5 years of diagnosis. RESULTS: 52.6% of patients were male; 86.1% were non-Hispanic Caucasian. The mean diagnostic age was 9.0+/-4.1 years. The mean number of HbA1c values/year/participant was 2.4+/-0.9. HbA1c trajectories differed markedly across age groups, with older patients experiencing greater deterioration than their younger counterparts (p<0.001). HbA1c trajectories, stratified by age, varied markedly by race (p for race*diagnostic age <0.001). Non-Hispanic African American patients experienced higher initial HbA1c (8.7% vs 7.6% (71.6 vs 59.6 mmol/mol); p<0.001), and greater deterioration in HbA1c than non-Hispanic Caucasian patients across diagnostic ages (rise of 2.04% vs 0.99% per year (22.3 vs 10.8 mmol/mol/year); p<0.0001). CONCLUSIONS: Older diagnostic age and black race are major risk factors for deterioration in glycemic control early in the course of T1DM. These findings can inform efforts to explore the reasons behind these differences and develop preventive interventions for high-risk patients. PMID- 25452877 TI - Diabetes care and outcomes for American Indians and Alaska natives in commercial integrated delivery systems: a SUrveillance, PREvention, and ManagEment of Diabetes Mellitus (SUPREME-DM) Study. AB - OBJECTIVE: To compare cardiovascular disease risk factor testing rates and intermediate outcomes of care between American Indian/Alaska Native (AI/AN) patients with diabetes and non-Hispanic Caucasians enrolled in nine commercial integrated delivery systems in the USA. RESEARCH DESIGN AND METHODS: We used modified Poisson regression models to compare the annual testing rates and risk factor control levels for glycated haemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), and systolic blood pressure (SBP); number of unique diabetes drug classes; insulin use; and oral diabetes drug medication adherence between insured AI/AN and non-Hispanic white adults with diabetes aged >=18 in 2011. RESULTS: 5831 AI/AN patients (1.8% of the cohort) met inclusion criteria. After adjusting for age, gender, comorbidities, insulin use, and geocoded socioeconomic status, AI/AN patients had similar rates of annual HbA1c, LDL-C, and SBP testing, and LDL-C and SBP control, compared with non-Hispanic Caucasians. However, AI/AN patients were significantly more likely to have HbA1c >9% (>74.9 mmol/mol; RR=1.47, 95% CI 1.38 to 1.58), and significantly less likely to adhere to their oral diabetes medications (RR=0.90, 95% CI 0.88 to 0.93) compared with non Hispanic Caucasians. CONCLUSIONS: AI/AN patients in commercial integrated delivery systems have similar blood pressure and cholesterol testing and control, but significantly lower rates of HbA1c control and diabetes medication adherence, compared with non-Hispanic Caucasians. As more AI/ANs move to urban and suburban settings, clinicians and health plans should focus on addressing disparities in diabetes care and outcomes in this population. PMID- 25452878 TI - The reliability of in-hospital diagnoses of diabetes mellitus in the setting of an acute myocardial infarction. AB - OBJECTIVE: Incident diabetes mellitus (DM) is important to recognize in patients with acute myocardial infarction (AMI). To develop an efficient screening strategy, we explored the use of random plasma glucose (RPG) at admission and fasting plasma glucose (FPG) to select patients with AMI for glycosylated hemoglobin (HbA1c) testing. DESIGN SETTING ANDPARTICIPANTS: Prospective registry of 1574 patients with AMI not taking glucose-lowering medication from 24 US hospitals. All patients had HbA1c measured at a core laboratory and admission RPG and >=2 FPGs recorded during hospitalization. We examined potential combinations of RPG and FPG and compared these with HbA1c>=6.5%-considered the gold standard for DM diagnosis in these analyses. RESULTS: An RPG>140 mg/dL or FPG>=126 mg/dL had high sensitivity for DM diagnosis. Combining these into a screening protocol (if admission RPG>140, check HbA1c; or if FPG>=126 on a subsequent day, check HbA1c) led to HbA1c testing in 50% of patients and identified 86% with incident DM (number needed to screen (NNS)=3.3 to identify 1 case of DM; vs NNS=5.6 with universal HbA1c screening). Alternatively, using an RPG>180 led to HbA1c testing in 40% of patients with AMI and identified 82% of DM (NNS=2.7). CONCLUSIONS: We have established two potential selective screening methods for DM in the setting of AMI that could identify the vast majority of incident DM by targeted screening of 40-50% of patients with AMI with HbA1c testing. Using these methods may efficiently identify patients with AMI with DM so that appropriate education and treatment can be promptly initiated. PMID- 25452879 TI - Plasma levels of galectin-3-binding protein reflect type I interferon activity and are increased in patients with systemic lupus erythematosus. AB - OBJECTIVE: Simple measures of type I interferon (IFN) activity constitute highly attractive biomarkers in systemic lupus erythematosus (SLE). We explore galectin 3-binding protein (G3BP) as a novel measure of type I IFN activity and serum/plasma biomarker in large independent cohorts of patients with SLE and controls. METHODS: Serum and plasma G3BP concentrations were quantified using ELISA. Type I IFN activity was assessed by Mx1 reporter gene expression assays and correlated to serum G3BP concentrations (SLE-IFN-alpha, n=26 and healthy controls (HCs), n=10). Plasma G3BP concentrations in the SLE-Denmark (DK) (n=70) and SLE-Sweden (SE) (n=68) cohorts were compared with the HC-DK (n=47) and HC-SE (n=50) cohorts and patients with systemic sclerosis (n=111). In 15 patients with SLE, serum G3BP in consecutive samples was correlated to disease activity. Correlation analysis between G3BP, clinical parameters including disease activity in the four SLE cohorts was performed. RESULTS: G3BP concentrations correlated significantly with the IFN-alpha reporter gene assay (r=0.56, p=0.0005) and with IFN-alpha gene expression scores (r=0.54, p=0.0002). Plasma concentrations were significantly increased in the SLE-DK and SLE-SE cohorts compared with HCs and patients with systemic sclerosis (p<0.0001 and p=0.0009). G3BP concentrations correlated with disease activity measures in the SLE-DK- and SLE-IFN-alpha cohorts (p=0.0004 and p=0.05) but not in the SLE-SE cohort (p=0.98). Markedly temporal variation was observed in G3BP levels in the consecutive SLE-samples and was significantly associated with changes in disease activity (r=0.44, p=0.014). CONCLUSIONS: G3BP plasma levels reflect type I IFN activity and are increased in SLE. Associations with disease activity or clinical manifestations are uncertain. This study highlights G3BP as a convenient measure of type I IFN-dependent gene activation. PMID- 25452881 TI - Pink Breast Milk: Serratia marcescens Colonization. AB - Background Breast milk can turn pink with Serratia marcescens colonization, this bacterium has been associated with several diseases and even death. It is seen most commonly in the intensive care settings. Discoloration of the breast milk can lead to premature termination of nursing. We describe two cases of pink colored breast milk in which S. marsescens was isolated from both the expressed breast milk. Antimicrobial treatment was administered to the mothers. Return to breastfeeding was successful in both the cases. Conclusions Pink breast milk is caused by S. marsescens colonization. In such cases,early recognition and treatment before the development of infection is recommended to return to breastfeeding. PMID- 25452880 TI - Patients with systemic lupus erythematosus and haematological malignancy at a tertiary care centre: timing, histopathology and therapy. AB - OBJECTIVES: Patients with systemic lupus erythematosus (SLE) are at higher risk of haematological malignancies (HMs) than the general population. Most reports have focused on HM diagnosed after SLE, and have excluded concurrent and preceding diagnoses. Information on response to therapy is also limited. METHODS: We identified 13 296 cases of HM and 10 539 potential patients with SLE at our centre; 45 patients were confirmed to have HM and SLE. Our retrospective case series was based on these 45 patients. RESULTS: Of the 45 patients, 64% were diagnosed with HM >=1 year after diagnosis with SLE, and 36% with HM before or concurrent with SLE. Of the 29 patients with HM after SLE, 13 had diffuse large B cell lymphoma (DLBCL), 6 indolent lymphoma, 4 leukaemia, 3 Hodgkin's disease, and 1 each Burkitt's lymphoma, T cell lymphoma and multiple myeloma. Eleven patients with DLBCL were treated with cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP) or rituximab-CHOP; hydroxydaunorubicin, oncovin and prednisone; only four achieved durable remission. Of the 16 patients diagnosed with HM before or concurrent with SLE, 9 were diagnosed with HM more than 2 years before SLE and tended to be in remission prior to SLE diagnosis. Seven patients were diagnosed with HM and SLE concurrently; in terms of their HM, six achieved remission or stable disease. CONCLUSIONS: In summary, DLBCL was the most common type of lymphoma in patients diagnosed with HM after SLE; these patients presented with advanced-stage disease and had poor outcomes. In contrast, patients diagnosed with HM before or concurrent with SLE had early stage disease and typically achieved remission. PMID- 25452882 TI - Microvillus inclusion disease associated with necrotizing enterocolitis in a premature infant. AB - Microvillus inclusion disease is one of the congenital diarrheal disorders characterized by the appearance of inclusion bodies on the intestinal epithelium. To date there are a few cases and also a few other associated finding reports related to this life-threatening disease in literature. In this report, we present a premature infant with microvillus inclusion disease that was associated with necrotizing enterocolitis. Thus, we should be aware of the appearance of necrotizing enterocolitis in patients with microvillus inclusion disease, especially when contributing factors are present. PMID- 25452883 TI - Ultrasonographic Evaluation of Uterine Scar Niche before and after Laparoscopic Surgical Repair: A Case Report. AB - Context Uterine scar defects or scar niche are relatively common after cesarean delivery. An association has been observed between the severity of scar defect, also known as isthmocele, some gynecologic symptoms, and the risk of uterine scar dehiscence at the next delivery. It has been suggested that surgical repair of scar defect could improve the gynecological symptoms, but it remains unclear whether such surgery mends the uterine scar itself. Case Report We report the case of a woman with uterine scar defect in whom laparoscopic repair significantly improved the gynecological symptoms without affecting the uterine scar, evaluated by hysterosonography. Conclusion This case highlights the significant dearth of knowledge surrounding the diagnosis, consequences, and benefits of surgical repair of uterine scar defect after cesarean. PMID- 25452884 TI - Purpura fulminans and late onset group B streptococcal sepsis in a premature twin. AB - INTRODUCTION: Purpura fulminans (PF) is a skin manifestation due to hemorrhagic infarction caused by intravascular thrombosis secondary to bacterial infections or deficiency of anticoagulants such as protein C and protein S. Neonatal PF is a rare but potentially disabling disorder associated with a high mortality and severe long term morbidity in those who survive. CASE DESCRIPTION: We report a case of a premature infant who developed extensive PF due to late onset group B streptococcus sepsis. Despite early identification and initiation of antibiotic therapy in our patient, PF progressed rapidly, leading to autoamputation of fingers and toes and severe brain injury. CONCLUSION: In conclusion, our case highlights the severe sequelae of PF due to late onset GBS sepsis in a premature infant. PMID- 25452885 TI - Severe cystic periventricular leukomalacia in a premature infant with capnocytophaga sepsis. AB - Capnocytophaga is an opportunistic gram-negative anaerobic bacillus found in the oropharyngeal cavity of mammals and is associated with periodontal disease in humans. Sepsis, osteomyelitis, lung abscess, endocarditis, and meningitis have been reported in humans following animal bites. Perinatal infection with Capnocytophaga is infrequent and is generally considered to have a low risk of morbidity to the mother and fetus. We report a case of neonatal Capnocytophaga sepsis associated with the development of severe cystic periventricular leukomalacia. PMID- 25452886 TI - Neonatal volkmann ischemic contracture: case report and review of literature. AB - Background Neonatal Volkmann ischemic contracture in newborns is a devastating condition with lifelong consequences. Case Report We report a neonate born with necrotic skin lesions and bullae on right dorsal thenar aspect of hand, who subsequently developed compartment syndrome requiring fasciotomy. Review and Conclusion Necrotic skin lesions with/without swelling, bullae are invariably present at birth in these patients and should be recognized as a sentinel finding of underlying tissue ischemia/compartment syndrome. Early recognition and prompt surgical intervention can be limb saving. A range of radiologic abnormalities and contractures were noted in upto 84% of such patients followed long term. Hence, we recommend close follow-up until occurrence of epiphyseal fusion in these patients. PMID- 25452887 TI - Infantile perineal protrusion in two monochorionic twins. AB - Case Report Two female monochorionic-monoamniotic twins showed the same kind of infantile perineal protrusion (IPP) at birth. Lesions in both twins progressively healed until resolution in 6 weeks' time; none of the twins have manifested, till date, alvus disturbances. Discussion and Literature Review A literature review numbers approximately 100 reports of IPP. This condition has been classically classified into three categories: congenital/familiar (i.e., female sex, positive parental history of IPP), acquired (mainly due to constipation), and associated with lichen sclerosus et atrophicus. Conclusions and Final Remarks This case report describes, for the first time, the presence of IPP in monochorionic monoamniotic twins, supporting the existence of hereditary/genetic factors in the developing of this condition. PMID- 25452888 TI - Prenatal diagnosis of coronary artery fistula: a case report and review of literature. AB - We report an antenatally diagnosed large distal coronary artery fistula (CAF) arising from an aneurysmal dilation right coronary artery (RCA) and draining in to the right ventricle (RV) just below the septal leaflet of tricuspid valve posteriorly. A postnatal echocardiogram confirmed the diagnosis. On the second day of life, a percutaneous partial closure of the fistula was performed by placing a Flipper coil (Cook Medical, Bloomington, IN) in the RCA just proximal to the drainage site in the cardiac catheterization laboratory. Follow-up echocardiogram on the day following the procedure showed improved forward flow in the descending aorta with decreased RV size. Our case report suggests that antenatal diagnosis of a CAF may aid in early intervention. Partial closure of the fistula in the cardiac catheterization laboratory is safe and effective. PMID- 25452889 TI - Life-Threatening QT Prolongation in a Preterm Infant. AB - Introduction Temporary QT-interval prolongation following intracranial hemorrhage and hydrocephalus has been repeatedly reported in adults. Case We report a case of excessive QT prolongation with sudden bradycardia resulting in 2:1 atrioventricular conduction in a preterm infant most likely associated with a congenital hydrocephalus. Pathomechanisms are discussed. Conclusion Congenital hydrocephalus predisposes to excessive QT prolongation in preterm infants. PMID- 25452890 TI - Counseling a patient with the antenatal diagnosis of a cerebellar abnormality and a pharyngeal cyst. AB - Introduction Prenatal counseling with regards to the prognosis of a cerebellar abnormality is hindered not only by the diverse clinical presentations but also by the presence of subtle findings. We present a case of a distinct combination of asymmetric cerebellar hypoplasia secondary to an anterior meningoencephalocele through a clival defect that caused a severe airway obstruction in the newborn. Case Description A 21-year-old gravida 4 para 0 mother with a dichorionic diamniotic twin pregnancy was referred for a second trimester sonographic survey. An asymmetric cerebellar hypoplasia, mega cisterna magna, and a pharyngeal cystic mass were noted on twin A. Magnetic resonance imaging report confirmed posterior fossa abnormalities and shed no light on the differential diagnosis of the cystic mass. The pregnancy ended by Cesarean delivery at 32 weeks' gestation after a preterm premature rupture of the membranes. Twin A had a severe airway obstruction. Postnatal evaluation confirmed a midline anterior meningoencephalocele through a defect in the clivus. The microarray chromosomal analysis demonstrated a 5q15 variant with uncertain clinical significance. Conclusion Antenatal recognition of the unique combination of a cerebellar hypoplasia with a pharyngeal cyst can impact the prenatal counseling as well as neonatal management. PMID- 25452891 TI - Neonatal hypercalcemia secondary to subcutaneous fat necrosis successfully treated with pamidronate: a case series and literature review. AB - Subcutaneous fat necrosis (SCFN) is a noninfectious panniculitis that occurs in term infants who experience significant distress in the 1st weeks of life, including hypoxic ischemic encephalopathy (HIE). Since the introduction of therapeutic hypothermia for HIE, there have been a few published case reports of SCFN, following this modality of treatment. Although, most cases of SCFN resolve spontaneously, SCFN may be associated with hypercalcemia, which may sometimes reach dangerous levels. Approaches used for the management of this potentially life-threatening condition, include hyperhydration, calciuric diuretics, corticosteroids, and in more resistant cases pamidronate, a bisphosphonate. We report our experience on the use of pamidronate in two cases of severe hypercalcemia associated with SCFN following therapeutic hypothermia for HIE. We believe that with increasing use of therapeutic hypothermia for HIE, clinicians are likely to encounter this condition more frequently. PMID- 25452892 TI - Prenatal diagnosis of fetal encephalomalacia after maternal diabetic ketoacidosis. AB - Introduction Encephalomalacia in a developing fetus is a rare and devastating neurological finding on radiologic imaging. Maternal diabetic ketoacidosis (DKA) can lead to metabolic and vascular derangements which can cause fetal encephalomalacia. Case We report the case of a 27-year-old pregnant woman with White's Class C diabetes mellitus who presented in the 25th week of gestation with DKA. Four weeks after her discharge, marked fetal cerebral ventriculomegaly was noted on ultrasound. A subsequent fetal magnetic resonance imaging (MRI) demonstrated extensive, symmetric cystic encephalomalacia, primarily involving both cerebral hemispheres. The pregnancy was continued with close fetal and maternal surveillance. The patient underwent a repeat cesarean delivery in her 37th week. The infant had a 1 month neonatal intensive care unit stay with care rendered by a multiple disciplinary team of pediatric subspecialists. The postnatal course was complicated by global hypotonia, poor feeding, delayed development and ultimately required anticonvulsants for recurrent seizures. He died at the age of 9 months from aspiration during a seizure. Discussion Although the maternal mortality from DKA has declined, DKA still confers significant neurological fetal morbidity to its survivors. PMID- 25452893 TI - Changes in computed tomography perfusion parameters after superficial temporal artery to middle cerebral artery bypass: an analysis of 29 cases. AB - Introduction Analysis of computed tomography perfusion (CTP) studies before and after superficial temporal artery to middle cerebral artery (STA-MCA) bypass is warranted to better understand cerebral steno-occlusive pathology. Methods Retrospective review was performed of STA-MCA bypass patients with steno occlusive disease with CTP before and after surgery. CTP parameters were evaluated for change after STA-MCA bypass. Results A total of 29 hemispheres were bypassed in 23 patients. After STA-MCA bypass, mean transit time (MTT) and time to peak (TTP) improved. When analyzed as a ratio to the contralateral hemisphere, MTT, TTP, and cerebral blood flow (CBF) improved. There was no effect of gender, double vessel versus single vessel bypass, or time until postoperative CTP study to changes in CTP parameters after bypass. Conclusions Blood flow augmentation after STA-MCA bypass may best be assessed by CTP using baseline MTT or TTP and ratios of MTT, TTP, or CBF to the contralateral hemisphere. The failure of cerebrovascular reserve to improve after cerebral bypass may indicate irreversible loss of autoregulation with chronic cerebral vasodilation or the inability of CTP to detect these improvements. PMID- 25452894 TI - Complex anatomy of the sphenoid sinus: a radiographic study and literature review. AB - Objectives Nasal endoscopic approaches to the sphenoid sinus are challenging. Variations in septation, shape, and dimensions have a critical impact on surgical planning of the skull base. Previous anatomical studies have small numbers or a limited description of this complex structure. The present study is a radiographic analysis of the septation and dimensions of the sphenoid sinus. Design and Methods High-resolution surgical-guidance computed tomography images of the sinuses from 90 patients at a tertiary care medical center between 2002 and 2007 were studied. Multiple anatomical measurements from axial and sagittal images were obtained and analyzed with imaging and statistical software. Results Of the 90 patients studied, 9% had presellar, 37% sellar, and 54% postsellar pneumatization. In 34%, the posterior extent of the intersinus septum involved the bony covering of the carotid artery. The average presellar width of the sinus was 1.3 cm, the average midline presellar depth was 1.4 cm, and the average infrasellar midline depth was 2.6 cm. Conclusions Approaching the skull base through the sphenoid sinus requires a tailored process based on anatomy. Septal involvement of the carotid artery occurs frequently. Pneumatization patterns are potentially disorienting, and awareness of the sinus's posterior and lateral extensions is critical. PMID- 25452895 TI - Treatment and Outcome of Patients with Skull Base Chordoma: A Meta-analysis. AB - Objective Chordoma is a locally aggressive tumor. The aim of this study was to assess the efficacy of different surgical approaches and adjuvant radiation modalities used to treat these patients. Design Meta-analysis. Main Outcome Measures Overall survival (OS), disease-specific survival (DSS), and progression free survival (PFS). Results The 5-year OS and PFS rates of the whole cohort (n = 467) were 86% and 65.7%, respectively. The 5-year DSS for patients who underwent open surgery and endoscopic surgery was 45% and 49%, respectively (p = 0.8); PFS was 94% and 79%, respectively (p = 0.11). The 5-year OS of patients treated with surgery followed by adjuvant radiotherapy was 90% compared with 70% of those treated by surgery alone (p = 0.24). Patients undergoing partial resection without adjuvant radiotherapy had a 5-year OS of 41% and a DSS of 45%, significantly lower than in the total-resection group (p = 0.0002 and p = 0.01, respectively). The complication rates were similar in the open and endoscopic groups. Conclusions Patients undergoing total resection have the best outcome; adjuvant radiation therapy improves the survival of patients undergoing partial resection. In view of the advantages of minimally invasive techniques, endoscopic surgery appears an appropriate surgical approach for this disease. PMID- 25452896 TI - Subtotal petrosectomy and cerebrospinal fluid leakage in unilateral anacusis. AB - Objective This study presents a group of patients experiencing recurrent cerebrospinal fluid (CSF) leakage associated with ipsilateral anacusis who underwent subtotal petrosectomies with the goal of stopping the CSF leak and preventing meningitis. Materials and Methods Eight patients with CSF leakage were enrolled: three patients with giant vestibular schwannomas had CSF leakage after gamma knife failure and subsequent removal via a retrosigmoid approach; two patients had malformations at the level of the inner ear with consequent translabyrinthine fistulas; two had posttraumatic CSF leakages; and one had a CSF leakage coexisting with an encephalocele. Two patients developed meningitis that resolved with antibiotic therapy. Each patient had preoperative anacusis and vestibular nerve areflexia on the affected side. Results The patients with congenital or posttraumatic CSF leaks had undergone at least one unsuccessful endaural approach to treat the fistula. All eight patients were treated successfully with a subtotal petrosectomy. The symptoms disappeared within 2 months postoperatively. No meningitis, signs of fistula, or other symptoms occurred during the follow-up. Conclusion A subtotal petrosectomy should be the first choice of treatment in patients with recurrent CSF leakage whenever there is associated unilateral anacusis. PMID- 25452897 TI - Outcomes and complications of gamma knife radiosurgery for skull base meningiomas. AB - Objective To review the outcomes and complications of meningiomas treated with gamma knife radiosurgery (GKRS) as a primary treatment as well as an adjunct therapy. Materials and Methods We performed a retrospective review (2000-2013) of 136 patients with meningiomas who received GKRS. Of 136 patients, 68 patients had recurrent or residual tumors after microsurgical resection, and the other 68 patients received GKRS alone. The study population was evaluated clinically and radiographically after GKRS treatment. Results GKRS in meningiomas showed significant variations in tumor growth control (decreased in 69 patients [50.7%], arrested growth in 47 patients [34.6%], and increased tumor size in 20 patients [14.7%]). Progression-free survival rates after GKRS at 3, 5, and 10 years were 98%, 95% and 85%, respectively. Overall improvement of signs and symptoms after GKRS was 30% (71% versus 41%) compared with pretreated sign and symptoms (p = 0.0001). The Karnofsky performance scale was significantly improved after GKRS compared with the pretreated status (92 versus 80). Twenty patients (14.7%) required resection after initial GKRS. Conclusion These study findings revealed that GKRS offers a high rate of tumor control, preservation of multiple nerve functions, and a good quality of life in both new and recurrent patients with meningiomas. PMID- 25452898 TI - Diagnosis and Management of Dural Sinus Thrombosis following Resection of Cerebellopontine Angle Tumors. AB - Objective Lateral sinus thrombosis is a potentially devastating but seldom studied complication of cerebellopontine angle (CPA) tumor surgery. Systemic anticoagulation in the early postoperative period has often been avoided due to the potential risks of intracranial hemorrhage. Design Retrospective review. Setting Tertiary referral center. Main Outcome Measures The goal of this study was to identify the frequency, treatment, and outcomes in patients who develop postoperative venous sinus thrombosis following CPA tumor surgery and receive early systemic anticoagulation. Results Of 43 patients with CPA tumors, we report five patients (11.6%) with transverse and/or sigmoid sinus thrombosis following resection of the tumor, four of which were detected on routine early postoperative noncontrast computed tomography (CT) scan. The thrombosis was confirmed in all cases with CT venography or magnetic resonance venography. Affected patients had significantly larger tumors than controls and tended to undergo longer operations. These patients were treated with immediate anticoagulation (intravenous heparin, followed by Coumadin for 6 months) without complication. Conclusion Venous sinus thrombosis is an underrecognized complication of CPA surgery, but it can be diagnosed in the early postoperative period by noncontrast CT imaging. Early postoperative initiation of systemic anticoagulation appears safe and effective to prevent the progression of thrombosis and its consequences. PMID- 25452899 TI - Radiosurgery is an Effective Treatment for Recurrent Esthesioneuroblastoma: A Multicenter Study. AB - Objective Esthesioneuroblastoma (ENB) is a rare malignant neuroendocrine neoplasm that is prone to both local and metastatic recurrence. Local recurrence may often be treated with repeat resection. However, stereotactic radiosurgery (SRS) offers a noninvasive option. Design Prospective database review. Participants Gamma knife prospective databases were queried at all institutions within the North American Gamma Knife Consortium, 16 at the time of this report. All patients who had undergone SRS for ENB were included. Main Outcome Measure Response of recurrent ENB to SRS. Results A total of 31 locally recurrent tumors in 13 patients were treated with SRS. The median age was 49 years (range: 19-79 years). At a median follow-up of 36 months (range: 1-100 months), 13 (48%) treated tumors were smaller, 11 (41%) were stable, and 3 (11%) showed continued growth following SRS. Univariate analysis did not find any significant factor relating to failure of treatment. Notably, no treatment-related complications (0%) were observed in this cohort. Conclusion SRS appears to provide a safe and effective option for treatment of recurrent intracranial ENB. Overall, 89% of treated tumors were controlled in this multi-institutional study. PMID- 25452900 TI - The endoscopic hemi-transseptal approach to the sella turcica: operative technique and case-control study. AB - Background The hemi-transeptal (Hemi-T) approach was developed to facilitate a binasal two-surgeon endoscopic approach for sellar tumors, with preservation of the nasoseptal flap and selective mobilization for reconstruction. Methods A retrospective case-control study was performed comparing the Hemi-T approach with previously used methods of sellar exposure and reconstruction. Outcome measures included operative time and postoperative nasal morbidity. Results A total of 23 patients underwent the Hemi-T approach versus 42 in whom traditional exposure was performed. Operative time was significantly shorter using the Hemi-T technique (152.6 +/- 56.8 versus 205.2 +/- 61.3 minutes; p = 0.001), as was the length of hospital stay (3.3 +/- 1.9 versus 5.4 +/- 3.6 days; p = 0.004). There was no difference in the rates of intraoperative or postoperative cerebrospinal fluid leak, cartilage necrosis, septal perforation, or mucosal adhesions. Conclusion The Hemi-T approach facilitates binasal two-surgeon access to the sella without compromise of the pedicle during the extended sphenoidotomies and tumor removal. Operative time and nasal morbidity is not increased, and iatrogenic injury to the nasal cavity is minimized when a flap is not required. PMID- 25452901 TI - Use of superior thyroid artery as a donor vessel in extracranial-intracranial revascularization procedures: a novel technique. AB - Objective To describe the use of the superior thyroid artery as a donor vessel in extracranial-intracranial (EC-IC) revascularization when a "low-flow" bypass is required and the superficial temporal artery is not available. Design Case report. Setting University hospital. Participants Four cases. Main Outcome Measures Postoperative course after EC-IC bypass surgery. Results In case 1, the parent vessel was occluded postoperatively. The radial bypass was sufficient to replace the internal carotid artery (ICA) flow, and a prophylactic was turned into a definitive bypass. In case 2, the superior thyroid artery was used because the radial artery was not long enough to reach the external carotid artery. The recipient vessel was modified from the middle cerebral artery to the ophthalmic segment of the ICA. In case 3, the graft was occluded after surgery because of carotid artery reconstruction. In case 4, after surgery/radiotherapy for meningioma, the patient developed wound dehiscence and was reoperated for bypass occlusion. The graft was weak and bled intraoperatively, without infarction. The three first patients are intact, and the fourth remains disabled (Glasgow Outcome Scale: 3; Rankin Scale: 5). Conclusion The superior thyroid artery was adequate for proximal anastomosis in EC-IC procedures in the situations described. PMID- 25452902 TI - Clinical correlates of the anatomical relationships of the foramen ovale: a radioanatomical study. AB - Introduction Endonasal endoscopic transpterygoid approaches are commonly used techniques to access the infratemporal fossa and parapharyngeal space. Important endoscopic endonasal landmarks for the poststyloid parapharyngeal space, hence the internal carotid artery, include the mandibular nerve at the level of foramen ovale and the lateral pterygoid plate. This study aims to define the anatomical relationships of the foramen ovale, establishing its distance to other important anatomical landmarks such as the pterygoid process and columella. Methods Distances between the foramen ovale, foramen rotundum, and fixed anatomical landmarks like the columella and pterygoid process were measured using computed tomography (CT) scans and cadaveric dissections of the pterygopalatine and infratemporal fossae. Results The mean distances from the foramen ovale to columella and from the foramen rotundum to columella were found to be 9.15 cm and 7.09 cm, respectively. Analysis of radiologic measurements detected no statistically significant differences between sides or gender. Conclusions The pterygoid plates and V3 are prominent landmarks of the endonasal endoscopic approach to the infratemporal fossa and poststyloid parapharyngeal space. A better understanding of the endoscopic anatomy of the infratemporal fossa and awareness of the approximate distances and geometry among anatomical landmarks facilitates a safe and complete resection of lesions arising or extending to these regions. PMID- 25452903 TI - The cadaveric perfusion and angiography as a teaching tool: imaging the intracranial vasculature in cadavers. AB - Background and Study Aim To enhance the visualization of the intracranial vasculature of cadavers under gross examination with a combination of imaging modalities. Material and Methods A total of 20 cadaver heads were used to test two different perfusion techniques. First, fixed cadaver heads were perfused with water; second, fresh cadavers were perfused with saline and 10% formalin. Subsequently, brains were removed and fixed. The compounds used were silicone rubber, silicone rubber mixed with powdered barium sulfate, and silicone rubber mixed with tantalum dioxide prepared by the first perfusion technique and gelatin mixed with liquid barium prepared with the second technique. Conventional X-ray imaging, computed tomography (CT), dynamic computed tomography (dCT), and postprocessing three-dimensional (3D) images were used to evaluate all the heads. Results Gelatinized barium was better visualized when compared with tantalum dioxide in conventional X-ray images. The blood vessels injected with either tantalum dioxide or gelatinized barium demonstrated a higher enhancement than the surrounding soft tissues with CT or dCT. The quality of the 3D reconstruction of the intracranial vasculature was significantly better in the CT images obtained from the gelatinized barium group. Conclusions Radiologic examinations of the heads injected with gelatinized barium facilitates the 3D understanding of cerebrovascular anatomy as an important tool for neuroanatomy training. PMID- 25452904 TI - The cost-utility of left ventricular assist devices for end-stage heart failure patients ineligible for cardiac transplantation: a systematic review and critical appraisal of economic evaluations. AB - BACKGROUND: A health technology assessment (HTA) of left ventricular assist devices (LVADs) as destination therapy in patients with end-stage heart failure was commissioned by the Dutch Health Care Insurance Board [College voor Zorgverzekeringen (CVZ)]. In this context, a systematic review of the economic literature was performed to assess the procedure's value for money. METHODS: A systematic search (updated in December 2013) for economic evaluations was performed by consulting various databases: the HTA database produced by the Centre for Reviews and Dissemination (CRD HTA), websites of HTA institutes, CRD's National Health Service Economic Evaluation Database (NHS EED), Medline (OVID) and EMBASE. No time or language restrictions were imposed and pre-defined selection criteria were used. The two-step selection procedure was performed by two people. References of the selected studies were checked for additional relevant citations. RESULTS: Six relevant studies were selected. Four economic evaluations relied on the results of the REMATCH trial to compare a pulsatile flow LVAD with optimal medical therapy (OMT). These evaluations were performed before the publication of the HeartMate II (HM-II) Destination Therapy Trial which compared a pulsatile-flow with a continuous-flow LVAD. Two more recent economic evaluations combined the results of both trials to make an indirect comparison of a continuous-flow LVAD with OMT. In all studies, the largest part of the incremental cost was due to the reimplantation cost of an LVAD, with a device cost of ?58,000-?75,000 and about ?55,000 for the surgical procedure. The survival gain was highest with a continuous-flow LVAD, up to about three life years gained (LYG) versus OMT in the most optimistic study. Quality of life (QoL) was improved but measures with a generic utility instrument were lacking, making estimates on quality-adjusted life-years (QALYs) gained more uncertain. Incremental cost-effectiveness ratios of the two most recent studies were on average ?107,600 and $198,184 (ca.?145,800) per QALY gained. CONCLUSIONS: Although LVAD destination therapy improves survival and QoL, it remains questionable as to whether it offers value for money. This conclusion may alter if the price of the device/procedure decreases sufficiently, in combination with further improved outcomes for mortality, adverse events and QoL. PMID- 25452905 TI - Pump thrombosis-A riddle wrapped in a mystery inside an enigma. AB - This manuscript reviews the state of the art regarding the subject of pump thrombosis (PT). The historical context of PT and the clinical data are described, the etiologic factors are elucidated, preventive strategies are explored, diagnostic modalities are reviewed, and management principles are defined. There clearly remains much work to be done towards solving this riddle wrapped in a mystery inside an enigma, but promising foundations are being established. PMID- 25452906 TI - Different surgical strategies for implantation of continuous-flow VADs-Experience from Deutsches Herzzentrum Berlin. AB - OBJECTIVE: This manuscript summarizes our surgical experience with the implantation of recent continuous-flow left ventricular assist devices (LVADs), with special emphasis on the HeartWare HVAD pump. METHODS: THE HEARTWARE HVAD IS, IN OUR EXPERIENCE CURRENTLY IMPLANTED IN FOUR DIFFERENT TECHNIQUES: (I) "Classical" LVAD implantation with heart-lung machine and median sternotomy; (II) "Minimally-invasive" implantation without sternotomy and without heart-lung machine; (III) "Lateral implantation" to the descending aorta; (IV) Using two continuous-flow LVADs for implantable biventricular support. RESULTS: Five hundred and four HeartWare HVADs have been implanted using the described techniques in our institution up to now. CONCLUSIONS: The HeartWare HVAD is a versatile device. It has been found to be eminently suited to these four different modes of implantation. PMID- 25452907 TI - Gastrointestinal bleed after left ventricular assist device implantation: incidence, management, and prevention. AB - BACKGROUND: Continuous-flow left ventricular assist devices (CF-LVADs) have become the standard of care for patients with end-stage heart failure (HF). While these devices have improved durability compared to earlier generation left ventricular assist devices (LVADs), increased frequency in some complications has been seen, including gastrointestinal bleeding (GIB), pump thrombosis and hemolysis. We discuss the incidence, management and prevention of GIB after CF LVAD implantation. METHODS: We reviewed the current literature available on the incidence, management and prevention of GIB after CF-LVAD implantation with a focus on our experience at the University of Minnesota, with data on nearly 300 patients who received a CF-LVAD from 2005 to 2013. RESULTS: The incidence of GIB after CF-LVAD varies between 18-40% in numerous studies. At the University of Minnesota, out of 233 patients who underwent HeartMate II (HMII) implantation between 2005-2013, 60 GIB episodes occurred in 51 patients (22%), with an event rate of 0.17 gastrointestinal bleeds/patient-year of support. The etiology of GIB appears to be multifactorial. The main factors which have been identified include the need for chronic anticoagulation, acquired von Willebrand syndrome, platelet dysfunction and increased incidence of arteriovenous malformations due to chronic low pulse pressure. When managing an LVAD patient with GIB, a multi-disciplinary approach is needed. The main goals of treatment are evaluating the location and severity of the bleed, holding anti-coagulants and resuscitation to maintain stable hemodynamics. CONCLUSIONS: GIB is a complication with considerable morbidity. Future efforts to further understand the etiology of GIB and optimize anti-coagulation are needed to improve outcomes following CF-LVAD implantation. PMID- 25452909 TI - Evaluation and treatment of pump thrombosis and hemolysis. AB - Ventricular assist devices (VADs) are not fully biocompatible, and are therefore predisposed to device thrombosis and subsequent pump dysfunction. Clinically significant hemolysis in VADs most often occurs as a result of device thrombosis, but can also be caused by other factors. Herein we describe the evaluation and management of VAD thrombosis and hemolysis. PMID- 25452908 TI - Clinical psychological and neuropsychological issues with left ventricular assist devices (LVADs). AB - BACKGROUND: Left ventricular assist devices (LVADs) are increasingly being used to treat patients in end-stage heart failure (HF) as bridge-to-transplantation, lifetime support or destination therapy. However, the importance of this newer technique for chronic cardiac support compared to heart transplantation is still open to discussion. To date, there are few studies that extensively explore the psychological and cognitive profiles of patient with ventricular assist devices (VADs). METHODS: We studied the psychological aspects, quality of life (QOL) and cognitive profiles of 19 patients with HF before VAD implantation and then at two, five and 16 months post-implantation. RESULTS: Our results showed that after VAD implantation, patients did not show any psychopathological problems such as anxiety and/or depression. More interestingly, despite the constant risk of neurological events determined by the continuous-blood-flow pump (CBFP), patients' cognitive functioning did not worsen. In fact, significant enhancements were observed over time. CONCLUSIONS: Psychological and cognitive deficits are common in advanced HF and often worsen over time. Appropriately designed and randomized studies are needed to demonstrate whether earlier VAD implantation is warranted to arrest cognitive decline and encourage better post-implantation adaptation. PMID- 25452911 TI - VAD infections: the lead, the graft and the pump. PMID- 25452910 TI - Cellular, molecular, genomic changes occurring in the heart under mechanical circulatory support. PMID- 25452912 TI - Mechanical circulatory support in pediatrics. AB - There is no reliable published data on the overall prevalence or incidence of heart failure (HF) in children. However, the success of mechanical circulatory support (MCS) in management of HF has raised the prospect of a previously unavailable treatment modality. Orthotopic heart transplant (OHTx) remains the gold standard treatment, but the number of patients requiring this treatment far outweighs the donor availability. It is therefore not surprising to see the popularity of various MCS modalities, with different devices ranging from veno arterial extra corporeal membrane oxygenation (VA-ECMO) to ventricular assist devices (VADs), which are either para-corporeal or intra-corporeal, with pulsatile or continuous flow. Indication, timing and the choice of the type of mechanical support are crucial so in order to avoid potential lethal complications such as hemorrhage, thrombo-embolism and infections. In the pediatric population, MCS is used mainly as bridge to transplantation but can be used as bridge to recovery in patients with acute myocarditis or following open heart surgery. Active research is currently underway to develop newer and more durable devices that will assist the pediatric population across all age groups. This research will support different pathologies that have lower incidences of major morbidities, particularly as greater durations of MCS are expected due to a paucity of donors for OHTx. The combined experience developed through the usage of different devices in pediatric and adult populations has led to the to the application of MCS in some subgroups of grown-up congenital heart diseases (CHDs) patients, particularly those with systemic right ventricular failure. PMID- 25452914 TI - The Jarvik-2000 ventricular assist device implantation: how we do it. AB - The Jarvik-2000 is a non-pulsatile axial-flow left ventricular assist device (LVAD) that is largely used in patients who present in end-stage heart failure, as a bridge to transplant support or destination therapy. From its first utilization, several implantation techniques have been elaborated, starting from a median sternotomy with cardiopulmonary bypass (CPB) support and moving towards a minimally invasive access with an off-pump strategy. Here we present the favored surgical technique used in our department to implant the Jarvik-2000, in a step-by-step fashion. PMID- 25452915 TI - Technique for implantation of HeartMate II left ventricular assist device with concurrent mitral and tricuspid valve repair. PMID- 25452913 TI - Mechanical circulatory support devices as destination therapy-current evidence. AB - Advanced heart failure is an increasing problem worldwide. Nowadays, mechanical circulatory support devices (MSCD) are an established therapeutic option for terminal heart failure after exhaustion of medical and conventional surgical treatment, and are becoming a realistic alternative to heart transplantation (HTX). There are a number of different treatment options for these patients, such as bridge to transplantation (BTT), bridge to candidacy (BTC), bridge to recovery (BTR) and the destination therapy (DT) option. The latter option has become more frequent throughout the last years, due to a donor organ shortage and an increasing number of older patients with terminal heart failure who are not eligible for HTX. These factors have led to a rapidly increasing number of LVAD implantations as well as centers which perform these procedures. This has also been due to improved LVAD survival rates and quality of life following the introduction of smaller, intrapericardial and more durable continuous flow left ventricular devices. The most common complications for these patients are device related problems, such as coagulation disorders, gastrointestinal bleeding, device related infection, pump thrombosis or cerebrovascular accidents. However, some questions still remain unanswered or under debate, such as the exact time point for LVAD implantation. In addition, aspects such as better biocompatibility for LVADs remain a major challenge. This review will concentrate on DT for terminal heart failure and provide an overview of the current evidence for LVAD implantation in this patient group, with particular emphasis on indication and time-point of implantation, choice of LVADs, and long term outcomes and quality of life. PMID- 25452916 TI - Implantation of the HeartWare HVAD: from full sternotomy to less invasive techniques. PMID- 25452917 TI - Anticoagulation assessment. PMID- 25452919 TI - Ventricular assist devices. PMID- 25452918 TI - Left ventricular assist device outflow graft: alternative sites. AB - We describe three alternative approaches for the left ventricular assist device (LVAD) outflow graft during implantation of the LVAD. The supraceliac abdominal aorta, innominate artery and left axillary artery were employed as alternative sites for the LVAD outflow graft in the setting of a heavily calcified ascending aorta or a hostile chest wall and mediastinum. The first approach involved the use of the supraceliac abdominal aorta. Given that the patient had a history of multiple previous breast surgeries and chest wall radiation for breast cancer treatment, a left subcostal incision was employed as a sternotomy-sparing approach. The second approach was the use of the innominate artery in a patient with a porcelain ascending aorta. The patient underwent pulmonary valve replacement, right ventricle outflow tract reconstruction and tricuspid valve annuloplasty in addition to the LVAD implantation. The third approach was the use of the left axillary artery. This patient had a history of LVAD implantation and subsequently developed infection with pseudoaneurysm formation at the aortic anastomosis of the outflow graft. We conclude that the supraceliac abdominal aorta, the innominate artery and the left axillary artery are potential alternative routes for the LVAD outflow graft in the settings of heavily calcified ascending aorta or a hostile chest wall and mediastinum. Although the described alternative approaches are safe and viable options, we highly recommend utilizing these approaches only in selected patients with significantly higher risks and hazards to the standard surgical approach. PMID- 25452920 TI - Sex hormones in gender-specific risk for head and neck cancer: A review. AB - Despite the fact that numerous researches have been carried out to prevent head and neck cancer (HNC) and treat those patients, there is no reduction in morbidity rate because the underlying molecular pathogenesis is still poorly understood. Endocrine microenvironment is another vital factor besides other traditional risk factors like tobacco smoking, infections, and alcohol. It has been proven that sex hormone receptors are also expressed in larynx and lungs, in addition to sex organs. Sex hormones play a vital role in gene expression involved in the plethora of biological and neoplastic processes. The role of sex hormones in HNC is still divisive and very few researches have been conducted to describe their role. So, this article is an effort to attract the attention of researchers, endocrinologists, pathologists, and clinicians toward the impending role of sex hormones, with special emphasis on progesterone, estrogen, and prolactin in HNC onset and progression, along with their therapeutic role. PMID- 25452921 TI - Oral health related knowledge, attitude and practices among the primary health care workers of a district in India. AB - AIM: To assess the knowledge, attitude, and practices of the primary health care workers in our country. MATERIALS AND METHODS: Data was gathered by means of a closed-ended questionnaire form. A total of 30 primary health centers (PHCs) and 60 subcenters (SCs) were included in the study. Frequency distribution was used together with Chi-square tests and analysis of variance (ANOVA) in this study. A P value of < 0.05 was considered significant. RESULTS: Only 40% of the primary health care workers knew that dental caries is multifactorial, majority of them could not identify the symptoms of gum diseases, a meager number of the primary health care workers (28%) knew about the oral health aspects of a pregnant lady, and with the exception of doctors, the other health care workers were not sure of the etiology of oral cancer. CONCLUSION: About one-tenth of the primary care workers had high knowledge regarding oral health, only one-tenth of them had highly favorable oral health attitudes, and 9% of them had highly favorable oral health practices. PMID- 25452922 TI - A study to find the status of probiotics in New Delhi, India and review of strains of bacteria used as probiotics. AB - CONTEXT: Probiotics are living microorganisms, principally bacteria, that are safe for human consumption and, when ingested in sufficient quantities, have beneficial effects on human health, beyond basic nutrition. However, in India people are not aware of their benefits and availability. AIMS: To find status of probiotics in India and to assess the awareness regarding probiotics among chemists in New Delhi, India. SETTINGS AND DESIGN: A cross-sectional survey was conducted among 300 chemist shops in different areas of New Delhi, India. MATERIALS AND METHODS: Data were collected through a structured questionnaire, which was responded by the chemist in the course of a telephonic interview. The questionnaire addressed on the availability of probiotic products at their chemist shop. STATISTICAL ANALYSIS USED: The data so gathered were subjected for descriptive analysis using t test. RESULTS: As per availability of probiotic products, total of 25 probiotic products were available at different chemist shops. None of the chemist shop had all the 25 products available. 10% shops had 75% products available and there were 5% such shops which didn't have any of the products available. CONCLUSION: Efforts should be made to increase the awareness among chemists about the probiotic products. PMID- 25452923 TI - A simplified method of preventing implant hex drive from aspiration or accidental swallowing during stage two implant recovery. AB - OBJECTIVES: To prevent accidental ingestion of implant hex dive. MATERIALS AND METHODS: Dental floss which is used to stabilize the hex drive is tied to the operator's finger ring to overcome sudden aspiration of fallen instrument. RESULTS: It showed excellent grip of the instrument during stage two uncover time and also saved operators time. CONCLUSIONS: Accidental aspiration or swallowing of the dental instruments during routine implant surgeries can be prevented by tying the implant instruments to the operator's ring with silk ligatures or dental floss. PMID- 25452924 TI - Comparative evaluation of bite forces in patients after treatment of mandibular fractures with miniplate osteosynthesis and internal locking miniplate osteosynthesis. AB - AIMS AND OBJECTIVES: The aim of present study was to compare the stability of fractured mandibular fragments under functional load, when fixed with conventional miniplate and internal locking miniplate. MATERIALS AND METHODS: Bite force (in kg) recorded in twenty mandible fractured patients and fifty normal healthy individuals. Bite force was measured at incisor and molar regions. Comparative evaluation of bite force generated was performed between 10 cases treated with conventional miniplates and 10 cases treated with internal locking miniplates. Bite force generated by patients in mandibular fracture between symphysis and the angle of mandible was recorded in incisor and molar regions preoperatively. The fracture fragments were fixed using the above fixation techniques. Then same recording was undertaken on the 7(th), 14(th), 21(st), 28(th), and 90(th) days postoperatively. RESULTS: Bite force generated by patients treated with locking plates at the 7(th), 14(th), 21(st), 28(th), and 90(th) postoperative days was significantly higher as compared to those in patients treated with miniplates. CONCLUSION: It was observed in our study that the locking plate/screw system offers significant advantages over the conventional plating system. There are no intraoperative difficulties associated with placement of the plate. PMID- 25452925 TI - Comparison of canine retraction by in vivo method using four brands of elastomeric power chain. AB - OBJECTIVE: To investigate the amount of space closure by movement of canines into the extraction spaces using four brands of elastomeric power chains (EPCs) by intraoral application with pre-adjusted appliance for 6 weeks. MATERIALS AND METHODS: The sample size calculation was based on the studies of Boester and Johnston and also with repeated measures analysis of variance (ANOVA) continuous data for force degradation, standard deviation of 24.9 g, and also from a pilot study, which totaled to around 17 patients with a mean age of 20 +/- 2 years and receiving fixed orthodontic treatment that required retraction of canines into the premolar extraction spaces in all four dental arch quadrants. Four brands of EPCs, namely the Ormco, 3M Unitek, Rocky Mountain, and Highland, which were closed-link with five loops delivering less than or equal to 250 g were used. The rates of canine retraction were measured between the attachment points on the canine bracket hook and first molar hook using a Mitutoyo Digital Vernier Caliper at the time of first application, after 3 weeks of use, and at the end of 6 weeks of use, and were subjected to statistical calculations. RESULTS: The distances recorded from canine retraction were similar with slight differences noticed in the four brands of EPCs. However, no statistically significant difference was observed in relation to the EPCs. CONCLUSION: Although all brands of the EPCs produced space closure of canines, it was observed that not much of a significant difference existed among the products tested. PMID- 25452926 TI - Efficacy of combination therapy using anorganic bovine bone graft with resorbable GTR membrane vs. open flap debridement alone in the management of grade II furcation defects in mandibular molars - A comparative study. AB - CONTEXT: Invasion of the bifurcation and trifurcation of the multi-rooted teeth resulting in furcation involvement is one of the serious complications of periodontitis. AIM: The purpose of the study was to evaluate the efficacy of combination therapy using anorganic bovine bone graft and resorbable guided tissue regeneration (GTR) membrane versus open flap debridement alone in the management of Grade II furcation defects in mandibular molars. MATERIALS AND METHODS: The study included a total number of 20 sites in 10 patients with bilateral mandibular furcation defects, out of which 10 sites were treated as test group and 10 as control group. The test group was treated with combination therapy and the control group with open flap debridement alone. The parameters were recorded on 0 day (baseline), 90th day, and 180th day, which included vertical probing depth and horizontal probing depth of the furcation defect, clinical attachment level, and defect fill. STATISTICAL ANALYSIS USED: Mean and standard deviation were calculated for different variables in each study group at different time points. Mean values were compared by using Wilcoxon signed ranks test, after adjusting the P values for multiple comparison by using Bonferroni correction method. RESULTS: Both the test and control groups showed a definitive improvement in clinical parameters, which was statistically significant. On comparison, the vertical probing depth showed significant reduction in the test group with a mean reduction of 3.1 +/- 0.7 mm, when compared to the control group which showed a mean reduction of 1.5 +/- 0.5 mm. The horizontal probing depth of furcation defects was also significantly reduced in the test group with a mean reduction of 2.2 +/- 0.6 mm, when compared to the control group in which the mean reduction was 0.9 +/- 0.3 mm. There was also significant gain in attachment level in the test group which showed a mean gain of 3.2 +/- 0.6 mm, when compared to the control group which showed a gain of 1.2 +/- 0.6 mm. Radiographic defect fill was found to be more in the test group with a mean gain of 2.0 +/- 0.1 mm, when compared to the control group which showed a defect fill of 0.2 +/- 0.1 mm. CONCLUSIONS: The results of this study demonstrated that the combined use of anorganic bovine bone graft and resorbable GTR membrane is effective than open flap debridement alone in the treatment of mandibular grade II furcation defects. PMID- 25452927 TI - Knowledge and attitude regarding management of tooth avulsion injuries among school teachers in rural India. AB - OBJECTIVES: Traumatic dento-alveolar injuries are frequent in children and adolescents, affecting teeth, their supporting structures, and adjacent soft tissues. Because school teachers are likely to be in contact with the child soon after injury, it is important to ascertain their knowledge and attitude about this. AIM: The study aimed to assess the knowledge and attitude of school teachers in Coorg with regard to immediate management of avulsed teeth. MATERIALS AND METHODS: This cross-sectional study was conducted among school teachers in Coorg district. A self-administered questionnaire containing 16 questions was given to a sample of 600 school teachers. RESULTS: Descriptive statistics and independent sample t-test were used for analysis. Only 24.7% teachers thought the tooth was important and wanted to search for the avulsed tooth. Regarding the knowledge about replantation of tooth, 25.7% teachers knew that a fallen tooth can be placed back in the socket. Extraoral time for replantation of the tooth that was opted by 44 teachers (30.3%) was <=30 min. CONCLUSION: This survey reflected the lack of experience and inadequate knowledge regarding dental trauma management among school teachers in Coorg. The implications of this study are directed toward education of these school teachers who are involved in the supervision of children in schools. PMID- 25452928 TI - An audit of school oral health education program in a developing country. AB - OBJECTIVE: The increasing prevalence of oral diseases in children in developing countries is a major public health concern and creates the need to review various preventive strategies put in place on oral health promotion. In the absence of formal national programs, tertiary health institutions have adopted low-budget school oral education programs targeted at improving oral health awareness and behavioral changes in school children. The aim of this study was to review the school oral health education programs conducted by the Community Dentistry Unit of a tertiary hospital in a major city in Nigeria. MATERIALS AND METHODS: An evaluation of the school oral health education programs conducted in the city over a 5-year period was done. Data collected included: venue of the program, the number of students and teachers educated in each school, screening and referrals, adequacy of teaching aids, desire for revisit, and barriers noted in its conduct. RESULTS: A total of 104 oral health education programs were conducted during this period involving 16,248 participants. The majority (80%) of the schools visited were primary schools and 54% were privately owned. Over half of the programs was conducted on assembly grounds, 21% in classrooms, and 13% in school halls. Challenges encountered included: lack of audiovisual aids, transportation problems, inadequacy of screening tools, and insufficient promotional materials. All the schools visited requested for (subsequent) regular visitation. CONCLUSION: The study showed the feasibility of low-budget oral health education and willingness of schools to benefit from such programs. There are barriers to effective communication, which can be mitigated in order to achieve an optimal school oral health education program in a low resource setting. PMID- 25452929 TI - Crosstalk between hormones and oral health in the mid-life of women: A comprehensive review. AB - Oral health is constantly shaped by the cross-talk between behavioral, biological, and social forces. Menopause is that time in a woman's life when menstrual cycles cease by reduced secretion of the ovarian hormones, such as, estrogen and progesterone. Diseases of the mouth itself are the most common reasons for pain and discomfort in the mouth. However, there are certain situations where oral symptoms are caused as a result of systemic diseases. This review article has emphasized on the diverse oral presentations of postmenopausal women by descriptive analysis of various underlying mechanisms associated with these conditions. Dentists should be aware of the possible association of menopause and various oral health problems. PMID- 25452930 TI - An assessment of pharmacy students' knowledge, attitude, and practice toward oral health: An exploratory study. AB - BACKGROUND: Community pharmacies are now frequently being visited by customers/patients to seek oral advice. Malaysian community pharmacists are also found to be experiencing an increased demand of oral health advices by their visiting customers. AIMS/OBJECTIVES: The aim of the study was to explore the knowledge, attitude, and practice of the final year Bachelor of Pharmacy students in a private university toward oral health, as these students will be the future pharmacists. MATERIALS AND METHODS: This cross-sectional study was carried out among final year undergraduate pharmacy students by using self-administered questionnaire. It was conducted as a classroom survey. Raosoft software was used to determine the minimum required sample size. RESULTS: The demographic distribution of the respondents was separated into gender, ethnicity, and state of origin. Over 83.8% of the participants were females, with Chinese ethnicity dominating (78.4%) compared to others, and the distribution showed 11 different states of origin. CONCLUSIONS: This research finding shows that pharmacy students have positive attitude toward oral health despite having poor knowledge and mediocre practice principles regarding oral health. PMID- 25452931 TI - Influence of aspirin on post-extraction bleeding - A clinical study. AB - AIM: The aim of the study was to evaluate the influence of aspirin on post extraction bleeding in a clinical setup. MATERIALS AND METHODS: Two hundred patients aged between 50 and 65 years who were indicated for dental extraction for endodontic reason were selected from the outpatient Department of Oral and Maxillofacial Surgery. The patients were randomly divided into aspirin continuing group (group A) and aspirin discontinuing group (group B). After checking all the vital signs, the extractions were carried out. Bleeding time and clotting time were recorded for evaluation by Chi-square test. RESULTS: Chi-square test revealed that the bleeding time increased (3.8 +/- 0.75) in group A patients continued with the aspirin therapy where as group B discontinued aspirin. Similarly, the clotting time increased in group B patients and decreased in group A patients. But in both the groups, bleeding and clotting time remained within normal limits. CONCLUSION: Reviewing most of the dental and medical literature, it can be concluded that there is absolutely no need to discontinue antiplatelet therapy for any ambulatory dental procedure, and even if the practitioner wishes to discontinue, it should not be for more than 3 daAQ2ys. This is also stated in the guidelines of the American Heart Association. PMID- 25452932 TI - Primary oral non-Hodgkin's lymphoma - A clinicopathologic study with immunohistochemical analysis. AB - CONTEXT: Non-Hodgkin's lymphoma (NHL) is a group of highly diverse malignancies whose prognosis depends on the histologic type and associated factors like HIV positivity. AIMS: The aim of this study was to evaluate eight cases of NHL for their histologic type and HIV positivity, since both are major prognostic factors for NHL. SETTINGS AND DESIGN: Eight cases of primary NHL of the oral cavity were evaluated for age, sex, clinical presentation, and the histologic type, along with immunohistochemistry. These cases were also evaluated for HIV positivity. MATERIALS AND METHODS: NHL cases which were diagnosed through the dental OPD and subsequent biopsy procedure were chosen. The patient data, including age, sex, location, clinical presentation, radiographic presentation, metastasis, and histologic subtype, according to the World Health Organization (WHO) classification were tabulated. Immunohistochemical markers were used to confirm the cell type. CD20 and CD3 were used for B cell and T cell, respectively. Subsequent western blot analysis was carried out for HIV detection. RESULTS: 75% of the NHL was of B-cell type; of this, 83% was found to be diffuse large B-cell lymphoma, which is an aggressive variant. 62.5% of cases were found to be HIV positive. CONCLUSIONS: This study emphasizes the need for HIV investigation in NHL cases and the need to determine the histologic type, both of which significantly affect the treatment outcome and prognosis. PMID- 25452933 TI - A Phase II Trial of Stereotactic Ablative Body Radiotherapy for Low-Risk Prostate Cancer Using a Non-Robotic Linear Accelerator and Real-Time Target Tracking: Report of Toxicity, Quality of Life, and Disease Control Outcomes with 5-Year Minimum Follow-Up. AB - PURPOSE/OBJECTIVE(S): Herein, we report the results of an IRB-approved phase II trial of Varian Trilogy/TrueBeam-based stereotactic ablative body radiotherapy (SABR) monotherapy for low-risk prostate cancer using the Calypso((r)) System to provide real-time electromagnetic tracking of the prostate's position during treatment delivery. MATERIALS/METHODS: A total of 102 low-risk patients completed protocol treatment between January 2007 and May 2009. A total dose of 40.0 Gy in 5 every-other-day fractions of 8.0 Gy was prescribed to the planning target volume. Target setup and tracking procedures were as follows: (1) the Calypso((r)) System was used to achieve target setup prior to each fraction; (2) conebeam CT imaging was then used for correction of setup error and for assessment of target and organs-at-risk deformations; (3) after treatment delivery was initiated, the Calypso((r)) System then provided real-time intrafractional target tracking. The NCI CTCAE v3.0 was used to assess urinary and rectal toxicity during treatment and at defined follow-up time points. Biochemical response and quality of life measurements were made at concurrent follow-up points. RESULTS: Urinary toxicities were most common. At 6 months, 19.6, 2.9, and 4.9% of patients reported grades 1-2 urinary frequency, dysuria, and retention, respectively. Rectal toxicities were uncommon. By 12 months, 2.9% of patients reported painless rectal bleeding with subsequent symptom resolution without requiring invasive interventions. Quality of life measurements demonstrated a significant decline over baseline in urinary irritative/obstructive scores at 1 month following SABR but otherwise did not demonstrate any difference for bowel, bladder, and sexual function scores at any other follow-up time point. One patient suffered biochemical recurrence at 6 years following SABR. CONCLUSION: At 5 years, minimum follow-up for this favorable patient cohort, prostate SABR resulted in favorable toxicity, quality of life, and biochemical outcomes. PMID- 25452934 TI - Evolution of hypofractionated accelerated radiotherapy for prostate cancer - the sunnybrook experience. AB - Stereotactic ablative body radiotherapy (SABR) is a newer method of ultra hypo fractionated radiotherapy that uses combination of image-guided radiotherapy (IGRT) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT), to deliver high doses of radiation in a few fractions to a target, at the same time sparing the surrounding organs at risk (OAR). SABR is ideal for treating small volumes of disease and has been introduced in a number of disease sites including brain, lung, liver, spine, and prostate. Given the radiobiological advantages of treating prostate cancer with high doses per fraction, SABR is becoming a standard of care for low and intermediate-risk prostate cancer patients based upon the results from Sunnybrook and also the US based prostate SABR consortium. This review examines the development of moderate and ultra hypo-fractionation schedules at the Odette Cancer centre, Sunnybrook Health Sciences. Moderate hypo-fractionation protocol was first developed in 2001 for intermediate-risk prostate cancer and from there on different treatment schedules including SABR evolved for all risk groups. PMID- 25452935 TI - The oncomodulatory role of human cytomegalovirus in colorectal cancer: implications for clinical trials. AB - Increasing evidence suggests that human cytomegalovirus (HCMV), a beta-herpes virus that chronically infects human beings, is associated with colorectal cancer (CRC). The viral nucleic acids specifically localized to the neoplastic mucosal epithelium of CRC, while tumoral presence of HCMV independently predicted a poor outcome in elderly patients. In the past decade, the concept of "oncomodulation" of HCMV in human cancers has been formulated. In CRC, changes in the tumor microenvironment are closely related to cancer behavior and prognosis, while the underlying mechanism driving these changes remains unclear. As HCMV affects multiple cellular functions, including signal pathways that regulate angiogenesis, apoptosis, cell invasiveness, and anti-cancer immunity, the virus potentially exerts oncomodulatory effects in the tumor microenvironment of CRC. Here, we summarize the current knowledge about the association between HCMV and CRC and suggest future perspectives on both research and anti-cancer therapy of CRC. PMID- 25452936 TI - Prom1 function in development, intestinal inflammation, and intestinal tumorigenesis. AB - Prom1/CD133 has been identified in colorectal, hepatocellular, and pancreatic cancer as a cancer stem cell marker and has been used as such to predict colon cancer recurrence in humans. Its potential molecular function as well as its role as a marker of intestinal regeneration is still not fully known. We evaluated the role of Prom1 in intestinal regeneration in inflammatory bowel disease (IBD), determined the function of Prom1, and characterized the effect of a lack of Prom1 on intestinal tumor formation in animal models. Our results suggest that Apc mutations lead to an increase in Prom1 expressing cells in the intestinal crypt stem cell compartment and in early intestinal adenomas. Also, Prom1 knockout mice are more susceptible to intestinal tumor formation. We conclude that Prom1 likely plays a role in regulating intestinal homeostasis and that these results clearly illustrate the role of Prom1 in intestinal regeneration. We further conclude that Prom1 may provide a novel therapeutic target for patients with gastrointestinal conditions such as IBD, short bowel syndrome, and colorectal cancer. PMID- 25452937 TI - Radiation therapy in management of sporadic and neurofibromatosis type 1 associated malignant peripheral nerve sheath tumors. AB - INTRODUCTION: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas in which complete surgical resection is the mainstay of therapy. However, the recurrence rate is high and few options remain for refractory or metastatic MPNST. This study examines the outcomes of adjuvant radiation therapy in MPNST in patients with and without neurofibromatosis type 1 (NF1) and reviews the literature on use of radiation for MPNST. METHODS: A retrospective review of 33 MPNST patients between 1990 and 2012 evaluated at the NIH. All diagnoses were pathologically confirmed at the NCI. Clinical presentation, treatment, and survival were analyzed. RESULTS: Thirty-three patients were included 18 NF1-associated, 15 sporadic tumors. Tumor location included extremity (58%), trunk (36%), and head/neck (6%). Histologic grade showed 25 high-grade tumors compared to 7 low-grade tumors. Twenty patients were treated with radiation therapy (median total dose of 58.5 Gy with 1.8 Gy/fraction). A median survival of all patients was 46.5 months and 43.7% overall 5-year survival. Prognostic factors include extent of resection, tumor location, and histology grade. Radiation was not found to be a prognostic factor for overall survival. CONCLUSION: This study is consistent with previous studies regarding the role of radiation in the management of MPNST. Prospective evaluation of adjuvant radiation will allow to more fully define the role of radiation in MPNST. PMID- 25452939 TI - Some problems facing scientific medical publications in Nigeria. AB - Although one of the earliest recorded medical publications was recorded in Europe about the middle of the 17(th) Century, the earliest medical publication in West Africa was in the 1920s - three centuries later. However, since then, a number of other biomedical journals have been published, a few of them regularly, and only a fraction of them have met the criteria for indexing in PubMed. This, therefore, has made a large number of medical articles published in Nigeria and West Africa unavailable to the outside world as the search engines would be unable to pick these publications. Despite the efforts of many researchers in Nigeria and other West African countries to publish in medical journals in the industrialized countries, most have not been able to meet the high standards of these journals due to paucity of resources, infrastructure and training. This, therefore, underpins the need for regular update courses on medical manuscript writing in the West African sub-region with a view to enable authors in the sub-region meet the standards set by indexed journals in various parts of the world; such courses will also help journal editors keep abreast with current demands in editing, review process and publication in order to meet the criteria for indexing. PMID- 25452940 TI - Viva voce in postgraduate surgical examinations in anglophone west Africa. AB - The Viva Voce is a form of assessment dating back to antiquity. It is widely used by the English-speaking West African Postgraduate Medical Colleges for intermediate and exit level examinations. Although it is still popular till the present day, there is a growing awareness of its limitation as an examination method. This paper explores the origin, format, advantages and limitations of oral examinations in postgraduate surgical assessment and proffers practical guidelines on its usage. PMID- 25452941 TI - Traditional versus orthodox fracture care in uyo, Nigeria. AB - Background The general perception in Uyo, the capital city of Akwa-Ibom State, is that the populace prefers Traditional Bone Setter (TBS) care to Modern Orthopaedic Fracture care. Aims and Objectives Given the option, this study aims to ascertain the attitude of the population on choice between TBS and orthopaedic fracture care and identify some of the reasons for such a preference, thus providing a basis for improving orthodox care delivery and increasing patronage of same. Design of the study This is a prospective observational study, using self-administered pre-tested questionnaires. Setting The study was carried out in two sites - the General Out-patient Department of the University of Uyo Teaching Hospital (UUTH) and in the major town based public transport park in Uyo. Materials and Methods This study was carried out on two populations: one in the General Out-patient Department of the University of Uyo Teaching Hospital over a three-day period, and the other in the general Uyo community over a five-day period, using a self-administered pre-tested questionnaire. The required sample size was determined to be 24 for both populations, using the Statcalc domain of Epi-info 3.4.1. However, 95 respondents were recruited into the GOP arm and 150 into the Community group. Consent for the study was obtained from the Ethical Research Board of the Hospital. Results Sixty percent (60%) of our hospital clients will opt for hospital care if they sustain a fracture. In the community, 64% prefer TBS treatment for a fracture, while 36% prefer hospital care for the same problem. When both sets of data were combined 134 people (54.7%) preferred TBS care. There was a positive correlation between the preference for hospital care and the highest level of education that the person achieved. People in the community indicated that the fear of a limb amputation was their main reason for preferring TBS care, if they or a relation sustained a fracture. Conclusion This study shows a greater preference for TBS care in Uyo, due to the fear of amputation, the long time to see the doctor, a presumed high cost of orthodox care and a lack of formal education. Religious concerns and the duration of care are not important determinants. Reducing the waiting time for seeing a doctor and the immediate cost of orthopaedic care; improving the patient - doctor relationship and public enlightenment about the processes of medical care (especially to allay the fear of amputation), will help to improve the proportion of the Uyo populace, who access and benefit from Orthopaedic fracture care. PMID- 25452938 TI - Treatment techniques to reduce cardiac irradiation for breast cancer patients treated with breast-conserving surgery and radiation therapy: a review. AB - Thousands of women diagnosed with breast cancer each year receive breast conserving surgery followed by adjuvant radiation therapy. For women with left sided breast cancer, there is risk of potential cardiotoxicity from the radiation therapy. As data have become available to quantify the risk of cardiotoxicity from radiation, strategies have also developed to reduce the dose of radiation to the heart without compromising radiation dose to the breast. Several broad categories of techniques to reduce cardiac radiation doses include breath hold techniques, prone positioning, intensity-modulated radiation therapy, and accelerated partial breast irradiation, as well as many small techniques to improve traditional three-dimensional conformal radiation therapy. This review summarizes the published scientific literature on the various techniques to decrease cardiac irradiation in women treated to the left breast for breast cancer after breast-conserving surgery. PMID- 25452942 TI - Small intestinal obstruction from peritoneal adhesions in children small intestinal obstruction from peritoneal adhesions in children. AB - PURPOSE: The purpose of this study was to assess the incidence of peritoneal adhesions leading to small intestinal obstruction after laparotomy in children in a tertiary paediatric surgical centre. METHODS: A retrospective review of 430 children aged <15 years who had trans-abdominal procedures over a 7 year period. RESULTS: Four hundred and fifty nine abdominal procedures were performed in 430 children during the study period. The follow up period ranged from 4 months - 7 years (Median 33 months). 22 (4.8%) had intra-operative confirmation of small intestinal obstruction. Their ages ranged from 21 days - 14 years (median 7 years). Postoperative adhesions due to laparotomy for typhoid perforation were the commonest, occurring in 10 (45%). Children undergoing emergency laparotomy were more likely to develop post operative small intestinal obstruction compared to elective laparotomy (p<0.025). Six (27.3%) children had bowel gangrene at laparotomy requiring bowel resection and anastomosis. Post-operative small intestinal obstruction developed in 6 (27.3%). One child died due to sepsis from intestinal gangrene. CONCLUSION: Small bowel obstruction due to adhesions requiring operative intervention in children in our setting is not un-common. Bowel gangrene is a common complication of postoperative small intestinal obstruction in children in our setting and should be suspected to avoid serious postoperative mortality and morbidity. PMID- 25452943 TI - Thoracic inlet located corrosive oesophageal strictures. AB - Background Cicatricial corrosive oesophageal strictures are usually multiple and occasionally single but the thoracic inlet segment of the oesophagus being a rapid transit section is not a common site for isolated strictures. Thoracic inlet located strictures pose two major problems. First, in cases with total obstruction of the oesophagus radiological assessment even with luminal contrast fails to delineate the lower limits and real extent of the lesions. The purported single stricture in such cases becomes merely a sentinel to perhaps a coexisting rosary of strictures more distally. Secondly, the technical difficulty associated with their surgical approach is inherent in the location. The customary anterior low cervical approach is often inadequate thereby making necessary a complementary high left posterolateral thoracotomy, partial anterior mediastinotomy or hiatal approach particularly in situations where the excision of the damaged gullet is advisable. MATERIALS AND METHODS: In a series of cases treated for cicatricial corrosive stricture those with apparently isolated strictures in the thoracic inlet formed the cohort for this study. Only oesophagoscopy and contrast barium studies were available for the definition of the lesions. Treatment varied from simple resection with end to end anastomosis in seven (7) to more extended resections with gastric or colonic conduits as replacement in four (4) who had extensive cicatricial obliteration of the lumen with tubularization and rigidity of the gullet distal to the apparently solitary stricture. In some of these cases transgastric retrograde bouginage was an option for a reasonable evaluation of the luminal state of the oesophagus distal to the proximal lesion at the thoracic inlet. The reconstructive oesophageal anastomoses were all placed in the neck; none was intrathoracic. RESULTS: In a series of 316 cases treated for cicatricial corrosive oesophageal strictures, 11 had isolated strictures located in the region of the thoracic inlet. Free swallowing was restored in all cases and where anastomotic leakage occurred they healed spontaneously. CONCLUSION: Isolated corrosive oesophageal strictures in the region of the thoracic inlet are uncommon and not necessarily single. There are finite diagnostic and operative challenges inherent in their location. PMID- 25452944 TI - Experience with vacuum-assisted closure device in the management of benign chronic leg ulcers. AB - BACKGROUND: Chronic leg ulcers are commonly encountered in clinical practice. They often last several months to years, with a negative social and economic impact on the patient. Rapidly effective modalities of treatment are therefore to be desired. Vacuum-Assisted-Closure (VAC) device in the management of benign chronic ulcers has been reported in the literature; however, there are limited reports on its use in the West African sub-region. AIM: To assess the efficacy of VAC therapy in the management of chronic leg ulcers in our patients. PATIENTS AND METHOD: Case records of patients with chronic leg ulcers presenting at the plastic surgery unit of Imo State University Teaching Hospital, who were managed using the Vacuum Assisted Closure (VAC) device were reviewed. The period of study was from July 2008 to June 2010 (24 months). Data obtained were analyzed using descriptive statistics. RESULTS: Forty one patients with 52 leg ulcers were managed in the period under review. M:F = 3:1 Their ages ranged from 13 to 82 years with a mean age of 43years. Sickle cell ulcers and Post traumatic ulcers were commoner in the young adults, while the vascular ulcers were commoner in the middle aged and elderly. Patients with sickle cell and vascular ulcers were more likely to have multiple ulcers. The sickle cell and venous ulcers had the longest duration but most rapid response to VAC therapy. The arterial ulcers showed poor response. Skin grafting after VAC therapy was excellent in all patients. CONCLUSION: VAC is a useful adjunct in the management of benign chronic leg ulcers. It is exceptionally effective in venous, sickle cell and post traumatic ulcers, which are quite common in this environment. PMID- 25452945 TI - Removal of orthopaedic implants: indications, outcome and economic implications. AB - INTRODUCTION: The removal of implants after fracture healing has always been a topical and controversial issue. Undisputed however, is the removal of implants which are associated with complications. In this paper, we evaluated the indications, the outcome and economic cost to the patient and the health system of routine removal of implants after union. PATIENTS AND METHODS: This is a two year comparative, prospective study carried out in three hospitals in North Central Nigeria. All patients who presented for implant removal and consented to the study were recruited. Fracture union was confirmed both clinically and radiological. Direct costs of treatment paid for by the patients and number of absences from work and school were used as economic indices. RESULTS: Forty-seven patients comprising 20(42.6%) males and 27(57,4%) females, mean age of 31.6 (+/ 13.4) years were analysed. Forty-two (89.4%) had fixation with plates and screws, three (6.4%) had screws with cerclage wire and two(4.2%) had tension band wiring. Patient request was the main indication for removal in 34(72.3%), surgeon's request without symptoms in 7(14.9%),six(10.7%) were symptomatic comprising four(8.5%) due to postoperative chronic osteomyelitis and intractable pain in two(4.3%). Total cost of implant removal was $33,293.59 ($ 708.37 +/-22.10; range $366.97-1,100.92). Total cost of removal in patients with symptomatic implants-in situ was $3,678,90( $ 613.15+/-14.50) One patient had a refracture. Mean duration away from work or school was 16 days. CONCLUSION: Routine removal of implants after fracture union constituted great waste of highly needed cash in both direct cost and loss of man-hour especially in a dwindling economy in an era of evidence based Medicare and best practice. It is recommended that each hospital adopts strict criteria for implant removal. PMID- 25452946 TI - Adeloye-odeku disease in aseer region of saudi arabia. AB - Adeloye-Odeku disease, also known as congenital inclusion dermoid cyst (CIDC) of the anterior fontanelle was first described in a publication in 1971 by Adeloye A and Odeku EL, as a solitary congenital subgaleal inclusion dermoid cyst of the anterior fontanelle in Nigerians. This rare lesion, (0.1-0.5% of all cranial tumors and 0.2% of all inclusion cysts), was initially thought to be an African cyst. The universal distribution of this cyst has subsequently been shown in accumulated literature of other ethnic distribution, Caucasians, Indians, Chinese, Japanese, Turkish and others. This is the first published report that we know of Adeloye-Odeku disease in Saudi Arab children in Abha, Saudi Arabia. Four patients with Adeloye-Odeku disease, two boys and two girls, Saudi patients with ages ranging from 3months to 9years are presented. All had CT and MRI brain scans. Successful surgical excision of the cyst was achieved in each of the three patients who consented for surgery and there was no recurrence. The parents of the oldest patient declined surgical intervention but agreed to outpatient follow up. PMID- 25452947 TI - Abdominal pregnancy- a case report. AB - A case of abdominal pregnancy in a 39 year old female gravida 4, para 0(+3) is presented. Ultrasonography revealed a viable abdominal pregnancy at 15 weeks gestational age. She was initially managed conservatively. Surgical intervention became necessary at 20 weeks gestational age following Ultrasound detection of foetal demise. The maternal outcome was favourable. This case is presented to highlight the dilemma associated with diagnosis and management of abdominal pregnancy with a review of literature. PMID- 25452948 TI - The Radial Forearm Flap in reconstruction of upper limb injuries: A case series. AB - BACKGROUND: The Radial Forearm Flap is a fasciocutaneous flap which has established its role in soft tissue reconstruction in the head and neck region as a free flap. Its value as a useful flap in soft tissue reconstruction in upper limb injuries has also been recognized. However there has been a dearth of report in our sub region on the use of this flap. OBJECTIVE: To report the use of Radial Forearm Flap in the reconstruction of traumatic defects in the elbow and hand in our centre. METHODS: Four cases in which pedicled island Radial Forearm Flaps were successfully used to reconstruct difficult defects in the elbow and hand following injuries were reviewed. RESULTS: Four pedicled island Radial Forearm Flaps were used to reconstruct soft tissue defects in four sites in the upper limb following trauma. One of the flaps was proximally based for coverage of lateral elbow defect while the others were used to cover defects of dorsum of wrist, mid palmar amputation and first web space. The first web space defect required a fascial flap and split skin graft cover. All the procedures were single staged and the flaps survived providing dependable soft tissue cover. CONCLUSION: The pedicled radial forearm flap was effective in providing skin cover of difficult soft tissue defects in the elbow, wrist and hand of our patients. It is a single stage procedure which allowed for early mobilization of the limb. Design and elevation of the flap was not as technically demanding as microsurgical tissue transfer which is still in its infancy in most developing countries like Nigeria. PMID- 25452949 TI - Re-exploration after open heart surgery at the madras medical mission, chennai, India. AB - BACKGROUND: Re-explorations after open-heart surgery is a necessity in this Cardiac Center when a patient is obviously bleeding or shows features of cardiovascular instability. Timely intervention may reduce morbidity and mortality. OBJECTIVES: This study aims to correlate the indications with the operative findings for re-explorations after open-heart surgeries as a way of justifying early surgical intervention. METHOD: Between May2005 and April2011, 10,083 open-heart surgeries were performed in the Adult Cardiac Surgical Unit of the department of cardiac surgery, Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, India. The demographic data, the initial diagnoses, the types of surgery, the indications for re-exploration, the intraoperative findings, the timing, the estimated blood loss and treatment for the 362 patients who had reexploration were analysed using the Predictive Analysis Soft ware(PASW)18. RESULT: Out of the 10,083 patients who had cardiac operation within the period of study, three hundred and sixty two (3.6%) patients had re exploration shortly after the operation. Males were 311(85.9%) while 51(14.1%) were female patients with mean age of 56.7+12.5years .The mean time interval between the primary surgery and the re-exploratory operation was 2.31+1.47hours and the mean chest tube drainage before re-exploration was 770.9+28.8ml. Coronary Artery Diseases (CAD) was the initial diagnosis 258 (71.3%) patients and Coronary Artery Bypass(CABG) operation was the initial surgery in 254(70.2%)patients, CABG and valve in 12(3.3%)patients, Valve surgery alone in 70(19.3%) patients, Bentall procedure(homograft aortic root replacement)in 13(3.6%) patients, others such as off-pump coronary artery bypass, Dor procedure(patch restoration of left ventricle by incising the aneurysm without excising it), pericardiectomy and thromboembelectomy in 13(3.6%). The indications for re-exploration were post operative haemorrhage in 283(78.2%) patients, Cardiac tamponade in 41(11.3%)patients, reactionary haemorrhage and cardiac tamponade in 12(3.3%)patients, clots In 20(5.5%) patients, open sternum 5(1.4%) and forgotten foreign body in 1(0.3%)patients. The intraoperative findings in 351(97.2%) patients revealed mediastinal clots and bleeding points, while no active bleeding was seen at re-operation in 11(2.8%) patients. Pearsons Chi-square test between the indications for re-exploration and the intraoperative findings was significant (p value<0.001). CONCLUSION: There is strong evidence supporting early re-exploration in patients after open-heart surgeries, complicated by reactionary haemorrhage, cardiac tamponade and intra-thoracic clots; early re exploration reduced morbidity and mortality. PMID- 25452950 TI - Electrical Burn Injury in MidWestern Nigeria. AB - Electrical burn injuries have not been well reported in the literature. Though uncommon, they nevertheless cause significant multisystem injury with significant morbidity and mortality and are often associated with a high amputation rate from tissue necrosis. We reviewed 15 patients out of a burn population of 229 patients managed at the Burn Service of the University of Benin Teaching Hospital, Nigeria from August 2009 to June 2011.There were 13 males and 2 females. The mean age was 27.7yrs ( Range 4-43). Ten (67%) suffered high voltage (>1000V) injuries, while 3 were from low voltage. Only one occurred in the home setting. Ten were work related and 4 occurred from fallen high tension cables. The mean burn size was 21% BSA ( Range 2- 43%).There were three deaths ( 20%). We identified electricity workers as target for preventive action and proper maintenance of overhead cables and poles as strategy to prevent electrocution from falling cables. PMID- 25452951 TI - Preferred methods of male neonatal circumcision among mothers in lagos Nigeria. AB - BACKGROUND: Although male neonatal circumcision is routinely done in many parts of Africa for cultural reasons, little is known about the reasons for neonatal circumcisions in metropolitan settings. OBJECTIVES: To elucidate from mothers reasons and preferred methods for circumcising male children in Lagos. SETTING: Lagos University Teaching Hospital, Lagos, Nigeria. PATIENTS MATERIALS AND METHOD: One thousand and two consecutive mothers of male children were interviewed through a questionnaire-based survey to determine the reasons why their male children were circumcised and their preferred method. RESULTS: A thousand and two mothers were interviewed. One thousand, seven hundred and seventy five (1775) male children from these mothers, comprising 59.7% of the children and all of whom had been circumcised in Lagos were the subjects of this study. The Plastibell kit method was preferred by 415 mothers (41.5%) of mothers while the open surgical dissection method was employed in 15%. The Gomco method was only requested by 16 mothers (1.6%). Six hundred and six mothers (60.6%) mothers circumcised their children for traditional reasons while 20.8% believed it fulfilled their religious obligations. CONCLUSION: Most male children in Lagos were circumcised for traditional and religious reasons. The Plastibell kit is the method of choice for male circumcision among mothers in Lagos. PMID- 25452952 TI - Experience with managing liver trauma in southeastern Nigeria. AB - BACKGROUND: All over the world, liver trauma occurs as a result of blunt or penetrating abdominal injury. AIM AND OBJECTIVE: To review the management, morbidity and mortality of liver trauma in our resource-deprived centre, and to see how we can improve these outcomes, our poor facilities notwithstanding. TYPE OF STUDY: This is a descriptive epidemiology. PLACE OF STUDY: Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria. PATIENTS AND METHODS: Patients who were treated for liver trauma in our centre between 2004 and 2010 were reviewed for aetiology of injury, management, morbidity and mortality. RESULTS: Of the 162 patients who were treated for liver trauma during the period, only 156 patients were recruited into the study. One hundred and nineteen (119) were males and 37 were females. Majority were blunt injuries while others were penetrating injuries. The blunt injuries were usually solitary, affecting only the liver whereas the penetrating injuries occasionally involved both the liver and some other organ(s). The commonest cause of blunt injuries was road traffic accident followed by fall from height. The commonest cause of penetrating injury was gunshot wound, followed by stab wound. CONCLUSION: Morbidity and mortality following liver trauma can be reduced by applying prompt and appropriate management modalities within the ambit of available resources. However, outcome will improve if adequate facilities are available. PMID- 25452953 TI - The burden of vesico-vaginal fistula in north central Nigeria. AB - BACKGROUND: Vesico Vaginal Fistula (VVF), as seen in this environment, is a major cause of severe morbidity and potential mortality, which can result in marital disruption, rejection and, eventual destitution. AIMS AND OBJECTIVES: To determine the socio-demographic characteristics, fistula features, and evaluate the intervention measures in Jos, North Central Nigeria. SETTING: This study was carried out at the VVF Centre, ECWA Evangel Hospital, Jos, North Central Nigeria. DESIGN OF THE STUDY: Descriptive retrospective study. MATERIALS AND METHODS: The patients' records from January 1 to December 31, 2007 were retrieved and analyzed for the demographics, clinical features, management and outcome using EPI Info version 3.4.3, 2008. RESULTS: A total of 314 patients were treated. The patients aged between 12 to 60 years (SD 6.19) with a mean parity of 3.7. Seventy percent (70%) of the patients were married and living with their husbands, while 65% of the patients were illiterate farmers. Christians and Muslims patients made up 60% and 40% respectively. Juxta-cervical (26%) and juxta-urethral fistulae (26%) were the commonest types, with obstructed labour being the causative factor in 82% of the patients. Ninety three percent of the repairs were repaired via the vaginal approach. The success rate at repair was 69%. Post-operative complications occurred in 16% of the patients. CONCLUSION: Vesico- vaginal fistula is a problem in this environment, occurring mainly amongst the illiterate farmers after prolonged obstructed labour. Public enlightenment and appropriate ante-natal care and delivery would reduce the incidence. PMID- 25452954 TI - The challenges of treating laryngeal carcinoma in jos, Nigeria. AB - BACKGROUND: Laryngeal cancers are not uncommon with several factors affecting its management in our environment compared to the developed countries. Such factors include the time of presentation and diagnosis, co-morbid disease, finance, consent, treatment options, surgical expertise and the problems of follow up. Thus this results to a lot management challenges to both the patients and the care givers. AIM: The aim of this paper is to highlight the challenges encountered in the management of laryngeal cancers at the Jos University Teaching Hospital, Nigeria. DESIGN OF STUDY: it is a retrospective study. SETTING: The study was carried out at the ENT department of the Jos University Teaching Hospital and Bingham (ECWA Evangel) Hospital Jos Nigeria. METHOD: This was a 48 month (October 2005 - September 2009) review of laryngeal cancers seen and treated in these hospitals. Data extracted included age, gender, histologic diagnosis and treatment modality. Data was analyzed using simple descriptive method and the result presented in tabular forms. RESULT: A total of twenty one (21) cases consisting of 20 males and a female were seen during the period. The age range was 30 years to 70 years. The average age was 56.14 years. The time of presentation ranged from 3 months (earliest) to 2years. Twenty cases (95.24%) were advanced diseases with only one early disease. The histological types were 6 each for well and moderately differentiated squamus cell carcinoma respectively, 2 each for poorly differentiated and squamus cell carcinoma (uncharacterized) and 1 carcinoma insitu. Two patients (a male and female) were seropositive for HIV type I. Twenty (95.24%) of the patients had tracheostomy at presentation with two having peristomal spread in the course of the disease. Eight (38.10%) patients had total laryngectomy out of which one was a salvage laryngectomy with subsequent right pectoralis major myocutaneous flap; 6 had concomitant chemoradiotherapy with one discontinuing after the first course and while the sixth total laryngectomee had no chemoradiotherapy. Three (14.29%) had primary radiotherapy; 2 of the cases were advanced diseases and one early disease. Eight (38.10%) had no treatment. Of the 6 laryngectomees, three had tracheo-oesophageal fistula post-operatively while one had disease recurrence and died. The first laryngectomy case is still on follow-up, disease free four years now while the rest have been lost to follow up. CONCLUSION: Education and provision of standard oncologic treatment centres with trained personnel will help in alleviating theses challenges by providing treatment, data for assessment and improving the standard of our treatment. PMID- 25452955 TI - Assessment of the risk approach in the reduction of maternal mortality in north central Nigeria. AB - INTRODUCTION: Risk screening during antenatal care has been traditionally believed to be impactful in maternal and newborn mortality reduction. Relative risk of death is commonly used as a guide for clinical practice. To inform good decision-making in planning maternal mortality reduction programs, the number of maternal deaths as well as the relative risk should be considered. The objective of this study was to predict the risk of death using the age distribution, parity and booking status of women who had maternal deaths in the four facilities during the 6 months study period. METHODS: This was a 6 month prospective, cross sectional study of maternal deaths from 1(st) January, 2011 to 30(th) June, 2011 using the emergency obstetric care register in four health facilities in Makurdi North-central Nigeria. RESULTS: Women aged 20-34 years accounted for 82% of deliveries and contributed 74% of maternal deaths. Primigravidae and grand multigravidae made up 569 (41%) of all deliveries but contributed 58% of all maternal deaths. Most (53%) maternal deaths occurred in booked women. This is contrary to conventional knowledge where primigravidae, grand multipara, women who are unbooked, less than 20 years, 35 years and above, were expected to have high risk of maternal mortality. CONCLUSION: This study shows that most maternal deaths occurred in the standard low risk women. Therefore age, parity and booking status do not predict maternal mortality accurately in this environment. All pregnant women should therefore be viewed as being at risk of maternal death all through pregnancy, delivery and puerperium. PMID- 25452956 TI - Evaluating the evaluators in postgraduate fellowship examinations - a viewpoint. AB - When the result of a medical examination for a group of candidates is bad, it may be because the candidates are bad; or the questions and the format of the examination are improper. The reason may also be because there is no teaching and preparation of the residents or the mode of examination and the methods of assessment are flawed. This paper tries to focus attention on the role of the examiners in conducting a medical postgraduate examination. It highlights the negative impact of the aggressiveness of the evaluators, the unnecessary interruption of the candidate by the examiners and flawed or inadequate assessment of the candidate by the examiners. PMID- 25452957 TI - Giant Retroperitoneal Liposarcoma Mimicking Ovarian tumour - A Case report. AB - Retroperitoneal liposarcomas are rare tumours representing less than 1% of all malignant tumours. They are generally slow growing and may attain enormous sizes. We report a case of a giant (9.8kg) retroperitoneal liposarcoma in a 65 years old lady which was initially misdiagnosed as an ovarian tumour. She had a successful surgical removal and has been followed up for more than one year with no evidence of recurrence. PMID- 25452958 TI - Anaesthetic management of giant phaeochromocytoma in a patient with chronic renal disease. AB - BACKGROUND: Phaeochromocytoma is a rare catecholamine secreting tumour characterized by increase in systemic vascular resistance and blood pressure. It account for 0.1% of hypertension in the general population. Early diagnosis and definitive treatment with surgical excision is generally advocated as complications of undiagnosed phaeochromocytoma may be fatal, especially in patients undergoing surgery for other disorders or in pregnant women during delivery. The diagnosis of phaeochromocytoma often requires detailed preparations because of the challenges its excision poses to the anaesthetist, the surgeons and other members of the management team especially where the incidence is low and experience in the management suboptimal. RESULTS: This report illustrates the perioperative management of a 29year old female who presented with severe hypertension complicated by chronic kidney disease and a huge left adrenal mass confirmed to be phaeochromocytoma. After preoperative optimization, the left adrenal tumour weighing 1,350g was successfully excised under general anaesthesia. Severe hypertensive crisis during surgery was successfully controlled with a combination of phentolamine, glycerine trinitrate and magnesium sulphate, while hypotension following removal of the tumour was managed with graded dosages of dopamine. Postoperative recovery was uneventful and she was discharged home in satisfactory condition seven days after surgery. CONCLUSION: Perioperative management of patients with phaeochromocytoma though challenging, can be successfully undertaken with adequate preoperative optimization, use of appropriate drugs and adequate perioperative monitoring. PMID- 25452959 TI - Osteogenesis imperfecta in a pediatric surgical center in dakar, senegal: clinical and radiological aspects. AB - INTRODUCTION: Osteogenesis imperfecta presents with a set of constitutional disorders of varying severity, genetically determined and characterized by an abnormal production of collagen and matrix of the bone leading to bone fragility responsible for multiple fractures and many skeletal deformities. The aim of our study was to analyze the clinical and radiological aspects of the pathology. PATIENTS AND METHODS: This was a retrospective study of 10 cases of children with osteogenesis imperfecta who consulted the Pediatric Surgery Unit of the University Center Aristide Le Dantec Hospital over a period of 6 years. The parameters analyzed were the reasons for consultation, physical examination findings and findings on standard radiographs. After collecting all the data, children were divided according to the classification of Silence and Glorieux. RESULTS: Pain was the reason for consultation in eight children. The saber blade deformity of the legs was found in nine children. Physical examination found tenderness in 80% of cases. Blue sclera was found in one child. The teeth were normal in eight patients. Standard radiographs showed an osteopenic skeleton with multiple fractures (3.7 fractures on the average) associated with vicious callus formation and deformity. According to the classification of Silence and Glorieux, six children were type VI, two children type IV, a child type III and one type I. CONCLUSION: Osteogenesis imperfecta is a rare disease. In our environment, the diagnosis is made late - a stage associated with deformity. Of these, the occurrence of sabber deformity of the lower limbs is the most common. Radiological aspects are dominated by vicious callus formation, deformed bones and osteopenia. Moderate forms are predominant. Parents need to be educated about the risk of repeat fractures and the need to present deformed children to hospital early. PMID- 25452960 TI - Pattern of hand injuries in osogbo, South-west Nigeria. AB - BACKGROUND: Injury to the hand leads to loss of function with attendant psychological consequences. Epidemiological studies of hand injuries from our environment are few; hence the need for this study. AIMS AND OBJECTIVES: To assess the epidemiology of hand injuries with a view to suggesting some methods of preventing the injuries in our environment. SETTING: This study was carried out in a Plastic surgery unit of a teaching hospital in Nigeria. METHODS: A retrospective review of the epidemiology of hand injuries in Osogbo, Nigeria was done. Sources of information include the case notes and operating registers. Information obtained includes biodata, aetiologies, pattern of injuries, presentation, treatment as well as complications. RESULTS: A total of 74 patients with hand injuries were managed during the study period comprising of 53 males and 21 females. The age group 21-30 was the most affected. Students form the largest group affected with 24(32.4%) followed by artisans, 16 (21.6%). The most common source of hand injuries was road traffic crash with 29 (39.2%) patients. Others were Blast injuries, 2 (2.8%), avulsion from grinding machines, 10 (13.5%), other domestic accidents, 6 (8.2%), broken bottles, 4 (5.4%), glass cut, 4 (5.4%), farm accidents, 6 (8.2%), electrical burns, 4 (5.4%), gunshot injuries, 3 (4.0%), thermal burns, 6 (8.1%) and constricting ring, 4 (5.4%). Injuries involved only the right hand in 36 (48.6%) patients, the left, 28 (37.8%) patients and both hands, 10 (13.5%) patients. Anatomical disruptions observed included avulsion, 14 (18.9%) patients, burn, 6 (8.1%)patients, bruises, 2 (2.7%) patients, crush injuries, 13 (17.6%), laceration, 24(33.8%), fractures/dislocation, 14(18,9%), and digital gangrene, 1(1.4%) patient. CONCLUSION: Hand injury prevention will include provision of safe road and education of the people on the use of tools and machines in our environment. PMID- 25452961 TI - Vaginal hysterectomy at jos university teaching hospital, jos, Nigeria. AB - BACKGROUND: Hysterectomy could be performed through the abdomen, via the vagina, as an open procedure or laparoscopically. The debate on whether the uterus should be removed vaginally or abdominally was sparked off when Langenbeck first performed a successful vaginal hysterectomy in 1813. The superiority of the vaginal route was highlighted when women who underwent vaginal hysterectomy experienced significantly fewer complications when compared to the others who had abdominal hysterectomy. OBJECTIVES: To determine the prevalence of vaginal hysterectomy, common indications, and outcome. PATIENTS AND METHODS: A total number of 49 vaginal hysterectomies were performed in the Department of Obstetrics and Gynaecology, Jos University Teaching Hospital, Jos, Nigeria between January 1998 and December 2007 were studied retrospectively. RESULTS: The combined hysterectomy (abdominal & vaginal) rate comprised 25% of all major gynaecological operations in this centre during the study period; vaginal hysterectomy alone comprised 3% of all the major gynaecological operations. The commonest indication for vaginal hysterectomy was uterine prolapse in 37(83.%) patients. The complication rate was 22%, with no mortality. CONCLUSION: Vaginal hysterectomy is safe and the complication few in experienced hands. Utero-vaginal prolapse was the commonest indication; public enlightenment to prevent prolapse would reduce the incidence and the need for repair. PMID- 25452962 TI - PILOT EXPERIENCE WITH Laparoscopic Cholecystectomy in Jos, Nigeria - CHALLENGES and prospects. AB - BACKGROUND: While laparoscopic cholecystectomy is the gold standard in developed countries for the removal of the diseased gallbladder, the procedure is just gaining popularity in Nigeria. This was a documentation of the authour's initial experience with laparoscopic cholecystectomy in a private hospital setting. AIMS & OBJECTIVES: To highlight the challenges of laparoscopic cholecystectomy in our environment and recommend solutions. MATERIALS AND METHODS: This was a prospective analysis of 35 consecutive patients presenting for laparoscopic cholecystectomy at a private hospital with special interest in endoscopy located in Jos, North Central Nigeria from June 2008 to May 2011. A Standard four-port laparoscopic cholecystectomy was performed in all the patients. The demographics, clinical features and management outcome were entered in a proforma and analyzed with Epi-info. RESULTS: A total of 35 laparoscopic cholecystectomies were performed during the study period. There were 5(14%) males and 30(86%) females giving a male: female ratio of 1:6. The mean age of the study population was 40.1+/- 11.4years and the mean operating time was 90 minutes with a range of 45 125 minutes. All the patients had chronic calculous cholecystitis and one (2.9%) of them also had empyema of the gall bladder. There were 2 conversions to open cholecystectomy in this study giving a conversion rate of 9.1%. CONCLUSION: Laparoscopic cholecystectomy is a safe and acceptable way of performing cholecystectomy in our environment even in a private hospital with careful patient selection, attention to details and performed by experienced surgeons. PMID- 25452963 TI - Effects of lidocaine and k-y jellies on sore throat, cough, and hoarseness following endotracheal anaesthesia. AB - Tracheal intubation for general anaesthesia is often associated with postoperative sore throat, hoarseness and cough which can be distressing to patients. We compared the effects of lidocaine and K-Y jellies on postoperative sore throat, cough and hoarseness of voice following endotracheal anaesthesia. METHODS: Ninety-two ASA I or II patients scheduled for elective surgery under endotracheal general anaesthesia were randomly allocated into two groups. Tracheal tubes were lubricated with either 2% lidocaine jelly (LJ) or K-Y jelly (KYJ) for the groups and the patients were interviewed at 1, 12 and 24 hours post extubation. RESULTS: The mean scores for sore throat were lower in the KYJ group than the LJ group but this was only statistically significant at 12 hours (p = 0.02). The incidence of sore throat, hoarseness and cough were also lower in the KYJ than in the LJ group but these were not significant. While the incidence of sore throat was comparable among both sexes in the LJ group, it was higher in females (55.6%) than in males (18.8%) in the KYJ group (p = 0.02). Whereas in patients older than 30 years the incidence of sore throat, hoarseness and cough were similar in both groups, in patients less than 30 years, there were significant differences (p = 0.01 and 0.02 respectively). The incidence of side effects was similar in both groups irrespective of duration of intubation. CONCLUSION: K-Y jelly is superior to lidocaine jelly in preventing postoperative sore throat, and in reducing the incidence of hoarseness of voice and cough. Postopearive throat complaints are more common in females than males. PMID- 25452964 TI - Opioid-sparing effect of bupivacaine wound infiltration after lower abdominal operations. AB - BACKGROUND: Pain management has traditionally been provided by opioid analgesics. However, the reluctance of some health personnel to prescribe or administer opioids because of the fear of side effects has hindered their use. Local anaesthetic wound infiltration has been shown to improve postoperative pain management. AIMS AND OBJECTIVES: To determine the efficacy of combined subfascial and subcutaneous infiltration of bupivacaine in providing an opioid- sparing effect following abdominal surgery. DESIGN OF THE STUDY: It was a prospective, randomized, double blind, placebo-controlled study. SETTING: The study was carried out at the University of Ilorin Teaching Hospital, Ilorin, Nigeria. PATIENTS AND METHODS: The study group received subcutaneous and subfascial infiltration with 40ml of 0.25% bupivacaine while the control group received 40ml of 0.9% saline administered by the surgeon after the closure of the peritoneum. Postoperative analgesia was provided with intramuscular morphine 0.1mg/kg 4hourly on demand and the time to first analgesic request was noted. Intravenous paracetamol was used as rescue analgesia. Postoperative pain was assessed using the verbal rating scale (VRS) at 6, 12 and 24 hours postoperatively at rest and during coughing. RESULTS: The mean time to first analgesic request was significantly prolonged (p <0.05) in the study group (174 +/- 117.6 min) than in the control group (102 +/- 84 min). The patients in the control group received more morphine which was not statistically significant (p > 0.05). Request for rescue analgesia and the patients' impression of the analgesia were not significant (Fishers exact test two tailed p-value = 0.7164 and 0.4506 respectively). CONCLUSION: Bupicacaine wound infiltration improved pain scores at rest within the first 6 hours and pain scores on coughing within the first 24 hours postoperatively. Although the technique increases the options available for postoperative pain relief after lower abdominal surgery, it cannot be used alone in this type of surgery. PMID- 25452965 TI - Traumatic Intracranial Aerocele With Progressive Blindness - A case report. AB - BACKGROUND: Traumatic intracranial aerocele, also known as pneumocephalus, is an uncommon condition that may be asymptomatic or may present with progressive neurological deficits and life threatening conditions that demand urgent decompressive craniotomy to reduce the acute rise in intracranial pressure and the sequelae. AIMS & OBJECTIVES: A high degree of suspicion and continuous neurological monitoring are essential for the early detection and the prompt neurosurgical intervention demanded for the achievement of a good outcome in patients following traumatic acute severe head injury with life threatening neurological complications. METHOD: Presentation of a young motorcyclist who was not wearing a crash helmet and was involved in a road traffic accident in which he sustained a compound cranio-facial injury with loss of consciousness and symptomatic intracranial aerocele. RESULTS: The case of a 28-year old motorcyclist without a helmet, following a road traffic accident, sustained compound skull fracture with CSF rhinorrhea, ventricular aerocele and progressive blindness who recovered his vision fully following bitemporal decompressive craniotomy. CONCLUSION: A high index of suspicion enabled early detection and prompt decompressive craniotomy that stemmed the progressive loss of vision in this patient with an uncommon but symptomatic intracranial aerocele and cranio facial compound head injury. PMID- 25452966 TI - Giant dumb-bell calculus complicating vesico-vaginal fistula - a case report. AB - A 34 year old, para 1(+0) woman was seen in February 2009. Her only confinement was 4 years earlier and was complicated by vesicovaginal fistula (VVF) due to prolonged obstructed labour. She had had 2 failed repairs of the VVF before presentation. About a month before the presentation, she started experiencing increasing perineal and suprapubic pain and the sensation of bearing down. A calculus was readily felt per vaginam and further evaluation revealed its extension into the urinary bladder incorporating nylon suture and vaginal tissues. The calculus was successfully excised by a combination of suprapubic and vaginal approaches. Public enlightenment should emphasize that the first attempt at VVF repair by an experienced surgeon in a proper surgical setting is the best chance for a successful outcome. PMID- 25452967 TI - Iatrogenic ureteric injuries complicating open obstetric and gynaecologic operations in South East Nigeria - case series. AB - BACKGROUND: Iatrogenic ureteric injury(IUI) in open obstetric and gynaecological surgeries is uncommon, with an incidence of 0.4-2.5%. It is however less uncommon in some specific vaginal and urethral suspension surgeries. The left ureter is more commonly damaged in the pelvis than the right ureter. The common mechanisms of injury include ligation, transection and crushing. Most of these injuries are unnoticed at the primary surgery, but are recognized in the immediate post operative period. Iatrogenic ureteric injury increases morbidity, though mortality is rare. RESULTS: A total of six patients had iatrogenic ureteric injuries during open pelvic operations in this study between January 2009 and December 2010. All the patients had a mean age of 38.5years and a range of 27-50 years. The primary surgery for three of the cases were done by consultant gynaecologists, two by medical officers who were yet to undergo residency training, while the status of the surgeon in one case could not be ascertained. The left ureter was injured in 5(83%) patients, with ligation being the commonest mechanism of injury in 83% of cases. Recognition of the ureteric injuries was in the post-operative period in all the cases in this report. The commonest presenting feature was leakage of urine via a uretero-vaginal fistula in 67% of cases and through the surgical wound in one(17%) patient. CONCLUSION: Iatrogenic ureteric injuries do complicate pelvic surgeries in this environment and often present as urinary fistula in the immediate post operative period; majority are missed intra-operatively. PMID- 25452968 TI - Failed spinal anaesthesia for caesarean section. AB - BACKGROUND: Spinal anaesthesia is the preferred regional technique for Caesarean section but failure sometimes occurs. AIMS AND OBJECTIVES: To determine the incidence of failure of spinal anaesthesia necessitating the conversion to general anaesthesia or the use of supplemental analgesia in women presenting for Caesarean section and to identify the contributory factor(s) to the failure. STUDY DESIGN: It was a prospective study of 414 women who had spinal anaesthesia for Caesarean section. SETTING: The study was carried out in a University Teaching Hospital in South-Western Nigeria. PATIENTS AND METHODS: Women who had single-shot spinal anaesthesia for Caesarean section from April 2010 to March 2011 were prospectively studied using a standard proforma to record details of their demographic, clinical features, surgical and anaesthetic data and outcome. RESULTS: The failed spinal anaesthesia rate in this study was 6.0%. The experience of the anaesthetist was a significant contributing factor for partial or complete failure necessitating conversion to general anaesthesia (p = 0.02). Intra-operative supplemental analgesic was required in 6.4% of those who had their surgery completed under spinal anaesthesia. Postpartum sterilization, exteriorization of the uterus during surgery, and surgical complications were significant risk factors for partial failure necessitating supplemental intra operative analgesic. CONCLUSION: Spinal anaesthesia conversion rate is high in this study when compared with reports from developed countries. Adequate training for residents in anaesthesia will decrease the failure rate. Parturients undergoing sterilization during Caesarean section may require supplementary analgesia. PMID- 25452969 TI - Instrumental vaginal delivery in bauchi, northeast Nigeria. AB - BACKGROUND: Instrumental vaginal delivery is an important procedure which can be used as an alternative to caesarean section when indicated and thus reduce the caesarean section rate. There is a need to maintain and improve the skills for this procedure through training and research in order to improve the benefits for both mothers and their babies. OBJECTIVE: To determine the incidence and indications of instrumental vaginal delivery and to compare the foetal and maternal outcome of vacuum and forceps deliveries. MATERIALS AND METHODS: This was a retrospective study on instrumental vaginal deliveries carried out between June 2009 and May 2011. The hospital records of all the patients who had had vacuum or forceps delivery were obtained and data on age, parity, booking status, and type of procedure performed, APGAR scores of babies delivered and complications were entered into a proforma and analyzed using SPSS software for Windows version 16.0. RESULTS: The rate of instrumental vaginal deliveries in this study was 0.69% of all deliveries. The rates were 0.54% and 0.15% for vacuum and forceps deliveries respectively. There was statistically significant difference in terms of APGAR scores <=6 at 5 minutes and maternal complications between the two groups as the p-value was 0.000. There was no statistically significant difference with respect to booking status and parity of patients between the two groups as the p-values were 0.073 and 0.976. CONCLUSION: The rate of instrumental vaginal deliveries in this institution is low and indications for the procedure are similar to those found elsewhere. There is statistically significant difference in terms of foetal and maternal outcomes between those who had forceps delivery and those who had vacuum delivery. PMID- 25452970 TI - Intra-aortic balloon pump in coronary artery bypass graft - factors affecting outcome. AB - BACKGROUND: The management of coronary artery bypass graft (CABG) patients, especially in high risk patients ,can be challenging as the postoperative periods may be characterized by a low cardiac output state. Inotropes used in the perioperative periods to increase cardiac output may be detrimental thus making the use of mechanical devices like intra-aortic Balloon pump (IABP) for circulatory assistance desirable. AIMS & OBJECTIVES: To study the use of intra aortic balloon pump in coronary artery bypass patients in preoperative and post operative settings and factors that affect morbidity and mortality. SETTING: Madras Medical Mission, Chennai, India. METHOD: A retrospective study of 3974 consecutive patients who had CABG done between March 2007 and February 2011 with or without additional procedures. One hundred and seven (2.7%) patients had IABP instituted either pre-operatively or postoperatively when it was obvious the patient will need cardiac assistance. The demographic data, clinical features, the indications for insertion, management offered and outcome , the creatinine levels, the duration of intraarortic balloon pump, the intensive care unit(ICU) and Hospital stay were analyzed for means and standard deviations and Pearsons Chi-square test using SPSS 10.0 window soft ware version with significant value of p-value<0.005. RESULT: The mean age of all the patients was 59.7 + SD 10.7, 85(79.4%) patients were males,22(20.6%) were females .Out of the 107 patient who had IABP insertion, 59(55.1%) patients had IABP inserted preoperatively and 48(44.9%) postoperatively. The creatinine levels after the insertion of IABP in 68 patients was<1.5mg/dl and in 39 patients was>1.5mg/dl with mortality of 15.0% for the preoperative insertion group versus 29.0% for the postoperative group respectively (p=0.005). The preoperative and postoperative insertion ICU stay were 8.3+4.7 days and 5.7+1.6days respectively (p=0.005) and mortality were16.8% and 27.1 %( p=0.005) respectively. CONCLUSION: Early institution of intra-aortic balloon pump gives a better outcome even in high risk coronary artery bypass graft patients as it reduces ICU stay and mortality, and elevated post-insertion creatinine levels has been shown to be an indicator of impending mortality and so an early warning for putting in place mitigating protocols. PMID- 25452971 TI - Some factors responsible for failure in fellowship examinations in surgery - a view point. AB - The major reasons for repeated failures at the Fellowship Examinations in Surgery are due to poor preparation and underrating the scope and depth of the expectations of the examiners. Attention to details and comprehensive answers to every question in the theory, clinical parts of the examination, viva voce and thesis are the linchpins to success. The answers should show mastery and up-to date information of the subjects under discussion. Adequate preparation for fellowship examination should include reading the appropriate textbooks and surgical journals thoroughly, participating actively in clinical case presentations before peers and trainers, as well as searching the internet for current concepts in the areas of interest. PMID- 25452972 TI - Unusual presentation of foreign body in the thigh - a case report. AB - Foreign bodies in the thigh are uncommon. Rarer is the presence of a foreign body in the posterior compartment of the thigh following a wood puncture injury to the anterior thigh compartment. The purpose of this report is to highlight this unusual presentation. We present a six-year old boy presenting with a tumor-like mass in the posterior compartment of the right thigh thirteen months after a puncture injury to the anterior compartment of the right thigh. He sustained the injury while playing with a sharp wooden object. Part of the foreign body was expressed out while part of it was unknowingly left behind. The patient presented 13 months after with a mass in the posterior compartment of the thigh. He was promptly evaluated and he had exploration of the mass. A plain wooden foreign body was extracted which measured 6cm by 2cm. He made an uneventful postoperative recovery and has been followed up for more than twelve months without further symptoms. Adequate initial wound exploration with removal of all foreign bodies and necrotic tissues would have prevented this prolonged morbidity. PMID- 25452973 TI - Hidradenitis suppurativa - a case report. AB - Hidradenitis suppurativa is a chronic and disfiguring skin disease characterized by multiple abscesses and sinuses. Often it is not recognized early in this environment as a result of limited awareness of this condition. The author sought to review available knowledge on this condition and report a case currently being managed in a general surgery unit. Literature search was conducted using the Google search engine and a patient who presented to the author's unit is presented. In conclusion, hidradenitis suppurativa is a distressing disease. High index of suspicion and relevant investigations would improve early diagnosis; several options are available for treatment with good outcome depending on the stage of the disease. PMID- 25452974 TI - Sonourethrography in the evaluation of anterior urethral stricture. AB - BACKGROUND: The management of urethral stricture is a challenge to both the urologists and the patients. Thoughtful and satisfactory preoperative evaluation remains important to achieving good outcome. Retrograde urethrography and Micturating Cystourethrography (RUG/MCUG) have been the gold standard imaging technique in the evaluation of anterior urethral stricture but are not without inherent limitations and side effects. Sonourethrography (SUG) could diagnose anterior urethral stricture, measure its length, and detect presence of complications and extent of spongiofibrosis. AIMS AND OBJECTIVES: To establish the sensitivity of sonourethrography in the identification of the anterior urethral stricture. To determine the accuracy of sonourethrography in measuring the length of anterior urethral stricture as well as to detecting spongiofibrosis. PATIENTS AND METHODS: This was a prospective study of 60 patients clinically diagnosed to have anterior urethral stricture. The patients included in the study underwent both SUG and RUG/MCUG. The sensitivity of SUG was then calculated. Paired t-test was used to determine its ability to measure the length of the anterior urethral stricture. The percentage of patients detected to have spongiofibrosis on SUG was also computed. RESULTS: The mean age of patients recruited for the study was 46 +/- 18 years (Range = 9-69). The sensitivity of SUG was 94%. The lengths of anterior urethral stricture were 14.1 +/- 1.9mm and 16.0 +/- 2.1mm for RUG/MCUG and SUG respectively. The mean difference is 2.0mm (Confidence interval, CI = 0.872 - 2.911, p<0.05). SUG correctly identified spongiofibrosis in 31(51.7%) patients that had anterior urethral stricture. CONCLUSION: This study has demonstrated that sonourethrography is a valuable diagnostic tool in the evaluation of anterior urethral stricture. PMID- 25452975 TI - Extremity amputations in warri, South-South Nigeria. AB - BACKGROUND: Amputation is one of the most common procedures in the practice of Orthopaedics and Traumatology in Nigeria. Many previous studies and reports from different centres show variations in the indications for this surgical procedure. AIMS & OBJECTIVES: The aim of this study is to find the most important indications for amputation in our immediate environment and make possible suggestions towards reducing the incidence. PATIENTS AND METHOD: This is a retrospective study of consecutive patients who had limb amputations at the Central Hospital, Warri between January, 2009 and December, 2011. Case notes of patients were retrieved, relevant information extracted and analysed. RESULTS: A total of 44 patients had 46 amputations within the study period. The age range of patients was between 8-88 years. Amputation in 63.6% of the patients was due to diabetic foot disease, followed by trauma in 20.5% of cases. About (62.5%) of the amputations were below knee amputations while toe amputations made up 17.4% of cases. The lower limb was involved in 91% of cases and upper limbs in 9% of cases. Complication rate was about 39.1% which was mostly as a result of wound infections. CONCLUSION: Diabetic foot disease was the most important indication for amputation in this study. Rigorous public enlightenment on the prevention and effective treatment of diabetes will reduce the incidence of lower limb amputations in this environment. PMID- 25452976 TI - Preliminary experience with radical cystectomy and w-ileal pouch for muscle invasive transitional cell bladder carcinoma. AB - BACKGROUND: Radical cystectomy and bilateral pelvic lymphadenectomy is considered the treatment of choice for patients with muscle invasive transitional cell bladder cancer. Following radical cystectomy the surgeon would choose an appropriate modality of urinary diversion from a plethora of methods. Radical cystectomy with any type of diversion remains a complication-prone surgery. This study aims at reviewing the peri-operative challenges and morbidities experienced with radical cystectomy and W-ileal pouch urinary diversion in a tertiary hospital in Nigeria. AIMS & OBJECTIVE: To report experience with radical cystectomy and W-ileal pouch construction in patients with muscle invasive transitional cell urinary bladder carcinoma. PATIENTS & METHODS: The case notes of patients diagnosed with muscle invasive transitional cell bladder carcinoma (T2/3NoMo) who underwent radical cystectomy and W-ileal pouch construction from December 2006 to December 2011 at the Jos University Teaching Hospital, Jos, Nigeria were retrospectively studied. Patients were evaluated for age, sex, duration of surgery, estimated blood loss, duration of hospital stay, and complications after surgery. RESULTS: Six patients had their records reviewed. Mean age was 55.8 years (range 32 - 66years). Male to female ratio was 5:1. Mean hospital stay was 31 days, with all of the patients requiring intensive care for a mean of 24 hours (range 24-72 hours). Mean hospital stay was 31 days (range 21 40 days). Mean estimated blood loss was 891 ml (range 720-1500ml). Mean duration of surgery was 10.3 hours (range 8-12 hours). Commonest complication was urine retention secondary to mucus plug in 50%. Operative mortality was 16.7%. CONCLUSION: Radical cystectomy and W-ileal pouch construction due to its technical complexity and challenging postoperative management necessitates a team approach with experienced surgeons, anesthetists, intensivists and stoma care specialist, among others. PMID- 25452977 TI - Evaluation of the cardiovascular stimulation effects after induction of anaesthesia with ketamine. AB - BACKGROUND: Ketamine is a common anaesthetic agent for surgical procedures in both paediatric and adult populations in our environment. In polytraumatised patients its cardio-stimulatory effects may be advantageous in supporting the cardiovascular system while awaiting the clinical effects of on-going resuscitative interventions. However, its clinical uses cause significant cardiovascular stimulations that may be deleterious in patients with cardiovascular diseases. AIM & OBJECTIVES: To evaluate the stimulatory effects of ketamine on cardiovascular system following induction of anaesthesia with ketamine. STUDY DESIGN: This was a prospective observational study of the haemodynamic responses of 52 consenting patients who underwent surgery surgeries under general anaesthesia with ketamine induction. The pulse rate and blood pressure were measured non-invasively and recorded every minute for ten minutes following ketamine induction. SETTING: University of Ilorin Teaching Hospital, Ilorin, Nigeria. MATERIALS & METHODS: Following approval of the Institutional Ethical Review committee, 52 consenting adult patients scheduled for surgery under general anaesthesia were premedicated with 10mg oral diazepam 90 minutes before the ketamine (2mg/kg intravenously) was intravenously administered as induction of anaesthesia. The pulse rate (PR) and mean arterial pressure (MAP) were measured non-invasively and recorded at 1 minute interval over 10 minutes after the induction of anaesthesia with intravenous ketamine 2mg/kg while the patients breathed 100% oxygen spontaneously. RESULTS: In the 52 patients studied, the values of pulse rate (PR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) were significantly elevated above the baseline values by 22+/-14bpm, 15+/-11mmHg, 19+/-15mmHg, and 12+/-10mmHg respectively, with p=0.0001. CONCLUSION: Ketamine induction of general anaesthesia exerts beneficial stimulatory effects on the cardiovascular system. PMID- 25452978 TI - Impalement head injury with serrated meat knife. AB - An unsuspecting motorcycle passenger was ambushed and impaled on the right side of the head with a 30cm serrated meat carving knife during a sectarian crisis in the city of Jos, Plateau State, Nigeria. The patient escaped running with the knife in his head and was rescued to a military hospital from where he was promptly transferred within 90 minutes of the incident to the Emergency Department of Jos University Teaching Hospital (JUTH), Jos. Prompt resuscitation and CT brain imaging facilitated a successful neurosurgical intervention and a good outcome in the management of this patient. PMID- 25452979 TI - Uncommon intracranial abscesses. AB - BACKGROUND: Intracranial abscess, though uncommon, have relatively higher occurrence in low socio-economic settings where previous antibiotic abuse and lack modern culture techniques makes isolation of organisms difficult. Diagnosis and treatment are further delayed by a poor referral system and low index for suspicion. Tuberculoma, cannabis abuse, ventriculo-peritoneal shunt catheters and cancer therapy are presented here as unusual causes of intracranial abscesses. AIMS & OBJECTIVES: To highlight less commonly encountered causes of an uncommon, but dreaded, neurosurgical condition, their diagnosis and treatment approaches. CASE REPORTS: Five patients who had surgical evacuation of intracranial abscesses not due to pathology from the more familiar spread from sinusitis, mastoid, middle ear, post-meningitic or post -traumatic aetiology are presented. Contrast computerised tomography (CT) brain scan was essential in clinching the diagnosis and determining the management options. CONCLUSIONS: Persistent headaches or features of intracranial involvement (in patients undergoing treatment for other conditions) should always warrant CT of the brain. However, there are several differential diagnoses of ring-enhancing lesions on CT which have to be excluded when considering an abscess. PMID- 25452980 TI - BICORNUATE UTERUS MIMICKING ECTOPIC PREGNANCY - A case report. AB - Uterine anomalies are uncommon and in our environment they are usually incidental findings. There are different types of uterine anomalies and most are known to influence reproductive outcomes of the affected women. We present a case of a 26 year old G6P5+0 (3 alive) with a bicornuate uterus who presented with 12 weeks history of amenorrhoea, lower abdominal pain and bleeding per vaginam. Pelvic ultrasound showed an empty uterus and a right adnexal mass which was misdiagnosed as an ectopic pregnancy. At surgery, she was found to have a bicornuate uterus with an intact pregnancy. The pregnancy aborted spontaneously shortly after discharge from hospital. The patient had had five previous successful pregnancies which she carried to term with three of her children alive. The objective of the report was to show that patients with uterine anomaly could have successful pregnancy outcome; the congenital anomaly could be discovered incidentally while being managed for other clinical conditions. PMID- 25452981 TI - Comicronngenital diaphragmatic hernia in dakar, senegal. AB - BACKGROUND: Congential diaphragmatic herniae pose serious challenges in their management in this environment.Aim & Objective: To determine the pattern, as well as the diagnostic and management challenges of congenital diaphragmatic hernia in Dakar, Senegal. PATIENTS AND METHODS: This is a retrospective review of 14 children with congenital diaphragmatic hernia (CDH) managed within eleven years in Dakar, Senegal. RESULTS: There were nine boys and five girls with the age range of one day to 22 months and a mean of 5 months. Respiratory signs (respiratory distress, cough, current pulmonary infection) were found in 13 patients and gastrointestinal symptoms (vomiting, Difficulty sucking, anorexia) in 6 patients. The thoracic-abdominal radiography was performed in all patients and revealed a Bochdalek hernia on the left in 10(71%) cases and 4(29%) were Morgagni hernia. Treatment was by repair of the diaphragmatic defect with non absorbable sutures. The postoperative course was uneventful in 13 children while one patient died on the first postoperative day one. CONCLUSION: Congenital diaphragmatic hernia presents mainly with postnatal respiratory features in this setting. Thoracic-abdominal radiography allows for early diagnosis, prompt and effective treatment with good outcome. KEYWORDS: Congenital diaphragmatic hernia, Respiratory insufficiency, Radiological features, Good surgical outcome. PMID- 25452982 TI - Ear, nose and throat lesions in hiv/aids patients in komfo anokye teaching hospital, kumasi, ghana. AB - BACKGROUND: HIV/AIDS is one of the devastating endemic diseases within the subregion. This condition may be associated with certain specific presentations of which may be confined to the ear, nose, throat and the neck region. OBJECTIVE: The main objective of this study was to evaluate ear, nose and throat (ENT) lesions which may be more associated with the HIV/AIDS infection. MATERIALS AND METHOD: Ninety-three patients who reported to the ENT Clinic of Komfo Anokye Teaching Hospital with certain ENT presentations were screened for HIV/AIDS infection. This was a five-year prospective study conducted at the ENT Clinic and the Microbiology laboratory (KATH). Ethical clearance was approved by the Joint Ethical Committee (KATH/KNUST). Those with other co-morbid pathologies were excluded. RESULT: In all 67.2% were found to be sero-positive. Among the common ENT manifestations include Herpes zoster oticus (Ramsay-Hunt syndrome) 33.9%, Cervical lymphadenopathy 21.0%, Fungal sinusitis 6.5%, Oropharyngeal candidiasis 17.7% etc. CONCLUSION: This study collaborates the knowledge that ENT lesions are more associated with the HIV/AIDS infection presence of which should always prompt the ENT surgeon to screen the patients for the HIV/AIDS. PMID- 25452983 TI - Substance abuse among antenatal patients at jos university teaching hospital, north central Nigeria. AB - BACKGROUND: Substance use in this country, among pregnant women, is a recent phenomenon as our women embrace western culture. More worrisome is the current finding showing no 'safe' level of alcohol exposure for possible adverse effect or harm to the developing child to occur. AIMS AND OBJECTIVES: To determine what substances are used and the prevalence of substance use among pregnant women attending the antenatal clinic of the Jos University Teaching Hospital, Jos, Northcentral Nigeria. DESIGN: Cross-sectional study. SETTING: Jos University Teaching Hospital. RESULTS: A total of 557 women were administered the pre-tested questionnaire. The mean age was 29.1 years, with a range of 15 to 48 years. The prevalence rate of substance used among the pregnant women was 43.8%. In all, 244 of the 557 women were taking one substance or the other. About 61.9% of the women abuse Kolanuts. There was no significant difference in the age group between those who sue it and those who do not (p-value 0.7411). Other substances were chlorpheniramine 10.6%, alcohol 8.6%, diazepam 4.5% and promethazine 2.5%, cigarettes/tobacco 2.9%, phenobarbitone 2.9%, cocaine 2.5%, codeine 2.0%, and marijuana 1.6%. A significant number 22.8% admit to using other substances in pregnancy. The commonest reason given for substance use is to control nausea and vomiting of early pregnancy. CONCLUSION: Nigerian pregnant women use and abuse a wide variety of substances and drugs during pregnancy just as their counterparts in the developed world. The high prevalence observed in this study was largely due to the consumption of locally available substances. PMID- 25452984 TI - Tramadol effects on perioperative shivering in lower limb orthopaedic surgeries under spinal anaesthesia. AB - BACKGROUND: Shivering is one of the common complications of regional technique. Although shivering may have beneficial thermoregulatory effects, it places the patient under increased physiological stress. AIMS AND OBJECTIVES: The study evaluated the efficacy of intravenous tramadol in the prevention and treatment of post-anaesthetic shivering following subarachnoid block for lower limb orthopaedic procedures. MATERIALS AND METHODS: This was a prospective, double blind, randomized controlled trial conducted at the University of Benin Teaching Hospital, Benin City. In this study, ninety-five ASA physical status 1 or 2 eligible patients aged between 16 and 65 years were randomly allocated to either the tramadol group or the saline group. A randomization schedule with sealed envelopes was used. Each patient received 10mg diazepam the night before and morning of surgery. Spinal anaesthesia was induced in the sitting position with 15mg hyperbaric bupivacaine. The tramadol group received 0.5mg/kg IV made up to 2ml with saline while the control group was given 2 ml saline IV to ensure blinding. RESULTS: The incidence of shivering in the tramadol and the saline groups was 13.93% and 16.28% respectively. The overall incidence was 15%, (n=13). There was no statistical difference in the occurrence of shivering in both groups. However all patients who shivered during the surgical procedures, did not have a recurrence of shivering after a rescue dose of i.v tramadol 1mg/kg was administered. CONCLUSION: Tramadol abolished shivering promptly when employed as a rescue medication with no recurrence. Also, tramadol reduces the severity of post-anaesthetic shivering. PMID- 25452985 TI - Experience with colonoscopy in the riverine southwestern Nigeria. AB - BACKGROUND: Colonoscopy is useful for diagnosis, treatment and surveillance of anal and colorectal lesions. It affords a good, less invasive and tolerable way to see and access the large intestine. AIM AND OBJECTIVE: To determine the indications, finding and diagnosis at colonoscopy in a riverine setting in Southwestern Nigeria. TYPE OF STUDY: Descriptive cross sectional study. PATIENTS AND METHODS: Patients who presented in the State Specialist Hospital, Okitipupa and requiring colonoscopy in their management between January 2011 to April 2013 were included in this study. They were reviewed and their demographic and clinical data, indications for colonoscopy, the findings and the pathological diagnosis were entered in a proforma. RESULTS: Colonoscopy was done in 100 patients out of which seventy seven (77%) were males and 23 (23%) were females. The indications were frank lower gastrointestinal bleeding 55 (55%) chronic diarrhea (11%), chronic constipation10(10%), occult gastrointestinal bleeding (7.0%), lower abdominal and anal pain 4 (4.0%), queried anorectal cancer 3 (3.0%) and enterocutaneous fistula 1(1%). Colonoscopic findings, include, normal finding 24(24%) colitis 24 (24.0%), hemorrhoid 20(20.0%), Anal fissure 16 (16.0%) colonic cancer 5 (5.0%), anorectal cancer 4 (4.0%), caecal cancer 2 (2.0%) faecal impaction 2 (2.0%), anal wart 2 (2.0%) , polyps 1 (1.0%) and anal fistula 1 (1.0%). The diagnostic yield was 76%. CONCLUSION: Bleeding from the lower gastrointestinal tract was the commonest indication for colonoscopy and the most frequent pathology was amoebic in the riverine Southwestern Nigeria. PMID- 25452986 TI - Chest trauma in a regional tRAUMA centRE. AB - BACKGROUND: Chest trauma is a major cause of morbidity and mortality worldwide. Hospital based studies in Nigeria show it predominantly affects the youth in society. Aim & Objectives: To determine the pattern and management outcomes of patient presenting with chest trauma at the University of Benin Teaching Hospital, Benin City, Nigeria. MATERIALS AND METHODS: This is a prospective study of 73 consecutive patients managed for chest injuries between January 2008 and February 2009 at the University of Benin Teaching Hospital, Benin City. RESULTS: A total of 73 patients were enrolled in the study. The mean age was 31.5years and median age of 29years. About 81% of the patients were 42yrs and below while 10% were more than 50yrs old. About 88% of the patients were males while 12% were females giving a male: female ratio of 1:7 Most (56%) of the patients were single. Motor Vehicular Accidents (MVAs) accounted for 52% while 43%% were due to violence or assaults. Motorcycle accidents accounted for 15% while Cars, Buses, Vans, Trucks accounted for 37%. Penetrating trauma accounted for 43% of which gunshot wounds accounted for 25%, and stab injuries accounted for 13(18%). About 53% were isolated blunt chest injuries whereas 43% were isolated penetrating chest injuries; 4% of the cases sustained both penetrating and blunt injuries. About 27% presented within an hour of injury, while in all, 95% of the patients presented within 24hours of injury. Diaphragmatic injuries were sustained in 6(8%) patients while cardiac injury was observed in one patient. CONCLUSION: Chest trauma predominantly affects the youth with high morbidity and mortality in this environment. Public enlightenment with prompt and effective treatment will impact positively on this persistent problem. PMID- 25452987 TI - OESOPHAGEAL IMPACTED Dentures AT THE University of Benin Teaching Hospital, BENIN CITY, nIGERIA. AB - BACKGROUND: Inadvertently swallowed dentures occur in senile patients, alcoholics and those with loose fitting dentures. In the oesophagus, they may lodge at the cricopharyngeal sphincter, point where the left main stem bronchus crosses the oesophagus or the lower oesophageal sphincter. When impacted they may cause pressure necrosis with time, suppuration and perforation, which may lead to mediastinitis. AIM OF THE STUDY: Audit of patients with swallowed dentures at the University of Benin Teaching Hospital, Benin. MATERIALS AND METHOD: This is a retrospective study of all cases of swallowed dentures seen from June 2005 to June 2012. RESULTS: The clinical records of 44 patients were extracted and analyzed. The mean age of the patients was 51.9 +/- 16.6yrs with a male: female ratio of 8:7. The mean age of the males was 52.6 +/- 14.3 years, and 46.6 +/- 19.0 years for females. 43 (96.7%) had rigid oesophagoscopy under general anaesthesia for extraction. Retrieval was successful at first attempt in 37(86.7%) while three had cervical oesophagotomy. One had successful removal of the impacted denture by flexible oesophagoscopy with the use of polyp snare while two had thoracotomy for extraction. Complications included perforation with subsequent mediastinitis and death in one patient and subsequent tracheo oesophageal fistula in one patient. CONCLUSION: Rigid oesophagoscopy and retrieval of ingested dentures is a safe procedure with good outcome and associated with minimal morbidity and mortality. PMID- 25452988 TI - AN UNUSUAL ECTOPIC OSSEOUS TONGUE MASS - A case report. AB - We report a case of tongue swelling resulting from ectopic osseous proliferation within a pseudocystic stroma in a 24 year old healthy female. The patient presented a history of dull pain and gradual onset of a swelling at the ventral aspect of the tongue. The lesion had a mixed consistency with areas of sponginess andfluctuancy interspersed with nodular bony hardness and yielded a sanguinous aspirate. Doppler ultrasonographic scan and magnetic resonance imaging revealed a pseudocystic mass containing nodules of calcified bodies. Excision biopsy under general anaesthesia and histopathologic studies confirmed a case of ectopic osseous proliferation within the tongue. The lesion was marginally excised, wound healed satisfactorily with no complications as at 8(th) month follow-up period. This is a case of a lesion with conflicting clinical and histological characteristics. It underscores the need for routine immunohistochemistry and comprehensive aspirate analysis in our environment. The case has been reported to sensitize clinicians to a new possibility in the differential diagnosis of tongue swelling. PMID- 25452989 TI - Unilateral multicystic dysplasia in a horseshoe kidney - a case report. AB - Multicystic dysplastic changes in one half of a horseshoe kidney is an uncommon presentation. Surgical resection of the affected kidney is the treatment of choice. Accurate pre-operative evaluation ensures adequate planning, treatment and optimal outcome. We report the successful management of a 2-year old male child with massive abdominal distension due to multicystic dysplasia of the left half of a horseshoe kidney. Existing literature is reviewed and the challenges of management in this environment are highlighted. PMID- 25452990 TI - Hypertrophic tonsils in sickle cell patients in ghana. AB - BACKGROUND: Sickle-cell disease (SCD) is one of the commonest genetic blood disorders in the world and principally affects people of African, Mediterranean and Asian origin. It is an established fact that SCD patients often present with hypertrophic tonsils and as such Objective: The aim of this study was to determine the prevalence of hypertrophic tonsils in sickle cell disease patients in Ghana. METHOD: This is a case control prospective study involving sickle cell disease-SS patients aged between 2 and 13 years and 40 aged-matched controls who met the inclusion criteria at the Komfo Anokye Teaching Hospital, Ghana. The participants were examined using head lamp and a Breuning's tongue depressor. The tonsils sizes were estimated using the Brodsky's criteria. RESULT: This study showed 93.1% of the patients presenting with various degrees of tonsillar hypertrophy. Thirty-four percent presented with grade 3 Brodsky's hypertrophy, 24. 6% with grade 2, 20.1% with grade 4 and 14.2% with grade 1. Only 6.9% presented with Brodsky grade 0. CONCLUSION: The prevalence of hypertrophic tonsils is very high among sickle cell patients in Kumasi, Ghana. PMID- 25452991 TI - Pattern of demand for endodontic treatment by adult patients in port-harcourt, South-South Nigeria. AB - BACKGROUND: Root canal therapy (RCT) is an efficacious therapeutic strategy to retain teeth with irreversible pulpal damage. RCT ensures that a tooth with irreversible pulpal damage retains its functional role in the oral cavity. Currently, there are limited epidemiologic studies relating to the pattern of demand of RCT in Nigeria particularly in the Niger Delta region of the country. AIM: To determine the pattern of demand and reasons for endodontic treatment among adult patients attending a tertiary Dental Centre in the Niger-Delta region of Nigeria. METHOD: A retrospective review of the hospital records of adult patients who attended the Conservative Dental Clinic of the University of Port Harcourt Teaching Hospital, Rivers State, Nigeria from April 2008 to April 2012 for root canal therapy (RCT) was done. The demographic and clinical data were retrieved from the patients' records and analyzed using the SPSS version 20. RESULTS: There were 213 patients comprising 93 (43.7%) males and 120 (56.3%) females, giving a male to female ratio of 1:1.3. The age range of the patients was 17- 65 years while the median age was 28.0 years. The highest incidence of root canal disease (42.7 %) was found in the 20-29 years age group. The commonest indication for RCT was Irreversible pulpitis (46.9%). A total number of 241 teeth were treated. The molars 102(42.3%) were the most endodontically treated teeth, followed by the anterior teeth 90(37.3%). Maxillary teeth underwent higher percentage of RCT (65.1%) as against mandibular teeth where the treatment was done in 34.9% of the cases. CONCLUSION: More female patients and younger age group demanded for root canal therapy. Irreversible pulpitis was responsible for the majority of the cases treated and highest number of procedure was performed on maxillary teeth. The molars were the most endodontically treated teeth. PMID- 25452992 TI - Augmented bupivacaine spinal anaesthesia in postoperative analgesia. AB - BACKGROUND: The addition of intrathecal magnesium to local anaesthetics for spinal anaesthesia had been shown to prolong the duration of spinal anaesthesia and reduced postoperative requirement for lower limb orthopaedic procedures and caesarean sections. Aim & Objectives: To determine the effect of intrathecal magnesium sulphate to bupivacaine spinal anaesthesia for transurethral resection of the prostate. METHODS: This prospective, randomized, double blind study involved fifty ASA I-II patients who underwent transurethral resection of prostate after informed consent was obtained. Patients were randomized to two groups. Group S received 3ml of 0.5% heavy bupivacaine in addition to 1ml saline while Group M received 100mg of MgSO4 in addition to 3ml of bupivacaine. Onset time of sensory and motor block, time maximal block height was reached, duration of spinal anaesthesia, pain scores and the total analgesics used in the postoperative period were all recorded and analyzed. RESULTS: Time to maximum sensory block height, regression to T12 segment, and duration of motor block were all longer in group M. The duration before the first request for analgesia was significantly prolonged in the magnesium group (242mins vs 197mins). The magnesium group had lower Numerical Rating Score (NRS) in general, lower NRS scores at request for analgesia and total analgesic consumption in 24 hours. CONCLUSION: In patients undergoing transurethral resection of the prostate, the addition of intrathecal magnesium sulphate to bupivacaine spinal anaesthesia significantly prolonged the duration of spinal anaesthesia and also reduced the postoperative analgesic requirement without additional side effects. PMID- 25452993 TI - Identification and interpretation of maxillofacial plain radiographs by junior dental trainees. AB - BACKGROUND: Accurate identification and interpretation of plain maxillofacial radiographs is key to making correct clinical decision. OBJECTIVE: To assess the ability of junior dental trainees to correctly identify and adequately interpret oral and maxillofacial plain radiographs. STUDY DESIGN: Comparative analysis Setting: University of Port Harcourt Teaching Hospital, Port Harcourt and University College Hospital, Ibadan. MATERIALS AND METHODS: Twenty six plain film radiographs were selected and serialized. The films were presented to three specialislts; a radiologist and two oral surgeons for independent identification and interpretation. The level of agreement between them was tested using kappa statistics (k) and intraclass coefficient (ICC). Minor areas of discrepancy were finally reconciled and the correct identification and interpretations of every radiograph confirmed. The same set of radiographs was subsequently presented to twenty junior dentists (House officers and Registrars) for identification and interpretation. Accuracy of performances in identification and interpretation exercises was assessed by a test of agreement using kappa statistics and a mathematical performance rating method respectively. RESULTS: In terms of identification, the agreement between the three specialists was very strong with ICC of 0.96. Kappa (k)-values of 1.00 suggesting perfect agreement was observed between the two oral surgeons. Agreement between each oral surgeon and the radiologist was very good (k= 0.84). The k-value for agreement in identification between trainees and specialists ranged between 0.23 and 1.00. As for interpretation, the percentage accuracy of the junior dental trainees ranged between 60.5% and 87.2% compared to specialists' range of 89.5% to 95.3%. The common areas of discrepancy in identification and interpretation are highlighted. CONCLUSION: Based on this study, dental trainees demonstrate varying levels of expertise in identification and interpretation of maxillofacial plain radiographs. Knowledge gaps were identified and modification of teaching method suggested. PMID- 25452995 TI - Opinion: a case against the membership programme proposal of the west african college of surgeons. PMID- 25452996 TI - The membership certification of the west african college of surgeons and its relevance to the needs of the west african sub-region. PMID- 25452994 TI - Management of prostate cancer in port harcourt, Nigeria: changing patterns. AB - BACKGROUND: This is a follow up to a study done at the University of Port Harcourt Teaching Hospital (UPTH) 11 years ago on the management of prostate cancer. AIMS: To assess the current pattern in the management of prostate cancer in Port Harcourt, Nigeria and the impact of changes in diagnosis and treatment. METHODS: All the case notes of prostate cancer presenting in the University of Port Harcourt Teaching Hospital between January 2003 and December 2012 were reviewed. Data on demography, clinical presentations, co-morbidities, investigations, treatment, complications and outcome of treatment were extracted and analyzed using SPSS 20.0 0 RESULTS: A total of 294 histologically confirmed patients with cancer of the prostate were treated within the study period. Out of these, 216 (73.5%) case notes were analysed. The mean age was 69.9 years (51 -90 years). All the patients had lower urinary tract symptoms, 30 (14.0%) had haematuria while 19(8.8%) presented with paraplegia. The prostate specific antigen (PSA) ranged from 0.5 - 760ng/ml. Two hundred and five (95%) received androgen deprivation therapy. Of these, 123 (60%) had bilateral subcapsular orchidectomy and anti androgen, 3 (1.4%) had abiraterone. Five (2.3%) had radical prostatectomy, 22 (10.2%) had chemotherapy while 16(7.4%) had radiotherapy. Seventy-two (33.5%) died within 2 years of diagnosis while 49(30.2%) survived more than 5 years. CONCLUSION: There is rising prevalence of carcinoma of the prostate in this centre. Many patients presented late. There has been expansion in diagnostic and therapeutic capabilities with attendant improvement in patients' survival. Co-morbidities adversely affected the outcome of treatment. PMID- 25452997 TI - Unsual foreign body in the throat: a report on 3 cases. AB - Coins, bones, food bolus etc. are some of the common foreign bodies that can get impacted in the throat. At times there may be some unusual foreign bodies that can also get impacted in the throat. The main aim and objective of this report is to highlight on some unusual or unexpected foreign bodies impaction in the throat. We present the case report of 3 patients who accidentally swallowed an unusual foreign body. PMID- 25452998 TI - Prostate cancer in the West African sub-region, the need to know. PMID- 25452999 TI - Experience with head and neck missile injuries at the yalgado university teaching hospital, ouagadougou, burkina faso. AB - BACKGROUND: To report the diagnostic and therapeutic options of missile head and neck injuries. AIM AND OBJECTIVES: To present our experience in the management of head and neck missile injuries as seen in our centre. METHODOLOGY: All the patients with head and neck missile injuries who were managed in the ENT and Dental services of Yalgado University Teaching Hospital, in Ouagadougou, the capital of Burkina Faso between January 2003 and December 2012 were reviewed. The data obtained from medical records included demographic data, history, physical findings, and site of injury, diagnosis, type of treatment/surgery, complications and outcome. RESULTS: Out of a total of 32 patients in this study, there were 26 males and 6 females with a sex ratio of 4.3:1. Their ages ranged from 18 to 63 years with a mean of 32 years +/- 5.2. The age range of 20-40 accounted for 68.7% of the patients. The injury was accidental in 37.5%, assault in 56.3 and self inflicted/suicide in 6.3%. Most (59.4%) of the patients had multiple injuries while in 50 % of the cases, the injuries affected the face. Surgical intervention was done in 59.4% of the patients and conservative treatment in 40.6 % of the patients. Complications were noted in 52% of the patients. Seven patients died given a mortality rate of 21.9%. CONCLUSION: The head and neck missile injuries are not uncommon in our environment with a high mortality and morbidity rates. PMID- 25453000 TI - Pattern of intracranial complications of sinusitis in komfo anokye teaching hospital. AB - BACKGROUND: Patients with intracranial complications of sinusitis present a major challenge to all, physicians, otorhinolaryngologists and neurosurgeons, because the purulent collection can be in areas that are not easily accessible like the interhemispheric and subfrontal areas of the brain and continue to exert toxic effects that account for the morbidity and mortality associated. AIMS AND OBJECTIVES: To determine the incidence, symptoms, pattern, the management and the outcome of intracranial complications of sinusitis in KomfoAnokye Teaching Hospital, Kumasi, Ghana. STUDY DESIGN: It was a prospective study of 39 patients who presented with intracranial complicationsof sinusitis. SETTING: The study was carried out in KomfoAnokye Teaching Hospital (KATH), in Kumasi, Ghana. PATIENTS AND METHODS: Patients who reported to KATH with sinugenic intracranial complications from January 2007 to December 2011 were prospectively studied using a standard proforma to record details of their demographic, clinical presentations, management data and outcome. RESULTS: The incidence rate of sinugenic intracranial complications was 3.2%. They consisted of 69.2% males and 30.8% females, with a male-to-female ratio of 2.3: 1 and a mean age of 25.3 years. The most common symptoms were headache in 100%, fever in 92.3%, nausea / vomiting in 30.8%, sinus tenderness in 10.3%, hemiparesis in 2.6%, proptosis in 12.8% and lethargy in 5.1% of the cases.Epidural abscess was the commonest sinugenic intracranial complication in 35.9%, sudural abscess in 25.6%, meningitis in 20.5%, cavernous sinus thrombosis in 12.8% and cerebral abscess in 5.2%. Sinus surgeries were performed in 71.8% and neurosurgical operations were also performed in 66.7% of the cases. Single modality treatment of sinus surgery was performed in 33.3% of the cases, neurosurgical procedure in 28.2% whereas a combined treatment was performed in 38.5%. The management outcomes were successful in 87.7% and unsuccessful in 2.6%. CONCLUSION: Even though the incidence rate of sinugenic intracranial complications was minimal as compared to some literatures, they still require a prompt and a collaborative management of the physician, otorhinolaryngologist and the neurosurgeon. PMID- 25453001 TI - Clinical evaluation of resin composite and resin-modified glass ionomer cement in non-carious cervical lesions. AB - BACKGROUND: The clinical performance of various tooth-coloured materials used to restore Non-Carious Cervical Lesions (NCCLs) has been evaluated. However, most of these evaluations were in western societies where soft diets requiring little mastication were common. The present study sets out to evaluate resin composite and RMGIC in the restoration of NCCLs among a Nigerian subpopulation group with fibrous diet requiring more rigorous mastication. PATIENTS & METHODS: The study included all adult patients that presented at the Dental Hospital, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria with non-carious cervical lesions over a period of six months. The teeth with non-carious cervical lesions in each patient were allocated into treatment with either resin composite or resin-modified glass ionomer cement by simple random sampling using ballots. The depth of the NCCLs was measured using a graduated flat ash periodontal probe. All the treatment was done by the first author according to the manufacturer's instructions. Patients were recalled and evaluated at 48- hours, 3- months, 6- months and 12- months using the USPHS criteria. Data analysis was done using SPSS version 15. The level of significance was put at 0.05. RESULTS: At the end of 12 months, 143 resin composite and 144 RMGIC restorations were evaluated, out of which 37 resin composite and 13 RMGIC restorations were dislodged, giving a retention rate of 74.1% and 91.0% respectively. The difference was statistically significant (p<0.05). For marginal discolouration, marginal adaptation, abrasion wear resistance, post operative sensitivity, and secondary caries, there were no statistically significant differences in the performance of resin composite and RMGIC. There was more retention failure of both resin composite and RMGIC restorations in NCCLs in mandibular teeth than in maxillary teeth. The differences were statistically significant (p<0.05). CONCLUSION: RMGIC demonstrated a higher retention rate in the restoration of non-carious cervical lesions than resin composite over a period of 12 month. PMID- 25453002 TI - Etiology of visual impairment among ophthalmic patients at Federal Medical Center, Abeokuta, Nigeria. AB - BACKGROUND: The Nigeria national blindness survey has documented region-specific prevalence and causes of visual impairment in the country. However, there is need for local studies to ascertain specific causes of visual impairment peculiar to each community, as this varies from one locality to another. AIM: To determine the causes of blindness and low vision among patients presenting to the Eye Clinic, Federal Medical Center Abeokuta, Nigeria. STUDY DESIGN: A retrospective study. MATERIALS AND METHODS: Medical records of all patients seen at the Eye Clinic, Federal Medical Center, Abeokuta, Nigeria between January 2011 and December 2012 were reviewed. RESULTS: Out of the 5,352 patients managed during the period, 474 (8.9%) were blind, 3,178 (59.4%) had low vision while 1,700 (31.7%) had "normal vision". The risk of visual impairment increased with age. The major causes of blindness were cataract (32.5%), glaucoma (20%) and age related macular degeneration (12.8%), while the most common causes of low vision were uncorrected refractive errors (20.5%), cataract (17.6%) and glaucoma (14.8%). CONCLUSION: Cataract, glaucoma and uncorrected refractive errors are the leading causes of visual impairment in Abeokuta, Nigeria. Public enlightenment coupled with prompt and effective management will reduce the burden of blindness in the country. PMID- 25453003 TI - Assessment of barriers to surgical ophthalmic care in South-Western Nigeria. AB - BACKGROUND: The prevalence of blindness and visual impairment are still of public health importance worldwide and yet underutilisation of available eyecare services are still rampant. Therefore, there is continuing need to study the barriers to eyecare uptake. AIM: To identify barriers to eye surgical uptake in the only teaching hospital in Sagamu, Ogun State, in South-Western Nigeria. SETTING: The study was done at the eye clinic of Olabisi Onabanjo University Teaching Hospital [OOUTH], Sagamu, Nigeria. This is the only state-owned tertiary eye centre in Ogun State. It serves an approximate population of 3 million. MATERIALS AND METHOD: All patients who had attended at least 2 follow-up clinics between February and June 2010, and consented to be included in the study were interviewed, and additional information from their case notes were coded and recorded in the software SPSS version 16. This was then analysed for frequencies of variables. RESULTS: One hundred and sixty-seven (167) respondents were interviewed, comprising 92 males and 75 females, with an age range between 1 and 90 years. 106(63.9%) indicated encountering one form of barrier or the other since attending the eye clinic, out of which 64 were females and 42 males. The types of barriers encountered were: Cost of hospital services [28.3%], fear of surgery [24.1%], long waiting time to see the doctor [23.5%], accessibility to the hospital [16.9%], lack of electricity in the hospital [10.8%], and frequent strikes by health workers [7.2%]. CONCLUSIONS: The commonest barriers to eye surgical care in this study are comparable to those in previous studies but in different proportions and calls for an urgent need to ensure affordable and sustainable surgical care, so as to achieve the goals of vision 2020. PMID- 25453004 TI - Comparison of intubating conditions with propofol suxamethonium versus propofol LIDOCAINE. AB - BACKGROUND: Suxamethonium is a depolarising muscle relaxant that provides rapid, excellent intubating condition and ease of intubation. Its adverse effects has led to the search for comparable alternatives. Propofol alone provides fair intubating conditions and ease of tracheal intubation. Addition of intravenous lidocaine to propofol has been reported to enhance intubating conditions. AIM: The study compared the intubating conditions and ease of tracheal intubation following intravenous administration of propofol and suxamethonium (PS) with propofol and lidocaine (PL). SETTING OF THE STUDY: The study was carried out in the department of Anaesthesia of the University of Benin Teaching Hospital, Benin City, Edo state, Nigeria. DESIGN OF THE STUDY: This is a prospective randomized double-blinded controlled study. Ethical approval was obtained from the University of Benin Ethics and Research committee. MATERIALS AND METHODS: Eighty eight eligible patients, aged 18-45 years, were prospectively randomized to 2 groups, PS and PL. Group PS received 2mg/kg propofol and 1.5mg/kg suxamethonium. Group PL had 2mg/kg propofol and 1.5mg/kg intravenous lidocaine. Intubating condition was determined, using a scale of 0 - 6 derived from jaw relaxation, ease of intubation and reflex response to intubation. Intubating condition was scored as good = 5-6, moderate = 3-4 and poor = 0-2. RESULTS: The propofol suxamethonium (PS) group had 100% good intubating condition and successful intubation. The propofol-lidocaine (PL) group had 59.1% moderate and 11.3% poor intubating conditions, with 70.5% successful and 29.5% failed intubation rates respectively. CONCLUSION: Laryngoscopy and endotracheal intubation are possible with appropriate doses of propofol and lidocaine, without the use of suxamethonium. PMID- 25453005 TI - Intra-operative implantation errors during hemiarthroplasty. AB - BACKGROUND: Hemiarthroplasty with Austin Moore endoprosthesis is an established treatment modality for displaced intracapsular femoral neck fractures in elderly patients above 60years.Technical errors in implantation of the un-cemented Austin Moore are common, and have been associated with complications that may culminate in early prosthetic failure requiring revision surgery. OBJECTIVE: To analyse the frequency of technical errors experienced by surgeons during implantation of uncemented Austin Moore endoprosthesis with the view to improving technique and minimizing early prosthetic failure. MATERIALS AND METHODS: This is a 5year retrospective analysis of radiographs of patients who had hemiarthroplasty with un-cemented Austin Moore endoprosthesis conducted at NKST rehabilitation hospital Mkar in Benue State, North- Central Nigeria with particular reference to intraoperative errors associated with early failure of the prosthesis. Data was analysed using SPSS version 21. RESULTS: A total of 48 patients were operated by 3 orthopaedic surgeons and 35patients met the required criteria for the study.Twenty five intraoperative errors in implantation were identified in 16(45.7%) patients. The commonest intraoperative error was inadequate length of the neck remnant in 13(37.1%) patients followed by inadequate calcar seating in 3 (8.6%) patients, incorrect prosthetic head size in 2(5.7%) patients, intraoperative periprosthetic fracture 2(5.7%) patients and inadequate proximal metaphyseal fill in 1(2.9%) patient. CONCLUSION: Hemiarthroplasty is a technically demanding procedure frequently associated with intraoperative implantation errors. Adequate pre-operative planning, Careful patient selection, proper training of surgeons as well as attention to detail is vital and may minimize technical errors during implantation and consequent early prosthetic failure. PMID- 25453007 TI - Fading Frontiers: Pragmatic Paradigm of Urologic Practice in a changing Africa. PMID- 25453006 TI - Gossypiboma and its implications. AB - Surgical materials are sometimes inadvertently left in the body after surgical operations. Cotton materials are the commonest objects forgotten. The implications for the patient and the surgeon are grave. The purpose of this presentation is to rekindle awareness of the phenomenon of gossypiboma, highlight the implications and stress prevention. Data were collected from hospital records which included their demographics, clinical features, management outcome and follow-up. Four cases of gossypiboma were found. Two had undergone caesarian section, one underwent pelvic floor repair for utero-vaginal prolapsed, and the fourth underwent transvesical prostatectomy. Their age, sex, causative operation and onset of symptoms, and salvage procedures were noted. Out of the 12304 surgical cases managed in our facility between November 1997 and December 2012, 4 (0.03%) cases of gossypiboma were recorded. Gauze extruded spontaneously from the abdominal scar in one patient who had undergone caesarian section. Intestinal obstruction occurred in another case of caesarian section and was relieved by intestinal resection and anastomosis. Also gauze extruded and was extracted from the urethra in the patient who underwent transvesical prostatectomy. Three (75%) patients survived while one (25%) died. We conclude that gossypiboma occurs most commonly after intra-abdominal operations. Women are at increased risk during obstetric and gynaecological operations, though both sexes are affected. The condition carries potentials for harm to the patient and medico-legal litigations. PMID- 25453008 TI - Characteristics and outcome of stroke patients with cerebrovascular accident at the intensive care unit of a tertiary hospital in Nigeria. AB - BACKGROUND: Patients with severe stroke defined as NIHSS score >17 constituting about 15-20% of cerebrovascular accident require admission into the Intensive Care Unit (ICU). However the benefit of ICU admission for stroke patients remains controversial. Aim & Objectives: To determine the characteristics and outcome of patients with cerebrovascular accident managed at the Intensive Care Unit of University of Benin Teaching Hospital. METHODOLOGY: Demographic characteristics, clinical features and course, treatment options and outcome of all stroke patients admitted in ICU from January 2002 to January 2012 were retrieved from the hospital records and analyzed. A patient before and after each stroke patient were selected as controls for the study. Primary outcome variable was ICU mortality, type of stroke whether ischemic or haemorrhagic, duration of stay, whether patients were transferred from the medical/stroke ward or from the accident and emergency department of the hospital. RESULTS: A total of thirty six (36) stroke patients were admitted into the ICU within the study period accounting for 5.6% of the total ICU admissions. The male: female ratio is 2:1 and patients aged >60 years accounted for 55.6%. Stroke patients admitted into ICU had a mortality rate of 77.8%. Patients with severe stroke admitted into the ICU were 4 times more likely to die compared to non-stroke patients in the ICU (p=0.002, OR=4.472). However, severe stroke had no significant impact on duration of ICU stay (p=0.454, OR=1.464). CONCLUSION: Stroke patients have a high mortality in the intensive care unit that is independent on the type and route of admission. Provision of the support equipment and instruments required for high dependency service in the intensive care unit and early admission should improve the outcome. PMID- 25453009 TI - Non-intubated Ambulatory Anaesthesia for Diagnostic gynaecological laparoscopy. AB - BACKGROUND: General endotracheal relaxant anaesthetic technique is favoured for laparoscopic gynaecological procedures, in order to prevent inadequate ventilation, regurgitation and aspiration resulting from pneumoperitoneum and steep trendelenburg position during the procedure. However, simple brief laparoscopic procedures have been performed safely over the years in adult population using alternative airway devices. We report our experience over a fifteen-year period, of using general anaesthesia by face mask ventilation for short diagnostic laparoscopy in gynaecologic practice. PATIENTS & METHODS: A retrospective, cross- sectional observational study involving 823 consecutive elective patients for diagnostic gynaecological laparoscopic procedures. The 823 patients were classified as American society of Anesthesiologists (ASA) I or II patients and were studied over the fifteen year period. They were all premedicated with atropine & metoclopramide after overnight fast, and had general anaesthesia by facemask with assisted ventilation; using thiopentone for induction, paracetamol & piroxicam for analgesia and oxygen-halothane via Bain's breathing circuit for maintenance. Monitoring procedures employed in this study included pulse rate (PR), non-invasive blood pressure (NIBP) and oxygen saturation (SPO2). RESULTS: Out of a total of 823 patients studied, majority (93.8%) of the patients were investigated for infertility. The mean duration for the procedure was 18.2+/-2.5 minutes. The complications observed included post operative nausea and vomiting in 58(7.0%) of the patients, regurgitation & desaturation in 2(0.2%) of patients each, while laryngeal spasm & colonic insufflations each occurred in 1(0.1%) patient. Three patients (0.3%) had unplanned admission for observation overnight. There was no case of mortality. CONCLUSION: General anaesthesia by facemask ventilation is a safe alternative to endotracheal intubation for short diagnostic gynaecological laparoscopy when fasting guidelines are observed. PMID- 25453010 TI - The impact of protective devices on the severity of road traffic maxillofacial injuries in ibadan, Nigeria. AB - BACKGROUND: Road traffic crashes related maxillofacial injuries constitute a major part of the trauma workload of the maxillofacial surgeon. These injuries are sometimes fatal and may be associated with long term psychosocial sequelae. Several devices have been designed to reduce the severity of these injuries and therefore diminish the associated morbidity and mortality. AIM AND OBJECTIVE: To evaluate the influence of restraints and protective devices on the severity of road traffic maxillofacial injuries. DESIGN OF THE STUDY: A prospective study. METHOD: A prospective study of patients managed at the University College Hospital, Ibadan for road traffic crashes-related oral and maxillofacial injuries. Demographic variables, types of vehicles involved (categorized into A- 2 wheelers and B- 4whellers), seat position, use or non-use of protective devices and type of injury sustained as well as injury severity assessed based on the Maxillofacial Injury Severity Scale (MFISS) were recorded in a proforma. Correlations between injury types, severity, and use of protective devices were determined using IBM SPSS version 20.0 RESULTS: Out of 155 patients reviewed, 134(86.5%) were males while 21(13.5%) were females. There were 84(54.2%) participants in Category A vehicles and 71(45.8%) in Category B vehicles. About 15.5% (13/84) in Category A and 22.5% (16/71) in Category B used protective devices (crash helmet and seat belt respectively). However, there was no statistically significant difference between the median MFISS score for those that used protective devices and those who did not in both categories (P= 0.862 for Category A; P = 0.64 for Category B) Conclusion: The rate of use of protective devices was relatively low among commuters in the study. However, it was noted that the use of the devices made no difference to the severity of maxillofacial injuries using the MFISS. Public enlightenment on the proper use of restraint devices should be intensified. PMID- 25453011 TI - The epidemiology and outcome of acute septic arthritis: a hospital based study. AB - BACKGROUND: Septic arthritis is an acute bacterial infection affecting synovial joints. It is an orthopaedic emergency with potential high morbidity and mortality. This study determined the epidemiological pattern and outcome of acute septic arthritis and analyzed factors affecting morbidity and mortality Methods:This is a 5 year (2007-2012) retrospective study conducted at NKST rehabilitation hospital Mkar, North -Central Nigeria. All patients with septic arthritis upon presentation were consecutively selected. Patients with clear, non purulent or haemorrhagic joint aspirate and those with incomplete data were excluded from the study. Data was analysed using SPSS version 21. RESULTS: A total of 30 patients with 35septic joints were studied. Eighteen (60%) were males and 12(40%) were female with a male to female ratio of 1.5:1. Age range was 3months and 75years. The knee was the commonest 16(45.7 %) joint involved followed by the hip joint 11(31.4%). Staphylococcus aureus was the commonest organism cultured in joint aspirate in 19 (54.3%) patients and postoperative complications include joint stiffness 2(5.7%), painand stiffness 3(8.6%), bony ankylosis2(5.7%) and limb shortening 1(2.9%). CONCLUSION: Early accurate diagnosis and prompt interventionare crucial for a successful outcome. Appropriate drainage of septic joints and antibiotic treatment can result in prompt recovery with minimum or no long term morbidity. Close follow-up is needed to monitor the growth of the affected limbs until skeletal maturity. There is a need to maintain a high index of suspicion and to educate patients about early presentation, early referral, avoidance of improper use of antibiotics and regular follow-up after the acute pathology. PMID- 25453012 TI - Comparison between rocuronium and suxamethonium muscle relaxants in ocular trauma surgery. AB - BACKGROUND: Suxamethonium causes a rise in intraocular pressure (IOP). Its use for intraocular surgical procedures especially management of the penetrating eye injury is controversial because of the risk of extrusion of vitreous contents. This risk can be avoided by substituting it with rocuronium. The aim of this study was to compare the IOP changes and intubating conditions following the use of both muscle relaxants. AIM AND OBJECTIVES: To compare the intraocular pressure changes and intubating conditions following the use of both suxamethonium and rocuronium. DESIGN OF STUDY: Prospective, randomized, double-blind study. STUDY SETTING: The operating theatres of the Lagos University Teaching Hospital Patients and Methods: A prospective, randomized study in which 70 patients received suxamethonium 1.5mg/kg or rocuronium 0.9mg/kg after induction with thiopentone 5mg/kg. Laryngoscopy was performed after 60 seconds. Measurements of IOP were taken before induction, 1 minute after administration of either muscle relaxant and at 1, 3 and 5 minutes after intubation. Intubating conditions were evaluated using a simple scoring system. RESULTS: Suxamethonium caused a significant rise in intraocular pressure throughout the study period (p < 0.005), maximal 1 minute after intubation (p < 0.001). Rocuronium caused a significant fall in intraocular pressure 1 minute after administration (p < 0.001) and this remained less than the baseline value in the post intubation period. Intubating conditions in both groups were similar. CONCLUSION: Rocuronium is preferred as muscle relaxant for tracheal intubation when a rise in intraocular pressure is undesirable. PMID- 25453013 TI - Caesarean delivery on maternal request: consultants' view and practice in the west african sub region. AB - BACKGROUND: Caesarean Delivery on Maternal Request (CDMR) is increasingly seen as a viable option to vaginal delivery even in the absence of medical or obstetric contraindications to vaginal delivery. MATERIAL AND METHODS: Self administered questionnaires were instituted to Senior Consultant Obstetricians attending the examiners' meeting of the faculty of obstetrics and gynaecology of the West African College of Surgeon in Ibadan, Nigeria on 17(th) April, 2013 and 23(th) October, 2013. This was to assess their experience and attitudes toward CDMR. The data were analysed with SPSS version 16.0 RESULTS: The majority of the consultants, 94.4%(85/90) have had antenatal client(s) ask for CDMR and 81.2%(69/85) of them have operated on at least a patient for CDMR. The reasons for the CDMR were: precious pregnancy/infertility, previous traumatic delivery and to avoid the stress of labour in 33%, 20.7% and 16.2% respectively. Eighty percent(68/85) consultants have counseled the women but only 11.8%(10/85) of them have had their patients change their minds and opted for vaginal delivery. Eighty eight(97.8%) of the obstetricians sampled are aware of the FIGO stand on Caesarean section however, 80(88.9%) of them opined that it is important to accommodate the feelings of the women and offer CDMR for the respect of the patient's autonomy. CONCLUSION: There are cases of CDMR in the West African sub region and increasing willingness of the consultants to oblige to the request. There is need to develop a treatment guidelines/protocols for CDMR that will suit our environment in order to avoid over burdening of the limited health resources. PMID- 25453014 TI - Multiple venous thrombosis complicating central venous cannulation in a non cancer patient - a case report. AB - Central venous catheterization is a common procedure for critically ill patients. Like all procedures, it has its complications, one of which is thrombosis. Reports of thrombosis are commoner among cancer patients. We present a 37 year old non cancer patient who developed thrombi in both right and left internal jugular veins, 10 and 13 days respectively after insertion of central venous catheter. This was detected by ultrasound scans of the neck while attempting re cannulation for parenteral feeding. She also had left lower limb deep venous thrombosis, confirmed by doppler scan, which was managed with low molecular weight heparin and warfarin. The patient was subsequently treated with streptokinase. A repeat scan of the internal jugular veins 4 days after thrombolysis revealed a reduction in size of the thrombi. Symptoms of deep venous thrombosis improved and she was transferred to the wards where she made remarkable improvement. This case illustrates the potential usefulness of ultrasound guided-central line insertion in patients who have had central venous lines inserted previously in order to detect thrombi. PMID- 25453015 TI - Rhinocerebral mucormycosis in a diabetic case report. AB - A 40 year old female Nigerian with uncontrolled diabetes mellitus was referred to a teaching hospital with four week history of facial rash that progressed to extensive ulceration of the mid face and bilateral visual loss. She had complete nasal bridge collapse, nasopalatal fistula with black eschars on the mucosa and markedly elevated fasting blood sugar. Her blood glucose was controlled on insulin, She had surgical debridement and histopathological study done revealed fungi hyphae. Systemic antifungal (ketoconazole) was given. Subsequently, she made a slow but steady progress and her wound became clean with healthy granulation tissue. Rhinocerebral mucormycosis still remains a poorly understood disease with high mortality rate. Presently, the triad of clinician's awareness, prompt initiation of treatment and timely surgical intervention represent the effective way of managing the disease. PMID- 25453016 TI - Allergic rhinitis among adult bronchial asthmatic patients in lagos, Nigeria. AB - BACKGROUND: Allergic rhinitis (AR) and asthma are different manifestations of allergic disease of the airway. Both can exist together or as separate disease entity in an individual. However, it is not known if the coexistence of the two diseases can make asthmatic control difficult or not in the black population. OBJECTIVE: To determine the prevalence of allergic rhinitis in asthmatics and its effects on bronchial asthmatic control among adult Nigerians.. DESIGN: A prospective case-control study. SETTING: Lagos University Teaching Hospital, Lagos, Nigeria. SUBJECTS: Cases were 160 adult patients with confirmed bronchial asthma and controls were 160 subjects without bronchial asthma. METHODS: Structured questionnaire adapted from the European Community Respiratory Health Survey was applied. Allergic rhinitis was clinically diagnosed if watery rhinorrhea, nasal blockage, and excessive bout of sneezing, itching of eye, ear, nose or throat were present. RESULTS: Amongst the asthmatics, 133 (83%) had concomitant allergic rhinitis while 30 (19%) controls had allergic rhinitis(x(2)=137.81, p<0.001). Seventy eight (59%) cases with allergic rhinitis had uncontrolled asthma while 9 (33%) cases without allergic rhinitis had uncontrolled asthma (x(2) = 8.8731, p=0.012). CONCLUSION: The prevalence of allergic rhinitis among adult asthmatics was high and the co-existence of allergic rhinitis was significantly associated with poor asthmatic control. PMID- 25453017 TI - Laparoscopic cholecystectomy in ibadan, southwest Nigeria. AB - BACKGROUND: Performing laparoscopic surgery in developing countries is challenging due to limited funds and instrumentation. Open cholecystectomy for the management of gallbladder pathologies is still rife in low income countries. The low incidence of post- operative morbidity and early return to activities of daily living makes laparoscopic surgery increasingly desirable. This retrospective study reviews the outcomes and challenges of laparoscopic cholecystectomies done over a two year period in a developing country. METHODS: We reviewed the records of all patients who consented to laparoscopic cholecystectomy at the Department of Surgery, University College Hospital (UCH) Ibadan between June 2011 and June 2013. RESULT: Of the 77 patients requiring gallbladder surgery during the study period 42 (54.5%) patients underwent laparoscopic cholecystectomy. Most patients were middle aged with a mean duration of symptoms of 20 months. None of the patients required biliary exploration. The most frequent operative complication was port site infection in 7 patients (14.3%). The average hospital stay was 2.7 days and most 27 (64%) patients were followed up at the outpatients department for over 6 months post- surgery with no identifiable morbidity. There were three conversions to open cholecystectomy. CONCLUSIONS: Despite the small number of patients in this study, laparoscopic cholecystectomy can be practiced with good outcome even in a limited resource setting. PMID- 25453018 TI - Outcome of treatment of fracture neck of femur using hemiarthroplasty versus dynamic hip screw. AB - BACKGROUND: Fracture neck of femur is a frequent and severe injury with consequent high morbidity and mortality. Surgical treatment has been established as the gold standard; however, the surgical option remains a dilemma. Hemiarthroplasty with and Dynamic hip screw are established treatment modalities for femoral neck fractures. OBJECTIVE: To give a comparative analysis of the two treatment modalities with respect to duration of surgery, blood transfusion, hospital stay, wound complications, number of revision surgeries, mortality rate and functional outcome. MATERIALS AND METHODS: Retrospective data was obtained over a 5 year period. All patients with femoral neck fractures treated with either hemiarthroplasty or Dynamic Hip screw were consecutively selected. Data was analysed using SPSS version 21. RESULTS: A total of 86 patients were studied with forty three patients each in the hemiarthroplasty and DHS study groups. The Mean duration of surgery was 107+/-28 and 109+/-29 minutes, mean estimated blood loss was 320+/-98mls and 341+/-122mls, rate of blood transfusion was 54% and 58%, and mean post-op hip score was 15+/-1 (Good) and17+/-1 (Very Good) for Hemiarthroplasty and DHS groups respectively. CONCLUSION: The two study groups were comparable with respect to duration of surgery, duration of hospital stay and early mobilization with external support. Hemiarthroplasty study group was superior with respect to estimated blood loss, requirements for blood transfusion, complications of mechanical failures and need for revision surgeries while the DHS study group had superior hip functional outcome. This result suggests that the DHS may allow better restoration of function and should be favoured for treatment of fracture neck of femur in well selected patients that meet the indications for surgery whenever the technical competence and facilities exist. PMID- 25453019 TI - Knowledge and attitude of pregnant women to caesarean section in a semi-urban community in northwest Nigeria. AB - BACKGROUND: Although Caesarean section (CS) is the commonest major surgery performed in Obstetrics and it has contributed to improved obstetric care throughout the world; there are still concerns about the attitude of rural Nigerian women towards it. OBJECTIVES: To ascertain what is known about CS and the attitude to it among pregnant women attending antenatal care in a rural health facility. DESIGN: Descriptive cross sectional Setting: The antenatal clinic of a semi-urban health facility in Nigeria. METHODOLOGY: An interviewer administered semi-structured pretested questionnaire was used to assess knowledge and attitude to CS among 401 pregnant women, which included first timers to experienced mothers. Each respondent's level of knowledge was determined using a scoring system and the total knowledge was categorised as inadequate (0 - 49%) and adequate (50-100%). RESULTS: Of the 401 respondents, 376 %(93.8) had heard of CS; 355( 94.4%) were aware that vaginal delivery was feasible after CS; 325( 86.4 %) knew that blood may be required during or after the procedure while only 10(2.7 %) were aware that the woman was required to give consent for CS. The total knowledge score was adequate in 154(40.9 %) and inadequate in 222(59. 1 %) respondents. CONCLUSION: Although majority of the women surveyed were aware and would accept to have CS if indicated, knowledge about CS is still low in our setting. The need for birth preparedness and complication readiness with the involvement of men is crucial to influencing the perception of women in this setting towards CS. PMID- 25453020 TI - Birth outcome in patients presenting for hospital delivery in the second stage of labour. AB - BACKGROUND: Even though women in labour are expected to be managed in the hospital under the care of an Obstetrician, a subset of women, who actually plan to have hospital delivery spent greater part of their labour at home without any medical assistance and only present to the labour room at full cervical dilatation. AIM AND OBJECTIVES: To compare the maternal and neonatal outcome in patients that present in the second stage of labour and those that present in the active phase of labour before full cervical dilatation. PATIENTS AND METHODS: This was a prospective case - control study comparing the maternal and neonatal outcomes of women who planned hospital delivery but presented to the labour ward of the University of Maiduguri Teaching Hospital at full cervical dilatation, following an unsupervised first stage at home. For each case, the next two patients that presented for delivery in the active phase of labour were used as controls. The study was conducted between 1st January 2013 to 31st December 2013 and only booked and low risk pregnancies were recruited. Independent sample t test was used to compare continuous variables. For categorical data, Pearson's chi-square or Fisher's exact test was utilized for comparisons. A P value less than 0.05 was considered significant RESULTS: The incidence of home labour was 11.54% (335/2902). The mean age, gestational age at delivery and birth weights were comparable in the 2 groups with p values of 0.724, 0.787 and 0.618 respectively. However, the parity and the estimated blood loss were significantly higher in the Home labour group compared to the Hospital labour group. Interventions such as augmentation of labour, episiotomy and caesarean delivery were higher among those that laboured in the hospital compared to those that laboured at home. However, post partum haemorrhage occurred in 6.3% of the Home labour group compared to 0.94% of the Hospital labour group and the differences were statistically significant. The neonatal outcomes were similar in the two groups. CONCLUSION: Our finding showed that women that present for hospital delivery in the second stage of labour have increased risk of post partum haemorrhage but the risk of labour augmentation, episiotomy and caesarean delivery is lowered. We advocate that women should be encouraged to present to the labour ward early in labour to avoid hasty delivery and risk post partum haemorrhage. PMID- 25453021 TI - Experience with Sonogram-guided hydrostatic reduction of Intussusception in Children in South-West Nigeria. AB - BACKGROUND: Intussusception is a common cause of intestinal obstruction in young children. The diagnosis and treatment of intussusception has evolved over the years with ultrasound being the first choice imaging technique and a major player in the non-operative reduction of intussusception owing to its advantage of reduced morbidity and non-exposure to ionizing radiation when compared to other modalities of treatment. Aim & Objectives: The aim of this study was to evaluate the efficiency of ultrasound guided hydrostatic reduction in the management of intussusception in children and assess the predictors of reducibility. METHODS: A prospective study of all infants and children who presented with uncomplicated intussusception was conducted between January, 2005 and September, 2013. The diagnosis of intussusception was made clinically and this was confirmed by an abdominal ultrasonography. Ultrasound guided hydrostatic reduction of intussusception was performed on the selected patients after they were adequately resuscitated. Failed reduction was abandoned in favour of operative reduction in some patients. Data collected included the age of the patients, duration of symptoms and the outcomes of the procedure and these were analyzed. RESULTS: Eighty-four patients with intussusception were treated over this period, 36(42.9%) patients were found suitable for hydrostatic reduction of intussusception. Twenty-four(66.7%) patients presented within 48 hours of onset of symptoms. Twenty-one(58.3%) patients had successful hydrostatic reduction of intussusception while 15(41.7%) patients had failed reduction. The procedure was successful in majority (58%) of the patients under the age of 1 year and one of the three (33%) patients older than one year. Hydrostatic reduction of intussusception was successful in 14 out of 24 patients (58.3%) who presented within 48 hours of onset of symptoms. CONCLUSION: Hydrostatic reduction of intussusception under ultrasound guidance is an effective and useful conservative method of management in carefully selected children with intussusception. Overall, this modality of treatment is cost effective and could readily be used for patients in resource poor environment. It also monitors the reduction process and visualizes the components of the intussusception including the lead points. PMID- 25453022 TI - Cannot intubate - cannot ventilate in a neonate due to giant sublingual CYST: a simple approach to airway management. AB - Congenital sublingual/lingual cysts are rare, and may present with feeding difficulty; and rarely with respiratory distress in the neonate. A seven days old male neonate weighing 2.6kg was referred to a teaching hospital in Nigeria with a swelling in the oral cavity noticed at birth; associated with symptoms of inability to breastfeed, close the mouth and partial airway obstruction. Complete airway obstruction occurred, with cannot intubate- cannot ventilate situation during inhalational anaesthesia for surgical treatment, which was successfully managed. We report the case to highlight the simple but life saving approach of needle aspiration in airway management for a cannot intubate- cannot ventilate situation due to a giant neonatal sublingual cyst. PMID- 25453023 TI - Tuberculous azoospermia - a case report. AB - This a case report of an immunocompetent (HIV negative) 54 years old man who had been diagnosed with epididymo-testicular tuberculosis. This happened 13 years after he had suffered from pulmonary tuberculosis. The diagnosis was made after a testicular biopsy for infertility. The outcome of anti-tuberculosis treatment was good although the azoospermia lasted. The aim of this report is to emphasize that the genital tuberculosis still exists in our sub-region and that high index of suspicion is required with effective anti-tuberculous therapy in order to achieve good outcome. PMID- 25453024 TI - Editorial: THE SURGICAL NEONATE IN WEST AFRICA. PMID- 25453025 TI - How Pediatric Urology Fellowships in the United States are Funded. AB - BACKGROUND: We desired to discover how pediatric urology fellowship positions in the United States were funded. METHODS: Approved pediatric urology fellowship directors (25) were contacted by e-mail and asked how the 2 years of fellowship were funded at their institutions. RESULTS: The response rate of the e-mail questions was 100%. The clinical year of the fellowship was 100% hospital-funded in 88% of the 25 fellowships. The second, American board of urology (ABU) required year was 100% hospital-funded in only 44% of the fellowships. Clinical funds generated by pediatric urology faculty provided funding for 24% of the fellows and institutes and grants funded 20% of the fellowship positions for the second year. Thirty-two percent of the fellowship positions have supplemental funding through charges generated from the fellow's clinical activities in patient care. CONCLUSION: All but three hospitals fund 100% of the clinical year of pediatric urology fellowship. Sources of funding for the second, ABU-required year vary widely among fellowship programs in the United States. PMID- 25453026 TI - Is there a need to modify existing coping scales to include using electronic media for coping in young people? PMID- 25453028 TI - The peer-reviewed literature on undergraduate education for public health in the United States, 2004-2014. AB - The education of undergraduate college students in the field of public health has burgeoned over the past decade. Professional literature in peer-reviewed journals is one indicator of the status of a field of study and its related body of knowledge. It is also a mechanism for sharing information among professionals about challenges, issues, experiences, and best practices. The purpose of the literature review conducted here was to describe the status of the peer-reviewed literature over the past decade pertaining to the education of undergraduates about the field of public health in the United States (U.S.). A literature search was conducted of three databases: PubMed, Scopus, and ERIC. Inclusion criteria were publication date from January 1, 2004 through July 31, 2014; written in the English language; pertaining to undergraduate education in the U.S.; and a focus on public health as the primary discipline. Public health was searched as an overarching discipline; articles focused on sub-disciplines or other health professions disciplines were excluded. The search resulted in 158 articles. Each of the authors reviewed the abstracts for all articles and read full articles when necessary. The result was 23 articles that were then considered in depth. The articles were categorized according to their primary theme: curriculum, courses, learning objectives (N = 14); evaluation of teaching method (N = 3); case study (N = 3); career path and advising (N = 2); accreditation (N = 1). Year of publication and journal were also examined. The results of the literature search lead to several observations about how the peer-reviewed literature has been used to date and how it could be used to advance the emerging field of undergraduate education for public health. PMID- 25453029 TI - Teledermatology in Low-Resource Settings: The MSF Experience with a Multilingual Tele-Expertise Platform. AB - INTRODUCTION: In 2010, Medecins Sans Frontieres (MSF) launched a tele-expertise system to improve the access to specialized clinical support for its field health workers. Among medical specialties, dermatology is the second most commonly requested type of tele-expertise. The aim of the present study was to review all MSF teledermatology cases in the first 4 years of operation. Our hypothesis was that the review would enable the identification of key areas for improvement in the current MSF teledermatology system. METHODS: We carried out a retrospective analysis of all dermatology cases referred by MSF field doctors through the MSF platform from April 2010 until February 2014. We conducted a quantitative and qualitative analysis based on a survey sent to all referrers and specialists involved in these cases. RESULTS: A total of 65 clinical cases were recorded by the system and 26 experts were involved in case management. The median delay in providing the first specialist response was 10.2 h (IQR 3.7-21.1). The median delay in allocating a new case was 0.96 h (IQR 0.26-3.05). The three main countries of case origin were South Sudan (29%), Ethiopia (12%), and Democratic Republic of Congo (10%). The most common topics treated were infectious diseases (46%), inflammatory diseases (25%), and genetic diseases (14%). One-third of users completed the survey. The two main issues raised by specialists and/or referrers were the lack of feedback about patient follow-up and the insufficient quality of clinical details and information supplied by referrers. DISCUSSION: The system clearly delivered a useful service to referrers because the workload rose steadily during the 4-year study period. Nonetheless, user surveys and retrospective analysis suggest that the MSF teledermatology system can be improved by providing guidance on best practice, using pre-filled referral forms, following-up the cases after teleconsultation, and establishing standards for clinical photography. PMID- 25453030 TI - Individual Public Transportation Accessibility is Positively Associated with Self Reported Active Commuting. AB - BACKGROUND: Active commuters have lower risk of chronic disease. Understanding which of the, to some extent, modifiable characteristics of public transportation that facilitate its use is thus important in a public health perspective. The aim of the study was to examine the association between individual public transportation accessibility and self-reported active commuting, and whether the associations varied with commute distance, age, and gender. METHODS: Twenty-eight thousand nine hundred twenty-eight commuters in The Capital Region of Denmark reported self-reported time spent either walking or cycling to work or study each day and the distance to work or study. Data were obtained from the Danish National Health Survey collected in February to April 2010. Individual accessibility by public transportation was calculated using a multi-modal network in a GIS. Multilevel logistic regression was used to analyze the association between accessibility, expressed as access area, and being an active commuter. RESULTS: Public transport accessibility area based on all stops within walking and cycling distance was positively associated with being an active commuter. Distance to work, age, and gender modified the associations. Residing within 10 km commute distance and in areas of high accessibility was associated with being an active commuter and meeting the recommendations of physical activity. For the respondents above 29 years, individual public transportation accessibility was positively associated with being an active commuter. Women having high accessibility had significantly higher odds of being an active commuter compared to having a low accessibility. For men, the associations were insignificant. CONCLUSION: This study extends the knowledge about the driving forces of using public transportation for commuting by examining the individual public transportation accessibility. Findings suggest that transportation accessibility supports active commuting and planning of improved public transit accessibility has thus a potential of providing health benefits to commuters. PMID- 25453031 TI - Hard template synthesis of metal nanowires. AB - Metal nanowires (NWs) have attracted much attention because of their high electron conductivity, optical transmittance, and tunable magnetic properties. Metal NWs have been synthesized using soft templates such as surface stabilizing molecules and polymers, and hard templates such as anodic aluminum oxide, mesoporous oxide, carbon nanotubes. NWs prepared from hard templates are composites of metals and the oxide/carbon matrix. Thus, selecting appropriate elements can simplify the production of composite devices. The resulting NWs are immobilized and spatially arranged, as dictated by the ordered porous structure of the template. This avoids the NWs from aggregating, which is common for NWs prepared with soft templates in solution. Herein, the hard template synthesis of metal NWs is reviewed, and the resulting structures, properties and potential applications are discussed. PMID- 25453027 TI - Pathogenic Landscape of Transboundary Zoonotic Diseases in the Mexico-US Border Along the Rio Grande. AB - Transboundary zoonotic diseases, several of which are vector borne, can maintain a dynamic focus and have pathogens circulating in geographic regions encircling multiple geopolitical boundaries. Global change is intensifying transboundary problems, including the spatial variation of the risk and incidence of zoonotic diseases. The complexity of these challenges can be greater in areas where rivers delineate international boundaries and encompass transitions between ecozones. The Rio Grande serves as a natural border between the US State of Texas and the Mexican States of Chihuahua, Coahuila, Nuevo Leon, and Tamaulipas. Not only do millions of people live in this transboundary region, but also a substantial amount of goods and people pass through it everyday. Moreover, it occurs over a region that functions as a corridor for animal migrations, and thus links the Neotropic and Nearctic biogeographic zones, with the latter being a known foci of zoonotic diseases. However, the pathogenic landscape of important zoonotic diseases in the south Texas-Mexico transboundary region remains to be fully understood. An international perspective on the interplay between disease systems, ecosystem processes, land use, and human behaviors is applied here to analyze landscape and spatial features of Venezuelan equine encephalitis, Hantavirus disease, Lyme Borreliosis, Leptospirosis, Bartonellosis, Chagas disease, human Babesiosis, and Leishmaniasis. Surveillance systems following the One Health approach with a regional perspective will help identifying opportunities to mitigate the health burden of those diseases on human and animal populations. It is proposed that the Mexico-US border along the Rio Grande region be viewed as a continuum landscape where zoonotic pathogens circulate regardless of national borders. PMID- 25453032 TI - Connections matter: channeled hydrogels to improve vascularization. AB - The use of cell-laden hydrogels to engineer soft tissue has been emerging within the past years. Despite, several newly developed and sophisticated techniques to encapsulate different cell types the importance of vascularization of the engineered constructs is often underestimated. As a result, cell death within a construct leads to impaired function and inclusion of the implant. Here, we discuss the fabrication of hollow channels within hydrogels as a promising strategy to facilitate vascularization. Furthermore, we present an overview on the feasible use of removable spacers, 3D laser-, and planar processing strategies to create channels within hydrogels. The implementation of these structures promotes control over cell distribution and increases oxygen transport and nutrient supply in vitro. However, many studies lack the use of endothelial cells in their approaches leaving out an important factor to enhance vessel ingrowth and anastomosis formation upon implantation. In addition, the adequate endothelial cell type needs to be considered to make these approaches bridge the gap to in vivo applications. PMID- 25453033 TI - An emerging role of the cellular prion protein as a modulator of a morphogenetic program underlying epithelial-to-mesenchymal transition. AB - Knowledge of phenotypic changes the cellular prion protein (PrP(C)) contributes to may provide novel avenues for understanding its function. Here we consider data from functional knockout/down studies and protein-protein interaction analyses from the perspective of PrP's relationship to its ancestral ZIP metal ion transporting proteins. When approached in this manner, a role of PrP(C) as a modulator of a complex morphogenetic program that underlies epithelial-to mesenchymal transition (EMT) emerges. To execute EMT, cells have to master the challenge to shift from cell-cell to cell-substrate modes of adherence. During this process, cell-cell junctions stabilized by E-cadherins are replaced by focal adhesions that mediate cell-substrate contacts. A similar reprogramming occurs during distinct organogenesis events that have been shown to rely on ZIP transporters. A model is presented that sees ZIP transporters, and possibly also PrP(C), affect this balance of adherence modes at both the transcriptional and post-translational levels. PMID- 25453034 TI - Comparative transcriptomics and metabolomics in a rhesus macaque drug administration study. AB - We describe a multi-omic approach to understanding the effects that the anti malarial drug pyrimethamine has on immune physiology in rhesus macaques (Macaca mulatta). Whole blood and bone marrow (BM) RNA-Seq and plasma metabolome profiles (each with over 15,000 features) have been generated for five naive individuals at up to seven timepoints before, during and after three rounds of drug administration. Linear modeling and Bayesian network analyses are both considered, alongside investigations of the impact of statistical modeling strategies on biological inference. Individual macaques were found to be a major source of variance for both omic data types, and factoring individuals into subsequent modeling increases power to detect temporal effects. A major component of the whole blood transcriptome follows the BM with a time-delay, while other components of variation are unique to each compartment. We demonstrate that pyrimethamine administration does impact both compartments throughout the experiment, but very limited perturbation of transcript or metabolite abundance was observed following each round of drug exposure. New insights into the mode of action of the drug are presented in the context of pyrimethamine's predicted effect on suppression of cell division and metabolism in the immune system. PMID- 25453036 TI - Sensitivity of near-infrared spectroscopy and diffuse correlation spectroscopy to brain hemodynamics: simulations and experimental findings during hypercapnia. AB - Near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) are two diffuse optical technologies for brain imaging that are sensitive to changes in hemoglobin concentrations and blood flow, respectively. Measurements for both modalities are acquired on the scalp, and therefore hemodynamic processes in the extracerebral vasculature confound the interpretation of cortical hemodynamic signals. The sensitivity of NIRS to the brain versus the extracerebral tissue and the contrast-to-noise ratio (CNR) of NIRS to cerebral hemodynamic responses have been well characterized, but the same has not been evaluated for DCS. This is important to assess in order to understand their relative capabilities in measuring cerebral physiological changes. We present Monte Carlo simulations on a head model that demonstrate that the relative brain-to-scalp sensitivity is about three times higher for DCS (0.3 at 3 cm) than for NIRS (0.1 at 3 cm). However, because DCS has higher levels of noise due to photon-counting detection, the CNR is similar for both modalities in response to a physiologically realistic simulation of brain activation. Even so, we also observed higher CNR of the hemodynamic response during graded hypercapnia in adult subjects with DCS than with NIRS. PMID- 25453038 TI - Solution immersed silicon (SIS)-based biosensors: a new approach in biosensing. AB - A novel, solution immersed silicon (SIS)-based sensor has been developed which employs the non-reflecting condition (NRC) for a p-polarized wave. The SIS sensor's response is almost independent of change in the refractive index (RI) of a buffer solution (BS) which makes it capable of measuring low-concentration and/or low-molecular-weight compounds. PMID- 25453035 TI - S-glutathionylation reactions in mitochondrial function and disease. AB - Mitochondria are highly efficient energy-transforming organelles that convert energy stored in nutrients into ATP. The production of ATP by mitochondria is dependent on oxidation of nutrients and coupling of exergonic electron transfer reactions to the genesis of transmembrane electrochemical potential of protons. Electrons can also prematurely "spin-off" from prosthetic groups in Krebs cycle enzymes and respiratory complexes and univalently reduce di-oxygen to generate reactive oxygen species (ROS) superoxide (O2*(-)) and hydrogen peroxide (H2O2), important signaling molecules that can be toxic at high concentrations. Production of ATP and ROS are intimately linked by the respiratory chain and the genesis of one or the other inherently depends on the metabolic state of mitochondria. Various control mechanisms converge on mitochondria to adjust ATP and ROS output in response to changing cellular demands. One control mechanism that has gained a high amount of attention recently is S-glutathionylation, a redox sensitive covalent modification that involves formation of a disulfide bridge between glutathione and an available protein cysteine thiol. A number of S glutathionylation targets have been identified in mitochondria. It has also been established that S-glutathionylation reactions in mitochondria are mediated by the thiol oxidoreductase glutaredoxin-2 (Grx2). In the following review, emerging knowledge on S-glutathionylation reactions and its importance in modulating mitochondrial ATP and ROS production will be discussed. Major focus will be placed on Complex I of the respiratory chain since (1) it is a target for reversible S-glutathionylation by Grx2 and (2) deregulation of Complex I S glutathionylation is associated with development of various disease states particularly heart disease. Other mitochondrial enzymes and how their S glutathionylation profile is affected in different disease states will also be discussed. PMID- 25453037 TI - A view of obesity as a learning and memory disorder. AB - This articles describes how a cascade of associative relationships involving the sensory properties of foods, the nutritional consequences of their consumption, and perceived internal states may play an important role in the learned control of energy intake and body weight regulation. In addition, we describe ways in which dietary factors in the current environment can promote excess energy intake and body weight gain by degrading these relationships or by interfering with the neural substrates that underlie the ability of animals to use them to predict the nutritive or energetic consequences of intake. We propose that an expanded appreciation of the diversity of orosensory, gastrointestinal, and energy state signals about which animals learn, combined with a greater understanding of predictive relationships in which these cues are embedded, will help generate new information and novel approaches to addressing the current global problems of obesity and metabolic disease. PMID- 25453039 TI - High throughput and multiplex localization of proteins and cells for in situ micropatterning using pneumatic microfluidics. AB - Micropatterning technologies are emerging as an enabling tool for various microfluidic-based applications in life sciences. However, the high throughput and multiplex localization of multiple bio-components in a microfluidic device has not yet been well established. In this paper, we describe a simple and in situ micropatterning method using an integrated microfluidic device with pneumatic microstructures (PMUSs) for highly controllable immobilization of both proteins and cells in a high throughput, geometry-dynamic, and multi-patterning way. The precise Pluronic F127 passivation of a microchamber surface except the PMUS-blocked regions was performed and characterized, and the spatial dynamics and consistency of both the PMUSs and protein/cell micropatterning were optically evaluated and quantitatively demonstrated too. Furthermore, a systematic investigation of PMUS-assisted micropatterning in microfluidics was carried out. The feature of high throughput and spatial control of micropatterning can be simply realized by using the well-designed PMUS arrays. Meanwhile, the co micropatterning of different proteins (bovine serum albumin and chicken egg albumin) and cells (human umbilical vein endothelial cells and human hepatocellular carcinoma cells) in a microfluidic device was successfully accomplished with the orderly serial manipulation of PMUS groups. We demonstrate that PMUS-assisted micropatterning can be applied as a convenient microfluidic component for large-scale and diversified protein/cell patterning and manipulation, which could be useful for cell-based tissue organization, high throughput imaging, protein-related interactions and immunoassays. PMID- 25453040 TI - Correction: Towards improved precision in the quantification of surface-enhanced Raman scattering (SERS) enhancement factors: a renewed approach. AB - Correction for 'Towards improved precision in the quantification of surface enhanced Raman scattering (SERS) enhancement factors: a renewed approach' by Arumugam Sivanesan et al., Analyst, 2015, DOI:10.1039/c4an01778a PMID- 25453041 TI - Perceived misinterpretation rates in oncologic 18F-FDG PET/CT studies: a survey of referring physicians. AB - Because only pathologic examination can confirm the presence or absence of malignant disease in cancer patients, a certain rate of misinterpretation in any kind of imaging study is inevitable. For the accuracy of interpretation to be improved, determination of the nature, causes, and magnitude of this problem is needed. This study was designed to collect pertinent information from physicians referring patients for oncologic (18)F-FDG PET/CT. METHODS: A total of 662 referring physicians completed an 11-question survey focused on their experience with the interpretation of oncologic (18)F-FDG PET/CT studies. The participants were oncologists (36.1%; n = 239), hematologists (14.5%; n = 96), radiation oncologists (7.4%; n = 49), surgeons (33.8%; n = 224), and other physicians (8.2%; n = 54). Questions were aimed at determining the frequency, nature, and causes of scan misinterpretations as well as potential solutions to reduce the frequency of misinterpretations. RESULTS: Perceived misinterpretation rates ranged from 5% to 20%, according to most (59.3%) of the participants; 20.8% of respondents reported rates of less than 5%. Overinterpretation rather than underinterpretation was more frequently encountered (68.9% vs. 8.7%, respectively). Limited availability of a patient's history and limited experience of interpreters were the major contributors to this phenomenon, according to 46.8% and 26.7% of the participants, respectively. The actions most commonly suggested to reduce misinterpretation rates (multiple suggestions were possible) were the institution of multidisciplinary meetings (59.8%), the provision of adequate history when ordering an examination (37.4%), and a discussion with imaging specialists when receiving the results of the examination (38.4%). CONCLUSION: Overinterpretation rather than underinterpretation of oncologic (18)F FDG PET/CT studies prevails in clinical practice, according to referring physicians. Closer collaboration of imaging specialists with referring physicians through more multidisciplinary meetings, improved communication, and targeted training of interpreting physicians are actions suggested to reduce the rates of misinterpretation of oncologic (18)F-FDG PET/CT studies. PMID- 25453042 TI - Diagnostic value of diffusion-weighted imaging in simultaneous 18F-FDG PET/MR imaging for whole-body staging of women with pelvic malignancies. AB - The aim of this study was to assess the diagnostic benefit of diffusion-weighted imaging (DWI) in an (18)F-FDG PET/MR imaging protocol for whole-body staging of women with primary or recurrent malignancies of the pelvis. METHODS: Forty-eight patients with a primary pelvic malignancy or suspected recurrence of a pelvic malignancy were included in our study. All patients underwent a whole-body (18)F FDG PET/MR imaging examination that included DWI. Two radiologists separately evaluated the PET/MR imaging datasets without DWI followed by a second interpretation with DWI. First, both readers identified all primary tumors, as well as lymph node and distant metastases. In a second session, PET and DWI data were assessed qualitatively. Image interpretation comprised lesion conspicuity defined as visual lesion-to-background contrast (4-point ordinal scale) and diagnostic confidence (3-point ordinal scale) for all tumors. The results from histopathologic examination and cross-sectional imaging follow-up (>=6 mo) were used as the reference standard. Statistical analysis was performed to assess the significance of differences between obtained values. RESULTS: Among the 122 suspected lesions seen, 98 (80.3%) were considered malignant. PET/MR imaging without DWI had a sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of 92.9%, 87.5%, 96.8%, 75.0%, and 91.8%, respectively, for the detection of malignant lesions. PET/MR imaging with DWI had slightly higher values (94.9%, 83.3%, 95.9%, 80.0%, and 92.6%, respectively), but the difference was not significant (P > 0.05). In the qualitative assessment of lesion-to-background contrast, PET had significantly (P < 0.05) higher values (3.79 +/- 0.58) than DWI (3.63 +/- 0.77). Furthermore, significantly (P < 0.05) higher scores were found for diagnostic confidence using PET (2.68 +/- 0.64) for the determination of malignant lesions, when compared with DWI (2.53 +/- 0.69). CONCLUSION: DWI in PET/MR imaging has no diagnostic benefit for whole-body staging of women with pelvic malignancies. The omission of DWI for staging or restaging gynecologic cancer may significantly reduce examination times, thus increasing patient comfort without a relevant decrease in diagnostic competence. PMID- 25453043 TI - 18F-FDG PET and perfusion SPECT in the diagnosis of Alzheimer and Lewy body dementias. AB - Brain imaging with glucose ((18)F-FDG) PET or blood flow (hexamethylpropyleneamine oxime) SPECT is widely used for the differential diagnosis of dementia, though direct comparisons to clearly establish superiority of one method have not been undertaken. METHODS: Subjects with Alzheimer disease (AD; n = 38) and dementia with Lewy bodies (DLB; n = 30) and controls (n = 30) underwent (18)F-FDG PET and SPECT in balanced order. The main outcome measure was area under the curve (AUC) of receiver-operating-characteristic analysis of visual scan rating. RESULTS: Consensus diagnosis with (18)F-FDG PET was superior to SPECT for both dementia vs. no-dementia (AUC = 0.93 vs. 0.72, P = 0.001) and AD vs. DLB (AUC = 0.80 vs. 0.58, P = 0.005) comparisons. The sensitivity and specificity for dementia/no-dementia was 85% and 90%, respectively, for (18)F-FDG PET and 71% and 70%, respectively, for SPECT. CONCLUSION: (18)F-FDG PET was significantly superior to blood flow SPECT. We recommend (18)F-FDG PET be performed instead of perfusion SPECT for the differential diagnosis of degenerative dementia if functional imaging is indicated. PMID- 25453044 TI - In vivo quantification of cerebral translocator protein binding in humans using 6 chloro-2-(4'-123I-iodophenyl)-3-(N,N-diethyl)-imidazo[1,2-a]pyridine-3-acetamide SPECT. AB - This study provides the first comprehensive quantification of translocator protein (TSPO) binding using SPECT and 6-chloro-2-(4'-(123)I-iodophenyl)-3-(N,N diethyl)-imidazo[1,2-a]pyridine-3-acetamide ((123)I-CLINDE) in neurologic patients. (123)I-CLINDE is structurally related to well-known PET ligands such as (18)F-PBR111 and (18)F-DPA-714. METHODS: Six patients with cerebral stroke and 4 patients with glioblastoma multiforme (GBM) underwent 150-min dynamic SPECT scans with arterial blood sampling. Four of the patients were rescanned. All patients were genotyped for the rs6971 polymorphism. Volumes of interest were delineated on the individual SPECT scans and the coregistered MR images. Compartmental and graphical models using arterial input or the cerebellum as a reference region were used to quantify (123)I-CLINDE binding. RESULTS: Among the 6 models investigated, the 2-tissue-compartment model with arterial input described the time-activity data best. Time-stability analyses suggested that acquisition time should be at least 90 min. Intersubject variation in the cerebellar distribution volume (VT) was clearly related to the TSPO genotype. In the stroke patients the VT in the periinfarction zone, compared with VT in the ipsilateral cerebellum, ranged from 1.4 to 3.4, and in the GBM patients the VT in the tumor, compared with the VT in the cerebellum, ranged from 1.8 to 3.4. In areas of gadolinium extravasation, (123)I-CLINDE binding parameters were not significantly changed. Thus, (123)I-CLINDE binding does not appear to be importantly affected by blood brain barrier disruption. CONCLUSION: As demonstrated within a group of stroke and GBM patients, (123)I-CLINDE SPECT can be used for quantitative assessment of TSPO expression in vivo. Because of the absence of a region devoid of TSPO, reference tissue models should be used with caution. The 2-tissue-compartment kinetic analysis of a 90-min dynamic scan with arterial blood sampling is recommended for the quantification of (123)I-CLINDE binding with SPECT. PMID- 25453046 TI - Respective performance of 18F-FDG PET and radiolabeled leukocyte scintigraphy for the diagnosis of prosthetic valve endocarditis. AB - Echocardiography plays a key role in the diagnosis of infective endocarditis (IE) but can be inconclusive in patients in whom prosthetic valve endocarditis (PVE) is suspected. The incremental diagnostic value of (18)F-FDG PET and radiolabeled leukocyte scintigraphy in IE patients has already been reported. The aim of this study was to compare the respective performance of (18)F-FDG PET and leukocyte scintigraphy for the diagnosis of PVE in 39 patients. METHODS: (18)F-FDG PET and leukocyte scintigraphy were performed on 39 consecutive patients admitted because of clinically suspected PVE and inconclusive echocardiography results. The results of (18)F-FDG PET and leukocyte scintigraphy were analyzed separately and retrospectively by experienced physicians masked to the results of the other imaging technique and to patient outcome. The final Duke-Li IE classification was made after a 3-mo follow-up. RESULTS: Of the 39 patients, 14 were classified as having definite IE, 4 as having possible IE, and 21 as not having IE. The average interval between (18)F-FDG PET and leukocyte scintigraphy was 7 +/- 7 d. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 93%, 71%, 68%, 94%, and 80%, respectively, for (18)F-FDG PET and 64%, 100%, 100%, 81%, and 86%, respectively, for leukocyte scintigraphy. Discrepancies between the results of (18)F-FDG PET and leukocyte scintigraphy occurred in 12 patients (31%). In patients with definite IE, 5 had true-positive (18)F-FDG PET results but false-negative leukocyte scintigraphy results. Of these 5 patients, 3 had nonpyogenic microorganism IE (Coxiella or Candida). Of patients for whom endocarditis had been excluded, 6 had true-negative leukocyte scintigraphy results but false-positive (18)F-FDG PET results. These 6 patients had been imaged in the first 2 mo after the last cardiac surgery. The last patient with a discrepancy between (18)F-FDG PET and leukocyte scintigraphy was classified as having possible endocarditis and had positive (18)F-FDG PET results and negative leukocyte scintigraphy results. CONCLUSION: (18)F-FDG PET offers high sensitivity for the detection of active infection in patients with suspected PVE and inconclusive echocardiography results. Leukocyte scintigraphy offers a higher specificity, however, than (18)F-FDG PET for diagnosis of IE and should be considered in cases of inconclusive (18)F-FDG PET findings or in the first 2 mo after cardiac surgery. PMID- 25453045 TI - First-in-human evaluation of 18F-mefway, a PET radioligand specific to serotonin 1A receptors. AB - The serotonin-1A (5-HT1A; 5-HT is 5-hydroxytryptamine) receptor is implicated in an array of neurologic and psychiatric disorders. Current PET radioligands targeting 5-HT1A receptors have limitations hindering widespread PET studies of this receptor system. The 5-HT1A-specific antagonist radioligand N-{2-[4-(2 methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(trans-4-(18)F fluoromethylcyclohexane)carboxamide ((18)F-mefway) exhibited promising in vivo properties in rhesus monkeys. The goal of this work was to examine the in vivo cerebral binding profile and metabolism of (18)F-mefway in humans. METHODS: Dynamic (18)F-mefway PET data were acquired for 6 healthy volunteers (4 women, 2 men; age, 22-38 y). Scans were initiated with the injection of 192-204 MBq of radiotracer, and data were acquired for 2 h. Venous blood samples were collected and assayed to examine the in vivo metabolism profile of (18)F-mefway. To examine the test-retest variability of (18)F-mefway, a second PET scan was acquired at least 2 wk later for 4 subjects. Regional binding potentials (BPNDs) were calculated with the multilinear reference tissue model, and voxelwise BPND maps were calculated with Logan graphical analysis. Regions surrounding the brain were carefully inspected for uptake of radiolabeled species in bone. RESULTS: (18)F mefway uptake in the brain occurred quickly, with a peak standardized uptake value (SUV) of 1.7. Rapid washout in the cerebellum resulted in SUVs of 0.2 at 120 min, whereas regions with specific 5-HT1A binding exhibited retention of radioligand, yielding SUVs of 0.4-0.9 at 120 min. Rapid metabolism of (18)F mefway was observed, with no detected (18)F-fluoride ions in plasma. BPND values of 2.4 were measured in the mesial temporal lobe, with values of 1.6 in the insular cortex and 0.7-1.0 in other cortical regions. Stable BPND estimates were obtained using 90 min of dynamic data. Average test-retest variability was 8%. No evidence of radioactivity uptake in bone was observed. CONCLUSION: (18)F-mefway exhibits favorable in vivo properties for serotonin 5-HT1A receptor measurements in humans. The simple radiosynthesis, high specific binding profile, and absence of PET signal in bone make (18)F-mefway an attractive radiotracer for PET experiments examining the 5-HT1A receptor in neuropsychiatric disorders and drug intervention. PMID- 25453048 TI - Using SUV as a guide to 18F-FDG dose reduction. AB - This article explores how one can lower the injected (18)F-FDG dose while maintaining validity in comparing standardized uptake values (SUVs) between studies. Variations of the SUV within each lesion were examined at different acquisition times. METHODS: Our protocol was approved by either the Human Investigation Committee or the Institutional Review Board. All 120 PET datasets were acquired continuously for 180 s per bed position in list mode and were reconstructed to obtain 30-, 60-, 90-, 120-, 150-, and 180-s-per-bed-position PET images with registration to a single set of nondiagnostic CT images. Qualitative assessment of the images was performed separately for correlation. The SUV measurements of each lesion were computed and normalized to the 180-s acquisition values to create a stabilization factor. These stabilization factors were used to demonstrate a predictable trend of stabilization over time. The variances of the stabilization factors over the entire dataset, composed of several tumor types over a range of sizes, were compared for each time point with the corresponding 150-s time point using a 2-sided F test, which has similar values to the 180-s time point. RESULTS: The variance of the data decreased with increasing acquisition time and with increasing dose but leveled off for sufficiently long acquisitions. CONCLUSION: Through the statistical analysis of SUVs for increasing acquisition times and visual evaluation of the plots, we developed and hereby propose an algorithm that can be used to seek the maximum reduction in administered (18)F-FDG dose while preserving the validity of SUV comparisons. PMID- 25453047 TI - Anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid: physiologic uptake patterns, incidental findings, and variants that may simulate disease. AB - Anti-1-amino-3-(18)F-fluorocyclobutane-1-carboxylic acid ((18)F-FACBC) is a synthetic amino acid analog PET radiotracer undergoing clinical trials for the evaluation of prostate and other cancers. We aimed to describe common physiologic uptake patterns, incidental findings, and variants in patients who had undergone (18)F-FACBC PET. METHODS: Sixteen clinical trials involving 611 (18)F-FACBC studies from 6 centers, which included dosimetry studies on 12 healthy volunteers, were reviewed. Qualitative observations of common physiologic patterns, incidental uptake, and variants that could simulate disease were recorded and compared with similar observations in studies of the healthy volunteers. Quantitative analysis of select data and review of prior published reports and observations were also made. RESULTS: The liver and pancreas demonstrated the most intense uptake. Moderate salivary and pituitary uptake and variable mild to moderate bowel activity were commonly visualized. Moderate bone marrow and mild muscle activity were present on early images, with marrow activity decreasing and muscle activity increasing with time. Brain and lungs demonstrated activity less than blood pool. Though (18)F-FACBC exhibited little renal excretion or bladder uptake during the clinically useful early imaging time window, mild to moderate activity might accumulate in the bladder and interfere with evaluation of adjacent prostate bed and seminal vesicles in 5%-10% of patients. Uptake might also occur from benign processes such as infection, inflammation, prostatic hyperplasia, and metabolically active benign bone lesions such as osteoid osteoma. CONCLUSION: Common physiologic uptake patterns were similar to those noted in healthy volunteers. The activity in organs followed the presence of amino acid transport and metabolism described with other amino acid based PET radiotracers. As with other PET radiotracers such as (18)F-FDG, focal nonphysiologic uptake may represent incidental malignancy. Uptake due to benign etiologies distinct from physiologic background also occurred and could lead to misinterpretations if the reader is unaware of them. PMID- 25453049 TI - Imaging DNA damage allows detection of preneoplasia in the BALB-neuT model of breast cancer. AB - A prominent feature of many human cancers is oncogene-driven activation of the DNA damage response (DDR) during early tumorigenesis. It has been shown previously that noninvasive imaging of the phosphorylated histone H2A variant H2AX, gammaH2AX, a DNA damage signaling protein, is possible using (111)In labeled anti-gammaH2AX antibody conjugated to the cell-penetrating peptide transactivator of transcription (TAT). The purpose of this study was to investigate whether (111)In-anti-gammaH2AX-TAT detects the DDR during mammary oncogenesis in BALB-neuT mice. METHODS: Mammary fat pads from BALB-neuT and wild type mice (age, 40-106 d) were immunostained for gammaH2AX. (111)In-anti gammaH2AX-TAT or a control probe was administered intravenously to BALB-neuT mice. SPECT was performed weekly and compared with tumor detection using palpation and dynamic contrast-enhanced MR imaging. RESULTS: gammaH2AX expression was elevated in hyperplastic lesions in the mammary fat pads of BALB-neuT mice aged 76-106 d, compared with normal fat pads from younger mice and carcinomas from older mice (13.5 +/- 1.2 gammaH2AX foci/cell vs. 5.2 +/- 1.5 [P < 0.05] and 3.4 +/- 1.1 [P < 0.001], respectively). Serial SPECT imaging revealed a 2.5-fold increase in (111)In-anti-gammaH2AX-TAT accumulation in the mammary fat pads of mice aged 76-106 d, compared with control probe (P = 0.01). The median time to detection of neoplastic lesions by (111)In-anti-gammaH2AX-TAT (defined as >5% injected dose per gram of tissue) was 96 d, compared with 120 and 131 d for dynamic contrast-enhanced MR imaging and palpation, respectively (P < 0.001). CONCLUSION: DDR imaging using (111)In-anti-gammaH2AX-TAT identified mammary tumors significantly earlier than MR imaging. Imaging the DDR holds promise for the detection of preneoplasia and as a technique for screening cancer-prone individuals. PMID- 25453050 TI - Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS. AB - KRAS gene mutations occur in approximately 40% of colorectal cancers (CRCs) and are associated with resistance to anti-epidermal growth factor receptor antibody therapy. We previously demonstrated that (18)F-FDG accumulation in PET was significantly higher in CRCs with mutated KRAS than in those with wild-type KRAS in a clinical setting. Here, we investigated the mechanisms by which mutated KRAS increased (18)F-FDG accumulation. METHODS: Using paired isogenic human CRC cell lines that differ only in the mutational status of the KRAS gene, we measured (18)F-FDG accumulation in these cells in vitro and in vivo. We also investigated the roles of proteins that have a function in (18)F-FDG accumulation. Finally, we examined the relationship among mutated KRAS, hypoxia-inducible factor 1alpha (HIF-1alpha), and maximum standardized uptake value with 51 clinical CRC samples. RESULTS: In the in vitro experiments, (18)F-FDG accumulation was significantly higher in KRAS-mutant cells than in wild-type controls under normoxic conditions. The expression levels of glucose transporter 1 (GLUT1) and hexokinase type 2 (HK2) were higher in KRAS-mutant cells, and (18)F-FDG accumulation was decreased by knockdown of GLUT1. Hypoxic induction of HIF-1alpha was higher in KRAS-mutant cells than in wild-type controls; in turn, elevated HIF-1alpha resulted in higher GLUT1 expression and (18)F-FDG accumulation. In addition, HIF-1alpha knockdown decreased (18)F-FDG accumulation under hypoxic conditions only in the KRAS-mutant cells. Small-animal PET scans showed in vivo (18)F-FDG accumulation to be significantly higher in xenografts with mutated KRAS than in those with wild-type KRAS. The immunohistochemistry of these xenograft tumors showed that staining of GLUT1 was consistent with that of HIF-1alpha and pimonidazole. In a retrospective analysis of clinical samples, KRAS mutation exhibited a significantly positive correlation with expressions of GLUT1 and HIF-1alpha and with maximum standardized uptake value. CONCLUSION: Mutated KRAS caused higher (18)F-FDG accumulation possibly by upregulation of GLUT1; moreover, HIF-1alpha additively increased (18)F-FDG accumulation in hypoxic lesions. (18)F-FDG PET might be useful for predicting the KRAS status noninvasively. PMID- 25453051 TI - Annotating STEAP1 regulation in prostate cancer with 89Zr immuno-PET. AB - Antibodies and antibody-drug conjugates targeting the cell surface protein 6 transmembrane epithelial antigen of prostate 1 (STEAP1) are in early clinical development for the treatment of castration-resistant prostate cancer (PCa). In general, antigen expression directly affects the bioactivity of therapeutic antibodies, and the biologic regulation of STEAP1 is unusually complicated in PCa. Paradoxically, STEAP1 can be induced or repressed by the androgen receptor (AR) in different human PCa models, while also expressed in AR-null PCa. Consequently, there is an urgent need to translate diagnostic strategies to establish which regulatory mechanism predominates in patients to situate the appropriate therapy within standard of care therapies inhibiting AR. METHODS: To this end, we prepared and evaluated (89)Zr-labeled MSTP2109A ((89)Zr-2109A), a radiotracer for PET derived from a fully humanized monoclonal antibody to STEAP1 in preclinical PCa models. RESULTS: (89)Zr-2109A specifically localized to the STEAP1-positive human PCa models CWR22Pc, 22Rv1, and PC3. Moreover, (89)Zr-2109A sensitively measured treatment-induced changes (~66% decline) in STEAP1 expression in CWR22PC in vitro and in vivo, a model we showed to express STEAP1 in an AR-dependent manner. CONCLUSION: These findings highlight the ability of immuno-PET with (89)Zr-2109A to detect acute changes in STEAP1 expression and argue for an expansion of ongoing efforts to image PCa patients with (89)Zr-2109A to maximize the clinical benefit associated with antibodies or antibody-drug conjugates to STEAP1. PMID- 25453055 TI - Ventilation-perfusion scanning: stuck in a rut, perhaps, but the road ahead is not so clear. PMID- 25453052 TI - Introduction of an 8-aminooctanoic acid linker enhances uptake of 99mTc-labeled lactam bridge-cyclized alpha-MSH peptide in melanoma. AB - The purpose of this study was to examine the effects of amino acid, hydrocarbon, and polyethylene glycol (PEG) linkers on the melanoma targeting and imaging properties of (99m)Tc-labeled lactam bridge-cyclized HYNIC-linker-Nle-CycMSHhex (hydrazinonicotinamide-linker-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2) peptides. METHODS: Four novel peptides (HYNIC-GGGNle-CycMSHhex, HYNIC-GSGNle-CycMSHhex, HYNIC-PEG2Nle-CycMSHhex, and HYNIC-AocNle-CycMSHhex) were designed and synthesized. The melanocortin-1 receptor binding affinities of the peptides were determined in B16/F1 melanoma cells. The biodistribution of (99m)Tc(ethylenediaminediacetic acid [EDDA])-HYNIC-GGGNle-CycMSHhex, (99m)Tc(EDDA)-HYNIC-GSGNle-CycMSHhex, (99m)Tc(EDDA)-HYNIC-PEG2Nle-CycMSHhex, and (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex were determined in B16/F1 melanoma-bearing C57 mice at 2 h after injection to select a lead peptide for further evaluation. The melanoma targeting and imaging properties of (99m)Tc(EDDA)-HYNIC-AocNle CycMSHhex were further examined because of its high melanoma uptake. RESULTS: The inhibitory concentrations of 50% (IC50) for HYNIC-GGGNle-CycMSHhex, HYNIC-GSGNle CycMSHhex, HYNIC-PEG2Nle-CycMSHhex, and HYNIC-AocNle-CycMSHhex were 0.7 +/- 0.1, 0.8 +/- 0.09, 0.4 +/- 0.08, and 0.3 +/- 0.06 nM, respectively, in B16/F1 melanoma cells. Among these four (99m)Tc-labeled peptides, (99m)Tc(EDDA)-HYNIC-AocNle CycMSHhex displayed the highest melanoma uptake (22.3 +/- 1.72 percentage injected dose/g) at 2 h after injection. (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex exhibited high tumor-to-normal-organ uptake ratios except for the kidneys. The tumor-to-kidney uptake ratios of (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex were 3.29, 3.63, and 6.78 at 2, 4, and 24 h, respectively, after injection. The melanoma lesions were clearly visualized by SPECT/CT using (99m)Tc(EDDA)-HYNIC-AocNle CycMSHhex as an imaging probe at 2 h after injection. CONCLUSION: High melanoma uptake and fast urinary clearance of (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex highlighted its potential for metastatic melanoma detection in the future. PMID- 25453056 TI - Ventilation-perfusion scanning: stuck in a rut, perhaps, but the road ahead is not so clear. PMID- 25453057 TI - Reply: ventilation-perfusion scanning: stuck in a rut, perhaps, but the road ahead is not so clear. PMID- 25453058 TI - Medical imaging: the challenges of radiation risk assessment. PMID- 25453061 TI - 2014 Cassen Lecture: What have we learned from the National Oncologic PET Registry? PMID- 25453062 TI - Tobacco smoking interferes with GABAA receptor neuroadaptations during prolonged alcohol withdrawal. AB - Understanding the effects of tobacco smoking on neuroadaptations in GABAA receptor levels over alcohol withdrawal will provide critical insights for the treatment of comorbid alcohol and nicotine dependence. We conducted parallel studies in human subjects and nonhuman primates to investigate the differential effects of tobacco smoking and nicotine on changes in GABAA receptor availability during acute and prolonged alcohol withdrawal. We report that alcohol withdrawal with or without concurrent tobacco smoking/nicotine consumption resulted in significant and robust elevations in GABAA receptor levels over the first week of withdrawal. Over prolonged withdrawal, GABAA receptors returned to control levels in alcohol-dependent nonsmokers, but alcohol-dependent smokers had significant and sustained elevations in GABAA receptors that were associated with craving for alcohol and cigarettes. In nonhuman primates, GABAA receptor levels normalized by 1 mo of abstinence in both groups--that is, those that consumed alcohol alone or the combination of alcohol and nicotine. These data suggest that constituents in tobacco smoke other than nicotine block the recovery of GABAA receptor systems during sustained alcohol abstinence, contributing to alcohol relapse and the perpetuation of smoking. PMID- 25453063 TI - Life-long in vivo cell-lineage tracing shows that no oogenesis originates from putative germline stem cells in adult mice. AB - Whether or not oocyte regeneration occurs in adult life has been the subject of much debate. In this study, we have traced germ-cell lineages over the life spans of three genetically modified mouse models and provide direct evidence that oogenesis does not originate from any germline stem cells (GSCs) in adult mice. By selective ablation of all existing oocytes in a Gdf9-Cre;iDTR mouse model, we have demonstrated that no new germ cells were ever regenerated under pathological conditions. By in vivo tracing of oocytes and follicles in the Sohlh1 CreER(T2);R26R and Foxl2-CreER(T2);mT/mG mouse models, respectively, we have shown that the initial pool of oocytes is the only source of germ cells throughout the life span of the mice and that no adult oogenesis ever occurs under physiological conditions. Our findings clearly show that there are no GSCs that contribute to adult oogenesis in mice and that the initial pool of oocytes formed in early life is the only source of germ cells throughout the entire reproductive life span. PMID- 25453065 TI - American mastodon extirpation in the Arctic and Subarctic predates human colonization and terminal Pleistocene climate change. AB - Existing radiocarbon ((14)C) dates on American mastodon (Mammut americanum) fossils from eastern Beringia (Alaska and Yukon) have been interpreted as evidence they inhabited the Arctic and Subarctic during Pleistocene full-glacial times (~ 18,000 (14)C years B.P.). However, this chronology is inconsistent with inferred habitat preferences of mastodons and correlative paleoecological evidence. To establish a last appearance date (LAD) for M. americanum regionally, we obtained 53 new (14)C dates on 36 fossils, including specimens with previously published dates. Using collagen ultrafiltration and single amino acid (hydroxyproline) methods, these specimens consistently date to beyond or near the ~ 50,000 y B.P. limit of (14)C dating. Some erroneously "young" (14)C dates are due to contamination by exogenous carbon from natural sources and conservation treatments used in museums. We suggest mastodons inhabited the high latitudes only during warm intervals, particularly the Last Interglacial [Marine Isotope Stage (MIS) 5] when boreal forests existed regionally. Our (14)C dataset suggests that mastodons were extirpated from eastern Beringia during the MIS 4 glacial interval (~ 75,000 y ago), following the ecological shift from boreal forest to steppe tundra. Mastodons thereafter became restricted to areas south of the continental ice sheets, where they suffered complete extinction ~ 10,000 (14)C years B.P. Mastodons were already absent from eastern Beringia several tens of millennia before the first humans crossed the Bering Isthmus or the onset of climate changes during the terminal Pleistocene. Local extirpations of mastodons and other megafaunal populations in eastern Beringia were asynchrononous and independent of their final extinction south of the continental ice sheets. PMID- 25453064 TI - Human infrared vision is triggered by two-photon chromophore isomerization. AB - Vision relies on photoactivation of visual pigments in rod and cone photoreceptor cells of the retina. The human eye structure and the absorption spectra of pigments limit our visual perception of light. Our visual perception is most responsive to stimulating light in the 400- to 720-nm (visible) range. First, we demonstrate by psychophysical experiments that humans can perceive infrared laser emission as visible light. Moreover, we show that mammalian photoreceptors can be directly activated by near infrared light with a sensitivity that paradoxically increases at wavelengths above 900 nm, and display quadratic dependence on laser power, indicating a nonlinear optical process. Biochemical experiments with rhodopsin, cone visual pigments, and a chromophore model compound 11-cis-retinyl propylamine Schiff base demonstrate the direct isomerization of visual chromophore by a two-photon chromophore isomerization. Indeed, quantum mechanics modeling indicates the feasibility of this mechanism. Together, these findings clearly show that human visual perception of near infrared light occurs by two photon isomerization of visual pigments. PMID- 25453067 TI - Carnivorous leaves from Baltic amber. AB - The fossil record of carnivorous plants is very scarce and macrofossil evidence has been restricted to seeds of the extant aquatic genus Aldrovanda of the Droseraceae family. No case of carnivorous plant traps has so far been reported from the fossil record. Here, we present two angiosperm leaves enclosed in a piece of Eocene Baltic amber that share relevant morphological features with extant Roridulaceae, a carnivorous plant family that is today endemic to the Cape flora of South Africa. Modern Roridula species are unique among carnivorous plants as they digest prey in a complex mutualistic association in which the prey derived nutrient uptake depends on heteropteran insects. As in extant Roridula, the fossil leaves possess two types of plant trichomes, including unicellular hairs and five size classes of multicellular stalked glands (or tentacles) with an apical pore. The apices of the narrow and perfectly tapered fossil leaves end in a single tentacle, as in both modern Roridula species. The glandular hairs of the fossils are restricted to the leaf margins and to the abaxial lamina, as in extant Roridula gorgonias. Our discovery supports current molecular age estimates for Roridulaceae and suggests a wide Eocene distribution of roridulid plants. PMID- 25453066 TI - Local plant names reveal that enslaved Africans recognized substantial parts of the New World flora. AB - How did the forced migration of nearly 11 million enslaved Africans to the Americas influence their knowledge of plants? Vernacular plant names give insight into the process of species recognition, acquisition of new knowledge, and replacement of African species with American ones. This study traces the origin of 2,350 Afro-Surinamese (Sranantongo and Maroon) plant names to those plant names used by local Amerindians, Europeans, and related groups in West and Central Africa. We compared vernacular names from herbarium collections, literature, and recent ethnobotanical fieldwork in Suriname, Ghana, Benin, and Gabon. A strong correspondence in sound, structure, and meaning among Afro Surinamese vernaculars and their equivalents in other languages for botanically related taxa was considered as evidence for a shared origin. Although 65% of the Afro-Surinamese plant names contained European lexical items, enslaved Africans have recognized a substantial part of the neotropical flora. Twenty percent of the Sranantongo and 43% of the Maroon plant names strongly resemble names currently used in diverse African languages for related taxa, represent translations of African ones, or directly refer to an Old World origin. The acquisition of new ethnobotanical knowledge is captured in vernaculars derived from Amerindian languages and the invention of new names for neotropical plants from African lexical terms. Plant names that combine African, Amerindian, and European words reflect a creolization process that merged ethnobotanical skills from diverse geographical and cultural sources into new Afro-American knowledge systems. Our study confirms the role of Africans as significant agents of environmental knowledge in the New World. PMID- 25453068 TI - Effects of biological explanations for mental disorders on clinicians' empathy. AB - Mental disorders are increasingly understood in terms of biological mechanisms. We examined how such biological explanations of patients' symptoms would affect mental health clinicians' empathy--a crucial component of the relationship between treatment-providers and patients--as well as their clinical judgments and recommendations. In a series of studies, US clinicians read descriptions of potential patients whose symptoms were explained using either biological or psychosocial information. Biological explanations have been thought to make patients appear less accountable for their disorders, which could increase clinicians' empathy. To the contrary, biological explanations evoked significantly less empathy. These results are consistent with other research and theory that has suggested that biological accounts of psychopathology can exacerbate perceptions of patients as abnormal, distinct from the rest of the population, meriting social exclusion, and even less than fully human. Although the ongoing shift toward biomedical conceptualizations has many benefits, our results reveal unintended negative consequences. PMID- 25453069 TI - Silencing urease: a key evolutionary step that facilitated the adaptation of Yersinia pestis to the flea-borne transmission route. AB - The arthropod-borne transmission route of Yersinia pestis, the bacterial agent of plague, is a recent evolutionary adaptation. Yersinia pseudotuberculosis, the closely related food-and water-borne enteric species from which Y. pestis diverged less than 6,400 y ago, exhibits significant oral toxicity to the flea vectors of plague, whereas Y. pestis does not. In this study, we identify the Yersinia urease enzyme as the responsible oral toxin. All Y. pestis strains, including those phylogenetically closest to the Y. pseudotuberculosis progenitor, contain a mutated ureD allele that eliminated urease activity. Restoration of a functional ureD was sufficient to make Y. pestis orally toxic to fleas. Conversely, deletion of the urease operon in Y. pseudotuberculosis rendered it nontoxic. Enzymatic activity was required for toxicity. Because urease-related mortality eliminates 30-40% of infective flea vectors, ureD mutation early in the evolution of Y. pestis was likely subject to strong positive selection because it significantly increased transmission potential. PMID- 25453070 TI - DNA methyltransferase 3B regulates duration of neural crest production via repression of Sox10. AB - Neural crest stem cells arise within the central nervous system but then undergo an epithelial-to-mesenchymal transition to migrate away and contribute to the peripheral nervous system and craniofacial skeleton. Here we show that DNA methyltransferase 3B (DNMT3B) is responsible for the loss of competence of dorsal neural tube cells to generate emigrating neural crest cells. DNMT3B knockdown results in up-regulation of neural crest markers, prolonged neural crest emigration, and subsequent precocious neuronal differentiation of the trigeminal ganglion. We find that DNMT3B binds to the promoter of Sox10, known to be important for neural crest emigration and lineage acquisition. Bisulfite sequencing further reveals methylation of the Sox10 promoter region upon cessation of emigration in normal embryos, whereas this mark is reduced after DNMT3B loss. Taken together, these results reveal the importance of DNA methylation in regulating the ability of neural tube cells to produce neural crest cells and the timing of peripheral neuron differentiation. PMID- 25453072 TI - The origin of risk aversion. AB - Risk aversion is one of the most basic assumptions of economic behavior, but few studies have addressed the question of where risk preferences come from and why they differ from one individual to the next. Here, we propose an evolutionary explanation for the origin of risk aversion. In the context of a simple binary choice model, we show that risk aversion emerges by natural selection if reproductive risk is systematic (i.e., correlated across individuals in a given generation). In contrast, risk neutrality emerges if reproductive risk is idiosyncratic (i.e., uncorrelated across each given generation). More generally, our framework implies that the degree of risk aversion is determined by the stochastic nature of reproductive rates, and we show that different statistical properties lead to different utility functions. The simplicity and generality of our model suggest that these implications are primitive and cut across species, physiology, and genetic origins. PMID- 25453071 TI - Conformational dynamics of a crystalline protein from microsecond-scale molecular dynamics simulations and diffuse X-ray scattering. AB - X-ray diffraction from protein crystals includes both sharply peaked Bragg reflections and diffuse intensity between the peaks. The information in Bragg scattering is limited to what is available in the mean electron density. The diffuse scattering arises from correlations in the electron density variations and therefore contains information about collective motions in proteins. Previous studies using molecular-dynamics (MD) simulations to model diffuse scattering have been hindered by insufficient sampling of the conformational ensemble. To overcome this issue, we have performed a 1.1-MUs MD simulation of crystalline staphylococcal nuclease, providing 100-fold more sampling than previous studies. This simulation enables reproducible calculations of the diffuse intensity and predicts functionally important motions, including transitions among at least eight metastable states with different active-site geometries. The total diffuse intensity calculated using the MD model is highly correlated with the experimental data. In particular, there is excellent agreement for the isotropic component of the diffuse intensity, and substantial but weaker agreement for the anisotropic component. Decomposition of the MD model into protein and solvent components indicates that protein-solvent interactions contribute substantially to the overall diffuse intensity. We conclude that diffuse scattering can be used to validate predictions from MD simulations and can provide information to improve MD models of protein motions. PMID- 25453073 TI - Climate change decouples oceanic primary and export productivity and organic carbon burial. AB - Understanding responses of oceanic primary productivity, carbon export, and burial to climate change is essential for model-based projection of biological feedbacks in a high-CO2 world. Here we compare estimates of productivity based on the composition of fossil diatom floras with organic carbon burial off Oregon in the Northeast Pacific across a large climatic transition at the last glacial termination. Although estimated primary productivity was highest during the Last Glacial Maximum, carbon burial was lowest, reflecting reduced preservation linked to low sedimentation rates. A diatom size index further points to a glacial decrease (and deglacial increase) in the fraction of fixed carbon that was exported, inferred to reflect expansion, and contraction, of subpolar ecosystems that today favor smaller plankton. Thus, in contrast to models that link remineralization of carbon to temperature, in the Northeast Pacific, we find dominant ecosystem and sea floor control such that intervals of warming climate had more efficient carbon export and higher carbon burial despite falling primary productivity. PMID- 25453074 TI - Multiple functional therapeutic effects of the estrogen receptor beta agonist indazole-Cl in a mouse model of multiple sclerosis. AB - Currently available immunomodulatory therapies do not stop the pathogenesis underlying multiple sclerosis (MS) and are only partially effective in preventing the onset of permanent disability in patients with MS. Identifying a drug that stimulates endogenous remyelination and/or minimizes axonal degeneration would reduce the rate and degree of disease progression. Here, the effects of the highly selective estrogen receptor (ER) beta agonist indazole chloride (Ind-Cl) on functional remyelination in chronic experimental autoimmune encephalomyelitis (EAE) mice were investigated by assessing pathologic, functional, and behavioral consequences of both prophylactic and therapeutic (peak EAE) treatment with Ind Cl. Peripheral cytokines from autoantigen-stimulated splenocytes were measured, and central nervous system infiltration by immune cells, axon health, and myelination were assessed by immunohistochemistry and electron microscopy. Therapeutic Ind-Cl improved clinical disease and rotorod performance and also decreased peripheral Th1 cytokines and reactive astrocytes, activated microglia, and T cells in brains of EAE mice. Increased callosal myelination and mature oligodendrocytes correlated with improved callosal conduction and refractoriness. Therapeutic Ind-Cl-induced remyelination was independent of its effects on the immune system, as Ind-Cl increased remyelination within the cuprizone diet induced demyelinating model. We conclude that Ind-Cl is a refined pharmacologic agent capable of stimulating functionally relevant endogenous myelination, with important implications for progressive MS treatment. PMID- 25453075 TI - Power transduction of actin filaments ratcheting in vitro against a load. AB - The actin cytoskeleton has the unique capability of producing pushing forces at the leading edge of motile cells without the implication of molecular motors. This phenomenon has been extensively studied theoretically, and molecular models, including the widely known Brownian ratchet, have been proposed. However, supporting experimental work is lacking, due in part to hardly accessible molecular length scales. We designed an experiment to directly probe the mechanism of force generation in a setup where a population of actin filaments grows against a load applied by magnetic microparticles. The filaments, arranged in stiff bundles by fascin, are constrained to point toward the applied load. In this protrusion-like geometry, we are able to directly measure the velocity of filament elongation and its dependence on force. Using numerical simulations, we provide evidence that our experimental data are consistent with a Brownian ratchet-based model. We further demonstrate the existence of a force regime far below stalling where the mechanical power transduced by the ratcheting filaments to the load is maximal. The actin machinery in migrating cells may tune the number of filaments at the leading edge to work in this force regime. PMID- 25453076 TI - Dendrites are dispensable for basic motoneuron function but essential for fine tuning of behavior. AB - Dendrites are highly complex 3D structures that define neuronal morphology and connectivity and are the predominant sites for synaptic input. Defects in dendritic structure are highly consistent correlates of brain diseases. However, the precise consequences of dendritic structure defects for neuronal function and behavioral performance remain unknown. Here we probe dendritic function by using genetic tools to selectively abolish dendrites in identified Drosophila wing motoneurons without affecting other neuronal properties. We find that these motoneuron dendrites are unexpectedly dispensable for synaptic targeting, qualitatively normal neuronal activity patterns during behavior, and basic behavioral performance. However, significant performance deficits in sophisticated motor behaviors, such as flight altitude control and switching between discrete courtship song elements, scale with the degree of dendritic defect. To our knowledge, our observations provide the first direct evidence that complex dendrite architecture is critically required for fine-tuning and adaptability within robust, evolutionarily constrained behavioral programs that are vital for mating success and survival. We speculate that the observed scaling of performance deficits with the degree of structural defect is consistent with gradual increases in intellectual disability during continuously advancing structural deficiencies in progressive neurological disorders. PMID- 25453077 TI - Hidden carbon in Earth's inner core revealed by shear softening in dense Fe7C3. AB - Earth's inner core is known to consist of crystalline iron alloyed with a small amount of nickel and lighter elements, but the shear wave (S wave) travels through the inner core at about half the speed expected for most iron-rich alloys under relevant pressures. The anomalously low S-wave velocity (vS) has been attributed to the presence of liquid, hence questioning the solidity of the inner core. Here we report new experimental data up to core pressures on iron carbide Fe7C3, a candidate component of the inner core, showing that its sound velocities dropped significantly near the end of a pressure-induced spin-pairing transition, which took place gradually between 10 GPa and 53 GPa. Following the transition, the sound velocities increased with density at an exceptionally low rate. Extrapolating the data to the inner core pressure and accounting for the temperature effect, we found that low-spin Fe7C3 can reproduce the observed vS of the inner core, thus eliminating the need to invoke partial melting or a postulated large temperature effect. The model of a carbon-rich inner core may be consistent with existing constraints on the Earth's carbon budget and would imply that as much as two thirds of the planet's carbon is hidden in its center sphere. PMID- 25453079 TI - Early inner solar system origin for anomalous sulfur isotopes in differentiated protoplanets. AB - Achondrite meteorites have anomalous enrichments in (33)S, relative to chondrites, which have been attributed to photochemistry in the solar nebula. However, the putative photochemical reactions remain elusive, and predicted accompanying (33)S depletions have not previously been found, which could indicate an erroneous assumption regarding the origins of the (33)S anomalies, or of the bulk solar system S-isotope composition. Here, we report well-resolved anomalous (33)S depletions in IIIF iron meteorites (<-0.02 per mil), and (33)S enrichments in other magmatic iron meteorite groups. The (33)S depletions support the idea that differentiated planetesimals inherited sulfur that was photochemically derived from gases in the early inner solar system (<~2 AU), and that bulk inner solar system S-isotope composition was chondritic (consistent with IAB iron meteorites, Earth, Moon, and Mars). The range of mass-independent sulfur isotope compositions may reflect spatial or temporal changes influenced by photochemical processes. A tentative correlation between S isotopes and Hf-W core segregation ages suggests that the two systems may be influenced by common factors, such as nebular location and volatile content. PMID- 25453078 TI - Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer. AB - A variety of human cancers, including nonsmall cell lung (NSCLC), breast, and colon cancers, are driven by the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. Having shown that bisphosphonates, a class of drugs used widely for the therapy of osteoporosis and metastatic bone disease, reduce cancer cell viability by targeting HER1, we explored their potential utility in the prevention and therapy of HER-driven cancers. We show that bisphosphonates inhibit colony formation by HER1(DeltaE746-A750)-driven HCC827 NSCLCs and HER1(wt)-expressing MB231 triple negative breast cancers, but not by HER(low)-SW620 colon cancers. In parallel, oral gavage with bisphosphonates of mice xenografted with HCC827 or MB231 cells led to a significant reduction in tumor volume in both treatment and prevention protocols. This result was not seen with mice harboring HER(low) SW620 xenografts. We next explored whether bisphosphonates can serve as adjunctive therapies to tyrosine kinase inhibitors (TKIs), namely gefitinib and erlotinib, and whether the drugs can target TKI resistant NSCLCs. In silico docking, together with molecular dynamics and anisotropic network modeling, showed that bisphosphonates bind to TKIs within the HER1 kinase domain. As predicted from this combinatorial binding, bisphosphonates enhanced the effects of TKIs in reducing cell viability and driving tumor regression in mice. Impressively, the drugs also overcame erlotinib resistance acquired through the gatekeeper mutation T790M, thus offering an option for TKI resistant NSCLCs. We suggest that bisphosphonates can potentially be repurposed for the prevention and adjunctive therapy of HER1-driven cancers. PMID- 25453080 TI - Hominids adapted to metabolize ethanol long before human-directed fermentation. AB - Paleogenetics is an emerging field that resurrects ancestral proteins from now extinct organisms to test, in the laboratory, models of protein function based on natural history and Darwinian evolution. Here, we resurrect digestive alcohol dehydrogenases (ADH4) from our primate ancestors to explore the history of primate-ethanol interactions. The evolving catalytic properties of these resurrected enzymes show that our ape ancestors gained a digestive dehydrogenase enzyme capable of metabolizing ethanol near the time that they began using the forest floor, about 10 million y ago. The ADH4 enzyme in our more ancient and arboreal ancestors did not efficiently oxidize ethanol. This change suggests that exposure to dietary sources of ethanol increased in hominids during the early stages of our adaptation to a terrestrial lifestyle. Because fruit collected from the forest floor is expected to contain higher concentrations of fermenting yeast and ethanol than similar fruits hanging on trees, this transition may also be the first time our ancestors were exposed to (and adapted to) substantial amounts of dietary ethanol. PMID- 25453082 TI - Trapping the ATP binding state leads to a detailed understanding of the F1-ATPase mechanism. AB - The rotary motor enzyme FoF1-ATP synthase uses the proton-motive force across a membrane to synthesize ATP from ADP and Pi (H2PO4(-)) under cellular conditions that favor the hydrolysis reaction by a factor of 2 * 10(5). This remarkable ability to drive a reaction away from equilibrium by harnessing an external force differentiates it from an ordinary enzyme, which increases the rate of reaction without shifting the equilibrium. Hydrolysis takes place in the neighborhood of one conformation of the catalytic moiety F1-ATPase, whose structure is known from crystallography. By use of molecular dynamics simulations we trap a second structure, which is rotated by 40 degrees from the catalytic dwell conformation and represents the state associated with ATP binding, in accord with single molecule experiments. Using the two structures, we show why Pi is not released immediately after ATP hydrolysis, but only after a subsequent 120 degrees rotation, in agreement with experiment. A concerted conformational change of the alpha3beta3 crown is shown to induce the 40 degrees rotation of the gamma subunit only when the betaE subunit is empty, whereas with Pi bound, betaE serves as a latch to prevent the rotation of gamma. The present results provide a rationalization of how F1-ATPase achieves the coupling between the small changes in the active site of betaDP and the 40 degrees rotation of gamma. PMID- 25453081 TI - Bisphosphonates inactivate human EGFRs to exert antitumor actions. AB - Bisphosphonates are the most commonly prescribed medicines for osteoporosis and skeletal metastases. The drugs have also been shown to reduce cancer progression, but only in certain patient subgroups, suggesting that there is a molecular entity that mediates bisphosphonate action on tumor cells. Using connectivity mapping, we identified human epidermal growth factor receptors (human EGFR or HER) as a potential new molecular entity for bisphosphonate action. Protein thermal shift and cell-free kinase assays, together with computational modeling, demonstrated that N-containing bisphosphonates directly bind to the kinase domain of HER1/2 to cause a global reduction in downstream signaling. By doing so, the drugs kill lung, breast, and colon cancer cells that are driven by activating mutations or overexpression of HER1. Knocking down HER isoforms thus abrogates cell killing by bisphosphonates, establishing complete HER dependence and ruling out a significant role for other receptor tyrosine kinases or the enzyme farnesyl pyrophosphate synthase. Consistent with this finding, colon cancer cells expressing low levels of HER do not respond to bisphosphonates. The results suggest that bisphosphonates can potentially be repurposed for the prevention and therapy of HER family-driven cancers. PMID- 25453084 TI - Explaining complex metals with polymers. PMID- 25453083 TI - Toward resolving the catalytic mechanism of dihydrofolate reductase using neutron and ultrahigh-resolution X-ray crystallography. AB - Dihydrofolate reductase (DHFR) catalyzes the NADPH-dependent reduction of dihydrofolate (DHF) to tetrahydrofolate (THF). An important step in the mechanism involves proton donation to the N5 atom of DHF. The inability to determine the protonation states of active site residues and substrate has led to a lack of consensus regarding the catalytic mechanism involved. To resolve this ambiguity, we conducted neutron and ultrahigh-resolution X-ray crystallographic studies of the pseudo-Michaelis ternary complex of Escherichia coli DHFR with folate and NADP(+). The neutron data were collected to 2.0-A resolution using a 3.6-mm(3) crystal with the quasi-Laue technique. The structure reveals that the N3 atom of folate is protonated, whereas Asp27 is negatively charged. Previous mechanisms have proposed a keto-to-enol tautomerization of the substrate to facilitate protonation of the N5 atom. The structure supports the existence of the keto tautomer owing to protonation of the N3 atom, suggesting that tautomerization is unnecessary for catalysis. In the 1.05-A resolution X-ray structure of the ternary complex, conformational disorder of the Met20 side chain is coupled to electron density for a partially occupied water within hydrogen-bonding distance of the N5 atom of folate; this suggests direct protonation of substrate by solvent. We propose a catalytic mechanism for DHFR that involves stabilization of the keto tautomer of the substrate, elevation of the pKa value of the N5 atom of DHF by Asp27, and protonation of N5 by water that gains access to the active site through fluctuation of the Met20 side chain even though the Met20 loop is closed. PMID- 25453085 TI - Crucial role of nonspecific interactions in amyloid nucleation. AB - Protein oligomers have been implicated as toxic agents in a wide range of amyloid related diseases. However, it has remained unsolved whether the oligomers are a necessary step in the formation of amyloid fibrils or just a dangerous byproduct. Analogously, it has not been resolved if the amyloid nucleation process is a classical one-step nucleation process or a two-step process involving prenucleation clusters. We use coarse-grained computer simulations to study the effect of nonspecific attractions between peptides on the primary nucleation process underlying amyloid fibrillization. We find that, for peptides that do not attract, the classical one-step nucleation mechanism is possible but only at nonphysiologically high peptide concentrations. At low peptide concentrations, which mimic the physiologically relevant regime, attractive interpeptide interactions are essential for fibril formation. Nucleation then inevitably takes place through a two-step mechanism involving prefibrillar oligomers. We show that oligomers not only help peptides meet each other but also, create an environment that facilitates the conversion of monomers into the beta-sheet-rich form characteristic of fibrils. Nucleation typically does not proceed through the most prevalent oligomers but through an oligomer size that is only observed in rare fluctuations, which is why such aggregates might be hard to capture experimentally. Finally, we find that the nucleation of amyloid fibrils cannot be described by classical nucleation theory: in the two-step mechanism, the critical nucleus size increases with increases in both concentration and interpeptide interactions, which is in direct contrast with predictions from classical nucleation theory. PMID- 25453086 TI - Self-assembled FUS binds active chromatin and regulates gene transcription. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Fused in sarcoma (FUS) is a DNA/RNA binding protein and mutations in FUS cause a subset of familial ALS. Most ALS mutations are clustered in the C-terminal nuclear localization sequence of FUS and consequently lead to the accumulation of protein inclusions in the cytoplasm. It remains debatable whether loss of FUS normal function in the nucleus or gain of toxic function in the cytoplasm plays a more critical role in the ALS etiology. Moreover, the physiological function of FUS in the nucleus remains to be fully understood. In this study, we found that a significant portion of nuclear FUS was bound to active chromatin and that the ALS mutations dramatically decreased FUS chromatin binding ability. Functionally, the chromatin binding is required for FUS transcription activation, but not for alternative splicing regulation. The N-terminal QGSY (glutamine-glycine-serine tyrosine)-rich region (amino acids 1-164) mediates FUS self-assembly in the nucleus of mammalian cells and the self-assembly is essential for its chromatin binding and transcription activation. In addition, RNA binding is also required for FUS self-assembly and chromatin binding. Together, our results suggest a functional assembly of FUS in the nucleus under physiological conditions, which is different from the cytoplasmic inclusions. The ALS mutations can cause loss of function in the nucleus by disrupting this assembly and chromatin binding. PMID- 25453088 TI - Detection of brown adipose tissue and thermogenic activity in mice by hyperpolarized xenon MRI. AB - The study of brown adipose tissue (BAT) in human weight regulation has been constrained by the lack of a noninvasive tool for measuring this tissue and its function in vivo. Existing imaging modalities are nonspecific and intrinsically insensitive to the less active, lipid-rich BAT of obese subjects, the target population for BAT studies. We demonstrate noninvasive imaging of BAT in mice by hyperpolarized xenon gas MRI. We detect a greater than 15-fold increase in xenon uptake by BAT during stimulation of BAT thermogenesis, which enables us to acquire background-free maps of the tissue in both lean and obese mouse phenotypes. We also demonstrate in vivo MR thermometry of BAT by hyperpolarized xenon gas. Finally, we use the linear temperature dependence of the chemical shift of xenon dissolved in adipose tissue to directly measure BAT temperature and to track thermogenic activity in vivo. PMID- 25453087 TI - Structural interactions of a voltage sensor toxin with lipid membranes. AB - Protein toxins from tarantula venom alter the activity of diverse ion channel proteins, including voltage, stretch, and ligand-activated cation channels. Although tarantula toxins have been shown to partition into membranes, and the membrane is thought to play an important role in their activity, the structural interactions between these toxins and lipid membranes are poorly understood. Here, we use solid-state NMR and neutron diffraction to investigate the interactions between a voltage sensor toxin (VSTx1) and lipid membranes, with the goal of localizing the toxin in the membrane and determining its influence on membrane structure. Our results demonstrate that VSTx1 localizes to the headgroup region of lipid membranes and produces a thinning of the bilayer. The toxin orients such that many basic residues are in the aqueous phase, all three Trp residues adopt interfacial positions, and several hydrophobic residues are within the membrane interior. One remarkable feature of this preferred orientation is that the surface of the toxin that mediates binding to voltage sensors is ideally positioned within the lipid bilayer to favor complex formation between the toxin and the voltage sensor. PMID- 25453089 TI - Speciation with gene flow in equids despite extensive chromosomal plasticity. AB - Horses, asses, and zebras belong to a single genus, Equus, which emerged 4.0-4.5 Mya. Although the equine fossil record represents a textbook example of evolution, the succession of events that gave rise to the diversity of species existing today remains unclear. Here we present six genomes from each living species of asses and zebras. This completes the set of genomes available for all extant species in the genus, which was hitherto represented only by the horse and the domestic donkey. In addition, we used a museum specimen to characterize the genome of the quagga zebra, which was driven to extinction in the early 1900s. We scan the genomes for lineage-specific adaptations and identify 48 genes that have evolved under positive selection and are involved in olfaction, immune response, development, locomotion, and behavior. Our extensive genome dataset reveals a highly dynamic demographic history with synchronous expansions and collapses on different continents during the last 400 ky after major climatic events. We show that the earliest speciation occurred with gene flow in Northern America, and that the ancestor of present-day asses and zebras dispersed into the Old World 2.1-3.4 Mya. Strikingly, we also find evidence for gene flow involving three contemporary equine species despite chromosomal numbers varying from 16 pairs to 31 pairs. These findings challenge the claim that the accumulation of chromosomal rearrangements drive complete reproductive isolation, and promote equids as a fundamental model for understanding the interplay between chromosomal structure, gene flow, and, ultimately, speciation. PMID- 25453090 TI - Neuromolecular responses to social challenge: common mechanisms across mouse, stickleback fish, and honey bee. AB - Certain complex phenotypes appear repeatedly across diverse species due to processes of evolutionary conservation and convergence. In some contexts like developmental body patterning, there is increased appreciation that common molecular mechanisms underlie common phenotypes; these molecular mechanisms include highly conserved genes and networks that may be modified by lineage specific mutations. However, the existence of deeply conserved mechanisms for social behaviors has not yet been demonstrated. We used a comparative genomics approach to determine whether shared neuromolecular mechanisms could underlie behavioral response to territory intrusion across species spanning a broad phylogenetic range: house mouse (Mus musculus), stickleback fish (Gasterosteus aculeatus), and honey bee (Apis mellifera). Territory intrusion modulated similar brain functional processes in each species, including those associated with hormone-mediated signal transduction and neurodevelopment. Changes in chromosome organization and energy metabolism appear to be core, conserved processes involved in the response to territory intrusion. We also found that several homologous transcription factors that are typically associated with neural development were modulated across all three species, suggesting that shared neuronal effects may involve transcriptional cascades of evolutionarily conserved genes. Furthermore, immunohistochemical analyses of a subset of these transcription factors in mouse again implicated modulation of energy metabolism in the behavioral response. These results provide support for conserved genetic "toolkits" that are used in independent evolutions of the response to social challenge in diverse taxa. PMID- 25453092 TI - Vibrio effector protein VopQ inhibits fusion of V-ATPase-containing membranes. AB - Vesicle fusion governs many important biological processes, and imbalances in the regulation of membrane fusion can lead to a variety of diseases such as diabetes and neurological disorders. Here we show that the Vibrio parahaemolyticus effector protein VopQ is a potent inhibitor of membrane fusion based on an in vitro yeast vacuole fusion model. Previously, we demonstrated that VopQ binds to the V(o) domain of the conserved V-type H(+)-ATPase (V-ATPase) found on acidic compartments such as the yeast vacuole. VopQ forms a nonspecific, voltage-gated membrane channel of 18 A resulting in neutralization of these compartments. We now present data showing that VopQ inhibits yeast vacuole fusion. Furthermore, we identified a unique mutation in VopQ that delineates its two functions, deacidification and inhibition of membrane fusion. The use of VopQ as a membrane fusion inhibitor in this manner now provides convincing evidence that vacuole fusion occurs independently of luminal acidification in vitro. PMID- 25453091 TI - (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. AB - Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malaria. We disclose herein that the clinical candidate (+)-SJ733 acts upon one of these targets, ATP4. ATP4 is thought to be a cation-transporting ATPase responsible for maintaining low intracellular Na(+) levels in the parasite. Treatment of parasitized erythrocytes with (+)-SJ733 in vitro caused a rapid perturbation of Na(+) homeostasis in the parasite. This perturbation was followed by profound physical changes in the infected cells, including increased membrane rigidity and externalization of phosphatidylserine, consistent with eryptosis (erythrocyte suicide) or senescence. These changes are proposed to underpin the rapid (+)-SJ733-induced clearance of parasites seen in vivo. Plasmodium falciparum ATPase 4 (pfatp4) mutations that confer resistance to (+)-SJ733 carry a high fitness cost. The speed with which (+)-SJ733 kills parasites and the high fitness cost associated with resistance-conferring mutations appear to slow and suppress the selection of highly drug-resistant mutants in vivo. Together, our data suggest that inhibitors of PfATP4 have highly attractive features for fast-acting antimalarials to be used in the global eradication campaign. PMID- 25453093 TI - Structure of the nonameric bacterial amyloid secretion channel. AB - Various strains of bacteria are able to produce a unique class of functional amyloids termed curli, which are critical for biofilm formation, host cell adhesion, and colonization of inert surfaces. Curli are secreted via the type VIII bacterial secretion system, and they share biochemical and structural characteristics with amyloid fibers that have been implicated in deleterious disease in humans. Here, we report the crystal structure of Escherichia coli CsgG, which is an essential lipoprotein component of the type VIII secretion system and which forms a secretion channel in the bacterial outer membrane for transporting curli subunits. CsgG forms a crown-shaped, symmetric nonameric channel that spans the outer membrane via a 36-strand beta-barrel, with each subunit contributing four beta-strands. This nonameric complex contains a central channel with a pore located at the middle. The eyelet of the pore is ~12 A in diameter and is lined with three stacked nine-residue rings consisting of Tyr-66, Asn-70, or Phe-71. Our structure-based functional studies suggest that Tyr-66 and Phe-71 residues function as gatekeepers for the selective secretion of curli subunits. Our study describes in detail, to our knowledge, the first core structure of the type VIII bacterial secretion machinery. Importantly, our structural analysis suggests that the curli subunits are secreted via CsgG across the bacterial outer membrane in an unfolded form. PMID- 25453094 TI - Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue. AB - Jervell and Lange-Nielsen syndrome (JLNS) is one of the most severe life threatening cardiac arrhythmias. Patients display delayed cardiac repolarization, associated high risk of sudden death due to ventricular tachycardia, and congenital bilateral deafness. In contrast to the autosomal dominant forms of long QT syndrome, JLNS is a recessive trait, resulting from homozygous (or compound heterozygous) mutations in KCNQ1 or KCNE1. These genes encode the alpha and beta subunits, respectively, of the ion channel conducting the slow component of the delayed rectifier K(+) current, IKs. We used complementary approaches, reprogramming patient cells and genetic engineering, to generate human induced pluripotent stem cell (hiPSC) models of JLNS, covering splice site (c.478-2A>T) and missense (c.1781G>A) mutations, the two major classes of JLNS-causing defects in KCNQ1. Electrophysiological comparison of hiPSC-derived cardiomyocytes (CMs) from homozygous JLNS, heterozygous, and wild-type lines recapitulated the typical and severe features of JLNS, including pronounced action and field potential prolongation and severe reduction or absence of IKs. We show that this phenotype had distinct underlying molecular mechanisms in the two sets of cell lines: the previously unidentified c.478-2A>T mutation was amorphic and gave rise to a strictly recessive phenotype in JLNS-CMs, whereas the missense c.1781G>A lesion caused a gene dosage-dependent channel reduction at the cell membrane. Moreover, adrenergic stimulation caused action potential prolongation specifically in JLNS CMs. Furthermore, sensitivity to proarrhythmic drugs was strongly enhanced in JLNS-CMs but could be pharmacologically corrected. Our data provide mechanistic insight into distinct classes of JLNS-causing mutations and demonstrate the potential of hiPSC-CMs in drug evaluation. PMID- 25453097 TI - In vivo selective cancer-tracking gadolinium eradicator as new-generation photodynamic therapy agent. AB - In this work, we demonstrate a modality of photodynamic therapy (PDT) through the design of our truly dual-functional--PDT and imaging--gadolinium complex (Gd-N), which can target cancer cells specifically. In the light of our design, the PDT drug can specifically localize on the anionic cell membrane of cancer cells in which its laser-excited photoemission signal can be monitored without triggering the phototoxic generation of reactive oxygen species--singlet oxygen--before due excitation. Comprehensive in vitro and in vivo studies had been conducted for the substantiation of the effectiveness of Gd-N as such a tumor-selective PDT photosensitizer. This treatment modality does initiate a new direction in the development of "precision medicine" in line with stem cell and gene therapies as tools in cancer therapy. PMID- 25453096 TI - Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells. AB - Triple negative breast cancers (TNBCs) are defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 expression, and are treated with cytotoxic chemotherapy such as paclitaxel or gemcitabine, with a durable response rate of less than 20%. TNBCs are enriched for the basal subtype gene expression profile and the presence of breast cancer stem cells, which are endowed with self-renewing and tumor initiating properties and resistance to chemotherapy. Hypoxia-inducible factors (HIFs) and their target gene products are highly active in TNBCs. Here, we demonstrate that HIF expression and transcriptional activity are induced by treatment of MDA-MB-231, SUM-149, and SUM-159, which are human TNBC cell lines, as well as MCF-7, which is an ER(+)/PR(+) breast cancer line, with paclitaxel or gemcitabine. Chemotherapy-induced HIF activity enriched the breast cancer stem cell population through interleukin-6 and interleukin-8 signaling and increased expression of multidrug resistance 1. Coadministration of HIF inhibitors overcame the resistance of breast cancer stem cells to paclitaxel or gemcitabine, both in vitro and in vivo, leading to tumor eradication. Increased expression of HIF 1alpha or HIF target genes in breast cancer biopsies was associated with decreased overall survival, particularly in patients with basal subtype tumors and those treated with chemotherapy alone. Based on these results, clinical trials are warranted to test whether treatment of patients with TNBC with a combination of cytotoxic chemotherapy and HIF inhibitors will improve patient survival. PMID- 25453095 TI - Direct interactions promote eviction of the Sir3 heterochromatin protein by the SWI/SNF chromatin remodeling enzyme. AB - Heterochromatin is a specialized chromatin structure that is central to eukaryotic transcriptional regulation and genome stability. Despite its globally repressive role, heterochromatin must also be dynamic, allowing for its repair and replication. In budding yeast, heterochromatin formation requires silent information regulators (Sirs) Sir2p, Sir3p, and Sir4p, and these Sir proteins create specialized chromatin structures at telomeres and silent mating-type loci. Previously, we found that the SWI/SNF chromatin remodeling enzyme can catalyze the ATP-dependent eviction of Sir3p from recombinant nucleosomal arrays, and this activity enhances early steps of recombinational repair in vitro. Here, we show that the ATPase subunit of SWI/SNF, Swi2p/Snf2p, interacts with the heterochromatin structural protein Sir3p. Two interaction surfaces are defined, including an interaction between the ATPase domain of Swi2p and the nucleosome binding, Bromo-Adjacent-Homology domain of Sir3p. A SWI/SNF complex harboring a Swi2p subunit that lacks this Sir3p interaction surface is unable to evict Sir3p from nucleosomes, even though its ATPase and remodeling activities are intact. In addition, we find that the interaction between Swi2p and Sir3p is key for SWI/SNF to promote resistance to replication stress in vivo and for establishment of heterochromatin at telomeres. PMID- 25453098 TI - Escherichia coli dihydrofolate reductase catalyzed proton and hydride transfers: temporal order and the roles of Asp27 and Tyr100. AB - The reaction catalyzed by Escherichia coli dihydrofolate reductase (ecDHFR) has become a model for understanding enzyme catalysis, and yet several details of its mechanism are still unresolved. Specifically, the mechanism of the chemical step, the hydride transfer reaction, is not fully resolved. We found, unexpectedly, the presence of two reactive ternary complexes [enzyme:NADPH:7,8-dihydrofolate (E:NADPH:DHF)] separated by one ionization event. Furthermore, multiple kinetic isotope effect (KIE) studies revealed a stepwise mechanism in which protonation of the DHF precedes the hydride transfer from the nicotinamide cofactor (NADPH) for both reactive ternary complexes of the WT enzyme. This mechanism was supported by the pH- and temperature-independent intrinsic KIEs for the C-H->C hydride transfer between NADPH and the preprotonated DHF. Moreover, we showed that active site residues D27 and Y100 play a synergistic role in facilitating both the proton transfer and subsequent hydride transfer steps. Although D27 appears to have a greater effect on the overall rate of conversion of DHF to tetrahydrofolate, Y100 plays an important electrostatic role in modulating the pKa of the N5 of DHF to enable the preprotonation of DHF by an active site water molecule. PMID- 25453100 TI - Social, institutional, and knowledge mechanisms mediate diverse ecosystem service benefits from coral reefs. AB - Ecosystem services are supplied by nature but, by definition, are received by people. Ecosystem service assessments, intended to influence the decisions people make regarding their interactions with nature, need to understand how people benefit from different ecosystem services. A critical question is therefore, What determines the distribution of ecosystem service benefits between different sections of society? Here, we use an entitlements approach to examine how people perceive ecosystem service benefits across 28 coral reef fishing communities in four countries. In doing so, we quantitatively show that bundles of benefits are mediated by key access mechanisms (e.g., rights-based, economic, knowledge, social, and institutional). We find that specific access mechanisms influence which ecosystem services people prioritize. Social, institutional, and knowledge mechanisms are associated with the largest number and diversity of benefits. However, local context strongly determines whether specific access mechanisms enable or constrain benefits. Local ecological knowledge enabled people to prioritize a habitat benefit in Kenya, but constrained people from prioritizing the same benefit in Madagascar. Ecosystem service assessments, and their resultant policies, need to include the broad suite of access mechanisms that enable different people to benefit from a supply of ecosystem services. PMID- 25453099 TI - Histone H3.3 and cancer: A potential reader connection. AB - The building block of chromatin is nucleosome, which consists of 146 base pairs of DNA wrapped around a histone octamer composed of two copies of histone H2A, H2B, H3, and H4. Significantly, the somatic missense mutations of the histone H3 variant, H3.3, are associated with childhood and young-adult tumors, such as pediatric high-grade astrocytomas, as well as chondroblastoma and giant-cell tumors of the bone. The mechanisms by which these histone mutations cause cancer are by and large unclear. Interestingly, two recent studies identified BS69/ZMYND11, which was proposed to be a candidate tumor suppressor, as a specific reader for a modified form of H3.3 (H3.3K36me3). Importantly, some H3.3 cancer mutations are predicted to abrogate the H3.3K36me3/BS69 interaction, suggesting that this interaction may play an important role in tumor suppression. These new findings also raise the question of whether H3.3 cancer mutations may lead to the disruption and/or gain of interactions of additional cellular factors that contribute to tumorigenesis. PMID- 25453101 TI - Stoichiometry and assembly of mTOR complexes revealed by single-molecule pulldown. AB - The mammalian target of rapamycin (mTOR) kinase is a master regulator of cellular, developmental, and metabolic processes. Deregulation of mTOR signaling is implicated in numerous human diseases including cancer and diabetes. mTOR functions as part of either of the two multisubunit complexes, mTORC1 and mTORC2, but molecular details about the assembly and oligomerization of mTORCs are currently lacking. We use the single-molecule pulldown (SiMPull) assay that combines principles of conventional pulldown assays with single-molecule fluorescence microscopy to investigate the stoichiometry and assembly of mTORCs. After validating our approach with mTORC1, confirming a dimeric assembly as previously reported, we show that all major components of mTORC2 exist in two copies per complex, indicating that mTORC2 assembles as a homodimer. Interestingly, each mTORC component, when free from the complexes, is present as a monomer and no single subunit serves as the dimerizing component. Instead, our data suggest that dimerization of mTORCs is the result of multiple subunits forming a composite surface. SiMPull also allowed us to distinguish complex disassembly from stoichiometry changes. Physiological conditions that abrogate mTOR signaling such as nutrient deprivation or energy stress did not alter the stoichiometry of mTORCs. On the other hand, rapamycin treatment leads to transient appearance of monomeric mTORC1 before complete disruption of the mTOR raptor interaction, whereas mTORC2 stoichiometry is unaffected. These insights into assembly of mTORCs may guide future mechanistic studies and exploration of therapeutic potential. PMID- 25453102 TI - Evolutionary limits to cooperation in microbial communities. AB - Microbes produce many compounds that are costly to a focal cell but promote the survival and reproduction of neighboring cells. This observation has led to the suggestion that microbial strains and species will commonly cooperate by exchanging compounds. Here, we examine this idea with an ecoevolutionary model where microbes make multiple secretions, which can be exchanged among genotypes. We show that cooperation between genotypes only evolves under specific demographic regimes characterized by intermediate genetic mixing. The key constraint on cooperative exchanges is a loss of autonomy: strains become reliant on complementary genotypes that may not be reliably encountered. Moreover, the form of cooperation that we observe arises through mutual exploitation that is related to cheating and "Black Queen" evolution for a single secretion. A major corollary is that the evolution of cooperative exchanges reduces community productivity relative to an autonomous strain that makes everything it needs. This prediction finds support in recent work from synthetic communities. Overall, our work suggests that natural selection will often limit cooperative exchanges in microbial communities and that, when exchanges do occur, they can be an inefficient solution to group living. PMID- 25453104 TI - Erythritol feeds the pentose phosphate pathway via three new isomerases leading to D-erythrose-4-phosphate in Brucella. AB - Erythritol is an important nutrient for several alpha-2 Proteobacteria, including N2-fixing plant endosymbionts and Brucella, a worldwide pathogen that finds this four-carbon polyol in genital tissues. Erythritol metabolism involves phosphorylation to L-erythritol-4-phosphate by the kinase EryA and oxidation of the latter to L-3-tetrulose 4-phosphate by the dehydrogenase EryB. It is accepted that further steps involve oxidation by the putative dehydrogenase EryC and subsequent decarboxylation to yield triose-phosphates. Accordingly, growth on erythritol as the sole C source should require aldolase and fructose-1,6 bisphosphatase to produce essential hexose-6-monophosphate. However, we observed that a mutant devoid of fructose-1,6-bisphosphatases grew normally on erythritol and that EryC, which was assumed to be a dehydrogenase, actually belongs to the xylose isomerase superfamily. Moreover, we found that TpiA2 and RpiB, distant homologs of triose phosphate isomerase and ribose 5-phosphate isomerase B, were necessary, as previously shown for Rhizobium. By using purified recombinant enzymes, we demonstrated that L-3-tetrulose-4-phosphate was converted to D erythrose 4-phosphate through three previously unknown isomerization reactions catalyzed by EryC (tetrulose-4-phosphate racemase), TpiA2 (D-3-tetrulose-4 phosphate isomerase; renamed EryH), and RpiB (D-erythrose-4-phosphate isomerase; renamed EryI), a pathway fully consistent with the isotopomer distribution of the erythrose-4-phosphate-derived amino acids phenylalanine and tyrosine obtained from bacteria grown on (13)C-labeled erythritol. D-erythrose-4-phosphate is then converted by enzymes of the pentose phosphate pathway to glyceraldehyde 3 phosphate and fructose 6-phosphate, thus bypassing fructose-1,6-bisphosphatase. This is the first description to our knowledge of a route feeding carbohydrate metabolism exclusively via D-erythrose 4-phosphate, a pathway that may provide clues to the preferential metabolism of erythritol by Brucella and its role in pathogenicity. PMID- 25453103 TI - hERG 1b is critical for human cardiac repolarization. AB - The human ether-a-go-go-related gene (hERG; or KCNH2) encodes the voltage-gated potassium channel underlying IKr, a repolarizing current in the heart. Mutations in KCNH2 or pharmacological agents that reduce IKr slow action potential (AP) repolarization and can trigger cardiac arrhythmias associated with long QT syndrome. Two channel-forming subunits encoded by KCNH2 (hERG 1a and 1b) are expressed in cardiac tissue. In heterologous expression systems, these subunits avidly coassemble and exhibit biophysical and pharmacological properties distinct from those of homomeric hERG 1a channels. Despite these findings, adoption of hERG 1a/1b heteromeric channels as a model for cardiac IKr has been hampered by the lack of evidence for a direct functional role for the 1b subunit in native tissue. In this study, we measured IKr and APs at physiological temperature in cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs). We found that specific knockdown of the 1b subunit using shRNA caused reductions in 1b mRNA, 1b protein levels, and IKr magnitude by roughly one-half. AP duration was increased and AP variability was enhanced relative to controls. Early afterdepolarizations, considered cellular substrates for arrhythmia, were also observed in cells with reduced 1b expression. Similar behavior was elicited when channels were effectively converted from heteromers to 1a homomers by expressing a fragment corresponding to the 1a-specific N-terminal Per-Arnt-Sim domain, which is omitted from hERG 1b by alternate transcription. These findings establish that hERG 1b is critical for normal repolarization and that loss of 1b is proarrhythmic in human cardiac cells. PMID- 25453105 TI - p53 prevents neurodegeneration by regulating synaptic genes. AB - DNA damage has been implicated in neurodegenerative disorders, including Alzheimer's disease and other tauopathies, but the consequences of genotoxic stress to postmitotic neurons are poorly understood. Here we demonstrate that p53, a key mediator of the DNA damage response, plays a neuroprotective role in a Drosophila model of tauopathy. Further, through a whole-genome ChIP-chip analysis, we identify genes controlled by p53 in postmitotic neurons. We genetically validate a specific pathway, synaptic function, in p53-mediated neuroprotection. We then demonstrate that the control of synaptic genes by p53 is conserved in mammals. Collectively, our results implicate synaptic function as a central target in p53-dependent protection from neurodegeneration. PMID- 25453106 TI - Antibody-driven design of a human cytomegalovirus gHgLpUL128L subunit vaccine that selectively elicits potent neutralizing antibodies. AB - The use of neutralizing antibodies to identify the most effective antigen has been proposed as a strategy to design vaccines capable of eliciting protective B cell immunity. In this study, we analyzed the human antibody response to cytomegalovirus (human cytomegalovirus, HCMV) infection and found that antibodies to glycoprotein (g)B, a surface glycoprotein that has been developed as a HCMV vaccine, were primarily nonneutralizing. In contrast, most of the antibodies to the complex formed by gH, gL, protein (p)UL128, pUL130, and pUL131 (the gHgLpUL128L pentamer) neutralized HCMV infection with high potency. Based on this analysis, we developed a single polycistronic vector encoding the five pentamer genes separated by "self-cleaving" 2A peptides to generate a stably transfected CHO cell line constitutively secreting high levels of recombinant pentamer that displayed the functional antigenic sites targeted by human neutralizing antibodies. Immunization of mice with the pentamer formulated with different adjuvants elicited HCMV neutralizing antibody titers that persisted to high levels over time and that were a hundred- to thousand-fold higher than those found in individuals that recovered from primary HCMV infection. Sera from mice immunized with the pentamer vaccine neutralized infection of both epithelial cells and fibroblasts and prevented cell-to-cell spread and viral dissemination from endothelial cells to leukocytes. Neutralizing monoclonal antibodies from immunized mice showed the same potency as human antibodies and targeted the same as well as additional sites on the pentamer. These results illustrate with a relevant example a general and practical approach of analytic vaccinology for the development of subunit vaccines against complex pathogens. PMID- 25453109 TI - Robert Steinberg, 1922-2014. PMID- 25453108 TI - Label-free imaging of Schwann cell myelination by third harmonic generation microscopy. AB - Understanding the dynamic axon-glial cell interaction underlying myelination is hampered by the lack of suitable imaging techniques. Here we demonstrate third harmonic generation microscopy (THGM) for label-free imaging of myelinating Schwann cells in live culture and ex vivo and in vivo tissue. A 3D structure was acquired for a variety of compact and noncompact myelin domains, including juxtaparanodes, Schmidt-Lanterman incisures, and Cajal bands. Other subcellular features of Schwann cells that escape traditional optical microscopies were also visualized. We tested THGM for morphometry of compact myelin. Unlike current methods based on electron microscopy, g-ratio could be determined along an extended length of myelinated fiber in the physiological condition. The precision of THGM-based g-ratio estimation was corroborated in mouse models of hypomyelination. Finally, we demonstrated the feasibility of THGM to monitor morphological changes of myelin during postnatal development and degeneration. The outstanding capabilities of THGM may be useful for elucidation of the mechanism of myelin formation and pathogenesis. PMID- 25453107 TI - Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence. AB - It is widely believed that epidemics in new hosts diminish in virulence over time, with natural selection favoring pathogens that cause minimal disease. However, a tradeoff frequently exists between high virulence shortening host survival on the one hand but allowing faster transmission on the other. This is the case in HIV infection, where high viral loads increase transmission risk per coital act but reduce host longevity. We here investigate the impact on HIV virulence of HIV adaptation to HLA molecules that protect against disease progression, such as HLA-B*57 and HLA-B*58:01. We analyzed cohorts in Botswana and South Africa, two countries severely affected by the HIV epidemic. In Botswana, where the epidemic started earlier and adult seroprevalence has been higher, HIV adaptation to HLA including HLA-B*57/58:01 is greater compared with South Africa (P = 7 * 10(-82)), the protective effect of HLA-B*57/58:01 is absent (P = 0.0002), and population viral replicative capacity is lower (P = 0.03). These data suggest that viral evolution is occurring relatively rapidly, and that adaptation of HIV to the most protective HLA alleles may contribute to a lowering of viral replication capacity at the population level, and a consequent reduction in HIV virulence over time. The potential role in this process played by increasing antiretroviral therapy (ART) access is also explored. Models developed here suggest distinct benefits of ART, in addition to reducing HIV disease and transmission, in driving declines in HIV virulence over the course of the epidemic, thereby accelerating the effects of HLA-mediated viral adaptation. PMID- 25453110 TI - Communication between oocytes and somatic cells regulates volatile pheromone production in Caenorhabditis elegans. AB - Males of the androdioecious species Caenorhabditis elegans are more likely to attempt to mate with and successfully inseminate C. elegans hermaphrodites that do not concurrently harbor sperm. Although a small number of genes have been implicated in this effect, the mechanism by which it arises remains unknown. In the context of the battle of the sexes, it is also unknown whether this effect is to the benefit of the male, the hermaphrodite, or both. We report that successful contact between mature sperm and oocyte in the C. elegans gonad at the start of fertilization causes the oocyte to release a signal that is transmitted to somatic cells in its mother, with the ultimate effect of reducing her attractiveness to males. Changes in hermaphrodite attractiveness are tied to the production of a volatile pheromone, the first such pheromone described in C. elegans. PMID- 25453112 TI - The second demographic transition: a concise overview of its development. AB - This article gives a concise overview of the theoretical development of the concept of the "second demographic transition" since it was coined in 1986, its components, and its applicability, first to European populations and subsequently also to non-European societies as well. Both the demographic and the societal contrasts between the first demographic transition (FDT) and the second demographic transition (SDT) are highlighted. Then, the major criticisms of the SDT theory are outlined, and these issues are discussed in the light of the most recent developments in Europe, the United States, the Far East, and Latin America. It turns out that three major SDT patterns have developed and that these evolutions are contingent on much older systems of kinship and family organization. PMID- 25453111 TI - Evolution-guided optimization of biosynthetic pathways. AB - Engineering biosynthetic pathways for chemical production requires extensive optimization of the host cellular metabolic machinery. Because it is challenging to specify a priori an optimal design, metabolic engineers often need to construct and evaluate a large number of variants of the pathway. We report a general strategy that combines targeted genome-wide mutagenesis to generate pathway variants with evolution to enrich for rare high producers. We convert the intracellular presence of the target chemical into a fitness advantage for the cell by using a sensor domain responsive to the chemical to control a reporter gene necessary for survival under selective conditions. Because artificial selection tends to amplify unproductive cheaters, we devised a negative selection scheme to eliminate cheaters while preserving library diversity. This scheme allows us to perform multiple rounds of evolution (addressing ~10(9) cells per round) with minimal carryover of cheaters after each round. Based on candidate genes identified by flux balance analysis, we used targeted genome-wide mutagenesis to vary the expression of pathway genes involved in the production of naringenin and glucaric acid. Through up to four rounds of evolution, we increased production of naringenin and glucaric acid by 36- and 22-fold, respectively. Naringenin production (61 mg/L) from glucose was more than double the previous highest titer reported. Whole-genome sequencing of evolved strains revealed additional untargeted mutations that likely benefit production, suggesting new routes for optimization. PMID- 25453113 TI - The vacuolar-type H+-ATPase at a glance - more than a proton pump. AB - The vacuolar H(+)-ATPase (V-ATPase) has long been appreciated to function as an electrogenic H(+) pump. By altering the pH of intracellular compartments, the V ATPase dictates enzyme activity, governs the dissociation of ligands from receptors and promotes the coupled transport of substrates across membranes, a role often aided by the generation of a transmembrane electrical potential. In tissues where the V-ATPase is expressed at the plasma membrane, it can serve to acidify the extracellular microenvironment. More recently, however, the V-ATPase has been implicated in a bewildering variety of additional roles that seem independent of its ability to translocate H(+). These non-canonical functions, which include fusogenicity, cytoskeletal tethering and metabolic sensing, are described in this Cell Science at a Glance article and accompanying poster, together with a brief overview of the conventional functions of the V-ATPase. PMID- 25453115 TI - Distinct pathways of cholesterol biosynthesis impact on insulin secretion. AB - Results from previous investigations have indicated that glucose-stimulated insulin secretion (GSIS) is affected by changes in cholesterol and its intermediates, but the precise link between secretion and cholesterol has not been thoroughly investigated. In this study, we show the contribution of both protein isoprenylation and cholesterol-dependent plasma membrane structural integrity to insulin secretion in INS-1E cells and mouse islets. Acute (2 h) inhibition of hydroxyl-methylglutaryl-CoA reductase by simvastatin (SIM) resulted in inhibition of GSIS without reduction in total cellular cholesterol content. This effect was prevented by cell loading with the isoprenyl molecule geranylgeranyl pyrophosphate. Chronic (24 h) inhibition of cholesterol biosynthesis resulted in inhibition of GSIS with a significant reduction in total cellular cholesterol content, which was also observed after the inhibition of cholesterol biosynthesis downstream of isoprenoid formation. Electron paramagnetic resonance analyses of INS-1E cells showed that the SIM-induced reduction in cholesterol increased plasma membrane fluidity. Thus, the blockade of cholesterol biosynthesis resulted in the reduction of availability of isoprenoids, followed by a reduction in the total cholesterol content associated with an increase in plasma membrane fluidity. Herein, we show the different contributions of cholesterol biosynthesis to GSIS, and propose that isoprenoid molecules and cholesterol-dependent signaling are dual regulators of proper beta cell function. PMID- 25453114 TI - Nanoclustering as a dominant feature of plasma membrane organization. AB - Early studies have revealed that some mammalian plasma membrane proteins exist in small nanoclusters. The advent of super-resolution microscopy has corroborated and extended this picture, and led to the suggestion that many, if not most, membrane proteins are clustered at the plasma membrane at nanoscale lengths. In this Commentary, we present selected examples of glycosylphosphatidyl-anchored proteins, Ras family members and several immune receptors that provide evidence for nanoclustering. We advocate the view that nanoclustering is an important part of the hierarchical organization of proteins in the plasma membrane. According to this emerging picture, nanoclusters can be organized on the mesoscale to form microdomains that are capable of supporting cell adhesion, pathogen binding and immune cell-cell recognition amongst other functions. Yet, a number of outstanding issues concerning nanoclusters remain open, including the details of their molecular composition, biogenesis, size, stability, function and regulation. Notions about these details are put forth and suggestions are made about nanocluster function and why this general feature of protein nanoclustering appears to be so prevalent. PMID- 25453117 TI - Repositioning suture of the erector spinae muscle for lumbar spine surgery via the posterior approach: a prospective randomized study. AB - We prospectively studied the effectiveness of the repositioning suture of the erector spinae muscle for lumbar spine surgery using the posterior approach. 393 patients undergoing lumbar spine surgery were randomized to receive the repositioning or conventional suture of the erector spinae muscle. Time to stitch removal and drainage volume was recorded at 24 and 48 h after operation. Hemoglobin loss rate was determined at 48 h post operation and the rate of malunion (redness, swelling and effusion at stitch removal and would disruption after stitch removal) was recorded. Low back pain was evaluated using the visual analog scale (VAS) preoperatively and 6 and 12 months after operation. Time to stitch removal was comparable in lumbar spine surgery patients receiving the repositioning or conventional suture of the erector spinae muscle (P > 0.05). Compared with the conventional suture, the repositioning suture was associated with significantly reduced drainage volume both at 24 (P < 0.01) and 48 h after operation (P < 0.05). Hemoglobin loss rate at 48 h post operation was also markedly lower in lumbar spine surgery patients receiving the repositioning suture than in those receiving the conventional suture (P < 0.01 or 0.05). Furthermore, the malunion rate in lumbar spine surgery patients using the repositioning suture was markedly lower than that in the conventional group (P < 0.05 or 0.001). There was no difference in preoperative VAS scores in both the groups (P > 0.05). Compared with the conventional suture, the repositioning suture was associated with significantly reduced VAS scores both at 24 and 48 h after operation (P < 0.01 in both). The repositioning suture of the erector spinae muscle is superior to the conventional suture in posterior lumbar spine surgery with marked lessened pain and reduced drainage volume. PMID- 25453118 TI - Calibration of the normal cutoff values of systolic dyssynchrony of the left ventricular synchronicity in normal subjects using real-time 3-dimensional echocardiography and the effects of age and heart rate. AB - The normal data of left ventricular (LV) synchronicity by real-time 3-dimensional echocardiography (RT3DE) are lacking. We assessed the normal range/cutoff values of LV dyssynchrony parameters by RT3DE. For this purpose, RT3DE was performed in 130 healthy subjects, aged 53 +/- 12 years. Time to the point of minimal regional systolic volume (Tmsv) was measured from time-volume curves in each segment. Standard deviation (SD) and maximal difference (Dif) of Tmsv were calculated from 16 (6 basal/6 mid/4 apical), 12 (6 basal/6 mid), and 6 (basal) LV segments together with the corresponding parameters adjusted by R-R interval. The data show non-significant difference between Tmsv-16-SD (9.24 +/- 3.54 ms) and Tmsv-12 SD (8.80 +/- 3.82 ms); with a correlation between two by both unadjusted (ms; r = 0.87) and adjusted (%R-R; r = 0.84) methods (P < 0.001). Heart rate correlated negatively with Tmsv (r = -0.13 to -0.34, P < 0.05-0.001) but had no effect on parameters adjusted for %R-R. Age and gender did not affect any of these parameters. Inter-observer variability was 3.3-4.6 % for 16, 4.8-9.1 % for 12, and 14.4-19.7 % for 6 segments. Thus, RT3DE is a reliable technique for detecting LV systolic dyssynchrony whereas the heart rate, but not age and gender, affects Tmsv parameters. Dyssynchrony parameters by 16 or 12 segments are superior to 6 segments in yielding comprehensive information and lower variability. PMID- 25453116 TI - Metamorphopsia and letter recognition. AB - Acuity is the most commonly used measure of visual function, and reductions in acuity are associated with most eye diseases. Metamorphopsia--a perceived distortion of visual space--is another common symptom of visual impairment and is currently assessed qualitatively using Amsler (1953) charts. In order to quantify the impact of metamorphopsia on acuity, we measured the effect of physical spatial distortion on letter recognition. Following earlier work showing that letter recognition is tuned to specific spatial frequency (SF) channels, we hypothesized that the effect of distortion might depend on the spatial scale of visual distortion just as it depends on the spatial scale of masking noise. Six normally sighted observers completed a 26 alternate forced choice (AFC) Sloan letter identification task at five different viewing distances, and the letters underwent different levels of spatial distortion. Distortion was controlled using spatially band-pass filtered noise that spatially remapped pixel locations. Noise was varied over five spatial frequencies and five magnitudes. Performance was modeled with logistic regression and worsened linearly with increasing distortion magnitude and decreasing letter size. We found that retinal SF affects distortion at midrange frequencies and can be explained with the tuning of a basic contrast sensitivity function, while object-centered distortion SF follows a similar pattern of letter object recognition sensitivity and is tuned to approximately three cycles per letter (CPL). The interaction between letter size and distortion makes acuity an unreliable outcome for metamorphopsia assessment. PMID- 25453119 TI - Efficacy and safety of parecoxib/phloroglucinol combination therapy versus parecoxib monotherapy for acute renal colic: a randomized, double-blind clinical trial. AB - To investigate whether the addition of phloroglucinol to parecoxib could improve the efficacy in patients with acute renal colic. Patients of acute renal colic were randomly allocated to receive intravenous Parecoxib 40 mg plus placebo or Parecoxib 40 mg plus phloroglucinol 80 mg, respectively. Pain intensity was recorded using a visual analog scale (VAS) before drug administration and 5, 15, 30, 60, and 120 min after treatment start. The primary outcome was the mean pain intensity difference (PID) at each checkpoint and the effectiveness of drugs (>= 50 % decrease in VAS score at the end checkpoint). The need for rescue analgesics and the incidence of adverse effects were considered as secondary outcome of the study. Among 236 patients enrolled in the study, 119 patients received intravenous parecoxib plus placebo and 114 patients received intravenous parecoxib plus phloroglucinol, the remaining 3 patients given up treatment. Baseline demographics were similar between two groups. There are significant differences in the PID at 15 and 30 min between two groups (P15 min = 0.011, P30 min = 0.013). Rescue analgesics were required by 17 patients (14.3 %) receiving parecoxib, 7 patients (6.1 %) receiving parecoxib plus phloroglucinol (P = 0.041). There were no differences in PID at other checkpoints between two groups, as well as in the incidence of adverse events and the drug effectiveness. Parecoxib in combination with phloroglucinol for acute renal colic has a faster action, also reduces the demand of rescue analgesics. PMID- 25453120 TI - Rapidly progressive neurological deterioration without magnetic resonance imaging abnormalities: intravascular lymphoma. PMID- 25453121 TI - Living in a family with a child with attention deficit hyperactivity disorder: a phenomenographic study. AB - AIMS AND OBJECTIVES: To describe experiences of everyday life in families with a child with attention deficit hyperactivity disorder. BACKGROUND: Attention deficit hyperactivity disorder is a highly prevalent, clinically heterogeneous disorder characterised by behavioural symptoms of inattention, hyperactivity and impulsivity that creates impairments for the child and affects the family life. The impairments vary with age and context, and the same symptoms do not necessarily have the same effects in different contexts and persons. DESIGN: A qualitative design with a phenomenographic approach. METHODS: Family members, mothers, fathers, siblings and children with attention deficit hyperactivity disorder (n = 17) were interviewed individually. RESULTS: The findings include two descriptive categories 'safeguarding a functioning family' and 'fighting for acceptance and inclusion'. To create a stable and structured family life to avoid conflicts within the family and manage their daily life were crucial. The child with attention deficit hyperactivity disorder and their parents developed special skills and strategies to live with attention deficit hyperactivity disorder in the family sphere and the social context. To apply for help before the problems in the family become too severe and to share responsibility with professionals, who have competence, to meet the families in their worries were stressed. The striving in the family strengthened the companionship in the families, and they conceived growth. CONCLUSIONS: This study contributes to knowledge of the parents, siblings and children with attention deficit hyperactivity disorder experiences of everyday life with a child with attention deficit hyperactivity disorder. All family members need support before their problems become too severe. RELEVANCE TO CLINICAL PRACTICE: There is a need of family-focused approach with a dialogue with family members to share the view of their situation and identify their individual resources and needs. Nurses should help these families with family supervision. PMID- 25453122 TI - Tensions of difference: reconciling organisational imperatives for risk management with consumer-focused care from the perspectives of clinicians and managers. AB - AIMS AND OBJECTIVES: To understand the impact of risk management and assessment on the delivery of mental health care from the perspectives of managers and clinicians. BACKGROUND: The concept of risk is now embedded in contemporary mental health services. A focus on risk has been identified as a barrier to the provision of consumer-focused care; however, there is a paucity of research in this area, particularly being drawn from key stakeholders in the field. DESIGN: Qualitative exploratory methods. METHODS: In-depth interviews were conducted with managers and clinicians from a large metropolitan aged-care mental health service in Australia. The participants represented a range of disciplines and expertise across practice settings (community, inpatient and residential). RESULTS: The theme tensions of difference emerged from this research. This theme referred to the tensions between accountability and attending to risk issues and consumer centred care, with concerns being raised that procedural and bureaucratic accountability influence (often negatively) the provision of care. Differences in the perspectives of clinicians and managers were also evident in the perceived contribution of evidence-based practice in relation to risk. CONCLUSIONS: Prioritising risk management may be interfering with the capacity of clinicians and managers to provide quality and consumer-focused mental health care. RELEVANCE TO CLINICAL PRACTICE: A deeper examination and reconceptualisation of the role and importance of risk in mental health care are needed to ensure the focus of service delivery remains consumer-focused. PMID- 25453123 TI - Intensive care nurses' experiences of providing end-of-life care after treatment withdrawal: a qualitative study. AB - AIMS AND OBJECTIVES: To explore the experiences of intensive care nurses who provided end-of-life care to adult patients and their families after a decision had been taken to withdraw treatment. BACKGROUND: End-of-life care following treatment withdrawal is a common phenomenon in intensive care. Less is known about nurses' experiences of providing care for the dying patient and their family in this context, when compared to specialist palliative care. DESIGN: Descriptive exploratory qualitative study. METHODS: A purposive sample of 13 intensive care nurses participated in a semistructured face-to-face interview. Transcribed data were analysed using the principles of interpretative phenomenological analysis. RESULTS: The essence of nurses' experiences of providing end-of-life care after the withdrawal of treatment was interpreted as 'doing the best to facilitate a comfortable and dignified death'. Four master themes included the following: caring for the dying patient and their family; providing and encouraging presence; reconnecting the patient and family; and dealing with emotions and ambiguity. Uncertainties were evident on processes and actions involved in treatment withdrawal, how to reconnect patients and their family effectively and how to reduce the technological environment. CONCLUSIONS: Providing end-of-life care after a decision has been taken to withdraw treatment was a common aspect of intensive care. It was evident that nurses were doing their utmost to support patients and families at the end of life, despite the multiple challenges they faced. RELEVANCE TO CLINICAL PRACTICE: The interpretive findings from this study should assist intensive care unit nurses to better understand and develop their role in providing high-quality end-of-life care after treatment withdrawal. Practice guidelines should be developed to reduce ambiguity and support the delivery of high-quality care for adults as they approach the final stages of life in intensive care units. PMID- 25453124 TI - How do Australian palliative care nurses address existential and spiritual concerns? Facilitators, barriers and strategies. AB - AIMS AND OBJECTIVES: To investigate the facilitators, barriers and strategies that Australian palliative care nurses identify in providing existential and spiritual care for patients with life-limiting illnesses. BACKGROUND: Palliative care aims to be holistic, incorporating all domains of personhood, but spiritual/existential domain issues are often undertreated. Lack of time and skills and concerns for what you may uncover hamper care provision. DESIGN: A qualitative study through semistructured interviews. METHODS: We interviewed 20 palliative care nurses from a cross section of area of work, place of work, years of experience, spiritual beliefs and importance of those beliefs within their lives. Questions focused on their current practices of existential and spiritual care, identification of facilitators of, barriers to and strategies for provision of that care. Their responses were transcribed and subjected to thematic analysis. RESULTS: The nurses' interviews yielded several themes including development of the nurse-patient relationship (14/20 nurses), good communication skills and examples of questions they use to 'create openings' to facilitate care. Barriers were identified as follows: lack of time (11/20 nurses), skills, privacy and fear of what you may uncover, unresolved symptoms and differences in culture or belief. Novel to our study, the nurses offered strategies that included the following: undertaking further education in this area, being self aware and ensuring the setting is conducive to in-depth conversations and interactions and documentation and/or interdisciplinary sharing for continuity of care. CONCLUSION: Palliative care nurses are well placed to provide existential and spiritual care to patients with the primary facilitator being the nurse patient relationship, the primary barrier being lack of time and the primary strategy being undertaking further education in this area. RELEVANCE TO CLINICAL PRACTICE: These findings could be used for nurse-support programmes, undergraduate or graduate studies or communication workshop for nurses. PMID- 25453125 TI - Living longer at home: a qualitative study of older clients' and practical nurses' perceptions of home care. AB - AIMS AND OBJECTIVES: To identify descriptions of older (75+) home care clients and practical nurses regarding the current structure of home care available for older clients and the elements promoting the ability of clients to continue living at home. BACKGROUND: The ageing population is a major global challenge in social and health care. In many countries, the focus of care for older clients has shifted from institutional care towards a model of home care. Increasing attention has been paid to maximising the resources of older clients and aiming to support their living at home for as long as possible. DESIGN: A descriptive qualitative study METHODS: Data were collected from individual interviews by using videotaped home care visits as a tool for stimulated recall interviews. Two groups of participants were interviewed: 14 practical nurses and 23 older clients. Data were analysed by using the inductive content analysis. RESULTS: Both participant groups, practical nurses and older home care clients, described home care as organisationally driven, but highlighted the importance of individual encounters. In addition, both groups noted that clients' living at home can be supported by offering individually designed care. Individually designed care refers to showing respect to clients' opinions and promoting their individual resources. CONCLUSION: In order to be able to promote older home clients' living at home, the provided home care needs to be individually designed and must take into account clients' resources and their perspectives of meaningful and inspirational activities. RELEVANCE TO CLINICAL PRACTICE: The information produced by this study can be used to promote older clients' living at home for as long as possible. Therefore, practical nurses are required the ability to recognise older clients' individual resources and design individual care plans accordingly. PMID- 25453126 TI - Perspectives of patients with acute abdominal pain in an emergency department observation unit and a surgical assessment unit: a prospective comparative study. AB - AIMS AND OBJECTIVES: To investigate the patient perspective when admitted with acute abdominal pain to an emergency department observation unit compared with the perspective when admitted to a surgical assessment unit. BACKGROUND: An increase in emergency department observation units has led to more short-term admissions and has changed the patient journey from admission to specialised wards staffed by specialist nurses to stays in units staffed by emergency nurses. DESIGN: A comparative field study. METHODS: The study included 21 patients. Participant observation and qualitative interviews were performed, and the analyses were phenomenological-hermeneutic. RESULTS: Emergency department observation unit patients had extensive interaction with health professionals, which could create distrust. Surgical assessment unit patients experienced lack of interaction with nurses, also creating distrust. Emergency department observation unit patients had more encounters with fellow patients than the surgical assessment unit patients did, which was beneficial when needing assistance, but disturbing when needing rest. The limited contact with other patients in the surgical assessment unit revealed the opposite effect. In both units, there was nonpersonalised care, making it difficult for patients to make informed decisions. CONCLUSION: The multibedded rooms in the emergency department observation unit had a positive influence on patient-nurse interaction, but a negative influence on privacy; the opposite was found in the surgical assessment unit with its rooms with fewer beds. The extensive professional-patient interactions in the emergency department observation unit created distrust. The limited professional-patient interaction in the surgical assessment unit did the same. That the emergency department observation unit was staffed by emergency nurses seemed to have a positive influence on the length of patient-nurse interactions, while the surgical assessment unit staffed by specialist nurses seemed to have the opposite effect. There was lack of information and personalised care in both units. RELEVANCE TO CLINICAL PRACTICE: Units receiving acute patients need to provide personalised care and information about how the unit functions and about care and treatment to improve the patients' ability to make decisions during admission. PMID- 25453127 TI - Psychosocial profiles of children with achondroplasia in terms of their short stature-related stress: a nationwide survey in Japan. AB - AIMS AND OBJECTIVES: To assess psychosocial profiles of children with achondroplasia using a nationwide survey. BACKGROUND: Achondroplasia, showing short stature and disproportionately short limbs, causes physical inconvenience such as difficulty in reaching high objects. It is, however, still controversial whether the condition is associated with psychological problems, especially in childhood. DESIGN: A cross-sectional descriptive design was employed. METHODS: To evaluate psychosocial profiles and adaptation processes in children with achondroplasia, we developed an inventory of scales based on the psychological stress model of which conceptual framework was comprised of stressor, coping process, coping resource and adaptation outcome domains. Participants were recruited nationwide through the largest advocacy support group for achondroplasia in Japan. Of the 130 group members, 73 X-ray-diagnosed patients, aged 8-18 years, completed the inventory of questionnaires to be analysed. RESULTS: As for the stressor domain, patients experienced short stature-related unpleasant experiences more frequently (z-score: +1.3 in average, +3.9 in physical inconvenience). Nevertheless, these experiences had little effect on the coping process (threat appraisal: -0.2, control appraisal: +0.1) and the adaptation outcome (stress response: +0.3, self-concept: 0.0). Interestingly, self-efficacy in the coping resource domain was noticeably increased (+3.1) and was strongly correlated with most variables in the coping process and in adaptation outcome domains. CONCLUSIONS: Although the children with achondroplasia experienced more short stature-related stressors, there was no evidence of any psychosocial maladaptation. This finding suggests that coping process as well as coping resources such as self-efficacy could be important targets for promoting psychological adjustment in children with achondroplasia. RELEVANCE TO CLINICAL PRACTICE: To help children with achondroplasia adapt socially, nurses and other healthcare providers should routinely assess their psychological adaptation process, especially cognitive appraisal and self efficacy. PMID- 25453128 TI - [Monitoring liver function]. PMID- 25453129 TI - An interview with Dr Buddy Wong. PMID- 25453130 TI - Gold grain implantation gun: Royal Marsden Hospital. PMID- 25453131 TI - Magical mystery tour: MLO proteins in plant immunity and beyond. AB - Stable heritable restriction of the ubiquitous powdery mildew disease is a desirable trait for agri and horticulture. In barley (Hordeum vulgare), loss-of function mutant alleles of the Mildew resistance locus o (Mlo) gene confer broad spectrum resistance to almost all known isolates of the fungal barley powdery mildew pathogen, Blumeria graminis f.sp. hordei. Despite extensive cultivation of barley mlo genotypes, mlo resistance has been durable in the field. Mlo genes are present as small families in the genomes of all higher plant species. The presumed negative regulatory role of particular members in plant immunity is evolutionarily conserved, as powdery mildew resistant mlo mutants have also been described in Arabidopsis thaliana, tomato(Solanum lycopersicum) and pea (Pisum sativum). Barley Mlo encodes a plasma membrane-localized seven-transmembrane domain protein of unknown biochemical activity. Here, we review the known requirements for mlo-mediated disease resistance in barley and Arabidopsis and reflect current views regarding Mlo function. We discuss additional mlo mutant phenotypes recently discovered in Arabidopsis and present a meta-analysis of the phylogenetic relationships within the Mlo family. Finally, we consider the novel versatile tools for functional analysis and targeted genome modification that can be used to induce mlo-based powdery mildew resistance in virtually any plant species. PMID- 25453132 TI - The squeeze cell hypothesis for the activation of jasmonate synthesis in response to wounding. AB - Jasmonates are lipid mediators that control defence gene expression in response to wounding and other environmental stresses. These small molecules can accumulate at distances up to several cm from sites of damage and this is likely to involve cell-to-cell jasmonate transport.Also, and independently of jasmonate synthesis, transport and perception, different long distance wound signals that stimulate distal jasmonate synthesis are propagated at apparent speeds of several cm min-1 to tissues distal to wounds in a mechanism that involves clade 3 GLUTAMATE RECEPTOR-LIKE (GLR) genes. A search for jasmonate synthesis enzymes that might decode these signals revealed LOX6, a lipoxygenase that is necessary for much of the rapid accumulation of jasmonic acid at sites distal to wounds. Intriguingly, the LOX6 promoter is expressed in a distinct niche of cells that are adjacent to mature xylem vessels,a location that would make these contact cells sensitive to the release of xylem water column tension upon wounding. We propose a model in which rapid axial changes in xylem hydrostatic pressure caused by wounding travel through the vasculature and lead to slower,radially dispersed pressure changes that act in a clade 3 GLR-dependent mechanism to promote distal jasmonate synthesis. PMID- 25453133 TI - Lipochitooligosaccharide recognition: an ancient story. AB - Chitin is the second most abundant polysaccharide in nature, found in crustacean shells, insect exoskeletons and fungal cell walls. The action of chitin and chitin derivatives on plants has become a very interesting story of late. Chitin is a b1-4-linked polymer of N-acetyl-Dglucosamine(GlcNAc). In this unmodified form, chitooligosaccharides (degree of polymerization(dp) = 6-8)) are strong inducers of plant innate immunity. By contrast, when these chitooligosaccharides are acylated (so-called lipochitooligosaccharides, LCOs) and further modified, they can act as Nod factors, the key signaling molecules that play an important role in the initiation of the legume-rhizobium symbiosis. In a similar form, these molecules can also act as Myc factors, the key signaling molecules involved in the arbuscular mycorrhizal (AM)symbiosis. It has been proposed that Nod factor perception might have evolved from the more ancient AM symbiosis. Increasing evidence now suggests that LCO perception might have evolved from plant innate immunity signaling. In this review, we will discuss the evolutionary origin of symbiotic LCO recognition. PMID- 25453137 TI - Ascending inguinal pseudohernia secondary to a giant epididymal cyst: ultrasonographic diagnosis. PMID- 25453136 TI - Diversity: Structural approach. PMID- 25453135 TI - Pegylated interferon alpha-2a plus ribavirin for decompensated hepatitis C virus related cirrhosis: relationship between efficacy and cumulative dose. AB - BACKGROUND & AIMS: A combination of pegylated interferon alpha-2a (Peg-IFNalpha 2a) and ribavirin (RBV) achieves a sustained virological response (SVR) in 40-50% of patients infected with genotype 1 hepatitis C virus (HCV), but efficacy rates are significantly lower in patients with decompensated HCV-induced cirrhosis. The efficacy and tolerability of Peg-IFNalpha-2a and RBV, the cumulative dose effect, time to achieve planned cumulative dose and role of HCV phenotype on treatment response were determined in patients with decompensated HCV-induced cirrhosis. METHODS: In this case-controlled study, 257 patients with decompensated HCV induced cirrhosis were enrolled, including patients treated with partial splenic embolization for leukopaenia. Of patients with sufficient blood cell counts, 130 patients opted for antiviral therapy (treatment group) consisting of 180 MUg/kg Peg-IFNalpha-2a for 48 weeks with 800-1200 mg/day RBV; the remaining 127 were considered the control group. Primary endpoints were SVR and absence of relapse; the secondary end point was assessment of disease progression. RESULTS: Sustained virological response was highest and relapse rates were lowest when cumulative doses of Peg-IFNalpha-2a and RBV were both >=80% of the prescribed dose. Patients achieving >=80% of the planned cumulative doses in 48 weeks had a significantly higher SVR compared with patients achieving this in 72 weeks. Patients with HCV genotype 1 had significantly lower SVR compared with patients with HCV genotype 2 (19.7% vs. 42.9%, respectively; P = 0.008). Treatment group patients had a significantly lower rate of SVR-independent liver disease-related mortality. CONCLUSIONS: Our findings provide additional evidence to support the use of Peg IFNalpha-2a and RBV therapy for decompensated HCV-induced cirrhosis. PMID- 25453134 TI - Fibrosis progression in maintenance liver transplant patients with hepatitis C recurrence: a randomised study of everolimus vs. calcineurin inhibitors. AB - BACKGROUND & AIMS: Robust clinical data evaluating fibrosis progression in hepatitis C virus (HCV) liver transplant patients receiving an mTOR inhibitor vs. calcineurin inhibitor (CNI) are lacking. To evaluate fibrosis progression in maintenance liver transplant patients receiving everolimus- or CNI-based immunosuppression. METHODS: In a randomised, multicentre, open-label study, 43 maintenance liver transplant patients with recurrent HCV infection were randomised to continue CNI-based immunosuppression or switch to everolimus. RESULTS: For patients with biopsy data at month 12, mean Ishak-Knodell fibrosis score at baseline was 2.6 +/- 0.9 (n = 14) with everolimus vs. 1.9 +/- 1.1 (n = 18) with CNI (P = 0.043), and 1.9 +/- 1.2 vs. 2.2 +/- 1.3 at month 12. Ishak Knodell fibrosis score decreased from baseline to month 12 by a mean of -0.7 +/- 1.1 with everolimus, but increased by 0.2 +/- 1.2 with CNI (P = 0.046). No acute rejection or graft losses occurred up to month 12. Estimated GFR at month 12 was 65.6 ml/min/1.73 m2 with everolimus and 62.2 ml/min/1.73 m2 with CNI [mean difference 3.4 ml/min/1.73 m2 compared to CNI control group, 95% CI -4.9, 11.8 ml/min/1.73 m2, P = 0.411 (analysis of covariance adjusting for baseline GFR)]. Adverse events occurred in 95.5% of everolimus patients and 71.4% of CNI patients (serious adverse events 31.8% and 0.0%, respectively). Adverse events led to everolimus discontinuation in five patients (22.7%). CONCLUSIONS: This exploratory study suggests that conversion from CNI to everolimus reduces progression of liver fibrosis, and preserves renal function without jeopardising efficacy in liver transplant recipients with recurrent HCV, but is associated with a higher incidence of adverse events and serious adverse events. These preliminary findings merit examination in a larger trial. PMID- 25453138 TI - [In Process Citation]. PMID- 25453139 TI - [70th anniversary]. PMID- 25453140 TI - In memoriam Professor Louis Gerald Keith, 1935-2014. PMID- 25453141 TI - Preface. PMID- 25453143 TI - [Not Available]. PMID- 25453142 TI - Plant and algal cell walls: diversity and functionality. AB - BACKGROUND: Although plants and many algae (e.g. the Phaeophyceae, brown, and Rhodophyceae, red) are only very distantly related they are united in their possession of carbohydrate-rich cell walls, which are of integral importance being involved in many physiological processes. Furthermore,wall components have applications within food, fuel, pharmaceuticals, fibres (e.g. for textiles and paper) and building materials and have long been an active topic of research. As shown in the 27 papers in this Special Issue, as the major deposit of photosynthetically fixed carbon, and therefore energy investment, cell walls are of undisputed importance to the organisms that possess them, the photosynthetic eukaryotes ( plants and algae). The complexities of cell wall components along with their interactions with the biotic and abiotic environment are becoming increasingly revealed. SCOPE: The importance of plant and algal cell walls and their individual components to the function and survival of the organism, and for a number of industrial applications, are illustrated by the breadth of topics covered in this issue, which includes papers concentrating on various plants and algae, developmental stages, organs, cell wall components, and techniques. Although we acknowledge that there are many alternative ways in which the papers could be categorized (and many would fit within several topics), we have organized them as follows: (1) cell wall biosynthesis and remodelling, (2) cell wall diversity, and (3) application of new technologies to cell walls. Finally, we will consider future directions within plant cell wall research. Expansion of the industrial uses of cell walls and potentially novel uses of cell wall components are both avenues likely to direct future research activities. Fundamentally, it is the continued progression from characterization (structure, metabolism, properties and localization) of individual cell wall components through to defining their roles in almost every aspect of plant and algal physiology that will present many of the major challenges in future cell wall research. PMID- 25453144 TI - [Not Available]. PMID- 25453145 TI - [Not Available]. PMID- 25453146 TI - [Not Available]. PMID- 25453147 TI - [Not Available]. PMID- 25453148 TI - [Not Available]. PMID- 25453149 TI - [Use of a pessary in Haiti. A simple method to prevent premature birth?]. PMID- 25453150 TI - [The Bluebirds during World War I]. PMID- 25453151 TI - You have the power to say no to unsafe workloads. PMID- 25453152 TI - New aged care funding arrangements. PMID- 25453153 TI - Newman government tells nurses and midwives to be happy with real-terms pay decrease. PMID- 25453154 TI - Pulse Health nurses secure much improved offer. . PMID- 25453155 TI - Your entitlement toolkit. PMID- 25453156 TI - Is it time to have a further look at breaks between shifts? PMID- 25453157 TI - 94% of nurses and midwives report unsafe workloads in private sector. PMID- 25453158 TI - It's time to end the targeting of Aboriginal women. PMID- 25453159 TI - QNU nurse named state's top dad. PMID- 25453164 TI - Disseminated sclerotic bone lesions with normal (18)F-fluorodeoxyglucose uptake in polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes syndrome. PMID- 25453166 TI - Smoking automaticity and tolerance moderate brain activation during explore exploit behavior. AB - The adaptive trade-off between exploration and exploitation is a key component in models of reinforcement learning. Over the past decade, these models have been applied to the study of reward-seeking behavior. Drugs of addiction induce reward seeking behavior and modify its underlying neurophysiological processes. These neurophysiological changes may underlie a behavioral shift from a flexible, exploratory mode to a focused, exploitative mode, which precedes the development of inflexible, habitual drug use. The goal of this study was to investigate the relationship between explore/exploit behavior and drug addiction by examining the neural correlates of this behavior in cigarette smokers. Participants (n=22) with a range of smoking behaviors completed a smoking dependence motives questionnaire and played a 6-armed bandit task while undergoing functional magnetic resonance imaging (fMRI). Exploratory behavior produced greater activation in the bilateral superior parietal and bilateral frontal cortices than exploitative behavior. Exploitative behavior produced greater activation in the bilateral superior and middle temporal gyri than exploratory behavior. fMRI data and orthogonalized smoking dependence motive scores were entered into multiple linear regression analyses. After controlling for nicotine tolerance, smoking automaticity positively correlated with activation in the same bilateral parietal regions preferentially activated by exploratory choices. These preliminary results link smoking dependence motives to variation in the neural processes that mediate exploratory decision making. PMID- 25453167 TI - Executive-affective connectivity in smokers viewing anti-smoking images: an fMRI study. AB - Despite knowledge of the harmful consequences of smoking on health, tobacco users continue to smoke. Neuroimaging studies have begun to provide insight into the mechanisms underlying this response. Regions involved in executive control and affective processing/persuasion are activated when viewing the negative value of smoking, but these systems can interact in ways that promote or hinder its impact on behavior. The goal of this functional magnetic resonance imaging (fMRI) study was to examine the dynamics between these systems during the processing of images designed to elicit a negative emotional response regarding tobacco smoking in a group of current smokers. Thirty chronic smokers passively viewed aversive smoking-related, aversive nonsmoking-related and neutral images presented in a block design while being scanned. Functional connectivity analyses showed that the left inferior frontal gyrus (IFG) is negatively associated to activity in medial frontal, cingulate, limbic, subcortical and parietal regions in chronic smokers during the processing of aversive smoking-related material, a pattern that was significantly greater when stimuli were drug-related compared with when they were nondrug-related. Our results suggest that individuals with tobacco dependence present different patterns of functional connectivity depending on whether the aversive stimuli are smoking- or nonsmoking-related. Activity in the left inferior frontal gyrus may act to down-regulate corresponding activity in regions key to an affective and persuasive response during the processing of anti smoking material. This mechanism may reduce the extent to which "feeling bad" brings about a change in behavior. PMID- 25453168 TI - Transcatheter closure of atrial septal defect with the Figulla((r)) ASD Occluder: a comparative study with the Amplatzer((r)) Septal Occluder. AB - BACKGROUND: Single-centre experience in transcatheter closure of atrial septal defect (ASD) using the Figulla((r)) ASD Occluder (FSO; Occlutech GmbH, Jena, Germany) and the Amplatzer((r)) Septal Occluder (ASO; Saint-Jude Medical, Zaventem, Belgium) has been reported. AIM: To perform a retrospective comparison of the two occluders. METHODS: From September 2009 to December 2012, 131 consecutive patients underwent percutaneous ASD occlusion: One hundred with the ASO device; 31 with the FSO device. RESULTS: There were no significant differences between the two groups regarding patient characteristics, stretched diameter, age and device size. In the ASO group, implantation succeeded in all but two patients because of deficient rim. Another patient had device embolization in the aorta retrieved percutaneously. During follow-up, 86 patients had no residual shunt and nine patients had a residual shunt (small in seven; moderate in two). Two other patients had persistent interatrial small shunt caused by an adjacent ASD close to the device. In the FSO group, implantation succeeded in all but two patients: one because of deficient posterior rim; and one because of complete atrioventricular block that resolved after device extraction. During follow-up, no shunt was observed in all but one patient. At late follow-up (up to 36months), full occlusion was observed in 88 (88.0%) patients in the ASO group and 28 (90.3%) patients in the FSO group (with no significant difference between groups). CONCLUSION: Transcatheter closure of ASD with the FSO is feasible and safe. FSO results compare favorably with ASO results. However, additional long-term studies that include more patients are mandatory. PMID- 25453165 TI - Subsequent memory effects in schizophrenia. AB - Differential neural activation at encoding can predict which stimuli will be subsequently remembered or forgotten, and memory deficits are pronounced in schizophrenia. We used event-related functional magnetic resonance imaging (fMRI) to investigate subsequent memory (SM) effects for visual fractals in patients with schizophrenia (n=26) and healthy controls (n=28). Participants incidentally encoded the fractals during an oddball task and 10 min later they made old/new recognition memory judgments on 30 target fractals and 30 foil fractals. We found evidence for subsequent memory (SM, subsequently remembered>subsequently forgotten) effects on regional brain activation in both groups but with distinct patterns. Region of interest (ROI) analyses in controls demonstrated SM activation in both medial temporal lobe (MTL) and fusiform cortex (FF), whereas patients showed SM effects only in the FF. There were no significant between group differences in MTL activation; however, patients demonstrated greater FF activation than controls. Notably, greater FF activation during successful encoding was associated with more severe negative symptoms. Exploratory whole brain analyses in patients demonstrated SM activation in the occipital pole, lateral occipital cortex, left inferior temporal gyrus, and fusiform cortex; whereas in controls there was no significant activation that survived correction for multiple comparisons. Our findings suggest that patients, particularly those with prominent negative symptoms, may activate FF as a compensatory strategy to promote successful encoding, with relatively less reliance on MTL recruitment. PMID- 25453169 TI - Revealing fibrinogen monolayer conformations at different pHs: electrokinetic and colloid deposition studies. AB - Adsorption mechanism of human fibrinogen on mica at different pHs is studied using the streaming potential and colloid deposition measurements. The fibrinogen monolayers are produced by a controlled adsorption under diffusion transport at pH of 3.5 and 7.4. Initially, the electrokinetic properties of these monolayers and their stability for various ionic strength are determined. It is shown that at pH 3.5 fibrinogen adsorbs irreversibly on mica for ionic strength range of 4*10(-4) to 0.15 M. At pH 7.4, a partial desorption is observed for ionic strength below 10(-2) M. This is attributed to the desorption of the end-on oriented molecules whereas the side-on adsorbed molecules remain irreversibly bound at all ionic strengths. The orientation of molecules and monolayer structure is evaluated by the colloid deposition measurements involving negatively charged polystyrene latex microspheres, 820 nm in diameter. An anomalous deposition of negative latex particles on substrates exhibiting a negative zeta potential is observed. At pH 3.5 measurable deposition of latex is observed even at low ionic strength where the approach distance of latex particles exceeded 70 nm. At pH 7.4 this critical distance is 23 nm. This confirms that fibrinogen monolayers formed at both pHs are characterized by the presence of the side-on and end-on oriented molecules that prevail at higher coverage range. It is also shown that positive charge is located at the end parts of the alphaA chains of the adsorbed fibrinogen molecules. Therefore, it is concluded that the colloid deposition method is an efficient tool for revealing protein adsorption mechanisms at solid/electrolyte interfaces. PMID- 25453170 TI - Powered two-wheeler drivers' risk of hitting a pedestrian in towns. AB - INTRODUCTION: The risk of collision between pedestrians and powered two-wheelers is poorly understood today. The objective of this research is to determine the risk for powered two-wheeler drivers of hitting and injuring a pedestrian per kilometer driven in towns and to compare this risk with that run by four-wheeled vehicle drivers. METHOD: Using the bodily injury accidents recorded by the police on nine roads in the city of Marseille in 2011 and a campaign of observations of powered two-wheeler traffic, we estimated the risk per kilometer driven by powered two-wheeler drivers of hitting a pedestrian and compared it with the risk run by four-wheeled vehicle drivers. RESULTS: The results show that the risk for powered two-wheeler drivers of hitting and injuring a pedestrian is significantly higher than the risk run by four-wheeled vehicle drivers. On the nine roads studied, it is on average 3.33 times higher (95% CI: 1.63; 6.78). Taking four more years into account made it possible to consolidate these results and to tighten the confidence interval. CONCLUSION: There does indeed seem to be problems in the interactions between pedestrians and powered two-wheeler users in urban traffic. These interaction problems lead to a higher risk of hitting and injuring a pedestrian for powered two-wheeler drivers than for four-wheeled vehicle drivers. The analysis of the police reports suggests that part of this increased risk comes from filtering maneuvers by powered two-wheelers. PRACTICAL APPLICATIONS: Possible countermeasures deal with the urban street layout. Measures consisting in reducing the width and the number of traffic lanes to a strict minimum and installing medians or pedestrian islands could be an effective way for the prevention of urban accidents between pedestrians and powered two wheelers. PMID- 25453171 TI - Pedestrian injuries due to collisions with bicycles in New York and California. AB - INTRODUCTION: Scant attention has been given to pedestrians injured in accidents resulting from collisions with cyclists. This scholarly neglect is surprising given the growing popularity of cycling. This study examines the incidence of pedestrians injured by cyclists in New York between 2004 to 2011 and in California from 2005 to 2011. The study also profiles the pedestrians injured in these two states during these two time frames. METHOD: The data for this study are based upon patient-level hospital records from New York and California. The data for New York comes from the Statewide Planning and Research Cooperative System (SPARCS) under the auspices of New York State's Department of Health. The data for California come from two sources: the Healthcare Cost and Utilization Project (HCUP) and the California Office of Statewide Health Planning and Development. RESULTS: The rate of pedestrians injured in collisions with cyclists has decreased over time. This decline has occurred despite the increase in the number of cyclists in these states during this same time period. Two possible explanations for this decline are: (a) less exposure of children to cyclists, and (b) improvements in the cycling infrastructure. PRACTICAL APPLICATIONS: Although the rate of injuries to pedestrians from collisions with cyclists has been decreasing, improvements to the cycling infrastructure will need to continue. Bike lanes, particularly protected bike lanes, have been shown to be an effective way of reducing cycling-pedestrian accidents. The results of the current study are consistent with this research. Educational campaigns aimed at cyclists that emphasize the safety of all road users--including pedestrians--will also need to continue to assure that this downward trend in the number of accidents is not reversed. PMID- 25453172 TI - The effect of the Swedish bicycle helmet law for children: an interrupted time series study. AB - BACKGROUND: Previous population-based research has shown that bicycle helmet laws can reduce head injury rates among cyclists. According to deterrence theory, such laws are mainly effective if there is a high likelihood of being apprehended. In this study, we investigated the effect of the Swedish helmet law for children under the age of 15, a population that cannot be fined. METHOD: An interrupted time series design was used. Monthly inpatient data on injured cyclists from 1998 2012, stratified by age (0-14, 15+), sex, and injury diagnosis, was obtained from the National Patient Register. The main outcome measure was the proportion of head injury admissions per month. Intervention effect estimates were obtained using generalized autoregressive moving average (GARMA) models. Pre-legislation trend and seasonality was adjusted for, and differences-in-differences estimation was obtained using adults as a non-equivalent control group. RESULTS: There was a statistically significant intervention effect among male children, where the proportion of head injuries dropped by 7.8 percentage points. There was no evidence of an intervention effect on the proportion of head injuries among female children. CONCLUSION: According to hospital admission data, the bicycle helmet law appears to have had an effect only on male children. PRACTICAL APPLICATIONS: This study, while quasi-experimental and thus not strictly generalizable, can contribute to increased knowledge regarding the effects of bicycle helmet laws. PMID- 25453173 TI - The impact of aggressive driving-related injuries in Ohio, 2004-2009. AB - OBJECTIVE: This study describes the medical and financial impact (hospital charges) of aggressive driving-related injuries in Ohio. METHODS: Statewide crash and hospital databases were probabilistically linked for 2004 through 2009. Descriptive analyses and multivariate regression modeling of multiply-imputed data on motor vehicle occupants involved in aggressive driving-related crashes were performed. RESULTS: There were 821,136 motor vehicle occupants involved in aggressive driving-related crashes in Ohio from 2004 through 2009; injuries were sustained by 15.0%. The rate of aggressive driving-related crashes was highest among drivers ages 16 to 19 years (3787.1 crashes per 100,000 licensed drivers). Aggressive driving-related inpatients accrued more than $250.8 million in hospital charges and 28,366 inpatient days of treatment in 2004 through 2009. Occupants ages 16 to 19 years had higher odds of sustaining injury when involved in aggressive driving-related crashes (OR = 1.10; 95% CI = 1.07, 1.12; p < 0.001), but lower odds of death, inpatient admission, ISS >= 16, and rehabilitation. DISCUSSION: Aggressive driving-related injuries have a substantial medical and financial impact in Ohio. PRACTICAL APPLICATIONS: Compared with other highway safety issues, prevention efforts aimed specifically at aggressive driving are lacking. Targeted enforcement and public awareness campaigns are needed. PMID- 25453174 TI - A speed limit compliance model for dynamic speed display sign. AB - INTRODUCTION: Violating speed limits is a major cause of motor vehicle crashes. Various techniques have been adopted to ensure that posted speed limits are obeyed by drivers. This study investigates the effect of dynamic speed display signs (DSDSs) on drivers' compliance with posted speed limit. METHOD: An extensive speed data collection upstream of, adjacent to, and downstream of DSDS locations on multiple road classes with different speed limits (25, 35, and 45 mph) was performed short-term and long-term after DSDS installation. Conventional statistical analysis, regression models, and a Bayesian network were developed to assess the DSDS's effectiveness. RESULTS' CONCLUSIONS: General compliance with speed limit (upstream of the DSDS location), time of day, day of week, duration of DSDS operation, and distance from the DSDS location were significantly correlated with speed limit compliance adjacent to the DSDS. While compliance with the speed limit due to the DSDS increased by 5%, speed reduction occurred in 40% of the cases. PRACTICAL APPLICATIONS: Since drivers were likely to increase their speed after passing the DSDS, it should be installed on critical points supplemented with enforcement. PMID- 25453175 TI - Motor vehicle driver injury severity study under various traffic control at highway-rail grade crossings in the United States. AB - INTRODUCTION: Based on the Federal Railway Administration (FRA) database, approximately 62% of the collisions at highway-rail crossings occurred at locations with active controls (gate and flashing lights), followed by passive controls (cross bucks and stop signs) with approximately 28% of accidents. METHOD: The study applied an ordered probit model to explore the determinants of driver injury severity under various control measures at highway-rail grade crossing in the United States. RESULTS: The analysis found that schedule factor (peak hour), visibility, motor vehicle speed, train speed, driver's age, area type, traffic volume and highway pavement impact driver injury severity at both active and passive highway-rail crossings. PRACTICAL APPLICATIONS: For both active and passive control highway-rail grade crossings, speed control for both trains and vehicles will significantly reduce driver injury severity. However, the level of influence by vehicle speed and train speed at passive control is higher compared with active control. Paving highways at highway-rail grade crossings will also help to reduce driver injury severity at highway-rail crossing accidents. PMID- 25453176 TI - Surveillance for work-related skull fractures in Michigan. AB - OBJECTIVES: The objective was to develop a multisource surveillance system for work-related skull fractures. METHODS: Records on work-related skull fractures were obtained from Michigan's 134 hospitals, Michigan's Workers' Compensation Agency and death certificates. Cases from the three sources were matched to eliminate duplicates from more than one source. Workplaces where the most severe injuries occurred were referred to OSHA for an enforcement inspection. RESULTS: There were 318 work related skull fractures, not including facial fractures, between 2010 and 2012. In 2012, after the inclusion of facial fractures, 316 fractures were identified of which 218 (69%) were facial fractures. The Bureau of Labor Statistic's (BLS) 2012 estimate of skull fractures in Michigan, which includes facial fractures, was 170, which was 53.8% of those identified from our review of medical records. The inclusion of facial fractures in the surveillance system increased the percentage of women identified from 15.4% to 31.2%, decreased severity (hospitalization went from 48.7% to 10.6% and loss of consciousness went from 56.5% to 17.8%), decreased falls from 48.2% to 27.6%, and increased assaults from 5.0% to 20.2%, shifted the most common industry from construction (13.3%) to health care and social assistance (15.0%) and the highest incidence rate from males 65+ (6.8 per 100,000) to young men, 20-24 years (9.6 per 100,000). Workplace inspections resulted in 45 violations and $62,750 in penalties. CONCLUSIONS: The Michigan multisource surveillance system of workplace injuries had two major advantages over the existing national system: (a) workplace investigations were initiated hazards identified and safety changes implemented at the facilities where the injuries occurred; and (b) a more accurate count was derived, with 86% more work-related skull fractures identified than BLS's employer based estimate. PRACTICAL APPLICATIONS: A more comprehensive system to identify and target interventions for workplace injuries was implemented using hospital and emergency department medical records. PMID- 25453177 TI - Modeling the safety impacts of driving hours and rest breaks on truck drivers considering time-dependent covariates. AB - INTRODUCTION: Driving hours and rest breaks are closely related to driver fatigue, which is a major contributor to truck crashes. This study investigates the effects of driving hours and rest breaks on commercial truck driver safety. METHOD: A discrete-time logistic regression model is used to evaluate the crash odds ratios of driving hours and rest breaks. Driving time is divided into 11 one hour intervals. These intervals and rest breaks are modeled as dummy variables. In addition, a Cox proportional hazards regression model with time-dependent covariates is used to assess the transient effects of rest breaks, which consists of a fixed effect and a variable effect. RESULTS: Data collected from two national truckload carriers in 2009 and 2010 are used. The discrete-time logistic regression result indicates that only the crash odds ratio of the 11th driving hour is statistically significant. Taking one, two, and three rest breaks can reduce drivers' crash odds by 68%, 83%, and 85%, respectively, compared to drivers who did not take any rest breaks. The Cox regression result shows clear transient effects for rest breaks. It also suggests that drivers may need some time to adjust themselves to normal driving tasks after a rest break. Overall, the third rest break's safety benefit is very limited based on the results of both models. PRACTICAL APPLICATIONS: The findings of this research can help policy makers better understand the impact of driving time and rest breaks and develop more effective rules to improve commercial truck safety. PMID- 25453178 TI - Compliance with the ANSI Z133.1 - 2006 safety standard among arborists in New England. AB - INTRODUCTION: Arboriculture is hazardous work. A consensus safety standard exists, but little is known about compliance with it. This study aimed to determine whether accreditation and certification are associated with safety practices and to identify specific safety practices adhered to most and least. METHOD: Sixty-three tree care companies in southern New England were directly observed on job sites. Adherence to the American National Standards for Arboricultural Operations (ANSI Z133.1 - 2006) was compared across companies that were accredited, non-accredited with certified arborists on staff, and non accredited without certified arborists on staff. RESULTS: Companies with accreditation or certified arborists demonstrated greater safety compliance than those without. However, low compliance was found across all company types for personal protective equipment (PPE) use, chain saw safety, and chipper safety. CONCLUSIONS: Greater attention to PPE, chain saw, and chipper practices is warranted across the industry. Safety in non-accredited companies without certified arborists especially needs improvement. PRACTICAL APPLICATION: Only partial compliance was found among accredited companies and companies with certified arborists. Intervention strategies are needed for all company types for the use of PPE and safer use of chain saws and chippers. PMID- 25453179 TI - Predicting on-road driving performance and safety in healthy older adults. AB - INTRODUCTION: This study evaluated the ability to predict the on-road driving of older drivers using a battery of laboratory-based instruments. METHODS: The Roadwise Review, a brief Hazard Perception Test and several tests of vision were given to 65 cognitively healthy, licensed older drivers (M = 74 years, SD = 9 years). They also participated in a standardized driving assessment of approximately 18 km, along a mixed residential and commercial route. RESULTS: Raw scores on the Roadwise Review did not predict accumulated points, or automatic disqualifications, but could predict who would pass or fail the on-road evaluation. The number of serious problems (excluding head and neck flexibility) that were identified by the Roadwise Review was a significant predictor of automatic disqualifications, and a significant predictor of passing or failing the on-road assessment. The Hazard Perception Test approached significance when predicting accumulated points and was a significant predictor of automatic disqualifications, as well as pass/fail outcomes. CONCLUSIONS: The best model for predicting passing or failing the on-road assessment included the Hazard Perception Test, color vision, and, a measure of walking speed from the Roadwise Review, which yielded a sensitivity of 82% and a specificity of 69% (AROC = .80). Future work will need to determine how these tests can be used with other information (e.g., medical history) to yield better diagnoses of fitness to drive, particularly among those who are medically at risk. PMID- 25453180 TI - Youth on racial minority operated U.S. farms, 2008: demographics and injuries. AB - INTRODUCTION: To obtain injury surveillance data for youth on racial minority operated farms, the National Institute for Occupational Safety and Health developed the Minority Farm Operator Childhood Agricultural Injury Survey (M CAIS) in collaboration with the U.S. Department of Agriculture. METHODS: Using a regionally stratified telephone survey of U.S. minority operated farm households, M-CAIS data were collected for youth less than 20 years of age. RESULTS: There were an estimated 37,443 youth living on racial minority operated U.S. farms in 2008, almost half (46%) of these youth worked on the farm. Racial minority farm operators hired 6,443 youth, and reported an estimated 775,991 youth relative and other visitors on the farm. These youth suffered an estimated 516 injuries (5.9 injuries/1000 farms). CONCLUSIONS: Household youth had an injury rate of 7.8 injuries/1000 household youth and a work-related injury rate of 6.9 injuries/1000 working household youth. PRACTICAL APPLICATIONS: The research enables agricultural safety and health researchers, practitioners, and educators to identify priorities and design trainings and interventions to minimize the risk of farm hazards to youth on racial minority farm operations in the United States. PMID- 25453181 TI - Risk for household safety hazards: Socioeconomic and sociodemographic factors. AB - INTRODUCTION: Many unintentional injuries to young children occur in the home. The current study examines the relation between family socioeconomic and sociodemographic factors and risk factors for home injury. METHODS: Presence of household hazards was examined in 80 families with toddler-aged children. Parental ability to identify household hazards in pictures was also assessed. ANOVAs and Pearson product-moment correlations examined the relationship between presence of household hazards, knowledge to identify hazards, and factors of yearly family income, parental age, parental education, parental marital status, child ethnicity, and the number of children living in the home. RESULTS: A greater number of hazards were found in the homes of both the lowest and highest income families, but poorer knowledge to identify household hazards was found only among parents of the lowest income families and younger parents. Across family socioeconomic status, parent knowledge of hazards was related to observed household hazards. CONCLUSIONS: The relationship between family income and risk for injury is complex, and children of both lower and higher SES families may be at risk for injury. PRACTICAL APPLICATIONS: While historically particular focus has been placed on risk for injury among children in low income families, injury prevention efforts should target reducing presence of household hazards in both high and low SES families. PMID- 25453182 TI - A data mining approach to investigate the factors influencing the crash severity of motorcycle pillion passengers. AB - INTRODUCTION: Motorcycle passengers comprise a considerable proportion of traffic crash victims. During a 5 year period (2006-2010) in Iran, an average of 3.4 pillion passengers are killed daily due to motorcycle crashes. This study investigated the main factors influencing crash severity of this group of road users. METHOD: The Classification and Regression Trees (CART) method was employed to analyze the injury severity of pillion passengers in Iran over a 4 y ear period (2009-2012). RESULTS: The predictive accuracy of the model built with a total of 16 variables was 74%, which showed a considerable improvement compared to previous studies. The results indicate that area type, land use, and injured part of the body (head, neck, etc.) are the most influential factors affecting the fatality of motorcycle passengers. Results also show that helmet usage could reduce the fatality risk among motorcycle passengers by 28%. PRACTICAL APPLICATIONS: The findings of this study might help develop more targeted countermeasures to reduce the death rate of motorcycle pillion passengers. PMID- 25453183 TI - Factors affecting tether use and correct use in child restraint installations. AB - INTRODUCTION: Field studies show that top tethers go unused in half of forward facing child restraint installations. METHOD: In this study, parent volunteers were asked to use the Lower Anchors and Tethers for Children (LATCH) to install child restraints in several vehicles to identify tether anchor characteristics that are associated with tether use. Thirty-seven volunteers were assigned to four groups. Each group tested two forward-facing child restraints in four of 16 vehicle models. Logistic regression models were used to identify predictors of tether use and correct use. RESULTS: Subjects used the tether in 89% of the 294 forward-facing child restraint installations and attached the tether correctly in 57% of the installations. Tethers were more likely to be used when the anchor was located on the rear deck as typically found in sedans compared with the seatback, floor, or roof. Tethers were less likely to be attached correctly when there was potentially confusing hardware present. No vehicle tether hardware characteristics or vehicle manual directions were associated specifically with correct tether routing and head restraint position. CONCLUSION: This study provides laboratory evidence that specific vehicle features are associated with tether use and correct use. PRACTICAL APPLICATIONS: Modifications to vehicles that make tether anchors easier to find and identify likely will result in increases in tether use and correct use. PMID- 25453184 TI - Dollars for lives: the effect of highway capital investments on traffic fatalities. AB - INTRODUCTION: This study examines the effect of highway capital investments on highway fatalities. METHODS: We used state-level data from the 48 contiguous states in the United States from 1968 through 2010 to estimate the effects on highway fatalities of capital expenditures and highway capital stock. We estimated these effects by controlling for a set of control variables together with state and year dummy variables and state-specific linear time trends. RESULTS: We found that capital expenditures and capital stock had significant and negative effects on highway fatalities. CONCLUSION: States faced with declines in gas tax revenues have already cut back drastically on spending on roads including on maintenance and capital outlay. If this trend continues, it may undermine traffic safety. PRACTICAL APPLICATION: While states and local governments are currently fiscally strained, it is important for them to continue investments in roadways to enhance traffic safety and, more significantly, to save lives. PMID- 25453185 TI - Rates of and circumstances surrounding work-related falls from height among union drywall carpenters in Washington State, 1989-2008. AB - BACKGROUND: Drywall installers are at high risk for work-related falls from height (FFH). METHODS: We defined a 20-year (1989-2008) cohort of 5,073 union drywall carpenters in Washington State, their worker-hours, and FFH. FFH rate patterns were examined using Poisson regression. RESULTS: Drywall installers' FFH rates declined over time and varied little by worker age and time in the union. However, among FFH involving drywall sheets, workers with <10 union years were at high risk. Narratives consistently described the surface from which workers fell, commonly scaffolds (33%), ladders (21%), and stilts (13%). Work task, height fallen, protective equipment use, work speed, weather, influence of other workers/workgroups, and tool/equipment specifics were not often reported. PRACTICAL APPLICATIONS: In addition to continued efforts to prevent falls from scaffolds and ladders, efforts should address stilt use and less experienced workers who may have greater exposure. Consistency in reported narrative elements may improve FFH risk factor identification and prevention effort evaluation. PMID- 25453186 TI - Variation among states in prescribing of opioid pain relievers and benzodiazepines--United States, 2012. AB - INTRODUCTION: Overprescribing of opioid pain relievers (OPR) can result in multiple adverse health outcomes, including fatal overdoses. Interstate variation in rates of prescribing OPR and other prescription drugs prone to abuse, such as benzodiazepines, might indicate areas where prescribing patterns need further evaluation. METHODS: CDC analyzed a commercial database (IMS Health) to assess the potential for improved prescribing of OPR and other drugs. CDC calculated state rates and measures of variation for OPR, long-acting/extended-release (LA/ER) OPR, high-dose OPR, and benzodiazepines. RESULTS: In 2012, prescribers wrote 82.5 OPR and 37.6 benzodiazepine prescriptions per 100 persons in the United States. State rates varied 2.7-fold for OPR and 3.7-fold for benzodiazepines. For both OPR and benzodiazepines, rates were higher in the South census region, and three Southern states were two or more standard deviations above the mean. Rates for LA/ER and high-dose OPR were highest in the Northeast. Rates varied 22-fold for one type of OPR, oxymorphone. CONCLUSIONS: Factors accounting for the regional variation are unknown. Such wide variations are unlikely to be attributable to underlying differences in the health status of the population. High rates indicate the need to identify prescribing practices that might not appropriately balance pain relief and patient safety. IMPLICATIONS FOR PUBLIC HEALTH: State policy makers might reduce the harms associated with the abuse of prescription drugs by implementing changes that will make the prescribing of these drugs more cautious and more consistent with clinical recommendations. PMID- 25453187 TI - Health-related quality of life of preschool children who stutter. AB - PURPOSE: The purpose of this study is to compare the health-related quality of life (HrQoL) of preschool children who stutter (CWS) and a reference population of children who do not stutter, and to evaluate the association between stuttering severity and HrQoL. METHODS: Baseline data were used from 197 children participating in a multicenter Randomized Clinical Trial in the Netherlands. Information on stuttering severity and time since onset (TSO) of stuttering was obtained from the baseline evaluation by speech- and language therapists. Stuttering severity was measured using the SSI-3. HrQoL was assessed using proxy versions of two Child Health Questionnaires (ITQOL-97 and CHQ-PF28), the Health Utility Index 3 (HUI3) and the EuroQoL EQ-VAS (EQ-VAS). RESULTS: While the outcomes on the EQ-VAS and the HUI3 showed that the HrQoL of CWS is slightly poorer than that of the Dutch reference population, results on the different dimensions of the CHQ-instruments did not reveal any difference in scores between stuttering children and reference groups. Within the group of CWS, two ITQOL-97 and four CHQ-PF28 scales showed statistically different scores for children in different SSI stuttering severity or TSO categories. However, the effect sizes showed that these differences were so small that they could be considered negligible. CONCLUSION: The results of this study do not reveal a diminished HrQoL for preschool CWS. Future research should include a larger cohort of children with severe stuttering, study the longitudinal course of HrQoL and incorporate additional parameters such as the characteristics of the child and his environment. EDUCATIONAL OBJECTIVES: The reader will be able to: (a) summarize the current evidence base on HrQoL in people who stutter; (b) describe the HrQoL of preschool CWS on different HrQoL measures; (c) describe the relationship between stuttering severity and HrQoL in preschool CWS. PMID- 25453188 TI - [Prophylactic surgery in patients mutated BRCA or high risk: retrospective study of 61 patients in the ICO]. AB - BACKGROUND: Genetic predisposition is involved in only 10% of patients with breast cancer. This study was to evaluate the impact of prophylactic surgery. PATIENTS AND METHODS: This is a retrospective study of 61 patients who received prophylactic breast surgery. Data collection was carried out through the computer file of the ICO. The inclusion criteria were: patients who benefited from a bilateral prophylactic mastectomy. There were no exclusion criteria. Patients received a satisfaction questionnaire to complete. RESULTS: Our study included 61 patients, 67% had a history of breast cancer. Bilateral prophylactic surgery was performed in 40 patients. It was made an average of two interventions, 44.3% of them presented postoperative complications, 18% recovery. Forty-three patients were satisfied with the medical information before surgery. The end result matched the expectations of 54.4% and 67.4% of patients would be ready to start. It was found pain associated with breast surgery in 56.5% of patients and almost half reported a change in their sexual life. DISCUSSION AND CONCLUSION: Prophylactic mastectomy is the most effective technique to prevent the risk of breast cancer. The consequences of such an action are important. It is necessary to better select patients who would benefit most from this type of surgery. PMID- 25453189 TI - The melanocortin-4 receptor is expressed in enteroendocrine L cells and regulates the release of peptide YY and glucagon-like peptide 1 in vivo. AB - The melanocortin-4 receptor (MC4R) is expressed in the brainstem and vagal afferent nerves and regulates a number of aspects of gastrointestinal function. Here we show that the receptor is also diffusely expressed in cells of the gastrointestinal system, from stomach to descending colon. Furthermore, MC4R is the second most highly enriched GPCR in peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) expressing enteroendocrine L cells. When vectorial ion transport is measured across mouse or human intestinal mucosa, administration of alpha-MSH induces a MC4R-specific PYY-dependent antisecretory response consistent with a role for the MC4R in paracrine inhibition of electrolyte secretion. Finally, MC4R-dependent acute PYY and GLP-1 release from L cells can be stimulated in vivo by intraperitoneal (i.p.) administration of melanocortin peptides to mice. This suggests physiological significance for MC4R in L cells and indicates a previously unrecognized peripheral role for the MC4R, complementing vagal and central receptor functions. PMID- 25453192 TI - Electroless preparation and ASAXS microstructural analysis of pseudocapacitive carbon manganese oxide supercapacitor electrodes. AB - Anomalous small angle X-ray scattering (ASAXS) has been utilized as a noninvasive, integral tool to access the structural properties of carbon xerogel manganese oxide electrodes with nanometer resolution. As these electrodes constitute the elementary functional units in supercapacitors and as their microstructure governs the macroscopic electrical performance, it is essential to gain a detailed morphological understanding of the underlying carbon particle scaffold coated with manganese oxide. We demonstrate that, in this regard, ASAXS provides a powerful technique and in combination with a theoretical core-shell model enables a quantitative estimation of the relevant structural parameters. As a result, we determined the thicknesses of the solution deposited MnO2 shells to range between 3 and 26 nm depending on the carbon particle size and thus on their effective surface area. By our core-shell modeling we conclude the revealed manganese oxide coatings on the carbon support to be rather thick, but nevertheless to show a high uniformity in thickness. At 1.8 +/- 0.2 to 2.2 +/- 0.1 g/cm(3) the related effective MnO2 densities of the shells are about 30% lower than the corresponding bulk density of 3.0 g/cm(3). This mainly originates from a substructure within the shell, whose growth is controlled by a pronounced reduction of the manganese precursor during layer formation. Finally, the presented ASAXS data are complemented by SEM and N2 sorption measurements, proving not only qualitatively the proposed flake-like MnO2 surface morphology but also confirming quantitatively the manganese shell thickness, complementary, on a local scale. PMID- 25453190 TI - O-GlcNAc protein modification in C2C12 myoblasts exposed to oxidative stress indicates parallels with endogenous antioxidant defense. AB - A growing body of evidence demonstrates the involvement of protein modification with O-linked beta-N-acetylglucosamine (O-GlcNAc) in the stress response and its beneficial effects on cell survival. Here we investigated protein O-GlcNAcylation in skeletal muscle cells exposed to oxidative stress and the crosstalk with endogenous antioxidant system. The study focused on antioxidant enzymes superoxide dismutase 2 (SOD2), catalase (CAT), and glutathione peroxidase 1 (GPX1), and transcriptional regulators proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) and forkhead box protein O1 (FOXO1), which play important roles in oxidative stress response and are known to be O-GlcNAc modified. C2C12 myoblasts were subjected to 24 h incubation with different reagents, including hydrogen peroxide, diethyl maleate, high glucose, and glucosamine, and the inhibitors of O-GlcNAc cycling enzymes. Surprisingly, O GlcNAc levels were significantly increased only with glucosamine, whilst other treatments showed no effect. Significant changes at the mRNA level were observed with concomitant upregulation of the genes for O-GlcNAc enzymes and stress related proteins with oxidizing agents and downregulation of these genes with agents promoting O-GlcNAcylation. Our findings suggest a role of O-GlcNAc in the stress response and indicate an inhibitory mechanism controlling O-GlcNAc levels in the muscle cells. This could represent an important homeostatic regulation of the cellular defense system. PMID- 25453191 TI - Physical and functional implications of aquatic exercise for nursing home residents with dementia. AB - Exercise has reported benefits for those with dementia. In the current study we investigated the feasibility of delivery and the physical and functional benefits of an innovative aquatic exercise program for adults with moderate to severe dementia living in a nursing home aged care facility. Ten adults (88.4 years, inter quartile range 12.3) participated twice weekly for 12 weeks. Anthropometric and grip strength data, and measures of physical function and balance were collected at baseline and post-intervention. Feasibility was assessed by attendance, participation, enjoyment and recruitment. Following exercise, participant's left hand grip strength had improved significantly (p = .017). Small to moderate effect sizes were observed for other measures. A number of delivery challenges emerged, but participant enjoyment, benefits and attendance suggest feasibility. Aquatic exercise shows promise as an intervention among those with dementia who live in a nursing home aged care facility. Greater program investigation is warranted. PMID- 25453193 TI - Noninvasive potassium determination using a mathematically processed ECG: proof of concept for a novel "blood-less, blood test". AB - OBJECTIVE: To determine if ECG repolarization measures can be used to detect small changes in serum potassium levels in hemodialysis patients. PATIENTS AND METHODS: Signal-averaged ECGs were obtained from standard ECG leads in 12 patients before, during, and after dialysis. Based on physiological considerations, five repolarization-related ECG measures were chosen and automatically extracted for analysis: the slope of the T wave downstroke (T right slope), the amplitude of the T wave (T amplitude), the center of gravity (COG) of the T wave (T COG), the ratio of the amplitude of the T wave to amplitude of the R wave (T/R amplitude), and the center of gravity of the last 25% of the area under the T wave curve (T4 COG) (Fig. 1). RESULTS: The correlations with potassium were statistically significant for T right slope (P<0.0001), T COG (P=0.007), T amplitude (P=0.0006) and T/R amplitude (P=0.03), but not T4 COG (P=0.13). Potassium changes as small as 0.2mmol/L were detectable. CONCLUSION: Small changes in blood potassium concentrations, within the normal range, resulted in quantifiable changes in the processed, signal-averaged ECG. This indicates that non-invasive, ECG-based potassium measurement is feasible and suggests that continuous or remote monitoring systems could be developed to detect early potassium deviations among high-risk patients, such as those with cardiovascular and renal diseases. The results of this feasibility study will need to be further confirmed in a larger cohort of patients. PMID- 25453194 TI - QTC intervals can be assessed with the AliveCor heart monitor in patients on dofetilide for atrial fibrillation. AB - We assessed the feasibility of AliveCor tracings for QTC assessment in patients receiving dofetilide. Five patients with persistent AF underwent the two-handed measurement (mimicks Lead I). On the ECG, Lead I or II was used. There was no significant difference between the AliveCor-QTC and ECG-QTC (all +/-20 msec). The AliveCor device can be used to monitor the QTC in these patients. PMID- 25453195 TI - Electrocardiographic repolarization-related predictors of coronary heart disease and sudden cardiac deaths in men and women with cardiovascular disease in the Atherosclerosis Risk in Communities (ARIC) study. AB - INTRODUCTION: We evaluated repolarization-related predictors of coronary heart disease (CHD) death and sudden cardiac death (SCD) in men and women with cardiovascular disease (CVD) in the Atherosclerosis Risk in Communities (ARIC) study. METHODS AND RESULTS: Hazard ratios (HR) from Cox regression were computed for 11 ECG measures of repolarization in 1384 subjects (50% women) 45 to 65years of age. The average follow-up was 14years. Based on electrophysiological considerations the spatial angle between Tpeak and normal repolarization reference vector [?(Tp|Tref)], STJV6 amplitude, QRS duration and Tonset and Tpeak vector magnitude ratio (ToV/TpV) were considered as primary candidates for independent mortality predictors, and as an alternative set TaVR and TV1 amplitudes and the spatial angle between the initial and terminal T vectors [?(Tinit|Tterm)]. From the primary set [?(Tp|Tref)] was a strong independent predictor for CHD death (nearly 4-fold increased risk in men and 2-fold increased risk in women) and for SCD [?(Tinit|Tterm)] in men (3.4-fold increased risk) and (ToV/TpV) in women (7.76-fold increased risk). From the alternative set of independent predictors TaVR amplitude negativity reduced to less than 150MUV (1.5mm) was a strong mortality predictor with an approximately 3-fold increased risk for CHD death and SCD in men and women. CONCLUSIONS: The strongest independent predictors of CHD death were [?(Tp|Tref)] in men and TaVR in women and of SCD were [?(Tp|Tref)] in men and ToV/TpV in women. Overall, TaVR amplitude negativity reduced to less than 150MUV (1.5mm) was the most consistent mortality predictor in all subgroups. These ECG variables may warrant consideration for identification of high risk men and women for more intense preventive intervention. PMID- 25453201 TI - Do service innovations influence the adoption of electronic health records in long-term care organizations? Results from the U.S. National Survey of Residential Care Facilities. AB - OBJECTIVE: Healthcare organizations including residential care facilities (RCFs) are diversifying their services to meet market demands. Service innovations have been linked to the changes in the way that healthcare organizations organize their work. The objective of this study is to explore the relationship between organizational service innovations and Electronic Health Record (EHR) adoption in the RCFs. METHODS: We used the data from the 2010 National Survey of Residential Care Facilities conducted by the Centers for Disease Control and Prevention. The outcome was whether an RCF adopted EHR or not, and the predictors were the organizational service innovations including provision of skilled nursing care and medication review. We also added facility characteristics as control variables. Weighted multivariate logistic regressions were used to estimate the relationship between service innovation factors and EHR adoption in the RCFs. RESULTS: In 2010, about 17.4% of the RCFs were estimated to use EHR. Multivariate analysis showed that RCFs employing service innovations were more likely to adopt EHR. The residential care facilities that provide skilled nursing services to their residents are more likely (OR: 1.42; 95% CI: 1.09-1.87) to adopt EHR. Similarly, RCFs with a provision of medication review were also more likely to adopt EHR (OR: 1.40; 95% CI: 1.00-1.95). Among the control variables, facility size, chain affiliation, ownership type, and Medicaid certification were significantly associated with EHR adoption. CONCLUSIONS: Our findings suggest that service innovations may drive EHR adoption in the RCFs in the United States. This can be viewed as a strategic attempt by RCFs to engage in a new business arrangement with hospitals and other health care organizations, where quality of care and interoperability of patients' records might play a vital role under the current healthcare reform. Future research could examine the relationship between service innovations and use of different EHR functionality in RCFs. PMID- 25453196 TI - Vectorcardiographic QRS area as a novel predictor of response to cardiac resynchronization therapy. AB - BACKGROUND: QRS duration and left bundle branch block (LBBB) morphology are used to select patients for cardiac resynchronization therapy (CRT). We investigated whether the area of the QRS complex (QRSAREA) on the 3-dimensional vectorcardiogram (VCG) can improve patient selection. METHODS: VCG (Frank orthogonal lead system) was recorded prior to CRT device implantation in 81 consecutive patients. VCG parameters, including QRSAREA, were assessed, and compared to QRS duration and morphology. Three LBBB definitions were used, differing in requirement of mid-QRS notching. Responders to CRT (CRT-R) were defined as patients with >=15% reduction in left ventricular end systolic volume after 6months of CRT. RESULTS: Fifty-seven patients (70%) were CRT-R. QRSAREA was larger in CRT-R than in CRT non-responders (140+/-42 vs 100+/-40 MUVs, p<0.001) and predicted CRT response better than QRS duration (AUC 0.78 vs 0.62, p=0.030). With a 98MUVs cutoff value, QRSAREA identified CRT-R with an odds ratio (OR) of 10.2 and a 95% confidence interval (CI) of 3.4 to 31.1. This OR was higher than that for QRS duration >156ms (OR=2.5; 95% CI 0.9 to 6.6), conventional LBBB classification (OR=5.5; 95% CI 0.9 to 32.4) or LBBB classification according to American guidelines (OR=4.5; 95% CI 1.6 to 12.6) or Strauss (OR=10.0; 95% CI 3.2 to 31.1). CONCLUSION: QRSAREA is an objective electrophysiological predictor of CRT response that performs at least as good as the most refined definition of LBBB. CONDENSED ABSTRACT: In 81 candidates for cardiac resynchronization therapy (CRT) we measured the area of the QRS complex (QRSAREA) using 3-dimensional vectorcardiography. QRSAREA was larger in echocardiographic responders than in non-responders and predicted CRT response better than QRS duration and than simple LBBB criteria. QRSAREA is a promising electrophysiological predictor of CRT response. PMID- 25453202 TI - Prevalence of antiphospholipid antibodies and risk of subsequent adverse obstetric outcomes in women with prior pregnancy loss. AB - The reported prevalence of antiphospholipid antibodies in women with a chief complaint of pregnancy loss varies, as does the risk of adverse outcomes in subsequent pregnancies. Our objectives were to assess the prevalence of antiphospholipid antibodies meeting revised Sapporo thresholds among women presenting with a chief complaint of pregnancy loss and risks in subsequent pregnancies for these women. We examined a retrospective cohort of patients presenting with a chief complaint of pregnancy loss between 2003 and 2012. Antiphospholipid antibodies were assessed at the providers' discretion, and patients were considered positive if they met the revised Sapporo criteria. Patient data were obtained by review of the medical records. 338/390 women (86.7%) presented with a chief complaint of pregnancy loss and had testing for antiphospholipid antibodies. 19/338 women (5.6%) persistently tested positive for at least one antiphospholipid antibody. Seven women who tested positive had isolated recurrent early pregnancy loss <=10 weeks, and 12 women who tested positive had venous thromboembolism (VTE), systemic lupus erythematosus (SLE), delivery <34 weeks for pre-eclampsia, and/or placental insufficiency, or fetal demise >10 weeks. Subsequent pregnancy outcomes were available for 13 patients. Compared with women with recurrent early pregnancy loss alone, subsequent obstetric morbidity was significantly more likely in those patients with a history of SLE and/or VTE (p=0.048). We conclude that the prevalence of positive antiphospholipid antibodies in women with a chief complaint of pregnancy loss and without autoimmune disease or prior thrombosis is low and that among these women, subsequent pregnancy outcomes are largely favorable. PMID- 25453203 TI - CD8 T cells and dendritic cells: key players in the attenuated maternal immune response to influenza infection. AB - Pregnancy provides a unique challenge for maternal immunity, requiring the ability to tolerate the presence of a semi-allogeneic foetus, and yet still being capable of inducing an immune response against invading pathogens. To achieve this, numerous changes must occur in the activity and function of maternal immune cells throughout the course of pregnancy. Respiratory viruses take advantage of these changes, altering the sensitive balance of maternal immunity, leaving the mother with increased susceptibility to viral infections and increased disease severity. Influenza virus is one of the most common respiratory virus infections during pregnancy, leading to an increased risk of ICU hospitalisations, pneumonia, acute respiratory distress syndrome and even death. Whilst much research has been performed to understand the changes that must take place in maternal immunity during pregnancy, considerable work is still needed to fully comprehend this tremendous feat. To date, few studies have focused on the alterations that occur in maternal immunity during respiratory virus infections. This review highlights the role of dendritic cells (DCs) and CD8 T cells during pregnancy, and the changes that occur in these antiviral cells following influenza virus infections. PMID- 25453205 TI - [Secondary postpartum hemorrhage]. AB - OBJECTIVES: To define secondary postpartum hemorrhage (HSPP), to discuss its main etiologies and suggest a proposal for its management. MATERIALS AND METHODS: Bibliographic research by crossing keywords: secondary postpartum hemorrhage, delayed postpartum hemorrhage, postpartum bleeding, placental remnant, placental and hysteroscopy. RESULTS: The HSPP (0.5 and 2%) is defined as bleeding occurring between 24hours and 6weeks after birth and requiring therapeutic action whatsoever (professional consensus). The most common etiology is retained placental fragments and/or endometritis, associated or not with incomplete uterine involution (Professional consensus). Among other etiologies: the pseudoaneurysms of the uterine artery, arteriovenous fistulae's, choriocarcinoma and coagulopathies. Management of HSPP depends on its etiology and the severity of bleeding. It includes antibiotics (grade A) and uterotonics (professional consensus). Antibiotherapy depends of the protocols of each department. Usually the patient will be hospitalized (Professional consensus). In case of persistent bleeding, suction curettage with or without hysteroscopy is recommended (Professional consensus). CONCLUSION: Although HSPP is an important source of maternal morbidity, it is concerned by a relatively few number of studies in the literature. Its management is based on a comprehensive etiological work-up in order to provide appropriate treatment. PMID- 25453204 TI - [Management of placenta previa and accreta]. AB - OBJECTIVE: Produce recommendations for the management of placenta previa and placenta accrete. METHODS: A literature search was conducted using Medline and the Cochrane Library over a period from 1950 to 31/12/2013. Recommendations of the latest scientific societies have also been consulted. RESULTS: In cases of placenta previa, if bleeding episode before 34weeks gestation occurs, a short hospitalization and tocolysis may help stop bleeding (grade C). Vaginal delivery is preferable when the distance between the internal cervical os and the placental edge is greater than 20mm. When this distance is less than 20mm, vaginal delivery is possible (professional consensus). Caesarean section is recommended in cases of placenta overlapping the internal os (professional consensus). Antenatal screening placenta accreta could improve care (EL3). Upon discovery of a placenta accreta during childbirth, it is better to avoid a forced removal of the placenta (grade C). Conservative treatment or cesarean hysterectomy are possible (grade C). The management of placental abnormalities should be planned and managed with a multidisciplinary team (professional consensus). The use of blood-saving techniques such as "cell saver" is possible in situations where early intraoperative bleeding would be>1500mL (grade C). There are no studies that have sufficient methodological value to recommend an anesthetic technique [general anaesthesia (GA) or neuraxial anaesthesia] over another in the context of placental abnormalities (grade B). When a major bleeding risk is identified, GA can be chosen in order to avoid emergency conversions in difficult conditions (professional consensus). CONCLUSION: Placental insertion abnormalities require anesthetic and obstetric coordination. Delivery must be planned in a suitable structure. PMID- 25453206 TI - [Postpartum hemorrhage: Guidelines for clinical practice - Text of the Guidelines (short text)]. PMID- 25453207 TI - Activation of AKT/GSK3beta pathway by TDZD-8 attenuates kainic acid induced neurodegeneration but not seizures in mice. AB - Activation of glycogen synthase kinase3beta (GSK3beta), an enzyme that regulates a multitude of cellular signaling pathways, is implicated in neurodegenerative processes observed in an array of CNS diseases. We examined the hypothesis that the pathological changes in an acute kainic acid (KA) induced excitotoxicity model, relevant to human temporal lobe epilepsy (TLE), could be sensitive to inhibition of GSK3beta by 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD 8) treatment in Swiss albino mice. Immediate seizure responses due to KA were recorded. Neurodegenerative and morphogenic changes were examined by western blot analysis and light microscopy, respectively, 48 h after KA administration. Although tonic-clonic seizure episodes evoked by KA were unaffected, TDZD-8 pretreatment decreased KA mediated elevation in caspase-3 cleavage as well as increased Bcl2 and phospho-GSK3beta (Ser9; pGSK3beta(Ser9)) expression. Likewise, microscopic examination also revealed that pretreatment with TDZD-8 attenuated cell damage elicited by KA in the CA1, CA3 and DG regions. In all the above parameters, the combined effect of a sub-effective dose of sodium valproate (SVP) with TDZD-8 was higher than that of solitary TDZD-8 treatment. The findings suggest that activated GSK3beta orchestrated neurodegenerative alterations following KA treatment and its inhibition by TDZD-8 affords a distinct neuroprotective profile by activating Akt/GSK3beta pathway which might act upstream of Bax/Bcl2 and caspase-3 pathways. Compounds targeting GSK3beta activity might represent a novel therapeutic option for exploration as an adjunct to conventional anti-epileptic drugs in preventing neurodegenerative processes in TLE. PMID- 25453209 TI - Enhanced photocatalytic-electrolytic degradation of Reactive Brilliant Red X-3B in the presence of water jet cavitation. AB - Photocatalysis, electrolysis, water jet cavitation (WJC), alone and in combinations were applied to degrade an azo dye, Reactive Brilliant Red X-3B (X 3B). Experiments were conducted in a 4.0 L aqueous solution with different initial dye concentrations, TiO2 dose, and solution pH. WJC substantially increased the photocatalytic, electrolytic and photocatalytic-electrolytic rates of the dye removal. The observed first-order rate of X-3B decolorization in the process of combined photocatalysis and electrolysis coupled with WJC was 1.6-2.9 times of that in the process of combined photocatalysis and electrolysis coupled with mechanical stirring. The rate enhancements may be attributed primarily to the reduced diffusion layer thickness on the electrodes and the deagglomeration of photocatalyst particles due to the chemical and physical effects of WJC. Under the conditions of 80 mg/L X-3B solution, 100 mg/L TiO2 dose and solution pH 6.3, 97% and 71% of color and chemical oxygen demand (CODCr) were removed, respectively, within 90-min photocatalytic-electrolytic treatment coupled with WJC. During this process, azo groups and naphthalene, benzene and triazine structures of the dye can be destroyed. Industrial textile effluent was also investigated, and a positive synergistic effect between photocatalytic electrolytic system and WJC was observed considering color removal. PMID- 25453208 TI - Fabrication of polymeric nanocapsules from curcumin-loaded nanoemulsion templates by self-assembly. AB - In this study, biodegradable polymeric nanocapsules were prepared by sequential deposition of food-grade polyelectrolytes through the self-assembling process onto the oil (medium chain triglycerides) droplets enriched with curcumin (lipophilic bioactive compound). Optimum conditions were used to prepare ultrasound-assisted nanoemulsions stabilized by octenyl-succinic-anhydride (OSA) modified starch. Negatively charged droplets (-39.4 +/- 1.84 mV) of these nanoemulsions, having a diameter of 142.7 +/- 0.85 nm were used as templates for the fabrication of nanocapsules. Concentrations of layer-forming cationic (chitosan) and anionic (carboxymethylcellulose) biopolymers were optimized based on the mean droplet/particle diameter (MDD/MPD), polydispersity index (PDI) and net charge on the droplets/capsules. Prepared core-shell structures or nanocapsules, having MPD of 159.85 +/- 0.92 nm, were characterized by laser diffraction (DLS), zeta-potential (ZP), atomic force microscopy (AFM), transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM). Furthermore, physical stability of curcumin-loaded nanocapsules in suspension was determined and compared at different storage temperatures. This study may provide information regarding the formation of ultrasound-assisted polymeric nanocapsules from the nanoemulsion templates which could be helpful in the development of delivery systems for lipophilic food bioactives. PMID- 25453211 TI - Ultrasound assisted formation of Al-Ni electrocatalyst for hydrogen evolution. AB - High intensity ultrasound treatment has been used to generate electrocatalytically active (toward hydrogen evolution) surface on AlNi (50 wt.% Ni) alloy particles. Acoustic cavitation is responsible for the initiation of redox processes on the catalyst surface leading to changes in its composition. Cavitation impact on the surface composition of the metal alloy could be controlled by manipulating the sonication medium during ultrasound treatment. Evaluation of electrocatalytic performance, as well as surface composition studies of ultrasonically generated catalysts showed the advantageous use of sonication medium with reducing ability and high vapor pressure for the generation of highly efficient interface on Al-Ni alloy particles for water splitting reaction. PMID- 25453210 TI - Ultrasonic pretreatment in lipase-catalyzed synthesis of structured lipids with high 1,3-dioleoyl-2-palmitoylglycerol content. AB - Production of structured lipid 1,3-dioleoyl-2-palmitoylglycerol (OPO), from tripalmitin (PPP) and oleic acid (OA) using lipases and ultrasonic pretreatment was conducted. Factors influencing both the ultrasonic conditions and enzymatic reaction were investigated. Optimum conditions could be attained with 6 min pretreatment time, 50% ultrasonic power, 3 s/9 s (work/pause) cycle of ultrasonic pulse, 1:8 PPP/OA molar ratio, 12% enzyme dosage and 50 degrees C temperature of. At the optimum conditions, the OPO yield of 51.8% could be achieved in 4h. Studies showed that the OPO content increased to 35.9% in 1h with ultrasonic pretreatment, in comparison to 4h without ultrasonic pretreatment. Reuse of Lipozyme RM IM for 10 cycles under ultrasonic irradiation did not cause essential damage to its lipase activity. Reaction kinetic model fitted well with the proposed Ping-Pong mechanism. The apparent kinetic constant (Vm'/K2) of ultrasound pretreatment reaction was 2.52 times higher than the conventional mechanical stirring, indicating that ultrasound pretreatment enhanced the substrates affinity to the enzyme. This study confirmed that ultrasonic pretreatment was more efficient in OPO production than conventional mechanical agitation. PMID- 25453213 TI - Unique sharp photoluminescence of size-controlled sonochemically synthesized zirconia nanoparticles. AB - The present study explores the features of tetragonally stabilized polycrystalline zirconia nanophosphors prepared by a sonochemistry based synthesis from zirconium oxalate precursor complex. The sonochemically prepared pristine zirconia, 3 mol%, 5 mol% and 8 mol% yttrium doped zirconia nanophosphors were characterized using thermo-gravimetric analysis (TGA), X-ray diffraction (XRD), Raman spectroscopy, field emission scanning electron microscopy (FE-SEM) with energy dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM), diffuse reflectance spectroscopy (DRS) and photoluminescence spectroscopy (PL). The reaction mechanism of formation of zirconia nanophosphors is discussed in detail. The probable sonochemical formation mechanism is being proposed. Stabilization of tetragonal phase of pristine zirconia even at room temperature was effectively established by controlling the particle size using ultrasonic waves. Improved phase purity and good surface morphology of the nanophosphors is being achieved via sonochemical route. FE-SEM micrographs reveal that the nanoparticles have uniform spherical shape and size. The narrow particle size distribution (~15-25 nm) of the zirconia nanoparticles was found from FE-SEM statistical analysis and further confirmed by TEM. Zirconia nanophosphors exhibit a wide energy band gap and which was found to vary with yttrium dopant concentration. The highlight of the present study is the synthesis of novel nanocrystalline ZrO2 and Y-ZrO2 phosphor which simultaneously emits extremely sharp as well as intense UV, violet and cyan light on exciting the host atom. The yttrium ion dopant further enhances the photoluminescence property of zirconia. These nanocrystalline phosphors are likely to have remarkable optical applications as light emitting UV-LEDs, UV lasers and multi color displays. PMID- 25453212 TI - Properties of ultrasound extracted bicomponent lignocellulose thin films. AB - Agricultural and forest residues obtained after harvesting are promising renewable sources, suitable as a source of pulp for cellulose nanocrystal manufacturing. Cavitation-assisted softening of the lignin-carbohydrate matrix offers sample opportunity for cellulose fibril liberation and degradation of amorphous cellulose. The present work addresses cavitation assisted cellulose fibril and crystal liberation and film forming properties of the supernatant phase of treated agricultural and forest residues. The effectiveness of this method has been evaluated according to crystallinity indices and hydrogen bond energies, as measured by FT-IR analysis. It has been observed that the use of cavitation increased the crystallinity and caused partial removal and degradation of the lignin matrix. Overall, it appears that considerable improvement of crystallinity can be obtained from agricultural and forest residues through the use of cavitation. PMID- 25453214 TI - Sonochemical syntheses of two new flower-like nano-scale high coordinated lead(II) supramolecular coordination polymers. AB - Two new neutral nano flower polymeric lead(II) coordination compounds, [Pb(tmph)(MU-SCN)2]n (1) and [Pb(tmph)(MU-NO3)2]n (2), [tmph=3,4,7,8-tetramethyl 1,10-phenanthroline], have been synthesized by a sonochemical process and characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), FT-IR spectroscopy and elemental analyses. SEM image shows the nano flower morphology for the products. Single-crystal X-ray studies show that the overall structure of the both 1 and 2 are 1D double chain net-like coordination polymers. Compound 1 has a very rare bridging cyanato pathway; a tetra dentate bridging between four Pb(II) centers. 1D double chains of compounds 1 and 2 further extended into two-dimensional (2D) and three dimensional (3D) supramolecular structures by strong pi-pi directional intermolecular interactions, respectively. PMID- 25453215 TI - Optimization of ultrasound assisted extraction of bioactive components from brown seaweed Ascophyllum nodosum using response surface methodology. AB - The objective of this study was to investigate the effect of key extraction parameters of extraction time (5-25 min), acid concentration (0-0.06 M HCl) and ultrasound amplitude (22.8-114 MUm) on yields of bioactive compounds (total phenolics, fucose and uronic acid) from Ascophyllumnodosum. Response surface methodology was employed to optimize the extraction variables for bioactive compounds' yield. A second order polynomial model was fitted well to the extraction experimental data with (R(2)>0.79). Extraction yields of 143.12 mgGAE/gdb, 87.06 mg/gdb and 128.54 mg/gdb were obtained for total phenolics, fucose and uronic acid respectively at optimized extraction conditions of extraction time (25 min), acid concentration (0.03 M HCl) and ultrasonic amplitude (114 MUm). Mass spectroscopy analysis of extracts show that ultrasound enhances the extraction of high molecular weight phenolic compounds from A. nodosum. This study demonstrates that ultrasound assisted extraction (UAE) can be employed to enhance extraction of bioactive compounds from seaweed. PMID- 25453216 TI - Effect of H2O2 bleaching with ultrasonication on the properties of thermomechanical pulp and unbleached kraft pulp. AB - H2O2 was used in the final stage of a multistage bleaching process to increase ISO brightness by 2-3%, because of the poor selectivity and bleachability. However, concerns about the environmental load of the bleaching process have led to the efficient use of oxygen-derived compounds, with a concomitant decrease in the quantity of chlorine-derived compounds consumed. In this study, thermomechanical pulp (TMP) and unbleached kraft pulp (UKP) were bleached with H2O2 and ultrasonicated in order to increase the bleaching efficiency, and the effects of some bleaching conditions such as treatment time, treatment concentration, and temperature were determined. The best bleaching efficiency of pulp was obtained using H2O2 with ultrasonication (at 20 kHz) of the pulp mixture at 45 degrees C for 30 min. The ISO brightness of the bleached pulp increased up to 1.9%, although the bleached pulp yield was slightly reduced to 1.5%. Magnesium sulfate was used as a bleaching stabilizer to increase the bleached pulp yield and viscosity. As a result, the bleached pulp yield and viscosity increased by 2.1% and 10%, compared with fully bleached pulp at the end of the process, respectively, despite a decrease in ISO brightness. PMID- 25453217 TI - Reusable tissue-mimicking hydrogel phantoms for focused ultrasound ablation. AB - The ability of N-isopropylacrylamide (NIPAM)-based hydrogel phantoms to mimic tissues with different acoustic and thermal properties under high-intensity focused ultrasound (HIFU) ablation was investigated. These phantoms were designed to model the formation of thermal lesions in tissues above the threshold temperature of protein denaturation. By adjusting the concentration of acrylic acid (AAc) in the NIPAM-based hydrogel phantoms, the cloud point (i.e., lower critical solution temperature) of the phantoms could be tailored to produce HIFU thermal lesions similar to those formed in different swine tissues in terms of size and shape. Additionally, energy thresholds for inducing transient or permanent bubbles in the phantoms during HIFU ablation were also identified to shed light on the onset of cavitation or material damage. The NIPAM-based hydrogel phantoms developed in this study possess major advantages such as transparent, reusable and tailorable properties, and are practical tools for characterizing an ablative device (or treatment) to determine its efficacy and safety. PMID- 25453218 TI - PLCepsilon mediated sustained signaling pathways. AB - Phospholipase C-epsilon (PLCepsilon) integrates signaling from G-protein coupled receptors (GPCRs) to downstream kinases to regulate a broad range of biological and pathophysiological responses. Relative to other PLCs, PLCepsilon is unique in that it not only serves a catalytic function in phosphoinositide hydrolysis but also functions as an exchange factor small the low molecular weight G-protein Rap1. PLCepsilon is selectively stimulated by agonists for GPCRs that couple to RhoA, which bind directly to the enzyme to regulate its activity. Rap1 also regulates PLCepsilon activity by binding to its RA2 domain and this generates a feedback mechanism allowing sustained signaling. As a result of its regulation by inflammatory ligands for GPCRs and its ability to promote chronic signals, PLCepsilon has been implicated in diseases ranging from cancer to ischemia/reperfusion injury. This review will discuss the regulation of PLCepsilon, molecular mechanisms that contribute to sustained signaling, and the role of the enzyme in various disease contexts. PMID- 25453219 TI - Roles of signaling pathways in drug resistance, cancer initiating cells and cancer progression and metastasis. AB - The EGFR/PI3K/PTEN/Akt/mTORC pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance, cancer initiating cells (CICs) and metastasis. The expression of this pathway is frequently altered in breast and other cancers due to mutations at or aberrant expression of: HER2, EGFR1, PIK3CA, and PTEN as well as other oncogenes and tumor suppressor genes. miRs and epigenetic mechanisms of gene regulation are also important events which regulate this pathway. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway has been associated with CICs and in some cases resistance to therapeutics. We will review the effects of activation of the EGFR/PI3K/PTEN/Akt/mTORC pathway primarily in breast cancer and development of drug resistance. The targeting of this pathway and other interacting pathways will be discussed as well as clinical trials with novel small molecule inhibitors as well as established drugs that are used to treat other diseases. In this manuscript, we will discuss an inducible EGFR model (v-ERB-B:ER) and its effects on cell growth, cell cycle progression, activation of signal transduction pathways, prevention of apoptosis in hematopoietic, breast and prostate cancer models. PMID- 25453221 TI - Energy landscapes, folding mechanisms, and kinetics of RNA tetraloop hairpins. AB - RNA hairpins play a pivotal role in a diverse range of cellular functions, and are integral components of ribozymes, mRNA, and riboswitches. However, the mechanistic and kinetic details of RNA hairpin folding, which are key determinants of most of its biological functions, are poorly understood. In this work, we use the discrete path sampling (DPS) approach to explore the energy landscapes of two RNA tetraloop hairpins, and provide insights into their folding mechanisms and kinetics in atomistic detail. Our results show that the potential energy landscapes have a distinct funnel-like bias toward the folded hairpin state, consistent with efficient structure-seeking properties. Mechanistic and kinetic information is analyzed in terms of kinetic transition networks. We find microsecond folding times, consistent with temperature jump experiments, for hairpin folding initiated from relatively compact unfolded states. This process is essentially driven by an initial collapse, followed by rapid zippering of the helix stem in the final phase. Much lower folding rates are predicted when the folding is initiated from extended chains, which undergo longer excursions on the energy landscape before nucleation events can occur. Our work therefore explains recent experiments and coarse-grained simulations, where the folding kinetics exhibit precisely this dependency on the initial conditions. PMID- 25453220 TI - Inositol pyrophosphates: why so many phosphates? AB - The inositol pyrophosphates (PP-InsPs) are a specialized group of "energetic" signaling molecules found in yeasts, plants and animals. PP-InsPs boast the most crowded three dimensional phosphate arrays found in Nature; multiple phosphates and diphosphates are crammed around the six-carbon, inositol ring. Yet, phosphate esters are also a major energy currency in cells. So the synthesis of PP-InsPs, and the maintenance of their levels in the face of a high rate of ongoing turnover, all requires significant bioenergetic input. What are the particular properties of PP-InsPs that repay this investment of cellular energy? Potential answers to that question are discussed here, against the backdrop of a recent hypothesis that signaling by PP-InsPs is evolutionarily ancient. The latter idea is extended herein, with the proposal that the primordial origins of PP-InsPs is reflected in the apparent lack of isomeric specificity of certain of their actions. Nevertheless, there are other aspects of signaling by these polyphosphates that are more selective for a particular PP-InsP isomer. Consideration of the nature of both specific and non-specific effects of PP-InsPs can help rationalize why such molecules possess so many phosphates. PMID- 25453222 TI - Do antipsychotic drugs increase seizure frequency in epilepsy patients? AB - To investigate whether addition of antipsychotic drugs (APD) would increase seizure frequency in epilepsy patients who were already treated with anti epileptic drugs (AED), we compared a one-year seizure control outcome in 150 epilepsy patients with APD treatment for psychiatric conditions and 309 epilepsy patients without APD treatment matched for ages at epilepsy onset and the baseline evaluation and types of epilepsy. The seizure frequency was recorded at the baseline (immediately before the start of APD) and after the 1st, 3rd, 6th and 12th months. The seizure outcome at each of the four follow-up points was compared with the baseline. The seizure outcome was compared between the two groups as a whole and according to the types of epilepsy (idiopathic generalized and partial epilepsies). In the APD group, the seizure outcome was also analyzed according to the types of APD (first and second generation APD and combination of first and second generation APD) and the types of psychiatric conditions (psychosis and non-psychosis). The seizure outcome was significantly better in the APD group than control group at all the four follow-up points. According to the epilepsy types, the improvement in the seizure outcome was only observed in the patients with partial epilepsy. Of the APD group, there was no significant difference in the seizure outcome according to the types of APD or the psychiatric conditions. In epilepsy patients who are already treated with AED, APD treatment seems safe in seizure control outcome for treatment of psychiatric conditions. PMID- 25453223 TI - Blood-brain barrier imaging in human neuropathologies. AB - The blood-brain barrier (BBB) is essential for normal function of the brain, and its role in many brain pathologies has been the focus of numerous studies during the last decades. Dysfunction of the BBB is not only being shown in numerous brain diseases, but animal studies have indicated that it plays a direct key role in the genesis of neurovascular dysfunction and associated neurodegeneration. As such evidence accumulates, the need for robust and clinically applicable methods for minimally invasive assessment of BBB integrity is becoming urgent. This review provides an introduction to BBB imaging methods in the clinical scenario. First, imaging modalities are reviewed, with a focus on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). We then proceed to review image analysis methods, including quantitative and semi-quantitative methods. The advantages and limitations of each approach are discussed, and future directions and questions are highlighted. PMID- 25453224 TI - Consequences of genomic diversity in Mycobacterium tuberculosis. AB - The causative agent of human tuberculosis, Mycobacterium tuberculosis complex (MTBC), comprises seven phylogenetically distinct lineages associated with different geographical regions. Here we review the latest findings on the nature and amount of genomic diversity within and between MTBC lineages. We then review recent evidence for the effect of this genomic diversity on mycobacterial phenotypes measured experimentally and in clinical settings. We conclude that overall, the most geographically widespread Lineage 2 (includes Beijing) and Lineage 4 (also known as Euro-American) are more virulent than other lineages that are more geographically restricted. This increased virulence is associated with delayed or reduced pro-inflammatory host immune responses, greater severity of disease, and enhanced transmission. Future work should focus on the interaction between MTBC and human genetic diversity, as well as on the environmental factors that modulate these interactions. PMID- 25453228 TI - Perspectives on host adaptation in response to Mycobacterium tuberculosis: modulation of inflammation. AB - Tuberculosis (TB) is the outcome of an insidious, protracted infection with Mycobacterium tuberculosis (Mtb). It primarily affects the lung and is characterized by extensive focal inflammation and development of granulomas. TB is therefore a chronic inflammatory condition in which regulatory and pro inflammatory processes, occurring mutually or stage-wise, contribute to disease establishment and progression. Most of the host components involved in TB inflammation, including cytokines (interferons, interleukin (IL)-1, IL-10, tumour necrosis factor) and cells (neutrophils, macrophages, regulatory T cells, type 1 helper lymphocytes, pneumocytes), exhibit dual features: they foster or repress local inflammatory events. As a consequence, selected inflammatory mediators can limit or facilitate TB depending on their temporal and tissue dynamics. Distinct host defence elements contribute not only to genesis of granulomas, but also to their progression to lung cavitation and implicitly TB transmission. Altogether, these pathogenesis traits highlight that the evolutionary success of Mtb relies on its capacity to modulate inflammation to its own benefit. Both pro- and anti inflammatory events are exploited as bacterial evasion strategies in host defence. PMID- 25453229 TI - Pro- and anti-inflammatory cytokines in tuberculosis: a two-edged sword in TB pathogenesis. AB - A major challenge in tuberculosis (TB) is to improve current vaccination and therapeutic strategies and this requires a fine understanding of the mechanisms that mediate protection and pathogenesis. We need to discern how the host perceives Mycobacterium tuberculosis (Mtb) infection, what are the danger signals that activate the immune system and, in turn, how the immune response controls the life-cycle of Mtb. Cytokines, because of their nature of soluble mediators, represent key elements in mediating and tuning these complex processes. In this review, we provide an overview of recent studies on cytokines expression and function in active (mainly human) TB. Understanding of the balance between pro- and anti-inflammatory networks is crucial to refine our knowledge on the immune responses directed against Mtb. PMID- 25453231 TI - The formation of the granuloma in tuberculosis infection. AB - The development of the granuloma and its subsequent degeneration and necrosis, is the hallmark of infection caused by Mycobacterium tuberculosis. These structures probably evolved as primitive particle responses, but in mammals they are facilitated by the emerging acquired immune response, in which cytokines and chemokines help control their formation and integrity. In this brief review we discuss the pathology of these lesions in the two most widely used animal models (mice and guinea pigs). In addition, we argue against the idea that there is a balance between host immunity and bacterial survival, and that the latter possess mechanisms that control this, as some currently believe, and moreover discuss newer information regarding the ability of bacilli to persist in these structures long enough to eventually escape and become retransmitted. PMID- 25453227 TI - Cell death and autophagy in tuberculosis. AB - Mycobacterium tuberculosis has succeeded in infecting one-third of the human race though inhibition or evasion of innate and adaptive immunity. The pathogen is a facultative intracellular parasite that uses the niche provided by mononuclear phagocytes for its advantage. Complex interactions determine whether the bacillus will or will not be delivered to acidified lysosomes, whether the host phagocyte will survive infection or die, and whether the timing and mode of cell death works to the advantage of the host or the pathogen. Here we discuss cell death and autophagy in TB. These fundamental processes of cell biology feature in all aspects of TB pathogenesis and may be exploited to the treatment or prevention of TB disease. PMID- 25453232 TI - Systems-level modeling of mycobacterial metabolism for the identification of new (multi-)drug targets. AB - Systems-level metabolic network reconstructions and the derived constraint-based (CB) mathematical models are efficient tools to explore bacterial metabolism. Approximately one-fourth of the Mycobacterium tuberculosis (Mtb) genome contains genes that encode proteins directly involved in its metabolism. These represent potential drug targets that can be systematically probed with CB models through the prediction of genes essential (or the combination thereof) for the pathogen to grow. However, gene essentiality depends on the growth conditions and, so far, no in vitro model precisely mimics the host at the different stages of mycobacterial infection, limiting model predictions. These limitations can be circumvented by combining expression data from in vivo samples with a validated CB model, creating an accurate description of pathogen metabolism in the host. To this end, we present here a thoroughly curated and extended genome-scale CB metabolic model of Mtb quantitatively validated using 13C measurements. We describe some of the efforts made in integrating CB models and high-throughput data to generate condition specific models, and we will discuss challenges ahead. This knowledge and the framework herein presented will enable to identify potential new drug targets, and will foster the development of optimal therapeutic strategies. PMID- 25453226 TI - Macrophage immunoregulatory pathways in tuberculosis. AB - Macrophages, the major host cells harboring Mycobacterium tuberculosis (M.tb), are a heterogeneous cell type depending on their tissue of origin and host they are derived from. Significant discord in macrophage responses to M.tb exists due to differences in M.tb strains and the various types of macrophages used to study tuberculosis (TB). This review will summarize current concepts regarding macrophage responses to M.tb infection, while pointing out relevant differences in experimental outcomes due to the use of divergent model systems. A brief description of the lung environment is included since there is increasing evidence that the alveolar macrophage (AM) has immunoregulatory properties that can delay optimal protective host immune responses. In this context, this review focuses on selected macrophage immunoregulatory pattern recognition receptors (PRRs), cytokines, negative regulators of inflammation, lipid mediators and microRNAs (miRNAs). PMID- 25453225 TI - Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-gamma immunity. AB - Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition characterized by predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy individuals with no overt abnormalities in routine hematological and immunological tests. MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis, and more rarely to infections with other intramacrophagic bacteria, fungi, or parasites, and even, perhaps, a few viruses. Since 1996, nine MSMD causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, and CYBB) genes have been discovered. The high level of allelic heterogeneity has already led to the definition of 18 different disorders. The nine gene products are physiologically related, as all are involved in IFN-gamma-dependent immunity. These disorders impair the production of (IL12B, IL12RB1, IRF8, ISG15, NEMO) or the response to (IFNGR1, IFNGR2, STAT1, IRF8, CYBB) IFN-gamma. These defects account for only about half the known MSMD cases. Patients with MSMD-causing genetic defects may display other infectious diseases, or even remain asymptomatic. Most of these inborn errors do not show complete clinical penetrance for the case-definition phenotype of MSMD. We review here the genetic, immunological, and clinical features of patients with inborn errors of IFN-gamma-dependent immunity. PMID- 25453234 TI - Factors Predisposing to Endograft Limb Occlusion after Endovascular Aortic Repair. AB - OBJECTIVES: The aim of this study was to investigate risk factors for endograft limb occlusion after endovascular abdominal aneurysm repair (EVAR), using a case control design. METHODS: All patients presenting with endograft limb occlusion after elective EVAR between January 2010 and June 2013, along with age, sex, and type of endograft matched controls were included in the study. The impact of atherosclerotic risk factors, anatomic characteristics of the aneurysm, procedural details, and antiplatelet therapy was investigated. Multivariate logistic regression analysis and conditional logistic regression analysis for 1:3 matched pairs deriving adjusted odds ratios (ORs) with 95% confidence intervals (CIs) in order to detect significant risk factors for endograft limb occlusion among cases and controls were modeled. RESULTS: Of the 439 patients treated by EVAR, 18 patients (4.1%) presented with endograft limb occlusion. These patients were compared to 54 matched controls. Limb occlusion was associated with iliac artery angulation >= 60 degrees (OR = 5.76, 95% CI =1.24-26.74; p = .03) or perimeter calcification >= 50% (OR =5.87, 95% CI = 1.10-31.32; p = .04). Limb occlusion was also associated with >= 15% endograft oversizing in the common iliac artery (OR = 5.54, 95% CI = 1.11-27.60; p = .04). No other risk factors for limb occlusion were recognized. CONCLUSIONS: The presence of significant angulation and calcification of the iliac arteries as well as excessive limb oversizing appear to be independent predictors of endograft limb occlusion after EVAR. PMID- 25453230 TI - Understanding and overcoming the barriers to T cell-mediated immunity against tuberculosis. AB - Despite the overwhelming success of immunization in reducing, and even eliminating, the global threats posed by a wide spectrum of infectious diseases, attempts to do the same for tuberculosis (TB) have failed to date. While most effective vaccines act by eliciting neutralizing antibodies, T cells are the primary mediators of adaptive immunity against TB. Unfortunately, the onset of the T cell response after aerosol infection with Mycobacterium tuberculosis (Mtb), the bacterium that causes TB, is exceedingly slow, and systemically administered vaccines only modestly accelerate the recruitment of effector T cells to the lungs. This delay seems to be orchestrated by Mtb itself to prolong the period of unrestricted bacterial replication in the lung that characterizes the innate phase of the response. When T cells finally arrive at the site of infection, multiple layers of regulation have been established that limit the ability of T cells to control or eradicate Mtb. From this understanding, emerges a strategy for achieving immunity. Lung resident memory T cells may recognize Mtb infected cells shortly after infection and confer protection before regulatory networks are allowed to develop. Early studies using vaccines that elicit lung resident T cells by targeting the lung mucosa have been promising, but many questions remain. Due to the fundamental nature of these questions, and the need to understand and manipulate the early events in the lung after aerosol infection, only coordinated approaches that utilize tractable animal models to inform human TB vaccine trials will move the field toward its goal. PMID- 25453235 TI - Abdominal Aortic Aneurysm Diameters: A Study on the Discrepancy between Inner to Inner and Outer to Outer Measurements. AB - INTRODUCTION: The NHS Abdominal Aortic Aneurysm Screening Programme (NAAASP) uses the maximal anterior to posterior (AP) inner-to-inner (ITI) wall diameter in sizing aortic dimensions when screening with ultrasound. It is recognised that ITI measurements are smaller than outer-to-outer (OTO) measurements, and the primary aim was to calculate the absolute difference in AP ITI and OTO measurements across varying aortic diameters. The secondary aim was to estimate the potential number of patients lost from the screening programme. METHODS: Since April 2012, patients outside the screening programme that undergo ultrasound of abdominal aortas have their ITI and OTO measurements recorded. These measurements were compared retrospectively and analysed for variability at threshold sizes of AAAs. RESULTS: From May 2012 to October 2013, 452 abdominal aortic ultransound scans recorded both ITI and OTO measurements. The majority (81%) were performed on men with the mean age of 78 years. The mean difference between ITI and OTO measurements was 4.21 mm (p < .001). There was no difference between the genders. Thresholds were created for analysis between different ITI and OTO aortic diameters; these were <3 cm, 3.1-4 cm, 4.1-5 cm, and >5 cm. There was no significant difference between the means at each threshold size for ITI diameter (p = .758). In the first 2 years from April 2012, 15,447 men underwent screening.Of these, 177 (1.14%) had sub-threshold ITI aortic diameters between 2.6 cm and 2.9 cm. This would upscale to 5,316 men nationally. CONCLUSION: We have demonstrated a consistent and significant 4mm difference between ITI and OTO diameters in live scanning. Lowering the threshold for entry into a surveillance AAAs to an ITI diameter of 26mm rather than the current 30 mm is advocated. An alternative cost-effective way is to rescreen this small sub-group at 5 or 7 years. PMID- 25453233 TI - Activation of phenylalanine hydroxylase by phenylalanine does not require binding in the active site. AB - Phenylalanine hydroxylase (PheH), a liver enzyme that catalyzes the hydroxylation of excess phenylalanine in the diet to tyrosine, is activated by phenylalanine. The lack of activity at low levels of phenylalanine has been attributed to the N terminus of the protein's regulatory domain acting as an inhibitory peptide by blocking substrate access to the active site. The location of the site at which phenylalanine binds to activate the enzyme is unknown, and both the active site in the catalytic domain and a separate site in the N-terminal regulatory domain have been proposed. Binding of catecholamines to the active-site iron was used to probe the accessibility of the active site. Removal of the regulatory domain increases the rate constants for association of several catecholamines with the wild-type enzyme by ~2-fold. Binding of phenylalanine in the active site is effectively abolished by mutating the active-site residue Arg270 to lysine. The k(cat)/K(phe) value is down 104 for the mutant enzyme, and the K(m) value for phenylalanine for the mutant enzyme is >0.5 M. Incubation of the R270K enzyme with phenylalanine also results in a 2-fold increase in the rate constants for catecholamine binding. The change in the tryptophan fluorescence emission spectrum seen in the wild-type enzyme upon activation by phenylalanine is also seen with the R270K mutant enzyme in the presence of phenylalanine. Both results establish that activation of PheH by phenylalanine does not require binding of the amino acid in the active site. This is consistent with a separate allosteric site, likely in the regulatory domain. PMID- 25453236 TI - Mid-Term Results of EVAR in Severe Proximal Aneurysm Neck Angulation. AB - OBJECTIVE: To determine if mid-term outcome following endovascular aneurysm repair (EVAR) with the Endurant Stent Graft (Medtronic, Santa Rosa, CA, USA) is influenced by severe proximal neck angulation. METHODS: A retrospective case control study was performed using data from a prospective multicenter database. All measurements were obtained using dedicated reconstruction software and center lumen line reconstruction. Patients with neck length >15 mm, infrarenal angle beta > 75 degrees , and/or suprarenal angle alpha > 60 degrees , or neck length >10 mm with beta > 60 degrees , and/or alpha > 45 degrees were compared with a matched control group. Primary endpoint was primary clinical success. Secondary endpoints were freedom from rupture, type 1A endoleak, stent fractures, freedom from neck-related reinterventions, and aneurysm-related adverse events. Morphological neck variation over time was also assessed. RESULTS: Forty-five patients were included in the study group and were compared with a matched control group with 65 patients. Median follow-up time was 49.5 months (range 30.5 58.4). The 4-year primary clinical success estimates were 83% and 80% for the angulated and nonangulated groups (p = .42). Proximal neck angulation did not affect primary clinical success in a multivariate model (hazard ratio 1.56, 95% confidence interval 0.55-4.41).Groups did not differ significantly in regard to freedom from rupture (p =.79), freedom from type 1A endoleak (p = .79), freedom from neck-related adverse events (p = .68), and neck-related reinterventions (p = .68). Neck angle reduction was more pronounced in patients with severe proximal neck angulation (mean deltaalpha -15.6 degrees , mean deltabeta -30.6 degrees ) than in the control group (mean deltaalpha -0.39 degrees , mean deltabeta -5.9 degrees ) (p < .001). CONCLUSION: Mid-term outcomes following EVAR with the Endurant Stent Graft were not influenced by severe proximal neck angulation in our population. Despite the conformability of the device, moderate aortic neck remodeling was identified in the group of patients with angulated neck anatomy on the first computed tomography scan after implantation with no important further remodeling afterwards. No device integrity failures were encountered. PMID- 25453238 TI - Re. 'Identification of patients with a histologically unstable carotid plaque using ultrasonic plaque image analysis'. PMID- 25453237 TI - Second Toe Systolic Pressure Measurements are Valid Substitutes for First Toe Systolic Pressure Measurements in Diabetic Patients: A Prospective Study. AB - OBJECTIVE: Toe systolic pressure is a component of the standard vascular and diabetic foot assessment. Until now,clinicians have measured only first toe pressure given a lack of evidence for measurements of the other toes. In diabetic patients, first toe measurements are often not possible because of ulceration or amputation. It was hypothesized that the adjacent second toe systolic pressure measurements would be interchangeable with those of the first toe. METHODS: A prospective study was performed on 100 participants with diabetes mellitus. Duplicate systolic toe pressures were measured in the first toe and adjacent second toe using the Systoe Automated Toe Pressure System, Systoe Photophlethysmograph Sensor Cuff, and occlusion cuffs measuring 120 x 25 mm for the first toe and 90 x 15 mm for the second toe. Correlation analysis was followed by Ordinary Least Products regression to detect and distinguish fixed and proportional bias between the two toe measurements. The acceptable limits of interchangeable results were defined as 5-10 mmHg. RESULTS: Correlation coefficient r 1/4 0.908; p < 0.001. Eighty-two percent of the variations in the second toe measurements were accounted for by knowing the first toe measurements and vice versa. Ordinary Least Products regression showed no fixed or proportional bias between the two methods of measurement: second toe systolic pressure = (-0.579) + (1.038) * first toe systolic pressure. Repeatability analysis showed a 0.5%variation between duplicate measurements. CONCLUSIONS: This is the first study which demonstrates that second toe systolic pressures are interchangeable with those of the first toe. Second toe pressures can be used in diabetic patients whose first toe pressures cannot be assessed. PMID- 25453239 TI - What does it take to have a high-quality journal? PMID- 25453240 TI - Nausea: current knowledge of mechanisms, measurement and clinical impact. AB - Nausea is a subjective sensation, which often acts as a signal that emesis is imminent. It is a widespread problem that occurs as a clinical sign of disease or as an adverse effect of a drug therapy or surgical procedure. The mechanisms of nausea are complex and the neural pathways are currently poorly understood. This review summarises the current knowledge of nausea mechanisms, the available animal models for nausea research and the anti-nausea properties of commercially available anti-emetic drugs. The review also presents subjective assessment and scoring of nausea. A better understanding of the underlying mechanisms of nausea might reveal potential clinically useful biomarkers for objective measurement of nausea in species of veterinary interest. PMID- 25453241 TI - Ethical considerations in feline renal transplantation. PMID- 25453242 TI - Behind the vertical and behind the times. PMID- 25453243 TI - Evaluation of a commercial in-clinic point-of-care polymerase chain reaction test for Ehrlichia canis DNA in artificially infected dogs. AB - A novel in-clinic point-of-care (ICPOC) polymerase chain reaction (PCR) test was evaluated for its ability to detect Ehrlichia canis DNA in artificially infected dogs compared to a real-time PCR assay. Six Beagle dogs negative for E. canis antibodies and PCR negative were artificially infected with an Israeli E. canis strain (611). All dogs developed IgG antibodies 8 days post infection (PI), and clinical and hematological abnormalities on day 10 PI. Only the real-time PCR detected E. canis DNA in the blood of five dogs at days 3 and 5 PI. At day 12 PI during the acute phase of the disease, 1 day after the initiation of doxycycline treatment, the ICPOC PCR assay detected E. canis DNA in all infected dogs, which were also positive by the real-time PCR. Two days later the ICPOC PCR assay was able to detect only 3/6 infected dogs, which were all positive by the real-time PCR. At days 17 and 19 PI, the ICPOC PCR assay did not detect E. canis DNA in the dogs while the real-time PCR detected all dogs as positive on day 17 PI and two dogs on day 19 PI. In conclusion, the sensitivity of the ICPOC PCR assay was 75% for the acute phase of the disease and 30% for the whole study, suggesting that this ICPOC assay has a potential utility for the diagnosis of acute canine monocytic ehrlichiosis. PMID- 25453244 TI - Neuroretinitis in ocular bartonellosis. PMID- 25453245 TI - Papillary thyroid carcinomas in patients under 21 years of age: clinical and histologic characteristics of tumors <=10 mm. AB - OBJECTIVE: To compare clinical and histologic characteristics of papillary thyroid carcinomas (PTCs) <=10 mm in patients <=21 years old with larger ones and with microcarcinomas in adults. STUDY DESIGN: Retrospective study of patients with PTC diagnosed between 1983 and 2012. Medical records were reviewed and information about age, sex, tumor size, intra/extrathyroid extension, lymph node, and distant metastases were collected. RESULTS: Patients <=21 years old (n = 93) and adults (n = 1235) with PTC were identified. Among the former, 34 had PTC <=10 mm (37.4%) and among the latter, 584 had papillary thyroid microcarcinoma (PTM) (47.3%), P = .082. Patients with tumors <=10 mm less frequently had extrathyroidal extension and lymph node metastases compared with larger tumors (8.8% vs 33.3%, P = .017, and 60.0% vs 95.2%, P = .001, respectively). The percentage of PTC <=10 mm increased with age (7.1%, 32.0%, and 48.1% in age groups <=15, 15-18, and >18 to <=21 years old, respectively; P = .016). Mean tumor size was larger (6.8 +/- 2.7 vs 5.8 +/- 2.8 mm, P = .030), and lymph nodes metastases were more frequent (41.2% vs 18.6%, P = .003) in patients <=21 years of age compared with adults with PTM. The frequency of multifocal cancers decreased between 1983-1992, 1993-2002, and 2003-2012 (66.7%, 53.6%, and 27.1%, respectively, P = .019). CONCLUSIONS: The frequency of PTC <=10 mm is low in children, increases in adolescents, and reaches that of adults at 18-21 years of age. Mean tumor size is larger and metastases to regional lymph nodes more frequent in comparison with PTM in adults. Whether their treatment and follow-up could be based on guidelines used for PTM in adults is questionable. PMID- 25453246 TI - Risk of cancer in children, adolescents, and young adults with autistic disorder. AB - OBJECTIVES: To investigate whether individuals with autism have an increased risk for cancer relative to the general population. STUDY DESIGN: We enrolled patients with autistic disorder from the Taiwan National Health Insurance database in years 1997-2011. A total of 8438 patients diagnosed with autism were retrieved from the Registry for Catastrophic Illness Patients database. The diagnosis of cancers was also based on the certificate of catastrophic illness, which requires histological confirmation. The risk of cancer among the autism cohort was determined with a standardized incidence ratio (SIR). RESULTS: During the observation period, cancer occurred in 20 individuals with autism, which was significantly higher than a total number of expected cancers with a SIR estimate of 1.94 (95% CI 1.18-2.99). The number of cancer in males was greater than the expected number with a SIR of 1.95 (1.11-3.16), but no excess risk was found for females with a SIR of 1.91 (0.52-4.88). Cancer developed more than expected in individuals age 15-19 years with the SIR of 3.58 (1.44-7.38), but did not differ in other age range groups. The number of cancers of genitourinary system was significantly in excess of the expected number (SIR 4.15; 95% CI 1.13-10.65), and increased risk was found in ovarian cancer with SIR of 9.21 (1.12-33.29). CONCLUSIONS: Our study demonstrated that patients with autistic disorder have an increased risk of cancer. PMID- 25453247 TI - New technique for umbilical artery catheter placement in the neonate. PMID- 25453248 TI - Persistence of pulmonary hypertension by echocardiography predicts short-term outcomes in congenital diaphragmatic hernia. AB - OBJECTIVES: To describe the natural history of pulmonary hypertension (PH) and the risk of death and pulmonary morbidity associated with the persistence of PH through the neonatal hospitalization for these infants. STUDY DESIGN: We performed a retrospective cohort study of infants with congenital diaphragmatic hernia (CDH) cared for at University of California San Francisco (2002-2012). Infants with other major anomalies or syndromes were excluded (n = 43). Clinical echocardiograms were performed weekly for up to 6 weeks or until PH resolved off respiratory support or until hospital discharge. Echocardiograms were re-read by a blinded reviewer and categorized by severity of elevation in estimated pulmonary arterial pressure. PH was defined as >=2/3 systemic blood pressure. Severity was determined by a hierarchy of ductus arteriosus level shunt, interventricular septal position, and tricuspid regurgitant jet velocity. RESULTS: Of 140 infants with >=1 echo, 98 resolved their PH prior to death/discharge. Mean time to resolution was 18 days (median 14 days, IQR 8, 21 days). Those with persistence of PH had a higher rate of extracorporeal membrane oxygenation (P < .001) and death (P < .001), and fewer ventilator-free days (P < .001). Persistence of PH at 14 days predicted mortality (area under the receiver operating characteristic curve 0.87) and adverse respiratory outcomes (area under the receiver operating characteristic curve 0.80-0.83). CONCLUSIONS: The majority of infants with CDH resolve PH between 1 and 3 weeks of life. At 2 weeks of age, severity of PH by echocardiogram strongly predicts short-term pulmonary morbidity and death. Further evaluation of physiological alterations during that time may lead to novel therapies for severe CDH. PMID- 25453251 TI - Planning the content of a brief educational course in maxillofacial emergencies for staff in accident and emergency departments: a modified Delphi study. AB - It is well known that staff in accident and emergency (A&E) departments lack the knowledge and confidence needed to deal with maxillofacial emergencies, and that it is related to limited education at undergraduate and postgraduate levels. We therefore aimed to design a syllabus for a short course to educate staff about the most common emergencies. To find out which learning outcomes should be included and to reach a consensus, we did a 3-stage modified Delphi study of the opinions of members of the British Association of Oral and Maxillofacial Surgeons (BAOMS). Of a possible 890 members, 188 responded (21%) in the second round and 105 in the third (12%). Eighteen (37%) of the 49 proposed learning outcomes were rated very important and all of them were retained in the syllabus after the third round. Thirty (61%) items were retained with a consensus of 51% or above in the final round. The Delphi technique is a useful addition to the armamentarium of those involved in education, and has been used effectively in syllabus design. We achieved good consensus on the items to be included and the syllabus will be piloted locally. PMID- 25453252 TI - Simple and atraumatic technique for the advancement of the genioglossus muscle for treatment of obstructive sleep apnoea. PMID- 25453253 TI - Update on patterns of mandibular fracture in Tasmania, Australia. AB - Mandibular fractures often present to hospital, so if we understand trends in patterns of fractures and their demographics it may help us to deliver a better service, and prevent these injuries. Here, we compare current data on mandibular fractures in Tasmania with data from 15 years ago, and with current world trends. Patients who presented to the Royal Hobart Hospital with fractured mandibles were audited, and the data analysed and compared with those from a previous study. About 37 fractured mandibles presented to hospital each year. Most patients were men aged 20-30 years old. Ninety-seven of the 159 fractures (61%) were secondary to assault, 27 (17%) were the result of sport, and 24 (15%) followed falls. Road crashes contributed only 5% of mandibular fractures. Sixty-six patients (60%) were intoxicated at the time of injury. The angle of the mandible was the most common site of fracture and open reduction and internal fixation was the treatment of choice. There have been important changes in mandibular fracture patterns in Tasmania in the last 15 years. There was a rise in alcohol-related interpersonal violence, and men were most commonly involved. There was also a decrease in mandibular fractures caused by road crashes, which suggests an improvement in road safety. PMID- 25453254 TI - Feasibility of robot-assisted neck dissection followed by transoral robotic surgery. AB - Our aim was to evaluate the feasibility of robot-assisted neck dissection (RAND) followed by transoral robotic surgery (TORS) in treatment of cancers of the head and neck, which is expected to improve cosmesis and function. We studied 37 patients with biopsy-confirmed cNO or cN+ tumours of the oropharynx (n=22), hypopharynx (n=8), larynx (n=6), and oral cavity (n=1) who were treated by RAND then TORS from May 2010 to December 2012. Patients' characteristics and clinical details were recorded, together with operative complications and functional variables such as management of the airway and nasogastric or enterogastric feeding. All endoscopic TORS and RAND were successful, with no serious intraoperative complications or need to convert to open operation. All patients were satisfied with the cosmesis according to the answers given to a questionnaire. RAND followed by TORS in some cancers of the head and neck are feasible and showed a clear cosmetic benefit, although the longer operating time is a drawback. Studies of more patients with longer follow-up are required to evaluate long-term oncological and functional outcomes in more detail. PMID- 25453257 TI - Alterations in brain leptin signalling in spite of unchanged CSF leptin levels in Alzheimer's disease. AB - Several studies support the relation between leptin and Alzheimer's disease (AD). We show that leptin levels in CSF are unchanged as subjects progress to AD. However, in AD hippocampus, leptin signalling was decreased and leptin localization was shifted, being more abundant in reactive astrocytes and less in neurons. Similar translocation of leptin was found in brains from Tg2576 and apoE4 mice. Moreover, an enhancement of leptin receptors was found in hippocampus of young Tg2576 mice and in primary astrocytes and neurons treated with Abeta1 42. In contrast, old Tg2576 mice showed decreased leptin receptors levels. Similar findings to those seen in Tg2576 mice were found in apoE4, but not in apoE3 mice. These results suggest that leptin levels are intact, but leptin signalling is impaired in AD. Thus, Abeta accumulation and apoE4 genotype result in a transient enhancement of leptin signalling that might lead to a leptin resistance state over time. PMID- 25453259 TI - Single molecule microscopy in 3D cell cultures and tissues. AB - From the onset of the first microscopic visualization of single fluorescent molecules in living cells at the beginning of this century, to the present, almost routine application of single molecule microscopy, the method has well proven its ability to contribute unmatched detailed insight into the heterogeneous and dynamic molecular world life is composed of. Except for investigations on bacteria and yeast, almost the entire story of success is based on studies on adherent mammalian 2D cell cultures. However, despite this continuous progress, the technique was not able to keep pace with the move of the cell biology community to adapt 3D cell culture models for basic research, regenerative medicine, or drug development and screening. In this review, we will summarize the progress, which only recently allowed for the application of single molecule microscopy to 3D cell systems and give an overview of the technical advances that led to it. While initially posing a challenge, we finally conclude that relevant 3D cell models will become an integral part of the on-going success of single molecule microscopy. PMID- 25453260 TI - In vitro microenvironments to study breast cancer bone colonisation. AB - Bone metastasis occurs frequently in patients with advanced breast cancer and is a major cause of morbidity and mortality in these patients. In order to advance current therapies, the mechanisms leading to the formation of bone metastases and their pathophysiology have to be better understood. Several in vitro models have been developed for systematic studies of interactions between breast cancer cells and the bone microenvironment. Such models can provide insights into the molecular basis of bone metastatic colonisation and also may provide a useful platform to design more physiologically relevant drug testing assays. This review describes different in vitro approaches and discusses their advantages and disadvantages. PMID- 25453258 TI - Virus integration and genome influence in approaches to stem cell based therapy for andro-urology. AB - Despite the potential of stem cells in cell-based therapy, major limitations such as cell retention, ingrowth, and trans-differentiation after implantation remain. One technique for genetic modification of cells for tissue repair is the introduction of specific genes using molecular biology techniques, such as virus integration, to provide a gene that adds new functions to enhance cellular function, and to secrete trophic factors for recruiting resident cells to participate in tissue repair. Stem cells can be labeled to track cell survival, migration, and lineage. Increasing evidence demonstrates that cell therapy and gene therapy in combination remarkably improve differentiation of implanted mesenchymal stromal cells (MSCs), revascularization, and innervation in genitourinary tissues, especially to treat urinary incontinence, erectile dysfunction, lower urinary tract reconstruction, and renal failure. This review discusses the benefits, safety, side effects, and alternatives for using genetically modified MSCs in tissue regeneration in andro-urology. PMID- 25453261 TI - Modeling human carcinomas: physiologically relevant 3D models to improve anti cancer drug development. AB - Anti-cancer drug development is inefficient, mostly due to lack of efficacy in human patients. The high fail rate is partly due to the lack of predictive models or the inadequate use of existing preclinical test systems. However, progress has been made and preclinical models were improved or newly developed, which all account for basic features of solid cancers, three-dimensionality and heterotypic cell interaction. Here we give an overview of available in vivo and in vitro models of cancer, which meet the criteria of being 3D and mirroring human tumor stroma interactions. We only focus on drug response models without touching models for pharmacokinetic and dynamic, toxicity or delivery aspects. PMID- 25453263 TI - Potential of stem cell treatment in detrusor dysfunction. AB - The current treatments of bladder dysfunctions, such as bladder overactivity and impaired ability to empty, have limitations, and new treatment alternatives are needed. Stem cell transplantation and tissue engineering have shown promising results in preclinical studies. Stem cells were originally thought to act by differentiating into various cell types, thereby replacing damaged cells and restoring functional deficits. Even if such a mechanism cannot be excluded, the current belief is that a main action is exerted by the stem cells secreting bioactive factors that direct other stem cells to the target organ. In addition, stem cells may exert a number of other effects that can improve bladder dysfunction, since they may have antiapoptotic, antifibrotic, and immunomodulatory properties, and can induce neovascularization. Tissue engineering for bladder replacement, which has had varying success in different animal species, has reached the proof-of-concept state in humans, but recent research suggests that the present approaches may not be optimal. Further studies on new approaches, using animal models with translational predictability, seem necessary for further progress. PMID- 25453264 TI - Stress urinary incontinence animal models as a tool to study cell-based regenerative therapies targeting the urethral sphincter. AB - Urinary incontinence (UI) is a major health problem causing a significant social and economic impact affecting more than 200million people (women and men) worldwide. Over the past few years researchers have been investigating cell therapy as a promising approach for the treatment of stress urinary incontinence (SUI) since such an approach may improve the function of a weakened sphincter. Currently, a diverse collection of SUI animal models is available. We describe the features of the different models of SUI/urethral dysfunction and the pros and cons of these animal models in regard to cell therapy applications. We also discuss different cell therapy approaches and cell types tested in preclinical animal models. Finally, we propose new research approaches and perspectives to ensure the use of cellular therapy becomes a real treatment option for SUI. PMID- 25453262 TI - Dynamic reciprocity in cell-scaffold interactions. AB - Tissue engineering in urology has shown considerable promise. However, there is still much to understand, particularly regarding the interactions between scaffolds and their host environment, how these interactions regulate regeneration and how they may be enhanced for optimal tissue repair. In this review, we discuss the concept of dynamic reciprocity as applied to tissue engineering, i.e. how bi-directional signaling between implanted scaffolds and host tissues such as the bladder drives the process of constructive remodeling to ensure successful graft integration and tissue repair. The impact of scaffold content and configuration, the contribution of endogenous and exogenous bioactive factors, the influence of the host immune response and the functional interaction with mechanical stimulation are all considered. In addition, the temporal relationships of host tissue ingrowth, bioactive factor mobilization, scaffold degradation and immune cell infiltration, as well as the reciprocal signaling between discrete cell types and scaffolds are discussed. Improved understanding of these aspects of tissue repair will identify opportunities for optimization of repair that could be exploited to enhance regenerative medicine strategies for urology in future studies. PMID- 25453265 TI - Regenerative medicine for the treatment of reproductive system disorders: current and potential options. AB - Regenerative medicine has opened new avenues for treating patients with severe reproductive system disorders, such as congenital abnormalities, cancer, trauma, infection, inflammation and iatrogenic injuries. Over the past two decades, scientists have advanced the field of reproductive tissue engineering to restore normal sexual function and preserve fertility in both female and male patients. In this review, we summarize recent advances in the use of cell, tissue, and organ-based regenerative medicine strategies for clinical application in reproductive system disorders. PMID- 25453267 TI - External physical and biochemical stimulation to enhance skeletal muscle bioengineering. AB - PURPOSE OF REVIEW: Cell based muscle tissue engineering carries the potential to revert the functional loss of muscle tissue caused by disease and trauma. Although muscle tissue can be bioengineered using various precursor cells, major limitations still remain. RECENT FINDINGS: In the last decades several cellular pathways playing a crucial role in muscle tissue regeneration have been described. These pathways can be influenced by external stimuli and they not only orchestrate the regenerative process after physiologic wear and muscle trauma, but also play an important part in aging and maintaining the stem cell niche, which is required to maintain long-term muscle function. SUMMARY: In this review article we will highlight possible new avenues using external physical and biochemical stimulation in order to optimize muscle bioengineering. PMID- 25453270 TI - Preclinical safety and efficacy models for pulmonary drug delivery of antimicrobials with focus on in vitro models. AB - New pharmaceutical formulations must be proven as safe and effective before entering clinical trials. Also in the context of pulmonary drug delivery, preclinical models allow testing of novel antimicrobials, reducing risks and costs during their development. Such models allow reducing the complexity of the human lung, but still need to reflect relevant (patho-) physiological features. This review focuses on preclinical pulmonary models, mainly in vitro models, to assess drug safety and efficacy of antimicrobials. Furthermore, approaches to investigate common infectious diseases of the respiratory tract, are emphasized. Pneumonia, tuberculosis and infections occurring due to cystic fibrosis are in focus of this review. We conclude that especially in vitro models offer the chance of an efficient and detailed analysis of new antimicrobials, but also draw attention to the advantages and limitations of such currently available models and critically discuss the necessary steps for their future development. PMID- 25453271 TI - Strategies employed in the design and optimization of synthetic antimicrobial peptide amphiphiles with enhanced therapeutic potentials. AB - Antimicrobial peptides (AMPs) which predominantly act via membrane active mechanisms have emerged as an exciting class of antimicrobial agents with tremendous potential to overcome the global epidemic of antibiotics-resistant infections. The first generation of AMPs derived from natural sources as diverse as plants, insects and humans has provided a wealth of compositional and structural information to design novel synthetic AMPs with enhanced antimicrobial potencies and selectivities, reduced cost of production due to shorter sequences and improved stabilities under physiological conditions. In this review, we will first discuss the common strategies employed in the design and optimization of synthetic AMPs, followed by highlighting the various approaches utilized to enhance the therapeutic potentials of designed AMPs under physiological conditions. Lastly, future perspectives on the development of improved AMPs for therapeutic applications will be presented. PMID- 25453272 TI - Laminar airflow and the prevention of surgical site infection. More harm than good? AB - INTRODUCTION: Laminar airflow (LAF) systems are thought to minimise contamination of the surgical field with airborne microbes and thus to contribute to reducing surgical site infections (SSI). However recent publications have questioned whether LAF ventilation confers any significant benefit and may indeed be harmful. METHODS: A detailed literature review was undertaken through www.Pubmed.com and Google scholar (http://scholar.google.com). Search terms used included "laminar flow". "laminar airflow", "surgical site infection prevention", "theatre ventilation" and "operating room ventilation", "orthopaedic theatre" and "ultra-clean ventilation". Peer-reviewed publications in the English language over the last 50 years were included, up to and including March 2014. RESULTS: Laminar airflow systems are predominantly used in clean prosthetic implant surgery. Several studies have demonstrated decreased air bacterial contamination with LAF using bacterial sedimentation plates placed in key areas of the operating room. However, apart from the initial Medical Research Council study, there are few clinical studies demonstrating a convincing correlation between decreased SSI rates and LAF. Moreover, recent analyses suggest increased post operative SSI rates. CONCLUSION: It is premature to dispense with LAF as a measure to improve air quality in operating rooms where prosthetic joint surgery is being carried out. However, new multi-centre trials to assess this or the use of national prospective surveillance systems to explore other variables that might explain these findings such as poor operating room discipline are needed, to resolve this important surgical issue. PMID- 25453268 TI - Clinical applications of pulmonary delivery of antibiotics. AB - The treatment of infection typically involves administration of antibiotics by a systemic route, such as intravenous or oral. However, pulmonary infections can also be approached by inhalation of antibiotics as the infection is more directly accessible via the airways, making inhalation delivery essentially topical administration. This approach offers deposition of high antimicrobial concentrations directly at the site of infection but with a potentially reduced systemic exposure. This review covers the evidence for aerosolized antibiotics for the treatment of a number of conditions such as cystic fibrosis (CF), where it has become the standard of care for chronic infection, as well as non-CF bronchiectasis, non-tuberculous mycobacteria, and ventilator-associated infection where such therapy does not have an approved indication but has been used with increasing frequency. PMID- 25453273 TI - The peace of paper: patient lists as work tools. AB - INTRODUCTION: Paper-based documents are subject to problems related to storage, loss, distribution and editing. Many organizations have introduced ICT-based processes to reduce the use of paper as primary documentation. Nevertheless, paper documents are still being used in healthcare. PURPOSE: To better understand this situation, we have studied the use of paper-based patient lists in two wards in a Norwegian hospital that has 'gone digital'. We seek to answer the question: "Why is it that paper-based patient lists are maintained in the ward of a hospital going digital?" METHODS: Participant observations and semi-structured interviews with stakeholders. RESULTS: Patient lists allow nurses to immediately record, retrieve, and share relevant patient information at the point of care in a way that is not immediately available through the EPR system. Paper-based tools continue to serve purposes beyond and outside what is currently supported by current electronic information systems. PMID- 25453275 TI - Accessing personal medical records online: a means to what ends? AB - BACKGROUND: Initiatives in the UK to enable patients to access their electronic health records (EHRs) are gathering momentum. All citizens of the European Union should have access to their records by 2015, a target that the UK has endorsed. OBJECTIVES: To identify the ways in which patients used their access to their EHRs, what they sought to achieve, and the extent to which EHR access was related to the concept of making savings. METHODS: An audit of patients' online access to medical records was conducted in July-August 2011 using a survey questionnaire. Two hundred and twenty six patients who were registered with two general practices in the National Health Service (NHS) located in the UK and who had accessed their personal EHRs at least twice in the preceding 12 months i.e. from July 2010 to July 2011, completed the questionnaire. Data analysis A thematic analysis of the comments that patients gave in response to the open ended questions on the questionnaire. RESULTS: Overall, evaluations of record access were positive. Four main themes relating to the ways in which patients accessed their records were identified: making savings, checking past activity, preparation for future action, and setting new expectations. CONCLUSIONS: Quite apart from any benefits of savings in healthcare resources, this study has provided qualitative evidence of the active ways in which patients may make use of access to their EHRs, many of which are in line with proportionate health management strategies. Access to personal EHRs may contribute to the development of new expectations among patients. PMID- 25453266 TI - Clinical implications of miRNAs in the pathogenesis, diagnosis and therapy of pancreatic cancer. AB - Despite considerable progress being made in understanding pancreatic cancer (PC) pathogenesis, it still remains the 10th most often diagnosed malignancy in the world and 4th leading cause of cancer related deaths in the United States with a five year survival rate of only 6%. The aggressive nature, lack of early diagnostic and prognostic markers, late clinical presentation, and limited efficacy of existing treatment regimens make PC a lethal cancer with high mortality and poor prognosis. Therefore, novel reliable biomarkers and molecular targets are urgently needed to combat this deadly disease. MicroRNAs (miRNAs) are short (19-24 nucleotides) non-coding RNA molecules implicated in the regulation of gene expression at post-transcriptional level and play significant roles in various physiological and pathological conditions. Aberrant expression of miRNAs has been reported in several cancers including PC and is implicated in PC pathogenesis and progression, suggesting their utility in diagnosis, prognosis and therapy. In this review, we summarize the role of several miRNAs that regulate various oncogenes (KRAS) and tumor suppressor genes (p53, p16, SMAD4, etc.) involved in PC development, their prospective roles as diagnostic and prognostic markers and as a therapeutic targets. PMID- 25453274 TI - Dashboards for improving patient care: review of the literature. AB - AIM: This review aimed to provide a comprehensive overview of the current state of evidence for the use of clinical and quality dashboards in health care environments. METHODS: A literature search was performed for the dates 1996-2012 on CINAHL, Medline, Embase, Cochrane Library, PsychInfo, Science Direct and ACM Digital Library. A citation search and a hand search of relevant papers were also conducted. RESULTS: One hundred and twenty two full text papers were retrieved of which 11 were included in the review. There was considerable heterogeneity in implementation setting, dashboard users and indicators used. There was evidence that in contexts where dashboards were easily accessible to clinicians (such as in the form of a screen saver) their use was associated with improved care processes and patient outcomes. CONCLUSION: There is some evidence that implementing clinical and/or quality dashboards that provide immediate access to information for clinicians can improve adherence to quality guidelines and may help improve patient outcomes. However, further high quality detailed research studies need to be conducted to obtain evidence of their efficacy and establish guidelines for their design. PMID- 25453276 TI - Understanding data requirements of retrospective studies. AB - BACKGROUND AND OBJECTIVE: Usage of data from electronic health records (EHRs) in clinical research is increasing, but there is little empirical knowledge of the data needed to support multiple types of research these sources support. This study seeks to characterize the types and patterns of data usage from EHRs for clinical research. MATERIALS AND METHODS: We analyzed the data requirements of over 100 retrospective studies by mapping the selection criteria and study variables to data elements of two standard data dictionaries, one from the healthcare domain and the other from the clinical research domain. We also contacted study authors to validate our results. RESULTS: The majority of variables mapped to one or to both of the two dictionaries. Studies used an average of 4.46 (range 1-12) data element types in the selection criteria and 6.44 (range 1-15) in the study variables. The most frequently used items (e.g., procedure, condition, medication) are often available in coded form in EHRs. Study criteria were frequently complex, with 49 of 104 studies involving relationships between data elements and 22 of the studies using aggregate operations for data variables. Author responses supported these findings. DISCUSSION AND CONCLUSION: The high proportion of mapped data elements demonstrates the significant potential for clinical data warehousing to facilitate clinical research. Unmapped data elements illustrate the difficulty in developing a complete data dictionary. PMID- 25453269 TI - How does the pathophysiological context influence delivery of bone growth factors? AB - "Orthobiologics" represents an important category of therapeutics for the regeneration of bone defects caused by injuries or diseases, and bone growth factors are a particularly rapidly growing sub-category. Clinical application of bone growth factors has accelerated in the last two decades with the introduction of BMPs into clinical bone repair. Optimal use of growth factor-mediated treatments heavily relies on controlled delivery, which can substantially influence the local growth factor dose, release kinetics, and biological activity. The characteristics of the surrounding environment, or "context", during delivery can dictate growth factor loading efficiency, release and biological activity. This review discusses the influence of the surrounding environment on therapeutic delivery of bone growth factors. We specifically focus on pathophysiological components, including soluble components and cells, and how they can actively influence the therapeutic delivery and perhaps efficacy of bone growth factors. PMID- 25453278 TI - Novel branch patterns and anticoagulant activity of glycosaminoglycan from sea cucumber Apostichopus japonicus. AB - A novel glucosidic pattern of fucose branches was found in the glycosaminoglycan from the sea cucumber Apostichopus japonicus in China. The methylation of desulfated/carboxyl-reduced polysaccharides and analysis of unsaturated disaccharides generated from the enzymolysis of the defucosed polysaccharides demonstrated that the branch is formed by one fucopyranosyl residue, 46.5% of which is linked through the O-3 position of beta-D-glucuronic acid, while 8.7% and 43.9% are linked through the O-6 and O-4 positions of the N acetylgalactosamine moiety. The beta-D-glucuronic acid, N-acetyl-beta-D galactosamine, alpha-L-fucose and sulfate ester with the molecular ratio of 0.97:1.00:1.13:3.85 composed the backbone -> 4)GlcUAbeta(1 -> 3)GalNAcbeta(1 -> and sulfated fucose branches. The sulfation patterns of fucose branches and the linkage pattern of the backbone structure were determined by 1/2 dimension NMR. The most abundant branch species were 2,4-di-O-sulfated and 3,4-di-O-sulfated fucose, but 4-mono-O-sulfated residue was also present. The structure of presently obtained glycosaminoglycan is different from that previously obtained from Stichopus japonicus (Kariya et al., Carbohyd. Res. 297 (1997) 273-279), which suggests that the structures of glycosaminoglycans from the same species of different regions somehow differ. The anticoagulant assay indicated that the polysaccharide possessed a high anticoagulant activity and the sulfated fucose branches were essential to the activity. PMID- 25453279 TI - Application of Box-Behnken design for ultrasonic-assisted extraction of polysaccharides from Paeonia emodi. AB - The objective of the present work was to study the ultrasonic assisted extraction and optimization of polysaccharides from Paeonia emodi and evaluation of its anti inflammatory response. Specifically, the optimization of polysaccharides was carried out using Box-Behnken statistical experimental design. Response surface methodology (RSM) of three factors (extraction temperature, extraction time and liquid solid ratio) was employed to optimize the percentage yield of the polysaccharides. The experimental data were fitted to quadratic response surface models using multiple regression analysis with high coefficient of determination value (R) of 0.9906. The highest polysaccharide yield (8.69%) as per the Derringer's desirability prediction tool was obtained under the optimal extraction condition (extraction temperature 47.03 degrees C, extraction time 15.68 min, and liquid solid ratio 1.29 ml/g) with a desirability value of 0.98. These optimized values of tested parameters were validated under similar conditions (n = 6), an average of 8.13 +/- 2.08% of polysaccharide yield was obtained in an optimized extraction conditions with 93.55% validity. The anti inflammatory effect of polysaccharides of P. emodi were studied on carrageenan induced paw edema. In vivo results showed that the P. emodi 200mg/kg of polysaccharide extract exhibited strong potential against inflammatory response induced by 1% suspension of carrageenean in normal saline. PMID- 25453277 TI - An exploratory study of inactive health information seekers. AB - PURPOSE: This study aims to identify people who do not actively seek out health information and the demographic characteristics of Inactive Seekers. The possible determinants of inactive seeking behaviors are also explored. DESIGN AND MEASUREMENTS: A total of 14,420 survey respondents were drawn from the 2009 Annenberg National Health Communication Survey (ANHCS) data. K-means clustering was used to discriminate Inactive Seekers from Active Seekers. The inactive information seeker group was formed based on their experience with health information seeking. The potential determinants that were tested to predict inactive seeking included the following: health condition, health service use, health media exposure, and computer/Internet activities. RESULTS: Within this national survey data, the respondents were more likely to be included in the Inactive Seekers (N=8312, 58.5%) compared to Active Seekers (N=5908, 41.5%). The demographic characteristics indicated that the Inactive Seekers were identified as younger, male, highly educated, White, and high household income people. The binary logistic regression results from the study model indicated that healthier people were less likely to seek out health information than their counterparts. In addition, those who were exposed to various media were almost 1.6 times more likely to seek out health information than those who were not exposed to such media. Within this study data, the statistically significant determinants identified were health condition and health media exposure while computer/Internet activities did not show strong indications in predicting inactive seeking behavior. CONCLUSION: The development of more generalizable measures for health literacy or behavioral patterns will bolster advanced study on inactive seeking relating to knowledge of technology and health context. Further study should be directed at estimating the negative aspects of information seeking such as information ignorance or information avoidance. PMID- 25453280 TI - Physicochemical and drug release characteristics of acetylated starches of five Lagenaria siceraria cultivars. AB - Modified starches play a crucial role in the pharmaceutical industries in controlling the drug release at a pre-determined rate. The effect of acetylation on the physicochemical and drug release characteristics of the starches from five different Indian L. siceraria cultivars was investigated. Starches isolated from the seeds of L. siceraria were subjected to varying degrees of acetylation. Using a range of characterization methods including amylose content, elemental analysis, light transmittance, swelling power, scanning electron microscopy, FT IR and X-ray diffraction, the effect of acetylation was determined. The swelling power of starch acetates improved significantly (P < 0.05) with the increase in degree of substitution. The increase in swelling shows that acetylation improved the accessibility of an amorphous area to the water. The formation of V-type of complex crystalline structures confirmed the acetylation of L. siceraria starch. Modification in the crystalline structure of starch acetate retarded the drug release, which is controlled by water uptake. The starch acetates from all the cultivars showed better sustained release properties with the increase in degree of substitution. Drug release through the swellable matrix was found to be controlled by fickian diffusion from the gel layer as indicated by Korsmeyer Peppas models (R(2)) 0.9885-0.9984. PMID- 25453281 TI - Apparent circular dichroism signature of stirring-oriented DNA and drug-DNA complexes. AB - It is shown that in water with no added salts calf-thymus DNA and its drug-loaded forms exhibit peculiar, completely reversible circular dichroism (CD) spectroscopic changes upon mechanical rotatory stirring. Due to the stirring induced spatial alignment of the helices, the CD spectra are overwhelmed by the much more intense linear dichroism contribution. This apparent chiroptical response can be generated and detected without using any sophisticated attachment. It is a technically simple complement to existing methods suitable to obtain additional structural information which can not be derived from isotropic spectra. Drug-DNA interactions generating no or very weak CD spectroscopic changes under isotropic conditions become easily detectable upon stirring the sample solution. Stirring-induced changes of the CD profile also enable to clarify the DNA binding mode of various compounds (e.g., imatinib, thioflavin T) which would remain ambiguous considering isotropic spectral data only. PMID- 25453282 TI - Effect of water-soluble chitosan on the osteoblast function in MC3T3-E1 cells. AB - In the present study, water-soluble chitosan (WSC) was prepared by hydrolysis of chitosan with commercial alpha-amylase, and the effect of WSC on osteoblast function, i.e. alkaline phosphatase activity (ALP), cell viability, mineralization, and reactive oxygen species (ROS) in osteoblastic MC3T3-E1 cells was investigated. Osteoblastic MC3T3-E1 cells were cultured in various concentrations of WSC solutions (1-5 mg/mL) for designated time and then the ALP, cell viability, mineralization, and ROS in the cells were evaluated. Treatments of osteoblastic with WSC caused a significant increase in ALP, cell viability, and mineralization in osteoblastic MC3T3-E1 cells. Moreover, treatments of osteoblastic with WSC decreased ROS level in osteoblastic MC3T3-E1 cells. The results demonstrate that the WSC may reduce or prevent osteoblasts degeneration through antioxidant activity. PMID- 25453283 TI - Fucoidan--a alpha-D-glucosidase inhibitor from Sargassum wightii with relevance to type 2 diabetes mellitus therapy. AB - The present study was conducted to screen the alpha-d-glucosidase inhibitory activity of fucoidan extracted from Sargassum wightii collected at Mandapam coastal area, Tamil Nadu, India. Fucoidan was extracted from the sporophyll of S. wightii using ethanol, acetone and CaCl2 precipitation. The average yield was 1.8 +/- 0.16% and the extracted fucoidan was found to contain 53 +/- 0.52% of fucose and 36 +/- 0.60% of sulphate. FT-IR, NMR and in vitro alpha-d-glucosidase activity of purified fucoidan were performed. Fucoidan at the concentration of 31.25, 62.5, 125 and 250 MUg exhibited 19, 31, 38 and 71% inhibition against alpha-d-glucosidase respectively in a dose dependent manner. The IC50 value against alpha-D-glucosidase of fucoidan is found to be 132.9 MUg which is more effective than that of acarbose (1mg). The diverse biological activities of Fucoidan include anticancer, anti inflammatory and antimicrobial but the alpha-d glucosidase inhibitory activity of native fucoidan from S. wightii for type 2 diabetes therapy is first of its kind. PMID- 25453284 TI - Isolation and characterization of lignin from the oak wood bioethanol production residue for adhesives. AB - Lignin was isolated from the residue of bioethanol production with oak wood via alkaline and catalyzed organosolv treatments at ambient temperature to improve the purity of lignin for the materials application. The isolated lignins were analyzed for their chemical composition by nitrobenzene oxidation method and their functionality was characterized via wet chemistry method, element analysis, (1)H NMR, GPC and FTIR-ATR. The isolated lignin by acid catalyzed organosolv treatment (Acid-OSL) contained a higher lignin content, aromatic proton, phenolic hydroxyl group and a lower nitrogen content that is more reactive towards chemical modification. The lignin-based adhesives were prepared and the bond strength was measured to evaluate the enhanced reactivity of lignin by the isolation. Two steps of phenolation and methylolation were applied for the modification of the isolated lignins and their tensile strengths were evaluated for the use as an adhesive. The acid catalyzed organosolv lignin-based adhesives had comparable bond strength to phenol-formaldehyde adhesives. The analysis of lignin-based adhesives by FTIR-ATR and TGA showed structural similarity to phenol adhesive. The results demonstrate that the reactivity of lignin was enhanced by isolation from hardwood bioethanol production residues at ambient temperature and it could be used in a value-added application to produce lignin-based adhesives. PMID- 25453286 TI - Adsorption of an anionic azo dye by cross-linked chitosan/bentonite composite. AB - In this study, cross-linked chitosan (CCS)/bentonite (BT) composite was prepared by the intercalation of chitosan in bentonite and the cross-linking reaction between chitosan and glutaraldehyde. CCS/BT composite was characterized by using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD) and thermal gravimetric analyses (TGA). Their adsorption characteristics were assessed by using an azo dye (Amido Black 10B) as a model adsorbate. The adsorption of Amido Black 10B onto the CCS/BT composite was found to be optimal at pH 2. The adsorption isotherm was well described by the Langmuir model and the maximum adsorption capacity was 323.6 mg/g at 293K and pH 2. Amido Black 10B adsorption kinetics followed a pseudo-second-order kinetic model. The calculated thermodynamic parameters showed that the adsorption of Amido Black 10B by CCS/BT composite was spontaneous and endothermic in nature. PMID- 25453285 TI - LAP3 promotes glioma progression by regulating proliferation, migration and invasion of glioma cells. AB - Leucine aminopeptidase 3 (LAP3), belonging to the M1 family, has been proved to catalyze the hydrolysis of leucine residues. Leucine aminopeptidases are involved in many pathological disorders and regulate cell proliferation, invasion and/or angiogenesis of tumor. Recent study showed that LAP3 is highly expressed in several malignant and affects tumor angiogenesis. We aimed at investigating the clinical significance of LAP3 expression in human gliomas and its biological function in glioma cells. RT-PCR, Western blot and immunohistochemistry analysis were used to detect the expression levels of LAP3 in 121 glioma tissues, high LAP3 expression was correlated with the grade of malignancy and poor prognosis of glioma patients. In vitro, after increasing of LAP3 by myc-LAP3 transfection and knockdown of LAP3 by siRNA transfection in glioma cells, cell viability, cell cycle, migration and invasion were determined with CCK8 assay, flow cytometry, wound healing and transwell invasion assays. The results indicated that increasing LAP3 could promte cell viability, cell cycle, migration and invasion, knockdown LAP3 could decrease cell viability, suppress cell proliferation, migration and invasion. Our findings uncover that LAP3 might be a new prognostic factor and be close correlation with glioma cell growth, migration, invasion. PMID- 25453287 TI - Optimised amylases extraction from oat seeds and its impact on bread properties. AB - Statistical approaches were employed for the optimisation of the extraction of amylolytic activity from oat (Avena sativa) seeds. The application of the response surface methodology allows us to determine a set of optimal conditions (ratio seed weight/buffer volume 0.1, germination days 10 days, temperature 20 degrees C and pH 5.6). Experiments carried out under these conditions led to amylase production yield of 91 U/g. Its maximal activity was in the pH 5.6 and at 55 degrees C. Study of the incorporation of the optimised oat extract into the bread formulation revealed an improvement of the sensory quality and the textural properties of fresh and stored bread. Three-dimensional elaborations of Confocal Laser Scanning Microscopy (CLSM) images were performed on crumb of the different breads to evaluate the influence of amylase activity on microstructure. The result showed improved baking characteristics as well as overall microscopic and macroscopic appearance. PMID- 25453288 TI - Synthesis of YF3: Yb, Er upconverting nanofluorophores using chitosan and their cytotoxicity in MCF-7 cells. AB - In this work, we described one pot hydrothermal synthesis of surface modified water soluble YF3: Yb, Er upconverting nanofluorophores (UCNFs) using natural biopolymer chitosan. The obtained nanocrystals have undergone X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), high resolution transmission electron microscopy (HRTEM) and photoluminescence (PL) studies. The nanoparticles possess uniform particle size distribution with average size about 27 nm. The cytotoxicity results revealed that the chitosan capped nanoparticles exhibit excellent biocompatibility in human breast cancer cells. In conclusion, the water soluble chitosan capped YF3: Yb, Er nanoparticles could be used as a potential candidate in bio-imaging and therapeutic applications. PMID- 25453289 TI - Structural, physicochemical and antioxidant properties of sodium alginate isolated from a Tunisian brown seaweed. AB - An original sodium alginate from Tunisian seaweed (Cystoseira barbata) was purified and characterized by circular dichroism (CD) and ATR-FTIR spectroscopies. ATR-FTIR spectrum of C. barbata sodium alginate (CBSA) showed the characteristic bands of mannuronic (M) and guluronic acids (G). The M/G ratio was estimated by CD (M/G = 0.59) indicating that CBSA was composed of 37% mannuronic acid and 63% guluronic acid. The analysis of viscosity of CBSA showed evidence of pseudoplastic fluid behaviour. The emulsifying capacity of CBSA was evaluated at different concentrations (0.25-3%), temperatures (25-100 degrees C) and pH (3.0 11.0). Compared to most commercial emulsifiers, the emulsion formulated by CBSA was found to be less sensitive to temperature changes and more stable at acidic pH. CBSA was examined for antioxidant properties using various antioxidant assays. CBSA exhibited important DPPH radical-scavenging activity (74% inhibition at a concentration of 0.5 mg/ml) and considerable ferric reducing potential. Effective hydroxyl-radical scavenging activity (82% at a concentration of 5 mg/ml) and potent protection activity against DNA breakage were also recorded for CBSA. However, in the linoleate-beta-carotene system, CBSA exerted moderate antioxidant activity (60% at a concentration of 1.5 mg/ml). Therefore, CBSA can be used as a natural ingredient in food industry or in the pharmaceutical field. PMID- 25453290 TI - Molecular characteristics of an exopolysaccharide from Lactobacillus rhamnosus KF5 in solution. AB - The molecular weight and chain conformation of an exopolysaccharide (EPS), S2, from Lactobacillus rhamnosus KF5 were determined by size-exclusion chromatography combined with multi-angle laser light scattering (SEC-MALLS), dynamic light scattering (DLS), viscometry and atomic force microscopy (AFM). The weight average molecular weight (Mw), intrinsic viscosity [n], radii of gyration (R(g)) and hydrodynamic radii (R(h)) were 7.5 * 10(5) Da, 2.331 dL/g, 44.3 nm and 29.4 nm, respectively. The conformational parameters were calculated from the above data according to the theory of dilute polymer solutions. The Mark-Houwink Sakurada exponent alpha was found to be 0.687, and the value of the structure sensitive parameter rho (R(g)/R(h)) was 1.51. The results revealed that the EPS S2 existed as a random coil conformation in 0.1M NaNO3 aqueous solution. AFM further confirmed the random coil morphology of this molecule in aqueous solution. EPS S2 present extended chains (fibrous morphology), with circular side chains, dispersed in SDS solution. PMID- 25453291 TI - Effect of selenylation modification on immune-enhancing activity of Atractylodes macrocephala polysaccharide. AB - The Atractylodes macrocephala polysaccharide (AMP) was extracted purified and modified in selenylation by Nitric acid-sodium selenite method to get nine selenizing AMPs (sAMPs), sAMP(1)-sAMP(9). In vitro test their effects on chicken peripheral lymphocyte proliferation were determined by MTT assay. The results showed that nine sAMPs and AMP at five concentrations could significantly promote lymphocyte proliferation, the actions in six sAMPs were significantly stronger than that in AMP, and in sAMP(9) was the strongest. In vivo test, 14-day-old chickens vaccinated with ND vaccine were injected respectively with sAMP(9) and AMP, the peripheral lymphocytes proliferation, serum antibody titer, IFN-gamma, IL-2 and IL-6 contents were determined. The results displayed that the sAMP could significantly promote lymphocyte proliferation and elevate the antibody titers and content of IFN-gamma, IL-2 and IL-6 in comparison with unmodified AMP. These results indicate that selenylation modification can significantly enhance the immune-enhancing activity of AMP. PMID- 25453292 TI - Amphotericin-B entrapped lecithin/chitosan nanoparticles for prolonged ocular application. AB - Fungal keratitis is the major cause of vision loss worldwide. Amphotericin-B is considered as the drug of choice for fungal infections. However, its use in ophthalmic drug delivery is limited by the low precorneal residence at ocular surface as a result of blinking reflex, tear turnover and nasopharyngeal drainage. We report Amphotericin-B loaded lecithin/chitosan nanoparticles for prolonged ocular application. The prepared nanoparticles were in the size range of 161.9-230.5 nm, entrapment efficiency of 70-75%, theoretical drug loading of 5.71% with positive zeta potential of 26.6-38.3 mV. As demonstrated by antifungal susceptibility against Candida albicans and Aspergillus fumigatus, nanoparticles were more effective than marketed formulation. They exhibited pronounced mucoadhesive properties. In-vivo pharmacokinetic studies in New Zealand albino rabbit eyes indicated improved bioavailablity (~ 2.04 fold) and precorneal residence time (~ 3.36 fold) by nanoparticles prepared from low molecular weight chitosan as compared with marketed formulation. PMID- 25453293 TI - Interaction of coumarin with calf thymus DNA: deciphering the mode of binding by in vitro studies. AB - DNA is the major target for a wide range of therapeutic substances. Thus, there has been considerable interest in the binding studies of small molecules with DNA. Interaction between small molecules and DNA provides a structural guideline in rational drug designing and in the synthesis of new and improved drugs with enhanced selective activity and greater clinical efficacy. Plant derived polyphenolic compounds have a large number of biological and pharmacological properties. Coumarin is a polyphenolic compound which has been extensively studied for its diverse pharmacological properties. However, its mode of interaction with DNA has not been elucidated. In the present study, we have attempted to ascertain the mode of binding of coumarin with calf thymus DNA (Ct DNA) through various biophysical techniques. Analysis of UV-visible absorbance spectra and fluorescence spectra indicates the formation of complex between coumarin and Ct-DNA. Several other experiments such as effect of ionic strength, iodide induced quenching, competitive binding assay with ethidium bromide, acridine orange and Hoechst 33258 reflected that coumarin possibly binds to the minor groove of the Ct-DNA. These observations were further supported by CD spectral analysis, viscosity measurements, DNA melting studies and in silico molecular docking. PMID- 25453294 TI - Psoriasis: in between the skin and the fat. AB - Substantial epidemiological evidence indicates that psoriasis associates with a predisposition to develop metabolic dysregulation leading to obesity and insulin resistance. However, the nature of this association and the potential underlying mechanisms remain unclear. In a recent report, Gerdes et al. explored the hypothesis that wingless-type MMTV integration site, Wnt5a, which has been linked to aberrant fat cell metabolism, may be driving this process. In this study, the authors compare circulating serum levels of Wnt5a in individuals with psoriasis and compare with healthy controls matched for age, gender and BMI. The bottom line results show higher levels of Wnt5a in psoriasis patients irrespective of BMI compared to the matched non-psoriatic controls, indicating that psoriasis per se may result in increased secretion of Wnt5a into the circulation. In addition, there was a significant difference among patients with higher levels of Wnt5a in the obese psoriasis population. The study, even though being purely descriptive, may serve to inspire a more mechanistic approach exploring not only Wnt5a, but other inflammatory pathways in between the skin and the fat. PMID- 25453295 TI - Optimizing LiFePO4@C core-shell structures via the 3-aminophenol-formaldehyde polymerization for improved battery performance. AB - Polyanion-type cathode materials are well-known for their low electronic conductivity; accordingly, the addition of conductive carbon in the cathode materials becomes an indispensable step for their application in lithium ion batteries. To maximize the contribution of carbon, a core-shell structure with a full coverage of carbon should be favorable due to an improved electronic contact between different particles. Here, we report the formation of a uniform carbon nanoshell on a typical cathode material, LiFePO4, with the shell thickness precisely defined via the 3-aminophenol-formaldehyde polymerization process. In addition to the higher discharge capacity and the improved rate capability as expected from the carbon nanoshell, we identified that the core-shell configuration could lead to a much safer cathode material as revealed by the obviously reduced iron dissolution, much less heat released during the cycling, and better cyclability at high temperature. PMID- 25453296 TI - Pakistan: the nidus for global polio re-emergence? PMID- 25453297 TI - Obesity and diabetes in an aging population: time to rethink definitions and management? AB - Regardless of pathophysiology and diagnostic criteria, the population of older adults with diabetes is highly heterogeneous. As adults with type 2 diabetes age and develop multiple comorbid health conditions, they may experience many challenges to good diabetes care and self-management. Age of diagnosis and duration of diabetes largely determine the likelihood for comorbidity. Treating such a diverse elderly population may result in inadequate glycemic control either because of overtreatment, leading to hypoglycemia, or because of other complications and preexisting comorbidities. It is imperative that treatment decisions are based on patient preferences, unique and likely evolving health status, and longevity. PMID- 25453298 TI - Antidiabetic medications and polypharmacy. AB - Polypharmacy, or the use of multiple medications, is a serious concern for providers who care for older adults, as polypharmacy is associated with medication nonadherence, drug-drug interactions, drug-disease interactions, and adverse drug events. Multiple medications, high chronic disease burden, and age related physiologic changes make management of older adults with diabetes increasingly difficult. Given high medication burden and potential for increased medication sensitivity in this patient population, it is prudent that providers are aware of potential risks and benefits of antidiabetic medications and implement shared decision-making practices to ensure appropriate care for older adults with diabetes. PMID- 25453299 TI - Atherosclerotic cardiovascular disease in older adults with diabetes mellitus. AB - Diabetes mellitus exerts a strong effect on atherosclerotic cardiovascular disease risk into older age (beyond ages 70-74 years). This effect is particularly noticeable with regard to coronary artery disease and cerebral microvascular disease. Thus, diabetes mellitus in older adults deserves the same careful medical attention as it does in middle age. PMID- 25453300 TI - The effect of type 2 diabetes on body composition of older adults. AB - This review describes the effect of type 2 diabetes on fat mass, fat distribution, and lean mass, and changes in these parameters, in older adults, focusing on observational studies. Studies show that type 2 diabetes is associated with an unfavorable body composition characterized by more visceral fat, less thigh subcutaneous fat, and more fat infiltration in the muscle compared with persons without the disease. Longitudinal studies found an accelerated decline in muscle mass in older persons with type 2 diabetes. Studies are needed to examine the consequences of these changes in body composition on physical functioning, morbidity, and mortality risk. PMID- 25453301 TI - Physical function and disability in older adults with diabetes. AB - Functional decline and physical disability are an important clinical and public health problem in older adults because they are associated with loss of independence, nursing home admission, and mortality. Several impairments and comorbidities related to or associated with diabetes are potential disabling conditions that could account for the excess risk of disability. But in most studies, no single condition explains this association. Accelerated loss of muscle strength is a potential mediator in the disabling effect of diabetes. Because some diabetes-related comorbidities are potential modifiable risk factors, preventing and reducing the excess risk of disability associated with diabetes needs further study. PMID- 25453303 TI - Falls risk in older adults with type 2 diabetes. AB - Falls are a major health issue for older adults, especially for those who develop type 2 diabetes who must contend with age-related declines in balance, muscle strength, and walking ability. They must also contend with health-related issues specific to the disease process. Given the general association between these variables and falls, being able to identify which measures negatively impact on balance in older diabetic persons is a critical step. Moreover, designing specific interventions to target these physiologic functions underlying balance and gait control will produce the greatest benefit for reducing falls in older persons with diabetes. PMID- 25453302 TI - Links between osteoarthritis and diabetes: implications for management from a physical activity perspective. AB - Osteoarthritis (OA) and type 2 diabetes mellitus (T2DM) often coexist in older adults. Those with T2DM are more susceptible to developing arthritis, which has been traditionally attributed to common risk factors, namely, age and obesity. Alterations in lipid metabolism and hyperglycemia might directly impact cartilage health and subchondral bone, contributing to the development/progression of OA. Adequate management of older persons with both conditions benefits from a comprehensive understanding of the associated risk factors. We discuss common risk factors and emerging links between OA and T2DM, emphasizing the importance of physical activity and the implications of safe and effective physical activity. PMID- 25453304 TI - Diabetes and cognition. AB - Dementia is a major cause of disability and death among older adults. Those with type 2 diabetes (T2D) are 50-100% more likely to develop dementia than those without T2D, but it is unknown whether this association reflects a causal relationship. Proposed mechanisms through which T2D could cause dementia include the effects of insulin dysregulation and chronic hyperglycemia on features of Alzheimer's disease and macrovascular and microvascular disorders in the brain. More research is needed to elucidate the link between T2D and dementia and identify strategies to maintain cognitive function among people with T2D. PMID- 25453307 TI - Diabetes and aging. PMID- 25453308 TI - Diabetes and aging. PMID- 25453305 TI - Depression among older adults with diabetes mellitus. AB - Older adults with Diabetes Mellitus (DM) experience greater risk for comorbid depression compared to those who do not have DM. Undetected, untreated or under treated depression impinges an individual's ability to manage their DM successfully, hinders their adherence to treatment regime, and undermines provider-patient relationships. Thus, in the context of caring for older adults with DM, comorbid depression presents special challenges and opportunities for clinicians. In this article, we summarize the clinical presentation of late-life depression, potential mechanisms of comorbidity of depression and DM, importance of depression in the successful management of DM, and available best practice models for depression treatment. PMID- 25453306 TI - Obstructive sleep apnea and type 2 diabetes in older adults. AB - Both obstructive sleep apnea (OSA) and type 2 diabetes mellitus are commonly seen in older adults. Over the last decade, there has been increasing recognition that OSA is highly prevalent in persons with type 2 diabetes and related metabolic conditions such as insulin resistance and glucose intolerance. Intermittent hypoxemia and recurrent arousals in OSA trigger a repertoire of pathophysiological events, which can in turn alter glucose homeostasis and possibly increase the risk for type 2 diabetes. Conversely, there is evidence that type 2 diabetes may alter the progression and expression of sleep-disordered breathing. PMID- 25453310 TI - [Xanthogranulomatous pyelonephritis in a child with severe malnutrition and recurrent fever]. AB - Xanthogranulomatous pyelonephritis is a rare inflammatory disease, characterized by replacement of renal parenchyma with granulomatous tissue. Initial clinical presentation includes abdominal pain and constitutional symptoms related to recurrent urinary infections. The microorganisms most commonly involved are Escherichia coli and Proteus mirabilis. Final diagnosis is made by histopathology, and the only curative treatment is total or partial nephrectomy. A recently diagnosed case in our unit is presented, as well as an update on the knowledge of this disease. PMID- 25453309 TI - [Antibiotic susceptibility of Streptococcus pneumoniae in healthy carrier children in Murcia (Spain)]. AB - INTRODUCTION AND OBJECTIVES: Streptococcus pneumoniae (SP) is a human pathogen that involves a high use of antibiotics. The objective of the study was to determine the susceptibility to commonly used antibiotics and their associated risk factors, in order to promote rational use of antibiotics. PATIENTS AND METHODS: In A multicentre study was conducted in summer 2009 and winter 2010 on children attending paediatric clinics in the Region of Murcia. A nasopharyngeal sample was collected and an epidemiological questionnaire was completed. The study included 1562 children aged 1 and 4 years old. RESULTS: Almost one-third (31.3%, 489/1562) of children were nasal carriers. A sensitivity study was carried out on 376 isolates, of which 343 were serotyped. Almost two-thirds (61.7%, 964/1562) of children had received at least one dose of PCV7 (heptavalent pneumococcal conjugate vaccine), and 12.8% (44/343) of the isolates belonged to PCV7 serotypes. The prevalence rates of penicillin resistance (meningitis infections criteria CMI>0.06mg/L) were 28.1%; however, this percentage was 54% in PCV7 serotypes. None of the isolates had (MIC >2mg/L), so prevalence rates of susceptibility with non-meningitis infections criteria were 100%. There was a high percentage of erythromycin resistance (45.7%). The factors favouring resistance to penicillin and cefotaxime were the consumption of antibiotics in the previous month and the carrying of vaccine serotypes. On the other hand, the age of 4 years old was a protective factor of resistance. The 14, 35B, 19A, 15A, and 19F serotypes were less susceptible to penicillin. CONCLUSIONS: Both oral amoxicillin given to outpatients and intravenous penicillin or ampicillin to hospitalized patients are excellent options for the treatment of non-meningeal infections, as seen with pneumonia in these kinds of environments, where there is low incidence of isolates highly resistant to penicillin (CMI >= 2mg/L). PMID- 25453311 TI - [Update of recommendations on the use of palivizumab as prophylaxis in RSV infections]. AB - The Standards Committee of the Spanish Neonatology Society (SENeo) considers that the new document from the American Academy of Pediatrics, including recommendations for palivizumab use to prevent serious infections produced by the Respiratory Syncytial Virus (RSV), provides no new scientific evidence which would justify the modification of the current recommendations of the SENeo. However, some adjustments to the criteria of the existing recommendations are proposed to reduce the cost of the drug by its correct and judicious management. PMID- 25453312 TI - Challenging issues and pitfalls for diagnosis of Human African trypanosomiasis in a Gabonese visitor, France. PMID- 25453313 TI - The use of fly larvae for organic waste treatment. AB - The idea of using fly larvae for processing of organic waste was proposed almost 100 years ago. Since then, numerous laboratory studies have shown that several fly species are well suited for biodegradation of organic waste, with the house fly (Musca domestica L.) and the black soldier fly (Hermetia illucens L.) being the most extensively studied insects for this purpose. House fly larvae develop well in manure of animals fed a mixed diet, while black soldier fly larvae accept a greater variety of decaying organic matter. Blow fly and flesh fly maggots are better suited for biodegradation of meat processing waste. The larvae of these insects have been successfully used to reduce mass of animal manure, fecal sludge, municipal waste, food scrapes, restaurant and market waste, as well as plant residues left after oil extraction. Higher yields of larvae are produced on nutrient-rich wastes (meat processing waste, food waste) than on manure or plant residues. Larvae may be used as animal feed or for production of secondary products (biodiesel, biologically active substances). Waste residue becomes valuable fertilizer. During biodegradation the temperature of the substrate rises, pH changes from neutral to alkaline, ammonia release increases, and moisture decreases. Microbial load of some pathogens can be substantially reduced. Both larvae and digested residue may require further treatment to eliminate pathogens. Facilities utilizing natural fly populations, as well as pilot and full-scale plants with laboratory-reared fly populations have been shown to be effective and economically feasible. The major obstacles associated with the production of fly larvae from organic waste on an industrial scale seem to be technological aspects of scaling-up the production capacity, insufficient knowledge of fly biology necessary to produce large amounts of eggs, and current legislation. Technological innovations could greatly improve performance of the biodegradation facilities and decrease production costs. PMID- 25453314 TI - Waste generation and utilisation in micro-sized furniture-manufacturing enterprises in Turkey. AB - The number of small-scale businesses within most national economies is generally high, especially in developing countries. Often these businesses have a weak economic status and limited environmental awareness. The type and amount of waste produced, and the recycling methods adopted by these businesses during their operation can have negative effects on the environment. This study investigated the types of waste generated and the recycling methods adopted in micro-sized enterprises engaged in the manufacture of furniture. An assessment was also made of whether the characteristics of the enterprise had any effect on the waste recycling methods that were practised. A survey was conducted of 31 enterprises in the furniture industry in Gumushane province, Turkey, which is considered a developing economy. Surveys were undertaken via face-to-face interviews. It was found that medium-density fibreboard (MDF), and to a lesser extent, chipboard, were used in the manufacture of furniture, and two major types of waste in the form of fine dust and small fragments of board are generated during the cutting of these boards. Of the resulting composite board waste, 96.9% was used for heating homes and workplaces, where it was burnt under conditions of incomplete combustion. Enterprises were found to have adopted other methods to utilise their wastes in addition to using them as fuel. Such enterprises include those operating from a basement or first floor of a building in the cities, those continuing production throughout the year, those in need for capital and those enterprises not operating a dust-collection system. PMID- 25453315 TI - A cost-benefit analysis of landfill mining and material recycling in China. AB - Landfill mining is an environmentally-friendly technology that combines the concepts of material recycling and sustainable waste management, and it has received a great deal of worldwide attention because of its significant environmental and economic potential in material recycling, energy recovery, land reclamation and pollution prevention. This work applied a cost-benefit analysis model for assessing the economic feasibility, which is important for promoting landfill mining. The model includes eight indicators of costs and nine indicators of benefits. Four landfill mining scenarios were designed and analyzed based on field data. The economic feasibility of landfill mining was then evaluated by the indicator of net present value (NPV). According to our case study of a typical old landfill mining project in China (Yingchun landfill), rental of excavation and hauling equipment, waste processing and material transportation were the top three costs of landfill mining, accounting for 88.2% of the total cost, and the average cost per unit of stored waste was 12.7USDton(-1). The top three benefits of landfill mining were electricity generation by incineration, land reclamation and recycling soil-like materials. The NPV analysis of the four different scenarios indicated that the Yingchun landfill mining project could obtain a net positive benefit varying from 1.92 million USD to 16.63 million USD. However, the NPV was sensitive to the mode of land reuse, the availability of energy recovery facilities and the possibility of obtaining financial support by avoiding post closure care. PMID- 25453316 TI - A new classification scheme of plastic wastes based upon recycling labels. AB - Since recycling of materials is widely assumed to be environmentally and economically beneficial, reliable sorting and processing of waste packaging materials such as plastics is very important for recycling with high efficiency. An automated system that can quickly categorize these materials is certainly needed for obtaining maximum classification while maintaining high throughput. In this paper, first of all, the photographs of the plastic bottles have been taken and several preprocessing steps were carried out. The first preprocessing step is to extract the plastic area of a bottle from the background. Then, the morphological image operations are implemented. These operations are edge detection, noise removal, hole removing, image enhancement, and image segmentation. These morphological operations can be generally defined in terms of the combinations of erosion and dilation. The effect of bottle color as well as label are eliminated using these operations. Secondly, the pixel-wise intensity values of the plastic bottle images have been used together with the most popular subspace and statistical feature extraction methods to construct the feature vectors in this study. Only three types of plastics are considered due to higher existence ratio of them than the other plastic types in the world. The decision mechanism consists of five different feature extraction methods including as Principal Component Analysis (PCA), Kernel PCA (KPCA), Fisher's Linear Discriminant Analysis (FLDA), Singular Value Decomposition (SVD) and Laplacian Eigenmaps (LEMAP) and uses a simple experimental setup with a camera and homogenous backlighting. Due to the giving global solution for a classification problem, Support Vector Machine (SVM) is selected to achieve the classification task and majority voting technique is used as the decision mechanism. This technique equally weights each classification result and assigns the given plastic object to the class that the most classification results agree on. The proposed classification scheme provides high accuracy rate, and also it is able to run in real-time applications. It can automatically classify the plastic bottle types with approximately 90% recognition accuracy. Besides this, the proposed methodology yields approximately 96% classification rate for the separation of PET or non-PET plastic types. It also gives 92% accuracy for the categorization of non-PET plastic types into HPDE or PP. PMID- 25453317 TI - Consequences of sludge composition on combustion performance derived from thermogravimetry analysis. AB - Wastewater treatment plants produce millions of tons of sewage sludge. Sewage sludge is recognized as a promising feedstock for power generation via combustion and can be used for energy crisis adaption. We aimed to investigate the quantitative effects of various sludge characteristics on the overall sludge combustion process performance. Different types of sewage sludge were derived from numerous wastewater treatment plants in Beijing for further thermogravimetric analysis. Thermogravimetric-differential thermogravimetric curves were used to compare the performance of the studied samples. Proximate analytical data, organic compositions, elementary composition, and calorific value of the samples were determined. The relationship between combustion performance and sludge composition was also investigated. Results showed that the performance of sludge combustion was significantly affected by the concentration of protein, which is the main component of volatiles. Carbohydrates and lipids were not correlated with combustion performance, unlike protein. Overall, combustion performance varied with different sludge organic composition. The combustion rate of carbohydrates was higher than those of protein and lipid, and carbohydrate weight loss mainly occurred during the second stage (175-300 degrees C). Carbohydrates have a substantial effect on the rate of system combustion during the second stage considering the specific combustion feature. Additionally, the combustion performance of digested sewage sludge is more negative than the others. PMID- 25453319 TI - Evaluating the methane generation rate constant (k value) of low-organic waste at Danish landfills. AB - The methane (CH4) generation rate constant (k value, yr(-1)) is an essential parameter when using first-order decay (FOD) landfill gas (LFG) generation models to estimate CH4 generation from landfills. Four categories of waste (street cleansing, mixed bulky, shredder, and sludge waste) with a low-organic content, as well as temporarily stored combustible waste, were sampled from four Danish landfills. Anaerobic degradation experiments were set up in duplicate for all waste samples and incubated for 405 days, while the cumulative CH4 generation was continuously monitored. Applying FOD equations to the experimental results, half life time values (t1/2, yr) and k values of various waste categories were determined. In general, similar waste categories obtained from different Danish landfills showed similar results. Sludge waste had the highest k values, which were in the range 0.156-0.189 yr(-1). The combustible and street cleansing waste showed k values of 0.023-0.027 yr(-1) and 0.073-0.083 yr(-1), respectively. The lowest k values were obtained for mixed bulky and shredder wastes ranging from 0.013 to 0.017 yr(-1). Most low-organic waste samples showed lower k values in comparison to the default numeric values in current FOD models (e.g., IPCC, LandGEM, and Afvalzorg). Compared with the k values reported in the literature, this research determined low-organic waste for the first time via reliable large scale and long-term experiments. The degradation parameters provided in this study are valuable when using FOD LFG generation models to estimate CH4 generation from modern landfills that receive only low-organic waste. PMID- 25453318 TI - Particle size fractionation as a method for characterizing the nutrient content of municipal green waste used for composting. AB - In order to better characterize mechanically shredded municipal green waste used for composting, five samples from different origins were separated into seven particle size fractions (>20mm, 10-20mm, 5-10mm, 2-5mm, 1-2mm, 0.5-1.0mm and <0.5mm diameter) and analyzed for organic C and nutrient content. With decreasing particle size there was a decrease in organic C content and an increase in macronutrient, micronutrient and ash content. This reflected a concentration of lignified woody material in the larger particle fractions and of green stems and leaves and soil in the smaller particle sizes. The accumulation of nutrients in the smaller sized fractions means the practice of using large particle sizes for green fuel and/or mulch does not greatly affect nutrient cycling via green waste composting. During a 100-day incubation experiment, using different particle size fractions of green waste, there was a marked increase in both cumulative CO2 evolution and mineral N accumulation with decreasing particle size. Results suggested that during composting of bulk green waste (with a high initial C/N ratio such as 50:1), mineral N accumulates because decomposition and net N immobilization in larger particles is slow while net N mineralization proceeds rapidly in the smaller (<1mm dia.) fractions. Initially, mineral N accumulated in green waste as NH4(+)-N, but over time, nitrification proceeded resulting in accumulation of NO3(-)-N. It was concluded that the nutrient content, N mineralization potential and decomposition rate of green waste differs greatly among particle size fractions and that chemical analysis of particle size fractions provides important additional information over that of a bulk sample. PMID- 25453320 TI - Processing and properties of a solid energy fuel from municipal solid waste (MSW) and recycled plastics. AB - Diversion of waste streams such as plastics, woods, papers and other solid trash from municipal landfills and extraction of useful materials from landfills is an area of increasing interest especially in densely populated areas. One promising technology for recycling municipal solid waste (MSW) is to burn the high-energy content components in standard coal power plant. This research aims to reform wastes into briquettes that are compatible with typical coal combustion processes. In order to comply with the standards of coal-fired power plants, the feedstock must be mechanically robust, free of hazardous contaminants, and moisture resistant, while retaining high fuel value. This study aims to investigate the effects of processing conditions and added recyclable plastics on the properties of MSW solid fuels. A well-sorted waste stream high in paper and fiber content was combined with controlled levels of recyclable plastics PE, PP, PET and PS and formed into briquettes using a compression molding technique. The effect of added plastics and moisture content on binding attraction and energy efficiency were investigated. The stability of the briquettes to moisture exposure, the fuel composition by proximate analysis, briquette mechanical strength, and burning efficiency were evaluated. It was found that high processing temperature ensures better properties of the product addition of milled mixed plastic waste leads to better encapsulation as well as to greater calorific value. Also some moisture removal (but not complete) improves the compacting process and results in higher heating value. Analysis of the post processing water uptake and compressive strength showed a correlation between density and stability to both mechanical stress and humid environment. Proximate analysis indicated heating values comparable to coal. The results showed that mechanical and moisture uptake stability were improved when the moisture and air contents were optimized. Moreover, the briquette sample composition was similar to biomass fuels but had significant advantages due to addition of waste plastics that have high energy content compared to other waste types. Addition of PP and HDPE presented better benefits than addition of PET due to lower softening temperature and lower oxygen content. It should be noted that while harmful emissions such as dioxins, furans and mercury can result from burning plastics, WTE facilities have been able to control these emissions to meet US EPA standards. This research provides a drop-in coal replacement that reduces demand on landfill space and replaces a significant fraction of fossil-derived fuel with a renewable alternative. PMID- 25453321 TI - Tribo-charging properties of waste plastic granules in process of tribo electrostatic separation. AB - Plastic products can be found everywhere in people's daily life. With the consistent growth of plastic consumption, more and more plastic waste is generated. Considering the stable chemical and physics characteristics of plastic, regular waste management methods are not suitable for recycling economic strategy of each government, which has become a serious environmental problem. Recycling plastic waste is considered to be the best way to treat it, because it cannot only deduce the waste but also save the energy to produce new virgin plastic. Tribo-electrostatic separation is strongly recommended for plastic separation as it can preserve the original properties of plastic and has little additional pollution. In this study, plastic granules are generated by crushing plastic waste in waste electric and electronic equipment. The tribo-charging properties of plastic waste were studied by vibrating tribo-charging and cyclone tribo-charging. The triboelectric series obtained by vibrating was: (-)-PE-PS-PC PVC-ABS-PP-(+), while the triboelectric series obtained by cyclone was (-)-PE-PS PC-PVC-ABS-PP-(+). Further, the cyclone charging was more effective and stable than vibrating charging. The impact factors experiments showed that small particle size was better changed than large ones and were more suitable recycled by tribo-electrostatic separation. High relative humidity was identified as impede charging effect. The results of this study will help defining the operating parameters of subsequent separator. PMID- 25453322 TI - Painful skin nodules. PMID- 25453323 TI - Computer-aided diagnosis system based on fuzzy logic for breast cancer categorization. AB - BACKGROUND: Fuzzy logic can help reduce the difficulties faced by computational systems to represent and simulate the reasoning and the style adopted by radiologists in the process of medical image analysis. The study described in this paper consists of a new method that applies fuzzy logic concepts to improve the representation of features related to image description in order to make it semantically more consistent. Specifically, we have developed a computer-aided diagnosis tool for automatic BI-RADS categorization of breast lesions. The user provides parameters such as contour, shape and density and the system gives a suggestion about the BI-RADS classification. METHODS: Initially, values of malignancy were defined for each image descriptor, according to the BI-RADS standard. When analyzing contour, for example, our method considers the matching of features and linguistic variables. Next, we created the fuzzy inference system. The generation of membership functions was carried out by the Fuzzy Omega algorithm, which is based on the statistical analysis of the dataset. This algorithm maps the distribution of different classes in a set. RESULTS: Images were analyzed by a group of physicians and the resulting evaluations were submitted to the Fuzzy Omega algorithm. The results were compared, achieving an accuracy of 76.67% for nodules and 83.34% for calcifications. CONCLUSIONS: The fit of definitions and linguistic rules to numerical models provided by our method can lead to a tighter connection between the specialist and the computer system, yielding more effective and reliable results. PMID- 25453324 TI - Nanogel tectonic porous gel loading biologics, nanocarriers, and cells for advanced scaffold. AB - We developed a new self-assembled amphiphilic nanogel-crosslinked porous (NanoCliP) gel that can trap proteins, liposomes, and cells. The NanoCliP gel was prepared by Michael addition of a self-assembled nanogel of acryloyl group modified cholesterol-bearing pullulan to pentaerythritol tetra (mercaptoethyl) polyoxyethylene, followed by freezing-induced phase separation. Dynamic rheological analysis revealed that the storage modulus (G') of the NanoCliP gel was approximately 10 times greater than that of a nonporous nanogel-crosslinked gel. Two-photon excitation deep imaging revealed that the NanoCliP gel comprises interconnected pores of several hundred micrometers in diameter. The NanoCliP gel trapped proteins and liposomes via hydrophobic interactions because its amphiphilic nanogels exhibit chaperone-like activity. Mouse embryonic fibroblasts penetrated the interconnected pores and adhered to the porous surface of fibronectin-complexed NanoCliP gel. In vivo, the NanoCliP gel enhanced cell infiltration, tissue ingrowth, and neovascularization without requiring exogenous growth factors, suggesting that the NanoCliP gel is a promising scaffold for tissue engineering. PMID- 25453325 TI - Hantaviruses--globally emerging pathogens. AB - Hantaviruses are emerging zoonotic viruses which cause human disease in Africa, America, Asia, and Europe. This review summarizes the progress in hantavirus epidemiology and diagnostics during the previous decade. Moreover, we discuss the influence of ecological factors on the worldwide virus distribution and give an outlook on research perspectives for the next years. PMID- 25453326 TI - Chikungunya, a paradigm of neglected tropical disease that emerged to be a new health global risk. AB - Chikungunya virus (CHIKV) is an alphavirus of the Togaviridae family that causes chronic and incapacitating arthralgia in human populations. Since its discovery in 1952, CHIKV was responsible for sporadic and infrequent outbreaks. However, since 2005, global Chikungunya outbreaks have occurred, inducing some fatalities and associated with severe and chronic morbidity. Chikungunya is thus considered as an important re-emerging public health problem in both tropical and temperate countries, where the distribution of the Aedes mosquito vectors continues to expand. This review highlights the most recent advances in our knowledge and understanding of the epidemiology, biology, treatment and vaccination strategies of CHIKV. PMID- 25453327 TI - Yellow fever. AB - Yellow fever, a mosquito-borne flavivirus disease occurs in tropical areas of South America and Africa. It is a disease of major historical importance, but remains a threat to travelers to and residents of endemic areas despite the availability of an effective vaccine for nearly 70 years. An important aspect is the receptivity of many non-endemic areas to introduction and spread of yellow fever. This paper reviews the clinical aspects, pathogenesis, and epidemiology of yellow fever, with an emphasis on recent changes in the distribution and incidence of the disease. Recent knowledge about yellow fever 17D vaccine mechanism of action and safety are discussed. PMID- 25453329 TI - Advances in the understanding, management, and prevention of dengue. AB - Dengue causes more human morbidity globally than any other vector-borne viral disease. Recent research has led to improved epidemiological methods that predict disease burden and factors involved in transmission, a better understanding of immune responses in infection, and enhanced animal models. In addition, a number of control measures, including preventative vaccines, are in clinical trials. However, significant gaps remain, including the need for better surveillance in large parts of the world, methods to predict which individuals will develop severe disease, and immunologic correlates of protection against dengue illness. During the next decade, dengue will likely expand its geographic reach and become an increasing burden on health resources in affected areas. Licensed vaccines and antiviral agents are needed in order to effectively control dengue and limit disease. PMID- 25453328 TI - Recent advances in research on Crimean-Congo hemorrhagic fever. AB - Crimean-Congo hemorrhagic fever (CCHF) is an expanding tick-borne hemorrhagic disease with increasing human and animal health impact. Immense knowledge was gained over the past 10 years mainly due to advances in molecular biology, but also driven by an increased global interest in CCHFV as an emerging/re-emerging zoonotic pathogen. In the present article, we discuss the advances in research with focus on CCHF ecology, epidemiology, pathogenesis, diagnostics, prophylaxis and treatment. Despite tremendous achievements, future activities have to concentrate on the development of vaccines and antivirals/therapeutics to combat CCHF. Vector studies need to continue for better public and animal health preparedness and response. We conclude with a roadmap for future research priorities. PMID- 25453330 TI - Detection of cytomegalovirus (CMV) by real-time PCR in fecal samples for the non invasive diagnosis of CMV intestinal disease. AB - BACKGROUND: Cytomegalovirus (CMV) infection of the gastrointestinal tract can cause CMV intestinal disease (CMV-ID), a severe complication in immunocompromised patients. Current gold standard for diagnosing CMV-ID requires the analysis of colon biopsies. Testing of fecal samples by CMV PCR might be a non-invasive diagnostic alternative, but data on this method is scarce. OBJECTIVES: To evaluate the use of quantitative CMV real-time PCR in fecal samples for diagnosing CMV-ID. STUDY DESIGN: Fecal samples and lower intestinal tract biopsies from 66 patients were analyzed by quantitative CMV PCR. To evaluate the diagnostic significance of CMV detection by PCR in fecal samples, patients were classified according to the etiology of their intestinal disease (based on results of endoscopy, histopathology and quantitative CMV DNA detection in biopsies) into three groups: "CMV-ID", "non-CMV-ID", and "equivocal". RESULTS: 10/66 fecal samples were tested positive by quantitative CMV PCR, but CMV DNA loads were low (range <1000-11,000copies/ml). CMV detection by PCR in fecal samples was positive in 8/12 patients of the CMV-ID group, resulting in a sensitivity of 67% for diagnosing CMV-ID. With two exceptions, fecal CMV PCR was negative in the non-CMV-ID group (45/47) indicating a good specificity (96%). Moreover, CMV DNA detection in feces was associated with high CMV DNA levels in intestinal biopsies. CONCLUSIONS: Negative CMV PCR results from fecal samples cannot exclude CMV-ID and thus have to be confirmed by analyzing intestinal biopsies. However, positive fecal PCR results are diagnostically useful and might help to circumvent invasive diagnostic procedures as endoscopy. PMID- 25453331 TI - Human papillomavirus typing by single tube multiplex amplification in real time (SMART): the PapillomaFinder(r) SMART 20 assay. AB - BACKGROUND: High-risk (hr) human papillomavirus (HPV) infections play a causal role in the development of cervical cancer. The detection of hrHPV is, therefore, advocated in cervical cancer screening programs. OBJECTIVES: The aim of this study was to determine the performance of a novel HPV typing assay, PapillomaFinder(r) SMART 20. This is a one-tube-per-sample method, to be performed on standard real-time PCR platforms, using melting curve analysis to distinguish targets. The assay detects all 14 hrHPV types, of which 16, 18, 31, 33, 35, 39, 45, 52, 56 and 58 individually. HrHPV types 51, 59, 66 and 68 are detected in an hrHPV pool, and low-risk (lr) HPV types 6, 11, 40, 42, 43 and 44 in an lrHPV pool. STUDY DESIGN: The method was tested on HPV plasmid models, WHO and QCMD proficiency panels and a series of clinical cytological samples (n=45), the latter in comparison with a clinically validated real-time quantitative PCR. RESULTS: Type-specificity of the test was 100% using plasmids, the WHO and QCMD panels. Sensitivity for hrHPV in single infections was 100% using the WHO and QCMD panels and cytological samples, with an analytical sensitivity of 10-25 copies per reaction for all HPV types tested. Of the 34 HPV types present in the 8 multiple infections in the WHO panel, 30 were detected. In all cytological samples at least one hrHPV type was found, in concordance with the clinically validated method. Only when the viral load of the dominant HPV types in multiple infections greatly exceeded that of the other types in the infection, those other types were not always detected. CONCLUSIONS: PapillomaFinder(r) SMART 20 is a rapid, easy to perform, single tube HPV typing assay. The assay detects the 14 hrHPV types, and the 6 most important lrHPV types with a high sensitivity and type-specificity. PMID- 25453332 TI - Genetic diversity and clinical impact of human rhinoviruses in hospitalized and outpatient children with acute respiratory infection, Argentina. AB - BACKGROUND: Human rhinoviruses (HRV) are recognized as a cause of upper and lower acute respiratory infections (ARI). The circulating species and their clinical impact were not described in Argentina. OBJECTIVES: To describe the molecular epidemiology of HRV in children and to determine the association of HRV species with outcome and severity. STUDY DESIGN: Hospitalized and outpatients children <6 years old with ARI without comorbidities (n=620) were enrolled (2008-2010). Demographic, clinical data and outcome were analyzed. HRV were identified by RT PCR. Phylogenetic analysis and demographic reconstruction for HRV were performed in selected samples. RESULTS: HRV were detected in 252/620 (40.6%) of children; 8.5% in viral coinfection. Bronchiolitis (55%) and pneumonia (13%) were the most frequent clinical diagnosis. Of 202 inpatients with HRV: 72% required oxygen supplementation, 11% intensive care unit and 3% mechanical ventilation. HRV were identified as a risk factor for hospitalization (OR: 2.47). All three HRV species were detected being HRV-A (55%) and HRV-C (43%) the most frequent; HRV-B was infrequent (2%). Of 44 sequenced HRV, 30 genotypes were detected. Seven of them were the most prevalent and circulated during limited periods of time. The demographic reconstruction revealed a constant population size and a high turnover rate of genotypes. Demographic and clinical outcome were similar for HRV A and HRV-C infections. CONCLUSION: This study highlights the clinical impact of HRV in children without comorbidities as a cause of lower ARI and hospitalization. The high frequency of HRV infections may be associated with the simultaneous circulation of genotypes and their high turnover rate. PMID- 25453334 TI - First dengue co-infection in a Belgian traveler returning from Thailand, July 2013. AB - We report a dengue virus (DENV) co-infection in a Belgian traveler after a three weeks holiday to Thailand. The patient recovered well without any complication. The infection was diagnosed by NS1 antigen testing and the concurrent presence of serotype DENV1 and DENV2 was demonstrated by reverse transcriptase polymerase chain reaction (RT-PCR) in acute phase serum sampled three days after symptoms onset. The predominant DENV1 serotype was identified as genotype I, lineage Asia 3 by sequencing. To our knowledge, this is the first time that a dengue co infection is reported in a European traveler. The co-infection accounts for 1.0% of the total number of RT-PCR-positive samples (n=105) diagnosed in the reference laboratory of Belgium between 2008 and 2013. We expect that the number of reports on acute co-infections will increase in the coming years considering the increasing number of regions that are progressively becoming hyperendemic, especially in Southeast Asia. PMID- 25453333 TI - The roles of ADAM33, ADAM28, IL-13 and IL-4 in the development of lung injuries in children with lethal non-pandemic acute infectious pneumonia. AB - BACKGROUND: ADAM28, ADAM33, IL-13, IL-4 and other cytokines (IL-6 and IL-10) seem to play important roles in the persistence and maintenance of acute inflammatory processes that ultimately lead to lung remodeling and pulmonary fibrosis, which may be responsible for the high morbidity and mortality rates associated with non pandemic acute viral pneumonias in childhood. OBJECTIVES: The aim of this study was to evaluate the roles of ADAM33, ADAM28, IL4, IL6, IL10 and IL13 in the development of inflammation and alveolar fibrosis due to lethal acute respiratory infections of the lower airway in a pediatric population, especially in those with viral etiology. STUDY DESIGN: For this study, 193 cases were selected, and samples from the cases were processed for viral antigen detection by immunohistochemistry and then separated into two groups: virus-positive (n=68) and virus-negative (n=125). Immunohistochemistry was performed to assess the presence of metalloproteinases (ADAM33 and ADAM28) and inflammatory cytokines (IL 4, IL-13, IL-6, IL-10) in the alveolar septa. RESULTS: The virus-positive group showed stronger immunolabeling for ADAM33, ADAM28, IL-4 and IL-13 (p<0.0001 for all variables). The staining intensities for ADAM33 and ADAM28 were directly proportional to the intensities for IL-4 and IL-13 (p<0.0001). CONCLUSIONS: The results of this study suggest that these proteins play important roles in pulmonary inflammatory reactions elicited against etiological viral agents. In addition, these mediators may affect the process of lung remodeling and the development of pulmonary fibrosis. PMID- 25453335 TI - Acute and regressive scleroderma concomitant to an acute CMV primary infection. AB - OBJECTIVES: To describe the pathophysiological mechanisms involving cytomegalovirus (CMV) primary infection and natural killer (NK) cell expansion in the development of localized scleroderma. RESULTS: A 43-year-old woman presented acute erythematous discoloration and skin thickening concerning face, neck, trunk, abdomen, and the four limbs, predominantly in proximal areas. Our case did not respond to systemic sclerosis criteria diagnosis. However, skin and muscle biopsy revealed early scleroderma associated with capillary thrombi, and tissue infiltration with NK cells (CD56+/Granzyme B). Scleroderma was attributed to CMV primary infection responsible for cytolytic hepatitis (7-fold over the limit) and circulating NK cell excess. After 6 months of prednisone and a 2-year follow-up, a complete resolution of symptoms was observed. CONCLUSION: Our observation suggests a potential triggering role of CMV primary infection in the development of scleroderma. Histological features from our observation addresses the role of CMV and NK cells in the development of endothelial damage and fibrotic process. PMID- 25453336 TI - An HIV-1 RNA test following a reactive fourth-generation antigen/antibody combination assay confirms a high proportion of HIV infections. PMID- 25453337 TI - Free estradiol and sex hormone-binding globulin. AB - SHBG is a plasma protein that participates in the regulation of free estradiol and free testosterone in plasma. We discuss the concept of the nature of a free estradiol and how best to ascertain its value. It can be measured or calculated; the ways in which this can be done are explored along with the advantages and disadvantages of each. PMID- 25453338 TI - Molecular cloning and expression analysis of 17b-hydroxysteroid dehydrogenase 1 and 12 during gonadal development, recrudescence and after in vivo hCG induction in catfish, Clarias batrachus. AB - In teleosts, the levels of steroids during critical period of sex differentiation are critical for gonadogenesis. Hence, steroidogenesis and expression of steroidogenic enzyme genes are very critical for gonadal development and function. In this regard, 17b-HSDs are important as they are involved in both 17b estradiol (E2) and testosterone (T) biosynthesis. Full length cDNAs of 17b-HSD 1 (1791 bp) and 12 (1073 bp) were cloned from catfish gonads which encodes a protein of 295 and 317 amino acids, respectively. To understand the importance of these enzymes in teleost reproduction, mRNA expression was analyzed during gonadal development, seasonal reproductive cycle and after human chorionic gonadotropin (hCG) induction. Phylogenetic analysis revealed that the 17b-HSD 1 and 12 share high homology with their respective 17b-HSD forms from other teleosts and both the 17b-HSD forms belong to short chain dehydrogenase/ reductase family. Tissue distribution analysis showed that the 17b-HSD 1 expression was higher in ovary and gills, while 17b-HSD 12 was higher expressed in testis, ovary, brain, intestine and head kidney compared to other tissues analyzed. Developing and mature ovary showed higher expression of 17b-HSD 1, while 17b-HSD 12 was higher in testis than the ovary of corresponding stages. Further, 17b-HSD 1 and 12 transcripts together with E2 and T levels were found to be modulated during different phases of the seasonal reproductive cycle. Expression of 17b-HSD 1 and 12 was upregulated after hCG induction which shows possible regulation by gonadotropin. Our findings suggest that 17b-HSD 1 and 12 might play important role in regulating gonadal development and gametogenesis through modulation of sex steroid levels. PMID- 25453339 TI - Steroidal saponins with induced platelet aggregation activity from the aerial parts of Paris verticillata. AB - In order to utilize and protect the resources of Rhizoma Paridis rationally, we carried out a phytochemical investigation on the non-medicinal (aerial) parts of Paris verticillata that led to the isolation of fifteen steroidal saponins. Among them, three are new spirostanol saponins, named parisverticosides A-C (1-3), as well as one new cholestane glycoside, named parisverticoside D (4). Their structures were elucidated by extensive spectroscopic analysis and acid hydrolysis. The aglycone of compound 1 is a new spirostane and identified as (23S,24S,25S)-spirost-5-en-1b,3b,23, 24-tetraol. The selected isolates were evaluated for induced platelet aggregation activity and compound 5 showed 62% maximal platelet aggregation rate at the concentration of 300 lg/mL. PMID- 25453341 TI - Binding of fusion protein FLSC IgG1 to CCR5 is enhanced by CCR5 antagonist Maraviroc. AB - The CCR5 chemokine receptor is crucial for human immunodeficiency virus type 1 (HIV-1) infection, acting as the principal coreceptor for HIV-1 entry and transmission and is thus an attractive target for antiviral therapy. Studies have suggested that CCR5 surface density and its conformational changes subsequent to virion engagement are rate limiting for entry, and consequently, infection. Not all CCR5 antibodies inhibit HIV-1 infection, suggesting a need for more potent reagents. Here we evaluated full length single chain (FLSC) IgG1, a novel IgG-CD4 gp120(BAL) fusion protein with several characteristics that make it an attractive candidate for treatment of HIV-1 infections, including bivalency and a potentially increased serum half-life over FLSC, the parental molecule. FLSC IgG1 binds two domains on CCR5, the N-terminus and the second extracellular loop, lowering the levels of available CCR5 viral attachment sites. Furthermore, FLSC IgG1 synergizes with Maraviroc (MVC), the only licensed CCR5 antagonist. In this study, we used both microscopy and functional assays to address the mechanistic aspects of the interactions of FLSC IgG1 and MVC in the context of CCR5 conformational changes and viral infection. We used a novel stochastic optical reconstruction microscopy (STORM), based on high resolution localization of photoswitchable dyes to visualize direct contacts between FLSC IgG1 and CCR5. We compared viral entry inhibition by FLSC IgG1 with that of other CCR5 blockers and showed FLSC IgG1 to be the most potent. We also showed that lower CCR5 surface densities in HIV-1 infected primary cells result in lower FLSC IgG1 EC50 values. In addition, CCR5 binding by FLSC IgG1, but not CCR5 Ab 2D7, was significantly increased when cells were treated with MVC, suggesting MVC allosterically increases exposure of the FLSC IgG1 binding site. These data have implications for future antiviral therapy development. PMID- 25453340 TI - Cidofovir and brincidofovir reduce the pathology caused by systemic infection with human type 5 adenovirus in immunosuppressed Syrian hamsters, while ribavirin is largely ineffective in this model. AB - There are no drugs approved specifically to treat disseminated adenovirus (Ad) infections in humans. Cidofovir is active against Ad in cell culture, and it is used frequently in the clinic with disseminated infection in pediatric transplant patients; however, controlled clinical studies have not been conducted to prove the anti-Ad efficacy of cidofovir. Brincidofovir, a lipid-linked derivative of cidofovir, which has strong activity against Ad in cell culture and in animal models, is a promising new drug currently in clinical trials. Ribavirin, which has modest activity against some Ad types in cell culture, has been used in the clinic against disseminated Ad, but the efficacy of ribavirin is unknown. In the current study, we have examined the activity of cidofovir, brincidofovir, and ribavirin against disseminated Ad5 infection in the immunosuppressed Syrian hamster model. Hamsters are immunosuppressed by treatment with cyclophosphamide, then infected intravenously with Ad5, leading to disseminated Ad5 infection, especially in the liver. We found that cidofovir and brincidofovir have excellent activity against Ad5 pathology and replication in the liver, even when administered therapeutically starting at 3 days post-challenge with Ad5. Ribavirin did not have anti-Ad5 activity in our model. Our data support the use of cidofovir and brincidofovir in humans for the treatment of disseminated Ad infections in humans. PMID- 25453342 TI - A stably expressed llama single-domain intrabody targeting Rev displays broad spectrum anti-HIV activity. AB - The HIV Rev protein mediates the transport of partially and unspliced HIV mRNA from the nucleus to the cytoplasm. Rev multimerizes on a secondary stem-loop structure present in the viral intron-containing mRNA species and recruits the cellular karyopherin CRM1 to export viral mRNAs from the nucleus to the cytoplasm. Previously we have identified a single-domain intrabody (Nb(190)), derived from a llama heavy-chain antibody, which efficiently inhibits Rev multimerization and suppresses the production of infectious virus. We recently mapped the epitope of this nanobody and demonstrated that Rev residues K20 and Y23 are crucial for interaction while residues V16, H53 and L60 are important to a lesser extent. Here, we generated cell lines stably expressing Nb(190) and assessed the capacity of these cell lines to suppress the replication of different HIV-1 subtypes. These cells stably expressing the single-domain antibody are protected from virus-induced cytopathogenic effect even in the context of high multiplicity of infection. In addition, the replication of different subtypes of group M and one strain of group O is significantly suppressed in these cell lines. Next, we analysed the natural variations of Rev amino acids in sequence samples from HIV-1 infected patients worldwide and assessed the effect of Nb(190) on the most prevalent polymorphisms occurring at the key epitope positions (K20 and Y23) in Rev. We found that Nb(190) was able to suppress the function of these Rev variants except for the K20N mutant, which was present in only 0.7% of HIV-1 sequence populations (n = 4632). Cells stably expressing the single-domain intrabody Nb(190) are protected against virus induced cytopathogenic effect and display a selective survival advantage upon infection. In addition, Nb(190) suppresses the replication of a wide range of different HIV-1 subtypes. Large-scale sequence analysis reveals that the Nb(190) epitope positions in Rev are well conserved across major HIV-1 subtypes and groups. Altogether, our results indicate that Nb(190) may have broad potential as a gene therapeutic agent against HIV-1. PMID- 25453343 TI - Toll-like receptor 3 signaling inhibits simian immunodeficiency virus replication in macrophages from rhesus macaques. AB - Toll-like receptor 3 (TLR3) recognizes double-stranded RNA and induces multiple intracellular events responsible for innate antiviral immunity against viral infections. Here we demonstrate that TLR3 signaling of monocyte-derived macrophages (MDM) from rhesus monkeys by poly I:C inhibited simian immunodeficiency virus (SIV) infection and replication. Investigation of the mechanisms showed that TLR3 activation resulted in the induction of type I and type III interferons (IFNs) and IFN-inducible antiviral factors, including APOBEC3G (A3G), tetherin and SAMHD1. In addition, poly I:C-treated macaque macrophages expressed increased levels of CC chemokines including CCL3, CCL4 and CCL5, the ligands for HIV or SIV coreceptor CCR5. Furthermore, TLR3 signaling of macaque macrophages induced the expression of cellular microRNAs (miR-29a, -29b, 146a and -9), the newly identified intracellular SIV restriction factors. TLR3 activation-mediated anti-SIV effect could be compromised by the knockdown of IRF3 and IRF7. These findings indicate that TLR3-mediated induction of multiple viral restriction factors contribute to the inhibition of SIV infection in macaque macrophages, which support future preclinical studies using rhesus macaques to determine whether in vivo TLR3 activation is safe and beneficial for treating people infected with HIV. PMID- 25453344 TI - Inhibition of large T antigen ATPase activity as a potential strategy to develop anti-polyomavirus JC drugs. AB - INTRODUCTION: This study evaluates polyomavirus JC (JCV) large T antigen (LTA) as a potential target for drug development. LTA is a hexameric protein with a helicase activity that is powered by ATP binding and hydrolysis. The helicase and ATPase function is critical for viral replication. METHODS: Recombinant JCV LTA was produced in an Escherichia coli based expression plasmid. ATPase activity was measured using the malachite green assay. A high throughput screen was completed using a brain-biased library of 75,000 drug-like compounds selected for physicochemical properties consistent with blood-brain barrier permeability. RESULTS: Five compounds showed non-competitive inhibition of ATPase activity with an EC50 ? 15 MUM. Modest antiviral activity was demonstrated in an immunofluorescence assay for JCV VP-1 expression in COS7 cells (EC50 15, 18, 20, 27, and 52 MUM respectively). The compounds also inhibited viral replication in a real time PCR assay at comparable concentrations. LD50 in the MTS96 and Cell TiterGlo assays was >100 MUM for all compounds in COS7 as well as HEK293 cells. However, two compounds inhibited cell proliferation in culture with IC50 values of 43 and 34 MUM respectively. Despite substantial amino acid similarity between polyomavirus JC, BK and SV40 proteins, these compounds differ from those previously reported to inhibit SV40 LTA ATPase in chemical structure as well as a non-competitive mechanism of inhibition. CONCLUSION: LTA ATPase is a valid target for discovery. Additional screening and chemical optimization is needed to develop clinically useful compounds with less toxicity, which should be measured by metabolic as well as cell proliferation assays. PMID- 25453345 TI - Risk factors differ between recurrent and incident preeclampsia: a hospital based cohort study. AB - PURPOSE: To examine whether risk factors, including prepregnancy body mass index (BMI), differ between recurrent and incident preeclampsia. METHODS: Data included electronic medical records of nulliparas (n = 26,613) delivering 2 times or more in Utah (2002-2010). Modified Poisson regression models were used to examine (1) adjusted relative risks (RR) of preeclampsia and 95% confidence intervals (CI) associated with prepregnancy BMI; (2) maternal risk factor differences between incident and recurrent preeclampsia among primiparous women. RESULTS: In the first pregnancy, compared with normal weight women (BMI: 18.5-24.9), preeclampsia risks for overweight (BMI: 25-29.9), obese class I (BMI: 30-34.9), and obese class II/III (BMI: >= 35) women were 1.82 (95% CI = 1.60-2.06), 2.10 (95% CI = 1.76-2.50), and 2.84 (95% CI = 2.32-3.47), respectively, whereas second pregnancy incident preeclampsia risks were 1.66 (95% CI = 1.27-2.16), 2.31 (95% CI = 1.67 3.20), and 4.29 (95% CI = 3.16-5.82), respectively. Recurrent preeclampsia risks associated with BMI were highest among obese class I women (RR = 1.60; 95% CI = 1.06-2.42) without increasing in a dose-response manner. Nonwhite women had higher recurrence risk than white women (RR = 1.70; 95% CI = 1.16-2.50), whereas second pregnancy-incident preeclampsia risk did not differ by race. CONCLUSION: Prepregnancy BMI appeared to have stronger associations with risk of incident preeclampsia either in the first or second pregnancy, than with recurrence risk. Nonwhite women had higher recurrence risk. PMID- 25453346 TI - Absence of circadian rhythms of preterm premature rupture of membranes and preterm placental abruption. AB - PURPOSE: Data regarding circadian rhythm in the onset of spontaneous preterm premature rupture of membranes (PROM) and placental abruption (PA) cases are conflicting. We modeled the time of onset of preterm PROM and PA cases and examined if the circadian profiles varied based on the gestational age at delivery. METHODS: We used parametric and nonparametric methods, including trigonometric regression in the framework of generalized linear models, to test the presence of circadian rhythms in the time of onset of preterm PROM and PA cases among 395 women who delivered a singleton between 2009 and 2010 in Lima, Peru. RESULTS: We found a diurnal circadian pattern, with a morning peak at 07:32 AM (95% confidence interval, 05:46 AM-09:18 AM) among moderate preterm PROM cases (P value < .001), and some evidence of a diurnal circadian periodicity among PA cases in term infants (P value = .067). However, we did not find evidence of circadian rhythms in the time of onset of extremely or very preterm PROM (P value = .259) and preterm PA (P value = .224). CONCLUSIONS: The circadian rhythms of the time of onset of preterm PROM and PA cases varied based on gestational weeks at delivery. Although circadian rhythms were presented among moderate preterm PROM and term PA cases, there was no evidence of circadian rhythms among preterm PA and very or extremely preterm PROM cases, underlying other mechanisms associated with the time of onset. PMID- 25453347 TI - Traffic-related air pollution and risk of preterm birth in the San Joaquin Valley of California. AB - PURPOSE: To evaluate associations between traffic-related air pollution during pregnancy and preterm birth in births in four counties in California during years 2000 to 2006. METHODS: We used logistic regression to examine the association between the highest quartile of ambient air pollutants (carbon monoxide, nitrogen dioxide, particulate matter <10 and 2.5 MUm) and traffic density during pregnancy and each of five levels of prematurity based on gestational age at birth (20-23, 24-27, 28-31, 32-33, and 34-36 weeks) versus term (37-42 weeks). We examined trimester averages and the last month and the last 6 weeks of pregnancy. Models were adjusted for birthweight, maternal age, race/ethnicity, education, prenatal care, and birth costs payment. Neighborhood socioeconomic status (SES) was evaluated as a potential effect modifier. RESULTS: There were increased odds ratios (ORs) for early preterm birth for those exposed to the highest quartile of each pollutant during the second trimester and the end of pregnancy (adjusted OR, 1.4-2.8). Associations were stronger among mothers living in low SES neighborhoods (adjusted OR, 2.1-4.3). We observed exposure-response associations for multiple pollutant exposures and early preterm birth. Inverse associations during the first trimester were observed. CONCLUSIONS: The results confirm associations between traffic-related air pollution and prematurity, particularly among very early preterm births and low SES neighborhoods. PMID- 25453348 TI - Longitudinal association of anthropometric measures of adiposity with cardiometabolic risk factors in postmenopausal women. AB - PURPOSE: Some studies suggest that anthropometric measures of abdominal obesity may be superior to body mass index (BMI) for the prediction of cardiometabolic risk factors; however, most studies have been cross-sectional. Our aim was to prospectively examine the association of change in BMI, waist-to-hip ratio (WHR), waist circumference (WC), and waist circumference-to-height ratio (WCHtR) with change in markers of cardiometabolic risk in a population of postmenopausal women. METHODS: We used a subsample of participants in the Women's Health Initiative aged 50 to 79 years at entry with available fasting blood samples and anthropometric measurements obtained at multiple time points over 12.8 years of follow-up (n = 2672). The blood samples were used to measure blood glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides at baseline, and at years 1, 3, and 6. We conducted mixed-effects linear regression analyses to examine associations at baseline and longitudinal associations between change in anthropometric measures and change in cardiometabolic risk factors, adjusting for covariates. RESULTS: In longitudinal analyses, change in BMI, WC, and WCHtR robustly predicted change in cardiometabolic risk, whereas change in WHR did not. The strongest associations were seen for change in triglycerides, glucose, and HDL-C (inverse association). CONCLUSION: Increase in BMI, WC, and WCHtR strongly predicted increases in serum triglycerides and glucose, and reduced HDL-C. WC and WCHtR were superior to BMI in predicting serum glucose, HDL-C, and triglycerides. WCHtR was superior to WC only in predicting serum glucose. BMI, WC, and WCHtR were all superior to WHR. PMID- 25453350 TI - Trends in the skewness of the body mass index distribution among urban Australian adults, 1980 to 2007. AB - PURPOSE: We analyzed the changes in the body mass index (BMI) distribution for urban Australian adults between 1980 and 2007. METHODS: We used data from participants of six consecutive Australian nation-wide surveys with measured weight and height between 1980 and 2007. We used quantile regression to estimate mean BMI (for percentiles of BMI) and prevalence of severe obesity, modeled by natural splines in age, date of birth, and survey date. RESULTS: Since 1980, the right skew in the BMI distribution for Australian adults has increased greatly for men and women, driven by increases in skew associated with age and birth cohort/period. Between 1980 and 2007, the average 5-year increase in BMI was 1 kg/m(2) (0.8) for the 95th percentile of BMI in women (men). The increase in the median was about a third of this, and for the 10th percentile, a fifth of this. We estimated that for the cohort born in 1960 around 31% of men and women were obese by age 50 years compared with 11% of the 1930 birth cohort. CONCLUSIONS: There have been large increases in the right skew of the BMI distribution for urban Australian adults between 1980 and 2007, and birth cohort effects suggests similar increases are likely to continue. PMID- 25453349 TI - Depressive symptoms and their relationship with endogenous reproductive hormones and sporadic anovulation in premenopausal women. AB - PURPOSE: To determine whether depressive symptoms are associated with ovulation or reproductive hormone concentrations in eumenorrheic women without a reported diagnosis of clinical depression. METHODS: A prospective cohort of 248 regularly menstruating women, aged 18 to 44 years (27.3 +/- 8.2) were evaluated for depressive symptoms at baseline using the 20-item Center for Epidemiological Studies Depression (CES-D) scale and categorized dichotomously (<16, no depressive symptoms [92%] vs. >= 16, depressive symptoms [8%]). Serum concentrations of estradiol, progesterone, luteinizing hormone, and follicle stimulating hormone were measured up to eight times per cycle for up to two menstrual cycles. Linear mixed models estimated associations between depressive symptoms and hormone concentrations, whereas generalized linear mixed models assessed their relationship with sporadic anovulation. RESULTS: No significant associations were identified between depressive symptoms and reproductive hormone levels (all P > .05) or the odds of sporadic anovulation (adjusted odds ratio, 1.1; 95% confidence interval, [0.02-5.0]), after adjusting for age, race, body mass index, perceived stress level, and alcohol consumption. CONCLUSIONS: Despite reported associations between mental health and menstrual cycle dysfunction, depressive symptoms were not associated with reproductive hormone concentrations or sporadic anovulation in this cohort of regularly menstruating women with no recent (within 1 year) self-reported history of clinical depression. PMID- 25453351 TI - Vulnerability to diabetes in Chinese: an age-period-cohort analysis. AB - PURPOSE: Hong Kong, in common with other Asian settings, has high rates of diabetes mellitus (DM) despite a relatively nonobese population. Given the rapid economic development in the region, most Asians grew up in limited living conditions. We examined the longitudinal mortality trends of DM. We assessed whether the first generation (birth cohorts in the 1930s) with late adolescence in a more economically developed environment had a lower risk of DM. METHODS: We used DM deaths and population figures in Hong Kong, 1976 to 2010. We fitted age period-cohort models to decompose mortality rates into effects for age at mortality, calendar period of mortality, and birth cohort. RESULTS: The risk of death from DM fell for the first generation (births in the early 1930s) with late adolescence in Hong Kong, but possibly the risk rose again for the first generation (birth 1960s) affected by the obesity epidemic. CONCLUSIONS: Adiposity might contribute to diabetes in Hong Kong, and similar Asian settings, however current vulnerability of many older Asians to DM in plentiful environments may be the result of limited living conditions until adulthood. Furthermore, our findings are more consistent with limited adolescent conditions than fetal undernutrition playing a role in vulnerability to DM. PMID- 25453352 TI - Low-to-moderate prenatal alcohol consumption and the risk of selected birth outcomes: a prospective cohort study. AB - PURPOSE: To estimate whether low-to-moderate prenatal alcohol exposure is associated with selected birth outcomes. METHODS: Low-to-moderate prenatal alcohol drinking and effects on low birthweight, preterm delivery, intrauterine growth restriction, and selected neonatal outcomes were evaluated among 4496 women and singleton infants. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression, controlling for confounding variables. RESULTS: Early pregnancy drinking was associated with reduced odds of low birthweight, OR, 0.66 (95% CI, 0.46-0.96) and birth length less than 10th percentile, OR, 0.74 (95% CI, 0.56-0.97). Drinking during the first 3 months showed lower odds for birth length and head circumference less than 10th percentile, OR, 0.56 (95% CI, 0.36-0.87) and OR, 0.69 (95% CI, 0.50 0.96), respectively. Third trimester drinking was associated with lower odds for low birthweight, OR, 0.56 (95% CI, 0.34-0.94) and preterm delivery, OR, 0.60 (95% CI, 0.42-0.87). CONCLUSIONS: Our results suggest low-to-moderate alcohol exposure during early and late gestation is not associated with increased risk of low birthweight, preterm delivery, intrauterine growth restriction, and most selected perinatal outcomes. PMID- 25453353 TI - A comparison of self-reported oral contraceptive use and automated pharmacy data in perimenopausal and early postmenopausal women. AB - PURPOSE: Oral contraceptive (OC) use can occur throughout a woman's reproductive life span with the potential for long-term impacts on health. To assess potential measurement error in prior OC use, this study compared level of agreement between self-reported prior OC use and pharmacy dispensing data in perimenopausal and/or early postmenopausal women. METHODS: The study's 1399 women (ages, 45-59 years) were participants in a population-based case-control study of the association between OC use and fracture risk. Episodes of lifetime self-reported OC use (in months) were collected, by telephone interview, for January 1, 2008 through November 25, 2012. Pharmacy fills, back to 1980, were collected from automated data. Agreement was measured using the prevalence-adjusted and bias-adjusted kappa index. RESULTS: The number of women with OC pharmacy fills was 11% to 45% higher than those who reported OC use during each time period. Between-measures agreement was better for more recent use. Prevalence-adjusted and bias-adjusted kappa index values ranged from 0.88 (95% confidence interval, 0.85-0.90) within 5 years from the reference date to 0.65 (95% confidence interval, 0.59-0.71) within 15 to 20 years. CONCLUSIONS: For studies designed to assess the long-term effects of OC use, the current results are reassuring in noting moderate agreement between self-reported OC use and pharmacy data for up to 15 to 20 years before the interview. PMID- 25453355 TI - [RALP: comparison of the oncological and functional outcomes of the intrafascial and the interfascial approaches]. PMID- 25453354 TI - [Holmium laser enucleation of the prostate as a day case surgery: prospective evaluation of the first 30 patients]. AB - OBJECTIVES: To evaluate the feasibility of holmium laser enucleation of the prostate (HoLEP) as a day case surgery. MATERIAL AND METHODS: Observational prospective study including 30 consecutive patients after exclusion of unstable diseases and anticoagulant therapy. Patients were discharged before 8PM and the urinary catheter was removed at home the next morning. The monitoring included a phone call after 24hours and clinical evaluations after 1 and 3month follow-up. Clinical data were prospectively collected and complications were classified according to the Clavien-Dindo classification. RESULTS: The mean age of the study population was 63.8, prostate volume was 75.3cc, maximum urinary flow rate was 9.5mL/s, and IPSS was 22.9. The conversion rate to conventional hospitalization was 3.3%. After 3months follow-up, readmission and reoperation rates were respectively 16.6% and 3.3%. The overall complication rate was 66% (Clavien I=57.7%, II=38.5%, III=3.8%). The satisfaction rate was 100% (score=9.2/10). The mean prostate volume at 3months follow-up was 23.3cc, maximum urinary flow was 25.6mL/s, and IPSS was 4.7. CONCLUSION: This study confirmed the feasibility of HoLEP as a day case surgery for selected patients. Conversion rate to conventional hospitalization and complications of grade >2 were less than 5% while the satisfaction rate was high. LEVEL OF EVIDENCE: 3. PMID- 25453356 TI - [Single procedure treatment of complex nephrolithiasis: about a modern series of anatrophic nephrolithotomy]. AB - PURPOSE: Advances in endourology have significantly reduced indications of open surgery in the treatment of staghorn calculi. However, in our experience, open surgery is still the treatment of choice in some cases. This study presents the results of a series of selected patients and discusses the results in terms of efficacy and morbidity. MATERIALS: A cohort of 26 patients underwent anatrophic nephrolithotomy by lombotomy to treat a complex staghorn calculus. RESULTS: The mean stone size was 68,5mm, 70% were complete staghorn calculi. The operative time was 100minutes. Blood loss was 225mL, with a postoperative transfusion rate of 15.4%. The hospital stay was 8.4 days. The stone free rate following the procedure was 92%. The creatinine clearance (MDRD) at 3 months was improved from 5.9mL/min/m(2) on average over the entire series. CONCLUSION: There are clearly still indications for open surgery in staghorn stones management, with good results in this contemporary series on both stone removal and nephronic preservation. Yet, it appears that this technique is no longer taught. LEVEL OF EVIDENCE: 5. PMID- 25453357 TI - [Evaluation of the impact of CTMH guidelines on the management of benign prostatic hyperplasia]. AB - INTRODUCTION: The French guidelines on the management of benign prostatic hyperplasia (BPH) have been published in 2012 by the LUTS committee of the French Urological Association. The aim of this study was to evaluate the impact of these guidelines on the BPH management by French urologists. MATERIAL AND METHODS: A questionnaire has been distributed by email to 1141 urologists members of the French Association of Urologists in November 2013. RESULTS: We collected 222 responses (response rate: 19%). The guidelines have been read by 73% of the urologists. The guidelines were followed most of the time by 76% of them, 11% followed them systematically and 4.5% did not follow them. The new terminology was used by 28 to 52% according to the items. The symptoms were evaluated by the IPSS score (33%), by interrogatory alone (64%) or by neither of them (3%). Prostate volume was not systematically taken for account in the treatment strategy by 57% of the urologists. Sexual function was assessed systematically by 28% of the urologists, 11% used a questionnaire (IIEF: 92%). PSA was tested respectively by 70 and 51% of the urologists at the initial evaluation and the follow-up. After introduction of a monotherapy, 56% of the urologists evaluated the efficacy at 3 months. CONCLUSION: The French guidelines for the management of benign prostatic hyperplasia (BPH) by the LUTS committee of the French Urological Association were well known and used by French urologists. Some improvements can be expected for the use of the IPSS score, the evaluation of the sexual function, and the use of the new terminology. LEVEL OF EVIDENCE: 4. PMID- 25453358 TI - Semi-automatic motion compensation of contrast-enhanced ultrasound images from abdominal organs for perfusion analysis. AB - This paper presents a system for correcting motion influences in time-dependent 2D contrast-enhanced ultrasound (CEUS) images to assess tissue perfusion characteristics. The system consists of a semi-automatic frame selection method to find images with out-of-plane motion as well as a method for automatic motion compensation. Translational and non-rigid motion compensation is applied by introducing a temporal continuity assumption. A study consisting of 40 clinical datasets was conducted to compare the perfusion with simulated perfusion using pharmacokinetic modeling. Overall, the proposed approach decreased the mean average difference between the measured perfusion and the pharmacokinetic model estimation. It was non-inferior for three out of four patient cohorts to a manual approach and reduced the analysis time by 41% compared to manual processing. PMID- 25453359 TI - TIL-type protease inhibitors may be used as targeted resistance factors to enhance silkworm defenses against invasive fungi. AB - Entomopathogenic fungi penetrate the insect cuticle using their abundant hydrolases. These hydrolases, which include cuticle-degrading proteases and chitinases, are important virulence factors. Our recent findings suggest that many serine protease inhibitors, especially TIL-type protease inhibitors, are involved in insect resistance to pathogenic microorganisms. To clarify the molecular mechanism underlying this resistance to entomopathogenic fungi and identify novel genes to improve the silkworm antifungal capacity, we conducted an in-depth study of serine protease inhibitors. Here, we cloned and expressed a novel silkworm TIL-type protease inhibitor, BmSPI39. In activity assays, BmSPI39 potently inhibited the virulence protease CDEP-1 of Beauveria bassiana, suggesting that it might suppress the fungal penetration of the silkworm integument by inhibiting the cuticle-degrading proteases secreted by the fungus. Phenol oxidase activation studies showed that melanization is involved in the insect immune response to fungal invasion, and that fungus-induced excessive melanization is suppressed by BmSPI39 by inhibiting the fungal cuticle-degrading proteases. To better understand the mechanism involved in the inhibition of fungal virulence by protease inhibitors, their effects on the germination of B. bassiana conidia was examined. BmSPI38 and BmSPI39 significantly inhibited the germination of B. bassiana conidia. Survival assays showed that BmSPI38 and BmSPI39 markedly improved the survival rates of silkworms, and can therefore be used as targeted resistance proteins in the silkworm. These results provided new insight into the molecular mechanisms whereby insect protease inhibitors confer resistance against entomopathogenic fungi, suggesting their potential application in medicinal or agricultural fields. PMID- 25453360 TI - Toward a quantitative theory of food consumption choices and body weight. AB - We propose a calibrated dynamic model of food consumption choices and body weight to study changes in daily caloric intake, weight, and the away-from-home share of calories consumed by adult men and women in the U.S. during the period between 1971 and 2006. Calibration reveals substantial preference heterogeneity between men and women. For example, utility losses stemming from weight gains are ten times greater for women compared to men. Counterfactual experiments show that changes in food prices and household income account for half of the increase in weight of adult men, but only a small fraction of women's weight. We argue that quantitative models of food consumption choices and body weight have a unique role to play in future research in the economics of obesity. PMID- 25453361 TI - Disease isolation: The challenges faced by mothers living with multiple myeloma in rural and regional Australia. AB - PURPOSE: To explore the interrelationship of two challenging aspects of the cancer experience: the diagnosis and experience of younger women living with multiple myeloma, and their geographical disadvantage. METHOD: A cross-sectional retrospective qualitative methodology was employed. Five women with dependent children and a diagnosis of myeloma, living in rural and regional Australia, were interviewed using a semi-structured technique. Interpretative phenomenological analysis provided the foundation for the data analysis and interpretation. RESULTS: The central concept of disease isolation emerged from the data and captured the interrelationship of the experience of living with a rare cancer, while living in a rural and regional area of Australia. Three strong themes emerged: 1) isolation due to living with a rare cancer, 2) isolation within the myeloma population, and 3) isolation due to the disease effects and treatment. In the context of these results, isolation depicted the sense of being alone or separated, both physically and psychologically, from potential sources of support, and of being different from others (both patients with cancer and patients with myeloma), which presented barriers to accessing support. CONCLUSION: The interrelationship of geographical isolation and living with multiple myeloma underpins the core issues relating to the main themes. Understanding the issues confronting younger women with myeloma living in rural and regional of Australia may assist health professionals to improve support for women in this situation. PMID- 25453362 TI - Characterization of resistance genes in 68 ESBL-producing Klebsiella pneumonia in Lebanon. AB - AIM: We studied 68 ESBL-producing Klebsiella pneumoniae strains isolated in Lebanon, determined their profile of resistance to antibiotics, and identified 6 ESBL genes. METHODOLOGY: The susceptibility to antibiotics was determined by the disk diffusion method. The MIC of carbapenems and cefepime was determined by the agar dilution method. ESBL genes were detected by PCR. RESULTS: A percentage of 88.2% and 86.7% of isolates carried the SHV and CTX-M gene respectively; combinations of more than 1 gene of resistance were detected in several isolates. Five strains were resistant to carbapenems; 4/5 carried the OXA-48 gene. CONCLUSION: Our study revealed the emergence of K. pneumoniae ESBL (+) strains carrying several types of genes involved in this phenotype; we also identified carbapenem-resistant strains due to the OXA-48 gene, which are a real threat for public health, especially in Lebanon. PMID- 25453363 TI - Conflict minerals in the compute sector: estimating extent of tin, tantalum, tungsten, and gold use in ICT products. AB - Recent legislation has focused attention on the supply chains of tin, tungsten, tantalum, and gold (3TG), specifically those originating from the eastern part of the Democratic Republic of Congo. The unique properties of these so-called "conflict minerals" lead to their use in many products, ranging from medical devices to industrial cutting tools. This paper calculates per product use of 3TG in several information, communication, and technology (ICT) products such as desktops, servers, laptops, smart phones, and tablets. By scaling up individual product estimates to global shipment figures, this work estimates the influence of the ICT sector on 3TG mining in covered countries. The model estimates the upper bound of tin, tungsten, tantalum, and gold use within ICT products to be 2%, 0.1%, 15%, and 3% of the 2013 market share, respectively. This result is projected into the future (2018) based on the anticipated increase in ICT device production. PMID- 25453364 TI - Targeting protein kinase C in sarcoma. AB - Protein kinase C (PKC) is a family of serine/threonine tyrosine kinases that regulate many cellular processes including division, proliferation, survival, anoikis and polarity. PKC is abundant in many human cancers and aberrant PKC signalling has been demonstrated in cancer models. On this basis, PKC has become an attractive target for small molecule inhibition within oncology drug development programmes. Sarcoma is a heterogeneous group of mesenchymal malignancies. Due to their relative insensitivity to conventional chemotherapies and the increasing recognition of the driving molecular events of sarcomagenesis, sarcoma provides an excellent platform to test novel therapeutics. In this review we provide a structure-function overview of the PKC family, the rationale for targeting these kinases in sarcoma and the state of play with regard to PKC inhibition in the clinic. PMID- 25453365 TI - Mechanisms of intimate and long-distance cross-talk between glioma and myeloid cells: how to break a vicious cycle. AB - Glioma-associated microglia and macrophages (GAMs) and myeloid-derived suppressor cells (MDSCs) condition the glioma microenvironment to generate an immunosuppressed niche for tumour expansion. This immunosuppressive microenvironment is considered to be shaped through a complex multi-step interactive process between glioma cells, GAMs and MDSCs. Glioma cells recruit GAMs and MDSCs to the tumour site and block their maturation. Glioma cell-derived factors subsequently skew these cells towards an immunosuppressive, tumour promoting phenotype. Finally, GAMs and MDSCs enhance immune suppression in the glioma microenvironment and promote glioma growth, invasiveness, and neovascularization. The local and distant cross-talk between glioma cells and GAMs and MDSCs is regulated by a plethora of soluble proteins and cell surface bound factors, and possibly via extracellular vesicles and platelets. Importantly, GAMs and MDSCs have been reported to impair the efficacy of glioma therapy, in particular immunotherapeutic approaches. Therefore, advancing our understanding of the function of GAMs and MDSCs in brain tumours and targeted intervention of their immunosuppressive function may benefit the treatment of glioma. PMID- 25453366 TI - Human leukocyte antigen (HLA)-G and cervical cancer immunoediting: a candidate molecule for therapeutic intervention and prognostic biomarker? AB - While persistent infection with oncogenic types of human Papillomavirus (HPV) is required for cervical epithelial cell transformation and cervical carcinogenesis, HPV infection alone is not sufficient to induce tumorigenesis. Only a minor fraction of HPV infections produce high-grade lesions and cervical cancer, suggesting complex host-virus interactions. Based on its pronounced immunoinhibitory properties, human leukocyte antigen (HLA)-G has been proposed as a possible prognostic biomarker and therapeutic target relevant in a wide variety of cancers and viral infections, but to date remains underexplored in cervical cancer. Given the possible influence of HLA-G on the clinical course of HPV infection, cervical lesions and cancer progression, a better understanding of HLA G involvement in cervical carcinogenesis might contribute to two aspects of fundamental importance: 1. Characterization of a novel diagnostic/prognostic biomarker to identify cervical cancer and to monitor disease stage, critical for patient screening; 2. Identification of HLA-G-driven immune mechanisms involved in lesion development and cancer progression, leading to the development of strategies for modulating HLA-G expression for treatment purposes. Thus, this systematic review explores the potential involvement of HLA-G protein expression and polymorphisms in cervical carcinogenesis. PMID- 25453373 TI - Current status and study activity of lung cancer in Japan. PMID- 25453374 TI - Prognosis of lung cancer patients in Japan according to data from the Japanese Joint Committee of Lung Cancer Registry. AB - An organ-based lung cancer registry is currently maintained by the Japan Joint Committee of Lung Cancer Registry; this registry contributes to the development of lung cancer treatments and provides TNM classification data. In Japan, the overall 5-year survival rate has improved over time to 52% in 2004; the corresponding rates for each pathologic stage have also improved. Previously, separate registries were maintained for surgical and non-biased cases, whereas a prospective registry for non-surgical cases was added in 2012, and a follow-up examination of those data will be conducted in 2016. In addition, a registry of surgical cases from 2010 will be constructed in 2016. The information provided by these registries should better reveal the status of lung cancer patients in Japan. PMID- 25453375 TI - Recent evidence, advances, and current practices in surgical treatment of lung cancer. AB - In the last 10-15 years, strategies and modalities of lung cancer treatment have changed dramatically. Meanwhile, the treatment objectives, the lung cancers themselves, have also changed, probably owing to early detection by computed tomography and aging of the population. In particular, the proportions of smaller lung cancers, lung adenocarcinomas with ground-glass opacity, and lung cancers in older patients are increasing. Along with these changes, surgeons have innovated and evaluated novel procedures for pulmonary resection. These include the application of minimally invasive surgical techniques, such as video-assisted thoracoscopic surgery (VATS) and robotic surgery, and sub-lobar resection, such as wedge resection and segmentectomy, for small peripheral lung cancers. Currently, VATS has gained wide acceptance and several institutions in Japan have started using robotic surgery for lung cancers. Two important clinical trials of sub-lobar resection for small peripheral lung cancers are now underway in Japan. In addition, surgery itself is of growing importance in lung cancer treatment. In particular, recent evidence supports the use of surgery in strictly selected patients with locally advanced disease, lung cancers with N2 lymph node metastases, small cell lung cancers, recurrent oligo-metastasis after pulmonary resection, or relapsed tumors after drug treatment. Surgical treatment also provides abundant tumor samples for molecular analysis, which can be used for drug selection in the adjuvant setting or after disease relapse. In the era of personalized treatment, surgery is still one of the most important treatment modalities to combat lung cancer. PMID- 25453376 TI - Anaplastic lymphoma kinase rearrangement in lung cancer: its biological and clinical significance. AB - Anaplastic lymphoma kinase (ALK) has been found to fuse with other partners, such as echinoderm microtubule-associated protein-like 4 (EML4), leading to potent malignant transformation in lung cancer, specifically non-small-cell lung cancer (NSCLC). The frequency of the ALK rearrangement in patients with NSCLC is reported to be 4-7%, and the rearrangement is frequently observed in relatively younger patients, non- or light smokers and those with adenocarcinoma histology without other genetic disorders, such as mutations of the epidermal growth factor receptor gene. Crizotinib, which is a first-in-class ALK tyrosine kinase inhibitor (TKI), was shown to be effective and well tolerated in ALK-positive NSCLC patients by a single-arm phase I study. Furthermore, a phase III randomized study demonstrated the superiority of crizotinib to standard chemotherapy (pemetrexed or docetaxel) in the treatment of NSCLC patients harboring the ALK rearrangement who had received one prior platinum-based chemotherapy. However, the mechanisms of resistance to crizotinib are major concerns when administering crizotinib to ALK-positive NSCLC patients, and they include second mutations and a gain in the copy number of the ALK gene, activation of other oncogenes, etc. Treatment strategies to overcome these mechanisms of resistance have been developed, including the use of second-generation ALK inhibitors, such as alectinib and ceritinib, heat shock protein 90 inhibitors and so on. In this article, we review the pre-clinical and clinical data regarding the biologal and clinical significance of the ALK rearrangement in lung cancer. PMID- 25453377 TI - Current status and future perspectives of cooperative study groups for lung cancer in Japan. AB - The performance of scientifically and ethically valid prospective clinical trials is the only means by which to obtain reliable clinical evidence that can improve clinical practice and thus the outcome of patients with lung cancer. The efficacy of treatment for advanced lung cancer remains limited; many cooperative study groups for lung cancer have been established in Japan since 1990s, and they have completed several landmark investigator-initiated clinical trials. This review highlights eight active Japanese cooperative study groups for lung cancer and summarizes their achievements made through clinical trials. In addition to their benefits, the existence of multiple study groups for a single disease such as lung cancer presents several challenges including the provision of infrastructure to ensure the scientific integrity of trial results, the unnecessary duplication of effort and the wasting of limited resources, and the accrual and completion of large-scale phase III trials in the shortest possible time. Collaboration among Japanese cooperative groups has recently increased in order to overcome these challenges. Although institutional barriers to the performance of such large intergroup trials remain, further harmonization and collaboration among cooperative groups will be vital in allowing Japanese investigators to make further important contributions for the development of new lung cancer therapies. PMID- 25453378 TI - Clinical significance of epidermal growth factor receptor tyrosine kinase inhibitors: sensitivity and resistance. AB - Gefitinib and erlotinib, which are epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), are highly effective against lung tumors with EGFR activating mutations. However, in 20-30% of cases, there is intrinsic resistance, and even if the treatment is effective, resistance is acquired in one to several years. Possible mechanisms of acquired resistance to EGFR-TKI, thus far, include a gatekeeper mutation of EGFR, activation of an alternate pathway, activation of EGFR downstream signals, transformation to small cell lung cancer, and epithelial-mesenchymal transition (EMT). Recently, BIM (BCL2L11), which is a BH3-only proapoptotic member of the Bcl-2 protein family, was shown to play a central role in inducing apoptosis in response to EGFR-TKI treatment in EGFR mutant lung cancer cells. Moreover, when the expression of active BIM protein was low, there was resistance to apoptosis induction by EGFR-TKI treatment and early disease progression. A polymorphism of the BIM gene unique to East Asian people has been detected and is now attracting attention as a factor causing resistance to EGFR-TKI due to decreased BIM activity. PMID- 25453380 TI - Efficacy and acceptance of a commercial Hoodia parviflora product for support of appetite and weight control in a consumer trial. AB - Species of Hoodia Sweet ex Decne., family Apocynaceae, a southern African succulent plant, have been recognized for their appetite suppressing properties. Products that support appetite and weight control have been developed in Israel from locally cultivated Hoodia spp. To study consumer acceptance, efficacy of, and tolerance for a frozen product based on whole aerial parts of Hoodia parviflora N.E. Br., we initiated and conducted this single-blind, randomized, placebo-controlled consumer trial. Volunteer participants ingested flavored 3 g frozen Hoodia or placebo cubes for 40 days. Subjects were weighed and measured and baseline body-mass index was determined. Adverse events were monitored and eight mild, transient, possible treatment-emergent events were reported. No moderate, severe, or chronic events were reported. On days 1, 10, and 40, subjects self-reported their perceptions of food consumption, hunger development, incidence and control of food cravings, and efficacy of the product. On day 40, the treatment group demonstrated a statistically significant decrease in measured quantitative parameters against the placebo and reported a positive perception of the product. PMID- 25453379 TI - Home-based pulmonary rehabilitation in patients with inoperable or residual chronic thromboembolic pulmonary hypertension: a preliminary study. AB - BACKGROUND: Management of chronic thromboembolic pulmonary hypertension (CTEPH) has recently improved because of advances in pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), and disease-targeted medications. However, patients with inoperable CTEPH or persistent pulmonary hypertension (PH) after these interventions continue to exhibit impaired exercise capacity and limited quality of life (QOL). METHODS: Eight patients with inoperable or residual CTEPH (mean age, 64+/-12 years; WHO functional class II/III, 6/2; mean pulmonary artery pressure, 47+/-13 mmHg) in stable condition and receiving disease-targeted medications participated in a 12-week home-based pulmonary rehabilitation program (muscle strength training, respiratory exercises, and walking) with supervised hospital sessions from March 2012 to January 2014. Efficacy parameters were prospectively evaluated at baseline and at completion of the 12-week program. RESULTS: After completion of the pulmonary rehabilitation program, the 6-minute walking distance (6MWD) (33.3+/-25.1 m), St. George's Respiratory Questionnaire activity score, quadriceps force, and 7-day physical activity level were significantly improved compared with baseline. All subjects completed the rehabilitation program. Although one patient experienced presyncope during the in hospital exercise sessions, no other severe adverse events or complications of pulmonary rehabilitation were observed. CONCLUSIONS: These findings suggest that home-based pulmonary rehabilitation with closely supervised sessions may safely improve exercise capacity, leg muscle strength, general activity in daily life and health-related QOL in CTEPH patients. PMID- 25453381 TI - An enhanced method for registration of dental surfaces partially scanned by a 3D dental laser scanning. AB - In this paper, we propose the fast and accurate registration method of partially scanned dental surfaces in a 3D dental laser scanning. To overcome the multiple point correspondence problems of conventional surface registration methods, we propose the novel depth map-based registration method to register 3D surface models. First, we convert a partially scanned 3D dental surface into a 2D image by generating the 2D depth map image of the surface model by applying a 3D rigid transformation into this model. Then, the image-based registration method using 2D depth map images accurately estimates the initial transformation between two consequently acquired surface models. To further increase the computational efficiency, we decompose the 3D rigid transformation into out-of-plane (i.e. x-, y-rotation, and z-translation) and in-plane (i.e. x-, y-translation, and z rotation) transformations. For the in-plane transformation, we accelerate the transformation process by transforming the 2D depth map image instead of transforming the 3D surface model. For the more accurate registration of 3D surface models, we enhance iterative closest point (ICP) method for the subsequent fine registration. Our initial depth map-based registration well aligns each surface model. Therefore, our subsequent ICP method can accurately register two surface models since it is highly probable that the closest point pairs are the exact corresponding point pairs. The experimental results demonstrated that our method accurately registered partially scanned dental surfaces. Regarding the computational performance, our method delivered about 1.5 times faster registration than the conventional method. Our method can be successfully applied to the accurate reconstruction of 3D dental objects for orthodontic and prosthodontic treatment. PMID- 25453382 TI - FDTD-based Transcranial Magnetic Stimulation model applied to specific neurodegenerative disorders. AB - Non-invasive treatment of neurodegenerative diseases is particularly challenging in Western countries, where the population age is increasing. In this work, magnetic propagation in human head is modelled by Finite-Difference Time-Domain (FDTD) method, taking into account specific characteristics of Transcranial Magnetic Stimulation (TMS) in neurodegenerative diseases. It uses a realistic high-resolution three-dimensional human head mesh. The numerical method is applied to the analysis of magnetic radiation distribution in the brain using two realistic magnetic source models: a circular coil and a figure-8 coil commonly employed in TMS. The complete model was applied to the study of magnetic stimulation in Alzheimer and Parkinson Diseases (AD, PD). The results show the electrical field distribution when magnetic stimulation is supplied to those brain areas of specific interest for each particular disease. Thereby the current approach entails a high potential for the establishment of the current underdeveloped TMS dosimetry in its emerging application to AD and PD. PMID- 25453383 TI - Growth plate stress distribution implications during bone development: a simple framework computational approach. AB - Mechanical stimuli play a significant role in the process of long bone development as evidenced by clinical observations and in vivo studies. Up to now approaches to understand stimuli characteristics have been limited to the first stages of epiphyseal development. Furthermore, growth plate mechanical behavior has not been widely studied. In order to better understand mechanical influences on bone growth, we used Carter and Wong biomechanical approximation to analyze growth plate mechanical behavior, and explore stress patterns for different morphological stages of the growth plate. To the best of our knowledge this work is the first attempt to study stress distribution on growth plate during different possible stages of bone development, from gestation to adolescence. Stress distribution analysis on the epiphysis and growth plate was performed using axisymmetric (3D) finite element analysis in a simplified generic epiphyseal geometry using a linear elastic model as the first approximation. We took into account different growth plate locations, morphologies and widths, as well as different epiphyseal developmental stages. We found stress distribution during bone development established osteogenic index patterns that seem to influence locally epiphyseal structures growth and coincide with growth plate histological arrangement. PMID- 25453384 TI - Appraisal of adaptive neuro-fuzzy computing technique for estimating anti-obesity properties of a medicinal plant. AB - This research examines the precision of an adaptive neuro-fuzzy computing technique in estimating the anti-obesity property of a potent medicinal plant in a clinical dietary intervention. Even though a number of mathematical functions such as SPSS analysis have been proposed for modeling the anti-obesity properties estimation in terms of reduction in body mass index (BMI), body fat percentage, and body weight loss, there are still disadvantages of the models like very demanding in terms of calculation time. Since it is a very crucial problem, in this paper a process was constructed which simulates the anti-obesity activities of caraway (Carum carvi) a traditional medicine on obese women with adaptive neuro-fuzzy inference (ANFIS) method. The ANFIS results are compared with the support vector regression (SVR) results using root-mean-square error (RMSE) and coefficient of determination (R(2)). The experimental results show that an improvement in predictive accuracy and capability of generalization can be achieved by the ANFIS approach. The following statistical characteristics are obtained for BMI loss estimation: RMSE=0.032118 and R(2)=0.9964 in ANFIS testing and RMSE=0.47287 and R(2)=0.361 in SVR testing. For fat loss estimation: RMSE=0.23787 and R(2)=0.8599 in ANFIS testing and RMSE=0.32822 and R(2)=0.7814 in SVR testing. For weight loss estimation: RMSE=0.00000035601 and R(2)=1 in ANFIS testing and RMSE=0.17192 and R(2)=0.6607 in SVR testing. Because of that, it can be applied for practical purposes. PMID- 25453385 TI - LabPush: a pilot study of providing remote clinics with laboratory results via short message service (SMS) in Swaziland, Africa - a qualitative study. AB - BACKGROUND: Developing countries are confronting a steady growth in the prevalence of the infectious diseases. Mobile technologies are widely available and can play an important role in health care at the regional, community, and individual levels. Although labs usually able to accomplish the requested blood test and produce the results within two days after receiving the samples, but the time for the results to be delivered back to clinics is quite variable depending on how often the motorbike transport makes trips between the clinic and the lab. OBJECTIVE: In this study, we seek to assess factors facilitating as well as factors hindering the adoption of mobile devices in the Swazi healthcare through evaluating the end-users of the LabPush system. METHODS: A qualitative study with semi-structured and in-depth one on one interviews were conducted over two month period July-August 2012. Purposive sampling was used; participants were those operating and using the LabPush system at the remote clinics, at the national laboratory and the supervisors of users at Swaziland. Interview questions were focused on perceived of ease of use and usefulness of the system. All interviews were recorded and then transcribed. RESULTS: This study had aimed its primary focus on reducing TAT, prompt patient care, reducing bouncing of patients and defaulting of patients which were challenges that the clinicians have always had. Therefore, the results revealed several barriers and facilitators to the adoption of mobile device by healthcare providers in the Swaziland. The themes Shortens TAT, Technical support, Patient-centered care, Mindset, Improved communication, Missing Reports, Workload, Workflow, Security of smart phone, Human error and Ownership are sorted by facilitators to barriers. CONCLUSION: Thus the end-users perspective, prompt patient care, reduced bouncing of patients, technical support, better communication, willing participant and social influence were facilitators of the adoption m-health in the Swazi healthcare. PMID- 25453386 TI - Measures of self-care in heart failure: how methodological queries are translated into clinical ones? PMID- 25453387 TI - Inflammation-induced atrial fibrillation: pathophysiological perspectives and clinical implications. AB - Although atrial fibrillation (AF) is the most common type of cardiac arrhythmia, its etiology is unknown in nearly 10% of cases. Growing evidence suggests that inflammation plays a significant role in the onset and recurrence of AF. The role of inflammation in the pathogenesis of AF has important clinical implications of which many practitioners are unfamiliar. In this article, we describe a case of a 29-year-old male, who presents the emergency department with inflammation-induced AF, secondary to acute appendicitis. The latter condition was initially missed due to the unclear link between both presentations. By the time the AF was pharmacologically managed, the inflamed appendix perforated, resulting in unnecessary pain and suffering. After the perforated appendix was drained and removed surgically, the patient recovered well, and a follow up echocardiogram was normal. Here we give a brief overview of the pathophysiological perspective linking AF to inflammation and subsequent clinical considerations in patient management. PMID- 25453388 TI - T-wave inversion in patients with acute pulmonary embolism: prognostic value. AB - INTRODUCTION: T-wave inversion (TWI) is a common ECG finding in patients with acute pulmonary embolism (APE). OBJECTIVES: To determine the prevalence of TWI in patients with APE and to describe their relationship to outcomes. METHODS: Retrospective study of 437 patients with APE. TWI patterns were described in two distributions: inferior (II, III, aVF) and precordial (V1-V6). RESULTS: TWI was observed in 258 (59%) patients. The mortality rate was significantly higher in the group with TWI in the inferior AND precordial leads compared to the group without TWI (OR: 2.74; p = 0.024) and the group with TWI in the inferior OR precordial leads (OR: 2.43; p = 0.035). As compared those with TWI in <5 leads, patients with TWI in >=5 leads experienced significantly higher rates of death (17.1% vs. 6.6%, OR: 2.92; p = 0.002) and complications. CONCLUSIONS: TWI and the quantitative assessment thereof can be useful to risk stratify patients with APE. PMID- 25453389 TI - A comparison of the health status and psychological distress of partners of patients with a left ventricular assist device versus an implantable cardioverter defibrillator: a preliminary study. AB - OBJECTIVE: To examine if the caregiving for patients with a left ventricular assist device (LVAD) is related to a poorer health status and more distress compared to patients with an implantable cardioverter defibrillator (ICD). BACKGROUND: Partners distress may influence patient outcomes and is therefore an important aspect in the care of LVAD and ICD patients. METHODS: Multi-center prospective observational study with 6 months follow-up of 33 LVAD partners (27% men; mean age = 54 +/- 10 years) and 414 ICD partners (22% men; mean age = 60 +/- 12 years). RESULTS: LVAD partners reported better physical (F = 10.71, p = .001) but poorer mental health status (F = 14.82, p < .001) and higher depression scores compared to ICD partners (F = 3.68, p = .05) at 6 months follow-up, also in adjusted analyses. There was no significant difference between groups on anxiety. CONCLUSION: Caregivers of LVAD patients show higher distress levels compared to caregivers of ICD patients. LVAD partners may have a need for support beyond what is offered currently in clinical practice. PMID- 25453390 TI - The prognostic significance of troponin elevation in patients with sepsis: a meta analysis. AB - OBJECTIVE: To confirm the association between troponin elevation in patients with sepsis and mortality. BACKGROUND: Cardiac troponins are sensitive and specific biomarkers of myocardial injury; however their prognostic significance in patients with sepsis is still debated. METHODS: PubMed and Ovid MEDLINE were searched for original articles using MeSH terms 'Troponin' and 'Sepsis.' Studies reporting on mortality in patients with sepsis, severe sepsis or septic shock who had troponin measured were eligible for inclusion. Meta-analysis was conducted with Review Manager. RESULTS: Seventeen studies, with total sample size of 1857 patients were included. Elevated troponin was found to be significantly associated with mortality (Risk ratio: 1.91; 95% CI: 1.65-2.22; p < 0.05). CONCLUSIONS: Troponin elevation in patients with sepsis confers poorer prognosis and is a predictor of mortality. Further studies are needed to see if more aggressive treatment of this subset of patients, or utilizing new therapeutic approaches will improve mortality. PMID- 25453391 TI - Intermittent positive pressure ventilation increases diastolic pulmonary arterial pressure in advanced COPD. AB - OBJECTIVES: To measure the impact of intermittent positive pressure ventilation (IPPV) on diastolic pulmonary arterial pressure (dPAP) and pulmonary pulse pressure in patients with advanced COPD. BACKGROUND: The physiological effects of raised intrathoracic pressures upon the pulmonary circulation have not been fully established. METHODS: 22 subjects with severe COPD receiving IPPV were prospectively assessed with pulmonary and radial arterial catheterization. Changes in dPAP were assessed from end-expiration to early inspiration during low and high tidal volume ventilation. RESULTS: Inspiration during low tidal volume IPPV increased the median [IQR] dPAP by 3.9 [2.5-4.8] mm Hg (P < 0.001). During high tidal volume, similar changes were observed. The IPPV-associated change in dPAP was correlated with baseline measures of PaO2 (rho = 0.65, P = 0.005), pH (rho = 0.64, P = 0.006) and right atrial pressure (rho = -0.53, P = 0.011). CONCLUSIONS: In severe COPD, IPPV increases dPAP and reduces pulmonary pulse pressure during inspiration. PMID- 25453392 TI - Cost comparison between home telemonitoring and usual care of older adults: a randomized trial (Tele-ERA). AB - BACKGROUND: From 1992 to 2008, older adults in the United States incurred more healthcare expense per capita than any other age group. Home telemonitoring has emerged as a potential solution to reduce these costs, but evidence is mixed. The primary aim of the study was to evaluate whether the mean difference in total direct medical cost consequence between older adults receiving additional home telemonitoring care (TELE) (n=102) and those receiving usual medical care (UC) (n=103) were significant. Inpatient, outpatient, emergency department, decedents, survivors, and 30-day readmission costs were evaluated as secondary aim. MATERIALS AND METHODS: Multivariate generalized linear models (GLMs) and parametric bootstrapping method were used to model cost and to determine significance of the cost differences. We also compared the differences in arithmetic mean costs. RESULTS: From the conditional GLMs, the estimated mean cost differences (TELE versus UC) for total, inpatient, outpatient, and ED were $9,537 (p=0.068), -$8,482 (p =0.098), -$1,160 (p=0.177), and $106 (p=0.619), respectively. Mean postenrollment cost was 11% lower than the prior year for TELE versus 22% higher for UC. The ratio of mean cost for decedents to survivors was 2.1:1 (TELE) versus 12.7:1 (UC). CONCLUSIONS: There were no significant differences in the mean total cost between the two treatment groups. The TELE group had less variability in cost of care, lower decedents to survivors cost ratio, and lower total 30-day readmission cost than the UC group. PMID- 25453393 TI - The association of leptin and homocysteine with renal function impairment in a population of Taiwanese adults. AB - BACKGROUND & AIMS: Higher levels of leptin and homocysteine (Hcy) have been evaluated as risk factors of chronic kidney disease in patients and general population. The aim of this study was to examine gender differences in the associations of leptin and Hcy levels and renal function a representative healthy young population in Taiwan. METHODS: The participants aged >=18 years who underwent health examinations were included and categorized into three groups by gender-specific tertiles of leptin and Hcy levels. Estimated glomerular filtration rates (eGFR) were estimated according to the modified equation of Modification of Diet in Renal Disease (MDRD). RESULTS: A higher mean Hcy level was found in male subjects than females. Mean values of metabolic syndrome risk factors significantly elevated with increasing leptin levels in both genders. Both male and female subjects with higher plasma Hcy levels were more likely to have a lower eGFR. Plasma Hcy levels were significantly negatively correlated with eGFR in linear regression models adjusted for age and smoking. The associations persisted even after mean arterial pressure and fasting plasma glucose were included for adjustments both genders. Plasma Hcy level was negatively associated eGFR and the association was more profound for females. CONCLUSIONS: Leptin levels did not reveal strong or consistent evidence to support a significant association with eGFR. Hcy had a more decisive effect on renal function impairment than leptin and may be considered a more sensitive biomarker for Taiwanese adults. PMID- 25453394 TI - Hyperinsulinemia is associated with the loss of appendicular skeletal muscle mass at 4.6 year follow-up in older men and women. AB - BACKGROUND & AIMS: Homeostasis model assessment as a marker of insulin resistance has been associated with the pronounced loss of appendicular skeletal muscle mass in older adults. In the present study, we hypothesized that hyperinsulinemia as an early predictor of insulin resistance may be associated with the loss of appendicular skeletal muscle mass (ASM). METHODS: This is a cohort study that included 147 well-functioning older men and women subjects who were followed for a period of 4.6 +/- 1.8 years. Lean tissue in arm and legs, or ASM, was derived from dual-energy X-ray absorptiometry at baseline with follow-up measurements to obtain the relative change. Hyperinsulinemia was defined empirically at the 75th percentile. RESULTS: The relative change in ASM was negative and significant throughout the quartiles of fasting insulin levels (p <= 0.05); however, the loss of ASM was more pronounced in the later quartiles (-0.7 kg) compared with the relative change in Q1 and Q2 (-0.5 kg and -0.3 kg). The unadjusted analysis indicates a significant association between hyperinsulinemia and the loss of ASM (beta = -0.28, 95% CI-0.57-0.009, p = 0.05), an association that remained significant after adjusting for several covariates. CONCLUSION: Hyperinsulinemia as an early marker of insulin resistance was associated with the loss of ASM in a cohort study of community-dwelling older men and women subjects without other chronic health conditions. The use of fasting insulin levels >8.4 MUU/mL may help clinicians identify individuals in the geriatric population who are at a high risk of loss of appendicular skeletal muscle mass. PMID- 25453396 TI - The effect of vitamin D supplementation on serum lipids in postmenopausal women with diabetes: A randomized controlled trial. AB - BACKGROUND & AIMS: Dyslipidemia is a risk factor for cardiovascular disease that has become an increasing public health problem. Dyslipidemia is especially relevant in vulnerable populations such as postmenopausal women. Low serum levels of 25-hydroxyvitamin D have been associated with an unfavourable lipid profile. Due to contradictory findings from intervention trials, we investigated the effect of vitamin D supplementation on serum lipids in postmenopausal women with type 2 diabetes. METHODS: A total of 104 postmenopausal women with type 2 diabetes were randomly assigned in a double-blind manner to 1 of 2 groups taking a daily tablet for 6 months: a group consuming 4000 IU tablets of a vitamin D supplement (vitamin D group n = 52) or a group consuming placebo tablets (placebo group n = 52). RESULTS: The study was completed by 99 participants. However, as the analysis was based on an intention-to-treat approach, all 104 women were included in the final analysis. In the vitamin D group mean serum levels of 25(OH)D3 improved significantly at the end of the follow-up period (+25.5 nmol/L; P = <0.001). Our findings revealed no significant changes in low density lipoproteins, high density lipoproteins and total cholesterol concentrations, but did identify a greater decrease in serum triglycerides in the vitamin D group. The average effect of supplementation on the treated group was -34.24 mg/dL (P = 0.021), while the average treatment effect was -31.8 mg/dL (P = 0.023). CONCLUSIONS: Our results suggest that supplementation with vitamin D (4000 IU/d) may have a beneficial effect on serum triglyceride levels without otherwise affecting levels of other lipids. TRIAL REGISTRATION: clinicaltrial.gov; identifier NCT01019642. PMID- 25453395 TI - Impact of personalized diet and probiotic supplementation on inflammation, nutritional parameters and intestinal microbiota - The "RISTOMED project": Randomized controlled trial in healthy older people. AB - OBJECTIVES: To assess the impact of a personalized diet, with or without addition of VSL#3 preparation, on biomarkers of inflammation, nutrition, oxidative stress and intestinal microbiota in 62 healthy persons aged 65-85 years. DESIGN: Open label, randomized, multicenter study. PRIMARY ENDPOINT: High-sensitivity C reactive protein. SETTING: Community. INTERVENTIONS: Eight week web-based dietary advice (RISTOMED platform) alone or with supplementation of VSL#3 (2 capsules per day). The RISTOMED diet was optimized to reduce inflammation and oxidative stress. MEASUREMENTS: Blood and stool samples were collected on days 1 and 56. RESULTS: Diet alone reduced ESR (p = 0.02), plasma levels of cholesterol (p < 0.01) and glucose (p = 0.03). Addition of VSL#3 reduced ESR (p = 0.05) and improved folate (p = 0.007), vitamin B12 (p = 0.001) and homocysteine (p < 0.001) plasma levels. Neither intervention demonstrated any further effects on inflammation. Subgroup analysis showed 40 participants without signs of low-grade inflammation (hsCRP<3 mg/l, subgroup 1) and 21 participants with low-grade inflammation at baseline (hsCRP>=3 mg/l, subgroup 2). In subgroup 2 addition of VSL#3 increased bifidobacteria (p = 0.005) in more participants and improved both folate (p = 0.015) and vitamin B12 (p = 0.035) levels compared with subgroup 1. The increases were positively correlated to the change in the bifidobacteria concentration for folate (p = 0.023) and vitamin B12 (p = 0.001). As expected change in homocysteine correlated negatively to change in folate (r = -0.629, p = 0.002) and vitamin B12 (r = -0.482, p = 0.026). CONCLUSIONS: Addition of VSL#3 increased bifidobacteria and supported adequate folate and vitamin B12 concentrations in subjects with low-grade inflammation. Decrease in homocysteine with VSL#3 was clinically relevant. suggesting protective potentials for aging associated conditions, e.g. cardiovascular or neurological diseases. ClinicalTrials.gov: NCT01069445-NCT01179789. PMID- 25453397 TI - Determinants of new-onset diabetes in older adults-Results of a national cohort study. AB - BACKGROUND & AIMS: Diabetes mellitus is prevalent in many countries around the world, but the potential causal factors are not clearly known. We attempted to determine the risk factors for new-onset diabetes in >=53-year old Taiwanese. METHODS: We analyzed the 1999 and 2003 datasets of the Taiwan Longitudinal Survey on Aging (TLSA). We performed logistic regression analyses to determine the cross sectional and longitudinal (1999-2003) associations of the sociodemographic, lifestyle, and health-related variables with diabetes and new-onset diabetes, respectively. We excluded those who were diabetic at baseline in the longitudinal analysis. RESULTS: Results of the cross-sectional analysis showed that higher weight, past betel-quid chewing, IADL dependency, hypertension, heart disease, chronic kidney disease and depressive symptoms were positively associated with diabetes while alcohol drinking was negatively associated with diabetes. Longitudinal analysis showed that excessive weight, physical inactivity, depressive symptoms, and hypertension were associated with increased likelihood of new-onset diabetes while higher physical activity was associated with reduced likelihood of new-onset diabetes. Cigarette-smoking and moderate alcohol drinking showed no clear impacts on new-onset diabetes in older Taiwanese. CONCLUSIONS: Results show that excessive weight, physical inactivity, hypertension and depressive symptoms are the major risk factors for new-onset diabetes for both Eastern and Western populations, whereas smoking and alcohol drinking have varying impacts among these populations. Better understanding of these relationships should be helpful for planning effective health promotion strategies for reducing the risk of new-onset diabetes in older adults. PMID- 25453398 TI - The conundrum of pre-cachexia existence. PMID- 25453399 TI - Concurrence of B-lymphoblastic leukemia and myeloproliferative neoplasm with copy neutral loss of heterozygosity at chromosome 1p harboring a MPL W515S mutation. AB - B-lymphoblastic leukemia (B-ALL) is a neoplasm of precursors committed to B-cell lineage, whereas myeloproliferative neoplasm (MPN) is a clonal proliferation derived from myeloid stem cells. Concurrent B-ALL with MPN is uncommon except in the presence of abnormalities of the PDGFRA, PDGFRB, or FGFR1 genes or the BCR ABL1 fusion gene. Herein, we describe a rare concurrence, B-ALL with MPN without the aforementioned genetic aberrations, in a 64-year-old male patient. The patient was initially diagnosed with B-ALL with normal karyotype and responded well to aggressive chemotherapy but had sustained leukocytosis and splenomegaly. The posttreatment restaging bone marrow was free of B-ALL but remained hypercellular with myeloid predominance. Using a single nucleotide polymorphism microarray study, we identified a copy neutral loss of heterozygosity at the terminus of 1p in the bone marrow samples taken at diagnosis and again at remission, 49% and 100%, respectively. Several additional genetic abnormalities were present in the initial marrow sample but not in the remission marrow samples. Retrospective molecular studies detected a MPL W515S homozygous mutation in both the initial and remission marrows for B-ALL, at 30-40% and 80% dosage effect, respectively. In summary, we present a case of concurrent B-ALL and MPN and demonstrate a stepwise cytogenetic and molecular approach to the final diagnosis. PMID- 25453401 TI - What is in the can? The dilemma with dietary supplements. PMID- 25453400 TI - Position statement on efficiency of technologies for diabetes management. AB - Di@bet.es study results are impressive, showing that diabetes affects 13.8% of the Spanish population. Not only the statistical facts are alarming, but the increasing incidence of this disease is a major problem, as pandemic proportions of type 2 diabetes are expected. Thus, the study of diabetes represents a challenge not only for health services, but also for the Ministries of Health and Finance. Technology has become an essential tool in the quality are of patients with diabetes, as it helps in the healthcare processes to obtain an optimum metabolic balance and prevent possible complications. Insulin pumps, continuous glucose monitoring nd self-monitoring blood glucose have all proved their efficiency, and telemedicine it is making good progress. The indirect costs of diabetes in Spain are much higher than the directones, showing the importance of inverting the paradox. The optimization of resources depends not only on the ability of the physicians, but also the administration, to implant and sustain technological innovations in our system, and with that make it effective in terms of benefits. Cost-effectiveness and cost-utility analysis are needed to prioritize and allow health management services to make the correct choices for approaching this prevalent chronic disease. PMID- 25453402 TI - Development of cerebellar pathology in the canine model of mucopolysaccharidosis type IIIA (MPS IIIA). AB - The temporal relationship between the onset of clinical signs in the mucopolysaccharidosis type IIIA (MPS IIIA) Huntaway dog model and cerebellar pathology has not been described. Here we sought to characterize the accumulation of primary (heparan sulfate) and secondary (G(M3)) substrates and onset of other changes in cerebellar tissues, and investigate the relationship to the onset of motor dysfunction in these animals. We observed that Purkinje cells were present in dogs aged up to and including 30.9 months, however by 40.9 months of age only ~12% remained, coincident with the onset of clinical signs. Primary and secondary substrate accumulation and inflammation were detected as early as 2.2 months and axonal spheroids were observed from 4.3 months in the deep cerebellar nuclei and later (11.6 months) in cerebellar white matter tracts. Degenerating neurons and apoptotic cells were not observed at any time. Our findings suggest that cell autonomous mechanisms may contribute to Purkinje cell death in the MPS IIIA dog. PMID- 25453404 TI - Cardioprotection for percutaneous coronary intervention--reperfusion quality as well as quantity. AB - Ischaemia-reperfusion (IR) injury is an important cause of myocardial damage during percutaneous coronary intervention (PCI). There are few therapies in widespread clinical use which impact on IR injury and it remains an important and underutilized target for treatment in acute myocardial infarction. This review will examine the translational scientific evidence for ischaemic conditioning and pharmacological agents including conditioning mimetics such as cyclosporine, anti inflammatory agents, and those which modify myocardial glucose metabolism. We will address the reasons why many trials have failed to demonstrate clinical benefit and emphasize the need to deliver the right therapy to the right patient, at the right time to achieve successful translation of cardioprotection from bench-to-bedside. We critique trial design and offer advice for future translational trials in the field to ensure that effective treatments can be demonstrated clinically to improve patient outcomes during PCI. PMID- 25453403 TI - Management of multivessel coronary disease in STEMI patients: a systematic review and meta-analysis. AB - BACKGROUND: Appropriate management for patients with multivessel coronary disease presenting with ST segment Elevation Myocardial Infarction (STEMI) remains to be defined. METHODS AND RESULTS: Medline and Cochrane Library were searched for randomized controlled trials (RCTs) or observational studies adjusted with multivariate analysis, reporting about STEMI patients with multivessel coronary disease treated with either a culprit only or complete revascularization strategy, excluding patients in cardiogenic shock. Prespecified analysis was performed according to the strategy of complete revascularization, either during the same procedure of primary percutaneous coronary intervention (PCI) or during the index hospitalization. MACE (a composite and mutually exclusive end point of death or myocardial infarction or revascularization) at follow-up of at least one year was the primary end point. 9 studies with 4686 patients compared culprit only versus complete PCI performed during the primary PCI. Rates of MACE did not differ at 90 days (OR 0.70 [0.38, 1.27], I(2)=0%) or at 1 year (1-2.5) (OR 0.70 [0.47, 1.03], I(2)=0%). No significant difference was found for the components of the primary outcome, apart from a reduction in repeated revascularization for patients undergoing complete PCI during the STEMI procedure (OR 0.62 [0.39, 0.98], I(2)=0%). 6 studies (1 RCT) with 5855 patients compared culprit only lesions versus complete PCI performed during index hospitalization. 90 day risk of MACE did not differ nor 1 year (1-2.5) MACE (OR 0.86 [0.62, 1.08], I(2)=0%), with a similar reduction in repeated revascularization (0.60 [0.40, 0.90], I(2)=0%). CONCLUSIONS: Complete revascularization performed during primary PCI or index hospitalizations for patients presenting with STEMI appears safe at short term follow-up and offers a reduction in repeated revascularization at one year. PMID- 25453406 TI - Twenty year follow-up after successful percutaneous balloon mitral valvuloplasty in a large contemporary series of patients with mitral stenosis. AB - BACKGROUND: Percutaneous balloon mitral valvuloplasty (PMV) is currently considered the standard of care for suitable patients with rheumatic mitral stenosis. We sought to assess very long-term outcome after PMV. METHODS: Between 1991 and 2010, 482 consecutive patients underwent successful PMV in a single center. Procedural success was defined as post-procedural valve area >= 1.5 cm(2) and regurgitation moderate or less, without in-hospital major adverse cardiac and cerebro-vascular events. The primary endpoint was 20-year incidence of major adverse cardiac events (MACE), including cardiovascular death and need for mitral surgery or repeat PMV. RESULTS: Long-term follow-up (mean 11.6 +/- 4.9 years; range 0.5 to 20) was completed in 441 (91.5%) patients. The incidence of the primary endpoint was 41.9% (95% confidence interval [CI]: 37.3 to 46.7%). The rate of cardiovascular death, need for mitral surgery or repeat PMV was 9.1% (95% CI: 6.6 to 12.1), 27% (95% CI: 22.9 to 31.4), and 5.9% (95% CI: 3.9 to 8.5), respectively. Cumulative MACE-free survival at 20 years was 35.9 +/- 4.7%. At multivariate analysis, male gender (hazard ratio [HR]: 1.99; 95% CI: 1.4-2.8, p < 0.001), echocardiographic score > 8 (HR: 2.19; 95% CI: 1.6-2.9, p < 0.001), atrial fibrillation (HR: 1.54; 95% CI: 1.2-2.1, p = 0.003) and valve area <= 1.75 cm(2) after PMV (HR: 3.1; 95% CI: 2.3-4.2, p < 0.001) were identified as independent predictors of the primary endpoint. CONCLUSIONS: Up to 20 years after successful PMV, a sizeable proportion of patients still exhibit a good clinical result. PMID- 25453405 TI - Educational inequalities in 28 day and 1-year mortality after hospitalisation for incident acute myocardial infarction--a nationwide cohort study. AB - BACKGROUND: There is little recent evidence on the impact of comorbidities and access to revascularisation procedures on educational inequalities in mortality after acute myocardial infarction (AMI). The aim of the study was to investigate educational inequalities in mortality among all patients hospitalised for an incident AMI during 2001-2009 in Norway. METHODS: Data were obtained through the Cardiovascular Disease in Norway (CVDNOR) project. Incident AMI was defined as an AMI-hospitalisation without any AMI-events in the previous 7 years. Education was categorised as basic, upper secondary or tertiary (college/university). Cox regression was used to assess educational differences in 28-day and 29-365-day mortality after an incident AMI in terms of hazard ratios and relative index of inequality (RII). RII can be interpreted as the ratio in mortality between the 0 th and the 100th percentile of the education distribution. RESULTS: 111 993 incident AMIs were included (39.4% women). Among patients aged 35-69, RIIs (95% CI) adjusted for age, sex and year were 1.86 (1.59-2.18) and 2.10 (1.69-2.59) for 28-day and 29-365-day mortality respectively. Among patients aged 70-94 the corresponding RIIs were 1.12 (1.06-1.30) and 1.28 (1.19-1.38). Educational inequalities in mortality were attenuated after adjustment for comorbidities and revascularisation, but were still significant. Educational inequalities did not decrease during 2001-2009. CONCLUSION: Educational inequalities in both 28-day and 29-365 day mortality were strong and persistent during 2001-2009. Further research is needed to investigate if these disparities are driven by inequalities in the severity of the AMI or by inequitable access to treatment and rehabilitation. PMID- 25453407 TI - Prognostic relevance of cardiac troponin T levels and their dynamic changes measured with a high-sensitivity assay in acute ischaemic stroke: analyses from the TRELAS cohort. AB - BACKGROUND/OBJECTIVES: To assess the prognostic relevance of cardiac troponin T (cTnT) values and their serial changes as measured with a high-sensitivity assay in acute ischaemic stroke. METHODS AND RESULTS: In total, 1016 consecutive acute ischaemic stroke patients were registered prospectively within a two-year period. High-sensitivity cTnT was quantitated on admission and the following day. Patients were stratified into three groups: below the 99 th percentile of a healthy reference population (< 14 ng/l; n = 409), moderately elevated cTnT (below the median of remaining patients, 14-30 ng/l; n=299) and high cTnT (> 30 ng/l; n = 308). Outcome measures were unfavourable outcome (modified Rankin Scale >= 2 at hospital discharge, n=604) and in-hospital mortality (n = 36). Peak cTnT levels were significantly associated with unfavourable outcome (adjusted odds ratios versus reference for moderately elevated cTnT 1.7, 95% confidence interval [CI] 1.1-2.7 and for high cTnT 3.1, 95% CI 1.8-5.6). The optimal cut-off for determining unfavourable outcome proved to be 16 ng/l. Adding this cut-off to clinical variables led to a significant improvement of c-statistics (0.851 versus 0.838, p=0.02). Dynamic changes (delta >= 50%) of cTnT were detected in 137 patients (13%). Multiple Cox regression analysis showed an independent association of dynamic changes in cTnT with in-hospital mortality (hazard ratio 2.3, 95% CI 1.1-4.7). The model-fitting (p<0.001) and c-statistics (0.889 versus 0.863, p = 0.08) improved most after dynamic change in cTnT had been added to a regression model which included clinical variables alone. CONCLUSIONS: Our study adds novel findings relevant for interpretation of highly sensitive cTnT assays in acute ischaemic stroke: a) Myocardial injury is detectable in more than half of patients; b) even moderately elevated cTnT is associated with unfavourable outcome (optimal cut-off 16 ng/l); and c) dynamic changes in cTnT indicate an increased risk of in-hospital death. PMID- 25453408 TI - Impact of remote physiological ischemic training on vascular endothelial growth factor, endothelial progenitor cells and coronary angiogenesis after myocardial ischemia. AB - OBJECTIVE: This experimental study investigates the potential role of physiological ischemic training (PIT) of remote limbs on vascular endothelial growth factor (VEGF), endothelial progenitor cells (EPCs) and myocardial angiogenesis after myocardial ischemia. METHODS: Forty-two rabbits were assigned into six groups at random: sham-operated (SO), training only (TO), myocardial ischemia (MI), PIT, EPC promoter (PIT+), and EPC inhibitor (PIT-). MI was experimentally induced by implanting a constrictor around the left ventricular branch. The PIT procedure included three 3-min cycles of cuff inflations on the hind limbs followed by a 5 min reperfusion. VEGF mRNA, protein and EPC numbers were measured in plasma and myocardium. Capillary density (CD), coronary blood flow (CBF) and coronary collateral blood flow (CCBF) were also determined. RESULTS: Groups were compared using non-parametric statistics and associations between agents were explored with fractional polynomial regression. VEGF-mRNA and -protein levels were highest in PIT+ and PIT. PIT differed significantly from SO, TO, MI, and PIT- regarding VEGF-mRNA and -protein in plasma and VEGF-protein in myocardium. EPCs were highest in PIT+ followed by PIT. PIT differed significantly from SO, TO, MI, and PIT- regarding plasma EPCs. CD, CCBF and CCBF/CBF were significantly increased in PIT+ and PIT as compared to controls. PIT- did not differ significantly from SO and TO. VEGF explained up to 43% of variance in EPCs. EPCs explained up to 87% of variance in CD. CD explained up to 97% of variance in CCBF and CCBF/CBF. CONCLUSION: PIT stimulates VEGF-mediated mobilization of EPCs as well as angiogenesis and might be proven as a new treatment strategy for patients with coronary heart disease. PMID- 25453409 TI - Incremental pacing maneuver for atrial flutter recurrence reduction after ablation: Valles: yield of incremental pacing after flutter ablation. AB - BACKGROUND: A < 20 ms increase in the interval between cavo-tricuspid isthmus (CTI) double potentials during incremental pacing (IP) is a highly specific marker differentiating functional from complete CTI block during typical flutter (AFL) ablation. Long-term effects of IP remain unclear. We aimed to assess the impact of IP in reducing AFL recurrences after CTI ablation. METHODS: One hundred and thirty-four patients (age 67 +/- 13 years, 78% males) undergoing successful CTI ablation were included and divided into 2 groups: Group 1 (n = 68), in which ablation was performed before the IP maneuver was incorporated, with CTI block confirmed by at least 1 non-local and 1 local electrogram-based previously established criteria; and Group 2 (n = 66), in which IP maneuver was used to confirm complete CTI block. RESULTS: No intergroup differences were noted in baseline characteristics, ablation settings and fluoroscopy/radiofrequency times. Long-term AFL recurrences were observed in 14 out of 134 patients (10.4%), and were more common in Group 1 (19%, vs 1.5% among Group 2 patients, p < 0,001). Despite a longer follow-up period among the former group (1603 +/- 734 vs. 964 +/ 289 days, respectively), the adjusted AFL recurrence rate was still higher among Group 1 patients (4.3%/year vs. 0.6%/year, p < 0,001). Cox-regression analysis confirmed inclusion in Group 1 as the only predictor of AFL recurrences (HR = 8.2, CI 1.04-64.7, p = 0.046). CONCLUSIONS: The addition of the IP maneuver for the diagnosis of complete CTI block reduces AFL long-term recurrences after ablation. PMID- 25453410 TI - Impact of final kissing balloon inflation after simple stent implantation for the treatment of non-left main true coronary bifurcation lesions in patients with acute coronary syndrome. AB - OBJECTIVES: We sought to evaluate the impact of final kissing balloon inflation (FKBI) after simple stent implantation for the treatment of non-left main true coronary bifurcation lesions in patients with acute coronary syndrome (ACS). BACKGROUND: Whether FKBI should be mandatory after simple stent implantation for the treatment of coronary bifurcation lesion is controversial. Besides, ACS patients who have undergone bifurcation percutaneous coronary intervention with simple stent implantation may experience worse prognosis compared to stable angina pectoris patients. METHODS: Two hundred and fifty one eligible patients (67.7% male, mean age 61.7 +/- 10.4 years) were enrolled. The study population was divided into two groups according to the performance of FKBI. The primary end points were major adverse cardiac event (MACE); target lesion revascularization (TLR), non-fatal myocardial infarction (MI) and cardiac death during the follow up period. RESULTS: Over a mean follow-up period of 3.0 +/- 1.9 years, there were 29 MACEs (10 TLR, 6 non-fatal MI, and 13 cardiac deaths), representing an event rate of 11.6%. Kaplan-Meier survival analysis revealed that FBKI group had favorable outcome compared to non-FKBI group with regard to hard events (p = 0.010) as well as composite MACEs (p = 0.008). In multivariable analysis, FKBI was a significant predictor of composite MACEs [hazard ratio 0.398 (95% confidence interval 0.190-0.836, p = 0.015)] and hard events [hazard ratio 0.325 (95% confidence interval 0.130-0.811, p = 0.016)]. CONCLUSIONS: In terms of prognosis, performing FKBI after simple stent implantation for the treatment of non-left main true coronary bifurcation lesions may be mandatory in ACS patients. PMID- 25453411 TI - Impact of C34T P2Y12 genotype on endothelial function and arterial stiffness in patients after percutaneous coronary intervention receiving clopidogrel. PMID- 25453413 TI - Evolving epidemiology and definitions of the acute respiratory distress syndrome and early acute lung injury. AB - This article reviews the evolving definitions and epidemiology of the acute respiratory distress syndrome (ARDS) and highlights current efforts to improve identification of high-risk patients, thus to target prevention and early treatment before progression to ARDS. This information will be important for general practitioners and intensivists interested in improving the care of patients at risk for ARDS, and clinical researchers interested in designing clinical trials targeting the prevention and early treatment of acute lung injury. PMID- 25453412 TI - The effect of right ventricular myocardial remodeling on ventricular function as assessed by two-dimensional speckle tracking echocardiography in patients with tetralogy of Fallot: a single center experience from China. AB - BACKGROUND: Published correlations between histological abnormalities and right ventricular (RV) function, as evaluated by speckle tracking echocardiography (STE), are scarce in patients with tetralogy of Fallot (TOF). The purpose of the study is to assess age-associated differences in the effect of RV myocardial remodeling on ventricular function in patients with TOF. METHODS: Operatively resected crista supraventricularis muscle from 30 patients (median age 12months) undergoing intracardiac repair of TOF were studied by light microscopy. The patients were divided into younger (age at surgery <=12months) and older (age at surgery >12months) subgroups. The RV global longitudinal peak systolic strain (GLS), strain rate (GLSRs) and early diastolic strain rate (GLSRe) were measured by two-dimensional STE before and 6months after repair. RESULTS: The histopathological data revealed hypertrophy of the cardiomyocytes, a thickened endocardium, and increased interstitial and perivascular collagen in RV, which were associated with older age at the time of repair. The RV global systolic and diastolic functions in patients with repaired TOF were increased compared with the preoperative values. The RV cardiomyocyte diameter and collagen volume fraction (CVF) correlated with the preoperative GLS, GLSRs and GLSRe, respectively, in the younger patients (r1=-0.566, P1=0.018; r2=-0.493, P2=0.004; r3=-0.504, P3=0.039). The RV cardiomyocyte diameter and CVF correlated with preoperative GLS, GLSRs and GLSRe, respectively, in the older patients (r1=-737, P1=0.004; r2=-0.588, P2=0.035; r3=-0.812, P3=0.001). The correlation of the RV cardiomyocyte diameter with the postoperative GLS and GLSRe (r1=-665, P1=0.036; r2=-0.787, P2=0.007) and the CVF with the postoperative GLSRs and GLSRe (r1=-762, P1=0.002; r2=-0.713, P2=0.004) were identified only in the older patients. Multivariate analysis indicated that the age at repair was an independent predictor of postoperative GLSRs and GLSRe in all of the patients (beta=-0.449, P=0.041; beta=-0.607, P=0.004). CONCLUSIONS: The effect of RV myocardial remodeling on preoperative RV function was more pronounced in the older patients with TOF than in the younger ones. Preoperative myocardial remodeling affected the postoperative RV function in the older but not in the younger patients. The age at the time of surgical repair was the independent determinant of the postoperative RV myocardial function. PMID- 25453414 TI - Environmental risk factors for acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality in critically ill patients. Over the past several decades, alcohol abuse and cigarette smoke exposure have been identified as risk factors for the development of ARDS. The mechanisms underlying these relationships are complex and remain under investigation but are thought to involve pulmonary immune impairment and alveolar epithelial and endothelial dysfunction. This review summarizes the epidemiologic data supporting links between these exposures and ARDS susceptibility and outcomes and highlights key mechanistic investigations that provide insight into the pathways by which each exposure is linked to ARDS. PMID- 25453415 TI - Clinical and biological heterogeneity in acute respiratory distress syndrome: direct versus indirect lung injury. AB - The acute respiratory distress syndrome (ARDS) is a heterogeneous group of illnesses affecting the pulmonary parenchyma with acute onset bilateral inflammatory pulmonary infiltrates with associated hypoxemia. ARDS occurs after 2 major types of pulmonary injury: direct lung injury affecting the lung epithelium or indirect lung injury disrupting the vascular endothelium. Greater understanding of the differences between direct and indirect lung injury may refine the classification of patients with ARDS and lead to development of new therapeutics targeted at specific subpopulations of patients with ARDS. PMID- 25453416 TI - Obesity and nutrition in acute respiratory distress syndrome. AB - This article discusses obesity, its contribution to clinical outcomes, and the current literature on nutrition. More than one third of Americans are obese. Literature suggests that, among critically ill patients, the relationship between obesity and outcomes is complex. Obese patients may be at greater risk of developing acute respiratory distress syndrome (ARDS) than normal weight patients. Although obesity may confer greater morbidity in intensive care, it seems to decrease mortality. ARDS is a catabolic state; patients demonstrate a profound inflammatory response, multiple organ dysfunction, and hypermetabolism, often with malnutrition. The concept of pharmaconutrition has emerged. PMID- 25453419 TI - Invasive diagnostic strategies in immunosuppressed patients with acute respiratory distress syndrome. AB - Immunosuppression predisposes the host to development of pulmonary infections, which can lead to respiratory failure and the development of acute respiratory distress syndrome (ARDS). There are multiple mechanisms by which a host can be immunosuppressed and each is associated with specific infectious pathogens. Early invasive diagnostic modalities such as fiber-optic bronchoscopy with bronchoalveolar lavage, transbronchial biopsy, and open lung biopsy are complementary to serologic and noninvasive studies and assist in rapidly establishing an accurate diagnosis, which allows initiation of appropriate therapy and may improve outcomes with relative safety. PMID- 25453420 TI - Clinical trial design in prevention and treatment of acute respiratory distress syndrome. AB - Our ability to define appropriate molecular targets for preclinical development and develop better methods needs to be improved, to determine the clinical value of novel acute respiratory distress syndrome (ARDS) agents. Clinical trials must have realistic sample sizes and meaningful end points and use the available observation and meta-analytical data to inform design. Biomarker-driven studies or defined ARDS subsets should be considered to categorize specific at-risk populations most likely to benefit from a new treatment. Innovations in clinical trial design should be pursued to improve the outlook for future interventional trials in ARDS. PMID- 25453417 TI - Beyond single-nucleotide polymorphisms: genetics, genomics, and other 'omic approaches to acute respiratory distress syndrome. AB - This article summarizes the contributions of high-throughput genomic, proteomic, metabolomic, and gene expression investigations to the understanding of inherited or acquired risk for acute respiratory distress syndrome (ARDS). Although not yet widely applied to a complex trait like ARDS, these techniques are now routinely used to study a variety of disease states. Omic applications hold great promise for identifying novel factors that may contribute to ARDS pathophysiology or may be appropriate for further development as biomarkers or surrogates in clinical studies. Opportunities and challenges of different techniques are discussed, and examples of successful applications in non-ARDS fields are used to illustrate the potential use of each technique. PMID- 25453418 TI - Approach to the patient with the acute respiratory distress syndrome. AB - Given the high incidence and mortality of acute respiratory distress syndrome (ARDS) in critically ill patients, every practitioner needs a bedside approach both for early identification of patients at risk for ARDS and for the appropriate evaluation of patients who meet the diagnostic criteria of ARDS. Recent advances such as the Lung Injury Prediction score, the Early Acute Lung Injury score, and validation of the SpO(2)/Fio(2) ratio for assessing the degree of hypoxemia are all practical tools to aid the practitioner in caring for patients at risk of ARDS. PMID- 25453421 TI - Beyond low tidal volumes: ventilating the patient with acute respiratory distress syndrome. AB - The cornerstone of lung protective ventilation in patients with acute respiratory distress syndrome (ARDS) is a pressure- and volume-limited strategy. Other interventions have also been investigated. Although no method for positive end expiratory pressure (PEEP) titration has proven most advantageous, experimental and clinical data support the use of higher PEEP in patients with moderate/severe ARDS. There is no benefit to the early use of high-frequency oscillatory ventilation (HFOV) in patients with moderate/severe ARDS, although it may be considered as rescue therapy. Further investigations of novel methods of bedside monitoring of mechanical ventilation may help identify the optimal ventilatory strategy. PMID- 25453422 TI - Prone positioning for acute respiratory distress syndrome. AB - Multiple animal and human studies have shown that prone positioning improves oxygenation and reduces ventilator-induced lung injury (VILI) in the setting of acute lung injury or acute respiratory distress syndrome (ARDS). In this article, the physiologic changes explaining the improvement in oxygenation are reviewed, how prone positioning reduces VILI is described, randomized controlled trials of prone ventilation in patients with ARDS are evaluated, the complications associated with prone ventilation are summarized, suggestions are made as to how these might be reduced or avoided, and when prone ventilation should start and stop and for what duration it should be used are discussed. PMID- 25453423 TI - The use of paralytics in patients with acute respiratory distress syndrome. AB - Interest in the role of neuromuscular blocking agents (NMBAs) in the treatment of acute respiratory distress syndrome (ARDS) has been renewed since a recent randomized clinical trial showed a reduction in mortality associated with the use of NMBAs. However, the role of paralytics in a protective mechanical ventilation strategy should be detailed. This review summarizes data in the literature concerning the clinical effects of NMBAs on the outcome of patients with ARDS, in an attempt to explain some pathophysiologic hypotheses concerning their action and to integrate them into the overall management strategy for the mechanical ventilation of ARDS patients. PMID- 25453424 TI - Extracorporeal circulatory approaches to treat acute respiratory distress syndrome. AB - The early history of extracorporeal membrane oxygenation (ECMO) for adult patients with the acute respiratory distress syndrome (ARDS) evolved slowly over decades, a consequence of extracorporeal technology with high risk and unclear benefit. However, advances in component technology, accumulating evidence, and growing experience in recent years have resulted in a resurgence of interest in ECMO. Extracorporeal support, though currently lacking high-level evidence, has the potential to improve outcomes, including survival, in ARDS. In the near future, novel extracorporeal management strategies may, in fact, lead to a new paradigm in the approach to certain patients with ARDS. PMID- 25453427 TI - Muscle wasting and early mobilization in acute respiratory distress syndrome. AB - Survivors of acute respiratory distress syndrome often sustain muscle wasting and functional impairment related to intensive care unit (ICU)-acquired weakness (ICUAW) and this disability may persist for years after ICU discharge. Early diagnosis in cooperative patients by physical examination is recommended to identify patients at risk for weaning failure and to minimize prolongation of risk factors for ICUAW. When possible, early rehabilitation in critically ill patients improves functional outcomes, likely by reducing disuse atrophy. Interventions designed to correct the functional impairment are lacking and further research to delineate the molecular pathways that give rise to ICUAW are needed. PMID- 25453425 TI - Steroids for acute respiratory distress syndrome? AB - The development and severity of acute respiratory distress syndrome (ARDS) are closely related to dysregulated inflammation, and the duration of ARDS and eventual outcomes are related to persistent inflammation and abnormal fibroproliferation. Corticosteroids are potent modulators of inflammation and inhibitors of fibrosis that have been used since the first description of ARDS in attempts to improve outcomes. There is no evidence that corticosteroids prevent the development of ARDS among patients at risk. High-dose and short-course treatment with steroids does not improve the outcomes of patients with ARDS. Additional studies are needed to recommend treatment with steroids for ARDS. PMID- 25453428 TI - ARDS: new mechanistic insights, new therapeutic directions. PMID- 25453426 TI - Endogenous and exogenous cell-based pathways for recovery from acute respiratory distress syndrome. AB - Regenerative medicine has entered a rapid phase of discovery, and much has been learned in recent years about the lung's response to injury. This article first summarizes the cellular and molecular mechanisms that damage the alveolar capillary barrier, producing acute respiratory distress syndrome (ARDS). The latest understanding of endogenous repair processes is discussed, highlighting the diversity of lung epithelial progenitor cell populations and their regulation in health and disease. Finally, the past, present, and future of exogenous cell based therapies for ARDS is reviewed. PMID- 25453429 TI - Enhancing microalgal photosynthesis and productivity in wastewater treatment high rate algal ponds for biofuel production. AB - With microalgal biofuels currently receiving much attention, there has been renewed interest in the combined use of high rate algal ponds (HRAP) for wastewater treatment and biofuel production. This combined use of HRAPs is considered to be an economically feasible option for biofuel production, however, increased microalgal productivity and nutrient removal together with reduced capital costs are needed before it can be commercially viable. Despite HRAPs being an established technology, microalgal photosynthesis and productivity is still limited in these ponds and is well below the theoretical maximum. This paper critically evaluates the parameters that limit microalgal light absorption and photosynthesis in wastewater HRAPs and examines biological, chemical and physical options for improving light absorption and utilisation, with the view of enhancing biomass production and nutrient removal. PMID- 25453430 TI - Dynamic biogas upgrading based on the Sabatier process: thermodynamic and dynamic process simulation. AB - This study aimed to investigate the feasibility of substitute natural gas (SNG) generation using biogas from anaerobic digestion and hydrogen from renewable energy systems. Using thermodynamic equilibrium analysis, kinetic reactor modeling and transient simulation, an integrated approach for the operation of a biogas-based Sabatier process was put forward, which was then verified using a lab scale heterogenous methanation reactor. The process simulation using a kinetic reactor model demonstrated the feasibility of the production of SNG at gas grid standards using a single reactor setup. The Wobbe index, CO2 content and calorific value were found to be controllable by the H2/CO2 ratio fed the methanation reactor. An optimal H2/CO2 ratio of 3.45-3.7 was seen to result in a product gas with high calorific value and Wobbe index. The dynamic reactor simulation verified that the process start-up was feasible within several minutes to facilitate surplus electricity use from renewable energy systems. PMID- 25453431 TI - Effects of nitrogen source availability and bioreactor operating strategies on lutein production with Scenedesmus obliquus FSP-3. AB - In this study, the effects of the type and concentration of nitrogen sources on the cell growth and lutein content of an isolated microalga Scenedesmus obliquus FSP-3 were investigated. With batch culture, the highest lutein content (4.61 mg/g) and lutein productivity (4.35 mg/L/day) were obtained when using 8.0 mM calcium nitrate as the nitrogen source. With this best nitrogen source condition, the microalgae cultivation was performed using two bioreactor strategies (namely, semi-continuous and two-stage operations) to further enhance the lutein content and productivity. Using semi-continuous operation with a 10% medium replacement ratio could obtain the highest biomass productivity (1304.8 mg/L/day) and lutein productivity (6.01 mg/L/day). This performance is better than most related studies. PMID- 25453432 TI - Isolation and characterization of microalgae for biodiesel production from seawater. AB - As green marine microalgae isolated from local seawater in Tianjin, China, Nannochloropsis gaditana Q6 was tolerant to the variation of salinity with the highest biomass and lipid concentration in natural seawater medium. Although this strain could grow mixotrophically with glycerol, the narrow gap between mixotrophic and autotrophic cultivation suggested that autotrophic cultivation was the optimal trophic type for N. gaditana Q6 growth. In addition, strain Q6 was more sensitive to the variance of NH4HCO3 concentration than NaH2PO4 concentration. Consequently, the lipid production could be maximized by the two stage cultivation strategy, with an initial high NH4HCO3 concentration for biomass production followed by low NH4HCO3 concentration for lipid accumulation. PMID- 25453433 TI - Combining urban wastewater treatment with biohydrogen production--an integrated microalgae-based approach. AB - The aim of the present work was the simultaneous treatment of urban wastewater using microalgae and the energetic valorization of the obtained biomass. Chlorella vulgaris (Cv), Scenedesmus obliquus (Sc) and a naturally occurring algal Consortium C (ConsC) were grown in an urban wastewater. The nutrient removals were quite high and the treated water fits the legislation (PT Dec-Lei 236/98) in what concerns the parameters analysed (N, P, COD). After nutrient depletion the microalgae remained two more weeks in the photobioreactor (PBR) under nutritional stress conditions, to induce sugar accumulation (22-43%). The stressed biomass was converted into biohydrogen (bioH2), a clean energy carrier, through dark fermentation by a strain of the bacteria Enterobacter aerogenes. The fermentation kinetics were monitored and fitted to a modified Gompertz model. The highest bioH2 production yield was obtained for S. obliquus (56.8 mL H2/gVS) which was very similar when using the same algae grown in synthetic media. PMID- 25453434 TI - Using recombinant cyanobacterium (Synechococcus elongatus) with increased carbohydrate productivity as feedstock for bioethanol production via separate hydrolysis and fermentation process. AB - In this work, a recombinant cyanobacterium strain with increased photosynthesis rate, cell growth and carbohydrate production efficiency was genetically engineered by co-expressing ictB, ecaA, and acsAB (encoded for bacterial cellulose) in Synechococcus elongatus PCC7942. The resulting cyanobacterial biomass could be effectively hydrolyzed with dilute acid (2% sulfuric acid), achieving a nearly 90% glucose recovery at a biomass concentration of 80 g/L. Bioethanol can be produced from fermenting the acidic hydrolysate of S. elongatus PCC7942 via separate hydrolysis and fermentation (SHF) process at a concentration of 7.2 g/L and with a 91% theoretical yield. PMID- 25453435 TI - Heterogeneous catalyst-assisted thermochemical conversion of food waste biomass into 5-hydroxymethylfurfural. AB - A novel thermochemical conversion route has been developed that yields 5 hydroxymethylfurfural (HMF) from food waste biomass (FWB) in the presence of a heterogeneous catalysts (zirconium phosphate (ZrP)). The ZrP catalyst was prepared by precipitation followed by calcination at 400 (ZrP-400) and 600 degrees C (ZrP-600) and was characterized by SEM, XRD, XPS, N2 sorption and NH3 TPD. The optimized reaction conditions were identified to maximize HMF yield by varying the type of catalyst, the catalyst loading and the reaction time. The highest HMF yield achieved was 4.3%. On average 33% higher yield for ZrP-600 was obtained compared to that for ZrP-400, which might be due to higher number of acid sites on ZrP-600. The ZrP catalyst was easily regenerated by thermal treatment and showed stable activity upon its reuse. Preliminary calculations of the "minimum selling price" of HMF suggest that it is economically attractive to make this industrially-relevant chemical from FWB. PMID- 25453436 TI - Rapid method to screen and sort lipid accumulating microalgae. AB - The present work established an efficient staining method for fluorescence activated cell sorting (FACS) with Chlorococcum littorale maintaining cellular viability. The method was designed to detect high-lipid cells and to guarantee cellular viability. BODIPY505/515 (BP) was more suitable to FACS when compared to Nile red. The optimum concentrations were 0.4 MUg ml(-1) of BP, 0.1% DMSO or 0.35% ethanol. Both ethanol and DMSO were equally efficient and assured cellular viability after the staining and sorting. Here a method is presented to rapidly screen and sort lipid rich cells of C. littorale with FACS, which can be used to produce new inoculum with increased cellular lipid content. PMID- 25453437 TI - Degradation efficiency of agricultural biogas plants--a full-scale study. AB - The degradation efficiency of 21 full-scale agricultural CSTR biogas plants was investigated. The residual methane potential of the digestion stages was determined in batch digestion tests (20.0 and 37.0 degrees C). The results of this study showed that the residual methane yield is significantly correlated to the HRT (r=-0.73). An almost complete degradation of the input substrates was achieved due to a HRT of more than 100 days (0.097+/-0.017 Nm(3)/kg VS). The feedstock characteristics have the largest impact to the degradation time. It was found that standard values of the methane yield are a helpful tool for evaluating the degradation efficiency. Adapting the HRT to the input materials is the key factor for an efficient degradation in biogas plants. No influence of digester series configuration to the VS degradation was found. The mean VS degradation rate in the total reactor systems was 78+/-7%. PMID- 25453438 TI - Pyrolysis of Mesua ferrea and Pongamia glabra seed cover: characterization of bio oil and its sub-fractions. AB - In the present study, pyrolysis of Mesua ferrea seed cover (MFSC) and Pongamia glabra seed cover (PGSC) was performed to investigate the characteristics of bio oil and its sub fractions. In a fixed bed reactor, the effect of temperature (range of 350-650 degrees C) on product yield and quality of solid product were monitored. The maximum bio-oil yield of 28.5 wt.% and 29.6 wt.% for PGSC and MFSC respectively was obtained at 550 degrees C at heating rate of 40 degrees C/min. The chemical composition of bio-oil and its sub fractions were investigated using FTIR and (1)H NMR. GC-MS was performed for both PGSC and MFSC bio-oils and their corresponding n-hexane fractions. The results showed that bio-oil from the feedstocks and its sub-fractions might be a potential source of renewable fuel and value added chemicals. PMID- 25453439 TI - The potentials and challenges of algae based biofuels: a review of the techno economic, life cycle, and resource assessment modeling. AB - Microalgae biofuel production has been extensively evaluated through resource, economic and life cycle assessments. Resource assessments consistently identify land as non-limiting and highlight the need to consider siting based on combined geographical constraints of land and other critical resources such as water and carbon dioxide. Economic assessments report a selling cost of fuel that ranges between $1.64 and over $30 gal(-1) consistent with large variability reported in the life cycle literature, -75 to 534 gCO2-eq MJ(-1). Large drivers behind such variability stem from differences in productivity assumptions, pathway technologies, and system boundaries. Productivity represents foundational units in these assessments with current assumed yields in various assessments varying by a factor of 60. A review of the literature in these areas highlights the need for harmonized assessments such that direct comparisons of alternative processing technologies can be made on the metrics of resource requirements, economic feasibility, and environmental impact. PMID- 25453440 TI - A review on the sustainability of constructed wetlands for wastewater treatment: Design and operation. AB - Constructed wetlands (CWs) have been used as a green technology to treat various wastewaters for several decades. CWs offer a land-intensive, low-energy, and less operational-requirements alternative to conventional treatment systems, especially for small communities and remote locations. However, the sustainable operation and successful application of these systems remains a challenge. Hence, this paper aims to provide and inspire sustainable solutions for the performance and application of CWs by giving a comprehensive review of CWs' application and the recent development on their sustainable design and operation for wastewater treatment. Firstly, a brief summary on the definition, classification and application of current CWs was presented. The design parameters and operational conditions of CWs including plant species, substrate types, water depth, hydraulic load, hydraulic retention time and feeding mode related to the sustainable operation for wastewater treatments were then discussed. Lastly, future research on improving the stability and sustainability of CWs were highlighted. PMID- 25453441 TI - Flux balance analysis of different carbon source fermentation with hydrogen producing Clostridium butyricum using Cell Net Analyzer. AB - A metabolic network model for Clostridium butyricum was developed using six different carbon sources (sucrose, fructose, galactose, mannose, trehalose and ribose) to study the fermentative H2 production. The model was used for investigation of H2 production and the ability of growth on different substrates to predict the maximum abilities for fermentative H2 production that each substrate can support. NADH fluxes were calculated by the model as an important cofactor affecting on H2 production. Butyrate and acetate production were used as model assumptions and biomass formation was chosen as the objective function for flux analysis calculations. Among the substrates selected, sucrose and trehalose supported the maximum growth and H2 yields. The Cell Net Analyzer metabolic network model developed for H2 estimation revealed good correlation with experimental data and could be further used to study the effect of environmental conditions and substrates concentration on H2 yield. PMID- 25453442 TI - Methane yields and methanogenic community changes during co-fermentation of cattle slurry with empty fruit bunches of oil palm. AB - The biomethane potential and structural changes of the methanogenic community in a solid-state anaerobic digestion process co-digesting cattle slurry and empty fruit bunches were investigated under mesophilic (37 degrees C) and thermophilic (55 degrees C) conditions. Phylogenetic microarrays revealed the presence of two hydrogenotrophic genera (Methanoculleus and Methanobrevibacter) and one acetoclastic genus (Methanosarcina). Methanosarcina numbers were found to increase in both mesophilic and thermophilic treatments of empty fruit bunches. Methanobrevibacter, which dominated in the cattle slurry, remained constant during anaerobic digestion (AD) at 37 degrees C and decreased in numbers during digestion at 55 degrees C. Numbers of Methanoculleus remained constant at 37 degrees C and increased during the thermophilic digestion. Physicochemical data revealed non-critical concentrations for important monitoring parameters such as total ammonia nitrogen, free ammonia nitrogen and volatile fatty acids in all treatments after AD. The biomethane potential of empty fruit bunches was higher under thermophilic conditions than under mesophilic conditions. PMID- 25453444 TI - The struggle of carotid artery stenting. PMID- 25453446 TI - Microsecond Molecular Dynamics Simulations Provide Insight into the Allosteric Mechanism of the Gs Protein Uncoupling from the beta2 Adrenergic Receptor. AB - Experiments have revealed that in the beta(2) adrenergic receptor (beta(2)AR)-Gs protein complex the alpha subunit (Galphas) of the Gs protein can adopt either an "open" conformation or a "closed" conformation. In the "open" conformation the Gs protein prefers to bind to the beta(2)AR, while in the "closed" conformation an uncoupling of the Gs protein from the beta(2)AR occurs. However, the mechanism that leads to such different behaviors of the Gs protein remains unclear. Here, we report results from microsecond molecular dynamics simulations and community network analysis of the beta(2)AR-Gs complex with Galphas in the "open" and "closed" conformations. We observed that the complex is stabilized differently in the "open" and "closed" conformations. The community network analysis reveals that in the "closed" conformation there exists strong allosteric communication between the beta(2)AR and Gbetagamma, mediated by Galphas. We suggest that such high information flows are necessary for the Gs protein uncoupling from the beta(2)AR. PMID- 25453445 TI - Bioactive acylphloroglucinols with adamantyl skeleton from Hypericum sampsonii. AB - Hyperisampsins A-D (1-4), with tetracyclo[6.3.1.1(3,10).0(3,7)]tridecane skeletons and seven biogenetically related congeners (5-11), were isolated from Hypericum sampsonii. Their structures were elucidated by comprehensive spectroscopic techniques. The absolute configuration of 1 was established by ECD calculations, and those of 5 and 9 were confirmed by single X-ray crystallographic analyses. Hyperisampsins A and D showed potent anti-HIV activities with EC50 of 2.97 and 0.97 MUM and selectivity index of 4.80 and 7.70, respectively. PMID- 25453447 TI - Raising standards in dementia care. PMID- 25453448 TI - Blood pressure control after stroke: too little, too late, or too soon to tell? PMID- 25453449 TI - Intermittent pneumatic compression after stroke. PMID- 25453450 TI - What is the course of Huntington's disease? PMID- 25453451 TI - Top ten research priorities for spinal cord injury. PMID- 25453452 TI - Neuropsychiatric outcomes after stroke. PMID- 25453453 TI - Neuropsychiatric outcomes after stroke--authors' reply. PMID- 25453454 TI - NeuroAccess: breaking the cycle in resource-poor settings. PMID- 25453443 TI - Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomised trial. AB - BACKGROUND: Stenting is an alternative to endarterectomy for treatment of carotid artery stenosis, but long-term efficacy is uncertain. We report long-term data from the randomised International Carotid Stenting Study comparison of these treatments. METHODS: Patients with symptomatic carotid stenosis were randomly assigned 1:1 to open treatment with stenting or endarterectomy at 50 centres worldwide. Randomisation was computer generated centrally and allocated by telephone call or fax. Major outcomes were assessed by an independent endpoint committee unaware of treatment assignment. The primary endpoint was fatal or disabling stroke in any territory after randomisation to the end of follow-up. Analysis was by intention to treat ([ITT] all patients) and per protocol from 31 days after treatment (all patients in whom assigned treatment was completed). Functional ability was rated with the modified Rankin scale. This study is registered, number ISRCTN25337470. FINDINGS: 1713 patients were assigned to stenting (n=855) or endarterectomy (n=858) and followed up for a median of 4.2 years (IQR 3.0-5.2, maximum 10.0). Three patients withdrew immediately and, therefore, the ITT population comprised 1710 patients. The number of fatal or disabling strokes (52 vs 49) and cumulative 5-year risk did not differ significantly between the stenting and endarterectomy groups (6.4% vs 6.5%; hazard ratio [HR] 1.06, 95% CI 0.72-1.57, p=0.77). Any stroke was more frequent in the stenting group than in the endarterectomy group (119 vs 72 events; ITT population, 5-year cumulative risk 15.2% vs 9.4%, HR 1.71, 95% CI 1.28-2.30, p<0.001; per-protocol population, 5-year cumulative risk 8.9% vs 5.8%, 1.53, 1.02 2.31, p=0.04), but were mainly non-disabling strokes. The distribution of modified Rankin scale scores at 1 year, 5 years, or final follow-up did not differ significantly between treatment groups. INTERPRETATION: Long-term functional outcome and risk of fatal or disabling stroke are similar for stenting and endarterectomy for symptomatic carotid stenosis. FUNDING: Medical Research Council, Stroke Association, Sanofi-Synthelabo, European Union. PMID- 25453455 TI - Adriano Chio: the constant collector. PMID- 25453456 TI - The tapeworm that turned. PMID- 25453461 TI - Pain assessment in elderly adults with dementia. AB - Chronic pain is highly prevalent in the ageing population. Individuals with neurological disorders such as dementia are susceptible patient groups in which pain is frequently under-recognised, underestimated, and undertreated. Results from neurophysiological and neuroimaging studies showing that elderly adults are particularly susceptible to the negative effects of pain are of additional concern. The inability to successfully communicate pain in severe dementia is a major barrier to effective treatment. The systematic study of facial expressions through a computerised system has identified core features that are highly specific to the experience of pain, with potential future effects on assessment practices in people with dementia. Various observational-behavioural pain assessment instruments have been reported to be both reliable and valid in individuals with dementia. These techniques need to be interpreted in the context of observer bias, contextual variables, and the overall state of the individual's health and wellbeing. PMID- 25453462 TI - Neuroimaging in amyotrophic lateral sclerosis: insights into structural and functional changes. AB - In the past two decades, structural and functional neuroimaging findings have greatly modified longstanding notions regarding the pathophysiology of amyotrophic lateral sclerosis (ALS). Neuroimaging studies have shown that anatomical and functional lesions spread beyond precentral cortices and corticospinal tracts, to include the corpus callosum; frontal, sensory, and premotor cortices; thalamus; and midbrain. Both MRI and PET studies have shown early and diffuse loss of inhibitory cortical interneurons in the motor cortex (increased levels of functional connectivity and loss of GABAergic neurons, respectively) and diffuse gliosis in white-matter tracts. In ALS endophenotypes, neuroimaging has also shown a diverse spreading of lesions and a dissimilar impairment of functional and structural connections. A possible role of PET in the diagnosis of ALS has recently been proposed. However, most neuroimaging studies have pitfalls, such as a small number and poor clinical characterisation of patients, absence of adequate controls, and scarcity of longitudinal assessments. Studies involving international collaborations, standardised assessments, and large patient cohorts will overcome these shortcomings and provide further insight into the pathogenesis of ALS. PMID- 25453460 TI - Clinical symptoms, diagnosis, and treatment of neurocysticercosis. AB - The infection of the nervous system by the cystic larvae of Taenia solium (neurocysticercosis) is a frequent cause of seizure disorders. Neurocysticercosis is endemic or presumed to be endemic in many low-income countries. The lifecycle of the worm and the clinical manifestations of neurocysticercosis are well established, and CT and MRI have substantially improved knowledge of the disease course. Improvements in immunodiagnosis have further advanced comprehension of the pathophysiology of this disease. This knowledge has led to individualised treatment approaches that account for the involvement of parenchymal or extraparenchymal spaces, the number and form of parasites, and the extent of degeneration and associated inflammation. Clinical investigations are focused on development of effective treatments and reduction of side-effects induced by treatment, such as seizures, hydrocephalus, infarcts, and neuroinjury. PMID- 25453463 TI - Restoring function after spinal cord injury: towards clinical translation of experimental strategies. AB - Spinal cord injury is currently incurable and treatment is limited to minimising secondary complications and maximising residual function by rehabilitation. Improved understanding of the pathophysiology of spinal cord injury and the factors that prevent nerve and tissue repair has fuelled a move towards more ambitious experimental treatments aimed at promoting neuroprotection, axonal regeneration, and neuroplasticity. By necessity, these new options are more invasive. However, in view of recent advances in spinal cord injury research and demand from patients, clinicians, and the scientific community to push promising experimental treatments to the clinic, momentum and optimism exist for the translation of candidate experimental treatments to clinical spinal cord injury. The ability to rescue, reactivate, and rewire spinal systems to restore function after spinal cord injury might soon be within reach. PMID- 25453459 TI - Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study. AB - BACKGROUND: Although the association between cytosine-adenine-guanine (CAG) repeat length and age at onset of Huntington's disease is well known, improved prediction of onset would be advantageous for clinical trial design and prognostic counselling. We compared various measures for tracking progression and predicting conversion to manifest Huntington's disease. METHODS: In this prospective observational study, we assessed the ability of 40 measures in five domains (motor, cognitive, psychiatric, functional, and imaging) to predict time to motor diagnosis of Huntington's disease, accounting for CAG repeat length, age, and the interaction of CAG repeat length and age. Eligible participants were individuals from the PREDICT-HD study (from 33 centres in six countries [USA, Canada, Germany, Australia, Spain, UK]) with the gene mutation for Huntington's disease but without a motor diagnosis (a rating below 4 on the diagnostic confidence level from the 15-item motor assessment of the Unified Huntington's Disease Rating Scale). Participants were followed up between September, 2002, and July, 2014. We used joint modelling of longitudinal and survival data to examine the extent to which baseline and change of measures analysed separately was predictive of CAG-adjusted age at motor diagnosis. FINDINGS: 1078 individuals with a CAG expansion were included in this analysis. Participants were followed up for a mean of 5.1 years (SD 3.3, range 0.0-12.0). 225 (21%) of these participants received a motor diagnosis of Huntington's disease during the study. 37 of 40 cross-sectional and longitudinal clinical and imaging measures were significant predictors of motor diagnosis beyond CAG repeat length and age. The strongest predictors were in the motor, imaging, and cognitive domains: an increase of one SD in total motor score (motor domain) increased the risk of a motor diagnosis by 3.07 times (95% CI 2.26-4.16), a reduction of one SD in putamen volume (imaging domain) increased risk by 3.32 times (2.37-4.65), and a reduction of one SD in Stroop word score (cognitive domain) increased risk by 2.32 times (1.88-2.87). INTERPRETATION: Prediction of diagnosis of Huntington's disease can be improved beyond that obtained by CAG repeat length and age alone. Such knowledge about potential predictors of manifest Huntington's disease should inform discussions about guidelines for diagnosis, prognosis, and counselling, and might be useful in guiding the selection of participants and outcome measures for clinical trials. FUNDING: US National Institutes of Health, US National Institute of Neurological Disorders and Stroke, and CHDI Foundation. PMID- 25453464 TI - Robust multi-scale superpixel classification for optic cup localization. AB - This paper presents an optimal model integration framework to robustly localize the optic cup in fundus images for glaucoma detection. This work is based on the existing superpixel classification approach and makes two major contributions. First, it addresses the issues of classification performance variations due to repeated random selection of training samples, and offers a better localization solution. Second, multiple superpixel resolutions are integrated and unified for better cup boundary adherence. Compared to the state-of-the-art intra-image learning approach, we demonstrate improvements in optic cup localization accuracy with full cup-to-disc ratio range, while incurring only minor increase in computing cost. PMID- 25453465 TI - A new classifier fusion method based on historical and on-line classification reliability for recognizing common CT imaging signs of lung diseases. AB - Common CT imaging signs of lung diseases (CISL) play important roles in the diagnosis of lung diseases. This paper proposes a new method of multiple classifier fusion to recognize the CISLs, which is based on the confusion matrices of the classifiers and the classification confidence values outputted by the classifiers. The confusion matrix reflects the historical reliability of decision-making of a classifier, while the difference between the classification confidence values reflects the on-line reliability of its decision-making. The two factors are merged to determine the weights of the classifiers' classification confidence values. Then the classifiers are fused in a weighted sum form to make the final decision. We apply the proposed classifier fusion method to combine five types of classifiers for CISL recognition, including support vector machine (SVM), back-propagation neural network (BPNN), Naive Bayes (NB), k-nearest neighbor (k-NN) and decision tree (DT). In the experiments on lung CT images, our method not only brought stable improvements of recognition performance, compared with single classifiers, but also outperformed two well known methods of classifier fusion, AdaBoost and Bagging. These results show that the proposed method is effective and promising. PMID- 25453466 TI - Six years of bilingual edition for The Annals of PRM are coming to an end. PMID- 25453468 TI - The effect of the decoy molecule PA401 on CXCL8 levels in bronchoalveolar lavage fluid of patients with cystic fibrosis. AB - BACKGROUND: The chemokine interleukin-8 (CXCL8) is a key mediator of inflammation in airways of patients with cystic fibrosis (CF). Glycosaminoglycans (GAGs) possess the ability to influence the chemokine profile of the CF lung by binding CXCL8 and protecting it from proteolytic degradation. CXCL8 is maintained in an active state by this glycan interaction thus increasing infiltration of immune cells such as neutrophils into the lungs. As the CXCL8-based decoy PA401 displays no chemotactic activity, yet demonstrates glycan binding affinity, the aim of this study was to investigate the anti-inflammatory effect of PA401 on CXCL8 levels, and activity, in CF airway samples in vitro. METHODS: Bronchoalveolar lavage fluid (BALF) was collected from patients with CF homozygous for the DeltaF508 mutation (n=13). CXCL8 in CF BALF pre and post exposure to PA401 was quantified by ELISA. Western blot analysis was used to determine PA401 degradation in CF BALF. The ex vivo chemotactic activity of purified neutrophils in response to CF airway secretions was evaluated post exposure to PA401 by use of a Boyden chamber-based motility assay. RESULTS: Exposure of CF BALF to increasing concentrations of PA401 (50-1000pg/ml) over a time course of 2-12h in vitro, significantly reduced the level of detectable CXCL8 (P<0.05). Interestingly, PA401 engendered release of CXCL8 from GAGs exposing the chemokine susceptible to proteolysis. Subsequently, a loss of PA401 was observed (P<0.05) due to proteolytic degradation by elastase like proteases. A 25% decrease in neutrophil chemotactic efficiency towards CF BALF samples incubated with PA401 was also observed (P<0.05). CONCLUSION: PA401 can disrupt CXCL8:GAG complexes, rendering the chemokine susceptible to proteolytic degradation. Clinical application of a CXCL8 decoy, such as PA401, may serve to decrease the inflammatory burden in the CF lung in vivo. PMID- 25453467 TI - Calcium mobilization is both required and sufficient for initiating chromatin decondensation during activation of peripheral T-cells. AB - Antigen engagement of the T-cell receptor (TCR) induces a rapid and dramatic decondensation of chromatin that is necessary for T-cell activation. This decondensation makes T-cells competent to respond to interleukin-2 providing a mechanism to ensure clonotypic proliferation during an immune response. Using murine T-cells, we investigated the mechanism by which TCR signaling can initiate chromatin decondensation, focusing on the role of calcium mobilization. During T cell activation, calcium is first released from intracellular stores, followed by influx of extracellular calcium via store operated calcium entry. We show that mobilization of intracellular calcium is required for TCR-induced chromatin decondensation. However, the decondensation is not dependent on the activity of the downstream transcription factor NFAT. Furthermore, we show that the influx of extracellular calcium is dispensable for initiating chromatin decondensation. Finally, we show that mobilization of calcium from intracellular stores is sufficient to induce decondensation, independent of TCR engagement. Collectively, our data suggest that chromatin decondensation in peripheral T-cells is controlled by modulating intracellular calcium levels. PMID- 25453469 TI - Differential binding kinetics of replication protein A during replication and the pre- and post-incision steps of nucleotide excision repair. AB - The ability of replication protein A (RPA) to bind single-stranded DNA (ssDNA) underlines its crucial roles during DNA replication and repair. A combination of immunofluorescence and live cell imaging of GFP-tagged RPA70 revealed that RPA, in contrast to other replication factors, does not cluster into replication foci, which is explained by its short residence time at ssDNA. In addition to replication, RPA also plays a crucial role in both the pre- and post-incision steps of nucleotide excision repair (NER). Pre-incision factors like XPC and TFIIH accumulate rapidly at locally induced UV-damage and remain visible up to 4h. However, RPA did not reach its maximum accumulation level until 3h after DNA damage infliction and a chromatin-bound pool remained detectable up to 8h, probably reflecting its role during the post-incision step of NER. During the pre incision steps of NER, RPA could only be visualized at DNA lesions in incision deficient XP-F cells, however without a substantial increase in residence time at DNA damage. Together our data show that RPA is an intrinsically highly dynamic ssDNA-binding complex during both replication and distinct steps of NER. PMID- 25453457 TI - Effects of long-term blood pressure lowering and dual antiplatelet treatment on cognitive function in patients with recent lacunar stroke: a secondary analysis from the SPS3 randomised trial. AB - BACKGROUND: The primary outcome results for the SPS3 trial suggested that a lower systolic target blood pressure (<130 mm Hg) might be beneficial for reducing the risk of recurrent stroke compared with a higher target (130-149 mm Hg), but that the addition of clopidogrel to aspirin was not beneficial compared with aspirin plus placebo. In this prespecified secondary outcome analysis of the SPS3 trial, we aimed to assess whether blood pressure reduction and dual antiplatelet treatment affect changes in cognitive function over time in patients with cerebral small vessel disease. METHODS: In the SPS3 trial, patients with recent (within 6 months) symptomatic lacunar infarcts from 81 centres in North America, Latin America, and Spain were randomly assigned, in a two-by-two factorial design, to target levels of systolic blood pressure (1:1; 130-149 mm Hg vs <130 mm Hg; open-label) and to a once-daily antiplatelet treatment (1:1; aspirin 325 mg plus clopidogrel 75 mg vs aspirin 325 mg plus placebo; double-blind). For this analysis, the main cognitive outcome was change in Cognitive Abilities Screening Instrument (CASI) during follow-up. Patients were tested annually for up to 5 years, during which time the mean difference in systolic blood pressure was 11 mm Hg (SD 16) between the two targets (138 mm Hg vs 127 mm Hg at 1 year). We used linear mixed models to compare changes in CASI Z scores over time. The SPS3 trial is registered with ClinicalTrials.gov, number NCT00059306. FINDINGS: The study took place between March 23, 2003, and April 30, 2012. 2916 of 3020 SPS3 participants (mean age 63 years [SD 11]) with CASI scores at study entry were included in the analysis, with a median follow-up of 3.0 years (IQR 1.0-4.9). Mean changes in CASI Z scores from study entry to assessment at years 1 (n=2472), 2 (n=1968), 3 (n=1521), 4 (n=1135), and 5 (n=803) were 0.12 (SD 0.83), 0.15 (0.84), 0.16 (0.95), 0.19 (0.99), and 0.14 (1.09), respectively. Changes in CASI Z scores over time did not differ between assigned antiplatelet groups (p=0.858) or between assigned blood pressure target groups (p=0.520). There was no interaction between assigned antiplatelet groups and assigned blood pressure target groups and change over time (p=0.196). INTERPRETATION: Cognitive function is not affected by short-term dual antiplatelet treatment or blood pressure reduction in fairly young patients with recent lacunar stroke. Future studies of cognitive function after stroke should be of longer duration or focus on patients with higher rates of cognitive decline. FUNDING: US National Institute of Neurological Disorders and Stroke. PMID- 25453470 TI - A C. elegans homolog of the Cockayne syndrome complementation group A gene. AB - Cockayne syndrome (CS) is a debilitating and complex disorder that results from inherited mutations in the CS complementation genes A and B, CSA and CSB. The links between the molecular functions of the CS genes and the complex pathophysiology of CS are as of yet poorly understood and are the subject of intense debate. While mouse models reflect the complexity of CS, studies on simpler genetic models might shed new light on the consequences of CS mutations. Here we describe a functional homolog of the human CSA gene in Caenorhabditis elegans. Similar to its human counterpart, mutations in the nematode csa-1 gene lead to developmental growth defects as a consequence of DNA lesions. PMID- 25453471 TI - Can red cell distribution width predict mortality rate in patients with necrotizing fasciitis? The Author's Reply. PMID- 25453472 TI - Can red cell distribution width predict mortality rate in patients with necrotizing fasciitis? PMID- 25453474 TI - A field survey of spinal cord injury in bodyboarders. PMID- 25453473 TI - Impact of case volume on outcome and performance of targeted temperature management in out-of-hospital cardiac arrest survivors. AB - PURPOSE: This study aimed to determine the effect of case volume on targeted temperature management (TTM) performance, incidence of adverse events, and neurologic outcome in comatose out-of-hospital cardiac arrest (OHCA) survivors treated with TTM. METHODS: We used a Web-based, multicenter registry (Korean Hypothermia Network registry), to which 24 hospitals throughout the Republic of Korea participated to study adult (>=18 years) comatose out-of-hospital cardiac arrest patients treated with TTM between 2007 and 2012. The primary outcome was neurologic outcome at hospital discharge. The secondary outcomes were inhospital mortality, TTM performance, and adverse events. We extracted propensity-matched cohorts to control for bias. Multivariate logistic regression analysis was performed to assess independent risk factors for neurologic outcome. RESULTS: A total of 901 patients were included in this study; 544 (60.4%) survived to hospital discharge, and 248 (27.5%) were discharged with good neurologic outcome. The high-volume hospitals initiated TTM significantly earlier and had lower rates of hyperglycemia, bleeding, hypotension, and rebound hyperthermia. However, neurologic outcome and inhospital mortality were comparable between high-volume (27.7% and 44.6%, respectively) and low-volume hospitals (21.1% and 40.5%) in the propensity-matched cohorts. The adjusted odds ratio for the high-volume hospitals compared with low-volume hospitals was 1.506 (95% confidence interval, 0.875 2.592) for poor neurologic outcome. CONCLUSIONS: Higher TTM case volume was significantly associated with early initiation of TTM and lower incidence of adverse events. However, case volume had no association with neurologic outcome and inhospital mortality. PMID- 25453475 TI - Acute cardiogenic pulmonary edema with normal BNP: the value of repeat BNP testing. PMID- 25453476 TI - Effects of ultrasound-guided radial artery catheterization: an updated meta analysis. AB - BACKGROUND: Previous meta-analyses have shown that ultrasound guidance is an effective technique for radial artery catheterization. However, these reports neglected to include several non-English language studies. Therefore, an updated meta-analysis including more eligible studies was performed to assess the effectiveness of ultrasound-guided radial artery catheterization. METHODS: Eligible studies were identified by systematically searching PubMed, EMBASE, Wanfang, and China National Knowledge Infrastructure literature databases. The outcome measure was the rate of first-attempt success. Two investigators identified the randomized controlled trials (RCTs) for inclusion and independently extracted data from these RCTs. The quality of the included studies was evaluated using the Jadad score. The relative risk (RR) for dichotomous outcomes and the 95% confidence intervals (CIs) were calculated and pooled using a random-effects model. RESULTS: Eleven RCTs involving 803 patients met the inclusion criteria. Ultrasound-guided radial artery catheterization was generally associated with a 47% improvement, as compared with the palpation technique, in terms of the rate of first-attempt success (RR, 1.47; 95% CI, 1.22-1.76; P < .0001). Specifically, the ultrasound-guided technique significantly improved the rate of first-attempt success for adult (RR, 1.39; 95% CI, 1.13-1.72; P = .002) and pediatric (RR, 1.68; 95% CI, 1.15-2.47; P = .008) patients. CONCLUSIONS: Adult and pediatric patients benefited from ultrasound-guided radial artery catheterization in terms of the rate of first-attempt success. Given the potential bias and significant heterogeneity of the available data in the present study, further investigation is required to confirm the present findings and to identify other effects of the ultrasound-guided technique. PMID- 25453477 TI - Civilian use of a conducted electrical weapon. PMID- 25453478 TI - ISEK congress 2014--Basmajian lecture. PMID- 25453479 TI - Stabilization strategies for unstable dynamics. AB - The stabilization of the human standing posture was originally attributed to the stiffness of the ankle muscles but direct measurements of the ankle stiffness ruled out this hypothesis, leaving open the possibility for a feedback stabilization strategy driven by proprioceptive signals. This solution, however, could be implemented with two different kinds of control mechanisms, namely continuous or intermittent feedback. The debate is now settled and the latter solution seems to be the most plausible one. Moreover, stabilization of unstable dynamics is not limited to bipedal standing. Indeed many manipulation tasks can be described in the same framework and thus a very general protocol for addressing this kind of problems is the use of haptic virtual reality where instability is generated by some kind of divergent or saddle-like force field. Several studies demonstrated that human subjects can choose to adopt a stiffness or feedback strategy as a combination of biomechanical and task constraints and can learn to switch from one strategy to the other if it is feasible or to use one or the other is infeasible. Understanding such mechanisms is relevant, for example, for the design of novel ergonomic man-machine interfaces in difficult, unstable tasks. PMID- 25453480 TI - Effectiveness of one-year pharmacological treatment of adult attention deficit/hyperactivity disorder (ADHD): an open-label prospective study of time in treatment, dose, side-effects and comorbidity. AB - How to generalize from randomized placebo controlled trials of ADHD drug treatment in adults to 'real-world' clinical practice is intriguing. This open labeled prospective observational study examined the effectiveness of long-term stimulant and non-stimulant medication in adult ADHD including dose, side-effects and comorbidity in a clinical setting. A specialized ADHD outpatient clinic gave previously non-medicated adults (n=250) with ADHD methylphenidate as first-line drug according to current guidelines. Patients who were non-tolerant or experiencing low efficacy were switched to amphetamine or atomoxetine. Primary outcomes were changes of ADHD-symptoms evaluated with the Adult ADHD Self-Report Scale (ASRS) and overall severity by the Global Assessment of Functioning (GAF). Secondary outcomes were measures of mental distress, and response on the Clinical Global-Impressions-Improvement Scale. Data at baseline and follow-ups were compared in longitudinal mixed model analyses for time on-medication, dosage, comorbidity, and side-effects. As results, 232 patients (93%) completed examination at the 12 month endpoint, and 163 (70%) remained on medication. Compared with the patients who discontinued medication, those still on medication had greater percentage reduction in ASRS-scores (median 39%, versus 13%, P<0.001) and greater improvement of GAF (median 20% versus 4%, P<0.001) and secondary outcomes. Continued medication and higher cumulated doses showed significant associations to sustained improvement. Conversely, psychiatric comorbidity and side-effects were related to lower effectiveness and more frequent termination of medication. Taken together, one-year treatment with stimulants or atomoxetine was associated with a clinically significant reduction in ADHD symptoms and mental distress, and improvement of measured function. No serious adverse events were observed. PMID- 25453481 TI - Dose-dependent changes in cognitive function with exercise augmentation for major depression: results from the TREAD study. AB - Cognitive dysfunction has been repeatedly observed in major depressive disorder (MDD), particularly in areas of attention, verbal and nonverbal learning and memory, and executive functioning. Exercise has been shown to improve cognitive outcomes in other populations, including age-associated cognitive decline, but has not to our knowledge been investigated as an augmentation strategy in depression. This study evaluated the effectiveness of exercise augmentation on cognitive performance in persons with MDD and residual symptoms that included cognitive complaints following initial treatment with a selective serotonin reuptake inhibitor (SSRI). Participants enrolled in the Treatment with Exercise Augmentation for Depression (TREAD) study were randomized to receive either a low or high dose exercise regimen. TREAD participants who provided informed consent for the current study completed Cambridge Neuropsychological Test Automated Battery measures assessing Attention, Visual Memory, Executive Function/Set shifting and Working Memory, and Executive Function/Spatial Planning domains. Data were analyzed for 39 participants completing both baseline and Week 12 cognitive testing. Overall tests indicated a significant task * group * time interaction for the Executive Function/Set-shifting and Working Memory domain. Post-hoc tests indicated improvements in high dose exercisers' spatial working memory, but decreases in spatial working memory and set-shifting outcomes in low dose exercisers. Both groups improved on measures of psychomotor speed, attention, visual memory and spatial planning. This study suggests a dose response effect of exercise in specific executive function and working memory tasks among depressed persons with a partial response to SSRI and cognitive complaints, with some cognitive functions improving regardless of exercise dose. PMID- 25453458 TI - Effect of intermittent pneumatic compression on disability, living circumstances, quality of life, and hospital costs after stroke: secondary analyses from CLOTS 3, a randomised trial. AB - BACKGROUND: The results of the CLOTS 3 trial showed that intermittent pneumatic compression (IPC) reduced the risk of deep vein thrombosis and improved survival in immobile patients with stroke. IPC is now being widely used in stroke units. Here we describe the disability, living circumstances, quality of life, and hospital costs of patients in CLOTS 3. METHODS: In CLOTS 3, a parallel group trial in 94 UK hospitals, immobile patients with stroke from days 0 to 3 of admission were assigned with a computer-generated allocation sequence in a 1:1 ratio to IPC or no IPC through a central randomisation system. We followed up patients at about 6 months with postal or telephone questionnaire to assess the secondary endpoints: disability (Oxford Handicap Scale [OHS]), living circumstances, health-related quality of life (EQ5D-3L), and hospital costs (based on use of IPC and length of hospital stay). Patients and carers who completed the postal questionnaires were not masked to treatment allocation, but telephone follow-up in non-responders was masked. All analyses were by intention to treat. This trial is registered, number ISRCTN93529999. FINDINGS: Between Dec 8, 2008, and Sept 6, 2012, we enrolled 2876 patients, with 1438 in each group. Despite the previously reported reduction in the risk of proximal deep vein thrombosis at 30 days (primary endpoint), there were no significant differences in disability (OHS 0-2 vs 3-6, adjusted odds ratio [OR] 0.98, 95% CI 0.80 to 1.19, p=0.83; adjusted ordinal analysis common OR 0.97, 95% CI 0.86 to 1.11), living circumstances (institutional care vs not; adjusted OR 1.11, 95% CI 0.89 to 1.37; p=0.358), or health-related quality of life (median utility value 0.26, IQR -0.07 to 0.66 with IPC, and 0.27, -0.06 to 0.64, with no IPC; p=0.952). The estimated cost of IPC was L64.10 per patient (SD 28.3). The direct costs of preventing a deep vein thrombosis and death were L1282 (95% CI 785 to 3077) and L2756 (1346 to not estimable), respectively, with IPC. Hospital costs increased by L451 with IPC compared with no IPC because of a longer stay in hospital (mean 44.5 days [SD 37.6] vs 42.8 days [37.2]; mean difference 1.8 days, 95% CI -1.0 to 4.5). By 6 months, despite an increase in survival (IPC 152.5 days [SD 60.6] vs no IPC 148.1 days [64.3]; mean difference 4.5 days, 95% CI -0.2 to 9.1), there was a non-significant increase in quality-adjusted survival associated with IPC (IPC 27.6 days [SD 40.6] vs no IPC 26.7 days [39.6]; mean difference 0.9 days, 95% CI -2.1 to 3.9). INTERPRETATION: IPC is inexpensive, prevents deep vein thrombosis, improves survival but not functional outcomes, and does not lead to a significant gain in quality-adjusted survival. When deciding whether to treat patients with IPC, clinicians need to take into account all these potential effects. FUNDING: National Institute of Health Research Health Technology Assessment Programme, Chief Scientist Office of Scottish Government, and Covidien. PMID- 25453483 TI - Glutaminase1 heterozygous mice show enhanced trace fear conditioning and Arc/Arg3.1 expression in hippocampus and cingulate cortex. AB - Mice heterozygous for a mutation in the glutaminase (GLS1) gene (GLS1 HZ mice), with reduced glutamate recycling and release, display reduced hippocampal function as well as memory of contextual cues in a delay fear conditioning (FC) paradigm. Here, we asked whether this deficit reflects an inability to process contextual information or a selective alteration in salience attribution. In addition, we asked whether baseline and activity-induced hippocampal activity were diminished in GLS1 HZ mice. For this purpose, we manipulated the relative salience of the conditioned stimulus (CS) and contextual cues in FC tasks, and examined gene expression of the immediate early gene Arc (Arc/Arg3.1) in hippocampus and anterior cingulate cortex (ACC) following trace FC (tFC). The results indicate that GLS1 HZ mice succeed in processing contextual information when the salient CS is absent or less predictive. In addition, in the hippocampus dependent tFC paradigm GLS1 HZ mice display enhanced CS learning. Furthermore, while baseline arc activation was reduced in GLS1 HZ mice in the hippocampus, in line with previous fMRI findings, it was enhanced in the hippocampus and anterior cingulate cortex following tFC. These findings suggest that GLS1 HZ mice have a pro-cognitive profile in the tFC paradigm, and this phenotype involves activation of both hippocampus and ACC. Taken together with previous work on the GLS1 HZ mouse, this study sheds light on the importance of glutamate transmission to memory processes that require the allocation of attentional resources, and extends our understanding of the underpinnings of attention deficits in SZ. PMID- 25453482 TI - Novel dimensions of D3 receptor function: Focus on heterodimerisation, transactivation and allosteric modulation. AB - The brain's complexity derives not only from the way the intricate network of neurons is wired, but also by protein complexes that recognize and decode chemical information. G protein-coupled receptors (GPCRs) represent the most abundant family of proteins mediating neurotransmission in the brain, and their ability to form homo- and heteromers which amplifies the scope for synaptic communication and fine-tuning. Dopamine receptors are important drug targets and members of both the D1/D5 and D2/D3/D4 receptor families form homo- and heteromers. The present article focuses on D3 receptor homo- and heteromers, in particular, those formed in association with their D2 counterparts. We highlight the binding profiles and mechanisms of interaction with D3-D3 homomers and D3-D2 heteromers of: first, the PET ligand and potent agonist [(11)C]-(+)-PHNO; second, the novel, bitopic/allosteric dopamine D3 receptor antagonist, SB269,652; and third, diverse partial agonists like antipsychotic and aripiprazole. Molecular mechanisms of interplay between the two protomers of heteromeric D3-D2 complexes are likewise discussed: for example, "transactivation", whereby recruitment of one member of a heteromer harnesses signalling pathways is normally coupled to the other protomer. Finally, D1 receptor heteromers are also taken into consideration in deciphering the nature of interfaces required to stabilize dimeric assemblies and permit their interaction with G proteins. Improved understanding of D3 as well as D2 and D1 receptor complexes should yield important insights into their physiological roles and pathological significance, and permit the development of novel drug classes with potentially distinctive functional profiles and improved therapeutic windows. PMID- 25453484 TI - Low neuropeptide Y in cerebrospinal fluid in bipolar patients is associated with previous and prospective suicide attempts. AB - The attempted and accomplished suicide rates in patients with bipolar disorder are 40-50% and 15-20%, respectively. No biological markers that help predict suicide been identified. Human and experimental animal data indicate that dysregulation of the neuropeptide Y (NPY) system plays a role in depression, anxiety, and posttraumatic stress disorder (PTSD). The aim of this study was to explore if low cerebrospinal fluid (CSF) NPY is associated with (1) past suicide attempts, (2) future suicide attempts, and (3) trait anxiety. Lumbar puncture was performed on 120 clinically stable patients with bipolar disorder enrolled in the St Goran Bipolar Project, where the number of previous suicide attempts was documented. NPY-like immunoreactivity (NPY-LI) was determined in cerebrospinal fluid (CSF). Patients were reexamined one year after the lumbar puncture and suicide attempts were recorded. NPY-LI was significantly lower in patients with a history of suicide attempt than in patients who had not attempted suicide prior to lumbar puncture. Importantly, NPY-LI was markedly lower in patients who made a suicide attempt during the follow-up period compared to patients who did not. Patients who attempted suicide during the follow-up also had markedly lower NPY LI than those with previous suicide attempts who did not reattempt. Our results suggest that low CSF NPY-LI predicts future suicide attempts. The data are in line with the hypothesis that NPY signaling is altered in affective disorders and states of emotional dysregulation. PMID- 25453485 TI - Antipsychotic use is associated with a blunted cortisol stress response: a study in euthymic bipolar disorder patients and their unaffected siblings. AB - There is ample evidence that the acute stress response is altered in schizophrenia and bipolar disorder. However, it is not clear whether such changes are related to the illness, a genetic vulnerability, or is the result of medication that is used in the majority of these patients. Therefore, we investigated determinants of the acute endocrine and autonomic stress response in healthy controls (n=48), euthymic BD1 patients (n=49) and unaffected siblings of BD1 patients (n=27). All participants completed a validated psychosocial stress task, the Trier Social Stress Test for Groups (TSST-G). Saliva levels of alpha amylase and cortisol were measured before, during, and after exposure to stress. Compared to controls, we found a significantly blunted cortisol stress response in BD1 patients. Conversely, BD1 patients displayed exaggerated alpha-amylase levels in response to stress. Antipsychotic use was a significant contributing factor to the blunted cortisol stress response in BD1 patients. Unaffected BD1 siblings displayed similar stress-induced cortisol and alpha-amylase levels as controls, suggesting that familial risk for BD1 did not have a large effect on the functionality of the stress system. In conclusion, this study shows that euthymic BD1 patients have a substantially blunted endocrine stress response but an exaggerated autonomic stress response and that the endocrine stress response differences can be largely contributed to antipsychotic use rather than constitute a specific BD1 phenotype or vulnerability. PMID- 25453487 TI - High prevalence of psychotropic drug use among persons with and without Alzheimer's disease in Finnish nationwide cohort. AB - Psychotropic drugs are used for treatment of behavioral and psychological symptoms of dementia (BPSD) although they are associated with serious adverse drug events. Objective of our study was to investigate prevalence of psychotropic drug use one year after diagnoses of Alzheimer's disease (AD), to compare prevalence to persons without AD and to assess changes in prevalence over time. Data from the MEDALZ (Medication use and Alzheimer's disease) cohort was utilized in the study including all 69,080 community-dwelling persons with new diagnosis of AD during years 2005-2011 in Finland. Four age-, gender- and region of residence-matched persons without AD were identified for each case. Register based data included prescription drug purchases and comorbidities from Special Reimbursement Register. Annual prevalence of psychotropic drug use one year after diagnosis was determined for each person. Psychotropic drugs were used by 53% of persons with AD compared with 33% of persons without AD during one year after diagnoses. Persons with AD were six times more likely to use antipsychotics and three times more likely to use antidepressants whereas benzodiazepine and related drug (BZDR) use was comparable between persons with and without AD. According to year of AD diagnoses during 2005-2011, antipsychotic use increased from 18% to 20% (p<0.0001) and BZDR use declined from 31% to 26% (p<0.0001) among persons with AD. Widespread utilization of psychotropic drugs was observed among persons with AD. Despite safety warnings of antipsychotic use for BPSD, antipsychotic use increased from 2005 to 2011 among newly diagnosed persons with AD in Finland. PMID- 25453486 TI - Efficacy and safety of extended-release guanfacine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder: a randomized, controlled, phase III trial. AB - Guanfacine extended-release (GXR), a selective alpha2A-adrenergic agonist, is a non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD). This study assessed the efficacy (symptoms and function) and safety of dose-optimized GXR compared with placebo in children and adolescents with ADHD. An atomoxetine (ATX) arm was included to provide reference data against placebo. Patients (6-17 years) were randomized at baseline to dose-optimized GXR (0.05-0.12mg/kg/day - 6 12 years: 1-4mg/day; 13-17 years: 1-7mg/day), ATX (10-100mg/day) or placebo for 4 or 7 weeks. The primary efficacy measure was change from baseline in ADHD Rating Scale version IV (ADHD-RS-IV). Key secondary measures were Clinical Global Impression-Improvement (CGI-I) and the Weiss Functional Impairment Rating Scale Parent Report (WFIRS-P; learning and school, and family domains). Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms and vital signs. A total of 272 (80.5%) patients from Europe, the USA and Canada completed the study. Significant differences were observed in least squares mean change from baseline in ADHD-RS-IV total score (placebo adjusted differences) (GXR: [-8.9, p<0.001]; ATX: [-3.8, p<0.05]), the difference from placebo in the percentage of patients showing improvement (1 ['very much improved'] or 2 ['much improved']) for CGI-I (GXR: [23.7, p<0.001]; ATX: [12.1, p<0.05]), WFIRS-P learning and school domain (GXR: [-0.22, p<0.01]; ATX: [-0.16, p<0.05]) and WFIRS-P family domain (GXR: [-0.21, p<0.01]; ATX: [-0.09, p=0.242]). Most common TEAEs for GXR were somnolence, headache and fatigue; 70.1% of GXR subjects reported mild-to-moderate TEAEs. GXR was effective and well tolerated in children and adolescents with ADHD. PMID- 25453488 TI - D-cycloserine prevents relational memory deficits and suppression of long-term potentiation induced by scopolamine in the hippocampus. AB - Previous research has demonstrated that systemic D-cycloserine (DCS), a partial agonist of the N-methyl-D-aspartate receptor (NMDAR), enhances memory processes in different learning paradigms and attenuates mnemonic deficits produced by diverse pharmacological manipulations. In the present study two experiments were conducted in rats to investigate whether DCS administered in the hippocampus may rescue relational memory deficits and improve deficient synaptic plasticity, both induced by an intracerebral injection of the muscarinic receptor antagonist scopolamine (SCOP). In experiment 1, we assessed whether DCS would prevent SCOP induced amnesia in an olfactory learning paradigm requiring the integrity of the cholinergic system, the social transmission of food preference (STFP). The results showed that DCS (10 MUg/site) injected into the ventral hippocampus (vHPC) before STFP acquisition compensated the 24-h retention deficit elicited by post-training intra-vHPC SCOP (40 MUg/site), although it did not affect memory expression in non-SCOP treated rats. In experiment 2, we evaluated whether the perfusion of DCS in hippocampal slices may potentiate synaptic plasticity in CA1 synapses and thus recover SCOP-induced deficits in long-term potentiation (LTP). We found that DCS (50 uM and 100 uM) was able to rescue SCOP (100 uM)-induced LTP maintenance impairment, in agreement with the behavioral findings. Additionally, DCS alone (50 uM and 100 uM) enhanced field excitatory postsynaptic potentials prior to high frequency stimulation, although it did not significantly potentiate LTP. Our results suggest that positive modulation of the NMDAR, by activation of the glycine-binding site, may compensate relational memory impairments due to hippocampal muscarinic neurotransmission dysfunction possibly through enhancements in LTP maintenance. PMID- 25453494 TI - Inhibitory effects of kaempferol on the invasion of human breast carcinoma cells by downregulating the expression and activity of matrix metalloproteinase-9. AB - Matrix metalloproteinases (MMPs) have been regarded as major critical molecules assisting tumor cells during metastasis, for excessive ECM (ECM) degradation, and cancer cell invasion. In the present study, in vitro and in vivo assays were employed to examine the inhibitory effects of kaempferol, a natural polyphenol of flavonoid family, on tumor metastasis. Data showed that kaempferol could inhibit adhesion, migration, and invasion of MDA-MB-231 human breast carcinoma cells. Moreover, kaempferol led to the reduced activity and expression of MMP-2 and MMP 9, which were detected by gelatin zymography, real-time PCR, and western blot analysis, respectively. Further elucidation of the mechanism revealed that kaempferol treatment inhibited the activation of transcription factor activator protein-1 (AP-1) and MAPK signaling pathway. Moreover, kaempferol repressed phorbol-12-myristate-13-acetate (PMA)-induced MMP-9 expression and activity through suppressing the translocation of protein kinase Cdelta (PKCdelta) and MAPK signaling pathway. Our results also indicated that kaempferol could block the lung metastasis of B16F10 murine melanoma cells as well as the expression of MMP-9 in vivo. Taken together, these results demonstrated that kaempferol could inhibit cancer cell invasion through blocking the PKCdelta/MAPK/AP-1 cascade and subsequent MMP-9 expression and its activity. Therefore, kaempferol might act as a therapeutic potential candidate for cancer metastasis. PMID- 25453498 TI - Controllable morphology and conductivity of electrodeposited Cu2O thin film: effect of surfactants. AB - Both the morphology and conductivity of Cu2O films are controlled in a facile electrodeposition process by tuning the concentration of surfactants. With the increase of the concentration of sodium dodecyl sulfate (SDS) in the plating solution, the average size of Cu2O crystals increases, and the electrical conductivity of Cu2O films changes from n-type to p-type. When the concentrations of SDS are lower than 0.85 mM, the electrodeposited Cu2O films show n-type conductivity because of the formation of oxygen vacancies or copper atoms. When the concentration of SDS is higher than 1.70 mM, the electrodeposited Cu2O films show p-type conductivity owing to the formation of copper vacancies. The concentrations of both the donors and the acceptors increase with the concentration of SDS. The effects of surfactants on the morphology and conductivity of electrodeposited Cu2O films are attributed to the adsorption of SDS molecules on the electrode substrate occupying the deposition sites of Cu(2+) ions and the adsorption of SDS micelles to Cu(2+) ions hindering the diffusion of Cu(2+) ions to the electrode, which affect the reduction rate of Cu(2+) ions and the formation of oxygen vacancies or copper vacancies during the electrodeposition. PMID- 25453499 TI - Efficient reactivation of p53 in cancer cells by a dual MdmX/Mdm2 inhibitor. AB - The aberrant interaction between p53 and Mdm2/MdmX is an attractive target for cancer drug discovery because the overexpression of Mdm2 and/or MdmX ultimately impairs the function of p53 in approximately half of all human cancers. Recent studies have shown that inhibition of both Mdm2 and MdmX is more efficient than that of a single target in promoting cellular apoptosis in cancers. In this study, we demonstrate that a dual small-molecule antagonist of Mdm2/MdmX can efficiently reactivate the p53 pathway in model cancer cells overexpressing MdmX and/or Mdm2. The dual antagonist was rationally designed based on segmental mutational analysis of the N-terminal domain of MdmX and the crystal structure of the N-terminal domain of Mdm2 in complex with nutlin-3a (an Mdm2-specific inhibitor). The current work establishes a small molecule therapeutic candidate that targets cancers overexpressing Mdm2 and/or MdmX. PMID- 25453500 TI - Ternary system based on fluorophore-surfactant assemblies--Cu2+ for highly sensitive and selective detection of arginine in aqueous solution. AB - A new cationic dansyl derivative-based (DIlSD) fluorescence probe was designed and synthesized. Its combination with anionic surfactant SDS assemblies shows enhanced fluorescence intensity and blue-shifted maximum wavelength. Its fluorescence can be slightly quenched by Cu(2+); however, the fluorescence quenching efficiency by Cu(2+) is highly increased upon titration of arginine (Arg). As a result, the ternary system containing the cationic fluorophore, anionic surfactant, and Cu(2+) functions as a highly sensitive and selective sensor to Arg. The optimized sensor system displays a detection limit of 170 nM, representing the highest sensitivity to Arg in total aqueous solution by a fluorescent sensor. Control experiments reveal that the imidazolium groups in the fluorophore, the anionic surfactant, and Cu(2+) all play important roles in the process of sensing Arg. The electrostatic interaction between the cationic fluorophore and anionic surfactants facilitates the binding of imidazolium rings with Cu(2+), the surfactant surface-anchored Cu(2+) is responsible for further binding of Arg, and the electrostatic interaction between anionic surfactants and positively charged amino acids accounts for the selective responses to Arg. PMID- 25453501 TI - Electrochemistry of transition metal dichalcogenides: strong dependence on the metal-to-chalcogen composition and exfoliation method. AB - Beyond MoS2 as the first transition metal dichalcogenide (TMD) to have gained recognition as an efficient catalyst for the hydrogen evolution reaction (HER), interest in other TMD nanomaterials is steadily beginning to proliferate. This is particularly true in the field of electrochemistry, with a myriad of emerging applications ranging from catalysis to supercapacitors and solar cells. Despite this rise, current understanding of their electrochemical characteristics is especially lacking. We therefore examine the inherent electroactivities of various chemically exfoliated TMDs (MoSe2, WS2, WSe2) and their implications for sensing and catalysis of the hydrogen evolution and oxygen reduction reactions (ORR). The TMDs studied are found to possess distinctive inherent electroactivities and together with their catalytic effects for the HER are revealed to strongly depend on the chemical exfoliation route and metal-to chalcogen composition particularly in MoSe2. Despite its inherent activity exhibiting large variations depending on the exfoliation procedure, it is also the most efficient HER catalyst with a low overpotential of -0.36 V vs RHE (at 10 mA cm(-2) current density) and fairly low Tafel slope of ~65 mV/dec after BuLi exfoliation. In addition, it demonstrates a fast heterogeneous electron transfer rate with a k0obs of 9.17*10(-4) cm s(-1) toward ferrocyanide, better than that seen for conventional glassy carbon electrodes. Knowledge of TMD electrochemistry is essential for the rational development of future applications; inherent TMD activity may potentially limit certain purposes, but intended objectives can nonetheless be achieved by careful selection of TMD compositions and exfoliation methods. PMID- 25453502 TI - Fear: "anxiety is fear in search of a cause.". PMID- 25453505 TI - FDA-approved drugs to treat schizophrenia. PMID- 25453506 TI - A proposed system for classifying psychotropic drugs. AB - Most drugs used in psychiatry are classified according to their initial or main therapeutic indications rather than by their pharmacological profiles. A proposed multi-axial, pharmacologically driven nomenclature system that would reclassify existing psychotropic drugs and provide a framework for classifying new drug compounds is described. The five axes of this system would describe a drug's primary pharmacological target and relevant mechanism; relevant neurotransmitter and mechanism; neurobiological activities; efficacy and side effects; and approved indications. The proposed multi-axial system is a common sense but scientifically informed approach for classifying psychotropic drugs that would be practically useful for prescribers, clinicians, and patients. PMID- 25453507 TI - Adolescents at risk: pain pills to heroin: part I. AB - Prescription pain medication has proliferated in the United States in the past 10 years, and opioid agents are the second most commonly abused substance in the United States. The opioid class comprises various prescription medications, including hydrocodone, as well as illicit substances, such as opium and heroin. The current article offers an example of one adolescent's history that began as weekend use of prescription opioid agents but expanded to daily use and physical dependence. Currently, a trend exists in which adolescents and young adults are moving from prescription opioid medication to heroin use due to increasing restrictions on prescription opioid agents. Nursing implications and web-based resources for teaching are also presented. PMID- 25453511 TI - Assessment of the air-soil partitioning of polycyclic aromatic hydrocarbons in a paddy field using a modified fugacity sampler. AB - Rice, one of the most widely cultivated crops, has received great attention in contaminant uptake from soil and air, especially for the special approaches used for its cultivation. The dry-wet alternation method can influence the air-soil partitioning of semivolatile organic compounds (SVOCs) in the paddy ecosystem. Here, we modified a fugacity sampler to investigate the air-surface in situ partitioning of ubiquitous polycyclic aromatic hydrocarbons (PAHs) at different growth stages in a suburban paddy field in South China. The canopy of rice can form a closed space, which acts like a chamber that can force the air under the canopy to equilibrate with the field surface. When we compared the fugacities calculated using a fugacity model of the partition coefficients to the measured fugacities, we observed similar trends in the variation, but significantly different values between different growing stages, especially during the flooding stages. However, the measured and calculated fugacity fractions were comparable when uncertainties in our calculations were considered, with the exception of the high molecular weight (HMW) PAHs. The measured fugacity fractions suggested that the HMW PAHs were also closed to equilibrium between the paddy field and atmosphere. The modified fugacity sampler provided a novel way of accurately determining the in situ air-soil partitioning of SVOCs in a wet paddy field. PMID- 25453510 TI - Mitochondrial oxidative stress as a novel therapeutic target to overcome intrinsic drug resistance in melanoma cell subpopulations. AB - Despite recent success in melanoma therapy, most patients with metastatic disease still undergo deadly progression. We have identified a novel mechanism of multidrug resistance allowing a small subpopulation of slow-cycling melanoma cells to survive based on elevated oxidative bioenergy metabolism. In this study, we asked whether such slow-cycling cells could be eliminated by co-treatment with the copper-chelator elesclomol. Elesclomol-copper complexes can cause oxidative stress by disruption of the mitochondrial respiration chain or by indirect non mitochondrial induction of reactive oxygen species. We have found that elesclomol effectively kills the slow-cycling subpopulation and prevents the selective enrichment for slow-cycling cells, which usually results after monotreatment. We hypothesize that elesclomol could overcome the multidrug resistance of slow cycling melanoma cells and prevent tumor repopulation in melanoma patients in future. PMID- 25453512 TI - Design, synthesis, biological evaluation, and molecular docking of novel benzopyran and phenylpyrazole derivatives as Akt inhibitors. AB - By inspiration of good Akt1 inhibitory and cytotoxic activity of our previously screened hits 1 and 2, a series of novel benzopyrans 3a-c, 4 and phenylpyrazoles 5a-c, 6a-b, and 7 were designed, synthesized, and biologically evaluated for their in vitro Akt1 inhibitory and cytotoxic activity. The results revealed that all of these compounds showed moderate-to-excellent antiproliferative effects against the tested cancer cell lines (i.e. HL-60, OVCAR, PC-3, and HepG2). Among them, compounds 3a and 3c exhibited preferable Akt1 inhibitory activities (IC(50) of 3a and 3c are 6.18 and 5.28 MUm, respectively), while compounds 4, 5a-c, 6a-b, and 7 only showed weak Akt1 inhibitory activities. Consequently, we used molecular docking and dynamic simulation to propose a mode of binding between Akt1 and the 3c compound. PMID- 25453513 TI - Green Tea Lowers Hepatic COX-2 and Prostaglandin E2 in Rats with Dietary Fat Induced Nonalcoholic Steatohepatitis. AB - Green tea extract (GTE) protects against nonalcoholic steatohepatitis (NASH) by decreasing hepatic steatosis and nuclear factor kappa B (NFkappaB) activation. We hypothesized that hypolipidemic and anti-inflammatory activities of GTE would protect against NASH by reducing cyclooxygenase-2 (COX-2), an NFkappaB-dependent enzyme, and prostaglandin E2 (PGE2) in a dietary fat-induced obese model. Male Wistar rats were fed a low-fat diet containing no GTE or a high-fat (HF) diet containing GTE at 0%, 1%, or 2% for 8 weeks. Insulin resistance and total hepatic fatty acids increased following HF feeding (P<.05) and these were normalized by GTE at 1-2%. GTE (1-2%) normalized hepatic malondialdehyde without affecting cytochrome P450 2E1 mRNA expression, which was otherwise increased by HF feeding. HF-mediated increases in hepatic COX-2 protein and activity as well as PGE2 concentrations were normalized by GTE (1-2%). COX-2 activity and PGE2 were correlated to each other, and to serum alanine aminotransferase (ALT) and hepatic NFkappaB-binding activity (P<.05; r=0.28-0.49). GTE attenuated HF-mediated increases in total hepatic n-6 and n-3, without affecting the n-6/n-3 ratio. GTE did not affect HF-mediated increases in n-6 in nonesterified fatty acid (NEFA) and phospholipid pools, whereas n-3 and n-6/n-3 in both pools were unaffected by GTE and HF feeding. GTE decreased total hepatic arachidonic acid without affecting HF-mediated increases in arachidonic acid in NEFA or phospholipid pools. Thus, GTE attenuates lipid peroxidation and PGE2 accumulation by decreasing COX-2 activity independent of arachidonic acid availability and supports an additional mechanism by which GTE protects against liver injury during NASH in an HF-feeding model. PMID- 25453514 TI - An ultrasound diagnostic aid in hand surgery: observation on a supernumerary muscle in the wrist. AB - The authors report on a case of dynamic compression of the ulnar nerve in the wrist by a supernumerary hypothenar muscle in a twenty-six-year-old female patient. For eight months, she had been suffering from acroparesthesias in the territory of the ulnar nerve with pain upon effort irradiating into the forearm. The initial clinical examination was rather non-conclusive and the electromyogram found no anomaly. Faced with this dynamic symptomatology, a provisional ultrasonography was performed, revealing a picture of apparent muscular appearance, confirmed on the MRI. Surgical exploration also confirmed the presence of this muscle located between the ulnar artery at the front and the ulnar nerve, which it was pressing against, at the back. It was a supernumerary fascicle of the flexor digiti minimi brevis for which was performed a complete surgical removal. At three months from neurolysis of the ulnar nerve and removal of the muscle, the preoperative symptoms had completely disappeared. This observation reminds us of the primordial role that imaging plays in detecting ulnar nerve compression at the wrist. Although the precision of an MRI as regards the description of supernumerary muscle of the wrist is not discussed, this case emphasizes the interest of ultrasonography. PMID- 25453515 TI - Acupuncture and immune function in chronic prostatitis/chronic pelvic pain syndrome: a randomized, controlled study. AB - OBJECTIVE: The immune system has been implicated as one mechanism underlying the benefits of acupuncture therapy. Evidence suggests that acupuncture can ameliorate symptoms of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), but the association between clinical response and the immune system has not been investigated. DESIGN/SETTING: We investigated 12 CP/CPPS patients participating in a prospective randomized clinical trial comparing acupuncture versus sham acupuncture for effects on cellular immunity. Blood samples were taken before the first needling and after the last of 20 treatment sessions (week 10). Patients also completed questionnaires examining their CP/CPPS symptoms and mood status at the baseline and end of study visits. RESULTS: At the end of study 8 of 12 participants (67%) were classified as treatment responders, four participants each from the acupuncture and sham groups. The acupuncture group averaged a 5% increase in natural killer cell levels compared to corresponding sham (-13%; p=0.03). Similarly, patients randomized to acupuncture reported a reduction in other white blood cell parameters examined, supporting the possibility that immunity might be important in the pathophysiology of CP/CPPS. CONCLUSIONS: The specific effect of acupuncture on CP/CPPS remains unclear. Further research is warranted to examine the mechanisms by which acupuncture therapy may improve clinical symptoms in patients with CP/CPPS. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00260637). PMID- 25453516 TI - A randomized clinical trial of the efficacy of applying a simple protocol of boiled Anethum Graveolens seeds on pain intensity and duration of labor stages. AB - OBJECTIVE: This study aimed to test the effects of boiled Anethum Graveolens seeds on pain intensity and duration of labor stages. METHODS: A randomized clinical trial was conducted on 153 eligible participants who had regular uterine contractions. Participants were allocated to either intervention or control group receiving boiled Anethum Graveolens seeds or routine care, respectively. Preparation of Anethum Graveolens boiled solution was as follows: 10g (two tablespoons) of seed in 100cc water boiled for 10min. After filtration, this solution used by intervention group only once after starting active phase (3-4cm of cervix dilatation). Participants were followed up to the delivery time. Data were analyzed using T, and Chi square tests. RESULTS: Findings showed that the length of the all stages of labor were significantly lower in intervention compared to control group in except for second stage in primiparous. The second stage of labor in primiparous participants in intervention group was shorter than control group, although the difference is not significant. Moreover, intervention group had a significantly better dilatation and effacement scores after 1, 2, 3 and 4h following the intervention compared to control group. CONCLUSION: Results supported the boiled Anethum Graveolens seeds as an effective way to progress of the labor. PMID- 25453518 TI - Activity of liver enzymes in multiple sclerosis patients with Hot-nature diet and co-supplemented hemp seed, evening primrose oils intervention. AB - BACKGROUND: It is unknown whether diets with a high dietary total antioxidant capacity (TAC) can modify oxidative stress, low-grade inflammation, or liver dysfunction, all of which are risk factors for multiple sclerosis disease. This study assesses alanine amino-transferase (ALT), aspartate-aminotransferase (AST) and gamma-glutamyl transferase (GGT) activities in MS patients treated with co supplemented hemp seed and evening primrose oils as well as Hot-nature diet and the therapeutic potential this intervention. METHODS AND MATERIALS: In this double blind, randomized trial, 100 MS patients with EDSS<6 were allocated into 3 groups: "group A", who received co-supplemented hemp seed and evening primrose oils with advised Hot-nature diet; "group B",who received olive oil; and "group C", who received the co-supplemented oils. Clinically, EDSS as well as serum level of liver enzymes (GGT, AST, and ALT) were assessed at baseline and after 6 months. RESULTS: Mean follow-up was 180+/-2.9 SD days (N=65, 23 M and 42 F aged 34.25+/-8.07 years with disease duration of 6.80+/-4.33 years). There was no significant difference in the study parameters at baseline. Serum levels of liver enzymes (GGT, AST, and ALT) were serially monitored. Intervention was associated with liver function alteration in three groups. Significance decreased in EDSS score and the levels of liver enzymes were found in groups A and C, whereas elevated serum liver enzymes and EDSS score were observed in group B after the intervention. CONCLUSION: Selecting foods according to their Total antioxidant capacity such as co-supplemented hemp seed and evening primrose oils with Hot nature diet affects antioxidant intake and can have beneficial effects on improving EDSS score and activity of liver enzymes in RRMS patients. PMID- 25453517 TI - Chinese herbal medicine formula Jieduhuayu granules improves cognitive and neurophysiological functions in patients with cirrhosis who have minimal hepatic encephalopathy: a randomized controlled trial. AB - BACKGROUND: Minimal hepatic encephalopathy (MHE) impairs patients' cognitive and neurophysiological functions. In this study, we investigated the effect of treatment-related improvement in cognitive and neurophysiological functions. METHODS: We measured psychometric performance by number connection tests part A (NCT-A), digit symbol test (DST), mini-mental state examination (MMSE) and event related potential P300 wave of 80 patients with cirrhosis who have minimal hepatic encephalopathy on inclusion into the study and 15 days later. They were randomly assigned in a 1:1:1:1 ratio to four groups, to receive treatment of Chinese herbal medicine formula (HMG) or lactulose (LG) or Chinese herbal medicine formula combined with lactulose (HMCLG) for 15 days (n=20) or no treatment (CG) (n=20). This study was not blind. RESULTS: The mean number of NCT A and MMSE scores improved significantly in patients in the HMG (0 day, 102.00+/ 24.49 for NCT-A, 18.55+/-2.89 for MMSE; 15 days, 78.30+/-22.55 for NCT-A, 24.20+/ 2.78 for MMSE) compared with patients in the CG after 15 days of follow-up (0 day, 103.00+/-24.98 for NCT-A, 17.90+/-2.99 for MMSE; 15 days, 95.65+/-24.34 for NCT-A, 18.85+/-3.12 for MMSE), P<0.05; the mean number of P300 latency (ms) and wave amplitude (MUV) improved significantly among patients in the HMG after 15 days of treatment (0 day, 341.90+/-14.04 for latency, 8.40+/-1.73 for wave amplitude; 15 days, 305.45+/-23.95 for latency, 13.00+/-3.80 for wave amplitude) compared with patients in the CG after 15 days of follow-up (0 day, 343.85+/ 14.88 for latency, 8.29+/-1.77 for wave amplitude; 15 days, 340.40+/-13.06 for latency, 8.50+/-1.82 for wave amplitude), P<0.05. Similar improvement were also found among patients in the LG and HMCLG; improvements among patients in the HMG were significantly greater than they were in the LG (P<0.05). Synergistic action were shown among patients in the HMCLG (P<0.05). CONCLUSION: Treatment with Chinese herbal medicine formula Jieduhuayu granules and lactulose may improve cognitive and neurophysiological functions in patients with cirrhosis who have MHE. Compared with lactulose alone, Chinese herbal medicine formula Jieduhuayu granules has higher efficacy of improving cognitive and neurophysiological functions in patients with cirrhosis who have MHE, and the two of them together show synergistic action. TRIAL REGISTRATION NUMBER: ACTRN12614000193673. PMID- 25453519 TI - Yoga leads to multiple physical improvements after stroke, a pilot study. AB - OBJECTIVE: To assess change in physical functioning (pain, range of motion (ROM), strength, and endurance) after 8 weeks of therapeutic-yoga. DESIGN: Planned analyses of data from a randomized pilot study of yoga after stroke. SETTING: University-based research laboratory. PARTICIPANTS: People with chronic stroke (N=47) randomized to therapeutic-yoga (n=37) or wait-list control (n=10). INTERVENTIONS: 16 sessions of therapeutic yoga (twice a week/8 weeks). Yoga was delivered in a standardized and progressive format with postures, breathing, and meditation, and relaxation in sitting, standing, and supine. MAIN MEASURES: Pain was assessed with the PEG, a 3-item functional measure of the interference of pain. ROM included neck and hip active and passive ROM measurements). Upper and lower extremity strength were assessed with the arm curl test and chair-to-stand test, respectively. Endurance was assessed with the 6-minute walk and modified 2 min step test. RESULTS: After a Bonferroni Correction, pain, neck ROM, hip passive ROM, upper extremity strength, and the 6-min walk scores all significantly improved after 8 weeks of engaging in yoga. No changes occurred in the wait-list control group. CONCLUSIONS: A group therapeutic-yoga intervention may improve multiple aspects of physical functioning after stroke. Such an intervention may be complementary to traditional rehabilitation. PMID- 25453520 TI - Anti-spastic effects of footbaths in post-stroke patients: a proof-of-principle study. AB - OBJECTIVES: To investigate whether a footbath inhibits spasticity in the hemiplegic lower limbs of post-stroke patients. DESIGN: Randomized, controlled study. SETTING: Rehabilitation education and research hospital. INTERVENTIONS: Twenty-two post-stroke patients were randomly allocated to control or experimental groups. After relaxing in a supine posture for 30min, the experimental group subject's legs were immersed in 41 degrees C water below the knee joint for 15min, while the control group remained in a resting posture. MAIN OUTCOME MEASURES: Modified Ashworth Scale (MAS) scores of the affected triceps surae muscle and F-wave parameters (i.e., F-wave amplitude, F/M ratio, and F-wave persistence) were recorded before, immediately after, and 30min after each intervention. Physiological parameters were simultaneously monitored to determine the thermo-therapeutic mechanisms and side effects of footbath usage. RESULTS: At the time immediately after the intervention, F-wave amplitudes decreased significantly in the experimental group, compared to the control group (p<0.01, difference: -106.8; 95% CI; -181.58 to -32.09). F-wave amplitudes decreased significantly after 30-min intervention in the experimental group, with a total reduction of 161.2MUV being recorded compared to 8.8MUV increase in the control group (p<0.01, difference: -170.0; 95% CI; -252.73 to -87.33). There were also significant differences between the experimental and control group for both F/M ratio and F-wave persistence, immediately after and 30min after the intervention. Further, there were significant differences between the experimental and control group for the MAS scores immediately after the intervention (p<0.05, difference: 0.72; 95% CI; -1.262 to -0.193), and 30min after the intervention (p<0.05, difference: -0.73; 95% CI; -1.162 to -0.293). CONCLUSION: These findings demonstrate that the use of footbaths is an effective non-pharmacological anti spastic treatment for use in stroke rehabilitation. PMID- 25453521 TI - Effect of gefitinib plus Chinese herbal medicine (CHM) in patients with advanced non-small-cell lung cancer: a retrospective case-control study. AB - BACKGROUND: Some patients with non-small-cell lung cancer (NSCLC) respond well to the EGFR tyrosine kinase inhibitor gefitinib. Chinese herbal medicine (CHM) was effective in improving the quality of life and prolonging overall survival in patient with NSCLC. We aim to determine whether gefitinib plus CHM could prolong the progression-free survival (PFS) or median survival time (MST) in patients with NSCLC than gefitinib alone. METHODS: We retrospectively analyzed 159 non small-cell lung cancer patients with the method of retrospective case-control study, matching factors included gender, age categories (30-39,40-49,50-59,60 69,70-79), pathological stage (IIIB or IV), smoking status (never: <100 lifetime cigarettes, or ever: >=100 lifetime cigarettes), pathology, and performance status. Among the 159 patients, 100 patients treated with gefitinib (250mg/day orally) plus CHM ("Fuzheng Kang'ai" decoction, a Chinese herbal medicine, 250ml/bid/day orally), 59 patients treated with gefitinib (250mg/day orally) only. PFS and MST were analyzed for the whole population. RESULTS: 58 pairs were matched successfully. 1 patient (treated with gefitinib) with the age of 27 years failed to be matched. Progression-free survival was significantly longer in patients treated with gefitinib plus CHM than with gefitinib: median PFS was 13.1 months (95% CI 6.50-19.70) with gefitinib plus CHM versus 11.43 months (95% CI 7.95-14.91) with gefitinib (log-rank P=0.013). Median overall survival was longer with gefitinib plus CHM than with gefitinib: median MST was 22.83 months (95% CI 17.51-28.16) with gefitinib plus CHM versus 18.7 months (95% CI 16.83-20.57) with gefitinib (log-rank P=0.049). The most common adverse event was rash, the incidence in the gefitinib plus CHM group was 41.38% while in the gefitinib group was 24.14% (P=0.048). CONCLUSIONS: This case-control analysis suggested that treatment with gefitinib plus CHM prolonged PFS and MST compared with gefitinib in patients with NSCLC, and it is worthy of further study. PMID- 25453522 TI - Effectiveness of aromatherapy in decreasing maternal anxiety for a sick child undergoing infusion in a paediatric clinic. AB - OBJECTIVES: We examined whether aromatherapy involving inhalation of yuzu (Citrus ichangensis*Citrus reticulata) oil was effective in decreasing mothers' anxiety for her sick child receiving an infusion at a paediatric clinic. DESIGN: Controlled clinical trial. SETTING: Mothers of sick children who arrived at the hospital were asked to complete an anonymous questionnaire. After a doctor examined the child and confirmed the necessity for infusion, the mothers who agreed to participate in our study were allocated to an aromatherapy or a control group. INTERVENTIONS: A diffuser was filled with yuzu oil before the subjects entered the aromatherapy room. The mother was shown how to use the aromatherapy diffuser while the child was receiving an infusion in the same room. Fifteen minutes after entering the room, the mothers were asked to complete an another questionnaire. MAIN OUTCOME MEASURES: We measured the mother's anxiety with the state anxiety score from the State-Trait Anxiety Inventory. RESULTS: There were 60 subjects in the aromatherapy group and 61 in the control group. Both groups were well balanced in terms of demographic characteristics. Using analysis of variance, we demonstrated a significant difference in two-factor interactions between the control and aromatherapy groups. Maternal state anxiety was significantly lower in the aromatherapy than in the control group. CONCLUSIONS: Inhalation of yuzu oil was shown to decrease maternal anxiety for a sick child. A multicentre randomized controlled trial or double-blind study is necessary to obtain objective evidence of this benefit of aromatherapy. PMID- 25453523 TI - Effects of olfactory stimulation with rose and orange oil on prefrontal cortex activity. AB - OBJECTIVES: People have been aware of essential oils, which are derived from plants, for a long time. Recently, we have become interested in physiological and subjective effects of daily exposure to essential oils. The primary aim of the present study was to clarify effects of olfactory stimulation with rose or orange oil on prefrontal cortex activity; subjective evaluations of relaxation were also determined. SETTING AND INTERVENTIONS: Subjects were exposed for 90s to air impregnated with either rose or orange essential oil. As a control, subjects wore the same device but inhaled only unimpregnated air. The three stimuli were randomly presented to each subject. MAIN OUTCOME MEASURES: Physiological effects were determined by near-infrared time-resolved spectroscopy and a modified semantic differential approach was used to determine subjective evaluations. RESULTS: The study participants were 20 female university students (mean age 22.5+/-1.6 years). Olfactory stimulation by rose or orange oil induced: (1) a significant decrease in oxyhemoglobin concentration in the right prefrontal cortex and (2) an increase in "comfortable," "relaxed," and "natural" feelings. CONCLUSION: These findings indicate that olfactory stimulation by rose or orange oil induces physiological and psychological relaxation. PMID- 25453524 TI - Wet-cupping removes oxidants and decreases oxidative stress. AB - OBJECTIVES: Wet-cupping therapy is one of the oldest known medical techniques. Although it is widely used in various conditions such as acute?chronic inflammation, infectious diseases, and immune system disorders, its mechanism of action is not fully known. In this study, we investigated the oxidative status as the first step to elucidate possible mechanisms of action of wet cupping. MATERIAL AND METHODS: Wet cupping therapy is implemented to 31 healthy volunteers. Venous blood samples and Wet cupping blood samples were taken concurrently. Serum nitricoxide, malondialdehyde levels and activity of superoxide dismutase and myeloperoxidase were measured spectrophotometrically. RESULTS: Wet cupping blood had higher activity of myeloperoxidase, lower activity of superoxide dismutase, higher levels of malondialdehyde and nitricoxide compared to the venous blood. CONCLUSION: Wet cupping removes oxidants and decreases oxidative stress. PMID- 25453525 TI - Effect of Yeonryeonggobon-dan (YRGBD), an herbal complex, on glycemic control in patients with Type 2 diabetes mellitus: a case series. AB - INTRODUCTION: Diabetes mellitus has significant effects on the human body. Recently, herbal medicines have received attention as complementary anti-diabetic agents on the basis of the results of several experimental studies. We present a series of 38 cases that demonstrate the positive effect of Yeonryeonggobon-dan (YRGBD), an herbal complex, in lowering blood sugar levels in patients with uncontrolled type 2 diabetes mellitus. METHODS: We reviewed the medical records of 38 patients treated with YRGBD. The types and doses of other hypoglycemic agents administered to the patients remained unchanged during treatment with YRGBD. RESULTS: After YRGBD therapy, the glycated haemoglobin level decreased from 76.16+/-19.90mmol/mol (9.11+/-1.82%) to 51.21+/-8.82mmol/mol (6.84+/-0.81%). There was a statistically significant difference between the glycated haemoglobin levels measured before and after treatment (paired t test, p<0.001). DISCUSSION: In the present study, we show the clinical effects of YRGBD on blood sugar control in patients with type 2 diabetes mellitus. Further clinical studies investigating the effects of YRGBD are needed. PMID- 25453526 TI - A tongue's tale - a case report of traditional Chinese medicine integration in the cardiology department. AB - The purpose of this case study is to provide a unique perspective on the integration of traditional Chinese medicine (TCM) in an acute care hospital setting. This case report tells the story of a patient who was hospitalized in the cardiac intensive care unit and received both western and TCM treatments. The patient's medical narrative is illustrated using pictures of her tongue that were taken along the course of her hospitalization. Analysis of the medical file, and each picture provide in-depth understanding of her medical condition from both western and TCM perspectives respectively. PMID- 25453527 TI - Use of complementary and alternative medicine across the childbirth spectrum in China. AB - BACKGROUND: Over the last decade, complementary and alternative medicine (CAM) has been widely used in maternity practice all over the world. Women from different cultural backgrounds prefer the use of specific CAM modalities. OBJECTIVE: The objectives of this study were to explore the use of CAM, the types of CAM practitioners consulted, and perceptions of the efficacy of CAM among a sample of Chinese postpartum women. The study's second objective was to investigate common patterns of CAM provided and the reasons for a CAM recommendation to childbearing women, from the perspective of obstetric staff. METHODS: This cross-sectional survey was undertaken at a university-affiliated general hospital and a maternity and child health hospital in Guangzhou, China. Patients were approached from both the postnatal wards and the postnatal outpatient departments, and healthcare professionals were obstetric staff, including doctors, midwives and nurses who work in the department of obstetrics. RESULTS: A total of 306 patients and 225 obstetric staff completed the questionnaire. The mean age of these patients and obstetric staff was 29.28 (SD 4.31), and 31.01 (SD 6.97) years old, respectively. Questionnaire data revealed the prevalence of CAM use among patients was 42.8%. Common types of CAM used and provided by the studied hospitals include acupressure (43.5%), massage therapy (32.0%), reflexology (30.2%), acupuncture (23.5%), and herbal medicine (20.0%). Most Chinese women used CAM therapies during the postnatal period (30.9%). These women mainly used CAM for pain relief (22.2%) and relaxation (18.3%). The most common reasons for health professionals to recommend CAM to patients, were patient demand (81.3%) and CAM's proven efficacy (81.3%). CONCLUSIONS: In order to communicate effectively about CAM, health professionals should undertake continuing professional development on updated perspectives of CAM use in obstetrics, and equip themselves with updated knowledge about the evidence-base for CAM, in order to provide efficient and qualified care to potential CAM users. PMID- 25453528 TI - Credibility of a comparative sham control intervention for Craniosacral Therapy in patients with chronic neck pain. AB - OBJECTIVES: Determining efficacy in complementary medicine research requires valid placebo/sham control groups that are credible to patients and ensure successful blinding. Within the scope of this study, a light touch sham-control intervention for trials of Craniosacral Therapy (CST) was developed and tested for its credibility. METHODS: Patients of a randomized controlled trial on chronic non-specific neck pain (NCT01526447) obtained the Credibility/Expectancy Questionnaire and the Helping Alliance/Satisfaction Questionnaire. Treatment and sham group respectively received 8 weekly sessions of CST or light touch. Data without (N=50) and with multiple imputation (N=54) were analyzed separately using logistic regression models. Adjusted odds ratios (AOR) and 95% confidence intervals (CI) were calculated to assess whether group outcome could be predicted from patients' credibility ratings. An additional t-test for analysis of the overall compliance/attendance was conducted. RESULTS: Patients' ratings of treatment expectancy, credibility and therapeutic alliance were not found to have significant power for classifying patients into CST or sham group (p>=.05). Only satisfaction with treatment revealed a significant impact (AOR: 6.83; 95% CI: [1.54|30.24]; p=.011) in the non-imputed analysis, but not in the multiple imputation analysis (AOR: 4.09; 95% CI: [0.94|17.76]; p=.060). Compliance of both groups was not significantly different (p>.05) as were reasons for non attendance. No serious adverse events were reported. CONCLUSIONS: Patients' expectancy, credibility and therapeutic alliance did not appear to affect study outcomes, blinding patients to group allocation was possible, and sham intervention was tolerable and safe. The design can therefore be recommended as control for non-specific treatment effects in future CST clinical trials. PMID- 25453529 TI - Rhubarb root and rhizome-based Chinese herbal prescriptions for acute ischemic stroke: a systematic review and meta-analysis. AB - BACKGROUND: Traditional Chinese Medicine has been using in stroke victims for thousands of years, and the rhubarb root and rhizome (RRR)-based Chinese herbal prescription is one of the principle treatments for stroke. The objective of this study is to systematically assess the clinical efficacy and safety of RRR-based prescriptions for acute ischemic stroke. METHODS: A systematic literature search in six databases was performed to identify randomized controlled trials (RCTs), which compared RRR-based prescriptions with western conventional medicine (WCM) for acute ischemic stroke. The methodological quality of RCTs was assessed independently based on the 12 criteria recommended by the Cochrane Back Review Group. RESULTS: A total of 968 participants were included in 12 eligible studies. All trials were deemed to have high a risk of bias. RRR-based prescriptions have a significant effect on the improvement of the clinical efficacy rate (n=10), Barthel Index scores (n=5), National Institutes of Health Stroke Scale scores (n=2), Glasgow Coma Scale scores (n=1), and neurological deficit scores (n=5) when compared with WCM controls (p<0.05 or p<0.01). Six trials reported that there were no adverse events, while no mention of adverse effect monitoring was reported in the other 6 studies. CONCLUSIONS: Despite the apparently positive findings, it is premature to recommend the routine use of RRR-based prescriptions for acute ischemic stroke because methodological flaws undermine the strength of our findings. However, this work identifies an area, which is worthy of improvement and development for further research. Larger sample-sizes and rigorously designed RCTs are required in the future. PMID- 25453530 TI - Benign Metastasizing Leiomyomatosis Presenting as Giant Pleural Mass Without Pulmonary Involvement. PMID- 25453531 TI - Fixed-altitude stair-climbing test replacing the conventional symptom-limited test. A pilot study. AB - INTRODUCTION: The objective of this study was to investigate whether a patient's maximum capacity is comparable in 2 different stair-climbing tests, allowing the simplest to be used in clinical practice. METHOD: Prospective, observational study of repeated measures on 33 consecutive patients scheduled for lung resection. Stair-climbing tests were: the standard test (climb to 27 m) and the alternative fixed-altitude test (climb to 12 m). In both cases, heart rate and oxygen saturation were monitored before and after the test. The power output of stair-climbing for each test (Watt1 for the standard and Watt2 for the fixed altitude test) was calculated using the following equation: Power (watt)=weight (kg)*9.8*height (m)/time (sec). Concordance between tests was evaluated using a regression model and the residuals were plotted against Watt1. Finally, power output values were analyzed using a Bland-Altman plot. RESULTS: Twenty-one male and 12 female patients (mean age 63.2+/-11.2) completed both tests. Only 12 patients finished the standard test, while all finished the fixed-altitude test. Mean power output values were Watt1: 184.1+/-65 and Watt2: 214.5+/-75.1. The coefficient of determination (R(2)) in the linear regression was 0.67. No fixed bias was detected after plotting the residuals. The Bland-Altman plot showed that 32 out of 33 values were within 2 standard deviations of the differences between methods. CONCLUSIONS: The results of this study show a reasonable level of concordance between both stair-climbing tests. The standard test can be replaced by the fixed-altitude test up to 12 m. PMID- 25453532 TI - Depression after traumatic brain injury: a biopsychosocial cultural perspective. AB - There are several challenges in diagnosing and treating mental illness amongst South Asians. Often times, formulating a patient's case presentation cannot adequately be accomplished strictly using a biopsychosocial model. The cultural components play an imperative role in explaining certain psychiatric symptoms and can guide treatment. With the growing population of immigrants coming to the United States, many of which require treatment for mental illness, it is essential that clinicians be cognizant in incorporating cultural perspectives when treating such patients. The authors describe the case of a 24-year old South Asian male who suffered an exacerbation of a depressive syndrome after a traumatic brain injury. Using a biopsychosocial cultural approach, this case highlights how South Asian cultural values can contribute to and incite psychiatric symptoms while simultaneously providing protective drivers for treatment outcomes. PMID- 25453533 TI - The 'snake' man: ophidianthropy in a case of schizophrenia, along with literature review. AB - Clinical lycanthropy is a rare form of reverse intermetamorphosis; intermatamorphosis being one of the delusional misidentification syndromes, in which patients believe that they are undergoing transformation or have transformed into a non-human animal. Psychiatric diseases commonly associated with it are schizophrenia, affective disorders, substance use, personality disorders and general medical conditions. Here we report the unique case of an ophidianthropy along with other psychopathologies in a patient of schizophrenia. The different neurochemicals associated with lycanthropy are also discussed. PMID- 25453534 TI - Comparative assessment of short-term adverse events in acute heart failure with cystatin C and other estimates of renal function: results from the ASCEND-HF trial. AB - OBJECTIVES: The purpose of this study was to investigate the predictive values of baseline and changes in cystatin C (CysC) and its derived equations for short term adverse outcomes and the effect of nesiritide therapy on CysC in acute decompensated heart failure (ADHF). BACKGROUND: Newer renal biomarkers or their derived estimates of renal function have demonstrated long-term prognostic value in chronic heart failure. METHODS: CysC levels were measured in sequential plasma samples from 811 subjects with ADHF who were enrolled in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) biomarker sub-study (randomized to nesiritide therapy vs. placebo), and followed for all-cause death (180 days) and recurrent hospital stay (30 days). RESULTS: Median CysC levels were 1.49 (interquartile range [IQR]: 1.20 to 1.96) mg/l at baseline, 1.56 (IQR: 1.28 to 2.13) mg/l at 48 to 72 h, and 1.58 (IQR: 1.24 to 2.11) mg/l at 30 days. Higher baseline (but not follow-up) CysC levels were associated with increased risk of 30-day adverse events and less improvement in dyspnea after 24 h as well as 180-day mortality, although not incremental to blood urea nitrogen. Worsening renal function (defined as a 0.3 mg/l increase in CysC) occurred in 161 of 701 (23%) patients, but it was not predictive of adverse events. Changes in CysC levels were similar between the nesiritide and placebo groups. CONCLUSIONS: Our findings confirmed the prognostic value of baseline CysC levels in the setting of ADHF. However, worsening renal function based on CysC rise was not predictive of adverse events. Nesiritide did not worsen renal function compared with placebo. PMID- 25453535 TI - The diastolic pulmonary gradient does not predict survival in patients with pulmonary hypertension due to left heart disease. AB - OBJECTIVES: This study sought to evaluate if diastolic pulmonary gradient (DPG) can predict survival in patients with pulmonary hypertension due to left heart disease (PH-LHD). BACKGROUND: Patients with combined post- and pre-capillary PH LHD have worse prognosis than those with passive pulmonary hypertension. The transpulmonary gradient (TPG) and pulmonary vascular resistance (PVR) have commonly been used to identify high-risk patients. However, these parameters have significant shortcomings and do not always correlate with pulmonary vasculature remodeling. Recently, it has been suggested that DPG may be better a marker, yet its prognostic ability in patients with cardiomyopathy has not been fully assessed. METHODS: A retrospective cohort of 1,236 patients evaluated for unexplained cardiomyopathy at Johns Hopkins Hospital was studied. All patients underwent right heart catheterization and were followed until death, cardiac transplantation, or the end of the study period (mean time 4.4 years). The relationships between DPG, TPG, or PVR and survival in subjects with PH-LHD (n = 469) were evaluated with Cox proportional hazards regression and Kaplan-Meier analyses. RESULTS: DPG was not significantly associated with mortality (hazard ratio [HR]: 1.02, p = 0.10) in PH-LHD whereas elevated TPG and PVR predicted death (HR: 1.02, p = 0.046; and HR: 1.11, p = 0.002, respectively). Similarly, DPG did not differentiate survivors from non-survivors at any selected cut points including a DPG of 7 mm Hg. CONCLUSIONS: In this retrospective study of patients with cardiomyopathy and PH-LHD, an elevated DPG was not associated with worse survival. PMID- 25453537 TI - Characterization of pulmonary hypertension in heart failure using the diastolic pressure gradient: limitations of a solitary measurement. PMID- 25453536 TI - Safety and tolerability of omecamtiv mecarbil during exercise in patients with ischemic cardiomyopathy and angina. AB - OBJECTIVES: The goal of this study was to assess the safety and tolerability of omecamtiv mecarbil treatment during symptom-limited exercise in patients with ischemic cardiomyopathy and angina. These patients may have increased vulnerability to prolongation of the systolic ejection time. BACKGROUND: Omecamtiv mecarbil is a selective cardiac myosin activator that augments cardiac contractility in patients with systolic heart failure through a dose-dependent increase in systolic ejection time. METHODS: In this double-blind, placebo controlled study, patients with chronic heart failure were randomized 2:1 to receive omecamtiv mecarbil or placebo in 2 sequential cohorts of escalating doses designed to achieve plasma concentrations previously shown to increase systolic function. Patients underwent 2 symptom-limited exercise treadmill tests (ETTs) at baseline (ETT1 and ETT2) and again before the end of a 20-h infusion of omecamtiv mecarbil (ETT3). RESULTS: The primary pre-defined safety endpoint (i.e., the proportion of patients who stopped ETT3 because of angina at a stage earlier than baseline) was observed in 1 patient receiving placebo and none receiving omecamtiv mecarbil. No dose-dependent differences emerged in the proportion of patients stopping ETT3 for any reason or in the pattern of adverse events. CONCLUSIONS: Doses of omecamtiv mecarbil producing plasma concentrations previously shown to increase systolic function were well tolerated during exercise in these study patients with ischemic cardiomyopathy and angina. There was no indication that treatment increased the likelihood of myocardial ischemia in this high-risk population. (Pharmacokinetics [PK] and Tolerability of Intravenous [IV] and Oral CK-1827452 in Patients With Ischemic Cardiomyopathy and Angina; NCT00682565). PMID- 25453538 TI - Patient characteristics associated with multiple pharmacy use in the U.S. population: Findings from the Medical Expenditure Panel Survey. AB - BACKGROUND: Multiple pharmacy use (MPU) is an important safety and quality issue, as it results in fragmented patient care. However, few studies have examined patient characteristics predicting the use of multiple pharmacies, and the findings have been inconsistent. OBJECTIVES: To identify patient characteristics associated with MPU using national data. METHODS: Data were obtained from the 2011 U.S. Medical Expenditure Panel Survey. The dependent variable was MPU, or the use of more than one pharmacy. The Andersen Behavioral Model of Health Service Use was used to guide the selection of independent variables, which were categorized as predisposing, enabling, and medical need related characteristics. Multivariable logistic regression analysis was conducted to identify the relationships between predisposing, enabling, and need variables and MPU in a hierarchical fashion. Point estimates were weighted to the U.S. non institutionalized population, and to adjust standard errors to account for the complex survey design. RESULTS: MPU was common, with a national prevalence of 41.3%. Individuals aged 40-64 and adults 65 and older were significantly less likely to use multiple pharmacies as patients aged 18-39 years (40-64 years OR: 0.67, CI: 0.58-0.77; >=65 years OR: 0.49, CI: 0.41-0.58). Females were significantly more likely to use multiple pharmacies than males (OR: 1.16, CI: 1.05-1.29). Individuals lacking health insurance were more likely to use multiple pharmacies as individuals with private health insurance (OR: 1.42, CI: 1.16 1.73); in contrast, individuals having drug insurance were more likely to use multiple pharmacies (OR: 1.25, CI: 1.06-1.47) relative to those without drug insurance. Any mail order use was the strongest predictor of MPU (OR: 6.94, CI: 5.90-8.18). CONCLUSIONS: Pharmacists and other health care providers need to be aware that their patients may be using multiple pharmacies, especially younger patients, those lacking access to health insurance, or those using mail order pharmacies. The findings from this study can be used to identify patients that may need additional monitoring to ensure safe and appropriate drug therapy, and has important implications as health care continues to shift toward performance based reimbursement and quality ratings. PMID- 25453540 TI - Effects of ventilator vs manual hyperinflation in adults receiving mechanical ventilation: a systematic review of randomised clinical trials. AB - BACKGROUND: Ventilator hyperinflation (VHI) and manual hyperinflation (MHI) are thought to improve secretion clearance, atelectasis and oxygenation in adults receiving mechanical ventilation. However, to the authors' knowledge, a systematic review of their relative effectiveness has not been undertaken previously. OBJECTIVE: To determine whether VHI is more effective than MHI for the improvement of clinical outcomes in adults receiving mechanical ventilation. DATA SOURCES: The electronic databases PubMed, Cochrane Library, CINHAL Plus, Wiley Online Library, ScienceDirect and PEDro were searched from January 1993 until August 2013. OpenGrey, the metaRegister of Controlled Trials (mRCT) and the reference lists of all potentially relevant studies were also searched. STUDY ELIGIBILITY CRITERIA: Full English reports of randomised clinical trials comparing at least one effect of VHI and MHI in adults receiving mechanical ventilation. STUDY SYNTHESIS AND APPRAISAL: Included studies were appraised using the Cochrane risk of bias tool. The findings were synthesised using a purely qualitative approach. RESULTS: All four included studies reported no significant differences in sputum wet weight, dynamic and static pulmonary compliance, oxygenation and cardiovascular stability between VHI and MHI. LIMITATIONS: All of the included studies had considerable limitations related to the protocols, equipment, participants and outcome measures. Furthermore, the overall risk of bias was judged to be high for three studies and unclear for one study. CONCLUSION: Only four studies, all of which had a high or unclear risk of bias and significant additional limitations, have compared the effects of VHI and MHI in adults receiving mechanical ventilation. As such, further research in this area is clearly warranted. PMID- 25453539 TI - Development of Patient-reported Outcomes Measure of Pharmaceutical Therapy for Quality of Life (PROMPT-QoL): A novel instrument for medication management. AB - BACKGROUND: Medicines can affect a patient's health-related quality of life (HRQoL), but there exists no standardized HRQoL measure for medication management. OBJECTIVES: To develop the new HRQoL instrument "Patient-reported Outcomes Measure of Pharmaceutical Therapy for Quality of Life" (PROMPT-QoL), and to evaluate its content validity and preliminary psychometrics using a Rasch model. METHODS: The PROMPT-QoL questionnaire was developed through the concept review, item generation, cognitive interviews, and initial psychometric evaluation. Its first draft was initially tested by Round-1 interviews of 120 adult outpatients taking their medicines at least three months continuously. The final draft with 43 items was then constructed and checked by 10 physicians and 5 pharmacists for the questionnaire importance and content validity. Round-2 interviews in six patient groups with 10 patients of each were conducted to elicit patients' understanding of the questionnaire and assess preliminary psychometrics using the Rasch analysis, including fit statistics, person and item reliabilities. RESULTS: The 43-item PROMPT-QoL comprised 10 domains: General Attitude toward Medication Use, Medicine Information, Disease Information, Medicine Effectiveness, Impacts of Medicines and Side-effects, Psychological Impacts of Medication Use, Convenience, Availability and Accessibility, Therapeutic Relationship with Healthcare Providers, and Overall QoL. Based on the patient interviews and expert review, the questionnaire was considered important, useful, and comprehensive. All items and domains yielded content validity indexes above the acceptable values of 0.80 and 0.90, respectively. In Round 2, thirty nine problems identified in Group 1 were reduced to two issues in Group 6 after amendments. The Rasch analysis revealed eight items were misfit and two domains were reliable for both personal and item aspects (Medicine Information and Psychological Impacts of Medication Use). CONCLUSION: The newly developed PROMPT QoL has favorable content validity and appropriate preliminary results. Further studies in large patient groups are required to test its complete psychometric properties. PMID- 25453542 TI - Increase in body mass index from normal weight to overweight in a cross-sectional sample of healthy research volunteers. AB - Current literature provides limited information about healthy volunteers serving as controls for biomedical research. This study describes trends in body mass index (BMI), a ratio of weight to height (kilograms per square meter), of the population of healthy volunteers at the National Institutes of Health Clinical Center (NIH CC) and compares these trends to a nationally representative sample, as reported by the National Health and Nutrition Examination Survey. We hypothesized that BMI trends at the NIH CC would follow those of the US population. This cross-sectional study examined the BMI of healthy volunteers at the NIH CC from 1976 to 1980, 1981 to 1987, 1988 to 1994, 1995 to 1998 and for all subsequent two-year periods onward until 2012. Study data were extracted from the NIH Biomedical Translational Research Information System. Subjects were selected based on a discharge code of "volunteer." Descriptive statistics of volunteers at the NIH CC were calculated for height, weight, age-adjusted BMI, age, and sex, and associations between categorical variables were analyzed using the chi2 test. Differences between BMI categories or periods for continuous independent variables were assessed using Kruskal-Wallis and post hoc Tamhane T2 tests. The 13 898 healthy volunteers with median age of 34 years were 53% female and primarily non-Hispanic whites. Mean BMI was within the normal category from 1976 to 1987. From 1988 on, mean BMI fluctuated but increased overall. The BMI of healthy volunteers at the NIH CC appears to follow national trends as described by National Health and Nutrition Examination Survey data of increasing body weight during the past three decades followed by a recent plateau. PMID- 25453541 TI - Consumption of a high glycemic load but not a high glycemic index diet is marginally associated with oxidative stress in young women. AB - Research studies have suggested that chronic consumption of high glycemic index foods may lead to chronically high oxidative stress. This is important because oxidative stress is suspected to be an early event in the etiology of many disease processes. We hypothesized that dietary glycemic index and glycemic load were positively associated with oxidative stress assessed by plasma F2 isoprostanes in healthy, premenopausal women (body mass index [BMI] = 24.7 +/- 4.8 kg/m(2) and age 25.3 +/- 3.5 years, mean +/- SD). We measured plasma F2 isoprostanes in 306 healthy premenopausal women at the baseline visit for the Women In Steady Exercise Research study, using gas chromatography-mass spectrometry. Dietary glycemic index and load were calculated from the National Cancer Institute Diet History Questionnaire, and participants were divided into quartiles of dietary glycemic index and of glycemic load. Plasma F2-isoprostanes were compared across quartile groups of dietary glycemic index and glycemic load using linear regression models. Plasma F2-isoprostanes (pg/mL) increased with quartile of glycemic load (test for linear trend, P = .033), and also increased with quartile of glycemic index in participants with BMI >= 25 (P = .035) but not in those with BMI <25 (P = .924). After adjustment for BMI, alcohol consumption and total energy intake, both these positive trends remained marginally significant (P = .123 for quartiles of glycemic index and P = .065 for quartiles of glycemic load). PMID- 25453544 TI - The most cited and downloaded papers in Epilepsy & behavior over its first 15 years. PMID- 25453543 TI - Epigallocatechin gallate prevents inflammation by reducing macrophage infiltration and inhibiting tumor necrosis factor-alpha signaling in the pancreas of rats on a high-fat diet. AB - In this study, we hypothesized that epigallocatechin gallate (EGCG) would suppress inflammation in the pancreas, and thus, we investigated the effects that EGCG administration had in the pancreas of rats fed a high-fat diet (HFD). To test our hypothesis, 30 male Sprague-Dawley rats were divided into 2 groups: normal diet (control) group and HFD group. When there was a significant difference in body weight between the 2 groups (P < .05), the HFD group was further divided into 2 subgroups: the HFD group (HFD, n = 10, 16 weeks) and the EGCG group (HFD + 3.2 g/kg EGCG, n = 10, 16 weeks). Metabolite levels and the expression of inflammatory markers (tumor necrosis factor alpha [TNF-alpha], interleukin 6 [IL-6], and toll-like receptor 4) were measured using standard biochemical techniques. Insulin secretion and pancreatic histology were also evaluated. Epigallocatechin gallate significantly decreased fasting insulin levels as well as the homeostasis model assessment-insulin resistance index. In the HFD group, the average glucose infusion rate and the TNF-alpha and IL-6 levels increased, whereas toll-like receptor 4 and TNF receptor-associated factor 6 did not. A pathologic analysis of pancreatic tissue revealed an increase in inflammatory TNF-alpha and infiltrating CD68+ macrophages in the islets of the HFD rats, but rarely is this observed in the in the HFD + EGCG rats. Overall, these data suggest that EGCG suppresses inflammation, partially reverses metabolic abnormalities, and ultimately increases insulin sensitivity in the pancreas of HFD rats. PMID- 25453545 TI - Comments on Beyenburg S et al. Anxiety in patients with epilepsy: systematic review and suggestions for clinical management. Epilepsy & behavior 2005;7:161 171. PMID- 25453546 TI - Comments on Ortinski P et al. Cognitive side effects of antiepileptic drugs. Epilepsy & behavior 2004;5(Suppl. 1):S60-65. PMID- 25453547 TI - Comments on Knake S, et al. Status epilepticus: a critical review. Epilepsy & behavior 2009;15:10-14. PMID- 25453549 TI - Some thoughts on 15 years of Epilepsy & behavior. PMID- 25453550 TI - 15th anniversary of Epilepsy & behavior: Challenging the complexities of epilepsies through real transdisciplinary research. PMID- 25453551 TI - Epilepsy & behavior: congratulations on your "sweet fifteen". PMID- 25453552 TI - Epilepsy & behavior: 15th anniversary research on omega-3 fatty acids for epilepsy. PMID- 25453554 TI - Epilepsy comorbidities: into the limelight. PMID- 25453555 TI - Significance of Epilepsy & behavior: my personal experience and views. PMID- 25453556 TI - Crimpy enables discrimination of presynaptic and postsynaptic pools of a BMP at the Drosophila neuromuscular junction. AB - Distinct pools of the bone morphogenetic protein (BMP) Glass bottom boat (Gbb) control structure and function of the Drosophila neuromuscular junction. Specifically, motoneuron-derived Gbb regulates baseline neurotransmitter release, whereas muscle-derived Gbb regulates neuromuscular junction growth. Yet how cells differentiate between these ligand pools is not known. Here we present evidence that the neuronal Gbb-binding protein Crimpy (Cmpy) permits discrimination of pre and postsynaptic ligand by serving sequential functions in Gbb signaling. Cmpy first delivers Gbb to dense core vesicles (DCVs) for activity-dependent release from presynaptic terminals. In the absence of Cmpy, Gbb is no longer associated with DCVs and is not released by activity. Electrophysiological analyses demonstrate that Cmpy promotes Gbb's proneurotransmission function. Surprisingly, the Cmpy ectodomain is itself released upon DCV exocytosis, arguing that Cmpy serves a second function in BMP signaling. In addition to trafficking Gbb to DCVs, we propose that Gbb/Cmpy corelease from presynaptic terminals defines a neuronal protransmission signal. PMID- 25453557 TI - Structural insights into the organization of the cavin membrane coat complex. AB - Caveolae are cell-surface membrane invaginations that play critical roles in cellular processes including signaling and membrane homeostasis. The cavin proteins, in cooperation with caveolins, are essential for caveola formation. Here we show that a minimal N-terminal domain of the cavins, termed HR1, is required and sufficient for their homo- and hetero-oligomerization. Crystal structures of the mouse cavin1 and zebrafish cavin4a HR1 domains reveal highly conserved trimeric coiled-coil architectures, with intersubunit interactions that determine the specificity of cavin-cavin interactions. The HR1 domain contains a basic surface patch that interacts with polyphosphoinositides and coordinates with additional membrane-binding sites within the cavin C terminus to facilitate membrane association and remodeling. Electron microscopy of purified cavins reveals the existence of large assemblies, composed of a repeating rod-like structural element, and we propose that these structures polymerize through membrane-coupled interactions to form the unique striations observed on the surface of caveolae in vivo. PMID- 25453558 TI - The Jak-STAT target Chinmo prevents sex transformation of adult stem cells in the Drosophila testis niche. AB - Local signals maintain adult stem cells in many tissues. Whether the sexual identity of adult stem cells must also be maintained was not known. In the adult Drosophila testis niche, local Jak-STAT signaling promotes somatic cyst stem cell (CySC) renewal through several effectors, including the putative transcription factor Chronologically inappropriate morphogenesis (Chinmo). Here, we find that Chinmo also prevents feminization of CySCs. Chinmo promotes expression of the canonical male sex determination factor DoublesexM (Dsx(M)) within CySCs and their progeny, and ectopic expression of DsxM in the CySC lineage partially rescues the chinmo sex transformation phenotype, placing Chinmo upstream of Dsx(M). The Dsx homolog DMRT1 prevents the male-to-female conversion of differentiated somatic cells in the adult mammalian testis, but its regulation is not well understood. Our work indicates that sex maintenance occurs in adult somatic stem cells and that this highly conserved process is governed by effectors of niche signals. PAPERCLIP: PMID- 25453559 TI - Abeta42 oligomers selectively disrupt neuronal calcium release. AB - Accumulation of amyloid-beta (Abeta) peptides correlates with aging and progression of Alzheimer's disease (AD). Abeta peptides, which cause early synaptic dysfunctions, spine loss, and memory deficits, also disturb intracellular Ca(2+) homeostasis. By cytosolic and endoplasmic reticulum Ca(2+) measurements, we here define the short-term effects of synthetic Abeta42 on neuronal Ca(2+) dynamics. When applied acutely at submicromolar concentration, as either oligomers or monomers, Abeta42 did not cause Ca(2+) release or Ca(2+) influx. Similarly, 1-hour treatment with Abeta42 modified neither the resting cytosolic Ca(2+) level nor the long-lasting Ca(2+) influx caused by KCl-induced depolarization. In contrast, Abeta42 oligomers, but not monomers, significantly altered Ca(2+) release from stores with opposite effects on inositol 1,4,5 trisphosphate (IP3)- and caffeine-induced Ca(2+) mobilization without alteration of the total store Ca(2+) content. Ca(2+) dysregulation by Abeta42 oligomers involves metabotropic glutamate receptor 5 and requires network activity and the intact exo-endocytotic machinery, being prevented by tetrodotoxin and tetanus toxin. These findings support the idea that Ca(2+) store dysfunction is directly involved in Abeta42 neurotoxicity and represents a potential therapeutic target in AD-like dementia. PMID- 25453560 TI - Total tau is increased, but phosphorylated tau not decreased, in cerebrospinal fluid in amyotrophic lateral sclerosis. AB - In amyotrophic lateral sclerosis (ALS), objective biomarkers are needed for early diagnosis and progression monitoring. Reduced phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) has recently been proposed to provide such a biomarker in ALS. Here, we aimed to scrutinize this notion, evaluating both p-tau and total tau (t-tau) in CSF of ALS patients and control subjects. CSF p-tau and t-tau levels were measured in 60 consecutive ALS patients and 120 control subjects without neurodegenerative disease, using an established specific enzyme-linked immunosorbent assay method. Contrary to recent reports, CSF p-tau was not significantly reduced in ALS patients compared with control subjects (p = 0.287). However, CSF t-tau was significantly increased (p < 0.001). Correspondingly, the ratio of p-tau to t-tau was significantly reduced in ALS (p < 0.001). The area under the curve demonstrated poor sensitivity and specificity for p-tau, but moderate sensitivity and specificity for t-tau and p-tau/t-tau ratio. Thus, CSF p tau by itself does not appear a suitable diagnostic biomarker for ALS, whereas CSF t-tau is a (probably unspecific) marker of the neuronal degeneration in ALS. PMID- 25453561 TI - Maintenance of youth-like processing protects against false memory in later adulthood. AB - Normal cognitive aging compromises the ability to form and retrieve associations among features of a memory episode. One indicator of this age-related deficit is older adults' difficulty in detecting and correctly rejecting new associations of familiar items. Comparing 28 younger and 30 older adults on a continuous recognition task with word pairs, we found that older adults whose activation patterns deviate less from the average pattern of younger adults while detecting repaired associations show the following: (1) higher overall memory and fewer false recognitions; (2) stronger functional connectivity of prefrontal regions with middle temporal and parahippocampal gyrus; and (3) higher recall and strategic categorical clustering in an independently assessed free recall task. Deviations from the average young-adult network reflected underactivation of frontoparietal regions instead of overactivation of regions not activated by younger adults. We conclude that maintenance of youth-like task-relevant activation patterns is critical for preserving memory functions in later adulthood. PMID- 25453562 TI - In vitro evaluation of the internal and marginal misfit of CAD/CAM zirconia copings. AB - STATEMENT OF PROBLEM: The constant updating of computer-aided design/computer aided manufacture (CAD/CAM) systems and the introduction of new systems confirm the need for scientific evidence on internal and marginal adaptation. PURPOSE: The purpose of this in vitro study was to measure and compare the degree of internal and marginal misfits of zirconia single-unit copings made by using 3 different CAD/CAM systems (Ceramill, Lava 3M, and Neoshape). MATERIAL AND METHODS: Twenty-four anatomic prefabricated abutments (Neodent) were used to fabricate zirconia copings in Ceramill (n=8), Lava (n=8), and Neoshape (n=8). All copings were cemented and cut with a precision cutting machine to obtain 5 surfaces (mesial, distal, buccal, palatal, and incisal) and angle regions (internal axiogingival and axioincisal angles). Measurements were obtained from images at a magnification of *100 and *200 made with a digital camera attached to an optical microscope and adapted with a measuring device. The data were statistically analyzed with the 2-way ANOVA and Tukey honestly significant difference tests (alpha=.05). RESULTS: In the internal misfit evaluation, the mean values observed for Ceramill, Lava, and Neoshape were palatal surface 76.5, 65.5, and 77.7 MUm (P=.003); angle regions 69.4, 68.6, and 74.5 MUm (P=.010); incisal surface 127.7, 97.2, and 182.2 MUm (P<.001); and overall mean 72.1, 69.4, and 76.4 MUm (P=.003). Significant differences were not found for mesial, distal, or buccal surfaces (P>.05). In the evaluation of marginal misfit (marginal discrepancy and absolute marginal discrepancy), the mean values found were 40.9 and 65.8 MUm for Ceramill, 34.2 and 70.0 MUm for Lava, and 39.3 and 74.5 MUm for Neoshape. No significant differences were found among the 3 systems (P>.05). CONCLUSIONS: Although the Lava system showed a significantly lower value of internal misfit than the Neoshape system, all systems showed clinically acceptable marginal misfit values. PMID- 25453563 TI - Experimental study on the use of spacer foils in two-step putty and wash impression procedures using silicone impression materials. AB - STATEMENT OF PROBLEM: The 2-step putty and wash impression technique is commonly used in fixed prosthodontics. However, cutting sluiceways to allow the light-body material to drain is time-consuming. A solution might be the use of a spacer foil. PURPOSE: The purpose of this study was to evaluate the influence of spacer foil on the margin reproduction and dimensional accuracy of 2-step putty and wash impressions. MATERIAL AND METHODS: Two methods of creating space for the wash material in a 2-step putty and wash impression were compared: the traditional cutout technique and a spacer foil. Eleven commercially available combinations of silicone impression materials were included in the study. The impressions and the cast production were carried out under standardized conditions. All casts were measured with a 3-dimensional (3D) coordinate measuring machine. Preparation margin reproduction and the diameters and spacing of the stone cast dies were measured (alpha=.05). RESULTS: The 2 methods showed significant differences (P<.05) in the reproduction of the preparation margins (complete reproduction cutout, 90% to 98%; foil, 74% to 91%). The use of a foil resulted in greater dimensional accuracy of the cast dies compared to the cutout technique. Cast dies from the cutout technique were significantly smaller than the metallic original cast (cutout median, 4.55 mm to 4.61 mm; foil median, 4.61 to 4.64). Spacing between the dies revealed only a few additional significant differences between the techniques. CONCLUSIONS: When spacer foils were used, dies were obtained that better corresponded to the original tooth. PMID- 25453564 TI - A clinical study relating CIELCH coordinates to the color dimensions of the 3D Master System in a Spanish population. AB - STATEMENT OF PROBLEM: The 3D-Master System comprises 26 physical shade tabs and intermediate shades. Determining the relationship among all the groups of lightness, chroma, and hue of the 3D-Master System (Vita Zahnfabrik) and the L*, C*, and h* coordinates is important, because according to the manufacturer, 2 Toothguide 3D-Master shades need to be mixed in a 50:50 ratio to create an intermediate shade. PURPOSE: The purpose of the study was to relate the lightness, chroma, and hue groups of the 3D-Master System with the polar coordinates of the CIELAB chromatic space, L*, C*, and h*, and to quantify the shades tabs and intermediate shades of the 3D-Master System according to color coordinates. MATERIAL AND METHODS: The middle third of the facial surface of a natural maxillary central incisor was measured with an Easyshade Compact spectrophotometer (Vita Zahnfabrik) in 1361 Spanish participants aged between 16 and 89 years. Natural tooth color was recorded in the 3D-Master nomenclature and in the CIE L*, C*, and h* coordinates system. The program used for the present descriptive statistical analysis of the results was SAS 9.1.3. RESULTS: In the L* variable, the minimum was found at 47.0 and the maximum at 91.3. In the C* variable, the minimum was found at 5.9 and the maximum at 49.8, while for h*, the minimum was 67.5 degrees and the maximum 112.0 degrees. CONCLUSIONS: Despite the limitations of this study, the 3D-Master System was found to be arranged according to L*, C*, and h* coordinates in groups of lightness, chroma, and hue. The corresponding groups of lightness, chroma, and hue can be estimated on the basis of L*, C*, and h* coordinates. PMID- 25453565 TI - Effect of surface treatments on the shear bond strength of luting cements to Y TZP ceramic. AB - STATEMENT OF PROBLEM: Because zirconia is a glass-free material, alternative surface treatments such as airborne-particle abrasion or silica coating should be used for long-term bonding. However, these surface treatments in combination with different bonding agents and luting cements have not yet been studied. PURPOSE: The purpose of the study was to evaluate the effect of surface treatments on the shear bond strength (SBS) of luting cements to Y-TZP ceramic. MATERIAL AND METHODS: Zirconia disks (N=240) were airborne-particle abraded with the following particles (n=48): 50 MUm Al2O3; 120 MUm Al2O3; 30 MUm silica-coated Al2O3 (Rocatec Soft); 120 MUm Al2O3+110 MUm silica-coated Al2O3 (Rocatec Plus); and Rocatec Plus. After silanization of the zirconia surface, composite resin disks were bonded with (n=12) RelyX Luting 2; RelyX ARC; RelyX U100; and Panavia F. The bonded specimens were thermocycled (10 000 cycles) and tested for SBS. Failure mode was determined with a stereomicroscope (*20). The morphology and elemental composition of airborne-particle abraded surfaces were evaluated with scanning electron microscopy (*500) and energy-dispersive x-ray spectroscopy (*50). RESULTS: Surface treatments, cements, and their interaction were significant (P<.001). For RelyX ARC, Rocatec Soft and Rocatec Plus provided the highest SBS. In general, surface treatments did not influence the SBS of RelyX U100 and Panavia F. Regardless of the cement, no significant difference was found between 50 MUm and 120 MUm Al2O3 particles, between Rocatec Soft and Rocatec Plus, or between Rocatec Plus and 120 MUm Al2O3 particles+Rocatec Plus. All groups showed adhesive failures. Different particle sizes provided differences in morphological patterns. The elemental composition comprised Al and Al/Si for alumina and silica abraded zirconia. CONCLUSIONS: Particle size did not influence the SBS of the groups abraded exclusively with alumina or silica-coated particles. RelyX ARC was more surface-treatment dependent than RelyX U100 or Panavia F. PMID- 25453566 TI - Comparison of urine and cervical samples for detecting human papillomavirus (HPV) with the Cobas 4800 HPV test. AB - BACKGROUND: Human papillomavirus (HPV) is the main cause of cervical cancer. The development of non-invasive self-sample collection methods would have the potential advantage of increasing the acceptance of the screening procedures. OBJECTIVES: To compare human papillomavirus (HPV) DNA detection and genotyping with the Cobas 4800 HPV test (Roche Diagnostic, Spain) on paired cervical and first voided urine. STUDY DESIGN: Paired urine and cervical samples were collected from 125 women referred for evaluation of abnormal Pap smear results. RESULTS: The overall percent agreement between HPV detection in urine and cervical samples was 88%. A substantial concordance rate of HPV DNA detection in both samples was observed (kappa=0.76; 95% IC: 64-87). In this high prevalence population the sensitivity, specificity, NPV and PPV for detection of HPV DNA from urine versus cervical samples were 90.5% (95% IC: 80-95%), 85%, (95% IC: 74 92%), 89.8% (95% IC: 79.5-95.3) and 86.4% (95% IC: 76.1-92.7) respectively. Compared to histologically confirmed CIN 2/3 disease, the clinical sensitivity and specificity for the detection of high-risk HPV in urine samples were 95% (95% IC: 76-97%) and 52.4% (95% IC: 40-64%) respectively. CONCLUSIONS: These results suggest that urine samples processed with Cobas 4800 HPV test may be useful for clinical management of HPV infection. PMID- 25453567 TI - Clinical influence of different intracanal medications on Th1-type and Th2-type cytokine responses in apical periodontitis. AB - INTRODUCTION: This clinical study assessed the influence of different intracanal medications on Th1-type and Th2-type cytokine responses in apical periodontitis and monitored the levels of bacteria from primarily infection during endodontic procedures. METHODS: Thirty primarily infected teeth were randomly divided into 3 groups according to the medication selected: chlorhexidine (CHX), 2% CHX gel; Ca(OH)2/SSL, Ca(OH)2 + SSL; and Ca(OH)2/CHX, Ca(OH)2 + 2% CHX gel (all, n = 10). Bacterial sample was collected from root canals, and the interstitial fluid was sampled from lesions. Culture techniques were used to determine bacterial counts (colony-forming units/mL). Th1 (tumor necrosis factor-alpha, interferon-gamma, and interleukin [IL]-2) and Th2 cytokines (IL-4, IL-5, and IL-13) were measured by enzyme-linked immunosorbent assay. RESULTS: All intracanal medication protocols were effective in reducing the bacterial load from root canals (all P < .05) and lowering the levels of Th1-type cytokines in apical lesions (all P < .05), with no differences between them (P > .05). Both Ca(OH)2 treatment protocols significantly increased the levels of Th2-type cytokines (P < .05), with no differences between them (P > .05). Thus, chlorhexidine medication showed the lowest effectiveness in increasing the levels of Th2-type cytokine. After treatment, regardless of the type of medication, the linear regression analysis indicated the down-regulation of Th2-type cytokines by Th1-type cytokines. CONCLUSIONS: All intracanal medication protocols were effective in reducing bacterial load and lowering the levels of Th1-type cytokines. Thus, the use of Ca(OH)2 medications contributed to the increase in the Th2-type cytokine response in apical periodontitis. PMID- 25453568 TI - Phytic acid: an alternative root canal chelating agent. AB - INTRODUCTION: The objectives of this study were to investigate the effect of phytic acid, inositol hexakisphosphate (IP6), as a final rinse on the surface of instrumented root canals and smear-layered flat dentin surfaces treated with sodium hypochlorite (NaOCl) and to evaluate its effect on the viability and alkaline phosphatase activity of osteoblast-like cells (MC3T3-E1). METHODS: The universally accepted chelating agent EDTA was used as the control in all conducted experiments. Root canals of human canines were instrumented with rotary files and irrigated with 5% NaOCl, followed by a final rinse of 17% EDTA (1 minute), 1% IP6 (1 minute or 30 seconds), or distilled water. NaOCl-treated flat coronal dentin surfaces were also treated with 17% EDTA (1 minute), 1% IP6 (1 minute or 30 seconds), or distilled water. The presence or absence of smear layer was evaluated with scanning electron microscopy. Cell viability and alkaline phosphatase assays were performed to evaluate the effect of IP6 and EDTA on cultured MC3T3-E1 cells. RESULTS: The results demonstrated the ability of IP6 to remove the smear layer from instrumented root canals and flat coronal dentin surfaces. When compared with EDTA, IP6 was less cytotoxic and did not affect the differentiation of MC3T3-E1 cells. CONCLUSIONS: IP6 shows the potential to be an effective and biocompatible chelating agent. PMID- 25453569 TI - Long-term survival of endodontically treated teeth at a public dental specialist clinic. AB - INTRODUCTION: The long-term survival of endodontically treated teeth is an issue of high priority focus in modern restorative dentistry. In available literature, survival is generally high and comparable with implants. For more compromised teeth treated in a specialist clinic, survival rate may be lower. This retrospective study aimed to investigate the 10-year survival rate of teeth treated in a public endodontic specialist clinic. METHODS: From a database of 15,000 examined teeth, 420 teeth in 330 patients were randomly selected and included. Available potential preoperative, intraoperative, and postoperative prognostic factors were registered. Ten-year tooth survival was recorded by scrutinizing records and by contacting referring dentists and patients. RESULTS: The overall Kaplan-Meier estimated 10-year survival rate was 81.5% (95% confidence interval [CI], 76.7%-85.5%). Placement of a crown, adjusted hazard ratio 0.27 (95% CI, 0.12-0.61), P = .0016, and age-adjusted hazard ratio 1.31 per 10 years (95% CI, 1.11-1.55), P = .0012, were significant independent predictors for estimated survival rate. Seventy-three teeth (17.4%) in 69 patients were extracted during the 10-year follow-up period. The declared reason for extraction was related to endodontic diagnoses in only 5 of the cases (6.8%). CONCLUSIONS: Approximately 80% of the teeth treated at this specialist clinic in endodontics survived at least for 10 years. Teeth in young persons and teeth restored with a crown postoperatively survived significantly better. To further explore the importance of the postoperative restoration in endodontically treated teeth, randomized controlled trials need be carried out. PMID- 25453570 TI - Varicella-zoster virus and virus DNA in the blood and oropharynx of people with latent or active varicella-zoster virus infections. AB - Varicella-zoster virus (VZV) can be detected in the blood from approximately 5 days before to 4 days after varicella. VZV DNA, primarily in T-lymphocytes, is detected as early as 8-10 days prior to rash and can persist for a week. The duration and magnitude of VZV DNAemia correlates with immune status and the efficacy of antiviral therapy. VZV DNA is also readily detected in the oropharynx just prior to rash and for 1-2 weeks thereafter. Detection of VZV DNA in blood and saliva has been useful for diagnosis and prognosis in atypical cases of varicella. Herpes zoster (HZ) is also characterized by VZV DNAemia at onset and for many weeks thereafter, and VZV DNA is present in the oropharynx shortly after HZ onset. Detection of VZV DNA in blood and saliva facilitates the diagnosis of zoster sine herpete and other atypical manifestations of VZV reactivation, such as neurologic syndromes when cerebrospinal fluid is not available, Bell's palsy, and atypical pain syndromes. VZV DNA is sometimes present in the blood and saliva of asymptomatic individuals. In total these observations extend understanding of the pathophysiology and epidemiology of VZV, and increasingly contribute to the clinical management of VZV infections. PMID- 25453571 TI - Evaluation of CMV-specific cellular immune response by EliSPOT assay in kidney transplant patients. AB - BACKGROUND: Immunological monitoring for CMV can be useful in transplant patients; however, few centers perform it on a routine basis. OBJECTIVES: In this study, CMV-specific cellular response was evaluated in a population of kidney transplant recipients and related to viral infection/reactivation and other demographic and clinical features. STUDY DESIGN: Three hundred and twenty-eight patients were studied by EliSPOT assay: 201 prospectively monitored in the first year posttransplantation, 127 with a single determination at >1 year. Clinical features, including occurrence of CMV-DNAemia, CMV serostatus, anti-viral strategies and immunosuppressive protocols, were evaluated. RESULTS: Overall, 66.5% of patients were CMV-responders at EliSPOT assay. No episode of infection occurred at follow-up (mean 24.5 months) in 73.4% responders versus 55.5% non responders (p<0.005); CMV-free period was significantly longer in responders (p<0.001). Although no significant difference of peak viral load was found, prevalence of CMV-DNAemia values >10(5)copies/mL was significantly higher in non responders versus responders (8.2% and 2.3%, p<0.05). Non-responder status was significantly associated to CMV-seronegativity (p<0.0001), anti-viral prophylaxis use (p<0.0001), and immunosuppression induction with basiliximab (p<0.005). No significant association was found for other clinical features and immunosuppressive protocols. CONCLUSIONS: Immunological data for CMV could be used in the clinical evaluation and decision-making process, in combination with virological monitoring, in kidney transplant recipients. PMID- 25453572 TI - The concordance of HPV DNA detection by Hybrid Capture 2 and careHPV on clinician and self-collected specimens. AB - BACKGROUND: careHPV is a new, lower-cost DNA test for human papillomavirus (HPV). There are limited analytic comparisons of careHPV against a referent HPV DNA test like Hybrid Capture 2 (HC2). OBJECTIVE: To assess the test agreement between careHPV and HC2 on self- and clinician-collected specimens. STUDY DESIGN: In a population of 7541 women living in rural China, women provided a self-collected (sc) and two clinician-collected (cc) specimens and underwent visual inspection after acetic acid (VIA). The sc specimen and one cc specimen were tested by careHPV and HC2; a random subset of specimens was tested for HPV genotypes. RESULTS: The percent positive on cc specimens and sc specimens was 14.69% and 14.97% for careHPV, respectively, and 15.05% and 18.53% for HC2, respectively; HC2 testing of sc specimens was more likely to test positive than other combinations of tests and specimens (p<0.0001 for all comparisons). The agreement between different tests on the same specimens (kappa=0.787 and 0.691 for cc and sc specimens, respectively) was better than the same test on different specimens (kappa=0.653 and 0.649 for HC2 and careHPV, respectively). Disagreement between the same test on different specimens increased with increasing participant age (ptrend=0.0001 for HC2 and 0.002 for careHPV). HC2-positive/careHPV-negative specimens were more likely to test positive for non-carcinogenic HPV genotype than test HPV negative whereas the converse was true for HC2-negative/careHPV positive specimens. DISCUSSION: The agreement for HPV DNA detection between careHPV and HC2 was good to very good. PMID- 25453573 TI - Tenofovir-induced Fanconi syndrome in chronic hepatitis B monoinfected patients that reverted after tenofovir withdrawal. AB - Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor widely used to treat patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. Despite the excellent safety records of this regimen, a few cases of acute renal failure and Fanconi syndrome have been reported among HIV patients exposed to TDF. In the HBV monoinfection scenario, only two cases of TDF-associated Fanconi syndrome have been reported thus far. Here, we describe two additional patients with chronic hepatitis B (CHB) who developed a TDF-induced Fanconi syndrome that reverted after TDF withdrawal and had viral replication fully suppressed upon switching to entecavir (ETV). Though the overall risk of TDF associated severe renal toxicity in HBV patients appears to be negligible, both glomerular and tubular function should be monitored in patients exposed to TDF, especially when other renal risk factors or a history of previous exposure to adefovir dipivoxil (ADV) are present. PMID- 25453574 TI - First report of severe parainfluenza virus 4B and rhinovirus C coinfection in a liver transplant recipient treated with immunoglobulin. AB - We describe the first reported case of severe pneumonia due to coinfection by parainfluenza virus type 4B and rhinovirus C in a liver transplant recipient. The patient responded promptly to intravenous immunoglobulin and timely infection control measures prevented spreading of the infections. This report highlights respiratory viral coinfections as a possible cause of severe morbidity in transplant recipients and the importance of efficient molecular diagnostic technologies with major impact on clinical practice in a transplant center. It also describes a potential therapeutic strategy for such patients. PMID- 25453575 TI - The saliva quantitative PCR assay is inadequate to detect and monitor human herpesvirus-7 and -6 reactivation in patients with Pityriasis rosea. PMID- 25453576 TI - Detection of human herpesviruses (HHVs) DNA in blood samples: a true marker of Fever of Unknown Origin (FUO)? PMID- 25453577 TI - High-intensity focused ultrasound: noninvasive treatment for local unresectable recurrence of osteosarcoma. AB - OBJECTIVE: Local unresectable recurrence of osteosarcoma is one of the most challenging tumors to treat. High-intensity focused ultrasound (HIFU) is a new, noninvasive technique with potential to ablate and inactivate tumors. Treatment of solid tumors with HIFU has been reported. In this study, we assessed safety and efficacy of HIFU in treating local unresectable recurrence of osteosarcoma. METHODS: We performed a retrospective analysis of 27 patients who had local unresectable recurrence of osteosarcoma from 2006 to 2010. Changes of biochemical markers and pain rating, response rate, disease control rate, local disease progression-free survival, progression-free survival (PFS) and overall survival (OS) were used to evaluate efficacy of HIFU treatment. RESULTS: HIFU resulted in a significant change in alkaline phosphatase and lactic acid dehydrogenase and a remarkably relief in pain rating, without severe side effects. According to MRI examination 4-6 weeks after HIFU treatment, 2 (7.4%) patients had complete response (CR), 12 (44.4%) had partial response (PR), 9 (33.3%) had stable disease (SD) and 4 (14.8%) had progression disease (PD). The response rate was 51.8% and the local disease control rate was 85.2%. The 1-, 2-, and 3-year local disease control rates were 59.2%, 40.7% and 33.1%, respectively. The median local disease progression-free time was 14 months, the median progression-free time was 13 months and the median over-all survival time was 21 months. Patients without pulmonary metastasis had a better local disease control rate at 1-,2-,3-year and a longer local disease progression-free time, progression-free time, over-all survival time than patients with pulmonary metastasis. CONCLUSION: HIFU is a safe and noninvasive treatment for local unresectable recurrence of osteosarcoma, with good local control and without severe complications. PMID- 25453578 TI - Expression of tumor suppressor genes in channel catfish after bacterial infections. AB - Tumor suppressor genes are negative regulators of tumor formation. While their anti-tumor functions have been well studied, they have been found to be also involved in immune responses and innate immunity. In this study, 21 tumor suppressor genes in channel catfish (Ictalurus punctatus) were characterized. Phylogenetic and syntenic analyses allowed annotation of all 21 catfish tumor suppressor genes. The expression profiles of the 21 catfish tumor suppressor genes were determined using the RNA-Seq datasets. After Edwardsiella ictaluri infection, expression of five of the 21 tumor suppressor genes was up-regulated at 3 days in the intestine, and four of the 21 genes were up-regulated in the liver 14 days post-infection. With Flavobacterium columnare infection, seven genes were up-regulated in the gill at 48 h post-infection. These results expanded our knowledge on the tumor suppressor genes in teleosts, setting a foundation for future studies to unravel functions of tumor suppressor genes in response to stresses, particularly after bacterial disease infections. PMID- 25453579 TI - Signatures of resistance to Lepeophtheirus salmonis include a TH2-type response at the louse-salmon interface. AB - Disease outbreaks with the salmon louse Lepeophtheirus salmonis cause significant economic losses in mariculture operations worldwide. Variable innate immune responses at the louse-attachment site contribute to differences in susceptibility among species such that members of Salmo spp. are more susceptible to infection than those of some Oncorhynchus spp. Relatively little is known about the mechanisms that contribute to disease resistance or susceptibility to L. salmonis in salmon. Here, we utilize histochemistry and transcriptomics in a comparative infection model with susceptible (Atlantic, sockeye) and resistant (coho) salmon. At least three cell populations (MHIIbeta+, IL1beta+, TNFalpha+) were activated in coho salmon skin during L. salmonis infection. Locally elevated expression of several pro-inflammatory mediators (e.g. IL1beta, IL8, TNFalpha, COX2, C/EBPbeta), and tissue repair enzymes (MMP9, MMP13) were detected in susceptible and resistant species. However, responses specific to coho salmon (e.g. IL4, IL6, TGFbeta) or responses shared among susceptible salmon (e.g. SAP, TRF, Cath in Atlantic and sockeye salmon) provide evidence for species-specific pathways contributing to resistance or susceptibility, respectively. Our results confirm the importance of an early pro-inflammatory TH1-type pathway as an initial host response during infection with Pacific sea lice, and demonstrate subsequent regulatory TH2-type processes as candidate defense mechanisms in the skin of resistant coho salmon. PMID- 25453580 TI - Cell type-specific differences in beta-glucan recognition and signalling in porcine innate immune cells. AB - beta-glucans exert receptor-mediated immunomodulating activities, including oxidative burst activity and cytokine secretion. The role of the beta-glucan receptors dectin-1 and complement receptor 3 (CR3) in the response of immune cells towards beta-glucans is still unresolved. Dectin-1 is considered as the main beta-glucan receptor in mice, while recent studies in man show that CR3 is more important in beta-glucan-mediated responses. This incited us to elucidate which receptor contributes to the response of innate immune cells towards particulate beta-glucans in pigs as the latter might serve as a better model for man. Our results show an important role of CR3 in beta-glucan recognition, as blocking this receptor strongly reduced the phagocytosis of beta-glucans and the beta-glucan-induced ROS production by porcine neutrophils. Conversely, dectin-1 does not seem to play a major role in beta-glucan recognition in neutrophils. However, recognition of beta-glucans appeared cell type-specific as both dectin-1 and CR3 are involved in the beta-glucan-mediated responses in pig macrophages. Moreover, CR3 signalling through focal adhesion kinase (FAK) was indispensable for beta-glucan-mediated ROS production and cytokine production in neutrophils and macrophages, while the Syk-dependent pathway was only partly involved in these responses. We may conclude that CR3 plays a cardinal role in beta-glucan signalling in porcine neutrophils, while macrophages use a more diverse receptor array to detect and respond towards beta-glucans. Nonetheless, FAK acts as a master switch that regulates beta-glucan-mediated responses in neutrophils as well as macrophages. PMID- 25453581 TI - Isolation and cytochemical characterization of melanomacrophages and melanomacrophage clusters from goldfish (Carassius auratus, L.). AB - Pigmented or "melano-" macrophages are prominent in lymphoid and non-lymphoid tissues of poikilotherms. Though they have been extensively studied in situ only recently has a means to isolate them from other cell types been established. We provide the first in vitro characterization of isolated melanomacrophage cytochemistry and survival in culture. Unlike non-pigmented tissue macrophages melanomacrophages do not adhere to polystyrene surfaces making them easy to separate from tissue macrophages. In vitro goldfish melanomacrophages are distinguishable from tissue macrophages and neutrophils by being Sudan Black B positive (unlike tissue macrophages) and non-specific esterase positive (unlike neutrophils). Like tissue macrophages they also express acid phosphatase and CSF 1R. As sorted cells melanomacrophages only survive a few days in culture. However in coarsely disaggregated spleen and kidney tissues melanomacrophages survive for at least 3 weeks. Furthermore after 5 days culture disaggregating tissue clumps revealed encapsulated melanomacrophage clusters that remained intact for at least another week. The encapsulated clusters were resilient enough to allow for their isolation for further imaging and isolation of RNA. In some cases the clusters had either melanomacrophages or non-fluorescent cells protruding and in the latter case these could initiate outgrowths onto the plates with subsequent collapse of the cluster. These approaches for the isolation of melanomacrophages and melanomacrophage clusters should allow further study into specific cell and cluster functions. PMID- 25453583 TI - Unmet contraceptive need among married Nigerian women: an examination of trends and drivers. AB - OBJECTIVE: The aim of this study is to examine trends in and drivers of unmet need for contraceptives among married Nigerian women between 2003 and 2013. METHODS: This analysis utilized combined data from the 2003, 2008 and 2013 cross sectional Nigerian Demographic Health Surveys, resulting in a sample size of 54,873 currently married women. Multinomial logistic regression examined associations between trends in unmet need for spacing and limiting, and the demographic, socioeconomic, and reproductive profiles of the respondents. RESULTS: Women in 2008 were 30% more likely to have an unmet need for spacing, relative to women in 2013. Despite these significant declines in unmet need to space fertility between 2008 and 2013, the adjusted results show that between 2003 and 2013, there was no significant change in the trends in unmet need to space fertility. Unmet need to limit fertility was significantly higher in 2003, adjusted, and 2008 relative to 2013. Younger, low-parity, Muslim women were significantly less likely than older, high-parity, non-Muslim women to have an unmet need to limit fertility. Women residing in the northeast and northwest of the country were significantly less likely than women residing in the south of the country to have an unmet need to limit fertility. Women whose most recent child had died were significantly less likely to have an unmet need to space and limit fertility. CONCLUSIONS: These data suggest that interventions to increase the knowledge of modern contraceptives, to reduce child mortality, and to improve women's decision-making power would all serve to increase demand for contraceptives, even in areas with high-fertility preferences. IMPLICATIONS: Nigeria has set a goal of a 36% contraceptive prevalence rate by 2018. With a current contraceptive prevalence rate of 15% reaching the additional 16% of women, who have articulated a demand for contraception, will almost reach that goal. Contraceptive use directly reduces maternal risk; implementing interventions to increase demand for contraception and meeting articulated demands for contraception would not only support women's (and men's) ability to realize their reproductive rights but also, ultimately, may reduce the burden of maternal deaths in Nigeria. PMID- 25453582 TI - A comparison of bleeding patterns and cycle control using two transdermal contraceptive systems: a multicenter, open-label, randomized study. AB - OBJECTIVE(S): To investigate the bleeding pattern and cycle control parameters of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a patch containing 0.6 mg EE and 6 mg norelgestromin (NGMN). STUDY DESIGN: In this phase III, open-label, randomized, parallel-group trial, healthy women aged 18-35 years (smokers aged 18-30 years) received either the EE/GSD patch (n=200) or the EE/NGMN patch (n=198). Treatment consisted of one patch per week for 3 weeks followed by a 7-day, patch-free interval for seven cycles. Bleeding control was assessed in two 90-day reference periods. RESULTS: In reference period 1, mean number of bleeding/spotting days was comparable across treatment groups (p>0.05). However, in reference period 2, there were fewer bleeding/spotting days in the EE/GSD patch group (15.7 versus 18.4; p<0.0001). Mean number of bleeding/spotting episodes was comparable across groups for both reference periods, but bleeding/spotting episodes were shorter for the EE/GSD patch than the EE/NGMN patch during reference period 1 (5.13 days versus 5.53 days, respectively; p<0.05) and reference period 2 (5.07 versus 5.66; p=0.0001). Both treatment groups showed a similar frequency of withdrawal bleeding episodes; however, across all seven cycles, the length of these episodes was consistently shorter with the EE/GSD patch (p<0.01). There were no notable treatment differences in intracyclic bleeding. CONCLUSION(S): Bleeding pattern and cycle control achieved with the EE/GSD patch was similar to that of the EE/NGMN patch. IMPLICATIONS STATEMENT: The paper presents data on the bleeding pattern and cycle control parameters of an investigational transdermal contraceptive patch containing EE and GSD compared with an approved contraceptive patch containing EE and NGMN. This descriptive study found that bleeding patterns associated with the EE/GSD patch were similar to those of an EE/NGMN patch providing higher EE exposure. PMID- 25453584 TI - Late termination of pregnancy for lethal fetal anomalies: a national survey of maternal-fetal medicine specialists. AB - OBJECTIVE: The objective was to ascertain the practices and opinions of US maternal-fetal medicine specialists regarding termination of pregnancy as a management option following late diagnosis of lethal fetal anomalies. STUDY DESIGN: We conducted a cross-sectional mail survey of all US members of the Society of Maternal Fetal Medicine to ascertain how they manage pregnancies diagnosed with lethal fetal anomalies after 24 weeks of gestation. We analyzed the proportion of respondents that discuss termination of pregnancy as a management option, barriers to offering or accessing late termination services, and respondents' opinions about what anomalies are lethal and when pregnancy termination should be permitted. RESULTS: The response rate was 41% (869/2119). Nearly all (93%) respondents discuss delivery near term or when complications arise, while 75% discuss the option of termination of pregnancy soon after the diagnosis of lethal fetal anomalies. Only 52% of the physicians indicated that their patients could obtain termination of pregnancy after 24 weeks at their affiliated medical centers or through providers within 50 miles. Real or perceived legal restrictions represented the most common reason for lack of local services. The proportion of respondents that felt strongly or very strongly that termination of pregnancy should be allowed was 76% for lethal anomalies and 58% for anomalies likely to result in significant long-term impairment. CONCLUSION: Although limited by a modest response rate, our study found that physicians do not consistently discuss immediate termination of pregnancy as an option following late diagnosis of lethal fetal anomalies, and they face numerous barriers to providing these services. IMPLICATIONS: This national survey supports the need for improved services for pregnant women who desire later termination of pregnancy following diagnosis of serious fetal anomalies. Helpful efforts might include educating physicians about the laws and regulations governing late termination of pregnancy, forging more consistent standards of care, and improving collaboration between MFM specialists and family planning providers to enhance access to care. PMID- 25453585 TI - Bleeding pattern and cycle control of a low-dose transdermal contraceptive patch compared with a combined oral contraceptive: a randomized study. AB - OBJECTIVE(S): The aim of this study was to investigate the bleeding pattern and cycle control of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a combined oral contraceptive (COC) containing 0.02 mg EE and 0.1 mg levonorgestrel (LNG). STUDY DESIGN: In this phase III, randomized, controlled, double-blind, double-dummy, multicenter trial, healthy women aged 18-45 years (smokers aged 18-35 years) received either the EE/GSD patch and a placebo tablet (n=171), or a placebo patch and the COC (n=175) for seven 28-day cycles. Bleeding control was assessed in two 90-day reference periods. RESULTS: Mean number of bleeding/spotting days was comparable across treatment groups in both reference periods (p>.05). Mean number of bleeding/spotting episodes was also comparable in reference period 1; however, there were fewer bleeding/spotting episodes for COC in reference period 2 (3.4 versus 3.1; p=.01). Mean length of bleeding/spotting episodes was comparable across treatment groups for both reference periods (p>.05). Withdrawal bleeding occurred consistently in both groups over the entire treatment period, but its absence was more common in the COC group in cycles 4 and 6 of reference period 2 (p<.01). Intracyclic bleeding was comparable between groups. CONCLUSION(S): Bleeding pattern and cycle control with the EE/GSD patch was comparable to an EE/LNG-containing COC. IMPLICATIONS STATEMENT: The findings suggest that bleeding patterns with the EE/GSD patch are similar to an EE/LNG-containing COC, except for absence of withdrawal bleeding, which was less common in patch users. The EE/GSD patch may constitute an additional contraceptive option for women. PMID- 25453586 TI - Safety and efficacy of two dose levels of taliglucerase alfa in pediatric patients with Gaucher disease. AB - Taliglucerase alfa is a plant cell-expressed beta-glucocerebrosidase approved in the United States, Israel, Australia, Canada, and other countries for enzyme replacement therapy in adults with Type 1 Gaucher disease (GD), for treatment of pediatric patients in the United States, Australia, and Canada, and for the hematologic manifestations of Type 3 GD in pediatric patients in Canada. This multicenter, randomized, double-blind, parallel-dose, 12-month study assessed efficacy and safety of taliglucerase alfa in pediatric patients with GD. Eleven children were randomized to taliglucerase alfa 30U/kg (n=6) or 60U/kg (n=5) per infusion every other week. From baseline to month 12, the following changes were noted in the taliglucerase alfa 30-U/kg and 60-U/kg dose groups, respectively: median hemoglobin concentrations increased by 12.2% and 14.2%; the interquartile ranges of median percent change in hemoglobin levels from baseline were 20.6 and 10.4, respectively; mean spleen volume decreased from 22.2 to 14.0 multiples of normal (MN) and from 29.4 to 12.9 MN; mean liver volume decreased from 1.8 to 1.5 MN and from 2.2 to 1.7 MN; platelet counts increased by 30.9% and 73.7%; and chitotriosidase activity was reduced by 58.5% and 66.1%. Nearly all adverse events were mild/moderate, unrelated to treatment, and transient. One patient presented with treatment-related gastroenteritis reported as a serious adverse event due to the need for hospitalization for rehydration. No patient discontinued. These data suggest that taliglucerase alfa has the potential to be a therapeutic treatment option for children with GD. This study was registered at www.clinicaltrials.gov as NCT01132690. PMID- 25453588 TI - Levels of craving influence psychological challenge and physiological reactivity. AB - Behavioural and cognitive pathways that lead to the activation and escalation of craving have been studied extensively. Conversely, limited efforts have been directed towards understanding how craving relates to motivational systems and neuroendocrine responses. These can be understood using the biopsychosocial model of challenge and threat. In the current study, forty participants with varying levels of chocolate craving undertook two word searches, with the prospect of winning a piece of chocolate. Amongst those with high levels of craving, participation in this task led to motivational states of challenge relative to those with lower levels. This was reflected by changes in cardiac reactivity driven by differences in sympathetic-adrenal-medullar and hypothalamic-pituitary adrenal axis activation. This finding suggests that craving can be associated with states of motivational challenge and thus affect cardiac reactivity. PMID- 25453587 TI - Effect of oxytocin receptor blockade on appetite for sugar is modified by social context. AB - Research on oxytocin (OT) has yielded two seemingly unrelated sets of discoveries: OT has prosocial effects, and it elicits termination of feeding, especially of food rich in carbohydrates. Here we investigated whether OT's involvement in food intake is affected by the social context in mice, with particular focus on the role of dominance. We used two approaches: injections and gene expression analysis. We housed two males per cage and determined a dominant one. Then we injected a blood-brain barrier penetrant OT receptor antagonist L 368,899 in either dominant or subordinate animals and gave them 10-min access to a sucrose solution in the apparatus in which social exposure was modified and it ranged from none to unrestricted contact. L-368,899 increased the amount of consumed sugar in dominant mice regardless of whether these animals had access to sucrose in the non-social or social contexts (olfactory-derived or partial social exposure). The antagonist also increased the proportion of time that dominant mice spent drinking the sweet solution in the paradigm in which both mice had to share a single source of sucrose. L-368,899-treated subordinate mice consumed more sucrose solution than saline controls only when the environment in which sugar was presented was devoid of social cues related to the dominant animal. Finally, we investigated whether hypothalamic OT gene expression differs between dominant and subordinate mice consuming sugar and found OT mRNA levels to be higher in dominant mice. We conclude that social context and dominance affect OT's effect on appetite for sucrose. PMID- 25453589 TI - Nutrition self-efficacy is unidirectionally related to outcome expectations in children. AB - OBJECTIVE: To clarify the underlying relationship between nutrition self-efficacy and outcome expectations because the direction of the relationship (unidirectional vs bidirectional) is debated in the literature. METHODS: Secondary data analysis of a 10-week, 10-lesson school-based nutrition education intervention among 3rd grade students (N = 952). Nutrition self-efficacy (7 items) and nutrition outcome expectations (9 items) were measured through student self-report at intervention pre- (time 1) and post- (time 2) assessments. A series of two time point, multi-group cross-lagged bivariate change score models were used to determine the direction of the relationship. RESULTS: A cross lag from nutrition self-efficacy at time 1 predicting changes in nutrition outcome expectations at time 2 significantly improved the fit of the model (Model 3), whereas a cross lag from nutrition outcome expectations at time 1 to changes in nutrition self-efficacy at time 2 only slightly improved the fit of the model (Model 2). Furthermore, adding both cross lags (Model 4) did not improve model fit compared to the model with only the self-efficacy cross lag (Model 3). Lastly, the nutrition outcome expectations cross lag did not significantly predict changes in nutrition self-efficacy in any of the models. CONCLUSIONS: Data suggest that there is a unidirectional relationship between nutrition self efficacy and outcome expectations, in which self-efficacy predicts outcome expectations. Therefore, theory-based nutrition interventions may consider focusing more resources on changing self-efficacy because it may also lead to changes in outcome expectations as well. PMID- 25453590 TI - Can you have your meat and eat it too? Conscientious omnivores, vegetarians, and adherence to diet. AB - As criticisms of factory farming continue to mount, an increasing number of individuals have changed their existing dietary practices. Perhaps the two most important food movements reacting against industrial farming are (1) vegetarianism, the avoidance of animal flesh; and (2) conscientious omnivorism (CO), the consumption of meat or fish only when it satisfies certain ethical standards. While the former group has been well-studied in the social science literature, there have been few, if any, studies specifically examining those who identify themselves as ethical meat eaters. The present research sought to determine if one particular diet was more greatly adhered to by its followers. Results revealed that COs were less likely to perceive their diet as something that they absolutely needed to follow, reported violating their diet more, felt less guilty when doing so, believed less in animal rights, were less disgusted by factory-farmed meat, rated its sensory characteristics more favorably, and were lower in ingroup identification than vegetarians. Mediation analysis demonstrated that differences in the amount of violations and guilt associated with these violations could in part be traced to practical and psychological factors, making it more difficult to follow conscientious omnivorism. PMID- 25453591 TI - Body weight and food intake in Parkinson's disease. A review of the association to non-motor symptoms. AB - Research on eating behaviours has extensively highlighted that cognitive systems interact with the metabolic system in driving food intake and in influencing body weight regulation. Parkinson's disease is a good model for studying these complex interactions since alterations in both body weight and cognitive domains have been frequently reported among these patients. Interestingly, even if different non-motor symptoms may characterize the course of the disease, their contribution to weight and food preference has been poorly investigated. This review describes body weight alterations and eating habits in patients with Parkinson's disease, including those who underwent deep brain stimulation surgery. In particular, the review considers the link between non-motor symptoms, affecting sensory perception, cognition, mood and motivation, and food intake and weight alterations. The take home message is twofold. First, we recommend a comprehensive approach in order to develop effective strategies in the management of patients' weight. Second, we also suggest that investigating this issue in patients with Parkinson's disease may provide some useful information about the mechanisms underlying food and weight regulation in healthy subjects. PMID- 25453592 TI - Consumer purchasing behaviour towards fish and seafood products. Patterns and insights from a sample of international studies. AB - The present systematic review was performed to assess consumer purchasing behaviour towards fish and seafood products in the wide context of developed countries. Web of Science, Scopus, ScienceDirect and Google Scholar engines were used to search the existing literature and a total of 49 studies were identified for inclusion. These studies investigated consumer purchasing behaviour towards a variety of fish and seafood products, in different countries and by means of different methodological approaches. In particular, the review identifies and discusses the main drivers and barriers of fish consumption as well as consumers' preferences about the most relevant attributes of fish and seafood products providing useful insights for both practitioners and policy makers. Finally, main gaps of the existing literature and possible trajectories for future research are also discussed. PMID- 25453593 TI - A step-by-step introduction to vegetables at the beginning of complementary feeding. The effects of early and repeated exposure. AB - Breastfeeding (BF) is associated with willingness to accept vegetables. This may be due to the variety of flavours delivered via breast milk. Some mothers add vegetables to milk during complementary feeding (CF) to enhance acceptance. The present study tested a step-by-step exposure to vegetables in milk then rice during CF, on intake and liking of vegetables. Just before CF, enrolled mothers were randomised to an intervention (IG, n = 18; 6 BF) or control group (CG, n = 18; 6 BF). IG infants received 12 daily exposures to vegetable puree added to milk (days 1-12), then 12 * 2 daily exposures to vegetable puree added to rice at home (days 13-24). Plain milk and rice were given to CG. Then both received 11 daily exposures to vegetable puree. Intake was weighed and liking rated on days 25-26 and 33-35 after the start of CF in the laboratory, supplemented by the same data recorded at home. Vegetables were rotated daily (carrots, green beans, spinach, broccoli). Intake, liking and pace of eating were greater for IG than CG infants. Intake and liking of carrots were greater than green beans. However, at 6m then 18m follow up, vegetable (carrot > green beans) but not group differences were observed. Mothers reported appreciation of the structure and guidance of this systematic approach. Early exposure to vegetables in a step-by-step method could be included in CF guidelines and longer term benefits assessed by extending the exposure period. PMID- 25453595 TI - Indications for the HPV vaccine in adolescents: a review of the literature. AB - BACKGROUND: The vaccine against human papillomavirus (HPV) was created to abrogate the risk that the virus presents for the development of cervical cancers. The prevalence of HPV infection among healthy individuals is significant (20%). We performed a review of the literature published in the period from 2008 to 2012 regarding the use of the vaccine against HPV specifically in adolescents. METHODS: The articles were selected from a search of the PubMed database with the key words "vaccine", "HPV" and "adolescent". This search identified 576 articles; based on readings of the titles and abstracts, the list of included article was reduced to 42. RESULTS: We observed that the majority of authors are in favor of the vaccine for adolescents particularly females. CONCLUSION: Recommending the use of the HPV vaccine and other vaccines represents an attempt to broaden the reach of these vaccines among both sexes of the adolescent population. Vaccination is a strategy for the prevention of pre-cancerous lesions in the genital and oropharyngeal regions. PMID- 25453594 TI - Maternal eating disorder and infant diet. A latent class analysis based on the Norwegian Mother and Child Cohort Study (MoBa). AB - Knowledge of infant diet and feeding practices among children of mothers with eating disorders is essential to promote healthy eating in these children. This study compared the dietary patterns of 6-month-old children of mothers with anorexia nervosa, bulimia nervosa, binge eating disorder, and eating disorder not otherwise specified-purging subtype, to the diet of children of mothers with no eating disorders (reference group). The study was based on 53,879 mothers in the Norwegian Mother and Child Cohort Study (MoBa). Latent class analysis (LCA) was used to identify discrete latent classes of infant diet based on the mothers' responses to questions about 16 food items. LCA identified five classes, characterized by primarily homemade vegetarian food (4% of infants), homemade traditional food (8%), commercial cereals (35%), commercial jarred baby food (39%), and a mix of all food groups (11%). The association between latent dietary classes and maternal eating disorders were estimated by multinomial logistic regression. Infants of mothers with bulimia nervosa had a lower probability of being in the homemade traditional food class compared to the commercial jarred baby food class, than the referent (O.R. 0.59; 95% CI 0.36-0.99). Infants of mothers with binge eating disorder had a lower probability of being in the homemade vegetarian class compared to the commercial jarred baby food class (O.R. 0.77; 95% CI 0.60-0.99), but only before adjusting for relevant confounders. Anorexia nervosa and eating disorder not otherwise specified-purging subtype were not statistically significantly associated with any of the dietary classes. These results suggest that maternal eating disorders may to some extent influence the child's diet at 6 months; however, the extent to which these differences influence child health and development remains an area for further inquiry. PMID- 25453596 TI - Spleen and liver enlargement in a patient with rheumatoid arthritis. AB - We describe the case of a 51-year-old woman with a seropositive, erosive, and non nodular rheumatoid arthritis of 15 year of evolution. The patient had poor compliance with medical visits and treatment. She came to the clinic with persistent pancytopenia and spleen and liver enlargement. Liver and bone marrow biopsies were carried out and amyloidosis, neoplasias and infections were ruled out. We discuss the differential diagnosis of pancytopenia and spleen and liver enlargement in a long-standing rheumatoid arthritis patient. PMID- 25453597 TI - Response to: fibromyalgia and chronic fatigue syndrome caused by non-celiac gluten sensitivity. PMID- 25453598 TI - Colchicine use in isolated renal AA amyloidosis. AB - We present the case of a 45-year-old woman, with two-year history of chronic renal insufficiency and proteinuria. A kidney biopsy showed the presence of AA amyloidosis (positive Congo red staining and immunohistochemistry). There was no evidence of amyloid deposits in other organs and there was no underlying disease. AA amyloidosis normally is secondary to chronic inflammatory or infectious diseases. High levels of IL-1, IL-6 and TNF-alpha play a role in the pathogenesis of amyloidosis and induce the synthesis of serum amyloid A protein (SAA), a precursor of tissue amyloid deposits. We empirically treated the patient with a low dose colchicine. The patient responded well. Colchicine has been used for the treatment of Familiar Mediterranean Fever and related auto-inflammatory diseases. To monitor treatment responses, we measured SAA finding low titers. Soon after treatment onset there were signs of improvement pertaining to proteinuria and stabilization of renal function. PMID- 25453599 TI - beta-Adrenergic modulation of myocardial conduction velocity: Connexins vs. sodium current. AB - The heart is capable of rapid changes in cardiac output: these are caused in large part by changes in the activity of the autonomic nervous system that alter heart rate, force and time course of contraction. While studies of autonomic control have focussed on heart rate and contractile mechanisms, fewer studies have considered the influence of electrical propagation across the chamber. Conduction velocity (CV) of the action potential (AP) is an important variable, which ensures efficient pumping action of the heart and, along with AP duration, is a determinant of the electrical stability of the myocardium. CV depends on multiple factors, including tissue excitability and intercellular resistance: the latter is controlled by the number and arrangement of gap junctions (GJs) linking adjacent cardiac cells. Whole heart studies (in vivo and in vitro) report variable effects of sympathetic nervous system stimulation on ventricular CV, a major complication in interpretation being the accompanying increase in heart rate. At the cellular level, changes in cardiomyocyte electrophysiology, mediated via beta-adrenoreceptor (beta-AR) activation, alter the AP shape and amplitude but the influence of these effects on the CV is unclear. Alternatively, CV changes may occur via altered GJ conductance, but despite detailed knowledge of the underlying channel protein (connexin), little consensus exists on the extent and time course of the change in GJ conductance induced by AR activation. This review will examine the literature on the modulation of ventricular AP conduction velocity by beta-AR activation in a range of physiological preparations and highlight unresolved issues. PMID- 25453600 TI - On the value of the phenotypes in the genomic era. AB - Genetic improvement programs around the world rely on the collection of accurate phenotypic data. These phenotypes have an inherent value that can be estimated as the contribution of an additional record to genetic gain. Here, the contribution of phenotypes to genetic gain was calculated using traditional progeny testing (PT) and 2 genomic selection (GS) strategies that, for simplicity, included either males or females in the reference population. A procedure to estimate the theoretical economic contribution of a phenotype to a breeding program is described for both GS and PT breeding programs through the increment in genetic gain per unit of increase in estimated breeding value reliability obtained when an additional phenotypic record is added. The main factors affecting the value of a phenotype were the economic value of the trait, the number of phenotypic records already available for the trait, and its heritability. Furthermore, the value of a phenotype was affected by several other factors, including the cost of establishing the breeding program and the cost of phenotyping and genotyping. The cost of achieving a reliability of 0.60 was assessed for different reference populations for GS. Genomic reference populations of more sires with small progeny group sizes (e.g., 20 equivalent daughters) had a lower cost than those reference populations with either large progeny group sizes for fewer genotyped sires, or female reference populations, unless the heritability was large and the cost of phenotyping exceeded a few hundred dollars; then, female reference populations were preferable from an economic perspective. PMID- 25453602 TI - Imaging and finite element analysis: a methodology for non-invasive characterization of aortic tissue. AB - Characterization of the mechanical properties of arterial tissues usually involves an invasive procedure requiring tissue removal. In this work we propose a non-invasive method to perform a biomechanical analysis of cardiovascular aortic tissue. This method is based on combining medical imaging and finite element analysis (FEA). Magnetic resonance imaging (MRI) was chosen since it presents relatively low risks for human health. A finite element model was created from the MRI images and loaded with systolic physiological pressures. By means of an optimization routine, the structural material properties were changed until average strains matched those measured by MRI. The method outlined in this work produced an estimate of the in situ properties of cardiovascular tissue based on non-invasive image datasets and finite element analysis. PMID- 25453604 TI - Estimating the scaled mutation rate and mutation bias with site frequency data. AB - The distribution of allele frequencies of a large number of biallelic sites is known as "allele-frequency spectrum" or "site-frequency spectrum" (SFS). Without selection and in regions of relatively high recombination rates, sites may be assumed to be independently and identically distributed. With a beta equilibrium distribution of allelic proportions and binomial sampling, a beta-binomial compound likelihood for each site results. The likelihood of the data and the posterior distribution of two parameters, scaled mutation rate theta and mutation bias alpha, is investigated in the general case and for small scaled mutation rates theta. In the general case, an expectation-maximization (EM) algorithm is derived to obtain maximum likelihood estimates of both parameters. With an appropriate prior distribution, a Markov chain Monte Carlo sampler to integrate the posterior distribution is also derived. As far as I am aware, previous maximum likelihood or Bayesian estimators of theta, explicitly or implicitly assume small scaled mutation rates, i.e., theta?1. For theta?1, maximum likelihood estimators are also derived for both parameters using a Taylor series expansion of the beta-binomial distribution. The estimator of theta is a variant of the Ewens-Watterson estimator and of the maximum likelihood estimator derived with the Poisson Random Field approach. With a conjugate prior distribution, marginal and conditional beta posterior distributions are also derived for both parameters. PMID- 25453601 TI - A family with paroxysmal nonkinesigenic dyskinesias (PNKD): evidence of mitochondrial dysfunction. AB - INTRODUCTION: Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare movement disorder characterized by sudden attacks of involuntary movements. Familial PNKD is an autosomal dominant trait, caused by mutations in the myofibrillogenesis regulator 1 (MR-1) gene on chromosome 2q35. Three different mutations have been described; all of them reside in the N-terminal region common to isoforms L and S, that has been suggested to code for a mitochondrial targeting sequence, necessary for the correct sub-cellular localization of the protein into mitochondria. METHODS: We report on four patients of the same family, affected by PNKD. Skin fibroblasts were used to analysed oxygen consumption and to measure mitochondrial matrix calcium response after agonist stimulation. Mitotracker based visualization was also used to assess fragmentation of the mitochondrial network. RESULTS: the paroxysmal movements were dystonic in two patients and dystonic/choreiform in the other ones; in three cases the symptoms started in one limb and then generalized, while in one case remained focal. Three had a very early onset, within the first two years of life. The frequency of episodes showed a great variability, ranging from 2 times a day to 3 times a year, while the duration of the attacks ranged from 2 min to 1,5 h, always with sudden onset and end and complete recover in between. All affected subjects harbored a heterozygous C to T substitution in MR-1, causing an Ala9Val amino acid change in the N-terminal region. A significant reduction of oxygen consumption and altered calcium homeostasis were found in mutant fibroblasts compared to controls, while no difference was detected in mitochondrial network. CONCLUSIONS: The data on reduced oxygen consumption and altered calcium homeostasis obtained on mutant fibroblasts are the first evidences, in physiological conditions, of a mitochondrial dysfunction in PNKD. PMID- 25453603 TI - New immunization protocol to produce crotalic antivenom combining Crotalus durissus terrificus venom and its PLA2. AB - Antivenoms are usually obtained by animal immunization with successive inoculations of increasing sublethal amounts of venom, which may impair the animal health. The high lethality of venom requires prolonged immunization plans with small amounts of venom. Thus, we propose an alternative plan that includes a pre-immunization of the animal with phospholipase A2, the main crotoxin component, which is responsible for the whole venom lethality. For comparison, three different immunization schemes were designed: high dose protocol (HDP; 0.5 27 mg of venom), low dose protocol (LDP; 0.1-7 mg of venom) and Mix protocol (MP; preimmunization 0.1-1.2 mg of crotalic PLA2, and then 4.5-8 mg of venom). Antibody titers were determined by ELISA, in blood plasma obtained from the marginal vein of the ear. The neutralizing ability of the different sera obtained by all protocols (HDS, LDS and MS) was tested against the most important pharmacological activities of whole venom: PLA2 activity, myotoxicity, thrombin like activity and lethality. MS showed the best neutralizing efficacy and at the same time, it was obtained by an immunization protocol that takes account of animal health care, since it requires low quantities of venoms in comparison to traditional protocols. PMID- 25453605 TI - The largest strongly connected component in the cyclical pedigree model of Wakeley et al. AB - We establish a link between Wakeley et al.'s (2012) cyclical pedigree model from population genetics and a randomized directed configuration model (DCM) considered by Cooper and Frieze (2004). We then exploit this link in combination with asymptotic results for the in-degree distribution of the corresponding DCM to compute the asymptotic size of the largest strongly connected component S(N) (where N is the population size) of the DCM resp. the pedigree. The size of the giant component can be characterized explicitly (amounting to approximately 80% of the total populations size) and thus contributes to a reduced 'pedigree effective population size'. In addition, the second largest strongly connected component is only of size O(logN). Moreover, we describe the size and structure of the 'domain of attraction' of S(N). In particular, we show that with high probability for any individual the shortest ancestral line reaches S(N) after O(loglogN) generations, while almost all other ancestral lines take at most O(logN) generations. PMID- 25453606 TI - Single generation cycles and delayed feedback cycles are not separate phenomena. AB - We study a simple model for generation cycles, which are oscillations with a period of one or a few generation times of the species. The model is formulated in terms of a single delay-differential equation for the population density of an adult stage, with recruitment to the adult stage depending on the intensity of competition during the juvenile phase. This model is a simplified version of a group of models proposed by Gurney and Nisbet, who were the first to distinguish between single-generation cycles and delayed-feedback cycles. According to these authors, the two oscillation types are caused by different mechanisms and have periods in different intervals, which are one to two generation times for single generation cycles and two to four generation times for delayed-feedback cycles. By abolishing the strict coupling between the maturation time and the time delay between competition and its effect on the population dynamics, we find that single-generation cycles and delayed-feedback cycles occur in the same model version, with a gradual transition between the two as the model parameters are varied over a sufficiently large range. Furthermore, cycle periods are not bounded to lie within single octaves. This implies that a clear distinction between different types of generation cycles is not possible. Cycles of all periods and even chaos can be generated by varying the parameters that determine the time during which individuals from different cohorts compete with each other. This suggests that life-cycle features in the juvenile stage and during the transition to the adult stage are important determinants of the dynamics of density limited populations. PMID- 25453607 TI - The probability of improvement in Fisher's geometric model: a probabilistic approach. AB - Fisher developed his geometric model to support the micro-mutationalism hypothesis which claims that small mutations are more likely to be beneficial and therefore to contribute to evolution and adaptation. While others have provided a general solution to the model using geometric approaches, we derive an equivalent general solution using a probabilistic approach. Our approach to Fisher's geometric model provides alternative intuition and interpretation of the solution in terms of the model's parameters: for mutation to improve a phenotype, its relative beneficial effect must be larger than the ratio of its total effect and twice the difference between the current phenotype and the optimal one. Our approach provides new insight into this classical model of adaptive evolution. PMID- 25453608 TI - Reward and punishment hyposensitivity in problem gamblers: A study of event related potentials using a principal components analysis. AB - OBJECTIVE: To investigate whether the latent neural correlates of incentive processing differ between problem gamblers (PGs) and healthy controls (HCs). METHODS: Event-related potential (ERP) data were derived while 16 PGs and 20 HCs played a computer electronic gaming machine (EGM) task. Psychophysiological responses to outcomes commonly encountered during EGM gambling, including Large wins, Small wins, Near-wins, and Losses, were examined using a spatiotemporal principal components analysis (PCA). Subjects also completed questionnaires that assessed their levels of impulsivity, attraction to appetitive stimuli, and avoidance of aversive stimuli. RESULTS: Losses elicited a feedback-related negativity (FRN), whereas wins elicited a feedback-related positivity (FRP) at the same latency and topography. PGs exhibited both attenuated FRN amplitudes following Losses and FRP amplitudes following Wins. Greater P3b amplitudes were found following Wins compared to Losses. FRN amplitudes following Near-wins were significantly reduced compared to Losses for both PGs and HCs. Trends for reduced P3b amplitudes following all outcome types, and for similar P3b amplitudes following Large and Small wins, were found for the PG group. CONCLUSIONS: We provide evidence that PGs are hyposensitive to both positive and negative outcomes. SIGNIFICANCE: The finding that PGs are hyposensitive to reward and punishment provides valuable insight into the nature of deficit in this disorder, and provides a foundation for future research and clinical interventions. PMID- 25453609 TI - Impaired pre-attentive auditory processing in fibromyalgia: A mismatch negativity (MMN) study. AB - OBJECTIVE: Fibromyalgia (FM) patients often show deficits in cognitive functions such as attention and working memory. We assumed that pre-attentive information processing, a crucial element in human perception and cognition, would be altered in FM patients. Thus, the objective of this study was to determine whether FM patients exhibit alterations in pre-attentive processing as assessed by auditory mismatch negativity (MMN). METHODS: Auditory evoked magnetic fields were recorded in FM patients (n=18) and healthy control subjects (n=21) during a duration deviant auditory oddball paradigm. The magnetic mismatch negativity (MMNm) was obtained by subtracting responses to standard tones from responses to deviant tones. Pressure pain thresholds over the thenar and trapezius muscles were determined using an algometer. RESULTS: MMNm peak amplitudes in right hemispheres were attenuated, and the directional asymmetry coefficient of the MMNm amplitude was lower in FM patients, indicating a more leftward asymmetry than in healthy control subjects. Smaller right MMNm amplitude was associated with lower pressure pain thresholds of thenar muscles in FM patients. CONCLUSIONS: Our results suggested that pre-attentive processing of auditory information is impaired in FM patients. SIGNIFICANCE: This study provided neurophysiological evidence of impaired pre-attentive sensory change detection in FM. PMID- 25453610 TI - Preliminary evaluation of the sensitivity to change of DE-STA motor unit number estimation in the upper trapezius muscle in amyotrophic lateral sclerosis. AB - OBJECTIVE: To compare the sensitivity to change of decomposition-enhanced spike triggered averaging (DE-STA) motor unit number estimation (MUNE) in the upper trapezius (UT) to that of various clinical outcome measures in subjects with amyotrophic lateral sclerosis (ALS). METHODS: Ten patients with clinically probable or definite ALS were assessed at baseline, 2, 4 and 6months with the following outcome measures: manual muscle testing in five upper extremity muscle groups, scapular elevation and elbow flexion peak force measured with hand-held dynamometry, MUNE, forced vital capacity and the Revised ALS Functional Rating Scale (ALSFRS-R). RESULTS: ALSFRS-R was the only outcome measure for which there was a significant difference between baseline and 6months (p=0.034). ALSFRS-R had the largest standardized response mean (SRM), and was thus the most sensitive to change. MUNE demonstrated a decline over 6months and a moderate SRM (-0.63). CONCLUSIONS: This study has demonstrated a moderate degree of sensitivity to change for DE-STA MUNE as applied to the UT in subjects with ALS. SIGNIFICANCE: In this preliminary study, DE-STA MUNE detected motor unit loss over 6months, with a moderate degree of sensitivity, in the upper trapezius of subjects with ALS. PMID- 25453611 TI - Background noise can enhance cortical auditory evoked potentials under certain conditions. AB - OBJECTIVE: To use cortical auditory evoked potentials (CAEPs) to understand neural encoding in background noise and the conditions under which noise enhances CAEP responses. METHODS: CAEPs from 16 normal-hearing listeners were recorded using the speech syllable/ba/presented in quiet and speech-shaped noise at signal to-noise ratios of 10 and 30dB. The syllable was presented binaurally and monaurally at two presentation rates. RESULTS: The amplitudes of N1 and N2 peaks were often significantly enhanced in the presence of low-level background noise relative to quiet conditions, while P1 and P2 amplitudes were consistently reduced in noise. P1 and P2 amplitudes were significantly larger during binaural compared to monaural presentations, while N1 and N2 peaks were similar between binaural and monaural conditions. CONCLUSIONS: Methodological choices impact CAEP peaks in very different ways. Negative peaks can be enhanced by background noise in certain conditions, while positive peaks are generally enhanced by binaural presentations. SIGNIFICANCE: Methodological choices significantly impact CAEPs acquired in quiet and in noise. If CAEPs are to be used as a tool to explore signal encoding in noise, scientists must be cognizant of how differences in acquisition and processing protocols selectively shape CAEP responses. PMID- 25453612 TI - Occurrence of epileptiform discharges and sleep during EEG recordings in children after melatonin intake versus sleep-deprivation. AB - OBJECTIVE: To determine if melatonin is equally efficient as partial sleep deprivation in inducing sleep without interfering with epileptiform discharges in EEG recordings in children 1-16 years old. METHODS: We retrospectively analysed 129 EEGs recorded after melatonin intake and 113 EEGs recorded after partial sleep deprivation. Comparisons were made concerning occurrence of epileptiform discharges, the number of children who fell asleep and the technical quality of EEG recordings. Comparison between different age groups was also made. RESULTS: No significant differences were found regarding occurrence of epileptiform discharges (33% after melatonin intake, 36% after sleep deprivation), or proportion of unsuccessful EEGs (8% and 10%, respectively). Melatonin and sleep deprivation were equally efficient in inducing sleep (70% in both groups). Significantly more children aged 1-4 years obtained sleep after melatonin intake in comparison to sleep deprivation (82% vs. 58%, p?0.01), and in comparison to older children with melatonin induced sleep (58-67%, p?0.05). Sleep deprived children 9-12 years old had higher percentage of epileptiform discharges (62%, p?0.05) compared to younger sleep deprived children. CONCLUSION: Melatonin is equally efficient as partial sleep deprivation to induce sleep and does not affect the occurrence of epileptiform discharges in the EEG recording. Sleep deprivation could still be preferable in older children as melatonin probably has less sleep inducing effect. SIGNIFICANCE: Melatonin induced sleep have advantages, especially in younger children as they fall asleep easier than after sleep deprivation. The procedure is easier for the parents than keeping a young child awake for half the night. PMID- 25453613 TI - Spatial and temporal analysis of postural control in dyslexic children. AB - OBJECTIVE: The aim of this study is to examine postural control of dyslexic children using both spatial and temporal analysis. METHODS: Thirty dyslexic (mean age 9.7+/-0.3years) and thirty non-dyslexic age-matched children participated in the study. Postural stability was evaluated using Multitest Equilibre from Framiral(r). Posture was recorded in the following conditions: eyes open fixating a target (EO) and eyes closed (EC) on stable (-S-) and unstable (-U-) platforms. RESULTS: The findings of this study showed poor postural stability in dyslexic children with respect to the non-dyslexic children group, as demonstrated by both spatial and temporal analysis. In both groups of children postural control depends on the condition, and improves when the eyes are open on a stable platform. Dyslexic children have spectral power indices that are higher than in non-dyslexic children and they showed a shorter cancelling time. CONCLUSION: Poor postural control in dyslexic children could be due to a deficit in using sensory information most likely caused by impairment in cerebellar activity. SIGNIFICANCE: The reliability of brain activation patterns, namely in using sensory input and cerebellar activity may explain the deficit in postural control in dyslexic children. PMID- 25453614 TI - Progressive demyelinating neuropathy correlates with clinical severity in Cockayne syndrome. AB - OBJECTIVE: Cockayne syndrome (CS) is characterized by postnatal growth failure and progressive multi-organ dysfunctions. CSA and CSB gene mutations account for the majority of cases and three degrees of severity are delineated. A peripheral neuropathy is known to be associated with CS but the type, severity and correlation of the nerve involvement with CS subtypes remain unknown in genetically identified patients. METHODS: Clinical and nerve conduction studies (NCS) in 25 CS patients with CSA (n=13) CSB (n=12) mutations. RESULTS: NCS show a widespread decrease in motor and sensory conduction velocities (CV) in all severe and classical form of CS. In one patient, CV were normal at age 8months but severe slowing was detected at 2years. Conduction block and/or temporal dispersion were observed in 68% of patients. CONCLUSIONS: CS is associated with a progressive sensory and motor neuropathy. Signs of segmental demyelination, including conduction blocks, may not be obvious before the age of 2years. CV slowing is correlated with the CS clinical severity. SIGNIFICANCE: NCS should be performed in patients with suspected CS as an additional tool to guide the diagnosis before molecular studies. Further studies focused on NCS course are required in order to assess its relevance as a biomarker in research therapy projects. PMID- 25453615 TI - Commentary on: The prevalence of cervical myelopathy among subjects with narrow cervical spinal canal in a population-based magnetic resonance imaging study: the Wakayama Spine Study. PMID- 25453616 TI - Commentary on: intraoperative fluoroscopy, portable X-ray, and CT: patient and operating room personnel radiation exposure in spinal surgery. PMID- 25453617 TI - Letter to the editor in response to Villa T, La Barbera L, Galbusera F, "comparative analysis of international standards for the fatigue testing of posterior spinal fixation systems". PMID- 25453618 TI - Reply to the letter to the editor entitled: response to "comparative analysis of international standards for the fatigue testing of posterior spinal fixation systems". PMID- 25453619 TI - Phase II clinical trial of S-1 plus oral leucovorin in previously treated patients with non-small-cell lung cancer. AB - BACKGROUND: S-1, a novel oral fluoropyrimidine, has potent antitumor activity against non-small-cell lung cancer (NSCLC). Meanwhile, leucovorin enhances the efficacy of 5-fluorouracil by inhibiting thymidylate synthase. Therefore, this phase II clinical trial evaluated the safety and efficacy of S-1 plus leucovorin combination therapy for previously treated patients with NSCLC. PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC were prospectively enrolled if they received 1 or 2 prior chemotherapy regimens. S-1 (40-60 mg) and leucovorin (25mg) were administered together orally twice per day for 7 consecutive days followed by 7 days of rest. This 2-week cycle was repeated for a maximum of 25 cycles until the onset of disease progression or unacceptable adverse events. Endpoints included objective tumor response, progression-free survival, overall survival, and safety. RESULTS: Among 33 patients, 6 (18.2%), 14 (42.4%), and 11 (33.3%) had partial response, stable disease, and progressive disease, respectively. Median progression-free and overall survival times were 3.5 and 11.7 months, respectively. The common grade 3 toxicities included stomatitis (18.2%), anorexia (12.1%), and neutropenia (9.1%). One patient had pneumatosis cystoides intestinalis, and another experienced paralytic ileus. There were no treatment related deaths. CONCLUSIONS: S-1 plus leucovorin combination therapy demonstrated promising efficacy and an acceptable toxicity profile in previously treated patients with NSCLC. PMID- 25453621 TI - Behavioral correlates of epileptiform abnormalities in autism. AB - There is a high incidence of epileptiform abnormalities in children with autism even in the absence of clinical seizures. These findings are most prominent during sleep recordings. The significance of these abnormalities is unclear. Although studies do not all agree, there may be some association between cognitive function, behavior, and the presence or absence of epileptiform discharges. Small studies of anticonvulsant treatment mostly suggest an improvement in certain aspects of cognitive or behavioral functioning in these children, but larger and more comprehensive studies are needed to determine the potential relationship between epileptiform discharges on EEG, cognitive and behavioral functioning, and treatment effects in the population with autism. This article is part of a Special Issue entitled "Autism and Epilepsy". PMID- 25453620 TI - Absence of occult Hepatitis E virus infection among HIV immunosuppressed patients. PMID- 25453622 TI - A brief history of Epilepsy & Behavior. AB - This article is part of a Special 15th Anniversary Issue. PMID- 25453623 TI - Metrics and Epilepsy & Behavior. AB - This article is part of a Special 15th AnniversaryIssue. PMID- 25453624 TI - Comments on Kanner AM et al. The use of sertraline in patients with epilepsy: is it safe? Epilepsy & Behavior 2000;1:100-105. AB - This article is part of a Special 15th AnniversaryIssue. PMID- 25453625 TI - A prospective, longitudinal study of patient satisfaction following total knee arthroplasty using the Short-Form 36 (SF-36) survey stratified by various demographic and comorbid factors. AB - The purpose of this study was to evaluate the longitudinal variations in SF-36 physical and mental scores and the effects of demographics and comorbidities after TKA. This prospective study evaluated 108 men and 173 women who had a mean age of 66 years. All patients were followed for a minimum of five years and SF-36 physical and mental component scores were evaluated longitudinally. Physical scores steadily increased during the first year whereas mental component scores initially decreased in the first six weeks and then subsequently increased and both plateaued at one year. Demographic and social factors had a greater effect on physical component scores and comorbidities were more predictive of poor mental scores. Surgeons should counsel their patients that they will likely perceive the full benefit of TKA by one year, but in the first months may perceive worse outcomes. PMID- 25453626 TI - Pelvic tilt in patients undergoing total hip arthroplasty: when does it matter? AB - Pelvic tilt (PT) affects the functional anteversion and inclination of acetabular components in total hip arthroplasty (THA). One-hundred and thirty-eight consecutive patients who underwent unilateral primary THA were reviewed. Most cases had some degree of pre-operative PT, with 17% having greater than 10 degrees of PT on standing pre-operative radiographs. There was no significant change in PT following THA. A computer model of a hemispheric acetabular component implanted in a range of anatomic positions in a pelvis with varying PT was created to determine the effects of PT on functional anteversion and inclination. Based on the study results, tilt-adjustment of the acetabular component position based on standing pre-operative imaging will likely improve functional component position in most patients undergoing THA. PMID- 25453627 TI - Radiographic comparison of mobile-bearing partial knee single-peg versus twin-peg design. AB - The femoral component and proprietary instrumentation of a mobile-bearing unicompartmental knee arthroplasty (UKA) was redesigned with an additional peg for enhanced fixation, 15 degrees of extra femoral surface for contact in deep flexion, more rounded profile, better fit into the milled surface, and redesigned intramedullary based instrumentation. To assess the benefit of these changes, we compared postoperative radiographs of 219 single-peg and 186 twin-peg UKAs done in 2008-2011. All surviving knees demonstrated satisfactory position and alignment with no radiolucencies observed. Radiographic analysis showed improved and consistent component positioning with the twin-peg design implanted with updated instrumentation compared with the single-peg. The radiographic benefits of improved implant positioning using the twin-peg component and updated instrumentation are clear and carry tremendous potential. More robust follow-up is imperative. PMID- 25453628 TI - Obesity, morbid obesity and their related medical comorbidities are associated with increased complications and revision rates after unicompartmental knee arthroplasty. AB - Recent studies have demonstrated clinical success in expanding the indications for unicompartmental knee arthroplasty (UKA) to patients with increased body mass index (BMI). This study utilized national databases to identify 15,770 unique patients who underwent UKA between 2005 and 2011. 18.7% of patients undergoing a UKA were obese or morbidly obese. Univariate analysis demonstrated that obesity and morbid obesity were associated with significantly higher complication rates within 90 days postoperatively compared to non-obese patients. The overall short term revision rate in obese and morbidly obese patients undergoing UKA was almost twice as high as the revision rate in non-obese patients. Obese and morbidly obese patients being considered for UKA should be counseled preoperatively regarding their increased risk of postoperative complications and revision surgery. PMID- 25453629 TI - Surprising results in an article in press from your journal. PMID- 25453630 TI - Mobile compression devices and aspirin for VTE prophylaxis following simultaneous bilateral total knee arthroplasty. AB - Recently, Levy et al questioned the effectiveness of mobile compression devices (MCDs) as the sole method of thromboprophylaxis following simultaneous bilateral total knee arthroplasty (TKA). This study's purpose was to assess if the addition of aspirin to MCDs improves venous thromboembolism (VTE) prevention following simultaneous bilateral TKA. Ninety-six patients (192 TKAs) were retrospectively reviewed: 47 patients received MCDs for 10 days and aspirin for 6 weeks postoperatively based on a risk stratification protocol, while 49 patients received warfarin for 4 weeks postoperatively. One symptomatic VTE was noted in the warfarin cohort, while one patient in the MCD/aspirin cohort and three patients in the warfarin cohort were readmitted within 3 months of surgery. In appropriately selected patients, MCDs with aspirin shows promise in VTE prevention following simultaneous bilateral TKA. PMID- 25453631 TI - Failure of a novel ceramic-on-ceramic hip resurfacing prosthesis. AB - We report the early failure of five ceramic-on-ceramic hip resurfacings (CoCHRs). The ceramic used for the acetabular liner was a novel ceramic-composite (two thirds polyurethane and one third alumina ceramic). All cases were revised for increasing metal ion levels (blood cobalt 3.93-208.0 MUg/l and chromium 1.57-17.5 MUg/l) due to ceramic liner fracture and/or accelerated wear of the ceramic femoral head coating. Patients underwent bearing exchange and revision using primary hip arthroplasty implants at a mean of 3.0 years following CoCHR. Intraoperatively all patients had metallosis. At 1 to 2 years of follow-up blood metal ions normalized with no complications. We do not recommend this particular type of ceramic-on-ceramic bearing for hip resurfacing. PMID- 25453632 TI - Anterior vs. posterior approach for total hip arthroplasty, a systematic review and meta-analysis. AB - The objective of this study is to compare the clinical, radiographic and surgical outcomes among patients undergoing primary THA performed via the anterior versus posterior approach. We searched numerous sources and eventually included 17 studies, totaling 2302 participants. In terms of post-operative pain and function, the anterior approach was significantly favored in 4 studies at short term follow-up. Pooled estimates showed a significant difference in favor of the anterior approach in terms of length of stay and dislocations. Current evidence comparing outcomes following anterior versus posterior THA does not demonstrate clear superiority of either approach. Until more rigorous, randomized evidence is available, we recommend choice of surgical approach for THA be based on patient characteristics, surgeon experience and surgeon and patient preference. PMID- 25453633 TI - Precision of robotic guided instrumentation for acetabular component positioning. AB - Robotic computerized instrumentation that guides bone preparation and cup implantation in total hip arthroplasty was studied. In 38 patients (43 hips) intraoperative cup inclination and anteversion were validated by postoperative CT scans. Planned inclination was 39.9 degrees +/-0.8 degrees and with robotic instrumentation was 38. 0 degrees +/-1.6 degrees with no outliers of 5 degrees ; on the postoperative CT scan there were 5 outliers (12%). Planned anteversion was 21.2 degrees +/-2.4 degrees and intraoperatively was 20.7 degrees +/-2.4 degrees with no outlier of 5 degrees ; on the CT there were 7 outliers (16%). The center of rotation (COR) was superior by a mean 0.9+/-4.2 mm and medial by 2.7+/-2.9 mm. This robotic instrumentation achieved precision of inclination in 88%, anteversion in 84% and COR in 81.5%. PMID- 25453634 TI - Is preoperative staphylococcal decolonization efficient in total joint arthroplasty. AB - Intranasal carrier status of Methicillin-sensitive Staphylococcus aureus (MSSA), and Methicillin-resistant Staphylococcus aureus (MRSA) has been shown to be a significant risk factor for developing surgical site infections. To determine if current treatment protocol for positive nasal screen was effective at decolonizing carriers 289 consecutive patients undergoing primary or revision total joint arthroplasty were screened preoperatively. Those patients with positive cultures were treated with a 5-day course of intranasal mupirocin. Preoperatively 44 (15.2%) patients tested positive for MSSA colonization, and 12 (4.2%) patients for MRSA. Testing on the day of surgery revealed 15 (5.2%) patients with MSSA positive cultures, and 1 (0.35%) patient with a MRSA positive culture. Reduction of MSSA and MRSA colonization was statistically significant (P=0.0341, P=0.0073 respectively). Our overall results indicate that our current decolonization protocol with nasal mupirocin was effective in reducing MSSA and MRSA colonization, although a significant number of patients remained positive for MSSA. PMID- 25453635 TI - Cognitive biases mediate the relationship between temperament and character and psychotic-like experiences in healthy adults. AB - Psychotic-like experiences (PLEs) are frequently reported in the general population. Healthy individuals reporting PLEs have a similar personality profile to people with psychosis; however, the mechanisms by which personality influences PLEs are unclear. This study tests the hypothesis that cognitive biases mediate the relationship between two dimensions of personality (i.e. temperament and character) and positive and negative PLEs. Two hundred and ninety-six healthy participants were assessed using the Community Assessment of Psychic Experiences scale, the Temperament and Character Inventory and the Davos Scale for Cognitive Biases. We performed multiple stepwise regression analysis and mediation analysis according to Baron and Kenny's method. Harm-avoidance and self-directedness personality dimensions significantly predicted PLEs frequency. High self transcendence and lower cooperativeness predicted positive PLEs. Cognitive biases were significant mediators in relationships between temperament, character and both positive and negative PLEs. In particular, attention to threat and external attribution biases fully mediate the relationship between cooperativeness and positive PLEs. Other cognitive biases partially mediate the relationships between self-transcendence and positive PLEs and self-directedness, harm-avoidance and negative PLEs. Our study tentatively suggests that personality may influence PLEs via the cognitive bias pathway. PMID- 25453638 TI - Neuropsychological profile and treatment-related features among patients with comorbidity between schizophrenia spectrum disorder and obsessive-compulsive disorder: is there evidence for a "schizo-obsessive" subtype? AB - Epidemiological studies have found that obsessive-compulsive disorder (OCD) is estimated to occur in 12% of patients with schizophrenia. Whether this "schizo obsessive" subgroup may be posited as a clinical entity with a distinct neuropsychological profile and treatment-related features remains unclear. A sample of 30 patients who met DSM-IV criteria for both schizophrenia/schizoaffective disorder and OCD was compared with 30 OCD subjects and with 37 patients with schizophrenia/schizoaffective disorder. Neuropsychological domains were measured by the Wechsler Adult Intelligence Scale - Third Edition (WAIS-III), the Trail Making Test (TMT), and the verbal fluency test (FAS). Treatment-related variables were assessed with the Clinical Global Improvement scale (CGI), the Drug Attitude Inventory (DAI), and dosage/type of antipsychotic medications. One-way analysis of variance revealed statistically significant differences among the three groups in "working memory," "block design," "semantic fluency," TMT-A, and TMT-B. However, the Bonferroni correction showed no statistical differences between both psychotic groups. In addition, there were no significant differences among the three groups in the CGI and DAI, although "schizo-obsessive" patients tended to display slightly higher scores on these variables than the other groups. Overall, these findings do not support the hypothesis that comorbidity between schizophrenia spectrum disorders and OCD may reflect a distinct clinical entity. However, further research with larger sample sizes and a more comprehensive clinical assessment are needed. Our findings also underscore the fact that divergences among assessment instruments, as well as confounding variables, may influence results on neuropsychological domains. PMID- 25453636 TI - Increased Interleukin-17 and decreased BAFF serum levels in drug-free acute schizophrenia. AB - Hypotheses regarding an immune-cytokine basis of schizophrenia have been postulated with controversial findings and a lack of data related to many cytokines. The aim of this study was to assess serum levels of Interferon-gamma (IFN-gamma), Interleukin-4 (IL-4), Transforming Growth Factor-beta (TGF-beta), Interleukin-17 (IL-17) and B-cell Activating Factor (BAFF) in schizophrenic patients and to determine correlations between cytokine levels and clinical parameters. Serum cytokine levels were measured with ELISA techniques in 60 neuroleptic-free patients on acute phase of the disease (BPRS>=40) and 28 healthy controls matched for age and sex. Current symptoms were assessed with Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS). No significant difference was found between patients and controls regarding IFN-gamma serum levels. IL-4 was not detected in both groups. Patients exhibited significantly higher IL-17 and lower BAFF serum levels. IL-17 and BAFF levels were negatively correlated in schizophrenic patients. SANS global score was negatively correlated with IL-17 and positively correlated with IFN-gamma serum levels. These results argue against the involvement of Th1 or Th2 population cells in schizophrenia. IL-17 and BAFF could be valuable markers for schizophrenia. PMID- 25453637 TI - Trauma exposure and PTSD in women with schizophrenia and coexisting substance use disorders: comparisons to women with severe depression and substance use disorders. AB - The present study compared rates of trauma exposure and PTSD among three groups of women at high trauma risk: those with substance use disorders (SUD) and schizophrenia (n=42), those with SUD and severe, nonpsychotic depression (n=38), and those with SUD and no other DSM-IV Axis I condition (n=37). We hypothesized that exposure to traumatic stressors and current diagnosis of PTSD would be more common in women with schizophrenia and SUD, when compared to the other two groups. Results indicate that women with schizophrenia and SUD had a more extensive trauma history than women with SUD only, and were also more likely to have PTSD. Women with schizophrenia had a fourfold greater likelihood of meeting criteria for current PTSD than were women with severe, nonpsychotic depression when potential confounds of age, race, education, severity of trauma history, and childhood trauma exposure were controlled. These results lend support to the possibility that women with psychosis have an elevated vulnerability to PTSD symptomology when exposed to life stressors that is distinct from the vulnerability associated with coexisting nonpsychotic SMI. The psychological sequelae of trauma are substantial and should be addressed in women seeking treatment for schizophrenia and problematic substance use. PMID- 25453639 TI - A comparison of capacities for social cognition and metacognition in first episode and prolonged depression. AB - There is a growing awareness that social cognition is a valuable construct for understanding the psycho-social disabilities in depressive illness. Numerous studies have linked affective disorders to impairments in social cognition and specifically the processing of discrete emotional stimuli. Only few studies have investigated the relation between the burden of depressive illness and social cognitive ability. To study these issues, we compared a group of first-episode depressed patients with a group of chronically depressed patients (duration >2 years) on a broad array of higher-order social cognitive measures including the metacognition assessment scale abbreviated. Contrary to prediction, deficits in social cognition were roughly equivalent between the two groups and there was no significant link between symptom severity and social cognitive ability. Having moderate to severe major depressive disorder (MDD) could be sufficient to predict the presence of deficits in social cognitive ability. PMID- 25453640 TI - Age structure at diagnosis affects aggression in a psychiatric inpatient population: age structure affecting inpatient aggression. AB - Study of inpatient aggression in psychiatric inpatient units (PIUs), where vulnerable patients interact intensely in small groups, is hampered by a lack of systematic monitoring of aggressive events in the context of group dynamics. Our current study examines the relationship between aggression and group structure in the PIU of a general tertiary-care hospital over a 9-month period. The severity of aggression was monitored daily using the Overt Aggression Scale (OAS). Clinical data including the daily number and mean age of subpopulations with different diagnoses were acquired. Cross-correlation function and autoregressive integrated moving average modeling were used to assess the effects of various group structure parameters on the incidence of aggressive events in the PIU. The daily total OAS score correlated positively with the daily mean age of patients with schizophrenia and bipolar disorder. By contrast, the OAS total score demonstrated a negative correlation with the daily mean age of patients with major depression. The age of the patients at diagnosis is an important group structure that affects the incidence of aggression in a PIU. PMID- 25453641 TI - Problems of reliability and validity with similarity derived from category fluency. AB - This study aims to assess the reliability and the validity of exemplar similarity derived from category fluency tasks. A homogeneous sample of 21 healthy participants completed a category fluency task twice with an interval of one week. They also rated pairs comprised of the most frequently generated exemplars in terms of similarity. Similarities were derived from the fluency data by determining the average distance between generated exemplars and correcting it for repetitions and response sequence length. We calculated the correlation between the similarities derived from the two sessions of the fluency task and between the derived similarities and the directly rated similarities. Spatial representations of the similarities were constructed using multidimensional scaling to visualize the differences between both sessions of the fluency task and the pairwise rating task. We find that the derived similarities are not stable in time and show little correspondence with directly rated similarities. The differences between similarities derived from category fluency tasks in healthy participants, indicate that similar differences between healthy controls and patients with mental disorders, do not necessarily point to a semantic impairment of the latter, but rather reflect the unreliability of the data. PMID- 25453642 TI - Personality traits as predictors for the outcome of lithium augmentation in treatment-resistant depression. AB - The NEO Personality Inventory-Revised (NEO) and the Temperament and Character Inventory (TCI) were administered to patients with treatment-resistant depression (n=21) before lithium augmentation. Analysis showed that the poor outcome group (n=11) had lower openness scores on the NEO, and lower cooperativeness scores on the TCI compared with the good outcome group (n=10). These findings may be predictors of poor responsiveness to lithium augmentation in the treatment of antidepressant-resistant depression. PMID- 25453643 TI - Accreditation program for blood banking and cell therapy services - a defining moment in the expansion and qualification of Brazilian services. PMID- 25453645 TI - Scientific comment on the theme of palliative care in pediatric hematological oncology patients. PMID- 25453644 TI - We need to talk more about transfusion-transmitted malaria in Plasmodium vivax endemic areas. PMID- 25453646 TI - 'Leaky gut' in hematological malignancies. PMID- 25453647 TI - Comment on "Nutritional status of patients submitted to transplantation of allogeneic hematopoietic stem cells: a retrospective study". PMID- 25453648 TI - Normative evaluation of blood banks in the Brazilian Amazon region in respect to the prevention of transfusion-transmitted malaria. AB - OBJECTIVE: To evaluate blood banks in the Brazilian Amazon region with regard to structure and procedures directed toward the prevention of transfusion transmitted malaria (TTM). METHODS: This was a normative evaluation based on the Brazilian National Health Surveillance Agency (ANVISA) Resolution RDC No. 153/2004. Ten blood banks were included in the study and classified as 'adequate' (>=80 points), 'partially adequate' (from 50 to 80 points), or 'inadequate' (<50 points). The following components were evaluated: 'donor education' (5 points), 'clinical screening' (40 points), 'laboratory screening' (40 points) and 'hemovigilance' (15 points). RESULTS: The overall median score was 49.8 (minimum=16; maximum=78). Five blood banks were classified as 'inadequate' and five as 'partially adequate'. The median clinical screening score was 26 (minimum=16; maximum=32). The median laboratory screening score was 20 (minimum=0; maximum=32). Eight blood banks performed laboratory tests for malaria; six tested all donations. Seven used thick smears, but only one performed this procedure in accordance with Ministry of Health requirements. One service had a Program of External Quality Evaluation for malaria testing. With regard to hemovigilance, two institutions reported having procedures to detect cases of transfusion-transmitted malaria. CONCLUSION: Malaria is neglected as a blood-borne disease in the blood banks of the Brazilian Amazon region. None of the institutions were classified as 'adequate' in the overall classification or with regard to clinical screening and laboratory screening. Blood bank professionals, the Ministry of Health and Health Surveillance service managers need to pay more attention to this matter so that the safety procedures required by law are complied with. PMID- 25453649 TI - Palliative care in pediatric hematological oncology patients: experience of a tertiary hospital. AB - OBJECTIVE: To evaluate the approach to palliative care for hematological oncology patients in the pediatric ward of a tertiary hospital. METHODS: This was a retrospective, descriptive study of 29 hematological oncology patients who died between 2009 and 2011. Data regarding the approach and prevalence of pain, prevalence of other symptoms, multidisciplinary team participation, communication between staff and family and limited invasive therapy were collected from the medical records. RESULTS: Twenty-seven (93.1%) patients displayed disease progression unresponsive to curative treatment. The median age at death was ten years old. Pain was the most prevalent symptom with all patients who reported pain receiving analgesic medications. The majority took weak (55.2%) and/or strong (65.5%) opioids. The patients were followed by pediatricians and a pediatric hematologist/oncologist. Participation of other professionals was also documented: 86.2% were followed by social services and 69% by psychologists, among others. There were explicit descriptions of limitation of invasive therapy in the medical records of 26 patients who died with disease progression. All these decisions were shared with the families. CONCLUSION: Although the hospital where this study was conducted does not have a specialized team in pediatric palliative care, it meets all the requirements for developing a specific program. The importance of approaching pain and other prevalent symptoms in children with cancer involving a comprehensive multidisciplinary team is evident. Discussions were had with most of the families on limiting invasive therapy, but no record of a well-defined and coordinated treatment plan for palliative care was found. PMID- 25453650 TI - Intestinal permeability in leukemic patients prior to chemotherapy. AB - OBJECTIVE: The objective of this study was to evaluate the intestinal barrier function in leukemia patients before the start of the chemotherapy with an intestinal permeability test using lactulose and mannitol as markers. METHODS: The study enrolled 20 patients diagnosed with leukemia (acute and chronic). Ten healthy volunteers were also submitted to the test as a control group. RESULTS: The median lactulose/mannitol ratio was 0.019 for the Leukemia Patient Group, whereas in healthy controls the median was 0.009 (p-value=0.244). The median lactulose/mannitol ratio in acute leukemia patients was 0.034 giving a p-value of 0.069 when compared to healthy controls. This same comparison was made between acute myeloid leukemia patients and healthy controls with a p-value of 0.149. There was no significant difference in the intestinal permeability between acute and chronic leukemia patients (p-value=0.098). CONCLUSION: The intestinal barrier function measured using the intestinal permeability test was similar in leukemic patients overall and healthy controls, but a tendency toward a different pattern was found in the intestinal barrier function of acute leukemia patients. PMID- 25453651 TI - Nutritional status of patients submitted to transplantation of allogeneic hematopoietic stem cells: a retrospective study. AB - OBJECTIVE: This study aimed to describe and compare the nutritional status of adult patients submitted to allogeneic hematopoietic stem cell transplantation at two different time points (admission and discharge). METHODS: A retrospective, descriptive and quantitative study was performed based on clinical, laboratory and nutritional data obtained from medical records of adult patients of both genders submitted to allogeneic hematopoietic stem cell transplantation in a bone marrow transplantation reference center in Rio de Janeiro in the period from 2010 to 2013. Statistical analysis was performed using the SPSS software (version 22.0). RESULTS: Sixty-four patients were evaluated. The mean age was 42.1+/-3.2 years and the most prevalent disease was acute myeloid leukemia (39%). There was a high prevalence of gastrointestinal symptoms including nausea (100%), vomiting (97%) and mucositis (93%). Between admission and discharge there was a significant decrease in the median weight (-2.5kg; 71.5 vs. 68.75kg; p value<0.001), body mass index (-0.9kg/m(2); 24.8 vs. 24.4kg/m(2); p-value<0.001), and serum albumin levels (-0.2g/dL; 3.7 vs. 3.6g/dL; p-value=0.024). The survival time after hematopoietic stem cell transplantation correlated negatively with C reactive protein at discharge (CC=-0.72; p-value<0.001) and positively with serum albumin levels (CC=0.56; p-value=0.004) and with high total protein level at discharge (CC=0.53; p-value=0.006). CONCLUSION: Our results suggest that patients submitted to allogeneic hematopoietic stem cell transplantation have compromised nutritional status during the hospital stay for transplantation. PMID- 25453652 TI - Nutritional status of children and adolescents at diagnosis of hematological and solid malignancies. AB - OBJECTIVE: To assess the nutritional status of child and adolescent patients with cancer at diagnosis. METHODS: A total of 1154 patients were included and divided into two groups: solid and hematological malignancies. The parameters used for nutritional assessment were weight, height, triceps skinfold thickness, mid-upper arm circumference, arm muscle circumference, body mass index and percentage weight loss. RESULTS: At diagnosis, below adequate body mass index was observed by anthropometric analysis in 10.85% of the patients - 12.2% in the solid tumor group and 9.52% in the hematologic group. The average weight loss adjusted for a period of 7 days was -2.82% in the hematologic group and -2.9% in the solid tumor group. CONCLUSIONS: The prevalence of malnutrition is higher among patients with malignancies than in the general population, even though no difference was observed between the two groups. PMID- 25453653 TI - Evaluation of red cell and reticulocyte parameters as indicative of iron deficiency in patients with anemia of chronic disease. AB - OBJECTIVE: The purpose of this study was to evaluate the effectiveness of mature red cell and reticulocyte parameters under three conditions: iron deficiency anemia, anemia of chronic disease, and anemia of chronic disease associated with absolute iron deficiency. METHODS: Peripheral blood cells from 117 adult patients with anemia were classified according to iron status, and inflammatory activity, and the results of a hemoglobinopathy investigation as: iron deficiency anemia (n=42), anemia of chronic disease (n=28), anemia of chronic disease associated with iron deficiency anemia (n=22), and heterozygous beta thalassemia (n=25). The percentage of microcytic red cells, hypochromic red cells, and levels of hemoglobin content in both reticulocytes and mature red cells were determined. Receiver operating characteristic analysis was used to evaluate the accuracy of the parameters in differentiating between the different types of anemia. RESULTS: There was no significant difference between the iron deficient group and anemia of chronic disease associated with absolute iron deficiency in respect to any parameter. The percentage of hypochromic red cells was the best parameter to discriminate anemia of chronic disease with and without absolute iron deficiency (area under curve=0.785; 95% confidence interval: 0.661-0.909, with sensitivity of 72.7%, and specificity of 70.4%; cut-off value 1.8%). The formula microcytic red cells minus hypochromic red cells was very accurate in differentiating iron deficiency anemia and heterozygous beta thalassemia (area under curve=0.977; 95% confidence interval: 0.950-1.005; with sensitivity of 96.2%, and specificity of 92.7%; cut-off value 13.8). CONCLUSION: The indices related to red cells and reticulocytes have a moderate performance in identifying absolute iron deficiency in patients with anemia of chronic disease. PMID- 25453655 TI - Hemophagocytic lymphohistiocytosis: a case series of a Brazilian institution. AB - OBJECTIVE: To describe the clinical and laboratory presentation of hemophagocytic lymphohistiocytosis in children treated at a referral institution. METHODS: A retrospective descriptive study was carried out of seven children diagnosed with hemophagocytic lymphohistiocytosis between 2010 and 2012. The criteria for diagnosis were those proposed by the Histiocyte Society. When indicated, immunochemotherapy was prescribed according to the HLH94 and HLH2004 protocols of the Histiocyte Society. RESULTS: The patients' ages at diagnosis ranged from one month to nine years. All patients had splenomegaly, fever, anemia, thrombocytopenia, hyperferritinemia and hypertriglyceridemia. Bone marrow hemophagocytosis was detected in six patients. In six cases, infectious diseases triggered the syndrome. In two cases, associated with visceral leishmaniasis, remission was achieved after treatment of the underlying infection. Three patients, who had Epstein-Barr-related hemophagocytic lymphohistiocytosis, required treatment with immunochemotherapy. They are alive and in remission; one patient had symptoms of juvenile rheumatoid arthritis and another, who was suspected of having primary hemophagocytic lymphohistiocytosis, entered into remission after bone marrow transplantation. Two deaths (28.6%) occurred in patients with suspected primary hemophagocytic lymphohistiocytosis; one whose clinical picture was triggered by cytomegalovirus infection did not respond to immunochemotherapy and the other died before any specific treatment was provided. CONCLUSION: As reported before, hemophagocytic lymphohistiocytosis has a multifaceted presentation with nonspecific signs and symptoms. In secondary forms, remission may be achieved by treating the underlying disease. In the primary forms, remission may be achieved with immunochemotherapy, but bone marrow transplantation is required for cure. PMID- 25453656 TI - Myelodysplastic syndrome with synchronous gastric cancer: when the symptoms suggest something else. AB - Although myelodysplastic syndromes have a clear definition in theory, the morphologic dysplasia associated with ineffective hematopoiesis may be subtle and difficult to recognize and can commonly be mimicked by systemic conditions, such as infections, autoimmune disorders, nutritional deficiencies, toxic factors and non-hematological malignancies. However, myelodysplastic syndromes may truly coexist with other systemic diseases, which can be masked when the patient's symptoms are attributed exclusively to myelodysplastic syndromes without further investigation. To better illustrate this, we herein describe two cases associated with synchronous gastric cancers. PMID- 25453654 TI - Klotho: its various functions and association with sickle cell disease subphenotypes. AB - The Klotho protein, whose gene has predominant renal expression, acts in the control of serum phosphorus and 1,25-dihydroxyvitamin D3 and regulates the function of ion channels. It also participates in the mechanism of protection against oxidative stress and acts on the vascular endothelium by inducing the production of nitric oxide. Mutations that reflect defects in the Klotho gene expression may be implicated in the onset of osteonecrosis, priapism, and leg ulcers in patients with sickle cell disease, as a result of oxidative stress and endothelial impairment, important factors in the development and severity of this disease. Previous reports regarding the association of Klotho single nucleotide polymorphisms with sickle cell disease subphenotypes have found that these polymorphisms are important to identify genetic markers of risk in these individuals and allow early and more effective therapeutic intervention. PMID- 25453657 TI - Accident involving a 2-year-old child and Lonomia obliqua venom: clinical and coagulation abnormalities. AB - Poisons of caterpillars have different effects on inflammatory and coagulation systems. This is a case report of a 2-year-old child that accidentally came in contact with several caterpillars of the species Lonomia obliqua. At first, the patient's exams presented abnormal coagulation and decreased fibrinogen, but the patient did not evolve to active bleeding or acute renal failure. The patient received antilonomic serum 15h after the accident and the treatment was repeated after another 12h due to persistent alterations shown by the coagulation exams. The venom of L. obliqua has several substances that act on the coagulation and inflammatory systems. The event is characterized by a hemorrhagic syndrome with decreases in fibrinogen. L. obliqua Stuart-factor activator (Losac) and L. obliqua prothrombin activator protease (Lopap) are components that act with procoagulatory effects. The pro-inflammatory action occurs due to metalloproteases, hyaluronidases and other substances with inflammatory activity. Studies on caterpillar venom can give new perspectives on the treatment of cancer and other diseases that cause dysfunction of the extra-cellular matrix. PMID- 25453658 TI - Prevalence of anemia in 2673 of 6- and 7-year-old schoolchildren from Sao Jose dos Campos, State of Sao Paulo. PMID- 25453659 TI - Guidelines on the treatment of anemia of chronic renal failure using recombinant human erythropoietin: Associacao Brasileira de Hematologia, Hemoterapia e Terapia Celular Guidelines Project: Associacao Medica Brasileira - 2014. PMID- 25453660 TI - Biocompatible long-sustained release oil-core polyelectrolyte nanocarriers: From controlling physical state and stability to biological impact. AB - It has been generally expected that the most applicable drug delivery system (DDS) should be biodegradable, biocompatible and with incidental adverse effects. Among many micellar aggregates and their mediated polymeric systems, polyelectrolyte oil-core nanocarriers have been found to successfully encapsulate hydrophobic drugs in order to target cells and avoid drug degradation and toxicity as well as to improve drug efficacy, its stability, and better intracellular penetration. This paper reviews recent developments in the formation of polyelectrolyte oil-core nanocarriers by subsequent multilayer adsorption at micellar structures, their imaging, physical state and stability, drug encapsulation and applications, in vitro release profiles and in vitro biological evaluation (cellular uptake and internalization, biocompatibility). We summarize the recent results concerning polyelectrolyte/surfactant interactions at interfaces, fundamental to understand the mechanisms of formation of stable polyelectrolyte layered structures on liquid cores. The fabrication of emulsion droplets stabilized by synergetic surfactant/polyelectrolyte complexes, properties, and potential applications of each type of polyelectrolyte oil-core nanocarriers, including stealth nanocapsules with pegylated shell, are discussed and evaluated. PMID- 25453661 TI - Evidence-based medicine for ultrasound-guided regional anesthesia. AB - Available evidence favoring the use of ultrasound for regional anesthesia is reviewed, updated, and critically assessed. Important outcome advantages include decreased time to block onset; decreased risk of local anesthetic systemic toxicity; and, depending on the outcome definition, increased block success rates. Ultrasound guidance, peripheral nerve blocks, and central neuraxial blocks are discussed. PMID- 25453662 TI - Role of regional anesthesia in orthopedic trauma. AB - Regional anesthesia plays a key role in the treatment of patients with orthopedic trauma. Trauma-induced pain can be in multiple locations, severe, and can predispose the patient to other morbidities. Additional complications as a result of the overdependence on opioids as a primary pain therapy that can be minimized or avoided with the use of regional anesthesia. Both neuraxial and peripheral regional techniques in patients with orthopedic trauma should be incorporated into the patient care plan and recognized as an essential therapeutic intervention in the overall treatment of this unique patient population. PMID- 25453663 TI - Which outcomes related to regional anesthesia are most important for orthopedic surgery patients? AB - An increasing body of evidence supports the benefits of regional anesthesia in orthopedic surgery. Compared with systemic anesthetic and analgesic approaches, these benefits include more focused and sustained pain control, less systemic side effects, improved patient comfort, earlier mobilization and hospital discharge, lower rates of advanced service requirements, and lower perioperative morbidity and mortality. However, there is discussion about the various outcomes as judged by patients and heath care practitioners. This article recapitulates the literature and presents an overview of endpoints. PMID- 25453664 TI - Optimizing perioperative care for patients with hip fracture. AB - Hip fracture is one of the most common orthopedic conditions associated with significant morbidity and mortality. Patients with hip fracture are usually older, with significant comorbidities. Delayed surgical treatment beyond 48 hours after admission is associated with significantly higher mortality. Hereby clinicians are presented with the challenge to optimize the complex hip fracture within a short time period. This article reviews the evidence regarding preoperative, intraoperative, and postoperative considerations, and provides insights into the best strategies with which to optimize the patient's condition and improve perioperative outcomes. PMID- 25453665 TI - Regional anesthesia-analgesia: relationship to cancer recurrence and infection. AB - The basic principles of perioperative immune function with regard to cancer recurrence and infection are reviewed. The role of regional anesthesia-analgesia in preservation of immune function and available published data are discussed. PMID- 25453666 TI - Developing a multidisciplinary fall reduction program for lower-extremity joint arthroplasty patients. AB - With the anticipated increase in the number of total joint arthroplasty surgeries and associated fall risks, a fall reduction program can provide greater safety for patients in the postoperative period. Although further prospective studies are needed among total joint arthroplasty patients, there is sufficient evidence to show that a successful fall reduction program can be implemented. Common components to date have included a multidisciplinary team, multicomponent interventions specific to the risks associated with total knee and hip arthroplasty patients, education of patients and staff, and strategies to promote adherence to the program. PMID- 25453667 TI - Optimizing perioperative management of total joint arthroplasty. AB - Clinical pathways for total joint arthroplasty have been shown to reduce costs and significantly impact perioperative outcomes mainly through reducing provider variability. Effective clinical pathways link evidence to individual practice and balance costs with local experience, outcomes, and access to resources for responsible perioperative management. Common components of clinical pathways with major impact on perioperative outcomes are: 1) implementing pathways designed to include multimodal analgesia with regional anesthesia, 2) use of tranexamic acid to reduce blood loss, and 3) preconditioning followed by participation in early, accelerated rehabilitation programs to prevent postoperative complications related to immobility. PMID- 25453668 TI - Preoperative evaluation and preparation of patients for orthopedic surgery. AB - Orthopedic patients frequently have multiple comorbidities when they present for surgery. This article discusses risk stratification of this population and the preoperative work-up for patients with specific underlying conditions who often require orthopedic procedures. Preoperative strategies to decrease exposure to allogeneic blood and advantages of the Perioperative Surgical Home model in this unique population are discussed. PMID- 25453669 TI - Setting up an acute pain management service. AB - Successful implementation of an acute pain management service involves a team approach in which team members have clearly defined roles. Clinical protocols are designed to help address common problems and prevent errors. As the complexity of surgery and patients' diseases continues to increase, current knowledge of new analgesic medications, acute pain literature, and skills in regional anesthesia techniques is imperative. Emphasizing a multimodal approach can improve analgesia and decrease opioid-related side effects. PMID- 25453670 TI - Setting up an ambulatory regional anesthesia program for orthopedic surgery. AB - This article presents an overview of how to set up an ambulatory regional anesthesia program for orthopedic surgery. This information is valuable to anesthesiologists who want to expand their regional anesthesia practice and provides a greater understanding of relevant issues and strategies to maximize success. PMID- 25453671 TI - Perioperative management of the opioid tolerant patient for orthopedic surgery. AB - The prevalence of opioid use in the North America and some countries of the European Union has resulted in an increase in the number of patients who may exhibit opioid tolerance when requiring postoperative pain management. The approach to postoperative pain control in these patients is different from the strategies used in opioid-naive patients. Better understanding of the cellular mechanisms of opioid tolerance in animals has resulted in the transfer of these concepts from the basic research to the clinical arena. This article presents new developments in opioid tolerance and how this knowledge can be applied to clinical practice. PMID- 25453673 TI - Orthopedic anesthesia. Preface. PMID- 25453674 TI - A time for giving. PMID- 25453675 TI - Shaping undergraduate professional identities through mentoring and promoting the future of nursing. PMID- 25453676 TI - Results of the 2014 AORN Salary and Compensation Survey. AB - AORN conducted its 12th annual compensation survey for perioperative nurses in June and July 2014. A multiple regression model was used to examine how a number of variables, including job title, education level, certification, experience, and geographic region, affect nurse compensation. Comparisons between the data from 2014 and data from previous years are presented. The effects of other forms of compensation (eg, on-call compensation, overtime, bonuses, shift differentials) on base compensation rates also are examined. Additional analyses explore the effect of the economic downturn on the perioperative work environment. PMID- 25453677 TI - Key issues in infection prevention: an overview. PMID- 25453678 TI - Patient care interventions to help reduce the risk of surgical site infections. PMID- 25453679 TI - The role of the OR environment in preventing surgical site infections. PMID- 25453680 TI - Endoscope reprocessing in 2014: why is the margin of safety so small? PMID- 25453681 TI - Going forward: preventing surgical site infections in 2015. PMID- 25453682 TI - RP implementation: specimen management. AB - Effective specimen management in the perioperative setting is essential for accurate patient diagnosis and intervention. AORN's "Recommended practices for specimen management" provides guidance to help perioperative nurses, in collaboration with a multidisciplinary team, implement a specimen management process that includes a needs assessment, site identification, collection and handling, transfer from the sterile field, containment, specimen identification and labeling, preservation, transport, disposition, and documentation. Accurate specimen management requires effective multidisciplinary communication and an awareness of the potential opportunities for error. Specimens discussed in the recommended practices document include breast cancer specimens, amputated digits and limbs to be reattached, forensic and radioactive specimens, and explanted medical devices and orthopedic hardware. The recommendations are applicable to both hospital and ambulatory settings. PMID- 25453683 TI - Comparative efficacy of alcohol-based surgical scrubs: the importance of formulation. AB - Alcohol-based surgical scrubs (ABSSs) are used to prevent surgical site infections. Chlorhexidine gluconate (CHG) often is added to enhance persistent germicidal activity. The aim of this study was to determine the influence of ABSS product formulation on efficacy. We evaluated three commercially available ABSS formulations and one control alcohol formulation according to the surgical scrub methodology specified by the US Food and Drug Administration (FDA). Only one ABSS formulation met FDA efficacy requirements when tested at the manufacturer's recommended dosage. In contrast, two ABSS formulations, one of which contained CHG, failed to meet the FDA acceptance criteria for a 3-log10 reduction on day 5, meaning the formulations did not sufficiently reduce bacteria levels on hands on the fifth day of product application. The data suggest that recommendations to include CHG in ABSS formulations should be reconsidered, and product efficacy, skin tolerability, and user acceptability should be evaluated on a case-by-case basis. PMID- 25453684 TI - Effectiveness of transmucosal sedation for special needs populations in the ambulatory care setting. AB - Transmucosal is an alternative route for administering medications (ie, dexmedetomidine, midazolam, naloxone) that can be effective for procedural or moderate sedation in patients with special needs when other routes are not practical or are contraindicated. Special needs populations include children, older adults, pregnant and breast-feeding women, and people with disabilities or conditions that limit their ability to function and cope. Understanding the perioperative nurse's role in the care of patients receiving medications via the transmucosal route can lead to better clinical outcomes. Successful use of the transmucosal route requires knowledge of when to administer a medication, how often and how much of a medication should be administered, the onset and duration of action, the adverse effects or contraindications, and the key benefits. In addition, a case study approach suggests that transmucosal sedation can decrease patient stress and anxiety related to undergoing medical procedures or surgery in the ambulatory care setting. PMID- 25453685 TI - Projects for increasing job satisfaction and creating a healthy work environment. AB - Workplace culture is one of the biggest factors driving employee commitment and engagement. Multiple studies have shown that hospitals will perform better over time if employees are committed to their jobs and engaged in what they do. By creating and implementing multiple projects during a three-year period, a team at the University of Florida Health Shands Hospital, Gainesville, increased job satisfaction. Projects included ensuring meal breaks were offered, creating a serenity area, developing the patient ambassador role, actively addressing bullying and unprofessional behavior, assigning a student mentee to work with staff members on culture change, offering regular fun activities, redesigning the unit, reorganizing schedules to reduce stress, implementing education and training initiatives, establishing a Unit Practice Council, and implementing reward and recognition programs. Survey results and anecdotal evidence suggest that these projects combined to increase employee satisfaction and employee retention rates. PMID- 25453686 TI - Computerized provider order entry: advancing technology today, saving lives tomorrow. PMID- 25453687 TI - Avoiding needlestick injuries: establishing a culture of safety in the or. PMID- 25453689 TI - Anesthesia: a weighty issue. PMID- 25453690 TI - Oppositional defiant disorder (ODD), the forerunner of alcohol dependence: a controlled study. AB - There are common genetic, neurobiological and psycho-social substrates for oppositional defiant disorder (ODD) and substance dependence. ODD can be regarded as the mildest and earliest form of disruptive behavioral disorder and also represents the threshold of vulnerability for substance dependence. But it is a less researched area. The aim of this research was to study any possible association between childhood ODD and adult alcohol dependence. Data are presented from a non probability sample of 100 adult alcohol dependent subjects and equal number of biologically unrelated control subjects. Assessment was conducted by the instrument Semi-Structured Assessment for the Genetics of Alcoholism for both the assessment of ODD and alcohol dependence. The results of this study demonstrated significant association between childhood ODD and adult alcohol dependence. The association remained significant even after the exclusion of the possible confounding effects of the presence of conduct disorder and attention deficit hyperactivity disorder. Our study should encourage further research in this area and is expected to open up an opportunity for preventive research. PMID- 25453691 TI - A naturalistic study of suicidal adolescents treated with an SSRI: suicidal ideation and behavior during 3-month post-hospitalization period. AB - OBJECTIVE: Describe suicidal ideation and suicide related/other emergencies (SRE), among depressed and acutely suicidal adolescents during a 3-month period following psychiatric hospitalization. METHODS: One hundred twenty adolescents, who were both depressed and suicidal, were receiving an SSRI either alone or in combination with other medications, remained on a consistent medication regimen between baseline and at 3-months and their 3-month outcome data were available. The participants were divided into four medication groups: SSRI antidepressant only (n=71); SSRI plus mood stabilizer (n=17); SSRI plus antipsychotic (n=20); and SSRI plus antipsychotic and mood stabilizer (n=12). Standardized instruments were used. RESULTS: Mean age=15.5+/-1.3, Caucasian=80.8%, female=74.2%, mean CDRS R=61.7+/-12.1, suicide attempt during month prior to hospitalization=58.6%. During the 3-month post-hospitalization period: (1) there were no suicides, six participants (5%) attempted suicide and 21 (17.5%) experienced an SRE; (2) decline in suicidal ideation and depression severity was noted; (3) SSRI plus an antipsychotic group reported the highest number of SREs; (4) higher baseline hopelessness and aggression scores were associated with greater reduction in suicidal ideation at 3-months. CONCLUSION: Declines in suicidal ideation, depression severity, and suicide attempts were noted, irrespective of psychotropic-combination received. A higher rate of SREs was associated with receiving an antipsychotic agent in combination with an SSRI. Given naturalistic design of study, cause-effect conclusions cannot be drawn. The lack of an objective measure to identify medication adherence is a study limitation. PMID- 25453692 TI - Trust in Physician Scale: factor structure, reliability, validity and correlates of trust in a sample of Nigerian psychiatric outpatients. AB - BACKGROUND: Trust is essential in the patient-physician relationship and has not been explored among Nigerian psychiatric outpatients. OBJECTIVES: The purpose of this study was to evaluate the psychometric characteristics of the Trust in Physician Scale among a cross-sectional sample of stable Nigerian outpatients receiving treatment for psychiatric disorders. METHODS: A consecutive sample of outpatients attending a Nigerian university teaching hospital psychiatric clinic in South-western Nigeria completed the scale (N=223). Factorial analysis, internal consistency, validity and correlates of the scale were evaluated. RESULTS: The structure of the Trust in Physician Scale was best explained by a 2 factor construct. Cronbach's alpha was 0.68, indicating a rather modest degree of internal consistency. The 2 factors extracted also had modest internal consistencies (Cronbach's alpha 0.66 and 0.76). A fair degree of construct validity was indicated by weak positive correlation of trust with medication adherence and the numbers of previous admissions. The mean trust score was relatively high. Significant positive correlations were observed between trust scores and adherence score, number of previous admissions and the number of schizophrenic relapses. CONCLUSION: The results suggest that despite the comparatively weak psychometric properties of the Trust in Physician Scale, it is still useful in the evaluation of trust among Nigerian psychiatric outpatients. More studies are needed to further explore and compare the properties of this scale across a wider range of patient groups in Nigeria, and to identify other factors that could interact with trust among the different patient populations in our environment. PMID- 25453693 TI - Examining posttraumatic stress disorder's latent structure between treatment seeking and non-treatment-seeking Filipinos. AB - BACKGROUND: The discourse of latent structure of posttraumatic stress disorder (PTSD) has been extensive in trauma literature. Although findings have been consistent in rejecting DSM-IV-TR's three-factor model, alternative models are still fervently argued. This study contributes to the discussion by examining and comparing PTSD factor structure of the three most validated models-numbing model (King et al., 1998), dysphoria model (Simms et al., 2002), and dysphoric arousal model (Elhai et al., 2011b)-and determining if these are generalizable across treatment-seeking and non-treatment-seeking Filipinos with exposure to trauma events. METHODS: Filipino-Tagalog version of Harvard Trauma Questionnaire (HTQ; Mollica et al., 1992) was administered to a sample of 737 treatment-seeking (n=526) and non-treatment-seeking (n=211) Filipinos who experienced and witnessed varied trauma events. Confirmatory factor analysis (CFA) was conducted involving the three models in order to determine the best-fitting model and generalizability across samples. RESULTS: Results showed that all three models achieved excellent fit, with dysphoric arousal model slightly fitting better than numbing and dysphoria models in both treatment-seeking and non-treatment-seeking samples. Series of invariance testing, however, indicated that although dysphoric arousal model fits significantly better than dysphoria model, it did not significantly differ from numbing model. Results revealed that aside from the factor loadings, the two groups are noninvariant in all parameters. Treatment seeking sample had larger intercepts, factor variances and covariances and factor means than non-treatment-seeking group. DISCUSSION: The findings strongly contribute to the literature by showing how the type of groupings (treatment seeking vs. non-treatment-seeking) moderates PTSD latent structure. It affirms the suggestion of Biehn et al. (2012) to be cautious in concluding the generalizability of PTSD models in the context that type of participants moderates PTSD's factor structure. PMID- 25453694 TI - Malaysian parent and teacher ratings of the oppositional defiant disorder symptoms: measurement invariance and parent-teacher agreement. AB - BACKGROUND: This study evaluated the measurement invariance and agreement across parent and teacher ratings of the DSM-IV-TR oppositional defiant disorder (ODD) symptoms. METHOD: Malaysian parents and teachers of 934 children (between 6 and 11 years of age) completed rating scales comprising the ODD symptoms. RESULTS: Findings showed support for full measurement invariance (configural, metric and thresholds). Additional results indicated low parent-teacher agreement for all symptoms. DISCUSSION: The theoretical and clinical and implications of these findings are discussed. PMID- 25453695 TI - Antipsychotic induced metabolic changes & treatment response: a prospective study. AB - BACKGROUND: Metabolic side effects of antipsychotics contribute to morbidity and non-compliance in treatment of psychosis. Multiple studies suggest that metabolic side effects correlate with response to antipsychotic treatment. However, few studies have systematically looked at this. We conducted an exploratory, naturalistic, prospective, trans-diagnostic study to examine this association. METHODS: 100 patients with psychosis, initiated on antipsychotic treatment alone, were assessed on Brief Psychiatric Rating Scale (BPRS), visual analog scale for appetite, anthropometric measurements (weight, waist circumference, body mass index), and fasting serum lipid and glucose profiles at baseline, 2-4 weeks (n=71) and 8-12 weeks (n=39). RESULTS: Subjects who dropped out at first/second follow-ups did not differ from those who followed-up, in age, sex, illness duration and BPRS scores. On forward stepwise multiple linear regression analysis, early (2-4 weeks) increase in appetite and triglyceride levels (R(2)=0.257; p=0.003) together predicted 26% variance in treatment response (BPRS score reduction) at first follow-up. At second follow-up 16% of variance in treatment response was predicted by early (2-4 weeks) increase in triglyceride levels (R(2)=0.169; p=0.009). CONCLUSIONS: Early appetite and triglyceride changes predicted antipsychotic treatment response. Involvement of dopaminergic, serotonergic and histaminergic neural pathways could explain the association between appetite and treatment response. Insulin signaling pathways have been implicated in lipid changes with antipsychotics. Study findings suggest metabolic side effects may be early predictors of antipsychotic response. These findings warrant further examination to elucidate the interaction between metabolic pathways and psychotic illnesses, and possibly mechanism of action of antipsychotics beyond dopamine blockade. PMID- 25453696 TI - Preliminary findings on lifetime trauma prevalence and PTSD symptoms among adolescents in Sarawak Malaysia. AB - OBJECTIVE: The objective of this study is to determine the prevalence of lifetime exposure to traumatic events and its relation to PTSD symptoms. METHODS: Participants were randomly selected from several schools located in the city of Kuching. There were 85 adolescents participating in this study, with ages ranging from 13 to 14 years old, of whom 31% (n=26) were males and 69% (n=59) females. The Child Posttraumatic Stress Index-Revised, The Harvard Trauma Questionnaire and a lifetime trauma checklist were used in this study. RESULTS: Results showed that 77.6% of participants were exposed to at least one lifetime trauma. The most frequently reported traumas were road accident (20.1%), death of a family member (19.7%), and almost drowning (10%). There was more indirect trauma than direct trauma exposure. Males were more likely to be involved in traumatic events than females. Results showed that 7.1% (6) exhibited PTSD symptoms. There was no significant difference in the mean score of CPTS-RI between genders and among ethnic groups. Total exposure to traumatic events was significantly correlated with PTSD symptoms. CONCLUSION: Findings suggest that number of lifetime traumatic events was quite high and multiple exposures to traumatic events were significantly related to PTSD symptoms. PMID- 25453697 TI - A study of worry and functional somatic symptoms in generalized anxiety disorder. AB - OBJECTIVE: To study the phenomenon of worry and functional somatic symptoms in Generalized Anxiety Disorder (GAD). METHOD: 40 subjects with the diagnosis of GAD were assessed by using Penn State Worry Questionnaire (PSWQ) and Bradford Somatic Inventory (BSI). Severity of GAD was rated on Generalized Anxiety Disorder -7 (GAD-7) scale. RESULTS: The mean total score on PSWQ was 59.62. All patients had somatic symptoms and the minimum number of somatic symptoms noted in a patient was 11 and maximum was 38. Seventy-five percent of the patients had more than 22 somatic symptoms as per BSI. Majority of the patients (90%) scored more than 10 on GAD-7 scale. CONCLUSION: Future nosological systems should not limit assessment of somatic symptoms to a list of 6 symptoms only in patients with GAD and should try to operationalise the definition of excessive worry by taking into consideration the common types of worries. PMID- 25453698 TI - Verbal self-monitoring in individuals with schizotypal personality traits: an exploratory ERP study. AB - INTRODUCTION: Individuals with schizophrenia have deficits in verbal self monitoring. This study aimed to assess whether individuals vulnerable to develop schizophrenia show similar difficulties. METHODS: Fifteen individuals with schizotypal personality traits and 15 healthy controls participated. All participants underwent an event-related potential (ERP) paradigm using a phoneme monitoring Go/No-Go task. RESULTS: Behavioural results showed that there was no significant difference between individuals with schizotypal personality traits and controls in post-error slowing, but schizotypal individuals had a significantly lower degree of error awareness and higher error rate. In the ERP data, when compared with controls, individuals with schizotypal personality traits showed similar error-related negativity (ERN) amplitude but significantly larger error positivity (Pe) amplitude. CONCLUSIONS: Results of this study suggest that verbal error detection may be intact in individuals with schizotypal personality traits. However, it seems that this vulnerable population may have a greater emotional evaluation of errors. PMID- 25453699 TI - 'SMS' for mental health-feasibility and acceptability of using text messages for mental health promotion among young women from urban low income settings in India. AB - OBJECTIVE: The current study assesses the acceptability and feasibility of mobile text messages for promoting positive mental health and as a helpline among young women in urban slums of Bangalore. METHODOLOGY: Forty girls in the age range of 16-18 years from urban slums received messages every day for a month. They could call or message back or give a 'missed call' to the same number whenever they had emotional problems or felt like talking to a counselor. The received responses in the form of return texts, missed calls and return phone calls were recorded. Feedback about the feasibility and acceptability of the mobile messages was collected after a month. RESULTS: 25 out of 40 (62.5%) participants called back, asking for mental health services and to say they felt good about the messages. 23 of 40 (57.5%) messaged back regarding their feelings. 62% reported that they felt supported with the mental health messages. Male family members of nearly half of the participants called back to check the authenticity of the source. Most women did not face any problems because of the messages. CONCLUSION: This pilot qualitative study indicates that mobile text messages are a feasible and culturally acceptable method for mental health promotion and prevention among young women from urban slums in India. Issues such as consent from the woman and family, ensuring confidentiality and providing authentic and reliable support services, need to be taken into account before attempting to scale up such a service, particularly in vulnerable groups. PMID- 25453700 TI - Insight in psychosis: an independent predictor of outcome or an explanatory model of illness? AB - While the traditional view within psychiatry is that insight is independent of psychopathology and predicts the course and outcome of psychosis, recent data from India argues that insight is secondary to interaction between progression of illness on one hand and local culture and social environment on the other. The findings suggest that "insight" is an explanatory model (EM) and may reflect attempts at coping with the devastating effects of mental disorders. Most societies are pluralistic and offer multiple, divergent and contradictory explanations for illnesses. These belief systems interact with the trajectory of the person's illness to produce a unique personal understanding, often based on a set of complex and contradictory EMs. Like all EMs, insight provides meaning to explain and overcome challenges including disabling symptoms, persistent deficits, impaired social relations and difficult livelihood issues. The persistence of distress, impairment, disability and handicap, despite regular and optimal treatment, call for explanations, which go beyond the simplistic concept of disease. People tend to choose EMs, which are non-stigmatizing and which seem to help explain and rationalize their individual concerns. The frequent presence of multiple and often contradictory EMs, held simultaneously, suggest that they are pragmatic responses at coping. The results advocate a non-judgmental approach and broad based assessment of EMs of illness and their comparison with culturally appropriate beliefs, attributions and actions. The biomedical model of illness should be presented without dismissing patient beliefs or belittling local cultural explanations for illness. Clinical practice demands a negotiation of shared model of care and treatment plan between patient and physician perspectives. The diversity of patients, problems, beliefs and cultures mandates the need to educate, match, negotiate and integrate psychiatric and psychological frameworks and interventions. It calls for multifaceted and nuanced understanding of "insight" and explanatory models of illness. PMID- 25453701 TI - Computerized cognitive behavior therapies in psychiatry: a viable option in India? PMID- 25453702 TI - "Where do patients with severe mental illness go after dropping out of psychiatric care?"-An exploratory study using pathways to care approach. PMID- 25453703 TI - Association between antipsychotic-induced metabolic side-effects and clinical improvement: a review on the evidence for metabolic threshold: author's response. PMID- 25453704 TI - Metabolic threshold does not describe it all. PMID- 25453705 TI - Appraisal systems for psychiatric residents: is it time for change? PMID- 25453707 TI - Multiple antipsychotic induced neutropenia-a possible genetic association. PMID- 25453708 TI - Association of foetal APGAR and maternal brain derived neurotropic factor levels in postpartum depression. PMID- 25453706 TI - Targeted, intermittent booster tDCS: a novel add-on application for maintenance treatment in a schizophrenia patient with refractory auditory verbal hallucinations. PMID- 25453709 TI - Child and adolescent changes to DSM-5. AB - AIM: To describe child and adolescent changes to the DSM-5 and discuss controversial changes. METHOD: Relevant changes to the structure and categorization of DSM-5 childhood conditions are examined, and controversial issues noted. RESULTS: Important overlaps between a number of new conditions are described, and questions raised in relation to underlying assumptions about some new categories. CONCLUSION: Further research is required to determine the validity of new conditions, and the clinical and service effects of structural changes, particularly in respect of overlapping disorders, and categorical vs severity descriptors. PMID- 25453710 TI - Separation anxiety disorder across the lifespan: DSM-5 lifts age restriction on diagnosis. AB - DSM-5 has lifted the age criterion in the definition of separation anxiety disorder thereby overturning the long-standing convention of restricting the diagnosis to childhood. Previously, adults with separation anxiety symptoms were assigned to other conventional categories such as panic disorder, agoraphobia or generalized anxiety disorder. Over the past two decades, an evolving body of research has identified separation anxiety disorder in adulthood, with 20-40% of adult psychiatric outpatients being assigned that diagnosis. In the US, the lifetime prevalence of the disorder in adulthood is 6.6%. The removal of the age restriction on diagnosis has important implications for clinical practice. Whereas parents (particularly mothers) of children with separation anxiety disorder commonly attracted the diagnosis of agoraphobia, the latter are more likely now to be diagnosed with the adult form of separation anxiety disorder, focusing attention on the importance of intervening with both members of the dyad to overcome mutual reinforcement of symptoms. In addition, adults with separation anxiety disorder have been found to manifest high levels of disability and they tend to show a poor response to conventional psychological and pharmacological treatments. There is an urgent need therefore to devise novel psychological and pharmacological interventions for the adult form of the disorder. The reformulation of separation anxiety disorder in DSM-5 therefore requires a paradigm shift in which clinicians are alerted to identifying and treating the condition in all age groups. Research across countries is needed to examine the new formulation of separation anxiety disorder amongst populations of diverse ethnic and cultural backgrounds. PMID- 25453711 TI - Disruptive behaviour disorders and DSM-5. AB - This article provides an overview of the revisions to the diagnoses of oppositional defiant disorder (ODD) and conduct disorder (CD) in DSM-5, and examines the key issues they raise. Particular attention is given to these changes in light of current treatment outcome evidence, including that published since the development of DSM-5. For both ODD and CD, DSM-5 retains the core features that previously defined the phenotypes for these diagnoses. DSM-5 nonetheless introduces a number of revisions pertaining to the guidelines for the application of these criteria, and markers for key individual differences in presentations of these disorders. These revisions reflect small but significant steps towards the perspective that children with disruptive behaviour problems are a highly heterogeneous population, and best characterised on the basis of both behavioural and emotional features. Importantly, there is growing evidence that the newly introduced changes to these diagnoses in DSM-5 may be better able to inform predictions regarding treatment response than previous diagnostic criteria. PMID- 25453712 TI - Tourette's: syndrome, disorder or spectrum? Classificatory challenges and an appraisal of the DSM criteria. AB - The fifth version of the Diagnostic and statistical manual of mental disorders (DSM-5) was released in May 2013 after 14 years of development and almost two decades after the last edition DSM-IV was published in 1994. We review the DSM journey with regards to Tourette Syndrome from the original publication of DSM 1 in 1952 till date. In terms of changes in DSM 5, the major shift has come in the placement of Tourette Syndrome under the 'Neurodevelopmental Disorders' alongside other disorders with a developmental origin. This review provides an overview of the changes in DSM-5 highlighting key points for clinical practice and research along with a snap shot of the current use of DSM as a classificatory system in different parts of the world and suggestions for improving the subtyping and the diagnostic confidence. PMID- 25453713 TI - DSM 5 and child psychiatric disorders: what is new? What has changed? AB - The significant changes in DSM 5 as these relate to a number of the child psychiatric disorders are reviewed by several authors in this special issue: In this paper we address some of the changes in the conceptual organisation of DSM 5 and specifically focus on anxiety and related disorders. In the case of child and adolescent psychiatry, the most notable feature is that the chapter on Disorders Usually First Diagnosed in infancy, Childhood or Adolescence has been deleted. Instead, a new chapter in DSM 5 describes Neurodevelopmental Disorders which typically manifest early in development. Further, an expectation had been built that DSM would be based on the latest data in neuroscience and that a clear direction towards a mixed dimensional and categorical approach would be evident. This has been the case with some disorders and a notable example is the removal of Obsessive Compulsive Disorder (OCD) from the Anxiety Disorder chapter and placement with other related disorders that share similar neurobiology and treatment response. In this regard, the addition in DSM 5 of a new specifier "tic related" to OCD is worth noting as there is emerging evidence that differential treatment response exists when tics are associated with OCD. The same situation applies to tics with ADHD, thus presenting the argument for a dimensional approach to Tic Spectrum Disorder (TSD) incorporating categories such as those with tics only, tics with OCD, tics with ADHD etc. to be given due consideration in the future. Another important change that clinicians in the field of child psychiatry will no doubt notice is the demise of the multiaxial classification. Instead, DSM 5 has moved back to a nonaxial documentation of diagnosis with separate notations for important psychosocial and contextual factors as well as level of functioning and disability. Clinicians are urged, however, to continue to recognise the need to understand how symptoms and behaviours might have arisen and assess relevant contextual factors such as the family relationships, quality of care, any history of abuse, and so on. Further, the move to harmonise DSM 5 with the structure of ICD 11 (scheduled for release in 2015) should make understanding and familiarising oneself with the two major classificatory systems easier in the future. PMID- 25453715 TI - Validation of the French version of the MacNew heart disease health-related quality of life questionnaire. AB - BACKGROUND: Assessment of health-related quality of life is widely recommended by European health agencies in relevant research studies as well as in clinical care. AIMS: To validate the French version of the MacNew heart disease health related quality of life questionnaire. METHODS: As part of the International HeartQoL Project, 323 French-speaking patients with ischaemic heart disease (angina, n=76; myocardial infarction [MI], n=155; heart failure, n=91; mean age 58.6+/-11.3 years) were recruited at seven cardiac rehabilitation centres. All patients completed the French versions of the MacNew questionnaire, the Short Form-36 Health Survey (SF-36) and the Hospital Anxiety and Depression Scale, to evaluate the psychometric properties of the French version of the MacNew instrument. RESULTS: The mean MacNew global scale scores were 4.6+/-0.8, 5.0+/ 1.0 and 4.8+/-0.9 in patients with angina, MI and heart failure, respectively (P<0.05, MI versus angina). We observed minimal missing items and ceiling effects and no floor effects. Factor analysis confirmed a three factorial structure explaining 55.9% of the observed variance. Internal consistency reliability (Cronbach's alpha) ranged from 0.86 to 0.94 and test-retest reliability ranged from 0.68 to 0.73 Convergent validity was confirmed in the total group and each diagnosis, although the correlations between the MacNew physical subscale and the SF-36 mental component summary were higher than expected. Discriminative validity was partially confirmed with the SF-36 health transition item and fully confirmed with anxiety and depression as predictor variables. CONCLUSION: The French version of MacNew questionnaire is recommended for assessing health-related quality of life in French-speaking patients with ischaemic heart disease. PMID- 25453716 TI - Multivariable assessment of the right ventricle by echocardiography in patients with repaired tetralogy of Fallot undergoing pulmonary valve replacement: a comparative study with magnetic resonance imaging. AB - BACKGROUND: Evaluation of the right ventricle (RV) using transthoracic echocardiography is challenging in patients with repaired tetralogy of Fallot (rTOF). AIMS: To evaluate the accuracy of conventional echocardiographic variables and real-time three-dimensional echocardiography (RT3DE) in assessing right ventricular (RV) volumes and function compared with magnetic resonance imaging (MRI), in adult patients with rTOF and referred for pulmonary valve replacement (PVR). METHODS: Complete echocardiography was performed on 26 consecutive patients referred for PVR, before and 1 year after surgery. All variables were compared with MRI. RESULTS: Correlations between conventional variables and MRI were absent or poor when assessing RV ejection fraction (RVEF), except for fractional area of change (FAC; r=0.70, P<0.01 before PVR; r=0.68, P<0.01 after PVR) and RT3DE (r=0.96, P<0.01 before PVR; r=0.98, P<0.01 after PVR). The RV volume correlation between RT3DE and MRI was excellent before and after surgery for RV end-diastolic volume (r=0.88, P<0.01 and r=0.91, P<0.01, respectively) and RV end-systolic volume (r=0.92, P<0.01 and r=0.95, P<0.01, respectively). The accuracy of these indices, as a diagnostic test for impaired RV (<45%), was good: Youden's indexes varied from 0.47 to 0.89; areas under the receiver operating characteristic curve before and after PVR were 0.86 and 0.81 for FAC and 0.98 and 0.97 for RT3DE, respectively. CONCLUSION: Commonly used echocardiography variables, such as tricuspid annular plane systolic excursion and tricuspid annular peak systolic velocity, did not sensitively evaluate global RVEF. A global approach, that includes the whole RV and integration of its different components, was more reliable in patients with rTOF. PMID- 25453714 TI - DSM-5: disruptive mood dysregulation disorder. AB - This paper will describe historical perspectives for the introduction of disruptive mood dysregulation disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), criteria for the diagnosis, as well as information on epidemiology, clinical presentation and longitudinal course, pathophysiology, and treatment. The diagnosis of disruptive mood dysregulation disorder requires frequent, persistent, severe temper outbursts out of proportion to the situation and developmental context in combination with persistent, angry/irritable mood between the temper outbursts. Because of the limited available data, the inclusion of this new diagnosis in DSM-5 has been controversial. Regardless of this controversy, it is clear that youth experiencing such symptoms are highly impaired and utilize significant health services. Therefore, we need to expand our efforts to better understand the complex construct of this phenotype in order to improve the assessment, diagnosis and treatment of this condition. PMID- 25453717 TI - Ischaemic postconditioning reduces infarct size: systematic review and meta analysis of randomized controlled trials. AB - BACKGROUND: Infarct size (IS) is a major determinant of patient outcome after acute ST-segment elevation myocardial infarction (STEMI). Interventions aimed at reducing reperfusion injury, such as cardiac ischaemic postconditioning (IPost), may reduce IS and improve clinical outcomes. IPost has been shown to be feasible in patients with STEMI treated by primary percutaneous coronary intervention (PPCI). AIMS: To provide an updated summary of the efficacy of IPost, assessed by analysing accurate surrogate markers of IS. METHODS: We performed a meta-analysis of randomized controlled trials that evaluated the efficacy of IPost in STEMI patients undergoing PPCI. The main outcome was area under the curve of serum creatine kinase release (CK-AUC). Secondary outcomes were other surrogate biomarkers of IS, complete ST-segment resolution, direct measurement of IS by single-photon emission computed tomography and estimation of IS by cardiac magnetic resonance (CMR-IS). RESULTS: Eleven studies were retrieved, including 1313 STEMI patients undergoing PPCI with or without IPost. Compared with controls, we observed a significant reduction in CK-AUC (standard mean difference [SMD] -2.84 IU/L, 95% CI -5.43 to -0.25 IU/L; P=0.03). Other surrogate markers, such as CMR-IS (SMD -0.36, 95% CI -0.88 to 0.15; P=0.16), showed a non significant IS reduction in the IPost group. CONCLUSIONS: This meta-analysis, dealing with accurate surrogate markers of IS, suggests that IPost reduces IS. However, results should be interpreted cautiously because of limited sample sizes and significant heterogeneity. Whether this translates into improvements in cardiac function and patient prognosis still needs to be demonstrated in larger prospective randomized controlled studies that are powered sufficiently. PMID- 25453719 TI - Prevalence of "red flags" among the internet user with low back pain seeking information on spinal health-a web survey. AB - BACKGROUND: In early management of low back pain (LBP) the identification of "red flags" (RFs) plays an important role, as this condition is highly prevalent, and advanced treatment would not be feasible in every case. These alarm signs are designed to detect serious causes requiring prompt interventions, such as malignancy, fracture, inflammation, or cauda equina syndrome. Although their predictive value has been questioned, they are commonly used in clinical practice. The use of RFs in Web applications has never been evaluated before. In theory, they should reduce risks related to online counseling on LBP, screening for possible potentially serious underlying conditions based on relatively simple questionnaires. This study was designed to assess the prevalence of RFs among Internet users with LBP seeking information about spinal disorders. MATERIALS AND METHODS: Of 2,471 respondents who completed the RF questionnaire, 2,349 entries were used for analysis. Of another 1,959 respondents who completed the additional questionnaire containing the Oswestry Disability Scale, data from 1,850 were included in the study. RESULTS: The majority of subjects (68.16%) reported at least one RF. The most prevalent RF was a foot weakness; the least prevalent was unexplained weight loss. Pain intensity was a significant risk factor for presence of at least one RF. CONCLUSIONS: The results show that RFs are highly prevalent and that most likely the negative predictive value of RFs will be low. Unfortunately, considering the nature of this study it was impossible to evaluate their sensitivity and specificity. In conclusion, although RFs are highly prevalent in the population studied, simple screening should be mandatory in all Web sites providing information on spinal health. Further research should be undertaken to optimize RFs. PMID- 25453718 TI - Melody (r) transcatheter pulmonary valve implantation: results from a French registry. AB - BACKGROUND: Percutaneous implantation of pulmonary valves has recently been introduced into clinical practice. AIM: To analyse data of patients treated in France between April 2008 and December 2010. METHODS: Prospective, observational, multi-centric survey by means of a database registry of the Filiale de cardiologie pediatrique et congenitale. RESULTS: Sixty-four patients were included, with a median (range) age of 21.4 (10.5-77.3) years. The majority (60.9%) of the patients were New York Heart Association (NYHA) class II. The most common congenital heart disease was tetralogy of Fallot with or without pulmonary atresia (50%). Indication for valve implantation was stenosis in 21.9%, regurgitation in 10.9% and association of stenosis and regurgitation in 67.2%. Implantation was successful in all patients. Pre-stenting was performed in 96.9% of cases. Median (range) procedure time was 92.5 (25-250) minutes. No significant regurgitation was recorded after the procedure, and the trans-pulmonary gradient was significantly reduced. Early minor complications occurred in five cases (7.8%). Three patients died during a median follow-up of 4.6 (0.2-5.2) years, two from infectious endocarditis and one from end-stage cardiac failure. Surgical reintervention was required in three patients. Follow-up with magnetic resonance imaging demonstrated significant improvements in right ventricular volumes and pulmonary regurgitation in mixed and regurgitant lesions. CONCLUSIONS: Transcatheter pulmonary valve implantation is highly feasible and mid-term follow up demonstrates sustained improvement of right ventricular function. Late endocarditis is of concern, therefore longer follow-up in more patients is urgently needed to better assess long-term outcome. CLINICAL TRIAL REGISTRATION: NCT01250327. PMID- 25453720 TI - Pneumatosis cystoides intestinalis as an infrequent cause of chronic abdominal pain. PMID- 25453721 TI - Clinical, radiologic, and endoscopic characteristics upon diagnosis of patients with prehepatic portal hypertension at the Instituto Nacional de Pediatria from 2001 to 2011. AB - BACKGROUND: Prehepatic portal hypertension in children can be asymptomatic for many years. Once diagnosed, the therapeutic measures (pharmacologic, endoscopic, and surgical) are conditioned by the specific characteristics of each patient. In Mexico, there are no recorded data on the incidence of the disease and patient characteristics. AIMS: To determine the main clinical, radiologic, and endoscopic characteristics upon diagnosis of these patients at the Instituto Nacional de Pediatria within the time frame of January 2001 and December 2011. METHODS: A cross-sectional, retrolective, descriptive, and observational study was conducted in which all the medical records of the patients with portal hypertension diagnosis were reviewed. RESULTS: There was a greater prevalence of prehepatic etiology (32/52) (61.5%) in the portal hypertension cases reviewed. Males (62.5%) predominated and 11 of the 32 patients were under 4 years of age. The primary reason for medical consultation was upper digestive tract bleeding with anemia (71.9%) and the main pathology was cavernomatous degeneration of the portal vein (65.6%). Splenoportography was carried out on 17 of the 32 patients. A total of 65.5% of the patients received the combination therapy of propranolol and a proton pump inhibitor. Initial endoscopy revealed esophageal varices in 96.9% of the patients, 12 of whom presented with gastroesophageal varices. Congestive gastropathy was found in 75% of the patients. The varices were ligated in 8 cases, sclerotherapy for esophageal varices was carried out in 5 cases (15.6%), and sclerotherapy for gastric varices was performed in 2 patients. Seventeen patients (53.1%) underwent portosystemic diversion: 10 of the procedures employed a mesocaval shunt and 7 a splenorenal shunt. Nine patients (28.1%) underwent total splenectomy. CONCLUSIONS: The primary cause of the disease was cavernomatous degeneration of the portal vein; it was predominant in males and the first symptom was variceal bleeding. PMID- 25453722 TI - Acute phlegmonous gastritis. PMID- 25453723 TI - The in vivo effect of prophylactic subchondral bone protection of osteoarthritic synovial membrane in bone-specific Ephb4-overexpressing mice. AB - Osteoarthritis (OA) is characterized by progressive joint destruction, including synovial membrane alteration. EphB4 and its ligand ephrin-B2 were found in vitro to positively affect OA subchondral bone and cartilage. In vivo in an experimental mouse model overexpressing bone-specific Ephb4 (TgEphB4), a protective effect was found on both the subchondral bone and cartilage during OA. We investigated in the TgEphB4 mouse model the in vivo effect on synovial membrane during OA. Knee OA was surgically induced by destabilization of the medial meniscus (DMM). Synovial membrane was evaluated using histology, histomorphometry, IHC, and real-time PCR. Compared to DMM-wild-type (WT) mice, DMM-TgEphB4 mice had a significant decrease in synovial membrane thickness, vascular endothelial growth factor, and the profibrotic markers fibrin, type 1 procollagen, type 3 collagen, connective tissue growth factor, smooth muscle actin-alpha, cartilage oligomeric matrix protein, and procollagen-lysine, and 2 oxoglutarate 5-dioxygenase 2. Moreover, factors known to modulate transforming growth factor-beta signaling, transforming growth factor receptor 1/ALK1, phosphorylated Smad-1, and heat shock protein 90beta were significantly decreased in DMM-TgEphB4 compared with DMM-WT mice. Ephb4 overexpression also exhibited a protective effect on synovial membrane thickness of aged (24-month-old) mice. Overexpression of bone-specific Ephb4 clearly demonstrated prevention of the development and/or progression of fibrosis in OA synovial membrane, reinforcing the hypothesis that protecting the subchondral bone prophylactically and during OA reduces the pathologic changes in other articular tissues. PMID- 25453724 TI - Immunosuppressive capabilities of mesenchymal stromal cells are maintained under hypoxic growth conditions and after gamma irradiation. AB - BACKGROUND AIMS: The discovery of regenerative and immunosuppressive capacities of mesenchymal stromal cells (MSCs) raises hope for patients with tissue-damaging or severe, treatment-refractory autoimmune disorders. We previously presented a method to expand human MSCs in a bioreactor under standardized Good Manufacturing Practice conditions. Now we characterized the impact of critical treatment conditions on MSCs with respect to immunosuppressive capabilities and proliferation. METHODS: MSC proliferation and survival after gamma irradiation were determined by 5-carboxyfluorescein diacetate N-succinimidyl ester and annexinV/4',6-diamidino-2-phenylindole (DAPI) staining, respectively. T-cell proliferation assays were used to assess the effect of gamma irradiation, passaging, cryopreservation, post-thaw equilibration time and hypoxia on T-cell suppressive capacities of MSCs. Quantitative polymerase chain reaction and beta galactosidase staining served as tools to investigate differences between immunosuppressive and non-immunosuppressive MSCs. RESULTS: gamma irradiation of MSCs abrogated their proliferation while vitality and T-cell inhibitory capacity were preserved. Passaging and long cryopreservation time decreased the T-cell suppressive function of MSCs, and postthaw equilibration time of 5 days restored this capability. Hypoxic culture markedly increased MSC proliferation without affecting their T-cell-suppressive capacity and phenotype. Furthermore, T-cell suppressive MSCs showed higher CXCL12 expression and less beta-galactosidase staining than non-suppressive MSCs. DISCUSSION: We demonstrate that gamma irradiation is an effective strategy to abrogate MSC proliferation without impairing the cells' immunosuppressive function. Hypoxia significantly enhanced MSC expansion, allowing for transplantation of MSCs with low passage number. In summary, our optimized MSC expansion protocol successfully addressed the issues of safety and preservation of immunosuppressive MSC function after ex vivo expansion for therapeutic purposes. PMID- 25453726 TI - The smoking habits of the family influence the uptake of e-cigarettes in US children. PMID- 25453725 TI - Individualized diagnosis interventions can add significant effectiveness in reducing human immunodeficiency virus incidence among men who have sex with men: insights from Southern California. AB - PURPOSE: In this article, we examine the effectiveness of a variety of HIV diagnosis interventions in recently HIV-diagnosed men who have sex with men (MSM). These interventions use the preventive potential of postdiagnosis behavior change (PDBC), as measured by the reduction in the number of new infections. Empirical evidence for PDBC was presented in the behavioral substudy of the Southern California Acute Infection and Early Disease Research Program. In previous modeling work, we demonstrated the existing preventive effects of PDBC. However, a large proportion of new infections among MSM are either undiagnosed or diagnosed late, and the preventive potential of PDBC is not fully utilized. METHODS: We derive empirical, stochastic, network-based models to examine the effectiveness of several diagnosis interventions that account for PDBC among MSM over a 10-year period. These interventions involve tests with shorter detection windows, more frequent testing, and individualized testing regimens. RESULTS: We find that individualized testing interventions (i.e., testing individuals every three partners or 3 months, whichever is first, or every six partners or 6 months, whichever is first) result in significantly fewer new HIV infections than the generalized interventions we consider. CONCLUSIONS: This work highlights the potential of individualized interventions for new public health policies in HIV prevention. PMID- 25453727 TI - Production of inflammatory mediators and extracellular traps by carp macrophages and neutrophils in response to lipopolysaccharide and/or interferon-gamma2. AB - Neutrophilic granulocytes and macrophages are crucial for the innate immune response against infections. They migrate into the focus of inflammation, where they efficiently bind, engulf and kill bacteria by proteolytic enzymes, antimicrobial peptides, reactive oxygen (ROS) and nitrogen (RNS) species. Moreover, activated neutrophils and macrophages can form extracellular traps (ETs). Fish neutrophils and macrophages are morphologically, histochemically, and functionally similar to their mammalian counterparts, but their significance for regulation of inflammatory responses and pathogen killing needs further elucidation. We compared the activity of head kidney monocytes/macrophages and neutrophilic granulocytes of common carp and established that upon lipopolysaccharide stimulation, not only neutrophils, but also carp monocytes/macrophages release extracellular DNA and are capable to form macrophage extracellular traps (METs). To clarify whether many specific LPS functions reported for piscine phagocytes might be due to impurities in the commonly used LPS preparations we studied expression of inflammatory mediators, release of DNA, ROS and RNS in cells stimulated with LPS or its highly purified form (pLPS). Also IFN-gamma2 stimulation and its synergism with LPS/pLPS in stimulating expression of pro-inflammatory mediators was studied. Results substantiate that a classical stimulation of TLR4 by LPS may indeed be absent in carp as most of the classically reported LPS effects are abolished or diminished when pLPS is used. Interestingly, we also observed a potent IL-10 expression in neutrophilic granulocytes upon LPS stimulation, which, apart from their pro inflammatory function, clearly indicates a role in restrictive control of the inflammatory reaction. PMID- 25453728 TI - Morphological changes in mitochondria during mechanical unloading observed on electron microscopy: a case report of a bridge to complete recovery in a patient with idiopathic dilated cardiomyopathy. AB - The recovery of the cardiac function under mechanical support has not been well documented from a histopathological point of view. We herein report a case of idiopathic dilated cardiomyopathy in which the patient showed a complete recovery of the systolic function following treatment with a left ventricular assist device (LVAD) for deteriorated heart failure. A light microscopic observation showed marked regression of hypertrophic myocytes with significant intracellular vacuolization and scarcity at the time of LVAD implantation after the administration of mechanical support. Furthermore, an electron microscopic observation revealed that these findings were regulated primarily by volumetric regression and morphometric improvements in cardiomyocytic mitochondria. PMID- 25453729 TI - Novel prognostic tissue markers in congestive heart failure. AB - Heart failure is a relatively common disorder associated with high morbidity, mortality, and economic burden. Better tools to predict outcomes for patients with heart failure could allow for better decision making concerning patient treatment and management and better utilization of health care resources. Endomyocardial biopsy offers a mechanism to pathologically diagnose specific diseases in patients with heart failure, but such biopsies can often be negative, with no specific diagnostic information. Novel tissue markers in endomyocardial biopsies have been identified that may be useful in assessing prognosis in heart failure patients. Such tissue markers include ubiquitin, Gremlin-1, cyclophilin A, and heterogeneous nuclear ribonucleoprotein C. In some cases, tissue markers have been found to be independent of and even superior to clinical indices and serum markers in predicting prognosis for heart failure patients. In some cases, these novel tissue markers appear to offer prognostic information even in the setting of an otherwise negative endomyocardial biopsy. PMID- 25453730 TI - Do dipeptidyl peptidase IV (DPP-IV) inhibitors cause heart failure? AB - PURPOSE: Although recent reports suggest an association between saxagliptin and an increased risk of admissions for heart failure, it is not clear whether dipeptidyl peptidase IV (DPP-IV) inhibition contributes to heart failure in high risk patients. The purpose of this research is to understand heart failure risk among high-risk patients with type 2 diabetes. METHODS: This is a systematic review of data published in full papers and abstract form using the terms DPP-IV inhibitors and heart failure published since October 2013. Data from insurance and hospital databases were combined with those from multiple published trials, including the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial; Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care (EXAMINE), and Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) trial as well as pooled analyses of linagliptin and saxagliptin placebo controlled trials to examine heart failure among patients represented in those datasets. FINDINGS: A meta-analysis of the 9 datasets showed an increase in heart failure with dipeptidyl peptidase IV inhibitors of 15% (P = 0.017). There was no statistical heterogeneity, nor was there a statistical difference between cohort studies and randomized, controlled trials (P = 0.3), even though cohort studies alone were not significant (relative risk: 1.1; P = 0.32). Removing SAVOR-TIMI 53 data produced an insignificant increase in heart failure of 12% (P = 0.09) in the rest of the studies. In the randomized, controlled trials, the increased risk was 24% (P = 0.002). There was no statistical difference between those studies with and without baseline cardiovascular disease (P = 0.58), although the cardiovascular disease studies were borderline significant (P = 0.06). There was no publication bias. IMPLICATIONS: There are data from studies using sitagliptin, saxagliptin, and alogliptin showing that these agents may increase the risk of hospitalization for heart failure. More data are required for a definitive conclusion. PMID- 25453731 TI - Critical appraisal of the SHARP trial: the results may be dull. AB - PURPOSE: The goal of this commentary was to provide a critical analysis of the SHARP (Study of Heart and Renal Protection) trial. Published in 2011, this study has been used by clinicians to justify the prescribing of statins (3-hydroxy-3 methylglutaryl-coenzyme A reductase inhibitors) +/-ezetimibe in patients with chronic kidney disease. METHODS: We conducted a critical appraisal of the SHARP trial and associated documents (ie, US Food and Drug Administration review, SHARP protocol). We also examined background reviews and studies conducted before the SHARP trial to provide additional context and background. FINDINGS: Our analysis provides clinicians with important criticisms of the SHARP trial, which suggest questionable clinical benefit to lipid-lowering therapy in patients with chronic kidney disease. IMPLICATIONS: Our hope is that clinicians limit the broad prescription of statins (+/-ezetimibe) in all patients with chronic kidney disease (both dialysis and nondialysis) unless there is a valid reason for statin therapy (eg, existing cardiovascular disease). PMID- 25453732 TI - Benzodiazepine and sedative-hypnotic use among older seriously Ill veterans: choosing wisely? AB - PURPOSE: The 2014 American Geriatrics Society's Choosing Wisely list cautions against the use of any benzodiazepines or other sedative-hypnotics (BSHs) as initial treatments for agitation, insomnia, or delirium in older adults. Because these symptoms are prevalent among hospitalized patients, seriously ill older adults are at risk of receiving these potentially inappropriate medications. The objectives of this study were to understand the extent to which potentially inappropriate BSHs are being used in hospitalized, seriously ill, older veterans and to understand what clinical and sociodemographic characteristics are associated with potentially inappropriate BSH use. METHODS: We reviewed medical records of 222 veterans aged >=65 years who were hospitalized in an acute care facility in the New York-New Jersey metropolitan region in fiscal years 2009 and 2010. Veterans had diagnoses of advanced cancer, chronic obstructive pulmonary disease, congestive heart failure, and/or HIV/AIDS and received inpatient palliative care. Associations among potentially inappropriate BSH use (BSHs for indications other than alcohol withdrawal and current generalized anxiety disorder or one-time use before a medical procedure) and clinical and sociodemographic characteristics were examined with multivariable logistic regression. FINDINGS: One-fifth of the sample was prescribed a potentially inappropriate BSH during the index hospitalization during the study period (n = 47). The most commonly prescribed potentially inappropriate medications were zolpidem (n = 26 [11.7%]) and lorazepam (n = 19 [8.9%]). Hispanic ethnicity was significantly associated with prescription of potentially inappropriate BSHs among the entire sample (adjusted odds ratio [AOR] = 3.79; 95% CI, 1.32-10.88) and among patients who survived until discharge (n = 164; AOR = 5.28; 95% CI, 1.64-17.07). Among patients who survived until discharge, black patients were less likely to be prescribed potentially inappropriate BSHs than white patients (AOR = 0.35; 95% CI, 0.13-0.997), and patients who had past-year BSH prescriptions were more likely to be prescribed a potentially inappropriate BSH than patients without past-year BSH use. IMPLICATIONS: The potentially inappropriate BSHs documented in our sample included short- and intermediate acting benzodiazepines, medications that were not identified as potentially inappropriate for older adults until after these data were collected. Few long acting benzodiazepines were recorded, suggesting that the older veterans in our sample were receiving medications according to the guidelines in place at the time of hospitalization. Clinicians may be able to reduce prescriptions of newly identified inappropriate BSHs by being aware of medications patients received before hospitalization and by being cognizant of racial/ethnic disparities in symptom management. Future studies should explore reasons for disparities in BSH prescriptions. PMID- 25453733 TI - [What if we seriously consider exercise in psychiatry?]. PMID- 25453734 TI - [Aripiprazole long-acting for the maintenance treatment of schizophrenia.] AB - Antipsychotics are the cornerstone for the maintenance treatment of schizophrenia patients. Their long-acting formulations are helpful for preventing relapses through improvement of adherence to medication and a better pharmacokinetic coverage. However, their use is often reserved for refractory or non-observant clinical forms because of limitations among both clinicians and patients. The development of a new formulation of long-acting injectable aripiprazole administered every 4 weeks is a new option. Two randomized controlled trials vs. placebo and vs. oral aripiprazole respectively show a superiority and non inferiority in terms of relapse prevention. Meanwhile, a mirror-image study demonstrates fewer hospitalizations. The safety profile is comparable to the oral formulation, particularly in terms of metabolic and neurological side-effects. As mentioned in various professional recommendations, long-acting injectable antipsychotics, so long-acting injectable aripiprazole, are one of the major strategies of the maintenance treatment for patients with schizophrenia. PMID- 25453735 TI - [Short-term efficacy and safety of lurasidone in the treatment of schizophrenia]. AB - Lurasidone is a new second-generation antipsychotic approved in October 2010 by the Food and Drug Administration and in March 2014 by the European Medicines Agency for the treatment of schizophrenia. Like other second-generation antipsychotics, lurasidone is an antagonist of D2 dopamine and 5HT2A serotonin receptors, but differs from the other second-generation antipsychotics in its action profile for certain receptors. Lurasidone is the second-generation antipsychotic with the greatest affinity for 5HT7 receptors and has a low affinity for alpha1 and alpha2C-adrenergic and 5HT2C serotonin receptors, and no affinity for histaminergic H1 or muscarinic M1 receptors. Lurasidone has demonstrated its efficacy in several short-term studies in acute schizophrenia with significantly reducing total scores of Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) compared with placebo. Early improvement was observed by days 3-7 for the 80-160 mg/day doses. Two studies with several methodological limitations showed that lurasidone might be involved in the improvement of cognitive performance in schizophrenic patients. Post hoc analysis of four pooled short-term studies showed significantly better effects on improving depressive symptoms associated with schizophrenia in patients treated with lurasidone as compared to patients treated with placebo. Lurasidone differs from the other second-generation antipsychotics by a good tolerability profile, in particular in terms of metabolic and cardiovascular profiles. Although results of the preclinical studies suggested that lurasidone had a low potential for causing clinically significant extrapyramidal symptoms, these were observed with a higher frequency than expected. It seems to have a significant though moderate link with the occurrence of akathisia, extrapyramidal symptoms, and hyperprolactinemia during initiation of treatment. This new tolerance profile greatly broadens the scope of second-generation antipsychotics and supports the view of some authors that the term second-generation antipsychotic is now outdated. Other therapeutic perspectives of lurasidone have been assessed, in particular in bipolar depression. PMID- 25453736 TI - Quantification of rolling circle amplified DNA using magnetic nanobeads and a Blu ray optical pick-up unit. AB - We present the first implementation of a Blu-ray optical pickup unit (OPU) for the high-performance low-cost readout of a homogeneous assay in a multichamber microfluidic disc with a chamber thickness of 600 MUm. The assay relies on optical measurements of the dynamics of magnetic nanobeads in an oscillating magnetic field applied along the light propagation direction. The laser light provided by the OPU is transmitted through the sample chamber and reflected back onto the photo detector array of the OPU via a mirror. Spectra of the 2nd harmonic photo detector signal vs. the frequency of the applied magnetic field show a characteristic peak due to freely rotating magnetic nanobeads. Beads bound to ~1 MUm coils of DNA formed off-chip by padlock probe recognition and rolling circle amplification show a different dynamics and the intensity of the characteristic peak decreases. We have determined the optimum magnetic bead concentration to 0.1mg/mL and have measured the response vs. concentration of DNA coils formed from Escherichia Coli. We have found a limit of detection of 10 pM and a dynamic range of about two orders of magnitude, which is comparable to the performance obtained using costly and bulky laboratory equipment. The presented device leverages on the advanced but low-cost technology of Blu-ray OPUs to provide a low-cost and high-performance magnetic bead-based readout of homogeneous bioassays. The device is highly flexible and we have demonstrated its use on microfluidic chambers in a disc with a thickness compatible with current optical media mass-production facilities. PMID- 25453737 TI - Olfactory biosensor for insect semiochemicals analysis by impedance sensing of odorant-binding proteins on interdigitated electrodes. AB - Insects can sensitively and selectively detect thousands of semiochemicals at very low concentrations by their remarkable olfactory systems. As one of the most important olfactory proteins, odorant-binding proteins (OBPs) from insects are the most promising candidates for fabricating biosensors to detect biochemical molecules in the chemical ecology as well as for other biotechnological applications. In this study, we designed an olfactory biosensor by immobilizing OBPs from oriental fruit fly on interdigitated electrodes to detect semiochemicals. After successfully separated and purified, OBPs were immobilized by the special designed polyethylene glycol (PEG), SH-PEG-COOH, to produce a robust sensing membrane. Based on electrochemical sensing, interactions between OBPs and different semiochemicals emitted from host plants of the insect, such as the isoamyl acetate, beta-ionone, and benzaldehyde, could be sensitively detected. With related amino acid residues in the hydrophobic cavities distinguished, the interaction forces between semiochemicals and OBPs were analyzed by molecular docking. Integrated biological olfaction proteins of insects, OBPs based biosensors could not only advance the progress in the understanding of chemical communication systems of insects, but also show promising potentials for biosensing applications in many fields. PMID- 25453738 TI - Highly sensitive silicon nanowire biosensor with novel liquid gate control for detection of specific single-stranded DNA molecules. AB - The study demonstrates the development of a liquid-based gate-control silicon nanowire biosensor for detection of specific single-stranded DNA (ssDNA) molecules. The sensor was fabricated using conventional photolithography coupled with an inductively coupled plasma dry etching process. Prior to the application of DNA to the device, its linear response to pH was confirmed by serial dilution from pH 2 to pH 14. Then, the sensor surface was silanized and directly aminated with (3-aminopropyl) triethoxysilane to create a molecular binding chemistry for biofunctionalization. The resulting Si-O-Si- components were functionalized with receptor ssDNA, which interacted with the targeted ssDNA to create a field across the silicon nanowire and increase the current. The sensor shows selectivity for the target ssDNA in a linear range from target ssDNA concentrations of 100 pM to 25 nM. With its excellent detection capabilities, this sensor platform is promising for detection of specific biomarkers and other targeted proteins. PMID- 25453739 TI - Responses of monkey prefrontal neurons during the execution of transverse patterning. AB - Recent functional imaging studies have suggested that the prefrontal cortex (PF) is engaged in the performance of transverse patterning (TP), which consists of 3 conflicting discriminations (A+/B-, B+/C-, C+/A-). However, the roles of PF in TP are still unclear. To address this issue, we examined the neuronal responses in 3 regions [the principal sulcus (PS), dorsal convexity (DC), and medial prefrontal cortex (MPF)] of the macaque PF during the performance of an oculomotor version of TP. A delayed matching-to-sample (DMS) task was used as a control task. The TP task-responsive neurons were most abundant in MPF. We analyzed the dependency of each neuronal response on the task type (TP or DMS), target shape (A, B, or C), and target location (left or right). Immediately after the choice cue presentation, many MPF neurons showed task dependency. Interestingly, some of them already exhibited differential activity between the 2 tasks before the choice cue presentation. Immediately before the saccade, the number of target location-dependent neurons increased in MPF and PS. Among them, many MPF neurons were also influenced by the task type, whereas PS neurons tended to show location dependency without task dependency. These results suggest that MPF and PS are involved in the execution of TP: MPF appears to be more important in the target selection based on the TP rule, whereas PS is apparently more related to the response preparation. In addition, some neurons showed a postsaccadic response, which may be related to the feedback mechanism. PMID- 25453740 TI - Exogenous GM1 ganglioside increases accumbal BDNF levels in rats. AB - Gangliosides are compounds that are abundant throughout the CNS, participating actively in neuroplasticity. We previously described that exogenous GM1 ganglioside pretreatment enhances the rewarding properties of cocaine, evidenced by a lower number of sessions and/or dosage necessary to induce conditioned place preference (CPP). Since GM1 pretreatment did not modify cocaine's pharmacokinetic parameters, we suspected that the increased rewarding effect found might be mediated by BDNF, a neurotrophic factor closely related to cocaine addiction. This study was performed to investigate the possibility that GM1 may induce changes in BDNF levels in the nucleus accumbens (NAc), a core structure in the brain's reward circuitry, of rats submitted to three conditioning sessions with cocaine (10 mg/kg, i.p.). The results demonstrate that GM1 administration, which showed no rewarding effect by itself in the CPP, induced a significant increase of BDNF protein levels in the NAc, which may account for the increased rewarding effect of cocaine shown in the CPP paradigm. PMID- 25453741 TI - The unidirectional prosaccade switch-cost: electroencephalographic evidence of task-set inertia in oculomotor control. AB - The execution of an antisaccade selectively increases the reaction time (RT) of a subsequent prosaccade (the unidirectional prosaccade switch-cost). To explain this finding, the task-set inertia hypothesis asserts that an antisaccade requires a cognitively mediated non-standard task-set that persists inertially and delays the planning of a subsequent prosaccade. The present study sought to directly test the theoretical tenets of the task-set inertia hypothesis by examining the concurrent behavioural and the event-related brain potential (ERP) data associated with the unidirectional prosaccade switch-cost. Participants pseudo-randomly alternated between pro- and antisaccades while electroencephalography (EEG) data were recorded. As expected, the completion of an antisaccade selectively increased the RT of a subsequent prosaccade, whereas the converse switch did not influence RTs. Thus, the behavioural results demonstrated the unidirectional prosaccade switch-cost. In terms of the ERP findings, we observed a reliable change in the amplitude of the P3 - time-locked to task-instructions - when trials were switched from a prosaccade to an antisaccade; however, no reliable change was observed when switching from an antisaccade to a prosaccade. This is a salient finding because extensive work has shown that the P3 provides a neural index of the task-set required to execute a to-be-completed response. As such, results showing that prosaccades completed after antisaccades exhibited increased RTs in combination with a P3 amplitude comparable to antisaccades provides convergent evidence that the unidirectional prosaccade switch-cost is attributed to the persistent activation of a non standard antisaccade task-set. PMID- 25453742 TI - Cerebral autoregulation in response to posture change in elderly subjects assessment by wavelet phase coherence analysis of cerebral tissue oxyhemoglobin concentrations and arterial blood pressure signals. AB - This study aims to assess the dynamic cerebral autoregulation (dCA) in response to posture change using wavelet phase coherence (WPCO) of cerebral tissue oxyhemoglobin concentrations (Delta [HbO2]) and arterial blood pressure (ABP) signals in healthy elderly subjects. Continuous recordings of near-infrared spectroscopy (NIRS) and ABP signals were obtained from simultaneous measurements in 16 healthy elderly subjects (age: 68.9+/-7.1 years) and 19 young subjects (age: 24.9+/-3.2 years). The phase coherence between Delta [HbO2] and ABP oscillations in six frequency intervals (I, 0.6-2 Hz; II, 0.15-0.6 Hz; III, 0.05 0.15 Hz; IV, 0.02-0.05 Hz, V, 0.0095-0.02 Hz and VI, 0.005-0.0095 Hz) was analyzed using WPCO. The sit-to-stand posture change induces significantly lower WPCO in interval III (F=5.50 p=0.025) in the elderly subjects than in the young subjects. However, the stand-to-sit posture change induces higher WPCO in intervals II (F=5.25 p=0.028) and V (F=6.22 p=0.018) in the elderly subjects than in the young subjects. The difference of WPCO in response to posture change between the elderly and the young subjects indicates an altered CA due to aging. This study provides new insight into the dynamics of CA and may be useful in identifying the risk for dCA processes. PMID- 25453743 TI - Comparison of the effects on brain stimulation reward of D1 blockade or D2 stimulation combined with AMPA blockade in the extended amygdala and nucleus accumbens. AB - This report compares the effects on medial forebrain bundle self-stimulation of injecting into either the sublenticular central extended amygdala (SLEAc) or nucleus accumbens shell (NAcS) the D1 dopamine receptor blocker SCH23390 or the D2 dopamine receptor agonist quinpirole alone or in combination with the AMPA glutamate receptor blocker NBQX. These manipulations all render affected neurons less excitable and therefore are expected to increase the stimulation pulse frequency required to maintain half-maximal response rate (required frequency, or RF). Injections were made ipsilateral and contralateral to the stimulation site but not bilaterally. Injecting quinpirole alone or in combination with NBQX was more effective in increasing RF than was injecting SCH23390 either alone or with NBQX. Quinpirole alone and in combination with NBQX was more effective when injected into the SLEAc than into the NAcS, and the combination injection was more effective than quinpirole alone, especially when injected into the SLEAc contralateral to the stimulation site. Maximum response rates were only modestly decreased by any drug injection. These data suggest a stronger role in brain stimulation reward for D2/glutamate than D1/glutamate interactions in the extended amygdala. PMID- 25453744 TI - 27-hydroxycholesterol mediates negative effects of dietary cholesterol on cognition in mice. AB - In spite of the fact that cholesterol does not pass the blood-brain barrier, treatment of mice with dietary cholesterol causes significant effects on a number of genes in the brain and in addition a memory impairment. We have suggested that these effects are mediated by 27-hydroxycholesterol, which is able to pass the blood-brain barrier. To test this hypothesis we utilized Cyp27-/- mice lacking 27 hydroxycholesterol. The negative effect on memory observed after treatment of wildtype mice with dietary cholesterol was not observed in these mice. The cholesterol diet reduced the levels of the "memory protein" Arc (Activity Regulated Cytoskeleton associated protein) in the hippocampus of the wildtype mice but not in the hippocampus of the Cyp27-/- mice. The results are consistent with 27-hydroxycholesterol as the mediator of the negative effects of cholesterol on cognition. PMID- 25453746 TI - Updating memories--the role of prediction errors in memory reconsolidation. AB - Memories are not static imprints of past experience, but rather are dynamic entities which enable us to predict outcomes of future situations and inform appropriate behaviours. In order to maintain the relevance of existing memories to our daily lives, memories can be updated with new information via a process of reconsolidation. In this review we describe recent experimental advances in the reconsolidation of both appetitive and aversive memory, and explore the neuronal mechanisms that underpin the conditions under which reconsolidation will occur. We propose that a prediction error signal, originating from dopaminergic midbrain neurons, is necessary for destabilisation and subsequent reconsolidation of a memory. PMID- 25453745 TI - The impact of fornix lesions in rats on spatial learning tasks sensitive to anterior thalamic and hippocampal damage. AB - The present study sought to understand how the hippocampus and anterior thalamic nuclei are conjointly required for spatial learning by examining the impact of cutting a major tract (the fornix) that interconnects these two sites. The initial experiments examined the consequences of fornix lesions in rats on spatial biconditional discrimination learning. The rationale arose from previous findings showing that fornix lesions spare the learning of spatial biconditional tasks, despite the same task being highly sensitive to both hippocampal and anterior thalamic nuclei lesions. In the present study, fornix lesions only delayed acquisition of the spatial biconditional task, pointing to additional contributions from non-fornical routes linking the hippocampus with the anterior thalamic nuclei. The same fornix lesions spared the learning of an analogous nonspatial biconditional task that used local contextual cues. Subsequent tests, including T-maze place alternation, place learning in a cross-maze, and a go/no go place discrimination, highlighted the impact of fornix lesions when distal spatial information is used flexibly to guide behaviour. The final experiment examined the ability to learn incidentally the spatial features of a square water maze that had differently patterned walls. Fornix lesions disrupted performance but did not stop the rats from distinguishing the various corners of the maze. Overall, the results indicate that interconnections between the hippocampus and anterior thalamus, via the fornix, help to resolve problems with flexible spatial and temporal cues, but the results also signal the importance of additional, non fornical contributions to hippocampal-anterior thalamic spatial processing, particularly for problems with more stable spatial solutions. PMID- 25453749 TI - Green space, health and wellbeing: making space for individual agency. AB - This essay examines the assumptions of green space use underpinning much existing green space and health research. It considers opportunities to move the field forward through exploring two often overlooked aspects of individual agency: the influence of shifting life circumstances on personal wellbeing priorities and place practices, and the role of personal orientations to nature in shaping how green space wellbeing opportunities are perceived and experienced. It suggests such efforts could provide more nuanced insights into the complex, personal factors that define and drive individual choices regarding the use of green spaces for wellbeing over time, thereby strengthening our understanding of the salutogenic potential (and limits) of green spaces. PMID- 25453747 TI - Antidepressant-like effects of buprenorphine in rats are strain dependent. AB - The prevalence of major depressive disorder and the limited efficacy of conventional drug treatments provide significant impetus to develop novel and more rapidly acting antidepressants for individuals with treatment resistant forms of depression. The primary goal of these studies was to ascertain whether buprenorphine (BPN), a medically available drug with mixed effects at opioid receptors, was effective in behavioral tests using the Wistar Kyoto (WKY) rat strain, a rodent model of exaggerated depressive and anxiety behaviors that demonstrates resistance to certain antidepressants. As WKY rats are maintained by different sources, we assessed the behavioral effects of BPN using the modified rat forced swim test (FST) and the emergence test in WKY rat colonies obtained from different vendors. BPN dose-dependently reduced immobility and increased swimming behavior in the FST and reduced emergence latencies in two WKY lines (Charles River (WKY/NCrl) and Harlan laboratories (WKY/NHsd)) that also showed high baseline immobility in the FST. WKY rats from Taconic (WKY/NTac) did not show high baseline immobility in the FST or anxiety as had been previously reported, suggesting a drift in the phenotype of rats from this supplier. Furthermore, BPN did not reduce immobility in the FST or reduce latencies in the emergence test in WKY rats from Taconic. BPN also failed to produce antidepressant-like effects in Wistar and Sprague-Dawley rats. These results indicate a striking strain-selectivity for the effects of BPN, producing antidepressant and anxiolytic-like responses in WKY/NCrl and WKY/NHsd lines but not in the normosensitive control Wistar and Sprague-Dawley strains. PMID- 25453748 TI - Neighbourhood characteristics and 10-year risk of depression in Canadian adults with and without a chronic illness. AB - The neighbourhood environment could play a role in the risk of depression in adults and those with a chronic illness. We investigated the effects of a range of neighbourhood characteristics on the 10-year risk of depression in a representative sample of 9026 Canadian adults and subsamples with a chronic condition. Characteristics of neighbourhoods were not significantly related to the risk of depression in the general sample and subsamples with a chronic condition. However, residing near a park was significantly associated with a lower risk of depression for people living in crowded households, and having a local health service nearby was protective for those living in materially deprived neighbourhoods. Living in a neighbourhood that was both socially advantaged and offered cultural services was also associated with lower risk of depression. Additional research is needed for smaller effect size detection. Future intervention research is warranted for health policy recommendations. PMID- 25453750 TI - Early pregnancy vitamin D and patterns of antenatal inflammation in African American women. AB - Vitamin D is essential for the health of both mother and fetus during pregnancy. In the nonpregnant state, vitamin D demonstrates anti-inflammatory effects, but little is known about this relationship during pregnancy. African-American women are at a higher risk of vitamin D deficiency and for altered inflammatory responses during pregnancy. Therefore, we investigated the association of early pregnancy vitamin D nutrition, as assessed by serum 25-hydroxyvitamin D (25-OHD), with second-trimester inflammatory biomarkers (high-sensitivity C-reactive protein, IL-6, IL-10, IL-1beta and TNF-alpha) in 178 pregnant African-American women. Mean serum 25-OHD was 13.4+/-8.4 ng/ml, and most women (n=147, 82.6%) had inadequate or deficient levels of 25-OHD (<20 ng/ml). Both serum 25-OHD and some inflammatory cytokines (IL-1beta and TNF-alpha) demonstrated significant seasonal variation. In univariate models, log transformed 25-OHD was significantly and inversely associated with log transformed IL-1beta (p=0.002) and log transformed IL-6 (p=0.032). After adjusting for covariates, including seasonality, only the inverse association with IL-1beta remained statistically significant (p=0.027). Early pregnancy vitamin D nutrition is associated with some inflammatory biomarkers in mid-pregnancy. Additional studies are needed to determine if low vitamin D nutrition is associated with birth outcomes via an inflammatory mediated pathway. PMID- 25453751 TI - Helios-positive functional regulatory T cells are decreased in decidua of miscarriage cases with normal fetal chromosomal content. AB - Regulatory (Treg) T cells play essential roles in the maintenance of allogeneic pregnancy in mice and humans. Recent data show that Foxp3 expression occurs in both immuno-suppressive Treg and -nonsuppressive effector T (Teff) cells upon activation in humans. Samstein et al. (2012) reported that inducible Treg (iTreg) cells enforce maternal-fetal tolerance in placental mammals. Therefore, we should reanalyze which types of Treg cell play an important role in the maintenance of allogeneic pregnancy. In this study, we studied the frequencies of naive Treg cells, effector Treg cells, Foxp3(+) Teff cells, Helios(+) naturally occurring Treg (nTreg) cells, and Helios(-) iTreg cells using flow cytometry. The frequencies of effector Treg cells and Foxp3(+) Teff cells among CD4(+)Foxp3(+) cells in the decidua of miscarriage cases with a normal embryo karyotype (n=8) were significantly lower (P=0.0105) and significantly higher (P=0.0258) than those in normally progressing pregnancies (n=11), respectively. However, these frequencies in miscarriages with an abnormal embryo karyotype (n=15) were similar to those in normally progressing pregnancies. The frequencies of these cell populations in the three groups were unchanged in peripheral blood; on the other hand, most of the effector Treg cells in the decidua were Helios(+) nTreg cells and these frequencies were significantly higher than those in peripheral blood, while those among effector Treg and naive Treg cells in the decidua and peripheral blood were similar among the three groups. These data suggest that decreased Helios(+) effector nTreg might play an important role in the maintenance of pregnancy in humans. PMID- 25453752 TI - TALEN gene knockouts reveal no requirement for the conserved human shelterin protein Rap1 in telomere protection and length regulation. AB - The conserved protein Rap1 functions at telomeres in fungi, protozoa, and vertebrates. Like yeast Rap1, human Rap1 has been implicated in telomere length regulation and repression of nonhomologous end-joining (NHEJ) at telomeres. However, mouse telomeres lacking Rap1 do not succumb to NHEJ. To determine the functions of human Rap1, we generated several transcription activator-like effector nuclease (TALEN)-mediated human cell lines lacking Rap1. Loss of Rap1 did not affect the other components of shelterin, the modification of telomeric histones, the subnuclear position of telomeres, or the 3' telomeric overhang. Telomeres lacking Rap1 did not show a DNA damage response, NHEJ, or consistent changes in their length, indicating that Rap1 does not have an important function in protection or length regulation of human telomeres. As human Rap1, like its mouse and unicellular orthologs, affects gene expression, we propose that the conservation of Rap1 reflects its role in transcriptional regulation rather than a function at telomeres. PMID- 25453753 TI - Complex relationship between ligand binding and dimerization in the epidermal growth factor receptor. AB - The epidermal growth factor receptor (EGFR) plays pivotal roles in development and is mutated or overexpressed in several cancers. Despite recent advances, the complex allosteric regulation of EGFR remains incompletely understood. Through efforts to understand why the negative cooperativity observed for intact EGFR is lost in studies of its isolated extracellular region (ECR), we uncovered unexpected relationships between ligand binding and receptor dimerization. The two processes appear to compete. Surprisingly, dimerization does not enhance ligand binding (although ligand binding promotes dimerization). We further show that simply forcing EGFR ECRs into preformed dimers without ligand yields ill defined, heterogeneous structures. Finally, we demonstrate that extracellular EGFR-activating mutations in glioblastoma enhance ligand-binding affinity without directly promoting EGFR dimerization, suggesting that these oncogenic mutations alter the allosteric linkage between dimerization and ligand binding. Our findings have important implications for understanding how EGFR and its relatives are activated by specific ligands and pathological mutations. PMID- 25453755 TI - Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic Slippage. AB - Tumor suppressor p53 is a major cellular guardian of genome integrity, and its inactivation is the most frequent genetic alteration in cancer, rising up to 80% in squamous cell carcinoma (SCC). By adapting the small hairpin RNA (shRNA) technology, we inactivated endogenous p53 in primary epithelial cells from the epidermis of human skin. We show that either loss of endogenous p53 or overexpression of a temperature-sensitive dominant-negative conformation triggers a self-protective differentiation response, resulting in cell stratification and expulsion. These effects follow DNA damage and exit from mitosis without cell division. p53 preserves the proliferative potential of the stem cell compartment and limits the power of proto-oncogene MYC to drive cell cycle stress and differentiation. The results provide insight into the role of p53 in self-renewal homeostasis and help explain why p53 mutations do not initiate skin cancer but increase the likelihood that cancer cells will appear. PMID- 25453754 TI - The oncogenic STP axis promotes triple-negative breast cancer via degradation of the REST tumor suppressor. AB - Defining the molecular networks that drive breast cancer has led to therapeutic interventions and improved patient survival. However, the aggressive triple negative breast cancer subtype (TNBC) remains recalcitrant to targeted therapies because its molecular etiology is poorly defined. In this study, we used a forward genetic screen to discover an oncogenic network driving human TNBC. SCYL1, TEX14, and PLK1 ("STP axis") cooperatively trigger degradation of the REST tumor suppressor protein, a frequent event in human TNBC. The STP axis induces REST degradation by phosphorylating a conserved REST phospho-degron and bridging REST interaction with the ubiquitin-ligase betaTRCP. Inhibition of the STP axis leads to increased REST protein levels and impairs TNBC transformation, tumor progression, and metastasis. Expression of the STP axis correlates with low REST protein levels in human TNBCs and poor clinical outcome for TNBC patients. Our findings demonstrate that the STP-REST axis is a molecular driver of human TNBC. PMID- 25453757 TI - Two-stage translational control of dentate gyrus LTP consolidation is mediated by sustained BDNF-TrkB signaling to MNK. AB - BDNF signaling contributes to protein-synthesis-dependent synaptic plasticity, but the dynamics of TrkB signaling and mechanisms of translation have not been defined. Here, we show that long-term potentiation (LTP) consolidation in the dentate gyrus of live rodents requires sustained (hours) BDNF-TrkB signaling. Surprisingly, this sustained activation maintains an otherwise labile signaling pathway from TrkB to MAP-kinase-interacting kinase (MNK). MNK activity promotes eIF4F translation initiation complex formation and protein synthesis in mechanistically distinct early and late stages. In early-stage translation, MNK triggers release of the CYFIP1/FMRP repressor complex from the 5'-mRNA cap. In late-stage translation, MNK regulates the canonical translational repressor 4E BP2 in a synapse-compartment-specific manner. This late stage is coupled to MNK dependent enhanced dendritic mRNA translation. We conclude that LTP consolidation in the dentate gyrus is mediated by sustained BDNF signaling to MNK and MNK dependent regulation of translation in two functionally and mechanistically distinct stages. PMID- 25453756 TI - A role for noncoding variation in schizophrenia. AB - A large portion of common variant loci associated with genetic risk for schizophrenia reside within noncoding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from the human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on colocalization of a risk SNP, eQTL, and regulatory element sequence. We identified potential physical interactions of noncontiguous proximal and distal regulatory elements. This was verified in prefrontal cortex and -induced pluripotent stem cell-derived neurons for the L-type calcium channel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia associated noncoding SNPs and 3D genome architecture associated with chromosomal loopings and transcriptional regulation in the brain. PMID- 25453758 TI - Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome. AB - Global patterns of DNA methylation, mediated by the DNA methyltransferases (DNMTs), are disrupted in all cancers by mechanisms that remain largely unknown, hampering their development as therapeutic targets. Combinatorial acute depletion of all DNMTs in a pluripotent human tumor cell line, followed by epigenome and transcriptome analysis, revealed DNMT functions in fine detail. DNMT3B occupancy regulates methylation during differentiation, whereas an unexpected interplay was discovered in which DNMT1 and DNMT3B antithetically regulate methylation and hydroxymethylation in gene bodies, a finding confirmed in other cell types. DNMT3B mediated non-CpG methylation, whereas DNMT3L influenced the activity of DNMT3B toward non-CpG versus CpG site methylation. Altogether, these data reveal functional targets of each DNMT, suggesting that isoform selective inhibition would be therapeutically advantageous. PMID- 25453759 TI - The initial uridine of primary piRNAs does not create the tenth adenine that Is the hallmark of secondary piRNAs. AB - PIWI-interacting RNAs (piRNAs) silence transposons in animal germ cells. PIWI proteins bind and amplify piRNAs via the "Ping-Pong" pathway. Because PIWI proteins cleave RNAs between target nucleotides t10 and t11-the nucleotides paired to piRNA guide positions g10 and g11-the first ten nucleotides of piRNAs participating in the Ping-Pong amplification cycle are complementary. Drosophila piRNAs bound to the PIWI protein Aubergine typically begin with uridine (1U), while piRNAs bound to Argonaute3, which are produced by Ping-Pong amplification, often have adenine at position 10 (10A). The Ping-Pong model proposes that the 10A is a consequence of 1U. We find that 10A is not caused by 1U. Instead, fly Aubergine as well as its homologs, Siwi in silkmoth and MILI in mice, have an intrinsic preference for adenine at the t1 position of their target RNAs; during Ping-Pong amplification, this t1A subsequently becomes the g10A of a piRNA bound to Argonaute3. PMID- 25453761 TI - Expression of nuclear and mitochondrial genes encoding ATP synthase is synchronized by disassembly of a multisynthetase complex. AB - In eukaryotic cells, oxidative phosphorylation involves multisubunit complexes of mixed genetic origin. Assembling these complexes requires an organelle independent synchronizing system for the proper expression of nuclear and mitochondrial genes. Here we show that proper expression of the F1FO ATP synthase (complex V) depends on a cytosolic complex (AME) made of two aminoacyl-tRNA synthetases (cERS and cMRS) attached to an anchor protein, Arc1p. When yeast cells adapt to respiration the Snf1/4 glucose-sensing pathway inhibits ARC1 expression triggering simultaneous release of cERS and cMRS. Free cMRS and cERS relocate to the nucleus and mitochondria, respectively, to synchronize nuclear transcription and mitochondrial translation of ATP synthase genes. Strains releasing asynchronously the two aminoacyl-tRNA synthetases display aberrant expression of nuclear and mitochondrial genes encoding subunits of complex V resulting in severe defects of the oxidative phosphorylation mechanism. This work shows that the AME complex coordinates expression of enzymes that require intergenomic control. PMID- 25453762 TI - Specificity in circadian clock feedback from targeted reconstitution of the NuRD corepressor. AB - Mammalian circadian rhythms are generated by a negative feedback loop in which PERIOD (PER) proteins accumulate, form a large nuclear complex (PER complex), and bind the transcription factor CLOCK-BMAL1, repressing their own expression. We found that mouse PER complexes include the Mi-2/nucleosome remodelling and deacetylase (NuRD) transcriptional corepressor. Unexpectedly, two NuRD subunits, CHD4 and MTA2, constitutively associate with CLOCK-BMAL1, with CHD4 functioning to promote CLOCK-BMAL1 transcriptional activity. At the onset of negative feedback, the PER complex delivers the remaining complementary NuRD subunits to DNA-bound CLOCK-BMAL1, thereby reconstituting a NuRD corepressor that is important for circadian transcriptional feedback and clock function. The PER complex thus acquires full repressor activity only upon successful targeting of CLOCK-BMAL1. Our results show how specificity is generated in the clock despite its dependence on generic transcriptional regulators and reveal the existence of active communication between the positive and negative limbs of the circadian feedback loop. PMID- 25453760 TI - A negative feedback loop of transcription factors specifies alternative dendritic cell chromatin States. AB - During hematopoiesis, cells originating from the same stem cell reservoir differentiate into distinct cell types. The mechanisms enabling common progenitors to differentiate into alternative cell fates are not fully understood. Here, we identify cell-fate-determining transcription factors (TFs) governing dendritic cell (DC) development by annotating the enhancer landscapes of the DC lineage. Combining these analyses with detailed overexpression, knockdown, and ChIP-Seq studies, we show that Irf8 functions as a plasmacytoid DC epigenetic and fate-determining TF, regulating massive, cell-specific chromatin changes in thousands of pDC enhancers. Importantly, Irf8 forms a negative feedback loop with Cebpb, a monocyte-derived DC epigenetic fate-determining TF. We show that using this circuit logic, a pulse of TF expression can stably define epigenetic and transcriptional states, regardless of the microenvironment. More broadly, our study proposes a general paradigm that allows closely related cells with a similar set of signal-dependent factors to generate differential and persistent enhancer landscapes. PMID- 25453763 TI - Exposure to a novel stimulus environment alters patterns of lateralization in avian auditory cortex. AB - Perceptual filters formed early in development provide an initial means of parsing the incoming auditory stream. However, these filters may not remain fixed, and may be updated by subsequent auditory input, such that, even in an adult organism, the auditory system undergoes plastic changes to achieve a more efficient representation of the recent auditory environment. Songbirds are an excellent model system for experimental studies of auditory phenomena due to many parallels between song learning in birds and language acquisition in humans. In the present study, we explored the effects of passive immersion in a novel heterospecific auditory environment on neural responses in caudo-medial neostriatum (NCM), a songbird auditory area similar to the secondary auditory cortex in mammals. In zebra finches, a well-studied species of songbirds, NCM responds selectively to conspecific songs and contains a neuronal memory for tutor and other familiar conspecific songs. Adult male zebra finches were randomly assigned to either a conspecific or heterospecific auditory environment. After 2, 4 or 9 days of exposure, subjects were presented with heterospecific and conspecific songs during awake electrophysiological recording. The neural response strength and rate of adaptation to the testing stimuli were recorded bilaterally. Controls exposed to conspecific environment sounds exhibited the normal pattern of hemispheric lateralization with higher absolute response strength and faster adaptation in the right hemisphere. The pattern of lateralization was fully reversed in birds exposed to heterospecific environment for 4 or 9 days and partially reversed in birds exposed to heterospecific environment for 2 days. Our results show that brief passive exposure to a novel category of sounds was sufficient to induce a gradual reorganization of the left and right secondary auditory cortices. These changes may reflect modification of perceptual filters to form a more efficient representation of auditory space. PMID- 25453764 TI - The ventral tegmentum and dopamine: A new wave of diversity. AB - Projection systems arising from the ventral tegmental area (VTA) and the substantia nigra (SN) have a critical role in a broad range of functions, as well as in the etiology, symptoms and treatment of neurological and psychiatric diseases. Mostly studied for its dopamine neurons, the ventral tegmentum is in fact heterogeneous at cellular and functional levels. This special issue of Neuroscience gathered some experts in the field to review the connectivity of the ventral mesencephalic dopaminergic complex, its cellular heterogeneity with attention given to glutamate neurons, the D2 autoreceptor and the cholinergic controls of dopamine activity, the influence of neurotrophins, the controls of bursting activity and the heterogeneity of neuronal activity across traits and states, the pedunculopontine tegmental and the sensory controls of dopamine activity, the sex-dependent diversity, the links between circadian and dopamine systems, the functional antero-posterior heterogeneity of the VTA and the role of its GABA tail (tVTA/rostromedial tegmental nucleus (RMTg)), the functional heterogeneity of the VTA outputs, the place of dopamine in cortico-basal ganglia circuitry, the different roles of the D1 and D2 striatal pathways and the role of dopamine in associative learning and memory. Recent progress also highlights the need for molecular markers of functional subpopulations within the ventral tegmentum, for deeper developmental knowledge of this region, and for a single cell level of connectomic. It also raises the question of inter-individual, sex, strain and species heterogeneity, and conversely the question of data generalization in a context of human pathology models, which warrant comparative studies and translational effort. PMID- 25453765 TI - Spinal cord injury induces a long-lasting upregulation of interleukin-1beta in astrocytes around the central canal. AB - Under inflammatory conditions, interleukin-1beta (IL-1beta) modulates neural stem cells at neurogenic niches. Here we show that spinal cord injury in rats increases IL-1beta expression in astrocytes located around the spinal cord ependyma, a region that also holds a neurogenic potential. IL-1beta increases from day 1 after lesion, reaches maximal levels between days 3 and 7, and declines from 14 days to low levels after 28 days. At the time of maximal expression, periependymal upregulation of IL-1beta extends beyond 5 mm from the epicenter of the lesion both rostral and caudally. Since IL-1beta controls proliferation and cell fate of neural stem/precursor cells, its modulation in periependymal astrocytes might create an appropriate environment for cell replacement after injury. PMID- 25453766 TI - The combined role of serotonin and interleukin-6 as biomarker for autism. AB - Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction and repetitive behaviors. Diagnosis of autism is currently phenotype based with no reliable laboratory test available to assist clinicians. It has been shown that dysfunction of serotonin (5-HT) and interleukin-6 (IL-6) are involved in autism. The goal of this study was to evaluate the combined role of 5-HT and IL-6 as potential biomarkers for autism. The whole blood concentration of 5-HT and plasma concentration of IL-6 of individuals with autism were significantly elevated compared with the control group, and the concentration of 5-HT and IL-6 had positive correlations with the severity of autism. The results of receiver operating characteristic (ROC) analysis indicated that the combination of 5-HT and IL-6 produced the best sensitivity and specificity for diagnosis of autism. Therefore, the present study has revealed a simple clinical method with great potential for assisting the diagnosis of autism. PMID- 25453767 TI - HMG-CoA reductase inhibitor rosuvastatin improves abnormal brain electrical activity via mechanisms involving eNOS. AB - Apart from its repressing effect on plasma lipid levels, 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors exert neuroprotective functions in animal models of neurodegenerative disorders. In view of these promising observations, we were interested in whether HMG-CoA reductase inhibition would affect epileptiform activity in the brain. To elucidate this issue, atorvastatin, simvastatin and rosuvastatin were administered orally at a dose of 20 mg/kg each for 3 days and their anti-epileptic activities were tested and compared in rats. Epileptiform activity in the brain was induced by an intracortical penicillin G injection. Among HMG-CoA reductase inhibitors, simvastatin-treatment was less effective in terms of spike frequency as compared with atorvastatin- and rosuvastatin-treated animals. Atorvastatin treatment reduced spike frequencies and amplitudes significantly throughout the experiment. However, the most pronounced anti-epileptic effect was observed in rosuvastatin treated animals, which was associated with improved blood-brain barrier (BBB) integrity, increased expression of endothelial nitric oxide synthase (eNOS) mRNA and decreased expressions of pro-apoptotic p53, Bax and caspase-3 mRNAs. Inhibition of eNOS activity with L-NG-Nitroarginine Methyl Ester (L-NAME) reversed the anti-epileptic effect of rosuvastatin significantly. However, L-NAME did not alter the effect of rosuvastatin on the levels of p53, Bax and caspase-3 mRNA expression. Here, we provide evidence that among HMG-CoA reductase inhibitors, rosuvastatin was the most effective statin on the reduction of epileptiform activity, which was associated with improved BBB permeability, increased expression of eNOS and decreased expressions of pro-apoptotic p53, Bax and caspase-3. Our observation also revealed that the anti-epileptic effect of rosuvastatin was dependent on the increased expression level of eNOS. The robust anti-epileptic effect encourages proof-of-concept studies with rosuvastatin in human epilepsy patients with hypercholesterolemia. PMID- 25453768 TI - Internal capsule stroke in the common marmoset. AB - White matter (WM) impairment and motor deficit after stroke are directly related. However, WM injury mechanisms and their relation to motor disturbances are still poorly understood. In humans, the anterior choroidal artery (AChA) irrigates the internal capsule (IC), and stroke to this region can induce isolated motor impairment. The goal of this study was to analyze whether AChA occlusion can injure the IC in the marmoset monkey. The vascular distribution of the marmoset brain was examined by colored latex perfusion and revealed high resemblance to the human brain anatomy. Next, a new approach to electrocoagulate the AChA was developed and chronic experiments showed infarction compromising the IC on magnetic resonance imaging (MRI) scanning (day 4) and histology (day 11). Behavioral analysis was performed using a neurologic score previously developed and our own scoring method. Marmosets showed a decreased score that was still evident at day 10 after AChA electrocoagulation. We developed a new approach able to induce damage to the marmoset IC that may be useful for the detailed study of WM impairment and behavioral changes after stroke in the nonhuman primate. PMID- 25453769 TI - Treatment with UDP-glucose, GDNF, and memantine promotes SVZ and white matter self-repair by endogenous glial progenitor cells in neonatal rats with ischemic PVL. AB - Periventricular leukomalacia (PVL) is one of the foremost neurological conditions leading to long-term abnormalities in premature infants. Since it is difficult to prevent initiation of this damage in utero, promoting the innate regenerative potential of the brain after birth may provide a more feasible, prospective therapy for PVL. Treatment with UDP-glucose (UDPG), an endogenous agonist of G protein-coupled receptor 17 (GPR17) that may enhance endogenous self-repair potentiality, glial cell line-derived neurotrophic factor (GDNF), a neurotrophic factor associated with the growth and survival of nerve cells, and memantine, a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptors that block ischemia-induced glutamate signal transduction, has been reported to achieve functional, neurological improvement in neonatal rats with PVL. The aim of the present study was to further explore whether UDPG, GDNF and/or memantine could promote corresponding self-repair of the subventricular zone (SVZ) and white matter (WM) in neonatal rats with ischemia-induced PVL. SVZ or WM tissue samples and cultured glial progenitor cells derived from a 5 day-old neonatal rat model of PVL were utilized for studying response to UDPG, GDNF and memantine in vivo and in vitro, respectively. Labeling with 5'-bromo-2'-deoxyuridine and immunofluorescent cell lineage markers after hypoxia-ischemia or oxygen-glucose deprivation (OGD) revealed that UDPG, GDNF and memantine each significantly increased glial progenitor cells and preoligodendrocytes (preOLs), as well as more differentiated immature and mature oligodendrocyte (OL), in both the SVZ and WM in vivo or in vitro. SVZ and WM glial cell apoptosis was also significantly reduced by UDPG, GDNF or memantine, both in vivo and in vitro. These results indicated that UDPG, GDNF or memantine may promote endogenous self-repair by stimulating proliferation of glial progenitor cells derived from both the SVZ and WM, activating their differentiation into more mature OLs, and raising the survival rate of these newly generated glial cells in neonatal rats with ischemic PVL. PMID- 25453770 TI - No evidence for role of extracellular choline-acetyltransferase in generation of gamma oscillations in rat hippocampal slices in vitro. AB - Acetylcholine (ACh) is well known to induce persistent gamma-oscillations in the hippocampus when applied together with physostigmine, an inhibitor of the ACh degrading enzyme acetylcholinesterase (AChE). Here we report that physostigmine alone can also dose-dependently induce gamma-oscillations in rat hippocampal slices. We hypothesized that this effect was due to the presence of choline in the extracellular space and that this choline is taken up into cholinergic fibers where it is converted to ACh by the enzyme choline-acetyltransferase (ChAT). Release of ACh from cholinergic fibers in turn may then induce gamma oscillations. We therefore tested the effects of the choline uptake inhibitor hemicholinium-3 (HC-3) on persistent gamma-oscillations either induced by physostigmine alone or by co-application of ACh and physostigmine. We found that HC-3 itself did not induce gamma-oscillations and also did not prevent physostigmine-induced gamma-oscillation while washout of physostigmine and ACh induced gamma-oscillations was accelerated. It was recently reported that ChAT might also be present in the extracellular space (Vijayaraghavan et al., 2013). Here we show that the effect of physostigmine was prevented by the ChAT inhibitor (2-benzoylethyl)-trimethylammonium iodide (BETA) which could indicate extracellular synthesis of ACh. However, when we tested for effects of extracellularly applied acetyl-CoA, a substrate of ChAT for synthesis of ACh, physostigmine-induced gamma-oscillations were attenuated. Together, these findings do not support the idea that ACh can be synthesized by an extracellularly located ChAT. PMID- 25453771 TI - Inflammation-induced increase in nicotinic acetylcholine receptor current in cutaneous nociceptive DRG neurons from the adult rat. AB - The goals of the present study were to determine (1) the properties of the nicotinic acetylcholine receptor (nAChR) currents in rat cutaneous dorsal root ganglion (DRG) neurons; (2) the impact of nAChR activation on the excitability of cutaneous DRG neurons; and (3) the impact of inflammation on the density and distribution of nAChR currents among cutaneous DRG neurons. Whole-cell patch clamp techniques were used to study retrogradely labeled DRG neurons from naive and complete Freund's adjuvant inflamed rats. Nicotine-evoked currents were detectable in ~70% of the cutaneous DRG neurons, where only one of two current types, fast or slow currents based on rates of activation and inactivation, was present in each neuron. The biophysical and pharmacological properties of the fast current were consistent with nAChRs containing an alpha7 subunit while those of the slow current were consistent with nAChRs containing alpha3/beta4 subunits. The majority of small diameter neurons with fast current were IB4- while the majority of small diameter neurons with slow current were IB4+. Preincubation with nicotine (1 MUM) produced a transient (1 min) depolarization and increase in the excitability of neurons with fast current and a decrease in the amplitude of capsaicin-evoked current in neurons with slow current. Inflammation increased the current density of both slow and fast currents in small diameter neurons and increased the percentage of neurons with the fast current. With the relatively selective distribution of nAChR currents in putative nociceptive cutaneous DRG neurons, our results suggest that the role of these receptors in inflammatory hyperalgesia is likely to be complex and dependent on the concentration and timing of acetylcholine release in the periphery. PMID- 25453772 TI - Age and lesion-induced increases of GDNF transgene expression in brain following intracerebral injections of DNA nanoparticles. AB - In previous studies that used compacted DNA nanoparticles (DNP) to transfect cells in the brain, we observed higher transgene expression in the denervated striatum when compared to transgene expression in the intact striatum. We also observed that long-term transgene expression occurred in astrocytes as well as neurons. Based on these findings, we hypothesized that the higher transgene expression observed in the denervated striatum may be a function of increased gliosis. Several aging studies have also reported an increase of gliosis as a function of normal aging. In this study we used DNPs that encoded for human glial cell line-derived neurotrophic factor (hGDNF) and either a non-specific human polyubiquitin C (UbC) or an astrocyte-specific human glial fibrillary acidic protein (GFAP) promoter. The DNPs were injected intracerebrally into the denervated or intact striatum of young, middle-aged or aged rats, and glial cell line-derived neurotrophic factor (GDNF) transgene expression was subsequently quantified in brain tissue samples. The results of our studies confirmed our earlier finding that transgene expression was higher in the denervated striatum when compared to intact striatum for DNPs incorporating either promoter. In addition, we observed significantly higher transgene expression in the denervated striatum of old rats when compared to young rats following injections of both types of DNPs. Stereological analysis of GFAP+ cells in the striatum confirmed an increase of GFAP+ cells in the denervated striatum when compared to the intact striatum and also an age-related increase; importantly, increases in GFAP+ cells closely matched the increases in GDNF transgene levels. Thus neurodegeneration and aging may lay a foundation that is actually beneficial for this particular type of gene therapy while other gene therapy techniques that target neurons are actually targeting cells that are decreasing as the disease progresses. PMID- 25453774 TI - Anandamide rescues retinal barrier properties in Muller glia through nitric oxide regulation. AB - The blood retinal barrier (BRB) can mitigate deleterious immune response. Dysfunction at the BRB can affect disease progression. Under inflammatory conditions Muller glia produce increased pro-inflammatory factors, like nitric oxide (NO). In this study we describe molecular events at the Muller glia during inflammation which could affect inner BRB properties. Griess assay and 4,5 diaminofluorescein diacetate (DAF-2DA) time-lapse fluorescence were used to measure NO production. Western blot was used to analyze the expression of inducible nitric oxide synthase (iNOS) and mitogen-activated protein kinases (MAPK) components. Lucifer Yellow was used to measure permeability. Griess assay and DAF-2DA time-lapse fluorescence images revealed that lipopolysaccharide (LPS) induced inflammation and increased NO production. In parallel, changes were observed in tight junction proteins, zona occludens 1 (ZO-1), connexin 43 (Cx43), and permeability. This was mediated through activation of iNOS and mitogen activated protein kinase phosphatase-1 (MKP-1), implicated in immune response. Endocannabinoids can exert a protective and anti-inflammatory effect. Exogenous arachidonoyl ethanolamide (AEA) inhibited NO generation and also abolished LPS induced increase in permeability. Our work suggests that subtle changes in Muller glia function, which act as part of the BRB, could contribute to retinal health. AEA which can reduce inflammatory cytotoxicity has potential as treatment in several ocular manifestations where the integrity of the BRB is crucial. PMID- 25453773 TI - Neuroestrogen signaling in the songbird auditory cortex propagates into a sensorimotor network via an 'interface' nucleus. AB - Neuromodulators rapidly alter activity of neural circuits and can therefore shape higher order functions, such as sensorimotor integration. Increasing evidence suggests that brain-derived estrogens, such as 17-beta-estradiol, can act rapidly to modulate sensory processing. However, less is known about how rapid estrogen signaling can impact downstream circuits. Past studies have demonstrated that estradiol levels increase within the songbird auditory cortex (the caudomedial nidopallium, NCM) during social interactions. Local estradiol signaling enhances the auditory-evoked firing rate of neurons in NCM to a variety of stimuli, while also enhancing the selectivity of auditory-evoked responses of neurons in a downstream sensorimotor brain region, HVC (proper name). Since these two brain regions are not directly connected, we employed dual extracellular recordings in HVC and the upstream nucleus interfacialis of the nidopallium (NIf) during manipulations of estradiol within NCM to better understand the pathway by which estradiol signaling propagates to downstream circuits. NIf has direct input into HVC, passing auditory information into the vocal motor output pathway, and is a possible source of the neural selectivity within HVC. Here, during acute estradiol administration in NCM, NIf neurons showed increases in baseline firing rates and auditory-evoked firing rates to all stimuli. Furthermore, when estradiol synthesis was blocked in NCM, we observed simultaneous decreases in the selectivity of NIf and HVC neurons. These effects were not due to direct estradiol actions because NIf has little to no capability for local estrogen synthesis or estrogen receptors, and these effects were specific to NIf because other neurons immediately surrounding NIf did not show these changes. Our results demonstrate that transsynaptic, rapid fluctuations in neuroestrogens are transmitted into NIf and subsequently HVC, both regions important for sensorimotor integration. Overall, these findings support the hypothesis that acute neurosteroid actions can propagate within and between neural circuits to modulate their functional connectivity. PMID- 25453775 TI - PKA is required for the modulation of spinal nociceptive information related to ephrinB-EphB signaling in mice. AB - EphB receptors and their ephrinB ligands are implicated in modulating of spinal nociceptive information processing. Here, we investigated whether protein kinase A (PKA), acts as a downstream effector, participates in the modulation spinal nociceptive information related to ephrinB-EphB signaling. Intrathecal injection of ephrinB2-Fc caused thermal hyperalgesia and mechanical allodynia, which were accompanied by increased expression of spinal PKA catalytic subunit (PKAca) and phosphorylated cAMP-response element-binding protein (p-CREB). Pre-treatment with H89, a PKA inhibitor, prevented the activation of CREB by ephrinB2-Fc. Inhibition of spinal PKA signaling prevented and reversed pain behaviors induced by the intrathecal injection of ephrinB2-Fc. Furthermore, blockade of the EphB receptors by intrathecal injection of EphB2-Fc reduced formalin-induced inflammatory, chronic constrictive injury (CCI)-induced neuropathic, and tibia bone cavity tumor cell implantation (TCI)-induced bone cancer pain behaviors, which were accompanied by decreased expression of spinal PKAca and p-CREB. Overall, these results confirmed the important involvement of PKA in the modulation of spinal nociceptive information related to ephrinBs-EphBs signaling. This finding may have important implications for exploring the roles and mechanisms of ephrinB EphB signaling in physiologic and pathologic pain. PMID- 25453776 TI - Probucol mitigates streptozotocin-induced cognitive and biochemical changes in mice. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss and cognitive impairments. Although AD is the most prevalent aging related neurodegenerative disease, therapeutic strategies remain palliative. Recent studies have shown that probucol presents neuroprotective effects in experimental models of neurodegenerative disease. The present study aimed to investigate the potential protective effects of probucol against streptozotocin (STZ)-induced cognitive impairment and hippocampal biochemical changes (oxidative stress-related parameters, acetylcholinesterase (AChE) activity, cholesterol levels and beta-secretase (BACE) protein levels) in mice. Adult Swiss mice received STZ [150 MUg/bilateral, i.c.v.], and treated daily with probucol (?10 mg/kg/day, in drinking water, for 5 weeks,). Twenty-one days after i.c.v. administrations, STZ-infused animals displayed significant deficits in cognition (evaluated in the displaced and new object recognition tasks), which were paralleled by a significant increase in hippocampal AChE activity. Moreover, STZ infused mice showed increased levels of BACE and decreased glutathione reductase (GR) activity in the hippocampus compared with the control group. Probucol treatment significantly protected against the behavioral and hippocampal biochemical changes induced by STZ. However, it was unable to prevent STZ-induced increase of hippocampal BACE levels and did not change hippocampal cholesterol levels. It is noteworthy that probucol treatment increased the glutathione peroxidase (GPx) activity per se independent of STZ injection. The present findings are the first to show that i.c.v. STZ infusions are able to increase hippocampal BACE expression. Moreover, the results also show that probucol can counteract STZ-induced cognitive impairments and biochemical parameters independently of potential modulator effects toward BACE levels. The study is the first to report the protective effects of probucol against STZ-induced biochemical hippocampal changes and behavioral impairments, rendering this compound a promising molecule for further pharmacological studies on the search for therapeutic strategies to treat or prevent AD. PMID- 25453778 TI - Hydrogen peroxide attenuates the dipsogenic, renal and pressor responses induced by cholinergic activation of the medial septal area. AB - Cholinergic activation of the medial septal area (MSA) with carbachol produces thirst, natriuresis, antidiuresis and pressor response. In the brain, hydrogen peroxide (H2O2) modulates autonomic and behavioral responses. In the present study, we investigated the effects of the combination of carbachol and H2O2 injected into the MSA on water intake, renal excretion, cardiovascular responses and the activity of vasopressinergic and oxytocinergic neurons in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Furthermore, the possible modulation of carbachol responses by H2O2 acting through K+ATP channels was also investigated. Male Holtzman rats (280-320 g) with stainless steel cannulas implanted in the MSA were used. The pre-treatment with H2O2 in the MSA reduced carbachol-induced thirst (7.9+/-1.0, vs. carbachol: 13.2+/-2.0 ml/60 min), antidiuresis (9.6+/-0.5, vs. carbachol: 7.0+/-0.8 ml/120 min,), natriuresis (385+/-36, vs. carbachol: 528+/-46 MUEq/120 min) and pressor response (33+/-5, vs. carbachol: 47+/-3 mmHg). Combining H2O2 and carbachol into the MSA also reduced the number of vasopressinergic neurons expressing c-Fos in the PVN (46.4+/-11.2, vs. carbachol: 98.5+/-5.9 c-Fos/AVP cells) and oxytocinergic neurons expressing c-Fos in the PVN (38.5+/-16.1, vs. carbachol: 75.1+/-8.5 c Fos/OT cells) and in the SON (57.8+/-10.2, vs. carbachol: 102.7+/-7.4 c-Fos/OT cells). Glibenclamide (K+ATP channel blocker) into the MSA partially reversed H2O2 inhibitory responses. These results suggest that H2O2 acting through K+ATP channels in the MSA attenuates responses induced by cholinergic activation in the same area. PMID- 25453777 TI - Co-administration of subtherapeutic diazepam enhances neuroprotective effect of COX-2 inhibitor, NS-398, after lithium pilocarpine-induced status epilepticus. AB - RATIONALE: Seizures during status epilepticus (SE) cause neuronal death and induce cyclooxygenase-2 (COX-2). Pilocarpine-induced SE was used to determine if COX-2 inhibition with NS-398, when administered alone or with diazepam, decreases the duration and/or intensity of SE and/or reduces neuronal injury in the rat hippocampus. METHODS: Electroencephalogram (EEG) electrodes were implanted in male Sprague-Dawley rats. SE was induced with lithium-pilocarpine, and continuous EEG and video monitoring were performed for 24 h. Rats were divided into four groups (n=8-14 rats/group) and received NS-398, diazepam, NS-398 and diazepam, or vehicle 30 min after the first motor seizure. Six hours later, NS-398 injection was repeated in the NS-398 and in the NS-398+diazepam groups. The duration of SE (continuous spiking) and the EEG power in the gamma-band were analyzed. FluoroJade B staining in the dorsal hippocampus at 24h after SE was analyzed semi quantitatively in the CA1, CA3 and hilus. RESULTS: The duration and intensity of electrographic SE was not significantly different across the four groups. In rats treated with NS-398 alone, compared to vehicle-treated rats, neuronal damage was significantly lower compared to vehicle-treated rats in the CA3 (27%) and hilus (27%), but neuroprotection was not detected in the CA1. When NS-398 was administered with diazepam, decreased neuronal damage was further obtained in all areas investigated (CA1: 61%, CA3: 63%, hilus: 60%). CONCLUSIONS: NS-398, when administered 30 min after the onset of SE with a repeat dose at 6h, decreased neuronal damage in the hippocampus. Administration of diazepam with NS-398 potentiates the neuroprotective effect of the COX-2 inhibitor. These neuroprotective effects occurred with no detectable effect on electrographic SE. PMID- 25453779 TI - De novo expression of Nav1.7 in injured putative proprioceptive afferents: Multiple tetrodotoxin-sensitive sodium channels are retained in the rat dorsal root after spinal nerve ligation. AB - Tetrodotoxin-sensitive (TTX-s) spontaneous activity is recorded from the dorsal roots after peripheral nerve injury. Primary sensory neurons in the dorsal root ganglion (DRG) express multiple TTX-s voltage-gated sodium channel alpha-subunits (Navs). Since Nav1.3 increases, whereas all other Navs decrease, in the DRG neurons after peripheral nerve lesion, Nav1.3 is proposed to be critical for the generation of these spontaneous discharges and the contributions of other Navs have been ignored. Here, we re-evaluate the changes in expression of three other TTX-s Navs, Nav1.1, Nav1.6 and Nav1.7, in the injured 5th lumbar (L5) primary afferent components following L5 spinal nerve ligation (SNL) using in situ hybridization histochemistry and immunohistochemistry. While the overall signal intensities for these Nav mRNAs decreased, many injured DRG neurons still expressed these transcripts at clearly detectable levels. All these Nav proteins accumulated at the proximal stump of the ligated L5 spinal nerve. The immunostaining patterns of Nav1.6 and Nav1.7 associated with the nodes of Ranvier were maintained in the ipsilateral L5 dorsal root. Interestingly, putative proprioceptive neurons characterized by alpha3 Na+/K+ ATPase-immunostaining specifically lacked Nav1.7 mRNA in naive DRG but displayed de novo expression of this transcript following SNL. Nav1.7-immunoreactive fibers were significantly increased in the ipsilateral gracile nucleus where central axonal branches of the injured A-fiber afferents terminated. These data indicate that multiple TTX-s channel subunits could contribute to the generation and propagation of the spontaneous discharges in the injured primary afferents. Specifically, Nav1.7 may cause some functional changes in sensory processing in the gracile nucleus after peripheral nerve injury. PMID- 25453780 TI - An accidental poisoning with mitragynine. AB - An increasing number of drugs of abuse are sold word wide over the internet. Names like "legal highs", "herbal highs" etc. give the impression that these are safe products, although the risk of fatal reactions might be substantial. Leaves from the plant Mitragyna speciosa, contain active compounds like mitragynine and 7-hydroxymitragynine. It has been reported that the potency of 7 hydroxymitragynine at the MU-opioid receptor is 30 times higher than that of mitragynine and 17 times higher than that of morphine. Case reports regarding poisoning with Kratom are reported, but the toxic or lethal ranges for the concentrations of the active substances have not been established, and concentrations of 7-hydroxymitragynine have not been reported previously. We present a case report where a middle aged man was found dead at home. The deceased had a history of drug abuse and mental illness for several years. At autopsy, there were no significant pathological findings. Post-mortem analysis of peripheral blood revealed: zopiclone 0.043mg/L, citalopram 0.36mg/L and lamotrigine 5.4mg/L, i.e. concentrations regularly seen after therapeutic ingestion of these drugs. Additionally mitragynine 1.06mg/L and 7 hydroxymitragynine 0.15mg/L were detected in blood and both also in urine. The high concentrations of mitragynine and 7-hydroxymitragynine indicate that the cause of death is intoxication by these substances; and the circumstances point toward the manner of death being accidental. We recommend that both mitragynine and 7-hydroxymitragynine are analyzed for in cases with suspected Kratom intoxication. PMID- 25453782 TI - Less than meets the eye: reappraising the clinical relevance of attentional bias in addiction. AB - Recent years have seen an explosion of interest in attentional bias in addiction, particularly its clinical relevance. Specifically, numerous articles claimed to demonstrate either that (1) attentional bias measured in treatment settings could predict subsequent relapse to substance use, or (2) direct modification of attentional bias reduced substance use and improved treatment outcomes. In this paper, we critically evaluate empirical studies that investigated these issues. We show that the evidence regarding both of these claims is decidedly mixed, and that many of the studies that appear to yield positive findings have serious methodological and statistical limitations. We contend that the available literature suggests that attentional bias for drug cues fluctuates within individuals because it is an output of the underlying motivational state at that moment in time, but there is no convincing evidence that it exerts a causal influence on substance use. Future research should make use of experience sampling methodology to characterise the clinical significance of fluctuations in attentional bias over time. PMID- 25453781 TI - Neonatal withdrawal syndrome after chronic maternal consumption of 4 methylethcathinone. AB - Synthetic cathinones have been markedly present in the Spanish drug market in recent years. These substances can be easily obtained in "smart shops", smoke shops, gas stations and web sites where they can be bought and received anonymously avoiding normal law controls. For the first time we present a case of a neonatal withdrawal syndrome in a baby born to a woman who was a chronic consumer of 4-methylethcathinone. The newborn presented with increased jitteriness and irritability, highpitched cry, hypertonia in the limbs and brisk tendon reflexes. 4-Methylethcathinone was identified and quantified by liquid chromatography tandem mass spectrometry in the four subsequent 3cm segments of maternal hair (4.3, 4.0, 4.0 and 3.9ng/mg hair starting from most proximal segment) accounting for maternal consumption during the whole pregnancy and before and in neonatal meconium (0.7ng/g) confirming fetal exposure during intrauterine life. Methadone and its metabolite were also measured in maternal and neonatal matrices. Counseling pregnant women and women who may become pregnant on the consequences of fetal drug exposure to new designer drugs like 4 methylethcathinone is critical to preventing poor neonatal outcomes. This case report is informative to those studying designer drugs and those clinically involved with pregnant women abusing psychoactive substances. PMID- 25453783 TI - Asthma, allergy and the risk of prostate cancer: results from the Montreal PROtEuS study. AB - BACKGROUND: The few previous studies examining the association between asthma or allergy and prostate cancer (PCa) risk were inconclusive. This study aimed to evaluate these associations, and to explore in details the possible influence of current versus former allergic condition, age at onset, time since onset, and duration of each allergic condition. METHODS: Detailed information on self reported asthma and allergy was collected in the context of a large population based case-control study conducted in Montreal, Canada. Study subjects included 1936 cases, diagnosed between 2005 and 2009, and 1995 population controls. Unconditional multivariate logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusting for age, ancestry and familial history of prostate cancer. RESULTS: The ORs were 1.11 (95% CI: 0.89-1.40) and 0.98 (95% CI: 0.84-1.14) for ever reporting of asthma and allergy, respectively. These ORs did not substantially vary according to status (former or current), age at onset, time since onset, and duration of each allergic condition. PCa screening was not associated with allergic diseases reporting. CONCLUSIONS: Overall, our findings are in line with the absence of an association between a history of asthma or allergy, and PCa risk. PMID- 25453789 TI - Photo-dependent protein biosynthesis using a caged aminoacyl-tRNA. AB - Translation systems with four-base codons provide a powerful strategy for protein engineering and protein studies because they enable site-specific incorporation of non-natural amino acids into proteins. In this study, a caged aminoacyl-tRNA with a four-base anticodon was synthesized. The caged aminoacyl-tRNA contains a photocleavable nitroveratryloxycarbonyl (NVOC) group. This study showed that the caged aminoacyl-tRNA was not deacylated, did not bind to EF-Tu, and was activated by light. Photo-dependent translation of an mRNA containing the four-base codon was demonstrated using the caged aminoacyl-tRNA. PMID- 25453788 TI - The biological characteristics of a novel camptothecin-artesunate conjugate. AB - A novel conjugate of camptothecin and artesunate (C-Q) was prepared and its cytotoxicity was evaluated using the MTT assay. In addition, the antitumour activity and toxicity of C-Q were investigated in mice, and interaction between transferrin (TF) and C-Q was investigated to evaluate its interaction with biological macromolecules. In the MTT assay, C-Q showed better inhibitory activity against MCF7 breast cancer cells and SMMC-7721 liver cancer cells than camptothecin or artesunate. In vivo, C-Q showed lower toxicity and better antitumour activity compared with camptothecin. Fluorescence spectroscopy showed static quenching of TF in the presence of C-Q, and thermodynamic parameters (DeltaH>0 and DeltaG<0) indicated that the reaction was spontaneous and endothermic. The main binding force between C-Q and TF was hydrophobic, as indicated by thermodynamic parameters (DeltaH>0 and DeltaS>0). Thus, synchronous fluorescence spectra showed that C-Q had no influence on the conformation of TF. Our results indicated that C-Q represents a novel potential anticancer therapeutic vector with advantages over current methods of CPT and ART administration. This novel drug delivery system allows the use of these drugs in a manner associated with few side effects for normal tissue, and which facilitates synergistic effects of anti-tumour drugs. PMID- 25453790 TI - 'Naked-eye' quinoline-based 'reactive' sensor for recognition of Hg2+ ion in aqueous solution. AB - A new 'naked-eye' quinoline-based 'reactive' ratiometric fluorescent probe was prepared. The reactive stoichiometry of the probe with Hg2+ ion was 2:1. The probe exhibited high selectivity towards Hg2+ ion to other metal ions with a 410 fold increase in absorbance intensity ratio (A402/A340) in aqueous solution over a wide-range pH value (2-12), accompanied by a resonance color change from colorless to pale yellow visible to naked-eye. PMID- 25453791 TI - Design and synthesis of novel small molecule CCR2 antagonists: evaluation of 4 aminopiperidine derivatives. AB - A novel N-(2-oxo-2-(piperidin-4-ylamino)ethyl)-3-(trifluoromethyl)benzamide series of human CCR2 chemokine receptor antagonists was identified. With a pharmacophore model based on known CCR2 antagonists a new core scaffold was designed, analogues of it synthesized and structure-affinity relationship studies derived yielding a new high affinity CCR2 antagonist N-(2-((1-(4-(3 methoxyphenyl)cyclohexyl)piperidin-4-yl)amino)-2-oxoethyl)-3 (trifluoromethyl)benzamide. PMID- 25453792 TI - Synthesis and characterization of norbelladine, a precursor of Amaryllidaceae alkaloid, as an anti-inflammatory/anti-COX compound. AB - Rising ROS and systemic inflammation is often a serious concern in many disease conditions including obesity. Therefore, compounds with both anti-oxidant and anti-inflammatory activities are considered beneficial in preventing/treating several human chronic diseases. Norbelladine is an amine compound, a precursor for Amaryllidaceae alkaloids (e.g., belladine, crinamine, lycorine, and galanthamine) found in plants traditionally used for treating a variety of human diseases. However, little information is available about its potential health effects. Therefore, the amine was first synthesized, and its anti-oxidant and anti-inflammatory activities were investigated in this study. Also, the potential effects of the amine on NF-kappaB activation were investigated due to the critical involvement of ROS in the activation. Norbelladine was synthesized with more than 60% yield, analyzed by a HPLC method, and verified using NMR spectroscopic method. Then, its radical scavenging activity was investigated using DPPH- and superoxide radical assays. At the concentration of 10 MUM, norbelladine was a compound able to quench DPPH-radical by 31% (P < 0.05) and reduce superoxide radicals from xanthine oxidase by 33% (P < 0.05). At the concentration of 0.25 MUM, the amine also inhibited both COX-1 and COX-2 enzymes by 51% and 25% (P < 0.05), respectively. Furthermore, at the concentration of 10 MUM, norbelladine inhibited NF-kappaB activation by 23% (P < 0.05). In summary, the data suggests that norbelladine may be a compound to quench radicals, inhibit COX enzymes as well as suppress NF-kappaB activation at relatively lower concentrations. PMID- 25453793 TI - Protective effects of aloe-emodin on scopolamine-induced memory impairment in mice and H2O2-induced cytotoxicity in PC12 cells. AB - Aloe-emodin (AE) is one of the most important active components of Rheum officinale Baill. The present study aimed to investigate that AE could attenuate scopolamine-induced cognitive deficits via inhibiting acetylcholinesterase (AChE) activity and modulating oxidative stress. Kunming (KM) mice were received intraperitoneal injection of scopolamine (2 mg/kg) to induce cognitive impairment. Learning and memory performance were assessed in the Morris water maze (MWM). After behavioral testing, the mice were sacrificed and their hippocampi were removed for biochemical assays (superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), AChE and acetylcholine (ACh)). In vitro, we also performed the AChE activity assay and H2O2-induced PC12 cells toxicity assay. After 2 h exposure to 200 MUM H2O2 in PC12 cells, the cytotoxicity were evaluated by cell viability (MTT), nitric oxide (NO)/lactate dehydrogenase (LDH) release and intracellular reactive oxygen species (ROS) production. Our results confirmed that AE showed significant improvement in cognitive deficit in scopolamine-induced amnesia animal model. Besides, it increased SOD, GPx activities and ACh content, while decreased the level of MDA and AChE activity in AE treated mice. In addition, AE was found to inhibit AChE activity (IC50 = 18.37 MUg/ml) in a dose-dependent manner. Furthermore, preincubation of PC12 cells with AE could prevent cytotoxicity induced by H2O2 and reduce significantly extracellular release of NO, LDH and intracellular accumulation of ROS. The study indicated that AE could have neuroprotective effects against Alzheimer's disease (AD) via inhibiting the activity of AChE and modulating oxidative stress. PMID- 25453794 TI - Novel 25-hydroxyprotopanaxadiol derivatives incorporating chloroacetyl chloride and their anti-tumor evaluation. AB - In the current work, 12 novel 25-hydroxyprotopanaxadiol (25-OH-PPD) derivatives were synthesized by reacting with chloroacetyl chloride. And their in vitro antitumor activities were evaluated on six human tumor cell lines by MTT assay. The results demonstrated that, as compared with 25-OH-PPD, compounds 4, 6 and 7 exhibited higher cytotoxic activity on all tested cell lines. Of them, compound 4 showed strongly inhibition against MCF-7, HCT-116 and Lovo cells with IC50 values of 1.7, 1.6 and 2.1 MUM, respectively. The IC50 values of compound 6 against HCT 116 and 7 against MCF-7 were the lowest (1.2 and 1.6 MUM, respectively). It was also noted that compound 4 showed a 20- to 100-fold greater growth inhibition than ginsenoside-Rg3 (an anti-cancer regular drug in China). In conclusion, the data revealed that compounds 4, 6 and 7 were potential candidates for anti-tumor treatment and may be useful for the development of novel antiproliferative agents. PMID- 25453795 TI - Lithocarpic acids O-S, five homo-cycloartane derivatives from the cupules of Lithocarpus polystachyus. AB - Chemical investigation of the cupules of Lithocarpus polystachyus resulted in the identification of four 3,4-seco-homo-cycloartane and one homo-cycloartane derivatives named lithocarpic acids O-S. Their structures were determined based on extensive 1D/2D NMR, IR, MS spectroscopic analyses and chemical methods. Lithocarpic acid O (1) exhibited inhibitory activities on mouse and human isozymes of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) with IC50 values of 0.49 and 1.1 MUM, respectively. PMID- 25453796 TI - Synthesis and evaluation of fluoro substituted pyridinylcarboxamides and their phenylazo analogues for potential dopamine D3 receptor PET imaging. AB - A series of fluoro substituted pyridinylcarboxamides and their phenylazo analogues with high affinity and selectivity for the dopamine D3 receptor was synthesized by the use of 6-fluoropyridine-3-carbonyl chloride (1) and fluorophenylazocarboxylic ester (2). Several of these compounds (9a-e and 10a-h) have been evaluated in vitro, among which 9b, 10a, 10c and 10d proved to have at least single-digit nanomolar affinity for D3. They also exhibit considerable selectivity over the other dopamine receptor subtypes and noteworthy selectivity over the structurally related serotonin receptor subtypes 5-HT(1A) and 5-HT2, offering potential radiotracers for positron emission tomography. PMID- 25453797 TI - Identification and characterization of an anti-pseudomonal dichlorocarbazol derivative displaying anti-biofilm activity. AB - Pseudomonas aeruginosa strains resistant towards all currently available antibiotics are increasingly encountered, raising the need for new anti pseudomonal drugs. We therefore conducted a medium-throughput screen of a small molecule collection resulting in the identification of the N-alkylated 3,6 dihalogenocarbazol 1-(sec-butylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2 ol (MIC = 18.5 MUg mL-1). This compound, compound 1, is bacteriostatic towards a broad spectrum of Gram-positive and Gram-negative pathogens, including P. aeruginosa. Importantly, 1 also eradicates mature biofilms of P. aeruginosa. 1 displays no cytotoxicity against various human cell types, pointing to its potential for further development as a novel antibacterial drug. PMID- 25453798 TI - Inhibitory effects of ginseng sapogenins on the proliferation of triple negative breast cancer MDA-MB-231 cells. AB - Because of poor prognosis, clinical treatment of triple-negative (TN) breast cancer remains the most challenging factor in cancer treatment. Extensive research into alternative cancer therapies includes studying the naturopathic effects of the medicinal herb ginseng. This study investigates the anti neoplastic properties of ginseng sapogenins and the derivatives: (1) (20(S) protopanaxadiol (PPD), (2) 20(S)-protopanaxatriol), (3) (20(S) dihydroprotopanaxadiol, and (4) 20(S)-dihydroprotopanaxatriol). These compounds were found to prevent the proliferation of MDA-MB-231 human breast cancer cells. PPD was the most potent inhibitor, exhibiting an IC50 (5.87 MUM) comparable to that of the chemotherapeutic drug taxol. Furthermore, PPD induced dose-dependent cleavage of caspase-8, caspase-3, and PARP in MDA-MB-231 cells. Thus, we propose that PPD acts as anti-cancer agent by stimulating caspase-dependent apoptosis in breast cancer cells. PMID- 25453799 TI - Design, synthesis and anticancer evaluation of tetrahydro-beta-carboline hydantoin hybrids. AB - A series of new tetrahydro-beta-carboline-hydantoin hybrids have been designed and synthesized based on the structure of the known Eg5 inhibitor HR22C16. These compounds have been evaluated for their anticancer activity against lung (A549), cervical (ME180, HeLa), prostate (PC-3) and breast (MCF-7) cancer cell lines by MTT assay. These hybrids have displayed significant in vitro cytotoxicity in comparison to etoposide against PC-3, A549, and MCF-7 cell lines. The hybrids 3a, 3b, 3c, 3e, 3f, 3g, 4b, 4c, 4e and 4f appear to be more effective against the PC 3 cell line, among which compound 4b displayed the highest cytotoxicity (6.08 +/- 0.2, IC50 MUM). Based on these results, an attempt was made to rationalize their mechanism of action through cell cycle analysis studies. The flow-cytometric analysis of compound 4b in PC-3 cells indicated a G2/M cell cycle arrest. Molecular docking studies substantiate that these compounds indeed bind to the allosteric site of Eg5 formed from Glu116, Gly117, Glu118, Trp127, Ala133, Ile136, Pro137, Tyr211, Leu214, and Glu215 residues with the most potent compound 4b showing the most favorable interaction. PMID- 25453800 TI - Synthesis and PGE2 production inhibition of s-triazine derivatives as a novel scaffold in RAW 264.7 macrophage cells. AB - We present the synthesis and biological evaluation of a collection of s-triazine derivatives as a novel scaffold of compounds with the capability to inhibit the PGE2 production in LPS-induced RAW 264.7 macrophage cells. A total of 12 derivatives were synthesized and assayed for PGE2 reduction at 10 MUM concentration. Two compounds (7b and 7i) exhibiting >90% inhibition of PGE2 production were found to have IC50 values of 5.76 and 5.52 MUM, respectively. They were counter screened for inhibition on COX-2 activity in a cell free assay. Specifically, compound 7i (R1 = 4-Bn-Ph, R2 = Cl, R3 = Ph, R5 = CO2Me) was highly active in cells while maintaining little COX-2 inhibition (~0% at 10 MUM). Molecular docking study provides the possibility that compound 7i could inhibit PGE2 production by blocking the PGH2 binding site of mPGES-1 instead of COX-2 enzyme. Based on this result, our synthetic efforts will focus on intensive structure-activity relationship (SAR) study of s-triazine scaffold to discovery a potential PGE2 synthesis inhibitor. PMID- 25453801 TI - Cycloartane-type triterpenes from Euphorbia fischeriana stimulate human CYP3A4 promoter activity. AB - A chemical study of the roots of Euphorbia fischeriana resulted in the isolation of seven triterpenes (1-7), including two new compounds: (24R,S)-3beta-24,31 epoxy-24-methylcycloartane (1) and (24R,S)-3beta,31-dihydroxy-24-methoxy-24 methylcycloartane (2). Their structures were elucidated through extensive spectroscopic analyses. Cycloartanes 1-4 showed significant human CYP3A4 promoter activity through a series of luciferase reporter assays. Of these compounds, 3 and 4 activated the pregnane X receptor (PXR) and induced CYP3A4 mRNA expression in human primary hepatocytes. However, despite showing the most potent human CYP3A4 promoter activity via a PXR-independent pathway, 2 did not affect CYP3A4 mRNA expression in human primary hepatocytes. This difference is correlated to substitutions in C-24 and C-25 of the cycloartane structure. PMID- 25453802 TI - Synthesis and anticancer evaluation of 3-aryl-6-phenylimidazo [2,1-b]thiazoles. AB - A series of new 3,6-diphenylimidazo[2,1-b]thiazole derivatives (4a-l) are synthesized and evaluated for their anticancer activity. Some of the synthesized compounds have shown potent anti-proliferative activity against HeLa, MDA-MB-231, A549 and THP1 human cancer cell lines. Among the active compounds, 3-(3 trifluoromethylphenyl)-6-phenylimidazo[2,1-b]thiazole (4j) has caused significant cytotoxicity in HeLa cells, with IC50 as low as 6.5 MUM. Compound 4j has induced caspase-3 and caspase-8 activation, leading to an apoptotic cell death. FACS analysis has revealed that compound 4j arrests cells in G0/G1 phase. The presence of 3-(3-trifluoromethylphenyl)- or 3-(3-chlorophenyl)-substituent, in that order, on the 6-phenylimidazo[2,1-b]thiazole impacts more positively than other aryl substituents, on the anti-proliferative properties of these compounds. PMID- 25453803 TI - 3-Arylcoumarins: synthesis and potent anti-inflammatory activity. AB - Chronic inflammation is the persistent and excessive immune response and can lead to a variety of diseases. Aiming to discover new compounds with anti-inflammatory activity, we report herein the synthesis and biological evaluation of 3 arylcoumarins. Thirty five 3-arylcoumarins were prepared through Perkin condensation and further acid-promoted hydrolysis if necessary. In lipopolysaccharide-activated mouse macrophage RAW264.7 cells, 6,8-dichloro-3-(2 methoxyphenyl)coumarin (16) and 6-bromo-8-methoxy-3-(3-methoxyphenyl)coumarin (25) exhibited nitric oxide production inhibitory activity with the IC50 values of 8.5 MUM and 6.9 MUM, respectively, providing a pharmacological potential as anti-inflammatory agents. PMID- 25453804 TI - Probing of CD4 binding pocket of HIV-1 gp120 glycoprotein using unnatural phenylalanine analogues. AB - CD4-gp120 interaction is the first step for HIV-1 entry into host cells. A highly conserved pocket in gp120 protein is an attractive target for developing gp120 inhibitors or novel HIV detection tools. Here we incorporate seven phenylalanine derivatives having different sizes and steric conformations into position 43 of domain 1 of CD4 (mD1.2) to explore the architecture of the 'Phe43 cavity' of HIV 1 gp120. The results show that the conserved hydrophobic pocket in gp120 tolerates a hydrophobic side chain of residue 43 of CD protein, which is 12.2 A in length and 8.0 A in width. This result provides useful information for developing novel gp120 inhibitors or new HIV detection tools. PMID- 25453805 TI - Discovery of the 1,7-diazacarbazole class of inhibitors of checkpoint kinase 1. AB - Checkpoint kinase 1 (ChK1) is activated in response to DNA damage, acting to temporarily block cell cycle progression and allow for DNA repair. It is envisaged that inhibition of ChK1 will sensitize tumor cells to treatment with DNA-damaging therapies, and may enhance the therapeutic window. High throughput screening identified carboxylate-containing diarylpyrazines as a prominent hit series, but with limited biochemical potency and no cellular activity. Through a series of SAR investigations and X-ray crystallographic analysis the critical role of polar contacts with conserved waters in the kinase back pocket was established. Structure-based design, guided by in silico modeling, transformed the series to better satisfy these contacts and the novel 1,7-diazacarbazole class of inhibitors was discovered. Here we present the genesis of this novel series and the identification of GNE-783, a potent, selective and orally bioavailable inhibitor of ChK1. PMID- 25453806 TI - Design, synthesis, and DNA sequence selectivity of formaldehyde-mediated DNA adducts of the novel N-(4-aminobutyl) acridine-4-carboxamide. AB - A novel derivative of the anti-tumor agent N-[2-(dimethylamino)ethyl]acridine-4 carboxamide (DACA) was prepared by reduction of 9-oxoacridan-4-carboxylic acid to acridine-4-carboxylic acid with subsequent conversion to N-(4-aminobutyl)acridine 4-carboxamide (C4-DACA). Molecular modeling studies suggested that a DACA analogue comprising a side chain length of four carbons was optimal to form formaldehyde-mediated drug-DNA adducts via the minor groove. An in vitro transcription assay revealed that formaldehyde-mediated C4-DACA-DNA adducts selectively formed at CpG and CpA dinucleotide sequences, which is strikingly similar to that of formaldehyde-activated anthracenediones such as pixantrone. PMID- 25453807 TI - A simple, general approach of allosteric coagulation enzyme inhibition through monosulfated hydrophobic scaffolds. AB - Allosteric inhibition of coagulation enzymes offers the advantage of controlled inhibition. In this study, a small library of mono sulfated indole and benzothiazole based molecules was synthesized and screened against the panel of coagulation proteases. The results reveal that selected molecules inhibit the thrombin, factor Xa and factor XIa with moderate potency. Compound 6a was found to have an allosteric mode of inhibition against thrombin. Plasma clotting assays suggest that selected inhibitors 14b, 14c and 14d prolong both prothrombin and activated partial thromboplastin time. Overall, this work presents the newer class of allosteric inhibitors of thrombin and factor XIa with improved aqueous solubility profile. PMID- 25453808 TI - Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus kinase (JAK) inhibitors. AB - A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNgamma production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2 methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay. PMID- 25453809 TI - Synthesis and biological evaluation of piperlongumine derivatives as potent anti inflammatory agents. AB - Piperlongumine (PL) and its derivatives were synthesized by the direct reaction between acid chloride of 3,4,5-trimethoxycinnamic acid and various amides/lactams. Later their anti-inflammatory effects were evaluated in lipopolysaccharide (LPS)-induced RAW-264.7 macrophages. Of the piperlogs prepared in this study, the maximum (91%) inhibitory activity was observed with PL (IC50=3 MUM) but showed cytotoxicity whereas compound 3 (IC50=6 MUM) which possess alpha,beta-unsaturated gamma-butyrolactam moiety offered good level (65%) of activity with no cytotoxicity. This study revealed that amide/lactam moiety connected to cinnamoyl group with minimum 3 carbon chain length and alpha,beta unsaturation is fruitful to show potent anti-inflammatory activity. PMID- 25453810 TI - Discovery of functionalized bisimidazoles bearing cyclic aliphatic-phenyl motifs as HCV NS5A inhibitors. AB - This Letter describes the discovery of a number of functionalized bisimidazoles bearing a cyclohexylphenyl, piperidylphenyl, or bicyclo[2,2,2]octylphenyl motif as HCV NS5A inhibitors. Compounds 2c, 4b and 6 have demonstrated low single-digit nM potency in gt-1a replicon and double-digit pM potency in gt-1b replicon, respectively. Moreover, both 4b and 6 have, respectively, exhibited good oral bioavailability in rats with a favorable liver/plasma ratio of the drug concentration. PMID- 25453811 TI - Potent bisimidazole-based HCV NS5A inhibitors bearing annulated tricyclic motifs. AB - This Letter describes the synthesis and biological evaluation of a number of functionalized bisimidazoles bearing annulated tricyclic motifs as potent inhibitors of HCV NS5A protein. Compound 4 h, which contains a substituted tricyclic 6-6-6 xanthene, demonstrated broad genotypic spectrum, compelling potency, and good oral bioavailability with dose-dependent drug exposure level in multiple animal species. PMID- 25453813 TI - Asymmetric synthesis of 2-arylpiperazines. AB - An asymmetric synthesis of 2-arylpiperazines starting from phenacyl bromides, a variety of which are easily available, has been established. The synthesis features a CBS reduction of phenacyl bromide to provide optically enriched compounds, an SN2 reaction of 1,2,3-oxathiazolidine 2-oxides with an azide anion with invert of configuration, and construction of the piperazine ring via reduction of piperazine-2,3-diones. PMID- 25453812 TI - New efficient imidazolium aldoxime reactivators for nerve agent-inhibited acetylcholinesterase. AB - Herein, we described a new class of uncharged non-pyridinium reactivators for nerve agent-inhibited acetylcholinesterase (AChE). Based on a dual site binding strategy, we conjugated the imidazolium aldoxime to different peripheral site ligands (PSLs) of AChE through alkyl chains. Compared with the known quaternary pyridinium reactivators, two of the resulting conjugates (7g and 7h) were highlighted to be the first efficient non-pyridinium oxime conjugates exhibiting similar or superior ability to reactivate sarin-, VX- and tabun-inhibited AChE. Moreover, they were more broad-spectrum reactivators. PMID- 25453814 TI - Synthesis and biological evaluation of novel biaryl type alpha-noscapine congeners. AB - Natural alpha-noscapine, a known antitussive drug, is also now known to possess weak anticancer efficacy with relatively safe toxicity profile. In this study, we report synthesis and evaluation of novel biaryl type alpha-noscapine congeners designed by adding aryl unit to the tetrahydroisoquinoline part of natural alpha noscapine core. Palladium catalyzed Suzuki cross coupling of 9-bromo alpha noscapine with aryl boronic acids was employed using mild and inexpensive reagents to attain desired noscapinoids 5a-g in excellent yields. Screening anti proliferative activity for new noscapinoids 5b-g, on human cancer cell lines resulted three compounds 5b, 5d and 5f as potent analogues, active against human breast epithelial (MCF-7), human cervix cancer (HeLa) and human lung adenocarcinoma epithelial (A549) cell lines. PMID- 25453815 TI - Oligonucleotides conjugated with short chemically defined polyethylene glycol chains are efficient antisense agents. AB - Ligand conjugation is an attractive approach to rationally modify the poor pharmacokinetic behavior and cellular uptake properties of antisense oligonucleotides. Polyethylene glycol (PEG) attachment is a method to increase solubility of oligonucleotides and prevent the rapid elimination, thus increasing tissue distribution. On the other hand, the attachment of long PEG chains negatively influences the pharmacodynamic effect by reducing the hybridization efficiency. We examined the use of short PEG ligands on the in vitro effect of antisense agents. Circular dichroism showed that the tethering of PEG12-chains to phosphodiester and phosphorothioate oligonucleotides had no influence on their secondary structure and did not reduce the affinity to the counter strand. In an in vitro tumor model, a luciferase reporter assay indicated unchanged gene silencing activity compared to unmodified compounds, and even slightly superior target down regulation was found after treatment with a phosphorothioate modified conjugate. PMID- 25453816 TI - Monocyclic 4-amino-6-(phenylamino)-1,3,5-triazines as inhibitors of human DNA topoisomerase IIalpha. AB - Human DNA topoisomerase IIalpha (htIIalpha) is a validated target for the development of anticancer agents. Starting from the available information about the binding of the purine-based htIIalpha inhibitors in the ATP binding site we designed a virtual screening campaign combining structure-based and ligand-based pharmacophores with a molecular docking calculation searching for compounds that would contain a monocycle mimetic of the purine moiety. We discovered novel 4 amino-6-(phenylamino)-1,3,5-triazines 6, 7 and 11 as monocyclic htIIalpha inhibitors targeting the ATP binding site. Compound 6 from the 1,3,5-triazine series also displayed cytotoxicity properties in hepatocellular carcinoma (HepG2) cell lines and selectivity against human umbilical vein endothelial (HUVEC) cell lines. PMID- 25453817 TI - A reversed sulfonamide series of selective RORc inverse agonists. AB - The identification of a new series of RORc inverse agonists is described. Comprehensive structure-activity relationship studies of this reversed sulfonamide series identified potent RORc inverse agonists in biochemical and cellular assays which were also selective against a panel of nuclear receptors. Our work has contributed a compound that may serve as a useful in vitro tool to delineate the complex biological pathways involved in signalling through RORc. An X-ray co-crystal structure of an analogue with RORc has also provided useful insights into the binding interactions of the new series. PMID- 25453818 TI - Novel indolizine derivatives with unprecedented inhibitory activity on human farnesyltransferase. AB - The rational structural modification of new substituted indolizin-3 yl(phenyl)methanones 1a-i, 2a-i and 3a-i has greatly improved human farnesyltransferase inhibition. The para-bromophenyl analog 2f bearing an ester unit on the indolizine ring demonstrates the highest inhibition potential, with IC50 value of 1.3+/-0.2 MUM. The amidic series 1a-i proves to be the most promising for future modulations, particularly at the triple bond level. PMID- 25453819 TI - Design and synthesis of substituted morpholin/piperidin-1-yl-carbamodithioates as promising vaginal microbicides with spermicidal potential. AB - A series of seventeen morpholin/piperidin-1-yl-carbamodithioate (3-19) were synthesized as topical vaginal microbicidal spermicides. The synthesized compounds were evaluated for their anti-Trichomonas activity against MTZ susceptible and resistant strains along with their spermicidal and antifungal potential. All the synthesized compounds were assessed for their safety through cytotoxic assay against human cervical cell line (HeLa) and compatibility with vaginal flora, Lactobacillus. The study identified eleven dually active compounds with apparent safety. The plausible mode of action of these compounds was through sulfhydryl binding, confirmed via reduction in available free thiols on human sperm. The most promising compound 9 significantly inhibited (P<0.001) thiol sensitive sperm hexokinase. The stability of compound 9 in simulated vaginal fluid (SVF) was performed via HPLC-PDA method, which supported its utility for vaginal administration. PMID- 25453820 TI - Tanzawaic acid derivatives from a marine isolate of Penicillium sp. (SF-6013) with anti-inflammatory and PTP1B inhibitory activities. AB - Chemical investigation of a marine-derived fungus Penicillium sp. SF-6013 resulted in the discovery of a new tanzawaic acid derivative, 2E,4Z-tanzawaic acid D (1), together with four known analogues, tanzawaic acids A (2) and D (3), a salt form of tanzawaic acid E (4), and tanzawaic acid B (5). Their structures were mainly determined by analysis of NMR and MS data, along with chemical methods. Preliminary screening for anti-inflammatory effects in lipopolysaccharide (LPS)-activated microglial BV-2 cells showed that compounds 1, 2, and 5 inhibited the production of nitric oxide (NO) with IC50 values of 37.8, 7.1, and 42.5 MUM, respectively. Compound 2 also inhibited NO production in LPS stimulated RAW264.7 murine macrophages with an IC50 value of 27.0 MUM. Moreover, these inhibitory effects correlated with the suppressive effect of compound 2 on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in LPS-stimulated RAW264.7 and BV2 cells. In addition, compounds 2 and 5 significantly inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with the same IC50 value (8.2 MUM). PMID- 25453821 TI - Synthesis and immunoregulatory activities of conjugates of a Toll-like receptor 7 inert ligand. AB - In the synthesis and modification of the analogs of an adenine type of Toll-like receptor (TLR) 7 agonists, we found a special compound, 9-propionyloxy-8-hydroxy 2-(2-methoxyethoxy)-adenine (6). It is a synthesized TLR7 inert ligand, which does not respond to TLR7 itself. However, it can be coupled with protein or peptide antigens via propionyloxy functional group to promote their immunogenicity significantly. The compound was covalently coupled to protein and peptide to get the conjugates. The inductivity of cytokine production by the conjugates was 872.4-fold compared with the unconjugated antigens in vitro by mouse splenocyte. These data show that the immunostimulatory activity of inert TLR7 ligand can be endowed, and the activity of antigens can be amplified by conjugation with various proteins and peptides, thus broadening the potential therapeutic application and reducing the risk of TLR7 agonists' side effects. PMID- 25453822 TI - Estimating the population attributable fraction for schizophrenia when Toxoplasma gondii is assumed absent in human populations. AB - There is increasing evidence that infection with Toxoplasma gondii, a common parasite of people, cats and rodents, is associated with an increased risk of a diagnosis of schizophrenia. Although the claim that infection with T. gondii is one of the component causes of a diagnosis of schizophrenia remains contentious it is worth asking how important a causal association might be if only to inform our attitude to further work on the subject. The appropriate measure of importance is the population attributable fraction (PAF). The PAF is the proportion of diagnoses of schizophrenia that would not occur in a population if T. gondii infections were not present. The assumptions that underlie the derivation of the standard formula for measuring the PAF are violated in the specific instance of T. gondii and schizophrenia and so the conventional estimation method cannot be used. Instead, the PAF was estimated using a deterministic model of Toxoplasma gondii infection and schizophrenia occurrence in a hypothetical cohort of people at risk of both conditions. The incidence of infection with T. gondii in the cohort was assumed to be constant. Under these circumstances, the life-time mean population attributable fraction was estimated to be 21.4%, but it could not be ruled out that it could be as high as 30.6% or as low as 13.7% given the 95% confidence interval pertaining to the point estimate of the OR that was central to the calculation. These estimates (even the lowest) are higher than those obtained using the standard method for the same system and underscore the importance of understanding the limitations of conventional epidemiological formulae. PMID- 25453823 TI - Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression. AB - Monocytes and macrophages are major components of the tumor microenvironment, but their contributions to human cancer are poorly understood. We used molecular profiling combined with functional assays to investigate the role of these cells in human renal cell carcinoma (RCC). Blood monocytes from RCC patients displayed a tumor-promoting transcriptional profile that supported functions like angiogenesis and invasion. Induction of this protumor phenotype required an interleukin-1 receptor (IL-1R)-dependent mechanism. Indeed, targeting of IL-1-IL 1R axis in a human RCC xenograft model abrogated the protumor phenotype of tumor associated macrophages (TAMs) and reduced tumor growth in vivo. Supporting this, meta-analysis of gene expression from human RCC tumors showed IL1B expression to correlate with myelomonocytic markers, protumor genes, and tumor staging. Analyzing RCC patient tumors confirmed the protumor phenotype of TAMs. These data provide direct evidence for a tumor-promoting role of monocytes and macrophages in human cancer and indicate IL-1-IL-1R as a possible therapeutic target. PMID- 25453824 TI - As time goes by: KRABs evolve to KAP endogenous retroelements. AB - Retroelements, constituting about 50% of the human genome, both contribute to its evolution and threaten its integrity and are thus silenced during development. Jacobs et al. (2014) identify sequence-specific KRAB-ZNF proteins that repress subsets of L1 and SVA retrotransposons in humans, highlighting the evolutionary interplay between retroelements and their hosts. PMID- 25453825 TI - RUVs drive chromosome decondensation after mitosis. AB - Condensation of chromosomes during mitosis is required for their segregation into daughter cells but must be reversed to allow for postmitotic functions. In this issue of Developmental Cell, Magalska et al. (2014) show that the ATPases RuvBL1/2 drive postmitotic chromatin decondensation, demonstrating that this is an active process. PMID- 25453826 TI - A competitive cell fate switch. AB - Whereas tissue development and homeostasis depend on stem cell self-renewal and differentiation, the mechanisms that balance these processes remain incompletely understood. Pan et al. (2014) now show that competitive protein-protein interactions between Bam and COP9 signalosome components regulate cell fate decisions within the Drosophila ovarian germline stem cell lineage. PMID- 25453827 TI - Dissecting intraflagellar transport, one molecule at a time. AB - Intraflagellar transport (IFT) is required for proper function of cilia, although many of the mechanistic details underlying this process are obscure. Two studies in this issue of Developmental Cell illuminate key functions of one IFT protein, IFT27, and offer clues into how IFT cargo is selected and transported. PMID- 25453828 TI - The conserved misshapen-warts-Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila. AB - Similar to the mammalian intestine, the Drosophila adult midgut has resident stem cells that support growth and regeneration. How the niche regulates intestinal stem cell activity in both mammals and flies is not well understood. Here, we show that the conserved germinal center protein kinase Misshapen restricts intestinal stem cell division by repressing the expression of the JAK-STAT pathway ligand Upd3 in differentiating enteroblasts. Misshapen, a distant relative to the prototypic Warts activating kinase Hippo, interacts with and activates Warts to negatively regulate the activity of Yorkie and the expression of Upd3. The mammalian Misshapen homolog MAP4K4 similarly interacts with LATS (Warts homolog) and promotes inhibition of YAP (Yorkie homolog). Together, this work reveals that the Misshapen-Warts-Yorkie pathway acts in enteroblasts to control niche signaling to intestinal stem cells. These findings also provide a model in which to study requirements for MAP4K4-related kinases in MST1/2 independent regulation of LATS and YAP. PMID- 25453829 TI - SRF regulates craniofacial development through selective recruitment of MRTF cofactors by PDGF signaling. AB - Receptor tyrosine kinase signaling is critical for mammalian craniofacial development, but the key downstream transcriptional effectors remain unknown. We demonstrate that serum response factor (SRF) is induced by both platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling in mouse embryonic palatal mesenchyme cells and that Srf neural crest conditional mutants exhibit facial clefting accompanied by proliferation and migration defects. Srf and Pdgfra mutants interact genetically in craniofacial development, but Srf and Fgfr1 mutants do not. This signal specificity is recapitulated at the level of cofactor activation: while both PDGF and FGF target gene promoters show enriched genome-wide overlap with SRF ChIP-seq peaks, PDGF selectively activates a network of MRTF-dependent cytoskeletal genes. Collectively, our results identify a role for SRF in proliferation and migration during craniofacial development and delineate a mechanism of receptor tyrosine kinase specificity mediated through differential cofactor usage, leading to a PDGF-responsive SRF-driven transcriptional program in the midface. PMID- 25453830 TI - HAND2 targets define a network of transcriptional regulators that compartmentalize the early limb bud mesenchyme. AB - The genetic networks that govern vertebrate development are well studied, but how the interactions of trans-acting factors with cis-regulatory modules (CRMs) are integrated into spatiotemporal regulation of gene expression is not clear. The transcriptional regulator HAND2 is required during limb, heart, and branchial arch development. Here, we identify the genomic regions enriched in HAND2 chromatin complexes from mouse embryos and limb buds. Then we analyze the HAND2 target CRMs in the genomic landscapes encoding transcriptional regulators required in early limb buds. HAND2 controls the expression of genes functioning in the proximal limb bud and orchestrates the establishment of anterior and posterior polarity of the nascent limb bud mesenchyme by impacting Gli3 and Tbx3 expression. TBX3 is required downstream of HAND2 to refine the posterior Gli3 expression boundary. Our analysis uncovers the transcriptional circuits that function in establishing distinct mesenchymal compartments downstream of HAND2 and upstream of SHH signaling. PMID- 25453831 TI - Toward a comprehensive map of the effectors of rab GTPases. AB - The Rab GTPases recruit peripheral membrane proteins to intracellular organelles. These Rab effectors typically mediate the motility of organelles and vesicles and contribute to the specificity of membrane traffic. However, for many Rabs, few, if any, effectors have been identified; hence, their role remains unclear. To identify Rab effectors, we used a comprehensive set of Drosophila Rabs for affinity chromatography followed by mass spectrometry to identify the proteins bound to each Rab. For many Rabs, this revealed specific interactions with Drosophila orthologs of known effectors. In addition, we found numerous Rab specific interactions with known components of membrane traffic as well as with diverse proteins not previously linked to organelles or having no known function. We confirm over 25 interactions for Rab2, Rab4, Rab5, Rab6, Rab7, Rab9, Rab18, Rab19, Rab30, and Rab39. These include tethering complexes, coiled-coiled proteins, motor linkers, Rab regulators, and several proteins linked to human disease. PMID- 25453833 TI - Cu/Fe-cocatalyzed Meyer-Schuster-like rearrangement of propargylic amines: direct access to E-beta-aminoacryaldehydes. AB - A simple and efficient method for the synthesis of beta-aminoacryaldehydes via Cu(OAc)2.H2O and FeCl3 cocatalyzed Meyer-Schuster-Like rearrangement of propargylic amines was developed. The reactions proceed selectively as the E isomers in generally good yields under aerobic conditions, and are compatible with a broad range of functional groups. This method combines C-N bond cleavage as well as the N-aryl group migration and provides a practical and mild synthetic approach to alpha,beta-unsaturated carbonyl compounds, which are useful precursors in a variety of functional group transformations. PMID- 25453832 TI - Sox5 Is a DNA-binding cofactor for BMP R-Smads that directs target specificity during patterning of the early ectoderm. AB - The SoxD factor, Sox5, is expressed in ectodermal cells at times and places where BMP signaling is active, including the cells of the animal hemisphere at blastula stages and the neural plate border and neural crest at neurula stages. Sox5 is required for proper ectoderm development, and deficient embryos display patterning defects characteristic of perturbations of BMP signaling, including loss of neural crest and epidermis and expansion of the neural plate. We show that Sox5 is essential for activation of BMP target genes in embryos and explants, that it physically interacts with BMP R-Smads, and that it is essential for recruitment of Smad1/4 to BMP regulatory elements. Our findings identify Sox5 as the long-sought DNA-binding partner for BMP R-Smads essential to plasticity and pattern in the early ectoderm. PMID- 25453834 TI - Occurrence of pharmaceuticals in a water supply system and related human health risk assessment. AB - A monitoring study of 31 pharmaceuticals along Lisbon's drinking water supply system was implemented, which comprised the analysis of 250 samples including raw water (surface water and groundwater), and drinking water. Of the 31 pharmaceutical compounds, only sixteen were quantified in the analyzed samples, with levels ranging from 0.005 to 46 ng/L in raw water samples and 0.09-46 ng/L in drinking water samples. The human health risk assessment performed showed that appreciable risks to the consumer's health arising from exposure to trace levels of pharmaceuticals in drinking water are extremely unlikely, as RQs values were all below 0.001. Also, pharmaceuticals were selected as indicators to be used as a tool to control the quality of raw water and the treatment efficiency in the drinking water treatment plants. PMID- 25453835 TI - Maintaining residual kidney function in dialysis patients-is there a role for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers? PMID- 25453836 TI - Catheter-based renal denervation in ADPKD: just for pain control? PMID- 25453837 TI - In reply to 'catheter-based renal denervation in ADPKD: just for pain control?'. PMID- 25453838 TI - A "lingering mystery" of postdialysis serum bicarbonate concentration. PMID- 25453839 TI - Abnormal serum bicarbonate concentration in hemodialysis patients. PMID- 25453840 TI - In reply to 'abnormal serum bicarbonate concentration in hemodialysis patients' and 'a "lingering mystery" of postdialysis serum bicarbonate concentration'. PMID- 25453841 TI - Direct targeted quantitative molecular imaging of neurotransmitters in brain tissue sections. AB - Current neuroimaging techniques have very limited abilities to directly identify and quantify neurotransmitters from brain sections. We have developed a molecular specific approach for the simultaneous imaging and quantitation of multiple neurotransmitters, precursors, and metabolites, such as tyrosine, tryptamine, tyramine, phenethylamine, dopamine, 3-methoxytyramine, serotonin, GABA, glutamate, acetylcholine, and L-alpha-glycerylphosphorylcholine, in histological tissue sections at high spatial resolutions. The method is employed to directly measure changes in the absolute and relative levels of neurotransmitters in specific brain structures in animal disease models and in response to drug treatments, demonstrating the power of mass spectrometry imaging in neuroscience. PMID- 25453842 TI - Descending control of itch transmission by the serotonergic system via 5-HT1A facilitated GRP-GRPR signaling. AB - Central serotonin (5-hydroxytryptophan, 5-HT) modulates somatosensory transduction, but how it achieves sensory modality-specific modulation remains unclear. Here we report that enhancing serotonergic tone via administration of 5 HT potentiates itch sensation, whereas mice lacking 5-HT or serotonergic neurons in the brainstem exhibit markedly reduced scratching behavior. Through pharmacological and behavioral screening, we identified 5-HT1A as a key receptor in facilitating gastrin-releasing peptide (GRP)-dependent scratching behavior. Coactivation of 5-HT1A and GRP receptors (GRPR) greatly potentiates subthreshold, GRP-induced Ca(2+) transients, and action potential firing of GRPR(+) neurons. Immunostaining, biochemical, and biophysical studies suggest that 5-HT1A and GRPR may function as receptor heteromeric complexes. Furthermore, 5-HT1A blockade significantly attenuates, whereas its activation contributes to, long-lasting itch transmission. Thus, our studies demonstrate that the descending 5-HT system facilitates GRP-GRPR signaling via 5-HT1A to augment itch-specific outputs, and a disruption of crosstalk between 5-HT1A and GRPR may be a useful antipruritic strategy. VIDEO ABSTRACT: PMID- 25453844 TI - Cortical fosGFP expression reveals broad receptive field excitatory neurons targeted by POm. AB - Neighboring cortical excitatory neurons show considerable heterogeneity in their responses to sensory stimulation. We hypothesized that a subset of layer 2 excitatory neurons in the juvenile (P18 to 27) mouse whisker somatosensory cortex, distinguished by expression of the activity-dependent fosGFP reporter gene, would be preferentially activated by whisker stimulation. In fact, two photon targeted, dual whole-cell recordings showed that principal whisker stimulation elicits similar amplitude synaptic responses in fosGFP-expressing and fosGFP(-) neurons. FosGFP(+) neurons instead displayed shorter latency and larger amplitude subthreshold responses to surround whisker stimulation. Using optogenetic stimulation, we determined that these neurons are targeted by axons from the posteromedial nucleus (POm), a paralemniscal thalamic nucleus associated with broad receptive fields and widespread cortical projections. We conclude that fosGFP expression discriminates between single- and multi-whisker receptive field layer 2 pyramidal neurons. PMID- 25453843 TI - Configural and elemental coding of natural odor mixture components in the human brain. AB - Most real-world odors are complex mixtures of distinct molecular components. Olfactory systems can adopt different strategies to contend with this stimulus complexity. In elemental processing, odor perception is derived from the sum of its parts; in configural processing, the parts are integrated into unique perceptual wholes. Here we used gas-chromatography/mass-spectrometry techniques to deconstruct a complex natural food smell and assess whether olfactory salience is confined to the whole odor or is also embodied in its parts. By implementing an fMRI sensory-specific satiety paradigm, we identified reward-based changes in orbitofrontal cortex (OFC) for the whole odor and for a small subset of components. Moreover, component-specific changes in OFC-amygdala connectivity correlated with perceived value. Our findings imply that the human brain has direct access to the elemental content of a natural food odor, and highlight the dynamic capacity of the olfactory system to engage both object-level and component-level mechanisms to subserve behavior. PMID- 25453845 TI - Cytokeratin 19 expression in primary thoracic tumors and lymph node metastases. AB - BACKGROUND: The use of one-step nucleic acid amplification (OSNA), which allows for the rapid intraoperative detection of lymph node (LN) metastasis, is becoming more widely accepted in breast cancer. To provide basic data for the development of this method for lung tumors, we conducted a large-scale investigation of cytokeratin (CK) 19 expression in thoracic tumors. PATIENTS AND METHODS: We examined CK19 expression in specimens from a total of 801 surgically resected samples of primary lung adenocarcinoma (ADC), squamous cell carcinoma (SQC), large-cell carcinoma (LCC), pleomorphic carcinoma (PC), large cell neuroendocrine carcinoma (LCNEC), small cell carcinoma (SCC), and carcinoid tumor (CT) as well as pleural malignant mesothelioma and lung metastatic deposits from breast cancer using tissue microarrays (TMAs) and whole sections. We also compared the CK19 expression status between primary sites and LN metastatic deposits. RESULTS: The overall rate of CK19 expression as observed on TMAs and whole sections in the 801 analyzed cases was 88.0%. CK19 expression was detected in 94.6% of ADCs, 93.6% of SQCs, 54.5% of LCCs, 54.8% of PCs, 77.4% of LCNECs, 31.8% of SCCs, 34.0% of CTs, and 92.9% of malignant mesotheliomas. Expression of CK19 was also detected in 90.9% of lung metastatic deposits from breast carcinomas. CK19 expression was maintained between CK19-positive primary sites and the corresponding LN metastatic deposits. Of note, a portion of CK19-negative primary tumors showed upregulation of CK19 protein expression in LN metastases. CONCLUSIONS: Most thoracic tumors, except for PCs, CTs, and SCCs, were positive for CK19. We also found that CK19 expression was maintained between CK19-positive primary tumors and the corresponding LN metastatic deposits. These results may be useful in the development of the OSNA method for the intraoperative detection of LN metastasis in non-small cell lung cancer (NSCLC). PMID- 25453846 TI - Gene mutations in small-cell lung cancer (SCLC): results of a panel of 6 genes in a cohort of Italian patients. AB - BACKGROUND: No target therapies are presently available in the treatment of small cell lung cancer (SCLC). We investigated the presence of potentially drugable mutations in the EGFR, c-MET, BRAF, KRAS, PDGFRa and c-KIT genes in a retrospective series of SCLC from 2 Italian Institutions. Correlations with immunohistochemical, clinical and outcome features were evaluated. MATERIALS AND METHODS: Genes were studied by direct sequencing of DNA extracted from formalin fixed paraffin-embedded tissues. Immunohistochemical expression of TTF-1, p63, chromogranin, synaptophysin, CD56 and bcl-2 was assessed. RESULTS: Samples from 113 SCLC patients were analyzed. All cases were wild-type for BRAF, KRAS, PDGFRa and c-KIT (data available for 82 patients). Two (1.8%) patients were EGFR-mutated (exon 19 delE746-A750 and exon 21 L858R); both were females, non-smoker and had limited disease. Overall survival of EGFR-mutated patients was 21 months as compared to 11 months in wild-type. Five (4.4%) patients were c-MET-mutated (4 on exon 14: 2 R988C, 1 D990N, 1 D102Y; 1 on exon 17 R1166Q); all were smokers, 3 were males and 4 had extensive disease. Their OS was comparable to wild-type cases (12 vs. 11 months). EGFR and c-MET mutations were mutually exclusive. Gene mutations did not correlate with immunophenotype. CONCLUSIONS: Targetable mutations are uncommon in SCLC. EGFR-mutated patients tended to be female and non smoker and experienced a prolonged OS suggesting a possible positive prognostic effect. c-MET mutations did not affect survival. Target therapy might be considered in EGFR and c-MET-mutated patients. PMID- 25453847 TI - Prophylactic cranial irradiation improved the overall survival of patients with surgically resected small cell lung cancer, but not for stage I disease. AB - OBJECTIVES: We conducted a retrospective study to evaluate the role of prophylactic cranial irradiation (PCI) on patients with surgically resected small cell lung cancer (SCLC). PATIENTS AND METHODS: Between January 2003 and December 2009, the records of completely resected patients who were diagnosed with SCLC and definitive pTNM stage on the basis of histological proof were reviewed. According to the therapy modality, patients were allocated to PCI group and non PCI group. RESULTS: A total of 193 patients were finally included, 67 patients in PCI group and 126 in non-PCI group. The OS rates at 2-year and 5-year in PCI group were 92.5%, and 54.9%, respectively, and those of non-PCI were 63.2% and 47.8%, respectively (p=0.005). The BMFS rate at 2-year and 5-year in PCI group was significantly better than those of non-PCI group (96.8%, 76.6% and 79.4%, 75.5%, respectively, p = 0.014). But PCI could not confer survival benefit in the patients with p-stage I. Multivariate analysis revealed that PCI (HR = 2.339; p = 0.001) was an independent prognostic factor of the overall survival. CONCLUSIONS: PCI could improve the OS of patients with surgically resected SCLC, but not for p stage I patients. PMID- 25453848 TI - Early venous thromboembolic events are associated with worse prognosis in patients with lung cancer. AB - OBJECTIVES: Venous thromboembolic events (VTE) are a leading cause of death in cancer patients. We hypothesized that early VTE (EVTE, within 3 months of diagnosis) in patients with lung cancer (LC) are associated with worse overall survival (OS). MATERIALS AND METHODS: We identified 727 patients with LC between 1998 and 2011. Late VTE (LVTE) were defined as VTE occurring after 3 months from LC diagnosis. Advance disease (AD) was defined as patients with Stage IV non small cell lung cancer (NSCLC) or extensive stage small cell lung cancer (SCLC), and non-advanced disease (non-AD) was defined as <= Stage III NSCLC or limited stage SCLC. RESULTS: Out of 727 patients included in our review, 617 patients had NSCLC (85%), 94 (13%) SCLC, and 16 (2%) low grade neuroendocrine tumors. Ninety five patients (13%) experienced VTE, 44 (6%) experienced an EVTE and 49 (7%) had a LVTE. Patients with an EVTE had worse OS when compared to all other patients (medians 4 vs. 17 months, p < 0.0001). EVTE were associated with worse OS in patients with non-AD (medians 12 vs. 42 months, p = 0.01) and AD (medians 4 vs. 6 months, p = 0.02). When considering patients with NSCLC only, in a multivariate model that included age, stage, performance status >2, administration of chemotherapy and Charlson comorbidity index, EVTE were an independent predictor of increased mortality (HR 2.4; 95% CI 1.6-3.3). CONCLUSIONS: EVTE are associated with worse OS, irrespective of stage of the disease. Our findings underscore the need for an efficient preventive strategy for VTE among patients with lung cancer. PMID- 25453849 TI - Additional prognostic role of EGFR activating mutations in lung adenocarcinoma patients with brain metastasis: integrating with lung specific GPA score. AB - OBJECTIVE: While several prognostic models have been presented in NSCLC patients with brain metastasis, none of these models have included molecular markers as an index. The aim of our study was to evaluate the prognostic value of EGFR mutations and to integrate these EGFR mutations into the prognostic index in NSCLC patients with brain metastasis. MATERIALS AND METHODS: We analyzed retrospectively 292 lung adenocarcinoma patients with brain metastasis. Clinico pathological features and overall survival (OS) were compared between patients with EGFR mutations and patients with EGFR wild type. EGFR mutation status was integrated with lung specific graded prognostic assessment (GPA) score. RESULTS: Among 292 patients, EGFR mutation status was tested in 183 patients. One hundred and five patients (57.4%) had EGFR activating mutations, 14 (7.7%) had EGFR non activating mutations and 64 (35.0%) had EGFR wild type. OS was significantly longer in patients with EGFR activating mutations than in those with EGFR wild type patients (20.4 vs. 10.1 months, p = 0.002). However, patients with EGFR non activating mutations did not show superior OS compared with EGFR wild type patients (14.6 vs. 10.1 months, p = 0.83). Multivariate analysis revealed that the presence of EGFR activating mutation is an independent positive prognostic factor for OS (adjusted hazard ratio 0.56, p = 0.002). CONCLUSIONS: EGFR activating mutations have a prognostic role in lung adenocarcinoma patients with brain metastasis that is independent of other known prognostic factors. The frequency of EGFR mutation was higher than expected. The presence of EGFR activating mutations should be included as an index in the prognostic models for lung adenocarcinoma patients with brain metastasis. PMID- 25453850 TI - Response to "Wound debridement". PMID- 25453851 TI - Posttraumatic carotid cavernous fistula that presented as seizure and focal neurological deficits with symptom resolution after therapeutic coil embolization. AB - BACKGROUND: A posttraumatic carotid cavernous fistula can remain unrecognized and ultimately present with symptoms characteristic for a middle cerebral artery stroke. Progressive neurologic deterioration can occur until the condition is diagnosed and treated. If unrecognized and untreated, permanent damage may result. CASE REPORT: A 46-year-old white man with the history of a motor vehicle crash 6 months prior presented with complaints of acute onset of expressive aphasia and seizure-like activity for 3 days. On presentation, the patient was noted to have moderate proptosis and chemosis of the left eye. Magnetic resonance imaging of the brain showed an arteriovenous fistula arising from the anterolateral precavernous left internal carotid artery. This was directly communicating with the adjacent cortical veins along the medial aspect of the left temporal lobe, resulting in venous congestion in the left frontal opercular region, the left insula, and subinsular tracks. The patient underwent an intracranial coil embolization of a left carotid cavernous fistula. No complications were encountered, and the patient had near-complete resolution of neurologic deficits and left eye proptosis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although posttraumatic carotid cavernous fistula is a rare condition, it is important to be aware of this entity because immediate diagnosis and treatment may improve outcome. PMID- 25453853 TI - Beta-blocker use for toxicity from "bath salts". PMID- 25453852 TI - Near drowning and adult respiratory distress syndrome. PMID- 25453854 TI - Ossified epidural hematoma. PMID- 25453855 TI - State laws governing physician assistant practice in the United States and the impact on emergency medicine. AB - BACKGROUND: Midlevel providers, including physician assistants (PA), have been recommended by some to fill the current inadequate supply of providers nationally, including in emergency medicine. OBJECTIVE: PA practice is governed by state law. We described the differences in qualifications, scope of practice, prescriptive authority, and physician supervision required by individual states for PA practice and describe the impact this may have on emergency medicine. METHODS: A cross-sectional analysis of United States laws governing PA practice by abstraction from each state's public website. State characteristics were collected from the American Academy of Physician Assistants and United States Census websites and dichotomized by median values. RESULTS: Only six states (12%), all of which were larger-population states, required physician review of medical records within 1 week of a PA-only patient encounter. However, one state (Virginia) explicitly required onsite physician presence for PA practice in the emergency department. All states allowed PAs to assist in invasive procedures, but 13 (25%) restricted independent performance. Restriction of this practice was more likely in states with a higher population (38%), lower rural proportion (40%), and lower number of PAs per population (40%). Eleven (22%) states restricted performance of sedation or general anesthesia. An expanded scope of practice for disaster situations was allowed by 24 (47%) states and was more likely in larger population states (62%). All but two states (Florida and Kentucky) allowed PA prescribing of schedule III-V medications, and 37 (73%) allowed prescribing of schedule II medications. CONCLUSIONS: Laws governing PA practice in emergency departments differ by state, but generally allow for a broad scope of practice and limited direct supervision. Smaller, rural states were less likely to have tighter restrictions or oversight. PMID- 25453856 TI - Acute dyspnea caused by hypocalcemia-related laryngospasm. AB - BACKGROUND: Laryngospasm is a rare cause of stridor in adults, and laryngospasm due to hypocalcemia is an unusual finding. CASE REPORT: We present a case of an adult woman with acute dyspnea. A week prior to presentation, she experienced short episodes of a pinching feeling in her throat and difficulty breathing. On primary assessment, stridor and a positive Trousseau sign were noted. Laboratory examination showed hypocalcemia. We concluded that the dyspnea was caused by laryngospasm due to hypocalcemia. Hypocalcemia was treated promptly, and stridor and dyspnea resolved rapidly. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Laryngospasm is a rare, but serious and potentially lethal, complication of hypocalcemia in adults. In every adult presenting with acute dyspnea and stridor, the possibility of hypocalcemia should be considered. Hypocalcemia should be treated promptly. PMID- 25453857 TI - Medical student perceptions on the instruction of the emergency medicine oral case presentation. AB - BACKGROUND: The emergency medicine oral case presentation (EM OCP) is the clinician's communication tool to justify whether urgent intervention is required, to argue for ruling out emergent disease states, and to propose safe disposition plans in the context of triaging patients for medical care and prioritization of resources. The EM OCP provides the representation of the practice of emergency medicine, yet we do not know the current level of effectiveness of its instruction. OBJECTIVES: We aimed to document medical student perceptions and expectations of the instruction of the EM OCP. METHODS: We surveyed medical students from five institutions after their emergency medicine clerkship on their instruction of the EM OCP. Analysis included univariate descriptive statistics and chi-squared analyses for interactions. RESULTS: One hundred fifty-five medical students (82%) completed the survey. Most medical students reported the EM OCP to be unique compared to that of other disciplines (86%), integral to their clerkship evaluation (77%), and felt that additional teaching was required beyond their current medical school instruction (78%). A minority report being specifically taught the EM OCP (37%), that their instruction was consistent (29%), or that expectations of the EM OCP were clear (21%). Respondents felt that brief instruction during their orientation (65%) and reading with a portable summary card (45%) would improve their EM OCP skills, whereas other modalities would be less helpful. CONCLUSION: This study identifies a need for additional specific and consistent teaching of the EM OCP to medical students and their preference on how to receive this instruction. PMID- 25453858 TI - Anaphylactic reaction after ongoing exposure to hair glue: a novel case report. AB - BACKGROUND: Latex allergy is thought to be present in up to 6.5% of the general population, and can be much higher among those with chronic exposure. It is, however, uncommonly associated with severe anaphylactic reactions. Hair-care practices, such as the application of a hair weave, are a potential cause of latex-related anaphylaxis because the adhesives often contain natural rubber latex. CASE REPORT: We report the first case in the emergency medicine literature of successful treatment of a patient with airway compromise secondary to hair glue exposure. This case involved a 29-year-old woman who presented to the emergency department with severe angioedema and airway compromise. The patient had recently had an adhesive substance applied to her scalp for a hair weave placement. The patient did respond initially to antihistamine and alpha adrenergic medication, however, because the allergen could not be removed, she relapsed, was subsequently intubated, and admitted to the intensive care unit. The latex-containing hair glue was removed over a period of several hours using an oil-based hair-conditioning product. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This unique and potentially lethal situation required innovative management. Successful resolution of this case required a high degree of cultural literacy leading to the correct diagnosis and treatment, and utilization of resources outside of the health care field. Clinicians treating patients in areas where similar hair-care practices are prevalent should be aware of this pathology, and consider similar management strategies. PMID- 25453859 TI - Baptisia poisoning: a new and toxic look-alike in the neighborhood. AB - BACKGROUND: Baptisia is commonly found in residential gardens as an ornamental plant, in municipal "rain gardens" for water control, as well as in native and restored prairie habitat. Cytisine, an alkaloid with nicotinic acetylcholine receptor agonist properties, is a component of Baptisia. CASE REPORT: Two patients poisoned after simultaneously ingesting Baptisia plant material are presented. In addition to findings of generalized nicotinic agonist toxicity, including generalized weakness and gastrointestinal symptoms, profound ataxia was present in both, consistent with recently described nicotinic subunit activity in the cerebellum. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Baptisia, a native prairie plant commonly found in restored prairie habitats and public spaces, has striking "look-alike" characteristics, in its immature state, to asparagus. As future exposures by foraging citizens will be likely, awareness of this relationship and the toxic manifestations of cytisine will be useful. PMID- 25453860 TI - Laryngeal mask, laryngeal tube, and Frova introducer in simulated difficult airway. AB - BACKGROUND: The use of supraglottic devices is rising in the prehospital management of difficult airway; moreover, we think that patients with multiple trauma or cervical instability can take advantage of these devices without opening or retiring the cervical collar. OBJECTIVE: To compare speed and ease of use between Laryngeal Tube S (LTS) and the Ambu AuraOnce laryngeal mask (LMA).Our second objective was to evaluate changing these devices to an endotracheal tube (ETT) using a Frova introducer. METHODS: We studied the use of LTS and LMA in an experimental model, represented by a manikin with a rigid cervical collar and a limited mouth opening. This study was carried out in Complutense University of Madrid with 145 2(nd)-year students for the degree in Dentistry who have knowledge of the airway but lack experience in intubation. Number of attempts and time for the device's insertion were measured, as well as time for the exchange maneuver using the Frova introducer. RESULTS: Insertion of all devices was possible on the first attempt; time for insertion was LTS 12.2 +/- 1.28 s and LMA 6.87 +/- 0.97 s. Once these devices were inserted, a Frova introducer is used to perform an exchange by an endotracheal tube; all devices could be exchanged on the first attempt, and exchange time was LTS 26.9 +/- 1.2 s and LMA 16.79 +/- 1.32 s. Results for both time for insertion and exchange of the LMA were significantly lower than those for the LTS (p < 0.001). CONCLUSION: The method used can be considered quick and easy, even for personnel inexperienced in intubation. This exchange maneuver has not been described previously, so we can consider it as a new application of the Frova introducer. PMID- 25453861 TI - Elevated lipase without pancreatitis in infectious colitis. AB - BACKGROUND: An elevated lipase typically confirms the diagnosis of pancreatitis. Elevated lipase may be associated with other disorders, typically with some influence on the pancreas. The differential is more limited than elevated amylase secondary to the mostly unique production of lipase in pancreatic acinar cells. Elevated lipase has been reported in patients with inflammatory bowel disease, but not previously reported in infectious colitis. CASE REPORT: A 65-year-old woman presented to the emergency department with left lower quadrant abdominal pain radiating to her left flank worsening over 2 days. She denied epigastric pain. She had occasional nausea and occasional nonbilious and nonbloody emesis, and also reported diarrhea and weight loss over the preceding months. Laboratory values were largely unremarkable except for a grossly elevated lipase level. Computed tomography scan of her abdomen was performed and revealed findings consistent with infectious colitis, without signs of pancreatic inflammation or other findings associated with pancreatitis. She was admitted to the hospital and treated for infectious colitis with antibiotics and improved over 2 days, and was subsequently discharged for follow-up with her gastroenterologist. This is the first reported case of elevated lipase without pancreatitis associated with infectious colitis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be aware of other potential causes of elevated lipase and not assume that all cases of elevated lipase are associated with pancreatitis. This may possibly avoid unnecessary admission in situations that are not clearly pancreatitis. PMID- 25453862 TI - The importance of victim chest exposure during cardiopulmonary resuscitation: a simulation study. AB - BACKGROUND: During cardiopulmonary resuscitation (CPR), inaccurate positioning of the rescuer's hand might damage internal organs due to compression around the xiphoid process. OBJECTIVE: This study aimed to determine whether exposing the victim's chest during CPR would help adequate positioning of a rescuer's hand on the chest. METHODS: This simulation study included 187 participants. We gave them four photographs each of exposed chests and unexposed chests. Participants were then asked to mark a cross at the center of the chest (CoC) and at the inter nipple line (INL), and we measured the width of participants' palms to estimate the range of hand contact with the victim's chest. Finally, we compared the position and distribution of the CoC and INL markings and analyzed whether the hand contact range on the victim's chest involved the xiphoid process. RESULTS: The participants' CoC markings were similar regardless of whether the pictures showed an exposed or unexposed chest (p = 0.638). However, the level of INL marking was significantly lower in pictures of an exposed chest (p < 0.001). When exposing the chest, the distribution of markings was narrower for both CoC (p = 0.001) and INL (p < 0.001). The proportion of CoC markings involving the xiphoid process were lower when the chest was exposed (10.7%) than when was clothed (12.3%) (p < 0.001). Similarly, INL markings involving the xiphoid process followed the same trend in exposed vs. unexposed chest images (0% vs. 1.6%, respectively). CONCLUSIONS: Exposing the chest during CPR can improve the rescuer's ability to recognize the CoC and INL, leading to more intense chest compression and reducing the risk of inaccurate compression. PMID- 25453863 TI - Intracranial tuberculoma presenting as an isolated oculomotor nerve paresis. AB - BACKGROUND: The differential diagnosis of isolated oculomotor nerve paresis ranges from benign to potentially lethal pathologies. Intracranial tuberculosis (TB), as in the case of this patient, carries a high morbidity and mortality. Early diagnosis is crucial to improve patient outcomes. CASE REPORT: We present the case of a 46-year-old man with a chief complaint of 5 days of diplopia. His examination was remarkable for right inferolateral exotropia and weakness of the right medial rectus. Due to the neurologic findings, we obtained a computed tomography brain scan, which revealed a ring-enhancing lesion within the central midbrain with vasogenic edema causing mass effect on the cerebral aqueduct. Further evaluation revealed tuberculosis (TB) as the underlying etiology. He was placed on steroids and a four-drug anti-TB regimen with resultant improvement of his symptoms. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Intracranial tuberculoma can present with an isolated oculomotor nerve paresis in the absence of pulmonary or systemic symptoms. This case emphasizes the importance of maintaining a broad differential when investigating isolated oculomotor nerve paresis. PMID- 25453864 TI - "Gallstone Ileus" by Collins et al. PMID- 25453865 TI - Gyral calcification in an adult masquerading as subarachnoid hemorrhage. PMID- 25453866 TI - Removing unwanted maggots. PMID- 25453867 TI - The histological classification of biopsy in celiac disease: time for a change? PMID- 25453868 TI - Entering a new era in the treatment of hepatitis C. PMID- 25453869 TI - Sofosbuvir as backbone of interferon free treatments. AB - Sofosbuvir is the first-in-class NS5B nucleotide analogues to be launched for hepatitis C virus (HCV) treatment. Its viral potency, pangenotypic activity and high barrier to resistance make it the ideal candidate to become a backbone for several IFN-free regimens. Recent data demonstrated that sofosbuvir either with ribavirin alone or in combination with other direct-acting antivirals (DAAs) as daclatasvir, ledipasvir or simeprevir are able to cure HCV in at least 90% or over of patients. Treatment experienced genotype 3 population may remain the most difficult to treat population, but ongoing DAA combination studies will help to fill this gap. Safety profile of sofosbuvir or combination with other DAAs is good. Resistance to sofosbuvir did not appear as a significant issue. The rationale for using this class of drug and the available clinical data are reviewed. PMID- 25453870 TI - Epidemiology of hepatitis C in Europe. AB - The advent of potent and safe direct-acting antivirals against the hepatitis C virus has the potential of fulfilling the dream of eliminating this infection and its impact on global public health. However, even if effective drugs are at hand, most patients remain unaware of their infection, which may be recognized only in late stages when dire complications have occurred. Europe is not spared by this scourge, with its estimated 19,000,000 persons infected, and knowledge of the epidemiology of HCV and its drivers is a critical tool in fighting this virus. A thorough review is provided on the extent of the HCV epidemic across Europe, with a discussion of the most important subgroups affected, and of the risk factors of infection, both traditional and new. PMID- 25453871 TI - Aggregates of mutant CFTR fragments in airway epithelial cells of CF lungs: new pathologic observations. AB - Cystic fibrosis (CF) is caused by a mutation in the CF transmembrane conductance regulator (CFTR) gene resulting in a loss of Cl(-) channel function, disrupting ion and fluid homeostasis, leading to severe lung disease with airway obstruction due to mucus plugging and inflammation. The most common CFTR mutation, F508del, occurs in 90% of patients causing the mutant CFTR protein to misfold and trigger an endoplasmic reticulum based recycling response. Despite extensive research into the pathobiology of CF lung disease, little attention has been paid to the cellular changes accounting for the pathogenesis of CF lung disease. Here we report a novel finding of intracellular retention and accumulation of a cleaved fragment of F508del CFTR in concert with autophagic like phagolysosomes in the airway epithelium of patients with F508del CFTR. Aggregates consisting of poly ubiquitinylated fragments of only the N-terminal domain of F508del CFTR but not the full-length molecule accumulate to appreciable levels. Importantly, these undegraded intracytoplasmic aggregates representing the NT-NBD1 domain of F508del CFTR were found in ciliated, in basal, and in pulmonary neuroendocrine cells. Aggregates were found in both native lung tissues and ex-vivo primary cultures of bronchial epithelial cells from CF donors, but not in normal control lungs. Our findings present a new, heretofore, unrecognized innate CF gene related cell defect and a potential contributing factor to the pathogenesis of CF lung disease. Mutant CFTR intracytoplasmic aggregates could be analogous to the accumulation of misfolded proteins in other degenerative disorders and in pulmonary "conformational protein-associated" diseases. Consequently, potential alterations to the functional integrity of airway epithelium and regenerative capacity may represent a critical new element in the pathogenesis of CF lung disease. PMID- 25453874 TI - Editorial: 15th International Winter Eicosanoid Conference. PMID- 25453873 TI - Identification of transcription factors involved in the transcriptional regulation of the CXCL12 gene in rat pancreatic insulinoma Rin-5F cell line. AB - Diabetes is characterized by a deficit in the number of functional pancreatic beta-cells. Understanding the mechanisms that stimulate neogenesis of beta-cells should contribute to improved maintenance of beta-cell mass. Chemokine CXCL12 has recently become established as a novel beta-cell growth factor, however the mechanisms controlling its expression require clarification. We investigated the proteins involved in the transcriptional regulation of the rat beta-cell CXCL12 gene (Cxcl12). Using the electrophoretic mobility shift assay and chromatin immunoprecipitation, we established the in vitro and in vivo binding of C/EBPbeta, C/EBPalpha, STAT3, p53, FOXO3a, and HMG I/Y to the Cxcl12 promoter. Co immunoprecipitation experiments revealed protein-protein interactions between YY1 and PARP-1, FOXO3a and PARP-1, Sp1 and PARP-1, p53 and PARP-1, C/EBPbeta and PARP 1, YY1 and p53, YY1 and FOXO3a, p53 and FOXO3a, Sp1 and FOXO3a, C/EBPbeta and FOXO3a, C/EBPalpha and FOXO3a, Sp1 and STAT3. Our data lay the foundation for research into the interplay of signaling pathways that determine the beta-cell Cxcl12 expression profile. PMID- 25453872 TI - Randomized controlled trial of biofilm antimicrobial susceptibility testing in cystic fibrosis patients. AB - This study aimed to determine whether antimicrobial susceptibility testing of Pseudomonas aeruginosa grown as a biofilm, rather than planktonically, improves efficacy of antibiotic treatment for pulmonary exacerbations. This was a multicenter randomized, double-blind controlled trial of 14 days of intravenous antibiotic treatment for pulmonary exacerbations chosen based on conventional vs. biofilm antimicrobial susceptibility results in CF patients with chronic P. aeruginosa infection. There were 74 exacerbations in 39 patients. A total of 46% (12/26) exacerbations in the conventional group compared to 40% (19/48) exacerbations in the biofilm group achieved a >=3 log drop in P. aeruginosa sputum density (difference -0.03, 95% CI -0.5 to 0.4, p=0.9). Lung function improvements were similar in both groups. Biofilm antimicrobial susceptibility testing did not lead to improved microbiological or clinical outcomes compared to conventional methods in the treatment of pulmonary exacerbations in CF patients with chronic P. aeruginosa. PMID- 25453875 TI - Panic disorder. PMID- 25453876 TI - Heparin-bonded stent-graft for the treatment of TASC II C and D femoropopliteal lesions: the Viabahn-25 cm trial. AB - Purpose: To confirm the performance and safety of the 25-cm Viabahn endoprosthesis with Propaten bioactive surface when used in the treatment of de novo and/or restenotic TransAtlantic Inter-Society Consensus II C and D lesions of the superficial femoral artery and proximal popliteal artery. Methods: The 25 cm Gore Viabahn Endoprosthesis study (ClinicalTrials.gov identifier NCT01263665) is a prospective, multicenter, single-arm study that enrolled 71 patients (50 men; mean age 66.7 +/- 8.34 years) with lifestyle-limiting claudication (Rutherford class 2 to 4) and lesions longer than 20 cm (mean length 26.5 +/- 5.31 cm, range 20-40). The majority of lesions (92.9%) were total occlusions. The primary performance outcome was post-deployment stent length within +/- 10% of the pre-deployment stent length determined angiographically by quantitative vascular analysis. The primary safety outcome was device- and procedure-related serious adverse events occurring within 30 days of the procedure. The patients underwent follow-up examinations at 1 month and 1 year. Results : The median follow-up was 12.3 months (mean 12.3 +/- 0.6). Nine (12.7%) patients discontinued the study due to different reasons including 2 bypass surgeries. Angiography was available in 60 patients to determine the primary performance outcome, which was met in all cases. Two (2.8%) patients experienced a procedure-/device-related adverse event (dissection) during the 30-day follow-up. Kaplan-Meier estimates for 1-year primary and secondary patency were 67.0% [95% confidence interval (CI) 53.5% to 77.3%] and 96.9% (95% CI 88.0% to 99.2%), respectively. Changes in ankle brachial index and Rutherford category at 1 and 12 months each showed sustained improvement. Conclusion : This study confirms that the 25-cm Viabahn endoprosthesis acutely performs as intended and is safe when used as indicated in complex femoropopliteal lesions. One-year primary and secondary patency rates are satisfying and comparable to historical prosthetic bypass graft outcomes. PMID- 25453877 TI - Antegrade pedal approach for recanalizing occlusions in the opposing circulatory pathway of the foot when a retrograde puncture is not possible. AB - PURPOSE: To describe a novel technical strategy to approach below-the-ankle chronic total occlusions after failed antegrade recanalization in patients who are not candidates for retrograde puncture. TECHNIQUE: After a failure of antegrade recanalization of the tibial and foot vessels, an antegrade pedal access can be performed in the pedal or plantar artery. After crossing the plantar arch and the occlusions in the opposing circulation pathway of the foot, a rendezvous with the antegrade catheter is performed, followed by final angioplasty and hemostasis. CONCLUSION: An antegrade pedal approach to the opposing circulation in the foot may be considered for below-the-ankle recanalization after standard antegrade recanalization failure in patients who are not candidates for a retrograde puncture. PMID- 25453878 TI - Commentary: Another back door to the endovascular future: an antegrade pedal approach for retrograde revascularization. PMID- 25453879 TI - Visceral branch occlusion following aneurysm repair using multibranched thoracoabdominal stent-grafts. AB - PURPOSE: To identify risk factors for late-occurring branch occlusion following multibranched endovascular repair of thoracoabdominal and pararenal aortic aneurysm. METHOD: Out of 120 patients who underwent multibranched endovascular aneurysm repair between September 2005 and May 2013, 100 (78 men; mean age 72.4 +/- 7.4 years) met the criteria for inclusion in the current retrospective analysis. Demographic data were gleaned from a prospectively maintained database. Mean aneurysm diameter was 66.7 +/- 11.7 mm. Multiplanar reconstructions of postoperative computed tomographic angiography were used to measure 6 parameters of renal branch morphology. RESULTS: All 100 patients had undergone successful placement of multibranched aortic stent-grafts with a total of 95 celiac branches, 100 superior mesenteric artery (SMA) branches, and 187 renal branches. During a mean follow-up of 25.6 months, there were no stent fractures or stent separations, no SMA occlusions, and only 2 (2.1%) celiac artery occlusions, neither of which required reintervention. In contrast, there were 18 (9.6%) renal branch occlusions in 16 patients, all men (p=0.02). Patients with renal branch occlusions were significantly more likely to have a history of myocardial infarction (p=0.004). The mean renal artery length was significantly greater in the occlusion group compared to the non-occlusion group (47.5 +/- 13.6 vs. 39.4 +/- 14.2, p=0.03). No other aspect of branch morphology was significantly different between the occlusion and non-occlusion groups. CONCLUSION: Renal branch occlusion was by far the commonest late failure mode after multibranched endovascular aneurysm repair. The current study provides no basis for a change in patient selection or stent-graft design, only a change in the components used to construct renal branches. It is too early to tell the effect this will have. PMID- 25453880 TI - Aortic hemodynamics after thoracic endovascular aortic repair, with particular attention to the bird-beak configuration. AB - PURPOSE: To quantitatively evaluate the impact of thoracic endovascular aortic repair (TEVAR) on aortic hemodynamics, focusing on the implications of a bird beak configuration. METHODS: Pre- and postoperative CTA images from a patient treated with TEVAR for post-dissecting thoracic aortic aneurysm were used to evaluate the anatomical changes induced by the stent-graft and to generate the computational network essential for computational fluid dynamics (CFD) analysis. These analyses focused on the bird-beak configuration, flow distribution into the supra-aortic branches, and narrowing of the distal descending thoracic aorta. Three different CFD analyses (A: preoperative lumen, B: postoperative lumen, and C: postoperative lumen computed without stenosis) were compared at 3 time points during the cardiac cycle (maximum acceleration of blood flow, systolic peak, and maximum deceleration of blood flow). RESULTS: Postoperatively, disturbance of flow was reduced at the bird-beak location due to boundary conditions and change of geometry after TEVAR. Stent-graft protrusion with partial coverage of the origin of the left subclavian artery produced a disturbance of flow in this vessel. Strong velocity increase and flow disturbance were found at the aortic narrowing in the descending thoracic aorta when comparing B and C, while no effect was seen on aortic arch hemodynamics. CONCLUSION: CFD may help physicians to understand aortic hemodynamic changes after TEVAR, including the change in aortic arch geometry, the effects of a bird-beak configuration, the supra-aortic flow distribution, and the aortic true lumen dynamics. This study is the first step in establishing a computational framework that, when completed with patient specific data, will allow us to study thoracic aortic pathologies and their endovascular management. PMID- 25453881 TI - Commentary: The bird-beak stent-graft configuration: the end of aortic arch endograft collapse? PMID- 25453882 TI - Transseptal ascending aortic access facilitates transcatheter embolization of proximal type I endoleak associated with bird-beak configuration of an endograft in the proximal aortic arch. AB - PURPOSE: To report the initial use of antegrade transseptal ascending aortic access to perform transcatheter embolization of a proximal type I endoleak associated with bird-beak configuration of an endograft in the proximal aortic arch. CASE REPORT: A 61-year-old man underwent endovascular repair of a large, symptomatic aortic arch aneurysm located distal to the left common carotid artery using a fenestrated endograft. Completion angiography showed bird-beak configuration of the proximal endograft and a large type Ia endoleak. In a separate procedure, the endoleak was embolized with cyanoacrylate glue via an antegrade ascending aortic access obtained through a transseptal sheath stabilized by an indwelling arteriovenous wire loop. This approach provided straight-line access into the endoleak with requisite catheter support, and complete thrombosis of the aneurysm sac was achieved. The patient's symptoms abated, and at 1-year follow-up, there was no endoleak, and the aneurysm sac had shrunken markedly. CONCLUSION: Antegrade transseptal ascending aortic access facilitates transcatheter embolization of type Ia endoleak in the proximal aortic arch. PMID- 25453884 TI - How does the multilayer flow modulator work? The science behind the technical innovation. PMID- 25453883 TI - Commentary: Transseptal salvation of a leaking thoracic stent-graft: "heart wiring" a path to the aortic arch. PMID- 25453885 TI - Safety and effectiveness of a novel vascular closure device: a prospective study of the ExoSeal compared to the Angio-Seal and ProGlide. AB - PURPOSE: To prospectively assess the safety and efficacy of a novel absorbable vascular closure device (ExoSeal) in patients undergoing cardiac catheterization with femoral access compared to the established collagen-based (Angio-Seal) and suture-mediated (ProGlide) closure devices. METHODS: This prospective, observational, dual-center, non-randomized, non-blinded study enrolled 1013 patients (65.1 +/- 11.8 years) undergoing cardiac catheterization via a common femoral artery access in which hemostasis was achieved using a vascular closure device (255 Angio-Seal, 258 ProGlide, and 500 ExoSeal). In hospital complications (bleeding, hematoma, pseudoaneurysm, vessel occlusion, dissection, and arteriovenous fistula) of the puncture site and device failures (persistent bleeding) were recorded and compared for ExoSeal vs. the established devices (Angio-Seal + ProGlide). RESULTS: There were more complications after utilization of ExoSeal compared to established devices (3.6% vs. 1.2%, p=0.012). No significant difference was observed in the device success rate between the established vascular closure devices (96.3%) and the novel device (94.8%, p=0.28). Considering each closure system, Angio-Seal had the lowest complication rate (0.4%) and the highest efficacy (99.2%); the latter differed significantly from ExoSeal (94.8%, p=0.001). Logistic regression analysis revealed a >3-fold odds of complications when using ExoSeal, which remained unchanged in multivariate analysis. CONCLUSION: Utilization of the novel vascular closure device is associated with a higher complication rate and a similar device failure rate compared to collagen-based and suture-mediated devices, with Angio-Seal having the lowest complication and device failure rates. PMID- 25453886 TI - Graft inflow stenosis induced by the inflatable ring fixation mechanism of the Ovation stent-graft system: hemodynamic and clinical implications. AB - PURPOSE: To investigate the observed inflow stenosis at the O-rings of the Ovation stent-graft and evaluate its hemodynamic and clinical impact. METHODS: The study involved 49 consecutive patients (48 men; mean age 71.2 +/- 7.7 years) treated successfully with the Ovation abdominal aortic stent-graft between June 2011 and January 2014 at a single center. Cross-sectional area and radius measurements of the infrarenal aorta just proximal to the sealing mechanism, as well at the site of stenosis, were measured from 3D reconstructions of the 1 month postoperative computed tomographic angiograms. Based on Poiseuille's law, the predicted pressure drop was calculated for each patient based on the length of the stenosis. Invasive blood pressure measurements at 3 levels (proximal to the inflatable rings, halfway inside the stenosis, and distal to the stenosis) were obtained in 10 patients intraoperatively. Ankle-brachial index (ABI) values preoperatively were compared to those after the procedure for all patients to assess the clinical impact of this phenomenon. RESULTS: Median internal cross sectional area at the site of the stenosis was significantly reduced compared to the area just proximal to the O-rings [57% reduction: 123 mm(2) (range 28-254) vs. 283 mm(2) (range 177-531), respectively; p<0.001]. The same was observed for the radius [6.5 mm (range 3-9) vs. 9.5 mm (range 7.5-13), respectively; p<0.001]. Based on the median 15 mm length of the stenosis (range 13-17) observed in the study population, a median pressure drop of 0.13 mmHg (range 0-0.25) along the stenosis was calculated. Invasive blood pressure measurements indicated a non significant pressure change along the stenosis (e.g., 0.7 mmHg between the proximal level and halfway inside the stenosis). ABI remained practically unchanged postoperatively. CONCLUSION: The advantages of the Ovation device's unique sealing mechanism come at the expense of a median area inflow stenosis of ~ 60%. This stenosis does not cause a hemodynamically significant pressure drop. Future modification of the graft ring design may be needed in order to reduce this stenosis. PMID- 25453887 TI - Commentary: Implications of Ovation's unique sealing mechanism. PMID- 25453889 TI - Commentary: Midterm Endurant results place more confidence in off-label use for EVAR. PMID- 25453888 TI - Midterm results of endovascular aneurysm repair using the Endurant stent-graft according to the instructions for use vs. off-label conditions. AB - PURPOSE: To compare the midterm results in patients treated with the Endurant stent-graft according to device-specific instructions for use (IFU) vs. those treated in an off-label (OL) situation. METHODS: Between November 2007 and March 2010, 177 patients (161 men; mean age 73.7 years) with abdominal aortic aneurysm were treated with the Endurant stent-graft at 2 European centers. Patients operated on according to the IFU (121, 68.4%) were compared with those who underwent endovascular aneurysm repair in OL circumstances (56, 31.6%) to evaluate estimated 5-year survival, freedom from any device-related reinterventions, freedom from graft thrombosis, and freedom from type I endoleak. Univariate and multivariate analyses were performed to identify independent predictors of poor outcomes in the OL group. RESULTS: Mean follow-up was 31.2 months (range 1-65). At 5 years, there were no differences in terms of survival (67.9% IFU vs. 54.1% OL, p=0.3), freedom from any device-related reintervention (91.2% IFU vs. 92.4% OL, p=0.8), or freedom from graft thrombosis (97.5% IFU vs. 92.7% OL, p=0.3). Estimated 5-year freedom from type I endoleak was significantly better in the IFU group than in OL (100% vs. 96.2%, respectively; p=0.03). In the OL group, multivariate analysis showed that female sex and coronary artery disease were independent predictors of poor survival. CONCLUSION: Off-label use of the Endurant stent-graft was associated with a greater but acceptable risk of type I endoleak. Otherwise, there was no difference between the IFU and off-label groups as regards survival, graft thrombosis, or reintervention. PMID- 25453891 TI - Commentary: Effect of graft fabric on pulse wave velocity following endovascular aneurysm repair. PMID- 25453890 TI - Differential effects of stent-graft fabrics on arterial stiffness in patients undergoing endovascular aneurysm repair. AB - PURPOSE: To evaluate the differential effects of endograft fabric types on pulse wave velocity (PWV), a valid, clinically feasible marker of arterial stiffness, in patients undergoing endovascular repair (EVAR) of abdominal aortic aneurysms (AAAs). METHODS: As part of a registered study (ClinicalTrials.gov identifier NCT00636766), 118 consecutive men (mean age 71 +/- 8 years) with AAA undergoing elective EVAR were divided into groups according to the type of fabric in the implanted endografts: 46 had polytetrafluoroethylene (PTFE)-covered stent-grafts and 72 received stent-grafts covered with polyester fabric. Patients with Marfan syndrome, collagen-related disorders, and end-stage renal failure were excluded. PWV, clinical characteristics (comorbidities, body mass index, blood pressure, lipids, and glucose profile), novel biomarkers [interleukin (IL)-6, IL-8, IL-10, and osteoprotegerin (OPG)] were determined at baseline and prospectively after 12 months. RESULTS: At baseline, standard multiple regression analysis revealed the independent association of mean blood pressure, OPG, and AAA diameter with PWV after adjustment for age (R(2)=0.729, p=0.036). At follow-up, serum levels of both IL-8 and IL-10 were significantly increased, while OPG decreased in both groups (p<0.05). However, between-group comparison revealed a more adverse effect of polyester covered endografts on serum IL-8 (p<0.001) and OPG (p=0.048) levels. At the same time, PWV was considerably increased in both polyester (+4.12+/-0.33 m/s, p<0.001) and PTFE (+2.82 +/- 0.25 m/s, p=0.003) groups; the effect was more pronounced in the former group (p=0.033). In multivariate analysis, the polyester endograft type emerged as an independent determinant of PWV change after EVAR (R(2)=0.460, p=0.040). CONCLUSION: Both endograft types increased PWV, while recipients of polyester covered stent-grafts showed greater PWV elevation. Further investigation will clarify the inflammatory response and the differential clinical impact of endograft types. PMID- 25453892 TI - Flow-independent dynamics in aneurysms: intra-aneurysm pressure measurements following complete flow cessation in internal carotid artery aneurysms. AB - PURPOSE: To determine if complete flow obliteration by covered stents reduces intra-aneurysm pressures in internal carotid artery (ICA) aneurysms. METHODS: A single lumen microcatheter was placed into the aneurysm sac prior to covered stent deployment in 3 patients and connected to a pressure monitoring system. The intra-aneurysm pressure was continuously monitored, and readings were recorded prior to and immediately after stent deployment and at 5-minute intervals up to 20 minutes after stent placement. Complete occlusion of flow into the aneurysms was confirmed by carotid angiography. RESULTS: There was no change in mean pressure within the aneurysm before and immediately after stent placement (80 mmHg) in any patient, nor was there a change in waveform of the intra-aneurysm pressure recording. The average of intra-aneurysm pressures among the 3 patients was higher (99 mmHg) at 10 and 15 minutes after stent placement. In 2 patients, the microcatheter was retracted into the parent arterial lumen; no difference in pressure was noted. CONCLUSION: Our observations suggest no change in the pressures within the aneurysm after complete flow cessation (flow-independent). These findings may assist clinicians in better understanding aneurysm hemodynamics and rupture after covered stent deployment. PMID- 25453894 TI - MTHFR C677T mutation increased the risk of Ischemic Stroke, especially in large artery atherosclerosis in adults: an updated meta-analysis from 38 researches. AB - BACKGROUND: To date, many publications have evaluated the correlation between the Ethylenetetrahydrofolate reductase gene (MTHFR) C677T and Ischemic Stroke susceptibility in adults. However, the results remain inconclusive. The meta analysis was performed to resolve the problem. METHODS: Based on 38 studies, dichotomous data were presented as the odds ratio (OR) with a 95% confidence interval (CI). RESULTS: This study found, the carriers of the MTHFR 677C->T variation were more likely to increase the risk of Ischemic Stroke susceptibility in all over pooled population, including Asian and European, but not in African population (Europe: TT vs. CC+TC: OR = 1.364 95% CI = 1.010-1.841 p = 0.043; Asia subgroup: T vs. C: OR = 1.245, 95% CI = 1.141-1.358, p < 0.001; Africa: T vs. C: OR = 1.202, 95% CI = 0.990-1.459, p = 0.062). Among etiology stratified analysis, only large-artery atherosclerosis subgroups had a significant different, and the p value was less than 0.01 in all genetic models (T vs. C: OR = 1.29, 95% CI = 1.09-1.52, p = 0.002; TT+TC vs. CC: OR = 1.27, 95% CI = 1.06-1.51, p = 0.009; TT vs. CC+TC: OR = 1.62, 95% CI = 1.19-2.19, p = 0.002). CONCLUSIONS: This meta analysis suggests that MTHFR C677T mutation increased the risk of Ischemic Stroke in adults, especially in large-artery atherosclerosis. PMID- 25453897 TI - Y-shaped ligand-driven gold nanoparticles for highly efficient tumoral uptake and photothermal ablation. AB - We report functional gold nanoparticles (AuNP) with antibody-like ligands. These particles consist of Y-shaped ligands and AuNP. Transferrin (Tf) and Tat peptide were linked to each head of a Y-shaped poly(ethylene glycol) (PEG)-containing dopamine at one tail site. Also, Y-shaped ligands (with Tf and Tat peptide) were anchored to the surface of the AuNP as the result of noncovalent conjugation of dopamine and the AuNP. Interestingly, the partial shielding of Tat peptides by large Tf molecules rather improved Tf-mediated endocytosis of the AuNP, while minimizing the natural nonspecific cell interaction of Tat peptides. This system resulted in highly improved in vitro/in vivo tumor-selective uptake over AuNP bearing a single ligand (Tf or Tat peptides). Furthermore, this system resulted in significant enhancement of in vivo photothermal tumor cell ablation under light-irradiation conditions for AuNP. We believe that this design is a promising method to easily modify conventional antibodies or ligands to improve their disease-recognition ability. PMID- 25453898 TI - Pt- and Ru-doped SnO2-Sb anodes with high stability in alkaline medium. AB - Different Pt- and Ru-doped Ti/SnO2-Sb electrodes were synthesized by thermal decomposition. The effect of the gradual substitution of Sb by Ru in the nominal composition on the physicochemical and electrochemical properties were evaluated. The electrochemical stability of the electrodes was estimated from accelerated tests at 0.5 A cm(-2) in 1 M NaOH. Both as-synthesized and deactivated electrodes were thoroughly characterized by scanning electron microscopy (SEM), energy dispersive X-ray microanalysis (EDX), transmission electron microscopy (TEM), X ray photoelectron spectroscopy (XPS) and X-ray diffraction analysis (XRD). The incorporation of a small amount (about 3 at. %) of both Pt and Ru into the SnO2 Sb electrodes produced a 400-times increase in their service life in alkaline medium, with no remarkable change in the electrocatalysis of the oxygen evolution reaction (OER). It is concluded that the deactivation of the electrodes is promoted by alkaline dissolution of metal species and coating detachment at high potentials. The introduction of Pt has a coating compacting effect, and Ru(IV), at low amounts until 9.75 at. %, replaces the Sn(IV) cations in the rutile-like SnO2 structure to form a solid solution that strongly increases the stability of the electrodes. The observed Ru segregation and decreased stability for larger Ru contents (x > 9.75 at. %), together with the selective dissolution of Ru after deactivation, suggest that the formation of a homogeneous (RudeltaSn1-delta)O2 single-phase is crucial for the stabilization of these electrodes. PMID- 25453899 TI - Helical gold nanorods as chiral recognition nanostructures: a relativistic density functional theory study. AB - We establish helical gold nanorods as the first examples of chiral recognition nanostructures by examining the simple chiral molecule CClHDT adsorbed on the helical Au40 nanorod. We calculate the vibrational circular dichroism (VCD) spectra of the R and S enantiomers of CClHDT adsorbed on the R (or S) enantiomer of Au40 using relativistic density functional theory. The highest adsorption energy is found when the Cl atom of CClHDT binds to a low-coordinated Au atom at the edge of Au40. There are three adsorption modes (essentially identical in energy) corresponding to three orientations of the HDT moiety. We show that, for each adsorption mode, the VCD spectra are distinctly different for the Au40(R) ClHDT(R) and Au40(R)-CClHDT(S) complexes, and we give a qualitative explanation for this based on the principle of chirality transfer. For comparison with the results for Au40, we calculate the VCD spectra of the R and S enantiomers of CClHDT adsorbed on the achiral Au20 tetrahedral cluster. Again, there are three adsorption modes (essentially identical in energy) corresponding to three orientations of the HDT moiety. However, we show that, for each adsorption mode, the VCD spectra are mirror symmetric but otherwise essentially identical for the Au20-CClHDT(R) and Au20-CClHDT(S) complexes. Thus, the inherent chirality of the helical Au40 nanorod is essential for its chiral recognition functionality. PMID- 25453900 TI - Kisspeptin regulates tuberoinfundibular dopaminergic neurones and prolactin secretion in an oestradiol-dependent manner in male and female rats. AB - Prolactin (PRL) secretion is inhibited by hypothalamic dopamine. Kisspeptin controls luteinising hormone (LH) secretion and is also involved in PRL regulation. We further investigated the effect of kisspeptin-10 (Kp-10) on the activity of tuberoinfundibular dopaminergic (TIDA) neurones and the role of oestradiol (E2 ) in this mechanism. Female and male rats were injected with i.c.v. Kp-10 and evaluated for PRL release and the activity of dopamine terminals in the median eminence (ME) and neurointermediate lobe of the pituitary (NIL). Kp 10 at the doses of 0.6 and 3 nmol increased plasma PRL and decreased 4 dihydroxyphenylacetic acid (DOPAC) levels in the ME and NIL of ovariectomised (OVX), E2 -treated rats but had no effect in OVX. In gonad-intact males, 3 nmol Kp-10 increased PRL secretion and decreased DOPAC levels in the ME but not in the NIL. Castrated males treated with either testosterone or E2 also displayed increased PRL secretion and reduced ME DOPAC in response to Kp-10, whereas castrated rats receiving oil or dihydrotestosterone were unresponsive. By contrast, the LH response to Kp-10 was not E2 -dependent in either females or males. Additionally, immunohistochemical double-labelling demonstrated that TIDA neurones of male rats contain oestrogen receptor (ER)-alpha, with a higher proportion of neurones expressing ERalpha than in dioestrous females. The dopaminergic neurones of periventricular hypothalamic nucleus displayed much lower ERalpha expression. Thus, TIDA neurones express ERalpha in male and female rats, and kisspeptin increases PRL secretion through inhibition of TIDA neurones in an E2 -dependent manner in both sexes. These findings provide new evidence about the role of kisspeptin in the regulation of dopamine and PRL. PMID- 25453901 TI - Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage. AB - Molecular mechanisms responsible for hepatocellular carcinoma (HCC) remain largely unknown. Using genetically engineered mouse models, we show that hepatocyte-specific expression of unconventional prefoldin RPB5 interactor (URI) leads to a multistep process of HCC development, whereas its genetic reduction in hepatocytes protects against diethylnitrosamine (DEN)-induced HCC. URI inhibits aryl hydrocarbon (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes implicated in L-tryptophan/kynurenine/nicotinamide adenine dinucleotide (NAD(+)) metabolism, thereby causing DNA damage at early stages of tumorigenesis. Restoring NAD(+) pools with nicotinamide riboside (NR) prevents DNA damage and tumor formation. Consistently, URI expression in human HCC is associated with poor survival and correlates negatively with L-tryptophan catabolism pathway. Our results suggest that boosting NAD(+) can be prophylactic or therapeutic in HCC. PMID- 25453902 TI - Modeling alveolar soft part sarcomagenesis in the mouse: a role for lactate in the tumor microenvironment. AB - Alveolar soft part sarcoma (ASPS), a deadly soft tissue malignancy with a predilection for adolescents and young adults, associates consistently with t(X;17) translocations that generate the fusion gene ASPSCR1-TFE3. We proved the oncogenic capacity of this fusion gene by driving sarcomagenesis in mice from conditional ASPSCR1-TFE3 expression. The completely penetrant tumors were indistinguishable from human ASPS by histology and gene expression. They formed preferentially in the anatomic environment highest in lactate, the cranial vault, expressed high levels of lactate importers, harbored abundant mitochondria, metabolized lactate as a metabolic substrate, and responded to the administration of exogenous lactate with tumor cell proliferation and angiogenesis. These data demonstrate lactate's role as a driver of alveolar soft part sarcomagenesis. PMID- 25453904 TI - Estimating pairwise relatedness between individuals with different levels of ploidy. AB - Estimates of relatedness coefficients, based on genetic marker data, are often necessary for studies of genetics and ecology. Whilst many estimates based on method-of-moment or maximum-likelihood methods exist for diploid organisms, no such estimators exist for organisms with multiple ploidy levels, which occur in some insect and plant species. Here, we extend five estimators to account for different levels of ploidy: one relatedness coefficient estimator, three coefficients of coancestry estimators and one maximum-likelihood estimator. We use arrhenotoky (when unfertilized eggs develop into haploid males) as an example in evaluations of estimator performance by Monte Carlo simulation. Also, three virtual sex-determination systems are simulated to evaluate their performances for higher levels of ploidy. Additionally, we used two real data sets to test the robustness of these estimators under actual conditions. We make available a software package, PolyRelatedness, for other researchers to apply to organisms that have various levels of ploidy. PMID- 25453905 TI - Steady-state kinetics and spectroscopic characterization of enzyme-tRNA interactions for the non-heme diiron tRNA-monooxygenase, MiaE. AB - MiaE [2-methylthio-N(6)-isopentenyl-adenosine(37)-tRNA monooxygenase] isolated from Salmonella typhimurium is a unique non-heme diiron enzyme that catalyzes the O2-dependent post-transcriptional allylic hydroxylation of a hypermodified nucleotide (ms(2)i(6)A37) at position 37 of selected tRNA molecules to produce 2 methylthio-N(6)-(4-hydroxyisopentenyl)-adenosine(37). In this work, isopentenylated tRNA substrates for MiaE were produced from small RNA oligomers corresponding to the anticodon stem loop (ACSL) region of tRNA(Trp) using recombinant MiaA and dimethylallyl pyrophosphate. Steady-state rates for MiaE catalyzed substrate hydroxylation were determined using recombinant ferredoxin (Fd) and ferredoxin reductase (FdR) to provide a catalytic electron transport chain (ETC) using NADPH as the sole electron source. As with previously reported peroxide-shunt assays, steady-state product formation retains nearly stoichiometric (>98%) E stereoselectivity. MiaE-catalyzed i(6)A-ACSL(Trp) hydroxylation follows Michaelis-Menten saturation kinetics with kcat, KM, and V/K determined to be 0.10 +/- 0.01 s(-1), 9.1 +/- 1.5 MUM, and ~11000 M(-1) s(-1), respectively. While vastly slower, MiaE-catalyzed hydroxylation of free i(6)A nucleoside could also be observed using the (Fd/FdR)-ETC assay. By comparison to the V/K determined for i(6)A-ACSL substrates, an ~6000-fold increase in enzymatic efficiency is imparted by ACSL(Trp)-MiaE interactions. The impact of substrate tRNA-MiaE interactions on protein secondary structure and active site electronic configuration was investigated using circular dichroism, dual-mode X-band electron paramagnetic resonance, and Mossbauer spectroscopies. These studies demonstrate that binding of tRNA to MiaE induces a protein conformational change that influences the electronic structure of the diiron site analogous to what has been observed for various bacterial multicomponent diiron monooxygenases upon titration with their corresponding effector proteins. These observations suggest that substrate-enzyme interactions may play a pivotal role in modulating the reactivity of the MiaE diiron active site. Moreover, the simplified monomeric (alpha) protein configuration exhibited by MiaE provide an unparalleled opportunity to study the impact of protein-effector interactions on non-heme diiron site geometry and reactivity. PMID- 25453903 TI - EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma. AB - The aberrant transcription factor EWS-FLI1 drives Ewing sarcoma, but its molecular function is not completely understood. We find that EWS-FLI1 reprograms gene regulatory circuits in Ewing sarcoma by directly inducing or repressing enhancers. At GGAA repeat elements, which lack evolutionary conservation and regulatory potential in other cell types, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors. These divergent chromatin-remodeling patterns repress tumor suppressors and mesenchymal lineage regulators while activating oncogenes and potential therapeutic targets, such as the kinase VRK1. Our findings demonstrate how EWS-FLI1 establishes an oncogenic regulatory program governing both tumor survival and differentiation. PMID- 25453906 TI - [Are patients in the postpartum period potential egg donors?]. AB - OBJECTIVES: In France, oocyte donation program is still underdeveloped because of lack of donors and this situation entails an important wave of cross border medical tourism to different European countries mainly Spain and Greece. In 2011, the General inspection of social affairs report recommended to the biomedicine agency to promote spontaneous oocyte donation via different channels of information to develop this national program. The main objective of this study is to assess the knowledge of women after baby delivery about oocyte donation. The second objective is the identification of ways to assure better information and to promote oocyte donation. PATIENTS AND METHODS: We conducted a prospective study with anonymous questionnaire distribution to women after delivery at obstetrics/gynecology department of the Regional University Hospital and Maternity-Children Unit "Victor-Pauchet" of Amiens, from December 2012 to January 2013. RESULTS: Two hundred and fifty-five questionnaires were distributed and 242 of them were analyzed (94.9%). About oocyte donation knowledge: 28% did not know it was possible, 45% did not know it was legal in France, 54% did not know who was concerned and 36% know that a treatment is necessary, 9% think that oocyte donation is paid and 10% it is non-anonymous. If 67% seems to be favorable to this initiative, only 35% could accept to realize it. About information efficiency, 88% think not to receive enough information, 64% would like to have more information. The health care professional wanted to give this information is an obstetrician (51%), a midwife (37%) and a nurse (12%). DISCUSSION AND CONCLUSION: Oocyte donation program is misoriented due to a lack of information. Obstetricians and midwives have an important educational and informative role to support oocyte donation. Specific strategy of communication and valuable targeted information are needed to motivate potential donor and achieve the objectives of the program. PMID- 25453908 TI - Thickness, composition, and molecular structure of residual thin films formed by forced dewetting of Ag from glycerol/D2O solutions. AB - The thickness, composition, and interfacial molecular structure of residual thin films retained on the surface of polycrystalline Ag substrates after being forcibly dewet from glycerol/D2O solutions are investigated using contact angle measurements, ellipsometry, and polarization modulation-infrared reflection absorption spectroscopy (PM-IRRAS). Residual film thicknesses are rationalized on the basis of the relevant long-range van der Waals and structural forces leading to residual film formation along with the interfacial glycerol and D2O structure. Unique interfacial composition, wherein glycerol preferentially segregates to the residual film interfaces, is substantiated by PM-IRRAS. Thus, the residual films possess composition and molecular structure that differ from those of bulk solution. Specifically, in the thinnest residual films, glycerol interacts strongly with the Ag substrate, leading to glycerol that is more ordered than the bulk liquid that coexists with bulk-like D2O. In thicker residual films, the glycerol mole fraction is still enhanced relative to the bulk solution, but both ordered and liquid-like glycerol species are observed along with D2O that is more strongly hydrogen-bonded than in the bulk. The creation of residual films by forced dewetting and their interrogation by spectroscopic methods are thus demonstrated to represent a powerful approach for characterizing interfacial liquid molecular structure near solid surfaces but beyond the first monolayer under ambient conditions. PMID- 25453907 TI - [New in hysteroscopy: hysteroscopic morcellators]. AB - A new technology recently appeared for the treatment of endo-uterine pathologies: hysteroscopic morcellators. It seemed to us useful to review this new technology. The morcellator we mostly experiment is the Myosure(r), in 14 patients, with a median age of 40.5 years (28-58). The time of procedure went from 5 to 75 min with a median time at 26 min. The median of the total fluid deficit was 300 mL (0 1500 mL). A conversion in traditional resectoscopy happened in 4 cases (29%). This results are not so good as in literature. This is probably bound to one the learning curve but also the type of pathology. For the operative time, all the studies agree that hysteroscopic morcellation is faster than hysteroscopic resection. The quantity of fluid used is also lesser, as the deficit of fluid when the morcellator is used. The percentage of success to remove the pathology is high, close to 100% for the polyps and 92% for the submucous myomas. The indications are the polyps and the submucous myomas type 0 or 1. The morcellation of remnant trophoblastic tissues is also described and seems effective. Others indications, as the removal of uterine septum or cure of uterine synechias, are criticisable. In conclusion, hysteroscopic morcellators are probably a great progress for the cure of the endo-uterine pathologies. They cannot yet concurrence the hysterosopic resectoscopes for the treatment of big submucous myoma or those with a large intramyometrial involvement. PMID- 25453909 TI - Global diversity of the Ganoderma lucidum complex (Ganodermataceae, Polyporales) inferred from morphology and multilocus phylogeny. AB - Species of the Ganoderma lucidum complex are used in many types of health products. However, the taxonomy of this complex has long been chaotic, thus limiting its uses. In the present study, 32 collections of the complex from Asia, Europe and North America were analyzed from both morphological and molecular phylogenetic perspectives. The combined dataset, including an outgroup, comprised 33 ITS, 24 tef1alpha, 24 rpb1 and 21 rpb2 sequences, of which 19 ITS, 20 tef1alpha, 20 rpb1 and 17 rpb2 sequences were newly generated. A total of 13 species of the complex were recovered in the multilocus phylogeny. These 13 species were not strongly supported as a single monophyletic lineage, and were further grouped into three lineages that cannot be defined by their geographic distributions. Clade A comprised Ganoderma curtisii, Ganoderma flexipes, Ganoderma lingzhi, Ganoderma multipileum, Ganoderma resinaceum, Ganoderma sessile, Ganoderma sichuanense and Ganoderma tropicum, Clade B comprised G. lucidum, Ganoderma oregonense and Ganoderma tsugae, and Clade C comprised Ganoderma boninense and Ganoderma zonatum. A dichotomous key to the 13 species is provided, and their key morphological characters from context, pores, cuticle cells and basidiospores are presented in a table. The taxonomic positions of these species are briefly discussed. Noteworthy, the epitypification of G. sichuanense is rejected. PMID- 25453910 TI - Comparative analysis of CYP93E proteins for improved microbial synthesis of plant triterpenoids. AB - Cytochrome P450-dependent monooxygenases (P450s) belonging to the CYP93E subfamily catalyze the C-24 oxidation of the triterpene backbone during the biosynthesis of triterpenoid saponins, which are bioactive plant natural products. In our attempts to produce plant triterpenoids in the yeast Saccharomyces cerevisiae, we observed a poor in vivo catalytic efficiency of the Medicago truncatula CYP93E2. To overcome this biosynthetic bottleneck, we screened publicly available plant genome and transcriptome data for CYP93E subfamily members. Six CYP93E orthologs, exclusively from leguminous plant species, were identified and functionally characterized in S. cerevisiae. Despite the high degree of amino acid conservation, the CYP93E orthologs showed large variations in enzymatic efficiency in yeast. The CYP93E9 from Phaseolus vulgaris showed the highest activity and converted ~80% of the accumulating in vivo produced substrate beta-amyrin to the products olean-12-ene-3beta,24-diol and probable 3beta-hydroxy olean-12-en-24-oic acid, with a catalytic efficiency that was 61 times higher than that of the M. truncatula CYP93E2. In conclusion, we have expanded the list of functional CYP93E orthologs to a total of nine proteins and show that there are large variations in their catalytic efficiencies when expressed in a heterologous host. Although demonstrated here for the CYP93E family involved in triterpenoid saponin biosynthesis, this phenomenon is undoubtedly extendable to other enzyme families involved in natural product synthesis. Hence, screening for homologous enzymes may become a valuable synthetic biologist's tool for engineering superior production chassis. PMID- 25453911 TI - Comparison of the chemical composition of three species of smartweed (genus Persicaria) with a focus on drimane sesquiterpenoids. AB - The genus Persicaria is known to include species accumulating drimane sesquiterpenoids, but a comparative analysis highlighting the compositional differences has not been done. In this study, the secondary metabolites of both flowers and leaves of Persicariahydropiper, Persicariamaculosa and Persicariaminor, three species which occur in the same habitat, were compared. Using gas chromatography-mass spectrometry (GC-MS) analysis of extracts, overall 21/29 identified compounds in extracts were sesquiterpenoids and 5/29 were drimanes. Polygodial was detected in all species, though not in every sample of P. maculosa. On average, P. hydropiper flowers contained about 6.2 mg g FW(-1) of polygodial, but P. minor flowers had 200-fold, and P. maculosa 100,000 fold lower concentrations. Comparatively, also other sesquiterpenes were much lower in those species, suggesting the fitness benefit to depend on either investing a lot or not at all in terpenoid-based secondary defences. For P. hydropiper, effects of flower and leaf development and headspace volatiles were analysed as well. The flower stage immediately after fertilisation was the one with the highest content of drimane sesquiterpenoids and leaves contained about 10-fold less of these compounds compared to flowers. The headspace of P. hydropiper contained 8 compounds: one monoterpene, one alkyl aldehyde and six sesquiterpenes, but none were drimanes. The potential ecological significance of the presence or absence of drimane sesquiterpenoids and other metabolites for these plant species are discussed. PMID- 25453912 TI - Quantification of chemical states, dissociation constants and contents of oxygen containing groups on the surface of biochars produced at different temperatures. AB - Surface functional groups such as carboxyl play a vital role in the environmental applications of biochar as a soil amendment. However, the quantification of oxygen-containing groups on a biochar surface still lacks systematical investigation. In this paper, we report an integrated method combining chemical and spectroscopic techniques that were established to quantitatively identify the chemical states, dissociation constants (pK(a)), and contents of oxygen containing groups on dairy manure-derived biochars prepared at 100-700 degrees C. Unexpectedly, the dissociation pH of carboxyl groups on the biochar surface covered a wide range of pH values (pH 2-11), due to the varied structural microenvironments and chemical states. For low temperature biochars (<= 350 degrees C), carboxyl existed not only as hydrogen-bonded carboxyl and unbonded carboxyl groups but also formed esters at the surface of biochars. The esters consumed OH(-) via saponification in the alkaline pH region and enhanced the dissolution of organic matter from biochars. For high temperature biochars (>= 500 degrees C), esters came from carboxyl were almost eliminated via carbonization (ester pyrolysis), while lactones were developed. The surface density of carboxyl groups on biochars decreased sharply with the increase of the biochar-producing temperature, but the total contents of the surface carboxyls for different biochars were comparable (with a difference <3-fold) as a result of the expanded surface area at high pyrolytic temperatures. Understanding the wide pKa ranges and the abundant contents of carboxyl groups on biochars is a prerequisite to recognition of the multifunctional applications and biogeochemical cycling of biochars. PMID- 25453913 TI - Unicondylar fractures of the distal femur. AB - BACKGROUND: Unicondylar fractures of the distal femur are rare, complex, intra articular fractures. The objective of this multicentre study was to assess the reduction and fixation of unicondylar fractures. HYPOTHESIS: Anatomic reduction followed by strong fixation allows early rehabilitation therapy and provides good long-term outcomes. MATERIAL AND METHODS: We studied 163 fractures included in two multicentre studies, of which one was retrospective (n=134) and the other prospective (n=29). Follow-up of at least 1 year was required for inclusion. The treatment was at the discretion of the surgeon. Outcome measures were the clinical results assessed using the International Knee Society (IKS) scores and presence after fracture healing of malunion with angulation, an articular surface step-off, and/or tibio-femoral malalignment. RESULTS: Mean age of the study patients was 50.9 +/- 24 years, and most patients were males with no previous history of knee disorders. The fracture was due to a high-energy trauma in 51% of cases; 17% of patients had compound fractures and 44% multiple fractures or injuries. The lateral and medial condyles were equally affected. The fracture line was sagittal in 82% of cases and coronal (Hoffa fracture) in 18% of cases. Non-operative treatment was used in 5% of cases and internal fixation in 95% of cases, with either direct screw or buttress-plate fixation for the sagittal fractures and either direct or indirect screw fixation for the coronal fractures. After treatment of the fracture, 15% of patients had articular malunion due to insufficient reduction, with either valgus-varus (10%) or flexion-recurvatum (5%) deformity; and 12% of patients had an articular step-off visible on the antero posterior or lateral radiograph. Rehabilitation therapy was started immediately in 65% of patients. Time to full weight bearing was 90 days and time to fracture healing 120 days. Complications consisted of disassembly of the construct (2%), avascular necrosis of the condyle (2%), and arthrolysis (5%). The material was removed in 11% of patients. At last follow-up, the IKS knee score was 71 +/- 20 and the IKS function score 64 +/- 7; flexion range was 106 +/- 28 degrees (<90 degrees in 27% of patients); and 12% of patients had knee osteoarthritis. CONCLUSION: Anatomic reduction of unicondylar distal femoral fractures via an appropriate surgical approach, followed by stable internal fixation using either multiple large-diameter screws or a buttress-plate, allows immediate mobilisation, which in turn ensures good long-term outcomes. LEVEL OF EVIDENCE: IV, cohort study. PMID- 25453914 TI - Clinical and MRI results in 67 patients operated for gluteus medius and minimus tendon tears with a median follow-up of 4.6 years. AB - INTRODUCTION: Although various techniques can be used to repair gluteal tendon tears, the long-term outcome is unclear and published studies typically involve only a small number of patients. The goals of this study were to determine (1) if functional improvement can be obtained, (2) if the repairs are continuous based on MRI, and (3) which factors determine success. HYPOTHESIS: Gluteus medius and minimus tears can be repaired effectively with an open double-row technique. MATERIAL AND METHODS: Seventy-three patients were operated on between 2003 and 2010. Of these patients, 67 (62 women, 5 men) were available for review consisting of functional clinical tests and MRI of the hip and pelvis. A double row repair was performed on all tendon tears, no matter the type of injury. Age, body mass index (BMI), fatty degeneration and muscle atrophy were also evaluated to determine if these variables affected the outcome. RESULTS: The average follow up was 4.6 years (range 1-8). The pre-operative scores had improved at the last follow-up: (1) pain (VAS): 8.7 +/- 1.1 versus 1.7 +/- 2.7 at the follow-up, (P<0.001), (2) Lequesne index: 12.3 +/- 2.6 versus 4.0 +/- 4.0 at the follow-up, (P<0.001), (3) Harris Hip Score: 50.5 +/- 8 versus 87.9 +/- 15.5 at the follow up, (P<0.001). There were 11 failures (16%) including two repeat tears that were reoperated successfully. In the other 56 patients, the MRI showed no signs of the initial tear or bursitis. Of the four factors (age, BMI, fatty degeneration, muscle atrophy) that were potential predictors of the outcome, only muscle atrophy had a negative impact on functional outcome (P<0.05). CONCLUSION: Using an open double-row technique to repair gluteal tendon tears led to 85% of patients having good clinical results with significant improvement in symptoms and disappearance of abnormal findings on MRI. This technique can be used with all types of tendon tears, but should be performed before muscle atrophy sets in. LEVEL OF PROOF: Level IV-retrospective study. PMID- 25453915 TI - Comments on: "Orthopedics coding and funding" by S. Baron, C. Duclos, P. Thoreux, published in Orthop Traumatol Surg Res 2014; 100: S99-S106. PMID- 25453916 TI - Response to the letter by J.L. Rouvillain, D. Courcier and O. Gagey. PMID- 25453917 TI - Response's preamble to the letter by J.L. Rouvillain, D. Courcier and O. Gagey. PMID- 25453918 TI - Response to M. Goldzak's letter. PMID- 25453919 TI - Response of the editorial team to M. Goldzak's letter. PMID- 25453920 TI - AKILETM total ankle arthroplasty: Clinical and CT scan analysis of periprosthetic cysts. AB - INTRODUCTION: Despite good clinical results following total ankle replacement (TAR), the development of large periprosthetic cysts (>400 mm(2)) in the medium term is a source of concern. OBJECTIVE: The primary objective of this study was to detect any large periprosthetic cysts in a cohort of AKILETM patients using radiographs and CT scans, and then to compare these findings to published ones. MATERIAL AND METHODS: A total of 127 TAR procedures were performed between June 1995 and January 2012. We retrospectively reviewed 68 cases with the newest AKILETM implant design that had a minimum follow-up of 36 months. The average follow-up was 81 +/- 33 months; eight patients were lost to follow-up. The outcomes consisted of analyzing radiographs (A/P and lateral weight bearing views, Meary view and lateral views of flexion/extension) and helical CT scans, performing clinical evaluations (range of motion, AOFAS score, Foot Function Index, pain levels) and determining the survivorship of TAR implants. RESULTS: TAR survival at 5 years was 79% for in situ implants and 62% for revision-free implants. The AOFAS score improved from 33.7 +/- 14.7 to 77.1 +/- 15.1 (out of 100) and the pain sub-score was 30.2 +/- 9.7 (out of 40) at the last follow-up. The average ankle range of motion was 32.3 degrees +/- 12.7 degrees on the radiographs. CT scan revealed Type A cysts (<200 mm(2)) under the talar implant in 52% of cases and in the tibia in 50% of cases; these cysts were smaller than 100 mm(2) in 80% of cases and had no effect on the implants. No periprosthetic cysts larger than 400 mm(2) in size were identified. DISCUSSION: The medium-term functional results and survivorship are comparable to those reported for other TAR designs. The incidence of cysts was low overall and there were no large diameter cysts, which should improve long-term survival. The implant's design and materials likely played a role in preserving the periprosthetic bone stock. The AKILETM TAR has distinctive features related to the low rate of large periprosthetic cysts in the medium-term. LEVEL OF EVIDENCE: IV (retrospective case series). PMID- 25453921 TI - The submuscular sliding plate technique for acetabular posterior wall fractures extending to the acetabular roof. AB - There is extension of the Kocher-Langenbeck approach using trochanteric osteotomy for posterior wall fracture extending to acetabular roof, but it exposes to complications such as nonunion, breakage, and heterotopic ossification. The current study introduces a submuscular sliding plate technique. We retrospectively analyzed 13 patients treated with this technique. It is based on conventional method for posterior wall fracture. After reduction of roof fragment with direct visualization, a pre-contoured plate was passed through a submuscular tunnel under the gluteus medius and minimus. A small split incision was performed on the muscles, and screws were inserted with a triple trocar complex safely under fluoroscopic imaging. All patients had fracture union without complications. X-rays results showed anatomical reduction in 10 cases and imperfect reduction in 3 cases. Our results were satisfactory, particularly without heterotopic ossifications despite no prophylactic regimen of NSAID was applied and no neurological complications, so we believe that this technique is a good option for posterior wall fractures extending to the acetabular roof. PMID- 25453922 TI - Reproducibility of condylar twist angle measurement using computed tomography and axial radiography of the distal femur. AB - INTRODUCTION: It is essential to understand rotational alignment of the distal femur when performing total knee arthroplasty (TKA). Several rotational landmarks including condylar twist angle (CTA) are used for preoperative planning and during TKA. Axial radiography of the distal femur is used for measuring the CTA, and assessing rotational alignment in TKA. The aim of this study was to investigate the reliability and the reproducibility of the CTA using two different methods and evaluate if CTA differed between varus and valgus knees and between normal and osteoarthritic knees. MATERIALS AND METHODS: CTA were obtained from 144 knees (77 patients) having total knee or hip arthroplasty using computed tomography (CT) and axial radiography. Subjects were divided into five groups based on femorotibial angle (FTA) and into four groups based on the severity of knee osteoarthritis. The intra-observer and inter-observer reliabilities of these methods and inter-method differences were evaluated. RESULTS: The mean CTA was 7.02 degrees with axial radiography, and 6.87 degrees with CT images. There were no significant differences among the five FTA groups and among the four osteoarthritis groups. In total, intra-/inter-observer, and inter-method intraclass correlation coefficients were substantial or almost perfect in the scoring system of Landis et al. However, discrepancies >= 2 degrees between the two methods were observed in more than 20% of knees. CONCLUSION: The CTA should be reassessed by more than two observers or two methods for precise preoperative TKA planning in cases where it is difficult to identify the bony landmarks for CTA measurements. LEVEL OF EVIDENCE: Level III. PMID- 25453923 TI - Burden of proximal humerus fractures in the French National Hospital Database. AB - OBJECTIVE: To describe the characteristics of patients hospitalized for osteoporotic proximal humerus fracture in 2009 in France, in-patient mortality, and further hospitalizations for hip fracture. METHODS: Data were extracted from the French Hospital National Database. We selected patients aged 40 years and over hospitalized for proximal humerus fracture in 2009, without cancer. Based on their unique identification number, we described the next hospitalizations occurring in 2009-2011 whatever the causes. Incidence, in-patient mortality, and hospital costs were calculated. RESULTS: We numbered 10,874 patients (77% of women, mean age 72.5 years). The incidence per million was 477 and 163 in women and men, respectively. This incidence increased with age and was higher in women (i.e. 1374 and 320 in women and men aged over 74 years, respectively). Surgical treatment was applied in 56% of patients; median hospital stay was 5 days. Rehabilitation unit was necessary in 26% of cases. In-patient mortality was 1.1%. The overall hospital costs was ?34 millions. Rehospitalizations occurred for 61% of the patients and had more co-morbidities than others. Near 8% of the rehospitalized patients were for hip fractures occurring in a median of 353 days after hospitalization for proximal humerus fracture. The hospital costs for these rehospitalizations was ?52 millions. CONCLUSION: Proximal humerus fractures incidence increases with aging, especially in women. These fractures are associated with a significant in-patient mortality and health care resources utilization. Patients with such fracture must receive high priority for optimal post fracture treatment. PMID- 25453925 TI - Horizontal posterior hamstring harvest. AB - Harvesting of the gracilis and semi-tendinosus (ST) hamstring tendons is usually performed by anteromedial approach. Harvesting by a horizontal posterior approach is possible. Based on a series of 90 patients, this technical note describes the perioperative difficulties and the characteristics of the harvested tendon(s) as well as any complications. Only one unsuccessful harvest was reported. Posterior harvesting of the gracilis and ST hamstring tendons is a reliable, reproducible surgical technique with a low rate of complications. PMID- 25453924 TI - Diagnosis and surgical treatment of dysplasia epiphysealis hemimelica. A report of nine cases. AB - BACKGROUND: Dysplasia epiphysealis hemimelica (DEH) is a rare developmental bone disorder with hemimelic involvement of one or more epiphysis. We report on nine new cases and discuss the clinical manifestations, the value of MRI, and the results of complete and early surgical resection of these lesions. MATERIALS AND METHODS: In this retrospective study, nine patients with a diagnosis of DEH were evaluated. Age at presentation ranged from 1 year to 12 years. The main complaint at diagnosis was a swelling bony mass. Angular deformities were recorded in two patients. All patients were surgically treated and followed up clinically and by imaging. Eight patients underwent excision only. RESULTS: The average follow-up was 5.6 years (range, 2-10.5 years). All patients had a good outcome without related symptoms. No epiphysiodesis, angular deformity or recurrence was observed. One patient with femoral lesion involving the distal medial part of the epiphysis developed, four months after surgical excision, a calcification outside the area of total excision. This calcification did not increase in size at two years follow-up. Another patient with lateral involvement of the proximal tibial epiphysis presented a postoperative nervous complication. Spontaneous nervous recovery occurred three months after surgery. DISCUSSION: MRI was useful to find a potential plane of cleavage between the epiphysis and the pathological tissue. We recommend early removing ossifications when a cleavage plane is identified. Waiting a possible complication or increasing of size does not seem logical. Of course, the treatment will be not the same if no cleavage plane is found on MRI. LEVEL OF EVIDENCE: IV. PMID- 25453926 TI - 45 degrees -45 degrees -30 degrees Frog-leg radiograph for diagnosing cam-type anterior femoroacetabular impingement: Reproducibility and thresholds. AB - BACKGROUND: The many radiographic views suggested for evaluating anterior femoroacetabular impingement (FAI), due to a cam effect, are not specific for this condition and have not been proven of diagnostic value in studies, including control groups. Using a new and specific radiographic view, we evaluated the reproducibility of the main radiographic criteria for FAI, determined normal values for these criteria in a control group, and established diagnostic threshold values. HYPOTHESIS: This specific view offers good reproducibility and effectively detects abnormal values of criteria for FAI. MATERIALS AND METHODS: Inter-observer and intra-observer reproducibility of specific radiographic criteria (alphaangle and modified head-neck offset [HNO]) were computed from preoperative and postoperative radiographs of 96 hips (75 patients, 61 males and 14 females) using the specific 45 degrees -45 degrees -30 degrees frog-leg view (F45 view). Values in the group with FAI were compared to those in a control group of asymptomatic volunteers (100 hips, 27 males and 23 females). RESULTS: Inter-observer and intra-observer reproducibility was very good, with intra-class correlation coefficients of 0.955and 0.987, respectively, for the alpha angle and of 0.895 and 0.984, respectively, for the HNO. Mean values of both parameters differed significantly between the FAI and control groups: 73.9 degrees (53 degrees to 96 degrees ) vs. 49.3 degrees (35 degrees to 69 degrees ) for the alphaangle, respectively; and 2.5mm (-4.6 to 9.4) vs. 7.6mm (1.7 to 11.8) for HNO, respectively. The normal values defined as the boundary of the 95% reference interval in the control group were<60.2 degrees for the alpha angle, and>4.6mm for the HNO. DISCUSSION: The45 degrees -45 degrees -30 degrees frog-leg view is useful for diagnosing FAI due to a cam effect. This view is easy to perform, and the thresholds determined in our study assist in its interpretation: alpha angle values>58 degrees in females and>63 degrees in males indicate cam-type femoral geometry. In both genders, HNO values<5mm support a diagnosis of anterior FAI. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 25453927 TI - Proximal femoral nails antirotation, Gamma nails, and dynamic hip screws for fixation of intertrochanteric fractures of femur: A meta-analysis. AB - BACKGROUND: Which surgical strategy is the best one for intertrochanteric fractures remains a controversial issue. Dynamic hip screw (DHS) and Gamma nail were commonly used but often associated with some complications, such as fixation failure and implant-related fractures. Meanwhile, proximal femoral nail anti rotation (PFNA) fixation has recently been developed for minimally invasive surgery to reduce the complications rate. To facilitate the clinical decision making, we conducted an updated meta-analysis to discuss the optimal treatment of intertrochanteric fractures aiming to determine which implant gives the lower rates of blood loss, complications (peri-implant fracture, fixation failure, infection, thromboembolic), reoperation, and mortality, as well as the minimal duration related to surgery (fluoroscopic exposure, surgery and hospital stay). PATIENTS AND METHODS: Seven electronic databases were searched for randomized controlled trials (including OVID, Springer, Google Scholar, PubMed, Cochrane library, Embase, and Web of Science). Fourteen studies with 1983 patients were included. The modified Jadad Scale was used to assess the methodological quality of these studies. Risk of bias in the included studies was assessed using the Cochrane Risk of Bias tool. Comparison among the three groups was based on twelve indicators, including operative time, fluoroscopy time, operative blood loss, length of hospital stays, wound infection or hematoma, pneumonia, thromboembolic complications, fixation failure, operative fracture of femur, later fracture of femur, reoperation, and mortality. RESULTS: (1) PFNA group versus DHS group: PFNA was associated with less blood loss (mean difference (MD) -253.86, 95% CI -270.25 to 237.47; P<0.00001) and lower rate of fixation failure (MD 0.20, 95% CI 0.07 to 0.59; P=0.004), but led to more fluoroscopy time (MD 2.11, 95% CI 1.78 to 2.43; P<0.00001). (2) PFNA group versus Gamma nail group: PFNA led to less blood loss (MD -55.30, 95% CI -60.07 to -50.53; P<0.00001), shorter fluoroscopy time (MD 0.50, 95% CI -0.55 to -0.45; P<0.00001) and length of hospital stay (MD -0.20, 95% CI -0.27 to -0.13; P<0.00001). (3) DHS group versus Gamma nail group: DHS was associated with lower rate of operative fracture of femur (MD 0.31, 95% CI 0.11 to 0.89; P=0.03), later fracture of femur (MD 0.16, 95% CI 0.06 to 0.43; P=0.0004), and reoperation (MD 0.49, 95% CI 0.27 to 0.88; P=0.02), but caused more blood loss (MD 29.49, 95% CI 8.27 to 50.70; P=0.006). In contrast, there was no difference regarding operative time, infection hematoma, pneumonia, thromboembolic events, and mortality. DISCUSSION: PFNA should be a priority choice for treatment of intertrochanteric fractures with minimal rate of fixation failure, less blood loss and shorter length of hospital stay. DHS has distinct advantages over Gamma nail with lower rate of plant-related complications and should be preferred device for intertrochanteric fractures. However, owing to the low quality evidence currently available, more high-quality RCTs are needed to confirm these findings. LEVEL OF EVIDENCE: Level II. PMID- 25453928 TI - External fixation of distal femoral fractures in adults' multicentre retrospective study of 43 patients. AB - BACKGROUND: A multicenter cohort of 43 adults with distal femoral fractures (DFFs) managed with external fixation was evaluated to determine the potential of this treatment. PATIENTS AND METHODS: The patients were young adults (mean age: 39.6 years) with high-energy trauma; 12 had polytrauma and 41 multiple fractures. Most patients (38/43) had compound DFFs. Fracture types were A in 3 patients, B in 3 patients, and C in 37 patients. A tibio-femoral construct was required in 11 patients and a femoro-femoral construct in 32 patients. RESULTS: The normal femoral axis was restored within 5 degrees in the coronal plane in 34 (79%) patients and in the sagittal plane in 22 (51%) patients. Axis restoration within 5 degrees in both planes was achieved in 19 (44.7%) patients. After femoro femoral external fixation, mean malalignment was 4.2 degrees in the coronal plane and 8.6 degrees in the sagittal plane; corresponding values after tibio femoral external fixation were 1.3 degrees and 8.6 degrees . In 23 patients (of whom 1 was lost to follow-up), external fixation was intended as the only and definitive treatment; among them, 1 required amputation after a failed revascularization procedure, 10 achieved fracture healing within a mean of 21.2 weeks, 6 required conversion to another technique, and 5 underwent non conservative procedures (total knee arthroplasty in 3 and arthrodesis in 2). In the remaining 20 patients, conversion to internal fixation was intended initially and performed within a mean of 4.7 weeks; 1 of these patients required amputation for ischemia, 3 did not achieve fracture healing, 12 achieved primary fracture healing, and 4 achieved fracture healing after repeated grafting (n=3) or osteotomy (n=1). At last follow-up (at least 1 year), the mean International Knee Society (IKS) Function Score was 67.3 and an IKS Knee Score of 68.5. Range of active flexion was 85.75 degrees overall, 62.3 degrees in the group with intended definitive external fixation and 101 degrees in the group with intended conversion to internal fixation. Healing without complications was achieved in 10 (43%) in the former group and 12 (60%) in the latter group. CONCLUSION: Our data support provisional external fixation followed by early conversion to internal fixation in patients with extensively compounded DFFs; patients with multiple fractures requiring several surgical procedures; and polytrauma patients awaiting hemodynamic, respiratory, or neurological stabilization. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 25453929 TI - Locking plate fixation versus antegrade nailing of 3- and 4-part proximal humerus fractures in patients without osteoporosis. Comparative retrospective study of 63 cases. AB - INTRODUCTION: There is no consensus on the treatment of proximal humeral fractures. The goal of the present retrospective observational study was to compare functional and radiological results and complications of internal fixation using locking plates versus antegrade nailing in the treatment of non osteoporotic Neer classification 3- and 4-part fractures after a least 1 year of follow-up. MATERIAL AND METHODS: Internal fixation was performed in 67 fractures (1 bilateral): 35 by locking plate (1 lost to follow-up, 1 deceased) and 32 by intramedullary nailing (2 lost to follow-up) between January 1st, 2004 and December 31st, 2010. Thus, the study included 33 plates (21 3-part and 12 4-part fractures) and 30 nails (21 3-part and nine 4-part fractures). Final functional assessment was based on the Oxford, Constant, Relative Constant and QuickDASH scores and percentage of handicap. Radiological follow-up included immediate postoperative, 6 weeks, 3 months and 1 year AP and Lamy lateral views. All complications were recorded prospectively. RESULTS: Mean Oxford, Constant, Relative Constant and QuickDASH scores and percentage of disability for the plate and nail groups respectively were: 23.8 vs. 23.3, 59.7 vs. 60 6, 73.5 vs 79.3, 20.9 vs 21.0, 22.6 vs 22.6. Multivariate analysis did not show any significant difference in functional scores or quality of reduction: final unsatisfactory reduction on AP view, 30.3 vs. 36.7%; lateral view, 3.2 vs. 10.0%; greater tuberosity, 9.1 vs. 16.7%. Four-part fracture (P<0.05), frontal reduction defect at follow-up (P<0.05) or greater tuberosity defect (P>0.05) had negative impacts on functional scores. The complication rates corresponded to those in the literature and did not differ between the techniques (P=0.1901) except for three infections in the plate group. DISCUSSION-CONCLUSION: Internal fixation is the treatment of choice for 3- and 4-part fractures in non-osteoporotic patients. Although no difference was found in the present study between locking plate and intramedullary nailing, the former seems to be less well adapted and more aggressive. TYPE OF STUDY: Retrospective observational study. LEVEL OF EVIDENCE: Level 4. PMID- 25453930 TI - Percutaneous Tenolig((r)) repair under intra-operative ultrasonography guidance in acute Achilles tendon rupture. AB - BACKGROUND: Acute Achilles tendon rupture can be treated conservatively or surgically. Open surgery restores tendon continuity but carries a risk of skin complications. Tenolig((r)) is a device designed for the percutaneous biological treatment of acute Achilles tendon rupture. Earlier studies found high rates of recurrent tears and nerve injury after Tenolig((r)) repair. HYPOTHESIS: We hypothesised that intra-operative ultrasonography during Tenolig((r)) repair would decrease the post-operative complication rate and improve functional outcomes. MATERIALS AND METHODS: We studied 75 consecutive patients with a mean age of 39.9 years. The injury was sports-related in 82.8% of cases. Mean distance from the calcaneal tendon attachment to the tear was 5cm and mean time from injury to repair was 4.2 days. All patients underwent Tenolig((r)) repair under ultrasound guidance followed by early rehabilitation therapy with partial weight bearing started after 3 weeks. RESULTS: Mean follow-up was 20.7 months and no patient was lost to follow-up. A single patient (1.3%) experienced rerupture and none had permanent sural nerve damage. Mean time to sports resumption was 8.6 months, with two-thirds of patients returning to their previous level of sporting activities. The mean AOFAS functional score was 95 and the mean ATRS score was 91.3. DISCUSSION: Our experience suggests that intra-operative ultrasonography, a non-invasive, widely available, and accurate tool, provided improved control of Tenolig((r)) suture position. Ultrasonography provided valuable guidance during this demanding procedure and allowed the very early initiation of rehabilitation therapy. Another crucial factor is patient education about the physical therapy programme. Attention to this point allowed us to obtain robust and reliable functional outcomes in a population predominantly composed of athletes. LEVEL OF EVIDENCE: Level IV. PMID- 25453931 TI - Comments on: "External fixation of the thalamic portion of a fractured calcaneus: A new surgical technique" by T. Begue, N. Mebtouche, J.-C. Auregan, G. Saintyves, S. Levante, P. Cottin, A.-C. Masquelet in Orthop Traumatol Surg Res 2014; 100: 429-32. PMID- 25453932 TI - Efficient method for the conversion of agricultural waste into sugar alcohols over supported bimetallic catalysts. AB - Promoter effect of Sn in the PtSn/gamma-Al2O3 (AL) and PtSn/C bimetallic catalysts is studied for the conversion of variety of substrates such as, C5 sugars (xylose, arabinose), C6 sugars (glucose, fructose, galactose), hemicelluloses (xylan, arabinogalactan), inulin and agricultural wastes (bagasse, rice husk, wheat straw) into sugar alcohols (sorbitol, mannitol, xylitol, arabitol, galactitol). In all the reactions, PtSn/AL showed enhanced yields of sugar alcohols by 1.5-3 times than Pt/AL. Compared to C, AL supported bimetallic catalysts showed prominent enhancement in the yields of sugar alcohols. Bimetallic catalysts characterized by X-ray diffraction study revealed the stability of catalyst and absence of alloy formation thereby indicating that Pt and Sn are present as individual particles in PtSn/AL. The TEM analysis also confirmed stability of the catalysts and XPS study disclosed formation of electron deficient Sn species which helps in polarizing carbonyl bond to achieve enhanced hydrogenation activity. PMID- 25453933 TI - Improved propionic acid production with metabolically engineered Propionibacterium jensenii by an oxidoreduction potential-shift control strategy. AB - In this study, a three-stage oxidoreduction potential (ORP) control strategy was developed to improve propionic acid (PA) production using engineered Propionibacterium jensenii ATCC 4868 (pZGX04-gldA) in a 3-L bioreactor. Specifically, ORP was controlled at -200mV from 0 to 36h, -300mV from 36 to 156h, and -400mV after 156h. The PA titer increased from 21.38 to 27.31g/L. The effects of ORP regulation on key intracellular metabolites were studied, demonstrating that ORP can both regulate NADH/NAD(+) ratio and the activities of some enzymes involved in electron transport and redistribute metabolic flux. We integrated the ORP control strategy with a fed-batch culture method and increased PA production to 39.53g/L. This new ORP control strategy may be useful in the optimization of other anaerobic processes. PMID- 25453934 TI - MicroRNA sequencing and molecular mechanisms analysis of the effects of gold nanoparticles on human dermal fibroblasts. AB - The aim of this study is to investigate the mechanism of the effects of gold nanoparticles (GNPs) on human dermal fibroblasts (HDFs) at the microRNA level. First, 20-nm GNPs were synthesized and their effect on HDF proliferation was assayed. SOLiD sequencing technology was then utilized to obtain the microRNA expression profile after GNP treatment. The microRNA expression data were compared with previously obtained mRNA and protein expression data to identify the microRNA target mRNAs/proteins. Moreover, bioinformatics analyses and validation experiments were conducted. Lastly, the roles of GNPs and silver nanoparticle (SNPs) on HDFs were compared at the microRNA level. The results showed that GNPs were not cytotoxic as 202 microRNAs were differentially expressed after treatment with 200 MUm GNPs for 1, 4 and 8 h. Bioinformatics analyses revealed that these dysregulated miRNAs mainly functioned in metabolic processes and participated in 71 biological pathways, including two key pathways in which the differentially expressed miRNA, target mRNAs and proteins were simultaneously joined, the mRNA processing pathway and MAPK signaling pathway. Biological experiments in cells confirmed that GNPs affected energy metabolism but did not induce apoptosis, destroy the cytoskeleton or induce reactive oxygen species (ROS) production. Comparing the mechanism of the effects of GNPs and SNPs on HDFs at the microRNA level, it was found that, unlike SNPs, GNPs impacted the cell cycle, weakened the ATP synthesis inhibition and cytoskeleton damage, suppressed apoptosis, and did not lead to cytotoxicity. The difference in ROS production by these two nanoparticles might partially explain the fact that GNPs showed no cytotoxic effects on HDFs, unlike SNPs. PMID- 25453936 TI - Developing robust, hydrogel-based, nanofiber-enabled encapsulation devices (NEEDs) for cell therapies. AB - Cell encapsulation holds enormous potential to treat a number of hormone deficient diseases and endocrine disorders. We report a simple and universal approach to fabricate robust, hydrogel-based, nanofiber-enabled encapsulation devices (NEEDs) with macroscopic dimensions. In this design, we take advantage of the well-known capillary action that holds wetting liquid in porous media. By impregnating the highly porous electrospun nanofiber membranes of pre-made tubular or planar devices with hydrogel precursor solutions and subsequent crosslinking, we obtained various nanofiber-enabled hydrogel devices. This approach is broadly applicable and does not alter the water content or the intrinsic chemistry of the hydrogels. The devices retained the properties of both the hydrogel (e.g. the biocompatibility) and the nanofibers (e.g. the mechanical robustness). The facile mass transfer was confirmed by encapsulation and culture of different types of cells. Additional compartmentalization of the devices enabled paracrine cell co-cultures in single implantable devices. Lastly, we provided a proof-of-concept study on potential therapeutic applications of the devices by encapsulating and delivering rat pancreatic islets into chemically induced diabetic mice. The diabetes was corrected for the duration of the experiment (8 weeks) before the implants were retrieved. The retrieved devices showed minimal fibrosis and as expected, live and functional islets were observed within the devices. This study suggests that the design concept of NEEDs may potentially help to overcome some of the challenges in the cell encapsulation field and therefore contribute to the development of cell therapies in future. PMID- 25453937 TI - Novel strategy for mechanically tunable and bioactive metal implants. AB - Metals have been used as biostructural materials because of outstanding mechanical reliability. However, low bioactivity and high stiffness in biological environments have been major issues of metals, causing stress shielding effects or foreign body reactions after implantation. Therefore, in this study, densified porous titanium has been introduced to achieve comparable mechanical properties to hard tissues and bioactivity that promote a better interface between the implant and bone. Porous titanium scaffolds were successfully fabricated through dynamic freezing casting, and were densified, controlling the degree of densification by applied strain. During densification, structural integrity of porous titanium was well maintained without any mechanical deterioration, exhibiting good pore connectivity and large surface area. Densified porous titanium possesses two important features that have not been achieved by either dense titanium or porous titanium: 1) mechanical tunability of porous scaffolds through densification that allows scaffolds to be applied ranging from highly porous fillers to dense load-bearing implants and 2) improved bioactivity through bioactive coating that is capable of sustainable release through utilizing high surface area and pore connectivity with controllable tortuosity. This simple, but effective post-fabrication process of porous scaffolds has great potential to resolve unmet needs of biometals for biomedical applications. PMID- 25453935 TI - Mechanical failure modes of chronically implanted planar silicon-based neural probes for laminar recording. AB - Penetrating intracortical electrode arrays that record brain activity longitudinally are powerful tools for basic neuroscience research and emerging clinical applications. However, regardless of the technology used, signals recorded by these electrodes degrade over time. The failure mechanisms of these electrodes are understood to be a complex combination of the biological reactive tissue response and material failure of the device over time. While mechanical mismatch between the brain tissue and implanted neural electrodes have been studied as a source of chronic inflammation and performance degradation, the electrode failure caused by mechanical mismatch between different material properties and different structural components within a device have remained poorly characterized. Using Finite Element Model (FEM) we simulate the mechanical strain on a planar silicon electrode. The results presented here demonstrate that mechanical mismatch between iridium and silicon leads to concentrated strain along the border of the two materials. This strain is further focused on small protrusions such as the electrical traces in planar silicon electrodes. These findings are confirmed with chronic in vivo data (133-189 days) in mice by correlating a combination of single-unit electrophysiology, evoked multi-unit recordings, electrochemical impedance spectroscopy, and scanning electron microscopy from traces and electrode sites with our modeling data. Several modes of mechanical failure of chronically implanted planar silicon electrodes are found that result in degradation and/or loss of recording. These findings highlight the importance of strains and material properties of various subcomponents within an electrode array. PMID- 25453938 TI - Design of self-assembling peptide hydrogelators amenable to bacterial expression. AB - Hydrogels formed from self-assembling peptides are finding use in tissue engineering and drug delivery applications. Given the notorious difficulties associated with producing self-assembling peptides by recombinant expression, most are typically prepared by chemical synthesis. Herein, we report the design of a family of self-assembling beta-hairpin peptides amenable to efficient production using an optimized bacterial expression system. Expressing peptides, EX1, EX2 and EX3 contain identical eight-residue amphiphilic beta-strands connected by varying turn sequences that are responsible for ensuring chain reversal and the proper intramolecular folding and consequent self-assembly of the peptide into a hydrogel network under physiological conditions. EX1 was initially used to establish and optimize the bacterial expression system by which all the peptides could be eventually individually expressed. Expression clones were designed to allow exploration of possible fusion partners and investigate both enzymatic and chemical cleavage as means to liberate the target peptide. A systematic analysis of possible expression systems followed by fermentation optimization lead to a system in which all three peptides could be expressed as fusions with BAD-BH3, the BH3 domain of the proapoptotic BAD (Bcl-2 Associated Death) Protein. CNBr cleavage followed by purification afforded 50, 31, and 15 mg/L yields of pure EX1, EX2 and EX3, respectively. CD spectroscopy, TEM, and rheological analysis indicate that these peptides fold and assembled into well defined fibrils that constitute hydrogels having shear-thin/recovery properties. PMID- 25453939 TI - Suppression of cell adhesion through specific integrin crosstalk on mixed peptide polysaccharide matrices. AB - Crosstalk of different integrins, which bind to distinct types of extracellular matrix proteins, promotes specific functions. This crosstalk has not been investigated in depth. Previously, we demonstrated that integrin-syndecan crosstalk accelerated cell adhesion. Here, we evaluated the crosstalk of two different integrins using mixed peptide-polysaccharide (chitosan or alginate) matrices. Two different integrin binding peptides, FIB1 (integrin alphavbeta3), EF1zz (integrin alpha2beta1), and 531 (integrin alpha3beta1), were mixed in various molar ratios (9:1, 4:1, 1:1) and conjugated on a polysaccharide matrix. The mixture of FIB1/EF1zz- and FIB1/531-polysaccharide matrices did not show any difference in human dermal fibroblast (HDF) adhesion against the mono polysaccharide matrices. Interestingly, the EF1zz/531-polysaccharide matrix (molar ratio = 1:4) exhibited significantly decreased cell adhesion, but other EF1zz/531-polysaccharide matrices did not show any difference. When we examined the signal transduction of the EF1zz/531(1:4), Y397 phosphorylation of FAK significantly decreased but Y514 phosphorylation of Src did not exhibit any differences. Further investigation revealed that this suppression was mediated by PI3K signaling through the activation of integrin, and PKA signaling modulated suppression of HDF attachment. These findings suggest that a mixed peptide polysaccharide matrix using receptor specific ligands can regulate cellular functions through receptor-specific crosstalk and is a useful approach to understand receptor specific crosstalk. PMID- 25453940 TI - Immobilisation of a thrombopoietin peptidic mimic by self-assembled monolayers for culture of CD34+ cells. AB - Compared to soluble cytokines, surface-tethered ligands can deliver biological signalling with precise control of spatial positioning and concentration. A strategy that immobilises ligand molecules on a surface in a uniform orientation using non-cleavable linkages under physiological conditions would enhance the specific and systemic delivery of signalling in the local environment. We used mixed self-assembled monolayers (SAMs) of oxyamine- and oligo(ethylene glycol) terminated thiols on gold to covalently install aldehyde- or ketone functionalised ligands via oxime conjugation. Characterisation by electrochemistry and X-ray photoelectron spectroscopy showed quantitative immobilisation of the ligands on SAM surfaces. The thrombopoietin mimetic peptide, RILL, was immobilised on SAMs and the bioactivity of the substrate was demonstrated by culturing factor-dependent cells. We also optimised the immobilisation and wash conditions so that the peptide was not released into the culture medium and the immobilised RILL could be re-used for consecutive cell cultures. The surface also supported the growth of haematopoietic CD34+ cells comparable to the standard thrombopoietin-supplemented culture. Furthermore, the RILL-immobilised SAM surface was as effective in expanding uncommitted CD34+ cells as standard culture. The stimulatory effect of surface-tethered ligands in haematopoietic stem cell expansion supports the use of ligand immobilisation strategies to replicate the haematopoietic stem cell niche. PMID- 25453941 TI - The effects of nanofiber diameter and orientation on siRNA uptake and gene silencing. AB - While substrate topography influences cell behavior, RNA interference (RNAi) has also emerged as a potent method for understanding and directing cell fate. However, the effects of substrate topography on RNAi remain poorly understood. Here, we report the influence of nanofiber architecture on siRNA-mediated gene silencing in human somatic and stem cells. The respective model cells, human dermal fibroblasts (HDFs) and mesenchymal stem cells (MSCs), were cultured onto aligned or randomly oriented electrospun poly(epsilon-caprolactone) fibers of different average diameters (300 nm, 700 nm and 1.3 MUm). In HDFs, decreasing fiber diameter from 1.3 MUm to 300 nm improved Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and Collagen-I silencing efficiencies by ~ 3.8 and ~4.4 folds respectively (p < 0.05) while the effective siRNA uptake pathway was altered from clathrin-dependent endocytosis to macropinocytosis. In MSCs, aligned fibers generated significantly higher level of gene silencing of RE-1 silencing transcription factor (REST) and green fluorescent protein (GFP) (~1.6 and ~1.5 folds respectively, p < 0.05), than randomly-oriented fibers. Aligned fiber topography facilitated functional siRNA uptake through clathrin-mediated endocytosis and membrane fusion. Taken together, our results demonstrated a promising role of three-dimensional fibrous scaffolds in modulating siRNA mediated gene-silencing and established the critical synergistic role of these substrates in modulating cellular behavior by RNAi. PMID- 25453942 TI - Modulation of the inflammatory response to chitosan through M2 macrophage polarization using pro-resolution mediators. AB - Tissue engineering and regenerative medicine have created a demand for biomaterials with specific functions such as the ability to modify the host immune response. The objective of this study was to evaluate the effect of two different pro-resolution lipid mediators, lipoxin A4 (LxA4) and resolvin D1 (RvD1), in the modulation of the inflammatory response to biomaterials through M2 macrophage polarization. This was investigated in vivo using a mouse air-pouch model of inflammation. Our results demonstrated that both LxA4 and RvD1 are able to shift the macrophage response to implanted Ch scaffolds to an M2 reparative response. The injection of these pro-resolution mediators caused a decrease in inflammatory cells recruited to the implant site together with higher numbers of F4/80(+)/CD206(+) cells (M2 macrophages) and lower numbers of F4/80(+)/CCR7(+) cells (M1 macrophages); it also induced a general decrease in several pro inflammatory cytokines; and caused a significant decrease in the thickness and area of the fibrous capsule formed around the implanted scaffolds. In conclusion, the use of either LxA4 or RvD1 allowed the in vivo control of macrophage phenotypic profile and thus may play a significant role in regenerative medicine applications, namely through modulation of the inflammatory response. PMID- 25453944 TI - Abnormal arrangement of a collagen/apatite extracellular matrix orthogonal to osteoblast alignment is constructed by a nanoscale periodic surface structure. AB - Morphological and directional alteration of cells is essential for structurally appropriate construction of tissues and organs. In particular, osteoblast alignment is crucial for the realization of anisotropic bone tissue microstructure. In this article, the orientation of a collagen/apatite extracellular matrix (ECM) was established by controlling osteoblast alignment using a surface geometry with nanometer-sized periodicity induced by laser ablation. Laser irradiation induced self-organized periodic structures (laser induced periodic surface structures; LIPSS) with a spatial period equal to the wavelength of the incident laser on the surface of biomedical alloys of Ti-6Al-4V and Co-Cr-Mo. Osteoblast orientation was successfully induced parallel to the grating structure. Notably, both the fibrous orientation of the secreted collagen matrix and the c-axis of the produced apatite crystals were orientated orthogonal to the cell direction. To the best of our knowledge, this is the first report demonstrating that bone tissue anisotropy is controllable, including the characteristic organization of a collagen/apatite composite orthogonal to the osteoblast orientation, by controlling the cell alignment using periodic surface geometry. PMID- 25453943 TI - Topographical cues regulate the crosstalk between MSCs and macrophages. AB - Implantation of scaffolds may elicit a host foreign body response triggered by monocyte/macrophage lineage cells. Growing evidence suggests that topographical cues of scaffolds play an important role in MSC functionality. In this work, we examined whether surface topographical features can regulate paracrine interactions that MSCs establish with macrophages. Three-dimensional (3D) topography sensing drives MSCs into a spatial arrangement that stimulates the production of the anti-inflammatory proteins PGE2 and TSG-6. Compared to two dimensional (2D) settings, 3D arrangement of MSCs co-cultured with macrophages leads to an important decrease in the secretion of soluble factors related with inflammation and chemotaxis including IL-6 and MCP-1. Attenuation of MCP-1 secretion in 3D co-cultures correlates with a decrease in the accumulation of its mRNA levels in MSCs and macrophages. Using neutralizing antibodies, we identified that the interplay between PGE2, IL-6, TSG-6 and MCP-1 in the co-cultures is strongly influenced by the micro-architecture that supports MSCs. Local inflammatory milieu provided by 3D-arranged MSCs in co-cultures induces a decrease in monocyte migration as compared to monolayer cells. This effect is partially mediated by reduced levels of IL-6 and MCP-1, proteins that up-regulate each other's secretion. Our findings highlight the importance of topographical cues in the soluble factor-guided communication between MSCs and macrophages. PMID- 25453945 TI - Cell guidance into quiescent state through chromatin remodeling induced by elastic modulus of substrate. AB - Substrate stiffness is known to strongly influence the fate of adhering cells. Yet, little is known about the influence of the substrate stiffness on chromatin. Chromatin integrates a multitude of biochemical signals interpreted by activation or gene silencing. Here we investigate for the first time the organization of chromatin of epithelial cells on substrate with various mechanical properties. On stiff substrates (100-200 kPa), where cells preferentially adhere, chromatin is mainly found in its euchromatin form. Decreasing the Young modulus to 50 kPa is correlated with a partial shift from euchromatin to heterochromatin. On very soft substrates (?10 kPa) this is accompanied by cell lysis. On these very soft substrates, histone deacetylase inhibition by adding a drug preserves acetylated histone and thus maintains the euchromatin form, thereby keeping intact the nuclear envelope as well as a residual intermediate filament network around the nucleus. This allows cells to survive in a non-adherent state without undergoing proliferation. When transfer on a stiff substrate these cells retain their capacity to adhere, to spread and to enter a novel mitotic cycle. A similar effect is observed on soft substrates (50 kPa) without need of histone deacetylase inhibition. These new results suggest that on soft substrates cells might enter in a quiescence state. Cell quiescence may thus be triggered by the Young modulus of a substrate, a major result for strategies focusing on the design of scaffold in tissue engineering. PMID- 25453946 TI - Spatiotemporal dynamics of microRNA during epithelial collective cell migration. AB - MicroRNAs (miRNAs) are small, noncoding RNAs variably involved in a wide variety of developmental and regenerative programs. Techniques for monitoring the spatiotemporal expression of miRNA in living cells are essential to elucidate the roles of miRNA during these complex regulatory processes. The small size, low abundance, sequence similarity, and degradation susceptibility of miRNAs, however, make their detection challenging. In this study, we detail a double stranded locked nucleic acid (dsLNA) probe for detecting intracellular miRNAs during epithelial collective migration. The dsLNA probe is capable of detecting the dynamic regulation and dose-dependent modulation of miRNAs. The probe is applied to monitor the spatial distribution of miRNA expression of a migrating epithelium. Our results reveal a gradient of miRNA over the first one hundred microns from the leading edge and show the involvement of miR-21 in the complex regulation of transforming growth factor beta modulated epithelial migration. With its ease of use and capacity for real-time monitoring of miRNAs in living cells, the dsLNA probe carries the potential for studying the function and regulation of miRNA in a wide spectrum of complex biological processes. PMID- 25453948 TI - Endochondral bone formation in gelatin methacrylamide hydrogel with embedded cartilage-derived matrix particles. AB - The natural process of endochondral bone formation in the growing skeletal system is increasingly inspiring the field of bone tissue engineering. However, in order to create relevant-size bone grafts, a cell carrier is required that ensures a high diffusion rate and facilitates matrix formation, balanced by its degradation. Therefore, we set out to engineer endochondral bone in gelatin methacrylamide (GelMA) hydrogels with embedded multipotent stromal cells (MSCs) and cartilage-derived matrix (CDM) particles. CDM particles were found to stimulate the formation of a cartilage template by MSCs in the GelMA hydrogel in vitro. In a subcutaneous rat model, this template was subsequently remodeled into mineralized bone tissue, including bone-marrow cavities. The GelMA was almost fully degraded during this process. There was no significant difference in the degree of calcification in GelMA with or without CDM particles: 42.5 +/- 2.5% vs. 39.5 +/- 8.3% (mean +/- standard deviation), respectively. Interestingly, in an osteochondral setting, the presence of chondrocytes in one half of the constructs fully impeded bone formation in the other half by MSCs. This work offers a new avenue for the engineering of relevant-size bone grafts, by the formation of endochondral bone within a degradable hydrogel. PMID- 25453947 TI - TGFbeta2 differentially modulates smooth muscle cell proliferation and migration in electrospun gelatin-fibrinogen constructs. AB - A main goal of tissue engineering is the development of scaffolds that replace, restore and improve injured tissue. These scaffolds have to mimic natural tissue, constituted by an extracellular matrix (ECM) support, cells attached to the ECM, and signaling molecules such as growth factors that regulate cell function. In this study we created electrospun flat sheet scaffolds using different compositions of gelatin and fibrinogen. Smooth muscle cells (SMCs) were seeded on the scaffolds, and proliferation and infiltration were evaluated. Additionally, different concentrations of Transforming Growth Factor-beta2 (TGFbeta2) were added to the medium with the aim of elucidating its effect on cell proliferation, migration and collagen production. Our results demonstrated that a scaffold with a composition of 80% gelatin-20% fibrinogen is suitable for tissue engineering applications since it promotes cell growth and migration. The addition of TGFbeta2 at low concentrations (<= 1 ng/ml) to the culture medium resulted in an increase in SMC proliferation and scaffold infiltration, and in the reduction of collagen production. In contrast, TGFbeta2 at concentrations >1 ng/ml inhibited cell proliferation and migration while stimulating collagen production. According to our results TGFbeta2 concentration has a differential effect on SMC function and thus can be used as a biochemical modulator that can be beneficial for tissue engineering applications. PMID- 25453949 TI - Fabrication of injectable, cellular, anisotropic collagen tissue equivalents with modular fibrillar densities. AB - Technological improvements in collagen gel fabrication are highly desirable as they may enable significant advances in the formation of tissue-equivalent biomaterials for regenerative medicine, three-dimensional (3D) in vitro tissue models, and injectable scaffolds for cell and drug delivery applications. Thus, strategies to modulate collagen gel fibrillar density and organization in the mesostructure have been pursued to fabricate collagenous matrices with extracellular matrix-like features. Herein, we introduce a robust and simple method, namely gel aspiration-ejection (GAE), to engineer 3D, anisotropic, cell seeded, injectable dense collagen (I-DC) gels with controllable fibrillar densities, without the use of crosslinking. GAE allows for the hybridization of collagen gels with bioactive agents for increased functionality and supports highly aligned homogenous cell seeding, thus providing I-DC gels with distinct properties when compared to isotropic DC gels of random fibrillar orientation. The hybridization of I-DC with anionic fibroin derived polypeptides resulted in the nucleation of carbonated hydroxyapatite within the aligned nanofibrillar network upon exposure to simulated body fluid, yielding a 3D, anisotropic, mineralized collagen matrix. In addition, I-DC gels accelerated the osteoblastic differentiation of seeded murine mesenchymal stem cells (m-MSCs) when exposed to osteogenic supplements, which resulted in the cell-mediated, bulk mineralization of the osteoid-like gels. In addition, and upon exposure to neuronal transdifferentiation medium, I-DC gels supported and accelerated the differentiation of m-MSCs toward neuronal cells. In conclusion, collagen GAE presents interesting opportunities in a number of fields spanning tissue engineering and regenerative medicine to drug and cell delivery. PMID- 25453951 TI - CPNE7, a preameloblast-derived factor, regulates odontoblastic differentiation of mesenchymal stem cells. AB - Tooth development involves sequential interactions between dental epithelial and mesenchymal cells. Our previous studies demonstrated that preameloblast conditioned medium (PA-CM) induces the odontogenic differentiation of human dental pulp cells (hDPCs), and the novel protein Cpne7 in PA-CM was suggested as a candidate signaling molecule. In the present study, we investigated biological function and mechanisms of Cpne7 in regulation of odontoblast differentiation. Cpne7 was expressed in preameloblasts and secreted extracellularly during ameloblast differentiation. After secretion, Cpne7 protein was translocated to differentiating odontoblasts. In odontoblasts, Cpne7 promoted odontoblastic markers and the expression of Dspp in vitro. Cpne7 also induced odontoblast differentiation and promoted dentin/pulp-like tissue formation in hDPCs in vivo. Moreover, Cpne7 induced differentiation into odontoblasts of non-dental mesenchymal stem cells in vitro, and promoted formation of dentin-like tissues including the structure of dentinal tubules in vivo. Mechanistically, Cpne7 interacted with Nucleolin and modulated odontoblast differentiation via the control of Dspp expression. These results suggest Cpne7 is a diffusible signaling molecule that is secreted by preameloblasts, and regulates the differentiation of mesenchymal cells of dental or non-dental origin into odontoblasts. PMID- 25453952 TI - Controlled dual delivery of BMP-2 and dexamethasone by nanoparticle-embedded electrospun nanofibers for the efficient repair of critical-sized rat calvarial defect. AB - There is an urgent need to develop biomimetic bone tissue engineering scaffolds for the repair of critical-sized calvarial defect. In this study, we developed a new nanoparticle-embedded electrospun nanofiber scaffold for the controlled dual delivery of BMP-2 and dexamethasone (DEX). The scaffold was achieved by (1) the encapsulation of BMP-2 into bovine serum albumin (BSA) nanoparticles to maintain the bioactivity of BMP-2 and (2) the co-electrospinning of the blending solution composed of the BSA nanoparticles, DEX and the poly(epsilon-caprolactone)-co poly(ethylene glycol) (PCE) copolymer. The in vitro studies showed that the bioactivity of DEX and BMP-2 was preserved in the dual-drug-loaded nanofiber scaffold, and a sequential release pattern in which most of the DEX was released in the original eight days and the BMP-2 release lasted up to 35 days was achieved. The in vitro osteogenesis study demonstrated that the drug-loaded groups exhibited a strong ability to induce differentiation toward osteoblasts. In vivo osteogenesis studies also revealed that the degrees of repair of rat calvarial defect achieved with the drug-loaded nanofiber scaffolds were significantly better than those obtained with the blank materials; in particular, the dual-drug-loaded nanofiber scaffold manifested the best repair efficacy due to a synergistic effect of BMP-2 and DEX. Therefore, the dual-drug-loaded nanofiber scaffold is deemed a strong potential candidate for the repair of bone defects in bone tissue engineering. PMID- 25453950 TI - Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds. AB - In normal tissue repair, macrophages exhibit a pro-inflammatory phenotype (M1) at early stages and a pro-healing phenotype (M2) at later stages. We have previously shown that M1 macrophages initiate angiogenesis while M2 macrophages promote vessel maturation. Therefore, we reasoned that scaffolds that promote sequential M1 and M2 polarization of infiltrating macrophages should result in enhanced angiogenesis and healing. To this end, we first analyzed the in vitro kinetics of macrophage phenotype switch using flow cytometry, gene expression, and cytokine secretion analysis. Then, we designed scaffolds for bone regeneration based on modifications of decellularized bone for a short release of interferon-gamma (IFNg) to promote the M1 phenotype, followed by a more sustained release of interleukin-4 (IL4) to promote the M2 phenotype. To achieve this sequential release profile, IFNg was physically adsorbed onto the scaffolds, while IL4 was attached via biotin-streptavidin binding. Interestingly, despite the strong interactions between biotin and streptavidin, release studies showed that biotinylated IL4 was released over 6 days. These scaffolds promoted sequential M1 and M2 polarization of primary human macrophages as measured by gene expression of ten M1 and M2 markers and secretion of four cytokines, although the overlapping phases of IFNg and IL4 release tempered polarization to some extent. Murine subcutaneous implantation model showed increased vascularization in scaffolds releasing IFNg compared to controls. This study demonstrates that scaffolds for tissue engineering can be designed to harness the angiogenic behavior of host macrophages towards scaffold vascularization. PMID- 25453953 TI - Ornamenting 3D printed scaffolds with cell-laid extracellular matrix for bone tissue regeneration. AB - 3D printing technique is the most sophisticated technique to produce scaffolds with tailorable physical properties. But, these scaffolds often suffer from limited biological functionality as they are typically made from synthetic materials. Cell-laid mineralized ECM was shown to be potential for improving the cellular responses and drive osteogenesis of stem cells. Here, we intend to improve the biological functionality of 3D-printed synthetic scaffolds by ornamenting them with cell-laid mineralized extracellular matrix (ECM) that mimics a bony microenvironment. We developed bone graft substitutes by using 3D printed scaffolds made from a composite of polycaprolactone (PCL), poly(lactic-co glycolic acid) (PLGA), and beta-tricalcium phosphate (beta-TCP) and mineralized ECM laid by human nasal inferior turbinate tissue-derived mesenchymal stromal cells (hTMSCs). A rotary flask bioreactor was used to culture hTMSCs on the scaffolds to foster formation of mineralized ECM. A freeze/thaw cycle in hypotonic buffer was used to efficiently decellularize (97% DNA reduction) the ECM-ornamented scaffolds while preserving its main organic and inorganic components. The ECM-ornamented 3D printed scaffolds supported osteoblastic differentiation of newly-seeded hTMSCs by upregulating four typical osteoblastic genes (4-fold higher RUNX2; 3-fold higher ALP; 4-fold higher osteocalcin; and 4 fold higher osteopontin) and increasing calcium deposition compared to bare 3D printed scaffolds. In vivo, in ectopic and orthotopic models in rats, ECM ornamented scaffolds induced greater bone formation than that of bare scaffolds. These results suggest a valuable method to produce ECM-ornamented 3D printed scaffolds as off-the-shelf bone graft substitutes that combine tunable physical properties with physiological presentation of biological signals. PMID- 25453954 TI - Engineered neural tissue with aligned, differentiated adipose-derived stem cells promotes peripheral nerve regeneration across a critical sized defect in rat sciatic nerve. AB - Adipose-derived stem cells were isolated from rats and differentiated to a Schwann cell-like phenotype in vitro. The differentiated cells (dADSCs) underwent self-alignment in a tethered type-1 collagen gel, followed by stabilisation to generate engineered neural tissue (EngNT-dADSC). The pro-regenerative phenotype of dADSCs was enhanced by this process, and the columns of aligned dADSCs in the aligned collagen matrix supported and guided neurite extension in vitro. EngNT dADSC sheets were rolled to form peripheral nerve repair constructs that were implanted within NeuraWrap conduits to bridge a 15 mm gap in rat sciatic nerve. After 8 weeks regeneration was assessed using immunofluorescence imaging and transmission electron microscopy and compared to empty conduit and nerve graft controls. The proportion of axons detected in the distal stump was 3.5 fold greater in constructs containing EngNT-dADSC than empty tube controls. Our novel combination of technologies that can organise autologous therapeutic cells within an artificial tissue construct provides a promising new cellular biomaterial for peripheral nerve repair. PMID- 25453955 TI - Fibril formation pH controls intrafibrillar collagen biomineralization in vitro and in vivo. AB - We demonstrate that intrafibrillar, homogenous collagen biomineralization can be achieved by controlling self-assembly under mildly alkaline conditions. Using dense collagen (DC) gels as an osteoid model, we modulated their fibrillogenesis environment to evaluate the effects of fibrillogenesis pH on the protein charge distribution and ultimately on biomineralization. Cationic and anionic dye staining and electron cryomicroscopy analyses established that fibrillogenesis under mildly alkaline conditions promotes the formation of electronegative charges within the protein (anionic DC gels). These charges are stable upon titration of the gel pH to physiological values. Subsequent exposure of anionic DC gels to simulated body fluid induced the intrafibrillar biomineralization of the gels, promoting a rapid, extensive formation of carbonated hydroxyapatite, and strongly impacting gel mechanical properties. The generality and significance of this approach has been addressed by implanting freshly made anionic DC gels in vivo, in a rat subcutaneous model. Subcutaneous implants showed an extensive, homogenous biomineralization as early as at day 7, indicating that anionic collagen gels rapidly self-mineralize upon contact with body fluids in a non osseous implantation site. The control of collagen fibrillogenesis pH provides not only new interpretations to what has been called the collagen mineralization enigma by demonstrating that neat collagen can intrafibrilarly self-mineralize, but it will also set a new starting point for the use of DC gels in bone regenerative medicine, in addition as potential applications as mineralized tissue model or as slow-release delivery carriers. PMID- 25453956 TI - Multifunctional near infrared-emitting long-persistence luminescent nanoprobes for drug delivery and targeted tumor imaging. AB - In this paper, near infrared-emitting long-persistence luminescent porous Zn1.1Ga1.8Ge0.1O4:Cr(3+), Eu(3+) @SiO2 nanoprobes have been prepared using mesoporous silica nanospheres both as morphology-controlling templates and as vessels. These nanoprobes possessed an excellent capacity for drug delivery and allowed for real-time monitoring of the delivery routes of the drug carriers in vivo. The nanoprobes demonstrated a typical mesoporous structure, a brighter NIR emission (696 nm) and a long afterglow luminescence that persisted for 15 d. Furthermore, after surface modification with folic acid (FA), a tumor-targeting group, these nanoprobes exhibited an excellent ability to target tumors with high sensitivity in vitro and in vivo. Importantly, these modified nanoprobes could accurately diagnose tumors and allow for long-term tumor monitoring via in situ and in vivo re-excitation by a red LED lamp. Furthermore, the drug release data demonstrated that the modified nanoprobes could be loaded with a large amount of doxorubicin hydrochloride (DOX) and showed sustained release behavior. Together, the results of this study indicate that these nanoprobes can accurately diagnose tumors, allow for long-term in vivo and in situ monitoring and release DOX in situ to cure tumors. PMID- 25453958 TI - Nanobubble-Affibody: Novel ultrasound contrast agents for targeted molecular ultrasound imaging of tumor. AB - Nanobubbles (NBs), as novel ultrasound contrast agents (UCAs), have attracted increasing attention in the field of molecular ultrasound imaging for tumors. However, the preparation of uniform-sized NBs is considered to be controversial, and poor tumor selectivity in in vivo imaging has been reported. In this study, we fabricated uniform nano-sized NBs (478.2 +/- 29.7 nm with polydispersity index of 0.164 +/- 0.044, n = 3) using a thin-film hydration method by controlling the thickness of phospholipid films; we then conjugated the NBs with Affibody molecules to produce nano-sized UCAs referred to as NB-Affibody with specific affinity to human epidermal growth factor receptor type 2 (HER2)-overexpressing tumors. NB-Affibody presented good ultrasound enhancement, demonstrating a peak intensity of 104.5 +/- 2.1 dB under ultrasound contrast scanning. Ex vivo experiments further confirmed that the NB-Affibody conjugates were capable of targeting HER2-expressing tumor cells in vivo with high affinity. The newly prepared nano-sized NB-Affibody conjugates were observed to be novel targeted UCAs for efficient and safe specific molecular imaging and may have potential applications in early cancer quantitative diagnosis and targeted therapy in the future. PMID- 25453959 TI - Insights into the membrane interaction mechanism and antibacterial properties of chensinin-1b. AB - Antimicrobial peptides (AMPs) with non-specific membrane disrupting activities are thought to exert their antimicrobial activity as a result of their cationicity, hydrophobicity and alpha-helical or beta-sheet structures. Chensinin 1, a native peptide from skin secretions of Rana chensinensis, fails to manifest its desired biological properties because its low hydrophobic nature and an adopted random coil structure in a membrane-mimetic environment. In this study, chensinin-1b was designed by rearranging the amino acid sequence of its hydrophilic/polar residues on one face and its hydrophobic/nonpolar residues on the opposite face according to its helical diagram, and by replacing three Gly residues with three Trp residues. Introduction of Trp residues significantly promoted the binding of the peptide to the bacterial outer membrane and exerted bactericidal activity through cytoplasmic membrane damage. Chensinin-1b demonstrates higher antimicrobial activity and greater cell selectivity than its parent peptide, chensinin-1. The electrostatic interactions between chensinin-1b and lipopolysaccharide (LPS) may have facilitated the uptake of the peptide into Gram-negative cells and be also helpful to disrupt the bacterial cytoplasmic membrane, as evidenced by depolarisation of the membrane potential and leakage of calceins from the liposomes of Escherichia coli and Staphylococcus aureus. Chensinin-1b was also found to penetrate mouse skin and was also effective in vivo, as measured by hydroxyproline levels in a wound infection mouse model, and could therefore act as an anti-infective agent for wound healing. PMID- 25453957 TI - LHT7, a chemically modified heparin, inhibits multiple stages of angiogenesis by blocking VEGF, FGF2 and PDGF-B signaling pathways. AB - Despite the therapeutic benefits of the angiogenesis inhibitors shown in the clinics, they have encountered an unexpected limitation by the occurrence of acquired resistance. Although the mechanism of the resistance is not clear so far, the upregulation of alternative angiogenic pathways and stabilization of endothelium by mural cells were reported to be responsible. Therefore, blocking multiple angiogenic pathways that are crucial in tumor angiogenesis has been highlighted to overcome such limitations. To develop an angiogenesis inhibitor that could block multiple angiogenic factors, heparin is an excellent lead compound since wide array of angiogenic factors are heparin-binding proteins. In previous study, we reported a heparin-derived angiogenesis inhibitor, LHT7, as a potent angiogenesis inhibitor and showed that it blocked VEGF signaling pathway. Here we show that LHT7 could block the fibroblast growth factor 2 (FGF2) and platelet-derived growth factor B (PDGF-B) in addition to VEGF. Simultaneous blockade of these angiogenic factors resulted in inhibition of multiple stages of the angiogenic process, including initial angiogenic response to maturation of the endothelium by pericyte coverage in vitro. In addition, the treatment of LHT7 in vivo did not show any sign of vascular normalization and directly led to decreased blood perfusion throughout the tumor. Our findings show that LHT7 could effectively inhibit tumor angiogenesis by blocking multiple stages of the angiogenesis, and could potentially be used to overcome the resistance. PMID- 25453961 TI - Enhanced transport of nanocage stabilized pure nanodrug across intestinal epithelial barrier mimicking Listeria monocytogenes. AB - Ligand grafted nanoparticles have been shown to enhance drug transport across epithelium barrier and are expected to improve drug delivery. However, grafting of these ligands to the surface of pure nanodrug, i.e., nanocrystals (NCs), is a critical challenge due to the shedding of ligands along with the stabilizer upon high dilution or dissolving of the drug. Herein, a non-sheddable nanocage-like stabilizer was designed by covalent cross-linking of poly(acrylic acid)-b poly(methyl acrylate) on drug nanocrystal surface, and a ligand, wheat germ agglutinin (WGA), was successfully anchored to the surface of itraconazole (ITZ) NCs by covalent conjugation to the nanocage (WGA-cage-NCs). The cellular study showed that large amount of WGA-cage-NCs were adhered to Caco-2 cell membrane, and invaded into cells, resulting in a higher drug uptake than that of ordinary NCs (ONCs). After oral administration to rats, WGA-cage-NC were largely accumulated on the apical side of epithelium cells, facilitating drug diffusing across epithelium barrier. Interestingly, WGA-cage-NCs were capable of invading rat intestinal villi and reaching to lamina propria by transcytosis across goblet cells, which behaved like a foodborne pathogen, Listeria monocytogenes. The WGA cage-NCs showed an improved oral bioavailability, which was 17.5- and 2.41-folds higher than that of coarse crystals and ONCs, respectively. To our best knowledge, this may represent the first report that a functional ligand was successfully anchored to the surface of pure nanodrug by using a cage-like stabilizer, showing unique biological functions in gastrointestinal tract and having an important significance in oral drug delivery. PMID- 25453960 TI - Intraperitoneal delivery of platinum with in-situ crosslinkable hyaluronic acid gel for local therapy of ovarian cancer. AB - Intraperitoneal (IP) chemotherapy is a promising post-surgical therapy of solid carcinomas confined within the peritoneal cavity, with potential benefits in locoregional and systemic management of residual tumors. In this study, we intended to increase local retention of platinum in the peritoneal cavity over a prolonged period of time using a nanoparticle form of platinum and an in-situ crosslinkable hyaluronic acid gel. Hyaluronic acid was chosen as a carrier due to the biocompatibility and biodegradability. We confirmed a sustained release of platinum from the nanoparticles (PtNPs) and nanoparticle/gel hybrid (PtNP/gel), receptor-mediated endocytosis of PtNPs, and retention of the gel in the peritoneal cavity over 4 weeks: conditions desirable for a prolonged local delivery of platinum. However, PtNPs and PtNP/gel did not show a greater anti tumor efficacy than CDDP solution administered at the same dose but rather caused a slight increase in tumor burdens at later time points, which suggests a potential involvement of empty carriers and degradation products in the growth of residual tumors. This study alerts that although several materials considered biocompatible and safe are used as drug carriers, they may have unwanted biological effects on the residual targets once the drug is exhausted; therefore, more attention should be paid to the selection of drug carriers. PMID- 25453962 TI - Mannosylated poly(beta-amino esters) for targeted antigen presenting cell immune modulation. AB - Given the rise of antibiotic resistance and other difficult-to-treat diseases, genetic vaccination is a promising preventative approach that can be tailored and scaled according to the vector chosen for gene delivery. However, most vectors currently utilized rely on ubiquitous delivery mechanisms that ineffectively target important immune effectors such as antigen presenting cells (APCs). As such, APC targeting allows the option for tuning the direction (humoral vs cell mediated) and strength of the resulting immune responses. In this work, we present the development and assessment of a library of mannosylated poly(beta amino esters) (PBAEs) that represent a new class of easily synthesized APC targeting cationic polymers. Polymeric characterization and assessment methodologies were designed to provide a more realistic physiochemical profile prior to in vivo evaluation. Gene delivery assessment in vitro showed significant improvement upon PBAE mannosylation and suggested that mannose-mediated uptake and processing influence the magnitude of gene delivery. Furthermore, mannosylated PBAEs demonstrated a strong, efficient, and safe in vivo humoral immune response without use of adjuvants when compared to genetic and protein control antigens. In summary, the gene delivery effectiveness provided by mannosylated PBAE vectors offers specificity and potency in directing APC activation and subsequent immune responses. PMID- 25453963 TI - Enhanced blood-brain barrier penetration and glioma therapy mediated by a new peptide modified gene delivery system. AB - Successful glioma gene therapy lays on two important factors, the therapeutic genes and efficient delivery vehicles to cross the blood-brain barrier (BBB) and reach gliomas. In this work, a new gene vector was constructed based on dendrigraft poly-l-lysines (DGL) and polyethyleneglycol (PEG), conjugated with a cell-penetrating peptide, the nucleolar translocation signal (NoLS) sequence of the LIM Kinase 2 (LIMK2) protein (LIMK2 NoLS peptide, LNP), yielding DGL-PEG-LNP. Plasmid DNA encoding inhibitor of growth 4 (ING4) was applied as the therapeutic gene. DGL-PEG-LNP/DNA nanoparticles (NPs) were monodispersed, with a mean diameter of 90.6 +/- 8.9 nm. The conjugation of LNP significantly enhanced the BBB-crossing efficiency, cellular uptake and gene expression within tumor cells. Mechanism studies suggested the involvement of energy, caveolae-mediated endocytosis and macropinocytosis in cellular uptake of LNP-modified NPs. MTT results showed that no apparent cytotoxicity was observed when cells were treated with synthesized vectors. Furthermore, LNP-modified NPs mediated strongest and most intensive apoptosis on the tumor site, and the longest median survival time of glioma-bearing mice. All the results demonstrated that LNP is a kind of efficient CPPs especially for BBB-crossing application, and DGL-PEG-LNP/DNA is a potential non-viral platform for glioma gene therapy via intravenous administration. PMID- 25453964 TI - Transferrin-mediated fullerenes nanoparticles as Fe(2+)-dependent drug vehicles for synergistic anti-tumor efficacy. AB - Artesunate (AS) is an iron-dependent drug, which has been used extensively as anti-malarial drugs worldwide with no obvious side effects. Recently, studies have shown that AS also possess profound cytotoxicity against tumor cells. However, simultaneous delivery of hydrophobic AS and Fe(2+) into tumor cells remains a major challenge. Herein, we report a new kind of active-targeting preparations which could not only specially target to tumor cells but also synchronously transfer AS and irons into tumor tissue. In this study, hyaluronic acid (HA) was grafted onto fullerene to get a water-soluble biomaterial (HA-C60) with excellent biocompatibility, and then combined with transferrin (Tf) to obtain a multi-functional drug delivery system (HA-C60-Tf) with significant tumor targeting efficacy and powerful photodynamic therapy capacity. Finally, AS was adsorbed on HA-C60-Tf with a high loading efficacy of 162.4% (weight ratio of AS: HA-C60-Tf). Compared with free AS, remarkably enhanced antitumor efficacy of AS loaded HA-C60-Tf nanoparticles was realized both in a cultured MCF-7 cells in vitro and in a tumor-bearing murine model in vivo, due to increased intracellular accumulation of AS in tumor and activated mechanism by co-delivery of Tf and AS analogs. Furthermore, with laser irradiation in vivo, the relative tumor volume (V/V0) of HA-C60-Tf/AS declined by half, from 1.72 +/- 0.12 to 0.84 +/- 0.07, suggesting a new way with multi-mechanism for tumor treatment was developed. PMID- 25453965 TI - Fluorescent cell-traceable dexamethasone-loaded liposomes for the treatment of inflammatory liver diseases. AB - Liposomes are routinely used carrier materials for delivering drug molecules to pathological sites. Besides in tumors and inflammatory sites, liposomes also strongly accumulate in liver and spleen. The potential of using liposomes to treat acute and chronic liver disorders, however, has not yet been evaluated. We here explored the therapeutic potential of dexamethasone (Dex)-loaded liposomes for inflammatory liver diseases, using experimental models of acute and chronic liver injury in mice. Fluorescently labeled liposomes predominantly accumulated in hepatic phagocytes, but also in T cells. Importantly, Dex-loaded liposomes reduced T cells in blood and liver, more effectively than free Dex, and endorsed the anti-inflammatory polarization of hepatic macrophages. In experimental chronic liver damage, Dex-loaded liposomes significantly reduced liver injury and liver fibrosis. In immune-mediated acute hepatitis Dex-loaded liposomes, but not free Dex, significantly reduced disease severity. T cells, not macrophages, were significantly depleted by Dex liposomes in liver disease models in vivo, as further supported by mechanistic cell death in vitro studies. Our data indicate that Dex liposomes may be an interesting treatment option for liver diseases, in particular for immune-mediated hepatitis. The depletion of T cells might represent the major mechanism of action of Dex liposomes, rather than their macrophage-polarizing activities. PMID- 25453966 TI - Novel protease inhibitor-loaded Nanoparticle-in-Microparticle Delivery System leads to a dramatic improvement of the oral pharmacokinetics in dogs. AB - With the advent of the Highly Active Antiretroviral Therapy, the morbidity and the mortality associated to HIV have been considerably reduced. However, 35-40 million people bear the infection worldwide. One of the main causes of therapeutic failure is the frequent administration of several antiretrovirals that results in low patient compliance and treatment cessation. In this work, we have developed an innovative Nanoparticle-in-Microparticle Delivery System (NiMDS) comprised of pure drug nanocrystals of the potent protease inhibitor indinavir free base (used as poorly water-soluble model protease inhibitor) produced by nanoprecipitation that were encapsulated within mucoadhesive polymeric microparticles. Pure drug nanoparticles and microparticles were thoroughly characterized by diverse complementary techniques. NiMDSs displayed an encapsulation efficiency of approximately 100% and a drug loading capacity of up to 43% w/w. In addition, mucoadhesiveness assays ex vivo conducted with bovine gut showed that film-coated microparticles were retained for more than 6 h. Finally, pharmacokinetics studies in mongrel dogs showed a dramatic 47- and 95 fold increase of the drug oral bioavailability and half-life, respectively, with respect to the free unprocessed drug. These results support the outstanding performance of this platform to reduce the dose and the frequency of administration of protease inhibitors, a crucial step to overcome the current patient-incompliant therapy. PMID- 25453967 TI - Genipin-crosslinked catechol-chitosan mucoadhesive hydrogels for buccal drug delivery. AB - Drug administration via buccal mucosa is an attractive drug delivery strategy due to good patient compliance, prolonged localized drug effect, and avoidance of gastrointestinal drug metabolism and first-pass elimination. Buccal drug delivery systems need to maintain an intimate contact with the mucosa lining in the wet conditions of the oral cavity for long enough to allow drug release and absorption. For decades, mucoadhesive polymers such as chitosan (CS) and its derivatives have been explored to achieve this. In this study, inspired by the excellent wet adhesion of marine mussel adhesive protein, we developed a buccal drug delivery system using a novel catechol-functionalized CS (Cat-CS) hydrogel. We covalently bonded catechol functional groups to the backbone of CS, and crosslinked the polymer with a non-toxic crosslinker genipin (GP). We achieved two degrees of catechol conjugation (9% and 19%), forming Cat9-CS/GP and Cat19 CS/GP hydrogels, respectively. We confirmed covalent bond formation during the catechol functionalization and GP crosslinking during the gel formation. The gelation time and the mechanical properties of Cat-CS hydrogels are similar to those of CS only hydrogels. Catechol groups significantly enhanced mucoadhesion in vitro (7 out of the 10 Cat19-CS hydrogels were still in contact with porcine mucosal membrane after 6 h, whereas all of the CS hydrogels lost contact after 1.5 h). The new hydrogel systems sustained the release of lidocaine for about 3 h. In-vivo, we compared buccal patches made of Cat19-CS/GP and CS/GP adhered to rabbit buccal mucosa. We were able to detect lidocaine in the rabbit's serum at concentration about 1 ng/ml only from the Cat19-CS patch, most likely due to the intimate contact provided by mucoadhesive Cat19-CS/GP systems. No inflammation was observed on the buccal tissue in contact with any of the patches tested. These results show that the proposed catechol-modified CS hydrogel is a promising mucoadhesive and biocompatible hydrogel system for buccal drug delivery. PMID- 25453968 TI - Co-delivery of all-trans-retinoic acid and doxorubicin for cancer therapy with synergistic inhibition of cancer stem cells. AB - Combination treatment through simultaneous delivery of two or more drugs with nanoparticles has been demonstrated to be an elegant and efficient approach for cancer therapy. Herein, we employ a combination therapy for eliminating both the bulk tumor cells and the rare cancer stem cells (CSCs) that have a high self renewal capacity and play a critical role in cancer treatment failure. All-trans retinoic acid (ATRA), a powerful differentiation agent of cancer stem cells and the clinically widely used chemotherapy agent doxorubicin (DOX) are simultaneously encapsulated in the same nanoparticle by a single emulsion method. It is demonstrated that ATRA and DOX simultaneous delivery-based therapy can efficiently deliver the drugs to both non-CSCs and CSCs to differentiate and kill the cancer cells. Differentiation of CSCs into non-CSCs can reduce their self renewal capacity and increase their sensitivity to chemotherapy; with the combined therapy, a significantly improved anti-cancer effect is demonstrated. Administration of this combinational drug delivery system can markedly augment the enrichment of drugs both in tumor tissues and cancer stem cells, prodigiously enhancing the suppression of tumor growth while reduce the incidence of CSC in a synergistic manner. PMID- 25453969 TI - Dynamic imaging of PEGylated indocyanine green (ICG) liposomes within the tumor microenvironment using multi-spectral optoacoustic tomography (MSOT). AB - Multispectral optoacoustic tomography (MSOT) is a powerful modality that allows high-resolution imaging of photo-absorbers deep within tissue, beyond the classical depth and resolution limitations of conventional optical imaging. Imaging of intrinsic tissue contrast can be complemented by extrinsically administered gold nanoparticles or fluorescent molecular probes. Instead, we investigated herein generation of re-engineered clinically-used PEGylated liposomes incorporating indocyanine green (LipoICG) as a contrast strategy that combines materials already approved for clinical use, with strong photo-absorbing signal generation available today only from some metallic nanoparticles (e.g. gold nanorods). Using MSOT we confirmed LipoICG as a highly potent optoacoustic agent and resolved tissue accumulation in tumor-bearing animals over time with high-sensitivity and resolution using two tumor models of different vascularisation. We further showcase a paradigm shift in pharmacology studies and nanoparticle investigation, by enabling detailed volumetric optical imaging in vivo through the entire tumor tissue non-invasively, elucidating never before seen spatiotemporal features of optical agent distribution. These results point to LipoICG as a particle with significant advantageous characteristics over gold nanoparticles and organic dyes. PMID- 25453970 TI - Tumor microenvironment sensitive doxorubicin delivery and release to glioma using angiopep-2 decorated gold nanoparticles. AB - Glioma is still hard to be treated due to their complex microenvironment. In this study, a gold nanoparticle-based delivery system was developed. The system, An PEG-DOX-AuNPs, was loaded with doxorubicin (DOX) through hydrazone, an acid responsive linker, and was functionalized with angiopep-2, a specific ligand of low density lipoprotein receptor-related protein-1 (LRP1), which could mediate the system to penetrate blood brain barrier and target to glioma cells. The particle size of An-PEG-DOX-AuNPs was 39.9 nm with a zeta potential of -19.3 mV, while the DOX loading capacity was 9.7%. In vitro, the release of DOX from DOX AuNPs was pH-dependent. At lower pH values, especially 5.0 and 6.0, release of DOX was much quicker than that at pH 6.8 and 7.4. After coating with PEG, the acid-responsive release of DOX from PEG-DOX-AuNPs was almost the same as that from DOX-AuNPs. Cellular uptake study showed obviously higher intensity of intracellular An-PEG-DOX-AuNPs compared with PEG-DOX-AuNPs. In vivo, An-PEG-DOX AuNPs could distribute into glioma at a higher intensity than that of PEG-DOX AuNPs and free DOX. Correspondingly, glioma-bearing mice treated with An-PEG-DOX AuNPs displayed the longest median survival time, which was 2.89-fold longer than that of saline. In conclusion, An-PEG-DOX-AuNPs could specifically deliver and release DOX in glioma and significantly expand the median survival time of glioma bearing mice. PMID- 25453971 TI - Unibody core-shell smart polymer as a theranostic nanoparticle for drug delivery and MR imaging. AB - Developing novel multifunctional nanoparticles (NPs) with robust preparation, low cost, high stability, and flexible functionalizability is highly desirable. This study provides an innovative platform, termed unibody core-shell (UCS), for this purpose. UCS is comprised of two covalent-bonded polymers differed only by the functional groups at the core and the shell. By conjugating Gd(3+) at the stable core and encapsulating doxorubicin (Dox) at the shell in a pH-sensitive manner, we developed a theranostic NPs (UCS-Gd-Dox) that achieved a selective drug release (75% difference between pH 7.4 and 5.5) and MR imaging (r1 = 0.9 and 14.5 mm(-1) s(-1) at pH 7.4 and 5.5, respectively). The anti-cancer effect of UCS-Gd Dox is significantly better than free Dox in tumor-bearing mouse models, presumably due to enhanced permeability and retention effect and pH-triggered release. To the best of our knowledge, this is the simplest approach to obtain the theranostic NPs with Gd-conjugation and Dox doping. PMID- 25453972 TI - Bi2S3-embedded mesoporous silica nanoparticles for efficient drug delivery and interstitial radiotherapy sensitization. AB - A novel design of Bi2S3 nanoparticles with a coating of mesoporous silica (BMSN) is obtained by a surfactant induced condensation method. It was found that BMSNs exhibited a high doxorubicin (DOX) loading efficiency of 45 wt% and pH-responsive controlled drug release owing to the electrostatic interaction between silanol surface and DOX molecules. The cell viability results demonstrated the encapsulation of DOX into BMSNs could lead to significantly enhanced therapeutic effect against multidrug-resistance cancer cells compared to that of free DOX drug. Furthermore, the comparable study of tumor growth by different treatments demonstrated that the introduction of BMSNs in the X-ray therapy could lead to higher therapeutic effect, with just 2.10-fold increase in tumor volume through 24 days, in comparison to 4.40-fold increase for X-ray beams treatment alone. Meanwhile, the in vitro interstitial radiotherapy experiments demonstrated that the cell inhibiting effect of P-32 interstitial radiotherapy combined with BMSNs (50 MUg/mL) was 1.55-fold higher than that of P-32 alone. Significantly, it is notable that the simultaneous chemo- and interstitial radiotherapy based on BMSNs could tremendously increase the therapeutic effect compared to those treatment alone. More importantly, the in vivo P-32 radiotherapy in conjunction with BMSNs was proved to present a significantly eradication of the tumor volumes by an average of 21% reduction to its initial values, in comparison to 2.01-fold increase in case of P-32 treatment alone. Thus, it is expected that the BMSNs could be applied as a highly efficient multifunctional nanosystem to realize the enhanced chemo- and radiotherapy in the further clinical applications. PMID- 25453973 TI - Telodendrimer nanocarrier for co-delivery of paclitaxel and cisplatin: A synergistic combination nanotherapy for ovarian cancer treatment. AB - Cisplatin (CDDP) and paclitaxel (PTX) are two established chemotherapeutic drugs used in combination for the treatment of many cancers, including ovarian cancer. We have recently developed a three-layered linear-dendritic telodendrimer micelles (TM) by introducing carboxylic acid groups in the adjacent layer via "thio-ene" click chemistry for CDDP complexation and conjugating cholic acids via peptide chemistry in the interior layer of telodendrimer for PTX encapsulation. We hypothesize that the co-delivery of low dosage PTX with CDDP could act synergistically to increase the treatment efficacy and reduce their toxic side effects. This design allowed us to co-deliver PTX and CDDP at various drug ratios to ovarian cancer cells. The in vitro cellular assays revealed strongest synergism in anti-tumor effects when delivered at a 1:2 PTX/CDDP loading ratio. Using the SKOV-3 ovarian cancer xenograft mouse model, we demonstrate that our co encapsulation approach resulted in an efficient tumor-targeted drug delivery, decreased cytotoxic effects and stronger anti-tumor effect, when compared with free drug combination or the single loading TM formulations. PMID- 25453974 TI - Near-infrared labeled, ovalbumin loaded polymeric nanoparticles based on a hydrophilic polyester as model vaccine: In vivo tracking and evaluation of antigen-specific CD8(+) T cell immune response. AB - Particulate antigen delivery systems aimed at the induction of antigen-specific T cells form a promising approach in immunotherapy to replace pharmacokinetically unfavorable soluble antigen formulations. In this study, we developed a delivery system using the model protein antigen ovalbumin (OVA) encapsulated in nanoparticles based on the hydrophilic polyester poly(lactide-co hydroxymethylglycolic acid) (pLHMGA). Spherical nanoparticles with size 300-400 nm were prepared and characterized and showed a strong ability to deliver antigen to dendritic cells for cross-presentation to antigen-specific T cells in vitro. Using near-infrared (NIR) fluorescent dyes covalently linked to both the nanoparticle and the encapsulated OVA antigen, we tracked the fate of this formulation in mice. We observed that the antigen and the nanoparticles are efficiently co-transported from the injection site to the draining lymph nodes, in a more gradual and durable manner than soluble OVA protein. OVA-loaded pLHMGA nanoparticles efficiently induced antigen cross-presentation to OVA-specific CD8+ T cells in the lymph nodes, superior to soluble OVA vaccination. Together, these data show the potential of pLHMGA nanoparticles as attractive antigen delivery vehicles. PMID- 25453975 TI - Cross-talk between TGF-beta/SMAD and integrin signaling pathways in regulating hypertrophy of mesenchymal stem cell chondrogenesis under deferral dynamic compression. AB - The molecular mechanisms of mechanotransduction in regulating mesenchymal stem cell (MSC) chondrogenesis are not fully understood and represent an area of growing investigation. In this study, human MSC was subjected to chondrogenic differentiation in chitosan-coated poly L-lactide-co-E-caprolactone scaffolds under free swelling or deferral dynamic compression conditions. The effect of deferral dynamic compression to MSC chondrogenesis and late stage hypertrophy development was investigated, and the involvement of TGF-beta/SMAD pathway and integrin beta1 signaling was analyzed. Deferral dynamic compression enhanced cartilage formation and suppressed chondrocyte hypertrophy. Differential cell morphology and cytoskeletal organization were induced under dynamic compression, together with the activation of TGF-beta/Activin/Nodal and suppression of the BMP/GDP signaling. This was accompanied by the repression of integrin/FAK/ERK signaling in the non-hypertrophic cells when compared to the free swelling samples. Inhibition studies blocking TGF-beta/Activin/Nodal signaling heightened hypertrophy, activate BMP/SMAD1/5/8 and integrin signaling, while inhibition of integrin-ECM interaction suppressed hypertrophy and activate TGF-beta/SMAD2/3 in the free-swelling samples. This study demonstrates the roles of TGF-beta/SMAD and integrin signaling, and suggests cross-talk between these two signaling pathways, in regulating the compression-driven hypertrophy development. PMID- 25453976 TI - Combining an optical resonance biosensor with enzyme activity kinetics to understand protein adsorption and denaturation. AB - Understanding protein adsorption and resultant conformation changes on modified and unmodified silicon dioxide surfaces is a subject of keen interest in biosensors, microfluidic systems and for medical diagnostics. However, it has been proven difficult to investigate the kinetics of the adsorption process on these surfaces as well as understand the topic of the denaturation of proteins and its effect on enzyme activity. A highly sensitive optical whispering gallery mode (WGM) resonator was used to study a catalytic enzyme's adsorption processes on different silane modified glass substrates (plain glass control, DETA, 13 F, and SiPEG). The WGM sensor was able to obtain high resolution kinetic data of glucose oxidase (GO) adsorption with sensitivity of adsorption better than that possible with SPR. The kinetic data, in combination with a functional assay of the enzyme activity, was used to test hypotheses on adsorption mechanisms. By fitting numerical models to the WGM sensograms for protein adsorption, and by confirming numerical predictions of enzyme activity in a separate assay, we were able to identify mechanisms for GO adsorption on different alkylsilanes and infer information about the adsorption of protein on nanostructured surfaces. PMID- 25453978 TI - Interactions between adiponectin, visfatin, and omentin in subcutaneous and visceral adipose tissues and serum, and correlations with clinical and peripheral metabolic factors. AB - Adiponectin, visfatin, and omentin are adipokines involved in insulin sensitivity. This study aimed to determine interactions between these adipokines in subcutaneous and visceral fat and in serum, and their associations with clinical factors. Adiponectin was present at the highest levels in subcutaneous and visceral fat and serum. Subcutaneous adiponectin showed positive correlations with serum adiponectin and the quantitative insulin sensitivity check index (QUICKI). Serum adiponectin correlated positively with QUICKI and serum omentin-1 but negatively with body weight, BMI, and homeostasis model assessment of insulin resistance (HOMA-IR). Subcutaneous omentin correlated positively with QUICKI but negatively with waist and hip circumferences. Serum omentin-1 correlated positively with QUICKI but negatively with body weight, BMI, waist and hip circumferences, weight gain, and HOMA-IR. Serum visfatin correlated positively with serum omentin-1 and negatively with weight gain. Serum peptide YY (PYY) levels were correlated positively with subcutaneous visfatin but negatively with visceral visfatin. Positive correlations were observed between subcutaneous expression of adiponectin, visfatin, and omentin and visceral expression of these genes. Multiple linear regression analysis showed that serum adiponectin was associated with BMI and QUICKI. Serum omentin-1 could be predicted from BMI, QUICKI, and weight gain. Weight gain, serum adiponectin, omentin-1, and DBP could be used to predict serum visfatin. In conclusion, adiponectin and omentin from subcutaneous fat displayed correlations with decreased obesity and increased insulin sensitivity while visfatin showed an association with serum PYY and weight gain. The expressions of these adipokines were correlated within each type of fat but not between different fat depots. PMID- 25453979 TI - Myristic acid conjugation of [D-Leu-4]-OB3, a biologically active leptin-related synthetic peptide amide, significantly improves its pharmacokinetic profile and efficacy. AB - We have previously described the pharmacokinetics of mouse [D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, following delivery by subcutaneous (SC), intraperitoneal (IP), and intramuscular (IM) injection, and by oral gavage and intranasal instillation. These profiles suggested that the observed efficacy of [D-Leu-4]-OB3 on energy balance, glycemic control, and bone turnover in ob/ob and db/db mice might be improved by efforts directed toward improving its bioavailability, i.e., increasing maximum uptake (Cmax), extending serum half-life (t1/2), and reducing plasma clearance (CL). To address these issues, myristic (tetradecanoic) acid was conjugated to the N-terminal of [D-Leu 4]-OB3 (designated MA-[D-Leu-4]-OB3), and the pharmacokinetics of MA-[D-Leu-4] OB3 in male Swiss Webster mice following SC, IP, and IM injection in PBS, and by oral and intranasal delivery in dodecyl maltoside (DDM, trade name Intravail(r)), a transmucosal absorption enhancing agent, were compared to those of [D-Leu-4] OB. At a dose of MA-[D-Leu-4]-OB3 10-fold lower than that used previously for [D Leu-4]-OB3 (0.1 mg vs.1.0 mg, respectively), Cmax of MA-[D-Leu-4]-OB3 was 11.1-, 7.5-, 1.9-, and 1.7-fold higher, t1/2 was 3.5-, 5.0-, 9.1-, and 86.7-fold longer, and CL was 17.0-, 11.6-, 5.7-, and 5.0-fold slower than [D-Leu-4]-OB3 following SC, IP, IM, and oral delivery, respectively. Furthermore, in leptin-resistant obese male db/db mice, oral delivery of MA-[D-Leu-4]-OB3 in DDM at concentrations up to 10-fold lower than those used with [D-Leu-4]-OB3 reduced fasting blood glucose levels in a dose-related manner. PMID- 25453977 TI - Tuning PEGylation of mixed micelles to overcome intracellular and systemic siRNA delivery barriers. AB - A series of endosomolytic mixed micelles was synthesized from two diblock polymers, poly[ethylene glycol-b-(dimethylaminoethyl methacrylate-co propylacrylic acid-co-butyl methacrylate)] (PEG-b-pDPB) and poly[dimethylaminoethyl methacrylate-b-(dimethylaminoethyl methacrylate-co propylacrylic acid-co-butyl methacrylate)] (pD-b-pDPB), and used to determine the impact of both surface PEG density and PEG molecular weight on overcoming both intracellular and systemic siRNA delivery barriers. As expected, the percent PEG composition and PEG molecular weight in the corona had an inverse relationship with mixed micelle zeta potential and rate of cellular internalization. Although mixed micelles were internalized more slowly, they generally produced similar gene silencing bioactivity (~ 80% or greater) in MDA-MB-231 breast cancer cells as the micelles containing no PEG (100 D/no PEG). The mechanistic explanation for the potent bioactivity of the promising 50 mol% PEG-b-DPB/50 mol% pD-b-pDPB (50 D) mixed micelle formulation, despite its relatively low rate of cellular internalization, was further investigated as a function of PEG molecular weight (5 k, 10 k, or 20 k PEG). Results indicated that, although larger molecular weight PEG decreased cellular internalization, it improved cytoplasmic bioavailability due to increased intracellular unpackaging (quantitatively measured via FRET) and endosomal release. When delivered intravenously in vivo, 50 D mixed micelles with a larger molecular weight PEG in the corona also demonstrated significantly improved blood circulation half-life (17.8 min for 20 k PEG micelles vs. 4.6 min for 5 kDa PEG micelles) and a 4-fold decrease in lung accumulation. These studies provide new mechanistic insights into the functional effects of mixed micelle-based approaches to nanocarrier surface PEGylation. Furthermore, the ideal mixed micelle formulation identified (50 D/20 k PEG) demonstrated desirable intracellular and systemic pharmacokinetics and thus has strong potential for in vivo therapeutic use. PMID- 25453980 TI - The role of renin-angiotensin system modulation on treatment and prevention of liver diseases. AB - The renin-angiotensin system (RAS) is now recognized as an important modulator of body metabolic processes. The discovery of angiotensin-converting enzyme 2 (ACE2) has renewed interest in the potential therapeutic role of RAS modulation. Recent studies have pointed out the importance of the local balance between ACE/Ang II/AT1 and ACE2/Ang-(1-7)/Mas arms to avoid liver metabolic diseases. Furthermore, non-alcoholic fatty liver disease is an increasing health problem that includes a spectrum of hepatic steatosis, steatohepatitis and fibrosis. Some new studies revealed that RAS imbalance appears to promote hepatic fibrogenesis; while the activation of ACE2/Ang-(1-7)/Mas counter-regulatory axis is able to prevent liver injuries. In this context, the aim of the present review is to discuss the importance of RAS in the development and prevention of liver disease. AT1 receptor activation by Ang II induces hepatic stellate cell contraction and proliferation, causes oxidative stress, endothelial dysfunction, cell growth and inflammation. In addition, both AT1 blocker administration and ACE inhibitors lead to a reduction in inflammation and improvement of hepatic fibrosis. Conversely, Ang-(1-7) infusion reduces fibrosis and proliferation mainly by suppression of hepatic stellate cell activation; Mas receptor antagonism aggravates liver fibrosis and severe liver steatosis. In conclusion, the use of ACE/Ang II/AT1 axis inhibitors associated with ACE2/Ang(1-7)/Mas axis activation is a promising new strategy serving as a novel therapeutic regimen to prevent and treat chronic liver diseases as well as acute liver injury. PMID- 25453981 TI - The non-opioid receptor, antioxidant properties of morphine and the opioid peptide analog biphalin. AB - Opioids participate in a broad spectrum of regulatory effects. The discovery of the opioid receptor system led to the initial belief that all of the observed effects in this system were associated with receptor activation. However, it must be considered that certain opioid properties are the result of the properties of other chemicals and their distribution. The presence of a tyramine moiety in opioids is suggestive of their potential antioxidant properties. Therefore, this study evaluated the antioxidant properties of opioids that are not related to opioid receptor activation. The morphine antioxidant capacity (IC50=81MUM) was 2.8 times lower than that of the reference ascorbic acid (IC50=29MUM). Surprisingly, the biphalin antioxidant capacity (IC50=8MUM) was 3.6 times higher than that of ascorbic acid and over 10 times higher than that of morphine. This unexpectedly high biphalin antioxidant capacity correlates with its neuroprotective properties. PMID- 25453983 TI - Senescent retinal pigment epithelial cells are more sensitive to vascular endothelial growth factor: implications for "wet" age-related macular degeneration. AB - PURPOSE: Senescence of the retinal pigment epithelial (RPE) cell layer has been implicated in the occurrence of age-related macular degeneration (AMD). The present study examines whether the ability of vascular endothelial growth factor (VEGF) to decrease the barrier function of RPE cells is enhanced in senescent RPE cells, which could contribute to the pathology of "wet" AMD. METHODS: Low or high population doubling level (PDL) range ARPE-19 human RPE cells were cultured in 6 well plates on membrane-containing inserts. After 2 weeks, the cells were treated with either VEGF or its vehicle and their transepithelial electrical resistance (TEER) was measured. One week later, the cells were stained for senescence associated beta-galactosidase (SABG) activity. RESULTS: VEGF was significantly more effective in reducing the TEER of the high PDL ARPE-19 cell layers than the low PDL layers (25% decrease vs. 6% decrease; t-test, P=0.0013). The low PDL cell layers had a modest uniform level of SABG staining. In contrast, the high PDL layers displayed darker and more mottled SABG staining indicative of the presence of senescent cells. CONCLUSIONS: The present results show that the ability of VEGF to reduce the barrier function of RPE cell layers is greater in high PDL layers, which display signs of senescence, than in low PDL layers. Senescence induced changes in the responsiveness of RPE cell layers to VEGF could contribute to the pathology of AMD. Agents that strengthen the barrier properties of RPE cells or reduce their responsiveness to VEGF could be effective in treating "wet" AMD. PMID- 25453982 TI - Mitochondrial cholesterol accumulation in alcoholic liver disease: Role of ASMase and endoplasmic reticulum stress. AB - Alcoholic liver disease (ALD) is a major cause of chronic liver disease and a growing health concern in theworld. While the pathogenesis of ALD is poorly characterized key players identified in experimental models and patients, such as perturbations in mitochondrial structure and function, selective loss of antioxidant defense and susceptibility to inflammatory cytokines, contribute to ALD progression. Both oxidative stress and mitochondrial dysfunction compromise essential cellular functions and energy generation and hence are important pathogenic mechanisms of ALD. An important process mediating the mitochondrial disruption induced by alcohol intake is the trafficking of cholesterol to mitochondria, mediated by acid sphingomyelinase-induced endoplasmic reticulum stress, which contributes to increased cholesterol synthesis and StARD1upregulation. Mitochondrial cholesterol accumulation not only sensitizes to oxidative stress but it can contribute to the metabolic reprogramming in ALD, manifested by activation of the hypoxia inducible transcription factor 1 and stimulation of glycolysis and lactate secretion. Thus, a better understanding of the mechanisms underlying alcohol-mediated mitochondrial impairment and oxidative stress may lead to the identification of novel treatments for ALD. The present review briefly summarizes current knowledge on the cellular and molecular mechanisms contributing to alcohol-induced mitochondrial dysfunction and cholesterol accumulation and provides insights for potential therapeutic targets in ALD. PMID- 25453984 TI - "Beauty is a light in the heart": the transformative potential of optogenetics for clinical applications in cardiovascular medicine. AB - Optogenetics is an exciting new technology in which viral gene or cell delivery is used to inscribe light sensitivity in excitable tissue to enable optical control of bioelectric behavior. Initial progress in the fledgling domain of cardiac optogenetics has included in vitro expression of various light-sensitive proteins in cell monolayers and transgenic animals to demonstrate an array of potentially useful applications, including light-based pacing, silencing of spontaneous activity, and spiral wave termination. In parallel to these developments, the cardiac modeling community has developed a versatile computational framework capable of realistically simulating optogenetics in biophysically detailed, patient-specific representations of the human heart, enabling the exploration of potential clinical applications in a predictive virtual platform. Toward the ultimate goal of assessing the feasibility and potential impact of optogenetics-based therapies in cardiovascular medicine, this review provides (1) a detailed synopsis of in vivo, in vitro, and in silico developments in the field and (2) a critical assessment of how existing clinical technology for gene/cell delivery and intra-cardiac illumination could be harnessed to achieve such lofty goals as light-based arrhythmia termination. PMID- 25453986 TI - Update on transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) is currently the treatment modality of choice for patients with symptomatic severe aortic stenosis who are inoperable or at high risk for surgical aortic valve replacement. TAVR has shown a clear mortality benefit compared to conservative treatment in inoperable patients and is at least non-inferior to surgical aortic valve replacement in high-risk operable patients. Through improvements in pre-procedural imaging, refinement in valve technologies, increasing operator and team experience, and continuous valuable research, TAVR has developed rapidly in the past few years and is expected to further boost in the near future. In this review, we highlight the current status of TAVR, summarize recent updates, and discuss briefly the future expectations of this rapidly evolving technology. PMID- 25453987 TI - Seeing is believing: new updates on coronary microvascular dysfunction. PMID- 25453988 TI - A genetic basis for coronary artery disease. AB - CAD and cancer account for over one-half of all deaths in the world. It is claimed that the 21st century is the last century for CAD. This is, in part, because CAD is preventable based on randomized, placebo-controlled clinical trials, which show modifying known risk factors such as cholesterol is associated consistently with 40-60% reduction in morbidity and mortality from CAD. Comprehensive prevention will require modifying genetic risk factors that are claimed to account for 40-60% of predisposition to CAD. The 21st century is meeting this challenge with over 50 genetic risk variants discovered and replicated in large genome-wide association studies involving over 200,000 cases and controls. Similarly, 157 genetic variants have been discovered that regulate plasma lipids including, LDL-C, HDL-C, triglycerides, and total cholesterol. A major finding from these studies is that only 15 of the 50 genetic variants for CAD act through known risk factors. Hence, the pathogenesis of CAD in addition to cholesterol and other known risk factors is due to various other factors, many of which remain unknown. Secondly, genes regulating the plasma triglyceride levels are strongly associated with the pathogenesis of CAD. Thirdly, Mendelian randomization studies show no protection from genes that increase plasma HDL cholesterol. This is contrary to current opinion. These genetic risk variants have provided new targets for the development of novel therapies to prevent CAD. Already a new and potent drug has been developed targeting PCSK9, which is in phase 3 clinical trials and shows great efficacy and safety for prevention of CAD. The 21st century is looking very bright for the prevention of CAD. PMID- 25453985 TI - Ischemic heart disease in women: a focus on risk factors. AB - Heart disease remains a major contributor to morbidity and mortality in women in the United States and worldwide. This review highlights known and emerging risk factors for ischemic heart disease (IHD) in women. Traditional Framingham risk factors such as hypertension, hyperlipidemia, diabetes, smoking, as well as lifestyle habits such as unhealthy diet and sedentary lifestyle are all modifiable. Health care providers should be aware of emerging cardiac risk factors in women such as adverse pregnancy outcomes, systemic autoimmune disorders, obstructive sleep apnea, and radiation-induced heart disease; psychosocial factors such as mental stress, depression, anxiety, low socioeconomic status, and work and marital stress play an important role in IHD in women. Appropriate recognition and management of an array of risk factors is imperative given the growing burden of IHD and need to deliver cost-effective, quality care for women. PMID- 25453989 TI - Fractional anisotropy in individuals with schizophrenia and their nonpsychotic siblings. AB - Fractional anisotropy (FA) was examined in a priori selected fiber tracts in individuals with schizophrenia (n=25) and their non-psychotic siblings (n=29) versus controls (n=35). FA was reduced in a portion of the fornix in individuals with schizophrenia (although this did not survive correction for the number of tracts investigated). FA in the siblings did not differ from that in controls in any of the investigated tracts. PMID- 25453990 TI - High frequency rTMS; a more effective treatment for auditory verbal hallucinations? AB - The great majority of studies on repetitive transcranial magnetic stimulation (rTMS) as a therapeutic tool for auditory verbal hallucinations (AVH) have used 1 Hz stimulation with inconsistent results. Recently, it has been suggested that 20 Hz rTMS has strong therapeutic effects. It is conceivable that this 20-Hz stimulation is more effective than 1-Hz stimulation. The aim of this preliminary study is to investigate the efficacy of 20-Hz rTMS compared with 1-Hz rTMS as a treatment for AVH. Eighteen schizophrenia patients with medication-resistant AVH were randomized over two treatment groups. Each group received either 20 min of 1 Hz rTMS or 13 trains of 20-Hz rTMS daily over 1 week. After week 1, patients received a follow-up treatment once a week for 3 weeks. Stimulation location was based on individual AVH-related activation patterns identified with functional magnetic resonance imaging. Severity of AVH was monitored with the Auditory Hallucination Rating Scale (AHRS). Both groups showed a decrease in AVH after week 1 of rTMS. This decrease was significant for the 20-Hz group and the 1-Hz group. When the two treatment types were compared, no treatment type was superior. Based on these results we cannot conclude whether high frequency rTMS is more effective against AVH than is traditional 1-Hz rTMS. More research is needed to optimize stimulation parameters and to investigate potential target locations for stimulation. PMID- 25453992 TI - Left frontal lobe hypoperfusion and depressive symptoms in Alzheimer's disease patients taking cholinesterase inhibitors. AB - Depressive symptoms are common in patients with Alzheimer's disease (AD) and increase the caregiver burden. Many studies have reported dorsolateral prefrontal hypometabolism or hypoperfusion in AD patients with depressive symptoms, most of whom did not take acetylcholinesterase inhibitors (AChEI). It is not clear, however, whether a similar condition is present in patients taking AChEI medication. Fifty-seven consecutive AD patients taking AChEI were recruited at a memory clinic. Objective depressive symptoms were evaluated using the depression domain of the Neuropsychiatric Inventory (NPI-dep). All patients underwent brain single photon emission computed tomography (SPECT) with (99m)Tc-ethylcysteinate dimer, and the SPECT images were analyzed using the Statistical Parametric Mapping 8 program. No significant differences between groups with positive and negative NPI-dep scores were found with respect to age, sex, years of education, and cognitive function. Compared with patients with negative NPI-dep scores, patients with NPI-dep scores >=1 showed significant hypoperfusion in the left middle frontal region. Our results indicate that the dorsolateral prefrontal area is significantly involved in the pathogenesis of depressive symptoms in AD patients being treated with AChEI. The area on the left side especially may be closely related to the depressive symptoms evaluated using the NPI. PMID- 25453991 TI - Cognitive and structural neuroimaging characteristics of schizophrenia patients with large, rare copy number deletions. AB - Large (>500 Kb), rare (frequency <1%) deletions are associated with risk for schizophrenia. The aim of the study was to characterise patients with these deletions using measures of cognition, grey-matter volume and white-matter integrity. Patients with schizophrenia and large, rare deletions (SZ-del) (n=17) were assessed on a test of intelligence, the Wechsler Abbreviated Scale of Intelligence (WASI), and compared with age- and sex-matched schizophrenia patients without large, rare deletions (SZ-nodel) (n=65), and healthy controls (HCs) (n=50). Regional grey-matter differences were investigated using voxel based morphometry (SZ-del=9; SZ-nodel=26; HC=19). White-matter integrity was assessed using fractional anisotropy (SZ-del=9; SZ-nodel=24; HC=15). Compared with schizophrenia patients without large, rare deletions, those with large, rare deletions had lower IQ; greater grey-matter volume in clusters with peaks in the left and right cerebellum, left hippocampus, and right rectal gyrus; and increased white-matter anisotropy in the body and genu of the corpus callosum. Compared with healthy controls, patients with large, rare deletions had reduced grey matter volume in the right calcarine gyrus. In sum, patients with large, rare deletions had structural profiles intermediate to those observed in healthy controls and schizophrenia patients without large, rare deletions, but had greater impairment in intelligence. PMID- 25453993 TI - Dietary and fluid restrictions in CKD: a thematic synthesis of patient views from qualitative studies. AB - BACKGROUND: Managing the complex fluid and diet requirements of chronic kidney disease (CKD) is challenging for patients. We aimed to summarize patients' perspectives of dietary and fluid management in CKD to inform clinical practice and research. STUDY DESIGN: Systematic review of qualitative studies. SETTING & POPULATION: Adults with CKD who express opinions about dietary and fluid management. SEARCH STRATEGY & SOURCES: MEDLINE, EMBASE, PsycINFO, CINAHL, Google Scholar, reference lists, and PhD dissertations were searched to May 2013. ANALYTICAL APPROACH: Thematic synthesis. RESULTS: We included 46 studies involving 816 patients living in middle- to high-income countries. Studies involved patients treated with facility-based and home hemodialysis (33 studies; 462 patients), peritoneal dialysis (10 studies; 112 patients), either hemodialysis or peritoneal dialysis (3 studies; 73 patients), kidney transplant recipients (9 studies; 89 patients), and patients with non-dialysis-dependent CKD stages 1 to 5 (5 studies; 80 patients). Five major themes were identified: preserving relationships (interference with roles, social limitations, and being a burden), navigating change (feeling deprived, disrupting held truths, breaking habits and norms, being overwhelmed by information, questioning efficacy, and negotiating priorities), fighting temptation (resisting impositions, experiencing mental invasion, and withstanding physiologic needs), optimizing health (accepting responsibility, valuing self-management, preventing disease progression, and preparing for and protecting a transplant), and becoming empowered (comprehending paradoxes, finding solutions, and mastering change and demands). LIMITATIONS: Limited data in non-English languages and low-income settings and for adults with CKD not treated with hemodialysis. CONCLUSIONS: Dietary and fluid restrictions are disorienting and an intense burden for patients with CKD. Patient-prioritized education strategies, harnessing patients' motivation to stay well for a transplant or to avoid dialysis, and viewing adaptation to restrictions as a collaborative journey are suggested strategies to help patients adjust to dietary regimens in order to reduce their impact on quality of life. PMID- 25453994 TI - Effect of CKD and dialysis modality on exposure to drugs cleared by nonrenal mechanisms. AB - BACKGROUND: Patients with kidney disease frequently experience adverse effects from medication exposure, even when drugs are cleared by nonrenal pathways. Although many studies suggest that nonrenal drug clearance is decreased in chronic kidney disease (CKD), there remains a paucity of in vivo studies in patients with varying degrees of decreased kidney function and those comparing the impact of dialysis modality (eg, hemodialysis [HD] and peritoneal dialysis [PD]). STUDY DESIGN: We performed in vivo clinical pharmacokinetic studies of midazolam, a nonrenally cleared specific probe for CYP3A4, and fexofenadine, a nonspecific probe for hepatic and intestinal transporters. SETTING & PARTICIPANTS: Healthy controls (n=8), patients with non-dialysis-dependent (NDD) CKD (n=8), and patients receiving HD (n=10) or PD (n=8). OUTCOMES: Exposure to midazolam and fexofenadine were quantified using area under the curve (AUC). Comprehensive pharmacokinetic parameters also were calculated for both probes. RESULTS: Midazolam AUC was significantly higher in the HD group (382.8 h.ng/mL) than in the healthy-control (63.0 h.ng/mL; P<0.001), NDD-CKD (84.5 h.ng/mL; P=0.002), and PD (47.4 h.ng/mL; P<0.001) groups. Fexofenadine AUC was significantly higher in each of the NDD-CKD (2,950 h.ng/mL; P=0.003), HD (2,327 h.ng/mL; P=0.01), and PD (2,095 h.ng/mL; P=0.04) groups compared with healthy controls (1,008 h.ng/mL). LIMITATIONS: Small study groups had different proportions of diabetic patients, early stages of CKD not available. CONCLUSIONS: Our data suggest that selection of dialysis modality is a major determinant of exposure to the CYP3A4 probe midazolam. Exposure to the intestinal and hepatic transporter probe fexofenadine is altered in patients with NDD-CKD and PD and HD patients. Thus, drug development and licensing of nonrenally cleared drugs should include evaluation in these 3 patient groups, with these results included in approved product information labeling. This reinforces the critical need for more in vivo studies of humans that evaluate the exposure to drugs cleared by these pathways. PMID- 25453995 TI - Vitamin K status and mortality after kidney transplantation: a cohort study. AB - BACKGROUND: Vitamin K modulates calcification by activating calcification inhibitors such as matrix Gla protein (MGP). In kidney transplant recipients, vitamin K insufficiency is common, but implications for long-term outcomes are unclear. STUDY DESIGN: Single-center observational study with a longitudinal design. SETTING & PARTICIPANTS: 518 stable kidney transplant recipients; 56% men; mean age, 51+/-12 (SD) years; and a median of 6 (IQR, 3-12) years after kidney transplantation. FACTOR: Plasma desphosphorylated-uncarboxylated MGP (dp-ucMGP) levels, reflecting vitamin K status. OUTCOMES: All-cause mortality and transplant failure. RESULTS: At inclusion, median dp-ucMGP level was 1,038 (IQR, 733-1,536) pmol/L, with 473 (91%) patients having vitamin K insufficiency (defined as dp ucMGP>500pmol/L). During a median follow-up of 9.8 (IQR, 8.5-10.2) years, 152 (29%) patients died and 54 (10%) developed transplant failure. Patients in the highest quartile of dp-ucMGP were at considerably higher mortality risk compared with patients in the lowest quartile (HR, 3.10; 95% CI, 1.87-5.12; P for trend<0.001; P for quartile 1 [Q1] vs Q4<0.001). After adjustment for potential confounders, including kidney function and exclusion of patients treated with a vitamin K antagonist, this association remained significant. Patients in the highest quartile also were at higher risk of developing transplant failure (HR, 2.61; 95% CI, 1.22-5.57; P for trend=0.004; P for Q1 vs Q4=0.01), but this association was lost after adjustment for baseline kidney function (HR, 1.20; 95% CI, 0.52-2.75; P for trend=0.6; P for Q1 vs Q4=0.7). LIMITATIONS: Although MGP exists as various species, only dp-ucMGP was measured. No data were available for vascular calcification as an intermediate end point. CONCLUSIONS: Vitamin K insufficiency, that is, a high circulating level of dp-ucMGP, is highly prevalent in stable kidney transplant recipients and is associated independently with increased risk of mortality. Future studies should address whether vitamin K supplementation may lead to improved outcomes after kidney transplantation. PMID- 25453997 TI - Introducing the well-being of adolescents in vulnerable environments study: methods and findings. PMID- 25453996 TI - Mineral metabolism and the right ventricle: the Multi-Ethnic Study of Atherosclerosis (MESA). PMID- 25453998 TI - A global study on the influence of neighborhood contextual factors on adolescent health. AB - PURPOSE: This study uses data collected as part of the Well-Being of Adolescents in Vulnerable Environments study to (1) compare the perceptions of neighborhood level factors among adolescents across five different urban sites; (2) examine the associations between factors within the physical and social environments; and (3) examine the influence of neighborhood-level factors on two different health outcomes-violence victimization in the past 12 months and ever smoked. METHODS: Across five urban sites (Baltimore, New Delhi, Johannesburg, Ibadan, and Shanghai), 2,320 adolescents aged 15-19 years completed a survey using audio computer-assisted self-interview technology. To recruit adolescents, each site used a respondent-driven sampling method, which consisted of selecting adolescents as "seeds" to serve as the initial contacts for recruiting the entire adolescent sample. All analyses were conducted with Stata 13.1 statistical software, using complex survey design procedures. To examine associations between neighborhood-level factors and among our two outcomes, violence victimization and ever smoked, bivariate and multivariate analyses were conducted. RESULTS: Across sites, there was great variability in how adolescents perceived their neighborhoods. Overall, adolescents from Ibadan and Shanghai held the most positive perceptions about their neighborhoods, whereas adolescents from Baltimore and Johannesburg held the poorest. In New Delhi, despite females having positive perceptions about their safety and sense of social cohesion, they had the highest sense of fear and the poorest perceptions about their physical environment. The study also found that one of the most consistent neighborhood level factors across sites and outcomes was witnessing community violence, which was significantly associated with smoking among adolescents in New Delhi and Johannesburg and with violence victimization across nearly every site except Baltimore. No other neighborhood-level factor exerted greater influence. CONCLUSIONS: This study confirms the important associations between perceptions of a neighborhood and adolescent health. At the same time, it demonstrates that not all neighborhood-level factors are associated with adolescent health outcomes in the same way across different urban contexts. Further longitudinal research is needed to examine the direction of causation between adolescent health neighborhood contexts and health outcomes and the reasons for why different urban contexts may exert varying levels of influence on the health of adolescents. PMID- 25453999 TI - Social capital and vulnerable urban youth in five global cities. AB - PURPOSE: Social capital is essential for the successful development of young people. The current study examines direct measures of social capital in young people in five urban global contexts. METHODS: The Well-Being of Adolescents in Vulnerable Environments is a global study of young people aged 15-19 years living in disadvantaged, urban settings. Respondent-driven sampling was used to recruit approximately 500 participants from each site. The sample included 2,339 young people (mean age 16.7 years; 47.5% female). We examined the associations between social capital in four domains-family, school, peers, and neighborhood and demographic characteristics-using gender-stratified ordinary least-squares regression. We also examined associations between self-reported health and the four social capital domains, which was minimal. RESULTS: School enrollment was positively associated with social capital for young women in Baltimore, Delhi, and Shanghai; the association was less consistent for young men. The same pattern is true for perceived wealth. Unstable housing was associated with low familial social capital in all groups except young women in Shanghai and young men in Ibadan and Johannesburg. Being raised outside a two-parent family has a widespread, negative association with social capital. Self-reported health had a mainly positive association with social capital with the most consistent association being neighborhood social capital. CONCLUSIONS: Different types of social capital interact with social contexts and gender differently. Strategies that aim to build social capital as part of risk reduction and positive youth development programming need to recognize that social capital enhancement may work differently for different groups and in different settings. PMID- 25454000 TI - The association between social support and mental health among vulnerable adolescents in five cities: findings from the study of the well-being of adolescents in vulnerable environments. AB - PURPOSE: Globally, adolescents are at risk of depression, traumatic stress, and suicide, especially those living in vulnerable environments. This article examines the mental health of 15- to 19-year-old youth in five cities and identifies the social support correlates of mental health. METHODS: A total of 2,393 adolescents aged 15-19 years in economically distressed neighborhoods in Baltimore, MD; New Delhi, India; Ibadan, Nigeria; Johannesburg, South Africa; and Shanghai, China were recruited in 2013 via respondent-driven sampling to participate in a survey using an audio computer-assisted self-interview. Weighted logistic regression and general linear models were used to explore the associations between mental health and social supports. RESULTS: The highest levels of depression and posttraumatic stress symptoms were displayed in Johannesburg among females (44.6% and 67.0%, respectively), whereas the lowest were among New Delhi females and males (13.0% and 16.3%, respectively). The prevalence of suicidal ideation ranged from 7.9% (New Delhi female adolescents) to 39.6% (Johannesburg female adolescents); the 12-month prevalence of suicide attempts ranged from 1.8% (New Delhi females) to 18.3% (Ibadan males). Elevated perceptions of having a caring female adult in the home and feeling connected to their neighborhoods were positively associated with adolescents' levels of hope across the sites while negatively associated with depression and posttraumatic stress symptoms with some variation across sites and gender. CONCLUSIONS: Adolescents living in the very economically distressed areas studied register high levels of depression and posttraumatic stress. Improving social supports in families and neighborhoods may alleviate distress and foster hope. In particular, strengthening supports from female caretakers to their adolescents at home may improve the outlooks of their daughters. PMID- 25454001 TI - Predictors of substance use among vulnerable adolescents in five cities: findings from the well-being of adolescents in vulnerable environments study. AB - PURPOSE: Adolescent substance use has numerous consequences. Our goals in this article are to compare the prevalence and correlates of substance use among ethnically diverse adolescents. METHODS: Data were from 2,332 adolescents aged 15 19 years recruited via respondent-driven sampling from disadvantaged settings in five cities. Multivariate logistic regression was used to identify correlates of current substance use. RESULTS: About half of the respondents were male. Most adolescents (73.4%) were currently enrolled in school and identified a father (86.2%) and mother (98.6%) figure and strong peer support. Sixty-two percent reported lifetime use of at least one substance. Overall, the most common substances ever used were alcohol (44.6%), cigarettes (26.2%), and marijuana (17.9%). Mean age at first use of alcohol was 14.2 +/- 3.1 years. Current alcohol use was highest in Johannesburg (47.4%) and lowest in Delhi (2.1%). The mean age at first use of cigarettes was 14.4 +/- 2.8 years. Current cigarette smoking was highest in Johannesburg (32.5%) and lowest in Delhi (3.7%). Male gender predicted current alcohol use in all sites, older age (17-19 years) was also a predictor in Baltimore. Male gender (Johannesburg and Shanghai), older age (Baltimore and Shanghai), and being out of school (Baltimore, Johannesburg, and Shanghai) predicted current cigarette smoking. Absence of a caring father figure was predictive for current alcohol use in Baltimore and Shanghai. Stronger peer support predicted alcohol (Johannesburg and Shanghai) and cigarette use (Johannesburg). CONCLUSIONS: Substance use is still a major issue among adolescents around the world, underscoring the need for continued research and interventions. PMID- 25454002 TI - Distressed communities as a breeding ground for noncommunicable conditions. AB - Recent research has driven home the close relationship between place and health. Geography is often a greater driver of adolescent morbidity and mortality than behavior. To elucidate these relationships, the Well-Being of Adolescents in Vulnerable Environments study has collected and analyzed data on the health and well-being of adolescents' lowest income communities of five cities: Baltimore, United States; Ibadan, Nigeria; Johannesburg, South Africa; New Delhi, India; and Shanghai, China. PMID- 25454006 TI - Chemoprevention and screening for lung cancer: changing our focus to former smokers. AB - Clinical trials of chemoprevention for lung cancer have yielded negative results, with suggested worsening of cancer incidence in those who continue to smoke. Continued smoking over age 55 is associated with decreased longevity and multiple comorbidities. It is possible that clinical trials focusing on former smokers in both prevention and screening trials will yield significant benefit, now masked by the population of continued smokers. PMID- 25454003 TI - Prevalence and determinants of adolescent pregnancy in urban disadvantaged settings across five cities. AB - PURPOSE: The impact of pregnancy on the health and livelihood of adolescents aged 15-19 years is substantial. This study explored sociodemographic, behavioral, and environmental-level factors associated with adolescent pregnancy across five urban disadvantaged settings. METHODS: The Well-Being of Adolescents in Vulnerable Environments study used respondent-driven sampling (RDS) to recruit males and females from Baltimore (456), Johannesburg (496), Ibadan (449), New Delhi (500), and Shanghai (438). RDS-II and poststratification age weights were used to explore the odds associated with "ever had sex" and "ever pregnant"; adjusted odds of pregnancy and 95% confidence interval were developed by site and gender. RESULTS: Among the sexually experienced, pregnancy was most common in Baltimore (females, 53% and males, 25%) and Johannesburg (females, 29% and males 22%). Heterosexual experience and therefore pregnancy were rare in Ibadan, New Delhi, and Shanghai. Current schooling and condom use at the first sex decreased the odds of pregnancy among females in Baltimore and Johannesburg participants. Factors associated with higher odds of pregnancy were early sexual debut (Johannesburg participants and Baltimore females) being raised by someone other than the two parents (Johannesburg females); alcohol use and binge drinking in the past month (Baltimore participants); greater community violence and poor physical environment (Baltimore males and Johannesburg participants). CONCLUSIONS: The reported prevalence of adolescent pregnancy varies substantially across similarly economically disadvantaged urban settings. These differences are related to large differences in sexual experience, which may be underreported, and differences in environmental contexts. Pregnancy risk needs to be understood within the specific context that adolescents reside with particular attention to neighborhood-level factors. PMID- 25454004 TI - Prevalence and Health Impact of Intimate Partner Violence and Non-partner Sexual Violence Among Female Adolescents Aged 15-19 Years in Vulnerable Urban Environments: A Multi-Country Study. AB - PURPOSE: Globally, adolescent women are at risk for gender-based violence (GBV) including sexual violence and intimate partner violence (IPV). Those in economically distressed settings are considered uniquely vulnerable. METHODS: Female adolescents aged 15-19 from Baltimore, Maryland, USA; New Delhi, India; Ibadan, Nigeria; Johannesburg, South Africa; and Shanghai, China (n = 1,112) were recruited via respondent-driven sampling to participate in a cross-sectional survey. We describe the prevalence of past-year physical and sexual IPV, and lifetime and past-year non-partner sexual violence. Logistic regression models evaluated associations of GBV with substance use, sexual and reproductive health, mental health, and self-rated health. RESULTS: Among ever-partnered women, past year IPV prevalence ranged from 10.2% in Shanghai to 36.6% in Johannesburg. Lifetime non-partner sexual violence ranged from 1.2% in Shanghai to 12.6% in Johannesburg. Where sufficient cases allowed additional analyses (Baltimore and Johannesburg), both IPV and non-partner sexual violence were associated with poor health across domains of substance use, sexual and reproductive health, mental health, and self-rated health; associations varied across study sites. CONCLUSIONS: Significant heterogeneity was observed in the prevalence of IPV and non-partner sexual violence among adolescent women in economically distressed urban settings, with upwards of 25% of ever-partnered women experiencing past year IPV in Baltimore, Ibadan, and Johannesburg, and more than 10% of adolescent women in Baltimore and Johannesburg reporting non-partner sexual violence. Findings affirm the negative health influence of GBV even in disadvantaged urban settings that present a range of competing health threats. A multisectoral response is needed to prevent GBV against young women, mitigate its health impact, and hold perpetrators accountable. PMID- 25454005 TI - Respondent-driven sampling for an adolescent health study in vulnerable urban settings: a multi-country study. AB - The global adolescent population is larger than ever before and is rapidly urbanizing. Global surveillance systems to monitor youth health typically use household- and school-based recruitment methods. These systems risk not reaching the most marginalized youth made vulnerable by conditions of migration, civil conflict, and other forms of individual and structural vulnerability. We describe the methodology of the Well-Being of Adolescents in Vulnerable Environments survey, which used respondent-driven sampling (RDS) to recruit male and female youth aged 15-19 years and living in economically distressed urban settings in Baltimore, MD; Johannesburg, South Africa; Ibadan, Nigeria; New Delhi, India; and Shanghai, China (migrant youth only) for a cross-sectional study. We describe a shared recruitment and survey administration protocol across the five sites, present recruitment parameters, and illustrate challenges and necessary adaptations for use of RDS with youth in disadvantaged urban settings. We describe the reach of RDS into populations of youth who may be missed by traditional household- and school-based sampling. Across all sites, an estimated 9.6% were unstably housed; among those enrolled in school, absenteeism was pervasive with 29% having missed over 6 days of school in the past month. Overall findings confirm the feasibility, efficiency, and utility of RDS in quickly reaching diverse samples of youth, including those both in and out of school and those unstably housed, and provide direction for optimizing RDS methods with this population. In our rapidly urbanizing global landscape with an unprecedented youth population, RDS may serve as a valuable tool in complementing existing household- and school-based methods for health-related surveillance that can guide policy. PMID- 25454007 TI - Impact of smoking status on EGFR-TKI efficacy for advanced non-small-cell lung cancer in EGFR mutants: a meta-analysis. AB - BACKGROUND: The strong association between smoking history and the presence of epidermal growth factor receptor (EGFR) mutations has been proven in non-small cell lung cancer (NSCLC), which explains the favorable response to EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy in nonsmoking NSCLC patients. However, few studies directly focus on the relationship between EGFR-TKI's efficacy and smoking history in NSCLC EGFR-mutant patients. METHODS: Electronic databases were searched for eligible literatures. Data on objective response rates, disease control rates, and progression-free survival (PFS) stratified by smoking status were extracted and synthesized on the basis of a random-effect model. Subgroup and sensitivity analyses were conducted. RESULTS: A total of 9 studies that involved a total of 1029 EGFR-mutant advanced NSCLC patients after EGFR-TKI treatment were included. In overall, nonsmoking was associated with significant prolonged PFS (HR, 0.73, 0.60 to 0.88; P = .001) compared to ever smokers. However, only marginal improvements without statistical significance in objective response rates (odds ratio, 1.11; 95% confidence interval, 0.85 to 1.46; P = .433) and disease control rate (odds ratio, 1.04; 95% confidence interval, 0.82 to 1.33; P = .740) were observed. Subgroup analyses showed that the benefits of PFS in nonsmokers were predominantly presented in pooled results of studies enrolling patients with active EGFR mutations, studies involving previously treated patients, and retrospective studies. Additionally, we failed to observe any significant benefit from nonsmokers in every subgroup for objective response rates and disease control rate. CONCLUSION: For advanced NSCLC patients with EGFR mutations, nonsmoking is associated with longer PFS than ever smoking after EGFR TKIs treatment. Smoking history should be considered an essential factor in studies regarding EGFR-targeted agents toward EGFR-mutant patients. PMID- 25454008 TI - Late onset of exercise induced focal ventricular tachycardia originating from the ventricular end of an A-V accessory pathway after elimination of conduction. AB - The authors report the unique case of remote onset of exercise induced focal ventricular tachycardia in a 40-year old male patient that originated from the ventricular end of an accessory atrioventricular pathway 18 months after a successful ablation. There was no residual conduction across the pathway after the first ablation. The ventricular tachycardia (VT) was mapped to and successfully ablated at the same site where the ventricular end of the pathway was previously ablated. The VT morphology was similar to that of the pre-excited QRS beats noted before. Thus far, in all reported cases of accessory pathway related automaticity there was intact conduction over the pathway or acute injury to it. To the best of our knowledge a case similar to our patient is not yet reported. PMID- 25454010 TI - The evolution of host resistance to disease in the presence of predators. AB - While theoretical models on the evolution of host defences against disease have been widely studied, the inclusion of predators and community interactions more generally, has often been overlooked. In this paper, we examine a host-parasite model with an additional predator and show that the predator changes the evolutionary behaviour of the host. We find that the hosts maximize their levels of resistance at intermediate predation rates, where the cost of infection and the risk of exposure to disease are both high. We show that this effect is heightened when parasites are highly virulent and when there is strong selective predation. We also show that the potential for evolutionary branching increases with the predation rate for regions where the susceptible and infected hosts coexist with the predator. Hence, our results reveal that there are considerable impacts of adding predators to a population. PMID- 25454009 TI - Prediction of beta-lactamase and its class by Chou's pseudo-amino acid composition and support vector machine. AB - beta-Lactam class of antibiotics is used as major therapeutic agent against a number of pathogenic microbes. The widespread and indiscriminate use of antibiotics to treat bacterial infection has prompted evolution of several evading mechanisms from the lethal effect of antibiotics. beta-Lactamases are endogenously produced enzyme that makes bacteria resistant against beta-lactam antibiotics by cleaving the beta-lactam ring. On the basis of primary structures, beta-lactamase family of enzymes is divided into four classes namely A, B, C and D. Class B are metallo-enzymes while A, C and D does not need any metal in the enzyme catalysis. In the present study we developed a SVM based two level beta lactamases protein prediction method, which differentiate beta-lactamases from non-beta-lactamases at first level and then classify predicted beta-lactamases into different classes at second level. We evaluated performance of different input vectors namely simple amino acid composition, Type-1 and Type-2 Chou's pseudo amino acid compositions. Comparative performances indicated that SVM model trained on Type-1 pseudo amino acid composition has the best performance. At first level we were able to classify beta-lactamases from non-beta-lactamases with 90.63% accuracy. At second level we found maximum accuracy of 61.82%, 89.09%, 70.91% and 70.91% of class A, class B, class C and class D, respectively. A web-server as well as standalone, PredLactamase, is also developed to make the method available to the scientific community, which can be accessed at http://14.139.227.92/mkumar/predlactamase. PMID- 25454011 TI - Competitive intransitivity, population interaction structure, and strategy coexistence. AB - Intransitive competition occurs when competing strategies cannot be listed in a hierarchy, but rather form loops-as in the game rock-paper-scissors. Due to its cyclic competitive replacement, competitive intransitivity promotes strategy coexistence, both in rock-paper-scissors and in higher-richness communities. Previous work has shown that this intransitivity-mediated coexistence is strongly influenced by spatially explicit interactions, compared to when populations are well mixed. Here, we extend and broaden this line of research and examine the impact on coexistence of intransitive competition taking place on a continuum of small-world networks linking spatial lattices and regular random graphs. We use simulations to show that the positive effect of competitive intransitivity on strategy coexistence holds when competition occurs on networks toward the spatial end of the continuum. However, in networks that are sufficiently disordered, increasingly violent fluctuations in strategy frequencies can lead to extinctions and the prevalence of monocultures. We further show that the degree of disorder that leads to the transition between these two regimes is positively dependent on population size; indeed for very large populations, intransitivity-mediated strategy coexistence may even be possible in regular graphs with completely random connections. Our results emphasize the importance of interaction structure in determining strategy dynamics and diversity. PMID- 25454012 TI - Asthma identification and medication administration forms in New York City schools. PMID- 25454013 TI - Successful prophylaxis with recombinant human C1 inhibitor in a patient with hereditary angioedema. PMID- 25454014 TI - Information and support from dietary consultation for mothers of children with food allergies. AB - BACKGROUND: Professional dietetic input is essential to ensure that children with diagnosed food allergies have an individualized avoidance plan and nutritionally adequate diet. However, it is not clear what dietary information and support parents require. OBJECTIVE: To explore what information and support parents of children with food allergies require from a dietary consultation. METHODS: Focus groups were conducted with 17 mothers who attend an allergy center for dietary advice for their food allergic child. A number of issues around food allergy dietary advice needs were explored and analyzed using thematic analysis. RESULTS: Six themes were identified. The mothers described how they sought to protect their child from harm, to maintain normality for their child, and to promote child independence. They described needing to become an expert in their child's food allergy and fight their corner when needed. The dietitian supported their needs by ensuring their child's diet was safe and nutritionally adequate and giving information and support to help them provide a normal life for their child. Dietitians also taught mothers about food allergy and provided advocacy and emotional support. CONCLUSION: Mothers of children with food allergies want to understand how to provide a nutritionally adequate, allergen-safe diet while maintaining a normal life. Hence, mothers value a range of support from dietitians, including monitoring their child's health and providing information, practical advice and support, and emotional support. PMID- 25454015 TI - Different sensitization to storage mites depending on the co-exposure to house dust mites. AB - BACKGROUND: Co-sensitization to house dust mites (HDMs) and storage mites (SMs) is very frequent, although the clinical relevance is not well established. OBJECTIVE: To describe the pattern of sensitization and immunologic characterization of patients with positive skin prick test reactions to HDMs and SMs in 4 areas of Spain, selected according to high exposure to HDMs and variable exposure to SMs. METHODS: One hundred sixty-nine individuals with positive skin prick test reactions to HDMs and SMs were included. Specific IgE levels to different mite species and to Der p 1, Der p 2, and Der p 10 were determined. Immunoblots to Dermatophagoides pteronyssinus, Lepidoglyphus destructor, and Tyrophagus putrescentiae extracts were carried out, and allergograms were obtained. Results of different areas were compared. RESULTS: A high rate of polysensitization to SMs was observed, although 12% of participants did not have specific IgE to any SM species. Sensitization to Dermatophagoides species, Der p 2, and L destructor were predominant, although significant differences were observed among areas depending on the grade of exposure to SMs. In areas with high exposure, the SM allergogram showed greater recognition of group 2 allergen. CONCLUSION: Sensitization patterns to SMs in patients sensitized to HDMs and SMs differ depending on the exposure to SMs. Sensitization, mainly to L destructor, seems to exist in areas with high exposure, possibly with group 2 allergens mainly involved. However, in areas with low SM populations, sensitizations observed by skin prick testing appear to be related to HDM exposure. PMID- 25454016 TI - Historical perspectives of allergy and immunology and allergen immunotherapy. PMID- 25454017 TI - Do not analyze too quickly a result: how spironolactone is always point at! PMID- 25454018 TI - Reply: To PMID 24846806. PMID- 25454019 TI - Behavioural Neurology, a new section in cortex. PMID- 25454022 TI - Consecutive exotropia: why does it happen, and can medial rectus advancement correct it? AB - PURPOSE: To investigate whether consecutive exotropia following medial rectus muscle recession is associated with muscle slippage and to assess the effectiveness of treating the condition with medial rectus advancement. METHODS: The records of patients with consecutive exotropia after medial rectus recession were reviewed to determine medial rectus muscle insertion location at the time of advancement surgery. Measurements before and after medial rectus advancement were compared. Success was defined as alignment within 10(Delta) of orthotropia. The dose effect of medial rectus advancement was determined by nonlinear regression. RESULTS: A total of 20 patients were included. The mean age (+/- standard deviation) at time of surgery was 19 +/- 19 years (range, 1.1-65.4). The mean preoperative exotropia was 28(Delta) +/- 16(Delta) (range, 12(Delta)-60(Delta)). Medial rectus slippage of 2.5 +/- 1.7 mm (range, 1.0-5.0 mm) was found in 14 patients (36%) who had previously undergone medial rectus recession. Surgery corrected about 4(Delta) of exotropia per mm total medial rectus advancement. Although 95% of patients were aligned successfully immediately after surgery, averaging 2(Delta) +/- 4(Delta) esotropia, there was significant late exodrift, averaging 17(Delta) at final follow-up. At final follow-up, 1.6 +/- 1.8 (range, 0.10-6.2) years after surgery, 50% of patients maintained alignment within 10(Delta) of orthotropia (mean, 3(Delta) +/- 4(Delta) exotropia); the rest experienced recurrent exotropia of 25(Delta) +/- 8(Delta). CONCLUSIONS: Medial rectus slippage is common in consecutive exotropia. Medial rectus advancement effectively treated consecutive exotropia, whether or not there was muscle slippage. It is however, associated with late exodrift; hence patients should be warned about potential for further XT recurrence. PMID- 25454020 TI - Quality control in eukaryotic membrane protein overproduction. AB - The overexpression of authentically folded eukaryotic membrane proteins in milligramme quantities is a fundamental prerequisite for structural studies. One of the most commonly used expression systems for the production of mammalian membrane proteins is the baculovirus expression system in insect cells. However, a detailed analysis by radioligand binding and comparative Western blotting of G protein-coupled receptors and a transporter produced in insect cells showed that a considerable proportion of the expressed protein was misfolded and incapable of ligand binding. In contrast, production of the same membrane proteins in stable inducible mammalian cell lines suggested that the majority was folded correctly. It was noted that detergent solubilisation of the misfolded membrane proteins using either digitonin or dodecylmaltoside was considerablyless efficient than using sodium dodecyl sulfate or foscholine-12, whilst these detergents were equally efficient at solubilising correctly folded membrane proteins. This provides a simple and rapid test to suggest whether heterologously expressed mammalian membrane proteins are indeed correctly folded, without requiring radioligand binding assays. This will greatly facilitate the high-throughput production of fully functional membrane proteins for structural studies. PMID- 25454023 TI - The role of sleep and the hypothalamic-pituitary-adrenal axis for behavioral and emotional problems in very preterm children during middle childhood. AB - Very preterm children are at higher risk to develop behavioral and emotional problems, poor sleep, and altered hypothalamic-pituitary-adrenocortical activity (HPAA). However, knowledge on objective sleep and HPAA as well as their role for the development of behavioral and emotional problems in very preterm children is limited. Fifty-eight very preterm children (<32nd gestational week) and 55 full term children aged 6-10 years underwent one night of in-home polysomnographic sleep assessment. HPAA was assessed with four saliva samples in the morning (morning cortisol secretion) and four saliva samples in the evening (evening cortisol secretion). Parents completed the Strengths and Difficulties Questionnaire (SDQ) to assess children's behavioral and emotional problems and a subscale of the Children's Sleep Habits Questionnaire to assess sleep disordered breathing. Very preterm children showed more behavioral and emotional problems (SDQ total behavioral/emotional difficulties, emotional symptoms), poorer sleep (more nocturnal awakenings, more stage 2 sleep, less slow wave sleep), and faster decreasing evening cortisol secretion compared to full-term children. Across the whole sample, more stage 2 sleep and/or less slow wave sleep were associated with more SDQ total behavioral/emotional difficulties, hyperactivity-inattention, and peer problems. Lower morning cortisol secretion and lower evening cortisol secretion were associated with more conduct problems. In very preterm children, increased SDQ total behavioral/emotional difficulties was partially explained by less restorative sleep including more stage 2 sleep and less slow wave sleep. This result points to the importance of restorative sleep for the behavioral and emotional development of very preterm children during middle childhood. PMID- 25454021 TI - A cost analysis of pediatric cataract surgery at two child eye health tertiary facilities in Africa. AB - PURPOSE: To determine the direct cost of pediatric cataract surgery at two child eye health tertiary facilities (CEHTFs) in Africa. METHODS: The direct cost of pediatric cataract surgery was determined by reviewing data collected from two CEHTFs in Zambia and Malawi. Inventory, cost, and usage data of all durable medical equipment, consumable equipment, personnel, and medications were collected and the direct cost per child calculated. RESULTS: For cataract surgery and related treatment during 2011, the total cost per child was calculated to be $202 for Malawi and $277 for Zambia using figures derived from estimating labor cost allocation proportional to employee time devoted to pediatric cataract management. The one-time equipment cost totaled $178,121 for Malawi and $179,832 for Zambia. CONCLUSIONS: These cost estimates may serve as a basis for economic decisions aimed at improving access to care, management, and follow-up for children with cataract and provide useful insights for programs dedicated to promoting organizational and financial sustainability for CEHTFs in Africa. PMID- 25454025 TI - From Hiroshima to Fukushima: PTSD symptoms and radiation stigma across regions in Japan. PMID- 25454024 TI - Does objectively assessed sleep at five years predict sleep and psychological functioning at 14 years? - Hmm, yes and no! AB - BACKGROUND: We tested the hypothesis that objectively assessed sleep at kindergarten level predicts sleep and psychological functioning in adolescence. METHOD: Thirty-seven adolescents aged 14 years (SD = 1.3), of 67 participants assessed as preschoolers, took part in a follow-up study nine years later. Participants completed a series of questionnaires related to sleep and psychological functioning. Sleep-EEG clusters of poor, normal and good sleepers assessed as children nine years earlier were used as predictors for subjective sleep and psychological functioning in adolescence. RESULTS: At the age of 14, those who were normal and good sleepers rather than poor sleepers at the age of five had more positive psychological functioning on dimensions including mental toughness, peer relationship, self-esteem, and perceived stress, but did not differ in current sleep patterns. CONCLUSIONS: Objectively assessed sleep patterns at the age of five are predictive of aspects of psychological functioning during adolescence. PMID- 25454027 TI - Mother and baby: intertwined. PMID- 25454026 TI - Subchronic effects of inhaled ambient particulate matter on glucose homeostasis and target organ damage in a type 1 diabetic rat model. AB - Epidemiological studies have reported associations between particulate matter (PM) and cardiovascular effects, and diabetes mellitus (DM) patients might be susceptible to these effects. The chief chronic injuries resulting from DM are small vascular injuries (micro-vascular complications) or large blood vessel injuries (macro-vascular complications). However, toxicological data regarding the effects of PM on DM-related cardiovascular complications is limited. Our objective was to investigate whether subchronic PM exposure alters glucose homeostasis and causes cardiovascular complications in a type 1 DM rat model. We constructed a real world PM2.5 exposure system, the Taipei Air Pollution Exposure System for Health Effects (TAPES), to continuously deliver non-concentrated PM for subchronic exposure. A type 1 DM rat model was induced using streptozotocin. Between December 22, 2009 and April 9, 2010, DM rats were exposed to PM or to filtered air (FA) using TAPES in Taipei, Taiwan, 24h/day, 7days/week, for a total of 16weeks. The average concentrations (mean [SD]) of PM2.5 in the exposure and control chambers of the TAPES were 13.30 [8.65] and 0.13 [0.05]MUg/m(3), respectively. Glycated hemoglobin A1c (HbA1c) was significantly elevated after exposure to PM compared with exposure to FA (mean [SD], 7.7% [3.1%] vs. 4.7% [1.0%], P<0.05). Interleukin 6 and fibrinogen levels were significantly increased after PM exposure. PM caused focal myocarditis, aortic medial thickness, advanced glomerulosclerosis, and accentuation of tubular damage of the kidney (tubular damage index: 1.76 [0.77] vs. 1.15 [0.36], P<0.001). PM exposure might induce the macro- and micro-vascular complications in DM through chronic hyperglycemia and systemic inflammation. PMID- 25454029 TI - Assembling the elephant: integrating perspectives in personality psychology: comment on "personality from a cognitive-biological perspective" by Y. Neuman. PMID- 25454028 TI - Medicaid and CHIP retention among children in 12 states. AB - OBJECTIVE: Though stable insurance is important to support optimal child health, the reproducibility of metrics to assess child health insurance retention at the state and county level has not been examined. We sought to determine reproducibility of public insurance retention rates for children using 3 different metrics at the state and county level. METHODS: Public health insurance retention for children was assessed using 3 different metrics calculated from 2006-2009 Medicaid Analytic Extract data from 12 selected states. The metrics were: 1) Duration: a prospective metric that quantifies the number of newly enrolled children continuously enrolled in public insurance 6, 12, and 18 months after initial enrollment during a selected period; (2) Infant Duration: assesses Duration only among infants born during a selected period; (3) Coverage: a prospective metric that quantifies the average percentage of time a selected population is enrolled over an 18-month interval. Reproducibility of the metrics was assessed using a range of sample sizes with resampling and determining changes in relative rankings of states/counties by retention rate. RESULTS: All 3 metrics demonstrated reproducible estimates at the state level with sample sizes of 2000, 5000, and 10,000. Reproducibility of relative rankings for child health insurance retention of counties within states were sensitive to county child population size and the amount of variability in retention rates within the county and at the state level. CONCLUSIONS: As health care reform unfolds, the complete set of these 3 reproducible metrics can be used to evaluate multipronged and multilevel strategies to retain eligible children in public health insurance. PMID- 25454030 TI - Evolutionary perspectives on human personality: comment on "personality from a cognitive-biological perspective" by Y. Neuman. PMID- 25454031 TI - Fundamental challenges of contemporary "personality" research: comment on "personality from a cognitive-biological perspective" by Y.Neuman. PMID- 25454032 TI - Exanthems associated with parvovirus B19 infection in adults. PMID- 25454033 TI - Diameter of dysplastic nevi is a more robust biomarker of increased melanoma risk than degree of histologic dysplasia: a case-control study. PMID- 25454034 TI - Gaps in pain management in dermatology: a needs assessment from Canada. PMID- 25454035 TI - Assessing adherence with phototherapy protocols. PMID- 25454036 TI - Diet in dermatology: Part I. Atopic dermatitis, acne, and nonmelanoma skin cancer. AB - Patients commonly inquire about dietary modifications as a means to prevent or manage skin disease. Answering these questions is often challenging, given the vast and conflicting evidence that exists on this topic. This 2-part continuing medical education article summarizes the evidence to date to enable physicians to answer patients' questions in an evidence-based manner. Part I includes atopic dermatitis, acne, and nonmelanoma skin cancer. The role of dietary supplementation, dietary exclusion, food allergy, maternal diet, and breastfeeding in the development and/or prevention of atopic dermatitis is summarized. The dermatoendocrinologic mechanism for the effects of glycemic index/glycemic load and milk on acne is described, as well as related clinical evidence for dietary modifications. Finally, evidence and recommendations for restriction or supplementation of dietary factors in the prevention of nonmelanoma skin cancer, including fat, vitamins A, C, D, and E, and selenium, are reported. PMID- 25454037 TI - Diet in dermatology: Part II. Melanoma, chronic urticaria, and psoriasis. AB - The roles of dietary factors in aggravating, preventing, or treating skin diseases are common questions encountered in dermatology practice. Part II of this two-part series reviews dietary modifications that can potentially be utilized in the management of melanoma, chronic urticaria, and psoriasis patients. Specifically, we examine the effect of alcohol consumption and supplementation with vitamins D and E, polyunsaturated fatty acids, selenium, green tea, resveratrol, and lycopene on melanoma risk. The relationships between chronic urticaria symptoms and dietary pseudoallergens, gluten, and vitamin D are analyzed. We explore weight loss, reduced alcohol consumption, and gluten avoidance as means of reducing psoriasis-associated morbidity, as well as the possible utility of supplementation with polyunsaturated fatty acids, folic acid, vitamin D, and antioxidants. With proper knowledge of the role of diet in these cutaneous disease processes, dermatologists can better answer patient inquiries and consider implementation of dietary modifications as adjuncts to other treatments and preventative measures. PMID- 25454038 TI - Acute rash on sun-exposed area during chemotherapy. PMID- 25454039 TI - Patient with numerous papules and spontaneous pneumothorax. PMID- 25454040 TI - An enlarging, fluctuant mass on the scalp. PMID- 25454041 TI - Necrotic skin lesions in a neutropenic patient. PMID- 25454042 TI - Progressive induration of the lower extremities. PMID- 25454043 TI - Penile ulceration in a child after bone marrow transplantation. PMID- 25454044 TI - Binder clips in the treatment of auricular keloids. PMID- 25454045 TI - Using better understanding of anatomy to improve surgical assistants' utility. PMID- 25454046 TI - Vulvar necrobiotic xanthogranuloma. PMID- 25454047 TI - Pedicure-associated Mycobacterium chelonae infection in a hospitalized patient. PMID- 25454048 TI - Facial erythromelalgia: a rare entity to consider in the differential diagnosis of connective tissue diseases. PMID- 25454049 TI - Painful plantar nodules: a specific manifestation of cutaneous macroglobulinosis. PMID- 25454050 TI - Letter from the guest editor: Neonatal imaging--Part 1. PMID- 25454051 TI - Neonatal imaging evaluation of common prenatally diagnosed genitourinary abnormalities. AB - With the implementation of prenatal screening with ultrasound (US) and, more recently, fetal magnetic resonance (MR) imaging, patterns of referral have changed. US remains the first-line imaging modality for evaluating the genitourinary system during the neonatal period and may be enhanced with the use of focused, high-resolution linear images of the pyramids. US has been successful because of its dynamic nature, the excellent morphologic visualization provided in neonates, lack of ionizing radiation, low cost, and lack of need for sedation to acquire the images. US is frequently coupled with mercaptoacetyltriglycine (MAG-3) scanning, providing a powerful combination for morphologic and functional assessment. MR imaging, specifically functional MR urography, has been increasingly used because of its excellent delineation of anatomy achieved without ionizing radiation. MR urography is regarded as a "one-stop-shop examination," as it can provide both anatomical and functional information. It also plays an important role in the evaluation of ureteral ectopia and genital anomalies. Review of available antenatal studies provides invaluable information that may have prognostic significance or may obviate the need for additional examinations or both. Fluoroscopy is typically reserved for assessing vesicoureteral reflux or for detecting urethral abnormalities. In this review, an update on the imaging strategies for common genitourinary anomalies in neonates is presented and illustrated. PMID- 25454052 TI - Imaging of malrotation in the neonate. AB - Intestinal malrotation is a congenital abnormal fixation of the bowel that predisposes to life threatening midgut volvulus. Most events of midgut volvulus occur in the first month of life with decreased risk with age. The most typical presentation is bilious vomiting. Upper gastrointestinal series is the study of choice for diagnosis of malrotation. For optimal results, the study should be well planned with meticulous attention to technique. In equivocal cases, small bowel follow-through study and ultrasound can be performed. PMID- 25454053 TI - Cystic lung lesions in newborns and young children: differential considerations and imaging. AB - Numerous diverse entities produce cystic lung changes in neonates and young children. This review provides an evidence-based, age-appropriate, differential diagnostic framework to use when confronted with pulmonary cystic changes. The categories of diseases that have been discussed include congenital cystic bronchopulmonary malformations, neoplastic conditions, infections, collagen or soft tissue abnormalities, and mimics of cystic lung disease. An understanding of the pathophysiology, imaging appearance, and demographics of these entities is essential in guiding optimal care. Important educational points include differentiating bronchopulmonary malformations from neoplasms and the management and surveillance of lung cysts in young children. PMID- 25454054 TI - Interventional radiology in the neonate and young infant. PMID- 25454055 TI - Quality improvement in neonatal digital radiography: implementing the basic quality improvement tools. AB - A quality improvement (QI) program may be implemented using the plan-do-study-act cycle (as a model for making improvements) and the basic QI tools (used to visually display and analyze variation in data). Managing radiation dose has come to the forefront as a safety goal for radiology departments. This is especially true in the pediatric population, which is more radiosensitive than the adult population. In this article, we use neonatal digital radiography to discuss developing a QI program with the principle goals of decreasing the radiation dose, decreasing variation in radiation dose, and optimizing image quality. PMID- 25454056 TI - Easily overlooked sonographic findings in the evaluation of neonatal encephalopathy: lessons learned from magnetic resonance imaging. AB - Findings of neonatal encephalopathy (NE) and specifically those of hypoxic ischemic injury are frequently evident on magnetic resonance imaging (MRI). Although MRI has become more widely used and has gained widespread acceptance as the study of choice for the evaluation of NE in recent years, its costs are high and access to MRI is sometimes limited for extremely sick neonates. Therefore, head sonography (US) continues to be the first-line imaging modality for the evaluation of the brain in neonates with NE; furthermore, in many of these infants, the diagnosis of NE may have first been made or suggested using head US. US is noninvasive, inexpensive, and portable, allowing examinations to be performed without moving the infant. However, many of the telltale signs of NE on US are subtle and may be easily overlooked, contributing to diagnostic delay or misdiagnosis. We aim to illustrate the spectrum of US findings in NE, with emphasis on those findings that may be easily overlooked on US. Recognition of these findings could potentially improve detection rates, reduce errors, and improve patient management. PMID- 25454057 TI - Spine ultrasound imaging in the newborn. AB - Ultrasound of the spine in the neonate is widely used as the initial modality to evaluate spinal canal anatomy, anatomical variants, and congenital malformations. The spinal canal and its contents are best visualized in the newborn and young infant owing to incomplete ossification of the posterior vertebral elements. PMID- 25454058 TI - Following leads to improve patient outcomes: it's about time. PMID- 25454060 TI - Episodic dizziness in a 74-year-old woman. PMID- 25454062 TI - Quantitative analyses of the effect of silk fibroin/nano-hydroxyapatite composites on osteogenic differentiation of MG-63 human osteosarcoma cells. AB - Silk fibroin (SF)/nano-hydroxyapatite (n-HA) composites are potential biomaterials for bone defect repair. Up to now, the biological evaluation studies of SF/n-HA composites have primarily concentrated on their biocompatibility at cell level such as cell viability and proliferation and tissue level such as material absorption and new bone formation. In this work, SF/n-HA composites were fabricated using a simplified coprecipitation methods and were deposited onto Ti alloy substrates. Then the cell adhesion ability of SF/n-HA composites was observed by SEM and cell proliferation ability of SF/n-HA composites was determined by MTT assay. The ALP activity, BGP contents, and Col I contents of MG 63 human osteosarcoma cells on SF/n-HA composites were quantitatively analyzed. HA nanocrystals were used as controls. These experiments showed that SF/n-HA composites had better cell adhesion and osteogenic differentiation abilities than n-HA materials. This work provides quantitative data to analyze the effect of SF/n-HA composites on cell osteogenic differentiation. PMID- 25454061 TI - Effects of type IV collagen on myogenic characteristics of IGF-I gene-engineered myoblasts. AB - Skeletal muscle regeneration requires migration, proliferation and fusion of myoblasts to form multinucleated myotubes. In our previous study, we showed that insulin-like growth factor (IGF)-I gene delivery stimulates the proliferation and differentiation of mouse myoblast C2C12 cells and promotes the contractile force generated by tissue-engineered skeletal muscles. The aim of this study was to investigate the effects of the extracellular matrix on IGF-I gene-engineered C2C12 cells in vitro. Retroviral vectors for doxycycline (Dox)-inducible expression of the IGF-I gene were transduced into C2C12 cells. When cultured on a type IV collagen-coated surface, we observed significant increases in the migration speed and number of IGF-I gene-engineered C2C12 cells with Dox addition, designated as C2C12/IGF (+) cells. Co-culture of C2C12/IGF (+) cells and parental C2C12 cells, which had been cultured in differentiation medium for 3 days, greatly enhanced myotube formation. Moreover, type IV collagen supplementation promoted the fusion of C2C12/IGF (+) cells with differentiated C2C12 cells and increased the number of myotubes with striations. Myotubes formed by C2C12/IGF (+) cells cultured on type IV collagen showed a dynamic contractile activity in response to electrical pulse stimulation. These findings indicate that type IV collagen promotes skeletal muscle regeneration mediated by IGF-I expressing myoblasts, which may have important clinical implications in the design of myoblast-based therapies. PMID- 25454063 TI - Awa1p on the cell surface of sake yeast inhibits biofilm formation and the co aggregation between sake yeasts and Lactobacillus plantarum ML11-11. AB - We examined mixed-species biofilm formation between Lactobacillus plantarum ML11 11 and both foaming and non-foaming mutant strains of Saccharomyces cerevisiae sake yeasts. Wild-type strains showed significantly lower levels of biofilm formation compared with the non-foaming mutants. Awa1p, a protein involved in foam formation during sake brewing, is a glycosylphosphatidylinositol (GPI) anchored protein and is associated with the cell wall of sake yeasts. The AWA1 gene of the non-foaming mutant strain Kyokai no. 701 (K701) has lost the C terminal sequence that includes the GPI anchor signal. Mixed-species biofilm formation and co-aggregation of wild-type strain Kyokai no. 7 (K7) were significantly lower than K701 UT-1 (K701 ura3/ura3 trp1/trp1), while the levels of strain K701 UT-1 carrying the AWA1 on a plasmid were comparable to those of K7. The levels of biofilm formation and co-aggregation of the strain K701 UT-1 harboring AWA1 with a deleted GPI anchor signal were similar to those of K701 UT 1. These results clearly demonstrate that Awa1p present on the surface of sake yeast strain K7 inhibits adhesion between yeast cells and L. plantarum ML11-11, consequently impeding mixed-species biofilm formation. PMID- 25454064 TI - Stabilization of mini-chromosome segregation during mitotic growth by overexpression of YCR041W and its application to chromosome engineering in Saccharomyces cerevisiae. AB - Chromosome engineering enables large-scale genome manipulation and can be used as a novel technology for breeding of yeasts. PCR-mediated chromosome splitting (PCS) offers a powerful tool for chromosome engineering by enabling a yeast chromosome to be split at any desired site. By applying PCS, a huge variety of chromosome combinations can be created and the best strain under specific conditions can be selected-a technology that we have called genome reorganization. Once the optimal strain is obtained, chromosome constitutions need to be maintained stably; however, mini-chromosomes of less than 50 kb are at relatively high frequency lost during cultivation. To overcome this problem, in this study we screened for multicopy suppressors of the high loss of mini chromosomes by using a multicopy genomic library of Saccharomyces cerevisiae. We identified a novel gene, YCR041W, that stabilizes mini-chromosomes. The translational product of YCR041W was suggested to play an important role in increasing stability for mini-chromosome maintenance, probably by decreasing the rate of loss during mitotic cell division. The stabilization of mini-chromosomes conferred by YCR041W overexpression was completely dependent on the silencing protein Sir4, suggesting that a process related to telomere function might be involved in mini-chromosome stabilization. Overexpression of YCR041W stabilized not only a yeast artificial chromosome vector, but also a mini-chromosome derived from a natural chromosome. Taking these results together, we propose that YCR041W overexpression can be used as a novel chromosome engineering tool for controlling mini-chromosome maintenance and loss. PMID- 25454065 TI - Optimization of isopropanol production by engineered cyanobacteria with a synthetic metabolic pathway. AB - Cyanobacterium is an attractive host for the production of various chemicals and alternative fuels using solar energy and carbon dioxide. In previous study, we succeeded to produce isopropanol using engineered Synechococcus elongatus PCC 7942 under dark and anaerobic conditions (0.43 mM, 26.5 mg/l). In the present study, we report the further optimization of this isopropanol producing condition. We then optimized growth conditions for production of isopropanol by the engineered cyanobacteria, including the use of cells in early stationary phase and buffering of the production medium to neutral pH. We observed that shifting of cultures from dark and anaerobic to light and aerobic conditions during the production phase dramatically increased isopropanol production by conversion to isopropanol from acetate, byproduct under dark and anaerobic condition. Under the optimized production conditions, the titer of isopropanol was elevated 6-fold, to 2.42 mM (146 mg/l). PMID- 25454066 TI - A state dependence of the response to N-methyl-D-aspartate receptor antagonism. PMID- 25454067 TI - Toward patient-specific targeting and parameter setting of deep brain stimulation for relief of depression. PMID- 25454069 TI - Information/education page. Returning to school after traumatic brain injury. PMID- 25454068 TI - Human megakaryocyte progenitors derived from hematopoietic stem cells of normal individuals are MHC class II-expressing professional APC that enhance Th17 and Th1/Th17 responses. AB - Platelets, like stromal cells, present antigen only via MHC class I, but the immune potential of their progenitors has not been explored in humans. We derived CD34(+)CD117(+)CD41(+)CD151(+) megakaryocyte progenitors (MKp) in vitro from mobilized peripheral blood hematopoietic stem and progenitor cells (HSPC) of normal subjects using culture conditions akin to bone marrow niche, or organs that support extramedullary hematopoiesis. The MKp expressed MHC Class II in contrast to platelets and functioned as professional APC before they matured further. Moreover, MKp constitutively expressed mRNA encoding mediators for human Th17 expansion, including IL-1, IL-18, IL-6, TGFbeta, IL-23, BAFF, and COX2. MKp also expressed high levels of type I interferon and IRF5 mRNA. In contrast to platelets, MKp augmented the expansion of Th17, Th1, and potent Th17/Th1 double positive cells in normal PBMC and CD4 line T cells from normal subjects or lupus patients. The Th cell augmentation involved pre-committed memory cells, and was significant although modest, because only non-cognate MKp-T cell interactions could be studied, under non-polarizing conditions. Importantly, the MKp-mediated expansion was observed in the presence or absence of direct MKp-T cell contact. Furthermore, MKp augmented Th17 responses against Candida albicans, a serious opportunistic pathogen. These results indicate an immunologic role of MKp in situations associated with extramedullary hematopoiesis and mobilization of HSPC. PMID- 25454071 TI - Rapid construction of a Bacterial Artificial Chromosomal (BAC) expression vector using designer DNA fragments. AB - Bacterial artificial chromosomal (BAC) vectors are increasingly being used in cloning large DNA fragments containing complex biosynthetic pathways to facilitate heterologous production of microbial metabolites for drug development. To express inserted genes using Streptomyces species as the production hosts, an integration expression cassette is required to be inserted into the BAC vector, which includes genetic elements encoding a phage-specific attachment site, an integrase, an origin of transfer, a selection marker and a promoter. Due to the large sizes of DNA inserted into the BAC vectors, it is normally inefficient and time-consuming to assemble these fragments by routine PCR amplifications and restriction-ligations. Here we present a rapid method to insert fragments to construct BAC-based expression vectors. A DNA fragment of about 130 bp was designed, which contains upstream and downstream homologous sequences of both BAC vector and pIB139 plasmid carrying the whole integration expression cassette. In Fusion cloning was performed using the designer DNA fragment to modify pIB139, followed by lambda-RED-mediated recombination to obtain the BAC-based expression vector. We demonstrated the effectiveness of this method by rapid construction of a BAC-based expression vector with an insert of about 120 kb that contains the entire gene cluster for biosynthesis of immunosuppressant FK506. The empty BAC based expression vector constructed in this study can be conveniently used for construction of BAC libraries using either microbial pure culture or environmental DNA, and the selected BAC clones can be directly used for heterologous expression. Alternatively, if a BAC library has already been constructed using a commercial BAC vector, the selected BAC vectors can be manipulated using the method described here to get the BAC-based expression vectors with desired gene clusters for heterologous expression. The rapid construction of a BAC-based expression vector facilitates heterologous expression of large gene clusters for drug discovery. PMID- 25454070 TI - Two replication initiators - one mechanism for replication origin opening? AB - DNA replication initiation has been well-characterized; however, studies in the past few years have shown that there are still important discoveries to be made. Recent publications concerning the bacterial DnaA protein have revealed how this replication initiator, via interaction with specific sequences within the origin region, causes local destabilization of double stranded DNA. Observations made in the context of this bacterial initiator have also been converging with those recently made for plasmid Rep proteins. In this mini review we discuss the relevance of new findings for the RK2 plasmid replication initiator, TrfA, with regard to new data on the structure of complexes formed by the chromosomal replication initiator DnaA. We discuss structure-function relationships of replication initiation proteins. PMID- 25454072 TI - Changes in fibrinolysis and severity of organ failure in sepsis: a prospective observational study using point-of-care test--ROTEM. AB - PURPOSE: We hypothesized that the thromboelastometry (ROTEM; Pentapharm GmbH, Munich, Germany) fibrinolysis parameter "maximum lysis" (ML) would have an independent inverse association with the severity of organ failure in sepsis. METHODS: Selected adult patients with sepsis (n = 77) were recruited within 24 hours of antibiotic commencement. Patients with Sequential Organ Failure Assessment score higher than 1 (n = 57) were followed for 72 hours. Prothrombin fragments 1 + 2, plasminogen activator inhibitor-1 (aPAI-1), ROTEM, and routine coagulation tests were measured daily along with Sequential Organ Failure Assessment scores. RESULTS: The activity of functional aPAI-1 increased with increasing severity of organ failure (P = .01) and was higher as compared with healthy controls (95% confidence interval, -65.4 to -29.9; P < .001). There was a decreasing trend in ML with increased organ failure (P = .001); however, there was no trend in d-dimer. Among all tests, only the lower ML (beta = -0.38, P < .001) and higher international normalized ratio (INR; beta = 0.32, P = .002) values significantly contributed to greater severity of organ failure (R(2) = 0.35, F2,73 = 19.29, P < .001). Despite an increase in INR, the prothrombin fragment remained unchanged (P = .89). Strong correlations were observed between early (24 hours) increase in fibrinolysis and recovery of organ failures for 48 hours (ML: r = 0.679, P = .001; aPAI-1: r = 0.694, P < .001). CONCLUSIONS: Lower ML and higher INR values predicted greater severity of organ failure at presentation. Further studies are required, as ROTEM could aid selection of patients and guide interventions aimed at fibrinolysis in severe sepsis. PMID- 25454073 TI - Venoarterial extracorporeal membrane oxygenation for patients in shock or cardiac arrest secondary to cardiotoxicant poisoning: a cost-effectiveness analysis. AB - PURPOSE: Venoarterial extracorporeal membrane oxygenation represents an emerging and recommended option to treat life-threatening cardiotoxicant poisoning. The objective of this cost-effectiveness analysis was to estimate the incremental cost-effectiveness ratio of using venoarterial extracorporeal membrane oxygenation for adults in cardiotoxicant-induced shock or cardiac arrest compared with standard care. MATERIALS AND METHODS: Adults in shock or in cardiac arrest secondary to cardiotoxicant poisoning were studied with a lifetime horizon and a societal perspective. Venoarterial extracorporeal membrane oxygenation cost effectiveness was calculated using a decision analysis tree, with the effect of the intervention and the probabilities used in the model taken from an observational study representing the highest level of evidence available. The costs (2013 Canadian dollars, where $1.00 Canadian = $0.9562 US dollars) were documented with interviews, reviews of official provincial documents, or published articles. A series of one-way sensitivity analyses and a probabilistic sensitivity analysis using Monte Carlo simulation were used to evaluate uncertainty in the decision model. RESULTS: The cost per life year (LY) gained in the extracorporeal membrane oxygenation group was $145 931/18 LY compared with $88 450/10 LY in the non-extracorporeal membrane oxygenation group. The incremental cost-effectiveness ratio ($7185/LY but $34 311/LY using a more pessimistic approach) was mainly influenced by the probability of survival. The probabilistic sensitivity analysis identified variability in both cost and effectiveness. CONCLUSION: Venoarterial extracorporeal membrane oxygenation may be cost effective in treating cardiotoxicant poisonings. PMID- 25454075 TI - The Durban World Congress Ethics Round Table IV: health care professional end-of life decision making. AB - INTRODUCTION: When terminal illness exists, it is common clinical practice worldwide to withhold (WH) or withdraw (WD) life-sustaining treatments. Systematic documentation of professional opinion and perceived practice similarities and differences may allow recommendations to be developed. MATERIALS AND METHODS: Speakers from invited faculty of the World Federation of Societies of Intensive and Critical Care Medicine Congress that took place in Durban (2013), with an interest in ethics, were approached to participate in an ethics round table. Key domains of health care professional end-of-life decision making were defined, explored by discussion, and then questions related to current practice and opinion developed and subsequently answered by round-table participants to establish the presence or absence of agreement. RESULTS: Agreement was established for the desirability for early goal-of-care discussions and discussions between health care professionals to establish health care provider consensus and confirmation of the grounds for WH/WD, before holding formal WH/WD discussions with patients/surrogates. Nurse and other health care professional involvement were common in most but not all countries/regions. Principles and practical triggers for initiating discussions on WH/WD, such as multiorgan failure, predicted short-term survival, and predicted poor neurologic outcome, were identified. CONCLUSIONS: There was majority agreement for many but not all statements describing health care professional end-of-life decision making. PMID- 25454074 TI - Intensive blood pressure control during the hyperacute phase of intracerebral hemorrhage in patients at risk for resistant hypertension: a retrospective cohort study. AB - INTRODUCTION: There are limited data evaluating intensive systolic blood pressure (SBP) control during the hyperacute phase of intracerebral hemorrhage (ICH) in patients with multiple risk factors for resistant hypertension. We evaluated the feasibility and safety of this intervention in a primary population that includes patients with multiple risk factors for resistant hypertension. MATERIALS AND METHODS: We conducted a retrospective analysis of ICH patients for which intensive SBP control (<140 mm Hg)- i.e. less than or equal to 140 was targeted. All patients possessed at least 2 risk factors that have been associated with resistant hypertension. Our primary objective was to determine the percentage of patients who achieved goal SBP within 1 hour of ICH diagnosis. Secondary objectives included identifying predictors of achieving goal SBP within 6 hours. RESULTS: Goal SBP within 1 hour was achieved in 8.1% of patients. The total number of risk factors a patient possessed was found to negatively predict ability to achieve goal SBP. For each risk factor possessed, the odds of achieving goal SBP within 6 hours are reduced by 31% (odds ratio, 0.69 [95% confidence interval, 0.54-0.89]). CONCLUSION: Intensive SBP control after ICH was difficult to achieve within 1 hour in those with risk factors for resistant hypertension. Patients' total risk factors were found to reduce the odds of achieving goal SBP within 6 hours. PMID- 25454076 TI - Status and determinants of individual actions to reduce health impacts of air pollution in US adults. AB - Although regulation of emissions is the primary strategy to reduce air pollution related morbidity, individual-level interventions are also helpful in mitigating health impacts. We used data from 2007-2008 National Health and Nutrition Examination Survey to study the prevalence of individual-level action among the US adult population if informed of air pollution, and to see if this differed by demographic and health factors. Only 13.5% (95% confidence interval [CI]: 11.6 15.4%) of participants aware of air quality reported changing their individual behaviors. Males (adjusted odds ratio [AOR]: 0.66, 95% CI: 0.56-0.77) and those without cardiovascular disease (AOR: 0.58, 95% CI: 0.47-0.71) were least likely to take action. Results show that individual action was infrequent among the population. Health promotion of individual intervention is necessary, and this effort may need to target specific subgroups of the population. Further studies on effective individual interventions are needed. PMID- 25454077 TI - The relationship of body mass to survival in persons with dementia: a nutritionist's viewpoint. PMID- 25454078 TI - Reference value of impulse oscillometry in taiwanese preschool children. AB - BACKGROUND: Impulse oscillometry is a potential technique for assessing the respiratory mechanism-which includes airway resistance and reactance during tidal breathing-in minimally cooperative young children. The reference values available in Asian preschool children are limited, especially in children of Chinese ethnicity. This study aimed to develop reference equations for lung function measurements using impulse oscillometry in Taiwanese children for future clinical application and research exploitation. METHODS: Impulse oscillometry was performed in 150 healthy Taiwanese children (aged 2-6 years) to measure airway resistance and reactance at various frequencies. We used regression analysis to generate predictive equations separately by age, body height, body weight, and gender. The stepwise regression model revealed that body height was the most significant determinant of airway resistance and reactance in preschool young children. RESULTS: With the growth in height, a decrease in airway resistance and a paradoxical increase in reactance occurred at different frequencies. The regression curve of resistance at 5 Hz was comparable to previous reference values. CONCLUSION: This study provided reference values for several variables of the impulse oscillometry measurements in healthy Taiwanese children aged 2-6 years. With these reference data, clinical application of impulse oscillometry would be expedient in diagnosing respiratory diseases in preschool children. PMID- 25454079 TI - Genetic Evaluation of Children with Global Developmental Delay--Current Status of Network Systems in Taiwan. AB - This review article aims to introduce the screening and referral network of genetic evaluation for children with developmental delay in Taiwan. For these children, integrated systems provide services from the medical, educational, and social welfare sectors. All cities and counties in Taiwan have established a network for screening, detection, referral, evaluation, and intervention services. Increased awareness improves early detection and intervention. There remains a gap between supply and demand, especially with regard to financial resources and professional manpower. Genetic etiology has a major role in prenatal causes of developmental delay. A summary of reports on some related genetic disorders in the Taiwanese population is included in this review. Genetic diagnosis allows counseling with regard to recurrence risk and prevention. Networking with neonatal screening, laboratory diagnosis, genetic counseling, and orphan drugs logistics systems can provide effective treatment for patients. In Taiwan, several laboratories provide genetic tests for clinical diagnosis. Accessibility to advanced expensive tests such as gene chips or whole exome sequencing is limited because of funding problems; however, the service system in Taiwan can still operate in a relatively cost-effective manner. This experience in Taiwan may serve as a reference for other countries. PMID- 25454081 TI - Plasmodium berghei glycine cleavage system T-protein is non-essential for parasite survival in vertebrate and invertebrate hosts. AB - T-protein, an aminomethyltransferase, represents one of the four components of glycine cleavage system (GCS) and catalyzes the transfer of methylene group from H-protein intermediate to tetrahydrofolate (THF) forming N(5), N(10)-methylene THF (CH2-THF) with the release of ammonia. The malaria parasite genome encodes T , H- and L-proteins, but not P-protein which is a glycine decarboxylase generating the aminomethylene group. A putative GCS has been considered to be functional in the parasite mitochondrion despite the absence of a detectable P protein homologue. In the present study, the mitochondrial localization of T protein in the malaria parasite was confirmed by immunofluorescence and its essentiality in the entire parasite life cycle was studied by targeting the T protein locus in Plasmodium berghei (Pb). PbT knock out parasites did not show any growth defect in asexual, sexual and liver stages indicating that the T protein is dispensable for parasite survival in vertebrate and invertebrate hosts. The absence of P-protein homologue and the non-essentiality of T protein suggest the possible redundancy of GCS activity in the malaria parasite. Nevertheless, the H- and L-proteins of GCS could be essential for malaria parasite because of their involvement in alpha-ketoacid dehydrogenase reactions. PMID- 25454080 TI - Human fetal ventricular cardiomyocyte, RL-14 cell line, is a promising model to study drug metabolizing enzymes and their associated arachidonic acid metabolites. AB - INTRODUCTION: RL-14 cells, human fetal ventricular cardiomyocytes, are a commercially available cell line that has been established from non-proliferating primary cultures derived from human fetal heart tissue. However, the expression of different drug metabolizing enzymes (DMEs) in RL-14 cells has not been elucidated yet. Therefore, the main objectives of the current work were to investigate the capacity of RL-14 cells to express different cytochrome P450 (CYP) isoenzymes and correlate this expression to primary cardiomyocytes. METHODS: The expression of CYP isoenzymes was determined at mRNA, protein and catalytic activity levels using real time-PCR, Western blot analysis and liquid chromatography-electron spray ionization-mass spectrometry (LC-ESI-MS), respectively. RESULTS: Our results showed that RL-14 cells constitutively express CYP omega-hydroxylases, CYP1A, 1B, 4A and 4F; CYP epoxygenases, CYP2B, 2C and 2J; in addition to soluble epoxide hydrolayse (EPHX2) at mRNA and protein levels. The basal expression of CYP omega-hydroxylases, epoxygenases and EPHX2 was supported by the ability of RL-14 cells to convert arachidonic acid to its biologically active metabolites, 20-hydroxyeicosatetraenoic acids (20-HETEs), 14,15 epoxyeicosatrienoic acids (14,15-EET), 11,12-EET, 8,9-EET, 5,6-EET, 14,15 dihydroxyeicosatrienoic acid (14,15-DHET), 11,12-DHET, 8,9-DHET and 5,6-DHET. Furthermore, RL-14 cells express CYP epoxygenases and omega-hydroxylase at comparable levels to those expressed in adult and fetal human primary cardiomyocytes cells implying the importance of RL-14 cells as a model for studying DMEs in vitro. Lastly, different CYP families were induced in RL-14 cells using 2,3,7,8-tetrachlorodibenzo-p-dioxin and fenofibrate at mRNA and protein levels. DISCUSSION: The current study provides the first evidence that RL 14 cells express CYP isoenzymes at comparable levels to those expressed in the primary cells and thus offers a unique in vitro model to study DMEs in the heart. PMID- 25454082 TI - Canine CD4(+)CD8(+) double-positive T cells can develop from CD4(+) and CD8(+) T cells. AB - For a long time the expression of the CD4 and CD8 receptor on peripheral blood T cells was thought to be mutually exclusive. However, in canine peripheral blood, similar to other species as swine or human for example, mature CD4(+)CD8(+) double-positive (dp) T cells exist which simultaneously express both surface receptors and have features of activated T cells. Canine CD4(+)CD8(+)dp T cells are heterogeneous and can be divided into three subpopulations by their intensity of CD4 and CD8alpha expression: CD4(bright)CD8alpha(bright), CD4(dim)CD8alpha(bright) and CD4(dim)CD8alpha(dim). The number of CD4(+)CD8alpha(+)dp T cells increases after in vitro stimulation of canine peripheral blood mononuclear cells (PBMC) raising the question of their progenitor(s). Thus, the aim of our study was to characterize the progenitor(s) of canine CD4(+)CD8alpha(+)dp T cells. By cell tracing experiments we identified both CD4(+) single-positive (sp) and also CD8alpha(+)sp T cells as progenitors of canine CD4(+)CD8alpha(+)dp T cells after in vitro stimulation. CD4(+)sp T cells almost exclusively upregulate a CD8alphaalpha homodimer, whereas CD8alpha(+)sp T cells can become CD4(+)CD8alphabeta(+) or CD4(+)CD8alphaalpha(+). Even in the absence of other cells, highly purified CD4(+)sp T cells can become double positive upon in vitro stimulation, whereas highly purified CD8alpha(+)sp T cells fail to do so. However, CD8alpha(+)sp T cells can additionally express CD4 when stimulated in the presence of CD4(-)CD8alpha(-) double-negative (dn) cells or more efficiently when stimulated in the presence of CD4(+)sp T cells. Soluble factors secreted by CD4(+)sp T cells are sufficient for the upregulation of CD4 on CD8alpha(+)sp T cells, but direct cell-cell contact between CD4(+)sp and CD8alpha(+)sp T cells is more efficient. mRNA analysis shows that additional CD4 expression on CD8alpha(+)sp T cells results from de novo synthesis. Thus, uptake of soluble CD4 or trogocytosis is less likely as mechanism for generation of canine double-positive T cells. CD4(+)CD8alpha(+)dp T cells are highly activated independent of their origin except when generated in coculture of CD8alpha(+)sp T cells with CD4(-)CD8alpha(-)dn cells. Overall, in dog, CD4(+)sp T cells are the more potent progenitors of CD4(+)CD8alpha(+)dp T cells compared to CD8alpha(+)sp T cells. PMID- 25454083 TI - Defensive response of European sea bass (Dicentrarchus labrax) against Listonella anguillarum or Photobacterium damselae subsp. piscicida experimental infection. AB - Sea bass were experimentally infected with Listonella anguillarum or Photobacterium damselae subsp. piscicida (Phdp). At 24 and 72h post-infection, the expression analysis of immune-relevant genes (IL-1beta, IL-6, IL-8, Hepcidin), the transcriptional level and detection of HSP70, and the quantification of serum iron were investigated in association with the histological analysis and the bacterial recognition in tissues by immunohistochemistry. At 15 days post-infection, the specific antibody response was detected in surviving fish, as well as the transcriptional levels of TcR and BcR sequences. Both experimental infections were characterized by a similar acute response, whereas different histological and immunohistochemistry evidences were observed. In particular, the early reaction appeared suitable for the clearance of L. anguillarum, thus limiting the histological lesions, the bacterial dissemination and the further development of acquired immunity in surviving fish. On the contrary, the innate response appeared not enough to resolve the Phdp infection, which was characterized by tissue damage, bacterial widespread and substantial detection of specific humoral immunity in surviving fish, also associated to lymphocytes clonal expansion. Besides the opportunistic conditions involved in fish vibriosis and pasteurellosis, the comparison between these experimental infection models seems to suggest that the rate of development of the acquired immunity is strictly linked to the activation of the host innate response combined to the degree of bacterial virulence. PMID- 25454084 TI - Dietary fucoidan enhance the non-specific immune response and disease resistance in African catfish, Clarias gariepinus, immunosuppressed by cadmium chloride. AB - Fucoidan is sulfated polysaccharide extracted from seaweed brown algae. This study was designed to evaluate the immunomodulatory effects and disease resistance of dietary fucoidan on catfish, Clarias gariepinus, immunosuppressed by cadmium. Three hundred and sixty African catfish, C. gariepinus, was allocated into six equal groups. The first group served as a control. Groups (F1 and F2) were fed on fucoidan supplemented ration at concentrations of 4 and 6g/kg diet respectively for 21 days. Groups (Cd, CdF1 and CdF2) were subjected throughout the experiment to a sub-lethal concentration of 5ppm cadmium chloride solution and groups (CdF1 and CdF2) were fed on a ration supplemented with fucoidan. Macrophages oxidative burst, phagocytic activity percentages and lymphocytes transformation index were a significant increase in the fucoidan-treated groups (F1 and F2), while serum lysozyme, nitric oxide and bactericidal activity were enhanced only in group (F2) when compared with controls. These parameters as well as absolute lymphocyte count and survival rate were significantly increased in group (CdF2) when compared with cadmium chloride immunosuppressed group (Cd). It could be concluded that the fucoidan can be used as immunostimulant for the farmed African catfish, C. gariepinus as it can improve its resistance to immunosuppressive stressful conditions. PMID- 25454085 TI - Analysis of blood leukocytes in a naturally occurring immunodeficiency of pigs shows the defect is localized to B and T cells. AB - Severe combined immunodeficiency (SCID) is the result of a set of inherited genetic defects which render components of the immune response nonfunctional. In Arabian horses, Jack Russell terriers, and mice, the disorder is a consequence of the absence of T and B lymphocytes, while natural killer (NK) cell and other leukocyte populations remain intact. Preliminary analysis of a naturally acquired form of inherited SCID in a line of pigs showed several defects in the architecture and composition of secondary lymphoid organs. In this study, a quantitative assessment of lymphocyte populations in affected and normal littermates showed depleted T or B lymphocyte populations in affected pigs; however, NK cells and neutrophils were present in numbers comparable to unaffected littermates. The results indicate that the immune defect in pigs shares the same features as other SCID-affected species. PMID- 25454086 TI - Bovine herpesvirus-1: evaluation of genetic diversity of subtypes derived from field strains of varied clinical syndromes and their relationship to vaccine strains. AB - Bovine herpesvirus-1 (BoHV-1) causes significant disease in cattle. Control programs in North America incorporate vaccination with modified live viral (MLV) or killed (KV) vaccine. BoHV-1 strains are isolated from diseased animals or fetuses after vaccination. There are markers for differentiating MLV from field strains using whole-genome sequencing and analysis identifying single nucleotide polymorphisms (SNPs). Using multiple primer sets and sequencing of products permits association of BoHV-1 isolates with vaccines. To determine association between vaccine virus and strains isolated from clinical cases following vaccination, we analyzed 12 BoHV-1 isolates from animals with various clinical syndromes; 9 corresponded to BoHV-1.1 respiratory group. The remaining three corresponded to BoHV-1.2b, typically found in genital tracts of cattle. Four BoHV 1 isolates were identical to a vaccine strain; three were from post-vaccination abortion episodes with typical herpetic lesions whose dams had received MLV vaccine during pregnancy, and one from a heifer given a related MLV vaccine; Sequences of two respiratory isolates perfectly matched mutations characterizing RLB106 strain, a temperature sensitive mutant used in intranasal and parenteral vaccines. The last three respiratory strains clearly appeared related to a group of MLV vaccines. Previously the MLV vaccines were grouped into four groups based on SNPs patterns. In contrast with above-mentioned isolates that closely matched SNP patterns of their respective MLV vaccine virus, these 3 strains both lacked some and possessed a number of additional mutations compared to a group of MLV vaccine viral genome. Finding BoHV-1.2b in respiratory cases indicates focus should be given BoHV-1.2b as an emerging virus or a virus not recognized nor fully characterized in BRD. PMID- 25454088 TI - The Plasmodium berghei sexual stage antigen PSOP12 induces anti-malarial transmission blocking immunity both in vivo and in vitro. AB - Anti-malarial transmission-blocking vaccines (TBVs) aim to inhibit the transmission of Plasmodium from humans to mosquitoes by targeting the sexual/ookinete stages of the parasite. Successful use of such interventions will subsequently result in reduced cases of malarial infection within a human population, leading to local elimination. There are currently only five lead TBV candidates under examination. There is a consequent need to identify novel antigens to allow the formulation of new potent TBVs. Here we describe the design and evaluation of a potential TBV (BDES-PbPSOP12) targeting Plasmodium berghei PSOP12 based on the baculovirus dual expression system (BDES), enabling expression of antigens on the surface of viral particles and within infected mammalian cells. In silico studies have previously suggested that PSOP12 (Putative Secreted Ookinete Protein 12) is expressed within the sexual stages of the parasite (gametocytes, gametes and ookinetes), and is a member of the previously characterized 6-Cys family of plasmodial proteins. We demonstrate that PSOP12 is expressed within the sexual/ookinete forms of the parasite, and that sera obtained from mice immunized with BDES-PbPSOP12 can recognize the surface of the male and female gametes, and the ookinete stages of the parasite. Immunization of mice with BDES-PbPSOP12 confers modest but significant transmission-blocking activity in vivo by active immunization (53.1% reduction in oocyst intensity, 10.9% reduction in oocyst prevalence). Further assessment of transmission-blocking potency ex vivo shows a dose-dependent response, with up to a 76.4% reduction in intensity and a 47.2% reduction in prevalence observed. Our data indicates that PSOP12 in Plasmodium spp. could be a potential new TBV target candidate, and that further experimentation to examine the protein within human malaria parasites would be logical. PMID- 25454087 TI - Epitope-focused peptide immunogens in human use adjuvants protect rabbits from experimental inhalation anthrax. AB - BACKGROUND: Anthrax represents a formidable bioterrorism threat for which new, optimized vaccines are required. We previously demonstrated that epitope-focused multiple antigenic peptides or a recombinant protein in Freund's adjuvant can elicit Ab against the loop neutralizing determinant (LND), a cryptic linear neutralizing epitope in the 2beta2-2beta3 loop of protective antigen from Bacillus anthracis, which mediated protection of rabbits from inhalation challenge with B. anthracis Ames strain. However, demonstration of efficacy using human-use adjuvants is required before proceeding with further development of an LND vaccine for testing in non-human primates and humans. METHODS: To optimize the LND immunogen, we first evaluated the protective efficacy and immune correlates associated with immunization of rabbits with mixtures containing two molecular variants of multiple antigenic peptides in Freunds adjuvant, termed BT LND(2) and TB-LND(2). TB-LND(2) was then further evaluated for protective efficacy in rabbits employing human-use adjuvants. RESULTS: Immunization of rabbits with TB-LND(2) in human-use adjuvants elicited protection from Ames strain spore challenge which was statistically indistinguishable from that elicited through immunization with protective antigen. All TB-LND(2) rabbits with any detectable serum neutralization prior to challenge were protected from aerosolized spore exposure. Remarkably, rabbits immunized with TB-LND(2) in Alhydrogel/CpG had significant anamnestic increases in post-challenge LND specific Ab and neutralization titers despite little evidence of spore germination in these rabbits. CONCLUSIONS: An LND-specific epitope-focused vaccine may complement PA-based vaccines and may represent a complementary stand alone vaccine for anthrax. PMID- 25454089 TI - The long-term efficacy of Chinese hamster ovary cell derived hepatitis B vaccine after being used for 14-16 years in Chinese rural communities. AB - OBJECTIVE: To evaluate the long-term efficacy of Chinese hamster ovary (CHO) cell derived hepatitis B vaccine after being used for 14-16 years in country community in Hebei province in China. METHOD: A cross-sectional investigation was carried out in 3 of 7 randomly selected rural communities in Zhengding County in 2013. The children who were born between 1997 and 1999 and were vaccinated with three doses of CHO-derived hepatitis B vaccine were eligible to participate in the study. Their sera samples were tested for HBV serological markers. For HBsAg positive children, their historical results were compared, in order to see whether these were new infections. RESULTS: Among the 920 participating children, the prevalence of HBsAg, anti-HBs and anti-HBc were 0.65%, 73.15% and 1.20% respectively. The differences between birth-year groups were not significant. When compared with baseline, the vaccine efficacy was 94.2% and the anti-HBs titers of 668 children with sole anti-HBs positivity were 178.8 mI U/ml. By comparing with historical data, no new infection was found in this latest survey. Among 6 mothers of HBsAg positive children, 4 were HBsAg positive, 1 was negative and 1 was unknown. CONCLUSION: The long-term efficacy of the CHO derived hepatitis vaccine is good and stable for 14-16 years after vaccination. A booster dose seems not necessary. Implementing mother-newborn blocking measures for newborns from HBsAg carrier mothers is urgently needed in the future. PMID- 25454090 TI - Protection against filarial infection by 45-49 kDa molecules of Brugia malayi via IFN-gamma-mediated iNOS induction. AB - Nitric oxide (NO) mediated mechanisms have been implicated in killing of some life-stages of Brugia malayi/Wuchereria bancrofti and protect the host through type 1 responses and IFN-gamma stimulated toxic mediators' release. However, the identity of NO stimulating molecules of the parasites is not known. Three predominantly NO-stimulating SDS-PAGE resolved fractions F8 (45.24-48.64 kDa), F11 (33.44-38.44 kDa) and F12 (28.44-33.44 kDa) from B. malayi were identified and their proteins were analyzed by 2-DE and MALDI-TOF/TOF. Tropomyosin, calponin and de novo peptides were identified by 2-DE and MALDI-TOF/TOF in F8 and immunization with F8 conferred most significant protection against L3-initiated infection in Mastomys coucha. Immunized animals showed upregulated F8-induced NO, IFN-gamma, TNF-alpha, IL-1beta, IL-10, TGF-beta release, cellular proliferative responses and specific IgG and IgG1. Anti-IFN-gamma, anti-TNF-alpha, and anti-IL 1beta significantly reduced F8-mediated NO generation and iNOS induction at protein levels. Anti-IFN-gamma treated cells showed maximum reduction (>74%) in NO generation suggesting a predominant role of IFN-gamma in iNOS induction. In conclusion, the findings suggest that F8 which contains tropomyosin, calponin and de novo peptides protects the host via IFN-gamma mediated iNOS induction and may hold promise as vaccine candidate(s). This is also the first report of identification of tropomyosin and calponin in B. malayi. PMID- 25454091 TI - Endocrine disruptors: new players in the pathophysiology of type 2 diabetes? AB - The prevalence of type 2 diabetes (T2D) has dramatically increased worldwide during the last few decades. While lifestyle factors, such as decreased physical activity and energy-dense diets, together with genetic predisposition, are well known actors in the pathophysiology of T2D, there is accumulating evidence suggesting that the increased presence of endocrine-disrupting chemicals (EDCs) in the environment, such as bisphenol A, phthalates and persistent organic pollutants, may also explain an important part in the incidence of metabolic diseases (the metabolic syndrome, obesity and T2D). EDCs are found in everyday products (including plastic bottles, metal cans, toys, cosmetics and pesticides) and used in the manufacture of food. They interfere with the synthesis, secretion, transport, activity and elimination of natural hormones. Such interferences can block or mimic hormone actions and thus induce a wide range of adverse effects (developmental, reproductive, neurological, cardiovascular, metabolic and immune). In this review, both in vivo and in vitro experimental data and epidemiological evidence to support an association between EDC exposure and the induction of insulin resistance and/or disruption of pancreatic beta-cell function are summarized, while the epidemiological links with disorders of glucose homoeostasis are also discussed. PMID- 25454092 TI - Impact of socioeconomic status and gender on glycaemic control, cardiovascular risk factors and diabetes complications in type 1 and 2 diabetes: a population based analysis from a Scottish region. AB - AIMS: In this cross-sectional study, the aims were to investigate the association of the socioeconomic status and gender on the prevalence of type 1 and 2 diabetes, glycaemic control, cardiovascular risk factors plus the complications of diabetes in a population-based analysis in the county of Ayrshire and Arran, Scotland. METHODS: Quality Outcome Framework data was obtained from General Practices in Ayrshire and Arran, Scotland (n=15,351 patients). RESULTS: In type 1 diabetes, there was an increasing linear trend in HbA1c across deprivation levels (P<0.01). In type 1 diabetes, obesity in women (P<0.01) and increased non-fasting triglyceride levels in both men and women were associated with deprivation (P<0.05). In type 2 diabetes, there was a significant prevalence trend with deprivation for women (P<0.01) but not with glycaemic control (P=0.12). Smoking, ischaemic heart disease and neuropathy (P<0.01) were all associated with increasing deprivation with gender differences. In type 2 diabetes, reduced HDL cholesterol (P<0.01 both genders), and percentage of people on lipid lowering therapy (men P<0.05; women P<0.01) were associated with deprivation. Smoking, ischaemic heart disease, peripheral vascular disease and neuropathy plus foot ulcers (P<0.05) were all associated with increasing deprivation with gender differences. CONCLUSIONS: Socioeconomic status and gender are associated with changes in glycaemic control and cardiovascular risk factors plus complication development in both type 1 and 2 diabetes. The mechanisms are unclear but follow up of these patients should allow greater understanding. PMID- 25454093 TI - A novel dual-frequency imaging method for intravascular ultrasound applications. AB - Intravascular ultrasound (IVUS), which is able to delineate internal structures of vessel wall with fine spatial resolution, has greatly enriched the knowledge of coronary atherosclerosis. A novel dual-frequency imaging method is proposed in this paper for intravascular imaging applications. A probe combined two ultrasonic transducer elements with different center frequencies (36 MHz and 78 MHz) is designed and fabricated with PMN-PT single crystal material. It has the ability to balance both imaging depth and resolution, which are important imaging parameters for clinical test. A dual-channel imaging platform is also proposed for real-time imaging, and this platform has been proven to support programmable processing algorithms, flexible imaging control, and raw RF data acquisition for IVUS applications. Testing results show that the -6 dB axial and lateral imaging resolutions of low-frequency ultrasound are 78 and 132 MUm, respectively. In terms of high-frequency ultrasound, axial and lateral resolutions are determined to be as high as 34 and 106 MUm. In vitro intravascular imaging on healthy swine aorta is conducted to demonstrate the performance of the dual-frequency imaging method for IVUS applications. PMID- 25454094 TI - Multiple beam splitting in elastic phononic crystal plates. AB - This work presents an experimental evidence for triple beam splitting in an elastic plate with an embedded elastic phononic crystal (PC) prism and elaborates on its working mechanism. While there were reports on negative refraction and double beam splitting with PCs, no experimental evidence on the splitting of triple or more ultrasonic elastic beams through PCs has been shown yet. After the experimental results are presented in case of triple beam splitting, further analysis is carried out to explain how triple or more beams can be split depending on elastic PC prism angles. PMID- 25454095 TI - A T-shape linear piezoelectric motor with single foot. AB - A new T-shape piezoelectric motor using the hybrid of two orthogonal longitudinal vibrations is proposed in this work. Six pieces of PZT ceramic plates are bonded on the upside and downside surfaces of a T-shape duralumin alloy base respectively to form the proposed motor. Elliptical movement can be generated on the driving tip by applying sine and cosine voltages to the PZT elements. The horizontal displacement of the driving tip will push the runner while the vertical displacement can overcome the preload. Finite element method is used to accomplish the design and analysis process. The resonance frequencies of the two vibration modes are tuned to be close by modal analysis, while the motion trajectory of the driving tip is observed by transient analysis. After the fabrication of a prototype, the vibration characteristics and mechanical output ability are measured. The no-load speed and the maximum output thrust force of the proposed motor are tested to be 718 mm/s and 3.5 N under an exciting frequency of 53.1 kHz. The proposed T-shape piezoelectric motor exhibits merits of simple structure, easy to realize miniaturization, easy to be fabricated, and high power-to-weight ratio. PMID- 25454096 TI - Ultrasonic test of resistance spot welds based on wavelet package analysis. AB - In this paper, ultrasonic test of spot welds for stainless steel sheets has been studied. It is indicated that traditional ultrasonic signal analysis in either time domain or frequency domain remains inadequate to evaluate the nugget diameter of spot welds. However, the method based on wavelet package analysis in time-frequency domain can easily distinguish the nugget from the corona bond by extracting high-frequency signals in different positions of spot welds, thereby quantitatively evaluating the nugget diameter. The results of ultrasonic test fit the actual measured value well. Mean value of normal distribution of error statistics is 0.00187, and the standard deviation is 0.1392. Furthermore, the quality of spot welds was evaluated, and it is showed ultrasonic nondestructive test based on wavelet packet analysis can be used to evaluate the quality of spot welds, and it is more reliable than single tensile destructive test. PMID- 25454097 TI - Perfusion pattern and time of vascularisation with CEUS increase accuracy in differentiating between benign and malignant tumours in 216 musculoskeletal soft tissue masses. AB - INTRODUCTION: Musculoskeletal Soft Tissue Tumours (STT) are frequent heterogeneous lesions. Guidelines consider a mass larger than 5 cm and deep with respect to the deep fascia potentially malignant. Contrast Enhanced Ultrasound (CEUS) can detect both vascularity and tumour neoangiogenesis. We hypothesised that perfusion patterns and vascularisation time could improve the accuracy of CEUS in discriminating malignant tumours from benign lesions. MATERIALS AND METHODS: 216 STT were studied: 40% benign lesions, 60% malignant tumours, 56% in the lower limbs. Seven CEUS perfusion patterns and three types of vascularisation (arterial-venous uptake, absence of uptake) were applied. Accuracy was evaluated by comparing imaging with the histological diagnosis. Univariate and multivariate analysis, Chi-square test and t-test for independent variables were applied; significance was set at p<0.05 level, 95% computed CI. RESULTS: CEUS pattern 6 (inhomogeneous perfusion), arterial uptake and location in the lower limb were associated with high risk of malignancy. CEUS pattern has PPV 77%, rapidity of vascularisation PPV 69%; location in the limbs is the most sensitive indicator, but NPV 52%, PPV 65%. The combination of CEUS-pattern and vascularisation has 74% PPV, 60% NPV, 70% sensitivity. No correlation with size and location in relation to the deep fascia was found. CONCLUSION: US with CEUS qualitative analysis could be an accurate technique to identify potentially malignant STT, for which second line imaging and biopsy are indicated in Referral Centers. Intense inhomogeneous enhancement with avascular areas and rapid vascularisation time could be useful in discriminating benign from malignant SST, overall when the lower limbs are involved. PMID- 25454098 TI - Breast MRI used as a problem-solving tool reliably excludes malignancy. AB - PURPOSE: To evaluate the diagnostic performance of breast MRI if used as a problem-solving tool in BI-RADS 0 cases. MATERIAL AND METHODS: In this IRB approved, single-center study, 687 women underwent high-resolution-3D, dynamic contrast-enhanced breast magnetic resonance imaging (MRI) between January 2012 and December 2012. Of these, we analyzed 111 consecutive patients (mean age, 51 +/- 12 years; range, 20-83 years) categorized as BI-RADS 0. Breast MRI findings were stratified by clinical presentations, conventional imaging findings, and breast density. MRI results were compared to the reference standard, defined as histopathology or an imaging follow-up of at least 1 year. RESULTS: One hundred eleven patients with BI-RADS 0 conventional imaging findings revealed 30 (27%) mammographic masses, 57 (51.4%) mammographic architectural distortions, five (4.5%) mammographic microcalcifications, 17 (15.3%) ultrasound-only findings, and two palpable findings without imaging correlates. There were 15 true-positive, 85 true-negative, 11 false-positive, and zero false-negative breast MRI findings, resulting in a sensitivity, specificity, PPV, and NPV of 100% (15/15), 88.5% (85/96), 57.7% (15/26), and 100% (85/85), respectively. Breast density and reasons for referral had no significant influence on the diagnostic performance of breast MRI (p>0.05). CONCLUSION: Breast MRI reliably excludes malignancy in conventional BI-RADS 0 cases resulting in a NPV of 100% (85/85) and a PPV of 57.7% (15/26). PMID- 25454099 TI - Abbreviated protocol for breast MRI: are multiple sequences needed for cancer detection? AB - OBJECTIVE: To evaluate the ability of an abbreviated breast magnetic resonance imaging (MRI) protocol, consisting of a precontrast T1 weighted (T1W) image and single early post-contrast T1W image, to detect breast carcinoma. MATERIALS AND METHODS: A HIPAA compliant Institutional Review Board approved review of 100 consecutive breast MRI examinations in patients with biopsy proven unicentric breast carcinoma. 79% were invasive carcinomas and 21% were ductal carcinoma in situ. Four experienced breast radiologists, blinded to carcinoma location, history and prior examinations, assessed the abbreviated protocol evaluating only the first post-contrast T1W image, post-processed subtracted first post-contrast and subtraction maximum intensity projection images. Detection and localization of tumor were compared to the standard full diagnostic examination consisting of 13 pre-contrast, post-contrast and post-processed sequences. RESULTS: All 100 cancers were visualized on initial reading of the abbreviated protocol by at least one reader. The mean sensitivity for each sequence was 96% for the first post-contrast sequence, 96% for the first post-contrast subtraction sequence and 93% for the subtraction MIP sequence. Within each sequence, there was no significant difference between the sensitivities among the 4 readers (p=0.471, p=0.656, p=0.139). Mean interpretation time was 44s (range 11-167s). The abbreviated imaging protocol could be performed in approximately 10-15 min, compared to 30-40 min for the standard protocol. CONCLUSION: An abbreviated breast MRI protocol allows detection of breast carcinoma. One pre and post contrast T1W sequence may be adequate for detecting breast carcinoma. These results support the possibility of refining breast MRI screening protocols. PMID- 25454100 TI - Breast imaging reporting and data system (BI-RADS) lexicon for breast MRI: interobserver variability in the description and assignment of BI-RADS category. AB - PURPOSE: To retrospectively evaluate interobserver variability between breast radiologists when describing abnormal enhancement on breast MR examinations and assigning a BI-RADS category using the Breast Imaging Reporting and Data System (BI-RADS) terminology. MATERIALS AND METHODS: Five breast radiologists blinded to patients' medical history and pathologic results retrospectively and independently reviewed 257 abnormal areas of enhancement on breast MRI performed in 173 women. Each radiologist described the focal enhancement using BI-RADS terminology and assigned a final BI-RADS category. Krippendorff's alpha coefficient of agreement was used to asses interobserver variability. RESULTS: All radiologists agreed on the morphology of enhancement in 183/257 (71%) lesions, yielding a substantial agreement (Krippendorff's alpha=0.71). Moderate agreement was obtained for mass descriptors - shape, margins and internal enhancement - (alpha=0.55, 0.51 and 0.45 respectively) and NME (non-mass enhancement) descriptors - distribution and internal enhancement - (alpha=0.54 and 0.43). Overall substantial agreement was obtained for BI-RADS category assignment (alpha=0.71). It was however only moderate (alpha=0.38) for NME compared to mass (alpha=0.80). CONCLUSION: Our study shows good agreement in describing mass and NME on a breast MR examination but a better agreement in predicting malignancy for mass than NME. PMID- 25454102 TI - Editors' message. PMID- 25454104 TI - Discussion. PMID- 25454101 TI - Lessons learnt on recruitment and fieldwork from a pilot European human biomonitoring survey. AB - Within the European Environment and Health Action Plan an initiative to establish a coherent human biomonitoring approach in Europe was started. The project COPHES (COnsortium to Perform Human biomonitoring on a European Scale ) developed recommendations for a harmonized conduct of a human biomonitoring (HBM) survey which came into action as the pilot study DEMOCOPHES (DEMOnstration of a study to COordinate and Perform Human biomonitoring on a European Scale). Seventeen European countries conducted a survey with harmonized instruments for, inter alia, recruitment, fieldwork and sampling, in autumn/winter 2011/2012. Based on the countries' experiences of conducting the pilot study, following lessons learnt were compiled: the harmonized fieldwork instruments (basic questionnaire, urine and hair sampling) turned out to be very valuable for future HBM surveys on the European scale. A school approach was favoured by most of the countries to recruit school-aged children according to the established guidelines and country specific experiences. To avoid a low participation rate, intensive communication with the involved institutions and possible participants proved to be necessary. The communication material should also include information on exclusion criteria and offered incentives. Telephone contact to the participants the day before fieldwork during the survey can prevent the forgetting of appointments and first morning urine samples. To achieve comparable results on the European scale, training of interviewers in all issues of recruitment, fieldwork and sampling through information material and training sessions is crucial. A survey involving many European countries needs time for preparation and conduct. Materials for quality control prepared for all steps of recruitment, fieldwork and sampling proved to be important to warrant reliable results. PMID- 25454103 TI - Management of the left subclavian artery and neurologic complications after thoracic endovascular aortic repair. AB - OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) of various pathologies has been associated with peri-interventional neurologic complication rates of up to 15%. The objective of this study was to determine the influence of the management of the left subclavian artery (LSA) on neurologic complications and to define subgroups that might benefit from LSA revascularization. METHODS: The Medtronic Thoracic Endovascular Registry (MOTHER; Medtronic, Santa Rosa, Calif), consists of data from five sponsored trials and one institutional series incorporating 1010 patients undergoing TEVAR from 2002 to 2010. Perioperative stroke and spinal cord injury (SCI) rates were described according to the management of the LSA and presenting pathology. Multivariate analysis was performed to determine factors associated with perioperative neurologic complications. RESULTS: Of 1002 patients included in the analysis, stroke occurred in 48 (4.8%), and SCI developed in 42 (4.2%) <= 30 days of surgery. The stroke rate was 2.2% in patients with no coverage of the LSA vs 9.1% with coverage alone and 5.1% in patients who underwent LSA revascularization before coverage (P < .001). This relationship was strongest in the aneurysm group. Coverage of the LSA without revascularization was independently associated with stroke (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.7-7.1), specifically in the posterior territory (OR, 11.7; 95% CI, 2.5-54.6), as was previous cerebrovascular accident (OR, 7.1; 95% CI, 2.2 23.1; P = .001), whereas a covered LSA was not associated with an increased risk of SCI. CONCLUSIONS: Coverage of the LSA without revascularization is an important modifiable risk factor for stroke in patients undergoing TEVAR for a thoracic aortic aneurysm. Prior revascularization appears to protect against posterior circulation territory stroke. PMID- 25454105 TI - The effect of Surgical Care Improvement Project measures on national trends on surgical site infections in open vascular procedures. AB - OBJECTIVE: The Surgical Care Improvement Project (SCIP) is a national initiative to reduce surgical complications, including postoperative surgical site infection (SSI), through protocol-driven antibiotic usage. This study aimed to determine the effect SCIP guidelines have had on in-hospital SSIs after open vascular procedures. METHODS: The Nationwide Inpatient Sample (NIS) was retrospectively analyzed using International Classification of Diseases, Ninth Revision, diagnosis codes to capture SSIs in hospital patients who underwent elective carotid endarterectomy, elective open repair of an abdominal aortic aneurysm (AAA), and peripheral bypass. The pre-SCIP era was defined as 2000 to 2005 and post-SCIP was defined as 2007 to 2010. The year 2006 was excluded because this was the transition year in which the SCIP guidelines were implemented. Analysis of variance and chi(2) testing were used for statistical analysis. RESULTS: The rate of SSI in the pre-SCIP era was 2.2% compared with 2.3% for carotid endarterectomy (P = .06). For peripheral bypass, both in the pre- and post-SCIP era, infection rates were 0.1% (P = .22). For open, elective AAA, the rate of infection in the post-SCIP era increased significantly to 1.4% from 1.0% in the pre-SCIP era (P < .001). Demographics and in-hospital mortality did not differ significantly between the groups. CONCLUSIONS: Implementation of SCIP guidelines has made no significant effect on the incidence of in-hospital SSIs in open vascular operations; rather, an increase in SSI rates in open AAA repairs was observed. Patient-centered, bundled approaches to care, rather than current SCIP practices, may further decrease SSI rates in vascular patients undergoing open procedures. PMID- 25454106 TI - Biomechanics and gene expression in abdominal aortic aneurysm. AB - OBJECTIVE: The aim of the study was to detect inter-relations between the mechanical conditions and material properties of abdominal aortic aneurysm (AAA) wall and the underlying local gene expression of destabilizing inflammatory, proteolytic, and structural factors. METHODS: During open surgery, 51 tissue samples from 31 AAA patients were harvested. Gene expression of collagen types I and III, inflammatory factors CD45 and MSR1, proteolytic enzymes matrix metalloproteinases 2 and 9, and tissue inhibitor of matrix metalloproteinase 1 was analyzed by reverse transcription-polymerase chain reaction. Material properties of corresponding AAA tissue samples were assessed by cyclic sinusoidal and destructive testing. Local mechanical conditions of stress and strain were determined by advanced nonlinear finite element analysis based on patient specific three-dimensional AAA models derived from preoperative computed tomography data. RESULTS: In the AAA wall, all parameters analyzed were significantly expressed at the messenger RNA level. With respect to mechanical properties of the aneurysmatic wall, expression of collagen III correlated with the stiffness parameter alpha (r = -0.348; P = .017), and matrix metalloprotease 2 correlated with the stiffness parameter beta and wall strength (r = -0.438 and 0.593; P = .005 and P < .001). Furthermore, significant relationships were observed between local AAA diameter and the expression of CD45, MSR1, and tissue inhibitor of matrix metalloproteinase 1 (r = 0.285, 0.551, 0.328; P < .05). However, we found no inter-relation of local calculated wall stresses and strains with gene expression. CONCLUSIONS: Our results show for the first time that gene expressions of destabilizing factors within AAA tissue might be correlated to geometric and mechanical properties of the AAA wall. However, we found no influence of local mechanical conditions on gene expression of these factors. Therefore, these preliminary results are still ambiguous. PMID- 25454107 TI - Computational fluid dynamic analysis of the effect of morphologic features on distraction forces in fenestrated stent grafts. AB - OBJECTIVE: Secure fixation of endovascular stent grafts is essential for successful endovascular aneurysm repair. Hemodynamic distraction forces are generated by blood pressure and blood flow and act against fixation force to encourage migration that may eventually lead to late stent graft failure. The aim of this in silico study was to determine which morphologic features were associated with greater distraction force. METHODS: Computer models of 54 in situ fenestrated stent grafts were constructed from postoperative computed tomography scans by use of image processing software. Computational fluid dynamic analysis was then performed by use of a commercial finite volume solver with boundary conditions representative of peak systole. Distraction force results were obtained for each component of the stent graft. Distraction force was correlated with lumen cross-sectional area (XSA) at the inlet and outlet of components and was compared between groups of components, depending on the magnitude of four predefined angles within the aortoiliac territory that we describe in detail. RESULTS: Median total resultant distraction force (RDF) acting on the fenestrated proximal bodies was 4.8 N (1.3-15.7 N); bifurcated distal bodies, 5.6N (1.0-8.0 N); and limb extensions, 1.7 N (0.6-8.4N). Inlet XSA exhibited strong, positive correlation with total RDF in proximal body and distal body components (Spearman correlation coefficient rho, 0.883 and 0.802, respectively). Outlet XSA exhibited a similarly strong, positive correlation with total RDF in limb extension components (rho, 0.822). Outlet angulation >= 45 degrees was associated with greater total RDF in the limb extension components only (P = .004). CONCLUSIONS: For a given blood pressure, XSA was the most important morphologic determinant of total RDF. Angulation within the aorta was not large enough to influence this, whereas iliac angulation affecting outlet angulation of limb extension components was associated with significantly greater total RDF. PMID- 25454108 TI - Fifty-nine-year-old man with abrupt-onset claudication. PMID- 25454109 TI - Aortic and inferior vena cava bifurcated stent graft application in the endovascular management of a ruptured abdominal aortic aneurysm with an aortocaval fistula. PMID- 25454110 TI - Discovering overtreatment: second-opinion dilemma. AB - An experienced vascular surgeon, Dr Al Wright, specializing in venous disease, often sees self-referred patients seeking second opinions primarily for ablation therapy and is deeply disturbed at what he finds. Some patients have no reflux on ultrasound examination and, thus, no treatment is indicated. Others were told they need a ludicrous three to seven ablations in each leg where only one or at most two are needed. Several advertise their services in the media. Dr Wright asked esteemed colleagues from the American Venous Forum what they recommended and they suggested sending a copy of his consultation to the first consultant with the goal of shaming him. He also notified the state medical board 2 years ago about one egregious repeat offender, without action. What should he do? A. Do as suggested, send your consult along with a harsh letter. B. Do nothing. It is none of your business. C. Notify the state medical board, again. D. Notify the insurance companies and regulators. E. There is no good venue to deal with the problem. PMID- 25454111 TI - Debate: Whether evidence supports reducing the threshold diameter to 5 cm for elective interventions in women with abdominal aortic aneurysms. AB - Current practice guidelines recommend repair of asymptomatic abdominal aortic aneurysms once they reach the 5.5-cm-diameter threshold and are based on information from randomized controlled trials. However, because aneurysms are more common in men, women are under-represented in these trials, and questions persist about whether this repair threshold should apply to them. In addition, women have smaller aortas to begin with and in most aneurysm cohorts are older, have more atherosclerotic risk factors, are less likely to be anatomic candidates for endovascular repair, and do poorer after emergency or elective repair of their aneurysm. These are just some of the issues that our discussants address in determining whether the repair threshold should be at a smaller diameter for women. PMID- 25454112 TI - Editors' commentary. PMID- 25454113 TI - A comparison of phantom scatter from flattened and flattening filter free high energy photon beams. AB - Flattening filter free (FFF) photon beams have different dosimetric properties from those of flattened beams. The aim of this work was to characterize the collimator scatter (Sc) and total scatter (Scp) from 3 FFF beams of differing quality indices and use the resulting mathematical fits to generate phantom scatter (Sp) data. The similarities and differences between Sp of flattened and FFF beams are described. Sc and Scp data were measured for 3 flattened and 3 FFF high-energy photon beams (Varian 6 and 10MV and Elekta 6MV). These data were fitted to logarithmic power law functions with 4 numerical coefficients. The agreement between our experimentally determined flattened beam Sp and published data was within +/- 1.2% for all 3 beams investigated and all field sizes from 4 * 4 to 40 * 40cm(2). For the FFF beams, Sp was only within 1% of the same flattened beam published data for field sizes between 6 * 6 and 14 * 14cm(2). Outside this range, the differences were much greater, reaching - 3.2%, - 4.5%, and - 4.3% for the fields of 40 * 40cm(2) for the Varian 6-MV, Varian 10-MV, and Elekta 6-MV FFF beams, respectively. The FFF beam Sp increased more slowly with increasing field size than that of the published and measured flattened beam of a similar reference field size quality index, i.e., there is less Phantom Scatter than that found with flattened beams for a given field size. This difference can be explained when the fluence profiles of the flattened and FFF beams are considered. The FFF beam has greatly reduced fluence off axis, especially as field size increases, compared with the flattened beam profile; hence, less scatter is generated in the phantom reaching the central axis. PMID- 25454114 TI - Impact of DSM-5 PTSD and gender on impaired eating behaviors in 512 Italian earthquake survivors. AB - Considerable comorbidity rates between Post-traumatic Stress Disorder (PTSD) and eating disorders have been recently reported, as well as increased obesity and underweight conditions. The aim of the present study was to investigate the possible associations between DSM-5 PTSD, gender and impaired eating habits in a sample of 512 Italian earthquake survivors evaluated by the Trauma and Loss Spectrum-Self Report (TALS-SR) and the Mood Spectrum-Self Report (MOODS-SR). Alterations in eating behaviors were assessed by means of four MOODS-SR items: n=150 (...there was no food that appealed to you or tasted good to you?), n=151 (...you constantly craved sweets or carbohydrates?), n=152 (...your appetite or weight decreased?), n=153 (...your appetite or weight increased?). In a Decision Tree procedure subjects with PTSD with respect to those without and, in the No PTSD subgroup, females with respect to males, had a significantly higher ratio of at least one MOODS-SR eating behavior item (MOODS-SR EB). In the No-PTSD subgroup only, subjects with at least one MOODS-SR EB presented a significantly higher mean TALS-SR symptomatological domains total score with respect to those without MOODS-SR EB. In conclusion, alterations in eating behaviors were associated with PTSD after the L'Aquila earthquake; among survivors without PTSD significant a correlation emerged between MOODS-SR EB and PTSD symptoms. PMID- 25454116 TI - Relationship between atypical depression and social anxiety disorder. AB - In this study, we aimed to investigate the effects of atypical and non-atypical depression comorbidity on the clinical characteristics and course of social anxiety disorder (SAD). A total of 247 patients with SAD were enrolled: 145 patients with a current depressive episode (unipolar or bipolar) with atypical features, 43 patients with a current depressive episode with non-atypical features and 25 patients without a lifetime history of depressive episodes were compared regarding sociodemographic and clinical features, comorbidity rates, and severity of SAD, depression and functional impairment. Thirty four patients with a past but not current history of major depressive episodes were excluded from the comparisons. 77.1% of current depressive episodes were associated with atypical features. Age at onset of SAD and age at initial major depressive episode were lower in the group with atypical depression than in the group with non-atypical depression. History of suicide attempts and bipolar disorder comorbidity was more common in the atypical depression group as well. Atypical depression group has higher SAD and depression severity and lower functionality than group with non-atypical depression. Our results indicate that the presence of atypical depression is associated with more severe symptoms and more impairment in functioning in patients with SAD. PMID- 25454115 TI - Assessing motivation orientations in schizophrenia: Scale development and validation. AB - Motivation deficits are common in several disorders including schizophrenia, and are an important factor in both functioning and treatment adherence. Self Determination Theory (SDT), a leading macro-theory of motivation, has contributed a number of insights into how motivation is impaired in schizophrenia. Nonetheless, self-report measures of motivation appropriate for people with severe mental illness (including those that emphasize SDT) are generally lacking in the literature. To fill this gap, we adapted and abbreviated the well validated General Causality Orientation Scale for use with people with schizophrenia and with other severe mental disorders (GCOS-clinical populations; GCOS-CP). In Study 1, we tested the similarity of our measure to the existing GCOS (using a college sample) and then validated this new measure in a schizophrenia and healthy control sample (Study 2). Results from Study 1 (N=360) indicated that the GCOS-CP was psychometrically similar to the original GCOS and provided good convergent and discriminant validity. In Study 2, the GCOS-CP was given to individuals with (N=44) and without schizophrenia (N=42). In line with both laboratory-based and observer-based research, people with schizophrenia showed lower motivational autonomy and higher impersonal/amotivated orientations. Additional applications of the GCOS-CP are discussed. PMID- 25454117 TI - The influence of personality on the sensitivity to subjective effects of Delta9 tetrahydrocannabinol. AB - The effects of drugs are not only determined by their pharmacological action, but also by user characteristics. This analysis explored the influence of personality on the differences in subjective effects in response to a standardized pharmacological challenge with the cannabinoid CB1/CB2 partial agonist Delta9 tetrahydrocannabinol (THC). To express the sensitivity to THC, pharmacokinetic pharmacodynamic (PK-PD) non-linear mixed effects modelling was applied to the subjective response of 184 healthy subjects to a pharmacological challenge with inhalation of THC. The subjective effects were measured using visual analogue scales and described by three clusters: 'perception', 'relaxation' and 'dysphoria'. The sensitivity for THC (described as EC50) was related to scores on Cloninger's temperament and character inventory (TCI) using multiple linear regression. Effect compartment models were used to describe the PK-PD relations of THC. Within the multivariate model, 'harm avoidance' was significantly correlated with changes in 'perception', and 'self-transcendence' with changes in 'dysphoria'. Within the psychobiological model of personality, 'harm avoidance' is related to serotonergic systems. Subjects with either very low (easy-going) or very high (cautious) scores were less sensitive to THC-induced changes in 'perception'. 'Self-transcendence' relates to schizotypy. Subjects with more schizotypy were more sensitive to the dysphoric subjective effects of THC. PMID- 25454118 TI - Gender differences in psychiatric disorders and clusters of self-esteem among detained adolescents. AB - Detained minors display substantial mental health needs. This study focused on two features (psychopathology and self-esteem) that have received considerable attention in the literature and clinical work, but have rarely been studied simultaneously in detained youths. The aims of this study were to examine gender differences in psychiatric disorders and clusters of self-esteem, and to test the hypothesis that the cluster of adolescents with lower (versus higher) levels of self-esteem have higher rates of psychiatric disorders. The prevalence of psychiatric disorders was assessed in 440 Belgian, detained adolescents using the Diagnostic Interview Schedule for Children-IV. Self-esteem was assessed using the Self-perception Profile for Adolescents. Model-based cluster analyses were performed to identify youths with lower and/or higher levels of self-esteem across several domains. Girls have higher rates for most psychiatric disorders and lower levels of self-esteem than boys. A higher number of clusters was identified in boys (four) than girls (three). Generally, the cluster of adolescents with lower (versus higher) levels of self-esteem had a higher prevalence of psychiatric disorders. These results suggest that the detection of low levels of self-esteem in adolescents, especially girls, might help clinicians to identify a subgroup of detained adolescents with the highest prevalence of psychopathology. PMID- 25454120 TI - Intelligence as a predictor of outcome in short- and long-term psychotherapy. AB - Intelligence has been suggested as a suitability factor for short-term therapy whereas its possible effect on short-term versus long-term therapy still is unknown. The aim of this study was to compare the prediction of intelligence on the level of psychiatric symptoms and psychosocial functioning in psychotherapies of different lengths. A total of 251 outpatients from the Helsinki Psychotherapy Study, aged 20-46 years, and suffering from mood or anxiety disorders were allocated to two long-term and two short-term therapies. Intelligence was assessed at baseline with the Wechsler Adult Intelligence Scale (WAIS-R). Psychiatric symptoms and psychosocial functioning were assessed 5-10 times during a 5-year follow-up using two primary symptom measures (HDRS and HARS) and one primary measure of psychosocial functioning (GAF). Short-term therapy was more effective than long-term therapy during the first year of follow-up. During the second to fourth follow-up year no differences between short- and long-term therapies or the intelligence groups were found. At the fifth follow-up year, however, long-term psychotherapy showed a statistically significantly larger change in all three primary measures compared to short-term therapy among those with higher intelligence. No differences between therapy groups were noted in those with lower intelligence. People with higher intelligence may benefit more from long-term than from short-term psychotherapy. These findings should be confirmed. PMID- 25454119 TI - Parents and friendships: a longitudinal examination of interpersonal mediators of the relationship between child maltreatment and suicidal ideation. AB - This study examined parental relationship quality, friendship quality, and depression as mediators of the association between child maltreatment (CM) and adolescent suicidal ideation (SI). Participants were 674 adolescents (46% female; 55% African American) involved in the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN). Data were collected via youth self-report at ages 12, 16, and 18. CM before age 12 predicted poor parental relationships and depression, but not poor friendships, at age 16. Age 16 depression was negatively associated with parental relationship quality and positively associated with SI at age 18. An indirect path from CM to SI via depression was significant, suggesting that the early CM affects depression severity, which in turn is associated with SI. Strong friendship quality (age 16) was associated with SI at age 18; however, there was no significant indirect path from CM to SI via friendships. Results suggest that: 1) CM before age 12 affects parental relationships in adolescence; 2) depression and friendships are related to suicide ideation in later adolescence; and 3) depression partially mediates the association between CM and SI. Results highlight the importance of assessing for a history of CM, quality of interpersonal relationships, and depression severity among youth reporting SI. PMID- 25454121 TI - Overexpression of NMDAR2B in an inflammatory model of Alzheimer's disease: modulation by NOS inhibitors. AB - BACKGROUND: Alzheimer's disease (AD) is a common form of age-related dementia, characterized by deposition of amyloid Abeta plaques, neuroinflammation and neurodegeneration. N-methyl-D-aspartate receptors (NMDAR) are postsynaptic glutamate receptors that play a role in memory formation and are targets for memantadine, an anti-AD drug. Nitric oxide (NO) signaling has been involved in both memory development through neuronal NO synthase (nNOS), and neuroinflammation through inducible NO synthase (iNOS) which mediates CNS inflammatory processes. AIM: To study the expression of the NMDAR2B subunit in an inflammatory model of AD before and after treatment with NO modulators. MATERIALS AND METHODS: AD was induced in mice by a single dose of lipopolysaccharide (LPS). Behavioral tests for spatial and non-spatial memories and locomotor activity were performed to assess disease severity and progression. The effects of L-NAME (general NOS inhibitor), 1400W (iNOS inhibitor), diflunisal (systemic anti inflammatory drug that does not cross the blood brain barrier), and L-arginine, the substrate for NOS was determined. Immunohistochemistry was done to confirm AD and brain lysates were tested for Abeta formation, levels of NMDAR2B subunits, and brain NO levels. RESULTS: Systemic LPS induced AD, as shown by cognitive impairment; increased levels of Abeta and concomitant increase in the brain NO concentrations. This was associated with overexpression of NMDAR2B. All tested drugs improved behavioral dysfunction, prevented Abeta formation and NMDAR overexpression, and lead to decrease in NO concentration in the brain. L-Arginine alone, however, did not produce similar improvements. CONCLUSION: NMDAR2B subunits are overexpressed in an inflammatory model of AD and NO inhibitors ameliorate this expression. PMID- 25454122 TI - Altered behavioral development in Nrf2 knockout mice following early postnatal exposure to valproic acid. AB - Early exposure to valproic acid results in autism-like neural and behavioral deficits in humans and other animals through oxidative stress-induced neural damage. In the present study, valproic acid was administered to genetically altered mice lacking the Nrf2 (nuclear factor-erythroid 2 related factor 2) gene on postnatal day 14 (P14). Nrf2 is a transcription factor that induces genes that protect against oxidative stress. It was found that valproic acid-treated Nrf2 knockout mice were less active in open field activity chambers, less successful on the rotorod, and had deficits in learning and memory in the Morris water maze compared to the valproic acid-treated wild type mice. Given these results, it appears that Nrf2 knockout mice were more sensitive to the neural damage caused by valproic acid administered during early development. PMID- 25454124 TI - Method development for simultaneous analyses of multiple legacy and emerging organic chemicals in sediments. AB - The objective of this work was to investigate the feasibility of using a single pretreatment procedure for the analyses of multiple groups of organics, which have a wide range of chemical structures and physicochemical properties, in sediment samples. Nine groups of 162 individual compounds (including 11 surrogates) were investigated, including polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), polychlorinated diphenyl ethers (PCDEs), polychlorinated naphthalenes (PCNs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), novel halogenated flame retardants (nXFRs), musk fragrances (MFs) and organophosphate flame retardants (OPFRs). The individual and grouped recoveries of spiked analytes from adsorption chromatographic columns using either only fully activated, neutral silica gel (SG) or the combinations of silica gel and alumina (Si/Al) sorbents were compared. The results showed a generally stronger adsorption and more effective fractionation on the Si/Al column than on the SG column. The dependence of fractionation on halogen substitution, molecular planarity, and polar functional groups was discussed. The effects of adding sulfuric acid with two different methods were investigated, and the recoveries of a number of MFs, OCPs, nXFRs and OPFRs were recovered less than 60%. Sodium hydroxide treatment of silica gel had minor effects on some OPFRs. Copper used to remove elemental sulfur did not affect the recoveries of all target analytes except chloroneb. The finalized method was validated by spiking the target analysts into the sediment samples and comparing the analytical results of this work on two standard reference materials for sediment (SRMs 1941b and 1944) with the certified or reference values. PMID- 25454125 TI - Preparation of durable graphene-bonded titanium fibers for efficient microextraction of phthalates from aqueous matrices and analysis with gas chromatography-mass spectrometry. AB - A solid-phase microextraction fiber (SPME) was synthesized for pre-concentration of 15 phthalates from aqueous samples. Graphene oxide was immobilized on Ti wire with titanol groups using a cross-linking agent and subsequently reduced to yield a folded and wrinkled graphene coating. This graphene-Ti fiber demonstrated durable mechanical robustness and enhanced stability for more than 200 extraction cycles due to the Ti substrate and chemical bond. The extraction efficiencies reached highest when the graphene layers were four and their performances were superior to commercial SPME fibers. The prepared fiber was used for pre concentration of phthalates from aqueous samples by direct immersion extraction and thermal desorption for gas chromatography-mass spectrometry analysis. The method was utilized for the simultaneous analysis of 15 phthalates with satisfactory recoveries in the range of 82.8-97.8% for bottled water and 73.3 102.0% for intravenous drips in plastic packaging. PMID- 25454123 TI - Rasgrf2 controls dopaminergic adaptations to alcohol in mice. AB - Alcohol abuse leads to serious health problems with no effective treatment available. Recent evidence suggests a role for ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) in alcoholism. Rasgrf2 is a calcium sensor and MAPK/ERK activating protein, which has been linked to neurotransmitter release and monoaminergic receptor adaptations. Rasgrf2 knock out (KO) mice do not develop a dopamine response in the nucleus accumbens after an alcohol challenge and show a reduced consumption of alcohol. The present study aims to further characterise the role of Rasgrf2 in dopaminergic activation beyond the nucleus accumbens following alcohol treatment. Using in vivo microdialysis we found that alcohol induces alterations in dopamine levels in the dorsal striatum between wildtype (WT) and Rasgrf2 KO mice. There was no difference in the expression of dopamine transporter (DAT), dopamine receptor regulating factor (DRRF), or dopamine D2 receptor (DRD2) mRNA in the brain between Rasgrf2 KO and WT mice. After sub-chronic alcohol treatment, DAT and DRRF, but not DRD2 mRNA expression differed between WT and Rasgrf2 KO mice. Brain adaptations were positively correlated with splenic expression levels. These data suggest that Rasgrf2 controls dopaminergic signalling and adaptations to alcohol also in other brain regions, beyond the nucleus accumbens. PMID- 25454127 TI - Evaluation of phenylene-bridged periodic mesoporous organosilica as a stationary phase for solid phase extraction. AB - A periodic mesoporous organosilica, in particular, a phenylene-bridged material (Ph-PMO), was evaluated for the first time as a sorbent for retaining and eluting fenuron, simazine, atrazine, carbaryl and terbutryn in grape must by solid phase extraction (SPE) prior to their determination with capillary electrophoresis coupled with ultraviolet detection (CE-UV). The analytes were used as model compounds to demonstrate the potential of Ph-PMO for increasing the sensitivity of CE. Under optimal conditions, the limits of detection for the analytes ranged from 0.6 to 4 MUg/L, and their limits of quantitation from 2 to 10 MUg/L. These values were comparable and, in some cases, even better than those obtained with C18 and HLB materials. Ph-PMO was characterized physicochemically by X-ray diffraction analysis, N2 adsorption-desorption measurements and laser diffraction particle sizing. The sorbent afforded the extraction of atrazine, carbaryl and terbutryn from grape must with mean recoveries ranging from 86 to 105%. Therefore, periodic mesoporous organosilicas possess a high potential as SPE materials. PMID- 25454126 TI - Ion exchange membranes as novel passive sampling material for organic ions: application for the determination of freely dissolved concentrations. AB - Many studies in pharmacology, toxicology and environmental science require a method for determining the freely dissolved concentration of a target substance. A recently developed tool for this purpose is equilibrium passive sampling with polymeric materials. However, this method has rarely been applied to ionic organic substances, primarily due to limited availability of convenient sorption materials. This study introduces ion exchange membranes (IEMs) as a novel passive sampling material for organic ions. The partitioning of 4-ethylbenzene-1 sulfonate, 2,4-dichlorophenoxyacetic acid and pentachlorophenol to one anion exchange membrane (FAS) and of difenzoquat, nicotine and verapamil to one cation exchange membrane (FKS) was investigated. All test substances exhibited a sufficiently high affinity for the respective IEM with logarithmic IEM-water partition coefficients >2.3. Sorption equilibrium was established quickly, within several hours for the FAS membrane and within 1-3 days for the FKS membrane. For permanently charged substances the partitioning to the IEMs was independent of pH, but was influenced by the salt composition of the test solution. For all test substances sorption to IEM was dependent on the substance concentration. Bovine serum albumin-water partition coefficients determined by passive sampling with IEMs agree well with those determined by the conventional dialysis method. The results of this study indicate that IEMs exhibit the potential to measure freely dissolved concentrations of organic ions in a simple and time-saving manner. PMID- 25454128 TI - Retention mechanism of hypercrosslinked polystyrene silica hybrid phase in normal phase chromatography. AB - Hypercrosslinked polystyrene phases have been described as quasi-normal phase because they lack discrete polar sites. Retention on the HC-Tol column is investigated using the Snyder-Soczewinski model. Solvent strength of different hexane-solvent binary mobile phase compositions can be predicted with solvent strength of pure dichloromethane (DCM, 0.159), tetrahydrofuran (THF, 0.22), and benzene (0.127). The HC-Tol column is shown to be a localizing adsorptive phase. Also, site-competition delocalization on HC-Tol demonstrates that whatever its adsorption groups are, they are able to participate in lateral interactions. PMID- 25454129 TI - Peptide imprinted receptors for the determination of the small cell lung cancer associated biomarker progastrin releasing peptide. AB - Peptide imprinted polymers were developed for detection of progastrin releasing peptide (ProGRP); a low abundant blood based biomarker for small cell lung cancer. The polymers targeted the proteotypic nona-peptide sequence NLLGLIEAK and were used for selective enrichment of the proteotypic peptide prior to LCMS based quantification. Peptide imprinted polymers with the best affinity characteristics were first identified from a 96-polymer combinatorial library. The effects of functional monomers, crosslinker, porogen, and template on adsorption capacity and selectivity for NLLGLIEAK were investigated and optimized. Ultimately, a solid phase extraction method was developed for highly selective enrichment of the target peptide from tryptic digests. PMID- 25454130 TI - Using contemporary liquid chromatography theory and technology to improve capillary gradient ion-exchange separations. AB - The gradient-performance limits of capillary ion chromatography have been assessed at maximum system pressure (34.5 MPa) using capillary columns packed with 4.1 MUm macroporous anion-exchange particles coated with 65 nm positively charged nanobeads. In analogy to the van-Deemter curve, the gradient performance was assessed applying different flow rates, while decreasing the gradient time inversely proportional to the increase in flow rate in order to maintain the same retention properties. The gradient kinetic-performance limits were determined at maximum system pressure, applying tG/t0=5, 10, and 20. In addition, the effect of retention on peak width was assessed in gradient mode for mono-, di-, and trivalent inorganic anions. The peak width of late-eluting ions can be significantly reduced by using concave gradient, resulting in better detection sensitivity. A signal enhancement factor of 8 was measured for a late-eluting ion when applying a concave instead of a linear gradient. For the analysis of a complex anion mixture, a coupled column with a total length of 1.05 m was operated at the kinetic-performance limit applying a linear 250 min gradient (tG/t0=10). The peak capacity varied between 200 and 380 depending on analyte retention, and hence on charge and size of the ion. PMID- 25454131 TI - Assessment of capillary anion exchange ion chromatography tandem mass spectrometry for the quantitative profiling of the phosphometabolome and organic acids in biological extracts. AB - Metabolic profiling has become an important tool in biological research, and the chromatographic separation of metabolites coupled with mass spectrometric detection is the most frequently used approach for such studies. The establishment of robust chromatographic methods for comprehensive coverage of the anionic metabolite pool is especially challenging. In this study, the development of a capillary ion exchange chromatography (capIC) - negative ESI tandem mass spectrometry (MS/MS) workflow for the quantitative profiling of the phosphometabolome (e.g., sugar phosphates and nucleotides) is presented. The chromatographic separation and MS/MS conditions were optimized, and the precision of repetitive injections and accuracy in terms of error percentage to true concentration were assessed. The precision is excellent for a capillary flow system with an average CV% of 8.5% for a 50-fmol standard injection and in the lower 2.4-4.4% range for higher concentrations (500-7,500 fmol). The limit of detection (LOD) ranges from 1 to 100 nM (5-500 fmol injected on column), and the limit of quantitation (LOQ) ranges from 1 to 500 nM (5-2,500 fmol injected on column). A fast gradient method with the injection of 50% methanol in water between analytical samples is needed to eliminate carry-over and ensure optimal re-equilibration of the column. Finally, the quantitative applicability of the system was tested on real biological matrices using the constant-volume standard addition method (SAM). Extracts of the human kidney Hek293 cell line were spiked with increasing concentrations of standards to determine the concentration of each metabolite in the sample. Forty-four metabolites were detected with an average uncertainty of 4.1%. Thus, the capIC-MS/MS method exhibits excellent selectivity, sensitivity and precision for the quantitative profiling of the phosphometabolome. PMID- 25454132 TI - Simultaneous detection and identification of precursors, degradation and co products of chemical warfare agents in drinking water by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. AB - Environmental markers of chemical warfare agents (CWAs) comprise millions of chemical structures. The simultaneous detection and identification of these environmental markers poses difficulty due to their diverse chemical properties. In this work, by using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF), a generic analytical method for the detection and identification of wide range of environmental markers of CWAs (including precursors, degradation and co-products of nerve agents and sesqui mustards) in drinking water, was developed. The chromatographic analysis of 55 environmental markers of CWAs including isomeric and isobaric compounds was accomplished within 20 min, using 1.8 MUm particle size column. Subsequent identification of the compounds was achieved by the accurate mass measurement of either protonated molecule [M+H](+) or ammonium adduct [M+NH4](+) and fragment ions. Isomeric and isobaric compounds were distinguished by chromatographic retention time, characteristic fragment ions generated by both in-source collision induced dissociation (CID) and CID in the collision cell by MS/MS experiments. The exact mass measurement errors for all ions were observed less than 3 ppm with internal calibration. The method limits of detection (LODs) and limits of quantification (LOQs) were determined in drinking water and found to be 1-50 ng mL(-1) and 5-125 ng mL(-1), respectively. Applicability of the proposed method was proved by determining the environmental markers of CWAs in aqueous samples provided by Organization for the Prohibition of Chemical Weapons during 34th official proficiency test. PMID- 25454133 TI - Dynamics of reactive chromatographic columns of inert core/hollow/film coated spherical packing: an analytical solution and applications. AB - The transient behavior of reactive-diffusive fixed-bed (chromatographic columns or reactors) packed with inert core/shell core/hollow/thin film coated monodisperse spherical rigid particles is investigated. We modeled the reactive sorption system with linear mass exchange law between the flowing and the stationary phases. The coupled governing partial differential equations were integrated analytically using Laplace transformations. The analytical closed form solution involves two infinite integrals. The closed form solution was integrated numerically and the breakthrough curves of the system were studied under the influence of the system parameters. The limiting cases are discussed, a simple asymptotic closed form solution for fixed-bed desorbers with monodisperse spherical particles is obtained, and results are generalized for similar kinetics of reactive chromatographic columns (fixed-beds) for diffusion/absorption into the inert core spherical packing. Further, potential applications of the mathematical model and results in processes such as liquid vapor extraction, various forms of chromatography, reactive sorption, multifunctional reactors, process intensification, and regeneration of ion exchange columns are briefly discussed. PMID- 25454134 TI - Using mass spectrometry to detect hydrolysed gluten in beer that is responsible for false negatives by ELISA. AB - Gluten is the collective name for a class of proteins found in wheat, rye, barley and oats. Eating gluten triggers an inappropriate auto-immune reaction in ~70 million people globally affected by coeliac disease, where the gut reacts to gluten proteins and this triggers an immune response, resulting in intestinal inflammation and damage. Gluten-free foods are now commonplace, however, it is difficult to accurately determine the gluten content of products claiming to be gluten-free using current methodologies as the antibodies are non-specific, show cross-reactivity and have different affinities for the different classes of gluten. The measurement of gluten in processed products is further confounded by modifications to the proteins that occur during processing and in some case hydrolysis of the proteins. In this study, LC-MS/MS was used to profile whole beer, and two beer fractions representing hydrolysed hordeins (<30 kDa) and hordein peptide fragments (<10 kDa). Subsequently, multiple reaction monitoring (MRM) MS enabled the relative quantification of selected peptide fragments in beer and revealed that certain classes of hordein were prone to hydrolysis (B- and D-hordein). Furthermore, select beers contained very high levels of gluten derived fragments. Strikingly, those beers that contained high levels of B hordein fragments gave near zero values by ELISA. The hydrolysed fragments that persist in beer show a dose-dependent suppression of ELISA measurement of gluten despite using a hordein standard for calibration of the assay. The development of MS-based methodology for absolute quantification of gluten is required for the accurate assessment of gluten, including hydrolysed forms, in food and beverages to support the industry, legislation and to protect consumers suffering from CD. PMID- 25454135 TI - Determination of aqueous two phase system binodal curves using a microfluidic device. AB - Aqueous two phase systems (ATPS) offer great potential for selective separation of a wide range of biomolecules by exploring differences in solubility in each of the two phases. However, their use has been greatly hindered due to poor theoretical understanding of the principles behind ATPS formation and the empirical and time-consuming techniques used for the determination of optimal extraction parameters including the binodal curves. In this work, characteristic ATPS binodal curves were determined by a novel technique in which the formation of an ATPS system is measured in a microfluidic device. Two solutions containing separate ATPS solution precursors were loaded into the side inlets of a three inlet microfluidic channel while milli-Q water was loaded into the middle inlet. By varying the flow rates of the three solutions, a wide range of concentrations inside the microchannel could be rapidly tested using limited volumes. Using optical microscopy, depending on the concentrations inside the microchannel, three different states could be observed at the end of the microchannel (i) the presence of an interface; (ii) no presence of an interface; or (iii) the presence of an unstable interface. The binodal curve was calculated using the points corresponding to unstable interfaces and compared to binodal curves obtained through the standard turbidometric titration method for both PEG/salt and PEG/dextran systems. PMID- 25454137 TI - Gradient retention prediction of acid-base analytes in reversed phase liquid chromatography: a simplified approach for acetonitrile-water mobile phases. AB - In previous work, a two-parameter model to predict chromatographic retention of ionizable analytes in gradient mode was proposed. However, the procedure required some previous experimental work to get a suitable description of the pKa change with the mobile phase composition. In the present study this previous experimental work has been simplified. The analyte pKa values have been calculated through equations whose coefficients vary depending on their functional group. Forced by this new approach, other simplifications regarding the retention of the totally neutral and totally ionized species also had to be performed. After the simplifications were applied, new prediction values were obtained and compared with the previously acquired experimental data. The simplified model gave pretty good predictions while saving a significant amount of time and resources. PMID- 25454136 TI - Separations of substituted benzenes and polycyclic aromatic hydrocarbons using normal- and reverse-phase high performance liquid chromatography with UiO-66 as the stationary phase. AB - Metal-organic frameworks (MOFs) have great potential for applications in chromatography due to their highly tailorable porous structures and unique properties. In this work, the stable MOF UiO-66 was evaluated as both a normal phase (NP-) and a reverse-phase (RP-) stationary phase in the high performance liquid chromatography (HPLC) to separate substituted benzenes (SBs) and polycyclic aromatic hydrocarbons (PAHs). It was found that the mobile phase composition has a significant effect on the HPLC separation. Baseline RP-HPLC separations of xylene isomers; naphthalene and anthracene; naphthalene and chrysene; and naphthalene, fluorene, and chrysene were achieved using MeOH/H2O ratios of 80:20, 75:25, 85:15, and 75:25, respectively, on the UiO-66 column. Similarly, baseline NP-HPLC separations of xylene isomers and ethylbenzene; ethylbenzene, styrene, o-xylene, and m-xylene; and several PAHs were also obtained on the UiO-66 column with different mobile phase compositions. The relative standard deviations (RSDs) of retention time, peak height, peak area, and half peak width for five replicate separations of the tested analytes were within the ranges 0.2-0.4%, 0.2-1.6%, 0.7-3.9%, 0.4-1.1%, respectively. We also evaluated other critical HPLC parameters, including injected sample mass, column temperature, and the thermodynamic characters of both the RP-HPLC and the NP-HPLC separation processes. It was confirmed that the separation of SBs on a UiO-66 column was an exothermic process, controlled by both enthalpy change (DeltaH) and entropy change (DeltaS). The reverse shape selectivity, size selectivity, stacking effect, and electrostatic force played vital roles in the separations of these analytes. To the best of our knowledge, this method is one of the very few examples of using MOFs as the stationary phase in both NP-HPLC and RP-HPLC. MOF based stationary phases may thus be applied in the separations and analyses of SBs and PAHs in environmental samples. PMID- 25454138 TI - Analysis of free amino acids in natural waters by liquid chromatography-tandem mass spectrometry. AB - This paper reports a new analytical method for the analysis of 18 amino acids in natural waters using solid-phase extraction (SPE) followed by liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS) operated in multiple reaction monitoring mode. Two different preconcentration methods, solid phase extraction and concentration under reduced pressure, were tested in development of this method. Although concentration under reduced pressure provided better recoveries and method limits of detection for amino acids in ultrapure water, SPE was a more suitable extraction method for real samples due to the lower matrix effects for this method. Even though the strong cation exchange resin used in SPE method introduced exogenous matrix interferences into the sample extracts (inorganic salt originating from the acid-base reaction during the elution step), the SPE method still incorporates a broad sample clean up and minimised endogenous matrix effects by reducing interferences originating from real water samples. The method limits of quantification (MLQ) for the SPE LC MS/MS method in ultrapure water ranged from 0.1 to 100 MUg L(-1) as N for the different amino acids. The MLQs of the early eluting amino acids were limited by the presence of matrix interfering species, such as inorganic salts in natural water samples. The SPE LC-MS/MS method was successfully applied to the analysis of amino acids in 3 different drinking water source waters: the average total free amino acid content in these waters was found to be 19 MUg L(-1) as N, while among the 18 amino acids analysed, the most abundant amino acids were found to be tyrosine, leucine and isoleucine. PMID- 25454139 TI - Oxidative protein refolding on size exclusion chromatography at high loading concentrations: fundamental studies and mathematical modeling. AB - Size exclusion chromatography has been demonstrated as an effective method for refolding a variety of proteins. However, to date process development mainly relies on laboratory experimentation of individual factors. A robust model is essential for high-throughput process screening and optimization of systems to provide higher productivity and refolding yield. In this work, a detailed kinetic scheme of oxidative refolding of a model protein (lysozyme) has been investigated to predict the refolding results in SEC. Non-reactive native, quenched and equilibrium studies were conducted to obtain the model parameters for the species formed during refolding of denatured/reduced lysozyme. The model was tested in various operating conditions, such as: protein loading concentration, injection volume, flow rate and composition of refolding buffer with and without the use of l-arginine additive. An apparent two-state mechanism was found adequate to describe refolding of lysozyme on SEC for the operating condition tested in this work. Furthermore, using low concentration of l-arginine combined with urea as common aggregation suppressor additives showed insignificant change in kinetics of refolding of lysozyme on SEC. However, addition of l-arginine changed mass transfer properties of some of the species formed in refolding reaction which was considered in the model to accurately predict the result of refolding on SEC. PMID- 25454140 TI - Preparative separation of quaternary ammonium alkaloids from Coptis chinensis Franch by pH-zone-refining counter-current chromatography. AB - pH-zone-refining counter-current chromatography was successfully applied to the preparative separation of five quaternary ammonium alkaloids from the crude extract of Coptis chinensis Franch. The separation was performed with a two-phase solvent system composed of chloroform-methanol-water (4:3:3, v/v), where the upper aqueous stationary phase was added with 60mM of hydrochloric acid and the lower organic mobile phase with 5mM of triethylamine. From 1.0 g of crude extract, 5.4 mg of columbamine at 96.6% purity, 6.1mg of jateorhizine at 98.8% purity, 58.3mg of coptisine at 99.5% purity, 25.6 mg of palmatine at 98.4% purity and 503.9 mg of berberine at 99.5% purity were obtained. The purities of the isolated alkaloids were analyzed by HPLC and the chemical structures were identified by electrospray ionization-mass spectrometry and (1)H NMR. PMID- 25454141 TI - Development and validation of a rapid resolution liquid chromatography method for the screening of dietary plant isoprenoids: carotenoids, tocopherols and chlorophylls. AB - A rapid resolution liquid chromatography (RRLC) method was developed and validated for the simultaneous determination of nine carotenoids compounds (violaxanthin, lutein, zeaxanthin, beta-cryptoxanthin, alpha-carotene, beta carotene, lycopene, phytoene, phytofluene), four tocopherols and four chlorophylls and derivates (chlorophylls and pheophytins). The methodology consisted in a micro-extraction procedure with or without saponification and subsequent analysis by RRLC. The limits of detection were <0.07 MUg for carotenoids and tocopherols and <0.08 MUg for chlorophylls and derivatives. The overall precision values (intra- and inter-day) were lower than 12% when samples were not saponified and <27.6%, when the saponification step was performed. The recovery of the method without the saponification step ranged from 92% to 107%, whilst that when saponification was carried out ranged from 60% for alpha tocopherol to 82% for beta-carotene. Finally, the applicability of the method was demonstrated by the identification and quantification of isoprenoids in different samples. The methodology is appropriate for the high-throughput screening of dietary isoprenoids in fruits and vegetables. PMID- 25454142 TI - Development of an analytical method for the determination of the misuse in sports of boldenone through the analysis of urine by on-line coupling liquid chromatography-gas chromatography-combustion-isotope ratio mass spectrometry. AB - Boldenone (Bo), androsta-1,4-dien-17beta-ol-3-one, is an anabolic androgenic steroid not clinically approved for human application. Despite this, many cases are reported every year of athletes testing positive for Bo or its main metabolite 5beta-androst-1-en-17beta-ol-3-one (BoM). Recently the capability of different human intestinal bacteria to produce enzymes able to modify endogenous steroids in Bo has been demonstrated. When a urinary concentration of Bo and/or BoM between 5 and 30 ng/mL is measured a complementary analysis by gas chromatography combustion isotope ratio mass spectrometry (GC-C-IRMS) must be carried out to discriminate the endogenous or exogenous origin. In the present work, a novel analytical method that couples LC-GC by means of the TOTAD interface with C-IRMS is described. The method is based on a first RPLC separation of unacetyled steroids, followed by acetylation and automated on-line LC-GC-C-IRMS, which includes a second RPLC clean-up of acetyl Bo and BoM, isolation of the two fractions in a fraction collector and their consecutive analysis by GC-C-IRMS. The method has been applied to the analysis of urine samples fortified at 5 and 10 ng/mL, where it has shown a good performance. PMID- 25454143 TI - A novel strategy for quantitative analysis of the formulated complex system using chromatographic fingerprints combined with some chemometric techniques. AB - In this work, a novel strategy based on chromatographic fingerprints and some chemometric techniques is proposed for quantitative analysis of the formulated complex system. Here, the formulated complex system means a formulated type of complicated analytical system containing more than one kind of raw material under some concentration composition according to a certain formula. The strategy is elaborated by an example of quantitative determination of mixtures consist of three essential oils. Three key steps of the strategy are as follows: (1) remove baselines of the chromatograms; (2) align retention time; (3) conduct quantitative analysis using multivariate regression with entire chromatographic profiles. Through the determination of concentration compositions of nine mixtures arranged by uniform design, the feasibility of the proposed strategy is validated and the factors that influence the quantitative result are also discussed. This strategy is proved to be viable and the validation indicates that quantitative result obtained using this strategy mainly depends on the efficiency of the alignment method as well as chromatographic peak shape of the chromatograms. Previously, chromatographic fingerprints were only used for identification and/or recognition of some products. This work demonstrates that with the assistance of some effective chemometric techniques, chromatographic fingerprints are also potential and promising in solving quantitative problems of complex analytical systems. PMID- 25454144 TI - Ad-hoc blocked design for the robustness study in the determination of dichlobenil and 2,6-dichlorobenzamide in onions by programmed temperature vaporization-gas chromatography-mass spectrometry. AB - An 'ad-hoc' experimental design to handle the robustness study for the simultaneous determination of dichlobenil and its main metabolite (2,6 dichlorobenzamide) in onions by programmed temperature vaporization-gas chromatography-mass spectrometry (PTV-GC-MS) is performed. Eighteen experimental factors were considered; 7 related with the extraction and clean up step, 8 with the PTV injection step and 3 factors related with the derivatization step. Therefore, a high number of experiments must be carried out that cannot be conducted in one experimental session and, as a consequence, the experiments of the robustness study must be performed in several sessions or blocks. The procedure to obtain an experimental design suitable for this task works by simultaneously minimizing the joint confidence region for the coefficient estimates and the correlation among them and with the block. In this way, the effect of the factors is not aliased with the block avoiding possible misinterpretations of the effects of the experimental factors on the analytical responses. The developed experimental design is coupled to the PARAFAC2 method, which allows solving some specific problems in chromatography when working with complex matrix such as co-elution of interferents (including silylation artifacts from the derivatization step) and small shifts in the retention time and, besides, the unequivocal identification of the target compounds according to document SANCO/12571/2013. PMID- 25454145 TI - Multidimensional analysis of cannabis volatile constituents: identification of 5,5-dimethyl-1-vinylbicyclo[2.1.1]hexane as a volatile marker of hashish, the resin of Cannabis sativa L. AB - The volatile constituents of drug samples derived from Cannabis sativa L. were investigated by means of headspace solid phase microextraction (HS-SPME) and gas chromatography techniques (GC-MS, GC*GC-MS). Samples of cannabis herb and hashish showed clear differences in their volatile chemical profiles, mostly resulting from photo-oxidation processes occurring during the transformation of fresh cannabis herb into hashish. Most unexpectedly, we could demonstrate hashish samples as containing remarkable amounts of a rare and unusual monoterpene - 5,5 dimethyl-1-vinylbicyclo[2.1.1]hexane - among the volatile compounds detected in their headspaces. We gave evidence for the formation of this compound from the light induced rearrangement of beta-myrcene during the manufacture of hashish. In view of its high abundance among volatile constituents of cannabis resin and its scarce occurrence in other natural volatile extracts, we propose to rename this specific monoterpene hashishene. PMID- 25454146 TI - Multivariate analysis of mainstream tobacco smoke particulate phase by headspace solid-phase micro extraction coupled with comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry. AB - A method involving headspace solid-phase microextraction (HS-SPME) and comprehensive two-dimensional gas chromatography (GC*GC) coupled to time-of flight mass spectrometry (TOFMS) was developed and applied to evaluate profiles of volatile compounds present in mainstream tobacco smoke particulate matter trapped on glass fiber filters. Six SPME fibers were tested for the extraction capacities toward selected compounds, showing the best results for the polyacrylate fiber. The optimization of the extraction conditions was carried out using multivariate response surface methodology. Two cigarette types differing in a filter design were analyzed using optimized conditions. A template was built in order to generate comprehensive chemical information, which conceded obtaining consistent information across 24 chromatograms. Principal component analysis (PCA) allowed a clear differentiation of the studied cigarette types. Fisher ratio analysis allowed identification of compounds responsible for the chemical differences between the cigarette samples. Of the selected 143 most important ones, 134 analytes were reduced by the active carbon filter, while for nine, classical cellulose acetate filter was more efficient. PMID- 25454147 TI - Metabolite profiling of Camellia sinensis by automated sequential, multidimensional gas chromatography/mass spectrometry reveals strong monsoon effects on tea constituents. AB - Seasonal variation in tea (Camellia sinensis (L.) Kuntze; Theaceae) chemistry was investigated using automated sequential, multidimensional gas chromatography/mass spectrometry (GC-GC/MS). Metabolite libraries were produced for teas harvested from the Bulang Mountains in Yunnan, China before and after the onset of the East Asian Monsoon. A total of 201 spring and 196 monsoon metabolites were identified, with 169 common and 59 seasonally unique compounds. An additional 163 metabolites were detected but their identity could not be confirmed. Spectral deconvolution of GC/MS data was used to measure the relative concentrations in the teas. Within each family individual metabolite concentrations increased, decreased and stayed the same. The major constituents in both teas were linalool (28%), geraniol (13%), alpha-terpineol (10%), hotrienol (4%) and nerol (3%). This work provides the foundation to monitor seasonal variations of tea chemistry. PMID- 25454148 TI - Evolution of strategies to achieve baseline separation of ten anionic, water soluble sulfated estrogens via achiral packed column supercritical fluid chromatography. AB - Near baseline separation of ten sulfated sodium salts of various structurally related estrogens employing a variety of bonded stationary phase packed columns was obtained using a conventional supercritical fluid chromatograph coupled with UV detection. Critical pairs 2/3 (8,9-dehydroestrone/17beta-dihydroequilin) and 6/7 (17alpha-estradiol or 17alpha-dihydroequilin/estrone), however, failed to baseline separate. In all preliminary separations, 10mM ammonium acetate and variable percentages of H2O were initially used as co-additives in conjunction with methanol as a modifier. Different modifier programs and temperatures were employed to optimize the separation in a timely manner. A 2-ethylpyridine column provided the best separation compared to bare silica, diol, and cyano-based bonded phase columns. The employment of both salt and water as additives to the methanol-modified CO2 mobile phase suggested a mixed mode separation mechanism involving both ion pairing of each anionic sulfated estrogen with ammonium ion and hydrophilic interaction facilitated by partitioning of analyte between the aqueous solvated stationary phase and the aqueous component of the mobile phase. Upon more extensive study with either iso-propylamine or formic acid-ammonium formate buffer, the critical anionic pairs were 95% baseline resolved. PMID- 25454149 TI - Thin-layer chromatography/direct analysis in real time time-of-flight mass spectrometry and isotope dilution to analyze organophosphorus insecticides in fatty foods. AB - To assess food safety emergencies caused by highly hazardous chemical-tainted foods, simultaneous analysis of organophosphorus insecticides in fatty foods such as precooked foods was conducted using thin-layer chromatography/direct analysis in real time time-of-flight mass spectrometry (TLC/DART-TOFMS) and isotope dilution technique. Polar (methamidophos and acephate) and nonpolar organophosphorus insecticides (fenitrothion, diazinon, and EPN) were studied. Experiments to ascertain chromatographic patterns using TLC/DART-TOFMS reveal that it was more useful than GC/MS or GC/MS/MS for the simultaneous analyses of polar and nonpolar pesticides, while obviating the addition of a protective agent for tailing effects of polar pesticides. Lower helium gas temperature (260 degrees C) for DART-TOFMS was suitable for the simultaneous analysis of target pesticides. Linearities were achieved respectively at a lower standard concentration range (0.05-5 MUg) for diazinon and EPN and at a higher standard concentration range (2.5-25 MUg) for methamidophos, acephate, and fenitrothion. Their respective coefficients of determination were >= 0.9989 and >= 0.9959. A few higher repeatabilities (RSDs) for diazinon and EPN were found (>20%), although isotope dilution technique was used. Application to the HPTLC plate without an automatic TLC sampler might be inferred as a cause of their higher RSDs. Detection limits were estimated in the higher picogram range for diazinon and EPN, and in the lower nanogram range for methamidophos, acephate, and fenitrothion. Aside from methamidophos, recovery results (n=3) obtained using a highly insecticide-tainted fatty food (dumpling) and raw food (grapefruit) samples (10mg/kg) using TLC/DART-TOFMS with both complex and simpler cleanups were not as susceptible to matrix effects (95-121%; RSD, 1.3-14%) as those using GC/MS/MS (102-117%; RSD, 0.4-8.5%), although dumpling samples using GC/MS were remarkably susceptible to matrix effects. The coupled method of TLC with simpler cleanup and DART-TOFMS can be regarded as the same analytical tool as GC/MS/MS, which is useful to assess food safety emergencies caused by highly hazardous chemical-tainted foods. PMID- 25454150 TI - Generalized polymer effective charge measurement by capillary isotachophoresis. AB - In this work, we have generalized the use of capillary isotachophoresis as a universal method for determination of effective charge of anionic and cationic (co)polymers on ordinary capillary electrophoresis instruments. This method is applicable to a broad range of strong or weak polyelectrolytes with good repeatability. Experimental parameters (components and concentrations of leading and terminating electrolytes, capillary diameters, constant electric current intensity) were optimized for implementation in 100 MUm i.d. capillaries for both polyanions and polycations. Determined values of polymer effective charge were in a very good agreement with those obtained by capillary electrophoresis with indirect UV detection. Uncertainty of the effective charge measurement using isotachophoresis was addressed and estimated to be ~5-10% for solutes with mobilities in the 20-50 * 10(-9)m(2)V(-1)s(-1) range. PMID- 25454151 TI - Rapid analysis of water- and fat-soluble vitamins by electrokinetic chromatography with polymeric micelle as pseudostationary phase. AB - A novel polymeric micelle, formed by random copolymer poly (stearyl methacrylate co-methacrylic acid) (P(SMA-co-MAA)) has been used as pseudostationary phase (PSP) in electrokinetic chromatography (EKC) for simultaneous and rapid determination of 11 kinds of water- and fat-soluble vitamins in this work. The running buffer consisting of 1% (w/v) P(SMA-co-MAA), 10% (v/v) 1-butanol, 20% (v/v) acetonitrile, and 30 mM Palitzsch buffer solution (pH 9.2) was applied to improve the selectivity and efficiency, as well as to shorten analysis time. 1 Butanol and acetonitrile as the organic solvent modifiers played the most important roles for rapid separation of these vitamins. The effects of organic solvents on microstructure of the polymeric micelle were investigated. The organic solvents swell the polymeric micelle by three folds, lower down the surface charge density and enhance the microenviromental polarity of the polymeric micelle. The 11 kinds of water- and fat-soluble vitamins could be baseline separated within 13 min. The method was applied to determine water- and fat-soluble vitamins in commercial vitamin sample; the recoveries were between 93% and 111% with the relative standard derivations (RSDs) less than 5%. The determination results matched the label claim. PMID- 25454152 TI - Policies and politics of the US food supply. PMID- 25454153 TI - Sodium intake and blood pressure: new controversies, new labels . . . new guidelines? PMID- 25454154 TI - Assessing good operating conditions for intraoperative imaging of melanoma sentinel nodes by a portable gamma camera. AB - OBJECTIVE: To provide guidance for reliable identification of low-activity sentinel nodes in the setting of melanoma surgery using a commercial hand-held gamma camera. METHODS: The average uptake of (99m)Tc nanocolloid by sentinel nodes was evaluated in 95 excised nodes using a Sentinella 102((r)) (Oncovision, Valencia, Spain) portable gamma camera. The device sensitivity was assessed for different source depths and collimator distances, imaging an 8-mm sphere filled with a known-activity solution of (99m)Tc. Five nuclear medicine physicians were asked to identify the source at different activity levels and positions within the field of view. For each image the number of signal counts inside a circular region of interest (ROI) was measured, while the variability of ROI counts among operators was assessed. The number of counts providing a minimal, near-constant inter-operator variability was determined as a criterion for a consistent identification of the source. Either the minimum activity or the acquisition time needed to collect the appropriate statistics were then calculated. RESULTS: The median SN uptake (0.5%) turned out to be compatible with values reported in the literature. The sensitivity of the compact gamma camera ranged from ~25 cpm/kBq to ~1 cpm/kBq. A total of 50 counts in the ROI circumscribing the lymph node simulating sphere appeared to be a robust criterion for identification of the source. CONCLUSIONS: Ten megabecquerels of injected activity at the time of surgery and one minute of acquisition allows reliable identification of sentinel nodes for collimator-to-source distances up to 10 cm. PMID- 25454155 TI - Samarium-153 EDTMP for metastatic bone pain palliation: the impact of europium impurities. AB - PURPOSE: To evaluate the impact on the radiation protection policies of the radiocontaminants in Samarium-153 ethylenediamine tetramethylene phosphonate ((153)Sm-EDTMP). METHODS: The internal contamination of patients treated with (153)Sm-EDMTP for palliation of painful disseminated multiple bone metastases due to long-lived impurities was assessed by direct measurements. These measurements were coupled with dose-rate measurements close to their bodies and spectroscopic analysis of the residual activity in post-treatment radiopharmaceutical vials. RESULTS: Whole-body counting carried out in six patients showed a 30-81-kBq europium -152 plus europium-154 contamination. The 0.85 mean (152)Eu- to -(154)Eu activity ratio obtained by direct counting was similar to that assessed by analysis of post-treatment residual activities in twelve radiopharmaceutical vials following radiopharmaceutical injection. CONCLUSIONS: The long-lived radiocontaminants in the patient's bodies and the treatment wastes require modifications of the applicable radiation protection policies. PMID- 25454156 TI - Trends in the management of recurrent respiratory papillomatosis in Japan. AB - OBJECTIVE: Recurrent respiratory papillomatosis (RRP) has historically been and still continues to be a difficult disease to treat. The present study aimed to characterize current practices in the treatment of RRP in Japan. METHODS: A questionnaire was posted to the Department of Otolaryngology of all 80 central university hospitals in Japan. RESULTS: A total of 56 universities responded to the survey. Regarding the use of surgical instruments, a trend toward a preference for lasers (50 hospitals) rather than a microdebrider (16 hospitals) or cold instruments (20 hospitals) was observed. Among the 50 hospitals frequently performing laser surgery, a carbon dioxide (CO2) laser was most commonly used, followed by a potassium-titanyl-phosphate (KTP) laser. The most favored adjuvant therapy was traditional Chinese medicine. Eight of the 56 university hospitals had an experience of using cidofovir, involving a total of 28 patients. CONCLUSION: The present study demonstrated the current trends in the management of RRP based on a questionnaire survey in a geographical area other than the US and UK for the first time. Treatment trends were generally similar in all three areas except for the least popular use of cidofovir in Japan. PMID- 25454157 TI - What are the boundaries of training for a visceral surgeon? PMID- 25454158 TI - The primary cause of oxidative stress is ultra-exogenous sulfide formation (USF). AB - The inorganic sulfur content of the Western Diet is more than six times greater than the minimal daily requirement. The non-adsorbed organic and inorganic sulfur supports high levels of sulfate reducing bacteria (SRB) in the large intestine. Over time, the combination of elevated dietary inorganic sulfur and high levels of SRB in the gut increases the potential of ultra-exogenous sulfide formation (USF). High levels of SRB in the right colon can sustain USF that overwhelms sulfide oxidation by the colon and sulfide enters into the capillary network of the right colon. White blood cells and platelets in this capillary network are exposed to the elevated sulfide concentration, which induces these cells to generate reactive oxygen species (ROS). An estimated 1.3% of the total cardiac output is impacted by the elevated sulfide every minute. USF for 10 and 78min per day could generate the 12% and 64% of ROS-positive blood cells that were observed in the arterial blood samples of non-hospitalized volunteers and congestive heart failure patients, respectively. More extreme USF is necessary to generate greater percentages of ROS-positive blood cells, since the recirculated blood will provide sulfide oxidation. The dietary inorganic sulfur consumption pattern dictates the abundance of SRB in the gut and therefore, the percent of ROS positive blood cells. Exposure of blood to a range of sulfide levels may determine the minimum sulfide concentration necessary to generate ROS-positive blood cells. After validation, patients with high levels of ROS-positive blood cells can be evaluated for reduction of oxidative stress by dietary inorganic sulfur control. If USF is confirmed as the source of ROS-positive blood cells, then the problem of oxidative stress becomes manageable through dietary changes, metals supplements, methanogenic probiotics, and antibiotics that target SRB. PMID- 25454160 TI - BDNF-trkB-KCC2-GABA pathway may be related to chronic stress-induced hyperalgesia at both the spinal and supraspinal level. AB - Chronic stresses can induce physiological and psychological changes and result in stress-related neuropsychiatry, sometimes they may also contribute to hypersensitivity to pain known as stress-induced hyperalgesia (SIH). Recently it was found that GABAergic disinhibition is closely related to morphine and chronic inflammation pain induced hyperalgesia in the PAG (periaqueductal gray)-RVM (rostral ventromedial medulla) -spinal descending facilitatory system, the changes of potassium-chloride co-transporter 2 (KCC2) function or expression modulated by brain-derived neurotrophic factor (BDNF) are involved in it. Similarly, chronic stress could induce changes of BDNF, KCC2 and a depolarizing shift in the GABA reversal potential (EGABA). Moreover, the descending facilitatory system has been suggested to be related with SIH, but whether it modulates SIH through disinhibition by the downregulation of KCC2 expression and/or transport function remains unknown. We therefore hypothesized that SIH may be owned to disinhibition caused by the activation of BDNF-trkB-KCC2-GABA pathway, which would provide a new understanding for SIH. PMID- 25454159 TI - Absence of skin rash in Goodpasture's syndrome: the hyaluronan effect. AB - Goodpasture's syndrome is a rare disease that involves rapidly progressive kidney failure as well as hemorrhagic lung disease. It is a form of autoimmune disorder with unusual features; marked male preponderance, in contrast with other autoimmune disease in which females are at far greater risk. The autoantibodies are directed again the carboxy-extension non-collagenous (NC1) portion of one of the basement membrane-specific collagen IV alpha 3 chains. Basal laminas throughout the body share this structure, including those in kidney, lung and skin. But curiously, skin is rarely involved in Goodpasture's syndrome. Hyaluronan is a large extracellular matrix carbohydrate polymer. Half of total body hyaluronan occurs in skin. High molecular weight hyaluronan, a potent immunosuppressive polymer, might be functioning as an immune shield for skin in Goodpasture's syndrome, and be the basis for the anomaly. A summary of this putative effect is described, including possible molecular mechanisms involved, and suggestions for testing this hypothesis. PMID- 25454166 TI - Intestinal schistosomiasis among preschool children along the shores of Lake Victoria in Uganda. AB - Schistosomiasis, a disease caused by Schistosoma trematode parasites, affects hundreds of millions of people and accounts for more than 40% of the global health burden due to neglected tropical diseases. In Uganda, intestinal schistosomiasis is endemic in 73 out of 112 districts and about 55% of the population of 36 million individuals are at risk. There is scanty information on the status and burden of schistosomiasis in preschool children less than six years of age in Uganda. This study aimed to assess the status of Schistosoma mansoni infections in children aged 1-5 years in Uganda. S. mansoni prevalence and intensity of infection were examined in 3058 children from 5 districts along Lake Victoria shoreline, eastern Uganda. For each child one stool sample was collected on three consecutive days. The Kato-Katz technique was used to prepare stool smears on slides for microscopic examination. Short interviews with a standardized pre-tested questionnaire prepared in the local language (Lusoga) were administered to each caregiver to identify risk factors associated with S. mansoni infection. An overall S. mansoni prevalence of 39.3% (95% CI: 38.0-41.1%) was estimated out of the 3058 stool samples examined. The geometric mean intensity of S. mansoni among the infected children was 273 (95% CI: 241-305) eggs per gram of faeces. Both prevalence and intensity of infection increased linearly with age (P<0.0001) and were highest in the age group 49-60 months. Majority (61%) of the children, especially in the age group 12-24 months (84.2%; 95% CI: 75.6-90.1%), were lightly infected. Short interviews with caregivers revealed that preschool children, 1-5 years old, get exposed to S. mansoni infested waters through bathing, playing or swimming. It is important that the Uganda national control programme for schistosomiasis takes preschool children into consideration and that health education on transmission of schistosomiasis is delivered to the endemic communities regularly. PMID- 25454167 TI - Isolated laryngeal myasthenia gravis for 26 years. AB - Laryngeal myasthenia gravis is a relatively rare variant of myasthenia gravis. A vast portion of patients with initial laryngeal myasthenia gravis develop involvement of ocular and/or extra-ocular muscles during the years after symptom onset although a minority of laryngeal myasthenia gravis patients continues to have isolated laryngeal muscle involvement for several years. We present a 58 year-old woman with recurrent episodic isolated dysphonia (associated with diffuse bilateral vocal cord paresis on laryngoscopy) since the age of 32. Dysphonia became permanent since 6 months. A diagnosis of laryngeal myasthenia gravis was made based on abnormal single-fiber electromyography and spectacular response to pyridostigmine treatment. Repetitive nerve stimulation was normal and anti-acetylcholine receptor and anti-muscle specific tyrosine kinase antibodies were absent. This case shows that laryngeal myasthenia gravis can be isolated during 26 years of follow-up. We propose that even when myasthenia gravis seems unlikely as underlying mechanism of isolated dysphonia (because of lack of antibodies, normal repetitive nerve stimulation, and absence of extra-laryngeal involvement after years of follow-up), single-fiber electromyography should be performed and myasthenia gravis treatment should be tried. PMID- 25454168 TI - Clinical and electrophysiological features in a French family presenting with seipinopathy. AB - Seipinopathies are a group of inherited diseases affecting upper and lower motor neurons due to mutations in the Berardinelli-Seip congenital lipodystrophy 2 gene (BSCL2). We report a French family carrying the N88S mutation in the BSCL2 gene. A 12-yr-old girl complained of bilateral asymmetrical pes cavus with right hand motor deficit and amyotrophy, asymmetrical leg amyotrophy and pyramidal signs. Electrophysiological examination showed axonal asymmetrical motor neuropathy with distal predominance. Her father complained of right hand rest tremor with bilateral hand weakness. Physical examination revealed left leg, hand and forearm amyotrophy, akinesia and right arm rigidity, brisk reflexes in the lower limbs and bilateral Babinski sign. Nerve conduction studies showed distal asymmetrical axonal neuropathy with slight sensitive impairment with moderate decrease of nerve conduction velocity in some nerves. DNA sequencing revealed the presence of the known N88S mutation in the BSCL2 gene (dideoxy-nucleotide method on a 3730 DNA Analyzer, Life Technologies). BSCL2 gene mutations are associated with a wide spectrum of clinical and electrophysiological phenotypes and should be suspected in cases of distal hereditary motor neuropathy with pyramidal signs or early hand involvement. There may also be associated mild demyelination which may vary in severity within the same family. Clinical diagnosis was more difficult in this particular case due to the association with Parkinson symptoms. PMID- 25454169 TI - Growing up with spinal muscular atrophy with respiratory distress (SMARD1). AB - Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an inherited neuromuscular condition resulting from recessive mutations in the immunoglobulin mu-binding protein (IGHMBP2) gene. Affected individuals characteristically present in infancy with progressive distal weakness and respiratory distress secondary to diaphragmatic weakness. Considerable clinical heterogeneity has been described both in its presentation and phenotype in childhood; however little data pertaining to phenotype in adulthood have been reported to date. This report describes a 21 year old woman with genetically confirmed SMARD1 who has stable muscle weakness, normal cognitive abilities and is able to lead a socially integrated lifestyle, using mechanical ventilation only overnight. This report adds new evidence for clinical variability throughout the course of SMARD1. PMID- 25454170 TI - Analysis of the targeting uncertainty of a stereotactic frameless radiosurgery technique for arteriovenous malformation. AB - In order to target arteriovenous malformations (AVM) in a frameless approach, registration of two-dimensional (2D) digital-subtracted-angiographs (DSA) with three-dimensional (3D) computed tomography (CT) is required. Targeting accuracy and delineation of a frameless 2D-DSA and 3D-CT image registration tool based on bony anatomy of the skull was evaluated. This frameless approach assures accurate target localization and can be used in a clinical setting. PMID- 25454171 TI - Evaluation of axillary dose coverage following whole breast radiotherapy: variation with the breast volume and shape. AB - OBJECTIVE: To evaluate the axillary dose coverage in patients treated with tridimensional whole breast radiotherapy (3D-WBRT), according to the breast volume and shape in treatment position. BACKGROUND: Several studies have demonstrated an insufficient dose contribution to the axillary levels, using 3D WBRT, remaining unclear whether the breast volume and shape can influence it. MATERIALS AND METHODS: We retrospectively delineated the axillary levels on planning CT-images of 100 patients, treated with 3D-WBRT along 2012 in our institution. To estimate the shape we established an anatomic CT-based interval, defined as the Thoracic Extent (TE). The breast volume matched its CTV. Mean dose levels and V95 (volume receiving at least 95% of the prescribed dose) were evaluated. RESULTS: Mean axillary level I (A1), II (A2) and III (A3) volume was 56.1 cc, 16.5 cc and 18.9 cc, respectively, and mean doses were 43.9 Gy, 38.6 Gy and 19.5 Gy. For breast volumes of <800 cc, 800-999 cc, 1000-1199 cc and >1200 cc, mean A1 V95 was 38%, 51%, 61.2% and 57.2% whereas median A2 V95 was 8.3%, 13.4%, 19.4% and 28% respectively. Regarding shape, where the breast relative position to the TE was categorized in intervals between 31% and 40%, 41% and 50%, 51% and 60%, and 61% and 70%, mean A1 V95 was 38.7%, 43.1%, 51.1% and 77.3% whereas mean A2 V95 was 6.1%, 11.2%, 17.1% and 37% respectively. CONCLUSIONS: We observed inadequate dose coverage to all axillary levels, even after applying a sub-analysis accounting for different breast volumes and shapes. Although higher doses were associated with the more voluminous and pendulous breasts, axillary coverage with 3D-WBRT seems to be inefficient, regardless of the breast morphology. PMID- 25454172 TI - Risk of second non-breast cancer after radiotherapy for breast cancer: a systematic review and meta-analysis of 762,468 patients. AB - BACKGROUND AND PURPOSE: Radiotherapy for breast cancer both decreases loco regional recurrence rates and improves overall survival. However, radiotherapy has also been associated with increased second cancer risk at exposed sites. In this meta-analysis, we estimated the risk of second non-breast cancers after radiotherapy for breast cancer. MATERIAL AND METHODS: The databases Medline/Pubmed, Cochrane, Embase and Cinahl were systematically searched, for cohort studies on second cancer after radiotherapy for breast cancer, from inception to August 1st 2013. Included studies were to report the relative risk (RR) of second cancers comparing irradiated female breast cancer patients to unirradiated patients. Primary endpoints were all second non-breast-cancers and second cancers of the lung, esophagus, thyroid and second sarcomas. RRs were pooled using random-effects meta-analysis. RESULTS: Thirteen studies comprising 762,468 breast cancer patients were included in the meta-analysis. Five or more years after breast cancer diagnosis radiotherapy was significantly associated with an increased risk of second non-breast cancer RR 1.12 (95% confidence interval [CI] 1.06-1.19), second cancer of the lung RR 1.39 (95% CI 1.28-1.51), esophagus RR 1.53 (95% CI 1.01-2.31) and second sarcomas RR 2.53 (95% CI 1.74 3.70). The risk increased over time, and was highest 15 or more years after breast cancer diagnosis, for second lung RR 1.66 (95% CI 1.36-2.01) and second esophagus cancer RR 2.17 (95% CI 1.11-4.25). There was no significant association between radiotherapy and second thyroid cancer. CONCLUSIONS: Radiotherapy for breast cancer is significantly associated with increased risks of second non breast cancer, overall and in organs adjacent to the previous treatment fields. Despite a relative small absolute risk, the growing number of long-time survivors after breast cancer warrants the need for normal tissue sparing radiotherapy techniques. PMID- 25454173 TI - Different treatment planning protocols can lead to large differences in organ at risk sparing. AB - BACKGROUND AND PURPOSE: Different planning protocols may define varying planning target volume (PTV) dose criteria. We investigated the hypothesis that this could result in differences in organ-at-risk (OAR) sparing. MATERIAL AND METHODS: Volumetric modulated arc therapy plans were created for ten locally advanced head and neck cancer patients following PTV criteria specified by the RTOG, EORTC and institutional (VUmc) protocols. Resulting plans were evaluated on the basis of the homogeneity index, calculated for the boost/elective PTVs as HIB/HIE=100%*(D2%-D98%)/D50% and mean dose to individual and composite salivary (compsal) and swallowing (compswal) OARs. RESULTS: RTOG plans were the most homogeneous, with mean HIB of 8.2+/-0.9%, compared to 9.5+/-1.0%/11.6+/-1.5% for the VUmc/EORTC plans. EORTC plans provided most OAR sparing, with compsal/compswal doses of 24.6+/-7.7/22.9+/-4.2Gy, compared to 32.2+/-9.7/29.9+/ 4.2Gy and 28.4+/-8.1/24.7+/-5.3Gy for RTOG and VUmc, respectively. EORTC provided 7.2/7.7Gy mean dose reductions to the contra/ipsilateral parotid glands compared to RTOG. CONCLUSIONS: Different planning protocols resulted in different levels of PTV dose homogeneity. We observed differences of up to ?7Gy in composite and individual mean OAR doses. This could influence rates of toxicity and should be taken into account when comparing clinical studies. A consensus should be reached between major trial groups on appropriate PTV parameters. PMID- 25454174 TI - Information science ontologies and metaphysics: in regard to an umbrella protocol for standardized data collection in rectal cancer by Meldolesi et al. PMID- 25454175 TI - No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR-RT). AB - BACKGROUND AND PURPOSE: To evaluate the effect of adjuvant chemotherapy (ACT) in locally advanced rectal cancer (LARC) after neoadjuvant chemoradiation (NACT-RT). The study was funded by the Italian National Research Council (CNR). METHODS: From September 1992 to January 2001, 655 patients with LARC (clinically T3-4, any N) treated with NACT-RT and surgery, were randomized in two arms: follow-up (Arm A) or 6 cycles of ACT with 5 fluorouracil (5FU)-Folinic Acid (Arm B). NACT-RT consisted of 45Gy/28/ff concurrent with 5FU (350mg/sqm) and Folinic Acid (20mg/sqm) on days 1-5 and 29-33; surgery was performed after 4-6weeks. Median follow up was 63.7months. Primary end point was overall survival (OS). RESULTS: 634/655 patients were evaluable (Arm A 310, Arm B 324); 92.5% of Arm A and 91% of Arm B patients received the preoperative treatment as in the protocol; 294 patients of Arm A (94.8%) and 296 of Arm B (91.3%) underwent a radical resection; complete pathologic response and overall downstaging rates did not show any significant difference in the two arms. 83/297 (28%) patients in Arm B, never started ACT. Five year OS and DFS did not show any significant difference in the two treatment arms. Distant metastases occurred in 62 patients (21%) in Arm A and in 58 (19.6%) in Arm B. CONCLUSIONS: In patients with LARC treated with NACT-RT, the addition of ACT did not improve 5year OS and DFS and had no impact on the distant metastasis rate. PMID- 25454197 TI - Depth profiles of radioactive cesium in soil using a scraper plate over a wide area surrounding the Fukushima Dai-ichi Nuclear Power Plant, Japan. AB - During the Fukushima Dai-ichi Nuclear Power Plant (NPP) accident, radioactive cesium was released in the environment and deposited on the soils. Depth profiles of radioactive cesium in contaminated soils provide useful information not only for radiation protection and decontamination operations but also for geoscience and radioecology studies. Soil samples were collected using a scraper plate three times between December 2011 and December 2012 at 84 or 85 locations within a 100 km radius of the Fukushima Dai-ichi NPP. In most of the obtained radioactive cesium depth profiles, it was possible to fit the concentration to a function of mass depth as either an exponential or hyperbolic secant function. By using those functions, following three parameters were estimated: (i) relaxation mass depth beta (g cm(-2)), (ii) effective relaxation mass depth betaeff (g cm(-2)), which is defined for a hyperbolic secant function as the relaxation mass depth of an equivalent exponential function giving the same air kerma rate at 1 m above the ground as the inventory, and (iii) 1/10 depth L1/10 (cm), at which the soil contains 90% of the inventory. The average beta value (wet weight) including ones by hyperbolic secant function in December 2012, was 1.29 times higher than that in December 2011. In fact, it was observed that depth profiles at some study sites deviated from the typical exponential distributions over time. These results indicate the gradual downward migration of radioactive cesium in the soils. The L1/10 values in December 2012 were summarized and presented on a map surrounding the Fukushima Dai-ichi NPP, and the average value of L1/10 was 3.01 cm (n = 82) at this time. It was found that radioactive cesium remained within 5 cm of the ground surface at most study sites (71 sites). The sech function can also be used to estimate the downward migration rate V (kg m(-2) y(-1)). The V values in December 2012 (n = 25) were in good agreement with those found by a realistic approach using a diffusion and migration model. Almost all values ranged between 1.7 and 9.6 kg m(-2) y(-1) in this study. PMID- 25454198 TI - COPD-related adenocarcinoma presents low aggressiveness morphological and molecular features compared to smoker tumours. AB - OBJECTIVES: Adenocarcinoma comprises a group of diseases with heterogeneous clinical and molecular characteristics. COPD and lung cancer are strictly related; to date it is unknown if COPD-associated cancers have different features from tumours arising in non-COPD patients. Our aim was to study COPD-associated adenocarcinoma phenotypes mainly focusing on morphological and molecular aspects, in comparison to smoke-related cancer without COPD. MATERIALS AND METHODS: From 2010 to 2013, 54 patients with adenocarcinoma (20 COPD and 34 smokers) were prospectively studied. Each patient underwent a complete clinical and instrumental assessment. Morphological studies included analysis of growth pattern, cell proliferation (Ki-67/MIB1 expression) and parameters of intra- and peri-tumoral remodelling (inflammation, fibrosis and necrosis). Genetic analysis of EGFR and KRAS mutations was also performed. RESULTS: The two groups were comparable for the main demographic and biohumoral parameters except for increased blood basophil cell count in the COPD group. Compared to COPD, tumours of smokers presented an increased percentage of solid component (median: 20% vs 5%, p=0.02), a reduced percentage of lepidic pattern (median: 0% vs 10%, p=0.06) and higher Ki-67/MIB1 median value (55% vs 30%, p=0.02). In multivariate analysis lepidic and solid histological pattern were significantly influenced by clinical group (p=0.03 and 0.05, respectively). Concerning EGFR mutation, no differences were found between groups while KRAS mutation presented a trend of higher percentage in smokers compared to COPD (41% vs 20%, p=NS). Adenocarcinoma with KRAS mutation showed a higher value of Ki-67/MIB1 (65% vs 35%, p=0.048) and prevalent solid pattern (35% vs 10%, p=0.019) in comparison to wild-type form. CONCLUSIONS: COPD-related adenocarcinoma presents molecular and morphological features of lower aggressiveness (increased lepidic component, reduced solid pattern, lower cell proliferation and less frequent KRAS mutation) compared to smokers. Different molecular mechanisms could be associated with the development of COPD associated cancer. PMID- 25454199 TI - Comparison of risk and predictors for early radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with radiotherapy with or without surgery. AB - OBJECTIVES: To investigate risk and predictors for radiation pneumonitis (RP) and tolerance of lung to radiation in patients treated with thoracic radiotherapy (RT) with or without surgery. METHODS AND MATERIALS: A total of 433 consecutive patients with locally advanced non-small cell lung cancer were followed after three-dimensional conformal radiotherapy. Among them 284 received RT without surgical intervention and 149 received postoperative radiotherapy (PORT). RP was graded according to Common Terminology Criteria for Adverse Events version 4.0. RESULTS: The rate of grade >= 2 and grade >= 3 RP was 50 and 16% in the PORT group compared with 38 and 9% in the non-surgical group (p < 0.05 for each comparison). The lung volume was significantly smaller in PORT group than in no surgical group (3181 +/- 915 cm(3) vs. 4010 +/- 1120 cm(3), p<0.05). Age, chemotherapy, mean lung dose (MLD) and planning target volume (PTV) were predictors of RP for both non-surgical group and PORT group. Mean heart dose (MHD) predicted RP in PORT group only (OR = 1.28, p = 0.003). Among patients who developed RP, V20, MLD, and MHD were significantly lower in PORT group than in no surgical group (p < 0.05 for each comparison). CONCLUSIONS: Except MHD predicting RP in PORT group only, most of predictors for RP were consistent in patients treated with RT with or without surgery. Patients receiving PORT had a higher risk of RP than patients receiving RT without surgery did, possibly due to decreased lung volume and lower tolerance of lung to chemoradiotherapy. PMID- 25454200 TI - In-treatment assessment of response in locally advanced NSCLC: paving the way for personalized medicine. PMID- 25454201 TI - Criofolinine and vernavosine, new pentacyclic indole alkaloids incorporating pyrroloazepine and pyridopyrimidine moieties derived from a common yohimbine precursor. AB - Two new indole alkaloids characterized by previously unencountered natural product skeletons, viz., criofolinine (1), incorporating a pyrroloazepine motif within a pentacyclic ring system, and vernavosine (2, isolated as its ethyl ether derivative 3, which on hydrolysis regenerated the putative precursor alkaloid 2), incorporating a pyridopyrimidine moiety embedded within a pentacyclic carbon framework, were isolated from a Malayan Tabernaemontana species. The structures and absolute configuration of these alkaloids were determined on the basis of NMR and MS analysis and confirmed by X-ray diffraction analysis. PMID- 25454202 TI - Assessment of mobility and bio-availability of heavy metals in dry depositions of Asian dust and implications for environmental risk. AB - We assess the potential mobility and bio-availability of selected metals (As, Cd, Co, Cr, Cu, Ni, Mo, Pb, S, Zn, and Zr) in the dry depositions of Asian and non Asian dust from the city of Daejeon, Korea. For this study, we applied Pb isotopes, total extraction and chemical sequential extraction methods to the dry depositions. In addition, microscopic analysis was performed using X-ray diffraction (XRD) and focused ion beam (FIB)-scanning electron microscopy (SEM EDS). FIB-SEM cross-section observations and Pb isotope data showed a black carbon is an important carrier of associated heavy metals originating from China. A five-step sequential extraction performed on the dry depositions showed that S and Cd are the most abundant elements in the water-soluble and cation exchangeable fraction. In addition, Zn and Pb appeared predominantly in the carbonate and reducible fractions. On the other hand, Cu, Mo and, to a lesser degree, As were significantly associated with the organic fraction, while Co, Ni, Cr and Zr were bound to the residual fraction. These results showed that S, Cd, Zn and Pb, which were highly concentrated in potentially mobile fractions, have potential environmental risk because potential changes in redox state and pH may remobilize these metals. In addition, the estimated remobilization concentrations of these metals were significant. Thus, this study shows that frequent and careful monitoring of S, Cd, Z, Pb and, to a lesser degree, Cu, Mo and As is very important for assessing environmental risk in Korea. PMID- 25454203 TI - A field-scale study of cadmium phytoremediation in a contaminated agricultural soil at Mae Sot District, Tak Province, Thailand: (1) Determination of Cd hyperaccumulating plants. AB - The cadmium (Cd) phytoremediation capabilities of Gynura pseudochina, Chromolaena odorata, Conyza sumatrensis, Crassocephalum crepidioides and Nicotiana tabacum were determined by conducting in-situ experiments in a highly Cd-contaminated agricultural field at Mae Sot District, Tak Province, Thailand. Most of these five plant species, which are commonly found in Thailand, previously demonstrated Cd-hyperaccumulating capacities under greenhouse conditions. This study represented an important initial step in determining if any of these plants could, under field-conditions, effectively remove Cd from the Mae Sot contaminated fields, which represent a health threat to thousands of local villagers. All plant species had at least a 95% survival rate on the final harvest day. Additionally, all plant species, except C. odorata, could hyperaccumulate the extractable Cd amounts present in the soil, based on their associated Bioaccumulation Factor (BAF), Translocation Factor (TF), and background Vegetation Factor (VF). Therefore, the four Cd-hyperaccumulating plant species identified in this study may successfully treat a majority of contaminated fields at Mae Sot, as it was previously reported that Cd amounts present in a number of these soils were mostly available. PMID- 25454204 TI - Bioaugmentation and its application in wastewater treatment: A review. AB - Bioaugmentation (the process of adding selected strains/mixed cultures to wastewater reactors to improve the catabolism of specific compounds, e.g. refractory organics, or overall COD) is a promising technique to solve practical problems in wastewater treatment plants, and enhance removal efficiency. The potential of this option can now be enhanced in order to take advantage of important advances in the fields of microbial ecology, molecular biology, immobilization techniques and advanced bioreactor design. Reports on bioaugmentation in WWT show the difficulties in evaluating the potential parameters involved, leading frequently to inconclusive outcomes. Many studies have been carried out on the basis of trial-and-error approaches, and it has been reported that reactors bioaugmented with pure cultures often fail to perform as well as the pure cultures under laboratory conditions. As an interesting technical challenge, the feasibility of bioaugmentation should ultimately be assessed by data from field implementation, and this review highlights several promising areas to explore in the future. PMID- 25454205 TI - (1)H and (13)C NMR spectroscopic studies of hexane-extractable lipids from soils under shelterbelts of different age and composition of plants. AB - Comparative study of the composition of lipids extracted with n-hexane from soils under shelterbelts of different age and composition of plants and adjoining cultivated fields in agrolandscape has been carried out with the application of (1)N and (13)S NMR spectroscopy. The lipid content correlates with the organic carbon content in soils and is the highest in the soil under the 200-years old shelterbelt. The data received indicate that hexane-extractable lipids from the soil under the 200-years old shelterbelt have undergone the most significant biochemical and chemical transformations (oxidation, hydrolysis, polymerization) with the accumulation of resistant compounds and destruction of esters of o phthalic acid as anthropogenic contaminants compared to the lipids from the soil under the 14-years old shelterbelt and soils of adjoining arable fields. PMID- 25454206 TI - Estimating the physicochemical properties of polyhalogenated aromatic and aliphatic compounds using UPPER: part 2. Aqueous solubility, octanol solubility and octanol-water partition coefficient. AB - The UPPER (Unified Physicochemical Property Estimation Relationships) model uses additive and non-additive parameters to estimate 20 biologically relevant properties of organic compounds. The model has been validated by Lian and Yalkowsky (2014) on a data set of 700 hydrocarbons. Recently, Admire et al. (2014) expanded the model to predict the boiling and melting points of 1288 polyhalogenated benzenes, biphenyls, dibenzo-p-dioxins, diphenyl ethers, anisoles and alkanes. In this work, 19 new group descriptors are determined and used to predict the aqueous solubilities, octanol solubilities and the octanol-water coefficients. PMID- 25454207 TI - Clinical impact of acute kidney injury on short- and long-term outcomes after transcatheter aortic valve implantation with the CoreValve prosthesis. AB - BACKGROUND: Acute kidney injury (AKI) after cardiac surgery is associated with increased mortality, but few data exist on the occurrence and clinical impact of AKI associated with transcatheter aortic valve implantation (TAVI). The objective of this study was to determine the incidence and prognosis of AKI after percutaneous implantation of the CoreValve((r)) (Medtronic, Minneapolis, MN, USA) prosthesis. METHODS: A total of 357 patients with severe aortic stenosis and 9 patients with pure native aortic regurgitation were treated with the CoreValve prosthesis. AKI was defined according to Valve Academic Research Consortium criteria as the absolute increase in serum creatinine >=0.3mg/dl at 72h post percutaneous procedure. RESULTS: AKI was identified in 58 patients (15.8%), none of whom required renal replacement therapy. In patients with AKI, the mortality at 30 days was 13.5% compared with 1.6% of patients without AKI, [odds ratio (OR)=12.2 (95% CI 3.53-41.9); p<0.001] and total mortality after a mean of 26.2+/ 17 months was 29.3% vs. 14.9% [OR=2.36 (95% CI 1.23-4.51), p=0.008]. In the multivariate analysis, AKI was an independent predictor of cumulative total mortality [hazard ratio=2.151, (95% CI from 1.169 to 3.957), p=0.014]. CONCLUSIONS: The deterioration of renal function in patients undergoing TAVI with the CoreValve prosthesis is a serious and frequent complication. The occurrence of AKI was associated with increased early mortality and was also a predictor of worse outcomes in follow-up. PMID- 25454209 TI - Atherosclerosis, trichinellosis and Egyptian mummies. PMID- 25454208 TI - Design of a prospective observational survey on landiolol in atrial fibrillation/atrial flutter patients with chronic heart failure - AF-CHF landiolol survey. AB - BACKGROUND: In Japan, intravenous digoxin was previously recommended as a standard drug for acute control of the heart rate in atrial fibrillation (AF)/atrial flutter (AFL) patients with chronic heart failure (CHF). Treatment alternatives for such cases were limited and new drugs for this purpose are needed. In November 2013, landiolol hydrochloride (Onoact((r)) 50 for Injection, Ono Pharamaceutical, Osaka, Japan) was approved with the indication for "tachyarrhythmia (AF/AFL) in patients with cardiac dysfunction." However, clinical experience with this condition is still insufficient. Therefore, it is important to conduct a surveillance of landiolol under actual clinical settings. In addition, collecting data on the mid- and long-term outcomes in patients treated with landiolol which have not been collected in clinical trials are indispensable. METHODS: This prospective survey will involve patients treated with landiolol for the treatment of tachyarrhythmia (AF/AFL) in cardiac dysfunction at Japanese medical facilities from June 2014 to May 2017. The planned number of patients for analysis is approximately 500. The evaluations will be made not only to identify the adverse events and clinical effectiveness of the drug, but also to characterize the mid- and long-term outcomes of patients receiving and switching to oral-beta-blockers after the discontinuation of landiolol. RESULTS: This study was started in June 2014 (registration period 2 years, survey period 3 years) and will end in May 2017. CONCLUSIONS: This survey will clarify both the characteristics and mid- and long-term outcome of using landiolol to treat AF/AFL patients with cardiac dysfunction in clinical practice. Moreover, this survey will simultaneously provide important data that will reveal the possible gap between clinical trials and clinical practice in these patients. PMID- 25454210 TI - Conservation of low-islands: high priority despite sea-level rise. A comment on Courchamp et al. PMID- 25454211 TI - Relict species: a relict concept? AB - Relict species have always beguiled evolutionary biologists and biogeographers, who often view them as fascinating 'living fossils' or remnants of old times. Consequently, they are believed to provide interesting and important information on a vanished past and are used to understand the evolution of clades and biotas. The information that relicts provide can, however, be misleading and overemphasised when it is not remembered that they belong to groups or biotas that are mostly extinct. For example, relict species imply regional extinctions and, for this reason, they cannot simultaneously provide evidence of local biota permanence. Here we consider carefully misconceptions about relict species and highlight more clearly their evolutionary and biogeographical significance. PMID- 25454212 TI - Open repair of asymptomatic popliteal artery aneurysm is associated with better outcomes than endovascular repair. AB - OBJECTIVE: Open (OPAR) and endovascular (EPAR) repair are both used to treat popliteal artery aneurysm (PAA). We assessed outcomes of both modalities in the treatment of asymptomatic PAAs. METHODS: Vascular Quality Initiative (VQI) databases (2010 to 2013) were queried for patients undergoing asymptomatic PAA repair using OPAR and EPAR. The groups were compared with respect to demographics, medical history, and procedural characteristics. Outcomes of interest were length of stay (LOS), major adverse limb events (MALE), MALE or perioperative death (MALE-POD), and loss of primary patency compared using Kaplan Meier estimates. Proportional hazard Cox regression was used to compare the outcomes across the treatment groups. Multivariable regression with backward elimination procedure (alpha = .5) was used to construct parsimonious models to predict MALE and MALE-POD. Gamma regression was used to compare LOS. RESULTS: From 2010 to 2013, 390 patients with asymptomatic PAAs were identified (221 OPAR, 169 EPAR) and included in this study. Preoperative comorbidities were similar between the two groups, except for a higher rate of congestive heart failure (19.5% vs 11.8%, P = .042) and chronic obstructive pulmonary disease (19.5% vs 11.8%, P = .042) in the EPAR group. No in-hospital mortality was observed. LOS was significantly longer in the OPAR group (3.8 +/- 2.5 vs 1.4 +/- 1.9 days; P < .001). OPAR patients had a significantly higher MALE-free survival (95% vs 80%; P < .001) as was MALE-POD-free survival (93% vs 80%; P < .001) rates at 1 year after the procedure. OPAR was associated with lower hazard of MALE (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.15-0.86; P < .05), MALE-POD (HR, 0.28; 95% CI, 0.13-0.63; P < .05), and primary patency loss (HR, 0.25; 95% CI, 0.10-0.58; P < .05). CONCLUSIONS: This retrospective analysis suggests that OPAR is associated with better outcomes than EPAR. Ultimately, the ongoing, adequately powered Open versus Endovascular Popliteal Artery Aneurysm Repair (OVERPAR) trial will definitively compare these procedures. PMID- 25454214 TI - Effect of incubation atmosphere on the production and composition of staphylococcal biofilms. AB - Staphylococcus aureus and Staphylococcus epidermidis are pathogenic bacteria that often cause invasive infections in humans. In this study, we characterized the composition and growth characteristics of staphylococcal biofilms under various incubation atmospheres. We assessed the effect of incubation atmosphere (aerobic, 5% CO2, anaerobic, and microaerobic) on the biofilm production capabilities of S. aureus strains isolated from healthy volunteers and from patients with catheter related bloodstream infection. In addition, the composition of S. aureus and S. epidermidis biofilms was determined by assessment of biofilm degradation after treatment with DNase I, proteinase K, and dispersin B. The strains obtained from healthy volunteers and patients showed similar biofilm formation capabilities. Biofilms of S. aureus were rich in proteins when developed under ambient atmospheric conditions, 5% CO2, and microaerobic condition, whereas S. epidermidis biofilms contained large amounts of poly-beta (1, 6)-N-acetyl-D glucosamine when developed under ambient atmospheric conditions and microaerobic condition. The biofilm-producing capability of S. epidermidis was considerably higher than that of S. aureus under aerobic condition. Staphylococcal isolates obtained from healthy individuals and patients with catheter-related infections have similar biofilm-forming capabilities. Under microaerobic conditions, S. aureus and S. epidermidis form protein-rich and poly-beta (1, 6)-N-acetyl-D glucosamine-rich biofilms, respectively. These components may play an important role in the development of biofilms inside the body and may be the target molecules to prevent catheter-related infections caused by these organisms. PMID- 25454213 TI - Pretreatment of pericardial patches with antibiotics does not alter patch healing in vivo. AB - BACKGROUND: Pretreatment with antibiotics is commonly performed before surgical implantation of prosthetic materials. We previously showed that pericardial patches are infiltrated by macrophages and arterial stem cells after implantation into an artery. We hypothesized that antibiotic pretreatment would diminish the number of cells infiltrating into the patch, potentially affecting early neointimal formation. METHODS: Bovine pericardial patches were pretreated with saline, bacitracin (500 U/mL), or cephalexin (10 mg/mL) for 30 minutes before implantation into the Wistar rat infrarenal aorta. Patches were retrieved on day 7 or day 30 and analyzed for histology and cell infiltration. Markers of proliferation, apoptosis, vascular cell identity, and M1 and M2 macrophage subtypes were examined using immunofluorescence and immunohistochemistry. Extracted proteins were analyzed by Western blot. RESULTS: At day 7, pericardial patches pretreated with bacitracin or cephalexin showed similar amounts of neointimal thickening (P = .55) and cellular infiltration (P = .42) compared with control patches. Patches pretreated with antibiotics showed similar proliferation (P = .09) and apoptosis (P = .84) as control patches. The cell composition of the neointima in pretreated patches was similar to control patches, with a thin endothelial layer overlying a thin layer of smooth muscle cells (P = .45), and containing similar numbers of CD34-positive (P = .26) and vascular endothelial growth factor receptor 2-positive (P = .31) cells. Interestingly, within the body of the patch, there were fewer macrophages (P = .0003) and a trend towards fewer endothelial progenitor cells (P = .051). No M1 macrophages were found in or around any of the patches. M2 macrophages were present around the patches, and there was no difference in numbers of M2 macrophages surrounding control patches and patches pretreated with antibiotics (P = .24). There was no difference in neointimal thickness at day 30 between control patches and patches pretreated with antibiotics (P = .52). CONCLUSIONS: Pretreatment of bovine pericardial patches with the antibiotics bacitracin or cephalexin has no detrimental effect on early patch healing, with similar neointimal thickness, cellular infiltration, and numbers of M2 macrophages compared with control patches. These results suggest that the host vessel response to patch angioplasty using pericardial patches is adaptive remodeling (eg, arterial healing). PMID- 25454215 TI - High rate of inducible clindamycin resistance in Staphylococcus aureus isolates- a multicenter study in Tokyo, Japan. AB - The resistance of Staphylococcus aureus (S. aureus) to antibiotics is an increasing problem. Clindamycin has been used as empiric therapy for the rising incidence of community-acquired methicillin-resistant S. aureus (MRSA). As such, the local rate of inducible resistance against clindamycin is an important consideration. This multicenter study was conducted to identify the incidence of inducible clindamycin resistance of S. aureus isolates in Tokyo, the most populous city in Japan. A total of 2408 adult and pediatric samples were collected from a university hospital and two pediatric hospitals between January 2011 and December 2011. Among the 2341 samples analyzed, the incidence of inducible clindamycin resistance in erythromycin-resistant and clindamycin susceptible/intermediate isolates was found to be 91% (n = 585), a figure much higher compared to most reports from other countries. In conclusion, we found a very high rate of inducible clindamycin resistance in macrolide-resistant S. aureus isolates in our geographic area. PMID- 25454216 TI - Impact of antibiotic exposure on occurrence of nosocomial carbapenem-resistant Acinetobacter baumannii infection: a case control study. AB - Carbapenem-resistant Acinetobacter baumannii (CRAB) infection is one of the most important healthcare associated diseases worldwide. Although antibiotic use is recognized as a risk factor for CRAB infection, the impact of antibiotic class and length of use on CRAB infection is still unclear. A case-control study was conducted in adult intensive care units and general wards of Songklanagarind Hospital, a tertiary-care hospital in southern Thailand, to investigate the effect of different antibiotic exposure and the duration of use on the risk of developing CRAB infection. Cases were defined as patients with carbapenem susceptible A. baumannii (CSAB) or CRAB infection. Controls were randomly selected from patients and matched 1:1 with cases using ward and date of admission. Multinomial logistic regression was used to compute relative risk ratios (RRR) and 95% confidence intervals (CI) for CRAB infection. Of 197 cases with A. baumannii infection, there were 139 with CRAB infection and 58 with CSAB infection. Compared to the control group, use of fluoroquinolones, broad-spectrum cephalosporins and carbapenems for more than three days increased the risk of CRAB infection with RRR (95% CI) of 81.2 (38.1-862.7), 31.3 (9.9-98.7) and 112.1 (7.1-1770.6), respectively. The RRR (95% CI) for one to three day treatment of fluoroquinolones, broad-spectrum cephalosporins and carbapenems were 5.4 (0.8 38.7), 6.2 (0.1-353.2) and 63.3 (15.6-256.9), respectively. Long-term use of certain antibiotics and even short term use of carbapenems increased the risk of CRAB infection. In this setting, use of these antibiotics, especially carbapenems, should be limited to reduce CRAB infection. PMID- 25454217 TI - Reply to the letter to the editor by Edelstein PH. PMID- 25454218 TI - The role of miR-29 in pulmonary fibrosis. AB - Pulmonary fibrosis is a pathological condition in which lungs become scarred due to the excess extracellular matrix (ECM) deposition and structural alterations in the interstitium of lung parenchyma. Many patients with interstitial lung diseases (ILDs) caused by long-term exposure to toxic substances, chronic infections, or autoimmune responses develop fibrosis. Etiologies for many ILDs are unknown, such as idiopathic pulmonary fibrosis (IPF), a devastating, relentless form of pulmonary fibrosis with a median survival of 2-3 years. Despite several decades of research, factors that initiate and sustain the fibrotic response in lungs remain unclear and there is no effective treatment to block progression of fibrosis. Here we summarize recent findings on the antifibrotic activity of miR-29, a small noncoding regulatory RNA, in the pathogenesis of fibrosis by regulating ECM production and deposition, and epithelial-mesenchymal transition (EMT). We also describe interactions of miR-29 with multiple profibrotic and inflammatory pathways. Finally, we review the antifibrotic activity of miR-29 in animal models of fibrosis and highlight miR-29 as a promising therapeutic reagent or target for the treatment of pulmonary fibrosis. PMID- 25454219 TI - Sources and remediation techniques for mercury contaminated soil. AB - Mercury (Hg) in soils has increased by a factor of 3 to 10 in recent times mainly due to combustion of fossil fuels combined with long-range atmospheric transport processes. Other sources as chlor-alkali plants, gold mining and cement production can also be significant, at least locally. This paper summarizes the natural and anthropogenic sources that have contributed to the increase of Hg concentration in soil and reviews major remediation techniques and their applications to control soil Hg contamination. The focus is on soil washing, stabilisation/solidification, thermal treatment and biological techniques; but also the factors that influence Hg mobilisation in soil and therefore are crucial for evaluating and optimizing remediation techniques are discussed. Further research on bioremediation is encouraged and future study should focus on the implementation of different remediation techniques under field conditions. PMID- 25454220 TI - Comparing human exposure to emerging and legacy flame retardants from the indoor environment and diet with concentrations measured in serum. AB - This study investigates associations between serum concentrations of emerging and legacy halogenated flame retardants (HFRs) in 46 Norwegian women and measured indoor air and dust concentrations of the HFRs as well as detailed information on diet and household factors. Hexabromobenzene (median 0.03ng/g lipid) and Dechlorane 602 (median 0.18ng/g lipid) were detected in about 50% of the samples and Dechlorane Plus syn (median 0.45ng/g lipid) and anti (median 0.85ng/g lipid) in more than 78%. The most abundant polybrominated diphenyl ethers were 2,2',4,4',5,5'-hexabromodiphenyl ether (BDE-153; median 0.82ng/g lipid) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47; median 0.49ng/g lipid) detected in more than 70% of the samples. In the bivariate analysis, no consistent associations were observed between the biomonitoring data and measured concentrations in indoor air and dust. On the other hand, consumption of specific food items (mainly lamb/mutton and margarine) correlated significantly with more than two HFR serum concentrations, while this was not the case for household factors (electronic appliances). Only the significant bivariate associations with diet were confirmed by multivariate linear regression analyses, which might indicate a higher contribution from food compared to the indoor environment to the variation of the body burden of these HFRs. PMID- 25454221 TI - Identification of a group of brominated flame retardants as novel androgen receptor antagonists and potential neuronal and endocrine disrupters. AB - Brominated flame-retardants (BFRs) are used in industrial products to reduce the risk of fire. However, their continuous release into the environment is a concern as they are often persistent, bioaccumulating and toxic. Information on the impact these compounds have on human health and wildlife is limited and only a few of them have been identified to disrupt hormone receptor functions. In the present study we used in silico modeling to determine the interactions of selected BFRs with the human androgen receptor (AR). Three compounds were found to dock into the ligand-binding domain of the human AR and these were further tested using in vitro analysis. Allyl 2,4,6-tribromophenyl ether (ATE), 2 bromoallyl 2,4,6-tribromophenyl ether (BATE) and 2,3-dibromopropyl-2,4,6 tribromophenyl ether (DPTE) were observed to act as AR antagonists. These BFRs have recently been detected in the environment, in house dust and in aquatic animals. The compounds have been detected at high concentrations in both blubber and brain of seals and we therefore also assessed their impact on the expression of L-type amino acid transporter system (LAT) genes, that are needed for amino acid uptake across the blood-brain barrier, as disruption of LAT gene function has been implicated in several brain disorders. The three BFRs down-regulated the expression of AR target genes that encode for prostate specific antigen (PSA), 5alpha-reductases and beta-microseminoprotein. The potency of PSA inhibition was of the same magnitude as the common prostate cancer drugs, demonstrating that these compounds are strong AR antagonists. Western blot analysis of AR protein showed that ATE, BATE and DPTE decreased the 5alpha-dihydrotestosterone-induced AR protein levels, further confirming that these BFRs act as AR antagonists. The transcription of the LAT genes was altered by the three BFRs, indicating an effect on amino-acid uptake across cellular membranes and blood-brain barrier. This study demonstrated that ATE, BATE and DPTE are potent AR antagonists and the alterations in LAT gene transcription suggest that these compounds can affect neuronal functions and should be considered as potential neurotoxic and endocrine disrupting compounds. PMID- 25454222 TI - A first European scale multimedia fate modelling of BDE-209 from 1970 to 2020. AB - The European Variant Berkeley Trent (EVn-BETR) multimedia fugacity model is used to test the validity of previously derived emission estimates and predict environmental concentrations of the main decabromodiphenyl ether congener, BDE 209. The results are presented here and compared with measured environmental data from the literature. Future multimedia concentration trends are predicted using three emission scenarios (Low, Realistic and High) in the dynamic unsteady state mode covering the period 1970-2020. The spatial and temporal distributions of emissions are evaluated. It is predicted that BDE-209 atmospheric concentrations peaked in 2004 and will decline to negligible levels by 2025. Freshwater concentrations should have peaked in 2011, one year after the emissions peak with sediment concentrations peaking in 2013. Predicted atmospheric concentrations are in good agreement with measured data for the Realistic (best estimate of emissions) and High (worst case scenario) emission scenarios. The Low emission scenario consistently underestimates measured data. The German unilateral ban on the use of DecaBDE in the textile industry is simulated in an additional scenario, the effects of which are mainly observed within Germany with only a small effect on the surrounding areas. Overall, the EVn-BTER model predicts atmospheric concentrations reasonably well, within a factor of 5 and 1.2 for the Realistic and High emission scenarios respectively, providing partial validation for the original emission estimate. Total mean MEC:PEC shows the High emission scenario predicts the best fit between air, freshwater and sediment data. An alternative spatial distribution of emissions is tested, based on higher consumption in EBFRIP member states, resulting in improved agreement between MECs and PECs in comparison with the Uniform spatial distribution based on population density. Despite good agreement between modelled and measured point data, more long-term monitoring datasets are needed to compare predicted trends in concentration to determine the rate of change of POPs within the environment. PMID- 25454224 TI - Applicability of a noise-based model to estimate in-traffic exposure to black carbon and particle number concentrations in different cultures. AB - Several studies show that a significant portion of daily air pollution exposure, in particular black carbon (BC), occurs during transport. In a previous work, a model for the in-traffic exposure of bicyclists to BC was proposed based on spectral evaluation of mobile noise measurements and validated with BC measurements in Ghent, Belgium. In this paper, applicability of this model in a different cultural context with a totally different traffic and mobility situation is presented. In addition, a similar modeling approach is tested for particle number (PN) concentration. Indirectly assessing BC and PN exposure through a model based on noise measurements is advantageous because of the availability of very affordable noise monitoring devices. Our previous work showed that a model including specific spectral components of the noise that relate to engine and rolling emission and basic meteorological data, could be quite accurate. Moreover, including a background concentration adjustment improved the model considerably. To explore whether this model could also be used in a different context, with or without tuning of the model parameters, a study was conducted in Bangalore, India. Noise measurement equipment, data storage, data processing, continent, country, measurement operators, vehicle fleet, driving behavior, biking facilities, background concentration, and meteorology are all very different from the first measurement campaign in Belgium. More than 24h of combined in-traffic noise, BC, and PN measurements were collected. It was shown that the noise-based BC exposure model gives good predictions in Bangalore and that the same approach is also successful for PN. Cross validation of the model parameters was used to compare factors that impact exposure across study sites. A pooled model (combining the measurements of the two locations) results in a correlation of 0.84 when fitting the total trip exposure in Bangalore. Estimating particulate matter exposure with traffic noise measurements was thus shown to be a valid approach across countries and cultures. PMID- 25454223 TI - Historical intake and elimination of polychlorinated biphenyls and organochlorine pesticides by the Australian population reconstructed from biomonitoring data. AB - Quantifying the competing rates of intake and elimination of persistent organic pollutants (POPs) in the human body is necessary to understand the levels and trends of POPs at a population level. In this paper we reconstruct the historical intake and elimination of ten polychlorinated biphenyls (PCBs) and five organochlorine pesticides (OCPs) from Australian biomonitoring data by fitting a population-level pharmacokinetic (PK) model. Our analysis exploits two sets of cross-sectional biomonitoring data for PCBs and OCPs in pooled blood serum samples from the Australian population that were collected in 2003 and 2009. The modeled adult reference intakes in 1975 for PCB congeners ranged from 0.89 to 24.5ng/kgbw/day, lower than the daily intakes of OCPs ranging from 73 to 970ng/kgbw/day. Modeled intake rates are declining with half-times from 1.1 to 1.3years for PCB congeners and 0.83 to 0.97years for OCPs. The shortest modeled intrinsic human elimination half-life among the compounds studied here is 6.4years for hexachlorobenzene, and the longest is 30years for PCB-74. Our results indicate that it is feasible to reconstruct intakes and to estimate intrinsic human elimination half-lives using the population-level PK model and biomonitoring data only. Our modeled intrinsic human elimination half-lives are in good agreement with values from a similar study carried out for the population of the United Kingdom, and are generally longer than reported values from other industrialized countries in the Northern Hemisphere. PMID- 25454225 TI - Recreational swimmers' exposure to Vibrio vulnificus and Vibrio parahaemolyticus in the Chesapeake Bay, Maryland, USA. AB - Vibrio vulnificus and Vibrio parahaemolyticus are ubiquitous in the marine estuarine environment, but the magnitude of human non-ingestion exposure to these waterborne pathogens is largely unknown. We evaluated the magnitude of dermal exposure to V. vulnificus and V. parahaemolyticus among swimmers recreating in Vibrio-populated waters by conducting swim studies at four swimming locations in the Chesapeake Bay in 2009 and 2011. Volunteers (n=31) swam for set time periods, and surface water (n=25) and handwash (n=250) samples were collected. Samples were analyzed for Vibrio concentrations using quantitative PCR. Linear and logistic regressions were used to evaluate factors associated with recreational exposures. Mean surface water V. vulnificus and V. parahaemolyticus concentrations were 1128CFUmL(-1) (95% confidence interval (CI): 665.6, 1591.4) and 18CFUmL(-1) (95% CI: 9.8, 26.1), respectively, across all sampling locations. Mean Vibrio concentrations in handwash samples (V. vulnificus, 180CFUcm(-2) (95% CI: 136.6, 222.5); V. parahaemolyticus, 3CFUcm(-2) (95% CI: 2.4, 3.7)) were significantly associated with Vibrio concentrations in surface water (V. vulnificus, p<0.01; V. parahaemolyticus, p<0.01), but not with salinity or temperature (V. vulnificus, p=0.52, p=0.17; V. parahaemolyticus, p=0.82, p=0.06). Handwashing reduced V. vulnificus and V. parahaemolyticus on subjects' hands by approximately one log (93.9%, 89.4%, respectively). It can be concluded that when Chesapeake Bay surface waters are characterized by elevated concentrations of Vibrio, swimmers and individuals working in those waters could experience significant dermal exposures to V. vulnificus and V. parahaemolyticus, increasing their risk of infection. PMID- 25454226 TI - Outdoor air pollution and term low birth weight in Japan. AB - INTRODUCTION: Evidence has accumulated on the association between ambient air pollution and adverse birth outcomes. However, most of the previous studies were conducted in geographically distinct areas and suffer from lack of important potential covariates. We examined the effect of ambient air pollution on term low birth weight (LBW) using data from a nationwide population-based longitudinal survey in Japan that began in 2001. METHODS: We restricted participants to term singletons (n=44,109). Air pollution concentrations during the 9months before birth were obtained at the municipality level and were assigned to the participants who were born in the corresponding municipality. We conducted multilevel logistic regression analyses adjusting for individual and municipality level variables. RESULTS: We found that air pollution exposure during pregnancy was positively associated with the risk of term LBW. In the fully adjusted models, odds ratios following one interquartile range increase in each pollutant were 1.09 (95% confidence interval: 1.00, 1.19) for suspended particulate matter (SPM), 1.11 (0.99, 1.26) for nitrogen dioxide (NO2), and 1.71 (1.18, 2.46) for sulfur dioxide (SO2). Specifically, effect estimates for SPM and NO2 exposure at the first trimester were higher than those at other trimesters, while SO2 was associated with the risk at all trimesters. Nonsmoking mothers were more susceptible to SPM and NO2 exposure compared with smoking mothers. CONCLUSIONS: Ambient air pollution increases the risk of term LBW in a nationally representative sample in Japan. PMID- 25454227 TI - Hazard quotient profiles used as a risk assessment tool for PFOS and PFOA serum levels in three distinctive European populations. AB - Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) blood levels are commonly used as biomarkers of human environmental exposure to these compounds. Many biomonitoring studies indicate 100% detection for PFOS and PFOA thus justifying a concern of possible risk for the most exposed individuals. This study addresses the predictive value of hazard quotients (HQs) calculated on the basis of serum PFOS and PFOA in male and female populations of reproductive age in Greenland, Poland and Ukraine. Overall, 2026 results of PFOS and PFOA serum concentrations (589 males, 1437 females) were obtained from the INUENDO database. HQs were calculated from the actual biomonitoring results and literature-based animal data linking toxicological outcomes and critical PFOS/PFOA serum levels. HQs for serum PFOS were calculated based on Points of Departure (PoD) at 13MUgmL( 1) (cynomolgus monkeys, 183days, changes in THS and T3) and for PFOA at 7.1MUgmL( 1) serum (male rats, 90days, hepatocellular necrosis, increased liver weight). Uncertainty factors were applied to reflect interspecies differences and human variability. Serum HQs were expressed as a ratio relative to the point of departure for each PFOS and PFOA. Only in the three cases of males in Greenland were there serum PFOS levels showing HQ values exceeding 1, so indicating that such serum levels may be of concern. The mean serum concentration of PFOS was significantly higher in male than in female populations. Despite significant differences between HQ profiles for PFOS and PFOA in donors from Greenland, Poland and Ukraine, the concentrations of these perfluoroalkylated compounds do not indicate a cause for concern, except for the three aforementioned cases from Greenland. This study demonstrates that the HQ approach can help to interpret human biomonitoring data and thus serve as a valuable tool in further risk assessment priority settings and may also be used as a basis for taking decisions in risk management. PMID- 25454228 TI - Targeted analytical toxicology: simultaneous determination of 17alpha ethynylestradiol and the estrogen-induced vitellogenin biomarker. AB - In most toxicological studies, chemical concentrations and its biological/molecular response (biomarker) levels are often quantified separately. We report a method, named as Targeted Analytical Toxicology (TAT), for the simultaneous determination of levels of chemicals and protein biomarkers in organisms by UPLC/ESI-MS/MS on the basis of targeted proteomics. The TAT method is successfully applied to detect the concentrations of 17alpha-ethynylestradiol (EE2) and EE2-induced vitellogenin (a biomarker for estrogens) in male zebrafish exposed to EE2. It is expected for TAT to have broad application in toxicology, especially in environmental toxicology, due to its high sensitivity, accuracy, reproducibility, high throughput, and the savings of time, cost and labor. PMID- 25454229 TI - Screening of hormone-like activities in bottled waters available in Southern Spain using receptor-specific bioassays. AB - Bottled water consumption is a putative source of human exposure to endocrine disrupting chemicals (EDCs). Research has been conducted on the presence of chemicals with estrogen-like activity in bottled waters and on their estrogenicity, but few data are available on the presence of hormonal activities associated with other nuclear receptors (NRs). The aim of this study was to determine the presence of endocrine activities dependent on the activation of human estrogen receptor alpha (hERa) and/or androgen receptor (hAR) in water in glass or plastic bottles sold to consumers in Southern Spain. Hormone-like activities were evaluated in 29 bottled waters using receptor-specific bioassays based on reporter gene expression in PALM cells [(anti-)androgenicity] and cell proliferation assessment in MCF-7 cells [(anti-)estrogenicity] after optimized solid phase extraction (SPE). All of the water samples analyzed showed hormonal activity. This was estrogenic in 79.3% and anti-estrogenic in 37.9% of samples and was androgenic in 27.5% and anti-androgenic in 41.3%, with mean concentrations per liter of 0.113pM 17beta-estradiol (E2) equivalent units (E2Eq), 11.01pM anti-estrogen (ICI 182780) equivalent units (ICI 182780Eq), 0.33pM methyltrienolone (R1881) equivalent units (R1881Eq), and 0.18nM procymidone equivalent units (ProcEq). Bottled water consumption contributes to EDC exposure. Hormone-like activities observed in waters from both plastic and glass bottles suggest that plastic packaging is not the sole source of contamination and that the source of the water and bottling process may play a role, among other factors. Further research is warranted on the cumulative effects of long-term exposure to low doses of EDCs. PMID- 25454230 TI - A review on the human health impact of airborne particulate matter. AB - Particulate matter (PM) is a key indicator of air pollution brought into the air by a variety of natural and human activities. As it can be suspended over long time and travel over long distances in the atmosphere, it can cause a wide range of diseases that lead to a significant reduction of human life. The size of particles has been directly linked to their potential for causing health problems. Small particles of concern include "inhalable coarse particles" with a diameter of 2.5 to 10MUm and "fine particles" smaller than 2.5MUm in diameter. As the source-effect relationship of PM remains unclear, it is not easy to define such effects from individual sources such as long-range transport of pollution. Because of the potent role of PM and its associated pollutants, detailed knowledge of their human health impacts is of primary importance. This paper summarizes the basic evidence on the health effects of particulate matter. An in depth analysis is provided to address the implications for policy-makers so that more stringent strategies can be implemented to reduce air pollution and its health effects. PMID- 25454231 TI - Temporal trends in concentrations and total serum burdens of organochlorine compounds from birth until adolescence and the role of breastfeeding. AB - INTRODUCTION: The aims of the present study are to assess the temporal trends of organochlorine compounds (OCs) concentrations and total serum burdens from birth until adolescence and the influence of breastfeeding in these temporal trends. METHODS: In 1997 two birth cohort studies were set up in Ribera d'Ebre (N=102) and the island of Menorca (N=482), Spain. Concentrations (ng/mL) of OCs [pentachlorobenzene (PeCB), four isomers of hexachlorocyclohexane (HCH), hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (4,4'-DDT), dichlorodiphenyldichloroethylene (4,4'-DDE) and seven polychlorobiphenyl congeners (Sigma7PCBs)] were measured in cord blood and at the age of 4 and 14years. The total serum burdens (ng) of these compounds were estimated based on the total blood volume (mL) of children at the different ages. We compared median concentrations and total serum burdens of these OCs at the different time-points of follow-up between children of Ribera d'Ebre and Menorca and between breastfed and non-breastfed children. RESULTS: From birth until adolescence concentrations of all OCs drastically reduced. These reductions were mainly derived from the dilution of OCs, associated to an increase in total blood volume of children at the age of 4 and 14years. Despite the reduction in OCs concentrations, the total serum burdens of 4,4'-DDE and Sigma7PCBs, were higher in adolescents than at birth. Increases in OCs total serum burden occurred both in breastfed and non breastfed children, but were significantly higher in the first. CONCLUSIONS: Even after decades of banning OCs production and use, current young generations in westernized countries are still bioaccumulating these compounds. Given the potential health effects of OCs, especial attention should be paid in the control of secondary emissions in the environment and in the control of food production and contamination. In countries with endemic malaria it is important to work towards effective alternatives to the use of DDT. PMID- 25454232 TI - Environmental determinants of different blood lead levels in children: a quantile analysis from a nationwide survey. AB - Blood lead levels (BLLs) have substantially decreased in recent decades in children in France. However, further reducing exposure is a public health goal because there is no clear toxicological threshold. The identification of the environmental determinants of BLLs as well as risk factors associated with high BLLs is important to update prevention strategies. We aimed to estimate the contribution of environmental sources of lead to different BLLs in children in France. We enrolled 484 children aged from 6months to 6years, in a nationwide cross-sectional survey in 2008-2009. We measured lead concentrations in blood and environmental samples (water, soils, household settled dusts, paints, cosmetics and traditional cookware). We performed two models: a multivariate generalized additive model on the geometric mean (GM), and a quantile regression model on the 10th, 25th, 50th, 75th and 90th quantile of BLLs. The GM of BLLs was 13.8MUg/L (=1.38MUg/dL) (95% confidence intervals (CI): 12.7-14.9) and the 90th quantile was 25.7MUg/L (CI: 24.2-29.5). Household and common area dust, tap water, interior paint, ceramic cookware, traditional cosmetics, playground soil and dust, and environmental tobacco smoke were associated with the GM of BLLs. Household dust and tap water made the largest contributions to both the GM and the 90th quantile of BLLs. The concentration of lead in dust was positively correlated with all quantiles of BLLs even at low concentrations. Lead concentrations in tap water above 5MUg/L were also positively correlated with the GM, 75th and 90th quantiles of BLLs in children drinking tap water. Preventative actions must target household settled dust and tap water to reduce the BLLs of children in France. The use of traditional cosmetics should be avoided whereas ceramic cookware should be limited to decorative purposes. PMID- 25454233 TI - Estimating human exposure to PFOS isomers and PFCA homologues: the relative importance of direct and indirect (precursor) exposure. AB - Contributions of direct and indirect (via precursors) pathways of human exposure to perfluorooctane sulfonic acid (PFOS) isomers and perfluoroalkyl carboxylic acids (PFCAs) are estimated using a Scenario-Based Risk Assessment (SceBRA) modelling approach. Monitoring data published since 2008 (including samples from 2007) are used. The estimated daily exposures (resulting from both direct and precursor intake) for the general adult population are highest for PFOS and perfluorooctanoic acid (PFOA), followed by perfluorohexanoic acid (PFHxA) and perfluorodecanoic acid (PFDA), while lower daily exposures are estimated for perfluorobutanoic acid (PFBA) and perfluorododecanoic acid (PFDoDA). The precursor contributions to the individual perfluoroalkyl acid (PFAA) daily exposures are estimated to be 11-33% for PFOS, 0.1-2.5% for PFBA, 3.7-34% for PFHxA, 13-64% for PFOA, 5.2-66% for PFDA, and 0.7-25% for PFDoDA (ranges represent estimated precursor contributions in a low- and high-exposure scenario). For PFOS, direct intake via diet is the major exposure pathway regardless of exposure scenario. For PFCAs, the dominant exposure pathway is dependent on perfluoroalkyl chain length and exposure scenario. Modelled PFOS and PFOA concentrations in human serum using the estimated intakes from an intermediate-exposure scenario are in agreement with measured concentrations in different populations. The isomer pattern of PFOS resulting from total intakes (direct and via precursors) is estimated to be enriched with linear PFOS (84%) relative to technical PFOS (70% linear). This finding appears to be contradictory to the observed enrichment of branched PFOS isomers in recent human serum monitoring studies and suggests that either external exposure is not fully understood (e.g. there are unknown precursors, missing or poorly quantified exposure pathways) and/or that there is an incomplete understanding of the isomer specific human pharmacokinetic processes of PFOS, its precursors and intermediates. PMID- 25454234 TI - Human health risk associated with brominated flame-retardants (BFRs). AB - The purposes of this review are to assess the human exposure and human and experimental evidence for adverse effects of brominated flame-retardants (BFRs) with specific focus on intake from seafood. The leakage of BFRs from consumer products leads to exposure of humans from fetal life to adulthood. Fish and fish products contain the highest levels of BFRs and dominate the dietary intake of frequent fish eaters in Europe, while meat, followed by seafood and dairy products accounted for the highest US dietary intake. House dust is also reported as an important source of exposure for children as well as adults. The levels of BFRs in the general North American populations are higher than those in Europe and Japan and the highest levels are detected in infants and toddlers. The daily intake via breast milk exceeds the RfD in 10% of US infants. BFRs including PBDEs, HBCDs and TBBP-A have induced endocrine-, reproductive- and behavior effects in laboratory animals. Furthermore, recent human epidemiological data demonstrated association between exposure to BFRs and similar adverse effects as observed in animal studies. Fish including farmed fish and crude fish oil for human consumption may contain substantial levels of BFRs and infants and toddlers consuming these products on a daily basis may exceed the tolerable daily intake suggesting that fish and fish oil alone represent a risk to human health. This intake comes in addition to exposure from other sources (breast milk, other food, house dust). Because potential harmful concentrations of BFRs and other toxicants occur in fish and fish products, research on a wider range of products is warranted, to assess health hazard related to the contamination of fish and fish products for human consumption. PMID- 25454235 TI - Theoretically exploring direct and indirect chemical effects across ecological and exposure scenarios using mechanistic fate and effects modelling. AB - Predicting ecosystem response to chemicals is a complex problem in ecotoxicology and a challenge for risk assessors. The variables potentially influencing chemical fate and exposure define the exposure scenario while the variables determining effects at the ecosystem level define the ecological scenario. In absence of any empirical data, the objective of this paper is to present simulations by a fugacity-based fate model and a differential equation-based ecosystem model to theoretically explore how direct and indirect effects on invertebrate shallow pond communities vary with changing ecological and exposure scenarios. These simulations suggest that direct and indirect effects are larger in mesotrophic systems than in oligotrophic systems. In both trophic states, interaction strength (quantified using grazing rates) was suggested a more important driver for the size and recovery from direct and indirect effects than immigration rate. In general, weak interactions led to smaller direct and indirect effects. For chemicals targeting mesozooplankton only, indirect effects were common in (simple) food-chains but rare in (complex) food-webs. For chemicals directly affecting microzooplankton, the dominant zooplankton group in the modelled community, indirect effects occurred both in food-chains and food webs. We conclude that the choice of the ecological and exposure scenarios in ecotoxicological modelling efforts needs to be justified because of its influence on the prevalence and magnitude of the predicted effects. Overall, more work needs to be done to empirically test the theoretical expectations formulated here. PMID- 25454236 TI - Impact of an asbestos cement factory on mesothelioma incidence: global assessment of effects of occupational, familial, and environmental exposure. AB - Few studies have examined the incidence of malignant mesothelioma (MM) associated with distinct sources of asbestos exposure (occupational, familial, or environmental). We assessed the impact of asbestos exposure-global and by source on the incidence of MM in Broni, an Italian town in which an asbestos cement factory once operated (1932-1993). Based on data collected by the Lombardy Mesothelioma Registry, we calculated the number of observed and expected MM cases among workers, their cohabitants, and people living in the area in 2000-2011. We identified 147 MM cases (17.45 expected), 138 pleural and nine peritoneal, attributable to exposure to asbestos from the factory. Thirty-eight cases had past occupational exposure at the factory (2.33 expected), numbering 32 men (26 pleural, six peritoneal) and six women (four pleural, two peritoneal). In the families of the workers, there were 37 MM cases (4.23 expected), numbering five men (all pleural) and 32 women (31 pleural, one peritoneal). Among residents in Broni or in the adjacent/surrounding towns, there were 72 cases of pleural MM (10.89 expected), numbering 23 men and 49 women. The largest MM excess was found in the towns of Broni (48 observed, 3.68 expected) and Stradella (16 observed, 1.85 expected). This study documents the large impact of the asbestos cement factory, with about 130 excess MM cases in a 12-year period. The largest MM burden was among women, from non-occupational exposure. Almost half of the MM cases were attributable to environmental exposure. PMID- 25454237 TI - Fifteen-year trends in criteria air pollutants in oil sands communities of Alberta, Canada. AB - An investigation of ambient air quality was undertaken at three communities within the Athabasca Oil Sands Region (AOSR) of Alberta, Canada (Fort McKay, Fort McMurray, and Fort Chipewyan). Daily and seasonal patterns and 15-year trends were investigated for several criteria air pollutants over the period of 1998 to 2012. A parametric trend detection method using percentiles from frequency distributions of 1h concentrations for a pollutant during each year was used. Variables representing 50th, 65th, 80th, 90th, 95th and 98th percentile concentrations each year were identified from frequency distributions and used for trend analysis. Small increasing concentration trends were observed for nitrogen dioxide (<1ppb/year) at Fort McKay and Fort McMurray over the period consistent with increasing emissions of oxides of nitrogen (ca. 1000tons/year) from industrial developments. Emissions from all oil sands facilities appear to be contributing to the trend at Fort McKay, whereas both emissions from within the community (vehicles and commercial) and oil sands facility emissions appear to be contributing to the trend at Fort McMurray. Sulfur dioxide (SO2) emissions from industrial developments in the AOSR were unchanged during the period (101,000+/-7000tons/year; mean+/-standard deviation) and no meaningful trends were judged to be occurring at all community stations. No meaningful trends occurred for ozone and fine particulate matter (PM2.5) at all community stations and carbon monoxide at one station in Fort McMurray. Air quality in Fort Chipewyan was much better and quite separate in terms of absence of factors influencing criteria air pollutant concentrations at the other community stations. PMID- 25454238 TI - Human dietary intake of organohalogen contaminants at e-waste recycling sites in Eastern China. AB - This study reports concentrations and human dietary intake of hexabromocyclododecanes (HBCDs), polychlorinated biphenyls (PCBs) as well as selected "novel" brominated flame retardants (NBFRs) and organochlorine pesticides, in ten staple food categories. Samples were sourced from areas in Taizhou City, eastern China, where rudimentary recycling and disposal of e-waste is commonplace, as well as from nearby non-e-waste impacted control areas. In most instances, concentrations in foods from e-waste recycling areas exceeded those from control locations. Concentrations of 2-ethylhexyl-2,3,4,5 tetrabromobenzoate (EH-TBB) and bis-(2-ethylhexyl)-3,4,5,6-tetrabromophthalate (BEH-TBP) in samples from e-waste sites were 3.09-62.2ng/g and 0.81-16.3ng/g lipid weight (lw), respectively; exceeding consistently those in foods acquired from control sites by an order of magnitude in many cases. In contrast, while concentrations of HBCD in some foods from e-waste impacted areas exceed those from control locations; concentrations in pork, shrimp, and duck liver are higher in control samples. This highlights the potential significance of non-e-waste sources of HBCD (e.g. building insulation foam) in our study areas. While concentrations of DDT in all foods examined except pork were higher in e-waste impacted samples than controls; our exposure estimates were well below the provisional tolerable daily intake of 0.01mg/kgbw/day derived by the Joint FAO/WHO Meeting on Pesticide Residues. Concentrations of SigmaPCBs resulted in exposures (650 and 2340ng/kgbw/day for adults and children respectively) that exceed substantially the Minimal Risk Levels (MRLs) for SigmaPCBs of 20ng/kgbw/day derived by the Agency for Toxic Substances & Disease Registry. Moreover, when expressed in terms of dioxin-like toxicity equivalency based on the four dioxin-like PCBs monitored in this study (DL-PCBs) (PCB-105, 118, 156, and 167); concentrations in e-waste impacted foods exceed limits set by the European Union in 6 of the 8 food groups studied and result in dietary exposures for children (10.2pgTEQ/kgbw/day) that exceed the WHO tolerable daily intake of 1 4pgTEQ/kgbw/day. PMID- 25454239 TI - Omics and biotechnology of arsenic stress and detoxification in plants: current updates and prospective. AB - Arsenic (As), a naturally occurring metallic element, is a dreadful health hazard to millions of people across the globe. Arsenic is present in low amount in the environment and originates from anthropogenic impact and geogenic sources. The presence of As in groundwater used for irrigation is a worldwide problem as it affects crop productivity, accumulates to different tissues and contaminates food chain. The consumption of As contaminated water or food products leads to several diseases and even death. Recently, studies have been carried out to explore the biochemical and molecular mechanisms which contribute to As toxicity, accumulation, detoxification and tolerance acquisition in plants. This information has led to the development of the biotechnological tools for developing plants with modulated As tolerance and detoxification to safeguard cellular and genetic integrity as well as to minimize food chain contamination. This review aims to provide current updates about the biochemical and molecular networks involved in As uptake by plants and the recent developments in the area of functional genomics in terms of developing As tolerant and low As accumulating plants. PMID- 25454240 TI - Aggregate dermal exposure to cyclic siloxanes in personal care products: implications for risk assessment. AB - Consumers who use personal care products (PCPs) are internally exposed to some of the organic components present of which some may be detected in exhaled air when eliminated. The aim of this study was the quantitative determination of octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) in end exhaled air to study dermal absorption of substances in PCPs. We exposed the forearm of fifteen healthy volunteers for 60min to pure D4 or D5 and to commercial products containing D4 and D5. Inhalation uptake was kept to a minimum by keeping the forearm in a flow cabinet during dermal exposure and supplying filtered air to the breathing zone of the volunteer during the post-exposure period. End-exhaled air was collected using a breath sampler (Bio-VOC), transferred to carbograph multi-bed adsorbent tubes and analyzed by thermal desorption gas chromatography mass spectrometry (TD-GC-MS). In the end-exhaled air of non-exposed volunteers background concentrations of D4 (0.8-3.5ng/L) and D5 (0.8-4.0ng/L) were observed. After exposing the volunteers, the level of D4 and D5 in end-exhaled air did not or barely exceed background concentrations. At t=90min, a sharp increase of the D4/D5 concentration in end-exhaled air was observed, which we attributed to the inhalation of the substances during a toilet visit without using inhalation protection devices. When this visit was taken out of the protocol, the sharp increase disappeared. Overall, the results of our study indicate that dermal absorption of D4 and D5 contributes only marginally to internal exposure following dermal applications. As in our study inhalation is the primary route of entry for these compounds, we conclude that its risk assessment should focus on this particular exposure route. PMID- 25454241 TI - Exposure to traffic-related air pollution and the risk of developing breast cancer among women in eight Canadian provinces: a case-control study. AB - A few recent studies have reported positive associations between long-term exposure to traffic-related air pollution and the incidence of breast cancer. We capitalized on an existing Canadian multi-site population-based case-control study to further investigate this association. We used the National Enhanced Cancer Surveillance System, a population-based case-control study conducted in eight of 10 Canadian provinces from 1994 to 1997. A total of 1569 breast cancer cases and 1872 population controls who reported at least 90% complete self reported addresses over the 1975-1994 exposure period were examined. Mean exposure levels to nitrogen dioxide (NO2) (an indicator of traffic-related air pollution) were estimated for this period using three different measures: (1) satellite-derived observations; (2) satellite-derived observations scaled with historical fixed-site measurements of NO2; and (3) a national land-use regression (LUR) model. Proximity to major roads was also examined. Using unconditional logistic regression, stratified by menopausal status, we estimated odds ratios (ORs) adjusted for many individual-level and contextual breast cancer risk factors. We observed positive associations between incident breast cancer and all three measures of NO2 exposure from 1975 to 1994. In fully adjusted models for premenopausal breast cancer, a 10ppb increase in NO2 exposure estimated from the satellite-derived observations, the scaled satellite-derived observations, and the national LUR model produced ORs of 1.26 (95% confidence intervals (CIs): 0.92 1.74), 1.32 (95% CI: 1.05-1.67) and 1.28 (95% CI: 0.92-1.79). For postmenopausal breast cancer, we found corresponding ORs of 1.10 (95% CI: 0.88-1.36), 1.10 (95% CI: 0.94-1.28) and 1.07 (95% CI: 0.86-1.32). Substantial heterogeneity in the ORs was observed across the eight Canadian provinces and reduced ORs were observed when models were restricted to women who had received routine mammography examinations. No associations were found for road proximity measures. This study provides some support for the hypothesis that traffic-related air pollution may be associated with the development of breast cancer, especially in premenopausal women. With the few studies available, further research is clearly needed. PMID- 25454242 TI - Aggregate consumer exposure to UV filter ethylhexyl methoxycinnamate via personal care products. AB - Ultraviolet (UV) filters are substances designed to protect our skin from UV induced damage and can be found in many categories of personal care products (PCPs). The potential endocrine-disrupting effects attributed to UV filter ethylhexyl methoxycinnamate (EHMC) are being debated. We evaluated the aggregate exposure of the Swiss-German population (N=1196; ages <=1-97years) to EHMC via the use of PCPs; thus we provide the first comprehensive information about the current EHMC exposure sources and aggregate exposure levels. In our probabilistic modeling method performed at an individual level, PCP use data obtained by a postal questionnaire were linked to concentration data on EHMC gained from chemical analyses of PCPs used by the questionnaire respondents. The modeled median and 99.9th percentile of the internal aggregate exposure for the general population were 0.012 and 0.873mgday(-1)kg(-1) and 0.008 and 0.122mgday(-1)kg(-1) for the summer/autumn and winter/spring period, respectively. The major contributors to internal aggregate exposure were sunscreen products in summer/autumn (females: 64%; males: 85%; children aged <=12years 93%). In winter/spring, lip care dominated for females (30%) and sunscreen for males (38%) and children aged <=12years (50%). Overall, the internal aggregate exposure estimates for the studied population are shown to be below the Derived No Effect Level (DNEL) for EHMC i.e., the level of exposure above which humans should not be exposed; however, when an intense short-term exposure via sunscreen is accounted for during a sunbathing day, at the high-end percentiles (99.9th) the predicted aggregate exposure exceeds the DNEL for thyroid-disrupting effects such as for children aged <=4years, who might be particularly susceptible to endocrine disrupting events. It is nevertheless critical to acknowledge that quantitative data on transdermal penetration of EHMC from PCPs are currently insufficient. Since long-term effects of endocrine disruptors are not known, future studies are warranted to provide accurate quantitative data on transdermal penetration of EHMC and to determine its metabolic fate in humans. PMID- 25454243 TI - Considerations in deriving quantitative cancer criteria for inorganic arsenic exposure via inhalation. AB - The inhalation unit risk (IUR) that currently exists in the United States Environmental Protection Agency's (US EPA's) Integrated Risk Information System was developed in 1984 based on studies examining the relationship between respiratory cancer and arsenic exposure in copper smelters from two US locations: the copper smelter in Anaconda, Montana, and the American Smelting And Refining COmpany (ASARCO) smelter in Tacoma, Washington. Since US EPA last conducted its assessment, additional data have become available from epidemiology and mechanistic studies. In addition, the California Air Resources Board, Texas Commission of Environmental Quality, and Dutch Expert Committee on Occupational Safety have all conducted new risk assessments. All three analyses, which calculated IURs based on respiratory/lung cancer mortality, generated IURs that are lower (i.e., less restrictive) than the current US EPA value of 4.3*10(-3) (MUg/m(3))(-1). The IURs developed by these agencies, which vary more than 20 fold, are based on somewhat different studies and use different methodologies to address uncertainties in the underlying datasets. Despite these differences, all were developed based on a cumulative exposure metric assuming a low-dose linear dose-response relationship. In this paper, we contrast and compare the analyses conducted by these agencies and critically evaluate strengths and limitations inherent in the data and methodologies used to develop quantitative risk estimates. In addition, we consider how these data could be best used to assess risk at much lower levels of arsenic in air, such as those experienced by the general public. Given that the mode of action for arsenic supports a threshold effect, and epidemiological evidence suggests that the arsenic concentration in air is a reliable predictor of lung/respiratory cancer risk, we developed a quantitative cancer risk analysis using a nonlinear threshold model. Applying a nonlinear model to occupational data, we established points of departure based on both cumulative exposure (MUg/m(3)-years) to arsenic and arsenic concentration (MUg/m(3)) via inhalation. Using these values, one can assess the lifetime risk of respiratory cancer mortality associated with ambient air concentrations of arsenic for the general US population. PMID- 25454244 TI - Contaminant levels in Norwegian farmed Atlantic salmon (Salmo salar) in the 13 year period from 1999 to 2011. AB - BACKGROUND: Environmental pollutants such as dioxins and PCBs, heavy metals, and organochlorine pesticides are a global threat to food safety. In particular, the aquatic biota can bioaccumulate many of these contaminants potentially making seafood of concern for chronic exposure to humans. OBJECTIVES: The main objective was to evaluate trends of contaminant levels in Norwegian farmed Atlantic salmon in light of the derived tolerable intakes. METHODS: Through an EU-instigated surveillance programme, the Norwegian Food Safety Authority (NFSA) has between 1999 and 2011 collected more than 2300 samples of Norwegian farmed Atlantic salmon (Salmo salar) for contaminant analyses. The fillets of these fish were homogenised and analysed for dioxins, PCBs, heavy metals and organochlorine pesticides. RESULTS: The levels of the contaminants mercury, arsenic, dioxins, dioxin-like PCBs and DDT in Norwegian farmed salmon fillet have decreased during our period of analyses. The levels of cadmium, lead and several organochlorine pesticides were too close to the limit of quantification to calculate time trends. For PCB6 and quantifiable amounts of pesticides, except DDT, stable levels were observed. CONCLUSION: The contaminant levels in Norwegian farmed salmon have generally decreased between 1999 and 2011. Excluding other dietary sources, the levels of dioxins and dioxin-like PCBs in 2011 allowed consumption of up to 1.3kg salmon per week to reach the tolerable weekly intake. The group of contaminants which was the limiting factor for safe consumption of Norwegian farmed salmon, based on currently established TWI values, is the sum of dioxins and dioxin-like PCBs. PMID- 25454245 TI - Traffic-related air pollution and health co-benefits of alternative transport in Adelaide, South Australia. AB - BACKGROUND: Motor vehicle emissions contribute nearly a quarter of the world's energy-related greenhouse gases and cause non-negligible air pollution, primarily in urban areas. Changing people's travel behaviour towards alternative transport is an efficient approach to mitigate harmful environmental impacts caused by a large number of vehicles. Such a strategy also provides an opportunity to gain health co-benefits of improved air quality and enhanced physical activities. This study aimed at quantifying co-benefit effects of alternative transport use in Adelaide, South Australia. METHOD: We made projections for a business-as-usual scenario for 2030 with alternative transport scenarios. Separate models including air pollution models and comparative risk assessment health models were developed to link alternative transport scenarios with possible environmental and health benefits. RESULTS: In the study region with an estimated population of 1.4 million in 2030, by shifting 40% of vehicle kilometres travelled (VKT) by passenger vehicles to alternative transport, annual average urban PM2.5 would decline by approximately 0.4MUg/m(3) compared to business-as-usual, resulting in net health benefits of an estimated 13deaths/year prevented and 118 disability adjusted life years (DALYs) prevented per year due to improved air quality. Further health benefits would be obtained from improved physical fitness through active transport (508deaths/year prevented, 6569DALYs/year prevented), and changes in traffic injuries (21 deaths and, 960 DALYs prevented). CONCLUSION: Although uncertainties remain, our findings suggest that significant environmental and health benefits are possible if alternative transport replaces even a relatively small portion of car trips. The results may provide assistance to various government organisations and relevant service providers and promote collaboration in policy-making, city planning and infrastructure establishment. PMID- 25454246 TI - Neonicotinoid contamination of global surface waters and associated risk to aquatic invertebrates: a review. AB - Neonicotinoids, broad-spectrum systemic insecticides, are the fastest growing class of insecticides worldwide and are now registered for use on hundreds of field crops in over 120 different countries. The environmental profile of this class of pesticides indicate that they are persistent, have high leaching and runoff potential, and are highly toxic to a wide range of invertebrates. Therefore, neonicotinoids represent a significant risk to surface waters and the diverse aquatic and terrestrial fauna that these ecosystems support. This review synthesizes the current state of knowledge on the reported concentrations of neonicotinoids in surface waters from 29 studies in 9 countries world-wide in tandem with published data on their acute and chronic toxicity to 49 species of aquatic insects and crustaceans spanning 12 invertebrate orders. Strong evidence exists that water-borne neonicotinoid exposures are frequent, long-term and at levels (geometric means=0.13MUg/L (averages) and 0.63MUg/L (maxima)) which commonly exceed several existing water quality guidelines. Imidacloprid is by far the most widely studied neonicotinoid (66% of the 214 toxicity tests reviewed) with differences in sensitivity among aquatic invertebrate species ranging several orders of magnitude; other neonicotinoids display analogous modes of action and similar toxicities, although comparative data are limited. Of the species evaluated, insects belonging to the orders Ephemeroptera, Trichoptera and Diptera appear to be the most sensitive, while those of Crustacea (although not universally so) are less sensitive. In particular, the standard test species Daphnia magna appears to be very tolerant, with 24-96hour LC50 values exceeding 100,000MUg/L (geometric mean>44,000MUg/L), which is at least 2-3 orders of magnitude higher than the geometric mean of all other invertebrate species tested. Overall, neonicotinoids can exert adverse effects on survival, growth, emergence, mobility, and behavior of many sensitive aquatic invertebrate taxa at concentrations at or below 1MUg/L under acute exposure and 0.1MUg/L for chronic exposure. Using probabilistic approaches (species sensitivity distributions), we recommend here that ecological thresholds for neonicotinoid water concentrations need to be below 0.2MUg/L (short-term acute) or 0.035MUg/L (long-term chronic) to avoid lasting effects on aquatic invertebrate communities. The application of safety factors may still be warranted considering potential issues of slow recovery, additive or synergistic effects and multiple stressors that can occur in the field. Our analysis revealed that 81% (22/27) and 74% (14/19) of global surface water studies reporting maximum and average individual neonicotinoid concentrations respectively, exceeded these thresholds of 0.2 and 0.035MUg/L. Therefore, it appears that environmentally relevant concentrations of neonicotinoids in surface waters worldwide are well within the range where both short- and long-term impacts on aquatic invertebrate species are possible over broad spatial scales. PMID- 25454247 TI - Correspondence to the Editor Re: maternal exposure to high levels of dioxins in relation to birth weight in women affected by Yusho disease. PMID- 25454248 TI - Response to: Correspondence to the Editor Re: Maternal exposure to high levels of dioxins in relation to birth weight in women affected by Yusho disease. PMID- 25454250 TI - Does CircuLite Synergy assist device as partial ventricular support have a place in modern management of advanced heart failure? AB - The discrepancy between the number of patients on the waiting list and available donor hearts has led to the successful development of left ventricular assist devices (LVAD) as a bridge to transplantation. The conventional LVADs are designed to provide full hemodynamic support for the end-stage failing heart. However, full-support LVAD implantation requires major surgery, sternotomy and cardiopulmonary bypass in majority of cases. The Synergy Micro-pump is the smallest implantable LVAD and provides partial flow support up to 3 l/min. It was shown that early intervention with this device can provide substantial benefits to patients with severe heart failure not yet sick enough for a full-support LVAD. Due the small dimensions it can be implanted without cardiopulmonary bypass or a sternotomy. The purpose of this article is to review the clinical use of the Synergy Micro-pump as partial hemodynamic support. PMID- 25454249 TI - Universal and blocking primer mismatches limit the use of high-throughput DNA sequencing for the quantitative metabarcoding of arthropods. AB - The quantification of the biological diversity in environmental samples using high-throughput DNA sequencing is hindered by the PCR bias caused by variable primer-template mismatches of the individual species. In some dietary studies, there is the added problem that samples are enriched with predator DNA, so often a predator-specific blocking oligonucleotide is used to alleviate the problem. However, specific blocking oligonucleotides could coblock nontarget species to some degree. Here, we accurately estimate the extent of the PCR biases induced by universal and blocking primers on a mock community prepared with DNA of twelve species of terrestrial arthropods. We also compare universal and blocking primer biases with those induced by variable annealing temperature and number of PCR cycles. The results show that reads of all species were recovered after PCR enrichment at our control conditions (no blocking oligonucleotide, 45 degrees C annealing temperature and 40 cycles) and high-throughput sequencing. They also show that the four factors considered biased the final proportions of the species to some degree. Among these factors, the number of primer-template mismatches of each species had a disproportionate effect (up to five orders of magnitude) on the amplification efficiency. In particular, the number of primer-template mismatches explained most of the variation (~3/4) in the amplification efficiency of the species. The effect of blocking oligonucleotide concentration on nontarget species relative abundance was also significant, but less important (below one order of magnitude). Considering the results reported here, the quantitative potential of the technique is limited, and only qualitative results (the species list) are reliable, at least when targeting the barcoding COI region. PMID- 25454252 TI - Structure and properties of citrate overlayers adsorbed at the aqueous Au(111) interface. AB - One of the most common means of gold nanoparticle (AuNP) biofunctionalization involves the manipulation of precursor citrate-capped AuNPs via ligand displacement. However, the molecular-level structural characteristics of the citrate overlayer adsorbed at the aqueous Au interface at neutral pH remain largely unknown. Access to atomistic-scale details of these interfaces will contribute much needed insight into how AuNPs can be manipulated and exploited in aqueous solution. Here, the structures of such citrate overlayers adsorbed at the aqueous Au(111) interface at pH 7 are predicted and characterized using atomistic molecular dynamics simulations, for a range of citrate surface densities. We find that the overlayers are disordered in the surface density range considered, and that many of their key characteristics are invariant with surface density. In particular, we predict the overlayers to have 3-D, rather than 2-D, morphologies, with the anions closest to the gold surface being oriented with their carboxylate groups pointing away from the surface. We predict both striped and island morphologies for our overlayers, depending on the citrate surface density, and in all cases we find bare patches of the gold surface are present. Our simulations suggest that both citrate-gold adsorption and citrate-counterion pairing contribute to the stability of these citrate overlayer morphologies. We also calculate the free energy of adsorption at the aqueous Au(111) interface of a single citrate molecule, and compare this with the corresponding value for a single arginine molecule. These findings enable us to predict the conditions under which ligand displacement of surface-adsorbed citrate by arginine may take place. Our findings represent the first steps toward elucidating a more elaborate, detailed atomistic-scale model relating to the biofunctionalization of citrate-capped AuNPs. PMID- 25454253 TI - Prevalence of malnutrition in children under five and school-age children in Milot Valley, Haiti. AB - OBJECTIVES: This research aims to provide child malnutrition prevalence data from Haiti's Milot Valley to inform the design and implementation of local health interventions. STUDY DESIGN: This cross-sectional study measured underweight, stunting, and wasting/thinness using international growth standards. METHODS: Anthropometric measurements (height/length and weight) were taken on a convenience sample of 358 children aged 0-14 years. Participants were recruited through door-to-door field visits at five recruitment sites in the Milot Valley, including individuals in the waiting area of the Pediatric Outpatient Clinic at Hopital Sacre Coeur. Caregivers were asked questions about the child's health history, including past and current feeding practices. RESULTS: Combining moderate and severe forms of malnutrition, 14.8% of children under five were stunted, 15.3% were wasted, and 16.1% were underweight. Among children 5-14 years of age, 14.1% were stunted, 7.6% were thin (low body mass index (BMI)-for-age), and 14.5% were underweight. For children under five, 42% of mothers ended exclusive breastfeeding before the recommended six months. CONCLUSION: This study illustrates the local magnitude of childhood malnutrition and can serve as a resource for future child health interventions in the Milot Valley. To fight malnutrition, a multipronged, integrated approach is recommended, combining effective community outreach and monitoring, inpatient and outpatient nutrition therapy, and expanded partnerships with nutrition-related organizations in the region. PMID- 25454254 TI - Ribosomal synthesis of an amphotericin-B inspired macrocycle. AB - Here we report in vitro ribosomal synthesis of a natural product-like macrocyclic peptide, inspired by the structure of amphotericin B (AmB), an amphiphilic and membrane-interacting antifungal natural product. This AmB-inspired macrocyclic peptide (AmP), one side of which is composed of hydrophobic terpene, and the other side comprises a peptidic chain, was synthesized utilizing flexizyme assisted in vitro translation via an unusual but successful initiation with a D cysteine derivative. The established method for the synthesis of AmPs is applicable to the generation of a diverse AmP library coupled with an in vitro display format, with the potential to lead to the discovery of artificial bioactive amphiphilic macrocycles. PMID- 25454255 TI - Facile synthesis of size controllable dendritic mesoporous silica nanoparticles. AB - The synthesis of highly uniform mesoporous silica nanospheres (MSNs) with dendritic pore channels, particularly ones with particle sizes below 200 nm, is extremely difficult and remains a grand challenge. By a combined synthetic strategy using imidazolium ionic liquids (ILs) with different alkyl lengths as cosurfactants and Pluronic F127 nonionic surfactants as inhibitors of particle growth, the preparation of dendritic MSNs with controlled diameter between 40 and 300 nm was successfully realized. An investigation of dendritic MSNs using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and nitrogen physisorption revealed that the synthesis of dendritic MSNs at larger size (100-300 nm) strongly depends on the alkyl lengths of cationic imidazolium ILs; while the average size of dendritic MSNs can be controlled within the range of 40-100 nm by varying the amount of Pluronic F127. The Au@MSNs can be used as a catalyst for the reduction of 4-nitrophenol by NaBH4 into 4-aminophenol and exhibit excellent catalytic performance. The present discovery of the extended synthesis conditions offers reproducible, facile, and large-scale synthesis of the monodisperse spherical MSNs with precise size control and, thus, has vast prospects for future applications of ultrafine mesostructured nanoparticle materials in catalysis and biomedicine. PMID- 25454256 TI - Rapid identification of bacterial biofilms and biofilm wound models using a multichannel nanosensor. AB - Identification of infectious bacteria responsible for biofilm-associated infections is challenging due to the complex and heterogeneous biofilm matrix. To address this issue and minimize the impact of heterogeneity on biofilm identification, we developed a gold nanoparticle (AuNP)-based multichannel sensor to detect and identify biofilms based on their physicochemical properties. Our results showed that the sensor can discriminate six bacterial biofilms including two composed of uropathogenic bacteria. The capability of the sensor was further demonstrated through discrimination of biofilms in a mixed bacteria/mammalian cell in vitro wound model. PMID- 25454257 TI - Structure and function of a decarboxylating Agrobacterium tumefaciens keto-deoxy d-galactarate dehydratase. AB - Agrobacterium tumefaciens (At) strain C58 contains an oxidative enzyme pathway that can function on both d-glucuronic and d-galacturonic acid. The corresponding gene coding for At keto-deoxy-d-galactarate (KDG) dehydratase is located in the same gene cluster as those coding for uronate dehydrogenase (At Udh) and galactarolactone cycloisomerase (At Gci) which we have previously characterized. Here, we present the kinetic characterization and crystal structure of At KDG dehydratase, which catalyzes the next step, the decarboxylating hydrolyase reaction of KDG to produce alpha-ketoglutaric semialdehyde (alpha-KGSA) and carbon dioxide. The crystal structures of At KDG dehydratase and its complexes with pyruvate and 2-oxoadipic acid, two substrate analogues, were determined to 1.7 A, 1.5 A, and 2.1 A resolution, respectively. Furthermore, mass spectrometry was used to confirm reaction end-products. The results lead us to propose a structure-based mechanism for At KDG dehydratase, suggesting that while the enzyme belongs to the Class I aldolase protein family, it does not follow a typical retro-aldol condensation mechanism. PMID- 25454258 TI - Multi-vessel versus culprit-vessel and staged percutaneous coronary intervention in STEMI patients with multivessel disease: a meta-analysis of randomized controlled trials. AB - INTRODUCTION: Percutaneous coronary intervention (PCI) is preferred in patients with acute ST-elevation myocardial infarction (STEMI). In patients with acute STEMI with multivessel disease (MVD), the guidelines recommend culprit vessel PCI (CV-PCI) in the absence of hemodynamic instability. We performed a meta-analysis of all randomized controlled trials (RCTs) comparing multi-vessel PCI (MV-PCI) with CV-PCI or staged PCI (S-PCI) in patients with acute STEMI and MVD. METHODS: PubMed, EMBASE and CENTRAL were searched for publications since inception to December 2013. Random effects model was used to compute summary effects. RESULTS: Four RCTs (840 patients) were identified. MV-PCI compared to CV-PCI significantly reduced the risks of major adverse cardiac events (MACE)-a composite of MI, revascularization and all-cause mortality (RR: 0.46, 95% CI: 0.35-0.60, P<0.00001) by reducing the risks of MI (0.35, 0.17-0.71, P=0.004) and revascularization (0.35, 0.24-0.52, P<0.00001). The risk of all-cause mortality was not different (0.69, 0.39-1.21, P=0.19). S-PCI and MV-PCI had similar risks of MACE (0.96, 0.59-1.57, P=0.87), MI (0.60, 0.20-1.78, P=0.36), revascularization (0.86, 0.47-1.54, P=0.60) and all-cause mortality (1.50, 0.44 5.07, P=0.57). CONCLUSIONS: MV-PCI compared to CV-PCI resulted in lower risks of MACE driven by lower MI and revascularization in patients with STEMI and multi vessel disease. PMID- 25454259 TI - Nanoparticle-supported lipid bilayers as an in situ remediation strategy for hydrophobic organic contaminants in soils. AB - Polycyclic aromatic hydrocarbons (PAHs) are persistent environmental organic contaminants due to their low water solubility and strong sorption onto organic/mineral surfaces. Here, nanoparticle-supported lipid bilayers (NP-SLBs) made of 100-nm SiO2 nanoparticles and the zwitterionic lipid 1,2-dimyristoyl-sn glycero-3-phosphocholine (DMPC) are investigated as constructs for removing PAHs from contaminated sites, using benzo[a]pyrene (BaP) as an example. DMPC in the form of small unilamellar vesicles (SUVs) or DMPC-NP-SLBs with excess DMPC-SUVs to support colloidal stability, when added to saturated BaP solutions, sorb BaP in ratios of up to 10/1 to 5/1 lipid/BaP, over a 2-week period at 33 degrees C. This rate increases with temperature. The presence of humic acid (HA), as an analog of soil organic matter, does not affect the BaP uptake rate by DMPC-NP SLBs and DMPC-SUVs, indicating preferential BaP sorption into the hydrophobic lipids. HA increases the zeta potential of these nanosystems, but does not disrupt their morphology, and enhances their colloidal stability. Studies with the common soil bacteria Pseudomonas aeruginosa demonstrate viability and growth using DMPC-NP-SLBs and DMPC-SUVs, with and without BaP, as their sole carbon source. Thus, NP-SLBs may be an effective method for remediation of PAHs, where the lipids provide both the method of extraction and stability for transport to the contaminant site. PMID- 25454260 TI - An epidemiological evaluation of salivary gland cancer in the Netherlands (1989 2010). AB - BACKGROUND: The relative 5-year survival rate of salivary gland cancer is moderate at best. This study was set up to evaluate whether the improvements in diagnosis and treatment in the last decades impacted the incidence, mortality and survival of salivary gland cancer. METHODS: Data on patients with salivary gland cancer from 1989 through 2010 were extracted from the Netherlands Cancer Registry (NCR); we examined incidence, mortality and relative survival. Furthermore, information on sex, age, tumor stage, histology, and treatment was taken into account. RESULTS: A total of 2737 patients were included. Fifty-three percent (53%) were males and 47% were females with a significant higher proportion of early stages in women. In 2010, the incidence rate (European Standardized Rate (ESR)) of salivary gland cancer was 0.9 per 100,000 per year. The estimated annual percentage change in incidence rate since 1989 equaled 0.6% (95%CI: -0.2 1.4). Mortality rates (ESR) decreased in men until 1997 and increased thereafter. Mortality in women remained stable at 1.5 per 100,000. Over time more patients were treated by surgery and radiotherapy (p<0.001). The relative five-year survival rate equaled 69% and did not change in time. CONCLUSION: We observed no relevant changes in incidence or mortality rates in the last two decades. Despite the increased combined treatment by surgery and radiotherapy, survival did not improve. This implies an urgent need for the development of new effective treatment modalities. PMID- 25454261 TI - Relative impact of earlier diagnosis and improved treatment on survival for colorectal cancer: a US database study among elderly. AB - PURPOSES: To estimate what proportion of improvement in relative survival was attributable to smaller stage/size due to early detection and what proportion was attributable to cancer chemotherapy in patients with colorectal cancer (CRC). METHODS: We studied 69,718 patients with CRC aged >= 66 years in 1992-2009 from Surveillance, Epidemiology, and End Results registries. Study periods were categorized into three periods according to the major changes or advances in screening and chemotherapy regimens: (1) Period-1 (1992-1995), during which there was no evidence-based recommendation for routine CRC screening and 5-fluorouracil was the mainstay for chemotherapy; (2) Period-2 (1996-2000), during which evidences and guidelines supported the use of fecal occult blood test (FOBT) and sigmoidoscopy for routine CRC screening; and (3) Period-3 (2001-2009), during which Medicare Program added the full coverage for colonoscopy screening to average-risk individuals, and several newly developed chemotherapy regimens were approved. Outcome variables included the likelihood of being diagnosed at an early stage or with a small tumor size, and improvement in relative survival. RESULTS: Compared to period-1, likelihood of being diagnosed with early stage CRC increased by 20% in period-2 (odds ratio = 1.2, 95%CI: 1.1-1.2) and 30% in period 3 (1.3, 1.2-1.4); and likelihood of being diagnosed with small-size CRC increased by 60% in period-2 and 110% in period-3. Similarly, 5-year overall relative survival increased from 51% in period-1 to 56% in period-2 and 60% in period-3. Increase in survival attributable to migration in stage/size was 9% in period-2 and 20% in period-3, while the remaining survival improvement during period-2 and period-3 were largely attributable to more effective chemotherapy regimens (>= 71.6%) and other treatment factors (<= 25%). CONCLUSIONS: Improvements in CRC screening resulted in a migration of CRC toward earlier tumor stage and smaller size, which contributed to <= 20% of survival increase. Survival improvement over the past 2 decades was largely explained by more effective chemotherapy regimens (>= 71.6%). PMID- 25454262 TI - Low use of surveillance and early diagnosis of hepatocellular carcinoma in Norway -a population-based cohort study. AB - BACKGROUND AND AIMS: Curative treatment of hepatocellular carcinoma (HCC) is dependent on early diagnosis. Surveillance of patients at high risk for HCC is a key determinant to achieve this goal, but may be an underutilized tool. The aim of this study was to determine the rate of pre-diagnosis surveillance in patients with HCC in a large population-based cohort and to assess to what extent cirrhosis was known prior to the diagnosis of HCC. METHODS: All patients diagnosed with HCC during 2000-2009 in The South-Eastern Regional Health Authority, representing 56% of the Norwegian population, were identified from The National Cancer Registry and the medical records were reviewed. RESULTS: Fifteen out of 486 patients (3%) were diagnosed by surveillance. Potential curative treatment was offered to 58% of the patients who underwent surveillance as opposed to 15% in the non-surveillance group. Only age <= 65 years was an independent predictor of screening in a multivariate model. Almost two thirds of the patients with cirrhosis were unrecognized prior to the HCC diagnosis. Two hundred and fourteen patients (44%) were non-cirrhotics. CONCLUSION: Regular HCC surveillance in at-risk populations is virtually not applied in Norway and this may contribute to inferior overall survival. Failure to recognize cirrhosis and a high rate of HCC in non-cirrhotic patients will be limiting factors for the overall effectiveness of a potential surveillance program. PMID- 25454263 TI - Response to "Methylenetetrahydrofolate reductase gene polymorphisms contribute to acute myeloid leukemia and chronic myeloid leukemia susceptibilities: appraisal of a recent meta-analysis" by Fang Wang and Prof. Guoping Sun. PMID- 25454265 TI - (11)C-choline PET/CT and multiparametric MRI in patients with biochemical relapse of prostate cancer. AB - CLINIC PROBLEM AND CASE SERIES: To assess the diagnostic usefulness of (11)C choline PET/CT vs. multi-parametric MRI in the prostate cancer relapse. A retrospective study of 21 patients with prostate cancer treated initially with surgery (n=12), radiotherapy (n=9). PSA levels were increased (post-surgery: .3 3.6 ng/ml; post-radiotherapy: 2.4-8.8 ng/ml). In an interval of time of 15 days all patients were underwent to: whole-body-dual-modality PET-CT carried out early after (11)C-choline (296 +/- 29 MBq) injection, and multiparametric prostate MRI with paramagnetic intravenous contrast (using anatomical imaging sequences, diffusion-weighted imaging and dynamic contrast-enhanced imaging). On the basis of our results, all patients were underwent to directed diagnosis and/or clinical, analytic and imaging follow-up. In 15 patients (71.4%) both procedures showed concordant results: 4 negative and 11 positive cases [7 local recurrences, 3 isolated pelvic lymph nodes (2 infracentimetric), 1 local relapse and only one M1 bone metastases]. The results were discordant in 6 patients (28.6%): 3 local relapses in MRI with no PET significance, 1 local relapse in PET with no MRI significance. 2 bone metastases were identified with PET (out of the field-of view of MRI). COMMENT: (11)C-choline PET/CT and multi-parametric MRI play a complementary role in the detection of local relapse in prostate cancer patients, with similar sensitivity for the detection of lymph involvement. Whole-body 11C choline PET/CT technique is also useful for bone staging. PMID- 25454264 TI - Consensus document of the Spanish Urological Association on the management of uncomplicated recurrent urinary tract infections. AB - INTRODUCTION: The clinical manifestations of urinary infections, commonly mild and uncomplicated, have resulted in a generally empirical therapeutic decision making process, which does not help fight resistances to antibacterial agents, thus causing a high rate of recurrence. OBJECTIVE: This study seeks to reduce the clinical variability in the diagnosis and treatment of uncomplicated recurrent urinary tract infections (RUTIs). MATERIAL AND METHOD: The consensus document was developed using a nominal group methodology, using scientific evidence on RUTIs extracted from a systematic (noncomprehensive) literature review, along with the expert judgment of specialists and their experience in clinical practice. RESULTS: RUTIs are considered the manifestation of at least 3 episodes of uncomplicated infection, with a positive culture in the past 12 months, in addition to (for men) the absence of structural or functional abnormalities. We maintain that the treatment should be empiric when suspecting RUTIs (prior to obtaining a urine sample for culture) in those patients who have a high probability of recurrence, associated risk factors and/or urinary or general symptoms, such as fever and chills. Homogeneous criteria are recommended for the diagnosis and treatment in order to fight the increased rates of resistance that the microorganisms develop against antimicrobial agents. CONCLUSION: Imprecision in the identification of the infection requires a search for agreements on homogenized criteria and decision algorithms that guide the management of these patients. PMID- 25454267 TI - Synthesis and antiprotozoal activity of oligomethylene- and p-phenylene bis(methylene)-linked bis(+)-huprines. AB - We have synthesized a series of dimers of (+)-(7R,11R)-huprine Y and evaluated their activity against Trypanosoma brucei, Plasmodium falciparum, rat myoblast L6 cells and human acetylcholinesterase (hAChE), and their brain permeability. Most dimers have more potent and selective trypanocidal activity than huprine Y and are brain permeable, but they are devoid of antimalarial activity and remain active against hAChE. Lead optimization will focus on identifying compounds with a more favourable trypanocidal/anticholinesterase activity ratio. PMID- 25454266 TI - The association between metabolic syndrome and prostate cancer: Effect on its aggressiveness and progression. AB - OBJECTIVES: To evaluate the impact of metabolic syndrome and its individual components on prostate biopsy findings, the radical prostatectomy specimen and on biochemical recurrence. MATERIAL AND METHODS: An observational study was conducted of 1319 men who underwent prostate biopsy between January 2007 and December 2011. The impact on the biopsy findings, the radical prostatectomy specimen and biochemical recurrence was evaluated using logistic regression and Cox regression. RESULTS: Of the 1319 patients, 275 (21%) had metabolic syndrome, and 517 prostate cancers were diagnosed. A greater percentage of metabolic syndrome was found among patients with prostate cancer than among patients without prostate cancer (25% vs. 18%; P=.002). Poorer results were found in the radical prostatectomy specimens (Gleason score >= 7, P<.001; stage >= T2c, P<.001; positive surgical margins, P<.001), and there was a greater percentage of biochemical recurrence in patients with metabolic syndrome than in those without metabolic syndrome (24% vs. 13%; P=.003). Metabolic syndrome behaved as an independent predictive factor of finding a Gleason score >= 7 for the specimen, as well as for finding a specimen stage >= T2c. Metabolic syndrome was also able to independently predict a greater rate of biochemical recurrence (OR: 3.6, P<.001; OR: 3.2, P=.03; HR: 1.7; respectively). CONCLUSIONS: Metabolic syndrome is associated with poorer findings in the radical prostatectomy specimens and is an independent prognostic factor of biochemical recurrence. PMID- 25454269 TI - Seizure prevention by the naturally occurring phenols, carvacrol and thymol in a partial seizure-psychomotor model. AB - The natural compounds carvacrol and thymol completely prevented seizures in the 6 Hz, 32 mA partial seizure model. Carvacrol and thymol, both exhibited an ED50 = 35.8 mg/kg, ip and yielded protective indices of 5.3 and 3.4, respectively. At 44 mA current intensity, carvacrol and thymol exhibited ED50s of 88.82 mg/kg (PI = 2.15) and 73.0 mg/kg (PI = 1.65), respectively. Thymol, but not carvacrol showed partial inhibitory activity in the maximal electroshock (MES), sc Metrazol (scMET) and Corneal-kindled models. These results suggest that carvacrol and thymol are more efficacious anticonvulsants than suggested by their lower efficacies in the conventional MES and scMET tests. PMID- 25454270 TI - Histone deacetylase inhibitors derived from 1,2,3,4-tetrahydropyrrolo[1,2 a]pyrazine and related heterocycles selective for the HDAC6 isoform. AB - Acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide are potent sub-type selective HDAC6 inhibitors. Constrained heterocyclic analogs based on 1,2,3,4 tetrahydropyrrolo[1,2-a]pyrazine show further enhanced HDAC6 selectivity and inhibitory activity in cells. Homology models suggest that the heterocyclic spacer can more effectively access the wider catalytic channel of HDAC6 compared to other HDAC sub-types. PMID- 25454268 TI - Discovery and optimization of novel small-molecule HIV-1 entry inhibitors using field-based virtual screening and bioisosteric replacement. AB - With the emergence of drug-resistant strains and the cumulative toxicities associated with current therapies, demand remains for new inhibitors of HIV-1 replication. The inhibition of HIV-1 entry is an attractive, yet underexploited therapeutic approach with implications for salvage and preexposure prophylactic regimens, as well as topical microbicides. Using the combination of a field derived bioactive conformation template to perform virtual screening and iterative bioisosteric replacements, coupled with in silico predictions of absorption, distribution, metabolism, and excretion, we have identified new leads for HIV-1 entry inhibitors. PMID- 25454271 TI - Antibacterial activities of novel nicotinic acid hydrazides and their conversion into N-acetyl-1,3,4-oxadiazoles. AB - Synthesis of a series of novel N-acylhydrazones of nicotinic acid hydrazides 3a-j via condensation of nicotinic acid hydrazide 1 with the corresponding aldehydes and ketones is described. The series 3a-j was evaluated for in vitro antibacterial activity against two gram negative (Pseudomonas aeruginosa and Klebsiella pneumoniae) and two gram positive (Streptococcus pneumoniae and Staphylococcus aureus) bacteria. The zone of inhibition was measured using the disk diffusion method, and in vitro minimum inhibitory concentration indicating that compounds 3a and 3e were effective against P. aeruginosa with MICs of 0.220 and 0.195 MUg respectively. PMID- 25454272 TI - Dilazep analogues for the study of equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2). AB - As ENT inhibitors including dilazep have shown efficacy improving oHSV1 targeted oncolytic cancer therapy, a series of dilazep analogues was synthesized and biologically evaluated to examine both ENT1 and ENT2 inhibition. The central diamine core, alkyl chains, ester linkage and substituents on the phenyl ring were all varied. Compounds were screened against ENT1 and ENT2 using a radio ligand cell-based assay. Dilazep and analogues with minor structural changes are potent and selective ENT1 inhibitors. No selective ENT2 inhibitors were found, although some analogues were more potent against ENT2 than the parent dilazep. PMID- 25454273 TI - Anilinotriazoles as potent gamma secretase modulators. AB - The design and synthesis of a novel series of potent gamma secretase modulators is described. Exploration of various spacer groups between the triazole ring and the aromatic appendix in 2 has led to anilinotriazole 28, which combined high in vitro and in vivo potency with an acceptable drug-like profile. PMID- 25454274 TI - Distinctive patterns of sonographic nerve enlargement in Charcot-Marie-Tooth type 1A and hereditary neuropathy with pressure palsies. AB - OBJECTIVE: The extent of sonomorphologic differences of peripheral nerves between CMT and HNPP is unknown. METHODS: We recruited 9 patients with CMT-1A and 9 with HNPP. Patients underwent a standardized sonographic protocol, which evaluated nerve size and vascularization. We quantitatively assessed fascicle size and echogenicity. RESULTS: All 18 patients demonstrated nerve enlargement, but no increased vascularization. HNPP demonstrated larger nerves at sites of entrapment (median nerve at the carpal tunnel p=0.049, ulnar nerve at the sulcus p<0.001), greater swelling ratios of median (p<0.001), ulnar (p=0.017) and fibular nerve (p=0.005) than CMT-1A. CMT-1A revealed larger nerves proximal to sites of entrapment (median and fibular nerve, brachial plexus p<0.001). Nerve fascicles where larger (p<0.001) and more hypo-echogenic in CMT-1A. Nerve, fascicle size nor echogenicity correlated with age, gender or MRC sum-score. CONCLUSIONS: Ultrasonography of nerves reveals specific phenotypes differentiating CMT-1A from HNPP. In CMT-1A enlargement of nerves and fascicles is multifocal among multiple nerves, whereas in HNPP nerve enlargement is restricted to sites of entrapment. SIGNIFICANCE: Our findings of specific sonomorphological phenotypes, differentiating CMT-1A from HNPP, may help to improve our pathophysiological insights in CMT and HNPP. PMID- 25454275 TI - The different ultrasound patterns in Charcot-Marie-Tooths raise the need of standardization. PMID- 25454276 TI - Further insights into the effect of BDNF genotype on non-invasive brain stimulation. PMID- 25454277 TI - Different responses to facilitatory rTMS according to BDNF genotype. AB - OBJECTIVE: To investigate whether there is a relation between the plasticity induced by different intensities of facilitatory rTMS with different intensities and brain-derived neurotrophic factor (BDNF) genotype. METHODS: Forty healthy volunteers (14 men, mean age 27.3years) were enrolled. All participants received three high-frequency rTMS applications in random order over the non-dominant primary motor cortex with more than a 24-h washout period: 1st condition, rTMS with sub-threshold intensity; 2nd condition, rTMS with supra-threshold intensity; and 3rd condition, sham rTMS. Cortical excitability was assessed before and after rTMS using motor-evoked potentials (MEPs). Data were analyzed using the BDNF genotype. RESULTS: Twelve, 19, and 9 participants were classified into Val/Val, Val/Met, and Met/Met groups, respectively. In each group, there were significant increases in the amplitude of MEPs after 1st and 2nd conditions (P<0.05), but not after 3rd condition. In Val/Val group, the increase ratio of MEPs' amplitude after 2nd condition was significantly higher than 1st condition (P<0.05). However, no significant amplitude differences in Val/Met and Met/Met groups were observed after 1st and 2nd conditions. CONCLUSIONS: High-frequency rTMS induces the facilitation of cortical excitability regardless of BDNF genotype. BDNF genotype might influence on different responses of plasticity based on the rTMS intensity. SIGNIFICANCE: BDNF genotype is one of influence factors on the plasticity after the facilitatory rTMS. PMID- 25454278 TI - Influence of motor imagination on cortical activation during functional electrical stimulation. AB - OBJECTIVE: Motor imagination (MI) and functional electrical stimulation (FES) can activate the sensory-motor cortex through efferent and afferent pathways respectively. Motor imagination can be used as a control strategy to activate FES through a brain-computer interface as the part of a rehabilitation therapy. It is believed that precise timing between the onset of MI and FES is important for strengthening the cortico-spinal pathways but it is not known whether prolonged MI during FES influences cortical response. METHODS: Electroencephalogram was measured in ten able-bodied participants using MI strategy to control FES through a BCI system. Event related synchronisation/desynchronisation (ERS/ERD) over the sensory-motor cortex was analysed and compared in three paradigms: MI before FES, MI before and during FES and FES alone activated automatically. RESULTS: MI practiced both before and during FES produced strongest ERD. When MI only preceded FES it resulted in a weaker beta ERD during FES than when FES was activated automatically. Following termination of FES, beta ERD returns to the baseline level within 0.5s while alpha ERD took longer than 1s. CONCLUSIONS: When MI and FES are combined for rehabilitation purposes it is recommended that MI is practiced throughout FES activation period. SIGNIFICANCE: The study is relevant for neurorehabilitation of movement. PMID- 25454279 TI - Altered brain spontaneous activity and connectivity network in irritable bowel syndrome patients: A resting-state fMRI study. AB - OBJECTIVE: We aimed to provide additional evidence that brain functional alterations induced by IBS are not limited to local changes but also express at a level of functional integration within related brain regions involved in processing of visceral afferent information and somatic pain. METHODS: With fMRI data acquired from 21 IBS and healthy control (HC) subjects. We investigated the amplitude of low-frequency fluctuation (ALFF) and region of interest (ROI)-based functional connectivity (FC) to reveal the changes of the brain spontaneous activity and the interaction among different related regions. RESULTS: IBS patients showed decreased ALFF values in the left superior frontal gyrus, right hippocampus, right middle frontal gyrus, bilateral postcentral, and right superior temporal pole, while increased ALFF values in the left median cingulate and left calcarine. There was significant correlation between ALFF values in the altered regions and duration of disease in IBS. FC analysis revealed the increased connectivity between cingulate and frontal cortex in IBS. CONCLUSIONS: Our findings could provide both regional and brain connectivity spontaneous neuronal activity properties in IBS. SIGNIFICANCE: Our study may lead to a better understanding of intrinsic functional architecture of brain activity in IBS and highlight the potential for using the ALFF and FC metrics as a disease biomarker. PMID- 25454280 TI - Variability in amplitude and stimulation threshold values in motor evoked potential (MEP) monitoring during the resection of brain lesions. AB - OBJECTIVE: Criteria for motor evoked potential (MEP) monitoring include the amplitude criterion and threshold criterion. The aim of our study for the amplitude criterion during removal of brain lesions was to determine a suitable stimulus intensity that can reduce the variability in amplitudes. We also assessed the usefulness of the threshold criterion and amplitude criterion by comparing the variability between the two methods as a preliminary study. METHODS: Seventeen patients including 12 cases with no neurological deterioration after surgery were enrolled in this study. The amplitudes in various stimulus intensities and the stimulation threshold (ST) were repeatedly measured during surgery. The stimulus intensities used in the amplitude criterion are described as 'the ST just after dura opening (ST(0))+additional intensity'. The variability was assessed with the coefficient of variation (CV). RESULTS: With direct cortical stimulation (DCS), the CVs of amplitudes were significantly lower at stimulus intensities of more than ST(0)+4 mA, with the smallest at ST(0)+10 mA. The CV of STs was significantly smaller than that of amplitudes. CONCLUSIONS: The variability in the amplitude criterion was significantly reduced using stimulus intensities of more than ST(0)+4 mA. The variability in the threshold criterion was significantly smaller than that of the amplitude criterion, even when using a strong stimulus intensity. SIGNIFICANCE: The maximal stimulus intensity with no body motion should be used in the amplitude criterion for intraoperative MEP elicited by DCS. PMID- 25454281 TI - Usefulness of phrenic latency and forced vital capacity in patients with ALS with latent respiratory dysfunction. AB - OBJECTIVES: The pulmonary function test (PFT) is a non-invasive and easily available technique to assess respiratory function in patients with amyotrophic lateral sclerosis (ALS); however, patients with dyspnea sometimes show normal PFT findings. Herein, we investigated whether phrenic nerve conduction study (NCS) and PFT are useful to evaluate respiratory function of patients with ALS with normal value ranges in the PFT. METHODS: We prospectively enrolled 34 patients with definite or probable ALS, who showed FVC (%) ?80 of predicted and 78 healthy subjects. PFT and phrenic NCS were performed with the measurement of forced vital capacity (FVC, %), forced expiratory volumes in 1s (FEV1, %), FEV1/FCV ratio (%), and phrenic compound muscle action potential amplitude, and latency. RESULTS: Compared to healthy controls, ALS patients showed delayed phrenic nerve latency and the decrease of FVC (%) (p=0.006 and p<0.0001, respectively). ROC curve analysis demonstrated that phrenic latency (AUC=0.7655) and FVC (%) (AUC=0.8239) discriminated ALS patients from healthy subjects. CONCLUSION: We demonstrated that ALS patients had early respiratory dysfunction, despite normal PFT findings. SIGNIFICANCE: Phrenic latency and FVC (%) can be helpful to discriminate ALS patients with latent respiratory dysfunction from healthy subjects. PMID- 25454283 TI - Extra Forces induced by wide-pulse, high-frequency electrical stimulation: Occurrence, magnitude, variability and underlying mechanisms. AB - OBJECTIVE: In contrast to conventional (CONV) neuromuscular electrical stimulation (NMES), the use of "wide-pulse, high-frequencies" (WPHF) can generate higher forces than expected by the direct activation of motor axons alone. We aimed at investigating the occurrence, magnitude, variability and underlying neuromuscular mechanisms of these "Extra Forces" (EF). METHODS: Electrically evoked isometric plantar flexion force was recorded in 42 healthy subjects. Additionally, twitch potentiation, H-reflex and M-wave responses were assessed in 13 participants. CONV (25Hz, 0.05ms) and WPHF (100Hz, 1ms) NMES consisted of five stimulation trains (20s on-90s off). RESULTS: K-means clustering analysis disclosed a responder rate of almost 60%. Within this group of responders, force significantly increased from 4% to 16% of the maximal voluntary contraction force and H-reflexes were depressed after WPHF NMES. In contrast, non-responders showed neither EF nor H-reflex depression. Twitch potentiation and resting EMG data were similar between groups. Interestingly, a large inter- and intrasubject variability of EF was observed. CONCLUSION: The responder percentage was overestimated in previous studies. SIGNIFICANCE: This study proposes a novel methodological framework for unraveling the neurophysiological mechanisms involved in EF and provides further evidence for a central contribution to EF in responders. PMID- 25454282 TI - Is hemifacial spasm a phenomenon of the central nervous system? --The role of desflurane on the lateral spread response. AB - OBJECTIVE: A signature EMG feature of hemifacial spasm (HFS) is the lateral spread response (LSR). Desflurane is a common anesthetic with potent effects on synaptic transmission. We tested the hypothesis that the LSR is mediated by corticobulbar components by comparing the LSR during total intravenous anesthesia (TIVA) or TIVA plus desflurane during microvascular decompression (MVD) surgery. METHODS: 22 HFS patients undergoing MVD surgery participated in this prospective study. The LSR data was recorded from the o. oculi, o. oris and mentalis muscles prior to opening dura. LSR onset latencies and amplitudes were determined under TIVA and TIVA/desflurane (0.5 and 1MAC). Facial muscle LSRs and EEG were analyzed. RESULTS: Desflurane (1MAC) significantly decreased the LSR amplitude in all 3 facial muscles (p<0.01). Pooled LSR data from all facial muscles showed desflurane inhibited the LSR amplitude by 43% compared to TIVA (p<0.001). No effects on the latency of the LSR or on EEG state were observed. CONCLUSIONS: LSR inhibition by desflurane suggests a central mechanism involvement in the genesis of this signature HFS response. SIGNIFICANCE: This study demonstrates that facial nerve vascular compression and plastic changes within the CNS are part of the pathophysiology of HFS. PMID- 25454284 TI - Decidual GM-CSF is a critical common intermediate necessary for thrombin and TNF induced in-vitro fetal membrane weakening. AB - INTRODUCTION: Inflammation/infection and decidual bleeding/abruption are highly associated with pPROM. As no animal model for pPROM exists, we have developed an in-vitro model system for the study of human fetal membrane (FM) weakening/rupture. Using it we have demonstrated that both TNF/IL-1 (modeling inflammation) and thrombin (modeling bleeding) weaken full thickness FM in a dose dependent manner concomitant with inducing biochemical changes similar to those seen in the FM physiological weak zone. METHODS: As the physiological site of infection and bleeding is the choriodecidua (CD), we modified our model system with full thickness FM tissue mounted on modified Transwell culture inserts to permit directional TNF/thrombin exposure on the decidua only (rather than both sides of the FM). After incubation, medium was sampled separately from the CD facing (maternal side) or from the amnion facing (fetal side) compartments and probed for cytokine release and confirmed with western blots. The FM was strength tested within the insert. RESULTS: Full-thickness FM fragments exposed to TNF or thrombin on CD side only showed dose dependent weakening and biochemical changes consistent with previous reports. Concomitantly, GM-CSF increased markedly on the CD but not the amnion side. Numerous proteases including MMP1 and MMP3 also increased on the CD side. Pre-incubation with GM-CSF antibody blocked both thrombin and TNF induced weakening. Finally, GM-CSF weakened FM in a dose dependent manner. DISCUSSION: GM-CSF is a critical common intermediate in the thrombin and TNF FM weakening pathways. PMID- 25454286 TI - Special issue on "Toward physiome based therapeutics". PMID- 25454285 TI - Differential regulation of the glutamate transporters GLT-1 and GLAST by GSK3beta. AB - The glutamate transporters GLAST and GLT-1 are mainly expressed in glial cells and regulate glutamate levels in the synapses. GLAST and GLT-1 are the targets of several signaling pathways. In this study we explore the possible functional interaction between these transporters and GSK3beta. This kinase is involved in multiple cellular processes including neuronal development and synaptic plasticity. To evaluate whether GLT-1 and GLAST were regulated by GSK3beta, we coexpressed these proteins in heterologous expression systems. In both COS-7 cells and Xenopus laevis oocytes, GSK3beta stimulated the activity of GLT-1 and reduced that of GLAST. These effects were associated with corresponding changes in the amounts of GLT-1 or GLAST in the plasma membrane. These effects were suppressed by inhibitors of GSK3beta or a catalytically inactive form of the kinase. GSK3beta also decreases the incorporation of (32)Pi into GLT-1 and increases GLAST phosphorylation. Pharmacological inhibition of endogenous GSK3beta in primary cultures of rat brain cortex also leads to a differential modulation of GLT-1 and GLAST. Our results suggest that constitutively active GSK3beta is important in controlling the expression of functional glutamate transporters on the plasma membrane. This regulation might be relevant in physiological and pathological conditions in which glutamate transporters and GSK3beta signaling are involved. PMID- 25454287 TI - [Intermaxillary fixation screws--complications]. PMID- 25454289 TI - Spatial analysis of gastroschisis in Massachusetts and Texas. AB - PURPOSE: Previous research has suggested gastroschisis, a congenital malformation, may be linked to environmental or infectious factors and cases can occur in clusters. The objective of this study was to identify geographic areas of elevated gastroschisis risk. METHODS: Cases of gastroschisis were identified from birth defect registries in Massachusetts and Texas. Random samples of live births were selected as controls. Generalized additive models were used to create a continuous map surface of odds ratios (ORs) by smoothing over latitude and longitude. Maternal age, race/ethnicity, education, cigarette smoking, and insurance status (MA only) were assessed for confounding. We used permutation tests to identify statistically significant areas of increased risk. RESULTS: An area of increased risk was identified in North Central Massachusetts but was not significant after adjustment (P value = .07; OR = 2.0). In Texas, two statistically significant areas of increased risk were identified after adjustment (P value = .02; OR = 1.3 and 1.2). Texas had sufficient data to assess the combination of space and time, which identified an increased risk in 2003 and 2004. CONCLUSIONS: This study suggests there were areas of elevated gastroschisis risk in Massachusetts and Texas, which cannot be explained by the risk factors we assessed. Additional exploration of underlying artifactual, environmental, infectious, or behavioral factors may further our understanding of gastroschisis. PMID- 25454291 TI - Taping across the upper trapezius muscle reduces activity during a standardized typing task - an assessor-blinded randomized cross-over study. AB - Clinically, taping is believed to alter muscle activity. The purpose of this study was to investigate: (1) whether taping across the upper trapezius (UT) muscle influenced the level of UT and lower trapezius (LT) muscle activity and the ratio of these activities (UT/LT ratio) during a static typing task; and (2) if the activity of these muscles varied with the application of tensioned taping. Forty-two healthy participants performed a 15-min typing task on three separate occasions under one of three conditions: taping applied perpendicular to the UT fibers with tension; taping without tension; and no taping. Activity of the UT and LT muscles was assessed using surface electromyography. Between conditions, significant differences were found in the change of the normalized amplitude in the UT activity (p=.027) and UT/LT ratio (p=.024) but not in the LT activity (p=.93). Compared with the no taping condition, the UT activity was less in both the tensioned taping (p=.009) and the non-tensioned taping (p=.004). There was no difference between the two taping conditions in the change of the UT (p=.91) activity and the UT/LT ratio (p=.92). In conclusion, both tensioned and non tensioned taping across the UT muscle reduces its activity during a typing task. PMID- 25454292 TI - Neuromuscular responses to mild-muscle damaging eccentric exercise in a low glycogen state. AB - The aim of this study was to examine the effect of low muscle glycogen on the neuromuscular responses to maximal eccentric contractions. Fourteen healthy men (22 +/- 3 years) performed single-leg cycling (20 min at ~75% maximal oxygen uptake (VO2 max); eight 90 s sprints at a 1:1 work-to-rest ratio (5% decrements from 90% to 55% VO2 max until exhaustion) the evening before 100 eccentric (1.57 rads(-1)) with reduced (RED) and normal glycogen (NORM). Neuromuscular responses were measured during and up to 48 h after with maximal voluntary and involuntary (twitch, 20 Hz and 50 Hz) isometric contractions. During eccentric contractions, peak torque decreased (RED: -16.1 +/- 2.5%; NORM: -6.2 +/- 5.1%) and EMG frequency increased according to muscle length. EMG activity decreased for RED only. After eccentric contractions, maximal isometric force was reduced up to 24h for NORM (-13.5 +/- 5.8%) and 48 h for RED (-7.4 +/- 10.9%). Twelve hours after eccentric contractions, twitch force and the 20:50 Hz ratio were decreased for RED but not for NORM. Immediate involuntary with prolonged voluntary force loss suggests that reduced glycogen is associated with increased susceptibility to mild muscle-damaging eccentric exercise with contributions of peripheral and central mechanisms to be different during recovery. PMID- 25454293 TI - Quadrupolar magic angle spinning NMR spectra fitted using the Pearson IV function. AB - The Pearson IV function was used to fit the asymmetric solid-state (27)Al NMR spectra of alumina based catalysts. A high convergence (correlation coefficient is no less than 0.997) between experimental and simulated spectra was achieved. The decomposition of the (27)Al NMR spectra of zinc/aluminum mixed oxides with different Zn/Al molar ratio revealed an increased fraction (6-9%) of pentacoordinated aluminum atoms in these oxides as compared to gamma-Al2O3. As the Zn/Al ratio is raised, the fraction of [AlO6] octahedral units decreases, while the fraction of [AlO4] tetrahedra increases. PMID- 25454290 TI - Are children and adolescents with food allergies at increased risk for psychopathology? AB - OBJECTIVE: Living with food allergy is a unique and potentially life-threatening stressor that requires constant vigilance to food-related stimuli, but little is known about whether adolescents with food allergies are at increased risk for psychopathology-concurrently and over time. METHODS: Data came from the prospective-longitudinal Great Smoky Mountains Study. Adolescents (N=1420) were recruited from the community, and interviewed up to six times between ages 10 and 16 for the purpose of the present analyses. At each assessment, adolescents and one parent were interviewed using the Child and Adolescent Psychiatric Assessment, resulting in N=5165 pairs of interviews. RESULTS: Cross-sectionally, food allergies were associated with more symptoms of separation and generalized anxiety, disorder, attention deficit and hyperactivity disorder, and anorexia nervosa. Longitudinally, adolescents with food allergy experienced increases in symptoms of generalized anxiety disorder and depression from one assessment to the next. Food allergies were not, however, associated with a higher likelihood of meeting diagnostic criteria for a psychiatric disorder. CONCLUSION: The unique constellation of adolescents' increased symptoms of psychopathology in the context of food allergy likely reflects an adaptive increase in vigilance rather than cohesive syndromes of psychopathology. Support and guidance from health care providers is needed to help adolescents with food allergies and their caregivers achieve an optimal balance between necessary vigilance and hypervigilance and unnecessary restriction. PMID- 25454294 TI - Chronic liver disease in the human immunodeficiency virus patient. AB - There are an estimated 40 million HIV infected individuals worldwide, with chronic liver disease being the 2nd leading cause of mortality in this population. Elevated liver functions are commonly noted in HIV patients and the etiologies are varied. Viral hepatitis B and C, fatty liver and drug induced liver injury are more common. Treatment options for viral hepatitis C are rapidly evolving and are promising, but treatments are limited for the other conditions and is primarily supportive. Opportunistic infections of the liver are now uncommon. Irrespective of etiology, management requires referral to specialized centers and with due diligence mortality can be reduced. PMID- 25454295 TI - Evaluation and management of hepatocellular carcinoma. AB - The burden of hepatocellular carcinoma is rising and anticipated to escalate and while the best chance for long term cure remains transplantation, however the shortage of available organs remains a limitation. Liver directed therapy can serve the role of bridge/downstaging to transplant or as palliative care. Despite an improved overall survival among patients with HCC, due to advancements in surgical techniques, liver directed and systemic therapy, the 5 year overall survival remains low at 18% high-lightening the need for novel therapies. Surveillance for HCC is key to detect disease at an early stage to increase the chances for a potentially curative option. PMID- 25454296 TI - Renal insufficiency in the patient with chronic liver disease. PMID- 25454297 TI - Diagnosis and management of autoimmune hepatitis. AB - Autoimmune hepatitis is characterized by increased serum aminotransferase levels, autoantibodies, hypergammaglobulinemia, and interface hepatitis. Presentation can be acute, severe (fulminant), asymptomatic, or chronic. Diagnosis requires multiple findings and exclusion of similar diseases. Treatment with prednisone or prednisolone with azathioprine is recommended. Budesonide with azathioprine has normalized laboratory test with few side effects, but histologic resolution, durability of response, and target population are uncertain. Progressive worsening, incomplete improvement, drug intolerance, and relapse after drug withdrawal are suboptimal outcomes. Calcineurin inhibitors and mycophenolate mofetil are salvage agents in small series and liver transplantation is effective for liver failure. PMID- 25454298 TI - Diagnosis and management of overlap syndromes. AB - Overlapping features between autoimmune hepatitis (AIH) and cholestatic disorders (primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or indeterminate cholestasis), so-called overlap syndromes, usually have a progressive course toward cirrhosis and liver failure without adequate treatment. The diagnosis of overlap syndrome requires the prominent features of classic AIH and secondary objective findings of PBC or PSC. Empiric treatment for patients with AIH-PBC overlap is immunosuppressive therapy plus ursodeoxycholic acid. Empiric treatment for patients with AIH-PSC and AIH-cholestatic overlap is immunosuppressive therapy with or without ursodeoxycholic acid. Liver transplantation is indicated for patients who have end-stage liver disease. PMID- 25454299 TI - The ins and outs of liver imaging. AB - Different imaging modalities including ultrasonography, computed tomography (CT), and MR imaging may be used in the liver depending on the clinical situation. The ability of dedicated contrast-enhanced liver MR imaging or CT to definitively characterize lesions as benign is crucial in avoiding unnecessary biopsy. Liver imaging surveillance in patients with cirrhosis may allow for detection of hepatocellular carcinoma at an earlier stage, and therefore may improve outcome. This article reviews the different imaging modalities used to evaluate the liver and focal benign and malignant hepatic lesions, and the basic surveillance strategy for patients at increased risk for hepatocellular carcinoma. PMID- 25454300 TI - Contemporary assessment of hepatic fibrosis. AB - Newer noninvasive tests have begun to replace liver biopsy for staging purposes. The clinician must evaluate these tools and apply them to individual patients. None of these modalities give the exact same staging of fibrosis as a liver biopsy, but they are excellent tools for risk stratification. Still, it should be recognized that there are disease-specific issues with different utilizations and cutoffs for different clinical diseases. This article provides a framework for incorporating the use of serum biomarkers and elastography-based approaches to stage fibrosis into clinical practice. This review also covers recent developments in this rapidly advancing area. PMID- 25454301 TI - Liver transplantation for the referring physician. AB - Liver transplantation has become the treatment of choice for nearly all causes of end-stage liver disease, fulminant liver failure, and selected primary hepatic malignancies. The demand for liver transplantation has persistently outmatched the availability of donor organs leading to the development of novel strategies to expand the donor pool. The authors review the process of liver transplant evaluation, methods used to address the donor shortage, and disease-specific outcomes and challenges and discuss posttransplant care. PMID- 25454302 TI - Assessment of jaundice in the hospitalized patient. AB - Jaundice in the hospitalized patient is not an uncommon consultation for the general gastroenterologist. It is essential to explore the underlying cause of jaundice because management is largely aimed at addressing these causes rather than the jaundice itself. Although the diagnostic evaluation for jaundice can be broad, clinical judgment must be used to prioritize between various laboratory tests and imaging studies. Most importantly, clinicians must understand which conditions are emergent and/or require evaluation for liver transplantation. Further studies need to be performed to better understand the outcomes of hospitalized patients who develop jaundice. PMID- 25454303 TI - Liver disease in the adolescent. AB - This article discusses common liver diseases in the adolescent. Briefly reviewed is the evaluation of the adolescent with new-onset liver enzyme elevation. Then the article discusses common liver diseases, such as nonalcoholic fatty liver disease, hepatitis, metabolic disease, biliary atresia, cystic fibrosis, and inherited disorders of cholestasis. Finally, a management approach to the adolescent with liver disease is outlined, noting the challenges that must be addressed to effectively care for not only liver disease in the adolescent but also the patient as a whole. PMID- 25454305 TI - Portal vein thrombosis. AB - Portal vein thrombosis (PVT) is a rare event in the general medical setting that commonly complicates cirrhosis with portal hypertension, and can also occur with liver tumors. The diagnosis is often incidental when a thrombus is found in the portal vein on imaging tests. However, PVT may also present with clinical symptoms and can progress to life-threatening complications of ischemic hepatitis, liver failure, and/or small intestinal infarction. This article reviews the pathophysiology of this disorder, with a major focus on PVT in patients with cirrhosis, and presents detailed guidelines on optimal diagnostic and therapeutic strategies. PMID- 25454304 TI - Diagnosis and management of hereditary hemochromatosis. AB - Hereditary hemochromatosis is a rare genetic disorder that can have significant clinical consequences. Hemochromatosis is associated with iron overload, and can initially be recognized through laboratory testing for serum ferritin and transferrin saturation. Genetic testing for the HFE mutation can be performed in patients with elevated iron indices and a suspicion for hemochromatosis or liver disease. The main pathway resulting in iron overload is through altered hepcidin levels. Treatment of patients with the clinical phenotype of hereditary hemochromatosis is commonly through phlebotomy for removal of excess iron stores. This article highlights the current information and data regarding the diagnosis and management of hemochromatosis. PMID- 25454306 TI - Consultations in liver disease. PMID- 25454308 TI - Plasma asymmetric dimethylarginine in infants with bronchopulmonary dysplasia: a promising biomarker despite uncertain pathogenic significance. PMID- 25454309 TI - Trichophagia: Rapunzel syndrome in a 7-year-old girl. PMID- 25454307 TI - Peripheral Quantitative Computed Tomography Predicts Humeral Diaphysis Torsional Mechanical Properties With Good Short-Term Precision. AB - Peripheral quantitative computed tomography (pQCT) is a popular tool for noninvasively estimating bone mechanical properties. Previous studies have demonstrated that pQCT provides precise estimates that are good predictors of actual bone mechanical properties at popular distal imaging sites (tibia and radius). The predictive ability and precision of pQCT at more proximal sites remain unknown. The aim of the present study was to explore the predictive ability and short-term precision of pQCT estimates of mechanical properties of the midshaft humerus, a site gaining popularity for exploring the skeletal benefits of exercise. Predictive ability was determined ex vivo by assessing the ability of pQCT-derived estimates of torsional mechanical properties in cadaver humeri (density-weighted polar moment of inertia [I(P)] and polar strength-strain index [SSI(P)]) to predict actual torsional properties. Short-term precision was assessed in vivo by performing 6 repeat pQCT scans at the level of the midshaft humerus in 30 young, healthy individuals (degrees of freedom = 150), with repeat scans performed by the same and different testers and on the same and different days to explore the influences of different testers and time between repeat scans on precision errors. IP and SSI(P) both independently predicted at least 90% of the variance in ex vivo midshaft humerus mechanical properties in cadaveric bones. Overall values for relative precision error (root mean squared coefficients of variation) for in vivo measures of IP and SSI(P) at the midshaft humerus were <1.5% and were not influenced by pQCT assessments being performed by different testers or on different days. These data indicate that pQCT provides very good prediction of midshaft humerus mechanical properties with good short term precision, with measures being robust against the influences of different testers and time between repeat scans. PMID- 25454310 TI - Neonatal airway infection due to herpes simplex virus. PMID- 25454311 TI - Referral of very low birth weight infants to high-risk follow-up at neonatal intensive care unit discharge varies widely across California. AB - OBJECTIVES: To determine rates and factors associated with referral to the California Children's Services high-risk infant follow-up (HRIF) program among very low birth weight (BW) infants in the California Perinatal Quality of Care Collaborative. STUDY DESIGN: Using multivariable logistic regression, we examined independent associations of demographic and clinical variables, neonatal intensive care unit (NICU) volume and level, and California region with HRIF referral. RESULTS: In 2010-2011, 8071 very low BW infants were discharged home; 6424 (80%) were referred to HRIF. Higher odds for HRIF referral were associated with lower BW (OR 1.9, 95% CI 1.5-2.4; <= 750 g vs 1251-1499 g), higher NICU volume (OR 1.6, 1.2-2.1; highest vs lowest quartile), and California Children's Services Regional level (OR 3.1, 2.3-4.3, vs intermediate); and lower odds with small for gestational age (OR 0.79, 0.68-0.92), and maternal race African American (OR 0.58, 0.47-0.71) and Hispanic (OR 0.65, 0.55-0.76) vs white. There was wide variability in referral among regions (8%-98%) and NICUs (<5%-100%), which remained after risk adjustment. CONCLUSIONS: There are considerable disparities in HRIF referral, some of which may indicate regional and individual NICU resource challenges and barriers. Understanding demographic and clinical factors associated with failure to refer present opportunities for targeted quality improvement initiatives. PMID- 25454312 TI - Growing skull fracture of midline posterior cranial vault. PMID- 25454313 TI - Family meals protect against obesity: exploring the mechanisms. PMID- 25454314 TI - Pott disease with cold abscess. PMID- 25454315 TI - Serum D-dimer concentrations are increased after pediatric traumatic brain injury. AB - OBJECTIVE: To determine whether D-dimer would be increased in children with traumatic brain injury (TBI), specifically mild abusive head trauma. STUDY DESIGN: D-dimer was measured using multiplex bead technology in 195 children <4 years old (n = 93 controls without TBI, n = 102 cases with TBI) using previously collected serum. D-dimer was then measured prospectively in a clinical setting in 44 children (n = 24 controls, n = 20 cases). Receiver operator curves were generated for prospective data. RESULTS: In both the retrospective and prospective cohorts, median (25th-75th percentile) D-dimer was significantly higher in cases vs controls. A receiver operator curve demonstrated an area under the curve of 0.91 (95% CI 0.83-0.99) in the prospective cohort. At a cut-off of 0.59 MUg/L, the sensitivity and specificity for identification of a case was 90% and 75%, respectively. CONCLUSIONS: Our data suggest that serum D-dimer may be able to be used to identify which young children at risk for abusive head trauma might benefit from a head computed tomography or other additional evaluation. Additional data are needed to better identify the clinical scenarios that may result in false positive or false negative D-dimer concentrations. PMID- 25454316 TI - Geriatricians and technology. PMID- 25454317 TI - Diabetes mellitus is independently associated with more severe cognitive impairment in Parkinson disease. AB - BACKGROUND: There is increasing interest in interactions between metabolic syndromes and neurodegeneration. Diabetes mellitus (DM) contributes to cognitive impairment in the elderly but its effect in Parkinson disease (PD) is not well studied. OBJECTIVE: To investigate effects of comorbid DM on cognition in PD independent from PD-specific primary neurodegenerations. METHODS: Cross-sectional study. Patients with PD (n = 148); age 65.6 +/- 7.4 years, Hoehn and Yahr stage 2.4 +/- 0.6, with (n = 15) and without (n = 133) comorbid type II DM, underwent [(11)C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging to assess cortical cholinergic denervation, [(11)C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation, and neuropsychological assessments. A global cognitive Z-score was calculated based on normative data. Analysis of covariance was performed to determine cognitive differences between subjects with and without DM while controlling for nigrostriatal denervation, cortical cholinergic denervation, levodopa equivalent dose and education covariates. RESULTS: There were no significant differences in age, gender, Hoehn and Yahr stage or duration of disease between diabetic and non-diabetic PD subjects. There was a non-significant trend toward lower years of education in the diabetic PD subjects compared with non-diabetic PD subjects. PD diabetics had significantly lower mean (+/-SD) global cognitive Z-scores (-0.98 +/- 1.01) compared to the non-diabetics (-0.36 +/- 0.91; F = 7.78, P = 0.006) when controlling for covariate effects of education, striatal dopaminergic denervation, and cortical cholinergic denervation (total model F = 8.39, P < 0.0001). CONCLUSION: Diabetes mellitus is independently associated with more severe cognitive impairment in PD likely through mechanisms other than disease specific neurodegenerations. PMID- 25454320 TI - Multiple readmissions: Problem or opportunity? PMID- 25454319 TI - Identification and characterization of B-cell epitopes of 3FTx and PLA(2) toxins from Micrurus corallinus snake venom. AB - The main goal of this work was to develop a strategy to identify B-cell epitopes on four different three finger toxins (3FTX) and one phospholipase A2 (PLA2) from Micrurus corallinus snake venom. 3FTx and PLA2 are highly abundant components in Elapidic venoms and are the major responsibles for the toxicity observed in envenomation by coral snakes. Overlapping peptides from the sequence of each toxin were prepared by SPOT method and three different anti-elapidic sera were used to map the epitopes. After immunogenicity analysis of the spot-reactive peptides by EPITOPIA, a computational method, nine sequences from the five toxins were chemically synthesized and antigenically and immunogenically characterized. All the peptides were used together as immunogens in rabbits, delivered with Freund's adjuvant for a first cycle of immunization and Montanide in the second. A good antibody response against individual synthetic peptides and M. corallinus venom was achieved. Anti-peptide IgGs were also cross-reactive against Micrurus frontalis and Micrurus lemniscatus crude venoms. In addition, anti-peptide IgGs inhibits the lethal and phospholipasic activities of M. corallinus crude venom. Our results provide a rational basis to the identification of neutralizing epitopes on coral snake toxins and show that their corresponding synthetic peptides could improve the generation of immuno-therapeutics. The use of synthetic peptide for immunization is a reasonable approach, since it enables poly-specificity, low risk of toxic effects and large scale production. PMID- 25454321 TI - Tumoral calcinosis associated with mixed connective tissue disease. PMID- 25454318 TI - Sensitive measures of executive dysfunction in non-demented Parkinson's disease. AB - BACKGROUND: We examined the sensitivity of different executive function measures for detecting deficits in Parkinson's disease patients without dementia. METHODS: Twenty-one non-demented PD subjects and 21 neurologically healthy controls were administered widely used clinical executive functioning measures as well as the NIH EXAMINER battery, which produces Cognitive Control, Working Memory, and Verbal Fluency scores, along with an overall Executive Composite score, using psychometrically matched scales. RESULTS: No significant differences between groups were observed on widely used clinical measures. The PD patients scored lower than controls on the EXAMINER Executive Composite, Cognitive Control, and Working Memory Scores. CONCLUSIONS: The NIH EXAMINER Executive Composite and Cognitive Control Scores are sensitive measures of executive dysfunction in non demented PD, and may be more sensitive than several widely used measures. Results highlight the importance of careful test selection when evaluating for mild cognitive impairment in PD. PMID- 25454322 TI - Acute lipoid pneumonia in a fire-eater. PMID- 25454323 TI - Systemic AL amyloidosis in 2014 - The challenges and promises. PMID- 25454324 TI - Osborn J waves and accidental hypothermia. PMID- 25454325 TI - Biclonal gammopathies: A different significance? PMID- 25454326 TI - Anomalous pulmonary venous connection and Gilbert's syndrome. PMID- 25454327 TI - Skin lesions secondary to hijama. PMID- 25454328 TI - The human acromion viewed from an evolutionary perspective. AB - The high prevalence of rotator cuff tendinopathy in modern humans may be partly related to the shape acquired by the scapula as species changed throughout evolution. Here, we compared the anatomic features of the scapula across members of the Hominoid group. The results support the hypothesis that the scapula of Homo sapiens sapiens exhibits distinctive anatomic characteristics compared to that of other Hominoids. We studied 89 scapulae from five species. For each scapula, we measured eight parameters and determined six index. We then compared the results across species. We identified two distinctive characteristics of the lateral aspect of the human scapula, namely, a lateral orientation of the glenoid cavity and a narrow coraco-acromial arch. Similar to the gorilla acromion, the human one is steeply sloped and, above all, larger and squarer than the acromion of other Hominoids. These features may explain, in part at least, the pathogenesis of rotator cuff tendinopathy in modern man. PMID- 25454329 TI - Do subacromial ultrasonography findings predict efficacy of intra-bursal injection? Prospective study in 39 patients. AB - BACKGROUND: Ultrasonography has become an investigation of choice in the management of shoulder pain. The objective of this study was to determine whether the efficacy of subacromial-subdeltoid bursa injection correlated with the ultrasound findings. MATERIAL AND METHODS: We prospectively recruited patients who were seen between November 2012 and November 2013 for subacromial pain and whose rotator cuff was either intact or showed a full-thickness tear less than 1cm in length. A standardised physical examination of the shoulder was followed immediately by static and dynamic ultrasonography, intra-bursal injection of lidocaine, and a repetition of the same physical examination. Recorded ultrasonography features were the appearance of the bursa, shape of the coraco acromial ligament, and bursal deformation induced by passage under the coraco acromial ligament during dynamic imaging. A response to the injection was defined as greater than 75% improvements in at least three of the physical examination parameters. RESULTS: We included 39 patients with a mean age of 56.7 years. Ultrasonography showed abnormalities of the bursa in 30 patients, including 1 with an intra-bursal effusion, 10 with thickening, and 19 with both. Deformation of the bursa under the coraco-acromial ligament was noted in 26 patients. The proportions of patients with bursal effusion and with bursal thickening were similar in the 20 responders and 19 non-responders. Neither were any significant differences found for coraco-acromial ligament shape or bursal deformation under the ligament. CONCLUSIONS: No correlation was found between ultrasonography findings and the efficacy of a local anaesthetic injection into the subacromial bursa. These findings suggest that ultrasound abnormalities may constitute mere physiological changes, in keeping with earlier studies in asymptomatic individuals. Thus, subacromial impingement may be currently overdiagnosed. PMID- 25454330 TI - Failed subacromial decompression. Risk factors. AB - BACKGROUND: Arthroscopic subacromial decompression (acromioplasty) is widely held to be effective, although pain may persist after the procedure. The objective of this study was to evaluate the proportion of patients with residual pain (i.e., the failure rate) after isolated subacromial decompression and to look for predictors of failure. MATERIAL AND METHOD: We conducted a retrospective multicentre study of 108 patients managed with isolated arthroscopic subacromial decompression between 2007 and 2011, for any reason. We excluded patients in whom surgical procedures on the rotator cuff tendons were performed concomitantly. Data were collected from the medical records, a telephone questionnaire, and radiographs obtained before surgery and at last follow-up. Failure was defined as persistent pain (visual analogue scale score>3) more than 6 months after surgery and at last follow-up. RESULTS: The failure rate was 29% (31/108). Two factors significantly predicted failure, namely, receiving workers' compensation benefits for the shoulder condition and co-planing. Heterogeneous calcific tendinopathy and deep partial-thickness rotator cuff tears were also associated with poorer outcomes, but the effect was not statistically significant. DISCUSSION: Co planing may predict failure of subacromial decompression, although whether this effect is due to an insufficient degree of co-planing or to the technique itself is unclear. Nevertheless, in patients with symptoms from the acromio-clavicular joint, acromio-clavicular resection is probably the best option. Receiving workers' compensation benefits was also associated with treatment failure, as a result of well-known parameters related to the social welfare system. CONCLUSION: Isolated arthroscopic subacromial decompression is effective in 70% of cases. We recommend the utmost caution if co-planing is considered and/or the patient receives workers' compensation benefits for the shoulder condition, as these two factors are associated with a significant increase in the failure rate. LEVEL OF EVIDENCE: IV (retrospective study). PMID- 25454331 TI - Management of combined anterior or posterior cruciate ligament and posterolateral corner injuries: a systematic review. AB - BACKGROUND: Combined injuries to the posterolateral corner and cruciate ligaments are uncommon. The heterogeneity of injury patterns in many studies complicates the assessment of outcomes. OBJECTIVE: To assess the prognosis and functional outcomes after surgery for combined injuries to the posterolateral corner and to the anterior cruciate ligament (ACL) or posterior cruciate ligament (PCL). MATERIAL AND METHODS: We systematically reviewed the literature for articles reporting outcomes 1 year or more after surgery for combined injuries to the posterolateral corner and ACL (n=4) or PCL (n=9). Patients with bicruciate injuries were not studied. RESULTS: Overall, 65% of patients were IKDC A or B after surgery. The mean Lysholm score improved from 67 to 90. Mean time to surgery was 4.43 months in the group with ACL tears and 18.4 months in the group with PCL tears, and mean follow-up was 34.4 and 40.7 months in these two groups, respectively. In the groups with ACL and PCL tears, the proportions of patients classified as IKDC A or B at last follow-up were 81.6% and 81.0%, respectively, whereas 88% and 99% of patients, respectively, were IKDC grade C or D before surgery. The mean Lysholm score improved from 77 to 92 in the group with ACL tears and from 65 to 89 in the group with PCL tears. Improvements in laxity ranged from 28% to 79% in the group with PCL tears. DISCUSSION: Most of the articles selected for our review provided level III or IV evidence. Functional outcomes were satisfactory but less good than those reported after surgical reconstruction of isolated cruciate ligament tears. Full reconstruction seems the best strategy in patients with combined ACL/posterolateral corner injuries. Outcomes were also good but more variable in the group with PCL/posterolateral corner injuries. The time to surgery, which reflected the time to diagnosis, was shorter in patients with ACL than with PCL tears in addition to the posterolateral corner injury. LEVEL OF EVIDENCE: Level III (systematic literature review). PMID- 25454332 TI - Actifit synthetic meniscal substitute: experience with 18 patients in Brest, France. AB - BACKGROUND: The management of post-meniscectomy pain is poorly standardised. Allogeneic transplantation may be appropriate in some patients after total meniscectomy. After partial meniscectomy, the synthetic meniscal substitute Actifit may constitute a valid option if the knee is stable or stabilised and aligned or re-aligned. The interconnected pore structure of Actifit promotes tissue regeneration from the meniscal wall. Arthroscopy is used to position the implant, which is then sutured to the remaining native meniscus using horizontal stitches and to the meniscal wall using vertical stitches. However, a burdensome programme of rigorous rehabilitation is required after Actifit implantation. HYPOTHESIS: We hypothesised that implantation of a meniscal substitute effectively alleviated pain without adversely affecting the knee. OBJECTIVES: To assess the intra-articular behaviour of Actifit and the outcomes of Actifit implantation in a prospective case-series of patients monitored using arthroscopy, pathology, and imaging studies, as well as the Lysholm score to assess clinical benefits on daily activities. MATERIALS AND METHODS: Between October 2009 and April 2012, 18 patients underwent Actifit implantation at the military hospital in Brest, France. All procedures were performed by the same surgeon, who had extensive experience with meniscal suturing. There were 13 males and 5 females aged 20 to 46 years. The medial meniscus was involved in 13 patients and the lateral meniscus in 5 patients. Actifit implantation was used alone in 6 patients and in combination with anterior cruciate ligament reconstruction and/or realignment osteotomy in 12 patients. All patients were followed-up for at least 2 years. RESULTS: The mean Lysholm score after 1 year was 92%, indicating excellent outcomes. Magnetic resonance imaging showed no damage to the implant or degeneration of the neighbouring cartilage. Histological examination of meniscal substitute biopsies taken 1 year after implantation showed polymer ingrowth by normal chondrocytes and fibrochondrocytes. The clinical and radiographic outcomes compared favourably with those seen after isolated procedures on bone or ligaments. DISCUSSION: Actifit has no deleterious effects on patients. The implant induces and promotes meniscal regeneration. Actifit constitutes a major addition to our therapeutic armamentarium. We provide convincing evidence that meniscal reconstruction can be highly beneficial in decreasing the risk of progression to knee osteoarthritis. LEVEL OF EVIDENCE: IV. PMID- 25454333 TI - Contribution of MRI and CT arthrography to the diagnosis of intra-articular tendinopathy of the long head of the biceps. AB - INTRODUCTION: Clinical diagnosis of biceps tendinopathy is difficult to make because of the poor sensitivity of existing clinical tests. The goal of this study was to determine whether MRI or CT arthrogram could contribute to the diagnosis of tendinopathy in the intra-articular portion of the long head of biceps (LHB), while using macroscopic findings during shoulder arthroscopy as a reference. MATERIAL AND METHODS: A prospective, single-centre study was performed over a 4-month period. The radiology part of the study was carried out by a radiologist experienced in shoulder imaging. The arthroscopy part of the study was conducted while the biceps was being evaluated for treatment purposes. The study included 87 patients having an average age of 45.7 years (range 17-78). Fifty-eight patients underwent CT arthrography and 38 underwent an MRI. Seven patients underwent both imaging exams. One patient was removed from the study because of a spontaneous LHB rupture. The demographics of the two study populations were equivalent. RESULTS: For the diagnosis of tendinopathy of the intra-articular portion of the long head of biceps, the CT arthrogram had a sensitivity of 71.43%, specificity of 100%, positive predictive value of 100% but a negative predictive value of 67.74%. For the diagnosis of tendinopathy of the intra-articular portion of the long head of biceps, the MRI had a sensitivity of 42.85%, specificity of 75%, positive predictive value of 50% but a negative predictive value of 69.23%. CONCLUSION: This study showed that radiological diagnosis of tendinopathy of the long head of biceps remains challenging. Nevertheless, CT arthrography is more sensitive and specific than MRI in identifying this disorder. LEVEL OF EVIDENCE: III (case-control study). PMID- 25454334 TI - Reducible valgus flat-foot: assessment of posterior subtalar joint surface displacement by posterior arthroscopy during sinus tarsi expansion screwing. AB - INTRODUCTION: Subtalar arthroereisis corrects childhood and adult reducible valgus flat-foot in certain indications. Inserting an expansion screw in the sinus tarsi simultaneously corrects the calcaneal valgus of the talocalcaneal divergence and first-ray pronation if these are reducible. The displacement induced in the posterior subtalar joint (decoaptation, translation, rotation) is, however, poorly known. The present study involved arthroscopic assessment of posterior subtalar joint surface displacement during insertion of a talocalcaneal arthroereisis screw, with the hypothesis that displacement varies in three dimensions according to screw size. MATERIAL AND METHOD: Eight specimens were used for the study. All ankles were supple, taken from adult subjects. A 4.5-mm arthroscope was used and measurements were taken with a graduated palpator in the posterior subtalar joint. Three sinus tarsi expansion screws of incremental diameter were assessed. Before and after insertion measurements were made of posterolateral and posteromedial talar exposure on the calcaneus, anteroposterior and lateromedial translation, and talocalcaneal joint-line opening. RESULTS: Medial rotation, varization and anterior translation of the calcaneus were comparable in all cases. Mean lateral opening of the posterior subtalar joint was 0.88 mm with 8-mm screws and 1.25 mm with 16-mm screws. Significant differences between 8 and 16 mm screws were found for lateral subtalar joint opening (P=0.028) and for lateromedial translation (P=0.004). CONCLUSION: Sinus tarsi expansion screwing corrects hindfoot valgus and talocalcaneal divergence by inducing medial translation of the calcaneus under the talus and talar medial rotation and varization, proportional to screw size (medial translation and lateral opening of the subtalar joint). LEVEL OF EVIDENCE: III. PMID- 25454335 TI - Interest of emergency arthroscopic stabilization in primary shoulder dislocation in young athletes. AB - INTRODUCTION: The recurrence rate after primary shoulder dislocation in young subjects with high functional demand is close to 75%. The present study assessed the interest of emergency arthroscopic stabilization in this specific population. MATERIAL AND METHODS: A non-randomized prospective study included 31 athletes under 30 years of age with primary anterior shoulder dislocation. Fifteen were offered emergency stabilization; after informed consent, 14 were enrolled in the "emergency stabilization" group. This was compared to a group matched for age, sport and lesion, managed 1 year previously by "non-operative" treatment (n=17), divided into 2 subgroups: "immobilization" and "secondary stabilization". Continuous prospective assessment of recurrence, return to sport and function (QuickDASH, QDsport, Duplay and Rowe scores) enabled comparison between the 3 groups. RESULTS: Mean follow-up was 19 months for the "emergency stabilization" group and 25 months for the "non-operative" group. There were no failures in the "emergency stabilization" group, compared to a 77% rate in the "non-operative" group with onset at a mean 7.5 months and a mean 2.6 episodes of recurrence. Seven (54%) of the failures of non-operative treatment required secondary stabilization. Ninety-three percent of the "emergency stabilization" group, 44% of the "immobilization" group and 71% of the "secondary stabilization" group resumed sport at least at their pre-dislocation level. Mean Quick DASH was 1.46 in the "emergency stabilization" group, versus 15.28 the "immobilization" group (P<0.05) and 16.96 in the "secondary stabilization" group. Mean Duplay and Rowe scores were respectively 92.9 and 95 in the "emergency stabilization" group, versus 59.44 and 61.1 in the "immobilization" group (P<0.05) and 85 and 93.57 in the "secondary stabilization" group. DISCUSSION: Emergency arthroscopic stabilization limits recurrence (Kirkley et al.), with better functional results than for secondary stabilization, lesion "freshness" providing a more favorable environment for labral and ligamentary healing. These encouraging results need confirmation over longer follow-up. PMID- 25454336 TI - Anatomical reconstruction of the anterior talofibular and calcaneofibular ligaments with an all-arthroscopic surgical technique. AB - Arthroscopy is becoming an essential tool for the treatment of chronic lateral ankle instability. It allows the surgeon to determine which ligaments are injured and choose the most appropriate surgical repair technique, and also to assess and treat any associated injuries. Several arthroscopic techniques for lateral ankle ligament repair have recently been developed. As a consequence, it may be possible to carry out complete lateral ligament reconstruction with an all arthroscopic procedure. Such an arthroscopic lateral ankle ligament reconstruction technique is described in this article. PMID- 25454337 TI - Pilot study of feasibility of the effect of treatment with tDCS in patients suffering from treatment-resistant depression treated with escitalopram. AB - OBJECTIVE: This double-blind, sham-controlled trial investigated the effects of two daily tDCS sessions over a 5-day period in treatment-resistant depression. METHOD: Twenty-four treatment-resistant depressed patients received two daily sessions of active or sham anodal tDCS to the left prefrontal cortex (2 mA, 10 sessions over 1 week). Depression severity, psychomotor retardation and cognitive function were assessed. RESULTS: Active tDCS was not significantly superior to sham tDCS on the HDRS at week 4, as well as on the MADRS and SRRS scales, and on neuropsychological tests. Response rates were not significantly higher with active tDCS. tDCS was well tolerated, with mild adverse events limited to transient scalp discomfort. CONCLUSION: tDCS did not induce clinically relevant antidepressant effect in active and sham stimulation groups. There was no impact on psychomotor and neuropsychological functioning. SIGNIFICANCE: tDCS efficacy on specific symptom profiles in pharmacotherapy-resistant depression is limited. The use of optimized stimulation protocol and longer period of follow up may valuably contribute to specify the place of tDCS in treatment-resistant depression. PMID- 25454339 TI - Subcortical activity in electrophysiological scalp recordings. PMID- 25454340 TI - Investigating the role of glutathione in mismatch negativity: An insight into NMDA receptor disturbances in bipolar disorder. AB - OBJECTIVE: We aim to provide a targeted integration to investigate neuronal mechanisms underlying mismatch negativity (MMN) in bipolar disorder (BD), by looking at the association between temporal MMN and in vivo hippocampal glutathione (GSH) measured via proton magnetic resonance spectroscopy ((1)H-MRS). METHODS: Twenty-eight people with BD and 22 matched controls underwent a two-tone passive, duration deviant MMN paradigm as well as (1)H-MRS. GSH concentration in the left hippocampus was determined and Pearson's correlations were used to identify associations between MMN amplitude and in vivo GSH concentration. RESULTS: In controls MMN amplitude was negatively associated with GSH at the left temporal site (r=-0.542, 95% C.I.: -0.810, -0.060), and a similar trend at the right (r=-0.374, 95% C.I.: -0.678, 0.007). There were no significant associations in BD. CONCLUSIONS: The results provide insight into the relationship between MMN and in vivo GSH, and demonstrate that the metabolite system regulating MMN is abnormal in BD, compared to controls. This may indicate a lack of tightly regulated hippocampal NMDA functioning, or that NMDA receptor regulation in BD is mediated by other factors. SIGNIFICANCE: These results provide insight into the underlying basis of hippocampal NMDA disturbances implicated in BD. PMID- 25454338 TI - Anterior cingulate activity to monetary loss and basal ganglia activity to monetary gain uniquely contribute to the feedback negativity. AB - OBJECTIVE: The feedback negativity (FN) is an event-related potential that differentiates unfavorable versus favorable outcomes. Although thought to reflect error-related activity within the anterior cingulate cortex, recent work indicates the FN may also reflect reward-related activity that has been linked to the basal ganglia. To date, it remains unclear how to reconcile these conflicting perspectives. METHODS: We decomposed the FN by applying time-frequency analysis to isolate activity unique to monetary losses and gains. The FN was recorded from 84 individuals during a laboratory gambling task. RESULTS: Two signals contributed to the FN elicited by unpredictable outcomes: theta activity (4-7Hz) was increased following monetary loss, and delta activity (<3Hz) was increased following monetary gain. Predictable outcomes elicited delta but not theta activity. Source analysis revealed distinct generators, with loss-related theta localized to the anterior cingulate cortex and gain-related delta to a possible source in the striatum. Symptoms of depression, anxiety, and stress reactivity were specifically associated with blunted gain-related delta. CONCLUSIONS: The FN may be a composite of loss- and gain-related neural activity, reflecting distinct facets of reward processing. SIGNIFICANCE: Gain-related delta activity may provide unique information about reward dysfunction in major depression and other internalizing psychopathology. PMID- 25454341 TI - Prospective multi-center study of an automatic online seizure detection system for epilepsy monitoring units. AB - OBJECTIVE: A method for automatic detection of epileptic seizures in long-term scalp-EEG recordings called EpiScan will be presented. EpiScan is used as alarm device to notify medical staff of epilepsy monitoring units (EMUs) in case of a seizure. METHODS: A prospective multi-center study was performed in three EMUs including 205 patients. A comparison between EpiScan and the Persyst seizure detector on the prospective data will be presented. In addition, the detection results of EpiScan on retrospective EEG data of 310 patients and the public available CHB-MIT dataset will be shown. RESULTS: A detection sensitivity of 81% was reached for unequivocal electrographic seizures with false alarm rate of only 7 per day. No statistical significant differences in the detection sensitivities could be found between the centers. The comparison to the Persyst seizure detector showed a lower false alarm rate of EpiScan but the difference was not of statistical significance. CONCLUSIONS: The automatic seizure detection method EpiScan showed high sensitivity and low false alarm rate in a prospective multi center study on a large number of patients. SIGNIFICANCE: The application as seizure alarm device in EMUs becomes feasible and will raise the efficiency of video-EEG monitoring and the safety levels of patients. PMID- 25454342 TI - Changing the brain with multimodal mirrors: Combining visual and somatosensory stimulation to enhance motor plasticity. PMID- 25454343 TI - Observing and perceiving: A combined approach to induce plasticity in human motor cortex. AB - OBJECTIVE: To test whether action observation combined with peripheral nerve electrical stimulation was able to evoke plasticity in the primary motor cortex (M1). METHODS: The stimulation protocol consisted in the observation of a video showing repetitive thumb-index tapping movements (AO) combined with peripheral electrical nerve stimulation (PNS) delivered on the median nerve (AO-PNS). M1 excitability, measured by means of transcranial magnetic stimulation, was compared with that assessed after AO and PNS alone. RESULTS: M1 excitability increased after AO-PNS, whilst no modifications occurred after AO and PNS alone. The increased M1 excitability after AO-PNS was long-lasting (45 min) and specific for the stimulated muscle. CONCLUSIONS: This study described an innovative stimulation paradigm that exploited the mirror neuron system to induce plasticity in M1. However, this occurred only when action observation was combined with afferent signals coming from periphery. SIGNIFICANCE: This study supports the literature proposing the mirror neuron system as neural substrate for rehabilitation and opens a debate on the rehabilitative treatments that employ AO to improve patients' motor functions. Indeed, these results suggest that AO has to be combined with afferent inputs from periphery to evoke plasticity in the human motor system. PMID- 25454344 TI - Enhanced slow waves at the periphery of human epileptic foci. AB - OBJECTIVE: Experimental epilepsy foci are surrounded by an enhanced inhibition zone. We looked for evidence of peripheral inhibition in human epilepsy foci by analyzing the waveforms of discharges. The sharp-wave of an epileptic discharge is thought to reflect EPSP synchronization, and the subsequent slow-wave to reflect inhibition. Ratios of amplitudes of the sharp- and slow-waves in human EEGs may show how excitatory and inhibitory processes relate to discharge spread implicating peripheral inhibition in human epilepsy, too. METHOD: In electrocorticography from 10 adult patients we compared amplitudes of sharp-waves and of slow-waves and their ratios in each electrodes as a function of their distance from the highest sharp-wave electrode. RESULTS: Sharp-wave amplitude decreases as a function of electrode distance from the highest sharp-wave electrode, but the slow-wave voltage exhibits a slight increase. The ratio slow wave/sharp-wave increases several-fold within 2-3 cm from the highest sharp-wave electrode. CONCLUSION: In human cortex epileptic discharges at the periphery of a focus exhibit a prevalent slow-wave consistent with a possible local enhanced inhibition. SIGNIFICANCE: Waveform analysis of electrocorticography epileptic discharges suggests the presence in human neocortex of surround inhibition, a basic mechanism limiting the spread of epileptic activity, long studied in experimental models. PMID- 25454346 TI - Bringing in health technology assessment and cost-effectiveness considerations at an early stage of drug development. AB - This paper reviews the issues involved in undertaking HTA studies early in the development of new cancer therapies, and discusses the data and methods for estimating the cost-effectiveness of new diagnostics and treatments. The value for patients of new cancer therapies is based on access to the treatment and optimal use. Realising potential value depends on successful completion of a series of steps, from the initial economic evaluations based on clinical trial data, to the reimbursement decisions based on the evaluations and the implementation of these decisions in clinical practice. Considerable resources have been devoted to the study of the cost-effectiveness of new cancer drugs as a basis for decisions about payment and use. Such resources could be used much more effectively if industry and HTA agencies were to collaborate at an early stage in the development process. The traditional clinical trial approach of using progression-free survival and cross-overs has serious shortcomings, producing data that cannot be used to determine outcomes and, so, cost-effectiveness. A new standard is needed; both regulatory and HTA authorities should be involved in its development. PMID- 25454345 TI - Detection of glyco-mucin profiles improves specificity of MUC16 and MUC1 biomarkers in ovarian serous tumours. AB - The CA125 assay detects circulating MUC16 and is one of the most widely used cancer biomarkers for the follow-up of ovarian cancer. We previously demonstrated that detection of aberrant cancer-associated glycoforms of MUC16 as well as MUC1 in circulation could improve the yield of these serum assays. Our aim was to refine ovarian cancer biomarkers by detection of aberrant glycoforms (Tn, STn, and T) of MUC16 and MUC1 in ovarian cancer tissue using Proximity Ligation Assays (PLA). We studied two series of serous ovarian tumours, a pilot series of 66 ovarian tumours (27 cystadenomas, 16 borderline tumours and 23 adenocarcinomas) from Centro Hospitalar S. Joao, Porto and a validation series of 89 ovarian tumours (17 cystadenomas, 25 borderline tumours and 47 adenocarcinomas) from the Portuguese Institute of Oncology Francisco Gentil, Lisbon. PLA reactions for MUC16/Tn, MUC16/STn, MUC1/Tn and MUC1/STn were negative in benign lesions but often positive in borderline and malignant lesions, in both series. An even better yield was obtained based on positivity for any of the four glyco-mucin profiles, further increasing sensitivity to 72% and 83% in the two series, respectively, with 100% specificity. The strategy is designated glyco-mucin profiling and provides strong support for development of PLA-based serum assays for early diagnosis. PMID- 25454349 TI - Introduction: Behavioural Processes. PMID- 25454347 TI - Increased extracellular pressure stimulates tumor proliferation by a mechanosensitive calcium channel and PKC-beta. AB - Large tumors exhibit high interstitial pressure heightened by growth against the constraining stroma. Such pressures could stimulate tumor proliferation via a mechanosensitive ion channel. We studied the effects of 0-80 mmHg increased extracellular pressure for 24 h on proliferation of SW620, Caco-2, and CT-26 colon; MCF-7 breast; and MLL and PC3 prostate cancer cells, and delineated its mechanism in SW620 cells with specific inhibitors and siRNA. Finally, we compared NF-kB, phospho-IkB and cyclin D1 immunoreactivity in the high pressure centers and low pressure peripheries of human tumors. Pressure-stimulated proliferation in all cells. Pressure-driven SW620 proliferation required calcium influx via the T-type Ca(2+) channel Cav3.3, which stimulated PKC-beta to invoke the IKK-IkB-NF kB pathway to increase proliferation and S-phase fraction. The mitotic index and immunoreactivity of NF-kB, phospho-IkB, and cyclin D1 in the center of 28 large human colon, lung, and head and neck tumors exceeded that in tumor peripheries. Extracellular pressure increases [Ca(2+)]i via Cav3.3, driving a PKC-beta- IKK- IkB-NF-kB pathway that stimulates cancer cell proliferation. Rapid proliferation in large stiff tumors may increase intratumoral pressure, activating this pathway to stimulate further proliferation in a feedback cycle that potentiates tumor growth. Targeting this pathway may inhibit proliferation in large unresectable tumors. PMID- 25454350 TI - Preliminary results on CSF biomarkers for hypothalamic dysfunction in Kleine Levin syndrome. AB - OBJECTIVE: To measure CSF biomarkers of hypothalamic dysfunction in patients with typical Kleine-Levin syndrome (KLS) during symptomatic and asymptomatic periods. PATIENTS/METHODS: Two patients with typical KLS were admitted during symptomatic and asymptomatic periods to a research Sleep Disorders Center. Cerebrospinalfluid (CSF) hypocretin-1, histamine (HA), and its major metabolite tele-methylhistamine (t-MHA) levels were measured in two KLS patients in and out of episode. RESULTS: CSF biomarkers of hypothalamic dysfunction measured in two KLS patients in and out of episode revealed low hypocretin levels (within the narcolepsy-cataplexy range) during a hypersomnia episode in the more severe patient, and a 42% decrease (although within normal range) in the second patient. CSF HA and t-MHA measurements in and out of episode revealed a two-fold in-episode decrease in HA in the more severe patient, with no significant change for the second patient, nor for t-MHA levels. CONCLUSION: We reported reversible changes in CSF hypothalamic biomarkers in a typical patient with KLS that reinforces the hypothesis that in some patients KLS episodes may be caused by recurrent functional alterations of the hypothalamus. PMID- 25454351 TI - Acoustic noise improves motor learning in spontaneously hypertensive rats, a rat model of attention deficit hyperactivity disorder. AB - The spontaneously hypertensive (SH) rat model of ADHD displays impaired motor learning. We used this characteristic to study if the recently described acoustic noise benefit in learning in children with ADHD is also observed in the SH rat model. SH rats and a Wistar control strain were trained in skilled reach and rotarod running under either ambient noise or in 75 dBA white noise. In other animals the effect of methylphenidate (MPH) on motor learning was assessed with the same paradigms. To determine if acoustic noise influenced spontaneous motor activity, the effect of acoustic noise was also determined in the open field activity paradigm. We confirm impaired motor learning in the SH rat compared to Wistar SCA controls. Acoustic noise restored motor learning in SH rats learning the Montoya reach test and the rotarod test, but had no influence on learning in Wistar rats. Noise had no effect on open field activity in SH rats, but increased corner time in Wistar. MPH completely restored rotarod learning and performance but did not improve skilled reach in the SH rat. It is suggested that the acoustic noise benefit previously reported in children with ADHD is shared by the SH rat model of ADHD, and the effect is in the same range as that of stimulant treatment. Acoustic noise may be useful as a non-pharmacological alternative to stimulant medication in the treatment of ADHD. PMID- 25454348 TI - Oncogenic signaling in amphiregulin and EGFR-expressing PTEN-null human breast cancer. AB - A subset of triple negative breast cancer (TNBC) is characterized by overexpression of the epidermal growth factor receptor (EGFR) and loss of PTEN, and patients with these determinants have a poor prognosis. We used cell line models of EGFR-positive/PTEN null TNBC to elucidate the signaling networks that drive the malignant features of these cells and cause resistance to EGFR inhibitors. In these cells, amphiregulin (AREG)-mediated activation of EGFR results in up-regulation of fibronectin (FN1), which is known to be a mediator of invasive capacity via interaction with integrin beta1. EGFR activity in this PTEN null background also results in Wnt/beta-catenin signaling and activation of NF kappaB. In addition, AKT is constitutively phosphorylated in these cells and is resistant to gefitinib. Expression profiling demonstrated that AREG-activated EGFR regulates gene expression differently than EGF-activated EGFR, and functional analysis via genome-scale shRNA screening identified a set of genes, including PLK1 and BIRC5, that are essential for survival of SUM-149 cells, but are uncoupled from EGFR signaling. Thus, our results demonstrate that in cells with constitutive EGFR activation and PTEN loss, critical survival genes are uncoupled from regulation by EGFR, which likely mediates resistance to EGFR inhibitors. PMID- 25454352 TI - Impact of heavy metal toxicity and constructed wetland system as a tool in remediation. AB - The objective of this review is to throw light upon the global concern of heavy metal-contaminated sites and their remediation through an ecofriendly approach. Accumulated heavy metals in soil and water bodies gain entry through the food chain and pose serious threat to all forms of life. This has engendered interest in phytoremediation techniques where hyperaccumulators are used. Constructed wetland has a pivotal role and is a cost-effective technique in the remediation of heavy metals. Metal availability and mobility are influenced by the addition of chelating agents, which enhance the availability of metal uptake. This review helps in identifying the critical knowledge gaps and areas to enhance research in the future to develop strategies such as genetically engineered hyperaccumulators to attain an environment devoid of heavy metal contamination. PMID- 25454353 TI - The two-process theory of face processing: modifications based on two decades of data from infants and adults. AB - Johnson and Morton (1991. Biology and Cognitive Development: The Case of Face Recognition. Blackwell, Oxford) used Gabriel Horn's work on the filial imprinting model to inspire a two-process theory of the development of face processing in humans. In this paper we review evidence accrued over the past two decades from infants and adults, and from other primates, that informs this two-process model. While work with newborns and infants has been broadly consistent with predictions from the model, further refinements and questions have been raised. With regard to adults, we discuss more recent evidence on the extension of the model to eye contact detection, and to subcortical face processing, reviewing functional imaging and patient studies. We conclude with discussion of outstanding caveats and future directions of research in this field. PMID- 25454354 TI - Oscillatory multiplexing of neural population codes for interval timing and working memory. AB - Interval timing and working memory are critical components of cognition that are supported by neural oscillations in prefrontal-striatal-hippocampal circuits. In this review, the properties of interval timing and working memory are explored in terms of behavioral, anatomical, pharmacological, and neurophysiological findings. We then describe the various neurobiological theories that have been developed to explain these cognitive processes - largely independent of each other. Following this, a coupled excitatory - inhibitory oscillation (EIO) model of temporal processing is proposed to address the shared oscillatory properties of interval timing and working memory. Using this integrative approach, we describe a hybrid model explaining how interval timing and working memory can originate from the same oscillatory processes, but differ in terms of which dimension of the neural oscillation is utilized for the extraction of item, temporal order, and duration information. This extension of the striatal beat frequency (SBF) model of interval timing (Matell and Meck, 2000, 2004) is based on prefrontal-striatal-hippocampal circuit dynamics and has direct relevance to the pathophysiological distortions observed in time perception and working memory in a variety of psychiatric and neurological conditions. PMID- 25454356 TI - The self to other model of empathy: providing a new framework for understanding empathy impairments in psychopathy, autism, and alexithymia. AB - Despite increasing empirical and theoretical work on empathy, particularly on the content of empathic representations, there is a relative lack of consensus regarding the information processing necessary for empathy to occur. Here we attempt to delineate a mechanistic cognitive model of empathy in order to provide a framework within which neuroimaging work on empathy can be located, and which may be used in order to understand various disorders characterised by atypical levels of empathy. To this end data from individuals with psychopathy, autism, and alexithymia inform the model, and the model is used to provide a unifying framework for any empathy impairments seen in these disorders. The model adopts a developmental framework and tries to address the four difficult questions of empathy: How do we know what another is feeling? What is the role of theory of mind in empathy? How does the state of another cause a corresponding state in the self? How do we represent another's emotion once emotional contagion has taken place? PMID- 25454355 TI - A general approach-avoidance hypothesis of oxytocin: accounting for social and non-social effects of oxytocin. AB - BACKGROUND: We critically reexamine extant theory and empirical study of Oxytocin. We question whether OT is, in fact, a "social neuropeptide" as argued in dominant theories of OT. METHOD: We critically review human and animal research on the social and non-social effects of Oxytocin, including behavioral, psychophysiological, neurobiological, and neuroimaging studies. RESULTS: We find that extant (social) theories of Oxytocin do not account for well-documented non social effects of Oxytocin. Furthermore, we find a range of evidence that social and non-social effects of Oxytocin may be mediated by core approach-avoidance motivational processes. CONCLUSIONS: We propose a General Approach-avoidance Hypothesis of Oxytocin (GAAO). We argue that the GAAO may provide a parsimonious account of established social and non-social effects of Oxytocin. We thus re conceptualize the basic function(s) and mechanism(s) of action of Oxytocin. Finally, we highlight implications of the GAAO for basic and clinical research in humans PMID- 25454357 TI - The Ultimatum Game and the brain: a meta-analysis of neuroimaging studies. AB - Social decision-making tasks involve psychological processes key to effective functioning in a complex, social world. The Ultimatum Game (UG) is a widely studied social decision-making task, which models responses to fairness. A number of neuroimaging studies have investigated the UG to identify neural correlates of unfairness and decisions to reject versus accept an offer. We present the first quantitative summary of neuroimaging studies in social decision-making with a meta-analysis of 11 fMRI studies of the UG, including data from 282 participants. Effect-Size Signed Differential Mapping was used to estimate effect sizes from statistical parametric maps and reported peak information before meta-analysing them. Consistent activations were seen in the anterior insula, anterior cingulate cortex (ACC), supplementary motor area (SMA) and cerebellum in response to unfair offers. Robust activations in the ACC, SMA and putamen were seen when deciding to reject rather than accept UG offers. These are consistent with models of motivational conflict during the UG decision-making process, a response to norm violations, with a possible role for the reward system. PMID- 25454358 TI - Impairments to visual disengagement in autism spectrum disorder: a review of experimental studies from infancy to adulthood. AB - Impairments in visual disengagement are a current focus of research in autism spectrum disorders (ASD) and may play a key role in the early expression of social-emotional deficits associated with the disorder. This review summarizes current knowledge of visual disengagement and orienting in ASD. Convergent reports from infancy to adulthood indicate that (1) impairments to visual disengagement are apparent on Gap-Overlap tasks, spatial orienting tasks, and tasks involving social stimuli; and (2) these impairments emerge in the first year of life and continue into adulthood. The relationships between visual disengagement, orienting, joint attention, emotional regulation, and IQ are discussed in relation to ASD. PMID- 25454360 TI - The use of repetitive transcranial magnetic stimulation for modulating craving and addictive behaviours: a critical literature review of efficacy, technical and methodological considerations. AB - OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) is a potential therapeutic intervention for the treatment of addiction. This critical review aims to summarise the recent developments with respect to the efficacy of rTMS for all types of addiction and related disorders (including eating disorders), and concentrates on the associated methodological and technical issues. METHODS: The bibliographic search consisted of a computerised screening of the Medline and ScienceDirect databases up to December 2013. Criteria for inclusion were the target problem was an addiction, a related disorder, or craving; the intervention was performed using rTMS; and the study was a clinical trial. RESULTS: Of the potential 638 articles, 18 met the criteria for inclusion. Most of these (11 of the 18) supported the efficacy of rTMS, especially in the short term. In most cases, the main assessment criterion was the measurement of craving using a Visual Analogue Scale. DISCUSSION: The results are discussed with respect to the study limitations and, in particular, the many methodological and technical discrepancies that were identified. Key recommendations are provided. PMID- 25454361 TI - NMR-based molecular ruler for determining the depth of intercalants within the lipid bilayer. Part V: a comparison of liposomes, bioliposomes and erythrocyte ghosts. AB - Afri et al. (2014a,b) have recently reported their mapping of DMPC liposomes using (13)C NMR in conjunction with a wide range of difunctional intercalants: n ketoesters, n-ketoacids and n-ketophosphatidylcholines. The present study initiates a comparable study of bioliposomes and erythrocyte ghosts. This required the (13)C NMR characterization of these systems for the first time, and further involved a determination of the signals of three doubly (13)C-labeled intercalants, in particular, n-ketophosphatidylcholines where n=4, 8 and 12. This study reveals that DMPC liposomes, bioliposomes and erythrocyte ghosts, with all their structural differences, are not radically different from the perspective of polarity gradient. Any differences observed reflect the additives often naturally present in these lipid systems. PMID- 25454362 TI - Effect of alpha-tocopherol on the hemin-catalyzed decomposition of 1-palmitoyl-2 linoleoyl-3-sn-phosphatidylcholine 13-hydroperoxide in micelles and liposomes. AB - The secondary process of lipid peroxidation produces some toxic aldehydes. Since this process takes place via free radical reaction in lipophilic circumstances, alpha-tocopherol would suppress the formation of such aldehydes by trapping free radical intermediates. This study reports the effect of alpha-tocopherol on the hemin-catalyzed decomposition of 1-palmitoyl-2-linoleoyl-3-sn-phosphatidylcholine 13-hydroperoxide (PLPC-OOH) in micelles and liposomes. PLPC-OOH and alpha tocopherol were reacted with hemin in micelles, and the reaction products were characterized to be 1-palmitoyl-2-(alpha-tocopheroxy-12,13-epoxyoctadecenoyl)-3 sn-phosphatidylcholines (T-epoxyPLPC) and known compounds, 1-palmitoyl-2-[(8a dioxy-alpha-tocopherone)-12,13-epoxyoctadecenoyl]-3-sn-phosphatidylcholines (TOO epoxyPLPC) and alpha-tocopherol dimer. The hemin-catalyzed decomposition of PLPC OOH in micelles produced hexanal as one of secondary aldehydic products. alpha Tocopherol suppressed the formation of hexanal, and alpha-tocopherylquinone, alpha-tocopherol dimer, TOO-epoxyPLPC, and T-epoxyPLPC were detected during the reaction. In liposomes, alpha-tocopherol could partially suppress the formation of hexanal, and the main products were TOO-epoxyPLPC and alpha-tocopherol dimer. The results indicate that alpha-tocopherol may suppress the formation of hexanal by trapping the epoxyperoxyl and epoxyalkyl radicals derived from PLPC-OOH. PMID- 25454363 TI - Capsular bag performance of a hydrophobic acrylic 1-piece intraocular lens. AB - PURPOSE: To compare parameters after 1-piece and 3-piece intraocular lens (IOL) implantation. SETTING: Moorfields West End Clinic, London, United Kingdom, and Hanusch Hospital, Vienna, Austria. DESIGN: Prospective randomized controlled trial. METHODS: Each eye of patients having bilateral surgery for age-related cataract was randomized to have implantation of a 1-piece IOL (Tecnis ZCB00) or a 3-piece IOL (Tecnis ZA9003). Changes in visual acuity, refraction, and anterior chamber depth (ACD) were evaluated during a 2-year follow-up. Intraocular lens tilt and decentration were evaluated using a Purkinje meter. Regeneratory posterior capsule opacification (PCO) was analyzed using retroillumination photographs in Automated Quantification of After-Cataract image-analysis software. RESULTS: This study comprised 100 eyes of 50 patients. No statistically significant differences were found in IOL tilt or decentration between groups (P>=.06). Minimal but statistically significant changes were observed in the vertical tilt component 12 months postoperatively in the 3-piece IOL group (P<.01). The tilt and decentration components did not correlate with changes in sphere or the regeneratory PCO score (r = 0.38, P>=.06). The ACD decreased significantly between 1 day and 1 month postoperatively in both groups (P<.01), with no significant changes afterward (P>=.22). The anterior chamber was significantly deeper in the 1-piece group at all follow-up visits (P<.01). CONCLUSIONS: Both the 1-piece IOL and the 3-piece IOL showed excellent positional stability in the capsular bag, resulting in good clinical outcomes. Regeneratory PCO levels were low and comparable between the IOLs. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25454359 TI - Childhood adversity and neural development: deprivation and threat as distinct dimensions of early experience. AB - A growing body of research has examined the impact of childhood adversity on neural structure and function. Advances in our understanding of the neurodevelopmental consequences of adverse early environments require the identification of dimensions of environmental experience that influence neural development differently and mechanisms other than the frequently-invoked stress pathways. We propose a novel conceptual framework that differentiates between deprivation (absence of expected environmental inputs and complexity) and threat (presence of experiences that represent a threat to one's physical integrity) and make predictions grounded in basic neuroscience principles about their distinct effects on neural development. We review animal research on fear learning and sensory deprivation as well as human research on childhood adversity and neural development to support these predictions. We argue that these previously undifferentiated dimensions of experience exert strong and distinct influences on neural development that cannot be fully explained by prevailing models focusing only on stress pathways. Our aim is not to exhaustively review existing evidence on childhood adversity and neural development, but to provide a novel framework to guide future research. PMID- 25454364 TI - [Place of the opioid system in biology and treatment of Alcohol Use Disorder]. AB - While the DSM 5 has formalized the terminology "Alcohol Use Disorders" (AUD) or "disorders of the use of alcohol" (UAW French translation in progress), the term "alcohol dependence" still used in ICD-10, apriority in the future ICD-11 and above in clinical practice. Addiction to alcohol is the cause of mortality and major morbidity. In terms of therapeutic strategies for its management, alongside the maintenance of abstinence after withdrawal (with a high rate of relapse), the reduction of alcohol consumption below certain thresholds of intake is emerging in order to reduce risk, improve health and regain control of consumption even be an intermediate step towards abstinence. The role of the endogenous opioid system in the modulation of the activity of dopaminergic neurons from the circuit of reward and motivation is well established. An unsteadiness of this system has been described in the alcohol dependence. Indeed, a hypofunction of the endorphin pathway and its mu receptor and a hyperactivity of the dynorphin pathway and its kappa receptor participate in the alcohol reinforcing effects (especially positive and negative). The development of active molecules in this system allows better management of alcohol dependence. Besides naltrexone (mu antagonist) allowed in the maintenance of abstinence after withdrawal, another molecule (nalmefene) with modulating properties of MU and kappa opioid receptors is the first drug having obtained an MA in reducing consumption in adult patients with alcohol dependence. Its modulating original pharmacological properties by targeting both the positive but also the negative reinforcing effects of alcohol, are responsible for its development in reducing consumption in the alcohol dependence. PMID- 25454365 TI - [Benefits in reducing alcohol consumption: how nalmefene can help]. AB - Alcohol consumption represents a significant factor for mortality in the world: 6.3% in men and 1.1% in women. Alcohol use disorder is also very common: 5.4% in men, 1.5% in women. Despite its high frequency and the seriousness of this disorder, only 8% of all alcohol-dependents are ever treated. Recent meta analyses have shown that if we can increase current figures by 40%, we could decrease alcohol-related morality rates by 13% in men and 9% in women. Thus, it is important to motivate both physicians and patients to participate in treatment in alcohol use disorder. Recent epidemiological data from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) are currently challenging the notion of alcohol use disorder as a fixed entity. Among a cohort of 4422 subjects initially diagnosed as having alcohol dependency, only 25% of these could still be diagnosed as alcohol-dependent one year later. Among the others, 27% were in partial remission, 12% had risk use, 18% low risk use and 18% were abstinent. Stable remission rates were observed in 30% of these subjects at 5 years. This study also argues in favour of the newer dimensional approach elaborated in the DSM 5. One potentially interesting treatment option is oriented toward reducing alcohol intake. In a study by Rehm and Roerecke (2013), they modelled the impact of reduced consumption in a typical alcoholic patient who drinks 8 glasses of alcohol per day (92 g of pure alcohol). If he decreases his alcohol intake by just one glass per day (12 g of alcohol per day), his one-year mortality risk falls from 180/100,000 to 120/100,000; if he decreases his intake by two glasses per day (24 g), this risk falls to 95/100,000, roughly half his baseline risk. These observations have resulted in integrating reduced consumption as an option into the treatment guidelines of several national institutions such as the National Institute for Clinical Excellence (NICE, UK), European Medicines Agency, as well as the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Decreasing stigmatisation of alcohol use disorder through public service announcements, in addition to more flexible physician attitudes concerning personal alcohol intake objectives may be key in getting increased numbers of patients into treatment programmes. In one study in Great Britain, 50% of patients in treatment for alcohol use disorder would prefer an initial objective of reduced consumption. A recent addition to the pharmacotherapy arsenal is nalmefene, which has been recently released as a medication to aid in reducing alcohol consumption. It is a strong MU and delta opioid receptor antagonist and a partial kappa opioid receptor agonist. Opioid receptor antagonism is associated with reduced reward in relation to alcohol use, thus helping patients in reducing their consumption. Patients are instructed to take one nalmefene tablet two hours prior to each drinking occasion. Nalmefene therapy is to be accompanied by a specific psychosocial programme called BRENDA. BRENDA consists of a biopsychosocial evaluation, restitution of the evaluation to the patient, an empathetic approach that responds to patient needs, offering direct advice and adjusting goals and treatment programmes as the patient makes progress. Nalmefene has been associated with decreased heavy drinking days in two clinical trials. Overall, the treatment is well tolerated; adverse effects are fairly mild and short-lived. In conclusion, an approach that integrates reduced alcohol consumption makes sense from both a public and personal standpoint. Medications such as nalmefene have shown efficacy in association with a biopsychosocial approach to help patients attain their personal objectives with respect to alcohol use. PMID- 25454366 TI - Resistin induces lipolysis and suppresses adiponectin secretion in cultured human visceral adipose tissue. AB - Resistin is an adipokine secreted from adipose tissue, which is likely involved in the development of obesity and insulin resistance via its interaction with other organs, as well as affecting adipose tissue function. The impact of resistin treatment on lipolysis and adiponectin secretion in human visceral adipose tissue is currently unknown. Mesenteric adipose tissue samples were obtained from 14 male subjects [age 54+/-6 yr, body mass index (BMI) 23.59+/-0.44 kg/m(2)] undergoing abdominal surgeries. Adipose tissues were cultured and treated with resistin (100 ng/mL, 24h) in the absence or presence of different signaling inhibitors: H89 (1 MUM), PD98059 (25 MUM) and SB201290 (20 MUM) for glycerol and non-esterified fatty acid (NEFA) measurement. Adiponectin level from media at 24 h was also measured via ELISA. Adipose tissue minces after resistin incubation (100 ng/mL, 24 h) were also collected for further Western blotting analysis. Resistin resulted in significant induction of glycerol (3.62+/-0.57 vs. 5.30+/-1.11 mmol/L/g tissue, p<0.05) and NEFA (5.99+/-1.06 vs. 8.48+/-1.57 mmol/L/g tissue, p<0.05) release at 24 h. H89 and PD98059 partially inhibited resistin induced glycerol and NEFA release, while SB201290 has no such effect. Resistin induced the phosphorylation of p-HSL at serine 563, PKA at ~62 kDa and ERK1/2 as measured by Western blotting. Resistin led to significant reduction of the secretion of adiponectin (38.16+/-10.43 vs. 21.81+/-4.21 ng/mL/g tissue, p<0.05). Our current findings implicate that resistin might play a significant role in obesity related pathologies in various tissues via its effect on adipose tissue function. PMID- 25454367 TI - Hypothalamic-pituitary thyroid axis alterations in female mice with deletion of the neuromedin B receptor gene. AB - Neuromedin B, a peptide highly expressed at the pituitary, has been shown to act as autocrine/paracrine inhibitor of thyrotropin (TSH) release. Here we studied the thyroid axis of adult female mice lacking neuromedin B receptor (NBR-KO), compared to wild type (WT) littermates. They exhibited slight increase in serum TSH (18%), with normal pituitary expression of mRNA coding for alpha-glycoprotein subunit (Cga), but reduced TSH beta-subunit mRNA (Tshb, 41%), lower intra pituitary TSH content (24%) and increased thyroid hormone transporter MCT-8 (Slc16a2, 44%) and thyroid hormone receptor beta mRNA expression (Thrb, 39%). NBR KO mice exhibited normal thyroxine (T4) and reduced triiodothyronine (T3) (30%), with no alterations in the intra-thyroidal content of T4 and T3 or thyroid morphological changes. Hypothalamic thyrotropin-releasing hormone (TRH) mRNA (Trh) was increased (68%), concomitant with a reduction in type 2 deiodinase mRNA (Dio2, 30%) and no changes in MCT-8 and thyroid hormone receptor mRNA expression. NBR-KO mice exhibited a 56% higher increase in serum TSH in response to an acute single intraperitoneal injection of TRH concomitant with a non-significant increase in pituitary TRH receptor (Trhr) mRNA at basal state. The phenotype of female NBR-KO mice at the hypothalamus-pituitary axis revealed alterations in pituitary and hypothalamic gene expression, associated with reduced serum T3, and higher TSH response to TRH, with apparently normal thyroid morphology and hormonal production. Thus, results confirm that neuromedin B pathways are importantly involved in secretory pathways of TSH and revealed its participation in the in vivo regulation of gene expression of TSH beta-subunit and pituitary MCT8 and Thrb and hypothalamic TRH and type 2 deiodinase. PMID- 25454368 TI - Influence of maternal depression on household food insecurity for low-income families. AB - OBJECTIVE: To examine whether maternal depression predicts future household food insecurity for low-income families. METHODS: This was a secondary data analysis using data from the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B). The study cohort consisted of 2917 low-income mothers, defined as <185% federal poverty level, who were food secure at baseline. Maternal data collected when children were 9 and 24 months of age were used. Data at 9 months were considered baseline, and data at 24 months were considered follow-up. Baseline maternal depressive symptoms were measured by a 12-item abbreviated version of the Center for Epidemiologic Studies Depression Scale. Household food insecurity at follow up was measured by the US Department of Agriculture Household Food Security Scale. RESULTS: At baseline, 16% of mothers were depressed (raw score >9). Most mothers were white, unemployed, and born in the United States. The majority received Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) (86%); 39% received Supplemental Nutrition Assistance Program (SNAP). At follow-up, 11.8% of mothers reported household food insecurity. In multivariable analysis, maternal depression at baseline was significantly associated with food insecurity at follow-up (adjusted odds ratio 1.50; 95% confidence interval 1.06 2.12). CONCLUSIONS: Our results suggest that maternal depression is an independent risk factor for household food insecurity in low-income families with young children. Multidisciplinary interventions embedded within and outside the pediatric medical home should be developed to identify depressed mothers and link them to community-based mental health and food resources. Further longitudinal and interventional studies are needed to understand and address the complex relationship between poverty, maternal depression, social safety nets, and food insecurity. PMID- 25454369 TI - Maternal mobile device use during a structured parent-child interaction task. AB - OBJECTIVE: To examine associations of maternal mobile device use with the frequency of mother-child interactions during a structured laboratory task. METHODS: Participants included 225 low-income mother-child pairs. When children were ~6 years old, dyads were videotaped during a standardized protocol in order to characterize how mothers and children interacted when asked to try familiar and unfamiliar foods. From videotapes, we dichotomized mothers on the basis of whether or not they spontaneously used a mobile device, and we counted maternal verbal and nonverbal prompts toward the child. We used multivariate Poisson regression to study associations of device use with eating prompt frequency for different foods. RESULTS: Mothers were an average of 31.3 (SD 7.1) years old, and 28.0% were of Hispanic/nonwhite race/ethnicity. During the protocol, 23.1% of mothers spontaneously used a mobile device. Device use was not associated with any maternal characteristics, including age, race/ethnicity, education, depressive symptoms, or parenting style. Mothers with device use initiated fewer verbal (relative rate 0.80; 95% confidence interval 0.63, 1.03) and nonverbal (0.61; 0.39, 0.96) interactions with their children than mothers who did not use a device, when averaged across all foods. This association was strongest during introduction of halva, the most unfamiliar food (0.67; 0.48, 0.93 for verbal and 0.42; 0.20, 0.89 for nonverbal interactions). CONCLUSIONS: Mobile device use was common and associated with fewer interactions with children during a structured interaction task, particularly nonverbal interactions and during introduction of an unfamiliar food. More research is needed to understand how device use affects parent-child engagement in naturalistic contexts. PMID- 25454371 TI - Smoking and osteoarthritis: a review of the evidence and its implications. AB - A number of reports including a recent publication in Osteoarthritis and Cartilage have suggested that smokers have a lower than expected prevalence of osteoarthritis (OA) than nonsmokers. We review the evidence linking smoking with OA, suggest approaches whereby the direct and indirect effects of smoking on OA might be distinguished, highlight two diseases, ulcerative colitis and Parkinson's disease, where smoking is protective, discuss mechanisms by which nicotine might act and lastly explore the association of smoking with enhanced musculoskeletal pain. PMID- 25454373 TI - Adjunctive, pain-modifying, analgesic drugs. AB - Outside the realm of nonsteroidal antiinflammatory drug(NSAID) and opioid exist a broad range of medications that exert an analgesic effect, or otherwise modify and protect against pain, by manipulating various targets along the nociceptive pathway. Strength of evidence for dogs and cats can vary widely, and this article will review the available literature that may guide clinical usage in these species. PMID- 25454370 TI - Optical clearing in collagen- and proteoglycan-rich osteochondral tissues. AB - OBJECTIVE: Recent developments in optical clearing and microscopy technology have enabled the imaging of intact tissues at the millimeter scale to characterize cells via fluorescence labeling. While these techniques have facilitated the three-dimensional (3D) cellular characterization within brain and heart, study of dense connective tissues of the musculoskeletal system have been largely unexplored. Here, we quantify how optical clearing impacted the cell and tissue morphology of collagen-, proteoglycan-, and mineral-rich cartilage and bone from the articulating knee joint. METHODS: Water-based fructose solutions were used for optical clearing of bovine osteochondral tissues, followed by imaging with transmission and confocal microscopy. To confirm preservation of tissue structure during the clearing process, samples were mechanically tested in unconfined compression and visualized by cryo-SEM. RESULTS: Optical clearing enhanced light transmission through cartilage, but not subchondral bone regions. Fluorescent staining and immunolabeling was preserved through sample preparations, enabling imaging to cartilage depths five times deeper than previously reported, limited only by the working distance of the microscope objective. Chondrocyte volume remained unchanged in response to, and upon the reversal, of clearing. Equilibrium modulus increased in cleared samples, and was attributed to exchange of interstitial fluid with the more viscous fructose solution, but returned to control levels upon unclearing. In addition, cryo-SEM-based analysis of cartilage showed no ultrastructural changes. CONCLUSION: We anticipate large-scale microscopy of diverse connective tissues will enable the study of intact, 3D interfaces (e.g., osteochondral) and cellular connectivity as a function of development, disease, and regeneration, which have been previously hindered by specimen opacity. PMID- 25454374 TI - Acupuncture for analgesia in veterinary medicine. AB - Acupuncture for analgesia is growing rapidly in popularity with veterinarians and pet owners. This article summarizes the mechanisms of analgesia derived from acupuncture and reviews current literature on the topic. Areas covered include the local effects at area of needle insertion, systemic effects secondary to circulating neurotransmitters and changes in cell signaling, central nervous system effects including the brain and spinal cord, and myofascial trigger point and pathology treatment. Clinical applications are discussed and suggested in each section. When used by appropriately trained professionals, acupuncture offers a compelling and safe method for pain management in our veterinary patients and should be strongly considered as a part of multimodal pain management plans. PMID- 25454375 TI - Introduction to myofascial trigger points in dogs. AB - In dogs, muscles make up 44%-57% of total body weight and can serve as source of both pain and dysfunction when myofascial trigger points are present. However, rarely is muscle mentioned as a generator of pain in dogs, and even less mentioned is muscle dysfunction. The veterinary practitioner with interest in pain management, rehabilitation, orthopedics, and sports medicine must be familiar with the characteristics, etiology, and precipitating factors of myofascial trigger points. Additionally, the development of examination and treatment skill is needed to effectively manage myofascial trigger points in dogs. PMID- 25454376 TI - Introduction to therapeutic lasers in a rehabilitation setting. AB - Laser therapy, or photobiostimulation, is becoming a popular modality in the animal rehabilitation setting. It is used widely for the treatment of pain reduction, reduction of inflammation, and wound care and healing. Applications in the rehabilitation setting include postoperative cases, osteoarthritis, treatment of pain of a known origin, soft tissue injuries, and wounds. PMID- 25454377 TI - Massage therapy for dogs and cats. AB - Massage is gaining recognition as a beneficial modality for the treatment of many ailments due to recent scientific research in humans. We can infer that these benefits apply to dogs and cats due to their similar physiology and anatomy. Defined as the therapeutic manipulation of soft tissues, massage has many effects on muscle, the circulatory system, the autonomic nervous system, and the mind. Various techniques are employed to achieve a desired effect in the treatment of many conditions, including but not limited to, swelling and edema, critical illness and prolonged recumbency, osteoarthritis and chronic pain, and palliative and hospice care. This article reviews the above topics and encourages the practitioner to seek out expert advice on massage in the care of companion animals. PMID- 25454378 TI - Does atrial fibrillation cause dementia? PMID- 25454379 TI - Colchicine for pericarditis. AB - Colchicine is one of the oldest available drugs. It has been used for centuries to treat and prevent gouty attacks and more recently to prevent attacks of autoinflammatory diseases such as Familial Mediterranean Fever. Its main mechanism of action is the capability to block the polymerization of tubulin, thus affecting the function of microtubules. The capability to concentrate in white blood cells, especially granulocytes, and interfere with their function explains its potentiality as an anti-inflammatory drug. Colchicine (0.5mg twice daily for patients >70kg or once daily for those weighing less) in addition to standard anti-inflammatory therapy, in either acute or recurrent pericarditis, may hasten the response to anti-inflammatory therapy and reduce the subsequent risk of recurrences. After exclusion of contraindication and appropriate dose adjustment, the drug is safe and well tolerated. The more common side effect is gastrointestinal intolerance occurring in 5-10% of cases and may be controlled by dose reduction or temporary discontinuation. PMID- 25454380 TI - Obesity-related cardiomyopathy is an adipocyte-mediated paracrine disease. PMID- 25454381 TI - J-wave syndrome(s). PMID- 25454382 TI - Maternal obesity and immune dysregulation in mother and infant: A review of the evidence. AB - Obesity is a worldwide public health epidemic. Increasing numbers of reproductive age women enter pregnancy overweight or obese and there is now convincing data that this adverse in utero environment impacts both fetal and lifelong development. Epidemiologic evidence has shown a simultaneous increase in obesity and asthma rates in developed countries and maternal obesity is a risk factor for infant asthma and wheeze. Here we review the state of research linking maternal obesity and immunomodulation in both mother and infant, with specific attention to the relationship between maternal obesity and offspring asthma. We will also propose several different mechanisms by which maternal obesity may predispose offspring to this chronic condition and briefly summarize interventions that have been trialed to limit this association. PMID- 25454383 TI - [Concomitant chemoradiotherapy for muscle-invasive bladder cancer: current knowledge, controversies and future directions]. AB - Radical cystectomy with lymphadenectomy is currently the standard of care for muscle-invasive urothelial bladder cancer; however and because of its morbidity and its impact on quality of life, there is a growing tendency for bladder sparing strategies. Initially reserved for elderly or unfit patients unable to undergo radical cystectomy, chemoradiotherapy became a true alternative to surgery for highly selected patients. Although there are no randomized trials comparing radical cystectomy with bladder preserving approaches, surgery remains the preferred treatment for many clinicians. Furthermore, comparison is even more difficult as modalities of radiotherapy are not consensual and differ between centers with a variability of protocols, volume of irradiation and type of chemotherapy. Several ongoing trials are attempting to optimize chemoradiotherapy and limit its toxicity, especially through techniques of adaptive radiotherapy or targeted therapies. PMID- 25454384 TI - The chestnut blight fungus for studies on virus/host and virus/virus interactions: from a natural to a model host. AB - The chestnut blight fungus, Cryphonectria parasitica, is an important plant pathogenic ascomycete. The fungus hosts a wide range of viruses and now has been established as a model filamentous fungus for studying virus/host and virus/virus interactions. This is based on the development of methods for artificial virus introduction and elimination, host genome manipulability, available host genome sequence with annotations, host mutant strains, and molecular tools. Molecular tools include sub-cellular distribution markers, gene expression reporters, and vectors with regulatable promoters that have been long available for unicellular organisms, cultured cells, individuals of animals and plants, and certain filamentous fungi. A comparison with other filamentous fungi such as Neurospora crassa has been made to establish clear advantages and disadvantages of C. parasitica as a virus host. In addition, a few recent studies on RNA silencing vs. viruses in this fungus are introduced. PMID- 25454385 TI - Implementing a clinical practice guideline for the treatment of bronchiolitis in a high-risk Hispanic pediatric population. AB - INTRODUCTION: Bronchiolitis is the leading cause of hospitalization among infants and young children. Because of its frequency, a clinical practice guideline for bronchiolitis was implemented in this population in an effort to decrease costs and the number of diagnostic evaluations performed and medications used without increasing length of stay or transfers to the pediatric intensive care unit. METHODS: A retrospective chart review of 322 pediatric admissions to a rural community hospital was conducted (169 before guideline implementation and 153 after guideline implementation), and data were categorically stratified into three groups for comparison purposes. Descriptive statistics were used to analyze the data, with a p value < .05 defining significance. RESULTS: During the project period, patients with a mean age of 9.6 months were admitted to the hospital with bronchiolitis. Statistically significant decreases in cost per day and decreases in use of antibiotics and chest radiographs were achieved without increasing length of stay or pediatric intensive care unit transfers. DISCUSSION: This project demonstrated feasibility in implementing an evidence-based clinical practice guideline in a rural hospital to improve patient outcomes. PMID- 25454387 TI - Calcified constrictive pericarditis. PMID- 25454386 TI - The relationship among playground areas and physical activity levels in children. AB - INTRODUCTION: Almost 20% of American children aged 6 to 11 years are obese. A decrease in physical activity has been associated with an increase in obesity. The school environment is one place where many children can be reached. This cross-sectional study determined which types of playground areas attract children and promote moderate to vigorous physical activity (MVPA) or sedentarism. METHOD: Children on two urban elementary school playgrounds (one of which offered a jogging program called Jog and Walk Stars [JAWS]) were observed before school with use of the System for Observing Play and Leisure Activity in Youth and System for Observing Play and Recreation in Communities observational tools. Descriptive statistics, paired-samples t tests, and independent-samples t tests were used to analyze the data. RESULTS: The highest populated areas for schools K and B on non-JAWS days were the general blacktop areas; however, approximately 50% of the children in these areas were sedentary. At school B on days when the JAWS program was offered, the highest populated area was the JAWS track, and 99% of those children participated in MVPA. There was a significant difference in counts for average total sedentary children per square foot between school K (M = 216.70) and school B on JAWS days: M = 80.38, t (22.02) = 2.24, p < .5, two tailed. DISCUSSION: A playground environment assessment to identify areas that promote MVPA, such as offering a JAWS program, may be one avenue to address the need for increasing MVPA levels in children in general, in addition to physical education class, and help them obtain the recommended 60 minutes of daily MVPA. PMID- 25454388 TI - Influence of soil composition on the major, minor and trace metal content of Velebit biomedical plants. AB - The use of medical herbs for the treatment of many human diseases is increasing nowadays due to their mild features and low side effects. Not only for their healing properties, but also for their nutritive value supplementation of diet with various herbs is recommended. Thus also their analysis is of rising importance. While total elemental compositions are published for many common herbs, the origin of toxic as well as beneficial elements is not yet well investigated. Thus different indigenous medicinal plants, namely Croatian spruce (Picea abies), savory (Satureja montana L.), mountain yarrow (Achillea clavennae), showy calamint (Calamintha grandiflora), micromeria (Micromeria croatica), yellow gentian (Gentiana lutea) and fir (Abies alba) together with soil samples were collected in the National Park Northern Velebit. The macro- and trace elements content, after microwave digestion, was determined by inductively coupled plasma-atomic emission spectroscopy (ICP-AES) and inductively coupled plasma mass spectroscopy (ICP-MS). The study focuses on the one hand on essential elements and on the other hand on non-essential elements which are considered as toxic for humans, covering in total Al, As, B, Ba, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, Pb, Sr and Zn. PMID- 25454389 TI - Urinary tract development: a model of cellular and molecular morphogenesis. PMID- 25454390 TI - Tight junctions in health and disease. PMID- 25454391 TI - A nationwide survey of opsoclonus-myoclonus syndrome in Japanese children. AB - BACKGROUND: Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disease characterized by opsoclonus, myoclonus, ataxia, and behavioral changes. The aim of our study was to investigate the epidemiological characteristics of OMS in Japan and to clarify the association between therapy and prognosis. METHODS: We retrospectively collected the data from 626 Japanese medical institutions from 2005 to 2010, and analyzed the clinical features of pediatric patients with OMS based on the data. RESULTS: In this survey, there were 23 patients (10 males and 13 females). The median ages at the disease onset and the time of study were 16.5 months (range: 11-152 months) and 54 months (range: 24-160 months), respectively. The principal symptoms were opsoclonus (23 patients, 100%), myoclonus (21 patients, 91.3%), and ataxia (23 patients, 100%). The related factors were neuroblastoma (10, 43.5%), infection (9, 39.1%), and immunization (2, 8.7%). The treatments for OMS were included intravenous immunoglobulin (17, 73.9%), methylprednisolone pulse (13, 56.5%), oral prednisolone (12 patients, 52.2%), and chemotherapy and/or operation for the underlying tumors (6, 26.1%), and rituximab (2, 8.7%). Complete remissions were obtained in 35.3%, 23.1%, 33.3%, 66.7%, and 100% of these treatments, respectively. At the latest follow-up period, 8 (34.8%) and 17 patients (73.9%) showed neurological sequelae of motor and intellectual functions, respectively. Patients whose treatment was started more than 30 weeks after the disease onset suffered from the severest neurological sequelae (OMS severity 4) more frequently than those less than 30 weeks (p=0.022). CONCLUSION: The annual incidence of OMS was estimated to be 0.27-0.40 cases per million in Japanese children. More than 70% of OMS patients had neurological sequelae, especially intellectual function. Early effective treatments within 30 weeks after the onset may be required to prevent the serious neurological outcome. PMID- 25454392 TI - Holoprosencephaly with cerebellar vermis hypoplasia in 13q deletion syndrome: Critical region for cerebellar dysgenesis within 13q32.2q34. AB - We describe two unrelated patients with terminal deletions in the long arm of chromosome 13 showing brain malformation consisting of holoprosencephaly and cerebellar vermis hypoplasia. Array comparative genomic hybridization analysis revealed a pure terminal deletion of 13q31.3q34 in one patient and a mosaic ring chromosome with 13q32.2q34 deletion in the other. Mutations in ZIC2, located within region 13q32, cause holoprosencephaly, whereas the 13q32.2q32.3 region is associated with cerebellar vermis hypoplasia (Dandy-Walker syndrome). The rare concurrence of these major brain malformations in our patients provides further evidence that 13q32.2q32.3 deletion, harboring ZIC2 and ZIC5, leads to cerebellar dysgenesis. PMID- 25454393 TI - An increased B-type natriuretic peptide in the absence of a cardiac abnormality identifies those whose left ventricular mass will increase over time. AB - OBJECTIVES: The purpose of this study was to identify the relationship of B-type natriuretic peptide (BNP) with evolution of left ventricular mass (LVM) in optimally treated primary prevention patients. BACKGROUND: Patients who have an elevated BNP no cardiac abnormality on echocardiography are common and at increased risk of adverse events. One hypothesis is that an elevated BNP is an early sensitive indicator of who will develop future structural abnormalities such as left ventricular (LV) hypertrophy. METHODS: We identified optimally treated primary prevention patients with no cardiac abnormality at baseline. In particular, they had no myocardial ischemia, LV hypertrophy, LV dysfunction, or left atrial enlargement. They had a diverse range of plasma BNP levels and underwent cardiac magnetic resonance at baseline and 3 years later on a 3-T scanner. RESULTS: Fifty patients with a diverse range of BNP were studied (with BNP <= 10 pg/ml in 25 patients and >10 pg/ml in 25 patients). LVM increased (+4.7 +/- 3.5 g) in 24 patients and decreased (-4.9 +/- 2.8 g) in 26 patients (p < 0.01). Blood pressure by 24-h monitoring was virtually identical between those whose LVM increased (systolic blood pressure 122 +/- 14 mm Hg) and those whose LVM decreased (systolic blood pressure 121 +/- 11 mm Hg, p = 0.77). Plasma BNP was nearly 3 times higher in those whose LVM increased versus those in whom LVM decreased (21 +/- 9.6 pg/ml vs. 7.9 +/- 3.9 pg/ml, p < 0.01). The c-statistic for BNP was 0.88. CONCLUSIONS: In optimally treated primary prevention patients, plasma BNP levels are able to distinguish between those whose LVM will increase during the next 3 years versus those whose LVM will decrease during the next 3 years. This may explain why individuals with high BNP are at increased risk even if no cardiac abnormality can be detected initially. PMID- 25454394 TI - Delineating survival outcomes in children <10 kg bridged to transplant or recovery with the Berlin Heart EXCOR Ventricular Assist Device. AB - OBJECTIVES: The goal of this study was to delineate outcomes of children weighing <10 kg supported with the Berlin Heart EXCOR Pediatric Ventricular Assist Device (EXCOR Pediatric, Berlin Heart Inc., The Woodlands, Texas) and to identify factors that increased the risk of all-cause mortality in this population. BACKGROUND: Ventricular assist devices have been shown to be an effective bridge to transplant, with improved outcomes compared with use of extracorporeal membrane oxygenation. Smaller patients may be at greatest risk for poor outcomes, but it remains unclear if mortality is uniform across all smaller candidates. METHODS: Patients included in the analysis were part of a multicenter prospective cohort study examining the use of the Berlin Heart EXCOR Pediatric Ventricular Assist Device as a bridge to transplant. All children who received the device between May 9, 2007 and December 31, 2010, and who were enrolled in the sponsor's U.S. regulatory database, were identified and analyzed. Multivariable analysis was performed to determine risk factors associated with mortality. RESULTS: A total of 97 children weighing <10 kg were included (median age 6.2 months; median weight 6.2 kg; median duration of support 26 days). Successful outcomes were achieved in 56.7% of patients. Independent risk factors for mortality in smaller children included pre-existing congenital heart disease (odds ratio: 4.8 [95% confidence interval: 1.5 to 15.0]; p = 0.007) and an elevated bilirubin level (odds ratio: 5.3 [95% confidence interval: 2.0 to 14.3]; p = 0.001). CONCLUSIONS: Overall results for children weighing <10 kg were inferior to those of their larger counterparts. This outcome was primarily influenced by congenital heart disease and presence of elevated pre-implant bilirubin levels. These factors should be taken into consideration at decision making because reasonable outcomes can be achieved in a select population of children weighing <10 kg. PMID- 25454395 TI - Treatment of dissecting aneurysms of the PICA: anatomical considerations and clinical outcome. AB - BACKGROUND AND PURPOSE: Posterior inferior cerebellar artery (PICA) dissecting aneurysms require rapid and aggressive treatment by sacrificing the parent vessel of the aneurysm-bearing dissected vessel. We assessed the clinical consequences of PICA occlusion in view of the local vascular anatomy. MATERIALS AND METHODS: We performed a retrospective search of our neurovascular database in the period 2007-2012. Patient characteristics, including clinical presentation, WFNS (World Federation of Neurosurgical Societies) grading and Glasgow Outcome Scale (GOS), were recorded. CT and CT angiographic findings as well as the detailed vascular anatomy including collateral circulation were assessed. RESULTS: We identified 10 patients (5 male; mean age 50 years). Eight patients presented with WFNS grade I and II, one with grade IV and one with grade V. All patients were treated with parent vessel occlusion (PVO). An extradural PICA origin was seen in three patients. Collateral circulation was visible before PVO in two and after PVO in seven additional patients. Despite the presence of collaterals, mild cerebellar ischemia occurred in three patients, without development of a Wallenberg syndrome. Outcome was favorable in 9 patients (8 patients GOS 5, one patient GOS 4). One patient died due to the mass effect of the initial cerebellar hematoma. CONCLUSION: PVO to treat PICA dissecting aneurysms was well tolerated with a 90% favorable outcome. Regional collateral circulation and vascular variations permitted relative safe vessel occlusion with only minor cerebellar symptoms in this small group of patients. PMID- 25454396 TI - Extensive acute toxic leukoencephalopathy induced by fludarabine: two months follow-up on brain MRI. PMID- 25454397 TI - Pilocytic astrocytoma presenting with atypical features on magnetic resonance imaging. AB - Pilocytic astrocytoma, which is classified as a grade I astrocytic tumor by the World Health Organization, is the most common type of glioma in children and young adults. Pilocytic astrocytoma generally appears as a well-circumscribed, contrast-enhancing lesion, frequently with cystic components on magnetic resonance imaging (MRI). However, it has been reported that the MRI appearance of pilocytic astrocytoma may be similar to that of high-grade gliomas in some cases. We here report on 6 cases of pilocytic astrocytoma with atypical MRI findings, including small cyst formation, heterogeneously enhancing tumor nodules, irregularly enhancing tumor nodules, and enhancing tumor nodules with internal hemorrhage. All tumors were successfully resected, and the histological diagnoses were pilocytic astrocytoma. When the tumor is located near a cerebral cistern or ventricle, the risk of leptomeningeal dissemination is increased. Furthermore, partial resection has also been associated with a higher risk of recurrence and leptomeningeal dissemination. To date, all but one patient are alive and recurrence-free. Because the preoperative diagnosis influences the decision on the extent of resection and because of the high risk of leptomeningeal dissemination associated with these tumors, careful and correct diagnosis by MRI is important. PMID- 25454398 TI - Detection and characterization of unruptured intracranial aneurysms: Comparison of 3T MRA and DSA. AB - PURPOSE: To compare magnetic resonance angiography (MRA) at 3 Tesla (3T) and digital subtraction angiography (DSA) for the detection and characterization of unruptured intracranial aneurysms (UIA). MATERIALS AND METHODS: This study has been approved by our local ethical committee. From February to August 2010, 40 consecutive patients with UIA contemporarily underwent MRA at 3T including time of-flight (TOF-MRA) and contrast enhanced (CE-MRA) techniques and DSA. MR images were independently reviewed by 3 radiologists and DSA images were reviewed by 2 radiologists together. Interobserver and intertechnique agreements were assessed for aneurysm detection and characterization including maximal diameter, neck width and the presence of a bleb or a branch arising from the sac. RESULTS: DS angiography revealed 56 aneurysms. Mean sensitivity and positive predictive value of MRA were 91.4% and 93.4% respectively. For UIA < 3 mm and those >= 3 mm, MRA had a mean sensitivity of 74.1% and 100% respectively. Intertechnique and interobserver agreements were substantial for the measurement of UIA maximal diameter (mean kappa, 0.607 and 0.601 respectively) and were moderate and fair for neck width measurement respectively (mean kappa, 0.456 and 0.285 respectively). For bleb detection, intertechnique and interobserver agreements were fair and slight respectively (mean kappa, 0.312 and 0.116 respectively) whereas both were slight for detection of branches arising from the sac (mean kappa, 0.151 and 0.070 respectively). CONCLUSION: MR angiography at 3T has a high sensitivity for the detection of UIA. However, it remains significantly inferior to DSA for morphological characterization of UIA. PMID- 25454399 TI - Reversible white matter edema in dialysis disequilibrium syndrome. PMID- 25454400 TI - Therapeutic efficacy of brain imaging in acute ischemic stroke patients. AB - This article reviews main pathological findings in ischemic stroke patients as imaged with CT, CTA, MRI, and MRA and discusses its clinical effectiveness on different levels: technical, diagnostic accuracy, impact on diagnosis and treatment decisions affecting patient clinical outcome. It emphasizes the importance of detecting ischemic brain tissue damage (infarction) early during a time period when reperfusion therapy may be beneficial and provides evidence that brain tissue hypoattenuation as displayed by non-enhanced CT represents net water uptake (ionic edema) that is highly accurate in defining brain tissue that will not recover with reperfusion whereas MRI is highly sensitive in detecting patterns of ischemic brain tissue even in stages that allow functional recovery. PMID- 25454401 TI - Computed tomography angiography source images closely reflect the integrity of collateral circulation. AB - BACKGROUND: We studied the interplay between collateral circulation, the location of the thrombus and infarct extent based on evaluation of CT angiography source images (CTA-SI) in predicting the clinical outcome of patients treated with intravenous thrombolytic therapy (<3h) in a retrospective cohort. METHODS: Anterior circulation occlusion was detected with CTA in 105 patients. The site of the occlusion was recorded, collaterals were assessed with Collateral Score (CS) and Alberta Stroke Program Early CT Score (ASPECTS) was evaluated from CTA-SI, and entered into logistic regression analysis to predict favorable clinical outcome (three-month modified Rankin Scale 0-2). RESULTS: CTA-SI ASPECTS was highly correlated with CS (Spearman's rho=0.63, P=0.01). Not a single patient with good collaterals (CS 2-4) had a poor CTA-SI scan (ASPECTS 0-7). The mean CTA SI ASPECTS score became progressively lower when the status of the collateral circulation deteriorated (ANOVA P<0.001). In univariate analysis a good CTA-SI scan at the admission predicted favorable three-month outcome (P<0.001). In a multivariate model containing CTA-SI ASPECTS, CS and the site of the occlusion along with significant clinical parameters, CTA-SI ASPECTS was rendered non significant (P=0.43) in the presence of CS. CONCLUSIONS: CTA-SI and CS convey overlapping information. CTA-SI is not a significant predictor of the clinical outcome three months after intravenous thrombolysis when the other CTA-based parameters, CS and the clot location, are considered simultaneously. CTA-SI may have a role in the assessment of the extent of irreversible ischemic changes at admission if contrast injection and image acquisition protocols are designed suitably. PMID- 25454403 TI - Editorial overview: anti-infectives: towards novel antiviral and antibacterial drugs? Current approaches to address a growing medical need. PMID- 25454402 TI - Reversible pseudo-tumoral brain lesion in patient with focal status epilepticus. PMID- 25454404 TI - Editorial overview: new technologies: how to put everything you need in a tiny pack and track its delivery? PMID- 25454405 TI - National record linkage study of mortality for a large cohort of opioid users ascertained by drug treatment or criminal justice sources in England, 2005-2009. AB - BACKGROUND: Globally, opioid drug use is an important cause of premature mortality. In many countries, opioid using populations are ageing. The current study investigates mortality in a large cohort of opioid users; with a focus on testing whether excess mortality changes with age. METHODS: 198,247 opioid users in England were identified from drug treatment and criminal justice sources (April, 2005 to March, 2009) and linked to mortality records. Mortality rates and standardised mortality ratios (SMRs) were calculated by age-group and gender. RESULTS: There were 3974 deaths from all causes (SMR 5.7, 95% Confidence Interval: 5.5 to 5.9). Drug-related poisonings (1715) accounted for 43% of deaths. Relative to gender-and-age-appropriate expectation, mortality was elevated for a range of major causes including: infectious, respiratory, circulatory, liver disease, suicide, and homicide. Drug-related poisoning mortality risk continued to increase beyond 45 years and there were age-related increases in SMRs for specific causes of death (infectious, cancer, liver cirrhosis, and homicide). A gender by age-group interaction revealed that whilst men have a greater drug-related poisoning mortality risk than women at younger ages, the difference narrows with increasing age. CONCLUSION: Opioid users' excess mortality persists into old age and for some causes is exacerbated. This study highlights the importance of managing the complex health needs of older opioid users. PMID- 25454406 TI - What we know, and don't know, about the impact of state policy and systems-level interventions on prescription drug overdose. AB - BACKGROUND: Drug overdose deaths have been rising since the early 1990s and is the leading cause of injury death in the United States. Overdose from prescription opioids constitutes a large proportion of this burden. State policy and systems-level interventions have the potential to impact prescription drug misuse and overdose. METHODS: We searched the literature to identify evaluations of state policy or systems-level interventions using non-comparative, cross sectional, before-after, time series, cohort, or comparison group designs or randomized/non-randomized trials. Eligible studies examined intervention effects on provider behavior, patient behavior, and health outcomes. RESULTS: Overall study quality is low, with a limited number of time-series or experimental designs. Knowledge and prescribing practices were measured more often than health outcomes (e.g., overdoses). Limitations include lack of baseline data and comparison groups, inadequate statistical testing, small sample sizes, self reported outcomes, and short-term follow-up. Strategies that reduce inappropriate prescribing and use of multiple providers and focus on overdose response, such as prescription drug monitoring programs, insurer strategies, pain clinic legislation, clinical guidelines, and naloxone distribution programs, are promising. Evidence of improved health outcomes, particularly from safe storage and disposal strategies and patient education, is weak. CONCLUSIONS: While important efforts are underway to affect prescriber and patient behavior, data on state policy and systems-level interventions are limited and inconsistent. Improving the evidence base is a critical need so states, regulatory agencies, and organizations can make informed choices about policies and practices that will improve prescribing and use, while protecting patient health. PMID- 25454407 TI - Personality as a risk factor for illicit opioid use and a protective factor for illicit opioid dependence. AB - BACKGROUND: Most studies investigating the role of personality as a risk factor for the development of opioid dependence compare dependent opioid users with healthy controls who never used heroin. In order to understand the potential protective role of personality, it is crucial to compare illicit opioid users who never became dependent with dependent opioid users. AIMS: This study aims to examine the role of personality as a risk factor for opioid use and as a protective factor for the development of opioid dependence. METHODS: Comparing personality factors between three groups: (1) 161 never-dependent illicit opioid users who have been using illicit opioids but never became opioid dependent; (2) 402 dependent opioid users in methadone maintenance treatment or heroin-assisted treatment; and (3) 135 healthy controls who never used heroin. Personality was assessed with a short version of Cloninger's Temperament and Character Inventory. RESULTS: Never-dependent opioid users reported more Novelty Seeking and Harm Avoidance and less Self-Directedness and Cooperativeness than healthy controls and more Reward Dependence and Self-Directedness, and less Harm Avoidance than dependent opioid users. Furthermore, never-dependent opioid users reported more Self-Transcendence than both dependent opioid users and healthy controls. CONCLUSIONS: Never-dependent opioid users may have started to use opioids partly due to their tendency to seek novel and/or spiritual experiences (high Novelty Seeking, high Self-Transcendence) and their tendency to avoid aversive stimuli (high Harm Avoidance), whereas they may have been protected against the development of dependence by their need for social approval (high Reward Dependence) and their self-efficacy (high Self-Directedness). PMID- 25454408 TI - Sources of nonmedically used prescription stimulants: differences in onset, recency and severity of misuse in a population-based study. AB - AIM: Epidemiological data indicate that nonmedical use of prescription stimulants has increased over the past decade. However, little is known regarding the source of the misused stimulants and whether different sources correspond to differences in risk profiles and associated social and health problems. METHOD: Data from the 2006 to 2011 National Survey on Drug Use and Health were used. A total of 4945 participants who used prescription stimulants nonmedically and also reported their source of misused stimulants were categorized by the source: friend/relative, physician and illegal. Logistic regression models compared the socio-demographic, mental health and behavioral problems, and stimulant use related problems (onset, recency, frequency, severity) according to the source of the misused stimulants. RESULTS: The most common sources of stimulants were friends/relatives, followed by physicians and illegal sources. Compared to participants reporting friends/relatives as the source, participants reporting an illegal source were more likely to be male, unemployed, have less than a high school education, a history of criminal behavior and an earlier age of use onset. Participants reporting a physician source were more likely to have mental health problems and mental health service use. Higher odds of past-month stimulant use, frequent use (>= 10 days per year), drug dependence and substance service use were found in individuals reporting physician and illegal sources. CONCLUSIONS: Identifying the source of misused stimulants may be useful in detecting distinct subgroups of nonmedical prescription stimulant users, which may inform development of tailored prevention and treatment programs and contribute to individual treatment planning. PMID- 25454409 TI - Assessing craving and its relationship to subsequent prescription opioid use among treatment-seeking prescription opioid dependent patients. AB - BACKGROUND: Craving is viewed as a core feature of substance use disorders and has been shown to predict future drug use, particularly over the short term. Accordingly, craving is often assessed in treatment settings as a marker of risk for subsequent drug use. The identification of the briefest measure that maintains predictive validity is of particular value for both clinical and research settings to minimize assessment burden while maintaining utility for the prediction of use. METHODS: Data from a multi-site clinical trial of treatment for prescription opioid dependence were examined to evaluate whether a brief, 3 item craving scale administered each week predicted urine-confirmed self report of prescription opioid use in the subsequent week. Logistic regression models examining the association between craving and presence or absence of opioid use in the following week were conducted, controlling for opioid use in the previous week, treatment condition, and lifetime history of heroin use. RESULTS: Greater craving was associated with a higher odds of prescription opioid use in the following week. For each one-unit increase on this 10-point scale, the odds of using opioids in the subsequent week was 17% higher. In addition to an item assessing urges, items assessing cue-induced craving and perceived likelihood of relapse in an environment where drugs were previously used contributed uniquely to this association. CONCLUSIONS: A brief measure of prescription opioid craving predicted prescription opioid use among individuals in treatment. This measure offers an efficient strategy to inform the assessment of risk for use in this population. PMID- 25454410 TI - Sex differences in drug use among polysubstance users. AB - BACKGROUND: Available evidence indicates women with substance use disorders may experience more rapid progression through usage milestones (telescoping). The few investigations of sex differences in treatment-seeking populations often focus on single substances and typically do not account for significant polysubstance abuse. The current study examined sex differences in a heterogeneous sample of treatment seeking polysubstance users. We examined patterns of drug use, age at drug use milestones (e.g., initial use, regular use), and progression rates between milestones. Nicotine and alcohol use were also evaluated. METHODS: Participants (n = 543; 288 women) completed personal histories of substance use, including chronicity, frequency, and regularity, as well as inventories assessing affect, and intellectual ability. RESULTS: Rates of drug use and milestone ages varied by sex and specific drug. Analyses suggested pronounced telescoping effects for pain medication and marijuana, with women progressing more rapidly through usage milestones. CONCLUSIONS: Our data were generally supportive of telescoping effects, although considerable variance in progression measures was noted. The contrast between the marked telescoping observed in pain medication use and the absence of telescoping in other opioids was of particular interest. The discrepancy in telescoping effects, despite shared pharmacologies, suggests the need for further work examining underlying psychosocial factors. These results highlight that the specific sample population, substance, and outcome measure should be carefully considered when interpreting sex differences in substance use. PMID- 25454411 TI - Effects of differential rearing on amphetamine-induced c-fos expression in rats. AB - BACKGROUND: Rearing rats in environmental enrichment alters psychostimulant induced locomotor activity as well as neurotransmitter expression. Exposure to novelty and psychostimulants induces c-fos expression in neurons in the mesolimbic dopamine (DA) pathway. Here we investigated changes in the expression of the immediate early gene c-fos in the mesolimbic DA pathway of enriched, isolated, or socially reared rats due to the neurobiological changes that result from rearing conditions and influence drug taking behavior. METHODS: Rats were reared in either enriched (EC), isolated (IC), or social (SC) conditions for 30 days, after which they received an acute amphetamine or saline injection (1.0 mg/kg) and locomotor activity was measured. Following immunohistochemical staining c-fos positive neurons were quantified in the NAcc, mPFC, and amygdala. RESULTS: Greater locomotor activity was observed in differentially reared rats treated with amphetamine compared to saline, as well as in SC compared to EC and IC rats. Rats reared in an IC context demonstrated greater c-fos expression than EC rats in the NAcc when treated with amphetamine, and EC saline rats demonstrated greater c-fos expression in the cingulate and prelimbic cortices compared to SC saline rats. Additionally, IC amphetamine rats displayed greater c fos expression in the NAcc compared to IC saline rats, while EC saline rats displayed greater c-fos expression in the prelimbic cortex compared to EC amphetamine rats. CONCLUSIONS: These results suggest regional specificity of psychostimulant-induced c-fos expression in the prelimbic/NAcc pathway that is altered in differential rearing, and influences initial c-fos activation following psychostimulant exposure. PMID- 25454412 TI - Bevacizumab combined with 5-FU/streptozocin in patients with progressive metastatic well-differentiated pancreatic endocrine tumours (BETTER trial)--a phase II non-randomised trial. AB - AIM OF THE STUDY: Neuroendocrine tumours are highly vascular neoplasms known to overexpress vascular endothelial growth factor (VEGF) and its receptor. Bevacizumab, an inhibitor of VEGF, was assessed in combination with chemotherapy in pancreatic neuroendocrine tumour (P-NET). PATIENTS AND METHODS: BETTER was a multicentre, open-label, non-randomised, two-group phase II trial. Patients with progressive metastatic, well-differentiated P-NET received a minimum of 6 month treatment of bevacizumab at 7.5 mg/kg IV on d1 q3w with 5-FU at 400 mg/m2/day and streptozocin at 500 mg/m2/day IV from d1 to d5 every 42 days. The primary end point was progression-free survival (PFS); secondary end-points were overall survival (OS), overall response rate, safety and quality of life. RESULTS: A total of 34 patients were included. Median age was 55 years, 65% of patients were men, 97% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and 97% had a Ki-67 proliferative index of <15%. After a maximum of 24 month follow-up per patient, the median PFS assessed by investigators was 23.7 months [95% confidence interval (CI): 13.1; not reached], 19 (56%) patients had a partial response and 15 (44%) had stable disease as best response. OS rate at 24 months was 88%. The most frequently reported grade 3-4 adverse events were hypertension (21% patients), abdominal pain (12%) and thromboembolic events (9%). CONCLUSION: Bevacizumab with 5-FU/streptozocin in the treatment of pancreatic NETs seems to be feasible with a PFS of 23.7 months, which deserves further attention. No unexpected toxicity was observed. PMID- 25454413 TI - Bevacizumab plus capecitabine in patients with progressive advanced well differentiated neuroendocrine tumors of the gastro-intestinal (GI-NETs) tract (BETTER trial)--a phase II non-randomised trial. AB - AIM OF THE STUDY: Gastro-intestinal neuroendocrine tumours (GI-NETs) are chemotherapy-resistant tumours. Bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), has shown promising results in several phase II trials of gastro-entero-pancreatic-NETs. We assessed bevacizumab combined with capecitabine, specifically in GI-NET patients. PATIENTS AND METHODS: BEvacizumab in The Treament of neuroEndocrine tumoRs (BETTER) was a multicentre, open-label, non-randomised, two-group phase II trial. Here we present the group of patients with progressive, metastatic, well-differentiated GI-NETs. Patients Eastern Cooperative Oncology Group-performance status (ECOG-PS)?2, Ki-67 proliferation rate <15% and no prior systemic chemotherapy were treated with bevacizumab (7.5 mg/kg/q3w) and capecitabine (1000 mg/m2 twice daily, orally d1-14, resumed on d22) for 6-24 months. The primary end-point was progression-free survival (PFS); secondary end-points included overall survival (OS), response rate, safety and quality of life. RESULTS: Of the 49 patients included, 53% were men, median age was 60 years (41-82), primary tumour site was ileal in 82% patients and Ki-67 was <15% in 48 patients and not available for one patient. After a maximum of 24 month follow-up per patient, the median PFS by investigator assessment was 23.4 months [95% confidence interval (CI): 13.2; not reached] and the overall disease control rate was 88% (18% partial response, 70% stable disease). The 2-year survival rate was 85%. Median OS was not reached. The most frequent grade 3-4 adverse events were hypertension (31%), diarrhoea (14%) and hand-foot syndrome (10%). CONCLUSION: The combination of bevacizumab and capecitabine showed clinical activity and a manageable safety profile in the treatment of GI-NETs that warrant confirmation in a randomised phase III trial. PMID- 25454414 TI - Fixed-dose rate gemcitabine alone or alternating with FOLFIRI.3 (irinotecan, leucovorin and fluorouracil) in the first-line treatment of patients with metastatic pancreatic adenocarcinoma: an AGEO randomised phase II study (FIRGEM). AB - BACKGROUND: Fluorouracil and irinotecan-based, and gemcitabine-based regimens, are the standard of care in the first-line treatment of patients with metastatic pancreatic cancer. New approaches are needed to improve survival and quality of life. Whether a sequential approach alternating irinotecan, fluorouracil and gemcitabine may be effective and tolerable in patients with metastatic pancreatic cancer is unknown. METHODS: In this randomised, multicentre, open-label, phase 2 trial, patients with metastatic pancreatic adenocarcinoma, World Health Organisation (WHO) performance status 0-1, and bilirubin levels <1.5 upper limit of normal values (ULN) were randomised 1:1 to receive as first-line treatment either FOLFIRI.3 (irinotecan, leucovorin and fluorouracil) alternating with fixed dose rate gemcitabine as 2-month periods (FIRGEM, arm A), or fixed-dose rate gemcitabine alone (arm B). Treatment was continued until disease progression or limiting toxicity. The primary end-point was the crude progression-free survival (PFS) rate at 6 months. The study is registered with EudraCT (N degrees 2006 005703-34). RESULTS: Between October 2007 and March 2011, 98 patients were enroled. The observed 6-month PFS rate was 43.5% (95% confidence interval (CI), [28.6-58.4%]) in arm A reaching the Fleming decision rules criteria to reject H0 and 26.1% (95% CI [12.9-39.3%]) in arm B. Objective response rates were 37% (23 51%) in arm A and 10% (1-19%) in arm B. Median PFS (5.0 versus 3.4 months, hazard ratio (HR)=0.59 [0.38-0.90]) and overall survival (11.0 versus 8.2 months, HR=0.71 [0.46-1.10]) were higher in arm A compared to arm B. The most frequent grade 3-4 toxicities were neutropenia (49%/24%; febrile neutropenia, 4%/0% in arms A/B), diarrhoea (arm A, 12% and arm B, 0%), and nausea/vomiting (8%/4%). No toxic deaths occurred. CONCLUSION: The FIRGEM strategy appears to be effective and feasible in patients with metastatic pancreatic cancer. PMID- 25454415 TI - Improved risk stratification by the integration of the revised international prognostic scoring system with the myelodysplastic syndromes comorbidity index. AB - Myelodysplastic syndromes (MDS) comprise bone marrow failure diseases with a diverse clinical outcome. For improved risk stratification, the International Prognostic Scoring System (IPSS) has recently been revised (IPSS-R). This single centre study aimed to validate the IPSS-R and to evaluate prior prognostic scoring systems for MDS. We retrospectively analysed 363 patients diagnosed with MDS according to the FAB criteria between 2000 and 2012. The IPSS, MD Anderson Risk Model Score (MDAS), World Health Organisation (WHO)-classification based Prognostic Scoring System (WPSS), refined WPSS (WPSS-R), IPSS-R and MDS Comorbidity Index (MDS-CI) were applied to 222 patients considered with primary MDS following the WHO criteria and their prognostic power was investigated. According to the IPSS-R, 18 (8%), 81 (37%), 50 (23%), 43 (19%) and 30 (13%) patients were classified as very low, low, intermediate, high and very high risk with, respectively, a median overall survival of 96 (95% Confidence interval (CI) not reached), 49 (95% CI 34-64), 22 (95% CI 0-49), 19 (95% CI 11-27) and 10 (95% CI 6-13) months (p<.000). The IPSS-R showed improved prognostic power as compared to the IPSS, MDAS, WPSS and WPSS-R. Furthermore, the MDS-CI refined the risk stratification of MDS patients stratified according to the IPSS-R. In conclusion, accounting for the disease status by means of the IPSS-R and comorbidity through the MDS-CI considerably improves the prognostic assessment in MDS patients. PMID- 25454418 TI - Photocatalytic degradation of gaseous toluene with multiphase Ti(x)Zr(1-x)O2 synthesized via co-precipitation route. AB - In the present work, the multiphase Ti(x)Zr(1-x)O2 particles containing cubic phase ZrO2 were fabricated via co-precipitation route. The mole ratios of Ti and Zr elements were controlled by three levels: Ti/Zr=7/3 (maximum), Ti/Zr=5/5 (medium), and Ti/Zr=3/7 (minimum). The materials prepared were characterized by using X-ray diffraction (XRD), field emission scanning electron microscope (FE SEM), energy-dispersive X-ray (EDX), X-ray photoelectron spectroscopy (XPS), UV vis diffuse reflectance spectra (DRS) and photoluminescence (PL) spectra. For the maximum usage of solar power with fabricated catalysts, elimination of gaseous toluene was chosen as a model to evaluate the performances under visible light. The results indicated that the degradation efficiency of toluene was about 80% after 6 h reaction using Ti(0.3)Zr(0.7)O2 as the photocatalyst. On the other hand, the multiphase Ti(x)Zr(1-x)O2 (x=0.7 or 0.5) photocatalysts showed significant enhancement in the activity, compared with the commercial TiO2 (Degussa P25). The enhanced performances of Ti(x)Zr(1-x)O2 might be attributed to the lower charge recombination rate of photoinduced electron-hole pairs. In addition, some intermediates (the benzaldehyde and benzoic acid) and final product (CO2) adsorbed on the surface of the particles were also detected by using in situ Fourier transform infrared (FTIR) spectroscopy. PMID- 25454417 TI - Saguenay Youth Study: a multi-generational approach to studying virtual trajectories of the brain and cardio-metabolic health. AB - This paper provides an overview of the Saguenay Youth Study (SYS) and its parental arm. The overarching goal of this effort is to develop trans generational models of developmental cascades contributing to the emergence of common chronic disorders, such as depression, addictions, dementia and cardio metabolic diseases. Over the past 10 years, we have acquired detailed brain and cardio-metabolic phenotypes, and genome-wide genotypes, in 1029 adolescents recruited in a population with a known genetic founder effect. At present, we are extending this dataset to acquire comparable phenotypes and genotypes in the biological parents of these individuals. After providing conceptual background for this work (transactions across time, systems and organs), we describe briefly the tools employed in the adolescent arm of this cohort and highlight some of the initial accomplishments. We then outline in detail the phenotyping protocol used to acquire comparable data in the parents. PMID- 25454419 TI - Isothermal titration calorimetric analysis on solubilization of an octane oil-in water emulsion in surfactant micelles and surfactant-anionic polymer complexes. AB - Polymers may alter the ability of surfactant micelles to solubilize hydrophobic molecules depending on surfactant-polymer interactions. In this study, isothermal titration calorimetry (ITC) was used to investigate the solubilization thermodynamics of an octane oil-in-water emulsion in anionic sodium dodecylsulphate (SDS), nonionic polyoxyethylene sorbitan monooleate (Tween 80), cationic cetyltrimethylammonium bromide (CTAB) surfactant micelles and respective complexes formed by these micelles and an anionic polymer (carboxymethyl cellulose). Results indicated that the oil solubilization in single ionic micelles was endothermic, while in nonionic micelles or mixed ionic/nonionic micelles it was exothermic. The addition of carboxymethyl cellulose did not influence the solubilization behavior in these micelles, but affected the solubilization capacities of these systems. The solubilization capacity of cationic micelles or mixed cationic/nonionic micelles was enhanced while that of nonionic or anionic micelles was decreased. Based on the phase separation model, a molecular pathway mechanism driven by enthalpy was proposed for octane solubilization in surfactant micelles and surfactant-polymer complexes. PMID- 25454420 TI - Fabrication of density-controlled graphene oxide-coated mesoporous silica spheres and their electrorheological activity. AB - A series of density-controlled graphene oxide-coated mesoporous silica spheres (GO/SiO2) are successfully synthesized to investigate the influence of the particle density on electrorheological (ER) activity. The particle density of mesoporous silica spheres is controlled by creating different sized pores via surfactant template and swelling agent incorporation method. Additionally, ball milled graphene oxide is successfully coated onto the surface of various silica spheres (SiO2) through amine-modification to enhance ER efficiency. In this study, we investigate that mesoporous silica spheres-based ER fluid (GO/epSiO2) with lowest particle density exhibit most increased ER performance, which is 3 fold higher than that of similar sized neat silica spheres-based ER fluid (GO/nSiO2) without pore. In addition, the relationship between particle density, anti-sedimentation property, and ER performance is examined by applying Stokes' law and practical sedimentation observation. Furthermore, dielectric loss model is used to clarify the influence of dielectric property on ER activity. This newly designed ER study offers insight into the influence of the particle density on the performance of ER fluids. PMID- 25454416 TI - The effects of puberty on white matter development in boys. AB - Neuroimaging studies demonstrate considerable changes in white matter volume and microstructure during adolescence. Most studies have focused on age-related effects, whilst puberty-related changes are not well understood. Using diffusion tensor imaging and tract-based spatial statistics, we investigated the effects of pubertal status on white matter mean diffusivity (MD) and fractional anisotropy (FA) in 61 males aged 12.7-16.0 years. Participants were grouped into early-mid puberty (<=Tanner Stage 3 in pubic hair and gonadal development; n=22) and late post puberty (>=Tanner Stage 4 in pubic hair or gonadal development; n=39). Salivary levels of pubertal hormones (testosterone, DHEA and oestradiol) were also measured. Pubertal stage was significantly related to MD in diverse white matter regions. No relationship was observed between pubertal status and FA. Regression modelling of MD in the significant regions demonstrated that an interaction model incorporating puberty, age and puberty*age best explained our findings. In addition, testosterone was correlated with MD in these pubertally significant regions. No relationship was observed between oestradiol or DHEA and MD. In conclusion, pubertal status was significantly related to MD, but not FA, and this relationship cannot be explained by changes in chronological age alone. PMID- 25454422 TI - Thin and transparent films of graphene/silver nanoparticles obtained at liquid liquid interfaces: preparation, characterization and application as SERS substrates. AB - We report here the synthesis and characterization of transparent and homogeneous thin films of reduced graphene oxide/silver nanoparticles (rGO/AgNPs) nanocomposites, starting from graphene oxide (GO) or reduced graphene oxide (rGO), directly obtained at a water/toluene liquid-liquid interface. Different films (obtained by varying the Ag/rGO or Ag/GO ratio) were prepared, deposited over glass or plastic substrates, and characterized by X-ray diffraction, UV-Vis and Raman spectroscopy, thermal analysis, transmission and scanning electron microscopy. Samples were evaluated as substrates for surface-enhanced Raman spectroscopy (SERS), using dilute solutions (1*10(-7) mol L(-1)) of a common probe molecule, 4-aminothiophenol (4-ATP). These materials exhibit significant high-quality SERS activity, and enhanced modes could be observed for 4-ATP, which suggested that charge transfer occurred between the Ag nanoparticles and 4-ATP molecules. PMID- 25454421 TI - Activity modulation of core and shell in nanozeolite@enzyme bi-functional catalyst for dynamic kinetic resolution. AB - A core-shell nanozeolite@enzyme bi-functional catalyst is prepared by using nanozeolite beta as acidic core and immobilized Candida antarctica lipase B (CALB) as enzyme shell for the purpose of dynamic kinetic resolution (DKR), and polydiallyldimethylammonium chloride (PDDA) is used as interlayer to compart core and shell. The activities of core and shell in bi-functional catalyst are modulated to achieve the matching between racemization and kinetic resolution (KR) rates in DKR, i.e., a slow racemization rate on core while a fast KR rate on shell. Nanozeolite beta with intermediate SiO2/Al2O3 ratio provides proper acid amount for racemization step. A relatively thick layer of PDDA not only improves the activity of CALB by its coverage for surface acidic sites but also limits the accessibility and diffusion of substrate towards the acidic core. The CALB shell with larger immobilized amount and higher enzyme activity offers enhanced driving force of DKR process, leading to higher conversion, selectivity and yield. The preparation and activity modulation of core-shell catalyst provide an ideal method to improve the catalytic performance of bi-functional catalyst. PMID- 25454423 TI - Interaction of cyclic and linear Labaditin peptides with anionic and zwitterionic micelles. AB - Conformational changes of the cyclic (Lo) peptide Labaditin (VWTVWGTIAG) and its linear analogue (L1) promoted by presence of anionic sodium dodecyl sulfate (SDS) and zwitterionic L-alpha-Lysophosphatidylcholine (LPC) micelles were investigated. Results from lambda(max) blue-shift of tryptophan fluorescence emission combined with Stern-Volmer constants values and molecular dynamics (MD) simulations indicated that L1 interacts with SDS micelles to a higher extent than does Lo. Further, the MD simulation demonstrated that both Lo and L1 interact similarly with LPC micelles, being preferentially located at the micelle/water interface. The peptide-micelle interaction elicits conformational changes in the peptides. Lo undergoes limited modifications and presents unordered structure in both LPC and SDS micelles. On the other hand, L1 displays a random-coil structure in aqueous medium, pH 7.0, and it acquires a beta-structure upon interaction with SDS and LPC, albeit with structural differences in each medium. PMID- 25454425 TI - Diglycolamic acid modified silica gel for the separation of hazardous trivalent metal ions from aqueous solution. AB - The surface of the silica gel was modified with diglycolamic acid moieties and the product (Si-DGAH) was characterized by elemental analysis, TG-DTA, (1)H and (29)Si NMR and scanning electron microscopy (SEM). The adsorption behavior of hazardous americium (III) and europium (III) in Si-DGAH was studied from aqueous nitric acid medium to examine the feasibility using the modified silica for the separation of Am(III) and Eu(III) from aqueous wastes. In this context, the effect of various parameters such as the duration of equilibration, and concentrations of europium, nitric acid, sodium nitrate and diethylenetriaminepentaacetic acid (DTPA) in aqueous phase, on the distribution coefficient (K(d)) of Am(III) and Eu(III) was investigated. The distribution coefficient of ~10(3) mL/g (>99.9% extraction) was obtained for both Am(III) and Eu(III) at pH 3, and the K(d) values decreased with increase in the concentration of nitric acid. Rapid kinetics of extraction in the initial stages of equilibration, followed by the establishment of equilibrium occurred within 30 min. The extraction data were fitted into Langmuir adsorption model and the apparent europium extraction capacity was determined. Europium loading capacity of the sorbent was determined at various feed pH by column method. The study indicated the possibility of using diglycolamic acid-modified silica for the separation of Eu(III) and Am(III) from aqueous wastes. PMID- 25454426 TI - Design and synthesis of hierarchically porous MnO2/carbon hybrids for high performance electrochemical capacitors. AB - In this study, various morphologies of manganese dioxide (MnO2), including solid spheres, yolk-shell structures, and hollow spheres, are synthesized through an ambient reaction between KMnO4 and carbon sphere. The diversity in crystal structure and morphology of these forms of MnO2 are investigated using detailed X ray diffraction (XRD), Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) observations, and a possible formation mechanism called "inward-outward growth" is proposed. Based on our experimental results, we believe that the final products form through a synergetic effect of outward diffusing carbonaceous fragments and inward diffusing aqueous KMnO4 solution. The rate of inward KMnO4 diffusion relative to the rate of outward carbon diffusion determines the morphology of the MnO2 product. Furthermore, a coated core structure consisting of an internal graphitized carbon sphere and an external MnO2 layer is successfully synthesized, which not only possesses high surface area and hierarchical porosity, but also has improved electrical conductivity. Such structural characteristics enable the obtained composite to show a specific capacitance of 583 F g(-1) at a current density of 1 A g(-1) in 0.1 M Na2SO4 electrolyte. PMID- 25454424 TI - Numerical study of homogeneous nanodroplet growth. AB - We investigate the axisymmetric homogeneous growth of 10-100 nm water nanodroplets on a substrate surface. The main mechanism of droplet growth is attributed to the accumulation of laterally diffusing water monomers, formed by the absorption of water vapour in the environment onto the substrate. Under assumptions of quasi-steady thermodynamic equilibrium, the nanodroplet evolves according to the augmented Young-Laplace equation. Using continuum theory, we model the dynamics of nanodroplet growth including the coupled effects of disjoining pressure, contact angle and monomer diffusion. Our numerical results show that the initial droplet growth is dominated by monomer diffusion, and the steady late growth rate of droplet radius follows a power law of 1/3, which is unaffected by the substrate disjoining pressure. Instead, the disjoining pressure modifies the growth rate of the droplet height, which then follows a power law of 1/4. We demonstrate how spatial depletion of monomers could lead to a growth arrest of the nanodroplet, as observed experimentally. This work has further implications on the growth kinetics, transport and phase transition of liquids at the nanoscale. PMID- 25454427 TI - The effect of gold nanoparticle size on osteogenic differentiation of adipose derived stem cells. AB - There have been many medical applications based on gold nanoparticles (GNPs) over the past several centuries. Recently, researchers have focused on bone tissue engineering applications utilizing GNPs. The effect of various sizes of gold nanoparticles on the differentiation of human adipose-derived stem cells (ADSCs) into osteoblasts was investigated. The concentration of gold nanoparticles was fixed at 1 MUM and varying sizes of 15, 30, 50, 75 and 100 nm (spherical GNPs) were used. The lack of cytotoxicity was confirmed by establishing viability of ADSCs using cell counting kit-8 (CCK-8) and live/dead assays. The results showed that each size of GNPs had no significant toxicity on ADSCs during 1 week of incubation. Osteogenic differentiation of ADSCs was confirmed by alkaline phosphatase (ALP) staining, ALP activity, calcium deposition, and real time PCR experiments. It was found, through dark field assays and microscope cell images, that 30 nm and 50 nm GNPs were preferentially up taken into the ADSCs. As expected, all sizes of gold nanoparticles promoted the differentiation of ADSCs toward osteoblasts more than control. Among all sizes, 30 and 50 nm GNPs appeared to have the highest differentiation rates. The data consistently demonstrated that 30 and 50 nm GNPs are the most effective in promoting osteogenic differentiation of ADSCs. PMID- 25454428 TI - Two-component self-assembly with solvent leading to "wet" and microcrystalline organogel fibers. AB - HYPOTHESIS: The microcrystalline fibers of N-(2-aminoethyl)-3alpha-hydroxy-5beta cholan-24-amide 1 provided a useful model system for studying the complex relationship between morphology, experimental parameters, solvent, and the phenomenon of organogelation. The presence of solvents in the solid forms of 1 along with crystallization behavior suggested solvate formation and polymorphic behavior. EXPERIMENTS: Forty solid state- and xerogel samples of 1 formed in organic solvents and in three categories of experimental conditions were analyzed with single crystal X-ray diffraction (XRD), powder X-ray diffraction (PXRD), Raman microscopy, and attenuated total reflection Fourier-transform infrared spectroscopy (ATR FTIR). FINDINGS: Two polymorphs and four isostructural aromatic solvates of 1 were found among some unknown forms in the samples. Single crystal X-ray structures of one polymorph and bromobenzene solvate were obtained, the latter from a xerogel. Multiple crystal forms could be present in a sample, and their contributions to gelation were estimated taking the experimental conditions into account. Gelator 1 could act as a variable component gelator, either alone or in combination with an aromatic solvent. The research brings new insight into the structures of microcrystalline organogel fibers, linking solvate/inclusion crystal formation with microcrystalline fibers of an organogelator for the first time. PMID- 25454429 TI - Fenton-like oxidation of 2,4-DCP in aqueous solution using iron-based nanoparticles as the heterogeneous catalyst. AB - In this report, various iron-based nanoparticles (nZVI, n-Ni/Fe, n-Pd/Fe) were used for both heterogeneous Fenton oxidation of 2,4-dichlorophenol (2,4-DCP) and reductive dechlorination of 2,4-DCP in order to understand their roles in the Fenton oxidation and the reductive degradation of 2,4-DCP. The dechlorination efficiency of 2,4-DCP using nZVI, n-Ni/Fe, n-Fe/Pd and Fe(2)(+) was 6.48%, 6.80%, 15.95%, 5.02%, while Fenton oxidation efficiency of 2,4-DCP was 57.87%, 34.23%, 27.94%, 19.61% after 180 min, respectively. The new findings included a higher dechlorination using n-Fe/Pd due to Pd effective catalysis and the effective heterogeneous Fenton oxidation using nZVI depending on reductive dechlorination and heterogeneous Fenton oxidation occurs simultaneously. However, nZVI as the potential catalyst for heterogeneous Fenton was observed, and SEM, EDS and XRD demonstrate that change on the nZVI surface occurred due to the Fe(2+) leaching, and Total Organic Carbon (TOC) (30.71%) shows that 2,4-DCP was degraded. Furthermore, the experiment indicates that the pH values and concentration of 2,4 DCP significantly impacted on the heterogeneous Fenton oxidation of 2,4-DCP and the data fits well with the pseudo first-order kinetic model, which was a diffusion-controlled reaction. Finally, a possible mechanism for degradation of 2,4-DCP was proposed. PMID- 25454430 TI - Polyelectrolyte complex-silica hybrid colloidal particles decorated with different polyelectrolytes. AB - We report the synthesis of polyelectrolyte-decorated hybrid colloidal particles by using negatively charged polyelectrolyte complex (PEC) micelles as colloidal templates for silica mineralization under ambient conditions. The negatively charged polyelectrolytes including poly(acrylic acid) (PAA), poly(L-glutamic acid) (PLGA), and poly(styrene sulfonate) (PSS) were complexed with poly(L lysine) at non-stoichiometric mixing weight percentage to form negatively charged PEC micelles. Varying the mixing weight percentage and molecular weight of polyelectrolytes led to the changes in the size and charge of the PEC particles. Silica mineralization in the complex core resulted in the colloidally stable hybrid particles decorated with different negatively charged polyelectrolytes. The colloidal properties of these polyelectrolyte-decorated hybrid particles were determined by the composition and decorated polyelectrolyte. This approach provided a simple and facile method to prepare polymer-decorated hybrid colloidal particles comprised of different polymers and their colloidal properties can be easily tuned by varying the decorated polymer and synthesis condition. PMID- 25454431 TI - Synthesis of sputter deposited CuO nanoparticles and their use for decontamination of 2-chloroethyl ethyl sulfide (CEES). AB - We report the synthesis of copper oxide (CuO) nanoparticles by dc magnetron sputtering for adsorptive degradation of 2-chloroethyl ethyl sulfide (CEES), a simulant of well-known chemical warfare agent sulfur mustard (HD). The synthesized CuO nanoparticles were characterized by XRD, TEM, FE-SEM, N2-BET, FT IR and TGA. The average particle size calculated from XRD pattern was found to be 7 nm for as-deposited and varied up to 86 nm after postannealing. The particle size was also calculated through TEM analysis. The surface area of the particles (~110-36 m(2)/g) is found to be enhanced significantly in comparison with reported in the literature. Degradation kinetics of CEES was investigated over the CuO nanoparticles and it was found that dc sputtered CuO nanoparticles give superior decontamination properties against CEES. The reactions seemed to be first order with rate constant (k) and half-life (t(1/2)) values in the range of 0.434-0.134 h(-1) and 1.59-5.17 h respectively. The reaction products were characterized by GC-MS and verified through FT-IR. The data reveal the role of hydrolysis reactions in the decontamination of CEES. PMID- 25454432 TI - Synthesis and self-assembly of chitosan-g-polystyrene copolymer: a new route for the preparation of heavy metal nanoparticles. AB - Amphiphilic graft copolymers made of a Chitosan (CS) backbone and three arm polystyrene (PS) grafts were prepared by "grafting onto" strategy using Toluene Diisocyanate. IR spectroscopy and SEC show the successful grafting process. SEM pictures of Chitosan-g-Polystyrene (CS-g-PS) indicate a spherulite like surface and exhibit properties that result from the disappearance of Chitosan crystallinity. The introduced polystyrene star grafts units improve hydrophobic properties considerably as confirmed by the very high solubility of (CS-g-PS) in organic solvents. The graft copolymer which self-assembles into polymeric micelles in organic media demonstrates much better adsorption of transition and inner transition metal ions than pure Chitosan whose amine groups are not necessarily available due to crystallinity. PMID- 25454433 TI - Realization of high sensitive SERS substrates with one-pot fabrication of Ag Fe3O4 nanocomposites. AB - Ag-Fe3O4 nanocomposites were synthesized by the redox reaction between Ag2O and Fe(OH)2 in the absence of additional reductant at moderate temperature and atmospheric condition. The as-synthesized Ag-Fe3O4 nanocomposites are assembled into an orderly arrayed SERS substrate holding clean and reproducible properties with an applied external magnetic field. 4-mercaptobenzoic acid (4-MBA) is chosen as the probe molecule to test the enhancement factors (EF), uniformity and reproducibility of the SERS substrate. Experimental results indicate that the EF of 4-MBA on our proposed SERS substrate is up to 5.2*10(6) and the detection limit is down to ~10(-10) M. The SERS spectra of 4-MBA molecules ranging from 200 cm(-1) to 2000 cm(-1) were randomly collected from a number of positions on the substrate and six Ag-Fe3O4 nanocomposites substrates are measured with the same procedure. It is shown that the SERS substrate have the good uniformity and reproducibility with low standard deviation, indicating our proposed Ag-Fe3O4 nanocomposites with external magnetic field control abilities have potential applications in the fields of magnetic separation and SERS techniques. PMID- 25454434 TI - A new metallate phase of V2O5 crystalline microstructure achieved in a facile route: synthesis, characterization, and measurement in catalytic reactions. AB - Experiencing a series of complicated changes, abundant orange crystals of novel metallic phase of vanadium pentoxide were obtained by a mild chemical method, the formula of which is defined as [V3(MU3-O)2?(MU1-OH)?O5]?H2O. Differ from the synthesis methods of vanadium oxide published, we have adopted a simple solution method that mixed starting materials are refluxing in the system of ethanol-water under a relatively lower temperature. Symmetry of the crystals is Monoclinic, with cell unit dimensions: a=4.9978(10)A, b=8.4273(17)A, c=7.8669(16)A, beta=96.44(3) degrees and space group of P21/m. The structure of the complex was characterized by elemental analysis, IR, UV-vis spectroscopy and single-crystal diffraction analysis. Powder X-ray diffraction (PXRD) was used to detect the purity of the crystals, and crystal morphology was detected by the scanning electron microscope (SEM). In addition, in order to extend application of oxidovanadium complexes, bromination catalytic activity about the complex in a single-pot reaction of the conversion of phenol red to bromophenol blue in a mixed solution of H2O-DMF at a constant temperature of 30+/-0.5 degrees C with a buffer solution of NaH2PO4Na2HPO4 (pH=5.8) was evaluated firstly, indicating that the complex can be considered as a potential functional model of bromoperoxidase, in the meantime, we have conducted the bromination catalytic reaction to simulate and measure the changes in reaction process indirectly. Besides, catalytic oxidation activity of the complex is also evaluated in the oxidation of cyclohexane (Cy) and cyclopentane with hydrogen peroxide promoted under mild conditions, showing potential catalytic activity of the complex by comparing TON (total turnover number) ratios of CyO/CyOH (CyO is the abbreviation of cyclohexanone and CyOH represents cyclohexanol) in the oxidation results. PMID- 25454435 TI - Enhancement of aqueous stability of allyl isothiocyanate using nanoemulsions prepared by an emulsion inversion point method. AB - Allyl isothiocyanate (AITC), an organosulfur compound in cruciferous vegetables, is a natural antimicrobial and potential chemopreventive agent. However, the instability of AITC in aqueous systems restrains its applications. In this study, oil-in-water AITC nanoemulsion was prepared by the emulsion inversion point (EIP) method, aiming at improving the aqueous stability of AITC. The optimal hydrophilic-lipophilic balance (HLB(op)) value of surfactants containing Tween 80 and Span 80 was established at 11.0-13.0, yielding nanodroplets with diameters of 137-215 nm. The mechanism of droplet formation within the HLP(op) region was discussed in terms of the possible structure of adsorbed surfactant layers at the oil-water interface in multiple emulsion droplets. In a 6.5-month storage test, the droplet sizes and the count rates (intensity of scattered light) of nanoemulsions decreased only slightly by 4-13% (depending on surfactant-to-oil ratio), even in highly diluted status, indicating the desirable stability of the nanoemulsions. Moreover, the nanoemulsion demonstrated superior protection against AITC degradation (78% remaining after 60 d at 30 degrees C), compared with protein nanoparticles as well as non-encapsulated aqueous dispersion. This work shows for the first time that AITC can be formulated into nanoemulsions and thus obtains satisfactory aqueous solubility and chemical stability. PMID- 25454436 TI - Integration of antifouling and bactericidal moieties for optimizing the efficacy of antibacterial coatings. AB - HYPOTHESIS: Surface coatings that are either antifouling or bactericidal can reduce bacterial colonization, but either type has certain drawbacks. We hypothesize that by integrating an antifouling polymer, poly(sulfobetaine methacrylate) (pSBMA), and a bactericidal polymer, N-[(2-hydroxy-3 trimethylammonium)propyl] chitosan chloride (HTCC), in one coating, these drawbacks can be overcome and the antibacterial efficacy can be greatly improved compared to an antifouling or bactericidal coating. EXPERIMENTS: A copolymer comprising chitosan and pSBMA in almost equal molar ratio was grafted onto an aminolyzed silicone surface via genipin-induced crosslinking reaction, and treated with glycidyltrimethylammonium chloride to endow the surface with quaternary ammonium groups. The antibacterial property and cytotoxicity of the resultant coating (HTCC-b-pSBMA) were tested. The possibility of incorporating heparin in the coating to improve blood compatibility was also investigated. FINDINGS: The HTCC-b-pSBMA coating reduced colonization by both planktonic bacteria from aqueous medium and aerosolized bacteria by approximately two orders of magnitude compared with the pristine surface. In comparison, surfaces coated with either the pSBMA or HTCC component are unable to achieve such efficacy. The heparin-loaded HTCC-b-pSBMA coating improved hemocompatibility without adversely affecting the antibacterial efficacy. No significant cytotoxicity of the coatings was observed with mammalian cells. PMID- 25454437 TI - Endowing manganese oxide with fast adsorption ability through controlling the manganese carbonate precursor assembled in ionic liquid. AB - Manganese oxides with desired structure are controllably obtained through annealing MnCO3 precursors with required structures. The structures of MnCO3 precursors are determined by a "mesocrystal formation" process in an ionic liquid system of a choline chloride/urea (CU) mixture. Without addition of surfactants, only CU solvent and manganese chloride are needed in the reaction system, in which the CU acts as reaction medium as well as control agent for particle growth. A shape transformation of MnCO3 particles from well-defined rhombohedral mesocrystals to ellipsoidal polycrystal ensembles, and to nanoparticulate aggregates is observed when heating the reaction system for 4 h at 120, 150, and 180 degrees C, respectively. With a longer aging time at 120 degrees C, etching and disassembly of MnCO3 mesocrystals happened. The correlation between the microstructure and the underlying formation mechanism is highlighted. Porous and nanowire-like MnO(x) nanostructures are obtained through a facile thermal conversion process from the diverse MnCO3 precursors, which are demonstrated as effective and efficient adsorbents to remove organic waste (e.g. Congo red) from water. Significantly, the nanowire-like MnO(x) nanostructures obtained by annealing the MnCO3 mesocrystals at 300 degrees C for 4 h can remove about 95% Congo red in waste water at room temperature in only one minute, which is superior to the reported hierarchical hollow nanostructured MnO2. PMID- 25454438 TI - Removal of strontium (Sr2+) from aqueous solutions with titanosilicates obtained by the sol-gel method. AB - Titanosilicates (TiSis) were synthesized from pure and technical precursors by the sol-gel method. X-ray diffraction (XRD) studies of TiSi identified amorphous phases. The Brunauer, Emmett and Teller (BET) surface area of TiSis obtained from pure and technical precursors measured using the low-temperature nitrogen adsorption/desorption technique were 270.3 and 158.7 m(2) g(-1), respectively. Micro-mesopore and micro- meso- macropore structures were attributed to TiSi prepared from pure and technical precursors, correspondingly. TiSis mass, solution pH, contact time, initial Sr(2+) concentration, temperature and background solution were investigated for their effect on sorption properties. TiSis were observed to have a high affinity for strontium in the pH range of 4 12. Strontium adsorption isotherms were established and fitted to the Langmuir, Freundlich, Redlich-Peterson, Sips and Toth models. Pseudo-first and pseudo second models were used to describe experimental kinetic data. X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX) data for TiSis were collected before and after adsorption. Heterophase was observed on the surfaces of both types of TiSi material after Sr(2+) uptake. The mechanism of Sr(2+) sorption on titanosilicates was suggested. PMID- 25454439 TI - Achieving phase transformation and structure control of crystalline anatase TiO2@C hybrids from titanium glycolate precursor and glucose molecules. AB - Considerable efforts have focused on functional TiO2@carbonaceous hybrid nanostructured materials (TiO2@C) to satisfy the future requirements of environmental photocatalysis and energy storage using these advanced materials. In this study, we developed a two-step solution-phase reaction to prepare hybrid TiO2@C with tuneable structure and composition from the hydrothermal carbonization (HTC) of glucose. X-ray diffraction (XRD), Raman spectroscopy, X ray photoelectron spectroscopy (XPS), and thermogravimetric analysis (TGA) were used to determine the crystallite size, composition, and phase purity. The results of scanning electron microscopy (SEM), transmission electron microscopy (TEM), and high resolution TEM (HRTEM) showed that the morphology of the as synthesized TiO2@C hybrids could be controlled by varying the amount of glucose, also acting as the carbon source. Based on the observations made with different glucose concentrations, a formation mechanism of nanoparticulate and nanoporous TiO2@C hybrids was proposed. In addition, the as-synthesized TiO2@C hybrids with different compositions and structures showed enhanced adsorption of visible light and improved dye-adsorption capacity, which supported their potential use as photocatalysts with good activity. This new synthetic approach, using a nanoprecursor, provides a simple and versatile way to prepare TiO2@C hybrids with tuneable composition, structures, and properties, and is expected to lead to a family of composites with designed properties. PMID- 25454440 TI - Inkjet ink spreading on polyelectrolyte multilayers deposited on pigment coated paper. AB - Mechanisms of inkjet ink spreading and absorption on a coated paper have been studied using a polyelectrolyte multilayering technique. By applying alternating sequences of cationic and anionic polyelectrolyte layers on a mineral coated paper, the role of the interfacial chemistry was evaluated. The polyelectrolyte multilayer was created to imitate a thin resin-like liquid-absorptive layer and to clarify the role of the charge of the protruding polyelectrolyte layer on ink spreading and colorant fixation. The formation of a thin polyelectrolyte layer and coating coverage was confirmed by X-ray photoelectron spectroscopy (XPS). A submolecular mechanical imaging of the polyelectrolyte complexes with an atomic force microscope (AFM) revealed differences in modulus and different nanosize agglomerates were identified which were ascribed to polyion complexes. The polyelectrolyte coatings significantly affect the solid-liquid interaction and particularly the ink spreading revealed as intercolor bleeding and wicking. The interfacial interaction between the ink and the applied polyelectrolyte layers showed differences between dye- and pigment-based colorants, which could be emphasized by the polyelectrolyte chemistry. PMID- 25454441 TI - Nitrogen-doped porous aromatic frameworks for enhanced CO2 adsorption. AB - Recently synthesized porous aromatic frameworks (PAFs) exhibit extremely high surface areas and exceptional thermal and hydrothermal stabilities. Using computer-aided design, we propose new PAFs, designated as NPAFs, by introducing nitrogen-containing groups to the biphenyl unit and predict their CO2 adsorption capacities with grand canonical Monte Carlo (GCMC) simulations. Among various NPAFs considered, one with imidazole groups shows the highest adsorption capacity for CO2 (11.5 wt% at 1 bar and 298 K), in comparison with 5 wt% for the parent PAF (PAF-1) at the same condition. At higher pressures (around 10 bar), however, another NPAF with pyridinic N groups performs much better than the rest due to its greater pore volume in addition to the N functionality. This study suggests that adding N functionality to the organic linkers is a promising way to increase CO2 adsorption capacity of PAFs at ambient condition. PMID- 25454442 TI - Diffusiophoresis of a soft, pH-regulated particle in a solution containing multiple ionic species. AB - The diffusiophoresis of a soft, pH-regulated particle comprising a rigid core and a polyelectrolyte (PE) layer in an aqueous salt solution containing multiple ionic species is modeled theoretically. We show that the diffusiophoretic behavior of a soft particle can be different appreciably from that of a rigid one. In particular, both the sign and the magnitude of the mobility of a soft particle can vary with the friction coefficient of its PE layer. In an aqueous KCl solution, if that coefficient is sufficiently large, the particle always moves towards the opposite direction as that of the applied concentration gradient, regardless of the pH level, an interesting observation which has not been reported previously. In an aqueous NaCl solution, if pH is sufficiently low, the particle mobility increases with increasing friction coefficient, an interesting and unexpected finding. The results obtained provide valuable and necessary information for both interpreting experimental data and design diffusiophoresis devices. PMID- 25454443 TI - Synthesis, characterization and activity of an immobilized photocatalyst: natural porous diatomite supported titania nanoparticles. AB - Diatomite, a porous non-metal mineral, was used as support to prepare TiO2/diatomite composites by a modified sol-gel method. The as-prepared composites were calcined at temperatures ranging from 450 to 950 degrees C. The characterization tests included X-ray powder diffraction (XRD), scanning electron microscopy (SEM) with an energy-dispersive X-ray spectrometer (EDS), high resolution transmission electron microscopy (HRTEM), X-ray photoelectron spectroscopy (XPS), and nitrogen adsorption/desorption measurements. The XRD analysis indicated that the binary mixtures of anatase and rutile exist in the composites. The morphology analysis confirmed the TiO2 particles were uniformly immobilized on the surface of diatom with a strong interfacial anchoring strength, which leads to few drain of photocatalytic components during practical applications. In further XPS studies of hybrid catalyst, we found the evidence of the presence of Ti-O-Si bond and increased percentage of surface hydroxyl. In addition, the adsorption capacity and photocatalytic activity of synthesized TiO2/diatomite composites were evaluated by studying the degradation kinetics of aqueous Rhodamine B under UV-light irradiation. The photocatalytic degradation was found to follow pseudo-first order kinetics according to the Langmuir Hinshelwood model. The preferable removal efficiency was observed in composites by 750 degrees C calcination, which is attributed to a relatively appropriate anatase/rutile mixing ratio of 90/10. PMID- 25454444 TI - Emulsion-directed liquid/liquid interfacial fabrication of lanthanide ion-doped block copolymer composite thin films. AB - An emulsion-directed assembly and adsorption approach has been used to fabricate composite films of polystyrene-b-poly(acryl acid)-b-polystyrene (PS-b-PAA-b-PS) and Eu(3+) and La(3+) ions at the planar liquid/liquid interface of the polymer DMF/chloroform (1:1, v/v) mixed solution (lower phase) and aqueous solutions of the corresponding salts (upper phase). The lower phase gradually transformed to a water-in-oil (W/O) emulsion via spontaneous emulsification due to the "ouzo effect". Polymer molecules and the metal ions assembled around emulsion droplets that adsorbed at the planar liquid/liquid interface at last, resulting in formation of composite films. The film morphologies and structures depend on Ln(3+) ions: polymer/Eu(3+) composite films were foam films composed of microcapsules ranging in size from several hundreds of nanometers to micrometers, while polymer/La(3+) composite films were composed of hollow spheres several tens of nanometers in size. Fourier transform infrared (FTIR) spectra revealed that the coordination modes of carboxyl groups to Eu(3+) and La(3+) were bridging bidentate and ionic, respectively, in the two types of composites. These results indicate that stable microcapsules can be fabricated around droplets for polymer/Eu(3+) systems, while microcapsules of polymer/La(3+) are unstable. This leads to different film morphologies and structures. Compositions of these films were characterized using energy-dispersive spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS). In addition, foam films of polymer/Eu(3+)/2,2' bipyridine (bpy) were fabricated using this approach, and their photoluminescence properties were investigated. PMID- 25454445 TI - Facile synthesis of tailored nanostructured ORMOSIL particles by a selective dissolution process. AB - Tailored nanostructured ORMOSIL particles, of raspberry shaped, hollow, and rattle type structures, were prepared by a selective dissolution of siloxane networks in composite ORMOSIL particles with a multi-layered structure. The synthesis of monodisperse ORMOSIL particles involved a one-pot process in an aqueous solution using a binary or ternary mixture from three organosilanes, (3 aminopropyl)trimethoxysilane (APTMS), vinyltrimethoxysilane (VTMS), and/or phenyltrimethoxysilane (PTMS). In the following step, ORMOSIL particles were treated with a mixture of water and alcohol with mild heating. This mild etching process was efficient to selectively dissolve some of organosilane functional groups within the ORMOSIL particles but not their main silica frameworks, leading to formation of mesoporous particles. The strategy developed in this study is not only very facile, economical, and less time-consuming, but also more environmentally friendly by avoiding the use of corrosive etching chemicals and harsh reaction conditions. Surface roughness, core diameter, and shell thickness of the resultant mesoporous ORMOSIL particles were controlled by manipulating synthetic parameters such as the relative ratios of the silane monomers as well as the dissolution parameters such as temperature and type of solvent. PMID- 25454446 TI - Arsenate removal with 3-mercaptopropanoic acid-coated superparamagnetic iron oxide nanoparticles. AB - In the present work, superparamagnetic iron oxide nanoparticles (SPION) surface coated with 3-mercaptopropanoic acid (3-MPA) were prepared and their feasibility for the removal of arsenate from dilute aqueous solutions was demonstrated. The synthesized 3-MPA-coated SPION was characterized using transmission electron microscopy (TEM), thermogravimetric analysis (TGA) and Fourier transform infra red spectrometry (FTIR). Separation efficiency of the coated nanoparticles and the equilibrium isotherm of arsenate adsorption were investigated. The obtained results reveal the arsenate adsorption to be highly pH-dependent, and the maximum adsorption was attained in less than 60 min. The resulting increase of 3-MPA coated SPION adsorption capacity to twice the adsorption capacity of SPION alone under the same conditions is attributed to the increase of active adsorption sites. An adsorption reaction is proposed. On the other hand, efficient recovery of arsenate from the loaded nanoparticles was achieved using nitric acid (HNO3) solution, which also provides a concentration over the original arsenate solution. PMID- 25454447 TI - Controlled heteroaggregation of two types of nanoparticles in an aqueous suspension. AB - Composite particles combining nanoparticles of different functional materials, as well as nanoclusters of nanoparticles of controlled size, can be synthesized by the assembly of nanoparticles in an aqueous suspension. Different interactions between the nanoparticles in the suspension can be applied for their heteroaggregation and controlled by engineering the surface properties of the nanoparticles. The heteroaggregation of nanoparticles in a suspension was studied on a model system composed of superparamagnetic carboxyl-functionalized silica coated maghemite nanoparticles (cMNPs) (24 nm in size) and larger, amino functionalized, silica nanoparticles (aSNPs) (92 nm). The heteroaggregates formed with electrostatic attractions between the nanoparticles displaying an opposite electrical surface charge, or with chemical interactions originating from covalent bonding between the molecules at their surfaces. The suspensions were characterized with measurements of the zeta-potential and dynamic light scattering (DLS). The heteroaggregates were analyzed by transmission (TEM) and scanning (SEM) electron microscopy. The kinetics of the heteroaggregation was followed by continuous monitoring of the changes in the average hydrodynamic size by DLS. The results show that covalent bonding is much more effective than attractive electrostatic interactions in terms of a much greater and more homogeneous coverage of the larger central aSNP by the smaller cMNPs in the outer layer. PMID- 25454448 TI - Characterization of citrates on gold and silver nanoparticles. AB - In this paper, we report different coordinations of citrates on gold (AuNP) and silver (AgNP) nanoparticles, as determined using Fourier transform infrared spectroscopy (FTIR) and molecular orbital (MO) calculations. AuNPs and AgNPs are found to have completely different interactions with the carboxylate anchoring groups, as indicated by their unique asymmetric stretching vibrations in the FTIR spectra. The nu(as) (COO(-)) of citrate exhibits a high-frequency shift resulting from the formation of a unidentate coordination on AuNPs, whereas this vibration exhibits a low-frequency shift as a result of ionic bond formation on AgNPs, as predicted from the MO calculations of the corresponding metal complex salts. The enhancement in the IR signals when their vibration direction was perpendicular to the nanoparticle surface revealed the influence of localized surface plasmons excited on the metal nanoparticles. PMID- 25454449 TI - Adsorption of tannic acid on polyelectrolyte monolayers determined in situ by streaming potential measurements. AB - Physicochemical characteristics of tannic acid (tannin) suspensions comprising its stability for a wide range of ionic strength and pH were thoroughly investigated using UV-vis spectrophotometry, dynamic light scattering and microelectrophoretic measurements. These studies allowed to determine the hydrodynamic diameter of the tannic acid that was 1.63 nm for the pH range 3.5 5.5. For pH above 6.0 the hydrodynamic diameter significantly decreased as a result of the tannin hydrolysis. The electrophoretic mobility measurements confirmed that tannic acid is negatively charged for these values of pH and ionic strength 10(-4)-10(-2) M. Therefore, in order to promote adsorption of tannin molecules on negatively charged mica, the poly(allylamine hydrochloride) (PAH) supporting monolayers were first adsorbed under diffusion transport conditions. The coverage of polyelectrolyte monolayers was regulated by changing bulk concentration of PAH and the adsorption time. The electrokinetic characteristics of bare and PAH-covered mica were determined using the streaming potential measurements. The zeta potential of these PAH monolayers was highly positive, equal to 46 mV for ionic strength of 10(-2) M. The kinetics of tannin adsorption on these PAH supporting monolayers was evaluated by the in situ the streaming potential measurements. The zeta potential of PAH monolayers abruptly decreases with the adsorption of tannin molecules that was quantitatively interpreted in terms of the three-dimensional electrokinetic model. The acid-base characteristics of tannin monolayers were acquired via the streaming potential measurements for a broad range of pH. The obtained results indicate that it is possible to control adsorption of tannin on positively charged surfaces in order to designed new multilayer structures of desirable electrokinetic properties and stability. PMID- 25454450 TI - Synthesis of high surface area, mesoporous MgO nanosheets with excellent adsorption capability for Ni(II) via a distillation treating. AB - Hexagonal mesoporous MgO nanosheets with a side length of 250 nm and specific surface area of 181.692 m(2)/g were fabricated by a three-step process. Firstly, MgO powders were obtained by sintered Mg5(OH)2(CO3)4?4H2O, which was synthesized by a wet precipitation process using ammonium hydrogen carbonate as precipitants. Secondly, the above-MgO were distilled 2 h in a three-necked bottle with condenser device. Lastly, we annealed the distilled-MgO at 500-800 degrees C to form mesoporous MgO nanosheets. We found the pore size distribution and the thicknesses of nanosheets were determined by the distillation process in step 2 and annealed temperature in step 3. By optimizing the experimental parameters, the mesoporous dis-MgO annealed at 600 degrees C displayed uniform hexagonal structure with the largest pore volume (0.875 cm(3)/g) and highest BET surface area (181.692 m(2)/g), as well as the maximum adsorption capability of 1684.25 mg/g for Ni(II). PMID- 25454451 TI - Synthesis of poly(methacrylic acid)-manganese oxide dihydroxide/silica core-shell and the corresponding hollow microspheres. AB - Poly(methacrylic acid)-MnO(OH)2/SiO2 core-shell microspheres were prepared by sol gel hydrolysis of tetraethylorthosilicate (TEOS) in the presence of poly(methacrylic acid)-Mn(II) (PMAA-Mn(2+)) as template with ammonium hydroxide anion as catalyst and n-octadecyltrimethoxysilane (C18TMS) as pore-directing reagent. The PMAA-Mn(2+) core was prepared by incubation of Mn(2+) cations with PMAA microspheres via the coordination between carboxylate anion group on PMAA microsphere and Mn(2+) cations. During this process, the Mn(II) species were formed as white Mn(OH)2 precipitates at first, which were subsequently oxidized into brown MnO(OH)2 in air. The Mn2O3/mesoporous silica (Mn2O3/m-SiO2) double shelled hollow microspheres (DSHMs) were prepared through calcination of the PMAA MnO(OH)2/SiO2 core-shell microspheres at 600 degrees C for the selective removal of PMAA template and pore-directing organic component from C18TMS, during which the crystalline structure of DSHM was developed into Braunite-1Q via the reaction between Mn2O3 inner-shell and silica outer-shell by annealing the DSHMs under higher temperatures of 800 and 900 degrees C. The Mn2O3 hollow microspheres (HMs) were prepared through the selective removal of the silica layer from the DSHMs by sodium hydroxide aqueous solution, which exhibited structure integrity and good ethanol dispersity due to the presence of mesoporous structure. PMID- 25454453 TI - Photoreduction of graphene oxide enhanced by sacrificial agents. AB - In this work, the photoreduction of graphene oxides (GOs) was carried out in the presence of a sacrificial agent of Na2S/Na2SO3 and triethanolamine (TEA) separately in the solution. The photoreduction of GOs was enhanced with the addition of the sacrificial agent, which was examined in terms of reduction extent and needed reduction period. The quench of the GO emission was observed in the photoluminescence spectra of both GO solutions with Na2S/Na2SO3 and TEA. Although both sacrificial agents facilitated the charge transfer in the irradiated GO solutions, the aggregation of GO/reduced GO (RGO) occurred in the Na2S/Na2SO3-contained solution during photoreduction, which limited further photoreduction of GOs with the assistance of Na2S/Na2SO3. By keeping good dispersion characteristic during the whole process, the photoreduction efficiency of GO in the presence of TEA was therefore superior to that with the assistance of Na2S/Na2SO3. PMID- 25454452 TI - Synergies of phenolic-acids' surface-modified titanate nanotubes (TiNT) for enhanced photo-catalytic activities. AB - The adsorption of chemically similar but differently oxygen reactive phenolic acid derivatives on the Ti-nanotubes (TiNTs) surfaces to increase and/or broaden their photo-induced activity was studied using Raman and X-ray photoelectron spectroscopies combined with zeta-potential analyses. Photo-catalytic activities and stabilities of newly synthesized particles were evaluated by using high resolution capillary electrophoresis in combination with cyclic voltammetry and spin-trapping EPR spectroscopy. The modification with caffeic acid (CA) resulted in well-oriented and dense but oxygen semi-stable thin layer (1-3 nm) of self assembled mono-molecular and/or bi-dentate coordinated molecules on the TiNTs' surfaces, which narrowed the band gap from 2.9 eV (for un-modified TiNTs) to 1.55 eV, but however restrict the hydroxyl radicals generation under both UV (320 nm) and VIS (450 nm) source radiations. On the other hand, the gallic acid (GA) resulted in situ polymerized GA layer through bi-dentate binding as highly-oxygen stabilized surface structure, yielding narrower band gap of 2.25 eV and increased hydroxyl radical's generation under both exposure lights. The third tested hydroxybenzoic acid (HA), resulted to an unstable layer bonded thorough single hydrogen bonding mechanism. This work offers a new modification strategy for stable (oxygen and photo-induction related) and highly visible-light responded TiNTs as photocatalyst. PMID- 25454455 TI - A comprehensive analysis of the evaporation of a liquid spherical drop. AB - In this paper, a new comprehensive analysis of a suspended drop of a pure liquid evaporating into air is presented. Based on mass and energy conservation equations, a quasi-steady model is developed including diffusive and convective transports, and considering the non-isothermia of the gas phase. The main original feature of this simple analytical model lies in the consideration of the local dependence of the physico-chemical properties of the gas on the gas temperature, which has a significant influence on the evaporation process at high temperatures. The influence of the atmospheric conditions on the interfacial evaporation flux, molar fraction and temperature is investigated. Simplified versions of the model are developed to highlight the key mechanisms governing the evaporation process. For the conditions considered in this work, the convective transport appears to be opposed to the evaporation process leading to a decrease of the evaporation flux. However, this effect is relatively limited, the Peclet numbers happening to be small. In addition, the gas isothermia assumption never appears to be valid here, even at room temperature, due to the large temperature gradient that develops in the gas phase. These two conclusions are explained by the fact that heat transfer from the gas to the liquid appears to be the step limiting the evaporation process. Regardless of the complexity of the developed model, yet excluding extremely small droplets, the square of the drop radius decreases linearly over time (R(2) law). The assumptions of the model are rigorously discussed and general criteria are established, independently of the liquid-gas couple considered. PMID- 25454454 TI - Magnetically controllable Pickering emulsion prepared by a reduced graphene oxide iron oxide composite. AB - Pickering emulsions stabilized by graphene oxide (GO) have attracted much attention owing to the unique 2-D structure and amphiphilic surface properties of GO. On the other hand, investigations on reduced GO (RGO) to prepare Pickering emulsions are still limited, especially for water-in-oil (W/O) emulsions. Considering growing interests for directing Pickering emulsions to a specific location, it is necessary to embed Pickering emulsions with responsiveness upon external driving forces such as magnetic fields. To that end, we developed magnetically responsive RGO (denoted as "MRGO") and used MRGO to prepare W/O Pickering emulsions. MRGO was synthesized by decorating iron oxide nanoparticles on the surface of RGO and characterized by SEM, EDS, TEM, FT-IR, Raman, XRD and SQUID. MRGO Pickering emulsion (MRGO-PE) was prepared by suspending MRGO sheets in dodecane and mixing with water vigorously. The amount of MRGO added to prepare MRGO-PE is related to the size distribution of the droplets of MRGO-PE and the relationship can be well-described using a mass balance model. The motion of droplets of MRGO-PE under an external magnetic field is demonstrated. We also investigated the adsorptive property of MRGO-PE by evaluating the removal of Nile Red dye from dodecane. The results shows that the dye removal by MRGO-PE is not just achieved by MRGO layer of MRGO-PE but also by water encapsulated by MRGO. Owing to their magnetic property, MRGO-PE can be utilized as a magnetically controlled carrier which can preserve and transport to specific locations certain compounds. PMID- 25454456 TI - Synthesis of magnetic ZnO/ZnFe2O4 by a microwave combustion method, and its high rate of adsorption of methylene blue. AB - The magnetic ZnO/ZnFe2O4 particles have been synthesized by a microwave combustion method using NaAc as fuel. The as-obtained ZnO/ZnFe2O4 was characterized and applied for the removal of methylene blue (MB) from aqueous solution in the batch system. The ZnO/ZnFe2O4 particles display larger S(BET) and smaller size with increase of NaAc dosage. Because a certain amount of gas is generated during NaAc decomposing and the gas prevent the particles from growing larger. More interestingly, even at neutral pH value, the ZnO/ZnFe2O4 obtained with 24 mL NaAc shows high-rate adsorption properties with the MB removal efficiency up to 90% in 0.5 min and a maximum adsorption capacity of 37.27 mg/g. PMID- 25454457 TI - Photocatalytic degradation of methyl orange by PbXO4 (X=Mo, W). AB - PbMoO4 and PbWO4 are prepared by the simple precipitation method in this work, they show the photocatalytic activities for the degradation of methyl orange in water under the UV light illumination. In the above photocatalytic degradation processes, methyl orange concentration decreases quickly, the total organic carbon (TOC) decreases slowly; inorganic ions (SO4(2-), NO3(-), NO2(-), NH4(+)) can be formed and measured by the ion chromatograph; the pH value in the systems decreases gradually; a small quantity of HO(-).can be generated and measured by the terephthalic acid (TA) indirectly. In order to estimate the roles of active species during the above photocatalytic degradation processes, isopropanol, (NH4)2C2O4, and 1,4-benzoquinone as the scavengers for HO, h(+), O2(-) are introduced into the systems, respectively. Isopropanol and (NH4)2C2O4 are effective scavengers for active species HO and h(+) respectively, but 1,4 benzoquinone is not a satisfactory scavenger in all cases to capture O2(-), at least in this work. At last, PbMoO4 and PbWO4 are characterized by nitrogen sorption, DRS, SEM, TEM and XRD. PMID- 25454458 TI - Hydrolyzable tannins from hydroalcoholic extract from Poincianella pluviosa stem bark and its wound-healing properties: phytochemical investigations and influence on in vitro cell physiology of human keratinocytes and dermal fibroblasts. AB - Extracts from Poincianella pluviosa stem bark are used in traditional medicine of South America for its wound healing properties. For validation of this traditional use and for rationalizing a potential pharmaceutical development towards standardized preparations bioassay-guided fractionation of EtOH-water (1:1v/v) extract (crude extract, CE) of P. pluviosa bark was performed. HaCaT keratinocytes cell line and human primary dermal fibroblasts (pNHDF) were used as in vitro systems. Significant stimulation of mitochondrial activity was found for CE on both cell types, which caused a strong increase of cell proliferation of keratinocytes. Fractionation of CE over Sephadex LH20 revealed two inactive fractions (FA and FB) and an active fraction FC, which was further fractionated by MPLC into 4 subfractions. Subfraction FC1 increased mitochondrial activity and proliferation of keratinocytes and dermal fibroblasts in a dose dependent manner (10 to 100 MUg/mL) and did not show necrotic cytotoxicity on keratinocytes (LDH release assay). FC1 was investigated by ESI-MS/MS and solid-state (13)C NMR which confirmed the presence of various polyphenols and hydrolyzable tannins. MS studies suggest the presence of pyrogallol (1), gallic acid (2), gallic acid methyl ester (3), ellagic acid (4), corilagin (5), 1,4,6-tri-O-galloyl-glucose (6), tellimagrandin I (7), 1,2,3,6-tetra-O-galloyl-glucose (8), mallotinic acid (9), tellimagrandin II (10), 1,2,3,4,6-penta-O-galloyl-glucose (11), geraniin (12), and mallotusinic acid (13). PMID- 25454459 TI - New antimicrobial pregnane glycosides from the stem of Ecdysanthera rosea. AB - Phytochemical investigation on the stem of Ecdysanthera rosea led to the isolation of eight new C-21 pregnane glycoside ecdysosides A-H (1-8), together with one known pregnane glycoside ecdysantheroside A (9). Their structures were elucidated based on extensive spectroscopic data (MS, IR, 1D and 2D NMR) analysis, as well as comparison with the reported literature data. Antimicrobial activities of all the compounds were evaluated against bacteria and yeasts. Compounds 1, 9, 3 and 5 exhibited moderate antibacterial activities against respective Enterococcus faecalis and Providensia smartii, with MIC value of 12.5 MUg/mL. Compound 8 showed significant anti-yeast activity against Cryptococcus neoformans with MIC value of 12.5 MUg/mL. PMID- 25454460 TI - Inhibition of hepatitis C virus replication by chalepin and pseudane IX isolated from Ruta angustifolia leaves. AB - Hepatitis C virus (HCV) infection is highly prevalent among global populations, with an estimated number of infected patients being 170 million. Approximately 70 80% of patients acutely infected with HCV will progress to chronic liver disease, such as liver cirrhosis and hepatocellular carcinoma, which is a substantial cause of morbidity and mortality worldwide. New therapies for HCV infection have been developed, however, the therapeutic efficacies still need to be improved. Medicinal plants are promising sources for antivirals against HCV. A variety of plants have been tested and proven to be beneficial as antiviral drug candidates against HCV. In this study, we examined extracts, their subfractions and isolated compounds of Ruta angustifolia leaves for antiviral activities against HCV in cell culture. We isolated six compounds, chalepin, scopoletin, gamma-fagarine, arborinine, kokusaginine and pseudane IX. Among them, chalepin and pseudane IX showed strong anti-HCV activities with 50% inhibitory concentration (IC50) of 1.7 +/- 0.5 and 1.4 +/- 0.2 MUg/ml, respectively, without apparent cytotoxicity. Their anti-HCV activities were stronger than that of ribavirin (2.8 +/- 0.4 MUg/ml), which has been widely used for the treatment of HCV infection. Mode-of action analyses revealed that chalepin and pseudane IX inhibited HCV at the post entry step and decreased the levels of HCV RNA replication and viral protein synthesis. We also observed that arborinine, kokusaginine and gamma-fagarine possessed moderate levels of anti-HCV activities with IC50 values being 6.4 +/- 0.7, 6.4 +/- 1.6 and 20.4 +/- 0.4 MUg/ml, respectively, whereas scopoletin did not exert significant anti-HCV activities at 30 MUg/ml. PMID- 25454461 TI - Effect of evodiagenine mediates photocytotoxicity on human breast cancer cells MDA-MB-231 through inhibition of PI3K/AKT/mTOR and activation of p38 pathways. AB - Photodynamic therapy (PDT), which is a form of phototherapy, uses nontoxic light sensitive compounds which upon exposure to selective wavelength of light become toxic to the target cells. These compounds are used clinically to treat a wide range of malignant cancers, and are recognized as a treatment strategy which is both minimally invasive and less toxic, compared with other treatments available. Photodynamic therapy (PDT) might be a useful method in the management of malignant cancers. In this study, the photo-cytotoxicity of evodiagenine (EVO) mediated PDT on highly invasive and metastatic human breast cancer cells (MDA-MB 231) is examined. After incubating cancer cells with EVO, the cells are irradiated under ultraviolet-light for 120 min. EVO-PDT strongly inhibits the survival of breast cancer cells, increases the ROS production and enhanced LDH release. Western blot analysis was applied to quantify extent of phosphorylation of apoptosis-related proteins (PI3K/AKT/mTOR/p38). Our results indicate that the photocytotoxic effect of EVO may be through the inhibition of PI3K/AKT/mTOR phosphorylation and increasing p38 phosphorylation. It can be concluded that EVO may be a potential anticancer photo-sensitive agent for cancer treatment. PMID- 25454462 TI - 4-Hydroxyisoleucine improves insulin resistance by promoting mitochondrial biogenesis and act through AMPK and Akt dependent pathway. AB - 4-Hydroxyisoleucine (4-HIL) is an unusual amino acid isolated from fenugreek seeds (Trigonella foenum graecum L). Various studies have shown that it acts as an antidiabetic agent yet its mechanism of action is not clear. We therefore investigated the effect 4-HIL on the high fructose diet fed streptozotocin induced diabetic rats and L6 myotubes. 4-HIL (50 mg/kg) has improved blood lipid profile, glucose tolerance and insulin sensitivity in a diabetic rat model. It has increased the glucose uptake in L6 myotubes in AMPK-dependent manner and upregulated the expression of genes (PGC-1alpha, PGC-1beta, CPT 1 and CPT 2), which have role in mitochondrial biogenesis and energy metabolism in the liver, skeletal muscles as well as in L6 myotubes. Interestingly, it also increased the AMPK and Akt expression along with their phosphorylated forms in the liver and muscle tissues of treated animals. Altogether we concluded that 4-HIL acts to improve insulin resistance by promoting mitochondrial biogenesis in high fructose diet fed STZ induced diabetic rats. PMID- 25454463 TI - Paeoniflorin alleviates liver fibrosis by inhibiting HIF-1alpha through mTOR dependent pathway. AB - HIF-1alpha/mTOR signaling pathway is considered to play a crucial role in genesis and progress of tissue fibrosis. The elevation of HIF-1alpha and mTOR is relevant to CCl4 induced liver fibrotic rats. Paeoniflorin has been consistently shown to exhibit multiple pharmacological effects in liver disease. However, so far, no research demonstrates the relationship between paeoniflorin and HIF-1alpha/mTOR fibrogenesis pathway in liver fibrosis. In this study, the liver fibrosis was performed by CCl4 rats and HSC-T6 cell line. The data demonstrated that paeoniflorin treatment could attenuate liver fibrosis and inhibit the activation of HSC. Moreover, paeoniflorin significantly enhanced hepatic function by decreasing serum level of ALT, AST and ALP, and increasing level of ALB, TP. Meanwhile, ECM degradation was modulated by paeoniflorin treated rats with a remarkable reduce of alpha-SMA and collagen III mRNA expression. Moreover, the alleviation effect of liver fibrosis was relevant to inhibiting HIF-1alpha and phosphor-mTOR. Our data indicate that paeoniflorin alleviates liver fibrosis by inhibiting HIF-1alpha expression partly through mTOR pathway and paeoniflorin may be a potential therapeutic agent for liver fibrosis. PMID- 25454464 TI - Unciflavones A-F, six novel flavonoids from Selaginella uncinata (Desv.) Spring. AB - Six new flavonoids, unciflavones A-F (1-6), have been isolated from medicinal plant Selaginella uncinata (Desv.) Spring. Their structures were established on the basis of extensive NMR analysis including 1D NMR ((1)H, (13)C and DEPT) and 2D NMR (COSY, HSQC, HMBC) experiments as well as HRESIMS analysis. All compounds possess exceptional structural features with an aryl substituent at the C-8 position, which are uncommonly encountered in natural resources and firstly reported in genus Selaginella. PMID- 25454465 TI - Can one and two-dimensional solid-state NMR fingerprint zeolite framework topology? AB - In this contribution, we have explored the potential and strength of one dimensional (1D) (29)Si and two-dimensional (2D) (29)S-(29)Si and (29)Si-(17)O NMR as invariants of non-oriented graph for fingerprinting zeolite frameworks. 1D and 2D (29)Si NMR can indeed provide indications on the graph vertices, edges and allow the construction of the adjacency matrix, i.e. the set of connections between the graph vertices. From the structural data, hypothetical 1D (29)Si and 2D (29)Si-(29)Si NMR signatures for 193 of the zeolite frameworks reported in the Atlas of Zeolite Structures have been generated. Comparison between all signatures shows that thanks to the 1D (29)Si NMR data only, almost 20% of the known zeolite frameworks could be distinguished. Further NMR signatures were generated by taking into account 2D (29)Si-(29)Si and (29)Si-(17)O correlations. By sorting and comparison of all the NMR data, up to 80% of the listed zeolites could be unambiguously discriminated. This work indicates that (i) solid-state NMR data indeed represent a rather strong graph invariant for zeolite framework, (ii) despite their difficulties and costs (isotopic labeling is often required, the NMR measurements can be long), (29)Si and (17)O NMR measurements are worth being investigated in the frame of zeolites structure resolution. This approach could also be generalized to other zeolite-related materials containing NMR measurable nuclides. PMID- 25454470 TI - Dietary effects of a mix derived from oregano (Origanum vulgare L.) essential oil and sweet chestnut (Castanea sativa Mill.) wood extract on pig performance, oxidative status and pork quality traits. AB - The effects of a pre-formulated commercial plant extract mix, composed of equal parts of oregano essential oil and sweet chestnut wood extract, on performance, oxidative status and pork quality traits were evaluated. In two 155-d studies, 60 pigs (mean liveweight: 42.9 kg) were assigned to either a control diet (CTR) or an identical diet supplemented (0.2%) with the plant extract mix (OC). No differences in the growth rate were observed. Glutathione peroxidase and glutathione reductase activities in the OC muscles (Longissimus lumborum) were higher than in CTR muscles. The lipid oxidation of meat was lower in the OC group. In the cooked meat samples, OC animals had the lowest L* and H degrees values and the highest a* values. The OC meat received higher scores for colour, taste and overall liking in both the blind and the labelled consumer tests. PMID- 25454469 TI - Immune response and functional role of antibodies raised in heifers against a Staphylococcus aureus CP5 lysate and recombinant antigens vaccine formulated with Iscom Matrix adjuvant. AB - Staphylococcus aureus is the most frequently isolated pathogen from bovine intramammary infections worldwide. Commercially available vaccines for mastitis control are composed either of S. aureus lysates or inactivated whole-cells formulated with traditional adjuvants. We recently showed the ability of a S. aureus CP5 lysate vaccine adjuvanted with Iscom Matrix to generate a longer lasting specific antibody response in blood and milk, with improved opsonic capacity, compared with a S. aureus CP5 whole-cell formulation. The aim of the present study was to obtain an experimental immunogen composed of lysed cells of a CP5 S. aureus strain supplemented with recombinant clumping factor A, fibronectin binding protein A and beta-toxin formulated with Iscom Matrix, characterize the immune response generated when immunizing pregnant heifers and assess the functional role of antibodies raised against this immunogen in experimental models. Both a lysate vaccine and a lysate+recombinant antigens vaccine elicited antibodies that promoted neutrophil phagocytosis and inhibited internalization into mammary epithelial cells, in vitro. Incorporation of defined antigenic molecules to the lysate formulation elicited a strong specific humoral immune response against both lysate and recombinant antigens and was associated with higher expression of regulatory and pro-inflammatory cytokines. In addition, antibodies were efficient for blocking S. aureus binding to bovine fibrinogen and fibronectin, and neutralizing beta-toxin effect in vitro, placing these antigens as candidates to be included in a formulation directed to prevent staphylococcal bovine mastitis. PMID- 25454471 TI - Interpedicular kinematics in an in vitro biomechanical assessment of a bilateral lumbar spondylolytic defect. AB - BACKGROUND: A spondylolytic defect in lumbar vertebra is a common condition during early childhood and adolescence, and is considered a precursor to spondylolisthesis. This study examined whether a bilateral spondylolytic defect in lumbar spine intrinsically results in increased intervertebral translations during different bending motions. METHODS: Seven fresh frozen cadaveric kangaroo lumbar (L1-L6) spine specimens were tested in a kinematic spine simulator; first in their intact state, followed by creating a bilateral spondylolytic defect at L4 and retesting. In addition to recording global and segmental range of motions, the pedicles at L3, L4, and L5 vertebrae were digitized bilaterally and virtually tracked throughout testing. Interpedicular kinematic metrics were employed to capture any changes in translatory motions during flexion-extension, bilateral bending, and axial torsion testing modes. FINDINGS: Following the defect, range of motion at the defect level (L4-L5) increased significantly in all the three motion planes. At L4-L5, normalized interpedicular displacement increased significantly in flexion-extension (median change +156%) and bilateral bending (median change +58%) motions, but changes in bending-plane and out-of-plane intervertebral translations were not significant in any of the testing modes. INTERPRETATION: In the absence of any significant changes in bending-plane and out-of-plane intervertebral translations at L4-L5, changes in interpedicular displacement would directly correspond with the stretching of posterior annulus of the L4-L5 intervertebral disc. A bilateral spondylolytic defect at L4 may result in significant overstretching of the posterior annulus of the L4-L5 disc during flexion-extension and bilateral bending motions. PMID- 25454472 TI - Labor inhibits placental mechanistic target of rapamycin complex 1 signaling. AB - INTRODUCTION: Labor induces a myriad of changes in placental gene expression. These changes may represent a physiological adaptation inhibiting placental cellular processes associated with a high demand for oxygen and energy (e.g., protein synthesis and active transport) thereby promoting oxygen and glucose transfer to the fetus. We hypothesized that mechanistic target of rapamycin complex 1 (mTORC1) signaling, a positive regulator of trophoblast protein synthesis and amino acid transport, is inhibited by labor. METHODS: Placental tissue was collected from healthy, term pregnancies (n = 15 no-labor; n = 12 labor). Activation of Caspase-1, IRS1/Akt, STAT, mTOR, and inflammatory signaling pathways was determined by Western blot. NFKB p65 and PPARgamma DNA binding activity was measured in isolated nuclei. RESULTS: Labor increased Caspase-1 activation and mTOR complex 2 signaling, as measured by phosphorylation of Akt (S473). However, mTORC1 signaling was inhibited in response to labor as evidenced by decreased phosphorylation of mTOR (S2448) and 4EBP1 (T37/46 and T70). Labor also decreased NFKB and PPARgamma DNA binding activity, while having no effect on IRS1 or STAT signaling pathway. DISCUSSION AND CONCLUSION: Several placental signaling pathways are affected by labor, which has implications for experimental design in studies of placental signaling. Inhibition of placental mTORC1 signaling in response to labor may serve to down-regulate protein synthesis and amino acid transport, processes that account for a large share of placental oxygen and glucose consumption. We speculate that this response preserves glucose and oxygen for transfer to the fetus during the stressful events of labor. PMID- 25454474 TI - LPS from bovine serum albumin drives TNF-alpha release during ex-vivo placenta perfusion experiments, contaminates the perfusion system but can be effectively removed by oxidative cleaning. AB - INTRODUCTION: The dual ex-vivo perfusion of human placental tissue is useful to study inflammatory pathways. We found significant TNF-alpha release in negative controls similar in concentration to lipopolysaccharide (LPS) stimulated placentas. The aim of the current study was to (i) identify sources driving TNF alpha release and (ii) develop an approach to control for it. METHOD: (i) To determine sources leading to TNF-alpha release, solutions frequently circulated through the perfusion system and perfusion media with different bovine serum albumin (BSA) quality were exposed to mouse macrophage cell lines (RAW264.7) and subsequently measured for TNF-alpha expression. (ii) To assess memory effects and validate cleaning procedures, sham perfusion experiments were conducted either in the presence or absence of exogenous LPS, in new tubing that was contaminated, cleaned and analyzed for the effectiveness of LPS removal. Oxidative and acid base cleaning were tested for their effectiveness to reduce LPS contamination. RESULTS: TNF-alpha release, observed in negative control experiments, was attributed to the use of LPS-contaminated BSA as well as inadequate cleaning of the perfusion system. Once introduced in the perfusion system, LPS accumulated and created a memory effect. Oxidative but not acid-base depyrogenation effectively reduced LPS levels to concentrations that were in accordance with FDA guidelines (<0.5 EU/mL) for medical equipment redeemed appropriate for re-use. DISCUSSION: LPS contamination of the placenta perfusion model could have confounding effects on experimental outcomes leading to misinterpretation of data. To circumvent LPS contamination LPS-free BSA and oxidative depyrogenation cleaning techniques should be implemented in future placental perfusion studies. PMID- 25454473 TI - ICAM-1 expression on immune cells in chronic villitis. AB - INTRODUCTION: ICAM-1 expression on the villous syncytiotrophoblast (ST) is believed to participate in migration of maternal cells into the inflamed villi regardless of villitis etiology. However, its expression on immune cells in chronic villitis (CV) has yet to be analyzed. ICAM-1 induces cell-cell adhesion allowing intercellular communication, T cell-mediated defense mechanism, and inflammatory response. MATERIAL AND METHODS: 21 cases of CV (all without an identifiable etiologic agent) and 3 control placentas were analyzed using ICAM-1, and for immune cells CD45, CD3 and CD68. These cells were subdivided according to their location in inflamed villi: a) within the inflamed villi and b) outside forming perivillous aggregates. RESULTS: Large amounts of CD45, CD3 and CD68 were found within the inflamed villi and forming perivillous aggregates attached to areas of trophoblastic loss. Inflamed villi usually showed ICAM-1+ ST. The majority of immune cells surrounding areas of trophoblastic rupture presented marked expression of ICAM-1. In contrast, a small number of immune cells within the inflamed villi exhibited ICAM-1 expression. Only some (<5%) inflamed villi without trophoblastic rupture and with ICAM-1+ ST presented adherence of immune cells. DISCUSSION: In inflamed villi of chronic villitis, the level of ICAM-1 expression on immune cells depends on their location: high in number of cells in the perivillous region and low within the villi. The strongest expression of ICAM 1 on immune cells attached to areas of trophoblastic rupture suggests that the loss of trophoblast can lead to an amplification of the inflammatory response. PMID- 25454475 TI - Placental SEMA3B expression is not altered in severe early onset preeclampsia. AB - Recent evidence suggests that Semaphorin 3B (SEMA3B) is upregulated in severe preeclampsia, and a major driver of cytotrophoblast aberrations in this disease. Here we independently assess whether SEMA3B expression is altered in a large cohort of severe early onset preeclamptic placentas. We demonstrate that SEMA3B relative mRNA expression and copy number are not changed in PE placentas. We confirm this at the protein level by western blot. Interestingly, exposure of term trophoblasts or explants to hypoxia induced a significant down regulation of SEMA3B mRNA, but a trend towards increased SEMA3B protein expression. We conclude that SEMA3B mRNA and protein is not altered in severe early onset preeclamptic placentas. PMID- 25454476 TI - Stability of absolute copy number of housekeeping genes in preeclamptic and normal placentas, as measured by digital PCR. AB - Measuring mRNA expression is fundamental to placental research. Ideally, mRNA transcript numbers are directly quantified. However, PCR analysis using the DeltaDeltaCT method relies on the stability of housekeeping genes and only reports relative expression. Digital PCR (dPCR) directly quantifies mRNA copy number and is more accurate than quantitative PCR. We quantified absolute mRNA copy number of housekeeping genes in normotensive pre-term (n = 20), severe preeclamptic (n = 11) and term (n = 12) placenta using dPCR. Whilst there was some variation, we confirm absolute mRNA copy number of GAPDH, TOP1, CYC1 and YWHAZ in placenta does not significantly alter between these cohorts, or across gestation. PMID- 25454477 TI - [Uncommon alopecic plaque]. PMID- 25454478 TI - Low-grade small round cell tumor of the cauda equina with EWSR1-WT1 fusion and indolent clinical course. AB - We report a case of a longstanding, large tumor involving spinal nerve roots of the cauda equina. The tumor showed small round cells arranged in nests and cords and immunophenotypic features of a glomus tumor, along with infrequent mitoses and a low Ki-67 labeling index, but exhibited some rosette-like structures, with focal CD99 and Neu-N expression. Subsequent molecular analysis showed the presence of an EWSR1-WT1 gene fusion by fluorescence in situ hybridization, which was confirmed by reverse- transcriptase polymerase chain reaction. To our knowledge, this is the first case reported with EWSR1-WT1 fusion in a small round blue cell tumor with smooth muscle differentiation and an indolent course. PMID- 25454479 TI - Erdheim-Chester disease involving the breast--a rare but important differential diagnosis. AB - Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by multisystem infiltration by foamy histiocytes surrounded by fibrosis. ECD often involves the long bones, skin, and retroperitoneum, whereas breast involvement is very rare with only 6 reported cases in English literature. We report a case of ECD presenting within the right breast as a clinically malignant tumor, in addition to bilateral sclerotic lesions of the femurs, bilateral soft tissue masses of the cerebellum, and multiple subcutaneous nodules on the abdominal wall in a 61-year-old woman. Histologically, there was a prominent infiltrate of foamy histiocytes with scattered Touton-type giant cells, lymphocytes, and plasma cells. The foamy histiocytes were arranged in small clusters or scattered singly in the background of fibrosis. However, in some areas, there was a prominent proliferation of fibrosis with scant cellular infiltrate including histiocytes. The diagnosis of ECD was made by characteristic histopathologic features in addition to clinical-radiographic features and the typical immunoprofile (positive for cluster of differentiation 68 [CD68], CD163, and p16; negative for CD1a and S-100). Although rare, ECD must be considered in the differential diagnosis of clinically malignant tumor of the breast. To our knowledge, this is the second case of ECD involving the breast in which a valine 600 glutamic acid mutation was detected, which probably represents a clonal disorder of non-Langerhans cells. PMID- 25454480 TI - Crystalline light chain proximal tubulopathy with chronic renal failure and silicone gel breast implants: 1 case report. AB - A 39-year-old female patient was admitted to explore chronic renal failure. Clinical history included silicone breast implants. Clinical examination was normal. Urinalysis revealed tubular proteinuria with Bence-Jones kappa protein. Monoclonal immunoglobulin G kappa and free monoclonal kappa-light chains (LCs) were revealed by serum protein immunoelectrophoresis. Bone marrow aspiration with karyotype analysis and skeletal radiologic survey were normal. Kidney biopsy revealed a peculiar pattern of proximal tubular cells with hypertrophy and clarification initially diagnosed as an osmotic nephrosis. Immunofluorescence study, including immunoglobulin LCs conjugates was normal. Immunoelectron microscopy finally revealed a crystalline LC proximal tubulopathy kappa. Our case presents some peculiarities: the absence of hematologic malignancy sign and the young patient's age. The silicone breast implants have been reported to be involved in the generation of monoclonal gammopathy. PMID- 25454481 TI - Pleuroparenchymal fibroelastosis: a pattern of chronic lung injury. AB - Pleuroparenchymal fibroelastosis (PPFE) is a rare condition currently described as an upper lobe subpleural and interstitial proliferation of predominantly elastic fibers. The etiology is unknown, and no specific diagnostic criteria have been reported. Here we report 5 cases of PPFE, 1 man and 4 women, 3 of them diagnosed at the time autopsy, 1 diagnosed in an explanted lung, and 1 diagnosed on a surgical wedge biopsy. The average age of diagnosis among this series is 73 years, and the duration of pulmonary symptoms ranged from 14 months to at least 9 years. Two patients had been exposed to specific medications (daptomycin and dapsone) preceding the development of pulmonary symptoms, and 1 patient developed eosinophilic pneumonia in the course of the disease. Four patients had clinical evidence of fibrous interstitial pneumonia. We found evidence of diffuse parenchymal fibroelastosis involving both upper and lower lobes in all 5 cases, suggesting that the disease may be a more diffuse condition than previously reported. PPFE may actually represent a pattern of chronic lung injury rather than a specific entity and may be seen in association with a variety of clinicoradiologic conditions. Based on our findings in this series and the most recent publications of the subject, we propose the following set of diagnostic criteria for PPFE: multilobar subpleural and/or centrilobular fibrous interstitial pneumonia characterized by an extensive (>80%) proliferation of elastic fibers in nonatelectatic lung, along with absent to mild chronic inflammation, and absent to rare granulomas. PMID- 25454483 TI - Of "Indian files", "Roman bridges" and "Swiss cheese": Analogies in breast pathology. PMID- 25454482 TI - Differences in interleukin 8 expression in Helicobacter pylori-infected gastric mucosa tissues from patients in Bhutan and the Dominican Republic. AB - The outcomes of Helicobacter pylori infection vary geographically. H pylori strains, disease presentation, and environments differ markedly in Bhutan and Dominican Republic. The aims were to compare the strains, histology, and expression of interleukin (IL) 8 and IL-10 from gastric mucosa from the 2 countries. H pylori status was assessed by the combination of rapid urease test, culture, and histology. Histology was evaluated using the updated Sydney System, and cytokines in gastric biopsies were measured using real-time polymerase chain reaction (PCR). There were 138 subjects from Bhutan and 155 from Dominican Republic. The prevalence of H pylori infection was 65% and 59%, respectively. The genotype of cagA was predominantly East Asian type in Bhutan versus Western type in Dominican Republic. Gastritis severity was significantly higher in H pylori infected subjects from Bhutan than those from Dominican Republic. IL-8 expression by H pylori infection was 5.5-fold increased in Bhutan versus 3-fold in Dominican Republic (P < .001); IL-10 expression was similar. IL-8 expression levels among H pylori-infected cases tended to be positively correlated with polymorphonuclear leucocyte and monocyte infiltration scores in both countries. IL-8 expression among those with grade 2 and 3 polymorphonuclear leucocyte and monocyte infiltration was significantly higher in Bhutan than in Dominican Republic. The difference in IL-8 expression in the 2 countries is reflected in the different disease pattern between them. Whether the dominant factor is differences in H pylori virulence, in host-H pylori-environmental interactions, genetic factors or all remains unclear. However, severity of inflammation appears to be a critical factor in disease pathogenesis. We compared IL-8 messenger RNA levels between the high gastric cancer risk country, Bhutan (mainly East Asian-type H pylori), and the lower gastric cancer risk country, Dominican Republic (mainly Western-type H pylori). PMID- 25454484 TI - False-positive fluorodeoxyglucose positron emission tomography results after chemotherapy in patients with metastatic seminoma. AB - INTRODUCTION: The treatment of residual masses after chemotherapy in seminomas remains a controversial topic. Postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) in all patients would lead to severe overtreatment with a high rate of complications and additional procedures. For this reason, fluorodeoxyglucose positron emission tomography (FDG-PET) was introduced. FDG-PET has an accuracy of 88%. In 15% of cases, FDG-PET findings are false positive (FP) with unclear consequences. Therefore, we retrospectively investigated the rate of unnecessary procedures due to FP results on FDG-PET. MATERIALS AND METHODS: Between July 2003 and September 2013 we performed 305 PC-RPLNDs in 277 patients, 22 because of metastatic seminoma. Of them, 11 patients had a preoperative FDG PET at least 6 weeks after chemotherapy. Indication for surgery was a marker negative progression of the lesion in 7 patients who did not undergo FDG-PET, a marker-negative progression with a negative result on FDG-PET in 2 patients, and a positive result on FDG-PET with normal markers in 9 patients. Furthermore, PC RPLND was indicated in 3 patients because of ureteral compression/infiltration with ureteral stents or nephrostomies. In 1 patient, there was uncertainty whether the initial retroperitoneal tumor contained choriocarcinoma elements. Standardized uptake values (SUVs) were recorded for all patients undergoing FDG PET. RESULTS: The FDG-PET findings were FP in 7 of 11 (64%) patients. The median age of the patients was 45.4 years (39-49). The median SUV in the patients was 6.6 (3.1-11.6), and the median diameter of the residual mass was 6.8 cm (2.9-11). In 4 of 7 patients, intraoperative or postoperative complications occurred (polar artery ligation with functional loss, bilateral non-nerve-sparing technique with retrograde ejaculation, ureteral replacement with an ileal segment, and pulmonary embolism). CONCLUSION: In patients with metastatic seminoma who received chemotherapy, FDG-PET is a valuable tool to evaluate whether the residual mass contains viable tumor tissue or only necrosis. Nevertheless, because of FP results, a subgroup is overtreated with consecutive mortality or morbidity. We suggest an alternative therapy algorithm. In case of a positive result on FDG-PET studies, at least 8 weeks after the end of the chemotherapy, only a minority require surgery (e.g., patients with ureteral compression, patients with high risk of recurrence, or patients with unclear initial histology). In all other cases, we suggest a repeat FDG-PET study at least 6 weeks after the initial PET scan. Only in cases of increased SUVs or progressive disease histology should be obtained, all others can be on active surveillance. PMID- 25454485 TI - Radiotherapy before and after radical prostatectomy for high-risk and locally advanced prostate cancer. AB - OBJECTIVES: Men with localized high-risk prostate cancer carry significant risk of prostate cancer-specific mortality. The best treatment approach to minimize this risk is unclear. In this review, we evaluate the role of radiation before and after radical prostatectomy. METHODS AND MATERIALS: A critical review of the literature was performed regarding the application of external radiation therapy (RT) in combination with prostatectomy for high-risk localized prostate cancer. RESULTS: Up to 70% of men with high-risk localized disease may require adjuvant therapy because of adverse pathologic features or biochemical recurrence in the absence of systemic disease. The utility of adjuvant RT among men with adverse pathologic features are well established at least regarding minimizing biochemical recurrence risk. The optimal timing of salvage radiation is the subject of ongoing studies. Neoadjuvant RT requires further study but is a potentially attractive method because of decreased radiation field sizes and potential radiobiologic benefits of delivering RT before surgery. Salvage prostatectomy is effective at treating local recurrence after radiation but is associated with significant surgical morbidity. CONCLUSIONS: Combining local therapies including radical prostatectomy and RT can be a reasonable approach. Care should be taken at the initial presentation of high-risk localized prostate cancer to consider and plan for the likelihood of multimodality care. PMID- 25454486 TI - Feasibility of obtaining biomarker profiles from endoscopic biopsy specimens in upper tract urothelial carcinoma: preliminary results. AB - OBJECTIVE: To prospectively evaluate the feasibility of obtaining a reliable histochemical assessment of cell cycle biomarkers from endoscopic biopsy specimens of patients with upper tract urothelial cancer. METHODS: Overall, 17 patients were identified who had an available biopsy as well as those who underwent subsequent radical nephroureterectomy (RNU) or segmental ureterectomy (SU) for clinically localized high-grade upper tract urothelial cancer of the renal pelvis or ureter. Of those 17 patients, 15 (88%) had sufficient tissue to undergo immunohistochemical staining. Biopsies were obtained using various endoscopic techniques. Tumor characteristics were recorded and prospectively evaluated for immunohistochemical expression of 5 biomarkers: p21, p27, p53, cyclin E, and Ki67/pRb. Unfavorable prognostic score (PS) was defined as>2 altered markers. RESULTS: The median age of the patients was 68 years (range: 53 82y) with 87% being males. Of the 15 specimens, 9 (60%) tumors were organ confined (T<=2 and N0), and all were high grade. Of the 15 patients, 4 (27%), 7 (46.6%), 3 (20%), and 1 (6.7%) individuals had 1, 2, 3, and 5 markers altered on biopsy marker profiling, respectively, with Ki67 being the most frequent alteration (13/15; 87.7%). An overall concordance rate of 60% (9/15) was seen between biopsy and RNU/SU PS. Those patients with favorable biopsy biomarker PS were less likely to display adverse pathological features, with organ-confined disease in 7/11 (63.6%) patients and 9/11 (81.8%) being free of carcinoma in situ in the final specimen. Additionally, 10/11 (91%) had no evidence of necrosis and 7/11 (64%) had no evidence of lymphovascular invasion on final pathologic evaluation. CONCLUSIONS: Preliminary results suggest that obtaining interpretable biomarker profile of ureteroscopic biopsy specimens is feasible. Tumor heterogeneity and limited biopsy material may account for the discordance between biopsy and RNU/SU specimens. Meaningful biopsy biomarker profiling could serve as a powerful tool for individualizing treatment regimens and augmenting current predictive variables. Further studies are needed to evaluate clinical applicability. PMID- 25454487 TI - Myeloid cells in cancer-related inflammation. AB - Myeloid cells are key elements of the cancer-related inflammation with the potential to support not only tumor growth but also invasion and metastasis. Tumor-derived factors affect myeloid cell differentiation inducing a phenotype that supports tumor growth, inducing immunosuppression, angiogenesis and tissue remodeling. Soluble mediators, produced at primary tumor site, can also act in a remote mode inducing the release from bone marrow of myeloid cells that have immunosuppressive activities in tumor-draining lymphoid organs and can predispose to colonization when migrate to metastatic organs. We will here review current knowledge on the contribution of tumor-derived signals that affect polarized activation of myeloid cells, their bone marrow release and recruitment to metastatic sites with a particular focus on the role of chemokines. PMID- 25454488 TI - Novel insights into the immunomodulatory role of the dendritic cell and macrophage-expressed C-type lectin MGL. AB - Based on their ability to balance tolerance and inflammation, antigen presenting cells, such as dendritic cells and macrophages contribute to the maintenance of immune homeostasis as well as the instigation of immune activation. Acting as key sensors of tissue integrity and pathogen invasion, they are well equipped with a wide variety of pattern recognition receptors, to which the C-type lectin family also belongs. C-type lectins are glycan-binding receptors that mediate cell-cell communication and pathogen recognition, besides participating in the endocytosis of antigens for presentation to T cells and the fine-tuning of immune responses. Here we review the current state-of-the-art on the dendritic cell and macrophage expressed C-type lectin macrophage galactose-type lectin (MGL), highlighting the binding specificities, signaling properties and modulation of innate and adaptive immunity by its human and murine orthologues. PMID- 25454489 TI - The activation status of human macrophages presenting antigen determines the efficiency of Th17 responses. AB - Macrophages are antigen presenting cells that can adopt different activation states as directed by microenvironmental stimuli. It is well-recognised how CD4(+) T helper (Th) signals drive macrophage activation, but the ability of differentially activated human macrophages to stimulate the major types of CD4(+) T helper (Th) response by presenting antigen have not been well defined. Previous studies have focussed on murine cells, undifferentiated human monocytes, or macrophage products, and have been limited to non-physiological mitogenic Th responses. The aim was therefore to compare the Th cell polarising abilities of different human macrophage subsets when presenting specific antigen. We demonstrate for the first time that the way macrophages are activated, while naturally presenting antigen, has profound effects on downstream adaptive immune responses. In autologous co-cultures, LPS-activation was the most potent stimulus for antigen-loaded macrophages to drive Th17 polarisation from both unfractionated CD4(+) T-cells and the CD45RO(+) memory population, while IFNgamma/LPS activated macrophages preferentially induced a Th1 phenotype. By contrast, IL-4-activated macrophages were ineffective in inducing responses by either Th subset. Although antigen-loaded dendritic cells were superior to macrophages in driving Th1 responses, the Th17 polarising capacity of the two antigen-presenting cell types was equivalent, and was strongly dependent on IL 1beta secretion. Taken together, these results clearly demonstrate for the first time how differentially activated human macrophages present antigen to bias specific, rather than mitogen-driven, Th responses and lead us to propose that they impact adaptive immunity in vivo, particularly in determining Th17 polarisation within inflamed tissues. PMID- 25454490 TI - Time-lapse videography of human oocytes following intracytoplasmic sperm injection: events up to the first cleavage division. AB - A total of 341 fertilized and 37 unfertilized oocytes from 63 intracytoplasmic sperm injection (ICSI) treatment cycles were included for retrospective assessment using the Embryoscope time-lapse video system. The second polar body (pb2) extrusion occurred at 2.9+/-0.1 h (range 0.70-10.15 h) relative to sperm injection. All oocytes reduced in size following sperm injection (p<0.05) with shrinkage ceasing after 2h in the unfertilized and at pb2 extrusion in the fertilized oocytes. Pb2 extrusion was significantly delayed for women aged >38 years compared to those <35 years (3.4+/-0.2 vs. 2.8+/-0.1, p<0.01) or 35-38 years (3.4+/-0.2 vs. 2.8+/-0.1, p<0.01), but timing was not related to the Day 3 morphological grades (1-4) of subsequent embryos (2.9+/-0.1, 2.9+/-0.1, 2.8+/-0.2 and 3.0+/-0.1; p>0.05 respectively). A shorter time of first cleavage division relative to either sperm injection or pb2 extrusion is associated with both top grade (AUC=0.596 or 0.601, p=0.006 or 0.004) and usable embryos (AUC=0.638 or 0.632, p=0.000 respectively) on Day 3. In summary, (i) pb2 of human oocytes extrudes at various times following sperm injection, (ii) the timing of pb2 extrusion is significantly delayed when female age >38 years, but not related to subsequent embryo development, (iii) all human oocytes reduce in size following sperm injection, (iv) completion of pb2 extrusion in the fertilized oocytes is a pivotal event in terminating shrinkage of the vitellus, and (v) time to first cleavage division either from sperm injection or pb2 extrusion is a significant predictive marker for embryo quality on Day 3. PMID- 25454491 TI - DNA integrity of fresh and frozen canine epididymal spermatozoa. AB - The aims of this study were to evaluate: (1) the effect of cryopreservation on DNA fragmentation of canine epididymal spermatozoa, and (2) the potential protective effect of melatonin on post-thaw sperm quality (motility, morphology, acrosomal and DNA integrity). Epididymal spermatozoa were collected after orchiectomy of ten dogs. Sperm samples were frozen in the presence or absence of melatonin (1mM). DNA fragmentation index (percentage of spermatozoa with fragmented DNA) was similar in fresh samples (3.3+/-3.6) and samples frozen with (4.2+/-3.8) or without (3.6+/-3.7) melatonin. Sperm motility was significantly (p<0.0001) higher in fresh compared to frozen samples. The presence of melatonin in the freezing extender did not affect the sperm motility. Proportions of spermatozoa with normal morphology were similar in fresh and frozen samples, irrespective of the presence of melatonin in the extender. Acrosome integrity was significantly decreased (p<0.01) by cryopreservation, and melatonin did not exert any beneficial effects. In conclusion, DNA fragmentation of canine epididymal spermatozoa was not affected by the freezing procedure, and the presence of melatonin did not preserve motility and acrosome integrity which were adversely affected by cryopreservation. The evaluation of DNA status of thawed gametes is particularly relevant for epididymal spermatozoa since these spermatozoa are usually stored and used in assisted reproductive techniques. PMID- 25454493 TI - mRNA expression pattern of gonadotropin receptors in bovine follicular cysts. AB - Follicular growth and steroidogenesis are dependent on gonadotropin binding to their receptors in granulosa and theca cells of ovarian follicles. The aim of the present study was to evaluate the expression patterns of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHCGR) in ovarian follicular structures from cows with cystic ovarian disease (COD) as compared with those of regularly cycling cows. Relative real-time RT-PCR analysis showed that the expression of FSHR mRNA in granulosa cells was highest in small antral follicles, then decreased significantly as follicles increased in size, and was lowest in cysts. FSHR mRNA was not detected in the theca cells of any follicular category, including cysts. LHCGR mRNA expression in granulosa cells was significantly higher in large antral follicles than in cysts, and not detected in granulosa cells of small and medium antral follicles. In theca cells, the expression level of LHCGR mRNA in medium antral follicles was higher than in small and large antral follicles, whereas that in follicular cysts it was similar to those in small and medium antral follicles, but higher than that in large antral follicles. Our findings provide evidence that there is an altered gonadotropin receptor expression in bovine cystic follicles, and suggest that in conditions characterized by altered ovulation, such as COD, changes in the signaling system of gonadotropins may play a fundamental role in their pathogenesis. PMID- 25454494 TI - Local transfer of testosterone and aromatase activity in the spermatic cord in wild boar/pig hybrids in short-daylight and long-daylight periods. AB - The local transfer of testosterone (T) and immunolocalization of cytochrome P450 aromatase (P450arom) in the spermatic cord vessels of ten male wild boar*domestic pig hybrids were examined in December (short-daylight period) and June (long daylight period). Total T concentration was determined in the jugular vein (JV) and free T concentration was estimated in the common carotid artery (CA), branches of the testicular artery supplying the testis (TA) and epididymis (EA), as well as in testicular veins draining blood from the testis (TV) and spermatic cord (SV). P450arom was immunolocalized in the arterial and venous vessels of the spermatic cord. The concentrations of total T in the JV and free T in the CA did not differ between the examined periods. However, in December, free T concentrations in the TA and EA were higher (p<0.01-0.001) than in the CA. In June, free T concentration was higher (p<0.01) in EA than in CA and TA. The concentrations of free T in the TV and SV were higher (p<0.001) than in the JV regardless of the period. Also, free T concentration in the SV was higher (p<0.05) in June than in December. P450arom was expressed in all layers of the arterial and venous vessels of the spermatic cord. In June, the intensity of the P450arom staining was higher than in December. The results suggest that the local supply of the male reproductive organs with steroid hormones operate in the hybrids of wild boar*domestic pig. This supply includes the local transfer of testosterone and the P450arom action. PMID- 25454492 TI - Human placenta-derived Wnt-5a induces the expression of ICAM-1 and VCAM-1 in CD133(+)CD34(+)-hematopoietic progenitor cells. AB - Angiogenesis and vascular development are essential for fetal development and growth, whereby early pregnancy loss and other pregnancy-related pathologies have been linked to aberrant vascular development. As Wnt signalling has been suggested to play a role in the vascularization of chorionic villi, we investigated the expression of Wnt family members in trophoblasts and stromal cells isolated from chorionic villi of early placenta and the influence of Wnt signalling on CD133(+)CD34(+)-hematopoietic progenitor (CD133(+)CD34(+)) cells. Wnt-5a was expressed in human placental stromal cells and to a lesser extent in human trophoblast cells. rWnt-5a impeded migration and induced adhesion of CD133(+)CD34(+) cells, in accordance with the expression of adhesion proteins, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). rWnt-5a-related regulation of the ICAM-1 and VCAM-1 expression were dependent on the release of Ca2+ and the activation of transcription factor - nuclear factor of activated T-cells (NF-AT). We propose that Wnt-5a is required during early placenta development to mediate adhesion and homing of CD133(+)CD34(+) cells. PMID- 25454495 TI - Morphological evaluation of sperm from infertile men selected by magnetic activated cell sorting (MACS). AB - Electron microscopy analysis performed in five infertile human subjects after sperm selection by swim-up followed by magnetic activated cell sorting (MACS) demonstrated a decrease in the number of spermatozoa with characteristics compatible with cell death. However, no significant differences were found when the swim-up/MACS semen fraction was compared with swim-up fraction alone. PMID- 25454496 TI - Differential expression of genes linked to the leukemia inhibitor factor signaling pathway during the estrus cycle and early pregnancy in the porcine endometrium. AB - The objective of this study was to determine the expression profiles of leukemia inhibitory factor (LIF) and its receptor (LIFR), interleukin 6 receptor (IL6R), tumor protein p53 (TP53) and B-cell CLL/lymphoma 2 (BCL2) in the porcine endometrium on selected days of the estrous cycle and pregnancy. Time- and reproductive status (estrous cycle/pregnancy)-specific patterns of expression were identified for all investigated genes. The most pronounced changes were seen on Days 12 and 14 of pregnancy when maternal recognition of pregnancy and implantation, respectively, occurs in pigs. PMID- 25454497 TI - Short-term glutamate administration positively affects the number of antral follicles and the ovulation rate in cyclic adult goats. AB - The acute effects of short-term glutamate administration on the number of antral follicles and ovulation rate were examined in adult goats. Neither live weight (44.5+/-1.3 kg) nor body condition (3.3+/-0.8 units) differed between the control (untreated) and glutamate-treated (0.175 mg/kg) animals (p>0.05). However, the number of antral follicles (3.4 vs. 2.1, p=0.05) and ovulation rate (2.5 vs. 1.5, p=0.05) was higher in the glutamate-administered group than in the controls. PMID- 25454498 TI - Validation of reference genes in the feline endometrium. AB - The aim of the study was to find the most stable reference genes from: ACTB, GAPDH, RPL30, CYC, RPL17, RPS7 and YWHAZ in the feline endometrium. Three free software packages, geNorm, NormFinder and BestKeeper were used. In geNorm analysis, the most stable gene was RPS7 (at a primer concentration 1000 nM) or YWHAZ (500 and 250 nM). According to NormFinder and BestKeeper, ACTB (at all examined primer concentrations) followed by RPS7 and CYC were the most stable genes. Based on geNorm results at least two genes from among RPS7, RPL30, ACTB or YWHAZ should be chosen for Real Time-PCR result normalization. PMID- 25454500 TI - Risk factors for post-stroke seizures: a systematic review and meta-analysis. AB - PURPOSE: To perform a systematic review and meta-analysis to identify risk factors associated with early seizure (ES) or late seizure (LS) onset in adults following stroke. DATA SOURCES: Electronic databases (MEDLINE and EMBASE), archives of stroke or epilepsy patients, and bibliographies of relevant articles, which were written in English. STUDY SELECTION: We included studies published since 1990 that reported the stroke and seizure outcomes of adult patients during follow-up. We independently performed title, abstract and full-text screening and resolved disagreements through discussion. DATA EXTRACTION: Two authors performed the data extraction. We recorded all possible risk factors predictive of seizure onset. DATA SYNTHESIS: We used odds ratios (ORs) or the mean difference (MD) to compare the pooled rates of seizure onset between the exposed group and the non exposed group. All meta-analyses were performed with Review Manager Software. RESULTS: Intracerebral hemorrhage (OR=1.88, 95% CI=1.43-2.47), cerebral infarction with hemorrhagic transformation (OR=3.28, 95% CI=2.09-5.16), stroke severity (OR=3.10, 95% CI=2.00-4.81, p<0.01, I(2)=0%; MD=3.98, 95% CI=1.06-6.90, p<0.01), and alcoholism (OR=1.70, 95% CI=1.23-2.34, p<0.01) were associated with a significantly greater probability of ES occurrence. There were significant effects of cortical involvement (OR=2.50, 95% CI=1.93-3.23) and stroke severity (MD=5.72, 95% CI=4.23-7.22, p<0.01, I(2)=0) on LS onset. However, there was no significant difference in the probability of single LS episode between patients with intracerebral hemorrhage and infarction stroke (OR=1.20, 95% CI=0.92-1.55). CONCLUSIONS: Evidence suggests that cortical involvement, stroke subtypes and stroke severity are significant predictors of seizure onset following stroke. However, we did not find a significant difference in the rate of onset of single LS episodes between patients with intracerebral hemorrhage and cerebral infarction. PMID- 25454499 TI - Design and nuclear magnetic resonance (NMR) structure determination of the second extracellular immunoglobulin tyrosine kinase A (TrkAIg2) domain construct for binding site elucidation in drug discovery. AB - The tyrosine kinase A (TrkA) receptor is a validated therapeutic intervention point for a wide range of conditions. TrkA activation by nerve growth factor (NGF) binding the second extracellular immunoglobulin (TrkAIg2) domain triggers intracellular signaling cascades. In the periphery, this promotes the pain phenotype and, in the brain, cell survival or differentiation. Reproducible structural information and detailed validation of protein-ligand interactions aid drug discovery. However, the isolated TrkAIg2 domain crystallizes as a beta strand-swapped dimer in the absence of NGF, occluding the binding surface. Here we report the design and structural validation by nuclear magnetic resonance spectroscopy of the first stable, biologically active construct of the TrkAIg2 domain for binding site confirmation. Our structure closely mimics the wild-type fold of TrkAIg2 in complex with NGF ( 1WWW .pdb), and the (1)H-(15)N correlation spectra confirm that both NGF and a competing small molecule interact at the known binding interface in solution. PMID- 25454501 TI - Valproate treatment normalizes EEG functional connectivity in successfully treated idiopathic generalized epilepsy patients. AB - AIM: To investigate the effect of chronic VPA treatment of EEG functional connectivity in successfully treated idiopathic generalized epilepsy (IGE) patients. PATIENTS AND METHODS: 19-channel waking, resting-state EEG records of 26 IGE patients were analyzed before treatment (IGE) and after the 90th day of treatment (VPA), in seizure-free condition. Three minutes of artifact-free EEG background activity (without epileptiform potentials) was analyzed for each patient in both conditions. A group of 26 age-matched healthy normative control persons (NC) was analyzed in the same way. All the EEG samples were processed to LORETA (Low Resolution Electromagnetic Tomography) to localize multiple distributed sources of EEG activity. Current source density time series were generated for 33 regions of interest (ROI) in each hemisphere for four frequency bands. Pearson correlation coefficients (R) were computed between all ROIs in each hemisphere, for four bands across the investigated samples. R values corresponded to intrahemispheric, cortico-cortical functional EEG connectivity (EEGfC). Group and condition differences were analyzed by statistical parametric network method. MAIN RESULTS: p<0.05, corrected for multiple comparisons: (1) The untreated IGE group showed increased EEGfC in the delta and theta bands, and decreased EEGfC in the alpha band (as compared to the NC group); (2) VPA treatment normalized EEGfC in the delta, theta and alpha bands; and (3) degree of normalization depended on frequency band and cortical region. CONCLUSIONS: VPA treatment normalizes EEGfC in IGE patients. PMID- 25454502 TI - Effectiveness of levetiracetam use following resective surgery in patients with refractory epilepsy: a prospective observational study. AB - PURPOSE: This study aimed to evaluate the effectiveness of levetiracetam (LEV) use for seizure control in patients who had undergone resective surgery for intractable epilepsy in routine clinical practice. METHODS: This was a prospective, observational study. Refractory epilepsy patients who underwent epilepsy surgery from January 2008 to December 2011 in the Department of Neurosurgery, West China Hospital were prospectively analyzed. Patients were divided into two groups according to antiepileptic drug (AED) treatment used immediately after epilepsy surgery (group A: therapy with LEV; group B: therapy without LEV). AED regimens were compared with regard to seizure-outcome for a period of more than 2 years. The International League Against Epilepsy (ILAE) classification was used to categorize seizure outcome. RESULTS: A total of 319 patients (184 male and 135 female patients; mean age 28.2+/-13.4 years) were studied. The mean postoperative follow-up period was 3.9+/-1.2 years. The two groups showed was no significant difference in preoperative baseline data. At the 6-month follow-up, the proportion of patients with seizure freedom was significantly higher in group A than in group B (78.8% vs. 67.5%, p=0.03). Seizure outcomes after 2 years were assessed using the ILAE classification. The proportion of patients under ILAE seizure-outcome classification I (seizure freedom) was significantly higher in group A than in group B (74.3% vs. 60.7%, p=0.01). Seizure recurrence rates at the final assessment, after planned reduction or withdrawal, were 26.3% for group A and 40.6% for group B (p=0.04). CONCLUSIONS: AED strategy after resective surgery may be a potentially modifiable prognostic indicator influencing seizure outcome in patients with intractable epilepsy. Compared to other AEDs, LEV appears to be more effective in controlling postoperative seizures in our long-term follow-up, and the advantage can be seen in early stage after surgery. PMID- 25454503 TI - Ketogenic diet in pediatric patients with refractory focal status epilepticus. AB - The ketogenic diet (KD) has been used as an alternative treatment for patients with refractory status epilepticus (SE). PURPOSE: In this retrospective study we assess the efficacy and tolerability of the KD in patients with refractory SE. METHODS: Between March 1, 2010 and January 1, 2014, 10 patients who met the diagnostic criteria of refractory SE seen at our department were placed on the KD and followed for a minimum of 6 months. RESULTS: Ketonuria was reached within 2-4 days (mean 3 days) for all patients. Seizures stopped in two patients and five patients had a 50-75% seizure reduction within 2-5 days (mean 2.5 days) following the onset of ketonuria and within 5-7 days (mean 5 days) following the onset of the diet. Three patients had a <50% seizure reduction and all of them had severe adverse events so the diet was discontinued. Seven patients remained on the diet for 6 months to 3 years (mean 1.5 years). In all seven patients within 4 months the seizures recurred, but their quality of life did not worsen. The frequency of the seizures consisted of weekly seizures in two, monthly seizures in two, occasional seizures in two, and isolated seizures in one. All of them kept a good tolerability of the diet. CONCLUSION: The KD is an effective and well-tolerated treatment option for patients with refractory SE. In patients with focal SE secondary to inflammatory or probably inflammatory diseases, the KD should be considered earlier in the course of the treatment. PMID- 25454504 TI - Screening for mental health disorders in active childhood epilepsy: population based data. AB - BACKGROUND: Children with epilepsy are at increased risk for behavioral and psychiatric disorders and it has been recommended that all children with epilepsy be screened for such conditions. There is thus a need to identify appropriate screening measures in this population. METHODS: Children with active epilepsy (on AEDs and/or had a seizure in the last year) with an IQ>34 (n=69) were screened for behavioral/psychiatric disorders using the parent and teacher versions of the Strengths and Difficulties Questionnaire (SDQ) in a population-based sample. Consensus clinical diagnoses were made with respect to DSM-IV-TR data. Parent and teacher responses on the SDQ total and subscales were compared using paired samples t-tests and Pearson's correlation. The screening properties of the SDQ were explored. Regression using generalized estimating equations was used to identify predictors of responses on the SDQ. RESULTS: 62% of children received a DSM-IV-TR diagnosis. On the total SDQ score the number of children identified at risk by parents (61%) was higher than the number identified by teachers (43%). Mean parent scores were significantly higher than teacher scores on the SDQ Conduct and Hyperactive subscales and total score after Bonferroni correction (adjusted alpha p<.007). Sensitivity and specificity of the SDQ total score were maximized by combining parent and teacher responses. The positive predictive values (PPVs) were much higher for the total score than the specific subscales suggesting that while the SDQ total score has good predictive ability the specific scales are less useful. Respondent (i.e., parent and teacher) was a significant predictor of scores for some but not all subscales. CONCLUSION: The SDQ can be considered a promising tool for screening children with active epilepsy provided the total score is used as a screener for the presence of any DSM-IV-TR disorder and multi-informant data are used. PMID- 25454505 TI - Arterial Spin Labeling MRI: a step forward in non-invasive delineation of focal cortical dysplasia in children. AB - The aim was to localize the interictal cerebral perfusion abnormalities of focal cortical dysplasia (FCD) in children with Arterial Spin Labeling MRI (ASL) in a retrospective study of nine consecutive children explored with multimodal investigation during interictal periods. We analyzed brain morphology with a 1.5T MRI and a dedicated protocol for epilepsy. Brain perfusion was quantified with pseudo continuous ASL. Brain metabolism was imaged with (18)FDG-PET in six patients. Microvessel histology was studied in five children who underwent epilepsy surgery with CD34 immunostaining on FCD and control samples. Localized decrease of cerebral blood flow (CBF) was found on visual analysis in all patients with ASL. It was co-localized with the structural MRI abnormalities in every case, with PET hypo-metabolism in 5/6 cases, and with histologically proven FCD type IIb in 5/5 cases (all seizure free after surgery). CBF was lower (Kruskal-Wallis test, p=0.001) in FCD than in normal cortex. The total count of CD34+ microvessels was similar in FCD and control cases, but microvasculature showed disorganized architecture. Interictal ASL is a non-invasive method that may help to localize the epileptogenic zone showing hypo-perfusion in FCD. Whether this finding could be generalized to MRI-negative FCD needs to be further studied. PMID- 25454506 TI - Can your protein be sumoylated? A quick summary and important tips to study SUMO modified proteins. AB - A diverse set of SUMO target proteins has been identified. Therefore, there is a growing interest in studying sumoylation and SUMO interactions in cells. When the sumoylation of a protein or a SUMO interaction is suspected, a standard co immunoprecipitation analysis using anti-SUMO and anti-target protein antibody is usually performed as a first step. However, the identification of endogenous sumoylated proteins is challenging because of the activity of isopeptidases, and often only a small fraction of a target protein is sumoylated at a given time. Here, we briefly summarize several important steps to ensure a successful co immunoprecipitation analysis to detect possible sumoylation. PMID- 25454507 TI - Development of an enzymatic chromatography strip with nicotinamide adenine dinucleotide-tetrazolium coupling reactions for quantitative l-lactate analysis. AB - In this study, a dry assay of l-lactate via the enzymatic chromatographic test (ECT) was developed. An l-lactate dehydrogenase plus a nicotinamide adenine dinucleotide (NADH) regeneration reaction were applied simultaneously. Various tetrazolium salts were screened to reveal visible color intensities capable of determining the lactate concentrations in the sample. The optimal analysis conditions were as follows. The diaphorase (0.5 MUl, 2(-6)U/MUl) was immobilized in the test line of the ECT strip. Nitrotetrazolium blue chloride (5 MUl, 12 mM), l-lactate dehydrogenase (1 MUl, 0.25U/MUl), and NAD(+) (2MUl, 1.5*10(-5)M) were added into the mobile phase (100 MUl) composed of 0.1% (w/w) Tween 20 in 10mM phosphate buffer (pH 9.0), and the process was left to run for 10 min. This detection had a linear range of 0.039 to 5mM with a detection limit of 0.047 mM. This quantitative analysis process for l-lactate was easy to operate with good stability and was proper for the point-of-care testing applications. PMID- 25454508 TI - Advances and limits of using population genetics to understand local adaptation. AB - Local adaptation shapes species diversity, can be a stepping stone to ecological speciation, and can facilitate species range expansion. Population genetic analyses, which complement organismal approaches in advancing our understanding of local adaptation, have become widespread in recent years. We focus here on using population genetics to address some key questions in local adaptation: what traits are involved? What environmental variables are the most important? Does local adaptation target the same genes in related species? Do loci responsible for local adaptation exhibit trade-offs across environments? After discussing these questions we highlight important limitations to population genetic analyses including challenges with obtaining high-quality data, deciding which loci are targets of selection, and limits to identifying the genetic basis of local adaptation. PMID- 25454510 TI - The evolution of allergen and non-specific immunotherapy: past achievements, current applications and future outlook. AB - Recent epidemiological studies estimated that more than 30% of European suffer from allergic rhinitis or conjunctivitis, while up to 20% suffer from asthma and 15% from allergic skin conditions, while for many other regions the prevalence is increasing. Allergen immunotherapy represents the only available treatment that can modify the allergic disease process, and thus is worth considering as a treatment in affected individuals. A beneficial effect of allergen immunotherapy has been shown in both adults and children affected by allergic rhinitis, allergic conjunctivitis, allergic asthma and hymenoptera venom allergy. The present study represents an overview on allergen immunotherapy, focusing on the principal aspects of the use of immunotherapy in the past, its recent clinical applications and future outlook. PMID- 25454511 TI - H3Africa and the African life sciences ecosystem: building sustainable innovation. AB - Interest in genomics research in African populations is experiencing exponential growth. This enthusiasm stems in part from the recognition that the genomic diversity of African populations is a window of opportunity for innovations in postgenomics medicine, ecology, and evolutionary biology. The recently launched H3Africa initiative, for example, captures the energy and momentum of this interest. This interdisciplinary socio-technical analysis highlights the challenges that have beset previous genomics research activities in Africa, and looking ahead, suggests constructive ways H3Africa and similar large scale science efforts could usefully chart a new era of genomics and life sciences research in Africa that is locally productive and globally competitive. As independent African scholars and social scientists, we propose that any serious global omics science effort, including H3Africa, aiming to build genomics research capacity and capability in Africa, needs to fund the establishment of biobanks and the genomic analyses platforms within Africa. Equally they need to prioritize community engagement and bioinformatics capability and the training of African scientists on these platforms. Historically, the financial, technological, and skills imbalance between Africa and developed countries has created exploitative frameworks of collaboration where African researchers have become merely facilitators of Western funded and conceived research agendas involving offshore expatriation of samples. Not surprisingly, very little funding was allocated to infrastructure and human capital development in the past. Moving forward, capacity building should materialize throughout the entire knowledge co production trajectory: idea generation (e.g., brainstorming workshops for innovative hypotheses development by African scientists), data generation (e.g., genome sequencing), and high-throughput data analysis and contextualization. Additionally, building skills for political science scholarship that questions the unchecked assumptions of the innovation performers be they funders, scientists, and social scientists, would enable collective innovation that is truly sustainable, ethical, and robust. PMID- 25454512 TI - Network analyses of sperm-egg recognition and binding: ready to rethink fertility mechanisms? AB - The rapid growth of published literature makes biomedical text mining increasingly invaluable for unpacking implicit knowledge hidden in unstructured text. We employed biomedical text mining and biological networks analyses to research the process of sperm egg recognition and binding (SERB). We selected from the literature the molecules expressed either on spermatozoa or on oocytes thought to be involved in SERB and, using an automated literature search software (Agilent Literature Search), we realized a network, SERBN, characterized by a hierarchical scale free and a small world topology. We used an integrated approach, either based on selection of hubs or by a cluster analysis, to discern the key molecules of SERB. We found that in most cases some of them are not directly situated on spermatozoa and oocyte, but are dispersed in oviductal fluid or embedded in exosomes present in the perivitelline space. To confirm and validate our results, we performed further analyses using STRING and Reactome FI software. Our findings underscore that the fertility is not a property of gametes in isolation, but rather depends on the functional integrity of the entire reproductive system. These observations collectively underscore the importance of integrative biology in exploring biological systems and in rethinking of fertility mechanisms in the light of this innovative approach. PMID- 25454513 TI - New insights into schizophrenia disease genes interactome in the human brain: emerging targets and therapeutic implications in the postgenomics era. AB - Schizophrenia, a complex neurological disorder, is comprised of interactions between multiple genetic and environmental factors wherein each of the factors individually exhibits a small effect. In this regard a network-based strategy is best suited to capture the combined effect of multiple genes with their definite pattern of interactions. Given that schizophrenia affects multiple regions of the brain, we postulated that instead of any single specific tissue, a mutual set of interactions occurs between different regions of brain in a well-defined pattern responsible for the disease phenotype. To validate, we constructed and compared tissue specific co-expression networks of schizophrenia candidate genes in twenty diverse brain tissues. As predicted, we observed a common interaction network of certain genes in all the studied brain tissues. We examined fundamental network topologies of the common network to sequester essential common candidates for schizophrenia. We also performed a gene set analysis to identify the essential biological pathways enriched by the common candidates in the network. Finally, the candidate drug targets were prioritized and scored against known available schizophrenic drugs by molecular docking studies. We distinctively identified protein kinases as the top candidates in the network that can serve as probable drug targets for the disease. Conclusively, we propose that a comprehensive study of the connectivity amongst the disease genes themselves may turn out to be more informative to understand schizophrenia disease etiology and the underlying complexity. PMID- 25454514 TI - Profilin-1 overexpression in MDA-MB-231 breast cancer cells is associated with alterations in proteomics biomarkers of cell proliferation, survival, and motility as revealed by global proteomics analyses. AB - Despite early screening programs and new therapeutic strategies, metastatic breast cancer is still the leading cause of cancer death in women in industrialized countries and regions. There is a need for novel biomarkers of susceptibility, progression, and therapeutic response. Global analyses or systems science approaches with omics technologies offer concrete ways forward in biomarker discovery for breast cancer. Previous studies have shown that expression of profilin-1 (PFN1), a ubiquitously expressed actin-binding protein, is downregulated in invasive and metastatic breast cancer. It has also been reported that PFN1 overexpression can suppress tumorigenic ability and motility/invasiveness of breast cancer cells. To obtain insights into the underlying molecular mechanisms of how elevating PFN1 level induces these phenotypic changes in breast cancer cells, we investigated the alteration in global protein expression profiles of breast cancer cells upon stable overexpression of PFN1 by a combination of three different proteome analysis methods (2-DE, iTRAQ, label-free). Using MDA-MB-231 as a model breast cancer cell line, we provide evidence that PFN1 overexpression is associated with alterations in the expression of proteins that have been functionally linked to cell proliferation (FKPB1A, HDGF, MIF, PRDX1, TXNRD1, LGALS1, STMN1, LASP1, S100A11, S100A6), survival (HSPE1, HSPB1, HSPD1, HSPA5 and PPIA, YWHAZ, CFL1, NME1) and motility (CFL1, CORO1B, PFN2, PLS3, FLNA, FLNB, NME2, ARHGDIB). In view of the pleotropic effects of PFN1 overexpression in breast cancer cells as suggested by these new findings, we propose that PFN1-induced phenotypic changes in cancer cells involve multiple mechanisms. Our data reported here might also offer innovative strategies for identification and validation of novel therapeutic targets and companion diagnostics for persons with, or susceptibility to, breast cancer. PMID- 25454515 TI - Bacillus subtilis chitinase identified by matrix-assisted laser desorption/ionization time-of flight/time of flight mass spectrometry has insecticidal activity against Spodoptera litura Fab. AB - An extracellular chitinase was identified and purified (CS1 and CS2) from Bacillus subtilis. The 16S rRNA sequencing was submitted in GenBank (accession numbers KC336487 and KC412256). The purified crude enzymes were identified through matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (MALDI-TOF MS) analysis. The peptide sequences were matched with chitinase sequences. The peak m/z with 1297. 592 and 3094.570 mascot search resulted sequence was blasted with NCBI protein sequences and confirmed that it is a chitinase enzyme. The effects of chitinase on gut enzymes lactate dehydrogenase, acid phosphatase, alkaline phosphatase and adenosine triphosphatase of the tobacco cutworm Spodoptera litura larvae were investigated. At all concentrations tested, chitinase decreased the activities of these gut enzymes relative to the control. When chitinase treated leaves were fed to larvae in bioassays, gut tissue and gut enzymes were affected. The histological study clearly shows the chitinase treated larval gut, peritrophic membrane and epithelial cells were affected significantly. Chitinase isolated from B. subtilis has effectively reduced the gut enzyme activity and growth of S. litura. The chitin based bioformulation may serve as an effective biocide against the polyphagous pest like S. litura. PMID- 25454517 TI - Biomineralization and formulation of endosulfan degrading bacterial and fungal consortiums. AB - Microbial degradation offers an effective approach to remove toxicants and in this study, a microbial consortium consisting of bacterial strains and fungal strains were originally obtained from endosulfan contaminated agricultural soils. Identification of the bacterial isolates by 16S rRNA sequences revealed the isolates to be Halophilic bacterium JAS4, Klebsiella pneumoniae JAS8, Enterobacter asburiae JAS5, and Enterobacter cloacae JAS7, whereas the fungal isolates were identified by 18S rRNA sequences and the isolates were Botryosphaeria laricina JAS6, Aspergillus tamarii JAS9 and Lasiodiplodia sp. JAS12. The biodegradation of endosulfan was monitored by using HPLC and FTIR analysis. The bacterial and fungal consortium could degrade 1000 mg l(-1) of endosulfan efficiently in aqueous medium and in soil. The infrared spectrum of endosulfan degraded samples in the aqueous medium by bacterial and fungal consortium showed bands at 1400 and 950 cm(-1) which are the characteristics of COOH group and acid dimer band respectively. In the present investigation, low cost solid materials such as sawdust, soil, fly ash, molasses and nutrients were used for the formulation of microbial consortium and to achieve greater multiplication and survival of the microbial strains. PMID- 25454516 TI - Dimethoate modifies enhanced UV-B effects on growth, photosynthesis and oxidative stress in mung bean (Vigna radiata L.) seedlings: implication of salicylic acid. AB - The present study is aimed to investigate implication of salicylic acid (SA) in regulation of dimethoate (30 and 150 ppm designated as D1 and D2, respectively) and enhanced UV-B radiation (ambient + supplemental; ambient + 4.0 kJ m(-2) and ambient + 8.0 kJ m(-2), designated as UV-B1 and UV-B2, respectively) induced responses in mung bean seedlings. Seeds of Vigna radiata L. cv. Narendra 1 were surface sterilized, washed thoroughly and soaked for 24 h in sterilized distilled water. Soaked seeds were sown in acid washed sterilized sand filled in plastic trays, and incubated in dark at 26 +/- 2 degrees C for 2 days. The seedlings were grown in growth chamber at 26 +/- 2 degrees C with 12 h photoperiod (350 umol photons m(-2 )s(-1), PAR) and watered regularly. Six day old seedlings of equal size were gently transferred in 0.2 strength Rorison nutrient medium (pH 6.8) for acclimatization. Thereafter, dimethoate (30 and 150 ppm designated as D1 and D2, respectively) and enhanced UV-B radiation treatments were given. On the 12th day, seedlings of each set were harvested and various parameters related to growth, pigments, photosynthesis, oxidative stress and antioxidant system were analyzed. The D2 dose of dimethoate and UV-B1 and UV-B2 alone and together significantly (P < 0.05) declined growth, photosynthetic pigments and photosynthesis (Fv/Fm and qP except NPQ) which were accompanied by significant decrease in SA level. Similarly, D2 and UV-B also enhanced (P < 0.05) accumulation of reactive oxygen species and concomitantly damaging effects on lipids, proteins and membrane stability were observed. In contrast, in SA pretreated seedlings damaging impacts of D2, UV-B1 and UV-B2 alone and together were significantly (P < 0.05) alleviated. Besides this, interestingly D1 dose of dimethoate alone had stimulatory effect on growth and it also ameliorated damaging effects of both the doses of UV-B. The activity of superoxide dismutase was stimulated by all the combinations. However, catalase, glutathione reductase and dehydroascorbate reductase activities were significantly (P < 0.05) inhibited by D2, UV-B1 and UV-B2 while SA-pretreatment ameliorated D2 and UV-B-induced inhibitions in activities of these enzymes. Total ascorbate and glutathione pools also decreased by D2 and both doses of UV-B; however, in SA-pretreated seedlings their amounts were significantly (P < 0.05) higher than D2, UV-B1 and UV-B2 alone. Interestingly, D1 also alleviated damaging impact of UV-B1 and UV-B2 on total ascorbate and glutathione pools. Results revealed that D2, UV-B1 and UV-B2 might alter SA biosynthesis that results into declined SA level which might be related with their toxicity. However, SA-pretreatment might act as a signal that reduces oxidative stress by triggering up-regulation of antioxidants hence improved growth and photosynthesis noticed. Alleviation of UV-B toxicity by D1 suggests about hormesis that triggers SA biosynthesis and hence protection against both doses of UV-B was observed. PMID- 25454518 TI - Evaluating the enantioselective degradation and novel metabolites following a single oral dose of metalaxyl in mice. AB - Metalaxyl [N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D,L-alaninemethylester] is a systemic fungicide widely used in agriculture. In this study, the enantioselective distribution, degradation and excretion of metalaxyl were investigated after oral gavage administration of rac-metalaxyl to mice. Concentration of metalaxyl and its enantiomers was determined by HPLC-MS/MS. The results showed that R-metalaxyl was much higher than S-metalaxyl in heart, liver, lung, urine and feces. As for the strong first pass effect, concentrations of metalaxyl in liver were much higher than those in other tissues. The total body clearance (CL) of metalaxyl in mice was 1.77 L h(-1 )kg(-1) and degradation half lives of (t1/2) of S-metalaxyl and R-metalaxyl in liver were 2.2 h and 3.0 h, respectively. Such results indicated the enantioselectivity of metalaxyl lies in distribution, degradation and excretion processes in mice. Main metabolites were also determined and biotransformation reactions were hydroxylation, demethylation and didemethylation. Furthermore, metabolite concentrations in urine and feces were much higher than those in tissues. These results may have potential implications to predict toxicity and provide additional information associated with adverse health effects for risk assessment of metalaxyl. PMID- 25454520 TI - Histomorphological and biochemical changes induced by triptolide treatment in male lesser bandicoot rat, Bandicota bengalensis. AB - Mature and healthy male lesser bandicoot rats, Bandicota bengalensis (n = 40) were fed on bait (mixture of cracked wheat and powdered sugar in 98:2) containing different concentrations of triptolide (0, 0.15, 0.20 and 0.25% w/w) for 15 days in two-choice trials. Results revealed no significant effect of triptolide treatment on weights of vital organs after 30 and 60 days of treatment withdrawal. A significant (P <= 0.05) increase in plasma levels of TP, ALP, ACP, ALT and AST in response to stress induced in groups of rats treated with 0.20 and 0.25% triptolide was observed after 30 days of treatment withdrawal. No significant effect of treatment was observed on histomorphology of liver. A significant (P <= 0.05) effect of triptolide treatment was, however, observed on testicular function in the form of reduced diameter of seminiferous tubules and number of various spermatogenic cells indicating effect on spermatogenesis and spermiogenesis. The cell stages affected did not recover fully within 60 days period following treatment withdrawal. The present study suggests the potential of triptolide in the reproductive management of B. bengalensis by way of affecting testicular function. PMID- 25454519 TI - In vivo and in vitro inhibition of Spodoptera littoralis gut-serine protease by protease inhibitors isolated from maize and sorghum seeds. AB - Seeds of cereals (Gramineae) are a rich source of serine proteinase inhibitors of most of the several inhibitor families. In the present study, trypsin and chymotrypsin inhibitory activities was detected in the seed flour extracts of three varieties of maize (Zea maize) and six varieties of sorghum (Sorghum bicolor). The maize variety, Hi Teck 2031 and the sorghum variety, Giza 10 were found to have higher trypsin and chymotrypsin inhibitory potentials compared to other tested varieties for which they have been selected for further purification studies using ammonium sulfate fractionation and DEAE-Sephadex A-25 column. Maize and sorghum purified proteins showed a single band on SDS-PAGE corresponding to molecular mass of 20.0 and 15.2 kDa for maize and sorghum PIs respectively. The purified inhibitors were stable at temperature below 60 degrees C and were active at wide range of pH from 2 to 12 pH. The kinetic analysis revealed non competitive type of inhibition for both inhibitors against both enzymes. The inhibitor constant (Ki) values suggested high affinity between inhibitors and enzymes. Purified inhibitors were found to have deep and negative effects on the mean larval weight, larval mortality, pupation and mean pupal weight of S.littoralis where maize PI was more effective than sorghum PI. It may be concluded that maize and sorghum protease inhibitor gene(s) could be potential targets for future studies in developing insect resistant transgenic plants. PMID- 25454522 TI - Susceptibility to insecticides and resistance mechanisms in Aedes aegypti from the Colombian Caribbean Region. AB - We determined the susceptibility to insecticides and the biochemical and molecular mechanisms involved in resistance in nine populations of Aedes aegypti (L.) of the Colombian Caribbean region. Bioassays were performed on larvae for susceptibility to temephos and on adults to the insecticides malathion, fenitrothion, pirimiphos-methyl, permethrin, deltamethrin, lambda-cyhalothrin and cyfluthrin. The resistance ratio (RR) for each insecticide in the populations was determined, using the susceptible Rockefeller strain as a susceptible control. Additionally, we evaluated the response of the populations to the diagnostic dose (DD) of the organochlorine pesticide DDT. The following biochemical mechanisms associated with resistance were studied: alpha-esterases, beta-esterases, mixed function oxidases (MFO), glutathione s-transferases (GST) and insensitive acetylcholinesterase (iAChE) as well as the presence of kdr I1,016 mutation and its frequency. All populations studied showed susceptibility to the organophosphates evaluated (RR < 5-fold), except for the Puerto Colombia and Soledad populations which showed high resistance (RR 15-fold) and moderate resistance (RR 5-fold) to temephos, respectively, and Sincelejo (Sucre) with moderate resistance to pirimiphos-methyl (RR 5-fold). All populations evaluated with DD of DDT were found to be resistant with 2-28% of mortality. Variability was observed in the resistance to pyrethroids: permethrin (RR 1.2- to 30.8-fold), deltamethrin RR 0.9- to 37.8-fold), lambda-cyalothrin (RR 3.4- to 83-fold) and cyfluthrin (RR 0.3- to 33.8-fold). Incipiently alpha-esterases and MFO levels were found in the Valledupar population; MFO showed the same profile in Cienaga and GST in the Sincelejo population, all other populations showed unaltered profiles of the enzymes evaluated. The kdr I1,016 mutation was found in all populations evaluated with variability in its allelic and genotypic frequencies. PMID- 25454521 TI - Various effects of the photosystem II--inhibiting herbicides on 5-n alkylresorcinol accumulation in rye seedlings. AB - The effect of three PSII-inhibiting herbicides, lenacil, linuron, and pyrazon, on the accumulation of 5-n-alkylresorcinols in rye seedlings (Secale cereale L.) grown under various light and thermal conditions was studied. All used chemicals increased resorcinolic lipid content in both green and etiolated plants grown at 29 degrees C. At 22 degrees C pyrazon and lenacil decreased the content of alkylresorcinols in plants kept in the darkness and increased their amount in the light-grown seedlings. In turn, level of resorcinolic lipids was decreased by linuron in both etiolated and green plants. At the lowest tested temperature lenacil enhanced production of alkylresorcinols only in etiolated rye seedlings, whereas the light-independent stimulatory action of pyrazon on alkylresorcinol accumulation in rye grown at 15 degrees C was observed. Additionally, only the latter did not exert a negative effect on rye seedling growth under any of tested conditions. Compared with respective controls, the herbicides used also markedly modified the qualitative pattern of resorcinolic homologs. Interestingly, the observed changes generally favored the enhanced antifungal activity of these compounds. Our study provides novel information on the influence of PSII inhibitors on alkylresorcinol metabolism in rye seedlings. The unquestionable achievement of this work is the observation that low dose of pyrazon mainly stimulated both growth and alkylresorcinol synthesis in rye seedlings, a non target plant. Moreover, our experimental work showed unambiguously that the observed pyrazon-driven accumulation and homolog pattern modification of alkylresorcinols dramatically improved the resistance of winter rye to infections caused by Rhizoctonia cerealis. PMID- 25454523 TI - Changes in mouse liver and chicken embryo yolk sac membrane soluble proteins due to an organophosphorous insecticide (OPI) diazinon linked to several noncholinergic OPI effects in mice and chicken embryos. AB - The objective of this study was to identify proteins in mouse livers and chicken embryo yolk sac membranes whose quantities were altered by an organophosphorous insecticide (OPI) treatment and which might be linked, based on their functionality, to the recognized noncholinergic effects of OPI. Mice and fertile chicken eggs were treated with an OPI representative diazinon. The quantitative changes in mouse liver and chicken embryo yolk sac membrane soluble proteins caused by diazinon were determined by two-dimensional electrophoresis. Proteins whose quantity was affected by diazinon were identified by the mass spectrometry. In mouse livers, the altered levels of several enzymes of glucose metabolism were considered with regards to amelioration of hyperglycemia due to diazinon; the reduced levels of 3-hydroxyanthranilate 3,4-dioxygenase to the changes in the l tryptophan to NAD metabolism caused by pyrimidinyl and crotonamide OPI; the reduced levels of catalase, peroxiredoxin and superoxide dismutase to OPI increased lipid and/or kynurenine oxidation, the latter effect resulting also in increased urinary excretion of xanthurenic and kynurenic acids; and an increase in glutathione S-methyltransferase to OPI detoxification. In chicken embryo yolk sac membranes, the reduced availability of procollagen-proline dioxygenase may be the factor in micromelia caused by OPI in chicken embryos. PMID- 25454524 TI - Structural features, substrate specificity, kinetic properties of insect alpha amylase and specificity of plant alpha-amylase inhibitors. AB - BACKGROUND: alpha-Amylase is an important digestive enzyme required for the optimal growth and development of insects. Several insect alpha-amylases had been purified and their physical and chemical properties were characterized. Insect alpha-amylases of different orders display variability in structure, properties and substrate specificity. Such diverse properties of amylases could be due to different feeding habits and gut environment of insects. KEY POINTS: In this review, structural features and properties of several insect alpha-amylases were compared. This could be helpful in exploring the diversity in characteristics of alpha-amylase between the members of the same class (insecta). Properties like pH optima are reflected in enzyme structural features. In plants, alpha-amylase inhibitors (alpha-AIs) occur as part of natural defense mechanisms against pests by interfering in their digestion process and thus could also provide access to new pest management strategies. AIs are quite specific in their action; therefore, these could be employed according to their effectiveness against target amylases. Potential of transgenics with alpha-AIs has also been discussed for insect resistance and controlling infestation. CONCLUSIONS: The differences in structural features of insect alpha-amylases provided reasons for their efficient functioning at different pH and the specificity towards various substrates. Various proteinaceous and non-proteinaceous inhibitors discussed could be helpful in controlling pest infestation. In depth detailed studies are required on proteinaceous alpha-AI-alpha-amylase interaction at different pH's as well as the insect proteinase action on these inhibitors before selecting the alpha-AI for making transgenics resistant to particular insect. PMID- 25454526 TI - Perturbed porphyrin biosynthesis contributes to differential herbicidal symptoms in photodynamically stressed rice (Oryza sativa) treated with 5-aminolevulinic acid and oxyfluorfen. AB - This paper focuses on the molecular mechanism of deregulated porphyrin biosynthesis in rice plants under photodynamic stress imposed by an exogenous supply of 5-aminolevulinic acid (ALA) and oxyfluorfen (OF). Plants treated with 5 mM ALA or 50 uM OF exhibited differential herbicidal symptoms as characterized by white and brown necrosis, respectively, with substantial increases in cellular leakage and malondialdehyde production. Protoporphyrin IX accumulated to higher levels after 1 day of ALA and OF treatment, whereas it decreased to the control level after 2 days of ALA treatment. Plants responded to OF by greatly decreasing the levels of Mg-protoporphyrin IX (MgProto IX), MgProto IX methyl ester, and protochlorophyllide to levels lower than control, whereas their levels drastically increased 1 day after ALA treatment and then disappeared 2 days after the treatment. Enzyme activity and transcript levels of HEMA1, GSA and ALAD for ALA synthesis greatly decreased in ALA- and OF-treated plants. Transcript levels of PPO1, CHLH, CHLI, and PORB genes involving Mg-porphyrin synthesis continuously decreased in ALA- and OF-treated plants, with greater decreases in ALA-treated plants. By contrast, up-regulation of FC2 and HO2 genes in Fe-porphyrin branch was noticeable in ALA and OF-treated plants 1 day and 2 days after the treatments, respectively. Decreased transcript levels of nuclear-encoded genes Lhcb1, Lhcb6, and RbcS were accompanied by disappearance of MgProto IX in ALA- and OF-treated plants after 2 days of the treatments. Under photodynamic stress imposed by ALA and OF, tight control of porphyrin biosynthesis prevents accumulation of toxic metabolic intermediates not only by down-regulation of their biosynthesis but also by photodynamic degradation. The up-regulation of FC2 and HO2 also appears to compensate for the photodynamic stress-induced damage. PMID- 25454525 TI - Bio-potency of a 21 kDa Kunitz-type trypsin inhibitor from Tamarindus indica seeds on the developmental physiology of H. armigera. AB - A trypsin inhibitor purified from the seeds of Tamarindus indica by Sephadex G 75, DEAE-Sepharose and Trypsin-Sepharose CL-4B columns was studied for its antifeedant, larvicidal, pupicidal and growth inhibitory activities against Helicoverpa armigera larvae. Tamarindus trypsin inhibitor (TTI) exhibited inhibitory activity towards total gut proteolytic enzymes of H. armigera (~87%) and bovine trypsin (~84%). Lethal doses which caused mortality and weight reduction by 50% were 1% w/w and 0.50% w/w, respectively. IC50 of TTI against Helicoverpa midgut proteases and bovine trypsin were ~2.10 ug/ml and 1.68 ug/ml respectively. In larval feeding studies the 21 kDa Kunitz-type protein was found to retard growth and development, prolonged the larval-pupal development durations along with adversely affecting the fertility and fecundity of H. armigera. In artificial diet at 0.5% w/w TTI, the efficiency of conversion of ingested food as well as of digested food, relative growth rate, growth index declined whereas approximate digestibility, metabolic cost, relative consumption rate, consumption index and total developmental period enhanced for H. armigera larvae. These results suggest that TTI has toxic and adverse effect on the developmental physiology of H. armigera and could be useful in controlling the pest H. armigera. PMID- 25454527 TI - Contemporary dental CAD/CAM: modern chairside/lab applications and the future of computerized dentistry. AB - CAD/CAM in dentistry has been particularly useful in enabling the fabrication of custom, patient-specific restorations and prosthetics without the need for traditional analog dental laboratory methods. While the optimal use of CAD/CAM technology must be determined on a case-by-case basis, it is important for clinicians to recognize the opportunity to utilize computerized technology in patient therapy to provide more highly efficient, accurate, and potentially ideal outcomes. This article will discuss and evaluate the state-ofthe- art of CAD/CAM dentistry for both chairside and laboratory-based solutions. Current options for CAD/CAM technology in the treatment of patients for comprehensive dentistry along with the most common uses of chairside and laboratory-based applications will be explored. The discussion will also identify recent and future trends in CAD/CAM applications in dentistry. PMID- 25454528 TI - CBCT technology for diagnosis and treatment planning: what general practitioners should consider. AB - The use of cone-beam computed tomography (CBCT) for diagnosis and treatment planning for a range of applications, including tooth removal, implant, endodontic, orthodontic, temporomandibular joint disorder, and obstructive airway cases, is well known. However, general practitioners should understand that beyond diagnosing fractures and tooth/root anomalies and assessing hard tissue before and after implant placement, this extraoral 3-dimensional (3-D) technology can be beneficial for performing more common diagnostic tasks, such as panoramic x-rays and bitewings. When used in place of intraoral sensors, it spares patients the discomfort of the rigid sensor. CBCT, which uses a fraction of the radiation dose of medical CT, can also be used to help clinicians create digital versions of their conventional impressions and poured models for digital transmission to other dental team members. For the growing number of practitioners who place implants, CBCT provides the ability to execute "top-down" treatment planning to offer patients restorative-based implant placement. PMID- 25454529 TI - Predictably replacing maxillary incisors with implants using 3-D planning and guided implant surgery. AB - Replacement of multiple adjacent teeth in the esthetic zone with dental implants is a surgical and restorative challenge, especially when an esthetic outcome is essential. Sound diagnosis and treatment planning can be combined with use of cone-beam computed tomography (CBCT) and 3-dimensional (3-D) software to achieve desired results. Placement of implants using guided surgical templates is critical when there is limited space between adjacent teeth or limited bone volume. Slight deviations in implant positioning during placement can lead to implants being too close to adjacent teeth, resulting in bone loss, recession, and encroachment upon adjacent papillae. Placement of implants in anatomically deficient or compromised areas is difficult when using a freehand drill protocol, because attaining the necessary precision cannot be achieved routinely. Esthetically demanding patients require precise implant placement. Use of guided surgical planning and implant placement enables the surgeon to take maximum advantage of available bone in anatomically restricted areas. Restoratively, ideal implant placement facilitates rehabilitation; therefore, all parameters must be observed in order to achieve an esthetically pleasing final restoration. PMID- 25454530 TI - Prevalence of periodontal disease by recorded indices among low income discount dental school patients. AB - OBJECTIVE: The purpose of this study was to evaluate the prevalence of periodontal disease among the patient population at the University of Pittsburgh who receive the Low Income Discount (LID) financial obligation reduction based on family income in relation to federal poverty guidelines. STUDY DESIGN: This was a retrospective study examining the Electronic Health Record at the University of Pittsburgh School of Dental Medicine (axiUm, Exan Group) from August 2008 to April 2013 (N = 7936). Records of the complete periodontal examination, income, age, gender, race, and other variables were collected and analyzed. RESULTS: Logistic regressions were performed, controlling for patients' age, ethnicity, smoking status, BMI, and diabetes. The odds of having periodontal disease for patients receiving the low income discount (LID) was higher (1.055), but the difference was not statistically significant (P = 0.35). SIGNIFICANCE: Patients receiving the low income discount did not have a higher prevalence of periodontal disease. Factors other than income appear to be more important to predict greater prevalence of periodontal disease, but this insight requires further investigation. PMID- 25454531 TI - Digital technology: dentistry must not overlook the big picture. AB - While the influx of digital technology has dramatically impacted dentistry, clinicians have a responsibility to promote safety, efficacy, and efficiency. Maintaining a dynamic approach to oral healthcare whereby patients and dental team members enter a process of co-discovery ensures a thorough diagnosis and treatment plan. PMID- 25454532 TI - Re: Hosking J, Considine J, Sands N. Recognising clinical deterioration in emergency department patients. Australas Emerg Nurs J 2014;17:59-67. PMID- 25454533 TI - Drospirenone detected in postmortem blood of a young woman with pulmonary thromboembolism: A case report and review of the literature. AB - Progestin/estrogen oral contraceptives have some side effects, including venous thromboembolism. To alleviate side effects, improvements have been made to low dose oral contraceptives, including reductions in the amount of estrogen and/or changes the type of progestin. A compound drug containing 3mg drospirenone and 20MUg ethinylestradiol (DRSP/EE20, YAZ(r)) was released in overseas markets in 2006, and in Japan in 2010 as a newly developed low-dose medicines. This drug is expected to have lower side effects. We received a medicolegal autopsy case of a young woman who had been prescribed YAZ for dysmenorrhea for 17months. The autopsy revealed a blood clot in her pulmonary artery bifurcation. Blood screening by ultra-performance liquid chromatography-mass spectrometry analysis did not detect any medicinal toxicants. However, from police investigations, it is strongly believed that she had been taking YAZ. Therefore we performed a single ion resolution mode assay and detected DRSP. A quantitative analysis revealed 32.3ng/mL of DRSP. As no other cause of the pulmonary thromboembolism was evident, we consider YAZ as the likely cause of the pulmonary thromboembolism. Recent reports from the past few years suggest a higher risk of venous thromboembolism with DRSP/EE20 than earlier progestin/estrogen oral contraceptives. Comparing the risk associated with DRSP/EE20 and DRSP/EE30, one report found no differences and another report showed DRSP/EE20 was associated with a higher risk than DRSP/EE30. No cases of thrombosis caused by progestin alone have been reported. But comparing the risk between DRSP/EE20 and other progestins/EE20, two studies reported DRSP/EE20 had a higher risk than other progestins/EE20. The incidence of venous thromboembolism is highest in the first year of use and decreases thereafter. Because DRSP/EE20 has been on the market for only a couple of years, it is necessary for clinicians to use the drug carefully and accumulate more side-effect data. It is important for forensic scientists to confirm all of the prescribed drugs in autopsy cases, search the risks of identified drugs, particularly new drugs, and provide relevant case information in a timely manner. PMID- 25454534 TI - The complexities of DNA transfer during a social setting. AB - When questions relating to how a touch DNA sample from a specific individual got to where it was sampled from, one has limited data available to provide an assessment on the likelihood of specific transfer events within a proposed scenario. This data is mainly related to the impact of some key variables affecting transfer that are derived from structured experiments. Here we consider the effects of unstructured social interactions on the transfer of touch DNA. Unscripted social exchanges of three individuals having a drink together while sitting at a table were video recorded and DNA samples were collected and profiled from all relevant items touched during each sitting. Attempts were made to analyze when and how DNA was transferred from one object to another. The analyses demonstrate that simple minor everyday interactions involving only a few items in some instances lead to detectable DNA being transferred among individuals and objects without them having contacted each other through secondary and further transfer. Transfer was also observed to be bi-directional. Furthermore, DNA of unknown source on hands or objects can be transferred and interfere with the interpretation of profiles generated from targeted touched surfaces. This study provides further insight into the transfer of DNA that may be useful when considering the likelihood of alternate scenarios of how a DNA sample got to where it was found. PMID- 25454535 TI - CT-guided percutaneous needle placement in forensic medicine. AB - We have developed a technique of CT-guided needle placement in the destructed human body in forensic practice. A sixty-year-old male was found in a burned car and he was also destructed severely. Although blood was needed for the external examination, it was difficult to approach the vessels because of the severely burned condition of the cadaver. Thus, we attempted to obtain a blood sample from a vessel using a CT-guided technique. Postmortem CT demonstrated the presence of blood-containing vessels in the pelvis. Indeed, CT-guided needle placement had no difficulty with surface markers, table location, or depth measurement from the surface. CT-guide needle placement is a feasible and reliable technique, so that when the tissue/blood sample is at risk of being spoiled, CT-guided needle placement could be a substitute for conventional sampling techniques. PMID- 25454536 TI - Genetic characterization of the Makrani people of Pakistan from mitochondrial DNA control-region data. AB - To estimate genetic and forensic parameters, the entire mitochondrial DNA control region of 100 unrelated Makrani individuals (males, n=96; females, n=4) living in Pakistan (Turbat, Panjgur, Awaran, Kharan, Nasirabad, Gwadar, Buleda, Karachi and Burewala) was sequenced. We observed a total of 70 different haplotypes of which 54 were unique and 16 were shared by more than one individual. The Makrani population showed a high genetic diversity (0.9688) and, consequently, a high power of discrimination (0.9592). Our results revealed a strongly admixed mtDNA pool composed of African haplogroups (28%), West Eurasian haplogroups (26%), South Asian haplogroups (24%), and East Asian haplogroups (2%), while the origin of the remaining individuals (20%) could not be confidently assigned. The results of this study are a valuable contribution to build a database of mtDNA variation in Pakistan. PMID- 25454537 TI - The effect of prior alcohol consumption on the ataxic response to alcohol in high alcohol preferring mice. AB - We have previously shown that ethanol-naive high-alcohol preferring (HAP) mice, genetically predisposed to consume large quantities of alcohol, exhibited heightened sensitivity and more rapid acute functional tolerance (AFT) to alcohol induced ataxia compared to low-alcohol preferring mice. The goal of the present study was to evaluate the effect of prior alcohol self-administration on these responses in HAP mice. Naive male and female adult HAP mice from the second replicate of selection (HAP2) underwent 18 days of 24-h, 2-bottle choice drinking for 10% ethanol vs. water, or water only. After 18 days of fluid access, mice were tested for ataxic sensitivity and rapid AFT following a 1.75 g/kg injection of ethanol on a static dowel apparatus in Experiment 1. In Experiment 2, a separate group of mice was tested for more protracted AFT development using a dual-injection approach where a second, larger (2.0 g/kg) injection of ethanol was given following the initial recovery of performance on the task. HAP2 mice that had prior access to alcohol exhibited a blunted ataxic response to the acute alcohol challenge, but this pre-exposure did not alter rapid within-session AFT capacity in Experiment 1 or more protracted AFT capacity in Experiment 2. These findings suggest that the typically observed increase in alcohol consumption in these mice may be influenced by ataxic functional tolerance development, but is not mediated by a greater capacity for ethanol exposure to positively influence within-session ataxic tolerance. PMID- 25454538 TI - Abnormal ultrastructure of intestinal epithelial barrier in mice with alcoholic steatohepatitis. AB - Intestinal barrier dysfunction caused by chronic alcohol consumption is closely associated with disruption of the intestinal epithelial apical junction complex. The present study was undertaken to directly display by transmission electron microscopy the abnormal ultrastructure of the intestinal epithelial barrier in mice with alcoholic steatohepatitis. The results showed that chronic alcohol consumption could induce obvious liver injury, with diffuse lipid accumulation and focal inflammatory cell infiltration in the liver, assessed by hematoxylin and eosin staining. The indicators of intestinal barrier dysfunction, d-lactic acid and lipopolysaccharide, were significantly higher in alcohol-fed mice than in control mice. Alcohol exposure obviously caused high permeability in the ileum to fluorescein isothiocyanate-dextran (FD-4; molecular weight 4000). Transmission electron microscopy demonstrated that tight junctions and adherens junctions expanded noticeably in alcohol-fed mice. Although the tight junction (TJ) length of alcohol-fed mice had no significant difference compared with control mice, the adherens junction (AJ) length of alcohol-fed mice significantly decreased compared with control mice. Additionally, the ratios of both TJmax/TJmin and AJmax/AJmin were significantly larger in alcohol-fed mice than in control liquid fed mice. In conclusion, high intestinal permeability caused by alcohol attributes to the irregular ultrastructure of the intestinal epithelial barrier. PMID- 25454558 TI - [The long walk of urethral injuries]. PMID- 25454557 TI - Within-population genetic effects of mtDNA on metabolic rate in Drosophila subobscura. AB - A growing body of research supports the view that within-species sequence variation in the mitochondrial genome (mtDNA) is functional, in the sense that it has important phenotypic effects. However, most of this empirical foundation is based on comparisons across populations, and few studies have addressed the functional significance of mtDNA polymorphism within populations. Here, using mitonuclear introgression lines, we assess differences in whole-organism metabolic rate of adult Drosophila subobscura fruit flies carrying either of three different sympatric mtDNA haplotypes. We document sizeable, up to 20%, differences in metabolic rate across these mtDNA haplotypes. Further, these mtDNA effects are to some extent sex specific. We found no significant nuclear or mitonuclear genetic effects on metabolic rate, consistent with a low degree of linkage disequilibrium between mitochondrial and nuclear genes within populations. The fact that mtDNA haplotype variation within a natural population affects metabolic rate, which is a key physiological trait with important effects on life-history traits, adds weight to the emergent view that mtDNA haplotype variation is under natural selection and it revitalizes the question as to what processes act to maintain functional mtDNA polymorphism within populations. PMID- 25454559 TI - Immunolocalization of RhoA and RhoB GTPases in pleomorphic adenoma of the parotid. AB - The pleomorphic adenoma of the parotid (PA) is characterized by the high tissues diversity. Rho GTPases participate in signal transduction pathways that regulate several biological processes, including cell differentiation. A quantitative analysis of RhoA and RhoB GTPases immunoexpression was performed in healthy parotids and in 23 PA cases, predominantly epithelial (PE) or mesenchymal (PM), followed by Student's t test. In PE cases, RhoA immunoexpression was higher in sheets and trabeculae (p < 0.05), whereas RhoB only in sheets (p < 0.05). In normal parotids, RhoA and RhoB were not detected in acinar cells. Ducts have expressed RhoA and RhoB in normal parotids and PA. RhoB was detected in myxoid and chondromyxoid cells. Normal parotids do not express RhoA and RhoB proteins in acinar cells, indicating a lack of function in secretory cells. Despite RhoA and RhoB GTPases are different in their biological roles, no significant difference in immunoexpression of the RhoA and RhoB GTPases in epithelial and mesenchymal structures of PA. PMID- 25454560 TI - Facile synthesis of AuPt alloy nanoparticles in polyelectrolyte multilayers with enhanced catalytic activity for reduction of 4-nitrophenol. AB - In this work, bimetallic AuPt alloy nanoparticles were synthesized in situ in polyelectrolyte multilayers (PEMs) via an ion-exchange and coreduction process, in which the PEM support also served to suppress the Au-Pt phase separation, and thus enabled formation of AuPt alloy nanoparticles over a wide composition range. The PEM supported AuPt alloy nanoparticles exhibited higher catalytic activity than Au and Pt monometallic ones for the reduction of 4-nitrophenol by NaBH4, showing synergistic effects between Au and Pt. This work provides a facile approach to in situ synthesis of polymer supported bimetallic nanoparticles of tailored composition for optimum performance in catalysis and other applications. PMID- 25454562 TI - Images in emergency medicine. Herpes simplex virus encephalitis. PMID- 25454561 TI - Balancing sample accumulation and DNA degradation rates to optimize noninvasive genetic sampling of sympatric carnivores. AB - Noninvasive genetic sampling, or noninvasive DNA sampling (NDS), can be an effective monitoring approach for elusive, wide-ranging species at low densities. However, few studies have attempted to maximize sampling efficiency. We present a model for combining sample accumulation and DNA degradation to identify the most efficient (i.e. minimal cost per successful sample) NDS temporal design for capture-recapture analyses. We use scat accumulation and faecal DNA degradation rates for two sympatric carnivores, kit fox (Vulpes macrotis) and coyote (Canis latrans) across two seasons (summer and winter) in Utah, USA, to demonstrate implementation of this approach. We estimated scat accumulation rates by clearing and surveying transects for scats. We evaluated mitochondrial (mtDNA) and nuclear (nDNA) DNA amplification success for faecal DNA samples under natural field conditions for 20 fresh scats/species/season from <1-112 days. Mean accumulation rates were nearly three times greater for coyotes (0.076 scats/km/day) than foxes (0.029 scats/km/day) across seasons. Across species and seasons, mtDNA amplification success was >=95% through day 21. Fox nDNA amplification success was >=70% through day 21 across seasons. Coyote nDNA success was >=70% through day 21 in winter, but declined to <50% by day 7 in summer. We identified a common temporal sampling frame of approximately 14 days that allowed species to be monitored simultaneously, further reducing time, survey effort and costs. Our results suggest that when conducting repeated surveys for capture-recapture analyses, overall cost-efficiency for NDS may be improved with a temporal design that balances field and laboratory costs along with deposition and degradation rates. PMID- 25454563 TI - Don't let herpes melt your brain! PMID- 25454564 TI - Happy meals for everyone? PMID- 25454565 TI - Commentary: Driver monitoring and feedback: not just "I told you so". PMID- 25454566 TI - I know where this is going. PMID- 25454567 TI - Annals of Emergency Medicine Journal Club. Is it time to raise the bar? Age adjusted D-dimer cutoff levels for excluding pulmonary embolism: answers to the July 2014 Journal Club questions. PMID- 25454568 TI - Images in emergency medicine. Scopolamine-associated mydriasis. PMID- 25454569 TI - Steroids and throat pain. PMID- 25454570 TI - Opioid pharmacokinetics depends on lipid solubility. PMID- 25454571 TI - In reply. PMID- 25454572 TI - Nonsteroidal anti-inflammatory drugs are an effective alternative to corticosteroids to treat pain in pharyngitis. PMID- 25454573 TI - In reply. PMID- 25454574 TI - Biphasic reactions-clinical practice. PMID- 25454575 TI - Postoperative interstitial brachytherapy for resectable squamous cell carcinoma of the tongue. AB - PURPOSE: To evaluate the efficiency and toxicity of postoperative brachytherapy (POBT) in the treatment of resectable mobile tongue squamous cell carcinoma. PATIENTS AND METHODS: This was a retrospective single-center study of patients with SSC of the mobile tongue who were treated between August 1992 and June 2013 by glossectomy and neck dissection followed by (192)Ir interstitial brachytherapy of the tumor bed. Endpoints were local control, cancer-specific survival (CSS), overall survival (OS), and morbidity. Independent prognostic factors were analyzed in a Cox regression model. RESULTS: A total of 112 patients were identified (median age, 55 years [range, 15-84]; 76% male). Patient and tumor characteristics were: T1T2N0 (85%), pN+ (13%), positive surgical margins (14%), negative margins <5 mm (29%), dysplasic margins (14%), lymphatic vessel invasion (5%), and perineural spread (5%). Median followup was 6.7 years (1.5 months to 17.7 years). Local control, CSS, and OS rates at 2 years were 79%, 81%, and 72%, respectively. The corresponding 5-year rates were 76%, 67%, and 56%, respectively. After POBT, 22% of patients presented grade >=2 necrosis and 8% experienced chronic pain. Independent prognostic factors were positive surgical margins for poor local control and tumor recurrence and lymphatic vessel invasion for poor OS. CONCLUSION: POBT provided good local control and better CSS and OS than reported for surgery alone. Morbidity was higher than that reported for brachytherapy alone but may be considered acceptable in a well-selected patient population at high risk of local recurrence. PMID- 25454577 TI - Total radiation dose and overall treatment time are predictive for tumor sterilization in cervical carcinoma treated with chemoradiation and pulsed-dose rate brachytherapy. AB - BACKGROUND AND PURPOSE: Treatment of locally advanced cervical cancer involves multidisciplinary care using external beam radiotherapy, chemotherapy, brachytherapy, and surgery. We aimed to compare both tumor and treatment characteristics between patients with complete pathologic response (CR) and patients with residual disease (RD). PATIENTS AND METHODS: This monocentric retrospective study included 40 consecutive patients, treated with external beam radiotherapy, pulsed-dose-rate brachytherapy, and completion surgery. Treatment planning was performed to obtain a cumulative D90 value for the intermediate-risk clinical target volume (CTV) >=60 Gy(alpha/beta=10). Different clinical and dosimetric parameters were analyzed and compared between patients with RD and those with CR. RESULTS: We observed 18 (45%) patients with CR and 22 (55%) patients with RD. In univariate analysis, patients with RD had a significantly longer overall treatment time than those with CR (59.5 vs. 53 days, p = 0.0321). The D90 value for the high-risk CTV (HR-CTV) was higher in the group with CR than in the group with RD (65.9 vs. 64.2 Gy(alpha/beta=10); p = 0.0439). In multivariate analysis, overall treatment time remained the only predictive factor for CR (p = 0.033), even if the difference for D90 HR-CTV kept a trend toward significance (p = 0.057). CONCLUSIONS: This study showed that tumor sterilization is significantly correlated with overall treatment time and probably with cumulative dose delivered to the HR-CTV. These results emphasize the attention that must be given to treatment organization and dosimetry optimization. PMID- 25454578 TI - Microemulsion systems for fiber deconstruction into cellulose nanofibrils. AB - A new method to produce cellulose nanofibrils (CNF) is proposed to reduce the energy demand during deconstruction of precursor fibers suspended in aqueous media. Microemulsions were formulated with aqueous solutions of urea or ethylenediamine and applied to disrupt interfibril hydrogen bonding. Compared to typical fibrillation of lignin-containing and lignin-free fibers, pretreatment with microemulsion systems allowed energy savings during microfluidization of 55 and 32%, respectively. Moreover, microemulsion processing facilitated smaller scale CNF structures (higher degrees of deconstruction), with higher water retention value (WRV) and surface area. Urea-containing microemulsions were found to be most effective in reducing energy consumption and in weakening the cellulosic matrix. Films prepared from CNF processed after pretreatment with urea containing microemulsions presented a more uniform fiber network and produced films with smoother surfaces compared to those based on ethylenediamine. The lignin-containing CNF (LCNF) produced denser films than those obtained from lignin-free CNF. The mechanical properties of films obtained after application of microemulsion pretreatment were compared, and the benefits of the proposed approach were further confirmed. Overall, fiber deconstruction after microemulsion treatment is a step toward energy-efficient production of nanocellulose. PMID- 25454576 TI - Is it necessary to perform week three dosimetric analysis in low-dose-rate brachytherapy for prostate cancer when day 0 dosimetry is done? A quality assurance assessment. AB - PURPOSE: To determine whether computed tomography/magnetic resonance imaging based day 0 (d0) dosimetry is a meaningful predictor of day 21 (d21) dosimetry in low-dose-rate brachytherapy for localized prostate cancer. METHODS AND MATERIALS: The study population consisted of 277 men with localized (T1-2 N0 M0), low /intermediate-risk prostate cancer treated with low-dose-rate brachytherapy. Computed tomography/magnetic resonance imaging fusion was used for postimplant dosimetry at d0 and d21. Logistic regression was used to construct receiver operating characteristic curves for achieving each constraint at d21, based on d0 D90 and V100, and Youden's index was used to evaluate cutpoints. Freedom from biochemical failure (FBCF) was estimated with the Kaplan-Meier method. RESULTS: The median d0 D90 increased from 133 to 150 Gy at d21, and median d0 V100 increased from 87% to 91%. For achieving the D90 constraint at d21, the optimal cut-point for d0 D90 was 135 Gy, with 84% of these patients maintaining a d21 D90 > 145 Gy. For achieving the D90 constraint at d21, the optimal cut-point for d0 V100 was 87%, with 83% of these patients maintained a d21 V100 > 90%. There was no improvement in FBCF in patients with a d0 D90 > 135 Gy or D90 > 145 Gy. Similarly, there was no improvement in FBCF in patients with a d0 V100 > 87% or V100 > 90%. CONCLUSIONS: Meeting dosimetric constraints on d0 does not obviate d21 dosimetric analysis. Constraints used for dose prescriptions on d0 are not the ideal predictors of d21 dosimetry. PMID- 25454579 TI - Smart human serum albumin-indocyanine green nanoparticles generated by programmed assembly for dual-modal imaging-guided cancer synergistic phototherapy. AB - Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a light-activated local treatment modality that is under intensive preclinical and clinical investigations for cancer. To enhance the treatment efficiency of phototherapy and reduce the light-associated side effects, it is highly desirable to improve drug accumulation and precision guided phototherapy for efficient conversion of the absorbed light energy to reactive oxygen species (ROS) and local hyperthermia. In the present study, a programmed assembly strategy was developed for the preparation of human serum albumin (HSA) indocyanine green (ICG) nanoparticles (HSA-ICG NPs) by intermolecular disulfide conjugations. This study indicated that HSA-ICG NPs had a high accumulation with tumor-to-normal tissue ratio of 36.12+/-5.12 at 24 h and a long-term retention with more than 7 days in 4T1 tumor-bearing mice, where the tumor and its margin, normal tissue were clearly identified via ICG-based in vivo near-infrared (NIR) fluorescence and photoacoustic dual-modal imaging and spectrum-resolved technology. Meanwhile, HSA-ICG NPs efficiently induced ROS and local hyperthermia simultaneously for synergetic PDT/PTT treatments under a single NIR laser irradiation. After an intravenous injection of HSA-ICG NPs followed by imaging guided precision phototherapy (808 nm, 0.8 W/cm2 for 5 min), the tumor was completely suppressed, no tumor recurrence and treatments-induced toxicity were observed. The results suggest that HSA-ICG NPs generated by programmed assembly as smart theranostic nanoplatforms are highly potential for imaging-guided cancer phototherapy with PDT/PTT synergistic effects. PMID- 25454581 TI - Pro-inflammatory cytokines in paraventricular nucleus mediate the cardiac sympathetic afferent reflex in hypertension. AB - Our previous studies showed that pro-inflammatory cytokines (PIC) in the hypothalamic paraventricular nucleus (PVH) potentiated the cardiac sympathetic afferent reflex (CSAR) in normotensive rats. This study determined whether PIC in the PVH mediate enhanced CSAR and over-excited sympathetic activity in spontaneously hypertensive rats (SHR). CSAR was evaluated by renal sympathetic nerve activity (RSNA) response to epicardial application of bradykinin (BK). Inflammatory cytokine levels were measured with ELISA. In both SHR and normotensive Wistar-Kyoto (WKY) rats, PVH microinjection of PIC, tumour necrosis factor (TNF)-alpha or interleukin (IL)-1beta, increased the baseline mean arterial blood pressure (MAP), RSNA and the CSAR, but anti-inflammatory cytokines (AIC), IL-4 or IL-13, only increased the baseline MAP. PVH pretreatment with PIC caused sub-response dose of angiotension (Ang) II to produce baseline RSNA and MAP elevation and the CSAR enhancement responses, but AIC (IL-4 or IL-13) did not. PVH microinjection of PIC induced greater changes in SHR than in normotensive WKY rats. In addition, stimulation of cardiac sympathetic afferents with epicardial application of BK increased PIC levels in the PVH in both SHR and WKY rats. Intrapericardial administration of resiniferatoxin (RTX) which abolished the CSAR decreased the PIC levels in the PVH to a lower level in SHR than in WKY rats. These results suggest that the increased PIC in the PVH in SHR mediated the increased sympathetic outflow and the enhanced CSAR, and that the augmented effect of Ang II in the PVH on sympathetic activity and the CSAR is also associated with PIC. PMID- 25454582 TI - Estrone degradation: does organic matter (quality), matter? AB - Understanding the parameters that drive E1 degradation is necessary to improve existing wastewater treatment systems and evaluate potential treatment options. Organic matter quality could be an important parameter. Microbial communities grown from activated sludge seeds using different dissolved organic matter sources were tested for E1 degradation rates. Synthetic wastewater was aged, filter-sterilized, and used as a carbon and energy source to determine if recalcitrant organic carbon enhances E1 degradation. Higher E1 degradation was observed by biomass grown on 8 d old synthetic wastewater compared to biomass grown on fresh synthetic wastewater (P = 0.033) despite much lower concentrations of bacteria. Minimal or no E1 degradation was observed in biomass grown on 2 d old synthetic wastewater. Organic carbon analyses suggest that products of cell lysis or microbial products released under starvation stress stimulate E1 degradation. Additional water sources were also tested: lake water, river water, and effluents from a municipal wastewater treatement plant and a treatment wetland. E1 degradation was only observed in biomass grown in treatment effluent. Nitrogen, dissolved organic carbon, and trace element concentrations were not causative factors for E1 degradation. In both experiments, spectrophotometric analyses reveal degradation of E1 is associated with microbially derived organic carbon but not general recalcitrance. PMID- 25454580 TI - Oxidation-reduction cycles of peroxiredoxin proteins and nontranscriptional aspects of timekeeping. AB - The circadian clock allows organisms to accurately predict the earth's rotation and modify their behavior as a result. Genetic analyses in a variety of organisms have defined a mechanism based largely on gene expression feedback loops. However, as we delve more deeply into the mechanisms of circadian timekeeping, we are discovering that post-translational mechanisms play a key role in defining the character of the clock. We are also discovering that these modifications are inextricably linked to cellular metabolism, including redox homeostasis. A robust circadian oscillation in the redox status of the peroxiredoxins (a major class of cellular antioxidants) was recently shown to be remarkably conserved from archaea and cyanobacteria all the way to plants and animals. Furthermore, recent findings indicate that cellular redox status is coupled not only to canonical circadian gene expression pathways but also to a noncanonical transcript-independent circadian clock. The redox rhythms observed in peroxiredoxins in the absence of canonical clock mechanisms may hint at the nature of this new and hitherto unknown aspect of circadian timekeeping. PMID- 25454584 TI - Orienting asymmetries in dogs' responses to different communicatory components of human speech. AB - It is well established that in human speech perception the left hemisphere (LH) of the brain is specialized for processing intelligible phonemic (segmental) content (e.g., [1-3]), whereas the right hemisphere (RH) is more sensitive to prosodic (suprasegmental) cues. Despite evidence that a range of mammal species show LH specialization when processing conspecific vocalizations, the presence of hemispheric biases in domesticated animals' responses to the communicative components of human speech has never been investigated. Human speech is familiar and relevant to domestic dogs (Canis familiaris), who are known to perceive both segmental phonemic cues and suprasegmental speaker-related and emotional prosodic cues. Using the head-orienting paradigm, we presented dogs with manipulated speech and tones differing in segmental or suprasegmental content and recorded their orienting responses. We found that dogs showed a significant LH bias when presented with a familiar spoken command in which the salience of meaningful phonemic (segmental) cues was artificially increased but a significant RH bias in response to commands in which the salience of intonational or speaker-related (suprasegmental) vocal cues was increased. Our results provide insights into mechanisms of interspecific vocal perception in a domesticated mammal and suggest that dogs may share ancestral or convergent hemispheric specializations for processing the different functional communicative components of speech with human listeners. PMID- 25454583 TI - Coincidence detection of single-photon responses in the inner retina at the sensitivity limit of vision. AB - BACKGROUND: Vision in starlight relies on our ability to detect single absorbed photons. Indeed, the sensitivity of dark-adapted vision approaches limits set by the quantal nature of light. This sensitivity requires neural mechanisms that selectively transmit quantal responses and suppress noise. Such mechanisms face an inevitable tradeoff because signal and noise cannot be perfectly separated, and rejecting noise also means rejecting signal. RESULTS: We report measurements of single-photon responses in the output signals of the primate retina. We find that visual signals arising from a few absorbed photons are read out fundamentally differently by primate On and Off parasol ganglion cells, key retinal output neurons. Off parasol cells respond linearly to near-threshold flashes, retaining sensitivity to each absorbed photon but maintaining a high level of noise. On parasol cells respond nonlinearly due to thresholding of their excitatory synaptic inputs. This nonlinearity reduces neural noise but also limits information about single-photon absorptions. CONCLUSIONS: The long standing idea that information about each photon absorption is available for behavior at the sensitivity limit of vision is not universally true across retinal outputs. More generally, our work shows how a neural circuit balances the competing needs for sensitivity and noise rejection. PMID- 25454585 TI - GABAergic modulation of visual gamma and alpha oscillations and its consequences for working memory performance. AB - BACKGROUND: Impressive in vitro research in rodents and computational modeling has uncovered the core mechanisms responsible for generating neuronal oscillations. In particular, GABAergic interneurons play a crucial role for synchronizing neural populations. Do these mechanistic principles apply to human oscillations associated with function? To address this, we recorded ongoing brain activity using magnetoencephalography (MEG) in healthy human subjects participating in a double-blind pharmacological study receiving placebo, 0.5 mg and 1.5 mg of lorazepam (LZP; a benzodiazepine upregulating GABAergic conductance). Participants performed a demanding visuospatial working memory (WM) task. RESULTS: We found that occipital gamma power associated with WM recognition increased with LZP dosage. Importantly, the frequency of the gamma activity decreased with dosage, as predicted by models derived from the rat hippocampus. A regionally specific gamma increase correlated with the drug-related performance decrease. Despite the system-wide pharmacological intervention, gamma power drug modulations were specific to visual cortex: sensorimotor gamma power and frequency during button presses remained unaffected. In contrast, occipital alpha power modulations during the delay interval decreased parametrically with drug dosage, predicting performance impairment. Consistent with alpha oscillations reflecting functional inhibition, LZP affected alpha power strongly in early visual regions not required for the task demonstrating a regional specific occipital impairment. CONCLUSIONS: GABAergic interneurons are strongly implicated in the generation of gamma and alpha oscillations in human occipital cortex where drug-induced power modulations predicted WM performance. Our findings bring us an important step closer to linking neuronal dynamics to behavior by embracing established animal models. PMID- 25454586 TI - Yorkie and Scalloped signaling regulates Notch-dependent lineage specification during Drosophila hematopoiesis. AB - Cellular microenvironments established by the spatial and temporal expression of specific signaling molecules are critical for both the maintenance and lineage specific differentiation of progenitor cells. In Drosophila, a population of hematopoietic progenitors, or prohemocytes, within the larval lymph gland gives rise to three mature cell types: plasmatocytes, lamellocytes, and crystal cells. Removal of the secreted signaling molecules Hedgehog and PVF1 from the posterior signaling center (PSC), which acts as a niche, leads to a loss of progenitors and complete differentiation of the lymph gland. Here, we characterize a novel population of signaling cells within the lymph gland, distinct from the PSC, that are required for lineage-specific differentiation of crystal cells. We provide evidence that Yorkie and Scalloped, the Drosophila homologs of YAP and TEAD, are required in lineage-specifying cells to regulate expression of Serrate, the Notch ligand responsible for the initiation of the crystal cell differentiation program. Genetic manipulation of yorkie and scalloped in the lymph gland specifically alters Serrate expression and crystal cell differentiation. Furthermore, Serrate expression in lineage-specifying cells is eliminated in the lymph gland upon the immune response induced by wasp parasitization to ensure the proper differentiation of lamellocytes at the expense of crystal cells. These findings expand the roles for Yorkie/Scalloped beyond growth to encompass specific cell-fate determination in the context of blood development. Similar regulatory functions may extend to their homologs in vertebrate progenitor cell niches that are required for specifying cell fate. PMID- 25454588 TI - The social dominance paradox. AB - Dominant individuals report high levels of self-sufficiency, self-esteem, and authoritarianism. The lay stereotype suggests that such individuals ignore information from others, preferring to make their own choices. However, the nonhuman animal literature presents a conflicting view, suggesting that dominant individuals are avid social learners, whereas subordinates focus on learning from private experience. Whether dominant humans are best characterized by the lay stereotype or the animal view is currently unknown. Here, we present a "social dominance paradox": using self-report scales and computerized tasks, we demonstrate that socially dominant people explicitly value independence, but, paradoxically, in a complex decision-making task, they show an enhanced reliance (relative to subordinate individuals) on social learning. More specifically, socially dominant people employed a strategy of copying other agents when the agents' responses had a history of being correct. However, in humans, two subtypes of dominance have been identified: aggressive and social. Aggressively dominant individuals, who are as likely to "get their own way" as socially dominant individuals but who do so through the use of aggressive or Machiavellian tactics, did not use social information, even when it was beneficial to do so. This paper presents the first study of dominance and social learning in humans and challenges the lay stereotype in which all dominant individuals ignore others' views. The more subtle perspective we offer could have important implications for decision making in both the boardroom and the classroom. PMID- 25454587 TI - The Hippo pathway regulates hematopoiesis in Drosophila melanogaster. AB - The Salvador-Warts-Hippo (Hippo) pathway is an evolutionarily conserved regulator of organ growth and cell fate. It performs these functions in epithelial and neural tissues of both insects and mammals, as well as in mammalian organs such as the liver and heart. Despite rapid advances in Hippo pathway research, a definitive role for this pathway in hematopoiesis has remained enigmatic. The hematopoietic compartments of Drosophila melanogaster and mammals possess several conserved features. D. melanogaster possess three types of hematopoietic cells that most closely resemble mammalian myeloid cells: plasmatocytes (macrophage like cells), crystal cells (involved in wound healing), and lamellocytes (which encapsulate parasites). The proteins that control differentiation of these cells also control important blood lineage decisions in mammals. Here, we define the Hippo pathway as a key mediator of hematopoiesis by showing that it controls differentiation and proliferation of the two major types of D. melanogaster blood cells, plasmatocytes and crystal cells. In animals lacking the downstream Hippo pathway kinase Warts, lymph gland cells overproliferated, differentiated prematurely, and often adopted a mixed lineage fate. The Hippo pathway regulated crystal cell numbers by both cell-autonomous and non-cell-autonomous mechanisms. Yorkie and its partner transcription factor Scalloped were found to regulate transcription of the Runx family transcription factor Lozenge, which is a key regulator of crystal cell fate. Further, Yorkie or Scalloped hyperactivation induced ectopic crystal cells in a non-cell-autonomous and Notch-pathway dependent fashion. PMID- 25454589 TI - Optic flow induces nonvisual self-motion aftereffects. AB - There is strong evidence of shared neurophysiological substrates for visual and vestibular processing that likely support our capacity for estimating our own movement through the environment. We examined behavioral consequences of these shared substrates in the form of crossmodal aftereffects. In particular, we examined whether sustained exposure to a visual self-motion stimulus (i.e., optic flow) induces a subsequent bias in nonvisual (i.e., vestibular) self-motion perception in the opposite direction in darkness. Although several previous studies have investigated self-motion aftereffects, none have demonstrated crossmodal transfer, which is the strongest proof that the adapted mechanisms are generalized for self-motion processing. The crossmodal aftereffect was quantified using a motion-nulling procedure in which observers were physically translated on a motion platform to find the movement required to cancel the visually induced aftereffect. Crossmodal transfer was elicited only with the longest-duration visual adaptor (15 s), suggesting that transfer requires sustained vection (i.e., visually induced self-motion perception). Visual-only aftereffects were also measured, but the magnitudes of visual-only and crossmodal aftereffects were not correlated, indicating distinct underlying mechanisms. We propose that crossmodal aftereffects can be understood as an example of contingent or contextual adaptation that arises in response to correlations across signals and functions to reduce these correlations in order to increase coding efficiency. According to this view, crossmodal aftereffects in general (e.g., visual-auditory or visual tactile) can be explained as accidental manifestations of mechanisms that constantly function to calibrate sensory modalities with each other as well as with the environment. PMID- 25454590 TI - Phylogenomic resolution of the hemichordate and echinoderm clade. AB - Ambulacraria, comprising Hemichordata and Echinodermata, is closely related to Chordata, making it integral to understanding chordate origins and polarizing chordate molecular and morphological characters. Unfortunately, relationships within Hemichordata and Echinodermata have remained unresolved, compromising our ability to extrapolate findings from the most closely related molecular and developmental models outside of Chordata (e.g., the acorn worms Saccoglossus kowalevskii and Ptychodera flava and the sea urchin Strongylocentrotus purpuratus). To resolve long-standing phylogenetic issues within Ambulacraria, we sequenced transcriptomes for 14 hemichordates as well as 8 echinoderms and complemented these with existing data for a total of 33 ambulacrarian operational taxonomic units (OTUs). Examination of leaf stability values revealed rhabdopleurid pterobranchs and the enteropneust Stereobalanus canadensis were unstable in placement; therefore, analyses were also run without these taxa. Analyses of 185 genes resulted in reciprocal monophyly of Enteropneusta and Pterobranchia, placed the deep-sea family Torquaratoridae within Ptychoderidae, and confirmed the position of ophiuroid brittle stars as sister to asteroid sea stars (the Asterozoa hypothesis). These results are consistent with earlier perspectives concerning plesiomorphies of Ambulacraria, including pharyngeal gill slits, a single axocoel, and paired hydrocoels and somatocoels. The resolved ambulacrarian phylogeny will help clarify the early evolution of chordate characteristics and has implications for our understanding of major fossil groups, including graptolites and somasteroideans. PMID- 25454591 TI - CREB regulates memory allocation in the insular cortex. AB - The molecular and cellular mechanisms of memory storage have attracted a great deal of attention. By comparison, little is known about memory allocation, the process that determines which specific neurons in a neural network will store a given memory. Previous studies demonstrated that memory allocation is not random in the amygdala; these studies showed that amygdala neurons with higher levels of the cyclic-AMP-response-element-binding protein (CREB) are more likely to be recruited into encoding and storing fear memory. To determine whether specific mechanisms also regulate memory allocation in other brain regions and whether CREB also has a role in this process, we studied insular cortical memory representations for conditioned taste aversion (CTA). In this task, an animal learns to associate a taste (conditioned stimulus [CS]) with the experience of malaise (such as that induced by LiCl; unconditioned stimulus [US]). The insular cortex is required for CTA memory formation and retrieval. CTA learning activates a subpopulation of neurons in this structure, and the insular cortex and the basolateral amygdala (BLA) interact during CTA formation. Here, we used a combination of approaches, including viral vector transfections of insular cortex, arc fluorescence in situ hybridization (FISH), and designer receptors exclusively activated by designer drugs (DREADD) system, to show that CREB levels determine which insular cortical neurons go on to encode a given conditioned taste memory. PMID- 25454592 TI - Circadian factor BMAL1 in histaminergic neurons regulates sleep architecture. AB - Circadian clocks allow anticipation of daily environmental changes. The suprachiasmatic nucleus (SCN) houses the master clock, but clocks are also widely expressed elsewhere in the body. Although some peripheral clocks have established roles, it is unclear what local brain clocks do. We tested the contribution of one putative local clock in mouse histaminergic neurons in the tuberomamillary nucleus to the regulation of the sleep-wake cycle. Histaminergic neurons are silent during sleep, and start firing after wake onset; the released histamine, made by the enzyme histidine decarboxylase (HDC), enhances wakefulness. We found that hdc gene expression varies with time of day. Selectively deleting the Bmal1 (also known as Arntl or Mop3) clock gene from histaminergic cells removes this variation, producing higher HDC expression and brain histamine levels during the day. The consequences include more fragmented sleep, prolonged wake at night, shallower sleep depth (lower nonrapid eye movement [NREM] delta power), increased NREM-to-REM transitions, hindered recovery sleep after sleep deprivation, and impaired memory. Removing BMAL1 from histaminergic neurons does not, however, affect circadian rhythms. We propose that for mammals with polyphasic/nonwake consolidating sleep, the local BMAL1-dependent clock directs appropriately timed declines and increases in histamine biosynthesis to produce an appropriate balance of wake and sleep within the overall daily cycle of rest and activity specified by the SCN. PMID- 25454594 TI - Ions channels/transporters and chloroplast regulation. AB - Ions play fundamental roles in all living cells and their gradients are often essential to fuel transports, to regulate enzyme activities and to transduce energy within and between cells. Their homeostasis is therefore an essential component of the cell metabolism. Ions must be imported from the extracellular matrix to their final subcellular compartments. Among them, the chloroplast is a particularly interesting example because there, ions not only modulate enzyme activities, but also mediate ATP synthesis and actively participate in the building of the photosynthetic structures by promoting membrane-membrane interaction. In this review, we first provide a comprehensive view of the different machineries involved in ion trafficking and homeostasis in the chloroplast, and then discuss peculiar functions exerted by ions in the frame of photochemical conversion of absorbed light energy. PMID- 25454593 TI - The yeast polo kinase Cdc5 regulates the shape of the mitotic nucleus. AB - Abnormal nuclear size and shape are hallmarks of aging and cancer. However, the mechanisms regulating nuclear morphology and nuclear envelope (NE) expansion are poorly understood. In metazoans, the NE disassembles prior to chromosome segregation and reassembles at the end of mitosis. In budding yeast, the NE remains intact. The nucleus elongates as chromosomes segregate and then divides at the end of mitosis to form two daughter nuclei without NE disassembly. The budding yeast nucleus also undergoes remodeling during a mitotic arrest; the NE continues to expand despite the pause in chromosome segregation, forming a nuclear extension, or "flare," that encompasses the nucleolus. The distinct nucleolar localization of the mitotic flare indicates that the NE is compartmentalized and that there is a mechanism by which NE expansion is confined to the region adjacent to the nucleolus. Here we show that mitotic flare formation is dependent on the yeast polo kinase Cdc5. This function of Cdc5 is independent of its known mitotic roles, including rDNA condensation. High resolution imaging revealed that following Cdc5 inactivation, nuclei expand isometrically rather than forming a flare, indicating that Cdc5 is needed for NE compartmentalization. Even in an uninterrupted cell cycle, a small NE expansion occurs adjacent to the nucleolus prior to anaphase in a Cdc5-dependent manner. Our data provide the first evidence that polo kinase, a key regulator of mitosis, plays a role in regulating nuclear morphology and NE expansion. PMID- 25454595 TI - Organellar mechanosensitive channels involved in hypo-osmoregulation in fission yeast. AB - MscS and MscL, bacterial mechanosensitive channels, play crucial roles in the hypo-osmotic shock response. However, only MscS has homologs in eukaryotes. These homologs are called MscS-like proteins or MSL proteins. MSL proteins have changed both structurally and functionally during evolution and are now localized not only to the membrane of the chloroplast, which is thought to be a descendant of an ancient, free-living bacterium, but also the cell membrane and the endoplasmic reticulum (ER) membrane, suggesting that the role of MSL proteins has diverged. In this brief review, we mainly focus on two MSL proteins in the fission yeast Schizosaccharomyces pombe that are localized in the ER membrane and protect cells from hypo-osmotic shock-induced death by regulating intracellular Ca(2+) concentrations. We also discuss Arabidopsis thaliana MSL proteins and other yeast ion channels in terms of osmoregulation in eukaryotes. PMID- 25454596 TI - [Primary signet-ring cell carcinoma of the terminal ileum]. PMID- 25454597 TI - [Fecal microbiota transplantation]. AB - Bacteria can no longer be seen as an enemy. Nowadays, there is enough evidence to place the microbiota as a key element in human homeostasis. Despite initial skepticism, fecal microbiota transplantation (FMT) is a real therapeutic alternative for patients with recurrent Clostridium difficile infection. Moreover, this procedure has shown promising results in ulcerative colitis and other non-gastrointestinal disorders. There is still a lack of knowledge and clinical trials with long- term follow-up. Therefore, the available data should be interpreted with caution. In this document we provide a detailed review of the literature on the intestinal microbiota and FMT. PMID- 25454598 TI - [Treatment with immunosupressants in a patient with Crohn's disease and common variable immunodeficiency]. PMID- 25454600 TI - [Gastrointestinal bleeding secondary to enteritis due to herpes virus in an immunosuppressed man]. PMID- 25454599 TI - [Drug Rash with Eosinophilia and Systemic Symptoms syndrome induced by telaprevir in a patient with chronic hepatitis C virus infection]. PMID- 25454602 TI - [Reccomendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) on the use of methotrexate in inflammatory bowel disease]. AB - Methotrexate is an immunosuppressant that may be useful in several clinical scenarios in inflammatory bowel disease. In this article, we review the available evidence in Crohn's disease and ulcerative colitis and establish general recommendations for its use in clinical practice. Although the available data are limited, it is very likely that methotrexate is underused because its effectiveness is underestimated and its toxicity is overestimated. Both in induction therapy and in maintenance of remission, methotrexate is useful in Crohn's disease. When prescribed in combination with biologic agents, immunogenicity is less frequent and consequently long-term response could potentially be improved. There are few published studies, but several data suggest that methotrexate could also be useful in ulcerative colitis. Although myelotoxicity and liver toxicity are well known risks, methotrexate is a drug that is well tolerated in many patients, even in the long term. PMID- 25454601 TI - [Frantz's tumor or solid-pseudopapillary tumor of the pancreas]. PMID- 25454603 TI - Growth of oleaginous Rhodotorula glutinis in an internal-loop airlift bioreactor by using lignocellulosic biomass hydrolysate as the carbon source. AB - The conversion of abundant lignocellulosic biomass (LCB) to valuable compounds has become a very attractive idea recently. This study successfully used LCB (rice straw) hydrolysate as a carbon source for the cultivation of oleaginous yeast-Rhodotorula glutinis in an airlift bioreactor. The lipid content of 34.3 +/ 0.6% was obtained in an airlift batch with 60 g reducing sugars/L of LCB hydrolysate at a 2 vvm aeration rate. While using LCB hydrolysate as the carbon source, oleic acid (C18:1) and linoleic acid (C18:2) were the predominant fatty acids of the microbial lipids. Using LCB hydrolysate in the airlift bioreactor at 2 vvm achieved the highest cell mass growth as compared to the agitation tank. Despite the low lipid content of the batch using LCB hydrolysate, this low cost feedstock has the potential of being adopted for the production of beta-carotene instead of lipid accumulation in the airlift bioreactor for the cultivation of R. glutinis. PMID- 25454604 TI - Lactobacillus acidophilus CP23 with weak immunomodulatory activity lacks anchoring structure for surface layer protein. AB - To determine the reason for the low levels of Surface layer protein A (SlpA) on CP23 cells, which might play a crucial role in the immunomodulatory effect of Lactobacillus acidophilus, the DNA sequence of the slpA gene of CP23 and L-92 strains, including the upstream region, were analyzed. Unexpectedly, there was no significant difference in the predicted amino acid sequence of the C-terminus needed for cell anchoring, and only an additional Ala-Val-Ala sequence inserted in the N-terminal region of the mature CP23 protein. Therefore, anchoring of SlpA on the cell wall of CP23 and L-92 was evaluated by a reconstitution assay, which showed that SlpA released by LiCl treatment from both CP23 and L-92 was successfully anchored on LiCl-treated L-92 cells, but not on LiCl-treated CP23 cells. Moreover, quantitative analysis of SlpA protein in the culture medium of CP23 and L-92 by ELISA revealed higher levels of SlpA secretion in CP23 cells than in L-92 cells. Collectively, these results suggest that the lower levels of SlpA on the surface of CP23 cells might be caused by less cell wall capacity for SlpA anchoring, leading to an accumulation of SlpA in the culture medium of CP23 cells. The present study supports the importance of cell surface structure of L. acidophilus L-92 for SlpA anchoring on the cell surface needed for immunomodulatory effect. PMID- 25454605 TI - Characterizing activities of eukaryotic-like protein kinases with atypical catalytic loop motifs from Myxococcus xanthus. AB - Myxococcus xanthus has eukaryotic-like protein kinases (EPKs) with different atypical catalytic loop motifs. Seven out of 14 recombinant M. xanthus EPKs containing atypical motifs in the catalytic loop showed protein kinase activity against myelin basic protein and four autophosphorylated EPKs were detected using anti-phosphotyrosine antibody by western blotting. PMID- 25454606 TI - Spotted fever group Rickettsia in Amblyomma dubitatum tick from the urban area of Campo Grande, Mato Grosso do Sul, Brazil. AB - Rickettsia infection of each tick was evaluated by the hemolymph test and polymerase chain reaction (PCR) targeting gltA and ompA genes. All hemolymph tests were negative and PCR of one A. dubitatum detected both Rickettsia genes. Sequence of ompA exhibited a 99% identity with Rickettsia parkeri and R. africae and a 98% identity with R. sibirica. Rickettsia of the spotted fever group in A. dubitatum is described for the first time in an urban area within the municipality of Campo Grande in the state of Mato Grosso do Sul (MS), Brazil. This finding reinforces the importance of more detailed studies to determine the role of A. dubitatum in the transmission of spotted fever agents. PMID- 25454608 TI - Reporting geographic and temporal trends in renal cell carcinoma: why is this important? PMID- 25454607 TI - Amblyomma americanum tick calreticulin binds C1q but does not inhibit activation of the classical complement cascade. AB - In this study we characterized Amblyomma americanum (Aam) tick calreticulin (CRT) homolog in tick feeding physiology. In nature, different tick species can be found feeding on the same animal host. This suggests that different tick species found feeding on the same host can modulate the same host anti-tick defense pathways to successfully feed. From this perspective it's plausible that different tick species can utilize universally conserved proteins such as CRT to regulate and facilitate feeding. CRT is a multi-functional protein found in most taxa that is injected into the vertebrate host during tick feeding. Apart from it's current use as a biomarker for human tick bites, role(s) of this protein in tick feeding physiology have not been elucidated. Here we show that annotated functional CRT amino acid motifs are well conserved in tick CRT. However our data show that despite high amino acid identity levels to functionally characterized CRT homologs in other organisms, AamCRT is apparently functionally different. Pichia pastoris expressed recombinant (r) AamCRT bound C1q, the first component of the classical complement system, but it did not inhibit activation of this pathway. This contrast with reports of other parasite CRT that inhibited activation of the classical complement pathway through sequestration of C1q. Furthermore rAamCRT did not bind factor Xa in contrast to reports of parasite CRT binding factor Xa, an important protease in the blood clotting system. Consistent with this observation, rAamCRT did not affect plasma clotting or platelet aggregation. We discuss our findings in the context of tick feeding physiology. PMID- 25454609 TI - Effect of BRCA Mutations on Metastatic Relapse and Cause-specific Survival After Radical Treatment for Localised Prostate Cancer. AB - BACKGROUND: Germline BRCA mutations are associated with worse prostate cancer (PCa) outcomes; however, the most appropriate management for mutation carriers has not yet been investigated. OBJECTIVE: To evaluate the response of BRCA carriers to conventional treatments for localised PCa by analysing metastasis free survival (MFS) and cause-specific survival (CSS) following radical prostatectomy (RP) or external-beam radiation therapy (RT). DESIGN, SETTING, AND PARTICIPANTS: Tumour features and outcomes of 1302 patients with local/locally advanced PCa (including 67 BRCA mutation carriers) were analysed. RP was undergone by 535 patients (35 BRCA); 767 received RT (32 BRCA). Median follow-up was 64 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Median survival and 3-, 5-, and 10-yr survival rates were estimated using the Kaplan-Meier method. Generated survival curves were compared using the log-rank test. Cox regression analyses were used to assess the prognostic value of BRCA mutations. RESULTS AND LIMITATIONS: A total of 67 BRCA carriers and 1235 noncarriers were included. At 3, 5, and 10 yr after treatment, 97%, 94%, and 84% of noncarriers and 90%, 72%, and 50% of carriers were free from metastasis (p<0.001). The 3-, 5- and 10-yr CSS rates were significantly better in the noncarrier cohort (99%, 97%, and 85%, respectively) than in carriers (96%, 76%, and 61%, respectively; p<0.001). Multivariate analysis confirmed BRCA mutations as an independent prognostic factor for MFS (hazard ratio [HR]: 2.36; 95% confidence interval [CI], 1.38-4.03; p=0.002) and CSS (HR: 2.17; 95% CI, 1.16-4.07; p=0.016). CONCLUSIONS: BRCA carriers had worse outcomes than noncarriers when conventionally treated for local/locally advanced PCa. PATIENT SUMMARY: Prostate cancer patients with germline BRCA mutations had worse outcomes than noncarriers when conventionally treated with surgery or radiation therapy. PMID- 25454610 TI - Prostate cancer outcomes: the three questions. AB - Enhanced survival and therapeutic choices for men with prostate cancer mandate the evaluation of the "quality of survival". An exciting series of local, national and international health outcome improvement initiatives offer the enticing prospect of assessing and improving this. PMID- 25454611 TI - Preliminary results of a randomised controlled trial of an online psychological intervention to reduce distress in men treated for localised prostate cancer. AB - BACKGROUND: Prostate cancer (PCa) poses many emotional and physical challenges for men following treatment. The unmet support needs of these men are well documented, and access to psychosocial support remains problematic. OBJECTIVES: To assess the efficacy of an online psychological intervention for men who have localised PCa. DESIGN, SETTING, AND PARTICIPANTS: We undertook a randomised controlled trial to evaluate the intervention. Participants were randomly allocated to one of three conditions: My Road Ahead (MRA) alone (MRA Only), MRA plus access to an online forum (MRA+Forum), and access to the forum alone (Forum). INTERVENTION: The intervention was a 10-week self-guided online psychological intervention called My Road Ahead that consisted of six themed modules designed to facilitate improved emotional well-being in the context of PCa as well as a moderated peer forum. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Pre- and postintervention assessments of psychological distress (the 21 question Depression, Anxiety and Stress Scale) [1] and the Prostate Cancer related Quality of Life scale [2] were conducted. Multivariate analysis of variance, regression, and structural equation modelling were used to analyse the data. RESULTS AND LIMITATIONS: In total, 142 participants were randomly allocated to one of the three intervention arms. The mean age of participants was 61 yr of age (standard deviation: 7), and 88% had undergone radical prostatectomy. A significant improvement in psychological distress was observed for participants who had access to the combined condition (MRA+Forum) with a moderate effect size (p=0.02; partial eta(2)=0.07). In particular, the decline in the mean level of psychological distress was 8.8 units larger for the MRA+Forum group than the Forum group (95% confidence interval [CI], 0.9-16.7). Although the decline in the mean level of psychological distress was 7.0 units larger for the MRA+Forum group than for the MRA Only group, this difference was not significant (95% CI, 1.1 15.1). Structural equation modelling indicated that reductions in health worry and regret contributed significantly to the reductions in psychological distress for the MRA+Forum condition. CONCLUSIONS: This study is the first, to our knowledge, that has evaluated a self-guided online psychological intervention tailored to the specific needs of men who have PCa. The findings of this study indicate the potential for this programme to deliver support that men may not otherwise receive. PATIENT SUMMARY: This study found that men who have localised prostate cancer who received access to the online psychological intervention called My Road Ahead combined with the online peer discussion forum had significantly improved reductions in distress compared with those who received access to the online intervention alone or the forum alone. PMID- 25454612 TI - Pilot Validation Study of the European Association of Urology Robotic Training Curriculum. AB - BACKGROUND: The development of structured and validated training curricula is one of the current priorities in robot-assisted urological surgery. OBJECTIVE: To establish the feasibility, acceptability, face validity, and educational impact of a structured training curriculum for robot-assisted radical prostatectomy (RARP), and to assess improvements in performance and ability to perform RARP after completion of the curriculum. DESIGN, SETTING, AND PARTICIPANTS: A 12-wk training curriculum was developed based on an expert panel discussion and used to train ten fellows from major European teaching institutions. The curriculum included: (1) e-learning, (2) 1 wk of structured simulation-based training (virtual reality synthetic, animal, and cadaveric platforms), and (3) supervised modular training for RARP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The feasibility, acceptability, face validity, and educational impact were assessed using quantitative surveys. Improvement in the technical skills of participants over the training period was evaluated using the inbuilt validated assessment metrics on the da Vinci surgical simulator (dVSS). A final RARP performed by fellows on completion of their training was assessed using the Global Evaluative Assessment of Robotic Skills (GEARS) score and generic and procedure-specific scoring criteria. RESULTS AND LIMITATIONS: The median baseline experience of participants as console surgeon was 4 mo (interquartile range [IQR] 0-6.5 mo). All participants completed the curriculum and were involved in a median of 18 RARPs (IQR 14-36) during modular training. The overall score for dVSS tasks significantly increased over the training period (p<0.001-0.005). At the end of the curriculum, eight fellows (80%) were deemed able by their mentors to perform a RARP independently, safely, and effectively. At assessment of the final RARP, the participants achieved an average score >=4 (scale 1-5) for all domains using the GEARS scale and an average score >10 (scale 4-16) for all procedural steps using a generic dedicated scoring tool. In performance comparison using this scoring tool, the experts significantly outperformed the fellows (mean score for all steps 13.6 vs 11). CONCLUSIONS: The European robot-assisted urologic training curriculum is acceptable, valid, and effective for training in RARP. PATIENT SUMMARY: This study shows that a 12-wk structured training program including simulation-based training and mentored training in the operating room allows surgeons with limited robotic experience to increase their robotic skills and their ability to perform the surgical steps of robot-assisted radical prostatectomy. PMID- 25454613 TI - Metabolic evaluation and recurrence prevention for urinary stone patients: EAU guidelines. AB - CONTEXT: An optimum metabolic evaluation strategy for urinary stone patients has not been clearly defined. OBJECTIVE: To evaluate the optimum strategy for metabolic stone evaluation and management to prevent recurrent urinary stones. EVIDENCE ACQUISITION: Several databases were searched to identify studies on the metabolic evaluation and prevention of stone recurrence in urolithiasis patients. Special interest was given to the level of evidence in the existing literature. EVIDENCE SYNTHESIS: Reliable stone analysis and basic metabolic evaluation are highly recommended in all patients after stone passage (grade A). Every patient should be assigned to a low- or high-risk group for stone formation. It is highly recommended that low-risk stone formers follow general fluid and nutritional intake guidelines, as well as lifestyle-related preventative measures to reduce stone recurrences (grade A). High-risk stone formers should undergo specific metabolic evaluation with 24-h urine collection (grade A). More specifically, there is strong evidence to recommend pharmacological treatment of calcium oxalate stones in patients with specific abnormalities in urine composition (grades A and B). Treatment of calcium phosphate stones using thiazides is only highly recommended when hypercalciuria is present (grade A). In the presence of renal tubular acidosis (RTA), potassium citrate and/or thiazide are highly recommended based on the relative urinary risk factor (grade A or B). Recommendations for therapeutic measures for the remaining stone types are based on low evidence (grade C or B following panel consensus). Diagnostic and therapeutic algorithms are presented for all stone types based on the best level of existing evidence. CONCLUSION: Metabolic stone evaluation is highly recommended to prevent stone recurrences. PATIENT SUMMARY: In this report, we looked at how patients with urolithiasis should be evaluated and treated in order to prevent new stone formation. Stone type determination and specific blood and urine analysis are needed to guide patient treatment. PMID- 25454614 TI - Preservation of the neurovascular bundles is associated with improved time to continence after radical prostatectomy but not long-term continence rates: results of a systematic review and meta-analysis. AB - CONTEXT: The aetiology of urinary incontinence following radical prostatectomy (RP) is incompletely understood. In particular, it is unclear whether there is a relationship between neurovascular bundle (NVB) sparing and post-RP urinary continence. OBJECTIVE: To review systematically the association of NVB sparing in RP with postoperative urinary continence outcomes and synthesise the results in a meta-analysis. EVIDENCE ACQUISITION: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. PubMed, Medline, and Cochrane Central Register of Controlled Trials were searched (December 2013), yielding 3413 unique records. A total of 27 longitudinal cohort studies were selected for inclusion. Studies were evaluated using a predefined criteria adapted from the Cochrane Tool to Assess Risk of Bias in Cohort Studies. EVIDENCE SYNTHESIS: Data from 13 749 participants in 27 studies were synthesised in a meta-analysis. An assessment of the study methodology revealed a high risk of bias due to differences in baseline characteristics, outcome assessment, and the likely presence of unreported confounding factors such as meticulous apical dissection. Meta-analysis demonstrated that nerve sparing (NS) compared with non nerve sparing (NNS) resulted in improved early urinary continence rates up to 6 mo postoperatively. Beyond this time, no significant difference was observed. This effect was seen most clearly for bilateral NS compared with NNS. A sensitivity analysis of prospective cohort studies revealed consistent results. CONCLUSIONS: This analysis demonstrates an association between NS and improved urinary continence outcomes up to 6 mo postoperatively. NS in men with poor preoperative erectile function should be considered in the context of oncologic risk stratification because it may improve time to continence recovery. The underlying cause of the relationship between NS and continence is unknown. It may represent preservation of the intrapelvic somatic nerves supplying the rhabdosphincter or the influence of other confounding factors. Future research should be directed towards improving understanding of the anatomy of urinary continence and the pathophysiology of post-RP incontinence. PATIENT SUMMARY: We found that avoiding damage to the nerves around the prostate improves urinary continence in the first 6 mo after surgery. After this time, there is no difference in continence between men who had these nerves removed and those who had them saved. This finding could be due to a true effect of saving these nerves or to a number of other factors affecting the research. PMID- 25454615 TI - A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer. AB - BACKGROUND: The 4Kscore combines measurement of four kallikreins in blood with clinical information as a measure of the probability of significant (Gleason >=7) prostate cancer (PCa) before prostate biopsy. OBJECTIVE: To perform the first prospective evaluation of the 4Kscore in predicting Gleason >=7 PCa in the USA. DESIGN, SETTING, AND PARTICIPANTS: Prospective enrollment of 1012 men scheduled for prostate biopsy, regardless of prostate-specific antigen level or clinical findings, was conducted at 26 US urology centers between October 2013 and April 2014. INTERVENTION: The 4Kscore. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was Gleason >=7 PCa on prostate biopsy. The area under the receiver operating characteristic curve, risk calibration, and decision curve analysis (DCA) were determined, along with comparisons of probability cutoffs for reducing the number of biopsies and their impact on delaying diagnosis. RESULTS AND LIMITATIONS: Gleason >=7 PCa was found in 231 (23%) of the 1012 patients. The 4Kscore showed excellent calibration and demonstrated higher discrimination (AUC 0.82) and net benefit compared to a modified Prostate Cancer Prevention Trial Risk Calculator 2.0 model and standard of care (biopsy for all men) according to DCA. A possible reduction of 30-58% in the number biopsies was identified with delayed diagnosis in only 1.3-4.7% of Gleason >=7 PCa cases, depending on the threshold used for biopsy. Pathological assessment was performed according to the standard of care at each site without centralized review. CONCLUSION: The 4Kscore showed excellent diagnostic performance in detecting significant PCa. It is a useful tool in selecting men who have significant disease and are most likely to benefit from a prostate biopsy from men with no cancer or indolent cancer. PATIENT SUMMARY: The 4Kscore provides each patient with an accurate and personalized measure of the risk of Gleason >=7 cancer to aid in decision-making regarding the need for prostate biopsy. PMID- 25454616 TI - PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate. AB - BACKGROUND: Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) occurs frequently in prostate cancers. Preclinical evidence suggests that activation of PI3K/AKT signaling through loss of PTEN can result in resistance to hormonal treatment in prostate cancer. OBJECTIVE: To explore the antitumor activity of abiraterone acetate (abiraterone) in castration-resistant prostate cancer (CRPC) patients with and without loss of PTEN protein expression. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified patients who had received abiraterone and had hormone-sensitive prostate cancer (HSPC) and/or CRPC tissue available for PTEN immunohistochemical analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was overall survival from initiation of abiraterone treatment. Relationship with outcome was analyzed using multivariate Cox regression and log-rank analyses. RESULTS AND LIMITATIONS: A total of 144 patients were identified who had received abiraterone post-docetaxel and had available tumor tissue. Overall, loss of PTEN expression was observed in 40% of patients. Matched HSPC and CRPC tumor biopsies were available for 41 patients. PTEN status in CRPC correlated with HSPC in 86% of cases. Loss of PTEN expression was associated with shorter median overall survival (14 vs 21 mo; hazard ratio [HR]: 1.75; 95% confidence interval [CI], 1.19-2.55; p=0.004) and shorter median duration of abiraterone treatment (24 vs 28 wk; HR: 1.6; 95% CI, 1.12-2.28; p=0.009). PTEN protein loss, high lactate dehydrogenase, and the presence of visceral metastases were identified as independent prognostic factors in multivariate analysis. CONCLUSIONS: Our results indicate that loss of PTEN expression was associated with worse survival and shorter time on abiraterone treatment. Further studies in larger and prospective cohorts are warranted. PATIENT SUMMARY: PTEN is a protein often lost in prostate cancer cells. In this study we evaluated if prostate cancers that lack this protein respond differently to treatment with abiraterone acetate. We demonstrated that the survival of patients with loss of PTEN is shorter than patients with normal PTEN expression. PMID- 25454617 TI - How does active surveillance for prostate cancer affect quality of life? A systematic review. AB - CONTEXT: The optimal management of screen-detected, localised prostate cancer remains controversial, related to overtreatment issues of screening and the nonrandomised evidence base. Active surveillance (AS) aims to delay or avoid curative therapy but may potentially harm patients' well-being through living with untreated prostate cancer. OBJECTIVE: To systematically review the literature on quality of life (QoL) in patients undergoing AS. EVIDENCE ACQUISITION: Embase, Medline, Psychinfo, Cochrane Central, Web of Science, and PubMed databases were searched in May 2014 using quality of life, active surveillance, prostate cancer, their synonyms, and targeted manual searches. The psychological dimensions related to health-related QoL (HRQoL) outcomes were anxiety and depression, distress, decisional conflict, and mental health. EVIDENCE SYNTHESIS: Ten clinical and research-based AS studies worldwide measured HRQoL and related psychological facets in six cross-sectional studies and four cohorts (follow-up: 9-36 mo; published: 2006-2014). Six studies were linked to published AS cohorts. In total, 966 men undergoing AS (mean: 102 per study) were assessed (mean age: 66 yr). AS patients had good overall HRQoL scores, which were comparable or better than those of patients undergoing postradical treatment (comparator group in four studies), men's partners (one study) and population based data (three studies). Anxiety and depression scores were favourable. Selection bias may be present, as none were randomised comparisons. Decreased psychological well-being may be partly predicted by AS patients' baseline and clinical characteristics. CONCLUSIONS: Patients undergoing AS reported good QoL and did not appear to suffer major negative psychological impacts. Longer follow up is required as well as investigation into which patients are predisposed to negative impact and leaving AS prematurely. PATIENT SUMMARY: We reviewed the published evidence for quality-of-life impact on men with prostate cancer being monitored by active surveillance. The men who were on active surveillance usually reported good levels of well-being and did not appear to suffer major negative psychological impacts. The research findings suggest little presence of anxiety and depression and high overall quality of life related to their disease. However, there are few long-term studies, so more high-quality research is needed to make definitive recommendations. PMID- 25454619 TI - Tregitope: Immunomodulation powerhouse. AB - IVIG is frequently used in the 'pre-conditioning' regimens for higher risk transplants; its effects are attributed in part to induction of Tregs. We have identified regulatory T cell (Treg) epitopes, now known as Tregitopes, in IgG, the main component of intravenous immunoglobulin therapy (IVIg). Tregitopes provide one explanation for the expansion and activation of Treg cells following IVIg treatment. Tregitopes are peptides that exhibit high affinity binding to multiple human HLA Class II DR; they are conserved across IgG isotypes and mammalian species. In vitro and in vivo, for human PBMC and in animal models, Tregitopes activate Tregs. Studies to delineate the mechanism of action have shown that Tregitopes' effects are very similar to IVIg in vitro. Here we demonstrate that Tregitopes induce Tregs to produce IL-10, leading to modulation of dendritic cell phenotype (down-regulation of Class II, CD80 and CD86 and up regulation of ILT3), and describe the effects of Tregitopes in the ABM-TCR transgenic skin transplantation model. The discovery of Tregitopes in IgG and other autologous proteins may contribute to improved understanding of the mechanism of action of IVIg and lead to the application of these powerful immunomodulators to improve transplantation success and suppress autoimmune disease, in the future. PMID- 25454618 TI - Detection of Clinically Significant Prostate Cancer Using Magnetic Resonance Imaging-Ultrasound Fusion Targeted Biopsy: A Systematic Review. AB - CONTEXT: The current standard for diagnosing prostate cancer in men at risk relies on a transrectal ultrasound-guided biopsy test that is blind to the location of the cancer. To increase the accuracy of this diagnostic pathway, a software-based magnetic resonance imaging-ultrasound (MRI-US) fusion targeted biopsy approach has been proposed. OBJECTIVE: Our main objective was to compare the detection rate of clinically significant prostate cancer with software-based MRI-US fusion targeted biopsy against standard biopsy. The two strategies were also compared in terms of detection of all cancers, sampling utility and efficiency, and rate of serious adverse events. The outcomes of different targeted approaches were also compared. EVIDENCE ACQUISITION: We performed a systematic review of PubMed/Medline, Embase (via Ovid), and Cochrane Review databases in December 2013 following the Preferred Reported Items for Systematic reviews and Meta-analysis statement. The risk of bias was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. EVIDENCE SYNTHESIS: Fourteen papers reporting the outcomes of 15 studies (n=2293; range: 13-582) were included. We found that MRI-US fusion targeted biopsies detect more clinically significant cancers (median: 33.3% vs 23.6%; range: 13.2-50% vs 4.8-52%) using fewer cores (median: 9.2 vs 37.1) compared with standard biopsy techniques, respectively. Some studies showed a lower detection rate of all cancer (median: 50.5% vs 43.4%; range: 23.7-82.1% vs 14.3-59%). MRI-US fusion targeted biopsy was able to detect some clinically significant cancers that would have been missed by using only standard biopsy (median: 9.1%; range: 5-16.2%). It was not possible to determine which of the two biopsy approaches led most to serious adverse events because standard and targeted biopsies were performed in the same session. Software-based MRI-US fusion targeted biopsy detected more clinically significant disease than visual targeted biopsy in the only study reporting on this outcome (20.3% vs 15.1%). CONCLUSIONS: Software-based MRI-US fusion targeted biopsy seems to detect more clinically significant cancers deploying fewer cores than standard biopsy. Because there was significant study heterogeneity in patient inclusion, definition of significant cancer, and the protocol used to conduct the standard biopsy, these findings need to be confirmed by further large multicentre validating studies. PATIENT SUMMARY: We compared the ability of standard biopsy to diagnose prostate cancer against a novel approach using software to overlay the images from magnetic resonance imaging and ultrasound to guide biopsies towards the suspicious areas of the prostate. We found consistent findings showing the superiority of this novel targeted approach, although further high quality evidence is needed to change current practice. PMID- 25454620 TI - Toll like receptors in self-recovering hepatitis E patients with or without pregnancy. AB - Hepatitis E virus (HEV) causes high mortality among pregnant women. Pathogenesis of HEV, especially during pregnancy, is poorly understood. Our aim was to assess the role of Toll-like-receptors (TLRs) in hepatitis E patients with pregnancy (Antenatal care, ANC) or without pregnancy (non-ANC). The patient categories included acute-phase, non-ANC (n=46) and ANC patients (2nd/3rd trimesters, n=13) and non-ANC patients (n=31) during convalescence. Controls included apparently healthy non-ANC (n=30) and ANC subjects in the first (n=10) and later (2nd/3rd, n=20) trimesters. TLR2/TLR3/TLR4/TLR7/TLR8 levels were determined by flow cytometry. Cytokine responses induced by TLR-specific-ligands-stimulated-PBMCs from ANC/non-ANC-patients and TLR-signaling-molecules (non-ANC-patients) were measured. PBMCs were used to assess gene expression levels by TaqMan-Low-Density Array. Compared to the temporal activation of TLR4/TLR7/TLR8 at protein and mRNA levels, the ANC-patients and controls exhibited reduced TLRs indicative of impaired TLR response. Stimulation of PBMCs with TLR-specific ligands led to the induction of type-I interferons, IFNbeta by the non-ANC group and IFNalpha by the ANC category. Involvement of MyD88-independent (TLR3/TLR4) and MyD88-dependent (TLR4/TLR7/TLR8) pathways and association of TLR4/TLR7/TLR8 with recovery was documented in the non-ANC-patients. Except for robust type-I-interferon response, HEV infection could not modulate pregnancy-related diminished immune response. The results have implications in the understanding of HEV pathogenesis. PMID- 25454621 TI - p38 Mitogen-Activated Protein Kinase in beryllium-induced dendritic cell activation. AB - Dendritic cells (DC) play a role in the regulation of immune responses to haptens, which in turn impact DC maturation. Whether beryllium (Be) is able to induce DC maturation and if this occurs via the MAPK pathway is not known. Primary monocyte-derived DCs (moDCs) models were generated from Be non-exposed healthy volunteers as a non-sensitized cell model, while PBMCs from BeS (Be sensitized) and CBD (chronic beryllium disease) were used as disease models. The response of these cells to Be was evaluated. The expression of CD40 was increased significantly (p<0.05) on HLA-DP Glu69+ moDCs after 100 MUM BeSO4-stimulation. BeSO4 induced p38MAPK phosphorylation, while IkappaB-alpha was degraded in Be stimulated moDCs. The p38 MAPK inhibitor SB203580 blocked Be-induced NF-kappaB activation in moDCs, suggesting that p38MAPK and NF-kappaB are dependently activated by BeSO4. Furthermore, in BeS and CBD subjects, SB203580 downregulated Be-stimulated proliferation in a dose-dependent manner, and decreased Be stimulated TNF-alpha and IFNgamma cytokine production. Taken together, this study suggests that Be-induces non-sensitized Glu69+ DCs maturation, and that p38MAPK signaling is important in the Be-stimulated DCs activation as well as subsequent T cell proliferation and cytokine production in BeS and CBD. In total, the MAPK pathway may serve as a potential therapeutic target for human granulomatous lung diseases. PMID- 25454623 TI - Meta-analysis of the relationship between 14bp insertion/deletion polymorphism of HLA-G gene and susceptibility to systemic lupus erythematosus. AB - We performed a meta-analysis to examine the relationship between the human leukocyte antigen-G (HLA-G) 14 base pairs sequence (14bp) insertion (ins)/deletion (del) polymorphism to systemic lupus erythematosus (SLE). Eligible studies were extracted in PubMed, Embase, Cochrane Library and CNKI (Chinese) up to March 31, 2014. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated to evaluate the strength of the association. Finally, 7 studies with 1864 cases and 2259 controls were involved in this meta-analysis. Overall, the HLA-G 14bp ins/del polymorphism was significantly associated with SLE susceptibility (ins vs. del: OR=1.179, 95%CI=1.037-1.341, P=0.012; ins/ins vs. del/del: OR=1.394, 95%CI=1.153-1.684, P=0.001; ins/del vs. del/del: OR=1.199, 95%CI=1.041-1.382, P=0.012; ins/ins+ins/del vs. del/del: OR=1.252, 95%CI=1.097 1.430, P=0.001). When stratified by ethnicity, significance was found in Asians (ins/ins vs. del/del: OR=1.326, 95%CI=1.001-1.756, P=0.049) and Caucasians (ins/ins vs. del/del: OR=1.454, 95%CI=1.126-1.878, P=0.004; ins/del vs. del/del: OR=1.288, 95%CI=1.051-1.579, P=0.015; ins/ins+ins/del vs. del/del: OR=1.340, 95%CI=1.106-1.623, P=0.003). Our results suggest that the HLA-G 14bp insertion allele might act as an increased risk against SLE. Besides, this is the first meta-analysis to report an association between the HLA-G 14bp ins/del polymorphism and SLE. Larger and well-designed studies are needed to further confirm these findings. PMID- 25454622 TI - A combination of single nucleotide polymorphisms in the 3'untranslated region of HLA-G is associated with preeclampsia. AB - Reduced expression of human leukocyte antigen-G (HLA-G) has been linked to onset of preeclampsia. Associations have also been reported between preeclampsia and single nucleotide polymorphisms (SNP) in the 3'-untranslated region (UTR) of the HLA-G gene. However, there are conflicting results between studies. This studied examined whether a SNP, by itself or in combination with other SNPs, in the 3'UTR of the HLA-G gene is associated with an increased risk of preeclampsia. Placenta samples were obtained from 47 preeclamptic and 68 control cases. DNA was extracted, and the 3'UTR was sequenced and analyzed for nine polymorphisms using different genetic models of inheritance. Four of these polymorphisms have never been analyzed for an association with preeclampsia. Disputing existing reports, preeclamptic cases were suggestively associated with a G/G-genotype at SNP +3187 (p<0.05). Several SNP combinations were more prevalent in preeclampsia cases. Following corrections for multiple testing, one SNP combination (+3027C/C and +3187G/G) was significantly more prevalent in preeclampsia cases using co dominant, additive, and dominant models (p<0.001). Taken together with the current literature, the data suggests that HLA-G 3'UTR SNP-pair associations, and not individual SNPs, could be useful in a predictive test for the susceptibility to preeclampsia. PMID- 25454624 TI - Analysis of genetic variants in the IL4 promoter and VNTR loci in Indian patients with Visceral Leishmaniasis. AB - Visceral Leishmaniasis (VL) is the most severest form of Leishmaniasis and resistance to infection is mediated by cellular immune responses. Interleukin 4 (IL-4) orchestrates of Th2 and Th1 immune responses during infections. In this study, we aimed to investigate possible association between three functional IL-4 polymorphisms -590C/T (rs2243250), -34C/T (rs2070874) and 70bp VNTR (rs79071878 in intron3) with VL in an Indian cohort comprising of 197 VL patients and 193 healthy controls. The three investigated IL-4 polymorphisms were in strong linkage disequilibrium. The investigated IL-4 alleles, genotypes and the reconstructed haplotypes were not significantly distributed between the VL patients and healthy controls. Our study signifies no possible association of functional IL-4 polymorphisms with Indian VL and postulate other vital genes involved in the IL-4 pathway may provide genetic clues to elucidate of IL-4 regulation and immune-pathogenesis during VL. PMID- 25454625 TI - Influence of glucose-lowering rate on CKMB and myoglobin serum levels in type-2 diabetes patients with coronary heart disease. AB - OBJECTIVE: To analyze the level of creatine kinase isoenzyme (CKMB), myoglobin, to explore the influence of different glucose-lowering rate on cardiac enzyme in type 2 diabetes mellitus patients with coronary heart disease (T2DMC), to search for the rational glucose-lowering rate. METHODS: A total number of 293 type 2 diabetic patients who were hospitalized in the First Affiliated Hospital of Harbin Medical University from May 2008 to December 2009 were recruited. Two groups were divided according to the coronary angiography. 142 subjects of type 2 diabetes mellitus (T2DM) and 151 subjects of T2DMC received intensive glucose therapy. After CKMB and myoglobin being measured, variation and correlation factors were evaluated. RESULTS: In T2DM group, the level of CKMB was significantly lower at follow-up than that before intensive therapy. Then, we got four subgroups according to the glucose-lowering rate. In T2DM group, when the fasting or postprandial glucose-lowering rate was no more than 6 mmolL(-1)d(-1), the level of CKMB and myoglobin were significantly lower than that before intensive therapy (P<0.05). When the fasting glucose-lowering rate is faster than 6 mmolL(-1)d(-1), the level of CKMB is significantly higher after intensive therapy than that before glucose-lowering (P<0.05). In T2DMC group, when the fasting or postprandial glucose-lowering rate was not more than 4 mmolL(-1)d(-1), the level of CKMB and myoglobin was significantly lower than that before intensive therapy (P<0.05, P<0.01). When the fasting glucose-lowering rate was faster than 4 mmolL(-1)d(-1), the level of CKMB and myoglobin was significantly higher at follow-up than that before intensive therapy (P<0.05). Before intensive therapy, high density lipoprotein cholesterol (HDL-C) has a negative linear regression relationship with CKMB (P<0.01). Low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) and glycosylated hemoglobin A1c (HbA1c) have a positive linear regression relationship with CKMB (P<0.05). HDL-C has a negative linear regression relationship with myoglobin (P<0.01). LDL-C and TG have a positive linear regression relationship with myoglobin (P<0.01). CONCLUSIONS: T2DM patients, no matter with CHD or not, all have a rational fasting glucose lowering rate; the fasting glucose-lowering rate is more susceptible to myocardial damage anticipation than the postprandial glucose-lowering rate. PMID- 25454626 TI - Significance of association of HLA-C and HLA-E with psoriatic arthritis. AB - Psoriatic arthritis (PsA) is a complex genetic disorder that results from an interplay between multiple genetic and environmental factors. The aim of the study was to assess the significance of the association between the HLA-C and HLA E allelic groups and PsA. Our results confirm the association between HLA-C(*)06 and PsA (OR=5.16, p<0.0001). Furthermore, HLA-C(*)06-positive patients develop more severe disease (p<0.01) and more frequently present with polyarticular pattern of PsA (p=0.08). Additionally our study revealed that the HLA-C(*)02 allele was more frequently observed in PsA patients (OR=5.40, p<0.0005) and also that the HLA-E(*)01:01 allele was significantly over-represented among HLA-C(*)02 negative patients in comparison to healthy individuals (OR=6.44, p=0.045). Therefore these results suggest that the HLA-E and HLA-C(*)02 molecules may also play an important role in determination immune response contributing to the PsA development. PMID- 25454630 TI - The relationship between unhealthy snacking at school and academic outcomes: a population study in Chilean schoolchildren. AB - OBJECTIVE: We examined the association between unhealthy snacking at school and academic outcomes in students from the Santiago Metropolitan Region (Chile). DESIGN: Cross-sectional population-based study. SETTING: We measured the nutritional quality of snacks at school using an FFQ, and accounting for the amounts of saturated fat, fibre, sugar and salt in the foods, and academic outcomes using national standardized test scores in Language and Mathematics. Multivariate regression analyses modelled the relationship between unhealthy snacking at school (exposure), potential confounders and performance in Mathematics and Language (outcomes). SUBJECTS: Random sample of 1073 students (13.1 (SD 2.3) years old) attending public, partially subsidized and private schools. RESULTS: Fifty-six per cent of students ate items at snack time that were high in fat, sugar, salt and energy, and thus were considered to have unhealthy snaking. Thirty-six per cent and 8% were considered to have poor-to fair and healthy snacking, respectively. Unhealthy snacking significantly lowered the odds of good academic performance in both domains. Students having unhealthy snacks were 56% less likely to pass in Language (fully adjusted OR = 0.44; 95% CI 0.23, 0.85) and 66% less likely to pass in Mathematics (fully adjusted OR = 0.34; 95% CI 0.19, 0.64) compared with students having healthy snack items. CONCLUSIONS: Schoolchildren eating unhealthy foods at snack time had worse academic performance in Language and Mathematics, as measured by a standardized test. Although association does not imply causation, these findings support the notion that academic and health-related behaviours are linked. More research is needed on the effect of school health programmes on educational outcomes. PMID- 25454631 TI - Controlling expansion and cardiomyogenic differentiation of human pluripotent stem cells in scalable suspension culture. AB - To harness the potential of human pluripotent stem cells (hPSCs), an abundant supply of their progenies is required. Here, hPSC expansion as matrix-independent aggregates in suspension culture was combined with cardiomyogenic differentiation using chemical Wnt pathway modulators. A multiwell screen was scaled up to stirred Erlenmeyer flasks and subsequently to tank bioreactors, applying controlled feeding strategies (batch and cyclic perfusion). Cardiomyogenesis was sensitive to the GSK3 inhibitor CHIR99021 concentration, whereas the aggregate size was no prevailing factor across culture platforms. However, in bioreactors, the pattern of aggregate formation in the expansion phase dominated subsequent differentiation. Global profiling revealed a culture-dependent expression of BMP agonists/antagonists, suggesting their decisive role in cell-fate determination. Furthermore, metallothionein was discovered as a potentially stress-related marker in hPSCs. In 100 ml bioreactors, the production of 40 million predominantly ventricular-like cardiomyocytes (up to 85% purity) was enabled that were directly applicable to bioartificial cardiac tissue formation. PMID- 25454632 TI - Direct lineage conversion of adult mouse liver cells and B lymphocytes to neural stem cells. AB - Overexpression of transcription factors has been used to directly reprogram somatic cells into a range of other differentiated cell types, including multipotent neural stem cells (NSCs), that can be used to generate neurons and glia. However, the ability to maintain the NSC state independent of the inducing factors and the identity of the somatic donor cells remain two important unresolved issues in transdifferentiation. Here we used transduction of doxycycline-inducible transcription factors to generate stable tripotent NSCs. The induced NSCs (iNSCs) maintained their characteristics in the absence of exogenous factor expression and were transcriptionally, epigenetically, and functionally similar to primary brain-derived NSCs. Importantly, we also generated tripotent iNSCs from multiple adult cell types, including mature liver and B cells. Our results show that self-maintaining proliferative neural cells can be induced from nonectodermal cells by expressing specific combinations of transcription factors. PMID- 25454633 TI - Low/negative expression of PDGFR-alpha identifies the candidate primary mesenchymal stromal cells in adult human bone marrow. AB - Human bone marrow (BM) contains a rare population of nonhematopoietic mesenchymal stromal cells (MSCs), which are of central importance for the hematopoietic microenvironment. However, the precise phenotypic definition of these cells in adult BM has not yet been reported. In this study, we show that low/negative expression of CD140a (PDGFR-alpha) on lin(-)/CD45(-)/CD271(+) BM cells identified a cell population with very high MSC activity, measured as fibroblastic colony forming unit frequency and typical in vitro and in vivo stroma formation and differentiation capacities. Furthermore, these cells exhibited high levels of genes associated with mesenchymal lineages and HSC supportive function. Moreover, lin(-)/CD45(-)/CD271(+)/CD140a(low/-) cells effectively mediated the ex vivo expansion of transplantable CD34(+) hematopoietic stem cells. Taken together, these data indicate that CD140a is a key negative selection marker for adult human BM-MSCs, which enables to prospectively isolate a close to pure population of candidate human adult stroma stem/progenitor cells with potent hematopoiesis supporting capacity. PMID- 25454635 TI - Patient characteristics associated with pregnancy ambivalence. AB - BACKGROUND: The objective of our study was to determine demographic characteristics, health and sexual behaviors, and psychological health associated with pregnancy ambivalence. We used a cross-sectional design for our study. METHODS: A self-administered cross-sectional survey was conducted among nonpregnant women 16-40 years old from southeast Texas from July 2010 to August 2011. The survey included questions pertaining to demographics, pregnancy intentions, health behaviors, sexual behaviors, violence exposure, pregnancy coercion, and psychological behaviors. Multivariate logistic regression analyses were performed to determine differences between ambivalent and nonambivalent females. RESULTS: Of the 1,388 women included in this analysis, 529 (38%) were ambivalent toward pregnancy. Ambivalent women were younger (p=0.03), had fewer children living at home (p<0.01), and were less likely to have been previously pregnant (p=0.01). Multivariate analysis showed that ambivalent women were more likely to smoke (p<0.01), sleep poorly (p=0.02), have had more sexual partners in the past month (p<0.01) and in their lifetime (p=0.01), not used contraception at last sex (p=0.01), be a victim of violence (p=0.01), and have experienced pregnancy coercion (p<0.01). In addition, these women exhibited higher scores on scales measuring depressive symptoms (p=0.01) and perceived stress (p<0.01). CONCLUSIONS: Women ambivalent toward pregnancy are not only less likely to use contraception but also more likely to have unhealthy behaviors and psychological risk factors. As this combination of characteristics may put a future pregnancy and child at risk, awareness about the possible consequences of pregnancy ambivalence needs to increase among the public and medical community. Providers need to focus efforts on screening for this patient population and preventive education through contraceptive counseling. PMID- 25454634 TI - 3D reconstitution of the patterned neural tube from embryonic stem cells. AB - Inducing organogenesis in 3D culture is an important aspect of stem cell research. Anterior neural structures have been produced from large embryonic stem cell (ESC) aggregates, but the steps involved in patterning such complex structures have been ill defined, as embryoid bodies typically contained many cell types. Here we show that single mouse ESCs directly embedded in Matrigel or defined synthetic matrices under neural induction conditions can clonally form neuroepithelial cysts containing a single lumen in 3D. Untreated cysts were uniformly dorsal and could be ventralized to floor plate (FP). Retinoic acid posteriorized cysts to cervical levels and induced localize FP formation yielding full patterning along the dorsal/ventral (DV) axis. Correct spatial organization of motor neurons, interneurons, and dorsal interneurons along the DV axis was observed. This system serves as a valuable tool for studying morphogen action in 3D and as a source of patterned spinal cord tissue. PMID- 25454637 TI - Cross-border mobility and social networks: Laotians seeking medical treatment along the Thai border. AB - Drawing upon research conducted on cross-border patients living in Laos and seeking care in Thailand, this paper examines the important role played by social networks in patients' decision-making and on the itineraries they choose to seek treatment on the Thai side of the border. Due to the vastly contrasting situations between the two countries in terms of healthcare supply, and considering Laotians' increasing demand for high quality healthcare, a number of them have managed to satisfy their needs by combining cross-border treatment with the use of the healthcare facilities provided by their own country. This study consisted first of household surveys conducted in five border areas (2006-2007) in Laos in order to quantify and map out cross-border healthcare-related travel patterns. Afterwards, interviews were conducted with cross-border patients (55), Laotian and Thai medical doctors (6), Thai social workers (5), and officials working in public institutions (12). While socioeconomic and spatial factors partly explain cross-border mobility, patients' social networks significantly influence treatment itineraries throughout the decision-making process, including logistical and financial considerations. The social networks existing at different geographical levels (neighbourhood, regional and global) are therefore a powerful analytical tool not only for understanding the emergence of these cross-border movements but also for justifying them in an authoritarian political environment such as Lao PDR's. PMID- 25454636 TI - Patient involvement in drug licensing: a case study. AB - Embodied health movements work on the boundary between lay and expert knowledge. Consumer groups, depending on their goals, may increase or decrease pharmaceuticalization. This paper reports a small case study about the retrospective evaluation of a specific second line treatment for type 2 diabetes by an existing patient involvement group. The group is part of a research collaboration between academia and the health service in England, and shares some characteristics of embodied health movements. We used the case study to explore whether an institutionally funded non activist patient group can make a more balanced contribution to drug licensing decisions than that made by either access oriented or injury-oriented consumer groups, without being co-opted by an institutional agenda. The questions we wished to address were how this group evaluated existing mechanisms for licensing drugs; how they balanced scientific and lay knowledge; how they made their decisions; and how they viewed their experiences as panel members. The five panel members were interviewed before and after the panel discussion in July 2013. They were critical of current licensing processes, and used their own embodied experiences of medicines to evaluate expert knowledge. Their decisions on the panel were informed either by a balancing of benefits and harms, or by trust in experts. The case study suggests that such a group may have the potential both to balance the pro pharmaceuticalization impact of access-oriented groups and to influence forms of pharmaceutical governance. PMID- 25454638 TI - Hereditary motor and sensory neuropathies or Charcot-Marie-Tooth diseases: an update. AB - Hereditary motor and sensory neuropathies (HMSN) or Charcot-Marie-Tooth (CMT) diseases are the most common degenerative disorders of the peripheral nervous system. However, the frequency of the different subtypes varies within distinct populations. Although more than seventy clinical and genetic forms are known to date, more than 80% of CMT patients in Western countries have genetic abnormalities associated with PMP22, MPZ, MFN2 and GJB1. Given the considerable genetic heterogeneity of CMT, we emphasize the interest of both clinical and pathological specific features such that focused genetic testing could be performed. In this regard, peripheral nerve lesions in GDAP1 mutations (AR CMT1A), such as mitochondrial abnormalities, have been newly demonstrated. Otherwise, while demyelinating autosomal recessive CMT used to be classified as CMT4 (A, B, C ...), we propose a simplified classification such as AR CMT1 (A, B, C ...), and AR CMT2 for axonal forms. Also, we stress that next generation sequencing techniques, now considered to be the most efficient methods of genetic testing in CMT, will be helpful in molecular diagnosis and research of new genes involved. Finally, while no effective therapy is known to date, ongoing new therapeutic trials such as PXT3003 (a low dose combination of the three already approved drugs baclofen, naltrexone, and D-sorbitol) give hopes for potential curative treatment. PMID- 25454639 TI - Vascular comorbidities in the onset and progression of multiple sclerosis. AB - Vascular comorbidities are common in the general population and are associated with adverse health outcomes. In people with multiple sclerosis (MS), an increasing amount of evidence suggests that vascular comorbidities are also common, but an association with MS risk and disability has not been conclusively established. This review aims to critically examine published data on the relationship between vascular comorbidities (including vascular risk factors) and MS. The evidence suggests an increased risk of MS in people with a high BMI during childhood or adolescence but not adulthood. People with established MS appear to have a slightly increased risk of cardiovascular disease and a greater proportion of people with MS die from cardiovascular disease, which has important implications for clinicians trying to identify risk factors for cardiovascular disease and reviewing treatment options. In relation to whether vascular comorbidities influence MS clinical disability or other aspects of the disease course, the key finding was that having type-2-diabetes, hypertension, dyslipidaemia or peripheral vascular disease at any point in the disease course may be associated with a greater progression in disability. Additionally, a negative effect of high cholesterol and triglycerides and a positive effect of higher HDL (high density lipoprotein) levels on acute inflammatory activity were observed on magnetic resonance imaging. The results of the published clinical trials of statins as an intervention in MS were however conflicting and care needs to be taken when treating people with MS with statins. Taken together, the literature seems to indicate a potential association of vascular comorbidities with MS risk and disability, but the number of prospective studies was sparse, thus precluding ascription of causality. We therefore recommend that future studies of the frequency and effects of vascular comorbidities on MS risk and disability should be prospective and objective where relevant. PMID- 25454640 TI - Comparison of hemihypoglossal- and accessory-facial neurorrhaphy for treating facial paralysis in rats. AB - The aim of this study was to determine the effectiveness of hypoglossal-facial nerve "side"-to-end (HemiHN-FN) and accessory-facial nerve end-to-end (AN-FN) neurorrhaphy using a predegenerated nerve graft (PNG) for reanimating facial paralysis in a rat FN injury model. A total of 25 rats with complete unilateral facial paralysis resulting from section of the right FN were divided into 5 groups (n=5 each) that were submitted to immediate, delayed (3 months after FN injury) or no (control) FN reconstruction procedures involving HemiHN-FN or AN-FN neurorrhaphy. Approximately 3 months after FN reconstruction, cholera toxin subunit B conjugate Alexa 555 (CTB-Alexa 555) was injected into the ipsilateral whisker pad muscle and CTB-Alexa 555-labeled neurons were observed in the hypoglossal or accessory nuclei of all the FN reconstruction rats, but none of these neurons were found in the controls. There were numerous myelinated and nonmyelinated axons in both PNG and repaired FN of the FN reconstruction rats. No differences were found for these numbers between the two neurorrhaphy methods for each of the treatment time points, indicating the equal effectiveness of axon regeneration. However, a significantly higher number of CTB-Alexa 555-labeled neurons was observed in the hypoglossal nucleus of the immediate HemiHN-FN neurorrhaphy-treated rats when compared to that in the accessory nucleus of the immediate AN-FN neurorrhaphy-treated rats, consistent with the surface values of the recorded MAPs at the whisker pad muscle while electro-stimulating the FN. These results suggest that HemiHN-FN neurorrhaphy produces more efficient innervation of the paralyzed facial muscles than AN-FN neurorrhaphy without sacrificing ipsilateral hypoglossal function. Taking into consideration the clinical relevance of these findings for postoperative complications and functional reanimation in relation to the central plasticity, we suggest that HemiHN-FN neurorrhaphy may be the preferable facial reanimation procedure after an FN injury. PMID- 25454641 TI - Carotid inflammation on 18F-fluorodeoxyglucose positron emission tomography associates with recurrent ischemic lesions. AB - BACKGROUND: Inflammation plays an important role in the development of ischemic stroke. We hypothesized that inflammation of carotid atherosclerosis, as measured by (18)F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET), associates with the early recurrent ischemic lesions (ERILs). METHODS: This prospective study included patients with symptomatic carotid atherosclerosis. ERILs were defined as newly developed ischemic lesions in the territory of symptomatic internal carotid artery stenosis, as detected by follow-up diffusion weighted imaging (DWI). The patients with and without ERILs were compared in terms of risk factors, inflammatory markers, and FDG uptake on PET. RESULTS: Of the 21 patients, 8 had ERILs (38.1%). Compared to the patients without ERILs, those with ERILs had higher FDG uptake (maximum standardized uptake value, 3.07 +/- 0.79 vs. 2.17 +/- 0.68, p=0.013) and were more likely to have irregular carotid plaques (100% vs. 38.5%, p=0.007). Inflammatory markers were not different between the two groups, and also did not correlate with FDG uptake. CONCLUSIONS: Increased carotid plaque inflammation, as measured by FDG uptake on PET, may be a useful marker for identifying patients with symptomatic carotid atherosclerosis who are at risk of recurrence. PMID- 25454642 TI - Information processing speed impairment and cerebellar dysfunction in relapsing remitting multiple sclerosis. AB - OBJECTIVE: The aim of this work is to study the relationship between information processing speed (IPS) impairment and motor testing that reflects cerebellar function in persons with multiple sclerosis (PwMS). METHODS: 60 persons with relapsing-remitting multiple sclerosis with a mean disease duration of 4.2 +/- 4 years were studied cross-sectionally. Motor cerebellar functioning was studied using the Nine-Hole Peg Test (NHPT) and the Kurtzke Functional Status Scales, and several cognitive domains were evaluated (IPS, working memory, episodic memory, attention, executive function). Correlations between the global NHPT score and neuropsychological test scores or impairment in each cognitive domain were studied using univariate and multivariate analyses. RESULTS: The NHPT and a test of IPS significantly differentiated PwMS with and without cerebellar impairment. The NHPT total score was correlated with measures of IPS. Multivariate analyses showed a correlation between the NHPT and measures of IPS, but not between the NHPT and other neuropsychological tests that did not have a speed component. CONCLUSION: In this sample of PwMS, motor cerebellar impairment assessed by the NHPT was correlated with IPS impairment. PMID- 25454643 TI - Melatonin ameliorates oxidative stress, modulates death receptor pathway proteins, and protects the rat cerebrum against bisphenol-A-induced apoptosis. AB - Epidemiological reports have indicated a correlation between the increasing of bisphenol-A (BPA) levels in the environment and the incidence of neurodegenerative diseases. In the present study, the protective effect of melatonin on oxidative stress and the death receptor apoptotic proteins in the cerebrum of the bisphenol-A-treated rats were examined. Adult male rats were orally administered melatonin (10mg/kg bw) concurrently with BPA (50mg/kg bw) 3 days a week for 6 weeks. BPA exposure resulted in significant elevations of oxidative stress, as evidenced by the increased malondialdehyde level and the decreased glutathione level and superoxide dismutase activity in the cerebrum. BPA caused an upregulation of p53 and CD95-Fas and activation of capsases-3 and 8, resulting in cerebral cell apoptosis. Melatonin significantly attenuated the BPA-evoked brain oxidative stress, modulated apoptotic-regulating proteins and protected against apoptosis. These data suggest that melatonin modulated important steps in the death receptor apoptotic pathway which likely related to its redox control properties. Melatonin is a promising pharmacological agent for preventing the potential neurotoxicity of BPA following occupational or environmental exposures. PMID- 25454644 TI - Usefulness of sacral nerve modulation in a series of multiple sclerosis patients with bladder dysfunction. AB - OBJECTIVE: Bladder dysfunctions are common in multiple sclerosis (MS) often causing the most distressing symptoms. The aim of this paper was to evaluate the effectiveness of sacral nerve modulation (SNM) in this disease. METHODS: We conducted an observational retrospective survey in 17 patients treated with SNM in the north-east of Italy, all complaining of bladder symptoms (storage in 41%, voiding in 24%, mixed in 35%) unresponsive to conventional therapies, with a mean follow-up of 52 +/- 26 months and mean Expanded Disability Status Scale score of 5.8 +/- 1.8. RESULTS: 75% of patients reported significant and lasting improvement in bladder symptoms and in quality of life. We observed a statistically significant improvement in frequency, urgency, number of pads, residual volumes, number of catheterizations and in the voided volumes. In 5 out of 6 cases with mixed symptoms the stimulation was discontinued (device totally explanted or turned off) after a mean time of 66 months (range 10-84 months) after the implant, for disease progression or loss of efficacy. CONCLUSION: SNM could be an option in very selected cases of storage and voiding symptoms refractory to conservative treatments caused by a stable or slowly progressive MS considering its minimal invasiveness and reversibility. The poor results observed suggest avoiding this therapy in mixed symptoms and in cases of advanced disability. PMID- 25454646 TI - Can dopamine agonists trigger tactile hallucinations in patients with Parkinson's disease? AB - Various hallucinations are unpleasant for patients with Parkinson's disease (PD). Hallucinations are often related to anti-parkinsonian drugs. Tactile hallucinations rarely occur in patients with PD. In contrast to other types of hallucinations, tactile hallucinations often make physicians wonder if a physical abnormality is the underlying cause. However, the relation of tactile hallucinations to anti-parkinsonian drugs remains uncertain because studies are scant. We describe three patients with PD who had tactile hallucinations that were triggered by dopamine agonists. In our patients, tactile hallucinations occurred in a clear sensorium and persisted for a prolonged time. Two patients had clear visual hallucinations such as of insects, which were associated with tactile hallucinations such as of insects tied to the body. Clear tactile sensoria were unpleasant. Dopamine agonists were initiated or the doses were increased during several periods immediately before the onset of tactile hallucinations. Although the other anti-parkinsonian drugs used, such as amantadine, zonisamide, or trihexyphenidyl, were likely to be partly responsible for the tactile hallucinations, our observations suggest that an increase in the dose of dopamine agonists can trigger tactile hallucinations. PMID- 25454645 TI - Single-subject classification of schizophrenia patients based on a combination of oddball and mismatch evoked potential paradigms. AB - OBJECTIVE: The diagnostic process for schizophrenia is mainly clinical and has to be performed by an experienced psychiatrist, relying primarily on clinical signs and symptoms. Current neurophysiological measurements can distinguish groups of healthy controls and groups of schizophrenia patients. Individual classification based on neurophysiological measurements mostly shows moderate accuracy. We wanted to examine whether it is possible to distinguish controls and patients individually with a good accuracy. To this end we used a combination of features extracted from the auditory and visual P300 paradigms and the mismatch negativity paradigm. METHODS: We selected 54 patients and 54 controls, matched for age and gender, from the data available at the UPC Kortenberg. The EEG-data were high- and low-pass filtered, epoched and averaged. Features (latencies and amplitudes of component peaks) were extracted from the averaged signals. The resulting dataset was used to train and test classification algorithms. First on separate paradigms and then on all combinations, we applied Naive Bayes, Support Vector Machine and Decision Tree, with two of its improvements: Adaboost and Random Forest. RESULTS: For at least two classifiers the performance increased significantly by combining paradigms compared to single paradigms. The classification accuracy increased from at best 79.8% when trained on features from single paradigms, to 84.7% when trained on features from all three paradigms. CONCLUSION: A combination of features originating from three evoked potential paradigms allowed us to accurately classify individual subjects as either control or patient. Classification accuracy was mostly above 80% for the machine learners evaluated in this study and close to 85% at best. PMID- 25454647 TI - Acute hemicerebellitis in a young adult: a case report and literature review. AB - Acute hemicerebellitis, marked by headache with or without cerebellar signs, is a rare clinical entity involving a unilateral cerebellar hemisphere. The pathogenesis of acute hemicerebellitis remains unclear, and the disease rarely occurs in adults. Here, we report an 18-year-old woman who presented with a lack of coordination of the right hand and leg lasting longer than one week, following a pulsatile headache. A neurological examination disclosed ocular dysmetria, right-sided limb ataxia and slight truncal ataxia. Cerebrospinal fluid analysis showed mononuclear pleocytosis. The serology and autoimmune studies were unremarkable. Brain magnetic resonance imaging (MRI) revealed a focal signal change in the right cerebellar hemisphere and vermis. Acute hemicerebellitis was diagnosed, and the patient was treated with intravenous methylprednisolone sodium succinate and acyclovir. Subsequently, the headache resolved, and the cerebellar signs were markedly improved. Twenty days after admission, she became asymptomatic and brain MRI showed resolution of cerebellar hyperintensity on the right side. In conclusion, we identified only 6 additional patients with adult onset acute hemicerebellitis from previous reports, highlighting the importance of recognizing this rare clinical entity. Its clinical outcome is usually favorable, but in the acute phase, attention should be directed toward clinical symptoms that are suggestive of increased intracranial pressure. PMID- 25454648 TI - Genetic analysis of SPG4 and SPG3A genes in a cohort of Chinese patients with hereditary spastic paraplegia. AB - Hereditary spastic paraplegia (HSP or SPG) is a group of genetically and clinically heterogeneous neurodegenerative disorders. At least 52 different gene loci have been identified so far, involving autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), and maternal inheritance. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes are responsible for about 50% of pure AD-HSP patients. In this study, SPAST and ATL1 mutations were screened in 36 unrelated HSP patients (17 probands with AD family history and 19 sporadic HSP patients) by direct sequencing and multiplex ligation dependent probe amplification (MLPA). We identified 3 micro-mutations and 2 exon deletions in SPAST gene and 2 micro mutations in ATL1 gene. Four of five micro-mutations were novel and del. ex. 13 15 in SPAST was not reported previously. In this cohort of Chinese patients with spastic paraplegia, SPAST and ATL1 mutations were found in 5 of 17 HSP probands with AD family history and in 2 of 19 sporadic HSP patients. Four novel micro mutations and one novel exon deletion were identified, which broadened the mutational spectrum of the genes. PMID- 25454650 TI - Hypertrophic spinal pachymeningitis: idiopathic vs. IgG4-related. PMID- 25454649 TI - A novel strumpellin mutation and potential pitfalls in the molecular diagnosis of hereditary spastic paraplegia type SPG8. AB - Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous, neurodegenerative movement disorder. A total of eight KIAA0196/strumpellin variants have thus far been associated with SPG8, a rare dominant HSP. We present a novel strumpellin alteration in a small family with clinically pure HSP. We corroborated its causality by comparing it to rare benign variants at several levels, and, along this line, also re-considered previous genetic reports on SPG8. These analyses identified significant challenges in the interpretation of strumpellin alterations, and suggested that at least two of the few families claimed to suffer from SPG8 may have been genetically misdiagnosed. PMID- 25454651 TI - Pathological features of intracardiac bacterial vegetation and intracranial arterial thrombus due to infective endocarditis in a stroke patient. PMID- 25454652 TI - Life-cycle phosphorus management of the crop production-consumption system in China, 1980-2012. AB - Phosphorus (P) is an essential resource for agriculture and also a pollutant capable of causing eutrophication. The possibility of a future P scarcity and the requirement to improve the environment quality necessitate P management to increase the efficiency of P use. This study applied a substance flow analysis (SFA) to implement a P management procedure in a crop production-consumption (PMCPC) system model. This model determined the life-cycle P use efficiency (PUE) of the crop production-consumption system in China during 1980-2012. The system includes six subsystems: fertilizer manufacturing, crop cultivation, crop processing, livestock breeding, rural consumption, and urban consumption. Based on this model, the P flows and PUEs of the subsystems were identified and quantified using data from official statistical databases, published literature, questionnaires, and interviews. The results showed that the total PUE of the crop production-consumption system in China was low, notably from 1980 to 2005, and increased from 7.23% in 1980 to 20.13% in 2012. Except for fertilizer manufacturing, the PUEs of the six subsystems were also low. The PUEs in the urban consumption subsystem and the crop cultivation subsystem were less than 40%. The PUEs of other subsystems, such as the rural consumption subsystem and the livestock breeding subsystem, were also low and even decreased during these years. Measures aimed to improve P management practices in China have been proposed such as balancing fertilization, disposing livestock excrement, adjusting livestock feed, changing the diet of residents, and raising the waste disposal level, etc. This study also discussed several limitations related with the model and data. Conducting additional related studies on other regions and combining the analysis of risks with opportunities may be necessary to develop effective management strategies. PMID- 25454653 TI - Polymeric embolization coil of bilayered polyvinyl alcohol strand for therapeutic vascular occlusion: a feasibility study in canine experimental vascular models. AB - PURPOSE: To investigate the feasibility of polyvinyl alcohol (PVA) polymer coil as a new endovascular embolic agent and to gauge the related histologic response in a canine vascular model. MATERIALS AND METHODS: PVA polymer coil was fabricated by cross-linking PVA and tantalum particles. Basic properties were then studied in vitro via swelling ratio and bending diameter. Normal renal segmental arteries and wide-necked aneurysms of carotid sidewalls served as canine vascular models. Endovascular PVA coil embolization of normal renal segmental arteries (N = 20) and carotid aneurysms (N = 8) was performed under fluoroscopic guidance in 10 dogs. Degree of occlusion was assessed immediately and at 4 weeks after embolization by conventional and computed tomographic angiography. Histologic features were also graded at acute (day 1, six segmental arteries and four aneurysms) and chronic phases (week 4, 14 segmental arteries and four aneurysms) after embolization to assess inflammation, organization of thrombus, and neointimal proliferation. RESULTS: Swelling ratio declined as concentrations of cross-linking agent increased. Mean bending diameters were 2.05 mm (range, 0.86-6.25 mm) in water at 37 degrees C and 2.29 mm (range, 0.94-6.38 mm) in canine blood samples at 37 degrees C. Occlusion of normal renal segmental arteries was sustained (complete occlusion at day 1, n = 20; at week 4, n = 14), whereas immediate outcomes in carotid aneurysms (day 1, complete occlusion, n = 5; residual neck only, n = 3) were not sustained (week 4, complete occlusion, n = 1; minor recanalization, n = 1; major recanalization, n = 2). At week 4, chronic inflammatory cells predominated, with progressive organization of thrombus and fibrocellular ingrowth. All aneurysms bore full neointimal linings on the coil mass in the chronic phase. CONCLUSIONS: Vascular occlusion by PVA polymer coil proved superior in normal renal segmental arteries and feasible in surgically constructed carotid aneurysms (with packing densities >= 30%), constituting acceptable radiologic feasibility and histologic response. PMID- 25454654 TI - Retrograde pedal access technique for revascularization of infrainguinal arterial occlusive disease. AB - PURPOSE: To evaluate limb salvage after recanalization of lower extremity arteries using retrograde pedal access in patients with critical limb ischemia (CLI). MATERIALS AND METHODS: A retrospective review was performed of all patients in whom retrograde pedal arterial access was used for recanalization of infrainguinal occlusive disease between September 2002 and January 2013. Treatment was performed in 99 limbs in 92 patients (64 men and 28 women; median age, 71.6 y; range, 44-91 y) with CLI and no appropriate venous conduit for surgical bypass. Treated limbs were classified as Rutherford class 5 or 6 in 88% and class 4 in 12%. Retrograde and antegrade accesses were combined when occlusions could not be crossed from the antegrade direction. The treated occlusive segments were limited to the femoropopliteal arteries in 22% of procedures, runoff arteries in 32%, or both segments in 46%. Technical success was defined as successful crossing of the lesion and achievement of inline flow to the pedal vessel. Kaplan-Meier analysis was performed to determine limb salvage rate. RESULTS: Technical success was achieved in 88 of 99 (89%) treated limbs. Stents were placed for suboptimal angioplasty results in 41 of 88 (47%) successfully treated limbs. Major complications occurred in 8 of 99 (8%) procedures, 3 of which resulted in periprocedural mortality. Median follow-up was 8 months (mean, 17 mo; range, 1-98 mo). The limb salvage rate for technically successful cases was 74% at 6 months, 64% at 12 months, and 55% at 24 months. CONCLUSIONS: Retrograde pedal access is a viable revascularization technique for achieving limb salvage in patients with CLI. PMID- 25454655 TI - Muraglitazar-eluting bioabsorbable vascular stent inhibits neointimal hyperplasia in porcine iliac arteries. AB - PURPOSE: To evaluate the biocompatibility of a new muraglitazar-eluting polylactide copolymer stent and investigate its ability to prevent the formation of intimal hyperplasia. MATERIALS AND METHODS: Ten self-expandable muraglitazar eluting poly-96 L/4D-lactic acid (PLA96) stents and 10 self-expandable control PLA96 stents were implanted into porcine common iliac arteries. After 28 days follow-up, all stent-implanted iliac arteries were harvested and prepared for quantitative histomorphometric analysis. RESULTS: Angiographic analysis revealed that one control PLA96 stent had occluded and one had migrated. Histomorphometric analysis demonstrated that, with the control PLA96 stent, the luminal diameter and area were decreased versus the muraglitazar-eluting PLA96 stents (means +/- standard error of the mean, 3.58 mm +/- 0.34 vs 4.16 mm +/- 0.14 and 9.83 mm(2) +/- 2.41 vs 13.75 mm(2) +/- 0.93, respectively). The control PLA96 stent induced more intimal hyperplasia than the bioactive muraglitazar-eluting PLA96 stent (557 um +/- 122 vs 361 um +/- 32). Vascular injury scores demonstrated only mild vascular trauma for both stents (muraglitazar-eluting, 0.68 +/- 0.07; control, 0.75 +/- 0.08). Inflammation scores also showed mild inflammation for both stents (muraglitazar-eluting, 1.05 +/- 0.17; control, 1.23 +/- 0.19). CONCLUSIONS: This new muraglitazar-eluting PLA96 stent was shown to be biocompatible with a tendency for better patency and less intimal hyperplasia compared with the control PLA96 stents. PMID- 25454656 TI - Rhelogical, dermal wound healing and in vitro antioxidant properties of exopolysaccharide hydrogel from Pseudomonas stutzeri AS22. AB - The in vitro antioxidant activity and the in vivo wound healing performance of the exopolysaccharide EPS22, produced by Pseudomonas stutzeri AS22, were investigated. Antioxidant activity was evaluated by three different tests. The scavenging effect on DPPH radicals at a concentration of 1mg/ml was 80+/-1.41%. The reducing power reached a maximum of 1.26+/-0.02 at 2 mg/ml. Moreover, EPS22 showed good chelating ability and chelated almost 88.5+/-0.7% of ferrous ions at 0.75 mg/ml. The rheological characterization of EPS22 gel (0.5%) showed a pseudoplastic behavior, high elasticity, good mechanical strength and stability with high water-absorption ability. The application of the EPS22 gel on dermal full-thickness excision wounds in a rat model every two days, enhanced significantly wound healing activity and a total closure was achieved after 12 days of wound induction. Further, histological examination of biopsies showed advanced tissue regeneration, characterized by the presence of well-organized stratum of both derma and epidermis. PMID- 25454657 TI - Covalent immobilisation of VEGF on plasma-coated electrospun scaffolds for tissue engineering applications. AB - Recent findings in the field of biomaterials and tissue engineering provide evidence that surface immobilised growth factors display enhanced stability and induce prolonged function. Cell response can be regulated by material properties and at the site of interest. To this end, we developed scaffolds with covalently bound vascular endothelial growth factor (VEGF) and evaluated their mitogenic effect on endothelial cells in vitro. Nano- (254+/-133 nm) or micro-fibrous (4.0+/-0.4 MUm) poly(E-caprolactone) (PCL) non-wovens were produced by electrospinning and coated in a radio frequency (RF) plasma process to induce an oxygen functional hydrocarbon layer. Implemented carboxylic acid groups were converted into amine-reactive esters and covalently coupled to VEGF by forming stable amide bonds (standard EDC/NHS chemistry). Substrates were analysed by X ray photoelectron spectroscopy (XPS), enzyme-linked immuno-assays (ELISA) and immunohistochemistry (anti-VEGF antibody and VEGF-R2 binding). Depending on the reaction conditions, immobilised VEGF was present at 127+/-47 ng to 941+/-199 ng per substrate (6mm diameter; concentrations of 4.5 ng mm(-2) or 33.3 ng mm(-2), respectively). Immunohistochemistry provided evidence for biological integrity of immobilised VEGF. Endothelial cell number of primary endothelial cells or immortalised endothelial cells were significantly enhanced on VEGF-functionalised scaffolds compared to native PCL scaffolds. This indicates a sustained activity of immobilised VEGF over a culture period of nine days. We present a versatile method for the fabrication of growth factor-loaded scaffolds at specific concentrations. PMID- 25454658 TI - Hydrophilic modification of PVDF microfiltration membranes by adsorption of facial amphiphile cholic acid. AB - Amphiphilic molecules have been widely used in surface modification of polymeric materials. Bile acids are natural biological compounds and possess special facial amphiphilic structure with a unusual distribution of hydrophobic and hydrophilic regions. Based on the facial amphiphilicity, cholic acid (CA), one of the bile acids, was utilized for the hydrophilic modification of poly(vinylidene fluoride) (PVDF) microfiltration membranes via the hydrophobic interactions between the hydrophobic face of CA and the membrane surfaces. Ethanol, methanol, and water were respectively used as solvent during CA adsorption procedure. Their polarity affects the CA adsorption amount, as similar to CA concentration and adsorption time. There are no changes on the membrane surface morphology after CA adsorption. The hydrophilicity of PVDF membranes is greatly enhanced and the water drops permeates into the CA modified membranes quickly after modification. All these factors benefit to the permeation flux of membrane for water. When CA concentration is higher than 0.088 M, the water permeation flux is doubled as compared with the nascent PVDF membrane and shows a good stability during filtration procedure. These results reveal the promising potential of facial amphiphilic bile acids for the surface modification of polymeric materials. PMID- 25454659 TI - Self-oriented nanoparticles for site-selective immunoglobulin G recognition via epitope imprinting approach. AB - Molecular imprinting is a polymerization technique that provides synthetic analogs for template molecules. Molecularly imprinted polymers (MIPs) have gained much attention due to their unique properties such as selectivity and specificity for target molecules. In this study, we focused on the development of polymeric materials with molecular recognition ability, so molecular imprinting was combined with miniemulsion polymerization to synthesize self-orienting nanoparticles through the use of an epitope imprinting approach. Thus, L-lysine imprinted nanoparticles (LMIP) were synthesized via miniemulsion polymerization technique. Immunoglobulin G (IgG) was then bound to the cavities that specifically formed for L-lysine molecules that are typically found at the C terminus of the Fc region of antibody molecules. The resulting nanoparticles makes it possible to minimize the nonspecific interaction between monomer and template molecules. In addition, the orientation of the entire IgG molecule was controlled, and random imprinting of the IgG was prevented. The optimum conditions were determined for IgG recognition using the imprinted nanoparticles. The selectivity of the nanoparticles against IgG molecules was also evaluated using albumin and hemoglobin as competitor molecules. In order to show the self orientation capability of imprinted nanoparticles, human serum albumin (HSA) adsorption onto both the plain nanoparticles and immobilized nanoparticles by anti-human serum albumin antibody (anti-HSA antibody) was also carried out. Due to anti-HSA antibody immobilization on the imprinted nanoparticles, the adsorption capability of nanoparticles against HSA molecules vigorously enhanced. It is proved that the oriented immobilization of antibodies was appropriately succeeded. PMID- 25454660 TI - Poly(3,4-ethylenedioxythiophene) coated chitosan modified disposable electrodes for DNA and DNA-drug interaction sensing. AB - The need for sensitive, selective, rapid and low-cost detection systems for DNA and DNA-drug interactions are in crucial demand for diagnostics and real-world applications. This work details the preparation of poly(3,4 ethylenedioxythiophene) (PEDOT) coated chitosan (CHIT) and the use of PEDOT coated CHIT modified disposable pencil graphite electrodes (PGEs) for DNA and DNA anticancer drug interaction sensing. PEDOT coated CHIT (PEDOT/CHIT) was prepared with rotating plasma polymerization using radio frequency (RF: 13.56 MHz) power generator. Then, modification of PEDOT/CHIT onto PGE was performed. The use of the prepared electrode was carried out using differential pulse voltammetry (DPV). Cyclic voltammetry (CV) and scanning electron microscopy (SEM) were used to characterize the PEDOT/CHIT/PGE. The performance of the electrode was compared with CHIT/PGE and unmodified PGE. The electrode exhibited high sensitivity for the investigation of DNA sensing and DNA-anticancer drug interaction. Such disposable sensing platform hold considerable promise for diverse bioapplications. PMID- 25454661 TI - Development of eco-friendly submicron emulsions stabilized by a bio-derived gum. AB - Many traditional organic solvents are being gradually replaced by ecofriendly alternatives. D-Limonene is a terpenic (bio)-solvent that fulfils the requirements to be considered a green solvent. D-Limonene sub-micron emulsions suffer from Ostwald ripening destabilization. In this study, we examined the influence of the addition of a natural gum (rosin gum) to D-limonene in order to prevent Ostwald ripening. This contribution deals with the study of emulsions formulated with a mixture of D-limonene and rosin gum as dispersed phase and Pluronic PE9400 as emulsifier. The procedure followed for the development of these formulations was based on the application of product design principles. This led to the optimum ratio rosin gum/D-limonene and subsequently to the optimum surfactant concentration. The combination of different techniques (rheology, laser diffraction and multiple light scattering) was demonstrated to be a powerful tool to assist in the prediction of the emulsions destabilization process. Not only did the addition of rosin gum highly increase the stability of these emulsions by inhibiting the Ostwald ripening, but it also reduced the emulsions droplet size. Thus, we found that stable sub-micron D-limonene-in-water emulsions have been obtained in the range 3-6 wt% Pluronic PE-9400 by means of a single-step rotor/stator homogenizing process. PMID- 25454662 TI - PPO/PEO modified hollow fiber membranes improved sensitivity of 3D cultured hepatocytes to drug toxicity via suppressing drug adsorption on membranes. AB - The three dimensional (3D) cell culture in polymer-based micro system has become a useful tool for in vitro drug discovery. Among those polymers, polysulfone hollow fiber membrane (PSf HFM) is commonly used to create a microenvironment for cells. However, the target drug may adsorb on the polymeric surface, and this elicits negative impacts on cell exposure due to the reduced effective drug concentration in culture medium. In order to reduce the drug adsorption, PSf membrane were modified with hydrophilic Pluronic (PEO-b-PPO-b-PEO) copolymers, L121, P123 and F127 (PEO contents increase from 10%, 30% to 70%), by physical adsorption. As a result, the hydrophilicity of HFMs increased at an order of PSfF127>P123>L121 HFMs. The three modified membrane all showed significant resistance to adsorption of acid/neutral drugs. More importantly, the adsorption of base drugs were largely reduced to an average value of 11% on the L121 HFM. The improved resistance to drug adsorption could be attributed to the synergy of hydrophobic/neutrally charged PPO and hydrophilic PEO. The L121 HFM was further assessed by evaluating the drug hepatotoxicity in 3D culture of hepatocytes. The base drugs, clozapine and doxorubicin, showed more sensitive hepatotoxicity on hepatocytes in L121 HFM than in PSf HFM, while the acid drug, salicylic acid, showed the similar hepatotoxicity to hepatocytes in both HFMs. Our finding suggests that PSf HFM modified by PEO-b-PPO-b-PEO copolymers can efficiently resist the drug adsorption onto polymer membrane, and consequently improve the accuracy and sensitivity of in vitro hepatotoxic drug screening. PMID- 25454663 TI - Transferrin conjugated poly (gamma-glutamic acid-maleimide-co-L-lactide)-1,2 dipalmitoylsn-glycero-3-phosphoethanolamine copolymer nanoparticles for targeting drug delivery. AB - Targeted drug delivery strategies have shown great potential in solving some problems of chemotherapy, such as non-selectivity and severe side effects, thus enhancing the anti-tumor efficiency of chemotherapeutic agents. In this work, we have prepared a novel nanoparticle consisted of amphiphilic poly(gamma-glutamic acid-maleimide-co-L-lactide)-1,2-dipalmitoylsn-glycero-3-phosphoethanolamine (gamma-PGA-MAL-PLA-DPPE) copolymer decorated with transferrin (Tf), which can specifically deliver anti-cancer drug paclitaxel (PTX) to the tumor cells for targeting chemotherapy. These nanoparticles (NPs) have preferable particle size, high encapsulation efficiency and a pH-dependent release profile. As expected, The Tf modification mediate specific targeting to nasopharyngeal carcinoma (C666 1) cells and human cervical carcinoma (Hela) cells with the transferrin receptor (TfR) overexpressed and enhance cellular uptake of the NPs, as demonstrated by flow cytometry and confocal microscopy assays. In vitro cytotoxicity studies reveal that the NPs have excellent biocompatibility, and the presence of Tf enhance the activity of PTX to the targeted cells. All these results prove that Tf modified gamma-PGA-MAL-PLA-DPPE NPs could facilitate the tumor-specific therapy. Therefore, such a targeting drug delivery system provides significant advances toward cancer therapy. PMID- 25454664 TI - Hyaluronic acid-quercetin conjugate micelles: synthesis, characterization, in vitro and in vivo evaluation. AB - A tumor cell-targeted prodrug was developed for quercetin, using hyaluronic acid as polymeric carrier. Hyaluronic acid-quercetin (HA-QT) bioconjugates were synthesized by linking the hydroxy of quercetin via a succinate ester to adipic dihydrazide-modified hyaluronic acid. The mirco-morphology demonstrated that the prepared prodrug could form self-assembled micelles possessing spherical shape, 172.1 nm average diameter and -20.30 mV surface potential. The HA-QT micelles exhibited significant sustained and pH-dependent drug release behaviors without dramatic initial burst. Compared to free quercetin solution, the HA-QT micelles were found a 4 times increase in cytotoxicity on MCF-7 cells (CD44-overexpressing cell lines), while weak enhancement in inhibitory activity was observed towards L929 cells (CD44 deficient cell lines). Promisingly, 20.1-fold increase in the half-life and 4.9-fold increase in the area-under-the-curve (AUC) of quercetin were achieved for the HA-QT micelles compared with the parent drug. In addition, the HA-QT micelles also showed excellent inhibition effect on tumor growth in H22 tumor-bearing mice. Hemolytic toxicity and vein irritation assay further suggested that the HA-QT micelles were a safe and potent drug delivery system for targeted antitumor therapy. PMID- 25454665 TI - Biomineralization on polymer-coated multi-walled carbon nanotubes with different surface functional groups. AB - Substrate-controlled mineralization from simulated body fluid (SBF) has been studied as a model for biomineralization and for the synthesis of bioinspired hybrid materials. The mineralization procedure is complex and the features of final minerals are affected by many factors. Surface functional groups are among them and play important roles in inducing nucleation, crystal growth and transformation. In this study, multi-walled carbon nanotubes (MWCNTs) were surface-modified with poly(acrylic acid), polyacrylamide or poly(hydroxyethyl methylacrylate), and used as templates for biomineralization. The polymer coating was gained via photo-initiated polymerization of monomers and adsorption of polymer chains onto MWCNTs in solution. Then, the modified MWCNTs with different surface functional groups were incubated in 1.5 times SBF for different times to compare the effect of carboxyl, acylamino and hydroxyl group on calcium phosphate formation. The study involved various characterizations such as morphology observation, weight increase, chemical and crystal structures of deposited minerals at different soaking time points. In all cases, carbonated calcium deficient hydroxyapatite (CDHA) was identified after 7 days immersion. The continuously growing mineral crystals would wrap MWCNTs into spherical composite particles ultimately. However, the rates of nucleation and crystal growth depended on the type of surface functional groups, in an order of COOH>CONH2>OH. And their different charge characteristics led to different Ca/P ratios in initially formed minerals. It revealed that acylamino group, which demonstrated the lowest Ca/P ratio in nucleation stage, was helpful to obtain c-axis preferentially oriented morphology resembling the HA structure in natural bone tissue. PMID- 25454666 TI - Biocompatible fluorescent organic nanoparticles derived from glucose and polyethylenimine. AB - Fluorescent organic nanoparticles (FONs) were facilely prepared from polyethylenimine and glucose at mild reaction condition, and further utilized for cell imaging with various fluorescent wavelengths. The as-prepared PEI-Glu FONs were fully characterized by a series of techniques including 1H NMR spectrum, X ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy, dynamic light scattering, UV-vis absorption spectrum, and fluorescence spectra. Such FONs were demonstrated with intense fluorescence and high water dispersibility. Biocompatibility evaluation and cell uptake behavior of these FONs were further investigated, which proved excellent biocompatibility and made them promising for cell imaging. PMID- 25454667 TI - Gold nanoparticles functionalization notably decreases radiosensitization through hydroxyl radical production under ionizing radiation. AB - The purpose of this work was to study the influence of gold nanoparticles (GNP) coating on hydroxyl radical (HO) production under ionizing radiation. Though radiosensitizing mechanisms are still unknown, radical oxygen species are likely to be involved, especially HO. We synthesized six different types of GNP, choosing relevant ligands such as polyethylene glycol or human serum albumin. A great attention was paid to characterize these GNP in terms of size, charge and number of atoms in the coating. Our results show that functionalization dramatically decreases HO production, which is correlated to reduced plasmidic DNA damages. These findings are of high importance as GNP translation from fundamental research to applied medicine requires their functionalization to increase blood circulation time and specific cancerous cells addressing. We suggest that to keep GNP efficient for radiotherapy, a wispy coating is required. PMID- 25454668 TI - Alternating-current electrophoretic adhesion of biodegradable hydrogel utilizing intermediate polymers. AB - The adhesion of anionic charged biodegradable hydrogels each other utilizing oppositely charged water-soluble polymers as a binder has been achieved by applying alternating-current (AC) electric fields. The two gelatin based dextran sulfate gels (DS gels) were molecularly sutured together by AC electrophoretic adhesion when cationic charged quaternary ammonium chitosan (TMC) was applied between and held in contact with the two DS gels. The adhesive strength of the gels increased with increasing periodicity when a square wave was applied. Hydrogel constructs composed of DS microgels were prepared simply by AC electrophoretic adhesion utilizing intermediate TMC. PMID- 25454669 TI - Nanoparticle delivery of photosensitive Pt(IV) drugs for circumventing cisplatin cellular pathway and on-demand drug release. AB - A photosensitive platinum(IV) prodrug (UVA-Pt2) was attached to a biodegradable polymer (PE, methoxyl-poly(ethylene glycol)-block-poly(lactide-co-2-methyl-2 carboxyl-propylene carbonate-ethanol amine)) and then the conjugate was self assembled to micelles (NP-UVA-Pt2). In vitro MTT assay of NP-UVA-Pt2 demonstrated an improved cytotoxicity against SKOV-3 cells than that of cisplatin. Confocal laser scanning microscopy (CLSM) indicated that NP-UVA-Pt2 were endocytosed rather than internalized by passive diffusion, and thus, this process has nothing to do with copper transporter protein (Ctr1) as reported for cisplatin, which is closely related to drug resistance of Pt based drugs. Intracellular platinum content measured by ICP-MS result suggested that NP-UVA-Pt2 expressed higher platinum intracellular uptake than cisplatin. NP-UVA-Pt2 demonstrated fast and robust response to photo irradiation while the nanoparticles were stable in PBS at PH7.4 in the dark. The great drug efficacy of NP-UVA-Pt2 under UVA irradiation and the ineffectiveness in the dark makes NP-UVA-Pt2 an ideal light responsive on demand drug delivery system. Hence, NP-UVA-Pt2 will be a promising platinum based drug in the near future. PMID- 25454670 TI - Electrochemical properties of honeycomb-like structured HFBI self-organized membranes on HOPG electrodes. AB - HFBI (derived from Trichoderma sp.) is a unique structural protein, which forms a self-organized monolayer at both air/water interface and water/solid interfaces in accurate two-dimensional ordered structures. We have taken advantage of the unique functionality of HFBI as a molecular carrier for preparation of ordered molecular phase on solid substrate surfaces. The HFBI molecular carrier can easily form ordered structures; however, the dense molecular layers form an electrochemical barrier between the electrode and solution phase. In this study, the electrochemical properties of HFBI self-organized membrane-covered electrodes were investigated. Wild-type HFBI has balanced positive and negative charges on its surface. Highly oriented pyrolytic graphite (HOPG) electrodes coated with HFBI molecules were investigated electrochemically. To improve the electrochemical properties of this HFBI-coated electrode, the two types of HFBI variants, with oppositely charged surfaces, were prepared genetically. All three types of HFBI-coated HOPG electrode perform electron transfer between the electrode and solution phase through the dense HFBI molecular layer. This is because the HFBI self-organized membrane has a honeycomb-like structure, with penetrating holes. In the cases of HFBI variants, the oppositely charged HFBI membrane phases shown opposite electrochemical behaviors in electrochemical impedance spectroscopy. HFBI is a molecule with a unique structure, and can easily form honeycomb-like structures on solid material surfaces such as electrodes. The molecular membrane phase can be used for electrochemical molecular interfaces. PMID- 25454671 TI - The role of high loop gain induced by intermittent hypoxia in the pathophysiology of obstructive sleep apnoea. AB - Intermittent hypoxia and unstable breathing are key features of obstructive sleep apnoea (OSA), the most common pathological problem of breathing in sleep. Unstable ventilatory control is characterised by high loop gain (LG), and likely contributes to cyclical airway obstruction by promoting airway collapse during periods of low ventilatory drive. Potential new strategies to treat OSA include manipulations designed to lower LG. However, the contribution of inherent versus induced LG abnormalities in OSA remains unclear. Hence, a better understanding of the mechanisms causing high LG in OSA is needed to guide the design of LG based treatments. OSA patients exhibit abnormal chemoreflex control which contributes to increased LG. These abnormalities have been shown to normalise after continuous positive airway pressure treatment, suggesting induced rather than inherent trait abnormalities. Experimental intermittent hypoxia, mimicking OSA, increases hypoxic chemosensitivity and induces long term facilitation; a sustained increase in ventilatory neural output which outlasts the original stimulus. These neuroplastic changes induce the same abnormalities in chemoreflex control as seen in OSA patients. This review outlines the evidence to support that a key component of high LG in OSA is induced by intermittent hypoxia, and is reversed by simply preventing this inducing stimulus. PMID- 25454672 TI - The insomnia and suicide link: toward an enhanced understanding of this relationship. AB - Despite current knowledge of risk factors for suicidal behaviors, suicide remains a leading cause of death worldwide. This suggests a strong need to identify and understand additional risk factors. A number of recent studies have identified insomnia as a modifiable, independent suicide risk factor. Although a link between insomnia and suicide is emerging, further research is required in order to understand the nature of the relationship. Accordingly, this paper presents an overview of the insomnia and suicide literature to-date, and a discussion of two major limitations within this literature that hinder its progress. First, the classification and assessment of insomnia and suicide-related thoughts and behaviors are inconsistent across studies; and second, there is a lack of empirical studies focused on investigating mediators of the insomnia and suicide relationship. Suggestions are offered within this paper for future studies to address these issues and facilitate new developments in this important research area. Following these suggested lines of research will ultimately inform whether insomnia treatments, particularly cognitive-behavioral therapy for insomnia, can be used to target suicide risk prevention and intervention. PMID- 25454673 TI - Restless legs syndrome in multiple sclerosis. AB - Restless legs syndrome (RLS) is a sleep-related sensory-motor disorder characterized by an irresistible urge to move the legs accompanied by unpleasant sensations in the lower extremities. According to many recent studies patients with multiple sclerosis (MS) suffer frequently from symptoms of RLS. The prevalence of RLS in MS patients varies 13.3%-65.1%, which is higher than the prevalence of RLS in people of the same age in the general population. MS patients with RLS have higher scores in the Expanded Disability Status Scale compared to MS patients without RLS. Presence of RLS has a negative impact on sleep quality and fatigue of MS patients. Iron deficiency and chronic inflammation may be factors contributing to development of RLS in MS. The relationship between the course and treatment of MS and RLS requires further prospective studies. PMID- 25454675 TI - A step towards stepped care: delivery of CBT-I with reduced clinician time. PMID- 25454676 TI - Evaluation of corneal stromal demarcation line depth following standard and a modified-accelerated collagen cross-linking protocol. PMID- 25454674 TI - The role of sleep hygiene in promoting public health: A review of empirical evidence. AB - The ineffectiveness of sleep hygiene as a treatment in clinical sleep medicine has raised some interesting questions. If it is known that, individually, each specific component of sleep hygiene is related to sleep, why wouldn't addressing multiple individual components (i.e., sleep hygiene education) improve sleep? Is there still a use for sleep hygiene? Global public health concern over sleep has increased demand for sleep promotion strategies accessible to the population. However, the extent to which sleep hygiene strategies apply outside clinical settings is not well known. The present review sought to evaluate the empirical evidence for sleep hygiene recommendations regarding exercise, stress management, noise, sleep timing, and avoidance of caffeine, nicotine, alcohol, and daytime napping, with a particular emphasis on their public health utility. Thus, our review is not intended to be exhaustive regarding the clinical application of these techniques, but rather to focus on broader applications. Overall, though epidemiologic and experimental research generally supported an association between individual sleep hygiene recommendations and nocturnal sleep, the direct effects of individual recommendations on sleep remains largely untested in the general population. Suggestions for clarification of sleep hygiene recommendations and considerations for the use of sleep hygiene in nonclinical populations are discussed. PMID- 25454677 TI - Newborn screening for medium chain acyl-CoA dehydrogenase deficiency: performance improvement by monitoring a new ratio. AB - Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is a fatty acid oxidation disorder included on newborn screening (NBS) panels in many regions that have expanded to using tandem mass spectrometry for acylcarnitine screening. False positive (FP) screening results for MCAD deficiency have previously been linked to very low birth weight (VLBW) infants and those who are heterozygous for the common mutation, p.K324E. Previous studies have identified these causes of FP screens by sequencing residual dried blood spots. From our cohort of FP screens in Georgia, we identified an elevation at the same mass as octenoylcarnitine (C8:1) causing elevations of octanoylcarnitine (C8) not due to MCAD deficiency. We reviewed biochemical results from 2011 to 2013 for all newborn screens positive for MCAD deficiency in Georgia to identify screening criteria to allow these cases to be identified prospectively, thus saving families the stress of additional testing on their newborn and reducing healthcare costs while improving screening performance for the screening program. We identified the C8/C8:1 ratio as an effective marker, and developed criteria that will reduce FP screening results due to this interfering substance. PMID- 25454678 TI - Controversies in the management of severe congenital diaphragmatic hernia. AB - Despite years of progress in perinatal care, severe congenital diaphragmatic hernia (CDH) remains a clinical challenge. Controversies include almost every facet of clinical care: the definition of severe CDH by prenatal and postnatal criteria, fetal surgical intervention, ventilator management, pulmonary hypertension management, use of extracorporeal membrane oxygenation, surgical considerations, and long-term follow-up. Breakthroughs are likely only possible by sharing of experience, collaboration between institutions and innovative therapies within well-designed multicenter clinical trials. PMID- 25454679 TI - Increased risk of hypertension in patients with anxiety disorders: a population based study. AB - OBJECTIVE: We designed this study to examine the prevalence and incidence of hypertension and risk factors in patients with anxiety disorders. METHODS: The National Health Research Institute provided a database of 1,000,000 random subjects for study. We obtained a random sample of 766,427 subjects aged >=18years in 2005. The differences in the prevalence of hypertension between patients with anxiety disorders and the general population in 2005 were tested by multiple logistic regression adjusted for other covariates, including age, sex, insurance amount, region, urbanicity and depression. The differences in the incidence of hypertension between patients with anxiety disorders and the general population according to age group and sex from 2006 to 2010 were tested by a Cox regression adjusted for the other covariates. RESULTS: The prevalence of hypertension in patients with anxiety disorders was higher than that in the general population (37.9% vs. 12.4%, odds ratio, 2.61; 95% confidence interval, 2.52-2.70) in 2005. The average annual incidence of hypertension in patients with anxiety disorders from 2006 to 2010 was also higher than that in the general population (3.63% vs. 1.95%, risk ratio, 1.29; 95% confidence interval, 1.23 1.36). Compared with the general population, patients with anxiety disorders had a higher incidence of hypertension in all age and sex groups. CONCLUSIONS: Patients with anxiety disorders had a higher prevalence and a higher incidence of hypertension than that in the general population. Age, male sex, diabetes, and hyperlipidemia were risk factors for hypertension in patients with anxiety disorders. PMID- 25454680 TI - Depression, anxiety and 6-year risk of cardiovascular disease. AB - OBJECTIVE: Depression and anxiety are considered etiological factors in cardiovascular disease (CVD), though their relative contribution and differentiation by clinical characteristics have not been studied intensively. We examined 6-year associations between depressive and anxiety disorders, clinical characteristics and newly-developed CVD. METHODS: DSM-IV diagnoses were established in 2510 CVD-free participants of the Netherlands Study of Depression and Anxiety. Data on subtype, severity, and psychoactive medication were collected. The 6-year incidence of CVD was assessed using Cox regression analyses adjusted for sociodemographic, health and lifestyle factors. RESULTS: One-hundred six subjects (4.2%) developed CVD. Having both current depressive and anxiety disorders (HR=2.86, 95%CI 1.49-5.49) or current depression only (HR=2.30; 95%CI 1.10-4.80) was significantly associated with increased CVD incidence, whereas current anxiety only (HR=1.48; 95%CI 0.74-2.96) and remitted disorders (HR=1.48; 95%CI 0.80-2.75) were not associated. Symptom severity was associated with increased CVD onset (e.g., Inventory of Depressive Symptomatology per SD increase: HR=1.51; 95%CI 1.25-1.83). Benzodiazepine use was associated with additional CVD risk (HR=1.95; 95%CI 1.16-3.31). CONCLUSIONS: Current depressive (but not anxiety) disorder independently contributed to CVD in our sample of initially CVD-free participants. CVD incidence over 6years of follow-up was particularly increased in subjects with more symptoms, and in those using benzodiazepines. PMID- 25454681 TI - Workplace bullying and depressive symptoms: a prospective study among junior physicians in Germany. AB - OBJECTIVE: The relationship between workplace bullying and depression may be bi directional. Furthermore, it has been suggested that the depressogenic effect of bullying may only become evident after reasonable periods of follow-up (i.e., >1 year). As prospective evidence remains sparse and inconsistent, we used data from a three-wave prospective study to disentangle this potentially bi-directional relationship. METHODS: In 2004, 621 junior hospital physicians participated in a survey and were followed-up 1.2 years and 2.8 years later. Prospective analyses were restricted to participants with complete data at all assessments (n=507 or 82%). To measure workplace bullying, a description of bullying at work was provided followed by an item inquiring whether the respondent felt she/he had been exposed. Depressive symptoms were assessed by the state scale of the German Spielberger's State-Trait Depression Scales. RESULTS: Multivariate linear regression suggested that workplace bullying at baseline predicted increased depressive symptoms both after 1 year (b=1.43, p=0.01) and after 3 years of follow-up (b=1.58, p=0.01). Multivariate Poisson regression models revealed that the depressive symptom z-score at baseline was associated with an increased risk of bullying at the 3-year follow-up (relative risk [RR]=1.49, 95% confidence interval [CI]=1.13-1.97). This association was less pronounced after 1 year of follow-up (RR=1.19, 95% CI=0.90-1.59). CONCLUSIONS: Our study suggests bi directional associations between depressive symptoms and victimization from bullying at the workplace. Future prospective studies are needed to examine underlying biopsychosocial mechanisms. PMID- 25454682 TI - The general approach to the poisoned patient. AB - The poisoned patient can present many challenges to the healthcare practitioner. An organized and thoughtful approach to the poisoned patient is necessary. Understanding the nuances of a toxicological history and physical examination can aid in the management of these patients. Supportive care with attention to the body systems at risk from the poisoning is the mainstay of therapy. Consultation with a medical toxicologist or regional poison control center can positively impact diagnosis, management, and disposition of poisoned patients. PMID- 25454683 TI - Adverse events among seniors receiving spinal manipulation and exercise in a randomized clinical trial. AB - Spinal manipulative therapy (SMT) and exercise have demonstrated effectiveness for neck pain (NP). Adverse events (AE) reporting in trials, particularly among elderly participants, is inconsistent and challenges informed clinical decision making. This paper provides a detailed report of AE experienced by elderly participants in a randomized comparative effectiveness trial of SMT and exercise for chronic NP. AE data, consistent with CONSORT recommendations, were collected on elderly participants who received 12 weeks of SMT with home exercise, supervised plus home exercise, or home exercise alone. Standardized questions were asked at each treatment; participants were additionally encouraged to report AE as they occurred. Qualitative interviews documented participants' experiences with AE. Descriptive statistics and content analysis were used to categorize and report these data. Compliance was high among the 241 randomized participants. Non serious AE were reported by 130/194 participants. AE were reported by three times as many participants in supervised plus home exercise, and nearly twice as many as in SMT with home exercise, as in home exercise alone. The majority of AE were musculoskeletal in nature; several participants associated AE with specific exercises. One incapacitating AE occurred when a participant fell during supervised exercise session and fractured their arm. One serious adverse event of unknown relationship occurred to an individual who died from an aneurysm while at home. Eight serious, non-related AE also occurred. Musculoskeletal AE were common among elderly participants receiving SMT and exercise interventions for NP. As such, they should be expected and discussed when developing care plans. PMID- 25454685 TI - Letter to the editor concerning: "reliability and validity of non-radiographic methods of thoracic kyphosis measurement: a systematic Areview." by Barrett E, McCreesh K, Lewis J. Man Ther. 2014 Feb; 19(1):10-7. PMID- 25454684 TI - Altered ventral neck muscle deformation for individuals with whiplash associated disorder compared to healthy controls - a case-control ultrasound study. AB - Previous studies have shown altered neck muscle function in individuals with chronic whiplash associated disorder (WAD). However, we lack real-time investigations with non-invasive methods that can distinguish between the different ventral neck muscle layers. This study investigated deformations and deformation rates in the sternocleidomastoid (SCM), longus capitis (Lcap), and longus colli (Lco) muscles with real-time ultrasonography. Twenty-six individuals with WAD were compared with 26 controls, matched for age and sex. Ultrasound imaging of the SCM, Lcap, and Lco were recorded during 10 repetitive arm elevations. The first and tenth arm elevations were post-process analyzed with speckle tracking. There were few significant differences in the deformations or deformation rates in the SCM, Lcap, and Lco between the WAD and control group. In controls, deformations and deformation rates showed linear positive relationships between SCM/Lcap, SCM/Lco, and Lcap/Lco which increased from the first arm elevation (R(2) = 0.14-0.70); to the tenth arm elevation (R(2) = 0.51-0.71). The WAD group showed similar or weaker linear relationship (R(2) < 0.19) during the tenth compared to the first (R(2) < 0.44) arm elevation except for deformations in Lcap/Lco (R(2) = 0.13-0.57). This result indicated that deformations and deformation rates in one muscle were correlated by similar deformations and deformation rates in other neck muscles in the control group, but this interplay between muscles was not found in the WAD group. PMID- 25454686 TI - Physiotherapists' assessment of patients' psychosocial status: are we standing on thin ice? A qualitative descriptive study. AB - Pain is a complex problem and one that confronts many physiotherapists' working in private practice on a daily basis. While physiotherapists' understanding of pain has matured a great deal in recent times, especially the role of psychosocial (PS) factors, it is unclear if and how, physiotherapists assess their patients' psychosocial status in clinical practice. The aim of this study was to explore private practice physiotherapists' assessment of patients' psychosocial status. A qualitative descriptive research design was used in this study. Participants were recruited through purposeful sampling and potential informants were invited to participate through letters or phone calls and data was collected via semi-structured interviews. Nine semi-structured interviews were conducted at the participants' workplaces. Data collection and analysis were conducted simultaneously and common concepts and themes were recognised, coded and grouped together into themes. Analysis of the data resulted in identification of various themes related to physiotherapists' assessment of patients' PS status. These themes relate to; physiotherapists capacity to conduct PS assessment, the barriers they face while conducting PS assessment and the suggestions they have provided to overcome these barriers. In general the physiotherapists' in this study demonstrated and acknowledged a poor understanding of the role of PS factors in their patients' clinical presentation. They were also unclear about the assessment of psychosocial factors. The barriers to assessment of psychosocial factors ranged from individual shortcomings to limitations in professional networks and time constraints. The most consistent barrier highlighted was participants' lack of formal education in PS theory and assessment. PMID- 25454687 TI - Receptor status change from primary to residual breast cancer after neoadjuvant chemotherapy and analysis of survival outcomes. AB - BACKGROUND: To evaluate the frequency of receptor change from pretreatment to residual breast cancer after NCT and their correlation with outcomes. PATIENTS AND METHODS: Three hundred ninety-eight women were identified retrospectively. Estrogen receptor, progesterone receptor, and HER2 were reviewed. Patients were classified as not having receptor change versus any receptor change. Kaplan-Meier was used to estimate survival outcomes according to changes. Cox proportional hazards models were used to determine the association of receptor status changes with outcomes after adjustment for patient and tumor characteristics. RESULTS: One hundred sixty-two (40.7%) patients had a change in at least 1 of the receptors from pretreatment to residual disease. Patients who had no change in receptor status had a significantly greater triple-negative breast cancer (TNBC) rate at baseline (P = .0001). Of the 193 hormone receptor (HR)-positive tumors, 9 (4.7%) and 29 (15.1%) became HER2-positive and TNBC, respectively. Of the 72 HER2 positive tumors, 20 (27.8%) and 9 (12.5%) became HR-positive and TNBC, respectively. Of the 128 TNBC tumors, only 2 (1.6%) and 33 (25.8%) became HER2 positive and HR-positive, respectively. At a median follow up of 40 months, 5 year overall survival (OS) was 73% and 63%; and 5-year relapse-free survival (RFS) was 63% and 48% for patients with or without any receptor change (P = .07 and P = .003), respectively. Any receptor change was associated with better RFS (hazard ratio, 0.63; 95% confidence interval [CI], 0.44-0.9) but not OS. (hazard ratio, 0.79; 95% CI, 0.53-1.18). CONCLUSION: Changes in receptor status between the pretreatment and residual disease after NCT are frequent and appear to be associated with improved RFS because of the receptor stability of TNBC. PMID- 25454688 TI - The efficacy and safety of preoperative chemotherapy with triweekly abraxane and cyclophosphamide followed by 5-Fluorouracil, epirubicin, and cyclophosphamide therapy for resectable breast cancer: a multicenter clinical trial. AB - BACKGROUND: It has been reported that tri-weekly Abraxane therapy has better outcomes in recurrent breast cancer than tri-weekly Cremophor-based taxol therapy, and that cyclophosphamide combined with taxane shows an enhanced antitumor effect. We conducted a phase II clinical trial of preoperative chemotherapy with a combination of TRI-ABC. PATIENTS AND METHODS: From September 2011 to September 2013, 4 cycles of preoperative chemotherapy with TRI-ABC followed by 4 cycles of FEC were administered in patients with resectable breast cancer. In patients with HER2-positive breast cancer, tri-weekly Trastuzumab was administered with TRI-ABC. The primary end point was the pathological complete response (pCR) rate in the breasts and lymph nodes. RESULTS: The treatment outcomes and safety were evaluated in 54 patients who received at least 1 dose of chemotherapy. All patients underwent radical surgery, and the overall pCR rate of 37% (20 of 54) was achieved. The pCR rates according to each subtype were 8% (2 of 24) in hormone receptor (HR)-positive HER2-negative breast cancer, 56% (5 of 9) in HR-positive HER2-positive breast cancer, 63% (5 of 8) in HR-negative HER2 positive breast cancer, and 62% (8 of 13) in triple-negative breast cancer. Multivariate analysis revealed that HR negativity and HER2 positivity were predictive factors of pCR. Clinical response was observed in 49 patients (91%). The safety profile was acceptable. CONCLUSION: Preoperative chemotherapy with TRI ABC followed by FEC showed high efficacy and excellent safety. Further clinical studies should be conducted to compare the efficacy of TRI-ABC followed by FEC with conventional taxane-anthracycline regimens. PMID- 25454689 TI - Loading dose ibandronate versus standard oral ibandronate in patients with bone metastases from breast cancer. AB - INTRODUCTION: In this phase II trial, the efficacy and safety of loading-dose I.V. ibandronate in patients with breast cancer with bone metastases were evaluated. PATIENTS AND METHODS: Thirty-four patients were randomized to receive a loading dose of 12 mg I.V. ibandronate on day 1 then oral ibandronate 50 mg daily (arm A), or standard oral therapy of 50 mg ibandronate daily from day 1 (arm B). The primary end point was percentage change in serum C-terminal crosslinking telopeptide of type I collagen (S-CTX) from baseline by day 5 of study. Secondary/exploratory end points included percentage change in other bone turnover markers (N-terminal cross-linking telopeptides of type I collagen [NTX], procollagen type I N propeptide, bone alkaline phosphatase) and change in average bone pain score. RESULTS: There was a significantly greater reduction in S-CTX at day 5 in arm A compared with arm B (median difference, 15.82%; P = .005). There was also a significantly greater reduction in urine NTX/creatinine at day 5 (P = .009) and at the end of weeks 1 to 8 (averaged; P = .006). Average bone pain score was lower in arm A at the end of 8 weeks (P = .012). There were no additional adverse events after administration of 12 mg I.V. loading dose of ibandronate. CONCLUSION: A 12-mg dose of I.V. ibandronate rapidly reduced markers of bone turnover and can be administered without additional toxicity. PMID- 25454690 TI - Detection of breast cancer in an FDG-PET cancer screening program: results of a nationwide Japanese survey. AB - BACKGROUND: The [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) cancer screening program is defined as cancer screening for asymptomatic subjects using FDG-PET/computed tomography with or without combination of other screening tests. The aim of this study was to analyze the detection rate and effectiveness of the FDG-PET cancer screening program for breast cancer between 2006 and 2009 in Japan. PATIENTS AND METHODS: A total of 62,054 asymptomatic female subjects underwent FDG-PET cancer screening. We analyzed 473 cases with findings of possible breast cancer in any screening tests. RESULTS: Among 473 possible cases, 161 were verified as breast cancer. The relative sensitivity and positive predictive value (PPV) of FDG-PET for breast cancer were 83.9% and 41.7%, respectively. The relative sensitivity and PPV of mammography (MMG) for breast cancer was less than for FDG-PET; results for breast ultrasonography (US) were close to FDG-PET. The combination of FDG-PET with MMG and US might contribute to increased sensitivity but does not improve PPV. Most breast cancer cases (83.0%) detected using the FDG-PET cancer screening program were stage 0 or I based on the Union for International Cancer Control criteria. CONCLUSION: The FDG-PET screening program in Japan detected breast cancer at an early stage. A combination of FDG-PET and MMG and/or breast US yields the best results for detecting breast cancer. The FDG-PET cancer-screening program alone cannot detect all breast cancers. PMID- 25454691 TI - Elevating the quality of disability and rehabilitation research: mandatory use of the reporting guidelines. PMID- 25454692 TI - Pain during injections of botulinum toxin in children: Influence of the localization technique. AB - OBJECTIVE: In this study, we consider two localization techniques used in injections of botulinium toxin in children: electrical stimulation and ultrasound. The hypothesis of this work was that injections performed without stimulation would be less painful. PATIENTS AND METHODS: Monocentric prospective study, with 107 sessions of lower limb injections. Two groups of children were compared: localization by ultrasound only (60 children), detection by stimulation only or by stimulation combined with ultrasound (47 children). Pain assessment was performed by the child or an accompanying party using the Visual Analog Scale (VAS) and by a health care team using the Face, Legs, Activity, Cry, Consolability (FLACC). RESULTS: A significant difference between the two groups was found in both self-report and by means of the behavioral observational pain scale. Indeed, VAS average and FLACC average were significantly higher with detection by stimulation than with ultrasound alone: 4.5cm+/-2.54 versus 2.7cm+/ 2.27; P<0.001 for VAS scale and 3.7+/-2.1 versus 2.7+/-2.3; P<0.05 for FLACC scale. CONCLUSION: When compared to ultrasound detection, localization by electrostimulation appears to increase the overall pain caused during injections of botulinum toxin in children. PMID- 25454694 TI - Biosorption of cationic basic dye and cadmium by the novel biosorbent Bacillus catenulatus JB-022 strain. AB - Biosorption of heavy metals and dyes is a promising technology that involves the removal of toxic metals from industrial wastes. The present study aims to screen the bacterial strains isolated from soils and polluted pond for their potential biosorption of both cationic dye and cadmium. Bacillus catenulatus JB-022 strain removed 58% and 66% of cationic basic blue 3 (BB3) and cadmium (Cd(II)) at the respective concentrations of 2000 mg/L and 150 mg/L. The biosorption equilibrium data were well fitted by the Langmuir adsorption isotherm, and the kinetic studies indicated that the biosorption followed the pseudo-second-order model. The biosorption kinetics showed that the equilibrium was reached within 10 min and 5 min for BB3 and Cd(II), respectively. According to the Langmuir model, the maximum uptakes of BB3 and Cd(II) by the JB-022 biomass were estimated to be 139.74 and 64.28 mg/g, respectively. To confirm the surface morphology and functional groups, field emission scanning electron microscope, energy-dispersive X-ray spectrometer, X-ray diffraction, and Fourier transform infrared spectroscopy analyses were carried out, and the results revealed that the biomass of JB-022 has carboxyl and phosphonate groups as potential surface functional groups capable of binding to cationic pollutants. In conclusion, B. catenulatus JB-022 is proposed as an excellent biosorbent with potentially important applications in removal of cationic pollutants from wastewaters. PMID- 25454693 TI - Effects of culture conditions of Pseudomonas aeruginosa strain RB on the synthesis of CdSe nanoparticles. AB - Cadmium selenide (CdSe) was synthesized by Pseudomonas aeruginosa strain RB in a culture containing lactic acid as a carbon source, 1 mM selenite, and 1 mM cadmium under various conditions. High purity (1.02-1.16 of the atomic ratio of Se to Cd) and efficient synthesis of biogenic CdSe nanoparticles were observed at 25-30 degrees C, 0.05-10 g L(-1) NaCl, and neutral pH conditions compared with other tested conditions. However, the size and shape of synthesized CdSe nanoparticles were not changed by changing culture conditions. The contents of S and Se in the particles respectively increased under alkaline and weak acidic conditions. Furthermore, high temperature (>37 degrees C), high salinity (>10 g L(-1) NaCl), and alkaline pH affected the CdSe-synthesizing rate by strain RB. This report is the first optimizing the culture conditions for synthesizing biogenic CdSe nanoparticles in a batch processing. PMID- 25454695 TI - Islets immunoisolation using encapsulation and PEGylation, simultaneously, as a novel design. AB - The most important obstacle in islets transplantation for the treatment of diabetes is graft rejection by the host immune system. To solve this problem, immunosuppressive drugs should be used, but they may have several side effects. To overcome these problems, islets immunoisolation systems such as encapsulation and PEGylation have been developed. The aim of this study was to investigate the possibility of using encapsulation and PEGylation techniques simultaneously (as a novel design) for immunocamouflaging the islets of Langerhans. For this purpose, the attachment of poly-L-ornithine (PLO) onto the surface of alginate microcapsules and activated methoxy polyethylene glycol (mPEG) onto alginate-PLO microcapsules was verified by Fourier transform infrared analysis and scanning electron microscopy. Viability of the free and encapsulated islets up to the 7th day was approved by acridine orange (AO)/propidium iodide (PI). The obtained results from lymphocytes co-culturing with free and encapsulated islets (in different designs of microcapsules with one to three layers) showed that encapsulation generally reduces the immune response against the islets. However, the addition of PLO and mPEG as second and third layers to the surface of alginate microcapsules decreased interleukine-2 (IL-2) secretion against the islets more and more. Finally, two different activated mPEG, mPEG-succinimidyl carbonate (mPEG-SC) and mPEG-succinimidylvaleric acid (mPEG-SVA), used separately on the surface of microcapsules were investigated, and the results showed that IL 2 secretion was reduced 14.3% and 37.5% in comparison with the alginate-PLO microcapsules, respectively. On the other hand, mPEG-SVA was more effective than mPEG-SC, so it decreased IL-2 secretion 27.1% more than mPEG-SC. PMID- 25454696 TI - Comparative study of fungal strains for thermostable inulinase production. AB - Fructose and fructo-oligosaccharides (FOS) are important ingredients in the food industry. Fructose is considered an alternative sweetener to sucrose because it has higher sweetening capacity and increases iron absorption in children, and FOS's are a source of dietary fiber with a bifidogenic effect. Both compounds can be obtained by enzymatic hydrolysis of inulin. However, inulin presents limited solubility at room temperature, thus, fructose and FOS production is carried out at 60 degrees C. Therefore, there is a growing interest to isolate and characterize thermostable inulinases. The aim of this work was to evaluate the capacity of different fungal strains to produce potential thermostable inulinases. A total of 27 fungal strains belonging to the genera Aspergillus, Penicillium, Rhizopus, Rhizomucor and Thermomyces were evaluated for production of inulinase under submerged culture using Czapek Dox medium with inulin as a sole carbon source. Strains were incubated at 37 degrees C and 200 rpm for 96 h. Crude enzyme extract was obtained to evaluate inulinase and invertase activity. In order to select the fungal strain with the highest thermostable inulinase production, a selection criterion was established. It was possible to determine the highest inulinase activity for Rhizopus microsporus 13aIV (10.71 U/mL) at 36 h with an optimum temperature of inulinase of 70 degrees C. After 6 h at 60 degrees C, the enzyme did not show any significant loss of activity and retained about 87% activity, while it only retains 57% activity at 70 degrees C. According to hydrolysis products, R. microsporus produced endo and exo-inulinase. PMID- 25454697 TI - Generation of monodisperse cell-sized microdroplets using a centrifuge-based axisymmetric co-flowing microfluidic device. AB - We report an easy-to-use generation method of biologically compatible monodisperse water-in-oil microdroplets using a glass-capillary-based microfluidic device in a tabletop mini-centrifuge. This device does not require complicated microfabrication; furthermore, only a small sample volume is required in experiments. Therefore, we believe that this method will assist biochemical and cell-biological experiments. PMID- 25454698 TI - Effective stimulating factors for microbial levan production by Halomonas smyrnensis AAD6T. AB - Levan is a bioactive fructan polymer that is mainly associated with high-value applications where exceptionally high purity requirements call for well-defined cultivation conditions. In this study, microbial levan production by the halophilic extremophile Halomonas smyrnensis AAD6(T) was investigated systematically. For this, different feeding strategies in fed-batch cultures were employed and fermentation profiles of both shaking and bioreactor cultures were analyzed. Initial carbon and nitrogen source concentrations, production pH, NaCl and nitrogen pulses, nitrogen and phosphorous limitations, trace elements and thiamine contents of the basal production medium were found to affect the levan yields at different extends. Boric acid was found to be the most effective stimulator of levan production by increasing the sucrose utilization three-fold and levan production up to five-fold. This significant improvement implied the important role of quorum sensing phenomenon and its regulatory impact on levan production mechanism. Levan produced by bioreactor cultures under conditions optimized within this study was found to retain its chemical structure. Moreover, its biocompatibility was assessed for a broad concentration range. Hence H. smyrnensis AAD6(T) has been firmly established as an industrially important resource microorganism for high-quality levan production. PMID- 25454699 TI - Cloning and heterologous expression of the ftfCNC-2(1) gene from Weissella confusa MBFCNC-2(1) as an extracellular active fructansucrase in Bacillus subtilis. AB - Fructan-exopolysaccharides (fructan-EPS) (inulin and levan) and their oligosaccharides (fructooligosaccharides, FOS) have drawn considerable interest in the food and pharmaceutical industries. EPS-producing lactic acid bacteria have been reported to produce beta-fructans (inulin and levan), as well as alpha glucans, by the function of sucrase enzymes, i.e., fructansucrase and glucansucrase. A fructansucrase ftfCNC-2(1) gene from Weissella confusa strain MBFCNC-2(1) was previously cloned in Escherichia coli. In this study, we aimed to express the ftf[CNC-2(1)] gene in Bacillus subtilis to obtain the active form of the extracellular recombinant protein FTF[CNC-2(1)]. This cloning was achieved by inserting the gene in-fusion with the signal sequence of the B. subtilis subtilisin E. SDS-polyacrylamide gel electrophoresis analysis and in situ activity assay with Periodic Acid-Schiff staining revealed that the recombinant FTF[CNC-2(1)] was successfully expressed as an extracellular protein from B. subtilis DB403 in its active form, which was confirmed using sucrose and raffinose. PMID- 25454701 TI - Hitting a target is fundamentally different from avoiding obstacles. AB - To successfully move our hand to a target, it is important not only to consider the target of our movements but also to consider other objects in the environment that may act as obstacles. We previously found that the time needed to respond to a change in position was considerably longer for a displacement of an obstacle than for a displacement of the target (Aivar, Brenner, & Smeets, 2008. Experimental Brain Research 190, 251-264). In that study, the movement constraints imposed by the obstacles differed from those imposed by the target. To examine whether the latency is really different for targets and obstacles, irrespective of any constraints they impose, we modified the design of the previous experiment to make sure that the constraints were matched. In each trial, two aligned 'objects' of the same size were presented at different distances to the left of the initial position of the hand. Each of these objects could either be a target or a gap (opening between two obstacles). Participants were instructed to pass through both objects. All possible combinations of these two objects were tested: gap-target, target-gap, gap-gap, target-target. On some trials one of the objects changed position after movement onset. Participants systematically responded faster to the displacement of a target than to the displacement of a gap at the same location. We conclude that targets are prioritized over obstacles in movement control. PMID- 25454702 TI - Quantifying interactions between accommodation and vergence in a binocularly normal population. AB - Stimulation of the accommodation system results in a response in the vergence system via accommodative vergence cross-link interactions, and stimulation of the vergence system results in an accommodation response via vergence accommodation cross-link interactions. Cross-link interactions are necessary in order to ensure simultaneous responses in the accommodation and vergence systems. The crosslink interactions are represented most comprehensively by the response AC/A (accommodative vergence) and CA/C (vergence accommodation) ratios, although the stimulus AC/A ratio is measured clinically, and the stimulus CA/C ratio is seldom measured in clinical practice. The present study aims to quantify both stimulus and response AC/A and CA/C ratios in a binocularly normal population, and determine the relationship between them. 25 Subjects (mean +/- SD age 21.0 +/- 1.9 years) were recruited from the university population. A significant linear relationship was found between the stimulus and response ratios, for both AC/A (r2 = 0.96, p < 0.001) and CA/C ratios (r2 = 0.40, p < 0.05). Good agreement was found between the stimulus and response AC/A ratios (95% CI -0.06 to 0.24 MA/D). Stimulus and response CA/C ratios are linearly related. Stimulus CA/C ratios were higher than response ratios at low values, and lower than response ratios at high values (95% CI -0.46 to 0.42 D/MA). Agreement between stimulus and response CA/C ratios is poorer than that found for AC/A ratios due to increased variability in vergence responses when viewing the Gaussian blurred target. This study has shown that more work is needed to refine the methodology of CA/C ratio measurement. PMID- 25454700 TI - On-line and model-based approaches to the visual control of action. AB - Two general approaches to the visual control of action have emerged in last few decades, known as the on-line and model-based approaches. The key difference between them is whether action is controlled by current visual information or on the basis of an internal world model. In this paper, we evaluate three hypotheses: strong on-line control, strong model-based control, and a hybrid solution that combines on-line control with weak off-line strategies. We review experimental research on the control of locomotion and manual actions, which indicates that (a) an internal world model is neither sufficient nor necessary to control action at normal levels of performance; (b) current visual information is necessary and sufficient to control action at normal levels; and (c) under certain conditions (e.g. occlusion) action is controlled by less accurate, simple strategies such as heuristics, visual-motor mappings, or spatial memory. We conclude that the strong model-based hypothesis is not sustainable. Action is normally controlled on-line when current information is available, consistent with the strong on-line control hypothesis. In exceptional circumstances, action is controlled by weak, context-specific, off-line strategies. This hybrid solution is comprehensive, parsimonious, and able to account for a variety of tasks under a range of visual conditions. PMID- 25454703 TI - Preface. NAD metabolism and signaling: Critical pathways in bacteria, yeast and mammals influencing genome stability, cell survival and disease. PMID- 25454704 TI - Foreword. PMID- 25454705 TI - Asymptomatic retained surgical sponge. PMID- 25454707 TI - Comment on "Efficacy of pancreatic stenting prior to extracorporeal shock wave lithotripsy for pancreatic stones" by Hiromu Kondo et al. [Digestive and Liver Disease 2014;46:639-44]. PMID- 25454708 TI - Clinical outcomes of endoscopic submucosal dissection for early stage esophagogastric junction cancer: a systematic review and meta-analysis. AB - BACKGROUND: Although endoscopic submucosal dissection has become widely used for the management of selected cases of early gastric cancer, the effects of endoscopic submucosal dissection for esophagogastric junction cancer have not been fully evaluated. METHODS: Medline, Embase, and the Cochrane Library were searched using the primary keywords "endoscopic submucosal dissection," "ESD," "endoscopic resection," "esophagogastric junction," "gastroesophageal junction," and "Barrett." Six short-term clinical outcomes and three long-term oncologic outcomes were extracted. RESULTS: A total of six studies provided data on 359 early stage esophagogastric junction cancers treated with endoscopic submucosal dissection. The pooled estimate of en bloc resection and complete resection was 98.6% (95% confidence interval 95.9-99.6%) and 87.0% (95% confidence interval 79.7-92.0%), respectively. The pooled estimate of stenosis was 6.9% (95% confidence interval 3.2-14.0%). In 269 lesions with curative resection, there was no local recurrence or distant metastasis. In contrast, three local recurrences and two distant metastases occurred in 90 lesions with non-curative resection. CONCLUSIONS: Endoscopic submucosal dissection for early stage esophagogastric junction cancer is a feasible treatment option with high en bloc resection, complete resection rates and an acceptable range of complications. When curative resections are achieved, good oncologic outcomes are likely in the management of early stage esophagogastric junction cancer by endoscopic submucosal dissection. PMID- 25454706 TI - Two-week, high-dose proton pump inhibitor, moxifloxacin triple Helicobacter pylori therapy after failure of standard triple or non-bismuth quadruple treatments. AB - BACKGROUND: Aim was to evaluate the efficacy and tolerability of a moxifloxacin containing second-line triple regimen in patients whose previous Helicobacter pylori eradication treatment failed. METHODS: Prospective multicentre study including patients in whom a triple therapy or a non-bismuth-quadruple-therapy failed. Moxifloxacin (400mg qd), amoxicillin (1g bid), and esomeprazole (40 mg bid) were prescribed for 14 days. Eradication was confirmed by (13)C-urea-breath test. Compliance was determined through questioning and recovery of empty medication envelopes. RESULTS: 250 patients were consecutively included (mean age 48 +/- 15 years, 11% with ulcer). Previous (failed) therapy included: standard triple (n = 179), sequential (n = 27), and concomitant (n = 44); 97% of patients took all medications, 4 were lost to follow-up. Intention-to-treat and per protocol eradication rates were 82.4% (95% CI, 77-87%) and 85.7% (95% CI, 81 90%). Cure rates were similar independently of diagnosis (ulcer, 77%; dyspepsia, 82%) and previous treatment (standard triple, 83%; sequential, 89%; concomitant, 77%). At multivariate analysis, only age was associated with eradication (OR = 0.957; 95% CI, 0.933-0.981). Adverse events were reported in 25.2% of patients: diarrhoea (9.6%), abdominal pain (9.6%), and nausea (9.2%). CONCLUSION: 14-day moxifloxacin-containing triple therapy is an effective and safe second-line strategy in patients whose previous standard triple therapy or non-bismuth quadruple (sequential or concomitant) therapy has failed, providing a simple alternative to bismuth quadruple regimen. PMID- 25454709 TI - PDX-1 mRNA expression in endoscopic ultrasound-guided fine needle cytoaspirate: perspectives in the diagnosis of pancreatic cancer. AB - BACKGROUND AND AIMS: Endoscopic ultrasound-guided fine needle aspiration is routinely used in the diagnostic work up of pancreatic cancer but has a low sensitivity. Studies showed that Pancreatic Duodenal Homeobox-1 (PDX-1) is expressed in pancreatic cancer, which is associated with a worse prognosis. We aimed to verify whether the assessment of PDX-1 in endoscopic ultrasound-guided fine needle aspiration samples may be helpful for the diagnosis of pancreatic cancer. METHODS: mRNA of 54 pancreatic cancer and 25 cystic lesions was extracted. PDX-1 expression was assessed by Real-Time PCR. RESULTS: In all but two patients with pancreatic cancer, PDX-1 was expressed and was found positive in 7 patients with pancreatic cancer in which cytology was negative. The positivity was associated with a probability of 0.98 (95% CI 0.90-1.00) of having cancer and the negativity with one of 0.08 (95% CI 0.01-0.27). The probability of cancer rose to 1.00 (95% CI 0.97-1.00) for patients positive to both PDX-1 and cytology and fell to 0.0 (95% CI 0.00-0.15) in patients negative for both. CONCLUSIONS: PDX-1mRNA is detectable in samples of pancreatic cancer. Its quantification may be helpful to improve the diagnosis of pancreatic cancer. PMID- 25454710 TI - [Summary of activities of the journal Archives of Mexican Cardiology in the period 2009-2014]. PMID- 25454711 TI - Creatures of habit. PMID- 25454712 TI - Incidental treatment of maxillary dysesthesia with maxillary sinus lift procedure -a case report. AB - A 54-year-old woman presented with an 8-month history of dysesthesia to the left palate with referred pain to the left infraorbital distribution after extraction of the left maxillary first and second premolars. The clinical and radiologic examination revealed an alveolar crestal bone dehiscence suggestive of an occult oral antral communication (OAC) that had spontaneously healed. Stimulation of the mucosa at this bony dehiscence consistently reproduced the dysesthesia. A sinus lift procedure was performed in this region for implant site development and also resulted in resolution of the dysesthesia. This case represents an instance in which surgical alteration of a trigger zone of neuropathic pain can result in its resolution. PMID- 25454713 TI - The impact of clinical prognostic factors on the survival of patients with oral squamous cell carcinoma. AB - PURPOSE: This study investigated prognostic factors and useful predictors for survival in patients with oral squamous cell carcinoma. PATIENTS AND METHODS: The medical records of all patients with oral squamous cell carcinoma who underwent curative surgery with or without adjuvant radiation from 2009 through 2011 were retrospectively reviewed. RESULTS: Seventy-seven patients (63 men and 14 women) were enrolled. The 2-year disease-free and overall survival rates were 67.5% and 74%, respectively. Multivariate analyses showed that a diagnostic delay longer than 2 months (hazard ratio [HR]=4.43; 95% confidence interval [CI], 1.26-15.51; P=.02), T3 or T4 tumor (HR=4.40; 95% CI, 1.91-10.12; P=.001), neck metastasis (HR=1.96; 95% CI, 1.21-4.37; P=.01), and stage III or IV disease (HR=3.94; 95% CI, 1.64-9.47; P=.002) were independent adverse factors for survival rate. CONCLUSION: Oral squamous cell carcinoma is an important health issue associated with poor survival. A diagnostic delay longer than 2 months, T3 or T4 tumor, neck metastasis, and stage III or IV disease were independent adverse factors for subsequent survival rate and locoregional recurrence in patients with oral squamous cell carcinoma. PMID- 25454714 TI - Multiple endocrine neoplasia type 2B: maxillofacial significance in 5 cases. AB - PURPOSE: This paper intends to review for the oral and maxillofacial surgery community the MEN abnormalities generally, to emphasize the maxillofacial abnormalities peculiar to the MEN2B variant particularly, and to demonstrate the importance of early recognition of its most important component, medullary thyroid carcinoma. PATIENTS AND METHODS: The findings in five individuals with confirmed diagnoses of MEN2B are arranged to demonstrate the various manifestations of the disorder, and together represent the largest single group in the oral and maxillofacial surgery literature to date. RESULTS: Tabulation of the patients' individual findings demonstrates the variants and severity of the disorder, discloses findings not previously emphasized in the literature, and stresses the significance of early recognition of medullary thyroid carcinoma. CONCLUSION: The evidence in this study group suggests that the oral mucosal lesions are more commonly neurofibromas than neuromas as previously reported, that the characteristic dental central diastemas may occur independent of tongue size or the presence of oral soft tissue lesions, and that the characteristic apertognathia potentially requires surgical correction. PMID- 25454715 TI - Prevalence of musculoskeletal disorders among immigrant Latino farmworkers and non-farmworkers in North Carolina. AB - This paper evaluates the variability in the prevalence of epicondylitis, rotator cuff syndrome, low back pain, and lower extremity pathology among immigrant Latino farmworkers and non-farmworkers. Data were collected from a study among 272 farmworkers and non-farmworkers. Participants were recruited in eastern and central North Carolina. A physical examination was conducted by trained physicians. Prevalence of musculoskeletal disorders (MSDs) among Latino manual workers is high compared with other workers in similar occupations. Non farmworkers (49%) had a higher prevalence of MSDs than farmworkers (35%). Epicondylitis (20.2%) and rotator cuff syndrome (19.1%) were most prevalent. Age was found to be significant among those who had epicondylitis (adjusted odds ratio [AOR] = 1.04) and lower extremity pathology (AOR = 1.07). Latino immigrant manual workers have high prevalence of MSDs. Further studies are needed to identify possible factors that make these populations more vulnerable to MSDs. PMID- 25454716 TI - Plasmodium falciparum avoids change in erythrocytic surface expression of phagocytosis markers during inhibition of nitric oxide synthase activity. AB - Nitric oxide (NO) accumulates in Plasmodium falciparum-infected erythrocytes. It may be produced by a parasite NO synthase (NOS) or by nitrate reduction. The parasite's benefit of NO accumulation is not understood. We investigated if inhibiting the P. falciparum NOS with specific and unspecific NOS inhibitors led to a decrease in intraerythrocytic NO accumulation and if this was associated with a change in surface expression of the phagocytosis markers CD47 and phosphatidyl serine. The specific inducible NOS inhibitors l-canavanine and GW274150 dose-dependently decreased intraerythrocytic NO while l-NMMA (an unspecific NOS inhibitor) and caveolin-1 scaffolding domain peptide (a specific endothelial NOS inhibitor) did not affect NO levels. Phosphatidyl serine externalization markedly increased upon P. falciparum infection. l-canavanine did not modify this whereas caveolin-1 scaffolding domain peptide increased the fraction of phosphatidyl serine exposing cells significantly. The infection did not change the level of expression of neither total CD47 nor its oxidized form. Unrelated to NOS inhibition, incubation with caveolin-1 scaffolding domain peptide lead to a decrease in oxidized CD47. In conclusion, the data imply that NOS inhibitors decrease NO accumulation in P. falciparum-infected erythrocytes but this does not correlate with the level of two major erythrocytic phagocytosis markers. PMID- 25454717 TI - Implementation of a companion diagnostic in the clinical laboratory: the BRAF example in melanoma. AB - A companion diagnostic test provides information that is essential for the safe and effective use of a corresponding therapeutic product as indicated in the drug instructions. The implementation of a companion diagnostic follows the rules of a molecular test for somatic mutations in a routine clinical laboratory environment and needs guidance on practical aspects, including the choice of the proper analytical method and the procedures for internal and external quality controls. Selection of the appropriate assay for detection of genetic alterations depends on several factors: the type of mutation under study, the sample to be assayed and its preparation procedure. In addition, the results of a molecular assay require a complex interpretation process of the analytical data as the patient's genotype, the translation of the identified variant into a predicted phenotype and knowledge on restrictions of the method used. In relation to these aspects herein we report an opinion paper of the Working Group Personalized Laboratory Medicine jointly constituted by the European Federation of Laboratory Medicine (EFLM) and by the European Society of Pharmacogenomics and Theranostics (ESPT) using, as an example, the BRAF genotype analysis in tumor tissue samples for identification of melanoma patients that can benefit treatment with BRAF inhibitors. The manuscript is focused on the following aspects: i) medical rationale, ii) methodologies of analysis, iii) laboratory performance evaluation and iv) the laboratory specific report for the clinicians. The critical evaluation of these aspects would be useful for the implementation of a companion diagnostic in the clinical laboratory. PMID- 25454718 TI - Rapid detection of CEA mRNA in peritoneal washes using One-Step Nucleic acid Amplification (OSNA) for gastric cancer patients. AB - BACKGROUND: Carcinoembryonic antigen (CEA) mRNA expression in peritoneal washes from gastric cancer patients has been reported as an indicator for survival or peritoneal recurrence. The whole process of CEA mRNA detection is time- and labor intensive. We report the potential of One-Step Nucleic acid Amplification (OSNA) as a rapid and simple system for CEA mRNA detection in peritoneal washes. METHODS: A total of 128 peritoneal washes were analyzed by cytological examination including immunocytochemistry. After the cytological examination, the CEA mRNA concentration in the residual cells was measured using the OSNA system. The CEA mRNA concentration in peritoneal washes was compared with the results of the cytological examination. RESULTS: CEA mRNA at concentrations from 10 to 10(7)copies/MUL was detected by the OSNA system within 10 min, and an excellent correlation was observed between the logarithmic CEA mRNA concentration and the detection time (r=0.998). The CEA mRNA cutoff value for distinguishing positive and negative cases through cytological examination was identified as 25 copies/MUL. At this cutoff value, the concordance rate with the cytological examination was 93.8%. The overall survival in CEA mRNA-positive versus -negative cases identified using the OSNA system was statistically significant. CONCLUSION: This CEA mRNA detection system shows potential for cancer cell detection and for routine use in the clinical laboratory because of its simplicity and rapidity. PMID- 25454722 TI - The year in burns 2013. AB - Approximately 3415 research articles were published with burns in the title, abstract, and/or keyword in 2013. We have continued to see an increase in this number; the following reviews articles selected from these by the Editor of one of the major journals (Burns) and colleagues that in their opinion are most likely to have effects on burn care treatment and understanding. As we have done before, articles were found and divided into the following topic areas: epidemiology of injury and burn prevention, wound and scar characterization, acute care and critical care, inhalation injury, infection, psychological considerations, pain and itching management, rehabilitation and long-term outcomes, and burn reconstruction. The articles are mentioned briefly with notes from the authors; readers are referred to the full papers for details. PMID- 25454720 TI - Caffeic acid phenethyl ester (CAPE) protects PC12 cells from MPP+ toxicity by inducing the expression of neuron-typical proteins. AB - Neurite loss is an early event in neurodegenerative diseases; therefore, the regeneration of the network of neurites constitutes an interesting strategy of treatment for such disorders. Neurotrophic factors play a critical role in neuronal regeneration, but their clinical use is limited by their inability to cross the blood brain barrier. Oxidative and inflammatory events are implicated in neurodegeneration and antioxidant compounds have been suggested as potential neuroprotectors. The protective potential of CAPE (caffeic acid phenethyl ester) has been shown in different models of neurotoxicity (in vitro and in vivo) and it has been associated with immune-modulatory, antioxidant and anti-inflammatory properties; however, other mechanisms might be involved. The present study demonstrates that CAPE protects PC12 cells from the cellular death induced by the dopaminergic neurotoxin MPP(+) by increasing the network of neurites. Results showed that CAPE induced the formation, elongation and ramification of neurites in PC12 cells non-stimulated with NGF (nerve growth factor) and inhibited the shortage of neurites induced by the dopaminergic neurotoxin. These effects were associated with increased expression of neuron-typical proteins responsible for axonal growth (GAP-43) and synaptogenesis (synaptophysin and synapsin I). It is noteworthy that, unlike neurotrophins, CAPE would be able to cross the blood brain barrier and exert its neurotrophic effects in the brain. This study corroborates the therapeutic potential of CAPE in neurodegenerative diseases while proposes the involvement of neuroplasticity in the mechanism of neuroprotection. PMID- 25454723 TI - Colony polymerase chain reaction of heme-accumulating bacteria. AB - Colony PCR of anaerobic black-pigmenting Bacteroidetes species Porphyromonas gingivalis and Prevotella intermedia was modified by addition of bovine serum albumin to reverse the inhibitory action of accumulated heme. PMID- 25454721 TI - Compounds with species and cell type specific toxicity identified in a 2000 compound drug screen of neural stem cells and rat mixed cortical neurons. AB - Human primary neural tissue is a vital component for the quick and simple determination of chemical compound neurotoxicity in vitro. In particular, such tissue would be ideal for high-throughput screens that can be used to identify novel neurotoxic or neurotherapeutic compounds. We have previously established a high-throughput screening platform using human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) and neurons. In this study, we conducted a 2000 compound screen with human NSCs and rat cortical cells to identify compounds that are selectively toxic to each group. Approximately 100 of the tested compounds showed specific toxicity to human NSCs. A secondary screen of a small subset of compounds from the primary screen on human iPSCs, NSC-derived neurons, and fetal astrocytes validated the results from >80% of these compounds with some showing cell specific toxicity. Amongst those compounds were several cardiac glycosides, all of which were selectively toxic to the human cells. As the screen was able to reliably identify neurotoxicants, many with species and cell-type specificity, this study demonstrates the feasibility of this NSC-driven platform for higher-throughput neurotoxicity screens. PMID- 25454725 TI - EUROP total knee prosthesis with or without posterior cruciate ligament retention? Comparative study at mid-term follow-up. AB - INTRODUCTION: The aim of the present study was to compare mid-term clinical and functional results of two fixed-bearing EUROP total knee arthroplasties (TKA) with the same design, one in which the posterior cruciate ligament was retained (CR) and the other with posterior-stabilization (PS). HYPOTHESIS: Mid-term results are similar. MATERIALS AND METHODS: In this prospective, single centre, comparative study, 104 patients (mean age 76) received 114 cemented fixed-bearing posterior cruciate-retaining or posterior-stabilized EUROP TKA. Only patients in whom the medial pivot and ligaments were intact received a CR prosthesis. The final decision to retain or not the posterior cruciate ligament was made if the flexion gap was well balanced above 90 degrees . Clinical evaluation was performed using the International Knee Society (IKS) score at a mean follow-up of 54 months. RESULTS: The preoperative IKS function score improved from 30 points in both groups, to 75 points in the CR group and to 65 points in the PS group postoperatively. The preoperative IKS knee score improved from 29 and 25 points in the CR and PS groups, respectively, to 87 points in both groups postoperatively. There was no significant difference in the pre- or postoperative scores between the two groups. Four prostheses underwent surgical revision, three CR and one PS. With revision for any reason as the end point, seven-year overall implant survival was 94.8% in the CR group and 97.5% in the PS group. There was no significant difference between the CR and PS groups. DISCUSSION: When the indications were followed, our study shows similar mid-term results for both types of TKA. LEVEL OF EVIDENCE: Level IV, prospective study. PMID- 25454724 TI - Vascular injuries during closing-wedge high tibial osteotomy: A cadaveric angiographic study. AB - INTRODUCTION: Closing-wedge high tibial osteotomy is a surgical option for patients with isolated medial compartment osteoarthritis and varus knee alignment. Vascular complications are rare, but incriminate the use of oscillating saw or osteotome. It is important to know the steps of this surgery that involve risk of vascular injury and what to do to decrease that risk. HYPOTHESIS: Performing the distal osteotomy cut using an oscillating saw is a step with high risk of vascular injury. A protective device behind the tibia may decrease this risk. MATERIALS AND METHODS: In this descriptive angiographic cadaver study, closing-wedge high tibial osteotomy was performed on 6 cadaveric knees in 90 degrees knee flexion, and the distance between the surgical instrument and the popliteal artery was measured on fluoroscopy with artery opacification at the various steps of surgery. RESULTS: Tibial osteotomy with oscillating saw involves high vascular risk: the mean distance between the saw blade and the popliteal artery is 10.6mm in 90 degrees knee flexion. Using a specific device placed behind the tibia protects the vascular structures. DISCUSSION: High tibial osteotomy is indicated in medial compartment osteoarthritis of the knee and can be performed by closing or opening-wedge. Vascular injuries in closing-wedge osteotomy exist and it is recommended to perform this surgery at 90 degrees knee flexion, although some studies report that this does not move the artery out of the way. A risk of vascular lesion should be kept in mind. The oscillation of the saw and the direction of the osteotomy should also be taken into consideration when performing a closing-wedge high tibial osteotomy in order to protect the popliteal artery. STUDY DESIGN: Descriptive cadaver study. Level IV. PMID- 25454719 TI - Sex-specific enhanced behavioral toxicity induced by maternal exposure to a mixture of low dose endocrine-disrupting chemicals. AB - Humans are increasingly and consistently exposed to a variety of endocrine disrupting chemicals (EDCs), chemicals that have been linked to neurobehavioral disorders such as ADHD and autism. Many of such EDCs have been shown to adversely influence brain mesocorticolimbic systems raising the potential for cumulative toxicity. As such, understanding the effects of developmental exposure to mixtures of EDCs is critical to public health protection. Consequently, this study compared the effects of a mixture of four EDCs to their effects alone to examine potential for enhanced toxicity, using behavioral domains and paradigms known to be mediated by mesocorticolimbic circuits (fixed interval (FI) schedule controlled behavior, novel object recognition memory and locomotor activity) in offspring of pregnant mice that had been exposed to vehicle or relatively low doses of four EDCs, atrazine (ATR - 10mg/kg), perfluorooctanoic acid (PFOA - 0.1mg/kg), bisphenol-A (BPA - 50 MUg/kg), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD - 0.25 MUg/kg) alone or combined in a mixture (MIX), from gestational day 7 until weaning. EDC-treated males maintained significantly higher horizontal activity levels across three testing sessions, indicative of delayed habituation, whereas no effects were found in females. Statistically significant effects of MIX were seen in males, but not females, in the form of increased FI response rates, in contrast to reductions in response rate with ATR, BPA and TCDD, and reduced short term memory in the novel object recognition paradigm. MIX also reversed the typically lower neophobia levels of males compared to females. With respect to individual EDCs, TCDD produced notable increases in FI response rates in females, and PFOA significantly increased ambulatory locomotor activity in males. Collectively, these findings show the potential for enhanced behavioral effects of EDC mixtures in males and underscore the need for animal studies to fully investigate mixtures, including chemicals that converge on common physiological substrates to examine potential mechanisms of toxicity with full dose effect curves to assist in interpretations of relevant mechanisms. PMID- 25454726 TI - Long live the rising generation of French arthroscopy! PMID- 25454727 TI - Peri-articular suprascapular neuropathy. AB - Suprascapular nerve entrapment was first described in 1959 by Kopell and Thompson. Although rare, this condition is among the causes of poorly explained shoulder pain in patients with manifestations suggesting a rotator-cuff tear but normal tendons by imaging studies. Suprascapular nerve entrapment may cause 2% of all cases of chronic shoulder pain. Among the many reported causes of suprascapular nerve entrapment, the most common are para-labral cysts, usually in the spinoglenoid notch, and microtrauma in elite athletes. The potential relevance of concomitant rotator-cuff tears remains debated. Less common causes include tumours, scapular fractures, and direct trauma involving traction. Early diagnosis and treatment are crucial to avoid the development of irreversible muscle wasting. Endoscopic surgery to treat the various causes of suprascapular nerve compression has superseded open nerve release. PMID- 25454728 TI - Single beta3-amino acid substitutions to MOG peptides suppress the development of experimental autoimmune encephalomyelitis. AB - CD4(+) T-cells play a key role in the pathogenesis of multiple sclerosis (MS). Altered peptide ligands capable of modulating T-cell autoreactivity are considered a promising strategy for development of antigen-specific therapies for MS. Since peptides are inherently unstable, the current study explored single beta-amino acid substitution as a means of stabilizing an epitope of myelin oligodendrocyte glycoprotein. beta-Amino acid substitution at position 44, the major T-cell receptor contact residue, increased the half-life of active metabolites. Vaccination with one altered peptide, MOG44betaF, conferred protection from EAE, decreased T-cell autoreactivity and pro-inflammatory cytokine production. Additional studies using MOG44betaF in an oral treatment regimen, administered after EAE induction, also attenuated disease severity. Thus, altered peptides such as those reported here may lead to the development of novel and more specific treatments for MS. PMID- 25454729 TI - Predicting therapeutic efficacy of intravenous immunoglobulin (IVIG) in individual patients with relapsing remitting multiple sclerosis (RRMS) by functional genomics. AB - PURPOSE: Only a fraction of patients do benefit from disease modifying treatments in RRMS and data on IVIG are controversial, it has been suggested that there is a subpopulation of patients with good clinical response to IVIG. METHODS: In the prospective, multicenter, open label, exploratory study RRMS patients receiving IVIG therapy were genotyped and several immune parameters were collected. RESULTS: To distinguish between potential responders and non-responders each of the observed genotypes was combined with the corresponding scores of 65 immune parameters in a stepwise approach. Non-responders were defined as being positive for 4 or more out of 9 individual scores. Responders scored either 0 or 1, while non-responders scored between 7 and 9 (p=1.2*10(-7)). CONCLUSIONS: In summary, combination of genomic and functional immune parameters allowed prospective discrimination between responders and non-responders towards IVIG therapy in this learning panel of RRMS patients and will be confirmed in a validation study. PMID- 25454730 TI - Left ventricular non-compaction cardiomyopathy associated with epidermolysis bullosa simplex with muscular dystrophy and PLEC1 mutation. AB - Plectin mutations have been reported in epidermolysis bullosa simplex with muscular dystrophy. We report the first case of left ventricular non-compaction in an 18-year-old male with epidermolysis bullosa simplex with muscular dystrophy. The patient was diagnosed with epidermolysis bullosa simplex after blistering was noted at birth. Motor function difficulties were first recognized at age 11, however the patient was lost to follow up. He was re-evaluated at age 17 and demonstrated significant ptosis, ophthalmoparesis, and pharyngeal muscle weakness. He had predominant proximal muscle weakness with the inability to raise arms against gravity. He was ambulatory for short distances but lost the ability to rise from the floor at 14 years. He was subsequently diagnosed with epidermyolysis bullosa simplex with muscular dystrophy and a PLEC1 mutation. Screening cardiovascular imaging revealed a diagnosis of isolated left ventricular non-compaction. This case highlights the potential for delayed onset muscular dystrophy in patients with epidermolysis bullosa simplex. Furthermore, this case also underscores the importance of long term, routine cardiac evaluation, including imaging and electrophysiologic evaluation, in patients with epidermolysis bullosa simplex with muscular dystrophy as the cardiac phenotype appears to parallel the variable severity and age of onset that characterize the neuromuscular phenotype. PMID- 25454732 TI - Suitability of North Star Ambulatory Assessment in young boys with Duchenne muscular dystrophy. AB - The aim of this study was to establish the suitability of the North Star Ambulatory Assessment for use in young boys with Duchenne muscular dystrophy. We studied 147 typically developing and 144 boys affected by Duchenne muscular dystrophy between the ages of 3 and 5 years. More than 85% of the typically developing boys by the age of 4 years had full scores on all the items with total scores >=33/34. Before the age of 4 years more than 15% of the typically developing boys did not achieve full scores on all the items. Some items, such as standing on one leg, showed significant improvement with age. In contrast, other activities were rarely achieved even in the older boys. Even if there was a progressive increase in scores with age, both total and individual item scores in Duchenne were still far from those obtained in the typically developing children of the same age. Our findings suggest that the North Star Ambulatory Assessment can be reliably used at least from the age of 4 years. Longitudinal natural history data studies are needed to assess possible changes over time and the possible effect of early steroids. PMID- 25454731 TI - Abnormal proliferation and spontaneous differentiation of myoblasts from a symptomatic female carrier of X-linked Emery-Dreifuss muscular dystrophy. AB - Emery-Dreifuss muscular dystrophy (EDMD) is a neuromuscular disease characterized by early contractures, slowly progressive muscular weakness and life-threatening cardiac arrhythmia that can develop into cardiomyopathy. In X-linked EDMD (EDMD1), female carriers are usually unaffected. Here we present a clinical description and in vitro characterization of a mildly affected EDMD1 female carrying the heterozygous EMD mutation c.174_175delTT; p.Y59* that yields loss of protein. Muscle tissue sections and cultured patient myoblasts exhibited a mixed population of emerin-positive and -negative cells; thus uneven X-inactivation was excluded as causative. Patient blood cells were predominantly emerin-positive, but considerable nuclear lobulation was observed in non-granulocyte cells - a novel phenotype in EDMD. Both emerin-positive and emerin-negative myoblasts exhibited spontaneous differentiation in tissue culture, though emerin-negative myoblasts were more proliferative than emerin-positive cells. The preferential proliferation of emerin-negative myoblasts together with the high rate of spontaneous differentiation in both populations suggests that loss of functional satellite cells might be one underlying mechanism for disease pathology. This could also account for the slowly developing muscle phenotype. PMID- 25454733 TI - Myotonic discharges discriminate chloride from sodium muscle channelopathies. AB - Non-dystrophic myotonic syndromes represent a heterogeneous group of clinically quite similar diseases sharing the feature of myotonia. These syndromes can be separated into chloride and sodium channelopathies, with gene-defects in chloride or sodium channel proteins of the sarcolemmal membrane. Myotonia has its basis in an electrical instability of the sarcolemmal membrane. In the present study we examine the discriminative power of the resulting myotonic discharges for these disorders. Needle electromyography was performed by an electromyographer blinded for genetic diagnosis in 66 non-dystrophic myotonia patients (32 chloride and 34 sodium channelopathy). Five muscles in each patient were examined. Individual trains of myotonic discharges were extracted and analyzed with respect to firing characteristics. Myotonic discharge characteristics in the rectus femoris muscle almost perfectly discriminated chloride from sodium channelopathy patients. The first interdischarge interval as a single variable was longer than 30 ms in all but one of the chloride channelopathy patients and shorter than 30 ms in all of the sodium channelopathy patients. This resulted in a detection rate of over 95%. Myotonic discharges of a single muscle can be used to better guide toward a molecular diagnosis in non-dystrophic myotonic syndromes. PMID- 25454734 TI - Assessment of ventricular function in mouse models of muscular dystrophy: a comparison of MRI with conductance catheter. AB - Outcomes of clinical trials depend on the quality of preceding preclinical research, yet functional assays and outcome measures for mouse models of disease are often poorly standardized or inappropriate. Muscular dystrophies are associated with cardiomyopathy so preclinical research requires reliable measures of cardiac function in animal models of the disease. MRI and conductance catheter were compared as preclinical tools to detect cardiomyopathy in two mouse models of muscular dystrophy. Sgcd-/-, mdx and C57Bl10 mice (n = 7/group) were assessed by catheter following MRI at an early stage of cardiomyopathy. Volumetric measurements were higher from MRI compared to catheter. In particular, by catheter, the measurement of end-systolic volume (and its related measures) was disproportionately lower in dystrophic mice compared to controls. This was related to greater calculated parallel conductance in dystrophic mice. Catheter highlighted differences in pressure generation between the two models while MRI detected differences in left ventricular hypertrophy and right ventricular function. Although MRI and conductance catheter provide unique but complimentary information regarding the nature of cardiomyopathy in dystrophic mice, we present the possibility that pathology itself may affect the accuracy of the catheter technique and that particular caution must be taken when interpreting catheter volume data in dystrophic mice. PMID- 25454735 TI - S.M.A.R.T. self-expanding nitinol stent for the treatment of atherosclerotic lesions in the superficial femoral artery (STROLL): 1-year outcomes. AB - PURPOSE: To assess safety and efficacy of the S.M.A.R.T. Vascular Stent System (Cordis Corp, Fremont, California) in obstructive superficial femoral artery (SFA) disease. MATERIALS AND METHODS: The single-arm, multicenter STROLL study (S.M.A.R.T. Nitinol Self-Expanding Stent in the Treatment of Obstructive Superficial Femoral Artery Disease) included 250 patients (250 lesions in SFA or proximal popliteal artery). The efficacy endpoint was primary patency defined by freedom from binary restenosis (peak systolic velocity ratio > 2.5) as derived by duplex ultrasound plus clinically driven target lesion revascularization (TLR) at 12 months. RESULTS: Mean age of patients was 67.7 years +/- 10.3; 47.2% of patients had diabetes; distribution of Rutherford/Becker classes 2, 3, and 4 was 45.8%, 51.4%, and 2.8%. Mean lesion length and reference vessel diameter were 77.3 mm +/- 35.3 and 4.9 mm +/- 0.7, respectively (23.6% cases with total occlusions). The 30-day freedom from major adverse events (death, index limb amputation, clinically driven TLR) was 100%. The 1-year primary patency was 81.7% by Kaplan-Meier estimate. The presence of diabetes or total occlusion had no effect on primary patency. Ankle-brachial index was 0.4-0.8 in 84.6% of patients at baseline and improved to > 0.8 in 81.0% of patients at 12 months. The proportion of patients in Rutherford/Becker class 3-4 was reduced from 54.2% at baseline to 8.0% at 12 months. Four patients (2.0%) experienced single-stent strut fracture (type I) at 1 year, without associated loss of stent patency. CONCLUSIONS: The S.M.A.R.T. Vascular Stent System proved to be safe and effective for endovascular treatment of obstructive SFA and proximal popliteal artery disease, based on 1-year vessel patency and associated hemodynamic and clinical improvements. PMID- 25454736 TI - Postpartum hemorrhage from extravasation or pseudoaneurysm: efficacy of transcatheter arterial embolization using N-butyl cyanoacrylate and comparison with gelatin sponge particle. AB - PURPOSE: To evaluate the safety and effectiveness of transcatheter arterial embolization (TAE) using N-butyl cyanoacrylate (NBCA) for the treatment of active postpartum hemorrhage (PPH) and compare the efficacy of NBCA with gelatin sponge particles. MATERIALS AND METHODS: From January 2004 to September 2013, 26 patients with PPH underwent TAE using NBCA as the primary embolic material. All patients were actively bleeding, and 12 (46.2%) had coagulopathy. TAE was performed using 1:2-1:4 mixtures of NBCA and ethiodized oil with or without use of a coil or gelatin sponge. To compare the efficacy of NBCA with conventional embolic material, 50 patients with active bleeding who underwent TAE using gelatin sponge were also analyzed. RESULTS: Angiograms demonstrated pseudoaneurysm or extravasation or both. The technical and clinical success rates were 100% and 92.3% (24 of 26 patients), respectively, for NBCA and 98% and 86.0% (43 of 50 patients), respectively, for gelatin sponge. In the NBCA group, one patient recovered with conservative management, and the other patient died because of multiorgan dysfunction. There were no major or minor procedure-related complications. CONCLUSIONS: TAE using NBCA as the primary embolic agent is an effective method for treating PPH with extravasation or pseudoaneurysm; NBCA is comparable to gelatin sponge particles. TAE using NBCA seems to fill pseudoaneurysms and make devascularization more effective than using gelatin sponge. PMID- 25454737 TI - Adenoma localization for recurrent or persistent primary hyperparathyroidism using dynamic four-dimensional CT and venous sampling. AB - PURPOSE: To determine if parathyroid venous sampling (PVS) combined with four dimensional (4D) computed tomography (CT) improves sensitivity and accuracy of identification of parathyroid adenoma in patients with recurrent or persistent primary hyperparathyroidism (pHPT) and negative technetium-99m methoxyisobutyl isonitrile ((99m)Tc-MIBI) and ultrasound (US) scans. MATERIALS AND METHODS: Both PVS and 4D CT were performed in 28 patients with recurrent or persistent pHPT and negative (99m)Tc-MIBI and US examinations. Localization by 4D CT alone and in combination with PVS and lateralization by PVS alone were retrospectively assessed for correlation with surgical results. Suspected adenomas on 4D CT were said to correlate with PVS if venous drainage identified on CT corresponded to sites of elevated parathyroid hormone concentration on PVS. Lesions difficult to identify on 4D CT were lesions < 1 cm in longest dimension. Results of 4D CT were classified as positive, negative, or equivocal. RESULTS: Surgery was performed in 22 of 28 patients. Surgery identified 23 parathyroid adenomas, 1 carcinoma, and 2 hyperplastic glands in 20 patients. 4D-CT alone localized 11 lesions in 10 patients. PVS helped localize 13 additional lesions in nine more patients and clarified two lesions that were equivocal on 4D CT. Comparing 4D CT alone with 4D CT plus PVS, the sensitivity increased from 50% to 95% (P = .004), and accuracy increased from 55% to 91% (P = .022). PVS lateralization had a sensitivity of 93.3%, positive predictive value of 66.7%, and accuracy of 63.6%. CONCLUSIONS: PVS significantly improves 4D CT localization of parathyroid adenomas in patients undergoing repeat surgery for pHPT with negative (99m)Tc-MIBI and US. PMID- 25454739 TI - Clinical presentation of extramammary paget disease of the axilla in a male patient. PMID- 25454738 TI - Identification of subgroups of early breast cancer patients at high risk of nonadherence to adjuvant hormone therapy: results of an Italian survey. AB - BACKGROUND: Adherence to adjuvant endocrine therapy (HT) is suboptimal among breast cancer patients. A high rate of nonadherence might explain differences in survival between clinical trial and clinical practice. Tailored interventions aimed at improving adherence can only be implemented if subgroups of patients at higher risk of poor adherence are identified. Because no data are available for Italy, we undertook a large survey on adherence among women taking adjuvant HT for breast cancer. PATIENTS AND METHODS: Patients were recruited from 10 cancer clinics in central Italy. All patients taking HT for at least 1 year were invited, during one of their follow-up visit, to fill a confidential questionnaire. The association of sociodemographic and clinical characteristics of participants with adherence was assessed using logistic regression. The RECPAM method was used to evaluate interactions among variables and to identify subgroups of patients at different risk of nonadherence. RESULTS: A total of 939 patients joined the study and 18.6% of them were classified as nonadherers. Among possible predictors, only age, working status, and switching from tamoxifen to an aromatase inhibitor were predictive of nonadherence in multivariate analysis. RECPAM analysis led to the identification of 4 classes of patients with a different likelihood of nonadherence to therapy, the lowest being observed in retired women with a low level of education, the highest in the group of unmarried, employed women, or housewives. CONCLUSION: The identification of these subgroups of "real life" patients with a high prevalence of nonadherers might be functional in designing intervention studies aimed at improving adherence. PMID- 25454740 TI - Brain metastasis and response to ado-trastuzumab emtansine: a case report and literature review. PMID- 25454741 TI - Efficacy of concurrent chemoradiotherapy for patients with locally recurrent or advanced inoperable breast cancer. AB - BACKGROUND: This study aimed to assess the efficacy and safety of chemoradiotherapy (CRT) for locally recurrent or advanced inoperable breast cancer. PATIENTS AND METHODS: Twenty patients treated between 2009 and 2013 were reviewed from a prospectively collected database. All patients had symptomatic recurrent or advanced breast cancer and had been deemed not to be ideal operative candidates. Treatment consisted of external beam radiotherapy to the primary tumor in the breast or regional lymph nodes, or both, concurrent with either capecitabine, paclitaxel, or cisplatin/etoposide chemotherapy. The grade of acute and late toxicity was evaluated, as was response to treatment, overall survival (OS), and local relapse-free survival (LRFS). RESULTS: Of the 20 patients, 9 (45%) presented with primary disease and 11 (55%) had recurrent disease. A total of 11 (55%) patients had evidence of metastatic disease. The overall clinical response rate was 100%, with a clinical complete response (CR) observed in 65% of patients and a clinical partial response (PR) observed in 35% of patients. At a median follow up of 25.3 months, 2-year LRFS was 73% and 2-year OS was 80%. Local control was significantly better in patients with an initial diagnosis (hazard ratio [HR], 0.139; 95% confidence interval [CI], 0.014-0.935) and in those who had not had previous in-field radiation (HR, 0.011; 95% CI, 0.005-0.512). The only grade >= 3 toxicity was acute dermatologic events (30%) and late dermatologic (15%) events. CONCLUSION: Concurrent CRT with capecitabine, paclitaxel, or cisplatin/etoposide for recurrent or advanced inoperable breast cancer is well tolerated with impressive clinical response rates and durable local control. PMID- 25454743 TI - [Iatrogenic digital ischemia in a child]. PMID- 25454744 TI - Health policies 25 years after the fall of the Iron Curtain. PMID- 25454742 TI - Assessment of lower leg muscle force distribution during isometric ankle dorsi and plantar flexion in patients with diabetes: a preliminary study. AB - AIM: The aim of this study was to evaluate the differences in ankle muscle strength using hand-held dynamometry and to assess difference in the isometric muscle force distribution between the people with diabetes and control participants. METHODS: The maximal muscle strength of ankle plantarflexion, dorsiflexion, eversion, inversion, lesser toes flexors and extensors, hallux flexors, and extensors was assessed in 20 people with diabetes and 20 healthy participants using hand-held dynamometry. The maximal isometric ankle plantarflexion and dorsiflexion were imported to OpenSim software to calculate 12 individual muscle (8 plantarflexors and 4 dorsiflexors) forces acting on ankle joint. RESULTS: A significant reduction in ankle strength for all measured actions and a significant decrease in muscle force for each of the 12 muscles during dorsi and plantar flexion were observed. Furthermore, the ratios of agonist to antagonist muscle force for 6 of the muscles were significantly different between the control group and the group with diabetes. CONCLUSIONS: It is likely that the muscles for which the agonist/antagonist muscle force ratio was significantly different for the healthy people and the people with diabetes could be more affected by diabetes. PMID- 25454745 TI - Proteomic analysis of 4-hydroxynonenal (4-HNE) modified proteins in liver mitochondria from chronic ethanol-fed rats. AB - Chronic ethanol-mediated oxidative stress and lipid peroxidation increases the levels of various reactive lipid species including 4-hydroxynonenal (4-HNE), which can subsequently modify proteins in the liver. It has been proposed that 4 HNE modification adversely affects the structure and/or function of mitochondrial proteins, thereby impairing mitochondrial metabolism. To determine whether chronic ethanol consumption increases levels of 4-HNE modified proteins in mitochondria, male rats were fed control and ethanol-containing diets for 5 weeks and mitochondrial samples were analyzed using complementary proteomic methods. Five protein bands (approx. 35, 45, 50, 70, and 90kDa) showed strong immunoreactivity for 4-HNE modified proteins in liver mitochondria from control and ethanol-fed rats when proteins were separated by standard 1D SDS-PAGE. Using high-resolution proteomic methods (2D IEF/SDS-PAGE and BN-PAGE) we identified several mitochondrial proteins immunoreactive for 4-HNE, which included mitofilin, dimethylglycine dehydrogenase, choline dehydrogenase, electron transfer flavoprotein alpha, cytochrome c1, enoyl CoA hydratase, and cytochrome c. The electron transfer flavoprotein alpha consistently showed increased 4-HNE immunoreactivity in mitochondria from ethanol-fed rats as compared to mitochondria from the control group. Increased 4-HNE reactivity was also detected for dimethylglycine dehydrogenase, enoyl CoA hydratase, and cytochrome c in ethanol samples when mitochondria were analyzed by BN-PAGE. In summary, this work identifies new targets of 4-HNE modification in mitochondria and provides useful information needed to better understand the molecular mechanisms underpinning chronic ethanol-induced mitochondrial dysfunction and liver injury. PMID- 25454747 TI - The impact of some behavioral aspects on periodontal disease in a group of Romanian students - an epidemiological survey. AB - AIMS: To investigate the prevalence of periodontitis in a young population representative for the North-western part of Romania (Transylvania) and to identify possible risk indicators of periodontitis. METHODS: The study is a cross sectional epidemiological survey. The subjects were students randomly sampled from three universities in Cluj-Napoca and high school students from the neighboring city of Bistrita. The sample size of the population was calculated. Overall, 623 subjects aged 16-35 years were evaluated, of which 488 were university students and 135 high school students. A structured questionnaire was administrated to collect information on socio-behavioral status and oral hygiene habits. Periodontal data was collected using a full-mouth methodology by trained examiners. A recent introduced case definition was used to pick up periodontitis cases. RESULTS: The older the subject, the more frequent toothbrushing, dental visits, and use of interproximal hygiene devices, but also addiction to tobacco and alcohol consumption. The prevalence of periodontitis was 0.96% (n=6). Half of these subjects (n=3, 0.48%) were considered to have aggressive periodontitis (AP). Low frequency of toothbrush changing was identified to influence the development of periodontitis. Smoking and lower socioeconomic level did not seem to correlate with periodontal disease in the present study. CONCLUSIONS: In order to better understand the prevalence of periodontal diseases and identify periodontitis cases as well as to evaluate the impact of specific behavioral factors on the disease development in individual and population levels, further extensive screenings are obviously required. Periodontal prevention programs focusing on oral health behavior are mandatory. PMID- 25454748 TI - [Effects of chronic uranium internal exposure on mortality: results of a pilot study among French nuclear workers]. AB - BACKGROUND: This article presents the mortality data compiled among a cohort of workers at risk of internal uranium exposure and discusses the extent to which this exposure might differentiate them from other nuclear workers. METHODS: The cohort consisted of 2897 Areva-NC-Pierrelatte plant workers, followed from 1st January 1968 through 31st December 2006 (79,892 person-years). Mortality was compared with that of the French population, by calculating Standardized Mortality Ratios (SMR) and 95% confidence intervals (CI95%). External radiation exposure was reconstructed using external dosimetry archives. Internal uranium exposure was assessed using a plant-specific job-exposure-matrix, considering six types of uranium compounds according to their nature (natural and reprocessed uranium [RPU] and solubility [fast-F, moderate-M, and slow-S]). Exposure-effect analyses were performed for causes of death known to be related to external radiation exposure (all cancers and circulatory system diseases) and cancer of uranium target-organs (lung and hematopoietic and lymphatic tissues, HLT). RESULTS: A significant deficit of mortality from all causes (SMR=0.58; CI95% [0.53-0.63]), all cancers (SMR=0.72; CI95% [0.63-0.82]) and smoking related cancers was observed. Non-significant 30%-higher increase of mortality was observed for cancer of pleura (SMR=2.32; CI95 % [0.75-5.41]), rectum and HLT, notably non-Hodgkin's lymphoma (SMR=1.38; CI95 % [0.63-2.61]) and chronic lymphoid leukemia (SMR=2.36; CI95% [0.64-6.03]). No exposure-effect relationship was found with external radiation cumulative dose. A significant exposure-effect relationship was observed for slowly soluble uranium, particularly RPU, which was associated with an increase in mortality risk reaching 8 to 16% per unit of cumulative exposure score and 10 to 15% per year of exposure duration. CONCLUSION: The Areva-NC-Pierrelatte workers cohort presents a non-significant over-mortality from HLT cancers, notably of lymphoid origin, unrelated to external radiation exposure. The pilot study suggests an association between mortality from the HLT and lung cancers and exposure to slowly soluble RPU compounds. The results of this study should be investigated further in more powerful studies, with a dose-response analysis based on individual assessment of uranium absorbed dose to uranium-target organs. PMID- 25454746 TI - Methodology to assay CYP2E1 mixed function oxidase catalytic activity and its induction. AB - The cytochrome P450 mixed function oxidase enzymes are the major catalysts involved in drug metabolism. There are many forms of P450. CYP2E1 metabolizes many toxicologically important compounds including ethanol and is active in generating reactive oxygen species. Since several of the contributions in the common theme series "Role of CYP2E1 and Oxidative/Nitrosative Stress in the Hepatotoxic Actions of Alcohol" discuss CYP2E1, this methodology review describes assays on how CYP2E1 catalytic activity and its induction by ethanol and other inducers can be measured using substrate probes such as the oxidation of para nitrophenol to para-nitrocatechol and the oxidation of ethanol to acetaldehyde. Approaches to validate that a particular reaction e.g. oxidation of a drug or toxin is catalyzed by CYP2E1 or that induction of that reaction is due to induction of CYP2E1 are important and specific examples using inhibitors of CYP2E1, anti-CYP2E1 IgG or CYP2E1 knockout and knockin mice will be discussed. PMID- 25454749 TI - [Dental health and dental care according diabetic status; results from 2008 ESPS study]. AB - BACKGROUND: Poorly controlled diabetes leads to serious complications including periodontal disease, oral disease leading to tooth loss. Diabetics benefit from care facilitated follow-up. Social inequalities are observed in oral health and diabetes. The objective of this study was to estimate the effect of the social factors on oral health and use of dental care for people with diabetes from the Health and Social Protection Survey 2008 (ESPS) and to compare it with that observed among non-diabetic people. METHODS: The ESPS is a representative survey of the French population. In 2008, data were derived from a self-administered health questionnaire given to all household members aged 16 or older. The scope of this study was restricted to persons aged 35 and over (12.082) having filled out their health survey (8961). Diabetes was defined from self-reports of disease or use of anti-diabetic medication. Oral health was estimated from perceived oral health and the number of missing teeth not replaced. Use of dental care was measured by self-report of a visit within the last two years. Socio-demographic and social coverage indicators were collected. RESULTS: The participation rate was 74.1% and prevalence of diabetes was 7.2% (648). People with diabetes had a poorer dental status (42.7% vs 26.5% - OR=1.22, 95% CI [1.01-1.47]), related to social characteristics. The effect of level of precariousness on dental health was equivalent in diabetic and non-diabetic populations. The use of dental care (73.4% of participants) was associated with social factors. Diabetics were less likely to consult dentists than non-diabetics (61.5% vs 74.4%), but this difference was not statistically significant (OR=0.86, 95%CI [0.72-1.04]). The effect of the level of precariousness on use of dental care was the same in both populations. CONCLUSION: This study raises the question of the impact of recommendations on monitoring dental health among diabetics especially for vulnerable populations despite better management and coverage. PMID- 25454750 TI - [Limiting a Medline/PubMed query to the "best" articles using the JCR relative impact factor]. AB - BACKGROUND: Medline/PubMed is the most frequently used medical bibliographic research database. The aim of this study was to propose a new generic method to limit any Medline/PubMed query based on the relative impact factor and the A & B categories of the SIGAPS score. MATERIAL AND METHODS: The entire PubMed corpus was used for the feasibility study, then ten frequent diseases in terms of PubMed indexing and the citations of four Nobel prize winners. The relative impact factor (RIF) was calculated by medical specialty defined in Journal Citation Reports. The two queries, which included all the journals in category A (or A OR B), were added to any Medline/PubMed query as a central point of the feasibility study. RESULTS: Limitation using the SIGAPS category A was larger than the when using the Core Clinical Journals (CCJ): 15.65% of PubMed corpus vs 8.64% for CCJ. The response time of this limit applied to the entire PubMed corpus was less than two seconds. For five diseases out of ten, limiting the citations with the RIF was more effective than with the CCJ. For the four Nobel prize winners, limiting the citations with the RIF was more effective than the CCJ. CONCLUSION: The feasibility study to apply a new filter based on the relative impact factor on any Medline/PubMed query was positive. PMID- 25454751 TI - [Sources of information on suicide attempts in the Nord - Pas-de-Calais (France). Contributions and limitations]. AB - BACKGROUND: There are very few permanent indicators of mental health in France; suicidal behavior is often only understood on the basis of deaths by suicide. METHOD: The epidemiological interest and methodological limits of four medico administrative databases from which data on suicide attempts can be extracted have been the subject of a study in the Nord - Pas-de-Calais Region of France: telephone calls for emergency medical assistance after suicide attempt (2009 to 2011), admissions in emergency services with a diagnosis of suicide attempt (2012), medical-surgical hospital admissions as a result of suicide attempt (2009 to 2011), and psychiatric admissions with a diagnosis of suicide attempt (2011). RESULTS: Usable data were provided by one of two emergency medical assistance units, five of thirty emergency departments and all medical-surgical and psychiatric units; in data from the latter two sources, a unique anonymous identifier gave individual statistics, while the first two covered only suicide attempts. In 2011, the number of suicide attempt calls per 100,000 inhabitants was 304, whereas the number of hospitalisations with this diagnosis was 275; rates are highest in men between 20 and 49 years of age, and in women below 20 years of age and between 40 and 49. Sources are seen to be very homogeneous with regards to the average age at which suicide took place (between 37.8 and 38.5 years, depending on the source), and to the sex (55.0% to 57.6% of women). In 2011, the number of patients with a diagnosis of suicide attempt treated in psychiatry is 2.6 times lower than the number hospitalised for suicide attempt in medical-surgical units (3563 vs 9327). CONCLUSION: Permanent gathering of data, and the large volume of data recorded, should encourage the use of these databases in the definition and assessment of mental health policy: an increased contribution from emergency call centers and emergency services, and the coding of the suicidal nature of intoxications by a few clearly under-declaring units, must however be achieved in order to improve this source of information. PMID- 25454752 TI - Promoting DNA loading on magnetic nanoparticles using a DNA condensation strategy. AB - Maximizing DNA loading on magnetic nanoparticles (MNPs) is crucial for their successful utilization in gene transfer, DNA isolation, and bio-analytical applications. This enhancement is typically achieved by altering particle size and surfaces as well as charge density and ionic strength. We demonstrate a novel route for promoting DNA loading on amino-modified silica-coated magnetic nanoparticles (ASMNPs) by prior condensation of elongated DNA to a compact globule before adsorption. The enhanced DNA-loading capacity, as demonstrated by a reduction in the number of ASMNPs needed to achieve complexation, was presumably due to the elimination of DNA wrapping around nanoparticles and substantially reduced electrostatic interactions of DNA with nanoparticles because the compacted DNA globule conformation decreases its exposed surface charge. The maximum loading capacity of ASMNPs for condensed DNA was 4.4 times greater than that for elongated coiled DNA, achieving the highest ever reported value of 385 MUg mg(-1). Practical applications for plasmid DNA isolation from cleared lysate confirmed the reliability of the proposed method. PMID- 25454753 TI - Development of a complex bone tissue culture system based on cellulose nanowhisker mechanical strain. AB - In bone tissue engineering, scaffolds have been investigated for their ability to support osteoblast growth and differentiation for recovery of damaged bones. Tunicate cellulose nanowhisker (CNW) film and mechanical strain were assessed for their suitability for osteoblasts. In this study, sulfuric acid hydrolysis extraction of tunicates integuments was conducted to obtain CNWs, which were found to be acceptable for adhering, growing, and differentiating osteoblasts without cytotoxicity. Mechanical stress enhanced osteoblast differentiation, and cell survival rate was recovered at around day 3, although there was a slight increase in cell death at day 1 after stimulation. We also found that intracellular flux of calcium ion was related to increased differentiation of CNWs under mechanical stress. Overall, we demonstrated the suitability of tunicate CNWs as a scaffold for bone tissue engineering and developed a complex system based on CNW for osteoblast growth and differentiation that will be useful for bone substitute fabrication. PMID- 25454754 TI - Electrochemical biosensor based on glucose oxidase encapsulated within enzymatically synthesized poly(1,10-phenanthroline-5,6-dione). AB - This study is focused on the investigation of electrocatalytic effect of glucose oxidase (GOx) immobilized on the graphite rod (GR) electrode. The enzyme modified electrode was prepared by encapsulation of immobilized GOx within enzymatically formed poly(1,10-phenanthroline-5,6-dione) (pPD) film. The electrochemical responses of such enzymatic electrode (pPD/GOx/GR) vs. different glucose concentrations were examined chronoamperometrically in acetate-phosphate buffer solution (A-PBS), pH 6.0, under aerobic or anaerobic conditions. Amperometric signals of the pPD/GOx/GR electrode exhibited well-defined hyperbolic dependence upon glucose concentration. Amperometric signals at 100mM of glucose were 41.17 and 32.27 MUA under aerobic and anaerobic conditions, respectively. Amperometric signals of the pPD/GOx/GR electrode decreased by 6% within seven days. The pPD/GOx/GR electrode showed excellent selectivity in the presence of dopamine and uric acid. Furthermore it had a good reproducibility and repeatability with standard deviation of 9.4% and 8.0%, respectively. PMID- 25454755 TI - Surface engineered nanostructured lipid carriers for targeting MDR tumor: Part II. In vivo biodistribution, pharmacodynamic and hematological toxicity studies. AB - Irinotecan loaded nanostructured lipid carrier (NLC-Ir) was surface decorated with hyaluronic acid graft polymer. Hyaluronic acid is a biocompatible, non antigenic and hydrophilic, CD-44 ligand that can impart many useful features to the nanocarrier for anticancer drug delivery. The present investigation demonstrated that hyaluronic acid coated HA-NLC had significantly lower haemolytic potential as compared to uncoated NLC. Further, HA-NLC had a reduced plasma protein interaction and low macrophage uptake. The in vivo tumor targeting and pharmacodynamics efficacy of HA-NLC was studied in Ehrlich's Ascites Tumor (EAT) allograft model. Radio scintigraphic biodistribution studies revealed that HA-NLC carrier got accumulated in the tumor tissues in good proportion. Additionally, the content of radioactivity associated with tumor tissues remained constant at 2, 4 and 24 h (2.41, 2.48 and 2.47%, respectively), while it got reduced in other organs. Furthermore, tumor to muscle ratio of radioactivity suggested a better accumulation of HA-NLC in tumor tissues that was significantly enhanced (P<0.05) with time. In vivo antitumor activity of hyaluronan coated HA NLC-Ir was 5.8 and 2.6 times higher as compared to control and free drug solution respectively. Furthermore, encapsulation of irinotecan in HA-NLC-Ir nanocarrier was found to have reduced the thrombocytopenia and neutropenia associated with free irinotecan. Thus, it can be inferred that the hyaluronic acid decorated nanocarrier can provide a haemo-compatible, non-toxic and target based delivery system for the effective management of cancer. PMID- 25454756 TI - Cell-mimetic coatings for immune spheres. AB - Extrinsically induced or engineered cells are providing new therapeutic means in emerging fields such as cell therapeutics, immunomodulation and regenerative medicine. We are demonstrating a spatial induction method using lipid coatings, which can change signal presentation strength from material surface to adherent macrophage cells, that induce early cell-cell interaction leading to organotypic morphology. For that, we have developed a cell mimetic lipid coating with a rafts size to the order of transmembrane proteins (<10 nm) with enhanced lateral elastic properties. Such surface coatings are capable of reducing adherent macrophage spreading, while enabling early induction of cell-cell interaction to form organotypic macrophage colonies or "spheres" (M-spheres). PMID- 25454757 TI - Electrochemical hydrogen peroxide sensors fabricated using cytochrome c immobilized on macroelectrodes and ultramicroelectrodes. AB - We report the design and fabrication of hydrogen peroxide (H2O2) sensors using heme proteins immobilized on macroelectrodes and ultramicroelectrodes (UMEs). In this sensor design, the heme centers are directly "wired" to the electrode via the use of an imidazole-terminated self-assembled monolayer. We have systematically evaluated the effect of electrode type and size on sensor performance. The limit of detection for H2O2 determined using a 10-MUm gold UME is significantly lower than that obtained using a stationary macroelectrode. Our results also highlight the advantages of using UMEs for enzyme kinetics analysis; the Km determined using a 10-MUm UME is similar to that obtained from a rotating disk electrode. PMID- 25454759 TI - Ultrasonically triggered drug delivery: breaking the barrier. AB - The adverse side-effects of chemotherapy can be minimized by delivering the therapeutics in time and space to only the desired target site. Ultrasound offers one fairly non-invasive method of accomplishing such precise delivery because its energy can disrupt nanosized containers that are designed to sequester the drug until the ultrasonic event. Such containers include micelles, liposomes and solid nanoparticles. Conventional micelles and liposomes are less acoustically sensitive to ultrasound because the strongest forces associated with ultrasound are generated by gas-liquid interfaces, which both of these conventional constructs lack. Acoustically activated carriers often incorporate a gas phase, either actively as preformed bubbles, or passively such as taking advantage of dissolved gasses that form bubbles upon insonation. Newer concepts include using liquids that form gas when insonated. This review focuses on the ultrasonically activated delivery of therapeutics from micelles, liposomes and solid particles. In vitro and in vivo results are summarized and discussed. Novel structural concepts from micelles and liposomes are presented. Mechanisms of ultrasonically activated release are discussed. The future of ultrasound in drug delivery is envisioned. PMID- 25454758 TI - PHEMA based composite cryogels with loaded hydrophobic beads for lysozyme purification. AB - The purpose of this study is to synthesize megaporous cryogel loaded with hydrophobic affinity beads which can be utilized for the purification of lysozyme from chicken egg-white. N-methacryloyl-(L)-tryptophan methylester (MATrp) was used as the hydrophobic ligand. In the first step, poly(glycidyl methacrylate-N methacryloyl-(L)-tryptophan methyl-ester) [PGMATrp] beads (2.2 MUm in diameter) were produced by dispersion polymerization. In the second step, the poly(2 hydroxyethyl methacrylate) (PHEMA) cryogel loaded with PGMATrp beads [PHEMA/PGMATrp composite cryogel] was polymerized initiated by N,N,N',N' tetramethylene diamine (TEMED) and ammonium persulfate (APS) at -12 degrees C. Lysozyme adsorption capacity of the PHEMA/PGMATrp composite cryogel (332.7 mg/g polymer) was improved significantly due to the loading of PGMATrp beads into the cryogel structure. The hydrophobic MATrp comonomer played a vital role in this binding mechanism. The PHEMA/PGMATrp composite cryogel could be used many times without decreasing the lysozyme adsorption amount significantly. The main advantage of the PHEMA/PGMATrp composite cryogel is the high adsorption capacity. PMID- 25454760 TI - Amphiphilic lipid derivatives of 3'-hydroxyurea-deoxythymidine: preparation, properties, molecular self-assembly, simulation and in vitro anticancer activity. AB - Lipid derivatives of nucleoside analogs and their nanoassemblies have become the research hotspot due to their unique function in cancer therapy. Six lipid derivatives of 3'-hydroxyurea-deoxythymidine were prepared with zidovudine as the raw material. The 5'-substituted lipid chains in the derivatives were from the various fatty acids including octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid and octadecanoic acid corresponding to the derivatives OHT, DHT, DDHT, TDHT, HDHT and ODHT. The amphiphilic derivatives formed Langmuir monolayers at the air/water interface with different surface pressure-molecular area isotherms depending on the length of lipid chains. The nanoassemblies of OHT, DHT, DDHT, TDHT and HDHT and the nanoscale precipitates of ODHT were obtained after we injected their tetrahydrofuran solutions doped with hydrophilic long chained polymers into water. Electron microscopy showed that the morphology of nanoassemblies may be vesicles or nanotubes depending on the length of lipid chains. The shorter the lipid chains were, the softer the nanoassemblies. Computer simulation supported the experimental results. The nanoassemblies and the nanoscale precipitates showed much higher anticancer effects on SW620 cells than the parent drug hydroxyurea. The nanostructures of the derivatives are promising anticancer nanomedicines. PMID- 25454761 TI - Surface engineered nanostructured lipid carriers for targeting MDR tumor: Part I. Synthesis, characterization and in vitro investigation. AB - Over expression of P-glycoprotein (P-gp) in cancer cells often results in highly aggressive, multi-drug resistant (MDR) phenotype. Such tumors are very difficult to treat with conventional therapy and often lead to failure of the treatment. In this work, we fabricated surface engineered hybrid lipid nanoparticles grafted with novel AL-HA polymer by mineralization technique. AL-HA graft polymer was prepared by covalent conjugation of alendronate sodium and hyaluronic acid. Compritol ATO 888 and capmule MCM C8 hybrid lipid mix was employed to prepare irinotecan containing nanostructured lipid carrier (NLC) by using functional excipients with P-gp inhibition activity. AL-HA was successfully grafted over NLC Ir (uncoated irinotecan loaded NLC) by calcium-assisted mineralization. HA-NLC-Ir (hyaluronic acid coated irinotecan loaded NLC) particles have a nanoscale size of 386+/-2.2 nm along with a zeta potential value of 19.7+/-1.2 mV. NLC-Ir as well as HA-NLC-Ir showed a slow and sustained drug release. In vitro cell line studies performed on HT-29 and Colo-320 colon cancer cells revealed a reduced IC50 even in MDR cells. Flowcytometry studies demonstrated the capability of the developed nanocarriers to deliver the P-gp substrate moieties in MDR cancer cells. Furthermore, the targeting potential of HA-NLC was confirmed by CLSM studies. The cell line studies also revealed that NLC formulation had a potential of inhibiting P-gp by affecting ATPase activity and MDR1 gene expression. PMID- 25454762 TI - Isobutyrylshikonin inhibits lipopolysaccharide-induced nitric oxide and prostaglandin E2 production in BV2 microglial cells by suppressing the PI3K/Akt mediated nuclear transcription factor-kappaB pathway. AB - Microglia are important macrophages to defend against pathogens in the central nervous system (CNS); however, persistent or acute inflammation of microglia lead to CNS disorders via neuronal cell death. Therefore, we theorized that a good strategy for the treatment of CNS disorders would be to target inflammatory mediators from microglia in disease. Consequently, we investigated whether isobutyrylshikonin (IBS) attenuates the production of proinflammatory mediators, such as nitric oxide (NO) and prostaglandin E2, in lipopolysaccharide (LPS) stimulated BV2 microglial cells. Treatment with IBS inhibited the secretion of NO and prostaglandin E2 (as well as the expression of their key regulatory genes), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2). Isobutyrylshikonin also suppressed LPS-induced DNA-binding activity of nuclear transcription factor kappaB (NF-kappaB), by inhibiting the nuclear translocation of p50 and p65 in addition to blocking the phosphorylation and degradation of IkappaBalpha. Pretreatment with pyrrolidine dithiocarbamate, a specific NF-kappaB inhibitor, showed the down-regulation of LPS-induced iNOS and COX-2 messenger RNA by suppressing NF-kappaB activity. This indirectly suggests that IBS-mediated NF kappaB inhibition is the main signaling pathway involved in the inhibition of iNOS and COX-2 expression. In addition, IBS attenuated LPS-induced phosphorylation of PI3K and Akt, which are upstream molecules of NF-kappaB, in LPS-stimulated BV2 microglial cells. The functional aspects of the PI3K/Akt signaling pathway were analyzed with LY294002, which is a specific PI3K/Akt inhibitor that attenuated LPS-induced iNOS and COX-2 expression by suppressing NF kappaB activity. These data suggest that an IBS-mediated anti-inflammatory effect may be involved in suppressing the PI3K/Akt-mediated NF-kappaB signaling pathway. PMID- 25454769 TI - Long-term changes in physical capacity after colorectal cancer treatment. AB - Older patients with colorectal cancer are faced with the dilemma of choosing between the short-term risks of treatment and the long-term risks of insufficiently treated disease. In addition to treatment-related morbidity and mortality, patients may suffer from loss of physical capacity. The purpose of this review was to gather all available evidence regarding long-term changes in physical functioning and role functioning after colorectal cancer treatment, by performing a systematic Medline and Embase search. This search yielded 27 publications from 23 studies. In 16 studies addressing physical functioning after rectal cancer treatment, a median drop of 10% (range -26% to -5%) in the mean score for this item at three months. At six months, mean score was still 7% lower than baseline (range -18% to 0%) and at twelve months 5% lower (range -13% to +5%). For role functioning (i.e. ability to perform daily activities) after rectal cancer treatment, scores were -18% (range -39% to -2%), -8% (range -23% to +6%) and -5% (range -17% to +10%) respectively. Elderly patients experience the greatest and most persistent decline in self-care capacity (up to 61% at one year). This systematic review demonstrates that both physical functioning and role functioning are significantly affected by colorectal cancer surgery. Although initial losses are recovered partially during follow-up, there is a permanent loss in both aspects of physical capacity, in patients of all ages but especially in the elderly. This aspect should be included in patient counselling regarding surgery. PMID- 25454768 TI - Prevention of post-operative delirium in older patients with cancer undergoing surgery. AB - Prevention has been shown to be the most effective strategy for minimizing the occurrence of delirium as well as delirium-associated complications.(5) Therefore prevention of delirium in older adults undergoing surgery is a top research priority given the extent of the problem in this patient population. In this review, we will describe the POD syndrome, previously identified risk factors that predict POD in surgical cancer patients, long-term outcomes of POD and both non-pharmacologic and pharmacologic therapies aimed at preventing POD. PMID- 25454770 TI - Systematic review of falls in older adults with cancer. AB - OBJECTIVES: Older adults frequently experience falls, at great cost to themselves and society. Older adults with cancer may be at greater risk for falls and have unique risk factors. MATERIALS AND METHODS: We undertook a systematic review of the available medical literature to examine the current evidence regarding factors associated with falls in older adults with cancer. PubMed, Embase, CINAHL, CENTRAL, DARE, Cochrane Database of Systematic Reviews and clinical trials.gov were searched using standardized terms for concepts of oncology/cancer, people 60 and older, screening, falls and diagnosis. Eligible studies included cohort or case-control studies or clinical trials in which all patients, or a subgroup of patients, had a diagnosis of cancer and in which falls were either the primary or secondary outcome. RESULTS: We identified 31 studies that met our inclusion criteria. Several studies suggest that falls are more common in older adults with a diagnosis of cancer than those without. Among the 11 studies that explored factors associated with outpatient falls, some risk factors for falls established in the general population were also associated with falls in older adults with cancer, including dependence in activities of daily living and prior falls. Other factors associated with falls in a general population, such as age, polypharmacy and opioid use, were not predictive of falls among oncology populations. Falls among older adults with cancer in the inpatient setting were associated with established risk factors for falls in people without cancer, but also with factors unique to an oncology population, such as brain metastases. CONCLUSIONS: Falls in older adults with cancer are more common than in the general population, and are associated with risk factors unique to people with cancer. Further study is needed to establish methods of screening older adults with cancer for fall risk and ultimately implement interventions to reduce their risk of falls. Identifying which older adults with cancer are at greater risk for falls is a requisite step to ultimately intervene and prevent falls in this vulnerable population. PMID- 25454772 TI - Large solitary fibrous tumor of the oral cavity--report of a case. AB - The solitary fibrous tumor (SFT) is a rare soft tissue tumor with a substantially benign clinical behavior. The SFT of the oral cavity is a very uncommon entity. It is also of complicated diagnosis because of its extensive morphologic diversity and because of its similarity to many mesenchymal tumors. A 44-year-old man was referred for management of an asymptomatic lesion in the left buccal mucosa, which had been identified 10 years earlier. Intra-oral examination revealed a well-demarcated, fibroelastic, rounded exophytic mass located in the left buccal mucosa. The mass was covered with a non-ulcerated mucosa of normal color and measured approximately 4.0 cm in diameter. Histopathological examination showed proliferation of spindle-shaped cells arranged in fascicles and in a patternless pattern, highly vascularized, with focal staghorn vessels. Immunohistochemical analysis revealed diffuse positivity for CD34 and focal positivity for Bcl-2. Awareness of the morphological diversity of SFT coupled to a judicious use of appropriate immunohistochemical probes should prove valuable to accurately segregate SFT from other spindle cell neoplasms. PMID- 25454771 TI - Revised histopathological consensus classification of joint implant related pathology. AB - This extended classification of joint implant related pathology is a practical histopathologic classification based on defined morphological criteria covering the complete spectrum of pathohistologic changes in periprosthetic tissues. These changes may occur as a consequence of endoprosthetic replacement of large joints and may lead to a reduction in the prosthesis survival rate. We describe the established consensus classification of the periprosthetic membrane, in which aseptic and septic prosthetic loosening can be subdivided into four histological types, as well as histopathological criteria for additional significant pathologies including endoprosthetic-associated arthrofibrosis, particle-induced immunological, inflammatory and toxic mechanisms (adverse reactions), and bone tissue pathologies. These characteristic tissue alterations and their relationships are summarized in the extended classification. Since particle heterogeneity in periprosthetic tissue is high and particle identification is a necessary part of diagnosis, the identification of different types of particles is described in the histopathological particle algorithm. The morphological qualities of prosthetic material particles and the demarcation between abrasion and non-abrasion endogenous particles are also summarized. This feasible classification which is based on low cost standard tissue processing and examination and on well-defined diagnostic criteria is a solid platform for the histological diagnosis of implant associated pathologies providing a stable and reproducible tool for the surgical pathologist. Since this classification is suitable for standardized histopathological diagnostics, it might also provide a useful data set for joint arthroplasty registers, particularly for registers based on so-called routine data. PMID- 25454773 TI - Timing vocal behavior: lack of temporal overlap avoidance to fluctuating noise levels in singing Eurasian wrens. AB - Many animals live in or near urban areas that have become increasingly widespread and noisy over the last century. Especially those species that rely heavily on acoustics for communication may be affected by these elevated anthropogenic noise levels. Many bird species that sing to defend their territories and to attract mates may have to exploit specific noise coping strategies to persist in such acoustically challenging conditions. Eurasian wrens (Troglodytes troglodytes), like several other bird species, have been shown in a previous experiment to time their vocalizations such that they avoid overlap with other singing birds. Here, we tested whether Eurasian wrens also time their songs to avoid overlap with fluctuating anthropogenic noise. However, we did not find any evidence in favor of this potential phenomenon. Territorial wrens persisted in singing without temporal adjustments in noisy territories with 'natural' fluctuations of traffic noise levels as well as during experimental exposure to intermittent white noise. PMID- 25454775 TI - Capsule endoscopy in Crohn's disease: is there enough light in the tunnel? PMID- 25454778 TI - [Guidance for the wise use of social media in medicine and in accordance with the Hippocratic Oath for French physicians]. PMID- 25454777 TI - [Exponential use of social media in medicine: example of the interest of Twitter((c)) in urology]. AB - AIM: Social media (#SoMe) has changed the face of modern medicine. Our purpose was to asses the potential interest of Twitter in the field of urology. MATERIAL AND METHODS: A systematic review of the literature has been performed using PubMed without timeline restriction with the following keywords (MeSH): social media; Web 2.0; Twitter; Internet; network; urology; journal club; education. RESULTS: There were 3 categories of interest of Twitter in the field of urology: spread of scientific knowledge, scientific interaction during medical conferences and medical education and international medical debates. The unique spread of evidence-based-medecine through traditional scientific journals in paper version is over. Main scientific journals in urology and scientific societies are now using a Twitter account and became virtual. They use new bibliometrics available on #SoMe to estimate the social impact. Twitter allows for a better interactivity of doctors attending scientific conferences. Exponential use of Twitter is in the interest of speakers and leaders, audience and scientific societies. Lastly, medical academic education and continuing medical education can be achieved through #SoMe. Twitter became a lively virtual platform for scientific debates for complex oncological cases (dematerialized tumor board). Twitter is also a place for intense scientific discussion during virtual journal club without geographic or timeline restriction. CONCLUSION: Physicians need to respect the rules for a wise use of #SoMe in order not to break the Hippocratic Oath. There is a revolution around #SoMe and Twitter in the spread of scientific knowledge and academic teaching. International urologists are already committed in this evolution and France should also get involved. PMID- 25454776 TI - [Management of low-risk prostate cancer]. AB - INTRODUCTION: The widespread use of prostate cancer screening has led to a stage migration resulting in an increase in the diagnosis of low-risk disease, which currently accounts for 40-50% of diagnosed forms. New therapeutic strategies have been developed in order to minimize the risk of overtreatment. METHODS: A systematic review of the literature over the past 20 years was performed using the Medline database. The literature selection was based on evidence and practical considerations. RESULTS: Low-risk tumors are conventionally defined by the d'Amico classification. The use of multiparametric MRI helps to better characterize these tumors. The contribution of molecular biology remains to be determined in clinical practice. Novel therapeutic options for low-risk disease are currently being evaluated. CONCLUSION: The new therapeutic strategies are evolving. They seek to reduce overtreatment without compromising oncological success. PMID- 25454774 TI - The mitochondrial permeability transition pore and its adaptive responses in tumor cells. AB - This review covers recent progress on the nature of the mitochondrial permeability transition pore (PTP) - a key effector in the mitochondrial pathways to cell death - and on the adaptive responses of tumor cells that desensitize the PTP to Ca(2+) and reactive oxygen species (ROS), thereby playing an important role in the resistance of tumors to cell death. The discovery that the PTP forms from dimers of F-ATP synthase; and the definition of the Ca(2+)- and ROS dependent signaling pathways affecting the transition of the F-ATP synthase from an energy-conserving to an energy-dissipating device open new perspectives for therapeutic intervention in cancer cells. PMID- 25454779 TI - Neanderthal megafaunal exploitation in Western Europe and its dietary implications: a contextual reassessment of La Cotte de St Brelade (Jersey). AB - The recurrent presence at Middle Palaeolithic sites of megafaunal remains, such as mammoth, elephant and rhinoceros, together with isotope analyses signalling meat as a prominent protein source, have been used to argue that these species played a central role in Neanderthal diet. Key to this model are the bone heap horizons from La Cotte de St Brelade (Jersey), which were previously interpreted as game drive debris resulting from systematic Neanderthal hunting. However, this hypothesis has never been rigorously tested, neither at a site-scale, incorporating taphonomic and contextual data, nor at a wider European scale. First, this paper provides a contextual reassessment of the faunal remains from La Cotte to fully understand Neanderthal behaviour at the site. Second, a comparative database of 30 well-published Middle Palaeolithic sites with megafauna permits a data-driven, broader spatial (European) and diachronic assessment of the role of megafauna in Neanderthal subsistence behaviour. Results suggest initial Neanderthal occupation at La Cotte was intensive although through time site visits became more infrequent, as highlighted by a reduction in cultural debris concurrent with a rise in carnivore presence. While mammoths, just as other large mammals and occasionally carnivores, were clearly butchered at this locality, their acquisition and role in Neanderthal diet remains ambiguous. Broader comparisons across Western Europe indicate a main focus on a range of large herbivores, with only a minor, opportunistic, role for megafauna. Whilst stable isotope analysis suggests that Neanderthal diet was meat-oriented, zooarchaeological data do not support the inference that megafauna were the major contributor of meat. PMID- 25454780 TI - Multilocus adaptation associated with heat resistance in reef-building corals. AB - The evolution of tolerance to future climate change depends on the standing stock of genetic variation for resistance to climate-related impacts, but genes contributing to climate tolerance in wild populations are poorly described in number and effect. Physiology and gene expression patterns have shown that corals living in naturally high-temperature microclimates are more resistant to bleaching because of both acclimation and fixed effects, including adaptation. To search for potential genetic correlates of these fixed effects, we genotyped 15,399 single nucleotide polymorphisms (SNPs) in 23 individual tabletop corals, Acropora hyacinthus, within a natural temperature mosaic in backreef lagoons on Ofu Island, American Samoa. Despite overall lack of population substructure, we identified 114 highly divergent SNPs as candidates for environmental selection, via multiple stringent outlier tests, and correlations with temperature. Corals from the warmest reef location had higher minor allele frequencies across these candidate SNPs, a pattern not seen for noncandidate loci. Furthermore, within backreef pools, colonies in the warmest microclimates had a higher number and frequency of alternative alleles at candidate loci. These data suggest mild selection for alternate alleles at many loci in these corals during high heat episodes and possible maintenance of extensive polymorphism through multilocus balancing selection in a heterogeneous environment. In this case, a natural population harbors a reservoir of alleles preadapted to high temperatures, suggesting potential for future evolutionary response to climate change. PMID- 25454781 TI - Conflict between groups promotes later defense of a critical resource in a cooperatively breeding bird. AB - Conflict between groups (intergroup conflict) is common in many social species and is widely discussed as an evolutionary driver of within-group dynamics and social structure. However, empirical studies investigating the impacts of intergroup conflict have focused on the immediate aftermath, when behavioral changes may be the direct result of elevated stress levels or territorial exclusions. Demonstrations of longer-term effects, with behavioral changes persisting once increases in stress have diminished and full access to resources is again possible, would support proposed links to individual fitness and social evolution. Here we show that conflicts between neighboring groups of cooperatively breeding green woodhoopoes (Phoeniculus purpureus) have a lasting influence on decisions concerning roost cavities, a limiting resource vital for survival and breeding. Groups involved in extended conflicts in the morning were more likely to return to the zone of conflict that evening, roosting closer to territorial borders, than when intergroup interactions were short or did not occur. Extended morning conflicts also increased the likelihood that groupmates roosted together and preened one another at the roost, suggesting that intergroup conflict promotes consensus decision-making, social bonding, and group cohesion. Border roost use and allopreening increased more following conflicts that were lost rather than won. By demonstrating that both the intensity and outcome of intergroup interactions affect resource defense and associated within-group behavior many hours later, our results begin to bridge the gap between the immediate impacts of intergroup conflict and its role in social evolution. PMID- 25454782 TI - Double jeopardy and global extinction risk in corals and reef fishes. AB - Coral reefs are critically important ecosystems that support the food security and livelihoods of hundreds of millions of people in maritime tropical countries, yet they are increasingly threatened by overfishing, coastal pollution, climate change, and other anthropogenic impacts, leading to concerns that some species may be threatened with local or even global extinction. The concept of double jeopardy proposes that the risk of species extinction is elevated if species that are endemic (small range) are also scarce (low local abundance). Traditionally, marine macroecology has been founded on patterns of species richness and presence absence data, which provide no information on species abundances or on the prevalence of double jeopardy. Here we quantify the abundances of >400 species of corals and fishes along one of the world's major marine biodiversity gradients, from the Coral Triangle hotspot to French Polynesia, a distance of approximately 10,000 km. In contrast to classical terrestrial studies, we find that the abundance of these species bears no relationship to the size of their geographic ranges. Consequently, double jeopardy is uncommon because endemics are often locally abundant, and conversely many pandemics are rare. The Coral Triangle hotspot has more numerically rare species (both endemic and pandemic) but also encompasses more species with intermediate and higher abundances. We conclude that conservation efforts in the sea should focus less on extinction risk and more on maintaining and rebuilding key ecological functions that are highly vulnerable to human pressures, even if species can avoid extinction. PMID- 25454783 TI - Age-related declines of stability in visual perceptual learning. AB - One of the biggest questions in learning is how a system can resolve the plasticity and stability dilemma. Specifically, the learning system needs to have not only a high capability of learning new items (plasticity) but also a high stability to retain important items or processing in the system by preventing unimportant or irrelevant information from being learned. This dilemma should hold true for visual perceptual learning (VPL), which is defined as a long-term increase in performance on a visual task as a result of visual experience. Although it is well known that aging influences learning, the effect of aging on the stability and plasticity of the visual system is unclear. To address the question, we asked older and younger adults to perform a task while a task irrelevant feature was merely exposed. We found that older individuals learned the task-irrelevant features that younger individuals did not learn, both the features that were sufficiently strong for younger individuals to suppress and the features that were too weak for younger individuals to learn. At the same time, there was no plasticity reduction in older individuals within the task tested. These results suggest that the older visual system is less stable to unimportant information than the younger visual system. A learning problem with older individuals may be due to a decrease in stability rather than a decrease in plasticity, at least in VPL. PMID- 25454784 TI - Balboa binds to pickpocket in vivo and is required for mechanical nociception in Drosophila larvae. AB - The Drosophila gene pickpocket (ppk) encodes an ion channel subunit of the degenerin/epithelial sodium channel (DEG/ENaC) family. PPK is specifically expressed in nociceptive, class IV multidendritic (md) neurons and is functionally required for mechanical nociception responses. In this study, in a genome-wide genetic screen for other ion channel subunits required for mechanical nociception, we identify a gene that we name balboa (also known as CG8546, ppk26). Interestingly, the balboa locus encodes a DEG/ENaC ion channel subunit highly similar in amino acid sequence to PPK. Moreover, laser-capture isolation of RNA from larval neurons and microarray analyses reveal that balboa is also highly enriched in nociceptive neurons. The requirement for Balboa and PPK in mechanical nociception behaviors and their specific expression in larval nociceptors led us to hypothesize that these DEG/ENaC subunits form an ion channel complex in vivo. In nociceptive neurons, Balboa::GFP proteins distribute uniformly throughout dendrites but remarkably localize to discrete foci when ectopically expressed in other neuron subtypes (where PPK is not expressed). Indeed, ectopically coexpressing ppk transforms this punctate Balboa::GFP expression pattern to the uniform distribution observed in its native cell type. Furthermore, ppk-RNAi in class IV neurons alters the broad Balboa::GFP pattern to a punctate distribution. Interestingly, this interaction is mutually codependent as balboa-RNAi eliminates Venus::PPK from the sensory dendrites of nociceptors. Finally, using a GFP-reconstitution approach in transgenic larvae, we directly detect in vivo physical interactions among PPK and Balboa subunits. Combined, our results indicate a critical mechanical nociception function for heteromeric PPK and Balboa channels in vivo. PMID- 25454785 TI - Asymmetric processing of visual motion for simultaneous object and background responses. AB - Visual object fixation and figure-ground discrimination in Drosophila are robust behaviors requiring sophisticated computation by the visual system, yet the neural substrates remain unknown. Recent experiments in walking flies revealed object fixation behavior mediated by circuitry independent from the motion sensitive T4-T5 cells required for wide-field motion responses. In tethered flight experiments under closed-loop conditions, we found similar results for one feedback gain, whereas intact T4-T5 cells were necessary for robust object fixation at a higher feedback gain and in figure-ground discrimination tasks. We implemented dynamical models (available at http://strawlab.org/asymmetric motion/) based on neurons downstream of T4-T5 cells-one a simple phenomenological model and another, physiologically more realistic model-and found that both predict key features of stripe fixation and figure-ground discrimination and are consistent with a classical formulation. Fundamental to both models is motion asymmetry in the responses of model neurons, whereby front-to-back motion elicits stronger responses than back-to-front motion. When a bilateral pair of such model neurons, based on well-understood horizontal system cells, downstream of T4-T5, is coupled to turning behavior, asymmetry leads to object fixation and figure ground discrimination in the presence of noise. Furthermore, the models also predict fixation in front of a moving background, a behavior previously suggested to require an additional pathway. Thus, the models predict several aspects of object responses on the basis of neurons that are also thought to serve a key role in background stabilization. PMID- 25454786 TI - Potential disruption of pollination in a sexually deceptive orchid by climatic change. AB - Warmer springs advance many phenological events, including flowering time in plants and the flight time of insects. Pollination by insects, an ecosystem service of immense economic and conservation importance, depends on synchrony between insect activity and flowering time. If plants and their pollinators show different phenological responses to climate warming, pollination could fail. Information about the effects of warming on specific plant-insect mutualisms is difficult to obtain from complex pollination networks. In contrast, the extraordinarily specific deceptions evolved by orchids that attract a very narrow range of pollinators allow direct examination of the potential for climatic warming to disrupt synchrony. Here we show that a sexually deceptive orchid and the solitary bee on which it depends for pollination will diverge in phenology with increasing spring temperature. Male bees inadvertently pollinate the orchid flowers during pseudocopulation. Analysis of museum specimens (1893-2007) and recent field-based records (1975-2009) showed that flight date of the solitary bee Andrena nigroaenea is advanced more by higher temperatures than is flowering date in the deceptive orchid Ophrys sphegodes. Male bees emerged slightly earlier than females, which attract male copulatory attentions away from the deceptive flowers. Warming by as little as 2 degrees C increased both the probability of male flight and the proportion of females flying in the bee population before orchid flowering; this would reduce the frequency of pseudocopulation and thus lower pollination success rate in the orchid. Our results demonstrate a significant potential for coevolved plant-pollinator relationships to be disrupted by climatic warming. PMID- 25454787 TI - Local mate competition mediates sexual conflict over sex ratio in a haplodiploid spider mite. AB - In haplodiploids, females pass their genes on to all their offspring, whereas a male's genes are only passed on to his daughters. Hence, males always benefit from female-biased sex ratios, whereas for females the optimal offspring sex ratio depends on the level of local mate competition (LMC), ranging from highly female-biased under strict LMC to unbiased in Panmixia. This generates a sexual conflict over sex ratio, the intensity of which depends on the LMC level, with most intense conflict in Panmixia. Such conflict might lead to an evolutionary arms race, with persistence traits evolving in males and resistance traits in females. Although this prediction is theoretically straightforward, it remains untested empirically. We addressed this by crossing spider mites that evolved under varying intensities of LMC (hence of sexual conflict), to mates from inbred lines. Under high levels of sexual conflict, both sexes evolved manipulative traits to shift the sex ratio to their own advantage. In females, this was partly achieved through changes in egg size. We thus show that (1) LMC levels modulate sexual conflict over sex ratio in haplodiploids, driving the evolution of manipulative traits, and (2) fathers can affect sex ratio, challenging conventional assumptions. PMID- 25454788 TI - Sexually coercive male chimpanzees sire more offspring. AB - In sexually reproducing animals, male and female reproductive strategies often conflict. In some species, males use aggression to overcome female choice, but debate persists over the extent to which this strategy is successful. Previous studies of male aggression toward females among wild chimpanzees have yielded contradictory results about the relationship between aggression and mating behavior. Critically, however, copulation frequency in primates is not always predictive of reproductive success. We analyzed a 17-year sample of behavioral and genetic data from the Kasekela chimpanzee (Pan troglodytes schweinfurthii) community in Gombe National Park, Tanzania, to test the hypothesis that male aggression toward females increases male reproductive success. We examined the effect of male aggression toward females during ovarian cycling, including periods when the females were sexually receptive (swollen) and periods when they were not. We found that, after controlling for confounding factors, male aggression during a female's swollen periods was positively correlated with copulation frequency. However, aggression toward swollen females was not predictive of paternity. Instead, aggression by high-ranking males toward females during their nonswollen periods was positively associated with likelihood of paternity. This indicates that long-term patterns of intimidation allow high ranking males to increase their reproductive success, supporting the sexual coercion hypothesis. To our knowledge, this is the first study to present genetic evidence of sexual coercion as an adaptive strategy in a social mammal. PMID- 25454789 TI - Association between salivary cotinine and cardiovascular biomarkers among nonsmokers and current smokers: cross-sectional study of 10,081 participants. AB - OBJECTIVE: Both active smoking and exposure to secondhand smoke (SHS) are associated with cardiovascular disease, but sidestream smoke contains higher levels of small particles and toxic gases than mainstream smoke. The relationship between the concentration of cotinine and a number of cardiovascular biomarkers among nonsmokers and active smokers was examined. METHODS: A cross-sectional study using the Scottish Health Surveys conducted between 1998 and 2010 was undertaken. Inclusion was restricted to participants aged >=16 years who had provided saliva and blood samples. Uni- and multivariate regression models were used to examine the relationships between the concentration of cotinine and C reactive protein (CRP), high-density lipoprotein (HDL) cholesterol, and fibrinogen concentrations, as well as total:HDL cholesterol ratios. RESULTS: Of the 10,018 eligible participants, 7,345 (73.3%) were confirmed to be nonsmokers (cotinine <15.0 ng/mL) and 2,673 (26.7%) were confirmed to be current smokers (cotinine >=15.0 ng/mL). CRP and total:HDL cholesterol increased, and HDL cholesterol decreased, with increasing cotinine concentration across nonsmokers and smokers (all p < .001). However, there were step changes at the interface, whereby nonsmokers with a high exposure to SHS had lower concentrations of cotinine than light active smokers but comparable concentrations of CRP (p = .709), HDL cholesterol (p = .931), and total:HDL cholesterol (p = .405). Fibrinogen concentrations were significantly raised in moderate and heavy active smokers only (both p < .001). CONCLUSION: Exposure to SHS is associated with disproportionately higher biomarkers of cardiovascular risk compared with active smoking. Protection from exposure to SHS should be a public health priority. PMID- 25454790 TI - Thrombolysis in carotid-related stroke patients: what about plaque hemorrhage and disruption? PMID- 25454791 TI - Podosomes revealed by advanced bioimaging: what did we learn? AB - Podosomes are micrometer-sized, circular adhesions formed by cells such as osteoclasts, macrophages, dendritic cells, and endothelial cells. Because of their small size and the lack of methods to visualize individual proteins and protein complexes, podosomes have long been considered a simple two-module structure with a protrusive actin core and a surrounding adhesive ring composed of integrins and cytoskeletal adaptor proteins such as vinculin and talin. In the past decade, the applications of fluorescence based techniques that circumvent the diffraction limit of conventional light microscopy took a major leap forward. Podosomes have been imaged by a variety of these super-resolution methods, and in this concise review we discuss how these super-resolution data have increased our understanding of the podosome ultra-structure and function. PMID- 25454792 TI - Characterization of illegal food items and identification of foodborne pathogens brought into the European Union via two major German airports. AB - Foods of animal origin brought illegally from third party countries into the European Community pose a risk for the introduction of diseases. This can lead to animal disease outbreaks with significant economic and social costs and subsequent severe trade restrictions. Further, disease outbreaks in humans due to illegally imported foods of animal origin have been described, yet, there are very few studies examining the potential human health impact. Passenger baggage is the most likely route by which illegal products enter a country. Therefore, the volume and geographic origin of foods of animal origin introduced illegally into Germany via the Frankfurt International Airport and Berlin-Schonefeld Airport by passenger luggage were characterized. Further, the occurrence of foodborne zoonotic bacteria such as Salmonella spp., Listeria spp., Campylobacter spp., Yersinia spp., Verocytotoxin-producing Escherichia coli (VTEC) and Brucella spp. and the microbial quality of the foods were analysed by total bacterial count. Between 2012 and 2013, a total of 663 food items were seized from 296 passengers arriving in Germany from 35 different departure countries. The majority of confiscates (51%) originated from Turkey and Russia. A selection of 474 samples was subjected to microbiological analyses. Twenty-three food products tested positive for at least one of the pathogens analysed. The majority of the contaminated foods were meat (33%) or meat products (42%), and milk products (21%). Considering that only a small fraction of arriving passengers is subjected to airport custom controls and only a small number of confiscated foods could be analysed during this study, further investigations are needed to understand the public health risks posed by illegally introduced food items. PMID- 25454793 TI - Identification and molecular characterization of pathogenic bacteria in foods confiscated from non-EU flights passengers at one Spanish airport. AB - Two hundred food samples of animal origin confiscated from passengers arriving on flights from non-European countries at the International Airport of Bilbao (Spain) were tested for the presence of four main bacterial foodborne pathogens (Campylobacter spp., Escherichia coli O157:H7, Listeria monocytogenes and Salmonella spp.) during 2012 and 2013. Overall, 20 samples were positive for L. monocytogenes (10%) and 11 for Salmonella spp. (5.5%), whereas Campylobacter spp. and E. coli O157:H7 were not detected in any sample. The positive isolates were widely clustered: 14 and 7 different pulsotypes for L. monocytogenes and Salmonella spp. isolates, respectively. Nine sequence types (ST) were detected for L. monocytogenes: ST2 (45%), ST9 (15% isolates), ST8 and ST87 (10%), and ST308, ST37, ST155 and ST378 (5%). The Salmonella spp. isolates belonged to seven serovars: monophasic serovar 4,12:d:- (3; 27.3%), Rauform (2; 18.2%), Anatum (2; 18.2%), Oranienburg, Enteritidis, Newport and Typhimurium (1; 9.1% each). Antibiotic resistance among L. monocytogenes isolates was high, especially for clindamycin and daptomycin (more than 95% of the isolates). These results indicate that food samples imported by travelers in their personal luggage may harbor the most prevalent L. monocytogenes genotypes and Salmonella spp. serovars responsible for foodborne outbreaks worldwide. Consequently, international travel can play an important role in the prevalence and dissemination of successful clones of foodborne pathogenic bacteria, and continuous monitoring of international movements is of importance to better understand clonal evolution and emergence and dissemination of successful lineages. PMID- 25454794 TI - Iterative conversion of cyclin binding groove peptides into druglike CDK inhibitors with antitumor activity. AB - The cyclin groove is an important recognition site for substrates of the cell cycle cyclin dependent kinases and provides an opportunity for highly selective inhibition of kinase activity through a non-ATP competitive mechanism. The key peptide residues of the cyclin binding motif have been studied in order to precisely define the structure-activity relationship for CDK kinase inhibition. Through this information, new insights into the interactions of peptide CDK inhibitors with key subsites of the cyclin binding groove provide for the replacement of binding determinants with more druglike functionality through REPLACE, a strategy for the iterative conversion of peptidic blockers of protein protein interactions into pharmaceutically relevant compounds. As a result, REPLACE is further exemplified in combining optimized peptidic sequences with effective N-terminal capping groups to generate more stable compounds possessing antitumor activity consistent with on-target inhibition of cell cycle CDKs. The compounds described here represent prototypes for a next generation of kinase therapeutics with high efficacy and kinome selectivity, thus avoiding problems observed with first generation CDK inhibitors. PMID- 25454795 TI - Impacts of aging and amyloid-beta deposition on plasminogen activators and plasminogen activator inhibitor-1 in the Tg2576 mouse model of Alzheimer's disease. AB - Plasminogen activators (PAs), which convert plasminogen into the fibrinolytic protease plasmin, may initiate the degradation of amyloid-beta (Abeta) to suppress the amyloid pathogenesis. In that way, tissue plasminogen activator (tPA)-mediated plasmin activation could maintain a low level of Abeta deposition to delay the pathogenesis of Alzheimer's disease (AD). In a previous study, we reported that tPA/plasmin proteolytic activity is attenuated throughout the brain during aging or with Abeta accumulation but clustered intense around the amyloid plaques in AD brain. The present study demonstrates that the altered proteolytic activity primarily results from the competition between the expressions of tPA and plasminogen activator inhibitor-1 (PAI-1) in the brains of Tg2576 Abeta transgenic mice, as revealed by immunohistochemistry and immunoblot assays. Compared with that in the brains of younger Tg2576 mice, tPA protein is generally reduced throughout the brain in older Tg2576 mice but elevated near amyloid plaques. In contrary, PAI-1 expression increases during aging or Abeta deposition with its clusters surrounding amyloid plaques. No significant alteration in the expression of urokinase plasminogen activator (uPA) is detected. These results suggest reciprocal feedback influences between tPA, PAI-1 and Abeta during aging and amyloid pathogenesis in AD brain; tPA-mediated plasmin activity is declined throughout the brain causing Abeta deposition during aging, and the Abeta deposits locally attract the cluster of tPA and/or PAI-1 around their deposits to competitively determine tPA/plasmin-mediated Abeta proteolysis. PMID- 25454796 TI - Neurotropin promotes NGF signaling through interaction of GM1 ganglioside with Trk neurotrophin receptor in PC12 cells. AB - Activation of the high-affinity nerve growth factor (NGF) receptor Trk occurs through multiple processes consisted of translocation and clustering within the plasma membrane lipid rafts, dimerization and autophosphorylation. Here we found that a nonprotein extract of inflamed rabbit skin inoculated with vaccinia virus (Neurotropin((r))) enhanced efficiency of NGF signaling. In rat pheochromocytoma PC12 cells overexpressing Trk (PCtrk cells), Neurotropin augmented insufficient neurite outgrowth observed at suboptimal concentration of NGF (2ng/mL) in a manner depending on Trk kinase activity. Cellular exposure to Neurotropin resulted in an accumulation of Trk-GM1 complexes without affecting dimerization or phosphorylation states of Trk. Following NGF stimulation, Neurotropin significantly facilitated the time course of NGF-induced Trk autophosphorylation. These observations provide a unique mechanism controlling efficiency of NGF signaling, and raise the therapeutic potential of Neurotropin for various neurological conditions associated with neurotrophin dysfunction. PMID- 25454797 TI - Comparing free water imaging and magnetization transfer measurements in schizophrenia. AB - Diffusion weighted imaging (DWI) has been extensively used to study the microarchitecture of white matter in schizophrenia. However, popular DWI-derived measures such as fractional anisotropy (FA) may be sensitive to many types of pathologies, and thus the interpretation of reported differences in these measures remains difficult. Combining DWI with magnetization transfer ratio (MTR) - a putative measure of white matter myelination - can help us reveal the underlying mechanisms. Previous findings hypothesized that MTR differences in schizophrenia are associated with free water concentrations, which also affect the DWIs. In this study we use a recently proposed DWI-derived method called free water imaging to assess this hypothesis. We have reanalyzed data from a previous study by using a fiber-based analysis of free-water imaging, providing a free water fraction, as well as mean diffusivity and FA corrected for free-water, in addition to MTR along twelve major white matter fiber bundles in 40 schizophrenia patients and 40 healthy controls. We tested for group differences in each fiber bundle and for each measure separately and computed correlations between the MTR and the DWI-derived measures separately for both groups. Significant higher average MTR values in patients were found for the right uncinate fasciculus, the right arcuate fasciculus and the right inferior-frontal occipital fasciculus. No significant results were found for the other measures. No significant differences in correlations were found between MTR and the DWI-derived measures. The results suggest that MTR and free-water imaging measures can be considered complementary, promoting the acquisition of MTR in addition to DWI to identify group differences, as well as to better understand the underlying mechanisms in schizophrenia. PMID- 25454798 TI - White matter diffusivity and microarchitecture among schizophrenia subjects and first-degree relatives. AB - BACKGROUND: Impairments in structural and functional connections are demonstrated in schizophrenia. Certain disconnectional patterns may be biomarkers of elevated risk for schizophrenia. Convergent examination of multiple diffusion parameters and cognitive performance better illustrates pathophysiological significance of such disconnectional patterns. METHODS: Diffusion Tensor Imaging data on 39 early course schizophrenia subjects, 21 adolescent/young adult first-degree relatives (FDR) of schizophrenia subjects and 29 healthy controls (HC) were examined for threshold-free clusters of fractional anisotropy (FA) and radial diffusivity (RD) differences correcting for multiple comparisons. Regression models examined the variance contributed by anisotropy differences, age and sex. Group-wise differences on sustained attention, verbal memory and executive functions were examined and correlated with diffusivity measures controlling for age and sex. RESULTS: Schizophrenia subjects showed significantly decreased FA and increased RD in the forceps minor and superior longitudinal fasciculus (SLF) compared to HC. FDR showed decreased forceps minor FA compared to HC, and decreased SLF RD compared to HC and schizophrenia subjects. Quantitative RD differences were 2-3 fold higher compared to FA. Besides, forceps minor RD was inversely correlated with sustained attention in schizophrenia. CONCLUSIONS: Schizophrenia and FDR subjects show different patterns of white matter diffusivity compared to HC. While forceps minor changes may be a disease marker, SLF changes may be risk markers. In addition, RD may be a more robust risk marker than FA. PMID- 25454800 TI - Violence and mental illness: what Lewis Carroll had to say. AB - In 1873 Skeffington Lutwidge, a Lunacy Commission inspector of asylums in England, was killed by an asylum patient. Lutwidge was the uncle and close friend of Charles Lutwidge Dodgson, also known as Lewis Carroll. One year later, Carroll began writing The Hunting of the Snark, a poem whose meaning has mystified Carroll enthusiasts. In fact, the poem is a description of the Lunacy Commission inspection team and reflects Carroll's personal understanding of, and reaction to, the killing of his uncle by an individual with a severe mental illness. Carroll's close relationship with his uncle also explains the prominence of psychotic thinking in Carroll's work, including the Mad Hatter's tea party. PMID- 25454799 TI - Consortium on the Genetics of Schizophrenia (COGS) assessment of endophenotypes for schizophrenia: an introduction to this Special Issue of Schizophrenia Research. AB - BACKGROUND: The COGS is a multi-site NIMH-sponsored investigation of the genetic basis of 12 primary and multiple secondary quantitative endophenotypes in schizophrenia. METHODS: Since 2003, COGS has completed studies using a family based ascertainment strategy (COGS-1), and a case-control ascertainment strategy (COGS-2) (cumulative "n">4000). RESULTS: COGS-1 family study confirmed robust deficits in, and heritability of, these endophenotypes in schizophrenia, and provided evidence for a coherent genetic architecture underlying the risk for neurocognitive and neurophysiological deficits in this disorder. COGS-2 case control findings, many reported herein, establish a foundation for fine genomic mapping and other analyses of these endophenotypes and risk genes for SZ. Several reports in this Special Issue compare findings of endophenotype deficits generated by fundamentally different COGS-1 vs. COGS-2 ascertainment strategies. Despite the expectation that family-based and case-control designs would establish demographically and potentially biologically distinct patient cohorts, findings generally revealed comparable patterns of endophenotype deficits across studies. The COGS-2 case-control design facilitated the accrual of a larger "n", permitting detailed analyses of factors moderating endophenotype performance. Some COGS-2 endophenotypes not assessed in COGS-1 are also reported, as is a new factor analytic strategy for identifying shared vs. unique factors among the COGS endophenotypes which can be used to develop composite variables with distinct genetic signatures. DISCUSSION: The path to date of COGS-1 endophenotype and genetic findings, followed by replication and extension in COGS-2, establishes benchmarks for endophenotype deficits in SZ and their moderation by specific factors, and clear expectations for informative findings from upcoming COGS-2 genetic analyses. PMID- 25454801 TI - Psychotic-like experiences in pregnant and postpartum women without a history of psychosis. AB - OBJECTIVES: This study investigated whether psychotic-like experiences (PLEs) are prevalent amongst women in pregnancy and/or in the early postnatal phase, and whether the predictors identified in the literature for non-puerperal psychosis apply in a general sample of perinatal women. METHOD: 101 women in their third trimester of pregnancy completed questionnaire measures of mood, subjective well being, sleep, expectations about labour, and PLEs. 66 of these participants also completed questionnaires shortly after giving birth. The main outcome measures were scores on the Peters Delusions Inventory (PDI) and the Launay-Slade Hallucination Scale-Revised (LSHS-R). RESULTS: During pregnancy, 80% of the samples endorsed at least one item on the PDI, and 76% endorsed at least one item on the LSHS-R. Endorsement rates were lower postnatally, with rates of 59% and 52% for the PDI and LSHS-R, respectively. Mean scores on the PDI were 3.07 during pregnancy and 1.61 postnatally. Mean scores on the LSHS-R were 8.38 during pregnancy and 5.24 postnatally. Hierarchical multiPLEs regression analyses revealed that ratings of depressive symptomatology significantly predicted PDI total score during pregnancy and LSHS-R total score postnatally, whilst postnatally, scores obtained on the PDI and LSHS-R postnatally were significantly predicted by scores on these measures during pregnancy. Fear in childbirth, but not in pregnancy, showed associations with PLEs but these associations were not maintained once multivariate analyses were conducted. CONCLUSIONS: The results of this study support the continuum model of psychosis, by illustrating that PLEs occur frequently in perinatal individuals without a diagnosis of severe mental illness. PMID- 25454803 TI - Identification of a novel non-coding mutation in C1qB in a Dutch child with C1q deficiency associated with recurrent infections. AB - INTRODUCTION: C1q deficiency is a rare genetic disorder that is strongly associated with development of systemic lupus erythematosus (SLE). Several mutations in the coding regions of the C1q genes have been described that result in stop-codons or other genetic abnormalities ultimately leading to C1q deficiency. Here we report on a Dutch boy suffering from recurrent infections with a complete C1q deficiency, without any SLE symptoms. METHODS: The presence of C1q in serum was assessed using ELISA and hemolytic assay. By western blot we examined the different C1q chains in cell lysates. We identified the mutation using deep-sequencing. By qPCR we studied the mRNA expression of C1qA, C1qB and C1qC in the PBMCs of the patient. RESULTS: Deep-sequencing revealed a homozygous mutation in the non-coding region of C1qB in the patient, whereas both parents were heterozygous. The mutation is located two nucleotides before the splice site of the second exon. In-silico analyses predict a complete abrogation of this natural splice site. Analyses of in vitro cultured cells from the patient revealed a lack of production of C1q and intracellular absence of C1qB in the presence of C1qA and C1qC peptides. Quantitative PCR analysis revealed total absence of C1qB mRNA, a reduced level of C1qA mRNA and normal levels of C1qC mRNA. CONCLUSION: In this study we report a new mutation in the non-coding region of C1qB that is associated with C1q deficiency. PMID- 25454802 TI - The impact of eszopiclone on sleep and cognition in patients with schizophrenia and insomnia: a double-blind, randomized, placebo-controlled trial. AB - BACKGROUND: Insomnia is frequent in schizophrenia and may contribute to cognitive impairment as well as overuse of weight inducing sedative antipsychotics. We investigated the effects of eszopiclone on sleep and cognition for patients with schizophrenia-related insomnia in a double-blind placebo controlled study, followed by a two-week, single-blind placebo phase. METHODS: Thirty-nine clinically stable outpatients with schizophrenia or schizoaffective disorder and insomnia were randomized to either 3mg eszopiclone (n=20) or placebo (n=19). Primary outcome measure was change in Insomnia Severity Index (ISI) over 8 weeks. Secondary outcome measure was change in MATRICS Consensus Cognitive Battery (MATRICS). Sleep diaries, psychiatric symptoms, and quality of life were also monitored. RESULTS: ISI significantly improved more in eszopiclone (mean=-10.7, 95% CI=-13.2; -8.2) than in placebo (mean=-6.9, 95% CI=-9.5; -4.3) with a between group difference of -3.8 (95% CI=-7.5; -0.2). MATRICS score change did not differ between groups. On further analysis there was a significant improvement in the working memory test, letter-number span component of MATRICS (mean=9.8+/-9.2, z= 2.00, p=0.045) only for subjects with schizophrenia on eszopiclone. There were improvements in sleep diary items in both groups with no between-group differences. Psychiatric symptoms remained stable. Discontinuation rates were similar. Sleep remained improved during single-blind placebo phase after eszopiclone was stopped, but the working memory improvement in patients with schizophrenia was not durable. CONCLUSIONS: Eszopiclone stands as a safe and effective alternative for the treatment of insomnia in patients with schizophrenia. Its effects on cognition require further study. PMID- 25454804 TI - Genetic polymorphisms of innate and adaptive immunity as predictors of outcome in critically ill patients. AB - Sepsis and septic shock frequently cause the admission or complicate the clinical course of critically ill patients admitted in the intensive care units (ICU). Genetic variations disrupting the immune sensing of infectious organisms, could affect the ability of the immune system to respond to infection, and may influence both the genetic predisposition to infection and the diversity of the clinical presentation of sepsis. The aim of this study was to uncover possible associations between common functional immune gene polymorphisms (of both innate and adaptive immunity) and ICU-acquired sepsis and mortality. The TLR4-D299G (rs4986790), TLR4-T399I (rs4986791), C2-c.841_849+19del28 (rs9332736), TACI-C104R (rs34557412), BAFFR-P21R (rs77874543), and BAFFR-H159Y (rs61756766) polymorphisms were detected in a cohort of 215 critically ill patients, admitted in an 8-bed medical/surgical ICU. Interestingly, TLR4-D299G, TLR4-T399I and BAFFR-P21R carriage was associated with a lower risk of ICU-acquired sepsis. This association applied particularly in medical patients, while in trauma and surgical patients no significant associations were observed. Moreover, carriers of TACI-C104R displayed an undiagnosed mild to moderate hypogammaglobulinemia along with a significantly lower survival rate in the ICU, although lethal events were not attributed to sepsis. These findings further elucidate the role that host immune genetic variations may play in the susceptibility to ICU-acquired sepsis and ICU mortality. PMID- 25454805 TI - Effect of exogenous MCP-1 on TLR-2 neutralized murine macrophages and possible mechanisms of CCR-2/TLR-2 and MCP-1 signalling during Staphylococcus aureus infection. AB - It has been reported that Staphylococcus aureus survives within macrophages by hijacking host cell surface Toll-like receptor-2 (TLR-2). Moreover, S. aureus infection induced activation of TLR-2 has been reported to downregulate the expression of CC-chemokine receptor-2 (CCR-2), a receptor essential for binding of chemokines to propagate phagocytosis. Thus, we hypothesized that prior blocking of TLR-2 may help normal expression of CCR-2 on cell surface; thereby, administration of exogenous MCP-1 (a CCR-2 ligand) to bind to its free receptors might result in activation of downstream inflammatory signalling cascade. In order to address this, we compared the ability of S. aureus to modulate CCR-2 expression in TLR-2 free or neutralized macrophages in presence or absence of exogenous MCP-1 and associated downstream signalling. Exogenous MCP-1 by interacting CCR-2 leads to the release of nitric oxide and ROS that are important for bacterial clearance. In this experimental setup, the possible molecular pathway connecting an increase in proinflammatory cytokine levels with increased ROS/NO production, and therefore increased killing activity, possibly by involving either MyD88 dependent or RhoA GTPases dependent NF-kappaB activation or endogenous synthesis of MCP-1, independent of TLR-2-MyD88 pathway. Thus, induction of CCR-2/MCP-1 signalling by macrophages depending on the availability of MCP-1 during S. aureus infection may be important for regulation of septic shock by induction of reactive oxygen species and various cytokines. PMID- 25454806 TI - Unfractionated heparin attenuates LPS-induced IL-8 secretion via PI3K/Akt/NF kappaB signaling pathway in human endothelial cells. AB - Unfractionated heparin (UFH) is largely used as anti-thrombotic drug. While UFH has been shown to suppress lipopolysaccharide (LPS)-induced nuclear factor-kappaB (NF-kappaB) activation, intracellular upstream events that cause NF-kappaB down regulation in response to UFH remain unclear. Thus, we investigated the involvement of phosphoinositide-3-OH kinase (PI3K)/Akt in the inhibition of LPS activated NF-kappaB pathway by UFH in human pulmonary microvascular endothelial cells (HPMECs). Pretreatment with UFH (0.1-1U/ml) significantly inhibited LPS (10MUg/ml)-stimulated interleukin (IL)-6 and IL-8 production in HPMECs. LPS activated Akt and NF-kappaB, whereas UFH suppresses LPS-induced Akt phosphorylation and NF-kappaB nuclear translocation, which were required for IL-6 and IL-8 gene transcription. Inhibition studies by using wortmannin abrogated NF kappaB-mediated IL-6 and IL-8 expression, suggesting the requirement of PI3K/Akt pathway. Our data provided the first evidence that UFH might repress LPS activated PI3K/Akt pathway, leading to inhibitory effect of NF-kappaB activation with diminished IL-6 and IL-8 expression in HPMECs. PMID- 25454807 TI - Temporary elimination of IL-10 enhanced the effectiveness of cyclophosphamide and BMDC-based therapy by decrease of the suppressor activity of MDSCs and activation of antitumour immune response. AB - The antitumour activity of the dendritic cell (DC)-based cellular vaccines is greatly reduced in hostile tumour microenvironment. Therefore, there are many attempts to eliminate or neutralize both suppressor cells and cytokines. The aim of the investigation was to verify if temporary elimination of IL-10 just before injection of bone marrow-derived DCs (BMDCs) enhance the antitumour activity of applied vaccines and help to overcome the immunosuppressive tumour barrier. Mice bearing colon carcinoma MC38 were given single dose of cyclophosphamide (CY) followed by alternate injections of anti-IL-10 antibodies and BMDC-based vaccines consisted of BMDCs stimulated with MC38 tumour antigen (BMDC/TAg) or the combination of BMDC/TAg with BMDCs transduced with IL-12 genes (BMDC/IL-12). The high tumour growth inhibition was observed in mice treated with CY+anti-IL 10+BMDC/TAg as well as CY+/-anti-IL-10+BMDC/TAg+BMDC/IL-12. However, the mechanisms of action of particular treatment schemes were diversified. Generally, it was observed that application of anti-IL-10 Abs reduced suppressor activity of myeloid-derived suppressor cells (MDSCs). However, anti-IL-10 Abs in combination with diversely composed BMDC-based vaccines induced different components of an antitumour response. The high cytotoxic activity of spleen-derived NK cells and increased influx of these cells into tumours of mice treated with CY+anti-IL 10+BMDC/TAg indicate that mice from the group developed strong NK-dependent response. Whereas, application of anti-IL-10 Abs just before injection of BMDC/TAg+BMDC/IL-12 did not enhanced NK cell activity. Furthermore, it significantly impaired effectiveness of therapy composed of CY+BMDC/TAg+BMDC/IL 12 vaccine in induction of Th1 type immune response. Taken together, our results indicate that temporary elimination of IL-10 is an important and effective way to decrease the immune suppression associated with MDSCs activity and represents a useful strategy for successful enhancement of the antitumour activity of BMDC/TAg based vaccines. PMID- 25454808 TI - Benzanthrone induced immunotoxicity via oxidative stress and inflammatory mediators in Balb/c mice. AB - Benzanthrone (BA) is an important dye intermediate which is used in the manufacturing of several polycyclic vat and disperse dyes in textile industries. Several studies have indicated that the general population is also exposed to BA owing to its release from furnace effluents and automobile exhausts in the environment. In several clinical studies, it has been shown that workers exposed to BA developed itching, burning sensation, erythema and hyperpigmentation of the skin, which could be an outcome of the dysregulated immune response. In this study, we have used female Balb/c mice as a model to study the immuno inflammatory changes after systemic administration of BA (7.5mg/kgb.w. and 15mg/kgb.w.) for one week. BA exposed animals exhibited the signs of intense systemic inflammation as evident by enhanced DTH response, MPO activity, hyperplastic and dysplastic histopathological organization of spleen and lung tissue. Splenic evaluation revealed enhanced oxidative stress, upregulation of prominent inflammatory markers like iNOS and COX-2 and DNA damage. In coherence with the observed immuno-inflammatory alterations, the levels of several inflammatory and regulatory cytokines (IL-17, TNF-alpha, IFN-gamma, IL-1, IL-10, IL-4) were significantly enhanced in serum as well as the spleen. In addition, BA administration significantly induced the activation of ERK1/2, p38, JNK MAPKs and their downstream transcription factors AP-1 (c-fos, c-jun), NF-kappaB and Nrf2 which comprise important mechanistic pathways involved in inflammatory manifestations. These results suggest the immunotoxic nature of the BA and have implications for the risk assessment and management of occupational workers, and even common masses considering its presence as an environmental contaminant. PMID- 25454809 TI - TLR9 is expressed in human papillomavirus-positive cervical cells and is overexpressed in persistent infections. AB - Control of human papillomavirus (HPV) infection involves the activation of Toll like receptors (TLRs), key components of the mucosal antiviral response. Available studies on TLR expression in HPV-positive cervical cells are limited and reported conflicting results. This study quantified TLR 2, 3, 4, 7 and 9 transcripts in low-risk (LR) and high-risk (HR) HPV-positive and HPV-negative cervical samples from 154 women attending a gynaecological clinic. Expression levels of TLR 2, 3, 4 and 7 did not differ among samples, whereas TLR9 levels were quite significantly higher in LR and marginally significant in HR HPV positive samples, with respect to the HPV-negative samples. Interestingly, in a subgroup of women with documented previous HPV-infection, TLR9 levels were extremely higher in patients persistently positive to the same HPV genotype for more than 1 year, with respect to women who cleared HPV infection and to those re infected with a different genotype. These findings implicate TLR9 in the response to LR and HR HPVs, including HPV 16 known to interfere with TLR9 transcription in cell lines. Elevated TLR9 levels without HPV clearance in persistently infected women could drive inflammation thereby contributing to cervical cancer risk. PMID- 25454810 TI - Experimental Chagas disease in Balb/c mice previously vaccinated with T. rangeli. II. The innate immune response shows immunological memory: reality or fiction? AB - Trypanosoma cruzi is a real challenge to the host's immune system, because it requires strong humoral and cellular immune response to remove circulating trypomastigote forms, and to prevent the replication of amastigote forms in tissues, involving many regulator and effector components. This protozoan is responsible for Chagas disease, a major public health problem in Latinamerica. We have developed a model of vaccination with Trypanosoma rangeli, a parasite closely related to T. cruzi, but nonpathogenic to humans, which reduces the infectiousness in three different species of animals, mice, dogs and guinea pigs, against challenge with T. cruzi. In a previous work, we demonstrated that mice vaccinated with T. rangeli showed important soluble mediators that stimulate phagocytic activity versus only infected groups. The aim of this work was to study the innate immune response in mice vaccinated or not with T. rangeli. Different population cells and some soluble mediators (cytokines) in peritoneal fluid and plasma in mice vaccinated-infected and only infected with T. cruzi were studied. In the first hours of challenge vaccinated mice showed an increase of macrophages, NK, granulocytes, and regulation of IL6, IFNgamma, TNFalpha and IL10, with an increase of IL12, with respect to only infected mice. Furthermore an increase was observed of Li T, Li B responsible for adaptative response. Finally the findings showed that the innate immune response plays an important role in vaccinated mice for the early elimination of the parasites, complementary with the adaptative immune response, suggesting that vaccination with T. rangeli modulates the innate response, which develops some kind of immunological memory, recognizing shared antigens with T. cruzi. These results could contribute to the knowledge of new mechanisms which would have an important role in the immune response to Chagas disease. PMID- 25454811 TI - Isofraxidin protects mice from LPS challenge by inhibiting pro-inflammatory cytokines and alleviating histopathological changes. AB - Isofraxidin (IF), the major bioactive component of Sarcandra glabra, has been reported to be an effective anti-inflammatory compound. In a previous study, we showed that IF acts via the MAPK pathway to produce anti-inflammatory effects, both in vivo and in vitro. However, the effect and mechanism of action of IF on inflammatory cytokines and NF-kappaB activation in vivo has not been investigated. We therefore aimed to evaluate how IF regulates the production of inflammatory cytokines in vivo by intraperitoneal injection of IF (1, 5 or 15mg/kg) prior to treatment with LPS (1mg/kg, i.p.). Macroscopic, biochemical and histopathological parameters were measured. Treatment with IF prior to LPS challenge decreased mortality rate, body weight loss, organ coefficient and histopathological changes. IF also suppressed the protein expression of NF kappaB, levels of NO and IL-6 in serum and production of TNF-alpha in liver. Our results show that pretreatment with IF increases the survival rate following LPS stimulation in mice. The effect involves regulation of NF-kappaB signal which, in turn, regulates production of inflammatory cytokine TNF-alpha, suggesting that IF may have a therapeutic effect against LPS-induced inflammatory disease. PMID- 25454812 TI - Anti-inflammatory activities of Physalis alkekengi var. franchetii extract through the inhibition of MMP-9 and AP-1 activation. AB - Physalis alkekengi has been traditionally used for the treatment of coughs, middle ear infections, and sore throats in Korea, Europe, and China. It exhibits a variety of pharmacological activities such as anti-inflammatory, anti-oxidant, and anti-cancer effects. The anti-inflammatory effects of the P. alkekengi methanol extract (PA) and its molecular mechanisms have not yet been fully investigated. In the present study, the chromatogram of PA was established by UPLC analysis. The anti-inflammatory effects of PA were also investigated using murine microphage cell lines, RAW 264.7 cells, and a murine model of OVA induced asthma. In LPS-stimulated RAW264.7 cells, PA reduced the MMP-9 expression with decreases in the production of nitric oxide, inteleukin-6, and tumor necrosis factor-alpha. Furthermore, PA suppressed the phosphorylation of MAPKs, which resulted in the inhibition of AP-1 activation. These effects of PA were consistent with the results of the in vivo experiment. PA-treated mice significantly inhibited inflammatory cell counts and cytokine production in bronchoalveolar lavage fluids and airway-hyperresponsiveness in OVA-induced asthmatic mice. PA treated mice also showed a marked inhibition of inducible nitric oxide synthase and MMP-9 expression. In conclusion, our results suggest that PA may be a valuable therapeutic material in treating various inflammatory diseases, including allergic asthma. PMID- 25454813 TI - Vibrations of bioionic liquids by ab initio molecular dynamics and vibrational spectroscopy. AB - Density functional theory and vibrational spectroscopy are used to investigate a class of bioionic liquids consisting of a choline cation and carboxylate anions. Through quantum mechanical studies of motionless ion pairs and molecular dynamics of small portions of the liquid, we have characterized important structural features of the ionic liquid. Hydrogen bonding produces stable ion pairs in the liquid and induces vibrational features of the carboxylate groups comparable with experimental results. Infrared and Raman spectra of liquids have been measured, and main bands have been assigned on the basis of theoretical spectra. PMID- 25454816 TI - Islet transplantation for Type 1 diabetes: where are we now? AB - Pancreatic islet transplantation is a minimally invasive procedure that can restore normoglycemia and insulin independence in Type 1 diabetics without the surgical complications associated with vascularized pancreas transplantation. The advances made in this field over the past decade have dramatically improved patient outcomes, and the procedure is now transitioning from an experimental treatment to a clinical reality. Nonetheless, a number of important issues continue to hamper the success of islet transplantation and must be addressed before there is widespread clinical acceptance. These include the relative inefficiency of the islet isolation process, the progressive loss of islet function over time and the need for multiple donors to achieve insulin independence. Here, we discuss the current status of islet transplantation and examine its future as a treatment for Type 1 diabetes. PMID- 25454817 TI - Xeroderma pigmentosa: three new cases with an in depth review of the genetic and clinical characteristics of the disease. AB - Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by hypersensitivity of the skin and eyes to UV-radiation as a result of a defect in one of eight genes. Seven genes (XPA-XPG) have a defect in Nucletoide Excision Repair (NER), while the eighth gene XPV has a defect in polymerase eta, which is responsible for replication of UV-damaged DNA to produce corrected daughter strands. We present the varied clinical courses of three African-American female patients with XP. Additionally, we present a review of the literature that focuses on the various clinical manifestations as well as the genetic and molecular mechanisms underlying this disease. PMID- 25454818 TI - An evaluation and comparison of the efficacy of nanocrystalline calcium sulfate bone grafts (NanoGen) and medical-grade calcium sulfate bone grafts (DentoGen) in human extraction sockets. AB - BACKGROUND: Grafting a fresh extraction socket is essential for successful regeneration of bone and maximizing volume preservation. Various synthetic grafts have been used to simulate bone formation. The purpose of the present study was to evaluate clinical, histomorphometric, and radiographic healing at 1-month, 3 month, and 4-month time points after tooth extraction with placement of calcium sulfate hemihydrate putty bone grafts NanoGen and DentoGen to determine their efficacy in ridge preservation following tooth extraction. METHOD: Sixty subjects who were in need of extraction were recruited. The subjects were randomly assigned their group based on computer software for both the test groups (NanoGen and DentoGen). DentoGen is a medical-grade calcium sulfate hemihydrate with particle of 30 um, and NanoGen is a nanocrystalline version of DentoGen with particle size 400 um to 800 um. Data were recorded at 1, 3, and 4 months after extraction socket grafting. Bone biopsies were taken at 4 months for histomorphometric analysis. RESULTS: The mean percentage of bone formed by NanoGen was 51.19 +/- 9.53% and by DentoGen 50.67 +/- 16.16% after 4 months. No statistically significant difference was noted in the mean bone formation by NanoGen and DentoGen at various time intervals; no bone graft remnants of DentoGen were found at 4 months. The mean percentage of bone graft remnants left after 4 months for NanoGen was 6.83 +/- 16% in the maxilla and 7.38 +/- 21% in the mandible. The mean percentage of soft tissue formed was significantly higher with DentoGen in mandibular socket sites. On radiographic evaluation the mean percentage of socket fill with DenoGen was found to be 23.1 +/- 11.65%, 50 +/- 9.6%, and 76.7 +/- 11% and with NanoGen was 29.2 +/- 12.8%, 52.8 +/- 15.6%, and 76.47 +/- 12.43% at 1 month, 3 months, and 4 months postoperative intervals, respectively. CONCLUSION: Both the materials investigated in the study showed excellent bone forming capacity, but the nanocrystalline version (NanoGen) of calcium sulfate was found to have clinical and biologic advantages over DentoGen. PMID- 25454819 TI - Thermal effects on pulp due to laser and handpiece usage. AB - OBJECTIVE: The study was designed to compare changes in pulpal temperature during ablation of dental hard tissue while using two established erbium dental laser systems, a new CO2 laser system, and a conventional high-speed handpiece. METHODS: Eighty non-carious human extracted molars were separated into four sample groups of 20 teeth each. Three laser systems were used, respectively, to ablate the occlusal surface of the teeth in three of the groups for 60 seconds each. The high-speed handpiece was used to drill the occlusal surface of the fourth group for 60 seconds. Pulpal temperatures were measured using thermocouples inserted into each tooth's pulpal chamber prior to ablation. RESULTS: None of the average temperature increases approached the threshold of 5.5 degrees C at which pulpal damage begins. On average, the pulpal temperature of teeth ablated with the Waterlase MD system increased the most (3.56 degrees C). The traditional handpiece caused the lowest average temperature increase (1.57 degrees C), followed by the LightWalker DT system (3.20 degrees C) and the Solea CO2 system (3.30 degrees C). PMID- 25454822 TI - Ultrasonically assisted extraction (UAE) of natural products some guidelines for good practice and reporting. AB - Over the years I have reviewed a large number of papers concerning the ultrasonically assisted extraction (UAE) of natural products and many of them suffer from common problems that make them unsuitable for publication. In this article I will identify these problems in the hope that new manuscripts can avoid such pitfalls. PMID- 25454820 TI - Deletion at 6q24.2-26 predicts longer survival of high-grade serous epithelial ovarian cancer patients. AB - Standard treatments for advanced high-grade serous ovarian carcinomas (HGSOCs) show significant side-effects and provide only short-term survival benefits due to disease recurrence. Thus, identification of novel prognostic and predictive biomarkers is urgently needed. We have used 42 paraffin-embedded HGSOCs, to evaluate the utility of DNA copy number alterations, as potential predictors of clinical outcome. Copy number-based unsupervised clustering stratified HGSOCs into two clusters of different immunohistopathological features and survival outcome (HR = 0.15, 95%CI = 0.03-0.81; Padj = 0.03). We found that loss at 6q24.2 26 was significantly associated with the cluster of longer survival independently from other confounding factors (HR = 0.06, 95%CI = 0.01-0.43, Padj = 0.005). The prognostic value of this deletion was validated in two independent series, one consisting of 36 HGSOCs analyzed by fluorescent in situ hybridization (P = 0.04) and another comprised of 411 HGSOCs from the Cancer Genome Atlas study (TCGA) (HR = 0.67, 95%CI = 0.48-0.93, Padj = 0.019). In addition, we confirmed the association of low expression of the genes from the region with longer survival in 799 HGSOCs (HR = 0.74, 95%CI = 0.61-0.90, log-rank P = 0.002) and 675 high FIGO stage HGSOCs (HR = 0.76, 95%CI = 0.61-0.96, log-rank P = 0.02) available from the online tool KM-plotter. Finally, by integrating copy number, RNAseq and survival data of 296 HGSOCs from TCGA we propose a few candidate genes that can potentially explain the association. Altogether our findings indicate that the 6q24.2-26 deletion is an independent marker of favorable outcome in HGSOCs with potential clinical value as it can be analyzed by FISH on tumor sections and guide the selection of patients towards more conservative therapeutic strategies in order to reduce side-effects and improve quality of life. PMID- 25454823 TI - Effect of ultrasound pre-treatment on the drying kinetics of brown seaweed Ascophyllum nodosum. AB - The effect of ultrasound pre-treatment on the drying kinetics of brown seaweed Ascophyllum nodosum under hot-air convective drying was investigated. Pretreatments were carried out at ultrasound intensity levels ranging from 7.00 to 75.78 Wcm(-2) for 10 min using an ultrasonic probe system. It was observed that ultrasound pre-treatments reduced the drying time required. The shortest drying times were obtained from samples pre-treated at 75.78 Wcm(-2). The fit quality of 6 thin-layer drying models was also evaluated using the determination of coefficient (R(2)), root means square error (RMSE), AIC (Akaike information criterion) and BIC (Bayesian information criterion). Drying kinetics were modelled using the Newton, Henderson and Pabis, Page, Wang and Singh, Midilli et al. and Weibull models. The Newton, Wang and Singh, and Midilli et al. models showed the best fit to the experimental drying data. Color of ultrasound pretreated dried seaweed samples were lighter compared to control samples. It was concluded that ultrasound pretreatment can be effectively used to reduce the energy cost and drying time for drying of A. nodosum. PMID- 25454821 TI - PHF21B as a candidate tumor suppressor gene in head and neck squamous cell carcinomas. AB - A significant association between DNA losses on 22q13.31 and head and neck squamous cell carcinomas (HNSCC) was previously reported by our group. Our data indicated that PHF21B gene, mapped on 22q13.31 and encoding a protein with function of chromatin-mediated transcriptional regulation, might be a putative tumor suppressor gene. To test this hypothesis, gene copy number was assessed in 75 HNSCC and 49 matched peripheral blood samples. PHF21B losses were detected in 43 tumors and were significantly associated with patients with familial history of cancer (P < 0.0001); i.e., 36/43 cases showed a positive family history of cancer and 22/36 had first-degree relatives with cancer (P = 0.049). In attempt to investigate other mechanisms for PHF21B loss of function, DNA sequencing was performed and no mutations were detected. We next evaluated the gene expression levels after inhibition of DNA methylation in nine HNSCC and breast carcinoma cell lines. Additionally, PHF21B expression levels were evaluated in colon cancer HCT116 cells as well as in its counterpart DKO (double knockout of DNMT1 and DNMT3B). The higher expression levels of PHF21B gene detected in DKO cells were inversely correlated with the DNA methylation. Further, DNA methylation in the specific promoter-associated CpG Island was investigated. Interestingly, gene hypermethylation was detected in 13/37 tumors: 5/13 HNSCC cases had family history of cancer in first-degree relatives and 8/13 showed both, DNA methylation and PHF21B losses in the tumor sample. One patient had PHF21B loss in the peripheral blood cells and PHF21B methylation in the tumor sample. Additionally, overexpression of PHF21B in cell lines drastically reduces clonogenic and migratory abilities. These data suggest that PHF21B is a novel tumor suppressor gene that can be inactivated by genetic and epigenetic mechanisms in the human cancer. PMID- 25454824 TI - Modeling and optimization of ultrasound-assisted extraction of polyphenolic compounds from Aronia melanocarpa by-products from filter-tea factory. AB - Aronia melanocarpa by-product from filter-tea factory was used for the preparation of extracts with high content of bioactive compounds. Extraction process was accelerated using sonication. Three level, three variable face centered cubic experimental design (FCD) with response surface methodology (RSM) was used for optimization of extraction in terms of maximized yields for total phenolics (TP), flavonoids (TF), anthocyanins (MA) and proanthocyanidins (TPA) contents. Ultrasonic power (X1: 72-216 W), temperature (X2: 30-70 degrees C) and extraction time (X3: 30-90 min) were investigated as independent variables. Experimental results were fitted to a second-order polynomial model where multiple regression analysis and analysis of variance were used to determine fitness of the model and optimal conditions for investigated responses. Three dimensional surface plots were generated from the mathematical models. The optimal conditions for ultrasound-assisted extraction of TP, TF, MA and TPA were: X1=206.64 W, X2=70 degrees C, X3=80.1 min; X1=210.24 W, X2=70 degrees C, X3=75 min; X1=216 W, X2=70 degrees C, X3=45.6 min and X1=199.44 W, X2=70 degrees C, X3=89.7 min, respectively. Generated model predicted values of the TP, TF, MA and TPA to be 15.41 mg GAE/ml, 9.86 mg CE/ml, 2.26 mg C3G/ml and 20.67 mg CE/ml, respectively. Experimental validation was performed and close agreement between experimental and predicted values was found (within 95% confidence interval). PMID- 25454825 TI - Prognostic factors after surgical resection of N1 non-small cell lung cancer. AB - OBJECTIVES: Non-small cell lung carcinoma (NSCLC) with N1 involvement is associated with 5-year survival rates ranging from 7% to 55%. Numerous factors have been independently reported to explain this heterogeneous prognosis, but their relative weight on long-term survival is unknown. METHODS: Patients who underwent surgical resection for NSCLC in two French centers from 1993 to 2010 were prospectively recorded and retrospectively reviewed. The overall survival (OS) of patients undergoing first-line surgery for pN1 disease was analyzed according to the type of extension, number of metastatic LN, number and anatomic location of metastatic stations. RESULTS: The study group included 450 patients (male 80.2%, mean age 63.3 +/- 9.9 years, 5-year overall survival 46%). The number of metastatic station was 1 in 340 (75.6%, single-station disease) and >=2 in 110 patients (24.4%, multi-station disease). The number of metastatic stations was correlated with the number of metastatic LN (p < .001), and associated with adverse OS (p = .0014). The presence of intralobar metastatic LN (station 12-13 14) was associated with a mechanism of direct extension (p < .001), but did not impact OS (p = .71). The location of metastatic stations was of prognostic significance only in case of multi-station disease, with hilar (station 10) involvement being associated with adverse OS (p = .005). The 110 patients with multi-station pN1 disease and the 134 patients operated on for single-station pN0N2 (skip-N2) disease during the study period yield comparable outcome (p = .52). CONCLUSIONS: In patients with resected pN1 NSCLC, the number of metastatic stations and their location in case of multi-station disease have a prognostic value. PMID- 25454826 TI - Contemporary 90-day mortality rates after radical cystectomy in the elderly. AB - INTRODUCTION: Existing radical cystectomy (RC) perioperative mortality estimates may underestimate the contemporary rates due to more advanced age, more baseline comorbidities and potentially broader inclusion criteria for RC, relative to past criteria. METHODS: Within the most recent Surveillance, Epidemiology, and End Results (SEER)-Medicare database we identified clinically non-metastatic, muscle invasive (T2-T4a) urothelial carcinoma of the urinary bladder (UCUB) patients, who underwent RC between 1991 and 2009. Mortality at 30- and 90-day after RC was quantified. Multivariable logistic regression analyses tested predictors of 90 day mortality. RESULTS: Within 5207 assessable RC patients 30- and 90-day mortality rates were 5.2 and 10.6%, respectively. According to age 65-69, 70-79 and >= 80 years, 90-day mortality rates were 6.4, 10.1 and 14.8% (p < 0.001). Additionally, 90-day mortality rates increased with increasing Charlson Comorbidity Index (CCI, 0, 1, 2 and >= 3): 6.3, 10.3, 12.6 and 15.9% (p < 0.001). 90-day mortality rate in unmarried patients was 13.0 vs. 9.3% in married individuals (p < 0.001). In multivariable logistic regression analyses, advanced age, higher CCI, low socioeconomic status, unmarried status and non organ confined stage were independent predictors of 90-day mortality (all p < 0.05). CONCLUSIONS: The contemporary SEER-Medicare derived 90-day mortality rates are substantially higher than previously reported estimates from centers of excellence, and even exceed previous SEER reports. More advanced age, higher CCI score, and other patient characteristics that distinguish the current population from others account for these differences. PMID- 25454827 TI - Correlation between radiological assessment and histopathological diagnosis in retroperitoneal tumors: analysis of 291 consecutive patients at a tertiary reference sarcoma center. AB - OBJECTIVES: Aim of study was to assess the correlation between computed tomography scan (CT) findings and histopathology. MATERIAL AND METHODS: Data were collected on consecutive patients with suspected retroperitoneal sarcoma (RPS) referred to a tertiary sarcoma center. Patients underwent contrast enhanced multi detector CT scans. Radiological features of lesions were classified according to the presence of a fatty (Group A) mass, or non-fatty (Group B) mass, both subdivided according to homogeneity and intralesional high-contrasted appearance. Radiological classification was compared with histopathological diagnosis. Sensitivity, specificity, positive/negative predictive value (PPV, NPV) were analyzed. RESULTS: Of 291 patients, 103/291 (35.4%) masses were classified in Group A and 188/291 (64.6%) in Group B. Diagnosis of mesenchymal tumor was obtained in 231/291 cases (79%) and non-mesenchymal tumor in 60/291 (21%). Sensitivity and specificity of Group A for liposarcoma were 76.7% and 92.0%; PPV and NPV were 86.4% and 85.6%. Sensitivity of Group B for a mesenchymal tumor was 55.4% and specificity was 0%; PPV and NPV were 68.1% and 0%. CONCLUSIONS: None of radiological criteria were sufficient to anticipate a specific diagnosis, with the only exception of well differentiated liposarcoma and angiomyolipoma. In a series of suspected RPS, 21% of the lesions were finally non-mesenchymal tumors. PMID- 25454828 TI - Sentinel node biopsy for lymph nodal staging of uterine cervix cancer: a systematic review and meta-analysis of the pertinent literature. AB - BACKGROUND: We reviewed the available literature on the accuracy of sentinel node mapping in the lymph nodal staging of uterine cervical cancers. METHODS: MEDLINE and Scopus were searched by using "sentinel AND (cervix OR cervical)" as key words. Studies evaluating the accuracy of sentinel node mapping in the lymph nodal staging of uterine cervical cancers were included if enough data could be extracted for calculation of detection rate and/or sensitivity. RESULTS: Sixty seven studies were included in the systematic review. Pooled detection rate was 89.2% [95% CI: 86.3-91.6]. Pooled sensitivity was 90% [95% CI: 88-92]. Sentinel node detection rate and sensitivity were related to mapping method (blue dye, radiotracer, or both) and history of pre-operative neoadjuvant chemotherapy. Sensitivity was higher in patients with bilaterally detected pelvic sentinel nodes compared to those with unilateral sentinel nodes. Lymphatic mapping could identify sentinel nodes outside the routine lymphadenectomy limits. CONCLUSION: Sentinel node mapping is an accurate method for the assessment of lymph nodal involvement in uterine cervical cancers. Selection of a population with small tumor size and lower stage will ensure the lowest false negative rate. Lymphatic mapping can also detect sentinel nodes outside of routine lymphadenectomy areas providing additional histological information which can improve the staging. Further studies are needed to explore the impact of sentinel node mapping in fertility sparing surgery and in patients with history of neoadjuvant chemotherapy. PMID- 25454829 TI - Present and future of radiotherapy before and after surgery for sarcoma patients. PMID- 25454830 TI - Clinical significance of skip lymph node metastasis in gastric cancer patients. AB - PURPOSE: Given the recent increase in the incidence of early gastric cancer, there is greater interest in identifying a minimally invasive therapy. The purpose of this study was to analyze the patterns of lymph node metastasis in patients with gastric cancer and to elucidate the clinical significance of skip metastasis. METHODS: We retrospectively analyzed patterns of lymph node metastasis (LNM) and clinicopathologic factors related to skip metastasis. RESULTS: Among 2963 patients with gastric cancer, 997 patients (33.6%) were detected as having LNM, and 27 patients (2.7%) with skip metastasis were detected among 997 patients with LNM. Skip metastasis were detected more frequently in the elderly. Compared with the N1 group, the skip metastasis group showed lower frequency of vascular invasion, and compared with the stepwise N2 group, the skip metastasis group showed smaller tumor size and a significantly higher incidence of negative lymphatic, vascular, and perineural invasion. CONCLUSIONS: Currently there is no way to predict N2 station LNM including skip metastasis, D2 LN dissection for gastric cancer is thought to be the appropriate treatment, even during early stage disease. Minimally invasive therapy should be performed cautiously in consideration of possible skip metastasis. PMID- 25454834 TI - The challenges of trigger ablation for ventricular fibrillation. PMID- 25454831 TI - Differences in pre-operative treatment for rectal cancer between Norway, Sweden, Denmark, Belgium and the Netherlands. AB - Several studies have shown remarkable differences in colorectal cancer survival across Europe. Most of these studies lacked information about stage and treatment. In this study we compared short-term survival as well as differences in tumour stage and treatment strategies between five European countries: Norway, Sweden, Denmark, Belgium, and the Netherlands. For this retrospective cohort study all patients aged 18 years or older and operated on adenocarcinoma of the rectum without distant metastases and diagnosed in 2008 and 2009 were selected in national audit registries from Norway, Sweden, Denmark, Belgium, and the Netherlands. Differences in pre-operative treatment between the countries were compared using univariable and multivariable logistic regression. One year relative survival and one year relative excess risk of death (RER) were compared between the five countries. Large variation in the use of preoperative radiotherapy and chemoradiation was found between the countries. Even though, there was little variation in relative survival between the countries, except Sweden, which had a significant better one year RER of death among the elderly patients after adjustment. The differences in survival are expected to be caused by differences in peri-operative care, selection of patients, and especially management of elderly patients. The effects of preoperative treatment are expected to be seen on long term follow-up. PMID- 25454835 TI - Autoimmune flares. The hows, whens, and whys of killing. PMID- 25454836 TI - Editor's perspectives--November 2014. PMID- 25454837 TI - Formation of wrinkled silica mesostructures based on the phase behavior of pseudoternary systems. AB - Water-surfactant-oil ternary systems have various phase behaviors and substructures that depend on their chemical composition and component ratio. These substructures can be used as templates for the synthesis of a variety of nanostructures. In this study, the phase behavior of a pseudoternary system consisting of aqueous urea-cetyltrimethylammonium bromide (and n-butanol) cyclohexane is analyzed. Additionally, wrinkled silica mesostructures (WSMs) with various morphologies are synthesized using the microemulsion layer in the multiphase areas of the pseudoternary system with restricted degrees of freedom as a template. The particle size of the wrinkled silica nanoparticles (WSNs) and the connective morphology of the WSMs can be controlled via the catalytic conditions. In addition, some materials that are difficult to produce, such as radially branched WSNs and shuttlecock-shaped Janus nanoparticles, are prepared using a gradual seed-growth mechanism of silica in the emulsion system. PMID- 25454841 TI - Strong, reversible underwater adhesion via gecko-inspired hydrophobic fibers. AB - Strong, reversible underwater adhesion using gecko-inspired surfaces is achievable through the use of a hydrophobic structural material and does not require surface modification or suction cup effects for this adhesion to be effective. Increased surface energy can aid in dry adhesion in an air environment but strongly degrades wet adhesion via reduction of interfacial energy underwater. A direct comparison of structurally identical but chemically different mushroom shaped fibers shows that strong, reversible adhesion, even in a fully wetted, stable state, is feasible underwater if the structural material of the fibers is hydrophobic and the mating surface is not strongly hydrophilic. The exact adhesion strength will be a function of the underwater interfacial energy between surfaces and the specific failure modes of individual fibers. This underwater adhesion has been calculated to be potentially greater than the dry adhesion for specific combinations of hydrophobic surfaces. PMID- 25454842 TI - Design and synthesis of stable cobalt-based weak ferromagnetic framework with large spin canting angle. AB - It still remains a great challenge to design and construct framework-structured weak ferromagnets with large canting angle which is an effective approach for high performance magnets. According to the strategy of antisymmetric interaction causing spin canting, we report the design of four cobalt compounds, which were tested by X-ray single crystal diffraction, TGA, PXRD, and magnetic measurement. Single-crystal structure analysis reveals that compound 1 has a 2D structure, complex 2 has a 3,4-connected 3D framework, and complex 3 exhibits a 3D net structure with rare 3,5-connected 2-nodal beta-SnF2 topology and the solvent MeOH trapped in the 3D channels as guests. The magnetic property of 3 is spin canting just as designed, with TN about 4.0 K and large canting angle of 14.8 degrees . Highly stable compound 3 sustains its framework in air for more than 12 months, in which the guest MeOH molecules can be replaced by water to form complex 4. PMID- 25454843 TI - The influence of psychological stress on arginine vasopressin concentration in the human plasma and cerebrospinal fluid. AB - Psychological stress is strain affecting the intangible self, caused by problems in adaptation, perception, and emotions. Previous studies have demonstrated that arginine vasopressin (AVP) plays an important role in psychological stress. The goal of present study was to investigate the interaction between AVP release and cardiovascular functions by measuring AVP concentration and recording blood pressure or heart rate during psychological stress in human. The results showed that (1) psychological stress not only increased the systolic blood pressure, diastolic blood pressure and heart rate, but also elevated the cortisol and AVP concentration in both plasma and CSF in a stress level-dependent manner; (2) there was a positive relationship between plasma AVP concentration and systolic blood pressure, diastolic blood pressure, heart rate or plasma cortisol concentration; (3) there was also a positive relationship between AVP concentrations in plasma and CSF AVP. The data suggested that plasma AVP, which might come from the central nervous system, might influence the cardiovascular functions during psychological stress in human. PMID- 25454844 TI - Sleep apnea and periodic leg movements in the first year after spinal cord injury. AB - BACKGROUND: Sleep disturbances are frequently reported by patients with spinal cord injury (SCI). Studies have shown an increased incidence of sleep-disordered breathing (SDB) and periodic leg movements during sleep (PLMS) in people with stable long-term SCI. METHODS: This was a prospective observational study in order to evaluate the features and possible predisposing factors of SDB and PLMS in a heterogenic population of consecutive SCI patients admitted at the Spinal Unit of the Niguarda Hospital within the first year after injury. Each patient underwent a clinical assessment, full polysomnography, and arterial blood gas analysis before and immediately after sleep. Multiple logistic regressions were applied in order to evaluate factors associated with SDB and PLMS. RESULTS: Thirty-five (15 tetraplegic and 20 paraplegic) patients were enrolled. Nine patients (25.7%) had an obstructive SDB and 10 (28.6%) had PLMS. The frequency of SDB was higher in tetraplegic with respect to paraplegic patients (Wald statistic: 7.71; P = 0.0055), whereas PLMs were significantly more frequent in patients with an incomplete motor lesion than in subjects with a complete motor lesion (Wald statistic: 6.14; P = 0.013). CONCLUSION: This study confirms a high frequency of SDB and PLMS in SCI patients in the first year following injury. Independently from possible sub-acute and chronic clinical variables, the level and the completeness of the spinal cord lesion are the main factors associated respectively with an early development of SDB and PLMS. PMID- 25454846 TI - Electroencephalographic slow waves prior to sleepwalking episodes. AB - OBJECTIVE: Recent studies have suggested that the onset of sleepwalking episodes may be preceded by fluctuations in slow-wave sleep electroencephalographic characteristics. However, whether or not such fluctuations are specific to sleepwalking episodes or generalized to all sleep-wake transitions in sleepwalkers remains unknown. The goal of this study was to compare spectral power for delta (1-4 Hz) and slow delta (0.5-1 Hz) as well as slow oscillation density before the onset of somnambulistic episodes versus non-behavioral awakenings recorded from the same group of sleepwalkers. A secondary aim was to describe the time course of observed changes in slow-wave activity and slow oscillations during the 3 min immediately preceding the occurrence of somnambulistic episodes. METHODS: Twelve adult sleepwalkers were investigated polysomnographically during the course of one night. RESULTS: Slow-wave activity and slow oscillation density were significantly greater prior to patients' somnambulistic episodes as compared with non-behavioral awakenings. However, there was no evidence for a gradual increase over the 3 min preceding the episodes. CONCLUSIONS: Increased slow-wave activity and slow oscillation density appear to be specific to sleepwalking episodes rather than generalized to all sleep-wake transitions in sleepwalkers. PMID- 25454847 TI - [Author's reply]. PMID- 25454845 TI - Melatonin therapy for REM sleep behavior disorder: a critical review of evidence. AB - Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia associated with dream enactment often involving violent or potentially injurious behaviors during REM sleep that is strongly associated with synucleinopathy neurodegeneration. Clonazepam has long been suggested as the first-line treatment option for RBD. However, evidence supporting melatonin therapy is expanding. Melatonin appears to be beneficial for the management of RBD with reductions in clinical behavioral outcomes and decrease in muscle tonicity during REM sleep. Melatonin also has a favorable safety and tolerability profile over clonazepam with limited potential for drug-drug interactions, an important consideration especially in elderly individuals with RBD receiving polypharmacy. Prospective clinical trials are necessary to establish the evidence basis for melatonin and clonazepam as RBD therapies. PMID- 25454848 TI - [Key messages to promote positive living with Parkinson's disease in the community]. PMID- 25454849 TI - [About the implications of medical schools in family medicine]. PMID- 25454850 TI - [Considerations for ezetimibe and renal impairment]. PMID- 25454851 TI - [Author's reply]. PMID- 25454852 TI - Recommendations for strengthening NITAG policies in developed countries. PMID- 25454853 TI - Seasonal influenza vaccine coverage among high-risk populations in Thailand, 2010 2012. AB - BACKGROUND: The Advisory Committee on Immunization Practice of Thailand prioritizes seasonal influenza vaccinations for populations who are at highest risk for serious complications (pregnant women, children 6 months-2 years, persons >=65 years, persons with chronic diseases, obese persons), and healthcare personnel and poultry cullers. The Thailand government purchases seasonal influenza vaccine for these groups. We assessed vaccination coverage among high risk groups in Thailand from 2010 to 2012. METHODS: National records on persons who received publicly purchased vaccines from 2010 to 2012 were analyzed by high risk category. Denominator data from multiple sources were compared to calculate coverage. Vaccine coverage was defined as the proportion of individuals in each category who received the vaccine. Vaccine wastage was defined as the proportion of publicly purchased vaccines that were not used. RESULTS: From 2010 to 2012, 8.18 million influenza vaccines were publicly purchased (range, 2.37-3.29 million doses/year), and vaccine purchases increased 39% over these years. Vaccine wastage was 9.5%. Approximately 5.7 million (77%) vaccine doses were administered to persons >=65 years and persons with chronic diseases, 1.4 million (19%) to healthcare personnel/poultry cullers, 82,570 (1.1%) to children 6 months-2 years, 78,885 (1.1%) to obese persons, 26,481 (0.4%) to mentally disabled persons, and 17,787 (0.2%) to pregnant women. Between 2010 and 2012, coverage increased among persons with chronic diseases (8.6% versus 14%; p<0.01) and persons >=65 years (12%, versus 20%; p<0.01); however, coverage decreased for mentally disabled persons (6.1% versus 4.9%; p<0.01), children 6 months-2 years (2.3% versus 0.9%; p<0.01), pregnant women (1.1% versus 0.9%; p<0.01), and obese persons (0.2% versus 0.1%; p<0.01). CONCLUSIONS: From 2010 to 2012, the availability of publicly purchased vaccines increased. While coverage remained low for all target groups, coverage was highest among persons >=65 years and persons with chronic diseases. Annual coverage assessments are necessary to promote higher coverage among high-risk groups in Thailand. PMID- 25454854 TI - The effect of bacille Calmette-Guerin vaccination at birth on immune response in China. AB - Bacille Calmette-Guerin (BCG) vaccine is still the most effective approach to prevent tuberculosis in childhood. In order to provide protection against severe forms of childhood tuberculosis, it is customary to give BCG vaccination at birth in China. Tuberculin skin testing after vaccination is usually used to evaluate the immunogenic activity and protective efficacy of the BCG. We report the results of a multi-site prospective cohort study to evaluate the immunological reactivity against BCG in four prefectural cities in China. A total of 59,022 newborn infants were vaccinated between January 2011 and March 2012, and follow up data on 27,517 vaccinated infants were available for this study. Of these, 679 (2.5%) had PPD readings of 0-5mm, 17,072 (62.0%) had PPD readings of 5-10 mm of induration, 8864 (32.2%) had readings of 10-15 mm, 815 (3.0%) had readings of 15 20 mm, and 87 (0.3%) had readings of >20 mm of induration. The size of PPD reaction varied significantly with the geographic location, gender, season of vaccination, and grade of hospital administering the BCG vaccine (P<0.001). 97.8% of the infants with a BCG scar of >1mm had a positive TST reaction. However, only 56.9% of infants without a BCG scar had a positive PPD reaction. Our results demonstrate that the BCG immunization among newborn infants in China induces satisfactory immune response. In addition, BCG scars provide a useful indicator of vaccination response in Chinese infants. PMID- 25454855 TI - Use of placebos in Phase 1 preventive HIV vaccine clinical trials. AB - Phase 1 preventive HIV vaccine trials are often designed as randomized, double blind studies with the inclusion of placebo recipients. Careful consideration is needed to determine when the inclusion of placebo recipients is highly advantageous and when it is optional for achieving the study objectives of assessing vaccine safety, tolerability and immunogenicity. The inclusion of placebo recipients is generally important to form a reference group that ensures fair evaluation and interpretation of subjective study endpoints, or endpoints whose levels may change due to exposures besides vaccination. In some settings, however, placebo recipients are less important because other data sources and tools are available to achieve the study objectives. PMID- 25454856 TI - Why German farmers have their animals vaccinated against Bluetongue virus serotype 8: results of a questionnaire survey. AB - In response to the Bluetongue disease epidemic in 2006-2007, Germany started in 2008 a country-wide mandatory vaccination campaign. By 2009 the number of new outbreaks had decreased so that vaccination became voluntary in 2010. We conducted a questionnaire survey in cattle and sheep farms in three German federal states, namely North-Rhine Westphalia, Rhineland Palatinate and Saxony Anhalt to estimate the vaccination uptake in 2010, the intention to vaccinate in 2011 and the main determinants of refusal or acceptance to do so. The results showed that 42.8% (40.6-45.1) of the cattle farmers and 33.8% (31.8-35.8) of the sheep farmers had their animals vaccinated in 2010, whereas 40.7% (38.5-43.0) of cattle and 37.93% (35.8-40.1) sheep farmers expressed their intention to vaccinate in 2011. The main reasons mentioned for having animals vaccinated against BTV-8 were ability to export animals, prevention of production losses, subsidized vaccination, and recommendation by the veterinarian. Motives for refusing vaccination were presumed low risk of infection, costs, absence of clinical BT symptoms, presumed negative cost-benefit ratio, and negative experience with previous vaccination events (side effects). We assume that in order to increase farmers' motivation to have their animals immunized against BTV 8, (1) the vaccination needs to be subsidized, (2) combined vaccines with several different BT serotypes or even other diseases should be available and (3) farmers need to be better informed about the safety and benefit of vaccination. PMID- 25454858 TI - Surveillance for congenital rubella in Australia since 1993: cases reported between 2004 and 2013. AB - OBJECTIVE: To describe the epidemiology of congenital rubella infections notified to the Australian Paediatric Surveillance Unit (APSU) from 2004 to 2013 and compare that with previously published APSU data for 1993-2003. METHODS: Active national surveillance for congenital rubella infection has been conducted through the APSU since 1993. Monthly reporting by child health clinicians according to pre-defined case criteria triggers requests for clinicians to provide de identified clinical, epidemiological, and laboratory information. Data were extracted for cases reported between January 2004 and December 2013 and compared with previous years. RESULTS: Five cases of confirmed congenital rubella infection were identified during the reporting period. All five infants had defects consistent with congenital rubella syndrome (CRS). Four of the infants were born in Australia during the study period, and all were born to mothers born overseas. Three of the five mothers had not had rubella vaccination, and in two vaccination status was unknown, although both were from countries without routine rubella immunization programmes. Since 1993, there have been 57 notifications of congenital rubella infection to the APSU; 40 of these infants were born between January 1993 and December 2013, of whom 34 had confirmed CRS. CONCLUSIONS: Congenital rubella infection in Australia is predominantly among children born to unimmunized immigrant mothers. Migrant women born in rubella endemic countries without routine immunization remain an important group to target for vaccination. Rubella-susceptible women, especially those in the early stages of pregnancy, should also carefully consider the risks of travelling to rubella endemic countries. PMID- 25454857 TI - The mucosal immune system for vaccine development. AB - Mucosal surfaces are continuously exposed to the external environment and therefore represent the largest lymphoid organ of the body. In the mucosal immune system, gut-associated lymphoid tissues (GALTs), including Peyer's patches and isolated lymphoid follicles, play an important role in the induction of antigen specific immune responses in the gut. GALTs have unique organogenesis characteristics and interact with the network of dendritic cells and T cells for the simultaneous induction and regulation of IgA responses and oral tolerance. In these lymphoid tissues, antigens are up taken by M cells in the epithelial layer, and antigen-specific immune responses are subsequently initiated by GALT cells. Nasopharynx- and tear-duct-associated lymphoid tissues (NALTs and TALTs) are key organized lymphoid structures in the respiratory tract and ocular cavities, respectively, and have been shown to interact with each other. Mucosal surfaces are also characterized by host-microbe interactions that affect the genesis and maturation of mucosa-associated lymphoid tissues and the induction and regulation of innate and acquired mucosal immune responses. Because most harmful pathogens enter the body through mucosal surfaces by ingestion, inhalation, or sexual contact, the mucosa is a candidate site for vaccination. Mucosal vaccination has some physiological and practical advantages, such as decreased costs and reduced risk of needle-stick injuries and transmission of bloodborne diseases, and it is painless. Recently, the application of modern bioengineering and biochemical engineering technologies, including gene transformation and manipulation systems, resulted in the development of systems to express vaccine antigens in transgenic plants and nanogels, which will usher in a new era of delivery systems for mucosal vaccine antigens. In this review, based on some of our research group's thirty seven years of progress and effort, we highlight the unique features of mucosal immune systems and the application of mucosal immunity to the development of a new generation of vaccines. PMID- 25454859 TI - Parental attitudes and decision-making regarding MMR vaccination in an anthroposophic community in Sweden--a qualitative study. AB - Measles outbreaks occur regularly throughout Europe, up to 31500 cases in the previous year, particularly where there are pockets of populations with lower vaccination coverage than the recommended >= 95%. Anthroposophic communities in Europe are one of several groups with relatively low vaccination coverage. In Sweden, outbreaks of measles and rubella were reported from an anthroposophic community. Thus the aim of this qualitative study was to explore facilitators and barriers to MMR vaccination among parents living in anthroposophic communities in Sweden. Twenty parents living in an anthroposophic community were interviewed, focusing on their views and decisions on MMR vaccination. The interviews were analyzed using qualitative content analysis. Two overarching views of health emerged, differentiating broadly parents who vaccinate vs. parents who do not vaccinate. Four themes describing parental attitudes toward measles vaccination were developed and three of these, the conformers, the pragmatists and the attentive delayers describe different approaches toward vaccinations among those who actually vaccinate. The last theme, promoters of natural immunity, represents those postponing or refusing vaccination beyond childhood. This study suggests that there is a spectrum of parental beliefs regarding MMR vaccination in this anthroposophic community. Interventions specifically targeted to the anthroposophic community and strengthening health workers capacity for a constructive dialog on vaccine's benefit and risks may contribute to higher vaccination coverage. This is believed to minimize the risk of future epidemics and contribute to the WHO European Region's goal of eliminating measles. PMID- 25454860 TI - The bovine viral diarrhea virus E2 protein formulated with a novel adjuvant induces strong, balanced immune responses and provides protection from viral challenge in cattle. AB - Bovine viral diarrhea virus (BVDV) is still one of the most serious pathogens in cattle, meriting the development of improved vaccines. Recently, we developed a new adjuvant consisting of poly[di(sodium carboxylatoethylphenoxy)]-phosphazene (PCEP), either CpG ODN or poly(I:C), and an immune defense regulator (IDR) peptide. As this adjuvant has been shown to mediate the induction of robust, balanced immune responses, it was evaluated in an E2 subunit vaccine against BVDV in lambs and calves. The BVDV type 2 E2 protein was produced at high levels in a mammalian expression system and purified. When formulated with either CpG ODN or poly(I:C), together with IDR and PCEP, the E2 protein elicited high antibody titers and production of IFN-gamma secreting cells in lambs. As the immune responses were stronger when poly(I:C) was used, the E2 protein with poly(I:C), IDR and PCEP was subsequently tested in cattle. Robust virus neutralizing antibodies as well as cell-mediated immune responses, including CD8(+) cytotoxic T cell (CTL) responses, were induced. The fact that CTL responses were demonstrated in calves vaccinated with an E2 protein subunit vaccine indicates that this adjuvant formulation promotes cross-presentation. Furthermore, upon challenge with a high dose of virulent BVDV-2, the vaccinated calves showed almost no temperature response, weight loss, leukopenia or virus replication, in contrast to the control animals, which had severe clinical disease. These data suggest that this E2 subunit formulation induces significant protection from BVDV 2 challenge, and thus is a promising BVDV vaccine candidate; in addition, the adjuvant platform has applications in bovine vaccines in general. PMID- 25454861 TI - A novel approach for the generation of Salmonella Gallinarum ghosts and evaluation of their vaccine potential using a prime-booster immunization strategy. AB - A novel, regulatory E-lysis cassette was used in this study to avoid the untimely expression of lysis gene E and to achieve stable and improved production of Salmonella Gallinarum (SG) ghosts. A prime-booster immunization strategy using these ghosts was subsequently utilized with the aim of inducing a robust immune response for the prevention of acute fowl typhoid infection. In the first animal experiment, a total of 54 chickens were equally divided into three groups (n=18): group A (non-immunized control), group B (prime-boost immunized), and group C (singly immunized). Chickens from both immunized groups demonstrated significant increases in plasma IgG, intestinal secretory IgA, and antigen-specific lymphocyte proliferative responses. After virulent SG challenge, group B chickens immunized with the prime-boost regimen showed optimized protection. In the second animal experiment, total 20 chickens were equally divided into two groups (n=10): group A (non-immunized control), group B (prime-boost immunized) and the immunogenicity of the ghosts was further evaluated after a booster dose of the immunization. In the second animal experiment, the population of CD3+CD4+ positive T cells in the immunized chickens was significantly higher after booster immunization. In addition, increased gene expression levels of Th1 cytokines, IFN gamma, and IL-2 were observed in SG-specific antigen stimulated peripheral blood mononuclear cells of prime-boost immunized chickens compared to non-immunized chickens. In summary, the current study describes a novel approach for stable production of a safety-enhanced SG ghost preparation, and demonstrates that utilization of a prime-boost immunization strategy has an advantage over single immunization because it induces a robust immune response for optimum protection against fowl typhoid. PMID- 25454862 TI - Enhanced immune response of BMDCs pulsed with H9N2 AIV and CpG. AB - Dendritic cells (DCs), professional antigen presenting cells, have demonstrated effective in controlling the initial of innate immune, while CpG could improve the performance of immune system. To explore the mechanism of CpG enhancing the immune response, we compared different stimulated mouse DCs with systemic approach microarrays. Analysis revealed 1840 differentially expressed genes in H9N2 stimulated group, more than 1728 altered genes in inactive H9N2 group. Investigation also proved that CpG/inactive H9N2 co-stimulation changed 2140 genes, more than that in H9N2 group, strongly demonstrated that CpG improved the performance of inactive H9N2 vaccination. Pathways analysis founded that DCs response rapid to shift in their maturation state, which involved Toll-like receptor (TLR) pathway significantly. Microarrays results were also verified by qRT-PCR with 14 elected representative genes. Further analysis proved that co stimulatory molecules (CD40, CD80, CD86 and MHC-II), regulatory protein (IRF-7 and TRAF-6) and pro-inflammatory cytokines (IL-1, IL-6 and IL-12) were all changed and involved in DCs maturation. At last we demonstrated TLR signalling pathway in chicken bone marrow-derived dendritic cells (chBM-DCs) stimulated with CpG. The distinct transcriptional profiles of DCs pulsed with various stimuli expanded our understanding of how DCs respond and recognize influenza. PMID- 25454863 TI - Curing cervical cancer or preventing it: A case of opportunity cost in the long run? PMID- 25454864 TI - Are influenza-associated morbidity and mortality estimates for those >= 65 in statistical databases accurate, and an appropriate test of influenza vaccine effectiveness? AB - PURPOSES: To assess the accuracy of estimates using statistical databases of influenza-associated morbidity and mortality, and precisely measure influenza vaccine effectiveness. PRINCIPAL RESULTS: Laboratory testing of influenza is incomplete. Death certificates under-report influenza. Statistical database models are used as an alternative to randomised controlled trials (RCTs) to assess influenza vaccine effectiveness. Evidence of the accuracy of influenza morbidity and mortality estimates was sought from: (1) Studies comparing statistical models. For four studies Poisson and ARIMA models produced higher estimates than Serfling, and Serfling higher than GLM. Which model is more accurate is unknown. (2) Studies controlling confounders. Fourteen studies mostly controlled one confounder (one controlled comorbidities), and limited control of confounders limits accuracy. EVIDENCE FOR VACCINE EFFECTIVENESS WAS SOUGHT FROM: (1) Studies of regions with increasing vaccination rates. Of five studies two controlled for confounders and one found a positive vaccination effect. Three studies did not control confounders and two found no effect of vaccination. (2) Studies controlling multiple confounders. Of thirteen studies only two found a positive vaccine effect and no mortality differences between vaccinees and non vaccinees in non-influenza seasons, showing confounders were controlled. Key problems are insufficient testing for influenza, using influenza-like illness, heterogeneity of seasonal and pandemic influenza, population aging, and incomplete confounder control (co-morbidities, frailty, vaccination history) and failure to demonstrate control of confounders by proving no mortality differences between vaccinees and non-vaccinees in non-influenza seasons. MAJOR CONCLUSIONS: Improving model accuracy requires proof of no mortality differences in pre influenza periods between the vaccinated and non-vaccinated groups, and reduction in influenza morbidity and mortality in seasons with a good vaccine match, more virulent strains, in the younger elderly with less immune senescence, and specific outcomes (laboratory-confirmed outcomes, pneumonia deaths). Proving influenza vaccine effectiveness requires appropriately powered RCTs, testing participants with RT-PCR tests, and comprehensively monitoring morbidity and mortality. PMID- 25454865 TI - Nasal immunization of mice with AFCo1 or AFPL1 plus capsular polysaccharide Vi from Salmonella typhi induces cellular response and memory B and T cell responses. AB - The response to infection against Salmonella involves both B and T cell mediated immunity. An effective immunization can activate an adequate immune response capable to control the primary infection and protect against a secondary infection. Mucosal vaccination, by inducing local pathogen-specific immune responses, has the potential to counter mucosally transmitted pathogens at the portal of entry, thereby increasing the efficacy of vaccines. The aim of this work was to explore the efficacy of AFCo1 or AFPL1, as mucosal adjuvants to stimulate cell immunity and memory responses against Vi polysaccharide antigen of Salmonella typhi (PsVi). Mice immunized with 3 intranasal doses exhibited high levels of PsVi-specific IgG (p<0.05), IgG2a and IgG2c subclasses. Also, an amplified recall response after a booster immunization with a plain polysaccharide vaccine was induced. Avidities index were higher in mice immunized with adjuvanted formulations at different chaotropic concentrations. Furthermore, IL-12 and IFN-gamma levels in nasally vaccinated mice with both adjuvants were induced. Moreover, priming with 3 doses followed by booster immunization with VaxTyVi((r)) resulted in high levels of anti-Vi specific IgG, IgG subclasses and antibody avidity. Long lived plasma cells in bone marrow, memory B cells and long term memory T cells after booster dose were induced. The combined formulation of Vi polysaccharide with mucosal adjuvants provides an improved immunogenicity, in particular with regard to cellular responses and long lasting cells responses. PMID- 25454866 TI - Investigation of immunity in sheep following footrot infection and vaccination. AB - Ovine footrot is a major disease affecting sheep welfare and production. The anaerobic Gram-negative bacterium Dichelobacter nodosus is the essential transmitting agent. Monovalent or bivalent vaccines induce high levels of D. nodosus antibodies and are the basis of several successful footrot treatment, control and eradication programs. Due to the rapid rate of disease transmission within a flock, the presence of therapeutic vaccination non-responders has major implications for a control program. The aim of this study was to assess the immunological basis of a therapeutic vaccination non-response. Sheep (n=120) were infected with D. nodosus in an artificial pen challenge. Once disease had established, animals were vaccinated with a serogroup specific D. nodosus fimbrial vaccine. Based on the response to therapeutic vaccination, animals were allocated into one of three groups: (i) TVNR where disease persisted despite vaccination (ii) non-diseased, where disease never established and (iii) TVR, where disease was established but resolved with vaccination. Factors related to both the innate and adaptive immune pathways were assessed. These included antigen-specific serum antibodies, interferon-gamma, interleukin-10, proliferation of lymphocyte subsets and phagocytic activity of leukocytes. There was no significant difference between the three groups of sheep for any of these parameters. All three groups of sheep produced antibody in excess of a previously published minimum antibody titre required for protection. Opsonising activity in sera from the three groups of sheep was also not significantly different and phagocytic cells from sheep from all three groups were able to destroy D. nodosus intracellularly. These findings show that the measured systemic adaptive and innate immune responses were unlikely to be the cause of a therapeutic vaccination non-response. They also show that the accepted minimum protective titre may be incorrect and may need further examination. PMID- 25454867 TI - The intention to get vaccinated against influenza and actual vaccination uptake of Dutch healthcare personnel. AB - Health Authorities recommend annual vaccination of healthcare personnel (HCP) against influenza to protect vulnerable patients. Nevertheless, vaccination rates have been low among European HCP. Here we report on a longitudinal survey study to identify social cognitive predictors of the motivation to obtain influenza vaccination, and to test whether intention is a good predictor of actual vaccination behaviour. Dutch HCP (N=1370) were invited to participate in a survey (baseline). To link intention to behaviour, participants who completed the first survey (N=556) were sent a second survey after vaccinations were offered (follow up). Multinominal regression analysis showed that HCP with a positive attitude and a higher frequency of past vaccinations were more likely to have a high intention to get vaccinated. A negative attitude, high feelings of autonomy in the decision whether to get vaccinated, a preference of inaction over vaccination, a lesser sense of personal responsibility, and high self-protection motives increased the probability of no intention to get vaccinated. Social cognitive predictors were identified that explain the intention to get vaccinated against influenza of HCP, which in turn proved to be a good predictor of behaviour. Future interventions should focus on these variables to increase vaccination coverage rates. PMID- 25454868 TI - A new recombinant SsnA protein combined with aluminum hydroxide protects mouse against Streptococcus suis. AB - An experimental challenge in a mouse model was used to select the most effective adjuvant in a vaccine formulation with the surface-anchored DNA-nuclease (SsnA). We used a protocol based on clinical, histopathological, bacterial kinetics and immune response against S. suis serotype 2 in infected animals. The three adjuvants used, aluminum hydroxide (ALOH), incomplete Freund's adjuvant (FIA), oil-in-water adjuvant (OW) showed a protective effect against death by S. suis serotype 2 in this mouse model, although aluminum hydroxide revealed as the best option. Subsequently, in a second experimental assay, we showed that a recombinant SsnA protein combined with ALOH as adjuvant allowed a significant decrease of clinical and lesional findings in animals, faster reduction of the bacteria from organs and a highest humoral response against S. suis after 3 days post-infection. The results show that this combination (rSsnA+AlOH) could be a good vaccine formulation against S. suis, although further studies are necessary to evaluate their use for swine and human species. PMID- 25454869 TI - Pertussis vaccine for adults: Knowledge, attitudes, and vaccine receipt among adults with children in the household. AB - BACKGROUND: Pertussis is a highly contagious vaccine preventable disease resulting in significant infant morbidity and mortality. Despite the recommendations for pertussis vaccine (Tdap) in adults, coverage rates in this age group remain suboptimal. We sought to determine factors associated with Tdap receipt among adults with children in the household who live in central New York. METHODS: The study team surveyed Tdap immunization status of adults who accessed medical services for their children provided by Golisano Children's Hospital, Syracuse, New York. Adults who did not know their Tdap vaccine status were excluded. Each participant was asked a standard set of questions to determine factors associated with Tdap receipt. Logistic regression was used to calculate simple and adjusted odds ratios for Tdap receipt in relation to adults' demographic characteristics, knowledge of Tdap and physician recommendations. RESULTS: Eight hundred twenty four participants were included in this study; 34% had received Tdap in the past 5 years; 58% reported that their provider or child's pediatrician recommended adult Tdap vaccination. Tdap receipt was associated with knowing the symptoms of pertussis infection, female gender, younger age, and provider recommendation (p<0.05). Participants whose provider recommended Tdap vaccine were 24.6 times more likely to receive vaccine when compared to those whose providers did not recommend vaccine (95% CI: 16.3, 37.2, p<0.05). CONCLUSION: Tdap coverage rates are low among this study population, with provider recommendation most strongly associated with Tdap receipt. Future steps to improve vaccine coverage should include both increasing community awareness and determining barriers to provider recommendation. PMID- 25454870 TI - Therapeutic immunisation plus cytokine and hormone therapy improves CD4 T-cell counts, restores anti-HIV-1 responses and reduces immune activation in treated chronic HIV-1 infection. AB - BACKGROUND: This randomised, open label, phase I, immunotherapeutic study investigated the effects of interleukin (IL)-2, granulocyte-macrophage colony stimulating factor (GM-CSF), recombinant human growth hormone (rhGH), and therapeutic immunisation (a Clade B DNA vaccine) on combination antiretroviral therapy (cART)-treated HIV-1-infected individuals, with the objective to reverse residual T-cell dysfunction. METHODS: Twelve HIV-1(+) patients on suppressive cART with baseline CD4 T-cell counts >400 cells/mm(3) blood were randomised into one of three groups: (1) vaccine, IL-2, GM-CSF and rhGH (n=3); (2) vaccine alone (n=4); or (3) IL-2, GM-CSF and rhGH (n=5). Samples were collected at weeks 0, 1, 2, 4, 6, 8, 12, 16, 24 and 48. Interferon (IFN)-gamma, IL-2, IL-4 and perforin ELISpot assays performed at each time point quantified functional responses to Gag p17/p24, Nef, Rev, and Tat peptides; and detailed T-cell immunophenotyping was undertaken by flow cytometry. Proviral DNA was also measured. RESULTS: Median baseline CD4 T-cell count was 757 cells/mm(3) (interquartile range [IQR] 567-886 cells/mm(3)), median age 48 years (IQR 42-51 years), and plasma HIV-1-RNA <50 copies/ml for all subjects. Patients who received vaccine plus IL-2, GM-CSF and rhGH (group 1) showed the most marked changes. Assessing mean changes from baseline to week 48 revealed significantly elevated numbers of CD4 T cells (p=0.0083) and improved CD4/CD8 T-cell ratios (p=0.0033). This was accompanied by a significant reduction in expression of CD38 on CD4 T cells (p=0.0194), significantly increased IFN-gamma and IL-2 production in response to Gag (p=0.0122) and elevated IFN-gamma production in response to Tat (p=0.041) at week 48 compared to baseline. Subjects in all treatment groups showed significantly reduced PD-1 expression at week 48 compared to baseline, with some reductions in proviral DNA. CONCLUSIONS: Multifarious immunotherapeutic approaches in the context of fully suppressive cART further reduce immune activation, and improve both CD4 T-lymphocyte counts and HIV-1-specific T-cell responses (NCT01130376). PMID- 25454871 TI - Increasing engagement of clinicians in adult immunizations: reflections on a decade and a half of research. PMID- 25454872 TI - A novel liposomal adjuvant system, CAF01, promotes long-lived Mycobacterium tuberculosis-specific T-cell responses in human. AB - Here, we report on a first-in-man trial where the tuberculosis (TB) vaccine Ag85B ESAT-6 (H1) was adjuvanted with escalating doses of a novel liposome adjuvant CAF01. On their own, protein antigens cannot sufficiently induce immune responses in humans, and require the addition of an adjuvant system to ensure appropriate delivery and concomitant immune activation. To date no approved adjuvants are available for induction of cellular immunity, which seems essential for a number of vaccines, including vaccines against TB. We vaccinated four groups of human volunteers: a non-adjuvanted H1 group, followed by three groups with escalating doses of CAF01-adjuvanted H1 vaccine. All subjects were vaccinated at 0 and 8 weeks and followed up for 150 weeks. Vaccination did not cause local or systemic adverse effects besides transient soreness at the injection site. Two vaccinations elicited strong antigen-specific T-cell responses which persisted after 150 weeks follow-up, indicating the induction of a long-lasting memory response in the vaccine recipients. These results show that CAF01 is a safe and tolerable, Th1-inducing adjuvant for human TB vaccination trials and for vaccination studies in general where cellular immunity is required. PMID- 25454873 TI - VP2-serotyped live-attenuated bluetongue virus without NS3/NS3a expression provides serotype-specific protection and enables DIVA. AB - Bluetongue virus (BTV) causes Bluetongue in ruminants and is transmitted by Culicoides biting midges. Vaccination is the most effective measure to control vector borne diseases; however, there are 26 known BTV serotypes showing little cross protection. The BTV serotype is mainly determined by genome segment 2 encoding the VP2 protein. Currently, inactivated and live-attenuated Bluetongue vaccines are available for a limited number of serotypes, but each of these have their specific disadvantages, including the inability to differentiate infected from vaccinated animals (DIVA). BTV non-structural proteins NS3 and NS3a are not essential for virus replication in vitro, but are important for cytopathogenic effect in mammalian cells and for virus release from insect cells in vitro. Recently, we have shown that virulent BTV8 without NS3/NS3a is non-virulent and viremia in sheep is strongly reduced, whereas local in vivo replication leads to seroconversion. Live-attenuated BTV6 without NS3/NS3a expression protected sheep against BTV challenge. Altogether, NS3/NS3a knockout BTV6 is a promising vaccine candidate and has been named Disabled Infectious Single Animal (DISA) vaccine. Here, we show serotype-specific protection in sheep by DISA vaccine in which only genome segment 2 of serotype 8 was exchanged. Similarly, DISA vaccines against other serotypes could be developed, by exchange of only segment 2, and could therefore safely be combined in multi-serotype cocktail vaccines with respect to reassortment between vaccine viruses. Additionally, NS3 antibody responses are raised after natural BTV infection and NS3-based ELISAs are therefore appropriate tools for DIVA testing accompanying the DISA vaccine. To enable DIVA, we developed an experimental NS3 ELISA. Indeed, vaccinated sheep remained negative for NS3 antibodies, whereas seroconversion for NS3 antibodies was associated with viremia after heterologous BTV challenge. PMID- 25454874 TI - Evaluation of cells and biological reagents for adventitious agents using degenerate primer PCR and massively parallel sequencing. AB - We employed a massively parallel sequencing (MPS)-based approach to test reagents and model cell substrates including Chinese hamster ovary (CHO), Madin-Darby canine kidney (MDCK), African green monkey kidney (Vero), and High Five insect cell lines for adventitious agents. RNA and DNA were extracted either directly from the samples or from viral capsid-enriched preparations, and then subjected to MPS-based non-specific virus detection with degenerate oligonucleotide primer (DOP) PCR. MPS by 454, Illumina MiSeq, and Illumina HiSeq was compared on independent samples. Virus detection using these methods was reproducibly achieved. Unclassified sequences from CHO cells represented cellular sequences not yet submitted to the databases typically used for sequence identification. The sensitivity of MPS-based virus detection was consistent with theoretically expected limits based on dilution of virus in cellular nucleic acids. Capsid preparation increased the number of viral sequences detected. Potential viral sequences were detected in several samples; in each case, these sequences were either artifactual or (based on additional studies) shown not to be associated with replication-competent viruses. Virus-like sequences were more likely to be identified in BLAST searches using virus-specific databases that did not contain cellular sequences. Detected viral sequences included previously described retrovirus and retrovirus-like sequences in CHO, Vero, MDCK and High Five cells, and nodavirus and endogenous bracovirus sequences in High Five insect cells. Bovine viral diarrhea virus, bovine hokovirus, and porcine circovirus sequences were detected in some reagents. A recently described parvo-like virus present in some nucleic acid extraction resins was also identified in cells and extraction controls from some samples. The present study helps to illustrate the potential for MPS-based strategies in evaluating the presence of viral nucleic acids in various sample types, including cell culture substrates and vaccines. PMID- 25454875 TI - Determinants of influenza vaccination coverage rates among primary care patients in Krakow, Poland and the surrounding region. AB - OBJECTIVE: Poland is significantly behind other European countries in terms of influenza vaccination coverage. In addition, the vaccination rate among health care personnel in Poland is also very low. The aim of this study was to determine the current barriers to achieving effective influenza vaccination coverage among primary health care (PHC) patients and physicians in Poland and to reveal any associations between the patients' and physicians' characteristics and the influenza vaccination coverage rate among patients. METHOD: A cross-sectional questionnaire-based survey was distributed among 18 PHC physicians and 533 their patients in Krakow, Poland and the surrounding region. The data from patients were associated with the doctors' characteristics. RESULTS: The reasons for not receiving the influenza vaccine differed between patients and their physicians. Among the patient population, the main reason behind vaccination non-compliance was the self-perception of good health, while forgetting about the vaccination was the main reason among the physicians. The factors that had the positive influence on the patients' decision to receive the vaccination involved: older age, being a widower, being retired, having a chronic disease, being vaccinated against influenza in the past and awareness of influenza complications. Moreover, those patients who had received sufficient influenza vaccination education from their healthcare provider and had been the patients of physicians who had been vaccinated against influenza, had significantly higher vaccination rates. CONCLUSION: Improved patients and doctors education strategies are needed to maximize influenza vaccination coverage rates. Information regarding the need and benefits of the influenza vaccine, along with details on where and when to receive vaccination will provide a positive influence on a patients' decision making process regarding vaccination compliance. Also, the free of charge influenza vaccinations for all primary health care workers should be considered. PMID- 25454876 TI - Qualitative motivators and barriers to pandemic vs. seasonal influenza vaccination among healthcare workers: a content analysis. AB - INTRODUCTION: Influenza is a major concern across healthcare environments. Annual vaccination of healthcare workers (HCW) remains a key mode of influenza prevention in healthcare settings. Yet influenza vaccine coverage among HCWs continues to be below recommended targets, in pandemic and non-pandemic settings. Thus, the primary objective of this analysis is to identify motivators and barriers to pandemic (panINFLU) and seasonal influenza vaccination (sINFLU) through the qualitative analysis of HCW provided reasons driving HCW's personal vaccination decisions. METHODS: Data were collected from a multi-professional sample of HCWs via a cross-sectional survey study, conducted at a tertiary-care hospital in Ontario, Canada. HCW provided and ranked qualitative reasons for personal (1) panINFLU (pH1N1) and (2) sINFLU (2008/2009 season) vaccine uptake and avoidance were used to identify key vaccination motivators and barriers through content analysis methodology. RESULTS: Most HCW vaccination motivators and barriers were found to be similar for panINFLU and sINFLU vaccines. Personal motivators had the greatest impact on vaccination (panINFLU 29.9% and sINFLU 33.9%). Other motivators included preventing influenza in loved ones, patients, and community, and awareness of HCW role in influenza transmission. In contrast, concerns of vaccine safety and limited HCW knowledge of influenza vaccines (panINFLU 46.2% and sINFLU 37.3%). HCW vaccination during the pandemic was motivated by panINFLU related fear, epidemiology, and workplace pro-vaccination policies. HCW perceptions of accelerated panINFLU vaccine development and vaccine safety compromises, negative views of external sources (i.e. media, pharmaceutical companies, and regulatory agencies) and pandemic management strategies were barriers specific to panINFLU vaccine. CONCLUSIONS: HCW panINFLU and sINFLU vaccine coverage can increase if future vaccination programs (1) highlight personal vaccination benefits (2) emphasize the impact HCW non vaccination on family members, patients and community, (3) address HCW vaccine related knowledge gaps, and (4) implement pro-vaccination workplace policies consistent with those in place at the study site during pH1N1. PMID- 25454877 TI - Number needed to vaccinate to prevent hospitalizations of pregnant women due to inter-pandemic influenza in Sweden, 2003-2009. AB - BACKGROUND: The evidence of increased risk of severe disease for healthy pregnant women due to inter-pandemic influenza consists mainly of observational studies of health service utilization in USA and Canada. However, these results can be context dependent and estimates in a European setting are sparse. For policy purposes we therefore decided to elucidate the potential value of vaccination in Sweden. MATERIALS AND METHODS: We conducted a retrospective, register-based study of hospitalizations due to inter-pandemic influenza or respiratory infection attributable to influenza in pregnant women in Sweden. With aggregated data from 2003 to 2009 we assessed the number needed to vaccinate (NNV) to prevent one such hospitalization. RESULTS: We included on average 96,000 pregnant women/year and identified 9-48 hospitalizations/season fulfilling the case definition. Assuming 80% vaccine effectiveness the NNV was >1,900 pregnant women. The estimate is higher than those found in the USA, Canada, and UK. The difference may be explained by differing methods to estimate NNV, but also differences in propensity to hospitalize and the basic health status of the pregnant women. CONCLUSIONS: Because of the increased risk associated with influenza A(H1N1)pdm09, vaccination is presently offered to all pregnant women in Sweden, but vaccination against other inter-pandemic influenza types seems disputable. The study illustrates the context dependence of preventive health measures and points to the need for national NNV estimates and international harmonization of study methods for comparisons between countries. PMID- 25454879 TI - Vaccination ethics. PMID- 25454878 TI - Randomized trial to compare the safety and immunogenicity of CSL Limited's 2009 trivalent inactivated influenza vaccine to an established vaccine in United States children. AB - A trivalent inactivated influenza vaccine (CSL's TIV, CSL Limited) was licensed under USA accelerated approval regulations for use in persons>=18 years. We performed a randomized, observer-blind study to assess the safety and immunogenicity of CSL's TIV versus an established US-licensed vaccine in a population>=6 months to <18 years of age. Subjects were stratified as follows: Cohort A (>=6 months to <3 years); Cohort B (>=3 years to <9 years); and Cohort C (>=9 years to <18 years). The subject's age and influenza vaccination history determined the dosing regimen (one or two vaccinations). Subjects received CSL's TIV (n=739) or the established vaccine (n=735) in the autumn of 2009. Serum hemagglutination-inhibition titers were determined pre-vaccination and 30 days after the last vaccination. No febrile seizures or other vaccine-related SAEs were reported. After the first vaccination for Cohorts A and B, respectively, the relative risks of fever were 2.73 and 2.32 times higher for CSL's TIV compared to the established vaccine. Irritability and loss of appetite (for Cohort A) and malaise (for Cohort B) were also significantly higher for CSL's TIV compared to the established vaccine. Post-vaccination geometric mean titers (GMTs) for CSL's TIV versus the established vaccine were 385.49 vs. 382.45 for H1N1; 669.13 vs. 705.61 for H3N2; and 100.65 vs. 93.72 for B. CSL's TIV demonstrated immunological non-inferiority to the established vaccine in all cohorts. PMID- 25454880 TI - What is the responsibility of national government with respect to vaccination? AB - Given the ethical aspects of vaccination policies and current threats to public trust in vaccination, it is important that governments follow clear criteria for including new vaccines in a national programme. The Health Council of the Netherlands developed such a framework of criteria in 2007, and has been using this as basis for advisory reports about several vaccinations. However, general criteria alone offer insufficient ground and direction for thinking about what the state ought to do. In this paper, we present and defend two basic ethical principles that explain why certain vaccinations are the state's moral-political responsibility, and that may further guide decision-making about the content and character of immunisation programmes. First and foremost, the state is responsible for protecting the basic conditions for public health and societal life. Secondly, states are responsible for promoting and securing equal access to basic health care, which may also include certain vaccinations. We argue how these principles can find reasonable support from a broad variety of ethical and political views, and discuss several implications for vaccination policies. PMID- 25454881 TI - How high is a high risk? Prioritising high-risk individuals in an influenza pandemic. AB - Pandemic contingency plans frequently define priority groups that are given preferential access to influenza vaccine. One of the most commonly named groups for prioritisation is that of high-risk individuals. However, current models of categorisation are unsatisfactory in a number of ways. It will be argued that existing vaccination strategies fail to adequately define what kind of risks are being considered and how, as well as on the basis of which information, these risks are calculated. Moreover, it will be suggested that existing vaccination strategies fail to specify of what magnitude a risk has to be, in order to be categorised as 'high'. Finally, it shall be argued that a mere focus on the size of a risk factor may lead policy makers to overlook underlying concerns of distributive justice. PMID- 25454882 TI - Ethical considerations in post-market-approval monitoring and regulation of vaccines. AB - The objective of this paper is to identify and articulate ethical considerations to help guide decision-making around the regulation and monitoring of vaccines post-licensure. While these considerations are not intended to be an exhaustive account of the ethical concerns, they can facilitate the explicit examination of ethical issues in this context. We identify the protection of public from harm as the primary consideration, and identify others that help in the discharging of this governmental obligation. Others include: transparency, a publicly acceptable risk-benefit profile, public trust, minimization of stigma, and special obligations to vulnerable populations. Regulators and researchers can use these ethical considerations to help enhance their reasoning and to improve the accountability of their decision-making. These considerations can be used to inform rational deliberations about how to balance the obligation to protect the public from harm with other relevant considerations such as the need to be transparent, while taking into account the contextual features of the situation. Further research and debate on the relevance and refinement of these ethical considerations is desirable. PMID- 25454883 TI - Varicella-zoster virus vaccination under the exogenous boosting hypothesis: two ethical perspectives. AB - The varicella-zoster virus (VZV) causes two diseases: varicella ('chickenpox') and herpes zoster ('shingles'). VZV vaccination of children reduces exposure to chickenpox in the population and it has been hypothesized that this could increase the prevalence of shingles. This 'exogenous boosting' effect of VZV raises an important equity concern: introducing a vaccination program could advance the health of one population group (children) at the expense of another (adults and elderly). We discuss the program's justifiability from two ethical perspectives, classic utilitarianism and contractualism. Whereas the former framework might offer a foundation for the case against introducing this vaccination, the latter offers a basis to justify it. PMID- 25454884 TI - The ethics of disease eradication. AB - This paper provides an examination of the ethics of disease eradication policies. It examines three arguments that have been advanced for thinking that eradication is in some way ethically exceptional as a policy goal. These are (1) global eradication has symbolic importance, (2) disease eradication is a global public good and (3) disease eradication is a form of rescue. It argues that none of these provides a good reason to think that individuals have special duties to facilitate eradication campaigns, or that public health authorities have special permissions to pursue them. But the fact that these arguments fail does not entail that global disease eradication is ethically problematic, or that it should not be undertaken. Global eradication of a disease, if successful, is a way of providing an enormous health benefit that stretches far into the future. There is no need to reach for the idea that there is a special duty to eradicate disease; the same considerations that are in play in ordinary public health policy--of reducing the burden of disease equitably and efficiently--suffice to make global disease eradication a compelling goal where doing so is feasible. PMID- 25454885 TI - Representing time in language and memory: the role of similarity structure. AB - Every day we read about or watch events in the world and can easily understand or remember how long they last. What aspects of an event are retained in memory? And how do we extract temporal information from our memory representations? These issues are central to human cognition, as they underlie a fundamental aspect of our mental life, namely our representation of time. This paper reviews previous language studies and reports a visual learning study indicating that properties of the events encoded in memory shape the representation of their duration. The evidence indicates that for a given event, the extent to which its associated properties or sub-components differ from one another modulates our representation of its duration. These properties include the similarity between sub-events and the similarity between the situational contexts in which an event occurs. We suggest that the diversity of representations that we associate with events in memory plays an important role in remembering and estimating the duration of experienced or described events. PMID- 25454886 TI - What's up? Emotion-specific activation of vertical space during language processing. AB - The relationship between language processing and vertical space has been shown for various groups of words including valence words, implicit location words, and words referring to religious concepts. However, it remains unclear whether these are single phenomena or whether there is an underlying common mechanism. Here, we show that the evaluation of word valence interacts with motor responses in the vertical dimension, with positive (negative) evaluations facilitating upward (downward) responses. When valence evaluation was not required, implicit location words (e.g., bird, shoe) influenced motor responses whereas valence words (e.g., kiss, hate) did not. Importantly, a subset of specific emotional valence words that are commonly associated with particular bodily postures (e.g., proud >upright; sad->slouched) did automatically influence motor responses. Together, this suggests that while the vertical spatial dimension is not directly activated by word valence, it is activated when processing words referring to emotional states with stereotypical bodily-postures. These results provide strong evidence that the activation of spatial associations during language processing is experience-specific in nature and cannot be explained with reference to a general mapping between all valence words and space (i.e., all positive and negative words generally relate to spatial processing). These findings support the experiential view of language comprehension, suggesting that the automatic reactivation of bodily experiences is limited to word groups referring to emotions or entities directly associated with spatial experiences (e.g., posture or location in the world). PMID- 25454887 TI - A few parting thoughts. PMID- 25454888 TI - The heroin epidemic and emergency nurses. PMID- 25454889 TI - Safety of black widow antivenin. PMID- 25454890 TI - Response. PMID- 25454892 TI - Response. PMID- 25454891 TI - Statistics for emergency nurses. PMID- 25454893 TI - A middle-aged woman falls in the emergency department. PMID- 25454895 TI - The physiological response to hemorrhagic shock. PMID- 25454897 TI - Organized chaos in Kupffer's vesicle: how a heterogeneous structure achieves consistent left-right patterning. AB - Successful establishment of left-right asymmetry is crucial to healthy vertebrate development. In many species this process is initiated in a ciliated, enclosed cavity, for example Kupffer's vesicle (KV) in zebrafish. The microarchitecture of KV is more complex than that present in the left-right organizer of many other species. While swirling flow in KV is recognized as essential for left-right patterning, its generation, nature and conversion to asymmetric gene expression are only beginning to be fully understood. We recently [Sampaio, P et al. Dev Cell 29:716-728] combined imaging, genetics and fluid dynamics simulation to characterize normal and perturbed ciliary activity, and their correlation to asymmetric charon expression and embryonic organ fate. Randomness in cilia number and length have major implications for robust flow generation; even a modest change in mean cilia length has a major effect on flow speed to due to nonlinear scaling arising from fluid mechanics. Wildtype, and mutant embryos with normal liver laterality, exhibit stronger flow on the left prior to asymmetric inhibition of charon. Our discovery of immotile cilia, taken with data on morphant embryos with very few cilia, further support the role of mechanosensing in initiating and/or enhancing flow conversion into gene expression. PMID- 25454898 TI - Effects of nonequilibrium growth, nonstoichiometry, and film orientation on the metal-to-insulator transition in NdNiO3 thin films. AB - Next-generation devices will rely on exotic functional properties not found in traditional systems. One class of materials of particular interest for applications are those possessing metal-to-insulator transitions (MITs). In this work, we probe the relationship between variations in the growth process, subsequent variations in cation stoichiometry, and the MIT in NdNiO3 thin films. Slight variations in the growth conditions, in particular the laser fluence, during pulsed-laser deposition growth of NdNiO3 produces films that are both single-phase and coherently strained to a range of substrates despite possessing as much as 15% Nd-excess. Subsequent study of the temperature-dependence of the electronic transport reveals dramatic changes in both the onset and magnitude of the resistivity change at the MIT with increasing cation nonstoichiometry giving rise to a decrease (and ultimately a suppression) of the transition and the magnitude of the resistivity change. From there, the electronic transport of nearly ideal NdNiO3 thin films are studied as a function of epitaxial strain, thickness, and orientation. Overall, transitioning from tensile to compressive strain results in a systematic reduction of the onset and magnitude of the resistivity change across the MIT, thinner films are found to possess sharper MITs with larger changes in the resistivity at the transition, and (001)-oriented films exhibit sharper and larger MITs as compared to (110)- and (111)-oriented films as a result of highly anisotropic in-plane transport in the latter. PMID- 25454900 TI - Self-citations should be counted. PMID- 25454899 TI - Poorer Survival in Stage IB Lung Cancer Patients After Pneumonectomy. AB - OBJECTIVE: Pneumonectomy may be needed in exceptional cases in patients with early stage NSCLC, especially in stage IB. The aim of this study was to evaluate whether overall survival in stage IB (T2aN0M0) NSCLC patients is worse after pneumonectomy. METHODS: Retrospective study of a series of pathological IB (pIB) patients who underwent either lobectomy or pneumonectomy between 2000 and 2011. The dependent variable was all-cause death. Operative mortality was excluded. The relationship between the age, FEV1%, Charlson index and performance of pneumonectomy variables and the dependent variable were analyzed using a Cox regression. Overall survival for both groups of patients was then plotted in Kaplan-Meier graphs and compared using the log-rank test. RESULTS: A total of 407 cases were analyzed (373 lobectomies and 34 pneumonectomies). According to Cox regression, age, FEV1% and pneumonectomy were associated with poorer survival (P<.05). Age-adjusted survival and FEV1% showed diminished survival in patients who underwent pneumonectomy (log-rank, P=.0357). CONCLUSIONS: In stage pIB NSCLC patients, pneumonectomy is associated with poorer survival compared to lobectomy. PMID- 25454901 TI - Prevalence of alpha-1 antitrypsin high-risk variants in Mexican mestizo population and their association with lung function values. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is characterized by restricted airflow. The best-documented genetic factor is alpha-1 antitrypsin (AAT). AAT is encoded by the SERPINA1 gene. The PiZ (rs28929474) and PiS (rs17580) variants are believed to cause severe AAT deficiency and are linked to a high risk of developing COPD. This study sought to identify whether genetic polymorphisms rs28929474 and rs17580 are associated with COPD susceptibility and lung function values in a Mexican mestizo population. METHODS: In this study, 558 smokers were included, of whom 279 had COPD and 279 did not (smokers without COPD - SWC). The PiS and PiZ variants were genotyped by allelic discrimination. Independent populations and lung function values were compared using the Kruskal Wallis test. A bivariate logistic regression analysis was also conducted. RESULTS: Stage I and iv COPD patients showed significant differences in the frequencies of both heterozygous genotypes compared to SWC. For PiS, individuals with the heterozygous genotype AT demonstrated a decreased FEV1/FVC ratio compared to subjects with the homozygous genotype AA (P=0.037). A significant association was found between the FEV1/FVC ratio and genotype AA for PiS (OR=0.982, beta coefficient=-0.019, 95% CI=0.966-0.997). CONCLUSIONS: COPD causing AAT deficiency risk alleles exist at a very low frequency among Mexican mestizo population. Although they are not directly linked in our study population with disease susceptibility, these risk alleles are associated with poorer lung function measurements. It is important to characterize how often these genetic risk variants occur in other Latin American populations. PMID- 25454902 TI - Cryobiopsy in the diagnosis of diffuse interstitial lung disease: yield and cost effectiveness analysis. AB - BACKGROUND: Assessment of patients with suspected interstitial lung disease (ILD) includes surgical lung biopsy (SLB) when clinical and radiological data are inconclusive. However, cryobiopsy is acquiring an important role in the ILD diagnostic process. The objective of this study was to evaluate the diagnostic yield, safety and economic costs of the systematic use of cryobiopsy in the assessment of patients with suspected ILD. METHODS: This was a retrospective observational study of patients who had undergone transbronchial cryobiopsy for evaluation of ILD from January 2011 to January 2014. The procedures were performed with a video bronchoscope using a cryoprobe for the collection of lung parenchyma specimens, which were analyzed by pathologists. Diagnostic yield, complications and economic costs of this technique were analyzed. RESULTS: Criobiopsy specimens from a total of 33 patients were included. A specific diagnosis was obtained in 26, producing a diagnostic yield of 79%. In 5 patients, SLB was required for a histopathological confirmation of disease, but the procedure could not be performed in 4, due to severe comorbidities. The most frequent complications were pneumothorax (12%) and gradei (9%) or gradeii (21%) bleeding. There were no life-threatening complications. The systematic use of cryobiopsy saved up to ?59,846. CONCLUSION: Cryobiopsy is a safe and potentially useful technique in the diagnostic assessment of patients with ILD. Furthermore, the systematic use of cryobiopsy has an important economic impact. PMID- 25454903 TI - Microvascular coronary dysfunction and ischemic heart disease: where are we in 2014? AB - Many patients with angina and signs of myocardial ischemia on stress testing have no significant obstructive epicardial coronary disease. There are many potential coronary and non-coronary mechanisms for ischemia without obstructive epicardial coronary disease, and prominent among these is coronary microvascular and/or endothelial dysfunction. Patients with coronary microvascular and/or endothelial dysfunction are often at increased risk of adverse cardiovascular events, including ischemic events and heart failure despite preserved ventricular systolic function. In this article, we will review the diagnosis and treatment of coronary microvascular and endothelial dysfunction, discuss their potential contribution to heart failure with preserved ejection fraction, and highlight recent advances in the evaluation of atherosclerotic morphology in these patients, many of whom have non-obstructive epicardial disease. PMID- 25454904 TI - Bilobectomy with superior pulmonary vein reconstruction with a greater saphenous vein autograft to avoid pneumonectomy. PMID- 25454905 TI - Bioprosthetic valve durability: the proof is in the pudding. PMID- 25454906 TI - Late clinical outcome of transient intraoperative systolic anterior motion post mitral valve repair. AB - OBJECTIVE: Systolic anterior motion (SAM) after mitral valve repair with significant mitral regurgitation requires immediate reintervention. Transient SAM immediately after repair is usually managed by hemodynamic maneuvers. We investigated the late clinical and echocardiographic significance of postoperative transient SAM. METHODS: Between 2004 and 2013, mitral valve repair was performed on 549 consecutive patients with degenerative mitral valve disease. Of the 45 patients (8.2%) identified with postrepair SAM, 5 needed immediate reintervention. Hemodynamic maneuvers, such as preload and afterload augmentation and rate control, effectively abolished SAM in 40 patients (SAM). They were followed and compared with the remaining 509 patients (non-SAM). RESULTS: Mean clinical follow-up was 54 +/- 28 and 31 +/- 26 months and was available in 100% and 95% (SAM and non-SAM) patients, respectively. One hospital death occurred in each group (P = .14). At follow-up, 2 patients (0.3%) showed significant SAM with left ventricular outflow tract obstruction, which resolved in 1 patient after beta-blocker therapy. SAM patients underwent exercise stress echocardiography: 1 patient showed left ventricular outflow tract obstruction that worsened after exercise. At 5 years, freedom from moderate or severe mitral regurgitation and New York Heart Association functional class III-IV was 85% versus 92% (P = .27) and 81% versus 92% (P = .15), and freedom from reoperation was 100% and 96% (P = .4), in SAM and non-SAM patients, respectively. CONCLUSIONS: Late postoperative exercise stress echocardiogram revealed low incidence of SAM in patients with immediate postrepair transient SAM. All other late clinical outcomes were similar to those of non-SAM repair patients. Conservative management of intraoperative transient SAM is both successful and reliable. PMID- 25454908 TI - A is A. PMID- 25454907 TI - A propensity-matched analysis comparing survival after primary minimally invasive esophagectomy followed by adjuvant therapy to neoadjuvant therapy for esophagogastric adenocarcinoma. AB - OBJECTIVES: Prognosis for patients with locally advanced esophagogastric adenocarcinoma (EAC) is poor with surgery alone, and adjuvant therapy after open esophagectomy is frequently not tolerated. After minimally invasive esophagectomy (MIE); however, earlier return to normal function may render patients better able to receive adjuvant therapy. We examined whether primary MIE followed by adjuvant chemotherapy influenced survival compared with propensity-matched patients treated with neoadjuvant therapy. METHODS: Patients with stage II or higher EAC treated with MIE (N = 375) were identified. Using 30 pretreatment covariates, propensity for assignment to either neoadjuvant followed by MIE (n = 183; 54%) or MIE as primary therapy (n = 156; 46%) was calculated, generating 97 closely matched pairs. Hazard ratios were adjusted for age, sex, body mass index, smoking, comorbidity, and final pathologic stage. RESULTS: In propensity-matched pairs, adjusted hazard ratio for death did not differ significantly for primary MIE compared with neoadjuvant (hazard ratio, 0.83; 95% confidence interval, 0.60 1.16). Recurrence patterns were similar between groups and 65% of patients with IIb or greater pathologic stage received adjuvant therapy. Clinical staging was inaccurate in 37 out of 105 patients (35%) who underwent primary MIE (n = 18 upstaged and n = 19 downstaged). CONCLUSIONS: Primary MIE followed by adjuvant chemotherapy guided by pathologic findings did not negatively influence survival and allowed for accurate staging compared with clinical staging. Our data suggest that primary MIE in patients with resectable EAC may be a reasonable approach, improving stage-based prognostication and potentially minimizing overtreatment in patients with early stage disease through accurate stage assignments. A randomized controlled trial testing this hypothesis is needed. PMID- 25454909 TI - Timing is everything--or is it? PMID- 25454910 TI - Vacuum-assisted closure device for the management of infected postpneumonectomy chest cavities. AB - BACKGROUND: Infected postpneumonectomy chest cavities may be related to chronic postpneumonectomy empyema or arise in rare situations of necrotizing pneumonia with complete lung destruction where pneumonectomy and pleural debridement are required. We evaluated the safety and efficacy of an intrathoracic vacuum assisted closure device (VAC) for the treatment of infected postpneumonectomy chest cavities. METHOD: A retrospective single institution review of all patients with infected postpneumonectomy chest cavities treated by VAC between 2005 and 2013. Patients underwent surgical debridement of the thoracic cavity, muscle flap closure of the bronchial stump when a fistula was present, and repeated intrathoracic VAC dressings until granulation tissue covered the entire chest cavity. After this, the cavity was obliterated by a Clagett procedure and closed. RESULTS: Twenty-one patients (14 men and 7 women) underwent VAC treatment of their infected postpneumonectomy chest cavity. Twelve patients presented with a chronic postpneumonectomy empyema (10 of them with a bronchopleural fistula) and 9 patients with an empyema occurring in the context of necrotizing pneumonia treated by pneumonectomy. In-hospital mortality was 23%. The median duration of VAC therapy was 23 days (range, 4-61 days) and the median number of VAC changes per patient was 6 (range, 2-14 days). Infection control and successful chest cavity closure was achieved in all surviving patients. One adverse VAC treatment related event was identified (5%). CONCLUSIONS: The intrathoracic VAC application is a safe and efficient treatment of infected postpneumonectomy chest cavities and allows the preservation of chest wall integrity. PMID- 25454911 TI - Postsurgical lobar torsion in an unusual setting. PMID- 25454912 TI - The 3f Enable sutureless bioprosthesis: Early results, safeguards, and pitfalls. AB - OBJECTIVE: The aim of the study was to evaluate the clinical and hemodynamic performance of the 3f Enable (Medtronic Inc, Minneapolis, Minn) sutureless bioprosthesis in the early postoperative period. Its implantation technique was also evaluated highlighting the modifications in regard to the original technique and mistakes made throughout the learning curve. METHODS: This is a prospective, nonrandomized study. From February 2011 to March 2014, a total of 60 patients underwent aortic valve replacement with the 3f Enable valve at the Hospiten Rambla. All intraoperative and postoperative data were prospectively collected. RESULTS: The mean age was 81.3 +/- 3.78 years. Mean logistic European System for Cardiac Operative Risk Evaluation I was 13.78%. An associated concomitant procedure was performed in 23 patients (38.3%). The extracorporeal circulation and crossclamping times were 49.8 +/- 15.7 minutes and 35.4 +/- 8.9 minutes, respectively. The average stay in the intensive care unit was 34.7 hours. Mean systolic pressure gradients ranged from 8.01 mm Hg (size 19 valve) to 7.2 mm Hg (size 25 valve). Mean effective orifice area ranged from 1.9 cm(2) (size 19 valve) to 2.5 cm(2) (size 25 valve). Severe mismatch (<0.65 cm(2)/m(2)) did not occur in any patient. Only 1.66% of patients had more than mild aortic insufficiency at discharge. The early (30-day) mortality was 6.6% (n = 4). CONCLUSIONS: The 3f Enable bioprosthesis is an important alternative to conventional prostheses, with reduction of surgery times and good hemodynamic results on discharge. It is especially useful for high-risk patients and octogenarians. Studies on a greater number of patients and long-term follow-ups are necessary. PMID- 25454913 TI - Spinal cord protection in surgical and endovascular repair of thoracoabdominal aortic disease. PMID- 25454914 TI - Physicians can justifiably euthanize certain severely impaired neonates. PMID- 25454915 TI - Early and late outcomes of acute type A aortic dissection with intramural hematoma. AB - INTRODUCTION: Controversy remains regarding management of acute type A dissection with intramural hematoma (IMH). Our purpose was to analyze our experience and report outcomes after repair of acute type A aortic dissection with IMH. METHODS: We analyzed all patients from a single center who underwent open repair for acute type A aortic dissection with IMH. RESULTS: Between 2000 and 2013, we performed 418 repairs for acute type A aortic dissection. These were divided into 2 groups of patients: 64 patients (15%) with type A IMH and 354 patients (85%) with typical dissection. Those with IMH were older (62.4 +/- 13.9 years vs 56.7 +/- 14.7 years; P < .0046) and presented with reduced renal function (ie, glomerular filtration rate) (P < .0341), less frequently with distal malperfusion, and less frequently with rupture (P < .0116). With IMH, the time from presentation to repair was, by strategy, longer (median, 67 vs 6 hours; P < .0001), but no mortality occurred within 3 days of presentation. Mortality with IMH did not differ from typical dissection: 7 out of 64 patients (10.9%) versus 52 out of 354 patients (14.7%; P = .4276). A lower incidence of postoperative dialysis in the IMH group approached significance: 6 out of 63 patients (9.5%) versus 64 out of 347 patients (18.4%; P = .0820). When adjusted for age and renal function, late survival was improved with IMH (P < .0343). CONCLUSIONS: Repair of acute type A aortic dissection with IMH is associated with significant early morbidity and mortality, differing minimally from typical aortic dissection. Although expectant repair within 3 days may be applied, the purposeful delay imparted little advantage. Improved late outcomes may be seen with IMH, but continued long-term surveillance is required for verification. PMID- 25454917 TI - Novel sequential bridge to lung transplant in an awake patient. PMID- 25454916 TI - Single-dose rosuvastatin ameliorates lung ischemia-reperfusion injury via upregulation of endothelial nitric oxide synthase and inhibition of macrophage infiltration in rats with pulmonary hypertension. AB - OBJECTIVE: Lung ischemia-reperfusion (IR) injury during cardiopulmonary surgery is associated with postoperative morbidity and mortality, particularly in patients with pulmonary hypertension (PH). Using a rat model for monocrotaline induced PH, we investigated the protective effect of rosuvastatin against IR injury in lungs affected by PH and attempted to elucidate its mechanism of action. METHODS: Male Sprague-Dawley monocrotaline-treated rats were divided into 4 groups (n = 8-9): sham, control + IR, statin + IR, and statin + mevalonolactone + IR. Lung ischemia was induced by left pulmonary artery occlusion (1 hour), followed by reperfusion (4 hours). Rosuvastatin (2 mg/kg) was injected 18 hours before reperfusion and mevalonolactone (1 mg/kg) was injected immediately before reperfusion. The arterial oxygen tension/inspired oxygen fraction ratio was used as a measure of lung oxygenation. Left lung tissue was analyzed for the wet-to dry lung weight ratio and protein expression of endothelial nitric oxide synthase (eNOS) and phospho-eNOS. Macrophage recruitment was assessed by CD68 immunostaining. RESULTS: Our results showed that rosuvastatin decreased IR lung injury (control + IR vs statin + IR) in terms of the arterial oxygen tension/inspired oxygen fraction ratio (272 +/- 43 vs 442 +/- 13), wet-to-dry ratio (5.7 +/- 0.7 vs 4.8 +/- 0.6), and macrophage infiltration (8.0 +/- 0.6/field vs 4.0 +/- 0.5/field) (P < .05 for all). eNOS and phospho-eNOS were downregulated by IR, which was blocked by rosuvastatin. Effects of rosuvastatin were blunted by mevalonolactone. CONCLUSIONS: Single-dose rosuvastatin decreased IR injury in lungs affected by PH via 2 anti-inflammatory mechanisms: preserving eNOS function and inhibiting macrophage infiltration. PMID- 25454918 TI - Survival probability loss from percutaneous coronary intervention compared with coronary artery bypass grafting across age groups. AB - BACKGROUND: Whether the survival benefit from coronary artery bypass grafting (CABG), compared with percutaneous coronary intervention (PCI), for multivessel disease extends to the older segment of the population remains unclear. We aimed to investigate whether the effect on survival of PCI compared with CABG is related to the age of the patient. METHODS: Propensity score-matching analysis was conducted on 6723 patients (PCI = 1097, CABG = 5626) with multivessel coronary artery disease. In the PCI group, drug-eluting stents were used in 917 (83.5%) patients; bare metal stents were used in only 180 patients (16.5%). Nonparametric, bootstrap, point-wise confidence limits were obtained for PCI:CABG odds and hazard ratios for early (within 12 months) and late hazard phase (beyond 12 months) for a variety of age groups. RESULTS: After a mean follow-up time of 5.5 +/- 3.2 years, a total of 301 deaths were recorded in the matched sample (208 in the PCI group and 93 in the CABG group). Overall survival was 95% +/- 0.6% versus 95% +/- 0.6% at 1 year, 84% +/- 1.0% versus 92.4% +/- 0.8% at 5 years, and 75% +/- 1.6% versus 90% +/- 1.0% at 8 years, for the PCI and CABG groups, respectively (log rank P < .001). PCI did not confer any significant benefit compared with CABG during the early hazard phase (within 12 months), but the survival-probability loss from PCI compared with CABG during the late hazard phase was present across all age groups. The hazard ratio declined from 3.8 to 3.4 and was statistically significant (lower limit >1 across all ages, ranging from 1.5 to 2.4). CONCLUSIONS: Compared with PCI, CABG leads to a significant reduction in late-phase mortality across all age groups. PMID- 25454919 TI - A central shunt to rehabilitate diminutive pulmonary arteries in patients with pulmonary atresia with ventricular septal defect. AB - OBJECTIVES: We evaluated our clinical experiences on rehabilitation of native pulmonary arteries (PAs) with a central shunt using an expanded polytetrafluoroethylene (ePTFE) tube graft in management of pulmonary atresia with ventricular septal defect (VSD) and major aortopulmonary collateral arteries (MAPCAs) with diminutive PAs. METHODS: From March 1993 to June 2013, a total of 28 consecutive patients underwent surgery for pulmonary atresia with VSD and MAPCAs. We identified 15 patients who underwent a central shunt procedure using an ePTFE tube graft. Median age and weight at the initial operation were 1.91 months and 5.22 kg, respectively. Ligation of MAPCAs was performed in 3 patients concomitantly. The techniques used were a U-shaped central shunt in 13 patients, and a side-to-side aorto-ePTFE tube graft anastomosis in 2 patients. RESULTS: There was no surgical mortality, and no shunt occlusion. The mean follow-up duration was 70.7 +/- 67.1 months. Complete repair was achieved in 13 patients (13 of 14 of the follow-up patients; 92.9%), and the remaining patient is waiting for complete repair. The median age at complete repair was 19.4 months. The mean PA index before the initial central shunt procedure was 22.7 +/- 13.2 mm(2)/m(2), which increased to 149.4 +/- 86.6 mm(2)/m(2) at the final recordings before shunt division, and 185.9 +/- 84.0 mm(2)/m(2) before complete repair. There were 2 late mortality cases. The overall survival rates were 92.9%, 82.5%, and 82.5%, at 1, 5, and 10 years, respectively. CONCLUSIONS: A central shunt, using an ePTFE tube graft, is an effective initial palliative procedure for rehabilitation of the diminutive PAs in patients with pulmonary atresia with VSD and MAPCAs. PMID- 25454921 TI - Spinal cord protection via alpha-2 agonist-mediated increase in glial cell-line derived neurotrophic factor. AB - OBJECTIVES: Delayed paraplegia secondary to ischemia-reperfusion injury is a devastating complication of thoracoabdominal aortic surgery. Alpha-2 agonists have been shown to attenuate ischemia-reperfusion injury, but the mechanism for protection has yet to be elucidated. A growing body of evidence suggests that astrocytes play a critical role in neuroprotection by release of neurotrophins. We hypothesize that alpha-2 agonism with dexmedetomidine increases glial cell line-derived neurotrophic factor in spinal cord astrocytes to provide spinal cord protection. METHODS: Spinal cords were isolated en bloc from C57BL/6 mice, and primary spinal cord astrocytes and neurons were selected for and grown separately in culture. Astrocytes were treated with dexmedetomidine, and glial cell-line derived neurotrophic factor was tested for by enzyme-linked immunosorbent assay. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to assess neuronal viability. RESULTS: Spinal cord primary astrocytes treated with dexmedetomidine at 1 MUmol/L and 10 MUmol/L had significantly increased glial cell-line-derived neurotrophic factor production compared with control (P < .05). Neurons subjected to oxygen glucose deprivation had significant preservation (P < .05) of viability with use of dexmedetomidine-treated astrocyte media. Glial cell-line-derived neurotrophic factor neutralizing antibody eliminated the protective effects of the dexmedetomidine-treated astrocyte media (P < .05). CONCLUSIONS: Astrocytes have been shown to preserve neuronal viability via release of neurotrophic factors. Dexmedetomidine increases glial cell-derived neurotrophic factor from spinal cord astrocytes via the alpha-2 receptor. Treatment with alpha-2 agonist dexmedetomidine may be a clinical tool for use in spinal cord protection in aortic surgery. PMID- 25454920 TI - The assisted bidirectional Glenn: a novel surgical approach for first-stage single-ventricle heart palliation. AB - BACKGROUND: Outcomes after a modified Blalock-Taussig shunt (mBTS) in neonates with single-ventricle physiology remain unsatisfactory. However, initial palliation with a superior cavopulmonary connection, such as a bidirectional Glenn (BDG), is discouraged, owing to potential for inadequate pulmonary blood flow (PBF). We tested the feasibility of a novel surgical approach, adopting the engineering concept of an ejector pump, whereby the flow in the BDG is "assisted" by injection of a high-energy flow stream from the systemic circulation. METHODS: Realistic 3-dimensional models of the neonatal mBTS and BDG circulations were created. The "assisted" bidirectional Glenn (ABG) consisted of a shunt between the right innominate artery and the superior vena cava (SVC), with a 1.5-mm clip near the SVC anastomosis to create a Venturi effect. The 3 models were coupled to a validated hydraulic circulation model, and 2 pulmonary vascular resistance (PVR) values (7 and 2.3 Wood units) were simulated. RESULTS: The ABG provided the highest systemic oxygen saturation and oxygen delivery at both PVR levels. In addition to achieving higher PBF than the BDG, the ABG produced a lower single ventricular workload than mBTS. SVC pressure was highest in the ABG model (ABG: 15; Glenn: 11; mBTS: 3 mm Hg; PVR = 7 Wood units), but at low PVR, the SVC pressure was significantly lower (ABG: 8; Glenn: 6; mBTS: <3 mm Hg). CONCLUSIONS: Adopting the principle of an ejector pump, with additional flow directed into the SVC in a BDG, the ABG appears to increase PBF with a modest increase in SVC and pulmonary arterial pressure. Although multiscale modeling results demonstrate the conceptual feasibility of the ABG circulation, further technical refinement and investigations are necessary, especially in an appropriate animal model. PMID- 25454922 TI - Strike up the band! PMID- 25454923 TI - Individualized treatment strategies for patients with aortic valve disease and porcelain aorta. PMID- 25454925 TI - Identifying severe asthma in pediatrics: the glass half full or half empty. PMID- 25454924 TI - Prognostic significance of a positive radial margin after esophageal cancer resection. AB - OBJECTIVE: The prognostic significance of an incomplete esophageal cancer resection due to a positive microscopic radial margin remains unclear. The aim of this study is to examine the relationship between radial margin status and oncologic outcomes. METHODS: We performed a retrospective review of esophageal cancer resections between 2004 and 2012. Radial margin status was defined according to the College of American Pathologists. Exclusion criteria were complete pathologic response (n = 12), positive proximal or distal margin (n = 11), R2 resection (n = 5), and carcinoma in situ (n = 2). RESULTS: Of 154 patients, 30 (19%) had a positive radial margin (RM+) and 124 (81%) had a complete resection (R0). The 2 groups were similar with respect to age, gender, proportion of squamous tumors, middle thoracic tumor location, rate of neoadjuvant chemoradiation and adjuvant radiation, transhiatal approach, number of examined lymph nodes, and length of proximal and distal margins. In patients with stage III, the locoregional recurrence-free interval was similar between groups; however, RM+ was associated with a 17-month decrease in the median time to distant recurrence (RM+ = 7 months [95% confidence interval, 4-14]; R0 = 24 months [median not reached]; P < .01). The median survival was also significantly decreased by 12 months in the RM+ group (RM+ = 13 months [95% confidence interval, 7-26]; R0 = 25 months [95% confidence interval, 20-30]; P = .04). CONCLUSIONS: An isolated, positive microscopic radial margin was associated with a greater risk for distant recurrence. There was no impact on locoregional disease control. The role of adjuvant, systemic therapy in patients with an isolated, microscopically RM+ merits further evaluation. PMID- 25454926 TI - Novel overgrowth syndrome phenotype due to recurrent de novo PDGFRB mutation. AB - Using exome analysis, we identified a novel overgrowth syndrome arising from a mutation in PDGFRB, which plays a critical role in growth and differentiation. This entity is characterized by somatic overgrowth, distinctive facial features, hyperelastic and fragile skin, white matter lesions, and neurologic deterioration. PMID- 25454927 TI - Weight fluctuation during childhood and cardiometabolic risk at young adulthood. AB - OBJECTIVES: To test the hypothesis that greater weight fluctuation between 2 and 6 years is associated with an increase in weight measures (such as body mass index [BMI]) and cardiometabolic risk in young adulthood. STUDY DESIGN: Weight fluctuation (determined by BMI SD scores) was measured at least 3 times between the ages of 2 and 6 years in 166 girls and 116 boys from the Terneuzen Birth Cohort. Cardiometabolic risk factors in young adulthood include components of the metabolic syndrome and weight. The extent of weight fluctuation was determined by assessing each individual's SE (or variation) around each individual's linear regression slope (or weight slope). The obtained variation scores were subsequently related to adult BMI, other weight measures, and cardiometabolic risk factors. RESULTS: In girls, greater weight fluctuation between 2 and 6 years was statistically significantly related to greater adult weight measures (1.08; 95% CI 1.01-1.15) and nonsignificantly with the metabolic syndrome. For boys weight fluctuation was not associated with adult weight (1.04; 95% CI 0.97-1.11), but weight slope was statistically significantly associated with adult overweight. CONCLUSIONS: The results suggest that weight fluctuations during early childhood are predictive for adult overweight in girls. For boys weight slope instead of weight fluctuation is predictive for adult overweight. PMID- 25454928 TI - Pediatric exposure to opioid and sedation medications during terminal hospitalizations in the United States, 2007-2011. AB - OBJECTIVE: To describe the use of opioids and sedatives to pediatric patients dying in the hospital in the 2 weeks preceding death. STUDY DESIGN: We conducted a retrospective study on opioid and sedation medication exposure among children who die in hospitals in the US by using large administrative data sources. We described patterns of exposure to these medications for deceased inpatients (<21 years of age) between 2007 and 2011 (n = 37,459) and factors associated with the exposure. Multivariable logistic regression models were used to estimate the ORs. RESULTS: Overall, 74% patients were exposed to opioids or sedatives in the 14 days before death. Among patients with 6 or more hospital days before death, the daily exposure rate ranged from 73% (the sixth day before death) to 89% (the day of death). The most commonly used medications were fentanyl (52%), midazolam (44%), and morphine (40%). Older age (ORs 1.6-3.7), black race (ORs 0.8), longer hospital stay (ORs 6.6-9.3), receiving medical interventions (including mechanical ventilation, surgery, and stay in the intensive care unit, ORs 1.7 2.6), having comorbidities (ORs 1.7-2.4), and being hospitalized in children's hospitals (ORs 4.0-4.5) were associated with exposure of opioid and sedation medication on adjusted analysis. CONCLUSION: Although most pediatric patients terminally hospitalized are exposed to opioid and sedation medication, some patients do not receive such medications before death. Given that patient and hospital characteristics were associated with opioid/sedative exposure, these findings suggest areas of potential quality improvement and further research. PMID- 25454929 TI - Objectively measured physical activity in young adults born preterm at very low birth weight. AB - Unimpaired adults born preterm at very low birth weight (<1500 g) consistently have lower conditioning physical activity than those born at term. We used wrist worn accelerometers to measure objectively physical activity in 57 very low birth weight and 47 control subjects aged 25 years. We found no difference in any physical activity measures. PMID- 25454930 TI - Hemodynamic effects of nasal continuous positive airway pressure in preterm infants with evolving chronic lung disease, a crossover randomized trial. AB - Previous studies suggest that high airway pressure may compromise cardiac output. We investigated the effect of 3 nasal continuous positive airway pressure levels on cardiac output in preterm infants with evolving chronic lung disease. We found that brief changes in continuous positive airway pressure did not affect cardiac output. PMID- 25454931 TI - Emergency department ondansetron use in children with type 1 diabetes mellitus and vomiting. AB - OBJECTIVE: To assess the hypothesis that ondansetron administration to children with type 1 diabetes mellitus (T1DM) presenting for emergency department (ED) care with intercurrent illness and vomiting improves clinical outcomes by reducing hospitalization rates (primary), length of ED stay, intravenous fluid (IVF) administration, and revisits (secondary outcomes). STUDY DESIGN: We conducted a single-center, 10-year retrospective cohort study of 345 ED encounters of children aged 6 months-8 years with T1DM and vomiting. We compared outcomes among children receiving and not receiving ondansetron. To avoid selection bias related to ondansetron administration, we also investigated outcomes by conducting comparisons by ondansetron usage periods (ie, low [2002 2004] vs high [2009-2011]). RESULTS: Ondansetron usage increased from 0% to 67% of ED encounters between 2002 and 2011. Admission rates were similar among those administered [54% (58/107)] and not administered ondansetron [55% (131/238)]. Length of stay was longer in children receiving ondansetron (409 vs 315 minutes; P = .03). IVF administration (77% vs 77%) and revisits (5.6% vs 5.9%) were similar. Ondansetron administration was not associated with reduced admission in logistic regression modeling. Admission rate (62%; 56/91 vs 49%; 57/111) (-13%, 95% CI -23%, 3%), length of stay (395 vs 327 minutes [IQR 164 501]; P < .001), and IVF administration decreased (84% [77/91] to 70% [78/111]; P = .02] when comparing low and high ondansetron usage periods. CONCLUSIONS: Ondansetron administration was not independently associated with lower admission rates. Over time, along with increasing ondansetron use, there have been reductions in admissions, length of stay, and IVF administration in children with T1DM. PMID- 25454932 TI - Newly diagnosed immune thrombocytopenic purpura in childhood: successful implementation of a limited intervention strategy in the setting of pediatric emergency care. AB - Immune thrombocytopenic purpura is a bleeding disorder for which management remains mainly guided by platelet counts. Pediatric hematologists and emergency physicians collaborated to set up a limited intervention strategy, focusing on clinical bleeding severity irrespective of platelet counts, starting in the emergency room. We report how this strategy was safely applied for 106 consecutive children admitted for newly diagnosed immune thrombocytopenic purpura. PMID- 25454933 TI - Health literacy and medication adherence in adolescents. AB - OBJECTIVE: To assess the relationship between health literacy levels and medication adherence in adolescents. STUDY DESIGN: A convenience sample of adolescents ages 12-21 years was recruited April-September 2011 at an urban adolescent health center. Health literacy and medication adherence was measured via the Rapid Estimate of Adult Literacy in Medicine-TEEN (REALM-TEEN) and Adherence to Refills and Medications Scale. The interrelated effects of age, sex, chronic illness, learning disability, health rating, and health literacy on adherence to medication were explored via the use of regression trees. RESULTS: Of 138 adolescents surveyed, 112 (81%) were included in the analysis because they reported ever taking a medication and completed all survey questions. Median participant age was 16.1 years, 94% were African American, and 64% were female. Median REALM-TEEN score was 57 (6th-7th grade; range 0-66). Median ARMS score was 21 (poor; range 0-56). A positive correlation was found between worse adherence (greater ARMS scores) and self-report of a learning disability (P = .041), and between ARMS scores and having a chronic illness (P = .003). The ARMS and REALM TEEN scores were not correlated (P = .069). Regression tree analysis indicated that adolescents with both a chronic illness and a learning disability had worse ARMS scores (median score 24), compared with adolescents having only a chronic illness (median score 22), independent of health literacy scores. CONCLUSION: Almost one-quarter of adolescents reported having a learning disability and had worse medication adherence independent of health literacy levels. This finding suggests other cognitive factors, beyond reading, may play a role in medication adherence. PMID- 25454934 TI - Association between timing of adiposity rebound and body weight gain during infancy. AB - OBJECTIVE: To investigate whether increments of weight gain in early infancy are related to the timing of adiposity rebound (AR). STUDY DESIGN: A total of 271 children (147 boys and 124 girls) in 1 community were enrolled in the study. Serial measurements of body mass index were carried out at the ages of 4, 8, and 12 months and 1.5, 2, 3, 4, 5, 6, 7, 8, 9, and 10 years, based on which the age of AR was determined. We also calculated body weight increments in 3 separate periods: birth to 4 months, 4-8 months, and 8-12 months. RESULTS: There was no significant relationship between weight gain in any period of infancy and the age of AR. Weight gain between birth and 4 months was positively correlated only with body mass index at 7 years of age. CONCLUSIONS: We could not find an association between body weight gain during infancy and the timing of AR. This suggests that infantile weight gain is not related to childhood obesity through AR. PMID- 25454935 TI - Universal maternal drug testing in a high-prevalence region of prescription opiate abuse. AB - OBJECTIVE: To evaluate the efficacy of a universal maternal drug testing protocol for all mothers in a community hospital setting that experienced a 3-fold increase in neonatal abstinence syndrome (NAS) over the previous 5 years. STUDY DESIGN: We conducted a retrospective cohort study between May 2012 and November 2013 after the implementation of universal maternal urine drug testing. All subjects with positive urine tests were reviewed to identify a history or suspicion of drug use, insufficient prenatal care, placental abruption, sexually transmitted disease, or admission from a justice center, which would have prompted urine testing using our previous risk-based screening guidelines. We also reviewed the records of infants born to mothers with a positive toxicology for opioids to determine whether admission to the special care nursery was required. RESULTS: Out of the 2956 maternal specimens, 159 (5.4%) positive results were recorded. Of these, 96 were positive for opioids, representing 3.2% of all maternity admissions. Nineteen of the 96 (20%) opioid-positive urine tests were recorded in mothers without screening risk factors. Seven of these 19 infants (37%) required admission to the special care nursery for worsening signs of NAS, and 1 of these 7 required pharmacologic treatment. CONCLUSION: Universal maternal drug testing improves the identification of infants at risk for the development of NAS. Traditional screening methods underestimate in utero opioid exposure. PMID- 25454936 TI - Health-related quality of life and asthma among United States adolescents. AB - OBJECTIVE: To examine the direction and the magnitude of associations between asthma and health-related quality of life (HRQoL) in a population-based sample of US adolescents. STUDY DESIGN: We obtained data from the 2001-2010 cross-sectional National Health and Nutrition Examination Survey. We used multinomial logistic regression and negative binomial regression to estimate corresponding percentages, prevalence ratios (PRs), and predicted days of 4 domains of HRQoL by 3 asthma status categories: never having asthma, having asthma without symptoms, and having asthma with symptoms. RESULTS: Compared with those who never had asthma, adolescents with asthma with symptoms of dry cough or wheezing reported significantly worse self-rated health (13.58% [95% CI, 10.32%-17.67%] vs 7.54% [95% CI, 6.50%-8.72%] for fair or poor health), significantly impaired physical health (PR = 1.34, P = .004; adjusted physically unhealthy days, 2.7 days vs 2 days), and impaired mental health (PR = 1.26, P = .025). Among adolescents having asthma with symptoms, those who currently smoked reported 1 more physically unhealthy day and 2.4 more mentally unhealthy days than those who did not smoke and did not have asthma. Those reporting limited physical functioning reported 2 more physically unhealthy days and 1.5 more mentally unhealthy days than those who did not report limited functioning. CONCLUSION: Adolescents with asthma and symptoms reported worse HRQoL compared with those with asthma not reporting symptoms and those without asthma. Those who smoked or reported limited physical functioning reported worse physical and mental HRQoL. Reducing symptoms, quitting smoking, and improving physical functioning may improve HRQoL among adolescents with asthma. PMID- 25454937 TI - Lipidomic analyses, breast- and formula-feeding, and growth in infants. AB - OBJECTIVE: To evaluate lipidomic differences between breast- and formula-fed infants. STUDY DESIGN: We utilized high-resolution mass-spectrometry methods to analyze 3.2 mm dried blood spot samples collected at ages 3 months (n = 241) and 12 months (n = 144) from a representative birth cohort study. Lipidomic profiles were compared between infants exclusively breast-fed, formula-fed, or mixed-fed, and related to 12-month infancy weight. Data analysis included supervised multivariate statistics (partial least squares discriminant analysis), and univariate analysis with correction for multiple testing. RESULTS: Distinct differences in 3-month lipidomic profiles were observed between exclusively breast-fed and formula-fed infants; mixed-fed infants showed intermediate profiles. Principle lipidomic characteristics of breast-fed infants were lower total phosphatidylcholines (PCs), with specifically lower short chain unsaturated PC but higher long chain polyunsaturated PC; higher cholesterol esters; and variable differences in sphingomyelins. At 12 months, lipidomic profiles were markedly different to those at 3 months, and differences between the earlier breast/formula/mixed-feeding groups were no longer evident. However, several specific lipid species, associated with breast-feeding at 3 months, also correlated with differences in 3- to 12-month weight. CONCLUSIONS: State-of-the art dried blood spot sample lipidomic profiling demonstrated striking differences between breast-fed and formula-fed infants. Although these changes diminished with age, breast-fed lipidomic profiles at 3 months were associated with infancy weight and could potentially represent biomarkers of infant nutrition. PMID- 25454938 TI - Effects of automated adjustment of the inspired oxygen on fluctuations of arterial and regional cerebral tissue oxygenation in preterm infants with frequent desaturations. AB - OBJECTIVE: To assess the effect of automated adjustment of the inspired oxygen fraction (FiO2) on arterial oxygen saturation (SpO2) and cerebral tissue oxygen saturation (SctO2) in very low birth weight infants with frequent fluctuations in oxygenation. STUDY DESIGN: Fifteen infants (median gestational age, 25 weeks [range, 23-28 weeks]; median age, 34 days [range, 19-74 days]) were assigned in random sequence to 24 hours of automated adjustment of FiO2 or manual adjustment of FiO2. Primary outcome measurements were time within the SpO2 target range and the area under the curve above and below a defined SctO2 range. RESULTS: Percentage of time within the SpO2 target range increased during automated FiO2 control (76.3% +/- 9.2% vs 69.1% +/- 8.2% for manual; P < .01). Prolonged episodes with SpO2 <88% of >60 seconds duration (median, 115 episodes [range, 67 240] vs 54 episodes [range, 7-184]; P < .01) and of >180 seconds duration (median, 13 episodes [range, 6-39] vs 2 episodes [range, 0-5]; P < .01) decreased significantly during the automated period. Percentage of time with SpO2 >96% decreased during automated control (6.6% +/- 4.4% vs 10.4% +/- 3.3%; P < .02). There was no significant difference in FiO2 exposure. The area (deviation * time) below and above the defined SctO2 threshold did not differ between the 2 periods (median, 59.7%*seconds [range, 17.2%-208.3%] for manual vs 49.0%*seconds [range, 4.3%-193.7%] for automated; P = .36). CONCLUSION: Automated FiO2 control in preterm infants with frequent SpO2 fluctuations significantly increased the time within the SpO2 target range and reduced the incidence of prolonged hypoxemic events compared with manual FiO2 adjustment, but did not significantly affect cerebral tissue oxygenation. PMID- 25454940 TI - Allergen skin prick testing in early childhood: reproducibility and prediction of allergic symptoms into early adulthood. AB - OBJECTIVE: To assess the predictive value of skin prick testing in early childhood on subsequent allergic symptoms up to adult age. STUDY DESIGN: A cohort of 200 unselected healthy newborns was prospectively followed from birth to 20 years of age. Of them, 163 (82%) were reassessed at age 5 years, 150 (76%) at age 11 years, and 164 (83%) at age 20 years with a skin prick test that included 11 common allergens. On the basis of clinical examination and structured interview, the occurrence of atopic dermatitis, allergic rhinoconjunctivitis, recurrent wheezing, and symptoms of food hypersensitivity were recorded at each of the follow-up visits. RESULTS: The reproducibility of skin prick test positivity at age 5 years was 100% at ages 11 and 20 years, ie, none of the skin prick-positive subjects turned negative during the follow-up. Gaining of new sensitizations to aeroallergens was common. Skin prick test positivity at age 5 years predicted allergic symptoms at ages 11 (sensitivity 28%, specificity 94%) and 20 years (sensitivity 23%, specificity 91%) but not atopic dermatitis. CONCLUSIONS: Skin prick test positivity at age 5 years strongly predicts later skin prick test positivity and is associated with respiratory symptoms, ie, allergic rhinoconjunctivitis and recurrent wheezing, at ages 11 and 20 years. However, skin prick test negativity at age 5 years does not exclude sensitization and allergic symptoms at a later age. PMID- 25454942 TI - Multicenter randomized controlled trial of inhaled nitric oxide for pediatric acute respiratory distress syndrome. AB - OBJECTIVES: To test the hypothesis that inhaled nitric oxide (iNO) would lead to improved oxygenation and a decrease in duration of mechanical ventilation in pediatric patients with acute respiratory distress syndrome. STUDY DESIGN: A total of 55 children with acute respiratory distress syndrome were enrolled from 9 centers. Patients were randomized to iNO or placebo and remained on the study drug until death, they were free of ventilator support, or day 28 after the initiation of therapy. RESULTS: Mean baseline oxygenation indexes (OIs) were 22.0 +/- 18.4 and 25.6 +/- 14.9 (iNO and placebo groups, respectively, P = .27). There was a trend toward an improved OI in the iNO group compared with the placebo group at 4 hours that became significant at 12 hours. There was no difference in the OI between groups at 24 hours. Days alive and ventilator free at 28 days was greater in the iNO group, 14.2 +/- 8.1 and 9.1 +/- 9.5 days (iNO and placebo groups, respectively, P = .05). Although overall survival at 28 days failed to reach statistical significance, 92% (22 of 24) in the iNO group and 72% (21 of 29) in the placebo group (P = .07), the rate of extracorporeal membrane oxygenation-free survival was significantly greater in those randomized to iNO 92% (22 of 24) vs 52% (15 of 29) for those receiving placebo (P < .01). CONCLUSION: The use of iNO was associated with a significantly reduced duration of mechanical ventilation and significantly greater rate of extracorporeal membrane oxygenation-free survival. PMID- 25454941 TI - The role of perceived discrimination during childhood and adolescence in understanding racial and socioeconomic influences on depression in young adulthood. AB - OBJECTIVE: To describe levels of perceived lifetime discrimination among young adults and determine its role in understanding this racial/ethnic disparity. STUDY DESIGN: Data were from the Princeton School District study, a 10-year cohort study in which investigators followed 545 non-Hispanic black (46%) and white initial 5-12 graders. Perceived lifetime racial discrimination was assessed with the General Ethnic Discrimination Scale and depressive symptoms with the Center for Epidemiological Studies Depression Scale. Stepped linear and logistic regression analyses assessed the relationships of race/ethnicity, parental education, and quintiles of discrimination to depressive symptoms. Stratification by race/ethnicity explored differences in the role of discrimination in explaining the relationship between parental education and depressive symptoms. RESULTS: Black students from professionally educated families had the greatest discrimination scores, 1.8 times greater than among their white peers (meanblack = 42.1 vs meanwhite = 22.8; P < .0001). Greater parental education was associated with lower depressive symptoms in all regression models. Race/ethnicity became predictive of depressive symptoms only after adjusting for discrimination, which was strongly associated with depressive symptoms. Stratified analysis suggested discrimination accounted for the relationship of parental education to depressive symptoms among whites. Among black subjects, accounting for discrimination unmasked a buffering effect of parental education. CONCLUSIONS: Greater levels of parent education are protective against depression for white youth. However, for black youth, greater parent education confers both risk and protective effects. The high discrimination among black youth from families with college or professionally educated parents overwhelms the protective effect of greater levels of parent education. PMID- 25454939 TI - Central adiposity is negatively associated with hippocampal-dependent relational memory among overweight and obese children. AB - OBJECTIVE: To assess associations between adiposity and hippocampal-dependent and hippocampal-independent memory forms among prepubertal children. STUDY DESIGN: Prepubertal children (age 7-9 years; n = 126), classified as non-overweight (<85th percentile body mass index [BMI]-for-age [n = 73]) or overweight/obese (>=85th percentile BMI-for-age [n = 53]), completed relational (hippocampal dependent) and item (hippocampal-independent) memory tasks. Performance was assessed with both direct (behavioral accuracy) and indirect (preferential disproportionate viewing [PDV]) measures. Adiposity (ie, percent whole-body fat mass, subcutaneous abdominal adipose tissue, visceral adipose tissue, and total abdominal adipose tissue) was assessed by dual-energy X-ray absorptiometry. Backward regression identified significant (P < .05) predictive models of memory performance. Covariates included age, sex, pubertal timing, socioeconomic status (SES), IQ, oxygen consumption, and BMI z-score. RESULTS: Among overweight/obese children, total abdominal adipose tissue was a significant negative predictor of relational memory behavioral accuracy, and pubertal timing together with SES jointly predicted the PDV measure of relational memory. In contrast, among non overweight children, male sex predicted item memory behavioral accuracy, and a model consisting of SES and BMI z-score jointly predicted the PDV measure of relational memory. CONCLUSION: Regional, but not whole-body, fat deposition was selectively and negatively associated with hippocampal-dependent relational memory among overweight/obese prepubertal children. PMID- 25454943 TI - Postconcussion symptoms are associated with cerebral cortical thickness in healthy collegiate and preparatory school ice hockey players. AB - OBJECTIVE: To investigate the degree to which concussion history and postconcussive symptoms are associated with cortical morphology among male hockey players. STUDY DESIGN: Male subjects (n = 29), ranging in age from 14 to 23 years (mean 17.8 years), were recruited from preparatory school and collegiate ice hockey teams and underwent neuroimaging and baseline Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) testing. Cerebral cortical thickness was regressed against ImPACT Total Symptom Score (TSS), concussion history, as well as baseline measures of psychopathology. Reconstruction of surfaces and cortical thickness analysis were conducted with FreeSurfer (version 5.3.0). RESULTS: ImPACT TSS was inversely associated with local cortical thickness in widespread brain areas. Associations were revealed in a host of frontal as well as bilateral temporoparietal cortices. Conversely, concussion history was not associated with cortical thickness. An "Age by Concussion History" interaction was associated with thickness in the right ventrolateral and right parietal cortices. Post-hoc analysis revealed that concussed participants did not exhibit age-related cortical thinning in these regions. CONCLUSION: We have identified an association between brain structure and postconcussive symptoms among young, otherwise-healthy male athletes. Postconcussive symptoms and related reductions in cortical thickness may be tied to participation in a full-contact sport that involves frequent blows to the head. PMID- 25454944 TI - Mgr2 functions as lateral gatekeeper for preprotein sorting in the mitochondrial inner membrane. AB - The majority of preproteins destined for mitochondria carry N-terminal presequences. The presequence translocase of the inner mitochondrial membrane (TIM23 complex) plays a central role in protein sorting. Preproteins are either translocated through the TIM23 complex into the matrix or are laterally released into the inner membrane. We report that the small hydrophobic protein Mgr2 controls the lateral release of preproteins. Mgr2 interacts with preproteins in transit through the TIM23 complex. Overexpression of Mgr2 delays preprotein release, whereas a lack of Mgr2 promotes preprotein sorting into the inner membrane. Preproteins with a defective inner membrane sorting signal are translocated into the matrix in wild-type mitochondria but are released into the inner membrane in Mgr2-deficient mitochondria. We conclude that Mgr2 functions as a lateral gatekeeper of the mitochondrial presequence translocase, providing quality control for the membrane sorting of preproteins. PMID- 25454945 TI - A divergent role of the SIRT1-TopBP1 axis in regulating metabolic checkpoint and DNA damage checkpoint. AB - DNA replication is executed only when cells have sufficient metabolic resources and undamaged DNA. Nutrient limitation and DNA damage cause a metabolic checkpoint and DNA damage checkpoint, respectively. Although SIRT1 activity is regulated by metabolic stress and DNA damage, its function in these stress mediated checkpoints remains elusive. Here we report that the SIRT1-TopBP1 axis functions as a switch for both checkpoints. With glucose deprivation, SIRT1 is activated and deacetylates TopBP1, resulting in TopBP1-Treslin disassociation and DNA replication inhibition. Conversely, SIRT1 activity is inhibited under genotoxic stress, resulting in increased TopBP1 acetylation that is important for the TopBP1-Rad9 interaction and activation of the ATR-Chk1 pathway. Mechanistically, we showed that acetylation of TopBP1 changes the conformation of TopBP1, thereby facilitating its interaction with distinct partners in DNA replication and checkpoint activation. Taken together, our studies identify the SIRT1-TopBP1 axis as a key signaling mode in the regulation of the metabolic checkpoint and the DNA damage checkpoint. PMID- 25454946 TI - Mutant p53 reprograms TNF signaling in cancer cells through interaction with the tumor suppressor DAB2IP. AB - Inflammation is a significant factor in cancer development, and a molecular understanding of the parameters dictating the impact of inflammation on cancers could significantly improve treatment. The tumor suppressor p53 is frequently mutated in cancer, and p53 missense mutants (mutp53) can acquire oncogenic properties. We report that cancer cells with mutp53 respond to inflammatory cytokines increasing their invasive behavior. Notably, this action is coupled to expression of chemokines that can expose the tumor to host immunity, potentially affecting response to therapy. Mechanistically, mutp53 fuels NF-kappaB activation while it dampens activation of ASK1/JNK by TNFalpha, and this action depends on mutp53 binding and inhibiting the tumor suppressor DAB2IP in the cytoplasm. Interfering with such interaction reduced aggressiveness of cancer cells in xenografts. This interaction is an unexplored mechanism by which mutant p53 can influence tumor evolution, with implications for our understanding of the complex role of inflammation in cancer. PMID- 25454947 TI - The yeast ER-intramembrane protease Ypf1 refines nutrient sensing by regulating transporter abundance. AB - Proteolysis by aspartyl intramembrane proteases such as presenilin and signal peptide peptidase (SPP) underlies many cellular processes in health and disease. Saccharomyces cerevisiae encodes a homolog that we named yeast presenilin fold 1 (Ypf1), which we verify to be an SPP-type protease that localizes to the endoplasmic reticulum (ER). Our work shows that Ypf1 functionally interacts with the ER-associated degradation (ERAD) factors Dfm1 and Doa10 to regulate the abundance of nutrient transporters by degradation. We demonstrate how this noncanonical branch of the ERAD pathway, which we termed "ERAD regulatory" (ERAD R), responds to ligand-mediated sensing as a trigger. More generally, we show that Ypf1-mediated posttranslational regulation of plasma membrane transporters is indispensible for early sensing and adaptation to nutrient depletion. The combination of systematic analysis alongside mechanistic details uncovers a broad role of intramembrane proteolysis in regulating secretome dynamics. PMID- 25454949 TI - A nonmetropolitan surgery clerkship increases interest in a surgical career. AB - BACKGROUND: The optimal way to recruit the best and brightest medical students to fill the impending shortfall of general surgeons is uncertain. METHODS: Forty three students were placed into nonmetropolitan sites for their basic surgical clerkship over 3 years. We surveyed students and compared match trends. RESULTS: When students selected to participate in the nonmetropolitan clerkship were examined, only 22% of students reported interest in a surgical career before their clerkship. This interest in surgery increased to 63% after the nonmetropolitan clerkship, P < .05. When match numbers were examined, students who completed the nonmetropolitan clerkship were significantly more likely to match to a general surgical residency than students who completed the standard clerkship (17% vs 6%, P < .02). CONCLUSIONS: These data challenge the perception that students should remain at a teaching university for their introductory clerkships. It may be that pairing students with individual faculty, or chief residents, could increase interest in a surgical career. PMID- 25454950 TI - The effect of blocked versus random task practice schedules on the acquisition and retention of surgical skills. AB - BACKGROUND: When learning multiple tasks, blocked or random training schedules may be used. We assessed the effects of blocked and random schedules on the acquisition and retention of laparoscopic skills. METHODS: Thirty-six laparoscopic novices were randomized to practice laparoscopic tasks using blocked, random, or no additional training. Participants performed immediate post tests, followed by retention tests 6 weeks later. Outcomes included previously validated Fundamentals of Laparoscopic Surgery (FLS) and hand-motion efficiency scores. RESULTS: Both blocked and random groups had significantly higher FLS and hand-motion efficiency scores over baseline on post-tests for each task (P < .05) and higher overall FLS scores than controls on retention tests (P < .01). No difference was seen between the blocked and random groups in the amount of skill acquired or skill retained. CONCLUSIONS: Both blocked and random training schedules can be considered as valid training options to allow programs and learners to tailor training to their individual needs. PMID- 25454948 TI - Adenylation of maternally inherited microRNAs by Wispy. AB - Early development depends heavily on accurate control of maternally inherited mRNAs, and yet it remains unknown how maternal microRNAs are regulated during maternal-to-zygotic transition (MZT). We here find that maternal microRNAs are highly adenylated at their 3' ends in mature oocytes and early embryos. Maternal microRNA adenylation is widely conserved in fly, sea urchin, and mouse. We identify Wispy, a noncanonical poly(A) polymerase, as the enzyme responsible for microRNA adenylation in flies. Knockout of wispy abrogates adenylation and results in microRNA accumulation in eggs, whereas overexpression of Wispy increases adenylation and reduces microRNA levels in S2 cells. Wispy interacts with Ago1 through protein-protein interaction, which may allow the effective and selective adenylation of microRNAs. Thus, adenylation may contribute to the clearance of maternally deposited microRNAs during MZT. Our work provides mechanistic insights into the regulation of maternal microRNAs and illustrates the importance of RNA tailing in development. PMID- 25454951 TI - Quantitative and qualitative analysis of performance during advanced laparoscopic fellowship: a curriculum based on structured assessment and feedback. AB - BACKGROUND: The objective of this study was to examine the acquisition of advanced laparoscopic technical and cognitive skills during a fellowship. METHODS: During a yearlong fellowship, consecutive assessments were completed by a fellow and 1 attending for 3 advanced procedures. The Global Operative Assessment of Laparoscopic Skills, Objective Structured Assessment of Technical Skills, and procedure-specific rating tools and free-text feedback were used. Descriptive statistics, the t test, linear mixed-effects regression, and qualitative analysis of feedback were performed. RESULTS: Seventy-six cases were included. Average ratings increased for each assessment area every month (P < .001). There were significant differences between ratings by assessors with more stringent ratings by the fellow. While the attending focused on efficiency and safety, the fellow focused on technical issues, with later expanded attention to advanced cognitive aspects. CONCLUSIONS: These assessment tools can be used as a quantitative index to monitor fellows' learning curve. In combination with narrative feedback, such data can provide measures to direct improvement during self-directed learning. PMID- 25454952 TI - Smartphones let surgeons know WhatsApp: an analysis of communication in emergency surgical teams. AB - BACKGROUND: Outdated communication technologies in healthcare can place patient safety at risk. This study aimed to evaluate implementation of the WhatsApp messaging service within emergency surgical teams. METHODS: A prospective mixed methods study was conducted in a London hospital. All emergency surgery team members (n = 40) used WhatsApp for communication for 19 weeks. The initiator and receiver of communication were compared for response times and communication types. Safety events were reported using direct quotations. RESULTS: More than 1,100 hours of communication pertaining to 636 patients were recorded, generating 1,495 communication events. The attending initiated the most instruction-giving communication, whereas interns asked the most clinical questions (P < .001). The resident was the speediest responder to communication compared to the intern and attending (P < .001). The participants felt that WhatsApp helped flatten the hierarchy within the team. CONCLUSIONS: WhatsApp represents a safe, efficient communication technology. This study lays the foundations for quality improvement innovations delivered over smartphones. PMID- 25454953 TI - Does laparoscopic simulation predict intraoperative performance? A comparison between the Fundamentals of Laparoscopic Surgery and LapVR evaluation metrics. AB - BACKGROUND: Considerable resources have been invested in low- and high-fidelity simulators in surgical training. To our knowledge, no investigation has compared the 2 head to head for operative assessment purposes. The purpose of this study was to assess the Fundamentals of Laparoscopic Surgery (FLS) low-fidelity video trainer and LapVR (high-fidelity virtual-reality simulator) for (1) construct and (2) predictive validity using a human cholecystectomy model. METHODS: Twenty-six participants performed tasks from the FLS program and the LapVR simulator as well as a human laparoscopic cholecystectomy. Performance was evaluated using FLS and LapVR metrics and the Objective Structured Assessment of Technical Skills previously validated rating scale. RESULTS: Construct and predictive validity were strongly demonstrated for FLS tasks but only incompletely for LapVR. CONCLUSIONS: Efforts should be focused on using the well-validated lower-cost FLS video trainer for assessment of laparoscopic skills. The high-cost LapVR remains experimental in resource-constrained training programs. PMID- 25454955 TI - Validity evidence for Surgical Improvement of Clinical Knowledge Ops: a novel gaming platform to assess surgical decision making. AB - BACKGROUND: Current surgical education curricula focus mainly on the acquisition of technical skill rather than clinical and operative judgment. SICKO (Surgical Improvement of Clinical Knowledge Ops) is a novel gaming platform developed to address this critical need. A pilot study was performed to collect validity evidence for SICKO as an assessment for surgical decision making. METHODS: Forty nine subjects stratified into 4 levels of expertise were recruited to play SICKO. Later, players were surveyed regarding the realism of the gaming platform as well as the clinical competencies required of them while playing SICKO. RESULTS: Each group of increasing expertise outperformed the less experienced groups. Mean total game scores for the novice, junior resident, senior resident, and expert groups were 5,461, 8,519, 11,404, and 13,913, respectively (P = .001). Survey results revealed high scores for realism and content. CONCLUSIONS: SICKO holds the potential to be not only an engaging and immersive educational tool, but also a valid assessment in the armamentarium of surgical educators. PMID- 25454954 TI - Research priorities for multi-institutional collaborative research in surgical education. AB - BACKGROUND: Research in surgical education has seen unprecedented growth but originates from single institutions and remains uncoordinated; this study aimed to generate a list of research priorities in surgical educational topics. METHODS: The membership of the Association for Surgical Education was asked to submit up to 5 research questions concerned with multi-institutional collaborative surgical education research and to identify challenges faced by surgical education researchers. A modified Delphi methodology was used to create the research agenda based on these responses. RESULTS: Surgical educators responded to 3 survey rounds. Categories of submitted questions included teaching methods and curriculum development; assessment and competency; simulation; medical student preparation and selection; impact of work hour restrictions; and faculty development. Participants cited institutional culture and practice variability and lack of institutional review board coordination as common barriers to collaborative research, while identifying extensive planning, frequent communication, and availability of dedicated research coordinators as the most important facilitators. CONCLUSIONS: Using a Delphi methodology, a prioritized agenda for multi-institutional surgical education research was developed that may help advance surgeon education. PMID- 25454956 TI - Cost and logistics for implementing the American College of Surgeons objective structured clinical examination. AB - BACKGROUND: The American College of Surgeons has developed a reliable and valid OSCE (objective structured clinical examination) to assess the clinical skills of incoming postgraduate year 1 surgery residents, but the cost and logistics of implementation have not been described. METHODS: Fixed costs included staff time, medical supplies, facility fee, standardized patient (SP) training time, and one OSCE session. Variable costs were incurred for additional OSCE sessions. Costs per resident were calculated and modeled for increasing the number of test takers. RESULTS: American College of Surgeons OSCE materials and examination facilities were free. Fixed costs included training 11 SPs for 4 hours ($1,540), moulage and simulation material ($469), and administrative effort for 44 hours ($2,200). Variable cost for each session was $1,540 (SP time). Total cost for the first session was $6,649 ($664/resident), decreased to $324/resident for 3 sessions, and projected to further decline to $239/resident for 6 sessions. CONCLUSIONS: The cost decreased as the number of residents tested increased. To manage costs, testing more trainees by regional collaboration is recommended. PMID- 25454957 TI - A multi-institutional study of the emotional intelligence of resident physicians. AB - BACKGROUND: Although emotional intelligence (EI) may have a role in the development of Accreditation Council for Graduate Medical Education core competencies, few studies have measured resident EI across specialties. This study aimed to describe the EI of resident physicians across multiple specialties. METHODS: Three hundred twenty five surgery, pediatric, and pathology residents at 3 large academic institutions were invited to complete the psychometrically validated Trait Emotional Intelligence Questionnaire. RESULTS: The response rate was 42.8% (n = 139). Global EI of all residents (101.0 +/- 8.1) was comparable with, but less variable than, the general population sample and was not statistically different between specialties. Compared with the norm sample, residents in the 3 specialty groups demonstrated unique combinations of areas of relative high and low development. CONCLUSIONS: There exist distinct strengths and opportunities for the development for surgery, pediatrics, and pathology residents. Future investigations could use EI profiling to create educational interventions to develop specific areas of EI and assess correlation with resident performance. PMID- 25454958 TI - A national survey of educational resources utilized by the Resident and Associate Society of the American College of Surgeons membership. AB - BACKGROUND: Contemporary surgical education includes online resources, mobile platform applications, and simulation training. The aim of this study was to characterize educational tools used by surgical residents. METHODS: An anonymous web-based survey was distributed to 9,913 members of the Resident and Associate Society of the American College of Surgeons. RESULTS: We received 773 completed surveys. To prepare for examinations and expand fund of knowledge, most respondents used printed textbooks, online textbooks, and Surgical Council on Resident Education modules, respectively. Respondents used online textbooks and journal articles most often to investigate timely patient care issues. In contrast, mobile platform applications and online videos/lectures were used least. Fewer than half of respondents used simulators, limited by clinical duties, absence of feedback/supervision, and lack of working supplies. CONCLUSIONS: Traditional educational resources dominate trainee preferences, although utilization of the Surgical Council on Resident Education curriculum continues to grow. Simulators remain a required tool for laparoscopic training, and incorporation of structured feedback and improved supervision may improve utilization. PMID- 25454959 TI - Systems-based practice: learning the concepts using a teamwork competition model. AB - BACKGROUND: Systems-based practice (SBP) is a core competency of the Accreditation Council for Graduate Medical Education (ACGME) that must be integrated into residency training. We sought to develop a method to improve resident understanding using a teamwork competition model. METHODS: The residents were given a pretest to assess their understanding of SBP followed by a didactic lecture. They were then divided into teams to solve a programmatic "problem" in the residency. Each team had to prove that their solution best fulfilled the expectations of SBP. Their solutions were then presented at a departmental conference followed by a post-test to evaluate knowledge. RESULTS: In the pretest, 33% of the residents understood what SBP meant and only 15% knew the components of SBP. In the post-test, this increased to 85% and 89%, respectively. CONCLUSIONS: SBP is a competency mandated by the Accreditation Council for Graduate Medical Education in residency training. Using a novel approach, we were able to improve the residents' understanding of SBP. PMID- 25454960 TI - A taxonomy of surgeons' guiding behaviors in the operating room. AB - BACKGROUND: This study explores the nature and the intention of attending surgeons' guiding behaviors performed in the operating room (OR) in order to build taxonomy of OR guiding behavior. METHODS: Nine attending surgeons and 8 surgical residents were invited to observe 8 prerecorded surgical cases from 4 common procedures and completed semistructured interviews. All video-based observations were videotaped. Thematic analysis was applied to identify surgeons' OR guiding behavior. RESULTS: Seven hundred eighty minutes of video-based observations with interviews were conducted. Sixteen types of OR guiding behaviors in 3 intention-based categories were identified: 3 of the 16 was "teaching" (18.75%), 8 of the 16 was "directing" (50%), and 5 of the 16 was "assisting" (31.25%). CONCLUSIONS: Surgeons' OR guiding behaviors were grounded in 3 behavioral intentions: teaching, directing, and assisting. This taxonomy of OR guiding behavior can be used as a basis for developing OR guiding strategy to improve residents' intraoperative competency, autonomy, and independence. PMID- 25454961 TI - Effects of disruptive surgeon behavior in the operating room. AB - BACKGROUND: Surgeons are the physician group most commonly identified as "disruptive physicians." The aim of this study was to develop a conceptual model of the results of disruptive surgeon behavior and to identify the coping strategies used by perioperative staff. METHODS: Perspectives of 19 individuals of diverse occupations in the perioperative setting were drawn together using a grounded theory methodology. RESULTS: Effects of disruptive behavior described by participants included shift in attention from the patient to the surgeon, increased mistakes during procedures, deterrence from careers in surgery, and diminished respect for surgeons. Individual coping strategies employed in the face of intimidation include talking to colleagues, externalizing the behavior, avoidance of perpetrators, and warning others. CONCLUSIONS: Using grounded theory analysis, we were able to elucidate the impact of disruptive surgeon behavior in the perioperative environment. This conceptual model may be used to understand and counter the negative effects of manipulation and intimidation of hospital staff and trainees and to build on current programmatic strengths to improve surgical environments and training. PMID- 25454962 TI - Use of decision-based simulations to assess resident readiness for operative independence. AB - BACKGROUND: Recent literature has called into question resident readiness for operative independence at the end of general surgery training. METHODS: We used a simulation-based exit examination to assess resident readiness. Six chief residents performed 3 simulated procedures: bowel anastomosis, laparoscopic ventral hernia (LVH) repair, and pancreaticojejunostomy. Faculty assessed resident performance using task-specific checklists, Objective Structured Assessment of Technical Skills (OSATS), and final product analysis. RESULTS: Residents' individual task-specific checklist scores ranged from 25% to 100% across all 3 procedures. Mean OSATS scores ranged from 4.06 to 4.23/5.0. Residents scored significantly higher on "instrument knowledge" (mean = 4.78, standard deviation [SD] = 23) than "time and motion" (mean = 3.94, SD = .48, P = .025) and "ability to adapt to individual pathologic circumstances" (mean = 4.06, SD =.12, P = .002). Final product analysis revealed a range of errors, including incorrect technique and poor intraoperative planning. CONCLUSIONS: Despite relatively high OSATS ratings, residents had a wide range of errors and procedure outcomes. Exit assessments using multiple evaluation metrics may improve awareness of residents' learning needs. PMID- 25454963 TI - A real-time mobile web-based module promotes bidirectional feedback and improves evaluations of the surgery clerkship. AB - BACKGROUND: We implemented a real-time mobile web-based reporting module for students in our surgery clerkship and evaluated its effect on student satisfaction and perceived abuse. METHODS: Third-year medical students in the surgery clerkship received surveys regarding intimidation, perceived abuse, satisfaction with clerkship resources, and interest in a surgical career. Survey data were analyzed to assess differences after implementing the mobile reporting system and to identify independent predictors of perceived abuse. RESULTS: With the reporting module, students perceived less intimidation by residents (P < .001) and by faculty (P = .008), greater satisfaction reporting feedback (P < .001), and greater interest in surgical careers (P = .003). Perceived abuse decreased without reaching statistical significance (P = .331). High ratings of intimidation by faculty independently predicted perceived abuse (odds ratio = 1.3), and satisfaction with anonymous reporting was a negative predictor (odds ratio = .2). CONCLUSIONS: A mobile web-based system for real-time reporting fosters open communication and bidirectional feedback and promotes greater satisfaction with the surgery clerkship and interest in a surgical career. PMID- 25454964 TI - Relationship between physiologic and psychological measures of autonomic activation in operating room teams during a simulated airway emergency. AB - BACKGROUND: Emotional stability is important for individual and team performance during operating room (OR) emergencies. We compared physiologic and psychological anxiety assessments in OR teams during simulated events. METHODS: Twenty-two teams participated in a "cannot intubate/cannot ventilate" simulation. Participants completed the State-Trait Anxiety Inventory and wore a galvanic skin response (GSR) sensor. Differences in State-Trait Anxiety Inventory scores and GSR levels were analyzed. Anxiety scores were correlated with GSR levels. RESULTS: Resident physicians had significantly higher trait anxiety than the nurses, certified registered nurse anesthetists, and surgical technicians (43.9 +/- 9.9 vs 38.3 +/- 9.3, P < .01). Senior practitioners had significantly higher trait anxiety than junior practitioners (43.7 +/- 9.6 vs 40.0 +/- 9.9, P = .03). All groups showed significant increases in GSR. Psychological and physiologic data did not correlate. CONCLUSIONS: Senior practitioners and residents have higher levels of baseline trait anxiety for unclear reasons. Also, OR team training results in physiological signs of anxiety that do not correlate to self reported psychological measurements. PMID- 25454965 TI - Student-led learning: a new teaching paradigm for surgical skills. AB - BACKGROUND: Competency-based education and simulation are being used more frequently in surgical skills curricula. We explored a novel student-led learning paradigm, which allows trainees to become more active participants in the learning process while maintaining expert guidance and supervision. METHODS: Twelve first-year orthopedic residents were randomized to either a student-led (SL) or a traditional instructor-led group during an intensive, month-long, laboratory-based technical skills training course. A rigorous qualitative description approach was used for analysis. RESULTS: Four prominent themes emerged: instructional style, feedback, peer and instructor collaboration, and self-efficacy. Compared with the instructor-led group, there was more peer assistance, feedback, collaboration, and hands-on and active learning observed in the SL group. CONCLUSIONS: The flexible and socially rich nature of the SL learning environment may aid in development of both technical and nontechnical skills early in residency and ultimately privilege later clinical learning. PMID- 25454966 TI - The association for surgical education CESERT grant program: the first 15 years. AB - BACKGROUND: The Association for Surgical Education established the Center for Excellence in Surgical Education Research and Training (CESERT) program in 1999 to support innovative research and education projects and programs that will advance surgical education. We sought to examine scholarly outcomes of the projects during the first 15 years of the program. METHODS: E-mail surveys were sent to the 24 researchers who were awarded CESERT grants. Data collection focused on recipient professional experiences, publications, and presentations stemming from CESERT-funded research and impact on career development. For grant recipients who were unable to complete the survey, we obtained publication information on studies authored by the grant recipients that described the same grant-funded topic, described similar methods, and fell within the study timeline. RESULTS: Complete survey data were obtained from 18 of the 24 grant recipients. Grants were most commonly awarded to General Surgeons (40%) and Education and Psychology PhDs (24%). Overall, 23 of the 25 projects had reached completion at the time of contact, and from these, 70 articles were published or in press. Abstract presentations were more common, with respondents documenting 84 projects locally, nationally, and internationally. Grant awards ranged from $8,122 to $97,000, with an average of $39,026. In total, the Association for Surgical Education Foundation distributed $988,000 in grant funding from 1999 to 2013. Respondents reported that CESERT funding was critical to their career as it legitimized their pursuit of educational research, helped them establish multidisciplinary and multi-institutional collaborations, provided greater visibility for their research, and helped them develop an understanding of educational principles and grant writing skills. CONCLUSIONS: Overall, the CESERT program has produced remarkable results. The careful review process and monitoring protocol have ensured that high-potential studies are funded and successful. These data support continued efforts to garner resources such that CESERT grants may be awarded to fund high-quality, high-impact projects. PMID- 25454967 TI - The therapeutic effect of collateral meridian therapy is comparable to acupoint pressure therapy in treating myofascial pain syndrome. AB - PURPOSE: This study compared the therapeutic effects of collateral meridian therapy (CMT) with traditional acupoint pressure therapy (APT) in patients with unilateral upper back pain. MATERIAL AND METHODS: Forty-nine patients with active myofascial trigger points in upper trapezius muscle were randomly allocated to the control (CTL), APT, or CMT group. Each subject in the CMT and APT groups received 2 sessions of treatment per week over 1 month. RESULTS: Patients in the APT and CMT groups showed significant improvements 1 month after treatment in visual analogue scale, range of motion, pain pressure threshold, regional superficial blood flow, and physical health, as compared to the CTL group. No significant differences in outcome measures were found between APT and CMT groups 1 month after treatment. CONCLUSION: Both APT and CMT have comparable therapeutic efficacy in the treatment of unilateral upper back pain with active myofascial trigger points in the upper trapezius muscle. PMID- 25454968 TI - Receiving or not receiving acupuncture in a trial: the experience of participants recovering from breast cancer treatment. AB - OBJECTIVE: To explore the experience of breast cancer patients who either received acupuncture or were allocated to the control group. METHODS: Focus group/interviews nested within our multi-site randomised controlled trial. Participants were recruited from the standard care and experimental arm. The interviews/focus groups were transcribed and analysed thematically. RESULTS: Of the 302 eligible participants 13% (n = 40) contributed to the focus groups/interviews, across three study sites in the UK. Five common themes were identified, including: drivers to take part, the experience of receiving acupuncture, being allocated standard care (control) and reflections on taking part in the trial. The subgroup of control group participants (n = 9) reported disappointment on hearing their allocation, but recognised the value of their role to the study. CONCLUSIONS: Recipients of acupuncture reported beneficial effects in managing fatigue and related symptoms. The finding that control participants were disappointed warrants further investigation and consideration when designing interventional studies. PMID- 25454969 TI - Xeno-immunogenicity of ice-free cryopreserved porcine leaflets. AB - BACKGROUND: Undesirable processes of inflammation, calcification, or immune mediated reactions are limiting factors in long-term survival of heart valves in patients. In this study, we target the modulatory effects of ice-free cryopreservation (IFC) of xenogeneic heart valve leaflet matrices, without decellularization, on the adaptive human immune responses in vitro. METHODS: We tested porcine leaflet matrices from fresh untreated, conventionally cryopreserved (CFC), and IFC pulmonary valves by culturing them with human blood mononuclear cells for 5 d in vitro. No other tissue treatment protocols to modify possible immune responses were used. Matrices alone or in addition with a low dose second stimulus were analyzed for induction of proliferation and cytokine release by flow cytometry-based techniques. Evaluation of the alpha-Gal epitope expression was performed by immunohistochemistry with fluorochrome-labeled B4 isolectin. RESULTS: None of the tested leaflet treatment groups directly triggered the proliferation of immune cells. But when tested in combination with a second trigger by anti-CD3, IFC valves showed significantly reduced proliferation of T cells, especially effector memory T cells, in comparison with fresh or CFC tissue. Moreover, the cytokine levels for interferon-gamma (IFNgamma), tumor necrosis factor alpha, and interleukin-10 were reduced for the IFC-treated group being significantly different compared with the CFC group. However, no difference between treatment groups in the expression of the alpha Gal antigen was observed. CONCLUSIONS: IFC of xenogeneic tissue might be an appropriate treatment method or processing step to prevent responses of the adaptive immune system. PMID- 25454970 TI - Hemostatic sponge effect on adhesion prevention in a porcine model. AB - BACKGROUND: In this work, we aimed to assess the preventive effect of an absorbable hemostatic collagen sponge (HCS) on the reduction of postsurgical gynecological adhesions in a porcine model. MATERIALS AND METHODS: Forty female pigs were subjected to a right uterine horn myotomy and left uterine horn deserosation. They were randomly divided into two groups, HCS application and control, which were rearranged into laparotomy and laparoscopy groups. Resulting adhesions were macroscopically and microscopically semiquantitatively analyzed after a 5 mo follow-up. RESULTS: The incidence of adhesion-free animals did not significantly differ between groups, although it increased when the HCS was placed in both laparotomy (from 10%-12.5%) and laparoscopy groups (from 20%-50%). On the contrary, a significant reduction was observed in adhesion severity when the HCS was applied in the laparotomy groups (P < 0.01). Regarding microscopic study, hemostatic sponge application significantly reduced the inflammation score in the laparoscopic approach (P < 0.01). Fibrosis, unlike inflammation, differs between both approaches. In the laparoscopic group, fibrosis was reduced with application of the HCS, whereas in the laparotomy group greater fibrosis was observed within the HCS group. CONCLUSIONS: HCS has shown to be safe for gynecological use. Although number and extent of adhesions did not decrease with HCS, inflammation and adhesions' severity were reduced in the laparoscopic and laparotomy approaches, respectively. PMID- 25454971 TI - Short-term effects of extracorporeal shock waves on microcirculation. AB - BACKGROUND: Extracorporeal shock wave application (ESWA) has the potential to qualify as an adjuvant therapy option for soft tissue disorders such as chronic wounds. As of today, little is known about its exact mechanism of action. For a better understanding of the pathophysiology, we investigated the effect of ESWA on microcirculation and leukocyte-endothelial interaction. MATERIALS AND METHODS: Intravital fluorescent microscopy was used to quantify microcirculatory parameters in the ears of hairless mice (n = 30). Values were obtained just before and 10 min after the ESWA (500 shots, 1 Hz, duration 500 s). Mice were randomly divided into three groups undergoing different shock wave intensities (energy flux density: control: 0.00 mJ/mm(2); low level: 0.015 mJ/mm(2); and higher level (hl): 0.04 mJ/mm(2); n = 10 mice per group). Histologic evaluations were taken after completion of the experiments. RESULTS: A significant increase in the venular diameter was observed in both the groups that underwent ESWA compared with the control group (hl: 118%, low level: 117%, and control: 96%; P < 0.004). Edema formation increased significantly in group I (P = 0.002). ESWA provoked an arteriolar constriction (hl: 93% versus control: 104%; P = 0.019) 10 min after treatment. The highest value of venular blood flow was found in group hl. Moreover, shock waves increased significantly the number of sticking leukocytes immediately after application (hl: 274%, P = 0.003). CONCLUSIONS: ESWA has a significant and immediate impact on microcirculation with endothelial integrity loss and increase of adherent leukocytes as part of a proinflammatory process. Although a dilation of venules was caused, arterioles primarily show a constriction. The study shows alterations in microcirculation that could help understand the mechanism of action in the future. PMID- 25454972 TI - Curcumin-induced angiogenesis hastens wound healing in diabetic rats. AB - BACKGROUND: Neovasculogenesis, vital for wound healing, gets compromised in diabetics patients, which consequently delayed wound healing. Previous studies have shown curcumin as both a stimulatory and an inhibitory agent in the neovasculogenesis process. So, present study was aimed to investigate the effects of curcumin on wound healing in diabetic rats and to explore the expressions of the various factors involved in neovasculogenesis. MATERIALS AND METHODS: Open excisional diabetic wound was created in sixty rats and divided into three groups viz. i) control, ii) pluronic gel-treated, and iii) curcumin-treated. The pluronic F-127 gel (25%) and curcumin (0.3%) in the pluronic gel were topically applied once daily for 19 d. The wound healing and neovasculogenesis among these groups were evaluated by gross appearance of wounds and microscopically by hematoxylin and eosin staining, immunohistochemistry for CD31, messenger RNA expressions of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-beta1, hypoxia-inducible growth factor-1 alpha, stromal cell-derived growth factor-1 alpha, and heme oxygenase-1, and Western blotting studies of VEGF and TGF-beta1 in granulation and/or healing tissue on days 3, 7, 14, and 19. RESULTS: Curcumin application caused markedly fast wound closure with well-formed granulation tissue dominated by fibroblast proliferation, collagen deposition, and complete early regenerated epithelial layer. Immunohistochemistry for CD31 revealed well-formed blood vessels with increased microvessel density on days 3, 7, and 14 in the curcumin-treated group. Expressions of VEGF and TGF-beta1 on days 3, 7, and 14, hypoxia-inducible growth factor-1 alpha, stromal cell-derived growth factor-1 alpha, and heme oxygenase-1 on days 3 and 7 were increased in curcumin-treated diabetic rats, as compared with other groups. CONCLUSIONS: Curcumin enhanced the neovasculogenesis and accelerated the wound healing in diabetic rats by increased expressions of various factors. PMID- 25454973 TI - Major hepatectomy in Bismuth types I and II hilar cholangiocarcinoma. AB - BACKGROUND: Historically, hilar bile duct resection (HBDR) has been regarded as the choice of treatment for Bismuth types I and II hilar cholangiocarcinoma (HCCA). The present study aimed to evaluate the advantages of major liver resection (MLR) in the treatment of patients with Bismuth types I and II HCCA when compared with HBDR. MATERIALS AND METHODS: Between January 2005 and September 2012, in total, 52 patients with Bismuth types I and II HCCA who underwent HBDR alone or MLR were included for retrospective analysis. The intraoperative outcomes, postoperative complications, and oncological outcomes including recurrence and overall or disease-free survival rate were compared. RESULTS: The MLR group had significantly higher curative resection rates compared with the HBDR group (95% versus 62.5%, P = 0.021) and lower tumor recurrence (28% versus 63%, P = 0.049), albeit with longer operating time (395.5 +/- 112.7 versus 270.9 +/- 98.8, P < 0.001), and higher blood transfusion requirements (70% versus 16%, P < 0.001). MLR resulted in significantly higher overall postoperative morbidity (70% versus 34.4%, P = 0.012), compared with HBDR alone. When restricted to R0 resections for all the procedures, MLR significantly increased the overall postoperative survival rate compared with the HBDR group (P = 0.016); the overall survival rate at 1, 3 y was 68.4% and 60.8% for MLR group and 59.6% and 21.9% for HBDR group, respectively. Also, the disease-free survival rate was significantly higher in patients who underwent MLR, as compared with those who underwent HBDR (53.2% versus 0% at 3 y, P = 0.005). CONCLUSIONS: Our study has shown that MLR results in higher curative resections, fewer recurrences, and increased postoperative survival rate for Bismuth types I and II HCCA as compared with HBDR alone. However, there is a need for well-designed, multicenter studies to be undertaken to better inform a decision on the standard treatment for Bismuth types I and II HCCA. PMID- 25454975 TI - Ultrasonographic evaluation of abdominal organs after cardiac surgery. AB - BACKGROUND: Disturbances of the hepatosplanchnic region may occur after cardiac operations. Experimental studies have implicated impairment of splanchnic blood supply in major abdominal organ dysfunction after cardiopulmonary bypass (CPB). We investigated the impact of the cardiac operation and CPB on liver, kidney, and renal perfusion and function by means of ultrasonography and biochemical indices in a selected group of cardiac surgery patients. MATERIALS AND METHODS: Seventy five patients scheduled for a major cardiac operation were prospectively included in the study. Criteria for selection were moderate or good left ventricular ejection fraction and absence of previous hepatic or renal impairment. Ultrasound examination of the hepatic and renal vasculature and examination of biochemical parameters were performed on the day preceding the operation (T0), on the first postoperative day (T1), and on the seventh postoperative day (T2). RESULTS: Portal vein velocity and flow volume increased significantly, whereas hepatic artery velocity and flow volume decreased at T1 in comparison with T0. Hepatic vein indices remained unaffected throughout the observation period. Renal artery velocity and flow decreased, whereas renal pulsatility index and renal resistive index increased at T1 as compared with T0. Aspartate aminotransferase and alanine aminotransferase values were increased as compared with baseline values 24 h postoperatively. All parameters displayed a trend to approach preoperative levels at T2. Strong negative correlations between alanine aminotransferase values at T1 and hepatic artery velocity and flow volume at the same time point were also demonstrated (R = 0.638, P < 0.001 and r = 0.662, P < 0.001, respectively). CONCLUSIONS: The increase in portal vein flow and velocity and the decrease in hepatic artery flow and velocity in the period after CPB might be attributed to the hypothermic bypass technique and the hepatic arterial buffer response, respectively. The decrease in renal blood flow and velocity and the parallel increase in Doppler renal pulsatility index and renal resistive index could be considered as markers of kidney hypoperfusion and intrarenal vasoconstriction. Maintaining a high index of suspicion for the early diagnosis of noncardiac complications in the period after CPB and institution of supportive care in case of compromised splanchnic perfusion are warranted. PMID- 25454974 TI - Postoperative pancreatic fistula after robot distal gastrectomy. AB - BACKGROUND: To compare the incidences of postoperative pancreatic fistula (POPF) between robot-assisted distal gastrectomy (RADG) and laparoscopy-assisted distal gastrectomy (LADG). MATERIALS AND METHODS: A total of 40 patients with gastric cancer who underwent RADG were compared with 40 initial patients who underwent LADG by a single surgeon. We evaluated and compared the clinicopathologic characteristics, surgical outcomes, and operative complications including POPF in two groups. RESULTS: The POPF was observed more frequently in the LADG group than in the RADG group (22.5% versus 10%, P < 0.001). Although the serum amylase levels in the 20 first-half cases did not statistically differ between LADG and RADG (P = 0.32), those in the 20 latter-half cases were significantly lower in the RADG group (P < 0.05). Univariate and multivariate analyses identified laparoscopic surgery and visceral fat area as POPF-associated risk factors. CONCLUSIONS: RADG is feasible and safe for distal gastrectomy in terms of POPF. PMID- 25454976 TI - Ursolic acid improves survival and attenuates lung injury in septic rats induced by cecal ligation and puncture. AB - BACKGROUND: Sepsis is characterized as a systemic inflammatory response syndrome during infection, which can result in multiple organ dysfunction and death. Ursolic acid (UA), a pentacyclic triterpene acid, has been reported to have potent anti-inflammatory and antioxidant properties. The aim of this study was to detect the possible protective effects of UA on sepsis-evoked acute lung injury. MATERIALS AND METHODS: A rat model of sepsis induced by cecal ligation and puncture (CLP) was used. Rats were injected intraperitoneally with UA (10 mg/kg) after CLP, and then the survival was determined twice a day for 4 d. The protective effects of UA on CLP-induced acute lung injury were assayed at 24 h after CLP. RESULTS: The results revealed that UA treatment markedly improved the survival of septic rats, and attenuated CLP-induced lung injury, including reduction of lung wet/dry weight ratio, infiltration of leukocytes and proteins, myeloperoxidase activity, and malondialdehyde content. In addition, UA significantly decreased the serum levels of tumor necrosis factor-alpha, interleukin-6, and interleukin-1beta, inhibited the expression of inducible nitric oxide synthase and cyclooxygenase-2 in the lung, which are involved in the productions of nitric oxide and prostaglandin E2. CONCLUSIONS: These findings indicate that UA exerts protective effects on CLP-induced septic rats. UA may be a potential therapeutic agent against sepsis. PMID- 25454977 TI - Portal vein embolization with plug/coils improves hepatectomy outcome. AB - BACKGROUND: Portal vein embolization (PVE) has become the standard of care before extended hepatectomy. Various PVE methods using different embolization materials have been described. In this study, we compared PVE with polyvinyl alcohol particles alone (PVA only) versus PVA with plug or coils (PVA + plug/coils). MATERIALS AND METHODS: Patients undergoing PVE before hepatectomy were included. PVA alone was used until December 2013, thereafter plug or coils were placed in addition. The volume of left lateral liver lobe (LLL), clinical parameters, and liver function tests were measured before PVE and resection. RESULTS: A total of 43 patients were recruited into the PVA only group and 42 were recruited into the PVA + plug/coils group. There were no major differences between groups except significantly higher total bilirubin level before PVE in the PVA only group, which improved before hepatectomy. Mean LLL volume increased by 25.7% after PVE in the PVA only group and by 44% in the PVA + plug/coils group (P < 0.001). Recanalization was significantly less common in the PVA + plug/coils group. In multivariate regression, initial LLL volume and use of plug or coils were the only parameters influencing LLL volume increase. The postoperative liver failure rate was significantly reduced in PVA + plug/coils group (P = <0.001). CONCLUSIONS: PVE using PVA particles together with plug or coils is a safe and efficient method to increase future liver remnant volume. The additional central embolization with plug or coils led to an increased hypertrophy, due to lower recanalization rates, and subsequently decreased incidence of postoperative liver failure. No additional procedure-specific complications were observed in this series. PMID- 25454980 TI - Survival of hepatocellular carcinoma patients is significantly improving: a population-based study from southern Switzerland. AB - BACKGROUND: During the last 20 years, relevant diagnostic procedures and advanced treatments have been progressively introduced in the management of hepatocellular carcinoma (HCC). The aim of the present study was to assess up-to-date survival trends for HCC in southern Switzerland, a region with one of the highest incidence rates in the country. METHODS: HCCs diagnosed in 1996-2009 were selected by the Ticino Cancer Registry. Cancer-specific survival (CSS) analysis was performed using the Kaplan-Meier method by calendar period: 1996-2000, 2001 2005 and 2006-2009. The log-rank test was used to detect differences in survival curves. Simultaneous assessment of prognostic factors was performed by a multivariate analysis using the Cox proportional-hazards regression model. RESULTS: 619 HCCs were analysed. There was a significant increase of patients undergoing transarterial chemoembolisation (TACE), whereas patients undergoing curative or palliative supportive treatments remained unchanged (p < 0.0001). No shift to earlier stages was detected. Significant differences in CCS were observed by age-group (p < 0.0001), diagnosis period (p < 0.0001), diagnosis technique (p = 0.0035), Barcelona-Clinic liver cancer stage (p < 0.0001), treatment (p < 0.0001). Multivariate analysis confirmed the independent impact on CSS of factors above mentioned, not including the diagnosis technique. Death risk was higher for patients diagnosed in 1996-2000 (HR: 1.32; 95% CI: 1.03; 1.68) and 2001-2005 (HR: 1.33; 95% CI: 1.05; 1.67) in comparison with 2006-2009 (reference group). CONCLUSIONS: The current population-based report describes a major increase in HCC survival. Simultaneously an increased use of TACE has been detected, probable cofactor of the observed survival increase. Possibly additional efforts could be made to decrease the HCC stage at diagnosis through active surveillance of cirrhotic patients to allow an increase in curative treatments. For sure efforts should be made to comply with a standardised staging system for HCC, particularly for comparative population-based issues. PMID- 25454978 TI - Ablation of 5-lipoxygenase mitigates pancreatic lesion development. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), which continues to have a dismal prognosis, is associated with a pronounced fibroinflammatory response. Inflammation in vivo can be mediated by 5-lipoxygenase (5LO), an enzyme that converts omega-6 fatty acids (FA) to eicosanoids, including leukotriene B4 (LTB4). We have previously shown that diets rich in omega-6 FA increase pancreatic lesions and mast cell infiltration in EL-Kras mice. In this study, we evaluated the role of 5LO in generating higher levels of LTB4 from human cells and in mediating lesion development and mast cell infiltration in EL-Kras mice. MATERIALS AND METHODS: Human pancreatic ductal epithelial and cancer cells were treated with omega-6 FA in vitro. EL-Kras mice lacking 5LO (EL-Kras/5LO(-/-)) mice were generated and fed standard chow or omega-6 FA diets. Pancreatic lesion frequency and mast cell infiltration were compared with EL-Kras/5LO(+/+) mice. Human PDAC tumors were evaluated for 5LO expression and mast cells. RESULTS: Human pancreatic ductal epithelial and pancreatic cancer cells treated with omega 6 FA generated increased LTB4 levels in vitro. EL-Kras/5LO(-/-) mice developed fewer pancreatic lesions and had decreased mast cell infiltration when compared with EL-Kras/5LO(+/+) mice. Human PDAC tumors with increased 5LO expression demonstrate increased mast cell infiltration. Additionally, diets rich in omega-6 FA failed to increase pancreatic lesion development and mast cell infiltration in EL-Kras/5LO(-/-) mice. CONCLUSIONS: The expansion of mutant Kras-induced lesions via omega-6 FA is dependent on 5LO, and 5LO functions downstream of mutant Kras to mediate inflammation, suggesting that 5LO may be a potential chemopreventive and therapeutic target in pancreatic cancer. PMID- 25454981 TI - Hypnotic use and fatigue in multiple sclerosis. AB - OBJECTIVES: Sleep disturbances and fatigue are common in patients with multiple sclerosis (MS), but little is known about hypnotic use patterns in MS, or the relationship between these medications and fatigue. The objectives of this study were to investigate the prevalence of prescription and over-the-counter (OTC) hypnotic use among MS patients, and to assess the relationships between fatigue severity and hypnotic use among persons with MS. METHODS: Data on hypnotic use frequency, hypnotic agents of choice, and clinical characteristics were extracted from medical records and a survey dataset from 190 MS patients who completed questionnaires regarding sleep quality, sleep quantity, nocturnal symptoms, sleepiness (Epworth Sleepiness Scale), obstructive sleep apnea risk (STOP-Bang questionnaire), insomnia (Insomnia Severity Index), and fatigue level (Fatigue Severity Scale - FSS). RESULTS: Eighty-nine subjects (47%) endorsed hypnotic use occasionally, frequently, or always. OTC diphenhydramine-containing products accounted for the majority of utilization, reported by 47 (25%). The occurrence of occasional or more frequent hypnotic use correlated with daytime fatigue (Spearman rho = 0.28, P = 0.0002), but not sleepiness. Regression of FSS scores on hypnotic use confirmed the association [beta (SE) = 0.55 (0.21), P = 0.0092] after adjustment for clinical and sleep-related confounds. In separate, similarly adjusted models, the use of OTC hypnotics but not prescription hypnotics was independently associated with higher FSS scores [0.54 (0.22), P = 0.0159]. An analogous association was observed more specifically for the use of diphenhydramine-containing products (0.49 (0.24), P = 0.044). CONCLUSIONS: Hypnotic use is highly prevalent among MS patients. Carryover effects from hypnotic agents, and in particular OTC diphenhydramine-containing products, could contribute to daytime fatigue. PMID- 25454983 TI - Sleepwalking into a paradigm shift? PMID- 25454982 TI - Prevalence of pre-stroke sleep apnea risk and short or long sleep duration in a bi-ethnic stroke population. AB - BACKGROUND: The ethnic disparity in ischemic stroke between Mexican Americans (MAs) and non-Hispanic whites (NHWs) may be partly attributable to disparities in sleep and its disorders. We therefore assessed whether pre-stroke sleep apnea symptoms (SA risk) and pre-stroke sleep duration differed between MAs and NHWs. METHODS: MA and NHW ischemic stroke survivors in the Brain Attack Surveillance in Corpus Christi (BASIC) project reported sleep duration and SA symptoms on the validated Berlin questionnaire, both with respect to their pre-stroke baseline. Log binomial and linear regression models were used to test the unadjusted and adjusted (demographics and vascular risk factors) associations of high-risk Berlin scores and sleep duration with ethnicity. RESULTS: Among 862 subjects, 549 (63.7%) were MA and 514 (59.6%) had a high risk of pre-stroke SA. The MA and NHW subjects showed no ethnic difference, after adjustment for potential confounders, in pre-stroke SA risk (risk ratio (95% confidence interval (CI)): 1.06 (0.93, 1.20)) or in pre-stroke sleep duration (on average MAs slept 2.0 fewer minutes than NHWs, 95% CI: -18.8, 14.9 min). CONCLUSIONS: Pre-stroke SA symptoms are highly prevalent, but ethnic differences in SA risk and sleep duration appear unlikely to explain ethnic stroke disparities. PMID- 25454979 TI - Descriptive epidemiology of Kaposi sarcoma in Europe. Report from the RARECARE project. AB - Kaposi sarcoma (KS) is a virus-related malignancy which most frequently arises in skin, though visceral sites can also be involved. Infection with Kaposi sarcoma herpes virus (KSHV or HHV-8) is required for development of KS. Nowadays, most cases worldwide occur in persons who are immunosuppressed, usually because of HIV infection or as a result of therapy to combat rejection of a transplanted organ, but classic Kaposi sarcoma is predominantly a disease of the elderly without apparent immunosuppression. We analyzed 2667 KS incident cases diagnosed during 1995-2002 and registered by 75 population-based European cancer registries contributing to the RARECARE project. Total crude and age-standardized incidence rate was 0.3 per 100,000 per year with an estimated 1642 new cases per year in the EU27 countries. Age-standardized incidence rate was 0.8 per 100,000 in Southern Europe but below 0.3 per 100,000 in all other regions. The elevated rate in southern Europe was attributable to a combination of classic Kaposi sarcoma in some Mediterranean countries and the relatively high incidence of AIDS in several countries. Five-year relative survival for 2000-2002 by the period method was 75%. More than 10,000 persons were estimated to be alive in Europe at the beginning of 2008 with a past diagnosis of KS. The aetiological link with suppressed immunity means that many people alive following diagnosis of KS suffer comorbidity from a pre-existing condition. While KS is a rare cancer, it has a relatively good prognosis and so the number of people affected by it is quite large. Thus it provides a notable example of the importance of networking in diagnosis, therapy and research for rare cancers. PMID- 25454985 TI - Convergent validity of the Child Behavior Checklist sleep items with validated sleep measures and sleep disorder diagnoses in children and adolescents referred to a sleep disorders center. AB - OBJECTIVE: The Child Behavior Checklist (CBCL) is a commonly used measure of child and adolescent functioning, and a handful of items from the CBCL are often used to measure sleep functioning. The objective of this study was to examine the convergent, discriminant, and external validity of the individual CBCL sleep items and a CBCL sleep composite with validated measures of sleep functioning and youth adjustment as well as sleep disorder diagnoses. METHODS: The participants were 383 youths (ages 6-18 years; 52.5% male; 80% non-Hispanic White) evaluated in a behavioral sleep medicine clinic. A sleep psychologist diagnosed sleep disorders following a comprehensive evaluation. Parents completed the CBCL in addition to the Children's Sleep Habits Questionnaire (CSHQ) and the Sleep Disorders Inventory for Students (SDIS). Adolescents completed the Adolescent Sleep-Wake Scale (ASWS). RESULTS: Individual CBCL sleep items were generally associated with sleep scales on validated sleep measures and with sleep disorder diagnoses. The CBCL sleep composite was associated with total scores on each of the sleep-specific measures, as well as with the CBCL attention, social, internalizing, and externalizing problems scales. CONCLUSIONS: Although the CBCL is inadequate for thoroughly assessing sleep problems and disorders, sleep items on the CBCL may be useful in epidemiological/archival studies that lack a more comprehensive sleep measure or to clinicians who do not use other validated sleep measures in their typical practice. Individual CBCL sleep items may be optimal when assessing specific facets of sleep functioning whereas the CBCL sleep composite may be optimal when examining overall sleep functioning and external correlates of sleep. PMID- 25454984 TI - Is it time for bed? Short sleep duration increases risk of obesity in Mexican American children. AB - OBJECTIVE: Cross-sectional studies show that sleep is related to childhood obesity. We aimed to examine the longitudinal impact of sleep on the risk of obesity in Mexican American children. DESIGN AND METHODS: We evaluated 229 Mexican American 8-10-year-olds and their mothers at baseline and at 12- and 24 month follow-ups. Sleep duration and anthropometrics were collected. Age- and gender-specific body mass index (BMI) z-scores (BMIz) were calculated based on Centers for Disease Control and Prevention guidelines. Sleep duration was estimated using accelerometry. Children were also categorized as long or short sleepers, using the National Sleep Foundation's recommendation to define adequate sleep duration (10-11 h for 5-12-year-olds). Using linear regressions, we examined whether sleep duration predicted BMIz, waist-to-height ratio (WHtR), and weight gain at 24 months. RESULTS: Children were mostly short sleepers (82%). Children who slept less were more likely to have a higher BMIz, WHtR, and weight gain at the 24-month follow-up (beta = -0.07, P = 0.01; beta = -0.11, P <0.01; and beta = -0.14, P = 0.02, respectively), after controlling for baseline weight status, child gender, maternal BMI, and occupation. CONCLUSION: In Mexican American children, shorter sleep duration at baseline was associated with increased weight status over 24 months. PMID- 25454986 TI - Trajectories of physiological dysregulation predicts mortality and health outcomes in a consistent manner across three populations. AB - Mechanistic and evolutionary perspectives both agree that aging involves multiple integrated biochemical networks in the organism. In particular, the homeostatic physiological dysregulation (PD) hypothesis contends that aging is caused by the progressive breakdown of key regulatory processes. However, nothing is yet known about the specifics of how PD changes with age and affects health. Using a recently validated measure of PD involving the calculation of a multivariate distance (DM) from biomarker data, we show that PD trajectories predict mortality, frailty, and chronic diseases (cancer, cardiovascular diseases, and diabetes). Specifically, relative risks of outcomes associated with individual slopes in (i.e. rate of) dysregulation range 1.20-1.40 per unit slope. We confirm the results by replicating the analysis using two suites of biomarkers selected with markedly different criteria and, for mortality, in three longitudinal cohort based studies. Overall, the consistence of effect sizes (direction and magnitude) across data sets, biomarker suites and outcomes suggests that the positive relationship between DM and health outcomes is a general phenomenon found across human populations. Therefore, the study of dysregulation trajectories should allow important insights into aging physiology and provide clinically meaningful predictors of outcomes. PMID- 25454988 TI - Maternal immunization to benefit the mother, fetus, and infant. AB - Pregnant women are at risk for the same infectious diseases as nonpregnant individuals and often have increased morbidity and mortality associated with infection. Thus, immunizing women during pregnancy with recommended vaccines provides direct maternal benefit. Furthermore, maternal immunization has the potential for both fetal and infant benefit by preventing adverse pregnancy outcomes and infection during early life through passive immunity. This article reviews current knowledge on the importance and benefits of maternal immunization, which are 3-fold: protecting the mother from antepartum infection; reducing poor pregnancy and fetal outcomes; and providing immunity for infants during the first few months of life. PMID- 25454987 TI - Short and long telomeres increase risk of amnestic mild cognitive impairment. AB - Peripheral blood telomere length has been associated with age-related conditions including Alzheimer's disease (AD). This suggests that telomere length may identify subjects at increased risk of AD. Thus, we investigated the associations of peripheral blood telomere length with amnestic mild cognitive impairment (aMCI), a putative precursor of AD, among Mayo Clinic Study of Aging participants who were prospectively followed for incident aMCI. We matched 137 incident aMCI cases (mean age 81.1 years, [range 70.9-90.8]; 49.6% men) by age and sex to 137 cognitively normal controls. We measured telomere length (T/S ratio) at baseline using quantitative PCR. Compared to the middle T/S quintile (Q3), the risk of aMCI was elevated for subjects with the shortest (Q1: HR, 2.85, 95% Confidence interval [CI] 0.98, 8.25; p=0.05) and the longest telomere lengths (Q5: HR, 5.58, 95%CI, 2.21, 14.11; p=0.0003). In this elderly cohort, short and long telomeres were associated with increased risk of aMCI. Our findings suggest that both long and short telomere lengths may play a role in the pathogenesis of aMCI, and may be markers of increased risk of aMCI. PMID- 25454989 TI - Prevention and management of influenza in pregnancy. AB - Influenza infections are an important global source of morbidity and mortality. Pregnant and postpartum women are at increased risk for serious disease, related complications, and death from influenza infection. This increased risk is thought to be mostly caused by the altered physiologic and immunologic specifics of pregnancy. The morbidity of influenza infection during pregnancy is compounded by the potential for adverse obstetric, fetal, and neonatal outcomes. Importantly, influenza vaccination to prevent or minimize the severity of influenza infection during pregnancy (and the neonatal period) is recommended for all women who are or will be pregnant during influenza season. PMID- 25454990 TI - Contemporary management of human immunodeficiency virus in pregnancy. AB - Contemporary management of HIV in pregnancy remains a moving target. With the development of newer antiretroviral agents with lower side-effect profiles and laboratory methods for detection and monitoring of HIV, considerable progress has been made. This review examines key concepts in the pathophysiology of HIV and pregnancy with emphasis on perinatal transmission and reviews appropriate screening and diagnostic testing for HIV during pregnancy. Current recommendations for medical, pharmacologic, and obstetric management of women newly diagnosed with HIV during pregnancy and for those women with preexisting infection are discussed. Preconception counseling for HIV+ women as well as postpartum issues are addressed. PMID- 25454991 TI - Prevention and management of viral hepatitis in pregnancy. AB - Of the 5 types of viral hepatitis (HAV-HEV), HBV and HCV are by far the most common causes of chronic hepatitis in both pregnant and nonpregnant populations, causing more than 50% of cirrhosis cases and 78% of cases of primary liver cancer. Infection during pregnancy can have adverse effects on both the mother and her fetus. For all 5 viral hepatitis syndromes, early identification allows appropriate measures to be taken to optimize pregnancy outcomes and minimize the risk of perinatal transmission. This article reviews the prevention and management of all 5 viral hepatitis syndromes during pregnancy. PMID- 25454993 TI - Herpes simplex virus infection during pregnancy. AB - Genital herpes in pregnancy continues to cause significant maternal morbidity, with an increasing number of infections being due to oral-labial transmission of herpes simplex virus (HSV)-1. Near delivery, primary infections with HSV-1 or HSV 2 carry the highest risk of neonatal herpes infection, which is a rare but potentially devastating disease for otherwise healthy newborns. Prevention efforts have been limited by lack of an effective intervention for preventing primary infections and the unclear role of routine serologic testing. PMID- 25454992 TI - Screening, prevention, and treatment of congenital cytomegalovirus. AB - Congenital cytomegalovirus (CMV) is a leading cause of permanent disability in children. The main source of maternal infection is from contact with young children. Primary maternal infection is diagnosed with demonstration of seroconversion or a positive CMV IgM in combination with a low-avidity CMV IgG. Fetal infection may be diagnosed with amniotic fluid polymerase chain reaction and culture. CMV-specific hyperimmune globulin has shown promise as a possible means to prevent congenital infection; large randomized trials are ongoing. To date, the only effective means of prevention is through reducing exposure to the virus. Rates of maternal infection may be reduced through education regarding sources of infection and improved hygiene. PMID- 25454994 TI - The role of Mycoplasma and Ureaplasma in adverse pregnancy outcomes. AB - Genital mycoplasmas are frequently found in the vaginal flora across socioeconomic and ethnic groups and have been demonstrated to be involved in adverse perinatal outcomes. Both Mycoplasma and Ureaplasma spp cause inflammation potentially leading to spontaneous preterm birth and PPROM as well as postdelivery infectious complications and neonatal infections. Herein we have provided an overview of the existing literature and supportive evidence for genital mycoplasma's role in perinatal complications. Future research will need to focus on clearly delineating the species, allowing for discrimination of their effects. PMID- 25454995 TI - Diagnosis and management of group B streptococcus in pregnancy. AB - Group B streptococcus (GBS) can cause significant maternal and neonatal morbidity. Over the past 30 years, reductions in early-onset GBS neonatal sepsis in the United States have been attributable to the guidelines from the Centers for Disease Control and Prevention for antepartum screening and treating this organism during labor. This article highlights the clinical implications, screening, diagnosis, prophylactic interventions, and future therapies for mothers with GBS during the peripartum period. PMID- 25454997 TI - Prevention and management of cesarean wound infection. AB - Cesarean wound infections represent a significant health and economic burden. Several modifiable risk factors have been identified for their development. Understanding these risks and techniques to manage cesarean wounds is essential for providers. In this article, these factors and prophylactic and therapeutic interventions are reviewed. PMID- 25454998 TI - Infectious diseases in pregnancy. PMID- 25454999 TI - Infectious diseases in pregnancy. PMID- 25454996 TI - Current management and long-term outcomes following chorioamnionitis. AB - Chorioamnionitis is the process of active infection within the amniotic cavity that induces an inflammatory response. A wide variety of pathologic organisms can cause chorioamnionitis. Prompt diagnosis and timely treatment with broad-spectrum antibiotics can help avert the significant short-term and long-term consequences that may result. This review aims to summarize the up-to-date diagnosis criteria, treatment protocols, and long-term sequelae of missed diagnoses or poorly treated disease. It also calls for future studies that aim to better understand the mechanism of disease and to develop better detection and intervention methods to prevent the significant associated morbidity. PMID- 25455000 TI - [Ancientness and maturity: two complementary qualities of forest ecosystems]. AB - Ancientness and maturity are two major qualities of forest ecosystems. They are components of naturalness and are affected by human impact. These qualities and the associated terms are often mixed up and incorrectly used. We have carried out a synthesis in order to propose an adapted French terminology based on international literature. The topics of ancientness and maturity for biodiversity and soil characteristics are explained. This review leads us to submit different potential thresholds for ancientness and maturity. An analysis on ancientness and maturity on forest data for France leads to the conclusion that about 29% of all forests can be considered "ancient woodland", and less than 3% of the even-age forest is older than the harvesting age. PMID- 25455001 TI - From the editor. PMID- 25455002 TI - Is all hypertension local? PMID- 25455003 TI - The effects of the spleen tyrosine kinase inhibitor fostamatinib on ambulatory blood pressure in patients with active rheumatoid arthritis: results of the OSKIRA-ABPM (ambulatory blood pressure monitoring) randomized trial. AB - Clinical trials of fostamatinib in patients with rheumatoid arthritis showed blood pressure (BP) elevation using clinic measurements. The OSKIRA-ambulatory BP monitoring trial assessed the effect of fostamatinib on 24-hour ambulatory systolic BP (SBP) in patients with active rheumatoid arthritis. One hundred thirty-five patients were randomized to fostamatinib 100 mg twice daily (bid; n = 68) or placebo bid (n = 67) for 28 days. Ambulatory, clinic, and home BPs were measured at baseline and after 28 days of therapy. Primary end point was change from baseline in 24-hour mean SBP. Fostamatinib increased 24-hour mean SBP by 2.9 mm Hg (P = .023) and diastolic BP (DBP) by 3.5 mm Hg (P < .001) versus placebo. Clinic/home-measured BPs were similar to those observed with ambulatory BP monitoring. After treatment discontinuation (1 week), clinic BP values returned to baseline levels. Fostamatinib induced elevations in 24-hour mean ambulatory SBP and DBP. BP elevations resolved with fostamatinib discontinuation. PMID- 25455004 TI - Pre-existing arterial hypertension as a risk factor for early left ventricular systolic dysfunction following (R)-CHOP chemotherapy in patients with lymphoma. AB - Experimental studies in animals suggest that arterial hypertension may be a specific risk factor predisposing to anthracycline cardiotoxicity. The aim was determination of the effect of pre-existing arterial hypertension on the development of early left ventricular systolic dysfunction (LVSD) directly after rituximab, cyclophosphamide, doxorubicin, vincristin, prednisone ([R]-CHOP) chemotherapy in patients with lymphomas.The study included 208 patients with non Hodgkin's lymphoma receiving conventional doxorubicin. LVSD was defined as a decrease of left ventricular ejection fraction below 50% and at least by 10 percentage points from baseline value. Patients with pre-existing hypertension more frequently developed new LVSD (19.7% vs. 6.6%; P = .004), pitting edema of the ankles (23.9% vs. 9.5%; P = .005), and nycturia (21.1% vs. 7.3%; P = .004) compared with patients without hypertension. As a consequence, the hypertension subgroup suffered from more delays of subsequent chemotherapy cycles (26.8% vs. 14.6%; P = .03), more reductions of doxorubicin doses (18.3% vs. 8.8%; P = .05), and premature discontinuations of chemotherapy (16.9% vs. 7.3%; P = .03). On logistic regression analyses, hypertension was one of the most important risk factors for developing new LVSD after (R)-CHOP chemotherapy.Arterial hypertension confers a significant risk of early LVSD in lymphoma patients treated with (R) CHOP chemotherapy, interfering with its recommended schedule of administration. PMID- 25455005 TI - Wrist circumference as a novel predictor of hypertension and cardiovascular disease: results of a decade follow up in a West Asian cohort. AB - No study has yet evaluated the effect of wrist circumference on risk of incident hypertension and cardiovascular disease (CVD) in an adult population. The present study included 3642 women, aged >=30 years, free of CVD at baseline, who had undergone health examinations between January 1999 and 2001 and were followed up until March 2010. Cox proportional hazard regression was performed to assess the hazard ratios (HRs) of wrist circumference for CVD and hypertension events. During 10 years of follow-up, 284 cases of first CVD and 615 cases of incident hypertension occurred. In a model adjusted for conventional CVD risk factors, the HR of 1 cm increase in wrist circumference was 1.15 (1.06-1.25) for hypertension and was marginally significant for CVD (HR, 1.12 [1.00-1.25]; P-value 0.052). After considering body mass index and waist circumference in the model, we found significant interaction between waist circumference and wrist circumference in risk prediction of hypertension and CVD (P < .001). In non-centrally obese women (waist circumference <95 cm), in multivariable model plus body mass index and waist circumference, increase in wrist circumference was independently associated with both hypertension (HR, 1.17 [1.02-1.35]) and CVD (HR, 1.29 [1.03-1.61]). However, among centrally obese women (waist circumference >=95 cm), wrist circumference increase could not predict either hypertension (HR, 0.97 [0.84 1.18]) or CVD events (HR, 0.90 [0.75-1.07]). Wrist circumference as a novel anthropometric measure was an independent predictor for incident hypertension and CVD events among non-centrally obese women. PMID- 25455006 TI - Stroke outcomes among participants randomized to chlorthalidone, amlodipine or lisinopril in ALLHAT. AB - The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in 33,357 high-risk hypertensive participants. ALLHAT compared cardiovascular disease outcomes in participants initially treated with an angiotensin-converting enzyme inhibitor (lisinopril), a calcium channel blocker (amlodipine), or a thiazide-type diuretic (chlorthalidone). We report stroke outcomes in 1517 participants in-trial and 1596 additional participants during post-trial passive surveillance, for a total follow-up of 8-13 years. Stroke rates were higher with lisinopril (6-year rate/100 = 6.4) than with chlorthalidone (5.8) or amlodipine (5.5) in-trial but not including post-trial (10-year rates/100 = 13.2 [chlorthalidone], 13.1[amlodipine], and 13.7 [lisinopril]). In-trial differences were driven by race (race-by lisinopril/chlorthalidone interaction P = .005, race-by-amlodipine/lisinopril interaction P = .012) and gender (gender-by-lisinopril/amlodipine interaction P = .041), separately. No treatment differences overall, or by race or gender, were detected over the 10-year period. No differences appeared among treatment groups in adjusted risk of all-cause mortality including post-trial for participants with nonfatal in-trial strokes. Among Blacks and women, lisinopril was less effective in preventing stroke in-trial than either chlorthalidone or amlodipine, even after adjusting for differences in systolic blood pressure. These differences abated by the end of the post-trial period. PMID- 25455007 TI - Impaired coronary microvascular function and increased intima-media thickness in preeclampsia. AB - There is an association between preeclampsia (PE) and excessive morbidity and mortality. Some recent studies have revealed the presence of endothelial dysfunction in PE patients with inflammatory activity. Moreover, it has been argued that the chronic inflammatory state involved in PE leads to an acceleration in atherosclerosis. Accordingly, our goal in this study is to determine whether there is any coronary microvascular dysfunction and increase in the intima-media thickness in patients who had mild PE 5 years before, without the presence of any traditional cardiovascular risk factors. The study included 33 mild PE patients (mild preeclampsia is classified as a blood pressure (BP) of 140/90 mm Hg or higher with proteinuria of 0.3 to 3 g/d) whose mean age was 33.7 years old, and 29 healthy women volunteers whose mean age was 36.1 years old. Each subject was examined using transthoracic echocardiography 5 years after their deliveries. During the echocardiographic examination, coronary flow reserve (CFR) and carotid intima-media thickness (IMT) were measured. There was a statistically lower CFR value in PE patients as compared with controls (2.39 +/- 0.48 vs. 2.90 +/- 0.49; P < .001). On the other hand, there was a significant increase in their IMT and high-sensitivity C-reactive protein (hs-CRP) values (respectively, 0.59 +/- 0.15 vs. 0.46 +/- 0.10; P < .001 and 3.80 +/- 2.10 vs. 2.33 +/- 1.79; P = .004). There was a negative correlation between the CFR values of the PE patients and hs-CRP (r = -0.568; P = .001) and IMT (r = -0.683, P < .001) results.We determined in the study that there was impaired CFR and increased carotid IMT in patients with PE, and, moreover, that these adverse effects were significantly correlated with hs-CRP. PMID- 25455008 TI - Onset of hypertension during pregnancy is associated with long-term worse blood pressure control and adverse cardiac remodeling. AB - Up to 20% of women with hypertensive pregnancy disorders might persist with chronic hypertension. This study compared clinical and echocardiographic features between women whose hypertension began as hypertensive pregnancy disorders (PH group) and women whose diagnosis of hypertension did not occur during pregnancy (NPH group). Fifty PH and 100 NPH women were cross-sectionally evaluated by clinical, laboratory, and echocardiography analysis, and the groups were matched by duration of hypertension. PH exhibited lower age (46.6 +/- 1.4 vs. 65.3 +/- 1.1 years; P < .001), but higher systolic (159.8 +/- 3.9 vs. 148.0 +/- 2.5 mm Hg; P = .009) and diastolic (97.1 +/- 2.4 vs. 80.9 +/- 1.3 mm Hg; P < .001) blood pressure than NPH, although used more antihypertensive classes (3.4 +/- 0.2 vs. 2.6 +/- 0.1; P < .001). Furthermore, PH showed higher left ventricular wall thickness and increased prevalence of concentric hypertrophy than NPH after adjusting for age and blood pressure. In conclusion, this study showed that PH may exhibit worse blood pressure control and adverse left ventricular remodeling compared with NPH. PMID- 25455009 TI - Maternal hypertensive pregnancy disorders and cognitive functioning of the offspring: a systematic review. AB - Hypertensive pregnancy disorders may affect the fetal developmental milieu and thus hint at mechanisms that link prenatal conditions with later developmental outcomes of the offspring. Here, we systematically review studies that have tested whether maternal pre-eclampsia, gestational hypertension, and hypertensive pregnancy disorders as a single diagnostic entity are associated with cognitive functioning of the offspring. Twenty-six studies were eligible for this review. Of them, 19 provided detailed methodological information deemed necessary to be included for a more detailed review. An overall conclusion is that, in the general population, maternal hypertensive disorders may be associated with lower cognitive ability of the offspring. Studies that extend to adulthood show the most consistent pattern of findings. It is possible that the associations arise during the lifetime or that the findings reflect improvements in management of these disorders. Evidence is, however, insufficient to conclude whether these associations are dissimilar in the offspring exposed to maternal pre-eclampsia and gestational hypertension, due to the varied criteria used across the different studies to distinguish between these conditions. The existing studies also vary in the definition of control groups, and very few have taken into account important confounding factors, including maternal pre-pregnancy obesity and lifestyle behaviors. Given the mixed pattern of findings and limitations related to internal and external validity, further studies are clearly warranted to clarify the associations. PMID- 25455010 TI - Diagnostic evaluation: target organ damage: cardiac. PMID- 25455011 TI - Diagnostic evaluation: target organ damage - cardiovascular. PMID- 25455012 TI - Hypertension and kidney disease. PMID- 25455013 TI - Urinary asbestos fibers and inorganic particles in past asbestos workers. AB - To assess the validity of the procedure as a test of asbestos exposure, we compared urinary asbestos fibers with occupational and environmental exposure data in a random sample of 48 subjects with high past asbestos exposure. Occupational and environmental exposure was estimated on questionnaire, pleural plaques were diagnosed with computed tomography, and inorganic fibers and particles were identified by scanning electron microscope with an energy dispersive spectrometry. Few urinary asbestos fibers (in 15% of workers and 17% of cases with pleural plaques) and high amount of urinary silicate (particularly nonfibrous particles) were detected. Asbestos undergoes dissolution in lung tissues, but the secondary minerals are largely unknown. These materials, possibly nonfibrous silicates or metals, could be excreted with urine. Therefore, another study including a control group is warranted to discriminate the occupational origin of minerals in the urine. PMID- 25455014 TI - Improved propionic acid and 5,6-dimethylbenzimidazole control strategy for vitamin B12 fermentation by Propionibacterium freudenreichii. AB - An efficient fermentation-strengthening approach was developed to improve the anaerobic production of vitamin B12 by cultivation process optimization with Propionibacterium freudenreichii. The effects of the byproduct propionic acid and the precursor 5,6-dimethylbenzimidazole (DMB) on vitamin B12 biosynthesis were investigated. Byproduct inhibition experiments showed that maintaining propionic acid concentration in broth below 10-20 g/L in the early stage and 20-30 g/L in the late stage can efficiently improve vitamin B12 biosynthesis. Batch fermentation indicated the occurrence of feed-back inhibition in intracellular intermediate biosynthesis. In addition, the incorporation of the precursor DMB depended on the fermentation level of the vitamin B12 intermediate. High vitamin B12 concentration (58.8 mg/L) and production (0.37 mg/g) were obtained with an expanded bed adsorption bioreactor by using the propionic acid and DMB control method. The optimum concentration and production of 59.5 and 0.59 mg/L h for vitamin B12 production were respectively achieved after five continuous batches. PMID- 25455015 TI - Online monitoring of P(3HB) produced from used cooking oil with near-infrared spectroscopy. AB - Online monitoring process for the production of polyhydroxyalkanoates (PHA), using cooking oil (UCO) as the sole carbon source and Cupriavidus necator, was developed. A batch reactor was operated and hydroxybutyrate homopolymer was obtained. The biomass reached a maximum concentration of 11.6+/-1.7gL(-1) with a polymer content of 63+/-10.7% (w/w). The yield of product on substrate was 0.77+/ 0.04gg(-1). Near-infrared (NIR) spectroscopy was used for online monitoring of the fermentation, using a transflectance probe. Partial least squares regression was applied to relate NIR spectra with biomass, UCO and PHA concentrations in the broth. The NIR predictions were compared with values obtained by offline reference methods. Prediction errors to these parameters were 1.18, 2.37 and 1.58gL(-1) for biomass, UCO and PHA, respectively, which indicate the suitability of the NIR spectroscopy method for online monitoring and as a method to assist bioreactor control. PMID- 25455016 TI - Insights into the annotated genome sequence of Methanoculleus bourgensis MS2(T), related to dominant methanogens in biogas-producing plants. AB - The final step of the biogas production process, the methanogenesis, is frequently dominated by members of the genus Methanoculleus. In particular, the species Methanoculleus bourgensis was identified to play a role in different biogas reactor systems. The genome of the type strain M. bourgensis MS2(T), originally isolated from a sewage sludge digestor, was completely sequenced to analyze putative adaptive genome features conferring competitiveness within biogas reactor environments to the strain. Sequencing and assembly of the M. bourgensis MS2(T) genome yielded a chromosome with a size of 2,789,773 bp. Comparative analysis of M. bourgensis MS2(T) and Methanoculleus marisnigri JR1 revealed significant similarities. The absence of genes for a putative ammonium uptake system may indicate that M. bourgensis MS2(T) is adapted to environments rich in ammonium/ammonia. Specific genes featuring predicted functions in the context of osmolyte production were detected in the genome of M. bourgensis MS2(T). Mapping of metagenome sequences derived from a production-scale biogas plant revealed that M. bourgensis MS2(T) almost completely comprises the genetic information of dominant methanogens present in the biogas reactor analyzed. Hence, availability of the M. bourgensis MS2(T) genome sequence may be valuable regarding further research addressing the performance of Methanoculleus species in agricultural biogas plants. PMID- 25455017 TI - Pulmonary tuberculosis induces a systemic hypercoagulable state. AB - OBJECTIVES: Human tuberculosis (TB) remains an important cause of death globally. Bangladesh is one of the most affected countries. We aimed to investigate the impact of pulmonary TB on pro- and anticoagulant mechanisms. METHODS: This prospective study was conducted in Chittagong, Bangladesh. We performed an in depth analysis of coagulation activation and inhibition in plasma obtained from 64 patients with primary lung TB and 11 patients with recurrent lung TB and compared these with 37 healthy controls. Additionally, in nine patients coagulation activation was studied in bronchoalveolar lavage fluid (BALF) harvested from the site of infection and compared with BALF from a contralateral unaffected lung subsegment. RESULTS: Relative to uninfected controls, primary and recurrent TB were associated with a systemic net procoagulant state, as indicated by enhanced activation of coagulation (elevated plasma levels of thrombin antithrombin complexes, D-dimer and fibrinogen) together with impaired anticoagulant mechanisms (reduced plasma levels of antithrombin, protein C activity, free protein S, and protein C inhibitor). Activation of coagulation did not correlate with plasma concentrations of established TB biomarkers. Coagulation activation could not be detected at the primary site of infection in a subset of TB patients. CONCLUSIONS: Pulmonary TB is associated with a systemic hypercoagulable state. PMID- 25455019 TI - A simple and low-cost biofilm quantification method using LED and CMOS image sensor. AB - A novel biofilm detection platform, which consists of a cost-effective red, green, and blue light-emitting diode (RGB LED) as a light source and a lens-free CMOS image sensor as a detector, is designed. This system can measure the diffraction patterns of cells from their shadow images, and gather light absorbance information according to the concentration of biofilms through a simple image processing procedure. Compared to a bulky and expensive commercial spectrophotometer, this platform can provide accurate and reproducible biofilm concentration detection and is simple, compact, and inexpensive. Biofilms originating from various bacterial strains, including Pseudomonas aeruginosa (P. aeruginosa), were tested to demonstrate the efficacy of this new biofilm detection approach. The results were compared with the results obtained from a commercial spectrophotometer. To utilize a cost-effective light source (i.e., an LED) for biofilm detection, the illumination conditions were optimized. For accurate and reproducible biofilm detection, a simple, custom-coded image processing algorithm was developed and applied to a five-megapixel CMOS image sensor, which is a cost-effective detector. The concentration of biofilms formed by P. aeruginosa was detected and quantified by varying the indole concentration, and the results were compared with the results obtained from a commercial spectrophotometer. The correlation value of the results from those two systems was 0.981 (N = 9, P < 0.01) and the coefficients of variation (CVs) were approximately threefold lower at the CMOS image-sensor platform. PMID- 25455018 TI - Tremor in a population-based cohort of children in New York City. AB - BACKGROUND: There have been virtually no surveys of the prevalence, clinical features, or correlates of tremor in children and none in the United States. METHODS: A total of 317 children (age 11.0 +/- 1.1 years; range, 9.0 to 14.7) underwent an evaluation at one time point. Each drew Archimedes spirals, which were rated by a senior neurologist specializing in movement disorders. RESULTS: A spiral score of 1 (mild but consistent tremor) was present in either hand in 105 (33.1%) children; a higher score (1.5, mild-to-moderate tremor) was present in either hand in 7 (2.2%) children. Higher spiral scores were associated with poorer motor hand function as assessed using the Purdue Pegboard test. Spiral scores were higher in boys than girls, were inversely associated with age, and were higher in the nondominant than dominant hand. Spiral scores were highest in children who were taking psychiatric medications and in children with psychiatric or neurological disorders. CONCLUSIONS: Mild tremor is common in children and covaries significantly with several demographic and clinical factors as well as usage of certain medications. It also lessens with advancing age. Rather than an isolated finding, tremor was associated with other measures of poorer motor hand function. PMID- 25455020 TI - Revisiting an agar-based plate method: what the static biofilm method can offer for biofilm research. AB - The development of biofilms in static plates was monitored. Glass coupons were placed on agar covered with filter paper, which was inoculated with suspended bacteria. The viable cell density, biofilms matrix and biomass were quantified. The method is excellent for adhesion and material studies, due to its simplicity and flexibility. PMID- 25455021 TI - A method for sampling microbial aerosols using high altitude balloons. AB - Owing to the challenges posed to microbial aerosol sampling at high altitudes, very little is known about the abundance, diversity, and extent of microbial taxa in the Earth-atmosphere system. To directly address this knowledge gap, we designed, constructed, and tested a system that passively samples aerosols during ascent through the atmosphere while tethered to a helium-filled latex sounding balloon. The sampling payload is ~ 2.7 kg and comprised of an electronics box and three sampling chambers (one serving as a procedural control). Each chamber is sealed with retractable doors that can be commanded to open and close at designated altitudes. The payload is deployed together with radio beacons that transmit GPS coordinates (latitude, longitude and altitude) in real time for tracking and recovery. A cut mechanism separates the payload string from the balloon at any desired altitude, returning all equipment safely to the ground on a parachute. When the chambers are opened, aerosol sampling is performed using the Rotorod(r) collection method (40 rods per chamber), with each rod passing through 0.035 m3 per km of altitude sampled. Based on quality control measurements, the collection of ~ 100 cells rod(-1) provided a 3-sigma confidence level of detection. The payload system described can be mated with any type of balloon platform and provides a tool for characterizing the vertical distribution of microorganisms in the troposphere and stratosphere. PMID- 25455022 TI - Carboxyfluorescein diacetate succinimidyl ester labeling method to study the interaction between Leptospira and macrophages. AB - Leptospirosis, which is caused by pathogenic species of the genus Leptospira, has emerged as one of the most widespread zoonotic diseases in the world. The exact mechanism of pathogenesis remains unknown, and the interaction between Leptospira and macrophages is not well understood. In this study, we report that carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) can efficiently label different Leptospira interrogans strains without affecting bacterial motility, viability, or virulence. Following co-incubation, CFDA-SE-labeled leptospires associated with macrophages were quantified by flow cytometry or confocal microscopy. In addition, we showed that trypan blue efficiently quenched the extracellular fluorescence from the adherent leptospires, which enabled intracellular and extracellular bacteria to be distinguished. PMID- 25455023 TI - A sensitive enhanced chemiluminescent-ELISA for the detection of Plasmodium falciparum circumsporozoite antigen in midguts of Anopheles stephensi mosquitoes. AB - Efforts to develop a successful malaria vaccine are hampered due to lack of assays that are predictive of protective immunity without conducting large clinical studies. The effect of experimental vaccines and drugs on malaria transmission is yet more difficult to measure. Knowledge on the Plasmodium infection rate in mosquito populations will aid the measurement of effects from intervention measures for malaria control. Here, we report the development of a chemiluminescent sandwich ELISA (ECL-ELISA) that can detect Plasmodium falciparum circumsporozoite protein (Pf CSP) produced in recombinant form at concentrations of 4.4pg and in P. falciparum sporozoites (Pf SPZ) derived from mosquito salivary glands at levels corresponding to 5 Pf SPZ. Most importantly, we demonstrate reliable Pf CSP-based detection of 0.056day 8 P. falciparum oocysts developing inside mosquito midguts in whole mosquito lysates. Cumulatively, the ECL-ELISA is 47* more sensitive for the detection of Pf CSP than a colorimetric ELISA while greatly simplifying sample preparation, obviating the need for cumbersome midgut dissections and allowing high throughput screening of Plasmodium infection in mosquito populations. The ECL-ELISA may also have broader application in diagnosis of infectious diseases and the prognostic value in cancer and other diseases such as auto-immunity and genetic disorders based on antigen detection, or quality validation of biological vaccine components. PMID- 25455024 TI - Analyzing the blood-brain barrier: the benefits of medical imaging in research and clinical practice. AB - A dysfunctional BBB is a common feature in a variety of brain disorders, a fact stressing the need for diagnostic tools designed to assess brain vessels' permeability in space and time. Biological research has benefited over the years various means to analyze BBB integrity. The use of biomarkers for improper BBB functionality is abundant. Systemic administration of BBB impermeable tracers can both visualize brain regions characterized by BBB impairment, as well as lead to its quantification. Additionally, locating molecular, physiological content in regions from which it is restricted under normal BBB functionality undoubtedly indicates brain pathology-related BBB disruption. However, in-depth research into the BBB's phenotype demands higher analytical complexity than functional vs. pathological BBB; criteria which biomarker based BBB permeability analyses do not meet. The involvement of accurate and engineering sciences in recent brain research, has led to improvements in the field, in the form of more accurate, sensitive imaging-based methods. Improvements in the spatiotemporal resolution of many imaging modalities and in image processing techniques, make up for the inadequacies of biomarker based analyses. In pre-clinical research, imaging approaches involving invasive procedures, enable microscopic evaluation of BBB integrity, and benefit high levels of sensitivity and accuracy. However, invasive techniques may alter normal physiological function, thus generating a modality based impact on vessel's permeability, which needs to be corrected for. Non invasive approaches do not affect proper functionality of the inspected system, but lack in spatiotemporal resolution. Nevertheless, the benefit of medical imaging, even in pre-clinical phases, outweighs its disadvantages. The innovations in pre-clinical imaging and the development of novel processing techniques, have led to their implementation in clinical use as well. Specialized analyses of vessels' permeability add valuable information to standard anatomical inspections which do not take the latter into consideration. PMID- 25455025 TI - Quality of life and satisfaction after multilevel surgery in cerebral palsy: confronting the experience of children and their parents. AB - OBJECTIVES: If the benefits of single-event multilevel surgery (SEMS) in ambulatory children with cerebral palsy have already been validated, especially in terms of functional outcomes, fewer studies have evaluated SEMS in terms of quality of life and satisfaction with surgical outcomes, especially pertaining to the opinions of children and their family. The objectives of this study were to confront the perceptions of parents and the experience of their operated children in terms of quality of life and surgical outcomes. MATERIALS AND METHODS: This was an observational, descriptive, single-center study conducted in a regional Pediatric Physical Medicine and Rehabilitation (PM&R) center, which is considered a reference center in this region of France. The subjects recruited were ambulatory children with cerebral palsy (CP) who had SEMS between 2009 and 2011, and one of their parents. The specific "child" and "parent" CP-related modules of the DISABKIDS questionnaire were used to assess these children's quality of life post-surgery. Perceptions of parents and children regarding gait evolution and satisfaction with surgical outcomes were analyzed via a questionnaire developed by the author. Regarding quality of life and surgical outcomes, the correlation between the perception of parents and experience of children was estimated using the intraclass correlation coefficient (ICC) or prevalence-adjusted bias-adjusted kappa values (PABAK). RESULTS: Twelve children (83% of them boys) and their parents participated in the study. For the DISABKIDS questionnaire, a moderate correlation was found regarding functional impact (ICC=0.58; P<0.0178) but a high correlation was reported for the communication item of the questionnaire (ICC=0.73; P=0.0025). Regarding satisfaction with surgical outcomes, results showed a good correlation (PABAK=0.64). CONCLUSION: Concerning quality of life and satisfaction with surgical outcomes, our study showed a good or even high correlation between parents' perceptions and their child's experience. It is however essential to privilege the child's opinion whenever possible. PMID- 25455026 TI - Use of psychoactive substances in persons with spinal cord injury: a literature review. AB - OBJECTIVE: To undertake a critical review of literature on use of legal and illegal psychoactive substances (PAS) in persons with spinal cord injury (SCI) before and after trauma. MATERIAL AND METHODS: Hundred and five articles published between 1980 and 2014 on alcohol and drug use in persons with SCI before and after trauma were retrieved from the PubMed and PsycInfo search engines. RESULTS: Before injury, 25% to 96% of people with SCI reported using alcohol, while 32% to 35% had used illegal drugs. At the time of injury, 31% to 50% of individuals with SCI were intoxicated with alcohol, 16% to 33% with drugs and 26% with a combination of drugs and alcohol. Among those reporting PAS use before injury, up to 50% stated that they had reduced their use during active rehabilitation, during which time only 6% consumed psychoactive substances for the first time. A variety of risk factors are associated with consumption subsequent to spinal cord injury: personality alteration (impulsiveness, aggressiveness), posttraumatic depression, poor coping skills, lack of social support and pain. PAS use can affect the process of rehabilitation, diminish the effectiveness of medication and result in various medical complications. DISCUSSION/CONCLUSIONS: Few studies have explored the use of alcohol, drugs and psychoactive medications before SCI and during active rehabilitation. To our knowledge, no study has analyzed the evolution of PAS use after hospital discharge, even though return home is associated with new stressors that may trigger risky behaviors. It should be a priority, as early as possible during rehabilitation, to detect persons at risk of developing PAS abuse. PMID- 25455027 TI - Enhancing Annals value through quality. PMID- 25455028 TI - Profound childhood hearing loss in a South Africa cohort: risk profile, diagnosis and age of intervention. AB - OBJECTIVE: To describe profound childhood hearing loss in a South African population of pediatric cochlear implant recipients in terms of risk profile, and age of diagnosis and intervention. METHODS: A retrospective review of patient files for 264 pediatric cochlear implant recipients from five cochlear implant programs was conducted. Data was captured from 264 eligible subjects, of which all were implanted between 1996 and 2013 and PCEHL was confirmed under the age of 5 years old. Data collected included demographical information, risk factors from case histories, diagnostic test procedures conducted, diagnosis (type, onset and degree of hearing loss) and documented ages of caregiver suspicion, initial diagnosis and intervention. RESULTS: Risk factors for permanent childhood hearing loss were present in 51.1% of cases, with the most prevalent risks being NICU admittance (28.1%), family history of childhood hearing loss (19.6%) and prematurity (15.1%). An associated syndrome was diagnosed in 10% of children and 23.5% presented with at least one additional developmental condition. Hearing loss for most (77.6%) children was confirmed as congenital/early onset, while 20.3% presented with postnatal onset of hearing loss. ANSD was diagnosed in 5% of children, with admittance to NICU (80%) and hyperbilirubinemia (50%) being the most prevalent risk factors for these cases. Hearing loss was typically diagnosed late (15.3 months), resulting in delayed initial hearing aid fitting (18.8 months), enrollment in early intervention services (19.5 months) and eventual cochlear implantation (43.6 months). CONCLUSION: Most prevalent risk factors in profound childhood hearing loss were admittance to NICU, family history and prematurity. Diagnosis and intervention was typically delayed predisposing this population to poorer outcomes. PMID- 25455029 TI - Two ancient human genomes reveal Polynesian ancestry among the indigenous Botocudos of Brazil. AB - Understanding the peopling of the Americas remains an important and challenging question. Here, we present (14)C dates, and morphological, isotopic and genomic sequence data from two human skulls from the state of Minas Gerais, Brazil, part of one of the indigenous groups known as 'Botocudos'. We find that their genomic ancestry is Polynesian, with no detectable Native American component. Radiocarbon analysis of the skulls shows that the individuals had died prior to the beginning of the 19th century. Our findings could either represent genomic evidence of Polynesians reaching South America during their Pacific expansion, or European mediated transport. PMID- 25455030 TI - A comprehensive biophysical description of pairwise epistasis throughout an entire protein domain. AB - BACKGROUND: Nonadditivity in fitness effects from two or more mutations, termed epistasis, can result in compensation of deleterious mutations or negation of beneficial mutations. Recent evidence shows the importance of epistasis in individual evolutionary pathways. However, an unresolved question in molecular evolution is how often and how significantly fitness effects change in alternative genetic backgrounds. RESULTS: To answer this question, we quantified the effects of all single mutations and double mutations between all positions in the IgG-binding domain of protein G (GB1). By observing the first two steps of all possible evolutionary pathways using this fitness profile, we were able to characterize the extent and magnitude of pairwise epistasis throughout an entire protein molecule. Furthermore, we developed a novel approach to quantitatively determine the effects of single mutations on structural stability (DeltaDeltaGU). This enabled determination of the importance of stability effects in functional epistasis. CONCLUSIONS: Our results illustrate common biophysical mechanisms for occurrences of positive and negative epistasis. Our results show pervasive positive epistasis within a conformationally dynamic network of residues. The stability analysis shows that significant negative epistasis, which is more common than positive epistasis, mostly occurs between combinations of destabilizing mutations. Furthermore, we show that although significant positive epistasis is rare, many deleterious mutations are beneficial in at least one alternative mutational background. The distribution of conditionally beneficial mutations throughout the domain demonstrates that the functional portion of sequence space can be significantly expanded by epistasis. PMID- 25455032 TI - Convergent genetic architecture underlies social organization in ants. AB - Complex adaptive polymorphisms are common in nature, but what mechanisms maintain the underlying favorable allelic combinations? The convergent evolution of polymorphic social organization in two independent ant species provides a great opportunity to investigate how genomes evolved under parallel selection. Here, we demonstrate that a large, nonrecombining "social chromosome" is associated with social organization in the Alpine silver ant, Formica selysi. This social chromosome shares architectural characteristics with that of the fire ant Solenopsis invicta, but the two show no detectable similarity in gene content. The discovery of convergence at two levels--the phenotype and the genetic architecture associated with alternative social forms--points at general genetic mechanisms underlying transitions in social organization. More broadly, our findings are consistent with recent theoretical studies suggesting that suppression of recombination plays a key role in facilitating coordinated shifts in coadapted traits. PMID- 25455033 TI - Ravens intervene in others' bonding attempts. AB - The competition for power in a complex social world is hypothesized to be a driving force in the evolution of intelligence. More specifically, power may be obtained not only by brute force but also by social strategies resembling human politics. Most empirical evidence comes from primate studies that report unprovoked aggression by dominants to maintain power by spreading fear and third party interventions in conflicts. Coalitionary support has also been described in other animals and is often linked to social bonding. As coalitions can lead to a gain in power and fitness benefits, individuals may try to prevent coalitionary support or indirectly prevent others from forming social bonds that might lead to coalitions. Although there is some empirical evidence that coalitionary support can be manipulated, little is known about the indirect strategy. We show here that wild ravens (Corvus corax) regularly intervene in affiliative interactions of others even though such interventions are potentially risky and without immediate benefits. Moreover, the identities of both interveners and intervened pairs are not randomly distributed. Ravens with existing ties initiate most interventions, and ravens that are creating new ties are most likely to be the targets of interventions. These patterns are consistent with the idea that interventions function to prevent others from forming alliances and consequently becoming future competitors. We thus show previously undescribed social maneuvers in the struggle for power. These maneuvers are likely to be of importance in other social species as well. PMID- 25455031 TI - Calcitonin gene-related peptide neurons mediate sleep-specific circadian output in Drosophila. AB - BACKGROUND: Imbalances in amount and timing of sleep are harmful to physical and mental health. Therefore, the study of the underlying mechanisms is of great biological importance. Proper timing and amount of sleep are regulated by both the circadian clock and homeostatic sleep drive. However, very little is known about the cellular and molecular mechanisms by which the circadian clock regulates sleep. In this study, we describe a novel role for diuretic hormone 31 (DH31), the fly homolog of the vertebrate neuropeptide calcitonin gene-related peptide, as a circadian wake-promoting signal that awakens the fly in anticipation of dawn. RESULTS: Analysis of loss-of-function and gain-of-function Drosophila mutants demonstrates that DH31 suppresses sleep late at night. DH31 is expressed by a subset of dorsal circadian clock neurons that also express the receptor for the circadian neuropeptide pigment-dispersing factor (PDF). PDF secreted by the ventral pacemaker subset of circadian clock neurons acts on PDF receptors in the DH31-expressing dorsal clock neurons to increase DH31 secretion before dawn. Activation of PDF receptors in DH31-positive DN1 specifically affects sleep and has no effect on circadian rhythms, thus constituting a dedicated locus for circadian regulation of sleep. CONCLUSIONS: We identified a novel signaling molecule (DH31) as part of a neuropeptide relay mechanism for circadian control of sleep. Our results indicate that outputs of the clock controlling sleep and locomotor rhythms are mediated via distinct neuronal pathways. PMID- 25455034 TI - Specular image structure modulates the perception of three-dimensional shape. AB - Retinal images are produced by interactions between a surface's 3D shape, material properties, and surrounding light field. In order to recover the 3D geometry of a surface, the visual system must somehow separate aspects of image structure generated by a surface's shape from structure generated by its material properties or the light field in which it is embedded. Attributing image structure to the wrong physical source would cause the visual system to interpret changes in one physical property (such as reflectance) as changes in another (such as shape). Many previous studies have shown that the visual system does not conflate image structure generated by specular reflectance with 3D shape, but they did not assess the physical conditions where it would be computationally most difficult to disentangle these different sources of image structure. Here, we show that varying the specular roughness and curvature of surfaces embedded in natural light fields can strongly modulate perceived shape. Despite the complexity of these interactions, we show how an image's gradient structure mediates its interpretation as a specular reflection or a change in 3D shape. Our findings provide a coherent explanation of when and why specular reflections impact perceived shape and reveal how the static surface properties, simplified light fields, and experimental methods used in previous studies may explain their inconsistent results. PMID- 25455035 TI - Dynamic control of auxin distribution imposes a bilateral-to-radial symmetry switch during gynoecium development. AB - Symmetry formation is a remarkable feature of biological life forms associated with evolutionary advantages and often with great beauty. Several examples exist in which organisms undergo a transition in symmetry during development. Such transitions are almost exclusively in the direction from radial to bilateral symmetry. Here, we describe the dynamics of symmetry establishment during development of the Arabidopsis gynoecium. We show that the apical style region undergoes an unusual transition from a bilaterally symmetric stage ingrained in the gynoecium due to its evolutionary origin to a radially symmetric structure. We also identify two transcription factors, INDEHISCENT and SPATULA, that are both necessary and sufficient for the radialization process. Our work furthermore shows that these two transcription factors control style symmetry by directly regulating auxin distribution. Establishment of specific auxin-signaling foci and the subsequent development of a radially symmetric auxin ring at the style are required for the transition to radial symmetry, because genetic manipulations of auxin transport can either cause loss of radialization in a wild-type background or rescue mutants with radialization defects. Whereas many examples have described how auxin provides polarity and specific identity to cells in a range of developmental contexts, our data presented here demonstrate that auxin can also be recruited to impose uniform identity to a group of cells that are otherwise differentially programmed. PMID- 25455036 TI - With age comes representational wisdom in social signals. AB - In an increasingly aging society, age has become a foundational dimension of social grouping broadly targeted by advertising and governmental policies. However, perception of old age induces mainly strong negative social biases. To characterize their cognitive and perceptual foundations, we modeled the mental representations of faces associated with three age groups (young age, middle age, and old age), in younger and older participants. We then validated the accuracy of each mental representation of age with independent validators. Using statistical image processing, we identified the features of mental representations that predict perceived age. Here, we show that whereas younger people mentally dichotomize aging into two groups, themselves (younger) and others (older), older participants faithfully represent the features of young age, middle age, and old age, with richer representations of all considered ages. Our results demonstrate that, contrary to popular public belief, older minds depict socially relevant information more accurately than their younger counterparts. PMID- 25455037 TI - Egg-laying demand induces aversion of UV light in Drosophila females. AB - Drosophila melanogaster females are highly selective about the chemosensory quality of their egg-laying sites, an important trait that promotes the survival and fitness of their offspring. How egg-laying females respond to UV light is not known, however. UV is a well-documented phototactic cue for adult Drosophila, but it is an aversive cue for larvae. Here, we show that female flies exhibit UV aversion in response to their egg-laying demand. First, females exhibit egg laying aversion of UV: they prefer to lay eggs on dark sites when choosing between UV-illuminated and dark sites. Second, they also exhibit movement aversion of UV: positional tracking of single females suggests that egg-laying demand increases their tendency to turn away from UV. Genetic manipulations of the retina suggest that egg-laying and movement aversion of UV are both mediated by the inner (R7) and not the outer (R1-R6) photoreceptors. Finally, we show that the Dm8 amacrine neurons, a synaptic target of R7 photoreceptors and a mediator of UV spectral preference, are dispensable for egg-laying aversion but essential for movement aversion of UV. This study suggests that egg-laying demand can temporarily convert UV into an aversive cue for female Drosophila and that R7 photoreceptors recruit different downstream targets to control different egg laying-induced behavioral modifications. PMID- 25455038 TI - Vitamin E Intake and Risk of Renal Cell Carcinoma: A Meta-Analysis of 7 Case Control Studies. AB - OBJECTIVE: Vitamin E intake may reduce the risk of renal cell carcinoma, but the results were inconsistent. Hence, we conducted a meta-analysis to assess the association between dietary vitamin E intake and the risk of renal cell carcinoma. METHODS: We searched PubMed to identify the relevant case-control studies up to June 2014. Reference lists of retrieved articles were also reviewed. Odds ratios and corresponding 95% confidence intervals were used to estimate the association between dietary vitamin E intake and the risk of renal cell carcinoma. RESULTS: We identified 7 case-control studies regarding dietary vitamin E intake and risk of renal cell carcinoma, involving 5789 cases and 14866 controls. The odds ratio of renal cell carcinoma for the highest compared with the lowest dietary vitamin E intake was 0.75 (95% confidence interval: 0.59 0.91), and heterogeneity was observed across studies. The association between dietary vitamin E intake and the risk of renal cell carcinoma was not significantly differed by gender, but this association were inconsistent in the North American and European populations. CONCLUSION: Our study provided a evidence that there was a significant inverse association of dietary vitamin E intake with risk of renal cell carcinoma. However, this finding was based on the case-control studies, more well-designed cohort studies are needed. PMID- 25455040 TI - Plasma ascorbic acid concentrations in prevalent patients with end-stage renal disease on hemodialysis. AB - OBJECTIVE: To determine the prevalence of vitamin C (ascorbic acid [AA]) deficiency in patients with end-stage renal disease, the effect of supplemental AA on plasma AA concentrations, and the extrinsic and intrinsic factors that affect plasma AA concentrations in this patient population. DESIGN: In study 1, we compared the effect of hemodialysis (HD) on plasma AA concentrations between patients with low and high pre-HD AA concentrations. In study 2, we analyzed kinetic and nonkinetic factors for their association with increased plasma AA concentrations in patients on maintenance HD. Study 1 was performed in a single outpatient HD clinic in Cherry Hill, New Jersey. Study 2 was performed in 4 outpatient HD clinics in Southern New Jersey. SUBJECTS AND INTERVENTION: In study 1, we collected plasma samples from 8 adult patients on maintenance HD at various time points around their HD treatment and assayed them for AA concentration. In study 2, we enrolled 203 adult patients and measured pre-HD plasma AA concentrations. We ascertained supplemental AA use and assessed dietary AA intake. MAIN OUTCOME MEASURE: In study 1, plasma AA concentrations were compared during the intradialytic and interdialytic period. In study 2, pre-HD plasma AA concentrations were correlated with supplement use and demographic factors. RESULTS: Study 1 showed that over the course of a single HD treatment, the plasma AA concentration decreased by a mean (+/-standard deviation) of 60% (+/-6.6). In study 2, the median pre-HD plasma AA concentration was 15.7 MUM (interquartile range, 8.7-66.8) in patients who did not take a supplement and 50.6 MUM (interquartile range, 25.1-88.8) in patients who did take a supplement (P < .001). Supplement use, increasing age, and diabetes mellitus were associated with a pre-HD plasma AA concentration >=30 MUM. CONCLUSION: HD depletes plasma AA concentrations, and AA supplementation allows patients to achieve higher plasma AA concentrations. PMID- 25455039 TI - Effect of a symbiotic gel (Lactobacillus acidophilus + Bifidobacterium lactis + inulin) on presence and severity of gastrointestinal symptoms in hemodialysis patients. AB - OBJECTIVE: The study aimed to assess the effect of a symbiotic gel on presence and severity of gastrointestinal symptoms (GIS) in hemodialysis patients. DESIGN: A double-blinded, placebo-controlled, randomized, clinical trial was designed. The study was conducted at 2 public hospitals in Guadalajara, Mexico. SUBJECTS AND INTERVENTION: Twenty-two patients were randomized to the intervention group (nutritional counseling + symbiotic gel) and 20 patients were randomized to the control group (nutritional counseling + placebo), during 2 months of follow-up. MAIN OUTCOME MEASURE: Presence and monthly episodes of GIS were assessed by direct interview and severity by using the self-administered GIS questionnaire. Additionally, biochemical parameters, inflammatory markers, and nutritional status (dietary intake, subjective global assessment, anthropometry, and body composition) were evaluated. RESULTS: After a 2-month treatment, intervention group had a significant reduction in prevalence and monthly episodes of vomit, heartburn, and stomachache, as well as a significant decrease in GIS severity compared with control group. Moreover, intervention group had a greater yet not significant decrease in the prevalence of malnutrition and a trend to reduce their C-reactive protein and tumor necrosis factor alpha levels compared with control group. No symbiotic-related adverse side effects were shown in these patients. Clinical studies with longer follow-up and sample size are needed to confirm these results. CONCLUSIONS: We concluded that administration of a symbiotic gel is a safe and simple way to improve common GIS in dialysis patients. PMID- 25455041 TI - 2014 update of recommendations on the prevention and treatment of glucocorticoid induced osteoporosis. AB - OBJECTIVES: To update the recommendations on the prevention and treatment of glucocorticoid-induced osteoporosis issued in 2003 by the French National Authority for Health (HAS). This update was performed under the aegis of the Bone Section of the French Society for Rheumatology (SFR) and Osteoporosis Research and Information Group (GRIO), in collaboration with four French learned societies (primary-care, gastroenterology, internal medicine, and nephrology). METHODS: A task force composed of members of the medical specialties involved in managing patients with glucocorticoid-induced osteoporosis conducted a systematic literature review according to the method developed by the HAS then used the results to develop updated recommendations. RESULTS: These recommendations are intended for all physicians involved in the management of patients who are scheduled to start, or are taking, long-term glucocorticoid therapy (>= 3 months) in any dose and for any reason. In postmenopausal women and men older than 50 years of age, treatment is warranted in the presence of any of the following risk factors for fracture: history of bone frailty fracture after 50 years of age, bone mineral density T-score <= -2.5 at one or more sites, age >= 70 years, and dosage >= 7.5 mg/d prednisone-equivalent for longer than 3 months. Bisphosphonates can be used in all these situations; teriparatide can be given as first-line therapy in patients at high fracture risk but is reimbursed by the French statutory health insurance system only in patients having two or more prevalent vertebral fractures. The fracture risk is lower in non-menopausal women and in men younger than 50 years of age,in whom treatment decisions should rest on a case-by-case evaluation. CONCLUSION: These recommendations are intended to clarify the pharmacological management of glucocorticoid-induced osteoporosis. PMID- 25455042 TI - Fate of anthropogenic cyclic volatile methylsiloxanes in a wastewater treatment plant. AB - The fate of cyclic volatile methylsiloxanes (cVMS) - octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclohexasiloxane (D6) - was evaluated in a typical secondary activated sludge wastewater treatment plant (WWTP). Water samples (influent, primary effluent, and final effluent) and sludge (primary sludge and waste activated sludge) samples were collected at overnight low, morning high, afternoon low, and evening high flows. Concentrations of cVMS in influents fluctuated with the influent flows, ranging from 0.166 to 1.13 MUg L(-1), 3.47-19.3 MUg L(-1), and 0.446-3.87 MUg L(-1) for D4, D5, and D6, respectively. Mass balance analysis of cVMS showed the average mass of D4, D5, and D6 entering and exiting the plant in influent and effluent, respectively, were 109 g d(-1), 2050 g d(-1), 280 g d(-1), and 1.41 g d(-1), 27.0 g d(-1), 1.90 g d(-1). The total removal efficiency of cVMS was >96%. To elucidate their detailed removal mechanisms, Mackay's fugacity-based treatment plant model was used to simulate the fate of cVMS through the WWTP. Due to the unusual combination of high hydrophobicity and volatility of cVMS, volatilization in the aeration tank and adsorption to sludge were the two main pathways of cVMS removal from water in this WWTP based on the experimental and modeled results. The morning and evening high influent mass flows contributed almost equally at approximately 40% of the total daily cVMS mass, with D5 accounting for the majority of this daily loading. PMID- 25455043 TI - Sulfate radical-based water treatment in presence of chloride: formation of chlorate, inter-conversion of sulfate radicals into hydroxyl radicals and influence of bicarbonate. AB - Sulfate radical (SO4(-)) based oxidation is discussed as a potential water treatment option and is already used in ground water remediation. However, the complex SO4(-) chemistry in various matrices is poorly understood. In that regard, the fast reaction of SO4(-) with Cl(-) is of high importance since Cl(-) belongs to the main constituents in aqueous environments. This reaction yields chlorine atoms (Cl) as primary products. Cl initiate a cascade of subsequent reactions with a pH dependent product pattern. At low pH (<5) formation of chlorine derived oxidation products such as chlorate (ClO3(-)) is favoured. This is undesired because ClO3(-) may reveal adverse effects on the environment and human health. At pH > 5 Cl mainly react with water yielding hydroxyl radicals. Thus, at moderate Cl(-) concentrations (mM range) the SO4(-)-based process may be converted into a conventional (hydroxyl radical -based) advanced oxidation process. The conversion of SO4(-) into OH, however, is interrupted in presence of bicarbonate by scavenging of Cl. PMID- 25455044 TI - Author's reply-fluorescein-related extensive jaundice. PMID- 25455045 TI - Lemierre syndrome and the role of modern antibiotics and therapeutic anticoagulation in its treatment. PMID- 25455046 TI - The association between ketamine given for prehospital chemical restraint with intubation and hospital admission. AB - INTRODUCTION: Intramuscular ketamine has become increasingly popular for prehospital chemical restraint of severely agitated or violent patients because of its favorable adverse effect profile, rapid onset, and wide therapeutic window. However, there is currently no literature quantifying the need for intubation or hospital admission for these patients once they reach the emergency department. METHODS: Medical records for patients receiving prehospital ketamine who were transported to a single level 1 trauma center were abstracted. Ketamine dose, patient weight, final disposition, and presence of intubation were recorded. Exclusion criteria were missing dose or weight and ketamine given for an indication other than chemical restraint. Statistical analysis was preformed with unadjusted Student t test. Statistical significance was defined as P < .05. RESULTS: A convenience sample of 51 consecutive patients was identified with 2 excluded because of missing data, leaving 49 for analysis. Ketamine dosing ranged from 2.25 to 9.42 mg/kg (mean, 5.26 +/- 1.65 mg/kg). Significant differences were noted between those who required intubation (n = 14) and those who did not (n = 35) (6.16 +/- 1.62 mg/kg vs 4.90 +/- 1.54 mg/kg, P = .02). No patients were intubated prehospital. There was an increased dose in patients admitted to a medical ward (57%, 28/49) that approached statistical significance (5.62 +/- 1.80 vs 4.78 +/- 1.31, P = .06). CONCLUSION: Intubation was observed in our emergency department in 29% of patients administered intramuscular ketamine for prehospital chemical restraint. There was a positive association between higher ketamine doses and both endotracheal intubation and hospital admission. Future research should aim to define the minimum effective ketamine dose for successful chemical restraint. PMID- 25455048 TI - Improper bystander-performed basic life support in cardiac arrests managed with public automated external defibrillators. AB - AIM: The aim of the study was to determine the quality of basic life support (BLS) in out-of-hospital cardiac arrests (OHCAs) receiving bystander cardiopulmonary resuscitation (CPR) and public automated external defibrillator (AED) application. METHODS: From January 2006 to December 2012, data were prospectively collected from OHCA) and impending cardiac arrests treated with and without public AED before emergency medical technician (EMT) arrival. Basic life support actions and outcomes were compared between cases with and without public AED application. Interruptions of CPR were compared between 2 groups of AED users: health care provider (HCP) and non-HCP. RESULTS: Public AEDs were applied in 10 and 273 cases of impending cardiac arrest and non-EMT-witnessed OHCAs, respectively (4.3% of 6407 non-EMT-witnessed OHCAs). Defibrillation was delivered to 33 (13.3%) cases. Public AED application significantly improved the rate of 1 year neurologically favorable survival in bystander CPR-performed cases with shockable initial rhythm but not in those with nonshockable rhythm. Emergency calls were significantly delayed compared with other OHCAs without public AED application (median: 3 and 2 minutes, respectively; P < .0001). Analysis of AED records obtained from 136 (54.6%) of the 249 cases with AED application revealed significantly lower rate of compressions delivered per minute and significantly greater proportion of CPR pause in the non-HCP group. Time interval between power on and the first electrocardiographic analysis widely varied in both groups and was significantly prolonged in the non-HCP group (P = .0137). CONCLUSIONS: Improper BLS responses were common in OHCAs treated with public AEDs. Periodic training for proper BLS is necessary for both HCPs and non-HCPs. PMID- 25455047 TI - Clinical and financial impact of removing creatine kinase-MB from the routine testing menu in the emergency setting. AB - CONTEXT: Cardiac troponins T and I have replaced creatine kinase-MB (CK-MB) as the criterion standard for diagnosing myocardial injury. However, many laboratories still routinely perform a high volume of CK-MB testing in conjunction with troponin. PURPOSE: The purpose of this study is to study the clinical and financial impact of removing CK-MB from the routine emergency department (ED) test menu at a large academic medical center. METHODS: Creatine kinase-MB was removed from ED ordering templates and laboratory requisitions (ie, intervention), although the test could still be manually ordered. Data for creatine kinase (CK), CK-MB, and troponin T (TnT) specimens ordered during a 12 month period (6 months preintervention and 6 months postintervention) (n = 14571) was downloaded from our laboratory information system. All specimens with (1) normal TnT (ie, <0.01 ng/mL), (2) elevated CK-MB (ie, >6.6 ng/mL), and (3) elevated CK-MB index (ie, >5) were considered discrepant and independently reviewed by 2 ED clinicians for the presence of an acute coronary syndrome and for documentation of final diagnosis. Creatine kinase, CK-MB, and TnT ED volumes preintervention and postintervention were analyzed to assess laboratory cost savings. RESULTS: Of the 6444 cases included in the analysis, only 17 were discrepant. Of all 17 cases, no patients were diagnosed with acute coronary syndrome. After removing CK-MB from the templates and requisitions, CK-MB and CK volumes decreased by 80% and 76%, respectively, translating to annual reagent cost savings of approximately $47000. CONCLUSIONS: Creatine kinase-MB can be removed from the routine ED test menu without adversely affecting patient care. In addition, substantial cost savings can be achieved by reducing unnecessary CK MB testing and associated CK orders. PMID- 25455049 TI - A retrospective review of the prehospital use of activated charcoal. AB - OBJECTIVE: We studied the complications and timing implications of prehospital activated charcoal (PAC). Appropriateness of PAC administration was also evaluated. METHODS: We retrospectively reviewed prehospital records over 32 months for overdose cases, where PAC was administered. Cases were assessed for amount and type of ingestant, clinical findings, timing of PAC, timing of transport and arrival into the emergency department (ED), and complications. Encounter duration in cases of PAC was compared with that, for all cases during the study period, where an overdose patient who did not receive activated charcoal was transported. RESULTS: Two thousand eight hundred forty-five total cases were identified. In 441 cases, PAC was given; and complications could be assessed. Two hundred eighty-one of these had complete information regarding timing of ingestion, activated charcoal administration, and transport. The average time between overdose and PAC was 49.8 minutes (range, 7-199 minutes; median, 41.0 minutes; SD, 30.4 minutes). Complications included emesis (7%), declining mental status (4%), declining blood pressure (0.4%), and declining oxygen saturation (0.4%). Four hundred seventeen cases of PAC had documentation of timing of emergency medical service (EMS) arrival on scene and arrival at the ED. Average EMS encounter time was 29 minutes (range, 10-53 minutes; median, 27.9 minutes). Two thousand forty-four poisoning patients were transported who did not receive PAC. The average EMS encounter time for this group was 28.1 minutes (range, 4-82 minutes; median, 27.3 minutes), not significantly different (P =.114). CONCLUSIONS: Prehospital activated charcoal did not appear to markedly delay transport or arrival of overdose patients into the ED and was generally safe. PMID- 25455051 TI - Using process indicators to optimize service completion of an ED drug and alcohol brief intervention program. AB - OBJECTIVE: The strongest evidence for effectiveness of screening, brief intervention, and referral to treatment (SBIRT) programs is in primary care settings. Emergency department (ED) studies have shown mixed results. Implementation of SBIRT into ED settings is complicated by the type of patients seen and the fast-paced, high-throughput nature of the ED environment that makes it difficult to reach patients flagged for SBIRT services. This study uses data from an ED-based SBIRT program to examine the relationship between screen positive rate, ED patient flow, and SBIRT service delivery. METHODS: Data for the study (N = 67137) were derived from weekly reports extracted directly from one hospital's electronic health record. Measures included time and day of patient entry, drug/alcohol screen result (positive or negative), and whether the patient was reached by SBIRT specialists. Factorial analysis of variance compared variations in screen-positive rates by day and time and the percentage of patients reached by SBIRT specialists during these periods. RESULTS: Overall, 56% of screen-positive patients received SBIRT services. Only 5% of patients offered SBIRT services refused. Day and time of entry had a significant interaction effect on the reached rate (F12,14166 =3.48, P < .001). Although patient volume was lowest between 11 pm and 7 am, screen-positive rates were highest during this period, particularly on weekends; and patients were least likely to be reached during these periods. CONCLUSIONS: When implementing an ED-based SBIRT program, thoughtful consideration should be given to patient flow and staffing to maximize program impact and increase the likelihood of sustainability. PMID- 25455050 TI - Pneumothorax is a rare complication of thoracic central venous catheterization in community EDs. AB - STUDY OBJECTIVES: The rate of iatrogenic pneumothorax associated with thoracic central venous catheterization in community emergency departments (EDs) is poorly described, although such information is vital to inform the procedure's risk/benefit analysis. We undertook this multicenter study to estimate the incidence of immediate catheter-related pneumothorax in community EDs and to determine associations with site of access, failed access, and positive pressure ventilation. METHODS: This was a secondary analysis of 2 retrospective cohort studies of adults who underwent attempted thoracic central venous catheterization in 1 of 21 EDs. Pneumothorax was identified by postprocedural anteroposterior chest radiograph or emergent evacuation for presumed tension pneumothorax. Frequencies were compared using Fisher's exact test. RESULTS: Among 1249 patient encounters, the initial vein of catheterization was internal jugular in 1054 cases (84.4%) and subclavian in 195 cases (15.6%). Success at the initial internal jugular vein was more common than at the initial subclavian vein (95.4% vs 83.6%, P < .001). Periprocedural positive pressure ventilation was administered in 316 patients (25.3%). We identified 6 pneumothoraces (0.5%; 95% confidence interval, 0.2%-1.1%). The incidence of pneumothorax was higher with the subclavian vein than the internal jugular vein (2.3% vs 0.1%, P < .001), with failed access at the initial vein (2.5% vs 0.3%, P = .05), and among patients receiving positive pressure ventilation (1.6% vs 0.1%, P < .01). CONCLUSION: The incidence of pneumothorax from thoracic central venous catheterization in community EDs is low. The risk of pneumothorax is higher with a subclavian vein approach, failed access at the initial vein, and positive pressure ventilation. PMID- 25455052 TI - Evaluation of the effectiveness of bedside point-of-care ultrasound in the diagnosis and management of distal radius fractures. AB - OBJECTIVE: The aim of the study was to compare the effectiveness of point-of-care ultrasound (POCUS) with direct radiography in diagnosis and management of the patients with distal radius fractures (DRFs). METHODS: In this study, patients between ages 5 and 55 years admitted to the emergency department with low energy upper extremity trauma with suspected DRF were evaluated with POCUS and direct radiography by emergency physicians (EPs) trained in either musculoskeletal (MSK) imaging or x-ray interpretation of DRF. The EP performing the POCUS examination was blinded to the x-ray results. RESULTS: A total of 83 patients with DRF were included in the study. There were 18 (22%) females, and 65 (78%) males enrolled in the study. Mean age was 13 +/- 14 years for males, and 15 +/- 13 years for females. Compared with direct radiography, POCUS yielded 98% sensitivity, 96% specificity, 98% positive predictive value, 96% negative predictive value, and 98% accuracy of the test in detecting fractures. POCUS yielded 96% sensitivity, 93% specificity value in detecting linear fractures; 78% sensitivity, 98% specificity in detecting torus-type fractures, and 100% specificity and sensitivity for detecting fissure fractures. Specificity of POCUS in the decision for reduction was 100% and sensitivity was 98%; specificity was 100% for splint application. CONCLUSION: In our study, it was shown that POCUS could be applied easily by EPs trained in MSK POCUS imaging with success in diagnosing DRF and determining the correct fracture type and required treatment methods. PMID- 25455053 TI - Noninvasive ventilation during procedural sedation in the ED: a case series. PMID- 25455054 TI - Regarding tumefactive demyelinating lesion, its image diagnosis, and discussion. PMID- 25455055 TI - Three cases of electrical storm in fulminant myocarditis treated by extracorporeal membrane oxygenation. PMID- 25455056 TI - Consideration of C-reactive protein and polyserositis in systemic lupus erythematosus presenting with cardiac symptoms. PMID- 25455057 TI - Quality of chest compression with CardioPump CPR compared to single rescuer standard BLS. PMID- 25455058 TI - Community-onset febrile illness in HIV-infected adults: variable pathogens in terms of CD4 counts and transmission routes. AB - OBJECTIVES: The objective of the study is to investigate the causes of febrile illness among HIV-infected adults visiting the emergency department (ED) of a designated hospital for HIV care in Taiwan, an area of a low HIV prevalence. METHODS: From January 2004 to December 2012, all febrile HIV-infected adults visiting the ED were retrospectively investigated. Recent CD4 lymphocyte counts near ED visits and HIV transmission route were designated as major predictors for the analyses. All variables and clinical information were derived from chart records. RESULTS: Of the 196 eligible HIV-infected adults, major causes of febrile illness were lower respiratory tract infections (68, 34.7%), skin and soft tissue infections (31, 15.8%), intra-abdominal infections (22, 11.2%), and urinary tract infections (11, 5.6%). There were 150 pathogens identified. Staphylococcus aureus (51, 34.0%) and Pneumocystis jirovecii (26, 17.3%) were the major pathogens. In a multivariate analysis, injection drug use (odds ratio, 15.18; P < .001) and skin and soft tissue infections (odds ratio, 18.45; P = .001) were independently associated with S aureus infections, and the proportion of S aureus increased steadily with CD4 lymphocyte count (gamma = 0.99; P = .01). Of pneumonic patients with recognized pathogens, P. jirovecii pneumonia was frequently associated with patients having a CD4 lymphocyte count of less than 100 cells/mm(3) (25/25, 100% vs 16/30, 53.3%; P < .001). CONCLUSIONS: The causes of febrile illness in HIV-infected adults visiting the ED varied according to CD4 count and transmission route. Two independent risk factors, intravenous drug use and skin and soft tissue infections, were associated with S aureus infections. For HIV-infected adults with lower respiratory tract infections, a CD4 lymphocyte count of less than 100 cells/mm(3) was a risk factor for P. jirovecii pneumonia. PMID- 25455059 TI - High-fat diets and seizure control in myoclonic-astatic epilepsy: a single center's experience. AB - PURPOSE: To determine the efficacy of the Modified Atkins Diet (MAD) and Ketogenic Diet (KD) in seizure control within a population of myoclonic-astatic epilepsy (MAE) patients. METHODS: This was a retrospective, single center study evaluating the seizure control by high fat diets. Seizure diaries kept by the parents performed seizure counts. All patients met the clinical criteria for MAE. RESULTS: Nine patients met the clinical criteria. We found that both the MAD and KD were efficacious in complete seizure control and allowed other medications to be stopped in seven patients. Two patients had greater than 90% seizure control without medications, one on the KD and the other on the MAD. Seizure freedom has ranged from 13 to 36 months, and during this time four patients have been fully weaned off of diet management. One patient was found to have a mutation in SLC2A1. CONCLUSION: Our results suggest that strictly defined MAE patients respond to the MAD with prolonged seizure control. Some patients may require the KD for seizure freedom, suggesting a common pathway of increased requirement for fats. Once controlled, those fully responsive to the Diet(s) could be weaned off traditional seizure medications and in many, subsequently off the MAD or KD. PMID- 25455060 TI - Correlation of saliva and serum free valproic acid concentrations in persons with epilepsy. AB - PURPOSE: Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) in serum is frequently used in clinical settings however saliva could be an alternative to measure free concentration of drugs. In the present study, we observed the possible correlation of VPA concentration between serum and saliva in persons with epilepsy (PWE). METHODS: A total of 59 paired serum and saliva samples were assayed from 65 consecutive PWE (51 males and 14 females; age range 9-65 years). Patients were subjected to either VPA monotherapy or its combination with other AEDs for at least three months. Steady state trough concentration of unbound VPA drug was quantified using HPLC. The correlation between serum and saliva free VPA concentration was evaluated. RESULTS: Out of 65 patients, 27 were on monotherapy of VPA and 38 were on VPA with other antiepileptic drugs. Saliva VPA concentration significantly correlated with serum free VPA concentration (p<0.05). Poor correlation was observed between serum and saliva VPA concentration with the daily dose (p>0.05) respectively. CONCLUSIONS: Our study reveals that serum and saliva VPA concentrations are significantly associated in PWE. These associations may facilitate monitoring and evaluation of VPA levels non-invasively for PWE. PMID- 25455061 TI - Measurement of stress. AB - This article provides information on psychological assessments based on the most influential stress theories. In understanding the stress response and its relation to disease, clinical vignettes are provided. Emphasis is placed on assessment measures for use in the general population and on providing an overview of evidence for more commonly used instruments in health care. Several advantages and disadvantages afforded by measurement approaches are also addressed (although a full examination of the extent of limitations and issues regarding assessment is beyond the scope of this article). Finally, future considerations regarding proposed research and necessary advances in measurement are discussed. PMID- 25455062 TI - Stress and anxiety: counterpart elements of the stress/anxiety complex. AB - The relationship between stress and anxiety is complicated. Stress initially arises from one's environment; anxiety overlays physiological arousal, cognitive appraisals, emotional states, and behavioral responses. Both are components of a stress-anxiety complex, which has evolved to enable individuals to adapt to their environment and achieve equilibrium. Anxiety disorders, which result when this mechanism goes awry, occur along a spectrum. One of the main variables affecting anxiety disorders is the extent of stress. Each anxiety disorder should be evaluated along a stress axis, leading to improved case conceptualization and intervention strategies. PMID- 25455063 TI - The effect of severe stress on early brain development, attachment, and emotions: a psychoanatomical formulation. AB - Child abuse is the most extreme form of stress in childhood and adolescence, and has severe effects on the child's development. Limbic nuclei and circuitry development are especially vulnerable to child abuse and neglect during the first year of life. Development at the neuronal level can be severely disturbed by trauma during early infancy, resulting in maladaptive synaptic formation, impeding experience-expectant brain development. Development of basic emotions may favor the development of negative instead of positive emotions. The new concept of psychoanatomical formulation is introduced. A case vignette is presented and analyzed, based on the disturbed neuroanatomy underlying symptom expression. PMID- 25455065 TI - Stress in service members. AB - Military service differs from civilian jobs in the stressors that service members experience, including frequent deployments (eg, to an area of combat operations), obedience, regimentation, subordination of self to the group, integrity, and flexibility. The military culture emphasizes teamwork and peer support. In some cases, service members cannot adapt to military life, become overwhelmed by stress, or cannot overcome a traumatic experience. Clinicians should conduct a thorough evaluation guided by an understanding of the military culture. Every effort should be made to identify the stress and the maladaptive response and provide early clinical interventions to prevent progression. PMID- 25455066 TI - Humor. AB - Humor has not been taken as seriously as it should be. Humor has many positive effects in the daily lives of patients and clinicians need to take advantage of these. Many indices of stress are attenuated and this serves to improve the therapeutic alliance. Freudian, rational emotive therapy, and kleinian views are presented, as well as examples of how to use playful therapy. In addition, advice on how to develop humor is given. PMID- 25455064 TI - The role of stress and fear in the development of mental disorders. AB - The most common pathologic manifestation of fear is posttraumatic stress disorder (PTSD). Developing PTSD is closely related with predisposing factors such as genes and early traumatic experiences. In PTSD, enhanced fear learning and poor extinction are common. Fear is manifested through autonomic responses and persistent memories of the traumatic event. These manifestations are related to stress responses modulated by the hypothalamic-pituitary-adrenal axis. This article evaluates the role of fear and stress in the course of PTSD. Findings on fear learning and extinction are presented in order to guide future treatments of patients with PTSD. PMID- 25455067 TI - Diet and stress. AB - Stress refers to a reaction given a particular stimulus. Stress is a common problem in most modern societies. Stress creates greater physiologic demands. Unhealthy eating patterns will only result in an increased level of stress, followed by further health problems if in the future if the issues are not resolved. Prolonged stress increases the metabolic needs of the body and causes many other changes. The increased metabolism can also cause an increase in the use and excretion of many nutrients. Although stress alters nutrient needs, if marginally deficient in a nutrient, stress can make that deficiency even worse. PMID- 25455068 TI - The role of nutrient-based epigenetic changes in buffering against stress, aging, and Alzheimer's disease. AB - Converging evidence identifies stress-related disorders as putative risk factors for Alzheimer Disease (AD). This article reviews evidence on the complex interplay of stress, aging, and genes-epigenetics interactions. The recent classification of AD into preclinical, mild cognitive impairment, and AD offers a window for intervention to prevent, delay, or modify the course of AD. Evidence in support of the cognitive effects of epigenetics-diet, and nutraceuticals is reviewed. A proactive epigenetics diet and nutraceuticals program holds promise as potential buffer against the negative impact of aging and stress responses on cognition, and can optimize vascular, metabolic, and brain health in the community. PMID- 25455069 TI - Dermatological manifestations of stress in normal and psychiatric populations. AB - This article explores the way stress affects the skin, both at the molecular level, where the skin has an intricate connection to the neurocutaneous and immune systems, and at the clinical level. The concept of psychodermatology is reviewed with regard to the way skin reacts to stress, how stress is a trigger for several common skin diseases, and how neuropsychiatric disorders may have skin manifestations. The article is directed at making the dermatologist, the psychiatrist, the psychologist, and the primary physician familiar with the brain skin mechanisms involved in stress and the resultant clinical expressions on the skin. PMID- 25455071 TI - The importance of glia in dealing with stress. AB - Glia are starting to be accepted as the equal of neurons. Their impact on intelligence, environmental enrichment, and cerebral dominance forms the basis for understanding the role of glia in stress. Along with neurons, astrocytes, microglia, NG2 cells, and oligodendrocytes all contribute. Glia can even be protective against drug abuse. Glial effects on depression, mood disorders and schizophrenia are reviewed. PMID- 25455072 TI - If life were easy they would have asked for volunteers. PMID- 25455073 TI - A network approach to clinical intervention in neurodegenerative diseases. AB - Network biology has become a powerful tool to dissect the molecular mechanisms triggering neurodegeneration. Recent developments in network biology have led to the discovery of disease-causing genes, diagnostic biomarkers, and therapeutic targets for several neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntington's diseases. Network-based approaches have provided the molecular rationale for the relationship among cancer, diabetes, and neurodegenerative diseases, and have uncovered unexpected links between apparently unrelated diseases. Here, we summarize the recent advances in network biology to untangle the molecular underpinnings giving rise to the most prevalent neurodegenerative diseases. We propose that network analysis provides a feasible and practical tool for identifying biologically meaningful biomarkers and potential therapeutic targets for clinical intervention in neurodegenerative diseases. PMID- 25455075 TI - [A case of severe sepsis with disseminated intravascular coagulation during Rickettsia sibirica mongolitimonae infection]. PMID- 25455074 TI - RB maintains quiescence and prevents premature senescence through upregulation of DNMT1 in mesenchymal stromal cells. AB - Many cell therapies currently being tested are based on mesenchymal stromal cells (MSCs). However, MSCs start to enter the senescent state upon long-term expansion. The role of retinoblastoma (RB) protein in regulating MSC properties is not well studied. Here, we show that RB levels are higher in early-passage MSCs compared with late-passage MSCs. RB knockdown induces premature senescence and reduced differentiation potentials in early-passage MSCs. RB overexpression inhibits senescence and increases differentiation potentials in late-passage MSCs. Expression of DNMT1, but not DNMT3A or DNMT3B, is also higher in early passage MSCs than in late-passage MSCs. Furthermore, DNMT1 knockdown in early passage MSCs induces senescence and reduces differentiation potentials, whereas DNMT1 overexpression in late-passage MSCs has the opposite effect. These results demonstrate that RB expressed in early-passage MSCs upregulates DNMT1 expression and inhibits senescence in MSCs. Therefore, genetic modification of RB could be a way to improve the efficiency of MSCs in clinical use. PMID- 25455076 TI - [National antibiotic stewardship policy: advocating a new strategy]. PMID- 25455077 TI - Epidemiology of pulmonary tuberculosis in France. Can the hospital discharge database be a reliable source of information? AB - OBJECTIVE: In France, tuberculosis surveillance is based on mandatory notification (MN) of cases. However, the MN does not allow the full description of cases, and underreporting limits data interpretation. Aiming at better describing the cases of tuberculosis, the hospital record database (PMSI) was analyzed. PATIENTS AND METHOD: Incident cases of active pulmonary tuberculosis identified in 2010 in France in the PMSI were included and their characteristics were compared with those of the cases identified through the MN. RESULTS: In 2010, 5158 incident cases of pulmonary tuberculosis were identified in the PMSI. The mean duration of hospitalization was higher for cases considered contagious - at least one positive test result on pulmonary sample - (22 vs 13 days, P < 0.001). Among all cases, 5% were infected by HIV. Death was reported for 4% of cases. The number of pulmonary TB cases reported in the MN was 3781 in 2010. PMSI data by sex, region of residence and month of diagnosis were similar with those of the MN but patients were older in the PMSI (52 vs 47 years, P < 0.001). Considering the PMSI as exhaustive, sensitivity of the MN was estimated at 73.3% in 2010. CONCLUSION: PMSI data were compatible with those of the MN and the estimation of the sensitivity was close to other French studies. PMSI can be considered as an interesting tool aiming at improving our knowledge about tuberculosis (TB) cases and strengthening awareness where the sensitivity of the MN is low. PMID- 25455078 TI - Prevalence and impact on quality of life of post-herpetic neuralgia in French medical centers specialized in chronic pain management: the ZOCAD study. AB - OBJECTIVES: (1) We had for aim to determine the rate of patients consulting for post-herpetic neuralgia (PHN) in centers specialized in the management of chronic pain, (2) to assess the burden of PHN, (3) to compare the impact of PHN between new (newly consulting for PHN) and known (already treated by pain specialists) patients. PATIENTS AND METHODS: We conducted a prospective multicenter observational study including all chronic pain outpatients consulting for 3 consecutive weeks. The impact of PHN was assessed with the ZBPI, SF12, HADS, and a non-validated disability questionnaire. RESULTS: Among the patients, 4518 consulted 54 specialized centers from January 24th to July 21st 2008: 2.6% of patients (but 10.9% of patients 70 years of age or more) reported PHN. The acute herpes zoster episode had occurred more than 13.3 months before inclusion for half of the patients. 108 of the 118 PHN patients (33 new and 75 known) completed the questionnaires. Their mean scores were 3.7 (SD, 2.6) for ZBPI and 34.4 (SD, 10.9) and 55.9 (SD, 11.4) for SF12 PCS and MCS; 38% and 42% of PHN patients had HADS anxiety and depression scores > 10. Nearly all PHN patients had received antiepileptic and analgesic drugs. Tricyclic antidepressants and lidocaine patches were more frequently administered to known than to new patients. Pain relief was more effective for known than for new patients. CONCLUSIONS: PHN is a frequent cause of visit in French medical centers specialized in chronic pain management long after the rash has disappeared, and a reason for treatment with drugs that should be prescribed cautiously in elderly patients. PMID- 25455079 TI - [Neurosyphilis in an immunocompetent female patient presenting with chronic polyradiculoneuropathy]. PMID- 25455070 TI - The role of glia in stress: polyamines and brain disorders. AB - This review focuses on the roles of glia and polyamines (PAs) in brain function and dysfunction, highlighting how PAs are one of the principal differences between glia and neurons. The novel role of PAs, such as putrescine, spermidine, and spermine and their precursors and derivatives, is discussed. However, PAs have not yet been a focus of much glial research. They affect many neuronal and glial receptors, channels, and transporters. They are therefore key elements in the development of many diseases and syndromes, thus forming the rationale for PA focused and glia-focused therapy for these conditions. PMID- 25455080 TI - [Social representations of contention in children: of the viewpoint of pediatric professionals]. AB - AIMS: This study is part of a current context raising questions on restraint practices in healthcare at the national and international level. It examines how social representations of restraint organize and shape the discourse of professionals within the context of healthcare and support for sick and/or disabled children. The main objective was to understand how these social representations were expressed in restraint practices. POPULATION AND METHODS: A qualitative method using semi-structured interviews was chosen to meet the goals set out. The research was conducted with 15 healthcare professionals in pediatrics, infant intensive care, and neurorespiratory rehabilitation at Raymond Poincare Hospital. The data were processed using a content analysis of the thematic type. RESULTS: The results suggest that social representations particularly affect the experience of these professionals and the representations they may have concerning the experience of children, parents, and the role played by the latter in restraint situations. They also show that restraint is a multidimensional object that is difficult to understand, particularly because of the current context of questioning this practice within pediatric departments. CONCLUSION: Despite certain methodological limitations, this study has contributed to a reflective process around restraint practices within a psychosocial approach of understanding the subject and its issues. PMID- 25455081 TI - [An epidemiological study of early consultations of newborns in pediatric emergency units]. AB - BACKGROUND: The number of visits to the pediatric emergency services has increased in the past 20 years in France and around the world, especially for neonates (under 28 days of age). OBJECTIVES: Determine for neonates the reasons requiring medical consultation in the emergency pediatric unit of Saint-Etienne University Hospital (France) and isolate the proportion of "non-urgent" preventable consultations that could be managed outside of emergency units. METHOD: Epidemiological, retrospective study on computerized data on neonates who were referred to the pediatric emergency unit of the Saint-Etienne University Hospital from 1 January to 31 December 2011. Four composite criteria "child not addressed by a healthcare professional; severity score G1, G2, G3 based on an internal scale; no further review undertaken; and return home" were used to define "non-urgent" consultations. RESULTS: A total of 419 infants were included in the study. The leading reasons for consultations were crying (14.1%), vomiting (11.9%), chest tightness (10.7%), fever (8.1%), and diarrhea (7%). The main diagnoses were acute nasopharyngitis (11.5%), gastroesophageal reflux (10%), colic (8.1%), and excessive parental anxiety (7.6%). The percentage of "non urgent" consultations was 52.4%. CONCLUSIONS: Final diagnoses are quite similar to the reasons for consultation. The baby's unexplained crying and the inexperience of young parents resulted in an irrational anxiety. This study highlights the need for parental support at home after discharge from the maternity ward and the use of large-scale educational initiatives. PMID- 25455083 TI - [Scurvy, an old disease still in the news: two case reports]. AB - Scurvy is the clinical manifestation of a deficiency in vitamin C, which is present in fresh fruits and vegetables. It is historically linked to the era of great maritime expeditions. Manifestations are misleading in children, in contrast with adults: bone disease and hemorrhagic syndrome are the earliest and most frequent manifestations due to a collagen biosynthesis defect. Scurvy is an old, potentially fatal disease but is easily curable with ascorbic acid. It can be prevented with vitamin C treatment in pediatric populations with unusual eating habits. We describe two cases of pediatric scurvy in two 7-year-old boys who had dietary restrictions stemming from developmental disorders. PMID- 25455084 TI - Detection of Equid herpesvirus type 2 and 5 DNA in uterine flushings of mares with reproductive disorders. AB - In recent years, there has been increasing evidence of the potential pathogenic significance of equine gammaherpesviruses in the horse. In humans, cattle and mice, gammaherpesviruses have already been associated with uterine infection. The aim of the present study was to investigate the presence of gammaherpesviruses in uterine flushings of mares with reproductive problems and to evaluate if there was a possible statistical association with clinical and laboratory findings in these cases. A total of 80 uterine flushings were collected from 61 mares with different reproductive problems and these were tested for equine herpesviruses (EHV) 1-5 by PCR. In the case of each mare in the study, the age, history of infertility, presence of anatomical defects in the reproductive tract, presence of systemic or local disease at time of sampling, phase in the oestrous cycle, post-partum interval, nature of uterine lavage performed (low versus large volume lavage), cytological and bacteriological examination results from the uterine flushing, and PCR herpesvirus results were recorded. Univariate analysis and multivariable logistic regression models were used to identify possible statistical associations and risk factors. Nine out of 61 mares (14.7%) had EHV-5 DNA in their uterine flushings. Co-infections with EHV-1 and EHV-2 were present in two cases. Of all the variables analyzed, only the cytological examination findings were associated with EHV-5 PCR positive results, both on univariate and multivariable analysis, especially in cases with an inflammation score of 3. It is postulated that presence of EHV-5 infection in the non-pregnant uterus may have a role to play in reproductive dysfunction and have a negative consequence on the pregnant uterus. Additional studies involving both healthy mares and mares with reproductive problems need to be performed, however, to elucidate whatever role equine gammaherpesviruses may play in the reproductive tract. This would be very worthwhile, since reproductive problems can have a significant impact on the equine breeding industry. Gaining a greater understanding of its causes could lead to new approaches for prevention and treatment. PMID- 25455085 TI - Supercritical fluid extraction of valuable compounds from microalgal biomass. AB - Many studies have demonstrated that the global demand for renewable biofuels, natural food pigments, and antioxidants has made microalgae a more attractive alternative resource. The application of supercritical fluid extraction (SFE) on the valuable compounds recovery from microalgal biomass has several advantages as compared to the conventional organic solvent extraction methods, especially for environmental considerations. This review presents comprehensive information on the current state of using SFE to recover valuable components from microalgal biomass, such as total lipids, long chain fatty acid and pigments, as well as the utilization and characteristics of the SFE technology. In addition, key factors and challenges that should be addressed during the application of SFE technology are also discussed. This report provides a useful guide that can aid in the future development of more efficient microalgae-based biorefinery process. PMID- 25455086 TI - Chemical characterization and anaerobic biodegradability of hydrothermal liquefaction aqueous products from mixed-culture wastewater algae. AB - This study examined the chemical characteristics and the anaerobic degradability of the aqueous product from hydrothermal liquefaction (HTL-ap) from the conversion of mixed-culture algal biomass grown in a wastewater treatment system. The effects of the HTL reaction times from 0 to 1.5 h, and reaction temperatures from 260 degrees C to 320 degrees C on the anaerobic degradability of the HTL ap were quantified using biomethane potential assays. Comparing chemical oxygen demand data for HTL-ap from different operating conditions, indicated that organic matter may partition from organic phase to aqueous phase at 320 degrees C. Moderate lag phase and the highest cumulative methane production were observed when HTL-ap was obtained at 320 degrees C. The longest lag phase and the smallest production rate were observed in the process fed with HTL-ap obtained at 300 degrees C. Nevertheless, after overcoming adaptation issues, this HTL-ap led to the second highest accumulated specific methane production. Acetogenesis was identified as a possible rate-limiting pathway. PMID- 25455087 TI - Kinetic study of solid waste pyrolysis using distributed activation energy model. AB - The pyrolysis characteristics of municipal solid waste, agricultural residues such as ground nut shell, cotton husk and their blends are investigated using non isothermal thermogravimetric analysis (TGA) with in a temperature range of 30-900 degrees C at different heating rates of 10 degrees C, 30 degrees C and 50 degrees C/min in inert atmosphere. From the thermograms obtained from TGA, it is observed that the maximum rate of degradation occurred in the second stage of the pyrolysis process for all the solid wastes. The distributed activation energy model (DAEM) is used to study the pyrolysis kinetics of the solid wastes. The kinetic parameters E (activation energy), k0 (frequency factor) are calculated from this model. It is found that the range of activation energies for agricultural residues are lower than the municipal solid waste. The activation energies for the municipal solid waste pyrolysis process drastically decreased with addition of agricultural residues. The proposed DAEM is successfully validated with TGA experimental data. PMID- 25455088 TI - Assessment of percolation through a solid leach bed in dry batch anaerobic digestion processes. AB - This work aimed at assessing water percolation through a solid cow manure leach bed in dry batch AD processes. A laboratory-scale percolation column and an experimental methodology were set up. Water behaviour was modelled by a double porosity medium approach. An experimental procedure was proposed to determine the main hydrodynamic parameters of the multiphase flow model: the porosity, the permeability and the term for water exchange from macro- to micro-porosity. Micro and macro-porosity values ranged from 0.42 to 0.70 m(3) m(-3) and 0.18 to 0.50 m(3) m(-3). Intrinsic permeability values for solid cow manure ranged from 5.55.10(-11) to 4.75.10(-9) m(2). The term for water exchange was computed using a 2nd order model. The CFD tool developed was used to simulate successive percolation and drainage operations. These results will be used to design leachate recirculation strategies and predict biogas production in full-scale dry AD batch processes. PMID- 25455089 TI - Metal catalysts for steam reforming of tar derived from the gasification of lignocellulosic biomass. AB - Biomass gasification is one of the most important technologies for the conversion of biomass to electricity, fuels, and chemicals. The main obstacle preventing the commercial application of this technology is the presence of tar in the product gas. Catalytic reforming of tar appears a promising approach to remove tar and supported metal catalysts are among the most effective catalysts. Nevertheless, improvement of catalytic performances including activity, stability, resistance to coke deposition and aggregation of metal particles, as well as catalyst regenerability is greatly needed. This review focuses on the design and catalysis of supported metal catalysts for the removal of tar in the gasification of biomass. The recent development of metal catalysts including Rh, Ni, Co, and their alloys for steam reforming of biomass tar and tar model compounds is introduced. The role of metal species, support materials, promoters, and their interfaces is described. PMID- 25455090 TI - Evaluation of simultaneous nitrification and denitrification under controlled conditions by an aerobic denitrifier culture. AB - Paracoccus versutus LYM was characterized with the ability of simultaneous nitrification and denitrification (SND) in presence of NH4(+)-N and NO3(-)-N (140mg/L-N each). However, there was approximate 95.80mg/L NO2(-)-N left during SND process. Fe(2+) was added in the SND medium and it benefited bacterial growth and further converted NO2(-)-N a little. Besides, remaining NO2(-)-N could be completely reduced by adding carbon donors in presence of NH4(+)-N and NO3(-)-N, whose converting efficiencies also reached 97.09% and 96.34%, respectively. And N2 stayed as the main product of SND process. While NO2(-)-N and NH4(+)-N were present simultaneously, strain LYM could also remove nitrogen compounds thoroughly with sufficient carbon source. But there was no NO2(-)-N reduced as sole nitrogen source in the medium even if C/N ratio reached as high as 30. PMID- 25455092 TI - GFR decline as an end point for clinical trials in CKD: a view from Europe. PMID- 25455091 TI - Effective CKD care in European countries: challenges and opportunities for health policy. AB - Chronic kidney disease (CKD) is an important global public health problem that is associated with adverse health outcomes and high health care costs. Effective and cost-effective treatments are available for slowing the progression of CKD and preventing its complications, including cardiovascular disease. Although wealthy nations have highly structured schemes in place to support the care of people with kidney failure, less consideration has been given to health systems and policy for the much larger population of people with non-dialysis-dependent CKD. Further, how to integrate such strategies with national and international initiatives for control of other chronic noncommunicable diseases (NCDs) merits attention. We synthesized the various approaches to CKD control across 17 European countries and present our findings according to the key domains suggested by the World Health Organization framework for NCD control. This report identifies opportunities to strengthen CKD-relevant health systems and explores potential mechanisms to capitalize on these opportunities. Across the 17 countries studied, we found a number of common barriers to the care of people with non-dialysis-dependent CKD: limited work force capacity, the nearly complete absence of mechanisms for disease surveillance, lack of a coordinated CKD care strategy, poor integration of CKD care with other NCD control initiatives, and low awareness of the significance of CKD. These common challenges faced by diverse health systems reflect the need for international cooperation to strengthen health systems and policies for CKD care. PMID- 25455093 TI - GFR decline as an alternative end point in clinical trials to prevent ESRD: are we increasing treatment uncertainty for the sake of feasibility? PMID- 25455097 TI - The Vigo grommet trainer. AB - INTRODUCTION: Transtympanic grommet placement is perhaps the most common otologic outpatient procedure and is the junior resident's first step in otologic surgery. Drain placement requires a high level of skill and only after painstaking practice, will the young physician be prepared to perform the procedure. TECHNICAL NOTE: We describe a home-made training model for grommet placement, consisting of a wooden base holding a syringe, with a sheet of latex simulating the tympanic membrane. RESULTS: The model is cheap and easy to build. It allows ear tube (grommet) placement to be simulated in a practical and risk-free manner. The technique is reproducible, allowing the young physician to develop his or her skills without patient involvement. CONCLUSION: Although a simulator cannot perfectly replicate surgery, the Vigo grommet trainer is an excellent tool to provide valuable practice in acquiring and developing the skills needed to perform drain placement in the operating theater. PMID- 25455098 TI - Anterior glenohumeral joint stabilization in tetraplegic patients by medializing the anterior head of deltoid muscle. AB - To improve control of the upper limb in high-level tetraplegic patients, the proximal shoulder must be the first consideration. Medialization of the anterior part of the deltoid muscle provides stabilization and is then an antagonist to the posterior deltoid when a pectoralis major palsy exists. It can also be performed in isolation in high-level tetraplegia even when there is little hope of distal extremity reconstruction to stabilize the shoulder. It also precedes the ability to restore elbow extension and perform further reconstructive hand surgery. We describe the surgical technique and report a clinical case. PMID- 25455094 TI - A dual vaccine against influenza & Alzheimer's disease failed to enhance anti beta-amyloid antibody responses in mice with pre-existing virus specific memory. AB - Novel dual vaccine, WSN-Abeta(1-10), based on the recombinant influenza virus, expressing immunodominant B-cell epitope of beta-amyloid, simultaneously induced therapeutically potent anti-Abeta and anti-influenza antibodies. In this study we showed that boosting of WSN-WT primed mice with WSN-Abeta(1-10) enhances anti viral, but fails to induce anti-Abeta antibody responses. This inhibition is associated with expression of Abeta(1-10) within the context of an inactivated influenza virus vaccine. These results demonstrate that the use of an inactivated influenza virus as a carrier for AD vaccine may not be applicable due to the possible inhibition of anti-Abeta antibody response in individuals previously vaccinated or infected with influenza. PMID- 25455099 TI - Molecular cloning, mRNA expression and tissue distribution analysis of Slc7a11 gene in alpaca (Lama paco) skins associated with different coat colors. AB - Slc7a11 encoding solute carrier family 7 member 11 (amionic amino acid transporter light chain, xCT), has been identified to be a critical genetic regulator of pheomelanin synthesis in hair and melanocytes. To better understand the molecular characterization of Slc7a11 and the expression patterns in skin of white versus brown alpaca (lama paco), we cloned the full length coding sequence (CDS) of alpaca Slc7a11 gene and analyzed the expression patterns using Real Time PCR, Western blotting and immunohistochemistry. The full length CDS of 1512bp encodes a 503 amino acid polypeptide. Sequence analysis showed that alpaca xCT contains 12 transmembrane regions consistent with the highly conserved amino acid permease (AA_permease_2) domain similar to other vertebrates. Sequence alignment and phylogenetic analysis revealed that alpaca xCT had the highest identity and shared the same branch with Camelus ferus. Real Time PCR and Western blotting suggested that xCT was expressed at significantly high levels in brown alpaca skin, and transcripts and protein possessed the same expression pattern in white and brown alpaca skins. Additionally, immunohistochemical analysis further demonstrated that xCT staining was robustly increased in the matrix and root sheath of brown alpaca skin compared with that of white. These results suggest that Slc7a11 functions in alpaca coat color regulation and offer essential information for further exploration on the role of Slc7a11 in melanogenesis. PMID- 25455100 TI - Transcriptome and metabolome analyses of sugar and organic acid metabolism in Ponkan (Citrus reticulata) fruit during fruit maturation. AB - Ponkan (Citrus reticulata Blanco cv. Ponkan) is an important mandarin citrus in China. However, the low ratio of sugars to organic acids makes it less acceptable for consumers. In this work, three stages (S120, early development stage; S195, commercial harvest stage; S205, delayed harvest stage) of Ponkan fruit were selected for study. Among 28 primary metabolites analyzed in fruit, sugars increased while organic acids in general decreased. RNA-Seq analysis was carried out and 19,504 genes were matched to the Citrus clementina genome, with 85 up regulated and 59 down-regulated genes identified during fruit maturation. A sucrose phosphate synthase (SPS) gene was included in the up-regulated group, and this was supported by the transcript ratio distribution. Expression of two asparagine transferases (AST), and a specific ATP-citrate lyase (ACL) and glutamate decarboxylase (GAD) members increased during fruit maturation. It is suggested that SPS, AST, ACL and GAD coordinately contribute to sugar accumulation and organic acid degradation during Ponkan fruit maturation. Both the glycolysis pathway and TCA cycle were accelerated during later maturation, indicating the flux change from sucrose metabolism to organic acid metabolism was enhanced, with citrate degradation occurring mainly through the gamma aminobutyric acid (GABA) and acetyl-CoA pathways. PMID- 25455101 TI - An evolutionarily conserved non-coding element in casein locus acts as transcriptional repressor. AB - In mammals, the casein locus consists of stretches of non-coding DNA, the functions of most of which are unknown. These regions are believed to harbour elements responsible for spatio-temporally regulated expression of genes in this locus and so far, only a few such elements have been identified. In this study, we report a novel regulatory element in the casein locus. Comparative analysis of genomic DNA sequences of casein loci from different mammals identified a 147bp long evolutionarily conserved region (ECR) upstream of Odam, a gene in this locus. The ECR was found in close proximity of Odam gene in all the mammals examined. In-silico analysis predicted the ECR as a potential regulatory element. Functional analysis in different cell lines identified it as a unidirectional repressor element. From our findings we speculate that the ECR may be involved in the repression of the Odam expression in the mammary gland during lactation. PMID- 25455102 TI - IDH1 mutations is prognostic marker for primary glioblastoma multiforme but MGMT hypermethylation is not prognostic for primary glioblastoma multiforme. AB - PURPOSE: To establish the frequency of IDH1 mutations and MGMT methylation in primary glioblastomas. EXPERIMENTAL DESIGN: We screened primary glioblastoma multiforme (GBM) in a population-based study for IDH1 mutations and MGMT methylation and correlated them with clinical data. RESULTS: IDH1 mutations were detected in 5 of 40 primary glioblastomas (12,5%). Primary GBM patients carrying IDH1 mutations were significantly younger, mean age of 41+/-5.06years, than patients with wild-type IDH1, mean age of 57+/-2,29years, p=0.011. The mean survival time of all GBM patients with and without IDH1 mutations was 19months (5 cases) and 16months (35 cases), respectively (p>0,05). MGMT methylation was detected in 13 of the 40 patients (32,5%). MGMT-promoter methylation did not correlate with overall survival (OS; p>0,05). CONCLUSION: In summary, our study is the first study to investigate the IDH1 mutation status and MGMT methylation in primary GBMs in Turkish population and confirmed IDH1 mutation as a genetic marker for also primary GBMs. Our data are still insufficient for definite ascertainment; and our preliminary results suggest: IDH1 status shows an association with younger age and there is a lack of association between IDH1 mutation and survival time. Furthermore MGMT promoter methylation had no prognostic value and lower frequency in primary glioblastomas. PMID- 25455103 TI - Shh regulates chick Ebf1 gene expression in somite development. AB - The chick early B-cell factor 1 (cEbf1) is a member of EBF family of helix loop helix transcription factors. Recently, we have proved that cEbf1 expression in feather is regulated by Shh. It is therefore possible that the somitic expression of cEbf1 is controlled by Shh signals from the notochord. To assess this hypothesis, the expression profile of cEbf1 was first detailed in somites of chick embryos (from HH8 to HH28). cEbf1 expression was mainly localised in the medial sclerotome and later around the vertebral cartilage anlagen of body and pedicles. Tissue manipulations (notochord ablation) and Shh gain and loss of function experiments were then performed to analyse whether the notochord and/or Shh regulate cEbf1 expression. Results from these experiments confirmed our hypothesis that the medial somitic expression of cEbf1 is regulated by Shh from the notochord. In conclusion, cEbf1 gene is considered as a medial sclerotome marker, downstream to and regulated by the notochord derived Shh, which may be functionally involved in somitogenesis. PMID- 25455104 TI - Testis mediated gene transfer: in vitro transfection in goat testis by electroporation. AB - Testis mediated gene transfer (TMGT) is a potential tool for making transgenic mice having more than 90% success rate. However, this method needs further standardization before it can be adapted in other species including livestock. In order to standardize the TMGT in goat, buck testes (n=20) collected from the slaughter house were injected with a vector driving green fluorescent protein (GFP) expression under a cytomegalovirus (CMV) promoter. Then, the testes were subjected to electroporation with predetermined voltage, pulse length, pulse interval and number of pulses. Seminiferous tubules were isolated from the electroporated testis and cultured in-vitro. The expression was checked at regular intervals. Green fluorescence was observed on different days in different samples. It suggests transient integration of the plasmid into the seminiferous tubules. This in-vitro transfection of seminiferous tubule using electroporation will provide valuable baseline information. PMID- 25455105 TI - Genetic and functional analysis of the TBX3 gene promoter in indirect inguinal hernia. AB - Inguinal hernia is a common developmental disease in children and most cases are indirect inguinal hernia (IIH). Genetic factors have been suggested to play important roles in IIH. Although IIH has been observed in several human syndromes, genetic causes and molecular mechanisms for IIH remain unknown. TBX3 is a member of the T-box family of transcription factors that are essential to the embryonic development. Human studies and animal experiments have demonstrated that TBX3 is required for the development of the heart, limbs, mammary glands and other tissues and organs. TBX3 gene expression has been detected in human fibroblast and tissues of abdominal wall. We speculated that TBX3 may be involved in the IIH formation. Since TBX3 activity is highly dosage-sensitive, a TBX3 gene promoter was genetically and functionally analyzed in IIH patients and ethnic matched controls in this study. One heterozygous deletion variant (g.4820_4821del) was identified in one IIH patient, but in none of controls. The variant significantly decreased TBX3 gene promoter activities, likely by creating a binding site for sex-determining region Y (SRY), mobility group transcription factor. One heterozygous insertion variant (g.3913_3914ins) was only found in one control, which did not affect TBX3 gene promoter activities. Taken together, TBX3 gene variants may contribute to IIH as a rare risk factor by reducing TBX3 levels. PMID- 25455106 TI - Analgesic topical capsaicinoid therapy increases somatostatin-like immunoreactivity in the human plasma. AB - The aim of the present study was to evaluate the therapeutic potential of local capsaicinoid (EMSPOMA((r)) cream) treatment on chronic low back pain in patients with degenerative spine diseases and to investigate the possible mechanism of action of the therapy. The qualitative and quantitative analyses of capsaicinoids in EMSPOMA((r)) cream were performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In the clinical study 20 patients with degenerative spine diseases were involved in a self-controlled examination. During the 21 day therapy they received 30 min daily treatment with capsaicinoid (EMSPOMA((r))) cream to the lumbar region of the back. The pain (VASs, Oswestry Disability Index) and the mobility of the lumbar region of the spine (Schober's, Domjan's L and R test) were detected at baseline and at the end of the 1st, 2nd and 3rd weeks. The plasma level of somatostatin-like immunoreactivity (SST-LI) was measured by radioimmunoassay (RIA) before and after the treatment on the first and the last day of the therapy. Nonivamide (0.01%) was identified as the only capsaicinoid molecule in the cream. In the clinical study the 21 day local nonivamide treatment reduced the pain sensation. Oswestry Disability Index decreased from 39 +/- 3.9% to 32.5 +/- 4.4%. VASs showed 37.29%-59.51% improvement. In the plasma level of SST-LI threefold elevation was observed after the first nonivamide treatment. We conclude that nonivamide treatment exerts analgesic action in chronic low back pain and causes the release of the antinociceptive and anti-inflammatory neuropeptide somatostatin which may play pivotal role in the pain-relieving effect. PMID- 25455109 TI - Understanding the fate and biological effects of Ag- and TiO2-nanoparticles in the environment: The quest for advanced analytics and interdisciplinary concepts. AB - Engineered inorganic nanoparticles (EINP) from consumers' products and industrial applications, especially silver and titanium dioxide nanoparticles (NP), are emitted into the aquatic and terrestrial environments in increasing amounts. However, the current knowledge on their environmental fate and biological effects is diverse and renders reliable predictions complicated. This review critically evaluates existing knowledge on colloidal aging mechanisms, biological functioning and transport of Ag NP and TiO2 NP in water and soil and it discusses challenges for concepts, experimental approaches and analytical methods in order to obtain a comprehensive understanding of the processes linking NP fate and effects. Ag NP undergo dissolution and oxidation with Ag2S as a thermodynamically determined endpoint. Nonetheless, Ag NP also undergo colloidal transformations in the nanoparticulate state and may act as carriers for other substances. Ag NP and TiO2 NP can have adverse biological effects on organisms. Whereas Ag NP reveal higher colloidal stability and mobility, the efficiency of NOM as a stabilizing agent is greater towards TiO2 NP than towards Ag NP, and multivalent cations can dominate the colloidal behavior over NOM. Many of the past analytical obstacles have been overcome just recently. Single particle ICP-MS based methods in combination with field flow fractionation techniques and hydrodynamic chromatography have the potential to fill the gaps currently hampering a comprehensive understanding of fate and effects also at a low field relevant concentrations. These analytical developments will allow for mechanistically orientated research and transfer to a larger set of EINP. This includes separating processes driven by NP specific properties and bulk chemical properties, categorization of effect-triggering pathways directing the EINP effects towards specific recipients, and identification of dominant environmental parameters triggering fate and effect of EINP in specific ecosystems (e.g. soil, lake, or riverine systems). PMID- 25455107 TI - Systematic optimization of long gradient chromatography mass spectrometry for deep analysis of brain proteome. AB - The development of high-resolution liquid chromatography (LC) is essential for improving the sensitivity and throughput of mass spectrometry (MS)-based proteomics. Here we present systematic optimization of a long gradient LC-MS/MS platform to enhance protein identification from a complex mixture. The platform employed an in-house fabricated, reverse-phase long column (100 MUm * 150 cm, 5 MUm C18 beads) coupled to Q Exactive MS. The column was capable of achieving a peak capacity of ~700 in a 720 min gradient of 10-45% acetonitrile. The optimal loading level was ~6 MUg of peptides, although the column allowed loading as many as 20 MUg. Gas-phase fractionation of peptide ions further increased the number of peptide identification by ~10%. Moreover, the combination of basic pH LC prefractionation with the long gradient LC-MS/MS platform enabled the identification of 96,127 peptides and 10,544 proteins at 1% protein false discovery rate in a post-mortem brain sample of Alzheimer's disease. Because deep RNA sequencing of the same specimen suggested that ~16,000 genes were expressed, the current analysis covered more than 60% of the expressed proteome. Further improvement strategies of the LC/LC-MS/MS platform were also discussed. PMID- 25455110 TI - Understanding fibroblast heterogeneity in the skin. AB - Fibroblasts are found in most tissues, yet they remain poorly characterised. Different fibroblast subpopulations with distinct functions have been identified in the skin. This functional heterogeneity reflects the varied fibroblast lineages that arise from a common embryonic precursor. In addition to autocrine signals, fibroblasts are highly responsive to Wnt-regulated signals from the overlying epidermis, which can act both locally, via extracellular matrix (ECM) deposition, and via secreted factors that impact the behaviour of fibroblasts in different dermal locations. These findings may explain some of the changes that occur in connective tissue during wound healing and cancer progression. PMID- 25455112 TI - Identification of novel informative loci for DNA-based X-inactivation analysis. AB - The HUMARA assay, the most common method for evaluation of X-inactivation skewing in blood cells, has been reported to be usable in only about 80% of females, emphasizing the need for alternative methods for testing of HUMARA-uninformative individuals. We conducted an in silico search for potentially polymorphic tri-to hexanucleotide repeats in the proximity of CpG islands located in 5' regions of X chromosome genes to design five candidate assays (numbered I, II, III, IV, and V) combining methylation-specific restriction digest with PCR amplification in a manner similar to the HUMARA assay. The results obtained by these assays in 100 healthy females were compared to X-inactivation skewing measured by the AR-MSP method which is based on methylation-specific PCR amplification of the first exon of the AR gene. On the basis of statistical evidence, three of the novel assays (II, IV, and V), which were informative in 18%, 61%, and 55% of females in the cohort, respectively, may be used as alternatives or conjointly with the HUMARA assay to improve its reliability. The three new assays were combined with the HUMARA assay into a novel X-inactivation test leading to the increase of informative females in the cohort from 67% to 96%. PMID- 25455113 TI - Physiodiversity - new tools allow physiologist to embrace biodiversity and reconstruct the evolution of 'physiologies'? PMID- 25455111 TI - Centrosome dynamics as a source of chromosomal instability. AB - Accurate segregation of duplicated chromosomes between two daughter cells depends on bipolar spindle formation, a metaphase state in which sister kinetochores are attached to microtubules emanating from opposite spindle poles. To ensure bi orientation, cells possess surveillance systems that safeguard against microtubule-kinetochore attachment defects, including the spindle assembly checkpoint and the error correction machinery. However, recent developments have identified centrosome dynamics--that is, centrosome disjunction and poleward movement of duplicated centrosomes--as a central target for deregulation of bi orientation in cancer cells. In this review, we discuss novel insights into the mechanisms that underlie centrosome dynamics and discuss how these mechanisms are perturbed in cancer cells to drive chromosome mis-segregation and advance neoplastic transformation. PMID- 25455114 TI - Intimate partner violence and human immunodeficiency virus risk among black and Hispanic women. AB - BACKGROUND: Approximately 80% of new HIV infections among U.S. women are among black/African American and Hispanic women. HIV risk may be associated with intimate partner violence (IPV); data regarding IPV for women in high-HIV prevalence areas are scarce. PURPOSE: To examine prevalence and correlates of IPV among women. METHODS: Heterosexual women and their male partners in cities with high HIV prevalence were enrolled. During 2006-2007, participants completed interviews about HIV risk factors and IPV (physical violence or forced sex) experiences. Data were analyzed during 2012-2013 using multivariate logistic regression to identify individual- and partner-level IPV correlates. RESULTS: Of 1,011 female respondents, 985 (97.4%) provided risk factor and demographic data. Most were non-Hispanic black/African American (82.7%); living at or below poverty (86.7%); and tested HIV-negative (96.8%). IPV-physical violence was reported by 29.1%, and IPV-forced sex by 13.7%. Being married/living with a partner (AOR=1.60, 95% CI=1.06, 2.40); non-injection drug use (AOR=1.74, 95% CI=1.22, 2.48); and ever discussing male partners' number of current sex partners (AOR=1.60, 95% CI=1.15, 2.24) were associated with IPV-physical violence. Women reporting concurrent sex partners (AOR=1.80, 95% CI=1.04, 3.13) and ever discussing number of male partners' past sex partners (AOR=1.85, 95% CI=1.13, 3.05) were associated with IPV-forced sex. Feeling comfortable asking a male partner to use condoms was associated with decreased IPV-physical violence (AOR=0.32, 95% CI=0.16,0.64) and -forced sex (AOR=0.37, 95% CI=0.16, 0.85). CONCLUSIONS: Prevention interventions that enhance women's skills to decrease HIV and IPV risk are important strategies for decreasing racial/ethnic disparities among women. PMID- 25455115 TI - Implementation intentions and colorectal screening: a randomized trial in safety net clinics. AB - CONTEXT: Low-income and racial/ethnic minority populations experience disproportionate colorectal cancer (CRC) burden and poorer survival. Novel behavioral strategies are needed to improve screening rates in these groups. BACKGROUND: The study aimed to test a theoretically based "implementation intentions" intervention for improving CRC screening among unscreened adults in urban safety-net clinics. DESIGN: Randomized controlled trial. SETTING/PARTICIPANTS: Adults (N=470) aged >=50 years, due for CRC screening, from urban safety-net clinics were recruited. INTERVENTION: The intervention (conducted in 2009-2011) was delivered via touchscreen computers that tailored informational messages to decisional stage and screening barriers. The computer then randomized participants to generic health information on diet and exercise (Comparison group) or "implementation intentions" questions and planning (Experimental group) specific to the CRC screening test chosen (fecal immunochemical test or colonoscopy). MAIN OUTCOME MEASURES: The primary study outcome was completion of CRC screening at 26 weeks based on test reports (analysis conducted in 2012-2013). RESULTS: The study population had a mean age of 57 years and was 42% non-Hispanic African American, 28% non-Hispanic white, and 27% Hispanic. Those receiving the implementation intentions-based intervention had higher odds (AOR=1.83, 95% CI=1.23, 2.73) of completing CRC screening than the Comparison group. Those with higher self-efficacy for screening (AOR=1.57, 95% CI=1.03, 2.39), history of asthma (AOR=2.20, 95% CI=1.26, 3.84), no history of diabetes (AOR=1.86, 95% CI=1.21, 2.86), and reporting they had never heard that "cutting on cancer" makes it spread (AOR=1.78, 95% CI=1.16, 2.72) were more likely to complete CRC screening. CONCLUSIONS: The results of this study suggest that programs incorporating an implementation intentions approach can contribute to successful completion of CRC screening even among very low-income and diverse primary care populations. Future initiatives to reduce CRC incidence and mortality disparities may be able to employ implementation intentions in large-scale efforts to encourage screening and prevention behaviors. PMID- 25455117 TI - Postdeployment resilience as a predictor of mental health in operation enduring freedom/operation iraqi freedom returnees. AB - BACKGROUND: Much of the research on the impact of trauma exposure among veterans has focused on factors that increase risk for mental health problems. Fewer studies have investigated factors that may prevent mental health problems following trauma exposure. This study examines resilience variables as factors that may prevent subsequent mental health problems. PURPOSE: To determine whether military service members returning from Afghanistan and Iraq who exhibit higher levels of resilience, including hardiness (encompassing control, commitment, and challenge), self-efficacy, and social support after returning from deployment are less vulnerable to subsequent mental health problems, alcohol, and drug use. METHODS: A national sample of 512 service members was surveyed between 3 and 12 months of return from deployment and 6-12 months later. Data were collected in 2008-2009 and analyzed in 2013. Regression analyses ascertained whether resilience 3-12 months after return predicted later mental health and substance problems, controlling for demographic characteristics, mental health, and risk factors, including predeployment stressful events, combat exposure, and others. RESULTS: Greater hardiness predicted several indicators of better mental health and lower levels of alcohol use 6-12 months later, but did not predict subsequent posttraumatic stress symptom severity. Postdeployment social support predicted better overall mental health and less posttraumatic stress symptom severity, alcohol, and drug use. CONCLUSIONS: Some aspects of resilience after deployment appear to protect returning service members from the negative effects of traumatic exposure, suggesting that interventions to promote and sustain resilience after deployment have the potential to enhance the mental health of veterans. PMID- 25455118 TI - Care provision to prevent chronic disease by community mental health clinicians. AB - BACKGROUND: People with a mental illness have higher prevalence of behavioral risks for chronic disease than the general population. Despite recommendations regarding the provision of preventive care by mental health services, limited research has examined the extent to which such care is provided. PURPOSE: To examine mental health clinician provision of care for preventable chronic disease risks, and whether such care was associated with the availability of practice support strategies. METHODS: A cross-sectional survey was undertaken of 151 community mental health clinicians in New South Wales, Australia regarding the provision of three elements of preventive care (i.e., assessment, brief advice, and referral/follow-up) for four health risk behaviors (i.e., tobacco smoking, inadequate fruit and vegetable consumption, harmful alcohol consumption, and inadequate physical activity). Clinicians reported the availability of 16 strategies to support such care delivery. Data were collected in 2010 and analyzed in 2012-2013. RESULTS: Preventive care provision varied by both care element and risk behavior. Optimal care (each care element provided to at least 80% of clients for all health behaviors) was provided by few clinicians: assessment (8.6%), brief advice (24.5%), and referral/follow-up (9.9%). Less than half of clinicians reported more than four support strategies were available (44.4%). The availability of five or more strategies was associated with increased optimal preventive care. CONCLUSIONS: The provision of preventive care focused on chronic disease prevention in community mental health services is suboptimal. Interventions to increase the routine provision of such care should involve increasing the availability of evidence-based strategies to support care provision. PMID- 25455119 TI - The Community Diabetes Education (CoDE) program: cost-effectiveness and health outcomes. AB - BACKGROUND: Limited evidence exists regarding the long-term effects of community health worker-led diabetes management programs on health outcomes and cost effectiveness, particularly in low-income, ethnic minority populations. PURPOSE: To examine the long-term cost-effectiveness and improvements in diabetes-related complications of a diabetes education and management intervention led by community health workers among uninsured Mexican Americans. METHODS: Clinical data, changes in hemoglobin A1c over 12 months, and costs from an RCT of 180 uninsured Mexican Americans with type 2 diabetes conducted in 2006 were utilized for secondary analyses in 2012. Simulation modeling was used to estimate long term cost and health outcomes using the validated Archimedes Model. The absolute differences for the incremental cost-effectiveness ratios and cumulative incidence of diabetes-related complications were derived by comparing intervention and control groups. RESULTS: During a 20-year time horizon, participants who received the intervention would be expected to have significantly lower hemoglobin A1c levels (p<0.001), fewer foot ulcers (p<0.001), and a reduced number of foot amputations (p=0.005) in comparison with a control group receiving usual medical care. An incremental cost-effectiveness ratio of $355 per quality-adjusted life year gained was estimated for intervention participants during the same time period. CONCLUSIONS: A simulated clinical trial suggests that a community health worker-led diabetes intervention is a cost effective way to reduce diabetes-related complications for uninsured Mexican Americans during a 20-year horizon in comparison to usual medical care. PMID- 25455116 TI - Effect of decision support on missed opportunities for human papillomavirus vaccination. AB - BACKGROUND: Missed opportunities for human papilloma virus (HPV) vaccination are common, presenting a barrier to achieving widespread vaccine coverage and preventing infection. PURPOSE: To compare the impact of clinician- versus family focused decision support, none, or both on captured opportunities for HPV vaccination. DESIGN: Twelve-month cluster randomized controlled trial conducted in 2010-2011. SETTING/PARTICIPANTS: Adolescent girls aged 11-17 years due for HPV Dose 1, 2, or 3 receiving care at primary care practices. INTERVENTION: Twenty two primary care practices were cluster randomized to receive a three-part clinician-focused intervention (educational sessions, electronic health record based alerts, and performance feedback) or none. Within each practice, girls were randomized at the patient level to receive family-focused, automated, educational phone calls or none. Randomization resulted in four groups: clinician-focused, family-focused, combined, or no intervention. MAIN OUTCOME MEASURES: Standardized proportions of captured opportunities (due vaccine received at clinician visit) were calculated among girls in each study arm. Analyses were conducted in 2013. RESULTS: Among 17,016 adolescent girls and their 32,472 visits (14,247 preventive, 18,225 acute), more HPV opportunities were captured at preventive than acute visits (36% vs 4%, p<0.001). At preventive visits, the clinician intervention increased captured opportunities by 9 percentage points for HPV-1 and 6 percentage points for HPV-3 (p<=0.01), but not HPV-2. At acute visits, the clinician and combined interventions significantly improved captured opportunities for all three doses (p<=0.01). The family intervention was similar to none. Results differed by practice setting; at preventive visits, the clinician intervention was more effective for HPV-1 in suburban than urban settings, whereas at acute visits, the clinician intervention was more effective for all doses at urban practices. CONCLUSIONS: Clinician-focused decision support is a more effective strategy than family-focused to prevent missed HPV vaccination opportunities. Given the persistence of missed opportunities even in intervention groups, complementary strategies are needed. This study is registered at clinicaltrials.gov NCT01159093. PMID- 25455120 TI - Impacts of the minimum legal drinking age on motor vehicle collisions in Quebec, 2000-2012. AB - BACKGROUND: International debates are occurring about the effectiveness of minimum legal drinking age laws. Most minimum legal drinking age evaluation studies have focused on motor vehicle collision outcomes, but this literature is primarily based on naturalistic experiments involving legislation changes in the U.S. in the mid-1980s. Few studies have provided up-to-date estimates of the impacts of Canadian drinking age laws on motor vehicle collisions to inform current policy discussions. PURPOSE: To estimate the impacts of minimum legal drinking age legislation on motor vehicle collisions occurring in 2000-2012 in Quebec, a province with a minimum legal drinking age of 18 years. METHODS: Using Quebec Ministry of Transportation records of police-reported motor vehicle collisions in 2000-2012, regression-discontinuity analyses were employed to assess the impacts of the minimum legal drinking age on motor vehicle collisions. All data were analyzed in 2013. RESULTS: Relative to individuals slightly younger than the minimum legal drinking age, male and female drivers just older than the minimum legal drinking age had a significant and abrupt increase of approximately 6% (men, 6.3%, p=0.003; women, 5.9%, p=0.047) in population-level motor vehicle collisions, as well as a significant 11.1% (p=0.001) rise in nighttime motor vehicle collisions (a proxy for alcohol-related collisions). CONCLUSIONS: Drinking-age laws continue to be an integral component of contemporary alcohol control and driving-related policies designed to limit motor vehicle collisions among youth. In addition, the regression-discontinuity approach can guide future work to estimate potential minimum legal drinking age impacts on other health outcomes. PMID- 25455121 TI - Pap test use is lower among female-to-male patients than non-transgender women. AB - BACKGROUND: A paucity of empirical research to date has examined cervical cancer screening in female-to-male (FTM) transgender men who retain their natal reproductive structures compared to non-transgender women. PURPOSE: To examine patient and provider characteristics associated with being up-to-date on Pap tests, with a focus on gender identity and sexual orientation. METHODS: Retrospective chart review of 5,232 patients (4,882 women, 350 FTM transgender men) at an urban community health center. All HIV-negative primary care patients aged 21-64 years (inclusive) with at least one medical visit during the 2012 calendar year and who had a cervix as of December 31, 2012, were included. Data were analyzed in 2013 using a multilevel logistic regression model nesting patients within providers. RESULTS: FTM patients were significantly less likely to be up-to-date on Pap tests (AOR=0.63, 95% CI=0.47, 0.85) compared to non transgender women, after adjusting for individual- and provider-level factors. Behaviorally bisexual patients, compared to patients who had sex with men exclusively, were more likely to be up-to-date (AOR=1.73, 95% CI=1.32, 2.26); patients reporting only sex with women were not significantly more or less likely to be up-to-date (AOR=1.01, 95% CI=0.83, 1.23). CONCLUSIONS: Transgender patients are not accessing the same level of preventive cervical screening care as non transgender female patients. There is a need to better understand barriers to care in this population. Contrary to findings in other settings, history of sex with women was not negatively associated with Pap utilization. PMID- 25455122 TI - Injury during U.S. Army basic combat training: a systematic review of risk factor studies. AB - CONTEXT: Approximately one quarter of men and half of women in U.S. Army basic combat training experience an injury. Preventing basic combat training-related injuries would reduce associated human and economic costs and discharges from the Army. Identification of risk factors for such injuries is a crucial step toward their prevention. Although some research has begun to address this need, prior studies of risk factors for training-related injury have not been reviewed systematically. This study systematically reviews the literature on risk factors for injury during U.S. Army basic combat training. EVIDENCE ACQUISITION: Original studies of risk factors for injury during U.S. Army basic combat training published since 1990 in peer-reviewed journals were identified using PubMed and manual searches of reference lists. This search was last performed in May 2013. Nineteen studies met the inclusion criteria. EVIDENCE SYNTHESIS: Methodologic quality and potential for bias were assessed. The findings of 11 studies deemed to be of high or medium quality were synthesized to determine the level of evidence supporting the association between each risk factor studied and risk of injury during basic combat training. Quality assessment and evidence synthesis were performed from June to September 2013. CONCLUSIONS: There is strong or moderate evidence supporting association of older age, history of smoking, and self-rated low physical activity level prior to basic combat training with increased risk of training-related injury among male trainees. There is limited, mixed, or insufficient evidence to identify risk factors for injury among female trainees. PMID- 25455124 TI - Firearm use in G- and PG-rated movies, 2008-2012. PMID- 25455123 TI - Promotion of tobacco use cessation for lesbian, gay, bisexual, and transgender people: a systematic review. AB - CONTEXT: Lesbian, gay, bisexual, and transgender (LGBT) people are at increased risk for the adverse effects of tobacco use, given their high prevalence of use, especially smoking. Evidence regarding cessation is limited. To determine if efficacious interventions are available and to aid the development of interventions, a systematic review was conducted of grey and peer-reviewed literature describing clinical, community, and policy interventions, as well as knowledge, attitudes, and behaviors regarding tobacco use cessation among LGBT people. EVIDENCE ACQUISITION: Eight databases for articles from 1987 to April 23, 2014, were searched. In February-November 2013, authors and researchers were contacted to identify grey literature. EVIDENCE SYNTHESIS: The search identified 57 records, of which 51 were included and 22 were from the grey literature; these were abstracted into evidence tables, and a narrative synthesis was conducted in October 2013-May 2014. Group cessation curricula tailored for LGBT populations were found feasible to implement and show evidence of effectiveness. Community interventions have been implemented by and for LGBT communities, although these interventions showed feasibility, no rigorous outcome evaluations exist. Clinical interventions show little difference between LGBT and heterosexual people. Focus groups suggest that care is needed in selecting the messaging used in media campaigns. CONCLUSIONS: LGBT-serving organizations should implement existing evidence-based tobacco-dependence treatment and clinical systems to support treatment of tobacco use. A clear commitment from government and funders is needed to investigate whether sexual orientation and gender identity moderate the impacts of policy interventions, media campaigns, and clinical interventions. PMID- 25455126 TI - Introduction to the 2013 SSIB Special Issue. PMID- 25455125 TI - Electronic cigarettes: from history to evidence-based medicine. PMID- 25455127 TI - Do salivary and serum collagenases have a role in an association between obstructive sleep apnea syndrome and periodontal disease? A preliminary case control study. AB - OBJECTIVES: Despite increasing evidence for an association of obstructive sleep apnea syndrome (OSAS) and periodontal disease, the pathophysiological linking mechanisms remain unclear. This study aims to evaluate the salivary and serum matrix metalloproteinase-2, -8, -9 (MMP-2, -8, -9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), myeloperoxidase (MPO), neutrophil elastase (NE), neutrophil gelatinase-associated lipocalin (NGAL), as well as degree of activation of MMP-2, -9 of patients with and without OSAS. DESIGN: A total of 50 individuals were included in the study. There were 13, 17 and 20 individuals, respectively in the control (non-OSAS) group, mild-to-moderate OSAS and severe OSAS groups. Saliva, serum samples and clinical periodontal parameters were collected. Biofluid samples were analysed by immunofluorometric assay (IFMA), enzyme-linked immunosorbent assay (ELISA), western immunoblotting and gelatine zymography. Statistical analyses were performed using D'Agostino-Pearson omnibus normality test, Kruskal-Wallis test and Spearman rho rank correlation analysis. RESULTS: There were no statistically significant differences in clinical periodontal parameters between the study groups. Salivary NE and proMMP-2 levels were significantly lower in the OSAS groups than the control group (p<0.05). Serum proMMP-9 concentration and the degree of MMP-9 activation in saliva were significantly lower in the severe OSAS group than the control group (p<0.05). There were significant correlations between salivary and serum proMMP-9 and -2 concentrations (p<0.05). Serum proMMP-2, NE and salivary proMMP-9 and -2 negatively correlated with indicators of OSAS severity (p<0.05). CONCLUSIONS: The present findings do not support a pathophysiological link between the severity of OSAS and clinical periodontal status via neutrophil enzymes or MMPs. PMID- 25455128 TI - Docosahexaenoic acid attenuates oxidative stress and protects human gingival fibroblasts against cytotoxicity induced by hydrogen peroxide and butyric acid. AB - OBJECTIVE: The oxidative burst of the host cells associated with bacterial pathogen infection contributes to the destruction of periodontal tissue. The present study investigates the effect of docosahexaenoic acid (DHA) on human gingival fibroblast (HGF) viability and ROS generation. METHODS: The cell viability by MTT assay, ROS level using H2DCF-DA probe, and protein thiol content were measured in HGFs after 24h preincubation with different concentrations of DHA followed by treatment with H2O2. The cell death rate was determined by Annexin V/propidium iodide staining, and mitochondrial membrane potential (DeltaPsim) was examined by MitoTracker Red probe in H2O2- and butyric acid treated HGFs. The fatty acid composition of plasma membranes after incubation with DHA was determined by gas chromatography mass spectrometry. RESULTS: DHA preincubation in a dose-dependent manner increased the viability of HGFs exposed to H2O2 and decreased ROS generation compared to the control cells. In HGFs preincubated with 30MUM DHA, the DeltaPsim significantly increased in both H2O2- and butyric acid-treated cells. Moreover, incubation with DHA preserved the protein thiol level as effectively as N-acetylcysteine. Application of 50MUM DHA increased the quantity of viable cells, decreased the number of necrotic cells after H2O2 treatment, and protected HGFs from apoptosis induced by butyric acid. DHA in the plasma membranes of these HGFs represented about 6% of the total amount of fatty acids. CONCLUSIONS: These results demonstrate that enrichment of HGFs with DHA reduces ROS generation and enhances the mitochondrial membrane potential protecting the fibroblasts against cytotoxic factors. PMID- 25455129 TI - Correlation of Streptococcus mutans and Streptococcus sanguinis colonization and ex vivo hydrogen peroxide production in carious lesion-free and high caries adults. AB - OBJECTIVE: This study was conducted to estimate oral colonization by Streptococcus mutans and Streptococcus sanguinis in adults with high and without any caries experience. Furthermore, differences in the amount of hydrogen peroxide (H2O2) produced by S. sanguinis isolated from both groups were assessed. DESIGN: Forty adults were divided into: (i) carious lesion-free, without any carious lesion, assessed by the International Caries Detection and Assessment System (ICDAS), or restoration, (CF) and (ii) high caries experience (HC). Saliva samples were collected and seeded on respective agar-plates for enumeration of total streptococci, S. mutans and S. sanguinis (CFU/mL) and compared between groups. Additionally, S. sanguinis colonies obtained from both groups were inoculated on Prussian blue agar for H2O2 detection. Production of H2O2 was quantified and compared between the two groups. S. sanguinis counts were significantly higher in CF than HC individuals (p<0.05). Conversely, S. mutans showed significantly higher levels in HC than CF subjects (p<0.001). S. sanguinis colonies from CF individuals produced significantly larger H2O2 halos compared with HC subjects. CONCLUSIONS: S. sanguinis predominates over S. mutans in saliva of adults without caries experience. In those people, S. sanguinis produces more H2O2ex vivo. PMID- 25455130 TI - IL-6 regulates stress-induced REX-1 expression via ATP-P2Y1 signalling in stem cells isolated from human exfoliated deciduous teeth. AB - OBJECTIVE: To investigate the relationship between ATP and IL-6 in mechanical stress-induced REX-1 expression in SHEDs. METHODS: Cells were stimulated with mechanical stress (0-2.5 gcm(-2)), IL-6 (0.1-5 ng/ml), or ATP (10-100 MUM) for 2h in serum-free media. IL-6 and REX-1 expression was examined by qualitative and quantitative polymerase chain reaction. ATP release was measured using a bioluminescence assay. The molecular mechanisms of the signalling pathways were investigated using chemical inhibitors. RESULTS: Mechanical stress induced IL-6 and REX-1 mRNA expression and ATP release. JAK inhibitor I inhibited the increase in REX-1 expression and ATP release but not IL-6 induction. Furthermore, suramin inhibited the upregulation of REX-1 mRNA expression but not ATP release. Exogenous IL-6 promoted both ATP release and REX-1 expression. The IL-6-induced REX-1 expression was attenuated by a P2Y1-specific receptor antagonist. Moreover, REX-1 expression was upregulated in a dose-dependent manner by the addition of ATP or a P2Y1 agonist. This inductive effect was abolished by the P2Y1-specific receptor antagonist. CONCLUSIONS: ATP-P2Y1 signalling is involved in IL-6 regulated stress-induced REX-1 expression in SHEDs. These results imply the participation of mechanical stress, IL-6, and ATP in regulating the expression of REX-1, a pluripotent stem cell marker. PMID- 25455131 TI - Effects of gallic acid on the morphology and growth of hydroxyapatite crystals. AB - OBJECTIVE: This study was designed to explore the effect of gallic acid (GA, one of the ingredients of chemical compounds from galla chinensis) on the morphology and growth of hydroxyapatite crystals. METHODS: The crystals was produced by mixing CaCl2 and KH2PO4 with or without GA (4g/L) at room temperature for 3, 12, 24h and 3, 7, 14 days. Subsequently, the micro-structure, morphology and composition of the crystals were investigated via SEM, XRD, ATR-FTIR and fluorescence microscopy. RESULTS: The mineral phase was hydroxyapatite in both groups after 14 days, but their processes and the morphology were completely different. The crystals from groups utilizing GA for 14 days were urchin-like, while loose needle-like crystals were observed in groups without GA. XRD results indicated that GA might limit the growth of the crystals, mainly on the 002 direction. The results of ATR-FTIR and fluorescence microscopy revealed that the unique structures might caused by the participation of GA during crystals formation. CONCLUSION: GA might affect and participate into the formation of the hydroxyapatite, and regulate the morphology and structure of the crystals, to enhance the remineralization process. PMID- 25455132 TI - The association between dental wear and reduced vertical dimension of the face: a morphologic study on human skulls. AB - OBJECTIVE: The aim of this study was to explore the relationship between dental wear and facial morphology, with particular reference to the occlusal vertical dimension, in modern human skulls. DESIGN: One hundred and three skulls (52 men and 51 women) between the ages of 20 and 50+ years old were studied. The selected skulls were from a modern period (the 17th and the 18th centuries) and included at least one entire condyle and had at least 3 posterior teeth (premolar or molar) in each quadrant to allow for dental articulation. Occlusal wear was evaluated using ordinal scale (0-4) and vertical occlusal dimension was evaluated by measuring upper facial height (UFH), lower facial height (LFH), LFH-to-UFH ratio (L-U-R) and dental wear. Based on the occlusal wear score, two groups were defined: with and without significant wear. RESULTS: Significant relation was observed between age and dental wear (P<0.01). No significant differences were found in the LFH (P=0.847) or UFH (P=0.108) between the two wear groups. In addition, no significant difference (P=0.132) was demonstrated in the LFH-to-UFH ratio between the groups. No difference was observed in the dental wear score between genders (P=0.321). CONCLUSION: Within its limitations, this study demonstrated that dental wear does not influence the vertical dimension of occlusion. Our assumption is that the dento-facial complex fully compensates for the dental effects of wear throughout life. PMID- 25455133 TI - The role of bite force in the formation of orthodentine microwear in tree sloths (Mammalia: Xenarthra: Folivora): Implications for feeding ecology. AB - OBJECTIVES: The purpose of this investigation was to explore the role and interplay that bite force has on the formation of microwear features upon the dentition of two- and three-fingered tree sloths (Choloepus and Bradypus, respectively), with the hypothesis that increasing relative bite force would correlate with an increase in frequency of microwear features. DESIGN: Microwear patterns were assessed by counting features (e.g. scratches, pits) seen within a standardized field of view on the mesio-labial facets casts of upper molariform series from sloth specimens using Scanning Electron Microscopy. Relative bite force was estimated using a geometric model to quantify the muscular inputs of the temporalis and masseter muscles with respect to the mandible at the centre of each lower tooth. RESULTS: Although relative bite force increases posteriorly along the toothrow, there is not a significant increase in frequency of scratches or pits in either sloth. Scratch width increases significantly as bite force increases in Choloepus. CONCLUSIONS: We reject the hypothesis that higher magnitude of bite force is correlated with an increased number of microwear features in tree sloths. Results here suggest that other endogenous variables (such as chewing direction, manipulation of food during mastication, amount of food ingested) play a more significant role in the formation of microwear in sloths than orthal closure force. This further supports the formation of microwear on teeth as an intricate process that has multiple influences beyond the texture of food particles. PMID- 25455134 TI - A photochemical method for in vitro evaluation of fluid flow in human dentine. AB - OBJECTIVE: To evaluate the flow dynamics of dentine fluid using a chemiluminescence method in vitro. MATERIALS AND METHODS: Horizontally sliced coronal dentine specimens with thicknesses of 1.4, 1.6, 1.8, and 2.0mm (n=10 each) were prepared from extracted human third molars. After cleaning with EDTA, a mounted specimen was clamped between 2 acrylic chambers attached to both the occlusal and pulpal sides. The occlusal chamber, which was closed with a glass coverslip, was filled with a chemiluminescent solution (0.02% luminol and 1% sodium hydroxide in water). A trigger solution of 1% hydrogen peroxide and 1% potassium ferricyanide was injected into the pulpal chamber at a constant pressure of 2.5 kPa, and allowed to immediately flow into the patent dentinal tubules. Four consecutive measurements (T1-T4) were performed on each sample by recording the emission of chemiluminescence with a photodetector. The relationship between the crossing time of the liquid through the slice and dentine thickness was examined. RESULTS: An apparent time delay was detected between the starting points of the trigger solution run and photochemical emission at T1. Dt (Dt, s) values of each thickness group were 13.6 +/- 4.25 for 1.4mm, 18.1 +/- 2.38 for 1.6mm, 28.0 +/- 2.46 for 1.8mm, and 39.2 +/- 8.61 for 2.0mm, respectively. Dt significantly decreased as dentine became thinner towards the pulp chamber (P<0.001). CONCLUSIONS: The velocity of fluid flow increased both with increasing dentine depth or reduction of remaining dentine thickness. PMID- 25455135 TI - Exposure to a continuous low dose of tetrachlorodibenzo-p-dioxin impairs the development of the tooth root in lactational rats and alters the function of apical papilla-derived stem cells. AB - OBJECTIVES: Ubiquitous environmental pollutants such as 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) cause abnormalities in reproduction and development. TCDD inhibits the development of teeth, and its effects depend on its dose and the developmental stage of the tooth. Our aim here was to investigate the effect of lower doses of TCDD on the development of the tooth root in vivo and in vitro. DESIGN: We observed tooth root development in lactational rats exposed to continuous low doses of TCDD starting on postnatal day 6 using Mico-CT analyses and histopathological examinations. And then the characteristics of stem cells derived from the apical papilla (SCAPs) were evaluated and compared with SCAPs induced by lower doses of TCDD both in vitro and in vivo. RESULTS: The results of experiments showed that rat pups exposed to low dose TCDD at prenatal stage developed, dentine hypoplasia, and hypomineralization. Further, TCDD impaired the functions of SCAPs in vivo by inhibiting cell proliferation and osteogenic and odontogenic differentiation. The impairment of SCAPs after TCDD exposure was accompanied by increased expression of AHR, down-regulation of the expression of Runx2, and alkaline phosphatase, suggesting that the AHR pathway mediated the effects of TCDD. CONCLUSION: These results provide the first insights into the toxicity of TCDD, which adversely affects the development of the tooth root through indirectly altering the function of SCAPs. PMID- 25455136 TI - Fluctuation dynamics of bilayer vesicles with intermonolayer sliding: experiment and theory. AB - The presence of coupled modes of membrane motion in closed shells is extensively predicted by theory. The bilayer structure inherent to lipid vesicles is suitable to support hybrid modes of curvature motion coupling membrane bending with the local reorganization of the bilayer material through relaxation of the dilatational stresses. Previous experiments evidenced the existence of such hybrid modes facilitating membrane bending at high curvatures in lipid vesicles [Rodriguez-Garcia, R., Arriaga, L.R., Mell, M., Moleiro, L.H., Lopez-Montero, I., Monroy, F., 2009. Phys. Rev. Lett. 102, 128201.]. For lipid bilayers that are able to undergo intermonolayer sliding, the experimental fluctuation spectra are found compatible with a bimodal schema. The usual tension/bending fluctuations couple with the hybrid modes in a mechanical interplay, which becomes progressively efficient with increasing vesicle radius, to saturate at infinity radius into the behavior expected for a flat membrane. Grounded on the theory of closed shells, we propose an approximated expression of the bimodal spectrum, which predicts the observed dependencies on the vesicle radius. The dynamical features obtained from the autocorrelation functions of the vesicle fluctuations are found in quantitative agreement with the proposed theory. PMID- 25455137 TI - Relationship of ceramide-, and free fatty acid-cholesterol ratios in the stratum corneum with skin barrier function of normal, atopic dermatitis lesional and non lesional skins. PMID- 25455138 TI - A nuclear factor kappa B-derived inhibitor tripeptide inhibits UVB-induced photoaging process. AB - BACKGROUND: Ultraviolet (UV) irradiation on the skin induces photoaging which is characterized by keratinocyte hyperproliferation, generation of coarse wrinkles, worse of laxity and roughness. Upon UV irradiation, nuclear factor kappa B (NF kappaB) is activated which plays a key role in signaling pathway leading to inflammation cascade and this activation stimulates expression of pro inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin-1alpha (IL-1alpha) and a stress response gene cyclooxygenase-2 (COX 2). In addition, activation of NF-kappaB up-regulates the expression of matrix metalloprotease-1 (MMP-1) and consequently collagen in dermis is degraded. OBJECTIVE: In this study, the effects of a NF-kappaB-derived inhibitor tripeptide on the UVB-induced photoaging and inflammation were investigated in vitro and in vivo. METHODS: A NF-kappaB-derived inhibitor tripeptide (NF-kappaB-DVH) was synthesized based on the sequence of dimerization region of the subunit p65 of NF kappaB. Its inhibitory activity was confirmed using chromatin immunoprecipitation assay and in situ proximate ligation assay. The effects of anti-photoaging and anti-inflammation were analyzed by Enzyme-linked immunosorbent assay (ELISA), immunoblotting and immunochemistry. RESULTS: NF-kappaB-DVH significantly decreased UV-induced expression of TNF-alpha, IL-1alpha, MMP-1 and COX-2 while increased production of type I procollagen. CONCLUSION: Results showed NF-kappaB DVH had strong anti-inflammatory activity probably by inhibiting NF-kappaB activation pathway and suggested to be used as a novel agent for anti-photoaging. PMID- 25455140 TI - Oculocutaneous albinism (OCA) in Colombia: first molecular screening of the TYR and OCA2 genes in South America. PMID- 25455139 TI - Influence of component 5a receptor 1 (C5AR1) -1330T/G polymorphism on nonsedating H1-antihistamines therapy in Chinese patients with chronic spontaneous urticaria. AB - BACKGROUND: The nonsedating H1-antihistamines are the first-line medicines for chronic spontaneous urticaria (CSU) patients. However, not all these patients respond well to the antihistamines, and the mechanisms underlying the interindividual differences are still unclear. C5AR1 gene encodes the component 5a receptor (C5aR) protein, which has been reported to play an important role in chronic spontaneous urticaria. OBJECTIVE: This study aimed to investigate whether the single nucleotide polymorphisms (SNPs) in C5AR1 are associated with CSU susceptibility and antihistamines therapeutic efficacy in Chinese CSU patients. METHODS: A total of 191 CSU patients and 102 healthy controls were prospectively studied in our study. CSU patients were treated by nonsedating H1-antihistamines monotherapy for 4 weeks. The C5AR1 -1330T/G (rs11673309) genotype was determined by Sequenom Massarray. RESULTS: Among these 191 CSU patients, there were 114 patients who were treated with desloratadine, 65 were treated with mizolastine, and 12 with fexofenadine. The-1330T alleles in CSU patients were significantly higher than controls (0.555 vs. 0.466, P=0.040, OR=1.429 [1.016-2.010]). The poorest response to desloratadine was observed in heterozygotes, when compared with either GG or TT homozgote (P=0.001). However, there was no significant difference in three genotypes when treated with mizolastine group (P=0.215). CONCLUSION: We concluded that the C5AR1 SNP -1330T/G may serve as a useful pharmacodynamic predictor of nonsedating H1-antihistamines efficacy in CSU patients, and -1330T alleles may be taken as a risk factor for the CSU. PMID- 25455141 TI - Effect of the phosphodiesterase 4 inhibitor E6005 on nerve growth factor elevation in irritated skin of NC/Nga mice. PMID- 25455142 TI - [Revisiting meibomian gland dysfunction]. AB - Meibomian gland dysfunctions (MGD) are frequent affections, sometimes asymptomatic, more often responsible for disabling, potentially severe, manifestations. MGD is indeed the most frequent cause of dry eye, through the induction of tear film instability. However, eyelid inflammation, microbial proliferation that modifies melting temperature of meibum, frequent association with skin diseases, as well as potentially severe corneal complications make them complex multifactorial disorders. Complementary mechanisms combine to actually result in a vicious circle, or more accurately a double vicious cycle. The first one is self-stimulated by the microbiological changes, which create their own conditions for MGD development. The second one is related to tear film instability that results from MGD and is also self-stimulated through hyperosmolarity and inflammatory phenomena, which are both consequence and cause of dry eye. We herein propose a new pathophysiological schema on MGD, in order to better identify mechanisms and more efficiently target therapeutics. PMID- 25455143 TI - [Focus on Susac's syndrome. A pediatric case report]. AB - INTRODUCTION: Susac's syndrome (SS) is a rare immune disorder. It combines encephalopathy, retinopathy and hearing loss. We report a new pediatric case, revealed by an occlusive retinal arteritis. CASE REPORT: A 12-year-old girl presented to the emergency room because of sudden onset of photopsias in her right temporal visual field. One year previously, she had developed an acute disseminated encephalomyelitis, resolving with steroids. Visual acuity was 10/10 P2 in both eyes. Fundus examination revealed a thin right inferior nasal artery. Fluorescein angiography revealed an occlusion of this artery and occlusive peripheral arterial vasculitis. An IV steroid bolus was administered urgently. Brain MRI showed high signal intensity abnormalities in the corpus callosum. The clinical triad was rapidly completed by a bilateral hearing loss. Intravenous immunoglobulins were initiated. The occurrence of contralateral occlusive retinal arteritis two months later led to treatment with cyclophosphamide. After 6 infusions, visual acuity was stable, but the visual field remained, and regression of the vasculitis remained incomplete. DISCUSSION: Three hundred cases of SS have been reported with predominance in young women. Pediatric cases are rare. Diagnosis is difficult, because the typical clinical triad is often incomplete. Occurrence of relapses is unpredictable. Visual prognosis depends on the location of the occluded retinal territories. Treatment, based on a combination of steroids, immunosuppressive and antiplatelet agents is not always able to prevent relapse, as in our case. CONCLUSION: Unpredictable progression of SS requires early diagnosis and treatment as well as close monitoring. It must always be considered in the case of any occlusive retinal arteritis, even in children. PMID- 25455144 TI - [Selective Laser Trabeculoplasty in the treatment of chronic open-angle glaucoma: retrospective analysis 12 years after treatment in a cohort of 28 patients]. AB - PURPOSE: To determine long-term efficacy of selective Laser Trabeculoplasty (SLT) over 12 years in chronic open-angle glaucoma (OAG) patients. METHODS: In this retrospective study, all patients treated by SLT between 1997 and 1999 for OAG were included and followed up every 6 months. The procedure was performed with a Coherent Selecta 7000 Nd:YAG with 100 +/- 10 non overlapping 400 MUm spots over 360 degrees centered on the trabecular meshwork. Patients were excluded in the case of prior filtration surgery or Argon laser trabeculoplasty. Our primary study parameter was the number of patients requiring filtration surgery within the follow-up period. Our secondary parameters were intraocular pressure (IOP) and SLT-related complications. RESULTS: We included 46 eyes of 28 patients. The 12-year success rate was 26.1%. Thirty-nine percent of all eyes underwent filtration surgery (failure) during the follow-up period, and 34.8% were lost to follow-up. In the pigmentary glaucoma (PG) subgroup, the 12-year success rate was 16%, while it was 37.5% in the Primary OAG subgroup. The overall mean IOP was 22.8 mm Hg (D.S. 3.78) prior to laser, 16.08 mm Hg (D.S. 2.7) at 1 year and 15 mm Hg (D.S. 1.8) at 12 years. The mean number of medications was 1.6 (D.S. 0.8) prior to SLT, 1.36 (D.S. 0.8) at 1 year, and 1.3 (D.S. 1.2), 12 years after SLT respectively. No patients had a second SLT treatment. No significant complications occurred during follow-up. CONCLUSION: Selective laser trabeculoplasty may at times be a useful resource to lower IOP in patients with OAG. Nonetheless, the failure rate is significant especially in PG, which requires confirmation by larger prospective studies. PMID- 25455147 TI - Anithiactins A-C, modified 2-phenylthiazoles from a mudflat-derived Streptomyces sp. AB - Intensive investigation of the chemical components of a Streptomyces sp. isolated from mudflat sediments collected on the southern coast of the Korean peninsula led to the isolation of three new compounds, anithiactins A-C (1-3). The chemical structures of anithiactins A and C were determined by interpretation of NMR data analyses, while the chemical structure of anithiactin B was established from a combination of NMR spectroscopic and crystallographic data analyses. The structure of anithiactin A was also confirmed by total synthesis. These three anithiactins displayed moderate acetylcholinesterase inhibitory activity with no significant cytotoxicity. PMID- 25455148 TI - Bone grafting: history, rationale, and selection of materials and techniques. AB - In the 100-year history of bone replacement in the human body for different purposes, a wide variety of surgical approaches and materials have been used. The techniques and materials selected significantly affect the outcome of bone replacement procedures in terms of bone formation volume and the quality and amount of vital bone. The choices facing the dental surgeon at the time of extraction, ridge augmentation, or sinus graft are wide-ranging. When choosing a bone graft material the surgeon should consider its ultimate effect on healing patterns in and around the alveolar bone at the endpoint of the procedure. As this article concludes, a better understanding of the materials and the results that can be predictably achieved with them can be valuable to the appropriately trained surgeon when preparing for these procedures. PMID- 25455149 TI - A new syringe-delivered, moldable, alloplastic bone graft substitute. PMID- 25455151 TI - Extended Y-rule method for the characterization of the aromatic sextets in cata condensed polycyclic aromatic hydrocarbons. AB - The location, number, and migrating behavior of the sextets in the cata-condensed benzenoid polycyclic aromatic hydrocarbons with available bay regions have been determined by a new proposed topological methodology called the extended Y-rule. The precursor of this rule is the well-known Y-rule method for determining sextets in peri-condensed polycyclic aromatic hydrocarbons. The new methodology has been successfully validated by means of literature information and by theoretical nucleus independent chemical shift (NICS) calculations. Even though the families of polycyclic aromatic hydrocarbons analyzed here comprise the C14H10, C18H12, C22H14, and C26H16 isomers, the procedure can practically be extended to the families C(10+4x)H(8+2x), where x = 1, ..., infinity. It is the first time that a straightforward procedure, easy to apply, has been proposed to obtain the sextets arrangement and behavior in the group of cata-condensed benzenoid polycyclic aromatic hydrocarbons. PMID- 25455150 TI - Extraction site preservation using an in-situ hardening alloplastic bone graft substitute. AB - This case report highlights the use of an in-situ hardening alloplastic bone grafting material composed of beta-tricalcium phosphate (beta-TCP) granules coated with poly(lactic-co-glycolic acid) (PLGA) to preserve the dimensions and architecture of the alveolar ridge after atraumatic extraction. This material provided a stable scaffold that, although left uncovered, deterred the ingrowth of unwanted soft tissue, allowing newly formed keratinized soft tissue to proliferate over the healing grafted socket and gradually cover the site. At re entry after 4 months adequate newly formed bone was observed, allowing for the correct positional placement of an implant. The results of this case suggest that an in-situ hardening alloplastic grafting material can be successfully utilized with minimally invasive procedures to preserve the bone and the soft-tissue profile of the alveolar ridge for future implant rehabilitation. PMID- 25455152 TI - Human rhinovirus infection and cirrhosis: a potential fatal complication. PMID- 25455153 TI - When should we consider transplantation in adult patients with sclerosing cholangitis due to multisystem Langerhans' cell histiocytosis? PMID- 25455154 TI - Incidence of microscopic colitis in the Netherlands. A nationwide population based study from 2000 to 2012. AB - BACKGROUND: Incidence rates of microscopic colitis are mainly based on regional data from a limited number of countries. To evaluate geographical differences and changes over time, more nationwide incidence rates are needed. AIMS: The aim of this retrospective study was to assess the incidence rate of microscopic colitis in the Netherlands in a nationwide cohort. METHODS: A search was performed in the Dutch pathology registry, covering records of all approximately 16.5 million inhabitants. Incident cases were defined as a first diagnosis of microscopic colitis (collagenous or lymphocytic colitis) between 2000 and 2012. RESULTS: In total, 7228 incident cases were identified with a mean annual incidence rate of 3.4 per 100,000 person years. Collagenous colitis was present in 3741 cases and lymphocytic colitis in 2718 cases, with a mean annual incidence rate of 1.8 and 1.3 per 100,000 person years, respectively. Remaining 769 cases were described as undefined microscopic colitis. Collagenous and lymphocytic colitis incidence rates increased significantly over time (p<0.001) with a male:female ratio of 1:3 and 1:2, respectively. CONCLUSION: The Dutch mean annual incidence rates of collagenous and lymphocytic colitis were considerably lower than previously reported by other countries. However, incidence rates increased gradually over time, with a clear female predominance. PMID- 25455155 TI - Zigzag stacks and m-regular linear stacks. AB - The contact map of a protein fold is a graph that represents the patterns of contacts in the fold. It is known that the contact map can be decomposed into stacks and queues. RNA secondary structures are special stacks in which the degree of each vertex is at most one and each arc has length of at least two. Waterman and Smith derived a formula for the number of RNA secondary structures of length n with exactly k arcs. Honer zu Siederdissen et al. developed a folding algorithm for extended RNA secondary structures in which each vertex has maximum degree two. An equation for the generating function of extended RNA secondary structures was obtained by Muller and Nebel by using a context-free grammar approach, which leads to an asymptotic formula. In this article, we consider m regular linear stacks, where each arc has length at least m and the degree of each vertex is bounded by two. Extended RNA secondary structures are exactly 2 regular linear stacks. For any m >= 2, we obtain an equation for the generating function of the m-regular linear stacks. For given m, we deduce a recurrence relation and an asymptotic formula for the number of m-regular linear stacks on n vertices. To establish the equation, we use the reduction operation of Chen, Deng, and Du to transform an m-regular linear stack to an m-reduced zigzag (or alternating) stack. Then we find an equation for m-reduced zigzag stacks leading to an equation for m-regular linear stacks. PMID- 25455156 TI - Current and future trends in biomarker discovery and development of companion diagnostics for arthritis. AB - Musculoskeletal diseases such as rheumatoid arthritis are complex multifactorial disorders that are chronic in nature and debilitating for patients. A number of drug families are available to clinicians to manage these disorders but few tests exist to target these to the most responsive patients. As a consequence, drug failure and switching to drugs with alternate modes of action is common. In parallel, a limited number of laboratory tests are available which measure biological indicators or 'biomarkers' of disease activity, autoimmune status, or joint damage. There is a growing awareness that assimilating the fields of drug selection and diagnostic tests into 'companion diagnostics' could greatly advance disease management and improve outcomes for patients. This review aims to highlight: the current applications of biomarkers in rheumatology with particular focus on companion diagnostics; developments in the fields of proteomics, genomics, microbiomics, imaging and bioinformatics and how integration of these technologies into clinical practice could support therapeutic decisions. PMID- 25455157 TI - Down-regulation of sphingosine kinase 2 (SphK2) increases the effects of all trans-retinoic acid (ATRA) on colon cancer cells. AB - Sphingosine kinase 2 (SphK2) is a type of sphingosine kinase, which express highly in most of cancers. SphK2 produce sphingosine-1-phosphate (S1P) and then accumulate in cancer cells. Our previous study showed that S1P antagonized the effects of all-trans-retinoic acid (ATRA) via the receptor-dependent and independent pathway. In this study, we aimed to investigate the roles of SphK2 in affecting ATRA's activity in human colon cancer cells. Cell proliferation was estimated by the clonogenic assay. The distribution of cell cycle was analyzed by flow cytometry assay. The apoptotic cells were determined by Annexin V-FITC/PI staining method. Western blotting assay was performed to analyze the levels of the proteins related to apoptosis and cell cycle. The mRNA levels of SphK2 and RARbeta were evaluated by real-time PCR assay. RNA interference assay was performed to evaluate SphK2 activity. S1P antagonized the effect of ATRA on HT-29 cell proliferation, the ATRA-induced RARbeta expression, the arrest of cell cycle in G1-phase, and induction of apoptosis. Down-regulation of SphK2 resulted in the reverse actions on the S1P-induced antagonistic effects on ATRA. Western blotting analysis indicated that down-regulation of SphK2 might activate apoptotic proteins, regulation of p53/p21(Waf1/Cip1) and EGFR and PI3K/AKT signaling pathways. In conclusion, down-regulation of SphK2 increased the effects of ATRA on colon cancer cells. PMID- 25455158 TI - A novel compound RY10-4 downregulates P-glycoprotein expression and reverses multidrug-resistant phenotype in human breast cancer MCF-7/ADR cells. AB - P-glycoprotein (P-gp), an important efflux transporter, is encoded by the MDR1 class of genes and is a major element of the multidrug resistance (MDR) phenomenon in breast cancers. The most common approved cause of MDR in cancer tissues is the over-expression of P-gp. At present, a novel potent anti-tumor compound RY10-4 has been synthesized by our team, which has a similar structure close to protoapigenone. We chose MCF-7/ADR cells, an adriamycin (ADR) - selected human breast tumor cell line with the MDR phenotype, to study the anticancer features of this novel compound in our experiments. In cytotoxicity and apoptosis tests, it was shown that RY10-4 significantly inhibited cell growth, induced apoptosis, potentiated ADR cytotoxicity and restored chemotherapy sensitivity in the MDR cancer cells. Furthermore, our results suggested that RY10-4 reversed MDR partially by down-regulation of P-gp and MDR1 expressions in the MCF-7/ADR cell line. Besides, it is seen that RY10-4 could reduce the intracellular ATP level. Our studies give the theoretical basis for the possible clinical applications of RY10-4 alone or in combination with other chemotherapeutic drugs in the treatment of MDR tumors. PMID- 25455159 TI - Prognostic value of miR-26a and HMGA1 in urothelial bladder cancer. AB - BACKGROUND: MicroRNA-26a (miR-26a) functions as a tumor suppressor by regulating its direct target gene high mobility group AT-hook 1 (HMGA1). This study was aimed to investigate the associations of differential expression of miR-26a and HMGA1 with tumor progression and prognosis in urothelial bladder cancer (UBC) patients. MATERIALS AND METHODS: One hundred and twenty-six UBC patients were selected and quantitative real-time PCR was performed to detect the expression of miR-26a and HMGA1 mRNA in the respective tumors. RESULTS: Our data showed the decreased expression of miR-26a and the increased expression of HMGA1 mRNA in UBC tissues compared with corresponding non-cancerous tissues (both P<0.001). Then, the expression levels of miR-26a in UBC tissues were negatively correlated with those of HMGA1 mRNA significantly (r=-0.72, P<0.001). In addition, UBC patients with combined miR-26a downregulation and HMGA1 upregulation (miR-26a-low/HMGA1 high) more frequently had advanced pathological stage (P<0.001) and high tumor grade (P<0.001). Moreover, miR-26a-low/HMGA1-high expression was associated with a significantly shortest disease-free survival (P<0.001) and overall survival (P<0.001) of all miR-26a/HMGA1 combined expression groups. Furthermore, multivariate analysis indicated that miR-26a/HMGA1 expression was an independent prognostic factor for both disease-free survival and overall survival (both P=0.001) in UBC patients. CONCLUSION: Interaction between miR-26a and its target gene HMGA1 may contribute to the malignant progression of human UBC. Tumors with miR-26a downregulation in combination with high expression of HMGA1 showed a worse prognosis than the other tumors. Combined detection of their expression might be particularly helpful for surveillance of disease progression and treatment stratification. PMID- 25455161 TI - Applications of biomaterials in corneal wound healing. AB - Disease affecting the cornea is a common cause of blindness worldwide. To date, the amniotic membrane (AM) is the most widely used clinical method for cornea regeneration. However, donor-dependent differences in the AM may result in variable clinical outcomes. To overcome this issue, biomaterials are currently under investigation for corneal regeneration in vitro and in vivo. In this article, we highlight the recent advances in hydrogels, bioengineered prosthetic devices, contact lenses, and drug delivery systems for corneal regeneration. In clinical studies, the therapeutic effects of biomaterials, including fibrin and collagen-based hydrogels and silicone contact lenses, have been demonstrated in damaged cornea. The combination of cells and biomaterials may provide potential treatment in corneal wound healing in the future. PMID- 25455160 TI - The association between miR-146a gene rs2910164 polymorphism and gastric cancer risk: a meta-analysis. AB - PURPOSE: Studies have demonstrated that single nucleotide polymorphisms (SNPs) in miRNAs may lead to varying functional outcomes by altering miRNAs expression, even leading to the development of cancers. The association between a single nucleotide polymorphism (SNP) in miR-146a rs2910164 and susceptibility to gastric cancer has been studied during the recent years, but the results are still inconclusive and inconsistent. We performed a meta-analysis to evaluate the relationship between miR-146a rs2910164 polymorphism and the risk of gastric cancer. MATERIALS AND METHODS: The databases of PubMed, MEDLINE and Web of Science were searched for suitable studies. A total of 8 published case-control studies on miR-146a rs2910164 polymorphism and gastric cancer risk including 4308 cases and 6370 controls were included. RESULTS: Overall, significant association was observed between rs2910164 and gastric cancer risk in allele model (OR=1.11, 95% CI=1.02-1.21); homozygote model (OR=1.26, 95% CI=1.10-1.43) and dominant model (OR=1.21, 95% CI=1.09-1.34). Stratified analysis by ethnicity showed significant association between rs2910164 polymorphism and gastric cancer susceptibility in Asians (OR=1.10, 95% CI=1.00-1.23 for G vs. C; OR=1.25, 95% CI=1.09-1.43 for GG vs. CC; OR=1.19, 95% CI=1.07-1.33 for GG vs. GC+CC, respectively). When stratified by genotyping methods and sample size, increased gastric cancer risk was only observed with the method by TaqMan and the sample size more than 1000. CONCLUSION: In summary, this meta-analysis indicated that miR-146a rs2910164 polymorphism was associated with the susceptibility to gastric cancer, especially in Asian population. PMID- 25455162 TI - A systematic review of genetic studies of thyroid disorders in Taiwan. AB - A systematic review of genetic studies of thyroid disorders in Taiwan identified studies of gene mutations involved in the synthesis and binding of thyroid hormone, as well as mutations of proto-oncogenes and tumor suppressor genes in thyroid cancer. Studies related to gene polymorphisms in patients with autoimmune thyroid disease (AITD) and thyroid cancer were also reviewed. The most prevalent mutations in the Han-Chinese population were c.2268insT in the thyroid peroxidase (TPO) gene and c.919-2A>G in the Pendred syndrome (PDS) gene. Additional mutations have also been revealed in the genes encoding TPO (n = 5), thyroglobulin (TG; n = 6), pendrin (n = 2), and thyroxine-binding globulin (TBG; n = 2), which were novel at the time they were reported. The prevalence of various somatic mutations in differentiated thyroid cancer was similar in Taiwan and Western countries, with the RAS kinase mutation and tyrosine receptor kinase (TRK) and rearranged during transfection (RET) proto-oncogenes being detected in lower frequencies and the B-type RAF kinase (BRAF) mutation accounting for the majority of cases. Recent microRNA analysis revealed an association between miR146b and the BRAF mutation, which was associated with poor prognosis of papillary thyroid carcinoma (PTC). Susceptibility to Graves' disease (GD) was linked to the human leukocyte antigen (HLA) region. The associated alleles were different in Han-Chinese and Caucasians; HLA-DPB1*0501, the major allele in Taiwan, has a low frequency in the West. By contrast, a high frequency of HLA DRB1*0301 was detected in Caucasians but not Han-Chinese. In addition to the HLA region, cytotoxic T lymphocyte-associated molecule-4 (CTLA4) gene polymorphisms +49G>A and +6230G>A (CT60) were positively associated with GD. The GG genotype and G allele of single nucleotide polymorphism (SNP) +49G>A were also related to relapse of Graves' hyperthyroidism after antithyroid drug withdrawal. Differences in the genetic patterns between Han-Chinese and Caucasians for some thyroid disorders suggest the importance of variable genetic influences in different populations. PMID- 25455163 TI - In vitro localisation of intracranial haematoma using electrical impedance tomography semi-array. AB - Electrical Impedance Tomography is a non-invasive and portable method that has good potential as an alternative to the conventional modalities for early detection of intracranial haematomas in high risk patients. Early diagnosis can reduce treatment delays and most significantly can impact patient outcomes. Two eight-electrode layouts, a standard ring full array (FA) and a semi-array (SA), were investigated for their ability to detect, localise and quantify simulated intracranial haematomas in vitro on ovine models for the purpose of early diagnosis. SA layout speeds up electrode application and avoids the need to move and lift the patient's head. Haematomas were simulated using gel samples with the same conductivity as blood. Both layouts, FA and SA, could detect the presence of haematomas at any location within the skull. The mean of the relative radial position error with respect to the brain radius was 7% for FA and 6% for SA, for haematomas close to the electrodes, and 11% for SA for haematomas far from the electrodes at the back of the head. Size estimation was not as good; the worst size estimation error for FA being around 30% while the best for SA was 50% for simulated haematomas close to the electrodes. PMID- 25455164 TI - Development and validation of a 3D-printed interfacial stress sensor for prosthetic applications. AB - A novel capacitance-based sensor designed for monitoring mechanical stresses at the stump-socket interface of lower-limb amputees is described. It provides practical means of measuring pressure and shear stresses simultaneously. In particular, it comprises of a flexible frame (20 mm * 20 mm), with thickness of 4mm. By employing rapid prototyping technology in its fabrication, it offers a low-cost and versatile solution, with capability of adopting bespoke shapes of lower-limb residua. The sensor was first analysed using finite element analysis (FEA) and then evaluated using lab-based electromechanical tests. The results validate that the sensor is capable of monitoring both pressure and shear at stresses up to 350 kPa and 80 kPa, respectively. A post-signal processing model is developed to induce pressure and shear stresses, respectively. The effective separation of pressure and shear signals can be potentially advantageous for sensor calibration in clinical applications. The sensor also demonstrates high linearity (approx. 5-8%) and high pressure (approx. 1.3 kPa) and shear (approx. 0.6 kPa) stress resolution performance. Accordingly, the sensor offers the potential for exploitation as an assistive tool to both evaluate prosthetic socket fitting in clinical settings and alert amputees in home settings of excessive loading at the stump-socket interface, effectively preventing stump tissue breakdown at an early stage. PMID- 25455166 TI - Design optimization of a deflectable guidewire. AB - Over the years, the design of the tip of available catheters and guidewires has evolved into various shapes whose geometry is mostly based on common sense and experimentation. However, while the tip shape of conventional instruments can be easily modified and tested, the length of the tip of a deflectable guidewire cannot. Hence, other approaches are necessary in order to determine the proper dimensions of original instruments. In this paper, we formulate the length of the different parts of the deflectable tip of a guidewire as an optimization problem with the objective to obtain a design that is suitable for cannulating several target bifurcations of the peripheral vasculature. A direct relationship between the design of the deflectable tip and the geometry of the target bifurcations was found and the optimal dimension of the tip of the instrument was computed. Following the length specifications defined by the optimization, a new prototype was assembled, and evaluated. The deflectable guidewire could successfully cannulate most of the pre-selected branches except those bifurcations with an angle alpha>70 degrees . The latter limitation could be ascribed to the mechanical properties of the instrument. PMID- 25455165 TI - Ultrasound-guided three-dimensional needle steering in biological tissue with curved surfaces. AB - In this paper, we present a system capable of automatically steering a bevel tipped flexible needle under ultrasound guidance toward a physical target while avoiding a physical obstacle embedded in gelatin phantoms and biological tissue with curved surfaces. An ultrasound pre-operative scan is performed for three dimensional (3D) target localization and shape reconstruction. A controller based on implicit force control is developed to align the transducer with curved surfaces to assure the maximum contact area, and thus obtain an image of sufficient quality. We experimentally investigate the effect of needle insertion system parameters such as insertion speed, needle diameter and bevel angle on target motion to adjust the parameters that minimize the target motion during insertion. A fast sampling-based path planner is used to compute and periodically update a feasible path to the target that avoids obstacles. We present experimental results for target reconstruction and needle insertion procedures in gelatin-based phantoms and biological tissue. Mean targeting errors of 1.46+/ 0.37 mm, 1.29+/-0.29 mm and 1.82+/-0.58 mm are obtained for phantoms with inclined, curved and combined (inclined and curved) surfaces, respectively, for insertion distance of 86-103 mm. The achieved targeting errors suggest that our approach is sufficient for targeting lesions of 3mm radius that can be detected using clinical ultrasound imaging systems. PMID- 25455167 TI - Characteristics of very slow stepping in healthy adults and validity of the activPAL3TM activity monitor in detecting these steps. AB - The use of activity monitors to objectively measure stepping activity allows the characterisation of free-living daily activity performance. However, they must be fully validated. The characteristics of very slow stepping were examined and the validity of an activity monitor, the activPAL3TM (PAL Technologies Ltd., Glasgow, UK) to detect these steps was assessed. 10M/10F healthy adults (36+/-10 y) performed a treadmill walking protocol from 1.0m/s down to 0.1m/s (0.1m/s increments) whilst wearing the monitor under video observation (gold standard). Within the 800 stepping periods recorded the proportion of the steps correctly detected by the activPAL3TM was explored against speed and cadence. Below 0.4 m/s walking began to be intermittent, stepping interspersed with stationary postures. At 0.1 m/s almost 90% of walking periods were intermittent. The percentage of steps detected was over 90% for walking speed at or above 0.5m/s and cadence at or above 69 steps/min. However, below these limits % steps detected reduced rapidly with zero steps detected at 0.1m/s and at or below 24 steps/min. When examining the stepping activity of groups with limited stepping cadence the above thresholds of performance should be considered to ensure that outcomes are not misinterpreted and important very slow stepping activity missed. PMID- 25455168 TI - Percutaneous nephrolithotomy and ureteroscopy in children: evolutions. AB - The increasing incidence of pediatric stone disease has coincided with significant advances in technology and equipment, resulting in drastic improvements in management. Miniaturization of both ureteroscopes and percutaneous nephrolithotomy (PCNL) equipment has facilitated access to the entirety of the urinary tract and has made ureteroscopy a first-line therapy option along with shock-wave lithotripsy for kidney and ureteral stones. Advances in PCNL have decreased patient morbidity while preserving stone clearance rates. In this review, the advances in operative approach for ureteroscopy and PCNL in children and its applicability to current surgical management of pediatric stone disease are discussed. PMID- 25455169 TI - Laparoscopic orchiopexy and varicocelectomy: is there really an advantage? AB - The role of laparoscopy in the case of nonpalpable cryptorchidism is both diagnostic and therapeutic. Laparoscopic orchiopexy for nonpalpable testes in the pediatric population has become the preferred surgical approach among pediatric urologists over the last 20 years. In contrast, laparoscopic varicocelectomy is considered one of several possible approaches to the treatment of a varicocele in an adolescent; however, it has many challengers and it has not gained universal acceptance as the gold standard. This article reviews the published evidence regarding these surgical techniques. PMID- 25455170 TI - Laparoscopic nephrectomy and partial nephrectomy: intraperitoneal, retroperitoneal, single site. AB - The indication for use of laparoscopy, in the pediatric population, was initially for diagnostic purposes. As confidence with the technology and utility grew, it began to be applied for therapeutic indications. With equivalent surgical outcomes and decreased morbidity, the usefulness of a laparoscopic approach became more apparent, and today minimally invasive surgery is an indispensable tool in the management of many pediatric urologic conditions. The management of renal pathologies using laparoscopy is now currently the approach of choice for most pediatric renal maladies. PMID- 25455171 TI - The laparoscopic pyeloplasty: is there a role in the age of robotics? AB - Ureteropelvic junction (UPJ) obstruction is a common anomaly, and presents clinically in all pediatric age groups. The past 3 decades have witnessed an evolution in the surgical correction of UPJ obstruction on several fronts, with open surgical techniques yielding way to endoscopic, laparoscopic, and robotic assisted approaches. Robotic-assisted surgery has several advantages in complex laparoscopic reconstructive procedures such as pyeloplasty. Comparative studies of laparoscopic and robot-assisted repairs have demonstrated similar success rates. Laparoscopic pyeloplasty is here to stay because of its advantages of safety, efficacy, decreased morbidity, reduced hospital stay, and, perhaps most importantly, cost-effectiveness. PMID- 25455172 TI - Vesicoscopic ureteral reimplant: is there a role in the age of robotics? AB - Vesicoscopic ureteral reimplantation is a challenging procedure to learn but does have outcomes equivalent to standard open repair. Children objectively have less pain than after an open cross-trigonal repair. Operative times compare favorably to other forms of minimally invasive surgery. PMID- 25455173 TI - Minimally invasive techniques for management of the ureterocele and ectopic ureter: upper tract versus lower tract approach. AB - The optimal management approach for children with ureterocele and complete pyeloureteral duplication, especially in the setting of high-grade ipsilateral vesicoureteral reflux, remains unclear. Trends in surgical management reflect a shift from single-stage open reconstruction toward conservative management and minimally invasive approaches. This article reviews lower tract approaches (endoscopic ureterocele incision and ipsilateral ureteroureterostomy), and upper tract approaches (ureterocele moiety heminephrectomy) in terms of selected operative techniques, patient selection, published outcomes, postoperative care, and follow-up. Current data support endoscopic puncture as a safe and effective treatment of symptomatic children with single-system intravesical ureteroceles. PMID- 25455174 TI - Management of the bladder and calyceal diverticulum: options in the age of minimally invasive surgery. AB - Bladder and calyceal diverticula are rare clinical entities in the pediatric population. Most of these diverticula are asymptomatic, incidentally detected, and may not require surgical intervention. However, if surgery is indicated, there are minimally invasive treatment options available that have success rates comparable with those of traditional open surgery. In addition, they offer several advantages including reduced morbidity, decreased hospital length of stay, improved cosmesis, and reduced pain medication requirements. In this review, the minimally invasive surgical techniques in the management of bladder and calyceal diverticula are discussed. PMID- 25455175 TI - The robotic-assisted laparoscopic pyeloplasty: gateway to advanced reconstruction. AB - Robotic pyeloplasty is now commonly performed for children with ureteropelvic junction obstruction. Because surgical robotics is a tool that facilitates pyeloplasty and other reconstructive urologic operations, the indications for robotic-assisted laparoscopic pyeloplasty are the same as those for an open pyeloplasty but offer distinct advantages with respect to visualization, range of motion, and ease of laparoscopic suturing. In this review, the authors discuss the operative approach for robotic pyeloplasty in children and the extensions of the basic techniques to challenging clinical scenarios. PMID- 25455176 TI - The robotic-assisted ureteral reimplantation: the evolution to a new standard. AB - The development of the robotic-assisted laparoscopic ureteral reimplantation has tracked a path searching for the optimal method of providing outcomes on par with the gold standard of open intravesical ureteral reimplantation combined with fewer complications and decreased discomfort for the patient. With this in mind, pioneers in pediatric urology minimally invasive surgery have put limits to the test with laparoscopic transvesicoscopic Cohen reimplants and laparoscopic extravesical Lich-Gregoir reimplants and then used the da Vinci platform to fine tune and bring these skills into the 21st century. PMID- 25455177 TI - Robotic-assisted bladder neck repair: feasibility and outcomes. AB - Minimally invasive techniques are rapidly being developed and integrated into urologic surgery. Over the past 5 years, the urologic literature is abound with novel techniques and adaptations to conventional laparoscopy. Pediatric urology is no exception to this trend, and the benefits of minimally invasive surgery may be accentuated in children given the relatively more confined working spaces and also a heightened awareness of cosmesis for the pediatric population. Increasingly, complex pediatric urologic procedures are being performed with robot assistance. The feasibility of nephrectomy, pyeloplasty, ureteral reimplantation, and bladder surgery has been clearly established. PMID- 25455178 TI - The robotic appendicovesicostomy and bladder augmentation: the next frontier in robotics, are we there? AB - There is growing interest in applying robotic-assisted laparoscopic techniques to complex reconstructive pelvic surgery owing to inherent benefits of precision, tissue handling, and articulating instruments for suturing. This review examines preliminary experiences with robotic-assisted laparoscopic augmentation ileocystoplasty and Mitrofanoff appendicovesicostomy (RALIMA) as either an isolated or combined procedure. These series suggest RALIMA is feasible, with the benefit of early recovery and improved cosmetic results in selected patients. The robotic approach incurs functional outcomes and complication rates similar to those of open techniques. Given the steep learning curve, only surgeons with extensive robotic experience are currently adopting this technique. PMID- 25455179 TI - MIS-behavior: practical heuristics for precise pediatric minimally invasive surgery. AB - Minimally invasive surgery (MIS) has changed pediatric urology and general surgery, offering less morbidity and new surgical options for many procedures. This promise goes unrealized when technical methods lag. Application of MIS in children is uneven after more than 2 decades of application. Principles of versatile and proficient technique may remain unstated and implicit in surgical training, often leaving surgical training an exercise in inference and imitation. This article describes some essential practical principles of precision MIS applied to patients of any size. PMID- 25455180 TI - Minimally invasive pediatric urologic surgery. PMID- 25455181 TI - Minimally invasive pediatric urologic surgery. PMID- 25455182 TI - Identification of a novel 2-pyridyl-benzensulfonamide derivative, RQ-00203078, as a selective and orally active TRPM8 antagonist. AB - A novel series of 2-pyridyl-benzensulfonamide derivatives have been identified as selective and orally active TRPM8 antagonists via high throughput screening (HTS). Exploration of the structure-activity relationships of compound 1 has led to the identification of RQ-00203078 (compound 36) as a highly selective, potent and orally available TRPM8 antagonist. RQ-00203078 demonstrated excellent in vivo activity in a dose dependent manner with an ED50 value of 0.65 mg/kg in the icilin-induced wet-dog shakes model in rats after oral administration and may become an important pharmacological tool for fully assessing the potential therapeutic use of the targets activated by cold stimulation. PMID- 25455183 TI - Synthesis of linear and cyclic guazatine derivatives endowed with antibacterial activity. AB - Antibiotic resistance has reached alarming levels in many clinically-relevant human pathogens, and there is an increasing clinical need for new antibiotics active on drug-resistant Gram-negative pathogens who rapidly evolve towards pandrug resistance phenotypes. Here, we report on two related classes of guanidinic compounds endowed with antibacterial activity. The two best compounds (9a and 13d) exhibited the most potent antibacterial activity with MIC values ranging 0.12-8 MUg/ml with most tested pathogens, including both Gram-positive and Gram-negative bacteria. Interestingly, MIC values were not affected (1-8 MUg/ml) when measured using recent clinical isolates with various antibiotic resistance determinants. The results reported herein identify guazatine derivatives as an interesting starting point for the optimization of a potentially novel class of antibacterial agents. PMID- 25455188 TI - Nonlinear ultrafast acoustics at the nano scale. AB - Pulsed femtosecond lasers can generate acoustic pulses propagating in solids while displaying either diffraction, attenuation, nonlinearity and/or dispersion. When acoustic attenuation and diffraction are negligible, shock waves or solitons can form during propagation. Both wave types are phonon wavepackets with characteristic length scales as short as a few nanometer. Hence, they are well suited for acoustic characterization and manipulation of materials on both ultrafast and ultrashort scales. This work presents an overview of nonlinear ultrasonics since its first experimental demonstration at the beginning of this century to the more recent developments. We start by reviewing the main properties of nonlinear ultrafast acoustic propagation based on the underlying equations. Then we show various results obtained by different groups around the world with an emphasis on recent work. Current issues and directions of future research are discussed. PMID- 25455185 TI - Surgical management of combined anterior or posterior cruciate ligament and posterolateral corner tears: for what functional results? AB - INTRODUCTION: Management of combined anterior or posterior cruciate ligament and posterolateral corner tears is still poorly codified. The aim of this study was to evaluate functional outcome after complete surgical treatment. MATERIALS AND METHODS: This retrospective multicenter study included 53 patients. Mean age was 29.8 yrs. (15-49). The anterior and posterior cruciate ligaments were involved in respectively 48 and 5 cases. Mean time to surgery was 25.6 months (0-184), and in 10 cases less than 21 days. Nine patients were sedentary workers and 29 non sedentary (13 laborers). All ligament injuries were treated surgically. Mean follow-up was 49 months (12-146). Last follow-up assessment used IKDC, Lysholm and KOOS scores. RESULTS: At last follow-up, IKDC score graded 14 patients A, 25 B, 8 C and 6 D, versus 0 A, 4 B, 25 C, 22 D and 2 ungraded preoperatively. Mean subjective IKDC and Lysholm scores were respectively 72.8 (11.5-100) and 77.5 (37 100). Mean KOOS scores (pain, symptoms, daily life, sports, quality of life) were respectively 78 (3-100), 70 (25-100), 88 (47-100), 53 (0-100) and 50 (0-100). Posterolateral laxity was corrected in all but two cases. All sedentary workers and 86.7% of non-sedentary workers could return to work. The job had to be changed in 10% of cases overall, but in 25% of cases for laborers. DISCUSSION: The present results are comparable with those of the literature. The strategy of combined surgical treatment showed functional efficacy, usually associated with return to work except for some laborers. There was a non-significant trend in favor of acute-phase ligament reconstruction. LEVEL OF EVIDENCE: IV (retrospective series). PMID- 25455187 TI - Energy characterisation of ultrasonic systems for industrial processes. AB - Obtaining accurate power characteristics of ultrasonic treatment systems is an important step towards their industrial scalability. Calorimetric measurements are most commonly used for quantifying the dissipated ultrasonic power. However, accuracy of these measurements is affected by various heat losses, especially when working at high power densities. In this work, electrical power measurements were conducted at all locations in the piezoelectric ultrasonic system equipped with 1/2" and 3/4" probes. A set of heat transfer calculations were developed to estimate the convection heat losses from the reaction solution. Chemical dosimeters represented by the oxidation of potassium iodide, Fricke solution and 4-nitrophenol were used to chemically correlate the effect of various electrical amplitudes and treatment regimes. This allowed estimation of sonochemical efficiency (SE) and energy conversion (XUS) of the ultrasonic system. Results of this study showed overall conversion efficiencies of 60-70%. This correlated well with the chemical dosimeter yield curves of both organic and inorganic aqueous solutions. All dosimeters showed bubble shielding and coalescence effects at higher ultrasonic power levels, less pronounced for the 1/2" probe case. SE and XUS values in the range of 10(-10) mol/J and 10(-3) J/J respectively confirmed that conversion of ultrasonic power to chemical yield declined with amplitude. PMID- 25455189 TI - THz acoustic phonon spectroscopy and nanoscopy by using piezoelectric semiconductor heterostructures. AB - Thanks to ultrafast acoustics, a better understanding of acoustic dynamics on a short time scale has been obtained and new characterization methods at the nanoscale have been developed. Among the materials that were studied during the development of ultrafast acoustics, nitride based heterostructures play a particular role due to their piezoelectric properties and the possibility to generate phonons with over-THz frequency and bandwidth. Here, we review some of the work performed using this type of structure, with a focus on THz phonon spectroscopy and nanoscopy. First, we present a brief description of the theory of coherent acoustic phonon generation by piezoelectric heterostructure. Then the first experimental observation of coherent acoustic phonon generated by the absorption of ultrashort light pulses in piezoelectric heterostructures is presented. From this starting point, we then present some methods developed to realize customizable phonon generation. Finally we review some more recent applications of these structures, including imaging with a nanometer resolution, broadband attenuation measurements with a frequency up to 1THz and phononic bandgap characterization. PMID- 25455190 TI - Ultrasound in arc welding: a review. AB - During the last decade, the introduction of ultrasound techniques in arc welding with the intention of improving the operational performance and technical characteristics of the welding processes have been studied intensively. In this work is presented a broad review of the literature surrounding the utilization of this technique. Firstly, we discuss the use of traditional mechanical transducers to generate ultrasound in arc welding. Furthermore, we describe the various methods and their application in arc-welding processes. After, is presented a recent method of introducing ultrasonic energy in arc welding, which forms a potential alternative to the use of traditional mechanical type transducers. This method was originally developed in the late 1990s and is called arc with ultrasonic excitation of current. Here, the arc acts not only as a thermal source but also as an emission mechanism for ultrasound, acting directly on the weld pool. We presented and discussed various innovative concepts based on this method, which allows the introduction of ultrasonic energy in the arc welding without the need of any auxiliary device of welding. In addition, we also presented the variations of this method reported in the literature. Finally, we have described the respective effects attributed to the use of this method in the welding of different materials using various welding processes. PMID- 25455191 TI - Enhancing acoustic cavitation using artificial crevice bubbles. AB - We study the response of pre-defined cavitation nuclei driven continuously in the kHz regime (80, 100 and 200 kHz). The nuclei consist of stabilized gaspockets in cylindrical pits of 30 MUm diameter etched in silicon or glass substrates. It is found that above an acoustic pressure threshold the dynamics of the liquid-gas meniscus switches from a stable drum-like vibration to expansion and deformation, frequently resulting in detachment of microbubbles. Just above this threshold small bubbles are continuously and intermittently ejected. At elevated input powers bubble detachment becomes more frequent and cavitation bubble clouds are formed and remain in the vicinity of the pit bubble. Surprisingly, the resulting loss of gas does not lead to deactivation of the pit which can be explained by a rectified gas diffusion process. PMID- 25455193 TI - Contribution of ultrasonic traveling wave to chemical-mechanical polishing. AB - The ultrasonic vibrators are introduced into the chemical-mechanical polishing devices, and in this polishing system, the ultrasonic vibrators generate ultrasonic traveling wave and keep coaxial with the polished silicon wafer rotating at given speed so as to compare the texture of the polished silicon wafers. And the experiments on the chemical-mechanical polishing with assisted ultrasonic vibration are accomplished in order to investigate the effect of the ultrasonic vibration on the chemical-mechanical polishing. Via comparing the roughness average of the two silicon wafers polished with assisted ultrasonic vibration and without assisted vibration, it is found that the morphology of the silicon wafer polished with assisted vibration is superior to that without assisted vibration, that is, this series of experiments indicate that the ultrasonic vibration is beneficial to the chemical-mechanical polishing. Aiming at understanding the contribution of the ultrasonic vibration to chemical mechanical polishing in detail, the model of the chemical-mechanical polishing with the assisted ultrasonic vibration is built up, which establishes the relationship of the removal rate and the polishing variables such as the rotary speed of silicon wafers, the amplitude and the frequency of vibrators, the particle density of polishing slurry and the characteristics of polishing pad etc. This model not only could be used to explain the experimental results but also to illuminate the roles played by the polishing variables. PMID- 25455194 TI - Relationship between second- and third-order acoustic nonlinear parameters in relative measurement. AB - The higher-order acoustic nonlinear parameters are considered effective damage indices in the field of nondestructive evaluation (NDE). They are defined by using the displacement amplitudes of the fundamental frequency and the harmonics, which are called the absolute nonlinear parameters. Generally, however, it is difficult to measure the very small displacement amplitudes of high-frequency harmonics. Therefore, the simplified parameters using the detected wave signal amplitudes, which are known as the relative nonlinear parameters, have been widely used, although their applications are limited to the relative comparison of before and after damage of a single material under consistent experimental circumstances. In this paper, in order to make clear the concept of relative parameter, we presented first that the relative ratio of the simplified parameters is identical to that of the absolute parameters when the detected signal amplitudes are linearly proportional to the actual displacement amplitudes with respect to the fundamental frequency and the harmonics. In addition, the new relationship between the relative ratio of simplified second-order parameter and the relative ratio of simplified third-order parameter was derived from the relationship between the absolute second- and third-order parameters. This new relationship was successfully verified based on experimental results obtained from Al 6061-T6 processed for different heat treatment times, where it was confirmed in advance that the PZT detection signal amplitudes at the fundamental frequency and its second- and third-order harmonics were linearly proportional to the displacement amplitudes. PMID- 25455192 TI - Changes in pulmonary artery pressure during early transitional circulation in healthy full-term newborns. AB - BACKGROUND: Although pulmonary artery systolic pressures (PASPs) are frequently measured in newborn infants using the tricuspid regurgitant jet velocity or ductal Doppler velocity, little is known about the reference range in the general population. METHODS: This was a retrospective study of 296 neonates less than 14 days of age who were evaluated using echocardiography. Patients included in this study did not have clinical or acquired cardiac disease. PASP was estimated using the ductal Doppler velocity and/or the tricuspid regurgitant jet velocity and the Bernoulli equation. RESULTS: The majority of the definite right-to-left through the ductus arteriosus was limited to the first 6 h after birth, and the majority of the left-to-right shunt was limited to 10 h after birth. After 10 h, 24 infants with Doppler color-flow imaging revealed a very small and transient jet. The percentage of measurable tricuspid regurgitation was 91% after 24 h. Multivariable regression analysis found that there was a significant correlation between neonatal age and PASP (determined from tricuspid regurgitant jet velocity and Bernoulli equation: r(2)=0.748, P<0.0001; and from ductal Doppler velocity: r(2)=0.179, P<0.001). The upper 95% limit for PASP measured in healthy neonates younger than 14 days was 39.1 mmHg. CONCLUSIONS: The ductal Doppler velocity is measured more easily for monitoring PASP than tricuspid regurgitant jet velocity in newborns soon after birth; however, in neonates older than 24 h, the tricuspid regurgitant jet velocity is easier for measurement. Age is an independent impact factor of PASP in the neonates. And PASP values gradually decreased to less than 39.1 mmHg by 14 days after birth. PMID- 25455195 TI - Reversible influence of ultrasound on gamma-irradiated Mo/n-Si Schottky barrier structure. AB - The influence of ultrasonic loading on current-voltage characteristics has been investigated in Mo/n-n(+)-Si structures irradiated by (60)Co gamma-rays. The longitudinal ultrasonic waves were of 9.6 MHz in frequency and had the intensity approaching 1.3 W/cm(2). The observed reversible acoustically induced increase in forward and reverse currents was as large as 60%. The ultrasound has been found to affect thermionic emission mainly due to Schottky barrier height decrease. The observed effects are related to acoustically induced ionization of the defects located at the metal-semiconductor interface. It has also been found that in the result of gamma-irradiation, the ultrasonic wave-defect interaction is modified. Ultrasonic loading, however, has been found to have no effect either on direct or phonon-assisted tunneling. PMID- 25455196 TI - ACR CT accreditation program and the lung cancer screening program designation. AB - The ACR recognizes that low-dose CT for lung cancer screening has the potential to significantly reduce mortality from lung cancer in the appropriate high-risk population. The ACR supports the recommendations of the US Preventive Services Task Force and the National Comprehensive Cancer Network for screening patients. To be effective, lung cancer screening should be performed at sites providing high-quality low-dose CT examinations overseen and interpreted by qualified physicians using a structured reporting and management system. The ACR has developed a set of tools necessary for radiologists to take the lead on the front lines of lung cancer screening. The ACR Lung Cancer Screening Center designation is built upon the ACR CT accreditation program and requires use of Lung-RADS or a similar structured reporting and management system. This designation provides patients and referring providers with the assurance that they will receive high quality screening with appropriate follow-up care. PMID- 25455197 TI - Carboxymethyl- and carboxyl-catechins from ripe Pu-er tea. AB - Ripe Pu-er tea, a special microbial postfermented tea originated from Yunnan Province, China, since ancient times, is made from green Pu-er tea prepared from the leaves of Camellia sinensis var. assamica (Theaceae). Chemical investigation on thearubigin (n-BuOH-soluble) fraction of the commercial ripe Pu-er tea, led to the identification of four new flavan-3-ol derivatives, 8-carboxymethyl-(+) catechin (1), 8-carboxymethyl-(+)-catechin methyl ester (2), 6-carboxymethyl-(+) catechin (3), and 6-carboxyl-(-)-gallocatechin (4), together with 18 known compounds, including other three flavan-3-ol derivatives (5-7), 10 flavonoid glycosides (8-17), two hydrolyzable tannins (18 and 19), two quinic acid derivatives (20-21), and a purine alkaloid (22). Flavonoid glycosides 8-11 are reported from tea plants for the first time. The thearubigin fraction of ripe Pu er tea was qualitatively analyzed by HPLC, and gallic acid was found to be the major component. Compounds 4, 6-17, 21 and 22 were tested for their acute activities on insulin sensitivity in differentiated 3T3-L1 adipocytes, but none of them showed significant bioactivity at a concentration of 10 MUM. PMID- 25455201 TI - A tribute to Sir John Gurdon. PMID- 25455202 TI - Lessons from a great developmental biologist. AB - The announcement that Sir John Gurdon had been awarded the 2012 Nobel Prize for Medicine or Physiology was received with great joy by developmental biologists. It was a very special occasion because of his total dedication to science and turning the Golden Rule of western civilization - love your neighbor as yourself into a reality in our field. This essay attempts to explain how John became such a great scientific benefactor, and to review some of his discoveries that are less well known than the nuclear transplantation experiments. A few personal anecdotes are also included to illustrate the profound goodness of this unique man of science. PMID- 25455203 TI - Templated electrodeposition and photocatalytic activity of cuprous oxide nanorod arrays. AB - Cuprous oxide (Cu2O) nanorod arrays have been prepared via a novel templated electrodeposition process and were characterized for their photocatalytic behavior in nonaqueous photoelectrochemical cells. Zinc oxide (ZnO) nanorod films serve as sacrificial templates for the in situ formation of polymer nanopore membranes on transparent conductive oxide substrates. Nitrocellulose and poly(lactic acid) are effective membrane-forming polymers that exhibit different modes of template formation, with nitrocellulose forming conformal coatings on the ZnO surface while poly(lactic acid) acts as an amorphous pore-filling material. Robust template formation is sensitive to the seeding method used to prepare the precursor ZnO nanorod films. Photoelectrochemical cells prepared from electrodeposited Cu2O films using methyl viologen as a redox shuttle in acetonitrile electrolyte exhibit significant charge recombination that can be partially suppressed by a combination of surface passivation methods. Surface passivated nanostructured Cu2O films show enhanced photocurrent relative to planar electrodeposited Cu2O films of similar thickness. We have obtained the highest photocurrent ever reported for electrodeposited Cu2O in a nonaqueous photoelectrochemical cell. PMID- 25455204 TI - Intracellular uptake and pH-dependent release of doxorubicin from the self assembled micelles based on amphiphilic polyaspartamide graft copolymers. AB - Biodegradable and pH-sensitive graft copolymers based on polysuccinimide (PSI) were synthesized as intracellular drug carriers. Hydrophobic octadecylamine (C18) and hydrophilic O-(2-aminoethyl) polyethylene glycol (PEG, Mw 5000) were grafted on a PSI backbone for amphiphilicity, enabling the formation of a self-assembled micellar structure in aqueous medium. Biotin was conjugated at the end of the PEG segment as the cell penetrating ligand, and hydrazone hydrate was introduced as a cleavable linkage for the release of pH sensitive drug, doxorubicin. The chemical structure of the polymer and degree of substitution of the graft segments were confirmed by Fourier transform infrared (FTIR) and (1)H NMR spectroscopy. The size and distribution of the polymer micelles were investigated by dynamic light scattering. The average diameter of the polymer micelles was 290-310 nm with a narrow distribution. Less than 30% of the total DOX loaded in the polymeric micelles was released at pH 7.4, whereas >75% was released at pH 5 in 70 h because of the cleavage of the hydrazone bond in acidic conditions. For the cytotoxicity test, the MCF-7 cell viability in the presence of biotin-conjugated polymer was much lower than that in the presence of a nonconjugated one, as the former had higher probability of cell penetration aided by a biotin ligand. The DOX uptake in MCF-7 cells was analyzed by the confocal laser scanning microscopy. More DOX uptake was observed in acidic conditions because of the cleavage of hydrazone groups in the polymer. PMID- 25455206 TI - Relationship between foot vibration threshold and walking and balance functions in people with Multiple Sclerosis (PwMS). AB - The aim of this study was to investigate the relationship between foot vibration threshold and walking and balance functions in people with Multiple Sclerosis (PwMS). The study sample consisted of 34 participants with mean age of 49.5 years (SD 11.13). Participants were able to walk independently or with an assistive device. Participants underwent vibration threshold testing using the Neurothesiometer (NT), followed by the 6 min walking test (6MWT), the Timed Up and Go test (TUG) and the Berg balance scale (BBS). We found a statistically significant relationship between foot vibration threshold and all outcome measures used. The first metatarsophalangeal joint had the strongest correlation with BBS (-0.585, p < 0.01), 6 MWT (-0.557, p < 0.01) and TUG (0.498, p < 0.01). We also found that vibration threshold scores differed between those people with MS with and without walking limitations (Mann-Whitney U test, p < 0.01 for all testing points). In conclusion, these findings confirm the relationship between foot vibration threshold and clinical measures of walking and balance in PwMS and add to literature predictive validity of foot vibration threshold. They also suggest that vibration threshold may be important to consider when identifying people in need of intervention or when evaluating the effect of rehabilitation and exercise interventions. PMID- 25455205 TI - Oxorhenium(V) complexes with phenolate-oxazoline ligands: influence of the isomeric form on the O-atom-transfer reactivity. AB - The bidentate phenolate-oxazoline ligands 2-(2'-hydroxyphenyl)-2-oxazoline (1a, Hoz) and 2-(4',4'-dimethyl-3',4'-dihydrooxazol-2'-yl)phenol (1b, Hdmoz) were used to synthesize two sets of oxorhenium(V) complexes, namely, [ReOCl2(L)(PPh3)] [L = oz (2a) and dmoz (2b)] and [ReOX(L)2] [X = Cl, L = oz (3a or 3a'); X = Cl, L = dmoz (3b); X = OMe, L = dmoz (4)]. Complex 3a' is a coordination isomer (N,N-cis isomer) with respect to the orientation of the phenolate-oxazoline ligands of the previously published complex 3a (N,N-trans isomer). The reaction of 3a' with silver triflate in acetonitrile led to the cationic compound [ReO(oz)2(NCCH3)](OTf) ([3a'](OTf)). Compound 4 is a rarely observed isomer with a trans-O?Re-OMe unit. Complexes 3a, 3a', [3a'](OTf), and 4 were tested as catalysts in the reduction of a perchlorate salt with an organic sulfide as the O acceptor and found to be active, in contrast to 2a and 2b. A comparison of the two isomeric complexes 3a and 3a' showed significant differences in activity: 87% 3a vs 16% 3a' sulfoxide yield. When complex [3a'](OTf) was used, the yield was 57%. Density functional theory calculations circumstantiate all of the proposed intermediates with N,N-trans configurations to be lower in energy compared to the respective compounds with N,N-cis configurations. Also, no interconversions between N,N-trans and N,N-cis configurations are predicted, which is in accordance with experimental data. This is interesting because it contradicts previous mechanistic views. Kinetic analyses determined by UV-vis spectroscopy on the rate-determining oxidation steps of 3a, 3a', and [3a'](OTf) proved the N,N cis complexes 3a' and [3a'](OTf) to be slower by a factor of ~4. PMID- 25455208 TI - Energy expended and knee joint load accumulated when walking, running, or standing for the same amount of time. AB - Evidence suggests prolonged bouts of sitting are unhealthy, and some public health messages have recently recommended replacing sitting with more standing. However, the relative benefits of replacing sitting with standing compared to locomotion are not known. Specifically, the biomechanical consequences of standing compared to other sitting-alternatives like walking and running are not well known and are usually not considered in studies on sitting. We compared the total knee joint load accumulated (TKJLA) and the total energy expended (TEE) when performing either walking, running, or standing for a common exercise bout duration (30 min). Walking and running both (unsurprisingly) had much more TEE than standing (+300% and +1100%, respectively). TKJLA was similar between walking and standing and 74% greater in running. The results suggest that standing is a poor replacement for walking and running if one wishes to increases energy expenditure, and may be particularly questionable for use in individuals at-risk for knee osteoarthritis due to its surprisingly high TKJLA (just as high as walking, 56% of the load in running) and the type of loading (continuous compression) it places on cartilage. However, standing has health benefits as an "inactivity interrupter" that extend beyond its direct energy expenditure. We suggest that future studies on standing as an inactivity intervention consider the potential biomechanical consequences of standing more often throughout the day, particularly in the case of prolonged bouts of standing. PMID- 25455207 TI - Further validation of the Six-Spot Step Test as a measure of ambulation in multiple sclerosis. AB - BACKGROUND: There is preliminary evidence regarding the validity of the Six-Spot Step Test (SSST) as a promising measure of ambulatory function in persons with multiple sclerosis (MS). To date, this assessment has not been subject to the same rigor and extent of psychometric evaluation as other widely-accepted measures of ambulatory (e.g., timed 25-foot walk (T25FW)). OBJECTIVE: This study aimed to provide additional validity evidence for the SSST in 96 persons with MS, based on construct validity and precision. Construct validity involves examining the pattern of associations between the SSST and other measures, and precision involves comparing SSST performance relative to other valid measures of ambulation for differentiating between levels of disability status, MS clinical course, and fall risk based on balance confidence. METHODS: All participants completed the SSST, T25FW, Timed Up-and-Go (TUG), six-minute walk, Multiple Sclerosis Walking Scale-12, Late-Life Function and Disability Inventory, Activities-specific Balance Confidence, and Paced Auditory Serial Addition Test. All participants further underwent a neurological examination for generating EDSS scores, and then wore an ActiGraph accelerometer for the waking hours of a 7-day period. RESULTS: SSST performance was strongly associated with other valid measures of ambulation (|rho| = .65-.90) and disability status (rho = .73), moderately-to-strongly associated with balance confidence (rho = .58), and weakly to-moderately associated with cognitive processing speed and non-ambulatory measures (|rho| = .35-.39). The SSST demonstrated stronger relative precision in discriminating between levels of disability status, MS clinical course, and fall risk based on balance confidence than the T25FW and TUG. CONCLUSIONS: We provide comprehensive validity evidence for the SSST that supports its consideration for inclusion alongside other highly-regarded objective measures of ambulatory function for clinical research and practice in persons with MS. PMID- 25455209 TI - Balance control impairment in obese individuals is caused by larger balance motor commands variability. AB - It is acknowledged that various factors impaired balance control. Among them, heavy body weight is associated with poor balance control because the location of the center of mass is further away from the ankle joint. Thus, a larger active ankle torque is required to counter the greater gravitational torque. Because balance motor commands have signal-dependent noise whose standard deviation increases with the absolute value of the neural control signal, it was hypothesized that faster center of pressure speed observed in obese individuals would be related to larger balance motor commands variability. A feedback-control model and parametric system identification technique was used to estimate the variability in the balance motor commands and neural controller parameters based on previously published experimental data. Results of the neuromechanical model confirmed that the balance motor commands of obese individuals are more variable than that of lean individuals. PMID- 25455210 TI - Changes in temporal parameters during performance of the Step Test in older adults. AB - The purpose of this cross-sectional study was to examine the changes in the temporal parameters measured during the performance of the Step Test, to evaluate the relationship between age and these measurements and to determine their relationships to aerobic endurance, muscular strength and mobility in a sample of older adults. Eighty-eight older adults (mean age = 73.0 years, SD = 5.4) participated in the study. During the Step Test, we collected measurements of the following temporal parameters using the Optojump system: step number, support time and executive time. We also evaluated the performance of the Six-Minute Walk Test, the 30-Second Chair Rise Test and the Timed Up and Go Test. We observed a significant decrease in the step number and an increase in the support time and executive time (p = .001) during each minute of the test. The results revealed that the relationship between age and Step Test performance was attenuated when we controlled for potential confounding variables. Controlling for age, gender and BMI, variance in support time during the Step Test was accounted for by variance in 30-Second Chair Rise Test performance (partial r = -.224). Moreover, variance in executive time was accounted for by variance in 30-Second Chair Rise Test (partial r = .234) and Timed Up and Go Test performance (partial r = -.259). Understanding the factors that are associated with the performance of the Step Test may provide new insights into the development of specific intervention programmes for older adults. PMID- 25455211 TI - Interaction between interpersonal and postural coordination during frequency scaled rhythmic sway: the role of dance expertise. AB - Light fingertip touch between partners swaying rhythmically side by side evokes interpersonal synchrony. In non-dancers and dancers swaying to a metronome, we examined the effects of frequency scaling and touch between the partners on both postural (ankle-hip) and inter-personal coordination. In both groups, touch did not interfere with the ankle-hip coordination. In non-dancers but not dancers, increasing frequency resulted in a loss of the ankle-hip coupling that was accompanied by a reduction of the touch mediated interpersonal synchrony. It is suggested that the effect of touch on interpersonal synchrony depends on the reliability of the haptic information sensed at the fingertip and assumes an in phase ankle-hip coupling. These findings have implications in clinical practice when using touch to help balance impaired individuals. PMID- 25455212 TI - Proactive gait strategies to mitigate risk of obstacle contact are more prevalent with advancing age. AB - The purposes of this study were to determine if healthy older adults adopt strategies to decrease the likelihood of obstacle contact, and to determine how these strategies are modified as a function of advancing age. Three age groups were examined: 20-25 yo (N = 19), 65-79 yo (N = 11), and 80-91 yo (N = 18). Participants stepped over a stationary, visible obstacle on a walkway. Step length and gait speed progressively decreased with advancing age; the shorter step length resulted in closer foot placement to the obstacle and an associated increased risk of obstacle contact. Lead (first limb to cross the obstacle) and trail (second) limb trajectories were examined for behavior that mitigated the risk of contact. (1) Consistent trail foot placement before the obstacle across all ages allowed space and time for the trail foot to clear the obstacle. (2) To avoid lead limb contact due to closer foot placement before and after the obstacle, the lead toe was raised more vertically after toe-off, and then the foot was extended beyond the landing position (termed lead overshoot) and retracted backwards to achieve the shortened step length. Lead overshoot progressively increased with advancing age. (3) Head angle was progressively lower with advancing age, an apparent attempt to gather more visual information during approach. Overall, a series of proactive strategies were adopted to mitigate risk of contact. However, the larger, more abrupt movements associated with a more vertical foot trajectory and lead overshoot may compromise whole body balance, indicating a possible trade-off between risk of contact and stability. PMID- 25455214 TI - Do family order and neighbor intervention against intimate partner violence protect children from abuse? Findings from Kathmandu. AB - Drawing on previous research on intimate partner violence, child maltreatment, and informal social control, we hypothesized relationships between child abuse severity and (1) protective informal social control of intimate partner violence (ISC_IPV) by neighbors, (2) intimate terrorism, (3) family order, and (4) the power of mothers in intimate relationships. In what we believe may be a first study of physical child abuse by parents in Nepal, we used a three stage cluster approach to draw a random sample of 300 families in Kathmandu. Random effects regression models were used to test the study hypotheses. The analyses found support for hypotheses one and two, but with an important caveat. Although observed (actual) protective ISC_IPV had the hypothesized negative association with child abuse severity, in one of our models perceived protective ISC_IPV was positively associated with child abuse severity. The models clarify that the overall direction of protective ISC_IPV appears to be negative (protective), but the positive finding is important to consider for both research and practice. A significant relationship between family order and child abuse severity was found, but the direction was negative rather than positive as in hypothesis three. Implications for neighborhood research and typological research on IPV and child maltreatment are discussed. PMID- 25455213 TI - Optimization of a plasma facilitated DNA delivery method. AB - Plasma-based methods have recently emerged as a technique for augmenting plasmid DNA delivery to skin. This delivery modality relies on the deposition of ionized gas molecules on to targeted cells or tissue to establish an electric field. It is hypothesized that this electric field results in the dielectric breakdown of cell membranes, making cells permeable to exogenous molecules. This in vivo investigation sought to optimize the intradermal delivery of a luciferase expressing plasmid DNA by modulating the total exposure to the plasma source and the plasmid DNA dose. Varying the plasma exposure time from 2, 5, 10, and 20 min allowed the conditions resulting in the highest expression of luciferase to be found. These conditions correlated to the 10 minute exposure time for a plasma derived from either +8 kV or -8 kV, when the generator was operated 3 cm from the epidermal tissue surface with a helium flow rate of 15 L/min. Exposing the injected flank skin for 10 min resulted in a rise of 37.3-fold for a plasma created with +8 kV and 27.1-fold for a plasma created with -8 kV. When using this treatment time with 50, 100, or 200 MUg of a luciferase expressing plasmid, it was found that 100 MUg resulted in the highest peak luminescence. PMID- 25455215 TI - Cognitive schemas and sexual offending: differences between rapists, pedophilic and nonpedophilic child molesters, and nonsexual offenders. AB - Empirical research has primarily focused on the differences between rapists and child molesters. Nonetheless, a greater understanding of specific needs of specific subtypes of sex offenders is necessary. The aim of the present study was to investigate the relationship between the early maladaptive schemas and different types of sexual offending behavior. Fifty rapists, 59 child molesters (19 pedophilic and 40 nonpedophilic), and 51 nonsexual offenders answered the Young Schema Questionnaire, the Brief Symptom Inventory, and the Socially Desirable Response Set Measure. Data were analyzed using sets of multinomial logistic regression, controlling for sociodemographic variables, psychological distress, and social desirability. Results showed that pedophilic offenders were more likely to hold the defectiveness and subjugation schemas compared to the other three groups. Likewise, nonpedophilic child molesters were more likely to hold the social isolation, enmeshment, and unrelenting standards schemas compared to rapists. Additionally, rapists were more likely to hold the vulnerability to harm, approval-seeking, and punitiveness schemas compared to nonpedophiles and/or nonsex offenders. Overall, our findings suggest that cognitive schemas may play a role in the vulnerability for sexual offending and corroborate the need to distinguish between the two subtypes of child molesters. Despite the need for further investigation, findings may have important implications for the treatment of sex offenders and for the prevention of sexual crimes. PMID- 25455216 TI - Relational trauma in the context of intimate partner violence. AB - The relational model of trauma (Scheeringa & Zeanah, 2001) proposes that infants' trauma symptoms may be influenced by their mothers' trauma symptoms and disruptions in caregiving behavior, although the mechanisms by which this occurs are less well understood. In this research, we examined the direct and indirect effects of a traumatic event (maternal intimate partner violence [IPV]), maternal trauma symptoms, and impaired (harsh and neglectful) parenting on infant trauma symptoms in a sample of mother-infant dyads (N=182) using structural equation modeling. Mothers completed questionnaires on IPV experienced during pregnancy and the child's first year of life, their past-month trauma symptoms, their child's past-month trauma symptoms, and their parenting behaviors. Results indicated that the effects of prenatal IPV on infant trauma symptoms were partially mediated by maternal trauma symptoms, and the relationship between maternal and infant trauma symptoms was fully mediated by neglectful parenting. Postnatal IPV did not affect maternal or infant trauma symptoms. Findings support the application of the relational model to IPV-exposed mother-infant dyads, with regard to IPV experienced during pregnancy, and help identify potential foci of intervention for professionals working with mothers and children. PMID- 25455217 TI - [Induced abortion and use of contraceptive methods among prostitutes in Almeria (Spain)]. AB - OBJECTIVE: To analyze the performance of induced abortion (IA) in prostitutes in Almeria (Spain) and its association with the use of contraceptive methods. METHODS: A cross-sectional study was conducted in 110 women. A bivariate analyses using either the chi(2) test or Fisher's exact test was carried out (significance level <0.05), with calculation of odds ratios and 95% confidence intervals. RESULTS: A total of 52.7% of women had undergone at least one IA. All of these women used condoms and 35.5% of them also used another contraceptive method. No statistically significant association was found between condom breakage and the performance of IA or in the use of other contraceptive methods. CONCLUSIONS: A high percentage of this group of women had undergone IA, despite widespread condom use. However, there was a high percentage of condom breakage and a low percentage of use of emergency contraceptive pills after risky sexual relationships. PMID- 25455218 TI - Endocytosis of Streptococcus pneumoniae via the polymeric immunoglobulin receptor of epithelial cells relies on clathrin and caveolin dependent mechanisms. AB - Colonization of Streptococcus pneumoniae (pneumococci) is a prerequisite for bacterial dissemination and their capability to enter the bloodstream. Pneumococci have evolved various successful strategies to colonize the mucosal epithelial barrier of humans. A pivotal mechanism of host cell invasion implicated with invasive diseases is promoted by the interaction of pneumococcal PspC with the polymeric Ig-receptor (pIgR). However, the mechanism(s) of pneumococcal endocytosis and the intracellular route of pneumococci upon uptake by the PspC-pIgR-interaction are not known. Here, we demonstrate by using a combination of pharmacological inhibitors and genetics interference approaches the involvement of active dynamin-dependent caveolae and clathrin-coated vesicles for pneumococcal uptake via the PspC-pIgR mechanism. Depleting cholesterol from host cell membranes and disruption of lipid microdomains impaired pneumococcal internalization. Moreover, chemical inhibition of clathrin or functional inactivation of dynamin, caveolae or clathrin by RNA interference significantly affected pneumococcal internalization suggesting that clathrin-mediated endocytosis (CME) and caveolae are involved in the bacterial uptake process. Confocal fluorescence microscopy of pIgR-expressing epithelial cells infected with pneumococci or heterologous Lactococcus lactis expressing PspC demonstrated bacterial co-localization with fluorescent-tagged clathrin and early as well as recycling or late endosomal markers such as Lamp1, Rab5, Rab4, and Rab7, respectively. In conclusion these data suggest that PspC-promoted uptake is mediated by both CME and caveolae. After endocytosis pneumococci are routed via the endocytic pathway into early endosomes and are then sorted into recycling or late endosomes, which can result in pneumococcal killing in phagolysosomes or transcytosis via recycling endosomes. PMID- 25455219 TI - Molecular epidemiology and virulence of Escherichia coli O16:H5-ST131: comparison with H30 and H30-Rx subclones of O25b:H4-ST131. AB - The present study was carried out to evaluate the prevalence of the clonal subgroup O16:H5-ST131 and the H30 and H30-Rx subclones among E. coli isolates causing extraintestinal infections and to know their virulence potential. The ST131 clonal group accounted for 490 (16%) of the 2995 isolates obtained from clinical samples in five Spanish hospitals during the study period (2005-2012). Among those 490 ST131 isolates, 456 belonged to serotype O25b:H4, 27 to O16:H5 and seven were O-non-typeable:H4 (ONT:H4). All 27 O16:H5 isolates showed fimH41, whereas fimH30 and fimH22 alleles were the most frequently detected among O25b:H4 isolates. The majority (381/490; 78%) of ST131 isolates belonged to H30 subclone, and 302 of 381 (79%) H30 isolates belonged to the H30-Rx subclone. Of the 27 O16:H5 isolates, 48% produced CTX-M-14; however, none produced CTX-M-15. In contrast, 46% of O25b:H4 isolates produced CTX-M-15 while only 2% produced CTX-M 14. More than a half of the O16:H5 isolates (56%) showed the ExPEC status which was significantly more prevalent within O25b:H4 isolates (81%) (P<0.01), especially among H30-Rx (97%) isolates. In the present study, a modified virotype scheme was applied within which approximately half (52%) of the O16:H5 isolates showed the C1 specific virotype. Despite their low virulence-gene score (mean of virulence genes 6.4 versus 8.5 in O25b:H4 isolates), six out of the 10 O16:H5 isolates assayed showed high virulence in the mouse model of sepsis (killed 90 100% of mice challenged). Furthermore, four O16:H5 isolates of virotypes A and C1, carrying K2 variant of group II capsule, showed lethality at 24h. Thus, certain O16:H5 fimH41 isolates show a similar in vivo virulence to that reported with the highly virulent O25b:H4 H30-Rx isolates (Mora et al., PLOS ONE 2014, e87025), supporting their potential virulence for humans. PMID- 25455221 TI - Animals and ethical research. PMID- 25455220 TI - Toxicological assessment of kretek cigarettes. Part 7: the impact of ingredients added to kretek cigarettes on inhalation toxicity. AB - The biological activity of mainstream smoke from experimental kretek cigarettes with and without three mixes of ingredients was assessed in a 90-day rat inhalation study and in a 4-day in vivo micronucleus assay. 350 ingredients, commonly used in various combinations and in a limited number in a given brand in the manufacture of marketed kretek cigarettes, were applied at a low and a high target level to test cigarettes with a typical Indonesian blend of tobaccos and cloves. In the 90-day inhalation study, effects commonly seen in rat inhalation studies with mainstream smoke were observed. In general, no ingredients-related histopathological changes were found in the respiratory tract. In the 4-day micronucleus assay exposure of male rats to mainstream smoke from the test cigarettes containing any of the three mixes did not increase the proportions of micronucleated cells in peripheral blood and bone marrow over the proportion of micronucleated cells in the control group. Based on the results of these studies, it can be concluded that the addition of ingredients commonly used in the manufacture of kretek cigarettes did not change the overall in vivo toxicity profile of the mainstream smoke. PMID- 25455222 TI - The sub-chronic oral toxicity of dearomatized hydrocarbon solvents in Sprague Dawley rats. AB - Dearomatized hydrocarbon solvents in the C9-C14 aliphatic carbon number range were developed as alternatives to traditional solvents such as mineral spirits, but with lower aromatic content. Previous subchronic toxicity studies (both published and unpublished) have shown minimal to no systemic effects with exposure to dearomatized solvents, with the exception of rat-specific renal effects that have no relevance to humans. In this study, Sprague-Dawley rats were exposed to 0, 500, 2500 and 5000mg/kg/day of a C10-C13 dearomatized solvent for 90days by oral gavage. Liver enlargement and centrilobular hypertrophy were observed in all treated groups but were considered adaptive consequences of hydrocarbon-induced microsomal enzyme induction. Clinical chemistry data showed elevations of alanine aminotransferase (ALT), gamma glutamyltransferase (GGT) and total bilirubin in mid (ALT alone) and high dose groups, suggesting potential hepatobiliary effects with high dose exposure. Increased absolute kidney weight changes were restricted to male rats and associated with renal lesions indicative of alpha-2u globulin-mediated nephropathy. One limitation of the NOAEL/LOAEL approach in selecting points of departure for exposure limits is its dependence on dose selection/study design. Hence, a more robust approach that incorporates all data points on the dose-response curve, such as bench mark modeling, is preferred. Overall, benchmark dose analysis estimated a BMDL of 1857mg/kg/day based on increased serum ALT. This value is consistent with studies of similar hydrocarbon substances showing a lack of systemic effects at doses up to 1000mg/kg/day in the same rat strain. PMID- 25455223 TI - Thyroid tumor formation in the male mouse induced by fluopyram is mediated by activation of hepatic CAR/PXR nuclear receptors. AB - Fluopyram, a broad spectrum fungicide, caused an increased incidence of thyroid follicular cell (TFC) adenomas in males at the highest dose evaluated (750ppm equating to 105mg/kg/day) in the mouse oncogenicity study. A series of short-term mechanistic studies were conducted in the male mouse to characterize the mode of action (MOA) for the thyroid tumor formation and to determine if No Observed Effect Levels (NOELs) exist for each key event identified. The proposed MOA consists of an initial effect on the liver by activating the constitutive androstane (Car) and pregnane X (Pxr) nuclear receptors causing increased elimination of thyroid hormones followed by an increased secretion of thyroid stimulating hormone (TSH). This change in TSH secretion results in an increase of TFC proliferation which leads to hyperplasia and eventually adenomas after chronic exposure. Car/Pxr nuclear receptors were shown to be activated as indicated by increased activity of specific Phase I enzymes (PROD and BROD, respectively). Furthermore, evidence of increased T4 metabolism was provided by the induction of phase II enzymes known to preferentially use T4 as a substrate. Additional support for the proposed MOA was provided by demonstrating increased Tsh beta transcripts in the pituitary gland. Finally, increased TFC proliferation was observed after 28days of treatment. In these dose-response studies, clear NOELs were established for phase 2 liver enzyme activities, TSH changes and TFC proliferation. Furthermore, compelling evidence for Car/Pxr activation being the molecular initiating event for these thyroid tumors was provided by the absence of the sequential key events responsible for the TCF tumors in Car/Pxr KO mice when exposed to fluopyram. In conclusion, fluopyram thyroid toxicity is mediated by activation of hepatic Car/Pxr receptors and shows a threshold dependent MOA. PMID- 25455224 TI - Total mercury concentrations in the general Korean population, 2008-2011. AB - The purpose of this study was to evaluate the blood mercury levels of the general Korean population. The data from subjects of all ages were pooled from recent national surveys. In the combined surveys, the geometric means (GMs) of the blood mercury concentrations in subjects aged 0-7, 8-18, and 19years and above were 2.05 (2010-2011), 2.12 (2010-2011), and 3.74MUg/L (2008-2011), respectively. There was an increasing trend in blood mercury levels with age until 59years and then a slight decline in the group above 60years. The time trend for exposure to mercury in Korea also showed a marked decline. In comparing estimated methylmercury exposure to the Korean health-based guidance value (tolerable weekly intake [TWI]: 2.0MUg/kgbw/week), the GMs of methylmercury exposure for subjects aged 0-7, 8-18, and 19years and above were 0.30, 0.31, and 0.43MUg/kgbw/week, respectively, while methylmercury exposure did not exceed the TWI (15.0%, 15.5%, and 21.5% compared to the TWI, respectively). The 95th percentiles of estimated methylmercury exposure ranged from 0.71 to 1.61MUg/kgbw/week, which was not above the TWI (range, 35.5-80.5%). PMID- 25455225 TI - Hep-2 cell based indirect immunofluorescence assay for antinuclear antibodies as a potential diagnosis of drug-induced autoimmunity in nonclinical toxicity testing. AB - Antinuclear antibodies (ANAs) are important biomarkers in the diagnosis of autoimmune diseases in humans; however, the diagnostic performance of ANA in nonclinical safety studies are not well understood. Here, we studied the use of ANAs as potential nonclinical biomarkers for drug-induced autoimmunity (DIA) using a Hep-2 based indirect immunofluorescence assay (IFA). Initially, MRL fas(lpr)/J mice and HgCl2-treated rats were used as SLE-positive models. Serum samples obtained from 94 normal mice or 204 normal rats aged one to four months served as the negative control. The IFA effectively distinguished ANAs-positive samples in both species with a cut-off titer of 1:100. Brown Norway rats were treated with 450 mg/kg D-penicillamine for 30 consecutive days. ANAs were generated and corresponded with DIA development. Human Hep-2 cells, mice Neuro 2A cells, and Chinese Hamster Lung cells served as antigen from different species, which were found cross-reactive with ANA-positive serum samples from mice, rats, and humans without any differences in diagnosis. This methodology showed no species-specificity for ANA detection. Furthermore, we found approximately 20 percentage of the mice aged seven to eight months demonstrated age-related ANAs, which was consistent with humans. Overall, our findings demonstrated the use of ANA detection using IFA in the nonclinical diagnosis of murine drug-induced autoimmunity, and age-related ANAs should be considered when aged animals are used. PMID- 25455226 TI - Toxicological assessment of kretek cigarettes Part 3: kretek and American-blended cigarettes, inhalation toxicity. AB - A typical Indonesian kretek cigarette brand and an experimental kretek reference cigarette were compared to the reference cigarette 2R4F in two 90-day inhalation studies. Male and female rats were exposed nose-only to mainstream smoke for 6 hours daily, for 90 consecutive days. Biological endpoints were assessed according to OECD guideline 413, with special emphasis on respiratory tract histopathology and on lung inflammation (broncho-alveolar lavage fluid levels of neutrophils, macrophages and lymphocytes). Histopathological alterations included: in the nose, hyperplasia and squamous metaplasia of the respiratory epithelium and squamous metaplasia and atrophy of the olfactory epithelium; in the larynx, epithelial squamous metaplasia and hyperplasia; in the lungs, accumulation of macrophages in alveoli and goblet cell hyperplasia in bronchial epithelium. The findings were qualitatively consistent with observations from previous similar studies on conventional cigarettes. Compared to 2R4F cigarette, however, kretek smoke exposure was associated with a pronounced attenuation of pulmonary inflammation and less severe histopathological changes in the respiratory tract. Neutrophilic inflammation was also significantly lower (>70%). These results are consistent with the observations made on smoke chemistry and in vitro toxicology. They do not support any increased toxicity of the smoke of kretek cigarettes compared to conventional American-blended cigarettes. PMID- 25455227 TI - Purification, characterization and anti-diabetic activity of a polysaccharide from mulberry leaf. AB - In the present study, a high-purity polysaccharide from mulberry leaf (MLP) was purified and characterized, and its anti-diabetic effects were investigated in streptozotocin (STZ)-induced diabetic rats. Our results showed that the obtained MLP (purity 99.8%) was determined to be composed of d-arabinose, d-xylose, d glucose, d-rhamnose and d-mannose with molar ratio of 1:2.13:6.53:1.04:8.73. Oral administration of MLP at 50-200mg/kgbodyweight daily for 5weeks significantly reduced the levels of fasting blood glucose (FBG), glycosylated serum protein (GSP), serum total cholesterol (TC), and serum triglyceride (TG), and increased the body weight, fasting insulin (FINS), C-peptide (C-P), liver glycogen, liver glucokinase, and serum high-density lipoprotein cholesterol (HDL-C). Moreover, MLP promoted marked pancreatic beta-cell regeneration and insulin secretion, and reduced liver fat accumulation in diabetic rats. The treatment effect of MLP on diabetes was similar to the effect of antidiabetic drug glibenclamide. These results clearly indicated that MLP may have a potential for the treatment of hyperglycemia and hyperlipidemia in diabetes. PMID- 25455228 TI - Response to Crump et al. PMID- 25455229 TI - The "bottom-up" approach does not necessarily bound low-dose risk. PMID- 25455232 TI - Feeding the world sustainably. PMID- 25455230 TI - Toxicological assessment of kretek cigarettes Part 4: mechanistic investigations, smoke chemistry and in vitro toxicity. AB - The smoke chemistry and in vitro toxicity of mainstream smoke (MS) was investigated in American-blended cigarettes with or without the addition of 2.5%, 5% or 10% eugenol to the tobacco and in Indonesian-blended cigarettes with and without the addition of cloves, cloves extracted with hot ethanol, and extracted cloves replenished with eugenol or clove oil. The addition of eugenol reduced the concentration of nearly all toxicants measured in MS as well as the in vitro cytotoxicity of the gas/vapor phase. Reductions were also seen in bacterial mutagenicity of the total particulate matter (TPM) assessed by the Ames Assay. The addition of extracted cloves led to increases and decreases of toxicant concentrations in MS. Replenishment with eugenol or clove oil decreased the toxicant concentrations; with most smoke constituent concentrations reduced below the concentration found in tobacco-only cigarettes. Cytotoxicity of the TPM was not affected by the clove preparations. However, GVP cytotoxicity was reduced (untreated cloves showing the highest reductions). Mutagenicity of TPM was decreased by the clove preparations. Mechanisms for the reductions, (up to 40%), are most likely due to dilution effects by eugenol, changed burning characteristics of the tobacco, and free radical scavenging by eugenol. PMID- 25455231 TI - Toxicological assessment of kretek cigarettes Part 5: mechanistic investigations, inhalation toxicity. AB - The biological effects of mainstream smoke (MS) from Indonesian-blended cigarettes with and without added cloves, cloves extracted with hot ethanol, and extracted cloves replenished with eugenol or clove oil were assessed in a 90-day inhalation study in rats. A separate 35-day inhalation study in rats was performed with MS from American-blended cigarettes with 0%, 2.5%, 5% or 10% added eugenol. Effects commonly seen in inhalation studies with MS were observed. These included histopathological changes indicative of irritation in the entire respiratory tract and inflammatory responses in the lung. Adding cloves to American- or Indonesian-blended cigarettes reduced the inflammatory response in the lung but with no difference between the two blend types. When the clove oil was extracted (~ 75% reduction of eugenol achieved) from cloves, the inflammatory response in the lung was still reduced similarly to whole cloves but the severity of histopathological changes in the upper respiratory tract was less reduced. Add back of clove oil or pure eugenol reduced this response to a level similar to what was seen with whole cloves. When eugenol was added to American-blended cigarettes, similar findings of reduced lung inflammation and severity of histopathological changes in respiratory the tract was confirmed. These studies demonstrate a clear effect of cloves, and in particular eugenol, in explaining these findings. PMID- 25455233 TI - Waste in the NHS. PMID- 25455234 TI - Prevention of harmful practices in women and children. PMID- 25455235 TI - No health without perinatal mental health. PMID- 25455236 TI - Advancing HIV prevention science: the roads from Cape Town. PMID- 25455237 TI - A new phenotypic marker of hypertrophic cardiomyopathy. PMID- 25455239 TI - Ebola: fever definitions might delay detection in non-epidemic areas. PMID- 25455240 TI - Tuberculosis control: hard questions. PMID- 25455241 TI - Tuberculosis control: hard questions - Authors' reply. PMID- 25455242 TI - Blood pressure lowering and cardiovascular risk. PMID- 25455243 TI - Blood pressure lowering and cardiovascular risk - Authors' reply. PMID- 25455244 TI - Blood pressure lowering and cardiovascular risk. PMID- 25455245 TI - Blood pressure lowering and cardiovascular risk. PMID- 25455246 TI - Mosquito control might not bolster imperfect dengue vaccines. PMID- 25455247 TI - Letter to global health agency leaders on the importance of surgical indicators. PMID- 25455248 TI - Non-psychotic mental disorders in the perinatal period. AB - Mental disorders are among the most common morbidities of pregnancy and the postnatal period, and can have adverse effects on the mother, her child, and family. This Series paper summarises the evidence about epidemiology, risk factors, identification, and interventions for non-psychotic mental disorders. Although the phenomenology and risk factors for perinatal mental disorders are largely similar to those for the disorders at other times, treatment considerations differ during pregnancy and breastfeeding. Most randomised controlled trials have examined psychosocial and psychological interventions for postnatal depression, with evidence for effectiveness in treating and preventing the disorder. Few high-quality studies exist on the effectiveness or safety of pharmacological treatments in the perinatal period, despite quite high prescription rates. General principles of prescribing of drugs in the perinatal period are provided, but individual risk-benefit analyses are needed for decisions about treatment. PMID- 25455249 TI - Bipolar disorder, affective psychosis, and schizophrenia in pregnancy and the post-partum period. AB - The perinatal period is associated with an increased risk of severe mental disorders. We summarise the evidence regarding the epidemiology, risk factors, and treatment of severe mental illness in relation to childbirth, focusing on bipolar disorder, affective psychosis, and schizophrenia. We discuss women with ongoing chronic conditions and those with the onset of new episodes of post partum psychosis. Despite the importance of perinatal episodes, with suicide a leading cause of maternal death, few studies are available to guide the management of women with severe mental disorders in pregnancy and the post-partum period. However, general principles of management are discussed, including the need for an individual risk-benefit analysis for each woman. PMID- 25455250 TI - Effects of perinatal mental disorders on the fetus and child. AB - Perinatal mental disorders are associated with increased risk of psychological and developmental disturbances in children. However, these disturbances are not inevitable. In this Series paper, we summarise evidence for associations between parental disorders and offspring outcomes from fetal development to adolescence in high-income, middle-income, and low-income countries. We assess evidence for mechanisms underlying transmission of disturbance, the role of mediating variables (underlying links between parent psychopathology and offspring outcomes) and possible moderators (which change the strength of any association), and focus on factors that are potentially modifiable, including parenting quality, social (including partner) and material support, and duration of the parental disorder. We review research of interventions, which are mostly about maternal depression, and emphasise the need to both treat the parent's disorder and help with associated caregiving difficulties. We conclude with policy implications and underline the need for early identification of those parents at high risk and for more early interventions and prevention research, especially in socioeconomically disadvantaged populations and low-income countries. PMID- 25455251 TI - A non-traumatic splenic rupture leads to diagnosis of underlying abnormality. PMID- 25455253 TI - Electromyographic analysis of shoulder muscles during press-up variations and progressions. AB - Due to the versatility of the press-up it is a popular upper extremity strengthening and rehabilitation exercise. Press-up programmes are often progressed by increasing weight-bearing load and using unstable bases of support. Despite the popularity of the press-up research examining press-up variations is limited. The aim of the study was to examine the influence of common press-up exercises on serratus anterior, infraspinatus, anterior deltoid, pectoralis major and latissimus dorsi muscles overall EMG activity. Twenty-one healthy individuals participated in this study. Surface electrodes were placed on pectoralis major, anterior deltoid, infraspinatus, serratus anterior and latissimus dorsi muscles. Participants were tested under 7 static press-up conditions that theoretically progressively increase weight-bearing load and proprioceptive challenge while surface electromyographic activity was recorded. There was a high correlation between increased weight-bearing load and increased EMG activity for all muscles in stable base conditions. The introduction of the unstable base conditions resulted in an activation decline in all muscles. Within the two-armed press-up the Swiss ball resulted in decreased activation in all muscles except pectoralis major. Serratus anterior demonstrated the greatest activation as a percentage of maximum isometric contraction across all exercises. The findings of this study indicate that by varying the weight-bearing load and base of support whilst in the press-up position results in significantly different demands on shoulder and scapula muscles. PMID- 25455254 TI - Personalized Coaching Systems to support healthy behavior in people with chronic conditions. AB - Chronic conditions cannot be cured but daily behavior has a major effect on the severity of secondary problems and quality of life. Changing behavior however requires intensive support in daily life, which is not feasible with a human coach. A new coaching approach - so-called Personal Coaching Systems (PCSs) - use on-body sensing, combined with smart reasoning and context-aware feedback to support users in developing and maintaining a healthier behavior. Three different PCSs will be used to illustrate the different aspects of this approach: (1) Treatment of neck/shoulder pain. EMG patterns of the Trapezius muscles are used to estimate their level of relaxation. Personal vibrotactile feedback is given, to create awareness and enable learning when muscles are insufficiently relaxed. (2) Promoting a healthy activity pattern. Using a 3D accelerometer to measure activity and a smartphone to provide feedback. Timing and content of the feedback are adapted real-time, using machine-learning techniques, to optimize adherence. (3) Management of stress during daily living. The level of stress is quantified using a personal model involving a combination of different sensor signals (EMG, ECG, skin conductance, respiration). Results show that Personal Coaching Systems are feasible and a promising and challenging way forward to coach people with chronic conditions. PMID- 25455255 TI - The minimum number of contractions required to examine the EMG amplitude versus isometric force relationship for the vastus lateralis and vastus medialis. AB - Studies have demonstrated that the electromyographic (EMG) amplitude versus submaximal isometric force relationship is relatively linear. The purpose of this investigation was to determine the minimum number of contractions required to study this relationship. Eighteen men (mean age = 23 years) performed isometric contractions of the leg extensors at 10-90% of the maximum voluntary contraction (MVC) in 10% increments while surface EMG signals were detected from the vastus lateralis and vastus medialis. Linear regression was used to determine the coefficient of determination, slope coefficient, and y-intercept for each muscle and force combination with successively higher levels included in the model (i.e., 10-30%,... 10-90% MVC). For the slope coefficients, there was a main effect for force combination (P < .001). The pairwise comparisons showed there was no difference from 10-60% through 10-90% MVC. For the y-intercepts, there were main effects for both muscle (vastus lateralis [4.3 MUV RMS] > vastus medialis [-3.7 MUV RMS]; P = .034) and force combination (P < .001), with similar values shown from 10-50% through 10-90% MVC. The linearity of the absolute EMG amplitude versus isometric force relationship for the vastus lateralis and vastus medialis suggests that investigators may exclude high force contractions from their testing protocol. PMID- 25455256 TI - Focusing on drug versus disease mechanisms and on clinical subgrouping to advance personalised medicine in psychiatry. AB - Personalised medicine has finally been featured in psychiatric journals, but psychiatrists have mainly focused on the promise of using disease mechanisms to personalise treatment. Psychiatric disorders such as schizophrenia and depression are not diseases, in the medical sense, and are probably more like syndromes. Instead of spending much time and effort focusing on the mechanisms of diseases that may instead be syndromes, the author believes that psychiatrists should (1) learn more about personalising prescription via drug mechanisms, a pharmacological approach to personalised medicine; and (2) reconsider prior attempts by traditional clinical psychopharmacologists to use sophisticated clinical approaches that try to subdivide psychiatric syndromes into groups that may be more homogenous for treatment response. PMID- 25455252 TI - Sleeping Beauty transposon system for genetic etiological research and gene therapy of cancers. AB - Carcinogenesis is etiologically associated with somatic mutations of critical genes. Recently, a number of somatic mutations and key molecules have been found to be involved in functional networks affecting cancer progression. Suitable animal models are required to validate cancer-promoting or -inhibiting capacities of these mutants and molecules. Sleeping Beauty transposon system consists of a transposon that carries gene(s) of interest and a transposase that recognizes, excises, and reinserts genes in given location of the genome. It can create both gain-of-function and loss-of-function mutations, thus being frequently chosen to investigate the etiological mechanisms and gene therapy for cancers in animal models. In this review, we summarized current advances of Sleeping Beauty transposon system in revealing molecular mechanism of cancers and improving gene therapy. Understanding molecular mechanisms by which driver mutations contribute to carcinogenesis and metastasis may pave the way for the development of innovative prophylactic and therapeutic strategies against malignant diseases. PMID- 25455257 TI - Neuroinflammation as a possible link between cannabinoids and addiction. AB - OBJECTIVE: Substance dependence disorder is a chronically relapsing condition characterised by neurobiological changes leading to loss of control in restricting a substance intake, compulsion and withdrawal syndrome. In the past few years, (endo)cannabinoids have been raised as a possible target in the aetiology of drug addiction. On the other hand, although the exact mechanisms of the genesis of addiction remain poorly understood, it is possible that neuroinflammation might also play a role in the pathophysiology of this condition. Studies demonstrated that (endo)cannabinoids act as immunomodulators by inhibiting cytokines production and microglial cell activation. Thus, in the present review, we explore the possible role of neuroinflammation on the therapeutic effects of cannabinoids on drug addiction. METHODS: We conducted an evidence-based review of the literature in order to assess the role of cannabinoids on the neuroinflammatory hypothesis of addiction (terms: addiction, cannabinoids and inflammation). We searched PubMed and BioMedCentral databases up to April 2014 with no date restrictions. RESULTS: In all, 165 eligible articles were included in the present review. Existing evidence suggests that disruption in cannabinoid signalling during the drug addiction process leads to microglial activation and neuroinflammation. CONCLUSION: The literature showed that inflammation and changes in endocannabinod signalling occur in drug abuse; however, it remains uncertain whether these changes are causally or coincidentally associated with addiction. Additional studies, therefore, are needed to elucidate the contribution of neuroinflammation on the behavioural and neuroprotective effects of cannabinoids on drug addiction. PMID- 25455259 TI - Semen effects on insemination outcomes in sows. AB - Sows (n=1205) were artificially inseminated with semen from single sires (n=166). Semen was previously analysed for sperm concentration, motility, velocity, morphology (using DIC microscopy) and membrane integrity, sperm clump score, temperature on arrival and pH. Percent normal sperm influenced both numbers of pigs born alive (P<0.01) and litter size (P<0.05) which, in turn, was also influenced by abnormal sperm head morphology (P<0.05) and retained distal cytoplasmic droplets (P<0.01). Percent stillbirths were influenced by sperm flagellar beat cross frequency (P<0.05) and semen arrival temperature (P<0.05). PMID- 25455258 TI - Shone variant with large eustachian valve: implication for repair and heart transplantation. AB - We present a case of a neonate with Shone complex in addition to the underdevelopment of the right ventricle associated with dysplasia and stenosis of the tricuspid valve. Because of lack of effective surgical options, the patient was transplanted at the age of 8days. A gradient was noted in the postoperative period across the inferior vena cava anastomosis. At reoperation, a prominent myxomatous Eustachian valve was resected. We believe the large Eustachian valve was likely responsible for the right-sided pathology. PMID- 25455260 TI - Roles of SIRT1 in granulosa cell apoptosis during the process of follicular atresia in porcine ovary. AB - Ovarian follicular atresia is characterized by granulosa cell apoptosis, however, the exact mechanism is still unclear. Sirtuin 1 (SIRT1) is a NAD(+)-dependent deacetylase, which is associated with apoptosis in several of cell types, but its exact role in ovarian granulosa cell apoptosis is not clearly defined. In present study, we identified the involvement of SIRT1 in the process of follicle degeneration, which is known as "follicular atresia", both from in vivo models and cell culture data. The results of immunohistochemistry showed that SIRT1 was widely detected in non-apoptotic granulosa cells of follicles, but significantly decreased during the process of granulosa cell apoptosis. Quantitative real-time PCR and Western blot analysis showed that the expression levels of SIRT1 mRNA and protein were increased (P<0.05) during follicular atresia. In order to provide more evidences elucidating the roles of SIRT1 during the process of follicular atresia, granulosa cells were cultured in vitro with resveratrol which acts as a potent activator of SIRT1. Results showed that resveratrol caused a dose dependent increase in both SIRT1 mRNA and protein levels. Meanwhile, apoptotic rate of granulosa cell was increased (P<0.01) in a dose-dependent manner. Additionally, resveratrol significantly increased the expression levels of Caspase-3 (P<0.01) and Bax mRNA (P<0.01), while Bcl-2 mRNA level was significantly decreased (P<0.01). Thus, our results suggest that SIRT1 may play important roles in the regulation of granulosa cell apoptosis during follicular atresia in porcine ovary. PMID- 25455261 TI - Testicular disorder of sex development in four cats with a male karyotype (38,XY; SRY-positive). AB - The molecular background of disorders of sex development (DSD) in cats is poorly recognized. In this study we present cytogenetic, molecular and histological analyses of four cats subjected for the analysis due to ambiguous external genitalia. Three cases, with rudimentary penises and an abnormal position of the urethral orifice, represented different types of hypospadias. The fourth case had a normal penis, a blind vulva and spermatogenetically active testes. Histological studies showed structures typical of testes, but spermatogenic activity was observed in two cats only. All the cats had a normal male chromosome complement (38,XY) and the Y-chromosome linked genes (SRY and ZFY) were also detected. Fluorescent in situ hybridization (FISH), with the use of the feline BAC probe harboring the SRY gene, excluded the possibility of chromosome translocation of the Y chromosome fragment carrying the SRY gene onto another chromosome. Sequencing of four candidate genes (SRY--sex determining region Y; AR--androgen receptor; SRD5A2--steroid-5-alfa reductase 2 and MAMLD1--mastermind-like domain containing (1) revealed one SNP in the SRY gene, one common polymorphism in exon 1 of the AR gene (tandem repeat of a tri-nucleotide motif--CAG), six polymorphisms (5 SNPs and 1 indel) in the SRD5A2 gene and one SNP in the MAMLD1 gene. Molecular studies of the candidate genes showed no association with the identified polymorphisms, thus molecular background of the studied DSD phenotypes remains unknown. PMID- 25455262 TI - Using health information technology to reduce regional health inequality in Taiwan. PMID- 25455263 TI - Percutaneous endoscopic gastrostomy placement in Taiwan. PMID- 25455264 TI - Reemerging threat of hepatitis A among men who have sex with men in Taiwan. PMID- 25455265 TI - Green tea extract supplementation depresses carbon tetrachloride-induced liver injury. PMID- 25455266 TI - Outdoor weathering of facial prosthetic elastomers differing in Durometer hardness. AB - STATEMENT OF PROBLEM: Facial prosthetic elastomers with wide ranges in hardness are available, yet material weatherability is unknown. PURPOSE: The purpose of this study was to assess color, Durometer hardness, and tensile property changes after 3000 hours of outdoor weathering. MATERIAL AND METHODS: Unpigmented elastomers with Durometer hardness 5, 30, 50, 70, and A-2186 were polymerized into dumbbells (ASTM D412) and disks, 34 mm in diameter by 6 mm thick. Materials were subjected to outdoor or time passage environments for 3000 hours. CIELab color (n=5), Durometer hardness (n=5), and tensile mechanical properties (n=10) were measured at 0 and 3000 hours, and group differences were assessed by material and weathering condition (ANOVA/Tukey, alpha=.05). RESULTS: Except for A 2186, the mean Durometer changes for all materials were 1 unit or less, with no significant differences observed between time passage and weathered groups (P>=.05). Three-thousand-hour tensile mechanical property results demonstrated nonsignificant differences between time passage and weathered materials but significantly changed properties from immediately tested materials (P<.001). Outdoor weathering induced perceptible but acceptable color changes (1.7<=DeltaE*<=2.6) for elastomers with Durometer hardness 5 and 30 and A-2186. CONCLUSIONS: With a few exceptions, outdoor weathering produced relatively small changes in color, Durometer hardness, or tensile properties compared with time passage. PMID- 25455267 TI - Mechanical behavior and color change of facial prosthetic elastomers after outdoor weathering in a hot and humid climate. AB - STATEMENT OF PROBLEM: A common reason for replacing a maxillofacial prosthesis is the deterioration of its properties. PURPOSE: The purpose of this study was to compare the effect of weathering in a hot and humid climate on the tear strength, tensile strength, modulus of elasticity, elongation percentage, and color of 3 maxillofacial materials. MATERIAL AND METHODS: Three silicone materials were tested. Specimens were exposed to outdoor weathering for 6 months in a hot and humid environment. Tear and tensile strengths were measured with a universal testing machine before and after outdoor weathering. Color change was evaluated by recording L*, a*, and b* values at base line and after outdoor weathering with a spectrophotometer. The DeltaE, DeltaL*, Deltaa*, and Deltab* of the specimens were calculated. Data were analyzed with 2-way ANOVA and the post hoc Scheffe test (alpha=.05). RESULTS: For all tested elastomers, outdoor weathering decreased the tear strength and modulus of elasticity values significantly (P<.001). Also, weathering reduced percentage elongation values significantly (P<.05). Tensile strength values were significantly reduced for TechSil S25 and MED-4210 specimens only (P<.05). The effect of weathering on the color of pigmented specimens was greater than the acceptable value (DeltaE>3.0). The color change (DeltaE) of pigmented specimens ranged from 4.31 to 6.68. A-2186 silicone elastomer experienced the greatest color changes (P<.05). Within nonpigmented specimens, none of the tested silicone elastomers showed significant color changes (P>.05). CONCLUSIONS: Outdoor weathering in a hot and humid climate adversely affected the properties of silicone elastomers. The heat-polymerized TechSil S25 elastomer showed better mechanical durability and color stability compared with the room-temperature polymerized A-2186 and MED-4210 materials. TechSil S25 showed the greater values of tear and tensile strengths and elongation of specimens exposed to outdoor weathering conditions. It also showed the least amount of color change among the pigmented specimens exposed to outdoor weathering. PMID- 25455268 TI - The increasing genomic complexity of acute myeloid leukemia. AB - Therapy of acute myeloid leukemia (AML) is impacted by the increasing genomic complexity of the disease. Multiple targets as expressed by genetics and mutations and the relationships between them add another layer of intricacy to the prognosis and treatment of the disease. It is becoming increasingly apparent that the interactions between mutations are of utmost importance, particularly from a prognostic standpoint. For example, inv(16) or 6(16; 16) AML frequently involves a second genetic lesion that significantly impacts prognosis. In addition, epigenetic changes, including DNA methylation, are becoming increasingly integrated into the genetic landscape and may also have prognostic impact. Despite increased understanding of the genetic and epigenetic aspects of AML, the outcome for AML patients has not changed significantly. Until it does, further inquiry into the genomic complexity of the disease and advances in drug development are needed. PMID- 25455269 TI - Fanconi anemia and the development of leukemia. AB - Fanconi anemia (FA) is a rare autosomal recessive cancer-prone inherited bone marrow failure syndrome, due to mutations in 16 genes, whose protein products collaborate in a DNA repair pathway. The major complications are aplastic anemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and specific solid tumors. A severe subset, due to mutations in FANCD1/BRCA2, has a cumulative incidence of cancer of 97% by age 7 years; the cancers are AML, brain tumors, and Wilms tumor; several patients have multiple events. Patients with the other genotypes (FANCA through FANCQ) have cumulative risks of more than 50% of marrow failure, 20% of AML, and 30% of solid tumors (usually head and neck or gynecologic squamous cell carcinoma), by age 40, and they too are at risk of multiple adverse events. Hematopoietic stem cell transplant may cure AML and MDS, and preemptive transplant may be appropriate, but its use is a complicated decision. PMID- 25455271 TI - Clonal evolution of pre-leukemic hematopoietic stem cells precedes human acute myeloid leukemia. AB - Massively parallel DNA sequencing has uncovered recurrent mutations in many human cancers. In acute myeloid leukemia (AML), cancer genome/exome resequencing has identified numerous recurrently mutated genes with an average of 5 mutations in each case of de novo AML. In order for these multiple mutations to accumulate in a single lineage of cells, they are serially acquired in clones of self-renewing hematopoietic stem cells (HSC), termed pre-leukemic HSC. Isolation and characterization of pre-leukemic HSC have shown that their mutations are enriched in genes involved in regulating DNA methylation, chromatin modifications, and the cohesin complex. On the other hand, genes involved in regulating activated signaling are generally absent. Pre-leukemic HSC have been found to persist in clinical remission and may ultimately give rise to relapsed disease through the acquisition of novel mutations. Thus, pre-leukemic HSC may constitute a key cellular reservoir that must be eradicated for long-term cures. PMID- 25455272 TI - Management of persistent AML at day 14. AB - A common occurrence in management of acute myeloid leukemia (AML) is persistence of disease in the first post-treatment marrow, typically obtained 14-21 days after initiation of therapy. Here we will briefly discuss the prognostic significance of this finding and the relative values of morphology and multiparameter flow cytometry (MPFC) in assessing persistent AML. We will then consider the therapeutic options for persistent AML: (a) repetition of the first course of therapy, most frequently 3 days of daunorubicin or idarubicin followed by 7 days of cytarabine (ara-C) (hereafter "3 + 7"), (b) change to different chemotherapy, often "high-dose ara-C" (HiDAC) +/- other agents, (c) immediate allogeneic hematopoietic cell transplantation (HCT), or (d) HiDAC with HCT done in HiDAC-induced aplasia and using a conditioning regimen other than HiDAC. Since it is generally accepted that response to azacitidine or decitabine requires several months, the remarks here principally apply to patients not given these drugs, but rather given ara-C-containing therapy. PMID- 25455270 TI - Advances in T-cell therapy for ALL. AB - CD19-directed chimeric antigen receptor T cells (CART19 or CTL019) have been used with success in pediatric and adult acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL) patients. While this therapy has caused toxicities, including cytokine release syndrome and macrophage activation syndrome, these conditions are reversible with IL-6 blockade using the monoclonal antibody tocilizumab. Furthermore, 90% of the very high-risk patients who underwent infusion with CTL019 achieved a complete response, despite the fact that they previously failed multiple therapies and/or transplant. With improved cell persistence, this immunotherapy may one day prove to be more than a bridge to transplant and may in fact be a transplant alternative. PMID- 25455273 TI - Are adjuncts to induction chemotherapy worthwhile in the treatment of acute myeloid leukemia? AB - Research in non-transplant therapy of patients with acute myeloid leukemia (AML) has been focused on approaches to improve the efficacy of the backbone of cytarabine and anthracycline induction and consolidation regimens through modifications of dose and schedule of these agents and the addition of other cytotoxic agents. More recent advances in understanding the molecular biology of the disease have not only led to better prediction of responsiveness to these traditional regimens, but have also led to the identification of molecular targets for development of novel agents. Future research is likely to focus on determining which candidates are the best among such novel agents and what is the most appropriate way of incorporating them into the existing chemotherapy regimens. Identification of potent targeted agents may even have the potential of replacing cytotoxic therapy at least in some subsets of AML. PMID- 25455275 TI - Optimal dose and schedule of consolidation in AML: is there a standard? AB - Approximately 35%-40% of younger adults with acute myeloid leukemia (AML) can be cured using higher doses of cytosine arabinoside (ara-C) as post remission consolidation. Earlier studies focused on higher doses of 3 gms/m(2), but since then numerous studies evaluating differences in dose, schedule, number of courses, and the addition of other agents, suggest that an intermediate-dose of ara-C may offer the greatest benefit to most patients with less toxicity than with higher dose regimens. In retrospect, this was predictable by the cellular pharmacology of ara-C. Perhaps most importantly, the overall outcome has not changed in the past 2-3 decades, indicating that the limits of available chemotherapy have been defined for AML. This review examines studies that have established the various dosing options and considers whether there is a true standard for post remission therapy for patients with AML. PMID- 25455274 TI - Will novel agents for ALL finally change the natural history? AB - Pediatric acute lymphoblastic leukemia (ALL) cure rates have markedly improved over the past years to approximately 85%, but remain at 40%-50% in adults. Redefining current adult chemotherapy regimens is likely to improve the natural course of the disease, but new agents are needed. Immunotherapy approaches for pre-B ALL are in the forefront of research on novel agents; in particular, advances are being made in manipulating autologous T cells either by infusion of a bifunctional antibody (eg, blinatumomab) or by ex vivo genetic modification of chimeric antigen receptors (CARs). The natural course of Philadelphia positive ALL has already improved by targeting ABL/BCR1. Other mutated genes are being discovered and novel small molecules that target their products are being studied in clinical trials. Finally, ALL is a heterogeneous disease and novel agents are likely to impact the natural course of smaller populations of biologically defined ALL subtypes. PMID- 25455276 TI - MRD in AML: it is time to change the definition of remission. AB - The possibility of defining residual disease far below the morphological level of 5% blast cells is changing the landscape of risk classification in acute myeloid leukemia (AML). The so-called minimal residual disease (MRD) approach at this time can establish the presence of leukemia cells down to levels of 1:1000 1:10(6) white blood cells, compared to 1:20 for morphology. Availability of the newer and more sensitive technology to quantify the level of leukemic burden raises the issue of whether MRD should emerge as a new definition of complete response. This paper explores some of the issues surrounding such a change in definition. PMID- 25455277 TI - Alternative donor transplantation for adults with acute leukemia. AB - Allogeneic hematopoietic cell transplantation (HCT) from a matched related donor (MRD) is the preferred therapy for many adults with acute leukemia. Yet most patients do not have matched siblings, and the numbers who do will continue to drop as the average number of children per couple in the United States continues to decline. Recent reports show little difference in the outcomes of matched related and matched unrelated transplants for acute leukemia. Additionally, survival rates at 3-5 years after transplant appear to be generally similar following matched related, matched unrelated, single antigen mismatched unrelated, double cord blood and, perhaps even after haplo-identical transplants. Nevertheless, there are differences between stem cell sources that should be considered in the choice of donor. The following review provides some perspective on the identification of the best stem cell sources for patients who do not have matches within their families. PMID- 25455278 TI - Unrelated donor transplantation: peripheral blood or bone marrow--does it matter? AB - Over the past decade, the use of peripheral blood progenitor cells (PBPC) has increased and now accounts for 70%-75% of grafts used for unrelated donor transplantation in adults with hematologic malignancy. It is important to recognize the shift in clinical practice from transplantation of bone marrow (BM) to PBPC occurred largely without adequate clinical data to support the change. It is presumed the change in clinical practice is attributed to results of randomized clinical trials in the setting of HLA-matched sibling transplantations. The results of these trials showed better engraftment but increased risk of acute graft-versus-host disease (GVHD) with PBPC and possibly better survival for advanced leukemia. However, the results of HLA-matched sibling transplants may differ from that after unrelated donor transplants. There is greater genetic diversity between unrelated adult donors and their recipients and therefore greater risks of GVHD even if the donor and recipient are fully HLA matched. This review explores the relative merits of transplantation of PBPC relative to BM for myeloablative and reduced-intensity conditioning unrelated donor transplantation for hematologic cancers in adults. PMID- 25455279 TI - Improved accuracy of acute graft-versus-host disease staging among multiple centers. AB - The clinical staging of acute graft-versus-host disease (GVHD) varies significantly among bone marrow transplant (BMT) centers, but adherence to long standing practices poses formidable barriers to standardization among centers. We have analyzed the sources of variability and developed a web-based remote data entry system that can be used by multiple centers simultaneously and that standardizes data collection in key areas. This user-friendly, intuitive interface resembles an online shopping site and eliminates error-prone entry of free text with drop-down menus and pop-up detailed guidance available at the point of data entry. Standardized documentation of symptoms and therapeutic response reduces errors in grade assignment and allows creation of confidence levels regarding the diagnosis. Early review and adjudication of borderline cases improves consistency of grading and further enhances consistency among centers. If this system achieves widespread use it may enhance the quality of data in multicenter trials to prevent and treat acute GVHD. PMID- 25455280 TI - The new thrombopoietic agenda: impact on leukemias and MDS. AB - The two generations of thrombopoietin (TPO) receptor (R) agonists have had utility in a number of hematologic conditions. However their use has often been surprisingly complex and drawbacks have been revealed in certain conditions more than in others. The first-generation megakaryocyte growth and development factor (MGDF) was discontinued due to the production of antibodies against it that cross reacted with native TPO. Nonetheless it was tested in a wide variety of thrombocytopenic conditions and showed unequivocal efficacy in increasing the number of platelets in certain ones. As a result of lessons learned with MGDF, second-generation TPO-R agonists romiplostim and eltrombopag were initially tested and have been approved for the treatment of chronic immune thrombocytopenia (ITP), thrombocytopenia in hepatitis C, and recently aplastic anemia. These agents have had more mixed outcomes in diseases such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Results of several studies will be discussed. PMID- 25455281 TI - Deriving blood stem cells from pluripotent stem cells for research and therapy. AB - Embryonic stem cells and induced pluripotent stem cells offer promise for research and treatment of hematologic diseases. While broad clinical application in humans is still a distant prospect, there are promising near-term applications in transfusion of platelets and red blood cells. PMID- 25455282 TI - Breast cancer with inguinal node recurrence. AB - Surgery and irradiation for breast cancer may interfere with conventional pathways of spread, leading to bizarre patterns of dissemination through lymphatics or through hematogenous route. Lymphoscintigraphic studies may help identify nodal involvement. Other possible reasons could be occurrence of primary breast cancer in accessory breast tissue retained in the vulva following involution of milk line. We describe a case of triple negative breast cancer, who developed contralateral breast cancer during treatment. Three years later, she developed isolated inguinal nodal metastases, which responded to local radiotherapy and chemotherapy. However, the patient relapsed after 2 years and could not be salvaged thereafter. PMID- 25455283 TI - Decline in facial trauma exposure for plastic surgical trainees? A survey of referrals of facial trauma in the UK. PMID- 25455284 TI - Cone Beam Computed Tomography as a guide to the management of proximal interphalangeal joint fractures. PMID- 25455285 TI - Surgical correction of complex syndactyly with bony fusion using adipofascial flaps for bone and joint surface coverage after finger separation. PMID- 25455286 TI - The anatomical relationship of the superficial radial nerve and the lateral antebrachial cutaneous nerve: A possible factor in persistent neuropathic pain. AB - The superficial branch of the radial nerve (SBRN) is known for developing neuropathic pain syndromes after trauma. These pain syndromes can be hard to treat due to the involvement of other nerves in the forearm. When a nerve is cut, the Schwann cells, and also other cells in the distal segment of the transected nerve, produce the nerve growth factor (NGF) in the entire distal segment. If two nerves overlap anatomically, similar to the lateral antebrachial cutaneous nerve (LACN) and SBRN, the increase in secretion of NGF, which is mediated by the injured nerve, results in binding to the high-affinity NGF receptor, tyrosine kinase A (TrkA). This in turn leads to possible sprouting and morphological changes of uninjured fibers, which ultimately causes neuropathic pain. The aim of this study was to map the level of overlap between the SBRN and LACN. Twenty arms (five left and 15 right) were thoroughly dissected. Using a new analysis tool called CASAM (Computer Assisted Surgical Anatomy Mapping), the course of the SBRN and LACN could be compared visually. The distance between both nerves was measured at 5-mm increments, and the number of times they intersected was documented. In 81% of measurements, the distance between the nerves was >10 mm, and in 49% the distance was even <5 mm. In 95% of the dissected arms, the SBRN and LACN intersected. On average, they intersected 2.25 times. The close (anatomical) relationship between the LACN and the SBRN can be seen as a factor in the explanation of persistent neuropathic pain in patients with traumatic or iatrogenic lesion of the SBRN or the LACN. PMID- 25455288 TI - Prepectoral implant placement and complete coverage with porcine acellular dermal matrix: a new technique for direct-to-implant breast reconstruction after nipple sparing mastectomy. AB - BACKGROUND: Nipple-sparing mastectomy (NSM) and implant-based breast reconstruction are increasingly replacing conventional mastectomy for risk reducing purposes in high-risk patients as well as for therapeutic purposes in breast cancer patients. For implant-based breast reconstruction, generally, subpectoral implant placement with partial detachment of the pectoralis major muscle (PMM) is recommended. The advantage of a potentially better cosmetic result has to be balanced with the disadvantages, such as partial injury of the PMM with subsequent muscular deficit, breast animation, and postoperative pain. We hypothesize that prepectoral implant placement and complete coverage with a porcine acellular dermal matrix (ADM) may provide an alternative to subpectoral implant placement with an excellent cosmetic result, avoiding the disadvantages of subpectoral implant placement. METHODS: In a total of 22 breasts in 13 patients (nine bilateral and four unilateral), NSM and immediate direct-to implant breast reconstruction were performed with prepectoral implant placement. The implant was completely covered by a porcine ADM, which was sutured to the fascia of the PMM and the inframammary fold to keep the implant in place. RESULTS: The cosmetic results were excellent and patients were fully satisfied at a median follow-up of 6 months. Breast animation and implant dislocation could not be observed. Implant rims were not visible, and capsular contractures grade III and IV could not be observed. The complications comprised minimal nipple necrosis in two patients and hemorrhage with evacuation in one patient. CONCLUSION: Prepectoral implant placement and complete coverage with porcine ADM represents a novel approach and a feasible alternative to subpectoral implant placement after NSM and implant-based breast reconstruction for patients who prefer their PMM to be left intact. PMID- 25455287 TI - Linear regression analysis of Hospital Episode Statistics predicts a large increase in demand for elective hand surgery in England. AB - INTRODUCTION: We integrated two factors, demographic population shifts and changes in prevalence of disease, to predict future trends in demand for hand surgery in England, to facilitate workforce planning. METHODS: We analysed Hospital Episode Statistics data for Dupuytren's disease, carpal tunnel syndrome, cubital tunnel syndrome, and trigger finger from 1998 to 2011. Using linear regression, we estimated trends in both diagnosis and surgery until 2030. We integrated this regression with age specific population data from the Office for National Statistics in order to estimate how this will contribute to a change in workload over time. RESULTS: There has been a significant increase in both absolute numbers of diagnoses and surgery for all four conditions. Combined with future population data, we calculate that the total operative burden for these four conditions will increase from 87,582 in 2011 to 170,166 (95% confidence interval 144,517-195,353) in 2030. DISCUSSION: The prevalence of these diseases in the ageing population, and increasing prevalence of predisposing factors such as obesity and diabetes, may account for the predicted increase in workload. The most cost effective treatments must be sought, which requires high quality clinical trials. Our methodology can be applied to other sub-specialties to help anticipate the need for future service provision. PMID- 25455289 TI - Never fear the venous-lymphatic coupler is here! PMID- 25455290 TI - Rectus sparing approach to left ventricular assist device exchange and use of the omental flap for coverage. PMID- 25455291 TI - Anatomical study of the vascular territories of the maxilla: role of the facial artery in allotransplantation. AB - BACKGROUND: Facial composite tissue allotransplantation has recently become a surgical option. The maxilla, which forms the upper jaw and plays an important role in facial allotransplantation, consists of the maxillary and facial arteries. The maxillary artery is located deep within the tissue and considered the main artery of the maxilla; however, the facial artery is easy to access. The objective of this study was to examine the territories of the maxillary and facial arteries within the maxilla. MATERIALS AND METHODS: We excised and examined 22 maxillae. Of these, 18 were injected with latex and four with India ink. RESULTS: We observed that the ascending palatine artery, which was collateral with the facial artery, vascularized the maxilla through its dorsal part. The facial artery vascularized the maxilla through its ventral part with the philtral and columellar branches of the superior labial artery. Therefore, the facial artery formed, through the nasal and palatine mucosa, an arterial circle with a dorsal and ventral pole. Angiosomes formed by both the facial and maxillary arteries were also observed. The India ink injected into the facial and maxillary arteries delineated specific territories for each artery. DISCUSSION: This study allowed us to determine the anatomical structures that provide vascularization to the maxilla and describe their different forms. The whole of the maxilla was vascularized by the facial artery, despite the caution imposed by several studies on the removal of the facial artery alone. Indeed, the removal technique was found to be safer when it preserved the anastomoses between the facial and maxillary arteries. Therefore, previous clinical experience and our anatomical study definitively demonstrate that the facial artery vascularizes the maxilla. PMID- 25455292 TI - Sexual reassignment surgery in female-to-male transsexuals: an algorithm for subcutaneous mastectomy. AB - INTRODUCTION: Subcutaneous mastectomy is one of the first steps in sexual reassignment in female-to-male transsexuals (FTMTS). The main goal is to masculinize the chest by removing the female contour. In this study, we introduce an algorithm to facilitate choosing the appropriate mastectomy technique depending on morphological aspects. PATIENTS AND METHODS: The records of 173 patients (346 mastectomies) from January 2008 to December 2013 were retrospectively reviewed. The authors conducted four different surgical techniques depending on breast volume, grade of ptosis and skin elasticity. The outcome parameters such as complication rate, patient satisfaction with the aesthetic result, nipple sensitivity and surgical correction rate were obtained and related to the employed technique. RESULTS: From January 2008 to December 2013, we performed 346 mastectomies, of which 48 breasts (13.9%) were treated by a semicircular incision in combination with water-jet-assisted liposuction, 66 breasts (19.1%) by an additional circumferential mastopexy, 170 breasts (49.1%) by an inferior pedicled mammaplasty and 62 breasts (17.9%) by mastectomy with free nipple grafting. The mean operation time lasted 103.6 min. The overall complication rate was 11.8%. Secondary revisions were necessary in 9%. Of the patients, 88% rated the aesthetic results as "very good" or "good." Nipple sensitivity was rated as "very good" or "good" in 80.3% of the breasts. CONCLUSION: FTMTS are a well-informed patient population and therefore increasingly more demanding for aesthetic outcomes. If possible, the most scar saving procedure should be preferred. With ascending degrees of ptosis, a larger skin envelope and lesser elastic skin, an extended-incision technique is required. The presented surgical algorithm facilitates the selection of the appropriate mastectomy technique and shows a high patient satisfaction with the aesthetic result, a preservation of nipple sensitivity and a low rate of complications and secondary aesthetic corrections. PMID- 25455293 TI - Cosmetic surgery and the press: a 22 year review of a growing relationship. PMID- 25455294 TI - Instruments in rhinoplasty: who is behind the name? AB - Rhinoplasty is considered one of the most commonly performed and most challenging operations in facial plastic surgery. The modern facial plastic surgeon utilizes many instruments in performing this procedure. Many of these instruments take their names from the pioneers who invented or designed them. Although meritorious, the recent trend in medicine to move away from eponyms in lieu of descriptive names should not come at the price of forgetting history. Although this communication does not seek to provide a comprehensive history of rhinoplasty or of its pioneers, our aim is to mention several of the salient contributing figures upon whose shoulders we stand and whose eponymous instruments we use commonly in rhinoplasty. PMID- 25455295 TI - Cephalic vein inconsistency in autologous breast reconstruction salvage. PMID- 25455296 TI - Unlilateral microtia, dextrocardia and situs inversus totalis: a possible new association. PMID- 25455297 TI - Public perception of Plastic Surgery. AB - BACKGROUND: Public perception of Plastic Surgery is strongly influenced by the media and may not reflect the broad scope of work within the speciality. The aim of this study was to provide an assessment of the general public's perception of plastic surgical practice and to report the perceived importance of Plastic Surgery relative to other specialities working within a large tertiary referral centre. METHODS: 899 members of the public who attended our Emergency Department completed a questionnaire where they matched eight surgical specialities with 30 operative procedures and ranked the importance of 30 different hospital specialities using a Likert scale. RESULTS: The majority of respondents correctly identified plastic surgeons as performing each of the cosmetic procedures listed (abdominoplasty 63.7%; breast augmentation 59.1%; facelift 61.35%; liposuction 59.7%). Plastic Surgery was identified as the primary speciality involved in breast reconstruction (49.3%) and burns surgery (43.0%). There was poor understanding of the role of plastic surgeons in hand surgery, with only 4.7% of respondents attributing tendon repair to plastic surgeons. Plastic Surgery ranked lowest of 30 specialities in terms of importance in providing care for patients within the hospital. CONCLUSION: Plastic Surgery is often misunderstood within the wider community and misconceptions reflect the influence of the media in highlighting certain aspects of the speciality. It behoves our professional organisations to highlight the importance of Plastic and Reconstructive Surgery within major tertiary referral centres. PMID- 25455298 TI - A novel treatment target for Parkinson's disease. AB - We hypothesize that GPR109A message and expression are up-regulated in individuals with Parkinson's disease (PD). GPR109A is a high-affinity niacin receptor. Niacin is a precursor for NAD-NADH which is needed for dopamine production. Thus, niacin supplementation may serve three purposes: reduce inflammation through GPR109A-related mechanisms, increase dopamine synthesis in the striatum through NADPH supply and increase NAD/NADH ratio to boost mitochondrial functions. GPR109A and its agonists are known to exert anti inflammatory actions in the skin, gut and retina. However these roles are neither anticipated nor established in the CNS. For the first time here we propose the roles of GPR109A and its agonists including niacin in CNS pathology. Moreover we predict that the neuroprotective roles of either niacin or butyrates in CNS occur via GPR109A. PMID- 25455299 TI - Investigating the minimal important difference in ambulation in multiple sclerosis: a disconnect between performance-based and patient-reported outcomes? AB - OBJECTIVE: We sought to estimate the MID on two patient-reported outcome (PRO) measures that are frequently used in multiple sclerosis (MS) clinical research: the MS Walking Scale and the MS Impact Scale-29. We anchored the Minimally Important Differences with an objective measure of ambulation, the accelerometer. METHODS: This secondary analysis used longitudinal data from an observational study of symptoms and physical activity in 269 people with Relapsing-Remitting Multiple Sclerosis. Participants completed a battery of PRO questionnaires, and then wore an accelerometer for seven days at each data collection time point every six months for 2.5 years. Statistical analysis first defined Change Groups on the basis of the performance-based accelerometer scores, anchored to 0.5 standard deviation change; then change was defined on the basis of published and linked MIDs for the PROs. RESULTS: The performance-based (accelerometer) and PRO based change distributions were stable over time. Raw scores among the accelerometer and PRO measures were associated with large effect sizes, and PRO change scores were associated with each other but not with accelerometer change scores. CONCLUSIONS: These findings contradict a central assumption that may underlie clinical research studies: that a cross-sectional correlation implies that change in PROs will correspond with change in behavior/performance. Possible explanations related to accuracy of the performance-based measure, as well as response shift effects on the PROs are discussed. PMID- 25455300 TI - Enriched environment induces angiogenesis and improves neural function outcomes in rat stroke model. AB - Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia/reperfusion injury has neuroprotective benefits in animal models, including enhancing functional recovery after ischemic stroke. However, the mechanism underlying this effect remains unclear. To clarify this critical issue, the current study investigated the effects of EE on the improvement of damaged neural function and the induction of angiogenesis. Adult rats were subjected to ischemia induced by middle cerebral artery occlusion followed by reperfusion. Neurological status scores were used to evaluate neural function on postoperative days 2, 7, and 14. A beam-walking task was used to test the recovery of motor behavior on postoperative days 2, 5, 10, and 15. We also used a Morris water maze task to examine whether EE protected learning and memory performance. The specific marker of angiogenesis of CD31 was examined by western blot. Angiogenesis around the peri-infarction region was assayed by laser scanning confocal microscopy (LSCM) after 14 days of EE exposure starting 24h after ischemia. Neurological status scores of animals in the EE group were significantly higher than those in the standard housing condition (SC) control group from the seventh day after ischemic. EE accelerated the recovery of motor coordination and integration and also improved learning and memory performance after cerebral ischemia. Furthermore, EE increased CD31 levels and promoted angiogenesis of cortex in the peri-infarction region compared to the SC group. Neural function outcomes are positively correlated with post-ischemia angiogenesis. These findings suggest that EE plays an important role in the recovery of damaged neural function via regulation of angiogenesis after ischemia. PMID- 25455302 TI - Somatosensory evoked magnetic fields following tongue and hard palate stimulation on the preferred chewing side. AB - Although oral sensory feedback is essential for mastication, whether the cortical activity elicited by oral stimulation is associated with the preferred chewing side (PCS) is unclear. Somatosensory evoked fields were measured in 12 healthy volunteers (6 with the right side as the PCS and 6 with the left side as the PCS) following tongue and hard palate stimulation. Three components were identified over the contralateral (P40m, P60m, and P80m) and ipsilateral [P40m(I), P60m(I), and P80m(I)] hemispheres. Since no component was consistently detected across subjects, we evaluated the cortical activity over each hemisphere using the activated root-mean-square (aRMS), which was the mean amplitude of the 18-channel RMS between 10 and 150ms. For tongue stimulation, the aRMS for each hemisphere was 8.23 +/- 1.55 (contralateral, mean +/- SEM) and 4.67 +/- 0.88 (ipsilateral)fT/cm for the PCS, and 5.11 +/- 1.10 (contralateral) and 4.03 +/- 0.82 (ipsilateral)fT/cm for the non-PCS. For palate stimulation, the aRMS was 5.35 +/- 0.58 (contralateral) and 4.62 +/- 0.67 (ipsilateral)fT/cm for the PCS, and 4.63 +/- 0.56 (contralateral) and 4.14 +/- 0.60 (ipsilateral)fT/cm for the non-PCS. For hard palate stimulation, the aRMS did not differ between the PCS and non-PCS, whereas for tongue stimulation, the contralateral hemisphere aRMS was significantly greater for the PCS than for the non-PCS. Thus, our results show that lateralized cortical activation was associated with the PCS for tongue, but not hard palate, stimulation; a potential reason for this may be the different sensory-inputs between these two areas, specifically the presence or absence of fine motor function. PMID- 25455301 TI - Central nervous system involvement of hypereosinophilic syndrome: a report of 10 cases and a literature review. AB - BACKGROUND: The central nervous system (CNS) may be affected in those cases of peripheral eosinophila without a secondary cause (hypereosinophilic syndrome, HES). The pathomechanism of CNS involvement in HES remained uncertain. METHODS: We included those with CNS symptoms and peripheral eosinophilia (>1500/MUl) at the time of presentation. Those with identifiable causes of eosinophilia were excluded. In addition to data analysis of our cases, we reviewed the literature using the Medline database. RESULTS: Ten patients were recruited. Half of them presented with altered mental status. None of the patients had significant risk factors such as endomyocardial disease (EMD). Their brain magnetic resonance imaging (MRI) showed multiple ischemic lesions in the border zone (BZ) and other cortical areas. In addition to our 10 cases we included 67 cases from a literature review. The total 77 cases were systemically analyzed. We found that the most common type of CNS involvement was cerebrovascular disease (CVD, 63.6%), multifocal lesions in BZ were the most common feature on MRI (45.5%), many patients presented with altered mental status (40.3%), and direct eosinophil infiltration into brain parenchyma was rare in pathologic studies and not found in the patients with CVD. Furthermore, although EMD was one of the major cardiac abnormalities (26.0%), cardiac workup more frequently showed non-EMD or normal findings. Cardiac abnormalities, altered mental status, and higher eosinophil counts were more common in those with poor outcomes, whereas an isolated CNS manifestation was more frequent in those with favorable outcomes. Finally, the presence of altered mental status was the most significant predictor of poor clinical outcomes, whereas isolated CNS involvement and corticosteroid treatment were significant predictors for favorable outcomes. CONCLUSIONS: Multiple lesions on MRI were suggestive of an embolic mechanism, but diagnostic workup failed to find significant risk factors such as EMD in the most cases. Impaired anticoagulation by eosinophilic cationic proteins could be an alternative mechanism. Direct invasion of eosinophils into the CNS was rare and those cases with isolated CNS manifestations showed a better prognosis. The preferential indirect involvement of CNS by eosinophils ("CNS-tropism") may underlie the neurological manifestations of HES. Early administration of corticosteroid after ruling out secondary causes can be beneficial in HES with CNS manifestation. PMID- 25455303 TI - Apathy in multiple sclerosis: a validation study of the apathy evaluation scale. AB - BACKGROUND: Apathy is defined as lack of motivation affecting cognitive, emotional, and behavioral domains and is usually assessed by standardized scales, such as the Apathy Evaluation Scale (AES). Recently, apathy has been recognized as a frequent behavioral symptom in multiple sclerosis (MS). OBJECTIVE: To evaluate applicability and clinical-metric properties of AES in MS and the agreement between patients' and caregivers' evaluation of apathy. MATERIALS AND METHODS: Seventy non-demented MS patients underwent a thorough clinical and neuropsychological assessment, including evaluation of apathy according to established clinical criteria. All patients also completed the self-report version of AES (AES-S). RESULTS: AES-S was easy to administer and acceptable, and showed fair internal consistency (Cronbach's alpha, alpha=0.87). The factorial analysis identified three factors, representing the cognitive dimension (alpha=0.87), a general aspect of apathy (alpha=0.84), and the behavioral emotional aspects (alpha=0.74), respectively. The factors were significantly correlated with the total AES score (all rrho>=0.73, p<0.001). The total AES score showed fair convergent validity (rrho=0.38) and discriminant validity when compared to Expanded Disability Status Scale (rrho=0.38), Mini Mental State Examination (rrho=-0.17), and Hamilton Depression Rating Scale (rrho=0.37). Receiver-operating characteristic curve analysis demonstrated that a cutoff>35.5 can identify clinically significant apathy with good sensitivity (88%) and specificity (72%); such a cutoff identified apathy in 35.7% of our sample of non demented MS patients. Total AES score was significantly correlated with reduced global cognitive efficiency and more severe frontal executive dysfunctions. CONCLUSION: AES-S can be considered as an easy and reliable tool to assess apathy in non-demented MS. The use of AES-S in non-demented MS patients is clinically important since apathy is relatively frequent and is correlated to more severe cognitive dysfunction. PMID- 25455304 TI - Calf muscle involvement in Becker muscular dystrophy: when size does not matter. AB - INTRODUCTION: Calf hypertrophy is a common feature in Becker muscular dystrophy (BMD), and it is still debated to which extent fatty degeneration or true muscle hypertrophy account for it. We wanted to investigate the relative contribution of these two components using a simple image analysis approach and their possible correlation with disease severity. METHODS: Twenty-nine BMD patients' MRI scans were analyzed. A semiquantitative visual score assessing fatty replacement of calf muscles (calf MRI score, CMS) was calculated and correlated with the cross sectional area (CSA) of lower leg posterior compartment muscles, digitally measured on acquired images. RESULTS: The correlation between CSA and CMS was not significant. CMS in contrast correlated with disease severity (p<0.001) while CSA did not (p=0.969). CONCLUSIONS: In BMD, a major contribution to calf hypertrophy is provided by real muscle hypertrophy rather than by fatty degeneration. CMS appears to be a potential surrogate marker of disease severity. PMID- 25455305 TI - Diagnosis of cystathionine beta-synthase deficiency by genetic analysis. AB - Intellectual disability like other common diseases is often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. We present diagnosis of cystathionine beta-synthase (CBS) deficiency in a multiply affected Iranian family with obvious intellectual disability based on whole genome SNP homozygosity mapping. Diagnosis based on clinical presentations had not been made because of unavailability of appropriate medical services. Genetic analysis led to identification of homozygous c.346G>A in CBS that causes p.Gly116Arg in the encoded protein, cystathionine beta-synthase. CBS is the most common causative gene of homocystinurea. Later, the same mutation was found in three other apparently unrelated Iranian homocystinuria patients. p.Gly116Arg was reported once before in a Turkish patient, suggesting it may be a common CBS deficiency causing mutation in the Middle East. Clinical features of the patients are reported that evidence to variable presentations caused by the same mutation. Finally, observations in heterozygous carriers of the mutation suggest data that a single allele of the p.Gly116Arg causing mutation may have phenotypic consequences, including cardiac related phenotypes. Our study attests to the powers of genetic analysis for diagnosis especially for some forms of intellectual disability, with known genetic causing agents. PMID- 25455306 TI - Faciobrachial dystonic seizures and antibodies to Lgi1 in a 92-year-old patient: a case report. PMID- 25455307 TI - Sensory ataxia associated with Graves' disease. PMID- 25455308 TI - Indirect meta-analytical comparison of azathioprine and of beta interferon effectiveness in all forms of multiple sclerosis pooled together. PMID- 25455310 TI - Appendicitis after right colectomy? How can this be possible? AB - This case report concerns a man with appendicitis following right colectomy. PMID- 25455311 TI - Sub-xiphoid surgical pericardial drainage for cardiac tamponnade. PMID- 25455309 TI - The fidelity of synaptonemal complex assembly is regulated by a signaling mechanism that controls early meiotic progression. AB - Proper chromosome segregation during meiosis requires the assembly of the synaptonemal complex (SC) between homologous chromosomes. However, the SC structure itself is indifferent to homology, and poorly understood mechanisms that depend on conserved HORMA-domain proteins prevent ectopic SC assembly. Although HORMA-domain proteins are thought to regulate SC assembly as intrinsic components of meiotic chromosomes, here we uncover a key role for nuclear soluble HORMA-domain protein HTP-1 in the quality control of SC assembly. We show that a mutant form of HTP-1 impaired in chromosome loading provides functionality of an HTP-1-dependent checkpoint that delays exit from homology search-competent stages until all homolog pairs are linked by the SC. Bypassing of this regulatory mechanism results in premature meiotic progression and licensing of homology independent SC assembly. These findings identify nuclear soluble HTP-1 as a regulator of early meiotic progression, suggesting parallels with the mode of action of Mad2 in the spindle assembly checkpoint. PMID- 25455312 TI - Towards novel therapeutics for HIV through fragment-based screening and drug design. AB - Fragment-based drug discovery has been applied with varying levels of success to a number of proteins involved in the HIV (Human Immunodeficiency Virus) life cycle. Fragment-based approaches have led to the discovery of novel binding sites within protease, reverse transcriptase, integrase, and gp41. Novel compounds that bind to known pockets within CCR5 have also been identified via fragment screening, and a fragment-based approach to target the TAR-Tat interaction was explored. In the context of HIV-1 reverse transcriptase (RT), fragment-based approaches have yielded fragment hits with mid-MUM activity in an in vitro activity assay, as well as fragment hits that are active against drug-resistant variants of RT. Fragment-based drug discovery is a powerful method to elucidate novel binding sites within proteins, and the method has had significant success in the context of HIV proteins. PMID- 25455313 TI - Prevention of perinatal transmission of human immunodeficiency virus. AB - The reproductive health needs of all women of childbearing age should routinely address effective and appropriate contraception, safer sex practices, and elimination of alcohol, illicit drugs and tobacco should pregnancy occur. Combined antepartum, intrapartum, and infant antiretroviral (ARV) prophylaxis are recommended because ARV drugs reduce perinatal transmission by several mechanisms, including lowering maternal viral load and providing infant pre- and post-exposure prophylaxis. Scheduled cesarean delivery at 38 weeks with IV AZT decreases the risk of perinatal transmission if the HIV RNA is greater than 1000 copies/mL or if HIV levels are unknown near the time of delivery. Oral AZT should generally be given for at least 6 weeks to all infants perinatally exposed to HIV to reduce perinatal transmission of HIV. PMID- 25455315 TI - Barrier methods for human immunodeficiency virus prevention. AB - Condoms remain the most effective barrier against the sexual transmission of the human immunodeficiency virus (HIV). Male condoms have proven to be 80% to 90% effective, and female condoms have similar results. Poor adherence and improper use limit their effectiveness. In addition to condoms, microbicides are a promising barrier against HIV transmission. More than 50 candidate topical microbicide compounds have undergone preclinical or clinical testing in the last 10 years, but there are currently no US Food and Drug Administration (FDA) approved compounds. Rectal microbicides are also being developed, as anal receptive sex is an effective mode of HIV transmission. PMID- 25455316 TI - HIV/AIDS. PMID- 25455314 TI - Pre-exposure prophylaxis for human immunodeficiency virus: the past, present, and future. AB - This article presents an overview of pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) prevention. The authors describe the past animal and human research that has been conducted that informs our current understanding of PrEP; summarize ongoing research in the area, including describing new regimens and delivery mechanisms being studied for PrEP; and highlight key issues that must be addressed in order to implement and optimize the use of this HIV prevention tool. PMID- 25455317 TI - From the Editor's perspective... PMID- 25455318 TI - Screening for peripheral arterial disease in a rural community health setting. AB - Peripheral arterial disease (PAD) is a slow, progressive disease associated with systemic atherosclerosis. It is common in older adults and often underdiagnosed and undertreated. Primary care providers play a key role in the early detection and treatment of PAD by screening patients in clinic who are symptomatic or at risk for PAD. We implemented a quality improvement project in a rural community health clinic to determine the accuracy of an ankle brachial index (ABI) in a clinic setting compared with ABI done in a hospital vascular laboratory before and after additional skills training for the primary care provider. The cost of an ABI screen in the hospital is considerably more than the screen done in a clinic setting. Improving accuracy in the performance of an ABI screen in a rural clinic to match that done in a hospital laboratory would be a considerable cost saving initiative. This project demonstrated that additional provider training, clinical experience, and modification of the procedure resulted in increased accuracy of clinic ABIs when matched with the local hospital vascular laboratory screen. PMID- 25455319 TI - Comparison of calf and brachial blood pressures in infants: is there a difference between calf and brachial blood pressures? AB - The standard of care is to obtain a noninvasive blood pressure (NIBP) measurement from the right upper arm. However, in the pediatric population it is common practice to take blood pressure (BP) measurements from the calf/upper ankle. Nurses commonly take calf NIBPs for many reasons, but there is little evidence to support calf BPs as a reliable site for BP measurement. Furthermore, there is conflicting evidence. Some studies suggest no difference between the calf and the upper arm BPs, whereas others conclude great variability between the two. The purpose of this study was to demonstrate the reliability of calf BPs, by showing no difference between brachial and calf BP measurements in neonates and infants <= 1 year old. From July 2008 to December 2008, a convenience sample of 52 subjects admitted to the Neonatal and Infant Critical Care Unit were enrolled into the study. Limb selection was not randomized. Three BPs were taken from the arm and 3 BPs were taken from the calf. Data were analyzed using a mixed analysis of variance (P = 0.05). The difference was not significant for systolic (P = 0.6159) or mean BP (P = 0.1298), but it was significant for diastolic (P = 0.0263). The authors concluded that these results support the current practice of bedside nurses and contribute to the limited knowledge on this topic. Because there was a difference in the diastolic BPs, further investigation is needed. PMID- 25455320 TI - The lived experiences of patients post coronary angioplasty: a qualitative study. AB - Few qualitative studies have focused on the experiences of patients post angioplasty. A deep understanding of patient experiences of care and the way a treatment can affect their everyday life is particularly important in chronic disease management. The aim of this study was to explore experiences that patients undergo after angioplasty. Using a phenomenological study design, 15 patients participated in individual, face-to-face, semistructured interviews. Data were analyzed using qualitative content analysis. The following core themes emerged from the analysis, which reflect the experiences of patients post angioplasty: (a) Angioplasty is a milestone in the patient's life, (b) living with a mended heart, and (c) psychological distress as an integral part of the patient's life. Participants after angioplasty went through both positive and negative changes in their life. Understanding these experiences is essential to modifying high-risk behaviors while supporting patients through their rehabilitation. PMID- 25455321 TI - Health promotion in the elderly with coronary artery disease. AB - The number of elderly Americans, those over the age of 65 years of age, continues to climb. A lifetime of poor nutrition and lack of exercise has led many elderly patients to experience coronary artery disease (CAD) later in life, leading to invasive procedures and other forms of disease management that contribute to mounting health care costs and lower quality of life. Although health promotion has been accepted as the necessary answer to this problem by many in the healthcare community, many physicians are still lacking in promoting this concept, often due to the lack of insurance reimbursements. This paper will explore three key disciplines linked to health promotion in the elderly and why this topic is so vital for our future. PMID- 25455322 TI - Review of article: Statins: the good, the bad, and the unknown by Gordon H. Sun, MD, MS. PMID- 25455323 TI - Ebola virus disease. PMID- 25455324 TI - A new era in geriatric nursing education. PMID- 25455325 TI - Improving the quality of geriatric nursing care: enduring outcomes from the geriatric nursing education consortium. AB - The nation's aging demography, few nursing faculty with gerontological nursing expertise, and insufficient geriatric content in nursing programs have created a national imperative to increase the supply of nurses qualified to provide care for older adults. Geriatric Nursing Education Consortium (GNEC), a collaborative program of the John A. Hartford Foundation, the American Association of Colleges of Nursing, and the New York University (NYU) Nursing Hartford Institute for Geriatric Nursing, was initiated to provide faculty with the necessary skills, knowledge, and competency to implement sustainable curricular innovations in care of older adults. This article describes the background, step-by-step process approach to the development of GNEC evidence-based curricular materials, and the dissemination of these materials through 6-, 2-, and a half-day national Faculty Development Institutes (FDIs). Eight hundred eight faculty, representing 418 schools of nursing, attended. A total of 479 individuals responded to an evaluation conducted by Baruch College that showed faculty feasibility to incorporate GNEC content into courses, confidence in teaching and incorporating content, and overall high rating of the GNEC materials. The impact of GNEC is discussed along with effects on faculty participants over 2 years. Administrative and faculty-level recommendations to sustain and expand GNEC are highlighted. PMID- 25455326 TI - Transforming graduate nursing education in the context of complex adaptive systems: implications for master's and DNP curricula. AB - The purpose of this article is to describe the evolution and implementation of a graduate nursing program's curricular framework. A number of factors contributed to the realization that the curricular framework needed revision. These factors included the rapid changes occurring in the U.S. health care system, the publication of the 2011 edition of the Essentials of Master's Education in Nursing, and the publication of the Institute of Medicine's report entitled The Future of Nursing: Leading Change, Advancing Health (2010). A careful analysis of key guiding documents resulted in the development of three central, interrelated concepts to guide this revision, namely, relationship-based care, creative inquiry, and leadership. PMID- 25455328 TI - Opportunities, hurdles, solutions, and approaches to transition military veterans into professional nursing programs. AB - Capitalizing on the almost 2.2 million service members returning from Operation Iraqi Freedom and New Dawn (OIF) in Iraq, and Operation Enduring Freedom (OEF) in Afghanistan, baccalaureate educators are encouraged to create realistic, applicable nursing transitional programs for the health and health-related oriented military veterans. Opportunities, hurdles, and solutions related to the veteran's unique socio-economic circumstances of education, finances, and advisement are provided so the potential veteran student is successful within the university's milieu. Transitional nursing educational interventions related to assessment, didactic, and clinical used by two baccalaureate nursing curriculums, including the eLineMilitary* (ELM) Program, provide approaches of how to propel the veteran's journey toward graduation in a professional nursing program. These interventions include modular didactic, competency based education, as well as the concentrated, collegial time within the Faculty/Clinical Coach triad for essential role modeling, care, and skills. PMID- 25455327 TI - A model to develop nurse leaders for rural practice. AB - Rural health disparities are due in part to access barriers to health care providers. Nursing education has been extended into rural areas, yet a limited rural research and practice literature informs the content and delivery of these educational programs. The University Of Virginia School of Nursing through a grant from the Health Resources and Services Administration developed the Nursing Leadership in Rural Health Care (NLRHC) Program. The transformational nursing leadership in rural health care (TNLRHC) model guided the development of NLRHC program content and teaching methods. This article describes the TNLRHC model and how it has steered the integration of rural content into advanced practice nursing (APN) education. The capacity of the TNLRHC model for promoting innovation in APN education is described. Recommendations regarding the future development of APN education are presented. PMID- 25455329 TI - Using a nursing student conduct committee to foster professionalism among nursing students. AB - This article explains how a university nursing program in the United States created and implemented a nursing student code of conduct and a faculty-led nursing student conduct committee to review and adjudicate violations of academic or professional misconduct. The need for and role of the nursing student conduct committee in providing substantive and fair due process is illustrated with two cases. Professional misconduct has been associated with preventable error and patient safety and is of great concern to nurse educators who are entrusted with producing the next generation of nursing professionals. Accountability and consequences for violations of professional standards must be an integral part of the nursing education curriculum throughout the world to ensure quality and safety and mitigate the adverse effects of nursing error. Given the professional and patient safety implication of such violations, the authors believe that it is prudent to have nursing programs adjudicate nursing majors' professional violations as an alternative or supplement to the general university judicial board. PMID- 25455330 TI - Rational versus empirical prediction of nursing student success. AB - Undergraduate and graduate nursing education programs can offer a very limited number of positions to a very large number of student applicants. Although practices vary widely across schools of nursing, it is common in many programs to use rational or holistic judgment when determining which student applicants to admit. The present applied study demonstrates a method and several examples of alternative selection models that can improve administrators' ability to efficiently and effectively identify student applicants with the highest probability of success. The example models are also tested within a sample of students (N = 283) from a very active bachelor of science in nursing program, and recommendations for use are provided. Results clearly support the use of admission formula scores generated from regression-based methods versus admission formula scores generated from a typical rational points-based method of weighting applicant admission criteria. PMID- 25455331 TI - Nursing doctoral faculty perceptions of factors that affect their continued scholarship. AB - This focus group study was undertaken as part of a larger investigation of how the demand for increased production of nurses with doctorates affects doctoral faculty's scholarly productivity. This study provided a basis for development of the national survey questionnaire. Two focus groups that included 29 faculty teaching in doctor of philosophy and/or doctor of nursing practice programs took place at one of two national conferences. The focus group interviews were transcribed and content analyzed for the identification of themes; all members of the research team reached consensus. The three major themes were the demands of teaching, the importance of institutional structure and climate, and the sustainability of one's self, the institution, and the discipline. Participants identified strategies for enhancing scholarly productivity. Findings are limited by the small sample size and the voluntary participation of conference attendees. The strength of emotion that participants revealed underscores the need for nursing leaders to address the increasing academic expectations for faculty. If the profession does not address the needs of its current and future faculty, goals explicated by the Institute of Medicine in The Future of Nursing cannot be achieved, and the health of the nation will suffer. PMID- 25455332 TI - Impact of learning adaptability and time management disposition on study engagement among Chinese baccalaureate nursing students. AB - The aim of this study was to explore the relationships among study engagement, learning adaptability, and time management disposition in a sample of Chinese baccalaureate nursing students. A convenient sample of 467 baccalaureate nursing students was surveyed in two universities in Tianjin, China. Students completed a questionnaire that included their demographic information, Chinese Utrecht Work Engagement Scale-Student Questionnaire, Learning Adaptability Scale, and Adolescence Time Management Disposition Scale. One-way analysis of variance tests were used to assess the relationship between certain characteristics of baccalaureate nursing students. Pearson correlation was performed to test the correlation among study engagement, learning adaptability, and time management disposition. Hierarchical linear regression analyses were performed to explore the mediating role of time management disposition. The results revealed that study engagement (F = 7.20, P < .01) and learning adaptability (F = 4.41, P < .01) differed across grade groups. Learning adaptability (r = 0.382, P < .01) and time management disposition (r = 0.741, P < .01) were positively related with study engagement. Time management disposition had a partially mediating effect on the relationship between study engagement and learning adaptability. The findings implicate that educators should not only promote interventions to increase engagement of baccalaureate nursing students but also focus on development, investment in adaptability, and time management. PMID- 25455333 TI - A study of the influence of nursing education on development of emotional intelligence. AB - The Future of Nursing, Leading Change, Advancing Health (Institute of Medicine 2011) challenged the profession of nursing to assume leadership of interdisciplinary health care teams. Leading these teams requires cognitive ability to manage highly charged and emotional work. Emotional intelligence (EI) is a characteristic necessary to process emotional information for creative problem solving. In addition, emerging evidence indicates there may be an association of nurses' EI and quality patient care (K. Adams et al., 2011). The foundation for development of competencies essential for nursing practice begins with nursing education. This quasi-experimental study investigated if baccalaureate-level nursing education increased the level of EI as operationalized by J. D. Mayer and P. Salovey's (2004) four-branch abilities model. Findings indicated that senior nursing students scored higher on the ability to understand and reason about emotions over pre-nursing students (P < .05); however, pre-nursing students scored higher than senior nursing students on the ability to accurately perceive emotions (P < .05). Regression analysis found that self-estimated grade point average was the only significant predictor of overall EI. Although the senior nursing students demonstrated strength in the ability to reason about emotion, the ability to perceive emotion seemed to have declined. This problem requires further research and action through transformed nursing education. PMID- 25455334 TI - Psychiatric severity and HIV-risk sexual behaviors among persons with substance use disorders. AB - OBJECTIVE: The relationship between mental illness and human-immunodeficiency virus (HIV)-risk sexual behavior among persons with substance use disorders is not well-established because of differences in assessing psychiatric factors (types, symptoms, severity), substance use (diagnosis, survey responses, past substance use), and HIV-risk sexual behaviors (individual measures, combination of sex/drug use risk behaviors) across studies. This study utilized a more global and dimensional aspect of psychiatric issues (problem severity) to examine the relationship with HIV-risk sexual behaviors and substance use among persons with substance use disorders. METHODS: Participants included 224 men and 46 women, with a mean age of 40.4 years (SD = 9.5). The most common substances were heroin/opiates, with 41.4% reporting use of these substances (n = 110), while 27.8% reported using cocaine (n = 74) and 12.8% reported using alcohol (n = 34). Of all participants, 39 (14.4%) were identified as having high psychiatric severity (defined using the psychiatric severity score from the Addiction Severity Index), which was used as an indication of probable comorbid psychiatric and substance use disorders. Among these participants likely to have comorbid disorders, hierarchical linear regression was conducted to examine HIV-risk sexual behaviors (number of partners and unprotected sexual behaviors in the past 30 days) in relation to psychiatric severity, substance use, and gender. RESULTS: Gender (women) and psychiatric severity (higher) were significantly related to greater HIV-risk sexual behaviors. After entering gender and substance use into the regression model, psychiatric severity accounted for another 21.9% of the variance in number of partners and 14.1% of the variance in unprotected sexual behaviors. Overall, the models accounted for 55.5% and 15.6% of the variance, respectively. A significant interaction was found for number of partners (but not frequency of unprotected behavior), such that those higher in psychiatric severity and higher in substance use had a greater number of sexual partners. The model including this interaction term accounted for 63.4% of the variance in number of partners. CONCLUSIONS: Findings suggest psychiatric severity is an underlying risk factor for HIV-risk sexual behavior among persons with substance use disorders who have various psychiatric comorbidities. PMID- 25455335 TI - Assembly of viroplasms by viral nonstructural protein Pns9 is essential for persistent infection of rice gall dwarf virus in its insect vector. AB - Rice gall dwarf virus (RGDV), a plant reovirus, is transmitted by leafhopper vector Recilia dorsalis in a persistent-propagative manner. In a sequential study of RGDV infection of its insect vector, the virus initially infected the filter chamber epithelium, then directly crossed the basal lamina into the visceral muscles, from where it spread throughout the entire midgut and hindgut. Finally, RGDV spread into the salivary glands. During RGDV infection of the continuous cultured cells of R. dorsalis, viroplasm that was mainly comprised of viral nonstructural protein Pns9 was formed and acted as the site of viral replication and assembly of progeny virions. Knockdown of Pns9 expression in cultured insect vector cells using synthesized dsRNAs from the Pns9 gene strongly inhibited viroplasm formation and viral infection. The microinjection of dsRNAs from the Pns9 gene strongly abolished viroplasm formation in the initially infected filter chamber epithelium and prevented viral spread into leafhopper visceral muscles. These results indicated that the assembly of viroplasms was essential for the persistent infection and spread of RGDV in its insect vector. PMID- 25455337 TI - A toolbox for residue iteration decomposition (RIDE)--A method for the decomposition, reconstruction, and single trial analysis of event related potentials. AB - BACKGROUND: Conventionally, event-related brain potentials (ERPs) are obtained by averaging a number of single trials. This can be problematic due to trial-to trial latency variability. Residue iteration decomposition (RIDE) was developed to decompose ERPs into component clusters with different latency variability and to re-synchronize the separated components into a reconstructed ERP. NEW METHOD: RIDE has been continuously upgraded and now converges to a robust version. We describe the principles of RIDE and detailed algorithms of the functional modules of a toolbox. We give recommendations and provide caveats for using RIDE from both methodological and psychological perspectives. RESULTS: RIDE was applied to several data samples to demonstrate its ability to decompose and reconstruct latency-variable components of ERPs and to retrieve single trial variability information. Different functionalities of RIDE were shown in appropriate examples. COMPARISON WITH EXISTING METHODS: RIDE employs several modules to achieve a robust decomposition of ERP. As main innovations RIDE (1) is able to extract components based on the combination of known event markers and estimated latencies, (2) prevents distortions much more effectively than previous methods based on least-square algorithms, and (3) allows time window confinements to target relevant components associated with sub-processes of interest. CONCLUSIONS: RIDE is a convenient method that decomposes ERPs and provides single trial analysis, yielding rich information about sub-components, and that reconstructs ERPs, more closely reflecting the combined activity of single trial ERPs. The outcomes of RIDE provide new dimensions to study brain-behavior relationships based on EEG data. PMID- 25455336 TI - Simian hemorrhagic fever virus: Recent advances. AB - The simian hemorrhagic fever virus (SHFV) genome differs from those of other members of the family Arteriviridae in encoding three papain-like one proteases (PLP1alpha, PLP1beta and PLP1gamma) at the 5' end and two adjacent sets of four minor structural proteins at the 3' end. The catalytic Cys and His residues and cleavage sites for each of the SHFV PLP1s were predicted and their functionality was tested in in vitro transcription/translation reactions done with wildtype or mutant polyprotein constructs. Mass spectrometry analyses of selected autoproteolytic products confirmed cleavage site locations. The catalytic Cys of PLP1alpha is unusual in being adjacent to an Ala instead of a Typ. PLP1gamma cleaves at both downstream and upstream sites. Intermediate precursor and alternative cleavage products were detected in the in vitro transcription/translation reactions but only the three mature nsp1 proteins were detected in SHFV-infected MA104 cell lysates with SHFV nsp1 protein-specific antibodies. The duplicated sets of SHFV minor structural proteins were predicted to be functionally redundant. A stable, full-length, infectious SHFV-LVR cDNA clone was constructed and a set of mutant infectious clones was generated each with the start codon of one of the minor structural proteins mutated. All eight of the minor structural proteins were found to be required for production of infectious extracellular virus. SHFV causes a fatal hemorrhagic fever in macaques but asymptomatic, persistent infections in natural hosts such as baboons. SHFV infections were compared in macrophages and myeloid dendritic cells from baboons and macaques. Virus yields were higher from macaque cells than from baboon cells. Macrophage cultures from the two types of animals differed dramatically in the percentage of cells infected. In contrast, similar percentages of myeloid dendritic cells were infected but virus replication was efficient in the macaque cells but inefficient in the baboon cells. SHFV infection induced the production of pro-inflammatory cytokines, including IL-1beta, IL-6, IL-12/23(p40), TNF-alpha and MIP-1alpha, in macaque cells but not baboon cells. PMID- 25455338 TI - Whole-scale neurobehavioral assessments of photothrombotic ischemia in freely moving mice. AB - BACKGROUND: Neurobehavioral assessments have been considered as an essential component of preclinical research in ischemic stroke. However, real-time neurobehavioral evaluation is seldom applied during ischemia induction as it is usually accompanied with anesthesia. NEW METHOD: We induced photothrombosis in freely moving mice after one-week recovery from cannula implantation surgeries. After rose bengal (RB) injection (100 mg/kg, i.p.), photothrombosis was induced in freely moving mice by 473 nm laser irradiation through the cannulas implanted into unilateral primary motor cortex beforehand. Mice received nimodipine (15 mg/kg, i.p.), a widely used anti-ischemic agent, or vehicle before irradiation. Motor coordination and equilibrium were evaluated by rotarod and rung walk tests throughout the whole process of ischemia. Endurance capacity was assessed by treadmill at 1 day and 7 days after irradiation. Mice were decapitated at different time points post irradiation for TTC (2,3,5-triphenyltetrazolium chloride) staining. RESULTS: Consistent with the results of TTC staining, motor deficits firstly occurred at 15-min post irradiation and aggravated 1-day later, while the capacity improved 3-days later and partially recovered 7-days post irradiation. And, the recovery process was accelerated by nimodipine application. COMPARISON WITH EXISTING METHODS: This method established a precise linkage between focal brain ischemia development and neurobehavioral deficits throughout a full scale of photothrombosis, which avoided the confounding factors of anesthetics and surgeries on neurobehavioral assessments, as infarct was induced in freely moving mice. CONCLUSIONS: This method with high temporal and spatial resolution will be an optimal model for neurobehavioral evaluation in preclinical anti-ischemic drug screening. PMID- 25455339 TI - The frequency and reliability of cortical activity using a novel strategy to present pressure pain stimulus over the lumbar spine. AB - BACKGROUND: The blocked stimulus presentation strategy, in fMRI study designs, is an important means to study brain function related to a particular stimulus. Specifically, applying pressure stimuli perceived as painful to different anatomical regions has been used to improve our understanding of central sensitization, which is an important clinical phenomenon in chronic pain. NEW METHOD: This paper introduces a novel MR-compatible device used to apply pressure pain stimuli to the lumbar spine of 13 subjects in the supine position. We present the frequency of individuals and within-subject reliability of cortical activity in the following brain regions: the primary somatosensory cortex, insula and anterior cingulate cortex bilaterally. RESULTS: Using the novel MR-compatible device, a high frequency of individuals showed cortical activity within the a priori brain regions. There was good to excellent run-to-run reliability for peak voxel, while cluster size was less reliable. We found a higher than expected association between stimulus presentation and movement artifacts. COMPARISON WITH EXISTING METHOD(S): Unlike previous methods, the current strategy can apply pressure stimuli to subjects over the lumbar spine while they lay supine. Previous methods required subjects to lay prone. CONCLUSIONS: This strategy could be used for evaluating pressure stimuli related central sensitization associated with back pain. PMID- 25455340 TI - Volumetric imaging of brain activity with spatial-frequency decoding of neuromagnetic signals. AB - BACKGROUND: The brain generates signals in a wide frequency range (~2840 Hz). Existing magnetoencephalography (MEG) methods typically detect brain activity in a median-frequency range (1-70 Hz). The objective of the present study was to develop a new method to utilize the frequency signatures for source imaging. NEW METHOD: Morlet wavelet transform and two-step beamforming were integrated into a systematic approach to estimate magnetic sources in time-frequency domains. A grid-frequency kernel (GFK) was developed to decode the correlation between each time-frequency representation and grid voxel. Brain activity was reconstructed by accumulating spatial- and frequency-locked signals in the full spectral data for all grid voxels. To test the new method, MEG data were recorded from 20 healthy subjects and 3 patients with verified epileptic foci. RESULTS: The experimental results showed that the new method could accurately localize brain activation in auditory cortices. The epileptic foci localized with the new method were spatially concordant with invasive recordings. COMPARISON WITH EXISTING METHODS: Compared with well-known existing methods, the new method is objective because it scans the entire brain without making any assumption about the number of sources. The novel feature of the new method is its ability to localize high-frequency sources. CONCLUSIONS: The new method could accurately localize both low- and high frequency brain activities. The detection of high-frequency MEG signals can open a new avenue in the study of the human brain function as well as a variety of brain disorders. PMID- 25455341 TI - Extracellular spike detection from multiple electrode array using novel intelligent filter and ensemble fuzzy decision making. AB - BACKGROUND: The information obtained from signal recorded with extracellular electrodes is essential in many research fields with scientific and clinical applications. These signals are usually considered as a point process and a spike detection method is needed to estimate the time instants of action potentials. In order to do so, several steps are taken but they all depend on the results of the first step, which filters the signals. To alleviate the effect of noise, selecting the filter parameters is very time-consuming. In addition, spike detection algorithms are signal dependent and their performance varies significantly when the data change. NEW METHODS: We propose two approaches to tackle the two problems above. We employ ensemble empirical mode decomposition (EEMD), which does not require parameter selection, and a novel approach to choose the filter parameters automatically. Then, to boost the efficiency of each of the existing methods, the Hilbert transform is employed as a pre-processing step. To tackle the second problem, two novel approaches, which use the fuzzy and probability theories to combine a number of spike detectors, are employed to achieve higher performance. RESULTS, COMPARISON WITH EXISTING METHOD(S) AND CONCLUSIONS: The simulation results for realistic synthetic and real neuronal data reveal the improvement of the proposed spike detection techniques over state of-the art approaches. We expect these improve subsequent steps like spike sorting. PMID- 25455342 TI - Controlling for experimental effects in event-related potentials by means of principal component rotation. AB - BACKGROUND: Misallocation of variance means that experimental effects do not only occur on the original event related potential (ERP) component, which should normally represent the respective experimental effect. Simulation studies have shown that misallocation of variance occurs when principal component analysis with subsequent Varimax-rotation is performed. Previous research has also shown that the amount of misallocation of variance substantially depends on component rotation. NEW METHOD: Accordingly, in this study component rotation has been conducted in a way that allows for a minimization of misallocation of variance. It is proposed to generate dummy variables representing the relevant effects and to generate a loading matrix from the covariances of the dummy variables and of the ERP waves with the components. In the next step, a target matrix for partial Procrustes-rotation is generated by means of specifying the target loadings of the dummy variables on the intended components according to theoretical expectations. RESULTS: The elimination of the misallocation of variance effect is shown in a simulation study. Comparison with Existing Method(s): Substantial misallocation of variance occurred for PCA with subsequent Varimax-rotation in the simulation study, but no misallocation of variance occurred with the new method. An empirical example showed how to improve the parietal topography of the late P3 by means of the new method. CONCLUSIONS: The study shows clearly that misallocation of variance is not due to PCA, but to component rotation. The new method of component rotation can be used in order to minimize misallocation of variance. PMID- 25455343 TI - Accuracy of measurement in electrically evoked compound action potentials. AB - BACKGROUND: Electrically evoked compound action potentials (ECAP) in cochlear implant (CI) patients are characterized by the amplitude of the N1P1 complex. The measurement of evoked potentials yields a combination of the measured signal with various noise components but for ECAP procedures performed in the clinical routine, only the averaged curve is accessible. To date no detailed analysis of error dimension has been published. The aim of this study was to determine the error of the N1P1 amplitude and to determine the factors that impact the outcome. NEW METHODS: Measurements were performed on 32 CI patients with either CI24RE (CA) or CI512 implants using the Software Custom Sound EP (Cochlear). N1P1 error approximation of non-averaged raw data consisting of recorded single-sweeps was compared to methods of error approximation based on mean curves. RESULTS: The error approximation of the N1P1 amplitude using averaged data showed comparable results to single-point error estimation. The error of the N1P1 amplitude depends on the number of averaging steps and amplification; in contrast, the error of the N1P1 amplitude is not dependent on the stimulus intensity. COMPARISON WITH EXISTING METHOD(S): Single-point error showed smaller N1P1 error and better coincidence with 1/?(N) function (N is the number of measured sweeps) compared to the known maximum-minimum criterion. CONCLUSION: Evaluation of N1P1 amplitude should be accompanied by indication of its error. The retrospective approximation of this measurement error from the averaged data available in clinically used software is possible and best done utilizing the D-trace in forward masking artefact reduction mode (no stimulation applied and recording contains only the switch-on-artefact). PMID- 25455344 TI - Mapping (and modeling) physiological movements during EEG-fMRI recordings: the added value of the video acquired simultaneously. AB - BACKGROUND: During resting-state EEG-fMRI studies in epilepsy, patients' spontaneous head-face movements occur frequently. We tested the usefulness of synchronous video recording to identify and model the fMRI changes associated with non-epileptic movements to improve sensitivity and specificity of fMRI maps related to interictal epileptiform discharges (IED). NEW METHODS: Categorization of different facial/cranial movements during EEG-fMRI was obtained for 38 patients [with benign epilepsy with centro-temporal spikes (BECTS, n=16); with idiopathic generalized epilepsy (IGE, n=17); focal symptomatic/cryptogenic epilepsy (n=5)]. We compared at single subject- and at group-level the IED related fMRI maps obtained with and without additional regressors related to spontaneous movements. As secondary aim, we considered facial movements as events of interest to test the usefulness of video information to obtain fMRI maps of the following face movements: swallowing, mouth-tongue movements, and blinking. RESULTS: Video information substantially improved the identification and classification of the artifacts with respect to the EEG observation alone (mean gain of 28 events per exam). COMPARISON WITH EXISTING METHOD: Inclusion of physiological activities as additional regressors in the GLM model demonstrated an increased Z-score and number of voxels of the global maxima and/or new BOLD clusters in around three quarters of the patients. Video-related fMRI maps for swallowing, mouth-tongue movements, and blinking were comparable to the ones obtained in previous task-based fMRI studies. CONCLUSIONS: Video acquisition during EEG-fMRI is a useful source of information. Modeling physiological movements in EEG-fMRI studies for epilepsy will lead to more informative IED related fMRI maps in different epileptic conditions. PMID- 25455345 TI - On the use of information theory for the analysis of synchronous nociceptive withdrawal reflexes and somatosensory evoked potentials elicited by graded electrical stimulation. AB - BACKGROUND: To date, few studies have combined the simultaneous acquisition of nociceptive withdrawal reflexes (NWR) and somatosensory evoked potentials (SEPs). In fact, it is unknown whether the combination of these two signals acquired simultaneously could provide additional information on somatosensory processing at spinal and supraspinal level compared to individual NWR and SEP signals. NEW METHOD: By using the concept of mutual information (MI), it is possible to quantify the relation between electrical stimuli and simultaneous elicited electrophysiological responses in humans based on the estimated stimulus-response signal probability distributions. RESULTS: All selected features from NWR and SEPs were informative in regard to the stimulus when considered individually. Specifically, the information carried by NWR features was significantly higher than the information contained in the SEP features (p<0.05). Moreover, the joint information carried by the combination of features showed an overall redundancy compared to the sum of the individual contributions. Comparison with existing methods MI can be used to quantify the information that single-trial NWR and SEP features convey, as well as the information carried jointly by NWR and SEPs. This is a model-free approach that considers linear and non-linear correlations at any order and is not constrained by parametric assumptions. CONCLUSIONS: The current study introduces a novel approach that allows the quantification of the individual and joint information content of single-trial NWR and SEP features. This methodology could be used to decode and interpret spinal and supraspinal interaction in studies modulating the responsiveness of the nociceptive system. PMID- 25455346 TI - Comments on the article "Clinical utility of the Revised Atlanta Classification of acute pancreatitis in a prospective cohort: have all loose ends been tied?". PMID- 25455347 TI - Patient quality of life and pain improve after autologous islet transplantation (AIT) for treatment of chronic pancreatitis: 53 patient series at the University of Arizona. AB - BACKGROUND/OBJECTIVES: Pancreatectomy with autologous islet transplantation has slowly been proving to be an effective way of treating chronic pancreatitis while lessening the effects of the concomitant surgical diabetes of pancreatectomy alone. Assessing patient quality of life and pain after the procedure is particularly important as intractable pain is the main complaint for which patients undergo total pancreatectomy. METHODS: We used the Rand SF-36 and McGill pain questionnaires, and Visual Analogue Scale to assess patients preoperatively for quality of life and pain resulting from life with chronic pancreatitis. After undergoing total pancreatectomy with autologous islet transplantation (TPAIT), patients were followed with surveys administered at 1 month, 6 months, and 1 year to evaluate changes in their quality of life and pain experienced. RESULTS: Significant improvement was reported in all components of every questionnaire within a year after surgery. Furthermore, patient reported mean scores on quality of life were found to fall within the range of the general population. CONCLUSIONS: From our experience with 53 patients at the University of Arizona, after pancreatectomy with autologous islet transplantation patients reported a higher quality of life when compared to preoperative values, as well as reduced levels of pain. PMID- 25455348 TI - Effect of percutaneous catheter drainage on pancreatic injury in rats with severe acute pancreatitis induced by sodium taurocholate. AB - OBJECTIVE: This study investigated the effect of percutaneous catheter drainage (PCD) on pancreatic injury in severe acute pancreatitis (SAP) rats. METHODS: Sixty Wistar rats were equally randomized into three groups: a sham operated control group, an SAP control group, and a PCD group. The levels of inflammatory cytokines, the activity of group II phospholipase A2 (PLA2) in blood and ascitic fluid, and the pancreas level of group II PLA2 and trypsin activity were measured 24 h after the operation. The apoptosis of the pancreatic cells, the expression of cycloxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), active caspase-3, Bcl-2 and Bax in the pancreas was detected. Pancreatic pathological changes were observed. RESULTS: The levels of proinflammatory cytokines, the activity of group II PLA2 and trypsin activity in pancreas in the SAP group were higher than those in the PCD group. The histopathological results revealed that the pancreatic injury was alleviated in the PCD group. The expression of COX-2 and iNOS in the pancreatic tissue in the SAP control rats was higher than that in the PCD rats. The expression of Bcl-2 was decreased and the expression of active caspase-3 and Bax was increased in the pancreas of PCD rats. The apoptosis index of the pancreatic cells in the PCD rats was higher than that in the SAP control rats. CONCLUSION: PCD can relieve SAP-induced pancreatic injury by inhibiting inflammatory reactions, and promoting apoptosis of pancreatic cells. PMID- 25455349 TI - Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline. AB - BACKGROUND: Alzheimer disease is characterized by cognitive decline, senile plaques of beta-amyloid (Abeta) peptides, neurofibrillary tangles composed of hyperphosphorylated tau proteins and neuronal loss. Abeta and tau are useful markers in the cerebrospinal fluid (CSF). C-Jun N-terminal kinases (JNKs) are serine-threonine protein kinases activated by phosphorylation and involved in neuronal death. METHODS: In this study, Western blots, enzyme-linked immunosorbent assay and histological approaches were used to assess the concentrations of Abeta, tau and JNK isoforms in postmortem brain tissue samples (10 Alzheimer disease and 10 control) and in CSF samples from 30 living patients with Alzheimer disease and 27 controls with neurologic disease excluding Alzheimer disease. Patients with Alzheimer disease were followed for 1-3 years and assessed using Mini-Mental State Examination scores. RESULTS: The biochemical and morphological results showed a significant increase of JNK3 and phosphorylated JNK levels in patients with Alzheimer disease, and JNK3 levels correlated with Abeta42 levels. Confocal microscopy revealed that JNK3 was associated with Abeta in senile plaques. The JNK3 levels in the CSF were significantly elevated in patients with Alzheimer disease and correlated statistically with the rate of cognitive decline in a mixed linear model. LIMITATIONS: The study involved different samples grouped into 3 small cohorts. Evaluation of JNK3 in CSF was possible only with immunoblot analysis. CONCLUSION: We found that JNK3 levels are increased in brain tissue and CSF from patients with Alzheimer disease. The finding that increased JNK3 levels in CSF could reflect the rate of cognitive decline is new and merits further investigation. PMID- 25455351 TI - Systems biology in 3D space--enter the morphome. AB - Systems-based understanding of living organisms depends on acquiring huge datasets from arrays of genes, transcripts, proteins, and lipids. These data, referred to as 'omes', are assembled using 'omics' methodologies. Currently a comprehensive, quantitative view of cellular and organellar systems in 3D space at nanoscale/molecular resolution is missing. We introduce here the term 'morphome' for the distribution of living matter within a 3D biological system, and 'morphomics' for methods of collecting 3D data systematically and quantitatively. A sampling-based approach termed stereology currently provides rapid, precise, and minimally biased morphomics. We propose that stereology solves the 'big data' problem posed by emerging wide-scale electron microscopy (EM) and can establish quantitative links between the newer nanoimaging platforms such as electron tomography, cryo-EM, and correlative microscopy. PMID- 25455350 TI - Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia--significance for activation of the kynurenine pathway. AB - BACKGROUND: Accumulating evidence indicates that schizophrenia is associated with brain immune activation. While a number of reports suggest increased cytokine levels in patients with schizophrenia, many of these studies have been limited by their focus on peripheral cytokines or confounded by various antipsychotic treatments. Here, well-characterized patients with schizophrenia, all receiving olanzapine treatment, and healthy volunteers were analyzed with regard to cerebrospinal fluid (CSF) levels of cytokines. We correlated the CSF cytokine levels to previously analyzed metabolites of the kynurenine (KYN) pathway. METHODS: We analyzed the CSF from patients and controls using electrochemiluminescence detection with regard to cytokines. Cell culture media from human cortical astrocytes were analyzed for KYN and kynurenic acid (KYNA) using high-pressure liquid chromatography or liquid chromatography/mass spectrometry. RESULTS: We included 23 patients and 37 controls in our study. Patients with schizophrenia had increased CSF levels of interleukin (IL)-6 compared with healthy volunteers. In patients, we also observed a positive correlation between IL-6 and the tryptophan:KYNA ratio, indicating that IL-6 activates the KYN pathway. In line with this, application of IL-6 to cultured human astrocytes increased cell medium concentration of KYNA. LIMITATIONS: The CSF samples had been frozen and thawed twice before analysis of cytokines. Median age differed between patients and controls. When appropriate, all present analyses were adjusted for age. CONCLUSION: We have shown that IL-6, KYN and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-D-aspartate receptor antagonist KYNA in patients with schizophrenia. PMID- 25455352 TI - Use of diagnostic modalities for assessing upper extremity vascular pathology. AB - Vascular pathology of the upper extremity requires consideration of constitutional, anatomic, and functional factors. The medical history and physical examination are essential. The Allen test can be performed alongside a handheld Doppler for arterial mapping. Useful studies include digital-brachial index measurements, digital plethysmography, laser Doppler, and color ultrasounds. Three-phase bone scintigraphy still plays a role in the evaluation of vascularity after of frostbite injury. Angiogram remains the gold standard radiographic instrument to evaluate vascular pathology of the upper extremity, but computed tomography and magnetic resonance scans have an increasing role in diagnosis of vascular pathology. PMID- 25455353 TI - The role of thrombolytics in acute and chronic occlusion of the hand. AB - Distal arm and hand ischemia from vessel thrombosis or embolism remains a difficult clinical challenge. The causes of ischemia are variable and include connective tissue disease, embolism, atherosclerosis, and iatrogenic etiology. Although reports are limited, treatment with catheter-directed thrombolysis has favorable results in cases of acute thrombosis, with most patients (80%) demonstrating improvement. Digital amputation rates are less than 10% and the hand is often salvaged. Bleeding and access-site complications remain prevalent in patients undergoing intra-arterial thrombolysis. This review discusses etiology, treatment approaches, outcomes, and complications when thrombolytic therapy is used for distal arm and hand ischemia. PMID- 25455354 TI - The role of botulinum toxin in vasospastic disorders of the hand. AB - Raynaud phenomenon may be a primary disorder or associated with a variety of other autoimmune processes. Raynaud phenomenon produces digital vasospasm, which can lead to ischemia and ulceration. The treatment of Raynaud phenomenon has been difficult because multiple medical treatments have not provided uniform resolution of symptoms. Many patients have turned to surgery and sympathectomies for the treatment of unrelenting vasospasm. Botulinum toxin has been shown to be an effective alternative to surgery, with a single treatment being capable of resolving pain and healing ulcer. This article reviews the use of botulinum toxin for the treatment of Raynaud phenomenon. PMID- 25455355 TI - Vascular injuries in the upper extremity in athletes. AB - Repetitive, high-stress, or high-impact arm motions can cause upper extremity arterial injuries. The increased functional range of the upper extremity causes increased stresses on the vascular structures. Muscle hypertrophy and fatigue induced joint translation may incite impingement on critical neurovasculature and can cause vascular damage. A thorough evaluation is essential to establish the diagnosis in a timely fashion as presentation mimics more common musculoskeletal injuries. Conservative treatment includes equipment modification, motion analysis and adjustment, as well as equipment enhancement to limit exposure to blunt trauma or impingement. Surgical options include ligation, primary end-to-end anastomosis for small defects, and grafting. PMID- 25455356 TI - Current options for treatment of hypothenar hammer syndrome. AB - Hypothenar hammer syndrome is a rare vascular condition resulting from injury to the ulnar artery at the level of Guyon canal. The ulnar artery at the wrist is the most common site of arterial aneurysms of the upper extremity and is particularly prone to injury. Signs and symptoms include a palpable mass, distal digital embolization to long, ring, or small fingers, pain, cyanosis, pallor, coolness, and recurrent episodes of vasospasm. Modalities for diagnosis, evaluation, and surgical planning include duplex study, contrast arteriography, and computerized tomographic angiography (CTA). Management includes medical, nonoperative, or operative treatments. Appropriate treatment options are reviewed. PMID- 25455357 TI - Connective tissue disorders associated with vasculitis and vaso-occlusive disease of the hand. AB - Hand ischemia caused by vasculitis is a secondary finding in many autoimmune processes. Many of these autoimmune diseases are managed primarily with medications that can prevent the development of occlusive disease, tissue ischemia, and tissue loss. Unfortunately several disease conditions can be recalcitrant to medical management and can result in ischemic changes within the hand, which may require operative intervention. This article briefly reviews the major connective tissue disorders associated with vasculitis and vaso-occlusive disease of the hand, including scleroderma, lupus, and Buerger disease, and their surgical treatment. PMID- 25455358 TI - Revascularization options for terminal distal ischemia. AB - Direct arterial bypass remains the best option in patients with terminal ischemia of the hand, if there is an adequate distal target vessel. In situ bypass is the procedure of choice in patients who are candidates for arterial bypass. Venous arterialization offers an option in patients in whom there is not adequate arterial runoff in the hand. Venous arterialization should be avoided in patients with significant wounds and/or active infection. In selected patients, microvascular omental transfer can offer an option for revascularization of the ischemic hand. PMID- 25455359 TI - Options for revascularization: artery versus vein: technical considerations. AB - Vascular grafts, as either interpositional conduits or bypass grafts, can be used for revascularization procedures in the upper extremity. Vein grafts are more readily available and can be easier to harvest. Arterial grafts may provide superior patency rates compared with vein grafts. Arterial grafts can be located and harvested with consistent and reliable anatomy throughout the body. PMID- 25455360 TI - Complications related to radial artery occlusion, radial artery harvest, and arterial lines. AB - Recent publications have suggested that there may be an important role for the radial artery regarding long-term perfusion of the hand. The increasing popularity of the radial artery as an access site for cardiac catheterization has also resulted in the recognition of acute and chronic radial artery occlusion, and cardiologists have placed renewed emphasis on preserving the patency of this artery for future interventional procedures. This article reviews the present literature on radial artery harvest and occlusion. Also discussed are the complications associated with radial artery occlusion and treatment options to prevent such complications. PMID- 25455361 TI - Role and rationale for extended periarterial sympathectomy in the management of severe Raynaud syndrome: techniques and results. AB - There is no consensus regarding etiology or best surgical technique for severe Raynaud syndrome in patients with connective tissue disease. Observations after 30 years' experience in more than 100 cases led to the conclusion that an extended periarterial sympathectomy (with or without vein-graft reconstruction) and adjunctive use of Botox topically will offer benefits that exceed palliation and reduce recurrent ulcerations. In this article the rationale for this approach is reviewed, techniques and results are outlined, and a hypothesis for the mechanism of Raynaud attacks is offered. PMID- 25455362 TI - Interpretation of upper extremity arteriography: vascular anatomy and pathology [corrected]. AB - Understanding the utility and interpretation of upper extremity angiography is critical for the hand surgeon treating vaso-occlusive diseases of the hand. Although invasive and requiring the use of contrast dye, it remains the gold standard for imaging of the vascular system of the upper extremity. Angiography may detect numerous variants of the upper limb arterial system which may contribute to surgical pathology. Extensive vascular collateralization helps to maintain perfusion to the hand and facilitates reconstruction of the upper extremity. It is paramount to remember that angiography is a dynamic study and should represent a "flexible roadmap" for surgical reconstruction. PMID- 25455363 TI - New developments in management of vascular pathology of the upper extremity. PMID- 25455364 TI - Interview with Arthur Christopoulos. PMID- 25455365 TI - A ventral view on antidepressant action: roles for adult hippocampal neurogenesis along the dorsoventral axis. AB - Adult hippocampal neurogenesis is implicated in antidepressant action, stress responses, and cognitive functioning. The hippocampus is functionally segregated along its longitudinal axis into dorsal (dHi) and ventral (vHi) regions in rodents, and analogous posterior and anterior regions in primates, whereby the vHi preferentially regulates stress and anxiety, while the dHi preferentially regulates spatial learning and memory. Given the role of neurogenesis in functions preferentially regulated by the dHi or vHi, it is plausible that neurogenesis is preferentially regulated in either the dHi or vHi depending upon the stimulus. We appraise here the literature on the effects of stress and antidepressants on neurogenesis along the hippocampal longitudinal axis and explore whether preferential regulation of neurogenesis in the vHi/anterior hippocampus contributes to stress resilience and antidepressant action. PMID- 25455366 TI - Low densities of drifting litter in the African sector of the Southern Ocean. AB - Only 52 litter items (>1cm diameter) were observed in 10,467 km of at-sea transects in the African sector of the Southern Ocean. Litter density north of the Subtropical Front (0.58 items km(-2)) was less than in the adjacent South Atlantic Ocean (1-6 items km(-2)), but has increased compared to the mid-1980s. Litter density south of the Subtropical Front was an order of magnitude less than in temperate waters (0.032 items km(-2)). There was no difference in litter density between sub-Antarctic and Antarctic waters either side of the Antarctic Polar Front. Most litter was made of plastic (96%). Fishery-related debris comprised a greater proportion of litter south of the Subtropical Front (33%) than in temperate waters (13%), where packaging dominated litter items (68%). The results confirm that the Southern Ocean is the least polluted ocean in terms of drifting debris and suggest that most debris comes from local sources. PMID- 25455367 TI - Utilization of a genetic algorithm for the automatic detection of oil spill from RADARSAT-2 SAR satellite data. AB - In this work, a genetic algorithm is applied for the automatic detection of oil spills. The procedure is implemented using sequences from RADARSAT-2 SAR ScanSAR Narrow single-beam data acquired in the Gulf of Mexico. The study demonstrates that the implementation of crossover allows for the generation of an accurate oil spill pattern. This conclusion is confirmed by the receiver-operating characteristic (ROC) curve. The ROC curve indicates that the existence of oil slick footprints can be identified using the area between the ROC curve and the no-discrimination line of 90%, which is greater than that of other surrounding environmental features. In conclusion, the genetic algorithm can be used as a tool for the automatic detection of oil spills, and the ScanSAR Narrow single beam mode serves as an excellent sensor for oil spill detection and survey. PMID- 25455368 TI - Mercury in Caribbean dolphins (Stenella longirostris and Stenella frontalis) caught for human consumption off St. Vincent, West Indies. AB - The island of St. Vincent in the Lesser Antilles supports an ongoing, legal cetacean hunt, which targets several species for human consumption. Little is known regarding the healthfulness and potential health risks of these foods in this setting. Following established methodologies we analyzed 39 raw muscle tissue samples and 38 raw blubber samples from two cetacean species for total mercury and methyl-mercury. We also analyzed samples of muscle tissue from an unknown cetacean species prepared for consumption. We report high concentrations of total mercury and methyl-mercury in these tissues as compared to published data for other seafood products. Further, our findings indicate that the traditional preparation method most often used locally in St. Vincent yields a finished food product with a much higher mercury concentration than the unprocessed tissue. Our results highlight the potential for negative human health effects related to the consumption of these food products in St. Vincent. PMID- 25455369 TI - Mobilisation and bioaccessibility of lead in paint from abandoned boats. AB - Fragments of leaded paint sampled from abandoned boats have been ground as a composite and added in different quantities to aliquots of clean estuarine sediment in order to examine the mobility and bioaccessibility of Pb. Concentrations of Pb mobilised by sea water increased with increasing quantity of paint present, but the percentage of total Pb mobilised was greatest from paint free sediment. Lead mobilisation was enhanced in the presence of the protein, bovine serum albumin, a surrogate for the digestive fluids of deposit-feeding invertebrates, but, likewise, the percentage of Pb mobilised was greatest from paint-free sediment. Lower percentage mobility and bioaccessibility in contaminated sediment than in paint-free sediment is attributed to the relatively low solubility and amenability of Pb compounds in the paint matrix. Despite the low mobility of Pb, however, sediment contaminated by as little as 0.2% paint is predicted to result in dissolved concentrations that exceed available water quality standards. PMID- 25455370 TI - Are fecal stanols suitable to record and identify a pulse of human fecal contamination in short-term exposed shellfish? A microcosm study. AB - In this study, the capacity of oysters to bioaccumulate fecal stanols and to record a source-specific fingerprint was investigated by the short-term contamination of seawater microcosms containing oysters with a human effluent. Contaminated oysters bioaccumulated the typical fecal stanols coprostanol and 24 ethylcoprostanol and their bioaccumulation kinetics were similar to that of the Fecal Indicator Bacteria Escherichia coli used in European legislation. Although stanol fingerprints of contaminated water allowed the identification of the human specific fingerprint, this was not the case for oysters. This discrepancy is attributed to (i) high concentrations of endogenous cholestanol and sitostanol, responsible for "unbalanced" stanol fingerprints, (ii) different accumulation/depuration kinetics of fecal coprostanol and 24-ethylcoprostanol and (iii) the limits of the analytical pathway used. These results show that fecal stanols bioaccumulated by oysters are useful to record fecal contamination but the usefulness of stanol fingerprints to identify specific sources of contamination in shellfish currently seems limited. PMID- 25455371 TI - Interannual heavy element and nutrient concentration trends in the top sediments of Venice Lagoon (Italy). AB - The elemental composition of surficial sediments of Venice Lagoon (Italy) in 1987, 1993, 1998 and 2003 were investigated. Zn and Cr concentrations resulted in higher than background levels, but only Cd and Hg were higher than legal quality standards (Italian Decree 2010/260 and Water Framework Directive 2000/60/EC). Contaminants with similar spatial distribution are sorted into three groups by means of correlation analysis: (i) As, Co, Cd, Cu, Fe, Pb, Zn; (ii) Ni, Cr; (iii) Hg. Interannual concentrations are compared by applying a factor analysis to the matrix of differences between subsequent samplings. A general decrease of heavy metal levels is observed from 1987 to 1993, whereas particularly high concentrations of Ni and Cr are recorded in 1998 as a consequence of intense clam fishing, subsequently mitigated by better prevention of illegal harvesting. Due to the major role played by anthropogenic sediment resuspension, bathymetric variations are also considered. PMID- 25455372 TI - Transcriptomic response to estrogen exposure in the male Zhikong scallop, Chlamys farreri. AB - The transcriptomes of Zhikong scallop exposed to 17beta-estradiol were determined using the Roche/454. A total of 51,997 unigenes, representing 45,030 contigs and 6967 singlets were obtained. And 14,028, 19,798 and 14,981 of these unigenes were annotated from the non-redundant nucleic acid database, non-redundant protein database and Swiss protein database, respectively. A total of 10,699 unigenes were further annotated to biological processes (9080), molecular functions (8692) and cellular components (7829) using the GO, and 8945 unigenes were mapped to biological pathways including the metabolism (2862) and genetic information processing (2263). Most importantly, 16,692 unigenes and 18,686 unigenes in testis, and 10,492 unigenes and 13,186 unigenes in digestive gland were up regulated significantly after exposure to 50 and 500 ng E2/L; while 10,212 unigenes and 9409 unigenes in testis and 10,629 unigenes and 9463 unigenes in digestive gland were down-regulated. These valuable information provides insights into the mechanisms in invertebrate exposure to EDCs. PMID- 25455373 TI - Revisiting methods for the determination of bioavailable metals in coastal sediments. AB - A simple methodology for the determination of bioavailability of fourteen metals in coastal sediments has been developed by simulating the conditions of digestive process of marine fishes. With this aim, a representative sediment composite sample was treated with hydrochloric acid solutions at different pH values, temperatures and contact times, in the presence and absence of Pepsin and Trypsin. The addition of Pepsin and Trypsin did not affect the extraction of most elements. As a result of the present study, the digestion with a hydrochloric acid solution at pH 1, 40 degrees C and 12h is proposed. Adjustments of the temperature and time reaction could be made according to the specific ecosystem under study. The amount of metal extracted by other methods based on acetic acid was lower than that extracted by HCl treatment proposed. PMID- 25455374 TI - Use of GIS for the evaluation of heavy metal contamination in the Cunha Canal watershed and west of the Guanabara Bay, Rio de Janeiro, RJ. AB - The Cunha Canal watershed, which is located in the municipality of Rio de Janeiro, suffered severe environmental degradation in recent decades due to rapid urban population growth. However, this substantial growth did not result in social development; instead, it exacerbated existing environmental and social problems. This study aimed to evaluate the pollution of the Canal do Cunha and Guanabara Bay, using GIS for mapping based on the result of the heavy metal concentrations obtained by spectrometry (ICP-OES). The analyzed data were monitored at five collection points. Five heavy metals (Cd, Pb, Cu, Ni and Zn) were evaluated. The results showed that the waters of the Cunha Canal watershed and the west side of Guanabara Bay have been altered and degraded. The concentration of heavy metals in the water was lower than the concentration in the sediments. The behaviors of the studied metals differed during the rainy and dry periods. PMID- 25455375 TI - Oil source-fingerprinting in support of polarimetric radar mapping of Macondo-252 oil in Gulf Coast marshes. AB - Polarimetric synthetic aperture radar (PolSAR) data exhibited dramatic, spatially extensive changes from June 2009 to June 2010 in Barataria Bay, Louisiana. To determine whether these changes were associated with the Deepwater Horizon (DWH) oil spill, twenty-nine sediment samples were collected in 2011 from shoreline and nearshore-interior coastal marsh locations where oil was not observed visually or with optical sensors during the spill. Oil source-fingerprinting and polytopic vector analysis were used to link DWH oil to PolSAR changes. Our results prove that DWH oil extended beyond shorelines and confirm the association between presence of DWH oil and PolSAR change. These results show that the DWH oil spill probably affected much more of the southeastern Louisiana marshland than originally concluded from ground and aerial surveys and verify that PolSAR is a powerful tool for tracking oil intrusion into marshes with high probability even where contamination is not visible from above the canopy. PMID- 25455376 TI - Population dynamics and antimicrobial susceptibility of Aeromonas spp. along a salinity gradient in an urban estuary in Northeastern Brazil. AB - The main objective of this study was to quantify population and identify culturable species of Aeromonas in sediment and surface water collected along a salinity gradient in an urban estuary in Northeastern Brazil. Thirty sediment samples and 30 water samples were collected from 3 sampling locations (A, B and C) between October 2007 and April 2008. The Aeromonas count was 10-7050CFU/mL (A), 25-38,500CFU/mL (B) and<10CFU/mL (C) for water samples, and ~100-37,500CFU/g (A), 1200-43,500CFU/g (B) and<10CFU/g (C) for sediment samples. Five species (Aeromonas caviae, A. sobria, A. trota, A. salmonicida and A. allosaccharophila) were identified among 41 isolates. All strains were sensitive to chloramphenicol and ceftriaxone, whereas 33 (80, 4%) strains were resistant to at least 2 of the 9 antibiotics tested. Resistance to erythromycin was mostly plasmidial. In conclusion, due to pollution, the Coco River is contaminated by pathogenic strains of Aeromonas spp. with a high incidence of antibacterial resistance, posing a serious risk to human health. PMID- 25455377 TI - Assessing coastal reclamation suitability based on a fuzzy-AHP comprehensive evaluation framework: A case study of Lianyungang, China. AB - Coastal reclamation suitability evaluation (CRSE) is a difficult, complex and protracted process requiring the evaluation of many different criteria. In this paper, an integrated framework employing a fuzzy comprehensive evaluation method and analytic hierarchy process (AHP) was applied to the suitability evaluation for coastal reclamation for future sustainable development in the coastal area of Lianyungang, China. The evaluation results classified 6.63%, 22.99%, 31.59% and 38.79% of the coastline as suitable, weakly suitable, unsuitable and forbidden, respectively. The evaluation results were verified by the marine pollution data and highly consistent with the water quality status. The fuzzy-AHP comprehensive evaluation method (FACEM) was found to be suitable for the CRSE. This CRSE can also be applied to other coastal areas in China and thereby be used for the better management of coastal reclamation and coastline protection projects. PMID- 25455378 TI - Spatial patterns of metals, PCDDs/Fs, PCBs, PBDEs and chemical status of sediments from a coastal lagoon (Pialassa Baiona, NW Adriatic, Italy). AB - The European Water Framework Directive (WFD) establishes a framework for the protection and improvement of all water bodies including transitional waters; its final objective is to achieve at least 'good status' by 2015. In the present work, a hierarchical sampling design was applied to analyze the influence of anthropogenic inputs on the spatial distribution of metals, polychlorinated dibenzo-p-dioxins (PCDDs) dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in sediment at four areas in Pialassa Baiona coastal lagoon. In order to assess the chemical status, levels of priority substances and other pollutants were compared with the recently developed national Environmental Quality Standards (EQS) and site specific background levels for metals. Levels of mercury and PCBs were particularly high and exceeded their national EQS values at all sampled areas, thus not contributing to the achievement of a good chemical status of this transitional water body according to the WFD classification. PMID- 25455379 TI - Highly contaminated areas as sources of pollution for adjoining ecosystems: The case of Augusta Bay (Central Mediterranean). AB - An assessment of trace element and polycyclic aromatic hydrocarbon (PAH) contamination based on surface sediments collected in summer 2012 was carried out in Priolo Bay adjoining one of the most polluted areas of the Mediterranean Sea, the industrial Augusta harbour (Italy, Central Mediterranean). Inorganic and organic contaminants were generally not remarkable. Occasional elevated concentrations of Hg, Cd, Ni and PAHs exceeding sediment quality guidelines were detected in the northern sector of Priolo Bay, close to Augusta harbour, possibly as a result of water drainage of industrialised and urbanised areas and/or potential direct export of contaminated material from Augusta harbour, whose influence on the adjoining Priolo Bay ecosystem cannot be ruled out. By domino effect, Priolo sediments may therefore become a potential source of pollutants and may represent a threat to the biota. PMID- 25455380 TI - Trace elements distribution and ecological risk assessment of seawater and sediments from Dingzi Bay, Shandong Peninsula, North China. AB - Selected trace elements (Hg, As, Pb, Cu, Cd, Cr and Zn) in seawater and sediments from Dingzi Bay, a semi-enclosed bay suffering from severe degradation located in the Shandong Peninsula, were investigated to evaluate the spatial distribution and potential ecological risk. Results indicated that higher concentrations occurred in the inner bay. Calculation of pollution load index (PLI) showed overall low values while the concentration factor (CF) indicated that Hg, As and Cd were at moderate risk levels in the region. Based on the effects-range classification, As was likely to pose environment risk. Principal component analysis (PCA) revealed that in addition to background contributions, the trace elements contamination could also be affected by anthropogenic pollution sources. The results of present study provide useful background information for further marine investigation and management in the region. PMID- 25455381 TI - [POLA network: a national network for high-grade oligodendroglial tumors]. PMID- 25455382 TI - Parametrial boosting in locally advanced cervical cancer: combined intracavitary/interstitial brachytherapy vs. intracavitary brachytherapy plus external beam radiotherapy. AB - PURPOSE: Parametrial boost (PB) with external beam radiotherapy (EBRT) aims to increase the dose in the parametrial regions where the contribution from intracavitary brachytherapy (IC BT) is insufficient. An alternative technique for parametrial boosting is combined intracavitary and interstitial (IC-IS) BT. We compared doses delivered by IC BT plus EBRT PB with doses delivered by IC-IS BT. METHODS AND MATERIALS: We reviewed 51 consecutive patients with locally advanced cervical cancer with parametrial involvement at diagnosis. At BT, 23 patients had persistent parametrial involvement and were treated with IC-IS BT. For the 23 patients, we simulated a treatment of IC BT combined with EBRT PB and compared it with the delivered IC-IS BT. Equivalent total doses in 2-Gy fractions of the target and organs at risk were evaluated, and the normal tissue volume irradiated to at least 60 Gy (V60). RESULTS: The mean high-risk clinical target volume D90 was comparable (p = 0.8) for both techniques. However, with the EBRT PB scenario, 3 patients received high-risk clinical target volume D90 of <79 Gy, whereas IC-IS BT resulted in D90 of >84 Gy for all patients. Organs at risk D(2cm(3)) were significantly higher by a mean of 4-6 Gy (p < 0.001) with EBRT PB. The PB scenario resulted in a significantly higher V60 of 594 +/- 596 cm(3) as compared with 228 +/- 82 cm(3) with IC-IS BT (p = 0.004). CONCLUSIONS: Combined IC-IS BT is superior than IC BT + EBRT PB both in terms of organ sparing and target coverage. The IC-IS BT was more conformal with less normal tissue exposure to intermediate doses (V60). PMID- 25455384 TI - Proton beam therapy: the context, future direction and challenges become clearer. PMID- 25455383 TI - Urethral toxicity after LDR brachytherapy: experience in Japan. AB - Urinary toxicity is common after low-dose-rate (LDR) brachytherapy, and the resolution of urinary toxicity is a concern. In particular, urinary frequency is the most common adverse event among the urinary toxicities. We have previously reported that approximately 70% of patients experience urinary frequency during the first 6 months after seed implantation. Most urinary adverse events were classified as Grade 1, and Grade 2 or higher adverse events were rare. The incidence of urinary retention was approximately 2-4%. A high International Prostate Symptom Score before seed implantation was an independent predictor of acute urinary toxicity of Grade 2 or higher. Several previous reports from the United States also supported this trend. In Japan, LDR brachytherapy was legally approved in 2003. A nationwide prospective cohort study entitled Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation was initiated in July 2005. It is an important issue to limit urinary toxicities in patients who undergo LDR brachytherapy. PMID- 25455385 TI - Effect of serogroup, surface material and disinfectant on biofilm formation by avian pathogenic Escherichia coli. AB - Avian pathogenic Escherichia coli (APEC) are responsible for significant economic losses in the poultry industry and are difficult to eradicate. Biofilm formation by APEC has the potential to reduce the efficacy of cleaning and disinfection. In this study, biofilm formation on materials used in poultry facilities by APEC strains from laying hens was determined. APEC strains were analysed for an association between biofilm forming capacity and O serogroup. The abilities of two routinely used disinfectants, hydrogen peroxide (H2O2) and a quaternary ammonium compound (QAC), to kill adherent cells of two strong APEC biofilm producers (05/503 and 04/40) and a non-biofilm producer (05/293) on polystyrene (PS) and polyvinylchloride (PVC) surfaces were tested. Most APEC strains were moderate (PS) or strong biofilm producers (polypropylene, PP, and PVC). Strains in serogroup O2 more often belonged to the moderate (PS) or strong (PP and PVC) biofilm producers than to other groups, while most O78 strains were weak biofilm producers. O78 strains were stronger biofilm producers on stainless steel than on PP and PVC, while O2 strains were stronger biofilm producers on PP and PVC. A concentration of 1% H2O2 killed all adherent bacteria of strains 05/503 and 04/40 on PP and PVC, while 0.5% H2O2 killed all adherent bacteria of strain 05/293. QAC at a concentration of 0.01% killed all adherent cells of strains 05/503, 04/40 and 05/293 under equal conditions. In conclusion, biofilm formation by APEC was affected by serogroup and surface material, and inactivation of APEC was dependent on the disinfectant and surface material. PMID- 25455386 TI - Attitudes of farmers and veterinarians towards pain and the use of pain relief in pigs. AB - A survey of UK-based pig farmers and veterinarians was conducted, in order to investigate attitudes to pain and the use of pain relief in pigs. Survey respondents were asked to indicate which anti-inflammatory drugs they used or prescribed for pigs, how often these were administered, and the level of pain they associated with particular conditions. The survey found that veterinarians used a range of anti-inflammatory products to treat pigs with lameness. While both farmers and veterinarians gave similar pain scores overall, farmers rated gastrointestinal disease as more painful and conversely veterinarians scored lameness higher. Female and younger respondents gave higher pain scores than males and older respondents. Overall, farmers and veterinarians had a positive attitude towards pain relief in pigs with the majority agreeing that animals recovered more promptly when pain relief was administered. Most farmers agreed that the recognition and management of pain is an important part of pig husbandry, and many expressed an interest in finding out more about identifying pain in this species as well as the treatment options available. The study highlighted potential barriers to the increased application of pain relief in pigs in that almost one-third of veterinarians and two-thirds of farmers did not agree that they discussed pain management with each other, while other respondents indicated that they found it difficult to recognise pain in pigs, and did not know how to treat it appropriately. PMID- 25455387 TI - Feline health care: in our veterinarian we trust. PMID- 25455393 TI - Sports-specific injuries of the hand and wrist. AB - This article provides a philosophic overview of the management of athletes at all levels from high school to professional. It further reviews sports-specific injury patterns and position-specific injury patterns. This aspect is crucial, as many injuries may be relatively common for specific sports but rare in the general population, so recognition of these injuries requires a high degree of suspicion. The guiding principles of management are also discussed. PMID- 25455394 TI - Surgical techniques for the treatment of carpal ligament injury in the athlete. AB - Treatment of intercarpal ligament injuries in the athlete requires special attention due to several practical and biomechanical considerations. Optimally, the athlete will maintain as much function and range of motion as possible with return to high-impact and load-bearing activity in a timely fashion. Several cutting-edge techniques have arisen in treatment. This article discusses injury patterns in the athlete with scapholunate injury, lunotriquetral injury, scaphotrapezial-trapezoidal injury, and extrinsic ligamentous injury, and the various approaches to addressing these injuries, with a review of the classic as well as newer, innovative techniques. PMID- 25455396 TI - Carpal fractures other than scaphoid. AB - Carpal fractures are uncommon, but if missed, can lead to morbidity and loss of function, especially in an athlete. Early diagnosis through physical examination, plain radiographs, and possibly advanced imaging is paramount. Treatment is specific to each fracture type, and return to play varies with each clinical scenario. This article organizes current knowledge of these potentially difficult fractures with a table of diagnoses and treatment guidelines. PMID- 25455395 TI - Scaphoid fractures. AB - Scaphoid fractures are the most common carpal bone fracture, usually occurring in young men, although the incidence in women has increased over the past decade. Snuffbox tenderness and/or pain with axial loading of the thumb should be treated as a scaphoid fracture until proved otherwise and the diagnosis confirmed with serial radiographs and/or advanced imaging. Nearly all displaced scaphoid fractures should undergo operative intervention to reduce the risk of nonunion. Nondisplaced fractures have high union rates with cast treatment, but require extended periods of immobilization. Consideration may be given to operative fixation of these fractures to allow early return to sport. PMID- 25455397 TI - Metacarpal and phalangeal fractures in athletes. AB - Metacarpal and phalangeal fractures are common skeletal injuries, accounting for 10% of all fractures. Approximately one-quarter of these injuries occur during athletic events. Although an acceptable and stable reduction remains a key principle in this patient group, early mobilization and return to play may be higher priorities than in other patient populations. Orthopedic implant designs and techniques are evolving to facilitate operative fracture stabilization, improve union rates, and accelerate the postoperative course with early range of motion and return to play. This article discusses common patterns of metacarpal and phalangeal fractures resulting from athletic injuries, and current treatment strategies. PMID- 25455398 TI - Finger joint injuries. AB - Finger joint dislocations and collateral ligament tears are common athletic hand injuries. Treatment of the athlete requires a focus on safe return to play and maximizing function. Certain dislocations, such as proximal interphalangeal and distal interphalangeal volar dislocations, may be associated with tendon injuries and must be treated accordingly. Treatment of other dislocations is ultimately determined by postreduction stability, with many dislocations amenable to nonoperative treatment (ie, immobilization followed by rehabilitation). Protective splinting does not necessarily preclude athletic participation. Minor bone involvement typically does not affect the treatment plan, but significant articular surface involvement may necessitate surgical repair or stabilization. Percutaneous and internal fixation are the mainstays of surgical treatment. Treatment options that do not minimize recovery or allow the patient to return to protected play, such as external fixation, are generally avoided during the season of play. Undertreated joint injuries and unrecognized ligament injuries can result in long term disability. PMID- 25455399 TI - Thumb ulnar collateral and radial collateral ligament injuries. AB - Thumb metacarpophalangeal ulnar and radial collateral ligament injuries occur frequently in the competitive athlete. Collateral ligament integrity is essential to joint stability, pinch strength, and pain-free motion. Acute rupture of the ulnar collateral ligament is due to a sudden radial deviation force on the abducted thumb and is referred to as skier's thumb. An ulnar-directed force causes injury to the radial collateral ligament. The degree of joint instability on clinical examination allows classification of these injuries and guides management. Surgical repair of acute, complete tears results in good outcomes and allows for return to sporting activity. PMID- 25455400 TI - Ulnar-sided wrist pain in the athlete. AB - The athlete's wrist, especially those using bats, sticks, racquets, or clubs, is subjected to extremely high torque loads during athletic activities. These loads stress the stabilizing elements of the ulnocarpal and distal radioulnar complexes. Lesions of these regions can lead to painful dysfunction and instabilities that negatively impact athletic performance. This article reviews some of the common ulnar-sided maladies focusing on anatomy, biomechanics, diagnosis, and treatment. PMID- 25455401 TI - Nonspecific wrist pain in gymnasts and cheerleaders. AB - Participation in gymnastics and other upper extremity weight-bearing sports frequently requires athletes to bear significant loads through their wrists. This requirement makes wrist pain and injury of significant concern to competitive gymnasts. Athletes' wrist pain, and their ultimate evaluation and treatment, are subject to many variables. Diagnosing the cause of wrist pain in a gymnast requires understanding of the interplay between sport-specific mechanics imparted to the wrist and the individual athlete's characteristics. Treatment entails the appropriate use of conservative measures or surgical intervention with an emphasis on collaborating with all members of the patient's treatment and training team. PMID- 25455402 TI - Evaluation and treatment of jersey finger and pulley injuries in athletes. AB - The flexor tendon system in the finger is complex and can be difficult to treat. Closed injuries to the flexor tendon or pulley system are not uncommon in high level athletes. Their treatment can be complicated by in-season play, position, and the number of people involved in the patient's care. Injuries can be misdiagnosed as "sprains" or unreported by some athletes at the time of injury. Some of these injuries, especially flexor tendon avulsions, require prompt recognition and appropriate treatment to prevent permanent disability to the hand and finger. PMID- 25455403 TI - Extensor tendons injuries. AB - Extensor mechanism injuries are frequently encountered in athletes and can lead to permanent disability or deformity if not promptly and properly treated. This article reviews basic anatomy, and then discusses mallet finger injuries, boutonniere deformity, and sagittal band rupture. Once treatment has begun, return to sport is highly variable because of the varied needs of each athlete and where they fall on the spectrum of disease. As such, each athlete must be carefully evaluated and closely followed to ensure a safe, prompt, and judicious return to athletic pursuits. PMID- 25455404 TI - Therapy challenges for athletes: splinting options. AB - Therapists treating athletes with hand and wrist injuries may be involved in all stages of recovery, from the acute phase to return to sport. This article gives case examples of how creative use of custom and commercially available orthoses, splints, tape, and braces can augment various stages of recovery. Understanding the specific demands of the sport and respect for the standards of care are imperative to fabricating or fitting an athlete with the best device or customization of the athlete's own equipment for a safe return to sport. PMID- 25455405 TI - Sports hand and wrist injuries. PMID- 25455406 TI - Sports hand and wrist injuries. PMID- 25455407 TI - Need for radiotherapy in low and middle income countries - the silent crisis continues. AB - About 57% of the total number of cancer cases occur in low and middle income countries. Radiotherapy is one of the main components of cancer treatment and requires substantial initial investment in infrastructure and training. Many departments continue to have basic facilities and to use simple techniques, while modern technologies have only been installed in big cities in upper-middle income countries. More than 50% of cancer patients requiring radiotherapy in low and middle income countries lack access to treatment. The situation is dramatic in low income countries, where the proportion is higher than 90%. The overall number of additional teletherapy units needed corresponds to about twice the installed capacity in Europe. The figures for different income level groups clearly show the correlation between gross national income per capita and the availability of services. The range of radiotherapy needs currently covered varies from 0% and 3 4% in low income countries in Latin America and Africa up to 59-79% in upper middle income countries in Europe and Central Asia. The number of additional radiation oncologists, medical physicist, dosimetrists and radiation therapists (RTTs) required to operate additional radiotherapy departments needed is 43 200 professionals. Training and education programmes are not available in every developing country and in many cases the only option is sending trainees abroad, which is not a cost-effective solution. The implementation of adequate local training should be the following step after establishing the first radiotherapy facility in any country. Joint efforts should be made to establish at least one radiotherapy facility in countries where they do not exist, in order to create radiotherapy communities that could be the base for future expansion. PMID- 25455408 TI - Evidence-based estimates of the demand for radiotherapy. AB - There are different methods that may be used to estimate the future demand for radiotherapy services in a population ranging from expert opinion through to complex modelling techniques. This manuscript describes the use of evidence-based treatment guidelines to determine indications for radiotherapy. It also uses epidemiological data to estimate the proportion of the population who have attributes that suggest a benefit from radiotherapy in order to calculate the overall proportion of a population of new cases of cancer who appropriately could be recommended to undergo radiotherapy. Evidence-based methods are transparent and adaptable to different populations but require extensive information about the indications for radiotherapy and the proportion of cancer cases with those indications in the population. In 2003 this method produced an estimate that 52.4% of patients with a registered cancer-type had an indication for radiotherapy. The model was updated in 2012 because of changes in cancer incidence, stage distributions and indications for radiotherapy. The new estimate of the optimal radiotherapy utilisation rate was 48.3%. The decrease was due to changes in the relative frequency of cancer types and some changes in indications for radiotherapy. Actual rates of radiotherapy utilisation in most populations still fall well below this benchmark. PMID- 25455409 TI - Monanchosterols A and B, bioactive bicyclo[4.3.1]steroids from a Korean sponge Monanchora sp. AB - Chemical investigation of a Korean marine sponge, Monanchora sp., led to the isolation of three new steroids (1-3). Compounds 1 and 2, designated as monanchosterols A and B, respectively, represent the first examples of steroids possessing the bicyclo[4.3.1] A/B ring system from a natural source. Compounds 1 3 were investigated for their anti-inflammatory activity by evaluating their inhibitory effects on the mRNA expression of IL-6, TNF-alpha, and COX-2 in the LPS-stimulated murine RAW264.7 macrophage cells. Compounds 2 and 3 exhibited significant inhibitory effects on the mRNA expression of IL-6 without notable cytotoxicity to the cells in a dose-dependent manner. PMID- 25455410 TI - Magnetic resonance colonography with a limited bowel preparation and automated carbon dioxide insufflation in comparison to conventional colonoscopy: patient burden and preferences. AB - OBJECTIVES: To evaluate patient burden and preferences for MR colonography with a limited bowel preparation and automated carbon dioxide insufflation in comparison to conventional colonoscopy. METHODS: Symptomatic patients were consecutively recruited to undergo MR colonography with automated carbon dioxide insufflation and a limited bowel preparation followed within four weeks by colonoscopy with a standard bowel cleansing preparation. Four questionnaires regarding burden (on a five-point scale) and preferences (on a seven-point scale) were addressed after MR colonography and colonoscopy and five weeks after colonoscopy. RESULTS: Ninety nine patients (47 men, 52 women; mean age 62.3, SD 8.7) were included. None of the patients experienced severe or extreme burden from the MR colonography bowel preparation compared to 31.5% of the patients for the colonoscopy bowel preparation. Colonoscopy was rated more burdensome (25.6% severe or extreme burden) compared to MR colonography (5.2% severe or extreme burden) (P<0.0001). When discarding the bowel preparations, the examinations were rated equally burdensome (P=0.35). The majority of patients (61.4%) preferred MR colonography compared to colonoscopy (29.5%) immediately after the examinations and five weeks later (57.0% versus 39.5%). CONCLUSION: MR colonography with a limited bowel preparation and automated carbon dioxide insufflation demonstrated less burden compared to colonoscopy. The majority of patients preferred MR colonography over colonoscopy. PMID- 25455411 TI - Contrast-enhanced magnetic resonance imaging of pulmonary lesions: description of a technique aiming clinical practice. AB - OBJECTIVE: To propose a technique for evaluation of pulmonary lesions using contrast-enhanced MRI; to assess morphological patterns of enhancement and correlate quantitative analysis with histopathology. MATERIAL AND METHODS: Thirty six patients were prospectively studied. Volumetric-interpolated T1W images were obtained during consecutive breath holds after bolus triggered contrast injection. Volume coverage of first three acquisitions was limited (higher temporal resolution) and last acquisition obtained at 4th min. Two radiologists individually evaluated the patterns of enhancement. Region-of-interest-based signal intensity (SI)-time curves were created to assess quantitative parameters. RESULTS: Readers agreed moderately to substantially concerning lesions' enhancement pattern. SI-time curves could be created for all lesions. In comparison to benign, malignant lesions showed higher values of maximum enhancement, early peak, slope and 4th min enhancement. Early peak >15% showed 100% sensitivity to detect malignancy, maximum enhancement >40% showed 100% specificity. CONCLUSIONS: The proposed technique is robust, simple to perform and can be applied in clinical scenario. It allows visual evaluation of enhancement pattern/progression together with creation of SI-time curves and assessment of derived quantitative parameters. Perfusion analysis was highly sensitive to detect malignancy, in accordance to what is recommended by most recent guidelines on imaging evaluation of pulmonary lesions. PMID- 25455412 TI - Non-mass-like breast lesions at ultrasonography: feature analysis and BI-RADS assessment. AB - OBJECTIVE: To analyze the features of non-mass-like (NML) breast lesions on ultrasound (US) and determine their corresponding malignancy rate and to stratify these lesion patterns according to US BI-RADS categories. MATERIALS AND METHODS: One hundred sixty-four consecutive lesions were retrospectively classified into four types according to the US features, the corresponding positive predictive values (PPVs) were obtained. Clinical, imaging, and histopathological findings were reviewed. RESULTS: Among the 164 lesions, 39 (24%) were classified as type Ia, 14 (8%) as type Ib, 39 (24%) as type IIa, 19 (12%) as type IIb, 19 (12%) as type III, and 34 (21%) as type IV. The PPVs for malignancy were 21% for type Ia, 79% for type Ib, 10% for type IIa, 58% for type IIb, 16% for type III, and 21% for type IV. All NML lesions were classified as BI-RADS category 4a (type IIa), 4b (type Ia, III and IV) and 4c (type Ib and IIb) according to their PPVs. There was a significantly higher frequency of malignancy among lesions of type Ib and type IIb compared with the other types (P<0.01 for each). Lesions with associated calcifications, presence of abnormal axillary nodes, or a mammographic finding of suspected malignancy had a higher probability of malignancy (P<0.05 for each). CONCLUSION: US is useful in clarifying the indication for biopsy of NML lesions. The types of US classifications used in our study establish reliable references for the NML patterns when stratified according to the BI-RADS categories. PMID- 25455413 TI - A combination of preoperative CT findings and postoperative serum CEA levels improves recurrence prediction for stage I lung adenocarcinoma. AB - OBJECTIVES: To assess the prognostic value of combined evaluation of preoperative CT findings and pre/postoperative serum carcinoembryonic antigen (CEA) levels for pathological stage I lung adenocarcinoma. METHODS: This retrospective study included 250 consecutive patients who underwent complete resection for <= 3-cm pathological stage I (T1-2aN0M0) adenocarcinomas (132 men, 118 women; mean age, 67.8 years). Radiologists evaluated following CT findings: maximum tumor diameter, percentage of solid component (%solid), air bronchogram, spiculation, adjacency of bullae or interstitial pneumonia (IP) around the tumor, notch, and pleural indent. These CT findings, pre/postoperative CEA levels, age, gender, and Brinkman index were assessed by Cox proportional hazards model to determine the best prognostic model. Prognostic accuracy was examined using the area under the receiver operating characteristic curve (AUC). RESULTS: Median follow-up period was 73.2 months. In multivariate analysis, high %solid, adjacency of bullae or IP around the tumor, and high postoperative CEA levels comprised the best combination for predicting recurrence (P<0.05). A combination of these three findings had a greater accuracy in predicting 5-year disease-free survival than did %solid alone (AUC=0.853 versus 0.792; P=0.023), with a sensitivity of 85.7% and a specificity of 74.3% at the optimal threshold. The best cut-off values of %solid and postoperative CEA levels for predicting high-risk patients were >= 48% and >= 3.7 ng/mL, respectively. CONCLUSION: Compared to %solid alone, combined evaluation of %solid, adjacency of bullae or IP change around the tumor, and postoperative CEA levels improves recurrence prediction for stage I lung adenocarcinoma. PMID- 25455414 TI - Reducing iodine load in hepatic CT for patients with chronic liver disease with a combination of low-tube-voltage and adaptive statistical iterative reconstruction. AB - PURPOSE: To prospectively assess the effect of reduced iodine load to contrast enhancement, image quality, and detectability of hepatocellular carcinomas (HCCs) in hepatic CT with a combination of 80 kVp tube voltage setting and adaptive statistical iterative reconstruction (ASIR) technique in patients with chronic liver disease. MATERIALS AND METHODS: This HIPAA-compliant study was approved by our institutional review board and written informed consent was obtained in all patients. During a recent 9-month period, 170 consecutive patients (114 men and 56 women; age range, 40-85 years; mean, 67.7 years) with suspected chronic liver diseases were randomized into three CT groups according to the following iodine load and tube-voltage protocols: 600 milligram per kilogram body weight (mg/kg) iodine load and 120 peak kilovolt (kVp) tube voltage setting (600-120 group), 500 mg/kg and 80 kVp (500-80 group), and 400mg/kg and 80 kVp (400-80 group). Analysis of variance was conducted to evaluate differences in CT number, background noise, signal-to-noise ratio (SNR), effective dose, HCC-to-liver contrast-to-noise ratio (CNR), and figure of merit (FOM). Sensitivity, specificity, and area under the receiver-operating-characteristic curve (AUC) were compared to assess the detectability of HCCs. RESULTS: Vascular and hepatic enhancement in the 400-80 and 500-80 groups was comparable to or greater than that in the 600-120 group (P<.05). Subjective image quality was comparable among the three groups. Sensitivity, specificity, and AUC for detecting HCCs were comparable among the groups. The effective dose was kept low (3.3-4.1 mSv) in all three groups. CONCLUSION: Iodine load can be reduced by 33% in CT of the liver with a combination of 80 kVp tube voltage setting and ASIR technique, without compromising the contrast enhancement, image quality, and detection of HCCs. PMID- 25455415 TI - A biochemical view: Increase in polyunsaturated fatty acid omega-6/omega-3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. PMID- 25455416 TI - Prospects for versatile phase manipulation in the TEM: beyond aberration correction. AB - In this paper we explore the desirability of a transmission electron microscope in which the phase of the electron wave can be freely controlled. We discuss different existing methods to manipulate the phase of the electron wave and their limitations. We show how with the help of current techniques the electron wave can already be crafted into specific classes of waves each having their own peculiar properties. Assuming a versatile phase modulation device is feasible, we explore possible benefits and methods that could come into existence borrowing from light optics where the so-called spatial light modulators provide programmable phase plates for quite some time now. We demonstrate that a fully controllable phase plate building on Harald Rose's legacy in aberration correction and electron optics in general would open an exciting field of research and applications. PMID- 25455417 TI - Multidrug resistance genes in staphylococci from animals that confer resistance to critically and highly important antimicrobial agents in human medicine. AB - Most antimicrobial resistance genes known so far to occur in staphylococci of animal origin confer resistance to a specific class of antimicrobial agents or to selected members within such a class. However, there are also a few examples of multidrug resistance (MDR) genes that confer resistance to antimicrobial agents of different classes by either target site methylation or active efflux via ATP binding cassette (ABC) transporters. The present review provides an overview of these MDR genes with particular reference to those genes involved in resistance to critically or highly important antimicrobial agents used in human and veterinary medicine. Moreover, their location on mobile genetic elements and colocated resistance genes, which may play a role in coselection and persistence of the MDR genes, are addressed. PMID- 25455419 TI - Bacterial microcompartments and the modular construction of microbial metabolism. AB - Bacterial microcompartments (BMCs) are protein-bound organelles predicted to be present across 23 bacterial phyla. BMCs facilitate carbon fixation as well as the aerobic and anaerobic catabolism of a variety of organic compounds. These functions have been linked to ecological nutrient cycling, symbiosis, pathogenesis, and cardiovascular disease. Within bacterial cells, BMCs are metabolic modules that can be further dissociated into their constituent structural and functional protein domains. Viewing BMCs as genetic, structural, functional, and evolutionary modules provides a framework for understanding both BMC-mediated metabolism and for adapting their architectures for applications in synthetic biology. PMID- 25455420 TI - The importance of vitamin K monitoring with warfarin (Coumadin) use in chronic kidney disease patients. PMID- 25455418 TI - Viral biocontrol: grand experiments in disease emergence and evolution. AB - Although viral emergence is commonly associated with cross-species transmission, the processes and determinants of viral evolution in a novel host environment are poorly understood. We address key questions in virus emergence and evolution using data generated from two unique natural experiments: the deliberate release of myxoma virus (MYXV) and rabbit hemorrhagic disease virus (RHDV) as biological control (biocontrol) agents against the European rabbit in Australia, and which have been of enormous benefit to Australia's ecosystem and agricultural industries. Notably, although virulence evolution in MYXV and RHDV followed different trajectories, a strongly parallel evolutionary process was observed in Australia and Europe. These biocontrol agents were also characterized by a lack of transmission to nontarget host species, suggesting that there are major barriers to successful emergence. PMID- 25455421 TI - Intradialytic protein supplementation reduces inflammation and improves physical function in maintenance hemodialysis patients. AB - OBJECTIVE: Protein malnutrition is both a cause and consequence of inflammation and related comorbidities for maintenance hemodialysis (MHD) patients. This study sought to determine if oral supplementation with soy or whey protein during dialysis treatment reduces inflammation and improves physical function and body composition in MHD patients. DESIGN: The design used in the study was randomized controlled trial, and the setting used was hemodialysis clinics in Champaign and Chicago, Illinois. SUBJECTS: Patients who received treatment >=3 days/week, were ages >=30 years did not have congestive heart failure or chronic obstructive pulmonary disease, and were receiving dialysis treatment for >=3 months were eligible for inclusion. INTERVENTION: Patients were randomized to oral supplementation with a whey protein, soy protein, or placebo beverage. Patients (WHEY, n = 11; SOY, n = 12; CON, n = 15) consumed their assigned beverage before every dialysis session for 6 months. MAIN OUTCOME MEASURES: Body composition was measured by dual-energy x-ray absorptiometry, physical function by gait speed and shuttle walk test, and markers of inflammation (C-reactive protein and interleukin 6) using commercially available enzyme-linked immunosorbent assay kits before and after the 6-month intervention. Dietary intake was assessed by 24 hour dietary recalls. RESULTS: Six months of whey or soy supplementation significantly reduced predialysis interleukin 6 levels (P < .05 for both), whereas there was a trend for a reduction in C-reactive protein when both protein groups were combined (P = .062). Gait speed and shuttle walk test performance also significantly improved in the protein groups (P < .05 for both). No changes in body composition were observed. However, alkaline phosphatase, a marker of bone turnover, was significantly reduced in the protein groups. CONCLUSIONS: Intradialytic protein supplementation during a 6-month intervention reduced inflammation and improved physical function and represents an affordable intervention to improve the health of MHD patients. PMID- 25455422 TI - The nutritional status of patients starting specialized predialysis care. AB - OBJECTIVE: To examine the prevalence of and risk factors for malnutrition at the start of specialized predialysis care. DESIGN: The present analysis was performed on cross-sectional data collected at inclusion in the study. The study included 25 outpatient clinics delivering specialized predialysis care in the Netherlands. SUBJECTS: Three hundred seventy-six incident patients with advanced chronic kidney disease attending one of the participating outpatient clinics. MAIN OUTCOME MEASURE: Subjective global assessment (SGA) of nutritional status. RESULTS: At the start of specialized predialysis care, 11% of patients suffer from moderate protein-energy wasting as measured by SGA. Independent risk factors are age >75 years (Odds ratio [OR], 3.88 [1.74-8.66]), female gender (OR, 2.95 [1.37-6.32]), and having a body mass index <25 kg/m(2) (OR, 2.56 [1.19-5.49]). Estimated glomerular filtration rate was not significantly associated with SGA (OR, 1.63 [0.76-3.48]). CONCLUSIONS: Eleven percent of patients started on specialized predialysis care suffer from moderate protein-energy wasting; risk factors are age >75 years, female gender, and BMI <25 kg/m(2). PMID- 25455423 TI - Noise and cardiovascular effects in workers of the sanitary fixtures industry. AB - The aim of the present study is to evaluate whether workers in the sanitary fixtures industry are a category at risk of developing cardiovascular diseases, and in particular, whether chronic noise exposure may play a role in cardiovascular effects in exposed workers. Seventy-five employees engaged in sanitation fixtures production and a control group of sixty-four office workers, who were not exposed to agents that could damage the cardiovascular system, participated in our study. The selected workers completed a clinical-anamnestic questionnaire, and underwent a medical examination, blood pressure test, electrocardiogram (ECG), blood tests, and audiometry. Measurements of environmental noise, dust, and lead were also carried out. The exposed workers, in comparison to the control group, showed a higher frequency of hypertension, systolic and diastolic blood pressure (p<0.05, p<0.05), as well as electrocardiographic abnormalities (p<0.05). There was also a higher frequency of hypertension and electrocardiographic abnormalities among subjects with audiometric deficit compared to normoacoustic subjects (p<0.05 and p<0.05). RESULTS: from our study suggest that work activity in the sanitary fixtures industry can have an influence on the cardiovascular system, and noise can be the main cause of damage for the cardiovascular system in exposed workers, as cardiovascular damage seems to be linked to hearing loss. PMID- 25455424 TI - Characterisation of mainstream and passive vapours emitted by selected electronic cigarettes. AB - Electronic cigarettes have achieved growing popularity since their introduction onto the European market. They are promoted by manufacturers as healthier alternatives to tobacco cigarettes, however debate among scientists and public health experts about their possible impact on health and indoor air quality means further research into the product is required to ensure decisions of policymakers, health care providers and consumers are based on sound science. This study investigated and characterised the impact of 'vaping' (using electronic cigarettes) on indoor environments under controlled conditions using a 30m(3) emission chamber. The study determined the composition of e-cigarette mainstream vapour in terms of propylene glycol, glycerol, carbonyls and nicotine emissions using a smoking machine with adapted smoking parameters. Two different base recipes for refill liquids, with three different amounts of nicotine each, were tested using two models of e-cigarettes. Refill liquids were analysed on their content of propylene glycol, glycerol, nicotine and qualitatively on their principal flavourings. Possible health effects of e-cigarette use are not discussed in this work. Electronic cigarettes tested in this study proved to be sources for propylene glycol, glycerol, nicotine, carbonyls and aerosol particulates. The extent of exposure differs significantly for active and passive 'vapers' (users of electronic cigarettes). Extrapolating from the average amounts of propylene glycol and glycerol condensed on the smoking machine filter pad to the resulting lung-concentration, estimated lung concentrations of 160 and 220mgm(-3) for propylene glycol and glycerol were obtained, respectively. Vaping refill liquids with nicotine concentrations of 9mgmL(-1) led to vapour condensate nicotine amounts comparable to those of low-nicotine regular cigarettes (0.15 0.2mg). In chamber studies, peak concentrations of 2200MUgm(-3) for propylene glycol, 136MUgm(-3) for glycerol and 0.6MUgm(-3) for nicotine were reached. Carbonyls were not detected above the detection limits in chamber studies. Particles in the size range of 20nm to 300nm constantly increased during vaping activity and reached final peak concentrations of 7*10(6)particlesL(-1). Moreover, the tested products showed design flaws such as leakages from the cartridge reservoirs. Possible long term effects of e-cigarettes on health are not yet known. E-cigarettes, the impact of vaping on health and the composition of refill liquids require therefore further research into the product characteristics. The consumers would benefit from harmonised quality and safety improvements of e-cigarettes and refill liquids. PMID- 25455425 TI - Genetic influences on the acquisition and inhibition of fear. AB - As a variant of the Pavlovian fear conditioning paradigm the conditional discrimination design allows for a detailed investigation of fear acquisition and fear inhibition. Measuring fear-potentiated startle responses, we investigated the influence of two genetic polymorphisms (5-HTTLPR and COMT Val(158)Met) on fear acquisition and fear inhibition which are considered to be critical mechanisms for the etiology and maintenance of anxiety disorders. 5-HTTLPR s allele carriers showed a more stable potentiation of the startle response during fear acquisition. Homozygous COMT Met-allele carriers, which had demonstrated delayed extinction in previous investigations, show deficient fear inhibition in presence of a learned safety signal. Thus, our results provide further evidence that 5-HTTLPR and COMT Val(158)Met genotypes influence the vulnerability for the development of anxiety disorders via different mechanisms. PMID- 25455426 TI - Surface Laplacian of scalp electrical signals and independent component analysis resolve EMG contamination of electroencephalogram. AB - The serious impact of electromyogram (EMG) contamination of electroencephalogram (EEG) is well recognised. The objective of this research is to demonstrate that combining independent component analysis with the surface Laplacian can eliminate EMG contamination of the EEG, and to validate that this processing does not degrade expected neurogenic signals. The method involves sequential application of ICA, using a manual procedure to identify and discard EMG components, followed by the surface Laplacian. The extent of decontamination is quantified by comparing processed EEG with EMG-free data that was recorded during pharmacologically induced neuromuscular paralysis. The combination of the ICA procedure and the surface Laplacian, with a flexible spherical spline, results in a strong suppression of EMG contamination at all scalp sites and frequencies. Furthermore, the ICA and surface Laplacian procedure does not impair the detection of well-known, cerebral responses; alpha activity with eyes-closed; ERP components (N1, P2) in response to an auditory oddball task; and steady state responses to photic and auditory stimulation. Finally, more flexible spherical splines increase the suppression of EMG by the surface Laplacian. We postulate this is due to ICA enabling the removal of local muscle sources of EMG contamination and the Laplacian transform being insensitive to distant (postural) muscle EMG contamination. PMID- 25455427 TI - Comparison of different spatial transformations applied to EEG data: A case study of error processing. AB - The purpose of this paper is to compare the effects of different spatial transformations applied to the same scalp-recorded EEG data. The spatial transformations applied are two referencing schemes (average and linked earlobes), the surface Laplacian, and beamforming (a distributed source localization procedure). EEG data were collected during a speeded reaction time task that provided a comparison of activity between error vs. correct responses. Analyses focused on time-frequency power, frequency band-specific inter-electrode connectivity, and within-subject cross-trial correlations between EEG activity and reaction time. Time-frequency power analyses showed similar patterns of midfrontal delta-theta power for errors compared to correct responses across all spatial transformations. Beamforming additionally revealed error-related anterior and lateral prefrontal beta-band activity. Within-subject brain-behavior correlations showed similar patterns of results across the spatial transformations, with the correlations being the weakest after beamforming. The most striking difference among the spatial transformations was seen in connectivity analyses: linked earlobe reference produced weak inter-site connectivity that was attributable to volume conduction (zero phase lag), while the average reference and Laplacian produced more interpretable connectivity results. Beamforming did not reveal any significant condition modulations of connectivity. Overall, these analyses show that some findings are robust to spatial transformations, while other findings, particularly those involving cross trial analyses or connectivity, are more sensitive and may depend on the use of appropriate spatial transformations. PMID- 25455429 TI - Regulatory focus moderates the relationship between task control and physiological and psychological markers of stress: a work simulation study. AB - This experiment examined whether trait regulatory focus moderates the effects of task control on stress reactions during a demanding work simulation. Regulatory focus describes two ways in which individuals self-regulate toward desired goals: promotion and prevention. As highly promotion-focused individuals are oriented toward growth and challenge, it was expected that they would show better adaptation to demanding work under high task control. In contrast, as highly prevention-focused individuals are oriented toward safety and responsibility they were expected to show better adaptation under low task control. Participants (N=110) completed a measure of trait regulatory focus and then three trials of a demanding inbox activity under either low, neutral, or high task control. Heart rate variability (HRV), affective reactions (anxiety & task dissatisfaction), and task performance were measured at each trial. As predicted, highly promotion focused individuals found high (compared to neutral) task control stress buffering for performance. Moreover, highly prevention-focused individuals found high (compared to low) task control stress-exacerbating for dissatisfaction. In addition, highly prevention-focused individuals found low task control stress buffering for dissatisfaction, performance, and HRV. However, these effects of low task control for highly prevention-focused individuals depended on their promotion focus. PMID- 25455428 TI - The face evoked steady-state visual potentials are sensitive to the orientation, viewpoint, expression and configuration of the stimuli. AB - Previous studies demonstrated that the steady-state visual-evoked potential (SSVEP) is reduced to the repetition of the same identity face when compared with the presentation of different identities, suggesting high-level neural adaptation to face identity. Here we investigated whether the SSVEP is sensitive to the orientation, viewpoint, expression and configuration of faces (Experiment 1), and whether adaptation to identity at the level of the SSVEP is robust enough to generalize across these properties (Experiment 2). In Experiment 1, repeating the same identity face with continuously changing orientation, viewpoint or expression evoked a larger SSVEP than the repetition of an unchanged face, presumably reflecting a release of adaptation. A less robust effect was observed in the case of changes affecting face configuration. In Experiment 2, we found a similar release of adaptation for faces with changing orientation, viewpoint and configuration, as there was no difference between the SSVEP for the same and different identity faces. However, we found an adaptation effect for faces with changing expressions, suggesting that face identity coding, as reflected in the SSVEP, is largely independent of the emotion displayed by faces. Taken together, these results imply that the SSVEP taps high-level face representations which abstract away from the changeable aspects of the face and likely incorporate information about face configuration, but which are specific to the orientation and viewpoint of the face. PMID- 25455430 TI - Hypertrophic olivary degeneration and cerebrovascular disease: movement in a triangle. AB - Hypertrophic olivary degeneration is a rare kind of trans-synaptic degeneration that occurs after lesions of the dentatorubro-olivary pathway. The lesions, commonly unilateral, may result from hemorrhage due to vascular malformation, trauma, surgical intervention or hypertension, tumor, or ischemia. Bilateral cases are extremely rare. This condition is classically associated with development of palatal tremor, but clinical manifestations can include other involuntary movements. We describe 2 cases: unilateral hypertrophic olivary degeneration in a 60-year-old man with contralateral athetosis and neurologic worsening developing several years after a pontine hemorrhage and bilateral hypertrophic olivary degeneration in a 77-year-old woman with development of palatal tremor, probably secondary to pontine ischemic lesions (small vessel disease). PMID- 25455431 TI - [International recommandations on physical exercise for pregnant women]. AB - Benefits of physical exercise on the physical and psychological health lead to specifics guidelines during pregnancy. For pregnant women, to take part in aerobics exercise (walking, biking) (i.e. 30 minutes, three times per week at 60 90% of the maximal heart rate) and strength training (i.e. one to two times per week) is recommended. Physical exercise programs during pregnancy have shown benefits for preventing and treating complications pregnancy (e.g. gestational diabetes mellitus, overweight). Benefits of exercise and risks associated with sedentary should be widely diffused among pregnant women and prenatal caregivers. PMID- 25455432 TI - Comparative efficacy of tadalafil once daily in men with erectile dysfunction who demonstrated previous partial responses to as-needed sildenafil, tadalafil, or vardenafil. AB - OBJECTIVE: Phosphodiesterase type-5 inhibitors (PDE5Is) are first-line therapies for erectile dysfunction (ED). Sildenafil (SIL) and vardenafil (VAR) are approved for as-needed (PRN) dosing; tadalafil (TAD) is approved for both PRN and once-a day (OaD) dosing for ED. Recent evidence suggests that TAD-OaD may be effective as therapy in men with an incomplete response to PRN-PDE5I therapy. This study evaluated whether TAD-OaD provides similar efficacy in men with ED who had previously demonstrated a partial response to PRN-PDE5I therapy. RESEARCH DESIGN AND METHODS: In this randomized, double-blind, placebo-controlled trial, men with a >=3 month ED history received SIL 100 mg, TAD 20 mg, or VAR 20 mg during a 4 week open-label lead-in period. Those with International Index of Erectile Function - Erectile Function (IIEF-EF) domain scores <26 following lead-in treatment completed a 4 week washout period, then randomized to TAD 2.5 mg up titrated to 5 mg, TAD 5 mg, or placebo (PBO) OaD for 12 weeks. MAIN OUTCOME MEASURES obtained from patients treated with TAD-OaD were compared to PBO-treated patients. Additionally, results of treatment with TAD-OaD were compared to results obtained from 4 week PRN-PDE5I therapy to determine whether OaD and PRN regimens provided comparable efficacy. CLINICAL TRIAL REGISTRATION: NCT01130532. MAIN OUTCOME MEASURES: International Index of Erectile Function (IIEF) domain scores; Sexual Encounter Profile (SEP) questions 2-5. RESULTS: Endpoint data was obtained from 590 men (391 TAD; 199 PBO). RESULTS for all IIEF and SEP measures were significantly better for TAD-OaD (p < 0.001 for all) compared to PBO and were comparable to those observed during PRN-PDE5I treatment. TAD 2.5 mg and TAD 5 mg OaD therapy were safe and generally well tolerated. CONCLUSION: Tadalafil once daily is a viable alternative to as-needed PDE5I therapy in men with ED. Key limitations include the lack of a PRN PDE5I study group during the double-blind period, and that many more patients took tadalafil than sildenafil or vardenafil during the PRN period. PMID- 25455433 TI - Pilot study demonstrating that sole mechanosensitivity can be affected by insole use. AB - Insoles are known to alter plantar loads and thus plantar sensory input. We therefore hypothesised that plantar somatosensory sensation could be modified over time by use of hard metatarsal pads. A sample of 12 healthy female participants was randomly allocated to either soft metatarsal pads (n=6, latex foam, Shore A11) or hard metatarsal pads groups (n = 6, thermoplastic, ShoreA65). All wore the same shoe type and pedometers measured daily activities. Using a bespoke actuated device, multiple mechanical stimuli were applied to the forefoot and rearfoot before and after 8 and 30 days of wearing the pads. A control test comprised estimation of multiple auditory sensations at day 0, 8 and 30. Changes in detection of the mechanical and sound stimuli were estimated using the Stevens power function, Psi = k * Phi(n) (estimate = Psi; stimulus = Phi). The k coefficient measured the sensitivity, i.e. the lowest detectable load/sound, and the n coefficient the gain in perception over time. After 30 days, hard metatarsal pads group had increased plantar sensitivity in the forefoot but not the rearfoot. The soft metatarsal pads group showed no changes in plantar sensitivity and the detection of auditory sensation remained stable over the 30 days.Metatarsal pads with relatively high hardness increased the perception of the lowest mechanical stimulus in the forefoot compared to soft metatarsal pads. This provides initial evidence of the potential for changes in plantar somatosensory sensation due to choice of orthotic designs in patients with foot related problems. PMID- 25455435 TI - Walking dynamic similarity induced by a combination of Froude and Strouhal dimensionless numbers: Modela-w. AB - The aim of this study was to assess the accuracy of a new dimensionless number associating Froude (Nfr) and Strouhal (Str) called Modela-w to induce walking dynamic similarity among humans of different sizes. Nineteen subjects walked in three experimental conditions: (i) constant speed, (ii) similar speed (Nfr) and (iii) similar speed and similar step frequency (Modela-w). The dynamic similarity was evaluated from scale factors computed with anthropometric, temporal, kinematic and kinetic data and from the decrease of the variability of the parameters expressed in their dimensionless form. Over a total of 36 dynamic parameters, dynamic similarity from scale factors was met for 11 (mean r = 0.51), 22 (mean r = 0.52) and 30 (mean r = 0.69) parameters in the first, the second and the third experimental conditions, respectively. Modela-w also reduced the variability of the dimensionless preceding parameters compared to the other experimental conditions. This study shows that the combination of Nfr and Str called Modela-w ensures dynamic similarity between different-sized subjects and allows scientists to impose similar experimental conditions removing all anthropometric effects. PMID- 25455434 TI - The influence of cognitive load and walking speed on gait regularity in children and young adults. AB - The dual-process account of sensorimotor-cognitive interactions postulates that easy cognitive tasks can lead to performance improvements in the motor domain (e.g., an increased stability while walking or balancing) across the lifespan. However, cross-domain resource competition can lead to performance decrements in motor tasks when the concurrent cognitive task is very difficult, and older adults have shown performance decrements in their motor functioning under such circumstances. Resource limitations are particularly pronounced not only in old adulthood, but also in childhood. The current study investigates the relationship of walking speed and cognitive load on walking regularity in 7- and 9-year olds and young adults, with 18 participants in each group. Participants were walking on a treadmill at their preferred speed, and with speeds that were 30% faster and 30% slower than preferred. Regularity of lower-body coordination was operationalized as the residual variance of principal component analyses performed on the data of a motion analysis system. All age groups showed a more regular gait with increasing walking speed. Young adults' gait regularity was not influenced by cognitive load, whereas children showed a U-shaped relationship of cognitive load and walking regularity, with the highest regularity when performing an easy cognitive task. It can be concluded that children are also influenced by cross-domain resources competition in challenging cognitive-motor dual-task situations. PMID- 25455436 TI - Uphill walking with a simple exoskeleton: plantarflexion assistance leads to proximal adaptations. AB - While level walking with a pneumatic ankle-foot exoskeleton is studied extensively, less is known on uphill walking. The goals of this study were to get a better understanding of the biomechanical adaptations and the influence of actuation timing on metabolic cost during uphill walking with a plantarflexion assisting exoskeleton. Seven female subjects walked on a treadmill with 15% inclination at 1.36 ms(-1) in five conditions (4 min): one condition with an unpowered exoskeleton and four with a powered exoskeleton with onset of pneumatic muscle actuation at 19, 26, 34 and 41% of stride. During uphill walking the metabolic cost was more than 10% lower for all powered conditions compared to the unpowered condition. When actuation onset was in between 26 and 34% of the stride, metabolic cost was suggested to be minimal. While it was expected that exoskeleton assistance would reduce muscular activity of the plantarflexors during push-off, subjects used the additional power to raise the body centre of mass in the beginning of each step to a higher point compared to unpowered walking. This reduced the muscular activity in the m. vastus lateralis and the m. biceps femoris as less effort was necessary to reach the highest body centre of mass position in the single support phase. In conclusion, subjects can use plantarflexion assistance during the push-off to reduce muscular activity in more proximal joints in order to minimize energy cost during uphill locomotion. Kinetic data seem necessary to fully understand this mechanism, which highlights the complexity of human-exoskeleton interaction. PMID- 25455437 TI - The effects of arm crank ergometry, cycle ergometry and treadmill walking on postural sway in healthy older females. AB - Older adults are increasingly being encouraged to exercise but this may lead to muscle fatigue, which can adversely affect postural stability. Few studies have investigated the effects of upper body exercise on postural sway in groups at risk of falling, such as the elderly. The purpose of this study was to compare the effects arm crank ergometry (ACE), cycle ergometry (CE) and treadmill walking (TM) on postural sway in healthy older females. In addition, this study sought to determine the time necessary to recover postural control after exercise. A total of nine healthy older females participated in this study. Participants stood on a force platform to assess postural sway which was measured by displacement of the centre of pressure before and after six separate exercise trials. Each participant completed three incremental exercise tests to 85% of individual's theoretical maximal heart rate (HRMAX) for ACE, CE and TM. Subsequent tests involved 20-min of ACE, CE and TM exercise at a relative workload corresponding to 50% of each individual's predetermined heart rate reserve (HRE). Post fatigue effects and postural control recovery were measured at different times after exercise (1, 3, 5, 10, 15 and 30-min). None of the participants exhibited impaired postural stability after ACE. In contrast, CE and TM elicited significant post exercise balance impairments, which lasted for ~ 10 min post exercise. We provide evidence of an exercise mode which does not elicit post exercise balance impairments. Older adults should exercise caution immediately following exercise engaging the lower limbs to avoid fall risk. PMID- 25455438 TI - Rotation effects on the target-volume margin determination. AB - Rotational setup errors are usually neglected in most clinical centers. An analytical formula is developed to determine the extra margin between clinical target volume (CTV) and planning target volume (PTV) to account for setup errors. The proposed formula corrects for both translational and rotational setup errors and then incorporated into margin determination for PTV. PMID- 25455439 TI - A newly-developed metal artifact reduction algorithm improves the visibility of oral cavity lesions on 320-MDCT volume scans. AB - PURPOSE: To investigate whether a newly-developed single-energy metal artifact reduction (SEMAR) algorithm applied to images acquired on a 320-MDCT volume scanner reduces image artifacts from dental metal. METHODS: We inserted the lower right teeth covered with a dental metal alloy and crown in a skull phantom and performed single-volume scanning on a second-generation 320-MDCT scanner. A 12-mm diameter spherical lesion was placed either close to or far from the dental metal. The tube voltage and current were 120 kVp and 80 or 155 mA, respectively. Images were reconstructed with filtered back projection (FBP) or iterative reconstruction (IR), with or without SEMAR. We calculated the signal-to-artifact ratios (SAR) to quantify the visibility of the lesion. Two radiologists inspected 96 images (48 with lesion and 48 without) for the presence or absence of the lesion using a 5-point ordinal scale (1 = definitely absent to 5 = definitely present). RESULTS: On images reconstructed with FPB and IR with SEMAR, streak artifacts from the dental metal were reduced substantially compared to images without SEMAR. At 155 mA with the lesion near the dental metal, the SARs were better on FBP and IR images (FBP: 1.7 and 0.5 with and without SEMAR, respectively; IR: 1.6 and 0.9 with and without SEMAR, respectively). The observer visual scores improved with SEMAR (FBP: 4.2 and 3.2 with and without SEMAR, respectively; IR: 4.2 and 3.0). CONCLUSION: The SEMAR algorithm reduces dental metal artifacts and improves lesion detectability and image quality in patients with oral cavity lesions. PMID- 25455440 TI - Image guided particle therapy in CNAO room 2: implementation and clinical validation. AB - In this contribution we describe the implementation of a novel solution for image guided particle therapy, designed to ensure the maximal accuracy in patient setup. The presented system is installed in the central treatment room at Centro Nazionale di Adroterapia Oncologica (CNAO, Italy), featuring two fixed beam lines (horizontal and vertical) for proton and carbon ion therapy. Treatment geometry verification is based on robotic in-room imaging acquisitions, allowing for 2D/3D registration from double planar kV-images or 3D/3D alignment from cone beam image reconstruction. The calculated six degrees-of-freedom correction vector is transferred to the robotic patient positioning system, thus yielding automated setup error compensation. Sub-millimetre scale residual errors were measured in absolute positioning of rigid phantoms, in agreement with optical- and laser based assessment. Sub-millimetre and sub-degree positioning accuracy was achieved when simulating setup errors with anthropomorphic head, thorax and pelvis phantoms. The in-house design and development allowed a high level of system customization, capable of replicating the clinical performance of commercially available products, as reported with preliminary clinical results in 10 patients. PMID- 25455441 TI - Photon-beam radiotherapy in pregnant patients: can the fetal dose be limited to 10 cGy or less? AB - PURPOSE: To estimate fetal dose and its components from three-dimensional conformal radiotherapy for several malignancies presented during pregnancy. MATERIALS AND METHODS: Fetal dose was measured from radiotherapy for Hodgkin's lymphoma and for tumors in the region of nasopharynx, breast and lung. Anthropomorphic phantoms were used to simulate an average pregnant patient at the first, second and third trimesters of gestation. Thermoluminescent dosemeters (TLD) were employed for fetal dose measurements. Phantom exposures were also performed to estimate fetal dose due to head leakage, scatter from collimators and beam modifiers and scatter generated inside the phantom (Din). All treatments were delivered for 6 MV photon beams. RESULTS: Radiotherapy of Hodgkin's lymphoma resulted in a fetal dose of 5.6-57.9 cGy depending upon the gestational age and the distance between the fetal level and the field edge. The corresponding dose ranges for treatment of nasopharyngeal, breast and lung cancer was 4.0-17.1 cGy, 3.9-24.8 cGy and 5.7-74.3 cGy, respectively. The Din at the first trimester of gestation was always smaller than 10 cGy for all examined malignancies. Pregnancy progression resulted in Din values above or below 10 cGy depending upon the treatment site and gestational age. CONCLUSION: This study provides data about the fetal exposure and the contribution of Din to the total fetal dose from conformal radiation therapy. The Din knowledge prior to patient's irradiation enables radiation oncologists and medical physicists to decide whether fetal dose may be limited to 10 cGy or less with or without the introduction of special shielding materials. PMID- 25455442 TI - Normal tissue complication probability models for severe acute radiological lung injury after radiotherapy for lung cancer. AB - PURPOSE: To derive Normal Tissue Complication Probability (NTCP) models for severe patterns of early radiological radiation-induced lung injury (RRLI) in patients treated with radiotherapy (RT) for lung tumors. Second, derive threshold doses and optimal doses for prediction of RRLI to be used in differential diagnosis of tumor recurrence from RRLI during follow-up. METHODS AND MATERIALS: Lyman-EUD (LEUD), Logit-EUD (LogEUD), relative seriality (RS) and critical volume (CV) NTCP models, with DVH corrected for fraction size, were used to model the presence of severe early RRLI in follow-up CTs. The models parameters, including alpha/beta, were determined by fitting data from forty-five patients treated with IMRT for lung cancer. Models were assessed using Akaike information criterion (AIC) and area under receiver operating characteristic curve (AUC). Threshold doses for risk of RRLI and doses corresponding to the optimal point of the receiver operating characteristic (ROC) curve were determined. RESULTS: The alpha/betas obtained with different models were 2.7-3.2 Gy. The thresholds and optimal doses curves were EUDs of 3.2-7.8 Gy and 15.2-18.1 Gy with LEUD, LogEUD and RS models, and MUd of 0.013 and 0.071 with the CV model. NTCP models had AUCs significantly higher than 0.5. Occurrence and severity of RRLI were correlated with patients' values of EUD and MUd. CONCLUSIONS: The models and dose levels derived can be used in differential diagnosis of tumor recurrence from RRLI in patients treated with RT. Cross validation is needed to prove prediction performance of the model outside the dataset from which it was derived. PMID- 25455443 TI - In regard to: "Dosimetric verification of a high dose rate brachytherapy treatment planning system in homogeneous and heterogeneous media". PMID- 25455444 TI - Biomonitoring occupational sevoflurane exposure at low levels by urinary sevoflurane and hexafluoroisopropanol. AB - This study aimed to correlate environmental sevoflurane levels with urinary concentrations of sevoflurane (Sev-U) or its metabolite hexafluoroisopropanol (HFIP) in order to assess and discuss the main issues relating to which biomarker of sevoflurane exposure is best, and possibly suggest the corresponding biological equivalent exposure limit values. Individual sevoflurane exposure was measured in 100 healthcare operators at five hospitals in north-east Italy using the passive air sampling device Radiello((r)), and assaying Sev-U and HFIP concentrations in their urine collected at the end of the operating room session. All analyses were performed by gas chromatography-mass spectrometry. Environmental sevoflurane levels in the operating rooms were also monitored continuously using an infrared photoacoustic analyzer. Our results showed very low individual sevoflurane exposure levels, generally below 0.5 ppm (mean 0.116 ppm; range 0.007-0.940 ppm). Sev-U and HFIP concentrations were in the range of 0.1-17.28 MUg/L and 5-550 MUg/L, respectively. Both biomarkers showed a statistically significant correlation with the environmental exposure levels (Sev U, r=0.49; HFIP, r=0.52), albeit showing fairly scattered values. Sev-U values seem to be influenced by peaks of exposure, especially at the end of the operating-room session, whereas HFIP levels by exposure on the previous day, the data being consistent with the biomarkers' very different half-lives (2.8 and 19 h, respectively). According to our results, both Sev-U and HFIP are appropriate biomarkers for assessing sevoflurane exposure at low levels, although with some differences in times/patterns of exposure. More work is needed to identify the best biomarker of sevoflurane exposure and the corresponding biological equivalent exposure limit values. PMID- 25455445 TI - Screening of population level biomonitoring data from the Canadian Health Measures Survey in a risk-based context. AB - Since 2007, the Canadian Health Measures Survey (CHMS) has been collecting biomonitoring data from the general Canadian population and has provided, to date, nationally representative concentrations for hundreds of environmental biomarkers in blood or urine. Biomonitoring Equivalents (BEs) have been developed as tools to help interpret biomonitoring data in a health risk context at a population level. In this paper, BEs are used to relate biomonitoring data from the CHMS (2007-2011) to existing exposure guidance values developed by Health Canada and other government agencies. Chemical-specific hazard quotients (HQs) and/or cancer risk estimates are calculated using existing BEs corresponding to environmental chemicals analyzed in the CHMS. For the majority of environmental chemicals, calculated HQ values are less than 1 indicating exposure is below published exposure guidance values. Individual biomonitoring data for two biomarkers of metal exposure (inorganic arsenic and cadmium) resulted in HQ values exceeding 1 suggesting that exposure may be above existing guidance values for a portion of the population, at least intermittently. This type of analysis may be used by researchers, risk assessors, and risk managers in prioritization efforts. PMID- 25455446 TI - Biomonitoring of N-ethyl-2-pyrrolidone in automobile varnishers. AB - N-alkyl-2-pyrrolidones are important organic solvents for varnishes in industry. This study investigates exposure to N-ethyl-2-pyrrolidone (NEP) in varnishing of hard plastic components in an automobile plant. Two specific biomarkers of exposure, 5-hydroxy-N-ethyl-2-pyrrolidone (5-HNEP) and 2-hydroxy-N ethylsuccinimide (2-HESI), were analyzed in urine samples of 14 workers. For this purpose, pre-shift, post-shift and next day pre-shift urine samples were collected midweek. Twelve workers performed regular work tasks (loading, wiping and packing), whereas two workers performed special work tasks including cleaning the sprayer system with organic solvents containing N-alkyl-2-pyrrolidones. Spot urine samples of nine non-exposed persons of the same plant served as controls. Median post-shift urinary levels of workers with regular work tasks (5-HNEP: 0.15 mg/L; 2-HESI: 0.19 mg/L) were ~5-fold higher compared to the controls (0.03 mg/L each). Continuously increasing metabolite levels, from pre-shift via post-shift to pre-shift samples of the following day, were observed in particular for the two workers with the special working tasks. Maximum levels were 31.01 mg/L (5 HNEP) and 8.45 mg/L (2-HESI). No clear trend was evident for workers with regular working tasks. In summary, we were able to show that workers can be exposed to NEP during varnishing tasks in the automobile industry. PMID- 25455447 TI - Uptake and elimination of permethrin related to the use of permethrin treated clothing for forestry workers. AB - Wearing of permethrin treated clothing usually implicates an uptake of permethrin by the user. Aim of our study was to examine the kinetics of internal permethrin exposure in volunteers during and after a single 8h-use of treated clothing as well as factors potentially influencing permethrin uptake. 28 male volunteers (age: 20-34 years) were equipped with permethrin treated jackets and pants from two different suppliers. The clothing was worn for 8h, simulating differing external conditions, including comfort conditions as well as conditions of increased temperature and humidity without and with additional physical workload. Internal permethrin exposure was monitored by determination of permethrin metabolites (DCCA and 3-PBA) in a set of 12 urine samples, covering a period of 504 h from the beginning of the wearing interval. Time-concentration curves showed an increase of internal exposure associated with wearing of the clothing (individual maximum: 109.5 MUg/L) followed by a first-order like decay (mean half life: 38.5 h). Metabolite excretion was affected by the make of clothing, which could be explained by differing permethrin contents of the garment. Furthermore, internal exposure increased with increasing temperature/humidity and additional physical workload. Assuming dermal uptake of permethrin, this may be ascribed to an alteration of the barrier function of the skin. PMID- 25455448 TI - Evaluation of three physiologically based pharmacokinetic (PBPK) modeling tools for emergency risk assessment after acute dichloromethane exposure. AB - INTRODUCTION: Physiologically based pharmacokinetic (PBPK) models may be useful in emergency risk assessment, after acute exposure to chemicals, such as dichloromethane (DCM). We evaluated the applicability of three PBPK models for human risk assessment following a single exposure to DCM: one model is specifically developed for DCM (Bos) and the two others are semi-generic ones (Mumtaz and Jongeneelen). MATERIALS AND METHODS: We assessed the accuracy of the models' predictions by simulating exposure data from a previous healthy volunteer study, in which six subjects had been exposed to DCM for 1h. The time-course of both the blood DCM concentration and percentage of carboxyhemoglobin (HbCO) were simulated. RESULTS: With all models, the shape of the simulated time course resembled the shape of the experimental data. For the end of the exposure, the predicted DCM blood concentration ranged between 1.52-4.19mg/L with the Bos model, 1.42-4.04mg/L with the Mumtaz model, and 1.81-4.31mg/L with the Jongeneelen model compared to 0.27-5.44mg/L in the experimental data. % HbCO could be predicted only with the Bos model. The maximum predicted % HbCO ranged between 3.1 and 4.2% compared to 0.4-2.3% in the experimental data. The % HbCO predictions were more in line with the experimental data after adjustment of the Bos model for the endogenous HbCO levels. CONCLUSIONS: The Bos Mumtaz and Jongeneelen PBPK models were able to simulate experimental DCM blood concentrations reasonably well. The Bos model appears to be useful for calculating HbCO concentrations in emergency risk assessment. PMID- 25455449 TI - Role of cytochrome P450-mediated metabolism and identification of novel thiol conjugated metabolites in mice with phenytoin-induced liver injury. AB - Phenytoin, 5,5-diphenylhydantoin (DPH), is widely used as an anticonvulsant agent. Severe hepatic injury rarely occurs in patients who received DPH. The development of liver injury is thought to be caused by reactive metabolites; however, the metabolites suggested to contribute to hepatotoxicity have not yet been detected in vivo and their effect on developing the liver injury is largely unknown. We recently demonstrated that DPH treatment decreased hepatic glutathione (GSH) contents, and GSH-depleted condition exacerbated DPH-induced liver injury in mice. The aim of the present study was to identify the reactive metabolite and to investigate the role of P450-mediated metabolisms in DPH induced liver injury. We identified a novel GSH-conjugated (GS)-DPH, a conjugate of putative electrophilic arene oxide intermediate with GSH, in the bile of mice with DPH-induced liver injury. In plasma, cysteine- or N-acetylcysteine conjugated DPH was detected, and these thiol conjugates levels were correlated with the plasma alanine aminotransferase (ALT) levels. These changes were significantly reduced by pretreatment with P450 inhibitor. Furthermore, the increases of hepatic P450 activities were in parallel with elevation of plasma thiol conjugates levels. These findings suggest that the arene oxide intermediate, which can be converted to thiol conjugates, is involved in DPH induced liver injury. PMID- 25455450 TI - The involvement of mitochondrial apoptotic pathway in eugenol-induced cell death in human glioblastoma cells. AB - Eugenol, a natural phenolic constituent of clove oil, has a wide range of applications in medicine as a local antiseptic and anesthetic. However, the effect of eugenol on human glioblastoma is unclear. This study examined whether eugenol elevated intracellular free Ca(2+) levels ([Ca(2+)]i) and induced apoptosis in DBTRG-05MG human glioblastoma cells. Eugenol evoked [Ca(2+)]i rises which were reduced by removing extracellular Ca(2+). Eugenol-induced [Ca(2+)]i rises were not altered by store-operated Ca(2+) channel blockers but were inhibited by the PKC inhibitor GF109203X and the transient receptor potential channel melastatin 8 (TRPM8) antagonist capsazepine. In Ca(2+)-free medium, pretreatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (TG) or 2,5-di-tert-butylhydroquinone (BHQ) abolished eugenol-induced [Ca(2+)]i rises. The phospholipase C (PLC) inhibitor U73122 significantly inhibited eugenol induced [Ca(2+)]i rises. Eugenol killed cells which were not reversed by prechelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy) ethane-N,N,N',N' tetraacetic acid-acetoxymethyl ester (BAPTA-AM). Eugenol induced apoptosis through increasing reactive oxygen species (ROS) production, decreasing mitochondrial membrane potential, releasing cytochrome c and activating caspase 9/caspase-3. Together, in DBTRG-05MG cells, eugenol evoked [Ca(2+)]i rises by inducing PLC-dependent release of Ca(2+) from the endoplasmic reticulum and caused Ca(2+) influx possibly through TRPM8 or PKC-sensitive channels. Furthermore, eugenol induced the mitochondrial apoptotic pathway. PMID- 25455451 TI - Species- and congener-differences in microcystin-LR and -RR GSH conjugation in human, rat, and mouse hepatic cytosol. AB - The accepted pathway for MC biotransformation is GSH conjugation, occurring either spontaneously or catalyzed by GST. In the present work, the already available information on human MC metabolism have been expanded and the capacity of human GST to conjugate MC-LR has been confirmed in human liver cytosol. At physiological GSH content the spontaneous reaction predominated on the enzymatic one; the prevalence of the enzymatic reaction occurred following GSH depletion, and the shift was detectable at higher GSH levels, the lower was MC concentration. However, at low MC-LR concentrations (<=10MUM), representative of repeated oral exposure, the relevance of the enzymatic reaction became predominant at GSH concentration between 1 and 2mM. MC-LR conjugate was detectable at >=0.5mM GSH, whereas, with 10MUM MC-RR detectable levels of conjugate were observed at 0.05mM GSH, a 10-fold lower concentration. Overall, our data indicate that MC-RR is more efficiently conjugated than MC-LR, especially at low concentrations. Cytosol samples from rat and mouse were used to characterize GSH conjugation of MC-LR and MC-RR, and to check for possible species differences. At physiological GSH content, in both rodent species the enzymatic reaction accounted for half of the total conjugate formation, reducing the impact of spontaneous reaction with respect to human. Rat and mouse GST showed similar MC-LR and-RR GSH conjugation, but a two-fold higher catalytic efficiency than human sample. This is mainly due to higher affinity for the substrate, with Kmapp values being an order of magnitude lower in the animal models than in human liver cytosol. More pronounced differences in the metabolism of the two variants were evidenced in rodents than in humans. PMID- 25455452 TI - Effect of lysine acetylsalicylate on aluminium accumulation and (Na(+)/K(+))ATPase activity in rat brain cortex synaptosomes after aluminium ingestion. AB - Aluminium is neurotoxic in humans and has been implicated in several neurological disorders. Chronic use of buffered aspirins, as aspegic, would likely constitute the major human aluminium uptake source. Low-dose aspirin is beneficial in secondary prevention of cardiovascular events, so it is widely used for long periods of time. We studied if oral administration of aspegic to rats modified the aluminium inhibitory effect on brain (Na(+)/K(+))ATPase due to alteration in synaptosomal membrane aluminium content. Adult male Wistar rats were submitted to sub-acute (1.00g/day during 10 days) and chronic (0.03g/day during 4 months) dietary AlCl3 exposure and/or to aspegic (0.11g/day). The exposure protocol increased the synaptosomal aluminium content especially after a long-term exposure to aluminium and aspegic. Although no alterations were observed in rat body weight gain and adenylate energy charge, the (Na(+)/K(+))ATPase activity was significantly reduced when aluminium was orally administered to rats. The oral administration of aspegic increased the synaptosomal aluminium content and concomitantly enhanced the (Na(+)/K(+))ATPase inhibition. In our exposure protocol the increase in synaptosomal aluminium content correlates with the reduction of the (Na(+)/K(+))ATPase activity. PMID- 25455453 TI - Screening of a chemical library reveals novel PXR-activating pharmacologic compounds. AB - The pregnane X receptor (PXR) is one of the master regulators of xenobiotic transformation. Interactions between pharmacologic compounds and PXR frequently result in drug-to-drug interactions, drug-induced hepatotoxicity, and the development of drug-resistant phenotypes in cancer cells. Potential PXR-mediated effects on drug metabolism can be predicted using high-throughput methods to detect PXR transactivation. We used the reporter cell line nhrtox-hepg2 to screen an 1120-compound library of pharmacologic substances. Using a three-stage screening process combined with a quantitative structure-activity relationships (QSAR) analysis, we detected 16 novel, previously unreported PXR activators capable of upregulating CYP450 expression. For some of these compounds such as mycophenolic acid, leflunomide, and trifluridine, the observed interactions with PXR occurred at clinically significant concentrations and could provide potential mechanistic explanations for observed drug-to-drug interactions and drug-induced toxicity. A parallel QSAR analysis revealed significant correlation between the experimentally measured PXR-dependent bioactivity and the calculated molecular descriptors of the PXR activators. PMID- 25455454 TI - Phenylbutyric acid inhibits epithelial-mesenchymal transition during bleomycin induced lung fibrosis. AB - A recent report showed that unfolded protein response (UPR) signaling was activated during bleomycin (BLM)-induced pulmonary fibrosis. Phenylbutyric acid (PBA) is an endoplasmic reticulum (ER) chemical chaperone that inhibits the UPR signaling. The present study investigated the effects of PBA on BLM-induced epithelial-mesenchymal transition (EMT) and pulmonary fibrosis. For induction of pulmonary fibrosis, all mice except controls were intratracheally injected with a single dose of BLM (3.0mg/kg). In PBA+BLM group, mice were intraperitoneally injected with PBA (150mg/kg) daily. Three weeks after BLM injection, EMT was measured and pulmonary fibrosis was evaluated. BLM-induced pulmonary UPR activation was inhibited by PBA. Moreover, BLM-induced pulmonary nuclear factor kappa B (NF-kappaB) p65 activation was blocked by PBA. In addition, BLM-induced up-regulation of pulmonary inflammatory cytokines was repressed by PBA. Further analysis showed that BLM-induced alpha-smooth muscle actin (alpha-SMA), a marker for EMT, was significantly attenuated by PBA. Moreover, BLM-induced pulmonary collagen (Col1alpha1 and Col1alpha2) was obviously inhibited by PBA. Importantly, BLM-induced pulmonary fibrosis, as determined using Sirius red staining, was obviously alleviated by PBA. Taken together, these results suggest that PBA alleviates ER stress-mediated EMT in the pathogenesis of BLM-induced pulmonary fibrosis. PMID- 25455455 TI - Proteomic analysis of changes in the protein composition of MCF-7 human breast cancer cells induced by all-trans retinoic acid, 9-cis retinoic acid, and their combination. AB - Retinoic acid (all-trans and 9-cis) isomers represent important therapeutic agents for many types of cancers, including human breast cancer. Changes in protein composition of the MCF-7 human breast cancer cells were induced by all trans retinoic acid, 9-cis retinoic acid, and their combination and subsequently proteomic strategies based on bottom-up method were applied. Proposed approach was used for the analysis of proteins extracted from MCF-7 human breast cancer cell line utilizing a commercially manufactured kit RIPA and separated on two dimensional (2D) sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) after treatment with both retinoic acid isomers. We found significant differences in occurrence of proteins probably affecting the cell migration process in tumour cells. Heat shock protein 27, ribonucleoprotein SmD3, and cofilin-1 were significantly upregulated after treatment with combination of individual retinoic acid isomers. On the other hand, AP-5 complex subunit beta-1 shows the different response. Thus, the results might help to find the answer to important medical questions on (i) the identification of signaling pathways affected by retinoic acid isomers or (ii) how the observed proteomic pattern might reflect the effectiveness of retinoic acids treatment. PMID- 25455456 TI - Diet supplementation with cholic acid promotes intestinal epithelial proliferation in rats exposed to gamma-radiation. AB - Consumption of a high-fat diet increases some secondary bile acids (BAs) such as deoxycholic acid (DCA) in feces. DCA is derived from cholic acid (CA), a primary BA. We evaluated intestinal epithelial proliferation and BA metabolism in response to oral administration of cholic acid (CA) in rats to determine the influence of a CA diet on the responses of gut epithelia to gamma-rays. WKAH/HkmSlc rats were divided into two dietary groups: control diet or CA supplemented (2g/kg diet) diet. Some of the rats from each group were irradiated with gamma-rays, and epithelial cell proliferation in the colon was analyzed histochemically. Unirradiated CA-fed rats had high levels of DCA and CA in the sera, as well as the presence of taurocholic acid in their feces. Significant increases were observed in both epithelial proliferation and the number of epithelial cells in the colon of the CA-fed rats, and this effect was observed at 8 weeks after gamma-ray exposure. Furthermore, extracts from both cecal contents and sera of the unirradiated CA-fed rats promoted proliferation of IEC-6 cells. These results indicate that BAs in enterohepatic circulation promote proliferation and survival of the intestinal epithelium after receiving DNA damage. PMID- 25455457 TI - Several transport systems contribute to the intestinal uptake of Paraquat, modulating its cytotoxic effects. AB - Paraquat (PQ) is an extremely toxic herbicide upon oral ingestion that lacks a specific antidote. In case of intoxication, treatment primarily relies on limiting its intestinal absorption. In this study, we elucidate the intestinal transport mechanisms of PQ uptake using Caco-2 cells as a model of the human intestinal epithelium. The cells were incubated with a wide range of PQ concentrations (0-5000MUM) for 24h with or without simultaneous exposure to different transporters substrates/inhibitors including, choline or hemicolinium-3 (for choline carrier-mediated transport system inhibition) and putrescine, trifluoperazine, valine, lysine, arginine or N-ethylmaleimide (for basic amino acid transport systems inhibition). PQ cytotoxicity was evaluated by the MTT reduction assay and correlated with PQ intracellular levels quantified by gas chromatography-ion trap-mass spectrometry (GC-IT/MS). Potential interactions of PQ with the substrates/inhibitors of the transport systems were investigated and discarded by infrared spectroscopy. Our results showed a significant reduction in PQ intracellular accumulation and, consequently, in PQ cytotoxicity, in the presence of both choline and hemicolinium-3, demonstrating that the choline carrier-mediated transport system is partially involved in PQ intestinal uptake. Likewise, PQ cytotoxicity and intracellular accumulation were significantly attenuated by simultaneous exposure to putrescine, trifluoperazine, valine, lysine, arginine and N-ethylmaleimide. These data suggested the involvement of more than one of the basic amino acids transport systems, including the y(+), b(0,+) or y(+)L systems. In conclusion, this study demonstrated that several transport systems mediate PQ intestinal absorption and, therefore, their modulation may provide alternative efficient pathways for limiting PQ toxicity in intoxication scenarios. PMID- 25455458 TI - Liver DNA methylation analysis in adult female C57BL/6JxFVB mice following perinatal exposure to bisphenol A. AB - Bisphenol A (BPA) is a compound released from plastics and other consumer products used in everyday life. BPA exposure early in fetal development is proposed to contribute to programming of chronic diseases like obesity and diabetes, by affecting DNA methylation levels. Previously, we showed that in utero and lactational exposure of C57BL/6JxFVB hybrid mice via maternal feed using a dose range of 0-3000MUg/kg body weight/day resulted in a sex-dependent altered metabolic phenotype in offspring at 23 weeks of age. The most univocal effects were observed in females, with reduced body weights and related metabolic effects associated with perinatal BPA exposure. To identify whether the effects of BPA in females are associated with changes in DNA methylation, this was analyzed in liver, which is important in energy homeostasis. Measurement of global DNA methylation did not show any changes. Genome-wide DNA methylation analysis at specific CpG sites in control and 3000MUg/kg body weight/day females with the digital restriction enzyme analysis of methylation (DREAM) assay revealed potential differences, that could, however, not be confirmed by bisulfite pyrosequencing. Overall, we demonstrated that the observed altered metabolic phenotype in female offspring after maternal exposure to BPA was not detectably associated with liver DNA methylation changes. Still, other tissues may be more informative. PMID- 25455460 TI - High-molecular-weight polyethylene glycol: a new strategy to limit ischemia reperfusion injury. PMID- 25455459 TI - Exposure to zearalenone mycotoxin alters in vitro porcine intestinal epithelial cells by differential gene expression. AB - The gut represents the main route of intoxication with mycotoxins. To evaluate the effect and the underlying molecular changes that occurred when the intestine is exposed to zearalenone, a Fusarium sp mycotoxin, porcine epithelial cells (IPEC-1) were treated with 10MUM of ZEA for 24h and analysed by microarray using Gene Spring GX v.11.5. Our results showed that 10MUM of ZEA did not affect cell viability, but can increase the expression of toll like receptors (TLR1-10) and of certain cytokines involved in inflammation (TNF-alpha, IL-1beta, IL-6, IL-8, MCP-1, IL-12p40, CCL20) or responsible for the recruitment of immune cells (IL 10, IL-18). Microarray results identified 190 genes significantly and differentially expressed, of which 70% were up-regulated. ZEA determined the over expression of ITGB5 gene, essential against the attachment and adhesion of ETEC to porcine jejunal cells and of TFF2 implicated in mucosal protection. An up regulation of glutathione peroxidase enzymes (GPx6, GPx2, GPx1) was also observed. Upon ZEA challenge, genes like GTF3C4 responsible for the recruitment of polymerase III and initiation of tRNA transcription in eukaryotes and STAT5B were significantly higher induced. The up-regulation of CD97 gene and the down regulation of tumour suppressor genes (DKK-1, PCDH11X and TC531386) demonstrates the carcinogenic potential of ZEA. PMID- 25455461 TI - Alternative access for balloon-expandable transcatheter aortic valve replacement: comparison of the transaortic approach using right anterior thoracotomy to partial J-sternotomy. AB - OBJECTIVES: For transcatheter aortic valve replacement (TAVR), transaortic (TAo) and transapical (TA) approaches are major alternatives in cases unsuitable for the transfemoral approach. Partial J-sternotomy is a widely used access for TAo. However, redo sternotomy or right-sided aorta may preclude this access, and right anterior thoracotomy is potentially beneficial in these cases. This study sought to evaluate the TAo approach using thoracotomy (T-TAo) and compare it to the TAo approach using a sternotomy (S-TAo) and a TA approach. METHODS: In a large single center series, consecutive TAVR patients were studied. Procedural/clinical outcomes of the T-TAo, S-TAo, and TA groups were compared up to a 30 days follow up period. RESULTS: Of 872 TAVR patients, 22 (2.5%) were T-TAo, 29 (3.3%) were S TAo, and 86 (9.9%) were TA approaches. The TA group showed the shortest intensive care unit stay, with a median 2.0 (interquartile range 1.0-3.0) days: for T-TAo it was 3.0 (2.0-5.3) and for S-TAo, 3.0 (3.5-5.0) (P < .001). Although it was not statistically significant, the T-TAo group showed numerically less mortality (1 [4.5%], 5 [17.9%], and 8 [9.4%] in the T-TAo, S-TAo, and TA groups, respectively; P = .30), with no difference in other endpoints, including stroke/transient ischemic attack, rehospitalization, and paravalvular leak. Additionally, computed tomographic assessment revealed that T-TAo facilitated a more coaxial approach than S-TAo: 20.4 degrees +/- 8.2 degrees versus 30.6 degrees +/- 8.2 degrees (P < .001). CONCLUSIONS: T-TAo is a feasible approach that can provide greater coaxiality. This option allows tailored and optimal access to the individual patient and facilitates a treatment strategy in nontransfemoral TAVR patients. PMID- 25455462 TI - Are you ever too old? PMID- 25455463 TI - Early effects of transcatheter aortic valve implantation and aortic valve replacement on myocardial function and aortic valve hemodynamics: insights from cardiovascular magnetic resonance imaging. AB - OBJECTIVES: There remains a paucity of mechanistic data on the effect of transcatheter aortic valve implantation (TAVI) on early left and right ventricular function and quantitative aortic valve regurgitation. We sought to assess and compare the early effects on myocardial function and aortic valve hemodynamics of TAVI and aortic valve replacement (AVR) using serial cardiovascular magnetic resonance (CMR) imaging and echocardiography. METHODS: A prospective comparison study of 47 patients with severe aortic stenosis undergoing either TAVI (n = 26) or high-risk AVR (n = 21). CMR (for left ventricle/right ventricle function, left ventricular mass, left atrial volume, and aortic regurgitation) was carried out before the procedure and early postprocedure (<14 days). RESULTS: Groups were similar with respect to Society of Thoracic Surgeons score (TAVI, 7.7 vs AVR, 5.9; P = .11). Preoperative left ventricular (TAVI, 69% +/- 13% vs AVR, 73% +/- 10%; P = .10) and right ventricular (TAVI, 61% +/- 11% vs AVR, 59% +/- 8%; P = .5) ejection fractions were similar. Postoperative left ventricular ejection fraction was preserved in both groups. In contrast, decline in right ventricular ejection fraction was more significant in the TAVI group (61%-54% vs 59%-58%; P = .01). Postprocedure aortic regurgitant fraction was significantly greater in the TAVI group (16% vs 4%; P = .001), as was left atrial size (110 vs 84 mL; P = .02). Further analysis revealed a significant relationship between the increased aortic regurgitant fraction and greater left atrial size (P = .006), and a trend toward association between the decline in right ventricle dysfunction and increased postprocedure aortic regurgitation (P = .08). CONCLUSIONS: There was no significant difference in early left ventricular systolic function between techniques. Whereas right ventricle systolic function was preserved in the AVR group, it was significantly impaired early after TAVI, possibly reflecting a clinically important pathophysiologic consequence of paravalvular aortic regurgitation. PMID- 25455465 TI - Do we have a novel, clinically applicable approach to spinal cord protection? PMID- 25455464 TI - Endobronchial elastography in the evaluation of esophageal invasion. PMID- 25455466 TI - Embrella embolic deflection device for cerebral protection during transcatheter aortic valve replacement. AB - AIMS: To compare the extent of cerebral ischemic injury after transcatheter aortic valve replacement (TAVR) with the use of an Embrella Embolic Deflector System versus unprotected TAVR. METHODS: Fifteen patients with severe symptomatic aortic stenosis underwent TAVR with use of the Embrella Embolic Deflector System for cerebral protection. Cerebral diffusion-weighted magnetic resonance imaging (DWI) was performed in all patients at day 4 after the procedure and images were retrospectively compared to 37 patients who had previously undergone TAVR without a protection device (TAVR-only group). RESULTS: Successful placement of the Embrella device was achieved in all patients. DWI revealed an increase in the number of ischemic lesions in the Embrella group compared with the TAVR-only group (9.0 vs 5.0, P = .044). The use of the Embrella device was however associated with a significant reduction in single-lesion volume: 9.7 MUL [5.8, 18.4] versus 17.8 MUL [9.5, 38.7] (P < .001). Moreover, total infarct volumes of more than 1000 MUL were only seen in the TAVR-only group. More lesions occurred in the right side of the brain in the Embrella group, whereas in the TAVR-only group lesions were distributed equally between left and right. One patient in the TAVR-only group suffered from a transient ischemic attack. Postoperative evaluation was clinically uneventful in the Embrella group. CONCLUSIONS: The use of the Embrella device during TAVR increased the number of cerebral ischemic lesions on postprocedural brain imaging. This increase in number was however accompanied by a significant reduction in single-lesion volume and the absence of large total infarct volumes. PMID- 25455468 TI - Unnoticed bilateral partial anomalous pulmonary vein connection. PMID- 25455469 TI - Involved radial margins: mountain or molehill? PMID- 25455467 TI - High-molecular-weight polyethylene glycol inhibits myocardial ischemia reperfusion injury in vivo. AB - OBJECTIVES: Cardiac ischemia-reperfusion (I-R) injury remains a significant problem as there are no therapies available to minimize the cell death that can lead to impaired function and heart failure. We have shown that high-molecular weight polyethylene glycol (PEG) (15-20 kD) can protect cardiac myocytes in vitro from hypoxia-reoxygenation injury. In this study, we investigated the potential protective effects of PEG in vivo. METHODS: Adult rats underwent left anterior descending artery occlusion for 60 minutes followed by 48 hours or 4 weeks of reperfusion. One milliliter of 10% PEG solution or phosphate-buffered saline (PBS) control (n = 10 per group) was administered intravenously (IV) immediately before reperfusion. RESULTS: Fluorescein-labeled PEG was robustly visualized in the myocardium 1 hour after IV delivery. The PEG group had significant recovery of left ventricular ejection fraction at 4 weeks versus a 25% decline in the PBS group (P < .01). There was 50% less LV fibrosis in the PEG group versus PBS with smaller peri-infarct and remote territory fibrosis (P < .01). Cell survival signaling was upregulated in the PEG group with increased Akt (3-fold, P < .01) and ERK (4-fold, P < .05) phosphorylation compared to PBS controls at 48 hours. PEG also inhibited apoptosis as measured by TUNEL-positive nuclei (56% decrease, P < .02) and caspase 3 activity (55% decrease, P < .05). CONCLUSIONS: High molecular-weight PEG appears to have a significant protective effect from I-R injury in the heart when administered IV immediately before reperfusion. This may have important clinical translation in the setting of acute coronary revascularization and myocardial protection in cardiac surgery. PMID- 25455470 TI - Duplicated connective tissue growth factor genes in hypoxia-sensitive blunt snout bream Megalobrama amblycephala and their in vivo expression. AB - Connective tissue growth factor (CTGF) is a peptide involved in tissue growth and development, and can be regulated by hypoxia stress. This study aimed to isolate and characterize duplicate Ctgf genes in blunt snout bream Megalobrama amblycephala, and determine their expression patterns and response to hypoxia. The blunt snout bream Ctgfa and Ctgfb were found to be highly divergent, sharing a relatively low sequence identity of 57%. During embryogenesis, Ctgfa mRNA expression levels were low, gradually decreased from zygotes to 12h post fertilization (hpf), markedly increased from 16 hpf, and then stabilized from 32 to 40 hpf. Ctgfb expression levels were constant but low from zygotes to 20 hpf, then gradually increased from 24 to 40 hpf. Ctgfa mRNA was expressed in the adaxial cells of the somites, floor plate, and tailbud at 24 hpf, and in the notochord and ethmoid plate at 36 hpf, whereas Ctgfb mRNA was weakly expressed in the adaxial cells and floor plate at 24 hpf, and in the notochord at 36 hpf. In adult fish, Ctgfa mRNA was strongly expressed in the kidney, brain, intestine, muscles, and skin, while Ctgfb mRNA was detected in all examined tissues. During hypoxic treatment, the mRNA levels of both Ctgfa and -b were significantly upregulated in the gill and liver, whereas Ctgfa mRNAs in the brain and kidney and Ctgfb mRNAs in the kidney significantly decreased. These results provide new insights into the functional conservation and divergence of Ctgf genes and reveal their responses to hypoxia. PMID- 25455471 TI - Dynamic changes in the accumulation of metabolites in brackish water clam Corbicula japonica associated with alternation of salinity. AB - The brackish water clam Corbicula japonica inhabits rivers and brackish waters throughout Japan where the major fishing grounds in the Ibaraki Prefecture, Japan, are located at the Hinuma Lake and Hinuma River. Water salinity in the Lake Hinuma is low and stable due to the long distance from the Pacific Ocean, whereas that in the downstream of the river varies daily due to a strong effect of tidal waters. In the present study, we dissected the gill and foot muscle of brackish water clam collected from these areas, and subjected them to metabolome analysis by capillary electrophoresis-time-of-flight mass spectrometry. More than 200 metabolites including free amino acids, peptides and organic acids were identified, and their amounts from the foot muscle tend to be higher than those from the gill. The principal component analysis revealed that the amount of each metabolite was different among sampling areas and between the gill and foot muscle, whereas no apparent differences were observed between male and female specimens. When the metabolites in the female clam at high salinity were compared with those at low salinity, concentrations of beta-alanine, choline, gamma aminobutyric acid, ornithine and glycine betaine were found to be changed in association with salinity. We also compared various metabolites in relation to metabolic pathways, suggesting that many enzymes were involved in their changes depending on salinity. PMID- 25455472 TI - Esophageal, gastric, and intestinal pneumatosis. PMID- 25455473 TI - Hydropneumothorax and trapped lung. PMID- 25455474 TI - An embedded finger ring. PMID- 25455475 TI - Acute urine retention with two giant urinary bladder diverticula. PMID- 25455476 TI - To cause or not to cause? That is the question, but identical twins might not have all of the answers. PMID- 25455477 TI - Growth hormone, enhancement and the pharmaceuticalisation of short stature. AB - This paper takes the biological drug human Growth Hormone (hGH) as a case study to investigate processes of pharmaceuticalisation and medicalisation in configuring childhood short stature as a site for pharmaceutical intervention. Human growth hormone is considered to have legitimate applications in treating childhood growth hormone deficiency and short stature associated with other recognised conditions. It is also regarded by bioethicists and others as a form of human biomedical enhancement when applied to children with idiopathic or 'normal' short stature. The purpose of this study is not to evaluate whether treatment of idiopathic short stature is enhancement or not, but to evaluate how some applications of hGH in treating short stature have come to be accepted and stabilised as legitimate 'therapies' while others remain contested as 'enhancements'. A comparative, historical approach is employed, drawing on approaches from medical sociology and Science and Technology Studies (STS) to set out a socio-technical history of hGH in the US and UK. Through this history the relative influence and interplay of drivers of pharmaceuticalisation, including industry marketing and networks of drug distribution, and processes of medicalisation will be employed to address this question and simultaneously query the value of enhancement as a sociological concept. PMID- 25455478 TI - The place of receptionists in access to primary care: Challenges in the space between community and consultation. AB - At the point of entry to the health care system sit general practice receptionists (GPRs), a seldom studied employment group. The place of the receptionist involves both a location within the internal geography of the clinic and a position within the primary care team. Receptionists literally 'receive' those who phone or enter the clinic, and are a critical influence in their transformation from a 'person' to a 'patient'. This process occurs in a particular space: the 'waiting room'. We explore the waiting room and its dynamics in terms of 'acceptability', an under-examined aspect of access to primary care. We ask 'How do GPRs see their role with regard to patients with complex health and social needs, in light of the spatio-temporal constraints of their working environments?' We engaged receptionists as participants to explore perceptions of their roles and their workspaces, deriving narrative data from three focus groups involving 14 GPRs from 11 practices in the Northland region of New Zealand. The study employed an adapted form of grounded theory. Our findings indicate that GPRs are on the edge of the practice team, yet carry a complex role at the frontline, in the waiting space. They are de facto managers of this space; however, they have limited agency within general practice settings, due to the constraints imposed upon them by physical and organisational structures. The agency of GPRs is most evident in their ability to shape the social dynamics of the waiting space, and to frame the health care experience as positive for people whose usual experience is marginalisation. We conclude that, if well supported, receptionists have the potential to positively influence health care acceptability, and patients' access to care. PMID- 25455479 TI - Response to Bell, K., The breast-cancer-ization of cancer survivorship: Implications for experiences of the disease, Social Science & Medicine (2014). AB - While there are multiple reasons for the prominence of breast cancer survivorship experience including high incidence, high numbers of cancer survivors and success of breast cancer treatments which may give the impression of the superior standing of breast cancer in the "hierarchy of cancer suffering ", the common way the breast cancer is depicted focuses on the positive, sanitised image of cancer survivor that is more acceptable to society and more commonly seen in popular media and occurs at the exclusion of experiences common to many other breast cancer patients. That polarisation within breast cancer is an example of "hierarchy of cancer suffering" in itself that warrants examination. One of the potential reasons for the positive bias and separation in the stories of cancer survivors may be the terminology of survivorship which implies special standing and distinct status that can lead to exclusion and polarisation between, as well as within, cancer types. PMID- 25455480 TI - Everyday drug diversions: a qualitative study of the illicit exchange and non medical use of prescription stimulants on a university campus. AB - This article investigates everyday experiences and practises that are associated with processes of pharmaceuticalization and with practices of 'drug diversion'- that is, the illicit exchange and non-medical use of prescription drugs. It reports results from a qualitative study that was designed to examine the everyday dimensions of non-medical prescription stimulant use among students on an American university campus, which involved 38 semi-structured interviews with individuals who used prescription stimulants as a means of improving academic performance. While discussions of drug diversion are often framed in terms of broad, population-level patterns and demographic trends, the present analysis provides a complementary sociocultural perspective that is attuned to the local and everyday phenomena. Results are reported in relation to the acquisition of supplies of medications intended for nonmedical use. An analysis is provided which identifies four different sources of diverted medications (friends; family members; black-market vendors; deceived clinicians), and describes particular sets of understandings, practices and experiences that arise in relation to each different source. Findings suggest that at the level of everyday experience and practice, the phenomenon of prescription stimulant diversion is characterised by a significant degree of complexity and heterogeneity. PMID- 25455481 TI - Amino acidic scaffolds bearing unnatural side chains: an old idea generates new and versatile tools for the life sciences. AB - The unnatural amino acids (UAAs) are members of a class of molecules with relevant impacts in the life sciences. Due to the role of these molecules in the modulation of the chemical and physical properties of biological and inorganic materials, UAAs have attracted increasing interest in recent years. The aim of this review is to highlight (i) the most recent and innovative synthetic routes for the preparation of UAAs, (ii) the recently marketed UAA-based drugs, and (iii) the most promising technological applications involving novel UAA containing molecular entities. PMID- 25455482 TI - Antibody-drug conjugates-a new wave of cancer drugs. AB - Antibody-drug conjugates (ADCs) consist of cytotoxic drugs covalently linked to monoclonal antibodies directed to antigens differentially overexpressed in tumor cells. These loaded antibodies are expected to selectively deliver lethal cargoes to tumor cells and provide sustained clinical benefit to pre-selected cancer patients while, at the same time, minimizing systemic toxicity. Although on target adverse events are not completely avoided and the true efficacy of these innovative agents still requires further clarification, proof-of-concept has already been achieved in clinical settings with immunoconjugates containing calicheamicin, auristatin or maytansine-based cytotoxic payloads. In this present article we review the characteristics of the preceding cytotoxic platforms and their chemical conjugation approaches. PMID- 25455483 TI - Discovery of potent iminoheterocycle BACE1 inhibitors. AB - The synthesis of a series of iminoheterocycles and their structure-activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Abeta40 levels upon subcutaneous and oral administration to rats. PMID- 25455485 TI - Synthesis of novel triazole-linked mefloquine derivatives: biological evaluation against Plasmodium falciparum. AB - Using 2,8-bis(trifluoromethyl)quinoline, the pharmacophore of mefloquine, as scaffold, eleven novel triazole-linked compounds have been synthesised by the application of CuAAC chemistry. The in vitro biological activity of the compounds on the Plasmodium falciparum chloroquine-sensitive strain NF54 was then determined. The compounds all showed IC50s in the lower MUM range with (1R,3S,5R) N-{[1-(2,8-bis(trifluoromethyl)quinoline-4-yl)-1H-1,2,3-triazol-4 yl]methyl}adamantan-2-amine (29) exhibiting the best activity of 1.00 MUM. PMID- 25455484 TI - The discovery of avanafil for the treatment of erectile dysfunction: a novel pyrimidine-5-carboxamide derivative as a potent and highly selective phosphodiesterase 5 inhibitor. AB - Novel pyrimidine-5-carboxamide derivatives bearing a 3-chloro-4 methoxybenzylamino group at the 4-position were identified as potent and highly selective phosphodiesterase 5 inhibitors. Among them, we successfully found 10j (avanafil) which exhibited a potent relaxant effect on isolated rabbit cavernosum (EC30=2.1 nM) and a high isozyme selectivity. PMID- 25455486 TI - Synthesis and antiproliferative evaluation of 2-hydroxylated (E)-stilbenes. AB - A simple synthesis of 2-hydroxylated (E)-stilbenes was accomplished in good yields via oxidative coupling of 2-hydroxystyrenes and arylboronic acids, with Rh(III)-catalyst and Cu(OAc)2 as oxidant. The antiproliferative evaluation of all the synthesized compounds were assessed on four different human cancer cell lines (Colo-205, MDA-468, HT29, and MGC80-3), and the results showed that several compounds exhibit strong antiproliferative activities (up to IC50=35 nM for MGC80 3). PMID- 25455487 TI - Serendipitous discovery of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine derivatives as novel HIV-1 replication inhibitors. AB - We identified a novel class of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine compounds as potent HIV-1 replication inhibitors serendipitously during the process of evaluation of triazolothienopyrimidine (TTPM) compounds. Herein, we report synthesis and biological evaluation of 2-((phenylsulfonyl)methyl) thieno[3,2-d]pyrimidine compounds using a cell-based full replication assay to identify thienopyrimidines 6 and 30, which could be further utilized as viable lead compounds. PMID- 25455488 TI - Novel tricyclic pyrazolopyrimidines as potent and selective GPR119 agonists. AB - Systematic SAR optimization of the GPR119 agonist lead 1, derived from an internal HTS campaign, led to compound 29. Compound 29 displays significantly improved in vitro activity and oral exposure, leading to GLP1 elevation in acutely dosed mice and reduced glucose excursion in an OGTT study in rats at doses ?10 mg/kg. PMID- 25455489 TI - A natural phenylpropionate derivative from Mirabilis himalaica inhibits cell proliferation and induces apoptosis in HepG2 cells. AB - Bioactivity-guided study led to the isolation of a natural phenylpropionate derivative, (E)-3-(4-hydroxy-2-methoxyphenyl)-propenoic acid 4-hydroxy-3 methoxyphenyl ester from the roots of Mirabilis himalaica. Cellular analysis showed that compound 1 specifically inhibited the cancer cell growth through the S phase arrest. Mechanistically, compound 1 was able to induce the apoptosis in HepG2 cells through mitochondrial apoptosis pathway in which Bcl-2 and p53 were required. Interestingly, the cellular phenotype of compound 1 were shown specifically in cancer cells originated from hepatocellular carcinoma (HepG2) while compromised influence by compound 1 were detected within the normal human liver cells (L-02). Consistently, the in vivo inhibitory effects of compound 1 on tumor growth were validated by the in xenograft administrated with HepG2 cells. Our results provided a novel compound which might serve as a promising candidate and shed light on the therapy of the hepatocellular carcinoma. PMID- 25455490 TI - The effect of pK(a) on pyrimidine/pyridine-derived histamine H4 ligands. AB - During the course of our efforts toward the discovery of human histamine H4 antagonists from a series of 2-aminiopyrimidines, it was noted that a 6 trifluoromethyl group dramatically reduced affinity of the series toward the histamine H4 receptor. This observation was further investigated by synthesizing a series of ligands that varied in pKa of the pyrimidine derived H4 ligands by over five orders of magnitude and the effect on histamine H4 affinity. This trend was then extended to the discovery of C-linked piperidinyl-2-amino pyridines as histamine H4 receptor antagonists. PMID- 25455491 TI - 2-Aminopyrimidin-4(1H)-one as the novel bioisostere of urea: discovery of novel and potent CXCR2 antagonists. AB - 2-Aminopyrimidin-4(1H)-one was proposed as the novel bioisostere of urea. Bioisosteric replacement of the reported urea series of the CXCR2 antagonists with 2-aminopyrimidin-4(1H)-ones led to the discovery of the novel and potent CXCR2 antagonist 3e. 2-Aminopyrimidin-4(1H)-one derivative 3e demonstrated a good developability profile (reasonable solubility and high permeability) and superior chemical stability especially in simulated gastric fluid (SGF) compared with ureas. PMID- 25455493 TI - 7-(4-Alkylidenylpiperidinyl)-quinolone bacterial topoisomerase inhibitors. AB - Novel antibacterial fluoroquinolone agents bearing a 4-alkylidenylpiperidine 7 position substituent are active against quinolone-susceptible and quinolone resistant gram-positive bacteria, including Streptococcus pneumoniae and MRSA. Analogs 22b, 23c, and 24 demonstrated superior in vitro and in vivo efficacy to ciprofloxacin against these cocci. PMID- 25455494 TI - Effect of acyclic monoterpene alcohols and their derivatives on TRP channels. AB - A series of thirty-six geraniol, nerol, citronellol, geranylamine, and nerylamine derivatives was synthesized and tested on TRPA1, TRPM8, and TRPV1 channels. Most of them acted as strong modulators of TRPA1 channels with EC50 and/or IC50 values <1 MUM. None was able to significantly activate TRPM8 channels, while thirteen of them behaved as 'true' TRPM8 antagonists. Little or no effect was generally observed on TRPV1 channels. Some of the compounds examined, that is, compounds 1d,g,n, 2c,d,h,i,o, 3b,e exhibited an appreciable selectivity for TRPA1 subtype. PMID- 25455492 TI - Aurones as histone deacetylase inhibitors: identification of key features. AB - In this study, a total of 22 flavonoids were tested for their HDAC inhibitory activity using fluorimetric and BRET-based assays. Four aurones were found to be active in both assays and showed IC50 values below 20 MUM in the enzymatic assay. Molecular modelling revealed that the presence of hydroxyl groups was responsible for good compound orientation within the isoenzyme catalytic site and zinc chelation. PMID- 25455495 TI - A simple route to [11C]N-Me labeling of aminosuberic acid for proof of feasibility imaging of the x(C)- transporter. AB - Oxidative stress has been implicated in a variety of conditions, including cancer, heart failure, diabetes, neurodegeneration and other diseases. A potential biomarker for oxidative stress is the cystine/glutamate transporter, system x(C)(-). L-Aminosuberic acid (L-ASu) has been identified as a system x(C)( ) substrate. Here we report a facile method for [(11)C]N-Me labeling of L-ASu, automation of the radiochemical process, and preliminary PET imaging with EL4 tumor bearing mice. The results demonstrate uptake in the tumor above background, warranting further studies on the use of radiolabeled analogs of L-ASu as a PET imaging agent for system x(C)(-). PMID- 25455496 TI - A highly water soluble benzimidazole derivative useful for the treatment of fasciolosis. AB - This study describes the synthesis of compound (7), a highly hydrosoluble phosphonooxymethyl prodrug of compound alpha (4). Compound (7) improved the aqueous solubility of its precursor compound (4) by 50,000 times and it is stable at neutral pH. The prodrug showed faciolicidal activity when evaluated in vitro against excysted Fasciola hepatica metacercariae. The in vivo evaluation of (7) was carried out via oral, intramuscular and subcutaneous administration in sheep artificially infected with F. hepatica metacercariae. At an intramuscular dose of 4 mg/kg, the activity of (7) was similar to that of compound alpha (4) at an oral dose of 15 mg/kg. PMID- 25455497 TI - Design, synthesis and structure-activity relationships of a novel class of sulfonylpyridine inhibitors of Interleukin-2 inducible T-cell kinase (ITK). AB - Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2. PMID- 25455498 TI - The antimicrobial activity of mono-, bis-, tris-, and tetracationic amphiphiles derived from simple polyamine platforms. AB - A series of 34 amphiphilic compounds varying in both number of quaternary ammonium groups and length of alkyl chains has been assembled. The synthetic preparations for these structures are simple and generally high-yielding, proceeding in 1-2 steps without the need for chromatography. Antibacterial MIC data for these compounds were determined, and over half boast single digit MIC values against a series of gram-positive and gram-negative bacteria. MIC variation mostly hinged on the length of the alkyl chain, where a dodecyl group led to optimal activity; surprisingly, the number of cations and/or basic nitrogens was less important in dictating bioactivity. Additional structural variation was prepared in a trisamine series dubbed 12,3,X,3,12, providing a series of potent amphiphiles functionalized with varied allyl, alkyl, and benzyl groups. Tetraamines were also investigated, culminating in a two-step preparation of a tetracationic structure that showed only modestly improved bioactivity versus amphiphiles with two or three cations. PMID- 25455499 TI - Synthesis and structure-activity relationships study of dithiolethiones as inducers of glutathione in the SH-SY5Y neuroblastoma cell line. AB - Parkinson's disease is a neurodegenerative disorder that involves the degeneration of nigrostriatal dopaminergic neurons. Elevated levels of reactive oxygen species have been shown to deplete cellular levels of the ubiquitous antioxidant glutathione, leading to oxidative stress and eventual neuronal cell death. Dithiolethiones, a class of sulfur-containing heterocyclic molecules, have been shown to induce cellular production of glutathione in a variety of tissues, but have not been extensively evaluated in neurons. Herein, we report the synthesis and preliminary structure-activity relationships study of several substituted dithiolethiones. Three molecules were identified (D3T, CPDT, and 2d) that potently induced cellular glutathione in the SH-SY5Y neuroblastoma cell line. Furthermore, these compounds were found to provide neuroprotection in the 6 hydroxydopamine model of neurotoxicity. This study suggests that dithiolethione mediated neuroprotection may have potential as a disease-modifying antiparkinsonian therapy. PMID- 25455502 TI - Oxorhenium(V) complexes with phenolate-pyrazole ligands for olefin epoxidation using hydrogen peroxide. AB - Oxorhenium(V) complexes of the general formula [ReOCl2(PPh3)(L)] (2a-c) and [ReOCl(L)2] (3a-c) with L being monoanionic, bidentate phenolate-pyrazole ligands 1a-c that bear substituents with various electronic features on the phenol ring (1a Br, 1b NO2, 1c OMe) were prepared. The compounds are stable toward moisture and air, allowing them to be handled in a normal lab atmosphere. All complexes were fully characterized by spectroscopic means and, in the case of 2b, 2c, 3b, and 3c, also by single-crystal X-ray diffraction analyses. Electrochemical investigations by cyclic voltammetry of complexes 3a-c showed a shift to more positive potentials for the Re(V)/Re(VI) redox couple in the order of 3b > 3a > 3c (R = NO2 > Br > OMe), reflecting the higher electrophilic character of the Re atom caused by the ligands 1a-c. Complexes 2a-c and 3a-c display excellent catalytic activity in the epoxidation of cyclooctene, where all six complexes give quantitative conversions to the epoxide within 3 h if tert butylhydroperoxide (TBHP) is employed as oxidant. Moreover, they represent rare examples of oxorhenium(V) catalysts capable of using the green oxidant hydrogen peroxide, leading to high yields up to 74%. Also, green solvents such as diethylcarbonate can be used successfully in epoxidation reactions, albeit resulting in lower yields (up to 30%). PMID- 25455500 TI - Elacridar enhances the cytotoxic effects of sunitinib and prevents multidrug resistance in renal carcinoma cells. AB - Intrinsic drug resistance occurs in many renal carcinomas and is associated with increased expression of multidrug resistant proteins, which inhibits intracellular drug accumulation. Multidrug resistant protein 1, also known as P glycoprotein, is a membrane drug efflux pump belonging to the ATP-binding cassette (ABC) transporter superfamily. ABC Sub-family B Member 2 (ABCG2) is widely distributed and is involved in the multidrug resistant phenotype. Sunitinib is a tyrosine kinase inhibitor used to treat kidney cancer that disrupts signaling pathways responsible for abnormal cancer cell proliferation and tumor angiogenesis. Multiple drug resistance is important in tyrosine kinase inhibitor-induced resistance. We hypothesized that inhibition of multidrug resistant transporters by elacridar (dual inhibitor of P-glycoprotein and ABCG 2) might overcome sunitinib resistance in experimental renal cell carcinoma. Human renal carcinoma cell lines 786-O, ACHN, and Caki-1 were treated with sunitinib or elacridar alone, or in combination. We showed that elacridar significantly enhanced sunitinib cytotoxicity in 786-O cells. P-glycoprotein activity, confirmed by P-glycoprotein function assay, was found to be inhibited by elacridar. ABCG2 expression was low in all renal carcinoma cell lines, and was suppressed only by combination treatment in 786-O cells. ABCG2 function was inhibited by sunitinib alone or combination with elacridar but not elacridar alone. These findings suggest that sunitinib resistance involves multidrug resistance transporters, and in combination with elacridar, can be reversed in renal carcinoma cells by P-glycoprotein inhibition. PMID- 25455503 TI - Treatment goals for psoriasis: Should PASI 90 become the standard of care? PMID- 25455501 TI - Cardioprotection of the enkephalin analog Eribis peptide 94 in a rat model of ischemia and reperfusion is highly dependent on dosing regimen and timing of administration. AB - Eribis Peptide 94 (EP94) is an enkephalin analog with cardioprotective properties in ischemia and reperfusion. The aim of the present study was to define the optimal timing and dosing of the administration of EP94 during ischemia and reperfusion in a rat model. 172 anesthetized and mechanically ventilated male Sprague-Dawley rats were randomly assigned to different administration protocols of EP94 and subjected to 30 or 40 min of coronary artery occlusion followed by 2h of reperfusion. EP94 was administered intravenously at different doses and time intervals. Area at risk (AAR) and infarct size (IS) were determined by staining with Evans Blue (EB) and Triphenyl tetrazolium chloride (TTC), respectively. EP94 reduced IS/AAR when administered as a double bolus (0.5 ug/kg per dose), whereas single (1 MUg/kg) or triple boluses (0.5 MUg/kg per dose) did not confer any protection. Reduction of IS/AAR was of highest magnitude if EP94 was administered 5 and 0 min before the 30 min ischemic period (47% reduction, P<0.05), with declining cardioprotective effect with later administration during ischemia. When EP94 was administered after 15 and 20 min of a 40-min ischemic period, reduction of IS/AAR was of the same magnitude as when given after 5 and 10 min of a 30-min ischemic period. It is concluded that EP94 confers cardioprotection after double bolus administration. The effects are highly dependent on the timing of administration in relation to ischemia and reperfusion. Time of reperfusion from drug administration seems to be more critical than the total duration of ischemia. PMID- 25455504 TI - Etanercept in the treatment of psoriatic arthritis. AB - The aim of the present review is to provide an update on the most important recent studies on the use of etanercept in psoriatic arthritis (PsA). Using various assessment tools, such as the Disease Activity Score 28-joint count (DAS28), the PsA Response Criteria (PsARC), and the American College of Rheumatology (ACR) score, several authors have shown that etanercept can reduce the signs and symptoms of psoriatic arthritis and inhibit radiographic progression in studies with follow-up periods of up to 2 years. There is evidence that etanercept is effective in the treatment of psoriatic enthesitis, dactylitis, and axial joint disease as well as in disease affecting the skin and nails. In clinical trials, etanercept had a safety profile similar to that of placebo and this profile did not change over time. Cost-effectiveness models have found etanercept to be the most cost-effective tumor necrosis factor inhibitor in patients with psoriatic arthritis and mild to moderate psoriasis. Etanercept has a favorable risk-benefit profile in the short term. The concomitant use of methotrexate does not alter etanercept survival. PMID- 25455505 TI - Disseminated bone metastases from occult thyroid cancer effectively treated with debulking surgery and a single dosimetry-guided administration of radioiodine. AB - In this paper we report on a successful management of multiple bone metastases from differentiated thyroid cancer. In 2007, a 75-year-old female patient, previously referred for thyroidectomy for multinodular goiter, underwent surgical removal of a lumbar mass with histological findings of metastasis from well differentiated thyroid cancer. After surgery, serum thyroglobulin (sTg) was 204.4 ng/mL. A diagnostic/dosimetric (123)I WBS was performed, following stimulation by rTSH. Serial WBSs were acquired, along with SPECT/CT and bone scan for localization of lesions. sTg raised to 3.810 ng/mL, and (123)I WBS showed thyroid remnants and numerous areas with high iodine-uptake corresponding to skeletal sites, the two largest loading on the skull, with osteolytic pattern. Calculated radiation absorbed dose for skull lesions, determined by mean of MIRD methodology, was 63.5 mGy/MBq. The patient underwent surgical removal of the two major skull lesions. Successively, 100 mCi (131)I was administered after stimulation by rTSH, with stimulated sTg 297 ng/mL. After 8 months, diagnostic WBS was negative both for remnants and metastases and rTSH-stimulated Tg was 0.6 ng/mL. To date, the patient has maintained sTg values <1 ng/mL during L-T4 suppressive therapy and after rTSH stimulations. In this unusual case of extensive bone cancerous involvement with high iodine avidity, a multidisciplinary approach based on surgery and dosimetry-guided radiometabolic therapy allowed to accurately assess the patient, execute a small number of treatments and achieve a complete remission of the disease in a very short time, with no additive morbidity. PMID- 25455506 TI - [Sentinel node in melanoma and breast cancer. Current considerations]. AB - The main objectives of sentinel node (SN) biopsy is to avoid unnecessary lymphadenectomies and to identify the 20-25% of patients with occult regional metastatic involvement. This technique reduces the associated morbidity from lymphadenectomy and increases the occult lymphatic metastases identification rate by offering the pathologist the or those lymph nodes with the highest probability of containing metastatic cells. Pre-surgical lymphoscintigraphy is considered a "road map" to guide the surgeon towards the sentinel nodes and to localize unpredictable lymphatic drainage patterns. The SPECT/CT advantages include a better SN detection rate than planar images, the ability to detect SNs in difficult to interpret studies, better SN depiction, especially in sites closer to the injection site and better anatomic localization. These advantages may result in a change in the patient's clinical management both in melanoma and breast cancer. The correct SN evaluation by pathology implies a tumoral load stratification and further prognostic implication. The use of intraoperative imaging devices allows the surgeon a better surgical approach and precise SN localization. Several studies reports the added value of such devices for more sentinel nodes excision and a complete monitoring of the whole procedure. New techniques, by using fluorescent or hybrid tracers, are currently being developed. PMID- 25455507 TI - [Selective biopsy of the sentinel lymph node in patients with breast cancer and previous excisional biopsy: is there a change in the reliability of the technique according to time from surgery?]. AB - AIM: To assess the influence of time on the reliability of sentinel lymph node biopsy (SLNB) in breast cancer patients with previous excisional biopsy (EB), analyzing both the sentinel lymph node detection and the lymph node recurrence rate. MATERIAL AND METHODS: Thirty-six patients with cT1/T2 N0 breast cancer and previous EB of the lesion underwent a lymphoscintigraphy after subdermal periareolar administration of radiocolloid, the day before SLNB. Patients were classified into two groups, one including 12 patients with up to 29 days elapsed between EB and SLNB (group A), and another with the remaining 24 in which time between both procedures was of 30 days or more (group B). Scintigraphic and surgical detection of the sentinel lymph node, histological status of the sentinel lymph node and of the axillary lymph node dissection, if performed, and lymphatic recurrences during follow-up, were analyzed. RESULTS: Sentinel lymph node visualization at the lymphoscintigraphy and surgical detection were 100% in both groups. Histologically, three patients showed macrometastasis in the sentinel lymph node, one from group A and two from group B. None of the patients, not even those with malignancy of the sentinel lymph node, relapsed after a medium follow-up of 49.5 months (24-75). CONCLUSION: Time elapsed between EB and SLNB does not influence the reliability of this latter technique as long as a superficial injection of the radiopharmaceutical is performed, proving a very high detection rate of the sentinel lymph node without evidence of lymphatic relapse during follow-up. PMID- 25455508 TI - Distinct proteomic profiles in post-mortem pituitary glands from bipolar disorder and major depressive disorder patients. AB - Disturbances of the hypothalamic-pituitary-adrenal axis have been implicated in the pathophysiology of bipolar disorder (BD) and major depressive disorder (MDD). To examine this further, we carried out proteomic profiling of post-mortem pituitaries from 13 BD and 14 MDD patients, in comparison to 15 controls. Liquid chromatography-mass spectrometry (LC-MS(E)) analysis showed that BD patients had significantly increased levels of the major pituitary hormones pro opiomelanocortin (POMC) and galanin. BD patients also showed changes in proteins associated with gene transcription, stress response, lipid metabolism and growth signalling. In contrast, LC-MS(E) profiling revealed that MDD patients had significantly decreased levels of the prohormone-converting enzyme carboxypeptidease E and follow-up enzymatic analysis showed decreased activity of prolyl-oligopeptidase convertase. This suggested that altered prohormone processing may occur in pituitaries of MDD patients. In addition, MDD patients had significant changes in proteins involved in intracellular transport and cytoskeletal signalling. Finally, we carried out selective reaction monitoring (SRM) mass spectrometry profiling for validation of protein changes in key biological pathways. This confirmed increased POMC levels in BD patients with no change in the levels of this prohormone in MDD. This study demonstrates that proteomic profiling analysis of the pituitary can lead to new insights into the pathophysiology of BD and MDD. Also, given that the pituitary directly releases a variety of bioactive molecules into the bloodstream, many of the proteins identified here could serve as focal points in the search for peripheral biomarkers in clinical or drug treatment studies of BD and MDD patients. PMID- 25455509 TI - Smoking and BDNF Val66Met polymorphism in male schizophrenia: a case-control study. AB - Some recent studies show an association between a functional polymorphism of BDNF gene (Val66Met) and the susceptibility to nicotine dependence and we hypothesized that this polymorphism was associated with smoking in both schizophrenia patients and healthy controls. The BDNF Val66Met gene polymorphism was genotyped in 690 chronic male schizophrenia patients (smoker/nonsmoker = 522/169) and 628 male controls (smoker/nonsmoker = 322/306) using a case-control design. Nicotine dependence (ND) was assessed by the cigarettes smoked per day (CPD), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). Patients also were rated on the Positive and Negative Syndrome Scale (PANSS). The results showed no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls or between smokers and nonsmokers in either patients or healthy controls alone. In patient groups, however, the smokers with the Met allele had significantly higher HSI scores (Met/Met: 2.8 +/- 1.7 vs. Met/Val: 2.2 +/- 1.7 vs. Val/Val: 2.0 +/- 1.6, p < 0.01) and a trend toward a significantly higher FTND score (p = 0.09) than those with the Val/Val genotype. In addition, the smokers showed significantly lower PANSS negative symptom and total scores, longer duration of illness and more hospitalizations (all p < 0.05). In the control group, the smokers with the Met allele started smoking significantly earlier than those with the Val/Val genotype (both p < 0.05). These results suggest that the BDNF Val66Met polymorphism may affect a smoker's response to nicotine in both schizophrenia and healthy controls from a Chinese Han population, but with differential effects in different aspects of smoking behaviors. PMID- 25455511 TI - Association between insulin resistance and cognition in patients with depressive disorders: exploratory analyses into age-specific effects. AB - The current preliminary cross sectional study sought to examine the effects of insulin resistance (IR) and body mass index (BMI) on cognitive performance in adult patients with a history depression, currently not in an acute Major Depressive Episode (MDD). As an exploratory post hoc investigation, special consideration was given to adults <45 years and >=45 years old. Subjects included men and women ages 19-71 (N = 39) with a history of a non-psychotic, non melancholic MDD. All subjects underwent an insulin suppression test to determine Steady-State Plasma Glucose (SSPG), a battery of neuropsychological tests, and measurement of BMI. Multiple linear regressions were conducted to determine whether there were differential effects of direct (SSPG) and indirect (BMI) measures on cognition in the whole sample and within dichotomized age groups (<45 and >=45 years). Preliminary results showed that in the sample as a whole, SSPG was not associated with worse performance on any cognitive variables, while higher BMI was associated with worse dominant hand fine motor skills. Within age groups, differential effects on cognition were found in relation to SSPG and BMI. Higher SSPG was associated with worse cognitive flexibility in the group <45 years, whereas higher BMI was associated with worse estimate of global intelligence in the group >=45 years. The potential negative impact of IR in younger adults with depression raises concerns regarding the long-term impact on cognition and risk for Alzheimer's disease in undiagnosed younger adults with IR and depression. These negative consequences may not be seen with indirect measures of IR in younger adult populations. Overweight and obesity in older adults with a history of depression appear to have further negative impacts on cognition similar to deficits seen in patients with diabetes. CLINICALTRIALSGOV IDENTIFIER: Clinical Trial NCT01106313. PMID- 25455510 TI - A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor. AB - Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1111 participants) examining the effect of exercise on BDNF levels in three exercise paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise, and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of exercise (Hedges' g = 0.46, p < 0.001). Further, regular exercise intensified the effect of a session of exercise on BDNF levels (Hedges' g = 0.59, p = 0.02). Finally, results indicated a small effect of regular exercise on resting BDNF levels (Hedges' g = 0.27, p = 0.005). When analyzing results across paradigms, sex significantly moderated the effect of exercise on BDNF levels, such that studies with more women showed less BDNF change resulting from exercise. Effect size analysis supports the role of exercise as a strategy for enhancing BDNF activity in humans, but indicates that the magnitude of these effects may be lower in females relative to males. PMID- 25455512 TI - Trait impulsivity and increased pre-attentional sensitivity to intense stimuli in bipolar disorder and controls. AB - Impulsivity and sensation seeking are stimulus-oriented traits. Because they differ in degree of intention and planning, they may have distinct neurophysiological mechanisms. Impulsivity is prominent in bipolar disorder, and may be related to pre-attentional information filtering and stimulus-orientation. We investigated specificity of relationships between impulsivity and sensitivity to stimulus intensity in bipolar disorder and controls, using intensity sensitivity of auditory evoked potentials. Seventy-six subjects (37 healthy controls, 39 with bipolar disorder) were administered an intensity-sensitivity paradigm. Additional measures included Barratt Impulsiveness Scale (BIS-11) and Eysenck Impulsivity and Venturesomeness scores. State-dependent rapid-response impulsivity was measured using the Immediate Memory Task. Intensity-sensitivities of the auditory evoked P1N1, N1P2, P1, N1, and P2 potentials were assessed as the slope of amplitude relative to loudness. Analyses used general linear models (GLM) with impulsivity-related measures as dependent variables and age, gender, education, and diagnosis as dependent variables. BIS-11 total, motor, and attentional impulsivity scores correlated positively with pre-attentional N1 and P1N1 intensity-sensitivity slopes in bipolar disorder, but not in controls. BIS 11 nonplanning and Eysenck Venturesomeness scores did not correlate with intensity-sensitivity. Intensity-sensitivity slopes did not correlate with rapid response impulsivity. Correlations between N1 or P1N1 slopes and BIS-11 scores in bipolar disorder were not affected by age, education, WAIS, treatment, symptoms, or gender. Trait impulsivity in bipolar disorder may be related to poorly modulated stimulus-driven late pre-attentional responses to stimuli, potentially resulting in exaggerated responses to intense stimuli even before conscious awareness. Components of trait impulsivity are physiologically heterogenous relative to intensity-sensitivity. PMID- 25455513 TI - Evaluation of cognitive function in bipolar disorder using the Brief Assessment of Cognition in Affective Disorders (BAC-A). AB - BACKGROUND: Although cognitive impairment is a core feature of bipolar disorder (BD) there is no instrument of choice for the assessment of bipolar patients. The aim of this study is to assess cognitive performance using the Brief Assessment of Cognition in Affective Disorders (BAC-A), a comprehensive test battery developed specifically for BD, and determine its suitability to estimate global functioning. METHODS: The BAC-A was administered to 93 BD patients (M +/- S.E: 35.18 +/- 1.39 years) and 56 healthy controls (HC - M +/- S.E: 36.17 +/- 1.91 years). The scores of the BAC-A were combined in eight summary scores: visuomotor, immediate affective and non-affective memory, verbal fluency, delayed affective and non-affective memory, inhibition, and problem solving. Post hoc analyses were performed on subtests of the summary scores found to be significantly different between BD patients and HC. Correlational analyses explored the association between the Global Assessment of Functioning (GAF) score and cognitive functioning. RESULTS: Compared to HC, BD patients showed a significant impairment in short-term non-affective memory and verbal fluency. Poorer performance in verbal memory and verbal fluency summary scores correlated positively with reduced GAF. CONCLUSIONS: Our results are consistent with previous reports of verbal memory and verbal fluency impairment in BD. The deficits in short-term memory and semantic fluency may indicate inefficient learning strategies and/or difficulties in retrieving information. The BAC-A could be used to estimate global functioning in BD patients. PMID- 25455518 TI - Classification and implementation of asthma phenotypes in elderly patients. AB - BACKGROUND: No attempt has yet been made to classify asthma phenotypes in the elderly population. It is essential to clearly identify clinical phenotypes to achieve optimal treatment of elderly patients with asthma. OBJECTIVES: To classify elderly patients with asthma by cluster analysis and developed a way to use the resulting cluster in practice. METHODS: We applied k-means cluster to 872 elderly patients with asthma (aged >= 65 years) in a prospective, observational, and multicentered cohort. Acute asthma exacerbation data collected during the prospective follow-up of 2 years was used to evaluate clinical trajectories of these clusters. Subsequently, a decision-tree algorithm was developed to facilitate implementation of these classifications. RESULTS: Four clusters of elderly patients with asthma were identified: (1) long symptom duration and marked airway obstruction, (2) female dominance and normal lung function, (3) smoking male dominance and reduced lung function, and (4) high body mass index and borderline lung function. Cluster grouping was strongly predictive of time to first acute asthma exacerbation (log-rank P = .01). The developed decision-tree algorithm included 2 variables (percentage of predicted forced expiratory volume in 1 second and smoking pack-years), and its efficiency in proper classification was confirmed in the secondary cohort of elderly patients with asthma. CONCLUSIONS: We defined 4 elderly asthma phenotypic clusters with distinct probabilities of future acute exacerbation of asthma. Our simplified decision tree algorithm can be easily administered in practice to better understand elderly asthma and to identify an exacerbation-prone subgroup of elderly patients with asthma. PMID- 25455519 TI - Lung function, airway remodeling, and inflammation in infants: outcome at 8 years. AB - BACKGROUND: Associations between early deficits of lung function, infant airway disease, and outcome at school age in symptomatic infants are still unclear. OBJECTIVE: To report follow-up data on a unique cohort of children investigated invasively in infancy to determine predictive value of airway disease for school aged respiratory outcomes. METHODS: Fifty-three infants previously studied using bronchoscopy and airway conductance were approached at 8 years of age. Symptoms, lung volumes, and airway responsiveness were reassessed. Data on lifetime purchase of asthma medication were obtained. Lung function was compared with that of 63 healthy nonasthmatic children. RESULTS: Forty-seven children were reevaluated. Physician-diagnosed asthma was present in 39 children (83%). Twenty five children (53%) had current and 14 children (30%) had past asthma. No pathologic feature in infancy correlated with any outcome parameter. As expected, study children had significantly reduced lung function and increased airway responsiveness compared with healthy controls, and very early symptoms were risk factors for reduced lung function. Current asthma was associated with reduced infant lung function and parental asthma. Reduced lung function in infancy was associated with purchase of inhaled corticosteroids when 6 to 8 and 0 to 8 years of age. CONCLUSION: The lack of predictive value of any pathologic measure in infancy, reported here for the first time to our knowledge, demonstrates that pathologic processes determining the inception of asthma, which are as yet undescribed, are different from the eosinophilic inflammation associated with ongoing disease. PMID- 25455520 TI - Correlation of basophil infiltration in nasal polyps with the severity of chronic rhinosinusitis. PMID- 25455522 TI - Animal models of chronic tympanic membrane perforation: a 'time-out' to review evidence and standardize design. AB - OBJECTIVE: To review the literature on techniques for creation of chronic tympanic membrane perforations (TMP) in animal models. Establishing such models in a laboratory setting will have value if they replicate many of the properties of the human clinical condition and can thus be used for investigation of novel grafting materials or other interventions. METHODS: A literature search of the PubMed database (1950-August 2014) was performed. The search included all English language literature published attempts on chronic or delayed TMP in animal models. Studies of non English-language or acute TMP were excluded. RESULTS: Thirty-seven studies were identified. Various methods to create TMP in animals have been used including infolding technique, thermal injury, re-myringotomy, and topical agents including chemicals and growth factor receptor inhibitors. The most common type of animal utilized was chinchilla, followed by rat and guinea pig. Twenty three of the 37 studies reported success in achieving chronic TMP animal model while 14 studies solely delayed the healing of TMP. Numerous experimental limitations were identified including TMP patency duration of <8 weeks, lack of documentation of total number of animals attempted and absence of proof for chronicity with otoscopic and histologic evidence. CONCLUSION: The existing literature demonstrates the need for an ideal chronic TMP animal model to allow the development of new treatments and evaluate the risk of their clinical application. Various identified techniques seem promising, however, a need was identified for standardization of experimental design and evidence to address multiple limitations. PMID- 25455521 TI - Exhaled nitric oxide in asthma care: the conundrum continues. PMID- 25455523 TI - The pediatric sedation unit: a prospective analysis of parental satisfaction. AB - As financial pressures drive health care to be more cost-effective and efficient, performing procedures outside the main operating room (MOR) is becoming more common. Pediatric sedation units (PSU) have proven both effective and safe at providing anesthesia for children. However, there is limited data available regarding the PSU and its potential application in pediatric otolaryngology. OBJECTIVE: To evaluate the experience of performing pediatric outpatient procedures in a PSU through a parental satisfaction survey. METHODS: Pediatric otolaryngology procedures performed in the PSU were prospectively recorded in a database. A prospective survey analysis was performed that measured parental satisfaction with scheduling/registration for surgery, nursing care, surgeon care, facility environment, timing/duration, and overall satisfaction. Parents completed this survey for outpatient procedures performed in either the PSU or in the MOR. The same attending surgeon was involved in all cases, with the only independent variable being the location of the surgery. Fifty surveys were collected for each group, and the surveys scores were statistically compared using nonparametric statistical analysis. RESULTS: Parental satisfaction was high in both the PSU and OR, with mean overall satisfaction scores of 4.8 and 4.9 (respectively) on an ordinal scale from 1 to 5. Parents reported greater clarity in preoperative information in the MOR (mean 4.8) compared to the PSU (mean 4.6) (p<0.006). Also, parents reported that MOR procedures started on time more often than those in the PSU (90-64%, p<0.002). There were no significant differences between locations in any other survey metrics, with mean satisfaction scores ranging from 4.5 to 5.0. CONCLUSIONS: The PSU is a satisfactory patient experience for outpatient procedures in pediatric otolaryngology at our institution. However, this parent survey has identified education prior to surgery and timeliness of surgery as two areas to improve to meet the satisfaction standard provided by the OR. PMID- 25455524 TI - Differential diagnosis in paradoxical vocal fold movement (PVFM): an interdisciplinary task. AB - OBJECTIVES: The objective of this study was to contribute to the discussion of differential diagnosis in paradoxical vocal fold movement (PVFM), a disorder frequently associated with episodes of breathing difficulty and stridor. Because of analogous respiratory symptoms, PVFM is often misdiagnosed as asthma. Additional evidence suggests the association of factors such as respiratory struggle during physical exertion, digestive reflux, and respiratory allergies with PVFM, particularly in athletes and young females. Interdisciplinary attention is warranted to avoid unnecessary utilization of medical resources and potential delay in the application of proper treatment. METHODS: A description of critical points in PVFM differential diagnosis is proposed, featuring the assessment of a seven-year-old female with a history of behaviors considered to exacerbate voice fatigue symptoms. Noticeably, the child has consistently demonstrated tiredness and respiratory difficulties during physical education classes. Past use of oral steroids to reduce respiratory problems was applied with no improvement; short-acting beta 2-agonists have been also tried with mild improvement. Indications of instability and effort associated with respiratory phonatory functions were demonstrated. Furthermore, there was evidence of GERD and seasonal allergies. RESULTS: The literature suggests an association of factors such as respiratory struggle during physical exertion, unwanted vocal effort, GERD, and respiratory allergies in individuals with PVFM, particularly in young females. A diagnosis of PVFM was suggested, in association with paradoxical vocal folds motion caused by respiratory difficulties verified by laryngeal examination. CONCLUSIONS: In PVFM, the vocal folds adduct during inhalation, thereby restricting the airway opening. Inconsistent vocal folds movement during phonation may also lead to PVFM symptoms. Acute bronchospasm/asthma-like symptoms, as well as additional morbidity may impact accuracy of diagnosis, leading to unnecessary use of asthma medications and office/emergency room consultations. PMID- 25455525 TI - Development and validation of a new Mandarin tone identification test. AB - OBJECTIVES: The objectives of this study were to develop a new Mandarin tone identification test (MTIT) to assess the Mandarin tone identification ability of children with hearing impairment (HI) and at age around 7 years; and to evaluate the reliability and sensitivity of the MTIT. METHODS: The word materials to be used in the MTIT were developed in Phase I. Monosyllables were chosen to represent the daily repertoire of young children and to avoid the influence of co articulation and intonation. Each test stimulus set contained four words, with one target, one containing contrastive tone, and two unrelated distracters. All words were depicted using simple pictures, and the test targets in quiet or in noise were presented using recorded stimuli on a custom software. Phase II evaluated the reliability and sensitivity of the MTIT. Participants were 50 normal-hearing native-Mandarin speakers around 7 years of age. RESULTS: In Phase I, the MTIT was developed as described above. The final test consists of 51 words that are within the vocabulary repertoire of children aged 7 years. In Phase II, with the Mandarin tone identification scores collected from 50 children, the repeated measure ANOVA showed a significant main effect of S/N on MTIT performance (p<0.001). Pairwise comparisons revealed a significant difference in performance across the five S/N conditions (p<0.01) when S/N varied from -30 to 10dB. Cronbach's alpha at -15dB S/N was 0.66, suggesting satisfactory internal consistency reliability. A paired-samples t-test showed that there was no significant difference between the test-retest scores across the five S/N conditions (p>0.05). CONCLUSIONS: Compared with the available Mandarin tone identification tools, MTIT systematically evaluated the tone identification performance in noisy environment for normal hearing children at age around 7 years. Results also showed satisfactory internal consistency reliability, good test-retest reliability and good sensitivity. In the near future, MTIT could be used to evaluate tone perception ability of children with hearing impairment and help to design hearing rehabilitation strategies for this population at the age critical for their language learning. PMID- 25455526 TI - Results in cochlear implanted children before 5 years of age. a long term follow up. AB - OBJECTIVE: To assess the hearing threshold and linguistic results of cochlear implanted children aged 10 months to 5 years, when they reached the age of 12. We studied the benefits of sequential bilateral implantation. METHOD AND RESULTS: This is an observational, descriptive, transversal study comprising 57 cochlear implanted subjects. We performed a free field tonal audiometry at 65dB SPL, speech tests and sentences in quiet and noise (SNR+10) tests. The Objective and Criterial Language Battery (BLOC) was used to assess linguistic competence, in its screening version. RESULTS: Children implanted under the age of 2 and with inter-implant period less than or equal to 4 years reached better statistically significant results in disyllabic and sentences with and without noise (p=0.006) tests and in the disyllabic test with noise (p=0.045) (the hardest speech test). This suggests the acquisition of binaurality, as opposed to children implanted after this age, with inter-implant period longer than 4 years, who do not reach the same performance levels. RESULTS: of language development in the group implanted at ages 10 months to 2 years are better with respect to implanted children at ages 3-5 (<0.05) in both unilateral and bilateral implanted children in relation to the age of implantation. CONCLUSION: Children with pre-lingual deafness implanted before the age of 2, when they are 12 years old obtain more benefits in their language development and in their linguistic competence than children implanted after this age. The audiology results are better in children implanted bilaterally under the age of 2. PMID- 25455527 TI - Accuracy of Internet guidance on pediatric otolaryngology procedures. AB - OBJECTIVES: To evaluate the reliability and accuracy of the most visited Internet websites for the frequently performed surgical pediatric otorhinolaryngology procedures. STUDY: A google.com search was used to determine the top 20 Internet sites for the terms 'adenoidectomy', 'tonsillectomy' and 'ventilation tube surgery'. The DISCERN plus questionnaire was used to score each website. Furthermore, a 'hit list' of reliable and accurate websites was created depending on the most clicked healthcare organizations with corporate identities and the personal websites of the otolaryngologists with academic titles who were members of the Turkish Society of Otolaryngology Head and Neck Surgery. The pages were also investigated as if they were in this list of accurate websites. RESULTS: Of the 60 websites viewed for the terms 'adenoidectomy', 'tonsillectomy' and 'ventilation tube surgery', only 23.3% were matching the list of accurate websites. The mean DISCERN plus score was 35.70 (16-58), 38.02 (16-80) and 39.08 (16-58) for adenoidectomy, tonsillectomy and ventilation tube surgery respectively. There was no significant difference between the three groups (p>0.05). The mean DISCERN plus score for all the websites was 37.37 out of the maximum score of 80. CONCLUSIONS: In the light of our results we can conclude that the quality of data on the Internet is not adequate enough to obtain information about the most frequent surgical procedures in pediatric otorhinolaryngology. Clinicians must be aware about this fact and warn the parents about the disinformation which may lead to wrong decisions. PMID- 25455528 TI - Letter to the Editor regarding "does septoplasty improve the quality of life in children?". PMID- 25455530 TI - Frailty, sarcopenia and diabetes. PMID- 25455529 TI - Response to the letter to the editor regarding "does septoplasty improve the quality of life in children?". PMID- 25455531 TI - Treatment of cachexia: an overview of recent developments. AB - Body wasting in the context of chronic illness is associated with reduced quality of life and impaired survival. Recent clinical trials have investigated different approaches to improve patients' skeletal muscle mass and strength, exercise capacity, and survival in the context of cachexia and body wasting, many of them in patients with cancer. The aim of this article was to summarize clinical trials published over the past 2 years. Therapeutic approaches discussed include appetite stimulants, such as megestrol acetate, L-carnitine, or melatonin, anti inflammatory drugs, such as thalidomide, pentoxyphylline, or a monoclonal antibody against interleukin-1alpha as well as ghrelin and the ghrelin agonist anamorelin; nutritional support, and anabolics, such as enobosarm and testosterone. PMID- 25455532 TI - [Christopher Wren: from early transfusion to Saint-Paul Cathedral]. PMID- 25455533 TI - Long-term results of vaginal construction with the use of Frank dilation and a peritoneal graft (Davydov procedure) in patients with Mayer-Rokitansky-Kuster syndrome. AB - OBJECTIVE: To describe long-term outcomes after nonsurgical and surgical treatment of vaginal agenesis in a cohort of girls and women with Mayer Rokitansky-Kuster (MRK) syndrome. DESIGN: Retrospective cohort study using a standardized case record form. SETTING: University hospital. PATIENT(S): All girls and women with vaginal agenesis due to MRK syndrome, presenting during a 40 year period (1962-2012). INTERVENTION(S): Frank dilation and surgical treatment (with the use of a peritoneal graft, i.e., the Davydov method) for vaginal agenesis. MAIN OUTCOME MEASURE(S): Functional vaginal depth and complications. RESULT(S): Two hundred fifty-four women with MRK visited the department. Urinary tract anomalies were found in 72 patients (31%), and other congenital anomalies in 59 (32%) of the patients with available data. One hundred sixty women were treated for vaginal agenesis. The mean follow-up time was 90 months (range 0-560 months). Sixty-eight patients had surgical treatment for vaginal agenesis with the use of a peritoneal graft (Davydov method) and reached a functional depth of the vagina of 7.8 cm (range 1-13 cm) Surgical therapy preceded by nonsurgical Frank dilation and/or attempted sexual intercourse did not result in more functional depth of the neovagina. The formation of granulation tissue (23%) and the tendency to obliterate (12%) were the major problems when using a peritoneal graft. CONCLUSION(S): Long-term results of both Frank dilation and Davydov neovagina procedure in experienced hands were good. The use of a peritoneal graft may be regarded as a good alternative to other widely used neovagina techniques using a graft, such as split-thickness skin graft or sigmoid neovagina. PMID- 25455534 TI - Expression of GRIM-19 in missed abortion and possible pathogenesis. AB - OBJECTIVE: To study the expression of a gene associated with retinoid-interferon (IFN)-induced mortality 19 (GRIM-19) in the villi of patients with missed abortion and possible pathogenesis. DESIGN: Case-control study. SETTING: University hospital. PATIENT(S): Villous samples were collected from a total of 50 women with missed abortion and 50 women with normal pregnancies. INTERVENTION(S): Villous samples from the missed-abortion group were collected by curettage or manual vacuum aspiration. The control villous samples were obtained by vacuum aspiration. MAIN OUTCOME MEASURE(S): Protein and messenger RNA levels of GRIM-19 in villous samples were measured by Western blot and real-time polymerase chain reaction, and the location of GRIM-19 in trophoblasts was detected by immunohistochemistry. Apoptotic cells and microvessel density in villous sample were assayed by TUNEL and immunostaining. Mitochondrial membrane potential and apoptotic changes of the HTR-8/SVneo cell line in response to down regulation of GRIM-19 were evaluated by 5,5',6,6'-Tetrachloro-1,1',3,3' tetraethyl-imidacarbocyanine iodide and annexin V/propidium iodide. Vascular endothelial growth factor production was measured by ELISA. RESULT(S): GRIM-19 protein and messenger RNA levels in the villi from women with missed abortion were found to be significantly lower than in women who had normal pregnancies. Many more apoptotic cells and lower microvessel density were detected in villi from patients with missed abortion. Knockdown of GRIM-19 in HTR-8/SVneo cells gave rise to a collapse of mitochondrial membrane potential and increase in apoptosis. Simultaneously, the vascular endothelial growth factor secretion in the HTR-8/SVneo cells culture medium decreased as GRIM-19 became down-regulated. CONCLUSION(S): The GRIM-19 deficiency in the villus may be associated with missed abortion via increasing apoptosis and affecting angiogenesis. PMID- 25455535 TI - Healthcare utilization and costs in women diagnosed with endometriosis before and after diagnosis: a longitudinal analysis of claims databases. AB - OBJECTIVE: To assess healthcare resource utilization and costs during the 5 years before and 5 years after diagnosis among women with endometriosis, in comparison with women without endometriosis. DESIGN: Longitudinal, retrospective, case control study. SETTING: None. PATIENT(S): A total of 37,570 matched pairs of women with and without (controls) endometriosis were identified from the Truven Health MarketScan claims database (2000-2010). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Annual healthcare resource utilization and costs (in 2010 US dollars) were evaluated for the 5 years before and 5 years after diagnosis. RESULT(S): Mean patient age at index (first diagnosis) date was 36.4 years for endometriosis patients and controls. Endometriosis patients had a higher utilization of outpatient and emergency room services during each pre- and postindex year, and a higher utilization of inpatient services during the last preindex year and all 5 postindex years. Total costs were highest in the first postindex year for endometriosis patients, reaching $13,199, compared with $3,747 for controls. Annual costs were significantly higher for patients than controls during each pre- and postindex year; overall, the cost difference was $26,305 over 10 years: $7,028 in the 5 years before diagnosis and $19,277 in the 5 years after diagnosis. CONCLUSION(S): Endometriosis poses a significantly high economic burden, both before and after diagnosis. The highest resource utilization and costs experienced by endometriosis patients occur in the first year after diagnosis. PMID- 25455536 TI - Aromatase inhibitors for subfertile women with polycystic ovary syndrome: summary of a Cochrane review. AB - Polycystic ovary syndrome (PCOS) is a common cause of anovulatory subfertility. We evaluated the effectiveness and safety of aromatase inhibitors compared with other methods of ovulation induction in women with anovulatory PCOS. PMID- 25455537 TI - Blastocyst transfer is not associated with increased rates of monozygotic twins when controlling for embryo cohort quality. AB - OBJECTIVE: To compare monozygotic twinning (MZT) rates in patients undergoing blastocyst or cleavage-stage ET. DESIGN: Retrospective cohort. SETTING: Academic research center. PATIENT(S): Autologous, fresh IVF cycles resulting in a clinical pregnancy from 1999 to 2014. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Monozygotic twin pregnancy in blastocyst-stage transfer vs. cleavage-stage transfer when controlling for patient prognosis and embryo cohort quality factors. RESULT(S): There were a total of 9,969 fresh transfer cycles resulting in a pregnancy during the study period. Of these pregnancies, 234 monozygotic twin pregnancies were identified (2.4%). Of all transfers, 5,191 were cleavage stage and 4,778 were blastocyst-stage transfers. There were a total of 99 MZT identified in the cleavage-stage group (1.9%) and 135 MZT in the blastocyst ET group (2.4%), which was significant. Multivariable logistic regression revealed that increasing age was associated with a significant reduction in MZT, regardless of transfer order. Embryo cohort quality factors, including the number and proportion of six- to eight-cell embryos and availability of supernumerary embryos, were also significant. When controlling for patient age, time period during which the cycle took place, the number and proportion of six- to eight cell embryos, and availability of supernumerary embryos, there was no longer a difference in MZT rate between blastocyst and cleavage transfer. CONCLUSION(S): Patient prognosis and embryo cohort quality seem to be major factors in MZT rate in women undergoing blastocyst transfer. Although technology-based effects cannot be excluded, patient and embryo characteristics play an important role. PMID- 25455538 TI - Fluid therapy in acute pancreatitis - aggressive or adequate? Time for reappraisal. PMID- 25455539 TI - A systematic review of the extra-pancreatic infectious complications in acute pancreatitis. AB - BACKGROUND AND AIM: Extra-pancreatic infectious complications in acute pancreatitis increase morbidity, but their incidence and association with infected pancreatic necrosis is unknown. Half of bacterial cultures of pancreatic necrosis are of non-enteric origin, raising the possibility of other sources of infection. The aim of this systematic review was to assess the incidence of extra pancreatic infectious complications in acute pancreatitis, their timing, and relation to severity of pancreatitis and mortality. METHODS: A systematic review was performed using Ovid MEDLINE, Embase and Cochrane Libraries, following PRISMA guidelines. Search terms were "Pancreatitis" AND "Infection" AND ("Complication" OR "Outcome"). RESULTS: 19 studies with 1741 patients were included. Extra pancreatic infectious complication incidence was 32% (95% CI 23-41%), with the commonest being respiratory infection (9.2%) and bacteraemia (8.4%). Extra pancreatic infectious complications were not associated with the predicted severity or the mortality of acute pancreatitis. Only 3 studies reported a relation of timing between extra-pancreatic and pancreatic infectious complications. CONCLUSIONS: This is the first systematic review to evaluate the incidence of extra-pancreatic infectious complications in acute pancreatitis, which a third of patients with acute pancreatitis will develop. Implications are vigilance and prompt treatment of extra-pancreatic infection, to reduce possibility of progression to infected pancreatic necrosis. PMID- 25455540 TI - Pain severity reduces life quality in chronic pancreatitis: Implications for design of future outcome trials. AB - BACKGROUND/OBJECTIVES: Chronic pancreatitis (CP) is a disabling disease characterised by abdominal pain, and various pancreatic and extra-pancreatic complications. We investigated the interactions between pain characteristics (i.e. pain severity and its pattern in time), complications, and quality of life (QOL) in patients with CP. METHODS: This was a cross-sectional study of 106 patients with CP conducted at two North European tertiary medical centres. Detailed information on clinical patient characteristics was obtained from interviews and through review of the individual patient records. Pain severity scores and pain pattern time profiles were extracted from the modified brief pain inventory short form and correlated to QOL as assessed by the EORTC QLQ-C30 questionnaire. Interactions with exocrine and endocrine pancreatic insufficiency, as well as pancreatic and extra-pancreatic complications were analysed using regression models. RESULTS: Pain was the most prominent symptom in our cohort and its severity was significantly correlated with EORTC global health status (r = 0.46; P < 0.001) and most functional and symptom subscales. In contrast the patterns of pain in time were not associated with any of the life quality subscales. When controlling for interactions from exocrine and endocrine pancreatic insufficiency no effect modifications were evident (P = 0.72 and P = 0.85 respectively), while the presence of pancreatic and extra-pancreatic complications was associated with an almost 15% decrease in life quality (P = 0.004). CONCLUSIONS: Pain severity and disease related complications significantly reduce life quality in patients with CP. This information is important in order to design more accurate and clinical meaningful endpoints in future outcome trials. PMID- 25455541 TI - There is grandeur in this view of Newton: Charles Darwin, Isaac Newton and Victorian conceptions of scientific virtue. AB - For Victorian men of science, the scientific revolution of the seventeenth century represented a moral awakening. Great theoretical triumphs of inductive science flowed directly from a philosophical spirit that embraced the virtues of self-discipline, courage, patience and humility. Isaac Newton exemplified this union of moral and intellectual excellence. This, at least, was the story crafted by scientific leaders like David Brewster, Thomas Chalmers, John Herschel, Adam Sedgwick and William Whewell. Not everyone accepted this reading of history. Evangelicals who decried the 'materialism' of mainstream science assigned a different meaning to Newton's legacy on behalf of their 'scriptural' alternative. High-church critics of science like John Henry Newman, on the other hand, denied that Newton's secular achievements carried any moral significance at all. These debates over Newtonian standards of philosophical behavior had a decisive influence on Charles Darwin as he developed his theory of evolution by natural selection. PMID- 25455542 TI - Charles Darwin's reputation: how it changed during the twentieth-century and how it may change again. AB - Charles Darwin died in 1882. During the twentieth century his reputation varied through time, as the scientific foundation of evolutionary theory changed. Beginning the century as an intellectual hero, he soon became a virtual footnote as experimental approaches to evolution began to develop. As the Modern Synthesis developed his reputation began to rise again until eventually he was identified as a founding father of the Modern Synthesis itself. In the meantime, developmental approaches to evolution began to challenge certain aspects of the Modern Synthesis. Synthesis authors attempted to refute the relevance of development by methodological arguments, some of them indirectly credited to Darwin. By the end of the century, molecular genetics had given new life to development approaches to evolution, now called evo devo. This must be seen as a refutation of the aforesaid methodological arguments of the Modern Synthesis advocates. By the way, we can also see now how the historiography that credited Darwin with the Synthesis was in error. In conclusion, one more historical revision is suggested. PMID- 25455543 TI - The Darwinian revolution in Germany: from evolutionary morphology to the modern synthesis. AB - The Darwinian revolution in the German speaking lands was the result of a variety of influences and disciplinary convergences. One of the paths led from pre Darwinian comparative morphology via Darwinian and Lamarckian evolutionary morphology to the Modern Synthesis. Our research demonstrates that there was no immediate replacement of one paradigm by another as described in the classical work of Thomas Kuhn. Rather, the development of novel conceptual structures looked like a Russian 'matryoshka doll' consisting of an over-arching 'meta paradigm' embracing conceptual structures of ever smaller scale. Such a meta paradigm for German life sciences was initially established by Johann Wolfgang von Goethe, which determined the specificity of German evolutionism throughout the 2nd half of the 19th and well into the 20th century. PMID- 25455544 TI - Hemodynamic outcomes of transcatheter aortic valve replacement and medical management in severe, inoperable aortic stenosis: a longitudinal echocardiographic study of cohort B of the PARTNER trial. AB - BACKGROUND: Inoperable aortic stenosis may be treated with either transcatheter aortic valve replacement (TAVR) or medical management (MM) with or without balloon aortic valvuloplasty (BAV). The aim of this study was to compare the long term echocardiographic findings among TAVR, MM, and BAV in patients with severe, inoperable aortic stenosis. METHODS: A total of 358 inoperable patients in the Placement of Aortic Transcatheter Valves trial were randomized to MM or TAVR. Echocardiograms obtained at baseline, 30 days, and 1, 2, and 3 years were analyzed by a central core laboratory. RESULTS: At baseline, TAVR and MM were similar, with more frequent Society of Thoracic Surgeons score > 10 (51.7% vs 65.0%, P = .03) and larger end-systolic volumes (54.5 +/- 29.3 vs 69.1 +/- 48.0 mL, P = .03) in MM. By 30 days after TAVR, mean aortic valve gradient had decreased (from 43.8 +/- 14.7 to 10.0 +/- 4.3 mm Hg, P < .001), ejection fraction had increased (from 53.2 +/- 12.4% to 56.7 +/- 10.0%, P < .001), and left ventricular (LV) mass index had decreased (from 144.7 +/- 36.1 to 140.0 +/- 37.9 gm/m(2), P < .05). After 1 year, aortic valve gradients and area were unchanged, while LV mass index had decreased by another 16 gm/m(2) (to 124 gm/m(2)). By 30 days after BAV, mean aortic valve gradient had decreased from 43.4 +/- 15.0 to 31.9 +/- 11.1 mm Hg, while ejection fraction and LV mass index were unchanged; gradient reverted to baseline at 1 year. No changes in gradients or mass were seen in MM patients. CONCLUSIONS: TAVR results in immediate and sustained relief in pressure overload and improved LV systolic function, with continued regression of hypertrophy over 3 years. Poor clinical results with BAV are explained by the modest and transient reductions in pressure overload with BAV, which were not accompanied by improved LV function or remodeling. TAVR is the preferred treatment in eligible inoperable patients (ClinicalTrials.gov identifier NCT00530894). PMID- 25455545 TI - Patterns of left ventricular longitudinal strain and strain rate in Olympic athletes. AB - BACKGROUND: Two-dimensional speckle-tracking echocardiography is an emerging modality for the assessment of systolic and diastolic myocardial deformation in a broad variety of clinical scenarios. However, normal values and physiologic limits of left ventricular strain and strain rate in trained athletes are largely undefined. METHODS: Two hundred consecutive Olympic athletes (grouped into skill, power, mixed, and endurance disciplines) and 50 untrained controls were evaluated by two-dimensional speckle-tracking echocardiography. Left ventricular global systolic longitudinal strain (GLS), systolic strain rate, early diastolic strain rate (SRE) and late diastolic strain rate (SRA) were calculated. RESULTS: GLS was normal, although mildly lower, in athletes compared with controls (-18.1 +/- 2.2% vs -19.4 +/- 2.3%, P < .001), without differences related to type of sport. Systolic strain rate was also lower in athletes (-1.00 +/- 0.15 vs -1.11 +/- 0.15 sec(-1), P < .001), with the lowest value in endurance disciplines (-0.96 +/- 0.13 sec(-1), P < .001). No difference existed for SRE (1.45 +/- 0.32 vs 1.51 +/- 0.35 sec(-1), P = .277), while SRA was lower in athletes (0.67 +/- 0.25 vs 0.81 +/- 0.20 sec(-1), P < .001). Both SRE (1.37 +/- 0.30 sec(-1), P < .001) and SRA (0.62 +/- 0.23 sec(-1), P < .001) showed the lowest values in endurance disciplines. The fifth and 95th percentiles calculated as reference values in athletes were as follows: for GLS, -15% and -22%; for systolic strain rate, -0.8 and -1.2 sec(-1); for SRE, 1.00 and 2.00 sec(-1); and for SRA, 0.30 and 1.20 sec( 1). CONCLUSION: The present study shows that highly trained athletes have normal GLS and strain rate parameters of the left ventricle, despite mild differences compared with untrained controls. These data may be implemented as reference values for the clinical assessment of the athletes and to support the diagnosis of physiologic cardiac adaptations in borderline cases. PMID- 25455546 TI - [A case of post-traumatic severe orbital emphysema: case report and literature review]. PMID- 25455547 TI - Ophthalmic artery occlusion as a complication of infectious endocarditis. PMID- 25455548 TI - The management of corneal melt occurring after collagen cross-linking for keratoconus. PMID- 25455549 TI - [Retinal detachment: wide field photography with the Optomap system]. PMID- 25455550 TI - Jerky seesaw nystagmus with internuclear ophthalmoplegia as the presenting finding in systemic lupus erythematosus. PMID- 25455551 TI - [Progression of a rare and serious ocular manifestation of Wegener's granulomatosis: occlusive retinal vasculitis]. PMID- 25455552 TI - [Posterior capsule opacification]. AB - Posterior capsule opacification (PCO) is the most common complication after cataract surgery, with an incidence of 30%. It tends to be considered a normal event in the natural history of cataract surgery. Better understanding of its pathophysiology and advancement of intraocular lens material and design along with the improvement of phacoemulsification technique have contributed to decrease the incidence of PCO. Although treatment by Nd: YAG laser posterior capsulotomy is quick and non-invasive, the opening of the posterior capsule may be associated with numerous complications. Prevention remains the best measure for controlling this pathology. PMID- 25455553 TI - [Preeclampsia and retinal complications]. PMID- 25455554 TI - [Optical coherence tomography of a retinal artery occlusion]. PMID- 25455555 TI - [Gelatinous drop-like corneal dystrophy]. PMID- 25455556 TI - [Extrusion of a hard silicone band through a palpebral fistula]. PMID- 25455557 TI - [Orbital inflammation]. AB - Orbital inflammation is a generic term encompassing inflammatory pathologies affecting all structures within the orbit : anterior (involvement up to the posterior aspect of the globe), diffuse (involvement of intra- and/or extraconal fat), apical (involvement of the posterior orbit), myositis (involvement of only the extraocular muscles), dacryoadenitis (involvement of the lacrimal gland). We distinguish between specific inflammation and non-specific inflammation, commonly referred to as idiopathic inflammation. Specific orbital inflammation corresponds to a secondary localization of a "generalized" disease (systemic or auto-immune). Idiopathic orbital inflammation corresponds to uniquely orbital inflammation without generalized disease, and thus an unknown etiology. At the top of the differential diagnosis for specific or idiopathic orbital inflammation are malignant tumors, represented most commonly in the adult by lympho-proliferative syndromes and metastases. Treatment of specific orbital inflammation begins with treatment of the underlying disease. For idiopathic orbital inflammation, treatment (most often corticosteroids) is indicated above all in cases of visual loss due to optic neuropathy, in the presence of pain or oculomotor palsy. PMID- 25455558 TI - Corneal Nocardiosis mistaken for fungal infection. PMID- 25455559 TI - Reversibility of topographic changes and visual symptoms induced by epithelial ingrowth post-LASIK: a case report. PMID- 25455561 TI - Transductive domain adaptive learning for epileptic electroencephalogram recognition. AB - OBJECTIVE: Intelligent recognition of electroencephalogram (EEG) signals is an important means for epilepsy detection. Almost all conventional intelligent recognition methods assume that the training and testing data of EEG signals have identical distribution. However, this assumption may indeed be invalid for practical applications due to differences in distributions between the training and testing data, making the conventional epilepsy detection algorithms not feasible under such situations. In order to overcome this problem, we proposed a transfer-learning-based intelligent recognition method for epilepsy detection. METHODS: We used the large-margin-projected transductive support vector machine method (LMPROJ) to learn the useful knowledge between the training domain and testing domain by calculating the maximal mean discrepancy. The method can effectively learn a model for the testing data with training data of different distributions, thereby relaxing the constraint that the data distribution in the training and testing samples should be identical. RESULTS: The experimental validation is performed over six datasets of electroencephalogram signals with three feature extraction methods. The proposed LMPROJ-based transfer learning method was compared with five conventional classification methods. For the datasets with identical distribution, the performance of these six classification methods was comparable. They all could achieve an accuracy of 90%. However, the LMPROJ method obviously outperformed the five conventional methods for experimental datasets with different distribution between the training and test data. Regardless of the feature extraction method applied, the mean classification accuracy of the proposed method is above 93%, which is greater than that of the other five methods with statistical significance. CONCLUSION: The proposed transfer-learning-based method has better classification accuracy and adaptability than the conventional methods in classifying EEG signals for epilepsy detection. PMID- 25455560 TI - Dendrimer nanocarriers for transport modulation across models of the pulmonary epithelium. AB - The purpose of this study was to determine the effect of PEGylation on the interaction of poly(amidoamine) (PAMAM) dendrimer nanocarriers (DNCs) with in vitro and in vivo models of the pulmonary epithelium. Generation-3 PAMAM dendrimers with varying surface densities of PEG 1000 Da were synthesized and characterized. The results revealed that the apical to basolateral transport of DNCs across polarized Calu-3 monolayers increases with an increase in PEG surface density. DNC having the greatest number of PEG groups (n = 25) on their surface traversed at a rate 10-fold greater than its non-PEGylated counterpart, in spite of their larger size. This behavior was attributed to a significant reduction in charge density upon PEGylation. We also observed that PEGylation can be used to modulate cellular internalization. The total uptake of PEG-free DNC into polarized Calu-3 monolayers was 12% (w/w) vs 2% (w/w) for that with 25 PEGs. Polarization is also shown to be of great relevance in studying this in vitro model of the lung epithelium. The rate of absorption of DNCs administered to mice lungs increased dramatically when conjugated with 25 PEG groups, thus supporting the in vitro results. The exposure obtained for the DNC with 25PEG was determined to be very high, with peak plasma concentrations reaching 5 MUg.mL(-1) within 3 h. The combined in vitro and in vivo results shown here demonstrate that PEGylation can be potentially used to modulate the internalization and transport of DNCs across the pulmonary epithelium. Modified dendrimers thereby may serve as a valuable platform that can be tailored to target the lung tissue for treating local diseases, or the circulation, using the lung as pathway to the bloodstream, for systemic delivery. PMID- 25455563 TI - Intra-axiom redundancies in SNOMED CT. AB - OBJECTIVE: Intra-axiom redundancies are elements of concept definitions that are redundant as they are entailed by other elements of the concept definition. While such redundancies are harmless from a logical point of view, they make concept definitions hard to maintain, and they might lead to content-related problems when concepts evolve. The objective of this study is to develop a fully automated method to detect intra-axiom redundancies in OWL 2 EL and apply it to SNOMED Clinical Terms (SNOMED CT). MATERIALS AND METHODS: We developed a software program in which we implemented, adapted and extended readily existing rules for redundancy elimination. With this, we analysed occurence of redundancy in 11 releases of SNOMED CT (January 2009 to January 2014). We used the ELK reasoner to classify SNOMED CT, and Pellet for explanation of equivalence. We analysed the completeness and soundness of the results by an in-depth examination of the identified redundant elements in the July 2012 release of SNOMED CT. To determine if concepts with redundant elements lead to maintenance issues, we analysed a small sample of solved redundancies. RESULTS: Analyses showed that the amount of redundantly defined concepts in SNOMED CT is consistently around 35,000. In the July 2012 version of SNOMED CT, 35,010 (12%) of the 296,433 concepts contained redundant elements in their definitions. The results of applying our method are sound and complete with respect to our evaluation. Analysis of solved redundancies suggests that redundancies in concept definitions lead to inadequate maintenance of SNOMED CT. CONCLUSIONS: Our analysis revealed that redundant elements are continuously introduced and removed, and that redundant elements may be overlooked when concept definitions are corrected. Applying our redundancy detection method to remove intra-axiom redundancies from the stated form of SNOMED CT and to point knowledge modellers to newly introduced redundancies can support creating and maintaining a redundancy-free version of SNOMED CT. PMID- 25455562 TI - From decision to shared-decision: Introducing patients' preferences into clinical decision analysis. AB - OBJECTIVE: Taking into account patients' preferences has become an essential requirement in health decision-making. Even in evidence-based settings where directions are summarized into clinical practice guidelines, there might exist situations where it is important for the care provider to involve the patient in the decision. In this paper we propose a unified framework to promote the shift from a traditional, physician-centered, clinical decision process to a more personalized, patient-oriented shared decision-making (SDM) environment. METHODS: We present the theoretical, technological and architectural aspects of a framework that encapsulates decision models and instruments to elicit patients' preferences into a single tool, thus enabling physicians to exploit evidence based medicine and shared decision-making in the same encounter. RESULTS: We show the implementation of the framework in a specific case study related to the prevention and management of the risk of thromboembolism in atrial fibrillation. We describe the underlying decision model and how this can be personalized according to patients' preferences. The application of the framework is tested through a pilot clinical evaluation study carried out on 20 patients at the Rehabilitation Cardiology Unit at the IRCCS Fondazione Salvatore Maugeri hospital (Pavia, Italy). The results point out the importance of running personalized decision models, which can substantially differ from models quantified with population coefficients. CONCLUSIONS: This study shows that the tool is potentially able to overcome some of the main barriers perceived by physicians in the adoption of SDM. In parallel, the development of the framework increases the involvement of patients in the process of care focusing on the centrality of individual patients. PMID- 25455565 TI - Neglected tools for neglected diseases: mathematical models in economic evaluations. AB - Despite many current interventions against neglected tropical diseases (NTDs) being highly cost-effective, new strategies are needed to reach the WHO's control and elimination goals. Here we argue for the importance of incorporating economic evaluations of new strategies in decisions regarding resource allocation. Such evaluation should ideally be conducted using dynamic transmission models that capture inherent nonlinearities in transmission and the indirect benefits ('herd effects') of interventions. A systematic review of mathematical models that have been used for economic analysis of interventions against the ten NTDs covered by the London Declaration reveals that only 16 out of 49 studies used dynamic transmission models, highlighting a fundamental--but addressable--gap in the evaluation of interventions against NTDs. PMID- 25455566 TI - Fighting the good fight: the role of militaries in malaria elimination in Southeast Asia. AB - Despite significant progress in malaria control in the Greater Mekong Subregion (GMS), malaria is still endemic, with more than 30 million people infected annually. Important gaps remain in case management, service delivery, prevention, and vector control, particularly in hard-to-reach mobile populations. Rapidly evolving drug resistance has created a new urgency to move aggressively toward elimination. However, no clear and cost-effective strategy has been identified. Although GMS militaries are under-recognized as a malaria transmission reservoir, they are an important focal point for elimination activities, given their high mobility, frequent malaria exposure, and potential for asymptomatic carriage. At the same time, military organizational capacity and proximity to other mobile populations could facilitate elimination efforts if relevant political barriers could be overcome. Here, we review considerations for military involvement in regional malaria elimination efforts. PMID- 25455564 TI - A noncanonical role for the CKI-RB-E2F cell-cycle signaling pathway in plant effector-triggered immunity. AB - Effector-triggered immunity (ETI), the major host defense mechanism in plants, is often associated with programmed cell death (PCD). Plants lack close homologs of caspases, the key mediators of PCD in animals. So although the NB-LRR receptors involved in ETI are well studied, how they activate PCD and confer disease resistance remains elusive. We show that the Arabidopsis nuclear envelope protein, CPR5, negatively regulates ETI and the associated PCD through a physical interaction with cyclin-dependent kinase inhibitors (CKIs). Upon ETI induction, CKIs are released from CPR5 to cause overactivation of another core cell-cycle regulator, E2F. In cki and e2f mutants, ETI responses induced by both TIR-NB-LRR and CC-NB-LRR classes of immune receptors are compromised. We further show that E2F is deregulated during ETI, probably through CKI-mediated hyperphosphorylation of retinoblastoma-related 1 (RBR1). This study demonstrates that canonical cell cycle regulators also play important noncanonical roles in plant immunity. PMID- 25455567 TI - Initial excited-state structural dynamics of 6-substituted uracil derivatives: femtosecond angle and bond lengthening dynamics in pyrimidine nucleobase photochemistry. AB - Substituents on the pyrimidine ring of nucleobases appear to play a major role in determining their initial excited-state structural dynamics and resulting photochemistry. To better understand the determinants of nucleobase initial excited-state structural dynamics, we have measured the absorption and resonance Raman excitation profiles of 6-deuterouracil (6-d-U) and 6-methyluracil (6-MeU). Simulation of the resonance Raman excitation profiles and absorption spectrum with a self-consistent, time-dependent formalism shows the effect of the deuterium and methyl group on the photochemically active internal coordinates, i.e. C5C6 stretch and C5X and C6X bends. The methyl group on either the C5 or C6 position of uracil equally increases the excited-state reorganization energies along the C5C6 stretch. However, a lower reorganization energy of the C5X + C6X bends in 6-MeU than uracil and 5-MeU shows that C6 methyl substituents reduce the bending reorganization energy. In addition, deuterium substitution at either C5 or C6 has a much smaller effect on the initial excited-state structural dynamics than methyl substitution, consistent with a mass effect. These results will be discussed in light of the resulting photochemistry of pyrimidine nucleobases. PMID- 25455568 TI - Enhancing treatment effects by combining continuous theta burst stimulation with smooth pursuit training. AB - Continuous theta burst stimulation (cTBS) represents a promising approach in the treatment of neglect syndrome. However, it is not known whether cTBS in conjunction with another technique may enhance the therapeutic effects. In the present sham-controlled study, we aimed to combine cTBS with smooth pursuit training (SPT), another method known to effectively improve neglect symptoms, and to evaluate whether this combination would result in a stronger effect than SPT alone. Eighteen patients with left spatial neglect after right-hemispheric stroke were included in the study and performed a cancellation task on a large 54.6" touchscreen monitor. A sequential application of cTBS and SPT induced a significantly greater improvement of neglect than SPT alone. After the combined application of these two methods, patients detected significantly more targets and their cancellation behaviour presented a significantly greater shift towards the contralesional hemispace. We suggest that a combined, sequential application of cTBS and SPT is a promising new approach to treat neglect. PMID- 25455570 TI - List constituency and orthographic and phonological processing: a shift to high familiarity words from low familiarity words. AB - Two lexical decision experiments build on established patterns of laterality and hemispheric interaction to test whether the presence of low familiarity words dynamically affects the use of an orthographic or phonological strategy for high familiarity words; and, if so, whether the hemispheres are similarly flexible in adapting to the constituency change. Experiment 1 restricted word strings to the highly familiar. Experiment 2 presented the same high familiarity words, along with an equal number of low familiarity words. Targets for lexical decision were presented at fixation to approximate normal viewing behaviour, either with or without a non-lexical distractor lateralized left visual field (LVF) or right visual field (RVF). Response time and accuracy were measured. Responses were faster in Experiment 1 than Experiment 2 to high familiarity words, pseudowords (orthographically correct), and non-words (orthographically incorrect), suggesting that a different strategy was used. A main effect of distractor location in Experiment 1 was due to more accurate responses to letter strings accompanied by a RVF distractor than no distractor, revealing a cost from hemispheric interaction compared to the right hemisphere when a task is simple. Experiment 2 found an interaction between distractor location and string type in both the response time and accuracy data. Separate analyses of word strings revealed a shift to a left hemisphere advantage: Accuracy to low familiarity words and speed to high familiarity words was better when accompanied by a LVF than a RVF distractor. Critical to a dynamic effect of list constituency is that the right hemisphere slowed to the same high familiarity words that had provoked speedier responses in Experiment 1. The findings are consistent with the use of an orthographic strategy in Experiment 1 and a phonological strategy in Experiment 2, and support the idea that right hemisphere access to familiar phonology is slower than the left hemisphere. Taken together, the findings suggest that the strategy used by both hemispheres is flexible, that both adapt to list constituency by adopting a strategy that is optimal for the task as a whole, and that there are different timelines of phonological activation in the two cerebral hemispheres. PMID- 25455569 TI - Weak language lateralization affects both verbal and spatial skills: an fMRI study in 297 subjects. AB - The present study reappraised the relationship between hemispheric specialization strength and cognitive skills in a sample of 297 individuals including 153 left handers. It additionally assessed the interaction with manual laterality factors, such as handedness, asymmetry of hand motor skills, and familial sinistrality. A Hemispheric Functional Lateralization Index (HFLI) for language was derived from fMRI. Through mixture Gaussian modeling, three types of language hemispheric lateralization were defined: typical (left hemisphere dominance with clear positive HFLI), ambilateral (no dominant hemisphere with HFLI values close to 0), and strongly-atypical (right-hemisphere dominance with clear negative HFLI values). Three cognitive scores were derived from 12 tests covering various aspects of verbal and spatial cognition. Compared to both typical and strongly atypical participants, those ambilateral for language production had lower performances in verbal and non-verbal domains, indicating that hemispheric specialization and cognitive skills are related in adults. Furthermore, this relationship was independent from handedness and asymmetry for motor skills, as no interaction was observed between these factors. On the other hand, the relationship between familial sinistrality and cognitive skills tended to differ according to language lateralization type. In contrast to previous reports in children, in the present adult population, we found no linear correlation between HFLI and cognitive skills, regardless of lateralization type. PMID- 25455571 TI - Changes in winter depression phenotype correlate with white blood cell gene expression profiles: a combined metagene and gene ontology approach. AB - In the present study we evaluate the feasibility of gene expression in white blood cells as a peripheral marker for winter depression. Sixteen patients with winter type seasonal affective disorder were included in the study. Blood was taken by venous puncture at three time points; in winter prior and following bright light therapy and in summer. RNA was isolated, converted into cRNA, amplified and hybridized on Illumina(r) gene expression arrays. The raw optical array data were quantile normalized and thereafter analyzed using a metagene approach, based on previously published Affymetrix gene array data. The raw data were also subjected to a secondary analysis focusing on circadian genes and genes involved in serotonergic neurotransmission. Differences between the conditions were analyzed, using analysis of variance on the principal components of the metagene score matrix. After correction for multiple testing no statistically significant differences were found. Another approach uses the correlation between metagene factor weights and the actual expression values, averaged over conditions. When comparing the correlations of winter vs. summer and bright light therapy vs. summer significant changes for several metagenes were found. Subsequent gene ontology analyses (DAVID and GeneTrail) of 5 major metagenes suggest an interaction between brain and white blood cells. The hypothesis driven analysis with a smaller group of genes failed to demonstrate any significant effects. The results from the combined metagene and gene ontology analyses support the idea of communication between brain and white blood cells. Future studies will need a much larger sample size to obtain information at the level of single genes. PMID- 25455573 TI - Maternal medication, drug use, and breastfeeding. AB - This article reviews the necessary skills required for clinicians to make informed decisions about the use of medications in breastfeeding women. Even without specific data on certain medications, this review of kinetic principles, mechanisms of medication entry into breast milk, and important infant factors can aid in clinical decision making. In addition, the article reviews common medical conditions (eg, depression, hypertension, infections) in breastfeeding women and their appropriate treatment. PMID- 25455572 TI - Identifying visual stress during a routine eye examination. AB - PURPOSE: To investigate whether the clinical tests used in routine eye examinations can identify adults whose reading rate increases with their preferred coloured overlay(s). METHODS: Routine optometric tests were used to measure 73 undergraduate students' refractive error, visual acuity, stereo acuity, amplitude of accommodation, near point of convergence, associated heterophoria at near, colour vision and ocular motility. Participants chose an overlay or combination of overlays with colour optimal for clarity, and completed the Wilkins Rate of Reading Test with and without an overlay(s) of this colour. RESULTS: Overall, there was a significant increase in reading speed with overlay (t(72)=-5.26, p<0.0005). Twenty-six participants (36%) increased their reading rate by >5% with their chosen coloured overlay(s). Ten participants (14%) had a reading speed increase of >10%. The increase in reading speed was not significantly associated with any clinical finding. CONCLUSION: Tests which are completed in routine eye examinations did not identify those participants who benefitted from coloured overlays in terms of reading speed. PMID- 25455574 TI - Challenges of managing pediatric mental health crises in the emergency department. AB - Children with mental health problems are increasingly being evaluated and treated in pediatric clinical settings. This article focuses on the epidemiology, evaluation, and management of the 2 most common pediatric mental health emergencies, suicidal and homicidal/aggressive patients, as well as the equally challenging population of children with autism or other developmental disabilities. PMID- 25455575 TI - Evaluation of child maltreatment in the emergency department setting: an overview for behavioral health providers. AB - Emergency providers are confronted with medical, social, and legal dilemmas with each case of possible child maltreatment. Keeping a high clinical suspicion is key to diagnosing latent abuse. Child abuse, especially sexual abuse, is best handled by a multidisciplinary team including emergency providers, nurses, social workers, and law enforcement trained in caring for victims and handling forensic evidence. The role of the emergency provider in such cases is to identify abuse, facilitate a thorough investigation, treat medical needs, protect the patient, provide an unbiased medical consultation to law enforcement, and provide an ethical testimony if called to court. PMID- 25455576 TI - Playing violent video games and desensitization to violence. AB - This article examines current research linking exposure to violent video games and desensitization to violence. Data from questionnaire, behavioral, and psychophysiologic research are reviewed to determine if exposure to violent video games is a risk factor for desensitization to violence. Real-world implications of desensitization are discussed. PMID- 25455577 TI - Psychosocial interventions in attention-deficit/hyperactivity disorder: update. AB - Attention-deficit/hyperactivity disorder (ADHD) is the most common reason for referral to child and adolescent psychiatry clinics. Although stimulant medications represent an evidence-based approach to managing ADHD, psychosocial interventions for child/adolescent ADHD target functional impairments as the intervention goal, and rely heavily on behavioral therapy techniques and operant conditioning principles. Evidence-based psychosocial interventions for managing pediatric ADHD include behavioral parent training, school-based interventions relying on behavioral modification, teaching skills, and operant conditioning principles, and intensive summer treatment programs. The use of conjoint psychosocial treatments with ADHD medications may enable lower doses of each form of treatment. PMID- 25455578 TI - Social skills training for youth with autism spectrum disorders: a follow-up. AB - In 2008, Bellini and Peters conducted a review of empirically based social skills training procedures for youth with autism spectrum disorders. The results of this review suggested that targeted intervention using social skills training programs that were intensive and implemented in a child's natural setting were best suited to meet the needs of children with autism spectrum disorders. In the current article, a review of the most recent meta-analyses is included. Detailed investigation regarding the effectiveness of 8 social skills training procedures is updated and reviewed. Finally, a discussion of assessment strategies is included. PMID- 25455579 TI - Complementary and alternative medicine treatments for children with autism spectrum disorders. AB - There are many treatments in current use for core and associated symptoms of autism spectrum disorders (ASD). This review discusses the complementary and alternative medical (CAM) treatments commonly added to conventional interventions for children with ASD, including natural products, mind and body practices, and other biomedical treatments. The article focuses on factors associated with use of CAM, the empirical evidence for the most frequently used treatments, and how clinicians work with families who choose CAM treatments. Some treatments have been ineffective, some have unacceptable potential side effects, and others require more study in depth. PMID- 25455580 TI - Primary sleep disorders in people with epilepsy: clinical questions and answers. AB - The questions facing clinicians with patients with sleep disorder and epilepsy are addressed in this article. Both adult and child epilepsy are discussed in the context of the most typical questions a clinician would have, such as "Are parasomnias more common in people with epilepsy?", "Is sleep architecture abnormal in children with epilepsy", along with outcomes of numerous questionnaire-based, case-based, and double-blind placebo studies on such aspects as sleep duration, daytime sleepiness, anxiety and fears, limb movement, nocturnal seizures, agitation, behavioral disorders, and learning disorders. PMID- 25455581 TI - Adolescent eating disorders: update on definitions, symptomatology, epidemiology, and comorbidity. AB - The prevalence of eating disorders among adolescents continues to increase. The starvation process itself is often associated with severe alterations of central and peripheral metabolism, affecting overall health during this vulnerable period. This article aims to convey basic knowledge on these frequent and disabling disorders, and to review new developments in classification issues resulting from the transition to DSM-5. A detailed description is given of the symptomatology of each eating disorder that typically manifests during adolescence. New data on epidemiology, and expanding knowledge on associated medical and psychiatric comorbidities and their often long-lasting sequelae in later life, are provided. PMID- 25455582 TI - Top topics in child and adolescent psychiatry. Preface. PMID- 25455583 TI - Sexual maturation of the Mongolian gerbil (Meriones unguiculatus): a histological, hormonal and spermatic evaluation. AB - This study determined the phases of sexual development of the male Mongolian gerbil (Meriones unguiculatus) based on an integrative analysis of testicular morphology, hormonal data and sperm parameters. Male gerbils were analysed at 1, 7, 14, 21, 28, 35, 42, 50, 60, 70, 90, 100 and 120 days of age. Body, testicular and epididymal weights increased up to Day 70, 60 and 90, respectively. The impuberal phase, characterised by the presence of gonocytes, extended until Day 14. The prepubertal period lasted until Day 42, when puberty was achieved and a drastic increase in serum testosterone levels, mature adult Leydig cells and elongated spermatids was observed. Gerbils at 60 days of age showed a remarkable number of spermatozoa in the testis, epididymidis caput/corpus and cauda, and at Day 70 the maximum daily sperm production was reached. However, the gerbil may be considered sexually mature only from Day 90 onward, when sperm reserves become stable. The total transit time of spermatozoa along the epididymis of sexually mature gerbils was 11 days, with 1 day in the caput/corpus and 10 days in the cauda. These data cover a lacuna regarding the reproductive parameters of this rodent and provide foundations for its use in testicular toxicology studies. PMID- 25455584 TI - A critical review of the efficacy of non-steroidal anti-inflammatory drugs in depression. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) require further investigation given mixed results regarding efficacy. We critically and systematically reviewed the literature to determine whether selective COX-2 and non-selective COX inhibitor NSAIDs as adjuncts or monotherapy affect depressive symptoms. Electronic databases including Embase, PsycINFO, Ovid Medline, ScienceDirect, Google Scholar and the Cochrane Central Register of Controlled Trials database were searched up to September 2013. We utilised randomised controlled trials (RCTs), cohort studies and an open label study examining the efficacy of NSAIDs as adjuncts or monotherapy on depressive symptoms in subjects without major comorbidities. There were a total of 6 studies exploring the efficacy of selective COX-2 inhibitor NSAIDs on depressive symptoms with a total of 2706 subjects from 6 RCTs. 4 of the RCTs showed a significant effect of NSAIDs; 2 demonstrated no effect. There were a total of 5 studies exploring the efficacy of non-selective COX inhibitor NSAIDs on depressive symptoms with a total of 7978 subjects. There was 1 RCT, 3 cohort studies and 1 open label pilot study. The RCT failed to show a significant result. 1 of the retrospective cohort studies showed a positive result, with the other 2 showing no effect. The pilot study showed a positive result for NSAIDs. These studies demonstrated significant methodological heterogeneity (i.e. age range, sex, presence of antidepressant use, method of depression measure, severity of depressive symptoms, duration and study design (RCT vs. cohort)). The efficacy of NSAIDs on depressive symptoms appears negligible, however firm conclusions are difficult given the inconsistent findings and substantial methodological heterogeneity. Further high quality research is needed to explore NSAID efficacy in clinical and biological subtypes of depression, as monotherapy and adjunct with various antidepressants, and across various ages. PMID- 25455585 TI - Prenatal LPS-exposure--a neurodevelopmental rat model of schizophrenia- differentially affects cognitive functions, myelination and parvalbumin expression in male and female offspring. AB - Maternal infection during pregnancy increases the risk for the offspring to develop schizophrenia. Gender differences can be seen in various features of the illness and sex steroid hormones (e.g. estrogen) have strongly been implicated in the disease pathology. In the present study, we evaluated sex differences in the effects of prenatal exposure to a bacterial endotoxin (lipopolysaccharide, LPS) in rats. Pregnant dams received LPS-injections (100 MUg/kg) at gestational day 15 and 16. The offspring was then tested for prepulse inhibition (PPI), locomotor activity, anxiety-like behavior and object recognition memory at various developmental time points. At postnatal day (PD) 33 and 60, prenatally LPS exposed rats showed locomotor hyperactivity which was similar in male and female offspring. Moreover, prenatal LPS-treatment caused PPI deficits in pubertal (PD45) and adult (PD90) males while PPI impairments were found only at PD45 in prenatally LPS-treated females. Following prenatal LPS-administration, recognition memory for objects was impaired in both sexes with males being more severely affected. Additionally, we assessed prenatal infection-induced alterations of parvalbumin (Parv) expression and myelin fiber density. Male offspring born to LPS-challenged mothers showed decreased myelination in cortical and limbic brain regions as well as reduced numbers of Parv-expressing cells in the medial prefrontal cortex (mPFC), hippocampus and entorhinal cortex. In contrast, LPS-exposed female rats showed only a modest decrease in myelination and Parv immunoreactivity. Collectively, our data indicate that some of the prenatal immune activation effects are sex dependent and further strengthen the importance of taking into account gender differences in animal models of schizophrenia. PMID- 25455586 TI - Effect of tryptophan hydroxylase-2 gene polymorphism G-703 T on personality in a population representative sample. AB - The tryptophan hydroxylase-2 gene (TPH2) is coding for the key enzyme of serotonin (5-HT) synthesis in the brain and has been associated with a number of psychiatric conditions. A functional variation in the TPH2 gene (G-703T, rs4570625) has been found to affect anxiety-related personality; however, information is very limited regarding the five factor model (FFM) personality traits. We have examined the association of the TPH2 G-703T polymorphism with FFM personality traits, and the possible modulation by the functional variation in the serotonin transporter gene (5-HTTLPR) in a large longitudinal population representative sample. The FFM personality traits were assessed in both birth cohorts of the Estonian Children Personality Behaviour and Health Study at ages 15 (n=742) and 18 (n=834). Significant association of the TPH2 genotype with Neuroticism and Conscientiousness was found at age 15, and with Extraversion and Conscientiousness at age 18. Participants with the T/T genotype scored significantly lower on Neuroticism and higher on Conscientiousness and Extraversion scales. In addition, a gene*gene interaction effect on Conscientiousness was revealed: the TPH2 genotype effect was evident only in the 5-HTTLPR S-allele carriers. These results provide further evidence on the possible role of genetic variations in 5-HT neurotransmission on development of personality traits, and suggest a functional interaction between two key proteins in the 5-HT-ergic system. PMID- 25455587 TI - Role of the adenosine system and glucose restriction in the acute anticonvulsant effect of caprylic acid in the 6 Hz psychomotor seizure test in mice. AB - Although several studies have reported the acute anticonvulsant activity of caprylic acid in animal seizure models, little is known about the mechanism underlying this effect. Recently, the role of adenosine in the efficacy of the ketogenic diet has been postulated. Therefore, the present study aimed to evaluate the possible involvement of the adenosine system (in non-fasted mice) as well as the role of glucose restriction (in fasted and non-fasted mice) in the acute anticonvulsant activity of caprylic acid in the 6 Hz psychomotor seizure threshold test. We showed that the anticonvulsant effect of caprylic acid (30 mmol/kg, p.o.) was reversed by a selective adenosine A1 receptor antagonist (DPCPX, 1mg/kg, i.p.) and a selective adenosine A2A receptor antagonist (KW-6002, 1 mg/kg, p.o.) but not by glibenclamide (1 pg/mouse, i.c.v.) - the ATP-sensitive potassium (KATP) channel blocker. Co-administration of an ineffective dose of caprylic acid (20 mmol/kg) with an ineffective dose of adenosine transporter inhibitor (dipyridamole, 50 mg/kg, i.p.) significantly raised the threshold for the 6 Hz-induced seizures. A high dose of glucose (2 g/kg) significantly only diminished the anticonvulsant effect of caprylic acid (30 mmol/kg) in non-fasted mice, and this was accompanied by an increase in blood glucose level and no changes in ketone body level as compared to the caprylic acid-treated group. In both fasted and non-fasted mice treated with glucose and caprylic acid, a significant decrease in trunk blood pH occurred as compared to the control group. No alternations in motor coordination or muscular strength were noted with any drug treatment, apart from the caprylic acid and glibenclamide combination, where a significant decrease in the muscle strength was observed. The present study provides a new insight into the role of the adenosine system and low glucose usage in the mechanisms underlying the anticonvulsant effects of caprylic acid in the 6 Hz seizure test. PMID- 25455588 TI - Deficits in emotion based decision-making in schizophrenia; a new insight based on the Iowa Gambling Task. AB - BACKGROUND: Defective decision-making is a symptom of impaired cognitive function observed in patients with schizophrenia. Impairment on the Iowa Gambling Task (IGT) has been reported in patients with schizophrenia, but these results are inconsistent among studies. METHODS: We differentiated subjects based on whether they expressed certainty at having deciphered an advantageous strategy in the course of the task. We investigated this impairment using the IGT in patients with schizophrenia and performed analysis different to standard advantageous decks minus disadvantageous decks in all 100 card choices, [C+D]-[A+B](1-100). We examined the effects on behavior after receiving a big penalty. RESULTS: Results were dependent on participants utilizing with or without certainty, the best strategy for positive gain. Schizophrenic patients without certainty failed to show card choice shift, from disadvantageous to advantageous decks. Differences in card choices on the IGT were clearly shown between patients with schizophrenia and normal controls by the use of improvement from block 1 to blocks 3-5, [C+D] [A+B]([41-100]-[1-20]) (P<0.001), rather than by the composite value of blocks 3 5, [C+D]-[A+B](41-100) (P=0.011). The deficit of emotion-based learning in schizophrenia without uncertainty were related to scores on the SANS and S5 attention. In addition, S1 affective flattering and S4 anhedonia-asociality were also related to these deficits. For a while, normal controls showed a smooth shift from disadvantageous to advantageous decks after big penalties, with or without a certainty for strategy. However, patients with schizophrenia failed to show switching from disadvantageous to advantageous decks, even after big penalties, under the same conditions. CONCLUSIONS: Our results highlight certainty of strategy and behavior after a big penalty, as two points of difference between patients with schizophrenia and normal controls in the accumulation of net scores. PMID- 25455589 TI - Transcranial electric stimulation and neurocognitive training in clinically depressed patients: a pilot study of the effects on rumination. AB - Rumination is a cognitive-affective thinking style that plays a key role in the onset and maintenance of depression. Recently, it was shown that clinically depressed patients who received a neurocognitive training - involving two weeks of repetitive cognitive control exercises that necessitate prefrontal engagement are more able to control over ruminative negative thoughts than patients who only received treatment as usual. Transcranial Direct Current Stimulation (tDCS) is a biological technique that can directly modulate prefrontal excitability via the manipulation of neural membrane potentials. In this randomized double-blind trial, we investigated whether bifrontal tDCS (anode over the left/cathode over the right dorsolateral prefrontal cortex (DLPFC)) would enhance the influence of a neurocognitive training on depressive brooding, the maladaptive form of rumination. Major depressed patients were trained using a procedure based on the Paced Auditory Serial Addition Task (PASAT), a task that relies heavily on working memory and is found to engage the DLPFC. One group (n=19) completed the PASAT training together with active tDCS and another group (n=14) completed the same training together with sham (placebo) tDCS. In both groups, depressive brooding was reduced following the PASAT training. Moreover, we observed that improvement in working memory over the course of the training was associated with a greater reduction in depressive brooding post- versus pre-intervention. However, tDCS did not moderate this association between changes in working memory and changes in depressive brooding. Possible explanations for this absent moderation of tDCS, as well as avenues for future research to influence ruminative thinking in depression, are discussed. PMID- 25455590 TI - External validation of bloodstream infection mortality risk score in a population based cohort. AB - A risk score was recently derived to predict mortality in adult patients with Gram-negative bloodstream infection (BSI). The aim of this study was to provide external validation of the BSI mortality risk score (BSIMRS) in a population based cohort. All residents of Olmsted County, Minnesota, with Escherichia coli and Pseudomonas aeruginosa BSI from 1 January 1998 to 31 December 2007 were identified. Logistic regression was used to examine the association between BSIMRS and mortality. Area under receiver operating characteristic curve (AUC) was calculated to quantify the discriminative ability of the BSIMRS to predict a variety of short-term and long-term outcomes. Overall, 424 unique Olmsted County residents with first episodes of E. coli and P. aeruginosa BSI were included in the study. Median age was 68 (range 0-99) years, 280 (66%) were women, 61 (14%) had cancer and 9 (2%) had liver cirrhosis. The BSIMRS was associated with 28-day mortality (p <0.001) with an AUC of 0.86. There was an almost 56% increase in 28 day mortality for each point increase in BSIMRS (OR 1.56, 95% CI 1.40-1.78). A BSIMRS >= 5 had a sensitivity of 74% and a specificity of 87% to predict 28-day mortality with a negative predictive value of 97%. The BSIMRS had AUC of 0.85, 0.85 and 0.81 for 7-, 14- and 365-day mortality, respectively. BSIMRS stratified mortality with high discrimination in a population-based cohort that included patients of all age groups who had a relatively low prevalence of cancer and liver cirrhosis. PMID- 25455591 TI - Exosomes in fetal bovine serum dampen primary macrophage IL-1beta response to lipopolysaccharide (LPS) challenge. AB - This study identifies a previously unknown immunological function of exosomes present in fetal bovine serum (FBS). Exosomes are small (40-100 nm), biologically active nanoparticles released from cells that associate with a variety of proteins and miRNA. Exosomes are present in nearly all biological fluids, including FBS, a common supplement to cell culture media. While there are a growing number of studies examining cellular responses to exosomes, there is no assessment of how FBS exosomes impact cellular responses to immunological challenges. Our results demonstrate that primary macrophages from Fisher 344 rats cultured with lipopolysaccharide (LPS) in the presence of FBS exosomes exhibit a dose-dependent reduction in IL-1beta compared to macrophages cultured in medium supplemented with exosome-depleted FBS. The addition of fetal bovine exosomes also reduced macrophage tumor necrosis factor-alpha (TNF-alpha) and IL-6, but not IL-10, monocyte chemotactic factor-1 (MCP-1), nitric oxide (NO), or lactose dehydrogenase (LDH) response to LPS. The selectivity of exosomal impact on macrophage IL-1beta and pro-inflammatory protein responses may implicate the potential role of exosome-inflammasome interactions. These findings suggest that researchers should consider the immunological influence of FBS exosomes, particularly on IL-1beta activity, when studying cells in culture. PMID- 25455592 TI - TCR and CD28 activate the transcription factor NF-kappaB in T-cells via distinct adaptor signaling complexes. AB - The transcription factor NF-kappaB is needed for the induction of inflammatory responses in T-cells. Whether its activation by the antigen-receptor and CD28 is mediated by the same or different intracellular signaling pathways has been unclear. Here, using T-cells from various knock-out (Cd28(-/-), adap(-/-)) and knock-in (i.e. Cd28 Y-170F) mice in conjunction with transfected Jurkat T-cells, we show that the TCR and CD28 use distinct pathways to activate NF-kappaB in T cells. Anti-CD28 ligation alone activated NF-kappaB in primary and Jurkat T-cells as measured by NF-kappaB reporter and EMSA assays. Anti-CD28 also activated NF kappaB normally in primary T-cells from adap(-/-) mice, while anti-CD3 stimulation required the adaptor ADAP. Over-expression of ADAP or its binding partner SKAP1 failed to enhance anti-CD28 activation of NF-kappaB, while ADAP greatly increased anti-CD3 induced NF-kappaB activity. By contrast, CD28 activation of NF-kappaB depended on GRB-2 binding to CD28 as seen in CD28 deficient Jurkat T-cells reconstituted with the CD28 YMN-FM mutant, and in primary T-cells from CD28 Y170F mutant knock-in mice. CD28 associated with GRB-2, and GRB-2 siRNA impaired CD28 NF-kappaB activation. GRB-2 binding partner and guanine nucleotide exchange factor, VAV1, greatly enhanced anti-CD28 driven activation of NF-kappaB. Further, unlike in the case of anti-CD28, NF-kappaB activation by anti-CD3 and its cooperation with ADAP was strictly dependent on LAT expression. Overall, we provide evidence that CD28 and the TCR complex regulate NF-kappaB via different signaling modules of GRB-2/VAV1 and LAT/ADAP pathways respectively. PMID- 25455593 TI - Five decades of Dutch immunology. PMID- 25455594 TI - 50 years of Dutch immunology--founders, institutions, highlights. AB - At the occasion of the 50th anniversary of the Dutch Society for Immunology (DSI, de Nederlandse Vereniging voor Immunologie), this contribution deals with some highlights of 50 years of Immunology in the Netherlands. It narrates about the founders and first board members of the DSI, their institutes, progeny and patrimony, describes major centers of immunological activities, mentions key persons in the field, and touches upon some events dear to the Society and its members. PMID- 25455595 TI - The innate immune response. AB - The innate immune response is of prime importance in the immediate recognition and elimination of invading micro-organisms. However, deregulation of this system is clearly associated with the pathogenesis of a wide range of inflammatory diseases. Innate immunity consists of a humoral and a cellular branch, which are closely interacting. An additional level of control is found at the level of neuronal reflexes that can fine-tune these immunological mechanisms. PMID- 25455596 TI - The activation of the adaptive immune system: cross-talk between antigen presenting cells, T cells and B cells. AB - The adaptive immune system consists of T and B cells that express clonally distributed antigen receptors. To achieve functional adaptive immune responses, antigen-specific T cell populations are stimulated by professional antigen presenting cells like dendritic cells (DCs), which provide crucial stimulatory signals for efficient expansion and development of effector functions. Antigen specific B cells receive costimulatory signals from helper T cells to stimulate affinity maturation and isotype switching. Here we elaborate on the interactions between DCs, T cells and B cells, and on the important signals for efficient induction of adaptive immune responses. PMID- 25455598 TI - Scientific contributions toward successful cancer immunotherapy in The Netherlands. AB - This historical overview shows that immunologists and clinicians from The Netherlands have contributed in a major way to better insights in the nature of cancer immunity. This work involved elucidation of the nature of cancer associated antigens in autologous and allogeneic settings in addition to understanding of the cellular basis of natural immune responses against cancers and of important immune evasion mechanisms. Insight into such basic immunological mechanisms has contributed to the development of innovating therapies. PMID- 25455597 TI - Inflammatory responses to infection: the Dutch contribution. AB - At any given moment, our body is under attack by a large variety of pathogens, which aim to enter and use our body to propagate and disseminate. The extensive cellular and molecular complexity of our immune system enables us to efficiently eliminate invading pathogens or at least develop a condition in which propagation of the microorganism is reduced to a minimum. Yet, the evolutionary pressure on pathogens to circumvent our immune defense mechanisms is immense, which continuously leads to the development of novel pathogenic strains that challenge the health of mankind. Understanding this battle between pathogen and the immune system has been a fruitful area of immunological research over the last century and will continue to do so for many years. In this review, which has been written on the occasion of the 50th anniversary of the Dutch Society for Immunology, we provide an overview of the major contributions that Dutch immunologists and infection biologists have made in the last decades on the inflammatory response to viral, bacterial, fungal or parasitic infections. We focus on those studies that have addressed both the host and the pathogen, as these are most interesting from an immunological point of view. Although it is not possible to completely cover this comprehensive research field, this review does provide an interesting overview of Dutch research on inflammatory responses to infection. PMID- 25455599 TI - Medical immunology: two-way bridge connecting bench and bedside. AB - Medical immunology in The Netherlands is a laboratory specialism dealing with immunological analyses as well as pre- and post-analytical consultation to clinicians (clinical immunologists and other specialists) involved in patients with immune mediated diseases. The scope of medical immunology includes immunodeficiencies, autoimmune diseases, allergy, transfusion and transplantation immunology, and lymphoproliferative disorders plus the monitoring of these patients. The training, professional criteria, quality control of procedures and laboratories is well organized. As examples of the bridge function of medical immunology between laboratory (bench) and patient (bedside) the contribution of medical immunologists to diagnosis and treatment of primary immunodeficiency diseases (in particular: humoral immunodeficiencies) as well as autoantibodies (anti-citrullinated proteins in rheumatoid arthritis) are given. PMID- 25455600 TI - Clinical immunology--autoimmunity in the Netherlands. AB - Clinical immunology is in the Netherlands a separate clinical specialty within internal medicine and pediatrics. Clinical immunologists work closely together with nephrologists, rheumatologists and many other medical specialists. Apart from research and teaching, clinical immunologists are taking care of patients with immune-deficiencies, vasculitides and systemic auto-immune diseases. Clinical immunology in the Netherlands has always been an important contributor to basic and clinical science in the Netherlands. Major scientific contributions were made in the field of Systemic Lupus Erythematosus and ANCA associated vasculitis. These Dutch contributions will be reviewed in this article. PMID- 25455601 TI - The interaction between cytomegalovirus and the human immune system. AB - Studies on antiviral immunity in man are hampered by the impossibility to standardize the infection as is done in experimental animal studies. An exception is the occurrence of cytomegalovirus infection transmitted by a donor organ into a transplant-recipient, where the time-point of infection is exactly known. Moreover, its strong interaction with the human immune system during evolution and the strong immunogenic properties of this persistent virus, as well as the need for intervention e.g. by vaccine development, all make studies towards the immune response against just this virus very attractive and relevant. In this work, we will present an overview of the studies on this topic that were performed in the departments of Experimental and Clinical Immunology in the AMC and Sanquin in Amsterdam. PMID- 25455603 TI - Autoimmunity: break-through in the diagnosis and treatment of immune-mediated inflammatory diseases. AB - The study of fundamental mechanisms of autoimmunity has been instrumental to clinical progress in the diagnosis and treatment of a range of immune-mediated inflammatory disorders. Dutch immunology has made major contributions to these developments, ranging from fundamental studies on immune cells, antibodies and cytokines to translational and clinical studies with targeted therapies in patients. In this paper we illustrate the progress made in our understanding of autoimmunity and the translational implications for human disease management by focusing on three areas: the autoantibody response in rheumatoid arthritis (RA), T-B cell interactions in Sjogren's syndrome (SS), and cytokine targeting in spondylarthritis (SpA). PMID- 25455602 TI - Half a century of Dutch transplant immunology. AB - The sixties have not only witnessed the start of the Dutch Society for Immunology (NvvI), but were also the flourishing beginning of the discipline of transplant immunology. The interest in immunology in the Netherlands had its start in the context of blood transfusions and not for instance in the field of infectious disease, as in many other countries. It began in the 1950-ties thanks to Joghem van Loghem at that time director of the Central Laboratory of Blood Transfusion in Amsterdam. The discoveries of these times have had major impact for transfusion medicine, hematopoietic stem cell transplantation and organ transplantation. In this review we will look back at some early highlights of Dutch transplant immunology and put them in the perspective of some recent developments. PMID- 25455604 TI - Historic overview of allergy research in the Netherlands. AB - Research in allergy has a long history in the Netherlands, although the relation with immunology has not always been appreciated. In many aspects Dutch researchers have made major contribution in allergy research. This ranges from the first characterization of house dust mite as an important allergen, the first characterization of human Th2 and Th1 T cell clones, to the development of diagnostic test systems. In this overview Aalberse and Knol have made an overview of the major contributions of Dutch immunologists in allergy. PMID- 25455605 TI - New possibility for providing protection against urinary tract infection caused by Pseudomonas aeruginosa by non-adjuvanted flagellin 'b' induced immunity. AB - In the present study we demonstrated a novel protective role of Pseudomonas aeruginosa PAO1 flagellin 'b' in prevention of urinary tract infection (UTI). P. aeruginosa is motile via single polar flagellum made up of polymerized flagellin proteins. It is a serious nosocomial pathogen causing UTIs. Predisposing factors include instrumentation and catheterization which enhance colonization with P. aeruginosa, leading to ascending infection. Hence for a newer, safer and effective approach, the present study focussed on the prophylaxis using bacterial flagellin, isolated and purified (PCR sequencing and MALDI-TOF) from P. aeruginosa PAO1 strain, which triggers immune response [both non-specific and specific (active and passive)] as defense against infection. Administration of flagellin 'b' via intraperitoneal route enhanced the clearance of homologous as well as heterologous bacteria (P. aeruginosa uroisolate carrying flagellin 'a') in renal tissue, decreased the levels of malondialdehyde (MDA) and reverted structural integrity of renal tissue to near normal in female LACA mice. Immunization suppressed the production of pro-inflammatory cytokines [interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha)] and activated humoral immune response. Anti-flagellin antibodies (quantified by ELISA) helped in the clearance of bacterial load by opsonophagocytosis. Adoptive transfer of antisera also protected mice from PAO1 challenge, indicating protective role of antibodies. In conclusion, this is the first report that describes flagellin as a potential prophylactic agent which downregulates inflammation and curbs UTIs. PMID- 25455606 TI - Menstrual blood-derived stromal stem cells inhibit optimal generation and maturation of human monocyte-derived dendritic cells. AB - INTRODUCTION: Menstrual blood stromal stem Cells (MenSCs) have shown promising potential for future clinical settings. Nonetheless, data regarding their interaction with immune cells is still scarce. Here, we investigated whether MenSCs could affect the generation and/or maturation of human blood monocyte derived dendritic cells (DCs). MATERIALS AND METHODS: MenSCs were isolated from menstrual blood of normal women through culture of adherent mononuclear cells. Magnetically-isolated peripheral blood monocytes were differentiated toward immature DCs (iDC) and mature DCs (mDCs) in the presence or absence of MenSCs. Monocyte-derived cells were assessed for the percentage of monocyte-, iDC-, and mDC-specific markers as well as the expression of costimulatory molecules. IL-6 and IL-10 levels were also determined in supernatants of MenSC-monocytes cocultures. RESULTS: Optimal phenotypic differentiation of monocytes into iDCs was inhibited upon coculture with MenSCs. Moreover, higher levels of IL-6 and IL 10 were detected in these settings. Even though addition of MenSCs to iDC cultures could not prevent iDC maturation, coculture of MenSCs with monocytes from the beginning of differentiation process could effectively hinder generation of fully mature DCs. CONCLUSION: This is the first study to address the inhibitory impact of MenSCs on generation and maturation of DCs. IL-6 and IL-10 could be partly held responsible for this effect. Given the central roles of DCs in regulation of immune responses, these results highlight the importance of further research on the potential modulatory impacts of MenSCs, as rather easily accessible and expandable stem cells, on the immune system-related cells. PMID- 25455607 TI - Variability in reference point microindentation and recommendations for testing cortical bone: maximum load, sample orientation, mode of use, sample preparation and measurement spacing. AB - Reference Point Indentation (RPI) is a novel microindentation tool that has emerging clinical potential for the assessment of fracture risk as well as use as a laboratory tool for straight-forward mechanical characterisation of bone. Despite increasing use of the tool, little research is available to advise the set-up of testing protocols or optimisation of testing parameters. Here we consider five such parameters: maximum load, sample orientation, mode of use, sample preparation and measurement spacing, to investigate how they affect the Indentation Distance Increase (IDI), the most published measurement parameter associated with the RPI device. The RPI tool was applied to bovine bone; indenting in the proximal midshaft of five femora and human bone; indenting five femoral heads and five femoral neck samples. Based on the findings of these studies we recommend the following as the best practice. (1) Repeat measurements should be utilised to reduce the coefficient of variation (e.g. 8-15 repeats to achieve a 5-10% error, however the 3-5 measurements used here gives a 15-20% error). (2) IDI is dependent on maximum load (r=0.45 on the periosteal surface and r=0.94 on the machined surface, p<0.05), mode of use (i.e. comparing the device held freehand compared to fixed in its stand, p=0.04) and surface preparation (p=0.004) so these should be kept consistent throughout testing. Though sample orientation appears to have minimal influence on IDI (p>0.05), care should also be taken in combining measurements from different orientations. (3) The coefficient of variation is higher (p=0.04) when holding the device freehand, so it should ideally be kept supported in its stand. (4) Removing the periosteum (p=0.04) and machining the surface of the bone (p=0.08) reduces the coefficient of variation, so should be performed where practical. (5) There is a hyperbolic relationship between thickness and IDI (p<0.001) with a sample thickness 10 fold greater than the maximum indentation depth recommended, to ensure a representative measurement. (6) Measurement spacing does not appear to influence the IDI (p>0.05), so it can be as low as 500 um. By following these recommendations, RPI users can minimise the potential confounding effects associated with the variables investigated here and reduce the coefficient of variation, hence achieving more consistent testing. This optimisation of the technique enhances both the clinical and laboratory potential of the tool. PMID- 25455608 TI - Strain rate and anisotropy effects on the tensile failure characteristics of human skin. AB - The anisotropic failure characteristics of human skin are relatively unknown at strain rates typical in impact biomechanics. This study reports the results of an experimental protocol to quantify the effect of dynamic strain rates and the effect of sample orientation with respect to the Langer lines. Uniaxial tensile tests were carried out at three strain rates (0.06s(-1), 53s(-1), and 167s(-1)) on 33 test samples excised from the back of a fresh cadaver. The mean ultimate tensile stress, mean elastic modulus and mean strain energy increased with increasing strain rates. While the stretch ratio at ultimate tensile stress was not affected by the strain rate, it was influenced by the orientation of the samples (parallel and perpendicular to the Langer lines. The orientation of the sample also had a strong influence on the ultimate tensile stress, with a mean value of 28.0 +/- 5.7 MPa for parallel samples, and 15.6 +/- 5.2 MPa for perpendicular samples, and on the elastic modulus, with corresponding mean values of 160.8 MPa +/- 53.2 MPa and 70.6 MPa +/- 59.5 MPa. The study also pointed out the difficulties in controlling the effective applied strain rate in dynamic characterization of soft tissue and the resulting abnormal stress-strain relationships. Finally, data collected in this study can be used to develop constitutive models where high loading rates are of primary interest. PMID- 25455609 TI - Effect of tonsillectomy on psoriasis: a systematic review. AB - BACKGROUND: Streptococcal infection is associated with psoriasis onset in some patients. Whether tonsillectomy decreases psoriasis symptoms requires a systematic review of the literature. OBJECTIVE: We sought to determine whether tonsillectomy reduces psoriasis severity through a comprehensive search of over 50 years of literature. METHODS: We searched MEDLINE, CINAHL, Cochrane, EMBASE, Web of Science, and OVID databases (from August 1, 1960, to September 12, 2013) and performed a manual search of selected references. We identified observational studies and clinical trials examining psoriasis after tonsillectomy. RESULTS: We included data from 20 articles from the last 53 years with 545 patients with psoriasis who were evaluated for or underwent tonsillectomy. Of 410 reported cases of patients with psoriasis who underwent tonsillectomy, 290 experienced improvement in their psoriasis. Although some patients who underwent tonsillectomy experienced sustained improvement in psoriasis, others experienced psoriasis relapse after the procedure. LIMITATIONS: Fifteen of 20 publications were case reports or series that lacked control groups. Publication bias favoring reporting improved cases needs to be considered. CONCLUSION: Tonsillectomy may be a potential option for patients with recalcitrant psoriasis associated with episodes of tonsillitis. Studies with long-term follow-up are warranted to determine more clearly the extent and persistence of benefit of tonsillectomy in psoriasis. PMID- 25455611 TI - Evaluating the advances and use of hypodermic needles in dentistry. AB - Different injection techniques and patient management methodologies have been proposed to decrease the fear patients may have concerning dental needles. Dental providers should have an understanding of the technological advances, changes in techniques, and patient perceptions associated with the hypodermic needle. This article provides an overview of the pain perception process associated with dental injections. It reviews the two main sensory nerve fibers associated with injection pain and discusses needle properties as well as complications and adverse occurrences. PMID- 25455610 TI - Topical rapamycin combined with pulsed dye laser in the treatment of capillary vascular malformations in Sturge-Weber syndrome: phase II, randomized, double blind, intraindividual placebo-controlled clinical trial. AB - BACKGROUND: Sturge-Weber syndrome (SWS) is characterized by port-wine stains (PWS) affecting the face, eyes, and central nervous system. Pulsed dye laser (PDL) is the standard treatment for PWS. Unfortunately, recurrence is frequent because of reformation and reperfusion of blood vessels. OBJECTIVE: We sought to assess the clinical efficacy of topical rapamycin combined with PDL in PWS of patients with SWS. METHODS: We conducted a phase II, randomized, double-blind, intraindividual placebo-controlled, clinical trial. We recruited 23 patients with SWS and facial PWS (12 women; median age 33 years, age range 17-65 years) from the University Clinic of Navarra, Spain. Four interventions were evaluated: placebo, PDL + placebo, rapamycin, and PDL + rapamycin. Clinical and histologic responses were evaluated using a chromatographic computerized system, spectrometry, and histologic analyses at 6, 12, and 18 weeks after the intervention. RESULTS: PDL + rapamycin yielded the lowest digital photographic image score and the lowest percentage of vessels in histologic analysis, and showed a statistically significant improvement compared with the other interventions. The treatment was generally well tolerated. LIMITATIONS: PDL was only applied to the lateral parts of the PWS area. CONCLUSION: Topical rapamycin associated with PDL seems to be an effective treatment for PWS in patients with SWS. PMID- 25455612 TI - Probiotics for bacterial disease treatment in the oral environment. AB - Probiotics use has been researched for gastrointestinal health. The oral cavity, of course, is not a separate component of the body, and because both periodontal disease and dental caries are bacterial diseases, a probiotics approach to treating these maladies is currently being evaluated. Several over-the-counter products claim to be formulated with probiotics and suitable for use for oral care. In this article, the authors define probiotics, review research that explores probiotics in relation to periodontal disease and caries, and identify available probiotics products aimed at promoting oral health. PMID- 25455613 TI - Formulating a global prognosis and treatment plan for the periodontally compromised patient: a reconstructive vs. an adaptive approach. AB - The clinician faces treatment planning challenges when patients present with generalized severe chronic periodontitis that may result in tooth loss. This article provides a treatment planning discussion along with approaches for treating such patients. It presents the clinical question: What is the best means for approaching treatment planning in a patient with severe periodontitis requiring extraction and replacement of some teeth? Two treatment approaches are discussed-a reconstructive approach versus an adaptive one-both of which have an end goal of achieving periodontal health and occlusal stability, and each has its own advantages and disadvantages. In conclusion, utilizing a global prognostic approach will assist clinicians anticipate the eventual restorative needs of patients and prescribe customized periodontal and restorative therapies that best address those needs. PMID- 25455614 TI - Custom abutments alone will not eliminate the clinical effects of poor cementation techniques around dental implants. AB - With proper planning, placement, prosthetic treatment, and maintenance, dental implants have been shown to be a predictable and reliable treatment option with a high success rate. Clinicians who place cement-retained implant restorations, however, should be aware of the potential and sometimes irreversible biological complications associated with residual excess cement and should be prepared to consider using different practices that may reduce the problem. The present case reports describe the use of custom abutments to restore deeply placed implants with the intent of minimizing residual excess cement. PMID- 25455615 TI - Achieving esthetic and functional objectives with additive equilibration. AB - In a case involving a patient with high esthetic demands who wanted to keep treatment conservative, minimal direct bonding was used to enhance anterior esthetics while creating acceptable function. Primary treatment goals in the case, in which the patient was diagnosed with a constricted chewing pattern, were to improve esthetics by lengthening the maxillary anterior teeth and to stop continued loss of anterior tooth structure. Through the use of a Kois deprogrammer, an additive equilibration with direct composite was done to provide proper occlusal function to support the esthetic outcome, and no tooth reduction was needed. PMID- 25455616 TI - Effectiveness of a combined in-office and take-home whitening system for teeth shades A3.5 to A4. AB - As teeth whitening increases in popularity, dental professionals are challenged to select the proper materials and technique to create esthetically whitened smiles for their patients. This study examined nine subjects with baseline shades of A3.5 to A4 on four to six of their maxillary anterior teeth with the VITA Classical (VC) shade guide. All subjects received one session of in-office whitening (Philips Zoom WhiteSpeed), 3 weeks of at-home tray whitening (Zoom NiteWhite), and the option of a second WhiteSpeed treatment. Subjects achieved, on average, documented change of 11.1 shades. Only two subjects reported any sensitivity, thereby demonstrating the effectiveness of a combined whitening system, including both chairside and take-home whitening, and a sensitivity prevention protocol. PMID- 25455618 TI - Laboratory technology 2014: identifying material and equipment trends and changes. PMID- 25455617 TI - Plaque reduction efficacy of an oscillating-rotating power brush with a novel brush head utilizing angled bristle tufts. AB - PURPOSE: To evaluate an oscillating-rotating power brush with a novel brush head utilizing angled bristle tufts versus a manual brush for plaque removal. METHODS: This was a single-center, randomized, open-label, examiner-blind, two-treatment, parallel-group study. Subjects brushed with their assigned toothbrush and a marketed dentifrice twice daily at home for 6 weeks. Plaque measurements were evaluated at baseline and week 6 using the Turesky Modified Quigley-Hein Plaque Index (TQHPI). Data was analyzed using the analysis of covariance (ANCOVA) with baseline as the covariate. RESULTS: Ninety-four subjects completed the study, with 46 in the manual group and 48 in the power group. The oscillating-rotating brush with the novel brush head demonstrated statistically significantly greater reductions in whole mouth and interproximal plaque measures compared to the manual toothbrush. The benefit for the oscillating-rotating brush over the manual control brush was 164.5% for whole mouth plaque and 167.4% for interproximal plaque (P < 0.001) measured 12 hours after brushing. Both brushes produced statistically significant reductions in plaque measures relative to baseline (P < 0.001 for both measures). There were no adverse events reported or observed for either brush. CONCLUSIONS: The oscillating-rotating brush with the novel brush head produced reductions in whole mouth and interproximal plaque more than twice that of the manual toothbrush. PMID- 25455619 TI - The clinical implications of placental diagnoses. AB - The clinical utility of placental pathology is both overestimated and underestimated, and the overall quality of placental pathology reporting, even at major medical centers, is highly variable. Clear benefits of examining placentas include the immediate diagnosis of treatable conditions in both the mother and the infant, clarification of the underlying etiology of adverse pregnancy outcomes, estimation of recurrence risk, and guidance for the management of future pregnancies. In order to realize these benefits and get the most out of their pathology departments, it is critical for clinicians to understand the range and implications of placental lesions. This article will review the nomenclature, diagnostic criteria and pitfalls, and clinical significance of seven common placental disease processes and a handful of other lesions. PMID- 25455620 TI - Examination of the twin placenta. AB - Twin birth rates have increased dramatically over the past three decades, and twins currently account for 3% of all pregnancies. Twin pregnancies of any type are at risk for prematurity. In addition, monochorionic twin pregnancies (25-30% of all twin pregnancies) are predisposed to a specific set of complications, including twin-to-twin transfusion syndrome (TTTS), twin reversed arterial perfusion syndrome (TRAP), malformations, and intertwin growth discordance. This article reviews the basic mechanisms underlying the twinning process, the relationship between zygosity and chorionicity, and the various types of twinning. We describe the major complications of monochorionic twinning in association with their reported placental characteristics (or lack thereof). Finally, a rational, evidence-based approach to examination of the twin placenta is presented. It is essential for the pathologist to understand the value, strengths, and limitations of examination of the twin placenta in order to provide a meaningful clinicopathological correlation in complicated (monochorionic) twin pregnancies. PMID- 25455621 TI - Chronic inflammatory lesions of the placenta. AB - The chronic inflammatory lesions of the placenta often run in the shadows of the better-known acute inflammatory processes of the placenta, such as acute chorioamnionitis and acute funisitis. A heterogeneous population of T-cell lymphocytes, plasma cells, and macrophages is the primary player in chronic villitis, chronic chorioamnionitis, chronic deciduitis, and chronic intervillositis, and eosinophils are an added component of eosinophilic/T-cell chorionic vasculitis. The histologic appearance, sites of occurrence in the placenta, and pathogeneses of these entities are reviewed. PMID- 25455624 TI - The co-occurrence of attention-deficit/hyperactivity disorder and unipolar depression in children and adolescents: a meta-analytic review. AB - This paper reviews the empirical literature on the association between attention deficit/hyperactivity disorder (ADHD) and depression (i.e., unipolar depressive disorders and symptoms) among children and adolescents. Findings from cross sectional and longitudinal studies published on the co-occurrence of ADHD and depression were summarized and subjected to a meta-analysis. Results (k=29, N=8755; rbar=0.22) indicated that ADHD and depression were positively related, but substantial variability existed across the studies. Subgroup analyses indicated medium positive effects for cross-sectional studies, studies that operationalized ADHD based on DSM-III or DSM-IV diagnostic criteria, and studies that did not include teacher report in the assessment of ADHD. Subgroup analyses showed a large positive effect for studies that operationalized ADHD based on DSM III-R criteria and studies using clinic referred samples. In contrast, subgroup analyses indicated a small negative and/or unreliable association between ADHD and depression for longitudinal studies, studies using DSM-II diagnostic criteria for hyperkinetic reaction of childhood or used a dichotomous motor hyperactivity criterion, studies that used nonreferred samples, and studies including teacher report in the assessment of ADHD. When studies that used DSM-II diagnostic criteria were removed, a reliable medium effect was found for studies that included teacher report. Similarly when the study that used idiosyncratic methods of diagnosing ADHD was excluded, a reliable medium effect was found for studies that used nonreferred samples. Potential explanations for the findings are discussed, including explanations based on sampling and base rates, artifacts of diagnostic criteria, inaccurate diagnostic boundaries, and etiological relationships. Directions for future research and clinical implications are discussed. PMID- 25455626 TI - The effect of self-imagery on symptoms and processes in social anxiety: a systematic review. AB - BACKGROUND: Cognitive models of Social Anxiety Disorder suggest that negative self-images maintain social fears despite repeated exposure to benign social situations. An accumulating body of evidence supports this notion, and preliminary data indicate that modifying self-imagery can potentially reduce fears of negative evaluation in socially anxious individuals. This systematic review aims to evaluate the existing research on the effect of self-imagery on symptoms and processes in social anxiety. METHODS: The following databases were searched: PsycInfo, Medline, PubMed, and Cochrane Central Register of Controlled Trials. Articles were limited to adult samples and English language papers that examined the effect of self-imagery on at least one measure related to social anxiety. Risk of bias and study results were reviewed for each study. RESULTS: In the 17 studies that were identified, negative self-imagery had a consistently adverse effect on anxiety, self and observer-rated performance appraisals, and negative thoughts for both socially anxious and non-clinical participants. Effects of negative self-imagery were generally not significantly greater for socially anxious participants. CONCLUSIONS: Further research is warranted to determine the precise role of different types of self-imagery for both clinical and non-clinical individuals. PMID- 25455627 TI - Outcomes associated with virtual reality in psychological interventions: where are we now? AB - The impending commercial release of affordable VR systems is likely to accelerate both the opportunity and demand for VR applications that specifically target psychological conditions. The aim of this study was to conduct a meta-analysis of outcomes associated with VR psychological interventions and to examine the methodological rigour used in these interventions. Literature search was conducted via Ovid, ProQuest Psychology Journals and ScienceDirect (Psychology) databases. Interventions were required to: be published between 1980 to 2014; use a randomised controlled trial design; be published in a scholarly journal; focused primarily on psychological/behavioural intervention; include validated measures; include reported means and standard deviations of outcome measures; and include one group with clinical/subclinical disorders, syndromes or distressing behaviours. Thirty eligible studies were identified. Random effects meta-analysis found an overall moderate effect size for VR interventions. Individual meta analyses found an overall large effect size against non-intervention wait-lists and an overall moderate effect size against active interventions. No correlation was found between treatment outcomes and methodological rigour. Limitations may include limited study numbers, the use of a single coder, a need for more in depth analyses of variation in form VR intervention, and omission of presence as a moderating factor. The current review supports VR interventions as efficacious, promising forms of psychological treatment. Use of reporting guidelines such as the CONSORT and CONSORT-EHEALTH statements should promote greater emphasis on methodological rigour, providing a firm foundation for the further development of clinical VR applications. PMID- 25455625 TI - Is parenting the mediator of change in behavioral parent training for externalizing problems of youth? AB - Change in parenting behavior is theorized to be the mediator accounting for change in child and adolescent externalizing problems in behavioral parent training (BPT). The purpose of this review is to examine this assumption in BPT prevention and intervention programs. Eight intervention and 17 prevention studies were identified as meeting all criteria or all but one criterion for testing mediation. Parenting behaviors were classified as positive, negative, discipline, monitoring/supervision, or a composite measure. Forty-five percent of the tests performed across studies to test mediation supported parenting as a mediator. A composite measure of parenting and discipline received the most support, whereas monitoring/supervision was rarely examined. More support for the mediating role of parenting emerged for prevention than intervention studies and when meeting all criteria for testing mediation was not required. Although the findings do not call BPT into question as an efficacious treatment, they do suggest more attention should be focused on examining parenting as a putative mediator in BPT. PMID- 25455628 TI - Meta-analysis of psychological treatments for posttraumatic stress disorder in adult survivors of childhood abuse. AB - Posttraumatic stress disorder (PTSD) is highly prevalent in adult survivors of childhood sexual and/or physical abuse. However, intervention studies focusing on this group of patients are underrepresented in earlier meta-analyses on the efficacy of PTSD treatments. The current meta-analysis exclusively focused on studies evaluating the efficacy of psychological interventions for PTSD in adult survivors of childhood abuse. Sixteen randomized controlled trials meeting inclusion criteria could be identified that were subdivided into trauma-focused cognitive behavior therapy (CBT), non-trauma-focused CBT, eye movement desensitization and reprocessing, and other treatments (interpersonal, emotion focused). Results showed that psychological interventions are efficacious for PTSD in adult survivors of childhood abuse, with an aggregated uncontrolled effect size of g=1.24 (pre- vs. post-treatment), and aggregated controlled effect sizes of g=0.72 (post-treatment, comparison to waitlist control conditions) and g=0.50 (post-treatment, comparison with TAU/placebo control conditions), respectively. Effect sizes remained stable at follow-up. As the heterogeneity between studies was large, we examined the influence of two a priori specified moderator variables on treatment efficacy. Results showed that trauma-focused treatments were more efficacious than non-trauma-focused interventions, and that treatments including individual sessions yielded larger effect sizes than pure group treatments. As a whole, the findings are in line with earlier meta-analyses showing that the best effects can be achieved with individual trauma-focused treatments. PMID- 25455630 TI - [Breast and ovarian cancer due to BRCA1&2 hereditary cancer predisposition syndrome and reproduction: literature review]. AB - INTRODUCTION: Germline mutations BRCA1&2 are responsible in women for breast and ovarian cancers that commonly occur at a young age: as such, there are strong interactions between the oncological risks and the events of reproductive life, pregnancy, breastfeeding, and management of infertility. MATERIALS AND METHODS: A review of the international literature from the PubMed database was conducted, and recommendations of French health agencies were exposed. Published studies are case-control and cohort studies in the majority, with a low level of evidence. RESULTS: Pregnancy and lactation have no effect on breast and ovaries or even decreases the risk. The sex ratio among patients carrying the mutation is in favor of girls. It is not observed more infertility in patients carrying a mutation despite a strong suspicion of premature ovarian failure, and infertility treatments do not increase breast and ovarian risk. There are ethical debates concerning the place of pre-natal diagnosis: both experts and concerned patients recommend a case-by-case analysis of the requests. PMID- 25455629 TI - RNA editing, epitranscriptomics, and processing in cancer progression. AB - The transcriptome is extensively and dynamically regulated by a network of RNA modifying factors. RNA editing enzymes APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and ADAR (adenosine deaminase, RNA-specific) irreversibly recode primary RNA sequences, whereas newly described methylases (writers) and de-methylases (erasers) dynamically alter RNA molecules in response to environmental conditions. RNA modifications can affect RNA splicing, nuclear cytoplasmic transport, translation, and regulation of gene expression by RNA interference. In addition, tRNA base modifications, processing, and regulated cleavage have been shown to alter global patterns of mRNA translation in response to cellular stress pathways. Recent studies, some of which were discussed at this workshop, have rekindled interest in the emerging roles of RNA modifications in health and disease. On September 10th, 2014, the Division of Cancer Biology, NCI sponsored a workshop to explore the role of epitranscriptomic RNA modifications and tRNA processing in cancer progression. The workshop attendees spanned a scientific range including chemists, virologists, and RNA and cancer biologists. The goal of the workshop was to explore the interrelationships between RNA editing, epitranscriptomics, and RNA processing and the enzymatic pathways that regulate these activities in cancer initiation and progression. At the conclusion of the workshop, a general discussion focused on defining the major challenges and opportunities in this field, as well as identifying the tools, technologies, resources and community efforts required to accelerate research in this emerging area. PMID- 25455631 TI - Potential role of parasitosis in tumorigenesis: case study of heart metastasis as the only presenting symptom of an ileal neuroendocrine tumor. PMID- 25455632 TI - [Current issues to improve care for COPD]. PMID- 25455633 TI - [Clinical and functional assessment in COPD: from case finding to follow-up]. AB - A spirometry with bronchodilator test is needed for the diagnosis of COPD. It is recommended to detect COPD only in subjects with symptoms (dyspnoea and/or chronic cough and/or chronic sputum production) and a history of exposure to risk factors for the disease (tobacco smoking and/or occupational exposure). Measurement of peak expiratory flow to detect COPD, although simpler than conventional spirometry, allows only detection of the most severe cases of COPD. Specialist referral is often useful in the diagnosis of COPD, to establish the presence of incompletely reversible airflow obstruction, assess severity (using clinical questionnaires, plethysmography, exercise testing and arterial blood gases when indicated) and define future management. The level of FEV1 is associated with individualized assessment of symptoms and evaluation of exacerbation risk in the management strategy of stable COPD. PMID- 25455634 TI - [Long-term treatment strategy in chronic obstructive pulmonary disease: how to change the course of the disease]. AB - COPD is a pulmonary disease with a systemic impact. The goals of COPD assessment are to determine the severity of the disease to guide management. Smoking cessation is a prime objective at all the stages of the disease to modify the long-term decline in lung function, reduce the COPD symptoms, and the frequency of exacerbations, improve health status and reduce mortality. The bronchodilators are central in the pharmacologic management of COPD. Long-acting bronchodilators are indicated as maintenance treatment to relieve COPD symptoms (particularly dyspnea) despite regular use of short-acting bronchodilators. Long-acting bronchodilators reduce the exacerbation rate. The choice between a long-acting beta2-adrenergic and an anticholinergic depends on the patient's perception of symptom relief. The inhaled corticoids are only indicated in COPD combined with long-acting beta2-adrenergic in patients with severe COPD and a history of repeated exacerbations, who have significant symptoms despite therapy with bronchodilators. The combination of an inhaled corticosteroid with a long-acting beta2-agonist reduces the exacerbation rate. The rehabilitation should be offered to all patients with dyspnea, exercise intolerance, or limitation in everyday activities related to COPD despite optimal pharmacological therapy and management of co-morbidities. Pulmonary rehabilitation is a multidisciplinary and tailored management of the COPD patients which enable to optimize exercise capacity, social reintegration, autonomy, reduce health care costs by decreasing the exacerbation rate, urgent visits and duration of hospitalisation. The rehabilitation is not just focusing on the improvement of exercise capacity, but also seeks sustained behavioural changes that are needed to achieve real improvement in health status and quality of life. Pulmonary rehabilitation is also an excellent opportunity for education which is critical in the healthcare pathway. PMID- 25455635 TI - Viruses associated with skin and mucosal cancers. PMID- 25455636 TI - Merkel cell carcinoma: The first human cancer shown to be associated with a polyomavirus. AB - Merkel cell carcinoma (MCC) is a rare, malignant primary neuroendocrine cancer of the skin, usually affecting elderly, white people in sun-exposed areas. This is a highly aggressive tumor with strong propensity to metastasize. Surgery and radiation therapy remain the mainstay of treatment, with no curative treatment in case of disseminated metastases. Until 2008, MCC was thought to be caused by the malignant transformation of resident Merkel cells, but no investigation of a predominant molecular pathway that could be involved in MCC pathogenesis was successful. A real revolution in MCC understanding and management occurred in 2008, when a new human polyomavirus (MCPyV) was found to be the main etiological agent of this skin cancer. Following the discovery of MCPyV, the association of MCPyV with MCC has been confirmed worldwide, with detection of MCPyV in about 80% of MCCs. At the same time it had been shown that MCPyV infection is almost ubiquitous in healthy subjects, and MCPyV is thought to be persistent resident of the skin microbiome although the route of transmission, the host cell, the viral cycle and/or latency remain unknown. Most studies suggest that there may be two subtypes of MCC: MCPyV-positive (80%) and MCPyV-negative (20%) MCCs, and various studies have reported a better prognosis associated with MCPyV infection. The discovery of MCPyV in MCC patients opens up new therapeutic insights. The necessity and persistence of expression of MCPyV oncoproteins during MCC development make these proteins promising therapeutic targets. PMID- 25455637 TI - HPV in genital cancers (at the exception of cervical cancer) and anal cancers. AB - Human papillomavirus (HPV) infection has been firmly established as a central and necessary cause of invasive cervical cancer and it has been etiologically linked to other anogenital (vulva, vagina, anus and penis) and head and neck cancers, particularly oropharyngeal. Although being rare, the incidence of some of these cancers in some countries has increased in the last decades. HPV-related anogenital tumors share many risk factors with cervical cancer. The HPV aetiological contribution differs in each anatomical location reflecting differences in the natural history and viral tissue tropism. The highest prevalence of HPV DNA in cancers other than cervix has been described for anal, followed by vagina, penile and vulvar cancers. HPV16 has been described as the most common type detected in all cancer sites with different contributions being the highest in anal carcinoma (around 80% of HPV DNA positive anal cancers) and the lowest in vaginal cancers with a contribution similar to that found in cervical cancers (around 60%). Current HPV vaccines have already demonstrated their efficacy in preventing anogenital pre-neoplastic lesions caused by vaccine HPV types. HPV-based prevention tools like HPV vaccination and to a lesser extend screening (e.g. for anal cancer) can be useful measures for reducing the burden of these anogenital cancers. PMID- 25455638 TI - Human papillomavirus (HPV) and oropharyngeal squamous cell carcinoma. AB - Numerous reports in recent decades have shown that, in addition to smoking and alcohol, human papillomavirus (HPV) is also associated with the development of oropharyngeal squamous cell carcinoma (OPSCC), predominantly in the tonsils and base of the tongue. In 2007, the International Agency on Research against Cancer (IARC) therefore declared HPV to be a risk factor for OPSCC and noted that 80% of those affected are men. In addition, patients with HPV-positive OPSCC, in particular never-smokers, have a much better clinical response to therapy than patients with HPV-negative OPSCC and other head and neck cancers. Most patients with HPV-positive OPSCC may thus not need the increasingly intensive chemo radiotherapy currently administered today to most patients with head neck cancers and associated with many adverse effects. Furthermore, an increase in the incidence of OPSCC has been observed in many western countries, accompanied by a rise in the proportion of HPV-positive tumors. Patients with HPV-positive OPSCC, like those with cervical cancer, more often have an earlier sexual debut and have more sexual partners. It has therefore been proposed that the increased incidence of OPSCC observed might be due to an epidemic of sexually transmitted HPV. The important issues today regarding this growing cohort of patients with HPV positive OPSCC are therefore individualized treatment and prevention. More specifically, selected HPV-positive OPSCC patients with biomarkers of good prognosis might be included in randomized trials with less intensive treatment. HPV vaccination should also be considered for boys, in addition to the current recommendations for immunization of girls. PMID- 25455639 TI - Selected hybrid natural products as tubulin modulators. AB - Modulators of microtubule dynamics have received increasing attention because of their potential to stop cancer growth. Although it belongs to the category of complex protein-protein interactions (PPIs), which are generally considered difficult to modulate through small molecules, the use of microtubule is considered a well-validated target. There are a number of bioactive natural products and related compounds that are currently in use as drugs or in clinical trials as next generation anti-cancer agents. The present review article is focused on two such bioactive natural products, epothilone and halichondrin B, and covers some of the key papers published after 2005 that outline various synthetic approaches to obtain next generation structural analogs as well as the synthesis of hybrid compounds. PMID- 25455641 TI - Development of esophageal cancer in Chaoshan region, China: association with environmental, genetic and cultural factors. AB - Esophageal squamous cell carcinoma (ESCC) is the eighth most common cancer by incidence worldwide. Although the cancer is located at a readily recognizable and accessible site in the body, it is the sixth most common cause of cancer death. The 1- and 5-year survival rates in China are 50% and 15%, respectively. Furthermore, the cancer has distinct geographic and etiological risk factors in different locations around the world. Since ESCC is highly prevalent in the Chaoshan (Southeastern) region of China, this report will focus on a review of risk factors for the cancer in this area. From the review, it is clear that some important and traditional factors are involved, e.g. environmental mutagens, genetic predisposition. However, unique factors, e.g. the drinking of very hot tea, may play an important role. This review highlights the role of complex risk factors (environmental, genetic and cultural) which contribute to the multistage development of cancer: localized injury, inflammation, mitogenesis, mutagenesis, carcinogenesis and eventually mortality. The latter is contributed by unnecessary delay in seeking medical care which may be culturally related. The review emphasizes the need to identify causal mechanisms for the complex carcinogenic process which can provide opportunity for prevention and treatment of this potentially curable cancer. PMID- 25455640 TI - Bioactive thiazole and benzothiazole derivatives. AB - The heterocycles are the versatile compounds existing in almost all natural products and synthetic organic compounds, usually associated with one or the other biological activity. Among the heterocycles the thiazoles and benzothiazoles occupy a prominent position. They possess a broad range of biological activities and are found in many potent biologically active molecules and drugs such as vitamin thiamine, sulfathiazol (antimicrobial drug), ritonavir (antiretroviral drug), abafungin (antifungal drug) and tiazofurin (antineoplastic drug). The thiazole moiety is abundantly found in natural products while benzothiazole moiety is rare. In this review we disclose the literature reports of thiazoles and benzothiazoles possessing different biological activities. PMID- 25455642 TI - Investigation of an outbreak of bloody diarrhea complicated with hemolytic uremic syndrome. AB - In July-August 2009, eight patients with bloody diarrhea complicated by hemolytic uremic syndrome (HUS) were admitted to hospitals in Tbilisi, Georgia. We started active surveillance in two regions for bloody diarrhea and post-diarrheal HUS. Of 25 case-patients who developed HUS, including the initial 8 cases, half were ?15 years old, 67% were female and seven (28%) died. No common exposures were identified. Among 20 HUS case-patients tested, Shiga toxin was detected in the stools of 2 patients (one with elevated serum IgG titers to several Escherichia coli serogroups, including O111 and O104). Among 56 persons with only bloody diarrhea, we isolated Shiga toxin-producing E. coli (STEC) O104:H4 from 2 and Shigella from 10; 2 had serologic evidence of E. coli O26 infection. These cases may indicate a previously unrecognized burden of HUS in Georgia. We recommend national reporting of HUS and improving STEC detection capacity. PMID- 25455643 TI - Evaluation of physical fitness and weight status among fisherwomen in relation to their occupational workload. AB - BACKGROUND: Fisherwomen contribute significantly to the coastal economy of Eastern India; however, data about their physical fitness and weight status are scant. OBJECTIVES: The present cross-sectional study was designed to investigate cardiorespiratory fitness and weight status of fisherwomen, which may be influenced by their occupational workload, using morphometric and anthropometric measures. METHODS: The study was conducted among young fisherwomen (mean age 23.7 years) randomly selected from Araku, Visakhapatnam, Andhra Pradesh, and among young women who are not engaged in the fishing industry but are residents of Araku, who served as controls (mean age 21.3 years). Measurements of body composition included several anthropometric variables, while physical efficiency parameters included a physical fitness index (PFI), VO2max, total energy expenditure, and anaerobic capacity. RESULTS: A significant difference (p<0.05) in body mass index (BMI), body surface area (BSA), body fat percentage, diastolic blood pressure, fitness index, total energy expenditure, and anaerobic power was found in fisherwomen compared with controls. Analysis of collected data showed that the majority of the fisherwomen studied have a normal range of BMI (42%), but 6% of them were found to be mildly overweight. They also showed lower fat mass (13.5 [ +/- 3.87]kg) and lower waist-to-hip ratio (WHR) and conicity index. Additionally, they were found to have a moderate level of physical fitness (64.3 [ +/- 1.97]%) and a higher total energy expenditure (4.92 [ +/- 0.52]k.cal.min( 2)). CONCLUSION: This study implies that physical fitness and weight status of young fisherwomen in Eastern India are influenced by their occupational workload. PMID- 25455644 TI - Knowledge about tobacco smoking among medical students in Saudi Arabia: findings from three medical schools. AB - INTRODUCTION: Tobacco smoking is the leading cause of preventable death worldwide. Educating and training medical students about tobacco dependence prevention and treatment will prepare them for the task of helping smokers quit. In Saudi Arabia, little is known about medical students' knowledge on this topic. METHODS: This study was conducted among 237 medical students (89% response rate) from three medical schools in Saudi Arabia. Students were asked to complete a 55 item questionnaire about the knowledge of smoking epidemiology, smoking cessation practice and benefits, and treatment of tobacco dependence. RESULTS: The majority of the students (91.4%) do not have adequate knowledge about the epidemiology of smoking. Students demonstrated a low knowledge of the health risks associated with tobacco use (average score 53%; SD=11.6), a fair understanding of the benefits of smoking cessation, and insufficient information about treatment of tobacco dependence. Respondents thought they were adequately prepared to counsel their patients to quit smoking. CONCLUSIONS: Medical students in Saudi Arabia are not well informed and trained in tobacco dependence and treatment. It is necessary to address this deficit by prioritizing these topics in medical education curricula. PMID- 25455645 TI - Change in the structures, dynamics and disease-related mortality rates of the population of Qatari nationals: 2007-2011. AB - BACKGROUND: Developing effective public health policies and strategies for interventions necessitates an assessment of the structure, dynamics, disease rates and causes of death in a population. Lately, Qatar has undertaken development resurgence in health and economy that resulted in improving the standard of health services and health status of the entire Qatari population (i.e., Qatari nationals and non-Qatari residents). No study has attempted to evaluate the population structure/dynamics and recent changes in disease-related mortality rates among Qatari nationals. OBJECTIVE: The present study examines the population structure/dynamics and the related changes in the cause-specific mortality rates and disease prevalence in the Qatari nationals. METHODS: This is a retrospective, analytic descriptive analysis covering a period of 5years (2007 2011) and utilizes a range of data sources from the State of Qatar including the population structure, disease-related mortality rates, and the prevalence of a range of chronic and infectious diseases. Factors reflecting population dynamics such as crude death (CDR), crude birth (CBR), total fertility (TFR) and infant mortality (IMR) rates were also calculated. RESULTS: The Qatari nationals is an expansive population with an annual growth rate of ~4% and a stable male:female ratio. The CDR declined by 15% within the study period, whereas the CBR was almost stable. The total disease-specific death rate, however, was decreased among the Qatari nationals by 23% due to the decline in mortality rates attributed to diseases of the blood and immune system (43%), nervous system (44%) and cardiovascular system (41%). There was a high prevalence of a range of chronic diseases, whereas very low frequencies of the infectious diseases within the study population. CONCLUSION: Public health strategies, approaches and programs developed to reduce disease burden and the related death, should be tailored to target the population of Qatari nationals which exhibits characteristics that vary from the entire Qatari population. PMID- 25455647 TI - Validation of the Arabic version of the Epworth sleepiness scale. AB - BACKGROUND: The Epworth Sleepiness Scale (ESS) is a questionnaire widely used in developed countries to measure daytime sleepiness and diagnose sleep disorders. OBJECTIVE: This study aimed to develop an ESS questionnaire for the Arabic population (ArESS), to determine ArESS internal consistency, and to measure ArESS test-retest reproducibility. It also investigated whether the normal range of ESS scores of healthy people in different cultures are similar. METHODS: The original ESS questionnaire was translated from English to Arabic and back-translated to English. In both the English and Arabic translations of the survey, ESS consists of eight different situations. The subject was asked to rate the chance of dozing in each situation on a scale of 0-3 with total scores ranging between 0 (normal sleep) and 24 (very sleepy). An Arabic translation of the ESS questionnaire was administered to 90 healthy subjects. RESULTS: Item analysis revealed high internal consistency within ArESS questionnaire (Cronbach's alpha=0.86 in the initial test, and 0.89 in the retest). The test-retest intra-class correlation coefficient (ICC) shows that the test-retest reliability was substantially high: ICC=0.86 (95% confidence interval: 0.789-0.909, p-value<0.001). The difference in ArESS scores between the initial test and retest was not significantly different from zero (average difference=-0.19, t=-0.51, df=89, p-value=0.611). In this study, the averages of the ESS scores (6.3 +/- 4.7, range 0-20 in the initial test and 6.5 +/- 5.3, range 0-20 in the retest) are considered high in Western cultures. CONCLUSIONS: The study shows that the ArESS is a valid and reliable tool that can be used in Arabic-speaking populations to measure daytime sleepiness. The current study has shown that the average ESS score of healthy Arabian subjects is significantly higher than in Western cultures. PMID- 25455646 TI - Prevalence and determinants of electrocardiographic abnormalities in African Americans with type 2 diabetes. AB - BACKGROUND: Electrocardiographic (ECG) abnormalities are independently associated with poor outcomes in the general population. Their prevalence and determinants were assessed in the understudied African American population with type 2 diabetes. METHODS: Standard 12-lead ECGs were digitally recorded in 635 unrelated African American-Diabetes Heart Study (AA-DHS) participants, automatically processed at a central lab, read, and coded using standard Minnesota ECG Classification. Age- and sex-specific prevalence rates of ECG abnormalities were calculated and logistic regression models were fitted to examine cross-sectional associations between participant characteristics and ECG abnormalities. RESULTS: Participants were 56% women with a mean age of 56 years; 60% had at least one minor or major ECG abnormality [23% ? 1 major (or major plus minor), and 37% ? 1 minor (with no major)]. Men had a higher prevalence of ? 1 minor or major ECG abnormality (66.1% men vs. 55.6% women, p=0.0089). In univariate analysis, age, past history of cardiovascular disease, diabetes duration, systolic blood pressure, sex and statin use were associated with the presence of any (major or minor) ECG abnormalities. In a multivariate model including variables, female sex (OR [95% CI] 0.79 [0.67, 0.93]), statin use (0.79 [0.67, 0.93]) and diabetes duration (1.03 [1.0, 1.05]) remained statistically significant. CONCLUSIONS: Nearly three out of five African Americans with diabetes had at least one ECG abnormality. Female sex and statin use were significantly associated with lower odds of any ECG abnormality and diabetes duration was significantly associated with higher odds of any ECG abnormality in the multivariable model. PMID- 25455649 TI - Changes in hand hygiene compliance after a multimodal intervention among health care workers from intensive care units in Southwestern Saudi Arabia. AB - The aim of this study is to measure the degree of compliance with hand hygiene practices among health-care workers (HCWs) in intensive care facilities in Aseer Central Hospital, Abha, Saudi Arabia, before and after a multimodal intervention program based on WHO strategies. Data were collected by direct observation of HCWs while delivering routine care using standardized WHO method: "Five moments for hand hygiene approach". Observations were conducted before (February-April 2011) and after (February-April 2013) the intervention by well-trained, infection control practitioners during their routine visits. The study included 1182 opportunities (observations) collected before and 2212 opportunities collected after the intervention. The overall, hand hygiene compliance increased significantly from 60.8% (95% CI: 57.9-63.6%) before the intervention to reach 86.4% (95% CI: 84.9-97.8%) post-intervention (P=0.001). The same trend was observed in different intensive care facilities. In logistic regression analyses, HCWs were significantly more compliant (aOR=3.2, 95% CI: 2.6-3.8) after the intervention. Similarly, being a nurse and events after patient contact were significant determinants of compliance. It is important to provide sustained intensified training programs to help embed efficient and effective hand hygiene into all elements of care delivery. New approaches like accountability, motivation and sanctions are needed. PMID- 25455648 TI - Awareness of pro-tobacco advertising and promotion and beliefs about tobacco use: findings from the Tobacco Control Policy (TCP) India Pilot Survey. AB - Tobacco companies are utilizing similar strategies to advertise and promote their products in developing countries as they have used successfully for over 50 years in developed countries. The present study describes how adult smokers, smokeless tobacco users, and non-users of tobacco from the Tobacco Control Project (TCP) India Pilot Survey, conducted in 2006, responded to questions regarding their perceptions and observations of pro-tobacco advertising and promotion and beliefs about tobacco use. Analyses found that 74% (n=562) of respondents reported seeing some form of pro-tobacco advertising in the last six months, with no differences observed between smokers (74%), smokeless tobacco users (74%), and nonsmokers (73%). More than half of respondents reported seeing pro-tobacco advertising on store windows or inside shops. Overall, this study found that a significant percentage of tobacco users and non-users in India report seeing some form of pro tobacco advertising and promotion messages. Additional analyses found that smokers were more likely to perceive tobacco use as harmful to their health compared with smokeless tobacco users and non-users (p<0.01). The findings from this study reiterate the need for stronger legislation and strict enforcement of bans on direct and indirect advertising and promotion of tobacco products in India. PMID- 25455650 TI - Use of footwear and foot condition among rural Ethiopian school children. AB - OBJECTIVE: To evaluate whether shoe-wearing affords foot protection among school children living in southern Ethiopia. METHODS: Data collectors conducted a standardized foot assessment with children in an elementary school in southern Ethiopia (N=168). RESULTS: 54% reported wearing shoes consistently in the prior three days. Children wearing closed-toed shoes showed less adherent soil and toe nail dystrophy than those wearing open-toed sandals. There were no differences by shoe type with regard to signs of foot trauma or heel fissures. CONCLUSIONS: Shoe wearing provided limited foot protection. Interventions are needed to build behavioral skills, including foot washing and wearing appropriate shoes that maximize foot protection. PMID- 25455651 TI - Socioeconomic status and obesity: causality of the association. PMID- 25455652 TI - Statin use and survival following glioblastoma multiforme. AB - AIM: While some studies indicate a potential chemopreventive effect of statin use on the risk of glioma, the effect of statins on the prognosis of brain tumours has not yet been examined. We thus conducted a cohort study evaluating the influence of statin use on survival in patients with glioblastoma multiforme (GBM). METHODS: We identified 1562 patients diagnosed with GBM during 2000-2009 from the Danish Cancer Registry and linked this cohort to Danish nationwide demographic and health registries. Within the GBM cohort, each patient recorded as using statins prior to diagnosis (defined as >= 2 redeemed prescriptions) was matched to two statin non-users (<2 redeemed prescriptions) by propensity scores based on age, gender, year of diagnosis, comorbidity, and use of selected drugs. Cox proportional hazard models were used to compute hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause death associated with prediagnostic statin use. RESULTS: A total of 339 GBM patients were included in the analyses. Of these, 325 died during median follow-up of 6.9 months (interquartile range: 3.8-13.4 months). Prediagnostic statin use was associated with a reduced HR of death (0.79; 95% CI: 0.63-1.00). The HRs decreased with increasing duration or intensity of prediagnostic statin use [long-term (>= 5 years) statin use: HR 0.75 (95% CI: 0.47-1.20); high-intensity statin use: HR 0.66 (95% CI: 0.44-0.98)]. Additional adjustment for oncotherapeutic modalities yielded similar results (overall HR 0.80, 95% CI: 0.63-1.01). CONCLUSION: Long-term prediagnostic statin use may improve survival following GBM. PMID- 25455654 TI - Methylenetetrahydrofolate reductase gene polymorphisms contribute to acute myeloid leukemia and chronic myeloid leukemia susceptibilities: appraisal of a recent meta-analysis. PMID- 25455653 TI - Current depression among adult cancer survivors: findings from the 2010 Behavioral Risk Factor Surveillance System. AB - BACKGROUND: A cancer diagnosis and subsequent treatments constitute a significantly increased psychological burden among cancer patients. This study examined the prevalence of current depression and the risk factors associated with a high burden of depression among cancer survivors in the US. METHODS: We analyzed data from 3550 cancer survivors (aged >= 18 years) and 26,917 adults without cancer who participated in the 2010 Behavioral Risk Factor Surveillance System. Depressive symptoms were assessed by the Patient Health Questionnaire-8 diagnostic algorithm. Participants with a total depression severity score of >= 10 were defined as having current depression. Prevalence and prevalence ratios were estimated by conducting log-linear regression analysis while controlling for potential confounders. RESULTS: Overall, 13.7% of cancer survivors (vs. 8.9% of adults without cancer, P < 0.001) reported having current depression; the prevalence varied significantly by cancer category. Among cancer survivors, after multivariate adjustment for covariates, cancer diagnosis within a year, being in 'other' racial/ethnic group, divorced, separated, widowed, or never married, current or former smoker, or having histories of diabetes, disability, or depression were associated with significantly higher prevalence ratios for current depression; whereas being at an advanced age (>= 60 years old), attaining educational levels of >high school graduate, or engaging in leisure-time physical activity were associated with significantly lower prevalence ratios for current depression. CONCLUSION: Our results indicate that cancer survivors are at increased risk of current depression. Targeting cancer survivors at high risk of depressive issues may be especially important for clinical support and interventions aimed at improving mental well-being. PMID- 25455655 TI - Outcome of pregnancy in chronic myeloid leukaemia patients treated with tyrosine kinase inhibitors: short report from a single centre. AB - BACKGROUND: The aim of this work was to report on the outcome of pregnancy in patients with chronic myeloid leukaemia who were on tyrosine kinase inhibitor treatment. PATIENTS AND METHODS: We report the result of 22 pregnancies in 14 patients (9 female and 5 male) who conceived or their partner conceived while being on tyrosine kinase inhibitors for their CML. RESULTS: All pregnancies except one were uneventful. 25 newborns were born and except in one case where small atrial septal defect was diagnosed, all infants were healthy and showed normal development after birth. CONCLUSION: This small series does indicate that parents can most likely expect an uneventful outcome to a pregnancy despite exposure of either partner to TKIs. There is no consensus or guideline regarding the best practice in case of pregnancy. More reports of similar nature would certainly be beneficial to practitioners and patients alike. As such it is still recommended to practice effective contraception during the period of TKI treatment. PMID- 25455656 TI - Bendamustine plus rituximab for relapsed or refractory diffuse large B cell lymphoma: a retrospective analysis. AB - For patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who are not eligible for intensive chemotherapy because of comorbidities, advanced age, or relapse after heavy salvage regimens, treatment options are very limited and prognosis is poor. We retrospectively analyzed 29 patients with relapsed/refractory DLBCL treated with combination bendamustine plus rituximab (BR) between July 2010 and January 2014 to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR) and treatment safety. Twenty-eight patients were available for this analysis. ORR was 50% (14 patients), with 39.3% CR (11 patients), and 10.7% PR (3 patients). SD was reported in 2 patients (7.2%) and PD in 12 patients (42.8%). At the median follow up of 8 months (range 1-37.4 months), the median PFS was 8 months for all patients (95% CI 5.5-26.6). The median DOR was 24.7 months (95% CI 3.2-24.7). Grade 3/4 toxicity observed included hematologic events: lymphopenia (42.8%), neutropenia (32.1%), anemia (17.2%), and thrombocytopenia (14.2%). BR can be considered to have a role in the treatment of patients with relapsed/refractory DLBCL with limited therapeutic options, in that it can induce long-term remission in some patients with an acceptable toxicity profile. PMID- 25455658 TI - [Healthcare and the sustainability of the public health system]. PMID- 25455659 TI - Introduction: Hazardous materials and radiologic/nuclear incidents: lessons learned? PMID- 25455657 TI - Self-adjuvanting lipoimmunogens for therapeutic HPV vaccine development: potential clinical impact. AB - The goal of therapeutic HPV vaccines is the induction of cytotoxic T lymphocyte immunity against HPV-associated cancers. Recombinant proteins and synthetic peptides have high safety profiles but low immunogenicity, which limits their efficacy when used in a vaccine. Self-adjuvanting lipid moieties have been conjugated to synthetic peptides or expressed as lipoproteins to enhance the immunogenicity of vaccine candidates. Mono-, di- and tri-palmitoylated peptides have been demonstrated to activate dendritic cells and induce robust cellular immunity against infectious diseases and cancer. Recently, a platform technology using the high-yield production of recombinant lipoproteins with Toll-like receptor 2 agonist activity was established for the development of novel subunit vaccines. This technology represents a novel strategy for the development of therapeutic HPV vaccines. In this review, we describe recent progress in the design of therapeutic HPV vaccines using lipoimmunogens. PMID- 25455660 TI - Toxic industrial chemicals and chemical weapons: exposure, identification, and management by syndrome. AB - Toxidromes aid emergency care providers in the context of the patient presenting with suspected poisoning, unexplained altered mental status, unknown hazardous materials or chemical weapons exposure, or the unknown overdose. The ability to capture an adequate chemical exposure history and to recognize toxidromes may reduce dependence on laboratory tests, speed time to delivery of specific antidote therapy, and improve selection of supportive care practices tailored to the etiologic agent. This article highlights elements of the exposure history and presents selected toxidromes that may be caused by toxic industrial chemicals and chemical weapons. Specific antidotes for toxidromes and points regarding their use, and special supportive measures, are presented. PMID- 25455661 TI - Hospital preparedness for chemical and radiological disasters. AB - Hospital planning for chemical or radiological events is essential but all too often treated as a low priority. Although some other types of disasters like hurricanes and tornadoes may be more frequent, chemical and radiological emergencies have the potential for major disruptions to clinical care. Thorough planning can mitigate the impact of a chemical or radiological event. Planning needs to include all 4 phases of an event: mitigation (preplanning), preparation, response, and recovery. Mitigation activities should include the performance of a hazards vulnerability analysis and identification of local subject-matter experts and team leaders. PMID- 25455662 TI - Personal protective equipment and decontamination of adults and children. AB - Accurate identification of the hazardous material is essential for proper care. Efficient hospital security and triage must prevent contaminated victims from entering the emergency department (ED) and causing secondary contamination. The decontamination area should be located outside the ambulance entrance. Decontamination priorities are protection of the health care worker, utilization of Level C personal protective equipment, and proper decontamination of the exposed patient. Decontamination proceeds in a head-to-toe sequence. Run-off water is a hazardous waste. Hospital and Community Management Planning for these emergencies is essential for proper preparation and effective response to the hazardous materials incident. PMID- 25455663 TI - Resources for toxicologic and radiologic information and assistance. AB - Most approaches toward chemical and radiological/nuclear (CRN) incidents focus on the clinical skills of the first receiver. These skills are certainly important and are addressed throughout this article. Management skills are often overlooked. The following are basic competencies in information management for the emergency medicine physician to handle large-scale CRN incidents: planning information; incident management information; toxicant management; disposition/definitive care management; and recovery management. Information management and synthesis are crucial throughout the phases of the disaster cycle: planning, response, mitigation, and recovery. PMID- 25455664 TI - Asphyxiants. AB - Asphyxiants deprive the body of oxygen. Simple asphyxiants displace oxygen from the lungs, whereas systemic asphyxiants interfere with transport of oxygen by hemoglobin or with mitochondrial oxidative phosphorylation. Asphyxiants may be gases, liquids, or solids, or their metabolites. The typical clinical picture of asphyxiant poisoning is one of progressive mental status changes, alteration of breathing, progressively abnormal vital signs, coma, seizures, and eventually cardiovascular collapse and death. Treatment of asphyxiant poisoning is aggressive supportive care, with control of the airway and ventilation and maintenance of cardiac output. Supportive care is often enhanced by the administration of specific antidotes. PMID- 25455665 TI - Irritants and corrosives. AB - This article reviews toxic chemicals that cause irritation and damage to single and multiple organ systems (corrosion) in an acute fashion. An irritant toxic chemical causes reversible damage to skin or other organ system, whereas a corrosive agent produces irreversible damage, namely, visible necrosis into integumentary layers, following application of a substance for up to 4 hours. Corrosive reactions can cause coagulation or liquefaction necrosis. Damaged areas are typified by ulcers, bleeding, bloody scabs, and eventual discoloration caused by blanching of the skin, complete areas of alopecia, and scars. Histopathology should be considered to evaluate questionable lesions. PMID- 25455667 TI - Intentional and inadvertent chemical contamination of food, water, and medication. AB - Numerous examples of chemical contamination of food, water, or medication have led to steps by regulatory agencies to maintain the safety of this critical social infrastructure and supply chain. Identification of contaminant site is important. Environmental testing and biomonitoring can define the nature and extent of the event and are useful for providing objective information, but may be unavailable in time for clinical care. Clinical diagnosis should be based on toxidrome recognition and assessment of public health implications. There are several resources available to assist and these can be accessed through regional poison control centers or local/state public health departments. PMID- 25455666 TI - Organophosphate and carbamate poisoning. AB - Organophosphates (OPs) and carbamates have a wide variety of applications, most commonly as pesticides used to eradicate agricultural pests or control populations of disease-carrying vectors. Some OP and carbamates have therapeutic indications such as physostigmine. Certain organophosphorus compounds, known as nerve agents, have been employed in chemical warfare and terrorism incidents. Both classes inhibit acetylcholinesterase (AChE) enzymes, leading to excess acetylcholine accumulation at nerve terminals. In the setting of toxicity from either agent class, clinical syndromes result from excessive nicotinic and muscarinic neurostimulation. The toxic effects from OPs and carbamates differ with respect to reversibility, subacute, and chronic effects. Decontamination, meticulous supportive care, aggressive antimuscarinic therapy, seizure control, and administration of oximes are cornerstones of management. PMID- 25455669 TI - Mental health consequences of chemical and radiologic emergencies: a systematic review. AB - This article reviews the literature pertaining to psychological impacts in the aftermath of technological disasters, focusing on the immediate psychological and mental health consequences emergency department physicians and first responders may encounter in the aftermath of such disasters. First receivers see a wide spectrum of psychological distress, including acute onset of psychiatric disorders, the exacerbation of existing psychological and psychiatric conditions, and widespread symptomatology even in the absence of a diagnosable disorder. The informal community support systems that exist after a natural disaster may not be available to communities affected by a technological disaster leading to a need for more formal mental health supportive services. PMID- 25455668 TI - Emergency department management of patients internally contaminated with radioactive material. AB - After a radiation emergency that involves the dispersal of radioactive material, patients can become externally and internally contaminated with 1 or more radionuclides. Internal contamination can lead to the delivery of harmful ionizing radiation doses to various organs and tissues or the whole body. The clinical consequences can range from acute radiation syndrome to the long-term development of cancer. Estimating the amount of radioactive material absorbed into the body can guide the management of patients. Treatment includes, in addition to supportive care and long term monitoring, certain medical countermeasures like Prussian blue, calcium diethylenetriamine pentaacetic acid (DTPA) and zinc DTPA. PMID- 25455671 TI - Management of hazardous materials emergencies. PMID- 25455670 TI - Checklists for hazardous materials emergency preparedness. AB - Preparation for, and response to, hazardous materials emergencies requires both preplanning and just-in-time information management. The development of an emergency operations plan and a hazardous materials incident response plan involves many steps and implicates numerous resources: institutional, governmental, and private. This article provides checklists for development of plans and guidelines, with numerous references to information and material resources. An important component of readiness is revision. The availability of resources, human and informatics, as well as the means for accessing them, inevitably changes over time. The reader is advised to update all links and telephone numbers on a regularly scheduled basis. PMID- 25455672 TI - Management of hazardous material emergencies. PMID- 25455673 TI - Protective balance and startle responses to sudden freefall in standing humans. AB - The aim of the present study was to investigate whether or not startle reactions contribute to the whole body postural responses following sudden freefall in standing humans. Nine healthy participants stood atop a moveable platform and received externally-triggered (EXT) and selftriggered (SLF) drop perturbations of the support surface. Electromyographic (EMG) activity was recorded bilaterally over the sternocleidomastoid (SCM), deltoid (DLT), biceps brachii (BIC), medial gastrocnemius (GAS), and tibialis anterior (TA) muscles. Whole-body kinematics were also recorded with motion analysis. Rapid phasic activation of SCM during the first trial response (FTR) was seen for all participants for EXT and for 56% of subjects for SLF. Reductions in EMG amplitude between the EXT FTR and later trial responses for SCM, DLT, and BIC and reduced arm movement acceleration indicative of habituation occurred and exceeded adaptive reductions for SLF. These findings suggested that a startle reflex contributes to the exaggerated postural FTR observed during externally-triggered whole-body free falls. PMID- 25455674 TI - Mechanistic study of fulvic acid assisted propranolol photodegradation in aqueous solution. AB - Laser flash (355 nm) and stationary (365 nm) photolysis were used to study the mechanisms of propranolol photolysis in the presence of fulvic acid in aqueous solutions. The FA-assisted photodegradation of propranolol was observed using UV A irradiation (where propranolol is stable). Direct evidence indicated that the photodegradation resulted from the static quenching of the FA triplet state by propranolol via the electron transfer mechanism. The triplet state yield (phiT~0.6%) and the T-T absorption coefficient (ET(620 nm)~5*10(4) M(-1) cm(-1)) were estimated for the first time by modeling the yields of the FA triplet state in the presence of propranolol. Thus, fulvic acid is a promising agent for accelerating propranolol photodegradation in aqueous solutions under UV-A light irradiation. PMID- 25455675 TI - Occurrence of perfluorinated alkylated substances in cereals, salt, sweets and fruit items collected in four European countries. AB - In the context of a European project, 12 perfluoroalkyl acids (PFAAs) were determined in 14 food items collected in four European countries representing northern, southern, eastern and western Europe. This study presents the results of PFAAs measured in fruit, cereals, sweets and salt. Out of the 12 PFAAs, 10 PFAAs were detected in 67% of the samples. Overall, PFOA was the most abundant compound and the highest concentrations were found for PFOS but all were less than 1ngg(-1). When comparing the four countries, highest levels and detection frequencies were observed in Belgium (Western Europe), followed by the Czech Republic (Eastern Europe), Italy (Southern Europe) and finally Norway (Northern Europe). Comparison of profiles and levels is difficult due to variations in constitution of the food categories in the investigated countries and countries of origin of the food items. Dietary intake assessments for PFOS and PFOA show that the daily intake of PFAAs is far below the existing tolerable levels. However, they contribute to the total dietary intake and should therefore be included in future dietary exposure assessments. PMID- 25455676 TI - Perfluoroalkylated substances (PFAS) affect oxidative stress biomarkers in vitro. AB - Perfluoroalkylated substances (PFAS) have been widely used since 1950s and humans are exposed through food, drinking water, consumer products, dust, etc. The long chained PFAS are persistent in the environment and accumulate in wildlife and humans. They are suspected carcinogens and a potential mode of action is through generation of oxidative stress. Seven long-chained PFAS found in human serum were investigated for the potential to generate reactive oxygen species (ROS), induce DNA damage and disturb the total antioxidant capacity (TAC). The tested PFAS were perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluoroctanoic acid (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA). Using the human hepatoma cell line (HepG2) and an exposure time of 24h we found that all three endpoints were affected by one or more of the compounds. PFHxS, PFOA, PFOS and PFNA showed a dose dependent increase in DNA damage in the concentration range from 2*10(-7) to 2*10(-5)M determined by the comet assay. Except for PFDoA, all the other PFAS increased ROS generation significantly. For PFHxS and PFUnA the observed ROS increases were dose-dependent. Cells exposed to PFOA were found to have a significant lower TAC compared with the solvent control, whereas a non significant trend in TAC decrease was observed for PFOS and PFDoA and an increase tendency for PFHxS, PFNA and PFUnA. Our results indicate a possible genotoxic and cytotoxic potential of the PFAS in human liver cells. PMID- 25455677 TI - Enhancing the CH4 yield of anaerobic digestion via endogenous CO2 fixation by exogenous H2. AB - A large amount (25-60%) of degraded organics is converted directly to CO2 during anaerobic digestion (AD) process, which substantially lowers the energy (methane, CH4) yield. In this study, endogenous CO2 fixation by H2 from in-situ iron corrosion was explored to enhancing the CH4 yield. The results demonstrated that a substantial enhancement (up to 61%) in the CH4 yield could be achieved with both nano-scale zero-valent iron (NZVI) and waste iron scraps (WIS) being the added iron. Additionally, the added iron could also achieve effective phosphorus removal from the AD supernatant. PMID- 25455678 TI - Engineering quorum sensing signaling of Pseudomonas for enhanced wastewater treatment and electricity harvest: A review. AB - Cell-cell communication that enables synchronized population behaviors in microbial communities dictates various biological processes. It is of great interest to unveil the underlying mechanisms of fine-tuning cell-cell communication to achieve environmental and energy applications. Pseudomonas is a ubiquitous microbe in environments that had wide applications in bioremediation and bioenergy generation. The quorum sensing (QS, a generic cell-cell communication mechanism) systems of Pseudomonas underlie the aromatics biodegradation, denitrification and electricity harvest. Here, we reviewed the recent progresses of the genetic strategies in engineering QS circuits to improve efficiency of wastewater treatment and the performance of microbial fuel cells. PMID- 25455679 TI - Platforms for energy and nutrient recovery from domestic wastewater: A review. AB - Alternative domestic wastewater treatment processes that recover energy and nutrients while achieving acceptable nutrient limits (<5mgNL(-1)) are a key challenge. Major drivers are value and availability of phosphorous, nitrogen, and potassium, and increasing energy costs. The two major platforms that can achieve this are (a) low energy mainline (LEM), with low strength anaerobic treatment, followed by mainline anaerobic nitrogen removal and chemical or adsorptive phosphorous removal and (b) partition-release-recover (PRR), in which carbon and nutrients are partitioned to solids through either heterotrophic or phototrophic microbes, followed by anaerobic digestion of these solids and recovery from the digestate. This paper reviews practical application of these processes, with a focus on energy costs. Compared to conventional processes which require 0.5kWhkL( 1) electricity (500mgCODL(-1) influent concentration), PRR requires only 0.05kWhkL(-1) electricity. LEM offers the possibility to recover 0.1kWhkL(-1) as electricity with net energy generation above 400mgCODL(-1)influent, while PRR becomes energy generating at >650mgCODL(-1). PRR offers the possibility for recovery of nitrogen and other nutrients (including potassium) through assimilative recovery. However, the energetic overhead of this is substantial, requiring 5kWhkgN(-1) as electricity, which compares to ammonia fixation costs. The lower energy costs, and near to market status of LEM treatment make it likely as a recovery platform in the shorter term, while ability to recover other elements such as nitrogen and potassium, as well as enhance favourability on concentrated wastewaters may enhance the desirability of partitioning in the longer term. PMID- 25455680 TI - Perfluoroalkyl substances (PFASs) and other halogenated compounds in fish from the upper Labe River basin. AB - This study summarizes results on levels of 25 perfluoroalkyl substances (PFASs), three hexabromocyclododecane isomers (HBCDs), tetrabromobisphenol A (TBBPA), three brominated phenols and four hydroxylated derivates of polybrominated diphenyl ethers (OH-PBDEs) in 59fish samples collected in nine localities on two major rivers from the Czech Republic. To identify potential sources of these chemicals, several sampling sites located close to highly industrialized areas were also involved. The major PFAS representatives, perfluorooctane sulfonate (PFOS), C9-C14 perfluoroalkyl carboxylic acids (PFCAs) and perfluorooctane sulfonamide (FOSA) were detected in 100% fish samples. The concentration ranges of individual substances in the respective groups of PFASs were as follows: 0.572 61.3ngg(-)(1) wet weight (ww) for Tot-PFOS, 0.007-0.121ngg(-)(1)ww for perfluoroalkane sulfonates (PFSAs) (without PFOS isomers), 0.007-22.0ngg(-)(1)ww for PFCAs and 0.026-7.76ngg(-)(1)ww for FOSA. The highest contents of ?PFASs (51.9ngg(-)(1)ww and 47.8ngg(-)(1)ww) were measured in fish muscle tissue from the locality Trmice situated on the Bilina River and Verdek on the Labe River, where chemical and/or textile industry is located. From 11 targeted BFRs, five compounds (alpha-HBCD, beta-HBCD, gamma-HBCD, TBBPA and 2,4,6-tribromophenol (TBP)) were determined in analyzed samples. The concentration ranged as follows: 3.15-1211ngg(-)(1) lipid weight (lw) for ?HBCD, 4.99-203ngg(-)(1)lw for TBBPA and 1.76-107ngg(-)(1)lw for 2,4,6-TBP. PMID- 25455682 TI - Comment on "absence of an association between anti-Ro antibodies and prolonged QTc interval in systemic sclerosis: a multicenter study of 689 patients". PMID- 25455681 TI - The effect of initiating pharmacologic insulin on serum uric acid levels in patients with diabetes: a matched cohort analysis. AB - OBJECTIVES: Gout is a common inflammatory arthropathy associated with hyperuricemia. Substantial evidence links hyperuricemia to the metabolic syndrome and diabetes. Rising serum insulin levels correlate with an increase in serum uric acid (UA). The current study evaluated the effect of pharmacologic insulin on serum UA levels in patients with diabetes. METHODS: We conducted a retrospective analysis of previously collected data. The study cohort consisted of patients with both gout and diabetes who had initiated insulin therapy and a matched set of non-insulin users. The change in UA levels was calculated in both groups and compared. Potential confounders were assessed and adjusted for in a matched linear regression model. RESULTS: In total, 23 patients met criteria for insulin initiators and were matched to 23 non-insulin users. In unadjusted analyses, patients started on insulin had a larger increase in UA (mean change = 1.25mg/dl, interquartile range, IQR: -0.7-2.3) in comparison to those not starting insulin (mean change = 0.06mg/dl, IQR: -1.1-0.9). After controlling for baseline UA and time between UA measurements, regression modeling showed that insulin use was significantly associated with an increase in UA (beta = 1.25mg/dl, p = 0.02). CONCLUSIONS: Initiation of insulin among patients with diabetes was associated with a statistically significant increase in serum UA levels. This may affect the risk of gout flares and might suggest the potential for prophylactic therapy. PMID- 25455683 TI - Cardiovascular events in ankylosing spondylitis: an updated meta-analysis. AB - OBJECTIVES: Rheumatoid arthritis is associated with increased cardiovascular risk. In the guidelines, ankylosing spondylitis (AS) is considered to have an equally high cardiovascular risk. The literature findings remain controversial. This study aims to assess the risk of myocardial infarction (MI) and stroke in AS patients. METHODS: An updated meta-analysis with a new systematic literature review using PubMed was conducted up to January 2014. Incidence of MI or stroke was calculated by metaproportion. RESULTS: In addition to the 11 previously included studies, six new studies assessed the occurrence of MI or stroke in AS patients. (1) MI. A total of 2131 MI were reported in AS patients (n = 27,532) over a mean follow-up of 15 years: incidence 5.3% (1.6%-11.0%), i.e., 0.36/100 pyrs. Seven studies revealed 17,410 MI [2.5% (95% CI: 1.8%-3.4%)] in the control group (n = 1,349,964). Meta-analysis of the seven longitudinal studies showed a significant increase in MI [OR = 1.60 (95% CI: 1.32-1.93)] in AS patients. (2) Stroke. In 11 longitudinal studies (n = 51,990), 1807 strokes were reported in AS patients over 17.6 years of follow-up: incidence 3.6% (1.5%-6.5%), i.e., 0.24/100 pyrs. Three studies reported 22,899 strokes in controls (n = 1,239,041), giving an incidence of 1.78% (1.75%-1.80%). A significant increase in stroke [OR = 1.50 (95% CI: 1.39-1.62)] in AS patients was found. CONCLUSION: AS patients appear to have a higher risk of MI and stroke. Management of cardiovascular risk factors and control of systemic inflammation should be taken into account in AS to decrease this high cardiovascular risk. PMID- 25455684 TI - Benign pneumatosis intestinalis in a pediatric patient with multiple risk factors including granulomatosis with polyangiitis: a case report and review of the literature. AB - OBJECTIVE: To describe the first reported case of pneumatosis intestinalis (PI) in a pediatric patient with granulomatosis with polyangiitis (GPA) and multiple other risk factors and review the literature for PI in adult and pediatric rheumatologic conditions. METHODS: A PubMed search was completed using the search phrase "pneumatosis intestinalis." Searches were limited to humans and the English language, and remaining articles involving patients with rheumatologic diagnoses were identified and included in our discussion. RESULTS: This is the first reported of case of PI in a patient with underlying GPA or antineutrophil cytoplasmic antibody-associated vasculitides. Out of 90 previously reported cases of PI in patients with rheumatologic conditions, 79 cases were in adults and 11 in children. There were 30 patients with systemic sclerosis, 18 with MCTD/overlap syndrome, 18 with dermatomyositis or polymyositis, 16 with SLE, and 8 with other diagnoses. Overall, 81% of the patients were on corticosteroids or other immunosuppressants prior to development of PI. The most common presenting symptom was abdominal pain, and 51% of patients had associated pneumoperitoneum. CONCLUSIONS: PI can be associated with a broad spectrum of rheumatic diseases, including GPA, and should be included in the differential diagnosis of patients with rheumatologic conditions and nonspecific gastrointestinal symptoms. PMID- 25455685 TI - Isolated pulmonary vasculitis: case report and literature review. AB - BACKGROUND AND OBJECTIVES: Single-organ vasculitis has been reported to affect the skin, kidneys, central nervous system, peripheral nerves, genitourinary tract, calf muscles, aorta, coronary arteries, retina, or gastrointestinal tract. However, isolated pulmonary vasculitis is a very rare entity. Our aims were to describe a case of localized pulmonary vasculitis affecting medium-sized vessels and review the literature. METHODS: A patient with localized pulmonary vasculitis affecting medium-sized vessels that presented as pulmonary arterial hypertension is described. A MEDLINE database search of cases with localized pulmonary vasculitis was also conducted. RESULTS: A 30-year-old man presented with pulmonary hypertension due to isolated pulmonary medium-sized vessel vasculitis that was confirmed histologically. Initially he responded to corticosteroids and vasodilator treatment, but therapy eventually lost efficacy. Treatment with rituximab was not effective, and as the clinical situation worsened, lung transplant was performed. Isolated large pulmonary vessel disease, often related to Takayasu disease or giant cell arteritis, may present as pulmonary artery hypertension, thus mimicking chronic thromboembolic disease. Medium- and small vessel pulmonary vasculitis usually develops in the context of a systemic disease. Some cases of isolated small-vessel vasculitis have been reported presenting as diffuse alveolar hemorrhage. In contrast, our case developed pulmonary artery hypertension secondary to medium-sized vessels vasculitis. To our knowledge, this is the first case of lung transplantation in isolated pulmonary vasculitis. CONCLUSIONS: Pulmonary isolated vasculitis is a rare cause of pulmonary hypertension but it must be taken into consideration after more common disorders are excluded. PMID- 25455686 TI - Impact of prostate inflammation on lesion development in the POET3(+)Pten(+/-) mouse model of prostate carcinogenesis. AB - Evidence linking prostatitis and prostate cancer development is contradictory. To study this link, the POET3 mouse, an inducible model of prostatitis, was crossed with a Pten-loss model of prostate cancer (Pten(+/-)) containing the ROSA26 luciferase allele to monitor prostate size. Prostatitis was induced, and prostate bioluminescence was tracked over 12 months, with lesion development, inflammation, and cytokine expression analyzed at 4, 8, and 12 months and compared with mice without induction of prostatitis. Acute prostatitis led to more proliferative epithelium and enhanced bioluminescence. However, 4 months after initiation of prostatitis, mice with induced inflammation had lower grade pre-neoplastic lesions. A trend existed toward greater development of carcinoma 12 months after induction of inflammation, including one of two mice with carcinoma developing perineural invasion. Two of 18 mice at the later time points developed lesions with similarities to proliferative inflammatory atrophy, including one mouse with associated carcinoma. Pten(+/-) mice developed spontaneous inflammation, and prostatitis was similar among groups of mice at 8 and 12 months. Analyzed as one cohort, lesion number and grade were positively correlated with prostatitis. Specifically, amounts of CD11b(+)Gr1(+) cells were correlated with lesion development. These results support the hypothesis that myeloid-based inflammation is associated with lesion development in the murine prostate, and previous bouts of CD8-driven prostatitis may promote invasion in the Pten(+/-) model of cancer. PMID- 25455688 TI - Intranasal versus intraperitoneal delivery of human umbilical cord tissue-derived cultured mesenchymal stromal cells in a murine model of neonatal lung injury. AB - Clinical trials investigating mesenchymal stromal cell (MSC) therapy for bronchopulmonary dysplasia have been initiated; however, the optimal delivery route and functional effects of MSC therapy in newborns remain incompletely established. We studied the morphologic and functional effects of intranasal versus i.p. MSC administration in a rodent model of neonatal lung injury. Cultured human cord tissue MSCs (0.1, 0.5, or 1 * 10(6) cell per pup) were given intranasally or i.p. to newborn severe combined immunodeficiency-beige mice exposed to 90% O2 from birth; sham controls received an equal volume of phosphate buffered saline. Lung mechanics, engraftment, lung growth, and alveolarization were evaluated 8 weeks after transplantation. High-dose i.p. MSC administration to newborn mice exposed to 90% O2 resulted in the restoration of normal lung compliance, elastance, and pressure-volume loops (tissue recoil). Histologically, high-dose i.p. MSC administration was associated with alveolar septal widening, suggestive of interstitial matrix modification. Intranasal MSC or lower-dose i.p. administration had no significant effects on lung function or alveolar remodeling. Pulmonary engraftment was rare in all the groups. These findings suggest that high-dose systemic administration of human cultured MSCs can restore normal compliance in neonatally injured lungs, possibly by paracrine modulation of the interstitial matrix. Intranasal delivery had no obvious pulmonary effects. PMID- 25455687 TI - FIH-1 disrupts an LRRK1/EGFR complex to positively regulate keratinocyte migration. AB - Factor inhibiting hypoxia-inducible factor 1 (FIH-1; official symbol HIF1AN) is a hydroxylase that negatively regulates hypoxia-inducible factor 1alpha but also targets other ankyrin repeat domain-containing proteins such as Notch receptor to limit epithelial differentiation. We show that FIH-1 null mutant mice exhibit delayed wound healing. Importantly, in vitro scratch wound assays demonstrate that the positive role of FIH-1 in migration is independent of Notch signaling, suggesting that this hydroxylase targets another ankyrin repeat domain-containing protein to positively regulate motogenic signaling pathways. Accordingly, FIH-1 increases epidermal growth factor receptor (EGFR) signaling, which in turn enhances keratinocyte migration via mitogen-activated protein kinase pathway, leading to extracellular signal-regulated kinase 1/2 activation. Our studies identify leucine-rich repeat kinase 1 (LRRK1), a key regulator of the EGFR endosomal trafficking and signaling, as an FIH-1 binding partner. Such an interaction prevents the formation of an EGFR/LRRK1 complex, necessary for proper EGFR turnover. The identification of LRRK1 as a novel target for FIH-1 provides new insight into how FIH-1 functions as a positive regulator of epithelial migration. PMID- 25455689 TI - Profiling of expression of human papillomavirus-related cancer miRNAs in penile squamous cell carcinomas. AB - Penile squamous cell carcinoma (PSCC) is a rare tumor associated with high-risk human papillomavirus (HR-HPV) infection in 30% to 60% of cases. Altered expression of miRNAs has been reported in HPV-related cervical and head and neck cancers, but such data have not been available for PSCC. We analyzed a series of 59 PSCCs and 8 condylomata for presence of HPV infection, for p16(INK4a), Ki-67, and p53 immunohistochemical expression, and for expression of a panel of cellular miRNAs (let-7c, miR-23b, miR-34a, miR-145, miR-146a, miR-196a, and miR-218) involved in HPV-related cancer. HR-HPV DNA (HPV16 in most cases) was detected in 17/59 (29%) PSCCs; all penile condylomata (8/8) were positive for low-risk HPV6 or HPV11. HR-HPV(+) PSCCs overexpressed p16(INK4a) in 88% cases and p53 in 35% of cases, whereas HR-HPV(-) PSCCs were positive for p16(INK4a) and p53 immunostaining in 9% and 44% of cases, respectively. Among the miRNAs investigated, expression of miR-218 was lower in PSCCs with HR-HPV infection and in p53(-) cancers. Hypermethylation of the promoter of the SLIT2 gene, which contains miR-218-1 in its intronic region, was frequently observed in PSCCs, mainly in those with low miR-218 expression. Epigenetic silencing of miR-218 is a common feature in HR-HPV(+) PSCCs and in HR-HPV(-) PSCCs without immunohistochemical detection of p53. PMID- 25455691 TI - Alterations of mean diffusivity of pedunculopontine nucleus pathway in Parkinson's disease patients with freezing of gait. AB - BACKGROUND: Although freezing of gait (FOG) is a common and disabling symptom in Parkinson's disease (PD), the underlying mechanism of FOG has not been clearly elucidated. Using analysis of diffusion tensor imaging (DTI), we investigated anatomic structures associated with FOG in PD patients. METHODS: We enrolled 33 controls and 42 PD patients (19 patients with FOG and 23 without FOG). DTI data were compared between PD patients and controls, and also between PD patients with and without FOG. Whole brain voxel-based analysis and regions of interest analysis in the pedunculopontine nucleus were used for DTI analysis. RESULTS: Compared with normal controls, PD patients showed microstructural changes in various subcortical structures (substantia nigra, globus pallidum and thalamus), frontal and insula cortex. PD patients with FOG demonstrated altered mean diffusivities in subcortical structures connected with pedunculopontine nucleus, such as basal ganglia, thalamus and cerebellum in voxel-based analysis. Using region of interest analysis of pedunculopontine nucleus, fractional anisotropy values were reduced and mean diffusivity values were increased bilaterally in PD patients with FOG. In correlation analysis, the fractional anisotropy value of the right pedunculopontine nucleus was moderately correlated with the severity of FOG. CONCLUSIONS: Based on our results, microstructural changes of pedunculopontine nucleus and connected subcortical structures are closely related with FOG in PD patients. PMID- 25455690 TI - Saccades and shifting receptive fields: anticipating consequences or selecting targets? AB - Saccadic eye movements cause frequent and substantial displacements of the retinal image, but those displacements go unnoticed. It has been widely assumed that this perceived stability emerges from the shifting of visual receptive fields from their current, presaccadic locations to their future, postsaccadic locations in anticipation of the retinal consequences of saccades. Although evidence consistent with this anticipatory remapping has accumulated over the years, more recent work suggests an alternative view. In this opinion article, we examine the evidence of presaccadic receptive field shifts and their relationship to the perceptual changes that accompany saccades. We argue that both reflect the selection of targets for saccades rather than the anticipation of a displaced retinal image. PMID- 25455692 TI - Rotigotine vs ropinirole in advanced stage Parkinson's disease: a double-blind study. AB - OBJECTIVE: To confirm the superiority of transdermal rotigotine up to 16 mg/24 h over placebo, and non-inferiority to ropinirole, in Japanese Parkinson's disease (PD) patients on concomitant levodopa therapy. METHODS: This trial was a randomized, double-blind, double-dummy, three-arm parallel group placebo- and ropinirole-controlled trial. Four-hundred and twenty PD patients whose motor symptoms were not well controlled by levodopa treatment were randomized 2:2:1 to receive rotigotine, ropinirole (up to 15 mg/day) or placebo during a 16-week treatment period followed by a 4-week taper period. The primary variable was change in the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (ON state) sum score from baseline to the end of the treatment period. RESULTS: The difference in the change in the UPDRS Part III (ON state) sum score from baseline to the end of treatment between rotigotine and placebo groups was -6.4 +/- 1.2 (95% CI: -8.7 to -4.1; p < 0.001), indicating superiority of rotigotine over placebo. The difference between rotigotine and ropinirole groups was -1.4 +/- 1.0 (95% CI: -3.2 to 0.5), below the non-inferiority margin, indicating the non inferiority of rotigotine to ropinirole. Application site reaction was seen in 57.7% of the patients in the rotigotine group and in 18.6% in the ropinirole group (P < 0.001). No other safety issue was noted. CONCLUSIONS: Rotigotine was well tolerated at doses up to 16 mg/24 h and showed similar efficacy to ropinirole except that the application site reaction was much higher in the rotigotine group. PMID- 25455693 TI - Dyskinesias and motor symptoms onset in Parkinson disease. AB - PURPOSE: To assess, using a longitudinal follow-up study design, the relationship between the body site of motor symptoms onset and that of dyskinesias (LID) onset in 70 PD patients in whom LID were absent at the baseline but appeared at one of the follow-up visits; to investigate the demographic and clinical features associated with different sites of LID onset. METHODS: Motor symptoms onset was retrospectively determined by asking patients which body part had first been affected by motor impairment. The site of LID onset was determined objectively in one of the follow-up visits. RESULTS: Motor symptoms started in the limbs in all patients (unilaterally in 91.4% and bilaterally in 8.6% of the patients). LID started unilaterally in the limbs in 25.8%, bilaterally in the limbs in 7.1%, in the cranio-cervical-axial region in 40% and in both the cranio-cervical-axial region and limbs in 27.1% of the patients. No significant association emerged between the site of motor symptoms onset and that of LID onset; a correlation did emerge between the site of motor symptoms onset and that of LID onset in patients with unilateral onset of both motor symptoms and LID. No differences were detected when the subgroups of patients with LID onset in different body regions were compared. CONCLUSIONS: The partial association between the body site of motor symptoms and of LID onset likely reflects pathophysiological mechanisms underlying LID. PMID- 25455694 TI - Functional tics and echophenomena. PMID- 25455695 TI - A personalized coaching program increases outdoor activities and physical fitness in sedentary Parkinson patients; a post-hoc analysis of the ParkFit trial. PMID- 25455697 TI - Scientific data support that ocular tremor is genuine and unrelated to head movement. PMID- 25455696 TI - Long-term effects of pedunculopontine nucleus stimulation for Pisa syndrome. PMID- 25455698 TI - Developmental epigenetic programming of caste-specific differences in social insects: an impact on longevity. AB - Social insects are an excellent model system for a deeper understanding of the mechanisms of longevity determination because they have a caste system in which the same genome, due to the differential gene expression, can produce both a short-lived worker and a long-lived queen. For example, in the honeybee, Apis mellifera, queens develop from fertilized eggs that are genetically not different from the eggs that develop into workers. They have, however, a much larger size and specialized anatomy, develop substantially faster and live much longer than worker bees. In many social insects including bees, ants, wasps, and termites, queens and workers show up to a 100-fold difference in lifespan, with reproductive queens having longer longevity than non-reproductive workers. Caste differentiation in social insect species is known to be dependent on the larval nutritional environment. In the honeybee, the caste switching is determined by distinguished feeding of larvae. There is accumulating evidence that queen phenotype is driven by epigenetic mechanisms of gene regulation. Dietary differences during the larval development have been found to lead to differential DNA methylation. This results in caste-biased patterns of gene expression, which, in turn, leads to caste-biased phenotypes, such as short-lived workers and long lived queens. The investigation of physiological, biochemical and molecular aspects of the biology of queens and workers seems to be a promising way to identifying pathways that control longevity and to developing the treatments designed to influence these pathways. PMID- 25455700 TI - Older adults who have previously fallen due to a trip walk differently than those who have fallen due to a slip. AB - Studying the relationships between centre of mass (COM) and centre of pressure (COP) during walking has been shown to be useful in determining movement stability. The aim of the current study was to compare COM-COP separation measures during walking between groups of older adults with no history of falling, and a history of falling due to tripping or slipping. Any differences between individuals who have fallen due to a slip and those who have fallen due to a trip in measures of dynamic balance could potentially indicate differences in the mechanisms responsible for falls. Forty older adults were allocated into groups based on their self-reported fall history during walking. The non-faller group had not experienced a fall in at least the previous year. Participants who had experienced a fall were split into two groups based on whether a trip or slip resulted in the fall(s). A Vicon system was used to collect full body kinematic trajectories. Two force platforms were used to measure ground reaction forces. The COM was significantly further ahead of the COP at heel strike for the trip (14.3 +/- 2.7 cm) and slip (15.3 +/- 1.1 cm) groups compared to the non-fallers (12.0 +/- 2.7 cm). COM was significantly further behind the COP at foot flat for the slip group (-14.9 +/- 3.6 cm) compared to the non-fallers (-10.3 +/- 3.9 cm). At mid-swing, the COM of the trip group was ahead of the COP (0.9 +/- 1.6 cm), whereas for the slip group the COM was behind the COP (-1.2 +/- 2.2 cm). These results show identifiable differences in dynamic balance control of walking between older adults with a history of tripping or slipping and non-fallers. PMID- 25455699 TI - Effect of age on the variability and stability of gait: a cross-sectional treadmill study in healthy individuals between 20 and 69 years of age. AB - Falls during walking are a major health issue in the elderly population. Older individuals are usually more cautious, walk more slowly, take shorter steps, and exhibit increased step-to-step variability. They often have impaired dynamic balance, which explains their increased falling risk. Those locomotor characteristics might be the result of the neurological/musculoskeletal degenerative processes typical of advanced age or of a decline that began earlier in life. In order to help determine between the two possibilities, we analyzed the relationship between age and gait features among 100 individuals aged 20-69. Trunk acceleration was measured during a 5-min treadmill session using a 3D accelerometer. The following dependent variables were assessed: preferred walking speed, walk ratio (step length normalized by step frequency), gait instability (local dynamic stability, Lyapunov exponent method), and acceleration variability (root mean square [RMS]). Using age as a predictor, linear regressions were performed for each dependent variable. The results indicated that walking speed, walk ratio and trunk acceleration variability were not dependent on age (R(2)<2%). However, there was a significant quadratic association between age and gait instability in the mediolateral direction (R(2)=15%). We concluded that most of the typical gait features of older age do not result from a slow evolution over the life course. On the other hand, gait instability likely begins to increase at an accelerated rate as early as age 40-50. This finding supports the premise that local dynamic stability is likely a relevant early indicator of falling risk. PMID- 25455701 TI - Integrated testing of standing balance and cognition: test-retest reliability and construct validity. AB - Balance and cognitive impairments which are common with aging often coexist, are prognostic of future adverse health events, including fall injuries. Consequently, dual-task assessment programs that simultaneously address both stability and cognition are important to consider in rehabilitation and benefit healthy aging. The objective of this study was to establish test-retest reliability and construct validity of a dual-task computer game-based platform (TGP) that integrates head tracking and cognitive tasks with balance activities. Thirty healthy, community-dwelling individuals median age 64 (range 60-67) were recruited from a certified Medical Fitness Facility. Participants performed a series of computerized head tracking and cognitive game tasks while standing on fixed and sponge surfaces. Testing was conducted on two occasions, one week apart. Moderate to high test retest reliability (ICC values of 0.55-0.75) was observed for all outcome measures representing balance, gaze performance, cognition, and dual-task performance. A significant increase in center of foot pressure (COP) excursion was observed during both head tracking and cognitive dual-task conditions. The results demonstrate the system's ability to reliably detect changes related to specific and integrated aspects of balance, gaze, and cognitive performance. PMID- 25455702 TI - Age-related differences when walking downhill on different sloped terrains. AB - Despite the common situation of walking on different sloped terrains, previous work on gait has focused on level terrain. This study aims to assess whether any age-related differences exist in spatiotemporal and stability parameters when walking downhill on three different sloped walkways. Two tri-axial accelerometers were used at the levels of head and pelvis to investigate spatiotemporal parameters, magnitude (root mean square, RMS), harmonic content of accelerations (harmonic ratios, HR) and attenuation between body levels (ATT) in 35 older adults (OA, 69 +/- 4.5 y.o.) and 22 young adults (YA, 22.1 +/- 1.9 y.o.). Older adults walked at the same speed and cadence as young adults in flat terrain (FL, 0%) and moderate hill (MH, 8%). In the highest slope (PH, 20%), older adults reduced speed and step length and both groups increased cadence. Age had no effect on attenuation and RMS profiles. RMS increased with slope in all directions at both head and pelvis, except, for medio-lateral direction (ML), with similar head RMS in all slopes. There is an important shift in ATT from anteroposterior direction (AP) to ML at the highest slope, resulting in smaller antero-posterior attenuation and greater medio-lateral attenuation. Age differences appeared in the smoothness (HR) at the flat terrain, with increased vertical and antero-posterior values for young adults. As slope increased, group differences disappeared and HR decreased for all directions of motion. In general, spatiotemporal adaptations to increased slope seem to be part of a mechanism to improve ML attenuation, in both young and old adults. PMID- 25455703 TI - Biomechanical organization of gait initiation depends on the timing of affective processing. AB - Gait initiation (GI) from a quiet bipedal posture has been shown to be influenced by the emotional state of the actor. The literature suggests that the biomechanical organization of forward GI is facilitated when pleasant pictures are shown, as compared to unpleasant pictures. However, there are inconsistencies in the literature, which could be due to the neural dynamics of affective processing. This study aimed to test this hypothesis, using a paradigm whereby participants initiated a step as soon as they saw an affective picture (i.e., onset), or as soon as the picture disappeared from the screen (i.e., offset). Pictures were a priori categorized as pleasant or unpleasant, and could also vary in their arousing properties. We analyzed center-of-pressure and center-of gravity dynamics as a function of emotional content. We found that gait was initiated faster with pleasant images at onset, and faster with unpleasant images at offset. Also, with offset GI the peak velocity of the COG was reduced, and subjects took smaller steps, with unpleasant images relative to pleasant images. The results are discussed in terms of current knowledge regarding temporal processing of emotions, and its effects on GI. PMID- 25455704 TI - Treatment of early episode in patients with schizophrenia: the role of long acting antipsychotics. AB - The use of long-acting injectable antipsychotics (LAIs) in schizophrenia is usually restricted to patients in long-term treatment, who prefer them to oral antipsychotics, and to patients with multiple relapses who have a history of non adherence. However, preliminary evidence from patients in the early phases of the disease suggest that second generation LAIs may be superior to second generation oral medications with regard to the control of negative symptoms and psychosocial functioning. Moreover, several studies have found that psychiatrists are generally reluctant to prescribe LAI antipsychotics and under-estimate their acceptability by patients. Key elements to take into account when offering a LAI in the early course of schizophrenia should include their potential superiority in allowing early detection of non-adherence and in reducing the number of rehospitalisations and relapses. PMID- 25455705 TI - Thalamic pathways underlying prefrontal cortex-medial temporal lobe oscillatory interactions. AB - As focus shifts to large-scale network interactions involved in memory, it is becoming increasingly clear that oscillatory dynamics are critically involved. A number of studies have shown a negative correlation between memory retrieval in alpha and beta power, and a positive correlation between retrieval and theta power. In this opinion article, we suggest three thalamic sub-regions responsible for the coordination of oscillatory activity and the facilitation of memory processes. Specifically, the medial dorsal nucleus is related to changes in beta synchrony, the pulvinar is responsible for alpha synchrony, and the anterior thalamus is related to theta synchrony. These pathways may be modulated via frontal control, and changes in oscillations could be used to track the engagement of underlying memory systems. PMID- 25455706 TI - Ionotropic glutamate receptors made crystal clear. AB - Two recent crystallographic studies of the full-length GluA2 AMPA receptor provide our first insights into how the modular domains of the tetrameric complex coordinate the process of activation. These findings herald a new era in the structure-function analyses of neurotransmitter receptors, a fitting achievement for the 'International Year of Crystallography'. PMID- 25455707 TI - Ebola: the new HIV? PMID- 25455708 TI - Toxic stress in childhood: why we all should be concerned. PMID- 25455709 TI - A transformative program, ahead of its time. PMID- 25455710 TI - Editorial overview: cell cycle, differentiation and disease. PMID- 25455712 TI - Epilepsy after neonatal seizures: literature review. AB - INTRODUCTION: Acute neonatal seizures are the most frequent neurological complication in the neonatal intensive care units and the seizing newborns have an increased risk of long-term morbidity. However, the relationship between neonatal seizures and the development of epilepsy later in life is still unclear. METHODS: We performed a literature review using the search terms "neonatal seizures AND outcome", "neonatal seizures AND epilepsy", "neonatal seizures AND post-neonatal epilepsy", including secondary sources of data such as reference lists of articles reviewed. From the studies in which data were available, the incidence of epilepsy was calculated by dividing the number of all subjects who developed epilepsy in the different studies considered with the number of all newborns enrolled to the studies less the number of patients lost at follow-up. RESULTS: We found 44 studies published between 1954 and 2013, of which 4 were population-based studies and the remaining were hospital-based case series. The overall population evaluated was 4538 newborns and 17.9% developed post-neonatal epilepsy, with an onset within the first year of life in 68.5% of the patients. In 80.7%, epilepsy was associated with other neurological impairments. CONCLUSION: Estimates on epilepsy after neonatal seizures vary widely depending on selection criteria and length of the follow-up. However, it represents a common outcome of these newborns, especially in those with severe brain injury and additional neurodevelopmental disabilities. PMID- 25455718 TI - Rheumatoid arthritis, a new focus on cardiovascular risk. PMID- 25455711 TI - Antecedents and correlates of visual field deficits in children born extremely preterm. AB - AIM: We sought to identify the antecedents and correlates of visual field deficits (VFDs) at age 2 years among infants born before the 28th week of gestation. METHODS: The visual fields of 1023 infants were assessed by confrontation at age 2 years. We compared the ante-and postnatal characteristics and exposures of the 65 infants with a VFD to their peers who did not have a VFD. We used time-oriented logistic regression risk models to assess the associations of potential antecedents and correlates with a VFD. RESULTS: In the final regression model, VFD was associated with maternal consumption of aspirin during the current pregnancy, recurring/persistent acidemia during the first 3 postnatal days, cerebral ventriculomegaly seen on neonatal ultrasound, prethreshold retinopathy of prematurity (ROP), and supplemental oxygen and ventilator dependence at 36 weeks post-menstrual age. Birth before the 27th week was also associated with increased risk, but its significance was diminished by the addition of postnatal variables. CONCLUSION: In this sample of extremely preterm born infants, antenatal as well as early and late postnatal characteristics and exposures are associated with an increased risk of having a VFD. Our study adds to our knowledge about the complex etiology of visual deficits of prematurity, and supports a multifactorial cause of these deficits. PMID- 25455719 TI - What is new in systemic lupus erythematosus. AB - Systemic lupus erythematosus is a heterogeneous rheumatic systemic disease with extremely varied clinical manifestations and a diverse pathogenesis, as illustrated in this review on the most relevant new knowledge related to the disease. Topics such as anemia, pathogenesis, cardiovascular risk assessment, antiphospholipid syndrome, prediction of damage and recent advances in treatment, including tolerogenic and biological agents, are discussed. Relevant contributions regarding classical therapies such as corticosteroid and antimalarials and their optimal use, as well as the roll of vitamin D, are also referred. PMID- 25455720 TI - Severe infections in patients with autoimmune diseases treated with cyclophosphamide. AB - INTRODUCTION: Infectious diseases are a significant cause of morbidity and mortality in patients with connective tissue diseases. Corticosteroids and immunosuppressive drugs, such as cyclophosphamide (CYC), increases the risk of infections. The objective of this study was to estimate the incidence rates of severe infections in patients who received treatment with CYC. PATIENTS AND METHODS: The records of 60 patients with systemic autoimmune diseases who received treatment with CYC were retrospectively reviewed. We evaluated the rate of severe infections that occurred during CYC therapy and the 3 subsequent months. RESULTS: Systemic lupus erythematosus was the most common disease, and diffuse proliferative glomerulonephritis the most frequent indication. Severe infection occurred in 9 patients (15%). Community acquired pneumonia was the most frequent infection with 3 cases (33%) followed by Herpes Zoster with 2 reports (22%). The cumulative dose of corticosteroid was the only significant risk factor for infection 32.8+/-16.7 vs. 20.1+/-15.3 P=.007. CONCLUSION: The use of lower doses of corticosteroids and an aggressive management of infectious complications, allows for an acceptable safety profile in patients treated with CYC. PMID- 25455721 TI - Effect of intermittent vitamin D3 on vascular function and symptoms in chronic fatigue syndrome--a randomised controlled trial. AB - BACKGROUND AND AIMS: Low 25-hydroxyvitamin D levels are common in patients with chronic fatigue syndrome; such patients also manifest impaired vascular health. We tested whether high-dose intermittent oral vitamin D therapy improved markers of vascular health and fatigue in patients with chronic fatigue syndrome. METHODS AND RESULTS: Parallel-group, double-blind, randomised placebo-controlled trial. Patients with chronic fatigue syndrome according to the Fukuda (1994) and Canadian (2003) criteria were randomised to receive 100,000 units oral vitamin D3 or matching placebo every 2 months for 6 months. The primary outcome was arterial stiffness measured using carotid-femoral pulse wave velocity at 6 months. Secondary outcomes included flow-mediated dilatation of the brachial artery, blood pressure, cholesterol, insulin resistance, markers of inflammation and oxidative stress, and the Piper Fatigue scale. As many as 50 participants were randomised; mean age 49 (SD 13) years, mean baseline pulse wave velocity 7.8 m/s (SD 2.3), mean baseline office blood pressure 128/78 (18/12) mmHg and mean baseline 25-hydroxyvitamin D level 46 (18) nmol/L. 25-hydroxyvitamin D levels increased by 22 nmol/L at 6 months in the treatment group relative to placebo. There was no effect of treatment on pulse wave velocity at 6 months (adjusted treatment effect 0.0 m/s; 95% CI -0.6 to 0.6; p = 0.93). No improvement was seen in other vascular and metabolic outcomes, or in the Piper Fatigue scale at 6 months (adjusted treatment effect 0.2 points; 95% CI -0.8 to 1.2; p = 0.73). CONCLUSION: High-dose oral vitamin D3 did not improve markers of vascular health or fatigue in patients with chronic fatigue syndrome. TRIAL REGISTRATION: www.controlled-trials.com, ISRCTN59927814. PMID- 25455722 TI - Pulmonary arterial hypertension-related myopathy: an overview of current data and future perspectives. AB - BACKGROUND AND AIM: Exercise intolerance is one of the key features of pulmonary arterial hypertension (PAH). The main determinants of exercise impairment include hypoxemia, reduced right ventricular output, perfusion/ventilation mismatch, and weakness of skeletal and breathing muscles. The aim of the current review is to describe the findings in the existing literature about respiratory and muscle dysfunction in PAH. Animal and clinical studies regarding both respiratory and peripheral skeletal muscles and the effect of exercise training on muscle function in PAH patients are analyzed. DATA SYNTHESIS: PAH myopathy is characterized by reduced skeletal muscle mass, reduced volitional and non volitional contractility, reduced generated force, a fiber switch from type I to type II, increased protein degradation through ubiquitin-proteasome system (UPS) activation, reduced mitochondrial functioning, and impaired activation contractility coupling. Increased inflammatory response, impaired anabolic signaling, hypoxemia, and abnormalities of mitochondrial function are involved in the pathophysiology of this process. Exercise training has been shown to improve exercise capacity, peak oxygen uptake, quality of life, and possibly clinical outcomes of PAH patients. CONCLUSIONS: The skeletal muscles of PAH patients show a wide spectrum of cellular abnormalities that finally culminate in muscle atrophy and reduced contractility. Exercise training improves muscle function and bears a positive impact on the clinical outcomes of PAH patients. PMID- 25455723 TI - Renal haemodynamics and severity of carotid atherosclerosis in hypertensive patients with and without impaired renal function. AB - BACKGROUND AND AIM: Renal resistance index (RRI), assessed by Duplex-Doppler sonography, has been classically considered as a mere expression of intrarenal vascular resistance. Recent studies, however, have showed that RRI is also influenced by upstream factors, especially arterial compliance, confirming its possible role as a marker of systemic vascular alterations. Several studies have shown that carotid intima-media thickness (cIMT) and carotid plaques (cP), assessed by ultrasonography, are documented markers of subclinical organ damage as well as expression of progressive atherosclerotic disease, and that they get worse with the progressive deterioration of renal function. The study was aimed to evaluate the relationship between RRI and severity of carotid atherosclerosis in hypertensive subjects with and without impaired renal function. METHODS AND RESULTS: The study population, including 263 hypertensive patients (30-70 years), was split into 3 groups based on cIMT and presence of cP (cIMT <= 0.9 mm and no cP; cIMT > 0.9 mm and no cP; cP). All patients were also divided into 2 subgroups (normal renal function; CKD stage I-IV). A stepwise increase in RRI corresponding to the groups of progressive severity of carotid atherosclerosis was observed (respectively 0.61 +/- 0.07, 0.65 +/- 0.06, 0.68 +/- 0.06; p < 0.001). A strong positive correlation was observed between RRI and cIMT in the whole population (r = 0.43; p < 0.001) and in the subgroups with (r = 0.42; p < 0.001) and without (r = 0.39; p < 0.001) CKD. These associations remained statistically significant even after adjustment for various confounding factors. CONCLUSION: Showing a close association between RRI and severity of carotid atherosclerosis, our results strengthen the concept that RRI is a marker of systemic vascular changes. PMID- 25455724 TI - Analytical approaches to investigating metal-containing drugs. AB - Many pharmaceuticals contain metals, either as part of the active compound or within the formulation. They are also found in related products such as dietary supplements and toiletries. Concentrations of metals in biological fluids or tissues from patients taking these agents, are measured where there may be an adverse reaction, dose-related toxicity or for therapeutic drug monitoring. Other situations, for analysis of environmental samples include occupational exposure (manufacture, administration to patients, pharmaceutical research) or in investigations of poisoning. Highly sensitive and accurate analytical methods are now available to determine the total metal concentration in a specific sample, but also to measure the specific chemical form of the drug, a metabolite of the drug, or the drug's interaction with important cellular components, such as DNA. The use of ICP-MS to measure total metal concentrations, or HPLC coupled to ICP MS for the more complex speciation measurements, will depend on the type of information that is required. For the investigation of the drug species present, other complementary analytical techniques such as electrospray mass spectrometry (LC-MS/MS) are required for a full structural elucidation of the analytes. In this current publication we highlight the measurement of two metal(loid) based pharmaceutical drugs for the treatment of cancer. One 4-(N-(S glutathionylacetyl)amino) phenylarsenoxide (GSAO) containing arsenic and under investigation for the treatment of solid tumours, and the second cis diamminedichloroplatinum (II) (cisplatin) containing platinum and widely used in the clinical setting as a front line treatment against various neplasias in particular testicular, ovarian, bladder and head and neck cancers. PMID- 25455725 TI - Hypoglycemia and risk of seizures: a retrospective cross-sectional study. AB - PURPOSE: Few studies have been dedicated to assess neurological symptoms in relations to hypoglycemia. In this study we investigated the association between different levels of hypoglycemia and the occurrence of epileptic seizures in patients without a prior diagnosis of epilepsy. METHOD: A retrospective cross sectional study. RESULTS: We identified 388 individuals from a laboratory database in Swedish regional hospital who had been found to have a glucose value of <=3.5 mM between January and December 2009. Medical records were reviewed. Hypoglycemia was defined at three different categories: 0-2 mM (40 patients), 2.1 3 mM (154 patients) and 3.1-3.5 mM (194 patients). 14 patients had disturbance of consciousness including 3 with seizures. The majority of cases had coma, a generalized tonic-clonic seizure was seen only when s-glucose dropped below 2.0 mM. Two cases with focal seizure were noted, one at s-glucose 2.0 mM, and one at s-glucose 3.3 mM. The absolute risks (95% confidence interval) for having major neurological symptoms at glucose levels of <=2.0 mM were 0.25 (0.13-0.41), 0.02 (0-0.06) at 2.1-3.0 mM and 0.01 (0-0.03) at 3.1-3.5 mM. CONCLUSION: Coma is the most common neurological symptom related to hypoglycemia. Epileptic seizures are rare and not as common as previously assumed. PMID- 25455726 TI - Characterization of acute post-craniectomy seizures in traumatically brain injured patients. AB - PURPOSE: Decompressive craniectomy (DC) is a life-saving measure for traumatic brain injury (TBI), but acute seizures following this procedure may have a devastating effect. We aim to investigate the clinical characteristics of acute post-craniectomy seizures. METHODS: For this retrospective study, we enrolled 195 patients undergoing DC for TBI. Acute post-craniectomy seizure was defined as seizures occurring within 7 days of DC. RESULTS: The incidence of acute seizure was 10.8% (21/195). 19 of 21 seizures occurred within 3 days following DC. None progressed to status epilepticus, but 16 of 21 patients (76.2%) with acute seizure developed epilepsy. There was no independent risk factor in the multivariate regression model. The mean hospital stay was 44.8 +/- 34.6 and 28.8 +/- 32.3 days for patients with and without acute seizures, respectively (p=0.035). The neurological outcome at discharge showed no inter-group difference (p=0.917). The in-hospital mortality rate was 28.6% for patients with seizures and 31.0% for patients without seizures (p=0.817). CONCLUSION: Acute seizures occur mostly within the first 3 days following DC. Neurological outcome and mortality rate at discharge does not differ between patients with or without seizures, but the duration of hospital stay is significantly longer for acute seizure patients. PMID- 25455727 TI - Increased interleukin-6 and high-sensitivity C-reactive protein levels in pediatric epilepsy patients with frequent, refractory generalized motor seizures. AB - PURPOSE: Recently, it was found that chronic inflammation contributes to the pathomechanism of diverse chronic diseases in various organs. There is accumulating evidence that inflammatory processes affect the pathophysiology of epilepsy. We investigated inflammatory markers to determine the chronic inflammatory process underlying the pathophysiology of intractable epilepsy presenting with frequent motor seizures in children. METHOD: In total, 29 patients with epilepsy and 15 children as control subjects were enrolled. Patients were divided into the DS (daily generalized motor seizures) and the IS (intermittent seizures) groups. Blood levels of serum high-sensitivity C-reactive protein (hs-CRP), plasma pentraxin 3 (PTX3), serum tumor necrosis factor (TNF) alpha, interleukin (IL)-6, and IL-beta1 were evaluated in all participants. RESULTS: Hs-CRP levels were significantly higher in the DS group (0.149 +/- 0.161 mg/dL) than in either the IS or control group (0.0156 +/- 0.0136 and 0.0253 +/- 0.0288 mg/dL, p<0.005 and p<0.05, respectively), while there was no significant difference between the IS and control groups. The IL-6 level was also significantly higher in the DS group (8.022 +/- 0.161 pg/mL) than in either the IS or the control group (7.783 +/- 0.0563 and 7.864 +/- 0.072 pg/mL; p<0.005 and p<0.05, respectively). There were no significant differences in PTX3, TNF-alpha, or IL-1beta levels. CONCLUSION: Our results suggest that daily generalized motor seizures result in elevated IL-6 levels, leading to increased CRP. A systemic inflammatory response in intractable patients with frequent generalized motor seizures may affect their prognosis. We may need therapeutic strategies, including methods to control the inflammatory process, to treat intractable epilepsy. PMID- 25455728 TI - Long-term seizure outcome for international consensus classification of hippocampal sclerosis: a survival analysis. AB - PURPOSE: Surgery is regarded as a common treatment option for patients with mesial temporal lobe epilepsy (MTLE) as a result of hippocampal sclerosis (HS). However, approximately one-third of patients with intractable epilepsy did not become seizure-free after tailored resection strategies. It would be compelling to identify predictive factors of postoperative seizure outcomes. Our aim was to assess the correlation between HS classification and long-term postoperative seizure outcome in patients with MTLE due to HS. METHODS: To investigate HS classification, semi-quantitative analysis and immunohistochemical staining of neuronal nuclei (NeuN) were performed on 100 postoperative hippocampal specimens. All patients had a 1-7 year postoperative follow-up. The postoperative seizure outcome was evaluated using International League Against Epilepsy (ILAE) outcome classification. RESULTS: Three types of HS were recognized. The highest incidence of initial precipitating injury (IPI) was noted in the HS ILAE type 1 group (53.1%). The most favorable long-term seizure outcome was also noted in the HS ILAE type 1 group. The shortest epilepsy duration was recorded in the HS ILAE type 2 group (mean epilepsy duration=6.64 +/- 5.83 years). The completely seizure free rate of patients in all groups declined with an increase in time. CONCLUSIONS: Our study for the first time demonstrated a significant correlation between HS ILAE types and long-term postoperative seizure outcome in patients with MTLE due to HS. Therefore, HS ILAE types have predictive value in long-term seizure outcome following epilepsy surgery. PMID- 25455729 TI - Orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers. AB - Nuclear receptors (NRs), a family of 48 transcriptional factors, have been studied intensively for their roles in cancer development and progression. The presence of distinctive ligand binding sites capable of interacting with small molecules has made NRs attractive targets for developing cancer therapeutics. In particular, a number of drugs have been developed over the years to target human androgen- and estrogen receptors for the treatment of prostate cancer and breast cancer. In contrast, orphan nuclear receptors (ONRs), which in many cases lack known biological functions or ligands, are still largely under investigated. This review is a summary on ONRs that have been implicated in prostate and breast cancers, specifically retinoic acid-receptor-related orphan receptors (RORs), liver X receptors (LXRs), chicken ovalbumin upstream promoter transcription factors (COUP-TFs), estrogen related receptors (ERRs), nerve growth factor 1B like receptors, and ''dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1'' (DAX1). Discovery and development of small molecules that can bind at various functional sites on these ONRs will help determine their biological functions. In addition, these molecules have the potential to act as prototypes for future drug development. Ultimately, the therapeutic value of targeting the ONRs may go well beyond prostate and breast cancers. PMID- 25455730 TI - p53 as a target for the treatment of cancer. AB - TP53 (p53) is the most frequently mutated gene in cancer, being altered in approximately 50% of human malignancies. In most, if not all, cancers lacking mutation, wild-type (WT) p53 is inactivated by interaction with cellular (MDM2/MDM4) or viral proteins, leading to its degradation. Because of its near universal alteration in cancer, p53 is an attractive target for the development of new targeted therapies for this disease. However, until recently, p53 was widely regarded as ''undruggable''. This situation has now changed, as several compounds have become available that can restore wild-type properties to mutant p53 (e.g., PRIMA-1 and PRIMA-1MET). Other compounds are available that prevent the binding of MDM2/MDM4 to WT p53, thereby blocking its degradation (e.g., nutlins). Anti-mutant p53 compounds are potentially most useful in cancers with a high prevalence of p53 mutations. These include difficult-totreat tumors such as high grade serous ovarian cancer, triple-negative breast cancer and squamous lung cancer. MDM2/4 antagonists, on the other hand, are likely to be efficacious in malignancies in which MDM2 or MDM4 is overexpressed such as sarcomas, neuroblastomas and specific childhood leukemias. Presently, early clinical trials are ongoing evaluating the anti-mutant p53 agent, PRIMA-1MET, and specific MDM2 p53 nutlin antagonists. PMID- 25455731 TI - Fabrication of SERS swab for direct detection of trace explosives in fingerprints. AB - Swab sampling is of great importance in surface contamination analysis. A cotton swab (cotton Q-tip) was successfully transformed into surface-enhanced Raman scattering (SERS) substrate (SERS Q-tip) through a bottom-up strategy, where Ag NPs were first self-assembled onto the Q-tip followed by in situ growing. The capability for direct swab detection of Raman probe Nile Blue A (NBA) and a primary explosive marker 2,4-dinitrotoluene (2,4-DNT) using the SERS Q-tip was explored. It was found that at optimum conditions, a femotogram of NBA on glass surface could be swab-detected. The lowest detectable amount for 2,4-DNT is only ~1.2 ng/cm(2) (total amount of 5 ng) on glass surface, 2 orders of magnitude more sensitive than similar surface analysis achieved with infrared technique, and comparable even with that obtained by ion mobility spectrometry-mass spectrometry. Finally, 2,4-DNT left on fingerprints was also analyzed. It was found that SERS signal of 2,4-DNT from 27th fingerprint after touching 2,4-DNT powder can still be clearly identified by swabbing with the SERS Q-tip. We believe this is the first direct SERS swabbing test of explosives on fingerprint on glass. Considering its relative long shelf life (>30 d), the SERS Q-tip may find great potential in future homeland security applications when combined with portable Raman spectrometers. PMID- 25455732 TI - Contemporary phase III clinical trial endpoints in advanced ovarian cancer: assessing the pros and cons of objective response rate, progression-free survival, and overall survival. AB - Among gynecologic cancers, ovarian cancer provides the greatest challenge because 75% to 80% of patients present with stage III/IV disease. Over the last 40 years, a series of large trials conducted by the Gynecologic Oncology Group and other cooperative groups has produced striking improvements in patient outcome; but the majority still dies of their disease. Further research in both the laboratory and the clinic is essential to continued improvement in patient management. Clinical trials, however, have become a major challenge because of issues with trial endpoints. Historically, overall survival (OS) has been regarded as the "gold standard" of endpoints. Lack of effective treatment for patients who progressed on or recurred after front-line therapy allowed trials to avoid obfuscation of OS by post-progression therapy. More recently, studies have identified over 20 agents active against ovarian cancer. Reasonable evidence shows that effective post-progression therapy with multiple lines of active agents can render the survival endpoint uninterpretable. Two other endpoints avoid this problem. The objective response rate, assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), is an accepted endpoint for accelerated approval in ovarian cancer. More importantly, progression-free survival (PFS), measured from study entry to progression of disease, avoids post-progression therapy completely. Without effective post-progression therapy (prior to 1990), data show that PFS is a surrogate for OS. Recent experience with 4 large trials of bevacizumab shows that PFS can be accurately assessed if progression is clearly defined and if timing of assessments is consistent in all study arms. Acceptance of PFS as the optimal endpoint for ovarian cancer trials by investigators and regulatory agencies is crucial to further advances in management because effective post progression therapy has rendered differences in OS virtually impossible to assess reliably. PMID- 25455734 TI - Survival differences of Asian and Caucasian epithelial ovarian cancer patients in the United States. AB - OBJECTIVE: To compare the racial differences in treatment and survival of Asian Americans and White patients with epithelial ovarian cancer. METHODS: Data were obtained from the Surveillance, Epidemiology, and End Results Program between 1988 and 2009 and analyzed using Chi-squared tests, Kaplan-Meier methods, and Cox regression analysis. RESULTS: Of the 52,260 women, 3932 (7.5%) were coded as Asian, and 48,328 (92.5%) were White. The median age of Asians at diagnosis was 56 vs. 64 years for the Whites (p<0.001). Asians were more likely to undergo primary surgery, have an earlier stage of disease, have a diagnosis of a non serous histology, and have lower grade tumors. The 5-year disease-specific survival (DSS) of Asians was higher compared to Whites (59.1% vs. 47.3%, p<0.001). On a subset analysis, Vietnamese, Filipino, Chinese, Korean, Japanese, and Asian Indian/Pakistani ethnicities had 5-year DSS of 62.1%, 61.5%, 61.0%, 59.0%, 54.6%, and 48.2%, respectively (p=0.015). On multivariate analysis, age at diagnosis, year of diagnosis, race, surgery, stage, and tumor grade were all independent prognostic factors for survival. Asians were further stratified to U.S. born versus those who were born in Asia and immigrated. Asian immigrants presented at a younger age compared to U.S. born Asians. Immigrants were found to have an improved 5-year DSS when compared to U.S. born Asians and Whites of 55%, 52%, and 48%, respectively (p<0.001). CONCLUSION: Asians were more likely to be younger, undergo primary surgery, have an earlier stage of disease, non-serous histology, lower grade tumors, and higher survival. PMID- 25455733 TI - Old drug, new trick: repurposing metformin for gynecologic cancers? AB - OBJECTIVE: There is increasing pre-clinical and clinical evidence that metformin, a commonly used diabetes medication, has a protective effect in cancer. The aim of this review is to discuss metformin's anti-cancer molecular mechanisms of action and to summarize the current literature demonstrating metformin's potential in gynecologic cancer prevention and treatment. METHODS: A PubMed search was conducted combining the keywords "metformin" with "neoplasm", "uterine neoplasms", "ovarian neoplasms", and "uterine cervical neoplasms". Studies published in English between 1994 and 2014 were included. RESULTS: Pre-clinical studies in endometrial, ovarian, and cervical cancer suggest that metformin inhibits the growth of cancer cells. The primary molecular mechanism mediating this effect appears to be the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of mammalian targets of rapamycin (mTOR). The pre clinical findings are augmented by clinical studies indicating that metformin use is associated with a reduced risk of cancer and improved survival in diabetic women with ovarian and endometrial cancers. No clinical analyses have evaluated metformin use and cervical cancer. Overall, the data showing a favorable effect of metformin is strongest for endometrial and ovarian cancer and prospective clinical testing is ongoing in these two malignancies. CONCLUSIONS: Numerous clinical studies have reported an association between metformin use by diabetic patients and improved outcomes in gynecologic cancers. In addition, pre-clinical reports have identified plausible biological mechanisms to explain the molecular mechanism of action of metformin in cancer. However, the most important question remains unanswered: Will metformin be effective against cancer in patients without diabetes? Until this question is answered with prospective clinical testing, the role of metformin in the treatment or prevention of gynecologic malignancies remains theoretical and the clinical use of metformin as a cancer therapeutic is experimental. PMID- 25455736 TI - Complete cage migration/subsidence into the adjacent vertebral body after posterior lumbar interbody fusion. AB - A variety of implant-related short and long-term complications after lumbar fusion surgery are recognized. Mid to long-term complications due to cage migration and/or cage subsidence are less frequently reported. Here, we report a patient with a complete cage migration into the superior adjacent vertebral body almost 20 years after the initial posterior lumbar interbody fusion procedure. In this patient, the cage migration/subsidence was clinically silent, but a selective decompression for adjacent segment degenerative lumbar spinal stenosis was performed. We discuss the risk factors for cage migration/subsidence in view of the current literature. PMID- 25455735 TI - Supratentorial extraventricular anaplastic ependymoma with extracranial metastasis. AB - Ependymoma is a relatively rare malignancy accounting for 2.0% of all primary central nervous system tumors in adults. Extracranial metastasis is a very uncommon complication of gliomas, especially of anaplastic ependymomas. The objective of this paper is to show that ependymomas can metastasize to soft tissue and lymph nodes as well as to share our approach to this challenge. We report a male patient with anaplastic ependymoma that recurred, metastasizing to the neck and lymph nodes. Metastatic disease was diagnosed based on clinical presentation of a palpable nodule on the right neck and diffuse cervical lymphadenopathies. A biopsy was obtained and pathology revealed anaplastic ependymoma. Whole-body fluorodeoxyglucose positron emission tomography scan showed metastatic disease in the right mastoid region with diffuse uptake in the cervical lymph nodes. Clinical and radiologic response was achieved after three chemotherapy cycles of etoposide, cisplatin, vincristine, and cyclophosphamide. This case highlights extracranial metastasis to the soft tissue as an atypical presentation of recurrent anaplastic ependymoma. Other reported instances of extracranial metastatic ependymoma with this presentation are discussed. The possible metastatic pathways of intracranial disease are discussed. It also illustrates how extracranial disease remains stable with systemic chemotherapy. PMID- 25455737 TI - Pituitary apoplexy following gonadotropin-releasing hormone agonist administration with gonadotropin-secreting pituitary adenoma. AB - Gonadotropin-releasing hormone (GnRH) agonists are widely used in hormone therapy for prostate cancer. We report a patient with pituitary apoplexy following this therapy as a rare complication and review the related literature. A 62-year-old man presented with elevated prostate specific antigen. Transrectal ultrasound guided biopsy of the prostate gland revealed adenocarcinoma. Whole-body (18)F fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed FDG-uptake in the pituitary region. MRI also demonstrated a pituitary tumor, diagnosed as an incidental non-functioning adenoma. The patient received his first dose of GnRH agonist (leuprolide 11.25mg) against prostate cancer. He complained of a severe headache 10 minutes after leuprolide administration and suffered from right third nerve palsy in the next 48 hours. MRI demonstrated a high intensity area on T1 weighted images, diagnosed as pituitary apoplexy. The patient underwent transsphenoidal surgery. Pathology revealed predominantly necrotic tissue and a gonadotropin secreting pituitary adenoma. Overall, 15 patients, including ours, have been reported with pituitary apoplexy after GnRH agonists with pathologic gonadotropin secreting adenoma. Fourteen of 15 patients were male. Pituitary apoplexy developed within 4 hours after administration of the agents in 8/15 patients. The combined data suggest that GnRH agonists have the potential to precipitate pituitary apoplexy in men with gonadotropin secreting adenoma. Therefore, prior to GnRH agonist therapy for prostate cancer, a known pituitary adenoma should be treated. Otherwise, the patients should be cautiously observed for any symptomatic change following drug administration. PMID- 25455738 TI - Rapid growth of an infectious intracranial aneurysm with catastrophic intracranial hemorrhage. AB - Infectious intracranial aneurysms are rare vascular lesions that classically occur in patients with infective endocarditis. We present a 49-year-old man with altered mental status and headache with rapid growth and rupture of an infectious intracranial aneurysm with catastrophic intracranial hemorrhage, and review issues related to open neurosurgical and endovascular interventions. PMID- 25455740 TI - Influence of inflammation on the immunological profile of adult-derived human liver mesenchymal stromal cells and stellate cells. AB - BACKGROUND AIMS: Stem cell therapy for liver diseases has recently emerged as a promising alternative to liver transplantation. Eligible cells should have an appropriate immunophenotype. The aim of the present study was to define the immunological profile of two human liver-derived mesenchymal stromal cell populations, namely, stem cells (ADHLSC) and hepatic stellate cells (HSC). METHODS: The study was conducted under normal and inflammatory conditions with the use of human bone marrow mesenchymal stromal cells (BM-MSC) as reference. RESULTS: Like BM-MSC and ADHLSC, HSC were negative for hematopoietic (CD45) and endothelial (CD34) markers but positive for stromal markers. All cell types were constitutively positive for HLA class I and negative for human leukocyte antigen (HLA) class II and co-stimulatory molecules (CD80, CD86, CD134 and CD252). Inflammation induced the expression of CD40 in all cell types, but the highest values were observed on HSCs; high CD252 expression was only observed on HSC as compared with ADHLSC and BM-MSC. The expression of various adhesion molecules (CD54, CD58, CD106 and CD166) was dissimilar in these three cell types and was differentially influenced by inflammation as well. ADHLSC and HSC constitutively expressed the immunosuppressive molecule HLA-G, whereas CD274 expression was induced by inflammation, as in the case of BM-MSC. Moreover, all cell types expressed the two major natural killer ligands CD112 and CD115. CONCLUSIONS: Toll like receptors (TLR) 1, 3, 4 and 6 messenger RNA was expressed by both cell types, whereas TLR 2, 5, 7, 9 and 10 were only expressed by ADHLSC. Inflammation increased the expression of TLR 2 and 3 by ADHLSC and HSC. Finally, both liver derived cell types were immunosuppressive because they inhibited the proliferation of mitogen-activated T cells. PMID- 25455741 TI - Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) in soils and groundwater of a U.S. metropolitan area: migration and implications for human exposure. AB - Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are emerging anthropogenic compounds that have recently become the target of global concern due to their ubiquitous presence in the environment, persistence, and bioaccumulative properties. This study was carried out to investigate the migration of PFOS and PFOA in soils and groundwater in a U.S. metropolitan area. We observed elevated levels in surface soils (median: 12.2 ng PFOS/g dw and 8.0 ng PFOA/g dw), which were much higher than the soil-screening levels for groundwater protection developed in this study. The measured levels in subsurface soils show a general increase with depth, suggesting a downward movement toward the groundwater table and a potential risk of aquifer contamination. Furthermore, concentrations of PFOS and PFOA in monitoring wells in the source zone varied insignificantly over 5 years (2009-2013), suggesting limited or no change in either the source or the magnitude of the source. The analysis also shows that natural processes of dispersion and dilution can significantly attenuate the groundwater contamination; the adsorption on aquifer solids, on the other hand, appears to have limited effects on the transport of PFOS and PFOA in the aquifer. The probabilistic exposure assessment indicates that ingestion of contaminated groundwater constitutes a much more important exposure route than ingestion of contaminated soil. Overall, the results suggest that (i) the transport of PFOS and PFOA is retarded in the vadose zone, but not in the aquifer; (ii) the groundwater contamination of PFOS and PFOA often follows their release to surface soils by years, if not decades; and (iii) the aquifer can be a major source of exposure for communities living near point sources. PMID- 25455739 TI - A reproducible immunopotency assay to measure mesenchymal stromal cell-mediated T cell suppression. AB - BACKGROUND AIMS: The T-cell suppressive property of bone marrow-derived mesenchymal stromal cells (MSCs) has been considered a major mode of action and basis for their utilization in a number of human clinical trials. However, there is no well-established reproducible assay to measure MSC-mediated T-cell suppression. METHODS: At the University of Wisconsin-Madison Production Assistance for Cellular Therapy (PACT) Center, we developed an in vitro quality control T-cell suppression immunopotency assay (IPA) that uses anti-CD3 and anti CD28 antibodies to stimulate T-cell proliferation. We measured MSC-induced suppression of CD4+ T-cell proliferation at various effector-to-target cell ratios with the use of defined peripheral blood mononuclear cells and in parallel compared with a reference standard MSC product. We calculated an IPA value for suppression of CD4+ T cells for each MSC product. RESULTS: Eleven MSC products generated at three independent PACT centers were evaluated for cell surface phenotypic markers and T-cell suppressive properties. Flow cytometry results demonstrated typical MSC cell surface marker profiles. There was significant variability in the level of suppression of T-cell proliferation, with immunopotency assay values ranging from 27% to 88%. However, MSC suppression did not correlate with human leukocyte antigen-DR expression. CONCLUSIONS: We have developed a reproducible immunopotency assay to measure allogeneic MSC-mediated suppression of CD4+ T cells. Additional studies may be warranted to determine how these in vitro assay results may correlate with other immunomodulatory properties of MSCs, in addition to evaluating the ability of this assay to predict in vivo efficacy. PMID- 25455742 TI - Study of the neural dynamics for understanding communication in terms of complex hetero systems. AB - The purpose of the research project was to establish a new research area named "neural information science for communication" by elucidating its neural mechanism. The research was performed in collaboration with applied mathematicians in complex-systems science and experimental researchers in neuroscience. The project included measurements of brain activity during communication with or without languages and analyses performed with the help of extended theories for dynamical systems and stochastic systems. The communication paradigm was extended to the interactions between human and human, human and animal, human and robot, human and materials, and even animal and animal. PMID- 25455743 TI - The role of shared neural activations, mirror neurons, and morality in empathy--a critical comment. AB - In the last decade, the phenomenon of empathy has received widespread attention by the field of social neuroscience. This has provided fresh insights for theoretical models of empathy, and substantially influenced the academic and public conceptions about this complex social skill. The present paper highlights three key issues which are often linked to empathy, but which at the same time might obscure our understanding of it. These issues are: (1) shared neural activations and whether these can be interpreted as evidence for simulation accounts of empathy; (2) the causal link of empathy to our presumed mirror neuron system; and (3) the question whether increasing empathy will result in better moral decisions and behaviors. The aim of our review is to provide the basis for critically evaluating our current understanding of empathy, and its public reception, and to inspire new research directions. PMID- 25455744 TI - Functional relevance of the precuneus in verbal politeness. AB - Non-competitive and non-threatening aspects of social hierarchy, such as politeness, are universal among human cultures, and might have evolved from ritualized submission in primates; however, these behaviors have rarely been studied. Honorific language is a type of polite linguistic communication that plays an important role in human social interactions ranging from everyday conversation to international diplomacy. Here, functional magnetic resonance imaging (fMRI) revealed selective precuneus activation during a verbal politeness judgment task, but not other linguistic-judgment or social-status recognition tasks. The magnitude of the activation was correlated with the task performance. Functional suppression of the activation using cathodal transcranial direct current stimulation reduced performance in the politeness task. These results suggest that the precuneus is an essential hub of the verbal politeness judgment. PMID- 25455746 TI - Short-course treatment with ceftriaxone for leptospirosis: a retrospective study in a single center in Eastern France. AB - Short-course (less than 7 days) antibiotic treatments have been rarely assessed in the management of leptospirosis. We analyzed the charts of patients hospitalized with confirmed and probable leptospirosis in a teaching hospital between 1994 and 2012. Of 89 patients with confirmed or probable leptospirosis, 21 patients (11 confirmed, 10 probable - 14 uncomplicated and 7 severe forms) admitted between 2001 and 2012 received ceftriaxone (1-2 g daily) for less than 7 days. Apyrexia was obtained within 2 days of treatment in all patients and no relapse was observed. These data support the hypothesis that short-course treatments of 3-6 days with ceftriaxone (1-2 g per day) may be an option in the treatment of uncomplicated and severe forms of leptospirosis responding quickly to therapy. This hypothesis deserves being confirmed in further clinical studies. PMID- 25455747 TI - Loop-mediated isothermal amplification with the Procedure for Ultra Rapid Extraction kit for the diagnosis of pneumocystis pneumonia. AB - Loop-mediated isothermal amplification (LAMP) is an innovative molecular technique requiring only a heating device and isothermal conditions to amplify a specific target gene. The results of current microscopic diagnostic tools for pneumocystis pneumonia are not sufficiently consistent for detecting infection with a low-density of Pneumocystis jirovecii. Although polymerase chain reaction (PCR) is highly sensitive, it is not suitable for resource-limited facilities. LAMP is a potential diagnostic replacement for PCR in such settings but a critical disadvantage of DNA extraction was still remained. Therefore, we employed the Procedure for Ultra Rapid Extraction (PURE) kit, which uses a porous material, to isolate the DNA from clinical samples in a simple way in combination with previously reported LAMP procedure for diagnosing PCP. The detection limit of the PURE-LAMP method applied to artificial bronchoalveolar lavage fluid samples was 100 copies/tube, even with the use of massive blood-contaminated solutions. In addition, we concluded the diagnostic procedure within 1 h without the need for additional equipment. PURE-LAMP coupled with suitable primers for specific pathogens has good potential for diagnosing various infectious diseases. PMID- 25455748 TI - Designing multiplex PCR system of Campylobacter jejuni for efficient typing by improving monoplex PCR binary typing method. AB - Campylobacter jejuni is responsible for the majority of Campylobacter infections. As the molecular epidemiological study of outbreaks, pulsed-field gel electrophoresis (PFGE) is performed in general. But PFGE has several problems. PCR binary typing (P-BIT) method is a typing method for Campylobacter spp. that was recently developed, and was reported to have a similar discriminatory power and stability to those of PFGE. We modified the P-BIT method from 18 monoplex PCRs to two multiplex PCR systems (mP-BIT). The same results were obtained from monoplex PCRs using original primers and multiplex PCR in the representative isolates. The mP-BIT can analyze 48 strains at a time by using 96-well PCR systems and can identify C. jejuni because mP-BIT includes C. jejuni marker. The typing of the isolates by the mP-BIT and PFGE demonstrated generally concordant results and the mP-BIT method (D = 0.980) has a similar discriminatory power to that of PFGE with SmaI digest (D = 0.975) or KpnI digest (D = 0.987) as with original article. The mP-BIT method is quick, simple and easy, and comes to be able to perform it at low cost by having become a multiplex PCR system. Therefore, the mP-BIT method with two multiplex PCR systems has high potential for a rapid first-line surveillance typing assay of C. jejuni and can be used for routine surveillance and outbreak investigations of C. jejuni in the future. PMID- 25455749 TI - Human recombinant apyrase therapy protects against canine pulmonary ischemia reperfusion injury. AB - BACKGROUND: There is accumulating evidence that extracellular adenosine triphosphate (eATP) promotes many of the underlying mechanisms that exacerbate acute lung injury. However, much of these data are from inbred rodent models, indicating the need for further investigation in higher vertebrates to better establish clinical relevance. To this end we evaluated a human recombinant apyrase therapy in a canine warm pulmonary ischemia-reperfusion injury (IRI) model and measured eATP levels in human lung recipients with or without primary lung graft dysfunction (PGD). METHODS: Warm ischemia was induced for 90 minutes in the left lung of 14 mongrel dogs. Seven minutes after reperfusion, the apyrase APT102 (1 mg/kg, n = 7) or saline vehicle (n = 7) was injected into the pulmonary artery. Arterial blood gases were obtained every 30 minutes up to 180 minutes after reperfusion. Bronchioalveolar lavage fluid (BALF) was analyzed for eATP concentration, cellularity, and inflammatory mediator accumulation. Thirty bilateral human lung transplant recipients were graded for immediate early PGD and assessed for BALF eATP levels. RESULTS: APT102-treated dogs had progressively better lung function and less pulmonary edema during the 3-hour reperfusion period compared with vehicle-treated controls. Protection from IRI was observed, with lower BALF eATP levels, fewer airway leukocytes, and blunted inflammatory mediator expression. Human lung recipients with moderate to severe PGD had significantly higher eATP levels compared with recipients without this injury. CONCLUSIONS: Extracellular ATP accumulates in acutely injured canine and human lungs. Strategies that target eATP reduction may help protect lung recipients from IRI. PMID- 25455750 TI - Risk factors for invasive fungal disease in heart transplant recipients. AB - BACKGROUND: Heart transplant (HT) recipients are at risk for invasive fungal disease (IFD), a morbid and potentially fatal complication. METHODS: We performed a retrospective cohort study to evaluate the incidence and risk factors for IFD in HT recipients from 1995 to 2012 at a single center. IFD cases were classified as proven or probable IFD according to current consensus definitions of the European Organization for Research and Treatment of Cancer/Mycoses Study Group. We calculated IFD incidence rates and used Cox proportional hazards models to determine IFD risk factors. RESULTS: Three hundred sixty patients underwent HT during the study period. The most common indications were dilated (39%) and ischemic (37%) cardiomyopathy. There were 23 (6.4%) cases of proven (21) or probable (2) IFD, for a cumulative incidence rate of 1.23 per 100 person-years (95% CI 0.78 to 1.84). Candida (11) and Aspergillus (5) were the most common etiologic fungi. Thirteen cases (56%) occurred within 3 months of HT, with a 3 month incidence of 3.8% (95% CI 2.2 to 6.4). Delayed chest closure (HR 3.3, 95% CI 1.4 to 7.6, p = 0.01) and the addition of OKT3, anti-thymocyte globulin or daclizumab to standard corticosteroid induction therapy (HR 2.7, 95% CI 1.1 to 6.2, p = 0.02) were independently associated with an increased risk of IFD. CONCLUSIONS: IFD incidence was greatest within the first 3 months post-HT, largely reflecting early surgical-site and nosocomial Candida and Aspergillus infections. Patients receiving additional induction immunosuppression or delayed chest closure were at increased risk for IFD. Peri-transplant anti-fungal prophylaxis should be considered in this subset of HT recipients. PMID- 25455751 TI - Mechanical circulatory support as a bridge to cardiac retransplantation: a single center experience. AB - BACKGROUND: Cardiac retransplantation is increasing in frequency. Recent data have shown that retransplantation outcomes are now comparable with primary transplantation. The use of mechanical circulatory support (MCS) as a bridge to retransplantation has similar post-retransplant outcomes to those without MCS, but the success of bridging patients to retransplant with MCS has not been well studied. METHODS: From January 2000 to February 2014 at Columbia University Medical Center, 84 patients were listed for retransplantation. Of this cohort, 48 patients underwent retransplantation, 15 were bridged with MCS, 24 died, and 6 clinically improved. A retrospective analysis was performed examining waiting list time, survival to retransplantation, and survival after retransplant. The effect of the United Network of Organ Sharing (UNOS) allocation policy change in 2006 on waiting list time and MCS use was also investigated. RESULTS: Of 48 patients who underwent retransplantation, 11 were bridged with MCS. Overall 1 year survival to retransplantation was 81.3%. There was no significant difference in waiting list survival (p = 0.71) in those with and without MCS. Death from cardiac arrest or multiorgan failure with infection was more frequent in the medically managed group (p = 0.002). After the UNOS 2006 allocation policy change, waiting list time (599 +/- 936 days in Era 1 vs 526 +/- 498 days in Era 2, p = 0.65) and waiting list survival (p = 0.22) between eras were comparable, but there was a trend toward greater use of MCS (p = 0.13). Survival after retransplant was acceptable. CONCLUSION: The use of MCS as a bridge to cardiac retransplantation is a reasonable strategy. PMID- 25455752 TI - Effect of infection with transmissible strains of Pseudomonas aeruginosa on lung transplantation outcomes in patients with cystic fibrosis. AB - BACKGROUND: Compared with patients infected with unique strains of Pseudomonas aeruginosa, patients with cystic fibrosis who are infected with transmissible strains of P aeruginosa, such as the Liverpool epidemic strain, have a 3-fold greater risk of death or lung transplant. We aimed to determine if pre-operative infection with transmissible strains of P aeruginosa was similarly associated with poor health outcomes after lung transplant. METHODS: We had prospectively identified and characterized endobronchial infections in 446 adult cystic fibrosis patients in Ontario, Canada, from September 2005 until December 2009. P aeruginosa isolated from sputum taken at 3-month intervals was genotyped, and patients were characterized as being infected with 1 of 2 transmissible strains or, alternatively, with unique strains of P aeruginosa. We monitored patients until 2013 and collected data on patients from the cohort who subsequently received a lung transplant. The primary outcome was survival after transplantation. RESULTS: We identified 56 lung transplant recipients from the cohort of 446 patients, including 18 infected with transmissible strains of P aeruginosa and 26 infected with unique P aeruginosa strains. Post-transplant survival at 3 years was 86% in the transmissible group and 84% in the unique group (p = 0.65). No significant differences between groups were found regarding bronchiolitis obliterans-free survival, the frequency of acute rejection episodes, the frequency of post-transplant respiratory tract infection, or the rate of change of post-transplant forced expiratory volume in 1 second. CONCLUSIONS: Pre-operative infection with transmissible strains of P aeruginosa is not associated with poorer post-transplant outcomes compared with patients infected with unique strains of P aeruginosa. PMID- 25455754 TI - Spanish Cardiac Catheterization and Coronary Intervention Registry. 23rd official report of the Spanish Society of Cardiology Working Group on Cardiac Catheterization and Interventional Cardiology (1990-2013). AB - INTRODUCTION AND OBJECTIVES: The Working Group on Cardiac Catheterization and Interventional Cardiology presents its yearly report on the data from the registry of the activity in Spain corresponding to 2013. METHODS: The centers introduce their data online voluntarily and the information is analyzed by the Steering Committee of the Working Group on Cardiac Catheterization. RESULTS: In 2013, 104 hospitals sent their data (72 public centers and 32 private). In all, 136 715 diagnostic studies were performed (120 358 coronary angiograms), with a slight decrease with respect to 2012, a reduction that was also observed in the rate, which was 2944 diagnostic studies per million population. A total of 65 912 interventional procedures were carried out during a phase of stability, for a rate of 1419 interventions per million population. Other techniques included the implantation of 99 417 stents and 1384 biodegradable intracoronary devices (64% of them drug-eluting devices). There were 18 337 procedures in acute myocardial infarction, for an increase of 7% with respect to 2012 and representing 27.8% of all the percutaneous coronary interventions. Radial access was the approach used in 71% of the diagnostic procedures and in 65% of the interventional procedures. The performance of renal denervation has nearly doubled with respect to 2012. For the first time, more than 1000 transcatheter aortic valve implantation procedures were carried out in 1 year, although the frequency increased only slightly (23%). CONCLUSIONS: There continued to be a slight increase in the activity in cardiac catheterization in association with ST-segment elevation myocardial infarction, whereas, with the exception of recently introduced, highly specific procedures, the use of the remainder of the procedures, among them transcatheter aortic valve implantation, leveled off. PMID- 25455753 TI - 5-Aminolevulinic acid with ferrous iron induces permanent cardiac allograft acceptance in mice via induction of regulatory cells. AB - BACKGROUND: 5-Aminolevulinic acid (5-ALA), a precursor of heme biosynthesis, plays a fundamentally important role in aerobic energy metabolism. Heme oxygenase (HO)-1 cleaves heme to form biliverdin, carbon monoxide (CO) and iron (Fe(2+)). The anti-inflammatory properties of biliverdin and CO help to alleviate ischemia/reperfusion injury as well as acute and/or chronic allograft rejection. We investigated whether 5-ALA and Fe(2+) exerts salutary effects in the setting of organ transplantation. METHODS: An in vitro mixed-lymphocyte reaction (MLR) assay and cardiac allotransplantation model (CBA to C57BL/10) were used to evaluate the effects of 5-ALA and Fe(2+) on transplantation tolerance. RESULTS: Treatment with 5-ALA and sodium ferrous citrate (SFC) resulted in permanent acceptance in the murine cardiac allografts in a dose-, SFC- and HO-1-dependent manner. The number of graft-infiltrating CD8 T cells was lower and the survival response of recipient spleen T cells to donor-type alloantigens was less compared with control recipients; however, numbers of both regulatory T cells and dendritic cells were significantly increased in 5-ALA/SFC-treated recipients. CONCLUSIONS: Our findings show that 5-ALA/SFC inhibits T-cell proliferation in response to alloantigens and an increased number of regulatory cells, resulting in permanent cardiac allograft acceptance in mice. These findings highlight the major roles of CO and/or HO-1 in inducing tolerance and suggest that 5-ALA/SFC may be a clinically effective treatment for allograft rejection. PMID- 25455755 TI - Spanish Pacemaker Registry. Eleventh official report of the Spanish Society of Cardiology Working Group on Cardiac Pacing (2013). AB - INTRODUCTION AND OBJECTIVES: The present report summarizes the analysis of pacemaker implantation and replacement data sent to the Spanish Pacemaker Registry in 2013, with specific discussion of pacing mode selection. METHODS: This study was based on information obtained from the European Pacemaker Patient Identification Card. RESULTS: Information was received on 118 hospital centers, with a total of 12 831 cards, or 35% of the estimated activity. There were 755 and 58.1 conventional and resynchronization devices per million population, respectively. The mean age of patients receiving an implant was 77.4 years. Men received 59.5% of first implantations and 56.6% of replacements. Most implantations and generator replacements were performed in patients older than 80 years. Almost all endocardial leads used were bipolar, and 78.7% of leads had an active fixation mechanism. Despite being in sinus rhythm, 24% of patients with sick sinus syndrome and 25% of those with atrioventricular block were paced in VVIR mode. CONCLUSIONS: The use of pacemaker generators and resynchronization devices per million population continues to increase in Spain. Active fixation mechanisms predominate for leads but just 20% of leads are compatible with magnetic resonance imaging. The factors influencing the correct selection of pacing mode were age and, to a lesser extent, the type of atrioventricular block, and sex. Implementation of home monitoring of pacemakers remains low. PMID- 25455756 TI - Spanish Heart Transplantation Registry. 25th official report of the Spanish Society of Cardiology Working Group on Heart Failure and Heart Transplantation (1984-2013). AB - INTRODUCTION AND OBJECTIVES: The present article reports the characteristics and outcome of heart transplantation in Spain since it was first performed in May 1984. METHODS: We provide a descriptive analysis of the characteristics of the recipients, the donors, the surgical procedure, and results of the heart transplantations performed in Spain until 31 December 2013. RESULTS: During 2013, a total of 248 transplantation procedures were carried out, bringing the time series to a total of 7023 transplantations. The temporal analysis confirms a significant deterioration in the clinical profile of the recipients (higher percentage of older patients, severe renal failure, insulin-dependent diabetes mellitus, previous heart surgery, mechanical ventilation), of the donors (higher proportion of older donors and greater weight mismatch), and of the procedure (higher percentage of emergency transplantations which, in 2013, reached 49%, and with ischemia times > 240min). There was a marked increase in the use of circulatory assist devices prior to transplantation which, in 2013, were employed in 25.2% of all the patients. The survivals at 1, 5, 10, and 15 years were 76%, 65%, 52%, and 37%, respectively, and have remained stable since 1995. CONCLUSIONS: Heart transplantation activity in Spain remains stable in recent years, with around 250 procedures a year. Despite the clear deterioration in the clinical characteristics of the donors and recipients, and lengthening of the operative times, the results in terms of mortality continue to be comparable to those reported in our neighboring countries, and a growing use of circulatory assist devices prior to transplantation is confirmed. PMID- 25455757 TI - Continuing medical education: a priority in Revista Espanola de Cardiologia. PMID- 25455758 TI - Transcribing through the nucleosome. AB - The packaging of DNA into chromatin limits sequence accessibility, which affects all DNA-based processes including transcription. Indeed, the fundamental unit of chromatin, the nucleosome, presents a strong barrier to transcription in vitro. Since the discovery of the nucleosome barrier, the question of how the RNA polymerase II (Pol II) machinery overcomes nucleosomes at high speeds in vivo has remained a central question in chromatin biology. In this review, we discuss the nature of the nucleosomal barrier to transcription and highlight recent findings that provide new insights into the mechanism of transcription through nucleosomes. PMID- 25455759 TI - A new kind of cell suicide: mechanisms and functions of programmed necrosis. AB - Classically, there are two major forms of cell death: necrosis, an unregulated digestion of cellular components; and apoptosis, a programmed mechanism that is promoted by caspases. However, another form of cell death has recently been identified that is inhibited by caspases, and yet occurs through a regulated mechanism, termed programmed necrosis or necroptosis. The biochemical basis of this program has begun to emerge, with the discovery of the receptor-interacting kinase RIP3 and its substrate, the pseudokinase mixed lineage kinase domain-like protein (MLKL), as core components. Furthermore, animal models have revealed significant functions for RIP3/MLKL-mediated necrotic cell death in immune responses against microbial infection and in the etiology of diseases involving tissue damage. This review discusses recent advances in our understanding of the mechanistic details and physiological functions of programmed necrosis. PMID- 25455760 TI - Challenges of managing medications for older people at transition points of care. AB - In clinical practice, pharmacists play a very important role in identifying and correcting medication discrepancies as older patients move across transition points of care. With increasing complexity of health care needs of older people, these discrepancies are likely to increase. The major concern with identifying and correcting medication discrepancies is that medication reconciliation is considered a retrospective problem--that is, dealing with medication discrepancies after they have occurred. It is argued here that a more proactive stance should be taken where doctors, nurses and pharmacists collectively work together to prevent medication discrepancies from happening in the first place. Improved involvement of patients and family members will help to facilitate better management of medications across transition points of care. Efficient use of information technology aids, such as electronic medication reconciliation tools, should also assist with organizational systems problems associated with the working culture, heavy workloads, and staff and skill mix of health professionals. PMID- 25455761 TI - [Paradoxical transtentorial herniation, extreme trephined syndrome sign: A case report]. AB - The current increasing use of decompressive craniectomy carries the implicit appearance of complications due to alterations in both intracranial pressure and in the hydrostatic-hemodynamic equilibrium. Paradoxical transtentorial herniation represents a rare manifestation, included in "trephine syndrome", extremely critical but with relatively simple treatment. We present the case of a 56-year old woman with no interesting medical history, who, after an olfactory groove meningioma surgery, presented a haemorrhage located in the surgical area with an important oedema. The patient required a second emergency surgery without any chance of conserving the cranial vault. During the post-operational period, great neurological deterioration in orthostatic position was noticed, which resolved spontaneously in decubitus. This deficit was resolved with bone replacement afterwards. We discuss possible predisposing factors and aetiologies of this pathology. PMID- 25455762 TI - [Patients with subarachnoid haemorrhage in poor grade neurological status: Study of prognostic factors]. AB - OBJECTIVE: To evaluate and predict factors influencing prognosis and/or clinical outcome at 6 months in patients with spontaneous subarachnoid haemorrhage, World Federation of Neurosurgical Societies (WFNS) grades iv and v. MATERIAL AND METHODS: This was a retrospective study of a consecutive series of 394 patients admitted to our hospital with clinical and radiological diagnosis of spontaneous subarachnoid haemorrhage, from 1 January 1999 to 30 June 2009. We selected 121 patients who met the criteria of being in WFNS grades iv or v before treatment; 3 patients were excluded due to loss of tracking. The outcome variable was assessed 6 months after the event using the Glasgow Outcome Scale. A P value<.05 was considered statistically significant. RESULTS: One hundred and twenty-one patients were included in the statistical analysis. The average age of the patients in the series was 54 years (14-92). Patients who had a mean Glasgow Coma Scale lower than 7 points (P<.0001), those who were grade v (P<.0001) in the pre treatment WFNS scale and those with pupillary disorder (P=.002) had a worse clinical outcome. Likewise, those with associated intraparenchymal hematoma (P=.020) and those not receiving any treatment (P=.020) were also associated with a poor clinical outcome. These results were statistically significant. CONCLUSIONS: Patients admitted with a WFNS grade v and/or presenting pupil disorder and/or intraparenchymal hematoma were associated with worse clinical outcomes. PMID- 25455763 TI - [Spinal cord stimulation and failed back surgery syndrome. Clinical results with laminectomy electrodes]. AB - INTRODUCTION: Spinal cord stimulation is a widely-accepted technique in the treatment of back pain resulting from failed back surgery. Classically, stimulation has been carried out with percutaneous electrodes implanted under local anaesthesia and sedation. However, the ease of migration and the difficulty of reproducing electrical paresthesias in large areas with such electrodes has led to increasing use of surgical plate leads, which have the disadvantage of the need for general anaesthesia and a laminectomy for implantation. OBJECTIVES: Our objective was to report the clinical results, technical details, advantages and benefits of laminectomy lead placement under epidural anaesthesia in failed back surgery syndrome cases. MATERIAL AND METHODS: Spinal cord stimulation was performed in a total of 119 patients (52 men and 67 women), aged between 31 and 73 years (average, 47.3). Epidural anaesthesia was induced with ropivacaine. In all cases we inserted the octapolar or 16-polar lead in the epidural space through a small laminectomy. The final position of the leads was the vertebral level that provided coverage of the patient's pain. The electrodes were connected at dual-channel or rechargeable pulse generators. RESULTS: After a mean follow-up of 4.7 years, the results in terms of improvement of the previous painful situation was satisfactory, with an analgesia level of 58% of axial pain and 60% of radicular pain in more than 70% of cases. None of the patients said that the surgery stage was painful or unpleasant. No serious complications were included in the group, but in 6 cases the system had to be explanted because of ineffectiveness or intolerance of long-term neurostimulation. CONCLUSIONS: This study, with a significant number of patients, used epidural anaesthesia for spinal cord stimulation of lead implants by laminectomy in failed back surgery syndromes. The technique seems to be safe and effective. PMID- 25455764 TI - [Description of functional outcome in pediatric traumatic brain injury after a comprehensive rehabilitation programme]. AB - INTRODUCTION: Traumatic brain injury is the leading cause of mortality and disability in children in the developed countries. Despite the plasticity of an infant's brain, injury at this early stage can lead to important sequelae that will affect functioning later in life. The understanding of the functional profile after a traumatic brain injury is important for planning interventions and treatment resources once the preventive phase has failed. MATERIAL AND METHODS: This was a retrospective study of the patients admitted in a neurorehabilitation unit with the aim of describing their functioning after an intensive rehabilitation programme. RESULTS: A total of 65 records of children with a mean age of 10.38 years that had been admitted to a rehabilitation programme were reviewed. Of the traumatic brain injuries, 89.2% were severe and 78.4% were secondary to traffic accidents. The mean length of stay was 79.35 days. At discharge, 72% were able to walk, but 76.9% showed some cognitive impairment. Despite good physical recovery, only 29.2% of the children were able to return to school. Permanence of deficits made 21.5% of the children unable to return to any type of education. CONCLUSIONS: The population under study was characterised by a good clinical outcome as well as good physical improvement. Nevertheless, cognitive problems were notable and were the main factor responsible for the changes in school attendance and return to normal life. PMID- 25455765 TI - Hepatocellular carcinoma dually-targeted nanoparticles for reduction triggered intracellular delivery of doxorubicin. AB - Hepatocellular carcinoma (HCC) dual targeted stimuli responsive nanoparticles (NPs) for intracellular delivery of doxorubicin (DOX) were developed based on a reduction cleavable hyaluronic acid-glycyrrhetinic acid conjugate (HA-Cyst-GA). HA-Cyst-GA conjugate readily formed NPs in aqueous milieu and exhibited a high drug loading capacity (33.9%). The NPs redox responsiveness evaluation showed a tendency to lose their structural integrity in response to a reductive stimulus while remaining stable at physiological conditions, and that drug release was dramatically accelerated in presence of an intracellular level of glutathione. Moreover, cellular uptake studies highlighted the affinity of hepatoma cells (HepG2) toward the NPs as compared to breast cancer cells (MDA-MB-231). HA-Cyst GA DOX-NPs displayed an increased cytotoxic potency over their non-responsive counterparts and free DOX with IC50 of 5.75, 9.33 and 10.23MUg/mL, respectively. CLSM observations showed that HA-Cyst-GA DOX-NPs mediated a faster intracellular release and nuclear delivery of DOX as compared to the insensitive control. In vivo imaging study performed on H22 tumor bearing mice revealed a selective accumulation of DiR labeled NPs in the tumor and liver upon systemic administration. The antitumor efficacy was evaluated in HepG2 tumor xenograft model. Overall HA-Cyst-GA NPs appear as a potential HCC targeted intracellular delivery platform for DOX. PMID- 25455766 TI - Investigation of a nanosuspension stabilized by Soluplus(r) to improve bioavailability. AB - The purpose of this work was to explore the feasibility of using Soluplus((r)) in preparing a fenofibrate (FBT) nanosuspension adopting wet media milling technology. HPMC and Soluplus((r)) were used as stabilizers to prepare FBT/HPMC nanosuspension (F1) and FBT/Soluplus((r)) nanosuspension (F2), respectively. The nanosuspensions were subjected to evaluations involving particle size, dissolution, preliminary stability and pharmacokinetic behavior. A marked reduction in particle size was achieved by nanosuspensions (from 17.55 MUm to 642 nm (F1) and 344 nm (F2)). The nanosuspensions displayed almost complete dissolution while percentages of 30% and 13% were obtained by physical mixtures and coarse FBT separately. Soluplus((r)) could stabilize the nanosuspension more effectively due to a weaker Ostwald ripening effect resulting from a slower diffusion of micelles formed by Soluplus((r)) entrapping dissolved FBT than FBT exposed to pure water directly. In the in vivo evaluation, larger AUC0-72h and Cmax, and shorter Tmax were obtained by the nanosuspensions. Significant differences were observed between the physical mixtures. The phenomenon of double peaks was present in this study. The major factor may be the multiple absorption sites of FBT. The current work indicated that Soluplus((r)) is well suited for preparation of a nanosuspension with good stability and improved dissolution and bioavailability. PMID- 25455767 TI - The high water solubility of inclusion complex of taxifolin-gamma-CD prepared and characterized by the emulsion solvent evaporation and the freeze drying combination method. AB - This study selected gamma-cyclodextrin (gamma-CD) as the inclusion material and prepared inclusion complex of taxifolin-gamma-CD by the emulsion solvent evaporation and the freeze drying combination method to achieve the improvement of the solubility and oral bioavailability of taxifolin. We selected ethyl acetate as the oil phase, deionized water as the water phase. The taxifolin emulsion was prepared using adjustable speed homogenate machine in the process of this experiment, whose particle size was related to the concentration of taxifolin solution, the volume ratio of water phase to oil phase, the speed and time of homogenate. We knew through the single-factor test that, the optimum conditions were: the concentration of taxifolin solution was 40 mg/ml, the volume ratio of water phase to oil phase was 1.5, the speed of homogenate was 5,000 rpm, the homogenate time was 11 min. Taxifolin emulsion with a MPS of 142.5 nm was obtained under the optimum conditions, then the high-concentration taxifolin solution (3mg/ml) was obtained by the rotary evaporation process. Finally, the inclusion complex of taxifolin-gamma-CD was prepared by vacuum freeze-dry. The characteristics of the inclusion complex of taxifolin-gamma-CD were analyzed using SEM, FTIR, XRD, DSC, and TG. The FTIR results analyzed the interaction of taxifolin and gamma-CD and determined the molecular structure of the inclusion complex of taxifolin-gamma-CD. The analysis results of XRD, DSC and TG indicated that the inclusion complex of taxifolin-gamma-CD was obtained and showed significantly different characteristics with taxifolin. In addition, dissolving capability test, antioxidant capacity test, solvent residue test were also carried out. The experimental datas showed that the solubility of inclusion complex of taxifolin-gamma-CD at 25 degrees C and 37 degrees C were about 18.5 times and 19.8 times of raw taxifolin, the dissolution rate of inclusion complex of taxifolin-gamma-CD were about 2.84 times of raw taxifolin, the bioavailability of inclusion complex of taxifolin-gamma-CD increased 3.72 times compared with raw taxifolin, and the antioxidant capacity of inclusion complex of taxifolin-gamma CD was also superior to raw taxifolin. Furthermore, the amounts of residual solvent of the inclusion complex of taxifolin-gamma-CD were suitable for pharmaceutical use. These results suggested that inclusion complex of taxifolin gamma-CD may have potential value to become a new oral taxifolin formulation with high solubility. PMID- 25455768 TI - Preparation, characterization and in vivo evaluation of formulation of repaglinide with hydroxypropyl-beta-cyclodextrin. AB - The therapeutic efficacy of repaglinide (RPG) is limited by the low and variable oral bioavailability owing to its limited aqueous solubility. In our present study, the development and evaluation of inclusion complex applying hydroxypropyl beta-cyclodextrin (HP-beta-CD) for the improvement of oral bioavailability of repaglinide was investigated systematically. The inclusion complex of repaglinide was prepared by lyophilization technique using drug: hydroxypropyl-beta cyclodextrin (1:15 mole). The prepared complexation was characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), NMR spectroscopy and evaluated by dissolution studies. The (1)H NMR was used in the structure study of repaglinide-HP-beta-CD (RPG-HP-beta-CD) inclusion complex. The analysis proved the higher probability of the repaglinide A-ring into the narrow rim of the beta-cyclodextrin molecule. All the characterization information confirmed the formation of RPG-HP-beta-CD inclusion complex. The in vivo pharmacokinetics of RPG-HP-beta-CD and their physical mixture were performed in beagle dogs. For the first time, a simple, rapid, and sensitive LC-MS/MS method for determination of RPG in beagle dog plasma was developed. The Cmax and AUC0-t of RPG-HP-beta-CD were 2.5 and 2 times higher than that of the physical mixture. These results suggested that the interaction of repaglinide with HP-beta-CD could notably improve the dissolution rate and bioavailability of repaglinide comparing with its physical mixture. PMID- 25455769 TI - In vivo SPECT imaging of [123I]-labeled pentamidine pro-drugs for the treatment of human African trypanosomiasis, pharmacokinetics, and bioavailability studies in rats. AB - Pentamidine is an effective antiparasitic agent and approved drug for the treatment of African trypanosomiasis (sleeping sickness). However, pentamidine suffers from poor orally bioavailability and lacks central nervous system (CNS) delivery. Therefore its applicability is limited to intravenous or intramuscular treatment of the first stage of the African trypanosomiasis. For this reason, several new pentamidine pro-drugs have been developed with the aim of providing improved orally availability and CNS penetration. AIM: this work aims to measure and to compare the distribution, bioavailability, and ability to cross the blood brain barrier of [(123)I]-labeled pentamidine and its pro-drugs, N,N' dihydroxypentamidine and N,N'-bis(succinyloxy) pentamidine, using SPECT (single photon emission computed tomography) after intravenously and per orally administration in rats. METHODS: a total of 60 male Sprague Dawley rats were examined. Each [(123)I]-labeled substance (n=3) was applied to 12 rats (n=6 i.v. and n=6 orally). In two additional test series both [(123)I]iodopentamidine (n=6) and N,N'-bis(succinyloxy)-[(123)I]iodopentamidine (n=6) were administered orally together with the non-radioactive homologues. To evaluate the in vivo stability of the labeled compounds, [(123)I]NaI solution was administered intravenously (n=6) and orally (n=6). In vivo SPECT images were acquired after 30 min, 4h, and 24h and blood samples were taken over 24h. The SPECT images were fusioned with previously acquired magnetic resonance images. After the last SPECT the rats were perfused, sacrificed and the organ gamma-radiation levels were determined with a gamma-counter. Analysis and quantification of the reconstructed SPECT images was performed using the region of interest technique. RESULTS AND CONCLUSION: the data showed a highly improved oral bioavailability of the [(123)I]-labeled pro drugs compared to [(123)I]-labeled pentamidine. While [(123)I]iodopentamidine was mainly renally eliminated the pro-drugs were primarily metabolized in the liver and underwent biliary elimination. Considering pentamidine's nephrotoxicity this feature has to be seen as an advantage of the pro-drug principle. Moreover, a significantly higher concentration in the brain was detected after intravenous injection of N,N'-dihydroxy[(123)I]iodopentamidine compared to [(123)I]iodopentamidine. The feasibility of an effective treatment of second stage African trypanosomiasis, in which the parasites already infected the brain, with the herein investigated pro-drugs remains to be clarified with infected animals in additional in vivo studies. PMID- 25455770 TI - Development of novel diolein-niosomes for cutaneous delivery of tretinoin: influence of formulation and in vitro assessment. AB - This work describes innovative niosomes, composed of diolein alone or in association with the hydrophilic penetration enhancer Labrasol((r)), as carriers for cutaneous drug delivery. The model drug was tretinoin and conventional, and Labrasol((r)) containing liposomes was used as controls to evaluate the influence of vesicle composition and the role of Labrasol((r)) on vesicle physico-chemical properties and performance as skin delivery system. Vesicles, prepared by the thin film hydration technique, were characterized in terms of size distribution, morphology, zeta potential, structure, incorporation efficiency, and rheological properties. The influence of carrier composition on tretinoin delivery to human skin was evaluated by in vitro percutaneous experiments, while formulation distribution on human skin and cellular uptake in human keratinocytes were studied using confocal laser scanning microscopy. RESULT: showed that tretinoin loaded diolein-niosomes formed unilamellar vesicles very similar in physico chemical properties to liposomes. The role of Labrasol((r)) was similar in niosomes and liposomes. Its addition affected vesicle structure and size, by formation of an interdigitate bilayer with higher curvature and larger vesicle size, and rheological properties. Indeed, the presence of Labrasol((r)) allowed both niosomes and liposomes to shift from Newtonian to pseudo-plastic behavior. Confocal laser microscopy highlighted an important contemporaneous deposition of hydrophilic and lipophilic vesicle components in stratum corneum and a high vesicle affinity for skin appendages when Labrasol((r)) was added to the diolein niosomes. Moreover, all samples were internalized in human keratinocytes in vitro. PMID- 25455771 TI - Hepatoma-targeting and pH-sensitive nanocarriers based on a novel D galactopyranose copolymer for efficient drug delivery. AB - Smart nanoparticles based on the mechanisms of asialoglycoprotein (ASGP)-mediated endocytosis and pH-induced drug release were developed for the efficient treatment of hepatoma using a newly developed copolymer, methoxy-polyethylene glycols (PEG)-b-poly (d-galactopyranose) (MPEG-b-PMaIPG). The particles exhibited spherical shapes, uniform particle size distribution (100 +/- 4.43 nm), negative zeta potential (-32.8 +/- 0.23 mV), high drug loading (24.77 +/- 2.68%) and encapsulation efficiency (66.12 +/- 9.44%). The in vitro drug release was also investigated, resulting that the release of drug from particles depended on different pH value. In vitro cell cytotoxicity and hemolysis assays were conducted to confirm the safety of the MPEG-b-PMaIPG nanoparticles. Anticancer activity showed that DOX-loaded MPEG-b-PMaIPG nanoparticles exhibited a high antitumor activity toward HepG2 cells, which was similar to free DOX, while blank MPEG-b-PMaIPG nanoparticles were non-toxic up to a tested concentration of 1.0mg/mL. Confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) were used to verify the targeting efficiency of d-galactopyranose-modified nanoparticles. The results clearly demonstrated that d-galactopyranose-modified nanoparticles were taken up quickly by the HepG2 cells, which suggests that MPEG b-PMaIPG nanoparticles with good biocompatibility and non-toxic for normal cells may be used as an effective cancer-targeting drug delivery system for chemotherapy. PMID- 25455772 TI - New drug-eluting lenses to be applied as bandages after keratoprosthesis implantation. AB - Corneal tissue is the most commonly transplanted tissue worldwide. This work aimed to develop a new drug-eluting contact lens that may be used as a bandage after keratoprosthesis. During this work, films were produced using poly(vinyl alcohol) (PVA) and chitosan (CS) crosslinked with glyoxal (GL). Vancomycin chlorhydrate (VA) was impregnated in these systems by soaking. Attenuated total reflectance - Fourier transform infrared spectroscopy was used to confirm crosslinking. The cytotoxic and drug release profile, hydrophilicity, thermal and biodegradation as well as swelling capacity of the samples were assessed through in vitro studies. PVA and PVA/CS films were obtained by crosslinking with GL. The films were transparent, flexible with smooth surfaces, hydrophilic and able to load and release vancomycin for more than 8h. Biodegradation in artificial lachrymal fluid (ALF) with lysozyme at 37 degrees C showed that mass loss was higher for the samples containing CS. Also, the samples prepared with CS showed the formation of pores which were visualized by SEM. All samples revealed a biocompatible character after 24h in contact with cornea endothelial cells. As a general conclusion it was possible to determine that the 70PVA/30CS film showed to combine the necessary features to prepare vancomycin-eluting contact lenses to prevent inflammation after corneal substitution. PMID- 25455773 TI - Oil-enriched, ultra-small nanostructured lipid carriers (usNLC): a novel delivery system based on flip-flop structure. AB - For the development of ultra-small NLC (usNLC) the determination of the required HLB (hydrophilic lipophilic balance) was found to be a suitable method, i.e., usNLC with a size below 50 nm were obtained by this method. Loading with 5% (w/w) coenzyme Q10 (Q10) led to usNLC with a size of about 85 nm. In comparison to classical NLC with a size of 230 nm and a nanoemulsion with similar size, the Q10 loaded usNLC show a higher release, a higher antioxidant capacity, and a better skin penetration for Q10. The reason for this is a flip-flop core-shell structure of the lipid matrix, i.e., the oil with dissolved active is surrounding the solid lipid based core. As the flip-flop structure was probably achieved by admixing high contents of liquid lipid, oil enriched usNLC might represent a novel and promising carrier system for the improved delivery of lipophilic actives. PMID- 25455774 TI - Synthesis and anticervical cancer activity of novel pH responsive micelles for oral curcumin delivery. AB - Curcumin (CM) has demonstrated safety and efficacy as a drug, but its pharmaceutical role is restricted as a result of extremely low aqueous solubility, rapid systemic elimination, inadequate tissue absorption and degradation at alkaline pH; properties that severely curtail its bioavailability. To address this issue, CM was encapsulated within pH responsive amphiphilic chitosan, resulting in the formation of 100 nm spontaneously self-assembled polymeric micelles in water. The amphiphilic chitosan, namely N-benzyl-N,O succinyl chitosan (BSCS), was prepared by reductive N-benzylation and N,O succinylation. The stability of micelles after being re-dispersed in water was investigated using glycine as a cryoprotectant, and the average sizes were shown to be maintained at a level lower than 200 nm for up to 4 months, at temperatures of 4 degrees C and 25 degrees C. In vitro drug release results showed that CM was slowly released from the micelles without any burst effect in the intestine (pH 5.5-7.4), with limited release in the stomach (pH 1.2). Cytotoxicity assays indicated that CM loaded micelles showed half maximal inhibitory concentrations (IC50) 4.7-, 3.6-, and 12.2-fold lower than that of free CM in HeLa, SiHa and C33a cervical cell lines, respectively. Cellular uptake of micelles was confirmed by confocal laser scanning microscopy and flow cytometry, with a 6-fold significant increase in the amount of CM loaded micelles compared to free CM in all cervical cancer cells. Notably, CM loaded micelles promoted an increase (30 55%) in the percentage of early apoptosis of HeLa, SiHa and C33a cells, compared to free CM. These results suggest that BSCS micelles may be a promising carrier for effective oral delivery of CM. PMID- 25455775 TI - Theoretical investigations into the influence of the position of a breaking line on the tensile failure of flat, round, bevel-edged tablets using finite element methodology (FEM) and its practical relevance for industrial tablet strength testing. AB - Flat, round tablets may have a breaking ("score") line. Pharmacopoeial tablet breaking load tests are diametral in their design, and industrially used breaking load testers often have automatic tablet feeding systems, which position the tablets between the loading platens of the machine with the breaking lines in random orientation to the applied load. The aim of this work was to ascertain the influence of the position of the breaking line in a diametral compression test using finite element methodology (FEM) and to compare the theoretical results with practical findings using commercially produced bevel-edged, scored tablets. Breaking line test positions at an angle of 0 degrees , 22.5 degrees , 45 degrees , 67.5 degrees and 90 degrees relative to the loading plane were studied. FEM results obtained for fully elastic and elasto-plastic tablets were fairly similar, but they highlighted large differences in stress distributions depending on the position of the breaking line. The stress values at failure were predicted to be similar for tablets tested at an angle of 45 degrees or above, whereas at lower test angles the predicted breaking loads were up to three times larger. The stress distributions suggested that not all breaking line angles would result in clean tensile failure. Practical results, however, did not confirm the differences in the predicted breaking loads, but they confirmed differences in the way tablets broke. The results suggest that it is not advisable to convert breaking loads obtained on scored tablets into tablet tensile strength values, and comparisons between different tablets or batches should carefully consider the orientation of the breaking line with respect to the loading plane, as the failure mechanisms appear to vary. PMID- 25455776 TI - Corneal targeted nanoparticles for sustained natamycin delivery and their PK/PD indices: an approach to reduce dose and dosing frequency. AB - Natamycin is the only approved medication for the treatment of mycotic keratitis. Current dosage regimen include one drop of natamycin suspension (5% w/v) instilled in the conjunctival sac at hourly or two hourly intervals for several days which has poor patient compliance. The purpose of the present study was to design a corneal targeted nanoformulation in order to reduce dose and dosing frequency of natamycin and evaluate its pharmacokinetic/pharmacodynamic indices in comparison with clinical marketed preparation. The nanoparticles prepared by nanoprecipitation method were in nanometer size range with high entrapment efficiency and positive surface charge. In-vitro release studies indicated prolonged release of natamycin up to 8h. In-vitro antifungal activity was comparable with marketed preparation. The performance of nanoformulations was evaluated in rabbit eyes. The concentration of natamycin in tear fluid was determined by using LC-MS/MS. The pharmacokinetic parameters such as area under the curve, t1/2 and mean residence time were significantly higher and clearance was significantly lower for nanoformulations with that of marketed preparation. The optimized dosing schedule to maintain natamycin concentration above tenfold of MIC90 was one instillation in every 5h. Moreover, 1/5th dose reduction of nanoformulation was also effective. PMID- 25455777 TI - The crystallinity of cellulose controls the physical distribution of sorbed water and the capacity to present water for chemical degradation of a solid drug. AB - The purpose of the research was to investigate the effect of moisture content of cellulose on the degradation of a drug in binary mixtures with cellulose. Physical mixtures of acetylsalicylic acid and two forms of cellulose, either microcrystalline cellulose or low crystalline cellulose, in the proportion 1:1 were stored at 50 degrees C at a series of relative humidities (0-90%) for up to 175 days. The degradation rate constant of the drug increased with increased cellulose moisture content in a bi-regional fashion, with a low and a high degradation rate region. The shift from region 1 to 2 occurred at higher moisture content for the low crystalline cellulose. The relationships between rate constant and the temperature of maximum endothermic value overlapped for the two celluloses. It is proposed that the amount of water available for degradation of a solid drug is controlled by the water presenting capacity of cellulose which is dependent of the mechanism of sorption of water in cellulose. The water sorption of water can for cellulose satisfactorily be described by a two-site residence model with cellulose crystallinity as the structural correlate to the distribution between the two residence sites. PMID- 25455778 TI - High-throughput manufacturing of size-tuned liposomes by a new microfluidics method using enhanced statistical tools for characterization. AB - Microfluidics has recently emerged as a new method of manufacturing liposomes, which allows for reproducible mixing in miliseconds on the nanoliter scale. Here we investigate microfluidics-based manufacturing of liposomes. The aim of these studies was to assess the parameters in a microfluidic process by varying the total flow rate (TFR) and the flow rate ratio (FRR) of the solvent and aqueous phases. Design of experiment and multivariate data analysis were used for increased process understanding and development of predictive and correlative models. High FRR lead to the bottom-up synthesis of liposomes, with a strong correlation with vesicle size, demonstrating the ability to in-process control liposomes size; the resulting liposome size correlated with the FRR in the microfluidics process, with liposomes of 50 nm being reproducibly manufactured. Furthermore, we demonstrate the potential of a high throughput manufacturing of liposomes using microfluidics with a four-fold increase in the volumetric flow rate, maintaining liposome characteristics. The efficacy of these liposomes was demonstrated in transfection studies and was modelled using predictive modeling. Mathematical modelling identified FRR as the key variable in the microfluidic process, with the highest impact on liposome size, polydispersity and transfection efficiency. This study demonstrates microfluidics as a robust and high-throughput method for the scalable and highly reproducible manufacture of size-controlled liposomes. Furthermore, the application of statistically based process control increases understanding and allows for the generation of a design space for controlled particle characteristics. PMID- 25455779 TI - Fast dissolving paracetamol/caffeine nanofibers prepared by electrospinning. AB - A series of polyvinylpyrrolidone fibers loaded with paracetamol (PCM) and caffeine (CAF) was fabricated by electrospinning and explored as potential oral fast-dissolving films. The fibers take the form of uniform cylinders with smooth surfaces, and contain the drugs in the amorphous form. Drug-polymer intermolecular interactions were evidenced by infrared spectroscopy and molecular modeling. The properties of the fiber mats were found to be highly appropriate for the preparation of oral fast dissolving films: their thickness is around 120 130 MUm, and the pH after dissolution in deionized water lies in the range of 6.7 7.2. Except at the highest drug loading, the folding endurance of the fibers was found to be >20 times. A flavoring agent can easily be incorporated into the formulation. The fiber mats are all seen to disintegrate completely within 0.5s when added to simulated saliva solution. They release their drug cargo within around 150s in a dissolution test, and to undergo much more rapid dissolution than is seen for the pure drugs. The data reported herein clearly demonstrate that electrospun PCM/CAF fibers comprise excellent candidates for oral fast dissolving films, which could be particularly useful for children and patients with swallowing difficulties. PMID- 25455780 TI - Evaluation of sorption capacity of antibiotics and antibacterial properties of a cyclodextrin-polymer functionalized hydroxyapatite-coated titanium hip prosthesis. AB - Infection still present as one of common complications after total hip replacement (~2.5%), which may cause serious outcomes. For preventing such risk, loading antibiotics onto implants for increasing local drug concentration at targeted sites could be a solution. This study aims at modifying the surface of hydroxyapatite (HA) coated titanium hip implant material (Ti-HA) with polymer of cyclodextrin (polyCD) for loading antibiotics, to achieve a sustained local drug delivery. Two widely applied antibiotics (tobramycin and rifampicin) in orthopedic surgery were loaded alone or in combination. The drug adsorption isotherm, drug release kinetics and drug's efficacy were thoroughly investigated. The results proved that polyCD coating significantly improved the affinity of both drugs to Ti-HA surface, while the mechanism of drug-polyCD interaction varies from the nature of drug, courtesy of the structural complex of polyCD. The advantage of dual-drug loading was highlighted by its strong efficacy against both Staphylococcus aureus and Enterobacter cloacae, which overcomes the limitation of mono-drug loading for an effective treatment against both bacterial strains. The prolonged antibacterial activity of antibiotic loaded Ti-HA-polyCD samples confirmed that polyCD could be a promising drug-delivery system, for sustained antibiotics release or other potential applications e.g., antimitotic agent release. PMID- 25455781 TI - Self-nanoemulsifying drug delivery systems for oral insulin delivery: in vitro and in vivo evaluations of enteric coating and drug loading. AB - This study aims at evaluating the combination of self-nanoemulsifying drug delivery systems (SNEDDS) and enteric-coated capsules as a potential delivery strategy for oral delivery of insulin. The SNEDDS preconcentrates, loaded with insulin-phospholipid complex at different levels (0, 2.5 and 10% w/w), were readily dispersed in water to form nanoemulsions of 35 nm and vesicles of 300 nm. The association efficiency of non-complexed insulin in the dispersed SNEDDS was 18.6%, and was increased to 73.1% for insulin-phospholipid complex (at 10% loading level). The morphology of the dispersed SNEDDS changed from nanoemulsion droplets to vesicular structures with increasing complex loading levels. A pH dependent insulin release profile was observed for SNEDDS filled into capsules coated with the enteric polymer, Eudragit((r)) L100. Using a Caco-2 cell model, it was observed that the transport of insulin was enhanced by factors of 7.7- and 9.3- for SNEDDS loaded with 2.5 and 10% complex, respectively. In healthy fasted rats, administration of SNEDDS (10% complex) filled in enteric-coated capsules produced a 2.7-fold and 3.4-fold enhancement in the relative bioavailability and glucose reduction, respectively. This study shows the effectiveness of combining SNEDDS (loaded with insulin-phospholipid complex) with enteric-coated capsules for enhancing the oral absorption and efficacy of insulin. PMID- 25455782 TI - The enhanced longevity and liver targetability of Paclitaxel by hybrid liposomes encapsulating Paclitaxel-conjugated gold nanoparticles. AB - Organic and inorganic drug delivery systems both demonstrate their own advantages and challenges in practical applications. Combining these two drug delivery strategies in one system is expected to solve their current issues and achieve desirable functions. In this paper, gold nanoparticles (GNPs) and liposomes have been chosen as the model systems to construct a hybrid system and investigate its performance for the tumor therapy of Paclitaxel (PTX). The thiol-terminated polyethylene glycol (PEG400)-PTX derivative has been covalently modified on the surface of GNPs, followed by the encapsulation of PTX-conjugated GNPs (PTX PEG400@GNPs) in liposomes. The hybrid liposomes solve the solubility and stability problems of gold conjugates and show high drug loading capacity. In vitro PTX release from the hybrid system maintains the similar sustained behavior demonstrated in its conjugates. Under the protection of a biocompatible liposome shell, encapsulated PTX shows enhanced circulation longevity and liver targetability compared to Taxol((r)) and PTX-PEG400@GNPs suspension in the pharmacokinetic and biodistribution studies. These indicate that encapsulating drug-conjugated inorganic nanoparticles inside organic carriers maintains the superiority of both vehicles and improves the performance of hybrid systems. Although these attributes of hybrid liposomes lead to a better therapeutic capacity in a murine liver cancer model than that of the comparison groups, it shows no significant difference from Taxol((r)) and conjugate suspension. This result could be due to the delayed and sustained drug release from the system. However, it indicates the promising potential for these hybrid liposomes will allow further construction of a compound preparation with improved performance that is based on their enhanced longevity and liver targetability of Paclitaxel. PMID- 25455783 TI - Pharmaceutical properties of a low-substituted hydroxypropyl cellulose (L-HPC) hydrogel as a novel external dressing. AB - Controlling the moisture balance between exudates and their transpiration from the surface of wounded skin is important for healing. Low-substituted hydroxypropyl cellulose (L-HPC) hydrogel sheets (HGSs) possessing high water retention and water vapor transmission properties were prepared by neutralizing the highly viscous alkaline liquid of 7-10% L-HPC. Glycerol-impregnated L-HPC hydrogel sheets (L-HPC G-HGSs) were obtained by exchanging aqueous liquid in L HPC HGSs. The physical characteristics required for wound dressings, i.e., mechanical strength, adhesive strength, and water retention properties, as well as the water vapor transmission (WVT) properties of L-HPC HGSs and L-HPC G-HGSs were evaluated. The mechanical strengths of L-HPC HGSs were enhanced with increases in the L-HPC content. The impregnation of glycerol in L-HPC HGSs yielded a significantly elasticated sheet. The adhesive strengths of L-HPC HGSs were significantly lower than those of commercial medical dressings. Water retention in L-HPC HGSs after being stored for 2h at 37 degrees C was approximately 50%. The WVT rate of 7% L-HPC HGS was approximately 40g/m(2)/h, which was markedly higher than that of silicone gel type medical dressings. In conclusion, L-HPC HGSs are promising dressings that maintain an adequate moisture balance by transpiring excessive wound exudates with less damage to the healing wound. PMID- 25455785 TI - Micronucleus test in fishes as indicators of environmental quality in subestuaries of the Rio de la Plata (Uruguay). AB - Genotoxic agents may exert damage that may be active through following generations. Micronuclei are cytoplasmic chromatin masses outside the main cell nucleus, indicators of chromosomal damage. This study applied micronuclei test to evaluate genetic damage of fish in three breeding and nursery areas of commercially important fishes exposed to differing degrees of anthropogenic impact: Pando, Solis Chico and Solis Grande sub-estuaries. The micronuclei test revealed differences in the presence and concentrations of genotoxic components in these sub-estuaries. Fish in the urban and industrialized Pando sub-estuary presented the highest percentages of micronuclei. The absence of seasonal changes in micronuclei in Pando fish could be explained by physical characteristics of the sub-estuary and by regional weather conditions. Odontesthes argentinensis (Valenciennes, 1835) was the species most susceptible to genotoxic components. It is recommended the use of a battery of biomarkers to better explain the health of organisms in that important nursery area. PMID- 25455784 TI - Bionanocomposites containing magnetic graphite as potential systems for drug delivery. AB - New magnetic bio-hybrid matrices for potential application in drug delivery are developed from the assembly of the biopolymer alginate and magnetic graphite nanoparticles. Ibuprofen (IBU) intercalated in a Mg-Al layered double hydroxide (LDH) was chosen as a model drug delivery system (DDS) to be incorporated as third component of the magnetic bionanocomposite DDS. For comparative purposes DDS based on the incorporation of pure IBU in the magnetic bio-hybrid matrices were also studied. All the resulting magnetic bionanocomposites were processed as beads and films and characterized by different techniques with the aim to elucidate the role of the magnetic graphite on the systems, as well as that of the inorganic brucite-like layers in the drug-loaded LDH. In this way, the influence of both inorganic components on the mechanical properties, the water uptake ability, and the kinetics of the drug release from these magnetic systems were determined. In addition, the possibility of modulating the levels of IBU release by stimulating the bionanocomposites with an external magnetic field was also evaluated in in vitro assays. PMID- 25455786 TI - Effects of subchronic exposure to glyphosate in juvenile oysters (Crassostrea gigas): From molecular to individual levels. AB - Glyphosate-based herbicides are extensively used and can be measured in aquatic ecosystems, including coastal waters. The effect of glyphosate on non-target organisms is an issue of worldwide concern. The aim of this study was to investigate the effects of subchronic exposure to glyphosate in juvenile oysters, Crassostrea gigas. Yearling oysters were exposed to three concentrations of glyphosate (0.1, 1 and 100MUgL(-1)) for 56days. Various endpoints were studied, from the individual level (e.g., gametogenesis and tissue alterations) to the molecular level (mRNA quantification), including biochemical endpoints such as glutathione-S-transferase (GST) and catalase activities and malondialdehyde content. No mortality and growth occurred during the experiment, and individual biomarkers revealed only slight effects. The levels of gene expression significantly increased in oysters exposed to the highest glyphosate concentration (GST and metallothioneins) or to all concentrations (multi xenobiotic resistance). These results suggested an activation of defence mechanisms at the molecular level. PMID- 25455787 TI - Spatial variability of three benthic indices for marine quality assessment in a subtropical estuary of Southern Brazil. AB - Indices based on macrobenthic responses to disturbance remain to be adequately tested for the detection of spatial variability by robust sampling designs. We present herein a congruence test to real-world data of the widely used indices AMBI, M-AMBI and BENTIX in tidal flats of a subtropical estuary. We used a hierarchical sampling design to evaluate the spatial variability of the indices in response to distinct levels of sewage contamination. Indices were then tested for correlations with chemical proxies of contamination and for the similarity of responses. BENTIX and M-AMBI produced over- and underestimations of ecological status. We found a low degree of similarity among indices as an expression of the spatial variation of macrofaunal assemblages on their performances. Only AMBI varied at the contamination scale (10(3)m) and was congruent with physical chemical proxies. Ambiguous responses indicated effects of natural inputs of organic matter rather than environmental quality associated to sewage. PMID- 25455788 TI - Characterization of harbor sediments from the English Channel: assessment of heavy metal enrichment, biological effect and mobility. AB - For a full assessment of the environmental risk posed by dredged sediments not only the anthropogenic enrichment of contaminants, but also their mobility and biological impact should be considered. This study reports on the enrichment factor (EF), mobility, and Adverse Effect Index (AEI) of metals and metalloids in nine dredged sediments. Significant enrichment of As, Cd, Pb and Zn with respect to background values is detected, and calculated AEI values for these elements suggest that it is possible that a corresponding biological effect may be observed. Correlation coefficients also reveal a link between mobility in HCl and enrichment for Cd, Cr, Ni, Pb and Zn, however As and Cu do not display such a link, possibly suggesting that the source of contamination for these elements is less recent. Mobility and enrichment are two parameters which are often studied separately; however this paper shows that in some cases strong correlations occur. PMID- 25455789 TI - Microbial activity in surface sediments of Chacopata-Bocaripo lagoon axis, Sucre State, Venezuela. AB - The aim of this work was to evaluate the microbial activity of the surface sediments (0-10 cm) of the Chacopata-Bocaripo lagoon axis (Ch-BLA) through microbiological parameters: microbial biomass (Cmic) dehydrogenase activity (DHS), fluorescein diacetate hydrolysis (HFDA), arginine ammonification (AA) and biochemical parameters: phosphatase (PHa) and urease (URa) activity. They were determined during transition (July 2010) and upwelling (March 2011) periods. Total organic carbon (TOC) did not vary significantly (p?0.05) between climatic periods. All the parameters studied were higher in upwelling season: Cmic (191.79 mg Cmic kg(-1)), DHS (228.70 MUg TFF g(-1) 24 h(-1)), HFDA (204.09 MUg fluorescein g(-1) 24 h(-1)), AA (13.09 MUg NH4-N g(-1) h(-1)), PHa (132.31 MUg pNF g(-1) h(-1)), URa (12.90 MUg NH4-N g(-1) h(-1)). They appear to be controlled by the availability and quality of nutrients in each climatic period, and were useful tools for evaluating changes in microbial activity in marine sediments. PMID- 25455790 TI - Oil spill hazard from dispersal of oil along shipping lanes in the Southern Adriatic and Northern Ionian Seas. AB - An assessment of hazard stemming from operational oil ship discharges in the Southern Adriatic and Northern Ionian (SANI) Seas is presented. The methodology integrates ship traffic data, the fate and transport oil spill model MEDSLIK-II, coupled with the Mediterranean Forecasting System (MFS) ocean currents, sea surface temperature analyses and ECMWF surface winds. Monthly and climatological hazard maps were calculated for February 2009 through April 2013. Monthly hazard distributions of oil show that the zones of highest sea surface hazard are located in the southwestern Adriatic Sea and eastern Ionian Sea. Distinctive "hot spots" appear in front of the Taranto Port and the sea area between Corfu Island and the Greek coastlines. Beached oil hazard maps indicate the highest values in the Taranto Port area, on the eastern Greek coastline, as well as in the Bari Port area and near Brindisi Port area. PMID- 25455791 TI - The barrier-belief approach in the counseling of physical activity. AB - OBJECTIVE: To understand inactivity and relapse from PA, and to develop theory based behavior change strategies to stimulate and support maintenance of PA. METHODS: We conducted a literature search to explore barriers to PA. Social cognitive theories and empirical evidence were evaluated and guided the process developing a theoretical framework and counseling strategies. RESULTS: A theoretical framework is presented to understand why people do not engage in PA and often relapse once they started PA. A distinction is made between three related types of BBs. In PA counseling these three beliefs are addressed using four different BB behavior change strategies. CONCLUSION: BB counseling aims to develop an individual pattern of PA for the long term that is adapted to the (often limited) motivation of the client, thereby preventing the occurrence of BBs. The client will learn to cope with factors that may inhibit PA in the future. PRACTICE IMPLICATIONS: The BBs approach composes a way of counseling around the central construct of barrier-beliefs to stimulate engagement in PA independently, in the long term. PMID- 25455792 TI - Overture, 1961: The power of focussed, expert physical examination and brief verbal reassurance. PMID- 25455794 TI - Functional, communicative and critical health literacy of chronic disease patients and their importance for self-management. AB - OBJECTIVE: To provide insight into the level of health literacy among chronic disease patients in the Netherlands, to identify subgroups with low literacy and to examine the associations between health literacy and self-management. METHODS: Self-report questionnaires were sent to a nationwide sample of 1.341 chronic disease patients. The Dutch Functional Communicative and Critical Health Literacy scale (FCCHL), the Partners in Health scale (PIH) and Perceived Efficacy in Patient-Doctor Interactions (PEPPI-5) were used to assess health literacy and aspects of self-management. RESULTS: In general, health literacy skills were good. A higher age, lower education, lower income, multi-morbidity and/or functional limitations were associated with lower levels of health literacy. Communicative and critical health literacy were related to some aspects of self management but not to all. Functional health literacy was less important. CONCLUSION: Communicative and critical health literacy play a role in successful self-management of chronic disease but the impact differs by context. Health literacy levels vary according to socio-demographic and disease characteristics of patients. PRACTICE IMPLICATIONS: Health care professionals should tailor their information and support to the health literacy skills and personal context of their patients. PMID- 25455793 TI - Understanding the influence of psychological and socioeconomic factors on diabetes self-care using structured equation modeling. AB - OBJECTIVE: To develop and test latent variables of the social determinants of health that influence diabetes self-care. METHODS: 615 adults with type 2 diabetes were recruited from two adult primary care clinics in the southeastern United States. Confirmatory factor analyses (CFA) identified the latent factors underlying socioeconomic determinants, psychosocial determinants, and self-care (diet, exercise, foot care, glucose testing, and medication adherence). Structured equation modeling (SEM) investigated the relationship between determinants and self-care. RESULTS: Latent variables were created for diabetes self-care, psychological distress, self-efficacy, social support and social status. The initial model (chi2(254) = 388.04, p < 0.001, RMSEA = 0.03, CFI = 0.98) showed that lower psychological distress (r = -0.13, p = 0.019), higher social support (r = 0.15, p = 0.008), and higher self-efficacy (r = 0.47, p < 0.001) were significantly related to diabetes self-care. Social status was not significantly related to self-care (r = 0.003, p = 0.952). In the trimmed model (chi2(189) = 211.40, p = 0.126, RMSEA = 0.01, CFI = 0.99) lower psychological distress (r = -0.13, p = 0.016), higher social support (r = 0.15, p = 0.007), and higher self-efficacy (r = 0.47, p < 0.001) remained significantly related to diabetes self-care. CONCLUSION: Based on theoretical relationships, three latent factors that measure social determinants of health (psychological distress, social support and self-efficacy) are strongly associated with diabetes self care. PRACTICE IMPLICATIONS: This suggests that social determinants should be taken into account when developing patient self-care goals. PMID- 25455795 TI - Training primary care clinicians in motivational interviewing: a comparison of two models. AB - OBJECTIVES: To evaluate implementing two training models for motivational interviewing (MI) to address tobacco use with primary care clinicians. METHODS: Clinicians were randomized to moderate or high intensity. Both training modalities included a single 1/2 day workshop facilitated by MI expert trainers. The high intensity (HI) training provided six booster sessions including telephone interactions with simulated patients and peer coaching by MI champions over 3 months. To assess performance of clinicians to deliver MI, an objective structured clinical evaluation (OSCE) was conducted before and 12 weeks after the workshop training. RESULTS: Thirty-four clinicians were enrolled; 18 were randomly assigned to HI. Compared to the moderate intensity group, the HI group scored significantly higher during the OSCE for three of six global Motivational Interviewing Treatment Integrity scale scores. There was also significant improvement for three of the four measures of MI counseling knowledge, skills and confidence. CONCLUSIONS: Using champions and telephone interactions with simulated patients as enhancement strategies for MI training programs is feasible in the primary care setting and results in greater gains in MI proficiency. PRACTICE IMPLICATIONS: Results confirm and expand evidence for use of booster sessions to improve the proficiency of MI training programs for primary care clinicians. PMID- 25455796 TI - Follow-up effects of a tailored pre-counseling website with question prompt in breast cancer genetic counseling. AB - OBJECTIVE: Pre-counseling education helps counselees to prepare for breast cancer genetic counseling and might subsequently result in more positive experiences, improved cognitive outcomes and more experienced control. This study assessed the effects of a website with tailored information and a blank sheet to fill in questions (question prompt; QP), at 1 week and 1 year post-counseling. METHODS: Consecutive counselees were randomized to the usual care group (UC) or the intervention group (UC+website+QP). Counselees completed questionnaires pre- and post-counseling and 1 year follow-up. We conducted multilevel regression analyses corrected for time. RESULTS: Intervention group counselees (n = 103) were more satisfied about their final visit (beta = .35; CI: .06-.65; P = .02; n = 156) than UC group counselees (n = 94). Intervention group counselees also reported more positive experiences with the counseling (beta = .32; CI: .06-.59; P = .02; n = 188) and higher perceived personal control 1 year post-counseling (beta = .51; CI: .18-.84; P = .002; n = 193). No significant effects were found on recall, knowledge, anxiety, cancer worry, risk perception alignment and adherence to breast surveillance advice. CONCLUSION: This study shows that pre-counseling education providing tailored information and QP, might lead to improvements in experiences with the counseling and perceived personal control 1 year post counseling. PRACTICE IMPLICATIONS: Online pre-visit information is a feasible tool to enhance counselees' experiences. PMID- 25455797 TI - The relationship between partner information-seeking, information-sharing, and patient medication adherence. AB - OBJECTIVES: We describe the medication information-seeking behaviors of arthritis patients' partners and explore whether partner medication information-seeking and information-sharing are associated with patient medication adherence. METHODS: Arthritis patients and their partners (n = 87 dyads) completed an on-line questionnaire. Partners indicated how often they obtained medication information from 14 sources, how much they trusted these sources, and whether they shared medication information with the patient. Patients reported their medication adherence. Bivariate associations were calculated to explore the relationships between partner information-seeking, information-sharing, and patient medication adherence. RESULTS: Partners sought little information about the patient's medications. Partners sought more information if the patient's medication regimen was more complex (r = 0.33, p = 0.002). Most partners (~ 98%) shared medication information with the patient; older partners shared more information with the patient (r = 0.25, p = 0.03). Neither partner information-seeking (r = 0.21, p = 0.06) nor partner information-sharing (r = 0.12, p = 0.31) were significantly associated with patient medication adherence. CONCLUSIONS: Although partners of arthritis patients do not seek large amounts of medication information, the vast majority share this information with the patient. PRACTICE IMPLICATIONS: Involving partners in medical consultations can help them better understand the patient's medications, have questions answered by providers, and engage in more informed discussions with patients about their medications. PMID- 25455798 TI - Battling tuberculosis in an island context with a high burden of communicable and non-communicable diseases: epidemiology, progress, and lessons learned in Kiribati, 2000 to 2012. AB - OBJECTIVES: To examine the epidemiology of tuberculosis (TB) in Kiribati from 2000 to 2012, document lessons learned, and recommend ways to mitigate the burden of TB in Kiribati. METHODS: A descriptive study was performed using data on TB case notifications, prevalence, incidence, mortality, and treatment outcomes from global reports and data files. Progress towards meeting the Millennium Development Goal TB target (to reduce TB incidence by 2015) and the Regional Strategy to Stop Tuberculosis in the Western Pacific 2011-2015 targets (to reduce TB prevalence and mortality by half by 2015 relative to the level in 2000) was examined. RESULTS: TB case notifications and the estimated incidence and prevalence have increased in Kiribati since 2000. From 2000 to 2012, Kiribati reported a total of 3863 TB notifications; in 2012, the case notification rate was 343/100 000 population. The majority (89%) of TB patients complete treatment and/or are cured, and the estimated TB mortality rate has remained relatively stable at around 16/100 000 population. HIV testing of TB patients has increased over recent years from 8% of notifications tested in 2003 to 43% tested in 2012. Of all 818 tests, only four (0.5%) patients were confirmed HIV-positive. Drug resistant TB has been detected in a small number of cases. CONCLUSIONS: TB rates continue to increase in Kiribati and the 2015 goals for TB control are unlikely to be met. This is probably due to the complex mix of risk factors present in Kiribati, including smoking, diabetes, alcohol use, crowded living, and poverty. A comprehensive approach to address these risk factors is needed to mitigate the burden of TB in Kiribati. PMID- 25455799 TI - Epidemiology and microbiology of sepsis in mainland China in the first decade of the 21st century. AB - OBJECTIVES: This study describes the epidemiological and microbiological profile of sepsis during the first decade of the 21(st) century in mainland China. METHODS: The sepsis-related mortality data from 2003 and 2007 were retrieved from the China Health Statistical Yearbook. The microbiology data were retrieved and selected from a literature search of the China Academic Journal Database between 2001 and 2009. A meta-analysis was performed to synthesize the available data on the proportion of positive blood cultures in septic patients and the microorganism distribution. RESULTS: The sepsis mortality in small and medium sized cities and rural areas declined obviously over time. The mortality of the subpopulations aged 1-54 years tended to be lower than the national averages. In contrast, the sepsis mortality among neonates and the elderly (>=75 years) was obviously higher than national averages. While the mortality in the elderly declined between 2003 and 2007, the neonate sepsis mortality increased dramatically, especially among male neonates. The overall positivity of blood culture were 17.0%, 13.3% and 10.6% among neonatal, pediatric and adult patients with suspected sepsis, respectively; this proportion tended to decrease over time. Among identified microorganisms, the proportions of Gram (+) and (-) bacteria were similar (47.2% vs. 44.5%) among adult patients, while Gram (+) bacteria was predominant among neonatal (77.4%) and pediatric (73.2%) patients and increased in prevalence over time. The positivity of blood cultures and proportions of microorganisms varied by geographical region across mainland China. Sepsis with fungus was rare but was more prevalent in adult sepsis patients (6.4%) than in neonatal patients (0.8%). CONCLUSIONS: The difference in sepsis mortality between urban and rural areas decreased over time. Males, the elderly, and neonates were found to be high-risk subpopulations. Gram (+) bacteria were predominant among neonates with sepsis, but the proportion of patients with Gram (+) or Gram (-) bacteria was similar among adults with sepsis. PMID- 25455800 TI - Detached ciliary tufts masquerading as free-living amoebae. PMID- 25455801 TI - [Breast reconstruction by latissimus dorsi flap: Towards an evolution of ideas]. AB - AIM OF THE STUDY: Breast reconstruction with latissimus dorsi flap and fat grafting is a technique widely used in current practice. Some operators still complain at the lack of final results at the first intervention and the need for repeated lipofilling sessions. The objective of this study was to compare the number of reoperations in patients who underwent reconstruction with latissimus dorsi with prosthesis versus without prosthesis. PATIENTS AND METHODS: We included all patients operated for breast reconstruction with latissimus dorsi flap, with or without prosthesis between 2008 and 2012 in our center. We noted the number of new surgical interventions in these patients on the reconstructed breast. We also noted the average weight of mastectomy in two groups each year. RESULTS: One hundred and eighty-six patients were included in this study. Ninety one patients underwent reconstruction with latissimus dorsi and prosthesis, and 95 patients reconstruction by latissimus dorsi and fat graft. It has not been demonstrated significant differences in the number of new surgical procedures between the two groups. The average weight of mastectomies in the autologous group has steadily increased over the five years. There was no significant difference in the average weight of mastectomies between the two groups over the last two years. CONCLUSION: For breast reconstruction with latissimus dorsi flap, surgical indications changed in our center to the absence of prosthetic implant, whatever the volume of the breast. PMID- 25455802 TI - Investigating sodium valproate as a treatment for McArdle disease in sheep. AB - McArdle disease is due to an absence of the enzyme muscle glycogen phosphorylase and results in significant physical impairment in humans. We hypothesised that sodium valproate, an HDAC inhibitor, might have the ability to up-regulate the enzyme. We treated McArdle sheep with sodium valproate given enterically at 20-60 mg/kg body wt. Compared with untreated control animals, there was increased expression of phosphorylase in muscle fibres. The response was dose dependent and reached a maximum 2 hours after the application and increased with repeated applications. Improvement in mobility could not be demonstrated. These findings suggest that sodium valproate is a potential therapeutic treatment for McArdle disease. PMID- 25455803 TI - Muscle ultrasound in classic infantile and adult Pompe disease: a useful screening tool in adults but not in infants. AB - A cohort of 4 infantile and 15 adult Pompe patients has been investigated regarding correlation between strength and ultrasound of skeletal musculature. In adults, muscle ultrasound is useful to assess clinical and subclinical involvement of muscles. In this study, visible sonographic changes were found in every clinically affected muscle, using a modified Heckmatt scale. In some muscles morphologic changes preceded weakness. Regarding the anatomical pattern of involvement, our findings do not support the hypothesis of a specific pattern with a higher vulnerability of vastus intermedius than rectus femoris, which has been postulated before. A frequent sparing of triceps brachii could be confirmed. Intramuscular abnormalities occurred in a focal, a diffuse, or an intermediate pattern, with characteristics of both. In contrast to muscular dystrophies, bone echogencity was not markedly decreased in Pompe disease even in an advanced stage. In infants, muscle ultrasound showed no distinct pathology even in clinically severely affected children and should not be used as a screening method for infantile Pompe disease. PMID- 25455805 TI - Preparation, formation, and structure of [(SnSe)1.04]m(MoSe2)n intergrowth compounds (0 < m and n < 32) from designed precursors. AB - A detailed synthetic approach, using the method of modulated elemental reactants, is described for the preparation of MX-TX(2) (M = metal, X = chalcogen, and T = transition metal) solid-state intergrowths with m and n values significantly larger than previously reported. As a specific example, we demonstrate the ability to synthesize more than 500 distinct intergrowth compounds in a single ternary system, Sn-Mo-Se. A simple method for determination of the chemical composition of the constituent layers in the precursor and product is described for cases in which both structural components contain one or more common elements. X-ray reflectivity, laboratory and synchrotron X-ray diffraction, scanning transmission electron microscopy, and high-resolution transmission electron microscopy imaging, and electron microprobe analysis provide conclusive evidence of the formation of layered intergrowths with well-defined structure and composition. The ability to access a large range of monochalcogenide thicknesses allows a size-dependent structural transition in the SnSe component to be controlled and tracked and indicates that intergrowth materials such as those described here comprise novel material systems in which size-dependent phenomena can be precisely controlled. PMID- 25455804 TI - Glutathionyl-hydroquinone reductases from poplar are plastidial proteins that deglutathionylate both reduced and oxidized glutathionylated quinones. AB - Glutathionyl-hydroquinone reductases (GHRs) catalyze the deglutathionylation of quinones via a catalytic cysteine. The two GHR genes in the Populus trichocarpa genome, Pt-GHR1 and Pt-GHR2, are primarily expressed in reproductive organs. Both proteins are localized in plastids. More specifically, Pt-GHR2 localizes in nucleoids. At the structural level, Pt-GHR1 adopts a typical GHR fold, with a dimerization interface comparable to that of the bacterial and fungal GHR counterparts. Pt-GHR1 catalyzes the deglutathionylation of both reduced and oxidized glutathionylated quinones, but the enzyme is more catalytically efficient with the reduced forms. PMID- 25455806 TI - Current applications of foams formed from mixed surfactant-polymer solutions. AB - Foams cannot be generated without the use of special foaming agents, as pure liquids do not foam. The most common foaming agents are surfactants, however often for foam stability one active agent is not enough, it is necessary to add other component to increase foam lifetime. Foams on everyday use are mostly made from mixture of different components. Properly chosen combinations of two active ingredients lead to a faster foam formation and increased foam stability. During the last decade polymers (mainly polyelectrolytes and proteins) have become frequently used additives to foaming solutions. Mixtures of surfactants and polymers often demonstrate different foaming properties in comparison to surfactant only or polymer only solutions. The nature of surfactant-polymer interactions is complicated and prediction of resulting foaming properties of such formulations is not straightforward. Properties and foaming of surfactant polymer mixtures are discussed as well as current applications of foams and foaming agents as foams are widely used in cosmetics, pharmaceutics, medicine and the food industry. PMID- 25455807 TI - Dynamics of Rear Stagnant Cap formation at the surface of spherical bubbles rising in surfactant solutions at large Reynolds numbers under conditions of small Marangoni number and slow sorption kinetics. AB - On the surface of bubbles rising in a surfactant solution the adsorption process proceeds and leads to the formation of a so called Rear Stagnant Cap (RSC). The larger this RSC is the stronger is the retardation of the rising velocity. The theory of a steady RSC and steady retarded rising velocity, which sets in after a transient stage, has been generally accepted. However, a non-steady process of bubble rising starting from the initial zero velocity represents an important portion of the trajectory of rising, characterized by a local velocity profile (LVP). As there is no theory of RSC growth for large Reynolds numbers Re " 1 so far, the interpretation of LVPs measured in this regime was impossible. It turned out, that an analytical theory for a quasi-steady growth of RSC is possible for small Marangoni numbers Ma " 1, i.e. when the RSC is almost completely compressed, which means a uniform surface concentration Gamma(theta)=Gamma(infinity) within the RSC. Hence, the RSC angle psi(t) is obtained as a function of the adsorption isotherm parameters and time t. From the steady velocity v(st)(psi), the dependence of non-steady velocity on time is obtained by employing v(st)[psi(t)] via a quasi-steady approximation. The measurement of LVP creates a promising new opportunity for investigation of the RSC dynamics and adsorption kinetics. While adsorption and desorption happen at the same localization in the classical methods, in rising bubble experiments desorption occurs mainly within RSC while adsorption on the mobile part of the bubble surface. The desorption flux from RSC is proportional to alphaGamma(infinity), while it is usually alphaGamma. The adsorption flux at the mobile surface above RSC can be assumed proportional to betaC0, while it is usually betaC0(1-Gamma/Gamma(infinity)). These simplifications may become favorable in investigations of the adsorption kinetics for larger molecules, in particular for globular proteins, which essentially stay at an interface once adsorbed. PMID- 25455808 TI - Reprint of "Safe places for pedestrians: using cognitive work analysis to consider the relationships between the engineering and urban design of footpaths". AB - Footpaths provide an integral component of our urban environments and have the potential to act as safe places for people and the focus for community life. Despite this, the approach to designing footpaths that are safe while providing this sense of place often occurs in silos. There is often very little consideration given to how designing for sense of place impacts safety and vice versa. The aim of this study was to use a systems analysis and design framework to develop a design template for an 'ideal' footpath system that embodies both safety and sense of place. This was achieved through using the first phase of the Cognitive Work Analysis framework, Work Domain Analysis, to specify a model of footpaths as safe places for pedestrians. This model was subsequently used to assess two existing footpath environments to determine the extent to which they meet the design requirements specified. The findings show instances where the existing footpaths both meet and fail to meet the design requirements specified. Through utilising a systems approach for footpaths, this paper has provided a novel design template that can inform new footpath design efforts or be used to evaluate the extent to which existing footpaths achieve their safety and sense of place requirements. PMID- 25455809 TI - The anxious heart in whose mind? A systematic review and meta-regression of factors associated with anxiety disorder diagnosis, treatment and morbidity risk in coronary heart disease. AB - OBJECTIVE: To (1) report the prognostic association between anxiety disorder subtypes and major adverse cardiac events (MACE), (2) report anxiety disorder prevalence in coronary heart disease (CHD), and (3) report the efficacy of anxiety disorder treatments in CHD. METHODS: A comprehensive electronic database search was performed in November 2013 for studies reporting anxiety disorder prevalence according to structured interview in CHD samples or MACE, and randomized controlled trials (RCTs) comparing anxiety disorder treatment with placebo or usual care. From 4041 articles 42 samples were selected for extraction (8 for MACE prognosis, 39 for prevalence, no RCTs were eligible). RESULTS: Five generalized anxiety disorder (GAD) studies reported 883 MACE events (combined n=2851). There was a non-significant association between GAD and MACE (risk ratio=1.20, 95% CI .86-1.68, P=.28) however the effect size was highly significant in outpatient samples (adjusted hazard ratio=1.94, 95% CI 1.45-2.60, P<.001). No other anxiety disorder subtype was associated with MACE. Prevalence data showed high comorbidity with depression (49.06%; 95% CI 34.28-64.01) and substantial heterogeneity between studies. Panic disorder prevalence was higher in psychiatrist/psychologist raters (9.92% vs. 4.74%) as was GAD (18.45% vs. 13.01%). Panic and GAD estimates were also heterogeneous according to DSM-III-R versus DSM-IV taxonomies. CONCLUSIONS: The paucity of extant anxiety disorder RCTs, alongside MACE risk for GAD outpatients, should stimulate further anxiety disorder intervention in CHD populations. Research should focus on depression and anxiety, thereby unraveling disorder specific and more generic pathways. PMID- 25455810 TI - PROFSS: a screening tool for early identification of functional somatic symptoms. AB - OBJECTIVE: To develop and validate a brief screening tool for predicting functional somatic symptoms (FSS) based on clinical and non-clinical information from the general practitioner referral letter, and to assess its inter-rater reliability. METHODS: The derivation sample consisted of 357 consecutive patients referred to an internal outpatient clinic by their general practitioner. Referral letters were scored for candidate predictors for the main outcome measure, which was a final diagnosis of FSS made by the internist. Logistic regression identified the following independent predictors: type of symptoms, somatic and psychiatric comorbidity, absence of abnormal physical findings by the general practitioner, previous specialist consultation, and the use of illness terminology. Temporal validation was performed in a cohort of 94 consecutive patients in whom predictors were scored by two independent raters. RESULTS: In both the derivation and validation sample, the discriminatory power of the model was good with areas under the receiver operating characteristic curves of 0.84 (95%confidence interval: 0.80-0.88) after bootstrapping and 0.82 (95%confidence interval: 0.73-0.91), respectively. Calibration of the models was excellent in both samples and the interobserver agreement in the validation sample was very good (intraclass coefficient: 0.82 (95%confidence interval: 0.75-0.88)). Based on this model, we constructed the brief screening tool PROFSS (Predicted Risk Of Functional Somatic Symptoms). PROFSS identified patient groups with risks of FSS ranging from 17% (95%CI: 10-26%) to 92% (95%CI:86-96%). CONCLUSION: The presence of FSS can be predicted with the brief screening tool PROFSS, based on a limited set of items present in the general practitioner referral letter. PMID- 25455811 TI - Bladder pain syndrome/interstitial cystitis as a functional somatic syndrome. AB - PURPOSE: To determine whether bladder pain syndrome/interstitial cystitis (BPS/IC) has the characteristics of a functional somatic syndrome (FSS). MATERIALS AND METHODS: There is no accepted definition of an FSS. Consequently, this paper reviewed the literature for common FSS characteristics and for reports that BPS/IC has these characteristics. RESULTS: Eleven articles met inclusion and exclusion criteria and yielded 18 FSS characteristics. BPS/IC patients manifest all but two: the exceptions were normal light microscopic anatomy (after hydrodistention under anesthesia, some BPS/IC bladders have Hunner's lesions and most have petechial hemorrhages) and normal laboratory tests (many BPS/IC patients have hematuria). Petechial hemorrhages and hematuria are probably related and may appear during naturally-occurring bladder distention. Without such distention, then, the 90% of BPS/IC patients without a Hunner's lesion have all the characteristics of an FSS. Comparisons in the opposite direction were consistent: several additional features of BPS/IC were found in FSSs. CONCLUSIONS: This systematic but untested method is consistent with but does not test the hypothesis that BPS/IC in some patients might best be understood as an FSS. Like most conditions, BPS/IC is probably heterogeneous; hence only a proportion of BPS/IC cases are likely to be manifestations of an FSS. This hypothesis has several implications. Explorations of processes that connect the FSSs might contribute to understanding the pathogenesis of BPS/IC. Patients with FSSs are at risk for BPS/IC and may benefit from future preventive strategies. Therapies that are useful in FSSs also may be useful in some cases of BPS/IC. PMID- 25455812 TI - Use, development and improvements in the protocol of whole-sediment toxicity identification evaluation using benthic copepods. AB - The whole-sediment Toxicity Identification Evaluation (TIE) approach is a useful technique that allows for the identification of the contaminants responsible for the toxicity of complex sediment samples. This study aimed to compare the effectiveness of this technique in identifying the causes of toxicity when the test organism used in the toxicity test is capable of ingesting sediment particles. Two forms of exposure were compared: whole-sediment (WS), which integrates dermic and dietary exposures; and sediment-water interface (SWI), which involves dermic exposure only. The combined analysis of the TIE experiments revealed that metals, ammonia and, at one station, organic compounds, were responsible for sediment toxicity. The integrated use of WS and SWI TIE manipulations provided a more complete overview of the causes of toxicity, and thus enabled a better comprehension of complex contamination situations and, consequently, a better ecological assessment. PMID- 25455813 TI - Mercury accumulation in sediments and seabird feathers from the Antarctic Peninsula. AB - In an effort to assess the impact of mercury in the Antarctic Peninsula, we conducted ecotoxicological research in this region during the summer of 2012 and 2013. The objectives were to assess: (a) mercury levels in sediment samples; (b) mercury accumulation in Antarctic seabird feathers: Catharacta lonnbergi (brown skua), Pygoscelis papua (gentoo penguin) and Pygoscelis antarctica (chinstrap penguin); and (c) biomagnification (BMF predator/prey) and biota sediment accumulation (BSAF skuas/sediment) factors. Mercury concentrations in sediment were relatively low. Mercury concentrations were significantly higher in brown skuas and gentoo penguins than in chinstrap penguins (2012), and significantly higher in brown skuas than in both penguins (2013). BMF indicated 2-7.5 times greater mercury levels in brown skuas than in penguins. BSAF values suggested an apparent temporal decrease of 18.2% of this ratio from 2012 to 2013. Long-range environmental transport is the likely route of entry of mercury into the Antarctic Peninsula. PMID- 25455814 TI - Effect of the invader Boccardia proboscidea (Polychaeta: Spionidae) on richness, diversity and structure of SW Atlantic epilithic intertidal community. AB - In Mar del Plata (Argentine, SW Atlantic), a large seaside resort, the sewage discharges impact the littoral ecosystem. The invader polychaete Boccardia proboscidea has developed reefs since spring of 2008. The effect of this species on the richness, diversity and structure of epilithic intertidal community was assessed through an MBACI design in both sewage-impacted and reference sites, and Before/After the invasion. The presence of reefs of B. proboscidea since spring 2008 has caused a significant reduction of total individuals, total taxa and diversity in sewage-impacted sites regarding the reference ones. The species analyzed showed a high variable response because patterns were dominated by small scale variability. Occasional peaks in abundance were observed on a single sampling site and time and a large variation among replicates. The associated fauna, formerly rich and diverse in impacted sites, shows a tendency to disappear as the ecosystem engineer Brachidontes rodriguezii is replaced by monocultures of B. proboscidea. PMID- 25455815 TI - Using a toxicity test with Ruppia maritima (Linnaeus) to assess the effects of Roundup. AB - Glyphosate, the active ingredient in Monsanto's broad-spectrum herbicide Roundup, consists of one of the most used pesticides worldwide, but its effects on the marine flora are still not well understood. Were examined Roundup toxic effects on Ruppia maritima specimens collected from Jansen Lagoon (Sao Luis, MA, Brazil) and acclimatized under laboratory conditions. The numbers of new and dead leaves, the root and leaf length, the chlorophyll a content, and the weight of R. maritima branches were determined before and after exposure to different Roundup concentrations for seven days. High concentrations caused a significant lethal effect. In addition, significant changes were observed in the wet and dry weights, the number and length of the leaves, and the chlorophyll a content. Leaf elongation was observed in the branches exposed to low concentrations, and this change was likely activated as a compensatory mechanism. The results indicate that high concentrations of this herbicide may compromise estuarine flora. PMID- 25455816 TI - Vertical distribution of (241)Pu in the southern Baltic Sea sediments. AB - The vertical distribution of plutonium (241)Pu in marine sediments can assist in determining the deposition history and sedimentation process of analyzed regions. In addition, (241)Pu/(239+240)Pu activity ratio could be used as a sensitive fingerprint for radioactive source identification. The present preliminary studies on vertical distribution of (241)Pu in sediments from four regions of the southern Baltic Sea are presented. The distribution of (241)Pu was not uniform and depended on sediment geomorphology and depth as well as location. The highest concentrations of plutonium were found in the surface layers of all analyzed sediments and originated from the Chernobyl accident. PMID- 25455818 TI - Insights into assessing water quality using taxonomic distinctness based on a small species pool of biofilm-dwelling ciliate fauna in coastal waters of the Yellow Sea, northern China. AB - The aim of this study is to determine the feasibility of using a small species pool from a raw dataset of biofilm-dwelling ciliates for bioassessment based on taxonomic diversity. Samples were collected monthly at four stations within a gradient of environmental stress in coastal waters of the Yellow Sea, northern China from August 2011 to July 2012. A 33-species subset was identified from the raw 137-species dataset using a multivariate method. The spatial patterns of this subset were significantly correlated with the changes in the nutrients and chemical oxygen demand. The taxonomic diversity indices were significantly correlated with nutrients. The pair-wise indices of average taxonomic distinctness (Delta(+)) and the taxonomic distinctness (Lambda(+)) showed a clear departure from the expected taxonomic pattern. These findings suggest that this small ciliate assemblage might be used as an adequate species pool for discriminating water quality status based on taxonomic distinctness in marine ecosystems. PMID- 25455817 TI - Reevaluation of Minamata Bay, 25 years after the dredging of mercury-polluted sediments. AB - A detailed investigation of mercury concentrations in the bottom sediments of Minamata Bay was performed in May, 2012. A total of 691 sediment samples were obtained from 107 sampling points in the bay. The weighted average total mercury concentration and the total mass of mercury in the bottom sediments of Minamata Bay were estimated to be 2.3mg/kg dry weight basis and 3.4 tons, respectively. The average concentration of total mercury in the surface layer of the sediments was 3.0mg/kg dry weight basis, and the distribution pattern of total mercury concentrations in the surface layer was found to have changed little in comparison to results reported 25 years ago. In addition, based on the results of seawater monitoring in Minamata Bay from 2010 to 2012, the amounts of total mercury and methylmercury mobilized from sediments and dissolved in the water column were 0.7 and 0.1 kg/yr, respectively. PMID- 25455819 TI - Occurrence and distribution of two phthalate esters in the sediments of the Anzali wetlands on the coast of the Caspian Sea (Iran). AB - This study provides the first data on distribution of phthalate Acid esters (PAEs) in surface sediment samples taken from Anzali Wetland, Iran. These samples were collected from 43 stations. Two PAEs consist of di(2-ethylhexylphthalate) (DEHP) and di-n-butyl phthalate (DnBP) were detected and the total concentrations of these two pollutants ranged from 0.25 to 43.12, 0.12 to 19.02MUgg(-1) dry weight, respectively. Among all the 43 samples analyzed, no sample was found to be free of DEHP and DBP, which indicates these two phthalate esters were ubiquitous in sediments. The concentrations in the near urban regions were higher than other regions because of higher discharge of PAEs from plastic materials in urbanized areas. Concentrations of PAEs were positively correlated with total organic carbon (TOC). Generally the median concentrations of DEHP and DnBP in the sediments were 15 and 14 times higher than the ERL. These results show that the Anzali wetland are highly polluted by major PAE congeners consist of DEHP and DnBP. PMID- 25455820 TI - Marine wildlife entanglement: Assessing knowledge, attitudes, and relevant behaviour in the Australian community. AB - Marine debris remains a global challenge, with significant impacts on wildlife. Despite this, there is a paucity of research examining public understanding about marine wildlife entanglement [MWE], particularly within an Australian context. The present study surveyed two hundred and thirteen participants across three coastal sites to assess familiarity with MWE and the effectiveness of a new community education initiative 'Seal the Loop' [STL]. Results revealed attitudes toward marine wildlife were very positive (M 40.5, SD 4.12); however 32% of participants were unable to correctly explain what MWE is and risks to wildlife were under-estimated. STL may be one method to enhance public understanding and engagement-if community familiarity with the program can be increased. For those aware of STL (<13% of the sample at the time of the study), findings revealed this was having a positive impact (e.g. learning something new, changed waste disposal behaviours). PMID- 25455821 TI - Contingency plan improvement for managing oil spills in the coastal waters of Thailand. AB - The estimated risks of being impacted by oil spills in the coastal waters were used to improve the oil spill contingency plan of Thailand. Functional roles of local agencies are integrated into the plan. Intensive measures are suggested for the coastal provinces located in high-very high risk zones, whereas light and moderate measures are suggested for the coastal provinces located in low and moderate risk zones, respectively. The estimated percentage risks due to simulated oil slicks hitting the coast and/or important resources (PRoilspill) were used to guide the year-round water activities that should be carefully handled at a certain radius with a low-moderate PRoilspill, whereas they should be avoided at a certain radius with a high-very high PRoilspill. Important measures before, during, and post periods of an oil spill incident are suggested to prevent and monitor oil spill incidents and mitigate their impacts on the environment. PMID- 25455822 TI - Potential impacts of historical disturbance on green turtle health in the unique & protected marine ecosystem of Palmyra Atoll (Central Pacific). AB - Palmyra Atoll, in the Central Pacific, is a unique marine ecosystem because of its remarkably intact food web and limited anthropogenic stressors. However during World War II the atoll was structurally reconfigured into a military installation and questions remain whether this may have impacted the health of the atoll's ecosystems and species. To address the issue we assessed green sea turtle (n=157) health and exposure to contaminants at this foraging ground from 2008 to 2012. Physical exams were performed and blood was sampled for testosterone analysis, plasma biochemistry analysis, hematology and heavy metal exposure. Hematological and plasma chemistries were consistent with concentrations reported for healthy green turtles. Heavy metal screenings revealed low concentrations of most metals, except for high concentrations of iron and aluminum. Body condition indices showed that <1% of turtles had poor body condition. In this study, we provide the first published blood values for a markedly healthy sea turtle population at a remote Central Pacific Atoll. PMID- 25455823 TI - Marine litter in Mediterranean sandy littorals: Spatial distribution patterns along central Italy coastal dunes. AB - Sandy shores are generally considered important sinks for marine litter and the presence of this litter may represent a serious threat to biotic communities and dune integrity mostly due to cleaning activities carried out through mechanical equipment. In spring (April-May) 2012 we sampled 153 2*2m random plots to assess the spatial distribution patterns of litter on Central Italy sandy shores. We analysed the relationship between the presence of litter and coastal dune habitats along the sea-inland gradient. Our results showed that the most frequent litter items were plastic and polystyrene. Differences of marine litter spatial distribution were found between upper beach and fore dune habitats and fixed dune habitats: embryo dune and mobile dune habitats show the highest frequency of litter, but, surprisingly, marine litter did not impact fixed dune habitats, these possibly acting as a natural barrier protecting the inner part of the coast from marine litter dispersion. PMID- 25455824 TI - Research on the fundamental principles of China's marine invasive species prevention legislation. AB - China's coastal area is severely damaged by marine invasive species. Traditional tort theory resolves issues relevant to property damage or personal injuries, through which plaintiffs cannot cope with the ecological damage caused by marine invasive species. Several defects exist within the current legal regimes, such as imperfect management systems, insufficient unified technical standards, and unsound legal responsibility systems. It is necessary to pass legislation to prevent the ecological damage caused by marine invasive species. This investigation probes the fundamental principles needed for the administration and legislation of an improved legal framework to combat the problem of invasive species within China's coastal waters. PMID- 25455829 TI - Voltage-gated sodium channel blockade for inhibition of EMT. PMID- 25455830 TI - Pilot the pulse: controlling the multiplicity of receptor dynamics. AB - G protein-coupled receptors (GPCRs) are involved in almost every (patho)physiological process, which explains their importance as drug targets. GPCRs have long been regarded as on/off-switches, which is reflected by direct activation or blockade of these receptors through the majority of marketed GPCR drugs. In recent years, however, our view of GPCRs has changed dramatically. GPCRs are now appreciated as integrative and highly dynamic signaling machines which can adopt numerous distinct conformations enabling them to initiate a highly ramified signaling network. We argue here that it may be possible to chemically encode distinct signaling profiles into ligands by rational ligand design. We exemplify our hypothesis by fine-tuning partial and biased agonism, thereby exploiting two new principles of GPCR modulation - dynamic and dualsteric ligand binding. We propose that the emerging understanding of the multiplicity of receptor dynamics will eventually lead to rationally designed new drugs which pilot the pulse; in other words, that stabilize distinct receptor states to fine tune GPCR signaling. PMID- 25455831 TI - Liraglutide treatment in a patient with HIV, type 2 diabetes and sleep apnoea hypopnoea syndrome. PMID- 25455832 TI - Manual and manipulative therapy in addition to rehabilitation for osteoarthritis of the knee: assessor-blind randomized pilot trial. AB - OBJECTIVES: The purpose of this study was to examine the methodological integrity, sample size requirements, and short-term preliminary clinical outcomes of manual and manipulative therapy (MMT) in addition to a rehabilitation program for symptomatic knee osteoarthritis (OA). METHODS: This was a pilot study of an assessor-blinded, randomized, parallel-group trial in 2 independent university based outpatient clinics. Participants with knee OA were randomized to 3 groups: 6 MMT sessions alone, training in rehabilitation followed by a home rehabilitation program alone, or MMT plus the same rehabilitation program, respectively. Six MMT treatment sessions (provided by a chiropractic intern under supervision or by an experienced chiropractor) were provided to participants over the 4-week treatment period. The primary outcome was a description of the research methodology and sample size estimation for a confirmatory study. The secondary outcome was the short-term preliminary clinical outcomes. Data were collected at baseline and 5weeks using the Western Ontario and McMasters Osteoarthritis Index questionnaire, goniometry for knee flexion/extension, and the McMaster Overall Therapy Effectiveness inventory. Analysis of variance was used to compare differences between groups. RESULTS: Eighty-three patients were randomly allocated to 1 of the 3 groups (27, 28, and 28, respectively). Despite 5 dropouts, the data from 78 participants were available for analysis with 10% of scores missing. A minimum of 462 patients is required for a confirmatory 3-arm trial including the respective interventions, accounting for cluster effects and a 20% dropout rate. Statistically significant and clinically meaningful changes in scores from baseline to week 5 were found for all groups for the Western Ontario and McMasters Osteoarthritis Index (P <= .008), with a greater change in scores for MMT and MMT plus rehabilitation. Between-group comparison did not reveal statistically significant differences between group scores at week 5 for any of the outcome measures (P >= .46). CONCLUSIONS: This pilot trial suggests that a confirmatory trial is feasible. There were significant changes in scores from baseline to week 5 across all groups, suggesting that all 3 treatment approaches may be of benefit to patients with mild-to-moderate knee OA, justifying a confirmatory trial to compare these interventions. PMID- 25455833 TI - Regional lumbar motion and patient-rated outcomes: a secondary analysis of data from a randomized clinical trial. AB - OBJECTIVE: The purpose of this study was to examine the relationship in change scores between regional lumbar motion and patient-rated pain of the previous week and back-related function in chronic low back pain patients enrolled in a randomized clinical trial and treated with either exercise therapy or spinal manipulation using 6 different motion parameters. METHODS: Regional lumbar motions were sampled using a 6 degrees of freedom instrumented spatial linkage system in 199 participants at baseline and 12-week follow-up. The regional lumbar motion data were analyzed as a total cohort as well as relative to subgroup stratifications; back pain only vs back and leg pain, and treatment modality. For identifying clinically meaningful improvements in the measurements of back pain and back-related function, we used a 30% threshold. RESULTS: The relationship between change scores in patient-rated outcomes and objective measures of regional lumbar motion was found to be weak. In contrast, distribution of pain and treatment received affected associations between motion parameters and patient-rated outcomes. Thus, stronger correlation coefficients and significant differences between clinically relevant improved vs no clinical relevant change were found in some motion parameters in the subgroup with back pain only and the treatment group receiving spinal manipulation. CONCLUSION: Overall, changes in regional lumbar motion were poorly associated with patient-rated outcomes measured by back-related function and back pain intensity scores. However, associations between regional lumbar motion vs patient-rated pain and back related function were different in relative subgroups (back pain only vs back and leg pain and treatment). PMID- 25455835 TI - Comparison of 2 methods of measuring spine angular kinematics during dynamic flexion movements: skin-mounted markers compared with markers affixed to rigid bodies. AB - OBJECTIVE: The purpose of this study was to compare the spine flexion angle time histories computed with the 2 described techniques (dot product [DP] and a modified joint coordinate system [JCS] approaches) that used vector algebra and used skin-mounted markers to the spine flexion angles derived using local coordinate systems constructed from rigid bodies affixed to the pelvis and thorax during spine flexion movements. METHODS: Discrepancies between the simplified marker setup and a criterion standard (CS) method for measuring spine kinematics were quantified. Sixteen participants performed full forward spine flexion. Three dimensional kinematic data were obtained from markers affixed bilaterally over the greater trochanters, iliac crests, and 10th ribs. Time varying spine flexion angles were derived from the 3-, and 2-dimensional marker data using a DP and a modified JCS approach. Criterion standard spine kinematics were obtained from clusters of markers adhered to 2 rigid fins that were affixed over the pelvis and trunk. The DP and JCS methods were compared with the CS by computing root mean squared differences and correlations during the spine flexion trials. Descriptive measurements of missing kinematic data were also obtained. RESULTS: On average, root mean squared differences were 30.1% lower for the JCS method of deriving spine flexion angles. Correlations were also higher for the JCS method by 2.5%, compared with the DP method. CONCLUSION: The findings suggest that the adapted JCS method is superior to the DP method for deriving spine flexion angles. This is especially true when only 2-dimensional coordinate data are available. PMID- 25455836 TI - The effect of body position on pulmonary function, chest wall motion, and discomfort in young healthy participants. AB - OBJECTIVE: The purpose of this study was to investigate the effect of different recumbent positions on pulmonary function, chest wall motion, and feelings of discomfort in young nonobese healthy volunteers. METHODS: Twenty healthy volunteers (age, 28.0+/-1.4 years; height, 167.5+/-10.1 cm; weight, 62.3+/-10.2 kg) were studied in the sitting position and in the following 6 recumbent positions: supine, left retroversion at a 45 degrees tilt, left anteversion at a 45 degrees tilt, right retroversion at a 45 degrees tilt, right anteversion at a 45 degrees tilt, and prone. After 5 minutes of a selected position, pulmonary functions, including vital capacity (VC), forced expiratory volume in 1 second, maximal inspiratory and expiratory mouth pressures (MIP and MEP, respectively), and breathing pattern components at the chest wall were assessed. Discomfort was assessed using a modified Borg scale. RESULTS: When participants changed position from sitting to each of the 6 recumbent positions, forced expiratory volume in 1 second values decreased significantly (P < .05). None of the participants showed changes in the MIP or MEP in any of the 6 recumbent positions. Rib cage motion was restricted in all recumbent positions except supine, left anteversion at a 45 degrees tilt, and prone. In all 6 recumbent positions, discomfort was experienced during the pulmonary tests. However, in the left retroversion at a 45 degrees tilt position, no discomfort was experienced during the MIP and MEP assessments. CONCLUSION: In young, nonobese, healthy volunteers, recumbent positions caused diminished pulmonary functions and induced feelings of discomfort. PMID- 25455834 TI - Prevalence of radiographic findings in individuals with chronic low back pain screened for a randomized controlled trial: secondary analysis and clinical implications. AB - OBJECTIVE: The purpose of this study is to measure the prevalence of graded disc degeneration, spondylolisthesis, transitional segmentation, and the distribution of sacral slope in patients 21 to 65 years of age with chronic low back pain (CLBP). METHODS: This retrospective study analyzed 247 digital lumbar radiographic series obtained during a randomized controlled trial of chiropractic patients with CLBP. Chronic low back pain was defined as pain in the low back lasting 12 weeks or longer. Radiographic findings of disc degeneration, spondylolisthesis, and lumbosacral transitional segmentation were graded by 2 authors using established classification criteria. Sacral slope was measured with a digital tool contained within imaging software. RESULTS: Lumbosacral transitional segments graded I to IV (Castellvi classification) were present in 14% of cases. Lumbar disc degeneration was most prevalent at L3-4 (49%), followed by L4-5 (42%), L2-3 (41%), L5-S1 (37%), and L1-2 (29%). Isthmic spondylolisthesis was present in 5% of cases, with L5 the most common location. Degenerative spondylolisthesis demonstrated a prevalence of 18%, most commonly occurring at L4. The prevalence of degenerative spondylolisthesis was 51% for women aged 50 to 59 years and 24% for men in the same age range. CONCLUSIONS: Moderate-severe disc degeneration, multilevel disc narrowing, and degenerative spondylolisthesis were common in individuals with CLBP with age more than 40 years. Isthmic spondylolisthesis was not more prevalent than what has been reported in other populations. Transitional segmentation was identified in a minority of participants, with some of these exhibiting accessory joints or fusion. Mean sacral slope in individuals with CLBP was not substantially different from mean slopes reported in other populations. PMID- 25455837 TI - Survey of new 2007 and 2011 Cochrane reviews found 37% of prespecified outcomes not reported. AB - OBJECTIVES: To survey the outcomes used in Cochrane Reviews, as part of our work within the Core Outcome Measures in Effectiveness Trials Initiative. STUDY DESIGN AND SETTING: A descriptive survey of Cochrane Reviews, divided by Cochrane Review Group (CRG), published in full for the first time in 2007 and 2011. Outcomes specified in the methods section of each review and outcomes reported in the results section of each review were of interest, in this exploration of the common use of outcomes and core outcome sets (COS). RESULTS: Seven hundred eighty eight reviews, specifying 6,127 outcomes, were included. When we excluded specified outcomes from the 86 reviews that did not include any studies, we found that 1,996 (37%) specified outcomes were not reported. Of the 361 new reviews with studies from 2011, 113 (31%) had a "summary of findings" table (SoF). Fifteen broad outcome categories were identified and used to manage the outcome data. We found consistency in the use of these categories across CRGs but inconsistency in outcomes within these categories. CONCLUSION: COS have been used rarely in Cochrane Reviews, but the introduction of SoF makes the development and application of COS timelier than ever. PMID- 25455838 TI - Systematic review recommends the European Organization for Research and Treatment of Cancer colorectal cancer-specific module for measuring quality of life in colorectal cancer patients. AB - OBJECTIVES: To critically appraise the measurement properties of standardized health-related quality of life (HRQOL) instruments for colorectal cancer (CRC) patients and to provide recommendations on the choice of HRQOL instruments. STUDY DESIGN AND SETTING: Systematic review of English language literature published between January 1985 and May 2014 identified through a database search of PubMed, Web of Science, Embase, and Ovid MEDLINE. HRQOL instruments were rated on methodological quality and overall levels of evidence using a Consensus-based Standards for the selection of health Measurement Instrument checklist. RESULTS: Internal consistency and hypothesis testing were evaluated most frequently in 63 studies identified. The Functional Assessment of Cancer Therapy-Colorectal (FACT C) was the most extensively evaluated. The highest number of positive ratings in the overall level of evidence was found in the CRC-specific quality of life questionnaire module (QLQ-CR38) in European Organization for Research and Treatment of Cancer (EORTC) module, followed by the Memorial Sloan Kettering Cancer Center Bowel instrument, FACT-C, and Quick-FLIC. The EORTC QLQ-CR38 had the most positive ratings on measurement property and was recommended. CONCLUSION: The EORTC QLQ-CR38 was recommended to assess HRQOL in patients with CRC, regardless of disease stage and primary tumor site. PMID- 25455839 TI - Gliotoxin from Aspergillus fumigatus reverses epithelial to mesenchymal transition: implications in renal fibrosis. AB - Fibrosis is generally characterized by an excessive accumulation and deposition of extracellular matrix (ECM) that progressively leads to the destruction of functional nephrons of the kidney. Current study is aimed to propose a probable antifibrotic mechanism of gliotoxin, isolated from marine Aspergillus fumigatus strain, in proximal tubule renal epithelial cells by inhibiting HIF-1alpha, Ang II and NF-kappaB in a dose dependent manner. GTX at a concentration of 1.6 ng/ml also showed more than 80% cell viability. Scanning Electron Microscopy, fluorescence microscopy, FACS, mRNA and protein profiles further confirmed that gliotoxin reverses the epithelial to mesenchymal transition in HK-2 cells by scavenging the production of reactive oxygen species (g=69.7) when compared to negative control (g=467.74). Under the light of obtained results, the present study holds immense promise for the biomedical implication of the fungal metabolite, Gliotoxin in medicine for treating various clinical cases of renal fibrosis. PMID- 25455840 TI - Acral lentiginous melanoma: who benefits from sentinel lymph node biopsy? AB - BACKGROUND: There are significant clinicopathological, genetic, and biological differences between acral lentiginous melanoma (ALM) and other types of melanoma. OBJECTIVE: We sought to investigate the use of sentinel lymph node (SLN) biopsy for patients with ALM. METHODS: This was a retrospective review of 116 patients with primary ALM. Melanoma-specific and disease-free survival were estimated using the Kaplan-Meier method, together with multivariate analyses using the Cox proportional hazards regression model. RESULTS: All patients were Japanese (48 male and 68 female). Metastases in SLN were noted in 13 of 84 patients who underwent SLN biopsy. No patients with thin ALM (<=1 mm) and only 2 patients with nonulcerated ALM had tumor-positive SLN. Patients with positive SLN had significantly shorter melanoma-specific survival (5-year survival rate, 37.5% vs 84.3%; P < .0001) and disease-free survival (5-year survival, 37.5% vs 77.9%; P = .0024). Among patients with thick (>1 mm) ALM, the influence of SLN positivity on melanoma-specific survival was increased (5-year survival, 22.7% vs 80.8%; P = .0005). LIMITATIONS: This was a retrospective study and had a small sample size. CONCLUSIONS: SLN biopsy should be considered for patients with thick or ulcerated ALM. For patients with thin or nonulcerated ones, it may be of limited importance. PMID- 25455841 TI - Cutaneous manifestations of human T-cell lymphotrophic virus type-1-associated adult T-cell leukemia/lymphoma: a single-center, retrospective study. AB - BACKGROUND: Limited data exist regarding cutaneous involvement of adult T-cell leukemia/lymphoma (ATLL), particularly in the United States. OBJECTIVE: We sought to characterize clinical and histopathologic features of ATLL in patients with skin involvement. METHODS: We retrospectively identified patients with ATLL from a single institution given a diagnosis during a 15-year period (1998-2013). Patients were categorized by the Shimoyama classification and stratified into skin-first, skin-second, and skin-uninvolved courses. RESULTS: The study population included 17 skin-first, 8 skin-second, and 29 skin-uninvolved cases. Skin-first patients (6 acute, 1 lymphoma, 4 chronic, 6 smoldering) were overwhelmingly of Caribbean origin (94%). They had longer median symptom duration (11.9 vs 1.9 months, P < .001) and overall survival (26.7 vs 10.0 months, P < .001) compared with skin-second/skin-uninvolved patients. Cutaneous lesion morphology at diagnosis included nodulotumoral (35%), multipapular (24%), plaques (24%), patches (12%), and erythroderma (6%). After initial skin biopsy, 14 of 17 received a non-ATLL diagnosis, most commonly mycosis fungoides (47%). Notable histopathologic findings from 43 biopsy specimens included greater than or equal to 20:1 CD4:CD8 ratio (79%), angiocentrism (78%), CD25(+) (71%), large cell morphology (70%), CD30(+) (68%), epidermal infiltration of atypical lymphocytes (67%) forming large Pautrier-like microabscesses (55%), and folliculotropism (65%). LIMITATIONS: This was a retrospective, single-center, tertiary referral center study with small sample size. CONCLUSION: Skin-first patients with ATLL in the United States are diagnostically challenging. Familiarity with clinicopathologic features may aid in diagnosis. PMID- 25455842 TI - C-reactive protein specifically enhances platelet-activating factor-induced inflammatory activity in vivo. AB - Platelet-activating factor (PAF) is a potent lipid mediator that is implicated in numerous inflammatory diseases. C-reactive protein (CRP) is an acute-phase plasma protein that increases rapidly and dramatically in response to inflammation. In this study, we investigated the effect of the interaction between CRP and PAF on inflammatory responses in vivo. From binding analysis using a time-resolved fluorometric assay, CRP bound to PAF and its precursor/metabolite lyso-PAF in a concentration-dependent manner. In addition, CRP bound to several phospholipids containing lysophosphatidylcholine, which bears structural resemblance to PAF and lyso-PAF, sphingosylphosphorylcholine, and lysophosphatidylethanolamine more readily than to lysophosphatidic acid and lysophosphatidylserine. In in vivo experiments using a rat model of hind paw oedema, CRP increased PAF-induced rat paw oedema in a dose-dependent manner, without causing the oedema itself, but it did not increase histamine and serotonin-induced paw oedema. Furthermore, the receptor for CRP, lectin-like oxidized low-density lipoprotein receptor 1 was not involved in the increase in PAF-induced inflammatory responses caused by CRP. These results indicate that CRP can specifically enhance PAF-induced inflammatory activity through binding to PAF and lyso-PAF. Therefore, CRP may accelerate the pathogenesis of numerous inflammatory diseases caused by PAF. PMID- 25455843 TI - Outcomes of primary lymphoma of the ocular adnexa (orbital lymphoma) treated with radiotherapy. AB - AIMS: Low-grade ocular adnexal lymphoma is a rare disease and often treated with local radiotherapy to varying doses. Most previously reported studies have a very heterogeneous patient population and treatments. We report the outcomes from a 10 year cohort of patients at our institution treated with primary radiation therapy. MATERIALS AND METHODS: We analysed a retrospective case series of patients with stage IE low-grade ocular adnexal lymphoma including a review of case notes, histological reports and radiotherapy charts. We assessed local and distant tumour control and relapse rates in addition to toxicity. Disease-free survival was estimated using the Kaplan-Meier method. RESULTS: In total, 81 patients and 85 orbits were treated with primary radiotherapy to a median dose of 30 Gy in 15 fractions over 3 weeks. Seventy-nine per cent were treated with standard MV external beam radiotherapy to the whole orbit and 21% with a lens sparing technique. The median follow-up was 4.4 years (range 0.2-10.4). Local control rates were 100%, with 5% of patients experiencing disease relapse elsewhere. No patients died from lymphoma. Cumulative acute toxicity rates were 51% (mainly erythema and conjunctivitis) and late toxicity rates were 8% (mainly cataract). The lens-sparing technique was associated with a significant reduction in cataract rate (P = 0.013) and an increase in acute toxicity (P < 0.001). CONCLUSIONS: This study has shown excellent local control rates and acceptable toxicity from the treatment of stage IE low-grade ocular adnexal lymphoma with localised radiotherapy to a median dose of 30 Gy in 15 fractions over 3 weeks. PMID- 25455844 TI - Estimation of an optimal chemotherapy utilisation rate for cancer: setting an evidence-based benchmark for quality cancer care. AB - There is wide variation in the proportion of newly diagnosed cancer patients who receive chemotherapy, indicating the need for a benchmark rate of chemotherapy utilisation. This study describes an evidence-based model that estimates the proportion of new cancer patients in whom chemotherapy is indicated at least once (defined as the optimal chemotherapy utilisation rate). The optimal chemotherapy utilisation rate can act as a benchmark for measuring and improving the quality of care. Models of optimal chemotherapy utilisation were constructed for each cancer site based on indications for chemotherapy identified from evidence-based treatment guidelines. Data on the proportion of patient- and tumour-related attributes for which chemotherapy was indicated were obtained, using population based data where possible. Treatment indications and epidemiological data were merged to calculate the optimal chemotherapy utilisation rate. Monte Carlo simulations and sensitivity analyses were used to assess the effect of controversial chemotherapy indications and variations in epidemiological data on our model. Chemotherapy is indicated at least once in 49.1% (95% confidence interval 48.8-49.6%) of all new cancer patients in Australia. The optimal chemotherapy utilisation rates for individual tumour sites ranged from a low of 13% in thyroid cancers to a high of 94% in myeloma. The optimal chemotherapy utilisation rate can serve as a benchmark for planning chemotherapy services on a population basis. The model can be used to evaluate service delivery by comparing the benchmark rate with patterns of care data. The overall estimate for other countries can be obtained by substituting the relevant distribution of cancer types. It can also be used to predict future chemotherapy workload and can be easily modified to take into account future changes in cancer incidence, presentation stage or chemotherapy indications. PMID- 25455845 TI - Assessment of 20 year survival in men with breast cancer. PMID- 25455846 TI - Dose-dense paclitaxel in advanced ovarian cancer. AB - Carboplatin and paclitaxel, delivered on a 3-weekly basis, is the historical standard for the management of advanced epithelial ovarian cancers (EOC). Increased dose intensity, the inclusion of additional active cytotoxic agents and lengthening treatment duration have failed to improve the outcomes seen with standard doses of carboplatin and paclitaxel in the treatment of EOC. Dose-dense (i.e. weekly) delivery of paclitaxel may exploit anticancer mechanisms such as anti-angiogenesis and the induction of apoptosis. Tumour regrowth may be more effectively impaired by the dose-dense delivery of paclitaxel. Non-randomised studies of dose-dense chemotherapy in EOC have been promising, particularly in heavily pretreated and platinum-resistant disease, with reported response rates as high as 60%. Dose-dense paclitaxel also seems to be well tolerated. These observations led to a number of comparative trials of dose-dense paclitaxel chemotherapy, three have been reported and four are ongoing. This review explores the rationale behind dose-dense delivery of paclitaxel and evaluates the results of completed phase III trials. PMID- 25455847 TI - Clinical experience of the use of voriconazole, caspofungin or the combination in primary and salvage therapy of invasive aspergillosis in haematological malignancies. AB - Invasive aspergillosis (IA) is a life-threatening infection in severely immunocompromised haematological malignancy patients. In this study, the efficacy and safety of caspofungin, voriconazole or the combination as primary and salvage therapy in patients with IA were compared. The study included 181 patients with haematological malignancies and IA who received primary or salvage therapy with caspofungin, voriconazole or the combination. In total, 138 patients who received treatment for >=7 days were analysed; 86 underwent primary antifungal therapy (15 with caspofungin, 38 with voriconazole and 33 with both). Among the salvage therapy patients, 17 received caspofungin, 24 received voriconazole and 35 received both. In the primary therapy group, no difference in therapy response was found, but caspofungin was associated with higher IA mortality rates. A multivariate competing risk analysis of primary antifungal therapy revealed that voriconazole was independently associated with lower IA-associated mortality rates than caspofungin (hazard ratio=0.2, 95% confidence interval 0.06-0.96; P=0.04). In the salvage therapy group, the three treatment groups had similar responses and IA-associated mortality rates. The combination of voriconazole and caspofungin did not result in better outcomes compared with voriconazole alone, as primary or salvage therapy, in haematological malignancy patients. However, voriconazole was associated with a lower Aspergillus-associated mortality rate compared with caspofungin monotherapy. PMID- 25455849 TI - Action of silver nanoparticles towards biological systems: cytotoxicity evaluation using hen's egg test and inhibition of Streptococcus mutans biofilm formation. AB - This study aimed to evaluate the cytotoxicity and bactericidal properties of four silver nanoparticle (AgNP) colloids and their ability to inhibit Streptococcus mutans biofilm formation on dental enamel. The cytotoxicity of AgNPs was evaluated based on signs of vascular change on the chorioallantoic membrane using the hen's egg test (HET-CAM). Bactericidal properties and inhibition of S. mutans biofilm formation were determined using a parallel-flow cell system and a dichromatic fluorescent stain. The percentage of viable cells was calculated from regression data generated from a viability standard. AgNP colloids proved to be non-irritating, as they were unable to promote vasoconstriction, haemorrhage or coagulation. AgNP colloids inhibited S. mutans biofilm formation on dental enamel, and cell viability measured by fluorescence was 0% for samples S1, S2, S3 and S4 and 36.5% for the positive control (diluted 30% silver diamine fluoride). AgNPs are new products with a low production cost because they have a lower concentration of silver, with low toxicity and an effective bactericidal effect against a cariogenic oral bacterium. Moreover, they do not promote colour change in dental enamel, which is an aesthetic advantage compared with traditional silver products. PMID- 25455848 TI - First-dose pharmacokinetics of aminoglycosides in critically ill haematological malignancy patients. AB - The primary objective of this study was to determine the volume of distribution (Vd) (L/kg) of intravenous aminoglycosides (AGs) in critically ill haematological malignancy patients. Secondary objectives were to determine the body weight (actual, ideal, adjusted or lean) that yields the most precise estimate of Vd when normalised in L/kg as well as the frequency that current first-dose strategies result in post-distributional peak concentrations (C(peak)) within the target range (tobramycin 16-24 mg/L; amikacin 32-48 mg/L). In total, 58 AG doses were included (tobramycin, n = 34; amikacin, n = 24). Median Vd was 0.38 L/kg normalised per the most precise dose weight, which was actual body weight (ABW). The median dose was 445 mg (5.8 mg/kg ABW) for tobramycin and 1200 mg (13.8 mg/kg ABW) for amikacin. Target C(peak) (tobramycin 20mg/L; amikacin 40 mg/L) was achieved in only 25% of all AG episodes, with 4% exceeding the target and 71% falling below the target. Twenty-four organisms were isolated in the study sample; target C(peak) achievement (tobramycin 20 mg/L; amikacin 40 mg/L) would yield a peak:minimum inhibitory concentration of 10 in 75% and 52% of organisms, respectively. In conclusion, an increased Vd of AGs was identified in this critically ill haematological malignancy patient sample, and current dosing yielded a suboptimal C(peak) in the majority of patients. PMID- 25455851 TI - Real-time video imaging as a new and rapid tool for antibiotic susceptibility testing by the disc diffusion method: a paradigm for evaluating resistance to imipenem and identifying extended-spectrum beta-lactamases. AB - The disc diffusion method has long been considered the standard technique for antibiotic susceptibility testing (AST) in clinical microbiology laboratories because of its simplicity, reproducibility and low cost compared with commercial automated microdilution systems that are usually more rapid but less sensitive for detecting important mechanisms of resistance. Here we measured reading zone diameters around antibiotics in a series of 25 well-characterised Gram-negative bacteria by the disc diffusion technique in real-time using an Advencis Bio System instrument consisting of a real-time high-resolution video imager in a dedicated incubator. The susceptibility of wild-type Gram-negative bacteria to imipenem, determined by reading the diameter of inhibition, was detectable as early as 3.5h (mean time 3.7 +/- 0.45 h), whereas carbapenemase-producing Gram negative bacteria could be correctly categorised as early as 3h (mean time 4.2 +/ 0.8 h) of incubation. Similarly, the characteristic champagne cork aspect of extended-spectrum beta-lactamase (ESBL) could be detected by the system as early as 3.5 h. Moreover, we present here for the first time video movies of the appearance of the diameter of inhibition by disc diffusion in real-time. This preliminary study using a new and innovative technology provides for a renewed interest for microbiologists who wish to continue to use the disc diffusion method as a reference method for AST. New video imaging technology presents a proof of concept that could improve the real-time management of patients with AST within a very rapid turnaround time and can provide a large financial saving for hospitals. PMID- 25455850 TI - High prevalence of carbapenem resistance among plasmid-mediated AmpC beta lactamase-producing Klebsiella pneumoniae during outbreaks in liver transplantation units. AB - During a prospective surveillance using PCR for the detection of plasmid-mediated AmpC beta-lactamase (pAmpC)-producing Enterobacteriaceae, outbreaks due to pAmpC producing Klebsiella pneumoniae (pAmpC-Kp) occurred in an adult liver transplantation unit (aLTU) and a paediatric liver transplantation unit (pLTU), with carbapenem-resistant (CR) variants. Between April 2010 and March 2012, a total of 32 patients infected with pAmpC-Kp were found by prospective surveillance using PCR detection at a Japanese university hospital. Multilocus sequence typing, analysis of outer membrane proteins, and detection of carbapenemases were performed. Clinical courses of patients with bloodstream infection (BSI) were reviewed. Of 32 pAmpC-Kp isolates from each patient, 20 (18 from aLTU patients) were DHA-1-producing sequence type 11 (DHA-1-ST11), 9 were CMY-2-ST45/778 (all from pLTU patients) and the other 3 isolates had different sequence types. CR variants were isolated from 8 aLTU patients with DHA-1-ST11 and from 1 pLTU patient with CMY-2-ST45. All of the pAmpC-Kp isolates, including CR variants, were negative for carbapenemases. All of the DHA-1-ST11 and CMY-2 ST45 isolates lacked OmpK35, and seven CR variants also lacked OmpK36. BSIs due to DHA-1-ST11 isolates, including CR variants, occurred in six aLTU patients, four of whom died. The outbreaks were controlled after application of intensified infection control measures. During pAmpC-Kp outbreaks involving 27 liver transplants, CR variants with porin loss developed in nine patients, and DHA-1 ST11 K. pneumoniae caused BSIs with high mortality. PMID- 25455852 TI - Concentration-response studies and modelling of the pharmacodynamics of linezolid: Staphylococcus aureus versus Enterococcus faecium. AB - For assessing antibiotic effects, the minimum inhibitory concentration (MIC) neglects that most antibiotics display different rates of bacterial killing. Time kill curves, on the other hand, provide details on these killing rates but their interpretation is more complex and hardly standardised. The aim of the present study was to develop an analysis method to easily compare the pharmacodynamics of linezolid (LZD) against Staphylococcus aureus and Enterococcus faecium via in vitro time-kill curve experiments and to describe it by mathematical modelling. The effect of LZD against both organisms was investigated in a static in vitro infection model using 0.5-32.0 MUg/mL LZD over 24h. LZD concentrations were quantified by a validated HPLC assay. A modified sigmoidal maximum effect (Emax) pharmacokinetic/pharmacodynamic (PK/PD) model that accounts for time-dependent effects was developed in 'R'. As a continuous, growth-control-normalised pharmacodynamic measure, the relative bacterial reduction (RBR) was introduced and derived. LZD was more effective against S. aureus than against E. faecium (Emax 1.8-fold higher) at a comparable potency (EC50, 3.02 MUg/mL vs. 1.80 MUg/mL). The time delay of the maximum effect was predominantly observed within 6h of exposure. Model evaluation demonstrated its precision, robustness and predictive performance. In conclusion, the presented PK/PD analysis method provides quantitative measures (EC50, Emax) for the antibacterial drug effect as easy to interpret as point estimates, but more informative than the MIC since time- and concentration-dependent effects were considered. Application of the presented model developed as a flexible, robust tool in the free software 'R' appears promising. PMID- 25455853 TI - Pharmacokinetics of meropenem in critically ill patients receiving continuous venovenous haemofiltration: a randomised controlled trial of continuous infusion versus intermittent bolus administration. AB - The objective of this study was to describe the pharmacokinetics of meropenem, administered by continuous infusion (CI) or intermittent bolus (IB), in critically ill patients receiving continuous venovenous haemofiltration (CVVH) and to evaluate the frequency of pharmacokinetic/pharmacodynamic target attainment with each dosing strategy. This was a prospective, randomised controlled trial in critically ill patients receiving CVVH and administered meropenem by CI or IB. Serial meropenem concentrations in plasma and ultrafiltrate were measured after administration of a standard total daily dose (4 g/day on Day 1, followed by 3g/day thereafter) on two occasions during antibiotic therapy. Meropenem pharmacokinetic parameters were calculated using a non-compartmental approach. Sixteen critically ill patients receiving CVVH concurrently treated with meropenem were randomised to CI (n = 8) or IB dosing (n = 8). IB administration resulted in higher maximum concentrations (C(max)) [64.7 (58.9-80.3) and 64.8 (48.5-81.8) mg/L, respectively] on both sampling occasions compared with CI (P < 0.01 and P = 0.04, respectively). CI resulted in a higher meropenem steady-state concentration (Css) on occasion 1 [26.0 (24.5-41.6) mg/L] compared with the minimum concentration (C(min)) observed for IB patients [17.0 (15.7-19.8)mg/L; P < 0.01]. CVVH contributed to ca. 50% of meropenem total clearance in these patients. The administered meropenem doses resulted in plasma drug concentrations that were >4* the targeted susceptibility breakpoint (2mg/L) for 100% of the dosing interval, for both groups, on both occasions. CI could be an alternative to IB for meropenem administration in critically ill patients receiving CVVH. PMID- 25455854 TI - Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration. AB - Fluconazole is a widely used antifungal agent in critically ill patients. It is predominantly (60-80%) excreted unchanged in urine. Sustained low-efficiency diafiltration (SLED-f) is increasingly being utilised in critically ill patients because of its practical advantages over continuous renal replacement therapy. To date, the effect of SLED-f on fluconazole pharmacokinetics and dosing has not been studied. The objective of this study was to describe the pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving SLED-f and to compare this with other forms of renal replacement therapy. Serial blood samples were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f and from an arterial catheter before and after SLED-f from three patients during one session. Fluconazole concentrations were measured using a validated chromatography method. Median clearance (CL) and 24-h area under the concentration-time curve (AUC0-24) were 2.1L/h and 152 mg.h/L, respectively, whilst receiving SLED-f. Moreover, 72% of fluconazole was cleared by a single SLED-f session (6h) compared with previous reports of 33-38% clearance by a 4-h intermittent haemodialysis session. CL and AUC0-24 were comparable with previous observations in a pre-dilution mode of continuous venovenous haemodiafiltration. The observed rebound concentration of fluconazole post SLED-f was <2%. Although a definitive dosing recommendation is not possible due to the small patient number, it is clear that doses >200mg daily are likely to be required to achieve the PK/PD target for common pathogens because of significant fluconazole clearance by SLED-f. PMID- 25455855 TI - Telling stories out of school: experiencing the paramedic's oral traditions and role dissonance. AB - Role dissonance is an uncomfortable experience for graduate paramedics, and some blame their university education for the problem. For paramedics the conflict is between identifying as a rescuer and acting largely as a care giver. With vocational pathways into so many uniformed professions closing down in preference for graduate entrants, young new professionals have to negotiate a rapidly changing work culture. Their older colleagues may be challenged and threatened by the new order. For paramedics the problem is compounded by the newness of its place in the tertiary landscape. Since 9/11 young people have been increasingly attracted to rescue roles. Yet in Australia there is increasing need and scope for health workers in remote and aging populations, a preference not immediately attractive to young people hoping for a more heroic future. While the near professions such as nursing have established their discourses around culture, role and pedagogy, paramedics is still trying to chisel its identity. The myths of paramedic glories past tend to add to the confusion of graduates. Due to a lack of empirical studies of non-clinical aspects of paramedicine, a bricolage methodology was used to refresh data from two discrete qualitative research projects conducted in 2011. Both projects had originally been interested in optimal paramedic preceptorship before and after graduation, but neither had explored the implicit theme which revealed the role of rescue experiences in paramedic culture and identity. The bricolage included a new search of literature from near professions and applied new theoretical frameworks to the analysis of the extant data, to demonstrate how storytelling as an element of paramedic collegiality perpetuates rescue stories that are then used to define paramedic work. PMID- 25455856 TI - Correlated Dynamics of the O((3)P) + CHD3(v=0) Reaction: A Joint Crossed-Beam and Quasiclassical Trajectory Study. AB - Crossed beam experiments and quasiclassical trajectory computations on an ab initio potential energy surface are performed for the O((3)P) + CHD3(v=0) -> OH(v'=0) + CD3(v2=0,2) and OD(v'=0,1) + CHD2(v=0) reactions. Both experiment and theory show that the excitation functions display a concave-up behavior and the angular distributions are backward scattered, indicating a direct rebound mechanism and a tight-bend transition state. The reaction produces mainly ground state products showing the dominance of a vibrationally adiabatic reaction pathway. The standard histogram binning cannot reproduce the observed vibrational adiabaticity, whereas Gaussian binning gives good agreement with experiment. PMID- 25455857 TI - The host antimicrobial peptide Bac71-35 binds to bacterial ribosomal proteins and inhibits protein synthesis. AB - Antimicrobial peptides (AMPs) are molecules from innate immunity with high potential as novel anti-infective agents. Most of them inactivate bacteria through pore formation or membrane barrier disruption, but others cross the membrane without damages and act inside the cells, affecting vital processes. However, little is known about their intracellular bacterial targets. Here we report that Bac71-35, a proline-rich AMP belonging to the cathelicidin family, can reach high concentrations (up to 340 MUM) inside the E. coli cytoplasm. The peptide specifically and completely inhibits in vitro translation in the micromolar concentration range. Experiments of incorporation of radioactive precursors in macromolecules with E. coli cells confirmed that Bac71-35 affects specifically protein synthesis. Ribosome coprecipitation and crosslinking assays showed that the peptide interacts with ribosomes, binding to a limited subset of ribosomal proteins. Overall, these results indicate that the killing mechanism of Bac71-35 is based on a specific block of protein synthesis. PMID- 25455858 TI - Quorum-sensing crosstalk-driven synthetic circuits: from unimodality to trimodality. AB - Widespread quorum-sensing (QS) enables bacteria to communicate and plays a critical role in controlling bacterial virulence. However, effects of promiscuous QS crosstalk and its implications for gene regulation and cell decision-making remain largely unknown. Here we systematically studied the crosstalk between LuxR/I and LasR/I systems and found that QS crosstalk can be dissected into signal crosstalk and promoter crosstalk. Further investigations using synthetic positive feedback circuits revealed that signal crosstalk significantly decreases a circuit's bistable potential while maintaining unimodality. Promoter crosstalk, however, reproducibly generates complex trimodal responses resulting from noise induced state transitions and host-circuit interactions. A mathematical model that integrates the circuit's nonlinearity, stochasticity, and host-circuit interactions was developed, and its predictions of conditions for trimodality were verified experimentally. Combining synthetic biology and mathematical modeling, this work sheds light on the complex behaviors emerging from QS crosstalk, which could be exploited for therapeutics and biotechnology. PMID- 25455859 TI - Rational design of small molecule inhibitors targeting the Ras GEF, SOS1. AB - Ras GTPases regulate intracellular signaling involved in cell proliferation. Elevated Ras signaling activity has been associated with human cancers. Ras activation is catalyzed by guanine nucleotide exchange factors (GEFs), of which SOS1 is a major member that transduces receptor tyrosine kinase signaling to Ras. We have developed a rational approach coupling virtual screening with experimental screening in identifying small-molecule inhibitors targeting the catalytic site of SOS1 and SOS1-regulated Ras activity. A lead inhibitor, NSC 658497, was found to bind to SOS1, competitively suppress SOS1-Ras interaction, and dose-dependently inhibit SOS1 GEF activity. Mutagenesis and structure activity relationship studies map the NSC-658497 site of action to the SOS1 catalytic site, and define the chemical moieties in the inhibitor essential for the activity. NSC-658497 showed dose-dependent efficacy in inhibiting Ras, downstream signaling activities, and associated cell proliferation. These studies establish a proof of principle for rational design of small-molecule inhibitors targeting Ras GEF enzymatic activity. PMID- 25455861 TI - The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases. AB - Alzheimer's (AD) and Parkinson's (PD) diseases are neurodegenerative diseases presently without effective drug treatments. AD is characterized by general cognitive impairment, difficulties with memory consolidation and retrieval, and with advanced stages episodes of agitation and anger. AD is increasing in frequency as life expectancy increases. Present FDA approved medications do little to slow disease progression and none address the underlying progressive loss of synaptic connections and neurons. New drug design approaches are needed beyond cholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists. Patients with PD experience the symptomatic triad of bradykinesis, tremor-at rest, and rigidity with the possibility of additional non-motor symptoms including sleep disturbances, depression, dementia, and autonomic nervous system failure. This review summarizes available information regarding the role of the brain renin-angiotensin system (RAS) in learning and memory and motor functions, with particular emphasis on research results suggesting a link between angiotensin IV (AngIV) interacting with the AT4 receptor subtype. Currently there is controversy over the identity of this AT4 receptor protein. Albiston and colleagues have offered convincing evidence that it is the insulin-regulated aminopeptidase (IRAP). Recently members of our laboratory have presented evidence that the brain AngIV/AT4 receptor system coincides with the brain hepatocyte growth factor/c-Met receptor system. In an effort to resolve this issue we have synthesized a number of small molecule AngIV-based compounds that are metabolically stable, penetrate the blood-brain barrier, and facilitate compromised memory and motor systems. These research efforts are described along with details concerning a recently synthesized molecule, Dihexa that shows promise in overcoming memory and motor dysfunctions by augmenting synaptic connectivity via the formation of new functional synapses. PMID- 25455860 TI - PMI: a DeltaPsim independent pharmacological regulator of mitophagy. AB - Mitophagy is central to mitochondrial and cellular homeostasis and operates via the PINK1/Parkin pathway targeting mitochondria devoid of membrane potential (DeltaPsim) to autophagosomes. Although mitophagy is recognized as a fundamental cellular process, selective pharmacologic modulators of mitophagy are almost nonexistent. We developed a compound that increases the expression and signaling of the autophagic adaptor molecule P62/SQSTM1 and forces mitochondria into autophagy. The compound, P62-mediated mitophagy inducer (PMI), activates mitophagy without recruiting Parkin or collapsing DeltaPsim and retains activity in cells devoid of a fully functional PINK1/Parkin pathway. PMI drives mitochondria to a process of quality control without compromising the bio energetic competence of the whole network while exposing just those organelles to be recycled. Thus, PMI circumvents the toxicity and some of the nonspecific effects associated with the abrupt dissipation of DeltaPsim by ionophores routinely used to induce mitophagy and represents a prototype pharmacological tool to investigate the molecular mechanisms of mitophagy. PMID- 25455862 TI - Behavioral study of non-evoked orofacial pain following different types of infraorbital nerve injury in rats. AB - Directed isolated face grooming following unilateral chronic constriction injury to the infraorbital nerve (IoN-CCI) is a unique measure of spontaneous neuropathic pain. Variability between rats and the limited duration of the increased face grooming behavior has hampered its usefulness. We studied three possible sources of variability: variations in surgery, pre-existing differences in nocifensive behavior between the rats and variation in time. Three different types of IoN lesion were performed: loose ligation (CCI), tight ligation (CCI-T) and partial tight ligation (PTL, Seltzer method); the latter two offer greater surgical standardization. Face grooming behavior following IoN injury, on the one hand, and during the orofacial formalin test, on the other hand, was analyzed and correlated. Significant differences in isolated face grooming behavior were found between the IoN groups. Interestingly, CCI-T rats continued to show significantly increased isolated face grooming for the duration of the experiment, i.e., up to 32 days post-operative, whereas CCI animals were no longer significantly different from sham animals after two weeks. Surprisingly, PTL operated rats only showed minor effects. Variability was not smaller in the CCI-T or PTL group. Face grooming behavior after IoN lesion was poorly correlated to that in the orofacial formalin test. It is therefore unclear if pre-existing behavioral differences between animals are a major cause of variability in the IoN-CCI model. Finally, repeated testing showed significant variability in time. It is concluded that tight ligation of the IoN nerve has long-lasting effects on face grooming behavior and that part of the variability in face grooming behavior may be reduced by performing repeated testing. PMID- 25455863 TI - Children's cortisol and salivary alpha-amylase interact to predict attention bias to threatening stimuli. AB - Physiological responses to threat occur through both the autonomic nervous system (ANS) and the hypothalamic pituitary adrenal (HPA) axis. Activity in these systems can be measured through salivary alpha-amylase (sAA) and salivary cortisol, respectively. Theoretical work and empirical studies have suggested the importance of examining the coordination of these systems in relation to cognitive functioning and behavior problems. Less is known, however, about whether these systems interactively predict more automatic aspects of attention processing such as attention toward emotionally salient threatening stimuli. We used a dot probe task to assess attention bias toward threatening stimuli in 347 kindergarten children. Cortisol and sAA were assayed from saliva samples collected prior to children's participation in assessments on a subsequent day. Using regression analyses, we examined relations of sAA and cortisol to attention bias. Results indicate that cortisol and sAA interact in predicting attention bias. Higher levels of cortisol predicted greater bias toward threat for children who had high levels of sAA, but predicted greater bias away from threat for children who had low levels of sAA. These results suggest that greater symmetry in HPA and ANS functioning is associated with greater reliance on automatic attention processes in the face of threat. PMID- 25455864 TI - Effects of gender on locomotor sensitivity to amphetamine, body weight, and fat mass in regulator of G protein signaling 9 (RGS9) knockout mice. AB - Regulator of G-protein signaling (RGS) protein 9-2 is enriched in the striatum where it modulates dopamine and opioid receptor-mediated signaling. RGS9 knockout (KO) mice show increased psychostimulant-induced behavioral sensitization, as well as exhibit higher body weights and greater fat accumulation compared to wild type (WT) littermates. In the present study, we found gender influences on each of these phenotypic characteristics. Female RGS9 KO mice exhibited greater locomotor sensitization to amphetamine (1.0mg/kg) treatment as compared to male RGS9 KO mice. Male RGS9 KO mice showed increased body weights as compared to male WT littermates, while no such differences were detected in female mice. Quantitative magnetic resonance showed that male RGS9 KO mice accumulated greater fat mass vs. WT littermates at 5months of age. Such observations could not be explained by increased caloric consumption since male and female RGS9 KO mice demonstrated equivalent daily food intake as compared to their respective WT littermates. Although indirect calorimetry methods found decreased oxygen consumption and carbon dioxide production during the 12-hour dark phase in male RGS9 KO vs. WT mice which are indicative of less energy expenditure, male RGS9 KO mice exhibited lower levels of locomotor activity during this period. Genotype had no effect on metabolic activities when KO and WT groups were compared under fasting vs. feeding treatments. In summary, these results highlight the importance of factoring gender into the experimental design since many studies conducted in RGS9 KO mice utilize locomotor activity as a measured outcome. PMID- 25455865 TI - Resveratrol exerts anti-inflammatory and neuroprotective effects to prevent memory deficits in rats exposed to chronic unpredictable mild stress. AB - A number of studies have recently focused on the neuroprotective and anti inflammatory effects of resveratrol. In prior studies, we described its beneficial effects on scopolamine-induced learning deficits in rats. The aim of this study was to investigate the effects of resveratrol on emotional and spatial cognitive functions, neurotropic factor expression, and plasma levels of proinflammatory cytokines in rats exposed to chronic unpredictable mild stress (CUMS), which is known to induce cognitive deficits. Resveratrol (5 or 20mg/kg) was administered intraperitoneally for 35 days. Rats in the CUMS group and in the 5mg/kg resveratrol+CUMS group performed poorly in tasks designed to assess emotional and spatial learning and memory. The 20mg/kg resveratrol+CUMS group showed improved performance compared to the CUMS group. In addition, the CUMS procedure induced lower expression of brain-derived neurotrophic factor and c-Fos in hippocampal CA1 and CA3 and in the amygdala of stressed rats. These effects were reversed by chronic administration of resveratrol (20mg/kg). In addition, plasma levels of tumor necrosis factor-alpha and interleukin-1 beta were increased by CUMS, but were restored to normal by resveratrol. These results indicate that resveratrol significantly attenuates the deficits in emotional learning and spatial memory seen in chronically stressed rats. These effects may be related to resveratrol-mediated changes in neurotrophin factor expression in hippocampus and in levels of proinflammatory cytokines in circulation. PMID- 25455866 TI - Prenatal hyperandrogenic environment induced autistic-like behavior in rat offspring. AB - Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persistent impairment in social communication and social interaction. Recent studies revealed that environmental factors, especially the intrauterine developmental environment, played important roles in the development of ASD. It is hypothesized that maternal hyperandrogenism during pregnancy may increase the susceptibility of the fetus to ASD. In the present study, pregnant rats were treated with a low dose of letrozole (1MUg/kg/day) in an attempt to produce a hyperandrogenic intrauterine environment for the developing fetus. Results showed that rat pups prenatally exposed to hyperandrogenic intrauterine environment emitted less number of ultrasonic vocalizations when isolated from their dams and littermates. Additionally, the female rats in the treatment group spent less time in social interaction in adolescence and exhibited impaired heterosexual interaction in adult. Moreover, the duration of social interaction and heterosexual interaction of the female offspring were negatively correlated with maternal serum testosterone levels during pregnancy. These results suggest that prenatal exposure to hyperandrogenic intrauterine environment could induce autistic-like behavior in female rats and maternal hyperandrogenism during pregnancy should be considered as a potential risk factor for the etiology of ASD. PMID- 25455867 TI - Physiological and neurobehavioral effects of cholinesterase inhibition in healthy adults. AB - INTRODUCTION: Based on common pharmacodynamic mechanisms, recent efforts to develop second generation alternatives for organophosphate (OP) prophylaxis have expanded to include cholinesterase (ChE) inhibiting compounds traditionally approved for use in the treatment of Alzheimer's disease (AD). The primary purpose of this study was to determine the extent to which low-dose huperzine A, galantamine, or donepezil selectively inhibited acetylcholinesterase (AChE) versus butyrylcholinesterase (BChE) activity in healthy adults and whether such inhibition impacted neurobehavioral performance. METHODS: In addition to hourly red blood cell cholinesterase sampling, neurobehavioral function was assessed before and after a single oral dose of huperzine A (100 or 200 MUg), galantamine (4 or 8 mg), donepezil (2.5 or 5mg), or placebo (n=12 subjects per drug/dose). RESULTS: Compared to placebo, both dosages of huperzine A and galantamine inhibited circulating AChE but not BChE. With the exception of huperzine A (200 MUg), which maintained declarative recall performance across sessions, compounds did not improve neurobehavioral performance. Some aspects of neurobehavioral performance correlated with AChE activity, although associations may have reflected time of day effects. DISCUSSION: Although huperzine A and galantamine significantly inhibited AChE (and likely increased central acetylcholine levels), neither compound improved neurobehavioral performance. The latter was likely due to ceiling effects in this young, healthy test population. Under conditions of reduced cholinergic activity (e.g., Alzheimer's disease), AChE inhibition (and corresponding maintenance of cholinergic tone) could potentially maintain/augment some aspects of neurobehavioral function. PMID- 25455868 TI - Muscle pain and blood pressure responses during isometric handgrip exercise in healthy African American and non-Hispanic White adults. AB - It has been shown that African Americans (AAs) are more sensitive to experimental pain stimuli compared to non-Hispanic Whites (NHWs). A single bout of exercise results in naturally-occurring muscle pain and elevation in blood pressure (BP); however, it is currently unclear whether AAs and NHWs differ in muscle pain and BP responses during exercise. Therefore, we examined the differences in muscle pain and blood pressure (BP) during isometric handgrip exercise in African Americans (AAs) and non-Hispanic Whites (NHWs). Fourteen AAs and 14 NHWs completed isometric exercise consisting of squeezing a hand dynamometer at 25% of maximal strength for 3 min. During exercise, muscle pain ratings (MPRs) were assessed every 30s, whereas systolic and diastolic BP (SBP and DBP) were recorded every minute. During exercise, AAs generally reported greater MPR than NHWs (p<0.001), and MPR increased more rapidly during exercise in AAs than NHWs (p<0.05). In contrast, SBP and DBP continued to increase similarly during exercise in both AAs and NHWs (p>0.05). The results suggest that AAs generally experienced a greater intensity of muscle pain than NHWs during isometric handgrip exercise, but both groups exhibited similar elevations in BP during exercise. PMID- 25455869 TI - Progesterone elevation on the day of human chorionic gonadotropin administration is not the only factor determining outcomes of in vitro fertilization. AB - OBJECTIVE: To assess whether progesterone elevation is the only factor in determining outcomes of in vitro fertilization (IVF). DESIGN: Retrospective cohort study. SETTING: Infertility clinic at Kaohsiung Chang Gung Memorial Hospital, Taiwan. PATIENT(S): One thousand five hundred eight women undergoing a total of 1,508 IVF cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy and live-birth rates. RESULT(S): Patients were classified into four subgroups according to their progesterone concentration on the day of human chorionic gonadotropin (hCG) triggering. The clinical pregnancy and live-birth rates were statistically significantly associated with the age of the woman, the day of embryo transfer, the progesterone concentration on the day of hCG administration, the number of transferred embryos, and the number of top-quality embryos transferred. However, after omitting the women with the highest progesterone concentration (>=1.94 ng/mL), only four factors-patient age, day of embryo transfer, number of transferred embryos, and number of top-quality embryos transferred-were statistically significantly associated with the clinical pregnancy and live-birth rates. CONCLUSION(S): Progesterone concentration on the day of hCG administration is not the only factor determining the clinical pregnancy and live-birth rates. Fresh embryos from women should be frozen with extremely high progesterone concentrations. Each patient's general condition and the capacity for frozen-thawed embryo transfer should be considered before implantation. PMID- 25455870 TI - Urinary tract endometriosis: a challenging disease. PMID- 25455871 TI - Quality of reporting in infertility journals. AB - OBJECTIVE: To evaluate whether fertility and top gynecology journals indexed in PubMed require the use of reporting guidelines and to identify the percentage of randomized controlled trials (RCTs) published in 2013 that were written following CONSORT guidelines in the top four fertility journals (by their highest impact factor). DESIGN: Cross-sectional study evaluating instructions for authors and RCTs published in fertility journals. SETTING: Academic institution. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Proportion of instruction for-authors documents that suggested or required the use of reporting guidelines, and proportion of RCTs published in 2013 that accomplished the CONSORT checklist. RESULT(S): In 47% (16/34) of the journals one or more reporting guidelines were mentioned in the instructions for authors' documents. PRISMA and CONSORT were the most commonly mentioned reporting guidelines. None of the analyzed RCTs completed the 25 items of CONSORT guideline. Sequence generation or allocation concealment was not described in 69% of the studies. One-third of the journals did not publish a flowchart, 72% did not show relative and absolute size-effect measures, and 42% did not use measures of imprecision. In the summaries, 42% did not discuss the limitations of the study and 78% did not mention the generalizability of the results. CONCLUSION(S): Less than half of the analyzed peer-reviewed journals request the authors to use reporting guidelines. Nevertheless, among the top fertility and gynecology journals, reporting guidelines are widely mentioned. Overall, accomplishment of CONSORT items was suboptimal. Editorial boards, reviewers, and authors should join efforts to improve the quality of reporting. PMID- 25455872 TI - Controversies concerning mitochondrial replacement therapy. PMID- 25455873 TI - Novel topical formulation of lidocaine provides significant pain relief for intrauterine device insertion: pharmacokinetic evaluation and randomized placebo controlled trial. AB - OBJECTIVE: To investigate the pharmacokinetics, safety, and analgesic efficacy of a novel topical formulation of lidocaine at insertion of an intrauterine device (IUD). DESIGN: Randomized controlled trial; phase-I and phase-II studies. SETTING: University and public hospitals. PATIENT(S): Women aged >=18 years who wanted to receive an IUD. Four women were parous in phase I; all in phase II were nulliparous. INTERVENTION(S): A single, 8.5-mL dose of lidocaine formulation (SHACT) was administered (to the portio, cervix, and uterus) with a specially designed applicator. MAIN OUTCOME MEASURE(S): The phase-I study (single-arm) was designed for pharmacokinetic assessment; the phase-II study (randomized) was intended for investigation of efficacy and safety. RESULT(S): From the phase-I study (15 participants), mean pharmacokinetic values were: maximum plasma concentration: 351 +/- 205 ng/mL; time taken to reach maximum concentration: 68 +/- 41 minutes; and area under the concentration-time curve from 0 to 180 minutes: 717 +/- 421 ng*h/mL. Pain relief was observed with lidocaine vs. placebo in the phase-II study (218 women, randomized). Mean visual analog scale score for maximum pain during the first 10 minutes after IUD insertion was 36% lower with lidocaine than with placebo (28.3 +/- 24.6 vs. 44.2 +/- 26.0). Pain intensity was also significantly lower in the lidocaine group at 30 minutes. On average, 3 of 4 patients will have less pain with lidocaine than with placebo. Adverse events were similar in the placebo and lidocaine groups. No serious adverse events were reported. CONCLUSION(S): Lidocaine provides pain relief lasting for 30-60 minutes for women undergoing IUD insertion, without any safety concerns. Further studies of this lidocaine formulation, for IUD insertion and other clinical applications, are planned. CLINICAL TRIAL REGISTRATION NUMBER: 2011-005660-18 and 2011-006220 20 (EudraCT). PMID- 25455874 TI - Perinatal outcome after fetal reduction from twin to singleton: to reduce or not to reduce? AB - OBJECTIVE: To determine whether reduction of twin gestation to singleton pregnancy is associated with improved perinatal outcome. DESIGN: A retrospective cohort study. SETTING: Single tertiary care medical center. PATIENT(S): A cohort of 63 singleton pregnancies after reduction from dichorionic-diamniotic twins gestation and 62 dichorionic-diamniotic nonreduced twins. INTERVENTION(S): Fetal reduction between 11 and 14 weeks of gestation. MAIN OUTCOME MEASURE(S): Obstetric outcome. RESULT(S): The rates of preterm delivery at <34 weeks (1.6% in pregnancies after reduction vs. 11.7% in nonreduced twins) and at <37 weeks of gestation (9.5% vs. 56.7%) were significantly lower in patients whose pregnancies were reduced to singletons. The rates of miscarriage of one twin (0% vs. 4.8%) and early pregnancy loss before 24 weeks of gestation as well as the rates of gestational diabetes (11.1% vs. 10%), hypertensive diseases of pregnancy (6.3% vs. 15%), and intrauterine growth restriction (0% vs. 3.3%) were similar in both groups. CONCLUSION(S): Fetal reduction of twins to singleton is associated with a lower risk of prematurity and superior perinatal outcome compared with nonreduced twins. Therefore, the option of fetal reduction should be considered in certain cases of twin pregnancies, where the risk for adverse outcome seems exceptionally high. PMID- 25455876 TI - [18F]-fluorodeoxyglucose PET imaging of atherosclerosis. AB - [(18)F]-fluorodeoxyglucose PET ((18)FDG PET) imaging has emerged as a promising tool for assessment of atherosclerosis. By targeting atherosclerotic plaque glycolysis, a marker for plaque inflammation and hypoxia, (18)FDG PET can assess plaque vulnerability and potentially predict risk of atherosclerosis-related disease, such as stroke and myocardial infarction. With excellent reproducibility, (18)FDG PET can be a surrogate end point in clinical drug trials, improving trial efficiency. This article summarizes key findings in the literature, discusses limitations of (18)FDG PET imaging of atherosclerosis, and reports recommendations to optimize imaging protocols. PMID- 25455875 TI - Follow-up to genome-wide linkage and admixture mapping studies implicates components of the extracellular matrix in susceptibility to and size of uterine fibroids. AB - OBJECTIVE: To conduct a follow-up association mapping to independent genome-wide linkage and admixture mapping studies of uterine leiomyoma. DESIGN: Case-control, cross-sectional study. SETTING: Not applicable. PATIENT(S): A total of 1,045 premenopausal North American participants in the National Institute of Environmental Health Sciences Uterine Fibroid Study. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We genotyped 2,772 single-nucleotide polymorphisms from candidate genes located in peaks of linkage (2q37, 3p21, 5p13, 10p11, 11p15, 12q14, and 17q25) or admixture linkage disequilibrium (2q37, 4p16.1, and 10q26) mapping and reported to have regulated expression in uterine fibroids. RESULT(S): We report significant associations of variant members of the collagen gene family with risk and tumor size, including missense variants in COL6A3 and COL13A, with replications in African American and European American study groups. Furthermore, the cell-matrix Rho GTPase-encoding ARHGAP26 gene, and MAN1C1, a gene encoding a Golgi mannosidase involved in the maturation of procollagens, emerged as new candidate uterine leiomyoma genes affecting both risk and tumor size. CONCLUSION(S): Our data converge onto a possible model of uterine leiomyoma pathogenesis resulting from altered regulation, maintenance, and/or renewal of the extracellular matrix. PMID- 25455877 TI - Assessment of treatment response using PET. AB - This article reviews the major treatment response evaluation guidelines in the domain of cancer imaging and how the potential of PET imaging, particularly with fluorodeoxyglucose, is increasingly explored in this important aspect of cancer management. Certain disease-specific response criteria (such as in lymphoma) are also reviewed with emphasis on the changes made over time and the main areas of concern in PET interpretation. The major present clinical applications are illustrated and potential new areas are discussed with regard to clinical applications in the future. Finally, the evolving role of newer and novel PET metrics, which hold promise in treatment response evaluation, is illustrated with examples. PMID- 25455878 TI - PET-based radiation therapy planning. AB - In this review, we review the literature on the use of PET in radiation treatment planning, with an emphasis on describing our institutional methodology (where applicable). This discussion is intended to provide other radiation oncologists with methodological details on the use of PET imaging for treatment planning in radiation oncology, or other oncologists with an introduction to the use of PET in planning radiation therapy. PMID- 25455879 TI - An update on novel quantitative techniques in the context of evolving whole-body PET imaging. AB - Since its foundation PET has established itself as one of the standard imaging modalities enabling the quantitative assessment of molecular targets in vivo. In the past two decades, quantitative PET has become a necessity in clinical oncology. Despite introduction of various measures for quantification and correction of PET parameters, there is debate on the selection of the appropriate methodology in specific diseases and conditions. In this review, we have focused on these techniques with special attention to topics such as static and dynamic whole body PET imaging, tracer kinetic modeling, global disease burden, texture analysis and radiomics, dual time point imaging and partial volume correction. PMID- 25455880 TI - 18F-fluorodeoxyglucose PET/computed tomography for primary brain tumors. AB - Structural imaging with computed tomography (CT) and MR imaging is the mainstay in primary diagnosis of primary brain tumors, but these modalities depend on morphologic appearance and an intact blood-brain barrier, and important aspects of tumor biology are not addressed. Such issues may be alleviated by (18)F fluorodeoxyglucose (FDG)-PET and FDG-PET/CT imaging, which may provide clinically important information with regard to primary differentiation between tumor types, initial staging and risk stratification, therapy planning, response evaluation, and recurrence detection. This article describes some of the potential contemporary applications of FDG and PET in primary brain tumors. PMID- 25455881 TI - 18F-fluorodeoxyglucose-positron emission tomography/computed tomography in malignancies of the thyroid and in head and neck squamous cell carcinoma: a review of the literature. AB - 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is a valuable diagnostic tool in a spectrum of malignant and benign conditions, because of a high sensitivity to detect even very small lesions with increased metabolism. This review focuses on the use of FDG-PET/CT in malignancies of the thyroid gland and in head and neck squamous cell carcinoma. PMID- 25455882 TI - [18F]fluorodeoxyglucose PET/computed tomography in breast cancer and gynecologic cancers: a literature review. AB - In this literature review, an update is provided on the role of [(18)F]fluorodeoxyglucose PET/computed tomography in different clinical settings of the 4 most frequent female-specific cancer types: breast, endometrial, ovarian, and cervical cancer. The most recent knowledge regarding primary diagnosis, staging, response evaluation, prognostic and predictive values, recurrence detection, and radiotherapy planning is evaluated, including, when clinically relevant, considerations with respect to the epidemiology, treatment, and course of the diseases. PMID- 25455883 TI - Cost-effectiveness of PET and PET/computed tomography: a systematic review. AB - The development of clinical diagnostic procedures comprises early-phase and late phase studies to elucidate diagnostic accuracy and patient outcome. Economic assessments of new diagnostic procedures compared with established work-ups indicate additional cost for 1 additional unit of effectiveness measure by means of incremental cost-effectiveness ratios when considering the replacement of the standard regimen by a new diagnostic procedure. This article discusses economic assessments of PET and PET/computed tomography reported until mid-July 2014. Forty-seven studies on cancer and noncancer indications were identified but, because of the widely varying scope of the analyses, a substantial amount of work remains to be done. PMID- 25455884 TI - FDG-PET/CT: whither I go, thou canst not follow me now; but thou shalt follow me afterwards. PMID- 25455885 TI - Controlled hydrostatic pressure stress downregulates the expression of ribosomal genes in preimplantation embryos: a possible protection mechanism? AB - The efficiency of various assisted reproductive techniques can be improved by preconditioning the gametes and embryos with sublethal hydrostatic pressure treatment. However, the underlying molecular mechanism responsible for this protective effect remains unknown and requires further investigation. Here, we studied the effect of optimised hydrostatic pressure treatment on the global gene expression of mouse oocytes after embryonic genome activation. Based on a gene expression microarray analysis, a significant effect of treatment was observed in 4-cell embryos derived from treated oocytes, revealing a transcriptional footprint of hydrostatic pressure-affected genes. Functional analysis identified numerous genes involved in protein synthesis that were downregulated in 4-cell embryos in response to hydrostatic pressure treatment, suggesting that regulation of translation has a major role in optimised hydrostatic pressure-induced stress tolerance. We present a comprehensive microarray analysis and further delineate a potential mechanism responsible for the protective effect of hydrostatic pressure treatment. PMID- 25455887 TI - Stakeholder attitudes towards cumulative and aggregate exposure assessment of pesticides. AB - This study evaluates the attitudes and perspectives of different stakeholder groups (agricultural producers, pesticide manufacturers, trading companies, retailers, regulators, food safety authorities, scientists and NGOs) towards the concepts of cumulative and aggregate exposure assessment of pesticides by means of qualitative in-depth interviews (n = 15) and a quantitative stakeholder survey (n = 65). The stakeholders involved generally agreed that the use of chemical pesticides is needed, primarily for meeting the need of feeding the growing world population, while clearly acknowledging the problematic nature of human exposure to pesticide residues. Current monitoring was generally perceived to be adequate, but the timeliness and consistency of monitoring practices across countries were questioned. The concept of cumulative exposure assessment was better understood by stakeholders than the concept of aggregate exposure assessment. Identified pitfalls were data availability, data limitations, sources and ways of dealing with uncertainties, as well as information and training needs. Regulators and food safety authorities were perceived as the stakeholder groups for whom cumulative and aggregate pesticide exposure assessment methods and tools would be most useful and acceptable. Insights obtained from this exploratory study have been integrated in the development of targeted and stakeholder-tailored dissemination and training programmes that were implemented within the EU-FP7 project ACROPOLIS. PMID- 25455886 TI - Polyester monomers lack ability to bind and activate both androgenic and estrogenic receptors as determined by in vitro and in silico methods. AB - The paper presents results from the screening of seven monomers used by Eastman Chemical to make various polymers. Ethylene glycol, diethylene glycol, polytetramethylene glycol, isophthalic acid, monosodium-5-sulfoisophthalic acid, 1,4-cyclohexanedicarboxylic acid, and dimethylcyclohexanedicarboxylate were screened for potential androgenicity or estrogenicity. The following studies were conducted: QSAR for binding to the AR and ER, in vitro Androgen Receptor Binding Assay, in vitro Estrogen Receptor Binding Assays (alpha and beta isoforms), in vitro Androgen Receptor Transactivation Assay in human cells, and in vitro Estrogen Receptor Transactivation Assay in human cells. None of the QSAR models predicted that any of the monomers possessed appreciable binding affinity for either AR or ER. Binding assays showed no evidence of interaction with either the AR or the alpha or beta ER receptors. Similarly, the AR and ER transactivation assays were negative. Moreover, six of the seven monomers have been subjected to 13-week and developmental toxicity studies in rats with no androgen- or estrogen related effects being noted. Given the negative results of the in vitro screening assays (except PMG which demonstrated cytotoxicity) as well as available repeated dose and developmental and reproductive studies, the data suggest that none of the monomers tested exhibit androgenic or estrogenic hazards. PMID- 25455888 TI - The MCRA model for probabilistic single-compound and cumulative risk assessment of pesticides. AB - Pesticide risk assessment is hampered by worst-case assumptions leading to overly pessimistic assessments. On the other hand, cumulative health effects of similar pesticides are often not taken into account. This paper describes models and a web-based software system developed in the European research project ACROPOLIS. The models are appropriate for both acute and chronic exposure assessments of single compounds and of multiple compounds in cumulative assessment groups. The software system MCRA (Monte Carlo Risk Assessment) is available for stakeholders in pesticide risk assessment at mcra.rivm.nl. We describe the MCRA implementation of the methods as advised in the 2012 EFSA Guidance on probabilistic modelling, as well as more refined methods developed in the ACROPOLIS project. The emphasis is on cumulative assessments. Two approaches, sample-based and compound-based, are contrasted. It is shown that additional data on agricultural use of pesticides may give more realistic risk assessments. Examples are given of model and software validation of acute and chronic assessments, using both simulated data and comparisons against the previous release of MCRA and against the standard software DEEM-FCID used by the Environmental Protection Agency in the USA. It is shown that the EFSA Guidance pessimistic model may not always give an appropriate modelling of exposure. PMID- 25455889 TI - Berberine protects liver from ethanol-induced oxidative stress and steatosis in mice. AB - Alcohol consumption is customary in many cultures and it is a common human behavior worldwide. Binge ethanol and chronic alcohol consumption, two usual drinking patterns of human beings, produce a state of oxidative stress in liver and disturb the liver function. However, a safe and effective therapy for alcoholic liver disease in humans is still elusive. This study identified the natural product berberine as a potential agent for treating or preventing ethanol induced liver injury. We demonstrated that berberine attenuated oxidative stress resulted from binge drinking in liver by reducing hepatic lipid peroxidation, glutathione exhaust and mitochondrial oxidative damage. Furthermore, berberine also prevented the oxidative stress and macrosteatosis in response to chronic ethanol exposure in mice. Either the total cytochrome P450 2E1 or the mitochondria-located cytochrome P450 2E1, which is implicated in ethanol-mediated oxidative stress, was suppressed by berberine. On the other hand, berberine significantly blunted the lipid accumulation in liver due to chronic alcohol consumption, at least partially, through restoring peroxisome proliferator activated receptor alpha/peroxisome proliferator-activated receptor-gamma Co activator-1alpha and hepatocyte nuclear factor 4alpha/microsomal triglyceride transfer protein pathways. These findings suggested that berberine could serve as a potential agent for preventing or treating human alcoholic liver disease. PMID- 25455890 TI - Assessment of estrogenic and anti-androgenic activities of the mycotoxin zearalenone and its metabolites using in vitro receptor-specific bioassays. AB - Zearalenone (ZEN) is a well-known mycotoxin present in numerous agricultural products. Humans and animals are therefore at a risk of exposure to zearalenone through consumption of contaminated food. After intake, ZEN is reduced to alpha- and beta-zearalenol (alpha-ZEL and beta-ZEL), zearalanone (ZAN), and alpha- and beta-zearalanol (alpha-ZAL and beta-ZAL). Although their estrogenicity has been well characterized, much less is known about their interaction with other nuclear receptors. This study was undertaken to investigate interactions of ZEN and its five metabolites, with the human androgen receptor (hAR) and estrogen receptor alpha (hERalpha). Their ability to induce hAR-mediated reporter gene expression was examined in androgen-sensitive PALM cells, whereas the effects on hERalpha function were assessed in MCF-7 cells using the E-Screen bioassay. We confirm that ZEN and its metabolites are full agonists for hERalpha and demonstrate that all six compounds tested possess hAR-mediated antagonistic activity in PALM cells, in which ZAN, alpha-ZAL, and beta-ZAL were the most effective hAR antagonists. Overall, the observed estrogenic and anti-androgenic potencies of ZEN and its metabolites suggest that these compounds may interfere with the endocrine system by various modes of action and that further investigation is warranted into their role as endocrine disrupters in animals and humans. PMID- 25455891 TI - Public health risk associated with the co-occurrence of mycotoxins in spices consumed in Sri Lanka. AB - A quantitative risk assessment of mycotoxins due to the consumption of chilli (Capsicum annum L.) and black pepper (Piper nigrum L.) was performed in Sri Lanka. A food frequency questionnaire was administered in order to collect the data on consumption of spices by households in the Northern and Southern region (n = 249). The mean chilli consumption in the North was significantly higher (p < 0.001) compared to the South. Mean exposure to aflatoxin B1 (AFB1) in the North (3.49 ng/kg BW/day) and South (2.13 ng/kg BW/day) have exceeded the tolerable daily intake due to chilli consumption at the lower bound scenario, while exposure to OTA was small. Dietary exposure to other mycotoxins, fumonisin B1, fumonisin B2, sterigmatocystin and citrinin due to spices were estimated. Margin of exposure estimations at the mean exposure to AFB1 were remarkably lower due to chilli (45-78) than for pepper (2315-10,857). Moreover, the hepato cellular carcinoma (HCC) risk associated with the mean AFB1 exposure through chilli at the lower bound was 0.046 and 0.028 HCC cases/year/100,000 based on the North and South consumption, respectively. AFB1 exposure via chilli should be considered as a great public health concern in Sri Lanka due to both high mycotoxin concentration and high consumption. PMID- 25455892 TI - Low doses of ochratoxin A induce micronucleus formation and delay DNA repair in human lymphocytes. AB - The contamination of food commodities by fungal toxins has attracted great interest because many of these mycotoxins are responsible for different diseases, including cancer and other chronic illnesses. Ochratoxin A (OTA) is a mycotoxin naturally present in food, and long-term exposure to food contaminated with low levels of OTA has been associated with renal cancer. In the present study, the cytotoxicity, cytostaticity, and genotoxicity of OTA (0.075-15 uM) in human lymphocytes were evaluated. A comet assay, a modified comet assay (DNA repair assay), which uses N-hydroxyurea (NHU) to detect non-repaired lesions produced by OTA, and a cytokinesis-blocked micronucleus assay were used. Treatments with OTA were not cytotoxic, but OTA caused a cytostatic effect in human lymphocytes at a concentration of 15 uM. OTA (0.075-5 uM) produced a slight increase in the percentage of DNA in the comets and a delay in the DNA repair capacity of the lymphocytes. Micronucleus (MN) induction was observed at OTA concentrations of 1.5 and 5 uM. Our results indicate that OTA induces DNA stable damage at low doses that are neither cytotoxic nor cytostatic, and OTA delays the DNA repair kinetics. These findings indicate that OTA affects two pivotal events in the carcinogenesis pathway. PMID- 25455893 TI - Inhibition of monoamine oxidase (MAO) by alpha-ethylphenethylamine and N,alpha diethylphenethylamine, two compounds related to dietary supplements. AB - Phenethylamines can interact with the metabolic enzyme monoamine oxidase (MAO), which can cause neurochemical dysfunction or changes in drug potency. A methamphetamine analog, N,alpha-diethylphenethylamine (N,alpha-DEPEA), was recently discovered in athletic performance-enhancing supplements, along with discovery of its metabolite, alpha-ethylphenethylamine (AEPEA). In vitro inhibition of human recombinant MAO by AEPEA and N,alpha-DEPEA was evaluated by measuring the fluorescence of 4-hydroxyquinoline produced from MAO substrate, kynuramine. AEPEA competitively inhibited human recombinant MAO A (Ki = 14.0 uM), which was 17-fold stronger compared to MAO B (Ki = 234 uM). Furthermore, N,alpha DEPEA was a weak inhibitor of both MAO A (Ki = 251 uM) and MAO B (Ki = 159 uM). Trends regarding MAO A inhibition were explored among structural analogs, yielding the following ranking: amphetamine (Ki = 5.3 uM), AEPEA (Ki = 14.0 uM), methamphetamine (Ki = 17.2 uM), phentermine (Ki = 196 uM), and N,alpha-DEPEA (Ki = 251 uM). This study provides important data relating chemical structures and biochemical effects for two emerging compounds associated with dietary supplements. PMID- 25455894 TI - Rosmarinic acid attenuates hepatic ischemia and reperfusion injury in rats. AB - Rosmarinic acid (RosmA) demonstrates antioxidant and anti-inflammatory properties. We investigated the effect of RosmA on liver ischemia/reperfusion injury. Rats were submitted to 60 min of ischemia plus saline or RosmA treatment (150 mg/kg BW intraperitoneally) followed by 6 h of reperfusion. Hepatocellular injury was evaluated according to aminotransferase activity and histological damage. Hepatic neutrophil accumulation was also evaluated. Oxidative/nitrosative stress was estimated by measuring the reduced glutathione, lipid hydroperoxide and nitrotyrosine levels. Endothelial and inducible nitric oxide synthase (eNOS/iNOS) and nitric oxide (NO) were assessed with immunoblotting and chemiluminescence assays. Hepatic tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta mRNA were assessed using real-time PCR, and nuclear factor kappaB (NF-kappaB) activation was estimated by immunostaining. RosmA treatment reduced hepatocellular damage, neutrophil infiltration and all oxidative/nitrosative stress parameters. RosmA decreased the liver content of eNOS/iNOS and NO, attenuated NF-kappaB activation, and down-regulated TNF-alpha and interleukin-1beta gene expression. These data indicate that RosmA exerts anti inflammatory and antioxidant effects in the ischemic liver, thereby protecting hepatocytes against ischemia/reperfusion injury. The mechanisms underlying these effects may be related to the inhibitory potential of RosmA on the NF-kappaB signaling pathway and the reduction of iNOS and eNOS expressions and NO levels, in addition to its natural antioxidant capability. PMID- 25455895 TI - The determination of possible genetic damage to women undergoing in vitro fertilization due to infertility caused by the male factor. AB - In this study, we aimed at determining possible genetic damage to women who were exposed to in vitro fertilization (IVF) due to infertility with male factor. Four different genotoxicity tests were used in human lymphocytes in this study with regard to chromosomal aberration (CA), sister chromatid exchange (SCE), micronucleus (MN), and comet tests. There was a statistically significant increase in sister chromatid exchange (SCE) test in the study group compared with the control group. In addition, a higher rate of MN frequency was determined only in the 21-30 age range study group compared with the control group in the same age range. On the other hand, MN frequency did not differ significantly between the control and total study groups. In addition, there was no significant difference between the control group and the study group in terms of mitotic (MI), replication (RI), and nuclear division (NDI) indices. Furthermore, there was no statistically significant increase for chromosomal aberration and DNA damage to the study groups. Our results showed that in vitro fertilization treatments have a weak risk at the genetic level in cultured human lymphocytes. PMID- 25455896 TI - Use of urinary renal biomarkers to evaluate the nephrotoxic effects of melamine or cyanuric acid in non-pregnant and pregnant rats. AB - Although traditional assessments of renal damage detect loss of kidney function, urinary renal biomarkers are proposed to indicate early changes in renal integrity. The recent adulteration of infant formula and other milk-based foods with melamine revealed a link between melamine ingestion and nephropathy. Thus, the effects of melamine and related analogs (e.g., cyanuric acid) should be assessed in other potentially sensitive groups. We evaluated whether urinary Kim 1, clusterin, and osteopontin could detect the effects of high doses of melamine or cyanuric acid in pregnant and non-pregnant female rats gavaged with 1000 mg/kg bw/day for 10 days. We demonstrate that these biomarkers can differentiate the severity of effects induced by melamine or cyanuric acid. All melamine-treated animals experienced adverse effects; however, pregnant rats were most sensitive as indicated by increased SCr, BUN, and kidney weights, decreased body weight, and presence of renal crystals. These effects coincided with elevated urinary biomarker levels as early as day 2 of exposure. One cyanuric acid-treated rat displayed effects similar to melamine, including increased urinary biomarker levels. This work illustrates that these biomarkers can detect early effects of melamine or cyanuric acid crystal-induced nephropathy and further supports the use of urinary protein immunoassays as a powerful, non-invasive method to assess nephrotoxicity. PMID- 25455897 TI - Reliability of the TTC approach: learning from inclusion of pesticide active substances in the supporting database. AB - Data on pesticide active substances were used to assess the reliability of the Threshold of Toxicological Concern (TTC) approach. Pesticides were chosen as a robust test because of their potential for toxicity. 328 pesticide substances were classified on the basis of their chemical structure, according to the generic scheme proposed by the European Food Safety Authority. 43 carbamates and organophosphates were allocated to the group for neurotoxicity alerts, and 279 substances to Cramer structural Class III. For Class III, the 5th percentile value as calculated from the cumulative distribution curve of the no-observed effect levels (0.20 mg/kg bw per day), was slightly higher than that determined by Munro (0.15 mg/kg bw per day) from his original database. The difference is explained by the inclusion of carbamates and organophosphates in Munro's Class III. Consideration of the acceptable daily intakes and their underlying toxicity data showed that the TTC approach is conservative for 96.2% of the substances. Overall, this analysis gives added support to the utility of the generic scheme of application of the TTC approach for hazard assessment of substances for which few or no experimental toxicity data are available. A convenient alternative to the Cramer decision tree is proposed. PMID- 25455898 TI - In vitro-to-in vivo correlation of the skin penetration, liver clearance and hepatotoxicity of caffeine. AB - This work illustrates the use of Physiologically-Based Toxicokinetic (PBTK) modelling for the healthy Caucasian population in in vitro-to-in vivo correlation of kinetic measures of caffeine skin penetration and liver clearance (based on literature experiments), as well as dose metrics of caffeine-induced measured HepaRG toxicity. We applied a simple correlation factor to quantify the in vitro and in vivo differences in the amount of caffeine permeated through the skin and concentration-time profiles of caffeine in the liver. We developed a multi-scale computational approach by linking the PBTK model with a Virtual Cell-Based Assay to relate an external oral and dermal dose with the measured in vitro HepaRG cell viability. The results revealed higher in vivo skin permeation profiles than those determined in vitro using identical exposure conditions. Liver clearance of caffeine derived from in vitro metabolism rates was found to be much slower than the optimised in vivo clearance with respect to caffeine plasma concentrations. Finally, HepaRG cell viability was shown to remain almost unchanged for external caffeine doses of 5-400 mg for both oral and dermal absorption routes. We modelled single exposure to caffeine only. PMID- 25455900 TI - Real-time PCR assay for specific detection of cowpox virus. AB - The species cowpox virus (CPXV), genus Orthopoxvirus (OPV), consists of isolates highly variable in their biological properties and their genotypes. A TaqMan PCR assay for the specific detection of CPXV DNA based on sequences of the ORF D11L has been developed recently. (Gavrilova et al., 2010; Shchelkunov et al., 2011); however, a rather limited panel of CPXV stains has been used. When a much larger panel of 47 CPXV DNAs has been tested, three strains could not be amplified at all because of large deletions in their respective ORF D11L. In addition, a deletion of 23bp led to low-efficiency detection of five other CPXV strains. To solve this problem a new primer/probe combinations was selected based on sequences of ORF D8L, and a new real-time PCR method for (i) a genus-specific detection of OPVs and (ii) a simultaneous CPXV-specific differentiation is described in this study. The specificity and sensitivity were assessed by analyzing DNA of 67 strains belonging to human-pathogenic OPV species, including variola virus, as well as specimens of CPXV-infected mice. PMID- 25455899 TI - Immunohistochemical analysis of RTKs expression identified HER3 as a prognostic indicator of gastric cancer. AB - Standard treatment in Japan for the 13th Japanese Gastric Cancer Association stage II/III advanced gastric cancer is postoperative adjuvant S-1 administration after curative surgery. High expression of receptor type tyrosine kinases (RTKs) has repeatedly represented poor prognosis for cancers. However it has not been demonstrated whether RTKs have prognostic relevance for stage II/III gastric cancer with standard treatment. Tumor tissues were obtained from 167 stage II/III advanced gastric cancer patients who underwent curative surgery and received postoperative S-1 chemotherapy from 2000 to 2010. Expression of the RTKs including EGFR, HER2, HER3, IGF-1R, and EphA2 was analyzed using immunohistochemistry (IHC). Analysis using a multivariate proportional hazard model identified the most significant RTKs that represented independent prognostic relevance. When tumor HER3 expression was classified into IHC 1+/2+ (n = 98) and IHC 0 (n = 69), the cumulative 5-year Relapse Free Survival (5y-RFS) was 56.5 and 82.9%, respectively (P = 0.0034). Significant prognostic relevance was similarly confirmed for IGF-1R (P = 0.014), and EGFR (P = 0.030), but not for EphA2 or HER2 expression. Intriguingly, HER3 expression was closely correlated with IGF-1R (P < 0.0001, R = 0.41), and EphA2 (P < 0.0001, R = 0.34) expression. Multivariate proportional hazard model analysis identified HER3 (IHC 1+/2+) (HR; 1.53, 95% CI, 1.11-2.16, P = 0.0078) as the sole RTK that was a poor prognostic factor independent of stage. Of the 53 patients who recurred, 40 patients (75.5%) were HER3-positive. Thus, of the RTKs studied, HER3 was the only RTK identified as an independent prognostic indicator of stage II/III advanced gastric cancer with standard treatment. PMID- 25455901 TI - Rapid detection and differentiation of dengue virus serotypes by NS1 specific reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay in patients presenting to a tertiary care hospital in Hyderabad, India. AB - Early and rapid detection of dengue virus (DENV) infection during the acute phase of illness is crucial for proper patient management and prevention of the spread of the infection. In the present study, the standardization and validation of a one step, four tube reverse transcription loop-mediated isothermal amplification assay (RT-LAMP) for rapid detection and serotyping of the DENV targeting NS1 gene using the Genie(r) II flourometer was carried out. The performance of the RT-LAMP was compared to RT-PCR, CDC 1-4 Real time PCR and the NS1 antigen ELISA, IgM and IgG anti DENV antibodies. Acute DENV infection was confirmed in 250/300 patients suspected clinically of DENV infection. RT- LAMP and CDC 1-4 Real time PCR assay was positive in 148/250 patients, while 92/250 patients were positive for anti- Dengue IgM and IgG antibodies. The RT-LAMP assay and the CDC real-time RT-PCR assay showed high concordance (k=1.0). The detection rate of acute DENV infection improved to 96% (240/250) when the results of RT-LAMP were combined with NS1 Ag, IgM and IgG ELISA. The RT-LAMP had a detection limit of 100 copies for DEN-1 and DEN-2, 10 copies for DEN-3 and DEN-4 compared to 1000 copies for DEN-1 and DEN-2, 100 copies for DEN-3 and DEN-4 by the conventional RT-PCR. The assay showed 100% specificity. The RT-LAMP assay developed in this study has potential use for early clinical diagnosis, serotyping and surveillance of DENV infection in endemic countries such as India. PMID- 25455902 TI - A simplified method for simultaneous detection of Rice stripe virus and Rice black-streaked dwarf virus in insect vector. AB - Rice stripe virus (RSV) and Rice black-streaked dwarf virus (RBSDV) are transmitted by their common vector small brown planthopper (SBPH) that cause serious crop losses in China. A simple reverse transcription-PCR method was developed for the simultaneous detection of RSV and RBSDV in single SBPH. Three primers targeted to RSV-RNA4 and RBSDV-S2 segments were designed to amplify respectively 1114-bp and 414-bp fragments in a reaction. The method is reliable, rapid and inexpensive for detecting the two viruses in vector, which could facilitate better forecasting and control of the virus diseases. Using this method, it was found that SBPH could carry RSV and RBSDV simultaneously. PMID- 25455903 TI - Development of an in situ hybridization assay for the detection of ostreid herpesvirus type 1 mRNAs in the Pacific oyster, Crassostrea gigas. AB - An in situ hybridization protocol for detecting mRNAs of ostreid herpesvirus type 1 (OsHV-1) which infects Pacific oysters, Crassostrea gigas, was developed. Three RNA probes were synthesized by cloning three partial OsHV-1 genes into plasmids using three specific primer pairs, and performing a transcription in the presence of digoxigenin dUTP. The RNA probes were able to detect the virus mRNAs in paraffin sections of experimentally infected oysters 26 h post-injection. The in situ hybridization showed that the OsHV-1 mRNAs were mainly present in connective tissues in gills, mantle, adductor muscle, digestive gland and gonads. DNA detection by in situ hybridization using a DNA probe and viral DNA quantitation by real-time PCR were also performed and results were compared with those obtained using RNA probes. PMID- 25455904 TI - Quantitation and localization of pospiviroids in aphids. AB - In this paper, the potential role of aphids in viroid transmission was explored. Apterous aphids were fed on pospiviroid-infected plants and viroid targets in the aphids were consequently quantified through RT-qPCR and localized within the aphid body using fluorescence in situ hybridization (FISH). Based on the analytical sensitivity test, the limit of detection (LOD) was estimated at 1.69*10(6) viroid copies per individual aphid body. To localize the viroids in the aphids, a pospiviroid-generic Cy5-labelled probe was used and the fluorescent signal was determined by confocal microscopy. Viroids were clearly observed in the aphid's stylet and stomach, but not in the embryos. Viroids were detected in 29% of the aphids after a 24h feeding period, which suggests only a partial and low concentration viroid uptake by the aphid population including viroid concentrations under the LOD. However, these results show that viroids can be ingested by aphids while feeding on infected plants, thus potentially increasing the transmission risk. The combination of FISH and RT-qPCR provides reliable and fast localization and quantitation of viroid targets in individual aphids and thus constitutes a valuable tool in future epidemiological research. PMID- 25455905 TI - Ten years of trauma in the 'top end' of the Northern Territory, Australia: a retrospective analysis. AB - AIM: To examine characteristics of traumatic injury in adults and children at the Royal Darwin Hospital (RDH) over a 10 year period. METHOD: A retrospective review of the RDH Trauma Registry data from 1 January 2003 to 31 December 2012, with analysis of patient demographics, mechanism of injury, Injury Severity Score (ISS), and outcome. PARTICIPANTS: Two thousand seven hundred twenty-five patients with an ISS greater than or equal to 9 and met all other study inclusion criteria. RESULTS: Motor vehicle crashes, assaults and falls consistently remained the three most common mechanisms of injury throughout the 10 year period. Indigenous admissions showed a significant downward trend (p = 0.009). Upward trends were noted in presentations from patients aged greater than 44 (p = 0.002), all-terrain vehicle accidents (p <0.001), and hangings (p = 0.003). No other trends were noted to significant at a p <0.05 level. Admitted Indigenous patients were significantly more likely to be present due to assault (p <0.001) and female patients were more likely to present due to assault, falls and motor vehicle crashes (p <0.01) than their counterparts. CONCLUSION: Presentations for traumatic injury to Royal Darwin Hospital have remained in the most part, consistently stable for the period of 2003-2012. Though there were some increases/decreases in regard to specific demographics and mechanisms, few were found to be statistically significant at a p < 0.05 level. PMID- 25455906 TI - Positive experiences of family members in emergency departments: a commentary. PMID- 25455907 TI - Decisions and delays within stroke patients' route to the hospital: a qualitative study. AB - STUDY OBJECTIVE: We examine acute stroke patients' decisions and delays en route to the hospital after onset of symptoms. METHODS: This was a qualitative study carried out in the West Midlands, United Kingdom. Semistructured interviews were conducted with 30 patients (6 accompanied by partners). Patients were asked about their previous experience of having had a stroke and their initial engagement with health services. "One sheet of paper" and thematic analyses were used. RESULTS: Three potential types of delay were identified from onset of symptoms to accessing stroke care in the hospital: primary delays caused by lack of recognition of symptoms or not dealing with symptoms immediately, secondary delays caused by initial contact with nonemergency services, and tertiary delays in which health service providers did not interpret the patients' presenting symptoms as suggestive of stroke. The main factors determining the speed of action by patients were the presence and influence of a bystander and the perceived seriousness of symptoms. CONCLUSION: Despite campaigns to increase public awareness of stroke symptoms, the behavior of both patients and health service providers apparently led to delays in the recognition of and response to stroke symptoms, potentially reducing access to optimum and timely acute specialist assessment and treatment for acute stroke. PMID- 25455908 TI - Ebola virus outbreak 2014: clinical review for emergency physicians. AB - The 2014 Ebola outbreak in West Africa is the largest in history. Ebola viral disease is a severe and fatal illness characterized by a nonspecific viral syndrome followed by fulminant septic shock and coagulopathy. Despite ongoing efforts directed at experimental treatments and vaccine development, current medical management of Ebola viral disease is largely limited to supportive therapy, thus making early case identification and immediate implementation of appropriate control measures critical. Because a case of Ebola viral disease was confirmed in the United States on September 30, 2014, emergency medicine providers should be knowledgeable about it for a number of reasons: we are being called on to answer questions about Ebola and allay public fears, we are likely to be first to encounter an infected patient, and there are increasing numbers of US emergency physicians working in Africa who risk coming in direct contact with the disease. This article seeks to provide emergency physicians with the essential and up-to-date information required to identify, evaluate, and manage Ebola viral disease and to join global efforts to contain the current outbreak. PMID- 25455909 TI - Does Initiation of Therapeutic Hypothermia in the Out-of-Hospital Environment Improve Neurologic Outcomes? PMID- 25455910 TI - Debriefing in the emergency department after clinical events: a practical guide. AB - One vital aspect of emergency medicine management is communication after episodes of care to improve future performance through group reflection on the shared experience. This reflective activity in teams is known as debriefing, and despite supportive evidence highlighting its benefits, many practitioners experience barriers to implementing debriefing in the clinical setting. The aim of this article is to review the current evidence supporting postevent debriefing and discuss practical approaches to implementing debriefing in the emergency department. We will address the who, what, when, where, why, and how of debriefing and provide a practical guide for the clinician to facilitate debriefing in the clinical environment. PMID- 25455912 TI - Mechanical ventilation in critically ill cancer patients. PMID- 25455911 TI - Weaned but weary: one third of adult intensive care patients mechanically ventilated for 7 days or more have impaired inspiratory muscle endurance after successful weaning. AB - OBJECTIVES: The purpose of this study was to establish whether intensive care unit (ICU) patients have impaired inspiratory muscle (IM) endurance immediately following weaning from prolonged mechanical ventilation (MV), and whether IM weakness is related to function or perceived exertion. BACKGROUND: Impaired IM endurance may hinder recovery from MV, however it is unknown whether this affects patients' function or perceived exertion. METHODS: Prospective observational study of 43 adult ICU patients following weaning from MV (>7 days duration). IM endurance was measured using the fatigue resistance index (FRI). RESULTS: IM endurance was impaired (FRI = mean 0.90, SD 0.31), with 37% scoring below 0.80. IM strength did not significantly correlate with function (r = 0.24, p = 0.12) or perceived exertion during exercise (r = -0.146, p = 0.37). CONCLUSIONS: IM endurance is reduced in one third of patients, while IM weakness does not appear closely associated with function or perceived exertion immediately following successful weaning. PMID- 25455913 TI - [Infectious diseases and use of health care resources in children less than 2 years-old who attend kindergarten]. AB - INTRODUCTION AND OBJECTIVES: Parents often ask paediatricians for advice about the best way to care for their children. There are discrepancies in the literature on this subject. The objective of this study is to evaluate the influence of attending kindergartens on the risk of acute infections and the use of health care resources in children less than 24 months. POPULATION AND METHODS: A prospective longitudinal study was conducted on two cohorts of children 0-24 months (born between 1 January and 30 September 2010), who were grouped according to whether they attended kindergarten or not, and were usually seen in 33 pediatric clinics of the Principality of Asturias Public Health Service. RESULTS AND CONCLUSIONS: A total of 975 children were studied, of whom 43.7% attended a kindergarten at 24 months. Attending kindergarten increases the risk of pneumonia by 131%, recurrent wheezing by 69%, bronchitis by 57%, and otitis media by 64%. Early exposure to kindergarten increases the risk of pneumonia from 2.31 to 2.81, and the mean emergency room visits from 1 to 2.3. The mean antibiotic cycle is 1.7 in children who do not go to kindergarten, 3.4 if started within the first 6 months, and 2 if they start at 18 months. Day-care attendance is a risk factor of infectious diseases that increases if attending kindergartens from an early age. PMID- 25455914 TI - [Gluten-free, casein-free diet in autism spectrum disorders; different perspectives]. PMID- 25455915 TI - [Early prediction of the neurological result at 12 months in newborns at neurological risk]. AB - INTRODUCTION: The aim of this study was to evaluate the Amiel-Tison neurological examination (AT) and cranial ultrasound at term for predicting the neurological result at 12 months in newborns with neurological risk. PATIENTS AND METHODS: The study included 89 newborns with high risk of neurological damage, who were discharged from the Neonatal Intensive Care of the Hospital Zonal Bariloche, Argentina. The assessment consisted of a neurological examination and cranial ultrasound at term, and neurological examination and evaluation of development at 12 months. The sensitivity, specificity, positive and negative predictor value was calculated. The relationship between perinatal factors and neurodevelopment at 12 month of age was also calculated using logistic regression models. RESULTS: Seventy children completed the follow-up. At 12 months of age, 14% had an abnormal neurological examination, and 17% abnormal development. The neurological examination and the cranial ultrasound at term had low sensitivity to predict abnormal neurodevelopment. At 12 months, 93% of newborns with normal AT showed normal neurological results, and 86% normal development. Among newborns with normal cranial ultrasound the percentages were 90 and 81%, respectively. Among children with three or more perinatal risk factors, the frequency of abnormalities in the neurological response was 5.4 times higher than among those with fewer risk factors, and abnormal development was 3.5 times more frequent. CONCLUSIONS: The neurological examination and cranial ultrasound at term had low sensitivity but high negative predictive value for the neurodevelopment at 12 months. Three or more perinatal risk factors were associated with neurodevelopment abnormalities at 12 months of age. PMID- 25455927 TI - The right staffing mix for inpatient care in rural multi-purpose service health facilities. AB - CONTEXT: The Multipurpose Service (MPS) model has been in existence in rural and remote Australia for more than 20 years yet there is little guidance about developing an appropriate staffing structure. ISSUES: Managers of these facilities face issues related to isolation, safety, funding models and the need to provide a variety of services with limited resources and staffing. Because MPS are designed to meet unique community needs, a single staffing structure is not suitable for every site. Managers need to consider these issues in order to determine the most effective staffing structure for their particular environment. LESSONS LEARNED: Issues and concerns for managers are highlighted including discussion which may enhance the ability of managers to make appropriate decisions for their unique site. PMID- 25455928 TI - What is depression and who is in depression studies? PMID- 25455929 TI - Impact of depression and mental illness on outcomes of medical illness in older adults. PMID- 25455930 TI - Opioid interruptions, pain, and withdrawal symptoms in nursing home residents. AB - PURPOSE: Interruptions in opioid use have the potential to cause pain relapse and withdrawal symptoms. The objectives of this study were to observe patterns of opioid interruption during acute illness in nursing home residents and examine associations between interruptions and pain and withdrawal symptoms. METHODS: Patients from 3 nursing homes in a metropolitan area who were prescribed opioids were assessed for symptoms of pain and withdrawal by researchers blinded to opioid dosage received, using the Brief Pain Inventory Scale and the Clinical Opioid Withdrawal Scale, respectively, during prespecified time periods. The prespecified time periods were 2 weeks after onset of acute illness (eg, urinary tract infection), and 2 weeks after hospital admission and nursing home readmission, if they occurred. Opioid dosing was recorded and a significant interruption was defined as a complete discontinuation or a reduction in dose of >50% for >=1 day. The covariates age, sex, race, comorbid conditions, initial opioid dose, and initial pain level were recorded. Symptoms pre- and post-opioid interruptions were compared and contrasted with those in a group without opioid interruptions. FINDINGS: Sixty-six patients receiving opioids were followed for a mean of 10.9 months and experienced a total of 104 acute illnesses. During 64 (62%) illnesses, patients experienced any reduction in opioid dosing, with a mean (SD) dose reduction of 63.9% (29.9%). During 39 (38%) illnesses, patients experienced a significant opioid interruption. In a multivariable model, residence at 1 of the 3 nursing homes was associated with a lower risk of interruption (odds ratio = 0.073; 95% CI, 0.009 to 0.597; P < 0.015). In patients with interruptions, there were statistically insignificant changes in mean (SD) pain score (difference -0.50 [2.66]; 95% CI, -3.16 to 2.16) and withdrawal score (difference -0.91 [3.12]; 95% CI, -4.03 to 2.21) after the interruption as compared with before interruption. However, when compared with patients without interruptions, patients with interruptions experienced larger increases in pain scores during the follow-up periods (difference 0.09 points per day; 95% CI, 0.01 to 0.019; P = 0.08). In particular, patients who received the highest quartile of opioid dose before interruption experienced increases in pain scores over time that were 0.22 points per day larger (95% CI, 0.02 to 0.41; P = 0.03) than those without interruption. Withdrawal scores were not associated with opioid interruption regardless of dose before interruption. IMPLICATIONS: Nursing home patients often experience interruptions in opioid dosing, which can be associated with worse pain, but not withdrawal symptoms, during acute illnesses. Clinicians should be aware of the potential risks and effects of opioid interruptions during acute illnesses in this patient group. PMID- 25455931 TI - Hypnotics in insomnia: the experience of zolpidem. AB - PURPOSE: One of the most commonly prescribed medications to treat insomnia is zolpidem, a nonbenzodiazepine compound that is available as an immediate-release oral tablet formulation, an extended-release oral formulation, an oral spray formulation, and as sublingual formulations. The purpose of this review was to summarize the data currently available on the efficacy and safety of zolpidem in the treatment of insomnia among adults. METHODS: Published studies on the use of zolpidem in the treatment of insomnia were identified by using combinations of relevant search terms in PubMed and Google Scholar. Studies were included if they were placebo- or active comparator-controlled studies, with the exception of trials on the long-term use of zolpidem. Studies were limited to those conducted in adults. Studies were not included if the patient population was small, if the study was not designed or powered to assess the efficacy or safety of zolpidem, if insomniac patients had a medical condition in addition to insomnia (with the exception of comorbid depression or anxiety for studies on comorbid insomnia), or if zolpidem was given concomitantly with any other therapy (with the exception of selective serotonin reuptake inhibitors for studies on comorbid insomnia). FINDINGS: Twenty-five studies designed to evaluate the efficacy of zolpidem in insomnia and 51 studies reporting the safety of zolpidem in insomnia were included in this review. IMPLICATIONS: The studies discussed in this review report the efficacy and safety of zolpidem in both young adults and the elderly. It can be used for either bedtime or middle-of-the-night administration, over the short or long term, with minimal risk of withdrawal or abuse. The use of zolpidem is associated with rebound insomnia, complex sleep-related behaviors, and next day residual effects (after middle-of-the-night dosing) on driving ability, memory, and psychomotor performance. PMID- 25455933 TI - Successful treatment of renal light chain (AL) amyloidosis with bortezomib and dexamethasone (VD). AB - OBJECTIVE: To assess the efficacy and tolerability of bortezomib with dexamethasone for patients with renal light chain (AL) amyloidosis. METHODS: Twelve newly diagnosed patients with renal AL amyloidosis were treated with a combination of bortezomib (1.3mg/m(2)/d iv, d1, 4, 8, 11) and dexamethasone (20mg/d iv drip, d1-4). RESULTS: Median follow-up time was 22.5 months (range, 2.1-53.6). Ten patients were evaluable. Five out of 10 (50%) patients achieved complete hematologic responses (CHR), and totally 8/10 (80%) achieved hematologic responses (HR). Median time to hematologic response was 1 month. All patients who received HR had no hematologic progression during follow-up period. Five patients (50%) had kidney responses and the other 5 patients (50%) were stable. Median time to kidney response was 3 months. No patients presented renal progression during follow-up. One patient achieved PR after 4 cycles of VD and then received autologous peripheral blood stem cell transplantation. Two out of 10 evaluable patients without hematologic response had died with median overall survival of 8.2 months. Eight of them who had HR were alive with median follow-up time of 28.5 months. Infection (6/12) and fatigue (5/12) were the most frequent side effects. Three patients developed herpes zoster and had to discontinue therapy. CONCLUSIONS: VD produces rapid, deep and durable hematological responses and renal responses in the majority of patients with newly diagnosed renal AL. It is well tolerated. This treatment may be a good option as first-line treatment for renal AL amyloidosis patients. PMID- 25455934 TI - Stage- and sex-specific heat tolerance in the yellow dung fly Scathophaga stercoraria. AB - Thermal tolerance varies at all hierarchical levels of biological organization: among species, populations, individuals, and even within individuals. Age- or developmental stage- and sex-specific thermal effects have received relatively little attention in the literature, despite being crucial for understanding thermal adaptation in nature and responses to global warming. We document stage- and sex- specific heat tolerance in the yellow dung fly Scathophaga stercoraria (Diptera: Scathophagidae), a species common throughout the northern hemisphere that generally favours cool climates. Exposure of eggs to temperatures up to 32 degrees C did not affect larval hatching rate, but subsequent egg-to-adult survival at a benign temperature was reduced. Permanent transfer from benign (18 degrees C) to hot temperatures (up to 31 degrees C) at different larval and pupal stages strongly decreased egg-to-adult survival, though survival continuously improved the later the transfer occurred. Temporary transfer for only two days increased mortality more weakly, survival being lowest when temperature stress was imposed early during the larval or pupal stages. Adult flies provided with sugar and water tolerated 31 degrees C longer than previously thought (5 days in males to 9 days in females). Eggs were thus less susceptible to thermal stress than larvae, pupae or adults, in agreement with the hypothesis that more mobile stages require less physiological protection against heat because they can behaviourally thermoregulate. The probability of mating, of laying a clutch, and hatching success were generally independently reduced by exposure of females or males to warm temperatures (24 degrees C) during the juvenile or adult stages, with some interactions evident. High temperature stress thus affects survival differentially depending on when it occurs during the juvenile or the pre reproductive adult life stage, and affects reproductive success via the mating behaviour of both sexes, female physiology in terms of oviposition, and fertility via sperm and/or egg quality. Our results illustrate that temperature stress, even when moderate and temporary, during early development can have profound lethal and non-lethal fitness-consequences later in life. PMID- 25455932 TI - The glycosyltransferase LARGE2 is repressed by Snail and ZEB1 in prostate cancer. AB - Reductions in both expression of the dystroglycan core protein and functional glycosylation of the alpha-dystroglycan (alphaDG) subunit have been reported in a number of cancers and may contribute to disease progression. In the case of prostate cancer, one mechanism that contributes to alphaDG hypoglycosylation is transcriptional down-regulation of LARGE2 (GYLTY1B), a glycosyltransferase that produces the functional (laminin-binding) glycan on alphaDG, but the mechanism(s) underlying reduction of LARGE2 mRNA remain unclear. Here, we show that alphaDG hypoglycosylation is associated with epithelial-to-mesenchymal transition (EMT) like status. We examined immunoreactivity for both functionally-glycosylated alphaDG and E-cadherin by flow cytometry and the relative expression of ZEB1 mRNA and the alphaDG glycosyltransferase LARGE2 mRNA in prostate and other cancer cell lines by quantitative RT-PCR. To study the role of ZEB1 and other transcription factors in the regulation of LARGE2, we employed overexpression and knockdown approaches. Snail- or ZEB1-driven EMT caused alphaDG hypoglycosylation by repressing expression of the LARGE2 mRNA, with both ZEB1-dependent and independent mechanisms contributing to Snail-mediated LARGE2 repression. To examine the direct regulation of LARGE2 by Snail and ZEB1 we employed luciferase reporter and chromatin immunoprecipitation assays. Snail and ZEB1 were found to bind directly to the LARGE2 promoter, specifically to E/Z-box clusters. Furthermore, analysis of gene expression profiles of clinical samples in The Cancer Genome Atlas reveals negative correlation of LARGE2 and ZEB1 expression in various cancers. Collectively, our results suggest that LARGE2 is negatively regulated by Snail and/or ZEB1, revealing a mechanistic basis for alphaDG hypoglycosylation during prostate cancer progression and metastasis. PMID- 25455935 TI - Incubation temperature fluctuation does not affect incubation length and hatchling phenotype in the Chinese skink Plestiodon chinensis. AB - Studies examining the effects of incubation temperature fluctuation on the phenotype of hatchling reptiles have shown species variation. To examine whether incubation temperature fluctuation has a key role in influencing the phenotype of hatchling Chinese skinks (Plestiodon chinensis), we incubated eggs produced by 20 females under five thermal regimes (treatments). Eggs in three treatments were incubated in three incubators, one set constant at 27 degrees C and two ramp programmed at 27 +/- 3 degrees C and 27 +/- 5 degrees C on a cycle of 12h (+) and 12h (-). The remaining eggs were incubated in two chambers: one inside a room where temperatures varied from 23.0 to 31.1 degrees C, with a mean of 27.0 degrees C; the other outside the room where temperatures varied from 20.2 to 35.3 degrees C, with a mean of 26.1 degrees C. We found that: (1) for eggs at a given embryonic stage at ovipositon, the mean rather than the variance of incubation temperatures determined the length of incubation; (2) most (egg mass, embryonic stage at oviposition, incubation length and all examined hatchling traits except tail length and locomotor performance) of the examined variables were affected by clutch; and (3) body mass was the only hatchling trait that differed among the five treatments, but the differences were tiny. These findings suggest that incubation temperature fluctuation has no direct role in influencing incubation length and hatchling phenotype in P. chinensis. PMID- 25455936 TI - Not all space is created equal: distribution of free space and its influence on heat-stress and the limpet Patelloida latistrigata. AB - For most marine benthic communities unoccupied primary substrata, or free space, is considered the principle limiting resource. Substratum temperatures, desiccation rates and hydrodynamic characteristics of free space, however, may vary depending on patch size and isolation and therefore potentially influence biotic processes. This paper investigates the relationship between small-scale changes in the availability and configuration of free space, heat stress and abundance of the small rocky intertidal gastropod Patelloida latistrigata within southeastern Australia. Using infrared thermography I show that heat stress of rocky intertidal communities increased linearly with increasing amounts of free space on three neighbouring shores during four separate sampling intervals from October 2009 to January 2010. Abundances of P. latistrigata generally declined with increasing availability of free space and the associated increases in heat stress. An experimental manipulation that altered the configuration but not the availability of free space demonstrated that both heat stress and P. latistrigata abundance are not affected by small-scale changes in the configuration of free space. The small-scale distribution of P. latistrigata, however, was significantly influenced by differences in the configuration of free space with limpets displaying bimodal distributions within areas characterised by unevenly distributed free space. Since the distribution of Patelloida varies depending on the configuration of free space but thermal properties at the scale of individual limpets do not then we might expect Patelloida to be responding to changes in other abiotic factors, such as hydrodynamic forces and desiccation rates, which may change with the configuration of free space. This study highlights the dynamic and usually unexamined relationship between abiotic stress and the availability and acquisition of resources by marine benthic invertebrates. PMID- 25455937 TI - Effect of rearing temperature on growth and thermal tolerance of Schizothorax (Racoma) kozlovi larvae and juveniles. AB - Effect of rearing temperature on growth and thermal tolerance of Schizothorax (Racoma) kozlovi Nikolsky larvae and juveniles was investigated. The fish (start at 12d post hatch) were reared for nearly 6 months at five constant temperatures of 10, 14, 18, 22 and 26 degrees C. Then juvenile fish being acclimated at three temperatures of 14, 18 and 22 degrees C were chosen to determine their critical thermal maximum (CTMax) and lethal thermal maximum (LTMax) by using the dynamic method. Growth rate of S. kozlovi larvae and juveniles was significantly influenced by temperature and fish size, exhibiting an increase with increased rearing temperature, but a decline with increased fish size. A significant ontogenetic variation in the optimal temperatures for maximum growth were estimated to be 24.7 degrees C and 20.6 degrees C for larvae and juveniles of S. kozlovi, respectively. The results also demonstrated that acclimation temperature had marked effects on their CTMax and LTMax, which ranged from 32.86 degrees C to 34.54 degrees C and from 33.79 degrees C to 34.80 degrees C, respectively. It is suggested that rearing temperature must never rise above 32 degrees C for its successful aquaculture. Significant temperature effects on the growth rate and thermal tolerance both exhibit a plasticity pattern. Determination of critical heat tolerance and optima temperature for maximum growth of S. kozlovi is of ecological significance in the conservation and aquaculture of this species. PMID- 25455938 TI - Rapid changes in cell physiology as a result of acute thermal stress house sparrows, Passer domesticus. AB - Given that our climate is rapidly changing, Physiological Ecologists have the critical task of identifying characteristics of species that make them either resilient or susceptible to changes in their natural air temperature regime. Because climate change models suggest that heat events will become more common, and in some places more extreme, it is important to consider how extreme heat events might affect the physiology of a species. The implications of more frequent heat wave events for birds have only recently begun to be addressed, however, the impact of these events on the cellular physiology of a species is difficult to assess. We have developed a novel approach using dermal fibroblasts to explore how short-term thermal stress at the whole animal level might affect cellular rates of metabolism. House sparrows, Passer domesticus were separated into a "control group" and a "heat shocked" group, the latter acclimated to 43 degrees C for 24h. We determined the plasticity of cellular thermal responses by assigning a "recovery group" that was heat shocked as above, but then returned to room temperature for 24h. Primary dermal fibroblasts were grown from skin of all treatment groups and the pectoralis muscle was collected. We found that glycolysis (ECAR) and oxygen consumption rates (OCR), measured using a Seahorse XF 96 analyzer, were significantly higher in the fibroblasts from the heat shocked group of House sparrows compared with their control counterparts. Additionally, muscle fiber diameters decreased and, in turn, Na(+)-K(+)-ATPase maximal activity in the muscle significantly increased in heat shocked sparrows compared with birds in the control group. All of these physiological alterations due to short-term heat exposure were reversible within 24h of recovery at room temperature. These results show that acute exposure to heat stress significantly alters the cellular physiology of sparrows, but that this species is plastic enough to recover from such a thermal insult within 24h. PMID- 25455939 TI - Dietary lecithin potentiates thermal tolerance and cellular stress protection of milk fish (Chanos Chanos) reared under low dose endosulfan-induced stress. AB - Endosulfan is an organochlorine pesticide commonly found in aquatic environments that has been found to reduce thermal tolerance of fish. Lipotropes such as the food additive, Lecithin has been shown to improve thermal tolerance in fish species. This study was conducted to evaluate the role of lipotropes (lecithin) for enhancing the thermal tolerance of Chanos chanos reared under sublethal low dose endosulfan-induced stress. Two hundred and twenty-five fish were distributed randomly into five treatments, each with three replicates. Four isocaloric and isonitrogenous diets were prepared with graded levels of lecithin: normal water and fed with control diet (En0/L0), endosulfan-treated water and fed with control diet (En/L0), endosulfan-treated water and fed with 1% (En/L1%), 1.5% (En/L 1.5%) and 2% (En/L 2%) lecithin supplemented feed. The endosulfan in treated water was maintained at the level of 1/40th of LC50 (0.52ppb). At the end of the five weeks, critical temperature maxima (CTmax), lethal temperature maxima (LTmax), critical temperature minima (CTmin) and lethal temperature minima (LTmin) were Determined. There was a significant (P<0.01) effect of dietary lecithin on temperature tolerance (CTmax, LTmax, CTmin and LTmin) of the groups fed with 1, 1.5 and 2% lecithin-supplemented diet compared to control and endosulfan-exposed groups. Positive correlations were observed between CT max and LTmax (R(2)=0.934) as well as between CTmin and LTmin (R(2)=0.9313). At the end of the thermal tolerance study, endosulfan-induced changes in cellular stress enzymes (Catalase, SOD and GST in liver and gill and neurotansmitter enzyme, brain AChE) were significantly (p<0.01) improved by dietary lecithin. We herein report the role of lecithin in enhancing the thermal tolerance and protection against cellular stress in fish exposed to an organochlorine pesticide. PMID- 25455940 TI - Interstitial hyperthermia treatment of countercurrent vascular tissue: a comparison of Pennes, WJ and porous media bioheat models. AB - Development of appropriate heat transfer models to investigate the thermal behavior of living tissues has become increasingly important in simulations of cancer hyperthermia. In this paper, a review is initially presented of the more important general models developed for heat transfer description of perfused tissues. Comparisons are then made between Pennes' simplified Weinbaum and Jiji "WJ" and the more recent porous media "PM" bioheat models. For this purpose, a mathematical model is developed for the heat transfer in a cylindrical medium containing parallel counter-current pairs of small vessels with characteristics as much as possible similar to those of living tissues. The validity of the models is examined and confirmed using the Pennes in vivo experiments and one dimensional analytical solutions. For consideration of interstitial hyperthermia treatment the smaller cylindrical zone with typical heat generation, is assumed in the center of the main cylinder. The numerical simulation results revealed that, despite difference in temperature distributions calculated by these three models at normal condition, the heat affected zone at hyperthermic condition predicted by all three models are similar. PMID- 25455941 TI - Body temperature regulation during acclimation to cold and hypoxia in rats. AB - Extreme environmental conditions present challenges for thermoregulation in homoeothermic organisms such as mammals. Such challenges are exacerbated when two stressors are experienced simultaneously and each stimulus evokes opposing physiological responses. This is the case of cold, which induces an increase in thermogenesis, and hypoxia, which suppresses metabolism conserving oxygen and preventing hypoxaemia. As an initial approach to understanding the thermoregulatory responses to cold and hypoxia in a small mammal, we explored the effects of acclimation to these two stressors on the body temperature (Tb) and the daily and ultradian Tb variations of Sprague-Dawley rats. As Tb is influenced by sleep-wake cycles, these Tb variations reflect underlying adjustments in set point and thermosensitivity. The Tb of rats decreased precipitously during initial hypoxic exposure which was more pronounced in cold (Tb=33.4 +/- 0.13) than in room temperature (Tb=35.74 +/- 0.17) conditions. This decline was followed by an increase in Tb stabilising at a new level ~0.5 degrees C and ~1.4 degrees C below normoxic values at room and cold temperatures, respectively. Daily Tb variations were blunted during hypoxia with a greater effect in the cold. Ultradian Tb variations exhibited daily rhythmicity that disappeared under hypoxia, independent of ambient temperature. The adjustments in Tb during hypoxia and/or cold are in agreement with the hypothesis that an initial decrease in the Tb set-point is followed by its partial re-establishment with chronic hypoxia. This rebound of the Tb set-point might reflect cellular adjustments that would allow animals to better deal with low oxygen conditions, diminishing the drive for a lower Tb set-point. Cold and hypoxia are characteristic of high altitude environments. Understanding how mammals cope with changes in oxygen and temperature will shed light into their ability to colonize new environments along altitudinal clines and increase our understanding of how Tb is regulated under stimuli that impose contrasting physiological constraints. PMID- 25455942 TI - Firefighter feedback during active cooling: a useful tool for heat stress management? AB - Monitoring an individual's thermic state in the workplace requires reliable feedback of their core temperature. However, core temperature measurement technology is expensive, invasive and often impractical in operational environments, warranting investigation of surrogate measures which could be used to predict core temperature. This study examines an alternative measure of an individual's thermic state, thermal sensation, which presents a more manageable and practical solution for Australian firefighters operating on the fireground. Across three environmental conditions (cold, warm, hot & humid), 49 Australian volunteer firefighters performed a 20-min fire suppression activity, immediately followed by 20 min of active cooling using hand and forearm immersion techniques. Core temperature (Tc) and thermal sensation (TS) were measured across the rehabilitation period at five minute intervals. Despite the decline in Tc and TS throughout the rehabilitation period, there was little similarity in the magnitude or rate of decline between each measure in any of the ambient conditions. Moderate to strong correlations existed between Tc and TS in the cool (0.41, p<0.05) and hot & humid (0.57, p<0.05) conditions, however this was resultant in strong correlation during the earlier stages of rehabilitation (first five minutes), which were not evident in the latter stages. Linear regression revealed TS to be a poor predictor of Tc in all conditions (SEE=0.45 0.54 degrees C) with a strong trend for TS to over-predict Tc (77-80% of the time). There is minimal evidence to suggest that ratings of thermal sensation, which represent a psychophysical assessment of an individual's thermal comfort, are an accurate reflection of the response of an individual's core temperature. Ratings of thermal sensation can be highly variable amongst individuals, likely moderated by local skin temperature. In account of these findings, fire managers require a more reliable source of information to guide decisions of heat stress management. PMID- 25455943 TI - Considerations for the measurement of core, skin and mean body temperatures. AB - Despite previous reviews and commentaries, significant misconceptions remain concerning deep-body (core) and skin temperature measurement in humans. Therefore, the authors have assembled the pertinent Laws of Thermodynamics and other first principles that govern physical and physiological heat exchanges. The resulting review is aimed at providing theoretical and empirical justifications for collecting and interpreting these data. The primary emphasis is upon deep body temperatures, with discussions of intramuscular, subcutaneous, transcutaneous and skin temperatures included. These are all turnover indices resulting from variations in local metabolism, tissue conduction and blood flow. Consequently, inter-site differences and similarities may have no mechanistic relationship unless those sites have similar metabolic rates, are in close proximity and are perfused by the same blood vessels. Therefore, it is proposed that a gold standard deep-body temperature does not exist. Instead, the validity of each measurement must be evaluated relative to one's research objectives, whilst satisfying equilibration and positioning requirements. When using thermometric computations of heat storage, the establishment of steady-state conditions is essential, but for clinically relevant states, targeted temperature monitoring becomes paramount. However, when investigating temperature regulation, the response characteristics of each temperature measurement must match the forcing function applied during experimentation. Thus, during dynamic phases, deep-body temperatures must be measured from sites that track temperature changes in the central blood volume. PMID- 25455944 TI - The use of reperfusion and revascularization procedures in acute coronary syndrome in Portugal: a systematic review. AB - INTRODUCTION AND OBJECTIVES: Reperfusion and revascularization therapies play an important role in the management of coronary heart disease and have contributed to decreases in case fatality rates. We aimed to describe the use of these therapies for the treatment of acute coronary syndrome (ACS) patients over time in Portugal. METHODS: PubMed was searched in July 2012. The proportion of patients treated with fibrinolysis, primary percutaneous coronary intervention (PCI), any PCI and coronary artery bypass grafting (CABG) was described according to type of ACS: STEMI (>=90% patients with ST-segment elevation or Q-wave myocardial infarction), NSTE-ACS (>=90% patients with non-ST-segment elevation ACS) and mixed ACS (all others). RESULTS: We identified 41 eligible studies, published between 1989 and 2011. Twenty-eight reported on samples considered representative of ACS patients treated in Portugal. The small number of estimates of the use of each treatment in STEMI and NSTE-ACS patients precluded identification of any time trend. In the last 20 years, the proportion of mixed ACS patients treated with fibrinolysis decreased and the use of PCI increased, while the use of CABG did not change. CONCLUSIONS: The general pattern of the use of reperfusion and revascularization is in accordance with that reported in other developed countries, reflecting a favorable trend in the quality of care of ACS patients. The relatively small number of estimates on the same procedure in comparable patients limits the generalizability of the conclusions, and highlights the need for systematic approaches to monitor the use of treatments over time. PMID- 25455945 TI - Assessment of interrupted aortic arch with magnetic resonance angiography. PMID- 25455946 TI - Massive calcification involving a left ventricular false tendon. PMID- 25455947 TI - Collateral damage from a coronary blush. PMID- 25455948 TI - Intravenous leiomyomatosis: a rare cause of intracardiac mass. AB - Intravenous leiomyomatosis is an unusual clinical condition characterized by histologically benign smooth muscle lesions extending from the uterus into pelvic and systemic veins and, more rarely, into the right cardiac chambers. We report the case of a 45-year-old woman who presented with a three-week history of dyspnea on exertion, shortness of breath and fatigue. Echocardiography showed a large mobile mass in the right atrium prolapsing into the right ventricle and extending to the inferior vena cava. A computed tomography scan revealed a large mass extending from the right atrium to the inferior vena cava and through the systemic veins as far as the popliteal veins. A presumptive diagnosis of large thrombus was made; the correct diagnosis of intravenous leiomyomatosis with intracardiac involvement was obtained only after surgical resection and histologic examination. PMID- 25455949 TI - Holt-Oram syndrome: a case report. AB - Holt-Oram syndrome is clinically characterized by morphological abnormalities of the upper limbs and congenital cardiac defects. Although the disease is congenital, the diagnosis may only be made later in life. It is a rare autosomal dominant disorder, caused by a mutation in the TBX5 gene located on chromosome 12, but sporadic cases have also been reported. We describe the case of a 75-year old man with known morphological alterations of the upper limbs since birth and congenital cardiac defect (atrial septal defect), who later in life also manifested with advanced atrioventricular block. PMID- 25455950 TI - Pacemaker lead-related tricuspid stenosis successfully treated with percutaneous balloon valvuloplasty guided by 3D echocardiography. AB - The most common etiology of tricuspid stenosis is rheumatic, and in most cases it is associated with valvular regurgitation. Interestingly, there have been reports of tricuspid stenosis without associated valvular regurgitation, mostly related to pacemaker leads. Percutaneous tricuspid valvuloplasty may be a therapeutic alternative to surgery in cases of pure tricuspid stenosis without other concomitant valvulopathies. We report the case of a 52-year-old woman with pacemaker lead-related tricuspid stenosis successfully treated with percutaneous valvuloplasty guided by 3D echocardiography. PMID- 25455951 TI - Idiopathic and secondary forms of retroperitoneal fibrosis: a diagnostic approach. AB - Retroperitoneal fibrosis (RPF) is an uncommon disease characterized by a fibrous reaction that takes place in the peri-aortic retroperitoneum and often entraps the ureters causing obstructive uropathy. RPF is idiopathic in the majority of cases, but can also be secondary to malignancies, infections, drugs, radiotherapy, and rare histiocytic disorders such as Erdheim-Chester disease. Idiopathic RPF is an immune-mediated disease, which can either be isolated, associated with other autoimmune diseases, or arise in the context of a multifocal fibro-inflammatory disorder recently renamed as IgG4-related disease. The differential diagnosis between idiopathic, IgG4-related and secondary RPF is crucial, essentially because the therapeutic approaches - especially of idiopathic vs. secondary RPF - can be dramatically different. This review focuses on the clinical, laboratory and imaging features of the different RPF forms, and also provides an overview of the available treatment options. PMID- 25455952 TI - [Fibromuscular dysplasia]. AB - Fibromuscular dysplasia is a segmentary, non-atherosclerotic, non-inflammatory vascular disease that may result in stenosis, occlusion, aneurysms or dissection of medium arteries. Renal involvement is the most frequent location, described in 60-100% of patients. Renal stenosis can be asymptomatic or complicated with arterial hypertension or less frequently with renal insufficiency. Carotid and vertebral involvements are less frequent (10-35%). Surgical management of fibromuscular dysplasia is now less common because of the better efficacy of percutaneous transluminal angioplasty. Thus, histologic characteristics are no longer relevant prognostic criteria. Clinical features and outcome vary according to angiographic presentation (focal or multifocal disease), with an increased recovery rate of hypertension with focal lesions. In the presence of renal fibromuscular dysplasia, only symptomatic patients are revascularized (recent or resistant hypertension) or patients with asymmetric renal size or impaired renal function. Transluminal angioplasty is the first-line treatment except for patients with complex lesions or stenosis associated with aneurysm. PMID- 25455953 TI - [The permanence of access to health care: a tradition of hospitality and innovative organizational model]. AB - The PASS ("Permanence d'Acces aux Soins de Sante") are hospital-based units providing primary care services to patients who lack health care coverage. Using a "whole person" approach and providing a combination of health and social care, the PASS offer an appropriately adapted response to complex health problems within a context of marked social vulnerability and contribute to reducing health inequalities. The PASS are an example of an interdisciplinary approach to health care which contrasts with the segmentary approach typical of conventional hospital departments. Operating at the interface between primary and secondary care, the PASS have the potential to become key players in developing models of patient pathways. Their presence reduces inappropriate emergency attendances and hospitalisation by offering medical care in a timely fashion, in an outpatient type setting. The PASS can provide a resource for research into optimum models of health care, where the social context of health needs are fully recognized and inform medical treatment appropriately. According to their potential development, PASS are living labs of an innovative organizational model of care. PMID- 25455955 TI - Sex differences in acute translational repressor 4E-BP1 activity and sprint performance in response to repeated-sprint exercise in team sport athletes. AB - OBJECTIVES: The physiological requirements underlying soccer-specific exercise are incomplete and sex-based comparisons are sparse. The aim of this study was to determine the effects of a repeated-sprint protocol on the translational repressor 4E-BP1 and sprint performance in male and female soccer players. DESIGN: Cross-over design involving eight female and seven male university soccer players. METHODS: Participants performed four bouts of 6 * 30-m maximal sprints spread equally over 40 min. Heart rate, sprint time and sprint decrement were measured for each sprint and during the course of each bout. Venous blood samples and muscle biopsies from the vastus lateralis were taken at rest, at 15 min and 2h post-exercise. RESULTS: While males maintained a faster mean sprint time for each bout (P < 0.05) females exhibited a greater decrement in sprint performance for each bout (P < 0.05), indicating a superior maintenance of sprint performance in males, with no sex differences for heart rate or lactate. Muscle analyses revealed sex differences in resting total (P < 0.05) and phosphorylated (P < 0.05) 4E-BP1 Thr37/46, and 15 min post-exercise the 4E-BP1 Thr37/46 ratio decreased below resting levels in males only (P < 0.05), indicative of a decreased translation initiation following repeated sprints. CONCLUSIONS: We show that females have a larger sprint decrement indicating that males have a superior ability to recover sprint performance. Sex differences in resting 4E-BP1 Thr37/46 suggest diversity in the training-induced phenotype of the muscle of males and females competing in equivalent levels of team-sport competition. PMID- 25455956 TI - Comparing three underwater trajectories of the swimming start. AB - Once a swimmer enters the water they will not increase velocity, instead they will decelerate. One factor that will influence the velocity maintained during the underwater phase is the trajectory the swimmer adopts. OBJECTIVES: Once a swimmer enters the water they will not increase velocity, instead they will decelerate. One factor that will influence the velocity maintained during the underwater phase is the trajectory the swimmer adopts. This study aimed to identify how different underwater trajectories affect start time in elite swimmers. METHODS: Fourteen swimmers performed three dives: a shallow dive with little underwater time (Dive 1), a flatter dive with intermediate time underwater (Dive 2) and a deep dive with lengthy underwater time (Dive 3). The proprietary 'Wetplate' analysis system was used to collect performance time (time to 15 m) and other dive parameters. RESULTS: A mixed modelling approach found Dive 1 was significantly slower than Dive 2 and 3 (time to 15 m). This indicated that both a shallow or deep dive slowed overall performance, with shallower dives adversely affecting performance the most. CONCLUSIONS: On average, using a flatter trajectory with a maximum depth of -0.92 +/- 0.16 m similar to Dive 2 may prove to be beneficial to start performance. More research is needed to examine the interaction between drag and depth for individual swimmers to better understand the mechanisms influencing these findings and to further explore the notion of an ideal underwater trajectory. PMID- 25455954 TI - [Screening and management of cardiovascular risk factors in systemic lupus erythematosus: Recommendations for clinical practice based on the literature and expert opinion]. AB - PURPOSE: To develop French recommendations about screening and management of cardiovascular risk factors in systemic lupus erythematosus (SLE). METHODS: Thirty-nine experts qualified in internal medicine, rheumatology and nephrology have selected recommendations from a list developed based on evidence from the literature. For each recommendation, the level of evidence and the level of agreement among the experts were specified. RESULTS: Experts recommended an annual screening of cardiovascular risk factors in SLE. Statins should be prescribed for primary prevention in SLE patients based on the level of LDL cholesterol and the number of cardiovascular risk factors, considering SLE as an additional risk factor. For secondary prevention, experts have agreed on an LDL cholesterol target of <0.7 g/L. Hypertension should be managed according to the 2013 European guidelines, using renin-angiotensin system blockers as first line agents in case of renal involvement. Aspirin can be prescribed in patients with high cardiovascular risk or with antiphospholipid antibodies. CONCLUSION: These recommendations about the screening and management of cardiovascular risk factors in SLE can be expected to improve clinical practice uniformity and, in the longer term, to optimize the management of SLE patients. PMID- 25455957 TI - Evaluation of the effect of four surface conditioning methods on the shear bond strength of metal bracket to porcelain surface. AB - OBJECTIVE: This study evaluated the effect of superpulse CO2 laser irradiation and deglazing of porcelain surfaces on the shear bond strength (SBS) of metal orthodontic brackets, and compared it with two conventional etching techniques. METHODS: Forty-eight Feldspathic porcelain fused to metal specimens embedded in cylindrical acrylic resin tubes were fabricated, and all the specimens were divided into four groups. In Group 1, the specimens were roughened with a diamond bur and etched with hydrofluoric acid (HFA) gel for 4 min. In Group 2, the specimens were roughened with a bur and irradiated by a CO2 laser with a 2 W power setting for 20 sec. In Group 3, the specimens were only irradiated by a CO2 laser. In Group 4, the porcelain surface was sandblasted with 50 MUm aluminum oxide. Before bonding, the bracket silane was applied on the porcelain surfaces. SBS was evaluated by a Universal testing machine (Zwickroll, Germany). The remaining adhesive after the bond failure was evaluated using an adhesive remnant index (ARI). Statistical analysis was conducted by analysis of variance (ANOVA), Tukey, and Kruskal-Wallis tests. RESULTS: ANOVA revealed significant differences in SBS among the four groups (p<0.001). Group 1 demonstrated significantly higher bond strength (13.13+/-2.47) when compared with the other groups. Group 2 showed higher bond strength (9.60+/-1.91) when compared with group 4 (6.40+/-1.67) (p=0.016). Group 1 displayed the highest ARI scores among the groups. CONCLUSIONS: Deglazing combined with HFA etching produced the highest bond strength, but CO2 laser irradiation provided adequate bond strength and allowed for elimination of the HFA step. Deglazing is not recommended as a preliminary step before CO2 laser conditioning. PMID- 25455958 TI - Preparation of sterically stabilized chitin nanowhisker dispersions by grafting of poly(ethylene glycol) and evaluation of their dispersion stability. AB - Sterically stabilized chitin nanowhiskers (ChNWs) were prepared by surface grafting monomethoxy poly(ethylene glycol) (mPEG) via reductive amination of primary amino groups on ChNWs and terminal aldehydes on mPEG. The amount of grafted mPEG was determined to be 0.2-0.3 g/g ChNWs, by conductometric titration, from the decrease in amino groups after grafting. ChNWs with controlled amounts of surface amino groups were obtained by deacetylation; however, this did not cause a drastic change in the amount of grafted mPEG. Grafting was confirmed by Fourier-transform infrared spectroscopy; however, X-ray diffractometry indicated no sign of mPEG. Thermogravimetry indicated a higher amount of mPEG than that from titration, suggesting an overestimation due to the facilitated combustion of grafted samples. In contrast to ungrafted samples, all grafted samples were stable in the presence of electrolytes. However, liquid-crystalline phase separation of grafted ChNWs was not observed, possibly owing to the high viscosity of the concentrated sample. PMID- 25455959 TI - Surgical strategy for low rectal cancers. AB - The two goals of surgery for lower rectal cancer surgery are to obtain clear "curative" margins and to limit post-surgical functional disorders. The question of whether or not to preserve the anal sphincter lies at the center of the therapeutic choice. Histologically, tumor-free distal and circumferential margins of>1mm allow a favorable oncologic outcome. Whether such margins can be obtained depends of TNM staging, tumor location, response to chemoradiotherapy and type of surgical procedure. The technique of intersphincteric resection relies on these narrow margins to spare the sphincter. This procedure provides satisfactory oncologic outcome with a rate of circumferential margin involvement ranging from 5% to 11%, while good continence is maintained in half of the patients. The extralevator abdominoperineal resection provides good oncologic results, however this procedure requires a permanent colostomy. A permanent colostomy alters several domains of quality of life when located at the classical abdominal site but not when brought out at the perineal site as a perineal colostomy. PMID- 25455960 TI - Anastomotic leakage after gastrointestinal surgery: diagnosis and management. AB - Anastomotic leakage represents a major complication of gastrointestinal surgery, leading to increased postoperative morbidity; it the foremost cause of mortality after intestinal resection. Identification of risk factors is essential for the prevention of AL. AL can present with various clinical pictures, ranging from the absence of symptoms to life-threatening septic shock. Contrast-enhanced CT scan is the most complete investigation to define AL and its consequences. Early and optimal multidisciplinary management is based on three options: medical management, radiologic or endoscopic intervention, or surgical re-intervention. Prompt treatment should help decrease postoperative morbidity and mortality, with the choice depending on the septic status of the patient. If the patient is asymptomatic, treatment can be medical only, coupled with close surveillance. Interventional management is indicated when the fistula is symptomatic but not life-threatening. On the other hand, when the vital prognosis is engaged, surgery is indicated, emergently, associated with intensive care. Even more than their prevention, early and appropriate management counts most to decrease their consequences. PMID- 25455961 TI - Adverse childhood experiences as risk factors for serious mental disorders and inpatient hospitalization among adolescents. PMID- 25455962 TI - Cumulative incidence of entry into out-of-home care: changes over time in Denmark and England. AB - Policies and thresholds vary for placing children into out-of-home care (OHC) at different ages. Evidence is lacking that quantifies the risk of entering OHC by age, and how this varies over time and between countries. We determined the age specific cumulative incidence of ever entering OHC during childhood in Denmark and in eight local authorities in England. We used administrative data for any form of OHC (except respite care) provided by children's social services in Denmark and England from 1992 to 2008. Using life tables and national population estimates, we calculated the cumulative incidence of entry into OHC by year of age for cohorts born in 1992-1994 through to 2006-2008. The cumulative incidence of entry into OHC decreased over time in Denmark and increased in England at all ages. Cumulative incidence of OHC in the first year of life was similar in Denmark and England for infants born in 1992-1994 (Denmark 2.83/1,000, England 2.89/1,000), but infants born in 2007-2008 were nearly three times as likely to enter OHC before their first birthday in England (4.50/1,000) than in Denmark (1.61/1,000). Entry into OHC during adolescence was more common in Denmark than in England so that by 16 years old the cumulative incidence of ever entering OHC during childhood was twice as high in Denmark (33.83/1,000) as in England (15.62/1,000). Diverging trends over time in the use of OHC in Denmark and England are likely to reflect changing policies in the two countries. PMID- 25455964 TI - Predicting re-involvement for children adopted out of a public child welfare system. AB - Some of the approximately 400,000 children currently placed out-of-home in a public child welfare system will not reunify with their family of origin. They may instead be adopted into a new family. Adoption placements can be characterized by poor adjustment for children; some such placements even result in disruption or dissolution. We conducted a stratified Cox regression of 4,016 children from the Colorado public child welfare system. All of the children had a finalized adoption during the years 2002 through 2006. The two outcomes analyzed were new child protection and youth-in-conflict referrals and assessments for these previously adopted children. New child welfare referrals and assessments may be early indicators of poor adjustment for adopted children within the adoptive family. Study results indicate that older children and Hispanic children had higher rates of referral and assessment. Children with a pre-adoption history including longer time out-of-home or a larger number of out-of-home placements also experienced higher referral and assessment rates. Additional factors which predicted subsequent system re-involvement included presence of paid adoption assistance, adoption by a non-relative foster parent and younger adoptive parent age. Several study results were moderated by the presence or absence of an ethnic match between the child and the adoptive parents. We provide an overview of the statistical model used for analysis and we discuss implications of the study results for child welfare practice. PMID- 25455963 TI - Subtypes of exposure to intimate partner violence within a Canadian child welfare sample: associated risks and child maladjustment. AB - Children exposed to intimate partner violence (IPV) are at increased risk of experiencing behavioral difficulties including externalizing and internalizing problems. While there is mounting evidence about mental health problems in children exposed to IPV, most of the research to date focuses on IPV exposure as a unitary, homogeneous construct. The purpose of this study was to examine the association between subtypes of IPV exposure on child functioning and presence of harm within a child welfare sample. Given the evidence of the "double whammy" effect, co-occurring IPV exposure was also examined. Using data from the Canadian Incidence Study of Reported Child Abuse and Neglect - 2008 (n=2,184) we examined whether specific IPV exposure subtypes or their co-occurrence resulted in a greater risk of child maladjustment. Information was obtained from child welfare workers' reports. Caregiver and household risk factors were also examined. Co occurring IPV exposure resulted in the greatest risk for reported child maladjustment. Exposure to emotional IPV and direct physical IPV were significantly associated with increased risk of internalizing problems and presence of harm. Caregiver mental health and lack of social support emerged as significant risk factors for behavior problems. This study adds to the evidence that exposure to subtypes of IPV may be differentially related to child functioning. Given that risk factors and child functioning is part of the decision-making framework for case worker referrals, this study provides important preliminary evidence about how the child welfare system operates in practice with respect to sub-types of exposure to IPV. These findings suggest that intervening with children exposed to different types of IPV may require a tailored approach. PMID- 25455966 TI - Association of CRISPR/Cas evolution with Vibrio parahaemolyticus virulence factors and genotypes. AB - Clustered regularly interspaced short palindromic repeats (CRISPR), which is considered to be an immune system for bacteria, has been widely used as a tool for genome editing and genotyping. It has also been reported to be associated with virulence factors in some bacteria. To understand the role of CRISPR in the virulence and evolution of pathogenic Vibrio parahaemolyticus, 154 V. parahaemolyticus strains isolated from clinical samples and 54 strains from food samples taken in Shenzhen, China were subjected to a correlation analysis of CRISPR and virulence factors TDH and TRH. We also performed multilocus sequence typing (MLST) for genotype analysis. Six different CRISPR sequence types (CSTs) of V. parahaemolyticus were identified, and CSTs were found to be significantly associated with the virulence factors tested and MLST genotype. Therefore, CSTs provide insight into the evolution of V. parahaemolyticus. Moreover, identification of CSTs may lend insight into the virulence potential of strains. PMID- 25455965 TI - Pathways from childhood abuse to prospective revictimization: depression, sex to reduce negative affect, and forecasted sexual behavior. AB - Research suggests that adverse events in childhood, such as childhood physical, sexual, and emotional abuse, confer risk for later sexual assault. Psychological distress, coping strategies, and sexual behavior may help explain the path from childhood abuse to revictimization. The present study explored how the use of sex to regulate negative affect (SRNA) operates independently, and in combination with other psychosocial factors to increase college women's (N=541) risk of experiencing prospective adult sexual assault (ASA). Sequential multiple mediator models in Mplus were used to assess the effect of three different forms of childhood abuse on prospective ASA, both independently and while controlling for other forms of childhood abuse. The indirect effect of adolescent sexual assault (AdolSA), depressive symptoms, SRNA, and participants' response to a sex-related vignette was tested using bias-corrected bootstrapping. In the full path model, childhood emotional abuse and AdolSA predicted ASA, while childhood physical and sexual abuse were directly associated with AdolSA, but not ASA. Additionally, depressive symptoms and participants' estimate of their likely behavior in a sex related vignette directly predicted prospective ASA. Results using bootstrapping revealed that a history of childhood abuse predicted prospective ASA via diverse direct and indirect paths, as well as through a similar multiple mediator path. Overall, findings suggest that a combination of affective, coping, and sexual expectancy factors contribute to risk for revictimization in adult survivors of childhood abuse. Future research directions and targets for risk-reduction programming are discussed. PMID- 25455967 TI - Rationality and coordination for Ebola outbreak in west Africa. PMID- 25455968 TI - Ebola: no time to waste. PMID- 25455969 TI - Modern twist on a classic formula for influenza vaccination. PMID- 25455970 TI - Hidden burden of undiagnosed Clostridium difficile infection. PMID- 25455971 TI - Is it time for an antibiotic prenuptial agreement? PMID- 25455972 TI - Influenza vaccine effectiveness in elderly people. PMID- 25455973 TI - Pre-entry, post-entry, or no tuberculosis screening? PMID- 25455974 TI - Interplay between childhood pneumonia and HIV infection. PMID- 25455976 TI - Antiretroviral treatment initiation. PMID- 25455977 TI - Antiretroviral treatment initiation. PMID- 25455978 TI - Antiretroviral treatment initiation--authors' reply. PMID- 25455979 TI - Choosing a metric for measurement of pre-exposure prophylaxis. PMID- 25455980 TI - Choosing a metric for measurement of pre-exposure prophylaxis. PMID- 25455981 TI - Barriers to simplified HIV treatment in low-resource settings. PMID- 25455982 TI - Antibiotic use worldwide. PMID- 25455983 TI - Antibiotic use worldwide. PMID- 25455984 TI - Therapeutic drug monitoring of antibiotics. PMID- 25455985 TI - Therapeutic drug monitoring of antibiotics--author's reply. PMID- 25455986 TI - Dynamics and control of Ebola virus transmission in Montserrado, Liberia: a mathematical modelling analysis. AB - BACKGROUND: A substantial scale-up in public health response is needed to control the unprecedented Ebola virus disease (EVD) epidemic in west Africa. Current international commitments seek to expand intervention capacity in three areas: new EVD treatment centres, case ascertainment through contact tracing, and household protective kit allocation. We aimed to assess how these interventions could be applied individually and in combination to avert future EVD cases and deaths. METHODS: We developed a transmission model of Ebola virus that we fitted to reported EVD cases and deaths in Montserrado County, Liberia. We used this model to assess the effectiveness of expanding EVD treatment centres, increasing case ascertainment, and allocating protective kits for controlling the outbreak in Montserrado. We varied the efficacy of protective kits from 10% to 50%. We compared intervention initiation on Oct 15, 2014, Oct 31, 2014, and Nov 15, 2014. The status quo intervention was defined in terms of case ascertainment and capacity of EVD treatment centres on Sept 23, 2014, and all behaviour and contact patterns relevant to transmission as they were occurring at that time. The primary outcome measure was the expected number of cases averted by Dec 15, 2014. FINDINGS: We estimated the basic reproductive number for EVD in Montserrado to be 2.49 (95% CI 2.38-2.60). We expect that allocating 4800 additional beds at EVD treatment centres and increasing case ascertainment five-fold in November, 2014, can avert 77 312 (95% CI 68 400-85 870) cases of EVD relative to the status quo by Dec 15, 2014. Complementing these measures with protective kit allocation raises the expectation as high as 97 940 (90 096-105 606) EVD cases. If deployed by Oct 15, 2014, equivalent interventions would have been expected to avert 137 432 (129 736-145 874) cases of EVD. If delayed to Nov 15, 2014, we expect the interventions will at best avert 53 957 (46 963-60 490) EVD cases. INTERPRETATION: The number of beds at EVD treatment centres needed to effectively control EVD in Montserrado substantially exceeds the 1700 pledged by the USA to west Africa. Accelerated case ascertainment is needed to maximise effectiveness of expanding the capacity of EVD treatment centres. Distributing protective kits can further augment prevention of EVD, but it is not an adequate stand-alone measure for controlling the outbreak. Our findings highlight the rapidly closing window of opportunity for controlling the outbreak and averting a catastrophic toll of EVD cases and deaths. FUNDING: US National Institutes of Health. PMID- 25455987 TI - Safety and immunogenicity of a modified-vaccinia-virus-Ankara-based influenza A H5N1 vaccine: a randomised, double-blind phase 1/2a clinical trial. AB - BACKGROUND: Modified vaccinia virus Ankara (MVA) is a promising viral vector platform for the development of an H5N1 influenza vaccine. Preclinical assessment of MVA-based H5N1 vaccines showed their immunogenicity and safety in different animal models. We aimed to assess the safety and immunogenicity of the MVA haemagglutinin-based H5N1 vaccine MVA-H5-sfMR in healthy individuals. METHODS: In a single-centre, double-blind phase 1/2a study, young volunteers (aged 18-28 years) were randomly assigned with a computer-generated list in equal numbers to one of eight groups and were given one injection or two injections intramuscularly at an interval of 4 weeks of a standard dose (10(8) plaque forming units [pfu]) or a ten times lower dose (10(7) pfu) of the MVA-H5-sfMR (vector encoding the haemagglutinin gene of influenza A/Vietnam/1194/2004 virus [H5N1 subtype]) or MVA-F6-sfMR (empty vector) vaccine. Volunteers and physicians who examined and administered the vaccine were masked to vaccine assignment. Individuals who received the MVA-H5-sfMR vaccine were eligible for a booster immunisation 1 year after the first immunisation. Primary endpoint was safety. Secondary outcome was immunogenicity. The trial is registered with the Dutch Trial Register, number NTR3401. FINDINGS: 79 of 80 individuals who were enrolled completed the study. No serious adverse events were identified. 11 individuals reported severe headache and lightheadedness, erythema nodosum, respiratory illness (accompanied by influenza-like symptoms), sore throat, or injection-site reaction. Most of the volunteers had one or more local (itch, pain, redness, and swelling) and systemic reactions (rise in body temperature, headache, myalgia, arthralgia, chills, malaise, and fatigue) after the first, second, and booster immunisations. Individuals who received the 10(7) dose had fewer systemic reactions. The MVA-H5-sfMR vaccine at 10(8) pfu induced significantly higher antibody responses after one and two immunisations than did 10(7) pfu when assessed with haemagglutination inhibition geometric mean titre at 8 weeks against H5N1 A/Vietnam/1194/2004 (30.2 [SD 3.8] vs 9.2 [2.3] and 108.1 [2.4] vs 15.8 [3.2]). 27 of 39 eligible individuals were enrolled in the booster immunisation study. A single shot of MVA-H5-sfMR 10(8) pfu prime immunisation resulted in higher antibody responses after the booster immunisation than did two shots of MVA-H5-sfMR at the ten times lower dose. INTERPRETATION: The MVA-based H5N1 vaccine was well tolerated and immunogenic and therefore the vaccine candidates arising from the MVA platform hold great promise for rapid development in response to a future influenza pandemic threat. However, the immunogenicity of this vaccine needs to be compared with conventional H5N1 inactivated non adjuvanted vaccine candidates in head-to-head clinical trials. FUNDING: European Research Council. PMID- 25455988 TI - Underdiagnosis of Clostridium difficile across Europe: the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID). AB - BACKGROUND: Variations in testing for Clostridium difficile infection can hinder patients' care, increase the risk of transmission, and skew epidemiological data. We aimed to measure the underdiagnosis of C difficile infection across Europe. METHODS: We did a questionnaire-based study at 482 participating hospitals across 20 European countries. Hospitals were questioned about their methods and testing policy for C difficile infection during the periods September, 2011, to August, 2012, and September, 2012, to August, 2013. On one day in winter, 2012-13 (December, 2012, or January, 2013), and summer, 2013 (July or August), every hospital sent all diarrhoeal samples submitted to their microbiology laboratory to a national coordinating laboratory for standardised testing of C difficile infection. Our primary outcome measures were the rates of testing for and cases of C difficile infection per 10 000 patient bed-days. Results of local and national C difficile infection testing were compared with each other. If the result was positive at the national laboratory but negative at the local hospital, the result was classified as undiagnosed C difficile infection. We compared differences in proportions with the Mann-Whitney test, or McNemar's test if data were matched. FINDINGS: During the study period, participating hospitals reported a mean of 65.8 tests (country range 4.6-223.3) for C difficile infection per 10 000 patient-bed days and a mean of 7.0 cases (country range 0.7-28.7) of C difficile infection per 10 000 patient-bed days. Only two-fifths of hospitals reported using optimum methods for testing of C difficile infection (defined by European guidelines), although the number of participating hospitals using optimum methods increased during the study period, from 152 (32%) of 468 in 2011 12 to 205 (48%) of 428 in 2012-13. Across all 482 European hospitals on the two sampling days, 148 (23%) of 641 samples positive for C difficile infection (as determined by the national laboratory) were not diagnosed by participating hospitals because of an absence of clinical suspicion, equating to about 74 missed diagnoses per day. INTERPRETATION: A wide variety of testing strategies for C difficile infection are used across Europe. Absence of clinical suspicion and suboptimum laboratory diagnostic methods mean that an estimated 40 000 inpatients with C difficile infection are potentially undiagnosed every year in 482 European hospitals. FUNDING: Astellas Pharmaceuticals Europe. PMID- 25455990 TI - Effectiveness of seasonal influenza vaccine in community-dwelling elderly people: a meta-analysis of test-negative design case-control studies. AB - BACKGROUND: The application of test-negative design case-control studies to assess the effectiveness of influenza vaccine has increased substantially in the past few years. The validity of these studies is predicated on the assumption that confounding bias by risk factors is limited by design. We aimed to assess the effectiveness of influenza vaccine in a high-risk group of elderly people. METHODS: We searched the Cochrane library, Medline, and Embase up to July 13, 2014, for test-negative design case-control studies that assessed the effectiveness of seasonal influenza vaccine against laboratory confirmed influenza in community-dwelling people aged 60 years or older. We used generalised linear mixed models, adapted for test-negative design case-control studies, to estimate vaccine effectiveness according to vaccine match and epidemic conditions. FINDINGS: 35 test-negative design case-control studies with 53 datasets met inclusion criteria. Seasonal influenza vaccine was not significantly effective during local virus activity, irrespective of vaccine match or mismatch to the circulating viruses. Vaccination was significantly effective against laboratory confirmed influenza during sporadic activity (odds ratio [OR] 0.69, 95% CI 0.48-0.99) only when the vaccine matched. Additionally, vaccination was significantly effective during regional (match: OR 0.42, 95% CI 0.30-0.60; mismatch: OR 0.57, 95% CI 0.41-0.79) and widespread (match: 0.54, 0.46 0.62; mismatch: OR 0.72, 95% CI 0.60-0.85) outbreaks. INTERPRETATION: Our findings show that in elderly people, irrespective of vaccine match, seasonal influenza vaccination is effective against laboratory confirmed influenza during epidemic seasons. Efforts should be renewed worldwide to further increase uptake of the influenza vaccine in the elderly population. FUNDING: None. PMID- 25455989 TI - Assessment of empirical antibiotic therapy optimisation in six hospitals: an observational cohort study. AB - BACKGROUND: Modification of empirical antimicrobials when warranted by culture results or clinical signs is recommended to control antimicrobial overuse and resistance. We aimed to assess the frequency with which patients were started on empirical antimicrobials, characteristics of the empirical regimen and the clinical characteristics of patients at the time of starting antimicrobials, patterns of changes to empirical therapy at different timepoints, and modifiable factors associated with changes to the initial empirical regimen in the first 5 days of therapy. METHODS: We did a chart review of adult inpatients receiving one or more antimicrobials in six US hospitals on 4 days during 2009 and 2010. Our primary outcome was the modification of antimicrobial regimen on or before the 5th day of empirical therapy, analysed as a three-category variable. Bivariate analyses were used to establish demographic and clinical variables associated with the outcome. Variables with p values below 0.1 were included in a multivariable generalised linear latent and mixed model with multinomial logit link to adjust for clustering within hospitals and accommodate a non-binary outcome variable. FINDINGS: Across the six study sites, 4119 (60%) of 6812 inpatients received antimicrobials. Of 1200 randomly selected patients with active antimicrobials, 730 (61%) met inclusion criteria. At the start of therapy, 220 (30%) patients were afebrile and had normal white blood cell counts. Appropriate cultures were collected from 432 (59%) patients, and 250 (58%) were negative. By the 5th day of therapy, 12.5% of empirical antimicrobials were escalated, 21.5% were narrowed or discontinued, and 66.4% were unchanged. Narrowing or discontinuation was more likely when cultures were collected at the start of therapy (adjusted OR 1.68, 95% CI 1.05-2.70) and no infection was noted on an initial radiological study (1.76, 1.11-2.79). Escalation was associated with multiple infection sites (2.54, 1.34-4.83) and a positive culture (1.99, 1.20-3.29). INTERPRETATION: Broad-spectrum empirical therapy is common, even when clinical signs of infection are absent. Fewer than one in three inpatients have their regimens narrowed within 5 days of starting empirical antimicrobials. Improved diagnostic methods and continued education are needed to guide discontinuation of antimicrobials. FUNDING: US Centers for Disease Control and Prevention, Division of Healthcare Quality Promotion; Robert Wood Johnson Foundation; US Department of Veterans Administration; US Department of Homeland Security. PMID- 25455991 TI - Pre-entry screening programmes for tuberculosis in migrants to low-incidence countries: a systematic review and meta-analysis. AB - BACKGROUND: Several high-income countries have pre-entry screening programmes for tuberculosis. We aimed to establish the yield of pre-entry screening programmes to inform evidence-based policy for migrant health screening. METHODS: We searched six bibliographic databases for experimental or observational studies and systematic reviews, which reported data on migrant screening for active or latent tuberculosis by any method before migration to a low-incidence country. Primary outcomes were principal reported screening yield of active tuberculosis, yield of culture-confirmed cases, and yield of sputum smear for acid-fast bacilli cases. Where appropriate, fixed-effects models were used to summarise the yield of pre-entry screening across included studies. FINDINGS: We identified 15 unique studies with data for 3 739 266 migrants screened pre-entry for tuberculosis between 1982 and 2010. Heterogeneity was high for all primary outcomes. After stratification by prevalence in country of origin, heterogeneity was reduced for culture-confirmed and smear-confirmed cases. Yield of culture-confirmed cases increased with prevalence in the country of origin, and summary estimates ranged from 19.7 (95% CI 10.3-31.5) cases identified per 100 000 individuals screened in countries with a prevalence of 50-149 cases per 100 000 population to 335.9 (283.0-393.2) per 100 000 in countries with a prevalence of greater than 350 per 100 000 population. INTERPRETATION: Targeting high-prevalence countries could result in the highest yield for active disease. Pre-entry screening should be considered as part of a broad package of measures to ensure early diagnosis and effective management of migrants with active tuberculosis, and be integrated with initiatives that address the health needs of migrants. FUNDING: Wellcome Trust, UK National Institute for Health Research, Medical Research Council, Public Health England. PMID- 25455992 TI - Global, regional, and national estimates of pneumonia burden in HIV-infected children in 2010: a meta-analysis and modelling study. AB - BACKGROUND: Globally, pneumonia is a leading cause of mortality and morbidity in children younger than 5 years. Underlying HIV infection is an important risk factor for pneumonia morbidity and mortality in children. There are, however, no global or country level estimates of pneumonia burden in HIV-infected children. We assessed the role of HIV in pneumonia incidence and mortality and estimated the number of pneumonia cases and deaths in HIV-infected children younger than 5 years in 133 high pneumonia-burden countries in 2010. METHODS: We estimated the risk of hospital admission and case fatality rate caused by pneumonia in HIV infected children compared with HIV-uninfected children from a systematic review of studies published in Medline, Embase, and Global Health between Jan 1, 1980, and Aug 31, 2013. We estimated nationwide pneumonia incidence and mortality with two different models that incorporated several risk factors for paediatric pneumonia hospital admission and mortality (including HIV infection). We then estimated the number of pneumonia episodes and deaths that occurred in HIV infected children in 2010. FINDINGS: The odds ratio (OR) for hospital admission for all-cause pneumonia in HIV-infected children compared with HIV-uninfected children was 6.5 (95% CI 5.9-7.2). The risk of death was higher in children with pneumonia and HIV compared with those with pneumonia only (OR 5.9, 95% CI 2.7 12.7). In 2010, 1.4 million pneumonia episodes (uncertainty range [UR] 0.6 million to 3.3 million) and 88 000 pneumonia deaths (UR 47 400-153 000) occurred in HIV-infected children in low-income countries. Of these, 1.2 million pneumonia episodes (UR 0.5 million-2.7 million) and 85 400 deaths (UR 46 000-147 300) were directly attributable to HIV. 1.3 million (90%) pneumonia episodes and 82 400 (93%) pneumonia deaths in HIV-infected children aged younger than 5 years occurred in the WHO African region. INTERPRETATION: Globally, a small proportion of pneumonia episodes and pneumonia deaths occur in HIV-infected children. However, in the highest HIV-burden countries in sub-Saharan Africa (ie, Swaziland, Lesotho, and Zimbabwe) up to a fifth of all pneumonia cases and 60% of pneumonia deaths occur in HIV-infected children. In these countries, major reductions in child pneumonia mortality can be achieved only if the systemic challenges plaguing the health system (poor coverage of early infant testing for HIV, of antiretroviral drugs in pregnant women and young children, of co trimoxazole prophylaxis, and of pneumococcal vaccination) can be overcome. FUNDING: WHO. PMID- 25455993 TI - Diagnostic significance of cell kinetic parameters in World Health Organization type A and B3 thymomas and thymic carcinomas. AB - The prognostic importance of histologic classifications of thymic epithelial neoplasms is controversial. Evidence suggests that difficulties in reproducibility affect prognostic studies. Two thoracic pathologists independently classified 80 cases of type A or B3 thymoma and thymic carcinoma according to World Health Organization (WHO) classification. Ki-67 labeling index (LI) was used to identify cutoff points between WHO types. Recursive partitioning (Rpart) and ad hoc methods separated the data points. The pathologists agreed on type A (n = 31), type B3 (n = 21), and thymic carcinoma (n = 14). Ki-67 LI differed between types A and B3 (P < .001) and between thymic carcinoma and type A (P < .001) or type B3 (P = .001). Mitotic activity differed between thymic carcinoma and type A (P < .001) or type B3 (P < .001). Rpart revealed Ki-67 LI greater than 14.0% only in thymic carcinoma; cases with Ki-67 LI less than 5.1% did not represent thymic carcinoma. Ad hoc analysis showed Ki-67 LI greater than or equal to 13.5% represents thymic carcinoma; only type A had Ki-67 LI less than 2%. The pathologists disagreed on histologic type in 14 cases. In 11 of 14 cases with available Ki-67, the Rpart method predicted the WHO type; in 7 of 14 cases, the ad hoc method predicted the WHO type. In conclusion, Ki-67 LI is helpful in differentiating thymic epithelial neoplasms, with Ki-67 LI less than 2% and greater than or equal to 13.5% distinguishing type A thymoma and thymic carcinoma, respectively. PMID- 25455994 TI - The clinical role of epithelial-mesenchymal transition and stem cell markers in advanced-stage ovarian serous carcinoma effusions. AB - We recently identified gene signatures that allow classification of ovarian carcinoma into 5 distinct clinically relevant groups. In the present study, we investigated the clinical role of 10 protein products of the discriminating genes, with focus on epithelial-mesenchymal transition and stem cell markers. Expression of E-cadherin, N-cadherin, P-cadherin, Zeb1, HMGA2, Rab25, CD24, NCAM (CD56), Sox11, and vimentin was assessed in 100 advanced-stage (International Federation of Gynecology and Obstetrics stages III-IV) serous ovarian carcinoma effusions using immunohistochemistry. Results were analyzed for association with clinicopathological parameters, including chemotherapy response, and survival. All 10 proteins were frequently expressed in carcinoma cells. HMGA2 expression was related to older age (P = .015). HMGA2 and NCAM expression was related to stage III disease (P = .011 and P = .023, respectively), and NCAM was overexpressed in peritoneal compared with pleural effusions (P = .001). Vimentin and Zeb1 expression was significantly related to poor chemotherapy response at diagnosis (P = .005 and P = .017, respectively). The associations between NCAM and peritoneal localization and of vimentin and poor chemoresponse were retained after Bonferroni correction. NCAM expression was associated with a trend for shorter overall survival in univariate survival analysis (P = .187), but emerged as an independent prognosticator in Cox multivariate analysis (P = .042). This study identifies vimentin and Zeb1 as markers of poor chemoresponse in metastatic serous ovarian carcinoma effusions and suggests NCAM as potential prognostic marker in metastatic disease. The generally limited prognostic role of the studied markers emphasizes the difficulty in applying data obtained in studies of primary ovarian carcinomas to analyses of ovarian carcinoma effusions, reflecting the unique biology of the latter. PMID- 25455995 TI - Pulmonary fibrosis in dyskeratosis congenita: report of 2 cases. AB - Dyskeratosis congenita (DC) is a disorder of poor telomere maintenance and is related to 1 or more mutations that involve the vertebrate telomerase RNA component. Most affected patients develop mucocutaneous manifestations and cytopenias in the peripheral blood between 5 and 15 years of age. DC patients may also develop pulmonary complications including fibrotic interstitial lung disease and pulmonary vascular abnormalities. The radiologic and pathologic features of pulmonary fibrosis associated with DC are poorly defined. Herein, we report 2 new DC cases and suggest that the radiologic and histopathologic findings may resemble usual interstitial pneumonia but may not neatly fit into the current classification of interstitial lung disease. PMID- 25455996 TI - Classification of microvascular patterns via cluster analysis reveals their prognostic significance in glioblastoma. AB - There are limited researches focusing on microvascular patterns (MVPs) in human glioblastoma and their prognostic impact. We evaluated MVPs of 78 glioblastomas by CD34/periodic acid-Schiff dual staining and by cluster analysis of the percentage of microvascular area for distinct microvascular formations. The distribution of 5 types of basic microvascular formations, that is, microvascular sprouting (MS), vascular cluster (VC), vascular garland (VG), glomeruloid vascular proliferation (GVP), and vasculogenic mimicry (VM), was variable. Accordingly, cluster analysis classified MVPs into 2 types: type I MVP displayed prominent MSs and VCs, whereas type II MVP had numerous VGs, GVPs, and VMs. By analyzing the proportion of microvascular area for each type of formation, we determined that glioblastomas with few MSs and VCs had many GVPs and VMs, and vice versa. VG seemed to be a transitional type of formation. In case of type I MVP, expression of Ki-67 and p53 but not MGMT was significantly higher as compared with those of type II MVP (P < .05). Survival analysis showed that the type of MVPs presented as an independent prognostic factor of progression-free survival (PFS) and overall survival (OS) (both P < .001). Type II MVP had a more negative influence on PFS and OS than did type I MVP. We conclude that the heterogeneous MVPs in glioblastoma can be categorized properly by certain histopathologic and statistical analyses and may influence clinical outcome. PMID- 25455997 TI - Performance of 18F fluoro-2-desoxy-D-glucose positron emission tomography/computed tomography for the diagnosis of venous thromboembolism. AB - INTRODUCTION: Thrombosis and inflammation are intimately linked. Inflammatory component of venous thromboembolism (VTE) may allow the use of FDG positron emission tomography / computed tomography (FDG PET/CT) in the detection of thrombotic process. Published studies remain limited and contradictory. We aimed at evaluating the performance of FDG PET/CT in the detection of VTE in a population of patients enrolled in a prospective study evaluating FDG PET/CT for cancer screening in etiological assessment of idiopathic VTE. MATERIALS AND METHODS: The first consecutive 100 patients who underwent FDG PET/CT were included. Visual and quantitative analyses of vascular axes was performed and compared with lower limb veins compression ultrasonography, lung scintigraphy and/or computed tomography pulmonary angiography. RESULTS: Out of the 100 patients, 63 presented lobar pulmonary embolism for a total of 217 embolic sites and 62 had a deep vein thrombosis for a total of 143 thrombotic sites. Regarding pulmonary embolism, sensitivity and specificity of FDG PET/CT were 3% (95%CI: 1 6%) and 99% (95%CI: 98-100%). SUV max ratio between pulmonary embolism location and non-pathological contralateral vessel was 1.04+/-0.18 (p=0.7). Regarding deep vein thrombosis, sensitivity and specificity were 31% (95%CI: 24-39%) and 88% (95%CI: 81-92%). The metabolic activity was significantly higher than in contralateral vessels (p<0.001), with a SUV max ratio of 1.25+/-0.53, but without any significant SUVmax threshold applicable in routine practice for deep vein thrombosis diagnosis. CONCLUSIONS: FDG PET/CT is not accurate enough for the diagnosis of VTE. PMID- 25455998 TI - Preoperative hypofibrinogenemia is associated with increased intraoperative bleeding in ruptured abdominal aortic aneurysms. AB - INTRODUCTION: Ruptured abdominal aortic aneurysm (rAAA) is associated with coagulopathy and intraabdominal hemorrhage. Fibrinogen acts as a key coagulation factor and has previously been suggested as a biomarker for increased perioperative bleeding in other surgical areas. The aim of the present study was to investigate fibrinogen and standard laboratory parameters and their association to preoperative hemodynamic status, intraoperative bleeding (IOB), and outcome in treatment of rAAA. METHODS: This is a single university center retrospective cohort study of 91 consecutive patients with rAAA undergoing open surgery or endovascular aneurysm repair (EVAR) between 2008 and 2013. Patients were analyzed using the Swedish Vascular Registry (Swedvasc), and local hospital medical and laboratory records. Laboratory data analyzed included fibrinogen, hemoglobin, platelet count, prothrombin time ratio, activated partial thrombin time, and creatinine. Odds ratios (OR) with 95% confidence intervals (CI) were calculated in a logistical regression model. RESULTS: In the study cohort (n = 91), median age was 74 (57-91) years; 80 % men; open surgical repair (n = 72; 77%); EVAR (n = 19; 23%). Median preoperative fibrinogen concentration was 1.8 g/L (IQR = 1.4) and varied significantly across bleeding groups: <=1999 ml 2.3g/L, IQR = 1.4 (n = 35); 2000-4999 ml 1.6 g/L, IQR = 1.5 (n = 33); >=5000 ml 1.4 g/L, IQR = 1.0 (n = 23) (P < 0.001). Preoperative fibrinogen concentration showed a linear relationship with preoperative blood pressure (r = .447, P = 0.01). When analyzing other preoperative laboratory values, only platelets showed a similar linear relationship with preoperative blood pressure (r = .247, P = 0.05). Patients with blood pressure <70 mmHg had an associated median fibrinogen concentration of less than 1.5 g/L (P = 0.001). In the multivariable logistic regression analysis, preoperative fibrinogen < 1.5 g/L [OR 10.0, CI (1.8-57.1), P = 0.009] was associated with IOB >2000 ml and preoperative blood pressure < 70 mmHg was associated with IOB >2 000 ml [OR 3.7, CI (1.1-12.6), P = 0.03] and >5000 ml [OR 5.2, CI (1.3-21.1), P = 0.02]. Low fibrinogen concentration (< 1.5 g/L) was associated with 30-day mortality in the univariate analysis but not in the multivariable logistic regression analysis. CONCLUSION: Low preoperative fibrinogen concentration was significantly associated with preoperative hypotension and increased intraoperative bleeding in patients with rAAA. Patients in hemodynamic shock with blood pressure <70 mmHg had an associated fibrinogen concentration of less than 1.5 g/L. A fibrinogen concentration less than 1.5 g/L was associated with a ten-fold increased risk of intraoperative hemorrhage of more than 2000 ml. PMID- 25455999 TI - Platelet hyperactivity in thalassemia patients with elevated tricuspid regurgitant velocity and the association with hemolysis. AB - INTRODUCTION: Pulmonary arterial hypertension is a life-threatening complication in thalassemia characterized by elevated pulmonary arterial pressure. Increased platelet activation is associated with this complication; however, its role remains unclear. METHODS: Platelet activation in splenectomized beta thalassemia/hemoglobin E (Hb E) patients was measured using flow cytometric determination of P-selectin and activated glycoprotein (aGP) IIb/IIIa expression, and platelet-leukocyte aggregates (platelet-neutrophil, platelet-monocyte and platelet-lymphocyte aggregates). Tricuspid regurgitant velocity (TRV) was measured and used as an indicator of pulmonary arterial pressure. Plasma hemoglobin served as markers of hemolysis. RESULTS: Fifteen of 27 patients had elevated TRV (>2.5m/s). Platelet expression of P-selectin and aGPIIb/IIIa, and platelet-leukocyte aggregates were higher in thalassemia patients with elevated TRV than healthy control. Platelet-neutrophil aggregates increased in thalassemia patients with elevated TRV compared to patients with normal TRV. The increase in P-selectin and aGPIIb/IIIa expression induced by adenosine diphosphate (ADP) was higher in patients with elevated TRV than those with normal TRV. Platelet P selectin expression and platelet-neutrophil aggregates correlated positively with TRV. Plasma hemoglobin levels in patients with elevated TRV were higher than those of the control subjects, and correlated with TRV. CONCLUSION: Thalassemia patients with elevated TRV have a further increase in platelet activation that correlates with hemolysis. PMID- 25456000 TI - Fever as a risk factor for increased response to vitamin K antagonists: a review of the evidence and potential mechanisms. AB - Numerous factors affect the response to vitamin K antagonists (VKA) including age, dietary vitamin K, other drugs, pharmacogenetics, and disease states. In antithrombotic guidelines, fever is mentioned as a factor that may increase response to VKA. The purpose of this article is to review the available evidence regarding the effect of fever on response to VKA, and to discuss possible mechanisms of this effect. We performed a search of the English literature from 1943 to June 2014, using the key words fever AND warfarin, acenocoumarol, phenprocoumon, coumarin anticoagulants and VKA; fever AND vitamin K dependent clotting factors II, VII, IX, and X. One animal investigation and 6 studies in humans suggest fever increases response to VKA, but one study did not find a significant effect. The magnitude of this effect is variable. Possible mechanisms for the increased effect of VKA associated with fever are increased catabolism of vitamin K dependent clotting factors, decreased vitamin K intake, and inhibition of VKA metabolism. More rigorous studies are needed to confirm that fever increases response to warfarin and other VKA. PMID- 25456001 TI - Risk of venous thromboembolism occurrence among adults with selected autoimmune diseases: a study among a U.S. cohort of commercial insurance enrollees. AB - OBJECTIVE: This study assessed the risk of venous thromboembolism (VTE) among privately insured adults in the U.S. with one or more of the following autoimmune diseases: autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). MATERIALS AND METHODS: Using the Truven Health MarketScan(r) Databases, patients 18-64 years of age with a diagnosis of AIHA, ITP, RA, or SLE in 2007 and a sex and age-group matched comparison group of enrollees were followed up through 2010 to identify VTE events. Survival curve and Cox proportional hazards analyses were conducted to assess differences between groups. RESULTS: Among patients with AIHA, ITP, RA, or SLE, or >1 of these diseases, the risk of at least one VTE event was 19.74, 7.72, 4.90, 9.89, and 13.35 per 1,000 person-years, respectively; among the comparison group, the risk was 1.91 per 1,000 person years. The adjusted hazard ratios (aHRs) for VTE among patients with AIHA, ITP, RA, or SLE, or >1 of these diseases (when compared with the comparison group) tended to decline over follow-up time; at 1year, the aHRs were 6.30 (95% confidence interval [CI]: 4.44-8.94), 2.95 (95% CI: 2.18-4.00), 2.13 (95% CI: 1.89-2.40), 4.68 (95% CI: 4.10-5.33), and 5.11 (95% CI: 4.26-6.14), respectively. CONCLUSION: Having AIHA, ITP, RA, or SLE, or >1 of these diseases was associated with an increased likelihood of a VTE event. More research is necessary to develop better understanding of VTE occurrence among people with autoimmune diseases. PMID- 25456002 TI - Incidence of a first thromboembolic event in carriers of isolated lupus anticoagulant. AB - Among the so called antiphospholipid (aPL) antibodies Lupus Anticoagulant (LAC) is considered the strongest risk factor for thromboembolic events. In individuals without a previous thromboembolic event (carriers), LAC is a risk factor when associated with the presence of anticardiolipin (aCL) and abeta2-Glycoprotein I (abeta2GPI) antibodies. On the other hand, data on carriers of isolated LAC positivity are sparse and inconclusive. The aim of this study was to prospectively determine the incidence of thrombosis in a cohort of carriers of isolated LAC positivity. One-hundred seventy-nine carriers of LAC confirmed twelve weeks apart and in a reference laboratory were studied. During a total follow up of 552 person-years, there were seven thromboembolic events (1.3% person-y). All the seven patients had at least one adjunctive major risk factor for thrombosis. The cumulative incidence of thromboembolic events was 3.1% (95% CI 0.6-5.6) after 2years, and 5.9% (95% CI 1.2-10.6) after 5 and 10years. On a multivariate regression analysis considering age, sex, autoimmune disease, risk factors for arterial and venous thrombosis, use of aspirin, only age was found to be an independent predictor of thromboembolic events (HR=1.1, 95% CI 1.0-1.2, p=0.02). These data might be relevant in clinical practice and underline the importance of differentiating LAC carriers in terms of isolated positivity or positivity associated with the presence of antibodies to aCL and beta2 glycoprotein I. PMID- 25456003 TI - How safe is acetaminophen use in patients treated with vitamin K antagonists? A systematic review and meta-analysis. AB - INTRODUCTION: Acetaminophen is a commonly prescribed and over-the-count used drug, and is considered to be the preferred treatment choice for anticoagulated patients requiring analgesic drug therapy. However, observational data have suggested that this drug combination may increase the International Normalized Ratio (INR) values and bleeding events in patients taking Vitamin K antagonists (VKAs). Still, the clinical impact of this putative effect remains unknown. Therefore, we performed a systematic review of randomized controlled trials (RCTs) to estimate the impact of concomitant use of acetaminophen and VKA in the INR measurements METHODS: Systematic review and meta-analysis of RCTs comparing acetaminophen versus placebo or no treatment, in VKA-treated patients and reporting INR estimates. Medline and Cochrane Library were searched up to April 2014. Primary outcome was the mean difference (MD) between the greatest INR elevations in each treatment arm. Random-effects meta-analysis was performed to derive pooled estimates and 95% Confidence Interval (CI). Heterogeneity was evaluated with I(2) test. RESULTS: Seven RCTs (n=225 patients) were included. Acetaminophen was associated with a mean 0.62 INR increase (95%CI: 0.46 to 0.78; I(2)=25%) compared to placebo in VKA-treated patients. Studies did not report any major bleeding event. Meta-regression showed a significant 0.17 mean increase of the INR per each daily gram of acetaminophen (95%CI: 0.004 to 0.33). CONCLUSION: Acetaminophen is associated with a statistically significant and possible clinically relevant increase in the INR, with a dose dependent relationship. Patients treated concomitantly with VKA and acetaminophen should be monitored more regularly for possible VKA dosage adjustment. PMID- 25456004 TI - Sox2 expression involvement in the oncogenicity and radiochemoresistance of oral cancer stem cells. AB - OBJECTIVES: Sox2, a high-mobility-group DNA binding protein, is part of the key set of transcription factors that are involved in the maintenance of pluripotency and self-renewal in undifferentiated stem cells. A recent study has further suggested cancer stem cells (CSCs) are key contributors to radiochemoresistance and are responsible for oral squamous cell carcinoma (OSCC) progression. The aim of this study was to determine the emerging role of Sox2 in radiochemosensitivity of oral CSCs. METHODS: We determined the function of Sox2 on oncogenicity and radiochemosensitivity of OSCC by overexpression or silencing Sox2 in vitro and in vivo. RESULTS: Initially, Sox2 expression was increased in OSCC cell lines and OSCC specimens. Upregulated Sox2 is correlated with poor survival outcome of OSCC patients. Overexpression of Sox2 was demonstrated to enhance invasiveness, anchorage-independent growth, xenotransplantation tumourigenicity in OSCC cells. Targeting Sox2 to spheroid cells (SC) and ALDH1+CD44+ cells from OSCC significantly inhibited their CSCs and tumorigenic abilities. Down regulation of SOX2 in OSCC-SC was found to repress invasiveness and diminish epithelail mesenchymal transition (EMT) traits. Furthermore, silencing Sox2 effectively suppressed the expression of drug-resistance and anti-apoptotic genes and increased the sensitivity of the cells to radiation combined cisplatin treatment. Finally, the in vivo therapeutic efficacy of targeting Sox2 synergistically suppressed tumorigenesis and improved the survival rate when used in combination with radiotherapy and cisplatin in OSCC-SC-transplanted immunocompromised mice. CONCLUSION: Sox2-mediated CSCs property is associated with the regulation of EMT and Sox2 s as therapeutic target in OSCC. PMID- 25456005 TI - Nuclear expression of WRAP53beta is associated with a positive response to radiotherapy and improved overall survival in patients with head and neck squamous cell carcinoma. AB - OBJECTIVES: Today there are no reliable predictive markers for radiotherapy response in head and neck squamous cell carcinoma (HNSCC), leading to both under- and over-treatment of patients, personal suffering, and negative socioeconomic effects. Inherited mutation in WRAP53beta (WD40 encoding RNA Antisense to p53), a protein involved in intracellular trafficking, dramatically increases the risk of developing HNSCC. The purpose of this study was to investigate whether WRAP53beta can predict response to radiotherapy in patients with HNSCC. MATERIALS AND METHODS: Tumor biopsies from patients with HNSCC classified as responders or non responders to radiotherapy were examined for the expression of the WRAP53beta protein and single nucleotide polymorphisms in the corresponding gene employing immunohistochemistry and allelic discrimination, respectively. In addition, the effect of RNAi-mediated downregulation of WRAP53beta on the intrinsic radiosensitivity of two HNSCC cell lines was assed using crystal violet and clonogenic assays. RESULTS: Nuclear expression of WRAP53beta was significantly associated with better response to radiotherapy and improved patient survival. Downregulation of WRAP53beta with siRNA in vitro enhanced cellular resistance to radiation. CONCLUSIONS: Our findings suggest that nuclear expression of WRAP53beta promotes tumor cell death in response to radiotherapy and is a promising predictor of radiotherapy response in patients with HNSCC. PMID- 25456007 TI - BDNF mediated TrkB activation contributes to the EMT progression and the poor prognosis in human salivary adenoid cystic carcinoma. AB - BACKGROUND: The aim of the present study was to investigate whether the expression of Brain-Derived Neurotrophic Factor (BDNF) and its receptor Tropomyosin-related kinase B (TrkB) is correlated with the clinical progression of salivary adenoid cystic carcinoma (SACC) and whether the BDNF/TrkB axis is associated with the induction of epithelial-mesenchymal transition (EMT) in SACC cells. METHOD: The expression of BDNF, TrkB, and E-cadherin (an EMT biomarker) in 76 primary SACC specimens and 20 normal salivary gland tissues was analyzed by immunohistochemistry. Additionally, the expression of BDNF, TrkB, and E-cadherin in SACC cell lines (SACC-83 and SACC-LM) was analyzed by RT-PCR and Western blotting. The biological role of the BDNF/TrkB axis in the EMT progression of SACC was evaluated after treatment with increased levels of BDNF and by inhibiting TrkB activity in SACC-83 cell line. The progression of SACC cells through EMT was assessed by RT-PCR, Western blotting, photography, migration and invasion assays. RESULTS: Elevated expression of TrkB (92.1%) and BDNF (89.5%), and downregulated expression of E-cadherin (47.4%) was found in SACC specimens, which was significantly correlated with the invasion and metastasis in SACC (P<0.05). The high expression of TrkB and the low expression of E-cadherin was significantly correlated with the poor prognosis of SACC patients (P<0.05). The expression of TrkB was inversely correlated with the expression of E-cadherin in both SACC cases and cell lines (P<0.05). Increasing BDNF levels after treatment with exogenous recombinant human BDNF (rhBDNF) at 100 ng/ml significantly promoted the activation of TrKB and the progression of EMT in SACC cells. While obstruction of TrkB by its inhibitor, k252a (100 nM), significantly inhibited the EMT progression of SACC cells. CONCLUSIONS: These results suggest that BDNF mediated TrkB activation contributes to the EMT progression and the poor prognosis in SACC. The present study demonstrated that the BDNF/TrkB axis promotes the migration and invasion of SACC cells via EMT in vitro. Targeting the inactivation of the BDNF/TrkB axis may be a potential strategy for the treatment of SACC. PMID- 25456008 TI - The high-temperature requirement factor A3 (HtrA3) is associated with acquisition of the invasive phenotype in oral squamous cell carcinoma cells. AB - OBJECTIVES: Previous studies have identified several genes involved in the carcinogenesis of oral cancer; however, the detailed mechanisms underlying this process have not been elucidated. Previously, we established a database of the transcriptional progression profile of oral carcinogenesis and identified 15 candidate genes with continuously increasing or decreasing expression (Sumino et al., 2013). MATERIALS AND METHODS: In the present study, using this database, we attempted to identify genes that may specifically contribute to progression from oral dysplastic lesions to invasive tumours. RESULTS: We identified 4 candidate genes. Using a literature survey, we narrowed down the candidates and focused on the high-temperature requirement factor A3 (HtrA3). Quantitative real-time reverse transcription polymerase chain reaction and immunohistochemical analysis confirmed that HtrA3 expression significantly increased during this process. In addition, high HtrA3 expression was significantly associated with decreased disease-free survival (P=0.045) and overall survival (P=0.003). Multivariate Cox proportional hazards analysis found that high HtrA3 expression significantly correlated with overall survival (P=0.018). CONCLUSION: The findings of this study demonstrated that the HtrA3 is likely to be associated with the acquisition of the invasive phenotype in oral squamous cell carcinoma cells and may be a potential prognostic marker for oral cancer. PMID- 25456006 TI - Perineural growth in head and neck squamous cell carcinoma: a review. AB - Perineural growth is a unique route of tumor metastasis that is associated with poor prognosis in several solid malignancies. It is diagnosed by the presence of tumor cells inside the neural space seen on histological or imaging evaluations. Little is known about molecular mechanisms involved in the growth and spread of tumor cells in neural spaces. The poor prognosis associated with perineural growth and lack of targeted approaches necessitates the study of molecular factors involved in communication between tumor and neural cells. Perineural growth rates, shown to be as high as 63% in head and neck squamous cell carcinoma (HNSCC), correlate with increased local recurrence and decreased disease-free survival. Here we describe the literature on perineural growth in HNSCC. In addition, we discuss factors implicated in perineural growth of cancer. These factors include brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 and -4, glial cell-line derived neurotrophic factor (GDNF), the neural cell adhesion molecule (NCAM), substance P (SP), and chemokines. We also explore the literature on membrane receptors, including the Trk family and the low-affinity nerve growth factor receptor. This review highlights areas for further study of the mechanisms of perineural invasion which may facilitate the identification of therapeutic targets in HNSCC. PMID- 25456009 TI - Differential expression levels of plasma-derived miR-146b and miR-155 in papillary thyroid cancer. AB - BACKGROUND: Specific circulating microRNAs (miRNAs) in each organ may contribute to the diagnosis and prognosis in some cancers. miRNA from papillary thyroid cancer (PTC) may be released into the bloodstream. This study was performed to detect miRNAs in the plasma and estimate their diagnostic usefulness for discriminating between benign and malignant lesions. METHODS: Patients who underwent thyroidectomy for benign thyroid nodules or PTC were enrolled in this study. The patients were divided into three groups: benign, PTC without lymph node metastasis (LNM), and PTC with LNM. The levels of miR-146b, miR-221, miR 222, and miR-155miRNA expression in blood samples before surgery were evaluated. RESULTS: Of 89 patients enrolled in this study, 19 and 70 had benign lesions (21.3%) and PTC (78.7%), respectively. The mean levels of miR-146b and miR-155 expression were higher in the PTC group than the benign group. For discrimination between benign and PTC lesions, the area under the ROC curve (AUC) for miR-146b was 0.649 with 61.4% sensitivity and 57.9% specificity. The AUC for miR-155 was 0.695 with 74.3% sensitivity and 63.2% specificity (P<0.05). The levels of miR 146b, miR-221, and miR-222 were slightly higher in the N1 group than the N0 group. The levels of miR-146b, miR-155, and miR-222 increased in proportion to tumor size. CONCLUSIONS: miR-146b and miR-155 helped to discriminate between benign and malignant lesions. Circulating miRNA is likely a useful alternate serological marker for PTC. This preliminary study suggested that circulating miRNAs may be useful as follow-up tools as well as diagnostic tools. PMID- 25456011 TI - The role of surgery for HPV-associated head and neck cancer. AB - The incidence of human papillomavirus (HPV)-associated oropharyngeal cancer continues to increase in contrast to other head and neck cancer sites. There is a growing role for upfront surgery to treat these cancers in the era of organ preservation treatment strategies. This is becoming especially important in younger, healthier patients with HPV-associated squamous cell carcinoma. Surgery for oropharyngeal cancer has evolved from large, open transcervical and transmandibular approaches to minimally-invasive transoral endoscopic techniques. Advances in transoral endoscopic surgery (TES) have led to renewed interest in upfront surgical treatment for oropharyngeal carcinoma. Transoral laser microsurgery (TLM) and transoral robotic surgery (TORS) are two techniques that allow for complete oncologic resection through the mouth in select patients, with minimal cosmetic deformity and optimal speech and swallow function after completion of therapy. In this article we will review transoral approaches to oropharyngeal carcinoma: its oncologic and functional outcomes, and its role in the multi-disciplinary treatment of oropharyngeal cancer. PMID- 25456010 TI - Histopathological grading of adenoid cystic carcinoma of the head and neck: analysis of currently used grading systems and proposal for a simplified grading scheme. AB - BACKGROUND: Histopathological grading of adenoid cystic carcinoma (ACC) is a controversial issue. It is generally agreed that solid type ACC has a relatively poor prognosis. However, the amount of solid regions within this often mixed type tumor that predicts a poor prognosis is not firmly established. Some authors stipulate that the presence of a solid component regardless of the amount is a poor prognosticator where others argue that the amount should be taken into consideration. Two grading systems most commonly used are those described by Perzin et al./Szanto et al. and Spiro et al., respectively. They report that prognosis of ACC is poor if >30% and >50% of the tumor volume has a solid growth pattern, respectively. MATERIAL AND METHODS: The described grading systems are applied to a series of 81 surgically treated cases of ACC at the VU University Medical Center, Amsterdam, The Netherlands. Moreover, we introduced an alternative grading system, in which the presence of a solid component, irrespective of its amount, is considered. All three systems of grading were tested for inter-observer concordance and prediction of prognosis. RESULTS: Inter observer concordance for grading ACC according to Perzin et al./Szanto et al. and Spiro et al., proved to be moderate with Kappa Scores of 0.393 and 0.433, respectively. Our alternative grading system yielded inter-observer concordance with a Cohen's kappa result of 0.990. All systems were comparable in discriminating patients with poor clinical outcome. Histopathological grade proved to be an independent prognosticator. CONCLUSION: The presence of any solid component in ACC is a negative prognosticator, and can histopathologically be diagnosed with a high reliability. These results suggest to merely register the presence or absence of a solid tumor component since its inter-observer variability is very low, its reproducibility is high and its predictive value is comparable to the traditional grading systems used. PMID- 25456012 TI - Swimming in Ireland: Immersions in therapeutic blue space. AB - This paper explores swimming as a healthy body-water engagement in blue space at selected outdoor Irish swimming spots. Associated theoretical underpinnings draw from non-representational theories (NRT). Taking as a starting point the idea of immersion, the paper argues for a deeper application of NRT to blue space settings. In addition, the paper reflects recent therapeutic geographies research on differential experiences of health and wellbeing linked to such immersions. Methodologically, the paper uses observer participation and swimmer's own voices to draw affective and embodied accounts from on and within water. The act of swimming as an emplaced and performed therapeutic encounter is highlighted along with a more critical discussion of contested narratives associated with risk and respect. Theoretical learning suggests the need for greater attention to the production of affect from across the life-course and a fuller articulation of the in-betweenness of theory and empirical testimonies. Swimming emerges from the study as a potentially valuable health and wellbeing resource that can be more fully harnessed to inform wider public health policy. PMID- 25456013 TI - The role of bluespaces in experiencing place, aging and wellbeing: Insights from Waiheke Island, New Zealand. AB - This paper examines how bluespaces inform experiences of place, being aged, and wellbeing among seniors on Waiheke, an island within the greater Auckland area in northern New Zealand. We draw on photo-elicitation interviews with seniors aged 65-94 to argue that bluespaces shape metaphors of 'islandness' that, in turn, help maintain wellbeing. We conclude that, although island settings pose unique challenges for seniors, (e.g. potential isolation, and a lack of advanced care), drawing on the qualities of bluespaces helps maintain a secure sense of self anchored in strong affective ties to place. PMID- 25456014 TI - Neighborhood effects in a behavioral randomized controlled trial. AB - Randomized controlled trials (RCTs) of interventions intended to modify health behaviors may be influenced by neighborhood effects which can impede unbiased estimation of intervention effects. Examining a RCT designed to increase colorectal cancer (CRC) screening (N=5628), we found statistically significant neighborhood effects: average CRC test use among neighboring study participants was significantly and positively associated with individual patient's CRC test use. This potentially important spatially-varying covariate has not previously been considered in a RCT. Our results suggest that future RCTs of health behavior interventions should assess potential social interactions between participants, which may cause intervention arm contamination and may bias effect size estimation. PMID- 25456015 TI - Response of host inflammasomes to viral infection. AB - Inflammasomes are multiprotein complexes that induce downstream immune responses to specific pathogens, environmental stimuli, and host cell damage. Components of specific viruses activate different inflammasomes; for example, the influenza A virus M2 protein and encephalomyocarditis virus (EMCV) 2B protein activate the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome, whereas viral double-stranded RNA (dsRNA) activates the retinoic acid inducible gene-I (RIG-I) inflammasome. Once activated in response to viral infection, inflammasomes induce the activation of caspases and the release of mature forms of interleukin-1beta (IL-1beta) and IL 18. Here we review the association between viral infection and inflammasome activation. Identifying the mechanisms underlying virus-induced inflammasome activation is important if we are to develop novel therapeutic strategies to target viruses. PMID- 25456016 TI - The role of NGOs in child injury prevention: an organizational assessment of one network of NGOs. AB - Unintentional injuries are estimated to claim the lives of more than 875,000 children each year; millions more live with long-term consequences and permanent disabilities. The epidemiology of injuries has become clearer in the past decade. NGOs need to work in concert with each other to address the global burden of injuries by sharing information. Several NGOs have heeded this call, and the field has seen the emergence of global organizations aimed at highlighting the burden of injuries and streamlining injury prevention activities worldwide. Safe Kids Worldwide Inc. (SKWW) is a global network in 16 countries whose mission is to address the burden of injuries in children under 15 by harnessing the potential of local NGOs. An organizational assessment was conducted of SKWW which included structured organizational assessment, functional organizational mapping and contextual analysis that allowed for an in-depth examination of the strengths and challenges of SKWW's injury prevention approach. Over one year, primary and secondary data were collected and analyzed from headquarters and individual country offices. SKWW appears to be an effective model and has experienced a strong momentum and growth over the last two decades. Global NGOs that address the burden of injuries should start by defining a clear and universal strategic goal, build on local successes, maximize their strengths, and create avenues for stronger country engagement. PMID- 25456017 TI - A comparative study of the role of disease severity in drug reimbursement decision making in four European countries. AB - Considerations beyond cost-effectiveness are important in reimbursement decision making. We assessed the importance of disease severity in drug reimbursement decision making in Belgium, France, The Netherlands and Sweden. We investigated scientific literature and policy documents and conducted three interviews in each country (four in The Netherlands) with persons involved in drug reimbursement. Disease severity is an important consideration, especially where the level is high. The Netherlands operationalizes disease severity using the proportional shortfall approach. Sweden uses categories to give an indication of the level of severity. In The Netherlands and Sweden, severity only implicitly plays a role in the decision whether to reimburse a drug, whereas in Belgium and France it also explicitly plays a role in determining the willingness to use public resources. Interviewees acknowledged that as well as a qualitative description of the disease, quantitative information may also be useful as input for decision making. None of them, however, considered this to be of decisive importance. Although disease severity is important in drug reimbursement decision making in all four countries, all seem to struggle in explicitly specifying its actual role. Belgium and France are the most explicit by using levels of severity in setting reimbursement levels; all four countries could, however, improve the transparency of its actual importance relative to the other criteria in the decision-making process. PMID- 25456018 TI - Association between all-cause mortality and insurance status transition among the elderly population in a rural area in Korea: Kangwha Cohort Study. AB - The study purpose was to examine the association between health insurance transition and all-cause mortality. 3206 residents in Korea who participated in two surveys in 1985 and 1994, were followed-up during 1994-2008. Adjusted hazard ratios (aHR) were calculated using Cox hazard model. Participants were divided into four groups by insurance transition (the "National Health Insurance (NHI) NHI", "NHI-Medicaid", "Medicaid-NHI", and "Medicaid-Medicaid" groups), where NHI Medicaid means participants covered by NHI in 1985 but by Medicaid in 1994. For men covered by NHI in 1985, the mortality risk in the NHI-Medicaid was higher (aHR=1.47) than in the NHI-NHI. For men and women, covered by Medicaid in 1985, aHR was non-significantly lower in the Medicaid-NHI than in the Medicaid Medicaid. When four groups were analyzed together, men in the Medicaid-Medicaid (aHR=1.67) and NHI-Medicaid (aHR=1.46) groups had higher mortality risk than males in the NHI-NHI, whereas no significant difference was observed for females. In conclusion, transition from NHI to Medicaid increases mortality risk, and transition from Medicaid to NHI may mitigate risk, while remaining on Medicaid pose the greatest risk, especially for men. Therefore, policy makers should strengthen coverage for Medicaid. The weak effects of transition from NHI to Medicaid on mortality for women require validation. PMID- 25456019 TI - Determinants of the choice of GP practice registration in England: evidence from a discrete choice experiment. AB - There have been growing concerns that general practitioner (GP) services in England, which are based on registration with a single practice located near the patient's home, are not sufficiently convenient for patients. To inform the decision as to whether to change registration rules allowing patients to register 'out-of-area' and to estimate the demand for this wider choice, we undertook a discrete choice experiment with 1706 respondents. Latent class models were used to analyse preferences for GP practice registration comparing preferences for neighbourhood and non-neighbourhood practices. We find that there is some appetite for registering outside the neighbourhood, but this preference is not uniformly shared across the population. Specifically individuals who are less mobile (e.g. older people and those with caring responsibilities), or satisfied with their local practice are less likely to be interested in registering at a practice outside their neighbourhood. Overall, people feel most strongly about obtaining an appointment with a GP as quickly as possible. Respondents regarded weekend opening as less important than other factors, and particularly less important than extended practice opening hours from Monday to Friday. Assuming a constant demand for GP services, a policy encouraging GP practices to extend their opening hours during the week is likely to decrease the average patient waiting time for an appointment and is likely to be preferred by patients. PMID- 25456020 TI - Re: "Early benefit assessment of new drugs in Germany--results from 2011 to 2012" [Health Policy 116 (2-3) (2014) 147-153]. PMID- 25456021 TI - Response to letter to the editor on "Early benefit assessment of new drugs in Germany--results from 2011 to 2012" [Health Policy 116(2-3) (2014) 147-153]. PMID- 25456022 TI - Effect of cumin powder on body composition and lipid profile in overweight and obese women. AB - INTRODUCTION: This study aimed to determine the effect of cumin powder on body composition and lipid profile in overweight and obese women. MATERIALS & METHODS: In this randomized clinical trial, 88 overweight/obese women were randomly assigned into two groups. The experimental group was asked to have 3 g/d cumin powder with yogurt at two meals for 3 months. The same amount of yogurt minus cumin powder was prescribed for the control group. All patients received nutrition counseling for weight loss in a similar manner. Anthropometric and biochemical parameters were determined before and after the intervention. RESULTS: Cumin powder reduced serum levels of fasting cholesterol, triglyceride, and LDL and increased HDL. Weight, BMI, waist circumference, fat mass and its percentage significantly reduced. It has no effect on FBS and fat-free mass. CONCLUSION: Cumin powder in a weight reduction diet showed improvement in anthropometric and biochemical parameters in overweight/obese women. PMID- 25456023 TI - Psychosocial factors that predict why people use complementary and alternative medicine and continue with its use: a population based study. AB - Studies have explored the predictors of CAM use but fewer data explain the psychosocial factors associated with this and why people continue with CAM. AIMS: To examine the psychosocial factors that predict CAM use; to explore the predictors of continuing with CAM. DESIGN: A cross sectional survey. METHODS: 1256 adults were interviewed as part of 2012 Queensland Social Survey. We included questions about CAM, perceived control, cognitive style, spirituality and openness. Relationships were explored using bivariate and multiple logistic regression. RESULTS: 79% of people had used CAM in the last 12 months. Socio demographics, health behaviours, spirituality, openness and prescribing sources were the strongest predictors of CAM use. General health, chronic illness and prescribing sources predicted continued CAM use. CONCLUSION: There was high CAM use in Queensland, Australia. Personal characteristics and psychosocial factors need to be considered as part of the individual's holistic assessment and on going care. PMID- 25456024 TI - A novel sensorimotor movement and walking intervention to improve balance and gait in women. AB - PURPOSE: This study evaluated the effectiveness of a 5-day mind-body exercise (MBE) program on measures of quality of life, balance, balance confidence, mobility and gait in community-dwelling women. METHODS: The MBE program was a 5 day retreat where multiple sessions of Feldenkrais((r))-based sensorimotor movement training and walking were performed daily. Forty-six women aged 40-80 years old participated in either the MBE program or maintained normal daily activity. Two-footed eyes-closed balance, gait characteristics, mobility via the Timed Up and Go test, balance confidence and quality of life were assessed before and after the intervention. RESULTS: Women in the MBE group experienced improvements in mobility (6%; p = 0.01), stride length (3%; p = 0.008), single limb support time (1.3%; 0.006), balance confidence (5.2%; p < 0.001) and quality of life (p < 0.05) while the control group did not change. CONCLUSION: This short term intensive program may be beneficial to women at risk of mobility limitations. PMID- 25456025 TI - Managing incidental thyroid nodules detected on imaging: white paper of the ACR Incidental Thyroid Findings Committee. AB - The incidental thyroid nodule (ITN) is one of the most common incidental findings on imaging studies that include the neck. An ITN is defined as a nodule not previously detected or suspected clinically, but identified by an imaging study. The workup of ITNs has led to increased costs from additional procedures, and in some cases, to increased risk to the patient because physicians are naturally concerned about the risk of malignancy and a delayed cancer diagnosis. However, the majority of ITNs are benign, and small, incidental thyroid malignancies typically have indolent behavior. The ACR formed the Incidental Thyroid Findings Committee to derive a practical approach to managing ITNs on CT, MRI, nuclear medicine, and ultrasound studies. This white paper describes consensus recommendations representing this committee's review of the literature and their practice experience. PMID- 25456026 TI - Image-based multichannel vaginal cylinder brachytherapy for vaginal cancer. AB - PURPOSE: To investigate the clinical feasibility and treatment outcomes of image based high-dose-rate (HDR) brachytherapy using an intracavitary multichannel vaginal cylinder for the definitive treatment of vaginal cancers. METHODS AND MATERIALS: A total of 41 patients with vaginal cancer (24% primary vaginal and 76% recurrence from other gynecologic primaries) treated with definitive radiotherapy +/- chemotherapy including image-based HDR brachytherapy with a multichannel vaginal cylinder were included in the study. Image-based brachytherapy was completed using either CT- (41%) or MR-based planning (59%) with each fraction. The high-risk clinical target volume was defined based on the pre- and postexternal beam radiotherapy gross tumor volume. Doses were converted to equivalent dose of 2Gy per fraction. Endpoints examined were dose-volume parameters and early clinical outcomes. RESULTS: The median high-risk clinical target volume was 24.2 cc (interquartile range [IQR], 12.6), with a median dose to 90% (D90) of 77.1 Gy (IQR, 3.4). The median dose to 2 cc (D(2 cc)) for the bladder, rectum, and sigmoid were 59.4 Gy (IQR, 5.6), 58.2 Gy (IQR, 4.1), and 52.3 Gy (IQR, 5.5), respectively. After a median followup of 16 months (range, 3 35), complete clinical response was documented in 98% of the patients. The 2-year local, regional, and distant control; and disease-free and overall survival were 93%, 100%, 81%, 78%, and 88%, respectively. The 2-year actuarial rate of late Grade 3 or higher toxicity was 4% overall with 0%, 0%, 0%, and 4% for vaginal, bladder, urethral, and gastrointestinal, respectively. CONCLUSIONS: Image-based HDR brachytherapy using an intracavitary multichannel cylinder seems feasible in definitive vaginal cancer treatment. The described clinical implementation shows promising early clinical outcomes with high rates of local control and little toxicity, which should be validated with extended followup. PMID- 25456027 TI - Postoperative brachytherapy for endometrial cancer using a ring applicator. AB - BACKGROUND: To evaluate the rate of vaginal, pelvic, and distant failures and acute toxicity after postoperative vaginal vault brachytherapy (VBT) delivered by a ring applicator in women with high intermediate-risk endometrial cancer. METHODS AND MATERIALS: A total of 100 patients were treated with VBT after a total abdominal hysterectomy and bilateral salpingo-oophorectomy for a Stage IA or IB (International Federation of Gynecology and Obstetrics 2009) intermediate risk endometrial cancer; 26 patients received 30-Gy low-dose-rate, 74 patients received 28-Gy pulsed-dose-rate brachytherapy. RESULTS: At a median followup of 37 months (range, 1-107), 6 (6%) patients showed failures. Three patients developed an in-field recurrence in the vaginal vault: 1 was isolate, whereas the other 2 showed simultaneous pelvic and/or distant failure. A fourth patient developed an out-of-field recurrence in the posterior vaginal wall of the proximal half of the vagina, including pelvic and distant failure. Two other patients showed only distant failure. The estimated 3-year actuarial rate of any vaginal recurrence was 2.6% (95% confidence interval, 0-6.3%). The 5-year overall survival was 84%, similar to that in the female Dutch population matched for age and date of diagnosis. The acute side effects were low, consisting mainly of the occurrence of temporary diarrhea (2%). CONCLUSION: Postoperative VBT by a ring applicator results in a low recurrence risk, survival rates comparable with the normal female population, and a very low risk of acute morbidity. PMID- 25456028 TI - Surgical outcomes of Baerveldt implants in pediatric glaucoma patients. AB - PURPOSE: To evaluate the efficacy of the Baerveldt glaucoma implant (BGI) in children. METHODS: The medical records of pediatric glaucoma patients aged 5 months to 19 years who underwent BGI placement by a single surgeon (JCS) between January 1, 2000, and March 1, 2010, were retrospectively reviewed. Patients were evaluated at 3-9 months, 12-18 months, and 24-30 months after surgery. We defined surgical success as a postoperative intraocular pressure (IOP) of >6 mm Hg and <21 mm Hg, without additional glaucoma surgery, loss of light perception, removal of the BGI, chronic hypotony, retinal detachment, malignant glaucoma, endophthalmitis, or phthisis bulbi. Additional outcome measures were tube erosion, corneal decompensation, tube retraction, visual acuity, clinical bleb encapsulation, and choroidal detachment. RESULTS: A total of 45 eyes of 36 patients were included. The mean preoperative IOP was 31.6 +/- 5.0 mm Hg; the mean postoperative IOP, 16.3 +/- 5.1 mm Hg at 3-9 months, 19.5 +/- 4.8 mm Hg at 12-18 months, and 18.3 +/- 4.8 mm Hg at 24-30 months. Cumulative probability of success was 93.3% at 3-9 months, 86.7% at 12-18 months, and 86.7% at 24-30 months. Overall, 6 eyes failed within 30 months because of uncontrolled IOP (3 eyes), replacement of the glaucoma drainage device (2 eyes), and no light perception (1 eye). CONCLUSIONS: In this study cohort, BGI surgery effectively reduced IOP in pediatric patients with refractory glaucoma. PMID- 25456029 TI - Quantitative measurement of retinal hemorrhages in suspected victims of child abuse. AB - PURPOSE: Child abuse is one of the leading causes of death in early childhood. The presence of retinal hemorrhages often supports the diagnosis. The purpose of this study was to determine whether the specific measurement of retinal hemorrhages when present on fundus photography correlates with other clinical findings typically seen in children suspected of having been abused. METHODS: The medical records of children with retinal hemorrhages who were suspected of being victims of abusive head trauma from June 2003 to June 2013 and who had widefield retinal photography performed were retrospectively reviewed. Data collected included hemorrhage-covered percentage (HCP) of the central retina (posterior pole or 40 degrees circle centered on fovea) measured by ImageJ in relation to death, length of hospital stay, presence of abnormal findings on neuroimaging or skeletal survey, and definite versus possible abuse. RESULTS: Significant difference in retinal hemorrhage measured on fundus photography was found in patients with axial skeletal fracture (P = 0.016), signs of severe brain trauma on neuroimaging (P = 0.014) and definite versus possible abuse (P = 0.023). No correlation of quantitative measurement of the retinal hemorrhage to length of hospital stay, death, or the presence of skull fracture was found in this cohort. CONCLUSIONS: The quantitative measurement of total retinal hemorrhage when present on fundus photography centered on posterior pole in children suspected of having been abused correlated with some but not all findings typically seen in abused children. PMID- 25456031 TI - Is anesthesia safe for young children? PMID- 25456030 TI - Electronic health record impact on productivity and efficiency in an academic pediatric ophthalmology practice. AB - PURPOSE: To measure the effect of electronic health record (EHR) implementation on productivity and efficiency in the pediatric ophthalmology division at an academic medical center. METHODS: Four established providers were selected from the pediatric ophthalmology division at the Oregon Health & Science University Casey Eye Institute. Clinical volume was compared before and after EHR implementation for each provider. Time elapsed from chart open to completion (OTC time) and the proportion of charts completed during business hours were monitored for 3 years following implementation. RESULTS: Overall there was an 11% decrease in clinical volume following EHR implementation, which was not statistically significant (P = 0.18). The mean OTC time ranged from 5.5 to 28.3 hours among providers in this study, and trends over time were variable among the four providers. Forty-four percent of all charts were closed outside normal business hours (30% on weekdays, 14% on weekends). CONCLUSIONS: EHR implementation was associated with a negative impact on productivity and efficiency in our pediatric ophthalmology division. PMID- 25456032 TI - (13)C metabolic flux analysis of recombinant expression hosts. AB - Identifying host cell metabolic phenotypes that promote high recombinant protein titer is a major goal of the biotech industry. (13)C metabolic flux analysis (MFA) provides a rigorous approach to quantify these metabolic phenotypes by applying isotope tracers to map the flow of carbon through intracellular metabolic pathways. Recent advances in tracer theory and measurements are enabling more information to be extracted from (13)C labeling experiments. Sustained development of publicly available software tools and standardization of experimental workflows is simultaneously encouraging increased adoption of (13)C MFA within the biotech research community. A number of recent (13)C MFA studies have identified increased citric acid cycle and pentose phosphate pathway fluxes as consistent markers of high recombinant protein expression, both in mammalian and microbial hosts. Further work is needed to determine whether redirecting flux into these pathways can effectively enhance protein titers while maintaining acceptable glycan profiles. PMID- 25456033 TI - Editorial overview: chemical biotechnology: the expansion of chemical biotechnology. PMID- 25456037 TI - Comparison of the analgesic effect of xylocaine only with xylocaine and corticosteroid injection after ultrasonographically-guided percutaneous treatment for rotator cuff calcific tendonosis. AB - BACKGROUND: The analgesic effect of xylocaine alone versus xylocaine with corticosteroid injection after ultrasonographically (US)-guided treatment of rotator cuff calcific tendonosis has not been described in English literature. The aim of this study was to compare the analgesic effect of xylocaine only with xylocaine and corticosteroid following US-guided percutaneous treatment of rotator cuff calcific tendonosis. METHODS: This prospective study enrolled 88 patients who were given different analgesic treatments [xylocaine only, n = 23; xylocaine with corticosteroid, n = 44; control (no xylocaine or corticosteroid), n = 21]. The assessment of a patient's painful symptoms was recorded before treatment, and 1 day, 1 week, 1 month and 3 months after treatment using the visual analogue scale (VAS). RESULTS: There were no significant differences in age, sex, calcification size before and after treatment, and amount of calcification decrease after treatment, but there was a significant difference in calcification morphology among the groups (p = 0.010). General linear model analysis indicated that the three groups had no difference in pain prior to treatment. After treatment, the xylocaine only and the xylocaine with corticosteroid groups had less pain than the control group at 1 day, 1 week, and 1 month after treatment. At 3 months after treatment, the xylocaine only group had less pain than the control group (p = 0.039), and the xylocaine with corticosteroid and control groups had similar levels of pain. CONCLUSION: Injection of xylocaine alone after US-guided treatment of rotator cuff calcific tendonosis provided a longer pain relief period than that of a mixture of xylocaine with corticosteroid. PMID- 25456038 TI - Early changes of the anemia phenomenon in male 100-km ultramarathoners. AB - BACKGROUND: Sports anemia is a widely observed phenomenon after prolonged running. There are various factors that contribute to sports anemia, including hemodilution, exercise-induced oxidative stress, iron deficiency, gastrointestinal bleeding, hematuria, and hemolysis resulting from foot-strike and/or from compression of contracting muscles on capillaries. Until now, there has been no published report that describes the overall hematological, urinary, and fecal consequences in Asian male ultramarathoners after a 100-km (62.5-mile) ultramarathon event. METHODS: A total of 25 male runners were recruited into our study. Blood was drawn 1 week before, immediately after, and then 24 hours subsequent to the race. Hematological samples were analyzed for the anemia phenomenon. Additionally, urinary and fecal samples were collected before and after the race for detection of occult blood. RESULTS: The blood hemoglobin and erythropoietin values of the recruited runners showed a statistically significant rise in the immediate post-race values and a rapid drop in values at 24 hours post-race. Blood concentrations of red blood cells and hematocrit were significantly lower at 24 hours post-race compared with pre-race. The white blood cell count, interleukin-6, tumor necrosis factor-alpha, high-sensitivity C reactive protein, and ferritin all showed significant increases both immediately after and 24 hours post-race compared with pre-race hematological values. There were immediate decreases of both haptoglobin and iron, as well as an increase of total iron-binding capacity levels in post-race blood tests. For both urinary and fecal samples, there was a statistically significant difference between the pre- and post-race results in occult blood. CONCLUSION: Running a 100-km ultramarathon will induce substantial sports anemia, and oxidative stress response, hemolysis, hematuria, and gastrointestinal bleeding are typical factors that contribute to its onset. PMID- 25456039 TI - Effect of pillow size preference on extensor digitorum communis muscle strength and electromyographic activity during maximal contraction in healthy individuals: a pilot study. AB - BACKGROUND: Cervical pillow height is an important factor that affects the perception of pillow comfort. However, few studies have addressed methods for predicting a patient's preferred cervical pillow size. We studied the effect of pillow size preference on the strength and electromyographic (EMG) signals of the upper extremity muscle. If the response of the upper extremity muscle is affected by pillow size preference, this would aid in devising an alternate strategy for selecting the optimal pillow size. METHODS: Twenty-nine healthy individuals (mean age: 28.6 years, range: 24-55 years) participated in this study. The participants performed isometric maximal finger extension in the supine position with their heads supported on four different size preferences of cervical pillow (the most comfortable, next most comfortable, worst, and next worst). Maximal contraction force and peak-to-peak EMG amplitude of the extensor digitorum communis (EDC) during contraction were measured. One-way repeated-measures analysis of variance was used to evaluate the effect of pillow size preference. We also explored the relationship between anthropometric parameters and the individual's cervical pillow height preference. RESULTS: The two most comfortable pillows were associated with significantly larger maximal EDC force than the two worst pillows. However, no significant differences in EMG were observed between pillows. No statistically significant correlation was found between anthropometric parameters and pillow height preference. CONCLUSION: The results suggest that anatomical body measurements are not good predictors of optimal pillow height. As EDC muscle strength is affected by pillow height preference, maximal EDC muscle strength may be a useful complement for selecting the optimal pillow size. PMID- 25456040 TI - Visual impairment and mortality: are they related? PMID- 25456041 TI - Teeth and dental pulp tissue: the origin for generating induced pluripotent stem cells? PMID- 25456042 TI - Is cloud-based technology a promising tool in the integrated care of patients with chronic kidney disease? PMID- 25456043 TI - Unmet diagnostic needs in infectious disease. AB - Accurate diagnosis is critical to providing appropriate care in infectious diseases (ID). New technologies for infectious disease diagnostics are emerging, but gaps remain in test development and availability. The Emerging Infections Network surveyed ID physicians to assess unmet diagnostic needs. Responses reflected the urgent need to identify drug-resistant infections and highlighted the potential for early diagnosis to improve antibiotic stewardship. Information gained from this survey can help inform recommendations for new diagnostic test development in the future. PMID- 25456044 TI - Characterization of ESBL-producing Escherichia coli ST131 isolates from Port Elizabeth. AB - This study investigated resistance determinants and genetic relatedness in extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolates. PCR and DNA sequencing were used for screening isolates for blaCTX-M, blaTEM, and blaSHV (qnrA, qnrB, qnrC, qnrD, qnrS, aac(6)-lb-cr, and qepA) resistance genes and the sequence type 131 (ST131) clone. Genetic relatedness of E. coli ST131 isolates was determined by pulsed-field gel electrophoresis. Twelve isolates belonged to the ST131 clonal complex, while 8 were positive for aac(6')-lb-cr with qnrB1 also detected in 1 isolate. This study describes the first occurrence of CTX-M-9, qnrB1+aac(6')-lb-cr and CTX-M-3+qnrS1 among E. coli ST131 isolates from South Africa and illustrates their genetic diversity. PMID- 25456045 TI - Thermally stable plasmonic nanocermets grown on microengineered surfaces as versatile surface enhanced Raman spectroscopy sensors for multianalyte detection. AB - Noble metal nanoparticle-based plasmonic sensors, fabricated by top-down and colloidal routes, are widely used for high sensitivity detection of diverse analyte molecules using surface enhanced Raman spectroscopy (SERS). However, most of these sensors do not show stability under harsh environments, which limits their use as versatile SERS substrates. In this work, we report the first use of plasmonic nanocermets, grown on microengineered Si surfaces, as potential candidates for a highly robust SERS sensor. The robustness of the sensor is attributed to the anchoring of the nanoparticles in the nanocermet, which is an important factor for exploiting its reusability. The fairly uniform distribution of nanoparticles in the sensor led to high enhancement factors (10(6)-10(7)) and enabled the detection of low concentrations of a wide range of analytes, including differently charged biomolecules, which is extremely difficult for other SERS sensors. With more precise control over the particle geometry and distribution, plasmonic nanocermets may play an important role in ultrasensitive SERS measurements in adverse conditions such as high temperature. PMID- 25456046 TI - Photoperiodic time measurement and seasonal immunological plasticity. AB - Seasonal variations in immunity are common in nature, and changes in day length are sufficient to trigger enhancement and suppression of immune function in many vertebrates. Drawing primarily on data from Siberian hamsters, this review describes formal and physiological aspects of the neuroendocrine regulation of seasonal changes in mammalian immunity. Photoperiod regulates immunity in a trait specific manner, and seasonal changes in gonadal hormone secretion and thyroid hormone signaling all participate in seasonal immunomodulation. Photoperiod driven changes in the hamster reproductive and immune systems are associated with changes in iodothyronine deiodinase-mediated thyroid hormone signaling, but photoperiod exerts opposite effects on select aspects of the epigenetic regulation of reproductive neuroendocrine and lymphoid tissues. Photoperiodic changes in immunocompetence may explain a proportion of the annual variance in disease incidence and severity in nature, and provide a useful framework to help understand brain-immune interactions. PMID- 25456048 TI - Ultrasensitivity part III: cascades, bistable switches, and oscillators. AB - Switch-like, ultrasensitive responses - responses that resemble those of cooperative enzymes but are not necessarily generated by cooperativity - are widespread in signal transduction. In the previous installments in this series, we reviewed several mechanisms for generating ultrasensitivity: zero-order ultrasensitivity; multistep ultrasensitivity; inhibitor ultrasensitivity; and positive feedback (or double negative feedback) loops. In this review, we focus on how ultrasensitive components can be important for the functioning of more complex signaling circuits. Ultrasensitivity can allow the effective transmission of signals down a signaling cascade, can contribute to the generation of bistability by positive feedback, and can promote the production of biochemical oscillations in negative feedback loops. This makes ultrasensitivity a key building block in systems biology and synthetic biology. PMID- 25456049 TI - Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: II. A focus on growth impairment in fish. AB - Adverse outcome pathways (AOPs) organize knowledge on the progression of toxicity through levels of biological organization. By determining the linkages between toxicity events at different levels, AOPs lay the foundation for mechanism-based alternative testing approaches to hazard assessment. Here, we focus on growth impairment in fish to illustrate the initial stages in the process of AOP development for chronic toxicity outcomes. Growth is an apical endpoint commonly assessed in chronic toxicity tests for which a replacement is desirable. Based on several criteria, we identified reduction in food intake to be a suitable key event for initiation of middle-out AOP development. To start exploring the upstream and downstream links of this key event, we developed three AOP case studies, for pyrethroids, selective serotonin reuptake inhibitors (SSRIs) and cadmium. Our analysis showed that the effect of pyrethroids and SSRIs on food intake is strongly linked to growth impairment, while cadmium causes a reduction in growth due to increased metabolic demands rather than changes in food intake. Locomotion impairment by pyrethroids is strongly linked to their effects on food intake and growth, while for SSRIs their direct influence on appetite may play a more important role. We further discuss which alternative tests could be used to inform on the predictive key events identified in the case studies. In conclusion, our work demonstrates how the AOP concept can be used in practice to assess critically the knowledge available for specific chronic toxicity cases and to identify existing knowledge gaps and potential alternative tests. PMID- 25456050 TI - Trauma to the hyoid bone and laryngeal cartilages in hanging: review of forensic research series since 1856. AB - Since 1856 lots of forensic reports, concerning trauma to the hyoid bone and laryngeal cartilages in hanging, have been published. Differences in percentage of injured neck complexes ranged from 0 to 83.3%. Simple arguments suggest that the reason for discrepancy is difference in scientific approach (retro- or prospective) and use of various research methods. Comparative analysis of widely used techniques shows considerable variety in their effectiveness. Plain radiography and palpatory method have fairly low sensitivity (33-60% for different elements of the neck complex) with relatively high specificity (89 98.5%). Reported sensitivity of postmortem CT in identification of different lesions (including fractures) in trauma victims for the head/neck region is higher than 53% in different series with possible false-positive findings. In clinical setting the whole-body CT (pan-scanning) in blunt trauma patients showed sensitivity for head and neck injuries at the level of 84.6%, and specificity - 98.9% (Stengel et al., 2012 [68]). Only complete preparation allows to identify all the damages to the laryngopharynx framework, to avoid false diagnostics and ascertain the exact location, morphology, mechanism and intravital nature of the neck trauma. Currently complete preparation can be regarded as the method of "gold standard". Use of this method shows the frequency of discovered injuries in hanging to be about 70% of cases. In practical use, one should consider radiological techniques and palpation as preliminary and orienting methods (rather excluding, than revealing anterior neck trauma). PMID- 25456051 TI - Age estimation based on bone length using 12 regression models of left hand X-ray images for Asian children below 19 years old. AB - Age estimation was used in forensic anthropology to help in the identification of individual remains and living person. However, the estimation methods tend to be unique and applicable only to a certain population. This paper analyzed age estimation using twelve regression models carried out on X-ray images of the left hand taken from an Asian data set for subjects under the age of 19. All the nineteen bones of the left hand were measured using free image software and the statistical analysis were performed using SPSS. There are two methods to determine age in this study which are single bone method and all bones method. For single bone method, S-curve regression model was found to have the highest R square value using second metacarpal for males, and third proximal phalanx for females. For age estimation using single bone, fifth metacarpal from males and fifth proximal phalanx from females can be used due to the lowest mean square error (MSE) value. To conclude, multiple linear regressions is the best techniques for age estimation in cases where all bones are available, but if not, S-curve regression can be used using single bone method. PMID- 25456052 TI - Enzymatically controlled material design with casein--from defined films to localized deposition of particles. AB - A new concept for deposition and material design of coatings from biological compounds is presented. An enzymatic reaction triggers the specific coagulation of particles on a support surface. The first examined model system is casein and is based on the natural rennet reaction as applied in the process of cheese making. The aspartic protease chymosin is immobilized on a support surface and cleaves the hydrophilic parts of the casein micelles, inducing deposition. The concept allows for a high level of control over film characteristics and enables the formation of site-specific film structures. The variability rages from formation of casein films with several micrometers film thickness to the targeted deposition of casein micelles. PMID- 25456053 TI - Advances in industrial biotechnology: synthetic pathways and reaction cascades. PMID- 25456047 TI - Neuroendocrine control of photoperiodic changes in immune function. AB - Seasonal variation in immune function putatively maximizes survival and reproductive success. Day length (photoperiod) is the most potent signal for time of year. Animals typically organize breeding, growth, and behavior to adapt to spatial and temporal niches. Outside the tropics individuals monitor photoperiod to support adaptations favoring survival and reproductive success. Changes in day length allow anticipation of seasonal changes in temperature and food availability that are critical for reproductive success. Immune function is typically bolstered during winter, whereas reproduction and growth are favored during summer. We provide an overview of how photoperiod influences neuronal function and melatonin secretion, how melatonin acts directly and indirectly to govern seasonal changes in immune function, and the manner by which other neuroendocrine effectors such as glucocorticoids, prolactin, thyroid, and sex steroid hormones modulate seasonal variations in immune function. Potential future research avenues include commensal gut microbiota and light pollution influences on photoperiodic responses. PMID- 25456054 TI - The genomics revolution and its impact on future biotechnology. PMID- 25456055 TI - Process optimization with alternative carbon sources and modulation of secondary metabolism for enhanced ansamitocin P-3 production in Actinosynnema pretiosum. AB - Ansamitocin P-3 (AP-3), synthesized by Actinosynnema pretiosum, is a microtubule disruptor with significant antitumor activity. Although efforts have been made for the study of ansamitocin biosynthetic gene clusters and its fermentation improvement, the yield and productivity of AP-3 are still limited. In this study, fructose was found to be more beneficial to AP-3 production than glucose, and the culture condition was optimized via single-factor experiments and response surface method. The AP-3 concentration in the Erlenmeyer flasks reached 144 mg/L with the optimized medium containing fructose 9.36 g/L, glycerol 26.79 g/L and soluble starch 3.03 g/L, increased by ninefold compared with that before optimization. The result of medium optimization showed that fructose was an important element for effective increase in AP-3 production. Transcription of genes involved in primary metabolism and ansamitocin biosynthetic pathway was investigated to elucidate metabolic responses of cell metabolism to the substitution of fructose for glucose. It was demonstrated that using fructose as the major carbon source could relieve glucose repression and therefore result in flux rearrangement in primary metabolism for better providing biosynthetic precursors and stimulating the secondary metabolism in A. pretiosum. The results obtained might be of particular benefit to further enhancement of ansamitocin productivity. PMID- 25456056 TI - Rapid quantification of Escherichia coli in food and media using bacteriophage T7 amplification and liquid chromatography-multiple reaction monitoring tandem mass spectrometry. AB - Conventional microbiological assays have been a valuable tool for specific enumeration of indicative bacteria of relevance to food and public health, but these culture-based methods are time-consuming and require tedious biochemical and morphological identification. In this work, we exploit the ability of bacteriophage T7 to specifically infect Escherichia coli and amplify nearly a 100 fold in 1-2 h. Bacteriophage amplification is integrated with liquid chromatography-multiple reaction monitoring tandem mass spectrometry (LC-MRM MS/MS) for quantitation of phage-specific peptides. Heavy isotopic 15N labeled T7 is introduced as the inoculum phage and internal standard. Quantification is performed by determining the ratio of phage-specific peptides over the internal standard which value is proportional to E. coli numbers. A broad dynamic range of 6-log orders ranging from 3.0 * 10(3) to 3.0 * 10(9) CFU/ml is attained in LB, while between 4.1 * 10(4)-2.7 * 10(9) CFU/ml and 1.9 * 10(3)-3.0 * 10(7) CFU/ml was enumerated respectively in coconut water and apple juice. With this method, viable E. coli are quantified in 4 h with a detection limit of 3.0 * 10(3) CFU/ml, 4.1 * 10(4) CFU/ml and 1.9 * 10(3) CFU/ml in LB, coconut water and apple juice, respectively. This method has potential as a rapid tool for detection of fecal contamination during food bioprocessing and distribution to safeguard public health. PMID- 25456057 TI - Complete genome sequence of the plant growth-promoting rhizobacterium Pseudomonas aurantiaca strain JD37. AB - Pseudomonas aurantiaca Strain JD37, a Gram-negative bacterium isolated from potato rhizosphere soil (Shanghai, China), is a plant growth-promoting rhizobacterium. The JD37 genome consists of only one chromosome with no plasmids. Its genome contains genes involved plant growth promoting, biological control, and other function. Here, we present the complete genome sequence of P. aurantiaca JD37. As far as we know, this is the first whole-genome of this species. PMID- 25456058 TI - Comparative evaluation of fermentative hydrogen production using Enterobacter cloacae and mixed culture: effect of Pd (II) ion and phytogenic palladium nanoparticles. AB - Palladium nanoparticles (PdNPs) were synthesized from PdCl2 using Coriandrum sativum leaf extract. The transmission electron microscopy (TEM) images confirm that the formation of PdNPs was mainly spherical in shape, with an average size of 87 nm. The influence of the PdCl2 and synthesized PdNPs on fermentative hydrogen production from glucose using Enterobacter cloacae and mixed culture was evaluated. In PdCl2 supplemented experiments, the hydrogen yields of E. cloacae and mixed culture were 1.39 +/- 0.07 and 2.11 +/- 0.11 mol H2/mol glucose, respectively, with 5.0 mg/L of PdCl2. The resulting hydrogen yield (P < 0.05) was lower than that of the control experiment (without supplementation), due to the soluble metabolites shift. However, the highest hydrogen yields of E. cloacae and mixed culture were 1.48 +/- 0.04 and 2.48 +/- 0.09 mol H2/mol glucose, respectively at 5.0 mg/L of PdNPs supplementation. The enhancement of biohydrogen production using mixed culture was significantly higher than that of E. cloacae as the same concentration of PdNPs. PMID- 25456059 TI - Light modulation of biomass and macromolecular composition of the diatom Skeletonema marinoi. AB - The biochemical profile and growth of the coastal diatom Skeletonema marinoi was investigated under four different daily blue light doses (sinusoidal light peaking at 88, 130, 250 and 450 MUmol photons m(-2) s(-1), respectively). Ability of cells to regulate the light energy input caused alterations in growth and different biosynthetic pathways. The light saturation index for photosynthesis (E(k)), which governs the photoacclimative processes, ranged between 250 and 300 MUmol photons m(-2) s(-1). Cells that were adapted to low light (=E(k)). Variations in fatty acid, pigment and amino acid compositions were a result of light adaptation. Our data show that light is a potent factor for manipulating biomass synthesis in microalgae, such as diatoms for microalgal biotechnology. PMID- 25456060 TI - Enrichment of Plasticicumulans acidivorans at pilot-scale for PHA production on industrial wastewater. AB - A PHA producing microbial culture dominated by Plasticicumulans acidivorans was enriched in a pilot plant using fermented wastewater from the Mars candy bar factory. The pilot plant comprised (1) anaerobic fermentation, (2) enrichment of a PHA-producing microbial community and (3) accumulation for maximization of the cellular PHA content. After anaerobic fermentation, the wastewater contained mainly VFAs (0.64 +/- 0.15 gCOD/gCOD) and ethanol (0.22 +/- 0.13 gCOD/gCOD). In the enrichment reactor (cycle 12 h, SRT 24 h) a feast-famine pattern was established with a feast phase of around 35 +/- 5 min. The culture was able to accumulate 0.70 +/- 0.05 gPHA/gVSS. The difference with previous lab-scale results from P. acidivorans, in which a PHA content of 0.90 gPHA/gVSS was achieved, could be attributed to the presence of solids in the influent, the growth of a side population and the accumulation of non-PHA storage compounds that appeared to be related to ethanol consumption. PMID- 25456061 TI - Enhanced production of n-alkanes in Escherichia coli by spatial organization of biosynthetic pathway enzymes. AB - Alkanes chemically mimic hydrocarbons found in petroleum, and their demand as biofuels is steadily increasing. Biologically, n-alkanes are produced from fatty acyl-ACPs by acyl-ACP reductases (AARs) and aldehyde deformylating oxygenases (ADOs). One of the major impediments in n-alkane biosynthesis is the low catalytic turnover rates of ADOs. Here, we studied n-alkane biosynthesis in Escherichia coli using a chimeric ADO-AAR fusion protein or zinc finger protein guided ADO/AAR assembly on DNA scaffolds to control their stoichiometric ratios and spatial arrangements. Bacterial production of n-alkanes with the ADO-AAR fusion protein was increased 4.8-fold (24 mg/L) over a control strain expressing ADO and AAR separately. Optimal n-alkane biosynthesis was achieved when the ADO:AAR binding site ratio on a DNA scaffold was 3:1, yielding an 8.8-fold increase (44 mg/L) over the control strain. Our findings indicate that the spatial organization of alkane-producing enzymes is critical for efficient n alkane biosynthesis in E. coli. PMID- 25456062 TI - Synthetic scaffold based on a cohesin-dockerin interaction for improved production of 2,3-butanediol in Saccharomyces cerevisiae. AB - Substrate channeling is a process of transferring an intermediate from one enzyme to the next enzyme without diffusion into the bulk phase, thereby leading to an enhanced reaction rate. Here, we newly designed substrate channeling modules in Saccharomyces cerevisiae based on a high affinity interaction between dockerin and cohesin domains, which is a key process in the formation of cellulosome structure. Synthetic scaffolds containing two, three, or seven cohesin domains were constructed, and the assembly of dockerin-tagged proteins onto the scaffolds was confirmed by pull-down assay and bimolecular fluorescent complementation (BiFC) assay in vivo. This system was applied to produce 2,3-butanediol in S. cerevisiae by using dockerin-tagged AlsS, AlsD, and Bdh1 enzymes, resulting in a gradual increase in 2,3-butanediol production depending on the number of cohesin domains in the scaffold. PMID- 25456063 TI - Semicarbazide-functionalized resin as a new scavenger for in situ recovery of 3 hydroxypropionaldehyde during biotransformation of glycerol by Lactobacillus reuteri. AB - 3-Hydroxypropionaldehyde (3HPA), a potential C3-platform chemical for a biobased industry, is produced from glycerol using Lactobacillus reuteri through its glycerol dehydratase activity. However, the process is characterized by low yield and productivity due to toxic effects of 3HPA on the biocatalyst activity. In this study, a semicarbazide-functionalized resin was prepared, evaluated for adsorption and in situ recovery of 3HPA during biotransformation of glycerol. Adsorption of 3HPA onto the resin was characterized as "S-curve model", increasing with increasing initial 3HPA concentration, and reached a maximum of 9.48 mmol/g(resin) at 71.54 mM 3HPA used. Desorption of 3HPA was evaluated using water and different acids, and was enhanced by acetic acid with organic modifiers. Repeated adsorption-desorption of 3HPA in batch resulted in elution of 13-66.5% of the bound 3HPA during at least three sequential cycles using water and acetic acid, respectively as eluants. Using the resin for in situ product removal led to more than 2 times higher productivity of 3HPA. PMID- 25456064 TI - Transcriptome analyses to understand effects of the Fusarium deoxynivalenol and nivalenol mycotoxins on Escherichia coli. AB - Fusarium spp. cause many diseases in farming systems and can produce diverse mycotoxins that can easily impact humans and animals through the ingestion of food and feed. Among these mycotoxins, deoxynivalenol (DON) and nivalenol (NIV) are considered the most important hazards because they can rapidly diffuse into cells and block eukaryotic ribosomes, leading to inhibition of the translation system. Conversely, the effects of DON and NIV mycotoxins on bacteria remain unclear. We employed RNA-seq technology to obtain information regarding the biological responses of bacteria and putative bacterial mechanisms of resistance to DON and NIV mycotoxins. Most differentially expressed genes down-regulated in response to these mycotoxins were commonly involved in phenylalanine metabolism, glyoxylate cycle, and cytochrome o ubiquinol oxidase systems. In addition, we generated an overall network of 1028 up-regulated genes to identify core genes under DON and NIV conditions. The results of our study provide a snapshot view of the transcriptome of Escherichia coli K-12 under DON and NIV conditions. Furthermore, the information provided herein will be useful for development of methods to detect DON and NIV. PMID- 25456065 TI - Cannabinoid type 1 (CB1) receptors on Sim1-expressing neurons regulate energy expenditure in male mice. AB - The paraventricular nucleus of the hypothalamus (PVN) regulates energy balance by modulating not only food intake, but also energy expenditure (EE) and brown adipose tissue thermogenesis. To test the hypothesis that cannabinoid type 1 (CB1) receptor in PVN neurons might control these processes, we used the Cre/loxP system to delete CB1 from single-minded 1 (Sim1) neurons, which account for the majority of PVN neurons. On standard chow, mice lacking CB1 receptor in Sim1 neurons (Sim1-CB1-knockout [KO]) had food intake, body weight, adiposity, glucose metabolism, and EE comparable with wild-type (WT) (Sim1-CB1-WT) littermates. However, maintenance on a high-fat diet revealed a gene-by-diet interaction whereby Sim1-CB1-KO mice had decreased adiposity, improved insulin sensitivity, and increased EE, whereas feeding behavior was similar to Sim1-CB1-WT mice. Additionally, high-fat diet-fed Sim1-CB1-KO mice had increased mRNA expression of the beta3-adrenergic receptor, as well as of uncoupling protein-1, cytochrome-c oxidase subunit IV and mitochondrial transcription factor A in the brown adipose tissue, all molecular changes suggestive of increased thermogenesis. Pharmacological studies using beta-blockers suggested that modulation of beta adrenergic transmission play an important role in determining EE changes observed in Sim1-CB1-KO. Finally, chemical sympathectomy abolished the obesity-resistant phenotype of Sim1-CB1-KO mice. Altogether, these findings reveal a diet-dependent dissociation in the CB1 receptor control of food intake and EE, likely mediated by the PVN, where CB1 receptors on Sim1-positive neurons do not impact food intake but hinder EE during dietary environmental challenges that promote body weight gain. PMID- 25456066 TI - Unliganded thyroid hormone receptor alpha controls developmental timing in Xenopus tropicalis. AB - Thyroid hormone (T3) affects adult metabolism and postembryonic development in vertebrates. T3 functions mainly via binding to its receptors (TRs) to regulate gene expression. There are 2 TR genes, TRalpha and TRbeta, with TRalpha more ubiquitously expressed. During development, TRalpha expression appears earlier than T3 synthesis and secretion into the plasma. This and the ability of TRs to regulate gene expression both in the presence and absence of T3 have indicated a role for unliganded TR during vertebrate development. On the other hand, it has been difficult to study the role of unliganded TR during development in mammals because of the difficulty to manipulate the uterus-enclosed, late-stage embryos. Here we use amphibian development as a model to address this question. We have designed transcriptional activator-like effector nucleases (TALENs) to mutate the TRalpha gene in Xenopus tropicalis. We show that knockdown of TRalpha enhances tadpole growth in premetamorphic tadpoles, in part because of increased growth hormone gene expression. More importantly, the knockdown also accelerates animal development, with the knockdown animals initiating metamorphosis at a younger age and with a smaller body size. On the other hand, such tadpoles are resistant to exogenous T3 treatment and have delayed natural metamorphosis. Thus, our studies not only have directly demonstrated a critical role of endogenous TRalpha in mediating the metamorphic effect of T3 but also revealed novel functions of unliganded TRalpha during postembryonic development, that is, regulating both tadpole growth rate and the timing of metamorphosis. PMID- 25456067 TI - Unliganded thyroid hormone receptor alpha regulates developmental timing via gene repression in Xenopus tropicalis. AB - Thyroid hormone (TH) receptor (TR) expression begins early in development in all vertebrates when circulating TH levels are absent or minimal, yet few developmental roles for unliganded TRs have been established. Unliganded TRs are expected to repress TH-response genes, increase tissue responsivity to TH, and regulate the timing of developmental events. Here we examined the role of unliganded TRalpha in gene repression and development in Xenopus tropicalis. We used transcription activator-like effector nuclease gene disruption technology to generate founder animals with mutations in the TRalpha gene and bred them to produce F1 offspring with a normal phenotype and a mutant phenotype, characterized by precocious hind limb development. Offspring with a normal phenotype had zero or one disrupted TRalpha alleles, and tadpoles with the mutant hind limb phenotype had two truncated TRalpha alleles with frame shift mutations between the two zinc fingers followed by 40-50 mutant amino acids and then an out of-frame stop codon. We examined TH-response gene expression and early larval development with and without exogenous TH in F1 offspring. As hypothesized, mutant phenotype tadpoles had increased expression of TH-response genes in the absence of TH and impaired induction of these same genes after exogenous TH treatment, compared with normal phenotype animals. Also, mutant hind limb phenotype animals had reduced hind limb and gill responsivity to exogenous TH. Similar results in methimazole-treated tadpoles showed that increased TH-response gene expression and precocious development were not due to early production of TH. These results indicate that unliganded TRalpha delays developmental progression by repressing TH-response genes. PMID- 25456068 TI - Relaxin peptide hormones are protective during the early stages of ischemic stroke in male rats. AB - The pregnancy hormone relaxin protects tissue from ischemic damage. The ability of relaxin-3, a relaxin paralog, to do so has not been explored. The cerebral expression levels of these peptides and their receptors make them logical targets for study in the ischemic brain. We assessed relaxin peptide-mediated protection, relative relaxin family peptide receptor (RXFP) involvement, and protective mechanisms. Sprague-Dawley rats receiving permanent (pMCAO) or transient middle cerebral artery occlusions (tMCAO) were treated with relaxin peptides, and brains were collected for infarct analysis. Activation of the endothelial nitric oxide synthase pathway was evaluated as a potential protective mechanism. Primary cortical rat astrocytes were exposed to oxygen glucose deprivation and treated with relaxin peptides, and viability was examined. Receptor involvement was explored using RXFP3 antagonist or agonist treatment and real-time PCR. Relaxin and relaxin-3 reduced infarct size after pMCAO. Both peptides activated endothelial nitric oxide synthase. Because relaxin-3 has not previously been associated with this pathway and displays promiscuous RXFP binding, we explored the receptor contribution. Expression of rxfp1 was greater than that of rxfp3 in rat brain, although peptide binding at either receptor resulted in similar overall protection after pMCAO. Only RXFP3 activation reduced infarct size after tMCAO. In astrocytes, rxfp3 gene expression was greater than that of rxfp1. Selective activation of RXFP3 maintained astrocyte viability after oxygen glucose deprivation. Relaxin peptides are protective during the early stages of ischemic stroke. Differential responses among treatments and models suggest that RXFP1 and RXFP3 initiate different protective mechanisms. This preliminary work is a pivotal first step in identifying the clinical implications of relaxin peptides in ischemic stroke. PMID- 25456069 TI - Regulation of mTOR activity in Snell dwarf and GH receptor gene-disrupted mice. AB - The involvement of mammalian target of rapamycin (mTOR) in lifespan control in invertebrates, calorie-restricted rodents, and extension of mouse lifespan by rapamycin have prompted speculation that diminished mTOR function may contribute to mammalian longevity in several settings. We show here that mTOR complex-1 (mTORC1) activity is indeed lower in liver, muscle, heart, and kidney tissue of Snell dwarf and global GH receptor (GHR) gene-disrupted mice (GHR-/-), consistent with previous studies. Surprisingly, activity of mTORC2 is higher in fasted Snell and GHR-/- than in littermate controls in all 4 tissues tested. Resupply of food enhanced mTORC1 activity in both controls and long-lived mutant mice but diminished mTORC2 activity only in the long-lived mice. Mice in which GHR has been disrupted only in the liver do not show extended lifespan and also fail to show the decline in mTORC1 and increase in mTORC2 seen in mice with global loss of GHR. The data suggest that the antiaging effects in the Snell dwarf and GHR-/- mice are accompanied by both a decline in mTORC1 in multiple organs and an increase in fasting levels of mTORC2. Neither the lifespan nor mTOR effects appear to be mediated by direct GH effects on liver or by the decline in plasma IGF-I, a shared trait in both global and liver-specific GHR-/- mice. Our data suggest that a more complex pattern of hormonal effects and intertissue interactions may be responsible for regulating both lifespan and mTORC2 function in these mouse models of delayed aging. PMID- 25456070 TI - The selective loss of the type 2 iodothyronine deiodinase in mouse thyrotrophs increases basal TSH but blunts the thyrotropin response to hypothyroidism. AB - The type 2 iodothyronine deiodinase (D2) is essential for feedback regulation of TSH by T4. We genetically inactivated in vivo D2 in thyrotrophs using a mouse model of Cga-driven cre recombinase. Pituitary D2 activity was reduced 90% in the Cga-cre D2 knockout (KO) mice compared with control Dio2(fl/fl) mice. There was no growth or reproductive phenotype. Basal TSH levels were increased 1.5- to 1.8 fold, but serum T4 and T3 were not different from the controls in adult mice. In hypothyroid adult mice, suppression of TSH by T4, but not T3, was impaired. Despite mild basal TSH elevation, the TSH increase in response to hypothyroidism was 4-fold reduced in the Cga-cre D2KO compared with control mice despite an identical level of pituitary TSH alpha- and beta-subunit mRNAs. In neonatal Cga cre D2KO mice, TSH was also 2-fold higher than in the controls, but serum T4 was elevated. Despite a constant TSH, serum T4 increased 2-3-fold between postnatal day (P) 5 and P15 in both genotypes. The pituitary, but not cerebrocortical, D2 activity was markedly elevated in P5 mice decreasing towards adult levels by P17. In conclusion, a congenital severe reduction of thyrotroph D2 causes a major impairment of the TSH response to hypothyroidism. This would be deleterious to the compensatory adaptation of the thyroid gland to iodine deficiency. PMID- 25456072 TI - Meclozine promotes longitudinal skeletal growth in transgenic mice with achondroplasia carrying a gain-of-function mutation in the FGFR3 gene. AB - Achondroplasia (ACH) is one of the most common skeletal dysplasias causing short stature owing to a gain-of-function mutation in the FGFR3 gene, which encodes the fibroblast growth factor receptor 3. We found that meclozine, an over-the-counter drug for motion sickness, inhibited elevated FGFR3 signaling in chondrocytic cells. To examine the feasibility of meclozine administration in clinical settings, we investigated the effects of meclozine on ACH model mice carrying the heterozygous Fgfr3(ach) transgene. We quantified the effect of meclozine in bone explant cultures employing limb rudiments isolated from developing embryonic tibiae from Fgfr3(ach) mice. We found that meclozine significantly increased the full-length and cartilaginous primordia of embryonic tibiae isolated from Fgfr3(ach) mice. We next analyzed the skeletal phenotypes of growing Fgfr3(ach) mice and wild-type mice with or without meclozine treatment. In Fgfr3(ach) mice, meclozine significantly increased the body length after 2 weeks of administration. At skeletal maturity, the bone lengths including the cranium, radius, ulna, femur, tibia, and vertebrae were significantly longer in meclozine treated Fgfr3(ach) mice than in untreated Fgfr3(ach) mice. Interestingly, meclozine also increased bone growth in wild-type mice. The plasma concentration of meclozine during treatment was within the range that has been used in clinical settings for motion sickness. Increased longitudinal bone growth in Fgfr3(ach) mice by oral administration of meclozine in a growth period suggests potential clinical feasibility of meclozine for the improvement of short stature in ACH. PMID- 25456071 TI - EB1 regulates tubulin and actin cytoskeletal networks at the sertoli cell blood testis barrier in male rats: an in vitro study. AB - During spermatogenesis, developing germ cells are transported across the seminiferous epithelium. Studies propose that because microtubules (MTs) serve as the tracks for transporting cell organelles, they may also serve a similar function in the transport of developing germ cells. Polarized MTs may provide the tracks along which polarized actin microfilaments, which act as vehicles to transport cargo, such as preleptotene spermatocytes through the blood-testis barrier (BTB) and spermatids across the epithelium. Yet the molecular mechanism(s) underlying these events remain unknown. Using an established in vitro Sertoli cell system to study BTB function, we demonstrated herein that a MT regulatory protein end-binding protein 1 (EB1) regulates the MT- and also the actin-based cytoskeleton of the Sertoli cell BTB in the rat. EB1 serves as a coordinator between the two cytoskeletons by regulating MT polymerization and actin filament bundling to modulate germ cell transport at the Sertoli cell BTB. A knockdown of EB1 by RNA interference was found to perturb the tight junction (TJ)-permeability barrier, as evidenced by mislocalization of junctional proteins critical for barrier function to facilitate spermatocyte transport, which was likely achieved by two coordinated events. First, EB1 knockdown resulted in changes in MT polymerization, thereby perturbing MT organization in Sertoli cells in which polarized MT no longer stretched properly across the cell cytosol to serve as the tracks. Second, EB1 knockdown perturbed actin organization via its effects on the branched actin polymerization-inducing protein called Arp3 (actin related protein 3), perturbing microfilament bundling capability based on a biochemical assay, thereby causing microfilament truncation and misorganization, disrupting the function of the vehicle. This reduced actin microfilament bundling capability thus perturbed TJ-protein distribution and localization at the BTB, destabilizing the TJ barrier, leading to its remodeling to facilitate spermatocyte transport. In summary, EB1 provides a functional link between tubulin- and actin-based cytoskeletons to confer spermatocyte transport at the BTB. PMID- 25456073 TI - Type 2 blindsight and the nature of visual experience. AB - Blindsight is a kind of residual vision found in people with lesions to V1. Subjects with blindsight typically report no visual awareness, but they are nonetheless able to make above-chance guesses about the shape, location, color and movement of visual stimuli presented to them in their blind field. A different kind of blindsight, sometimes called type 2 blindsight, is a kind of residual vision found in patients with V1 lesions in the presence of some residual awareness. Type 2 blindsight differs from ordinary visual experience in lacking the particularity, transparency and fine-grainedness often taken to be essential to visual experience, at least in veridical cases. I argue that the case of type 2 blindsight provides a counterexample to the view that these characteristics are essential to veridical visual experience and that this gives us reason to resist the view that visual experience is essentially a perceptual relation to external objects. In the second part of the paper I argue that the case of type 2 blindsight yields important insights into the effects of attentional modulation on perceptual content and that cases of attentional modulation of appearance are not at odds with the view that the phenomenology of visual experience flows from its content. PMID- 25456074 TI - Influenza A virus transmission bottlenecks are defined by infection route and recipient host. AB - Despite its global relevance, our understanding of how influenza A virus transmission impacts the overall population dynamics of this RNA virus remains incomplete. To define this dynamic, we inserted neutral barcodes into the influenza A virus genome to generate a population of viruses that can be individually tracked during transmission events. We find that physiological bottlenecks differ dramatically based on the infection route and level of adaptation required for efficient replication. Strong genetic pressures are responsible for bottlenecks during adaptation across different host species, whereas transmission between susceptible hosts results in bottlenecks that are not genetically driven and occur at the level of the recipient. Additionally, the infection route significantly influences the bottleneck stringency, with aerosol transmission imposing greater selection than direct contact. These transmission constraints have implications in understanding the global migration of virus populations and provide a clearer perspective on the emergence of pandemic strains. PMID- 25456075 TI - Cyclic side-chain-linked opioid analogs utilizing cis- and trans-4 aminocyclohexyl-D-alanine. AB - Cyclization of linear sequences is a well recognized tool in opioid peptide chemistry for generating analogs with improved bioactivities. Cyclization can be achieved through various bridging bonds between peptide ends or side-chains. In our earlier paper we have reported the synthesis and biological activity of a cyclic peptide, Tyr-c[D-Lys-Phe-Phe-Asp]NH2 (1), which can be viewed as an analog of endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2). Cyclization was achieved through an amide bond between side-chains of D-Lys and Asp residues. Here, to increase rigidity of the cyclic structure, we replaced d-Lys with cis- or trans-4 aminocyclohexyl-D-alanine (D-ACAla). Two sets of analogs incorporating either Tyr or Dmt (2',6'-dimethyltyrosine) residues in position 1 were synthesized. In the binding studies the analog incorporating Dmt and trans-D-ACAla showed high affinity for both, MU- and delta-opioid receptors (MOR and DOR, respectively) and moderate affinity for the kappa-opioid receptor (KOR), while analog with Dmt and cis-D-ACAla was exceptionally MOR-selective. Conformational analyses by NMR and molecular docking studies have been performed to investigate the molecular structural features responsible for the noteworthy MOR selectivity. PMID- 25456076 TI - An efficient synthesis and biological screening of benzofuran and benzo[d]isothiazole derivatives for Mycobacterium tuberculosis DNA GyrB inhibition. AB - A series of twenty eight molecules of ethyl 5-(piperazin-1-yl)benzofuran-2 carboxylate and 3-(piperazin-1-yl)benzo[d]isothiazole were designed by molecular hybridization of thiazole aminopiperidine core and carbamide side chain in eight steps and were screened for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antitubercular activity, cytotoxicity and protein-inhibitor interaction assay through differential scanning fluorimetry. Also the orientation and the ligand protein interactions of the top hit molecules with MS DNA gyrase B subunit active site were investigated applying extra precision mode (XP) of Glide. Among the compounds studied, 4-(benzo[d]isothiazol-3-yl)-N-(4-chlorophenyl)piperazine-1 carboxamide (26) was found to be the most promising inhibitor with an MS GyrB IC50 of 1.77 +/- 0.23 MUM, 0.42 +/- 0.23 against MTB DNA gyrase, MTB MIC of 3.64 MUM, and was not cytotoxic in eukaryotic cells at 100 MUM. Moreover the interaction of protein-ligand complex was stable and showed a positive shift of 3.5 degrees C in differential scanning fluorimetric evaluations PMID- 25456077 TI - Antioxidant and antimicrobial studies on fused-ring pyrazolones and isoxazolones. AB - A series of 3-nitrochalcones have been synthesized enroute towards fused ring pyrazolones and isoxazolones. Base catalyzed condensation of the chalcones with ethylacetoacetate yielded cyclohexenones in good yields (74-76%). The treatment of cyclohexenones with hydrazine hydrate or hydroxylamine chloride in the presence of a base afforded the corresponding fused-ring pyrazolinones (70-78% yield) and isoxazolinones (58-66% yield). The newly synthesized compounds were characterized by IR, 1D and 2D NMR and HRMS spectral analysis. The compounds were screened for their antioxidant and antimicrobial activities. Pyrazolinones showed good DPPH radical scavenging and iron metal chelating properties. The para hydroxy group was important for a compound to have enhanced antioxidant activity. Pyrazolinones and isoxazolinone exhibited a wider range of antimicrobial activities compared to cyclohexenones. Pyrazolinones and isoxazolinone bearing a thiophene ring were the most potent type of compounds against Bacillus subtilis and Candida albicans with MIC values of 0.313-1.25 MUg/mL. Some of the synthesized compounds were found to have promising antioxidant, metal chelation and antimicrobial activities. PMID- 25456078 TI - Synthesis, anti-inflammatory activity and modeling studies of cycloartane-type terpenes derivatives isolated from Parthenium argentatum. AB - The 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced edema model in mice determined the anti-inflammatory activities in vivo of argentatins A, B and D, the main cycloartenol-type triterpenes present in Parthenium argentatum. Our results showed that argentatin B (ED50=1.5*10(-4)mmol/ear) and argentatin A (ED50=2.8*10(-4)mmol/ear) were more potent anti-inflammatory agents than indomethacin (ED50=4.5*10(-4)mmol/ear), the reference drug. Based on these findings, we decided to evaluate 13 derivatives of argentatins A and B. All the derivatives showed anti-inflammatory activity in the TPA-induced edema model in mice. The most active compound was 25-nor-cycloart-3, 16-dione-17-en-24-oic acid, obtained from argentatin A (ED50=1.4*10(-4)mmol/ear). Argentatin B was assayed as inhibitor of COX-2 activity one of the key enzymes involved in the TPA assay. The results showed that argentatin B at 15MUM doses inhibited 77% COX-2 activity. Docking studies suggest that argentatin B interacts with Arg 120, a key residue for COX-2 activity. PMID- 25456079 TI - Discovery of novel tetrahydroisoquinoline derivatives as orally active N-type calcium channel blockers with high selectivity for hERG potassium channels. AB - N-type calcium channels represent a promising target for the treatment of neuropathic pain. The selective N-type calcium channel blocker ziconotide ameliorates severe chronic pain but has a narrow therapeutic window and requires intrathecal administration. We identified tetrahydroisoquinoline derivative 1a as a novel potent N-type calcium channel blocker. However, this compound also exhibited potent inhibitory activity against hERG channels. Structural optimizations led to identification of (1S)-(1-cyclohexyl-3,4-dihydroisoquinolin 2(1H)-yl)-2-{[(1-hydroxycyclohexyl)methyl]amino}ethanone ((S)-1h), which exhibited high selectivity for hERG channels while retaining potency for N-type calcium channel inhibition. (S)-1h went on to demonstrate in vivo efficacy as an orally available N-type calcium channel blocker in a rat spinal nerve ligation model of neuropathic pain. PMID- 25456080 TI - Structural analogues of the natural products magnolol and honokiol as potent allosteric potentiators of GABA(A) receptors. AB - Biphenylic compounds related to the natural products magnolol and 4'-O methylhonokiol were synthesized, evaluated and optimized as positive allosteric modulators (PAMs) of GABA(A) receptors. The most efficacious compounds were the magnolol analog 5-ethyl-5'-hexylbiphenyl-2,2'-diol (45) and the honokiol analogs 4'-methoxy-5-propylbiphenyl-2-ol (61), 5-butyl-4'-methoxybiphenyl-2-ol (62) and 5 hexyl-4'-methoxybiphenyl-2-ol (64), which showed a most powerful potentiation of GABA-induced currents (up to 20-fold at a GABA concentration of 3MUM). They were found not to interfere with the allosteric sites occupied by known allosteric modulators, such as benzodiazepines and N-arachidonoylglycerol. These new PAMs will be useful as pharmacological tools and may have therapeutic potential for mono-therapy, or in combination, for example, with GABA(A) receptor agonists. PMID- 25456081 TI - Anti-fibrillogenic properties of phthalocyanines: effect of the out-of-plane ligands. AB - The axially-coordinated phthalocyanines were previously reported as agents possessing strong anti-fibrillogenic properties. In the presented study we used the atomic force microscopy to investigate the intermediates and the products of insulin aggregation reaction formed in the presence of Zr and Hf phthalocyanine complexes that contain out-of-plane ligands of different size and nature. It is shown that while phthalocyanine-free insulin generated mostly amyloid fibrils with a diameter of 2-8nm and a length of up to 5MUm, the presence of phthalocyanines with spatial bulky ligands (PcZrDbm2) leads to the redirection of the fibrillization reaction to the formation of the spherical oligomer aggregates with a diameter of 4-12nm. At the same time the phthalocyanine complex PcHfCl2 having the small-volume ligands induces the formation of large size insulin aggregates with a height of about 100nm that are supposed to be amorphous species. The study of the aggregation intermediates showed the certain similarity of the reaction passing for phthalocyanine-free insulin and insulin in the presence of PcZrDbm2. The large-size amorphous species were observed at the beginning of reaction, later they dissociated, leading to the formation and growth of the smaller size particles. The amyloid-sensitive cyanine dye 7519 demonstrates the strong fluorescent response both in the presence of fibrils and spherical oligomers, while it is non-sensitive to amorphous aggregates. PMID- 25456082 TI - Glaser oxidative coupling on peptides: stabilization of beta-turn structure via a 1,3-butadiyne constraint. AB - The Glaser-Eglinton reaction between either two C or N propargylglycine (Pra or NPra) amino acids, in the presence of copper(II), led to cyclic hexa- and octapeptides constrained by a butadiyne bridge. The on-resin cyclization conditions were analyzed and optimized. The consequences of this type of constraint on the three dimensional structure of these hexapeptides and octapeptides were analyzed in details by NMR and molecular dynamics. We show that stabilized short cyclic peptides could be readily prepared via the Glaser oxidative coupling either with a chiral (Pra), or achiral (NPra) residue. The 1,3 butadiyne cyclization, along with disulfide bridged and lactam cyclized hexapeptides expands the range of constrained peptides that will allow exploring the breathing of amino acids around a beta-turn structure. PMID- 25456084 TI - 4-Functionalized 1,3-diarylpyrazoles bearing 6-aminosulfonylbenzothiazole moiety as potent inhibitors of carbonic anhydrase isoforms hCA I, II, IX and XII. AB - A series of 24 novel heterocyclic compounds-functionalized at position 4 with aldehyde (5a-5f), carboxylic acid (6a-6f), nitrile (7a-7f) and oxime (8a-8f) functional groups-bearing 6-aminosulfonybenzothiazole moiety at position 1 of pyrazole has been synthesized and investigated for the inhibition of four isoforms of the alpha-class carbonic anhydrases (CAs, EC 4.2.1.1), comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor associated isozymes). Against the human isozyme hCA I, compounds 6a-6f showed medium-weak inhibitory potential with Ki values in the range of 157-690nM with 6a showing better potential than the standard drug acetazolamide (AZA). Against hCA II, all the compounds showed excellent to moderate inhibition with Ki values of compounds 5a, 5d, 5f, 6a-6f, 8d and 8f lower than 12nM (Ki of AZA). Against hCA IX, all the compounds showed moderate inhibition with the exception of 6e which showed nearly 9 fold a better profile compared to AZA, whereas against hCA XII, four compounds 6e, 7a, 7b and 7d showed Ki in the same order as that of AZA. Carboxylic acid 6e was found to be an excellent inhibitor of both hCA IX and XII, with Ki values of 2.8nM and 5.5nM, respectively. PMID- 25456083 TI - Targeting (cellular) lysosomal acid ceramidase by B13: design, synthesis and evaluation of novel DMG-B13 ester prodrugs. AB - Acid ceramidase (ACDase) is being recognized as a therapeutic target for cancer. B13 represents a moderate inhibitor of ACDase. The present study concentrates on the lysosomal targeting of B13 via its N,N-dimethylglycine (DMG) esters (DMG-B13 prodrugs). Novel analogs, the isomeric mono-DMG-B13, LCL522 (3-O-DMG-B13.HCl) and LCL596 (1-O-DMG-B13.HCl) and di-DMG-B13, LCL521 (1,3-O, O-DMG-B13.2HCl) conjugates, were designed and synthesized through N,N-dimethyl glycine (DMG) esterification of the hydroxyl groups of B13. In MCF7 cells, DMG-B13 prodrugs were efficiently metabolized to B13. The early inhibitory effect of DMG-B13 prodrugs on cellular ceramidases was ACDase specific by their lysosomal targeting. The corresponding dramatic decrease of cellular Sph (80-97% Control/1h) by DMG-B13 prodrugs was mainly from the inhibition of the lysosomal ACDase. PMID- 25456085 TI - Synthesis and biological evaluation of novel oxindole-based RTK inhibitors as anti-cancer agents. AB - Given that receptor tyrosine kinases (RTKs) have emerged as key regulators of all aspects of cancer development, including proliferation, invasion, angiogenesis and metastasis, the RTK family represents an important therapeutic target for anti-cancer drug development. Oxindole structure has been used in RTK inhibitors such as SU4984 and intedanib. In this study, two series of new heterocyclic compounds containing oxindole scaffold have been designed and synthesized, and their inhibitory activity against the proliferation of nine cancer cell lines has been evaluated. Among them, compounds 9a and 9b displayed the strongest anti proliferative activity with the IC50s below 10MUM. Flow cytometric analysis showed that the compounds 9a and 9b dose-dependently arrested the cell cycle at G0/G1 phase. Although the leading compounds SU4984 and intedanib targets FGFR1, the kinase activity test revealed that these compounds only showed slight inhibitory activity on FGFR1 kinase. Further enzymatic test aided by molecular docking simulation in the ATP-binding site demonstrated that 9a and 9b are potent inhibitors of c-Kit kinase. These compounds are worthy of further evaluation as anticancer agents. PMID- 25456086 TI - [Facial papules: A warning sign]. PMID- 25456087 TI - [Hypertensive nephroangiosclerosis, presentation of a case with nephrotic range proteinuria, with no hypoalbuminemia or edema]. PMID- 25456088 TI - Perception and coding of interaural time differences with bilateral cochlear implants. AB - Bilateral cochlear implantation is increasingly becoming the standard in the clinical treatment of bilateral deafness. The main motivation is to provide users of bilateral cochlear implants (CIs) access to binaural cues essential for localizing sound sources and understanding speech in environments of interfering sounds. One of those cues, interaural level differences, can be perceived well by CI users to allow some basic left versus right localization. However, interaural time differences (ITDs) which are important for localization of low-frequency sounds and spatial release from masking are not adequately represented by clinical envelope-based CI systems. Here, we first review the basic ITD sensitivity of CI users, particularly their dependence on stimulation parameters like stimulation rate and place, modulation rate, and envelope shape in single electrode stimulation, as well as stimulation level, electrode spacing, and monaural across-electrode timing in multiple-electrode stimulation. Then, we discuss factors involved in ITD perception in electric hearing including the match between highly phase-locked electric auditory nerve response properties and binaural cell properties, the restricted stimulation of apical tonotopic pathways, channel interactions in multiple-electrode stimulation, and the onset age of binaural auditory input. Finally, we present clinically available CI stimulation strategies and experimental strategies aiming at improving listeners' access to ITD cues. This article is part of a Special Issue entitled . PMID- 25456089 TI - Deep electrode insertion and sound coding in cochlear implants. AB - Present-day cochlear implants demonstrate remarkable speech understanding performance despite the use of non-optimized coding strategies concerning the transmission of tonal information. Most systems rely on place pitch information despite possibly large deviations from correct tonotopic placement of stimulation sites. Low frequency information is limited as well because of the constant pulse rate stimulation generally used and, being even more restrictive, of the limited insertion depth of the electrodes. This results in a compromised perception of music and tonal languages. Newly available flexible long straight electrodes permit deep insertion reaching the apical region with little or no insertion trauma. This article discusses the potential benefits of deep insertion which are obtained using pitch-locked temporal stimulation patterns. Besides the access to low frequency information, further advantages of deeply inserted long electrodes are the possibility to better approximate the correct tonotopic location of contacts, the coverage of a wider range of cochlear locations, and the somewhat reduced channel interaction due to the wider contact separation for a given number of channels. A newly developed set of strategies has been shown to improve speech understanding in noise and to enhance sound quality by providing a more "natural" impression, which especially becomes obvious when listening to music. The benefits of deep insertion should not, however, be compromised by structural damage during insertion. The small cross section and the high flexibility of the new electrodes can help to ensure less traumatic insertions as demonstrated by patients' hearing preservation rate. This article is part of a Special Issue entitled . PMID- 25456090 TI - Disparities in auditory physiology and pathology between C57BL/6J and C57BL/6N substrains. AB - C57BL/6 inbred mice are frequently used as models in auditory research, mostly the C57BL/6J and C57BL/6N substrains. Genetic variation and phenotypic disparities between these two substrains have been extensively investigated, but conflicting information exists about differences in their auditory and vestibular phenotypes. Literature-based comparisons are rendered difficult or impossible because most auditory publications do not designate the substrain used. We therefore evaluated commercial C57BL/6N and C57BL/6J mice for their baseline auditory brainstem response (ABR) thresholds at 3 months of age as well as their susceptibility to noise exposure and aminoglycoside antibiotics. Both substrains have similar thresholds at 4 and 12 kHz, but C57BL/6N show significantly higher baseline thresholds at 24 and 32 kHz. Because of these elevated thresholds, the N substrain is unsuitable as a model for drug ototoxicity, which primarily affects high frequencies. Exposure to 2-20 kHz broadband noise for 2 h at 110 dB produced significantly higher threshold shifts in the J substrain. These results suggest caution in the selection of C57BL/6 substrains for auditory research and indicate the need to specify substrains, age and the breeding source in all publications. PMID- 25456092 TI - African American cocaine users' preferred treatment site: variations by rural/urban residence, stigma, and treatment effectiveness. AB - To encourage access, policy makers and providers need information about variations in drug users' treatment preferences. This study examined how rural/urban residence, stigma surrounding drug use, and perceived treatment availability and effectiveness are associated with African American cocaine users' preferences for the site of treatment (local, or in one's home town; nearby, or in a town nearby; and distant, or in a town farther away). Two hundred rural and 200 urban cocaine users were recruited using respondent-driven sampling and completed in-person interviews. Multinomial logit regression analyses were conducted to estimate the relative odds of preferring local vs. nearby and local vs. distant treatment. Rural cocaine users preferred distant (58%), and urban users preferred local (57%) treatment. Rural residence and a lifetime history of treatment were associated with higher odds of preferring nearby vs. local treatment; older age and greater perceived local treatment effectiveness were associated with lower odds of preferring nearby vs. local treatment. Rural residence, access to an automobile, higher rejection/discrimination stigma scores, and higher Brief Symptom Inventory-Global Severity Index scores were associated with higher odds of preferring distant vs. local treatment; older age, lower educational attainment, and greater perceived discrimination after treatment were associated with lower odds of preferring distant vs. local treatment. The findings from this study suggest that a regional approach to organizing drug use treatment services could better satisfy the preferences of rural African American cocaine users, whereas local treatment services should be expanded to meet the needs of urban cocaine users. PMID- 25456093 TI - Opioid addicted buprenorphine injectors: drug use during and after 12-weeks of buprenorphine-naloxone or methadone in the Republic of Georgia. AB - AIMS: The aim of this study is to assess the prevalence of non-opioid drug use among opioid-addicted, buprenorphine injecting individuals in Georgia, during and after a 12-week course of buprenorphine-naloxone (Suboxone(r)) or methadone. METHODS: Randomized controlled trial with daily observed Suboxone(r) or methadone and weekly counseling, urine tests and timeline followback (TLFB) in weeks 0-12 and 20, and the Addiction Severity Index (ASI) at weeks 0, 4, 8, 12, 20. RESULTS: Of the 80 patients (40/group, 4 women), 68 (85%) completed the 12-weeks of study treatment and 66 (82.5%) completed the 20-week follow-up. At baseline, injecting more than one drug in the last 30 days was reported by 68.4% of patients in the methadone and 72.5% in the Suboxone(r) groups. Drug use was markedly reduced in both treatment conditions but there were significant differences in the prevalence of specific drugs with more opioid (1.5 vs. 0.2%; p=0.03), less amphetamine (0.2 vs. 2.8%; p<0.001) and less marijuana (1.7 vs. 10.2%; p<0.001) positive urine tests in the methadone vs. Suboxone(r) groups. At the 20-week follow-up, TLFB results on the 34 that continued methadone or the 3 on Suboxone(r) showed less opioid (5.6 vs. 27.6%; p<0.001), illicit buprenorphine (2.7 vs. 13.8%; p=0.005), benzodiazepine (13.5 vs. 34.5%; p<0.001), and marijuana (2.8 vs. 20.7%; p<0.001) use than the 29 who did not continue opioid substitution therapy. CONCLUSIONS: Despite small but significant differences in opioid and other drug use, both treatments were highly effective in reducing opioid and non opioid drug use. PMID- 25456091 TI - Effect of an organizational linkage intervention on staff perceptions of medication-assisted treatment and referral intentions in community corrections. AB - INTRODUCTION: Medication-assisted treatment (MAT) is effective for alcohol and opioid use disorders but it is stigmatized and underutilized in criminal justice settings. METHODS: This study cluster-randomized 20 community corrections sites to determine whether an experimental implementation strategy of training and an organizational linkage intervention improved staff perceptions of MAT and referral intentions more than training alone. The 3-hour training was designed to address deficits in knowledge, perceptions and referral information, and the organizational linkage intervention brought together community corrections and addiction treatment agencies in an interagency strategic planning and implementation process over 12 months. RESULTS: Although training alone was associated with increases in familiarity with pharmacotherapy and knowledge of where to refer clients, the experimental intervention produced significantly greater improvements in functional attitudes (e.g. that MAT is helpful to clients) and referral intentions. Corrections staff demonstrated greater improvements in functional perceptions and intent to refer opioid dependent clients for MAT than did treatment staff. CONCLUSION: Knowledge, perceptions and information training plus interorganizational strategic planning intervention is an effective means to change attitudes and intent to refer clients for medication assisted treatment in community corrections settings, especially among corrections staff. PMID- 25456095 TI - Metabolic syndrome and risk of cancer: which link? AB - Metabolic syndrome (MS) is characterized by a group of metabolic disturbances which lead to an enhanced risk of cardiovascular diseases and type 2 diabetes mellitus. MS constitutes a preoccupant issue with elevated prevalence in the western countries and is often related with cancer development. Elucidating the mechanisms linking these two pathologies is, therefore, essential to identify potential therapeutic molecular targets for cancer treatment in MS patients. The main goals of this review are, to identify the relation between MS and cancer development, handling specifically each one of the main players on this process: insulin and IGF system, estrogen, pro-inflammatory cytokines and others; and, given that colorectal cancer is one of the most prevalent types of cancer in MS patients, we intend to particularly highlight the mechanisms that promote colorectal cancer development in MS individuals. Finally, we will also focus on the clinical implications of the presented mechanisms on cancer therapy and care. PMID- 25456094 TI - Effectiveness of the Treatment Readiness and Induction Program for increasing adolescent motivation for change. AB - Success in substance abuse treatment is improved by problem recognition, desire to seek help, and readiness to engage in treatment, all of which are important aspects of motivation. Interventions that facilitate these at treatment induction for adolescents are especially needed. The purpose of this study is to assess the effectiveness of TRIP (Treatment Readiness and Induction Program) in promoting treatment motivation. Data represent 519 adolescents from 6 residential programs who completed assessments at treatment intake (time 1) and 35 days after admission (time 2). The design consisted of a comparison sample (n=281) that had enrolled in treatment prior to implementation of TRIP (standard operating practice) and a sample of clients that had entered treatment after TRIP began and received standard operating practice enhanced by TRIP (n=238). Repeated measures ANCOVAs were conducted using each time 2 motivation scale as a dependent measure. Motivation scales were conceptualized as representing sequential stages of change. LISREL was used to test a structural model involving TRIP participation, gender, drug use severity, juvenile justice involvement, age, race-ethnicity, prior treatment, and urgency as predictors of the stages of treatment motivation. Compared to standard practice, adolescents receiving TRIP demonstrated greater gains in problem recognition, even after controlling for the other variables in the model. The model fit was adequate, with TRIP directly affecting problem recognition and indirectly affecting later stages of change (desire for help and treatment readiness). Future studies should examine which specific components of TRIP affect change in motivation. PMID- 25456097 TI - Leptin in nonalcoholic fatty liver disease: a narrative review. AB - Leptin, the first described adipokine, interplays with hepatic metabolism. The aim of this review was to summarize available data on the association between leptin and nonalcoholic fatty liver disease (NAFLD). Leptin has a potential dual action on NAFLD experimental models, exerting a possible anti-steatotic, but also a proinflammatory and profibrogenic action. Observational clinical studies have shown higher or similar leptin levels between simple steatosis and nonalcoholic steatohepatitis (NASH) compared with controls. Interventional studies showed that circulating leptin diminishes together with body mass index after successful weight loss following lifestyle modifications or bariatric surgery. Studies providing evidence for the effect of other medications on leptin levels in NAFLD populations are limited and of low power. Data from small studies claim that recombinant leptin administration had a possibly beneficial effect on steatosis, but not fibrosis, in NAFLD patients with hypoleptinemia. Although the aforementioned dual leptin action has not yet been validated in humans, leptin administration in NAFLD patients with normoleptinemia or hyperleptinemia is discouraged. Further well-controlled studies in cautiously selected populations are needed to elucidate whether leptin has any prognostic and therapeutic role in NAFLD patients. PMID- 25456096 TI - Association of soda consumption with subclinical cardiac remodeling in the Framingham heart study. AB - OBJECTIVE: Diet soda consumption increases cardiometabolic risk. The aim of this investigation was to assess the relations between self-reported soda consumption and subclinical cardiac remodeling. METHODS: We assessed the relations between self-reported soda consumption and left ventricular mass (LVM) and left atrial dimension (LAD) (both standardized within sex) in a sample of middle-aged attendees from the Framingham Heart Offspring cohort examination 5 and 6. RESULTS: The overall mean age was 55 years and 59% of the participants were women. Compared to non-consumers (n=1010), soda consumers (n=3192) had greater body weight (mean 86 vs. 82 kg among men, and 70 vs. 67 kg among women). Compared with non-consumers, age- and height-adjusted LAD was increased (standard deviation units) among soda consumers by 0.15 standard error 0.042, (p<0.001) for those drinking >0-7 diet soda (n=1023), -0.010 (0.043, p=0.82) for people drinking >0-7 regular soda (n=907), 0.22 (0.057, p<0.0001) for individuals consuming >7 diet soda (n=372), and 0.20 (0.092, p=0.034) for participants drinking >7 regular soda (n=116) per week. LVM was increased among participants consuming diet soda (p<0.05), but not in regular soda consumers (p>0.05). Upon adjustment for weight, however, all aforementioned associations were attenuated. CONCLUSION: The observed associations between soda consumption and LAD or LVM were likely related to the greater body weight of soda drinkers relative to non drinkers. PMID- 25456098 TI - Glucose-dependent leukocyte activation in patients with type 2 diabetes mellitus, familial combined hyperlipidemia and healthy controls. AB - BACKGROUND: Leukocyte activation has been associated with vascular complications in type 2 diabetes mellitus (T2DM). Hyperglycemia may be involved in this leukocyte activation. Our aim was to investigate the role of elevated glucose concentrations on leukocyte activation in patients with a wide range of insulin sensitivity. METHODS: Leukocyte activation was determined after ingestion of 75 gram glucose in subjects with T2DM, familial combined hyperlipidemia (FCH) and healthy controls. Leukocyte activation markers were measured by flow cytometry. Postprandial changes were calculated as the area under the curve (AUC), and the incremental area under the curve corrected for baseline values (dAUC). RESULTS: 51 Subjects (20 T2DM, 17 FCH and 14 controls) were included. Fasting neutrophil CD66b expression and CD66b-AUC were respectively 36% and 39% higher in T2DM patients than in controls (p=0.004 and p=0.003). Fasting neutrophil CD66b expression correlated positively with glucose-AUC (Spearman's rho 0.481, p<0.001) and HbA1c (rho 0.433, p=0.002). Although fasting monocyte CD11b expression was not significantly different between subjects, monocyte CD11b-AUC was 26% higher in T2DM than in controls (p=0.006). Similar trends were observed for FCH patients. Monocyte CD11b-dAUC correlated positively with glucose-AUC (rho 0.322, p=0.022) and HbA1c (rho 0.319, p=0.023). CONCLUSIONS: These data suggest that both acute and chronic hyperglycemia, associated with insulin resistance as seen in T2DM and FCH, are involved in the increased fasting and postprandial leukocyte activation observed in these conditions. PMID- 25456100 TI - Ebola virus disease: a highly fatal infectious disease reemerging in West Africa. AB - Ebolavirus can cause a highly fatal and panic-generating human disease which may jump from bats to other mammals and human. High viral loads in body fluids allow efficient transmission by contact. Lack of effective antivirals, vaccines and public health infrastructures in parts of Africa make it difficult to health workers to contain the outbreak. PMID- 25456099 TI - The effect of intensive glucose lowering therapy among major racial/ethnic groups in the Veterans Affairs Diabetes Trial. AB - OBJECTIVE: To examine the effect of intensive glycemic control on cardiovascular disease events (CVD) among the major race/ethnic groups in a post-hoc analysis of the VADT. MATERIALS AND METHODS: Participants included 1111 non-Hispanic Whites, 307 Hispanics and 306 non-Hispanic Blacks randomized to intensive or standard glucose treatment in VADT. Multivariable Cox proportional hazards models were constructed to assess the effect of intensive glucose treatment on CVD events among race/ethnic groups. RESULTS: Mean age was 60.4 years and median follow-up was 5.6 years. By design, modifiable risk factors were managed equally well in both treatment arms and only differed modestly between race/ethnic groups. HbA(1c) decreased significantly from baseline with intensive glucose treatment in each race/ethnic group, with a trend for a greater response in Hispanics (P=0.02 for overall comparison between groups). Intensive glucose treatment was associated with reduced risk of CVD events for Hispanics but not for others (hazard ratios ranged from 0.54 to 0.75 for Hispanics whereas they were consistently close to 1 for others). Sensitivity analyses with different definitions of race/ethnicity or limited to individuals free of previous known CVD yielded similar results. CONCLUSIONS: The results of these analyses support the hypothesis that race/ethnicity is worthy of consideration when tailoring intensive treatment for individuals with long-standing type 2 diabetes. However, additional studies are needed to confirm the findings of this post-hoc analysis. PMID- 25456102 TI - What should be the width of radiological margin to optimize resection of non palpable invasive or in situ ductal carcinoma? AB - PURPOSE: the aim of our study was to investigate whether there is radiological margin that optimize resection of non-palpable invasive or in situ ductal carcinoma. MATERIALS AND METHODS: Data were collected for all patients undergoing wire localization prior to therapeutic surgical excision between January 2010 and December 2013 at our institution. A 5 and 10-mm radiological margins were considered adequate for invasive ductal carcinoma (IDC) and in situ ductal carcinoma (DCIS) respectively. Clear histological margins were defined as no ink on the tumor for IDC and >=2 mm for DCIS. Data were analyzed both in order to assess accuracy of the technique and in order to determine what radiological threshold should be taken. RESULTS: Three hundred seventy seven women were included to the study. The radiological thresholds permitted negative histological margins in 94.7%, 60.9% and 80.9% in the pure invasive ductal carcinoma group (IDC, n = 133), the pure ductal carcinoma in situ group (DCIS, n = 92) and the mixed group (both IDC and DCIS, n = 152) respectively. In an ROC analysis evaluating the ability of radiological thresholds to obtain free pathological margins: the AUC was 0.79 (0.71-0.87, 95% confident interval, p = .0007) for Pure IDC group, 0.67 (0.57-0.87, 95% confident interval, p = .0005) for pure DCIS group, and 0.72 (0.62-0.80, 95% confident interval, p < .0001) for the mixed group. CONCLUSION: We found that a radiological margin of 10 mm is needed in presence of an in situ component and 5-mm radiological margin seems enough in case of pure IDC tumors. PMID- 25456101 TI - Development of human neutralizing monoclonal antibodies for prevention and therapy of MERS-CoV infections. AB - The recent Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak poses a serious threat to public health. Here, we summarize recent advances in identifying human neutralizing monoclonal antibodies (mAbs) against MERS-CoV, describe their mechanisms of action, and analyze their potential for treatment of MERS-CoV infections. PMID- 25456103 TI - Women's perceptions of breast cancer screening. Spanish screening programme survey. AB - OBJECTIVES: Participants in breast cancer screening programmes may benefit from early detection but may also be exposed to the risks of overdiagnosis and false positives. We surveyed a sample of Spanish women to assess knowledge, information sources, attitudes and psychosocial impact. MATERIALS AND METHODS: A total of 434 breast cancer screening programme participants aged 45-69 years were administered questionnaires regarding knowledge, information sources, attitudes and psychosocial impact. Scores of 5 or more (out of 10) and 12 or less (out of 24) were established as indicating adequate knowledge and a positive attitude, respectively. Psychosocial impact was measured using the Hospital Anxiety and Depression Scale and the Cancer Worry Scale. RESULTS: Only 42 women (9.7%) had adequate knowledge. The mean (SD) knowledge score was 2.97 (1.16). Better educated women and women without previous false positives had higher scores. The main sources of information were television, press, Andalusian Health Service documentation and family and friends. Most participants (99.1%) had a positive attitude, with a mean (SD) score of 3.21 (2.66). Mean (SD) scores for anxiety, depression and cancer worry were 1.86 (3.26), 0.72 (1.99) and 9.4 (3.04), respectively. CONCLUSION: Women have a very positive attitude to breast cancer screening, but are poorly informed and use television as their main information source. They experience no negative psychosocial impact from participation in such programmes. PMID- 25456104 TI - Does short-term fasting lead to stressed-out parents? A study of incubation commitment and the hormonal stress responses and recoveries in snow petrels. AB - The hormonal stress response is flexible and can be modulated by individuals according to its costs and benefits. Therefore, it is predicted that parents in poor body condition should modify their hormonal stress response, and thus, redirect energy allocation processes from parental care to self-maintenance when stressors occur. To test this prediction, most studies on free-living vertebrates have only focused on the stress response while the stress recovery - how quickly hormonal levels return to baseline values - has been neglected. Moreover, most studies have only focused on corticosterone - the primary mediator of allostasis without paying attention to prolactin despite its major role in mediating parental behaviors. Here, we examined the effect of a short-term fasting event on the corticosterone and prolactin stress responses and recoveries, and we subsequently explored their relationships with parental decision in the snow petrel (Pagodroma nivea). By comparing the hormonal profiles of fasting and non fasting snow petrels, we showed that parents modulate their corticosterone (but not prolactin) stress response according to their energetic status. We also described for the first time the hormonal stress recoveries in wild birds and found that they did not differ between fasting and non-fasting birds. Importantly, egg neglect was negatively correlated with circulating prolactin but not corticosterone levels in this species, demonstrating therefore a complex link between body condition, parental behavior and circulating corticosterone and prolactin levels. We suggest that both corticosterone and prolactin play a major role in the way parents adjust to stressors. This multiple signaling may allow parents to fine-tune their response to stressors, and especially, to activate specific allostasis-related mechanisms in a timely manner. PMID- 25456106 TI - A highly sensitive C3-symmetric Schiff-base fluorescent probe for Cd2+. AB - A new C3-symmetric Schiff-base fluorescent probe (L) based on 8-hydroxy-2 methylquinoline has been developed. As expected, the probe L can display high fluorescent selectivity for Cd(2+) over Zn(2+) and most other common ions in neutral ethanol aqueous medium. Moreover, the mechanism of the L-Cd(2+) complex has been confirmed by X-ray crystallography and density functional theory calculation results. More importantly, L could be used to image Cd(2+) within living cells. PMID- 25456105 TI - Cocaine-induced sensitization correlates with testosterone in male Japanese quail but not with estradiol in female Japanese quail. AB - Research has indicated that gonadal hormones may mediate behavioral and biological responses to cocaine. Estrogen, in particular, has been shown to increase behavioral responding to cocaine in female rats relative to male rats. The current study investigated the effect of cocaine on locomotor activity and hormonal correlates in male and female Japanese quail (Coturnix japonica). In Japanese quail, circulating hormone levels can be manipulated without surgical alterations via modifying the photoperiod. Male and female quail were housed on either 8L:16D (light:dark) or 16L:8D (light:dark) cycle for 21days. Blood samples were taken prior to the beginning of the experiment and assays were performed to determine the levels of testosterone (T) and estradiol (E2). Quail were given injections of saline or cocaine (10 or 20mg/kg) once a day for 10days. Immediately after each injection, birds were placed in open field arenas and distance traveled was measured for 30min. Results showed that male quail housed under long-light conditions exhibited cocaine-induced sensitization to 10mg/kg cocaine which was correlated with the high levels of plasma T. Female quail housed under short-light conditions demonstrated sensitization to 10mg/kg cocaine, but this was not correlated with the levels of plasma E2. The current findings suggest that cocaine-induced locomotor activity was associated with T in males but not with E2 in females. PMID- 25456107 TI - Acute parvovirus B19 infection in adults. PMID- 25456108 TI - Response to "acute parvovirus B19 infection in adults: a retrospective study of 49 cases". PMID- 25456109 TI - Models of melanoma spread and final results of the Multicenter Selective Lymphadenectomy Trial-I. PMID- 25456110 TI - Herpes zoster in children vaccinated against varicella-zoster virus: experience in our hospital. PMID- 25456111 TI - Phrynoderma after biliopancreatic diversion. PMID- 25456112 TI - Prognostic value of biomarkers in metastatic colorectal cancer patients. AB - BACKGROUNDS: The prognostic value of biomarkers in metastatic colorectal cancer (mCRC) patients with liver metastases remains unclear. We assessed the difference of expression of biomarkers between primary tumors and liver metastases treated with chemotherapy in mCRC patients, as well as the prognostic value of these markers. METHODS: Forty-three mCRC patients with liver-limited disease from January 2007-November 2011 were analyzed. They all received resection of primary tumors followed by oxaliplatin-based chemotherapy. After chemotherapy, they all received hepatic resection. Forty-three paired primary and metastatic tumor specimens were collected to measure the messenger RNA expression of six biomarkers by the Danenberg tumor profile method (thymidylate synthase, dihydropyrimidine dehydrogenase [DPD], excision repair cross-complementing gene1, thymidine phosphorylase [TP], folylpolyglutamate synthase, and regenerating islet derived family, member 4). RESULTS: Thirty-six patients' messenger RNA was used for analysis. All markers showed similar expression between primary and metastatic sites. The low-expression group of Danenberg tumor profile and TP in the primary tumor showed significantly higher overall survival than the high expression group (P < 0.001 and P = 0.033), but for DPD and TP in liver metastases, there were no significant differences of overall survival between the two groups. The ratios of marker expression in liver metastatic site to that in primary site of DPD and TP were significantly higher in chemo-responders than in non-chemo-responders (P = 0.034 and P = 0.022). CONCLUSIONS: Biomarkers' expressions in liver metastases were similar to those in the primary tumor. DPD and TP in the primary lesion may be a prognostic factor in chemotherapy-naive mCRC patients with liver-limited disease, but those in liver tumor were not. Further validated analysis to our results would be warranted. PMID- 25456113 TI - Clinical benefits of aortic cross-clamping versus limb remote ischemic preconditioning in coronary artery bypass grafting with cardiopulmonary bypass: a meta-analysis of randomized controlled trials. AB - BACKGROUND: We assessed whether aortic cross-clamping or limb remote ischemic preconditioning improved postoperative outcomes, reduced myocardial injury and incidences of postoperative complications in patients undergoing on-pump coronary artery bypass grafting (CABG). MATERIALS AND METHODS: PubMed, EMBASE, the Cochrane Library, and ClinicalTrials databases were searched for studies comparing the effects of ischemic preconditioning with no preconditioning in adult patients undergoing on-pump CABG. The primary end points were mechanical ventilation time, the length of stay in intensive care unit and hospital, whereas the secondary end points were peak values of myocardial biomarkers and postoperative complications. Mean differences were estimated for the primary end points, as well as standard mean differences and odds ratios for the secondary end points. RESULTS: A total of 29 randomized controlled trials with 1791 patients were included. Compared with control group, aortic cross-clamping preconditioning reduced mechanical ventilation time (mean difference [95% confidence interval {CI}]) (-5.59 h [-9.21 to -1.96]), whereas limb remote ischemic preconditioning was not associated with improvement of postoperative outcomes. For myocardial biomarkers, both aortic cross-clamping and limb remote ischemic preconditioning reduced peak values of myocardial biomarkers (standard mean difference [95% CI]) (-0.48 [-0.81 to -0.14]; -0.19 [-0.36 to -0.02], respectively). Subgroup analysis showed that aortic cross-clamping preconditioning protocols with ischemia episodes <5 min did reduce the release of biomarkers (-0.69 [-1.04 to -0.34]) but those with 5 min ischemia episodes elevated them (0.40 [0.04-0.75]). Cardiovascular, cerebrovascular, renal, and intestinal complications were reported, and aortic cross-clamping preconditioning seemed to reduce the incidences of cardiac arrhythmia (odds ratio [95% CI]) (0.46 [0.27-0.80], P = 0.006). CONCLUSIONS: Cardiac surgeons could consider aortic cross-clamping or limb remote ischemic preconditioning to reduce myocardial injury during CABG. Moreover, aortic cross-clamping preconditioning is associated with a decreased risk of postoperative respiratory failure and cardiac arrhythmia. PMID- 25456114 TI - Morphomic analysis as an aid for preoperative risk stratification in patients undergoing major head and neck cancer surgery. AB - BACKGROUND: Patients undergoing major head and neck cancer surgery (MHNCS) may develop significant postoperative complications. To minimize the risk of complications, clinicians often assess multiple measures of preoperative health in terms of medical comorbidities. One emerging method to decrease surgical complications is preoperative assessment of patient frailty measured by specific tissue characteristics. We hypothesize that morphomic characteristics of the temporalis region serve as predictive markers for the development of complications after MHNCS. METHODS: We performed a retrospective review of 69 patients with available computed tomography (CT) imaging who underwent MHNCS from 2006-2012. To measure temporalis region characteristics, we used morphomic analysis of available preoperative CT scans to map out the region. All available CT scans had been performed as part of the patient's routine work-up and were not ordered for morphomic analysis. We describe the correlation among temporalis fat pad volume (TFPV), mean zygomatic arch thickness, and incidence of postoperative complications. RESULTS: We noted significant difference in the zygomatic bone thickness and TFPV between patients who had medical complications, surgical complications, or total major complications and those who did not. Furthermore, by use of binary logistic regression, our data suggest decreased TFPV and zygomatic arch thickness are stronger predictors of developing postoperative complications than previously studies preoperative characteristics. CONCLUSIONS: We describe morphomic analysis of the temporalis region in patients undergoing MHNCS to identify patients at risk for complications. Regional anatomic morphology may serve as a marker to objectively determine a patient's overall health. Use of the temporalis region is appropriate in patients undergoing MHNCS because of the availability of preoperative scans as part of routine work up for head and/or neck cancer. PMID- 25456116 TI - Effects of dexmedetomidine on patients undergoing radical gastrectomy. AB - BACKGROUND: Surgical stress may cause immunosuppression especially in patients who have surgery for primary tumor removed. This study aimed to explore the effects of dexmedetomidine on immune and inflammatory response in patients undergoing radical gastrectomy. METHODS: After the institutional review board approval and written informed consent, forty patients undergoing radical gastrectomy were equally randomized to receive dexmedetomidine infusion (Dex group; 0.5 MUg . kg(-1) initial dose followed by a maintenance dose of 0.4 MUg . kg(-1) h(-1)) or normal saline infusion (NS group). Helper T lymphocytes (T helper 1 [Th1] and T helper 2 [Th2]), tumor necrosis factor-alpha, and interleukin-6 were measured during and after surgeries. Plasma catecholamine levels were also measured during surgery. Postoperative pain was measured by a visual analog scale. RESULTS: The percentage of Th1 increased significantly at the end of surgery, 24 h after surgery (P = 0.045 and 0.048, respectively), and Th2 decreased notably at the end of surgery in the Dex group (P = 0.030). Plasma levels of tumor necrosis factor-alpha (P = 0.045 and 0.036, respectively) and interleukin-6 (P = 0.049 and 0.042, respectively) differed significantly at the end of surgery and 24 h after surgery. Plasma epinephrine and norepinephrine levels decreased significantly at the beginning of surgery in the Dex group (P = 0.020 and 0.015, respectively). At the end of surgery, plasma dopamine levels decreased significantly in the Dex group (P = 0.048), but increased in the NS group. The visual analog scale pain score was lower in the Dex group than in the NS group 24 h after surgery (P = 0.046). CONCLUSIONS: Dexmedetomidine has been shown to reduce surgical stresses and maintain Th1/Th2 balance. It has been shown to reduce inflammatory responses and exerts immunoprotective effect. PMID- 25456115 TI - Adenosine monophosphate-activated protein kinase activation protects against sepsis-induced organ injury and inflammation. AB - BACKGROUND: Mortality in sepsis is most often attributed to the development of multiple organ failure. In sepsis, inflammation-mediated endothelial activation, defined as a proinflammatory and procoagulant state of the endothelial cells, has been associated with severity of disease. Thus, the objective of this study was to test the hypothesis that adenosine monophosphate-activated protein kinase (AMPK) activation limits inflammation and endothelium activation to protect against organ injury in sepsis. 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), which is an adenosine monophosphate analog, has been used to upregulate activity of AMPK. Compound C is a cell-permeable pyrrazolopyrimidine compound that inhibits AMPK activity. METHODS: Wild-type mice underwent cecal ligation and puncture (CLP) or sham surgery. Mice were randomized to vehicle, AICAR, or compound C. Mouse kidney endothelial cells were used for in vitro experiments. Renal and liver function were determined by serum cystatin C, blood urea nitrogen (BUN), creatinine, and alanine aminotransferase. Serum cytokines were measured by enzyme-linked immunosorbent assay. Microvascular injury was determined using Evans blue dye and electron microscopy. Immunohistochemistry was used to measure protein levels of phospho-AMPK (p-AMPK), microtubule-associated protein 1A/1B light chain 3 (LC3), and intracellular adhesion molecule. LC3 levels were used as a measure of autophagosome formation. RESULTS: AICAR decreased liver and kidney injury induced by CLP and minimized cytokine elevation in vivo and in vitro. CLP increased renal and hepatic phosphorylation of AMPK and autophagic signaling as determined by LC3. Inhibition of AMPK with compound C prevented CLP-induced autophagy and exacerbated tissue injury. Additionally, CLP led to endothelial injury as determined by electron microscopy and Evans blue dye extravasation, and AICAR limited this injury. Furthermore, AICAR limited CLP and lipopolysaccharide (LPS)-induced upregulation of intracellular adhesion molecule in vivo and in vitro and decreased LPS-induced neutrophil adhesion in vitro. CONCLUSIONS: In this model, activation of AMPK was protective, and AICAR minimized organ injury by decreasing inflammatory cytokines and endothelial activation. These data suggest that AMPK signaling influences sepsis or LPS-induced endothelial activation and organ injury. PMID- 25456121 TI - A simple method for 3D analysis of immunolabeled axonal tracts in a transparent nervous system. AB - Clearing techniques have been developed to transparentize mouse brains, thereby preserving 3D structure, but their complexity has limited their use. Here, we show that immunolabeling of axonal tracts followed by optical clearing with solvents (3DISCO) and light-sheet microscopy reveals brain connectivity in mouse embryos and postnatal brains. We show that the Robo3 receptor is selectively expressed by medial habenula axons forming the fasciculus retroflexus (FR) and analyzed the development of this commissural tract in mutants of the Slit/Robo and DCC/Netrin pathways. Netrin-1 and DCC are required to attract FR axons to the midline, but the two mutants exhibit specific and heterogeneous axon guidance defects. Moreover, floor-plate-specific deletion of Slit ligands with a conditional Slit2 allele perturbs not only midline crossing by FR axons but also their anteroposterior distribution. In conclusion, this method represents a unique and powerful imaging tool to study axonal connectivity in mutant mice. PMID- 25456120 TI - iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson's disease. AB - Parkinson's disease (PD) has been attributed to a combination of genetic and nongenetic factors. We studied a set of monozygotic twins harboring the heterozygous glucocerebrosidase mutation (GBA N370S) but clinically discordant for PD. We applied induced pluripotent stem cell (iPSC) technology for PD disease modeling using the twins' fibroblasts to evaluate and dissect the genetic and nongenetic contributions. Utilizing fluorescence-activated cell sorting, we obtained a homogenous population of "footprint-free" iPSC-derived midbrain dopaminergic (mDA) neurons. The mDA neurons from both twins had ~50% GBA enzymatic activity, ~3-fold elevated alpha-synuclein protein levels, and a reduced capacity to synthesize and release dopamine. Interestingly, the affected twin's neurons showed an even lower dopamine level, increased monoamine oxidase B (MAO-B) expression, and impaired intrinsic network activity. Overexpression of wild-type GBA and treatment with MAO-B inhibitors normalized alpha-synuclein and dopamine levels, suggesting a combination therapy for the affected twin. PMID- 25456122 TI - Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. AB - It has long been speculated that metabolites, produced by gut microbiota, influence host metabolism in health and diseases. Here, we reveal that indole, a metabolite produced from the dissimilation of tryptophan, is able to modulate the secretion of glucagon-like peptide-1 (GLP-1) from immortalized and primary mouse colonic L cells. Indole increased GLP-1 release during short exposures, but it reduced secretion over longer periods. These effects were attributed to the ability of indole to affect two key molecular mechanisms in L cells. On the one hand, indole inhibited voltage-gated K(+) channels, increased the temporal width of action potentials fired by L cells, and led to enhanced Ca(2+) entry, thereby acutely stimulating GLP-1 secretion. On the other hand, indole slowed ATP production by blocking NADH dehydrogenase, thus leading to a prolonged reduction of GLP-1 secretion. Our results identify indole as a signaling molecule by which gut microbiota communicate with L cells and influence host metabolism. PMID- 25456123 TI - Hormone-induced calcium oscillations depend on cross-coupling with inositol 1,4,5 trisphosphate oscillations. AB - Receptor-mediated oscillations in cytosolic Ca(2+) concentration ([Ca(2+)]i) could originate either directly from an autonomous Ca(2+) feedback oscillator at the inositol 1,4,5-trisphosphate (IP3) receptor or as a secondary consequence of IP3 oscillations driven by Ca(2+) feedback on IP3 metabolism. It is challenging to discriminate these alternatives, because IP3 fluctuations could drive Ca(2+) oscillations or could just be a secondary response to the [Ca(2+)]i spikes. To investigate this problem, we constructed a recombinant IP3 buffer using type-I IP3 receptor ligand-binding domain fused to GFP (GFP-LBD), which buffers IP3 in the physiological range. This IP3 buffer slows hormone-induced [IP3] dynamics without changing steady-state [IP3]. GFP-LBD perturbed [Ca(2+)]i oscillations in a dose-dependent manner: it decreased both the rate of [Ca(2+)]i rise and the speed of Ca(2+) wave propagation and, at high levels, abolished [Ca(2+)]i oscillations completely. These data, together with computational modeling, demonstrate that IP3 dynamics play a fundamental role in generating [Ca(2+)]i oscillations and waves. PMID- 25456124 TI - Simple and rapid in vivo generation of chromosomal rearrangements using CRISPR/Cas9 technology. AB - Generation of genetically engineered mouse models (GEMMs) for chromosomal translocations in the endogenous loci by a knockin strategy is lengthy and costly. The CRISPR/Cas9 system provides an innovative and flexible approach for genome engineering of genomic loci in vitro and in vivo. Here, we report the use of the CRISPR/Cas9 system for engineering a specific chromosomal translocation in adult mice in vivo. We designed CRISPR/Cas9 lentiviral vectors to induce cleavage of the murine endogenous Eml4 and Alk loci in order to generate the Eml4-Alk gene rearrangement recurrently found in non-small-cell lung cancers (NSCLCs). Intratracheal or intrapulmonary inoculation of lentiviruses induced Eml4-Alk gene rearrangement in lung cells in vivo. Genomic and mRNA sequencing confirmed the genome editing and the production of the Eml4-Alk fusion transcript. All mice developed Eml4-Alk-rearranged lung tumors 2 months after the inoculation, demonstrating that the CRISPR/Cas9 system is a feasible and simple method for the generation of chromosomal rearrangements in vivo. PMID- 25456126 TI - Independent component analysis uncovers the landscape of the bladder tumor transcriptome and reveals insights into luminal and basal subtypes. AB - Extracting relevant information from large-scale data offers unprecedented opportunities in cancerology. We applied independent component analysis (ICA) to bladder cancer transcriptome data sets and interpreted the components using gene enrichment analysis and tumor-associated molecular, clinicopathological, and processing information. We identified components associated with biological processes of tumor cells or the tumor microenvironment, and other components revealed technical biases. Applying ICA to nine cancer types identified cancer shared and bladder-cancer-specific components. We characterized the luminal and basal-like subtypes of muscle-invasive bladder cancers according to the components identified. The study of the urothelial differentiation component, specific to the luminal subtypes, showed that a molecular urothelial differentiation program was maintained even in those luminal tumors that had lost morphological differentiation. Study of the genomic alterations associated with this component coupled with functional studies revealed a protumorigenic role for PPARG in luminal tumors. Our results support the inclusion of ICA in the exploitation of multiscale data sets. PMID- 25456127 TI - Hematopoietic stem cells are intrinsically protected against MLL-ENL-mediated transformation. AB - Studies of developmental pathways of hematopoietic stem cells (HSCs) have defined lineage relationships throughout the blood system. This is relevant to acute myeloid leukemia (AML), where aggressiveness and therapeutic responsiveness can be influenced by the initial stage of transformation. To address this, we generated a mouse model in which the mixed-lineage leukemia/eleven-nineteen leukemia (MLL-ENL) transcription factor can be conditionally activated in any cell type. We show that AML can originate from multiple hematopoietic progenitor subsets with granulocytic and monocytic potential, and that the normal developmental position of leukemia-initiating cells influences leukemic development. However, disease failed to arise from HSCs. Although it maintained or upregulated the expression of target genes associated with leukemic development, MLL-ENL dysregulated the proliferative and repopulating capacity of HSCs. Therefore, the permissiveness for development of AML may be associated with a narrower window of differentiation than was previously appreciated, and hijacking the self-renewal capacity of HSCs by a potent oncogene is insufficient for leukemic development. PMID- 25456125 TI - Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes. AB - Somatic mutations in cancer are more frequent in heterochromatic and late replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC(-/-) background. XPC(-/-) cells lack global genome nucleotide excision repair (GG NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk. PMID- 25456128 TI - An active role for the ribosome in determining the fate of oxidized mRNA. AB - Chemical damage to RNA affects its functional properties and thus may pose a significant hurdle to the translational apparatus; however, the effects of damaged mRNA on the speed and accuracy of the decoding process and their interplay with quality-control processes are not known. Here, we systematically explore the effects of oxidative damage on the decoding process using a well defined bacterial in vitro translation system. We find that the oxidative lesion 8-oxoguanosine (8-oxoG) reduces the rate of peptide-bond formation by more than three orders of magnitude independent of its position within the codon. Interestingly, 8-oxoG had little effect on the fidelity of the selection process, suggesting that the modification stalls the translational machinery. Consistent with these findings, 8-oxoG mRNAs were observed to accumulate and associate with polyribosomes in yeast strains in which no-go decay is compromised. Our data provide compelling evidence that mRNA-surveillance mechanisms have evolved to cope with damaged mRNA. PMID- 25456129 TI - Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation. AB - The paracaspase Malt1 is a central regulator of antigen receptor signaling that is frequently mutated in human lymphoma. As a scaffold, it assembles protein complexes for NF-kappaB activation, and its proteolytic domain cleaves negative NF-kappaB regulators for signal enforcement. Still, the physiological functions of Malt1-protease are unknown. We demonstrate that targeted Malt1-paracaspase inactivation induces a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration in vivo. Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-kappaB inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2, and Regnase-1, and paracaspase inactivation results in excessive interferon gamma (IFNgamma) production by effector lymphocytes that drive pathology. Together, our results reveal distinct threshold and modulatory functions of Malt1 that differentially control lymphocyte differentiation and activation pathways and demonstrate that selective paracaspase blockage skews systemic immunity toward destructive autoinflammation. PMID- 25456131 TI - JNK suppresses tumor formation via a gene-expression program mediated by ATF2. AB - JNK and p38 phosphorylate a diverse set of substrates and, consequently, can act in a context-dependent manner to either promote or inhibit tumor growth. Elucidating the functions of specific substrates of JNK and p38 is therefore critical for our understanding of these kinases in cancer. ATF2 is a phosphorylation-dependent transcription factor and substrate of both JNK and p38. Here, we show ATF2 suppresses tumor formation in an orthotopic model of liver cancer and cellular transformation in vitro. Furthermore, we find that suppression of tumorigenesis by JNK requires ATF2. We identify a transcriptional program activated by JNK via ATF2 and provide examples of JNK- and ATF2-dependent genes that block cellular transformation. Significantly, we also show that ATF2 dependent gene expression is frequently downregulated in human cancers, indicating that amelioration of JNK-ATF2-mediated suppression may be a common event during tumor development. PMID- 25456132 TI - Parallel in vivo and in vitro melanoma RNAi dropout screens reveal synthetic lethality between hypoxia and DNA damage response inhibition. AB - To identify factors preferentially necessary for driving tumor expansion, we performed parallel in vitro and in vivo negative-selection short hairpin RNA (shRNA) screens. Melanoma cells harboring shRNAs targeting several DNA damage response (DDR) kinases had a greater selective disadvantage in vivo than in vitro, indicating an essential contribution of these factors during tumor expansion. In growing tumors, DDR kinases were activated following hypoxia. Correspondingly, depletion or pharmacologic inhibition of DDR kinases was toxic to melanoma cells, including those that were resistant to BRAF inhibitor, and this could be enhanced by angiogenesis blockade. These results reveal that hypoxia sensitizes melanomas to targeted inhibition of the DDR and illustrate the utility of in vivo shRNA dropout screens for the identification of pharmacologically tractable targets. PMID- 25456130 TI - Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis. AB - Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis. PMID- 25456133 TI - Nonenzymatic role for WRN in preserving nascent DNA strands after replication stress. AB - WRN, the protein defective in Werner syndrome (WS), is a multifunctional nuclease involved in DNA damage repair, replication, and genome stability maintenance. It was assumed that the nuclease activities of WRN were critical for these functions. Here, we report a nonenzymatic role for WRN in preserving nascent DNA strands following replication stress. We found that lack of WRN led to shortening of nascent DNA strands after replication stress. Furthermore, we discovered that the exonuclease activity of MRE11 was responsible for the shortening of newly replicated DNA in the absence of WRN. Mechanistically, the N-terminal FHA domain of NBS1 recruits WRN to replication-associated DNA double-stranded breaks to stabilize Rad51 and to limit the nuclease activity of its C-terminal binding partner MRE11. Thus, this previously unrecognized nonenzymatic function of WRN in the stabilization of nascent DNA strands sheds light on the molecular reason for the origin of genome instability in WS individuals. PMID- 25456134 TI - FXR1P limits long-term memory, long-lasting synaptic potentiation, and de novo GluA2 translation. AB - Translational control of mRNAs allows for rapid and selective changes in synaptic protein expression that are required for long-lasting plasticity and memory formation in the brain. Fragile X Related Protein 1 (FXR1P) is an RNA-binding protein that controls mRNA translation in nonneuronal cells and colocalizes with translational machinery in neurons. However, its neuronal mRNA targets and role in the brain are unknown. Here, we demonstrate that removal of FXR1P from the forebrain of postnatal mice selectively enhances long-term storage of spatial memories, hippocampal late-phase long-term potentiation (L-LTP), and de novo GluA2 synthesis. Furthermore, FXR1P binds specifically to the 5' UTR of GluA2 mRNA to repress translation and limit the amount of GluA2 that is incorporated at potentiated synapses. This study uncovers a mechanism for regulating long-lasting synaptic plasticity and spatial memory formation and reveals an unexpected divergent role of FXR1P among Fragile X proteins in brain plasticity. PMID- 25456136 TI - Repulsive guidance molecule-a is involved in Th17-cell-induced neurodegeneration in autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammation, demyelination, and neurodegeneration in the CNS. Although it is important to prevent neurodegeneration for alleviating neurological disability, the molecular mechanism of neurodegeneration remains largely unknown. Here, we report that repulsive guidance molecule-a (RGMa), known to regulate axonal growth, is associated with neurodegeneration in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. RGMa is highly expressed in interleukin-17-producing CD4(+) T cells (Th17 cells). We induced EAE by adoptive transfer of myelin oligodendrocyte glycoprotein (MOG)-specific Th17 cells and then inhibited RGMa with a neutralizing antibody. Inhibition of RGMa improves EAE scores and reduces neuronal degeneration without altering immune or glial responses. Th17 cells induce cultured cortical neuron death through RGMa-neogenin and Akt dephosphorylation. Our results demonstrate that RGMa is involved in Th17 cell-mediated neurodegeneration and that RGMa-specific antibody may have a therapeutic effect in MS. PMID- 25456135 TI - Identification of Ppk26, a DEG/ENaC Channel Functioning with Ppk1 in a Mutually Dependent Manner to Guide Locomotion Behavior in Drosophila. AB - A major gap in our understanding of sensation is how a single sensory neuron can differentially respond to a multitude of different stimuli (polymodality), such as propio- or nocisensation. The prevailing hypothesis is that different stimuli are transduced through ion channels with diverse properties and subunit composition. In a screen for ion channel genes expressed in polymodal nociceptive neurons, we identified Ppk26, a member of the trimeric degenerin/epithelial sodium channel (DEG/ENaC) family, as being necessary for proper locomotion behavior in Drosophila larvae in a mutually dependent fashion with coexpressed Ppk1, another member of the same family. Mutants lacking Ppk1 and Ppk26 were defective in mechanical, but not thermal, nociception behavior. Mutants of Piezo, a channel involved in mechanical nociception in the same neurons, did not show a defect in locomotion, suggesting distinct molecular machinery for mediating locomotor feedback and mechanical nociception. PMID- 25456138 TI - Distinct Roles for JNK and IKK Activation in Agouti-Related Peptide Neurons in the Development of Obesity and Insulin Resistance. AB - Activation of c-Jun N-terminal kinase 1 (JNK1)- and inhibitor of nuclear factor kappa-B kinase 2 (IKK2)-dependent signaling plays a crucial role in the development of obesity-associated insulin and leptin resistance not only in peripheral tissues but also in the CNS. Here, we demonstrate that constitutive JNK activation in agouti-related peptide (AgRP)-expressing neurons of the hypothalamus is sufficient to induce weight gain and adiposity in mice as a consequence of hyperphagia. JNK activation increases spontaneous action potential firing of AgRP cells and causes both neuronal and systemic leptin resistance. Similarly, activation of IKK2 signaling in AgRP neurons also increases firing of these cells but fails to cause obesity and leptin resistance. In contrast to JNK activation, IKK2 activation blunts insulin signaling in AgRP neurons and impairs systemic glucose homeostasis. Collectively, these experiments reveal both overlapping and nonredundant effects of JNK- and IKK-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome. PMID- 25456137 TI - The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. AB - The ADAR RNA-editing enzymes deaminate adenosine bases to inosines in cellular RNAs. Aberrant interferon expression occurs in patients in whom ADAR1 mutations cause Aicardi-Goutieres syndrome (AGS) or dystonia arising from striatal neurodegeneration. Adar1 mutant mouse embryos show aberrant interferon induction and die by embryonic day E12.5. We demonstrate that Adar1 embryonic lethality is rescued to live birth in Adar1; Mavs double mutants in which the antiviral interferon induction response to cytoplasmic double-stranded RNA (dsRNA) is prevented. Aberrant immune responses in Adar1 mutant mouse embryo fibroblasts are dramatically reduced by restoring the expression of editing-active cytoplasmic ADARs. We propose that inosine in cellular RNA inhibits antiviral inflammatory and interferon responses by altering RLR interactions. Transfecting dsRNA oligonucleotides containing inosine-uracil base pairs into Adar1 mutant mouse embryo fibroblasts reduces the aberrant innate immune response. ADAR1 mutations causing AGS affect the activity of the interferon-inducible cytoplasmic isoform more severely than the nuclear isoform. PMID- 25456139 TI - Characterization of the usage of the serine metabolic network in human cancer. AB - The serine, glycine, one-carbon (SGOC) metabolic network is implicated in cancer pathogenesis, but its general functions are unknown. We carried out a computational reconstruction of the SGOC network and then characterized its expression across thousands of cancer tissues. Pathways including methylation and redox metabolism exhibited heterogeneous expression indicating a strong context dependency of their usage in tumors. From an analysis of coexpression, simultaneous up- or downregulation of nucleotide synthesis, NADPH, and glutathione synthesis was found to be a common occurrence in all cancers. Finally, we developed a method to trace the metabolic fate of serine using stable isotopes, high-resolution mass spectrometry, and a mathematical model. Although the expression of single genes didn't appear indicative of flux, the collective expression of several genes in a given pathway allowed for successful flux prediction. Altogether, these findings identify expansive and heterogeneous functions for the SGOC metabolic network in human cancer. PMID- 25456140 TI - Principles of bacterial cell-size determination revealed by cell-wall synthesis perturbations. AB - Although bacterial cell morphology is tightly controlled, the principles of size regulation remain elusive. In Escherichia coli, perturbation of cell-wall synthesis often results in similar morphologies, making it difficult to deconvolve the complex genotype-phenotype relationships underlying morphogenesis. Here we modulated cell width through heterologous expression of sequences encoding the essential enzyme PBP2 and through sublethal treatments with drugs that inhibit PBP2 and the MreB cytoskeleton. We quantified the biochemical and biophysical properties of the cell wall across a wide range of cell sizes. We find that, although cell-wall chemical composition is unaltered, MreB dynamics, cell twisting, and cellular mechanics exhibit systematic large-scale changes consistent with altered chirality and a more isotropic cell wall. This multiscale analysis enabled identification of distinct roles for MreB and PBP2, despite having similar morphological effects when depleted. Altogether, our results highlight the robustness of cell-wall synthesis and physical principles dictating cell-size control. PMID- 25456141 TI - Systematic perturbation of cytoskeletal function reveals a linear scaling relationship between cell geometry and fitness. AB - Diversification of cell size is hypothesized to have occurred through a process of evolutionary optimization, but direct demonstrations of causal relationships between cell geometry and fitness are lacking. Here, we identify a mutation from a laboratory-evolved bacterium that dramatically increases cell size through cytoskeletal perturbation and confers a large fitness advantage. We engineer a library of cytoskeletal mutants of different sizes and show that fitness scales linearly with respect to cell size over a wide physiological range. Quantification of the growth rates of single cells during the exit from stationary phase reveals that transitions between "feast-or-famine" growth regimes are a key determinant of cell-size-dependent fitness effects. We also uncover environments that suppress the fitness advantage of larger cells, indicating that cell-size-dependent fitness effects are subject to both biophysical and metabolic constraints. Together, our results highlight laboratory based evolution as a powerful framework for studying the quantitative relationships between morphology and fitness. PMID- 25456142 TI - Parkin sensitizes toward apoptosis induced by mitochondrial depolarization through promoting degradation of Mcl-1. AB - Mitochondrial depolarization promotes Parkin- and PTEN-induced kinase 1 (PINK1) dependent polyubiquitination of multiple proteins on mitochondrial outer membranes, resulting in the removal of defective mitochondria via mitophagy. Because Parkin mutations occur in Parkinson's disease, a condition associated with the death of dopaminergic neurons in the midbrain, wild-type Parkin is thought to promote neuronal survival. However, here we show that wild-type Parkin greatly sensitized toward apoptosis induced by mitochondrial depolarization but not by proapoptotic stimuli that failed to activate Parkin. Parkin-dependent apoptosis required PINK1 and was efficiently blocked by prosurvival members of the Bcl-2 family or knockdown of Bax and Bak. Upon mitochondrial depolarization, the Bcl-2 family member Mcl-1 underwent rapid Parkin- and PINK1-dependent polyubiquitination and degradation, which sensitized toward apoptosis via opening of the Bax/Bak channel. These data suggest that similar to other sensors of cell stress, such as p53, Parkin has cytoprotective (mitophagy) or cytotoxic modes (apoptosis), depending on the degree of mitochondrial damage. PMID- 25456143 TI - Childhood bone tuberculosis from Roman Pecs, Hungary. AB - A child from a Roman necropolis in Pecs, Hungary (4th century CE) was initially diagnosed with severe spinal osteomyelitis. The post-cranial skeleton displayed bone alterations in the lower thoracic and upper lumbar segments, including vertebral body destruction, collapse and sharp kyphosis, and additional multiple rib lesions, suggesting a most likely diagnosis of pulmonary and spinal tuberculosis. This study discusses a number of selected diagnoses in the context of our pathological findings, complementing the macroscopic examination with radiological and biomolecular analyses. PMID- 25456144 TI - Image fusion of Ultrasound Computer Tomography volumes with X-ray mammograms using a biomechanical model based 2D/3D registration. AB - Ultrasound Computer Tomography (USCT) is a promising breast imaging modality under development. Comparison to a standard method like mammography is essential for further development. Due to significant differences in image dimensionality and compression state of the breast, correlating USCT images and X-ray mammograms is challenging. In this paper we present a 2D/3D registration method to improve the spatial correspondence and allow direct comparison of the images. It is based on biomechanical modeling of the breast and simulation of the mammographic compression. We investigate the effect of including patient-specific material parameters estimated automatically from USCT images. The method was systematically evaluated using numerical phantoms and in-vivo data. The average registration accuracy using the automated registration was 11.9mm. Based on the registered images a method for analysis of the diagnostic value of the USCT images was developed and initially applied to analyze sound speed and attenuation images based on X-ray mammograms as ground truth. Combining sound speed and attenuation allows differentiating lesions from surrounding tissue. Overlaying this information on mammograms, combines quantitative and morphological information for multimodal diagnosis. PMID- 25456145 TI - Interactive 3D medical data cutting using closed curve with arbitrary shape. AB - Interactive 3D cutting is widely used as a flexible manual segmentation tool to extract medical data on regions of interest. A novel method for clipping 3D medical data is proposed to reveal the interior of volumetric data. The 3D cutting method retains or clips away selected voxels projected inside an arbitrary-shaped closed curve which is clipping geometry constructed by interactive tool to make cutting operation more flexible. Transformation between the world and screen coordinate frames is studied to project voxels of medical data onto the screen frame and avoid computing intersection of clipping geometry and volumetric data in 3D space. For facilitating the decision on whether the voxels should be retained, voxels through coordinate transformation are all projected onto a binary mask image on screen frame which the closed curve is also projected onto to conveniently obtain the voxels of intersection. The paper pays special attention to optimization algorithm of cutting process. The optimization algorithm that mixes octree with quad-tree decomposition is introduced to reduce computation complexity, save computation time, and match real time. The paper presents results obtained from raw and segmented medical volume datasets and the process time of cutting operation. PMID- 25456146 TI - Fourier-ring descriptor to characterize rare circulating cells from images generated using immunofluorescence microscopy. AB - We address the problem of subclassification of rare circulating cells using data driven feature selection from images of candidate circulating tumor cells from patients diagnosed with breast, prostate, or lung cancer. We determine a set of low level features which can differentiate among candidate cell types. We have implemented an image representation based on concentric Fourier rings (FRDs) which allow us to exploit size variations and morphological differences among cells while being rotationally invariant. We discuss potential clinical use in the context of treatment monitoring for cancer patients with metastatic disease. PMID- 25456147 TI - The impact of land use on microbial surface water pollution. AB - Our knowledge relating to water contamination from point and diffuse sources has increased in recent years and there have been many studies undertaken focusing on effluent from sewage plants or combined sewer overflows. However, there is still only a limited amount of microbial data on non-point sources leading to diffuse pollution of surface waters. In this study, the concentrations of several indicator micro-organisms and pathogens in the upper reaches of a river system were examined over a period of 16 months. In addition to bacteria, diffuse pollution caused by Giardia lamblia and Cryptosporidium spp. was analysed. A single land use type predestined to cause high concentrations of all microbial parameters could not be identified. The influence of different land use types varies between microbial species. The microbial concentration in river water cannot be explained by stable non-point effluent concentrations from different land use types. There is variation in the ranking of the potential of different land use types resulting in surface water contamination with regard to minimum, median and maximum effects. These differences between median and maximum impact indicate that small-scale events like spreading manure substantially influence the general contamination potential of a land use type and may cause increasing micro-organism concentrations in the river water by mobilisation during the next rainfall event. PMID- 25456148 TI - Urinary concentrations of polycyclic aromatic hydrocarbons in Israeli adults: demographic and life-style predictors. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants associated with adverse health outcomes, including cancer, asthma, and reduced fertility. Because data on exposure to these contaminants in Israel and the Middle East are very limited this study was conducted to measure urinary levels of PAHs in the general adult population in Israel and to identify demographic and life-style predictors of exposure. We measured concentrations of five PAH metabolites: 1-hydroxypyrene (1OH_pyrene) and four different hydroxyphenanthrenes (1-hydroxyphenanthrene, 2-hydroxyphenanthrene, 3-hydroxyphenanthrene, 4 hydroxyphenanthrene), as well as cotinine in urine samples collected from 243 Israeli adults from the general population. We interviewed participants using structured questionnaires to collect detailed demographic, smoking and dietary data. For over 99% of the study participants, urinary concentration of at least one of the PAHs was above both the limit of detection (LOD) and the limit of quantification (LOQ). All PAHs were significantly correlated (rho=0.67-0.92). Urinary concentration of hydroxyphenanthrenes, but not 1OH_pyrene, was significantly higher among Arabs and Druze study participants (N=56) compared to Jewish participants (N=183). For 4-hydroxyphenanthrene, concentration in Arabs and Druze was 1.95 (95% CI 1.50-2.52) that of Jews, after controlling for creatinine, age and cotinine levels. Urinary concentrations of all PAHs were significantly higher among current smokers or participants with higher cotinine levels and increased significantly with smoking frequency. While PAHs concentrations were not associated with cotinine concentrations in nonsmokers in the overall study population, PAHs concentration was significantly higher among nonsmoking Jews with cotinine >=LOQ (1MUg/L), which represents exposure to environmental tobacco smoking, compared to nonsmoking Jews with cotinine concentrations 40 mmol/d, however the mechanisms for this effect remain unclear. Potassium may improve measures of vascular function however this effect may be dependent on the effect of potassium on blood pressure. The effect of fruit and vegetables on endothelial function independent of confounding variables is less clear. Increased fruit and vegetable intake may improve vascular function only in high risk populations. CONCLUSION: Increasing dietary potassium appears to improve vascular function but the effect of increasing fruit and vegetable intake per se on vascular function is less clear. PMID- 25456153 TI - Effects of lutein-enriched egg yolk in buttermilk or skimmed milk on serum lipids & lipoproteins of mildly hypercholesterolemic subjects. AB - BACKGROUND AND AIMS: Earlier studies in our group suggested that traditionally prepared buttermilk influences cholesterol metabolism. We therefore designed a study to evaluate whether traditionally prepared buttermilk lowers serum low density lipoprotein cholesterol (LDL-C) and/or prevents the LDL-C raising effect of egg yolks. METHODS AND RESULTS: Mildly hypercholesterolemic subjects were randomly allocated to one of four diet groups consuming daily at lunch 80 ml skimmed milk with (n = 23) or without (n = 25) lutein-enriched egg yolk (28 g from 1.5 eggs providing 323 mg cholesterol) or traditionally prepared buttermilk with (n = 23) or without (n = 21) lutein-enriched egg yolk during a 12 week period. Fasting blood samples were taken to measure concentrations of serum lipids, (apo)lipoproteins, liver and kidney function markers, and plasma lutein, zeaxanthin and high-sensitive C-reactive protein (hsCRP). Egg yolk consumption significantly increased serum total cholesterol (total-C) (p = 0.035) and LDL-C concentrations (p = 0.022). Buttermilk did not change the effects of egg yolk on serum lipids and (apo)lipoproteins. There was a trend towards significant lower total-C (p = 0.077), but not LDL-C (p = 0.204) concentrations in the buttermilk groups. Plasma lutein and zeaxanthin concentrations increased significantly (p < 0.001) in the egg yolk groups. CONCLUSION: In mildly hypercholesterolemic subjects, daily consumption of traditionally prepared buttermilk for 12 weeks did not lower serum total-C or LDL-C concentrations, nor did it prevent the serum total-C and LDL-C raising effect of daily egg yolk consumption. REGISTRATION NUMBER: This study is registered at www.clinicaltrials.gov as NCT01566305. PMID- 25456154 TI - Non-alcoholic fatty liver disease is associated with progression of arterial stiffness. AB - BACKGROUND AND AIMS: NAFLD is an independent risk factor for increased cardiovascular disease. Arterial stiffness is an index of subclinical atherosclerosis. The aims of this study were to examine prospectively the relationship between Non-alcoholic fatty liver disease (NAFLD) and the progression of arterial stiffness. METHODS AND RESULTS: A prospective study of 728 men and 497 women free of hypertension, and diabetes at the baseline were conducted. The subjects were followed for 5 years. The progression rate of arterial stiffness was measured by calculating the increase in brachial-ankle pulse wave velocity (baPWV) the changes of the baPWV (adjusted for age) during the study period was significantly greater in the patients with NAFLD (172.4 +/- 42.1 cm/s for men, 95.8 +/- 36.7 cm/s for women) than in the subjects without NAFLD (70.3 +/- 56.5 cm/s for men, 55.4 +/- 42.2 cm/s for women). For the subjects with metabolic syndrome, after adjusting for multiple risk factors, NAFLD was a significant predictor of baPWV progression (for male, beta = 0.843; P < 0.001; for female, beta = 0.575; P < 0.001, respectively). In addition, results were unmodified in subjects without metabolic syndrome. CONCLUSIONS: NAFLD was found to be an independent predictor of faster progression of baPWV even after adjusting other cardiovascular risk factors. These prospective data support a pathogenic role for NAFLD in the development of arterial stiffness. PMID- 25456157 TI - Development and construct validity of a low-fidelity training platform for driving large and small suture needles. AB - BACKGROUND: The objective of this study was to describe and validate a novel training platform for driving large and small suture needles, which can ultimately be used for elemental vascular surgical training. METHODS: We developed a novel trainer and proficiency-based training curriculum that provides a platform for practice with handling fine vascular tools and needles as well as precision in suture targeting. The trainer comprises 2 concentric circles printed on cotton fiber material with 8 evenly spaced targets on each circle. The first exercise was designed for practice with Castroviejo needle drivers and a fine needle such that the needle is passed through all targets in sequential order. A second, larger figure serves the same function but is designed for conventional needle drivers and a larger needle. A total of 5 attending surgeons from vascular and trauma surgery were recruited to serve as "expert" participants. These surgeons completed 3 repetitions of each task, which were used to develop proficiency timing and quality standards for practice. The curriculum was validated by recruiting 10 senior surgical residents and 12 surgical interns. Senior residents completed 3 repetitions of each task. Each first-year resident completed a proctored pretest, trained to proficiency by self-paced practice on the trainer according to standards set by the attending surgeons, and completed a proctored posttest. RESULTS: First-year residents performed significantly worse on the pretest compared with senior residents and faculty surgeons on both exercises (small figure = 58.9 vs 174.2 vs 201.3, p < 0.001; large figure = 112.1 vs 202.9 vs 198.1, p < 0.001). After proficiency-based practice, first-year residents improved significantly from pretest to posttest (small figure = 216.0 vs 58.9, p < 0.001; large figure = 211.7 vs 112.1, p = 0.001). CONCLUSIONS: The vascular trainer platform demonstrated construct validity for self-paced elemental vascular surgical practice. PMID- 25456156 TI - Pharmaceutical industry interactions of psychiatric trainees from 20 European countries. AB - BACKGROUND: Interactions between the pharmaceutical industry (PI) and psychiatrists have been under scrutiny recently, though there is little empirical evidence on the nature of the relationship and its intensity at psychiatry trainee level. We therefore studied the level of PI interactions and the underlying beliefs and attitudes in a large sample of European psychiatric trainees. METHODS: One thousand four hundred and forty-four psychiatric trainees in 20 European countries were assessed cross-sectionally, with a 62-item questionnaire. RESULTS: The total number of PI interactions in the preceding two months varied between countries, with least interactions in The Netherlands (M (Mean)=0.92, SD=1.44, range=0-12) and most in Portugal (M=19.06, SD=17.44, range=0-100). Trainees were more likely to believe that PI interactions have no impact on their own prescribing behaviour than that of other physicians (M=3.30, SD=1.26 vs. M=2.39, SD=1.06 on a 5-point Likert scale: 1 "completely disagree" to 5 "completely agree"). Assigning an educational role to the pharmaceutical industry was associated with more interactions and higher gift value (IRR (incidence rate ratio)=1.21, 95%CI=1.12-1.30 and OR=1.18, 95%CI=1.02-1.37). CONCLUSIONS: There are frequent interactions between European psychiatric trainees and the PI, with significant variation between countries. We identified several factors affecting this interaction, including attribution of an educational role to the PI. Creating alternative educational opportunities and specific training dedicated to PI interactions may therefore help to reduce the impact of the PI on psychiatric training. PMID- 25456158 TI - Composite method for implicit representation of solvent in dimethyl sulfoxide and acetonitrile. AB - A composite method for implicit representation of solvent previously developed to compute aqueous free energies of solvation is extended to accommodate the polar aprotic solvents dimethyl sulfoxide and acetonitrile. The method combines quantum mechanical calculation of the solute electronic structure with a modern dielectric continuum model for long-range electrostatic interactions with solvent and individual models for short-range interactions arising from dispersion, exchange, and hydrogen bonding. The few parameters involved are optimized to fit a standard data set of experimental solvation energies for neutrals and ions. Results are better than other models in the literature, with average errors for ions comparable to or smaller than the estimated experimental errors. Some circumstantial evidence is also obtained to support one of the competing extrathermodynamic arguments recently used to determine the solvation energies of the proton, which are needed to separate measurements of paired cation plus anion solvation energies into absolute single ion solvation energies in these solvents. PMID- 25456159 TI - Cutaneous innate immune sensing of Toll-like receptor 2-6 ligands suppresses T cell immunity by inducing myeloid-derived suppressor cells. AB - Skin is constantly exposed to bacteria and antigens, and cutaneous innate immune sensing orchestrates adaptive immune responses. In its absence, skin pathogens can expand, entering deeper tissues and leading to life-threatening infectious diseases. To characterize skin-driven immunity better, we applied living bacteria, defined lipopeptides, and antigens cutaneously. We found suppression of immune responses due to cutaneous infection with Gram-positive S. aureus, which was based on bacterial lipopeptides. Skin exposure to Toll-like receptor (TLR)2-6 binding lipopeptides, but not TLR2-1-binding lipopeptides, potently suppressed immune responses through induction of Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs). Investigating human atopic dermatitis, in which Gram-positive bacteria accumulate, we detected high MDSC amounts in blood and skin. TLR2 activation in skin resident cells triggered interleukin-6 (IL-6), which induced suppressive MDSCs, which are then recruited to the skin suppressing T cell mediated recall responses such as dermatitis. Thus, cutaneous bacteria can negatively regulate skin-driven immune responses by inducing MDSCs via TLR2-6 activation. PMID- 25456161 TI - A discussion supporting presumed consent for posthumous sperm procurement and conception. AB - Conception of a child using cryopreserved sperm from a deceased man is generally considered ethically sound provided explicit consent for its use has been made, thereby protecting the man's autonomy. When death is sudden (trauma, unexpected illness), explicit consent is not possible, thereby preventing posthumous sperm procurement (PSP) and conception according to current European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine guidelines. Here, we argue that autonomy of a deceased person should not be considered the paramount ethical concern, but rather consideration of the welfare of the living (widow and prospective child) should be the primary focus. Posthumous conception can bring significant advantages to the widow and her resulting child, with most men supporting such practice. We suggest that a deceased man can benefit from posthumous conception (continuation of his 'bloodline', allowing his widow's wishes for a child to be satisfied), and has a moral duty to allow his widow access to his sperm, if she so wishes, unless he clearly indicated that he did not want children when alive. We outline the arguments favouring presumed consent over implied or proxy consent, plus practical considerations for recording men's wishes to opt-out of posthumous conception. PMID- 25456160 TI - The chemokine receptor CXCR6 controls the functional topography of interleukin-22 producing intestinal innate lymphoid cells. AB - Interleukin-22 (IL-22) plays a critical role in mucosal defense, although the molecular mechanisms that ensure IL-22 tissue distribution remain poorly understood. We show that the CXCL16-CXCR6 chemokine-chemokine receptor axis regulated group 3 innate lymphoid cell (ILC3) diversity and function. CXCL16 was constitutively expressed by CX3CR1(+) intestinal dendritic cells (DCs) and coexpressed with IL-23 after Citrobacter rodentium infection. Intestinal ILC3s expressed CXCR6 and its ablation generated a selective loss of the NKp46(+) ILC3 subset, a depletion of intestinal IL-22, and the inability to control C. rodentium infection. CD4(+) ILC3s were unaffected by CXCR6 deficiency and remained clustered within lymphoid follicles. In contrast, the lamina propria of Cxcr6(-/-) mice was devoid of ILC3s. The loss of ILC3-dependent IL-22 epithelial stimulation reduced antimicrobial peptide expression that explained the sensitivity of Cxcr6(-/-) mice to C. rodentium. Our results delineate a critical CXCL16-CXCR6 crosstalk that coordinates the intestinal topography of IL-22 secretion required for mucosal defense. PMID- 25456162 TI - Ovarian response is affected by a specific histidine-rich glycoprotein polymorphism: a preliminary study. AB - Genetic polymorphisms involved in angiogenesis, apoptosis and chemokine signalling are associated with varying ovarian response and oocyte quality. The protein, histidine-rich glycoprotein (HRG), is involved in these processes, but its effect on ovarian response in IVF has not been previously studied. A single nucleotide polymorphism (SNP) in the HRG gene (C633T) seems to affect pregnancy results in IVF. Women with the C/C genotype had higher pregnancy rates, C/T had moderate rates and none of those in the T/T group conceived. The aim of this study was to investigate if the HRG C633T SNP affects ovarian response. The HRG C633T SNP genotype of 67 women with unexplained infertility undergoing IVF was analysed and related to medical data. The T/T genotype obtained fewer oocytes, including mature oocytes, despite higher dosages of FSH administered. Additionally, the highest proportion of women who had exclusively poor-quality embryos was in the T/T group. No differences in demographic factors known to affect these parameters were found. The results suggest that the HRG C633T SNP influences ovarian response. Further studies of this SNP may increase knowledge about the biological processes involved in oocyte development and, furthermore, improve predicted ovarian response and fertilization. PMID- 25456163 TI - Assisted reproductive technologies in Latin America: the Latin American Registry, 2012. AB - Multinational data on assisted reproduction technologies were collected from 155 institutions in 14 Latin American countries during 2012. Case-by-case data included 47,326 assisted reproduction technology cycles covering over 80% of cycles carried out in Latin America. Treatments included IVF, intracytoplasmic sperm injection (ICSI), frozen embryo transfers, oocyte donations and fertility preservation. Embryo transfer and IVF-ICSI was carried out in 39% of women aged 35-39 years and 31% of women aged 40 years or over. Delivery rate per oocyte retrieval was 20.9% for ICSI and 26.5% for IVF. Multiple births comprised 20.6% twins and 1.2% triplets and over. In oocyte donations, twins reached 27.8% and triplets and over 2.4%. Pre-term births in singletons were 14%. The relative risk of prematurity increased by 4.30 (95% CI 4.1 to 4.6) in twins and 43.8 (95% CI 28.5 to 67.4) in triplets and higher. Perinatal mortality increased from 25.2 per thousand in singletons to 44.4 in twins and 80.7 in triplets and over. Elective single embryo transfer was carried out in only 1.4%, of cycles, with a delivery rate of 30% in women 34 years or younger, and should be considered the way forward provided access is facilitated with public funding. PMID- 25456164 TI - Causes, effects and molecular mechanisms of testicular heat stress. AB - The process of spermatogenesis is temperature-dependent and occurs optimally at temperatures slightly lower than that of the body. Adequate thermoregulation is imperative to maintain testicular temperatures at levels lower than that of the body core. Raised testicular temperature has a detrimental effect on mammalian spermatogenesis and the resultant spermatozoa. Therefore, thermoregulatory failure leading to heat stress can compromise sperm quality and increase the risk of infertility. In this paper, several different types of external and internal factors that may contribute towards testicular heat stress are reviewed. The effects of heat stress on the process of spermatogenesis, the resultant epididymal spermatozoa and on germ cells, and the consequent changes in the testis are elaborated upon. We also discuss the molecular response of germ cells to heat exposure and the possible mechanisms involved in heat-induced germ cell damage, including apoptosis, DNA damage and autophagy. Further, the intrinsic and extrinsic pathways that are involved in the intricate mechanism of germ cell apoptosis are explained. Ultimately, these complex mechanisms of apoptosis lead to germ cell death. PMID- 25456165 TI - Incidence of infertility and risk factors of impaired fecundity among newly married couples in a Chinese population. AB - The aims of this study were to obtain the incidence of infertility, to examine the causes of infertility and to explore risk factors for impaired fecundity in a rural region of northern China using a prospective follow-up design. A total of 2151 newly married couples planning to become pregnant within the next 12 months were enrolled between 2009 and 2012 from two counties of Shanxi Province in northern China. Couples were followed up for at least 1 year or until a clinical pregnancy occurred. Information about clinical pregnancy was obtained. The 12 month and 24-month infertility rates were 13.6% (95% CI 11.9 to 15.3) and 8.5% (95% CI 6.7 to 10.3), respectively. About 63% of women became pregnant within 6 months of follow up, and 86% did so within 12 months of follow up. The main causes of female infertility were ovulation disorders, fallopian tube problems and polycystic ovary syndrome. The primary cause of male infertility was sperm quality problems. Couples who used coal as cooking fuel, women with a higher body mass index, women with long-term health problems, and men who had married at later ages were more likely to have delayed pregnancies. PMID- 25456166 TI - GnRH agonist plus vaginal progesterone for luteal phase support in ICSI cycles: a randomized study. AB - In this prospective randomized study, the effect of daily gonadotrophin-releasing hormone agonist (GnRHa) in the luteal phase on IVF and intracytoplasmic sperm injection (ICSI) outcomes was assessed. Women (n = 446) were counselled for IVF ICSI, and randomized on the day of embryo transfer to group 1 (daily 0.1 mg subcutaneous GnRHa until day of beta-HCG) (n = 224) and group 2 (stopped GnRHa on day of HCG injection) (n = 222). Both groups received daily vaginal progesterone suppositories. Primary outcome was clinical pregnancy rate. Secondary outcome was ongoing pregnancy rate beyond 20 weeks. Mean age, oestradiol on day of HCG, number of oocytes retrieved, number of embryos transferred, and clinical and ongoing pregnancy rates were 28.9 +/- 4.5 years, 2401 +/- 746 pg/mL; 13.5 +/- 6.0 oocytes; 2.6 +/- 0.6 embryos, and 36.2% and 30.4% consecutively in group 1 compared with 29.7 +/- 4.7 years, 2483 +/- 867 pg/mL, 13.7 +/- 5.5 oocytes, 2.7 +/- 0.6 embryos, 30.6% pregnancy rate, and 25.7% ongoing pregnancy rate in group 2. No significant difference was found between the groups. Subcutaneous GnRHa during the luteal phase of long GnRHa protocol cycles does not increase clinical or ongoing pregnancy rates after IVF-ICSI. PMID- 25456167 TI - Failed organ preservation strategy for adult laryngeal embryonal rhabdomyosarcoma. AB - PURPOSE: To present a case of embryonal rhabdomyosarcoma of the intrinsic laryngeal musculature and discuss the treatment of this rare tumor. METHODS AND MATERIALS: A 45year-old male presented with an eleven month history of hoarseness. A mass of the posterior glottis was noted on fiberoptic laryngoscopy. Computed tomography indicated a 1.5*2.5cm laryngeal mass without cartilage involvement. Direct laryngoscopy and biopsy were consistent with embryonal rhabdomyosarcoma involving the interarytenoid muscle. A multidisciplinary tumor board recommended multimodality therapy including total laryngectomy. His case was reviewed along with the available English language literature. RESULTS: The patient refused surgery, and he qualified for a pediatric rhabdomyosarcoma treatment protocol with induction chemotherapy followed by combined chemoradiation. There was no noted response and the patient was taken off protocol to increase the radiation dose without chemotherapy. Fifteen weeks following radiation, a repeat biopsy revealed viable tumor. The patient elected further experimental chemotherapy at an outside hospital. The patient currently is alive at 34months post-treatment with suspected persistent disease and continues to refuse surgery. CONCLUSIONS: Embryonal rhabdomyosarcoma involving the larynx is an extremely rare tumor usually seen in children. There have been few previous adult cases reported and treatment options are not well described. We present a case of chemoradiation failure in an adult with embryonal rhabdomyosarcoma refusing surgical intervention. Although pediatric tumors can be effectively treated with organ preservation strategies, adult tumors may have a poorer response. Based upon our experience and existing literature regarding adult embryonal rhabdomyosarcoma of the larynx, multimodality therapy including surgical resection should be the treatment of choice. PMID- 25456168 TI - Round and oval window reinforcement for the treatment of hyperacusis. AB - PURPOSE: To present the outcomes of two patients (three ears) with hyperacusis treated with round and oval window reinforcement. MATERIALS AND METHODS: Transcanal placement of temporalis fascia on the round window membrane and stapes footplate was performed. Loudness discomfort level testing was performed. Results of pre and post-operative hyperacusis questionnaires and audiometric testing were reviewed. RESULTS: Two patients (three ears) underwent surgery. Results from the hyperacusis questionnaire improved by 21 and 13 points, respectively. Except for a mild loss in the high frequencies, no change in hearing was noted post operatively. Both patients reported no negative effects from surgery, marked improvement in ability to tolerate noise, and would recommend the procedure to others. There were no complications. CONCLUSIONS: Round and oval window reinforcement is a minimally invasive option for treating hyperacusis when usual medical therapies fail. Further studies are needed to evaluate the effectiveness of the procedure in reducing noise intolerance. PMID- 25456169 TI - Tonsillectomy on rivaroxaban. AB - OBJECTIVE: The objective of this case report is to increase awareness regarding a new category of drugs, new direct oral anticoagulants (specifically, rivaroxaban), which are increasingly being used instead of the more traditional vitamin K antagonists, to highlight the current recommendations for perioperative management of rivaroxaban, and to demonstrate a clinical scenario where a tonsillectomy was successfully performed in a patient requiring anticoagulation with rivaroxaban. METHODS: A literature review and a case report are presented. PubMed was reviewed for evidence based recommendations regarding the perioperative management of rivaroxaban and the recommendations for reversal in the event of a hemorrhagic complication. There is no evidence in the literature regarding the use of rivaroxaban in patients undergoing tonsillectomy. We present the case of a 38year old female on rivaroxaban for history of deep vein thrombosis and pulmonary embolism who successfully underwent tonsillectomy using the current recommendations for perioperative management of rivaroxaban. RESULTS: Our patient had no thrombotic or hemorrhagic complications during the postoperative period. This is the first report in the literature regarding the use of a new direct oral anticoagulant, rivaroxaban, in the setting of tonsillectomy. This case report suggests that tonsillectomy can be performed in patients anticoagulated with rivaroxaban. CONCLUSION: With the increasingly common use of new direct oral anticoagulants for short and long-term anticoagulation, further research is necessary to compare the efficacy and safety profile of the new direct oral anticoagulants to the more traditional vitamin K antagonists when performing tonsillectomy. Otolaryngologists should be familiar with the new oral anticoagulants and understand the proposed perioperative management as practitioners are increasingly likely to encounter patients using this new class of medication in clinical practice. PMID- 25456170 TI - Synthesis and biological evaluation of novel sarsasapogenin derivatives as potential anti-tumor agents. AB - Based on the fact that timosaponin A-III (TA-III) exhibits potent cytotoxic effects and has been considered as a potential anti-tumor agent, a range of novel sarsasapogenin derivatives 1, 2a-2g, 3, 4, 5, 6a-6g have been synthesized by a simple and facile synthetic route. The in vitro cytotoxic activity of these synthetic compounds has been evaluated against ten human cancer cell lines. The pharmacological results showed that most of the sarsasapogenin derivatives displayed excellent selective cytotoxicity toward the cancer cell lines. An amino group at C-3 or C-26 position of the sapogenin had a profound influence on the cytotoxic activity. In particular, compound 6c exhibited significantly inhibitory activity against A375-S2 (IC50=0.56MUM) and HT1080 (IC50=0.72MUM) cells. However, introducing a bromo or morpholinyl substituent at the C-3 and C-26 position of the sapogenin generally rendered it inactive against the human cancer cell lines. This research provides a theoretical reference for the exploration of new anti tumor drugs. PMID- 25456193 TI - Impact of equine herpesvirus type 1 (EHV-1) infection on the migration of monocytic cells through equine nasal mucosa. AB - The mucosal surfaces are important sites of entry for a majority of pathogens, and viruses in particular. The migration of antigen presenting cells (APCs) from the apical side of the mucosal epithelium to the lymph node is a key event in the development of mucosal immunity during viral infections. However, the mechanism by which viruses utilize the transmigration of these cells to invade the mucosa is largely unexplored. Here, we establish an ex vivo explant model of monocytic cell transmigration across the nasal mucosal epithelium and lamina propria. Equine nasal mucosal CD172a(+) cells (nmCD172a(+) cells), blood-derived monocytes and monocyte-derived DCs (moDCs) were labeled with a fluorescent dye and transferred to the apical part of a polarized mucosal explant. Confocal imaging was used to monitor the migration patterns of monocytic cells and the effect of equine herpesvirus type 1 (EHV-1) on their transmigration. We observed that 16 26% of mock-inoculated nmCD172a(+) cells and moDCs moved into the nasal epithelia, and 1-7% moved further in the lamina propria. The migration of EHV-1 inoculated monocytic cells was not increased in these tissues compared to the mock-inoculated monocytic cells. Immediate early protein positive (IEP(+)) cells were observed beneath the basement membrane (BM) 48 hours post addition (hpa) of moDCs and nmCD172a(+) cells, but not blood-derived monocytes. Together, our finding demonstrate that monocytic cells may become infected with EHV-1 in the respiratory mucosa and transport the virus from the apical side of the epithelium to the lamina propria en route to the lymph and blood circulation. PMID- 25456195 TI - This issue publishes papers on many different topics. PMID- 25456197 TI - Official documents available from the american occupational therapy association. PMID- 25456194 TI - Analysis of mRNA expression for genes associated with regulatory T lymphocytes (CD25, FoxP3, CTLA4, and IDO) after experimental infection with bovine viral diarrhea virus of low or high virulence in beef calves. AB - Immunosuppression caused by bovine viral diarrhea virus (BVDV) has been associated with lymphocyte depletion, leukopenia and impairment of leukocyte function; however, no work has been done on the relationship between BVDV and regulatory T lymphocytes (Tregs). The objective of this study was to compare the mRNA expression of genes associated with Tregs (CD25, FoxP3, CTLA4, and IDO), after experimental infection of beef calves with low (LV) or high (HV) virulence BVDV. Thirty BVDV-naive calves were randomly assigned to three groups. Calves were intra-nasally inoculated with LV (n=10, strain SD-1) or HV (n=10, strain 1373) BVDV or BVDV-free cell culture medium (control, n=10). Quantitative RT-PCR was used to determine the expression of target genes in tracheo-bronchial lymph nodes and spleen on day 5 post-infection. The mRNA expression of CD25 was up regulated in tracheo-bronchial lymph nodes of LV (P<0.05), but not in HV compared to the control group. The expression of FoxP3 and CTLA4 was not increased in tracheo-bronchial lymph nodes of either of the BVDV-inoculated groups. A dramatic up-regulation of IDO mRNA was observed in tracheo-bronchial lymph nodes of LV (P<0.05), but not HV compared to the control calves. In conclusion, experimental infection with BVDV did not provide evidence of Treg activation based on expression of FoxP3 and CTL4. Differential expression of CD25 and IDO mRNA on day 5 post-infection with HV or LV BVDV might reflect temporal differences in transcription occurring during the immune response elicited by these viral strains, or differences in viral infectivity of the host cells. PMID- 25456198 TI - Guidelines for supervision, roles, and responsibilities during the delivery of occupational therapy services. PMID- 25456199 TI - Occupational Therapy's Commitment to Nondiscrimination and Inclusion. PMID- 25456201 TI - Enforcement procedures for the occupational therapy code of ethics and ethics standards. PMID- 25456200 TI - The role of occupational therapy in primary care. PMID- 25456202 TI - Scope of practice. PMID- 25456203 TI - 2014 AOTA/AOTF Award Recipients. PMID- 25456204 TI - 2014 representative assembly summary of minutes. PMID- 25456205 TI - The AOTA 94th Annual Business Meeting. PMID- 25456206 TI - List of educational programs in occupational therapy. PMID- 25456207 TI - Guidelines for Contributors to AJOT. PMID- 25456208 TI - How surgical mentors teach: a classification of in vivo teaching behaviors part 1: verbal teaching guidance. AB - OBJECTIVES: To illuminate surgical teaching at a fine level of detail by filming intraoperative communication between surgical attending physicians and trainees and provide a naturalistic categorization and analysis of verbal teaching behaviors. DESIGN: Live, intraoperative verbal exchanges between surgical attending physicians and their trainees (residents and fellows) were filmed, and key verbal teaching moments were transcribed. In follow-up interviews, attending physicians and trainees watched video clips of their teaching case and answered open-ended questions about their surgical teaching methods. Using a grounded theory approach, we examined the videos and interviews for what might be construed as a teaching behavior and refined verbal teaching categories through constant comparison. SETTING: We filmed 5 cases in the operating suite of a university teaching hospital that provides gynecologic surgical care. PARTICIPANTS: We included 5 attending gynecologic surgeons, 3 fellows, and 5 residents for this study. RESULTS: More than 6 hours of film, 3 hours of interviews, and more than 400 verbal teaching utterances from our participating attending surgeons were transcribed. We found that attending surgeons used unique types of verbal guidance to describe relevant anatomy, explain the rationale behind a specific surgical action, command the trainee to perform the next step, reference a specific aspect of the surgery, and provide an indirect verbal construct. Attending physicians prefixed speech with polite terms and used terse language, colorful verbal analogies, and sometimes humor. Our participants denied a significant Hawthorne effect. Interrater reliability was high using Cohen kappa with 0.77 for the verbal categories. CONCLUSIONS: Our categorization of live intraoperative verbal teaching can provide a measurable, replicable basis for studying how spoken guidance can lead to the best intraoperative learning. Because surgical teaching occurs on a microscopic level, film review is important when analyzing intraoperative teaching behaviors. PMID- 25456209 TI - Structure elucidation of secondary metabolites isolated from the leaves of Ixora undulate and their inhibitory activity toward advanced glycation end-products formation. AB - Three aromatic glycosides (1-3), two sulfur and nitrogen-containing compound glucosides (4, 5), and one flavonoid glycoside (6) were isolated from the leaves of Ixora undulata. Their structures were established by extensive 1D, 2D NMR, and HRESIMS experiments, and structure 4 was further confirmed by single crystal X ray diffraction analysis. Of the assayed compounds, 7, 11 and 12 showed strong inhibitory activity toward advanced glycation end-products formation with IC50 values of 86.0 MUM, 76.6 MUM and 98.6 MUM, respectively. PMID- 25456210 TI - Geographical altitude, size, mass and body surface area in children (1-4 years) in the Province of Jujuy (Argentina). AB - BACKGROUND: Highland child populations show low growth rates. AIM: To evaluate the variation of size, mass and body surface area of Jujenean infants (1-4 years) as a function of geographic altitude. SUBJECTS AND METHODS: Nutritional status of 8059 healthy infants was determined based on weight and height data; body mass index, ponderal index, body surface area, body surface area/mass and ectomorphy were calculated. Variables were standardized with a provincial mean and WHO references. Data were grouped by age, sex and geographic altitude: Highlands (>=2500 masl) and Lowlands (<2500 masl). Chi-square, correlation and t-tests were applied. RESULTS: Highlands infants had higher prevalence of stunting, reduced height, weight, body surface area and ectomorphy; also higher body mass index, ponderal index and body surface area/mass. The population average z-score for height, weight and body surface area was positive in Lowlands and negative in Highlands. The opposite happened with body mass index, ponderal index and body surface area/mass. In Highlands and Lowlands the average z-score reference was negative for weight and height and positive for body mass index. Correlations between indices were high and significant, higher in Highlands. CONCLUSION: Jujenean children differ in size, mass and body surface area based on the geographical altitude and adverse nutritional and socioeconomic factors. PMID- 25456211 TI - AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell. AB - Recent studies demonstrated that metformin exerts anti-neoplastic effect in a spectrum of malignancies. However, the mechanism whereby metformin affects various cancers, including gastric cancer, is poorly elucidated. Considering apoptosis plays critical role in tumorigenesis, we, in the present study, investigated the in vitro apoptotic effect of metformin on human gastric cancer cell and the underlying mechanism. Three differently-differentiated gastric cancer cell lines, MKN-28, SGC-7901 and BGC-823, along with one noncancerous gastric cell line GES-1 were used. We found that metformin treatment selectively induces apoptosis in the 3 cancer cell lines, but not the noncancerous one, as confirmed by flow cytometry, Caspase-Glo assay and western blotting against PARP and cleaved caspase 3. Moreover, the apoptotic effect of metformin seems to correlate negatively with the differentiation degree of gastric cancer. Metformin induced apoptosis may be partially mediated through inhibition of anti-apoptotic survivin. Additionally, AMPK and mTOR, 2 important regulatory molecules responsible for metformin action, were investigated for their possible involvements in metformin-induced apoptosis of gastric cancer cell. AMPK knockdown by siRNA restores metformin-inhibited survivin expression and partially abolishes metformin-induced apoptosis. Similarly, forced overexpression of mTOR downstream effector p70S6K1 relieves metformin-induced inhibition of survivin and partly attenuates metformin-induced apoptosis. More importantly, survivin overexpression alleviates metformin-induced apoptosis. Xenograft nude mouse experiment also confirmed that AMPK/mTOR-mediated decrease of suvivin is in vivo implicated in metformin-induced apoptosis. Taken together, these evidences suggest that AMPK/mTOR-mediated inhibition of survivin may partly contribute to metformin-induced apoptosis of gastric cancer cell. PMID- 25456212 TI - Autoimmune hepatitis in children: progression of 20 cases in northern Mexico. AB - BACKGROUND: Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver with nonspecific clinical manifestations that causes greater liver damage in children than in adults. AIMS: To analyze the clinical progression, biochemical profiles, histopathologic changes, and treatment response in 20 children with AIH. MATERIAL AND METHODS: A retrospective study was carried out on the variables associated with clinical progression, diagnosis, and treatment response in children seen at the the Unidad Medica de Alta Especialidad (UMAE) No. 71 IMSS in Torreon, Coahuila, Mexico, from 1992 to 2012. RESULTS: Twenty patients were analyzed, 75% with type 1 AIH (AIH-1) and 25% with type 2 AIH (AIH 2). Girls predominated with a 3:1 ratio of girls to boys. The mean age was 10.07 +/- 6.53 years for the AIH-1 cases and 6.75 +/- 3.77 years for the AIH-2 cases. There was an association with immunologic diseases in 40% of the patients. The patients in the AIH-2 group had greater biochemical profile alterations and IgA deficiency. Anti-nuclear antibody and anti-smooth muscle antibody were positive in 100% of the patients with AIH-1, and anti-liver kidney microsomal type 1 antibody was positive in 100% of the AIH-2 patients. Liver biopsy revealed interface hepatitis in both groups. The AIH-2 group responded more quickly to treatment, but had a higher recurrence rate. CONCLUSIONS: Autoimmune hepatitis in the pediatric patient should be suspected in order to make an early diagnosis and thereby establish opportune treatment. Determining the type of AIH is necessary for making adequate diagnosis and for achieving a better outcome in relation to recurrence and complication rates. PMID- 25456213 TI - Mid-term outcomes in patients following transcatheter aortic valve implantation in the CoreValve Australia and New Zealand Study. AB - BACKGROUND: Although numerous studies have reported the safety and effectiveness of transcatheter aortic valve implantation (TAVI), integration of this therapy into standard of care varies widely by region. We evaluated mid-term follow-up in 540 patients with severe symptomatic AS at high risk of surgical AV replacement, enrolled in the ongoing Medtronic CoreValve Australia-New Zealand Study. METHODS: Between August 2008 and July 2013, 10 centres in Australia/New Zealand enrolled 540 patients, which includes initial use of the CoreValve System for all investigators. Patients were deemed suitable for TAVI based on consensus of a multidisciplinary Heart Team. Primary endpoints were cardiovascular death and major adverse cardiovascular and cerebrovascular events (MACCE) at 30 days. Data were fully monitored, and an independent Clinical Events Committee employed. RESULTS: Baseline characteristics include; 45% female, mean age 84 years, EuroSCORE 17.3+/-10.7%, and 74.9% had New York Heart Association III/IV symptoms. At 30 days, all deaths were cardiovascular (4.1%); MACCE was 11.5%. At one and two years, all-cause mortality was 11.9% and 21.2%; cardiovascular mortality, 9.9% and 15.2%; and stroke, 8.2% and 10.1%, respectively. CONCLUSIONS: Early experience with the CoreValve System in a large cohort of fully-monitored patients was associated with good early- and mid-term safety outcomes. PMID- 25456214 TI - Radiation exposure during cardiac catheterisation is similar for both femoral and radial approaches. AB - OBJECTIVES: Radial approach invasive coronary angiography has been shown to be superior to the femoral approach in terms of reducing vascular access complications and improving patient comfort. However, one major limitation has been the perception of higher patient radiation exposure, with guidelines recommending 7mSv as an appropriate average effective dose (E) for routine coronary angiography. Therefore, we sought here to assess differences in radiation exposure between the femoral and radial access routes in patients undergoing diagnostic coronary angiography with or without angioplasty (CA +/- PCI), as performed by two operators, experienced in both techniques. METHODS: Consecutive patients (n=870) from July 2011-December 2012, undergoing routine CA +/- PCI at Royal Prince Alfred Hospital, Sydney by two experienced interventional cardiologists were identified. Radiation doses were automatically recorded as dose area products (DAPs) at procedure time and converted into E using a conversion factor of 0.18 mSv/(Gycm2), as validated by the National Radiological Protection Board (NRPB). RESULTS: Of the 870 patients, 598 underwent diagnostic CA (347 femoral, 251 radial); and 272 underwent CA+ PCI (179 femoral, 93 radial). The mean age of the patients was 65+/-12 years and the majority (n=617, 71%) were male. Both groups were well matched with respect to baseline demographics, clinical presentation and angiographic characteristics, though there was an excess of patients with a history of coronary grafts in the femoral group, due to operator preference. In the patients who underwent diagnostic CA, there was no significant difference in the average effective radiation dose for femoral versus radial arterial access (E=7.9+/-8.2 vs. 8.3+/-10.6mSv; p=0.66). Similarly, there was also no difference in average effective radiation dose for femoral versus radial arterial access in patients undergoing CA+PCI (E=13.2+/-8.1 vs E=14.4+/ 8.3 mSv; p=0.26). CONCLUSION: In our high volume cardiac catheterisation laboratory, radiation doses for routine angiography were near UNSC targets. Patient radiation exposure was comparable between femoral and radial approaches, for both CA and CA +/- PCI. Thus, our results allay concerns that radial cardiac catheterisation might be associated with greater radiation exposure. PMID- 25456215 TI - A 65 year-old woman with an echodense mitral annular mass. AB - Caseous calcification of the mitral annulus (CCMA) is a rare variant of mitral annular calcification which usually represents an incidental finding during cardiac imaging. Differential diagnosis from significant lesions such as myocardial abscesses or tumours may be problematic. Herein, we present the case of a 65 year-old woman with CCMA who was managed conservatively. Besides providing useful diagnostic clues, we briefly discuss management issues for this under-recognised clinical entity. PMID- 25456216 TI - Characterization of cadmium plasma membrane transport in gills of a mangrove crab Ucides cordatus. AB - Membrane pathway for intracellular cadmium (Cd(2+)) accumulation is not fully elucidated in many organisms and has not been studied in crab gill cells. To characterize membrane Cd(2+) transport of anterior and posterior gill cells of Ucides cordatus, a hypo-hyper-regulating crab, a change in intracellular Cd(2+) concentration under various experimental conditions was examined by using FluoZin, a fluorescent probe. The membrane Cd(2+) transport was estimated by the augmentation of FluoZin fluorescence induced by extracellular application of CdCl2 and different inhibitors. Addition of extracellular calcium (Ca(2+)) to the cells affected little the fluorescence of FluoZin, confirming that Cd(2+) was the main ion increasing intracellular fluorescence. Ca(2+) channels blockers (nimodipine and verapamil) decreased Cd(2+) influx as well as vanadate, a Ca(2+) ATPase blocker. Chelating intracellular Ca(2+) (BAPTA) decreased Cd(2+) influx in gill cells, while increasing intracellular Ca(2+) (caffeine) augmented Cd influx. Cd(2+) and ATP added at different temporal conditions were not effective at increasing intracellular Cd(2+) accumulation. Ouabain (Na(+)/K(+)-ATPase inhibitor) increased Cd(2+) influx probably through a change in intracellular Na and/or a change in cell membrane potential. Routes of Cd(2+) influx, a non essential metal, through the gill cell plasma membrane of crabs are suggested. PMID- 25456217 TI - iTRAQ-based quantitative proteomic analyses on the gender-specific responses in mussel Mytilus galloprovincialis to tetrabromobisphenol A. AB - Tetrabromobisphenol A (TBBPA) accounts for the largest production of brominated flame-retardants (BFRs) along the Laizhou Bay in China and is the most widely used BFR in industrial products. It can induce diverse toxicities including hepatotoxicity, nephrotoxicity, neurotoxicity and endocrine disrupting effects in mammalian and fish models. In this work, we applied iTRAQ-based proteomics to investigate the gender-specific responses in mussel Mytilus galloprovincialis to TBBPA. Thirty-one proteins were differentially expressed in hepatopancreas between male and female mussels, which clearly indicated the biological differences between male and female mussels at the protein level. After exposure of TBBPA (18.4 nmol/L) for one month, a total of 60 proteins were differentially expressed in response to the TBBPA treatment in mussel hepatopancreas, among which 33 and 29 proteins were significantly altered in TBBPA-treated male and female mussel samples, respectively. Only two of the 60 proteins were commonly altered in both male and female mussel samples exposed to TBBPA. Based on KEGG analysis, these differentially expressed proteins of TBBPA-induced effects were assigned to several groups, including cytoskeleton, reproduction and development, metabolism, signal transduction, gene expression, stress response and apoptosis. Overall, results indicated that TBBPA exposure could induce apoptosis, oxidative and immune stresses and disruption in energy, protein and lipid metabolisms in both male and female mussels with different mechanisms. This work suggested that the gender differences should be considered in ecotoxicoproteomics. PMID- 25456218 TI - Toxicity of exposure to binary mixtures of four anti-neoplastic drugs in Daphnia magna and Ceriodaphnia dubia. AB - Anticancer drugs, interfering with DNA in every living organism, may pose a threat to aquatic environment, even more when they occur as complex mixtures. We investigated the combined long term toxic potential of four anti-neoplastic drugs (5-fluorouracil [5-FU], cisplatin [CDDP], etoposide [ET] and imatinib mesylate [IM]) testing their binary mixtures on two primary consumers of the freshwater aquatic chain with close phylogenetic relationship: Daphnia magna and Ceriodaphnia dubia. The combined toxicities were assessed using two distinct effect sizes that should be observed if Bliss independence holds. Direct statistical comparison by analysis of variance of single and combined toxicities under the assumption of Bliss independence allowed to accept or reject the independency hypothesis. Independency was confirmed for all mixtures both in D. magna and in C. dubia, except for IM+ ET and IM+CDDP in D. magna and for ET+CDDP and ET+5-FU in C. dubia which at the highest concentrations showed an antagonistic interaction. A synergic tendency was found testing IM+CDDP on C. dubia at the lowest concentration selected. Thus, the chronic ecotoxicological data evaluated in this study show not only a potential environmental risk of anticancer drugs, especially considering their potential synergistic effects, but also the necessity to integrate statistical models with experimental data to establish the real environmental impact of such compounds. PMID- 25456219 TI - Proteomic changes in brain tissues of marine medaka (Oryzias melastigma) after chronic exposure to two antifouling compounds: butenolide and 4,5-dichloro-2-n octyl-4-isothiazolin-3-one (DCOIT). AB - SeaNine 211 with active ingredient of 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT) has been used as a "green" antifouling agent worldwide but has raised serious biosafety concerns in coastal environments. DCOIT has the potential to disrupt the neurotransmission in nervous system, but the underlying mechanism has not been clarified. In the present study, we used TMT six-plex labeling coupled with two-dimensional LC-MS/MS analysis to investigate the protein expression profiles in brain tissues of the marine medaka (Oryzias melastigma) after a 28 day exposure to environmentally-realistic concentration of DCOIT at 2.55 MUg/L (0.009 MUM) or butenolide, one promising antifouling compound, at 2.31 MUg/L (0.012 MUM). DCOIT and butenolide induced differential expression of 26 and 18 proteins in male brains and of 27 and 23 proteins in female brains, respectively. Distinct mechanisms of toxicity were initiated by DCOIT and butenolide in males, whereas the protein expression profiles were largely similar in females treated by these two compounds. In males, DCOIT exposure mainly led to disruption of mitogen-activated protein kinase (MAPK) signaling pathway, while butenolide affected proteins related to the cytoskeletal disorganization that is considered as a general response to toxicant stress. Furthermore, a sex-dependent protein expression profile was also noted between male and female fish, as evident by the inverse changes in the expressions of common proteins (5 proteins for butenolide- and 2 proteins for DCOIT-exposed fish). Overall, this study provided insight into the molecular mechanisms underlying the toxicity of DCOIT and butenolide. The extremely low concentrations used in this study highlighted the ecological relevance, arguing for thorough assessments of their ecological risks before the commercialization of any new antifouling compound. PMID- 25456220 TI - Influence of short-term exposure to low levels of 17alpha-ethynylestradiol on expression of genes involved in immunity and on immune parameters in rainbow trout, Oncorhynchus mykiss. AB - Fish are exposed to endocrine-disrupting chemicals (EDC), which are well known to disturb not only the reproductive system but also the immune system in vertebrates. However, the mechanisms by which these compounds are able to modify fish immunity are not well understood. In order to test the EE2 effects on immunity in selected organs, we exposed rainbow trout male juveniles for 3 weeks to EE2 concentrations ranging from 0.01 to 1 MUg/L. The results of this study suggest that EE2 affects the immunity of rainbow trout in a tissue dependent manner. This molecule affects both cellular and humoral immune systems. Indeed, blood leukocyte populations, as well as hepatic and plasma lysozyme, plasma MPO and renal complement activities, are modulated by EE2. Moreover, EE2 alters the gene expression of some mucus compounds, hepatic expression of complement sub unit and lysozyme, or genes involved in the hepatic phagocytosis and transport of immunoglobulin across the liver. PMID- 25456221 TI - Arsenic accumulation and tolerance in rootless macrophyte Najas indica are mediated through antioxidants, amino acids and phytochelatins. AB - Arsenic (As) accumulation and tolerance response of a submerged rootless macrophyte Najas indica were evaluated during arsenate (As(V); 10-250 MUM) and arsenite (As(III); 1-50 MUM) exposure. Higher As accumulation at As(III) exposure and more tolerance upon As(V) exposure resulted in more toxicity during As(III) stress than As(V), which was evident through measurement of growth parameters and oxidative stress related parameters viz., lipid peroxidation (MDA content), electrical conductivity (EC) and hydrogen peroxide (H2O2) levels. Antioxidant enzymes and various amino acids were more prominent during moderate exposure of As(V), suggesting their possible role in As tolerance and detoxification. Various non-enzymatic antioxidant metabolites viz., ascorbic acid (ASC), glutathione (GSH), non-protein thiols (NPTs) and phytochelatins (PCs) biosynthesis involving phytochelatin synthase (PCS) activity increased more significantly during As(III) stress. However, PCs content seems inadequate in response to As accumulation leading to lower PC-SH:As molar ratio and higher As phytotoxicity during As(III) stress. N. indica may prove useful plant species for phytoremediation purpose in moderately As contaminated water bodies due to high As accumulation and tolerance potential. PMID- 25456222 TI - Acute and chronic toxicities of zinc pyrithione alone and in combination with copper to the marine copepod Tigriopus japonicus. AB - Zinc pyrithione (ZnPT) is a widely used booster biocide in combination with copper (Cu) in antifouling paints as a substitute for tributyltin. The co occurrence of ZnPT and Cu in coastal marine environments is therefore very common, and may pose a higher risk to marine organisms if they can result in synergistic toxicity. This study comprehensively investigated the combined toxicity of ZnPT and Cu, on the marine copepod Tigriopus japonicus, for the first time, based on both 96-h acute toxicity tests using adult copepods and chronic full-life cycle tests (21 d) using nauplii <24-h old. As ZnPT has been reported to be easily trans-chelated to copper pyrithione (CuPT) in the presence of Cu, the acute toxicities of CuPT alone and in combination with Cu on adult copepods were also assessed. Our results showed that ZnPT and Cu exhibited a strong synergistic toxic effect on the copepod in both acute and chronic tests. During the acute test, the mortalities of adult copepods increased dramatically even with an addition of Cu at concentrations as low as 1-2 MUg/L compared with those exposed to ZnPT alone. Severe chronic toxicities were further observed in the copepods exposed to ZnPT-Cu mixtures, including a significant increase of naupliar mortality, postponing of development from naupliar to copepodid and from copepodid to adult stage, and a significant decrease of intrinsic population growth when compared with those of copepods exposed to ZnPT or Cu alone. Such synergistic effects might be partly attributable to the formation of CuPT by the trans-chelation of ZnPT and Cu, because CuPT was found to be more toxic than ZnPT based on the acute toxicity results. Mixtures of CuPT and Cu also led to synergistic toxic effects to the copepod, in particular at high Cu concentrations. A novel non-parametric response surface model was applied and it proved to be a powerful method for analysing and predicting the acute binary mixture toxicities of the booster biocides (i.e., ZnPT and CuPT) and Cu on the copepod. To better protect precious marine resources, it is necessary to revise and tighten existing water quality criteria for biocides, such as ZnPT and CuPT, to account for their synergistic effects with Cu at environmentally realistic levels. PMID- 25456223 TI - Effect of sodium dodecyl sulfate (SDS) on stress response in the Mediterranean mussel (Mytilus Galloprovincialis): regulatory volume decrease (Rvd) and modulation of biochemical markers related to oxidative stress. AB - In this study the effects of an anionic surfactant, sodium dodecyl sulfate (SDS), are assessed on the Mediterranean mussel (Mytilus galloprovincialis), exposed for 18 days at a concentration ranging from 0.1 mg/l to 1 mg/l. The effects are monitored using biomarkers related to stress response, such as regulatory volume decrease (RVD), and to oxidative stress, such as reactive oxygen species (ROS), endogenous antioxidant systems and Hsp70 levels. The results demonstrate that cells from the digestive gland of M. galloprovincialis, exposed to SDS were not able to perform the RVD owing to osmotic stress. Further, SDS causes oxidative stress in treated organisms, as demonstrated by the increased ROS production, in comparison to the controls (p<0.05). Consequently, two enzymes involved in ROS scavenging, superoxide dismutase (SOD) and catalase (CAT) have higher activities and the proportion of oxidized glutathione (GSSG) is higher in hepatopancreas and mantle of treated animals, compared to untreated animals (p<0.05). Furthermore Hsp70 demonstrates an up-regulation in all the analyzed tissues of exposed animals, attesting the stress status induced by the surfactant with respect to the unexposed animals. The results highlight that SDS, under the tested concentrations, exerts a toxic effect in mussels in which the disruption of the osmotic balance follows the induction of oxidative stress. PMID- 25456224 TI - Trophic transfer of differently functionalized zinc oxide nanoparticles from crustaceans (Daphnia magna) to zebrafish (Danio rerio). AB - The potential uptake and trophic transfer of nanoparticles (NP) is not well understood so far and for ZnO NP the data presented in peer-reviewed literature is limited. In this paper the influence of surface functionalization on the uptake and depuration behavior of ZnO NP, ZnO-OH NP and ZnO-octyl NP in D. magna was studied. Bulk ZnO particles (<=5 MUm) and ZnCl2 were used as references for uptake of particles and dissolved species of Zn, respectively. Furthermore, the trophic transfer of ZnO NP and ZnO-octyl NP from daphnids (Daphnia magna) to zebra fish (Danio rerio) was studied. For ZnO NP and ZnO-octyl NP fast uptakes in D. magna were observed, whereas no measurable uptake took place for ZnO-OH NP. Lower body burden of ZnCl2 was found compared to both ZnO NP and ZnO-octyl. Contrary, the body burden for bulk ZnO was higher than that of ZnO NP but lower than ZnO-octyl. The higher body burdens found for functionalized ZnO-octyl NP than for non-functionalized ZnO NP showed that that the functionalization of the NP has a high influence on the uptake and depuration behavior. Though no mortality was observed, the resulting body burdens were 9.6 times (ZnO NP) and 47 times (ZnO-octyl NP) higher than toxic levels reported for zinc in D. magna. Consequently, the zinc recovered in the animals was not solely due to soluble zinc, but agglomerates/aggregates of ZnO NP or ZnO-octyl NP contributed to the body burdens. The trophic transfer study showed uptake of both ZnO NP and ZnO octyl NP reaching more than tenfold higher levels than those obtained through aqueous exposure in other studies. This study contributes to expand the available data on uptake behavior of differently functionalized ZnO NP in D. magna and the potential trophic transfer from zooplankton to fish. PMID- 25456225 TI - Influences of sediment geochemistry on metal accumulation rates and toxicity in the aquatic oligochaete Tubifex tubifex. AB - Metal bioaccumulation and toxicity in the aquatic oligochaete Tubifex tubifex exposed to three metal-contaminated field-sediments was studied in order to assess whether sediment-geochemistry (AVS, TOC) plays a major role in influencing these parameters, and to assess if the biodynamic concept can be used to explain observed effects in T. tubifex tissue residues and/or toxicity. An active autotomy promotion was observed in three studied sediments at different time points and reproduction impairment could be inferred in T. tubifex exposed to two of the tested sites after 28 days. The present study showed that sediment metal concentration and tissue residues followed significant regression models for four essential metals (Cu, Co, Ni and Zn) and one non-essential metal (Pb). Organic content normalization for As also showed a significant relationship with As tissue residue. Porewater was also revealed to be an important source of metal uptake for essential metals (e.g. Cu, Ni and Zn) and for As, but AVS content was not relevant for metal uptake in T. tubifex in studied sediments. Under the biodynamic concept, it was shown that influx rate from food (IF, sediment ingestion) in T. tubifex, in a range of sediment geochemistry, was able to predict metal bioaccumulation, especially of the essential metals Cu, Ni and Zn, and for the non-essential metal Pb. Additionally, IF appeared to be a better predictor for metal bioaccumulation in T. tubifex compared to sediment geochemistry normalization. PMID- 25456226 TI - The effect of cold stress on the proteome of the marine bacterium Pseudomonas fluorescens BA3SM1 and its ability to cope with metal excess. AB - This study examined the effect of cold stress on the proteome and metal tolerance of Pseudomonas fluorescens BA3SM1, a marine strain isolated from tidal flat sediments. When cold stress (+10 degrees C for 36 h) was applied before moderate metal stress (0.4 mM Cd, 0.6 mM Cd, 1.5 mM Zn, and 1.5 mM Cu), growth disturbances induced by metal, in comparison with respective controls, were reduced for Cd and Zn while they were pronounced for Cu. This marine strain was able to respond to cold stress through a number of changes in protein regulation. Analysis of the predicted differentially expressed protein functions demonstrated that some mechanisms developed under cold stress were similar to those developed in response to Cd, Zn, and Cu. Therefore, pre-cold stress could help this strain to better counteract toxicity of moderate concentrations of some metals. P. fluorescens BA3SM1 was able to remove up to 404.3 mg Cd/g dry weight, 172.5 mg Zn/g dry weight, and 11.3 mg Cu/g dry weight and its metal biosorption ability seemed to be related to the bacterial growth phase. Thus, P. fluorescens BA3SM1 appears as a promising agent for bioremediation processes, even at low temperatures. PMID- 25456227 TI - Influence of the perivitelline space on the quantification of internal concentrations of chemicals in eggs of zebrafish embryos (Danio rerio). AB - The chorion and the perivitelline space which surround unhatched zebrafish embryos (ZFE, Danio rerio) may affect the determination of internal concentrations of study compounds taken up in early life-stages of ZFE. Internal concentration-time profiles were gathered for benzocaine, caffeine, clofibric acid, metribuzin and phenacetin as study compounds over 96 h of exposure starting with ZFE at 4h post-fertilization. Liquid chromatography coupled to tandem-mass spectrometry (LC-MS/MS) was used to determine the concentration of the study compounds from intact (i.e. unhatched), dechorionated and from hatched ZFE. The mass of the study compounds per ZFE was 5-30 ng higher for intact ZFE compared to dechorionated ones. Thus, internal concentrations were overestimated if only intact ZFE were analyzed. Dechorionation of unhatched ZFE after their exposure is proposed to determine the true internal concentration in the embryo. For the compounds studied here the mass of the study compounds determined in unhatched ZFE after a short term (5 min) exposure provided a reasonable estimate of the mass taken up by the chorion and the PVS. This mass can be subtracted from the total mass found in unhatched ZFE to calculate the true internal mass. Estimating the mass in the chorion and the PVS from the concentration of the study compound in the external exposure medium and the volume of the PVS provided no reasonable results. PMID- 25456228 TI - Transient exposure to environmental estrogen affects embryonic development of brown trout (Salmo trutta fario). AB - Transient exposure of brown trout embryos from fertilization until hatch (70 days) to 17beta-estradiol (E2) was investigated. Embryos were exposed to 3.8 and 38.0 ng/L E2 for 2h, respectively, under four scenarios: (A) exposure once at the day of fertilization (0 days post-fertilization, dpf), (B) once at eyeing stage (38 dpf), (C) weekly exposure until hatch or (D) bi-weekly exposure until hatch. Endpoints to assess estrogen impact on embryo development were fertilization success, chronological sequence of developmental events, hatching process, larval malformations, heart rate, body length and mortality. Concentration-dependent acceleration of development until median hatch was observed in all exposure scenarios with the strongest effect observed for embryos exposed once at 0 dpf. In addition, the hatching period was significantly prolonged by 4-5 days in groups receiving single estrogen exposures (scenarios A and B). Heart rate on hatching day was significantly depressed with increasing E2 concentrations, with the strongest effect observed for embryos exposed at eyeing stage. Estrogenic exposure at 0 dpf significantly reduced body length at hatch, not depending on whether this was a single exposure or the first of a series (scenarios A and D). The key finding is that even a single, transient E2 exposure during embryogenesis had significant effects on brown trout development. Median hatch, hatching period, heart rate and body length at hatch were found to be highly sensitive biomarkers responsive to estrogenic exposure during embryogenesis. Treatment effects were observable only at the post-hatch stage. PMID- 25456229 TI - Lack of variation in voltage-gated sodium channels of common bottlenose dolphins (Tursiops truncatus) exposed to neurotoxic algal blooms. AB - In coastal marine ecosystems, neurotoxins produced by harmful algal blooms (HABs) often result in large-scale mortality events of many marine species. Historical and frequent exposure to HABs therefore may provide a strong selective pressure for adaptations that result in toxin resistance. Neurotoxin resistance has independently evolved in a variety of terrestrial and marine species via mutations in genes encoding the toxin binding sites within the voltage-gated sodium channel gene complex. Accordingly, we tested the hypothesis that genetic variation in the putative binding site of brevetoxins in common bottlenose dolphins (Tursiops truncatus) explains differences among individuals or populations in resistance to harmful Karenia brevis blooms in the Gulf of Mexico. We found very little variation in the sodium channel exons encoding the putative brevetoxin binding site among bottlenose dolphins from central-west Florida and the Florida Panhandle. Our study included samples from several bottlenose dolphin mortality events associated with HABs, but we found no association between genetic variation and survival. We observed a significant effect of geographic region on genetic variation for some sodium channel isoforms, but this can be primarily explained by rare private alleles and is more likely a reflection of regional genetic differentiation than the cause of different levels of HAB resistance between regions. In contrast to many other previously studied neurotoxin-resistant species, we conclude that bottlenose dolphins have not evolved resistance to HABs via mutations in genes encoding the brevetoxin binding site on the voltage-gated sodium channels. PMID- 25456230 TI - Prymnesium parvum revisited: relationship between allelopathy, ichthyotoxicity, and chemical profiles in 5 strains. AB - Bioassay-guided discovery of ichthyotoxic algal compounds using in vivo fish assays is labor intensive, costly, and highly regulated. Since the mode of action of most known algal-mediated fish-killing toxins is damage to the cell membranes in the gills, various types of cell-based bioassays are often used for bioassay guided purification of new ichthyotoxins. Here we tested the hypothesis that allelopathy is related to ichthyotoxicity and thus that a microalgal bioassay can be used as a proxy for ichthyotoxicity by comparing the toxicity of five strains of Prymnesium parvum toward rainbow trout (Oncorhynchus mykiss, 10 g) and the microalga Teleaulax acuta. No relationship between median effective concentrations (EC50s) on fish and median lethal concentrations (LC50s) on algae was observed in the 5 strains showing that a microalgal bioassay cannot be used as a proxy for ichthyotoxicity. Fish were more sensitive to P. parvum with EC50s ranging from 6*10(3) to 40*10(3) cells ml(-1), compared to the test alga where LC50s ranged from 30*10(3) to nearly non-toxic at 500*10(3) cells ml(-1). In addition, the cellular concentrations of two recently suggested ichthyotoxins produced by P. parvum, the "golden algae toxins", GAT 512 and a novel GAT 510, did not show any relationship to either ichthyotoxicity or allelopathy, and are not the biologically relevant toxins, but are simply lipids found in algal chloroplasts. Finally, we demonstrate that the recently suggested ichthyotoxin, oleamide, could not be detected in any of the five P. parvum strains above the limit of detection, nor was it found in a (13)C-labeled strain. Instead we document that oleamide can easily be extracted from plastic materials, which may have been the source of oleamide reported previously. PMID- 25456231 TI - Effects of nitrogen and phosphorus on arsenite accumulation, oxidation, and toxicity in Chlamydomonas reinhardtii. AB - We studied arsenite (iAs(III)) accumulation, oxidation, and toxicity in the freshwater green alga Chlamydomonas reinhardtii under nutrient-enriched (+NP), phosphorus-limited (-P), and nitrogen-limited (-N) conditions. The -P alga (55.1 MUM) had a Michaelis constant (Kd) for uptake approximately one tenth of the +NP (419 MUM) and -N (501 MUM) cells, indicating iAs(III) uptake inhibition by extracellular phosphate. This conclusion was supported by the hyperbolic reduction in iAs(III) uptake rate (V) from 9.2 to 0.8 MUmol/g-dw/h when the extracellular phosphate concentration went up from 0 to 250 MUM. The maximal iAs(III) uptake rate (Vmax) of the -N alga (24.3 MUmol/g-dw/h) was twice as much as that of the +NP (12 MUmol/g-dw/h) and -P (8.1 MUmol/g-dw/h) cells. It implies that more arsenic transporters were synthesized under the -N condition. Once accumulated, iAs(III) was oxidized and a higher proportion of arsenate (iAs(V)) was observed at lower [As]dis or under nutrient-limited conditions. Nevertheless, iAs(III) oxidation mainly occurred outside the cells with the extent of oxidation reciprocal to [As]dis. Based on the logistic modeling of the concentration response curves in the +NP, -P, and -N toxicity tests, iAs(III) had an [As]dis based EC50 of 1763, 13.1, and 1208 MUM and an intracellular arsenic concentration based EC50 of 35.6, 28.8, and 195 MUmol/g-dw, respectively. Higher iAs(III) toxicity to the -P cells occured because of their increased iAs(III) accumulation, whereas the underlying mechanisms why the -N alga was more tolerant need to be further revealed. Overall, both N and P had remarkable effects on the behavior and effects of iAs(III), which cannot be disregarded in the biogeochemical cycling research of arsenic. PMID- 25456232 TI - Hypoxia acclimation protects against oxidative damage and changes in prolactin and somatolactin expression in silver catfish (Rhamdia quelen) exposed to manganese. AB - The aim of this study was to assess the Mn toxicity to silver catfish considering Mn accumulation and oxidative status in different tissues, as well as pituitary hormone expression after acclimation to hypoxia. Silver catfish acclimated to hypoxia for 10 days and successively exposed to Mn (9.8 mg L(-1)) for an additional 10 days exhibited lower Mn accumulation in plasma, liver, kidneys and brain and prevented the hematocrit decrease observed in the normoxia group. Hypoxia acclimation also modified Mn-induced oxidative damage, which was observed by lower reactive species (RS) generation in gills and kidneys, decreased lipid peroxidation (LP) levels in gills, liver and kidneys and decreased protein carbonyl (PC) levels in liver, kidneys and brain. Manganese accumulation showed positive correlations with LP levels in gills and kidneys, as well as with PC levels in gills, liver and brain. In addition, hypoxia acclimation and Mn exposure increased catalase (CAT) activity in gills and kidneys and Na(+)/K(+) ATPase activity in gills, liver and brain. Silver catfish that were acclimated under normoxia and exposed to Mn displayed increased pituitary prolactin (PRL) and decreased somatolactin (SL) expression. Interestingly, hypoxia acclimation prevented hormonal fluctuation of PRL and SL in fish exposed to Mn. These findings indicate that while the exposure of silver catfish to Mn under normoxia was related to metal accumulation and oxidative damage in tissues together with endocrine axis disruption, as represented by PRL and SL, hypoxia acclimation reduced waterborne Mn uptake, thereby minimizing oxidative damage and changes in hormonal profile. We hypothesized that moderate hypoxia is able to generate adaptive responses, which may be related to hormesis, thereby ameliorating Mn toxicity to silver catfish. PMID- 25456233 TI - Impact of co-exposure with lead and decabromodiphenyl ether (BDE-209) on thyroid function in zebrafish larvae. AB - Polybrominated diphenyl ethers (PBDEs) and metals are the main contaminants at waste electrical and electronic equipment ("e-waste") recycling sites. However, the potential environmental health effects of mixtures of PBDEs and metals are not known. We investigated co-exposure of lead (Pb) with decabromodiphenyl ether (BDE-209) on thyroid function in zebrafish larvae. Seven groups of embryos/larvae of zebrafish were treated with Pb (0, 2, 5, 10, 15, 20, and 30 MUg/L), six groups were exposed to BDE-209 (0, 50, 100, 200, 400, and 800 MUg/L), and nine groups of zebrafish larvae were treated with Pb and BDE-209 (5, 10, and 20 MUg/L Pb; 50, 100, and 200 MUg/L BDE-209). Embryos/larvae were exposed from 2h post fertilization (hpf) until 144 hpf, and thyroid hormone (TH) content measured. Pb exposure significantly decreased whole-body TH contents (triiodothyroxine (T3) and thyroxine (T4)) but BDE-209 exposure significantly increased T3 and T4 levels. Pb or BDE-209 treatment alone caused a predicted downregulation of TH transport (i.e., expression of the mRNA or proteins of transthyretin). Chemical analyses showed Pb uptake to be increased by BDE-209, but BDE-209 bioconcentration was decreased and the ability to metabolize BDE-209 was reduced in the presence of Pb. We also found that a mixture of the two chemicals had a synergistic effect on TH levels in zebrafish. PMID- 25456234 TI - Effects of cadmium on cell proliferation, apoptosis, and proto-oncogene expression in zebrafish liver cells. AB - Cadmium (Cd) is one of the major transitional metal that has toxic effects in aquatic organisms and their associated ecosystem; however, its hepatic toxicity and carcinogenicity are not very well characterized. We used a zebrafish liver (ZFL) cell line as a model to investigate the mechanism of Cd-induced toxicity on hepatocytes. Our results showed that Cd can be effectively accumulated in ZFL cells in our exposure experiments. Cell cytotoxicity assays and flow cytometer measurements revealed that Cd(2+) stimulated ZFL cell proliferation with decreasing apoptotic cell numbers indicating potentially tumorigenic effects of Cd in ZFL cells. Gene expression profiles also indicated that Cd downregulated oncogenes p53 and rad51 and upregulated immediate response oncogenes, growth arrest and DNA damage-inducible (gadd45) genes, and growth factors. We also found dramatic changes in the gene expression of c-jun and igf1rb at different exposure time points, supporting the notion that potentially tumorigenic of Cd-is involved in the activation of immediate early genes or genes related to apoptosis in cancer promotion. PMID- 25456235 TI - Population-level effects in Amphiascus tenuiremis: contrasting matrix- and individual-based population models. AB - Environmental risk assessment (ERA) is generally based on individual-level endpoints, even though protection goals in ERA intend higher biological levels. Population models have the potential to translate individual-level endpoints to population-level responses and range from simple demographic equations to highly complex individual based models (IBMs). The aims of the current study were to develop a matrix model (MM) with the structure and parameterization proposed in the draft OECD guideline "Harpacticoid copepod development and reproduction test with Amphiascus tenuiremis", and an IBM with the same data requirements. Experimental data from lindane exposure from validation studies of the OECD guideline was projected to the population level. Lindane does not only cause effects on survival and reproduction, but also on the time it takes to develop from larvae to adults. The two model approaches were contrasted in terms of their ability to properly project these effects on development. The MM projected smaller effects of the lindane treatments on population growth rate compared to the IBM since in its proposed structure, it did not include the delay in development explicitly. Population-level EC10 for population growth rate in the IBM was at the same level as the most sensitive individual-level endpoint, whereas the EC10 from the MM was not as sensitive. Based on these findings, our conclusion is that the IBM (or an improved MM) should be used for datasets including shifts in development, whereas the simpler MM is sufficient for datasets where only mortality and reproduction are affected, or as a screening tool in lower-tier population-level ERA. PMID- 25456236 TI - Morphological alterations and acetylcholinesterase and monoamine oxidase inhibition in liver of zebrafish exposed to Aphanizomenon flos-aquae DC-1 aphantoxins. AB - Aphanizomenon flos-aquae is a cyanobacterium that produces neurotoxins or paralytic shellfish poisons (PSPs) called aphantoxins, which present threats to environmental safety and human health via eutrophication of water bodies worldwide. Although the molecular mechanisms of this neurotoxin have been studied, many questions remain unsolved, including those relating to in vivo hepatic neurotransmitter inactivation, physiological detoxification and histological and ultrastructural alterations. Aphantoxins extracted from the natural strain of A. flos-aquae DC-1 were analyzed by high-performance liquid chromatography. The main components were gonyautoxins 1 and 5 (GTX1, GTX5) and neosaxitoxin (neoSTX), which comprised 34.04%, 21.28%, and 12.77% respectively. Zebrafish (Danio rerio) were exposed intraperitoneally to 5.3 or 7.61 MUg STX equivalents (eq)/kg (low and high doses, respectively) of A. flos-aquae DC-1 aphantoxins. Morphological alterations and changes in neurotransmitter conduction functions of acetylcholinesterase (AChE) and monoamine oxidase (MAO) in zebrafish liver were detected at different time points 1-24h post-exposure. Aphantoxin significantly enhanced hepatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histological and ultrastructural damage in zebrafish liver at 3-12 h post-exposure. Toxin exposure increased the reactive oxygen species content and reduced total antioxidative capacity in zebrafish liver, suggesting oxidative stress. AChE and MAO activities were significantly inhibited, suggesting neurotransmitter inactivation/conduction function abnormalities in zebrafish liver. All alterations were dose- and time-dependent. Overall, the results indicate that aphantoxins/PSPs induce oxidative stress through inhibition of AChE and MAO activities, leading to neurotoxicity in zebrafish liver. The above parameters may be useful as bioindicators for investigating aphantoxins/PSPs and cyanobacterial blooms in nature. PMID- 25456237 TI - PFOS affects posterior swim bladder chamber inflation and swimming performance of zebrafish larvae. AB - Perfluorooctane sulphonate (PFOS) is one of the most commonly detected perfluorinated alkylated substances in the aquatic environment due to its persistence and the degradation of less stable compounds to PFOS. PFOS is known to cause developmental effects in fish. The main effect of PFOS in zebrafish larvae is an uninflated swim bladder. As no previous studies have focused on the effect of PFOS on zebrafish swim bladder inflation, the exact mechanisms leading to this effect are currently unknown. The objective of this study was to determine the exposure windows during early zebrafish development that are sensitive to PFOS exposure and result in impaired swim bladder inflation in order to specify the mechanisms by which this effect might be caused. Seven different time windows of exposure (1-48, 1-72, 1-120, 1-144, 48-144, 72-144, 120-144h post fertilization (hpf)) were tested based on the different developmental stages of the swim bladder. These seven time windows were tested for four concentrations corresponding to the EC-values of 1, 10, 80 and 95% impaired swim bladder inflation (EC1=0.70 mg L(-1), EC10=1.14 mg L(-1), EC80=3.07 mg L(-1) and EC95=4.28 mg L(-1)). At 6 days post fertilization, effects on survival, hatching, swim bladder inflation and size, larval length and swimming performance were assessed. For 0.70 mg L(-1), no significant effects were found for the tested parameters while 1.14 mg L(-1) resulted in a reduction of larval length. For 3.07 and 4.28 mg L(-1), the number of larvae affected and the severity of effects caused by PFOS were dependent on the time window of exposure. Exposure for 3 days or more resulted in significant reductions of swim bladder size, larval length and swimming speed with increasing severity of effects when the duration of exposure was longer, suggesting a possible effect of accumulated dose. Larvae that were only exposed early (1-48 hpf) or late (120-144 hpf) during development showed no effects on the studied endpoints. The results demonstrate that PFOS does not affect the budding phase, and does not cause deflation of already inflated swim bladders. PFOS clearly affects processes that take place during the inflation phase and might also have an effect on the formation of the tissue layers forming the swim bladder. PMID- 25456238 TI - Organic acid blend with pure botanical product treatment reduces Escherichia coli and Salmonella populations in pure culture and in in vitro mixed ruminal microorganism fermentations. AB - Foodborne pathogenic bacteria can live in the intestinal tract of food animals and can be transmitted to humans via food or indirectly through animal or fecal contact. Organic acid blend products have been used as nonantibiotic modifiers of the gastrointestinal fermentation of food animals to improve growth performance efficiency. However, the impact of these organic acid products on the microbial population, including foodborne pathogens, remains unknown. Therefore, this study was designed to examine the effects of a commercial organic acid and botanical blend product (OABP) on populations of the foodborne pathogenic bacteria, Escherichia coli O157:H7 and Salmonella Typhimurium. Pure cultures (2*10(6) colony-forming units [CFU]/mL) of each pathogen were added to tubes that contained water-solubilized OABP added at concentrations of 0, 0.1, 0.5, 1, 2, 5, and 10% (vol/vol; n=3). Water-solubilized OABP reduced (p<0.05) the growth rate and final populations of E. coli O157:H7 and Salmonella Typhimurium in pure culture at concentrations >2%. E. coli O157:H7 and Salmonella Typhimurium were added (2*10(5) and 3*10(6) CFU/mL, respectively) to in vitro mixed ruminal microorganism fermentations that contained water-solubilized OABP at concentrations of 0, 1, 2, 5, and 10% (vol/vol; n=3) that were incubated for 24 h. OABP addition reduced (p<0.05) final populations of E. coli O157:H7 and Salmonella Typhimurium in the ruminal fluid at concentrations >=5%. The acetate to-propionate ratios from the in vitro fermentations were reduced (p<0.05) by OABP treatment >=5%. Treatments to reduce foodborne pathogens must be economically feasible to implement, and results indicate that organic acid products, such as OABP, can enhance animal growth efficiency and can be used to reduce populations of pathogenic bacteria. PMID- 25456239 TI - Vasculitic pleural effusion. PMID- 25456240 TI - Letter on the article "Malignant head/neck paragangliomas. Comparative study". PMID- 25456241 TI - Authors' response to the letter on the article: "Malignant head/neck paragangliomas. Comparative study". PMID- 25456244 TI - Relationships between cooperation and goal orientation among male professional and semi-professional team athletes. AB - In team sports, athletes' goals may focus on the task (enhancing performance, developing better skills, etc.) or on ego (being better than the others, achieving superiority, etc.). This study investigated the relationships between athletes' goal orientation and their tendency to cooperate with teammates and coaches. 158 professional men (M age = 24.1 yr., SD = 4.6) who played on various sport teams participated in this study. Goal orientation was measured with the Portuguese version of the Task and Ego Orientation in Sport Questionnaire, and cooperation was measured with the Questionario de Cooperacao Desportiva. Cooperation was positively correlated with task orientation, and negatively correlated with ego orientation. Overall, the findings support that in sports, directing the players' focus on task may promote prosocial behavior. PMID- 25456242 TI - Consensus document for prescription of nebulization in rhinology. AB - OBJECTIVES: The French Society of ORL set up a work group to draw up a consensus document on the prescription of nebulization in rhinology. The document deals with the principles of and indications for rhinologic aerosol therapy. MATERIALS AND METHODS: The work group's methodology followed the rules published by the French health authority (Haute Autorite de sante [HAS]) in January 2006: "Methodological foundations for drawing up professional guidelines by formalized consensus" (available on the HAS website athttp://www.has-sante.fr). The method used is the short version (without editorial group) of the RAND/UCLA Appropriateness Method; the short version was chosen because this particular consensus conference was dealing with a very precise topic with very few experts in the field. RESULTS: Sonic aerosol therapy with nasal plug is the preferred modality, delivering treatment into the middle meati. The group recommends that drugs with market authorization for use in bronchopulmonary pathology should be nebulized in two 10-minute sessions per day for at least seven days. Indications for rhinologic aerosol therapy are: purulent edematous rhinosinusitis, subacute rhinosinusitis (4-12 weeks' evolution), exacerbations of chronic rhinosinusitis, and postoperative (>1 month) rhinosinus suppuration.Audiometric monitoring is required in iterative aminoside nebulization.Conclusion: Rhinologic aerosol therapy can be used in purulent edematous rhinosinusitis, subacute rhi nosinusitis, exacerbations of chronic rhinosinusitis and postoperative rhinosinus suppuration. The rules for prescription contained in the present document optimize efficacy. PMID- 25456245 TI - Does pilates exercise increase physical activity, quality of life, latency, and sleep quantity in middle-aged people? AB - This prospective study assessed the effects of a 12-wk. exercise program based on the Pilates method (2 one-hr. sessions per week) on 99 sedentary middle-aged volunteers (M age = 47.6 yr., SD = 0.8), using an accelerometry, the Pittsburgh Sleep Quality Index, and the SF-36 questionnaire to measure changes in physical activity, quality of life, sleep latency, and quantity. The variables (quality of life, sleep latency, and quantity) were compared before and after applying the Pilates program. All of the physical and emotional components of the SF-36 questionnaire showed significant improvement, and the latency and sleep quantity also showed significant increases. The results indicate that Pilates is an accessible, interesting exercise program that can generate important changes in middle age. PMID- 25456243 TI - Guidelines of the French Society of Otorhinolaryngology (SFORL), short version. Extension assessment and principles of resection in cutaneous head and neck tumors. AB - Cutaneous head and neck tumors mainly comprise malignant melanoma, squamous cell carcinoma, trichoblastic carcinoma, Merkel cell carcinoma, adnexal carcinoma, dermatofibrosarcoma protuberans, sclerodermiform basalioma and angiosarcoma. Adapted management requires an experienced team with good knowledge of the various parameters relating to health status, histology, location and extension: risk factors for aggression, extension assessment, resection margin requirements, indications for specific procedures, such as lateral temporal bone resection, orbital exenteration, resection of the calvarium and meningeal envelopes, neck dissection and muscle resection. PMID- 25456246 TI - A situated analysis of football goalkeepers' experiences in critical game situations. AB - This study described elite football (soccer) goalkeepers' activity and performance in critical game situations. The 11 best French players (M age = 15.5 yr., SD = 0.5) participated in the study. Interviews focused on goalkeepers' experiences were conducted to identify meaningful events involved in failed actions. Players formulated 23 critical game situations. Verbatim encoding using a thematic analysis indicated that four main categories (coming off the line, goal-line clearance, one-on-one, and diving) represented the most critical situations encountered during matches. The relations among experience and action, inner states, background, attention contents, and intentions were elucidated. The discussion is grounded on the properties of such critical game situations and their implications for improving goalkeepers' performance. PMID- 25456247 TI - Effect of intrinsic motivation on affective responses during and after exercise: latent curve model analysis. AB - Understanding the relationship between affect and exercise is helpful in predicting human behavior with respect to exercise participation. The goals of the present study were to investigate individual differences in affective response during and after exercise and to identify the role of intrinsic motivation in affective changes. 30 active male college students (M age = 21.4 yr.) who regularly participated in sports activities volunteered to answer a questionnaire measuring intrinsic motivation toward running activities and performed a 20-min. straight running protocol at heavy intensity (about 70% of VO2max). Participants' affective responses were measured every 5 min. from the beginning of the run to 10 min. after completing the run. Latent curve model analysis indicated that individuals experienced different changes in affective state during exercise, moderated by intrinsic motivation. Higher intrinsic motivation was associated with more positive affect during exercise. There were no significant individual differences in the positive tendency of the participants' affective responses after exercise over time. Intrinsic motivation seems to facilitate positive feelings during exercise and encourages participation in exercise. PMID- 25456248 TI - Effects of set configuration of resistance exercise on perceived exertion. AB - Set configuration refers to the repetitions performed with regard to the maximum possible number of repetitions, a factor affecting RPE that has not been previously studied. This study analyzed the effect of set configuration and muscle mass on RPE. Eight students (M age = 23.7 yr. +/- 1.7) completed four sessions corresponding to types of exercise with different amount of muscle mass (bench press and parallel squat) and two set configurations: a session with five sets of repetitions to failure and a cluster session. The cluster session involved the same intensity, volume, and rest than the failure session, guaranteeing the same work-to-rest ratio. RPE was higher in Failure vs Cluster sessions and higher in parallel squat vs bench press. This suggests that set configuration influences RPE. Similarly, RPE can be affected by the muscle mass of the exercise performed. PMID- 25456249 TI - Measuring soccer technique with easy-to-administer field tasks in female soccer players from four different competitive levels. AB - Soccer is a multidimensional sport that requires skills in many different domains. Reports from competitions at the highest levels around the world suggest that a particularly decisive performance factor is a team's technical execution. Testing of technical skills in soccer has been infrequent compared with testing of physiological variables, and there has been a lack of consensus as to which tasks should be included in test batteries. In this study, the validity of four field tasks (heading, long pass, juggling, and hit-the-post) was examined by testing 108 female soccer players from four different competitive levels, representing a hierarchy of skill levels. Correlation analysis indicated that the tasks' results appeared statistically unrelated (Spearman's rho <= .36). Statistical comparisons across competitive levels showed that task performance was closely correlated with players' competition level, with regression analysis indicating that 92% of the variance in mean rankings across tasks could be explained by competitive level. As the easily administered and low-cost tasks identified differences in technical skills across competitive levels, such tasks appear valid for inclusion in tests of technical skills. PMID- 25456250 TI - Vividness and transformation of mental images in karate and ballet. AB - While imagery research has become popular in recent years, little research has specifically investigated differences in imagery ability between open- and closed skill sport activities. The purpose of this study was to investigate whether the type of task, open or closed, affects vividness and controllability differently. Thirty female classic dancers (closed skill), 30 female karate athletes (open skill), and 30 female non-athlete students, between 14 and 20 years of age (M = 17.0, SD = 1.6), participated. They completed the Vividness of Visual Imagery Questionnaire, the Vividness of Movement Imagery Questionnaire, and the Subtraction of Parts Task. There was no difference in imagery ability between open- and closed-skill sport groups. Furthermore, dancers and karatekas had higher mean scores on imagery ability than the non-athlete group. A positive correlation was observed between the two questionnaires, supporting findings on the componential basis of imagery. This study contributed to increase the research in the specific area of open- and closed-skill sports and imagery ability. PMID- 25456251 TI - How important is it to score a goal? The influence of the scoreline on match performance in elite soccer. AB - The goal of this study was to examine the effects of three different scorelines (1 Goal Up, Level Score, 1 Goal Down) on match performance indicators in elite soccer. Ball possession decreased when teams were 1 goal up. High Range Budget Clubs (HRBC) and Upper-Mid Range Budget Clubs (UMRBC) dominated possession against their opponents whether winning, losing, or drawing. Lower-Mid Range Budget Clubs (LMRBC) and Low Range Budget Clubs (LRBC) had less possession than HRBC. The probability of reaching the final one-third of the pitch decreased when teams were 1 goal up. LMRBC and LRBC had less match final third entries than HRBC. Similarly, shots on goal decreased when teams were 1 goal up. These findings could be used by coaches and match analysts when they evaluate performance and develop training drills. PMID- 25456252 TI - Classifying young soccer players by training performances. AB - Players within the same age group may present different physical and physiological profiles. This study classified young soccer players according to their physical and physiological profiles obtained during the training sessions and compared classification by age and playing position criteria. 151 male elite Portuguese soccer players (under 15, under 17, and under 19 years old) participated. Time-motion and body acceleration and deceleration data were collected using GPS technology with heart rate monitored continuously across the selected training sessions. The data were grouped using two-step cluster analysis to classify athletes. A repeated-measures factorial ANOVA was performed to identify differences in the variables. Three clusters comprised 15.2%, 37.1%, and 47.7% of the total sample, respectively. Players of the same ages and playing experience had different performance profiles. Grouping players with similar physiological profiles during training sessions may allow coaches to balance oppositions and reduce the variability of the physiological outcomes. PMID- 25456253 TI - Factors associated with student learning processes in primary health care units: a questionnaire study. AB - BACKGROUND: Clinical placement plays a key role in education intended to develop nursing and caregiving skills. Studies of nursing students' clinical learning experiences show that these dimensions affect learning processes: (i) supervisory relationship, (ii) pedagogical atmosphere, (iii) management leadership style, (iv) premises of nursing care on the ward, and (v) nursing teachers' roles. Few empirical studies address the probability of an association between these dimensions and factors such as student (a) motivation, (b) satisfaction with clinical placement, and (c) experiences with professional role models. OBJECTIVE: The study aimed to investigate factors associated with the five dimensions in clinical learning environments within primary health care units. DESIGN AND METHODS: The Swedish version of Clinical Learning Environment, Supervision and Teacher, a validated evaluation scale, was administered to 356 graduating nursing students after four or five weeks clinical placement in primary health care units. Response rate was 84%. Multivariate analysis of variance is determined if the five dimensions are associated with factors a, b, and c above. RESULTS: The analysis revealed a statistically significant association with the five dimensions and two factors: students' motivation and experiences with professional role models. The satisfaction factor had a statistically significant association (effect size was high) with all dimensions; this clearly indicates that students experienced satisfaction. CONCLUSIONS: These questionnaire results show that a good clinical learning experience constitutes a complex whole (totality) that involves several interacting factors. Supervisory relationship and pedagogical atmosphere particularly influenced students' satisfaction and motivation. These results provide valuable decision-support material for clinical education planning, implementation, and management. PMID- 25456254 TI - Establishing and maintaining the clinical learning environment for nursing students: a qualitative study. AB - BACKGROUND: Experience in the clinical setting is viewed as a crucial aspect of nursing education. Evidence suggests that students experience acceptance to alienation on the clinical unit. Little is known about preceptor beliefs underlying their approach with students, and the perspective of unit management is absent. OBJECTIVES: To provide a description of the beliefs and processes that emerge at the unit level regarding the clinical learning environment for nursing students. DESIGN: Multiple case study design. SETTING: Four units from across an urban university health center who have a demonstrated ability to accept students. PARTICIPANTS: A purposive sample of four nurse managers, four assistant nurse managers, three advanced practice nurses, and six staff nurses with recent and recurrent precepting experience were recruited from across four units. METHODS: Semi-structured focus group interviews were conducted with all participants from each unit. Content analysis was used to identify major themes and categories in the interview data. RESULTS: Two overarching themes were revealed: (1) Influencing factors included cultural factors and contextual factors that either inform units' beliefs about the ideal learning environment, or affect their ability to provide it. (2) Willingness refers to a willingness to invest in students and the forms that investment takes. It includes openness, taking them under wing, and structuring to meet goals. The influencing factors provide the foundation upon which the unit's work to accommodate students is built. CONCLUSIONS: The degree to which a unit is able to manage the contextual factors determines how well they can shape the students' environment. The sturdiness of their culture with regard to hosting students determines the pervasiveness of their approach by staff on the unit. PMID- 25456255 TI - The sum of all parts: an Australian experience in improving clinical partnerships. AB - AIM: To create a collaborative partnership between the education provider (University) and the placement provider (Hospital) to facilitate the identification and development of strategies to improve capacity and capability for nursing clinical placements. This partnership was labelled (TULIP) to identify the two partners and it purpose as a learning investment project. BACKGROUND: The quality of clinical learning is interdependent on the collaborative clinical health partnerships between Hospital, University, preceptors/facilitators and students. Success is dependent on communication between all key stakeholders within the partnership, to meet capacity and capability demand. DESIGN: Collaborative quality assurance project in combination with two research projects. METHOD: Quantitative and qualitative measurements of student perceptions, preceptor understanding and organisation partnership capacity and capability over a three year period in an acute care hospital. RESULTS: Qualitative and quantitative data from students and preceptors, and hospital quality assurance data linked to become the TULIP framework for a clinical placement development model that addresses the key components of strategic communication, resourcing and staff acknowledgement between stakeholders. CONCLUSIONS: The outcomes achieved demonstrated student engagement, clinical leadership from registered nursing staff, and the establishment of a collaborative partnership between hospital executives and staff, and the university resulting in an increased capacity. The TULIP project has provided both partners with a sustainable plan for growth in student placements, improved strategies to develop clinical leadership practice in individual nurses and a better clinical learning environment for staff that uses a framework that is transferrable to other health settings. PMID- 25456256 TI - The development and issues of nursing education in China: a national data analysis. AB - BACKGROUND: The development of and the issues arising in the nursing educational sector as the provider for nursing workforce have drawn increasing attention. OBJECTIVES: To describe the development of nursing education in mainland China and to analyze related issues. DESIGN: A retrospective, descriptive study with secondary data analysis. METHODS: The scale and composition of nursing education programs from 2006 to 2012 in mainland China were analyzed, and changes in the scale of the nursing workforce from 2002 to 2013 were compared to facilitate an interpretation of nursing education. RESULTS: The scale of initial nursing education was large and expanded rapidly. In 2012, the total recruitment was 515,710, including 39,747 (7.71%) students training for a baccalaureate degree, 143,726 (27.87%) students training for an advanced diploma, and 332,237 (64.42%) students training in secondary diploma programs. The nursing workforce in China grew dramatically, with an increase of 120,000 to 286,000 nurses each year since 2006, but the nurse shortage remained existed (there were only 2.05 nurses per 1000 population, and the nurse to doctor ratio was 1:1 in 2013). The recruitment of nursing students per 1000 population was greater in the west (0.51) and middle (0.40) regions than in the east region (0.28), while the number of nurses per 1000 population had the opposite pattern (1.71, 1.75, and 2.02 nurses per 1000 population in the west, middle, and east regions, respectively) in 2012. CONCLUSIONS: Nursing education in China has developed rapidly, and some issues require attention. We suggest that initial nursing education be improved by increasing the recruitment to advanced diploma and baccalaureate programs and decreasing the recruitment to secondary diploma programs and by ensuring the quality of education. Multiple strategies should be taken to effectively raise the social status and prestige of the nursing profession and to ease the nurse shortage. PMID- 25456257 TI - Comparison of meaningful learning characteristics in simulated nursing practice after traditional versus computer-based simulation method: a qualitative videography study. AB - BACKGROUND: Nursing educators must ensure that nursing students acquire the necessary competencies; finding the most purposeful teaching methods and encouraging learning through meaningful learning opportunities is necessary to meet this goal. We investigated student learning in a simulated nursing practice using videography. OBJECTIVES: The purpose of this paper is to examine how two different teaching methods presented students' meaningful learning in a simulated nursing experience. DESIGN: The 6-hour study was divided into three parts: part I, general information; part II, training; and part III, simulated nursing practice. Part II was delivered by two different methods: a computer-based simulation and a lecture. SETTINGS: The study was carried out in the simulated nursing practice in two universities of applied sciences, in Northern Finland. PARTICIPANTS: The participants in parts II and I were 40 first year nursing students; 12 student volunteers continued to part III. METHODS: Qualitative analysis method was used. The data were collected using video recordings and analyzed by videography. RESULTS: The students who used a computer-based simulation program were more likely to report meaningful learning themes than those who were first exposed to lecture method. CONCLUSION: Educators should be encouraged to use computer-based simulation teaching in conjunction with other teaching methods to ensure that nursing students are able to receive the greatest educational benefits. PMID- 25456258 TI - Comparison of knowledge, confidence in skill performance (CSP) and satisfaction in problem-based learning (PBL) and simulation with PBL educational modalities in caring for children with bronchiolitis. AB - BACKGROUND: In most nursing curricula, simulation and problem-based learning (PBL) are used separately as individual learning methods. Nursing educators are in a unique position to improve students' clinical performance and critical thinking skills by utilizing varied educational modalities. PURPOSE: This study attempted to compare changes in nursing students' knowledge, confidence in skill performance (CSP), and satisfaction resulting from training using three educational modalities. PARTICIPANTS: Data from a convenient sample of 205 senior nursing students from three nursing schools in Seoul and Chuncheon, South Korea, was obtained between September 1 and December 10, 2013. METHODS: This comparison study used three groups: the PBL group, simulation with the PBL group, and the control group. For data analysis, descriptive statistics, paired t-test, one-way ANOVA, and post-hoc tests (Duncan test) were performed. RESULTS: No significant difference in the students' baseline knowledge of patient care for patients with bronchiolitis was found. There were significant differences in the mean scores of knowledge (F=14.718, p<.001), CSP (F=12.693, p<.001), and students' satisfaction (F=93.471, p<.001) among the three groups. CONCLUSION: The positive impact of PBL and a combined learning method in this study suggests that it can be an effective approach in pediatric nursing practice. These results provide a much-needed template and starting point for educators introducing active learning approaches for pediatric nursing courses. PMID- 25456259 TI - Use of mobile devices in nursing student-nurse teacher cooperation during the clinical practicum: an integrative review. AB - OBJECTIVES: To identify and appraise study findings on the use of mobile devices, in particular for what purposes and how, in nursing student-nurse teacher cooperation during the clinical practicum. DATA SOURCES: A systematic literature search was conducted using the PubMed/Medline, CINAHL, PsycINFO and ERIC for primary empirical studies published in English. REVIEW METHODS: An integrative literature review was undertaken. Quality appraisal of the included studies was conducted using design-specific standardized checklists. Studies were thematically analyzed. RESULTS: Based on the inclusion and exclusion criteria, eleven studies were included in the review. Weaknesses in designs, samples, questionnaires and results, compromised comparison and/or generalization of the findings of the studies. Three main themes were identified: (1) features of mobile devices (2) utility of mobile devices and (3) barriers to the use of mobile devices. Problems of connectivity were the main challenges reported in the use of mobile devices. Participants used mobile devices primarily as reference tools, but less frequently as tools for reflection, assessment or cooperation during the clinical practicum. Interest in mobile device use during the clinical practicum was reported, but training and ongoing support are needed. CONCLUSIONS: As only a small number of eligible primary empirical studies were found, it is not possible to draw firm conclusions on the results. In the future, rigorous primary empirical studies are needed to explore the potential of mobile devices in providing a supplementary pedagogical method in nursing student-nurse teacher cooperation during the clinical practicum. Robust study designs, including experimental ones, are clearly needed to assess the effectiveness of mobile devices in nursing student-nurse teacher cooperation during the clinical practicum. PMID- 25456260 TI - Comparison of effects of training programs for final year nursing students in Turkey: differences in self-efficacy with regard to information literacy. AB - BACKGROUND: Information literate person are aware of where and how they can obtain the information they need. Little is known about student nurses information literacy skills in different education programs. OBJECTIVES: To find out how final year nursing students rated their own abilities to acquire new information. DESIGN AND PARTICIPANTS: This study used comparative and descriptive cross-sectional surveys. Participants were final year students in two different programs, in two different universities in Turkey. METHODS: The study sample consisted of final year nursing students who received training in Classic Learning (N: 61) and Problem-Based Learning (N: 96). As an evaluation instrument for the perceptions of the students their own information literacy, a scale consisting of 28 questions with 7 Likert ratings for each was used (min: 28, max: 196). RESULTS: The return rates of the surveys were 96.7% in the school with classic training and 81.2% in the school with PBL. It was found that the average scores of the students were high, with a mean of 137+/-29 in the school where the classic training program was carried out, and 163+/-21 in the school where the training was PBL. A statistically significant difference was found by comparing the average scores of the two independent groups (t : -6.0; p<0.05). CONCLUSIONS: Students in both of the training programs rated themselves as high. However, PBL training had a stronger influence on the development of their self-perceptions regarding information literacy. We conclude that training programs should be reviewed, and new methods should be developed based on these concepts. PMID- 25456261 TI - Wisdom, prudence and academic freedom. PMID- 25456262 TI - Treating hypertension and prehypertension in older people: when, whom and how. AB - Prehypertension should be treated with lifestyle measures and not with antihypertensive drug therapy in older adults. Lifestyle measures should be encouraged both to retard development of hypertension and as adjunctive therapy in those with hypertension. A meta-analysis of 11 randomized controlled trials of 40,325 older persons showed that antihypertensive drug therapy significantly reduced all-cause mortality 13% (7-19%), cardiovascular death 18% (7-27%), cardiovascular events 21% (13-27%), stroke 30% (23-37%), and fatal stroke by 33% (9-50%) (Ostrowski et al., 2014 [32]). The American College of Cardiology/American Heart Association 2011 expert consensus document on hypertension in the elderly recommended that the systolic blood pressure be lowered to <140 mm Hg in older persons younger than 80 years and to 140-145 mm Hg if tolerated in adults aged 80 years and older. A meta-analysis of 147 randomized trials including 464,000 persons with hypertension showed that except for the extra protective effect of beta blockers given after myocardial infarction and a minor additional effect of calcium channel blockers in preventing stroke, the use of beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), diuretics, and calcium channel blockers cause a similar reduction in coronary events and stroke for a given decrease in blood pressure. The choice of specific antihypertensive drugs such as diuretics, ACE inhibitors, ARBs, beta blockers, or calcium channel blockers depends on efficacy, tolerability, presence of specific comorbidities and cost. PMID- 25456263 TI - Hyperaggregability and impaired nitric oxide production in platelets from postmenopausal women. AB - OBJECTIVE: Cardiovascular mortality increases after menopause in women. Nitric oxide is essential for proper platelet function inhibiting its aggregation and maintaining vascular haemostasis. Here, we investigated whether platelet function and intraplatelet l-arginine-nitric oxide pathway are impaired in postmenopausal women. STUDY DESIGN: Cross-sectional. MAIN OUTCOMES MEASURES: Blood was collected from 16 premenopausal and 12 postmenopausal women without any additional risk factor for cardiovascular disease. Platelet reactivity was measured by light transmission aggregometry. l-Arginine-nitric oxide pathway was assessed measuring transmembrane l-[(3)H]-arginine transport, nitric oxide synthase activity by the citrulline assay, and arginase activity by the conversion of l-[(14)C]arginine to l-[(14)C]-urea. The activity of antioxidant enzymes was measured by spectrophotometric assays. Protein expression was determined by Western blotting. RESULTS: Platelet aggregation was increased in postmenopausal compared to premenopausal women. Postmenopausal women demonstrated reduced plasma levels of l arginine, a lower nitric oxide synthase activity, similar endothelial and inducible nitric oxide synthase expression, and a compensatory increase in l arginine transmembrane transport. Arginase expression and activity did not differ between groups. In regard to oxidative stress, no differences between groups were observed NAPDH oxidase subunits expression and protein carbonylation. However, the activity of the antioxidant enzyme superoxide dismutase and catalase protein levels in platelets were higher in postmenopausal women. CONCLUSION: Postmenopausal women present increased platelet reactivity, which may be due to a reduction in intraplatelet nitric oxide synthesis. Platelet hyperaggregability is known to be associated with arterial and venous thromboembolic event; therefore, it may contribute to the heightened risk of cardiovascular adverse events in this population. PMID- 25456264 TI - Biotransformation in vitro: An essential consideration in the quantitative in vitro-to-in vivo extrapolation (QIVIVE) of toxicity data. AB - Early consideration of the multiplicity of factors that govern the biological fate of foreign compounds in living systems is a necessary prerequisite for the quantitative in vitro-in vivo extrapolation (QIVIVE) of toxicity data. Substantial technological advances in in vitro methodologies have facilitated the study of in vitro metabolism and the further use of such data for in vivo prediction. However, extrapolation to in vivo with a comfortable degree of confidence, requires continuous progress in the field to address challenges such as e.g., in vitro evaluation of chemical-chemical interactions, accounting for individual variability but also analytical challenges for ensuring sensitive measurement technologies. This paper discusses the current status of in vitro metabolism studies for QIVIVE extrapolation, serving today's hazard and risk assessment needs. A short overview of the methodologies for in vitro metabolism studies is given. Furthermore, recommendations for priority research and other activities are provided to ensure further widespread uptake of in vitro metabolism methods in 21st century toxicology. The need for more streamlined and explicitly described integrated approaches to reflect the physiology and the related dynamic and kinetic processes of the human body is highlighted i.e., using in vitro data in combination with in silico approaches. PMID- 25456265 TI - Ethanol induced impairment of glucose metabolism involves alterations of GABAergic signaling in pancreatic beta-cells. AB - Alcohol overindulgence is a risk factor of type 2 diabetes mellitus. However, the mechanisms by which alcohol overindulgence damages glucose metabolism remain unclear. Pancreatic islet beta-cells are endowed with type-A gamma-aminobutyric acid receptor (GABAAR) mediated autocrine signaling mechanism, which regulates insulin secretion and fine-tunes glucose metabolism. In neurons GABAAR is one of the major targets for alcohol. This study investigated whether ethanol alters glucose metabolism by affecting GABAAR signaling in pancreatic beta-cells. Blood glucose level of test mice was measured using a blood glucose meter. Insulin secretion by the pancreatic beta-cell line INS-1 cells was examined using a specific insulin ELISA kit. Whole-cell patch-clamp recording was used to evaluate GABA-elicited current in INS-1 cells. Western blot and immunostaining were used to measure the expression of GABAAR subunits in mouse pancreatic tissues or in INS-1 cells. Intraperitoneal (i.p.) administration of ethanol (3.0g/kg body weight) to mice altered glucose metabolism, which was associated with decreased expression of GABAAR alpha1- and delta- subunits on the surface of pancreatic beta-cells. Acute treatment of cultured INS-1cells with ethanol (60mM) decreased the GABA-induced current and reduced insulin secretion. In contrast, treating INS 1 cells with GABA (100MUM) largely prevented the ethanol-induced reduction of insulin release. Importantly, pre-treating mice with GABA (i.p., 1.5mg/kg body weight) partially reversed ethanol-induced impairment of glucose homeostasis in mice. Our data suggest a novel role of pancreatic GABA signaling in protecting pancreatic islet beta-cells from ethanol-induced dysfunction. PMID- 25456266 TI - Microcystin-LR induces anoikis resistance to the hepatocyte uptake transporter OATP1B3-expressing cell lines. AB - Microcystin-LR is a cyclic peptide released by several bloom-forming cyanobacteria. Understanding the mechanism of microcystin-LR toxicity is important, because of the both potencies of its acute cytotoxicity and tumor promoting activity in hepatocytes of animals and humans. Recently, we have reported that the expression of human hepatocyte uptake transporter OATP1B3 was critical for the selective uptake of microcystin-LR into hepatocytes and for induction of its fatal cytotoxicity. In this study, we demonstrated a novel function of microcystin-LR which induced bipotential changes including anoikis resistance and cytoskeleton reorganization to OATP1B3-transfected HEK293 cells (HEK293-OATP1B3). After exposure to microcystin-LR, HEK293-OATP1B3 cells were divided to the floating cells and remaining adherent cells. After collection and reseeding the floating cells into a fresh flask, cells were confluently proliferated (HEK293-OATP1B3-FL) under the microcystin-LR-free condition. Both the proliferated HEK293-OATP1B3-FL and remaining adherent HEK293-OATP1B3-AD cells changed the character with down- and up-regulation of E-cadherin, respectively. Additionally, these cells acquired resistance to microcystin-LR. These results suggest that microcystin-LR could be associated with not only tumor promotion, but also epithelial-mesenchymal transition-mediated cancer metastasis. Furthermore, microcystin-LR might induce the cytoskeleton reorganization be accompanied epithelial-mesenchymal transition. PMID- 25456267 TI - Comparative in vivo and in vitro analysis of possible estrogenic effects of perfluorooctanoic acid. AB - Previous studies suggested that perfluorooctanoate (PFOA) could activate the estrogen receptor (ER). The present study examined the hypothesis that PFOA can activate ER using an in vivo uterotrophic assay in CD-1 mice and an in vitro reporter assay. Pre-pubertal female CD-1 mice fed an estrogen-free diet from postnatal day (PND)14 through weaning on PND18 were administered 0, 0.005, 0.01, 0.02, 0.05, 0.1, or 1mg/kg PFOA or 17beta-estradiol (E2, 0.5mg/kg) from PND18-20. In contrast to E2, PFOA caused no changes in the relative uterine weight, the expression of ER target genes, or the morphology of the uterus/cervix and/or vagina on PND21. Treatment of a stable human cell line containing an ER-dependent luciferase reporter construct with a broad concentration range of PFOA caused no change in ER-dependent luciferase activity; whereas E2 caused a marked increase of ER-dependent luciferase activity. These data indicate that PFOA does not activate mouse or human ER. PMID- 25456268 TI - Genetic variation influences immune responses in sensitive rats following exposure to TiO2 nanoparticles. AB - This study examines the immunological responses in rats following inhalation to titanium dioxide nanoparticles (TiO2 NPs), in naive rats and in rats with induced allergic airway disease. The responses of two different inbred rat strains were compared: the Dark Aguoti (DA), susceptible to chronic inflammatory disorders, and the Brown Norwegian (BN), susceptible to atopic allergic inflammation. Naive rats were exposed to an aerosol of TiO2 NPs once daily for 10 days. Another subset of rats was sensitized to the allergen ovalbumin (OVA) in order to induce airway inflammation. These sensitized rats were exposed to TiO2 NPs before and during the allergen challenge. Naive rats exposed to TiO2 NPs developed an increase of neutrophils and lymphocytes in both rat strains. Airway hyperreactivity and production of inflammatory mediators typical of a T helper 1 type immune response were significantly increased, only in DA rats. Sensitization of the rats induced a prominent OVA-specific-IgE and IgG response in the BN rat while DA rats only showed an increased IgG response. Sensitized rats of both strains developed airway eosinophilia following allergen challenge, which declined upon exposure to TiO2 NPs. The level of neutrophils and lymphocytes increased upon exposure to TiO2 NPs in the airways of DA rats but remained unchanged in the airways of BN rats. In conclusion, the responses to TiO2 NPs were strain-dependent, indicating that genetics play a role in both immune and airway reactivity. DA rats were found to be higher responder compared to BN rats, both when it comes to responses in naive and sensitized rats. The impact of genetically determined factors influencing the inflammatory reactions pinpoints the complexity of assessing health risks associated with nanoparticle exposures. PMID- 25456269 TI - Application of RNA interference to improve mechanistic understanding of omics responses to a hepatotoxic drug in primary rat hepatocytes. AB - Inhibition of the glucagon receptor (GCGR) has been identified as a potential therapeutic approach for the treatment of type 2 diabetes. However, a small molecule drug candidate antagonizing GCGR (BAY16) failed during preclinical drug development, in part due to drug induced hepatotoxicity in animals. Since there is evidence to suggest that endogenous GCGR signaling might be important for hepatocyte survival, we hypothesized that on-target effects, i.e., modulation of GCGR activity by BAY16, may contribute to BAY16 hepatotoxicity and associated gene expression changes in rats. To understand the role of GCGR inhibition in BAY16 toxicity, we analyzed cell viability and gene expression profiles in non silenced and GCGR-targeting siRNA transfected primary rat hepatocytes with and without exposure to BAY16 to discriminate between on- and off-target effects of BAY16. siRNA-mediated silencing of the GCGR did not affect cell viability in primary rat hepatocytes, indicating that cytotoxicity of BAY16 occurs independent of its pharmacological effects. In support of this, gene expression analysis of GCGR silenced hepatocytes revealed no transcriptional alterations relevant to toxicity. In contrast, BAY16 caused a concentration-dependent decrease in cell viability, along with changes in the expression of genes associated with altered xenobiotic metabolism, oxidative stress, increased fatty acid synthesis, and alterations in cholesterol and bile acid metabolic processes. Based on gene expression data, it appears that hepatocytes inhibit cholesterol synthesis and increase detoxifying and eliminating processes in order to protect themselves from accumulation of bile acids, cholesterol or drug intermediates. Importantly, comparison of transcriptional changes in the absence and presence of GCGR revealed that the same pathways were affected in both silenced and non-silenced hepatocytes, indicating that BAY16 toxicity occurs independent of the GCGR receptor. PMID- 25456270 TI - Phosgene- and chlorine-induced acute lung injury in rats: comparison of cardiopulmonary function and biomarkers in exhaled breath. AB - This study compares changes in cardiopulmonary function, selected endpoints in exhaled breath, blood, and bronchoalveolar lavage fluid (BAL) following a single, high-level 30-min nose-only exposure of rats to chlorine and phosgene gas. The time-course of lung injury was systematically examined up to 1-day post-exposure with the objective to identify early diagnostic biomarkers suitable to guide countermeasures to accidental exposures. Chlorine, due to its water solubility, penetrates the lung concentration-dependently whereas the poorly water-soluble phosgene reaches the alveolar region without any appreciable extent of airway injury. Cardiopulmonary endpoints were continually recorded by telemetry and barometric plethysmography for 20h. At several time points blood was collected to evaluate evidence of hemoconcentration, changes in hemostasis, and osteopontin. One day post-exposure, protein, osteopontin, and cytodifferentials were determined in BAL. Nitric oxide (eNO) and eCO2 were non-invasively examined in exhaled breath 5 and 24h post-exposure. Chlorine-exposed rats elaborated a reflexively-induced decreased respiratory rate and bradycardia whereas phosgene exposed rats developed minimal changes in lung function but a similar magnitude of bradycardia. Despite similar initial changes in cardiac function, the phosgene exposed rats showed different time-course changes of hemoconcentration and lung weights as compared to chlorine-exposed rats. eNO/eCO2 ratios were most affected in chlorine-exposed rats in the absence of any marked time-related changes. This outcome appears to demonstrate that nociceptive reflexes with changes in cardiopulmonary function resemble typical patterns of mixed airway-alveolar irritation in chlorine-exposed rats and alveolar irritation in phosgene-exposed rats. The degree and time-course of pulmonary injury was reflected best by eNO/eCO2 ratios, hemoconcentration, and protein in BAL. Increased fibrin in blood occurred only in chlorine-exposed rats 1-day post-exposure. Hence, the analysis of NO and CO2 in exhaled breath, including endpoints in blood mirroring changes in the peripheral to pulmonary fluid distribution, seem to be sensitive diagnostic endpoints readily available for early prognostic assessment of severity of injury and efficacy of any chosen countermeasure. PMID- 25456271 TI - Autophagy and senescence, stress responses induced by the DNA-damaging mycotoxin alternariol. AB - The mycotoxin alternariol (AOH), a frequent contaminant in fruit and grain, is known to induce cellular stress responses such as reactive oxygen production, DNA damage and cell cycle arrest. Cellular stress is often connected to autophagy, and we employed the RAW264.7 macrophage model to test the hypothesis that AOH induces autophagy. Indeed, AOH treatment led to a massive increase in acidic vacuoles often observed upon autophagy induction. Moreover, expression of the autophagy marker LC3 was markedly increased and there was a strong accumulation of LC3-positive puncta. Increased autophagic activity was verified biochemically by measuring the degradation rate of long-lived proteins. Furthermore, AOH induced expression of Sestrin2 and phosphorylation of AMPK as well as reduced phosphorylation of mTOR and S6 kinase, common mediators of signaling pathways involved in autophagy. Transmission electron microscopy analyzes of AOH treated cells not only clearly displayed structures associated with autophagy such as autophagosomes and autolysosomes, but also the appearance of lamellar bodies. Prolonged AOH treatment resulted in changed cell morphology from round into more star-shaped as well as increased beta-galactosidase activity. This suggests that the cells eventually entered senescence. In conclusion, our data identify here AOH as an inducer of both autophagy and senescence. These effects are suggested to be to be linked to AOH-induced DSB (via a reported effect on topoisomerase activity), resulting in an activation of p53 and the Sestrin2-AMPK-mTOR-S6K signaling pathway. PMID- 25456272 TI - Interactive cervical motion kinematics: sensitivity, specificity and clinically significant values for identifying kinematic impairments in patients with chronic neck pain. AB - Chronic neck pain has been consistently shown to be associated with impaired kinematic control including reduced range, velocity and smoothness of cervical motion, that seem relevant to daily function as in quick neck motion in response to surrounding stimuli. The objectives of this study were: to compare interactive cervical kinematics in patients with neck pain and controls; to explore the new measures of cervical motion accuracy; and to find the sensitivity, specificity, and optimal cutoff values for defining impaired kinematics in those with neck pain. In this cross-section study, 33 patients with chronic neck pain and 22 asymptomatic controls were assessed for their cervical kinematic control using interactive virtual reality hardware and customized software utilizing a head mounted display with built-in head tracking. Outcome measures included peak and mean velocity, smoothness (represented by number of velocity peaks (NVP)), symmetry (represented by time to peak velocity percentage (TTPP)), and accuracy of cervical motion. Results demonstrated significant and strong effect-size differences in peak and mean velocities, NVP and TTPP in all directions excluding TTPP in left rotation, and good effect-size group differences in 5/8 accuracy measures. Regression results emphasized the high clinical value of neck motion velocity, with very high sensitivity and specificity (85%-100%), followed by motion smoothness, symmetry and accuracy. These finding suggest cervical kinematics should be evaluated clinically, and screened by the provided cut off values for identification of relevant impairments in those with neck pain. Such identification of presence or absence of kinematic impairments may direct treatment strategies and additional evaluation when needed. PMID- 25456273 TI - Sensibility of a new instrument to assess clinical reasoning in post-graduate orthopaedic manual physical therapy education. AB - Sound application of clinical reasoning (CR) by the physical therapist is critical to achieving optimal patient outcomes. As such, it is important for institutions granting certification in orthopaedic manual physical therapy (OMPT) to ensure that the assessment of CR is sufficiently robust. At present, the dearth of validated instruments to assess CR in OMPT presents a serious challenge to certifying institutions. Moreover, the lack of documentation of the development process for instruments that measure CR pose additional challenges. The purpose of this study is to evaluate the sensibility of a newly developed instrument for assessing written responses to a test of CR in OMPT; a 'pilot' phase that examines instrument feasibility and acceptability. Using a sequential mixed-methods approach, Canadian OMPT examiners were recruited to first review and use the instrument. Participants completed a sensibility questionnaire followed by semi-structured interviews, the latter of which were used to elaborate on questionnaire responses regarding feasibility and acceptability. Eleven examiners completed the questionnaire and interviews. Questionnaire results met previously established sensibility criteria, while interview data revealed participants' (dis)comfort with exerting their own judgment and with the rating scale. Quantitative and qualitative data provided valuable insight regarding content validity and issues related to efficiency in assessing CR competence; all of which will ultimately inform further psychometric testing. While results suggest that the new instrument for assessing clinical reasoning in the Canadian certification context is sensible, future research should explore how rater judgment can be utilized effectively and the mental workload associated with appraising clinical reasoning. PMID- 25456275 TI - Low-voltage origami-paper-based electrophoretic device for rapid protein separation. AB - We present an origami paper-based electrophoretic device (oPAD-Ep) that achieves rapid (~5 min) separation of fluorescent molecules and proteins. Due to the innovative design, the required driving voltage is just ~10 V, which is more than 10 times lower than that used for conventional electrophoresis. The oPAD-Ep uses multiple, thin (180 MUm/layer) folded paper layers as the supporting medium for electrophoresis. This approach significantly shortens the distance between the anode and cathode, and this, in turn, accounts for the high electric field (>1 kV/m) that can be achieved even with a low applied voltage. The multilayer design of the oPAD-Ep enables convenient sample introduction by use of a slip layer as well as easy product analysis and reclamation after electrophoresis by unfolding the origami paper and cutting out desired layers. We demonstrate the use of oPAD Ep for simple separation of proteins in bovine serum, which illustrates its potential applications for point-of-care diagnostic testing. PMID- 25456274 TI - Multi-centered investigation of a point-of-care NT-proBNP ELISA assay to detect moderate to severe occult (pre-clinical) feline heart disease in cats referred for cardiac evaluation. AB - OBJECTIVE: To prospectively evaluate the diagnostic accuracy of a point-of-care (POC) N-terminal pro-B-type natriuretic peptide (NT-proBNP) ELISA to assess the likelihood of moderate to severe occult heart disease (OcHD) in a clinical population of cats suspected to have heart disease. ANIMALS: One hundred and forty-six asymptomatic client-owned cats with a heart murmur, gallop rhythm, arrhythmia, or cardiomegaly. METHODS: Physical examination, blood pressure measurement and echocardiography were performed prospectively. Point-of-care ELISA was visually assessed as either positive or negative by a reader blinded to the echocardiographic results. RESULTS: Forty-three healthy cats, 50 mild OcHD, 31 moderate OcHD, 6 severe OcHD, and 16 cats equivocal for OcHD were examined. Cats with OcHD included 65 with hypertrophic cardiomyopathy, 6 with restrictive or unclassified cardiomyopathy, 1 with arrhythmogenic right ventricular cardiomyopathy, and 15 with non-cardiomyopathic forms of heart disease. Point-of care ELISA differentiated cats with moderate or severe OcHD with sensitivity/specificity of 83.8%/82.6% and overall accuracy of 82.9%. Positive POC ELISA increased likelihood of moderate or severe OcHD by a factor of 4.8 vs. those that tested negative. Point-of-care ELISA differentiated cats with moderate or severe cardiomyopathic OcHD with sensitivity/specificity of 88.6%/81.3% and overall accuracy of 83.2%. CONCLUSION: In a select sample of cats referred for cardiac evaluation, positive POC NT-proBNP ELISA increases likelihood of moderate to severe OcHD while negative POC NT-proBNP ELISA result excludes moderate to severe OcHD. PMID- 25456276 TI - Dysfunction of phospholipase Cgamma in immune disorders and cancer. AB - The surge in genetic and genomic investigations over the past 5 years has resulted in many discoveries of causative variants relevant to disease pathophysiology. Although phospholipase C (PLC) enzymes have long been recognized as important components in intracellular signal transmission, it is only recently that this approach highlighted their role in disease development through gain-of function mutations. In this review we describe the new findings that link the PLCgamma family to immune disorders and cancer, and illustrate further efforts to elucidate the molecular mechanisms that underpin their dysfunction. PMID- 25456277 TI - Childhood EEG frontal alpha power as a predictor of adolescent antisocial behavior: a twin heritability study. AB - High EEG frontal alpha power (FAP) is thought to represent a state of low arousal in the brain, which has been related in past research to antisocial behavior (ASB). We investigated a longitudinal sample of 900 twins in two assessments in late childhood and mid-adolescence to verify whether relationships exist between FAP and both aggressive and nonaggressive ASB. ASB was measured by the Child Behavioral Checklist, and FAP was calculated using connectivity analysis methods that used principal components analysis to derive power of the most dominant frontal activation. Significant positive predictive relationships emerged in males between childhood FAP and adolescent aggressive ASB using multilevel mixed modeling. No concurrent relationships were found. Using bivariate biometric twin modeling analysis, the relationship between childhood FAP and adolescent aggressive ASB in males was found to be entirely due to genetic factors, which were correlated r=0.22. PMID- 25456278 TI - The effects of epinephrine and dobutamine on skin flap viability in rats: a randomized double-blind placebo-controlled study. AB - BACKGROUND: Intraoperative reduction in arterial pressure may cause hypoperfusion of skin flaps, which may increase the risk of flap failure. There is no international consensus regarding the use of vasoactive or inotropic agents to restore or maintain flap perfusion. The purpose of this study was to evaluate the effects of the intraoperative administration of epinephrine and dobutamine on axial-pattern skin flap survival in rats. METHODS: Fifty-four Sprague Dawley rats were randomized into three groups (n = 18). A tubed axial-pattern skin flap was performed. Animals were randomized to receive an intraperitoneal injection of epinephrine 0.1 mg/kg, dobutamine 0.3 mg/kg, or saline (0.5 ml). The rats were euthanized after 7 days and the viable area of the flap was compared between the groups using a digital imaging and computer software. RESULTS: Seven rats/flaps were excluded from the study due to autocannibalism (n = 3), postoperative tracheal obstruction (n = 2), anesthesia-induced respiratory arrest (n = 1), and abnormal behavior requiring euthanization (n = 1). The mean flap survival was 46% +/- 9% in the saline group (n = 17), 41% +/- 9% in the epinephrine group (n = 14) (p = 0.088 compared to the saline group), and 54% +/- 9% in the dobutamine group (n = 16) (p = 0.02 compared to the saline group and p = 0.001 compared to the epinephrine group). CONCLUSIONS: Intraoperative intraperitoneal injection of dobutamine improves skin flap survival in rats, whereas intraperitoneal epinephrine tends to decrease skin flap survival. PMID- 25456279 TI - Serial reconstruction of anophthalmic orbits with 'bag-shaped' flaps. AB - BACKGROUND: The author's goal was to present an approach for serial surgical reconstruction of anophthalmic orbits with 'bag-shaped' flaps and cartilage transplantation. METHODS: A review was performed of 53 patients who underwent serial physiological orbital reconstruction between 2006 and 2013. Orbital reconstruction was performed serially in stages, including "bag-shaped" flap transplantation, medial and lateral canthoplasty, tarsus reconstruction, and improvement of the strength of the levator palpebrae superior muscles. Curative effects were evaluated by the surgeons and patients jointly. RESULTS: Among the total of 53 cases, the curative effects were assessed as excellent in 28 patients, good in 17 patients, moderate in 6 patients, and poor in 2 patients. Two cases suffered necrosis of the bag-shaped flap, which was remedied with a frontal island flap and skin grafting; 4 cases experienced shallowness of the lower fornix, of which three were remedied by deepening of the lower fornix and the other by lower eyelid suspension. The appearance of the reconstructed eye socket was acceptable, natural and persistent. CONCLUSION: This procedure offers staged and serial reconstruction of anophthalmic orbits, according to the orbital shape and the volume loss of the orbital soft tissue. It is an ideal approach to reconstruct eye sockets, with a high survival rate of the flaps, acceptable appearance of the reconstructed eye socket, and stable depth of the upper and lower eyelid fornices. PMID- 25456280 TI - Treatment of male genital lymphedema: an integrated concept. AB - Genital lymphedema is a debilitating condition. Currently, therapeutic concepts include conservative and surgical measures of genital volume reduction, but no therapy standards exist. The aim of this study was to analyze our experience with the treatment of male genital lymphedema and to describe our integrated concept, which combines perioperative complex decongestive physiotherapy (CDP) with surgical reduction. We conducted a retrospective study of 51 male patients who were treated in our clinic between 1998 and 2013, acquiring data on etiology, performed therapy, and complication rates. Forty-three (84%) of our patients suffered from primary and eight (16%) from secondary lymphedema. Two patients (4%) exhibited isolated penile affection and 22 (43%) isolated scrotal affection, while the majority (27 or 53%) exhibited penoscrotal lymphedema. All patients underwent inpatient CDP preceding and following surgery. Surgical therapy involved debulking the scrotum in 25 patients (49%), isolated penile reduction in two (4%), and penoscrotal reduction in 24 (47%). Hydrocoelectomy was performed in 22 (43%) patients. Following resection of the diseased tissue, the defects were closed primarily using adjacent healthy skin. There was no need for local flaps or skin grafts. Three patients suffered from complications requiring revision surgery: hematoma in two patients (4%) and wound dehiscence in one (2%). We measured the change in quality of life that was achieved by these procedures using the Glasgow Benefit Inventory questionnaire. The patients reported improvement in general functioning and physical health, whereas the social support score was largely unaffected by the procedure. Our results show that genital lymphedema patients can be reliably treated by combining conservative and surgical therapy. Prior conservative reduction of the genitals facilitates surgery and allows consistent results at a low complication rate, whereas surgical reduction serves to enhance and stabilize the results of conservative treatment. PMID- 25456281 TI - Body dysmorphic disorder should not be considered an exclusion criterion for cosmetic surgery. PMID- 25456282 TI - The point of the barb. PMID- 25456283 TI - Bilateral simultaneous breast reconstruction with transverse musculocutaneous gracilis flaps. AB - BACKGROUND: A transverse musculocutaneous gracilis flap provides good autologous reconstruction for small- and medium-sized breasts. Although the procedure is well adapted for bilateral breast reconstruction, no publication has specifically addressed simultaneous bilateral cases. METHODS: From 2010 to 2014, the authors performed seven simultaneous bilateral breast reconstructions using transverse musculocutaneous gracilis flaps. The results with respect to operative data, immediate complications, second-stage reconstruction, and patient satisfaction after >1 year of follow-up were studied retrospectively. RESULTS: The mean operative time was 7 h and 48 min (range, 6-9 h). Three minor complications occurred: two cases of limited flap necrosis and one case of donor-site wound dehiscence. Surgical revision was not required, and there was no flap failure. A second-stage operation was performed in 71% of the patients to improve the aesthetic results and flap volume. On average, 167 cm(3) of fat was injected per breast. After a mean follow-up of 27 months, the satisfaction rate was 86% without significant functional deficits. CONCLUSIONS: A transverse musculocutaneous gracilis flap is an effective and safe option for simultaneous bilateral reconstruction. The operating time is shorter than that for other autologous procedures with similar complication rates and high patient satisfaction levels. PMID- 25456284 TI - Combined use of fenestrated-type artificial dermis and topical negative-pressure wound therapy to treat the complex wound in the lower leg. PMID- 25456286 TI - Spontaneous late haematomas at latissimus dorsi flap donor sites: an unusual complication of breast reconstruction. PMID- 25456285 TI - Evaluation of cutaneous sensibility of the internal pudendal artery perforator (IPAP) flap after perineal reconstructions. AB - BACKGROUND: In oncological perineal reconstructions, the internal pudendal artery perforator (IPAP) flap is our flap of choice, supplied by perforator vessels from the internal pudendal artery and innervated by branches from the pudendal nerve and the posterior femoral cutaneous nerve. Data related to the evaluation of its cutaneous sensibility are scarce, discrepant, and subject to methodological criticism. OBJECTIVE: The objective of this study was to evaluate the cutaneous sensibility of the IPAP flap 12 months after perineal reconstruction and compare it with the preoperative cutaneous sensibility of the gluteal fold (flap donor area). METHODS: A prospective study of 25 patients undergoing abdominoperineal excision of rectum (APER) and reconstruction with bilateral VY advancement IPAP flap was conducted. The tactile, pain, thermal, and vibration sensibilities were analyzed in four areas of the gluteal fold preoperatively and in the four corresponding areas of the flap 12 months after surgery. Tactile sensibility was assessed using the Pressure Specified Sensory DeviceTM (PSSDTM), which measures the pressure applied to the skin. The other types of sensibility were analyzed using a needle for pain, hot/cold contact for thermal, and a tuning fork for vibration sensibility. RESULTS: A comparison between tactile sensibility thresholds on the gluteal fold preoperatively and on the flap 12 months after surgery showed no statistically significant difference, with p values>0.05 in all four areas evaluated. All patients had preserved pain, thermal, and vibration sensibility in all four areas, postoperatively. CONCLUSION: In oncological perineal reconstructions after APER, it is expected that the cutaneous sensibility on the IPAP flap be maintained. PMID- 25456287 TI - Thoracodorsal nerve division in latissimus dorsi breast reconstruction to avoid unwanted breast animation: a safe and simple technique to ensure division of all branches. PMID- 25456288 TI - Suspension of abdominal apron in massive panniculectomy: a novel technique. PMID- 25456289 TI - Intraoperative perfusion management impacts postoperative outcomes: an analysis of 682 autologous breast reconstruction patients. AB - INTRODUCTION: Anesthetic management remains an understudied aspect of free autologous breast reconstruction. This study aims to critically examine intraoperative anesthetic management as it relates to free flap perfusion and its effect on major complications. METHODS: A retrospective cohort study was performed examining all abdominally based free autologous breast reconstructions from 2005 to 2011 at a single institution. Analysis focused on perioperative care and specifically fluid administration, urine output (UOP), vasopressor administration, and case duration. Outcomes included major intraoperative and postoperative complications. A post-hoc analysis was performed to determine anesthetic factors associated with thrombotic events. RESULTS: Overall, 682 patients (1033 flaps) were included. Patients with low UOP had lower rates of intraoperative fluid infusion rates/kg (p=0.0001), Estimated Blood Loss (EBL) (p=0.006) and pressor administration (p=0.03), but no significant differences were noted in intraoperative thrombotic events according to UOP. However, the below normal UOP cohort demonstrated a significant increased rate of delayed postoperative thromboses (p=0.03). A post hoc analysis of postoperative thrombotic events revealed that low rates of fluid resuscitation (OR=3.01, p=0.04) and low intraoperative UOP (OR=3.67, p=0.04) were independently associated with delayed thrombosis. A sub-analysis demonstrated that patients with >=2 comorbidities and below normal UOP were at particular risk (any delayed thrombotic event OR=4.3, p=0.03; any delayed venous thrombosis OR=9.1, p=0.03). CONCLUSIONS: This study demonstrates that intraoperative fluid under resuscitation may place patients at increased risk for postoperative flap thrombosis, and low UOP is an important metric whereby intraoperative resuscitation should be gauged. Patients with comorbid conditions and below normal intraoperative UOP should be monitored particularly closely for delayed thrombotic events. LEVEL OF EVIDENCE: Prognostic/risk category, level II. PMID- 25456291 TI - Breast size and breast cancer: a systematic review. AB - BACKGROUND: There are many known breast cancer risk factors, but traditionally the list has not included breast size. The aim of this study was to synthesize the literature on breast size as a risk factor for breast carcinoma by examining studies addressing this question both directly and indirectly. METHODS: A systematic review was performed searching MEDLINE from 1950 to November 2010, and updated again in February 2014. Literature was sought to assess the relationship between the following variables and breast cancer: 1) breast size; 2) breast reduction; 3) breast augmentation; and 4) prophylactic subcutaneous mastectomy. Findings were summarized and the levels of evidence were assessed. RESULTS: 50 papers were included in the systematic review. Increasing breast size appears to be a risk factor for breast cancer, but studies are limited by their retrospective nature, imperfect size measurement techniques and confounding variables. The evidence is stronger for risk reduction with breast reduction, including prophylactic subcutaneous mastectomy at the extreme. Generally the breast augmentation population has a lower risk of breast cancer than the general population, but it is unclear whether or not this is related to the bias of small breasts in this patient population and the presence of other confounders. CONCLUSIONS: There is direct and indirect evidence that breast size is an important factor in the risk of developing breast cancer. Plastic surgeons are in a unique position to observe this effect. Well-designed prospective studies are required to further assess this risk factor. PMID- 25456290 TI - Abdominoplasty and seroma: a prospective randomised study comparing scalpel and handheld electrocautery dissection. AB - BACKGROUND: Seroma formation remains a significant problem in abdominoplasty procedures--the cause of which remains to be elucidated. It has been suggested that one of the causative factors for seroma formation is the use of handheld electrocautery as opposed to scalpel for abdominal flap dissection. METHODS: Prospective trial in 102 consecutive abdominoplasty patients randomised to have abdominal flap dissection with either handheld electrocautery device on 'coagulation setting' or sharp dissection with scalpel and monopolar electrocautery forceps for haemostasis. In all other aspects the surgical technique was identical between the two groups. All drains were removed at 48 h, irrespective of drain volume. Primary outcome measure is postoperative seroma formation on clinical examination, secondary outcome measures are drain volume, weight of tissue removed, effect of liposuction and patient BMI. RESULTS: Both study groups were similar in demographics with no significant difference in weight of tissue excised, BMI, drain output or post operative complictions. There was no significant difference in seroma formation rates between the handheld electrocautery group (17.2%) and the sharp dissection group (20.1%). Overall, the seroma rate was 18.6%. Liposuction to the flanks at the time of abdominoplasty was found to significantly increase the incidence of seroma, compared to patients having abdominoplasty alone. CONCLUSIONS: Use of handheld electrocautery rather than scalpel for tissue dissection does not lead to increased seroma formation in abdominoplasty patients. Concomitant liposuction at the time of abdominoplasty increases the risk of seroma formation compared to patients having abdominoplasty alone. PMID- 25456292 TI - Osteoarthritis year in review 2014: clinical. AB - A systematic search was conducted for the time period April 1 2013 to March 30 2014 using PubMed to identify major osteoarthritis (OA) clinical research themes of the past year. Articles within each theme were selected for inclusion in this review based on study quality and relevance. Two major themes emerged, which relate to the current understanding of OA as a heterogeneous condition with multiple pathogenic mechanisms and clinical manifestations. Theme 1 stems from the role of systemic inflammation in OA pathogenesis, and the concept of 'metabolic OA'. Over the past year, research has examined the effect of OA on incidence and progression of other 'metabolic syndrome'-related conditions, especially cardiovascular disease (CVD) and diabetes and the impact of multi morbidity on the clinical management of OA. Theme 2 focuses on the concept of personalized medicine as it relates to the treatment of OA. It is hypothesized that the modest efficacy of available OA treatments is a result of inclusion of heterogeneous groups of OA patients in clinical trials. Prognostic studies in the past year have been helpful in identifying 'OA phenotypes' that are more or less likely to respond to treatments--e.g., the presence of synovitis on imaging, central pain sensitization on quantitative sensory testing (QST), or coping efficacy by self-reported patient questionnaire. Their findings are being increasingly used to target interventions to these identified 'OA responder' subgroups with the hopes that treatment effect will be amplified. PMID- 25456293 TI - Osteoarthritis year in review 2014: rehabilitation and outcomes. AB - OBJECTIVE: To highlight research studies examining rehabilitation for hip and knee osteoarthritis (OA), as well as the outcome measures used to assess treatment efficacy, published in 2013. DESIGN: A systematic search was performed in Medline, CIHAHL and Embase databases from January to December 2013. The search was limited to 2013, human studies, and English. Rehabilitation intervention studies included were prospective controlled designs. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the quality of evidence. First, individual articles were rated for quality. Second, articles were grouped based on outcome: OA disease markers, pain, physical function (self-reported, performance), and health. RESULTS: Of 503 titles reviewed, 36 studies were included. The outcome measures related to OA disease markers were organized into subthemes of anthropometrics, biomechanics and physiology. The quality of evidence was of moderate, high, and low quality for anthropometric, biomechanical and physiological measures respectively. These studies supported the use of diet for weight loss combined with exercise. Bodies of evidence that showed the efficacy of exercise and passive strategies (thermal/electrical modalities, traction, manual therapy) for reducing pain were of low and moderate quality respectively. The evidence supporting diet and exercise, physiotherapy, and passive strategies to improve physical function was of moderate quality. Evidence supporting exercise to improve psychological factors was of moderate quality. CONCLUSIONS: Exercise combined with diet for weight loss should be the mainstays of rehabilitation for people with knee and hip OA to provide benefit to OA disease markers, pain, physical function, and health. PMID- 25456294 TI - Osteoarthritis year in review 2014: mechanics--basic and clinical studies in osteoarthritis. AB - The purpose of this review was to highlight recent research in mechanics and osteoarthritis (OA) by summarizing results from selected studies spanning basic and clinical research methods. Databases were searched from January 2013 through to March 2014. Working in pairs, reviewers selected 67 studies categorized into four themes--mechanobiology, ambulatory mechanics, biomechanical interventions and mechanical risk factors. Novel developments in mechanobiology included the identification of cell signaling pathways that mediated cellular responses to loading of articular cartilage. Studies in ambulatory mechanics included an increased focus on instrumented knee implants and progress in computational models, both emphasizing the importance of muscular contributions to load. Several proposed biomechanical interventions (e.g., shoe insoles and knee braces) produced variable changes in external knee joint moments during walking, while meta-analysis of randomized clinical trials did not support the use of lateral wedge insoles for decreasing pain. Results from high quality randomized trials suggested diet with or without exercise decreased indicators of knee joint load during walking, whereas similar effects from exercise alone were not detected with the measures used. Data from longitudinal cohorts suggested mechanical alignment was a risk factor for incidence and progression of OA, with the mechanism involving damage to the meniscus. In combination, the basic and clinical studies highlight the importance of considering multiple contributors to joint loading that can evoke both protective and damaging responses. Although challenges clearly exist, future studies should strive to integrate basic and clinical research methods to gain a greater understanding of the interactions among mechanical factors in OA and to develop improved preventive and therapeutic strategies. PMID- 25456295 TI - Osteoarthritis year in review 2014: imaging. AB - PURPOSE: This narrative review covers original publications related to imaging in osteoarthritis (OA) published in English between April 2013 and March 2014. In vitro data, animal studies and studies with less than 20 observations were not included. METHODS: To extract relevant studies, an extensive PubMed database search was performed based on, but not limited to the query terms "Osteoarthritis" in combination with "MRI", "Imaging", "Radiography", "Ultrasound", "Computed Tomography" and "Nuclear Medicine". Publications were sorted according to relevance based on potential impact to the OA research community with the overarching goal of a balanced overview covering all aspects of imaging. Focus was on publications in high impact special interest journals. The literature will be presented in a methodological fashion covering radiography, ultrasound, compositional and morphologic Magnetic resonance imaging (MRI), and from an anatomic perspective including bone, muscle, meniscus and synovitis. RESULTS AND CONCLUSIONS: Imaging research in OA in the last year was characterized by a strong focus on MRI-based studies dealing with epidemiological and methodological aspects of the disease. Ultrastructural tissue assessment specifically of cartilage and meniscus using compositional MRI is evolving further. Additional subsets of the large publicly available Osteoarthritis Initiative (OAI) MRI dataset are being analyzed at present and have been published with muscle analyses coming increasingly into the focus of the community. Bone parameters were evaluated using varying technology and a persistent interest in inflammatory disease manifestations has been noted. Other modalities than MRI have been less explored. To date most OA imaging research is still focused on the knee joint. PMID- 25456296 TI - Osteoarthritis year in review 2014: highlighting innovations in basic research and clinical applications in regenerative medicine. AB - Regenerative medicine is an emerging area that will influence the treatment of joint diseases in the future. It involves the use of biomaterials, cell therapy, and bioactive factors such as growth factors, drugs and small molecules, to regenerate damaged tissues. This "year in review" highlights a personal selection of promising studies published between March 2013 and March 2014 that inform on the direction in which this field is moving. This multidisciplinary field has been very active, with rapid development of new technologies that emerge from basic sciences such as the possibility to generate pluripotent stem cells without genetic modification and genetic engineering of growth factors to enhance their capacity to induce tissue repair. The increasing knowledge of the interaction between all tissues in the joint, such as the effect of bone remodeling and synovial inflammation on cartilage repair, will eventually make tissue regeneration in a compromised joint environment possible. PMID- 25456297 TI - Osteoarthritis year in review 2014: genetics and genomics. AB - Recent developments in genetics/genomics of osteoarthritis (OA) are discussed to improve our understanding of OA pathophysiology. The discovery of a novel variant near the NCOA3 (nuclear receptor coactivator 3) gene associated with hip OA and the regulation of GDF5 gene by four transcription factors via the OA susceptibility locus rs143383 are among important findings in OA genetics. Several microarray-based gene expression studies were published for different tissues of the joint. In OA synovium elevation of collagens and cross-linking enzymes (COL1A1, COL5A1, PLOD2, LOX and TIMP1) responsive to TGF-beta was found as well as differential expression pattern between different areas of the osteoarthritic synovial membrane. In OA peripheral blood the role of apoptotic genes was highlighted, while whole genome expression profiling in OA subchondral bone and cartilage revealed common genes in cartilage and bone to be involved in OA development. In epigenetics, several microRNAs (miRNAs) were found to regulate genes' expression in chondrocytes, among which miR-125, miR-127b miR-21, miR-148a and their use as potential drug targets was highlighted. Future studies must focus on the integration of genetics, genomics and epigenetics for the identification of signaling pathways and regulatory networks responsible for OA development. PMID- 25456298 TI - Osteoarthritis year in review 2014: we need more biochemical biomarkers in qualification phase. AB - The current diagnosis of osteoarthritis (OA) relies on the description of pain symptoms, affected joint stiffness, and radiography used as the reference technique for determining the grade of joint destruction. Limitations of the presently available diagnostic tests have provided an impetus for the substantial increase in interest in finding new specific biological markers for cartilage degradation to facilitate the early diagnosis of joint destruction, evaluate disease progression and improve disease prognosis. Biomarkers for OA are also useful for drug development, treatment monitoring, and as a basis for personalized evidence-based action plans. This review summarizes 29 manuscripts published during 2013 with a focus on soluble biochemical biomarkers, primarily those utilizing proteomic, metabolomics, lipidomic and imaging mass spectrometry technologies. PMID- 25456299 TI - Universal cranial ultrasound screening in preterm infants with gestational age 33 36 weeks. A retrospective analysis of 724 newborns. AB - BACKGROUND: Cranial ultrasonography is a useful tool to detect intracranial lesions in premature neonates at risk. Our primary aim was to determine the number of patients with abnormal cranial ultrasonography. Secondary aims were to evaluate the usefulness of universal cranial ultrasonography screening in moderately preterm infants. METHODS: All infants born from 2007 to 2012 at the University Hospital of Ferrara (Italy), with gestational age of 33-36 weeks, were included in the study. Cranial ultrasonography findings were retrospectively classified into nonsignificant and significant. RESULTS: All the 724 babies born were screened. Intracranial lesions were in 13% of neonates (3.7% at 36 weeks to 27.1% at 33 weeks of gestational age). Babies born at 33-34 weeks of gestational age were four times more likely to have an abnormal cranial ultrasonography than those at 35-36 weeks. Statistical analysis revealed no association between cranial ultrasonography abnormalities and being small for gestational age or mode of delivery. A significant association was present between the presence of head circumference less than the third percentile, the need for ventilation or surfactant, low Apgar index at fifth minute, and neurological abnormalities. The presence of at least one considered risk factor increases the probability of cranial ultrasonography abnormalities twice in infants born at 33-34 weeks and 15 times in born at 35-36 weeks. CONCLUSIONS: A considerable number of infants born between 33 and 36 weeks have cranial ultrasonography abnormalities. We suggest that screening should be performed or at least that a uniform protocol should be developed for the early detection of all significant cranial ultrasonography abnormalities. PMID- 25456300 TI - Corpus callosotomy for childhood-onset drug-resistant epilepsy unresponsive to vagus nerve stimulation. AB - PURPOSE: Corpus callosotomy and vagus nerve stimulation are common palliative options for people with drug-resistant epilepsy when resective epilepsy surgery is not feasible. Because most of the published corpus callosotomy experience comes from a period before vagus nerve stimulation was approved and widely used, there is a paucity of data about efficacy of corpus callosotomy in patients with inadequate response to vagus nerve stimulation. METHODS: We report seven patients who had complete corpus callosotomy after an inadequate response to vagus nerve stimulation. At the time of surgery, these patients had failed a median of six antiseizure medications, three patients also had failed a trial of ketogenic diet, and all the patients had a vagus nerve stimulation implanted for a mean duration of 2.5 years with maximal tolerated settings. RESULTS: There was a decrease in total daily seizure frequency of 34.7% (+/- 94.7; median, 71.4%; interquartile range, 55.3) after corpus callosotomy at a mean follow-up of 2.6 years (+/- 1.4). One patient achieved complete seizure freedom and five patients had >= 50% reduction in seizure frequency. Six patients continued to have partial onset seizures though the frequency was decreased. Drop attacks and tonic seizures stopped in all the patients. CONCLUSION: Seizure outcomes after corpus callosotomy in our series are most likely a result of complex dynamic interaction between the natural history of epilepsy, the effect of the surgery, ongoing vagus nerve stimulation modulation, and modification in antiseizure drugs. Our study supports the clinical decision to try corpus callosotomy in patients having nonlateralizing drug-resistant epilepsy with inadequate response to vagus nerve stimulation. PMID- 25456302 TI - Head circumference growth reference charts of children younger than 7 years in Chinese rural areas. AB - BACKGROUND: The head circumference growth reference charts for children in China are presently based on urban children. However, the references may not apply to rural children because of the differences between urban and rural areas, such as economy, culture, and dietary habits. Our objective was to provide a reliable continuous set of head circumference growth reference charts for male and female children less than 7 years of age in Chinese rural areas. METHODS: Children in our study were identified by multistage stratified cluster sampling from rural areas of 10 provinces in China. Questionnaire survey and anthropometric measurements were conducted in data collection. Head circumference was measured with a nonelastic tape on a line passing over the glabella and posterior occipital protrusion in children. We compared the fiftieth percentile of our cross-sectional data with the data of Chinese cities, World Health Organization, and the United States. RESULTS: A total of 95,904 children (48,722 boys and 47,182 girls) were included in the study. We present age- and sex-appropriate head circumference growth charts younger than 7 years for Chinese rural areas. The head circumference percentiles of the children in rural China are much smaller than the children in Chinese urban areas, World Health Organization, and the US percentiles after 2 years old. CONCLUSIONS: Head circumference percentiles can be applied in growth monitoring, but current head circumference growth references promulgated in urban China may not be suitable for rural areas in China. Providing head circumference growth reference charts for rural Chinese children who are younger than 7 years old is very important. PMID- 25456301 TI - Brain malformations associated with Knobloch syndrome--review of literature, expanding clinical spectrum, and identification of novel mutations. AB - BACKGROUND: Knobloch syndrome is a rare, autosomal recessive, developmental disorder characterized by stereotyped ocular abnormalities with or without occipital skull deformities (encephalocele, bone defects, and cutis aplasia). Although there is clear heterogeneity in clinical presentation, central nervous system malformations, aside from the characteristic encephalocele, have not typically been considered a component of the disease phenotype. METHODS: Four patients originally presented for genetic evaluation of symptomatic structural brain malformations. Whole-genome genotyping, whole-exome sequencing, and confirmatory Sanger sequencing were performed. Using immunohistochemical analysis, we investigated the protein expression pattern of COL18A1 in the mid fetal and adult human cerebral cortex and then analyzed the spatial and temporal changes in the expression pattern of COL18A1 during human cortical development using the Human Brain Transcriptome database. RESULTS: We identified two novel homozygous deleterious frame-shift mutations in the COL18A1 gene. On further investigation of these patients and their families, we found that many exhibited certain characteristics of Knobloch syndrome, including pronounced ocular defects. Our data strongly support an important role for COL18A1 in brain development, and this report contributes to an enhanced characterization of the brain malformations that can result from deficiencies of collagen XVIII. CONCLUSIONS: This case series highlights the diagnostic power and clinical utility of whole-exome sequencing technology-allowing clinicians and physician scientists to better understand the pathophysiology and presentations of rare diseases. We suggest that patients who are clinically diagnosed with Knobloch syndrome and/or found to have COL18A1 mutations via genetic screening should be investigated for potential structural brain abnormalities even in the absence of an encephalocele. PMID- 25456303 TI - Role of plasma amino acids and urinary organic acids in diagnosis of mitochondrial diseases in children. AB - BACKGROUND: Diagnostic difficulty in mitochondrial diseases (MD) results not only from the wide spectrum of symptoms and signs but also from the absence of a reliable screening or diagnostic biomarker. AIM: To investigate the likelihood of MD in patients with symptoms and signs impressive of MD through quantitative measurement of plasma amino acids, and urinary organic acids. METHODS: Twenty patients with symptoms and signs suggestive of MD were further evaluated by quantitative plasma amino acids and urinary organic acids assay and neuroimaging. RESULTS: Plasma amino acid results revealed elevation of alanine in 11, glycine in five, and proline in two patients. Abnormal urinary organic acid analysis was present in six patients; increased urinary lactate (20%), dicarboxylicaciduria (15%), and urinary ketone bodies (10%). Upon enrollment our patients scored as possible MD according to the MD scoring system. At the end of the study, five patients still scored as possible MD, eight patients as probable MD, and seven patients as definite MD. All patients with definite MD had elevated serum lactate. In three patients, elevated urinary lactate was the only abnormality. Alanine was elevated in all patients with definite MD, whereas proline was elevated in only one. Magnetic resonance imaging of the brain showed atrophic changes in one patient and bilateral basal ganglia hyperintensity in another. CONCLUSION: Urinary organic acids and quantitative plasma amino acids can help in the diagnosis of MD, especially when the economic burden and absence of specialized centers limits the diagnosis. PMID- 25456304 TI - Neurodegeneration with brain iron accumulation disorder mimics autism. PMID- 25456305 TI - Dual-polarization interferometry: a novel technique to light up the nanomolecular world. PMID- 25456307 TI - On the mis-use of mathematics: a comment on "How confident are we about the chronology of the transition between Howieson's Poort and Still Bay?" by Guerin et al (2013). PMID- 25456308 TI - Diet as driver and constraint in human evolution. PMID- 25456306 TI - Determinants of participation in prostate cancer screening: a simple analytical framework to account for healthy-user bias. AB - In Japan at present, fecal occult blood testing (FOBT) is recommended for cancer screening while routine population-based prostate-specific antigen (PSA) screening is not. In future it may be necessary to increase participation in the former and decrease it in the latter. Our objectives were to explore determinants of PSA-screening participation while simultaneously taking into account factors associated with FOBT. Data were gathered from a cross-sectional study conducted with random sampling of 6191 adults in Osaka city in 2011. Of 3244 subjects (return rate 52.4%), 936 men aged 40-64 years were analyzed using log-binomial regression to explore factors related to PSA-screening participation within 1 year. Only responders for cancer screening, defined as men who participated in either FOBT or PSA-testing, were used as main study subjects. Men who were older (prevalence ratio [PR] [95% confidence interval (CI)] = 2.17 [1.43, 3.28] for 60 64 years compared with 40-49 years), had technical or junior college education (PR [95% CI] = 1.76 [1.19, 2.59] compared with men with high school or less) and followed doctors' recommendations (PR [95% CI] = 1.50 [1.00, 2.26]) were significantly more likely to have PSA-screening after multiple variable adjustment among cancer-screening responders. Attenuation in PR of hypothesized common factors was observed among cancer-screening responders compared with the usual approach (among total subjects). Using the analytical framework to account for healthy-user bias, we found three factors related to participation in PSA screening with attenuated association of common factors. This approach may provide a more sophisticated interpretation of participation in various screenings with different levels of recommendation. PMID- 25456309 TI - On harnessing the power of medical students to reach their peers. PMID- 25456310 TI - Breaking the barriers of resolution. PMID- 25456311 TI - Bilateral total ovarian hypoplasia in a Holstein Friesian heifer. AB - A report of a female Holstein Friesian heifer with ovarian hypoplasia is presented. The heifer had normal female external genitalia, but showed neither estrus nor became pregnant after siring with a fertile bull. At necropsy the vagina, uterine body and uterine horns appeared normal. Bilateral streak structures surrounded by mesovarium were observed and dissected for further investigation. Histological investigation revealed that a case of bilateral total ovarian hypoplasia was the cause of infertility. This is the first published report of ovarian hypoplasia from Antalya province in Turkey. PMID- 25456312 TI - The effect of hibernation on the morphology and histochemistry of the intestine of the greater mouse-eared bat, Myotis myotis. AB - Seasonal variations in morphometry and histochemistry of the intestine have been examined in the active and hibernating greater mouse-eared bat, Myotis myotis, using histological and histochemical techniques. The results of morphometric analyses indicated that hibernation affected the villus height, villus width, crypt depth and crypt width of the duodenum, jejunum and ileum. Histochemical analysis showed that goblet cells of the small and large intestine contain acidic and neutral mucosubstances. According to the results obtained with Alcian Blue (pH 5.8)/PAS staining, hyaluronic acid is dominant in the goblet cells of the small and large intestine during both the hibernation and active periods. Chondroitin sulfate and dermatan sulfate, which are sulfated GAGs, were dominant, and very little heparan sulfate, heparin and keratan sulfate were present. Moreover, sulfated glycoproteins were also detected in the goblet cells of the small intestine in the active animals. The present study demonstrates that hibernation altered the examined morphometric and histochemical parameters of the intestine. PMID- 25456313 TI - Scale evolution in Paraphysomonadida (Chrysophyceae): Sequence phylogeny and revised taxonomy of Paraphysomonas, new genus Clathromonas, and 25 new species. AB - Heterotrophic chrysomonads of the genus Paraphysomonas are ubiquitous phagotrophs with diverse silica scale morphology. Over 50 named species have been described by electron microscopy from uncultured environmental samples. Sequence data exist for very few, but the literature reveals misidentification or lumping of most previously sequenced. For critically integrating scale and sequence data, 59 clonal cultures were studied light microscopically, by sequencing 18S ribosomal DNA, and recording scale morphology by transmission electron microscopy. We found strong congruence between variations in scale morphology and rDNA sequences, and unexpectedly deep genetic diversity. We now restrict Paraphysomonas to species with nail-like spine scales, establishing 23 new species and eight subspecies (Paraphysomonadidae). Species having base-plates with dense margins form three distinct subclades; those with a simple margin only two. We move 29 former Paraphysomonas species with basket scales into a new genus, Clathromonas, and describe two new species. Clathromonas belongs to a very distinct rDNA clade (Clathromonadidae fam. n.), possibly distantly sister to Paraphysomonas. Molecular and morphological data are mutually reinforcing; both are needed for evaluating paraphysomonad diversity and confirm excessive past lumping. Former Paraphysomonas species with neither nail-like nor basket scales are here excluded from Paraphysomonas and will be assigned to new genera elsewhere. PMID- 25456314 TI - Cavity- and waveguide-resonators in electron paramagnetic resonance, nuclear magnetic resonance, and magnetic resonance imaging. AB - Cavity resonators are widely used in electron paramagnetic resonance, very high field magnetic resonance microimaging and also in high field human imaging. The basic principles and designs of different forms of cavity resonators including rectangular, cylindrical, re-entrant, cavity magnetrons, toroidal cavities and dielectric resonators are reviewed. Applications in EPR and MRI are summarized, and finally the topic of traveling wave MRI using the magnet bore as a waveguide is discussed. PMID- 25456316 TI - NMR-based metabolomics: from sample preparation to applications in nutrition research. AB - Metabolomics is the study of metabolites present in biological samples such as biofluids, tissue/cellular extracts and culture media. Measurement of these metabolites is achieved through use of analytical techniques such as NMR and mass spectrometry coupled to liquid chromatography. Combining metabolomic data with multivariate data analysis tools allows the elucidation of alterations in metabolic pathways under different physiological conditions. Applications of NMR based metabolomics have grown in recent years and it is now widely used across a number of disciplines. The present review gives an overview of the developments in the key steps involved in an NMR-based metabolomics study. Furthermore, there will be a particular emphasis on the use of NMR-based metabolomics in nutrition research. PMID- 25456317 TI - Imaging evidence and recommendations for traumatic brain injury: conventional neuroimaging techniques. AB - Imaging plays an essential role in identifying intracranial injury in patients with traumatic brain injury (TBI). The goals of imaging include (1) detecting injuries that may require immediate surgical or procedural intervention, (2) detecting injuries that may benefit from early medical therapy or vigilant neurologic supervision, and (3) determining the prognosis of patients to tailor rehabilitative therapy or help with family counseling and discharge planning. In this article, the authors perform a review of the evidence on the utility of various imaging techniques in patients presenting with TBI to provide guidance for evidence-based, clinical imaging protocols. The intent of this article is to suggest practical imaging recommendations for patients presenting with TBI across different practice settings and to simultaneously provide the rationale and background evidence supporting their use. These recommendations should ultimately assist referring physicians faced with the task of ordering appropriate imaging tests in particular patients with TBI for whom they are providing care. These recommendations should also help radiologists advise their clinical colleagues on appropriate imaging utilization for patients with TBI. PMID- 25456315 TI - Nonuniform sampling and non-Fourier signal processing methods in multidimensional NMR. AB - Beginning with the introduction of Fourier Transform NMR by Ernst and Anderson in 1966, time domain measurement of the impulse response (the free induction decay, FID) consisted of sampling the signal at a series of discrete intervals. For compatibility with the discrete Fourier transform (DFT), the intervals are kept uniform, and the Nyquist theorem dictates the largest value of the interval sufficient to avoid aliasing. With the proposal by Jeener of parametric sampling along an indirect time dimension, extension to multidimensional experiments employed the same sampling techniques used in one dimension, similarly subject to the Nyquist condition and suitable for processing via the discrete Fourier transform. The challenges of obtaining high-resolution spectral estimates from short data records using the DFT were already well understood, however. Despite techniques such as linear prediction extrapolation, the achievable resolution in the indirect dimensions is limited by practical constraints on measuring time. The advent of non-Fourier methods of spectrum analysis capable of processing nonuniformly sampled data has led to an explosion in the development of novel sampling strategies that avoid the limits on resolution and measurement time imposed by uniform sampling. The first part of this review discusses the many approaches to data sampling in multidimensional NMR, the second part highlights commonly used methods for signal processing of such data, and the review concludes with a discussion of other approaches to speeding up data acquisition in NMR. PMID- 25456318 TI - Claudin 4 expression in triple-negative breast cancer: correlation with androgen receptors and Ki-67 expression. AB - Breast cancer is the most common malignancy in women and the leading cause of cancer mortality worldwide. Triple-negative breast cancer (TNBC) is an important phenotype of breast cancer that accounts for a relatively small number of breast cancer cases but still represent a focus of increasing interest at the clinical, biological, and epidemiological level. Claudins are the major component of the tight junction, and only a few studies have addressed the role of claudins in breast cancer, especially TNBC. Androgen receptors (ARs), as members of the nuclear receptor superfamily, are known to be involved in a complex network of signaling pathways that collectively regulate cell proliferation. However, roles of AR in breast cancer development and progression have not been very clearly understood. The proliferation marker Ki-67 has been confirmed as an independent predictive and prognostic factor in early breast cancer. The aims of this study are to identify the clinicopathologic associations and prognostic value of claudin 4 expression in TNBC and to correlate claudin 4 expression with AR status and Ki-67 expression. Paraffin blocks obtained from 56 female patients with triple-negative primary invasive ductal breast carcinomas were analyzed for claudin 4, AR, and Ki-67 immunohistochemical expression. High levels of claudin 4 expression were detected in 66.1% of TNBC cases. There was a significant positive correlation with age, tumor size, grade, nodal status, metastasis, and Ki-67 expression (all P < .05) and negative correlation with AR status (P < .001). Androgen receptor showed positivity in 29 cases (51.78%). There was a statistical negative correlation with the all the studied clinicopathologic parameters, claudin 4 and Ki-67 expression. High claudin 4 expression, negative AR expression, and high Ki-67 index would provide a strong prognostic power to differentiate the patients with worse outcome among TNBC patients. Moreover, target treatment for TNBC cells expressing claudin 4 or AR enriched would be valuable for future therapies. PMID- 25456319 TI - Lung epithelial NOX/DUOX and respiratory virus infections. AB - Determining the role of NADPH oxidases in the context of virus infection is an emerging area of research and our knowledge is still sparse. The expression of various isoforms of NOX/DUOX (NADPH oxidase/dual oxidase) in the epithelial cells (ECs) lining the respiratory tract renders them primary sites from which to orchestrate the host defence against respiratory viruses. Accumulating evidence reveals distinct facets of the involvement of NOX/DUOX in host antiviral and pro inflammatory responses and in the control of the epithelial barrier integrity, with individual isoforms mediating co-operative, but surprisingly also opposing, functions. Although in vivo studies in mice are in line with some of these observations, a complete understanding of the specific functions of epithelial NOX/DUOX awaits lung epithelial-specific conditional knockout mice. The goal of the present review is to summarize our current knowledge of the role of individual NOX/DUOX isoforms expressed in the lung epithelium in the context of respiratory virus infections so as to highlight potential opportunities for therapeutic intervention. PMID- 25456320 TI - Fatty acids and the risk of death during acute myocardial ischaemia. AB - Plasma free fatty acids (non-esterified fatty acids) increase in the first hour of the onset of acute myocardial ischaemia. This results from catecholamine stimulation of adipose tissue lipolysis. It can lead to a metabolic crisis in the injured myocardium with the development of ventricular arrhythmias and increased early mortality. Preconditioning, beta-adrenergic blockade and glucose-insulin potassium are possible therapeutic approaches, but anti-lipolytic agents, such as some nicotinic acid derivatives, can reduce plasma free fatty acid concentrations within minutes and have untried potential. A clinical trial of their effectiveness is needed from the first moment when a patient with an acute coronary syndrome is seen by paramedics. PMID- 25456324 TI - Supervised injection services: what has been demonstrated? A systematic literature review. AB - BACKGROUND: Supervised injection services (SISs) have been developed to promote safer drug injection practices, enhance health-related behaviors among people who inject drugs (PWID), and connect PWID with external health and social services. Nevertheless, SISs have also been accused of fostering drug use and drug trafficking. AIMS: To systematically collect and synthesize the currently available evidence regarding SIS-induced benefits and harm. METHODS: A systematic review was performed via the PubMed, Web of Science, and ScienceDirect databases using the keyword algorithm [("supervised" or "safer") and ("injection" or "injecting" or "shooting" or "consumption") and ("facility" or "facilities" or "room" or "gallery" or "centre" or "site")]. RESULTS: Seventy-five relevant articles were found. All studies converged to find that SISs were efficacious in attracting the most marginalized PWID, promoting safer injection conditions, enhancing access to primary health care, and reducing the overdose frequency. SISs were not found to increase drug injecting, drug trafficking or crime in the surrounding environments. SISs were found to be associated with reduced levels of public drug injections and dropped syringes. Of the articles, 85% originated from Vancouver or Sydney. CONCLUSION: SISs have largely fulfilled their initial objectives without enhancing drug use or drug trafficking. Almost all of the studies found in this review were performed in Canada or Australia, whereas the majority of SISs are located in Europe. The implementation of new SISs in places with high rates of injection drug use and associated harms appears to be supported by evidence. PMID- 25456325 TI - Association of anxiety disorders with the risk of smoking behaviors: a meta analysis of prospective observational studies. AB - OBJECTIVE: Published articles reported controversial results about the association of anxiety disorders with the risk of smoking behaviors. A meta analysis was performed to assess this association between anxiety disorders and smoking behaviors. METHODS: A comprehensive search was performed to identify prospective observational studies (from January, 1990 to March, 2014) of the aforementioned association. The Q test and I(2) statistic were used to examine between-study heterogeneity. Fixed or random effect model was selected based on heterogeneity test among studies. Meta-regression and the "leave one out" sensitive analysis were used to explore potential sources of between-study heterogeneity. Publication bias was estimated using Egger's regression asymmetry test. RESULTS: Fifteen articles were included. After excluding studies that were the key contributors to between-study heterogeneity, the meta-analysis showed a significant association of anxiety disorders with increased risk of regular smoking (OR = 1.41, 95% CI: 1.23-1.62) and nicotine dependence (OR = 1.58, 95% CI: 1.45-1.73). No significant influence and publication bias were observed both before and after excluding the key contributors to heterogeneity. CONCLUSION: This meta-analysis suggested that anxiety disorders had significant positive effect on the risk of smoking behaviors. This association needs to be confirmed by further studies. PMID- 25456327 TI - Impairment due to amphetamines and benzodiazepines, alone and in combination. AB - INTRODUCTION: The impairing effects of combined use of amphetamines and benzodiazepines among recreational drug users are not well described, but knowledge about this is important in the risk assessment of such combined drug use. The aim of this study was to compare the impairment, among apprehended drivers, as judged by a clinical test of impairment (CTI), in cases where a combination of amphetamines and benzodiazepines was detected, in blood, with cases where only one of the two drug groups was detected. METHODS: The results of CTI judgments were compared to toxicological drug tests of blood samples that were obtained at the time of CTI screening in cases containing amphetamines only, cases containing different benzodiazepines only, and cases containing a combination of amphetamines and benzodiazepines. RESULTS: There were significantly more drivers being judged as impaired in the combined group (n = 777), compared both with amphetamines alone (n = 267, chi(2) = 47.8, p < 0.001) and benzodiazepines alone (n = 153, chi(2) = 7.0, p = 0.008). This was also seen when only including the lowest concentrations of benzodiazepines (chi(2) = 4.3, p = 0.038). The concentrations of the drugs were higher in the single drug groups, compared with the combined group. CONCLUSION: This study indicates that during real-life driving, those influenced by both amphetamines and benzodiazepines are more impaired, as judged by the CTI, compared with those influenced by either drug alone, although the combined group showed lower drug concentrations. PMID- 25456328 TI - Differences in HIV risk behaviors among people who inject drugs by gender and sexual orientation, San Francisco, 2012. AB - BACKGROUND: Sharing of drug injection equipment is a well-established risk factor for the transmission of viral infections, such as human immunodeficiency virus (HIV). However, there are multiple mechanisms through which people who inject drugs (PWID) can acquire and transmit HIV. Differences in drug using and sexual behaviors among heterosexual males, males who have sex with males (MSM), and females who inject drugs may explain health disparities. METHODS: Data were collected in San Francisco by the National HIV Behavioral Surveillance (NHBS) System of PWID in 2012, and were analyzed to compare the sexual behaviors, drug use behaviors, and prevalence of viral infections among heterosexual males, MSM, and females. RESULTS: Using a weighted analysis for the RDS sampling design, we estimate that 3.7% of heterosexual males who inject drugs, 24.0% of MSM, and 13.0% of females who inject drugs are living with HIV. Females and heterosexual males primarily injected heroin, while MSM primarily injected methamphetamine. MSM were most likely to have received goods or money for sex and have unprotected intercourse. CONCLUSION: These data demonstrate differences in risk behaviors and prevalence of viral infections among heterosexual males, MSM, and females. The results also suggest that public health programs prioritizing the different populations of PWID are necessary. PMID- 25456326 TI - Co-morbid pain and opioid addiction: long term effect of opioid maintenance on acute pain. AB - INTRODUCTION: Medication assisted treatment for opioid dependence alters the pain experience. This study will evaluate changes pain sensitivity and tolerance with opioid treatments; and duration of this effect after treatment cessation. METHOD: 120 Individuals with chronic pain were recruited in 4 groups (N = 30): 1 methadone for opioid addiction; 2-buprenorphine for opioid addiction; 3-history of opioid maintenance treatment for opioid addiction but with prolonged abstinence (M = 121 weeks; SD = 23.3); and 4-opioid naive controls. Participants completed a psychological assessment and a cold water task including, time to first pain (sensitivity) and time to stopping the pain task (tolerance). Data analysis used survival analyses. RESULTS: A Kaplan-Meier-Cox survival analysis showed group differences for both pain sensitivity (log rank = 15.50; p < .001) and tolerance (log rank = 20.11; p < .001). Current or historical use of opioid maintenance resulted in differing pain sensitivity compared to opioid naive (p's < .01). However, tolerance to pain was better among those with a history of opioid maintenance compared to active methadone patients (p < .05), with the highest tolerance found among opioid naive control group participants (p's < .001). Correlations within the prolonged abstinent group indicated pain tolerance was significantly improved as length of opioid abstinence increased (R = .37; p < .05); but duration of abstinence did not alter sensitivity (ns). CONCLUSION: Among individuals with a history of prolonged opioid maintenance, there appears to be long-term differences in pain sensitivity that do not resolve with discontinuation of opioid maintenance. Although pain sensitivity does not change, pain tolerance does improve after opioid maintenance cessation. Implications for treating co-morbid opioid addiction and pain (acute and chronic) are discussed. PMID- 25456329 TI - Ethnic and genetic factors in methadone pharmacokinetics: a population pharmacokinetic study. AB - BACKGROUND: Treatment of opiate use disorders with methadone is complicated by wide interindividual variability in pharmacokinetics. To identify potentially contributing covariates in methadone pharmacokinetics, we used population pharmacokinetic modeling to estimate clearance (CL/F) and volume of distribution (V/F) for each methadone enantiomer in an ethnically diverse methadone maintained population. METHODS: Plasma levels of the opiate-active R-methadone and opiate inactive S-methadone were measured in 206 methadone maintained subjects approximately two and twenty-three hours after a daily oral dose of rac methadone. A linear one-compartment population pharmacokinetic model with first order conditional estimation with interaction (FOCE-I) was used to evaluate methadone CL/F and V/F. The influence of covariates on parameter estimates was evaluated using stepwise covariate modeling. Covariates included ethnicity, gender, weight, BMI, age, methadone dose, and 21 single nucleotide polymorphisms in genes implicated in methadone pharmacokinetics. RESULTS: In the final model, for each enantiomer, Hmong ethnicity reduced CL/F by approximately 30% and the rs2032582 (ABCB1 2677G>T/A) GG genotype was associated with a 20% reduction in CL/F. The presence of the rs3745274 minor allele (CYP2B6 515G>T) reduced CL/F by up to 20% for S-methadone only. A smaller effect of age was noted on CL/F for R methadone. CONCLUSION: This is the first report showing the influence of the rs2032582 and rs3745274 variants on methadone pharmacokinetics rather than simply dose requirements or plasma levels. Population pharmacokinetics is a valuable method for identifying the influences on methadone pharmacokinetic variability. PMID- 25456330 TI - Prenatal cocaine exposure and age of sexual initiation: direct and indirect effects. AB - BACKGROUND: Prenatal cocaine exposure (PCE) has been linked to child behavior problems and risky behavior during adolescence such as early substance use. Behavior problems and early substance use are associated with earlier initiation of sexual behavior. The goal of this study was to examine the direct and indirect effects of PCE on sexual initiation in a longitudinal birth cohort, about half of whom were exposed to cocaine in utero. METHODS: Women were interviewed twice prenatally, at delivery, and 1, 3, 7, 10, 15, and 21 years postpartum. Offspring (52% female, 54% African American) were assessed at delivery and at each follow up phase with age-appropriate assessments. At age 21, 225 offspring reported on their substance use and sexual behavior. RESULTS: First trimester cocaine exposure was a significant predictor of earlier age of first intercourse in a survival analysis, after controlling for race, sociodemographic characteristics, caregiver pre- and postnatal substance use, parental supervision, and child's pubertal timing. However, the association between PCE and age of first sexual intercourse was mediated by adolescent marijuana and alcohol use prior to age 15. CONCLUSIONS: Most of the effect of PCE on age of sexual initiation occurred between the ages of 13-18, when rates of initiation were approximately 10% higher among exposed offspring. This effect was mediated by early adolescent substance use. These results have implications for identification of the exposed offspring at greatest risk of HIV risk behaviors and early, unplanned pregnancy. PMID- 25456332 TI - Modeling substance use in emerging adult gay, bisexual, and other YMSM across time: the P18 cohort study. AB - OBJECTIVE: To examine patterns of substance use over time in a new generation of emerging adult gay, bisexual, and other young men who have sex with men (YMSM). METHODS: Data were drawn from the first four waves of on ongoing prospective cohort study of YMSM who were ages 18 to 19 at baseline and were assessed each 6 months for substance use via calendar based methods. Latent growth curve modeling was utilized to assess changes over time for four drug use categories: alcohol, marijuana, inhalant nitrates, and other drugs (e.g., cocaine, ecstasy) and between groups (race/ethnicity, perceived familial socioeconomic status; SES). RESULTS: Use of all substances increased steadily across the follow-up period. White YMSM demonstrated higher levels of alcohol use at the 18-mo follow-up visit compared to other racial/ethnic groups, while rates of change across groups were similar. Marijuana use at 18 months was highest for Hispanics who also indicated the highest rate of change. Finally, YMSM who reported higher perceived SES reported the lowest use and lowest rates of change for other drug use. Controlling for perceived SES, differences in patterns of drug use by race/ethnicity were evident but differences were not as large. CONCLUSIONS: Increases in substance use in the emerging adulthood of YMSM indicate the need for structural and behavioral interventions tailored to address substance use in these young men before chronic patterns of use develop. Differences in patterns of drug use across racial/ethnic and SES groups suggest that interventions need to consider person-level differences. PMID- 25456331 TI - Maternal risk factors for fetal alcohol spectrum disorders in a province in Italy. AB - BACKGROUND: Maternal risk factors for fetal alcohol spectrum disorders (FASD) in Italy and Mediterranean cultures need clarification, as there are few studies and most are plagued by inaccurate reporting of antenatal alcohol use. METHODS: Maternal interviews (n = 905) were carried out in a population-based study of the prevalence and characteristics of FASD in the Lazio region of Italy which provided data for multivariate case control comparisons and multiple correlation models. RESULTS: Case control findings from interviews seven years post-partum indicate that mothers of children with FASD are significantly more likely than randomly-selected controls or community mothers to: be shorter; have higher body mass indexes (BMI); be married to a man with legal problems; report more drinking three months pre-pregnancy; engage in more current drinking and drinking alone; and have alcohol problems in her family. Logistic regression analysis of multiple candidate predictors of a FASD diagnosis indicates that alcohol problems in the child's family is the most significant risk factor, making a diagnosis within the continuum of FASD 9 times more likely (95%C.I. = 1.6 to 50.7). Sequential multiple regression analysis of the child's neuropsychological performance also identifies alcohol problems in the child's family as the only significant maternal risk variable (p < .001) when controlling for other potential risk factors. CONCLUSIONS: Underreporting of prenatal alcohol use has been demonstrated among Italian and other Mediterranean antenatal samples, and it was suspected in this sample. Nevertheless, several significant maternal risk factors for FASD have been identified. PMID- 25456333 TI - Double trouble: Exploring the association between waterpipe tobacco smoking and the nonmedical use of psychoactive prescription drugs among adolescents. AB - BACKGROUND: In youth, both waterpipe tobacco smoking (WTS) and nonmedical use of prescription drugs (NMUPD) are globally growing concerns. This study assesses for the first time the lifetime and past-year associations between WTS and four classes of psychoactive prescription drugs. METHODS: Cross-sectional data (2011) on 986 high school students attending public and private high schools in Beirut (Lebanon) was analyzed. Schools were selected using proportionate random cluster sampling from a comprehensive list of schools provided by the Ministry of Education. RESULTS: Almost half (46%) had tried WTS compared to 25% who had ever tried cigarettes. Lifetime prevalence estimates of NMUPD were: pain relievers (8.2%), sedatives/tranquilizers (5.6%), stimulants (3.5%), antidepressants (2.5%), and sleeping pills (2.3%). WTS was associated with increased odds of sedatives/tranquilizer use (OR = 3.22, 95% CI: 1.25, 8.25), pain reliever use (OR = 4.31, 95% CI: 2.02, 9.17), and sleeping medication use (OR = 8.31, 95% CI: 2.37, 29.20), controlling for sex, age, school type, and other substance use. For cigarettes, the associations were consistently either weaker or non-existent, except with stimulant use (OR = 5.29, 95% CI: 1.55, 18.05). CONCLUSIONS: While public health professionals have watched with caution the global prevalence of youth cigarette use-worldwide, an insidious alternative form of tobacco use has grown. Further research is needed to understand the unique risk factors and motives associated with WTS and how these relate to NMUPD in order to inform the development of effective intervention programs and policies that support youth positive health decisions. PMID- 25456334 TI - Excessive suicide mortality and risk factors for suicide among patients with heroin dependence. AB - BACKGROUND: The mortality risk is high among individuals dependent on heroin, and suicide is a severe consequence of long-term heroin use. We estimated the incidence of suicide mortality and its risk factors in a large Asian cohort with heroin dependence. METHODS: A consecutive series of 2750 inpatients dependent on heroin admitted to a psychiatric center in northern Taiwan between 1990 and 2010 were retrospectively enrolled as the study cohort. These patients were linked to the Taiwan National Mortality Database to obtain each mortality event. We determined the Standardized Mortality Ratio (SMR) for each cause of death. Among the deceased, 69 deaths were due to suicide (cases); 138 controls were randomly selected using risk-set density sampling based on a nested case-control design. We collected clinical information from subjects' medical records. Multivariate conditional logistic regression was employed to explore the correlates of suicide mortality. RESULTS: The findings showed a 7.9-fold SMR for all-cause mortality among heroin users compared to the general population while the SMR for suicide mortality was 16.2. Multivariate analysis showed that suicide attempt as the reason for the index admission (adjusted risk ratio [RR] = 4.29, p = 0.035) and depressive syndrome anytime during life (adjusted RR = 2.61, p = 0.019) were associated with the risk of suicide mortality. CONCLUSIONS: Individuals dependent on heroin are more likely to die of suicide compared to the general population. We recommend that clinical psychiatric staff carefully gather information related to the identified risk factors to prevent suicide among heroin users. PMID- 25456335 TI - Selenium deficiency associated porcine and human cardiomyopathies. AB - Selenium (Se) is a trace element playing an important role in animal and human physiological homeostasis. It is a key component in selenoproteins (SeP) exerting multiple actions on endocrine, immune, inflammatory and reproductive processes. The SeP family of glutathione peroxidases (GSH-Px) inactivates peroxides and thereby maintains physiological muscle function in humans and animals. Animals with high feed conversion efficiency and substantial muscle mass have shown susceptibility to Se deficiency related diseases since nutritional requirements of the organism may not be covered. Mulberry Heart Disease (MHD) in pigs is an important manifestation of Se deficiency often implicating acute heart failure and sudden death without prior clinical signs. Post-mortem findings include hemorrhagic and pale myocardial areas accompanied by fluid accumulation in the pericardial sac and pleural cavity. Challenges in MHD are emerging in various parts of the world. Se is of fundamental importance also to human health. In the 1930s the Se deficiency associated cardiomyopathy named Keshan Disease (KD) was described for the first time in China. Various manifestations, such as cardiogenic shock, enlarged heart, congestive heart failure, and cardiac arrhythmias are common. Multifocal necrosis and fibrous replacement of myocardium are characteristic findings. Pathological findings in MD and KD show striking similarities. PMID- 25456336 TI - A modified paravertebral block to reduce risk of mortality in a patient with multiple rib fractures. PMID- 25456337 TI - Characteristics of trauma patients overimmobilized by prehospital providers. PMID- 25456338 TI - Reversal of electrical storm after intraaortic balloon pump counterpulsation in a patient with acute myocardial infarction. PMID- 25456339 TI - Epiglottic abscess. PMID- 25456341 TI - Coronary aneurysms in patients with systemic lupus erythematosus. PMID- 25456340 TI - Inaccuracy of patient care reports for identification of critical resuscitation events during out-of-hospital cardiac arrest. AB - OBJECTIVE: Out-of-hospital cardiac arrest (OHCA) is a leading cause of mortality in the United States. We sought to evaluate the accuracy of the patient care report (PCR) for detection of 2 clinically important events: return of spontaneous circulation (ROSC) and rearrest (RA). METHODS: We used defibrillator recordings and PCRs for Emergency Medical Services-treated OHCA collected by the Resuscitation Outcomes Consortium's Pittsburgh site from 2006 to 2008 and 2011 to 2012. Defibrillator data included electrocardiogram rhythm tracing, chest compression measurement, and audio voice recording. Sensitivity analysis was performed by comparing the accuracy of the PCR to detect the presence and number of ROSC and RA events to integrated defibrillator data. RESULTS: In the 158 OHCA cases, there were 163 ROSC events and 53 RA events. The sensitivity of PCRs to identify all ROSC events was 85% (confidence interval [CI], .795-.905); to identify primary ROSC events, it was 85% (CI, .793-.907); and to identify secondary ROSC events, it was 78% (CI, .565-.995). The sensitivity of PCRs to identify the presence of all RA events was .60 (CI, .469-.731); to identify primary RA events, it was 71% (CI, .578-.842); and to identify secondary RA events, it was 0. Of the 32 RA incidents captured by the PCR, only 15 (47%) correctly identified the correct lethal arrhythmia. CONCLUSIONS: We found that PCRs are not a reliable source of information for assessing the presence of ROSC and post-RA electrocardiogram rhythm. For quality control and research purposes, medical providers should consider augmenting data collection with continuous defibrillator recordings before making any conclusions about the occurrence of critical resuscitation events. PMID- 25456342 TI - Posterior approach for medial column beam screw in midfoot Charcot reconstruction: technique and structures at risk. AB - Charcot neuroarthropathy is frequently recognized as a major cause of morbidity in patients with neuropathic diabetes mellitus. Recently, intramedullary beam screw fixation has been used for midfoot Charcot reconstructions. Ten below-the knee cadaveric specimens were used to demonstrate an antegrade, posterior approach for placement of a medial column beam screw, with specific attention to the proximity of the anatomic structures at risk. Six structures at risk were identified, including the sural nerve, ankle joint, flexor hallucis longus tendon, Achilles tendon, neurovascular bundle, and peroneal tendon sheath. The sural nerve was the most commonly injured structure, injured in 50% of the limbs. The Achilles and flexor hallucis longus tendons were injured in 20% and the ankle joint in 10% of the limbs. The neurovascular bundle and peroneal tendon sheath were located over 1 cm from the reference guidewire and were considered safe structures in this approach. Our results have demonstrated an alternative posterior approach to the delivery of an intramedullary medial column beam screw, instead of a retrograde technique beginning in the metatarsal heads. Our results have also made clear the need to be aware of the potential for damage to the sural nerve, Achilles tendon, flexor hallucis longus tendon, and ankle joint. PMID- 25456343 TI - Use of a definitive cement spacer for simultaneous bony and soft tissue reconstruction of mid- and hindfoot diabetic neuroarthropathy:a case report. AB - The prevalence of diabetes mellitus has been increasing, and <=25.8 million people, or 8.3% of the US population, have diabetes. Diabetic Charcot arthropathy and foot ulcers are serious complications of diabetes mellitus. They have been associated with greater risks of lower extremity amputation and mortality. Studies have shown that the amputation risk relative to patients with Charcot arthropathy alone is 7 times greater for patients with a foot ulcer, and 12 times greater for patients with Charcot arthropathy and a foot ulcer. Surgical reconstruction of Charcot arthropathy of the foot is often difficult, because of bone loss, deformities, vasculopathy, and the presence of active infection with or without soft tissue loss. It will be even more challenging if >1 region of the foot has been affected, such as the mid- and hindfoot. In such situations, an amputation would usually be the surgical option. We present a case of limb threatening Charcot deformity with instability complicated by osteomyelitis, bone loss, and a large soft tissue defect. We used a limb salvage strategy with hindfoot fusion combined with an antibiotic-impregnated cement spacer for reconstruction of the midfoot, which was performed simultaneously with a local adipofascial flap for soft tissue coverage, resulting in a plantigrade, painless, and functional foot. PMID- 25456344 TI - Enhanced Lapidus arthrodesis: crossed screw technique with middle cuneiform fixation further reduces sagittal mobility. AB - Persistent medial column sagittal mobility can be encountered despite successful first tarsometatarsal stabilization if fixation has been limited to the first tarsometatarsal joint. The purpose of the present cadaveric research was to quantify the effect of a third point of fixation from the base of the first metatarsal to the middle cuneiform compared with the traditional isolated first tarsometatarsal fixation. Ten matched pairs of below-the-knee specimens, with a known cause of death, sex, ethnicity, and age, height, weight, and body mass index at death, were used for our examination. Portable fluoroscopy aided with the accurate placement of all points of fixation. Measurements of movement were obtained using the validated Klaue device. The 20 matched below-the-knee specimens were from 10 cadavers (2 female and 8 male donors, aged 72.8 +/- 9.3 years, body mass index 21.1 +/- 4.2 kg/m(2)). The sagittal plane motion of the first ray was 7.45 +/- 1.82 mm before fixation. With isolated first tarsometatarsal fixation, the sagittal motion decreased to 4.41 +/- 1.51 mm and decreased further to 3.12 +/- 1.06 mm, with the addition of middle cuneiform fixation. Statistically significant enhancement of the stability of sagittal first ray motion was noted with the addition of the first metatarsal to middle cuneiform pin, even after simulated Lapidus fixation. Our findings suggest that first metatarsal to middle cuneiform fixation can be beneficial if excessive sagittal motion is present after standard 2-point fixation and can play a role in the prevention of recurrence and complications. PMID- 25456345 TI - Tendoscopic Excision of an Intratendinous Ganglion in the Flexor Hallucis Longus Tendon: A Case Report. AB - Intratendinous ganglion cysts are rare lesions of unknown etiology that originate within a tendon. We report the case of a 34-year-old female with an intratendinous ganglion in the plantar portion of the flexor hallucis longus tendon. The intratendinous ganglion recurred after ultrasound-guided needle aspiration. Tendoscopic excision of the intratendinous ganglion cyst achieved a satisfactorily result without recurrence. PMID- 25456348 TI - Core-size-dependent catalytic properties of bimetallic Au/Ag core-shell nanoparticles. AB - Bimetallic core-shell nanoparticles have recently emerged as a new class of functional materials because of their potential applications in catalysis, surface enhanced Raman scattering (SERS) substrate and photonics etc. Here, we have synthesized Au/Ag bimetallic core-shell nanoparticles with varying the core diameter. The red-shifting of the both plasmonic peaks of Ag and Au confirms the core-shell structure of the nanoparticles. Transmission electron microscopy (TEM) analysis, line scan EDS measurement and UV-vis study confirm the formation of core-shell nanoparticles. We have examined the catalytic activity of these core shell nanostructures in the reaction between 4-nitrophenol (4-NP) and NaBH4 to form 4-aminophenol (4-AP) and the efficiency of the catalytic reaction is found to be increased with increasing the core size of Au/Ag core-shell nanocrystals. The catalytic efficiency varies from 41.8 to 96.5% with varying core size from 10 to 100 nm of Au/Ag core-shell nanoparticles, and the Au100/Ag bimetallic core shell nanoparticle is found to be 12-fold more active than that of the pure Au nanoparticles with 100 nm diameter. Thus, the catalytic properties of the metal nanoparticles are significantly enhanced because of the Au/Ag core-shell structure, and the rate is dependent on the size of the core of the nanoparticles. PMID- 25456346 TI - Genomic predictors of combat stress vulnerability and resilience in U.S. Marines: A genome-wide association study across multiple ancestries implicates PRTFDC1 as a potential PTSD gene. AB - BACKGROUND: Research on the etiology of post-traumatic stress disorder (PTSD) has rapidly matured, moving from candidate gene studies to interrogation of the entire human genome in genome-wide association studies (GWAS). Here we present the results of a GWAS performed on samples from combat-exposed U.S. Marines and Sailors from the Marine Resiliency Study (MRS) scheduled for deployment to Iraq and/or Afghanistan. The MRS is a large, prospective study with longitudinal follow-up designed to identify risk and resiliency factors for combat-induced stress-related symptoms. Previously implicated PTSD risk loci from the literature and polygenic risk scores across psychiatric disorders were also evaluated in the MRS cohort. METHODS: Participants (N=3494) were assessed using the Clinician Administered PTSD Scale and diagnosed using the DSM-IV diagnostic criterion. Subjects with partial and/or full PTSD diagnosis were called cases, all other subjects were designated controls, and study-wide maximum CAPS scores were used for longitudinal assessments. Genomic DNA was genotyped on the Illumina HumanOmniExpressExome array. Individual genetic ancestry was determined by supervised cluster analysis for subjects of European, African, Hispanic/Native American, and other descent. To test for association of SNPs with PTSD, logistic regressions were performed within each ancestry group and results were combined in meta-analyses. Measures of childhood and adult trauma were included to test for gene-by-environment (GxE) interactions. Polygenic risk scores from the Psychiatric Genomic Consortium were used for major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia (SCZ). RESULTS: The array produced >800K directly genotyped and >21M imputed markers in 3494 unrelated, trauma exposed males, of which 940 were diagnosed with partial or full PTSD. The GWAS meta-analysis identified the phosphoribosyl transferase domain containing 1 gene (PRTFDC1) as a genome-wide significant PTSD locus (rs6482463; OR=1.47, SE=0.06, p=2.04*10(-9)), with a similar effect across ancestry groups. Association of PRTFDC1 with PTSD in an independent military cohort showed some evidence for replication. Loci with suggestive evidence of association (n=25 genes, p<5*10( 6)) further implicated genes related to immune response and the ubiquitin system, but these findings remain to be replicated in larger GWASs. A replication analysis of 25 putative PTSD genes from the literature found nominally significant SNPs for the majority of these genes, but associations did not remain significant after correction for multiple comparison. A cross-disorder analysis of polygenic risk scores from GWASs of BPD, MDD, and SCZ found that PTSD diagnosis was associated with risk sores of BPD, but not with MDD or SCZ. CONCLUSIONS: This first multi-ethnic/racial GWAS of PTSD highlights the potential to increase power through meta-analyses across ancestry groups. We found evidence for PRTFDC1 as a potential novel PTSD gene, a finding that awaits further replication. Our findings indicate that the genetic architecture of PTSD may be determined by many SNPs with small effects, and overlap with other neuropsychiatric disorders, consistent with current findings from large GWAS of other psychiatric disorders. PMID- 25456349 TI - Antiepileptogenic and neuroprotective effects of losartan in kainate model of temporal lobe epilepsy. AB - Recently, we have shown that the blockade of AT1 receptor might be useful as an adjuvant treatment strategy for the prevention of oxidative stress and neurotoxicity caused by status epilepticus (SE) in rats. The purpose of the present study was to further assess the efficacy of long-term treatment with losartan (10mg/kg), the selective AT1 receptor antagonist, during kainate (KA) induced epileptogenesis in Wistar rats. Losartan treatment started after onset of SE and continued for 4weeks. The rats were video- and EEG-recorded for 3months. Locomotor activity, anxiety and depressive-like behavior were evaluated 9weeks after SE, when all rats had developed chronic epileptic state. Neuronal damage in hippocampus was analyzed by hematoxylin while serotonin (5-HT) levels in hippocampus by HPLC. AT1 receptor antagonism increased the latent seizure-free period and decreased the frequency of spontaneous motor seizures. Losartan positively affected epilepsy-provoked behavioral changes, including impulsivity, low anxiety level and depression in a phase-dependent manner and restored the changes in diurnal fluctuation of motor activity. Losartan exerted neuroprotection selectively in the CA1 area of the hippocampus in the KA-treated rats and lowered the 5-HT levels both in normal and abnormal conditions. Our findings suggest that the AT1 receptor antagonist exerts disease-modifying effects during KA-induced epileptogenesis and neuronal damage in CA1 hippocampal area, attenuated some of the behavioral changes and restored diurnal variability in locomotor activity. PMID- 25456350 TI - Addressing the burden of cancer in the Gulf. PMID- 25456347 TI - Translational evidence for a role of endocannabinoids in the etiology and treatment of posttraumatic stress disorder. AB - INTRODUCTION: Posttraumatic stress disorder (PTSD) is a prevalent, chronic, and disabling anxiety disorder that may develop following exposure to a traumatic event. Despite the public health significance of PTSD, relatively little is known about the etiology or pathophysiology of this disorder, and pharmacotherapy development to date has been largely opportunistic instead of mechanism-based. Recently, an accumulating body of evidence has implicated the endocannabinoid system in the etiology of PTSD, and targets within this system are believed to be suitable for treatment development. METHODS: Herein, we describe evidence from translational studies arguing for the relevance of the endocannabinoid system in the etiology of PTSD. We also show mechanisms relevant for treatment development. RESULTS: There is convincing evidence from multiple studies for reduced endocannabinoid availability in PTSD. Brain imaging studies show molecular adaptations with elevated cannabinoid type 1 (CB1) receptor availability in PTSD which is linked to abnormal threat processing and anxious arousal symptoms. CONCLUSION: Of particular relevance is evidence showing reduced levels of the endocannabinoid anandamide and compensatory increase of CB1 receptor availability in PTSD, and an association between increased CB1 receptor availability in the amygdala and abnormal threat processing, as well as increased severity of hyperarousal, but not dysphoric symptomatology, in trauma survivors. Given that hyperarousal symptoms are the key drivers of more disabling aspects of PTSD such as emotional numbing or suicidality, novel, mechanism-based pharmacotherapies that target this particular symptom cluster in patients with PTSD may have utility in mitigating the chronicity and morbidity of the disorder. PMID- 25456351 TI - Dacomitinib: another option for EGFR-mutant lung cancer? PMID- 25456352 TI - A practice-changing step forward in germ-cell cancer? PMID- 25456353 TI - Harnessing GVHD by interleukin-6 receptor blockade. PMID- 25456354 TI - Non-coding RNAs as biomarkers for metastatic prostate cancer. PMID- 25456355 TI - How can we improve adjuvant chemotherapy for colon cancer? PMID- 25456356 TI - Predicting pathological complete response in breast cancer early. PMID- 25456357 TI - An oral proteasome inhibitor for multiple myeloma. PMID- 25456358 TI - The mTOR inhibitor revolution rolls on. PMID- 25456359 TI - Chromoplexy and hypoxic microenvironment drives prostate cancer. PMID- 25456360 TI - Global uptake of BHGI guidelines for breast cancer. PMID- 25456361 TI - Blurring of boundaries in the doctor-patient relationship. PMID- 25456362 TI - Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial. AB - BACKGROUND: Patients with EGFR-mutant non-small-cell lung cancer generally have a progression-free survival of 9-13 months while being treated with the EGFR tyrosine-kinase inhibitors gefitinib or erlotinib. However, resistance inevitably develops, and more effective EGFR inhibitors are needed. Dacomitinib is a covalent pan-HER inhibitor that has shown clinical activity in patients previously treated with gefitinib or erlotinib. We did a trial of dacomitinib as initial systemic therapy in clinically and molecularly selected patients with advanced non-small-cell lung cancer. METHODS: In this open-label, multicentre, phase 2 trial, we enrolled treatment-naive patients with advanced lung cancer who had clinical (never-smokers [<100 cigarettes per lifetime] or former light smokers [<10 pack-years per lifetime] and >=15 years since last cigarette) or molecular (EGFR mutation, regardless of smoking status) characteristics associated with response to EGFR inhibitors. We gave dacomitinib orally once daily (45 mg or 30 mg) until progressive disease, unacceptable toxicity, or patient withdrawal. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.0) to investigate the activity of dacomitinib in all patients with a baseline scan and at least one post-treatment scan, with investigator assessment of response and progression. The primary endpoint was progression-free survival at 4 months in the as-enrolled population, with a null hypothesis of progression free survival at 4 months of 50% or less. The study is registered with ClinicalTrials.gov, number NCT00818441, and is no longer accruing patients. FINDINGS: Between March 11, 2009, and April 1, 2011, we enrolled 89 patients from 25 centres, including 45 (51%) with EGFR-activating mutations in exon 19 (n=25) or exon 21 (n=20). Progression-free survival at 4 months was 76.8% (95% CI 66.4 84.4) in the as-enrolled population, and was 95.5% (95% CI 83.2-98.9) in the EGFR mutant population. The most common all-grade treatment-related adverse events were diarrhoea in 83 (93%) patients, dermatitis acneiform in 69 (78%) patients, dry skin in 39 (44%) patients, and stomatitis in 36 (40%) patients. Two patients (2%) had grade 4 treatment-related events (one with hypokalaemia and one with dyspnoea). No grade 5 toxicities were recorded. INTERPRETATION: Dacomitinib had encouraging clinical activity as initial systemic treatment in clinically or molecularly selected patients with advanced non-small-cell lung cancer. FUNDING: Pfizer. PMID- 25456363 TI - Personalised chemotherapy based on tumour marker decline in poor prognosis germ cell tumours (GETUG 13): a phase 3, multicentre, randomised trial. AB - BACKGROUND: Poor prognosis germ-cell tumours are only cured in about half of patients. We aimed to assess whether treatment intensification based on an early tumour marker decline will improve progression-free survival for patients with germ-cell tumours. METHODS: In this phase 3, multicentre, randomised trial, patients were enrolled from France (20 centres), USA (one centre), and Slovakia (one centre). Patients were eligible if they were older than 16 years, had evidence of testicular, retroperitoneal, or mediastinal non-seminomatous germ cell tumours based on histological findings or clinical evidence and highly elevated serum human chorionic gonadotropin or alfa-fetoprotein concentrations that matched International Germ Cell Cancer Consensus Group poor prognosis criteria. After one cycle of BEP (intravenous cisplatin [20 mg/m(2) per day for 5 days], etoposide [100 mg/m(2) per day for 5 days], and intramuscular or intravenous bleomycin [30 mg per day on days 1, 8, and 15]), patients' human chorionic gonadotropin and alfa-fetoprotein concentrations were measured at day 18-21. Patients with a favourable decline in human chorionic gonadotropin and alfa-fetoprotein continued BEP (Fav-BEP group) for 3 additonal cycles, whereas patients with an unfavourable decline were randomly assigned (1:1) to receive either BEP (Unfav-BEP group) or a dose-dense regimen (Unfav-dose-dense group), consisting of intravenous paclitaxel (175 mg/m(2) over 3 h on day 1) before BEP plus intravenous oxaliplatin (130 mg/m(2) over 3 h on day 10; two cycles), followed by intravenous cisplatin (100 mg/m(2) over 2 h on day 1), intravenous ifosfamide (2 g/m(2) over 3 h on days 10, 12, and 14), plus mesna (500 mg/m(2) at 0, 3, 7 and 11 h), and bleomycin (25 units per day, by continuous infusion for 5 days on days 10-14; two cycles), with granulocyte-colony stimulating factor (lenograstim) support. Centrally blocked computer-generated randomisation stratified by centre was used. The primary endpoint was progression-free survival and the efficacy analysis was done in the intention-to-treat population. The planned trial accrual was completed in May, 2012, and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00104676. FINDINGS: Between Nov 28, 2003, and May 16, 2012, 263 patients were enrolled and 254 were available for tumour marker assessment. Of these 51 (20%) had a favourable marker assessment, and 203 (80%) had an unfavourable tumour marker decline; 105 were randomly assigned to the Unfav-dose-dense group and 98 to the Unfav-BEP group. 3 year progression-free survival was 59% (95% CI 49-68) in the Unfav-dose-dense group versus 48% (38-59) in the Unfav-BEP group (HR 0.66, 95% CI 0.44-1.00, p=0.05). 3-year progression-free survival was 70% (95% CI 57-81) in the Fav-BEP group (HR 0.66, 95% CI 0.49-0.88, p=0.01 for progression-free survival compared with the Unfav-BEP group). More grade 3-4 neurotoxic events (seven [7%] vs one [1%]) and haematotoxic events occurred in the Unfav-dose-dense group compared with in the Unfav-BEP group; there was no difference in grade 1-2 febrile neutropenia (18 [17%] vs 18 [18%]) or toxic deaths (one [1%] in both groups). Salvage high-dose chemotherapy plus a stem-cell transplant was required in six (6%) patients in the Unfav-dose-dense group and 16 (16%) in the Unfav-BEP group. INTERPRETATION: Personalised treatment with chemotherapy intensification reduces the risk of progression or death in patients with poor prognosis germ-cell tumours and an unfavourable tumour marker decline. FUNDING: Institut National du Cancer (Programme Hospitalier de Recherche Clinique). PMID- 25456364 TI - Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial. AB - BACKGROUND: Interleukin 6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem-cell transplantation (allogeneic SCT) and represents an attractive therapeutic target. We aimed to assess whether the humanised anti interleukin-6 receptor monoclonal antibody, tocilizumab, could attenuate the incidence of acute GVHD. METHODS: We undertook a single-group, single-institution phase 1/2 study at the Royal Brisbane and Women's Hospital Bone Marrow Transplantation unit, QLD, Australia. Eligible patients were 18-65 years old and underwent T-replete HLA-matched allogeneic SCT with either total body irradiation based myeloablative or reduced-intensity conditioning from unrelated or sibling donors. One intravenous dose of tocilizumab (8 mg/kg, capped at 800 mg, over 60 mins' infusion) was given the day before allogeneic SCT along with standard GVHD prophylaxis (cyclosporin [5 mg/kg per day on days -1 to +1, then 3 mg/kg per day to maintain therapeutic levels (trough levels of 140-300 ng/mL) for 100 days plus methotrexate [15 mg/m(2) on day 1, then 10 mg/m(2) on days 3, 6, and 11]). The primary endpoint was incidence of grade 2-4 acute GVHD at day 100, assessed and graded as per the Seattle criteria. Immunological profiles were compared with a non-randomised group of patients receiving allogeneic SCT, but not treated with tocilizumab. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12612000726853. FINDINGS: Between Jan 19, 2012, and Aug 27, 2013, 48 eligible patients receiving cyclosporin and methotrexate as GVHD prophylaxis were enrolled into the study. The incidence of grade 2-4 acute GVHD in patients treated with tocilizumab at day 100 was 12% (95% CI 5-24), and the incidence of grade 3-4 acute GVHD was 4% (1-13). Grade 2-4 acute GVHD involving the skin developed in five (10%) patients of 48 treated with tocilizumab, involving the gastrointestinal tract in four (8%) patients; there were no reported cases involving the liver. Low incidences of grade 2-4 acute GVHD were noted in patients receiving both myeloablative total body irradiation based conditioning (12% [95% CI 2-34) and fludarabine and melphalan reduced intensity conditioning (12% [4-27]). Immune reconstitution was preserved in recipients of interleukin-6 receptor inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways. INTERPRETATION: Interleukin 6 is the main detectable and dysregulated cytokine secreted after allogeneic SCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution; a randomised, controlled trial assessing tocilizumab in addition to standard GVHD prophylaxis in these patients is warranted. FUNDING: National Health and Medical Research Council and Queensland Health. PMID- 25456365 TI - Changes in bone mineral density at 3 years in postmenopausal women receiving anastrozole and risedronate in the IBIS-II bone substudy: an international, double-blind, randomised, placebo-controlled trial. AB - BACKGROUND: Aromatase inhibitors prevent breast cancer in postmenopausal women at high risk of the disease but are associated with accelerated bone loss. We assessed effectiveness of oral risedronate for prevention of reduction in bone mineral density (BMD) after 3 years of follow-up in a subset of patients in the IBIS-II trial. METHODS: The double-blind IBIS-II trial recruited 3864 healthy, postmenopausal women at increased risk of breast cancer and randomly allocated them oral anastrozole (1 mg/day) or matched placebo. 1410 (36%) postmenopausal women were then enrolled in a bone substudy and stratified at baseline according to their lowest baseline T score at spine or femoral neck (stratum I: T score at least -1.0; stratum II: T score at least -2.5 but less than -1.0; stratum III: T score less than -2.5 but greater than -4.0). Women in stratum I were monitored only; women in stratum III were all given risedronate (35 mg/week). Women in stratum II were randomly assigned (1:1) to risedronate (35 mg/week) or matched placebo by use of a block randomisation schedule via a web-based programme. The primary outcome of this per-protocol analysis (done with all women with a baseline and 3 year DXA assessment) was the effect of risedronate versus placebo for osteopenic women in stratum II randomly allocated to anastrozole (1 mg/day). Secondary outcomes included effect of anastrozole (1 mg/day) on BMD in women not receiving risedronate (strata I and II) and in osteoporotic women who were all treated with risedronate (stratum III). The trial is ongoing, but no longer recruiting. This trial is registered, number ISRCTN31488319. FINDINGS: Between Feb 2, 2003, and Sept 30, 2010, 150 (58%) of 260 women in stratum II who had been randomly allocated to anastrozole and either risedronate or placebo had baseline and 3 year assessments. At the lumbar spine, 3 year mean BMD change for the 77 women receiving anastrozole/risedronate was 1.1% (95% CI 0.2 to 2.1) versus -2.6% (-4.0 to -1.3) for the 73 women receiving anastrozole/placebo (p<0.0001). For the total hip, 3 year mean BMD change for women receiving anastrozole/risedronate was -0.7% (-1.6 to 0.2) versus -3.5% (-4.6 to -2.3) for women receiving anastrozole/placebo (p=0.0001). 652 (65%) of 1008 women in strata I and II who were not randomly allocated to risedronate had both baseline and 3 year assessments. Women not receiving risedronate in stratum I and II who received anastrozole (310 women) had a significant BMD decrease after 3 years of follow-up compared with women who received placebo (342 women) at the lumbar spine (-4.0% [ 4.5 to -3.4] vs -1.2% [-1.7 to -0.7], p<0.0001) and total hip (-4.0% [-4.4 to 3.6] vs -1.8% [-2.1 to -1.4], p<0.0001). 106 (79%) of 149 women in stratum III had a baseline and a 3 year assessment. The 46 women allocated to anastrozole had a modest BMD increase of 1.2% (-0.1 to 2.6) at the spine compared with a 3.9% (2.6 to 5.2) increase for the 60 women allocated to placebo (p=0.006). For the total hip, a small 0.3% (-0.9 to 1.5) increase was noted for women allocated anastrozole compared with a 1.5% (0.5 to 2.5) increase for women allocated placebo, but the difference was not significant (p=0.12). The most common adverse event reported was arthralgia (stratum I: 94 placebo and 114 anastrozole; stratum II: 39 placebo/placebo, 25 placebo/risedronate, 34 anastrozole/placebo, and 34 anastrozole/risedronate; stratum III: 21 placebo/risedronate, 17 anastrozole/risedronate). Other adverse events included hot flushes, alopecia, abdominal pain, and back pain. INTERPRETATION: Risedronate counterbalances the effect of anastrozole-induced bone loss in osteopenic and osteoporotic women and might be offered in combination with anastrozole treatment to provide an improved risk-benefit profile. FUNDING: Cancer Research UK (C569/A5032), National Health and Medical Research Council Australia (GNT300755, GNT569213), Sanofi-Aventis, and AstraZeneca. PMID- 25456366 TI - RNA biomarkers associated with metastatic progression in prostate cancer: a multi institutional high-throughput analysis of SChLAP1. AB - BACKGROUND: Improved clinical predictors for disease progression are needed for localised prostate cancer, since only a subset of patients develop recurrent or refractory disease after first-line treatment. Therefore, we undertook an unbiased analysis to identify RNA biomarkers associated with metastatic progression after prostatectomy. METHODS: Prostate cancer samples from patients treated with radical prostatectomy at three academic institutions were analysed for gene expression by a high-density Affymetrix GeneChip platform, encompassing more than 1 million genomic loci. In a discovery cohort, all protein-coding genes and known long non-coding RNAs were ranked by fold change in expression between tumours that subsequently metastasised versus those that did not. The top ranked gene was then validated for its prognostic value for metastatic progression in three additional independent cohorts. 95% of the gene expression assays were done in a Clinical Laboratory Improvements Amendments certified laboratory facility. All genes were assessed for their ability to predict metastatic progression by receiver-operating-curve area-under-the-curve analyses. Multivariate analyses were done for the primary endpoint of metastatic progression, with variables including Gleason score, preoperative prostate-specific antigen concentration, seminal vesicle invasion, surgical margin status, extracapsular extension, lymph node invasion, and expression of the highest ranked gene. FINDINGS: 1008 patients were included in the study: 545 in the discovery cohort and 463 in the validation cohorts. The long non-coding RNA SChLAP1 was identified as the highest-ranked overexpressed gene in cancers with metastatic progression. Validation in three independent cohorts confirmed the prognostic value of SChLAP1 for metastatic progression. On multivariate modelling, SChLAP1 expression (high vs low) independently predicted metastasis within 10 years (odds ratio [OR] 2.45, 95% CI 1.70-3.53; p<0.0001). The only other variable that independently predicted metastasis within 10 years was Gleason score (8-10 vs 5-7; OR 2.14, 95% CI 1.77 2.58; p<0.0001). INTERPRETATION: We identified and validated high SChLAP1 expression as significantly prognostic for metastatic disease progression of prostate cancer. Our findings suggest that further development of SChLAP1 as a potential biomarker, for treatment intensification in aggressive prostate cancer, warrants future study. FUNDING: Prostate Cancer Foundation, National Institutes of Health, Department of Defense, Early Detection Research Network, Doris Duke Charitable Foundation, and Howard Hughes Medical Institute. PMID- 25456367 TI - Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post relapse survival: a pooled analysis of individual patient data from four randomised controlled trials. AB - BACKGROUND: Oxaliplatin-based adjuvant therapy is the standard of care for stage III colon cancer. Adjuvant capecitabine with or without oxaliplatin versus leucovorin and fluorouracil with or without oxaliplatin has not been directly compared; therefore, we aimed to analyse the efficacy and safety of these treatments using individual patient data pooled from four randomised controlled trials. We also assessed post-relapse survival, which has been postulated to be worse in patients receiving adjuvant oxaliplatin. METHODS: Patients with resected stage III colon cancer who were 18 years of age or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from four randomised controlled trials (NSABP C-08, XELOXA, X-ACT, and AVANT; 8734 patients in total) were pooled and analysed. The treatment regimens included in our analyses were: XELOX (oxaliplatin and capecitabine); leucovorin and fluorouracil; capecitabine; FOLFOX-4 (leucovorin, fluorouracil, and oxaliplatin); and modified FOLFOX-6 (mFOLFOX-6). Disease-free survival was the primary endpoint for all trials that supplied patients for this analysis. Here, we compared disease-free, relapse free, and overall survival between the patient groups who received capecitabine with or without oxaliplatin and those who received leucovorin and fluorouracil with or without oxaliplatin. Post-relapse survival was compared between the combined XELOX and FOLFOX groups, and the leucovorin and fluorouracil groups. Post-relapse survival was also compared between the capecitabine with or without oxaliplatin and leucovorin and fluorouracil with or without oxaliplatin groups. FINDINGS: Disease-free survival did not differ significantly between patients who received leucovorin and fluorouracil versus those who received capecitabine in adjusted analyses (hazard ratio [HR] 1.02 [0.93-1.11; p=0.72]) or in unadjusted analyses (HR 1.01 [95% CI 0.92-1.10; p=0.86]). Relapse-free survival was similar (adjusted HR 1.02 [0.93-1.12; p=0.72] and unadjusted HR 1.01 [95% CI 0.92-1.11; p=0.86]), as was overall survival (adjusted HR 1.04 [95% CI 0.93-1.15; p=0.50] and unadjusted HR 1.02 [0.92-1.14]; p=0.65). For overall survival, a significant interaction between oxaliplatin and fluoropyrimidine was recorded in the multiple Cox regression analysis (p=0.014). Post-relapse survival was similar in adjusted (p=0.23) and unadjusted analyses (p=0.33) for the comparison of XELOX or FOLFOX versus leucovorin and fluorouracil, and was also similar for capecitabine-based regimens versus leucovorin and fluorouracil-based regimens (unadjusted p=0.26). INTERPRETATION: Combination therapy with oxaliplatin provided consistently improved outcomes without adversely affecting post-relapse survival in the adjuvant treatment of stage III colon cancer, irrespective of whether the fluoropyrimidine backbone was capecitabine or leucovorin and fluorouracil. These data add to the existing evidence that oxaliplatin plus capecitabine or leucovorin and fluorouracil is the standard of care for the adjuvant treatment of stage III colon cancer, and offers physicians flexibility to treat patients according to the patients' overall physical performance and preference. FUNDING: Genentech Inc. PMID- 25456368 TI - Use of [(18)F]-FDG PET to predict response to neoadjuvant trastuzumab and docetaxel in patients with HER2-positive breast cancer, and addition of bevacizumab to neoadjuvant trastuzumab and docetaxel in [(18)F]-FDG PET-predicted non-responders (AVATAXHER): an open-label, randomised phase 2 trial. AB - BACKGROUND: An effective and well tolerated treatment is needed for patients with early HER2-positive breast cancer who do not achieve a pathological complete response after neoadjuvant therapy. The AVATAXHER trial aimed to predict pathological complete response early with the use of PET and to investigate whether the addition of bevacizumab could improve the proportion of patients achieving a pathological complete response in patients unlikely to respond to treatment. METHODS: AVATAXHER was a randomised, open-label, non-comparative, multicentre phase 2 study that enrolled women (>=18 years of age) with early stage HER2-positive breast cancer from 26 oncology centres in France. Patients initially received two cycles of neoadjuvant docetaxel (100 mg/m(2) intravenously every 3 weeks) plus trastuzumab (8 mg/kg intravenously every 3 weeks then 6 mg/kg intravenously every 3 weeks for the second course). Before the first and second cycles, [(18)F]-fluorodeoxyglucose (FDG) PET was done and the change in standardised uptake value was used to predict pathological complete response in each patient. Patients who were predicted to be responders on PET continued to receive standard therapy. Predicted non-responders were randomly assigned (2:1) to receive four cycles of docetaxel (100 mg/m(2) intravenously every 3 weeks) and trastuzumab (6 mg/kg intravenously every 3 weeks) plus bevacizumab (15 mg/kg intravenously every 3 weeks; group A) or continue on docetaxel plus trastuzumab alone (group B). Randomisation was open label and was done by an adaptive minimisation method. Although investigators and patients were aware of group assignment, the anatomo-pathologist in charge of centralised review of surgical samples and lymph nodes was masked to treatment assignment. The primary endpoint was centrally assessed pathological complete response according to the Chevallier classification. Efficacy analyses were done in the intention-to-treat population. Safety analyses in this Article were done on all patients who received at least one dose of treatment starting from cycle 3. Survival outcomes are not yet mature. This study is registered with ClinicalTrials.gov (NCT01142778) and EUDRACT (2009-013410-26). FINDINGS: Between May 19, 2010, and Oct 1, 2012, 152 patients were recruited for the study. Ten patients were subsequently excluded, leaving 142 patients in the intention-to-treat population. Of these 142 patients, 69 were predicted by [(18)F]-FDG PET to be treatment responders after two cycles of treatment. The 73 predicted non-responders were randomly assigned to group A (n=48) and group B (n=25). Pathological complete responses were noted in 37 (53.6%, 95% CI 41.2-65.7) of the PET responders, 21 (43.8%, 29.5-58.8) of those in group A, and six (24.0%, 9.4-45.1) of those in group B. Incidences of grade 3 4 adverse events were similar in all three groups. The most common grade 3-4 adverse events were neutropenia (four in PET responders, five in group A, and three in group B), febrile neutropenia (one, three, and one, respectively), and myalgia (four, none, and one, respectively). Overall, 24 serious adverse events were reported in 15 patients (PET responders: nine events in four [6%] of 67 patients; group A: 14 events in ten [21%] of 47 patients; group B: one event in one [4%] of 25 patients). No deaths occurred during the study. INTERPRETATION: In patients with HER2-positive breast cancer, early PET assessment can help to identify non-responders to neoadjuvant docetaxel plus trastuzumab therapy. In these patients, the addition of bevacizumab can increase the proportion of patients achieving a pathological complete response. This potential new role for PET and the activity of bevacizumab in this setting need to be confirmed in larger phase 3 trials. FUNDING: Roche France. PMID- 25456369 TI - Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. AB - BACKGROUND: The combination of bortezomib, lenalidomide, and dexamethasone is a highly effective therapy for newly diagnosed multiple myeloma. Ixazomib is an investigational, oral, proteasome inhibitor with promising anti-myeloma effects and low rates of peripheral neuropathy. In a phase 1/2 trial we aimed to assess the safety, tolerability, and activity of ixazomib in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma. METHODS: We enrolled patients newly diagnosed with multiple myeloma aged 18 years or older with measurable disease, Eastern Cooperative Oncology Group performance status 0 2, and no grade 2 or higher peripheral neuropathy, and treated them with oral ixazomib (days 1, 8, 15) plus lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to 12 28-day cycles, followed by maintenance therapy with ixazomib alone. In phase 1, we gave patients escalating doses of ixazomib (1.68-3.95 mg/m(2)) to establish the recommended dose for phase 2. The primary endpoints were maximum tolerated dose for phase 1, and the rate of very good partial response or better for phase 2. Safety analyses were done in all patients who received at least one dose of study drug; efficacy analyses were done in all patients who received at least one dose of study drug at the phase 2 dose, had measurable disease at baseline, and had at least one post-baseline response assessment. This study is registered at ClinicalTrials.gov, number NCT01217957. FINDINGS: Between Nov 22, 2010, and Feb 28, 2012, we enrolled 65 patients (15 to phase 1 and 50 to phase 2). Four dose-limiting toxic events were noted in phase 1: one at a dose of ixazomib of 2.97 mg/m(2) and three at 3.95 mg/m(2). The maximum tolerated dose of ixazomib was established as 2.97 mg/m(2) and the recommended phase 2 dose was 2.23 mg/m(2), which was converted to a 4.0 mg fixed dose based on population pharmacokinetic results. Grade 3 or higher adverse events related to any drug were reported in 41 (63%) patients, including skin and subcutaneous tissue disorders (11 patients, 17%), neutropenia (eight patients, 12%), and thrombocytopenia (five patients, 8%); drug-related peripheral neuropathy of grade 3 or higher occurred in four (6%) patients. Five patients discontinued because of adverse events. In 64 response-evaluable patients, 37 (58%, 95% CI 45-70) had a very good partial response or better. INTERPRETATION: The all-oral combination of weekly ixazomib plus lenalidomide and dexamethasone was generally well tolerated and appeared active in newly diagnosed multiple myeloma. These results support the phase 3 trial development of this combination for multiple myeloma. FUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company. PMID- 25456370 TI - Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. AB - BACKGROUND: In the EXIST-1 trial, initiated on Aug 10, 2009, more than 35% of patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex had at least 50% reduction in SEGA volume after 9.6 months of treatment with everolimus. In this Article, we report interim data (up to Jan 11, 2013) to support longer-term tolerability and efficacy of everolimus from the continuing 4-year extension phase of EXIST-1. METHODS: We assessed data from a prospective, open-label extension of a multicentre, phase 3, randomised, double blind, placebo-controlled study in patients with tuberous sclerosis complex who had SEGA that was growing and needed treatment. In this extension study, we included all patients who had been assigned everolimus during the double-blind, randomised phase of the trial and those patients who crossed over from the placebo group to receive everolimus during the randomised phase or at the start of the extension phase. All patients received oral everolimus at a starting dose of 4.5 mg/m(2) per day. Everolimus dose was subsequently adjusted subject to tolerability to attain blood trough concentrations of 5-15 ng/mL. An independent central radiology review team assessed SEGA response (at least a 50% reduction from baseline in total volume of all target SEGAs; the primary endpoint) by MRI at 12, 24, and 48 weeks, then every year thereafter in all patients who received at least one dose of everolimus. This study was registered with ClinicalTrials.gov, number NCT00789828. FINDINGS: Of the original 117 randomly assigned patients, 111 were given everolimus between Aug 20, 2009, and Jan 11, 2013 (date of data cutoff); we included these patients in our longer-term analysis. Median duration of everolimus exposure was 29.3 months (IQR 19.4-33.8). Median follow-up was 28.3 months (IQR 19.3-33.0). 54 (49%) patients had a response of 50% or greater reduction in SEGA volume (95% CI 39.0-58.3), and duration of response was between 2.1 and 31.1 months (median not reached). SEGA volume was reduced by 50% or more in 39 (37%) of 105 patients at 24 weeks, 48 (46%) of 104 patients at 48 weeks, 36 (47%) of 76 patients at 96 weeks, and 11 (38%) of 29 patients at 144 weeks. Stomatitis (48 [43%] patients) and mouth ulceration (33 [30%] patients) were the most frequent treatment-related adverse events; infections were the most commonly reported treatment-related serious adverse event, occurring in 15 (14%) patients. 35 (32%) patients reported treatment-related grade 3 or 4 adverse events, the most common of which were stomatitis (nine [8%]) and pneumonia (nine [8%]). 18 (16%) patients had treatment related serious adverse events. Six (5%) patients withdrew because of adverse events. INTERPRETATION: These results support the longer-term use of everolimus in patients who have few treatment options and who need continued treatment for tuberous sclerosis complex and its varied manifestations. Reduction or stabilisation of tumour volume with everolimus will hopefully provide long-term clinical benefit in patients with SEGA. FUNDING: Novartis Pharmaceuticals. PMID- 25456372 TI - FOLFIRI with cetuximab or bevacizumab: FIRE-3. PMID- 25456371 TI - Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. AB - BACKGROUND: Clinical prognostic groupings for localised prostate cancers are imprecise, with 30-50% of patients recurring after image-guided radiotherapy or radical prostatectomy. We aimed to test combined genomic and microenvironmental indices in prostate cancer to improve risk stratification and complement clinical prognostic factors. METHODS: We used DNA-based indices alone or in combination with intra-prostatic hypoxia measurements to develop four prognostic indices in 126 low-risk to intermediate-risk patients (Toronto cohort) who will receive image-guided radiotherapy. We validated these indices in two independent cohorts of 154 (Memorial Sloan Kettering Cancer Center cohort [MSKCC] cohort) and 117 (Cambridge cohort) radical prostatectomy specimens from low-risk to high-risk patients. We applied unsupervised and supervised machine learning techniques to the copy-number profiles of 126 pre-image-guided radiotherapy diagnostic biopsies to develop prognostic signatures. Our primary endpoint was the development of a set of prognostic measures capable of stratifying patients for risk of biochemical relapse 5 years after primary treatment. FINDINGS: Biochemical relapse was associated with indices of tumour hypoxia, genomic instability, and genomic subtypes based on multivariate analyses. We identified four genomic subtypes for prostate cancer, which had different 5-year biochemical relapse-free survival. Genomic instability is prognostic for relapse in both image-guided radiotherapy (multivariate analysis hazard ratio [HR] 4.5 [95% CI 2.1-9.8]; p=0.00013; area under the receiver operator curve [AUC] 0.70 [95% CI 0.65-0.76]) and radical prostatectomy (4.0 [1.6-9.7]; p=0.0024; AUC 0.57 [0.52-0.61]) patients with prostate cancer, and its effect is magnified by intratumoral hypoxia (3.8 [1.2-12]; p=0.019; AUC 0.67 [0.61-0.73]). A novel 100-loci DNA signature accurately classified treatment outcome in the MSKCC low-risk to intermediate-risk cohort (multivariate analysis HR 6.1 [95% CI 2.0-19]; p=0.0015; AUC 0.74 [95% CI 0.65-0.83]). In the independent MSKCC and Cambridge cohorts, this signature identified low-risk to high-risk patients who were most likely to fail treatment within 18 months (combined cohorts multivariate analysis HR 2.9 [95% CI 1.4-6.0]; p=0.0039; AUC 0.68 [95% CI 0.63-0.73]), and was better at predicting biochemical relapse than 23 previously published RNA signatures. INTERPRETATION: This is the first study of cancer outcome to integrate DNA-based and microenvironment-based failure indices to predict patient outcome. Patients exhibiting these aggressive features after biopsy should be entered into treatment intensification trials. FUNDING: Movember Foundation, Prostate Cancer Canada, Ontario Institute for Cancer Research, Canadian Institute for Health Research, NIHR Cambridge Biomedical Research Centre, The University of Cambridge, Cancer Research UK, Cambridge Cancer Charity, Prostate Cancer UK, Hutchison Whampoa Limited, Terry Fox Research Institute, Princess Margaret Cancer Centre Foundation, PMH-Radiation Medicine Program Academic Enrichment Fund, Motorcycle Ride for Dad (Durham), Canadian Cancer Society. PMID- 25456373 TI - FOLFIRI with cetuximab or bevacizumab: FIRE-3. PMID- 25456374 TI - FOLFIRI with cetuximab or bevacizumab: FIRE-3. PMID- 25456375 TI - FOLFIRI with cetuximab or bevacizumab: FIRE-3-authors' reply. PMID- 25456376 TI - Does cilengitide deserve another chance? PMID- 25456377 TI - Does cilengitide deserve another chance?-Authors' reply. PMID- 25456379 TI - Infection control issues in patients with haematological malignancies in the era of multidrug-resistant bacteria. AB - Drug-resistant Gram-negative and Gram-positive bacteria are now increasingly identified as a cause of infections in immunocompromised hosts. Bacteria identified include the multidrug-resistant (MDR) and even pandrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, as well as carbapenem resistant Enterobacteriaceae spp. The threat from MDR pathogens has been well documented in the past decade with warnings about the consequences of inappropriate use of antimicrobial drugs. Resistant bacteria can substantially complicate the treatment of infections in critically ill patients and can have a substantial effect on mortality. Inappropriate antimicrobial treatment can affect morbidity, mortality, and overall health-care costs. Evidence-based data for prevention and control of MDR pathogen infections in haematology are scarce. Although not yet established a bundle of infection control and prevention measures with an anti-infective stewardship programme is an important strategy in infection control, diagnosis, and antibiotic selection with optimum regimens to ensure a successful outcome for patients. PMID- 25456378 TI - Regulatory and clinical considerations for biosimilar oncology drugs. AB - Biological oncology products are integral to cancer treatment, but their high costs pose challenges to patients, families, providers, and insurers. The introduction of biosimilar agents-molecules that are similar in structure, function, activity, immunogenicity, and safety to the original biological drugs provide opportunities both to improve health-care access and outcomes, and to reduce costs. Several international regulatory pathways have been developed to expedite entry of biosimilars into global marketplaces. The first wave of oncology biosimilar use was in Europe and India in 2007. Oncology biosimilars are now widely marketed in several countries in Europe, and in Australia, Japan, China, Russia, India, and South Korea. Their use is emerging worldwide, with the notable exception of the USA, where several regulatory and cost barriers to biosimilar approval exist. In this Review, we discuss oncology biosimilars and summarise their regulatory frameworks, clinical experiences, and safety concerns. PMID- 25456380 TI - High-dose re-irradiation following radical radiotherapy for non-small-cell lung cancer. AB - As the prognosis of lung cancer patients improves, more patients are at risk of developing local recurrence or a new primary tumour in previously irradiated areas. Technological advances in radiotherapy and imaging have made treatment of patients with high-dose re-irradiation possible, with the aim of long-term disease-free survival and even cure. However, high-dose re-irradiation with overlapping volumes of previously irradiated tissues is not without risks. Late, irreversible, and potentially serious normal tissue damage may occur because of injury to surrounding thoracic structures and organs at risk. In this Review, we aimed to report the efficacy and toxic effects of high-dose re-irradiation for locoregional recurrent non-small-cell lung cancer. Our findings indicate that high-dose re-irradiation might be beneficial in selected patients; however, patients and physicians should be aware of the scarcity of high-quality data when considering this treatment. PMID- 25456382 TI - Natural hydrazine-containing compounds: Biosynthesis, isolation, biological activities and synthesis. AB - Hydrazine, hydrazone and hydrazide derivatives are nitrogen-nitrogen bond containing compounds. Such molecules are relatively scarce in nature and have been isolated from plants, marine organisms and microorganisms. These compounds exhibit remarkable structural diversity and relevant biological activities. The enzymes involved in the formation of the N-N bond are still unknown, but many lines of evidence support the involvement of N-nitrosation and N-hydroxylation activating steps. Beside the challenging N-N bond, N-acylases catalyzing the C-N bond formation contribute to the chemical diversity of N-N-containing natural products (N2NP). This review examines the state of knowledge regarding the biosynthesis of N2NP, for which only two biosynthetic gene clusters have been investigated. Biological properties and chemical synthesis of hydrazines, hydrazones and hydrazides are also reported. PMID- 25456381 TI - Epidemiology, biology, and treatment of triple-negative breast cancer in women of African ancestry. AB - Breast cancer incidence is increasing worldwide, and breast cancer-related mortality is highest in women of African ancestry, who are more likely to have basal-like or triple-negative breast cancer (TNBC) than are women of European ancestry. Identification of cultural, epidemiological, and genetic risk factors that predispose women of African ancestry to TNBC is an active area of research. Despite the aggressive behaviour of TNBC, achievement of a pathological complete response with chemotherapy is associated with good long-term survival outcomes, and sensitivity to chemotherapy does not seem to differ according to ethnic origin. Discovery of the molecular signalling molecules that define TNBC heterogeneity has led to the development of targeted agents such as inhibitors of poly (ADP-ribose) polymerase-1 and mTOR and immunomodulatory drugs that are in the early stages of clinical testing. First, we summarise the existing published work on the differences reported on the epidemiology, biology, and response to systemic treatment of TNBC between women of African ancestry and white women, and identify some gaps in knowledge. Second, we review the opportunities for development of new therapeutic agents in view of the potential high clinical relevance for patients with TNBC irrespective of race or ethnic origin. PMID- 25456383 TI - Synthesis and preliminary biological evaluation of potent and selective 2-(3 alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility. AB - We report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl) quinolines as potent and selective PDE10A inhibitors. Structure-activity studies improved the solubility (pH 7.4) and maintained high PDE10A activity compared to initial lead compound 3, with select compounds demonstrating good oral bioavailability. X ray crystallographic studies revealed two distinct binding modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy assay in rats demonstrated that this series of compounds covered the target within the striatum. PMID- 25456384 TI - Structural modifications of coumarin derivatives: Determination of antioxidant and lipoxygenase (LOX) inhibitory activity. AB - In the present project, a series of coumarin analogues, were synthesised and evaluated for their antioxidant and soybean lipoxygenase inhibitory activity. A variety of structural modifications on the coumarin scaffold revealed interesting structure-activity relationships concerning the different biological assays. Prenyloxy-coumarins 9 and 10 displayed the best combined inhibition of lipid peroxidation and soybean lipoxygenase. Thiocoumarins 11 and 14 were identified as potent lipoxygenase inhibitors whereas hydrazone analogues 15 and 16 were efficient DPPH radical scavengers. PMID- 25456385 TI - Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles. AB - With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties. PMID- 25456386 TI - Synthesis of pyrazolo[4,3-e][1,2,4]triazine sulfonamides, novel Sildenafil analogs with tyrosinase inhibitory activity. AB - Tyrosinase is a multifunctional, glycosylated and copper-containing oxidase which catalyzes the first two steps in mammalian melanogenesis and is responsible for enzymatic browning reactions in damaged fruits during post-harvest handling and processing. Neither hyperpigmentation in human skin nor enzymatic browning in fruits are desirable. These phenomena have encouraged researchers to seek new potent tyrosinase inhibitors for use in foods and cosmetics. This article surveys tyrosinase inhibitors, newly discovered from natural and synthetic sources. The inhibitory strength is comparable to that of the standard inhibitor kojic acid. Also their inhibitory mechanisms are discussed. The new obtained compounds were also tested as PDE5 inhibitors and did not show significant inhibitory effect. PMID- 25456388 TI - Oseltamivir hydroxamate and acyl sulfonamide derivatives as influenza neuraminidase inhibitors. AB - Tamiflu, the ethyl ester form of oseltamivir carboxylic acid (OC), is the first orally available anti-influenza drug for the front-line therapeutic option. In this study, the OC-hydroxamates, OC-sulfonamides and their guanidino congeners (GOC) were synthesized. Among them, an OC-hydroxamate 7d bearing an O-(2 indolyl)propyl substituent showed potent NA inhibition (IC50 = 6.4 nM) and good anti-influenza activity (EC50 = 60.1 nM) against the wild-type H1N1 virus. Two GOC-hydroxamates (9b and 9d) and one GOC-sulfonamide (12a) were active to the tamiflu-resistant H275Y virus (EC50 = 2.3-6.9 MUM). PMID- 25456387 TI - Design, synthesis and biological evaluation of FLT3 covalent inhibitors with a resorcylic acid core. AB - A series of simplified ring-opened resorcylic acid lactone (RAL) derivatives were conveniently synthesized to target FLT3 and its mutants either irreversibly or reversibly. Our design of covalent FLT3 inhibitors is based on cis-enone RALs (e.g., L-783,277) that have a beta-resorcylic acid as the core structure. The designed compounds contain three types of Michael acceptors (acrylamide, vinylsulfonamide and maleimide) as potential covalent traps of a cysteine residue at the binding site of kinases. A variety of functional substitutions were also introduced to maximize the binding interactions. Biological evaluations revealed that compound 17, despite the presence of a highly reactive maleimide Michael acceptor, is a potent covalent FLT3 inhibitor which shows some specificity in cellular assays. On the other hand, compounds 2 and 6 containing acrylamide or vinylsulfonamide groups are reversible towards FLT3 binding, and are potent and selective inhibitors of mutant FLT3-ITD versus wt-FLT3. They also inhibit cell proliferation in FLT3-ITD expressing cell line MV-4-11 as compared to wt-FLT3 expressing cell line THP-1 and non-FLT3 cell lines (K562, HL60 and Hek-293T). PMID- 25456389 TI - Synthesis and antiviral activities of 3-deaza-3-fluoroaristeromycin and its 5' analogues. AB - The naturally occurring adenine based carbocyclic nucleosides aristeromycin and neplanocin A and their 3-deaza analogues have found a prominent place in the search for diverse antiviral activity agent scaffolds because of their ability to inhibit S-adenosylhomocysteine (AdoHcy) hydrolase. Following the lead of these compounds, their 3-deaza-3-fluoroaristeromycin analogues have been synthesized and their effect on S-adenosylhomocysteine hydrolase and RNA and DNA viruses determined. PMID- 25456390 TI - Synthesis and evaluation of the 2,4-diaminoquinazoline series as anti-tubercular agents. AB - The 2,4-diaminoquinazoline class of compounds has previously been identified as an effective inhibitor of Mycobacterium tuberculosis growth. We conducted an extensive evaluation of the series for its potential as a lead candidate for tuberculosis drug discovery. Three segments of the representative molecule N-(4 fluorobenzyl)-2-(piperidin-1-yl)quinazolin-4-amine were examined systematically to explore structure-activity relationships influencing potency. We determined that the benzylic amine at the 4-position, the piperidine at 2-position and the N 1 (but not N-3) are key activity determinants. The 3-deaza analog retained similar activity to the parent molecule. Biological activity was not dependent on iron or carbon source availability. We demonstrated through pharmacokinetic studies in rats that good in vivo compound exposure is achievable. A representative compound demonstrated bactericidal activity against both replicating and non-replicating M. tuberculosis. We isolated and sequenced M. tuberculosis mutants resistant to this compound and observed mutations in Rv3161c, a gene predicted to encode a dioxygenase, suggesting that the compound may act as a pro-drug. PMID- 25456391 TI - Design and synthesis of 21-alkynylaryl pregnenolone derivatives and evaluation of their anticancer activity. AB - A series of novel C21-alkynylaryl derivatives of pregnenolone were synthesized and screened for anticancer activity against a panel of seven human cancer cell lines (LNCaP, A549, MCF7, HeLa, A431, HepG2, HT29). The data revealed that these compounds can be potential antitumour agents against the specific cell models. Compound 6f bearing a 2-trifluoromethylphenyl group displayed improved cytotoxicity towards all cancer cell lines used. A431 cells were the most sensitive with derivatives 6e-6h bearing electron withdrawing substituents exhibiting high potency with IC50 values ranging between 2.18 and 0.54MUM and drastic inhibition of the prosurvival PI3K-Akt/PKB pathway. PMID- 25456392 TI - Large B-cell lymphoma with T-cell-rich background and nodules lacking follicular dendritic cell meshworks: description of an insufficiently recognized variant. AB - Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is characterized by nodular or nodular and diffuse growth of scattered large neoplastic B cells associated with follicular dendritic cell (FDC) meshworks. Variant patterns, which at least focally show a T-cell-rich background, and rare cases lacking FDC meshworks that overlap with T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) are also recognized. We reviewed 195 cases spanning the diagnostic spectrum of NLPHL and THRLBCL and identified 5 cases with distinctive features that were difficult to classify according to the World Health Organization criteria or previously described variants. Clinically, they involved peripheral and central lymph node sites or the mediastinum, and the majority also had recurrent disease. Four cases showed large T-cell-rich nodules with fibrosis, and 1 showed diffuse THRLBCL-like pattern with a minor component of nodularity. All cases completely lacked FDC meshworks despite a prominent nodular growth pattern. Large atypical cells in all cases were CD20+ CD30- CD15- B cells, although a small subset (<10%) of CD30+ and CD15+ large cells were seen in 1 case. In 4 cases, the background mainly contained CD4+ PD-1+ or CD57+ T cells that ringed large atypical B cells. In 1 case, B-cell predominance and a ringing pattern of CD57+ T cells were noted in nodules, whereas they were lacking in the diffuse areas. Recognition of these variant cases expands the spectrum between NLPHL and THRLBCL and points to the need for further refinement of diagnostic criteria for appropriate classification and clinical management. PMID- 25456393 TI - Lymph node metastases of melanoma: challenges for BRAF mutation detection. AB - Detection of B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations is required to predict response to BRAF or mitogen-activated protein kinase kinase 1 and 2 inhibitors in metastatic melanoma. Lymph node (LN) specimens carrying melanoma cells intermingled with abundant lymphocytes often contain low tumor cellularity. This study is aimed to examine challenges in the clinical detection of BRAF mutations in LN specimens with metastatic melanoma and to illustrate characteristic features of p.V600E and non-p.V600E mutations. In this retrospective study for quality assessment of the pyrosequencing assay, we compared characteristics of 53 LN and 135 non-LN formalin-fixed, paraffin embedded specimens with metastatic melanoma submitted for BRAF mutation detection over a 40-month period. LN specimens showed a significantly higher incidence of p.V600E mutations than non-LN specimens (49% versus 22%, P < .01) but a significantly lower tumor cellularity, particularly in the case of subcapsular or infiltrative metastases. Mutant allele-specific imbalance of the p.V600E mutation was predominantly present in specimens with distant organ metastases (79% versus 27% in LN metastases versus 13% in primary cutaneous tumors or adjacent soft tissue, P < .001). p.V600K was detected in 23% of men older than 60 years old, compared with 6% in women older than 60 years old and 2% in both men and women younger than 60 years old (P < .001). LN specimens with low tumor cellularity due to numerous adjacent lymphocytes may pose a challenge to clinical detection of BRAF mutations of melanoma. The higher incidence of p.V600E mutations in LNs may prompt further studies to elucidate if the p.V600E mutation in primary tumors is associated with a higher risk of LN metastasis. PMID- 25456394 TI - Characterization of mammary analogue secretory carcinoma of the salivary gland: discrimination from its mimics by the presence of the ETV6-NTRK3 translocation and novel surrogate markers. AB - Mammary analogue secretory carcinoma (MASC) is a recently recognized salivary gland tumor harboring an ETV6-NTRK3 translocation similar to secretory carcinoma of the breast. Histologically, MASC mimics papillary-cystic, microcystic, and follicular-type acinic cell carcinoma (AciCC) and low-grade cribriform cystadenocarcinoma (LGCCC) of the salivary gland. Using histology, immunohistochemistry (IHC), and molecular genetic techniques, we reevaluated 18 cases originally diagnosed as AciCC between 1993 and 2012. The last of these methods was used to detect the ETV6-NTRK3 translocation. The results reconfirmed 6 cases as AciCC (3 men; average age, 63 years) and helped us reclassify 10 cases as MASC (6 men; mean age, 46 years) and 2 as LGCCC (2 women; mean age, 48 years). Using IHC, we identified the 3 histologic types according to the expression patterns of vimentin, high-molecular-weight cytokeratin, cytokeratin 19, S-100, mammaglobin, MUC1, GATA-binding protein 3, adipophilin, alpha-amylase, DOG-1, SOX 10, and p63. The number of tumors diagnosed as MASC indicates that AciCC includes bona fide MASC cases. Because differential diagnosis among zymogen granule-poor AciCC, MASC, and LGCCC tumors is challenging, we recommend using molecular genetic tests for ETV6-NTRK3 for accurate diagnosis. Furthermore, detailed analyses of hematoxylin and eosin-stained tissues and IHC studies using the markers described here should be incorporated into routine practices. PMID- 25456396 TI - Morphological and stent design risk factors to prevent migration phenomena for a thoracic aneurysm: a numerical analysis. AB - The primary mechanically related problems of endovascular aneurysm repair are migration and type Ia endoleaks. They occur when there is no effective seal between the proximal end of the stent-graft and the vessel. In this work, we have developed several deployment simulations of parameterized stents using the finite element method (FEM) to investigate the contact stiffness of a nitinol stent in a realistic Thoracic Aortic Aneurysm (TAA). Therefore, we evaluated the following factors associated with these complications: (1) Proximal Attachment Site Length (PASL), (2) stent oversizing value (O%), (3) different friction conditions of the stent/aorta contact, and (4) proximal neck angulation alpha. The simulation results show that PASL>18 mm is a crucial factor to prevent migration at a neck angle of 60 degrees , and the smoothest contact condition with low friction coefficient (MU=0.05). The increase in O% ranging from 10% to 20% improved the fixation strength. However, O%>=25% at 60 degrees caused eccentric deformation and stent collapse. Higher coefficient of friction MU>0.01 considerably increased the migration risk when PASL=18 mm. No migration was found in an idealized aorta model with a neck angle of 0 degrees , PASL=18 mm and MU=0.05. Our results suggest carefully considering the stent length and oversizing value in this neck morphology to strengthen the contact and prevent migration. PMID- 25456397 TI - Computational analysis of the radial mechanical performance of PLLA coronary artery stents. AB - Stents have been an effective tool to restore and maintain the patency of narrowed blood vessels, but they must have sufficient radial strength. Biodegradable stent materials have substantially lower mechanical properties than permanent stents. The stent geometry and material properties must be considered simultaneously when assessing stent performance. Material tests were performed to determine the mechanical characteristics of high-molecular-weight poly-l-lactic acid (PLLA). The results were used to calibrate an anisotropic elastic-plastic material model. Three distinct geometries were analysed with a range of material stiffness values in a finite element analysis to investigate their comparative effect on the radial strength, recoil, and radial stiffness. The performance of the different geometries varies substantially, with one particular geometry, with the highest material stiffness of 9 GPa, exceeding the desired radial strength of 300 mmHg. PMID- 25456395 TI - Expression of lactate/H+ symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: immunohistochemical and The Cancer Genome Atlas data analyses. AB - Clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel Lindau protein, leading to the accumulation of hypoxia-inducible factor-alpha (HIF-alpha). HIF-1alpha induces aerobic glycolysis, the Warburg effect, whereas HIF-2alpha functions as an oncoprotein. Lactate transport through monocarboxylate transporters (MCTs) and the chaperone CD147 is essential for high glycolytic cancer cell survival. To elucidate the clinical significance of MCT1, MCT4, and CD147 expression, we investigated their expressions by immunohistochemistry in ccRCC specimens and validated the results by an open-access The Cancer Genome Atlas data analysis. Overexpression of MCT1, MCT4, and CD147 was observed in 49.4% (89/180), 39.4% (71/180), and 79.4% (143/180) of ccRCC patients, respectively. High MCT1 expression was associated with older age (P = .017), larger tumor size (P = .015), and advanced TNM stage (P = .012). However, MCT4 overexpression was not related to any variables. CD147 overexpression correlated with high grade (P = .005), tumor necrosis (P = .016), and larger tumor size (P = .038). In univariate analysis, high expression of MCT1 (P < .001), MCT4 (P = .016), and CD147 (P = .02) was linked to short progression-free survival. In multivariate analysis, high MCT1 expression was associated with worse progression free survival (P = .001). In conclusion, high expression of MCT1 and CD147 is associated with poor prognostic factors. Overexpression of MCT1, MCT4, and CD147 predicts tumor progression. Reversing the Warburg effect by targeting the lactate transporters may be a useful strategy to prevent ccRCC progression. PMID- 25456398 TI - In-vivo quantification of human breast deformation associated with the position change from supine to upright. AB - Stereophotographic imaging and digital image correlation are used to determine the variation of breast skin deformation as the subject orientation is altered from supine to upright. A change in subject's position from supine to upright can result in significant stretches in some parts of the breast skin. The maximum of the major principal stretch ratio of the skin is different in different subjects and varies in the range of 1.25-1.60. It is also found that the boundaries of the breast move significantly relative to the skeletal structure and other fixed points such as the sternal notch. Such measurements are crucial since they provide basic data for validation of biomechanical breast models based on finite element formulations. PMID- 25456399 TI - Modified bone density-dependent orthotropic material model of human mandibular bone. AB - The prediction accuracy of computational simulations of various biomechanical problems of human bones depends on proper modelling of the problem geometry and boundary conditions but it is also essentially dependent on proper description of the mechanical properties of the all constitutive elements. As the human mandibular bone is a very important load-carrying element in biomechanics, the main aim of this research was to develop an innovative, not yet described in literature, spatial and bone density-dependent orthotropic material model of the human mandibular bone for use in the computational simulations. We compared it with the most used constitutive material models in the computational simulations of the human mandibular bone behaviour with inserted dental implant. The results show that the von Mises equivalent stress distribution values in the bone density dependent orthotropic model are higher in comparison with other models but the highest are on the top of the alveolar ridge and higher in the lingual than in the buccal part of the lower jaw. PMID- 25456400 TI - A multi-scale feedback ratio analysis of heartbeat interval series in healthy vs. cardiac patients. AB - The second-order difference plot, as a modified Poincare plot, is one of the important approaches for assessing the dynamics of heart rate variability. However, corresponding quantitative analysis methods are relatively limited. Based on the second-order difference plot, we propose a novel method, called the multi-scale feedback ratio analysis, which can measure the feedback properties of heart rate fluctuations on different temporal scales. The index [R(TF([tau(1), tau(2)]) is then defined to quantify the average feedback ratio through a definite scale range. Analysis of Gaussian white, 1/f and Brownian noises show that the feedback ratios are indeed on different levels. The method is then applied to heartbeat interval series derived from healthy subjects, subjects with congestive heart failure and subjects with atrial fibrillation. Results show that, for all groups, the feedback ratios vary with increasing time scales, and gradually reach relatively stable states. The R(TF)([10,20]) values of the three groups are significantly different. Thus, R(TF)([10,20]) becomes an effective parameter for distinguishing healthy and pathologic states. In addition, RTF([10,20]) for healthy, congestive failure and atrial fibrillation subjects are close to those of the 1/f, Brownian and white noises respectively, indicating different intrinsic dynamics. PMID- 25456401 TI - Parkinson's disease as a member of Prion-like disorders. AB - Parkinson's disease is one of several neurodegenerative diseases associated with a misfolded, aggregated and pathological protein. In Parkinson's disease this protein is alpha-synuclein and its neuronal deposits in the form of Lewy bodies are considered a hallmark of the disease. In this review we describe the clinical and experimental data that have led to think of alpha-synuclein as a prion-like protein and we summarize data from in vitro, cellular and animal models supporting this view. PMID- 25456402 TI - Decoding the function of the N-terminal tail of the cellular prion protein to inspire novel therapeutic avenues for neurodegenerative diseases. AB - The cellular prion protein (PrP(C)), a cell surface glycoprotein involved in prion disorders, has been shown to mediate the toxicity of several pathological aggregates, including its own misfolded state and some oligomeric assemblies of the amyloid beta peptide, which are thought to be primarily responsible for the synaptic dysfunction characterizing Alzheimer's disease. Thus, elucidating the physiological function of PrP(C), and how it could be corrupted by the interaction with misfolded proteins, may provide important insights to understand the pathological processes of prion and Alzheimer's diseases, and possibly other neurodegenerative disorders. In this manuscript, we review the data supporting a role for PrP(C) at the intersection of different neurodegenerative diseases, discuss potential mechanisms by which this protein could mediate neurotoxic signals, and examine therapeutic approaches that may arise from the identification of PrP(C)-directed compounds. PMID- 25456403 TI - The haemagglutination activity of equine herpesvirus type 1 glycoprotein C. AB - Equine herpesvirus type 1 (EHV-1) has haemagglutination (HA) activity toward equine red blood cells (RBCs), but the identity of its haemagglutinin is unknown. To identify the haemagglutinin of EHV-1, the major glycoproteins of EHV-1 were expressed in 293T cells, and the cells or cell lysates were mixed with equine RBCs. The results showed that only EHV-1 glycoprotein C (gC)-producing cells adsorbed equine RBCs, and that the lysate of EHV-1 gC-expressing cells agglutinated equine RBCs. EHV-1 lacking gC did not show HA activity. HA activity was inhibited by monoclonal antibodies (MAbs) specific for gC, but not by antibodies directed against other glycoproteins. In addition, HA activity was not inhibited by the addition of heparin. These results indicate that EHV-1 gC can bind equine RBCs irrespective of heparin, in contrast to other herpesvirus gC proteins. PMID- 25456404 TI - Interchange of L polymerase protein between two strains of viral hemorrhagic septicemia virus (VHSV) genotype IV alters temperature sensitivities in vitro. AB - Viral hemorrhagic septicemia virus (VHSV) has four genotypes (I-IV) and sub lineages within genotype I and IV. Using a reverse genetics approach, we explored the importance of the L gene for growth characteristics at different temperatures following interchange of the L gene within genotype IV (IVa and IVb) strains. VHSV strains harboring heterologous L gene were recovered and we show that the L gene determines growth characteristics at different temperatures in permissive cell lines. PMID- 25456406 TI - The operative dictation: a review of how this skill is taught and assessed in surgical residency programs. AB - BACKGROUND: The operative dictation (OD) is the cornerstone of surgical communication, yet there appears to be a lack of formal education of this skill by training programs. We conducted a review of the literature to assess the teaching and quality of OD in surgical residency programs. STUDY DESIGN: Multiple databases were searched for studies pertaining to "OD," "surgical education," and "formal teaching." Of 50 the studies, 13 were retained and assigned to one or more of the following categories: (1) surveys of the surgical community evaluating current perceptions of formal OD education (n = 5), (2) studies assessing the quality of OD performed by residents (n = 5), and (3) educational interventions for improving OD skills (n = 4). RESULTS: (1) Between 12% and 25% of survey respondents reported formal teaching of OD skills in their surgical programs. Surveyed residents and program directors were in favor of the implementation of structured teaching 60% to 91% of the time. (2) Multiple studies demonstrated significant deficiencies in residents' ODs, with key information missing in up to 76% of cases. The completeness of OD did not consistently correlate with level of training. (3) In one of the studies, a formal educational session was found to improve OD quality scores (p < 0.001). In 2 studies, the use of synoptic report maximized the completion rate of OD up to 92% from less than 70%. Synoptic reports were significantly more complete than conventional ODs with regard to general information (p < 0.001) and procedural aspects (p < 0.001). A single randomized trial demonstrated an improvement in junior residents' ODs after the implementation of a template (p = 0.02). CONCLUSION: Current evidence suggests that only a small proportion of residency programs offer formal OD instruction, despite a demonstrable need for improvement in residents' OD skills. Educational interventions and synoptic reporting present possible solutions, although this continues to be an area of evolving interest. PMID- 25456405 TI - Pyrrolidine dithiocarbamate inhibits enterovirus 71 replication by down regulating ubiquitin-proteasome system. AB - Enterovirus 71 (EV71) is the main causative pathogen of hand, foot, and mouth disease (HFMD). The severe neurological complications caused by EV71 infection and the lack of effective therapeutic medicine underline the importance of searching for antiviral substances. Pyrrolidine dithiocarbamate (PDTC), an antioxidant, has been reported to inhibit the replication of coxsackievirus B (CVB) through dysregulating ubiquitin-proteasome system (UPS). In this study, we demonstrated that PDTC exerted potent antiviral effect on EV71. Viral RNA synthesis, viral protein expression, and the production of viral progeny were significantly reduced by the treatment of PDTC in Vero cells infected with EV71. Similar to the previous report about the inhibitory effect of PDTC on UPS, we found that PDTC treatment led to decreased levels of polyubiquitinated proteins in EV71-infected cells. The inhibitory effect of PDTC on UPS was further confirmed by the increased accumulation of cell cycle regulatory proteins p21 and p53, which are normally degraded through UPS, while the expression levels of both proteins remained unchanged. We also showed that PDTC had no impact on the activity of proteasome. Thus, we demonstrated that the down-regulation of PDTC on UPS was the result of its inhibition on ubiquitination. More importantly, this study provides evidence that the inhibition on UPS was required for the antiviral activity of PDTC, since MG132, a potent proteasome inhibitor, significantly inhibited the cytopathic effect and viral protein synthesis in EV71-infected cells. We also found that the antioxidant property of PDTC did not contribute to its antiviral effect, since N-acetyl-l-cysteine, a potent antioxidant, could not inhibit viral replication. In addition, CPE and viral protein synthesis were not inhibited in the cells pretreated with PDTC 2h before viral infection and then cultured in the media with no PDTC supplement, while the antioxidant effect of PDTC was retained. PDTC also showed significant inhibition on apoptosis induced by EV71 infection when it was applied at the early stage of viral infection. Our results collectively suggest that PDTC could be a potential anti-EV71 compound which possesses both antiviral and anti-apoptotic capacity. PMID- 25456407 TI - Planning to avoid trouble in the operating room: experts' formulation of the preoperative plan. AB - OBJECTIVE: The purpose of this study was to capture the preoperative plans of expert hepato-pancreato-biliary (HPB) surgeons with the goal of finding consistent aspects of the preoperative planning process. DESIGN: HPB surgeons were asked to think aloud when reviewing 4 preoperative computed tomography scans of patients with distal pancreatic tumors. The imaging features they identified and the planned actions they proposed were tabulated. Surgeons viewed the tabulated list of imaging features for each case and rated the relevance of each feature for their subsequent preoperative plan. Average rater intraclass correlation coefficients were calculated for each type of data collected (imaging features detected, planned actions reported, and relevance of each feature) to establish whether the surgeons were consistent with one another in their responses. Average rater intraclass correlation coefficient values greater than 0.7 were considered indicative of consistency. SETTING: Division of General Surgery, University of Toronto. PARTICIPANTS: HPB surgeons affiliated with the University of Toronto. RESULTS: A total of 11 HPB surgeons thought aloud when reviewing 4 computed tomography scans. Surgeons were consistent in the imaging features they detected but inconsistent in the planned actions they reported. Of the HPB surgeons, 8 completed the assessment of feature relevance. For 3 of the 4 cases, the surgeons were consistent in rating the relevance of specific imaging features on their preoperative plans. CONCLUSION: These results suggest that HPB surgeons are consistent in some aspects of the preoperative planning process but not others. The findings further our understanding of the preoperative planning process and will guide future research on the best ways to incorporate the teaching and evaluation of preoperative planning into surgical training. PMID- 25456408 TI - The effect of a simulation training package on skill acquisition for duplex arterial stenosis detection. AB - OBJECTIVES: In vascular surgery, duplex ultrasonography is a valuable diagnostic tool in patients with peripheral vascular disease, and there is increasing demand for vascular surgeons to be able to perform duplex scanning. This study evaluates the role of a novel simulation training package on vascular ultrasound (US) skill acquisition. MATERIALS AND METHODS: A total of 19 novices measured predefined stenosis in a simulated pulsatile vessel using both peak systolic velocity ratio (PSVR) and diameter reduction (DR) methods before and after a short period of training using a simulated training package. The training package consisted of a simulated pulsatile vessel phantom, a set of instructional videos, duplex ultrasound objective structured assessment of technical skills (DUOSATS) tool, and a portable US scanner. Quantitative metrics (procedure time, percentage error using PSVR and DR methods, DUOSAT scores, and global rating scores) before and after training were compared. RESULTS: Subjects spent a median time of 144 mins (IQR: 60-195) training using the simulation package. Subjects exhibited statistically significant improvements when comparing pretraining and posttraining DUOSAT scores (pretraining = 17 [16-19.3] vs posttraining = 30 [27.8 31.8]; p < 0.01), global rating score (pretraining = 1 [1-2] vs posttraining = 4 [3.8-4]; p < 0.01), percentage error using both the DR (pretraining = 12.6% [9 29.6] vs posttraining = 10.3% [8.9-11.1]; p = 0.03) and PSVR (pretraining = 60% [40-60] vs posttraining = 20% [6.7-20]; p < 0.01) methods. CONCLUSION: In this study, subjects with no previous practical US experience developed the ability to both acquire and interpret arterial duplex images in a pulsatile simulated phantom following a short period of goal direct training using a simulation training package. A simulation training package may be a valuable tool for integration into a vascular training program. However, further work is needed to explore whether these newly attained skills are translated into clinical assessment. PMID- 25456409 TI - Interventions that affect resident performance on the American Board of Surgery In-Training Examination: a systematic review. AB - OBJECTIVE: To systematically review the published literature on the effectiveness of interventions intended to improve residents' American Board of Surgery In Training Examination (ABSITE) performances. DESIGN: A systematic review was conducted by 2 independent investigators to identify all publications that examined the effect of specific interventions on residents' ABSITE performances from 1975 to 2013. RESULTS: Overall, 26 published articles met study criteria. Structured reading programs and setting clear expectations with mandatory remedial programs were consistently effective in improving ABSITE performance, whereas the effect of didactic teaching conferences and problem-based learning groups was mixed. There was marked heterogeneity in the usage of study designs and reporting of results. CONCLUSIONS: Structured reading programs and mandatory remedial programs appear to be consistently effective measures that can improve residents' ABSITE performances. There is a need for improved study design and reporting in future research conducted in this field. PMID- 25456410 TI - The effect of a new surgery residency program on case volume and case complexity in a sub-Saharan African hospital. AB - BACKGROUND: Improved access to surgical care could prevent a significant burden of disease and disability-adjusted life years, and workforce shortages are the biggest obstacle to surgical care. To address this shortage, a 5-year surgical residency program was established at Kamuzu Central Hospital (KCH) in July 2009. As the residency enters its fourth year, we hypothesized that the initiation of a general surgical residency program would result in an increase in the overall case volume and complexity at KCH. METHODS: We conducted a retrospective analysis of operated cases at KCH during the 3 years before and the third year after the implementation of the KCH surgical residency program, from July 2006 to July 2009 and the calendar year 2012, respectively. RESULTS: During the 3 years before the initiation of the surgical residency, an average of 2317 operations were performed per year, whereas in 2012, 2773 operations were performed, representing a 20% increase. Before residency, an average of 1191 major operations per year were performed, and in 2012, 1501 major operations were performed, representing a 26% increase. CONCLUSION: Our study demonstrates that operative case volume and complexity increase following the initiation of a surgical residency program in a sub-Saharan tertiary hospital. We believe that by building on established partnerships and emphasizing education, research, and clinical care, we can start to tackle the issues of surgical access and care. PMID- 25456411 TI - The TLQP-21 peptide activates the G-protein-coupled receptor C3aR1 via a folding upon-binding mechanism. AB - TLQP-21, a VGF-encoded peptide is emerging as a novel target for obesity associated disorders. TLQP-21 is found in the sympathetic nerve terminals in the adipose tissue and targets the G-protein-coupled receptor complement-3a receptor1 (C3aR1). The mechanisms of TLQP-21-induced receptor activation remain unexplored. Here, we report that TLQP-21 is intrinsically disordered and undergoes a disorder to-order transition, adopting an alpha-helical conformation upon targeting cells expressing the C3aR1. We determined that the hot spots for TLQP-21 are located at the C terminus, with mutations in the last four amino acids progressively reducing the bioactivity and, a single site mutation (R21A) or C-terminal amidation abolishing its function completely. Additionally, the human TLQP-21 sequence carrying a S20A substitution activates the human C3aR1 receptor with lower potency compared to the rodent sequence. These studies reveal the mechanism of action of TLQP-21 and provide molecular templates for designing agonists and antagonists to modulate C3aR1 functions. PMID- 25456412 TI - Molecular basis for DPY-30 association to COMPASS-like and NURF complexes. AB - DPY-30 is a subunit of mammalian COMPASS-like complexes (complex of proteins associated with Set1) and regulates global histone H3 Lys-4 trimethylation. Here we report structural evidence showing that the incorporation of DPY-30 into COMPASS-like complexes is mediated by several hydrophobic interactions between an amphipathic alpha helix located on the C terminus of COMPASS subunit ASH2L and the inner surface of the DPY-30 dimerization/docking (D/D) module. Mutations impairing the interaction between ASH2L and DPY-30 result in a loss of histone H3K4me3 at the beta locus control region and cause a delay in erythroid cell terminal differentiation. Using overlay assays, we defined a consensus sequence for DPY-30 binding proteins and found that DPY-30 interacts with BAP18, a subunit of the nucleosome remodeling factor complex. Overall, our results indicate that the ASH2L/DPY-30 complex is important for cell differentiation and provide insights into the ability of DPY-30 to associate with functionally divergent multisubunit complexes. PMID- 25456414 TI - Prospective, multi-center evaluation of a silicon carbide coated cobalt chromium bare metal stent for percutaneous coronary interventions: two-year results of the ENERGY Registry. AB - BACKGROUND: Novel bare metal stents with improved stent design may become a viable alternative to drug-eluting stents in certain patient groups, particularly, when long-term dual antiplatelet therapy should be avoided. PURPOSE: The ENERGY registry aimed to assess the safety and benefits of a cobalt chromium thin strut bare metal stent with a passive coating in a large series of patients under real-world conditions. METHODS AND MATERIALS: This prospective registry recruited 1016 patients with 1074 lesions in 48 centers from April to November 2010. The primary endpoint was the rate of major adverse cardiac events (MACEs), a composite of cardiac death, myocardial infarction and clinically driven target lesion revascularization. RESULTS: More than half of the lesions (61.0%) were type A/B1 lesions, mean lesion length was 14.5+/-6.5mm and mean reference vessel diameter 3.2+/-0.5mm. MACE rates at 6, 12 and 24months were 4.9%, 8.1% and 9.4%, target lesion revascularization rates 2.8%, 4.9% and 5.4% and definite stent thrombosis rates 0.5%, 0.6% and 0.6%. Subgroups showed significant differences in baseline and procedural characteristics which did not translate into significantly different clinical outcomes. Specifically, MACE rates at 24months were 13.5% in diabetics, 8.6% in small stents and 9.6% in acute coronary syndrome patients. CONCLUSION: The population of ENERGY reflects real world conditions with bare metal stents being mainly used in simple lesions. In this setting, percutaneous coronary intervention using a cobalt-chromium thin strut bare metal stent with a passive coating showed very good results up to 24months. (ClinicalTrials.gov:NCT01056120) SUMMARY FOR ANNOTATED TABLE OF CONTENTS: The ENERGY international registry evaluated the safety and benefits of a cobalt-chromium thin strut bare metal stent with passive coating in 1016 patients under real-world conditions until 2years. Results were encouraging with a low composite rate of cardiac death, myocardial infarction and clinically driven target lesion revascularization, even in the pre-defined high risk groups of diabetes, stents <=2.75mm and acute coronary syndrome. PMID- 25456415 TI - Clinical validation of a novel software for quantitative analysis of coronary intravascular ultrasound. AB - PURPOSE: CAAS IntraVascular (CAAS-IV) is a recently released software that provides options for sophisticated quantitative coronary ultrasound (QCU) analysis. The aim of this study was to validate CAAS-IV for QCU in diseased human coronaries. METHODS: Ten preprocedural and 5 postprocedural IVUS studies were derived from daily practice. Intraobserver, interobserver, intersoftware (CAAS-IV vs. Curad) and interplatform (CAAS-IV vs. Volcano console) variability were assessed for cross-sectional area (CSA) measurements. Interobserver and intersoftware comparisons were made for volume measurements. RESULTS: Measurements of lumen, EEM, plaque and stent CSA demonstrated small differences in the intraobserver (0.0+/-3.7%, -0.7+/-2.8%, -0.5+/-7.0% and -0.9+/-3.4%), interobserver (0.1+/-4.4%, 0.1+/-3.4%, -0.5+/-8.2% and -0.8+/-4.3%), intersoftware (-0.3+/-4.5%, 0.2+/-2.4%, 0.4+/-6.8% and -0.5+/-3.2%) and interplatform (0.7+/-7.9%, 0.9+/-4.0%, -1.1+/-12%, -1.8+/-3.6%) comparisons. For lumen, EEM, plaque and stent volume, the interobserver (-2.1+/-9.3%, 0.9+/-5.6%, 3.4+/-7.2% and -0.2+/-3.6%) and intersoftware (-2.2+/-6.2%, -2.6+/-6.1%, -2.7+/ 12% and -4.1+/-3.2%) differences were substantially larger. Excluding large side branches and calcifications, post-hoc measurements of lumen, EEM, plaque and stent volume showed small differences in the interobserver (-0.3+/-3.2%, 0.9+/ 2.4%, 2.9+/-4.4% and -1.3+/-1.8%) and intersoftware (0.5+/-2.5%, -1.2+/-1.7%, 3.4+/-5.1% and -1.5+/-2.2%) comparisons. Analysis time for entire pullbacks was reduced by 19.2 [14.9-30.0]% using CAAS-IV (p<0.01). CONCLUSIONS: CAAS-IV demonstrated reliable QCU with excellent agreement with previously validated software and the IVUS imaging console. Precision and reproducibility of measurements were high, proving CAAS-IV to be a valid option for QCU analysis in clinical practice and research. Interactive contour editing reduced analysis time by 20%. PMID- 25456413 TI - Controlled bacterial lysis for electron tomography of native cell membranes. AB - Cryo-electron tomography (cryoET) has become a powerful tool for direct visualization of 3D structures of native biological specimens at molecular resolution, but its application is limited to thin specimens (<300 nm). Recently, vitreous sectioning and cryoFIB milling technologies were developed to physically reduce the specimen thickness; however, cryoET analysis of membrane protein complexes within native cell membranes remains a great challenge. Here, we use phage PhiX174 lysis gene E to rapidly produce native, intact, bacterial cell membranes for high resolution cryoET. We characterized E gene-induced cell lysis using FIB/SEM and cryoEM and showed that the bacteria cytoplasm was largely depleted through spot lesion, producing ghosts with the cell membranes intact. We further demonstrated the utility of E-gene-induced lysis for cryoET using the bacterial chemotaxis receptor signaling complex array. The described method should have a broad application for structural and functional studies of native, intact cell membranes and membrane protein complexes. PMID- 25456416 TI - Transcatheter valve-in-valve replacement of degenerated bioprosthetic aortic valves: a single Australian Centre experience. AB - BACKGROUND: Patients with degenerated surgical bioprosthetic valves may be at high risk for further surgery because of age, comorbidities and the difficulties of repeat procedures. Percutaneous valve-in-valve implantation offers what may be a simpler and safer procedure. METHODS: From May 2009 to March 2014 at the Prince Charles Hospital 1625 patients underwent surgical aortic valve replacement while 262 underwent transcatheter aortic valve implantation. Twelve patients had valve in-valve implants for degenerated bioprosthetic aortic valves. RESULTS: These implants were deployed successfully without major valvular or paravalvular regurgitation. There were no periprocedural deaths, myocardial infarcts, neurological events or major vascular complications. Two patients died after 1624 and 1319days. Median survival for the remainder is 581days; they are stable with New York Heart Association class I/II functional status although 4 have a degree of patient-prosthesis mismatch, one has moderate aortic regurgitation and one required surgery for a late aortic dissection. CONCLUSION: Transcatheter valve-in valve implantation is safe and effective treatment for patients with failed bioprosthetic aortic valves for whom reoperation is considered to be hazardous. PMID- 25456417 TI - Coronary artery bypass surgery or coronary stenting in diabetic patients: too soon to make a statement? AB - Diabetic patients have been associated with poor procedural and long term outcome if they were treated either with percutaneous coronary interventions or coronary artery bypass surgery. Recently several randomized clinical trials (RCT) in this subset of patients have been published showing a greater incidence of major adverse cardiovascular events, death/myocardial infarction/stroke, if they were treated with first generation drug eluting stents (DES) which was not observed previously in the bare metal stent era. However, almost simultaneously with this data, several RCT demonstrated better safety profile with new generation DES including biocompatible polymers, biodegradable polymers and lately complete absorbable DES, all of them showed reduction in adverse cardiac events compared to 1st generation DES in patients with diabetes. In this editorial we review the old and new randomized data in diabetic patients and conclude that there are many unresolved issues to make a definitive statement regarding which is the best revascularization preference in diabetic patients and the measured final efficacy of PCI and CABG will not be reached until the arrival of RCT using next generation DES, including complete absorbable scaffolds. PMID- 25456418 TI - Lipopeptide biosurfactant from Bacillus thuringiensis pak2310: A potential antagonist against Fusarium oxysporum. AB - OBJECTIVES: The aims of the study were to evaluate the effects of a biosurfactant obtained from a novel Bacillus thuringiensis on Fusarium oxysporum to determine the morphological changes in the structure of the fungi and its biofilm in the presence of the biosurfactant and to evaluate the toxicity of the biosurfactant on HEp-2 human epithelial cell lines. MATERIALS AND METHODS: The strain was screened and isolated from petroleum contaminated soil based on the E24 emulsification index. The biosurfactant was produced on glycerol, extracted using chloroform:methanol system and purified using HPLC. The purified fraction showing both surface activity (emulsification and oil-spread activity) and anti-fusarial activity (agar well diffusion method) was studied using FT-IR and MALDI-TOF MS, respectively. The minimum inhibitory concentration (MIC) and the biofilm inhibitory concentration (BIC) were determined using dilution method. The effect of biosurfactant on the morphology of Fusarium oxysporum was monitored using light microscopy and confocal laser scanning microscopy (for biofilm). RESULTS: The purified surfactant showed the presence of functional groups like that of surfactin in the FT-IR spectra and MALDI-TOF MS estimated the molecular weight as 700Da. The MIC and BIC were estimated to be 0.05 and 0.5mg/mL, respectively. The molecule was also non-toxic to HEp-2 cell lines at 10* MIC. CONCLUSION: A non toxic and effective anti-Fusarium biosurfactant, that is both safe for human use and to the environment, has been characterized. The growth and metabolite production using glycerol (major byproduct of biodiesel and soap industries) also adds up to the efficiency and ecofriendly nature of this biosurfactant. PMID- 25456419 TI - The anti-dermatophyte activity of Allium hirtifolium Boiss aqueous extract. AB - In an attempt at demonstrating the efficacy of Allium hirtifolium aqueous extract in control of skin fungal infections as traditional use, we evaluated the anti dermatophyte activities of A. hirtifolium aqueous extract from bulbs and of ketoconazole against Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis, M. gypseum, Trichophyton schoenleinii and Trichophyton verrucosum var. album by food poisoning technique, disc diffusion and micro broth dilution assays. The anti-fungal activity of A. hirtifolium was excellent when it was compared with ketoconazole. The anti-fungal evaluation by food poisoning method showed that A. hirtifolium extract inhibited the growth of dermatophytes dose-dependently. The inhibition zone diameter (IZ) of A. hirtifolium extract (15 MUg/disc) was in the range of 28.8 +/- 0.31 to 67.7 +/- 1.5mm, while ketoconazole (15 MUg/disc) had the IZ lower than 13mm. The MIC and MFC values of A. hirtifolium extract were in the range of 0.2-1.7 and 0.4-0.7 MUg/mL; respectively. Therefore, A. hirtifolium extract showed a strong anti-fungal activity against human and animal dermatophytes. PMID- 25456421 TI - The enriched fraction of Vernonia cinerea L. induces apoptosis and inhibits multi drug resistance transporters in human epithelial cancer cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Vernonia cinerea Less. (VC) of the family Asteraceaes is considered as the sacred plant; 'Dasapushpam' which is ethnopharmacologically significant to the people of Kerala in India. In fact, VC has been used in the traditional system of medicine (Ayurveda) for the treatment of various ailments including cancer. MATERIALS AND METHODS: Cytotoxicity of the ethanolic extract of VC (VC-ET), petroleum ether fraction (VC-PET), dichloromethane fraction (VC-DCM), n-butyl alcohol fraction (VC-BT), and rest fraction (VC-R) was evaluated in cervical carcinoma (HeLa), lung adenocarcinoma (A549), breast cancer (MCF-7), and colon carcinoma (Caco-2) cells using Sulforhodamine B (SRB) assay. The apoptotic effects of VC-DCM were assessed in cancer cells using Annexin V assay. The effects of VC-DCM on multi-drug resistance (MDR) transporters in HeLa, A549, MCF-7, and Caco-2 cells were evaluated using flow cytometry based functional assays. Similarly, drug uptake in cancer cells and sensitization of cancer cells towards chemotherapeutic drugs in the presence of VC-DCM were studied using Daunorubicin (DNR) accumulation assay and SRB assay, respectively. RESULTS: Cytotoxicity assay revealed that the enriched fraction of VC (VC-DCM) possessed dose-dependent cytotoxic effects in human epithelial cancer cells (HeLa, A549, MCF-7, and Caco-2). Further, treatment of cancer cells (HeLa, A549, MCF-7, and Caco-2) with VC-DCM led to a significant increase in both early and late apoptosis, indicating the induction of apoptosis. Interestingly, VC-DCM significantly inhibited functional activity of MDR transporters (ABC-B1 and ABC-G2), enhanced DNR-uptake in cancer cells, and sensitized cancer cells towards chemotherapeutic drug-mediated cytotoxicity, thus indicating the ability of VC-DCM to reverse MDR in cancer and enhance the cytotoxic effects of anticancer drugs. CONCLUSIONS: A methodological investigation on the anti-cancer properties of Vernonia cinerea Less. (VC) revealed that an enriched fraction of VC (VC-DCM) possessed cytotoxic effects, triggered apoptosis, inhibited MDR transporters, enhanced drug uptake, and sensitized cancer cells towards anticancer drug-mediated cytotoxicity in human epithelial cancer cells. Thus, VC appears to be promising for an effective treatment of various drug-resistant human epithelial cancers. PMID- 25456420 TI - The comparative clinical study of efficacy of Gamisoyo-San (Jiaweixiaoyaosan) on generalized anxiety disorder according to differently manufactured preparations: multicenter, randomized, double blind, placebo controlled trial. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gamisoyo-San (GSS) is a well-known Traditional Korean Medicine shown to be effective on mood disorders. AIM OF THE STUDY: The purpose of this research is to examine the effect of Gamisoyo-San on generalized anxiety disorder by its differently manufactured preparations. MATERIALS AND METHODS: Multicenter, randomized, double-blinded, placebo-controlled study was set for 147 patients with generalized anxiety disorder recruited from November 1st 2009 to December 16th 2010. They were given Gamisoyo-San individual extract mixture (extraction done for each crude materia medica separately) or Gamisoyo San multi-compound extract (extraction done for whole materia medica at once) or controlled medication. Hamilton Rating Scale for Anxiety (HAM-A), Korean State Trait Anxiety Inventory (K-STAI), Penn State Worry Questionnaire (PSWQ), Korean Beck Depression Inventroy (K-BDI), Symptom Checklist-90-Revised (SCL-90-R), and Korean WHO Quality of Life Scale Abbreviated Version (WHOQOL-BREF) were evaluated. We also applied Pattern Identification tool for 'JingJi and ZhengChong (, Traditional Korean Medicine term which correlates with generalized anxiety disorder)' to patients to evaluate different responses among 9 patterns. RESULTS: HAM-A scores of Gamisoyo-San multi-compound extract group showed greater decrease compared to Gamisoyo-San individual extract mixture group and placebo group, but the difference was insignificant. WHOQOL-BREF scores of Gamisoyo-San multi compound extract group showed significant increase compared to Gamisoyo-San individual extract mixture group and placebo group. In Heart blood deficiency pattern, the Gamisoyo-San multi-compound extract group showed significant decrease in K-BDI compared to the Gamisoyo-San individual extract mixture group. CONCLUSION: Gamisoyo-San did not improve anxiety level of GAD patients. However, it can be useful to improve quality of life, and reduce depressive, obsessive compulsive, somatic symptoms of generalized anxiety disorder. Gamisoyo-San multi compound seemed more effective than Gamisoyo-San individual extract mixture, especially in Heart blood deficiency pattern. PMID- 25456422 TI - Geospatial patterns in traditional knowledge serve in assessing intellectual property rights and benefit-sharing in northwest South America. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Without an understanding of the geography of traditional knowledge, implementing the Nagoya Protocol and national or regional strategies for benefit-sharing with local and indigenous communities will be difficult. We evaluate how much traditional knowledge about medicinal palm (Arecaceae) uses is unique and how much is shared across (i) four countries (Colombia, Ecuador, Peru, Bolivia), (ii) two cultural groups (Amerindian and non Amerindian), (iii) 52 Amerindian tribes, (iv) six non-Amerindian groups, (v) 41 communities, and (vi) individuals in the 41 communities. MATERIALS AND METHODS: We first sampled traditional knowledge about palms from 255 references and then carried out 2201 field interviews using a standard protocol. Using the combined data set, we quantified the number of "singletons" that were unique to one of the analyzed scales. For the 41 communities, we evaluated how many uses were cited by <10% and by >=50% of informants. We performed a Kruskal-Wallis test to evaluate whether the number of unshared uses (cited by <10%) differed significantly in relation to the informants' gender and degree of expertise, and performed a two way ANOVA to test for differences in the number of unshared and shared uses accounted for by the five birth cohorts. RESULTS: We found that most knowledge was not shared among countries, cultural groups, tribes, communities, or even individuals within them. Still, a minor knowledge component was widely shared, even across countries. General informants cited a significantly higher number of unshared uses than experts, whereas no significant differences were found in the number of unshared uses cited by men and women or by different age groups. CONCLUSION: Our region-wide analysis highlights the geospatial complexity in traditional knowledge patterns, underscoring the need for improved geographic insight into the ownership of traditional knowledge in areas where biocultural diversity is high. This high geographic complexity needs consideration when designing property right protocols, and calls for countrywide compilation efforts as much localized knowledge remains unrecorded. PMID- 25456423 TI - LC-MS/MS determination and pharmacokinetic study of seven flavonoids in rat plasma after oral administration of Cirsium japonicum DC. extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cirsium japonicum DC., a Traditional Chinese Medicine, has the curative effect of antihemorrhagic and antitumor. Pharmacological studies prove that the curative effect may relate to the flavonoids. A simple and rapid resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was first developed and validated for the quantification of seven flavonoids including pectolinarin, linarin, pectolinarigenin, hispidulin, diosmetin, acacetin and apigenin in rat plasma after oral administration of Cirsium japonicum DC. extract. MATERIALS AND METHODS: The chromatographic separation was achieved on a C18 column with gradient elution by using a mixture of 0.1% formic acid aqueous solution and methanol as the mobile phase at a flow rate of 0.8mL/min. A tandem mass spectrometric detection was conducted using multiple-reaction monitoring (MRM) via an electrospray ionization (ESI) source in positive and negative ionization mode simultaneously. Samples were pre-treated by a single-step protein precipitation with methanol, and sulfamethoxazole was used as internal standard (IS). RESULTS: The optimized mass transition ion-pairs (m/z) for quantization were 623.4/315.2 for pectolinarin, 593.3/285.1 for linarin, 315.3/300.2 for pectolinarigenin, 301.2/286.2 for hispidulin, 301.2/258.2 for diosmetin, 283.0/267.9 for acacetin, 269.0/117.0 for apigenin and 252.2/155.8 for IS. After oral administration of 6mL/kg Cirsium japonicum DC. extract in rats, the maximum plasma concentration (Cmax) of pectolinarin, linarin, pectolinarigenin, hispidulin, diosmetin, acacetin and apigenin were 876.77+/-97.34ng/mL, 86.79+/ 1.70ng/mL, 6.13+/-0.12ng/mL, 32.85+/-2.50ng/mL, 37.2+/-2.04ng/mL, 19.02+/ 1.29ng/mL and 148.26+/-20.63ng/mL, respectively. The time to reach the maximum plasma concentration (Tmax) was 5min for pectolinarin, linarin, pectolinarigenin, hispidulin, diosmetin, acacetin and 360min for apigenin. The intra-day and inter day precisions (RSD%) for seven compounds were less than 13.16% and 7.77% and the accuracy (RE%) range from -7.92% to 14.77%. CONCLUSIONS: This is the first research on the pharmacokinetic study of bioactive components in rat plasma after oral administration of Cirsium japonicum DC. extract. The results provided a meaningful basis for better understanding the absorption mechanism of Cirsium japonicum DC. and evaluating the clinical application of this herb medicine. PMID- 25456424 TI - Neuroprotective effects of Gualou Guizhi decoction in vivo and in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gualou Guizhi decoction (GLGZD) prescribed in traditional Chinese medicine has been reported to have protective effects on ischemic stroke. The present study is to investigate the therapeutic effect of GLGZD on ischemic stroke and explore its mode of action. MATERIALS AND METHODS: GLGZD was studied on transient middle cerebral artery occlusion (MCAO) followed by reperfusion in vivo, as well as on hippocampal primary neuron cultures in vitro. RESULTS: In vivo, it was shown that GLGZD treatment for 7 days could ameliorate transient middle cerebral artery occlusion (MCAO)-induced neurological deficit, histopathology changes and decrease infarct area. Further study demonstrated that GLGZD inhibited over-activation of astrocytes and apoptosis of neurons and GLGZD promoted up-regulation of neuronal specific marker neuron specific nuclear (NeuN) and microtubule-associated protein 2 (MAP-2) in brain. Moreover, the in vitro study revealed that GLGZD treatment protected against NMDA induced cell apoptosis and neuronal loss, and promoted up-regulation of neuronal specific marker NeuN. CONCLUSIONS: Taken together, the present study demonstrates that GLGZD produces a protection in the MCAO model rats via inhibiting over activation of astrocytes, apoptosis of neurons and up-regulation of neuronal specific marker NeuN and MAP-2. Our study reveals that GLGZD might be a potential neuroprotective agent for stroke and can provide basic data for clinical use. PMID- 25456425 TI - The most potent antilithiatic agent ameliorating renal dysfunction and oxidative stress from Bergenia ligulata rhizome. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Bergenia ligulata is referred by the Ayurvedic system for the treatment of kidney stone since decades and a few, in vitro and in vivo studies also support it. To identify the main phytochemical constituent(s) responsible for antilithiatic activity of its rhizome. MATERIALS AND METHODS: In order to identify the most potent antilithiatic metabolite, the crude extract of rhizome was fractionated using in vitro Calcium oxalate (CaOx) crystal growth inhibitory activity guided fractionation followed by its characterization via LC-MS, FTIR and NMR. Further, the antioxidant potential of purified molecule was assessed using in vitro assays (FRAP and H2O2 scavenging). In vivo activity of the metabolite was evaluated in hyperoxaluric rats given 0.4% ethylene glycol (EG) and 1.0% ammonium chloride (NH4Cl) for 9 days. RESULTS: Activity guided fractionation led to the isolation of most potent antilithiatic metabolite from the rhizome of Bergenia ligulata and spectroscopic analysis revealed it as bergenin. Bergenin showed reducing ability and H2O2 scavenging activity comparable with commercially available anitioxidant, alpha-tocopherol. At a dose of 10mg/kg body weight of the treated rat, it protected against deleterious effects of lithogenic treatment including weight loss, impaired renal function and oxidative stress, manifested as increased malondialdehyde, reduced redox ratio and decreased antioxidant enzyme activities in the kidneys of hyperoxaluric rats. The creatinine clearance and kidney damage were more improved by bergenin as compared to crude extract of rhizome. CONCLUSIONS: Since, bergenin maintained oxidant/antioxidant balance in hyperoxaluric rats, thus mechanistic insight of its antilithiatic activity was attributed to the antioxidant capability of bergenin. The results of the present study provide significant evidence that bergenin is an active component present in the rhizome of Bergenia ligulata for managing CaOx calculi. PMID- 25456426 TI - Drynaria fortunei J. Sm. improves the bone mass of ovariectomized rats through osteocalcin-involved endochondral ossification. AB - AIM OF THIS STUDY: Our previous study showed that Drynaria fortunei J. Sm. (Kunze), a traditional Chinese medical herb, can promote osteoblast differentiation and maturation. This study was further aimed to confirm the traditional effects of Kunze on the bone mass of ovariectomized rats. MATERIALS AND METHODS: Female Wistar rats were given an ovariectomy and then administered the water extract of Kunze (WEK). Systemic and tissue toxicities of WEK were assessed. A biomechanical test, bone mineral contents, and bone histomorphometry were analyzed to determine the effects of the WEK on the bone mass. Levels of osteocalcin (OCN) in bone tissues were determined by immunohistochemistry and immunoblotting. The effects of naringin, one of the bioactive compounds of the WEK, on the bone mass were evaluated. RESULTS: A bilateral ovariectomy in rats caused a time-dependent decrease in levels of serum 17beta-estradiol. Exposure of ovariectomized rats to the WEK at 0.5 and 1g/kg body weight/day for 1, 2, 3, and 6 months did not induce systemic or tissue toxicities. Biomechanical testing and a bone mineral content analysis showed that the ovariectomy decreased the bone torsion force and bone ash in time-dependent manners. In comparison, after exposure to the WEK, the ovariectomy-induced reductions in the bone torsion force and bone ash were significantly alleviated. In parallel, results of a bone histomorphometric assay further revealed that the ovariectomy caused significant diminution in the production of prehypertrophic chondrocytes and trabecular bone but enhanced hypertrophic chondrocyte numbers in the growth plate. However, exposure to the WEK lowered ovariectomy-induced changes in these cellular events. As to the mechanism, the WEK increased OCN biosynthesis in bone tissues of ovariectomized rats. Administration of naringin to ovariectomized rats caused significant amelioration of the bone strength, bone mineral contents, and trabecular bone amounts. CONCLUSIONS: This study shows that the WEK can translationally promote the bone mass in ovariectomized rats through stimulating OCN-involved endochondral ossification. PMID- 25456427 TI - Effects of hippadine on the blood pressure and heart rate in male spontaneously hypertensive Wistar rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hippadine is an alkaloid isolated from Crinum macowanii. Crinum macowanii is used in South Africa to treat oedema, 'heart disease', rheumatic fever, cancer and skin diseases, and belongs to the plant family Amaryllidaceae, assumed to have originated in the South African region. The aim of this study was to evaluate the effect of hippadine, an alkaloid extracted from Crinum macowanii, on the blood pressure (BP) and heart rate (HR) in anaesthetized male spontaneously hypertensive Wistar rats (SHR); and to find out if alpha1 and?or beta1 adrenoceptors contribute to its effects. MATERIALS AND METHODS: Hippadine (2.5-12.5mg/kg), adrenaline (0.05-0.20mg/kg), atenolol (0.5 40mg/kg) and prazosin hydrochloride (100-500ug/kg) were infused intravenously, and the BP and HR measured via a pressure transducer connecting the femoral artery and the PowerLab. Adrenaline increased the systolic, diastolic and mean arterial BP, while hippadine, atenolol and prazosin respectively decreased the systolic, diastolic and mean arterial BP. Increases in HR were observed with both adrenaline and prazosin, while reductions in HR were observed with atenolol and hippadine. Infusion of adrenaline in rats pre-treated with atenolol (30mg/kg), prazosin (400ug/kg), and hippadine (10mg/kg) led to similar increases in BP and HR in all groups. All changes in HR or BP were significant (p<0.05) and dose dependent. CONCLUSION: Hippadine decreases the BP and HR in SHR, and these effects may be due to alpha1 and beta1 adrenoceptor inhibition. PMID- 25456429 TI - Acute and sub-chronic oral toxicity profiles of the aqueous extract of Cortex Dictamni in mice and rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cortex Dictamni is used in Chinese folk medicine for the treatment of jaundice, cough, rheumatism and some skin diseases; however, its possible toxicity has not been rigorously studied. The present investigation was carried out to evaluate the safety of Cortex Dictamni aqueous extract (CDAE) by acute and sub-chronic toxicity studies. MATERIALS AND METHODS: In acute toxicity tests, seven groups of mice (n=5/group/sex) were orally treated with doses of 0, 28.7, 33.6, 39.7, 46.7, 54.9 and 64.6g/kg of CDAE and general behavior, adverse effects and mortality were recorded for up to 14 days. In sub chronic toxicity assays, animals received CDAE by gavage at the doses of 0, 3.0, 6.0 or 12.0g/kg/day (n=10/group/sex) for 4 weeks and then followed for a 2-week recovery period. The biochemical, hematological and morphological parameters were determined. RESULTS: In adult mice, single oral administrations of CDAE (0 64.6g/kg body weight) induced an increase in the incidence of general behavioral adverse effects. The mortality rate also increased with increasing dosage (LD50=48.2g/kg). In rats, daily single oral doses of CDAE were well tolerated behaviorally after 4 weeks and induced no significant changes in body weights. However, the absolute and relative liver weight at the end of both administration and recovery periods were significantly elevated, although the histological examination of various organs revealed no differences between the control and the treated groups. The hematological and biochemical parameters were significantly changed; lymphocytes, alanine transaminase, alkaline phosphatase levels showed a significant decrease while neutrophilic granulocyte, albumin, total cholesterol, glucose and blood urea nitrogen levels showed a significant increase, suggesting disturbances of hematopoiesis and liver and kidney functions. CONCLUSIONS: Overall, the acute toxicity of CDAE was not clearly observed. However, it is possible that CDAE has a selective toxicity considering the changes in some hematological and liver function parameters and the liver-body weight ratios in the sub-chronic oral toxicity study. PMID- 25456428 TI - Evaluation of in vitro inhibition and induction of cytochrome P450 activities by hydrolyzed ginkgolides. AB - ETHNOPHARMACOLOGICAL RELAVANCE: The extracts of Ginkgo biloba leaves are effective in treating cerebral infarction, of which ginkgolides have been demonstrated to be the active ingredients. The purpose of this study was to determine whether hydrolyzed ginkgolides would cause potential drug-drug interactions (DDI) during its clinical use via inhibition or induction of the major human cytochrome P450s (CYPs). MATERIALS AND METHODS: The inhibition (direct and metabolism-dependent inhibiton on CYP activities) and induction (mRNA expression level and activity of CYPs) by the hydrolyzed ginkgolides were evaluated in human liver microsomes and cryopreserved human hepatocytes, respectively. RESULTS: Within 0.1 to 10MUg/mL, the hydrolyzed ginkgolides showed negligible direct inhibition against CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4m (midazolam as substrate) and 3A4t (testosterone as substrate), with IC50 values determined to be >10MUg/mL (concentrations expressed as the sum of equivalent concentrations of ginkgolide A, B and K). For the metabolism-dependent inhibition studies, the preincubation of 30min did not substantially alter the IC50 values when compared with the corresponding values in the direct inhibition studies. The activities and mRNA expression levels for CYP1A2 and 2B6 within each drug-treated group (0.1, 1 and 10MUg/mL) were not affected after the 48-h incubation. For CYP3A4, the activity and mRNA expression level were not altered when incubated with 0.1 and 1MUg/mL of hydrolyzed ginkgolides. When incubated with hydrolyzed ginkgolides at 10MUg/mL, the relative activity and relative mRNA expression level of CYP3A4 remarkably increased to 4.59+/-3.67 and 17.2+/-9.16-fold of the corresponding vehicle control values, respectively. CONCLUSIONS: The hydrolyzed ginkgolides is not likely to cause DDI via inhibition of the major human CYPs. However, the CYP3A4 induction might be clinically relevant. PMID- 25456430 TI - Traditional uses of medicinal plants in gastrointestinal disorders in Nepal. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gastrointestinal disorders cause morbidity and can lead to mortality, especially in the developing world where sanitation is deficient. A large part of the human population relies on medicinal plants for treating various diseases, including gastrointestinal disorders. The present review summarizes the traditional uses of medicinal plants of Nepal used to treat gastrointestinal disorders, and evaluates their bio-efficacy based on a review of the available phytochemical and pharmacological literature. MATERIAL AND METHODS: We searched different electronic databases and libraries for the literature on medicinal plants used in Nepal to treat gastrointestinal disorders. For each species, we also searched the literature for information on conservation status, as well as for phytochemical and pharmacological studies in support of the ethnobotanical information. We used principal component analysis to explore the relation among disorders and plant families, plant life forms, plant parts and preparation modes. We also performed permutation tests to determine if botanical families were used more often than expected considering their availability in the Nepali flora. RESULTS: We documented a total of 947 species belonging to 158 families and 586 genera used to treat gastrointestinal disorders in Nepal. Diarrhea was the disorder treated by the highest number of species (348), followed by stomachache (340) and dysentery (307). Among the reported species, five were endemic to Nepal, whereas 16 orchid species were protected under CITES Appendices II and III. The randomization test showed that species belonging to 14 families were used less often than expected, whereas plants belonging to 25 families were used more often than expected. The PCA scatter plot showed distinct groups of gastrointestinal disorders treated with similar plant life forms, plant parts, and/or preparation modes. We found 763 phytochemical studies on 324 species and 654 pharmacological studies on 269 species. CONCLUSION: We showed the diversity and importance of medicinal plants used to treat gastrointestinal disorders in the traditional health care system of Nepal. As such disorders are still causing several deaths each year, it is of the utmost importance to conduct phytochemical and pharmacological studies on the most promising species. It is also crucial to increase access to traditional medicine, especially in rural areas. Threatened species need special attention for traditional herbal medicine to be exploited sustainably. PMID- 25456431 TI - Mistletoe alkaloid fractions alleviates carbon tetrachloride-induced liver fibrosis through inhibition of hepatic stellate cell activation via TGF-beta/Smad interference. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Mistletoe (Viscum coloratum (Kom.) Nakai) has long been categorized as a traditional herbal medicine in Asia. In addition to its application in cancer therapy, mistletoe has also been used in the treatment of chronic hepatic disorders in China. In the present study, we investigated the antifibrotic effect and mechanisms of action of mistletoe extracts in a rat model of carbon tetrachloride (CCl4)-induced hepatotoxicity. MATERIALS AND METHODS: An experimental model of hepatic fibrosis was established by intraperitoneal injection of rats with CCl4 for 8 weeks. Rats were subsequently treated with a mistletoe alkaloid fraction preparation via oral administration (120mg/kg daily for 8 weeks) or with distilled water as a control. Histopathological changes were observed by hematoxylin and eosin staining and Masson's trichrome staining. The expression of markers relevant to hepatic stellate cell (HSC) activation in the liver was assessed by real-time reverse transcription-polymerase chain reaction, immunohistochemistry and western blotting. The anti-fibrosis activity and mechanisms of action of mistletoe alkaloid fractions were further investigated in the HSC-T6 HSC line, following treatment with mistletoe alkaloid fractions (12mg/ml) for 48h. RESULTS: Hepatic fibrosis decreased markedly in CCl4-treated animals following treatment with mistletoe alkaloid fractions, compared to controls. The mRNA levels of transforming growth factor-beta1 (TGF-beta1), procollagen I and tissue inhibitors of metalloproteinases (TIMPs) were significantly downregulated, by about 40%, 40% and 45%, respectively, in liver tissues from rats treated with mistletoe alkaloid fractions. Furthermore, significant downregulation of TGF-beta1, TGF-beta1 receptor, phosphorylated Smad 2 and alpha smooth muscle actin (alpha-SMA) proteins, by about 45%, 30% and 40%, respectively, was also observed in liver tissues from mistletoe alkaloid fractions-treated rats. In contrast, Smad 7 levels were significantly increased by about 30% in mistletoe alkaloid fractions-treated rats. Treatment of HSC-T6 cells with mistletoe alkaloid fractions significantly induced Smad 7 expression and inhibited the expression of alpha-SMA, TGFbeta1, TGF-beta1 receptor, Smad 2 and TIMP-1, in vitro. CONCLUSION: We demonstrate that mistletoe alkaloid fractions decrease extracellular matrix accumulation by inhibiting HSC activation. Mechanistically, this may occur via inhibition of TGF-beta1/Smad 2 and Smad 7 signal transduction, thereby blocking the synthesis of procollagen I and TIMP-1. These findings suggest that mistletoe alkaloid fractions may be a potential therapeutic agent for the treatment of hepatic fibrosis. PMID- 25456432 TI - Protective effects of water fraction of Fructus Ligustri Lucidi extract against hypercalciuria and trabecular bone deterioration in experimentally type 1 diabetic mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Ligustri Lucidi (FLL), the fruit of Ligustrum lucidum Ait, is a commonly prescribed herb to nourish the endocrine and renal systems and to strengthen the bones in Traditional Chinese Medicine. This study was aimed to determine the effects of water fraction of FLL ethanol extract (WF-EE) on urinary calcium excretion and trabecular bone properties in type 1 diabetic mice. MATERIALS AND METHODS: The DBA/2J mice with type 1 diabetes induced by streptozotocin injection were orally administered with WF-EE. After 6 weeks of treatment, the level of biomarkers, including serum calcium, parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF-23) and urine calcium, was measured. Micro-CT was performed to detect trabecular bone properties of the proximal tibial metaphysis. The expression of active calcium transporting proteins in kidney and duodenum was determined by RT-PCR, immunoblotting and immunostaining. RESULTS: Type 1 diabetes induced hypercalciuria and trabecular bone deterioration. The WF-EE could significantly inhibit hypercalciuria and ameliorate the micro-structure of trabecular bone as well as increase serum PTH and FGF-23 levels in type 1 diabetic mice. The gene expressions of active calcium transporting proteins in duodenum were up-regulated, and the gene and protein expressions of calcium-sensing receptor (CaSR) in kidney were dramatically down regulated in diabetic mice in response to the treatment with WF-EE. CONCLUSIONS: The present study demonstrated the protective effects of the water fraction of Fructus Ligustri Lucidi ethanol extract against hypercalciuria and trabecular bone deterioration in experimentally type 1 diabetic mice, and the underlying mechanism may be attributed to its regulations on duodenal calcium transporting proteins and renal CaSR. PMID- 25456433 TI - Specific binding and characteristics of geissoschizine methyl ether, an indole alkaloid of Uncaria Hook, in the rat brain. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Geissoschizine methyl ether (GM) is an indole alkaloid that is a component of Uncaria Hook, and has been identified as the active component responsible for the anti-aggressive effects of the Uncaria Hook containing traditional Japanese medicine, yokukansan. Recently, GM was shown to reach the brain by crossing the blood-brain barrier in rats following the oral administration of yokukansan. This finding suggested that there may be specific binding sites for GM in the brain. Here we show evidence that tritium-labeled GM ([(3)H]GM) binds specifically to several brain areas of rats. MATERIALS AND METHODS: Male rats were used. [(3)H]GM was synthesized from a demethylated derivative of GM. Specific binding sites of [(3)H]GM on brain sections were determined by quantitative autoradiography, and maximum binding densities (Bmax) and dissociation constants (Kd) were calculated. Several chemical compounds were used to clarify the molecules that recognize [(3)H]GM in the completion-binding assay. Emulsion microautoradiography was also performed to identify the cells that bind [(3)H]GM. RESULTS: Specific binding of [(3)H]GM was observed in the frontal cortex, including the prefrontal cortical region (e.g., prelimbic cortex (PrL)), hippocampus, caudate putamen, amygdala, central medial thalamic nucleus, dorsal raphe nucleus (DR), and cerebellum. Bmax ranged between 0.65 and 8.79pmol/mg tissue, and Kd was between 35.0 and 232.6nM. Specific binding with relatively high affinity (Kd less than 62nM) was dense in the frontal cortical region, moderate in the DR, and sparse in the cerebellum. The specific binding of [(3)H]GM in the PrL was significantly replaced by the serotonin 1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT), 5-HT2A receptor antagonist ketanserin, 5-HT2B receptor agonist BW 723C86, 5-HT2C receptor agonist RO60-0175, adrenergic alpha2A receptor antagonist yohimbine, L-type Ca(2+) channel blocker verapamil, and MU-opioid receptor antagonist naloxone. Similar results were obtained in the frontal cortex and DR, but not in the cerebellum. Microautoradiography revealed that [(3)H]GM signals were distributed throughout the frontal cortex, which included neuron-like large cells. CONCLUSION: These results demonstrate that specific binding sites for GM exist in rat brain tissue, and suggest that the pharmacological actions of GM are mainly associated with 5 HT receptors in the frontal cortex and DR. These results provide an insight into the neuropharmacology of GM and GM-containing herbal medicines. PMID- 25456434 TI - Evaluation of the efficacy and safety of different Tripterygium preparations on collagen-induced arthritis in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium preparations (TPs), a traditional Chinese Medicines extracted from Tripterygium wilfordii Hook f., are widely used for treatment of rheumatoid arthritis (RA). However, TPs from different Pharmaceutical factory have different efficacy and side effects for RA treatment. AIM OF THE STUDY: The purpose of the current study is to evaluate the efficacy and safety of four TPs from different Pharmaceutical factory in china on the treatment of collagen-induced arthritis (CIA) rats and provide a theoretical and experimental basis for the individualized use of TPs. MATERIALS AND METHODS: The model of wistar rats of CIA was made, and the rats were perfused a stomach with four TPs for 3 weeks continuously. Then arthritis severity was determined by visual examination of the paws and histopathologic changes of joint, liver, kidney and testis were determined by hematoxylin-eosin (H&E) staining. The expression of inflammatory cytokines (IL-1beta, TNF-alpha, IL-17 and IL-6) in the joint was analyzed by real-time PCR, and the count and motion parameters (sperm motility and progressive sperm) of sperm in cauda epididymis were assessed with computer-assisted sperm analysis (CASA) system. Routine blood tests were conducted using automated hematology analyzer, and the aspartate aminotransferase (AST), alanine aminotransferase (ALT) activities, creatinine (Cr), and blood urea nitrogen (BUN) in serum of CIA rats were measured using a UniCel DxC 880i autoanalyzer. RESULTS: All of tested TPs could reduce inflammatory score, histopathological arthritis severity and joint's inflammatory cytokines (IL 1beta, TNF-alpha, IL-17 and IL-6) expression in CIA rats, however, TP-D showed stronger inhibitory effect for inflammatory score compared with other three TPs in vivo. All of tested TPs did not show hepatotoxicity and nephrotoxicity and also had little effect for the concentration of hemoglobin (Hb) and the count of white blood cell (WBC). Analysis of red blood cell (RBC) number showed that TP-C and TP-D could reverse lower RBC number in untreated CIA rats to normal level. Interestingly, the results showed TPs named TP-C and TP-D could decrease platelet (PLT) number which significantly increases in untreated CIA rats. Reproductive toxicity, the main side effect of TPs, assay showed that the sperm quality (density, viability, and motility) in four of TPs-treated CIA rats were decreased significantly, consistently with spermatogenic cell density reduced. However parallel analysis showed that in four TPs-treated rats, the number of sperm, motile sperm and progressive sperm were highest in TP-D group, in contrast, were lowest in TP-C group. CONCLUSIONS: These findings suggested that four TPs showed significantly therapeutic effect on ameliorating inflammation of CIA rats, with no obvious hepatotoxicity and nephrotoxicity in vivo. TP-D showed advantages with its higher efficacy and less reproductive toxicity as well as increasing RBC number, decreasing PLT number in CIA treatment. Thus, in the development of individualized treatment plan for RA patients, TP-D might be considered preferentially. PMID- 25456435 TI - The combination of astragalus membranaceus and ligustrazine ameliorates micro haemorrhage by maintaining blood-brain barrier integrity in cerebrally ischaemic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Haemorrhagic transformation is an asymptomatic event that frequently occurs after following ischaemic stroke, particularly when pharmaceutical thrombolysis is used. However, the mechanism responsible for haemorrhagic transformation remains unknown, and therapeutics have not been identified. In this study, we administered a combination of astragalus membranaceus and ligustrazine to rats with cerebral ischaemia that had undergone thrombolysis. We analysed the effect of this combination on the attenuation of haemorrhagic transformation and the maintenance of blood-brain barrier integrity. METHODS: A rat model of focal cerebral ischaemia was induced with autologous blood clot injections. Thrombolysis was performed via the intravenous injection of rt-PA. Astragalus membranaceus, ligustrazine or a combination of Astragalus membranaceus and ligustrazine was administered immediately after the clot injection. The cerebral infarct area, neurological deficits, blood-brain barrier integrity, and cerebral haemorrhage status were determined after 3, 6 and 24h of ischaemia. The ultrastructure of the blood-brain barrier was examined with a transmission electron microscope. The expression of tight junction proteins, including claudin-1, claudin-5, occludin, and zonula occludens-1, and matrix metallopeptidase-9 activation was further evaluated in terms of their roles in the protective effects of the combination drug on the integrity of the blood brain barrier. RESULTS: Ischaemia-induced Evans blue leakage and cerebral haemorrhage were markedly reduced in the combination drug-treated rats compared to the rats treated with either astragalus membranaceus or ligustrazine alone (p<0.05). The disruption of the ultrastructure of the blood-brain barrier and the neurological deficits were ameliorated by the combination treatment (p<0.05). The reductions in the expression of laudin-1, claudin-5, occludin, and ZO-1 were smaller in the rats that received the combination treatment. In addition, MMP-9 activity was suppressed in the combination-treated rats compared to the controls (p<0.05). CONCLUSIONS: Treatment with a combination of astragalus membranaceus and ligustrazine alleviated ischaemia-induced micro-haemorrhage transformation by maintaining the integrity of the blood-brain barrier. PMID- 25456436 TI - In vitro studies of berberine metabolism and its effect of enzyme induction on HepG2 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Berberine (BER) and BER-original herbal medicines have a variety of pharmacological functions and have been widely used in clinical. However, its effect of enzyme induction on cytochrome P450 (CYP) in human hepatocytes is unknown. MATERIAL AND METHOD: Metabolism of berberine and its effect on main metabolic enzymes in HepG2 cell in vitro was investigated. Cocktail probe drugs, mRNA expression and protein expression were used to evaluate the metabolism potency. Meanwhile, an UPLC-MS/MS method was validated for the analysis of BER and four probe drugs in HepG2 cell. RESULT: BER significantly increased the metabolism of midazolam, phenacetin and tolbutamide by inducing the CYP1A2 and 3A4 enzyme in a dose-dependent manner, the mRNA and protein expression of CYP1A2 and 3A4 were increased by berberine at 1000ng.mL( 1). The activity of CYP1A2 and 3A4 could be induced by BER more than 500ng.mL(-1) in HepG2 cell, which was confirmed by the increase of its mRNA and protein expression. CONCLUSION: BER increases the metabolism of cocktail drugs such as midazolam, phenacetin and tolbutamide by increasing the mRNA and protein expression of CYP1A2 and 3A4. PMID- 25456437 TI - Hedyotis diffusa Willd extract inhibits the growth of human glioblastoma cells by inducing mitochondrial apoptosis via AKT/ERK pathways. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hedyotis diffusa Willd (Rubiaceae) (HDW) has been widely applied for the treatment of tumors, inflammation and toxication in traditional Chinese medicine. The antitumor effect of HDW on glioblastoma has been rarely reported. We aim to evaluate the activity of this extract and explore the underlying mechanism in U87 human glioblastoma cell line. MATERIALS AND METHODS: Cytotoxicity of HDW extract on U87 cells was measured by MTT assay. Apoptosis, cell cycle arrest and mitochondrial membrane potential (MMP) collapse induced by HDW extract were determined by flow cytometry. Caspase activity was analyzed based on colorimetric assay with a microplate spectrophotometer. Protein expression was examined by Western blot. RESULTS: HDW extract suppressed U87 cells growth in a dose- and time-dependent manner. Flow cytometry showed that HDW extract induced significant apoptosis, S/G2-M phase arrest and MMP collapse in U87 cells. Furthermore, dose-dependent activation of caspase-3, Bcl-2, Bax and ERK was observed with HDW extract treatment. Decreased Bcl-2/Bax ratio and Akt suppression were readily found as well. CONCLUSIONS: Induction of mitochondria mediated apoptosis played an essential role in antitumor activity of HDW extract in U87 cells, in which ERKs and Akt signaling proteins were also involved. These findings contributed to the feasibility of using HDW extract in glioblastoma treatment and the understanding of the molecular mechanism. PMID- 25456438 TI - The effects of Acorus tatarinowii Schott on 5-HT concentrations, TPH2 and 5-HT1B expression in the dorsal raphe of exercised rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acorus tatarinowii Schott (Shi Chang Pu) belongs to the family of Acoraceae. The plant is used as an important herb for prolonging life many years in traditional Chinese medicine. It is an ancient herbal tonic nutriment and can be used as anti-fatigue medicine. However, the effects of Acorus tatarinowii Schott on the endurance exercise in relation to central nervous system have not yet been clarified. In this study, the effects of Acorus tatarinowii Schott on treadmill running endurance, 5-HT concentrations, TPH2, 5 HT1B expression in the dorsal raphe of exercised rats were investigated. MATERIALS AND METHODS: Sixty adult male Sprague-Dawley rats were randomly divided into six groups: the normal group, the exercise group, the exercise and the rhizomes of Acorus tatarinowii Schott (ATS)(1mg/kg)-treated group, the exercise and ATS (10mg/kg)-treated group, the exercise and ATS (100mg/kg)-treated group, the exercise and caffeine (10mg/kg)-treated group. The effects of Acorus tatarinowii Schott on endurance exercise were determined by the time to exhaustion during treadmill exercise. The detection of 5-HT concentrations in the dorsal raphe was performed by HPLC analysis. The levels of TPH2, 5-HT1A and 5 HT1B expression were measured by western blot analysis and real-time PCR. RESULTS: We found Acorus tatarinowii Schott could prolong the time to exhaustion in treadmill exercise and suppress the exercise-induced increase of 5-HT synthesis, TPH2 mRNA and protein expression and prevent the exercise-induced decrease of 5-HT1B mRNA and protein expression in the dorsal raphe. Acorus tatarinowii Schott was as effective as caffeine in prolonging the exhaustion time in treadmill running and in decreasing the exercise-induced increase of 5-HT synthesis and TPH2 mRNA and protein expression and in preventing the exercise induced decrease of 5-HT1B mRNA and protein expression in the dorsal raphe. CONCLUSIONS: The results indicated that the effects of Acorus tatarinowii Schott in inhibiting the exercise-induced synthesis of 5-HT and TPH2 expression and in preventing the exercise-induced decrease of 5-HT1B expression in the dorsal raphe might be the anti-fatigue mechanism of Acorus tatarinowii Schott. PMID- 25456440 TI - Major wound complication risk factors following soft tissue sarcoma resection. AB - BACKGROUND AND OBJECTIVES: Wound-healing complications represent an important source of morbidity in patients treated surgically for soft tissue sarcomas (STS). The purpose of this study was to determine which factors are predictive of major wound complication rates following STS resection, including tumor site, size, grade, and depth, as well as radiotherapy and chemotherapy. METHODS: We reviewed 256 cases of STS treated surgically between 2000 and 2011. The primary outcome was occurrence of major wound complications post STS resection. RESULTS: Major wound complications were more likely to occur post STS resection with larger tumor diameters (p = 0.001), high grade tumors (p = 0.04), location in the proximal lower extremity (p = 0.01), and use of preoperative radiotherapy (p = 0.01). Tumors located in the adductor compartment were at highest risk of complications. We did not demonstrate a significant difference in complications rates based on method of closure. Diabetes, smoking, obesity, tumor diameter, tumor location in the proximal lower extremity, and preoperative radiotherapy were independent predictors on multivariate analysis. CONCLUSIONS: There are multiple predictors for major wound complications post STS resection. A more aggressive resection irradiated soft tissues, combined with primary reconstruction, should be considered in cases with multiple risk factors. PMID- 25456439 TI - Screening of Vietnamese medicinal plants for NF-kappaB signaling inhibitors: assessing the activity of flavonoids from the stem bark of Oroxylum indicum. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Seventeen plants used in Vietnamese traditional medicine for the treatment of inflammatory disorders were screened for NF-kappaB inhibitory activity. Oroxylum indicum, which exhibited activity, was investigated in detail. MATERIALS AND METHODS: Forty plant extracts from 17 species were prepared by maceration using dichloromethane and methanol and were tested (10ug/mL) to evaluate their ability to inhibit NF-kappaB activation using TNF alpha-stimulated HEK-293 cells stably transfected with a NF-kappaB-driven luciferase reporter. The active extract of Oroxylum indicum was subsequently fractionated by different chromatographic techniques. After isolation, all single compounds were identified by spectroscopic methods and assessed for NF-kappaB inhibitory effects. RESULTS: The dichloromethane extracts obtained from Chromolaena odorata leaves and the stem bark of Oroxylum indicum showed distinct inhibitory effects on NF-kappaB activation at a concentration of 10ug/mL. The active extract of Oroxylum indicum was subjected to further phytochemical studies resulting in identification of four flavonoid aglyca and six flavonoid glycosides. Pharmacological evaluation of the obtained compounds identified oroxylin A as the most active substance (IC50=3.9 uM, 95% CI: 3.5-4.4 uM), while chrysin and hispidulin showed lower activity with IC50=7.2uM (95% CI: 6.0-8.8 uM) and 9.0 uM (95% CI: 7.9-10.2 uM), respectively. Interestingly, in this study the activity of baicalein (IC50=28.1 uM, 95% CI: 24.6-32.0 uM) was weak. The isolated glycosides showed no inhibitory activity when tested at a concentration of 30 uM. Quantification of the four active flavonoids in extracts and plant materials suggested that oroxylin A contributes to the NF-kappaB inhibitory activity of the stem barks of Oroxylum indicum to a greater extent than baicalein which was thought to be responsible for the anti-inflammatory activity of this plant. CONCLUSIONS: The screening presented in this study identified the dichloromethane extracts of Chromolaena odorata and Oroxylum indicum as promising sources for NF kappaB inhibitors. Hispidulin, baicalein, chrysin and oroxylin A, isolated from Oroxylum indicum, were identified as inhibitors of NF- kappaB activation. PMID- 25456441 TI - Optimal medical, rehabilitation and behavioral management in the setting of failed back surgery syndrome. AB - INTRODUCTION: Failed back surgery syndrome (FBSS) constitutes a constellation of symptoms grouped together and attributed to prior surgical intervention. Clinicians often poorly understand the heterogeneity of this condition combined with the etiological factors responsible for its development. Therefore, it would follow that an algorithmic treatment approach to patients diagnosed with this syndrome might pose challenges. The clinical work-up of the patient involves history, examination and appropriate diagnostic imaging as well as behavioral assessment. MATERIALS AND METHODS: We sought to conduct a narrative review of the available literature focused on the medical, rehabilitative and behavioral treatment of FBSS. To that end, we conducted a literature search using PubMed (through March 2013). We focused on studies published over the last 20years. Only English language articles were included. Search terms included "failed back surgery syndrome", "FBSS", "failed back syndrome", and "post-laminectomy syndrome". Studies included in our review focused on randomized controlled trials (RCTs), prospective cohort studies, and case series (retrospective and prospective). Studies were organized by intervention (e.g. medical management, physical therapy and rehabilitation, and psychosocial) and presented to emphasize the quality of evidence (e.g. RCTs, prospective studies, etc.). CONCLUSION: Overall, the literature provides very limited guidance on the comprehensive management of patients suffering from FBSS. There are rehabilitative interventions and behavioral protocols that demonstrate promise. Pathways based on medication management remain difficult to clearly define. PMID- 25456443 TI - Pathophysiological characterisation of back pain generators in failed back surgery syndrome (part B). AB - INTRODUCTION: Low back surgery, including as many type of spine procedures as the multitude of failed back surgery syndrome (FBSS) etiologies, is not always the answer for patients with chronic low back pain. Paradoxically, although a patient is considered to present FBSS because he has already undergone spinal surgery, any new symptom in the back or deterioration of back pain must not be immediately attributed to FBSS, but could be related to another cause independently of the initial mechanical problem. The aim of this paper is to extensively review the potential back pain generators in FBSS patients and to discuss their respective roles and interactions in back pain pathophysiology. METHODS: Literature searches included an exhaustive review of 643 references and 74 book chapters updated by searching the major electronic databases from 1930 to August 2013. RESULTS: Nociceptive fibres innervating any of the back anatomical structures can all play a part in the pathogenesis of the low back pain component in FBSS. The main spinal pain generators are not only myofascial syndrome or muscle spasm but also the facets, the disc complex or a sagittal imbalance and should therefore be carefully reviewed. Only after these steps and appropriate imaging, would it be justified to irremediably diagnose the patient with a refractory chronic condition, requiring no further spine surgery and to propose "palliative" pain treatment options. CONCLUSION: Clinical investigations of the low back pain component in FBSS patients should be based on meticulous dissection of all potential triggers that could be a source of the nociceptive pain characteristics and possibly amenable to further aetiological treatment. Clinicians should therefore refine pain management strategies to ensure that the chronic nature of the pain becomes the guiding principle for multidisciplinary assessment. PMID- 25456442 TI - Multicolumn spinal cord stimulation for significant low back pain in failed back surgery syndrome: design of a national, multicentre, randomized, controlled health economics trial (ESTIMET Study). AB - BACKGROUND: Many studies have demonstrated the efficacy of spinal cord stimulation (SCS) for chronic neuropathic radicular pain over recent decades, but despite global favourable outcomes in failed back surgery syndrome (FBSS) with leg pain, the back pain component remains poorly controlled by neurostimulation. Technological and scientific progress has led to the development of new SCS leads, comprising a multicolumn design and a greater number of contacts. The efficacy of multicolumn SCS lead configurations for the treatment of the back pain component of FBSS has recently been suggested by pilot studies. However, a randomized controlled trial must be conducted to confirm the efficacy of new generation multicolumn SCS. Evaluation medico-economique de la STImulation MEdullaire mulTi-colonnes (ESTIMET) is a multicentre, randomized study designed to compare the clinical efficacy and health economics aspects of mono- vs. multicolumn SCS lead programming in FBSS patients with radicular pain and significant back pain. MATERIALS AND METHODS: FBSS patients with a radicular pain VAS score>=50mm, associated with a significant back pain component were recruited in 14 centres in France and implanted with multicolumn SCS. Before the lead implantation procedure, they were 1:1 randomized to monocolumn SCS (group 1) or multicolumn SCS (group 2). Programming was performed using only one column for group 1 and full use of the 3 columns for group 2. Outcome assessment was performed at baseline (pre-implantation), and 1, 3, 6 and 12months post implantation. The primary outcome measure was a reduction of the severity of low back pain (bVAS reduction>=50%) at the 6-month visit. Additional outcome measures were changes in global pain, leg pain, paraesthesia coverage mapping, functional capacities, quality of life, neuropsychological aspects, patient satisfaction and healthcare resource consumption. TRIAL STATUS: Trial recruitment started in May 2012. As of September 2013, all 14 study centres have been initiated and 112/115 patients have been enrolled. Preliminary results are expected to be published in 2015. TRIAL REGISTRATION: Clinical trial registration information-URL: www.clinicaltrials.gov. Unique identifier NCT01628237. PMID- 25456445 TI - Hypoxia facilitates the survival of nucleus pulposus cells in serum deprivation by down-regulating excessive autophagy through restricting ROS generation. AB - Nucleus pulposus (NP) cells reside in a hypoxic environment in vivo, while the mechanisms of how NP cells maintain survival under hypoxia are not clear. Autophagy is an important physiological response to hypoxia and implicated in the survival regulation in most types of cells. This study was designed to investigate the role of autophagy in the survival of NP cells under hypoxia. We found that appropriate autophagy activity was beneficial to the survival of NP cells in serum deprivation, while excessive autophagy led to death of the NP cells. Hypoxia facilitated the survival of NP cells in serum deprivation by down regulating excessive autophagy. Hypoxia down-regulated the autophagy activity of NP cells through restricting the production of reactive oxygen species (ROS) and inactivating the AMPK/mTOR signaling pathway, and possibly through a pathway involving HIF-1alpha. We believed that understanding the autophagy response of NP cells to hypoxia and its role in cell survival had important clinical significance in the prevention and treatment of degenerative discogenic diseases. PMID- 25456444 TI - Proteome-wide lysine acetylation profiling of the human pathogen Mycobacterium tuberculosis. AB - N(E)-Acetylation of lysine residues represents a pivotal post-translational modification used by both eukaryotes and prokaryotes to modulate diverse biological processes. Mycobacterium tuberculosis is the causative agent of tuberculosis, one of the most formidable public health threats. Many aspects of the biology of M. tuberculosis remain elusive, in particular the extent and function of N(E)-lysine acetylation. With a combination of anti-acetyllysine antibody-based immunoaffinity enrichment with high-resolution mass spectrometry, we identified 1128 acetylation sites on 658 acetylated M. tuberculosis proteins. GO analysis of the acetylome showed that acetylated proteins are involved in the regulation of diverse cellular processes including metabolism and protein synthesis. Six types of acetylated peptide sequence motif were revealed from the acetylome. Twenty lysine-acetylated proteins showed homology with acetylated proteins previously identified from Escherichia coli, Salmonella enterica, Bacillus subtilis and Streptomyces roseosporus, with several acetylation sites highly conserved among four or five bacteria, suggesting that acetylated proteins are more conserved. Notably, several proteins including isocitrate lyase involved in the persistence, virulence and antibiotic resistance are acetylated, and site directed mutagenesis of isocitrate lyase acetylation site to glutamine led to a decrease of the enzyme activity, indicating major roles of KAc in these proteins engaged cellular processes. Our data firstly provides a global survey of M. tuberculosis acetylation, and implicates extensive regulatory role of acetylation in this pathogen. This may serve as an important basis to address the roles of lysine acetylation in M. tuberculosis metabolism, persistence and virulence. PMID- 25456446 TI - A growth-cone model for the spread of object-based attention during contour grouping. AB - BACKGROUND: Object-based attention can group image elements of spatially extended objects into coherent representations, but its mechanisms have remained unclear. The mechanisms for object-based attention may include shape-selective neurons in higher visual cortical areas that feed back to lower areas to simultaneously enhance the representation of all image elements of a relevant shape. Another, nonexclusive mechanism is the spread of attention in early visual cortex according to Gestalt rules, which could successively add new elements to a growing object representation. RESULTS: We investigated the dynamics of object based attention in the primary visual cortex of monkeys trained to perform a contour-grouping task. The animals mentally traced a target curve through the visual field and ignored a distracting curve. Neuronal responses elicited by the target curve were enhanced relative to those elicited by distracting curve. Remarkably, the response enhancement was delayed for neurons with receptive fields farther from the start of the tracing process. We could therefore measure propagation speed and found that it was low if curves were nearby and that it increased if curves were far apart. The results are well explained by an "attentional growth-cone" model, which holds that the response enhancement can spread in multiple visual cortical areas with different receptive field sizes at a speed of approximately 50 ms per receptive field. CONCLUSIONS: Our findings support an active role for early visual areas in object-based attention because neurons in these areas gradually spread enhanced activity over the representation of relevant objects. PMID- 25456447 TI - Trehalose is a versatile and long-lived chaperone for desiccation tolerance. AB - BACKGROUND: Diverse organisms across taxa are desiccation tolerant, capable of surviving extreme water loss. Remarkably, desiccation tolerant organisms can survive years without water. However, the molecular mechanisms underlying this rare trait are poorly understood. RESULTS: Here, using Saccharomyces cerevisiae, we show that intracellular trehalose is essential for survival to long-term desiccation. The time frame for maintaining long-term desiccation tolerance consists of a balance of trehalose stockpiled prior to desiccation and trehalose degradation by trehalases in desiccated cells. The activity of trehalases in desiccated cell reveals the stunning ability of cells to retain enzymatic activity while desiccated. Interestingly, the protein chaperone Hsp104 compensates for loss of trehalose during short-term, but not long-term, desiccation. We show that desiccation induces protein misfolding/aggregation of cytoplasmic and membrane proteins using luciferase and prion reporters. We demonstrate that trehalose, but not Hsp104, mitigates the aggregation of both cytoplasmic and membrane prions. We propose that desiccated cells initially accumulate both protein and chemical chaperones, like Hsp104 and trehalose, respectively. As desiccation extends, the activities of the protein chaperones are lost because of their complexity and requirement for energy, leaving trehalose as the major protector against the aggregation of cytoplasmic and membrane proteins. CONCLUSIONS: Our results suggest that trehalose is both a more stable and more versatile protectant than protein chaperones, explaining its important role in desiccation tolerance and emphasizing the translational potential of small chemical chaperones as stress effectors. PMID- 25456449 TI - Dopamine-induced dissociation of BOLD and neural activity in macaque visual cortex. AB - Neuromodulators determine how neural circuits process information during cognitive states such as wakefulness, attention, learning, and memory. fMRI can provide insight into their function and dynamics, but their exact effect on BOLD responses remains unclear, limiting our ability to interpret the effects of changes in behavioral state using fMRI. Here, we investigated the effects of dopamine (DA) injections on neural responses and haemodynamic signals in macaque primary visual cortex (V1) using fMRI (7T) and intracortical electrophysiology. Aside from DA's involvement in diseases such as Parkinson's and schizophrenia, it also plays a role in visual perception. We mimicked DAergic neuromodulation by systemic injection of L-DOPA and Carbidopa (LDC) or by local application of DA in V1 and found that systemic application of LDC increased the signal-to-noise ratio (SNR) and amplitude of the visually evoked neural responses in V1. However, visually induced BOLD responses decreased, whereas cerebral blood flow (CBF) responses increased. This dissociation of BOLD and CBF suggests that dopamine increases energy metabolism by a disproportionate amount relative to the CBF response, causing the reduced BOLD response. Local application of DA in V1 had no effect on neural activity, suggesting that the dopaminergic effects are mediated by long-range interactions. The combination of BOLD-based and CBF-based fMRI can provide a signature of dopaminergic neuromodulation, indicating that the application of multimodal methods can improve our ability to distinguish sensory processing from neuromodulatory effects. PMID- 25456448 TI - Neural correlates of auditory short-term memory in rostral superior temporal cortex. AB - BACKGROUND: Auditory short-term memory (STM) in the monkey is less robust than visual STM and may depend on a retained sensory trace, which is likely to reside in the higher-order cortical areas of the auditory ventral stream. RESULTS: We recorded from the rostral superior temporal cortex as monkeys performed serial auditory delayed match-to-sample (DMS). A subset of neurons exhibited modulations of their firing rate during the delay between sounds, during the sensory response, or during both. This distributed subpopulation carried a predominantly sensory signal modulated by the mnemonic context of the stimulus. Excitatory and suppressive effects on match responses were dissociable in their timing and in their resistance to sounds intervening between the sample and match. CONCLUSIONS: Like the monkeys' behavioral performance, these neuronal effects differ from those reported in the same species during visual DMS, suggesting different neural mechanisms for retaining dynamic sounds and static images in STM. PMID- 25456450 TI - Color constancy for an unseen surface. AB - The illumination of a scene strongly affects our perception of objects in that scene, e.g., the pages of a book illuminated by candlelight will appear quite yellow relative to other types of artificial illuminants. Yet at the same time, the reader still judges the pages as white, their surface color unaffected by the interplay of paper and illuminant. It has been shown empirically that we can indeed report two quite different interpretations of "color": one is dependent on the constant surface spectral reflectance of an object (surface color) and the other on the power of light of different wavelengths reflected from that object (reflected color). How then are these two representations related? The common view, dating from Aristotle, is that our experience of surface color is derived from reflected color or, in more familiar terms, that color perception follows from color sensation. By definition, color constancy requires that vision "discounts the illuminant"; thus, it seems reasonable that vision begins with the color of objects as they naively appear and that we infer from their appearances their surface color. Here, we question this classic view. We use metacontrast masked priming and, by presenting the unseen prime and the visible mask under different illuminants, dissociate two ways in which the prime matched the mask: in surface color or in reflected color. We find that priming of the mask occurs when it matches the prime in surface color, not reflected color. It follows that color perception can arise without prior color sensation. PMID- 25456451 TI - Metabolic efficiency in courtship favors males with intermediate mass in the Australian redback spider, Latrodectus hasselti. AB - Recent studies have suggested that metabolic efficiency may be an important factor in male mating success when females require vigorous and/or prolonged courtship. In capital breeding animals in which a male's resource pool is fixed at adulthood the relationship between energy expenditure and courtship performance may be especially important, as males are expected to utilize their finite resources efficiently when soliciting mates. Males may benefit from being efficient, i.e., achieving a sufficiently high level of courtship signaling at low energetic cost, if it enables them to acquire mates before their limited energy reserves are depleted. We investigated the relationship between metabolic efficiency and courtship vibrational signaling in the Australian redback spider, Latrodectus hasselti, a semelparous capital breeder where males invest heavily in courtship to secure a mating. We assessed metabolic rate in a sample of males and measured two courtship components (duty cycle and amplitude) that reflected the energy content of web-borne vibrations. We then calculated two indices of metabolic efficiency for these courtship properties. There was a quadratic relationship between mass and duty cycle such that the highest duty cycle signals were performed by males having intermediate mass. Furthermore, intermediate-mass males were also the most metabolically efficient. Prolonged courtship is necessary in L. hasselti for successful mating, and the results of this study suggest that intermediate-mass males are superior courters because they utilize their finite resource pool most efficiently to produce high energy vibrational signals. PMID- 25456452 TI - Differential viral levels and immune gene expression in three stocks of Apis mellifera induced by different numbers of Varroa destructor. AB - The viral levels and immune responses of Italian honey bees (IHB), Russian honey bees (RHB) and an outcross of Varroa Sensitive Hygienic bees (POL) deliberately infested with one or two foundress Varroa were compared. We found that the Deformed wing virus (DWV) level in IHB inoculated with one or two foundress Varroa increased to about 10(3) or 10(5) fold the levels of their uninfested brood. In contrast, POL (10(2) or 10(4) fold) and RHB (10(2) or l0(4) fold) supported a lower increase in DWV levels. The feeding of different stages of Varroa nymphs did not increase DWV levels of their pupal hosts. Analyses of their corresponding Varroa mites showed the same trends: two foundress Varroa yielded higher DWV levels than one foundress, and the addition of nymphs did not increase viral levels. Using the same pupae examined for the presence of viruses, 16 out of 24 genes evaluated showed significant differential mRNA expression levels among the three honey bee stocks. However, only four genes (Defensin, Dscam, PPOact and spaetzle), which were expressed at similar levels in uninfested pupae, were altered by the number of feeding foundress Varroa and levels of DWV regardless of stocks. This research provides the first evidence that immune response profiles of different honey bee stocks are induced by Varroa parasitism. PMID- 25456453 TI - Polymer adsorption and electrokinetic potential of dispersed particles in weak and strong electric fields. AB - A review on the effects of adsorbed non-ionic polymers and polyelectrolytes on the electrophoresis of dispersed particles is given. The variety of changes in the electrical double layer (EDL) structure and, in particular, electrokinetic potential in weak electric fields as a result of polymer adsorption is discussed. Examples on the dependence of zeta potential of particles on the adsorbed amount of polymers are described. An analysis of the influence of various complicating factors, namely polarization of the EDL, curvature of the surface and the presence of electrolytes, on the calculation of polymer layer thickness from electrophoretic data has been performed. Results of electrophoretic measurements in suspensions of non-conventional particles (TiC, SiC and Si3N4) having adsorbed polyethylene oxide are presented. Regularities of the effect of anionic and cationic polyelectrolytes (PEs) and their binary mixtures on the electrokinetic potential of dispersed particles (polystyrene, silica, bentonite and kaolin) as a function of the polymer dose, pH, charge density (CD) of the polyelectrolyte, as well as the mixture composition and the sequence of component addition are described. It has been shown that addition of increasing amount of anionic PEs increases the absolute value of the negative zeta potential of particles, while adsorption of cationic PEs results in a significant decrease in the negative zeta potential and overcharging the particle surface; changes in the zeta-potential are more pronounced for samples with higher CD. In mixtures of cationic and anionic PEs, in a wide range of their composition, the zeta-potential of negatively charged particles is determined by the adsorbed amount of the anionic polymer independently of the CD of polyelectrolyte and the sequence of the mixture component addition. The role of coulombic and non-coulombic forces in the mechanism of polyelectrolyte adsorption and structure of adsorbed layers formed is discussed. The results of comparative investigations on the effect of adsorbed polymers on the electrophoresis of dispersed particles in weak and strong electric fields are presented. It is shown that adsorption of non-ionic polymers only slightly (by about 20-50%) decreases the electrophoretic velocity (V(ef)) of polystyrene, graphite and aluminium-oxide particles in strong fields (100-400 V/cm). This is in contrast to the electrophoresis in weak fields (5-20 V/cm) in which adsorption of these polymers gives a drop in V(ef) by an order of magnitude or even more. In line with our theoretical predictions, it means that the non linear ("cubic") electrophoresis, that arises in strong electric fields, is independent of the position of the shear plane, i.e. the zeta potential value. It is determined mainly by the surface conductivity of particles, i.e. by the Dukhin number that characterizes the polarization of the electric double layer. PMID- 25456454 TI - Selective gas transfer through binary polymeric systems based on block copolymers. AB - Evaluation of several versions of phenomenological theory of gas permeability in selective polymeric membranes is presented, along with the appropriate experimental methods for verification of these versions. The main focus is on a description of stationary mass transfer across membranes (films) containing dispersion inclusions of various shapes of one polymer in a matrix of another. Considering heterogeneous media as a membrane material, it was assumed that diffusion and sorption properties of inclusions are different from those of the dispersing medium. The problem of choosing optimal shape of inclusions is evaluated from the point of view of targeted permeability and selectivity of a membrane with respect to gases. To confirm this theoretical approach, the experimental results of the studies of diffusion (permeability) of permanent gases in polymeric membranes of different structures were used. The target gases included noble gases, hydrogen, nitrogen, oxygen, CO2, and methane. The target polymers included glassy polyvinyltrimethylsilane (PVTMS, T(gl)=155-180 degrees C), rubberlike polydimethylsiloxane (PDMS, T(gl)=-120 degrees C), and two-phase block-copolymers based on these materials within a wide range of composition, including the region of phase inversion. In addition, available experimental literature data on gas permeation parameters for polyarylat-polysiloxane, polysulfon-polysiloxane, and polycarbonate-polysiloxane block-copolymers are utilized. In order to describe the stationary gas permeability for two-phase systems (from diluted dispersion of one polymer in another to concentrated dispersion and complete phase inversion) the empiric approaches based on modified Maxwell equations are offered. The requirements for two-phase systems with high permeability and selectivity parameters for gas separation are identified. The permeability parameters are predicted for C1-C4 hydrocarbons in block-copolymers based on PDMS dispersion in PVTMS, phase inversion, and PVTMS dispersion in PDMS. Thus, the perspectives of designing heterogeneous membranes based on block copolymers with predetermined molecular-selective properties are demonstrated. PMID- 25456455 TI - Surface dilational moduli of polymer and blended polymer monolayers spread at air water interfaces. AB - Surface dilational moduli of polymer monolayers, blended polymer monolayers, and polymer particle monolayers spread at air-water interfaces are reviewed, focusing on measurements using surface pressure isotherm, surface pressure relaxation, and oscillating barrier methods. Differences between the surface dilational moduli of condensed polymer monolayers and expanded polymer monolayers are explored. Moreover, the features of the surface dilational moduli in blended polymer monolayers are discussed in terms of their miscibility. PMID- 25456457 TI - Incretin therapy and beta cell function. PMID- 25456456 TI - Over-expression of Follistatin-like 3 attenuates fat accumulation and improves insulin sensitivity in mice. AB - OBJECTIVE: Follistatin-like 3 (fstl3), a natural inhibitor of members of the TGF beta family, increases during resistance training in human plasma. Fstl3 primarily binds myostatin and activin A, and thereby inhibits their functions. We hypothesize that blocking myostatin and activin A signalling through systemic fstl3 over-expression protects against diet-induced obesity and insulin resistance. METHODS: Fstl3 was over-expressed by DNA electrotransfer in tibialis anterior, quadriceps and gastrocnemius muscles in female C57BL/C mice, and the mice were subsequently randomized to chow or high-fat feeding. Body weight, food intake, fat accumulation by MR scanning, and glucose, insulin and glucagon tolerance were evaluated, as was the response in body weight and metabolic parameters to 24h fasting. Effects of fstl3 on pancreatic insulin and glucagon content, and pancreatic islet morphology were determined. RESULTS: Fstl3 over expression reduced fat accumulation during high-fat feeding by 16%, and liver fat by 50%, as determined by MRI. No changes in body weight were observed, while the weight of the transfected muscles increased by 10%. No transcriptional changes were found in the subcutaneous adipose tissue. Fstl3 mice displayed improved insulin sensitivity and muscle insulin signalling. In contrast, glucose tolerance was impaired in high-fat fed fstl3 mice, which was explained by increased hepatic glucagon sensitivity and glucose output, as well as a decrease in the pancreatic insulin/glucagon ratio. Accordingly, fstl3 transfection improved counter regulation to 24h fasting. CONCLUSION: Fstl3 over-expression regulates insulin and glucagon sensitivities through increased muscular insulin action, as well as increased hepatic glucagon sensitivity and pancreatic glucagon content. PMID- 25456458 TI - Iron metabolism in neuromyelitis optica patients. AB - OBJECTIVE: The aim of this study was to investigate whether there was any relationship between iron metabolism and clinical features of NMO patients. METHODS: We measured serum iron, ferritin, and transferrin levels in 25 patients with NMO and 25 controls. RESULTS: The patients with NMO had significantly decreased serum iron and increased serum ferritin (P=0.001 and 0.002, respectively), both of which were in normal ranges. The serum iron level of NMO patients was not correlated with disease duration, relapse number, or magnetic resonance imaging lesions. After multivariate linear regression analysis, the serum iron level was correlated with age (P=0.003) but not EDSS score. CONCLUSIONS: The iron metabolism might reflect the chronic oxidative injury in NMO patients. It is still unclear whether iron metabolism is implicated in the pathogenesis of NMO. PMID- 25456459 TI - Impact of tetrabenazine on gait and functional mobility in individuals with Huntington's disease. AB - Chorea may contribute to balance problems and walking difficulties that lead to higher fall rates in individuals with Huntington's disease (HD). Few studies have examined the effects of tetrabenazine (TBZ), an anti-choreic drug, on function and mobility in HD. The purpose of this study was to compare: 1) gait measures in forward walking, 2) balance and mobility measures, and 3) hand and forearm function measures on and off TBZ. We hypothesized that use of TBZ would improve gait, transfers and hand and forearm function. Eleven individuals with HD on stable doses of TBZ were evaluated while off medication and again following resumption of medication. Significant improvements were found on the Unified Huntington's Disease Rating Scale (UHDRS) motor scores, Tinetti Mobility Test (TMT) total (t=4.20, p=0.002) and balance subscale (t=-4.61, p=0.001) scores, and the Five Times Sit-to-Stand test (5TSST, t=3.20, p=.009) when on-TBZ compared to off-TBZ. Spatiotemporal gait measures, the Six Condition Romberg test, and UHDRS hand and forearm function items were not changed by TBZ use. Improved TMT and 5TSST performance when on drug indicates that TBZ use may improve balance and functional mobility in individuals with HD. PMID- 25456460 TI - Relationship between gray matter volume and cognitive learning in CIS patients on disease-modifying treatment. AB - BACKGROUND: Repeated administration of Paced Auditory Serial Addition Test (PASAT) results in a considerable learning effect in short- or long-term follow up studies. However, the relationship between PASAT learning and changes in magnetic resonance imaging (MRI) parameters is yet to be investigated. OBJECTIVES: The aim of this study is to determine if change in brain MRI metrics predicts evolution of PASAT in high functioning clinically isolated syndrome (CIS) patients on disease-modifying treatment (DMT). METHODS: This prospective 48 month observational study examined 128 CIS patients treated with 30 MUg of intramuscular interferon beta-1a once a week. The correlation between PASAT and MRI measures was assessed at baseline, at 6 months and then annually over the 48 month follow up. Linear mixed model analysis adjusted for age, gender, education and DMT was used to model the temporal association between MRI measures and PASAT performance. RESULTS: MRI revealed 2.5% gray matter (GM) volume loss and 4.3 point increase in PASAT score over 48 months. MS patients evidenced significantly greater PASAT score absolute change, had lower loss of GM volume (p=.008) but not significant change in cortical (p=.061), white matter (p=.086) or whole brain volumes (p=.879). CONCLUSIONS: The present study reveals a significant relationship between higher PASAT learning effect and less GM atrophy in CIS patients on DMT. These findings suggest that change in PASAT associated more with GM than WM pathology, and that treatment strategies oriented toward GM volume preservation may play an important role in prevention of cognitive deterioration in CIS patients. PMID- 25456461 TI - Should spinocerebellar ataxias be included in the differential diagnosis for Huntington's diseases-like syndromes? AB - In this article, we describe three patients with different spinocerebellar ataxia (SCA) subtypes presenting with unusual movement disorders predominantly characterized by choreoathetosis, which, together with their autosomal dominant pattern of inheritance, resembled the Huntington-like syndromes. From a large SCA cohort, we have observed chorea in 1/35 SCA2, 1/112 SCA3/MJD, and 1/30 SCA7 patients. Twenty-eight patients with SCA1, 11 patients with SCA6, and 3 patients with SCA10 were also evaluated, and none of them presented chorea. We provide a brief report of the three cases, with a video demonstrating chorea. Although a debate regarding the frequency of chorea in SCA patients is a fact, its occurrence, together with the autosomal dominant pattern of inheritance, clearly imposes SCA in the differentials of Huntington-like syndromes. There is some debate about what to include in a list of Huntington-like disorders, with several review articles about Huntington-like syndromes not including SCA in the differential diagnosis, except for SCA17. We believe that SCAs-at least SCA1, SCA2, SCA3/MJD, SCA7 and DRPLA-should be thought in the diagnostic workout of at least the atypical cases, such as those presented in this report. PMID- 25456462 TI - MRI negative meningeal myeloma with abducens nerve palsies responding to intrathecal chemotherapy. AB - Meningeal involvement of multiple myeloma is rare. A patient with multiple myeloma presented with bilateral abducens nerve palsies. In the MRI neither lytic skull lesions nor meningeal enhancement could be found. The diagnosis was based on CSF studies and cytology. A neurologic remission was achieved with intrathecal chemotherapy. PMID- 25456463 TI - Infliximab monotherapy for neuro-Behcet's disease: a case report. PMID- 25456464 TI - Vitamin D supplementation in multiple sclerosis: making a case for clarity. PMID- 25456469 TI - Sleep disturbances of adult women suffering from fibromyalgia: a systematic review of observational studies. AB - Although sleep complaints are often reported in patients with fibromyalgia syndrome (FMS), there is no conclusive evidence that these complaints represent symptomatic disorders of sleep physiology. Thus, the question of the role of sleep disturbances as an etiological or maintenance factor in FMS remains open. This study identifies the subjective and objective characteristics of sleep disturbances in adult women diagnosed with FMS. We carried out a systematic review of publications since 1990, the publication year of the American College of Rheumatology criteria of FMS. We selected empirical studies comparing sleep characteristics of adult women with FMS and healthy women or women with rheumatic diseases. We identified 42 articles. Patients with FMS were more likely to exhibit sleep complaints and also a less efficient, lighter and fragmented sleep. The evidence of a FMS signature on objective measures of sleep is inconsistent, however, as the majority of studies lacks statistical power. Current evidence cannot confirm the role played by sleep physiology in the pathogenesis or maintenance of FMS symptoms; nonetheless, it is clear that sleep disturbances are present in this syndrome. PMID- 25456470 TI - Snoring--obnoxious (but medically innocent) noise or wakeup call for sleep medicine? PMID- 25456471 TI - [Not Available]. PMID- 25456472 TI - [Not Available]. PMID- 25456473 TI - [Not Available]. PMID- 25456474 TI - [Not Available]. PMID- 25456475 TI - [Not Available]. PMID- 25456476 TI - [Not Available]. PMID- 25456477 TI - [Not Available]. PMID- 25456478 TI - [Not Available]. PMID- 25456479 TI - [Not Available]. PMID- 25456480 TI - [Not Available]. PMID- 25456482 TI - [Not Available]. PMID- 25456481 TI - [Not Available]. PMID- 25456483 TI - [Not Available]. PMID- 25456484 TI - [Not Available]. PMID- 25456485 TI - [Not Available]. PMID- 25456486 TI - [Not Available]. PMID- 25456487 TI - [Not Available]. PMID- 25456488 TI - [Place of simulation in gynecologic surgical training in France]. PMID- 25456489 TI - [Nuchal translucency: this is not so simple!]. PMID- 25456490 TI - [Use of glue in laparoscopic sacrocolpopexy. A comparative study about 32 cases]. AB - AIM: To study the impact of the use of glue instead of some laparoscopic sutures, on the operative time, the morbidity, and the short-term anatomical and functional results in the laparoscopic sacrocolpopexy (LSCP). PATIENTS AND METHODS: Thirty-two patients underwent a LSCP at Poissy-St-Germain-en-Laye University Hospital. The fixation of prostheses was made either exclusively by sutures (Group S), or by associating sutures (on traction sites) and biological glue (GroupC). Comparison was made after pairing on the number of prostheses associated surgery. Patients' satisfaction was assessed thanks to the validated PGI-I questionnaire. RESULTS: The mean operative time (178.7 [Group S] vs 173.1 minutes [Group C]) and the mean hospital stay (3.94 [Group S] vs 3.31 days [Group C]) were not significantly different. Anatomical results (POP-Q) and the mean satisfaction rate in the short-term were similar in both groups (1.67 [Group S] vs 1.30 [Group C]. Morbidity was also similar in both groups; no serious complications have been experienced. DISCUSSION AND CONCLUSION: The use of the glue in the LSCP did not significantly reduce the operative time. However, the use of glue for the adhesion of prostheses in addition to sutures has shown its safety and efficacy compared to the conventional technique (sutures exclusively) since the morbidity, the anatomical results and satisfaction rate are identical in the short-term. A study involving a larger number of patients with a longer follow-up seems necessary. PMID- 25456491 TI - [Sexual activity and quality of life in patients with Mayer-Rokitansky-Kuster Hauser syndrome]. AB - OBJECTIVES: This study evaluated the sexual activity and the quality of life in patients with a Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. PATIENTS AND METHODS: The study is based on a series of patients hospitalized for the treatment of MRKH syndrome in CMCO between 1997 and 2010. Through the medical reports, we recovered information about the pathology, the treatment given and the psychological support proposed to or wished by the patients. The patients also had to answer a questionnary concerning the quality of the informations they received about the treatment, the different types of supports proposed and wanted, their life as a couple and how they communicated about their disease. RESULTS: Eleven medical reports have been reviewed. The patients were aged 21 in average at the moment of the treatment. Three patients had some associated malformations. Different methods of treatment were represented (Frank's method, Vecchietti's technique, sigmoid vaginoplasty, McIndoe's technique). Sexual intercourse was assessed as satisfactory by 4 patients. In 8 cases, the partner accepted well the pathology. Only 4 out of the eleven medical reports mentioned a psychological support. Nine out of the eleven patients accepted to answer the questionnary. DISCUSSION AND CONCLUSION: The review of the literature and our own results show that the patients with MRKH syndrome have a real need for psychological support. They are able to have sexual intercourse that is satisfactory in the domains of excitation, lubrification and desire, especially after treatment. The main problem is the inability to bear children, a problem which might by solved by the future researches about uterus graft and the evolution of the laws concerning gestational surrogacy. PMID- 25456492 TI - [Response from G. Legendre et al. to the article from E. Brazet et al. Previa uterine leiomyoma: a rare case of bowel obstruction during pregnancy. Gynecol Obstet Fertil 2014;42:806-9]. PMID- 25456493 TI - Tungsten phosphide nanorod arrays directly grown on carbon cloth: a highly efficient and stable hydrogen evolution cathode at all pH values. AB - We report the development of tungsten phosphide nanorod arrays on carbon cloth (WP NAs/CC) through a two-step strategy: hydrothermally growing WO3 nanorod arrays on CC (WO3 NAs/CC) first, followed by phosphidation to chemically convert the WO3 NAs/CC precursor into WP NAs/CC. As a novel integrated 3D hydrogen evolution cathode in acidic media, the WP NAs/CC electrode exhibits excellent catalytic activity and durability. It needs overpotentials of 130 and 230 mV to afford current densities of 10 and 100 mA cm(-2), respectively, and its catalytic activity is maintained for at least 70 h. Remarkably, this electrode also works efficiently in both neutral and alkaline solutions. PMID- 25456494 TI - Dynamic intraligamentary stabilization and primary repair: a new concept for the treatment of knee dislocation. AB - BACKGROUND: Traumatic knee dislocation represents a rare but devastating injury. Several controversies persist regarding type of treatment, surgical timing, graft selection, repair versus reconstruction of the medial and lateral structures, surgical techniques and postoperative rehabilitation. A new technique for primary ACL stabilization, dynamic intaligamentary stabilization (DIS) was developed at the authors' institution. The purpose of this study was to analyze the clinical and radiological outcomes of surgically treated traumatic knee dislocations by means of the DIS technique for the ACL, primary suturing for PCL, MCL and LCL. METHODS: Between 2009 and 2012, 35 patients treated surgically for traumatic knee dislocation with primary anterior cruciate ligament (ACL) reconstruction with DIS, suturing of the posterior cruciate ligament (PCL) and primary complete repair of collaterals, were evaluated clinically (IKDC score, SF12 health survey, Lysholm score, Tegner score) and radiologically with a mean follow up of 2.2 years (range 1.00-3.50 years) years. Instrumented anterior-posterior translation was measured (KT-2000). RESULTS: Anterior/posterior translation (KT-2000) for the healthy and injured limb was 4.8mm (range 3-8mm) and 7.3mm (range 5-10) (89N) respectively. Valgus and varus stress testing in 30 degrees flexion was normal in 26 (75%) and 29 (83%) patients, respectively. The IKDC score was B in 29 (83%) and C in 6 (17%) patients, while the mean Tegner score was 6 (range 4-8). The mean Lysholm score was 90.83 (range 81-95) and mean SF-12 physical and mental scores were 54.1 (range 45-60) and 51.0 (range 39-62) respectively. In 2 patients, a secondary operation was performed. CONCLUSIONS: Early, one stage reconstruction with DIS can achieve good functional results and patient satisfaction with overall restoration of sports and working capacity without graft requirements. PMID- 25456495 TI - The role of pleiotrophin in bone repair. AB - Bone has an enormous capacity for growth, regeneration, and remodelling, largely due to induction of osteoblasts that are recruited to the site of bone formation. Although the pathways involved have not been fully elucidated, it is well accepted that the immediate environment of the cells is likely to play a role via cell-matrix interactions, mediated by several growth factors. Formation of new blood vessels is also significant and interdependent to bone formation, suggesting that enhancement of angiogenesis could be beneficial during the process of bone repair. Pleiotrophin (PTN), also called osteoblast-specific factor 1, is a heparin-binding angiogenic growth factor, with a well-defined and significant role in both physiological and pathological angiogenesis. In this review we summarise the existing evidence on the role of PTN in bone repair. PMID- 25456496 TI - Skeletal reconstruction of the forearm with a double-barrel fibular flap and second metatarsal head. PMID- 25456497 TI - An unconventional glutamatergic circuit in the retina formed by vGluT3 amacrine cells. AB - In the vertebrate retina, glutamate is traditionally thought to be released only by photoreceptors and bipolar cells to transmit visual signals radially along parallel ON and OFF channels. Lateral interactions in the inner retina are mediated by amacrine cells, which are thought to be inhibitory neurons. Here, we report calcium-dependent glutamate release from vGluT3-expressing amacrine cells (GACs) in the mouse retina. GACs provide an excitatory glutamatergic input to ON OFF and ON direction-selective ganglion cells (DSGCs) and a subpopulation of W3 ganglion cells, but not to starburst amacrine cells. GACs receive excitatory inputs from both ON and OFF channels, generate ON-OFF light responses with a medium-center, wide-surround receptive field structure, and directly regulate ganglion cell activity. The results reveal a functional glutamatergic circuit that mediates noncanonical excitatory interactions in the retina and probably plays a role in generating ON-OFF responses, crossover excitation, and lateral excitation. PMID- 25456498 TI - An eIF4E1/4E-T complex determines the genesis of neurons from precursors by translationally repressing a proneurogenic transcription program. AB - Here, we have addressed the mechanisms that determine genesis of the correct numbers of neurons during development, focusing on the embryonic cortex. We identify in neural precursors a repressive complex involving eIF4E1 and its binding partner 4E-T that coordinately represses translation of proteins that determine neurogenesis. This eIF4E1/4E-T complex is present in granules with the processing body proteins Lsm1 and Rck, and disruption of this complex causes premature and enhanced neurogenesis and neural precursor depletion. Analysis of the 4E-T complex shows that it is highly enriched in mRNAs encoding transcription factors and differentiation-related proteins. These include the proneurogenic bHLH mRNAs, which colocalize with 4E-T in granules and whose protein products are aberrantly upregulated following knockdown of eIF4E, 4E-T, or processing body proteins. Thus, neural precursors are transcriptionally primed to generate neurons, but an eIF4E/4E-T complex sequesters and represses translation of proneurogenic proteins to determine appropriate neurogenesis. PMID- 25456502 TI - Saphenous vein to internal mammary artery end-to-end composite grafts for coronary artery bypass. Late follow-up. AB - BACKGROUND: Internal mammary artery (IMA) grafts provide equal or superior graft patency compared to other conduits. The IMA length limits extensive myocardial revascularisation with IMA grafts alone. This study aimed to determine the results of lengthening free IMAs with a short proximal segment of saphenous vein (SV) to enable more extensive myocardial revascularisation. METHODS: Patients (n=92) who underwent end-to-end composite SV-IMA grafts were followed up through cardiology and death register databases. RESULTS: The mean patient age was 57.5 years and median follow up 10.9 years. There was no perioperative mortality and 10-year survival was 89.6%. Thirty-one patients (34%) underwent repeat angiography at a median of 2.8 years postoperatively. The 10-year freedom from angiography showing SV segment occlusion was 89% with a median time to angiography of 2.3 years (nine patients). The number of distal anastomoses was the only independent predictor of SV segment occlusion HR per anastomosis=0.26 (p=0.01). In five sequential grafts to the circumflex and right coronary systems, the IMA portion of the graft remained patent following SV segment occlusion. CONCLUSIONS: Graft patency is improved by a greater number of coronary artery anastomoses. PMID- 25456499 TI - MST3 kinase phosphorylates TAO1/2 to enable Myosin Va function in promoting spine synapse development. AB - Mammalian Sterile 20 (Ste20)-like kinase 3 (MST3) is a ubiquitously expressed kinase capable of enhancing axon outgrowth. Whether and how MST3 kinase signaling might regulate development of dendritic filopodia and spine synapses is unknown. Through shRNA-mediated depletion of MST3 and kinase-dead MST3 expression in developing hippocampal cultures, we found that MST3 is necessary for proper filopodia, dendritic spine, and excitatory synapse development. Knockdown of MST3 in layer 2/3 pyramidal neurons via in utero electroporation also reduced spine density in vivo. Using chemical genetics, we discovered thirteen candidate MST3 substrates and identified the phosphorylation sites. Among the identified MST3 substrates, TAO kinases regulate dendritic filopodia and spine development, similar to MST3. Furthermore, using stable isotope labeling by amino acids in culture (SILAC), we show that phosphorylated TAO1/2 associates with Myosin Va and is necessary for its dendritic localization, thus revealing a mechanism for excitatory synapse development in the mammalian CNS. PMID- 25456501 TI - Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult. AB - Ankyrin-B protein is involved in regulating expression and localisation of cardiac ion channels and transporters. Mutations of the ANK2 gene in the rare condition Ankyrin-B syndrome result in loss of function of the ankyrin-B protein which in turn leads to abnormal regulation of intracellular sodium and calcium and a predisposition to cardiac arrhythmia including torsades de pointes. We describe a rare case of this condition characterised by sinus node dysfunction, atrial fibrillation and prolonged QT syndrome in a young patient with a family history of sudden death. The management of Ankyrin-B syndrome may include avoidance of QT prolonging medications, insertion of a permanent pacemaker for sinus node dysfunction, or a cardioverter defibrillator for those at high-risk of sudden death from torsades de pointes. PMID- 25456500 TI - Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer's disease. AB - Dendritic structure critically determines the electrical properties of neurons and, thereby, defines the fundamental process of input-to-output conversion. The diversity of dendritic architectures enables neurons to fulfill their specialized circuit functions during cognitive processes. It is known that this dendritic integrity is impaired in patients with Alzheimer's disease and in relevant mouse models. It is unknown, however, whether this structural degeneration translates into aberrant neuronal function. Here we use in vivo whole-cell patch-clamp recordings, high-resolution STED imaging, and computational modeling of CA1 pyramidal neurons in a mouse model of Alzheimer's disease to show that structural degeneration and neuronal hyperexcitability are crucially linked. Our results demonstrate that a structure-dependent amplification of synaptic input to action potential output conversion might constitute a novel cellular pathomechanism underlying network dysfunction with potential relevance for other neurodegenerative diseases with abnormal changes of dendritic morphology. PMID- 25456503 TI - Extracellular matrix biomarker, fibulin-1 and its association with soluble uPAR in a bi-ethnic South African population: the SAfrEIC study. AB - BACKGROUND: Fibulin-1 and soluble urokinase-type plasminogen activator receptor (suPAR) emerged as mediators in the development of sclerotic disease. SuPAR along with C-reactive protein (CRP) and albumin delineate inflammatory processes associated with extracellular matrix turnover in atherosclerosis. We explored the independent relationship of fibulin-1 with these inflammatory markers in a bi ethnic South African population. METHODS: This study included 290 Africans (men: n=130 and women: n=160) and 343 sex- and age-matched Caucasians (men: n=160 and women: n=183). Serum fibulin-1, suPAR, CRP and albumin levels were measured along with conventional cardiovascular and metabolic variables. RESULTS: In both single and age-adjusted regression analyses, fibulin-1 correlated with both suPAR and albumin in African men and with suPAR in Caucasian men. These findings were absent in women. In multivariate regression analysis, these associations were confirmed in African men (R(2)=0.22; beta=0.329; p<0.001) and Caucasian men (R(2)=0.14; beta=0.234; p=0.008). Fibulin-1 independently associated positively with suPAR in all men, but inversely with albumin in African men only. CONCLUSIONS: These results are indicating the presence of potential subclinical inflammation (suPAR) within the extracellular matrix of endothelial tissue, contributing to the potential onset of cardiac fibrosis or vascular sclerosis among these South African men with lower albumin levels. PMID- 25456504 TI - Transapical transcatheter valve-in-valve replacement for deteriorated mitral valve bioprosthesis without radio-opaque indicators: the "invisible" mitral valve bioprosthesis. AB - In view of the high number of bioprosthetic valves implanted during the past 30 years, an increasing number of patients are coming to medical attention because of degenerated bioprostheses. Transcatheter aortic valve-in-valve implantation has been described as a less invasive alternative to re-operation to treat severe structural valve deterioration. As far as degenerated mitral valve bioprostheses are concerned, transcatheter transapical mitral valve-in-valve replacement (TMVR) has been less commonly performed, but may also become a viable alternative to re do replacement surgery. We describe treatment of a degenerated bioprosthetic mitral valve, characterised by complete absence of any radio-opaque landmarks making the TMVR procedure very challenging. PMID- 25456505 TI - The Australian and New Zealand cardiac pacemaker and implantable cardioverter defibrillator survey: calendar year 2013. AB - BACKGROUND: A pacemaker (PM) and implantable cardioverter-defibrillator (ICD) survey was undertaken in Australia and New Zealand for calendar year 2013. RESULTS AND CONCLUSIONS: For 2013, PMs sold as new implants in Australia was 15,203 (12,523 in 2009) and implanted in New Zealand were 1,641 (1,277 in 2009). The number of new PM implants per million population 652 for Australia (565 were in 2009) and 367 for New Zealand (299 in 2009). Although PM replacements rose in New Zealand, there was a fall in Australia as a result of improved power source service life. Pulse generator types sold in Australia were predominantly dual chamber 74% (71% in 2009) and implanted in New Zealand 59% (54% in 2009). There were 661 biventricular PMs implanted in Australia (446 in 2009) and 83 in New Zealand (45 in 2009). Transvenous pacing leads were overwhelmingly bipolar with preferences for active fixation leads, although, since 2009, there has been a minor resurgence in Australia of passive fixation lead usage in the atrium from 20 to ~24%. There was also a marked increase in the ICD implants with 3904 new implants in Australia (3555 in 2009) and 423 in New Zealand (329 in 2009). The new ICD implants per million population were 167 for Australia (160 in 2009) and 95 for New Zealand (77 in 2009). Biventricular ICD implants increased significantly in both Australia (2211) and New Zealand (118). PMID- 25456506 TI - Catheter ablation of atrial fibrillation in patients with concomitant left ventricular impairment: a systematic review of efficacy and effect on ejection fraction. AB - INTRODUCTION: Catheter ablation of atrial fibrillation (AF) is an established rhythm control strategy; however, the impact of co-existing LV systolic dysfunction (LVSD) on ablation success is less well understood. This systematic review compiles the outcomes of catheter ablation of atrial fibrillation in patients with LVSD. METHODS: An electronic database (Pubmed, Scopus, Embase) search using the keywords 'atrial fibrillation AND ablation AND (ventricular dysfunction OR heart failure OR cardiomyopathy)' was performed for English scientific literature up to 01/01/2014. 2484 references were retrieved and evaluated for relevance by three reviewers. Reviews and reference lists of retrieved articles were also examined to ensure all relevant studies were included. Data was extracted from 19 studies, including a total of 914 patients. RESULTS: Single-procedure success in LVSD patients for AF ablation was 56.5% (95% CI: 48%-64%). Overall multiple-procedure (including the use of anti-arrhythmic drugs) in LVSD patients for AF ablation was 81.8% (95% CI: 75%-87%). The mean increase in LVEF following AF ablation was 13.3% (95% CI: 10.8%-15.9%). Seven studies reported improvements in exercise capacity and quality of life information using standardised criteria. The pooled rate of serious adverse events was 5.5% (95% CI: 3.7%-8.1%). CONCLUSIONS: Catheter ablation may be an effective therapy in AF patients with left ventricular systolic impairment, and can be associated with improvements in left ventricular function, quality of life, exercise capacity, and modest rates of serious adverse events. PMID- 25456507 TI - Shorter ischaemic time and improved survival with pre-hospital STEMI diagnosis and direct transfer for primary PCI. AB - BACKGROUND: We sought to determine if our regional program for pre-hospital STEMI diagnosis and direct transfer for primary PCI (PPCI) was associated with shorter ischaemic times and improved survival compared with ED diagnosis. METHODS: STEMI diagnosis was made at the scene by pre-hospital ECG or in local EDs depending on patient presentation. Ambulance ECGs were transmitted to our ED for cath lab activation. Patient variables and outcomes at 12 months were recorded. RESULTS: We treated 782 consecutive patients with PPCI during January 2008-June 2013. Cath lab activation was initiated prior to hospital arrival (pre-hospital) in 24% of cases and by ED in 76% of cases. Median total ischaemic time was 154 min for pre hospital and 211 minutes for ED patients (p<0.0001). Mortality at 12 months was 7.9% in the ED group compared with 3.7% in the pre-hospital group (p=0.036). On multivariate Cox regression analysis including baseline and procedural variables, pre-hospital activation remained an independent predictor of mortality (HR 0.45, 95% CI 0.20-1.0, p=0.03). CONCLUSIONS: Pre-hospital diagnosis of STEMI and direct transfer to the cath lab reduced total ischaemic time by 57 minutes and mortality by >50% following PPCI. Further efforts are needed to increase the proportion of STEMI patients treated using this strategy. PMID- 25456508 TI - Sudden cardiac death in the young: what we know, what we don't know and what we need to do. PMID- 25456509 TI - The effect of 2100 MHz radiofrequency radiation of a 3G mobile phone on the parotid gland of rats. AB - PURPOSE: We aimed to evaluate the effect of 2100 MHz radiofrequency radiation on the parotid gland of rats in short and relatively long terms. MATERIAL AND METHODS: Thirty Wistar albino rats were divided into four groups. Groups A and B served as the control groups (for 10 days and 40 days, respectively), and each group included six rats. Groups C and D were composed of nine rats each, and they were the exposure groups. The rats were exposed to 2100 MHz radiofrequency radiation emitted by a generator, simulating a third generation mobile phone for 6 hours/day, 5 days/week, for 10 or 40 days. Following exposure, the rats were sacrificed and parotid glands were removed. Histopathological and biochemical examinations were performed. RESULTS: Although there were no histopathological changes in the control groups except for two animals in group A and three animals in group B, the exposure groups C (10 days) and D (40 days) showed numerous histopathological changes regarding salivary gland damage including acinar epithelial cells, interstitial space, ductal system, vascular system, nucleus, amount of cytoplasm and variations in cell size. The histopathological changes were more prominent in group D compared to group C. There was statistically significant different parameter regarding variation in cell size between the groups B and D (p=0.036). CONCLUSION: The parotid gland of rats showed numerous histopathological changes after exposure to 2100 MHz radiofrequency radiation, both in the short and relatively long terms. Increased exposure duration led to an increase in the histopathological changes. PMID- 25456510 TI - Quality of life outcomes after functional endoscopic sinus surgery for nasal polyposis. AB - PURPOSE: The objective of this study is to determine the results of functional endoscopic sinus surgeries (FESS) for chronic rhinosinusitis with polyps and assess the association between surgery and specific quality of life outcomes. MATERIALS AND METHODS: A prospective study was performed in a tertiary referral center. Fifty-eight patients affected by chronic rhinosinusitis with nasal polyposis underwent endoscopic sinus surgery from January 2011 to April 2013 and followed for 1 year. The rhinosinusitis disability index (RSDI), a validated disease-specific instrument, was used to quantify the patient's symptoms before and 12 months after surgery. RESULTS: A strongly statistically significant reduction was seen between the mean scores on RSDI before and after FESS [86.43 (IQR=16.10) versus 51.16 (IQR=18.95), Wilcoxon signed-rank test, p<0.0001]. In multiple regression model, only four preoperative characteristics predicted the outcomes. The high mucosal eosinophilia density was the most important preoperative predictor. CONCLUSIONS: There is evidence which supports the efficacy of FESS to improve long-term QOL outcomes in patients with CRS. The mucosal eosinophilia density and prior sinus surgery appeared to be the most predictive factors of surgical outcomes. PMID- 25456511 TI - The one-cut meatoplasty: novel surgical technique and outcomes. AB - PURPOSE: To present the surgical technique and clinical outcomes of a novel modification to conventional meatoplasty. MATERIALS AND METHODS: All consecutive patients undergoing canal wall down tympanomastoidectomy incorporating the one cut meatoplasty technique between January 2009 and February 2013 were evaluated. Primary outcome measures included meatal stenosis requiring revision surgery, frequency of drainage beyond 2months postoperatively and results of a composite patient questionnaire incorporating the Chronic Ear Survey. RESULTS: Twenty-eight of 36 (78%) eligible patients completed a questionnaire and were included. All ears underwent canal wall down tympanomastoidectomy utilizing the one-cut meatoplasty technique. At a mean follow-up of 38.0months, the average Chronic Ear Survey score was 78.6+/-2.6 points. There was only one case of postoperative meatal stenosis. Intermittent otorrhea developed in 14.3% of cases but was remedied by conservative measures including in-office cleaning, ototopical therapy and water precautions. Eighty-nine percent of patients denied any self consciousness about the aesthetic appearance of the ear. CONCLUSIONS: The one-cut meatoplasty is an effective alternative to traditional techniques that is simple to perform. The results of the Chronic Ear Survey indicate that the one-cut meatoplasty supports a stable and healthy, open cavity with functional results that compare favorably to other series evaluating canal wall down tympanomastoidectomy with traditional meatoplasty. Additionally, patients report high satisfaction with the appearance of their ear, and all hearing aid users could continue to utilize a hearing aid without feedback, pain, or other difficulties related to poor fitting. PMID- 25456513 TI - Prevention of airway fires: testing the safety of endotracheal tubes and surgical devices in a mechanical model. AB - OBJECTIVES: This study was designed to assess the ability of carbon dioxide (CO2) lasers and radiofrequency ablation devices (Coblator) (ArthoCare Corporation, Sunnyvale, CA) to ignite either a non-reinforced (polyvinylchloride) endotracheal tube (ETT) or an aluminum and fluoroplastic wrapped silicon ("laser safe") ETT at varying titrations of oxygen in a mechanical model of airway surgery. METHODS: Non-reinforced and laser safe ETTs were suspended in a mechanical model imitating endoscopic airway surgery. A CO2 laser set at 5-30 watts was fired at the ETT at oxygen concentrations ranging from 21% to 88%. The process was repeated using a radiofrequency ablation (RFA) device. All trials were repeated to ensure accuracy. RESULTS: The CO2 laser ignited a fire when contacting a non-reinforced ETT in under 2 seconds at oxygen concentrations as low as 44%. The CO2 laser could not ignite a laser safe ETT under any conditions, unless it struck the non reinforced distal tip of the ETT. With the RFA, a fire could not be ignited with either reinforced or non-reinforced ETTs. CONCLUSIONS: RFA presents no risk of ignition in simulated airway surgery. CO2 lasers should be utilized with a reinforced ETT or no ETT, as fires can easily ignite when lasers strike a non reinforced ETT. Decreasing the fraction of inspired oxygen reduces the risk of fire. PMID- 25456512 TI - Diagnostic advantages of intratympanically gadolinium contrast-enhanced magnetic resonance imaging in patients with bilateral Meniere's disease. AB - PURPOSE: The aim of the study is to probe whether intratympanically gadolinium contrast-enhanced three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging, together with magnetic resonance imaging scoring system of the perilymphatic space, had advantages in diagnosing patients with bilateral Meniere's disease. MATERIALS AND METHODS: Eight patients diagnosed as 'definite' bilateral Meniere's disease and two patients considered as 'possible' Meniere's disease were selected for the current study. All ten patients underwent caloric test, vestibular evoked myogenic potential and intratympanically gadolinium enhanced magnetic resonance imaging. The perilymphatic space of scanned images were analyzed to investigate the presence of endolymphatic hydrops. The positive rates (bilaterally abnormal patients/patients tested) of the three examinations in the eight patients with bilateral Meniere's disease were calculated respectively. We also selected eight patients with unilateral Meniere's disease as the control group by the method of simple random sampling without replacement. RESULTS: According to the magnetic resonance imaging scoring system, 100% (8/8) of the patients with bilateral Meniere's disease had bilateral endolymphatic hydrops. The positive rates of vestibular evoked myogenic potential and caloric test were 50% (4/8) and 25% (2/8), respectively. There was a significant difference among the positive rates of the three examinations (P<.05). Two patients with 'possible' Meniere's disease had bilateral endolymphatic hydrops by magnetic resonance imaging. Eight patients with unilateral Meniere's disease displayed endolymphatic hydrops of the affected ears. CONCLUSIONS: Intratympanically gadolinium-enhanced magnetic resonance imaging has a relatively high positive rate of exhibiting bilateral endolymphatic hydrops. This technique with the magnetic resonance imaging scoring system is valuable when diagnosing bilateral Meniere's disease. PMID- 25456514 TI - Retromolar trigone squamous cell carcinoma treated with radiotherapy alone or combined with surgery: a 10-year update. AB - PURPOSE/OBJECTIVES: Treatment outcomes were analyzed for patients who received radiotherapy for squamous cell carcinoma of the retromolar trigone at a single institution. MATERIALS/METHODS: We reviewed the medical records of 110 patients treated with radiotherapy alone (n=36) or radiotherapy combined with surgical resection of the primary tumor (n=74) between June 1966 and October 2013. The median follow-up was 4.5years for all patients and 11.8years for living patients (range, 1.3-23.5years). RESULTS: The 5-year local-regional control rates after definitive radiotherapy versus surgery and radiotherapy for stages I-III were 52% and 89% and for stage IV they were 46% and 58%, respectively. The 5-year cause specific survival rates after definitive radiotherapy compared with surgery and radiotherapy for stages I-III were 57% and 82% and for stage IV they were 45% and 43%, respectively. Multivariate analyses revealed that the likelihood of cure was better with surgery and radiotherapy compared with radiotherapy alone (p=0.041). CONCLUSION: Patients treated with surgery and radiotherapy had a better chance of cure than those treated with radiotherapy alone. Complications of treatment were common in both groups but more common in patients who underwent surgery. PMID- 25456515 TI - Erythrocyte membrane antigen frequencies in patients with Type II congenital smell loss. AB - OBJECTIVE: The objective of this study was to determine whether there are genetic factors associated with Type II congenital smell loss. STUDY DESIGN: The expression frequencies of 16 erythrocyte antigens among patients with Type II congenital smell loss were determined and compared to those of a large control group. METHODS: Blood samples were obtained from 99 patients with Type II congenital smell loss. Presence of the erythrocyte surface antigens A, B, M, N, S, s, Fy(a), Fy(b), D, C, c, E, e, K, Jk(a), and Jk(b) was analyzed by blood group serology. Comparisons of expression frequencies of these antigens were made between the patients and a large control group. RESULTS: Patients tested for the Duffy b antigen (Fy(b) haplotype) exhibited a statistically significant 11% decrease in expression frequency compared to the controls. There were no significant differences between patients and controls in the expression frequencies for all other erythrocyte antigens (A, B, M, N, S, s, Fy(a), D, C, c, E, e, K, Jk(a), or Jk(b)). CONCLUSIONS: These findings describe the presence of a previously unrevealed genetic tendency among patients with Type II congenital smell loss related to erythrocyte surface antigen expression. The deviation in expression rate of Duffy b suggests a target gene and chromosome region in which future research into this form of congenital smell loss may reveal a more specific genetic basis for Type II congenital smell loss. PMID- 25456516 TI - Therapeutic effect of combined steroid-lipoprostaglandin E1 for sudden hearing loss: a propensity score-matched analysis. AB - OBJECTIVES: The aim of this study is to analyze the synergistic effect of combined steroid-lipoprostaglandin E1 for the treatment of sudden hearing loss. METHODS: A prospective observational, non-randomized study with a historical cohort was performed at a university hospital. Between 2005 and 2012, 421 patients with idiopathic sudden sensorineural hearing loss were enrolled in this study and treated with combined steroid-lipoprostaglandin E1 treatment. Additionally, 132 patients were prospectively enrolled and treated with steroid treatment alone between January 2013 and March 2014. After performing a propensity score-matched analysis, final hearing levels and the degree of recovery were compared according to treatment options. RESULTS: A total of 240 patients were enrolled after propensity score-matching, with 180 patients classified as combined steroid-lipoprostaglandin E1 treatment group (group I) and 60 patients as steroid treatment alone group (group II). The final hearing level (35.56+/-34.64dB) in group I was not significantly different from that in group II (34.64+/-24.67dB) (p<0.05). Logistic regression analysis revealed that the combined treatment did not influence recovery, and the probability of recovery was 1.881 times higher in the absence of dizziness (95% confidence interval: 1.022-3.464, p=0.042), and 1.026 times higher in patients with better hearing in healthy ears (95% confidence interval: 1.010-1.041, p=0.001). CONCLUSION: Compared to steroid treatment alone, combined steroid-lipoprostaglandin E1 treatment failed to improve sudden hearing loss. PMID- 25456518 TI - Ansa to recurrent laryngeal neurorrhaphy in the setting of laryngeal nerve sacrifice: a cadaveric study to evaluate a reconstructive option. AB - OBJECTIVE: In certain cases, the recurrent laryngeal nerve (RLN) has to be sacrificed. This often results in an inadequate length of residual RLN to be used in a reinnervation procedure. We investigated the length of the distal stump of the RLN from the inferior border of the inferior pharyngeal constrictor muscle (IPCM), where it is frequently compromised, to its entrance into the larynx. Our objective was to determine whether this residual nerve stock was sufficient for margin clearance and neurorrhaphy. STUDY DESIGN: Cadaveric study METHODS: Recurrent laryngeal nerves were identified in fresh frozen cadavers. The IPCM was divided, revealing the distal stump of the RLN, which was measured. RESULTS: Dissection was performed in 20 cadavers (40 nerves). The average length of the right RLN and the left RLN from the IPCM until it entered the larynx was 15mm and 14mm, respectively. All residual RLN remnants were of sufficient length for neurorrhaphy. CONCLUSION: Concomitant RLN reinnervation procedures in the setting of nerve sacrifice are not well described. A barrier to reinnervation in this setting may be insufficient residual nerve length for a neurorrhaphy. Often, when the RLN is sacrificed intraoperatively either iatrogenically or due to tumor invasion, it is close to the cricoarytenoid joint, at the inferior border of the IPCM. This study demonstrates that by splitting the IPCM, sufficient length can be obtained for neurorrhaphy. PMID- 25456517 TI - Extra-nodal B-cell non-Hodgkin's lymphomas of the head and neck: a study of 68 cases. AB - OBJECTIVES: The objectives of this study are to describe the distinctive characteristics of extra-nodal B-cell non-Hodgkin's lymphomas (BNHLs) located in the head and neck in a series of patients, to discuss patient survival, and to compare the oral versus the non-oral locations of the extra-nodal BNHLs of the head and neck. MATERIAL AND METHODS: We studied 68 patients with BNHL of the head and neck. We analyzed the clinical and survival characteristics. Additionally, we performed Kaplan-Meier and Cox regression analyses to determine the influence of the different factors on survival. RESULTS: This study included 68 non-nodal lymphomas; 30 lymphomas (31.9%) were located intraorally, with the gingiva as the most frequent location. The oral lymphomas in stages 1 and 2 showed a prevalence of 60% (18/30). The Kaplan-Meier analysis showed that the stage of disease and the oral versus non-oral extranodal lymphomas were significant prognostic factors (p<0.05). However, the multivariate Cox analysis indicated that only complete remission and oral versus non-oral location were significant prognostic factors (p<0.01). CONCLUSIONS: The gingiva was the most common location of the intraoral lymphomas. Complete remission and non-oral location were the only significant survival factors in the multivariate Cox regression analysis. PMID- 25456520 TI - Resting state networks in major depressive disorder. AB - Resting state functional magnetic resonance imaging (fMRI) examines the spontaneous low frequency neural activity of the brain to reveal networks of correlated neural activity. A number of different methodologies, each with its own advantages and disadvantages, have been used to examine networks of neural activity that may be related to clinical presentation. Major depressive disorder (MDD) research has largely focused on the default mode network (DMN), which is most active at rest and may relate to negative rumination. However, other networks can be discerned in the resting state such as salience and affective and cognitive control networks, all of which may be relevant to MDD psychopathology. This article reviews the rapidly increasing literature on resting state networks. A number of state- and trait-dependent abnormalities have been reported in MDD in a wide variety of regions including the cerebellum, lingual gyrus, anterior cingulate cortex (ACC), middle frontal gyrus (MFG), dorsolateral prefrontal cortex (dlPFC), amygdala and insula. Current and chronic medication is often a potential confound. Few trials have examined the immediate or delayed effects of antidepressants on resting state networks. This article presents a novel approach to the analysis of drug effects, the identification of signatures of efficacy, and thus for drug development. PMID- 25456519 TI - Iron increases APP translation and amyloid-beta production in the retina. AB - Age-related macular degeneration (AMD) is the most common cause of blindness among older adults in developed countries, and retinal iron accumulation may exacerbate the disease. Iron can upregulate the production of amyloid precursor protein (APP). Since amyloid-beta (Abeta), a byproduct of APP proteolysis, is found in drusen, the histopathological hallmark of AMD, we tested the role of iron in regulating APP and Abeta levels in the retinal pigment epithelial cell line ARPE-19. We found that treatment with ferric ammonium citrate (FAC) increases APP at the translational level. FAC treatment also results in increased generation of APP C-terminal fragments C83 and C99, the products of APP proteolysis by alpha- and beta-secretase, respectively, as well as levels of Abeta42, a highly aggregative amyloid species. Additionally, retinal tissue sections from a patient with aceruloplasminemia, a disease causing iron overload in the retinal pigment epithelium (RPE), showed increased Abeta deposition in the RPE and drusen. Overall, our results suggest that RPE iron overload could contribute to Abeta accumulation in the retina. PMID- 25456522 TI - Obsessive-compulsivity and working memory are associated with differential prefrontal cortex and insula activation in adolescents with a recent diagnosis of an eating disorder. AB - The role of rumination at the beginning of eating disorder (ED) is not well understood. We hypothesised that impulsivity, rumination and restriction could be associated with neural activity in response to food stimuli in young individuals with eating disorders (ED). We measured neural responses with functional magnetic resonance imaging (fMRI), tested working memory (WM) and administered the eating disorders examination questionnaire (EDE-Q), Barratt impulsivity scale (BIS-11) and obsessive-compulsive inventory (OCI-R) in 15 adolescent females with eating disorder not otherwise specified (EDNOS) (mean age 15 years) and 20 age-matched healthy control females. We found that EDNOS subjects had significantly higher scores on the BIS 11, EDE-Q and OCI-R scales. Significantly increased neural responses to food images in the EDNOS group were observed in the prefrontal circuitry. OCI-R scores in the EDNOS group also significantly correlated with activity in the prefrontal circuitry and the cerebellum. Significantly slower WM responses negatively correlated with bilateral superior frontal gyrus activity in the EDNOS group. We conclude that ruminations, linked to WM, are present in adolescent females newly diagnosed with EDNOS. These may be risk factors for the development of an eating disorder and may be detectable before disease onset. PMID- 25456521 TI - Relationship between amygdala volume and emotion recognition in adolescents at ultra-high risk for psychosis. AB - Amygdala volume has been proposed as a neural risk biomarker for psychotic illness, but findings in the ultra-high risk for psychosis (UHR) population have been somewhat inconsistent, which may be related to underlying social cognitive abilities. The current study investigated whether amygdala volumes were related to emotion-recognition impairments in UHR individuals, and whether volumes differed by sex. Secondary aims were to assess whether (a) emotion-recognition performance was associated with interhemispheric amygdala volume asymmetry and (b) amgydala volume and volume asymmetry acted as a mediator between emotion recognition and outcome measures. The amygdala was manually delineated from magnetic resonance images for 39 UHR individuals who had also completed facial and prosody emotion-recognition tasks. Partial correlations were conducted to examine associations between amydgala volume/asymmetry and recognition of negative emotions. Mediation analyses were conducted using regression and bootstrapping techniques. Amygdala volume was positively correlated with sadness emotion recognition, in particular prosody, for females only. Left amygdala volume mediated the effect of sadness recognition on depressive symptoms, negative symptoms, overall psychopathology, and global functioning in females. Findings suggest a complex relationship between emotion recognition, the structure of the amygdala and illness outcome, where recognition of sadness appears to be the precipitator of this relationship in UHR females. Further research is needed to determine illness specificity and to confirm our sex- and emotion-specific results. PMID- 25456523 TI - Recurrence analysis of the EEG during sleep accurately identifies subjects with mental health symptoms. AB - Analysis of brain recurrence (ABR) is a novel computational method that uses two variables for sleep depth and two for sleep fragmentation to quantify temporal changes in non-random brain electrical activity. We postulated that ABR of the sleep-staged EEG could identify an EEG signature specific for the presence of mental health symptoms. Using the Mental Health Inventory Questionnaire (MHI-5) as ground truth, psychological distress was assessed in a study cohort obtained from the Sleep Heart Health Study. Subjects with MHI-5 <50 (N=34) were matched for sex, BMI, age, and race with 34 subjects who had MHI-5 scores >50. Sixteen ABR markers derived from the EEG were analyzed using linear discriminant analysis to identify marker combinations that reliably classified individual subjects. A biomarker function computed from 12 of the markers accurately classified the subjects based on their MHI-5 scores (AUROC=82%). Use of additional markers did not improve classification accuracy. Subgroup analysis (20 highest and 20 lowest MHI-5 scores) improved classification accuracy (AUROC=89%). Biomarker values for individual subjects were significantly correlated with MHI-5 score (r=0.36, 0.54 for N=68, 40, respectively). ABR of EEGs obtained during sleep successfully classified subjects with regard to the severity of mental health symptoms, indicating that mood systems were reflected in brain electrical activity. PMID- 25456524 TI - Feeling but not caring: empathic alteration in narcissistic men with high psychopathic traits. AB - Psychopathy is a personality disorder characterized by specific interpersonal affective deficits and social deviance often marked by reduced empathy and decreased affective response to the suffering of others. However, recent findings in community samples suggest that the somatosensory resonance to other's pain measured with electroencephalography (EEG) is increased by psychopathic traits. This study aimed at comparing both the response to physical pain and the observation of pain being inflicted to another person in individuals with clinically significant psychopathic traits, namely patients with severe narcissistic personality disorder (NPD, n=11), and community controls (CC, n=13). The gating of somatosensory responses to a tactile steady-state stimulation (25 Hz) during the observation of pain-evoking and non-painful visual stimuli of hands was measured using EEG. Pain thresholds were assessed with a quantitative sensory testing (QST) battery. NPD compared with CC subjects showed similar thermal pain thresholds, but significantly higher pain pressure thresholds (PPT). Significantly greater somatosensory gating (SG) during the anticipation and the observation of pain in others was observed in NPD compared with CC subjects, but this difference was not associated with differences in self-pain perception. SG to pain observation was positively correlated with the Impulsivity-Egocentricity (IE) dimension of psychopathy. These findings demonstrated a stronger somatosensory resonance in the high psychopathic trait NPD group that suggests an increased somatic representation of observed pain despite lower dispositional empathy. PMID- 25456525 TI - Myocardial calcifications: pathophysiology, etiologies, differential diagnoses, and imaging findings. AB - Myocardial calcifications are not uncommonly encountered by the cardiac imager and may have a range of imaging appearances, from focal calcific deposits to diffuse myocardial involvement. A number of pathological processes can both cause and result from myocardial calcification; therefore, accurate identification and characterization are important. This pictorial essay will review the mechanisms, etiologies, imaging features, and differential diagnoses of myocardial calcification with imaging examples. PMID- 25456526 TI - On the sociology of Mycobacterium tuberculosis. PMID- 25456527 TI - Fraction of exhaled nitric oxide in healthy Chilean schoolchildren aged 8-15 years. AB - BACKGROUND: The fraction of exhaled nitric oxide (FENO) measured using portable devices is increasingly used in the clinical setting to assess asthmatic children. However, there is little and variable information on the reference values obtained using these devices in healthy children from different populations. METHODS: 190 healthy non-smoker children (8-15 years old) were randomly selected from public schools participating in this study. The objective was to determine FENO reference values for healthy Chilean schoolchildren. Healthy individuals were identified by medical interview and parent questionnaire on the use of asthma medications, and current and past symptoms of asthma, rhinoconjunctivitis and eczema. FENO was measured at schools using a portable device with electrochemical sensor (NIO MINOX). Reference values of FENO were expressed as geometric mean and upper limit of the 95% reference interval (right sided). The relationship of FENO with gender, age, height, body mass, and other factors was assessed by multiple regression, and the difference between groups was contrasted by ANOVA. RESULTS: The FENO geometric mean was 15.4ppb with a 95% reference interval upper limit (right-sided), of 27.4ppb (90%CI 25.6-29.2). The 5th and 95th percentiles were 9.0ppb and 28.0ppb, respectively. Height was the only factor significantly associated to FENO (p=0.022). There was no significant difference in mean FENO regarding age, gender, weight, parent reported rhinoconjunctivitis and eczema. CONCLUSION: This study suggests that FENO values higher than 27ppb are likely to be abnormal and would reflect airway inflammation in children as those in the present study. PMID- 25456528 TI - When should the skin prick tests not be performed? PMID- 25456529 TI - Many respiratory viruses have temporal association with meningococcal disease. AB - BACKGROUND: Previous ecological studies have shown a temporal and spatial association between influenza epidemics and meningococcal disease (MNG); however, none have examined more than two respiratory viruses. METHODS: Data were obtained in Chile between 2000 and 2005 on confirmed cases of MNG and all confirmed cases of respiratory viruses (influenza A and B; parainfluenza; adenovirus; and respiratory syncytial virus [RSV]). Both variables were divided by epidemiological weeks, age range, and regions. Models of transference functions were run for rates of MNG. RESULTS: In this period, 1022 reported cases of MNG and 34,737 cases of respiratory virus were identified (25,137 RSV; 4300 parainfluenza; 2527 influenza-A; 356 influenza-B; and 2417 adenovirus). RSV was the major independent virus temporally associated to MNG (it appears one week before MNG), followed by parainfluenza, influenza-B, adenovirus, and influenza-A. CONCLUSIONS: The rate of MNG in Chile is temporally associated to all of the respiratory viruses studied, but with variability according age range, and regions. PMID- 25456530 TI - Respiratory allergy in immigrants to a highly industrialised area in Italy according to area of origin and time period. AB - BACKGROUND: Migrants from developing to Western countries tend to become more sensitised to host than to origin country allergens, although substantial changes in migration patterns have occurred in recent decades. METHODS: We investigated adult immigrants with respiratory allergy, first tested for allergic sensitisation between 1985 and 2012 in a highly industrialised area in Italy. A comparison was made of the sensitisation pattern between immigrants and a random sample of native-born subjects affected by a respiratory allergy, and among immigrants according to macro-region of origin and time period. RESULTS: Between 1985 and 2012, 480 immigrants with respiratory allergy had a first positive allergy test. Immigrants were sensitised mainly to grass (67.1%), house dust mites (HDM) (38.5%) and birch (27.5%), with a pattern of sensitisation very similar to that observed in Italians (native-born). An increase in the proportion of subjects with asthma and of subjects with polysensitisation was observed from the first (1985-2002) to the middle (2003-2007) and the most recent period (2008 2012). In recent years, the proportion of subjects with polysensitisation in immigrants is higher than in Italians (native-born) (53.3% vs. 40.1%). Among immigrants, the risk of sensitisation to grass was higher in those from Sub Saharan Africa (odds ratio, OR=2.76) and Latin America (OR=2.49), whereas risk of sensitisation to HDM was higher among immigrants from South Asia (OR=2.71), compared to immigrants from Eastern Europe. CONCLUSIONS: Immigrants develop multiple sensitisations more frequently than native-born people, and are especially sensitised to local allergens; the country of origin seems to play a role. PMID- 25456531 TI - Contact urticaria on eczematous skin by kiwifruit allergy. In vivo component resolved diagnosis. AB - BACKGROUND: Kiwifruit allergy has been responsible for a variety of clinical manifestations, ranging from mild reactions, such as localised oral symptoms, to severe systemic symptoms, such as anaphylaxis. No cases of isolated contact urticaria (ICU) due to IgE-mediated allergy to kiwifruit have been reported in the literature so far. Here we describe the first three cases of ICU due to kiwi and we hypothesise about a kiwifruit allergen not described yet. METHODS: Using the available in vivo allergy tests, we performed a component-resolved diagnosis to detect the allergen involved. All the patients underwent prick-by-prick with raw and boiled kiwi pulp and latex glove, skin prick test with commercial extracts of kiwifruit, birch, latex, palm profilin and peach lipid transfer protein, rub test with raw and boiled kiwi and oral food challenges with the raw fruit. RESULTS: We found that, in our patients, the kiwifruit allergen responsible for ICU is thermolabile, gastrosensitive, and it does not show any of the most common kiwi-attributed cross-reactivity (latex, birch, profiling and lipid transfer protein). None of the 13 kiwifruit allergens already known shows all these features. CONCLUSIONS: Kiwifruit allergy can also occur with ICU, probably due to a native protein that is not yet identified. In this case the elimination diet is not required. PMID- 25456532 TI - Comparison of major lymphocyte subpopulations and recent thymic emigrants in patients with ataxia telangiectasia and age-matched healthy groups. AB - BACKGROUND: Ataxia telangiectasia (A-T) is a genetic disorder caused by the homozygous mutation of the A-T mutated gene. It is frequently associated with variable degrees of cellular and humoral immunodeficiency. However, the immune defects in A-T patients are not well characterized. To the best of our knowledge, no studies have focused on the major lymphocyte subpopulations and recent thymic emigrants of A-T patients in comparison with age-matched healthy controls. METHODS: Following the European Society for Immunodeficiencies criteria, 17 patients diagnosed with A-The, and 12 age-matched healthy children were assigned to the study. Both patients and healthy controls were grouped as 1-5, 6-10, 11 15, and 15+ years. By using a flow cytometer, major lymphocyte subpopulations and CD4+CD45RA+CD31+ recent thymic emigrants were determined as percentage and absolute cell numbers and compared. RESULTS: No significant differences in all lymphocyte subpopulations were observed between the age groups of A-T patients. Compared to the healthy controls, there was a decrease in T cells, effector memory T4 cells, B cells, naive B cells, naive T4 cells, switched B cells, and recent thymic emigrants and an increase in active T8 cells and non-switched B cells in the percentage and absolute number of some cell populations in the A-T group. CONCLUSIONS: This study showed that effector functions in some cell lymphocyte populations were decreased in A-T patients. PMID- 25456533 TI - Hospital admission due to respiratory viral infections in moderate preterm, late preterm and term infants during their first year of life. AB - BACKGROUND: Respiratory viral infections are a major cause of hospitalisation in infants <1 year and might cause severe symptoms in preterm infants. Our aim was to analyse admissions due to respiratory infections in moderate, late and term infants, and to identify risk factors for hospitalisation in preterm versus term. METHODS: Prospective study in a cohort of moderate and late preterm, and term infants born between October/2011 and December/2012. Admissions due to respiratory infections during the first year of life were analysed and compared among moderate (32-33), late (34-36) and term infants. Sixteen respiratory viruses were detected by RT-PCR. Clinical data were collected. RESULTS: 30 (20.9%) out of 143 preterm infants required admission for respiratory infection, versus 129 (6.9%) of 1858 term infants born in the same period (p<0.0001, OR: 3.6 CI 2.0 to 5.0). Hospitalised children had a higher prevalence of hyaline membrane disease (HMD) at birth (p<0.001, OR: 7.7 CI: 2.121 to 27.954) and needed more mechanical ventilation (p<0.001, OR: 5.7 CI: 1.813 to 18.396). Virus was identified in 25/30 (83%) preterm babies, and in 110/129 (85%) term infants. The most frequent viruses in preterm infants were RSV (76%) rhinovirus (20%). Clinical and epidemiological characteristics among term and preterm infants were similar. CONCLUSIONS: The risk of respiratory admissions during the first year of life is up to 3.6 times higher in moderate and late preterm. Once admitted, clinical features of respiratory episodes requiring hospitalisation are similar among term and preterm infants. Hyaline membrane disease and mechanical ventilation were also risk factors for respiratory admissions. PMID- 25456534 TI - Effect of pacing mode and pacing site on torsional and strain parameters and on coronary flow. AB - BACKGROUND: Right ventricular apical pacing may induce detrimental effects on left ventricular function and coronary flow. In this study, the effects of pacing site and mode on cardiac mechanics and coronary blood flow were evaluated. METHODS: This prospective study included 25 patients who received dual-chamber pacemakers with the ventricular lead placed in the right ventricular apex and presented in sinus rhythm (SR) at their regularly scheduled visits at the pacemaker clinic. Patients underwent complete transthoracic echocardiographic examinations while in SR, followed by noninvasive Doppler assessment of coronary flow in the left anterior descending coronary artery (LAD) and speckle-tracking echocardiography of short-axis planes in SR, atrial pacing (AAI-P), atrioventricular (dual-chamber) pacing (DDD-P), and ventricular pacing (VVI-P). RESULTS: Rotation of the base was significantly decreased with VVI-P compared with AAI-P. Left ventricular twist decreased significantly with DDD-P compared with AAI-P. Circumferential strain of the base significantly decreased with DDD-P and VVI-P compared with SR. The velocity-time integral of diastolic flow in the LAD decreased significantly with DDD-P compared with SR (10.7 +/- 2.2 vs 10.2 +/- 2.2 vs 8.9 +/- 1.6 vs 8.7 +/- 2.6 cm in SR and with AAI-P, DDD-P, and VVI-P, respectively, P = .003). Basal rotation and time from onset of the QRS complex to peak basal rotation as a percentage of systole were independently associated with the velocity-time integral of diastolic flow in the LAD during SR and the three pacing modes. CONCLUSIONS: Acute right ventricular apical pacing showed a detrimental effect on left ventricular twist and basal mechanics, with the latter being independently associated with decreased LAD diastolic flow velocity parameters. PMID- 25456558 TI - Pharmacokinetics and pharmacodynamics of setrobuvir, an orally administered hepatitis C virus non-nucleoside analogue inhibitor. AB - PURPOSE: New antiviral agents with activity against hepatitis C virus (HCV) are needed to optimize treatment for chronic hepatitis C (CHC). We evaluated the pharmacokinetics of setrobuvir (a non-nucleoside HCV polymerase inhibitor) in healthy volunteers (study 1 & 2) and its antiviral efficacy in patients with genotype 1, noncirrhotic treatment-naive CHC (study 3). METHODS: Three studies investigated the pharmacokinetics and pharmacodynamics of setrobuvir. First, sequential cohorts of volunteers were randomly assigned to receive single oral doses of setrobuvir 400 to 3000 mg or placebo in a double-blind, ascending dose study. In the second study, volunteers were randomly assigned to receive multiple doses of setrobuvir (400 or 800 mg once daily [QD] or 600 mg twice a day [BID]). In the third study, patients with genotype 1 CHC received setrobuvir (200, 400, or 800 mg) or placebo BID for 3 days. FINDINGS: After single doses of setrobuvir (400-3000 mg) to volunteers in a fasted state, peak Cmax and AUC0-infinity increased in a less than dose-proportional manner. The mean apparent t1/2z ranged from 22.0 to 31.3 hours and was not dose related. Cmax and AUC increased significantly (4.3- and 6.3-fold, respectively) in volunteers who received 2000 mg with a high-fat meal versus fasting. After multiple oral doses, steady state was achieved after 7 days of dosing (400 or 800 mg QD and 600 mg BID) and accumulation was dose-independent. Mean day 14 plasma exposure increased in a less than dose-proportional manner in volunteers who received 400 and 800 mg QD, but it was more than dose-proportional in volunteers receiving 600 mg BID. Dose did not affect the mean t1/2z (range, 24.1-26.6 hours), apparent oral clearance (0.254-0.516 L/h), or apparent volume of distribution (9.60-18.1 L). In patients with CHC, dose-related reductions in HCV RNA concentration were apparent within 24 hours of the start of treatment. Reductions from baseline to the end of treatment (day 3) in patients treated with setrobuvir 200, 400, and 800 mg BID were -2.1, -2.2, and -2.9 log10 IU/mL, respectively (vs <=0.1 log10 IU/mL with placebo). Reductions in HCV RNA were greater in patients with genotype 1b (range, -2.7 to -3.1 log10 IU/mL) than in patients with genotype 1a (range, -1.3 to -2.7 log10 IU/mL). Setrobuvir was well tolerated, with no serious adverse events. IMPLICATIONS: The steady state pharmacokinetics of setrobuvir appear to be dose proportional, and setrobuvir produces a mean reduction of 2.9 log10 IU/mL in HCV RNA over 3 days in patients with genotype 1 (a and b) treated with 800 mg BID. ClinicalTrials.gov identifier: NCT00782353. PMID- 25456559 TI - Computed tomography image analysis before and after treatment of anti-neutrophil cytoplasmic antibody-associated pulmonary interstitial fibrosis in 8 patients. AB - PURPOSE: The purpose of this study was to observe the treatment response of anti neutrophil cytoplasmic antibody (ANCA)-associated pulmonary interstitial fibrosis in 8 patients before and after glucocorticoid or immunosuppressive therapy. METHODS: The clinical features and computed tomography imaging findings of the 8 patients in our hospital from October 2011 to October 2013, were retrospectively analyzed. FINDINGS: Mean age of the 8 patients was 72.6 (range 60-80) years. Five patients exhibited cough, sputum, and chest tightness, including 2 patients with fever. One patient developed hemoptysis, 1 patient exhibited abnormal urinalysis and developed renal insufficiency, and 1 patient developed limb pain. Two patients exhibited high urine erythrocytes and 2 patients had renal dysfunction and urinary abnormalities. One of the latter patients, upon renal biopsy, had focal proliferative necrotizing glomerulonephritis (consistent with vasculitis damage) with stage II to III mild nephropathy. Seven cases were anti myeloperoxidase-ANCA, and 1 case was anti-proteinase 3-ANCA. All 8 cases exhibited streaks and grid shadows in chest imaging; 2 cases exhibited limited ground-glass patches; 1 case displayed multiple large patches of exudative shadows, indicating diffuse alveolar hemorrhage; 2 cases exhibited obvious honeycomb manifestations; and 1 case exhibited significant traction bronchiectasis. The ground-glass opacities disappeared after corticosteroid or immunosuppressive therapy; however, for streaks and grid shadows, no significant changes in the images were observed after treatment from 2 weeks to 10 months. IMPLICATIONS: ANCA-associated pulmonary interstitial fibrosis most often in elderly patients with many complications. In these patients ground-glass opacities in computed tomography images, corticosteroid or immunosuppressant therapy may be effective. Clinicians should consider the poor efficacy and side effects of these therapies in the fibrosis stage of the disease. PMID- 25456560 TI - Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers. AB - PURPOSE: Samidorphan (3-carboxamido-4-hydroxy naltrexone) is a novel opioid receptor antagonist that is currently in clinical development. The oral dose pharmacokinetics, safety, and tolerability of samidorphan were evaluated in 2 double-blind, placebo-controlled, randomized studies in healthy adults. METHODS: The first study investigated single, ascending doses of 3.7 to 55.7 mg of samidorphan in 16 healthy adults; the second study evaluated multiple ascending doses of 10 or 20 mg of samidorphan administered for 7 days in 30 healthy adults. FINDINGS: Across the two studies, 39 of 46 subjects were male; 32 were white, 11 were black, and 3 were hispanic. Mean age was 34.9 years and mean weight was 84.2 kg. In both studies, samidorphan was rapidly absorbed, with a Tmax of 1 hour, and AUC increased with increasing dose. Samidorphan plasma levels declined in a monoexponential manner, with a half-life of ~7 to 9 hours. After multiple doses, steady state was approached by day 6 and achieved by day 7 after the 10-mg dose, but steady state was not reached for the 20-mg dose. Accumulation was low, with accumulation ratios <1.65. In both studies, samidorphan was generally well tolerated, with somnolence reported as the most common adverse event. IMPLICATIONS: In these single- and multiple-dose studies in healthy volunteers, samidorphan exhibited a pharmacokinetic profile consistent with once-daily dosing. ClinicalTrials.gov identifier: NCT00800319. PMID- 25456562 TI - Patient-level medication regimen complexity in older adults with depression. AB - PURPOSE: Polypharmacy and medication adherence are well known challenges facing older adults. Medication regimen complexity increases the demands of self-care in the home. Some medication regimens may be more complex than others, especially when dosage form, frequency of dosing, and additional usage directions are included in complexity along with the number of medications In older adults with depression, it is unknown what features of their medications most influence their medication regimen complexity. METHODS: A sample cohort of 100 adults >=65 years old with a diagnosis of depression was randomly selected from electronic medical records (EMR) in ambulatory clinics at the University of Colorado (CU) and University of San Diego (SD). Demographic, medical history, and medication related information was extracted from the EMR. Complexity was determined using the Medication Regimen Complexity Index (MRCI). IRB approval was obtained. FINDINGS: The cohort mean age was 74.3 years (SD) and 79.7 years (CU). The mean unweighted Charlson comorbidity index for 1.0 (SD) and 1.8 (CU). The mean number of medications was 7.1 and 8.0, with 1.1 and 1.2 depression meds, 5.4 and 4.3 non depression prescription meds, and 0.6 and 2.4 OTC meds for the SD and CU cohorts, respectively. 66% of SD adults and 70% of CU adults took six or more meds. Individual MRCI scores were on average 17.62 (SD) and 19.36 (CU). Dosing frequency contributed to 57-58% of the MRCI score, with patients facing an average of 7-8 unique dosing frequencies in their regimen. In both cohorts, there was an average of 3 additional directions added to the regimens to clarify dosing. IMPLICATIONS: As expected, in our older adult cohorts with depression the majority of patients took multiple medications. Using a standardized instrument, we characterized the regimen complexity and found that it was increasingly complex due to numerous dosing forms, frequencies and additional directions for use. Patient-level medication regimen complexity should go beyond depression medication to encompass the patient's entire regimen for opportunities to reduce complexity and improve ease of self-care. PMID- 25456563 TI - Body mass index and body adiposity index in relation to percent body fat: a study in adult men of three endogamous groups of South Bengal. AB - Body adiposity index (BAI), based on height and hip circumference data from Mexican-Americans and African-Americans established its relation to body fat (BF). The aim of our study was to compare body mass index (BMI) and BAI in relation to BF%. Participants were adult men of three endogamous social groups (Brahmin, Muslim and Namasudra) in a village of South 24 Parganas district in West Bengal, India. Height, weight and hip circumference of 952 individuals (370 Brahmins, 307 Muslims and 275 Namasudras) were recorded. The BMI-based nutritional status and bioelectrical impedance-based BF% were evaluated. Namasudras (33.8%) and Muslims (33.6%) had high frequency undernutrition compared to Brahmins (7.3%). High prevalence (46.22%) of excess weight (overweight+obesity) was recorded only among Brahmins. There was significant social group difference in rates of nutritional status (chi(2) = 93.10, p < 0.0001). The BF% had higher correlation with BMI than BAI. A cut-off value of BAI (22%) was determined by binomial logistic regression analysis (BLRA). The value had best estimated relation to BF% and also coincided with WHO standard mean BF (22%) for overweight adults at BMI (>= 25 kg/m(2)). However, greater area under the receiver operating characteristic curve, higher correct prediction rate, and other results of BLRA for the cut-off value of BMI-based overweight (>= 25 kg/m(2)) showed its better relation to BF% than that observed for BAI cut-off at 22%. The BMI was observed to be a better indicator of adiposity compared to BAI in relation with body fat (%). PMID- 25456561 TI - Depression, coronary artery disease, and physical activity: how much exercise is enough? AB - PURPOSE: The mechanisms by which depressive symptoms negatively affect clinical outcomes in patients with coronary artery disease (CAD) remain poorly understood. Previous interventions that have attempted to treat depressive symptoms in patients with CAD to improve their clinical outcomes have been disappointing. Our objectives were, among a cohort of CAD patients, to evaluate the impact of depressive symptoms over time, controlling for comorbidity, in determining both successful long-term lifestyle change (ie, increased physical activity), and cardiovascular morbidity and mortality outcomes. In addition, we examined the impact of physical activity changes over time on 2 known mediators of cardiovascular morbidity: parasympathetic tone and inflammation. METHODS: Clinical data were previously collected (2004-2006) from 242 elective/urgent coronary angioplasty patients who participated in a prospective randomized controlled trial evaluating the efficacy of a behavioral intervention versus an educational control to motivate physical activity over 12 months. Exclusion criteria included: (1) inability to walk; (2) enrollment in other risk-reduction trials; (3) non-English speaking; and (4) lack of cardiologist's permission to increase physical activity. Participants were assessed every 2 months for interval clinical events and physical activity. In addition, biomarkers were collected at baseline and at 12 months in a subset of 54 participants; these biomarkers included low-frequency heart rate variability (lfHRV), high-frequency heart rate variability (hfHRV), serum C-reactive protein, interleukin-6, and salivary cortisol. FINDINGS: The mean age of participants was 63 years and 30% were female. Overall, 37% had high depressive symptoms at baseline. Patients with high depressive symptoms who achieved an increase in physical activity of >=336 kilocalories(kcal)/week by 12 months had significantly lower rates of cardiovascular morbidity/mortality (5.1% vs. 21.3%; odds ratio [OR], 0.20, [95% CI, 0.04-0.98]; P = 0.03). In a multivariate model examining cardiovascular morbidity/mortality in patients with high depressive symptoms, an increase in physical activity of >=336 kcal/week reduced the risk of new cardiovascular morbidity/mortality (OR, 0.11 [95% CI, 0.02-0.81]; P < 0.03), and comorbidity increased the risk (OR, 1.58 [95% CI, 1.18-2.13]; P = 0.002). In a generalized structural equation model, increasing physical activity by >=336 kcal/week decreased the risk of complications, and comorbidity increased the risk. Furthermore, increasing physical activity (>=336 kcal/week) predicted an increase in hfHRV, a marker of parasympathetic tone, and the increase in hfHRV predicted a reduction in the proinflammatory mediators interleukin-6 and C-reactive protein. IMPLICATIONS: This study found a threshold in physical activity in CAD patients with depressive symptoms that is associated with a decrease in cardiovascular morbidity and mortality. Exercise maintenance at this level may improve clinical outcomes via enhanced parasympathetic tone and decreased inflammation. ClinicalTrials.gov identifier: NCT00248846. PMID- 25456564 TI - Supernumerary fourth molar and dental pathologies in a Chalcolithic individual from the El Mirador Cave site (Sierra de Atapuerca, Burgos, Spain). AB - We present a middle-aged Chalcolithic male with a supernumerary distomolar in the mandible. The prevalence of supernumerary teeth in present-day populations is low, ranging from 0.1% to 3.4%; most supernumerary teeth are documented in the anterior and molar regions of the maxilla in present populations. However, the prevalence of supernumerary molars in past populations is still unknown. Moreover, a complete pathological study has been done of this individual. Maxilla, mandible and teeth have been analyzed searching for dental pathologies. A cone-beam computed tomography (CBCT) analysis of mandibular and maxillary fragments was performed to check the evidence of hyperdontia. Dental wear and maxillary alveolar bone have been analyzed with environmental scanning electron microscope (ESEM) to improve the diagnosis of an abscess and evidence of tooth picking. This individual shows a left distomolar in the mandible without any evidence of other supernumerary teeth. The fourth molar is not associated with any congenital disease. However, this individual suffered severe dental wear and a variety of oral pathologies such as, dental decay, abscesses, pulpitis, periodontal disease, toothpicking marks in an upper molar, arthritis of the temporomandibular joint and malocclusion associated with high masticatory loads. To our knowledge, this individual from El Mirador Cave (Sierra de Atapuerca, Spain) shows the most ancient case of a fourth molar documented. The poor oral health of this individual corresponds to the general dental health of Chalcolithic populations. PMID- 25456565 TI - Boiling sheep liver or lung for 30 minutes is necessary and sufficient to kill Echinococcus granulosus protoscoleces in hydatid cysts. AB - Proper disposal of carcasses and offal after home slaughter is difficult in poor and remote communities and therefore dogs readily have access to hydatid cysts containing offal from livestock, thus completing the parasite cycle of Echinococcus granulosus and putting communities at risk of cystic echinococcosis. Boiling livers and lungs which contain hydatid cysts could be a simple, efficient and energy- and time-saving way to kill the infectious protoscoleces. The aim of this study was to provide precise practical recommendations to livestock owners. Our results show that boiling the whole sheep liver and/or lung, with single or multiple hydatid cysts, for 30 min is necessary and sufficient to kill E. granulosus protoscoleces in hydatid cysts. Advertising on this simple rule in at risk communities would be an efficient and cheap complement to other veterinary public health operations to control cystic echinococcosis. PMID- 25456567 TI - Special Issue on "freshwater and marine toxins". PMID- 25456568 TI - Forcing the enemy to come out and surrender: a strategy for an AIDS cure. PMID- 25456570 TI - Modulatory effects of TAOK3 variants on morphine requirement in acute postoperative pain: an early genome wide association study contribution to the field of pediatric pain. PMID- 25456566 TI - The uncertain outcome of prefrontal tDCS. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is increasingly used in research and clinical settings, and the dorsolateral prefrontal cortex (DLPFC) is often chosen as a target for stimulation. While numerous studies report modulation of cognitive abilities following DLPFC stimulation, the wide array of cognitive functions that can be modulated makes it difficult to predict its precise outcome. OBJECTIVE: The present review aims at identifying and characterizing the various cognitive domains affected by tDCS over DLPFC. METHODS: Articles using tDCS over DLPFC indexed in PubMed and published between January 2000 and January 2014 were included in the present review. RESULTS: tDCS over DLPFC affects a wide array of cognitive functions, with sometimes apparent conflicting results. CONCLUSION: Prefrontal tDCS has the potential to modulate numerous cognitive functions simultaneously, but to properly interpret the results, a clear a priori hypothesis is necessary, careful technical consideration are mandatory, further insights into the neurobiological impact of tDCS are needed, and consideration should be given to the possibility that some behavioral effects may be partly explained by parallel modulation of related functions. PMID- 25456569 TI - 2-weekly docetaxel: issues for clinical practice. AB - In the phase III trial comparing 2 docetaxel schedules (3-weekly versus 2-weekly) as first-line chemotherapy for CRPC, recently published in The Lancet Oncology, fewer serious adverse events, particularly hematologic toxicities, and longer times on treatment, in favor of the 2-weekly regimen are reported. (1,2,3.) PMID- 25456572 TI - Treatment use, perceived need, and barriers to seeking treatment for substance abuse and mental health problems among older adults compared to younger adults. AB - BACKGROUND: This study examined age group differences in and correlates of treatment use and perceived treatment need for substance use disorders (SUD) and mental health (MH) problems as well as self-reported barriers to treatment among people 65+ years old vs. 26-34, 35-49, and 50-64 years old. METHODS: Data are from the 2008 to 2012 National Survey on Drug Use and Health (NSDUH) (N = 96,966). Age group differences were examined using descriptive bivariate analyses and binary logistic regression analyses. RESULTS: The 65+ age group was least likely to use treatment and perceive treatment need, but the 50-64 age group was more similar to the younger age groups than the 65+ age group. Controlling for age, other predisposing, and enabling factors, alcohol and illicit drug dependence and comorbid SUD and MH problems increased the odds of SUD treatment use. Of MH problems, anxiety disorder had the largest odds for MH treatment use. Bivariate analyses showed that lack of readiness to stop using and cost/limited insurance were the most frequent barriers to SUD and MH treatment, respectively, among older adults, and they were less likely than younger age groups to report stigma/confidentiality concerns for MH treatment. CONCLUSIONS: Older adults will become a larger portion of the total U.S. population with SUD and/or MH problems. Healthcare providers should be alert to the need to help older adults with SUD and/or MH problems obtain treatment. PMID- 25456571 TI - A randomized, controlled trial of combined cognitive-behavioral therapy plus prize-based contingency management for cocaine dependence. AB - BACKGROUND: Cocaine has become one of the drugs of most concern in Switzerland, being associated with a wide range of medical, psychiatric and social problems. Available treatment options for cocaine dependence are rare. The study sought to compare combined prize-based contingency management (prizeCM) plus cognitive behavioral therapy (CBT) to CBT alone in cocaine-dependent patients. METHODS: Sixty cocaine-dependent patients participated in a randomized, controlled trial with two treatment conditions. The participants were randomly assigned to the experimental group (EG; n = 29), who received CBT combined with prizeCM, or to the control group (CG; n = 31), who received CBT only during 24 weeks. The primary outcome measures were retention, at least 3 consecutive weeks of cocaine abstinence, the maximum number of consecutive weeks of abstinence and proportions of cocaine-free urine samples during the entire 24-week and at 6-month follow-up. RESULTS: Sixty-three percent of the participants completed the study protocol. Participants in both groups significantly reduced cocaine use over time. Overall, no difference in cocaine-free urine screens was found across the two treatment groups, except at weeks 8, 9, 10, 17 and 21 in favor of the EG. CONCLUSIONS: The addition of prizeCM to CBT seems to enhance treatment effects, especially in the early treatment period, supporting results from previous studies. Both the combined intervention and CBT alone, led to significant reductions in cocaine use during treatment and these effects were sustained at 6-month follow-up. These findings underline the importance in implementing CM and CBT interventions as treatment options for cocaine dependence in the European context. PMID- 25456574 TI - Observed transition from opioid analgesic deaths toward heroin. AB - BACKGROUND: In the United States, overdose mortality from controlled substances has increased over the last two decades, largely involving prescription opioid analgesics. Recently, there has been speculation on a transition away from prescription opioid use toward heroin, however the impact on overdose deaths has not been evaluated. METHODS: Time series study of North Carolina residents, 2007 through 2013. Monthly ratio of prescription opioid-to-heroin overdose deaths. Non parametric local regression models used to ascertain temporal shifts from overdoses involving prescription opioids to heroin. RESULTS: There were 4332 overdose deaths involving prescription opioids, and 455 involving heroin, including 44 where both were involved (total n = 4743). A gradual 6-year shift toward increasing heroin deaths was observed. In January, 2007, for one heroin death there were 16 opioid analgesic deaths; in December, 2013 there were 3 prescription opioid deaths for each heroin death. The transition to heroin appears to have started prior to the introduction of tamper-resistant opioid analgesics. The age of death among heroin decedents shifted toward younger adults. Most heroin and opioid analgesic deaths occurred in metropolitan areas, with little change between 2007 and 2013. CONCLUSIONS: The observed increases in heroin overdose deaths can no longer be considered speculation. Deaths among younger adults were noted to have increased in particular, suggesting new directions for targeting interventions. More research beyond vital statistics is needed to understand the root causes of the shift from prescription opioids to heroin. PMID- 25456573 TI - Test-retest reliability of eye tracking during the visual probe task in cocaine using adults. AB - BACKGROUND: Stimuli associated with cocaine use capture attention. Evidence suggests that fixation time measured on the visual probe task is a valid measure of cocaine cue attentional bias. The aim of this experiment was to demonstrate the test-retest reliability of cocaine cue attentional bias as measured by fixation time during the visual probe task. METHODS: In a within-subject, repeated-measures design, thirty-six non-treatment seeking cocaine-using adults completed a visual probe task with eye tracking. RESULTS: Participants displayed an attentional bias to cocaine-related images as measured by fixation time across two occasions (F (1, 35) = 56.5, p < 0.0001). A Pearson correlation indicated significant test-retest reliability for this effect (r = 0.51, p = 0.001). Response time failed to detect an attentional bias and test-retest reliability was low (r = 0.24, p = 0.16). CONCLUSION: Fixation time during the visual probe task is a reliable measure of cocaine cue attentional bias in cocaine-using adults across time. PMID- 25456575 TI - Cardiac rehabilitation for people with heart disease: an overview of Cochrane systematic reviews. AB - INTRODUCTION: Overviews are a new approach to summarising evidence and synthesising results from related systematic reviews. OBJECTIVES: To conduct an overview of Cochrane systematic reviews to provide a contemporary review of the evidence for cardiac rehabilitation (CR), identify opportunities for merging or splitting existing Cochrane reviews, and identify current evidence gaps to inform new review titles. METHODS: The Cochrane Database of Systematic Reviews was searched to identify reviews that address the objectives of this overview. Data presentation is descriptive with tabular presentations of review- and trial-level characteristics and results. RESULTS: The six included Cochrane systematic reviews were of high methodological quality and included 148 randomised controlled trials in 97,486 participants. Compared to usual care alone, exercise based CR reduces hospital admissions and improves patient health related quality of life (HRQL) in low to moderate risk heart failure and coronary heart disease (CHD) patients. At 12 months or more follow-up, there was evidence of some reduction in mortality in patients with CHD. Psychological- and education-based interventions appear to have little impact on mortality or morbidity but may improve HRQL. Home- and centre-based programmes are equally effective in improving HRQL at similar costs. Selected interventions can increase the uptake of CR programmes but evidence to support interventions that improve adherence is weak. CONCLUSIONS: This overview confirms that exercise-based CR is effective and safe in the management of clinically stable heart failure and post-MI and PCI patients. We discuss the implications of this overview on the future direction of the Cochrane CR reviews portfolio. PMID- 25456576 TI - Remote ischemic preconditioning preserves mitochondrial function and activates pro-survival protein kinase Akt in the left ventricle during cardiac surgery: a randomized trial. AB - BACKGROUND: Understanding the intracellular mechanisms induced by remote ischemic preconditioning (RIPC) in the human left ventricle opens new possibilities for development of pharmacological cardioprotection against ischemia and reperfusion injury. In this study we investigated the effects of RIPC on mitochondrial function, activation of pro-survival protein kinase Akt and microRNA expression in left ventricular biopsies from patients undergoing coronary artery bypass surgery (CABG). METHODS: Sixty patients were randomized to control (n=30) or RIPC (n=30). A blood pressure cuff was applied to the arm of all patients preoperatively. The cuff remained deflated in control group, whereas RIPC was performed by 3 cycles of cuff inflation to 200 mm Hg for 5 min, separated by 5 min deflation intervals. Left ventricular biopsies were obtained before and 15 min after aortic declamping. The primary outcome was mitochondrial respiration measured in situ. Secondary outcomes were activation of protein kinase Akt, assessed by western immunoblotting, and expression of microRNAs assessed by array and real-time polymerase chain reaction. RESULTS: Mitochondrial respiration was preserved during surgery in patients receiving RIPC (+0.2 MUmol O2/min/g, p=0.69), and reduced by 15% in controls (-1.5 MUmol O2/min/g, p=0.02). Furthermore, RIPC activated protein kinase Akt before aortic clamping (difference from control +43.3%, p=0.04), followed by increased phosphorylation of Akt substrates at reperfusion (+26.8%, p<0.01). No differences were observed in microRNA expression. CONCLUSIONS: RIPC preserves mitochondrial function and activates pro-survival protein kinase Akt in left ventricle of patients undergoing CABG. Modulation of mitochondrial function and Akt activation should be further explored as cardioprotective drug targets. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov, unique identifier: NCT01308138. PMID- 25456577 TI - Presence of ventricular aneurysm predicts poor clinical outcomes in patients with cardiac sarcoidosis. PMID- 25456578 TI - Gender differences in impact of vascular endothelial dysfunction on clinical outcome following coronary stenting in patients with coronary heart disease. PMID- 25456579 TI - Does ivabradine really limit dobutamine-induced tachycardia in stable heart failure patients: parallax in significance. PMID- 25456580 TI - Brachydactyly and atrial septal defect: when the digits point to the heart. PMID- 25456581 TI - Concentration-dependent effect of platelet-rich plasma on keratinocyte and fibroblast wound healing. AB - BACKGROUND AIMS: Platelet-rich plasma (PRP) has been found to contain a high concentration of growth factors that are present during the process of healing. Studies conducted found that application of PRP accelerates wound healing. In this study, we characterized the skin cell suspension harvested using the co isolation technique and evaluated the effects of PRP (10% and 20%, v/v) on co cultured keratinocytes and fibroblasts in terms of wound healing. METHODS: Human keratinocytes and fibroblasts were harvested via co-isolation technique and separated via differential trypsinization. These cells were then indirectly co cultured in medium supplemented with 10% or 20% PRP for 3 days without medium change for analysis of wound-healing potential. The wound-healing potential of keratinocytes and fibroblasts was evaluated in terms of growth property, migratory property, extracellular matrix gene expression and soluble factor secretion. RESULTS: The co-isolation technique yielded a skin cell population dominated by fibroblasts and keratinocytes, with a small amount of melanocytes. Comparison between the 10% and 20% PRP cultures showed that the 10% PRP culture exhibited higher keratinocyte apparent specific growth rate, and secretion of hepatocyte growth factor, monocyte chemoattractant protein-1, epithelial-derived neutrophil-activating protein 78 and vascular endothelial growth factor A, whereas the 20% PRP culture has significantly higher collagen type 1 and collagen type 3 expressions and produced more granulocyte-macrophage colony-stimulating factor. CONCLUSIONS: PRP concentration modulates keratinocyte and fibroblast wound healing potential, whereby the 10% PRP promotes wound remodeling, whereas the 20% PRP enhances inflammation and collagen deposition. PMID- 25456582 TI - Application of two-dimensional chromatography in the analysis of Chinese herbal medicines. AB - For the purpose of better understanding the complex Chinese herbal medicines (CHMs) and controlling their quality, powerful analytical techniques are essential. Although conventional one-dimensional (1D) chromatographic approaches have been widely used for the analysis of multiple components in CHMs, the complexity of CHM samples often exceeds the maximal capacity of any single separation mode. Therefore, in past decades, many researchers have attempted to explore the coupling of independent separation techniques to improve the resolving power for complex CHM samples. Two-dimensional (2D) separation systems, based on two independent columns with different separation mechanisms, have proven to be more powerful than 1D techniques and have been used successfully to separate and analyze CHM samples with excellent performance. This article aims to review the most recent advances in the strategies for analyzing CHMs using 2D chromatography. For this purpose, some remarkable applications of the commonly used couplings, mainly including 2D-GC and 2D-LC for analysis of CHMs, are described. Moreover, their major advantages and shortcomings are discussed, which might be helpful to the researchers who focus on quality control of CHMs. PMID- 25456583 TI - Development of ultrasonic-assisted closed in-syringe extraction and derivatization for the determination of labile abietic acid and dehydroabietic acid in cosmetics. AB - Two resin acids, abietic acid (AA) and dehydroabietic acid (DHAA), in cosmetics may cause allergy or toxicoderma, but remain inaccurately investigated due to their lability. In this work, an accurate, sensitive, efficient and convenient method, utilizing the ultrasonic-assisted closed in-syringe extraction and derivatization (UCSED) prior to high performance liquid chromatography (HPLC) coupled with fluorescence detection (FLD) and on-line tandem mass spectra (MS/MS), has been developed. Analytes are extracted by acetonitrile (10/1, v/m) in a sealed syringe under safe condition (60 degrees C; 15 min; nitrogen atmosphere) and then in-syringe derivatized by 2-(2-(anthracen-10-yl)-1H naphtho[2,3-d]imidazol-1-yl) ethyl-p-toluenesulfonate (ANITS) (8-fold, 93 degrees C, 30 min, DMF as co-solvent, K2CO3 as catalyst). In UCSED, derivatization contributes to increase both analytical sensitivity and stability of analytes. Excellent linearity (r2>=0.9991) is achieved in wide range (75-3000 ng/mL (AA); 150-4500 ng/mL (DHAA)). Quite low detection limits (AA: 8.2-10.8 ng/mL; DHAA: 19.4-24.3 ng/mL) and limits of analyte concentration (LOAC) (AA: 30.0-44.5 ng/mL; DHAA: 70.9-86.7 ng/mL) ensure the trace analysis. This method is applied to the analysis of cosmetic samples, including depilatory wax strip, liquid foundation, mascara, eyeliner, eyebrow pencil and lip balm. No additional purification is required and no matrix effect is observed, demonstrating obvious advantages over conventional pretreatment such as solid phase extraction (SPE). Accuracy (RE: 3.2% to 2.51%), precision (RSD: 1.29-2.84%), recovery (95.20-103.63%; 95.51 104.22%) and repeatability (<0.23%; <2.87%) are significantly improved. Furthermore, this work plays a guiding role in developing a reasonable method for labile analytes. PMID- 25456584 TI - Microextraction by packed sorbent coupled with gas chromatography-mass spectrometry: a comparison between "draw-eject" and "extract-discard" methods under equilibrium conditions for the determination of polycyclic aromatic hydrocarbons in water. AB - In this work, two different extraction procedures for the analysis of different polycyclic aromatic hydrocarbons (PAHs) in water by microextraction by packed sorbent (MEPS) have been compared in terms of sensitivity, reliability and time of analysis. The first method, called "draw-eject", consists of a sequence of cycles of aspirations and injections in the same vial; the second one, called "extract-discard", consists of a similar cycle sequence, but the aspired sample in this case is discarded into waste. The relevant partition equilibriums and extraction rates have been calculated by multivariate regression from the data obtained after MEPS gas chromatography-mass spectrometry (MEPS-GC-MS) analysis of 16 PAHs from water samples. Partitioning parameters for a priori prediction of solute sorption equilibrium, recoveries and preconcentration effects in aqueous and solvent systems have been calculated and compared for the two extraction procedures. Finally, real samples from sea, agricultural irrigation wells, streams and tap water were analyzed. Detection (S/N>=3) and quantification (S/N>=10) limits were calculated for the extraction processes. Under the experimental conditions used for the "draw-eject" procedure, these values were in the range 0.5-2 ng L(-1) and 1.6-6.2 ng L(-1), while for the "extract-discard" procedure they ranged from 0.2 to 0.8 ng L(-1) and from 0.8 to 2.0 ng L(-1), respectively. PMID- 25456585 TI - Simplified matrix solid phase dispersion procedure for the determination of parabens and benzophenone-ultraviolet filters in human placental tissue samples. AB - In recent decades, the industrial development has resulted in the appearance of a large amount of new chemicals that are able to produce disorders in the human endocrine system. These substances, so-called endocrine disrupting chemicals (EDCs), include many families of compounds, such as parabens and benzophenone-UV filters. Taking into account the demonstrated biological activity of these compounds, it is necessary to develop new analytical procedures to assess the exposure in order to establish, in an accurate way, relationships between EDCs and harmful health effects in population. In the present work, a new method based on a simplified sample treatment by matrix solid phase dispersion (MSPD) followed by ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC MS/MS) analysis, is validated for the determination of four parabens (methyl-, ethyl-, propyl- and butylparaben) and six benzophenone-UV filters (benzophenone 1, benzophenone-2, benzophenone-3, benzophenone-6, benzophenone-8 and 4 hydroxybenzophenone) in human placental tissue samples. The extraction parameters were accurately optimized using multivariate optimization strategies. Ethylparaben ring-13C6 and benzophenone-d10 were used as surrogates. The found limits of quantification ranged from 0.2 to 0.4 ng g(-1) and inter-day variability (evaluated as relative standard deviation) ranged from 5.4% to 12.8%. The method was validated using matrix-matched standard calibration followed by a recovery assay with spiked samples. Recovery rates ranged from 96% to 104%. The method was satisfactorily applied for the determination of compounds in human placental tissue samples collected at the moment of delivery from 10 randomly selected women. PMID- 25456586 TI - Preparation of high efficiency and low carry-over immobilized enzymatic reactor with methacrylic acid-silica hybrid monolith as matrix for on-line protein digestion. AB - In this work, a novel kind of organic-silica hybrid monolith based immobilized enzymatic reactor (IMER) was developed. The monolithic support was prepared by a single step "one-pot" strategy via the polycondensation of tetramethoxysilane and vinyltrimethoxysilane and in situ copolymerization of methacrylic acid and vinyl group on the precondensed siloxanes with ammonium persulfate as the thermal initiator. Subsequently, the monolith was activated by N-(3-dimethylaminopropyl) N'-ethylcarbodiimide (EDC) and N-hydroxysuccinimide (NHS), followed by the modification of branched polyethylenimine (PEI) to improve the hydrophilicity. Finally, after activated by EDC and NHS, trypsin was covalently immobilized onto the monolithic support. The performance of such a microreactor was evaluated by the in sequence digestion of bovine serum albumin (BSA) and myoglobin, followed by MALDI-TOF-MS analysis. Compared to those obtained by traditional in-solution digestion, not only higher sequence coverages for BSA (74+/-1.4% vs. 59.5+/-2.7%, n=6) and myoglobin (93+/-3% vs. 81+/-4.5%, n=6) were obtained, but also the digestion time was shortened from 24h to 2.5 min, demonstrating the high digestion efficiency of such an IMER. The carry-over of these two proteins on the IMER was investigated, and peptides from BSA could not be found in mass spectrum of myoglobin digests, attributed to the good hydrophilicity of our developed monolithic support. Moreover, the dynamic concentration range for protein digestion was proved to be four orders of magnitude, and the IMER could endure at least 7-day consecutive usage. Furthermore, such an IMER was coupled with nano RPLC-ESI/MS/MS for the analysis of extracted proteins from Escherichia coli. Compared to formerly reported silica hybrid monolith based IMER and the traditional in-solution counterpart, by our developed IMER, although the identified protein number was similar, the identified distinct peptide number was improved by 7% and 25% respectively, beneficial to improve the reliability of protein identification. The IMER was further online integrated with two dimensional nano-HPLC-MS/MS system for the analysis of protein extracts from hepatocellular carcinoma (HCC) cells with low metastasis rate, and more than 3000 protein groups were identified, with only 46 proteins identified from the residues of the IMER. All these results demonstrated that such a hybrid monolith based IMER would be of great promise in the high throughput and high confidence proteome analysis. PMID- 25456587 TI - Effervescence assisted on-site liquid phase microextraction for the determination of five triazine herbicides in water. AB - A novel effervescence assisted on-site liquid phase microextraction has been developed for the determination of five triazine herbicides in water. The use of an effervescent tablet composed of citric acid, sodium bicarbonate and 1 undecanol (extraction solvent) was the core of the method. The triazine herbicides in water were extracted by 1-undecanol released from tablet under effervescence and determined by ultra-high pressure liquid chromatography tandem mass spectrometer. The experimental variables, including NaCl concentration, temperature, weight of effervescent tablet, volume of extraction solvent and pH value, were screened by a Plackett-Burman design and optimized by a Box-Behnken design. Under the optimized conditions, good linearity was obtained in the range of 0.05-10 MUg L(-1) with correlation coefficients ranging from 0.9936 to 0.9988. The limits of quantification were between 7.6 and 26.4 ng L(-1), and the recoveries were in 71.4-93.2% with relative standard deviations of 2.5-10.9%. This method, which does not require centrifugation and any special apparatus, was successfully applied to determine triazine herbicides in real waters, promising to be a way to speed field sampling procedures for the organic pollutants monitoring in water. PMID- 25456588 TI - Multi-volatile method for aroma analysis using sequential dynamic headspace sampling with an application to brewed coffee. AB - A novel multi-volatile method (MVM) using sequential dynamic headspace (DHS) sampling for analysis of aroma compounds in aqueous sample was developed. The MVM consists of three different DHS method parameters sets including choice of the replaceable adsorbent trap. The first DHS sampling at 25 degrees C using a carbon-based adsorbent trap targets very volatile solutes with high vapor pressure (>20 kPa). The second DHS sampling at 25 degrees C using the same type of carbon-based adsorbent trap targets volatile solutes with moderate vapor pressure (1-20 kPa). The third DHS sampling using a Tenax TA trap at 80 degrees C targets solutes with low vapor pressure (<1 kPa) and/or hydrophilic characteristics. After the 3 sequential DHS samplings using the same HS vial, the three traps are sequentially desorbed with thermal desorption in reverse order of the DHS sampling and the desorbed compounds are trapped and concentrated in a programmed temperature vaporizing (PTV) inlet and subsequently analyzed in a single GC-MS run. Recoveries of the 21 test aroma compounds for each DHS sampling and the combined MVM procedure were evaluated as a function of vapor pressure in the range of 0.000088-120 kPa. The MVM provided very good recoveries in the range of 91-111%. The method showed good linearity (r2>0.9910) and high sensitivity (limit of detection: 1.0-7.5 ng mL(-1)) even with MS scan mode. The feasibility and benefit of the method was demonstrated with analysis of a wide variety of aroma compounds in brewed coffee. Ten potent aroma compounds from top-note to base-note (acetaldehyde, 2,3-butanedione, 4-ethyl guaiacol, furaneol, guaiacol, 3 methyl butanal, 2,3-pentanedione, 2,3,5-trimethyl pyrazine, vanillin, and 4-vinyl guaiacol) could be identified together with an additional 72 aroma compounds. Thirty compounds including 9 potent aroma compounds were quantified in the range of 74-4300 ng mL(-1) (RSD<10%, n=5). PMID- 25456589 TI - A simple solvothermal process for fabrication of a metal-organic framework with an iron oxide enclosure for the determination of organophosphorus pesticides in biological samples. AB - An active magnetic metal-organic framework (MOF) hybrid material was prepared using a novel in situ solvothermal method in the presence of magnetite (Fe3O4) particles, that holds much promise for large-scale synthesis. MIL-101(Fe), an iron terephthalate with pore structure and high resistance to water and common solvents, was functionalized as a model with superparamagnetic qualities, using Fe3O4. The electrostatic interaction between Fe3O4 and metal ions was thereby used to chemically stabilize magnetic nanoparticles, and thus MOF crystals were uniformly enclosed by Fe3O4 to form a homogeneous magnetic product identified as a Fe3O4/MIL-101 composite. This hybrid material with magnetic susceptibility but with the lowest possible loading amount of Fe3O4 was examined, and its potential application for magnetic solid-phase extraction of six organophosphorus pesticides (OPPs) from human hair and urine samples, followed by gas chromatography analysis, was assessed. The main effect parameters including solution ionic strength, desorption solvent, extraction time and desorption time were investigated in sequence. Under optimized conditions, this method showed low detection limits (0.21-2.28 ng/mL), wide linearity, and good precision (1.8-8.7% for intra-day, 2.9-9.4% for inter-day). The matrix interference produced by hair or urine could be effectively eliminated using this method, and satisfactory recoveries of the spiked samples were 76.8-94.5% and 74.9-92.1%, respectively, indicating that the Fe3O4/MIL-101 sorbents are feasible for the analysis of trace analytes from biological samples. PMID- 25456590 TI - Analysis of free drug fractions by ultrafast affinity extraction: interactions of sulfonylurea drugs with normal or glycated human serum albumin. AB - Ultrafast affinity extraction and a multi-dimensional affinity system were developed for measuring free drug fractions at therapeutic levels. This approach was used to compare the free fractions and global affinity constants of several sulfonylurea drugs in the presence of normal human serum albumin (HSA) or glycated forms of this protein, as are produced during diabetes. Affinity microcolumns containing immobilized HSA were first used to extract the free drug fractions in injected drug/protein mixtures. As the retained drug eluted from the HSA microcolumn, it was passed through a second HSA column for further separation and measurement. Items that were considered during the optimization of this approach included the column sizes and flow rates that were used, and the time at which the second column was placed on-line with the HSA microcolumn. This method required only 1.0 MUL of a sample per injection and was able to measure free drug fractions as small as 0.09-2.58% with an absolute precision of +/-0.02-0.5%. The results that were obtained indicated that glycation can affect the free fractions of sulfonylurea drugs at typical therapeutic levels and that the size of this effect varies with the level of HSA glycation. Global affinity constants that were estimated from these free drug fractions gave good agreement with those predicted from previous binding studies or determined through a reference method. The same approach could be utilized with other drugs and proteins or modified binding agents of clinical or pharmaceutical interest. PMID- 25456591 TI - Identification of protein O-glycosylation site and corresponding glycans using liquid chromatography-tandem mass spectrometry via mapping accurate mass and retention time shift. AB - We reported an improved combinatorial approach for identifying site-specific O glycosylation using both glycan cleaved and non-cleaved methods. In this approach, a non-reducing beta-elimination kit coupled with non-specific enzymes performed efficient digestion, O-glycan cleavage, and partial dephosphorylation without significant side reactions, thus enabling an automatic database search for the cleaved O-glycosylation or serine/threonine (S/T) phosphorylation sites. From the same sample concurrently prepared without beta-elimination, the corresponding intact O-glycopeptides were mapped by accurate precursor ion mass using an in-house glycan database majorly composed of GalNAc (mucin-type) core and the retention-time shift (DeltaRt). Each glycopeptide assignment was verified by the detection of glycan-specific fragments using collision-induced dissociation (CID) to estimate False Discovery Rate (FDR). Using fetuin as a model, all identified S/T elimination sites were matched to multiple intact glycopeptides with a 31% FDR. This considerably reduced to 0% FDR by DeltaRt filtering. This approach was then applied to a protein mixture composed of therapeutic Factor IX and Enbrel((r)) mixed with fetuin and kappa-casein. A total of 26 glycosylation sites each of which corresponds to 1-4 glycans were positively mapped and confirmed. The FDR decreased from 33% to 3.3% by DeltaRt filtering and exclusion of repeated peptide tags that covered the same glycosylation sites. Moreover, the phosphorylation and O-glycosylation on the same site such as T159 of Factor IX and T170 of kappa-casein were able to be unambiguously differentiated. Thus, our approach is useful for in-depth characterization of site-specific O-glycosylation of a simple mixture such as protein-based therapeutics. PMID- 25456592 TI - Ultraviolet-vis degradation of iprodione and estimation of the acute toxicity of its photodegradation products. AB - The UV-vis photodegradation of iprodione in water was investigated with a high pressure mercury lamp photoreactor. Five photoproducts of iprodione were characterized by LC-HR-MS/MS and isotopic labeling; none of them has been reported in previous studies. Three of them result from the elimination of one or two chlorine atoms followed by hydroxy or hydrogen addition while the two others are cyclic isomers of iprodione. An ICR mass spectrometer was used for by products identification; concentrations of photoproducts were estimated with a triple quadrupole instrument, using iprodione-D5 as an internal standard. Phototransformation mechanisms were postulated to rationalize photoproducts formation. In silico QSAR toxicity predictions were conducted with the Toxicity Estimation Software Tool (T.E.S.T.) considering oral rat LD50, mutagenicity and developmental toxicity. Low oral rat LD50 values of 350 mg/kg and 759 mg/kg were predicted for cyclic isomers of iprodione, compared to that of the parent molecule (2776 mg/kg). Toxicity estimations exhibited that all the iprodione photoproducts could be mutagenic while the parent compound is not. In vitro assays on Vibrio fischeri were achieved on both irradiated and non-irradiated aqueous solutions of iprodione and on HPLC fractions containing isolated photoproducts. Phenolic photoproducts were shown to be mainly responsible for toxicity enhancement with EC50 values of 0.3 and 0.5 ppm, for the bi- and mono phenolic compounds issued from chlorine elimination. PMID- 25456593 TI - Analysis of serum phospholipid profiles by liquid chromatography-tandem mass spectrometry in high resolution mode for evaluation of atherosclerotic patients. AB - Atherosclerosis is one of the most frequent etiology for myocardial infarction and death. It is also the main cause of angina pectoris, a perceived symptom that results of a mismatch between myocardial supply and demand, caused by the partial obstruction of the arteries. The correct diagnosis of atherosclerosis can led to a reduction of mortality. In this research, the phospholipids profile of serum samples from patients diagnosed with stable angina and non-ST elevation myocardial infarction (NSTEMI) or unstable angina was obtained by selective solid phase extraction (SPE) and subsequent LC-QTOF MS/MS analysis in high resolution mode. Comparative statistical analysis allowed finding four potential markers to discriminate between stable angina and NSTEMI/unstable angina: lysoPC(20:5), PC(18:1/18:2), PC(18:0/20:4) and SM(d18:2/14:0). The panel generated by multivariate ROC analysis by combination of the four compounds provided a disease prediction capability in the training set of 70.7 and 66.0% for stable angina and NSTEMI patients, respectively. On the other hand, external validation by application to an independent cohort improved the predictive power for angina stable patients (92.3%), while this was slightly decreased up to 50.0% for NSTEMI/unstable angina patients. In this way, LC-QTOF MS/MS has shown to be a useful strategy for phospholipid profiling in serum and development of tools to aid in clinical diagnostic. PMID- 25456594 TI - Development of a separation method for molybdenum from zirconium, niobium, and major elements of rubble samples. AB - A method for separation of Mo from Zr, Nb, and other major elements of rubble samples from the Fukushima Daiichi Nuclear Power Station (FDNPS) was developed to enable 93Mo assay of the rubble samples. Although (93)Mo analysis has been reported in a few studies, the known separation method is tedious and time consuming, or the target is a simple material. Therefore, a simple and rapid protocol for the separation of a complex material, i.e., the rubble sample, was developed in this study. Firstly, loss of Mo during the digestion of simulated rubble samples was evaluated. Next, weight distribution coefficients (Kd's) of Zr, Nb, and Mo between an extraction chromatographic resin (tetra valent actinide resin, TEVA resin) and acid solutions (HF-HCl and HF-HNO3 solutions) were determined to obtain suitable solution conditions for the separation of Mo from Zr and Nb. Based on the obtained Kd's, a chromatographic separation scheme was designed and applied to the digested solution of the simulated rubble sample. Consequently, Mo was successfully separated from Zr, Nb and other major metal ions of the simulated rubble sample. PMID- 25456595 TI - New method for the speciation of ruthenium-based chemotherapeutics in human serum by conjoint liquid chromatography on affinity and anion-exchange monolithic disks. AB - An important step in pharmacological characterisation of a candidate drug is the study of the drugs interactions with serum proteins. In the present work, conjoint liquid chromatography (CLC) was used for separation of ruthenium (Ru) based drug candidates in human serum. CIM Protein G and CIM DEAE disks were assembled together in a single housing forming a CLC monolithic column. By applying isocratic elution with Tris-HCl-NaHCO3 buffer (pH 7.4) in the first min, followed by gradient elution with 1 mol L(-1) NH4Cl (pH 7.4) in the next 9 min, immunoglobulins (IgG) were retained by the Protein G disk enabling subsequent separation of unbound Ru species from Ru species bound to human serum transferrin (Tf) and albumin (HSA) on the CIM DEAE disk. Finally, elution with acetic acid (AcOH) in the next 3 min allowed separation of Ru species associated with IgG. Protein elution was followed on-line with UV detection at 278nm, while the separated Ru species were quantified by post-column isotope dilution inductively coupled plasma mass spectrometry (ID-ICP-MS). The instrumental set-up enabled fast two-dimensional separation by affinity and ion-exchange modes to be carried out in a single chromatographic run. Two Ru-based chemotherapeutics: a newly synthesised compound chlorido(eta6-p-cymene)(nalidixicato-kappa2O,O)Ru(II) (1) and (H2im)[trans-Ru(III)Cl4(Him)2] (2; KP418), which is currently undergoing preclinical studies, were investigated. The CLC procedure applied is sensitive with low limit of detection (LOD) (0.027 MUg Ru mL(-1) for (1)) and good method repeatability (RSD+/-3.5%). The experimental data revealed that it enables investigation of the kinetics of interaction of positively charged and neutral complexes of metallodrugs with serum proteins as well as the distribution of metallodrug species in human serum. However, negatively charged metallic complexes co-eluted with Tf and HSA and thus hindered their speciation analysis. An example of successful application of the kinetic studies on the CLC column is (1), a neutral Ru complex that hydrolyses to a positively charged species. For comparison, speciation data obtained for serum samples spiked with cisplatin are also shown. PMID- 25456596 TI - Effect of injection matrix concentration on peak shape and separation efficiency in ion chromatography. AB - In HPLC, injection of solvents that differ from the eluent can result in peak broadening due to solvent strength mismatch or viscous fingering. Broadened, distorted or even split analyte peaks may result. Past studies of this injection induced peak distortion in reversed phase (RPLC) and hydrophilic interaction (HILIC) liquid chromatography have led to the conclusion that the sample should be injected in the eluent or a weaker solvent. However, there have been no studies of injection-induced peak distortion in ion chromatography (IC). To address this, injection-induced effects were studied for six inorganic anions (F , Cl-, NO2-, Br-, NO3- and SO4(2-)) on a Dionex AS23 IC column using a HCO3 /CO3(2-) eluent. The VanMiddlesworth-Dorsey injection sensitivity parameter (s) showed that IC of anions has much greater tolerance to the injection matrix (HCO3 /CO3(2-) herein) mismatch than RPLC or HILIC. Even when the injection contained a ten-fold greater concentration of HCO3-/CO3(2-) than the eluent, the peak shapes and separation efficiencies of six analyte ions did not change significantly. At more than ten-fold greater matrix concentrations, analyte anions that elute near the system peak of the matrix were distorted, and in the extreme cases exhibited a small secondary peak on the analyte peak front. These studies better guide the degree of dilution needed prior to IC analysis of anions. PMID- 25456597 TI - A liquid chromatography-tandem mass spectrometry-based method for the simultaneous determination of hydroxy sterols and bile acids. AB - Recently, hydroxy sterols and bile acids have gained growing interest as they are important regulators of energy homoeostasis and inflammation. The high number of different hydroxy sterols and bile acid species requires powerful analytical tools to quantify these structurally and chemically similar analytes. Here, we introduce a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method for rapid quantification of 34 sterols (hydroxy sterols, primary, secondary bile acids as well as their taurine and glycine conjugates). Chromatographic baseline separation of isomeric hydroxy sterols and bile acids is obtained using a rugged amide embedded C18 (polar embedded) stationary phase. The current method features a simple extraction protocol validated for blood plasma, urine, gall bladder, liver, feces, and adipose tissue avoiding solid phase extraction as well as derivatization procedures. The total extraction recovery for representative analytes ranged between 58-86% in plasma, 85% in urine, 79-92% in liver, 76-98% in adipose tissue, 93-104% in feces and 62-79% in gall bladder. The validation procedure demonstrated that the calibration curves were linear over the selected concentration ranges for 97% of the analytes, with calculated coefficients of determination (R2) of greater than 0.99. A feeding study in wild type mice with a standard chow and a cholesterol-enriched Western type diet illustrated that the protocol described here provides a powerful tool to simultaneously quantify cholesterol derivatives and bile acids in metabolically active tissues and to follow the enterohepatic circulation. PMID- 25456598 TI - Ultrahigh-performance liquid chromatography-ultraviolet absorbance detection-high resolution-mass spectrometry combined with automated data processing for studying the kinetics of oxidative thermal degradation of thyroxine in the solid state. AB - Levothyroxine as active pharmaceutical ingredient of formulations used for the treatment of hypothyroidism is distributed worldwide and taken by millions of people. An important issue in terms of compound stability is its capability to react with ambient oxygen, especially in case of long term compound storage at elevated temperature. In this study we demonstrate that ultrahigh-performance liquid chromatography coupled to UV spectrometry and high-resolution mass spectrometry (UHPLC-UV-HRMS) represent very useful approaches to investigate the influence of ambient oxygen on the degradation kinetics of levothyroxine in the solid state at enhanced degradation conditions. Moreover, the impurity pattern of oxidative degradation of levothyroxine is elucidated and classified with respect to degradation kinetics at different oxygen levels. Kinetic analysis of thyroxine bulk material at 100 degrees C reveals bi-phasic degradation kinetics with a distinct change in degradation phases dependent on the availability of oxygen. The results clearly show that contact of the bulk material to ambient oxygen is a key factor for fast compound degradation. Furthermore, the combination of time resolved HRMS data and automated data processing is shown to allow insights into the kinetics and mechanism of impurity formation on individual compound basis. By comparing degradation profiles, four main classes of profiles linked to reaction pathways of thyroxine degradation were identifiable. Finally, we show the capability of automated data processing for the matching of different stressing conditions, in order to extract information about mechanistic similarities. As a result, degradation kinetics is influenced by factors like availability of oxygen, stressing time, or stressing temperature, while the degradation mechanisms appear to be conserved. PMID- 25456599 TI - Structures of multidomain proteins adsorbed on hydrophobic interaction chromatography surfaces. AB - In hydrophobic interaction chromatography (HIC), interactions between buried hydrophobic residues and HIC surfaces can cause conformational changes that interfere with separations and cause yield losses. This paper extends our previous investigations of protein unfolding in HIC chromatography by identifying protein structures on HIC surfaces under denaturing conditions and relating them to solution behavior. The thermal unfolding of three model multidomain proteins on three HIC surfaces of differing hydrophobicities was investigated with hydrogen exchange mass spectrometry (HXMS). The data were analyzed to obtain unfolding rates and Gibbs free energies for unfolding of adsorbed proteins. The melting temperatures of the proteins were lowered, but by different amounts, on the different surfaces. In addition, the structures of the proteins on the chromatographic surfaces were similar to the partially unfolded structures produced in the absence of a surface by temperature as well as by chemical denaturants. Finally, it was found that patterns of residue exposure to solvent on different surfaces at different temperatures can be largely superimposed. These findings suggest that protein unfolding on various HIC surfaces might be quantitatively related to protein unfolding in solution and that details of surface unfolding behavior might be generalized. PMID- 25456600 TI - Characterization of novel metallacarborane-based sorbents by linear solvation energy relationships. AB - Two novel metallacarborane-based stationary phases for high performance liquid chromatography were synthesized and characterized utilizing linear solvation energy relationships concept. Interactions taking place between selected probes (45 analytes) and the stationary phases and the mobile phases consisting of a mixture of acetonitrile with buffer were described by the linear solvation energy relationship model in a broad range of acetonitrile/buffer ratios. The interaction properties of the metallacarborane phases were compared with plain silica, the starting material for the preparation of the metallacarborane phases, and with a typical silica-based reversed-phase sorbent. It was clearly demonstrated that the metallacarborane sorbents provide qualitatively and quantitatively different interactions with respect to both the plain silica and reversed-phase stationary phase. It was shown that these novel phases might have also a separation potential in the area of hydrophilic interaction liquid chromatography. PMID- 25456601 TI - Characterization and quantification of silver nanoparticles in nutraceuticals and beverages by asymmetric flow field flow fractionation coupled with inductively coupled plasma mass spectrometry. AB - This study evaluated the feasibility of asymmetric flow field flow fractionation coupled with inductively coupled plasma mass spectrometry (AF4-ICP-MS) for separation, characterization and quantification of silver nanoparticles (AgNPs) in complex nutraceutical and beverage samples. For improved determination, different analysis conditions were proposed depending on the NP size, i.e. below 20 nm and in the 20-60 nm range. After optimization of the different experimental parameters affecting the AF4 separation process and the analyte detection, the proposed methods showed a wide dynamic linear range (i.e., in the 10-1000 MUg L( 1)) and limits of detection below 28 ng L(-1). A previous probe ultrasonication for 90 s (corresponding to 45 pulses of 2 s) of the tested samples resulted in complete AgNPs disaggregation. As a result, a fast accurate determination was achieved (complete analysis was done in ca. 37 min). The practicality of the proposed methodology for the intended determination was demonstrated by successful determination of the AgNPs present in a variety of nutraceuticals and a beverage at concentration levels in the 0.7-29.5*10(3) MUg L(-1) range. A good agreement was observed among these concentration data and those determined by more conventional sample preparation techniques, such as ultracentrifugation and acid digestion. Also, the estimated NP sizes using AF4 compared satisfactorily with those determined by image techniques, i.e. transmission electron microscopy (TEM). All together demonstrated the utility of this novel analytical methodology for the analysis of AgNPs of different size in complex matrices. PMID- 25456602 TI - Separation performance of cucurbit[7]uril in ionic liquid-based sol-gel coating as stationary phase for capillary gas chromatography. AB - Here we report the separation performance of a new stationary phase of cucurbit[7]uril (CB7) incorporated into an ionic liquid-based sol-gel coating (CB7-SG) for capillary gas chromatography (GC). The CB7-SG stationary phase showed an average polarity of 455, suggesting its polar nature. Abraham system constants revealed that its major interactions with analytes include H-bond basicity (a), dipole-dipole (s) and dispersive (l) interactions. The CB7-SG stationary phase achieved baseline separation for a wide range of analytes with symmetrical peak shapes and showed advantages over the conventional polar stationary phase that failed to resolve some critical analytes. Also, it exhibited different retention behaviors from the conventional stationary phase in terms of retention times and elution order. Most interestingly, in contrast to the conventional polar phase, the CB7-SG stationary phase exhibited longer retentions for analytes of lower polarity but relatively comparable retentions for polar analytes such as alcohols and phenols. The high resolving ability and unique retention behaviors of the CB7-SG stationary phase may stem from the comprehensive interactions of the aforementioned interactions and shape selectivity. Moreover, the CB7-SG column showed good peak shapes for analytes prone to peak tailing, good thermal stability up to 280 degrees C and separation repeatability with RSD values in the range of 0.01-0.11% for intra-day, 0.04 0.41% for inter-day and 2.5-6.0% for column-to-column, respectively. As demonstrated, the proposed coating method can simultaneously address the solubility problem with CBs for the intended purpose and achieve outstanding GC separation performance. PMID- 25456603 TI - Comparison of liquid chromatography and supercritical fluid chromatography coupled to compact single quadrupole mass spectrometer for targeted in vitro metabolism assay. AB - The goal of this study was to evaluate the combination of powerful chromatographic methods and compact single quadrupole MS device for simple in vitro cytochrome P450 (CYP) inhibition assay, instead of more expensive triple quadrupole MS/MS detectors. For this purpose, two modern chromatographic approaches (ultra-high pressure liquid chromatography (UHPLC) and ultra-high performance supercritical fluid chromatography (UHPSFC)) were tested in combination with simple MS detector. To show the applicability for an in vitro CYP-mediated metabolism assay using the cocktail approach, a method was first developed in UHPLC-MS to separate a mixture of 8 probe substrates and 8 CYP specific metabolites. A screening procedure was initially applied to determine the best combination of a column, an organic modifier and a mobile-phase pH, followed by fine tuning of the conditions (i.e., gradient profile, temperature and pH) using HPLC modelling software. A similar sequential method development procedure was also evaluated for UHPSFC-MS. For method development, where peak tracking is necessary, the use of single quadrupole MS was found to be extremely valuable for following the investigated analytes. Ultimately, a baseline separation of the 16 compounds was achieved in both UHPLC-MS and UHPSFC-MS with an analysis time of less than 7 min. In a second series of experiments, sensitivity was evaluated, and LOQ values were between 2 and 100 ng/mL in UHPLC MS, while they ranged from 2 to 200 ng/mL in UHPSFC-MS. Based on the concentrations employed for the current in vitro phase I metabolism assay, these LOQ values were appropriate for this type of application. Finally, the two analytical methods were applied to in vitro CYP-dependent metabolism testing. Two well-known phytochemical inhibitors, yohimbine and resveratrol, were investigated, and reliable conclusions were drawn from these experiments with both UHPLC-MS and UHPSFC-MS. At the end, the proposed strategy of optimized chromatography combined with simple MS device has been shown to potentially compete with the widely used combination of generic chromatography and highly selective MS/MS device for simple in vitro CYP inhibition assays. In addition, our analytical method may be easier to use in a routine environment; the instrument cost is significantly reduced and the two developed methods fit for purpose. PMID- 25456604 TI - Preparation and characterization of surfactin-modified silica stationary phase for reversed-phase and hydrophilic interaction liquid chromatography. AB - Surfactants are good candidates as selectors in mixed-mode reversed-phase liquid chromatography (RPLC)/hydrophilic interaction liquid chromatography (HILIC) because they contain both a hydrophobic and a hydrophilic moiety. Surfactin, a cyclic heptapeptide, is an efficient biosurfactant produced by Bacillus subtilis that comprises seven amino acids and a beta-hydroxyl fatty acid. A surfactin modified silica (SMS) stationary phase was prepared by amide bond formation between amino groups on aminopropyl silica and the carboxylic acid groups of L Glu and L-Asp residues in surfactin. The resulting SMS stationary phase was characterized in both RPLC and HILIC mode using different mobile phases. The SMS column was found to separate analytes in both modes. The retention of polar solutes exhibited "U-shaped" curves, depending on the acetonitrile content. "U shaped" curves are an indicator of RPLC/HILIC mixed-mode retention behavior. The presence of hydrophobic and hydrophilic moieties in surfactin provides unique properties that allow the SMS column to be used for both RPLC and HILIC separations, simply by changing the mobile phase composition. PMID- 25456605 TI - Observation of enhanced heat dissipation in columns packed with superficially porous particles. AB - At high flow rates and pressures, columns packed with sub-2 MUm particles suffer from efficiency losses due to frictional heating. The thermal environment of the column (insulated or isothermal) can decrease or magnify these losses. While a number of studies have been conducted demonstrating the improved performance (partially due to the benefits of enhanced thermal conductivity) of columns packed with superficially porous particles, none have made a comparison between sub-2 MUm fully and superficially porous particles in an isothermal environment where radial thermal gradients are maximized and thermal broadening is amplified. Here we show that when such columns are characterized in a recirculating water jacket (providing an isothermal environment), efficiency loss and changes in retention and mobile phase temperature are reduced for sub-2 MUm superficially porous particles compared to sub-2 MUm fully porous particles. PMID- 25456606 TI - Bacteria and fungi controlling plant growth by manipulating auxin: balance between development and defense. AB - Plant diseases cause huge losses by changing the quality and quantity of harvested crops. Many disease symptoms caused by bacteria or fungi rely on the involvement of plant hormones, while other plant hormones act as defense signals in the plant. In this review the role of auxins in these processes will be evaluated. Some growth promoting plant hormones cause disease symptoms. For example auxins stimulate cell division and cell elongation in a healthy plant, but tumor formation after bacterial infection. Thus, control of auxin levels and auxin signaling pathways significantly contribute to the defense network in plants. Auxin can also act directly as defense molecule with antimicrobial activity. Since much research has been done in the recent years on auxin as a pathogenicity factor for many diseases, several examples will be presented to highlight the complexity between normal plant growth, which is regulated by auxin, and processes determining resistance or susceptibility, triggered by the same class of molecules. PMID- 25456607 TI - Prevalence, virulence, and antimicrobial resistance of Campylobacter jejuni and Campylobacter coli in white stork Ciconia ciconia in Poland. AB - The aim of this study was to investigate the role of white stork Ciconia ciconia as a potential reservoir of Campylobacter spp. Antimicrobial resistance and the presence of putative virulence genes of the isolates were also examined. A total of 398 white stork chicks sampled in Western Poland in habitats with high density of breeding were examined. Rectal swabs were collected during breeding season 2009-2012 from storks developing in a relatively pure environment (Odra meadows), in polluted areas (a copper mining-smelting complex), and in suburbs. Of the anal swabs collected, 7.6% were positive for Campylobacter among chicks (5.3% samples positive for C. jejuni and 2.3% samples positive for C. coli). Samples from polluted areas had the highest prevalence of Campylobacter (12.2%). The prevalence of resistance among C. jejuni and C. coli isolates from young storks was as follows: to ciprofloxacin (52.4%, 44.4%), and to tetracycline (19%, 77.8%). All of the analyzed isolates were susceptible to macrolides. The resistance to both classes of antibiotics was found in the 23.3% of Campylobacter spp. All Campylobacter spp. isolates had cadF gene and flaA gene responsible for adherence and motility. CdtB gene associated with toxin production was present in 88.9% of C. coli isolates and 57.1% of C. jejuni isolates. The iam marker was found more often in C. coli strains (55.6%) compared to C. jejuni isolates (42.9%). Our results confirm the prevalence of Campylobacter spp. in the white stork in natural conditions and, because it lives in open farmlands with access to marshy wetlands, the environmental sources such as water reservoirs and soil water can be contaminated from white stork feces and the pathogens can be widely disseminated. We can thus conclude that Campylobacter spp. may easily be transmitted to waterfowl, other birds, and humans via its environmental sources and/or by immediate contact. PMID- 25456608 TI - A systematic review and meta-analysis of the prebiotics and synbiotics effects on glycaemia, insulin concentrations and lipid parameters in adult patients with overweight or obesity. AB - BACKGROUND & AIMS: Several studies have reported the effects of prebiotics and synbiotics supplementation in lipid profile and glucose homeostasis, however a pooled analysis of clinical trials that assessed these parameters has not been performed in overweight or obese individuals. The aim of this study was to evaluate the effects of prebiotics and synbiotics on plasma lipid profile, fasting insulin and fasting glucose in adults with overweight or obesity. METHODS: Randomized controlled trials were systematically searched before May 2014 in electronic databases and screening reference lists. Combined and stratified (diabetics and non-diabetics trials) meta-analyzes were performed. RESULTS: Thirteen trials, representing 513 adult participants with Body Mass Index >=25 kg/m2 were included. Prebiotic supplementation reduced plasma total cholesterol (SMD -0.25; 95% CI -0.48, -0.02) and LDL-c (SMD -0.22; 95% CI -0.44, 0.00) concentrations in overall analysis, and reduced triglycerides (SMD -0.72; 95% CI -1.20, -0.23) and increased HDL-c (SMD 0.49; 95% CI 0.01, 0.97) concentrations in diabetic trials. Synbiotic supplementation reduced plasma fasting insulin (SMD -0.39; 95% CI -0.75, -0.02) and triglycerides (SMD -0.43; 95% CI -0.70, -0.15) concentrations. CONCLUSIONS: The improvement of the evaluated parameters supports prebiotics and synbiotics supplementation as an adjuvant therapy in obesity-related comorbidities, such as dyslipidemia and insulin resistance. PMID- 25456609 TI - Individualized measurement of disease-related malnutrition's costs. AB - BACKGROUND & AIMS: Disease-related malnutrition has a significant economic impact in hospitals, but accurate measurements of these costs have rarely been reported. The aim of this study is to calculate the actual costs of disease-related malnutrition in hospitals, taking into account every cost that patients generate during their hospital stay. METHODS: Patients admitted to medical wards were included in this study. Nutritional evaluation was carried out by two methods (Nutritional Risk Screening 2002 and Short Nutritional Assessment Questionnaire) at admission and/or at discharge. Hospitalization costs were measured for each patient individually, considering the cost of the bed, the Intensive Care Unit, the physicians' services, the laboratory tests and diagnostic procedures, and the drug costs. Differences in costs between malnourished patients and non malnourished patients were calculated. RESULTS: Malnourished patients incurred higher costs than non-malnourished ones. The cost increase for malnourished patients ranged between 45% and 102%. The nutritional status accounted for most of this increase. The most outstanding difference in patients' costs was between those patients who maintained their nutritional status, either well or malnourished, during their hospital stay. CONCLUSIONS: Disease-related malnutrition clearly has an impact on the cost of hospital care provision, particularly in malnourished patients who do not improve their nutritional status during their hospital stays. Individualized cost analyses are needed to identify the real costs of malnutrition. PMID- 25456610 TI - Psychometric Properties of the Canadian Little Developmental Coordination Disorder Questionnaire for Preschool Children. AB - AIMS: Test the psychometric properties and cut-off scores for the Canadian Little Developmental Coordination Disorder Questionnaire (Little DCDQ), which screens for coordination difficulties in children aged 3 to 4 years. METHODS: Parents of children with typical development (n = 108) and children at risk for motor problems (n = 245) completed the questionnaire. A subgroup (n = 119) of children was tested with the Movement Assessment Battery for Children-2 (MABC-2) and the Beery-Buktenica Developmental Test of visual-motor integration (VMI) to determine motor impairment (MI). RESULTS: Test-retest reliability (r = 0.956, p < .001) and internal consistency (Cronbach's alpha = 0.94) were high. Construct validity was supported by a factor analysis and significant difference in scores of children who were typically developing and were at risk. Concurrent validity was evaluated for the children who received standardized motor testing, with significant difference between children with and without MI. Discriminant function analysis showed that all 15 items were able to distinguish the two groups. The questionnaire correlated well with the MABC-2 and VMI. Validity as a screening tool was assessed using logistic regression modeling (X(2)(5) = 25.87, p < .001) and receiver operating curves, establishing optimal cut-off values with adequate sensitivity. CONCLUSIONS: The Little DCDQ is a reliable, valid instrument for early identification of children with motor difficulties. PMID- 25456611 TI - Hyperbaric oxygen therapy accelerates osteoblast differentiation and promotes bone formation. AB - OBJECTIVES: Hyperbaric oxygen therapy (HBO) has been used as an adjunctive therapy in the treatment of radiotherapy or bisphosphonate-induced osteonecrosis of the jaw however the effect of HBO on osteoblast formation and mineralisation has not been extensively studied. The current study therefore examined the effects of HBO, elevated pressure or elevated oxygen alone on osteoblast differentiation and bone nodule formation. METHODS: Saos-2 human osteoblast cells were exposed to HBO (2.4 ATA, 97.9% O2, 90 min per day), elevated pressure alone (2.4 ATA, 8.8% O2, 90 min per day) or elevated oxygen alone (1 ATA, 95% O2, 90 min per day) after culturing under normoxic or hypoxic conditions and osteoblast differentiation and bone formation assessed by alkaline phosphatase activity and calcein incorporation. Expression of key regulators of osteoblast differentiation and bone matrix proteins were assessed by quantitative PCR. RESULTS: Daily exposure to HBO accelerated the rate of osteoblast differentiation as determined by increased alkaline phosphatase activity and expression of type I collagen and Runx-2 mRNA during the early stages of culture. HBO also augmented bone nodule formation in hypoxic conditions. HBO had a more pronounced effect on these key markers of osteoblast differentiation than elevated oxygen or pressure alone. CONCLUSIONS: The data from this study shows that daily HBO treatment accelerated the rate of osteoblast differentiation leading to an increase in bone formation. CLINICAL SIGNIFICANCE: These studies add to our understanding of HBO's reparative action in osteonecrotic bone loss. In addition to stimulating angiogenesis HBO may also improve surgical outcomes through a direct beneficial effect on osteoblast differentiation generating a larger bone mass available for reconstruction. PMID- 25456612 TI - Effects of using different criteria for caries removal: a systematic review and network meta-analysis. AB - OBJECTIVES: Conventionally, caries excavation is performed until only hard dentine remains, while more selective and reliable criteria might be available. We aimed at systematically comparing the effects of using different excavation criteria via network meta-analysis. SOURCES: Electronic databases were searched for randomised or non-randomised clinical trials (RCTs/NRCTs) evaluating excavation of cavitated lesions. DATA: Criteria were divided into six groups: Excavation until pulpo-proximal dentine on the cavity floor was (1) either hard on probing, (2) slightly softened on probing, (3) not stainable by caries detector-dye, or until (4) self-limiting polymer burs, (5) fluorescence-assisted devices or (6) chemo-mechanical gels indicated termination of the excavation. Evaluation of risk of complications, risk of pain/discomfort, excavation time, and number of remaining bacteria were then undertaken using Bayesian network meta analysis. STUDY SELECTION: 28 studies (19 RCTs, 9 NRCTs) with 1782 patients (2555 lesions), most of them investigating primary teeth, were included. Risk of complications was highest when excavating until only non-stainable dentine remained, and lowest when not attempting to remove all softened dentine. Risk of pain significantly decreased if self-limiting chemo-mechanical excavation or fluorescence-assisted lasers were used instead of excavating until all dentine was hard. When not attempting to remove all softened dentine, the time required for excavation was shortest, whilst the greatest number bacteria remained. CONCLUSIONS: Not attempting to remove all softened or stainable dentine might reduce the risk of complications. Data regarding self-limiting excavation is insufficient for definitive conclusions. Excavation criteria should be validated against clinically relevant outcomes. CLINICAL SIGNIFICANCE: Given current evidence, dentists might not need to attempt excavation until only hard dentin remains in proximity to the pulp. Instead, their choice of excavation criterion or method should be guided by clinical requirements and outcomes. PMID- 25456613 TI - A randomised clinical trial investigating calcium sodium phosphosilicate as a dentine mineralising agent in the oral environment. AB - OBJECTIVE: The ability of a dentifrice containing the bioactive material calcium sodium phosphosilicate (CSPS) to remineralise the surface of dentine and physically occlude patent tubules was investigated in a 20 day in situ randomised clinical study. METHODS: Changes in surface microhardness and surface topography of dentine specimens treated for 5, 10, 15 and 20 days, twice daily with either a dentifrice containing 5% CSPS or a fluoride-only containing placebo dentifrice were compared. The substantivity of any mineral deposits formed on the surface of dentine were investigated by the application of an intra-oral dietary acid challenge twice daily during the final 10 days of treatment. RESULTS: After 5 and 10 days of treatment, the dentine samples in both treatment groups demonstrated an increase in surface microhardness. After 10 days of treatment the increase in surface hardness was directionally greater for the specimens treated with 5% CSPS dentifrice. Introducing an intra-oral acid exposure resulted in a reduction in surface microhardness which was significantly greater for the specimens treated with the placebo dentifrice compared to the dentifrice containing 5% CSPS, at day 20. Occlusion of the patent tubules was evident at each time-point and was significantly greater for the 5% CSPS containing dentifrice on days 5 and 10. On day 15 both dentifrices demonstrated the same degree of occlusion. CONCLUSION: This in situ study demonstrated that dentifrice containing 5% CSPS may have potential to mineralise and occlude the dentine in the oral environment. CLINICAL SIGNIFICANCE: This work provides evidence of potential agents that can be used to reduce the pain of dentine hypersensitivity when formulated into dentifrice and applied as part of a normal oral hygiene routine. PMID- 25456614 TI - The effects of ferrule configuration on the anti-fracture ability of fiber post restored teeth. AB - OBJECTIVES: To evaluate the fracture resistance of fibre post-restored teeth with various ferrule configurations by using fracture failure tests and extended finite element analysis (XFEM). METHODS: 60 Maxillary central incisors were collected and divided into six groups (n=10) according to various ferrule configurations with different ferrule heights in the labial or palatal region. All of the teeth were endodontically treated and restored by using fibre posts, composite cores and metal crowns. Fracture failure tests were performed on the post retained restorations until fracture occurred. The ultimate load was recorded and analyzed by one way analysis of variance (ANOVA). The fractured specimens were longitudinal sectioned and investigated by micro-stereomicroscope and scanning electronic microscope. XFEM was used to model the fracture of the post-restored teeth and exhibit crack initiation and propagation in the cement layers. RESULTS: Fracture failure tests indicated that the palatal ferrule significantly enhanced the fracture resistance of the post-restored teeth, regardless the height of the labial ferrule. The fractography investigation exhibited that the crack initiated at the palatal margin of the cement layer and propagated to the cervical region of the root. XFEM confirmed these findings and demonstrated that increasing of the palatal ferrule could effectively enhance the anti-fracture ability of the adhesive cement and protected the integrity of adhesive cement. CONCLUSION: Adhesive interface was the susceptible structure of the post retained restorations. Increasing palatal ferrule height could effectively reduce the stress concentrated within the palatal adhesive cement. CLINICAL SIGNIFICANCE: "Ferrule effect" exhibits the protection of the interity of cement layer. Increasing the ferrule height, especially in the palatal side, can significantly enhance the anti-fracture ability of fibre post-restored teeth. PMID- 25456615 TI - European college of orthodontics: commission of affiliation and titularisation. AB - Date of birth: 08/06/1996; sex: female. A PRETREATMENT RECORDS: (4/2007; 10.10 years). DIAGNOSIS: Class II division 2, agenesis of 22, tooth-size discrepancy (TSD) due to relative microdontia. TREATMENT: Multiattachment treatment and reopening of the space at 22. B POST-TREATMENT RECORDS: (6/2011; 14.12 years). RETENTION: Fiber splint from 13 to 23 including 22. Bonded wire from 33 to 43. C POST-RETENTION RECORDS: (3/2013; 15.10 years). PMID- 25456616 TI - Moving as a gift: relocation in older adulthood. AB - While discussions of accessibility, mobility and activities of daily living frame relocation studies, in older adulthood, the paper explores the emotional motivation of gift giving as a rationale for moving. This ethnographic study investigates the processes of household disbandment and decision-making of older adults in the Midwestern United States relocating in post-Global Financial Crisis contexts. In this study, relationships are created and sustained through the process of moving, linking older adults (n=81), their kin (n=49), and professionals (n=46) in the Midwestern United States. Using Marcel Mauss' The Gift (1925/1990) as a theoretical lens, relocation in older adulthood is conceptualized as a gift in two ways: to one's partner, and one's kin. Partners may consider gift-giving in terms of the act of moving to appease and honor their partner. Kin who were not moving themselves were also recipients of the gift of moving. These gifts enchain others in relationships of reciprocity. However these gifts, like all gifts, are not without costs or danger, so this paper examines some of the challenges that emerge along with gift-giving. PMID- 25456617 TI - Wellbeing in retirement villages: eudaimonic challenges and opportunities. AB - A retirement village consists of a collection of privately owned or leased flats or maisonettes for elderly adults that are supported by a central hub that provides catering, medical care and social activities. There have been studies of the psychological experience and impacts of such environments, however, there is lack of research that links the retirement village experience to overarching theories of eudaimonic wellbeing, and that uses qualitative methods to find out about how wellbeing manifests for the individual. This study used Ryff's (1989) model of wellbeing as a framework for analysis, while aiming to gain an in-depth understanding of the experiences and sources of wellbeing in residents of two retirement villages in the South East of England. Semi-structured interviews were carried out with 18 residents. Thematic analysis revealed a dialectical tension to retirement village living: while facilitating all six core components of eudaimonic wellbeing as conceptualized by Ryff's model, individuals living within the retirement villages also experience challenges to wellbeing on the same dimensions. An integrative model of these tensions between positive and negative experiences is presented and discussed. PMID- 25456618 TI - Challenging stereotypes? The older woman in the TV series Brothers & Sisters. AB - The TV series, Brothers & Sisters, broadcast from 2006 to 2011 by ABC (USA) and a year later by Channel 4 (UK) with quite high audience rates, starts when the patriarchal figure, William Walker, dies of a heart attack and two female figures around their sixties come center stage: his wife, Nora Walker, and his long-term lover, Holly Harper. Once the patriarchal figure disappears, the female characters regain visibility by entering the labor market and starting relationships with other men. In that sense, both protagonists experience aging as a time in which they are increasingly freed from social and family constraints. However, their roles as nurturers keep on bringing them back to the domestic space in which they are safe from being involved in uncomfortable and unsuitable situations. Drawing on previous studies on the representation of the older woman in fictional media, this article intends to discern to what extent stereotypes related to the older woman are challenged through the two main protagonists of a contemporary TV series. PMID- 25456619 TI - Aging and masculinity: portrayals in men's magazines. AB - Textual and visual representations of age are instructive as they suggest ideals towards which individuals should strive and influence how we perceive age. The purpose of our study was to investigate textual and visual representations of later life in the advertisements and interest stories of six widely read North American male-oriented magazines (namely, Esquire, GQ, Maxim, Men's Health, Men's Journal, and Zoomer). Through a content analysis and a visual textual analysis, we examined how older men were depicted in the magazine images and accompanying texts. Our findings revealed that older men were largely absent, and when portrayed, were positively depicted as experienced and powerful celebrities or as healthy and happy unknown individuals. The magazine advertisements and interest stories collectively required individuals to engage in consumer culture in order to achieve age and masculinity ideals and stave off the transition from the Third Age to the Fourth Age. We consider our findings in relation to theorizing about ageism, age relations, the Third and Fourth Ages, and idealized aging masculinity. PMID- 25456620 TI - Self-realization and cultural narratives about later life. AB - In late modern circumstances, aging individuals are confronted with the task of creating a meaningful individual life trajectory. However, these personal narratives are situated in the context of broader cultural narratives. It is argued that current cultural narratives about aging are often stereotyping and demeaning, being based on either a decline ideology or an age-defying ideology. This complicates the ascription of meaning to later life. We argue that narrative gerontology could profit from integrating a more cultural critical stance in its investigations. Dominant cultural narratives need to be challenged by viable counter narratives aimed at repairing and strengthening the moral agency of aging individuals. We discuss the criteria such counter narratives have to answer to and consider how the moral discourse on self-realization can provide an ideological foundation for meaning-generating cultural counter narratives on aging. PMID- 25456621 TI - "Small" things matter: residents' involvement in practice improvements in long term care facilities. AB - PURPOSE OF THE STUDY: The process of involving older clients with regard to their care arrangements has been the subject of previous studies. However, a more general overview of the issues addressed by older people living in long-term care (LTC) facilities, in order to inform practice improvements, is missing. This article explores which aspects of care that older people in LTC facilities want to improve, by means of a collective policy agenda-setting project, during which the participants voice their own experiences and concerns regarding LTC. DESIGN AND METHODS: Seven LTC facilities for older people in the Netherlands joined a collective agenda-setting project in which a total of 58 residents participated. Qualitative methods were used: participant observations (80 h in total) and semi structured interviews (n=16), which were analysed according to the principles of a qualitative content analysis. FINDINGS: There were many similarities between the seven organisations with regard to the proposed practice improvements. Nine topics were found to be important in improving the lives of older residents: a sense of community, feeling at home, social contacts between residents, independence, maintaining own hobbies and lifestyle, interpersonal conduct between residents and caregivers, being informed, security within the LTC facility, and food. IMPLICATIONS: Narratives about the daily lives and experiences of residents provided a rich understanding of what living in a LTC facility means, as well as the changes the residents wish to see. We found that according to the residents, the relatively 'small things' in life may have a big influence on improving the quality of life within LTC facilities. PMID- 25456622 TI - Aging gracefully: a comparative study of Japanese and Malaysian women aged 65-75. AB - Longer lives and extended retirement have created a 'young old age' stage of life. How people spend their "young old age" has become increasingly important. This research aims to investigate the different ageing experiences of Japanese and Malaysian women and the activities they engaged in their "young old age". In depth interviews were conducted to collect data and an adapted grounded theory approach was used for data analysis. Findings reveal many common characteristics for both groups of research participants. The emerging themes show that Japanese and Malaysian Chinese have different life missions evident in their daily activities, one passing on culture and the other passing on family values and life experience. They also differ in their choice of living arrangement (independent versus dependent/interdependent), attitudes to life (fighting versus accepting) and activities in which to engage (aesthetic pursuits versus family oriented activities). PMID- 25456623 TI - Understanding the personhood of Deaf people with dementia: methodological issues. AB - This article concerns Deaf people in the United Kingdom, who use sign language, who have a formal diagnosis of dementia and who have participated in interviews in British Sign Language (BSL) about their experience of living with dementia. We address the methodological challenges involved in enabling culturally meaningful participation in circumstances where the non-verbal is not equivalent to the non linguistic. We demonstrate the use of interpretative narrative representation of data for purposes of cultural brokering. We explore the contribution of Deaf people's experiences and the analysis of their visual, spatial narratives to debates about personhood and the embodied self in dementia studies. Finally, we consider the significance of the situational as cultural in relation to holistic interpretation of narrative. PMID- 25456624 TI - "Not a replacement": emotional experiences and practical consequences of Israeli second couplehood stepfamilies constructed in old age. AB - The increase in life expectancy enhances phenomena such as second couplehood in old age following widowhood or divorce as an alternative way of coping with changes that occur with aging. Research on the phenomenon has focused mainly on individual and dyadic perspectives of the repartnered. The aim of this article was to explore repartnering from the stepfamily's perspective, which has scarcely been studied. Nineteen Israeli stepfamilies (38 multigenerational families) were recruited using criterion sampling, of men who repartnered at age 65+ and women at 60+, with children and grandchildren from a lifelong marriage that ended in widowhood or divorce. We audio-recorded and transcribed verbatim 107 semi structured, qualitative interviews with older partners, their adult children, and grandchildren. Analysis was based on grounded theory and dyadic analysis principles adapted to families. It showed how repartnering in old age changed the family structure, constructing complex stepfamilies, which require further study. Emotional experiences refer to repartnering being a replacement for couplehood but not for parenthood/grandparenthood. Practical consequences refer to "knowing their place" within the stepfamily and included the following subthemes: showing affection; participating in memorials for the deceased spouse; sharing, listening, and assisting. Findings are discussed regarding life course and family life cycle perspectives. PMID- 25456625 TI - Embodied ageing and categorisation work amongst retirees in the Faroe Islands. AB - This paper addresses ageing and embodiment and explores how age is negotiated in interaction using Membership Categorisation Work. Data were derived from group and individual interviews with home-dwelling retirees in the Faroe Islands. The analysis showed that the interviewees negotiated age by drawing on two contrasting categories, placing themselves and others in the categories of 'old' or 'not old'. Good health was the main predicate tied to the category 'not old' and keeping busy and taking care of oneself were the main activities that the interviewees ascribed to the category 'not old'. The analysis also demonstrated how health as a moral discourse was actualised during the interviews. Staying active and in good health were not just talked about as ways to achieve personal well-being. The interviewees talked about having a responsibility to stay 'fit' for as long as possible to avoid being a burden to the society or to their families. PMID- 25456626 TI - The appraisal of difference: critical gerontology and the active-ageing-paradigm. AB - The article deals with the re-negotiation of old age in current times of flexible capitalism and its analysis by Critical Gerontologists who criticize this process as age denial and midlife-imperialism. Starting out from the instructive critique of active ageing and consumer-based anti-ageing strategies, rooted in the heterogeneous field of Critical Gerontology, the here presented contribution aims at critically reviewing and discussing this critique. The article exposes theoretical pitfalls that make this critique run into a dead-end, since old age tends to be homogenized and sometimes even naturalized within Critical Gerontology: Though certainly often unintended, the appreciation of old age as being positively different from midlife ends up with sheltering "old people" as "the others" from the impositions of active society. After elaborating on this difference perspective and discussing its problems, I will finally sketch some conceptual ideas, inspired by poststructuralist thinking, on how to overcome the fruitless dichotomy of imperialism/sameness ("they have to be like us") and difference ("they are the others"). PMID- 25456627 TI - Defining aging in cyborgs: a bio-techno-social definition of aging. AB - Initially the aim of this article was to discuss and define aging at the intersection point between biology and sociology. However, recent biomedical and technological advances are changing the discourse on aging, and against this background the author of this article argues that current definitions of aging should be improved. The author emphasizes that there is a need to update current definitions of aging, or to formulate new multidisciplinary ones. The author suggests that (besides biology, psychology and sociology) the technological discipline should be included in the integrative gerontology model. Finally, in this article a new definition of aging is put forward. According to the author of this article, human bio-techno-social aging is characterized by: (a) a time-bound process of change including, (b) both reversible and irreversible biological processes, (c) social processes forming an irreversible chain of events, and (d) an increasing use of technological artifacts whose purpose is to support or replace damaged biological functions; and/or an increasing use of technological artifacts whose purpose is to facilitate or enable interaction. PMID- 25456628 TI - All the things I have - handling one's material room in old age. AB - The article explores how old people who live in their ordinary home, reason and act regarding their 'material room' (technical objects, such as household appliances, communication tools and things, such as furniture, personal belongings, gadgets, books, paintings, and memorabilia). The interest is in how they, as a consequence of their aging, look at acquiring new objects and phasing out older objects from the home. This is a broader approach than in most other studies of how old people relate to materiality in which attention is mostly paid either to adjustments to the physical environment or to the importance of personal possessions. In the latter cases, the focus is on downsizing processes (e.g. household disbandment or casser maison) in connection with a move to smaller accommodation or to a nursing home. The article is based on a study in which thirteen older people (median age 87), living in a Swedish town of medium size were interviewed (2012) for a third time. The questions concerned the need and desire for new objects, replacement of broken objects, sorting out the home or elsewhere, most cherished possessions, and the role of family members such as children and grandchildren. The results reveal the complexity of how one handles the material room. Most evident is the participants' reluctance to acquire new objects or even to replace broken things. Nearly all of them had considered, but few had started, a process of sorting out objects. These standpoints in combination resulted in a relatively intact material room, which was motivated by an ambition to simplify daily life or to facilitate the approaching dissolution of the home. Some objects of special value and other cherished objects materialized the connections between generations within a family. Some participants wanted to spare their children the burden of having to decide on what to do with their possessions. Others (mostly men), on the contrary, relied on their children to do the sorting out after they had died. PMID- 25456629 TI - Participation and power in care: exploring the "client" in client engagement. AB - Despite growing recognition in health and care services of the necessity for client engagement, it is still not easily put into practice. This is owing to a range of factors relating to participating staff and clients, as well as the broader institutional context. One of the central factors affecting client engagement is the challenge it poses to traditional power relations inherent in care relationships and contexts. This is particularly the case in aged care services, which have traditionally positioned older adults in passive roles as "recipients" of care, or as lacking capacity to participate in care decision making. This paper presents an exploration of client engagement practices within a large aged care service provider in Australia. Interviews and focus group discussions with clients and staff were analysed for the ways in which clients were positioned - by both themselves and by staff - in terms of the roles that they hold within engagement practices. Four positions were identified: "Passivity, disempowerment and bestowal of power", "Role of expert/consumer", "Resistance, compliance and manageability", and "Complexity, diversity and uniqueness". While clients were positioned at times in empowering roles, they were simultaneously limited by personal, relational, or organisational constraints, making opportunities for client engagement provisional. This reflects a tension between passive and empowered client roles in the context of aged care provision. PMID- 25456630 TI - Administering questionnaires to older people: rigid adherence to protocol may deny and disacknowledge emotional expression. AB - This paper draws on data from a larger study conducted in care home facilities in: Seattle, USA; West Sussex and Surrey in the UK; and in the lower North Island in New Zealand. Two extracts from interactions between the researchers and an older person during the administration of The Philadelphia Geriatric Morale Scale in a care home facility in New Zealand were analysed following Houtkoop-Steenstra and using a Conversation Analysis (CA) approach. In the first extract the audio recorded transcript was examined for events of institutional talk and rephrasing of questionnaire questions. We also examined the transcript for missed cues and the impact of closed questions when administrating questionnaires to older people living in care home facilities. We then present an extract where the researcher uses a conversational approach during the administration of the same questionnaire. We conclude that rigid adherence to interview protocols when administering questionnaires to older people who cannot complete these themselves disables the interviewer from interacting and engaging in a meaningful conversation or responding to cues that indicate distress or expressions of grief. The effect of this approach may deny and disacknowledge older persons' emotional experiences and for the older person the interview may not be a therapeutic encounter. Based on our analysis and experiences of conducting this research we support recommendations that a collaborative approach, allowing an interactional exchange between interviewer and respondent, be used when administering questionnaires to older people in care home facilities. PMID- 25456631 TI - Successful ageing: a historical overview and critical analysis of a successful concept. AB - Since the late 1980s, the concept of 'successful ageing' has set the frame for discourse about contemporary ageing research. Through an analysis of the reception to John W. Rowe and Robert L. Kahn's launch of the concept of 'successful ageing' in 1987, this article maps out the important themes and discussions that have emerged from the interdisciplinary field of ageing research. These include an emphasis on interdisciplinarity; the interaction between biology, psycho-social contexts and lifestyle choices; the experiences of elderly people; life-course perspectives; optimisation and prevention strategies; and the importance of individual, societal and scientific conceptualisations and understandings of ageing. By presenting an account of the recent historical uses, interpretations and critiques of the concept, the article unfolds the practical and normative complexities of 'successful ageing'. PMID- 25456632 TI - 'Comfortable in my own skin': a new form of sexual freedom for ageing baby boomers. AB - 'Freedom of sexual expression' is a slogan that has long been synonymous with the generation known as the baby boomers during the 1960s and 1970s. But does this catchphrase still have currency for the men and women in this cohort who are mostly now over the age of fifty? This paper explores the question by reporting on qualitative data from a multi-method Australian study about the influence of growing older on baby boomers' sexual expression. The sample comprised ten interview participants and fifty-seven Internet survey respondents, aged between 50 and 70 years. Following a theoretical perspective known as the sociology of emotions, the analysis of data reveals that baby boomers' emotional experiences range from constraining to liberating sexual expression, to a paradoxical combination of both. The article argues that while sexual freedom is still an important concept to baby boomers, there are new emotional dimensions to its expression, particularly in the form of comfort and confidence, that come with age. PMID- 25456633 TI - Perceived control in health care: a conceptual model based on experiences of frail older adults. AB - Frail older adults are increasingly encouraged to be in control of their health care, in Western societies. However, little is known about how they themselves perceive control in health care. Therefore, this study aims to investigate the concept of health care-related perceived control from the viewpoint of frail older adults. A qualitative interview study was conducted following a Grounded Theory approach. Thirty-two Dutch frail older adults, aged 65 and over, participated in 20 in-depth interviews (n=20) and three focus group discussions (n=12). Data were analysed according to techniques of coding and constant comparison. From this analysis constituting factors of perceived control emerged, providing elements of a conceptual model. Perceived control reflects the feeling or belief that health care is under control, which is constituted by five, either internal or external, factors: (I) self-confidence in organising professional and/or informal care, (II) self-confidence in health management in the home setting, (III) perceived support from people in the social network, (IV) perceived support from health care professionals and organisations, and (V) perceived support from (health care) infrastructure and services. Therefore, the concept does not only consist of people's own perceived efforts, but also includes the influence of external sources. Our conceptual model points out what external factors should be taken into consideration by health care professionals and policy makers when enhancing older people's perceived control. Moreover, it can serve as the basis for the development of a measurement instrument, to enable future quantitative research on health care-related perceived control among older adults. PMID- 25456635 TI - Total hip arthroplasty after rotational acetabular osteotomy. AB - In this study, we aimed to determine whether the outcomes of total hip arthroplasty (THA) after rotational acetabular osteotomy (RAO) are equal to those of primary THA, and to elucidate the characteristics of THA after RAO. The clinical and radiographic findings of THA after RAO (44 hips), with minimum 24 months of follow-up, were compared with a matched control group of 58 hips without prior RAO. We found that the outcomes in terms of functional scores and complication rates did not differ between THA after RAO and THA without previous pelvic osteotomy, indicating that the results of THA after RAO are equivalent to those of primary THA. Although THA after RAO requires technical considerations, similar clinical outcomes to primary THA can be expected. PMID- 25456634 TI - From whom do older persons prefer support? The case of rural Thailand. AB - This study explores rural elderly preferences for support across a multi dimensional measure of elderly care needs. Applying a framework developed in the U.S. to Thailand for the first time, five diverse types of support are considered: meal preparation, personal care, transportation, financial support, and emotional support. The emphasis is on preferences for care and not actual care received. The data are from focus group discussions conducted in seven villages in Nang Rong district, northeastern Thailand. Thailand and the study site represent the social and economic conditions faced by many rapidly industrializing places-where there has been a dramatic demographic transition (lowered fertility and substantial out-migration), growing numbers of older persons remaining in rural settings, and limited publically-financed elderly care or market-based elder care available for purchase. For this study, in each village, male and female older persons aged 60 and over participated in the focus group discussions. As part of the discussion, focus group participants were asked to rank their first four preferences by type of support. Male and female older persons' preferences were slightly different for genderized tasks. In addition, social closeness and geographical proximity mattered. Traditional matrilocal residence patterns contributed to the perceptions of the older persons. Neighbors were preferred when kin were not available. Preferences inform strategic choices by older persons given the context of available resources. Understanding preferences and strategic choices among the older persons can help policy makers tailor programs more effectively and efficiently, without jeopardizing elderly well-being. PMID- 25456636 TI - Radiographic parameters associated with pain following total hip and surface arthroplasty. AB - Pain following total hip arthroplasty (THA) and surface arthroplasty (SRA) remains a significant source of patient dissatisfaction. Two hundred twenty-four SRA and 196 THA patients completed a pain drawing questionnaire and postoperative radiographic measurements of component positioning were performed. In the SRA cohort, 11 of 21 patients (52%) with acetabular uncoverage of >=5 mm versus 43 of 147 (29%) with acetabular uncoverage of <=4.9 mm reported groin pain (P=.03). In the THA cohort, an increased distal-third canal fill ratio and a lower canal calcar ratio trended towards a higher incidence of thigh pain (P=.10 and .06), while a decreased mid-third canal fill ratio was associated with increased severity of thigh pain (P=.04). This study identifies associations between radiographic findings and pain following THA and SRA. PMID- 25456637 TI - Primary collared uncemented total hip arthroplasties in the elderly: a safe and reliable treatment option. AB - The age of patients undergoing primary Total Hip Arthroplasty (THA) remains fairly constant despite an increasingly elderly population, possibly owing to concern over postoperative complications. This study evaluated 90-day outcomes in patients over 80, undergoing uncemented collared primary THA for osteoarthritis in a high volume unit. Data were recorded from 153 consecutive patients. There were 0.65% mortality rate and 1.3% major systemic complication rate. American Society of Anesthesiologist (ASA) grade was an independent predictor of inpatient complications. Mean preoperative and 90-day postoperative Oxford Hip Score was 24 and 46 respectively. No radiological evidence of femoral stem migration was seen. Our cohort shows low morbidity and mortality rates. ASA not age helps predict inpatient complications. Uncemented collared femoral prosthesis resulted in excellent functional and radiological outcomes. PMID- 25456638 TI - What is the level of evidence substantiating the Medicare local coverage determinations? AB - Total joint arthroplasty (TJA) accounts for large expenditures of Medicare resources. Recovery audit contractors (RACs) utilize Local Coverage Determinations (LCDs) documents to retrospectively assess the medical necessity of performed procedures. The Florida LCD requires 3 months of documented unsuccessful nonoperative care prior to TJA. The purpose of our study was to evaluate the applicability and quality of the evidence cited in the Florida LCD for patients undergoing TJA. Applicability was assessed by evaluating the efficacy of nonoperative treatment in candidates for TJA. There were 23 citations, of which 11 mentioned nonoperative treatment and only 5 provided references. No citations provided Level I or II evidence substantiating the effectiveness of 3 months of nonoperative treatment in patients who would otherwise be candidates for TJA. PMID- 25456639 TI - The comparison of genotyping, antibiogram, and antimicrobial resistance genes between carbapenem-susceptible and -resistant Acinetobacter baumannii. AB - This study was conducted to explore the epidemiological and molecular differences between carbapenem-susceptible Acinetobacter baumannii (CSAB) and carbapenem resistant A. baumannii (CRAB) isolates. Thirty-two CSAB and 55 CRAB isolates were collected in 2010. By multilocus sequence typing analysis, 31 (56%) CRAB isolates and 11 (34%) CSAB isolates belonged to ST2. Twenty-one (38%) CRAB isolates, and 4 (13%) CSAB isolates belonged to a new type, ST129. The blaIMP, blaVIM, and blaOXA 58-like were not detected in our study isolates. blaOXA-23 and blaOXA-24/40-like were not detected in all CSAB isolates. On the contrary, blaOXA-23 was detected in 51 (93%) CRAB isolates. Class 1 integron was detected in 19 (35%) CRAB isolates and 8 (25%) CSAB isolates (p>0.05). In conclusion, the ST2 and ST129 were the major sequence types in both CSAB and CRAB isolates. The blaOXA-23 is the primary carbapenem-resistance gene in CRAB isolates from hospitalized patients and the specimens collected from hospital environment. PMID- 25456640 TI - Update on diabetes classification. AB - This article highlights the difficulties in creating a definitive classification of diabetes mellitus in the absence of a complete understanding of the pathogenesis of the major forms. This brief review shows the evolving nature of the classification of diabetes mellitus. No classification scheme is ideal, and all have some overlap and inconsistencies. The only diabetes in which it is possible to accurately diagnose by DNA sequencing, monogenic diabetes, remains undiagnosed in more than 90% of the individuals who have diabetes caused by one of the known gene mutations. The point of classification, or taxonomy, of disease, should be to give insight into both pathogenesis and treatment. It remains a source of frustration that all schemes of diabetes mellitus continue to fall short of this goal. PMID- 25456641 TI - Internet blood glucose monitoring systems provide lasting glycemic benefit in type 1 and 2 diabetes: a systematic review. AB - Internet blood glucose monitoring systems (IBGMS) are associated with improved glycemic control in patients with type 2 diabetes (T2D) who are pharmacologically managed, using oral agents or insulin. IBGMS improves glycemic levels in patients with type 1 diabetes (T1D). IBGMS has not led to increased hypoglycemia. Mechanisms underlying IBGMS-associated glycemic improvement extend beyond optimizing insulin dose titration. The most important effects seem to be associated with increased patient self-motivation and improved patient-physician communication. IBGMS have been recommended in clinical practice guidelines, and their effectiveness and safety in trials suggest that this approach is appropriate for patients with T1D or T2D. PMID- 25456642 TI - Monitoring glycemia in diabetes. AB - Monitoring of glycemic control is a key component of the diabetes treatment plan. Patients who are not meeting targets often require more intensive monitoring, ranging from frequent self-monitored glucose to continuous glucose monitoring in order to facilitate medication and lifestyle changes. However, more intensive monitoring demands more training and a structured plan for interpretation and use of the data. Better patient and provider tools to support decision-making and progress toward an artificial pancreas may help to alleviate this burden. PMID- 25456643 TI - Glycemic targets: what is the evidence? AB - Hyperglycemia is the unifying metabolic abnormality for all forms of diabetes mellitus, forming the basis for its diagnosis and treatment. The strong epidemiologic associations between hyperglycemia and the complications of diabetes have given rise to the glucose hypothesis-that the complications of diabetes are caused by hyperglycemia and that they can be prevented by normalizing glucose levels. Herein the authors review the epidemiologic relationships between hyperglycemia and the complications of diabetes, the major trials of glucose lowering, and the extent to which the glucose hypothesis is supported by these studies and how this information can be translated into clinical practice. PMID- 25456644 TI - Lifestyle intervention: nutrition therapy and physical activity. AB - Diabetes now affects more than 29 million Americans, and more than 9 million of these people do not know they have diabetes. In adults, type 2 diabetes accounts for about 90% to 95% of all diagnosed cases of diabetes and is the focus of this article. Lifestyle intervention is part of the initial treatment as well as the ongoing management of type 2 diabetes. Lifestyle intervention encompasses a healthful eating plan, physical activity, and often medication to assist in achievement of glucose, lipid, and blood pressure goals. Patient education and self-care practices are also important aspects of disease management. PMID- 25456645 TI - Oral antihyperglycemic treatment options for type 2 diabetes mellitus. AB - Table 3 provides an overview of the oral antihyperglycemic drugs reviewed in this article. A 2011 meta-analysis by Bennett and colleagues found low or insufficient quality of evidence favoring an initial choice of metformin, SUs, glinides, TZDs, or (table see text) DPP-4 inhibitors (alpha-glucosidase inhibitors, bromocriptine mesylate, and SGLT2 inhibitors were not included in this meta-analysis) with regard to the outcomes measures of all-cause mortality, cardiovascular events and mortality, and incidence of microvascular disease (retinopathy, nephropathy, and neuropathy) in previously healthy individuals with newly diagnosed T2DM. Likewise, the Bennett and colleagues meta-analysis judged these drugs to be of roughly equal efficacy with regard to reduction of HbA1c (1%-1.6%) from the pretreatment baseline. The ADOPT clinical trial of 3 different and, at the time, popular, oral monotherapies for T2DM provides support for the consensus recommendation of metformin as first-line therapy. The ADOPT trial showed slightly superior HbA1c reduction for rosiglitazone compared with metformin, which was in turn superior to glyburide. However, significant adverse events, including edema, weight gain, and fractures, were more common in the rosiglitazone-treated patients. The implication of this trial is that the combination of low cost, low risk, minimal adverse effects, and efficacy of metformin justifies use of this agent as the cornerstone of oral drug treatment of T2DM. Judicious use of metformin in groups formerly thought to be at high risk for lactic acidosis (ie, those with CHF, chronic kidney disease [eGFR >30 mL/min/1.73 m2], and the elderly) may be associated with mortality benefit rather than increased risk. Secondary and tertiary add-on drug therapy should be individualized based on cost, personal preferences, and overall treatment goals, taking into account the wishes and priorities of the patient. PMID- 25456646 TI - Incretin-based therapies. AB - Incretin-based therapies are steadily gaining clinical popularity, with many more products in the developmental pipeline. Current treatment recommendations incorporate GLP-1 RAs and DPP-4 inhibitors as important agents for consideration in the treatment of T2DM owing to their low hypoglycemia risk, ability to address postprandial hyperglycemia (DPP-4 inhibitors and short-acting GLP-1 RAs), and potential for weight reduction (GLP-1 RAs). These properties may likewise prove advantageous in older adults in whom hypoglycemia is particularly undesirable, although older adults may be more prone to the nausea and vomiting associated with GLP-1 RA therapy. Other safety issues for incretin-based therapies, such as pancreatitis, C-cell hyperplasia, and renal failure, should be considered when choosing an appropriate patient to receive such therapies. Ongoing CV outcome studies will further inform the health care community regarding the CV safety of incretin-based therapies. The availability of both short-acting and long-acting GLP-1 RAs currently allows practitioners to consider individualized blood glucose trends and therapeutic needs when choosing an optimal agent. PMID- 25456648 TI - Insulin therapy in type 1 diabetes. AB - Although not curable, type 1 diabetes is eminently controllable. IIT, as guided by the results of landmark studies such as the DCCT, provides primary care providers with a blueprint for reducing the frequency of the devastating complications of diabetes that were all too common in the recent past. Considering the remarkable advances in contemporary therapy, including MDI and CSII, the likelihood of even greater future improvements in quality of life and survivability can be anticipated. Success requires patient engagement and education, an informed primary care provider, and an interdisciplinary team to maximize the benefits of insulin therapy and avoid the risks of hypoglycemia. PMID- 25456647 TI - Sodium glucose cotransporter 2 inhibitors. AB - SGLT2 inhibition offers a novel mechanism to mitigate hyperglycemia in patients with diabetes and the introduction of SGLT2 has added a significant new tool to the antihyperglycemic armamentarium. At present, 2 agents are approved for use in the United States and several more are in development. SGLT2 inhibitors are generally associated with a reduction in A1C of between 0.5% and 1%. SGLT2 inhibitors are associated with an increased incidence of urinary tract and genital infections but these infections are typically mild, responsive to treatment, and are not use limiting. PMID- 25456649 TI - Insulin tactics in type 2 diabetes. AB - Insulin is the most powerful glycemic control agent available. However, its use as a therapeutic modality requires education of the patient and regimentation of food intake, exercise, and frequent glucose monitoring. Such regimentation is particularly important when using a basal-bolus therapy approach. The introduction of many novel noninsulin drugs in the past decade has resulted in better glycemic control and often a need to reduce previously instituted insulin therapy. Although many of these novel therapies by themselves do not cause hypoglycemia, by reducing the overall glycemic burden through a myriad of mechanisms, they function in an insulin-sparing fashion. The doses of exogenously administered insulin may therefore need to be reduced in the presence of these new drugs to mitigate hypoglycemia. For insulin therapy (or any other drug treatment) to be successful, it is critical that the physician not only establish glycemic goals, but communicate these goals to the patient. The measurement of HbA1c helps in achieving a long-term goal, but on a day-today basis, patients need to be cognizant of their own BG goals and what they need to do if falling outside of target. The patients' understanding of self-management skills and empowerment are therefore foundational to insulin therapy. PMID- 25456650 TI - Nonglycemic targets in diabetes. AB - In conclusion, targets for patients with diabetes have actually become simpler with the release of new guidelines. The targets discussed in this article are summarized in Box 3. Finally, as clinicians and patients with diabetes struggle with the overwhelming burden of care, clinicians should consider the increasingly codified ethic of minimally disruptive medicine, which considers not just what patients and doctors can do but what patients' priorities, wishes, and needs are rather than the many specialist tests and treatment options available. Finding the balance may be easier with the new evidence-based and more straightforward guidelines. PMID- 25456651 TI - Screening and treatment by the primary care provider of common diabetes complications. AB - Diabetes is the leading cause of end-stage renal disease, blindness, and nontraumatic lower-limb amputation. The largest reductions in cardiovascular events are seen when multiple risk factors are addressed simultaneously. The benefit of aspirin as secondary prevention in patients with previous stroke or myocardial infarction has been well established. Regular, dilated eye examinations are effective in detecting sight-threatening diabetic retinopathy and have been shown to prevent blindness. The use of appropriate tools and clinical examination/inspection provides greater than 87% specificity in detecting diabetic peripheral neuropathy. Early treatment of risk factors, including hypertension, hyperglycemia, and dyslipidemia can delay or prevent diabetic nephropathy. PMID- 25456654 TI - Diabetes management. Preface. PMID- 25456652 TI - Polycystic ovarian syndrome. AB - Women with PCOS present with signs of chronic anovulation, hyperandrogenism, and metabolic abnormalities. The NIH recently embraced the Rotterdam criteria to broadly identify all the phenotypes of PCOS. Women with PCOS are often obese with insulin resistance and hence have an increased susceptibility to glucose intolerance and type 2 diabetes. Future research should focus on the genetic, epigenetic, and environmental determinants of PCOS to develop new therapies to address the prevention of this disorder and its long-term complications. PMID- 25456655 TI - Restrained tibial rotation may prevent ACL injury during landing at different flexion angles. AB - BACKGROUND: Internal tibial rotation is a risk factor for anterior cruciate ligament (ACL) injury. The effect of restraining tibial rotation (RTR) to prevent ACL injury during single-leg landing is not well understood. We aimed to investigate the effect of impact load and RTR on ACL injury with respect to flexion angle. We hypothesized that RTR could protect the knee from ACL injury compared to free tibial rotation (FTR) regardless of flexion angle and create a safety zone to protect the ACL. METHODS: Thirty porcine specimens were potted in a rig manufactured to replicate single-leg landing maneuvers. A mechanical testing machine was used to apply external forces in the direction of the tibial long axis. A 3D displacement sensor measured anterior tibial translation (ATT). The specimens were divided into 3 groups of 10 specimens and tested at flexion angles of 22 +/- 1 degrees , 37 +/- 1 degrees and 52 +/- 1 degrees (five RTR and five FTR) through a consecutive range of actuator displacements until ACL failure. After dissection, damage to the joint was visually recorded. Two-way ANOVA were utilized in order to compare compressive forces, torques and A/P displacements with respect to flexion angle. RESULTS: The largest difference between peak axial compressive forces (~3.4 kN) causing ACL injury between RTR and FTR was reported at a flexion angle of 22 degrees . Tibial torques with RTR was in the same range and < 20 Nm at the instance and just before ACL failure, compared to a significant reduction when cartilage/bone damage (no ACL failure) was reported. Isolated ACL injuries were observed in ten of the 15 FTR specimens. Injuries to bone and cartilage were more common with RTR. CONCLUSIONS: RTR increases the threshold for ACL injury by elevating the compressive impact load required at lower flexion angles. These findings may contribute to neuromuscular training programs or brace designs used to avoid excessive internal/external tibial rotation. Caution must be exercised as bone/cartilage damage may result. PMID- 25456656 TI - Competitive binding of Chlorin p6 and Dansyl-l-Proline to Sudlow's site II of human serum albumin. AB - The binding of chlorin p6, a model photosensitizer for photodynamic therapy (PDT), to the Sudlow's site II of Human Serum Albumin (HSA) has been monitored by different spectroscopic methods. Displacement of Dansyl-l-Proline (DP) from its conjugate with HSA is manifested in the spectral shift and decrease in its fluorescence intensity as well as the emergence of component with lifetime of 2 3ns, which is characteristic of free DP. As DP is known to bind specifically to the Sudlow's site II of human serum albumin, its displacement by chlorin p6 indicates the residence of the photosensitizer in the same site, in addition to Sudlow's site I. The binding constants for Sudlow's site II, determined by the stopped-flow technique, are found to be two orders of magnitude smaller than that for Sudlow's site I. PMID- 25456657 TI - Photoisomerization mechanism of 1,1'-dimethyl-2,2'-pyridocyanine in the gas phase and in solution. AB - The trans->cis and cis->trans photoisomerization mechanisms of 1,1'-dimethyl-2,2' pyridocyanine have been investigated theoretically in the gas phase and in methanol. Two-dimensional potential energy surfaces were computed for the ground and first excited singlet states of the isolated molecule using complete active space self-consistent field method. Our computations suggest that the torsion around the central C-C bonds with carbon-out-of-plane motion is the preferred photoisomerization mechanism. In the gas phase, conical intersections were found near the minima of excited state. The excited-state decay follows a barrierless minimum-energy pathway before the molecule moves to the excited-state global minimum (minS1) and the system relaxes to the ground state through a conical intersection. In methanol, the system would first reach a stationary structure of C2 symmetry after the trans form is electronically excited. Solvent polarity effects were investigated in chloroform, dichloromethane, 1-propanol, ethanol, methanol, and water. There is a significant barrier between the stationary structure of C2 symmetry and minS1 in the excited state in high polarity solvents. Thus, Me-1122P has a much longer lifetime of the excited state in solvents of high polarity. PMID- 25456658 TI - Stability indicating spectrophotometric and spectrodensitometric methods for the determination of diatrizoate sodium in presence of its degradation product. AB - Three sensitive, selective, and precise stability indicating methods for the determination of the X-ray contrast agent, diatrizoate sodium (DTA), in the presence of its acidic degradation product (highly cytotoxic 3,5 diamino metabolite) and in pharmaceutical formulation were developed and validated. The first method is a first derivative (D1) spectrophotometric one, which allows the determination of DTA in the presence of its degradate at 231.2 nm (corresponding to zero crossing of the degradate) over a concentration range of 2-24 MUg/mL with mean percentage recovery 99.95+/-0.97%. The second method is the first derivative of the ratio spectra (DD1) by measuring the peak amplitude at 227 nm over the same concentration range as D1 spectrophotometric method, with mean percentage recovery 99.99+/-1.15%. The third method is a TLC-densitometric one, where DTA was separated from its degradate on silica gel plates using chloroform:methanol:ammonium hydroxide (20:10:2 by volume) as a developing system. This method depends on quantitative densitometric evaluation of thin layer chromatogram of DTA at 238 nm over a concentration range of 4-20 MUg/spot, with mean percentage recovery 99.88+/-0.89%. The selectivity of the proposed methods was tested using laboratory-prepared mixtures. The proposed methods have been successfully applied to the analysis of DTA in pharmaceutical dosage forms without interference from other dosage form additives. The results were statistically compared with the official US pharmacopeial method. No significant difference for either accuracy or precision was observed. PMID- 25456659 TI - Intracellular synthesis of silver nanoparticle by actinobacteria and its antimicrobial activity. AB - Intracellular synthesis of silver nanoparticles (AgNPs) using Rhodococcus spp. is demonstrated. The synthesized nanoparticles were characterized by UV-Vis spectroscopy, X-ray diffraction, energy dispersive spectroscopy, Fourier trans form infrared spectroscopy, and transmission electron microscopy. Transmission electron microscopy study of microorganisms' revealed synthesis of nanoparticle was occurring inside the cell, in the cytoplasm. AgNPs ranged from 5 to 50 nm. Formed nanoparticles were stable in the colloidal solution due to presence of proteins on the surface. AgNPs showed excellent bactericidal and bacteriostatic activity against pathogenic microorganisms. PMID- 25456660 TI - High performance liquid chromatography coupled with resonance Rayleigh scattering for the detection of three fluoroquinolones and mechanism study. AB - A reliable and versatile high performance liquid chromatography coupled with resonance Rayleigh scattering method was established for the determination of three fluoroquinolones, including levofloxacin, norfloxacin and enrofloxacin in water sample and human urine sample. In pH 4.4-4.6 Britton-Robinson buffer medium, the fluoroquinolones separated by high performance liquid chromatography could react with erythrosine to form 1:1 ion-association complexes, which could make contributions to the great enhancement of RRS. The resonance Rayleigh scattering signal was recorded at lambdaex=lambdaem=330 nm. The resonance Rayleigh scattering spectral characteristics of the drugs and the experimental conditions such as pH, detection wavelength, erythrosine concentration, flow rate, the length of reaction tube were studied. Quantum chemistry calculation, Fourier transform infrared spectroscopy and absorption spectroscopy were used to discuss the reaction mechanism. The recoveries of samples added standard ranged from 97.53% to 102.00%, and the relative standard deviation was below 4.64%. The limit of detection (S/N=3) of 0.05-0.12 MUg mL(-1) was reached, and the linear regression coefficients were all above 0.999. The proposed method was proved as a simple, low cost and high sensitivity method. PMID- 25456661 TI - A new pyrazoline-based fluorescent sensor for Al3+ in aqueous solution. AB - A new pyrazoline-based fluorescent sensor was synthesized and the structure was confirmed by single crystal X-ray diffraction. The sensor responds to Al(3+) with high selectivity among a series of cations in aqueous methanol. This sensor forms a 1:1 complex with Al(3+) and displays fluorescent quenching. PMID- 25456662 TI - Nature and origin of white efflorescence on bricks, artificial stones, and joint mortars of modern houses evaluated by portable Raman spectroscopy and laboratory analyses. AB - Bricks and mortar currently constitute one of the most important building materials used in the construction of most modern facades. The deterioration of these materials is caused primarily by the impact of numerous external stressors, while poor manufacturing quality, particularly of mortars, can also contribute to this process. In this work, the non-invasive Raman spectroscopy technique was used to identify the recently formed deterioration compounds (primarily sulfates and nitrates) in bricks, artificial stones, and joint mortars from detached houses in the Bilbao metropolitan area (Basque Country, North of Spain), as well as to investigate the deterioration processes taking place in these materials. Additionally, to confirm and in some cases complement the results obtained with Raman spectroscopy, SEM-EDS and XRD measurements were also carried out. PMID- 25456663 TI - Structural, spectroscopic and theoretical studies of dimethylphenyl betaine complex with two molecules of 2,6-dichloro-4-nitro-phenol. AB - The 1:2 complex (1) of dimethylphenyl betaine (DMPB) with two molecules of 2,6 dichloro-4-nitro-phenol (DCNP) was prepared and characterized by X-ray diffraction, B3LYP/6-311++G(d,p) and B3LYP-D3/6-311++G(d,p)calculations, FTIR and NMR spectroscopies. The crystal is monoclinic, space group P21/c with Z=4. The protons at the oxygen atoms of phenols are bonded to each oxygen atoms of the DMPB carboxylate group by two nonequivalent H-bonds with the OH?O distances of 2.473(5) and 2.688(4)A. Both H-bonds in the optimized structures 2 (in vacuum), 3 (in DMSO solution) and dispersion-correlated functional (D3) 4 (in vacuum) are comparable and are slightly shorter than O(6)H(O6)?O(2) in the crystal. The FTIR spectrum of 1 shows a broad absorption in the 3400-2000cm(-1) region corresponding to a longer hydrogen bond and a broad absorption in the 1800-500cm( 1) region caused by the shorter H-bond. The relations between the experimental (13)C and (1)H chemical shifts (deltaexp) of the investigated compound 1 in DMSO solution and GIAO/B3LYP/6-311++G(d,p) magnetic isotropic shielding constants (sigmacalc) obtained by using the screening solvation model (COSMO) for 3 are linear and reproduce well the experimental chemical shifts described by the equation: deltaexp=a+b sigmacalc. PMID- 25456664 TI - Molecular structure, vibrational spectra, AIM, HOMO-LUMO, NBO, UV, first order hyperpolarizability, analysis of 3-thiophenecarboxylic acid monomer and dimer by Hartree-Fock and density functional theory. AB - In this work, the molecular structure, harmonic vibrational frequencies, UV, NBO and AIM of 3-thiophenecarboxilic acid (abbreviated as 3-TCA) monomer and dimer has been investigated. The FT-IR and FT-Raman spectra were recorded. The ground state molecular geometry and vibrational frequencies have been calculated by using the Hartree-Fock (HF) and density functional theory (DFT)/B3LYP methods and 6-311++G(d,p) as a basis set. The fundamental vibrations were assigned on the basis of the total energy distribution (TED) of the vibrational modes, calculated with VEDA program. Comparison of the observed fundamental vibrational frequencies of 3-TCA with calculated results by HF and DFT methods indicates that B3LYP is better to HF method for molecular vibrational problems. The difference between the observed and scaled wavenumber values is very small. The theoretically predicted FT-IR and FT-Raman spectra of the title compound have been constructed. A study on the Mulliken atomic charges, the electronic properties were performed by time-dependent DFT (TD-DFT) approach, frontier molecular orbitals (HOMO-LUMO), molecular electrostatic potential (MEP) and thermodynamic properties have been performed. The electric dipole moment (MU) and the first hyperpolarizability (beta) values of the investigated molecule have been also computed. PMID- 25456665 TI - Study on optical properties of l-valine doped ADP crystal. AB - Single crystal of l-valine doped ammonium dihydrogen phosphate has been grown by slow evaporation method at room temperature. The crystalline nature of the grown crystal was confirmed using powder X-ray diffraction technique. The different functional groups of the grown crystal were identified using Fourier transform infrared analysis. The UV-visible studies were employed to examine the high optical transparency and influential optical constants for tailoring materials suitability for optoelectronics applications. The cutoff wavelength of the title crystal was found to be 280nm with wide optical band gap of 4.7eV. The dielectric measurements were carried to determine the dielectric constant and dielectric loss at room temperature. The grown crystal has been characterized by thermogravimetric analysis. The second harmonic generation efficiency of the grown crystal was determined by the classical Kurtz powder technique and it is found to be 1.92 times that of potassium dihydrogen phosphate. The grown crystal was identified as third order nonlinear optical material employing Z-scan technique using He-Ne laser operating at 632.8nm. PMID- 25456666 TI - Procedure optimization for green synthesis of silver nanoparticles by aqueous extract of Eucalyptus oleosa. AB - The present study is dealing with the green synthesis of silver nanoparticles using the aqueous extract of Eucalyptus oleosa as a green synthesis procedure without any catalyst, template or surfactant. Colloidal silver nanoparticles were synthesized by reacting aqueous AgNO3 with E. oleosa leaf extract at non photomediated conditions. The significance of some synthesis conditions such as: silver nitrate concentration, concentration of the plant extract, time of synthesis reaction and temperature of plant extraction procedure on the particle size of synthesized silver particles was investigated and optimized. The participations of the studied factors in controlling the particle size of reduced silver were quantitatively evaluated via analysis of variance (ANOVA). The results of this investigation showed that silver nanoparticles could be synthesized by tuning significant parameters, while performing the synthesis procedure at optimum conditions leads to form silver nanoparticles with 21nm as averaged size. Ultraviolet-visible spectroscopy was used to monitor the development of silver nanoparticles formation. Meanwhile, produced silver nanoparticles were characterized by scanning electron microscopy, energy dispersive X-ray, and FT-IR techniques. PMID- 25456667 TI - FTIR spectroscopy of woods: A new approach to study the weathering of the carving face of a sculpture. AB - Fourier transform infrared spectroscopy (FTIR), a useful method to study woods, has been applied in order to measure an eventual gradient of water absorbed (more precisely, hydroxyl groups, OH) between the surface and the inner part of an ancient and a modern wooden sculptures. The methodology adopted has consisted in comparing FTIR bands within two spectral ranges, one corresponding to the OH content in the wood (around 3400cm(-1)) and the other to the lignin molecules (aromatic CC, around 1610cm(-1)). The ratio between the intensities of the peaks leads to a self-normalization of the measurements which avoids the effects of some experimental parameters (such as sample preparation). The results obtained show that there is a significant and progressive penetration of OH groups from the surface to the inside part of the ancient sculpture (more OH on the surface than inside the wood, due to the aging of the surface and the creation of sites which are able to fix OH groups). In contrary, for the modern one, we measure an increase of OH contents from the surface to the inner part of the sculpture. PMID- 25456668 TI - Quantum mechanical study and spectroscopic (FT-IR, FT-Raman, (13)C, (1)H) study, first order hyperpolarizability, NBO analysis, HOMO and LUMO analysis of 2 acetoxybenzoic acid by density functional methods. AB - In this work, colorless crystals of 2-acetoxybenzoic acid were grown by slow evaporation method and the FT-IR and FT-Raman spectra of the sample were recorded in the region 4000-500cm(-1) and 4000-100cm(-1) respectively. Molecular structure is optimized with the help of density functional theory method (B3LYP) with 6 31+G(d,p), 6-311++G(d,p) basis sets. Stability of the molecule arising from hyperconjugation and charge delocalization is confirmed by the natural bond orbital analysis (NBO). The results show that electron density (ED) in the sigma(*) antibonding orbitals and E(2) energies confirms the occurrence of intramolecular charge transfer (ICT) within the molecule. The assignments of the vibrational spectra have been carried out with the help of normal coordinate analysis following the scaled quantum mechanical force field (SQMFF) methodology. The results of the calculations were applied to simulated spectra of the title compound, which show excellent agreement with observed spectra. The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by GIAO method. Mulliken population analysis on atomic charges is also calculated. The calculated HOMO and LUMO energy gap shows that charge transfer occurs within the molecule. PMID- 25456669 TI - Novel indole based dual responsive "turn-on" chemosensor for fluoride ion detection. AB - An efficient new dual channel chemosensor 2,3-bis((E)-(1H-indole-3 yl)methyleneamino)maleonitrile (DN) which exhibits selective sensing of F(-) ions in DMSO, was synthesized by a facile one step condensation reaction of indole-3 carboxaldehyde with diaminomaleonitrile. The probe DN was characterized by elemental analysis, (1)H, (13)C-NMR, ESI-MS and IR spectral techniques. Upon addition of F(-), DN induces remarkable changes in both absorption and fluorescence spectra on the basis of charge transfer mechanism. The receptor DN serves for highly selective, sensitive detection of F(-) without the interference of other relevant anions. The Job's plot analysis indicates the binding stoichiometry to be 1:1 (host/guest). PMID- 25456670 TI - Monitoring simultaneous photocatalytic-ozonation of mixture of pharmaceuticals in the presence of immobilized TiO2 nanoparticles using MCR-ALS: Identification of intermediates and multi-response optimization approach. AB - The present study has focused on the degradation of a mixture of three pharmaceuticals, i.e. methyldopa (MDP), nalidixic acid (NAD) and famotidine (FAM) which were quantified simultaneously during photocatalytic-ozonation process. The experiments were conducted in a semi-batch reactor where TiO2 nanoparticles (crystallites mean size 8nm) were immobilized on ceramic plates irradiated by UV A light in the proximity of oxygen and/or ozone. The surface morphology and roughness of the bare and TiO2-coated ceramic plates were analyzed using scanning electron microscopy (SEM) and atomic force microscopy (AFM). An analytical methodology was successfully developed based on both recording ultraviolet visible (UV-Vis) spectra during the degradation process and a data analysis using multivariate curve resolution with alternating least squares (MCR-ALS). This methodology enabled the researchers to obtain the concentration and spectral profiles of the chemical compounds which were involved in the process. A central composite design was used to study the effect of several factors on multiple responses namely MDP removal (Y1), NAD removal (Y2) and FAM removal (Y3) in the simultaneous photocatalytic-ozonation of these pharmaceuticals. A multi-response optimization procedure based on global desirability of the factors was used to simultaneously maximize Y1, Y2 and Y3. The results of the global desirability revealed that 8mg/L MAD, 8mg/L NAD, 8mg/L FAM, 6L/h ozone flow rate and a 30min reaction time were the best conditions under which the optimized values of various responses were Y1=95.03%, Y2=84.93% and Y3=99.15%. Also, the intermediate products of pharmaceuticals generated in the photocatalytic-ozonation process were identified by gas chromatography coupled to mass spectrometry. PMID- 25456671 TI - The photophysical behavior of the photochromic naphthopyran derivative having photo-switching ability. AB - The photophysical behavior of the photochromic naphthopyran derivative 9 with photo-switching ability has been investigated in solution phase as well as in crystalline form. The proposed switching motifs might be a versatile framework in the development of photonic devices whose properties can be toggled between two states on exposure to electromagnetic radiations. The closed form of 9 undergoes reversible transformation upon irradiation with light by changing the molecular structure from ring closed conformation 9 to the ring opened form 10. The compound 9 exhibited first absorption signal at 238nm with shoulder peak at 261nm and second absorption signal at 353nm while on photo-irradiation, the colorless solution of 9 turn to colored and there was ratiometric downfall in the signal intensity for shoulder signal at 261nm as well as second absorption signal at 353nm and ultimately results in the disappearance of these both signal after 20min of irradiations. Meanwhile, the colorimetric change in the reaction solution and considerable shift in the absorption and emission signal intensity as well as position suggest the conformational changes in the molecules from less conjugate conformation 9 to the extended conjugated conformation 10. PMID- 25456672 TI - A combined theoretical and experimental study of chelidamate cadmium (II) complex, [Cd2(dpa)2(chel)2]?2[Cd(dpa)(chel)]?6H2O. AB - A new chelidamate complex of Cd (II) ion, [Cd2(dpa)2(chel)2]?2[Cd(dpa)(chel)]?6H2O [(chel: chelidamate or 4-hydroxypyridine 2,6-dicarboxylate, dpa: di (2-picolyl)amine)] was synthesized and characterized by spectroscopic (UV-Vis and FT-IR spectroscopy) and structural (single-crystal X ray diffraction) methods. Quantum chemical calculations were carried out by using Hartree Fock (HF) and Density Functional Theory (DFT)/B3LYP methods Stuttgart/Dresden (SDD) basis set. The asymmetric unit of the title compound contains two symmetry unrelated monomeric units, one dimeric unit and six water molecules of crystallization. The geometries around the Cd (II) metal centers in the units can be described as distorted octahedral for the monomeric units and distorted monocapped trigonal prism for the dimeric unit. The electronic structure of the complex was calculated using time dependent DFT (TD-DFT) method with polarizable continuum model (PCM). Molecular stability and bond strength were investigated by applying natural bond orbital analysis (NBO). The computed frequencies were compared with experimental frequencies. PMID- 25456673 TI - A study of selective spectrophotometric methods for simultaneous determination of Itopride hydrochloride and Rabeprazole sodium binary mixture: Resolving sever overlapping spectra. AB - Itopride hydrochloride (IT) and Rabeprazole sodium (RB) are co-formulated together for the treatment of gastro-esophageal reflux disease. Three simple, specific and accurate spectrophotometric methods were applied and validated for simultaneous determination of Itopride hydrochloride (IT) and Rabeprazole sodium (RB) namely; constant center (CC), ratio difference (RD) and mean centering of ratio spectra (MCR) spectrophotometric methods. Linear correlations were obtained in range of 10-110MUg/MUL for Itopride hydrochloride and 4-44MUg/mL for Rabeprazole sodium. No preliminary separation steps were required prior the analysis of the two drugs using the proposed methods. Specificity was investigated by analyzing the synthetic mixtures containing the two cited drugs and their capsules dosage form. The obtained results were statistically compared with those obtained by the reported method, no significant difference was obtained with respect to accuracy and precision. The three methods were validated in accordance with ICH guidelines and can be used for quality control laboratories for IT and RB. PMID- 25456674 TI - Accurate spectroscopic properties of 19 low-lying states of PCl radical including the electronic transition properties. AB - The spectroscopic properties are in detail studied for the 1(1)Sigma(-), 2(1)Sigma(-), b(1)Sigma(+), c(1)Pi, 2(1)Pi, 3(1)Pi, a(1)Delta, 2(1)Delta, X(3)Sigma(-), C(3)Sigma(-), 3(3)Sigma(-), 1(3)Sigma(+), A(3)Pi, B(3)Pi, 3(3)Pi, 1(3)Delta, 2(3)Delta, 1(5)Sigma(-) and 1(5)Pi states, which are yielded from the first two dissociation limits, P((4)Su)+Cl((2)Pu) and P((2)Du)+Cl((2)Pu), of the PCl radical. Of the nineteen states, the 3(3)Sigma(-), 1(3)Sigma(+), 1(3)Delta, 2(3)Delta and 1(5)Pi states are the repulsive ones. The 2(1)Sigma(-), 2(1)Delta and 1(5)Sigma(-) states and the second well of A(3)Pi state are very weakly-bound ones. The A(3)Pi and B(3)Pi states, the B(3)Pi and 3(3)Pi states, and the 2(1)Pi and 3(1)Pi states have the avoided crossings. The A(3)Pi state is found to possess the double well. The potential energy curves (PECs) are calculated with the CASSCF method followed by the internally contracted MRCI approach with Davidson correction together with the Dunning's correlation-consistent basis sets, aug-cc-pV6Z. To improve the quality of PECs, core-valence correlation and scalar relativistic correction calculations are included simultaneously. The PECs are extrapolated to the complete basis set limit. The vibrational properties are evaluated for several weakly-bound states. The spectroscopic parameters are determined, and compared with those available in the literature. The Franck Condon factors and radiative lifetimes of the transitions from the A(3)Pi, B(3)Pi and 3(3)Pi states to the X(3)Sigma(-) state and from the c(1)Pi, 2(1)Pi and 3(1)Pi states to the a(1)Delta state are calculated for several low vibrational states. And some necessary discussion is performed. Analyses demonstrate that the spectroscopic properties of PCl radical reported in this paper can be expected to be reliably predicted ones. PMID- 25456675 TI - A carbon dots-CdTe quantum dots fluorescence resonance energy transfer system for the analysis of ultra-trace chlortoluron in water. AB - In this paper, a fluorescence resonance energy transfer (FRET) system between fluorescence carbon dots (CDs, donor) and CdTe quantum dots (CdTe, acceptor) was constructed, and a novel platform for sensitive and selective determination of chlortoluron was accordingly proposed. It was found that in Tris-HCl buffer solution at pH=8.7, energy transfer from CDs to CdTe occurred, which resulted in a great enhancement of the fluorescence intensity of CdTe. Upon the addition of chlortoluron, in terms of strong interaction between chlortoluron and CdTe QDs through the formation of chlortoluron-CdTe ground state complex, resulted in CdTe fluorescence quenching. Under optimal conditions, in range of 2.4*10(-10)molL(-1) 8.5*10(-8)molL(-1), the change of CdTe fluorescence intensity was in good linear relationship with the chlortoluron concentration, and the detection limit was 7.8*10(-11)molL(-1) (S/N=3). Most of common relevant substance, cations and anions did not interfere with the detection of chlortoluron. The proposed method was applied to determine chlortoluron in water samples with satisfactory results. PMID- 25456676 TI - Mononuclear dioxomolybdenum(VI) thiosemicarbazonato complexes: Synthesis, characterization, structural illustration, in vitro DNA binding, cleavage, and antitumor properties. AB - Four dioxomolybdenum(VI) complexes were synthesized by reacting [MoO2(acac)2] with N-ethyl-2-(5-bromo-2-hydroxybenzylidene) hydrazinecarbothioamide (1), N ethyl-2-(5-allyl-3-methoxy-2-hydroxybenzylidene) hydrazinecarbothioamide (2), N methyl-2-(3-tert-butyl-2-hydroxybenzylidene) hydrazinecarbothioamide (3), and N ethyl-2-(3-methyl-2-hydroxybenzylidene) hydrazinecarbothioamide (4). The molecular structures of 1, 2, and all the synthesized complexes were determined using single crystal X-ray crystallography. The binding properties of the ligand and complexes with calf thymus DNA (CT-DNA) were investigated via UV, fluorescence titrations, and viscosity measurement. Gel electrophoresis revealed that all the complexes cleave pBR 322 plasmid DNA. The cytotoxicity of the complexes were studied against the HCT 116 human colorectal cell line. All the complexes exhibited more pronounced activity than the standard reference drug 5 fluorouracil (IC50 7.3MUM). These studies show that dioxomolybdenum(VI) complexes could be potentially useful in chemotherapy. PMID- 25456677 TI - [Characteristics of group A streptococcal meningitis in children]. AB - Group A streptococcal (GAS) meningitis in children are rare. The aim of this study was to analyze the clinical, biological and outcome data on GAS meningitis recorded in the Bacterial Meningitis (BM) French Surveillance Network (GPIP/ACTIV). From 2001 through 2012, 4,564 children suffering from proven bacterial meningitis were recorded in the data base. Among them, 0.7 % were GAS infections. The median age was 5.6 years. A history of community acquired infection before the onset of GAS meningitis was frequent. Apart from the identification of the bacterial species, GAS meningitis were clinically and biologically indistinguishable from meningitis caused by other pathogens notably S. pneumoniae. Case fatality rate was 8 %. PMID- 25456678 TI - [Multifocal invasive infection due to Streptococcus pyogenes in a 20 month-old infant: case report]. AB - This case report describes a 20 months-old toddler with a multifocal S. pyogenes invasive infection cutaneous and articular, which outcome was favorable after implementation of a medical and surgical treatment. The antibiotic treatment was based on the association of amoxicillin and clindamycin which duration was guided by the clinical course and the secondary locations. A surgical management with joint irrigation lavage and drainage was necessary to induce a complete recovery. PMID- 25456679 TI - [Controversies on antibiotics for common group A streptococcus infections]. AB - Management of common group A streptococcus (GAS) infections remains controversial. French recommendations advocate systematic treatment of streptococcal tonsillitis after confirmation by rapid diagnostic test. Oral amoxicillin twice daily for 6 days is the first-line treatment. Antibiotic prophylaxis is restricted to at-risk patients after contact with invasive GAS case. These recommendations take into consideration the prevention of complications, even if they are rare, the reduction of infectiousness and the reduction of the duration of symptoms. Different recommendations have been issued in other countries, particularly in Europe and are based on different considerations. These differences do not originate in the absence of demonstrative scientific studies but rather in societal considerations, themselves guided by the history of each different health system (and also judicial system). This is probably necessary to obtain physicians and public support. The French attitude reflects these considerations. However, its lack of enforcement needs to question about its origins. PMID- 25456680 TI - [Streptococcus pyogenes/group a streptococcus: an extra-cellular bacteria whose only known reservoir is man]. PMID- 25456681 TI - [Streptococcus pyogenes pathogenic factors]. AB - The pathogenicity of beta-hemolytic group A streptococcus (GAS) is particularly diverse, ranging from mild infections, such as pharyngitis or impetigo, to potentially debilitating poststreptococcal diseases, and up to severe invasive infections such as necrotizing fasciitis or the dreaded streptococcal toxic shock syndrome. This variety of clinical expressions, often radically different in individuals infected with the same strain, results from a complex interaction between the bacterial virulence factors, the mode of infection and the immune system of the host. Advances in comparative genomics have led to a better understanding of how, following this confrontation, GAS adapts to the immune system's pressure, either peacefully by reducing the expression of certain virulence factors to achieve an asymptomatic carriage, or on the contrary, by overexpressing them disproportionately, resulting in the most severe forms of invasive infection. PMID- 25456683 TI - [Epidemiology of Streptococcus pyogenes infections in developing countries]. AB - Group A streptococcal (GAS) infections are frequent in developing countries but the epidemiology is incompletely known. In 2005, 90 % of symptomatic pharyngitis, 96 % of invasive diseases and 97 % of deaths due to GAS were observed in these countries. Clinical features of GAS invasive infections are identical to those reported in developed countries, but frequency and mortality are higher, as is the number of the different emm types involved. In the world, from 15.6 to 19.6 millions of persons are affected by rheumatic heart disease (282,000 new cases and 233,000-468,000 deaths per year). Incidence of acute post-streptococcal glomerulonephritis varies with time and location: in 2005, 472,000 new cases have been reported in the world (83 % in a developing country). World Heart Federation recently aimed at reducing the burden of rheumatic heart diseases by 25 % among < 25 years persons in 2025. PMID- 25456682 TI - [Epidemiology of Streptococcus pyogenes invasive diseases in France (2007-2011)]. AB - Group A Streptococcus (GAS) is a human pathogen responsible for a wide range of clinical manifestations. An increase of GAS invasive infections has been described since the mid 1980s. To study the French epidemiology of invasive infections (i) we characterized all GAS invasive strains received at the French National Reference Center for streptococci (CNR-Strep) between 2007 and 2011; (ii) we analyzed the epidemiological data on the corresponding strains. For each strain, emm genotype, superantigen genes and antibiotics susceptibility were determined. Among the 2 603 non redundant invasive GAS strains, 65.1 % (n=1 695) were isolated from blood culture. A streptococcal toxic shock syndrome (STSS) was described in 16.4 % (n=428) of cases, mostly associated with necrotizing fasciitis (NF), pleuropulmonary or osteoarticular infections (p <=0.001). The case fatality rate was 10.6 %. A total of 102 different emm genotypes were identified. Three emm genotypes predominated, reaching nearly 60 % of the strains: emm 1 (26.7 %), emm 28 (16.4 %), and emm 89 (12.8 %). The proportion of each emm genotype varied according to the year and the age of patients. Among those < 15 years old, the three main genotypes were emm 1 (36.8 %), emm 12 (12.9 %) and emm 4 (9.5 %). The distribution of superantigen genes (SpeA, SpeC and Ssa) was restricted to several emm genotypes. Between 2007 and 2011, the rate of macrolides resistant GAS strains decreased from 7.8 to 5.5 %. emm 1 strains are still the most common especially in most severe clinical manifestations including STSS and NF. PMID- 25456684 TI - [Epidemiology of invasive group A streptococcal infections in developed countries : the Canadian experience with necrotizing fasciitis]. AB - In industrialized countries, group A streptococcal infections were a source of concern, mainly due to the occurrence of rheumatic fever and its cardiac complications. At present, the incidence of rheumatic fever is decreasing in these countries, giving way to an increasing occurrence of invasive streptococcal group A infections with high level of morbidity and mortality. Streptococcal necrotizing fasciitis, a specific entity, emerged these last decades, often in association with chickenpox. The introduction of the varicella vaccine in the province of Quebec routine immunization program, was followed by a significant decrease in the number of necrotizing fasciitis or other skin and soft-tissues infections in our pediatric population. However, in our experience at the CHU Sainte-Justine, this immunization program has not been helpful to reduce the overall incidence of invasive group A streptococcal infections. Conversely, an increase in the number of pleuro-pulmonary and osteo-articular infections was observed. PMID- 25456685 TI - [Rapid antigen detection tests for group A streptococcus in children with pharyngitis]. AB - Group A streptococcus (GAS) is the most frequently identified bacterium in children with acute pharyngitis. Clinical signs and symptoms cannot distinguish accurately between viral and GAS pharyngitis. Rapid antigen detection tests (RADTs) can identify GAS by an immunologic reaction within a few minutes. Compared to throat culture, most RADTs have a high specificity (around 95 %), allowing antibiotic prescribing on the basis of a positive RADT result. Similarly, the negative predictive value of RADTs seems sufficiently high (around 95 %) to ensure against the presence of GAS in case of a negative RADT result. Among several factors affecting RADT sensitivity, the training and expertise of the person performing the test and the quality of the throat swab specimen seem to be key determinants. Available evidence suggests that clinical prediction rules for the triage of children who should undergo GAS testing are not sufficiently accurate. Implementing RADTs into clinical practice has an important impact on antibiotic prescription rates, for a reduction of about 30 %. French guidelines that recommend using RADTs in all children above 3 years of age presenting with pharyngitis without backup culture of negative tests seem relevant in this context. PMID- 25456686 TI - [Use of group A streptococcal rapid diagnostic test in extra-pharyngeal infections]. AB - The purpose of this study was to assess the performances of the group A streptococcus (GAS) rapid antigen diagnostic tests (RADTs) in extra-pharyngeal infections. Between October 2009 and June 2014, 368 patients (median age: 48 months) were enrolled. The pathologies involved were : 160 perineal infections (44 %), 69 blistering distal dactylitis (19 %), 55 cervical lymphadenitis (15 %), 31 crusty or bleeding rhinitis (8 %), and 53 other diseases (14 %). The sensitivity of GAS-RADT used was 96 % (95 % CI: 92-99 %), the specificity 81 % (95 % CI: 75- 86 %), the negative predictive value 97 % (CI 95 %: 93-99 %), and the positive predictive value 79 % (95 % CI: 73-85 %). Finally, positive and negative likelihood ratio were 5 (95 % CI: 4-7) and 0.05 (95 % CI: 0.02-0.11) respectively. The GAS-RADTs developed for pharyngitis have comparable performances in these settings and therefore can be used. PMID- 25456687 TI - [Management of severe invasive group A streptococcal infections]. AB - The group A streptococcus (GAS) is the 5(th) responsible pathogen of invasive infections in children in France. These particularly severe diseases are dominated in children by soft tissue infection, isolated bacteremia but also osteoarthritis. Other complications are rare in France such as lung infections, necrotizing fasciitis (NF) and streptococcal toxic shock syndrome (STSS). More unusual localizations such as meningitis, neonatal infections, severe ear and throat and gastrointestinal infections and vascular disorders are also described. Based on published series, mortality ranging from 0-8 % of cases, is high but still lower than that observed in adults. Probabilistic antibiotherapy includes a beta-lactam with anti-SGA but also anti-staphylococcal (predominantly methi-S in France) activity such as clavulanic acid- amoxicillin followed by amoxicillin as soon as identification of SGA is performed. The addition of an anti-toxin antibiotic such as clindamycin is recommended particularly in NF or STSS or clinical signs suggestive of toxin production by the SGA (rash, gastrointestinal signs, hemodynamic disorders). The use of intravenous polyvalent immunoglobulins must also be discussed in NF and STSS. In all cases surgery should be discussed. The prognosis of these potentially very severe infections is related to their early diagnosis and treatment. A better understanding of the pathophysiology of these infections may optimize their management but also their prevention. PMID- 25456688 TI - [Diagnostic of group A streptococcal blistering distal dactylitis]. AB - Blistering distal dactylitis is a distinct clinical entity, generally due to S. pyogenes, unfrequently reported. Characteristically, blistering distal dactylitis is described as a localized infection involving the distal phalanx of the digits, and it usually presents as a fluid-filled blister. Between October 2009 and June 2014, 69 children (median age: 60 months, extremes: 0,6-176) were enrolled. The sensitivity of GAS rapid antigen detection test was 97 % (CI 95 %: 83-100 %), the specificity was 76 % (CI 95 %: 60-89 %), the negative predictive value was 97 % (CI 95 %: 83-100 %), and the positive predictive value 76 % (CI 95 %: 60-89 %). All patients with a positive GAS rapid antigen test were treated with antibiotics (amoxicillin essentially) and cured without surgery. PMID- 25456689 TI - [Group A streptococcal perineal infection in children]. AB - Perineal diseases in children are usually caused by group A streptococcus (GAS). If the natural course of untreated cases is not known, it is well known that symptoms do not resolve spontaneously and can persist often for many months, until appropriate diagnosis and effective treatment are instituted. Furthermore, failures and recurrences after penicillin treatment are frequent. From 2009 to 2014, 165 perineal infections (median age: 48 months, extremes: 0.4-139) were enrolled by 15 pediatricians: 4 balanitis, 29 vulvo-vaginal diseases and 132 perianal infections. Painful defecation, anal fissures and macroscopic blood in stools were significantly more frequent in GAS perianal infections than negative GAS infections (p<0.01). The performance of GAS-rapid antigen test compared to the GAS culture was : sensitivity 97 % [CI 95 %: 89-100 %], specificity 76 % [CI 95 %: 66-84 %], negative predictive value 97 % [CI 95 %: 91-100 %], positive predictive value 71 % [CI 95 %: 60-80 %]. PMID- 25456690 TI - Factor XI rs2036914 gene polymorphism and occurrence of adverse events after percutaneous coronary intervention. A prospective evaluation. PMID- 25456691 TI - Management of peripartum cardiomyopathy. PMID- 25456693 TI - Acute pulmonary embolism with ST-segment elevation in the inferior leads. PMID- 25456692 TI - Association of quality of life with anticoagulant control in patients with heart failure: the Warfarin and Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial. PMID- 25456694 TI - VEGF tonically sustains myocardial performance via fetal liver kinase-1 in the heart. PMID- 25456695 TI - Catecholaminergic polymorphic ventricular tachycardia (CPVT) initially diagnosed as idiopathic ventricular fibrillation: the importance of thorough diagnostic work-up and follow-up. PMID- 25456696 TI - Follow-up evaluation of unapposed bioresorbable vascular scaffold at a coronary bifurcation using optical coherence tomography. PMID- 25456697 TI - Non-invasive imaging for cardiac amyloidosis - delaying the obvious? PMID- 25456698 TI - Galectin-3 predicts short- and long-term outcome in patients undergoing transcatheter aortic valve implantation (TAVI). AB - Until now, no reliable biomarker has become available for short- or long-term outcome prediction in patients undergoing transcatheter aortic valve implantation (TAVI). Our goal was to investigate whether galectin-3 is also suited for risk assessment in TAVI patients. Galectin-3, a novel marker indicative for myocardial fibrosis, has prognostic value in heart failure. We included 101 patients undergoing TAVI in this prospective, single-center, observational study. Baseline galectin-3 levels were correlated to the VARC 30-day safety and one-year efficacy endpoint as well as to total mortality and cardiovascular events at one year. At baseline, mean galectin-3 level for the entire group was 18.1 (+/- 11.1) ng/ml. Of the 101 patients, 36 had a galectin-3 value above the cut off value of 17.8 ng/ml. These patients had significantly higher systolic pulmonary artery and capillary wedge pressures. The hazard ratio in patients with galectin-3 > 17.8 ng/ml was 3.36 (95% confidence interval, CI: 1.47-7.69; p=0.004) for the VARC 30 day safety endpoint, 5.12 (95% CI: 2.10-12.47; p<0.001) for one-year cardiovascular events, and 4.48 (95% CI: 1.56-12.91; p=0.005) for all-cause mortality. This prediction remained stable even after adjusting for possible confounders including age, sex, glomerular filtration rate, and NT-proBNP. Furthermore, the prediction was even more valuable when combining galectin-3 with NTproBNP. In summary elevated galectin-3 levels are associated with adverse outcome after TAVI. Combining galectin-3 with NT-proBNP provides additive predictive value of risk stratification. PMID- 25456699 TI - Disrupted right ventricular force-frequency relationships in adults operated for ventricular septal defect as toddlers: abnormal peak force predicts peak oxygen uptake during exercise. AB - Recent studies have shown markedly reduced functional capacity in long-term survivors of ventricular septal defect (VSD), and in order to explore possible mechanisms, we performed non-invasive assessment of ventricular force-frequency relationships during exercise in adults operated for VSD in early childhood. We conducted a prospective study at a tertiary referral center. Patients (n=23) and healthy controls (n=20) underwent continuous Doppler-echocardiographic imaging during supine bicycle ergometry. The cycling workload was individually and manually incremented during the test session in response to heart rate. The heart was imaged in an apical 4-chamber view, and color-coded myocardial velocities were recorded. Post hoc, peak systolic velocity and isovolumetric acceleration (IVA) were blindly determined in the basal ventricular segments. VSD-operated patients differed markedly in all right ventricular endpoints compared with controls. IVA was lower prior to the test, 70 +/- 30 cm/s(2) vs. 150 +/- 60 cm/s(2) among controls, and during the entire test session ending at a heart rate of 160 beats/min; 140 +/- 50 cm/s(2) vs. 300 +/- 30 cm/s(2), p < 0.01 at both points. A similar pattern was revealed in terms of peak right ventricular systolic velocity. Left ventricular and septal measurements showed a similar, although less significant, tendency with a clearly lower left ventricular optimum heart rate among patients: 140 beats/min vs. 154 beats/min among controls. In the diseased cohort biventricular force-frequency relationships were directly correlated to peak oxygen uptake. VSD repair in early childhood is associated with disruption of the right ventricular force-frequency relationship, which may contribute to the previously observed reduction in functional capacity. PMID- 25456700 TI - Circulating cardiac troponin T is not influenced by postural changes during venous blood collection. PMID- 25456701 TI - Reserpine, mecamilamine, guanethidine, atropine for patients with Takotsubo syndrome? PMID- 25456702 TI - Response to "Cardioprotective effect of isoflurane anesthesia from takotsubo syndrome and its implications". PMID- 25456703 TI - Comparison of second-generation drug-eluting versus bare-metal stents in octogenarian patients with ST-segment elevation myocardial infarction. PMID- 25456704 TI - Frequency and clinical characteristics of acute heart failure patients at INCMNSZ, Mexico City, Mexico. PMID- 25456705 TI - Success of left ventricular assist device therapy in uninsured patients. PMID- 25456706 TI - Relationships among different glycemic variability indices obtained by continuous glucose monitoring. AB - The aim of this study was to assess the relationships among indices of glycemic variability obtained by continuous glucose monitoring (CGM). CGM was performed in 88 patients with diabetes (20 type 1 and 68 type 2 diabetes, age 59 +/- 15 years) admitted to our hospital (Keio University Hospital, Tokyo, Japan) between 2010 and 2012. Mean glucose, glucose standard deviation (SDglu) and other glycemic indices such as index of glycemic control (ICG), J-index, mean of daily differences (MODD), continuous overlapping net glycemic action 1 (CONGA1), mean amplitude of glycemic excursions (MAGE) and M value were calculated from CGM data, and the correlations among these indices were assessed. There were strong correlations between SDglu and the indices MAGE, CONGA1, MODD and M value (all r > 0.8, P < 0.05). On the other hand, mean glucose was strongly correlated with J index and M value (both r > 0.8, P < 0.05). SDglu and other glycemic variability indices were more strongly correlated with hypoglycemia than was mean glucose, and the combination of mean glucose and SDglu was useful for predicting hypoglycemia in patients with diabetes. In this study, we demonstrated the characteristics of various glycemic variability indices in relation to mean glucose and SDglu. This information will help physicians to understand the characteristics of various glycemic variability indices and to select an appropriate index for their purpose. Our results also underpin the importance of glycemic variability in relation to risk of hypoglycemia in patients with diabetes. PMID- 25456707 TI - Genome-wide analysis of long noncoding RNA signature in human colorectal cancer. AB - Long noncoding RNAs (lncRNAs) have been widely regarded as crucial regulators in various biological processes involved in carcinogenesis. However, the comprehensive lncRNA expression signature in colorectal cancer remains fully unknown. We performed a high throughput microarray assay to detect lncRNA expression profile in three paired human colorectal cancer tissues and their adjacent normal tissues. Additional 90 paired colorectal samples were collected to verify differently expression levels of two selected lncRNAs using q-RT-PCR assay. Bioinformatic approaches were performed to explore into the functions of these differently expressed lncRNAs. Microarray assay showed a series of lncRNAs were differently expressed in colorectal cancer. Two of the lncRNAs, HOTAIR and a novel lncRNA, lncRNA-422 were confirmed in more samples (P=0.015 for HOTAIR and P=0.027 for lncRNA-422, respectively). GSEA indicated that gene sets most correlated with them were those named up-regulated in KRAS-over, down-regulated in JAK2-knockout, down-regulated in PDGF-over and down-regulated in TBK1 knockout, all of which were cancer-related. Subsequently, GO analyses of most significantly correlated coding genes of HOTAIR and lncRNA-422 showed that these two lncRNAs may participate in carcinogenesis by regulating protein coding genes involved in special biological process relevant to cancer. Our study demonstrated that different lncRNA expression patterns were involved in colorectal cancer. Besides, HOTAIR and lncRNA-422 were identified to participate in colorectal cancer. Further studies into biological mechanisms of differently expressed lncRNAs identified in our study will help to provide new perspective in colorectal cancer pathogenesis. PMID- 25456708 TI - Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR). AB - The Belgian severe asthma registry is a web-based registry encompassing demographic, clinical, functional and inflammatory data of severe asthmatics (SA), aiming at improving awareness, knowledge on its natural history and subphenotypes, and offering tools to optimize care of this asthma population. METHODS: The cross-sectional analyses of this registry included 350 SA as defined by the ATS (2000) from 9 Belgian centres, with at least one year follow up. RESULTS: Mean age was 55 +/- 14 yrs. SA were more frequently female (57%) and atopic (70%). Late-onset asthma (>=40 yr) was observed in 31% of SA. Current smokers represented 12% while 31% were ex-smokers. In addition to high doses ICS + LABA, 65% of patients were receiving LTRA, 27% anti-IgE and 24% maintenance oral corticosteroids (8 mg (Interquartile range-IQR:4-8) methylprednisolone). Despite impaired airflow (median FEV1:67%; IQR: 52-81) only 65% had a post bronchodilator FEV1/FVC ratio <70%. The median blood eosinophil count was 240/mm3. The median FENO was 26 ppb (IQR: 15-43) and 22% of SA had FENO >= 50 ppb. Induced sputum was successful in 86 patients. Eosinophilic asthma (sputum Eos >= 3%) was the predominant phenotype (55%) while neutrophilic (sputum Neu >= 76%) and paucigranulocytic asthma accounted for 22% and 17% respectively. Comorbidities included rhinitis and chronic rhinosinusitis (49%), nasal polyposis (19%), oesophageal reflux (36%), overweight and obesity (47%) and depression (19%). In addition, 8% had aspirin-induced asthma and 3% ABPA. Asthma was not well-controlled in 83% according to ACT < 20 and 77% with ACQ > 1.5. CONCLUSION: In this cohort of patients with severe asthma, the majority displayed indices of persistent airflow limitation and eosinophilic inflammation despite high-dose corticosteroids, suggesting potential for eosinophil-targeted biotherapies. PMID- 25456709 TI - The association of exposure to hepatitis B and C viruses with lung function and respiratory disease: a population based study from the NHANES III database. AB - BACKGROUND: Globally, 500 million people are chronically infected with Hepatitis B virus (HBV) and Hepatitis C virus (HCV). While these viruses are notorious for their detrimental effect on the liver they are also known to affect multiple organs in the body including the lungs. AIM: To investigate if exposure to HBV and HCV is associated with lung function and respiratory diseases. METHODS: Data from the Third National Health and Nutrition Examination Survey (NHANES III) was analysed using multiple linear regressions to investigate the association between exposure to HBV and HCV with the various measures of lung function, while multiple logistic regressions were used to evaluate the association with the respiratory diseases asthma and chronic obstructive pulmonary disease (COPD). RESULTS: Exposure to HCV was significantly associated with an increase in Forced Expiratory Volume in 1 s, FEV1 (Coef: 97.94 ml, 95% CI: 38.87 to 157.01) and Full Vital Capacity, FVC (Coef: 90 ml, 95% CI: 14.50 to 166.24). Individuals who had been exposed to both HBV and HCV also had a significantly higher FEV1 (Coef: 145.82, CI: 60.68 to 230.94) and FVC (Coef: 195.09, CI: 78.91 to 311.26). There was also a significant association between exposure to HBV and asthma (OR: 1.28, 95% CI: 1.05 to 1.58). These associations were no longer significant after additionally adjusting for cocaine and marijuana use as well as poverty income ratio. CONCLUSION: Our research implies that hepatotropic viruses may affect the respiratory system, but more work at a population level is needed to further explore these associations. PMID- 25456710 TI - Randomized trial of non-invasive ventilation combined with exercise training in patients with chronic hypercapnic failure due to chronic obstructive pulmonary disease. AB - BACKGROUND: Non-invasive ventilation and exercise training might prove beneficial in the management of COPD patients. OBJETIVE: to compare the combined use of exercise training and non-invasive ventilation with the two interventions separately in chronic respiratory failure due to chronic obstructive pulmonary disease. As primary objective exercise capacity and secondary objectives gas exchange, peripheral muscle strength, BODE index, quality of life and systemic inflammatory response. METHODS: Forty-five patients with severe chronic obstructive pulmonary disease were randomized into three groups for an intervention of 12 weeks: exercise training alone, ventilation alone and combined treatment. We assessed exercise capacity, pulmonary function, BODE index, perception of dyspnoea, quality of life and several biomarkers. RESULTS: All exercise capacity parameters improved after training and the combined treatment. In addition, peripheral muscle strength and six-minute walk distance increased after ventilation. We found differences between the combined group and the ventilation group in submaximal effort and in oxygen consumption. Changes in respiratory function were observed in blood gases that improved after ventilation and the combined treatment, with differences between these groups. BODE index, perception of dyspnoea and quality of life improved in all three groups without differences between groups. Levels of interleukin 8 and tumour necrosis factor alpha decreased after ventilation, and interleukin 8, C-reactive protein and surfactant protein D decreased after training, while all four of these markers fell after the combined treatment. No differences between groups were found. CONCLUSIONS: The combination of ventilation and exercise training had greater benefits than the separate treatments: improvements were observed in both blood gases and the levels of more biomarkers decreased. In addition, submaximal exercise capacity increased in all groups. The improvements seen in BODE index, perception of dyspnoea and quality of life were similar in all groups. PMID- 25456712 TI - Anatomy of the triceps surae: a pictorial essay. AB - Gastrocnemius contracture has recently gained relevance owing to its suggested relationship with foot disorders such as metatarsalgia, plantar fasciopathy, hallux valgus, and others. Consequently this has induced a renewed interest in surgical lengthening techniques, including proximal gastrocnemius release, to resolve gastrocnemius contracture in patients with foot disorders. This article describes and discusses the general anatomy of the triceps surae and the surgical anatomy of the gastrocnemius. PMID- 25456711 TI - Topical dsRNA challenges may induce overexpression of airway antiviral cytokines in symptomatic allergic disease. A pilot in vivo study in nasal airways. AB - BACKGROUND: Airway challenge with dsRNA is of interest since this agent acts on TLR3 and mimics rhinoviral (RV) infection-induced interferons/cytokines. Contrasting frequent employment of dsRNA in epithelial cell cultures there is no information on effects of dsRNA administered to human airways in vivo. Here we explore effects of nasal dsRNA challenges in subjects with seasonal allergic rhinitis inside and outside Swedish birch pollen season. METHODS: We examined effects of dsRNA in seven patients with seasonal allergic rhinitis. By being studied both inside and outside of an active pollen season they served as their own controls. Based on pilot experiments a repeat dose regimen of dsRNA, 4 * 100 MUg, was given daily into the right nostril on two consecutive days; left nostril received corresponding saline challenges. Airway cells for gene analyses were obtained by nasal brushing shortly before the first challenge and 48 h after challenges. RESULTS: Pollen counts and nasal symptoms indicated a significant season of allergic rhinitis. At the height of the pollen season, dsRNA challenges increased three antiviral proteins, interferons beta and lambda1 and IL-32, compared to saline challenges. By contrast, outside the pollen season dsRNA did not increase the expression of these antiviral proteins. dsRNA did not cause any symptoms outside the season nor did it increase the allergic symptoms evoked by natural pollen exposure. CONCLUSION: These findings suggest the possibility that active mucosal inflammation, induced by natural allergen exposure in human airways, transiently increases in vivo antiviral responsiveness of airway surface cells. PMID- 25456713 TI - The gastrocnemius: a new paradigm for the human foot and ankle. AB - A silent gastrocnemius contracture can gradually do so much harm when left undetected and unattended. The calf is a common source of a majority of acquired, nontraumatic adult foot and ankle problems. When it comes to surgical lengthening procedures, whether at the Achilles, at the musculotendinous junction, or more proximal, the search must move on to find the safest, most accurate, and quickest recovery method possible. Addressing the calf contracture as definitive treatment and, better yet, as prevention will no doubt become a mainstay of the treatment of many foot and ankle problems. PMID- 25456714 TI - Effects of gastrocnemius tightness on forefoot during gait. AB - The gastrocnemius is the main muscle of the posterior compartment of the leg. As a biarticular muscle it has specific biomechanical propertiess. This article discusses these properties combining the major biomechanical topics of anatomy, dynamics, kinetics, and electromyography. This muscle is remarkable in that it has very low energy consumption and very high mechanical efficacy. In addition to the biomechanical features, the consequences of its tightness are discussed. The dysfunction also appears in all the biomechanical topics and clarifies the reasons of the location of symptoms in the midfoot and on the plantar aspect of the forefoot. PMID- 25456715 TI - Clinical diagnosis of gastrocnemius tightness. AB - The diagnosis of gastrocnemius tightness is primarily clinical using the Silfverskiold test, which shows an equinus deformity at the ankle with the knee extended but that disappears with the knee flexed. The manner in which the Silfverskiold test is performed must be consistent with respect to the applied strength of the maneuver, correction of a flexible hindfoot valgus deformity while performing the test, and reproducibility. Although this is a diagnosis based on the clinical examination, this article presents additional clinical signs that can help to make the diagnosis when the retraction is not clinically evident. These include knee recurvatum, hip flexion, lumbar hyperlordosis, and forefoot overload. PMID- 25456716 TI - Functional hallux rigidus and the Achilles-calcaneus-plantar system. AB - Functional hallux rigidus is a clinical condition in which the mobility of the first metatarsophalangeal joint is normal under non-weight-bearing conditions, but its dorsiflexion is blocked when first metatarsal is made to support weight. In mechanical terms, functional hallux rigidus implies a pattern of interfacial contact through rolling, whereas in a normal joint contact by gliding is established. Patients with functional hallux rigidus should only be operated on if the pain or disability makes it necessary. Gastrocnemius release is a beneficial procedure in most patients. PMID- 25456717 TI - The effect of the gastrocnemius on the plantar fascia. AB - Although anatomic and functional relationship has been established between the gastrocnemius muscle, via the Achilles tendon, and the plantar fascia, the exact role of gastrocnemius tightness in foot and plantar fascia problems is not completely understood. This article summarizes past and current literature linking these 2 structures and gives a mechanical explanation based on functional models of the relationship between gastrocnemius tightness and plantar fascia. The effect of gastrocnemius tightness on the sagittal behavior of the foot is also discussed. PMID- 25456718 TI - Gastrocnemius shortening and heel pain. AB - Pain and reduced function caused by disorders of either the plantar fascia or the Achilles tendon are common. Although heel pain is not a major public health problem it affects millions of people each year. For most patients, time and first-line treatments allow symptoms to resolve. A proportion of patients have resistant symptoms. Managing these recalcitrant cases is a challenge. Gastrocnemius contracture produces increased strain in both the Achilles tendon and the plantar fascia. This biomechanical feature must be properly assessed otherwise treatment is compromised. PMID- 25456719 TI - The use of ultrasound to isolate the gastrocnemius-soleus junction prior to gastrocnemius recession. AB - Gastrocnemius recession has become a popular procedure to release isolated gastrocnemius tightness. Using visual anatomic landmarks alone to plan the incision can be deceiving. The use of ultrasound preoperatively has been highly reproducible in isolating the gastrocnemius-soleus junction in the authors' practice. This provides confidence for incision placement, a smaller incision, and isolated release of the gastrocnemius fascia while leaving the underlying soleus undisturbed. PMID- 25456720 TI - Surgical techniques of gastrocnemius lengthening. AB - This article summarizes the various alternatives for direct gastrocnemius lengthening and elucidates the relative strengths and tradeoffs of each as a means of providing balanced perspective in selecting the appropriate procedure for any given patient. PMID- 25456721 TI - Gastrocnemius recession. AB - The Grand Rapids Arch Collapse classifications create a novel system for categorizing and correlating numerous common foot and ankle conditions related to a falling arch. The algorithm for treating these conditions is exceptionally replicable and has excellent outcomes. Gastrocnemius equinus diagnosis plays a crucial role in the pathology of arch collapse. A contracture of the gastrocnemius muscle is increasingly recognized as the cause of several foot and ankle conditions. The authors have expanded their indications for gastrocnemius recession to include arch pain without radiographic abnormality, calcaneus apophysitis, plantar fasciitis/fibromas, Achilles tendonosis, early-onset diabetic Charcot arthropathy, and neuropathic forefoot ulcers. PMID- 25456722 TI - Endoscopic gastrocnemius release. AB - Endoscopic gastrocnemius release (EGR) is a recently developed procedure that is a reliable option for surgical management of ankle equinus contracture. Comfort with endoscopic equipment and surgical anatomy, especially the sural nerve, is of paramount importance for performing the procedure safely, effectively, and efficiently. The primary advantage of the procedure is improved cosmesis and decreased wound complications of the smaller surgical scars. The current body of literature of clinical outcomes for EGR consists of limited level IV case series with broad variations in study rigor, author training background, and the surgical technique itself. PMID- 25456723 TI - Technique, indications, and results of proximal medial gastrocnemius lengthening. AB - Gastrocnemius proximal lengthening was first performed to correct spasticity in children, and was adapted for the patient with no neuromuscular condition in the late 1990s. Since then, the proximal gastrocnemius release has become less invasive and has evolved to include only the fascia overlying the medial head of the gastrocnemius muscle. The indications for performing this procedure are a clinically demonstrable gastrocnemius contracture that influences a variety of clinical conditions in the forefoot, hindfoot, and ankle. It is a safe and easy procedure that can be performed bilaterally simultaneously, and does not require immobilization of the ankle after surgery. PMID- 25456724 TI - The effect of gastrocnemius tightness on the pathogenesis of juvenile hallux valgus: a preliminary study. AB - Hallux valgus is the most common foot disorder associated with gastrocnemius tightness, and there is a particularly strong association with juvenile hallux valgus. This article describes an oblique windlass mechanism that can be a causative or a contributory factor in the pathogenesis of juvenile hallux valgus. This article presents a study of 108 patients who underwent a proximal gastrocnemius release and hallux valgus correction using a scarf osteotomy. We believe that assessment of gastrocnemius tightness in juvenile hallux valgus is important and that gastrocnemius lengthening should be routinely considered as part of the operative strategy. PMID- 25456725 TI - Foreword: gastrocnemius on foot and ankle pathology. PMID- 25456726 TI - In memoriam Pau Golano (1965-2014)-anatomist, scientist, artist, teacher, and friend. PMID- 25456727 TI - Introduction to gastrocnemius tightness. PMID- 25456728 TI - In memory of Pau Golano 1964-2014. PMID- 25456730 TI - Prognostic role of heart-type fatty acid binding protein in pulmonary embolism: a meta-analysis. AB - INTRODUCTION: Pulmonary embolism (PE) has a high morbidity and mortality. Hence it is important to recognize factors associated with higher risk of adverse outcomes in hemodynamically stable patients. Heart-type fatty acid binding protein (H-FABP) is a novel marker evaluated in recent years for prognosis in acute PE. Our aim was to evaluate the available evidence on the accuracy of H FABP for predicting the prognosis of adverse clinical outcomes (defined as the occurrence of any of the following: death, cardiopulmonary resuscitation, endotracheal intubation, use of vasopressors, thrombolysis, surgical embolectomy, or admission to the intensive care unit) or mortality in patients with acute PE. METHODS: Unrestricted searches of PubMed, the Cochrane Library, Web of Science and Science Direct were performed using the terms of "H-FABP" or "heart-type fatty acid binding protein" and ("pulmonary embolism" or "pulmonary thromboembolism"). A random-effect model was used to pool study results; chi(2) and I(2) testing was used to test for heterogeneity. Data of six studies were included in this analysis. RESULTS: 34 of 119(28.57%; 95%CI, 20.42%-36.72%) patients with elevated H-FABP levels had adverse events during follow-up compared with 24 of 475 (5.05%; 95%CI, 3.08%-7.02%) patients with normal levels. High H FABP levels were associated with a high risk of occurrence of adverse clinical outcome (pooled OR, 10.81; 95%CI, 3.92-29.83). CONCLUSION: The results of this meta-analysis indicate that H-FABP is a good predictor for adverse outcomes in patients with acute PE. PMID- 25456731 TI - Synergistic effect of signaling from receptors of soluble platelet agonists and outside-in signaling in formation of a stable fibrinogen-integrin alphaIIbbeta3 actin cytoskeleton complex. AB - INTRODUCTION: Thrombus formation in the injured vessel wall is a highly complex process involving various blood-born components that go through specific temporal and spatial changes as observed by intravital videomicroscopy. Platelets bind transiently to the developing thrombus and may either become stably incorporated into or disengage from the thrombus. The aim of the present study was to reveal the processes involved in the formation of a stable thrombus. METHODS: Platelet rich plasma and washed platelets were studied by the aggregometer. The aggregate stability was challenged by eptifibatide. Platelet Triton-insoluble fraction was prepared and the actin and alphaIIb content in the cytoskeleton was analyzed by western blot. RESULTS: Maximal actin polymerization is achieved 1min after platelet activation while maximal alphaIIbbeta3-actin cytoskeleton association requires 5 to 10min of activation and fibrinogen-mediated platelet-to-platelet bridging. Thus, actin polymerization is dependent on platelet activation and requires neither alphaIIbbeta3 integrin occupation nor platelet aggregation. Formation of a stable aggregate requires platelet activation for more than 1min, complete increase in actin cytoskeleton fraction and partial association of alphaIIbbeta3 with the actin cytoskeleton. However, direct alphaIIbbeta3 activation is not sufficient for cytoskeleton complex formation. Thus, stable alphaIIbbeta3-fibrinogen interaction, representing stable aggregate, is achieved after more than 1min agonist activation, involving inside-out and outside-in signaling but not after direct integrin activation, involving only outside-in signaling. CONCLUSIONS: Formation of a stable fibrinogen-alphaIIbbeta3-actin cytoskeleton complex is the result of the combined effect of platelet stimulation by soluble agonists, activation of alphaIIbbeta3, fibrinogen binding and platelet to-platelet bridging. PMID- 25456732 TI - Cost-effectiveness analysis of pharmacogenetic-guided warfarin dosing in Thailand. AB - INTRODUCTION: Pharmacogenetic (PGx) test is a useful tool for guiding physician on an initiation of an optimal warfarin dose. To implement of such strategy, the evidence on the economic value is needed. This study aimed to determine the cost effectiveness of PGx-guided warfarin dosing compared with usual care (UC). METHODS: A decision analytic model was used to compare projected lifetime costs and quality-adjusted life years (QALYs) accrued to warfarin users through PGx or UC for a hypothetical cohort of 1,000 patients. The model was populated with relevant information from systematic review, and electronic hospital-database. Incremental cost-effectiveness ratios (ICERs) were calculated based on healthcare system and societal perspectives. All costs were presented at year 2013. A series of sensitivity analyses were performed to determine the robustness of the findings. RESULTS: From healthcare system perspective, PGx increases QALY by 0.002 and cost by 2,959 THB (99 USD) compared with UC. Thus, the ICER is 1,477,042 THB (49,234 USD) per QALY gained. From societal perspective, PGx results in 0.002 QALY gained, and increases costs by 2,953 THB (98 USD) compared with UC (ICER 1,473,852 THB [49,128 USD] per QALY gained). Results are sensitive to the risk ratio (RR) of major bleeding in VKORC1 variant, the efficacy of PGx guided dosing, and the cost of PGx test. CONCLUSION: Our finding suggests that PGx-guided warfarin dosing is unlikely to be a cost-effective intervention in Thailand. This evidence assists policy makers and clinicians in efficiently allocating scarce resources. PMID- 25456733 TI - Phloroglucinol suppresses metastatic ability of breast cancer cells by inhibition of epithelial-mesenchymal cell transition. AB - Metastasis is a challenging clinical problem and the primary cause of death in breast cancer patients. However, there is no therapeutic agent against metastasis of breast cancer cells. Here we report that phloroglucinol, a natural phlorotannin component of brown algae suppresses metastatic ability of breast cancer cells. Treatment with phloroglucinol effectively inhibited mesenchymal phenotypes of basal type breast cancer cells through downregulation of SLUG without causing a cytotoxic effect. Importantly, phloroglucinol decreased SLUG through inhibition of PI3K/AKT and RAS/RAF-1/ERK signaling. In agreement with in vitro data, phloroglucinol was also effective against in vivo metastasis of breast cancer cells, drastically suppressing their metastatic ability to lungs, and extending the survival time of mice. Collectively, our findings demonstrate a novel anticancer activity of phloroglucinol against metastasis of breast cancer cells, implicating its clinical relevance. PMID- 25456735 TI - Notch1 controls cell invasion and metastasis in small cell lung carcinoma cell lines. AB - INTRODUCTION: Notch signaling plays a key role in a wide variety of human neoplasms, and it can be either oncogenic or anti-proliferative. Moreover, Notch function in regulating cancer is unpredictable, and its outcome is strictly context-dependent. AIM: To study the role of Notch1 signaling in human small cell lung carcinoma (SCLC) and its effect on cell invasion and metastasis. MATERIALS AND METHODS: We used small interfering RNA (siRNA) technology, to down-regulate the expression of Notch1 in H69AR and SBC3 SCLC cells. On the other hand, we up regulated Notch1 in H69 and H1688 SCLC cells through transfection with venus Notch1 intracellular domain (v.NICD) plasmid. In addition, H69 cells with v.NICD were xenotransplanted into immune-compromised Rag2(-/-) Jak3(-/-) mice, for analysis of ex vivo tumor epithelial mesenchymal transition (EMT) phenotype and for detection of metastatic cancer cells in the lung tissues. Moreover, we examined the metastatic ability for H69AR and SBC3 cells transfected with siRNA against Notch1, compared to their subsequent controls, by use of tail vein xenograft mouse models. RESULTS: Notch1 controls cell adhesion and EMT. Overexpression of Notch1 in SCLC switched off EMT, cell motility and cell metastatic potential. CONCLUSION: Our results demonstrate that activation of Notch1 signaling pathway may represent a new strategy for treating human SCLC. PMID- 25456734 TI - Serum vitamin D, vitamin D binding protein, and lung cancer survival. AB - OBJECTIVES: Vitamin D may prolong cancer survival by inhibiting tumor progression and metastasis, however, there are limited epidemiologic studies regarding the association between circulating 25-hydroxyvitamin D (25(OH)D) and lung cancer survival. The aim of this study was to examine the relationship between serum 25(OH)D and lung cancer specific survival and to evaluate whether vitamin D binding protein (DBP) concentration modified this association. MATERIALS AND METHODS: 25(OH)D and DBP were measured in fasting serum samples from 500 male lung cancer cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for lung cancer related death according to quartiles of season-specific 25(OH)D, DBP, and the molar ratio of 25(OH)D:DBP, a proxy for free circulating 25(OH)D. RESULTS: Comparing highest to lowest quartiles, serum 25(OH)D (HR=1.18; 95% CI: 0.89-1.56) and DBP (HR=0.95; 95% CI: 0.71-1.26) were not associated with lung cancer survival and DBP concentration did not modify the association with 25(OH)D (p for interaction=0.56). There was suggestion of an association between higher serum 25(OH)D and better survival from adenocarcinoma (HR=0.64; 95% CI: 0.17-2.45) and small cell carcinoma (HR=0.55; 95% CI: 0.21-1.45), but these estimates were based on a relatively small number of cases. CONCLUSION: Serum 25(OH)D was not associated with overall lung cancer survival regardless of DBP concentration, however, these findings should be examined in other studies that include women and subjects with higher 25(OH)D levels. PMID- 25456736 TI - Recurrent TERT promoter mutations in non-small cell lung cancers. AB - INTRODUCTION: The recurrent TERT promoter mutations have been recently described in diverse human cancers. We previously showed that over 60% of non-small cell lung cancer from East Asian harbored well-known oncogenic mutations in EGFR and KRAS. Here, we sought to determine the incidence, clinicopathologic characteristics, and association with known oncogenic mutations. PATIENTS AND METHODS: A total of 467 patients treated surgically for primary lung cancer were examined for mutations in TERT promoter using polymerase chain reaction (PCR) followed by Sanger sequencing. Immunohistochemical (IHC) staining was performed to detect the expression of TERT. Clinical characteristics including gender, age, smoking status, tumor size, differentiation, lymph node metastasis, TNM stage, overall survival and relapse-free survival were analyzed. RESULTS: Of 467 patients with non-small cell lung cancer, the TERT promoter mutation was detected in 12 patients. Of the 12 patients, 3 with C228T, 2 with C250T, 2 with C216T, 1 with C228A, 1 with C229G, 1 with G267C, 1 with C295T and 1 with G233C. Compared to the TERT mutation negative group, patients with TERT promoter mutation were significantly associated with older age (>= 60 years, p = 0.039). No significant difference was found in overall survival (OS) or relapse-free survival (RFS) between TERT with mutation and TERT without mutation. CONCLUSIONS: TERT promoter mutations are recurrent mutated in 2.57% of NSCLCs and are highly enriched in older patients. It may play an important role in the pathogenesis of NSCLC and may serve as a potential target for therapy. PMID- 25456737 TI - Metformin: from mechanisms of action to therapies. AB - Metformin is currently the first-line drug treatment for type 2 diabetes. Besides its glucose-lowering effect, there is interest in actions of the drug of potential relevance to cardiovascular diseases and cancer. However, the underlying mechanisms of action remain elusive. Convincing data place energy metabolism at the center of metformin's mechanism of action in diabetes and may also be of importance in cardiovascular diseases and cancer. Metformin-induced activation of the energy-sensor AMPK is well documented, but may not account for all actions of the drug. Here, we summarize current knowledge about the different AMPK-dependent and AMPK-independent mechanisms underlying metformin action. PMID- 25456738 TI - A new biology of diabetes revealed by leptin. AB - A variety of leptin actions require a re-examination of classic concepts of metabolic diseases. Here we present evidence for two physiologic pathways: a pathway that protects nonadipose tissues from overaccumulation of potentially toxic lipids and unrecognized paracrine interactions between alpha and beta cells revealed by leptin's ability to suppress diabetic hyperglucagonemia. These observations strongly point to new therapeutic possibilities for both type 1 and type 2 diabetes. PMID- 25456739 TI - DNA damage response and metabolic disease. AB - Accumulation of DNA damage has been linked to the process of aging and to the onset of age-related diseases including diabetes. Studies on progeroid syndromes have suggested that the DNA damage response is involved in regulation of metabolic homeostasis. DNA damage could impair metabolic organ functions by causing cell death or senescence. DNA damage also could induce tissue inflammation that disturbs the homeostasis of systemic metabolism. Various roles of molecules related to DNA repair in cellular metabolism are being uncovered, and such molecules could also have an impact on systemic metabolism. This review explores mechanisms by which the DNA damage response could contribute to metabolic dysfunction. PMID- 25456740 TI - Intracellular inactivation of thyroid hormone is a survival mechanism for muscle stem cell proliferation and lineage progression. AB - Precise control of the thyroid hormone (T3)-dependent transcriptional program is required by multiple cell systems, including muscle stem cells. Deciphering how this is achieved and how the T3 signal is controlled in stem cell niches is essentially unknown. We report that in response to proliferative stimuli such as acute skeletal muscle injury, type 3 deiodinase (D3), the thyroid hormone inactivating enzyme, is induced in satellite cells where it reduces intracellular thyroid signaling. Satellite cell-specific genetic ablation of dio3 severely impairs skeletal muscle regeneration. This impairment is due to massive satellite cell apoptosis caused by exposure of activated satellite cells to the circulating TH. The execution of this proapoptotic program requires an intact FoxO3/MyoD axis, both genes positively regulated by intracellular TH. Thus, D3 is dynamically exploited in vivo to chronically attenuate TH signaling under basal conditions while also being available to acutely increase gene programs required for satellite cell lineage progression. PMID- 25456741 TI - Loss of white adipose hyperplastic potential is associated with enhanced susceptibility to insulin resistance. AB - Fat mass expansion occurs by adipocyte hypertrophy or recruitment of differentiating adipocyte progenitors, the relative balance of which may impact systemic metabolism. We measured adipogenesis in murine subcutaneous (sWAT) and visceral white adipose tissue (vWAT) using stable isotope methodology and then modeled adipocyte turnover. Birth and death rates were similar within depots; however, turnover was higher in vWAT relative to sWAT. In juvenile mice, obesity increased adipogenesis, but in adults, this was only seen in vWAT after prolonged high-fat feeding. Statistical modeling suggests differentiation of adipocyte progenitors without an accompanying self-renewing division step may partially explain the age-dependent decline in hyperplastic potential. Additional metabolic interrogation of obese mice demonstrated an association between adipocyte turnover and insulin sensitivity. These data therefore identify adipocyte hypertrophy as the dominant mechanism of adult fat mass expansion and support the paradoxical concept that metabolic disease ensues due to a failure of adipose tissue plasticity. PMID- 25456742 TI - Molecular and biochemical characterization of Mottled-dappled, an embryonic lethal Menkes disease mouse model. AB - Mottled-dappled (Mo-dp) is a mouse model of Menkes disease caused by a large, previously uncharacterized deletion in the 5' region of Atp7a, the mouse ortholog of ATP7A. Affected mutants die in utero at embryonic day 17, and show bending and thickening of the ribs and distortion of the pectoral and pelvic girdles and limbs. To characterize this allele, we designed a custom 4x180K microarray on the mouse X chromosome and performed comparative genomic hybridization using extracted DNA from normal and carrier Mo-dp females, and identified an approximately 9 kb deletion. We used PCR to fine-map the breakpoints and amplify a junction fragment of 630 bp. Sequencing of the junction fragment disclosed the exact breakpoint locations and that the Mo-dp deletion is precisely 8990 bp, including approximately 2 kb in the promoter region of Atp7a. Western blot analysis of Mo-dp heterozygous brains showed diminished amounts of Atp7a protein, consistent with reduced expression due to the promoter region deletion on one allele. In heterozygous females, brain copper levels tended to be lower compared to wild type whereas neurochemical analyses revealed higher dihydroxyphenylacetic acid:dihydroxyphenylglycol (DOPAC:DHPG) and dopamine:norepinephrine (DA:NE) ratios compared to normal (P=0.002 and 0.029, respectively), consistent with partial deficiency of dopamine-beta-hydroxylase, a copper-dependent enzyme. Heterozygous females showed no significant differences in body weight compared to wild type females. Our results delineate the molecular details of the Mo-dp mutation for the first time and define novel biochemical findings in heterozygous female carriers of this allele. PMID- 25456743 TI - Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies. AB - BACKGROUND: Auto-antibodies against folate receptor alpha (FRalpha) at the choroid plexus that block N(5)-methyltetrahydrofolate (MTHF) transfer to the brain were identified in catatonic schizophrenia. Acoustic hallucinations disappeared following folinic acid treatment. Folate transport to the CNS prevents homocysteine accumulation and delivers one-carbon units for methyl transfer reactions and synthesis of purines. The guanosine derivative tetrahydrobiopterin acts as common co-factor for the enzymes producing dopamine, serotonin and nitric oxide. METHODS: Our study selected patients with schizophrenia unresponsive to conventional treatment. Serum from these patients with normal plasma homocysteine, folate and vitamin B12 was tested for FR autoantibodies of the blocking type on serial samples each week. Spinal fluid was analyzed for MTHF and the metabolites of pterins, dopamine and serotonin. The clinical response to folinic acid treatment was evaluated. RESULTS: Fifteen of 18 patients (83.3%) had positive serum FR auto-antibodies compared to only 1 in 30 controls (3.3%) (chi(2)=21.6; p<0.0001). FRalpha antibody titers in patients fluctuated over time varying between negative and high titers, modulating folate flux to the CNS, which explained low CSF folate values in 6 and normal values in 7 patients. The mean+/-SD for CSF MTHF was diminished compared to previously established controls (t-test: 3.90; p=0.0002). A positive linear correlation existed between CSF MTHF and biopterin levels. CSF dopamine and serotonin metabolites were low or in the lower normal range. Administration of folinic acid (0.3-1mg/kg/day) to 7 participating patients during at least six months resulted in clinical improvement. CONCLUSION: Assessment of FR auto-antibodies in serum is recommended for schizophrenic patients. Clinical negative or positive symptoms are speculated to be influenced by the level and evolution of FRalpha antibody titers which determine folate flux to the brain with up- or down-regulation of brain folate intermediates linked to metabolic processes affecting homocysteine levels, synthesis of tetrahydrobiopterin and neurotransmitters. Folinic acid intervention appears to stabilize the disease process. PMID- 25456744 TI - Homocysteine and DNA methylation: a review of animal and human literature. AB - Homocysteine (Hcy) is a sulfur-containing non-protein forming amino acid, which is synthesized from methionine as an important intermediate in the one-carbon pathway. High concentrations of Hcy in a condition called hyperhomocysteinemia (HHcy) are an independent risk factor for several disorders including cardiovascular diseases and osteoporotic fractures. Since Hcy is produced as a byproduct of the methyltransferase reaction, alteration in DNA methylation is studied as one of the underlying mechanisms of HHcy-associated disorders. In animal models, elevated Hcy concentrations are induced either by diet (high methionine, low B-vitamins, or both), gene knockouts (Mthfr, Cbs, Mtrr or Mtr) or combination of both to investigate their effects on DNA methylation or its markers. In humans, most of the literature involves case-control studies concerning patients. The focus of this review is to study existing literature on HHcy and its role in relation to DNA methylation. Apart from this, a few studies investigated the effect of Hcy-lowering trials on restoring DNA methylation patterns, by giving a folic acid or B-vitamin supplemented diet. These studies which were conducted in animal models as well as humans were included in this review. PMID- 25456745 TI - Fast clinical molecular diagnosis of hyperphenylalaninemia using next-generation sequencing-based on a custom AmpliSeqTM panel and Ion Torrent PGM sequencing. AB - Hyperphenylalaninemia (HPA) can be classified into phenylketonuria (PKU) and tetrahydrobiopterin deficiency (BH4D), according to the defect of enzyme activity, both of which vary substantially in severity, treatment, and prognosis of the disease. To set up a fast and comprehensive assay in order to achieve early etiological diagnosis and differential diagnosis for children with HPA, we designed a custom AmpliSeqTM panel for the sequencing of coding DNA sequence (CDS), flanking introns, 5' untranslated region (UTR) and 3' UTR from five HPA causing genes (PAH, PTS, QDPR, GCH1, and PCBD1) using the Ion Torrent Personal Genome Machine (PGM) Sequencer. A standard group of 15 samples with previously known DNA sequences and a test group of 37 HPA patients with unknown mutations were used for assay validation and application, respectively. All variations were confirmed by Sanger sequencing. In the standard group, all the known mutations were detected and were consistent with the results of previous Sanger sequencing. In the test group, we identified mutations in 71 of 74 alleles, with a mutation detection rate of 95.9%. We also found a frame shift deletion p.Ile25Metfs*13 in PAH that was previously unreported. In addition, 1 of 37 in the test group was inconsistent with either the molecular diagnosis or clinical diagnosis by traditional differential methods. In conclusion, our comprehensive assay based on a custom AmpliSeqTM panel and Ion Torrent PGM sequencing has wider coverage, higher throughput, is much faster, and more efficient when compared with the traditional molecular detection method for HPA patients, which could meet the medical need for individualized diagnosis and treatment. PMID- 25456746 TI - Neurodevelopmental profiles of children with very long chain acyl-CoA dehydrogenase deficiency diagnosed by newborn screening. AB - BACKGROUND: Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is a disorder of fatty acid oxidation with an estimated incidence of between 1:31,500 and 1:125,000. There is limited information regarding neurodevelopmental outcomes, probably because the disorder is perceived as affecting the skeletal and heart muscles, and many children are deemed asymptomatic. The aim of this study was to utilise a comprehensive neuropsychological assessment battery that assessed IQ, language, attention, memory, executive functioning, motor skills, behaviour, and social skills in children 4 to 10 years old diagnosed with VLCAD deficiency through newborn screening. METHOD: Seven children completed neuropsychological assessment and one child was only involved in part of the study (2 female, 6 male). Parents completed questionnaires regarding executive functioning, behaviour and social skills. RESULTS: IQ scores ranged from average to the superior range. No deficits were found in fine or gross motor skills. One patient had a mild language deficit, and two patients had previously required speech therapy. Verbal memory, attention and executive functioning skills were generally average or above. Visual memory scores were mostly above average. Parents' questionnaires identified one child as having social skills deficits, and two as having behavioural problems such as hyperactivity. One child rated high on an autism spectrum subscale; another was formally diagnosed with autism spectrum disorder-both children were symptomatic at birth. CONCLUSIONS: VLCAD deficiency does not have a significant impact on cognitive or motor skills. Some children may be vulnerable to speech, social and behavioural issues. PMID- 25456747 TI - The individual (single patient) IND for inborn errors of metabolism. AB - Under the United States Food and Drug Administration's Expanded Access program, a physician may treat a single patient with an experimental medication under an individual investigational new drug application (iIND). Metabolic geneticists may be among the specialists most likely to be asked to obtain an iIND, because there are many experimental treatments for inborn errors of metabolism which work in animals but suffer delays in translation to the bedside. The iIND has the potential to help bridge that gap, by gathering initial evidence in support of the use of an experimental drug in humans. If done with experimental rigor, the data will be useful, despite being limited to a single patient. However, iINDs may pose risks to drug development if patients are not carefully selected. Whatever their advantages and disadvantages, iIND studies are here to stay. Metabolic specialists should cautiously consider the iIND as a tremendous opportunity for therapeutic experimentation. PMID- 25456753 TI - Understanding and treating pulmonary hypertension in congenital diaphragmatic hernia. AB - Lung hypoplasia and pulmonary hypertension are classical features of congenital diaphragmatic hernia (CDH) and represent the main determinants of survival. The mechanisms leading to pulmonary hypertension in this malformation are still poorly understood, but may combine altered vasoreactivity, pulmonary artery remodeling, and a hypoplastic pulmonary vascular bed. Efforts have been directed at correcting the "reversible" component of pulmonary hypertension of CDH. However, pulmonary hypertension in CDH is often refractory to pulmonary vasodilators. A new emerging pattern of late (months after birth) and chronic (months to years after birth) pulmonary hypertension are described in CDH survivors. The true incidence and implications for outcome and management need to be confirmed by follow-up studies from referral centers with high patient output. In order to develop more efficient strategies to treat pulmonary hypertension and improve survival in most severe cases, the ultimate therapeutic goal would be to promote lung and vascular growth. PMID- 25456748 TI - Subcutaneous panniculitis-like T-cell lymphoma in children: a detailed clinicopathological description of 11 multifocal cases with a high frequency of haemophagocytic syndrome. PMID- 25456754 TI - Novel non-surgical prenatal approaches to treating congenital diaphragmatic hernia. AB - This review focuses on the emerging field of non-surgical in-utero therapies in the management of fetal pulmonary hypoplasia and pulmonary hypertension associated with congenital diaphragmatic hernia (CDH). These experimental approaches include pharmacologic as well as stem-cell-based strategies. Current barriers of non-surgical therapies toward clinical translation are emphasized. As the severity of CDH will likely influence the efficacy of any in-utero therapy, the current status of prenatal imaging and the role of novel biomarkers, especially those related to fetal inflammation, are also reviewed. PMID- 25456756 TI - Strengthening the Achilles heel of high-risk plaques. PMID- 25456755 TI - Effect of atorvastatin therapy on fibrous cap thickness in coronary atherosclerotic plaque as assessed by optical coherence tomography: the EASY-FIT study. AB - BACKGROUND: The detailed mechanism of plaque stabilization by statin therapy is not fully understood. OBJECTIVES: The aim of this study was to assess the effect of lipid-lowering therapy with 20 mg/day of atorvastatin versus 5 mg/day of atorvastatin on fibrous cap thickness in coronary atherosclerotic plaques by using optical coherence tomography (OCT). METHODS: Seventy patients with unstable angina pectoris and untreated dyslipidemia were randomized to either 20 mg/day or 5 mg/day of atorvastatin therapy. OCT was performed to assess intermediate nonculprit lesions at baseline and 12-month follow-up. RESULTS: Serum low-density lipoprotein cholesterol level was significantly lower during therapy with 20 mg/day compared with 5 mg/day of atorvastatin (69 mg/dl vs. 78 mg/dl; p = 0.039). The increase in fibrous cap thickness was significantly greater with 20 mg/day compared with 5 mg/day of atorvastatin (69% vs. 17%; p < 0.001). The increase in fibrous cap thickness correlated with the decrease in serum levels of low-density lipoprotein cholesterol (R = -0.450; p < 0.001), malondialdehyde-modified low density lipoprotein (R = -0.283; p = 0.029), high-sensitivity C-reactive protein (R = -0.276; p = 0.033), and matrix metalloproteinase-9 (R = -0.502; p < 0.001), and the decrease in grade of OCT-derived macrophages (R = -0.415; p = 0.003). CONCLUSIONS: Atorvastatin therapy at 20 mg/day provided a greater increase in fibrous cap thickness in coronary plaques compared with 5 mg/day of atorvastatin. The increase of fibrous cap was associated with the decrease in serum atherogenic lipoproteins and inflammatory biomarkers during atorvastatin therapy. (Effect of Atorvastatin Therapy on Fibrous Cap Thickness in Coronary Atherosclerotic Plaque as Assessed by Optical Coherence Tomography: The EASY-FIT Study; NCT00700037). PMID- 25456757 TI - Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. AB - BACKGROUND: The long-term outcome of atrial fibrillation (AF) ablation demonstrates attrition. This outcome may be due to failure to attenuate the progressive substrate promoted by cardiovascular risk factors. OBJECTIVES: The goal of this study was to evaluate the impact of risk factor and weight management on AF ablation outcomes. METHODS: Of 281 consecutive patients undergoing AF ablation, 149 with a body mass index >=27 kg/m(2) and >=1 cardiac risk factor were offered risk factor management (RFM) according to American Heart Association/American College of Cardiology guidelines. After AF ablation, all 61 patients who opted for RFM and 88 control subjects were assessed every 3 to 6 months by clinic review and 7-day Holter monitoring. Changes in the Atrial Fibrillation Severity Scale scores were determined. RESULTS: There were no differences in baseline characteristics, number of procedures, or follow-up duration between the groups (p = NS). RFM resulted in greater reductions in weight (p = 0.002) and blood pressure (p = 0.006), and better glycemic control (p = 0.001) and lipid profiles (p = 0.01). At follow-up, AF frequency, duration, symptoms, and symptom severity decreased more in the RFM group compared with the control group (all p < 0.001). Single-procedure drug-unassisted arrhythmia-free survival was greater in RFM patients compared with control subjects (p < 0.001). Multiple-procedure arrhythmia-free survival was markedly better in RFM patients compared with control subjects (p < 0.001), with 16% and 42.4%, respectively, using antiarrhythmic drugs (p = 0.004). On multivariate analysis, type of AF (p < 0.001) and RFM (hazard ratio 4.8 [95% confidence interval: 2.04 to 11.4]; p < 0.001) were independent predictors of arrhythmia-free survival. CONCLUSIONS: Aggressive RFM improved the long-term success of AF ablation. This study underscores the importance of therapy directed at the primary promoters of the AF substrate to facilitate rhythm control strategies. PMID- 25456758 TI - Catheter ablation of atrial fibrillation: on the pathophysiology of the arrhythmia and the impact of cardiac risk factor management. PMID- 25456759 TI - Multicenter evaluation of a next-generation balloon-expandable transcatheter aortic valve. AB - BACKGROUND: The SAPIEN 3 (Edwards Lifesciences Inc., Irvine, California) transcatheter valve incorporates features designed to address the well-known deficiencies of transcatheter aortic valve replacement (TAVR). An ultra-low profile delivery system facilitates safe, controlled, and accurate implantation and an external seal minimizes paravalvular regurgitation. OBJECTIVES: The study evaluated whether TAVR with this third-generation valve would be a viable alternative to high- or intermediate-risk surgery for severe aortic stenosis. METHODS: The prospective study enrolled 150 patients at 16 sites in Europe and Canada. Clinical and echocardiographic outcomes were assessed at baseline, post procedure, and 30 days. New sizing recommendations were developed during the course of the study. RESULTS: Patients were 83.6 +/- 5.0 years of age, with multiple comorbidities reflected by a Society of Thoracic Surgeons score of 7.4 +/- 4.5% and logistic EuroSCORE of 21.6 +/- 12.3%. A transfemoral approach was chosen in 64.0% and alternative access (transapical/direct aortic) in the remainder. At 30 days, paravalvular regurgitation was none to mild in 96.4% and moderate in 3.5%. No patient had severe regurgitation. Transfemoral implantation was associated with low mortality (2.1%), no disabling stroke (0.0%), and fully percutaneous access and closure in 95.8%. Nontransfemoral alternative access was associated with higher rates of mortality (11.6%) and stroke (5.6%). CONCLUSIONS: This third-generation device addresses major deficiencies of earlier valves in terms of ease of use, accuracy of positioning, and paravalvular sealing. The rates of mortality and stroke with transfemoral access are among the lowest reported and support further evaluation as an alternative to open surgery in intermediate-risk patients. (Safety and Performance Study of the Edwards SAPIEN 3 Transcatheter Heart Valve [SAPIEN3]; NCT01808287). PMID- 25456760 TI - New transcatheter aortic valve prosthesis sets a new standard. PMID- 25456762 TI - Confronting the Tower of Babel in guideline development: can we unify the process? PMID- 25456763 TI - Training in structural heart interventions. PMID- 25456764 TI - Normalization of low-density lipoprotein receptor expression in receptor defective homozygous familial hypercholesterolemia by inhibition of PCSK9 with alirocumab. PMID- 25456761 TI - Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. AB - Heart failure patients are classified by ejection fraction (EF) into distinct groups: heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF). Although patients with heart failure commonly have multiple comorbidities that complicate management and may adversely affect outcomes, their role in the HFpEF and HFrEF groups is not well characterized. This review summarizes the role of noncardiac comorbidities in patients with HFpEF versus HFrEF, emphasizing prevalence, underlying pathophysiologic mechanisms, and outcomes. Pulmonary disease, diabetes mellitus, anemia, and obesity tend to be more prevalent in HFpEF patients, but renal disease and sleep-disordered breathing burdens are similar. These comorbidities similarly increase morbidity and mortality risk in HFpEF and HFrEF patients. Common pathophysiologic mechanisms include systemic and endomyocardial inflammation with fibrosis. We also discuss implications for clinical care and future HF clinical trial design. The basis for this review was discussions between scientists, clinical trialists, and regulatory representatives at the 10th Global CardioVascular Clinical Trialists Forum. PMID- 25456765 TI - The global cardiovascular crisis: glove up. PMID- 25456766 TI - Effect of computed tomography imaging on rhythm devices in real-world practice. PMID- 25456768 TI - Editorial overview: Allergy and hypersensitivity. PMID- 25456767 TI - Reply: Effect of computed tomography imaging on rhythm devices in real-world practice. PMID- 25456769 TI - Editorial overview: Autoimmunity. PMID- 25456771 TI - Subcutaneous emphysema in the lower extremities-always an emergency? Complications from minimally invasive surgery-a case report. AB - BACKGROUND: Lower-extremity subcutaneous emphysema is an unusual presentation in the emergency department, and it is often associated with gas-forming bacterial infections that confer significant morbidity and mortality. Because the presence of subcutaneous emphysema in an extremity can be alarming, physicians often pursue aggressive diagnostic and therapeutic strategies to identify and treat the underlying cause. In some cases, however, subcutaneous emphysema does not represent a life-threatening medical condition. The source of the subcutaneous air may not always be immediately recognized and can lead to either over- or under-utilization of resources to direct patient care. CASE REPORT: We describe a case of bilateral lower-extremity subcutaneous emphysema after recent robotic surgery. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: As the role of minimally invasive surgery and the push for shorter hospitalizations continue to rise, we are likely to see an increase in patients with complications from such procedures in the emergency department setting. Familiarity with the potential complications of these procedures is essential to differentiating between life threatening and non-life-threatening conditions. PMID- 25456770 TI - Sputum club cell protein concentration is associated with pulmonary exacerbation in cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) patients exhibit a progressive decline in lung function accelerated by intermittent pulmonary exacerbations. There are urgent needs for clinically relevant biomarkers to aid in the diagnosis and management of a CF pulmonary exacerbation, in addition to providing insight into its pathophysiology. Club cell secretory protein (CCSP) is produced by bronchial epithelial cells, known to have anti-inflammatory properties and may play a role in CF pulmonary exacerbations. Our objective was to measure sputum CCSP concentration during hospitalizations for CF pulmonary exacerbation and during quarterly outpatient clinic visits for 2 years. We explored the correlations between CCSP concentration, lung function and markers of inflammation and infection. METHODS: In this prospective, longitudinal cohort study, expectorated sputum, blood and lung function data were collected from 45 CF patients during 68 hospitalizations for pulmonary exacerbation and 193 clinic visits. Sputum CCSP concentration was measured and sputum and blood were assayed with a panel of inflammatory cytokines. We used a repeated measures model to compare log transformed sputum CCSP concentrations across multiple time points and to correlate those concentrations with related clinical variables. RESULTS: Our population had a mean age of 29 (16-58 years), and a median FEV(1) %predicted of 60% (18-105%). Sputum CCSP concentration was significantly lower in the initial, interim and final exacerbation samples (p=0.0021, p=0.0005 and p=0.0274, respectively) compared to outpatient visits. Sputum CCSP concentration was negatively associated with sputum neutrophil elastase concentration (p=0.0373). Patients with Pseudomonas aeruginosa mucoid had a significantly lower sputum CCSP concentration (p=0.0129). CONCLUSION: Sputum CCSP concentration is associated with CF pulmonary exacerbation. PMID- 25456772 TI - Left atrial myoxma presenting as headache in the pediatric patient. AB - BACKGROUND: Cardiac myxomas rarely occur in children or adolescents. In addition, it is even more rare for the adolescent patient to present with neurological symptoms only. Early diagnosis is difficult because the symptoms of left atrial myxoma are frequently nonspecific. If delayed or left undiagnosed, severe and fatal complications, such as systemic embolism, heart failure, and pulmonary hypertension, may occur. CASE REPORT: A 13-year-old girl was admitted to our resuscitation room because of loss of consciousness for the preceding 2 h; she had a longstanding history of headache and dizziness for the previous 18 months. Repeated investigations at her local hospital did not reveal any abnormalities. During this admission, routine chest x-ray study found an abnormal bulge of a segment of the pulmonary artery and elevated cardiac enzymes. Emergency bedside echocardiography was performed and revealed a myxoma in the left atria. Subsequent computed tomography head revealed cardiogenic cerebral embolism. When her condition was stable, the patient was taken to the operating room, where a tumorectomy was performed successfully. The patient was then treated with oral anticoagulants and an uneventful recovery was made. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: In order to avoid delayed diagnosis and treatment of its potentially fatal complications, it is important for the emergency clinician to have a high level of suspicion for a cardiac myxoma when attending to young patients that present with syncope. We therefore recommend that, as routine practice, bedside echocardiography to be carried in the emergency department for young patients that present with syncope. PMID- 25456773 TI - Takotsubo cardiomyopathy induced by suicidal neck hanging. AB - BACKGROUND: Takotsubo cardiomyopathy (TC) is an uncommon immune-endocrinologic cause of acute reversible heart failure, generally caused by some form of stress. CASE REPORT: We report a case of TC after hanging for attempted suicide. Upon admission, the patient demonstrated an almost entirely normal electrocardiogram (ECG) and mild hypotension. However, on the third day after hanging, she developed chest and back pain with inverted T waves and QTc prolongation on ECG. Her coronary arteries were normal on angiogram, but the left ventricle showed apical ballooning, consistent with TC. She was treated with an intra-aortic balloon pump and fully recovered. We observed that the QTc interval seemed to be a good guide for clinical course in this case. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: TC should be considered in any acute stressful presentation, and to assist in the diagnosis as TC, we suggest following the QTc on ECG. TC should be taken into consideration in patients after suicide attempt with low blood pressure or an abnormal ECG, including ST segment elevation, T wave inversion, and QTc prolongation. PMID- 25456774 TI - A survey of simulation fellowship programs. AB - BACKGROUND: A number of specialized educational programs (i.e., simulation fellowships) have been developed, but their characteristics are not well known. OBJECTIVE: We studied the characteristics of existing simulation fellowship programs. METHODS: Fellowships were identified and characteristics determined from public sources and direct survey. RESULTS: Seventeen fellowships were identified. The sponsoring academic unit was emergency medicine in 53%, pediatric emergency medicine in 7%, urology in 7%, emergency medicine/anesthesiology in 13%, and interdisciplinary units in 20%. Fifty-nine percent were open to emergency medicine residency graduates, and 12% were open to either anesthesia or emergency medicine graduates, or 12% to physician graduates of any specialty. One fellowship was open to pediatric emergency medicine graduates only and another specifically to surgically trained physicians. Seventy-eight percent indicated that fellows were required to work clinically as part of the fellowship, averaging 19 hours per week. Twenty-seven percent of fellowships were 1 year in length and 13% were 2 years. Common (47%) was the option of a 1- or 2-year fellowship, with those in the 2-year track earning a graduate degree or certificate. Most programs accepted a single fellow each year, and some accepted either one or two. Fellowships reported a high fill rate. CONCLUSIONS: The 17 identified fellowship programs differed greatly in length, sponsoring academic unit, and prerequisites. The majority require their fellows to provide clinical service. Fellowships reported a high fill rate, suggesting substantial interest in simulation among current residents. PMID- 25456775 TI - Reply to "statistical errors in a recent article in the journal". PMID- 25456776 TI - Fatal pulmonary embolization after negative serial ultrasounds. AB - BACKGROUND: Isolated distal deep vein thrombosis (DVT) is not traditionally viewed as a potentially life-threatening condition. There are conflicting recommendations regarding its evaluation and treatment, and wide variability in clinical practice. The presentation of this case highlights the fatal potential of this condition. CASE REPORT: This is the report of a previously healthy young woman who presented to the emergency department with calf pain concerning for a DVT. She received two radiologist-performed duplex ultrasound examinations of the affected extremity, both of which were negative, but suffered a sudden cardiac arrest several hours after the second study. Autopsy attributed the death to DVT and pulmonary embolism. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case highlights the risk for fatal pulmonary embolization, even after normal serial ultrasound examinations to exclude DVT. PMID- 25456777 TI - Evaluation of a liquid dressing for minor nonbleeding abrasions and class I and II skin tears in the emergency department. AB - BACKGROUND: Minor abrasions and skin tears are usually treated with gauze dressings and topical antibiotics requiring frequent and messy dressing changes. OBJECTIVE: We describe our experience with a low-cost, cyanoacrylate-based liquid dressing applied only once for minor abrasions and skin tears. METHODS: We conducted a single-center, prospective, noncomparative study in adult emergency department (ED) patients with minor nonbleeding skin abrasions and class I and II skin tears. After cleaning the wound and achieving hemostasis, the wounds were covered with a single layer of a cyanoacrylate liquid dressing. Patients were followed every 1-2 days until healing. RESULTS: We enrolled 40 patients with 50 wounds including 39 abrasions and 11 skin tears. Mean (standard deviation) age was 54.5 (21.9) years and 57.5% were male. Wounds were located on the face (n = 16), hands (n = 14), legs (n = 11), and arms (n = 9). Pain scores (0 to 10 from none to worst) after application of the liquid dressing were 0 in 62% and 1-3 in the remaining patients. Follow-up was available on 36 patients and 46 wounds. No wounds re-bled and there were no wound infections. Only one wound required an additional dressing. Median (interquartile range [IQR]) time to complete sloughing of the adhesive was 7 (5.5-8) days. Median (IQR) time to complete healing and sloughing of the overlying scab was 10 (7.4-14) days. CONCLUSIONS: Our study suggests that a single application of a low-cost cyanoacrylate-based liquid adhesive is a safe and effective treatment for superficial nonbleeding abrasions and class I and II skin tears that eliminates the need for topical antibiotics and dressings. PMID- 25456778 TI - A prospective cohort study of medication reconciliation using pharmacy technicians in the emergency department to reduce medication errors among admitted patients. AB - BACKGROUND: The collection of a complete, verified medication history is essential to patient safety. The involvement of clinical pharmacists has been shown to improve the completeness and accuracy of medication histories; however, to our knowledge, involvement of pharmacy technicians has not been studied. OBJECTIVE: Our aim was to determine whether verification of medication histories by pharmacy technicians in the emergency department (ED) would result in fewer errors in inpatient medication regimens compared to verification by the admitting physician team. METHODS: We performed a prospective cohort study of adult ED patients admitted for continuing care. In the intervention group, medication reconciliation was performed by pharmacy technicians in the ED before the creation of physician admitting orders. In the control group, pharmacy technicians conducted their history taking later, after admission. Initial admitting orders were then compared to the pharmacy technicians' medication reconciliation taken before admission (intervention group) or after admission (control group). Medication discrepancies were classified and determined to be justified or unjustified. Unjustified discrepancies were rated for harm potential. RESULTS: In our cohort of 113 intervention and 75 control subjects, the mean age was 55 years (standard deviation [SD] 16 years); 96 patients (51%) were male. In the intervention group, 566 changes to home medications were observed on admission; 352 (62%) were unjustified. Among controls, 406 changes to home medications were observed; 228 (56%) were unjustified. This difference was not statistically significant (p = 0.0586). The rate of unjustified medication changes per patient was likewise not significantly different (3.14 [SD 2.98] in interventions vs. 3.17 [SD 2.81] in controls; p = 0.9570). The rate of medical errors did not differ between study groups, nor did severity ratings of unjustified changes. CONCLUSIONS: Medication reconciliation by pharmacy technicians in the ED did not lead to a significant reduction in unjustified medication discrepancies. PMID- 25456779 TI - Wilson reply to Ryan. PMID- 25456780 TI - Profound symptomatic bradycardia requiring transvenous pacing after a single dose of tizanidine. AB - BACKGROUND: We report a case of profound symptomatic bradycardia after a single dose of tizanidine. CASE REPORT: A 93-year-old female became altered and was found to have hypotension and profound symptomatic bradycardia 30 min post ingestion of a single 4-mg dose of tizanidine at her physician's office. Emergency Medical Services was called to scene and patient was transported to our tertiary medical center. In the emergency department, the patient required intubation, vasopressor support, and transcutaneous pacing. An electrocardiogram revealed atrial fibrillation with slow ventricular response with a heart rate of 19 beats/min. The patient was transferred to the intensive care unit and subsequently taken for cardiac catheterization, where a transvenous pacer was placed. During the next few days, her vital signs and mental status improved, allowing for successful extubation. Before discharge, the patient received a single-chamber pacemaker. DISCUSSION: Profound symptomatic bradycardia from a single dose of tizanidine has not been reported. A review of the patient's medications did not reveal a significant cytochrome P450 drug interaction to result in an adverse effect as previously reported in the literature. CONCLUSIONS: Tizanidine should be used cautiously in elderly population and drug interactions screening should be performed. PMID- 25456781 TI - Impact of three-dimensional reconstruction technique in the operation planning of centrally located hepatocellular carcinoma. AB - BACKGROUND: The aim of this retrospective study was to compare the outcomes of operations based on 3-dimensional (3D) operation planning with non 3D-assisted operations in the treatment of centrally located hepatocellular carcinoma. STUDY DESIGN: From April 2008 to March 2014, 116 patients with centrally located hepatocellular carcinoma received surgical treatment in our department. Among these cases, a total of 60 patients received resection with operation planning based on 3D reconstructions (group A); the remaining 56 received treatment with the aid of traditional imaging (group B). Three-dimensional surgical planning, including the classification system for centrally located hepatocellular carcinoma, was elaborated in the study. RESULTS: Compared with group B, group A was linked to shorter operation time (294.5 +/- 61.9 minutes vs 324.3 +/- 83.1 minutes; p = 0.028) and lower rate of hepatic inflow occlusion (51.7% vs 71.4%; p = 0.029). No differences were found in surgical methods, intraoperative blood transfusion, and intraoperative blood loss. The groups were similar in their rates of complications, except that group B was more liable to have Clavien Grade III to V complications (3.3% vs 14.3%; p = 0.048). In addition, a significant difference in ascites was found across the 2 cohorts (2 in group A and 8 in group B; p = 0.048), and the 2 groups also differed significantly in total bilirubin (23.2 +/- 16.1 g/L vs 31.1 +/- 24.1 g/L; p = 0.032) and albumin (29.3 +/- 5.2 g/L vs 27.8 +/- 7.9 g/L; p = 0.033). CONCLUSIONS: Compared with non 3D-assisted operations, the operation planning based on 3D reconstruction is a more effective and reasonable method in the treatment of centrally located hepatocellular carcinoma. In addition, the classification system may facilitate the 3D operation planning. PMID- 25456782 TI - Optimizing feedback from a designated level 1 trauma/burn center to referring hospitals. AB - BACKGROUND: The American College of Surgeons Committee on Trauma (ACS-COT) is dedicated to improving the quality of care for severely injured patients. The ACS COT charges designated centers with providing feedback to referring hospitals. There are no guidelines or recommendations as to what should be included in the feedback or how it should be used. STUDY DESIGN: The objectives of this study were to evaluate current feedback efforts regarding patients transferred to Harborview Medical Center (HMC), a regional level 1 trauma and burn center, to better understand how the feedback is used, and to evaluate what types of feedback are most useful to the referring hospitals. An analysis of U-link (password-protected access to patient's electronic medical record) and other forms of feedback was performed. A survey was sent to 82 Washington State hospitals in the regionalized trauma system to evaluate the current feedback process and its utility. RESULTS: During 1 year, HMC admitted 5,988 trauma and 763 burn patients; 54.8% of trauma and 66.5% of burn admissions were transferred from referring hospitals. Currently, 90 different referring hospitals have acquired a U-link account to follow their patients. Discharge summaries were the primary source of information used. When hospitals were asked how this information is used, education (100%), systems analysis (98.5%), and quality assurance (92%) were most common. CONCLUSIONS: There is significant interest on the part of referring hospitals to receive feedback from a designated level 1 trauma/burn center to improve quality of care. A system like U-link can allow secure access to review patient charts for quality improvement and feedback purposes, in a manner that is efficient for the referring and receiving hospitals. PMID- 25456783 TI - Distal pancreatectomy: a single institution's experience in open, laparoscopic, and robotic approaches. AB - BACKGROUND: The indications for minimally invasive (MIS) pancreatectomy have slowly increased as experience, techniques, and technology have improved and evolved to manage malignant lesions in selected patients without compromising safety and oncologic principles. There are sparse data comparing laparoscopic, robotic, and open distal pancreatectomy (DP). STUDY DESIGN: All patients undergoing DP at Memorial Sloan Kettering Cancer Center between 2000 and 2013 were analyzed from a prospective database. Clinicopathologic and survival data were analyzed to compare perioperative and oncologic outcomes in patients who underwent DP via open, laparoscopic, and robotic approaches. RESULTS: Eight hundred five DP were performed during the study period, comprising 37 robotic distal pancreatectomies (RDP), 131 laparoscopic distal pancreatectomies (LDP), and 637 open distal pancreatectomies (ODP). The 3 groups were similar with respect to American Society of Anesthesiologists (ASA) score, sex ratio, body mass index, pancreatic fistula rate, and 90-day morbidity and mortality. Patients in the ODP group were generally older (p = 0.001), had significantly higher intraoperative blood loss (p < 0.001), and had a trend toward a longer hospital stay (p = 0.05). Of the significant preoperative variables, visceral fat was predictive of conversion on multivariate analysis (p = 0.003). Oncologic outcomes in the adenocarcinoma cases were similar for the 3 groups, with high rates of R0 resection (88% to 100%). The ODP group had a higher lymph node yield than the LDP and RDP groups (15.4, [SD 8.7] vs 10.4 [SD 8.0] vs 12[SD 7.2], p = 0.04). CONCLUSIONS: The RDP and LDP were comparable with respect to most perioperative outcomes, with no clear advantage of one approach over the other. Both of these MIS techniques may have advantages over ODP in well-selected patients. All approaches achieved a similarly high rate of R0 resection for patients with adenocarcinoma. PMID- 25456784 TI - Transforming hemoglobin measurement in trauma patients: noninvasive spot check hemoglobin. AB - BACKGROUND: Technological advances now allow for noninvasive Hbg measurements. Previous studies have reported on the efficacy of continuous noninvasive Hgb devices. Recently, a new device, Pronto-7, a spot check pulse CO-oximeter has become available. The aim of our study was to assess noninvasive Hgb measurement in trauma patients. METHODS: We performed a prospective cohort analysis of all trauma patients presenting to our Level I trauma center. Invasive Hgb and spot check Hgb measurements were obtained simultaneously at presentation. Spot check was measured 2 times with each invasive Hgb value. Normal Hgb was defined as >8 mg/dL. Spearman correlation and Bland-Altman analysis was performed. RESULTS: A total of 525 patients had attempted spot check Hgb measurements with a success rate of 86% (n = 450). A total of 450 invasive and 1,350 spot check Hgb measurements were obtained. Mean +/- SD age was 41 +/- 21 years, 74% were male, and mean Injury Severity Score was 21 +/- 13. Thirty-eight percent (n = 173) of patients had Hgb <=8 mg/dL at presentation. Mean invasive Hgb was 11.5 +/- 4.36 g/dL, mean spot check Hgb 11.1 +/- 3.60 g/dL, and mean difference was 0.3 +/- 1.3 g/dL. Spot check Hgb values had strong correlation with invasive Hgb measurements (R(2) = 0.77; R = 0.86; p = 0.04) with 76% accuracy and 95.4% sensitivity. CONCLUSIONS: Spot check Hgb monitoring had excellent correlation with invasive Hgb measurements. Application of spot check has more clinical use as compared with previous continuous Hgb monitoring. This novel technology allows immediate and accurate Hgb measurements in trauma patients. PMID- 25456785 TI - Measuring variation in use of the WHO surgical safety checklist in the operating room: a multicenter prospective cross-sectional study. AB - BACKGROUND: Full implementation of safety checklists in surgery has been linked to improved outcomes and team effectiveness; however, reliable and standardized tools for assessing the quality of their use, which is likely to moderate their impact, are required. STUDY DESIGN: This was a multicenter prospective study. A standardized observational instrument, the "Checklist Usability Tool" (CUT), was developed to record precise characteristics relating to the use of the WHO's surgical safety checklist (SSC) at "time-out" and "sign-out" in a representative sample of 5 English hospitals. The CUT was used in real-time by trained assessors across general surgery, urology, and orthopaedic cases, including elective and emergency procedures. RESULTS: We conducted 565 and 309 observations of the time out and sign-out, respectively. On average, two-thirds of the items were checked, team members were absent in more than 40% of cases, and they failed to pause or focus on the checks in more than 70% of cases. Information sharing could be improved across the entire operating room (OR) team. Sign-out was not completed in 39% of cases, largely due to uncertainty about when to conduct it. Large variation in checklist use existed between hospitals, but not between surgical specialties or between elective and emergency procedures. Surgical safety checklist performance was better when surgeons led and when all team members were present and paused. CONCLUSIONS: We found large variation in WHO checklist use in a representative sample of English ORs. Measures sensitive to checklist practice quality, like CUT, will help identify areas for improvement in implementation and enable provision of comprehensive feedback to OR teams. PMID- 25456786 TI - The body has a brake: micrin is a postulated new gonadal hormone curbing tissue overgrowth and restricting reproduction. AB - There is evidence for an unrecognised classical hormone secreted by the mammalian gonad. This postulated hormone--'micrin' (pronounced 'my-crin')--represents the body's brake against tissue overgrowth. When oestrogens are administered in high doses to female rats there is a considerable (non-artefactual) increase in the relative size and weight of organs such as the pituitary, adrenals, uterus and liver--suggesting an organotrophic (organ-building) role for endogenous oestrogens. This effect is exaggerated if the animals are first ovariectomized, indicating the removal of a negative ovarian factor, micrin. These organ enlargements can be reduced by pretreating the rats with large doses of antioestrogens such as clomiphene and tamoxifen. This antiestrogenic blockade of exogenous oestrogens is itself blunted by prior removal of the ovaries. It is proposed that antioestrogens (e.g. tamoxifen in breast cancer treatment) antagonize the organotrophic effects of oestrogens by competing for the oestrogen receptor peripherally and centrally and via an increase in the secretion of ovarian micrin. It is deduced that micrin is the testicular 'inhibin' proposed in the 1930s, not the molecule that now bears that name, which acts at the pituitary tier as a downregulator of follicle-stimulating hormone. The hallmark of micrin deficiency in the male rat is a pituitary hypertrophy that follows castration. This is reversible with a steroid-depleted aqueous bovine testicular extract, the micrin within which suppresses the hypothalamus, normalizing the pituitary. Micrin probably acts as a brake on peripheral tissues directly but also indirectly at the meta-level via the hypothalamic-pituitary axis, resetting a hypothalamic 'organostat' controlling organ and tissue masses, part of the 'organotrophic system' of internal size regulation. Besides endocrine (circulating) micrin from the gonads there is probably paracrine (locally acting) micrin produced in the brain. This is involved in a somatic cueing system for puberty: the brake comes off at an appropriate body tissue mass disinhibiting the hypothalamus and accelerating the organism towards sexual maturity and full adult stature. This suggests the use in reproductive disorders of micrin-related drugs. These could also be inhibitors of breast, prostate and other cancers, while protecting the bone marrow via a trophic effect on the adrenals (the lack of which protection causes lethal bone marrow depression in oestrogen-treated ferrets and dogs). Benign prostatic hyperplasia is asserted to be a micrin deficiency disorder, involving insufficiently opposed androgen. The rise in cancers with age could be associated with a reduction in micrin protection and a relative lack of this hormone could partly explain why men die younger than women. Micrin is dissimilar in activity to any known molecule and could usefully be isolated, characterised and exploited therapeutically. PMID- 25456787 TI - Allogeneic and autologous mode of stem cell transplantation in regenerative medicine: which way to go? AB - Stem cell transplantation is a generic term covering different techniques. However there is argument over the pros and cons of autologous and allogeneic transplants of mesenchymal stem cells (MSCs) for regenerative therapy. Given that the MSCs have already been proven to be safe in patients, we hypothesize that allogeneic transplantation could be more effective and cost-effective as compared to autologous transplantation specifically in older subjects who are the likely victims of degenerative diseases. This analysis is based on the scientific logic that allogeneic stem cells extracted in large numbers from young and healthy donors could be physiologically, metabolically and genetically more stable. Therefore stem cells from young donors may be expected to exhibit higher vigor in secreting trophic factors leading to activation of host tissue-specific stem cells and also be more efficient in remodeling the micro-environmental niche of damaged tissue. PMID- 25456788 TI - Intracranial hypertension associated with obstructive sleep apnea: a discussion of potential etiologic factors. AB - Obstructive sleep apnea has been shown to increase intracranial pressure, and to be a secondary cause of intracranial hypertension. There are a few theories that attempt to explain this relationship, however there is little data, and even less recognition among physicians that this actually occurs. This paper discusses multiple pieces of data, from anatomical correlates to biochemical information involving neuro-excitotoxicity, as well as hematologic factors and issues surrounding brain edema and blood-brain barrier dysfunction. A complex paradigm for how obstructive sleep apnea may lead to increased intracranial pressure is thus proposed. In addition, suggestions are made for how obstructive sleep apnea must as a result be managed differently in the setting of idiopathic intracranial hypertension. PMID- 25456789 TI - Nonalcoholic fatty liver disease (NAFLD)--is it a new marker of hyporesponsiveness to recombinant human erythropoietin in patients that are on chronic hemodialysis? AB - Anemia is a major consequence of chronic kidney disease (CKD) that develops early in the course of illness and affects most patients who exhibit some degree of reduced renal function. Erythropoietin (EPO) deficiency is considered the most important cause of anemia in CKD. Renal anemia has serious clinical consequence. In addition to reducing patient physical capacity and quality of life, anemia induces adaptive cardiovascular mechanisms that increase the risk of cardiovascular disease and death. Thus, treatment of anemia in CKD is very important. While EPO is effective in correcting anemia in most cases, up to 10% of patients however, have an inadequate response to therapy. The two most common and important reasons why patients become relatively unresponsive to EPO therapy are the development of true iron deficiency and the onset of an inflammatory state that impairs the response to EPO. Indeed, the role of inflammation and pro inflammatory cytokines in resistance to EPO therapy is gaining increasing recognition. On the other hand, the main organ for C-reactive protein (CRP) synthesis is the liver and it is well known that the synthesis of an acute-phase proteins by the liver is up regulated by inflammation. The main consequence of nonalcoholic fatty liver disease (NAFLD) is sub-chronic liver inflammation that leads and contributes to dyslipidemia, inflammation, enhanced oxidative stress and endothelial dysfunction. Considering the recent data about high prevalence of NAFLD in CKD patients, probably due to shared metabolic risk factors, we hypothesized that end-stage renal disease (ESRD) patients with NAFLD will need a much higher dose of EPO to achieve the target hemoglobin levels in comparison with ESRD patients without NAFLD. The possible underlying mechanism is sub chronic liver inflammation in NAFLD patients that leads and contributes to poor response to EPO. Therefore, we believe that NAFLD could be a new clinical marker of poor response to EPO therapy in ESRD patients. Optimizing response to EPO therapy is important for both patient outcomes and the cost of treatment, and require consideration of a growing number of factors. Detection of NAFLD by some of non-invasive methods in ESRD patients could identify responsiveness and resistance to EPO therapy. Furthermore, we propose that all the patients who undergo dialysis treatment should be screened for NAFLD in order to identify the patients that will have a poor response to EPO therapy. The work could help to determine whether we have a new marker of poor EPO response in ESRD patients. PMID- 25456790 TI - Does metabolic failure at the synapse cause Alzheimer's disease? AB - Alzheimer's disease (AD) a neurodegenerative disorder of widely distributed cortical networks evolves over years while A beta (Abeta) oligomer neurotoxicity occurs within seconds to minutes. This disparity combined with disappointing outcomes of anti-amyloid clinical trials challenges the centrality of Abeta as principal mediator of neurodegeneration. Reconsideration of late life AD as the end-product of intermittent regional failure of the neuronal support system to meet the needs of vulnerable brain areas offers an alternative point of view. This model introduces four ideas: (1) That Abeta is a synaptic signaling peptide that becomes toxic in circumstances of metabolic stress. (2) That intense synaptic energy and maintenance requirements of cortical hubs may exceed resources during peak demand initiating a neurotoxic cascade in these selectively vulnerable regions. (3) That axonal transport to and from neuron soma cannot account fully for high mitochondrial densities and other requirements of distant terminal axons. (4) That neurons as specialists in information management, delegate generic support functions to astrocytes and other cell types. Astrocytes use intercellular transport by exosomes and tunneling nanotubes (TNTs) to deliver mitochondria, substrates and protein reprocessing services to axonal sites distant from neuronal soma. This viewpoint implicates the brain's support system and its disruption by various age and disease-related insults as significant mediators of neurodegenerative disease. A better understanding of this system should broaden concepts of neurodegeneration and facilitate development of effective treatments. PMID- 25456791 TI - Can the season of birth risk factor for schizophrenia be prevented by bright light treatment for the second trimester mother around the winter solstice? AB - The season of birth risk factor for schizophrenia exerts a pervasive effect on the global population, particularly at northerly latitudes. The winter infection hypothesis and the low vitamin D hypothesis are both compelling but lack conclusive clinical data. The present work develops a maternal-fetal chronobiological hypothesis for this season of birth risk factor and its prevention by maternal bright light treatment. Around the winter solstice, due to decreased sunlight, the chronobiological apparatus of the at-risk second trimester mother is characterized by a reduced amplitude circadian pacemaker, and a reduced maximum of her nocturnal plasma melatonin concentrations (MTmax) and an increased minimum of her nocturnal core body temperatures (Tmin)--both of which exert adverse effects on the fetal hippocampus and dorsal striatum. The consequences for the fetus include reduced volume and increased excitability of the hippocampus, ventral striatal dysfunction, increased presynaptic nigrostriatal dopamine transmission, and increased propensity for pathological nigrostriatal neuronal phasic firing. Thus, the maternal-fetal chronobiological hypothesis fully accounts for the fetal precursors of the major pathognomonic abnormalities in adults with schizophrenia. Bright light treatment for the second trimester mother around the winter solstice, by increasing maternal circadian amplitude, could possibly prevent the fetal hippocampal and striatal abnormalities and eliminate the season of birth risk factor for schizophrenia. PMID- 25456792 TI - Microwave annealing effect for highly reliable biosensor: dual-gate ion-sensitive field-effect transistor using amorphous InGaZnO thin-film transistor. AB - We used a microwave annealing process to fabricate a highly reliable biosensor using amorphous-InGaZnO (a-IGZO) thin-film transistors (TFTs), which usually experience threshold voltage instability. Compared with furnace-annealed a-IGZO TFTs, the microwave-annealed devices showed superior threshold voltage stability and performance, including a high field-effect mobility of 9.51 cm(2)/V.s, a low threshold voltage of 0.99 V, a good subthreshold slope of 135 mV/dec, and an outstanding on/off current ratio of 1.18 * 10(8). In conclusion, by using the microwave-annealed a-IGZO TFT as the transducer in an extended-gate ion-sensitive field-effect transistor biosensor, we developed a high-performance biosensor with excellent sensing properties in terms of pH sensitivity, reliability, and chemical stability. PMID- 25456793 TI - Low-technology assisted reproduction and the risk of preterm birth in a hospital based cohort. AB - OBJECTIVE: To estimate the risk of preterm birth in singleton infants conceived through low-technology assisted reproduction (intrauterine insemination and/or ovulation induction/stimulation). DESIGN: Hospital-based cohort study. SETTING: University-affiliated hospital. PATIENT(S): Singleton babies born between 2001 and 2007 to 16,712 couples with no reported infertility (reference category), 378 babies conceived with low-technology treatment; 437 conceived with high technology treatment; and 620 conceived naturally after a period of infertility. INTERVENTION(S): None. Treatment data were obtained from couples undergoing standard infertility investigation and care. MAIN OUTCOME MEASURE(S): Preterm birth, defined at three clinical endpoints: <37, <35, and <32 weeks of completed gestation. RESULT(S): After adjustment for age, parity, education, smoking, alcohol/drug use, and body mass index, the risk ratios and 95% confidence intervals (CI) of preterm birth for low technology were: 1.49 (CI: 1.12-2.00); 2.02 (CI: 1.30-3.13); and 2.93 (CI: 1.63-5.26) at <37, <35, and <32 weeks gestation, respectively, not dissimilar from the estimates for in vitro fertilization. Restricting the analysis to primiparas strengthened the association between treatment and preterm birth at the lower gestational endpoints. The increased risk persisted when the untreated group was used as the reference category, although the estimates were attenuated. CONCLUSION(S): In this large hospital-based cohort study, low-technology assisted reproduction appeared to be a moderately strong predictor of preterm birth, with similar associations observed in the high-technology treatment group. After adjusting for confounders, as well as the shared characteristics of infertile couples, associations were attenuated but remained significant, suggesting that part of the risk is likely attributable to the treatment. PMID- 25456794 TI - Dietary fatty acid intakes and asthenozoospermia: a case-control study. AB - OBJECTIVE: To investigate the association between dietary fatty acids intakes and asthenozoospermia. DESIGN: Case-control study. SETTING: Infertility clinics. PATIENT(S): A total of 107 men with incident asthenozoospermia and 235 age matched controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Assessments of dietary intakes, semen quality, anthropometry, endocrine parameters, and demographic information. RESULT(S): According to the fully adjusted model, being in the highest tertile of total saturated fatty acids (odds ratio [OR] = 1.85, 95% confidence interval [CI] 1.24-2.96), total trans-fatty acids (OR = 2.53, 95% CI 1.54-3.92), palmitic acid (OR = 1.90, 95% CI 1.26-2.74), and stearic acid (OR = 2.13, 95% CI 1.29-3.88) was positively associated with asthenozoospermia. Whereas higher intakes of omega-3 polyunsaturated (OR = 0.68, 95% CI 0.58-0.94) and of docosahexaenoic (OR = 0.53, 95% CI 0.29-0.89) fatty acids were significantly associated with reduced odds of asthenozoospermia. CONCLUSION(S): Our findings suggest that the high intake of saturated and trans-fats was positively related to the odds of having asthenozoospermia. Conversely, inverse and dose-dependent associations were found between asthenozoospermia and intake of omega-3 polyunsaturated fatty acids. The observed associations of different types of fatty acids underline the importance of the type of fat in the etiology of asthenozoospermia. PMID- 25456795 TI - Assisted reproductive technology and breastfeeding outcomes: a case-control study. AB - OBJECTIVE: To determine if breastfeeding outcomes differ between mothers who conceived spontaneously compared with those who conceived with assisted reproductive technology (ART). DESIGN: Matched case-control study. SETTING: Teaching hospital. PATIENT(S): Ninety-four women having a singleton baby conceived with ART, matched by maternal age, parity, mode of delivery, and gestational age to controls who conceived spontaneously. INTERVENTION(S): Cases and controls were interviewed using a standardized, structured questionnaire, to obtain information on lactation. Exposure to maternity care practices contributing to breastfeeding success was investigated. MAIN OUTCOME MEASURE(S): Initiation, exclusivity, and continuation of breastfeeding. RESULT(S): Cases were as likely as controls to initiate breastfeeding (89.4% vs. 90.4%), but by 6 weeks postpartum, a greater proportion of mothers who conceived through ART has ceased breastfeeding (20.2% vs. 5.3%). The percentage of mothers who exclusively breastfed their child for 6 months was similar among the 2 groups. On univariate conditional logistic regression, a history of using ART was the only predictor of early breastfeeding cessation (odds ratio = 65.3 [95% confidence interval: 1.5 2889.3]). CONCLUSION(S): Women who have conceived with ART should be regarded as being at higher risk for early breastfeeding cessation. This study serves as a first step in the investigation of potential modifiable factors that contribute to breastfeeding failure among women who give birth after using ART, and may help in efforts to customize breastfeeding support strategies. PMID- 25456796 TI - Perspectives on the assessment of human sperm chromatin integrity. AB - Apoptosis plays a significant role in regulating germ cell development by removing damaged germ cells from seminiferous tubules, thereby safeguarding the genome of a given species. The unique chromatin-packing process of the spermatozoon has important implications for both the development of male infertility screening tests and understanding of sperm chromatin characteristics, which may affect assisted reproductive technology outcomes. Sperm deoxyribonucleic acid (DNA) integrity tests have been proposed as a means to assess male gamete competence. Although these assays are currently gaining popularity, and are more often used as a supplement to traditional semen analysis, the point at which DNA damage occurs during spermiogenesis, and to what degree, remains to be elucidated. Here, we examined current studies of DNA fragmentation, to understand its origin and import, as well as its impact on pre- and post-implantation development. As the DNA fragmentation index is strongly correlated with the motility characteristics of a semen specimen, controlling for this factor may be helpful. Utilization of more sensitive assays, possibly on the actual spermatozoa used for insemination, may generate healthier conceptuses. PMID- 25456798 TI - The impact of Playworks on students' physical activity during recess: findings from a randomized controlled trial. AB - OBJECTIVE: To evaluate the impact of Playworks on students' physical activity during recess. METHOD: Twenty-seven elementary schools from six U.S. cities were grouped into blocks and randomly assigned to implement Playworks (treatment) or not (control) during an entire school year (either 2010-2011 or 2011-2012). Study data were collected at the end of the school year only. Fourth- and 5th-grade students (n=2278) reported on their physical activity during recess, and a subset (n=1537) wore accelerometers during recess. Teachers (n=111) also reported on their students' physical activity during recess. RESULTS: A significantly higher percentage of teachers in treatment schools reported that their students engaged in an intense physical activity during recess (p=0.01). Marginally significant differences between treatment and control groups were found for the mean number of accelerometer intensity counts recorded per minute during recess (p=0.10) and the mean percentage of time spent in vigorous physical activity during recess (p=0.07). No significant differences were found for student reports about their physical activity during recess (p=0.92). CONCLUSION: Teachers in Playworks schools reported that students were more active during recess, but accelerometer and student survey measures showed either no impacts or marginally significant impacts. PMID- 25456799 TI - How can schools help youth increase physical activity? An economic analysis comparing school-based programs. AB - OBJECTIVE: For optimal health, physical activity should be an integral and routine part of daily life. Youth spend a significant amount of time at school yet rarely achieve the recommended 60 min of moderate and vigorous physical activity in physical education (PE) classes or recess. This study assessed the following types of school-based opportunities to improve physical activity for youth: after-school programs, before-school programs, PE classes, extended-day PE, and short physical activity breaks during the school day. METHOD: An economic analysis conducted in 2013 compared school-based approaches to increasing physical activity. Analysis factors included costs, reach, effects on physical activity gains, cost-effectiveness, and other potentially augmenting benefits. RESULTS: Two programs were significantly superior in terms of reach and cost per student: (1) extending the school day with mandatory PE participation and (2) offering short (10-minute) physical activity breaks during regular classroom hours. After-school program costs per student are high and the programs have a smaller reach, but they offer benefits (such as childcare) that may justify their higher costs. Before-school programs did not appear feasible. CONCLUSION: Incorporating short physical activity breaks into the existing school day would be a cost-effective way to increase school-based activity. This type of program is inexpensive and has broad reach. Inserting activity breaks throughout the day is appropriate, especially when youth are otherwise largely sedentary. PMID- 25456800 TI - Overcoming the challenges of conducting physical activity and built environment research in Latin America: IPEN Latin America. AB - OBJECTIVE: There is evidence linking the built environment (BE) with physical activity (PA), but few studies have been conducted in Latin America (LA). State of-the-art methods and protocols have been designed in and applied in high-income countries (HIC). In this paper, we identify key challenges and potential solutions to conducting high-quality PA and BE research in LA. METHODS: The experience of implementing the IPEN data collection protocol (IPEN: International Physical Activity Environment Network) in Curitiba, Brazil; Bogota, Colombia; and Cuernavaca, Mexico (2010-2011); is described to identify challenges for conducting PA and BE research in LA. RESULTS: Five challenges were identified: lack of academic capacity (implemented solutions (IS): building a strong international collaborative network); limited data availability, access and quality (IS: partnering with influential local institutions, and crafting creative solutions to use the best-available data); socio-political, socio cultural and socio-economic context (IS: in-person recruitment and data collection, alternative incentives); safety (IS: strict rules for data collection procedures, and specific measures to increase trust); and appropriateness of instruments and measures (IS: survey adaptation, use of standardized additional survey components, and employing a context-based approach to understanding the relationship between PA and the BE). Advantages of conducting PA and BE research in LA were also identified. CONCLUSIONS: Conducting high-quality PA and BE research in LA is challenging but feasible. Networks of institutions and researchers from both HIC and LMIC play a key role. The lessons learned from the IPEN LA study may be applicable to other LMIC. PMID- 25456801 TI - Primary prevention of anxiety disorders in primary care: A systematic review. AB - OBJECTIVE: Anxiety disorders are the most prevalent psychiatric disorders in primary care and have significant social, economic, and interpersonal costs. Primary care is an ideal setting to prevent the appearance of anxiety disorders. The aim of this study was to evaluate the efficacy and cost-effectiveness of primary prevention interventions in anxiety disorders in the adult population receiving primary health care. METHODS: A literature search was carried out in four databases-PubMed, PsycInfo, Cochrane, and Web of Science-from January 1980 to November 2013. Clinical trials and systematic reviews published in English and non-English languages and that evaluated the efficacy and/or cost-effectiveness of interventions of primary prevention for anxiety in primary care in the general adult population were included. Risk of bias was assessed by the Cochrane Risk Bias Tool and Overview Quality Assessment Questionnaire. RESULTS: No high-quality research was identified that studied primary prevention of anxiety disorders in the adult population in the primary care setting. The few studies that exist focus on the child-adolescent population or on other types of interventions, usually as secondary prevention. CONCLUSION: This study emphasizes the need for the development of high-quality clinical trials on the prevention of anxiety disorders in primary care. PMID- 25456802 TI - Bicycle boulevards and changes in physical activity and active transportation: findings from a natural experiment. AB - OBJECTIVE: This study evaluates changes in physical activity and active transportation associated with installation of new bicycle boulevards. METHODS: This natural experiment study uses data from a longitudinal panel of adults with children (n=353) in Portland, OR. Activity and active transportation outcomes were measured with GPS and accelerometers worn for up to 5 days in 2010-11 and 2012-13. The effect of the treatment was estimated using difference in differences estimation and multivariate regression models. RESULTS: In five of the seven models, the interaction term was not significant, indicating that after controlling for the main effects of time and exposure separately, there was no correlation between being in a treatment area and minutes of moderate and vigorous physical activity (MVPA) per day, bicycling >10 min, walking >20 min, minutes of walking (if >20), or making a bike trip. Significant covariates included rain, being female, living closer to downtown, and attitudes towards bicycling, walking, and car safety. CONCLUSION: This study could not confirm an increase in physical activity or active transportation among adults with children living near newly installed bicycle boulevards. Additional pre/post studies are encouraged, as well as research on the length of time after installation that behavior change is likely to occur. PMID- 25456803 TI - School gardens and physical activity: a randomized controlled trial of low-income elementary schools. AB - OBJECTIVE: This study examines effects of a school garden intervention on elementary school children's physical activity (PA). METHOD: Twelve schools in New York were randomly assigned to receive the school garden intervention (n=6) or to the waitlist control group that later received gardens (n=6). PA was measured by self-report survey (Girls Health Enrichment Multi-site Study Activity Questionnaire) (N=227) and accelerometry (N=124, 8 schools) at baseline (Fall 2011) and follow-up (Spring 2012, Fall 2012, Spring 2013). Direct observation (N=117, 4 schools) was employed to compare indoor (classroom) and outdoor (garden) PA. Analysis was by general linear mixed models. RESULTS: Survey data indicate garden intervention children's reports of usual sedentary activity decreased from pre-garden baseline to post-garden more than the control group children's (Delta=-.19, p=.001). Accelerometry data reveal that during the school day, children in the garden intervention showed a greater increase in percent of time spent in moderate and moderate-to-vigorous PA from baseline to follow-up than the control group children (Delta=+.58, p=.010; Delta=+1.0, p=.044). Direct observation within-group comparison of children at schools with gardens revealed that children move more and sit less during an outdoor garden-based lesson than during an indoor, classroom-based lesson. CONCLUSION: School gardens show some promise to promote children's PA. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov # NCT02148315. PMID- 25456804 TI - Behavior change, health, and health disparities: an introduction. AB - This Special Issue of Preventive Medicine (PM) focuses on behavior change, health, and health disparities, topics of fundamental importance to improving population health in the U.S. and other industrialized countries. While the U.S. health care system and those of other industrialized countries were developed to manage infectious disease and acute illnesses, it is chronic health conditions that most need to be understood and managed in the 21st century. The evidence is clear that personal behavior patterns like cigarette smoking and physical inactivity/obesity are critically important proximal causes of chronic disease (cardiovascular disease, site-specific cancers, type-2 diabetes) and as such behavior change will need to be a key component of their management. As the outstanding contributions to this Special Issue illustrate, substantial headway is being made in advancing knowledge including developing effective prevention and treatment strategies, with cigarette smoking being an excellent example that change is possible. That said, cigarette smoking continues to be responsible for approximately 480,000 premature deaths annually in the U.S. alone and 5 million globally. So more needs to be done, especially in economically disadvantaged populations. The same certainly applies to the challenges of the obesity epidemic, which of course is a more recent problem and understandably efforts to curtail it are in earlier stages of development. PMID- 25456805 TI - Standing time and all-cause mortality in a large cohort of Australian adults. AB - OBJECTIVE: To determine the association between standing time and all-cause mortality. METHODS: Prospective questionnaire data from 221,240 individuals from the 45 and Up Study were linked to mortality data from the New South Wales Registry of Deaths (Australia) from February 1, 2006 to June 17, 2012. Hazard ratios for all-cause mortality according to standing time at baseline were estimated in 2013 using Cox regression modelling, adjusted for sex, age, education, urban/rural residence, physical activity, sitting time, body mass index, smoking status, self-rated health and disability. RESULTS: During 937,411 person years (mean follow-up=4.2 yr) 8009 deaths occurred. All-cause mortality hazard ratios were 0.90 (95% CI 0.85-0.95), 0.85 (95% CI 0.80-0.95), and 0.76 (95% CI 0.69-0.95) for standing 2-<=5h/d, 5-<=8h/d, or >8h/d respectively, compared to standing two or less hours per day. Further analyses revealed no significant interactions between standing and sex (p=0.93), the presence/absence of cardiovascular disease or diabetes (p=0.22), BMI (p=0.78), physical activity (p=0.16) and sitting time (p=0.22). CONCLUSION: This study showed a dose-response association between standing time and all-cause mortality in Australian adults aged 45 years and older. Increasing standing may hold promise for alleviating the health risks of prolonged sitting. PMID- 25456806 TI - Body mass index of children and youth with an intellectual disability by country economic status. AB - OBJECTIVE: Individuals with intellectual disabilities are at higher risk for health disparities including overweight and obesity; however, little is known at the population level about the BMI status of children and youth with intellectual disabilities. This study is a secondary analysis of BMI status (underweight, normal weight, overweight and obese) in children and youth (8-<18years) participating in Special Olympics by country economic status. METHODS: A total of 14,032 participants (n=8,856 male) measured height and weight records were available from the Special Olympics International Health Promotion database. The 141 countries in the database were re-coded according to the World Bank's classification of country economic status. BMI prevalence rates were calculated for underweight, normal weight, overweight, and obesity for children and youth using IOTF cutoffs by economic status. Chi-squared analyses and Fisher's exact test were used to examine differences in weight status by economy and sex. FINDINGS: Overall, 27.87% of Special Olympics participants from low-income economies, 31.04% from lower middle-income, 25.29% from upper middle-income, and 42.36% from high-income economies had BMI levels outside of the normal range. The low-income countries had higher rates of underweight and the high-income countries had higher rates of obesity. CONCLUSIONS: The high levels of both underweight and overweight/obesity found in this population of children and youth participating in Special Olympics represents a double burden of health risk. More research is needed to understand why this population experiences such disparities in BMI status and to develop health promotion initiatives targeted at this population. PMID- 25456807 TI - School food reduces household income disparities in adolescents' frequency of fruit and vegetable intake. AB - OBJECTIVE: The aim of this study is to examine whether school food attenuates household income-related disparities in adolescents' frequency of fruit and vegetable intake (FVI). METHOD: Telephone surveys were conducted between 2007 and 2008 with adolescent-parent dyads from Northern New England; participants were randomly assigned to be surveyed at different times throughout the year. The main analysis comprised 1542 adolescents who typically obtained breakfast/lunch at school at least once/week. FVI was measured using 7-day recall of the number of times adolescents consumed fruits and vegetables. Fully adjusted linear regression was used to compare FVI among adolescents who were surveyed while school was in session (currently exposed to school food) to those who were surveyed when school was not in session (currently unexposed to school food). RESULTS: Mean FVI was 8.0 (SD=5.9) times/week. Among adolescents unexposed to school food, household income and FVI were strongly, positively associated. In contrast, among adolescents exposed to school food, FVI was similar across all income categories. We found a significant cross-over interaction between school food and household income in which consuming food at school was associated with higher FVI among adolescents from low-income households versus lower FVI among adolescents from high-income households. CONCLUSION: School food may mitigate income disparities in adolescent FVI. The findings suggest that the school food environment positively influences FVI among low-income adolescents. PMID- 25456808 TI - Reducing tobacco smoke exposure in children aged below 4 years - a randomized controlled trial. AB - OBJECTIVE: To explore the reach of a German population-based household sample using proactive recruitment and to test the efficacy of a behavioral change counseling intervention including feedback about children's urine cotinine level (CUCL). METHODS: A randomized controlled trial (2008-2010) was conducted in households with at least one child aged below 4years and at least one current smoker. The study area comprised of 3570 households. A screening assessment was provided in 2641 households; 1282 included one current smoker and 852 completed the study protocol. The intervention group (IG; n=428) received feedback about CUCL and up to two counseling sessions. The control group (CG; n=424) received a leaflet. Assessments were provided at baseline and 12-month follow-up. Heckman's selection model analysis was used to consider the detection limit of cotinine in urine (10ng/ml). RESULTS: CUCL below the detection limit in the IG was found in 43.2% at baseline and 44.6% at follow-up and in 44.8% of the CG at baseline and 47.2% at follow-up. The CUCL difference between follow-up and baseline was smaller in the CG than in the IG. The effect was not significant. CONCLUSIONS: Data revealed a high reach of the target population but failed to identify an intervention effect. Clinical Trial Registration www.clinicaltrials.gov (NCT00647413). PMID- 25456809 TI - Factors affecting the uptake of vaccination by the elderly in Western society. AB - OBJECTIVE: To present the results of a literature review on factors related to vaccine uptake by elderly persons. METHODS: A systematic literature search was performed using Medline, Embase, and SciSearch to collect all publications available on factors related to vaccine uptake from 1966 until October 2012 for West European and North American societies. In total, 1001 articles were identified and 60 were included in the review. RESULTS: We identified six main themes that influence the willingness to be vaccinated: 1) attitudes and beliefs regarding vaccination in general including positive and negative attitudes and beliefs; 2) perceived risk and severity including knowledge, perceived susceptibility and severity and personal experience; 3) vaccine characteristics including side-effects, effectiveness, content of the vaccine and knowledge; 4) advice and information including influence of the healthcare worker and relatives and the information source and format; 5) general health-related behavior including previous vaccinations, visiting GP or senior center and other preventive behaviors; and 6) accessibility and affordability including logistics, combinations of vaccines and costs. CONCLUSION: The most important factors related to vaccine uptake are people's attitudes and beliefs regarding vaccination (especially their negative attitudes), recommendations of healthcare workers, side effects and effectiveness of the vaccine, and perceived susceptibility. PMID- 25456810 TI - A systematic review of health effects of electronic cigarettes. AB - OBJECTIVE: To provide a systematic review of the existing literature on health consequences of vaporing of electronic cigarettes (ECs). METHODS: Search in: PubMed, EMBASE and CINAHL. INCLUSION CRITERIA: Original publications describing a health-related topic, published before 14 August 2014. PRISMA recommendations were followed. We identified 1101 studies; 271 relevant after screening; 94 eligible. RESULTS: We included 76 studies investigating content of fluid/vapor of ECs, reports on adverse events and human and animal experimental studies. Serious methodological problems were identified. In 34% of the articles the authors had a conflict of interest. Studies found fine/ultrafine particles, harmful metals, carcinogenic tobacco-specific nitrosamines, volatile organic compounds, carcinogenic carbonyls (some in high but most in low/trace concentrations), cytotoxicity and changed gene expression. Of special concern are compounds not found in conventional cigarettes, e.g. propylene glycol. Experimental studies found increased airway resistance after short-term exposure. Reports on short term adverse events were often flawed by selection bias. CONCLUSIONS: Due to many methodological problems, severe conflicts of interest, the relatively few and often small studies, the inconsistencies and contradictions in results, and the lack of long-term follow-up no firm conclusions can be drawn on the safety of ECs. However, they can hardly be considered harmless. PMID- 25456812 TI - Quantifying independent risk factors for failing to rescreen in a breast cancer screening program in Flanders, Belgium. AB - BACKGROUND: Mammographic screening may reduce breast cancer mortality by about 20%, provided participation is high and women screen regularly. We quantified independent risk factors for failing to rescreen and built a model to predict how rescreening rates change if these risk factors would be modified. METHODS: Multivariate analysis was used to analyze data from a prospective study which included a self-administered questionnaire and rescreening status 30months after a t0 mammogram, using a random sample of women 50-67years (Belgium 2010-2013). RESULTS: A false positive result at the most recent past mammogram (Odds Ratio=5.0, 95% Confidence Interval 3.6-6.8), an interval until new invitation greater than 25months (Odds Ratio=4.8 for >29months, 95% Confidence Interval 2.9 8.1), waiting times in the mammography unit >1h (Odds Ratio=2.1, 95% Confidence Interval 1.2-3.7) and difficulties in reaching the unit (Odds Ratio=2.5, 95% Confidence Interval 1.4-4.4) were the strongest independent predictors for failing to rescreen. The area under the curve of the receiver operating characteristic analysis was 0.705 for the model development stage and 0.717 for the validation stage and goodness-of-fit was good. CONCLUSIONS: Maintaining an invitation cycle of maximum 25months, limiting waiting time in the mammography unit and lowering the number of false positives could increase breast cancer screening compliance. PMID- 25456811 TI - A randomized trial to evaluate primary care clinician training to use the Teachable Moment Communication Process for smoking cessation counseling. AB - OBJECTIVE: To implement and evaluate the impact of a Teachable Moment Communication Process (TMCP) training intervention on clinicians' smoking cessation counseling behaviors in practice. METHOD: Using a group randomized trial, 31 community-based, primary care clinicians in Northeast Ohio received either TMCP training or an attention control (2010-2012). TMCP training consisted of two, three-hour sessions involving didactic instruction, skill practice with standardized patients, and coaching. Clinician performance of TMCP elements was assessed by coding audio-recordings of routine visits with smokers at baseline and post-intervention (n=806). RESULTS: Baseline performance of all TMCP elements was similar in the two groups. After the intervention, TMCP-trained clinicians were more often observed advising patients to quit while linking smoking to the patient's concern (58% vs. 44%, p=0.01), expressing optimism (36% vs. 3%, p<0.001), expressing partnership (40% vs. 12%, p=0.003) and eliciting the patient's readiness to quit (84% vs. 65%, p=0.006) than clinicians in the comparison group. TMCP-trained clinician responses were also better aligned with patients' expressed readiness to quit smoking than comparison group clinicians (p<0.001). CONCLUSION: The intervention significantly changed the content of clinicians' smoking cessation communication in ways consistent with the TMCP model for health behavior change. PMID- 25456814 TI - Evolutionary origins of the multienzyme architecture of giant fungal fatty acid synthase. AB - Fungal fatty acid synthase (fFAS) is a key paradigm for the evolution of complex multienzymes. Its 48 functional domains are embedded in a matrix of scaffolding elements, which comprises almost 50% of the total sequence and determines the emergent multienzymes properties of fFAS. Catalytic domains of fFAS are derived from monofunctional bacterial enzymes, but the evolutionary origin of the scaffolding elements remains enigmatic. Here, we identify two bacterial protein families of noncanonical fatty acid biosynthesis starter enzymes and trans-acting polyketide enoyl reductases (ERs) as potential ancestors of scaffolding regions in fFAS. The architectures of both protein families are revealed by representative crystal structures of the starter enzyme FabY and DfnA-ER. In both families, a striking structural conservation of insertions to scaffolding elements in fFAS is observed, despite marginal sequence identity. The combined phylogenetic and structural data provide insights into the evolutionary origins of the complex multienzyme architecture of fFAS. PMID- 25456813 TI - Characterization of the redox transition of the XRCC1 N-terminal domain. AB - XRCC1, a scaffold protein involved in DNA repair, contains an N-terminal domain (X1NTD) that interacts specifically with DNA polymerase beta. It was recently discovered that X1NTD contains a disulfide switch that allows it to adopt either of two metamorphic structures. In the present study, we demonstrate that formation of an N-terminal proline carbimate adduct resulting from the nonenzymatic reaction of Pro2 with CO2 is essential for stabilizing the oxidized structure, X1NTDox. The kinetic response of X1NTDred to H2O2, monitored by NMR, was determined to be very slow, consistent with involvement of the buried, kinetically trapped Cys12 residue, but was significantly accelerated by addition of protein disulfide isomerase or by Cu(2+). NMR analysis of a sample containing the pol beta polymerase domain, and both the reduced and oxidized forms of X1NTD, indicates that the oxidized form binds to the enzyme 25-fold more tightly than the reduced form. PMID- 25456815 TI - Activation route of the Schistosoma mansoni cathepsin B1 drug target: structural map with a glycosaminoglycan switch. AB - Cathepsin B1 (SmCB1) is a digestive protease of the parasitic blood fluke Schistosoma mansoni and a drug target for the treatment of schistosomiasis, a disease that afflicts over 200 million people. SmCB1 is synthesized as an inactive zymogen in which the N-terminal propeptide blocks the active site. We investigated the activation of the zymogen by which the propeptide is proteolytically removed and its regulation by sulfated polysaccharides (SPs). We determined crystal structures of three molecular forms of SmCB1 along the activation pathway: the zymogen, an activation intermediate with a partially cleaved propeptide, and the mature enzyme. We demonstrate that SPs are essential for the autocatalytic activation of SmCB1, as they interact with a specific heparin-binding domain in the propeptide. An alternative activation route is mediated by an S. mansoni asparaginyl endopeptidase (legumain) which is downregulated by SPs, indicating that SPs act as a molecular switch between both activation mechanisms. PMID- 25456816 TI - Structural basis of a point mutation that causes the genetic disease aspartylglucosaminuria. AB - Aspartylglucosaminuria (AGU) is a lysosomal storage disease caused by a metabolic disorder of lysosomes to digest Asn-linked glycoproteins. The specific enzyme linked to AGU is a lysosomal hydrolase called glycosylasparaginase. Crystallographic studies revealed that a surface loop blocks the catalytic center of the mature hydrolase. Autoproteolysis is therefore required to remove this P loop and open up the hydrolase center. Nonetheless, AGU mutations result in misprocessing of their precursors and are deficient in hydrolyzing glycoasparagines. To understand the catalytic and structural consequences of AGU mutations, we have characterized two AGU models, one corresponding to a Finnish allele and the other found in a Canadian family. We also report a 2.1 A resolution structure of the latter AGU model. The current crystallographic study provides a high-resolution structure of an AGU mutant. It reveals substantial conformation changes at the defective autocleavage site of the AGU mutant, which is trapped as an inactive precursor. PMID- 25456817 TI - Structural characterization of a flexible two-domain protein in solution using small angle X-ray scattering and NMR data. AB - Multidomain proteins in which individual domains are connected by linkers often possess inherent interdomain flexibility that significantly complicates their structural characterization in solution using either nuclear magnetic resonance (NMR) spectroscopy or small-angle X-ray scattering (SAXS) alone. Here, we report a protocol for joint refinement of flexible multidomain protein structures against NMR distance and angular restraints, residual dipolar couplings, and SAXS data. The protocol is based on the ensemble optimization method principle (Bernado et al., 2007) and is compared with different refinement strategies for the structural characterization of the flexible two-domain protein sf3636 from Shigella flexneri 2a. The results of our refinement suggest the existence of a dominant population of configurational states in solution possessing an overall elongated shape and restricted relative twisting of the two domains. PMID- 25456818 TI - Diabetic symmetric polyneuropathy is associated with increased aortal stiffening but not cerebral angiopathy in type 1 diabetes. AB - INTRODUCTION: Diabetic symmetric polyneuropathy (DSP) and cerebral microangiopathy are common complications of type 1 diabetes (T1DM). However, little is known about associations between DSP, cerebral microcirculation and macrovascular injury in T1DM. We aimed to assess relationships between those complications. MATERIAL AND METHODS: We examined 42 patients (25 females; mean age 37.1+/-5.6years) with T1DM (mean disease duration 20.6+/-6.1years). DSP was diagnosed with the use of quantitative vibration sensory testing (QVST) and Michigan Neuropathy Screening Instrument (MNSI). Cerebral microvasculature was evaluated with measurements of vasomotor reactivity reserve (VMR) and pulsatility index (PI) of middle cerebral artery, macroangiopathic injury by measuring intima media complex thickness (IMT) in the common carotid artery and carotid-femoral pulse-wave velocity (PWV). RESULTS: Patients with DSP (33.3%) showed higher PWV than those without DPS (10.5 vs 9.1m/s; P=0.03); no differences concerning VMR, PI or IMT existed. There were correlations between PWV and vibration perception thresholds (VPT) (r=0.44; P=0.004) and MNSI score (r=0.43; P=0.003); VPT showed impact on PWV (beta 0.34; P<0.03). CONCLUSIONS: DSP is associated with systemic macroangiopathy, reflected by increased carotid-femoral PWV, but not with the cerebral macro- and microangiopathy. PMID- 25456819 TI - Long-acting hypoglycemic effects of PEGylated FGF21 and insulin glargine in mice with type 1 diabetes. AB - OBJECTIVE: In this study, we compared the long-acting hypoglycemic effect of PEGylated FGF21 (PEG-FGF21) with insulin glargine in mice with STZ-induced type 1 diabetes. METHODS: PEG-FGF21 and insulin glargine were administered once daily for two months, and blood glucose was measured prior to the next administration. Real-time PCR was used to measure mRNA expression of glucokinase (GK), glucose 6 phosphatase (G6pase), phosphoenolpyruvate carboxykinase (PEPCK), glucose transporter 1 (GLUT1) and glucose transporter 4 (GLUT4). RESULTS: During long term treatment, the blood glucose of untreated mice remained at 25.0 to 28.0mmol/L for the whole experiment, and the blood glucose of mice treated with insulin glargine remained at 16.5 to 18.0mmol/L. However, mice treated with PEG FGF21 had lower blood glucose levels of 8.0 to 9.0mmol/L on day 10 and maintained this level until the end of the experiment. qRT-PCR showed that PEG-FGF21 up regulated mRNA expression of GK and GLUT1, and down-regulated mRNA expression of G6Pase and PEPCK. Insulin glargine up-regulated mRNA expression of GLUT4, but had no effect on GK, G6Pase, PEPCK or GLUT1. CONCLUSIONS: PEG-FGF21 has a better long acting efficacy than insulin glargine. PEG-FGF21 achieves glucose clearance by accelerating glycolysis by up-regulating expression of GK and GLUT1 and inhibiting gluconeogenesis via down-regulation of G6Pase and PEPCK expression. PMID- 25456820 TI - High-intensity statin therapy and regression of coronary atherosclerosis in patients with diabetes mellitus. AB - Recommended low-density lipoprotein cholesterol (LDL-C) levels for patients with documented cardiovascular disease (CVD) are <100mg/dL (2.6mmol/l) with further reduction to <70mg/dL (1.8mmol/l) for higher-risk patients. High-intensity statin treatment may halt the progression as well as stabilize and induce regression of coronary atheromatous plaques while lowering CVD event rates. Diabetes mellitus (DM) is a major negative determinant of coronary artery plaque regression during statin therapy. However, regression of coronary atherosclerosis in DM patients is feasible to the same degree as in those without DM when very low LDL-C values (<70mg/dL; 1.8mmol/l) are achieved with high intensity statin treatment. The recent 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults suggest to abandon specific LDL-C treatment targets. This strategy may deprive high risk patients, such as those with DM, from very high intensity statin treatment or drug combinations aiming to achieve very low LDL-C levels in order to reduce clinical events. PMID- 25456822 TI - New dating of the Homo erectus cranium from Lantian (Gongwangling), China. AB - The Homo erectus cranium from Gongwangling, Lantian County, Shaanxi Province is the oldest fossil hominin specimen from North China. It was found in 1964 in a layer below the Jaramillo subchron and was attributed to loess (L) L15 in the Chinese loess-palaeosol sequence, with an estimated age of ca. 1.15 Ma (millions of years ago). Here, we demonstrate that there is a stratigraphical hiatus in the Gongwangling section immediately below loess 15, and the cranium in fact lies in palaeosol (S) S22 or S23, the age of which is ca. 1.54-1.65 Ma. Closely spaced palaeomagnetic sampling at two sections at Gongwangling and one at Jiacun, 10 km to the north, indicate that the fossil layer at Gongwangling and a similar fossil horizon at Jiacun were deposited shortly before a short period of normal polarity above the Olduvai subchron. This is attributed to the Gilsa Event that has been dated elsewhere to ca. 1.62 Ma. Our investigations thus demonstrate that the Gongwangling cranium is slightly older than ca. 1.62 Ma, probably ca. 1.63 Ma, and significantly older than previously supposed. This re-dating now makes Gongwangling the second oldest site outside Africa (after Dmanisi) with cranial remains, and causes substantial re-adjustment in the early fossil hominin record in Eurasia. PMID- 25456823 TI - Environmental change and hominin exploitation of C4-based resources in wetland/savanna mosaics. AB - Eastern and southern Africa experienced ongoing climatic and tectonic instability in the Plio-Pleistocene, alongside declining forests and expanding grasslands. Most known hominin genera (Australopithecus spp., Kenyanthropus, Paranthropus spp., Homo spp.) appear roughly between 4.2 and 1.8 Ma (millions of years ago). Explanations for these speciation events have focused on adaptations to environmental change, particularly in terrestrial biomes. However, the links between environmental change and hominin adaptations have not always been clear. Often overlooked is that Plio-Pleistocene vegetation included not just terrestrial environments, but a large component of edaphic (wet) C4 grasses and sedges. In this paper it is suggested that in response to environmental fluctuations, hominins engaged in conservative long-term ecological and dietary patterns, based on predictable C4/C3 wetland and terrestrial resources. Data are presented from six hominin locales, which demonstrate reliance on plant-based resources (sedges, grasses, and other vegetation) in C4-inclusive wetland/savanna mosaics. After roughly 2.4 Ma, severe climate variability is associated with early Homo and perhaps Paranthropus boisei broadening their diet to familiar but less preferred foods: vertebrates and invertebrates. These foods consistently provided early Homo with essential nutrients, which reduced selection pressures and allowed for increases in brain size. After 1.65 Ma, a 20% increase in the C4 dietary component of Homo occurs alongside increased relative brain size. P. boisei also increases its C4 dietary component by 15% after 1.65 Ma. These increases imply that both taxa continued to broaden their diet within the C4 based wetlands/savanna biome, with Homo putting a greater emphasis on mammals. PMID- 25456821 TI - The impact of a patient's concordant and discordant chronic conditions on diabetes care quality measures. AB - AIMS: Most patients with diabetes have comorbid chronic conditions that could support (concordant) or compete with (discordant) diabetes care. We sought to determine the impact of the number of concordant and discordant chronic conditions on diabetes care quality. METHODS: Logistic regression analysis of electronic health record data from 7 health systems on 24,430 patients with diabetes aged 18-75 years. Diabetes testing and control quality care goals were the outcome variables. The number of diabetes-concordant and the number of diabetes-discordant conditions were the main explanatory variables. Analysis was adjusted for health care utilization, health system and patient demographics. RESULTS: A higher number of concordant conditions were associated with higher odds of achieving testing and control goals for all outcomes except blood pressure control. There was no to minimal positive association between the number of discordant conditions and outcomes, except for cholesterol testing which was less likely with 4+ discordant conditions. CONCLUSIONS: Having more concordant conditions makes diabetes care goal achievement more likely. The number of discordant conditions has a smaller, inconsistently significant impact on diabetes goal achievement. Interventions to improve diabetes care need to align with a patient's comorbidities, including the absence of comorbidities, especially concordant comorbidities. PMID- 25456824 TI - Ecogeography, genetics, and the evolution of human body form. AB - Genetic resemblances among groups are non-randomly distributed in humans. This population structure may influence the correlations between traits and environmental drivers of natural selection thus complicating the interpretation of the fossil record when modern human variation is used as a referential model. In this paper, we examine the effects of population structure and natural selection on postcranial traits that reflect body size and shape with application to the more general issue of how climate - using latitude as a proxy - has influenced hominin morphological variation. We compare models that include terms reflecting population structure, ascertained from globally distributed microsatellite data, and latitude on postcranial phenotypes derived from skeletal dimensions taken from a large global sample of modern humans. We find that models with a population structure term fit better than a model of natural selection along a latitudinal cline in all cases. A model including both latitude and population structure terms is a good fit to distal limb element lengths and bi iliac breadth, indicating that multiple evolutionary forces shaped these morphologies. In contrast, a model that included only a population structure term best explained femoral head diameter and the crural index. The results demonstrate that population structure is an important part of human postcranial variation, and that clinally distributed natural selection is not sufficient to explain among-group differentiation. The distribution of human body form is strongly influenced by the contingencies of modern human origins, which calls for new ways to approach problems in the evolution of human variation, past and present. PMID- 25456825 TI - Dating human occupation at Toca do Serrote das Moendas, Sao Raimundo Nonato, Piaui-Brasil by electron spin resonance and optically stimulated luminescence. AB - Excavation of Toca do Serrote das Moendas, in Piaui state, Brazil revealed a great quantity of fossil wild fauna associated with human remains. In particular, fossils of a cervid (Blastocerus dichotomus) were found, an animal frequently pictured in ancient rock wall paintings. In a well-defined stratum, two loose teeth of this species were found in close proximity to human bones. The teeth were independently dated by electron spin resonance (ESR) in two laboratories. The ages obtained for the teeth were 29 +/- 3 ka (thousands of years) and 24 +/- 1 ka. The concretion layer capping this stratum was dated by optically stimulated luminescence (OSL) of the quartz grains to 21 +/- 3 ka. As these values were derived independently in three different laboratories, using different methods and equipment, these results are compelling evidence of early habitation in this area. PMID- 25456826 TI - Viewpoint: challenges in our understanding of neuroleptic induced parkinsonism. AB - Parkinsonism remains a common and often overlooked adverse effect of almost all neuroleptic drugs, including the "atypical," or "second generation" antipsychotics. While neuroleptic induced parkinsonism (NIP) is often thought to be well understood in terms of its clinical course, pathophysiology, and treatment, this is clearly not the case, and almost all our current beliefs are based on data published decades ago of dubious merit, and recent studies which are confounded by design conflicts. This article attempts to highlight gaps in our knowledge. While there are data on the stigma associated with idiopathic Parkinson's disease, there are none on NIP, where the problem is most likely much greater. The natural course of NIP remains unknown, including the question of whether this is a risk factor for the later development of tardive dyskinesia. While treatment with anticholinergics or amantadine is the norm, there are weak and conflicting data on whether these have much value. Why quetiapine and clozapine do not worsen motor function in people with idiopathic PD, while all other neuroleptic do, remains uncertain. Neuroleptics are among the most widely prescribed medications in the United States, with 20% of nursing home residents taking them, with an increasing use for treating depression as well as psychosis, underscoring the importance of understanding NIP, the most important adverse motor effect of this class of drugs. PMID- 25456827 TI - Swallowing disturbances in Parkinson's disease: a multivariate analysis of contributing factors. AB - BACKGROUND: Swallowing disturbances are an important issue in Parkinson's disease (PD) as several studies have shown that they are associated with increased risk of aspiration pneumonia and mortality. Information about factors related to swallowing disturbances, such as disease duration, age at assessment and concomitant dementia, is limited and would be useful for their management. METHODS: All consecutive PD out-patients evaluated at a movement disorders clinic over a 7-year period (2007-2014), were included in the present retrospective study. Presence of symptomatic swallowing disturbances was assessed using the specific item of the Non Motor Symptom Questionnaire. RESULTS: In the whole PD population (N = 6462), prevalence of symptomatic swallowing disturbances was 11.7% (95%CI, 10.9-12.5). Multivariable logistic regression analysis (adjusted for education) disclosed a significant interaction between disease duration and gender (P = 0.009). In both gender strata, swallowing disturbances were significantly associated with longer disease duration and dementia (P < 0.001 for all). A significant effect for age at assessment was also found in male patients. In non-demented patients, swallowing disturbances were associated with male gender, age and disease duration (P < 0.02 for all). In demented patients an association was found only with male gender (P = 0.018) and disease duration (P < 0.001). CONCLUSIONS: Gender, age, disease duration and dementia all seem to contribute to the occurrence of swallowing disturbances independently. However, the role played by these factors in sub-groups of patients stratified by gender and concomitant dementia suggests that swallowing disturbances are likely related to different neuro-degenerative patterns within the brain. The underlying mechanisms deserve further investigation. PMID- 25456828 TI - Three-Dimensional Renal Parenchymal Volume as a Surrogate for Renal Function Estimation in Obstructed Kidneys Undergoing Surgical Repair. AB - PURPOSE: To investigate the relationship between renal parenchymal volume (RPV) and renal function in obstructed kidneys using a novel three-dimensional (3D) volume-rendering technique. MATERIALS AND METHODS: Forty-seven consecutive patients who underwent pyeloplasty, ureteroureterostomy, or ureteroneocystostomy at a single institution between 2007 and 2013 were reviewed. Patients with preoperative CT scan and split differential functional (SDF) assessment by diuretic renography were included. Those with solitary kidneys and bilateral obstruction were excluded. Baseline serum creatinine (Cr) and estimated glomerular filtration rate (eGFR) as calculated by the modification of diet in renal disease equation were determined. Percent of total RPV for the obstructed kidney was determined using 3D reconstruction software by drawing regions of interest around the borders of the kidney on CT. The renal pelvis, hilar vessels, and hilar fat were excluded. Percent of total RPV was then correlated with SDF. RESULTS: Nineteen patients with both preoperative CT and diuretic renal scans were included. Two underwent ureteroneocystostomy, 1 underwent ureteroureterostomy, and 16 underwent pyeloplasty. Mean serum Cr was 1.07+/-0.26 mg/dL with a mean eGFR of 69.43+/-18.90 mL/minute. Mean SDF was 37.32%+/-11.66% in the obstructed kidneys. There was a statistically significant correlation between percent of total RPV and SDF (R(2)=0.28, p=0.02). CONCLUSIONS: There is a significant correlation between percent total RPV determined by 3D reconstruction of CT scan images and SDF as determined by diuretic renography in obstructed kidneys. CT-based percent RPV has potential as a functional assessment tool in obstructed kidneys. With further validation, it may be used to counsel patients considering surgical repair of ureteral or ureteropelvic junction obstruction. PMID- 25456830 TI - Nano-engineered mesenchymal stem cells as targeted therapeutic carriers. AB - Poor availability in deep-seated solid tumors is a significant challenge that limits the effectiveness of currently used anticancer drugs. Approaches that can specifically enhance drug delivery to the tumor tissue can potentially improve therapeutic efficacy. In our current studies, we used nano-engineered mesenchymal stem cells (nano-engineered MSCs) as tumor-targeted therapeutic carriers. In addition to their exquisite tumor homing capabilities, MSCs overexpress efflux transporters such as P-glycoprotein and are highly drug resistant. The inherent tumor-tropic and drug-resistant properties make MSCs ideal carriers for toxic payload. Nano-engineered MSCs were prepared by treating human MSCs with drug loaded polymeric nanoparticles. Incorporating nanoparticles in MSCs did not affect their viability, differentiation or migration potential. Nano-engineered MSCs induced dose-dependent cytotoxicity in A549 lung adenocarcinoma cells and MA148 ovarian cancer cells in vitro. An orthotopic A549 lung tumor model was used to monitor the in vivo distribution of nanoengineered MSCs. Intravenous injection of nanoparticles resulted in non-specific biodistribution, with significant accumulation in the liver and spleen while nano-engineered MSCs demonstrated selective accumulation and retention in lung tumors. These studies demonstrate the feasibility of developing nano-engineered MSCs loaded with high concentration of anticancer agents without affecting their tumor-targeting or drug resistance properties. PMID- 25456829 TI - RGD peptide conjugated liposomal drug delivery system for enhance therapeutic efficacy in treating bone metastasis from prostate cancer. AB - Targeting alphavbeta3 integrin is particularly promising for the treatment of bone metastases by targeting integrin-rich tumor cells and by inhibiting integrin involved bone metastases. In this work, a liposomal drug delivery system conjugated with cyclic arginine-glycine-aspartic acid-tyrosine-lysine peptide (cRGDyk) as alphavbeta3 integrin ligand was thus developed to improve therapeutic efficacy in a mice model of bone metastasis from prostate cancer. The resultant liposomes were characterized in terms of size, morphology, zeta potential, stability, drug encapsulation percentage and loading efficiency, and drug release. Compared with free cisplatin and cRGDyk-free liposomes, cRGDyk conjugated liposomes showed significantly higher cellular uptake and higher cytotoxicity of loaded cisplatin, as evidenced by in vitro cell experiments. In vivo results revealed that free cisplatin and free cRGDyk could relieve tumor induced pain but had no contributions to tumor regression and overall survival improvement. cRGDyk-free liposomal drug system with prolonged blood circulation time could accumulated in the tumor sites in the bone through enhanced permeability and retention (EPR) effects and however, did not exhibit desirable therapeutic efficacy superior to free cisplatin and free cRGDyk. This strongly suggested that ERP effects were not effective in treating metastases. By taking advantages of targeted drug delivery and synergistic antitumor activity of cRGDyk and loaded cisplatin, cRGDyk conjugated liposomal drug system could inhibit osteoclastic and osteoblastic bone lesions, relieve pain, and improve overall survival. Inspired by their enhanced therapeutic efficacy and low organ toxicity, cRGDyk conjugated liposomes could serve as an effective drug system for targeted and synergistic therapy of bone metastases. PMID- 25456832 TI - Monoclonal antibody-targeted, temperature-sensitive liposomes: in vivo tumor chemotherapeutics in combination with mild hyperthermia. AB - The development of actively targeted, responsive delivery vectors holds great promise for cancer therapy. Here, we investigated whether enhanced therapeutic activity of temperature sensitive liposomes (TSL) could be obtained by mild hyperthermia-triggered release of the chemotherapeutic drug doxorubicin (DOX) after hCTMO1 monoclonal antibody (anti-MUC-1) binding and uptake into cancer cells. We showed that traditional TSL (TTSL) liposome systems maintained their physicochemical and thermal properties after conjugation to hCTMO1 full IgG. Receptor-mediated cellular uptake and cytotoxic efficacy of antibody-targeted TTSL (TTSL-Ab) were investigated using 2D and 3D cell culture models. Significant enhancement in cellular uptake and cytotoxic activity after 1h of heating at 42 degrees C was observed for TTSL-Ab compared to non-targeted liposomes in MUC-1 over-expressing breast cancer cells (MDA-MB-435). Tissue distribution and in vivo therapeutic activity were studied using different heating protocols to explore the effect of mild hyperthermia on the tumor accumulation of targeted TTSL and their therapeutic effect. Application of local, mild hyperthermia (42 degrees C) significantly increased the tumor accumulation of targeted TSL compared to non targeted liposomes, associated with a moderate improvement in therapeutic activity and survival. PMID- 25456831 TI - An improved D-alpha-tocopherol-based nanocarrier for targeted delivery of doxorubicin with reversal of multidrug resistance. AB - Nanocarriers have recently emerged as an attractive platform for the delivery of various types of therapeutics including anticancer agents. Previously, we developed an improved TPGS delivery system (PEG5K-VE2) which demonstrated improved colloidal stability and greater in vivo antitumor activity. Nevertheless, the application of this system is still limited by a relatively low drug loading capacity (DLC). In this study we report that incorporation of a fluorenylmethyloxycarbonyl (Fmoc) motif at the interfacial region of PEG5K-VE2 led to significant improvement of the system through the introduction of an additional mechanism of drug/carrier interaction. Doxorubicin (DOX) could be effectively loaded into PEG5K-Fmoc-VE2 micelles at a DLC of 39.9%, which compares favorably to most reported DOX nanoformulations. In addition, PEG5K-Fmoc-VE2/DOX mixed micelles showed more sustained release of DOX in comparison to the counterpart without Fmoc motif. MTT assay showed that PEG5K-Fmoc-VE2/DOX exerted significantly higher levels of cytotoxicity over DOX, Doxil as well as PEG5K VE2/DOX in PC-3 and 4T1.2 cells. A cytotoxicity assay with NCI/ADR-RES, a drug resistant cell line, suggested that PEG5K-Fmoc-VE2 may have the potential to reverse multidrug resistance, which was supported by its inhibition of P-gp ATPase. Pharmacokinetic (PK) and biodistribution studies showed an increased half life in blood circulation and more effective tumor accuulation for DOX formulated in PEG5K-Fmoc-VE2 micelles. More importantly, DOX-loaded PEG5K-Fmoc-VE2 micelles showed an excellent safety profile with a MTD (~30 mgDOX/kg) that is about 3 times as much as that for free DOX. Finally, superior antitumor activity was demonstrated by PEG5K-Fmoc-VE2/DOX in both drug-sensitive (4T1.2 and PC-3) and drug-resistant (KB 8-5) tumor models compared to DOX, Doxil, and PEG5K-VE2/DOX. PMID- 25456833 TI - Insights into accelerated liposomal release of topotecan in plasma monitored by a non-invasive fluorescence spectroscopic method. AB - A non-invasive fluorescence method was developed to monitor liposomal release kinetics of the anticancer agent topotecan (TPT) in physiological fluids and subsequently used to explore the cause of accelerated release in plasma. Analyses of fluorescence excitation spectra confirmed that unencapsulated TPT exhibits a red shift in its spectrum as pH is increased. This property was used to monitor TPT release from actively loaded liposomal formulations having a low intravesicular pH. Mathematical release models were developed to extract reliable rate constants for TPT release in aqueous solutions monitored by fluorescence and release kinetics obtained by HPLC. Using the fluorescence method, accelerated TPT release was observed in plasma as previously reported in the literature. Simulations to estimate the intravesicular pH were conducted to demonstrate that accelerated release correlated with alterations in the low intravesicular pH. This was attributed to the presence of ammonia in plasma samples rather than proteins and other plasma components generally believed to alter release kinetics in physiological samples. These findings shed light on the critical role that ammonia may play in contributing to the preclinical/clinical variability and performance seen with actively-loaded liposomal formulations of TPT and other weakly-basic anticancer agents. PMID- 25456835 TI - An exploration of men's knowledge, attitudes, and perceptions of HIV, HIV risk, and willingness to test for HIV in Yendi District, Northern Ghana. AB - We explored men's HIV knowledge, perceptions of HIV risk, and willingness to test for HIV in preparation for the initiation of formalized voluntary counseling and testing (VCT) services at Yendi Hospital in Yendi District, Ghana. A multi-method approach was used, including surveys of 129 male hospital patrons, three men-only focus group discussions, and eight interviews with clinical staff at the hospital. History of condom use, perception of risk, paying for an HIV test, and age were all significantly associated (p < .05) with willingness to test. An aversion to the hospital was the most prominent theme among participants. Aversion was due to perceived lack of confidentiality, preference for traditional healers, perceived costs, and fear of testing. Our participants (a) expressed the need for VCT services, (b) recommended that VCT target men for HIV prevention and VCT patronage, and (c) thought locations outside of hospitals should provide testing services. PMID- 25456836 TI - Standing in solidarity with Rosemary. PMID- 25456837 TI - MicroPET/CT imaging of patient-derived pancreatic cancer xenografts implanted subcutaneously or orthotopically in NOD-scid mice using (64)Cu-NOTA-panitumumab F(ab')2 fragments. AB - INTRODUCTION: Our objective was to study microPET/CT imaging of patient-derived pancreatic cancer xenografts in NOD-scid mice using F(ab')2 fragments of the fully-human anti-EGFR monoclonal antibody, panitumumab (Vectibix) labeled with (64)Cu. More than 90% of pancreatic cancers are EGFR-positive. METHODS: F(ab')2 fragments were produced by proteolytic digestion of panitumumab IgG or non specific human IgG, purified by ultrafiltration then modified with NOTA chelators for complexing (64)Cu. Panitumumab IgG and Fab fragments were similarly labeled with (64)Cu. EGFR immunoreactivity was determined in competition and direct (saturation) cell binding assays. The biodistribution of (64)Cu-labeled panitumumab IgG, F(ab')2 and Fab was compared in non-tumor-bearing Balb/c mice. MicroPET/CT and biodistribution studies were performed in NOD-scid mice engrafted subcutaneously (s.c.) or orthotopically with patient-derived OCIP23 pancreatic tumors, or in NOD-scid with s.c. PANC-1 human pancreatic cancer xenografts. RESULTS: Panitumumab F(ab')2 fragments were produced in high purity (>90%), derivitized with 3.2+/-0.7 NOTA/F(ab')2, and labeled with (64)Cu (0.3 3.6MBq/MUg). The binding of (64)Cu-NOTA-panitumumab F(ab')2 to OCIP23 or PANC-1 cells was decreased significantly by an excess of panitumumab IgG. The Kd for binding of (64)Cu-NOTA-panitumumab F(ab')2 to EGFR on PANC-1 cells was 0.14+/ 0.05nmol/L. F(ab')2 fragments exhibited more suitable normal tissue distribution for tumor imaging with (64)Cu than panitumumab IgG or Fab. Tumor uptake at 48h post injection (p.i.) of (64)Cu-NOTA-panitumumab F(ab')2 was 12.0+/-0.9% injected dose/g (ID/g) in s.c. and 11.8+/-0.9% ID/g in orthotopic OCIP23 tumors vs. 6.1+/ 1.1% ID/g in s.c. PANC-1 xenografts. Tumor/Blood (T/B) ratios were 5:1 to 9:1 for OCIP23 and 2.4:1 for PANC-1 tumors. Tumor uptake of (64)Cu-NOTA-non-specific F(ab')2 in OCIP23 xenografts was 5-fold lower than (64)Cu-panitumumab F(ab')2. All tumor xenografts were clearly imaged by microPET/CT at 24 or 48h p.i. of (64)Cu-NOTA-panitumumab F(ab')2. CONCLUSIONS: (64)Cu-panitumumab F(ab')2 fragments bound with high affinity to EGFR on pancreatic cancer cells in vitro and localized specifically in patient-derived pancreatic cancer xenografts in mice in vivo, allowing tumor visualization by microPET/CT at 24 or 48h p.i. PMID- 25456834 TI - m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. AB - N6-methyl-adenosine (m(6)A) is the most abundant modification on messenger RNAs and is linked to human diseases, but its functions in mammalian development are poorly understood. Here we reveal the evolutionary conservation and function of m(6)A by mapping the m(6)A methylome in mouse and human embryonic stem cells. Thousands of messenger and long noncoding RNAs show conserved m(6)A modification, including transcripts encoding core pluripotency transcription factors. m(6)A is enriched over 3' untranslated regions at defined sequence motifs and marks unstable transcripts, including transcripts turned over upon differentiation. Genetic inactivation or depletion of mouse and human Mettl3, one of the m(6)A methylases, led to m(6)A erasure on select target genes, prolonged Nanog expression upon differentiation, and impaired ESC exit from self-renewal toward differentiation into several lineages in vitro and in vivo. Thus, m(6)A is a mark of transcriptome flexibility required for stem cells to differentiate to specific lineages. PMID- 25456838 TI - Efficacy and Safety of Sequential Use of Everolimus in Patients With Metastatic Renal Cell Carcinoma Previously Treated With Bevacizumab With or Without Interferon Therapy: Results From the European AVATOR Study. AB - BACKGROUND: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor. It gained approval based on the results of the RECORD-1 (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism 1) trial, which included patients with metastatic renal cell carcinoma (mRCC) whose disease progressed after receiving vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Bevacizumab is a monoclonal antibody targeting angiogenesis that is approved in patients with mRCC. The sequence of everolimus second-line therapy after failure of bevacizumab +/- interferon (IFN) first-line therapy has not yet been studied. METHODS: AVAstin((r)) followed by afiniTOR((r)) (AVATOR) was a noninterventional retrospective multicenter European observational study of 42 unselected patients with mRCC who were previously or currently treated with everolimus after failure of bevacizumab +/- IFN. The primary end point was everolimus progression-free survival (PFS). Secondary end points were related to the overall survival (OS) of patients receiving the drug sequence and everolimus treatment and safety. RESULTS: Exploring the duration of second-line everolimus treatment, 63.8% of patients received at least 3 months of everolimus and 28.8% received at least 8 months of treatment. At the time of data analysis, 15 patients (36%) were still receiving everolimus, 40% had stopped because of progressive disease, and 24% had discontinued treatment for other reasons. Patients receiving everolimus after bevacizumab experienced a median PFS of 17 months (95% confidence interval [CI], 5 [not reached]). Median OS was not reached with everolimus second-line therapy. At 32 months after the start of first-line therapy, 53.3% of patients were still alive. All grades of common adverse events (AEs) were consistent with the known safety profile of everolimus. CONCLUSION: The AVATOR-studied sequence displayed a longer than expected median PFS. Further prospective exploratory studies need to be performed to confirm these encouraging results in a larger cohort of patients. PMID- 25456839 TI - Adjuvant chemotherapy is possibly beneficial for locally advanced or node positive bladder cancer. AB - BACKGROUND: This study aimed to evaluate the outcomes of cisplatin-based adjuvant chemotherapy (AC) after radical cystectomy (RC) in non-organ-confined bladder cancer. METHODS: Sixty-one patients who did not receive neoadjuvant chemotherapy (NAC) underwent RC for locally advanced (pT3-4) or node-positive (pN1-3) bladder cancer, or both, between 1990 and 2012. Of these patients, 39 (64%) received cisplatin-based AC after RC (AC group) and the remaining 22 patients (36%) did not (non-AC group). Cancer-specific survival (CSS) and recurrence-free survival (RFS) were compared between the groups. RESULTS: The AC group was significantly younger (P = .004), but no significant differences were noted between the groups for pT stage, pN stage, nuclear grade, renal function, and salvage chemotherapy rates after recurrence. During a follow-up of 29 months (median), 40 patients (67%) experienced recurrence/metastasis and 34 (56%) died of recurrent bladder cancer. The AC group showed better RFS than the non-AC group, but the difference was not statistically significant (median survival time [MST], 23.7 vs. 11.4 months, respectively; P = .154). CSS was significantly better for the AC group than for the non-AC group (MST, 57.4 vs. 17.9 months, respectively; P = .008). On multivariate analysis, AC was an independent predictive factor for both RFS (hazard ratio [HR], 0.325; P = .005) and CSS (HR, 0.186; P < .001), along with surgical margin status and lymphovascular invasion (LVI). In a subgroup analysis of 31 node-positive cases, the AC group had a significantly better CSS compared with the non-AC group (P = .029). Analysis of node-negative cases (n = 30) yielded no significant benefit for AC. CONCLUSION: Our observations suggest that postoperative cisplatin-based AC improves survival in locally advanced or node positive bladder cancer, especially in node-positive cases. PMID- 25456840 TI - Effect of sex on prognosis of urothelial carcinoma: propensity score matching analysis. AB - BACKGROUND: The aim of the present study was to evaluate the effect of differences between the sexes on the prognosis of urothelial carcinoma after adjusting for other factors by using propensity score matching. PATIENTS AND METHODS: Between 2000 and 2011, 678 consecutive patients who had undergone radical cystectomy or radical nephroureterectomy for urothelial carcinoma were enrolled in this study. Propensity score methodology was used to adjust for selection bias with 10 and 12 perioperative variables for urothelial carcinoma of the bladder (UCB) and upper tract urothelial carcinoma (UTUC). By a 2:1 male-to female patient matching ratio, we selected 38 and 66 pairs of patients with UCB and UTUC. RESULTS: The number of male patients was 573 (84.5%), and there were 105 female patients (15.5%). The mean follow-up was 55.5 +/- 38.4 months. There were no significant differences in the perioperative variables of age, pathologic T (pT) stage, grade, lymphovascular invasion (LVI), and concomitant carcinoma in situ (CIS) between the sexes. Neither cancer-specific survival (CSS) or overall survival (OS) was associated with sex in a multivariate Cox proportional hazard model. In propensity score matching analysis, female sex was not an independent risk factor for CSS and OS in urothelial carcinoma. In patients with UCB, body mass index (BMI) and pT stage were independently associated with CCS. For the patients with UTUC, age, pT stage, LVI, adjuvant chemotherapy, bladder cuffing, and location were significantly correlated. CONCLUSION: After adjusting for other risk factors with propensity score matching, female sex may not be an independent risk factor in prognosis for urothelial carcinoma (UC). PMID- 25456841 TI - Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer's disease. AB - Many different environmental factors (nutrients, pollutants, chemicals, physical activity, lifestyle, physical and mental stress) can modulate epigenetic markers in the developing and adult organism. Epigenetics, in turn, can cause and is associated with several neurodegenerative and aging-dependent human diseases. Alzheimer's disease certainly represents one of the most relevant neurodegenerative disorders due to its incidence and its huge socio-economic impact. Therefore, it is easy to understand why recent literature focuses on the epigenetic modifications associated with Alzheimer's disease and other neurodegenerative disorders. One of the most intriguing and, at the same time, worrying evidence is that even "mild" environmental factors (such as behavioral or physical stress) as well as the under-threshold exposure to pollutants and chemicals, can be effective. Finally, even mild nutrients disequilibria can result in long-lasting and functional alterations of many epigenetic markers, although they don't have an immediate acute effect. Therefore, we will probably have to re-define the current risk threshold for many factors, molecules and stresses. Among the many different environmental factors affecting the epigenome, nutrition represents one of the most investigated fields; the reasons are probably that each person interacts with nutrients and that, in turn, nutrients can modulate at molecular level the epigenetic biochemical pathways. The role that nutrition can exert in modulating epigenetic modifications in Alzheimer's disease will be discussed with particular emphasis on the role of B vitamins and DNA methylation. PMID- 25456842 TI - Normal aging in rats and pathological aging in human Alzheimer's disease decrease FAAH activity: modulation by cannabinoid agonists. AB - Anandamide is an endocannabinoid involved in several physiological functions including neuroprotection. Anandamide is synthesized on demand and its endogenous level is regulated through its degradation, where fatty acid amide hydrolase plays a major role. The aim of this study was to characterize anandamide breakdown in physiological and pathological aging and its regulation by CB1 and CB2 receptor agonists. Fatty acid amide hydrolase activity was analyzed in an independent cohort of human cortical membrane samples from control and Alzheimer's disease patients, and in membrane and synaptosomes from adult and aged rat cerebral cortex. Our results demonstrate that fatty acid amide hydrolase activity decreases in the frontal cortex from human patients with Alzheimer's disease and this effect is mimicked by Abeta(1-40) peptide. This activity increases and decreases in aged rat cerebrocortical membranes and synaptosomes, respectively. Also, while the presence of JWH-133, a CB2 selective agonist, slightly increases anandamide hydrolysis in human controls, it decreases this activity in adults and aged rat cerebrocortical membranes and synaptosomes. In the presence of WIN55,212-2, a mixed CB1/CB2 agonist, anandamide hydrolysis increases in Alzheimer's disease patients but decreases in human controls as well as in adult and aged rat cerebrocortical membranes and synaptosomes. Although a similar profile is observed in fatty acid amide hydrolase activity between aged rat synaptic endings and human Alzheimer's disease brains, it is differently modulated by CB1/CB2 agonists. This modulation leads to a reduced availability of anandamide in Alzheimer's disease and to an increased availability of this endocannabinoid in aging. PMID- 25456843 TI - Validation of the NANA (Novel Assessment of Nutrition and Ageing) touch screen system for use at home by older adults. AB - Prospective measurement of nutrition, cognition, and physical activity in later life would facilitate early detection of detrimental change and early intervention but is hard to achieve in community settings. Technology can simplify the task and facilitate daily data collection. The Novel Assessment of Nutrition and Ageing (NANA) toolkit was developed to provide a holistic picture of an individual's function including diet, cognition and activity levels. This study aimed to validate the NANA toolkit for data collection in the community. Forty participants aged 65 years and over trialled the NANA toolkit in their homes for three 7-day periods at four-week intervals. Data collected using the NANA toolkit were compared with standard measures of diet (four-day food diary), cognitive ability (processing speed) and physical activity (self-report). Bland Altman analysis of dietary intake (energy, carbohydrates, protein fat) found a good relationship with the food diary and cognitive processing speed and physical activity (hours) were significantly correlated with their standard counterparts. The NANA toolkit enables daily reporting of data that would otherwise be collected sporadically while reducing demands on participants; older adults can complete the daily reporting at home without a researcher being present; and it enables prospective investigation of several domains at once. PMID- 25456844 TI - Methyl 3,4-dihydroxybenzoate extends the lifespan of Caenorhabditis elegans, partly via W06A7.4 gene. AB - To identify and analyze the compounds that delay aging and extend the lifespan is an important aspect of the gerontology research. A number of compounds, including the ones with the antioxidant properties, have been shown to extend the lifespan of Caenorhabditis elegans. Here, we report that methyl 3,4-dihydroxybenzoate (MDHB), a small antioxidant molecule, prolongs the C. elegans' lifespan under normal as well as stress conditions, delays the age-associated decline in the pharyngeal pumping rate, and obviously enhances the abilities of scavenging intracellular reactive oxygen species (ROS). To further investigate the mechanism underlying the anti-aging action of MDHB, microarray analyses were performed, which demonstrated that 13 genes were differentially expressed in worms treated with MDHB for 48 and 144 h in common. RNA interference of W06A7.4 (NM_001269697.1), the most significantly up-regulated gene, shortened the lifespan of worms by 14%, compared with the L4440 control. Our findings demonstrate that W06A7.4 is a potentially positive determinant of the MDHB induced C. elegans' lifespan extension effect. PMID- 25456845 TI - Possible protective role of the 489C>T P2X7R polymorphism in Alzheimer's disease. AB - Inflammation is a key factor in the onset and progression of Alzheimer's disease (AD). The P2X7 receptor (P2X7R) is increasingly recognized as key pro inflammatory receptor. A recent study has shown that activation of microglia by amyloid beta (Abeta) and associated release of IL-1beta, requires P2X7R expression. In this study we assessed by RT-PCR in genomic DNA samples, the frequency of two single-nucleotide polymorphisms (SNP) of P2X7R in AD patients compared to age-matched non demented elderly. Our data show that the 489C>T SNP was significantly less frequent in AD patients than in controls (p=0.01), whereas there was no statistical difference in 1513A>C frequency in either groups. In addition, presence of the 1513C allele and absence of the 489C allele decreased the probability of having AD by about four fold. In conclusion, our data show a strong negative association between the P2X7R 489C>T polymorphism and AD, especially in the presence of the 1513C allele. PMID- 25456846 TI - The altered vestibular-evoked myogenic and whole-body postural responses in old men during standing. AB - Age-related decrements within the sensorimotor system may lead to alterations and impairments in postural control, but a link to a vestibular mechanism is unclear. The purpose of the present study was to determine whether vestibular control of standing balance is altered with adult aging. Eight old (~77 years) and eight young (~26 years) men stood without aids on a commercially available force plate with their head turned to the right, arms relaxed at their sides and eyes closed while receiving stochastic vestibular stimuli (0-25 Hz, root mean square amplitude=0.85 mA). Surface electromyography signals were sampled from the left soleus, medial gastrocnemius and tibialis anterior. Whole-body balance, as measured by the anteroposterior forces and muscle responses, was quantified using frequency (coherence and gain functions) and time (cumulant density function) domain correlations with the vestibular stimuli. Old men exhibited a compressed frequency response of the vestibular reflex with a greater relative gain at lower frequencies for the plantar flexors and anteroposterior forces than young. In the time domain, the peak amplitude of the short latency response was 45-64% lower for the plantar flexors and anteroposterior forces (p<=0.05) in the old than young, but not for the tibialis anterior (p=0.21). The old men had a 190% and 31% larger medium latency response for only the tibialis anterior and anteroposterior forces, respectively, than young (p<=0.01). A strong correlation between the tibialis anterior and the force response was also detected (r=0.80, p<0.01). In conclusion, net vestibular-evoked muscle responses led to smaller short and larger medium latency peak amplitudes in anteroposterior forces for the old. The present results likely resulted from a compressed and lower operational frequency range of the vestibular reflexes and the activation of additional muscles (tibialis anterior) to maintain standing balance. PMID- 25456848 TI - The transcriptional repressor CTBP-1 functions in the nervous system of Caenorhabditis elegans to regulate lifespan. AB - C-terminal binding proteins (CtBPs) are recruited by a variety of transcription factors to mediate gene repression. Nematode CTBP-1 has previously been shown to play a role in the regulation of lifespan; Caenorhabditis elegans strains carrying a deletion in the ctbp-1 gene showed a 10-20% increase in mean and maximal lifespan compared with wild-type control strains. We set out to identify the tissues in which CTBP-1 functions to regulate lifespan in C. elegans. Our analysis of reporter genes shows that CTBP-1 is predominantly expressed in the nervous system with lower levels detectable in the hypodermis. Tissue-specific rescue experiments demonstrated that CTBP-1 functions in the nervous system to regulate lifespan. Previously, the lifespan extension in a ctbp-1 mutant was attributed, at least in part, to the misregulation of a lipase gene, lips-7. We therefore focussed on lips-7 and found that expressing CTBP-1 solely in the nervous system of a ctbp-1 mutant significantly reduced lips-7 transcription. In addition, we studied another ctbp-1 mutant allele that also displayed a long lived phenotype. In this case, lips-7 expression was unaffected. This observation argues that, while lips-7 may play a role in lifespan, its de-repression is not essential for the extension of lifespan phenotype. We show that a prominent site of LIPS-7 expression is the hypodermis, one of the sites of fat storage in C. elegans. Interestingly, we did not observe co-localisation of CTBP-1 and lips-7 transcription in the nervous system, indicating that CTBP-1 may be acting indirectly, in a cell non-autonomous manner. In summary, our data confirm that CTBP-1 is involved in the regulation of lips-7 transcription but suggest that it may perform additional roles in the nervous system that contribute to the regulation of longevity. PMID- 25456847 TI - Royalactin extends lifespan of Caenorhabditis elegans through epidermal growth factor signaling. AB - Royalactin is a glycoprotein essential for the development of long-lived queen honeybees. Only larvae fed with royal jelly, containing royalactin, develop into queens. Royalactin plays a central role in this process by switching on the epidermal growth factor (EGF) receptor signaling pathway which ultimately leads to epigenetic changes and a long-lived queen phenotype. Recently it was shown that royalactin by itself also extends lifespan in Drosophila melanogaster. Yet, the mechanism by which royalactin promotes longevity remains largely unknown. We set out to characterize the effects of royalactin on Caenorhabditis elegans lifespan, and clarify the possible involvement of EGF signaling in this process. We demonstrate that royalactin extends lifespan of this nematode and that both EGF (LIN-3) and its receptor (LET-23) are essential to this process. To our knowledge, this is the first report of royalactin-mediated lifespan extension in a non-insect species. Additionally, we show that royalactin enhances locomotion in adult nematodes, implying that royalactin also influences healthspan. Our results suggest that royalactin is an important lifespan-extending factor in royal jelly and acts by promoting EGF signaling in C. elegans. Further work will now be needed to clarify which (secondary) signaling pathways are activated by royalactin, and how this ultimately translates into an extended health- and lifespan. PMID- 25456849 TI - Reply to the comment on "Lower lean mass and higher percent fat mass in patients with Alzheimer's disease". PMID- 25456851 TI - Antiproliferation and induction of caspase-8-dependent mitochondria-mediated apoptosis by beta-tocotrienol in human lung and brain cancer cell lines. AB - The pure vitamin isomer, beta-tocotrienol has the least abundance among the other vitamin E isomers that are present in numerous plants. Hence, it is very scarcely studied for its bioactivity. In this study, the antiproliferative effects and primary apoptotic mechanisms of beta-tocotrienol on human lung adenocarcinoma A549 and glioblastoma U87MG cells were investigated. It was evidenced that beta tocotrienol had inhibited the growth of both A549 (GI50=1.38+/-0.334MUM) and U87MG (GI50=2.53+/-0.604MUM) cells at rather low concentrations. Cancer cells incubated with beta-tocotrienol were also found to exhibit hallmarks of apoptotic morphologies including membrane blebbing, chromatin condensation and formation of apoptotic bodies. The apoptotic properties of beta-tocotrienol in both A549 and U87MG cells were the results of its capability to induce significant (P<0.05) double-strand DNA breaks (DSBs) without involving single-strand DNA breaks (SSBs). beta-Tocotrienol is said to induce activation of caspase-8 in both A549 and U87MG cells guided by no activation when caspase-8 inhibitor, z-IETD-fmk was added. Besides, disruption on the mitochondrial membrane permeability of the cells in a concentration- and time-dependent manner had occurred. The induction of apoptosis by beta-tocotrienol in A549 and U87MG cells was confirmed to involve both the death-receptor mediated and mitochondria-dependent apoptotic pathways. These findings could potentiate the palm oil derived beta-tocotrienol to serve as a new anticancer agent for treating human lung and brain cancers. PMID- 25456852 TI - Curcumin ameliorates epithelial-to-mesenchymal transition of podocytes in vivo and in vitro via regulating caveolin-1. AB - AIMS: Epithelial-mesenchymal transition (EMT) is recognized to play a key role in diabetic nephropathy (DN). Curcumin, the main active component of turmeric extracted from the roots of the Curcuma longa plant, has been reported for its anti-fibrotic effects in kidney fibrosis. The purpose of our study was to investigate the effects of curcumin in reversing epithelial-to-mesenchymal transition (EMT) of podocytes in vivo and in vitro. MATERIALS/METHODS: In vivo streptozotocin (STZ)-induced diabetic rats received vehicle or curcumin, and podocytes were treated with high glucose (HG) in the presence or absence of curcumin in vitro. And we investigated the effect of curcumin on HG-induced phosphorylation of cav-1 on the stability cav-1 and beta-catenin using immunoprecipitation and fluorescence microscopy analysis. RESULTS: Curcumin treatment dramatically ameliorated metabolic parameters, renal function, morphological parameters in diabetic rats. We found that HG treatment led to significant down-regulation of p-cadherin and synaptopodin, as well as remarkable up-regulation of alpha-SMA and FSP-1 in vivo and in vitro. Furthermore, curcumin inhibited HG-induced caveolin-1 (cav-1) Tyr(14) phosphorylation associating with the suppression of stabilization of cav-1 and beta-catenin. CONCLUSIONS: In summary, these findings suggest that curcumin prevents EMT of podocytes, proteinuria, and kidney injury in DN by suppressing the phosphorylation of cav-1, and increasing stabilization of cav-1 and beta-catenin. PMID- 25456850 TI - Extension of Drosophila lifespan by cinnamon through a sex-specific dependence on the insulin receptor substrate chico. AB - Cinnamon is a spice commonly used worldwide to flavor desserts, fruits, cereals, breads, and meats. Numerous health benefits have been attributed to its consumption, including the recent suggestion that it may decrease blood glucose levels in people with diabetes. Insulin signaling is an integral pathway regulating the lifespan of laboratory organisms, such as worms, flies, and mice. We posited that if cinnamon truly improved the clinical signs of diabetes in people that it would also act on insulin signaling in laboratory organisms and increase lifespan. We found that cinnamon did extend lifespan in the fruit fly, Drosophila melanogaster. However, it had no effect on the expression levels of the 3 aging-related Drosophila insulin-like peptides nor did it alter sugar, fat, or soluble protein levels, as would be predicted. In addition, cinnamon exhibited no protective effects in males against oxidative challenges. However, in females it did confer a protective effect against paraquat, but sensitized them to iron. Cinnamon provided no protective effect against desiccation and starvation in females, but sensitized males to both. Interestingly, cinnamon protected both sexes against cold, sensitized both to heat, and elevated HSP70 expression levels. We also found that cinnamon required the insulin receptor substrate to extend lifespan in males, but not females. We conclude that cinnamon does not extend lifespan by improving stress tolerance in general, though it does act, at least in part, through insulin signaling. PMID- 25456853 TI - Multistep galvanic exchange synthesis yielding fully reduced Pt dendrimer encapsulated nanoparticles. AB - Here we outline a new method for synthesizing fully reduced Pt dendrimer encapsulated nanoparticles (DENs). This is achieved by first synthesizing Cu DENs of the appropriate size through sequential dendrimer loading and reduction steps, and then galvanically exchanging the zerovalent Cu DENs for Pt. The properties of Pt DENs having an average of 55, 140, and 225 atoms prepared by direct chemical reduction and by galvanic exchange are compared. Data obtained by UV-vis spectroscopy, X-ray absorption spectroscopy, X-ray photoelectron spectroscopy, and high-resolution electron microscopy confirm only the presence of fully reduced Pt DENs when synthesized by galvanic exchange, while chemical reduction leads to a mixture of reduced DENs and unreduced precursor. These results are significant because Pt DENs are good models for developing a better understanding of the effects of finite size on catalytic reactions. Until now, however, the results of such studies have been complicated by a heterogeneous mixture of Pt catalysts. PMID- 25456854 TI - Involvement of Toxoplasma gondii in reproductive disorders in Swiss pig farms. AB - To determine the role of Toxoplasma gondii in reproductive failure, 108 of 113 sows that had aborted or delivered stillborn or weak piglets from 58 Swiss farms were serologically tested for specific antibodies against T. gondii tachyzoite antigens by ELISA. Additionally, formalin-fixed and paraffin-embedded tissues from 123 foetuses or stillborn piglets derived from 25 seropositive and 27 seronegative sows were analyzed by real-time PCR for T. gondii DNA. Tissues from animals showing a positive reaction in real-time PCR were subsequently tested by immunohistochemistry for the presence of T. gondii antigens. Antibodies against T. gondii were detected in 24.1% (26 out of 108) of sows with reproductive failure, and 37.3% (22 of 58) of the 58 tested farms had seropositive sows. No significant differences in the prevalences were observed in relation to the housing system (exclusive indoor housing, indoor housing with outdoor yard and exclusive outdoor housing) neither at the individual nor at the farm levels. By real time-PCR, T. gondii DNA was detected in three placentas from one seropositive sow (abortion at 71 gestation days [gd]), and in brain tissues from one foetus (abortion at 76 gd), one stillborn (116 gd) and one mummy (112 gd) delivered by three further seropositive sows, but in no sample derived from seronegative dams. By immunohistochemical staining, the presence of T. gondii could be confirmed only in placenta samples. In one of the cases, a co-infection with porcine parvovirus (PPV) was detected. These results suggest vertical transmission of T. gondii and/or placental infection in at least 3.5% (4 of 113) of sows with reproductive disorders. Therefore, T. gondii should be more frequently included in the routine differential diagnosis of reproductive failure in sows. In addition, a proper disposal of placentas and abortion material beyond the reach of cats could help to interrupt the further dissemination of this parasite at the farm level. PMID- 25456855 TI - Tariquidar inhibits P-glycoprotein drug efflux but activates ATPase activity by blocking transition to an open conformation. AB - P-glycoprotein (P-gp, ABCB1) is a drug pump that confers multidrug resistance. Inhibition of P-gp would improve chemotherapy. Tariquidar is a potent P-gp inhibitor but its mechanism is unknown. Here, we tested our prediction that tariquidar inhibits P-gp cycling between the open and closed states during the catalytic cycle. Transition of P-gp to an open state can be monitored in intact cells using reporter cysteines introduced into extracellular loops 1 (A80C) and 4 (R741C). Residues A80C/R741C come close enough (<7A) to spontaneously cross-link in the open conformation (<7A) but are widely separated (>30A) in the closed conformation. Cross-linking of A80C/R741C can be readily detected because it causes the mutant protein to migrate slower on SDS-PAGE gels. We tested whether drug substrates or inhibitors could inhibit cross-linking of the mutant. It was found that only tariquidar blocked A80C/R741C cross-linking. Tariquidar was also a more potent pharmacological chaperone than other P-gp substrates/modulators such as cyclosporine A. Only tariquidar promoted maturation of misprocessed mutant F804D to yield mature P-gp. Tariquidar interacted with the transmembrane domains because it could rescue a misprocessed truncation mutant lacking the nucleotide-binding domains. These results show that tariquidar is a potent pharmacological chaperone and inhibits P-gp drug efflux by blocking transition to the open state during the catalytic cycle. PMID- 25456856 TI - Information structure and organisation in change of shift reports: An observational study of nursing hand-offs in a Paediatric Intensive Care Unit. AB - Patient hand-offs involve the exchange of critical information. Ineffective hand offs can result in reduced patient safety by leading to wrong treatment, delayed diagnoses or other outcomes that can negatively affect the healthcare system. The objectives of this study were to uncover the structure of the information conveyed during patient hand-offs and look for principles characterising the organisation of the information. With an observational study approach, data was gathered during the morning and evening nursing change of shift hand-offs in a Paediatric Intensive Care Unit. Content analysis identified a common meta structure used for information transfer that contained categories with varying degrees of information integration and the repetition of high consequence information. Differences were found in the organisation of the hand-off structures, and these varied as a function of nursing experience. The findings are discussed in terms of the potential benefits of computerised tools which utilise standardised structure for information transfer and the implications for future education and critical care skill acquisition. PMID- 25456858 TI - Spin crossover in tetranuclear Fe(II) complexes, {[(tpma)Fe(MU-CN)]4}X4 (X = ClO4(-), BF4(-)). AB - Two Fe(II) complexes, {[(tpma)Fe(MU-CN)]4}X4 (X = ClO4(-) (1a), BF4(-) (1b); tpma = tris(2-pyridylmethyl)amine), were prepared by reacting the {Fe(tpma)}(2+) building block with (Bu4N)CN. The crystal structures of 1a and 1b feature a tetranuclear cation composed of cyanide-bridged Fe(II) ions, each capped with a tetradentate tpma ligand. The Fe4(MU-CN)4 core of the complex is strongly distorted, assuming a butterfly-like geometry. Both complexes exhibit gradual temperature-driven spin crossover (SCO) associated with the high-spin (HS) <-> low-spin (LS) transition at two out of four metal centers. The evolution of HS and LS Fe(II) ions with temperature was followed by a combination of X-ray crystallography, magnetic measurements, and Mossbauer spectroscopy. Only the Fe(II) ions surrounded by six N atoms undergo the SCO. A comparison of the temperature-dependent SCO curves for the samples stored under solvent and the dried samples shows that the former exhibit a much more abrupt SCO. This finding was interpreted in terms of the increased structural disorder and decreased crystallinity caused by the loss of the interstitial solvent molecules in the dried samples. PMID- 25456857 TI - Blockade of EMAP II protects cardiac function after chronic myocardial infarction by inducing angiogenesis. AB - Promoting angiogenesis is a key therapeutic target for protection from chronic ischemic cardiac injury. Endothelial-Monocyte-Activating-Polypeptide-II (EMAP II) protein, a tumor-derived cytokine having anti-angiogenic properties in cancer, is markedly elevated following myocardial ischemia. We examined whether neutralization of EMAP II induces angiogenesis and has beneficial effects on myocardial function and structure after chronic myocardial infarction (MI). EMAP II antibody (EMAP II AB), vehicle, or non-specific IgG (IgG) was injected ip at 30 min and 3, 6, and 9 days after permanent coronary artery occlusion in mice. EMAP II AB, compared with vehicle or non-specific antibody, significantly, p<0.05, improved the survival rate after MI, reduced scar size and attenuated the development of heart failure, i.e., left ventricular ejection fraction was significantly higher in EMAP II AB group, fibrosis was reduced by 24%, and importantly, more myocytes were alive in EMAP II AB group in the infarct area. In support of an angiogenic mechanism, capillary density (193/HPF vs. 172/HPF), doubling of the number of proliferating endothelial cells, and angiogenesis related biomarkers were upregulated in mice receiving EMAP II AB treatment as compared to IgG. Furthermore, EMAP II AB prevented EMAP II protein inhibition of in vitro tube formation in HUVECs. We conclude that blockade of EMAP II induces angiogenesis and improves cardiac function following chronic MI, resulting in reduced myocardial fibrosis and scar formation and increased capillary density and preserved viable myocytes in the infarct area. PMID- 25456859 TI - RE-CIRCUIT study-randomized evaluation of Dabigatran etexilate compared to warfarin in pulmonary vein ablation: assessment of an uninterrupted periprocedural anticoagulation strategy. PMID- 25456861 TI - The two extremes of cardiac sarcoidosis and the effect of Prednisone therapy. AB - Described herein are clinical and morphologic findings in 2 patients who underwent heart transplantation because of severe heart failure resulting from cardiac sarcoidosis. Although the explanted hearts in each patient had characteristic gross changes of cardiac sarcoidosis, one patient who had been treated with prednisone, had no residual sarcoid granulomas in the myocardium, whereas the other patient, in whom diagnosis was not made until heart transplantation, had innumerable sarcoid granulomas in her heart. This report suggests that prednisone can eliminate sarcoid granulomas in the heart but that their replacement is by dense fibrous tissue, something also likely the result of the granulomas themselves, creating a situation where the treated (prednisone) and the non-treated sarcoid heart may appear similar by gross examination. PMID- 25456860 TI - Trends in pulmonary valve replacement in children and adults with tetralogy of fallot. AB - Operative correction of tetralogy of Fallot frequently results in pulmonary insufficiency and chronic volume overload, which have been linked to increased risk for adverse outcomes. No consensus recommendations for the timing of pulmonary valve replacement (PVR) exist. The aim of this study was to examine the pattern of PVR in the United States from 2004 to 2012. The Pediatric Health Information Systems database was used to perform an observational study of children and adults >=10 years of age with diagnoses of tetralogy of Fallot who underwent PVR at 35 centers in the United States from 2004 and 2012, to assess the rate of PVR and the age at which is performed. Mixed-effects multivariate regression was used to account for patient-level covariates and center-level covariance. Additional analyses assessed for trends in cost, hospital length of stay (LOS), intensive care unit LOS, and in-hospital mortality over the study period. In total, 799 subjects at 35 centers underwent PVR over the study period. The number of PVRs performed per year increased significantly over the study period. There was significant between-center heterogeneity in age at PVR (p <0.001). Age at PVR, intensive care unit LOS, hospital LOS, and cost did not change over the study period. In conclusion, PVR in patients with tetralogy of Fallot is being performed more frequently, without an accompanying change in the age at PVR or other measurable outcomes. There is significant variability in the age at which PVR is performed among centers across the United States. This highlights the need for additional research guiding the optimal timing of PVR. PMID- 25456862 TI - Commonalities of cardiac rupture (left ventricular free wall or ventricular septum or papillary muscle) during acute myocardial infarction secondary to atherosclerotic coronary artery disease. AB - Although mortality rates during acute myocardial infarction (AMI) continue to drop, cardiac rupture (left ventricular free wall [LVFW] or ventricular septum [VS] or papillary muscle [PM] or combination) remains relatively common. The aim was to identify commonalities among patients with AMI complicated by cardiac rupture. During a 22-year period (1993-2014) 64 patients hospitalized for AMI were studied and clinical and morphologic variables in those with (25 patients) - vs - those without (39 patients) cardiac rupture were compared, and previous reports on this topic were reviewed. Compared to the non-rupture cases, the rupture group was significantly older (71 years - vs - 60 years); had a much higher frequency of huge deposits of adipose tissue in the heart (floated in formaldehyde) (88% - vs - 20%) but a lower mean body mass index (28.2 Kg/m(2) - vs - 33.2 Kg/m(2)); a much lower frequency of healed myocardial infarct (scar) (4% - vs - 28%); a lower frequency of diabetes mellitus (24% - vs - 47%), and a higher frequency of thrombolytic therapy during the fatal AMI (32% - vs - 10%). None of the rupture cases had evidence of dilated left ventricular cavities or evidence of heart failure before the AMI complicated by rupture. In conclusion, cardiac rupture appears to account for a high percent of deaths during a first AMI. It most commonly occurs in patients with extremely fatty hearts and in those without evidence of prior heart failure. PMID- 25456863 TI - Impact of postdischarge statin withdrawal on long-term outcomes in patients with acute myocardial infarction. AB - Many patients discontinue statin after acute myocardial infarction (AMI) despite its necessity. However, limited data are available describing the clinical impact of statin withdrawal after AMI. This study enrolled 3,807 patients in the Korean multicenter registry who survived for 1 year after AMI. All patients were prescribed statin at discharge and were divided into 2 groups on the basis of statin withdrawal history; 603 patients had a history of statin discontinuation and 3,204 patients continued statin therapy. The primary outcome was mortality from any cause. We also analyzed the incidence of cardiac death, nonfatal myocardial infarction, any revascularization, and stroke. The duration of follow up was 4 years after AMI. Statin withdrawal was associated with higher mortality than continued statin treatment (hazard ratio 3.45, 95% confidence interval 2.81 to 4.24, p <0.001), primarily as the result of increased cardiac mortality (hazard ratio 4.65, 95% confidence interval 3.14 to 6.87, p <0.001). However, the incidences of nonfatal myocardial infarction, any revascularization, and stroke were not different between the groups. Analysis by propensity score matching did not affect the results. In conclusion, many patients experienced statin withdrawal after AMI, which significantly increased long-term mortality in the present study. Careful education and monitoring are needed to reduce adverse cardiac outcomes in patients after AMI. PMID- 25456864 TI - Revisiting cardiac injury during acute heart failure: further characterization and a possible target for therapy. PMID- 25456865 TI - Gender disparities in evidence-based statin therapy in patients with cardiovascular disease. AB - Studies have shown gender disparities in cholesterol care in patients with cardiovascular disease (CVD), with women less likely than men to have low-density lipoprotein cholesterol levels <100 mg/dl. Whether this is related to a lower evidence-based statin or high-intensity statin use is not known. We used a national cohort of 972,532 patients with CVD (coronary heart disease, peripheral artery disease, and ischemic stroke) receiving care in 130 Veterans Health Administration facilities from October 1, 2010, to September 30, 2011, to identify the proportion of male and female patients with CVD receiving any statin and high-intensity statin. Women with CVD (n = 13,371) were less likely than men to receive statins (57.6% vs 64.8%, p <0.0001) or high-intensity statins (21.1% vs 23.6%, p <0.0001). Mean low-density lipoprotein cholesterol levels (99 vs 85 mg/dl) were higher in women compared with men (p <0.0001). In adjusted models, female gender was independently associated with a lower likelihood of receiving statins (odds ratio 0.68, 95% confidence interval 0.66 to 0.71) or high-intensity statins (odds ratio 0.76, 95% confidence interval 0.73 to 0.80). The median facility-level rate of statin and high-intensity statin use among female patients (57.3% [interquartile range = 8.93%] for statin, 20% [interquartile range = 7.7%] for high-intensity statin use) showed significant variation. In conclusion, women with CVD are less likely to receive evidence-based statin and high-intensity statins compared with men, although, their use remains low in both genders. There is a significant facility-level variation in evidence-based statin or high intensity statin use in female patients with CVD. With the "statin dose-based approach" proposed by the recent cholesterol guidelines, these results highlight areas for quality improvement. PMID- 25456866 TI - Outcomes of patients calling emergency medical services for suspected acute cardiovascular disease. AB - Adequate health care is increasingly dependent on prehospital systems and cardiovascular (CV) disease remains the most common cause for hospital admission. However the prevalence of CV dispatches of emergency medical services (EMS) is not well reported and survival data described in clinical trials and registries are subject to selection biases. We aimed to describe the prevalence and prognosis of acute CV disease and the effect of invasive treatment, in an unselected and consecutive prehospital cohort of 3,410 patients calling the national emergency telephone number from 2005 to 2008 with follow-up in 2013. Individual-level data from national registries were linked to the dedicated EMS database of primary ambulance dispatches supported by physician-manned emergency units. Outcome data were obtained from the Central Population Registry, the National Patient Registry, and the National Registry of Causes of Death. In patients calling the national emergency telephone number, a CV related ambulance alarm code was given in 2,541 patients of 3,410 patients (74.5%) resulting in 2,056 of 3,410 primary CV discharge diagnoses (60.3%) with a 30-day and 5-year all-cause mortality of 24.5% and 46.4%, respectively. Stroke, acute heart failure, and ST-segment elevation myocardial infarction (STEMI) carried a 25- to 50-fold adjusted mortality hazard during the first 4 days. In patients with suspected STEMI, 90.5% had an acute angiography performed. Nontransferred, nonreperfused patients with STEMI (9.1%) carried 80% short-term mortality. Noninvasive management of non-ST-segment elevation myocardial infarction was common (37.9%) and associated with an increased adjusted long-term mortality hazard (hazard ratio 4.17 [2.51 to 8.08], p <0.001). Survival in 447 out-of hospital cardiac arrest patients (13.1%) was 11.6% at 30 days. In conclusion, patients with a CV ambulance alarm call code and a final CV discharge diagnosis constitute most patients handled by EMS with an extremely elevated short-term mortality hazard and a poor long-term prognosis. Although co-morbidities and frailty may influence triage, this study emphasizes the need for an efficient prehospital phase with focus on CV disease and proper triage of patients suitable for invasive evaluation if the outcomes of acute heart disease are to be improved further in the current international context of hospitals merging into highly specialized entities resulting in longer patient transfers. PMID- 25456867 TI - Effects of Prolastin C (Plasma-Derived Alpha-1 Antitrypsin) on the acute inflammatory response in patients with ST-segment elevation myocardial infarction (from the VCU-alpha 1-RT pilot study). AB - Alpha-1 antitrypsin (AAT) has broad anti-inflammatory and immunomodulating properties in addition to inhibiting serine proteases. Administration of human plasma-derived AAT is protective in models of acute myocardial infarction in mice. The objective of this study was to determine the safety and tolerability of human plasma-derived AAT and its effects on the acute inflammatory response in non-AAT deficient patients with ST-segment elevation myocardial infarction (STEMI). Ten patients with acute STEMI were enrolled in an open-label, single-arm treatment study of AAT at 60 mg/kg infused intravenously within 12 hours of admission and following standard of care treatment. C-reactive protein (CRP) and plasma AAT levels were determined at admission, 72 hours, and 14 days, and patients were followed clinically for 12 weeks for the occurrence of new onset heart failure, recurrent myocardial infarction, or death. Twenty patients with STEMI enrolled in previous randomized trials with identical inclusion and/or exclusion criteria, but who received placebo, served as historical controls. Prolastin C was well tolerated and there were no in-hospital adverse events. Compared with historical controls, the area under the curve of CRP levels was significantly lower 14 days after admission in the Prolastin C group (75.9 [31.4 to 147.8] vs 205.6 [78.8 to 410.9] mg/l, p = 0.048), primarily due to a significant blunting of the increase occurring between admission and 72 hours (delta CRP +1.7 [0.2 to 9.4] vs +21.1 [3.1 to 38.0] mg/l, p = 0.007). Plasma AAT levels increased from admission (149 [116 to 189]) to 203 ([185 to 225] mg/dl) to 72 hours (p = 0.005). In conclusion, a single administration of Prolastin C in patients with STEMI is well tolerated and is associated with a blunted acute inflammatory response. PMID- 25456868 TI - Relation of physical activity to prevalence of nonalcoholic Fatty liver disease independent of cardiometabolic risk. AB - Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and insulin resistance and has been linked with increased cardiovascular risk. Although physical activity (PA) and lifestyle modification are often recommended in patients at cardiovascular risk, the benefit across the cardiometabolic risk spectrum is unclear. We aimed to evaluate the relation of PA and NAFLD independent of metabolic syndrome (MS) or obesity. We evaluated 5,743 healthy Brazilian subjects (43 +/- 10 years, 79% men) without clinical coronary heart disease from December 2008 to December 2010. NAFLD was diagnosed using ultrasounds, and self-reported PA was assessed using the International Physical Activity Questionnaire scale. In a multivariate logistic regression adjusted for cardiometabolic risk factors, we evaluated for an independent association of NAFLD and PA. In the total study population, NAFLD prevalence was 36% (n = 2,075), obesity 23% (1,300), and MS 20% (1,152). NAFLD was more prevalent in subjects with MS (74%) than those without (26%) and in those obese (73%) than in those nonobese (25%). Overall, 1,305 (23%) subjects reported low activity, 1,990 (35%) moderate activity, and 2,448 (42%) high activity. NAFLD prevalence was lower at higher levels of reported PA (low 45%, moderate 38%, and high 30%, p <0.001). After adjusting for risk factors, subjects with high activity had lower odds of having NAFLD. The favorable association was independent of obesity or MS. In conclusion, PA presents a dose-response association with NAFLD independent of the MS or obesity. Our results are compatible with the idea that benefits of PA are relevant to everyone regardless of cardiometabolic risk. PMID- 25456869 TI - Heterogeneity in statin indications within the 2013 american college of cardiology/american heart association guidelines. AB - A standard ("core") implementation of American College of Cardiology/American Heart Association 2013 lipid guidelines (based on 10-year risk) dramatically increases the statin-eligible population in older Americans, raising controversy in the cardiovascular community. The guidelines also endorse a more "comprehensive" risk approach based in part on lifetime risk. The impact of this broader approach on statin eligibility remains unclear. We studied the impact of 2 different implementations of the new guidelines ("core" and "comprehensive") using the National Health and Nutrition Examination Survey. Although "core" guidelines led to 72.0 million subjects qualifying for statin therapy, the broader "comprehensive" application led to nearly a twofold greater estimate for statin-eligible subjects (121.2 million), with the greatest impact among those aged 21 to 45 years. Subjects indicated for statin therapy under comprehensive guidelines had a greater burden of cardiovascular risk factors and a higher lifetime risk of cardiovascular disease than those not indicated for statins. In particular, men aged 21 to 45 years had a 3.13-fold increased odds of being eligible for statin therapy only under the "comprehensive" guidelines (vs standard "core" guidelines; 95% confidence interval 2.82 to 3.47, p <0.0001). There were no racial differences. In conclusion, the "comprehensive" approach to statin eligibility espoused by the American College of Cardiology/American Heart Association 2013 guidelines would increase the statin-eligible population to over 120 million Americans, particularly targeting younger men with high-risk factor burden. PMID- 25456870 TI - Comparison of safety of left atrial catheter ablation procedures for atrial arrhythmias under continuous anticoagulation with apixaban versus phenprocoumon. AB - Apixaban is increasingly used for stroke prevention in patients with atrial fibrillation. Data about the safety of left atrial radiofrequency ablation procedures under continuous apixaban therapy are lacking. We performed a matched cohort study of patients undergoing left atrium ablation procedures for atrial fibrillation or left atrial flutter. For each patient on apixaban, 2 patients on phenprocoumon were matched by age, gender, and type of arrhythmia. The primary safety end point was a composite of bleeding, thromboembolic events, and death. We identified 105 consecutive patients (35 women; mean age 63 years) on apixaban and matched 210 phenprocoumon patients (70 women, mean age 64 years). The primary end point was met in 11 patients of the apixaban group and 26 patients of the phenprocoumon group (10.5% vs 12.3%, p = 0.71). Major bleeding complications occurred in 1 patient of the apixaban group and 1 patient of the phenprocoumon group (1% vs 0.5%, p >0.99). Minor bleeding complications were observed in 10 patients of the apixaban group and 25 patients of the phenprocoumon group (9.5% vs 11.9%, p = 0.61). No patient in either group experienced a thromboembolic event and no patient died. In patients on apixaban, no clinical variable was predictive for bleeding complications. Left atrial ablation procedures under continuous oral anticoagulation with apixaban are feasible and as safe as under continuous oral anticoagulation with phenprocoumon. PMID- 25456871 TI - Comparison of frequency and outcome of major gastrointestinal hemorrhage in patients with atrial fibrillation on versus not receiving warfarin therapy (from the ATRIA and ATRIA-CVRN cohorts). AB - To date, there have been few studies evaluating outcomes of patients with atrial fibrillation (AF) who have experienced gastrointestinal (GI) hemorrhages. We examined short- and long-term mortality of major GI hemorrhage in patients with AF on and off warfarin in recent clinical care. We evaluated this association in the large Anticoagulation and Risk Factors in Atrial fibrillation (ATRIA) and ATRIA-Cardiovascular Research Network (CVRN) California community-based cohorts of patients with AF (study years 1996 to 2003 and 2006 to 2009, respectively), where all events were clinician adjudicated. We used proportional hazards regression with propensity score adjustment to estimate the short- (30 days) and long-term (>30 days for 1 year) mortality rate ratio for patients using warfarin compared with those who were not using warfarin at the time of GI hemorrhage. In the 414 ATRIA participants with major GI hemorrhage, 54% were taking warfarin at the time of the hemorrhage; in the 361 ATRIA-CVRN participants with major GI hemorrhage, 58% were taking warfarin. Warfarin use at the time of GI hemorrhage was not associated with 30-day mortality in the ATRIA cohort but was associated with significantly reduced 30-day mortality in the ATRIA-CVRN cohort (adjusted mortality rate ratio [95% confidence interval], ATRIA 0.97 [0.54 to 1.74]; ATRIA CVRN 0.38 [0.17 to 0.83]). There was a modest suggestion of lower mortality on warfarin after 30 days in both cohorts. In conclusion, our study demonstrates that GI hemorrhages on warfarin are certainly no worse and may be less life threatening than those occurring off warfarin. These findings are in stark contrast to the deleterious effect of warfarin on mortality from intracranial hemorrhage and add another factor favoring anticoagulation in clinical decision making for patients with AF. PMID- 25456872 TI - Prevalence of type 1 brugada electrocardiographic pattern evaluated by twelve lead twenty-four-hour holter monitoring. AB - Patients with drug-induced type 1 Brugada electrocardiograms (BrECGs) are considered to have good prognosis. Spontaneous type 1 is, instead, considered a risk factor; however, it is probably underestimated because of the BrECG fluctuations. The aim of this study was to analyze, in a large population of patients with Br, the real prevalence of type 1 BrECG using 12-lead 24-hour Holter monitoring (12L-Holter) and its correlation with the time of the day. We recorded 303 12L-Holter in 251 patients. Seventy-five (30%) patients exhibited spontaneous type 1 BrECG at 12-lead ECG (group 1) and 176 (70%) had only drug induced type 1 (group 2). Type 1 BrECG was defined as "persistent" (>85% of the recording), "intermittent" (<85%), or "absent." In group 1, 12% showed persistent type 1 at 12L-Holter, 57% intermittent type 1%, and 31% never had type 1; in group 2, none had persistent type 1, 20% had intermittent type 1%, and 80% never showed type 1. To evaluate the circadian fluctuations of BrECG, 4 periods in the day were considered. Type 1 BrECG was more frequent between 12-noon and 6 p.m. (52%, p <0.001). In conclusion, in patients with drug-induced type 1, spontaneous type 1 BrECG can be detected more frequently with 12L-Holter than with conventional follow-up with periodic ECGs and this has important implications in the risk stratification. 12L-Holter recording might avoid 20% of the pharmacological challenges with sodium channel blockers, which are not without risks, and should thus be considered as the first screening test, particularly in children or in presence of borderline diagnostic basal ECG. PMID- 25456873 TI - Usefulness of neutrophil-to-lymphocyte ratio in risk stratification of patients with advanced heart failure. AB - Elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with increased mortality in patients with acute heart failure (HF) and neoplastic diseases. We investigated the association between NLR and mortality or cardiac transplantation in a retrospective cohort of 527 patients presented to the Cleveland Clinic for evaluation of advanced HF therapy options from 2007 to 2010. Patients were divided according to low, intermediate, and high tertiles of NLR and were followed longitudinally for time to all-cause mortality or heart transplantation (primary outcome). The median NLR was 3.9 (interquartile range 2.5 to 6.5). In univariate analysis, intermediate and highest tertiles of NLR had a higher risk than the lowest tertile for the primary outcome and all-causes mortality. Compared with the lowest tertile, there was no difference in the risk of heart transplantation for intermediate and high tertiles. In multivariate analysis, compared with the lowest tertile, the intermediate and high NLR tertiles remained significantly associated with the primary outcome (hazard ratio [HR] = 1.61, 95% confidence interval [CI] 1.10 to 2.37 and HR = 1.55, 95% CI 1.02 to 2.36, respectively) and all-cause mortality (HR = 1.83, 95% CI 1.07 to 3.14 and HR = 2.16, 95% CI 1.21 to 3.83, respectively). In conclusion, elevated NLR is associated with increased mortality or heart transplantation risk in patients with advanced HF. PMID- 25456874 TI - Vascular complications after transcatheter aortic valve implantation and their association with mortality reevaluated by the valve academic research consortium definitions. AB - Vascular complications (VC) after transcatheter aortic valve implantation (TAVI) are reported using various criteria and several access site approaches. We aimed to describe them in a solely percutaneous transfemoral TAVI approach and their association with survival using both the updated Valve Academic Research Consortium (VARC)-2 criteria and the former VARC-1 criteria. From March 2009 to September 2013, 403 consecutive patients at a mean age (+/-SD) of 83 +/- 6 years underwent percutaneous transfemoral TAVI. VC were defined by both VARC-1 and VARC 2 criteria and analyzed separately. Cox proportional hazard ratio models for all cause mortality were adjusted separately as defined by each criteria. VARC-1 defined and VARC-2-defined VC occurred in 71 (18%) and 78 (19%) patients, respectively, with 15 (4%) and 33 (8%) defined as major VC. The difference in frequency of major and minor VC was mainly driven by VARC-2 implementation of major bleeding events. With either VARC definition, patients with minor VC had similar mortality and complications rates as those patients without VC. In multivariate analyses, referenced to patients with minor or no VC, only VARC-1 defined major VC were significantly associated with increased mortality (hazard ratio 3.52; confidence interval 1.5 to 8.4; p = 0.005), whereas VARC-2-defined major VC were found to be only marginally significant (hazard ratio 1.9; confidence interval 0.9 to 3.9; p = 0.08). In conclusion, the implementation of the VARC-2 criteria resulted in a higher rate of reported major VC after TAVI compared with VARC-1 criteria, mainly by the inclusion of major bleeding events and a reduced association with patient mortality. PMID- 25456875 TI - Relation of dyspnea severity on admission for acute heart failure with outcomes and costs. AB - Hospitalization for heart failure (HF) is frequently related to dyspnea, yet associations among dyspnea severity, outcomes, and health care costs are unknown. The aim of this study was to describe the characteristics of patients hospitalized for acute HF by dyspnea severity and to examine associations among dyspnea severity, outcomes, and costs. Registry data for patients hospitalized for HF were linked with Medicare claims to evaluate dyspnea and outcomes in patients >=65 years of age. We classified patients by patient-reported dyspnea severity at admission. Outcomes included length of stay, mortality 30 days after admission, days alive and out of the hospital, readmission, and Medicare payments 30 days after discharge. Of 48,616 patients with acute HF and dyspnea, 4,022 (8.3%) had dyspnea with moderate activity, 19,619 (40.3%) with minimal activity, and 24,975 (51.4%) at rest. Patients with dyspnea with minimal activity or at rest had greater co-morbidities, including renal insufficiency. Greater severity of baseline dyspnea was associated with mortality (moderate activity, 6.3%; minimal activity, 7.6%; at rest, 11.6%) and HF readmission (7.2%, 9.0%, and 9.4%). After multivariate adjustment, dyspnea at rest was associated with greater 30-day mortality and HF readmission, fewer days alive and out of the hospital, longer length of stay, and higher Medicare payments compared with dyspnea with moderate activity. In conclusion, dyspnea at rest on presentation was associated with greater mortality, readmission, length of stay, and health care costs in patients hospitalized with acute HF. PMID- 25456876 TI - Predictors and progression of aortic stenosis in patients with preserved left ventricular ejection fraction. AB - We aimed to characterize the hemodynamic progression of aortic stenosis (AS) in a contemporary unselected cohort of patients with preserved left ventricular ejection fraction. Current guidelines recommend echocardiographic surveillance of hemodynamic progression. However, limited data exist on the expected rate of progression and whether clinical variables are associated with accelerated progression in contemporarily managed patients with AS. We conducted a retrospective analysis of patients presenting with AS and explored the trajectory of AS mean gradient over time using generalized estimating equations and fit a longitudinal linear regression model with adjustment for baseline clinical variables. A total of 1,558 patients (median age 72; interquartile range 65 to 79) having mild (n = 982), moderate (n = 363), or severe AS (n = 213) were included. In patients with mild AS at baseline (n = 983), 303 (31%) had progressed to moderate/severe AS/AVR within 5 years of the index echo. In patients with moderate AS, 159 of 363 (44%) had progressed to severe AS/AVR within 2 years of the index echo. The annual change in mean gradient was dependent on baseline AS severity. Average annual increases in mean gradient were 6.8% (95% confidence interval 6.0 to 7.6) and 7.1% (95% confidence interval 4.8 to 9.3) in patients with mild and moderate AS, respectively. In the subset of patients with mild AS at baseline, age (p = 0.0310) and gender (p = 0.0270) had significant interaction with change in mean gradient over time. In patients with moderate AS, age (p <0.0001), gender (p = 0.0346), renal dysfunction (p = 0.0036), and hyperlipidemia (p = 0.0010) demonstrated significant interaction with change in mean gradient over time. In conclusion, although average disease progression was slower than previously reported, a significant proportion of patients with mild and moderate AS progressed to higher grades within the currently recommended time windows for echocardiographic follow-up. PMID- 25456877 TI - Development of chagas cardiac manifestations among Texas blood donors. AB - Chagas disease, infection with the parasite Trypanosoma cruzi, has recently been identified as an important emerging parasitic disease in the United States. To describe the cardiac abnormalities in T. cruzi-positive blood donors in southeastern Texas, a pilot study of donors who had screened positive from 2007 to 2012 was performed. This one-time assessment included (1) a questionnaire to evaluate the source of infection, cardiac symptoms, and health co-morbidities; (2) electrocardiography; (3) echocardiography if electrocardiographic findings were abnormal; and (4) measurement of a high-sensitivity troponin T biomarker. Of those with confirmed infection, 41% (7 of 17) had electrocardiographic abnormalities consistent with Chagas cardiomyopathy. In addition, 36% (6 of 17) were suspected to be locally acquired cases. High-sensitivity troponin T serum levels increased with cardiac severity. In conclusion, cardiologists should consider Chagas disease in their differential diagnoses for patients who may have clinically compatible electrocardiographic changes or nonischemic cardiomyopathy, even if the patients have no histories of residing in Chagas-endemic countries. PMID- 25456878 TI - Comparison of three contemporary surgical scores for predicting all-cause mortality of patients undergoing percutaneous mitral valve repair with the MitraClip system (from the multicenter GRASP-IT registry). AB - The aim of this study was to explore the adaptability of 3 contemporary surgical scores (Logistic EuroSCORE [LES], EuroSCORE II [ESII], and Society of Thoracic Surgeons Predicted Risk of Mortality [STS-PROM]) for prediction of mortality after percutaneous mitral valve repair with the MitraClip system. A total of 304 patients from the multicenter Getting Reduction of mitrAl inSufficiency by Percutaneous clip implantation in ITaly registry (GRASP-IT) were stratified based on LES, ESII, and STS-PROM tertiles and analyzed by different measurements of discrimination, calibration, and global accuracy with focus on 30-day and 1-, 2-, and 3-year mortality. A statistically significant gradient in the distribution of mortality was observed at all time points with ESII, at 2 years with LES, and at 2 and 3 years with STS-PROM. ESII had the best discrimination at 30 days (C statistic 0.80), which remained acceptable at later follow-up, being significantly superior to that of LES at each time point (p = 0.003 at 30 days, p = 0.005 at 1 year, p = 0.011 at 2 years, and p = 0.029 at 3 years). Compared with STS-PROM, ESII showed better discrimination at 30 days (C-statistic 0.80 vs 0.62, p = 0.023). All scores overpredicted the risk of mortality at 30 days and were miscalibrated at 2 and 3 years. At 1 year, there was a good agreement between the observed and predicted probabilities for ESII and STS-PROM, whereas LES remained overpredictive. ESII showed the best global accuracy at 30 days and 1 year, whereas no notable differences were noted versus LES and STS-PROM at 2 and 3 years. In conclusion, lacking specific tools for risk stratification of patients undergoing MitraClip implantation, ESII holds favorable prognostic characteristics, which makes it a valid surrogate. PMID- 25456879 TI - Predictors of natriuretic peptide non-response in patients hospitalized with acute heart failure. AB - Increasing natriuretic peptide (NP) levels are associated with worse heart failure (HF) outcomes. Predictors of NP nonresponse have not been studied. The aim of this study was to identify predictors of nondecreasing NP levels during episodes of acute HF. A retrospective analysis was conducted in patients prospectively included in a registry of acute HF, with the primary diagnosis of acute HF. The objective under analysis was B-type NP (BNP) response, defined as a >30% decrease in BNP during hospitalization. Percentage of BNP variation was calculated as: % BNP variation = [(admission BNP - discharge BNP)/admission BNP] * 100. A logistic regression analysis was performed to study potential predictors of NP nonresponse. A multivariate model was built. A total of 496 patients were studied: 28.2% were considered nonresponders to the implemented HF treatment strategy. Identified predictors of nonresponse were older age, chronic HF, lower admission systolic blood pressure, anemia, renal dysfunction, and lower sodium on admission, as well as lower admission albumin and lower admission total cholesterol. Admission BNP was not a predictor of response. The only identified independent predictor of nonresponse was a low admission total cholesterol level (cutoff 125 mg/dl), with an odds ratio of 2.55 (95% confidence interval 1.59 to 4.11). This remained valid when the analysis was stratified according to admission BNP (cutoff 2,000 pg/ml) and according to statin use. In conclusion, a low admission total cholesterol level was a strong and independent predictor of BNP nonresponse in patients admitted with acute HF. The ability of cholesterol to predict BNP nonresponse was valid for patients with intrinsically low cholesterol and in those with statin-induced low cholesterol. PMID- 25456880 TI - Potassium toxicity at low serum potassium levels with refeeding syndrome. AB - Refeeding syndrome is a life-threatening condition occurring in severely malnourished patients after initiating feeding. Severe hypophosphatemia with reduced adenosine triphosphate production has been implicated, but little data are available regarding electrolyte abnormalities. In this case, we report electrocardiographic changes consistent with hyperkalemia during potassium replacement after a serum level increase from 1.9 to 2.9 mEq/L. This was reversed by lowering serum potassium back to 2.0 mEq/L. In conclusion, the patient with prolonged malnutrition became adapted to low potassium levels and developed potassium toxicity with replacement. PMID- 25456885 TI - Longitudinal association between habitual walking and fall occurrences among community-dwelling older adults: analyzing the different risks of falling. AB - The purpose of this longitudinal study was to examine the association between habitual walking and multiple or injurious falls (falls) among community-dwelling older adults, by considering the relative risk of falling. A cohort of Japanese community-dwelling older adults (n=535) aged 60-91 years (73.1+/-6.6 year, 157 men and 378 women) who underwent community-based health check-ups from 2008 to 2012 were followed until 2013. Incidence rate of falls between walkers and non walkers was compared separately by the number of risk factors (Groups R0, R1, R2, R3 and R4+). The Cox proportional hazard model was used to assess the association between habitual walking and falls separately by lower- (R<2) and higher- (R>=2) risk groups. In Groups R0 and R1, the incidence of falls was lower in walkers than non-walkers; however, in Groups R2, R3, and R4+, the incidence of falls was higher in walkers. The Cox proportional hazard model showed that habitual walking was not significantly associated with falls (hazard ratio (HR): 0.88, 95% confidence interval (CI): 0.48-1.62) among the lower risk group but that it was significantly associated with increased falls (HR: 1.89, 95% CI: 1.04-3.43) among the higher risk group. The significant interaction between habitual walking and higher risk of falling was found (P<0.05). When individuals have two or more risk factors for falling, caution is needed when recommending walking because walking can actually increase their risk of experiencing multiple or injurious falls. PMID- 25456886 TI - Pro-inflammatory cytokines correlate with classical risk factors for atherosclerosis in the admixed Brazilian older women. AB - AIM: Measurement of inflammatory markers for risk stratification of vascular disorders has been the focus of numerous investigations worldwide, and usually reveals augmented levels of circulating cytokines/chemokines among carriers of classic risk factors for atherosclerosis. Nonetheless, this low-grade inflammatory milieu detected in aged individuals tends to be influenced by body composition. Moreover, cardiovascular risk factors have a complex genetic etiology, and disregarding the genetic heritage may produce spurious results owing to interethnic differences. In this complex scenario, our study was designed to verify the existence and strength of the association between selected mediators of systemic inflammation and classic risk factors of cardiovascular diseases (CVD). METHODS: In a sample of post-menopausal older women, correlation analyses explored the association of circulating levels of IL1alpha, IL1beta, IL8, IL10 and IL12 with atherosclerosis-related clinical/metabolic parameters, using age, body mass index (BMI), genetic ancestry estimates as standard correction factors. Further adjustment for use of therapeutic agents was applied when appropriate. RESULTS: Our analyses revealed association of log10-transformed IL-12 titers with VLDL-c levels (r=.192; p=.002) and with SBP (r-.185; p=.003), and of log10-transformed IL-8 titers with GLY (r=.235; p<.001). CONCLUSION: Interpretation to the results account to a possible dysregulation of the PPAR signaling pathway to explain the association of IL12 and VLDL-c, and to IL8 driven mechanisms to promote dysglycemia. No previous report sought to investigate the relationship between this set of inflammatory markers and classic risk factors for atherosclerosis correcting for the heterogeneity in genetic admixture and body composition of Brazilian post-menopausal women. PMID- 25456887 TI - Supplementing vitamin D through sunlight: associating health literacy with sunlight exposure behavior. AB - PURPOSE OF THE RESEARCH: To test whether health literacy is associated with sunlight exposure behavior, we interviewed 648 Chinese adults aged 65 years or older. METHODS: Using the information-motivation-behavioral skills model and structural equation modeling, we tested whether health literacy was associated with the complex relationships among knowledge about vitamin D, attitudes toward sunlight exposure, doctor recommendations regarding sunlight exposure, and sunlight exposure behavior. RESULTS: Health literacy was directly associated with sunlight exposure (beta=.20, p<.01). Indirect relationships also existed between knowledge and sunlight exposure through health literacy (beta=.46, p<.001) and between attitudes and sunlight exposure through health literacy (beta=-.12, p<.05). The model had good fit (chi(2)/df=2.79; RMSEA=.053, p=.346; CFI=.95; TLI=.92). CONCLUSIONS: Health literacy should be considered when educating older adults about vitamin D supplements and sunlight exposure. Providing relevant knowledge or making doctor recommendations might not be effective. Training should focus on individuals with low health literacy who may be less likely to receive sunlight exposure. PMID- 25456888 TI - Effects of dancing on the risk of falling related factors of healthy older adults: a systematic review. AB - INTRODUCTION: Deficits of balance or postural control in persons of advanced age are one of the factors that influence the risk of falling. The most appropriate treatment approaches and their benefits are still unknown. OBJECTIVE: The aim of this article is to systematically review the scientific literature to identify the therapeutic effects of dancing as a physical exercise modality on balance, flexibility, gait, muscle strength and physical performance in older adults. METHODS: A systematic search of Pubmed, Cochrane Library Plus, PEDro, Science Direct, Dialnet and Academic Search Complete using the search terms "dance", "older", "dance therapy", "elderly", "balance", "gait" and "motor skills". The eligibility criteria were: studies written in English and Spanish, published from January 2000 to January 2013, studies which analyzed the effects of dance (ballroom dance and/or dance based exercise) in older adults over 60 years of age with no disabling disease and included the following variables of study: balance, gait, risk of falls, strength, functionality, flexibility and quality of life. RESULTS: 123 articles were found in the literature. A final selection of seven articles was used for the present manuscript. Although the selected studies showed positive effects on the risk of falling related to factors (balance, gait and dynamic mobility, strength and physical performance), there were some aspects of the studies such as the methodological quality, the small sample size, the lack of homogeneity in relation to the variables and the measurement tools, and the existing diversity regarding the study design and the type of dance, that do not enable us to confirm that dance has significant benefits on these factors based on the scientific evidence. PMID- 25456889 TI - Cognitive function and associated factors among older people in Taiwan: age and sex differences. AB - PURPOSE: The aim of this study was to examine cognitive function and the risk and the protective factors by age and sex among Taiwanese older people. METHODS: The data were from a nation-representative panel of older people in Taiwan. The participants completing both the 2003 and 2007 waves were included for analysis in this study (n=3228). Descriptive analysis and generalized linear model were applied, and the samples were stratified by age groups and by sex. RESULTS: The factors related to higher cognitive function at the intercept included being younger, male, higher education, and doing unpaid work. At the time slope, the age effect and physical function difficulties would reduce the cognitive function across time, while education and providing informational support would increase the cognitive function across time. There were age- and sex-differences in the factors related to cognitive function, particularly on the working status and social participation. CONCLUSION: Different health promotion strategies to target these populations should be accordingly developed. PMID- 25456890 TI - Training older adults on Theory of Mind (ToM): transfer on metamemory. AB - BACKGROUND: Research on aging has shown a significant decline in ToM after 65 years of age. Despite these age-related difficulties, no study has yet investigated the possibility to improve ToM in older adults. To address this gap we tested the efficacy of a conversation-based ToM training with age-appropriate ToM tasks and its transfer effects on metamemory. METHOD: We examined 72 older adults (Mage=67.61 years, SD=6.39 years) assigned to three training conditions: a ToM training, a physical-conversation training and a social-contact group. All participants took part in two 2-h testing and to two 2-h training sessions. RESULTS: Results showed that after the intervention, older adults in the ToM training group improved their mental states' understanding significantly more than participants in the physical-conversation training and in the social-contact groups. Crucially, the positive effect of the ToM intervention generalized to metamemory knowledge. CONCLUSIONS: This is the first study investigating the efficacy of a ToM training and its transfer effect on metacognition in older adults. From a theoretical point of view, it supports the relation between ToM and metamemory. Practical implications of these data are discussed. PMID- 25456891 TI - High sensitive C-reactive protein (hsCRP), cardiovascular events and mortality in the aged: a prospective 9-year follow-up study. AB - OBJECTIVE: The clinical utility of application of hsCRP categorization and the association of hsCRP with vascular disease (VD) events are less studied among the aged. This study investigated whether an elevated hsCRP has an additive effect on conventional vascular risk factors in predicting cardiovascular morbidity and all cause mortality among the aged. METHODS AND RESULTS: a prospective population based study with a 9-year follow-up among persons aged >=64 and without VD and C reactive protein (CRP)<10mg/L at baseline (n=771). Adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs) for VDs and all-cause mortality predicted by hsCRP level were estimated. During the follow-up, there were 151 major VD events, and 217 subjects died. After the adjustment for age and gender or risk factors related to VD events or a metabolic syndrome (MetS), hsCRP was not related to incident VD events (HR 1.14, 95% CI 0.96-1.35, p=.127 or 1.11, 0.94-1.32, p=.212, respectively). hsCRP predicted all-cause mortality after the adjustment for age and gender (1.18, 1.03-1.36, p=.020) and multiple factors (1.16, 1.00-1.33, p=.046) but not beyond conventional risk factors. High risk participants (hsCRP 3.0-9.9mg/L) had higher age and gender adjusted (1.50, 1.07 2.10, p=.018) and tended to have higher risk factor adjusted all-cause mortality (1.41, 1.00-2.00, p=.052) compared with low risk participants (hsCRP<1mg/L). CONCLUSIONS: hsCRP may not be useful in prediction of cardiovascular events. PMID- 25456892 TI - The effect of integrated health management model on the health of older adults with diabetes in a randomized controlled trial. AB - The objective of this study was to evaluate the effect of integrated health management model on the health of older adults with diabetes. The 100 older adults with diabetes who gave informed consent were randomly allocated 1:1 into management and control groups. The integrated health management model was applied in the former while the latter was only given usual care. This model included the following components: health record establishment, health evaluation and health management (such as: diet advice, psychological aspects of health, education/skills training on health self-management, regular blood glucose monitoring, long-term diabetes drug monitoring, etc.). After 18 months, differences in three categories of variables (subjective grading items, objective measurement health indices and health service utilization) between the two groups before and after the intervention were assessed with t-test, chi(2)-test and mixed model analysis. The management group demonstrated improvement on the following variables: health knowledge score, self-evaluated psychological conditions, overall self-evaluated health conditions, diet score, physical activity duration per week, regular blood sugar monitoring, waist-to-hip ratio, diastolic blood pressure and fasting blood sugar, the days of hospital admissions in the preceding 6 months. Mixed model analysis showed that gender, age, self evaluated health status, self-evaluated psychological status, education level and resident status were important factors affecting health indices. This study demonstrated that integrated health management model was effectiveness in improving the health of older adults with diabetes. PMID- 25456893 TI - In vitro activity of potential old and new drugs against multidrug-resistant gram negatives. AB - BACKGROUND: The aim of this study was to evaluate the in vitro susceptibility of MDR gram-negatives bacteria to old drugs such as polymyxin B, minocycline and fosfomycin and new drugs such as tigecycline. METHODS: One hundred and fifty three isolates from 4 Brazilian hospitals were evaluated. Forty-seven Acinetobacter baumannii resistant to carbapenens harboring adeB, blaOxA23, blaOxA51, blaOxA143 and blaIMP genes, 48 Stenotrophomonas maltophilia including isolates resistant to levofloxacin and/or trimethoprim-sulfamethoxazole harboring sul-1, sul-2 and qnrMR and 8 Serratia marcescens and 50 Klebsiella pneumoniae resistant to carbapenens harboring blaKPC-2 were tested to determine their minimum inhibitory concentrations (MICs) by microdilution to the following drugs: minocycline, ampicillin-sulbactam, tigecycline, and polymyxin B and by agar dilution to fosfomycin according with breakpoint criteria of CLSI and EUCAST (fosfomycin). In addition, EUCAST fosfomycin breakpoint for Pseudomonas spp. was applied for Acinetobacter spp and S. maltophilia, the FDA criteria for tigecycline was used for Acinetobacter spp and S. maltophilia and the Pseudomonas spp polymyxin B CLSI criterion was used for S. maltophilia. RESULTS: Tigecycline showed the best in vitro activity against the MDR gram-negative evaluated, followed by polymyxin B and fosfomycin. Polymyxin B resistance among K. pneumoniae was detected in 6 isolates, using the breakpoint of MIC > 8 ug/mL. Two of these isolates were resistant to tigecycline. Minocycline was tested only against S. maltophilia and A. baumannii and showed excellent activity against both. CONCLUSIONS: Fosfomycin seems to not be an option to treat infections due to the A. baumannii and S. maltophilia isolates according with EUCAST breakpoint, on the other hand, showed excellent activity against S. marcescens and K. pneumoniae. PMID- 25456894 TI - Diagnosis and management of deep neck infections in children: the experience of an Italian paediatric centre. AB - Deep neck infection (DNI) is a severe occurrence in children. We've examined the presenting signs and symptoms, the value of single diagnostic procedures, the rate of complications and the impact of the therapeutic options on the final outcome, in children with a DNI. We retrospectively evaluated patients, aged 0-18 years, who were admitted for a DNI, from January 2006 through December 2012, at Regina Margherita Children's Hospital, Turin, Italy. We subdivided them on the basis of type of treatment: pharmacological treatment alone or antimicrobial treatment plus surgery. An univariate analysis has been performed to examine the differences between the two groups. Sixty patients (32 males, 28 females) with diagnosis of DNI were enrolled; 33 children only received medical treatment (group 1), whereas 27 patients underwent also surgical interventions (group 2). The mean abscess size was significantly higher in group 2 than in group 1 (p = 0.01). The predominant organisms were Streptococcus sp. (11 cases, 52.4%, mostly Streptococcus pyogenes). The most frequent antibiotic regimen was a beta lactam alone (either III generation cephalosporin or amoxicillin/clavulanate). The duration of intravenous antibiotic varied between the two groups, without statistical significance (p = 0.052); whereas the oral antibiotic administration was significantly shorter in group 1 than in group 2 (p = 0.0003). Three patients (5%) developed complications. This research confirms that the medical approach, with high doses of intravenous antibiotics for a minimum of 5 days, could be a tolerable and safe option for the treatment of patients with stable condition and/or small DNIs. PMID- 25456895 TI - Comparison of cystatin C and creatinine to determine the incidence of composite adverse outcomes in HIV-infected individuals. AB - BACKGROUND: Cystatin C is an overall biomarker of pathophysiologic abnormalities that accompany chronic kidney disease (CKD). The utility of cystatin C is not fully understood in an HIV-infected population. METHODS: This prospective study investigated 661 HIV-infected individuals for 4 years to determine the incidence of adverse outcomes, including all-cause mortality, cardiovascular disease, and renal dysfunction. The risk of developing the outcomes was discriminated with a 4 color-coded classification in a 3 * 6 contingency table, that combined 3 grades of dipstick proteinuria with 6 grades of estimated glomerular filtration rate (eGFR) calculated using either serum creatinine (eGFRcr) or cystatin C (eGFRcy): green, low risk; yellow, moderately increased risk; orange, high risk; and red, very high risk. The cumulative incidence of the outcomes was assessed by the Kaplan-Meier method, and the association between color-coded risk and the time to outcome was evaluated using multivariate proportional hazards analysis. RESULTS: Compared with eGFRcr, the use of eGFRcy reduced the prevalence of risk >= orange by 0.8%. The adverse outcomes were significantly more likely to occur to the patients with baseline risk category >=orange than those with <= yellow, independent of risk categories based on eGFRcr or eGFRcy. However, in multivariate analysis, risk category >=orange with eGFRcy-based classification was significantly associated with adverse outcomes, but not the one with eGFRcr. CONCLUSIONS: Replacing creatinine by cystatin C in the CKD color-coded risk classification may be appropriate to discriminate HIV-infected patients at increased risk of a poor prognosis. PMID- 25456896 TI - Expression of marA is remarkably increased from the early stage of development of fluoroquinolone-resistance in uropathogenic Escherichia coli. AB - BACKGROUND: Analyses of efflux pumps overexpression and mutations in quinolone resistance determining region (QRDR) in early stage of development of resistance to fluoroquinolones (FQs) are valuable to discuss countermeasures against them. We induced levofloxacin (LVFX)-resistant strains from susceptible uropathogenic Escherichia coli in vitro to analyze the mechanisms of development of FQs resistance. METHODS: 89 strains were exposed to discontinuous elevation of LVFX dose, and mRNA level of efflux pumps and their regulators as well as mutations developed in QRDR of LVFX-resistant strains were analyzed. RESULTS: In 5 strains, a stepwise increase in MIC to LVFX (up to >128 MUg/ml)was observed. Compared to the parent strains, additional mutations in QRDR were observed in the strains developing high MIC. Remarkable increase of marA expression was observed even in the early stage of LVFX-resistance development, and it lasted until high-level resistance was developed. On the other hand, moderate increase in acrB expression but only low increase in yhiU, yhiV, mdfA, tolC and sdiA were observed. CONCLUSIONS: These results suggested that marA expression is a sensitive marker for early detection of development of LVFX-resistance. PMID- 25456897 TI - A novel rat model of incisional surgical site infection model developed using absorbable multifilament thread inoculated with Escherichia coli. AB - The development of an effective rat model of incisional surgical site infection (SSI) has so far proven difficult. In this study, we created a novel incisional SSI model and validated it in terms of both macroscopic and microscopic aspects including its response to treatment using antimicrobial wound-dressing, Aquacel Ag((r)). Wounds were created on the dorsum of rats. 3-0 Vicryl((r)) threads inoculated with Escherichia coli were inserted in the wound beds in the infection group (n = 6). The wounds were closed for two days to induce infection and then opened and covered with polypropylene sheets during the study. Aquacel Ag was placed under the polypropylene sheet in the infected wounds of the Aquacel Ag group rats (n = 6). The wounds in the control group (n = 6) contained sterile Vicryl thread that had not been inoculated with E. coli. The macroscopic appearance, wound area, bacterial counts, and histology of each group were evaluated. The infection group demonstrated significantly lower wound healing (p < 0.001), greater bacterial counts (median [interquartile range] ratings, 2.15 * 10(7) [0.51 * 10(7)-53.40 * 10(7)] vs 2.07 * 10(4) [0.60 * 10(4)-4.45 * 10(4)] CFU/g, respectively; p < 0.01), and severer histological inflammation (p < 0.001) than the control group. The Aquacel Ag group was only able to show significantly better wound healing than the infection group (p < 0.001). The new incisional SSI model exhibited all clinical manifestations of incisional SSI. It could be utilized to assess the effectiveness of newly developed treatments for incisional SSI. PMID- 25456898 TI - 2014 American Association of Endocrine Surgeons presidential address: evolution. PMID- 25456899 TI - Limiting the risks of radiation exposure in diagnostic imaging. PMID- 25456900 TI - The effect of cinacalcet on intraoperative findings in tertiary hyperparathyroidism patients undergoing parathyroidectomy. AB - INTRODUCTION: Tertiary hyperparathyroidism (3HPTH) patients who undergo parathyroidectomy (PTX) are often managed with calcium lowering medications such as cinacalcet (Sensipar) before surgery. Here, we assess how cinacalcet treatment influences intraoperative parathyroid hormone (IOPTH) kinetics and surgical findings in 3HPTH patients undergoing PTX. METHODS: We reviewed retrospectively 113 patients 3HPTH who underwent PTX, 14 of whom were taking cinacalcet and 112 who were not taking the drug. IOPTH levels fitted to linear curves versus time were used to evaluate the role of cinacalcet. RESULTS: Cinacalcet did not correlate with rates of cure (P = .41) or recurrence (P = .54). Patients taking cinacalcet experienced a steeper decrease in IOPTH compared with those not taking the medication (P = .005). Cinacalcet treatment was associated with an increase in rate of hungry bones (P = .04). Weights of the heaviest glands resected (P = .02) and preoperative PTH levels (P = .0004) were greater among patients taking cinacalcet. CONCLUSION: Perioperative cinacalcet treatment in patients with 3HPTH alters IOPTH kinetics by causing a steeper decrease in IOPTH, but does not require modification of the standard IOPTH protocol. Although cinacalcet use does not adversely affect cure rates, it is associated with greater preoperative PTH and an increased incidence of hungry bones, hence serving as an indicator of more severe disease. Cinacalcet does not need to be held before operation. PMID- 25456903 TI - Is central lymph node dissection necessary for parathyroid carcinoma? AB - BACKGROUND: Parathyroid carcinoma is a rare cancer. Unlike other more common malignancies, the importance of lymph node (LN) status remains controversial. The purpose of this study was to determine the relative importance of LN metastases in disease-specific survival (DSS). METHODS: A retrospective review of the Surveillance, Epidemiology, and End Result database was performed on parathyroid carcinoma cases diagnosed between 1988 and 2010. RESULTS: We identified 405 parathyroid carcinoma patients. Among 114 patients with LNs examined at operation, only 12 (10.5%) had positive LNs. Sensitivity analysis found that a tumor size threshold of 3 cm best divided the cohort by DSS. Only tumors >= 3 cm and distant metastasis but not LN metastases were independent prognostic factors on multivariate analysis. When examining factors associated with LN status, only tumors >= 3 cm predicted LN metastasis. LN metastases were 7.5 times more likely in patients with tumors >= 3 cm than those with tumors <3 cm. CONCLUSION: Tumors >= 3 cm were associated with LN metastases in parathyroid carcinoma, but positive LN status was not associated with DSS. Tumor size can potentially risk stratify patients by their risk of LN metastases. PMID- 25456905 TI - Dicer expression and microRNA dysregulation associate with aggressive features in thyroid cancer. AB - BACKGROUND: Altered miRNA expression and down-regulation of Dicer has been shown in various cancers. We investigated Dicer expression and global miRNA environment in correlation with malignant features of thyroid tumors. METHODS: Dicer gene expression was assessed for 22 normal thyroids, 16 follicular adenomas, 28 papillary thyroid cancers (PTCs), 10 tall-cell variants of PTC, 11 follicular variants of PTC, as well as the four thyroid cell lines BCPAP, TPC1, KTC1, and TAD2 via quantitative polymerase chain reaction. BRAF((V600E)) mutation screening was completed for 31 neoplasms. Next-generation sequencing was performed on a subset of PTC and normal thyroid. Protein levels were assessed via Western blotting and immunohistochemistry. RESULTS: Dicer mRNA was down-regulated in malignant thyroid samples and cell lines compared with normal tissues, benign neoplasms, and the fetal cell line TAD2. Decreased Dicer gene expression in malignant tissues was correlated greatly with aggressive features: extrathyroidal extension, angiolymphatic invasion, multifocality, lymph node and distant metastasis, recurrence, and BRAF((V600E)) mutation. Conversely, increased levels of Dicer protein were observed in malignant tissues and cell lines. Sequencing yielded 19 differentially expressed miRNAs. Eight samples had a nonsignificant a global down-regulation in malignant tissues. CONCLUSION: Dysregulation of Dicer and possibly altered expression of miRNAs are associated with aggressive features in thyroid cancers. These findings suggest that disruption in normal miRNA processing involving Dicer may play a role in thyroid cancer progression. PMID- 25456907 TI - Preliminary whole-exome sequencing reveals mutations that imply common tumorigenicity pathways in multiple endocrine neoplasia type 1 patients. AB - BACKGROUND: Whole-exome sequencing studies have not established definitive somatic mutation patterns among patients with sporadic hyperparathyroidism (HPT). No sequencing has evaluated multiple endocrine neoplasia type 1 (MEN1)-related HPT. We sought to perform whole-exome sequencing in HPT patients to identify somatic mutations and associated biological pathways and tumorigenic networks. METHODS: Whole-exome sequencing was performed on blood and tissue from HPT patients (MEN1 and sporadic) and somatic single nucleotide variants (SNVs) were identified. Stop-gain and stop-loss SNVs were analyzed with Ingenuity Pathways Analysis (IPA). Loss of heterozygosity (LOH) was also assessed. RESULTS: Sequencing was performed on 4 MEN1 and 10 sporadic cases. Eighteen stop-gain/stop loss SNV mutations were identified in 3 MEN1 patients. One complex network was identified on IPA: Cellular function and maintenance, tumor morphology, and cardiovascular disease (IPA score = 49). A nonsynonymous SNV of TP53 (lysine-to glutamic acid change at codon 81) identified in a MEN1 patient was suggested to be a driver mutation (Cancer-specific High-throughput Annotation of Somatic Mutations; P = .002). All MEN1 and 3/10 sporadic specimens demonstrated LOH of chromosome 11. CONCLUSION: Whole-exome sequencing revealed somatic mutations in MEN1 associated with a single tumorigenic network, whereas sporadic pathogenesis seemed to be more diverse. A somatic TP53 mutation was also identified. LOH of chromosome 11 was seen in all MEN1 and 3 of 10 sporadic patients. PMID- 25456909 TI - A practical method to determine the site of unknown primary in metastatic neuroendocrine tumors. AB - INTRODUCTION: The site of a primary neuroendocrine tumor (NET) tumor is unknown before treatment in approximately 20% of small bowel (SBNET) and pancreatic (PNET) cases despite extensive workup. It can be difficult to discern a PNET from an SBNET on hematoxylin and eosin stains, and thus, more focused diagnostic tests are required. Immunohistochemistry (IHC) and gene expression profiling are two methods used to identify the tissue of origin from biopsied metastases. METHODS: Tissue microarrays were created from operative specimens and stained with up to seven antibodies used in the NET-specific IHC algorithm. Expression of four genes for differentiating between PNETs and SBNETs was determined by quantitative polymerase chain reaction and then used in a previously validated gene expression classifier (GEC) algorithm designed to determine the primary site from gastrointestinal NET metastases. RESULTS: The accuracy of the IHC algorithm in identifying the primary tumor site from a set of 37 metastases was 89%, with only one incorrect call. Three other samples were indeterminate as the result of pan negative staining. The GEC's accuracy in a set of 136 metastases was 94%. The algorithm identified the primary tumor site in all cases in which IHC failed. CONCLUSION: Performing IHC, followed by GEC for indeterminate cases, identifies accurately the primary site in SBNET and PNET metastases in virtually all patients. PMID- 25456911 TI - Metastatic carcinoid: don't forget the surgical consultation. PMID- 25456912 TI - Expanded criteria for carcinoid liver debulking: Maintaining survival and increasing the number of eligible patients. AB - BACKGROUND: Cytoreduction of carcinoid liver metastases typically aims for >= 90% debulking in patients without extrahepatic disease. Data on the impact of less restrictive resection criteria and other clinical and tumor-specific factors on outcomes are limited. METHODS: Records of carcinoid patients undergoing liver debulking from 2007 to 2011 were reviewed. Debulking threshold was 70%, extrahepatic disease did not preclude cytoreduction, and positive margins were allowed. Kaplan-Meier liver progression-free (PFS) and disease-specific (DSS) survival were calculated and compared by log-rank analysis and statistical significance of differences in distributions of factors between patient groups was determined by chi-squared analysis. RESULTS: Fifty-two patients were identified. Complete resection of intrahepatic and extrahepatic gross disease was achieved in 12 patients. All primaries reviewed were low grade, but one third of patients had at least one intermediate-grade metastasis. Fifteen patients (29%) had liver progression; median PFS was 72 months. Five-year DSS was 90%, with all deaths from liver failure. Only age was an important prognostic factor for PFS and DSS. Five-year DSS for patients <50 years was 73% and was 97% for patients 50 or older (P = .03). CONCLUSION: The use of expanded criteria for debulking resulted in 90% 5-year DSS. Although younger age portends a poorer prognosis, the favorable PFS and DSS justify also using expanded criteria in this subgroup. PMID- 25456914 TI - A novel staging system for adrenocortical carcinoma better predicts survival in patients with stage I/II disease. AB - BACKGROUND: Current American Joint Committee on Cancer/International Union against Cancer (AJCC/UICC) and European Network for the Study of Adrenal Tumors staging for adrenocortical carcinoma (ACC) have not shown a survival difference between patients with stage I/II disease. This study evaluates current staging systems for survival prediction using a larger cohort and assesses whether incorporating age into ACC staging improves survival predictions. METHODS: Patients in the National Cancer Data Base (1985-2006) with a diagnosis of ACC were identified and staged using a novel TNM-A staging system: Stage I (T1/T2N0M0, age <= 55), stage II (T1/T2N0M0, age >55), stage III (T1/T2N1M0 or T3/T4N0-N1M0, any age), or stage IV (any T any NM1, any age). Differences in overall survival (OS) by stage were compared using a Cox proportional hazards model. RESULTS: Staging was derived for 1,579 of 3,262 patients. Median age was 54 years; mean tumor size was 11.6 cm. Using current staging, differences in 5 year OS was observed only between patients with stages II/III and III/IV ACC. With TNM-A staging, differences in 5-year OS between all stages was significant (I/II [P < .003], II/III [P < .0001], III/IV [P < .0001]). CONCLUSION: A staging system that incorporates patient age better predicts 5-year OS among patients with stages I/II ACC. Consideration should be given to including age in staging for ACC, because it may better inform providers about treatment and prognosis. PMID- 25456916 TI - Aldosteronoma resolution score predicts long-term resolution of hypertension. AB - BACKGROUND: The Aldosteronoma Resolution Score (ARS) takes into consideration four, readily available, preoperative clinical parameters in predicting the likelihood of resolution of hypertension in patients 6 months after undergoing unilateral adrenalectomy for aldosterone-producing adenoma (APA). We sought to determine the durability of this predictive model after 1 year. METHODS: Sixty patients who underwent unilateral adrenalectomy for APA at a single institution between 2004 and 2013 were reviewed retrospectively. Patients who were normotensive without any antihypertensive medication requirement at greater than 1-year follow-up were considered to have complete resolution of hypertension. RESULTS: Forty-seven patients had data available for analysis. Median follow-up was 1,135 days (371-3,202). Forty-five percent of patients had complete resolution, 45% had improvement, and 10% had no improvement in hypertension. Applying the ARS, we found there was complete resolution of hypertension in 73% of patients with ARS 4-5, 53% of patients with ARS 2-3, and 24% of patients with ARS 0-1 compared with 75% (P = .9), 46% (P = .66), and 28% (P = .76), respectively, in the original cohort used to create the ARS. CONCLUSION: Most patients (90%) have long-term improvement or complete resolution of hypertension after unilateral adrenalectomy for APA. The ARS predicts accurately a patient's likelihood of complete resolution of hypertension beyond 1 year. PMID- 25456918 TI - Long-term blood pressure control in patients undergoing adrenalectomy for primary hyperaldosteronism. AB - BACKGROUND: Data on long-term blood pressure (BP) control after adrenalectomy for primary hyperaldosteronism are limited. We analyzed long-term outcomes to identify factors predictive of cure. METHODS: We performed a retrospective cohort study of patients undergoing adrenalectomy for primary hyperaldosteronism (1997 2013). BP and antihypertensive medications were assessed at long-term follow-up (>= 12 months). Primary outcome was cure, defined as normotension off antihypertensives. RESULTS: Of 85 patients, 15.3% (n = 13) were cured, 54.1% (n = 46) were normotensive while remaining on anti-hypertensives, and 30.6% (n = 26) were hypertensive. Younger age (P = .011), female sex (P < .001), lesser body mass index (P = .018), shorter duration of hypertension (P = .002), lower creatinine (P = .001), and fewer preoperative antihypertensive medications (P < .001) were associated with cure. Female sex, body mass index <= 25 kg/m(2), hypertension <5 years, creatinine <= 0.8 mg/dL, and <2 antihypertensives were incorporated into a scoring system. For a score of 0-1 (n = 61) the cure rate was 3%; 100% of patients with a score of 4-5 (n = 3) were cured. This scoring system performed comparably to the Aldosterone Resolution Score, which has been used to evaluate short-term postoperative outcomes. CONCLUSION: This is the largest study to identify factors associated with long-term BP control after adrenalectomy and incorporate these into a scoring system. These data provide a potential tool to guide preoperative patient counseling. PMID- 25456920 TI - Hypoglycemia after resection of pheochromocytoma. AB - BACKGROUND: Hypoglycemia after resection of pheochromocytoma is a rare and poorly understood complication thought to be secondary to rebound hyperinsulinemia and increased peripheral glucose uptake. We examined the incidence of this complication and aimed to identify predisposing risk factors. METHODS: Patients who underwent pheochromocytoma resection between 1993 and 2013 at 2 large academic medical centers were identified retrospectively from a research patient data registry. The primary end point was postoperative hypoglycemia defined as blood glucose <55 mg/dL. RESULTS: A total of 213 patients underwent resection of pheochromocytoma for a total of 215 operations. Nine patients (4.2%) experienced postoperative hypoglycemia, with 8 of 9 episodes occurring in the first 24 hours. Patients who developed hypoglycemia were more likely to have greater preoperative 24-hour urinary metanephrine (4,726 vs 2,461 MUg/24 h, P = .05) and experienced longer operative times (270 vs 142 minutes, P < .01) with larger neoplasms (7.6 vs 4.6 cm, P = .02). Postoperatively, patients with hypoglycemia required intensive care level monitoring more frequently (88.9% vs 34.5%, P < .01), but there was no difference in duration of hospital stay (5 vs 3 days, P = .10). CONCLUSION: Our data demonstrate that hypoglycemia is a rare complication after resection of pheochromocytoma and may be more common in patients with epinephrine predominant neoplasms and longer operative times. PMID- 25456922 TI - Both preoperative alpha and calcium channel blockade impact intraoperative hemodynamic stability similarly in the management of pheochromocytoma. AB - BACKGROUND: Alpha-blockade is the standard management preoperatively to prevent intraoperative hemodynamic instability (IHD) during resection of a pheochromocytoma. Calcium channel blockers also have been shown to lessen the risk of IHD. We aim to determine differences between these classes of antihypertensive agents in minimizing IHD. METHODS: This was a retrospective analysis from a tri-institutional database. Inclusion criteria were unilateral transabdominal adrenalectomy for pheochromocytomas between 2002 and 2012. IHD was defined as at least one systolic blood pressure (SBP) measurement >160 mm Hg and at least one episode of mean arterial pressure 60 mm Hg. RESULTS: A total of 155 patients were included: 110 receiving calcium channel blockers, 41 alpha blockade, and 4 no medication. Intraoperatively, mean maximal SBP was less after alpha-blockade (P < .0001) as well as the incidence and duration of episodes of SBP >200 mm Hg (P < .01); however, severe hypotensive episodes (MAP <60 mm Hg) were more frequent (P < .001) and longer (P < .0001) with alpha-blockade. Consequently, intraoperative vasoactive drugs were used more frequently (P = .03), and mean fluid volume infused was larger (P < .001). Fifty-four patients had IHD, but these were independent of type of preoperative medication used. Familial disease was the only independent predictor of IHD. CONCLUSION: IHD was independent of type of preoperative medical management but was dependent on familial disease. These findings broaden options for clinicians in the preoperative management of pheochromocytoma. PMID- 25456924 TI - Readmission after thyroidectomy and parathyroidectomy: What can we learn from NSQIP? PMID- 25456925 TI - Risk factors for 30-day hospital readmission after thyroidectomy and parathyroidectomy in the United States: An analysis of National Surgical Quality Improvement Program outcomes. AB - BACKGROUND: The 30-day readmission rate is a quality metric under the Affordable Care Act. Readmission rates after thyroidectomy and parathyroidectomy and associated factors remain ill-defined. We evaluated patient and perioperative factors for association with readmission after thyroidectomy and parathyroidectomy. METHODS: The American College of Surgeons National Surgical Quality Improvement Program Participant Use File (2011) data for thyroid (n = 3,711) and parathyroid (n = 3,358) resections were analyzed. Patient- and operation-related factors were assessed by univariate and multivariate analyses. RESULTS: Among 7,069 patients, 30-day readmission rate was 4.0%: 4.1% after thyroidectomy and 3.8% after parathyroidectomy. Significant associations for 30 day readmission included declining functional status (odds ratio [OR], 6.4-10.1), preoperative hemodialysis (OR, 2.6; 95% CI, 1.5-4.7), malnutrition (OR, 3.4; 95% CI, 1.2-10.1), increasing American Society of Anesthesiologists class (OR 1.3 4.7), unplanned reoperation (OR, 61.6), and length of stay (LOS) <24 hours (OR, 0.61; 95% CI, 0.45-0.85; all P < .05). Readmission was associated with greater total and postoperative LOS and major postoperative complications, including renal insufficiency (all P < .01). CONCLUSION: Thirty-day readmission after cervical endocrine resection occurs in 4% of patients. Discharge within 24 hours of operation does not affect the likelihood of readmission. Risk factors for readmission are multifactorial and driven by preoperative conditions. Decreasing the index hospital stay and preventing major postoperative complications may decrease readmissions and improve quality metrics. PMID- 25456927 TI - Risk scoring can predict readmission after endocrine surgery. AB - BACKGROUND: Hospitals and surgeons simultaneously are pressured to decrease readmissions and duration of stay. We hypothesized that readmissions after endocrine surgery could be predicted by using a novel risk-score. METHODS: The National Surgical Quality Improvement Program database was queried for cervical endocrine operations performed during 2011 and 2012. The primary end point was unplanned readmission within 30 days. Multivariable logistic regression was used to create and validate a scoring system to predict unplanned readmissions. RESULTS: Overall, 34,046 cases were included with a readmission rate of 2.8% (n = 947). The most frequent reasons for readmission were hypocalcemia (32.4%) surgical-site infection (8.4%), and hematoma (8.0%) (2012 data only). The readmission risk score was created using the following factors: thyroid malignancy, hypoalbuminemia, renal insufficiency, American Society of Anesthesiologists class, and duration of stay >1 day. Predicted readmission rate by number of risk factors was 1.7 % for 0 risk factors, 3.2% for 1 risk factor (5 11 points), 5.8% for 2 risk factors, 10.5% for 3 risk factors, and 18.0% for 4 risk factors. The model had good predictive ability with c = 0.646. CONCLUSION: Readmissions after cervical endocrine operations can be predicted. This risk score could be used to direct resource use for preoperative, inpatient, and outpatient care delivery to reduce readmissions. PMID- 25456929 TI - Streamlining variability in hospital charges for standard thyroidectomy: Developing a strategy to decrease waste. AB - BACKGROUND: We assessed the efficiency, consistency, and appropriateness of perioperative processes for standard (total) thyroidectomy and devised a valuable strategy to decrease variability and waste. METHODS: Our multidisciplinary team evaluated <23-hour stay standard thyroidectomy performed by 3 surgical endocrinologists. We used the nominal group technique, process flowcharts, and root cause analysis to evaluate 6 perioperative processes. Anticipated decreases in costs, charges, and resources from improvements were calculated. RESULTS: Median total charge for standard thyroidectomy was $27,363 (n = 80; $48,727 variation). Perioperative coordination between surgery and anesthesia clinics could eliminate unnecessary testing (potential decrease in charges of $1,505). Nonoperating room time was less in the outpatient operating room (43 vs 52 minutes; P < .001). Consistent scheduling could decrease charges by $585.49 per case. By decreasing 20% of nondisposable instruments on the surgical tray, we could decrease sterile processing costs by $13.30 per case. Modification of postoperative orders could decrease charges by $643 per patient. Overall, this comprehensive analysis identified an anticipated decrease in cost/charge of >$200,000 annually. CONCLUSION: Perioperative process analyses revealed wide variability for a single, presumed uniform procedure. Systematic assessment helped to identify opportunities to improve efficiency, decrease unnecessary waste and procedures/instrument usage, and focus on patient-centered, quality care. This multidisciplinary strategy could substantially decrease costs/charges for common operative procedures. PMID- 25456931 TI - Surgeon volume and adequacy of thyroidectomy for differentiated thyroid cancer. AB - INTRODUCTION: We aimed to determine influence of surgeon volume on (1) frequency of appropriate initial surgery for differentiated thyroid cancer (DTC) and (2) completeness of resection. METHODS: We reviewed all initial thyroidectomies (Tx; lobectomy and total) performed in a health system during 2011; surgeons were grouped by number of Tx cases per year. For patients with histologic DTC >= 1 cm, surgeon volume was correlated with initial extent of the operation, and markers of complete resection including uptake on I(123) prescan, thyrotropin-stimulated thyroglobulin levels, and I(131) dose administered. RESULTS: Of 1,249 patients who underwent Tx by 42 surgeons, 29% had DTC >= 1 cm without distant metastasis. At a threshold of >= 30 Tx per year, surgeons were more likely to perform initial total Tx for DTC >= 1 cm (P = .01), and initial resection was more complete as measured by all 3 quantitative markers. For patients with advanced stage disease, a threshold of >= 50 Tx per year was needed before observing improvements in I(123) uptake (P = .004). CONCLUSION: Surgeons who perform >= 30 Tx a year are more likely to undertake the appropriate initial operation and have more complete initial resection for DTC patients. Surgeon volume is an essential consideration in optimizing outcomes for DTC patients, and even higher thresholds (>= 50 Tx/year) may be necessary for patients with advanced disease. PMID- 25456933 TI - Endocrine surgery in present-day academia. AB - BACKGROUND: Endocrine surgery is a specialty that is evolving constantly. In this study, we sought to delineate the practice patterns of surgeons taking care of endocrine diseases in present-day academic centers. METHODS: A review of the Faculty Practice Solutions Center database was conducted for the years 2005, 2009, and 2013. Practice patterns were determined by International Classification of Diseases, 9th Revision and Current Procedural Terminology codes, and analyzed for practice composition, regional variability, and volume of endocrine operations. RESULTS: Of 97 national academic centers, 52 were identified to have 120 practicing American Association of Endocrine Surgeons (AAES) surgeons in the study. On average, endocrine operations comprise ~65% of the AAES surgeon's practice, and 51% are considered high-volume surgeons for thyroidectomy, parathyroidectomy, and adrenalectomy. Most non-AAES surgeons who perform endocrine operations are otolaryngologists (24.5%) and other general surgeons (18.5%). Overall, non-AAES surgeons perform the majority of endocrine operations at academic institutions (61.6%), and low-volume surgeons perform most of these operations (55.6%). CONCLUSION: Research has shown that high-volume surgeons have improved outcomes. Even in academia, however, the majority of endocrine operations are performed by low-volume surgeons, suggesting that there is an opportunity for expanding the number of surgeons with expertise in endocrine surgery in present-day academic centers. PMID- 25456935 TI - Preoperative laryngoscopy in thyroid surgery: Do patients' subjective voice complaints matter? AB - BACKGROUND: Although routine preoperative laryngoscopy has been standard practice for many thyroid surgeons, there is recent literature that supports selective laryngoscopy. We hypothesize that patients' preoperative voice complaints do not correlate well with abnormalities seen on preoperative laryngoscopy. METHODS: A retrospective chart review of a 3-year, single-surgeon experience was performed. Records of patients undergoing thyroid surgery were reviewed for patient voice complaints, prior neck surgery, surgeon-documented voice quality, and results of laryngoscopy. RESULTS: Of 464 patients, 6% had abnormal laryngoscopy findings, including 11 cord paralyses (2%). Preoperatively, 39% of patients had voice complaints, but only 10% had a corresponding abnormality on laryngoscopy. Only 4% of patients had a surgeon-documented voice abnormality with 72% corresponding abnormalities on laryngoscopy, including 8 cord paralyses. When eliminating patient voice complaints and using only history of prior neck surgery and surgeon documented voice abnormality as criteria for preoperative laryngoscopy, only 1 cord paralysis is missed and sensitivity (91%) and specificity (86%) were high. Also, when compared with routine laryngoscopy, 84% fewer laryngoscopies are performed. CONCLUSION: When using patients' voice complaints as criteria for preoperative laryngoscopy, the yield is low. We recommend using surgeon documented voice abnormalities and history of prior neck surgery as criteria for preoperative laryngoscopy. PMID- 25456937 TI - Comparable outcomes for patients with pT1a and pT1b differentiated thyroid cancer: Is there a need for change in the AJCC classification system? AB - INTRODUCTION: The current American Joint Committee on Cancer TNM classification for differentiated thyroid cancer (DTC) separates T1 status into T1a and T1b based on a 1-cm cutoff for maximal tumor dimension. In 2009, the American Thyroid Association recommended total thyroidectomy for tumors >1 cm in contrast to the possibility of lobectomy for tumors <= 1 cm. Our aim was to investigate the prognostic significance of a 1-cm tumor cutoff. METHODS: From an institutional database of 3,664 patients with DTC, 1,522 patients with T1 tumors without neck disease or distant metastases were identified. Patient, tumor, and treatment characteristics were compared. Disease-specific survival (DSS) and recurrence free survival (RFS) outcomes were analyzed. RESULTS: Total thyroidectomy rates were similar between patients with T1a and T1b tumors (P = .307). With a median follow-up of 46 months (range, 1-320), there were no disease-specific deaths in the T1a or T1b groups. In total, 18 patients (1.2%) experienced a recurrence. Five-year RFS was comparable for patients with T1a and T1b tumors (98.6 vs 98.6%; P = .224). CONCLUSION: T1a and T1b tumors have similar prognosis both in terms of DSS and RFS. It seems that a distinction between tumors of <1 and >1 cm is of no prognostic benefit. PMID- 25456939 TI - The utility of lymph node mapping sonogram and thyroglobulin surveillance in post thyroidectomy papillary thyroid cancer patients. AB - BACKGROUND: The American Thyroid Association recommends lymph node mapping (LNM) ultrasonography 6-12 months after thyroidectomy for patients with papillary thyroid cancer (PTC). The yield of LNM over thyroglobulin (TG) screening is not well defined. We sought to investigate this relationship. METHODS: Post thyroidectomy LNM was performed on 163 patients with PTC. LNM was considered positive based on these criteria: Loss of fatty hilum (LOFH), microcalcifications, hypervascularity, architectural distortion, or short axis (>8 mm). Serum TG levels were compared to LNM and fine needle aspiration (FNA). RESULTS: Sixty-nine patients had suspicious LNM (42%) and 17 had PTC on FNA (25%). There were 135 suspicious lymph nodes described with malignant nodes found in 6 of 65 patients (9%) with LOFH, 13 of 18 patients (76%) with microcalcifications, 11 of 12 patients (92%) with hypervascularity, 16 of 28 patients (52%) with architectural distortion, and 4 of 7 patients (52%) with enlarged size on FNA. The positive predictive value of LNM was 0.34, increasing to 0.66 when LOFH was excluded. Among 152 patients with documented TG data, LNM identified cervical nodal metastasis in 4 patients with TG < 0.5 pg/mL (anti-TG antibody negative, thyroid-stimulating hormone suppressed). Of the 15 patients with positive anti-TG antibody, 3 with recurrence were found on LNM. CONCLUSION: LNM can detect recurrent PTC when TG level is undetectable, and LOFH is a low yield sonographic characteristic. PMID- 25456941 TI - Reappraisal of lymphatic mapping for midgut neuroendocrine patients undergoing cytoreductive surgery. AB - BACKGROUND: We previously reported that midgut neuroendocrine tumors (NETs) often develop alternative lymphatic drainage owing to lymphatic obstructions from extensive mesenteric lymphadenopathy, making intraoperative lymphatic mapping mandatory. We hypothesize that this innovative approach needs a longer term validation. METHODS: We updated our results by reviewing 303 patients who underwent cytoreduction from November 2006 to October 2011. Of these patients, 112 had lymphatic mappings and 98 were for midgut NET primaries. Among them, 77 mappings were for the initial cytoreduction and 35 were for reexploration and further cytoreduction. The operative findings, pathology reports, and long-term surgical outcomes were reviewed. RESULTS: Lymphatic mapping changed traditional resection margins in 92% of patients. Of the 35 patients who underwent reexploration without initial mapping, 19 (54%) showed a recurrence at or near the anastomotic sites. In contrast, none of the 112 mapped patients had shown signs of recurrence in a 1- to 5-year follow-up. Additionally, 20 of 45 ileocecal valves (44.4%) were spared in patients whose tumors were at the terminal ileum that, traditionally, would call for a right hemicolectomy. CONCLUSION: With a longer follow-up, lymphatic mapping has proven to be a safe and effective way to prevent local recurrences and preserve the ileocecal valve for selected patients. PMID- 25456943 TI - Comparison of tumor markers for predicting outcomes after resection of nonfunctioning pancreatic neuroendocrine tumors. AB - BACKGROUND: This study compares the predictability of 5 tumor markers for distant metastasis and mortality in pancreatic neuroendocrine tumors (PNETs). METHODS: A total of 128 patients who underwent pancreatectomy for nonfunctioning PNETs between 1998 and 2011 were evaluated. Tumor specimens were stained via immunochemistry for cytoplasmic and nuclear survivin, cytokeratin 19 (CK19), c KIT, and Ki67. Univariate and multivariate regression analyses and receiver operating characteristics curve were used to evaluate the predictive value of these markers. RESULTS: A total of 116 tumors (91%) were positive for cytoplasmic survivin, 95 (74%) for nuclear survivin, 85 (66.4%) for CK19, 3 for c-KIT, and 41 (32%) for Ki67 >3%. Twelve (9%) tumors expressed none of the markers. Survivin, CK19, and c-KIT had no substantial effect on distant metastasis or mortality. Age >55 years, grade 3 histology, distant metastasis, and Ki67 >3% were associated with mortality (P < .05). A cut-off of Ki67 >3% was the best predictor (83%) of mortality with an area under the curve of 0.85. Ki67 >3% also predicted occurrence of distant metastases with odds ratio of 9.22 and 95% confidence interval of 1.55-54.55 (P < .015). CONCLUSION: Of the 5 markers studied, only Ki67 >3% was greatly associated with distant metastasis and death. Survivin, CK19, and c-KIT had no prognostic value in nonfunctioning PNETs. PMID- 25456945 TI - Peritoneal carcinomatosis from small intestinal neuroendocrine tumors: Clinical course and genetic profiling. AB - BACKGROUND: One-fifth of all patients with small-intestinal neuroendocrine tumors (SI-NETs) present with or develop peritoneal carcinomatosis (PC). Our aim was to determine the prognosis and genetic profiles of tumors in patients with PC compared with tumors in patients without PC. METHODS: We included SI-NET patients (cases with PC, n = 73, and controls without PC, n = 468) who underwent operation between 1985 and 2012. The Lyon prognostic index was used to correlate the amount of PC to survival. DNA samples from patients with (n = 8) and without (n = 7) PC were analyzed with a single-nucleotide polymorphism array (HumanOmni2.5 BeadChip, Illumina) to investigate genetic disparities between groups. RESULTS: Patients with PC had poorer survival (median 5.1 years) than controls (11.1 years). An advanced postoperative Lyon prognostic index was a negative prognostic marker for survival by multivariable analysis (P = .042). Patients with and without PC clustered differently based on loss of heterozygosity and copy number variation data from single-nucleotide polymorphism array of the primary tumors (P = .042). CONCLUSION: SI-NET patients with PC have poor survival, which diminishes with increasing PC load after surgery. Clustering based on copy number variation and loss of heterozygosity data suggests different genotypes in primary tumors comparing patients with and without PC. PMID- 25456947 TI - Predictors of recurrence in pheochromocytoma. AB - BACKGROUND: The recurrence rate of pheochromocytoma after adrenalectomy is 6.5 16.5%. This study aims to identify predictors of recurrence and optimal biochemical testing and imaging for detecting the recurrence of pheochromocytoma. METHODS: In this retrospective study we reviewed all patients who underwent adrenalectomy for pheochromocytoma during a 14-year period at a single institution. RESULTS: One hundred thirty-five patients had adrenalectomy for pheochromocytoma. Eight patients (6%) developed recurrent disease. The median time from initial operation to diagnosis of recurrence was 35 months. On multivariate analysis, tumor size >5 cm was an independent predictor of recurrence. One patient with recurrence died, 4 had stable disease, 2 had progression of disease, and 1 was cured. Recurrence was diagnosed by increases in plasma and/or urinary metanephrines and positive imaging in 6 patients (75%), and by positive imaging and normal biochemical levels in 2 patients (25%). CONCLUSION: Patients with large tumors (>5 cm) should be followed vigilantly for recurrence. Because 25% of patients with recurrence had normal biochemical levels, we recommend routine imaging and testing of plasma or urinary metanephrines for prompt diagnosis of recurrence. PMID- 25456949 TI - Surgery is associated with improved survival for adrenocortical cancer, even in metastatic disease. AB - BACKGROUND: Adrenocortical carcinoma (ACC) is a rare but lethal tumor. Predictors of survival include earlier stage at presentation and complete operative resection. We assessed effect of treatment and demographic variables on survival. METHODS: ACC cases were abstracted from the California Cancer Registry and Office of Statewide Health Planning and Development (1999-2008). Predictors included patient demographics, comorbidities, tumor size, stage, and treatment (none, surgery, chemotherapy and/or radiation [CRT], and surgery plus CRT). RESULTS: We studied 367 patients with median tumor size of 10 cm. At presentation, 37% had localized, 17% had regional, and 46% had metastatic disease. Median survival was 1.7 years (7.4 years local, 2.6 years regional, and 0.3 years metastatic, P < .0001). One-year and 5-year survival was: 92%/62% (local); 73%/39% (regional); and 24%/7% (metastatic). Increased age (hazard ratio [HR] 1.16) and Cushing's syndrome (HR 1.66) worsened survival (P < .05). Low socioeconomic status worsened survival in local and regional disease (P < .05). In multivariable regression, both surgery (regional HR 0.13; metastatic HR 0.52) and surgery plus CRT (regional HR 0.15; metastatic HR 0.31) improved survival compared with no treatment (P < .02). CONCLUSION: In ACC, surgery is associated with improved survival, even in metastatic disease. Surgery should be considered for select patients as part of multimodality treatment. PMID- 25456951 TI - SIN1, a critical component of the mTOR-Rictor complex, is overexpressed and associated with AKT activation in medullary and aggressive papillary thyroid carcinomas. AB - BACKGROUND: Mammalian target of rapamycin (mTOR) forms 2 active complexes in the cell: the rapamycin-sensitive mTOR-Raptor (mTORC1) and the rapamycin-insensitive mTOR-Rictor (mTORC2). The latter activates AKT kinase, which promotes tumor cell survival and proliferation by multiple downstream targets. Mammalian stress activated protein kinase interacting protein 1 (SIN1), an essential subunit of the mTORC2 complex, maintains the integrity of the complex and substrate specificity and regulates Akt activation. The role of mTOR-Rictor complex activation in thyroid carcinogenesis remains unknown. Therefore, we investigated expression patterns of Sin1 in the cells lines of thyroid carcinoma and tumors and their association with AKT activation, histologic type, and tumor aggressiveness. METHODS: Tissue specimens from 42 patients with thyroid cancer, including follicular (5), papillary (18), medullary (16), and poorly differentiated (3) carcinomas were analyzed via immunohistochemistry for SIN1 expression and AKT phosphorylation at Ser473 residue (Ser473-p-AKT). Eight of 18 papillary carcinomas were aggressive histologic variants. In addition, expression of Sin1 and activation of AKT kinase were analyzed in fresh-frozen tissue samples (normal/tumor), primary cell cultures (papillary thyroid carcinoma [PTC]), and an established thyroid cancer cell line (medullary thyroid carcinoma) by Western blotting. RESULTS: With immunohistochemistry, we found that Sin1 was overexpressed in medullary thyroid carcinomas and aggressive variants of papillary thyroid carcinoma compared with conventional papillary and follicular carcinomas (P < .001). Sin1 expression correlated with AKT activation in the entire study group (P = .002). Using Western blot analysis, we found that Sin1 and p-AKT were detected at a greater level in cultured primary cells from aggressive PTC compared with conventional PTC as well as in cell lines of medullary and anaplastic thyroid carcinoma. High expression levels of SIN1 were detected in papillary thyroid carcinomas compared with benign nodules in immunoblots in which we used fresh-frozen patient samples. Two of the Sin1 protein isoforms, p76 and p55, were detected predominantly in PTC samples. CONCLUSION: Sin1, a critical factor of the mTORC2 complex is overexpressed in clinically aggressive thyroid cancer types and is associated strongly with activation of AKT kinase. Sin1-dependent AKT activation might represent a target for experimental therapy. PMID- 25456953 TI - E-selectin expression and BRAF status in papillary thyroid carcinomas: Correlation with clinicopathologic features. AB - BACKGROUND: Cell adhesion molecules, represented by the immunoglobulin family and selectins, play an important role in the progression of cancer. A correlation between selectins and tumor aggressiveness has been demonstrated in several reports. METHODS: Eighty-eight patients (mean age, 41.0 +/- 14 years) with papillary thyroid carcinoma (conventional variant and sized approximately 20 mm) were divided in 2 groups: 41 with encapsulated tumors and 47 with tumors with extrathyroidal extension. E-selectin expression was evaluated by immunohistochemical staining and semiquantitative real-time reverse-transcription polymerase chain reaction and normalized by calculating the z-score (positive: value above the population mean; negative: below the mean). RESULTS: Lymph node metastasis (LNM) was found in 2 of 41 encapsulated tumors (4.8%) and in 19 of 47 tumors (40.4%) with extrathyroidal extension. BRAF mutation was present in 21 encapsulated tumors (51.2%) and in 31 tumors with extrathyroidal extension (65.9%). The mean E-selectin z-score was -0.32 for encapsulated tumors and 0.28 for tumors with extrathyroidal extension. E-selectin expression correlates with neoplastic infiltration (P = .04), the American Joint Commission on Cancer stage (P = .02), and BRAF mutation (P = .03). CONCLUSION: E-selectin overexpression in association with BRAF mutation status could promote a more aggressive phenotype in papillary thyroid carcinoma. PMID- 25456958 TI - The importance of sonographic landmarks by transcutaneous laryngeal ultrasonography in post-thyroidectomy vocal cord assessment. AB - INTRODUCTION: During examination of the vocal cords (VC) using transcutaneous laryngeal ultrasonography (TLUSG), 3 sonographic landmarks (namely, false VC [FC], true VC [TC], and arytenoids [AR]) are often seen. However, it remains unclear which landmark provides a more reliable assessment and whether seeing more landmarks improves the diagnostic accuracy and reliability. METHODS: We evaluated prospectively 245 patients from 2 centers. One assessor from each center performed all TLUSG examinations and their findings were validated by direct laryngoscopy. All 3 sonographic landmarks were routinely visualized whenever possible. The rate of visualization and diagnostic accuracy between the 3 landmarks were compared. RESULTS: Eighteen patients suffered postoperative VC palsy (VCP). Both centers had comparable visualization or assessability rate of >= 1 sonographic landmark (94.9 and 95.3%; P = 1.000) and 100% sensitivity on postoperative TLUSG. The rates of FC, TC, and AR visualization were 92.7%, 36.7%, and 89.8%, respectively. The sensitivity, specificity, and diagnostic accuracy and the proportion of true positives, false positives, and true negatives between using 1, 2, landmarks and 3 landmarks were comparable (P > .05). CONCLUSION: Each sonographic landmark had similar reliability and diagnostic accuracy. Identifying all 3 sonographic landmarks was not mandatory and visualizing normal movement in one of the sonographic landmarks would be sufficient to exclude VCP. PMID- 25456960 TI - The effects of acupuncture after thyroid surgery: A randomized, controlled trial. AB - BACKGROUND: Acupuncture is a safe and well-tolerated treatment for pain relief. Previous studies supported the effectiveness of several acupuncture techniques for postoperative pain. The aim of this randomized, controlled trial was to evaluate the efficacy of acupuncture in reducing pain after thyroid surgery. METHODS: We randomized 121 patients to a control group (undergoing only standard postoperative analgesic treatment with acetaminophen) and an acupuncture group, undergoing also either electroacupuncture (EA) or traditional acupuncture (TA). Pain was measured according to intraoperative remifentanil use, acetaminophen daily intake, Numeric Rating Scale (NRS), and McGill Pain Questionnaire on postoperative days (POD) 1-3. RESULTS: Acupuncture group required less acetaminophen than controls at POD 2 (P = .01) and 3 (P = .016). EA patients required less remifentanil (P = .032) and acetaminophen than controls at POD 2 (P = .004) and 3 (P = .008). EA patients showed a trend toward better NRS and McGill scores from POD 1 to 3 compared with controls. EA patients had a lower remifentanil requirement and better NRS and McGill scores than TA patients. No differences occurred between TA patients and controls. CONCLUSION: Acupuncture may be effective in reducing pain after thyroid surgery. EA is more useful; TA achieves no significant effects. PMID- 25456955 TI - Expression of the embryonic morphogen Nodal in differentiated thyroid carcinomas: Immunohistochemistry assay in tissue microarray and The Cancer Genome Atlas data analysis. AB - BACKGROUND: Nodal, an embryonic morphogen, plays a role in tumorigenesis of melanoma, breast, and prostate cancer; however, its role in thyroid carcinoma is unknown. We examined Nodal expression in thyroid tumors by immunohistochemistry assay and The Cancer Genome Atlas (TCGA) analysis. METHODS: An immunohistochemistry assay was performed in a tissue microarray comprising 128 classic papillary thyroid carcinomas (PTC), 58 follicular thyroid carcinomas (FTC), 19 follicular variants of PTC (FVPTC), 57 follicular adenomas (FA), 54 adenomatous goiters (AG), and 5 normal thyroid tissues. The TCGA database was examined to evaluate the expression of Nodal mRNA in normal thyroid and PTC. RESULTS: The proportion of tumors showing negative Nodal expression in PTC, FTC, FVPTC, FA, and AG was 0%, 1.7%, 0%, 14%, and 41%, respectively. For the diagnosis of malignant tumors, the sensitivity, specificity, positive predictive value, and negative predictive value of positive Nodal staining was 99%, 27%, 72%, and 97%, respectively. High Nodal expression was associated with older age and BRAF mutation in PTC. TCGA analysis revealed PTC had greater Nodal mRNA expression than normal thyroid (P = .012). CONCLUSION: Nodal staining might be useful "rule out test" for the diagnosis of malignant thyroid tumor. Nodal may be associated with the tumorigenesis of thyroid malignancy. PMID- 25456962 TI - Fibromyalgia symptoms and medication requirements respond to parathyroidectomy. AB - BACKGROUND: Fibromyalgia (FM), an ill-defined symptom complex, is characterized by musculoskeletal pain, headache, depression, fatigue, and cognitive decline, symptoms also seen commonly in primary hyperparathyroidism (PHP). Prevalence of concurrent PHP and FM and response to parathyroidectomy (PTX) of those with both conditions are unknown. METHODS: We reviewed prospective data of 4,000 patients with sporadic PHP who had PTX from 1995 to 2013 examining perioperative symptoms and medication usage for those with diagnosed FM. Cure was defined by normocalcemia at >= 6 months. RESULTS: Of 2,184 patients, 80 (4%) had a prior diagnosis of FM. Of evaluable FM patients, 97.3% had definitive cure of PHP. After PTX, 89% had improvement in >= 1 symptom attributed to FM, with improved cognition/memory most common (80%). Improvement in >= 2, >= 3, and >= 4 FM symptoms was appreciated by 71%, 43%, and 25%, respectively. Quality of life and wellness improved in >50%. Postoperative use of drugs prescribed for FM often improved or resolved (narcotics, 77%; anti-inflammatories, 74%; "FM-specific medications," 33%; antidepressants, 30%); 21% discontinued all FM medications postoperatively. CONCLUSION: FM is common in patients operated on for sporadic PHP. Of those with both conditions, after PTX 89% appreciate symptom response and 77% and 21% had a decrease in or discontinuation or medications, respectively. Before diagnosing FM, providers should exclude PHP, which is surgically correctable. PMID- 25456964 TI - Parathyroid carcinoma in more than 1,000 patients: A population-level analysis. AB - BACKGROUND: Parathyroid carcinoma (PC) is a rare malignancy with a moderate prognosis. The staging system, prognostic indicators, and optimal surgical management are still under debate. This large cohort explores prognostic factors for PC. METHODS: 1,022 cases of PC in the 1998-2011 National Cancer Data Base that underwent surgery were examined for predictors of lower overall survival (OS) and relative risk (RR) of death at 5 years. RESULTS: The 5-year OS was 81.1% in 528 patients with >= 60 months of follow-up. The overall cohort was mainly non Hispanic (96.5%), white (77.4%), and insured (94.3%), with a median age of 57 years. Mean OS was lower and RR of death greater in older (P < .001), black (P = .007) patients with a secondary malignancy (P = .015) and >= 2 comorbidities (P = .005), whose surgical specimen had positive surgical margins (P = .026) or positive lymph nodes (P < .001). Multivariate cox regression demonstrated that positive lymph nodes (hazard ratio [HR], 6.47; 95% CI, 1.81-23.11) and older age (HR, 2.35; 95% CI, 1.25-4.43) were associated with lower OS. CONCLUSION: PC is a rare malignancy with a 5-year OS of 81.1%. Positive lymph nodes and older age predict lower OS and an increased risk of death. PMID- 25456966 TI - Predictors of tertiary hyperparathyroidism: Who will benefit from parathyroidectomy? AB - BACKGROUND: Tertiary hyperparathyroidism (3 degrees HPT) is hyperparathyroidism with hypercalcemia after renal transplantation. With unclear guidelines for parathyroidectomy (PTX), this study aims to determine which renal transplant patients develop 3 degrees HPT and would benefit from PTX. METHODS: We performed a retrospective review of patients who received a renal transplant between 1994 and 2013; 105 patients who underwent near total PTX (NTPTX) were compared with 180 renal transplant control patients who did not undergo NTPTX. RESULTS: Calcium and PTH varied significantly between groups (P < .001). One year before transplant, the mean serum calcium was 9.7 +/- 1.1 mg/dL in the NTPTX group versus 9.1 +/- 0.9 mg/dL in the control group (P < .01). One month after transplant, the mean calcium in the NTPTX group was 10.4 +/- 1.1 versus 9.4 +/- 0.6 mg/dL in the control group (P < .001). One year before renal transplant, the median serum PTH level was 723 pg/mL (range, 557-919) in the NTPTX group versus 212 pg/mL (range, 160-439) in the control group (P < .01). One-month post renal transplant, the NTPTX group had a median PTH of 351 pg/mL (range, 199-497) versus 112 pg/mL (range, 73-178) pg/mL in the control group (P < .01). CONCLUSION: Before and after renal transplantation, PTH and calcium levels can serve as predictors of 3 degrees HPT. PMID- 25456968 TI - A novel, ultrarapid parathyroid hormone assay to distinguish parathyroid from nonparathyroid tissue. AB - BACKGROUND: Frozen section is the gold standard for distinguishing parathyroid tissue from lymph nodes, thyroid nodules, or fat during parathyroidectomy and thyroidectomy. Although a very accurate procedure, it can be time-consuming and costly. We hypothesize that the extremely high concentrations of parathyroid hormone (PTH) in parathyroid tissue allow for modification of a standard PTH assay that would distinguish parathyroid from nonparathyroid tissue in substantially less time than frozen section or any currently available PTH assay. METHODS: A prospective, single-institution study using a modified PTH assay protocol and a manual luminometer was undertaken by testing 20 parathyroid adenomas and 9 control tissues. Analyses were performed simultaneously by the modified PTH protocol and the conventional intraoperative PTH assay. RESULTS: PTH luminescence values from parathyroid tissue and control tissue aspirates were significantly different at 60 seconds (P = .015). ROC curve analysis showed the assay to be 100% sensitive and 100% specific in differentiating parathyroid from nonparathyroid tissue. CONCLUSION: Our novel PTH assay accurately and reliably differentiates parathyroid from nonparathyroid tissue within 60 seconds of measurement onset. This assay provides a great advantage in time savings compared with frozen section as well as any currently existing PTH assays. PMID- 25456969 TI - Unintended pregnancy and associated risk factors among young pregnant women. AB - OBJECTIVE: To assess pregnancy intention and the associated risks among young pregnant women. METHODS: In a descriptive study, pregnant women aged 15-24 years were recruited at a prenatal clinic in Chiang Mai University Hospital, Thailand, between March 1, 2012, and February 28, 2013. Participants were interviewed by trained interviewers using a standardized questionnaire to elicit information about baseline characteristics, pregnancy intention, and contraception practice. RESULTS: Overall, 250 participants were recruited (mean age 20.7+/-2.4 years), and 163 (65.2%) declared that the pregnancy was unintended. The odds of the pregnancy being unintended were increased in students (P=0.006), women aged 20 years or younger (P=0.024), and women whose partner was a similar age (P=0.026). A higher percentage of women with unintended pregnancy than with intended pregnancy reported having no time to use contraception, a perceived difficulty of regular contraceptive use, fear of parents finding out about sexual activity, and embarrassment about using contraception. CONCLUSION: Pregnancy among young pregnant women in Thailand was often unintended. Educational status, age, and age difference between the couple were independently associated with unintended pregnancy. PMID- 25456970 TI - The effect of antibiotic prophylaxis guidelines on surgical-site infections associated with cesarean delivery. AB - OBJECTIVE: To evaluate the effect of Norwegian antibiotic prophylaxis guidelines on rates of superficial and deep surgical-site infections (SSIs) associated with cesarean delivery (CD). METHODS: A cross-sectional study was conducted that analyzed the physician-diagnosed SSIs by regimen of antibiotic prophylaxis among women who underwent planned or emergency CD at one of 42 hospitals between January 1, 2008, and December 31, 2010. The antibiotic prophylaxis regimen was verified using a hospital survey, whereas guideline compliance was assessed as part of the mandatory Norwegian Surveillance System for Healthcare-Associated Infections. RESULTS: Data for 4498 patients were used. Hospitals that practiced antibiotic prophylaxis for all CDs (n=4) provided antibiotics more often in both emergency and planned CDs than did those that used this approach for emergency CDs only (n=33) or had no written guidelines or used prophylaxis on indication only (n=5) (P<0.001). The provision of antibiotic prophylaxis for all cases of CD was associated with markedly lowered rates of superficial SSIs among planned CDs, whereas no differences in rates of deep SSIs were observed between the guidelines in either planned or emergency CDs. CONCLUSION: Hospitals that provided antibiotic prophylaxis to all women undergoing CD reported high compliance and had reduced rates of superficial SSIs among planned CDs. PMID- 25456972 TI - Caregiving burden and health-promoting behaviors among the family caregivers of cancer patients. AB - PURPOSE: The role of family caregivers in cancer care continues to expand, and it has been suggested that the caregiving influences health-promoting behaviors. The purpose was to describe the caregiving burden and health-promoting behaviors of the family caregivers of cancer patients and to determine the relationship between caregiving burden and health-promoting behaviors. METHOD: A cross sectional descriptive study was conducted involving 227 family caregivers of adult cancer patients. Caregiving burden was measured using the Korean version of the Zarit Burden Interview (K-ZBI), and health-promoting behaviors were determined using structured questionnaires. RESULTS: Considerable burden was experienced by the caregivers of cancer patients (K-ZBI score of 36.51 +/- 12.54, mean +/- SD). However, caregiving burden did not influence caregivers' physical activity, diet, smoking, alcohol consumption, or adherence to cancer screening tests. When the caregivers were compared to controls from the Korea National Health and Nutrition Examination Survey V utilizing adjusted proportions, caregivers were less likely to perform physical activities (16.0% vs. 29.1%, p < 0.001), but more likely to adhere to alcohol consumption recommendations (76.3% vs. 35.0%, p < 0.001) and receive cancer screening services for stomach (68.5% vs. 56.8%, p < 0.011), breast (81.4% vs. 58.8%, p < 0.001), and cervical cancer (75.3% vs. 55.0%, p < 0.001). CONCLUSIONS: The caregivers of cancer patients reported considerable caregiving burden. However the burden was not associated with health-promoting behaviors. Physical inactivity among caregivers may require interventions to promote health of caregivers. IMPLICATIONS FOR PRACTICE: Relieving caregiving burden and improving caregivers' physical activities need to be considered as separate care issues in planning interventions for caregivers of cancer patients. PMID- 25456971 TI - Oxysterols regulate encephalitogenic CD4(+) T cell trafficking during central nervous system autoimmunity. AB - Perturbation of steroids pathways is linked to inflammation and chronic diseases, however the underlying mechanism remains unclear. Oxysterols, oxidized forms of cholesterol, are not only essential for bile synthesis and sterol transportation but have recently been shown to contribute to the immune response. In addition, serum oxysterols levels have been proposed as suitable candidate biomarkers for neurological diseases such as multiple sclerosis (MS). However how oxysterols modulate adaptive immunity is unknown and their functions in autoimmunity have not been investigated. The enzyme cholesterol 25 hydroxylase (Ch25h) is the rate limiting step to synthesize the oxysterol 7alpha,25-dihydroxycholesterol (7alpha,25-OHC) from cholesterol. We here report, using the MS murine model experimental autoimmune encephalomyelitis (EAE), that Ch25h deletion significantly attenuated EAE disease course by limiting trafficking of pathogenic CD4(+) T lymphocytes to the central nervous system (CNS). Mechanistically, we show a critical involvement for oxysterols in recruiting leukocytes into inflamed tissues and propose that 7alpha,25-OHC preferentially promotes the migration of activated CD44(+)CD4(+) T cells by binding the G protein-coupled receptor called Epstein-Barr virus induced gene 2 (EBI2). Collectively, our results support a pro inflammatory role for oxysterols during EAE and identify oxysterols as a potential therapeutic target to treat autoimmune diseases. PMID- 25456974 TI - Psychometric properties and performance of the 17-item Benefit Finding Scale (BFS) in an outpatient population of men with prostate cancer. AB - PURPOSE: To analyse the psychometric properties and performance of the 17-item Benefit Finding Scale (BFS) in an Australian outpatient sample of men with prostate cancer. METHODS: The instrument's psychometric properties and performance were rated against established criteria for reliability (internal consistency), construct validity (instrument dimensionality) and variability (floor and ceiling effects). RESULTS: Internal consistency reliability was satisfactory as evidenced by a Cronbach's alpha of 0.95 Dimensionality analysis confirmed a unidimensional structure indicating construct validity. A greater than 15% floor effect suggested limited data variability. CONCLUSION: The 17-item BFS seems to have satisfactory psychometric properties for use in an outpatient sample of men with prostate cancer, with some questions regarding detection of variability. The high internal consistency reliability points to the instruments ability to reliably capture the benefit finding construct in this population. The evidence for instrument dimensionality indicates a unidimensional scale, and thus a calculation of a single total score can be recommended. The >15% floor effect suggests that there may be issues with the instrument's ability to detect variance, and thus some questions remain regarding the instrument's ability to discern change in health status over time. Nevertheless, the findings of this study together with previous evidence indicate that the 17-item BFS can be recommended as the tool of choice when exploring benefit finding in adult cancer populations. PMID- 25456973 TI - Relationship between patterns of daily physical activity and fatigue in cancer survivors. AB - PURPOSE: This study investigated: (1) physical activity behaviour of cancer survivors throughout the day, (2) the relationship between objective and subjective measures of physical activity, and (3) the relationship between daily physical activity and fatigue. METHOD: Physical activity was measured objectively using 3D-accelerometry (expressed in counts per minute (cpm)), and subjectively using a Visual Analogue Scale (VAS; 0-10) implemented on a smartphone in 18 cancer survivors (6 male; age 55.7 +/- 10.2 yrs; free from cancer, last treatment >=three months previously), and matched controls. Fatigue was scored thrice daily on a smartphone (0-10 VAS). RESULTS: Mean daily physical activity of cancer survivors did not deviate from controls (1108 +/- 287 cpm versus 1223 +/- 371 cpm, p = .305). However, in cancer survivors physical activity significantly decreased from morning to evening (p < .01) and increased levels of fatigue throughout the day were reported (p < .01). Furthermore, a positive correlation was found between levels of fatigue and the magnitude of the decline in physical activity from afternoon to evening (p < .05). Objective and subjective measured physical activity showed low correlations. CONCLUSIONS: This study demonstrated imbalanced activity patterns in cancer survivors. Also, the more a survivor felt fatigued, the greater the decline in activity behaviour throughout the day. The low correlation between objective and subjective physical activity suggests low awareness in cancer survivors about their daily physical activity performed. Ambulatory monitoring provides new insights in both patterns of physical activity and fatigue, which might be a valuable tool to provide activity management more efficiently during treatment of fatigue. PMID- 25456976 TI - Function and position determine relative proportions of different fiber types in limb muscles of the lizard Tropidurus psammonastes. AB - Skeletal muscles can be classified as flexors or extensors according to their function, and as dorsal or ventral according to their position. The latter classification evokes their embryological origin from muscle masses initially divided during limb development, and muscles sharing a given position do not necessarily perform the same function. Here, we compare the relative proportions of different fiber types among six limb muscles in the lizard Tropidurus psammonastes. Individual fibers were classified as slow oxidative (SO), fast glycolytic (FG) or fast oxidative-glycolytic (FOG) based on mitochondrial content; muscles were classified according to position and function. Mixed linear models considering one or both effects were compared using likelihood ratio tests. Variation in the proportion of FG and FOG fibers is mainly explained by function (flexor muscles have on average lower proportions of FG and higher proportions of FOG fibers), while variation in SO fibers is better explained by position (they are less abundant in ventral muscles than in those developed from a dorsal muscle mass). Our results clarify the roles of position and function in determining the relative proportions of the various muscle fibers and provide evidence that these factors may differentially affect distinct fiber types. PMID- 25456977 TI - Venom regeneration in the centipede Scolopendra polymorpha: evidence for asynchronous venom component synthesis. AB - Venom regeneration comprises a vital process in animals that rely on venom for prey capture and defense. Venom regeneration in scolopendromorph centipedes likely influences their ability to subdue prey and defend themselves, and may influence the quantity and quality of venom extracted by researchers investigating the venom's biochemistry. We investigated venom volume and total protein regeneration during the 14-day period subsequent to venom extraction in the North American centipede Scolopendra polymorpha. We further tested the hypothesis that venom protein components, separated by reversed-phase fast protein liquid chromatography (RP-FPLC), undergo asynchronous (non-parallel) synthesis. During the first 48 h, volume and protein mass increased linearly. Protein regeneration lagged behind volume regeneration, with 65-86% of venom volume and 29-47% of protein mass regenerated during the first 2 days. No additional regeneration occurred over the subsequent 12 days, and neither volume nor protein mass reached initial levels 7 months later (93% and 76%, respectively). Centipede body length was negatively associated with rate of venom regeneration. Analysis of chromatograms of individual venom samples revealed that 5 of 10 chromatographic regions and 12 of 28 peaks demonstrated changes in percent of total peak area (i.e., percent of total protein) among milking intervals, indicating that venom proteins are regenerated asynchronously. Moreover, specimens from Arizona and California differed in relative amounts of some venom components. The considerable regeneration of venom occurring within the first 48 h, despite the reduced protein content, suggests that predatory and defensive capacities are minimally constrained by the timing of venom replacement. PMID- 25456975 TI - Sick leave and work disability in primary care patients with recent-onset multiple medically unexplained symptoms and persistent somatoform disorders: a 10 year follow-up of the FIP study. AB - OBJECTIVE: The objective was to explore patient characteristics and 10-year outcome of sick leave and work disability for patients with recent-onset multiple medically unexplained symptoms (MUS) and persistent somatoform disorders (SD). METHOD: Consecutive patients consulting their family physician (FP) completed a preconsultation questionnaire on symptoms and mental illness (n=1785). The main problem was categorized by the FP after the consultation, and a stratified subsample was examined using a standardized diagnostic interview (n=701). Patients were grouped into three cohorts: recent onset of multiple MUS (n=84); Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, persistent SD (n=183); and reference group with well-defined physical disease according to FP (n=833). Register data on sick leave and disability pension were obtained. RESULTS: At index consultation, disability pension was received by 8.3% (n=7) in the recent-onset multiple MUS group, 19.1% (n=35) in the SD group and 3.5% (n=29) in the reference group. Both the recent-onset multiple MUS group [hazard ratio (HR)=2.28, 95% confidence interval (CI): 1.14-4.55] and the SD group (HR=3.26, 95% CI:1.93-5.51) had increased risk of new disability pension awards. Furthermore, the SD group had increased risk of sick leave. CONCLUSIONS: Both recent-onset and persistent MUS have significant long-term impact on patient functioning in regard to working life; this calls for early recognition and adequate management of MUS in primary care. PMID- 25456978 TI - Single-molecule electrochemical transistor utilizing a nickel-pyridyl spinterface. AB - Using a scanning tunnelling microscope break-junction technique, we produce 4,4' bipyridine (44BP) single-molecule junctions with Ni and Au contacts. Electrochemical control is used to prevent Ni oxidation and to modulate the conductance of the devices via nonredox gating--the first time this has been shown using non-Au contacts. Remarkably the conductance and gain of the resulting Ni-44BP-Ni electrochemical transistors is significantly higher than analogous Au based devices. Ab-initio calculations reveal that this behavior arises because charge transport is mediated by spin-polarized Ni d-electrons, which hybridize strongly with molecular orbitals to form a "spinterface". Our results highlight the important role of the contact material for single-molecule devices and show that it can be varied to provide control of charge and spin transport. PMID- 25456979 TI - Prolonged continuous theta-burst stimulation is more analgesic than 'classical' high frequency repetitive transcranial magnetic stimulation. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) at high frequency (>5 Hz) induces analgesic effects, probably by activating pain modulation systems. A new rTMS paradigm--theta burst stimulation (TBS)--consists of bursts of three pulses at 50 Hz repeated five times per second. Like high frequency rTMS, both intermittent and prolonged continuous TBS (iTBS and pcTBS) lead to a facilitation of cortical excitability. OBJECTIVES: (1) to evaluate the analgesic effects of neuronavigated iTBS and pcTBS, comparing them with those of classical high frequency rTMS (10 Hz) over the left M1, (2) to elucidate the role of conditioned pain modulation (CPM) in the antinociceptive effect of rTMS and (3) to investigate possible correlations between analgesia and cortical excitability. METHODS: Fourteen healthy volunteers participated in four experimental sessions, carried out in a random order (iTBS, pcTBS, 10 Hz rTMS or sham). Cold pain threshold, CPM and cortical excitability measurements were carried out before and after rTMS. RESULTS: We found that the analgesic effects of 10 Hz rTMS and pcTBS were significantly superior to those of sham rTMS. Moreover, pcTBS was significantly more effective than 10 Hz rTMS (P = 0.026). Analgesia did not seem to be driven by changes in CPM or cortical excitability. CONCLUSION: Prolonged cTBS has considerable clinical potential, as it has a shorter treatment duration (by a factor 8) and stronger analgesic effects than the classical high frequency protocol. Studies in patients are required to confirm the potential of this new stimulation paradigm for clinical applications. PMID- 25456980 TI - The outlook for non-invasive electrical brain stimulation. PMID- 25456982 TI - Enhancing cognitive-behavioral therapy with repetitive transcranial magnetic stimulation in refractory obsessive-compulsive-disorder: a case report. PMID- 25456981 TI - Methods for specific electrode resistance measurement during transcranial direct current stimulation. AB - BACKGROUND: Monitoring of electrode resistance during tDCS is considered important for tolerability and safety. Conventional resistance measurement methods do not isolate individual electrode resistance and for HD-tDCS devices, cross talk across electrodes makes concurrent resistance monitoring unreliable. OBJECTIVE: We propose a novel method to monitor individual electrode resistance during tDCS, using a super-position of direct current with a test-signal (low intensity and low frequency sinusoids with electrode-specific frequencies) and a sentinel electrode (not used for DC). METHODS: We developed and solved lumped parameter models of tDCS electrodes with or without a sentinel electrode to validate this methodology. Assumptions were tested and parameterized in participants using forearm stimulation combining tDCS (2 mA) and test-signals (38 and 76 MUA pk-pk at 1 Hz, 10 Hz, & 100 Hz) and an in vitro test (creating electrode failure modes). DC and AC component voltages across the electrodes were compared and participants were asked to rate subjective pain. RESULTS: A sentinel electrode is required to isolate electrode resistance in a two-electrode tDCS system. Cross talk aggravated with electrode proximity and resistance mismatch in multi-electrode resistance tracking could be corrected using proposed approaches. Average voltage and pain scores were not significantly different across test current intensities and frequencies. CONCLUSION: Using our developed method, a test signal can predict DC electrode resistance. Since unique test frequencies can be used at each tDCS electrode, specific electrode resistance can be resolved for any number of stimulating channels - a process made still more robust by the use of a sentinel electrode. PMID- 25456983 TI - Chitosan stabilized Prussian blue nanoparticles for photothermally enhanced gene delivery. AB - The lack of biosafety and insufficient delivery efficiency of gene-carriers are still obstacles to human gene therapy. This paper reported highly biocompatible chitosan (CS) functionalized Prussian blue (PB) nanoparticles (designated as CS/PB NPs) for photocontrollable gene delivery. The ultra-small size (~3 nm), positive charge and high physiological stability of CS/PB NPs make it suitable to be a nonviral vector. In addition, CS/PB NPs could effectively convert the near infrared (NIR) light into heat due to its strong absorption in the NIR region, assisting the uptake of NPs by cells. Upon NIR light irradiation, CS/PB NPs showed superior gene transfection efficiency, much higher than that of free polyethylenimine (PEI). Both in vitro and in vivo experiments demonstrated that CS/PB NPs had excellent biocompatiblity. This work also encourages further exploration of the CS/PB NPs as a photocontrollable nanovector for combined photothermal and gene therapy. PMID- 25456984 TI - Design and evaluation of a highly sensitive nanostructure-based surface modification of glassy carbon electrode for electrochemical studies of hydroxychloroquine in the presence of acetaminophen. AB - N,N'-bis[(E)-(1-pyridyl) methylidene]-1,3-propanediamine (PMPDA) self-assembled monolayer (SAM) was covalently prepared on a glassy carbon electrode (GCE). The electrode surface modification was characterized by scanning electron microscopy (SEM), electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) techniques. Then GC-PMPDA SAM modified electrode was used to investigate the electrochemical behavior of hydroxychloroquine (HQ) using CV, double potential step chronocoulometry and linear sweep voltammetry (LSV) techniques. Using these techniques, the diffusion coefficient (D), electron transfer coefficient (alpha) and exchanging current density (j0) for HQ were calculated. Furthermore the modified electrode was applied as a high sensitive biosensor for determination of HQ in the presence of acetaminophen (AC). The GC-PMPDA SAM modified electrode provides two linear responses for HQ in the presence of AC in the concentration ranges from 0.09 to 10.21 MUM and 10.21 to 98.29 MUM by differential pulse voltammetry (DPV). The detection limit (three times the signal blank/slope) was 4.65 nM. Finally the modified electrode was satisfactorily used for determining of HQ in human body fluids. PMID- 25456985 TI - Investigation of size, surface charge, PEGylation degree and concentration on the cellular uptake of polymer nanoparticles. AB - In this work a large number of polymer nanoparticles (NPs) with different features have been synthesized through emulsion polymerization-based methods. Poly(methyl methacrylate) (PMMA), poly-E-caprolactone (PCL), and poly(lactic acid) (PLA) based NPs with different size, hydrophobicity, surface charge, PEGylation degree, type of emulsifier and zeta potential have been produced and characterized. All the different NPs have been adopted for cellular uptake studies, leading to a precise quantification of the number of internalized NPs into a selected tumor cell line. The experiments summarize, emphasize and improve the comprehension of the influence of NPs features on the uptake efficiency. In detail, a linear relationship between uptake and both size and NP concentration independently upon other NP characteristics was found. Moreover, it was confirmed that cells are able to internalize and retain for a long time preferentially positively charged NPs. Finally, by coupling results of uptake studies with cell viability measurements, an easy and fast check to control the effectiveness of a selected polymer as drug carrier has been proposed. In particular, we observed that biodegradable PLA-based NPs with high molecular weight, non-PEGylated and positively charged PCL NPs are the better choice to maximize the uptake and minimize side effect against cells. PMID- 25456986 TI - Biophysical studies of interaction between hydrolysable tannins isolated from Oenothera gigas and Geranium sanguineum with human serum albumin. AB - Tannins, secondary plant metabolites, possess diverse biological activities and can interact with biopolymers such as lipids or proteins. Interactions between tannins and proteins depend on the structures of both and can result in changes in protein structure and activity. Because human serum albumin is the most abundant protein in plasma and responsible for interactions with important biological compounds (e.g. bilirubin) and proper blood pressure, therefore, it is very important to investigate reactions between HSA and tannins. This paper describes the interaction between human serum albumin (HSA) and two tannins: bihexahydroxydiphenoyl-trigalloylglucose (BDTG) and 1-O-galloyl-4,6 hexahydroxydiphenoyl-beta-d-glucose (OGbetaDG), isolated from Geranium sanguineum and Oenothera gigas leafs, respectively. Optical (spectrofluorimetric) and chiral optical (circular dichroism) methods were used in this study. Fluorescence analysis demonstrated that OGbetaDG quenched HSA fluorescence more strongly than BDTG. Both OGbetaDG and BDTG formed complexes with albumin and caused a red shift of the fluorescence spectra but did not significantly change the protein secondary structure. Our studies clearly demonstrate that the tested tannins interact very strongly with human serum albumin (quenching constant K=88,277.26+/ 407.04 M(-1) and K=55,552.67+/-583.07 M(-1) respectively for OGbetaDG and BDTG) in a manner depending on their chemical structure. PMID- 25456987 TI - BSA/polyelectrolyte core-shell nanoparticles for controlled release of encapsulated ibuprofen. AB - Bovine serum albumin (BSA) based core-shell nanoparticles were developed as carrier systems for drug transportation. At pH=3, the oppositely charged polyelectrolytes: poly(sodium-4-styrene)sulphonate (PSS) and the chitosan (Chit) bind to the positively charged protein via electrostatic interactions. We applied ibuprofen (IBU) as model molecule which has low solubility. The changes in the BSA's secondary structure during the steps of the synthesis were inspected by FT IR measurements. The size and the zeta potential were determined by dynamic light scattering (DLS). The changes in the structure and in the size were investigated by small angle X-ray scattering (SAXS) too, for each composite. The release of the ibuprofen was studied by vertical diffusion cell (Franz cell) at pH 7.4 at 25 and 37.5 degrees C. The structure of the core-shell nanoparticles have significantly changed as the pH has risen from 3.0 to 7.4. Kinetic models were used to describe the release mechanism. The experimental results demonstrated that the BSA has an ordered structure at pH=3 which will become random coil by adding ibuprofen. The first shell restores the ordered structure of the protein. The controlled release was carried out; the IBU release decreased by 40% in the case of two-layered composites compared with the "naked" BSA. PMID- 25456988 TI - The height of cell-adhesive nanoposts generated by block copolymer/surfactant complex systems influences the preosteoblast phenotype. AB - In tissue engineering, the nanoscale topography of the substrate is important, because transplanted cells can recognize and respond to topographical patterns, allowing control of gene expression and tissue formation. In this study, we hypothesized that the height of cell-adhesive nanoposts could regulate cell phenotype. Nano-patterned surfaces were generated via self-assembly of polystyrene-b-poly(ethylene oxide)/dodecylbenzenesulfonic acid (PS-b-PEO/DBSA) complex systems. The height of PS nanoposts, which are considered to be cell adhesion domains, was varied from 11 to 43 nm, while nanopost size and the center to-center distance between nanoposts were kept constant. Adhesion, growth, and differentiation of mouse preosteoblasts (MC3T3-E1) cultured on the nano-patterned surfaces were significantly influenced by nanopost height. This approach therefore holds great promise for the design of biomedical devices, as well as tissue engineering scaffolds. PMID- 25456989 TI - A study of chitosan hydrogel with embedded mesoporous silica nanoparticles loaded by ibuprofen as a dual stimuli-responsive drug release system for surface coating of titanium implants. AB - In this study, the complex pH and electro responsive system made of chitosan hydrogel with embedded mesoporous silica nanoparticles (MSNs) was evaluated as a tunable drug release system. As a model drug, ibuprofen (IB) was used; its adsorption in MSNs was evidenced by Fourier transform infrared spectroscopy (FT IR), scanning electron microscopy (SEM) and thermogravimetric analysis (TG). In order to prepare the complex drug release system, the loaded particles IB-MSNs were dispersed in chitosan solution and then the complex IB-MSNs/chitosan film of 2mm thickness was deposited as a hydrogel on the titanium electrode. The codeposition of components was performed under a negative biasing of the titanium electrode at -0.75 mA/cm2 current density during 30 min. The IB release from the IB-MSNs/chitosan hydrogel film was studied as dependent on pH of the release media and electrical conditions applied to the titanium plate. When incubating the complex hydrogel film in buffers with different pH, the IB release followed a near zero-order profile, though its kinetics varied. Compared to the spontaneous IB release from the hydrogel in 0.9% NaCl solution (at 0 V), the application of negative biases to the coated titanium plate had profound effluences on the release behavior. The release was retarded when -1.0 V was applied, but a faster kinetics was observed at -5.0 V. These results imply that a rapid, mild and facile electrical process for covering titanium implants by complex IB MSNs/chitosan hydrogel films can be used for controlled drug delivery applications. PMID- 25456990 TI - Size and charge of nanoparticles following incubation with human plasma of healthy and pancreatic cancer patients. AB - When nanoparticles (NPs) enter a biological environment, proteins bind to their surface forming a protein coating, which alters NP features giving it a biological identity, which controls its physiological response. The NP biological identity (size, charge and aggregation state) does strictly correlate with its physicochemical properties and the nature of the biological environment. While the former relationship has been extensively investigated, whether and how alterations in the physiological environment affect the biological identity of the NPs remains unclear. In this work we enrolled healthy and histologically proven pancreatic cancer patients. A statistically significant reduction in the level of clinically relevant proteins in cancer patients occurred. Positively and negatively charged lipid nanoparticles with two different surface chemistries (plain and PEGylated) were incubated with human plasma from both groups and characterized thoroughly by dynamic light scattering and zeta potential measurements. Only when plain positively charged NPs were tested, significant difference in zeta-potential between healthy and pancreatic cancer groups was found. This result implies that pooling human plasma from healthy volunteers might lead to a bias and thus unpredictable consequences in regard to previously optimized targeting profile. PMID- 25456991 TI - Needle-free transdermal delivery using PLGA nanoparticles: effect of particle size, injection pressure and syringe orifice diameter. AB - The aim of this study is to investigate the effects of particle size and other injection factors on the skin penetration of nanoparticles delivered with a needle-free injector. Experimental and simulation tests were carried out at various parameters. In addition to testing different sizes of nanoparticles, we also observed the effects of several injection pressures and syringe orifice diameters (SOD) on the dispersion pattern of the nanoparticles after injection. Our results showed that as the nanoparticle size increased from 45 nm to 452 nm, the resulting puncture opening, channel diameter, and depth of the nanoparticle dispersion decreased, but the width of the dispersion increased. Conversely, as the SOD increased, the puncture opening, channel diameter, and depth of the dispersion increased, but width of the dispersion decreased. Increasing the injection pressure also decreased the size, depth, and width of the puncture opening. These results identify how these three parameters affect nanoparticle delivery from a needle-free injector; therefore, our findings will be beneficial for optimization and further study of needle-free injectors as a mechanism for transdermal delivery of nanoparticles. PMID- 25456992 TI - Surfactant induced complex formation and their effects on the interfacial properties of seawater. AB - The effect of a cationic surfactant, hexadecyltrimethylammonium bromide (CTAB), on the interfacial properties of seawater has been studied by dynamic and equilibrium surface tension and by dilational rheology essays. Important modifications of the surface tension and dilational rheology response have been observed already at the very low CTAB concentrations, where the effects due to the high ionic strength are negligible. The comparison with the effects of CTAB in different seawater models, or in natural seawater fractions, points out the establishment of strong interactions between the surfactant molecules and the lipophilic fraction of organic material dispersed/dissolved in seawater, affecting the interfacial activity of the molecules. Considering the biochemical richness of seawater, these results can be explained assuming interaction mechanisms and adsorption schemes similar to those speculated for protein and other macromolecules in the presence of surfactants, which in fact show similar features. Thus already at the low concentrations the surfactant molecules form highly surface-active complexes with part of the organic fraction of seawater. At the larger surfactant concentrations these complexes compete for adsorption with an excess of free CTAB molecules which, according to the thermodynamic conditions, are most favoured to occupy the liquid interface. The results of this study underline the important role of the sea organic content in enhancing the surface-activity of surfactants, which is relevant for a deeper understand of the direct and indirect effects of these types of pollutants on the physico-chemical environment in the sea coastal areas and develop mitigation strategies. PMID- 25456993 TI - Modulation of the carotenoid bioaccessibility through liposomal encapsulation. AB - The low bioaccessibility of carotenoids is currently a challenge to their incorporation in pharmaceutics, nutraceuticals and functional foods. The aim of this study was to evaluate the modulating effects of liposome encapsulation on the bioaccessibility, and its relationship with carotenoid structure and incorporated concentration. The physical stability of liposomes, lipid digestibility, carotenoids release and bioaccessibility were investigated during incubation in a simulated gastrointestinal tract. Analysis on the liposome size and morphology showed that after digestion, the majority of particles maintained spherical shape with only an increase of size in liposomes loading beta-carotene or lutein. However, a large proportion of heterogeneous particles were visible in the micelle phase of liposomes loading lycopene or canthaxanthin. It was also found that the release of lutein and beta-carotene from liposomes was inhibited in a simulated gastric fluid, while was slow and sustained in a simulated intestinal fluid. By contrast, lycopene and canthaxanthin exhibited fast and considerable release in the gastrointestinal media. Both carotenoid bioaccessibility and micellization content decreased with the increase of incorporated concentration. Anyway, the bioaccessibility of carotenoids after encapsulated in liposomes was in the following order: lutein>beta carotene>lycopene>canthaxanthin. Bivariate correlation analysis revealed that carotenoid bioaccessibility depended strongly on the incorporating ability of carotenoids into a lipid bilayer, loading content, and nature of the system. PMID- 25456994 TI - Statistical analysis of gold nanoparticle-induced oxidative stress and apoptosis in myoblast (C2C12) cells. AB - Nanoscale gold particles (Au-NPs) with a diameter below 20nm are notably important candidates for various important applications because of their extraordinary quantum size effects. Their high surface area-to-volume ratio facilitates their very high reactivities; therefore, they can be utilised in different ways in biomedical applications. For example, these nanoparticles can penetrate into cells and bind with proteins or DNA and are therefore potential nanostructures employed for sensing and detecting various biological identities. In the present work, we synthesised Au-NPs via a colloidal process using chloroauric acid (HAuCl4.4H2O) and trisodium citrate dihydrate (N3C6H5O7) as a reducing agent. The shape evolution and the structural properties of these NPs were investigated in detail using TEM and high resolution HR-TEM investigations. Different doses of Au NPs have been applied to treat C2C12 myoblast cells in a 24 h incubation period, and a dose-dependent study has also been performed. The cells were cultivated in DMEM with FBS and antibiotics (strepto-penicillin) at 37 degrees C in a 5% humidified environment of CO2 and 95% air. Cell viability analysis using MTT assays revealed that increased concentration of Au NPs (100 1000 ng/mL) resulted in a decreased density of cells. The amount of reactive oxygen species (ROS) in C2C12 cells analysed with Au-NPs (in a dose-dependent manner), and the RT-PCR data demonstrated the up-regulation of caspase-3 and caspase-7 genes in C2C12 cells after treatment with Au-NPs. These results have been confirmed by detailed confocal microscopy (CLSM) studies. In addition, the quantitative analysis of the Au-NPs was also confirmed by statistical analytical parameters, such as precision, accuracy, linearity, limits of detection (LOD) and limit of quantitation (LOQ), quantitative recoveries and relative standard deviation (RSD), and the analyses again exhibited a significant and large effect of Au NPs on C2C12 cells. PMID- 25456996 TI - Role of ultrasensitive prostate-specific antigen in the follow-up of prostate cancer after radical prostatectomy. AB - OBJECTIVE: Prostate-specific antigen (PSA) is an important tool in the follow-up of prostate cancer after radical prostatectomy (RP). However, the relevance of ultrasensitive PSA (uPSA) after RP is not well defined. The aim of this study was to investigate the value of uPSA in follow-up after RP and to determine whether ultrasensitive PSA doubling time (uDT) correlates with traditional PSA doubling time (tDT). PATIENTS AND METHODS: In total, 604 consecutive patients undergoing open RP and pelvic lymphadenectomy between 2004 and 2008 (minimum 5y of follow up) were studied. To evaluate the postsurgical uPSA level, scatter plot statistics were used. To correlate uDT and tDT in patients with a biochemical recurrence (PSA >=0.2ng/ml), at least 2 uPSA and 2 PSA measurements without salvage treatment were required and a weighted Cohen kappa statistic and receiver operating characteristic curve were used to test agreement across the categories. RESULTS: There were 229 patients without biochemical recurrence who did not have 3 rising PSA values after nadir within ultrasensitive area. Their highest uPSA value was between 0.003 and 0.1ng/ml. In 97.4% of patients, the highest uPSA value was less than 0.03ng/ml, and in 89% of these patients, the values were less than 0.02ng/ml. The median uDT and tDT were 10.2 and 11.4 months, respectively. The weighted Cohen kappa statistic between these 2 groups was 0.30 (95% CI:-0.09 to 0.50), demonstrating a poor agreement of PSA doubling time across categories. The predictive capability of uDT was tested with tDT <9 months. A receiver operating characteristic curve area under the curve value was 0.737 (95% CI: 0.577 to 0.897) demonstrating a fair agreement between the groups. CONCLUSIONS: uPSA values>0.03ng/ml seems to be valid and can be used in a clinical setting. There was a poor to fair agreement between tDT and uDT. The accuracy of uDT improves when it approaches the traditional PSA threshold of 0.1ng/ml. Also according to our results, there is no prognostic benefit of uDT calculation. PMID- 25456995 TI - Enhanced antitumor efficacy of vitamin E TPGS-emulsified PLGA nanoparticles for delivery of paclitaxel. AB - Nanoparticles are efficient delivery vehicles for cancer therapy such as paclitaxel (PTX). In this study, we formulated PTX into PLGA polymeric nanoparticles. Vitamin E TPGS was used as an emulsifier to stabilize the nanoparticle formulation. PTX was encapsulated in TPGS-emulsified polymeric nanoparticles (TENPs) by a nanoprecipitation method in ethanol-water system. The resultant PTX-TENPs showed a very uniform particle size (~100 nm) and high drug encapsulation (>80%). The cytotoxicity of PTX-TENPs was examined in A549 lung cancer cell line. Preferential tumor accumulation of TENPs was observed in the A549 lung cancer xenograft model. Tumor growth was significantly inhibited by intravenous injection of PTX-TENPs. Our results suggested that the modified nanoprecipitation method holds great potential for the fabrication of the PTX loaded polymeric nanoparticles. TPGS can be used in the manufacture of polymeric nanoparticles for the controlled release of PTX and other anti-cancer drugs. PMID- 25456999 TI - Effect of surgical margin status after radical prostatectomy on health-related quality of life and illness perception in patients with prostate cancer. AB - OBJECTIVE: The aim of the study was to evaluate the effect of positive surgical margins (PSM) on health-related quality of life and illness perception after radical prostatectomy in patients with prostate cancer. METHODS: Of all patients with prostate cancer diagnosed between 2006 and 2009 in 7 participating hospitals in the Eindhoven region of the Netherlands Cancer Registry, 197 patients who underwent radical prostatectomy were invited to fill in a questionnaire. Data from the Netherlands Cancer Registry were combined with questionnaire data (including European Organization for Research and Treatment of Cancer quality of life questionnaire-C30, quality of life questionnaire-Prostate Module 25, and the Brief Illness Perception Questionnaire). Mean scores per margin status group were compared in multivariate linear regression. RESULTS: Of the addressed patients, 166 (84%) responded to the questionnaire. At time of questioning, their surgery was 1.7 to 6.4 years ago. The prevalence of PSM was 34%. On most scales, patients with PSM reported more favorable scores than patients with negative surgical margins. However, differences were mostly trivial (<5 points on 100-point scales), or of small (5-10) to medium (10-20) clinical importance. Only differences on hormonal complaints and illness comprehensibility were statistically significant. Effect of PSM on scores did not vary between patients who were at different time points after surgery. CONCLUSION: Although patients with PSM showed a trend toward more favorable scores, these differences were of little or no clinical importance. Additional research is needed to evaluate how patients value these differences with respect to oncological outcomes. PMID- 25457000 TI - Biography: Professor Vernon J. Louw. PMID- 25456998 TI - Statin use is associated with improved survival in patients undergoing surgery for renal cell carcinoma. AB - PURPOSE: To determine whether statin use at time of surgery is associated with survival following nephrectomy or partial nephrectomy for renal cell carcinoma (RCC). Statins are thought to exhibit a protective effect on cancer incidence and possibly cancer survival in a number of malignancies. To date, no studies have shown an independent association between statin use and mortality in RCC. METHODS: A retrospective cohort study of 916 patients who underwent radical or partial nephrectomy for RCC from 2000 to 2010 at a single institution was performed. Primary outcomes were overall (OS) and disease-specific survival (DSS). Univariable survival analyses were performed using the Kaplan-Meier and the log-rank methods. Multivariable analysis was performed using a Cox proportional hazards model. The predictive discrimination of the models was assessed using the Harrell c-index. RESULTS: The median follow-up of the entire cohort was 42.5 months. The 3-year OS estimate was 83.1% (95% CI: 77.6%-87.3%) for statin users and 77.3% (95% CI: 73.7%-80.6%) for nonstatin users (P = 0.53). The 3-year DSS was 90.9% (95% CI: 86.3%-94.0%) for statin users and 83.5% (95% CI: 80.1%-86.3%) for nonstatin users (P = 0.015). After controlling for age, American Society of Anesthesiology class, pT category, pN category, metastatic status, preoperative anemia and corrected hypercalcemia, and blood type, statin use at time of surgery was independently associated with improved OS (hazard ratio = 0.62; 95% CI: 0.43-0.90; P = 0.011) and DSS (hazard ratio = 0.48; 95% CI: 0.28-0.83; P = 0.009). The multivariable model for DSS had excellent predictive discrimination with a c-index of 0.91. CONCLUSIONS: These data suggest that statin usage at time of surgery is independently associated with improved OS and DSS in patients undergoing surgery for RCC. PMID- 25457001 TI - Transfusion education and practice in South Africa. PMID- 25457002 TI - Hematopoietic stem cells: an overview. AB - Considerable efforts have been made in recent years in understanding the mechanisms that govern hematopoietic stem cell (HSC) origin, development, differentiation, self-renewal, aging, trafficking, plasticity and transdifferentiation. Hematopoiesis occurs in sequential waves in distinct anatomical locations during development and these shifts in location are accompanied by changes in the functional status of the stem cells and reflect the changing needs of the developing organism. HSCs make a choice of either self renewal or committing to differentiation. The balance between self-renewal and differentiation is considered to be critical to the maintenance of stem cell numbers. It is still under debate if HSC can rejuvenate infinitely or if they do not possess ''true" self-renewal and undergo replicative senescence such as any other somatic cell. Gene therapy applications that target HSCs offer a great potential for the treatment of hematologic and immunologic diseases. However, the clinical success has been limited by many factors. This review is intended to summarize the recent advances made in the human HSC field, and will review the hematopoietic stem cell from definition through development to clinical applications. PMID- 25457003 TI - What is happening? The evolving role of the blood bank in the management of the bleeding patient: The impact of TEG as an early diagnostic predictor for bleeding. AB - Despite recent advances in the understanding and treatment of coagulopathy, the management of the bleeding patient remains as a major challenge. Traditionally, the main task of the blood bank has been to guarantee the supply of high quality blood and blood components/products to the hospital. Decisions regarding the use of blood components have always been the clinicians' responsibility, with little active involvement of the transfusion service. In the last years, many hospitals have implemented the use of "acute transfusion packages" for massively bleeding patients and point-of-care (POC) instruments such as TEG and RoTEM for monitoring coagulation status in this patient group. This, in addition to the implementation of patient blood management programs in the hospitals, has led to an increasing involvement of transfusion medicine specialists in transfusion decision making, especially regarding strategies for monitoring and treatment of the massively bleeding patient. This new trend may contribute to a more optimal management and monitoring of the bleeding patient, as POC testing may be used as an early predictor for blood usage. The blood bank should optimise the use of POC testing to provide accurate information in a cost-effective way. PMID- 25457004 TI - Therapeutic plasmapheresis in geriatric patients: favorable results. AB - Therapeutic plasma exchange is generally a tolerable procedure, although several complications should be considered. Since geriatric population has been growing worldwide, the aim of this study was to retrospectively analyze 4709 TPE data from 981 geriatric procedures (20.8%) and to compare them with 3728 non-geriatric procedures (79.2%). The most common indications for TPE in both groups were sepsis/adult respiratory distress syndrome and multiple organ dysfunction. In geriatric patient group, contrary to expectations of aggravation, complication rate was statistically similar with non-geriatric group (P > 0.05). Therefore, TPE appeared to be a safe procedure in geriatric patients when performed by experienced practitioners. PMID- 25457005 TI - Determining the outcomes for clinicians completing a postgraduate diploma in transfusion medicine. AB - BACKGROUND: Much is known about outcomes and content of training programs in blood banking, but only a limited amount of formal research has been done on the outcomes required for a postgraduate training program aimed at medical doctors working in clinical practice. STUDY DESIGN AND METHODS: A formal qualitative and semi-quantitative research approach was followed to determine and test the factors considered important in determining the outcomes for clinicians completing a postgraduate diploma in transfusion medicine, and consisted of a literature survey, followed by semi-structured interviews and a Delphi survey. RESULTS: After a series of semi-structured interviews, based on an extensive literature survey, 42 factors were identified. These factors were categorized into eight groups and tested in a Delphi survey to determine which of these would be essential outcomes of a postgraduate training program in transfusion medicine. After three rounds of the Delphi survey, consensus was reached on 27 factors and stability on 14 factors. On one factor, neither consensus nor stability could be reached. Twenty-six factors were identified as essential outcomes. CONCLUSION: This research provides support for the essential outcomes to be considered in any postgraduate training program in transfusion medicine aimed at clinicians. PMID- 25457006 TI - The future of transfusion medicine in under resourced countries. PMID- 25457007 TI - An audit of the use of platelet transfusions at Universitas Academic Hospital, Bloemfontein, South Africa. AB - An audit was performed at a tertiary hospital in Bloemfontein, South Africa, to establish whether clinicians adhered to local platelet transfusion guidelines. The audit showed poor compliance with local guidelines, with 34% of platelet transfusions not aligned with guidelines and 29.9% of transfusions administered to patients with platelet counts of >= 150 * 10(9)/L. When compared to medical disciplines, surgical disciplines tended significantly more to transfuse platelets inappropriately (17.1% and 53.7%, respectively; p < 0.0001). Documentation was poor and in 48.4% of orders for platelets, the indication for the platelet transfusion was not clearly stated. Considerable cost could be avoided with improved adherence to guidelines. This study emphasises the need for improving education in transfusion medicine amongst medical doctors. It is hoped that the information gleaned from this study would assist in the design of educational programmes in transfusion medicine as we attempt to close the existing gaps in knowledge and skills in the field, while ensuring that blood is transfused in a cost-effective and appropriate manner. PMID- 25457009 TI - The long-term effects of training interventions on transfusion practice: a follow up audit of red cell concentrate utilisation at Kimberley Hospital, South Africa. AB - This audit in chronically anaemic adult patients assesses whether red cell concentrate is transfused according to guidelines, and evaluates the impact of training interventions, compared with a similar audit conducted in 2010. Retrospectively, 25 transfusion episodes were audited for appropriateness, the investigation of anaemia, threshold achievement, wastage, and informed consent. After training interventions, a further 25 episodes were prospectively analysed. The effects of current training interventions were not shown to have a statistically significant impact. Compared to a 2010 audit, however, a statistically significant improvement was demonstrated in transfusion practice, suggesting that training interventions may lead to sustainable long-term improvements. PMID- 25457008 TI - The impact of HIV-associated anaemia on the incidence of red blood cell transfusion: implications for blood services in HIV-endemic countries. AB - Cytopaenias, especially anaemia, are common in the HIV-infected population. The causes of HIV related cytopaenias are multi-factorial and often overlapping. In addition, many of the drugs used in the management of HIV-positive individuals are myelosuppresive and can both cause and exacerbate anaemia. Even though blood and blood products are still the cornerstone in the management of severe cytopaenias, how HIV may affect blood utilisation is not well understood. The impact of HIV/AIDS on blood collections has been well documented. As the threat posed by HIV on the safety of the blood supply became clearer, South Africa introduced progressively more stringent donor selection criteria, based on the HIV risk profile of the donor cohort from which the blood collected. The implementation of new testing technology in 2008 which significantly improved the safety of the blood supply enabled the removal of what was perceived by many as a racially based donor risk model. However, this new technology had a significant and sustained impact on the cost of blood and blood products in South Africa. In contrast, it would appear little is known of how HIV influences the utilisation of blood and blood products. Considering the high prevalence of HIV among hospitalised patients and the significant risk for anaemia among this group, there would be an expectation that the transfusion requirements of an HIV infected patient would be higher than that of an HIV-negative patient. However, very little published data is available on this topic which emphasises the need for further large-scale studies to evaluate the impact of HIV/AIDS on the utilisation of blood and blood products and how the large-scale roll-out of ARV programs may in future play a role in determining the country's blood needs. PMID- 25457011 TI - Patients' recall and perceptions regarding consent to blood transfusion at Universitas Academic Hospital, Bloemfontein, South Africa. AB - We studied the recall and perceptions of transfused patients at a single centre. Fifty-three patients were included. In 11 (20.8%) cases, no written informed consent document could be traced. Four patients who had informed consent documents in their records had no recollection of the consent process. Approximately 11% of patients stated that the consent process was performed using unfamiliar terms. When compared to Caucasian and mixed race respondents, more African respondents (83%) would have preferred the presence of a family member (p < 0.01). Although not all the patients experienced the informed consent positively, it did not impact on their perception of the blood transfusion itself. PMID- 25457010 TI - RHD genotyping and its implication in transfusion practice. AB - BACKGROUND: The limitations of serology can be overcome by molecular typing. In order to evaluate the contribution of RH systematic genotyping and its implication in transfusion practice, a genotyping of D- blood donors was initiated. METHODS: Blood samples were collected from 400 unrelated D- individuals. All samples were tested by RHD exon 10 PCR. In order to clarify the molecular mechanisms of RHD gene carrier, we applied molecular tools using different techniques: PCR-multiplex, and PCR-SSPs. RESULTS: Among 400 D- subjects tested, 390 had RHD gene deletion; and 10 had RHD exon 10 of which seven were associated with the presence of the C or E antigens. Among D- carriers, we observed in five cases the presence of RHD-CE-Ds hybrid, in four cases the presence of pseudogene RHD psi and in one case the presence of weak D type 4. CONCLUSION: Since the majority of aberrant alleles were associated with C or E antigens and the preliminary infrastructure for molecular diagnostic were absent in all Tunisia territory, we recommend to reinforce transfusion practice to consider D- donors but C+/E+ antigens as D+ donors and the application of RHD molecular typing only to solve serologic problems. PMID- 25457012 TI - The difference in scope of practice between a specialist in transfusion medicine and the clinician who deals with transfusion on an ad hoc basis. AB - BACKGROUND: In designing a training program in transfusion medicine, a range of factors needs to be taken into account. One of these is delineating the scope of practice of students in order to ensure a program that will be appropriate in terms of content, level of difficulty, and the requirements of the student's working environment. Very little has been done in terms of scientifically studying the differences in scope of practice of a specialist in transfusion medicine compared to a clinician who deals with blood transfusion on an intermittent basis. STUDY DESIGN AND METHODS: A formal qualitative and semi quantitative research approach was followed to determine and test the factors considered important in determining the difference in scope of practice between a specialist in transfusion medicine and the clinician who deals with transfusion on an ad hoc basis, and consisted of a literature survey, followed by semi structured interviews and a Delphi survey. RESULTS: Nineteen factors were identified, through semi-structured interviews, as being particularly descriptive of the scope of practice of a full-time specialist in transfusion medicine that differentiated them from clinicians dealing with blood transfusion on an ad hoc basis. Nine factors were identified as being descriptive of the scope of practice of clinicians dealing with blood transfusion on an ad hoc basis, which differentiate them from full-time specialists in transfusion medicine. CONCLUSION: Designing a training program with the end in mind requires an understanding of the variable contexts within which clinicians, who deal with blood transfusion, work. The findings of this study provide a framework for planning a curriculum that takes such differing scopes of practice into account. PMID- 25457013 TI - Editorial. PMID- 25457015 TI - Natural History after Biochemical Failure Following Dose-escalated External Beam Radiation: An Opportunity to Improve Outcomes? PMID- 25457016 TI - The evolving picture of lower urinary tract symptom management. PMID- 25457014 TI - Active surveillance for prostate cancer: a systematic review of clinicopathologic variables and biomarkers for risk stratification. AB - CONTEXT: Active surveillance (AS) is an important strategy to reduce prostate cancer overtreatment. However, the optimal criteria for eligibility and predictors of progression while on AS are debated. OBJECTIVE: To review primary data on markers, genetic factors, and risk stratification for patient selection and predictors of progression during AS. EVIDENCE ACQUISITION: Electronic searches were conducted in PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 2014 for original articles on biomarkers and risk stratification for AS. EVIDENCE SYNTHESIS: Patient factors associated with AS outcomes in some studies include age, race, and family history. Multiple studies provide consistent evidence that a lower percentage of free prostate-specific antigen (PSA), a higher Prostate Health Index (PHI), a higher PSA density (PSAD), and greater biopsy core involvement at baseline predict a greater risk of progression. During follow-up, serial measurements of PHI and PSAD, as well as repeat biopsy results, predict later biopsy progression. While some studies have suggested a univariate relationship between urinary prostate cancer antigen 3 (PCA3) and transmembrane protease, serine 2-v-ets avian erythroblastosis virus E26 oncogene homolog gene fusion (TMPRSS2:ERG) with adverse biopsy features, these markers have not been consistently shown to independently predict AS outcomes. No conclusive data support the use of genetic tests in AS. Limitations of these studies include heterogeneous definitions of progression and limited follow-up. CONCLUSIONS: There is a growing body of literature on patient characteristics, biopsy features, and biomarkers with potential utility in AS. More data are needed on practical applications such as combining these tests into multivariable clinical algorithms and long-term outcomes to further improve AS in the future. PATIENT SUMMARY: Several PSA-based tests (free PSA, PHI, PSAD) and the extent of cancer on biopsy can help to stratify the risk of progression during active surveillance. Investigation of several other markers is under way. PMID- 25457017 TI - Patterns of Declining Use and the Adverse Effect of Primary Androgen Deprivation on All-cause Mortality in Elderly Men with Prostate Cancer. AB - BACKGROUND: Primary androgen deprivation therapy (pADT) is commonly used to treat elderly men diagnosed with localized prostate cancer (CaP), despite the lack of evidence supporting its use. OBJECTIVE: To examine the effect of pADT on mortality and to assess contemporary trends of pADT use in elderly men with CaP. DESIGN, SETTING, AND PARTICIPANTS: Men older than 65 yr residing in Surveillance, Epidemiology, and End Results (SEER) registry areas diagnosed with localized or locally advanced CaP between 1992 and 2009 and not receiving definitive therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Propensity score (PS)-weighted Cox proportional hazards models were used to estimate the effect of pADT use on overall survival among patients receiving pADT. The interaction between comorbidity-adjusted life expectancy (LE) and pADT use was assessed within the Cox and PS-weighted models. Contemporary (2004-2009) trends for pADT use were analyzed by linear regression. RESULTS AND LIMITATIONS: The primary cohort included 46 376 men, of whom 17 873 received pADT (39%). Patients with >10 yr LE had lower pADT utilization rates than patients with short LE. Between 2004 and 2009, the use of pADT in men with localized CaP decreased by 14% (from 36% to 22%). Relative to observation, pADT was associated with a survival disadvantage, with a hazard ratio for all-cause mortality of 1.37 (95% confidence interval 1.20 1.56). Limitations included biases not accounted for by the PS-weighted model, changes in CaP staging over the study period, the absence of prostate-specific antigen (PSA) data prior to 2004, and the limits of retrospective analysis to demonstrate causality. CONCLUSIONS: The use of pADT in elderly men with localized CaP has decreased over time. For men forgoing primary definitive therapy, the use of pADT is not associated with a survival benefit compared to observation, and denies men an opportunity for cure with definitive therapy. The deleterious effect of pADT is most pronounced in men with prolonged LE. PATIENT SUMMARY: In this report, we assessed the effect of primary androgen deprivation (pADT) on prostate cancer mortality and determined current trends in the use of pADT. We showed that use of pADT in men aged >65 yr with localized prostate cancer has decreased over time. We also found that pADT is detrimental to men with localized prostate cancer, and particularly men with longer life expectancy. Therefore, we conclude that ADT should not be used as a primary treatment for men with prostate cancer that has not spread beyond the prostate. PMID- 25457018 TI - Degree of preservation of the neurovascular bundles during radical prostatectomy and urinary continence 1 year after surgery. AB - BACKGROUND: Many elderly or impotent men with prostate cancer may not receive a bundle-preserving radical prostatectomy as a result of uncertainty regarding the effect on urinary incontinence. OBJECTIVE: We searched for predictors of urinary incontinence 1 yr after surgery among surgical steps during radical prostatectomy. DESIGN, SETTING, AND PARTICIPANTS: More than 100 surgeons in 14 centers prospectively collected data on surgical steps during an open or robot assisted laparoscopic radical prostatectomy. At 1 yr after surgery, a neutral third-party secretariat collected patient-reported information on urinary incontinence. After excluding men with preoperative urinary incontinence or postoperative irradiation, data were available for 3379 men. INTERVENTION: Surgical steps during radical prostatectomy, including dissection plane as a measure of the degree of preservation of the two neurovascular bundles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Urinary incontinence 1 yr after surgery was measured as patient-reported use of pads. In different categories of surgical steps, we calculated the percentage of men changing pads "about once per 24 h" or more often. Relative risks were calculated as percentage ratios between categories. RESULTS AND LIMITATIONS: A strong association was found between the degree of bundle preservation and urinary incontinence 1 yr after surgery. We set the highest degree of bundle preservation (bilateral intrafascial dissection) as the reference category (relative risk = 1.0). For the men in the remaining six groups, ordered according to the degree of preservation, we obtained the following relative risks (95% confidence interval [CI]): 1.07 (0.63-1.83), 1.19 (0.77-1.85), 1.56 (0.99-2.45), 1.78 (1.13-2.81), 2.27 (1.45-3.53), and 2.37 (1.52 3.69). In the latter group, no preservation of any of the bundles was performed. The pattern was similar for preoperatively impotent men and for elderly men. Limitations of this analysis include the fact that noise influences the relative risks, due to variations between surgeons in the use of undocumented surgical steps of the procedure, variations in surgical experience and in how the surgical steps are reported, as well as variations in the metrics of patient-reported use of pads. CONCLUSIONS: We found that the degree of preservation of the two neurovascular bundles during radical prostatectomy predicts the rate of urinary incontinence 1 yr after the operation. According to our findings, preservation of both neurovascular bundles to avoid urinary incontinence is also meaningful for elderly and impotent men. PATIENT SUMMARY: We studied the degree of preservation of the two neurovascular bundles during radical prostatectomy and found that the risk of incontinence decreases if the surgeon preserves two bundles instead of one, and if the surgeon preserves some part of a bundle rather than not doing so. PMID- 25457019 TI - Response to crizotinib in a patient with MET-mutant papillary renal cell cancer after progression on tivantinib. PMID- 25457021 TI - EAU guidelines on penile cancer: 2014 update. AB - CONTEXT: Penile cancer has high mortality once metastatic spread has occurred. Local treatment can be mutilating and devastating for the patient. Progress has been made in organ-preserving local treatment, lymph node management, and multimodal treatment of lymphatic metastases, requiring an update of the European Association of Urology guidelines. OBJECTIVE: To provide an evidence-based update of treatment recommendations based on the literature published since 2008. EVIDENCE ACQUISITION: A PubMed search covering the period from August 2008 to November 2013 was performed, and 352 full-text papers were reviewed. Levels of evidence were assessed and recommendations graded. Because there is a lack of controlled trials or large series, the levels of evidence and grades of recommendation are low compared with those for more common diseases. EVIDENCE SYNTHESIS: Penile squamous cell carcinoma occurs in distinct histologic variants, some of which are related to human papilloma virus infection; others are not. Primary local treatment should be organ preserving, if possible. There are no outcome differences between local treatment modes in superficial and T1 disease. Management of inguinal lymph nodes is crucial for prognosis. In impalpable nodes, invasive staging should be done depending on the risk factors of the primary tumour. Lymph node metastases should be treated by surgery and adjuvant chemotherapy in N2/N3 disease. CONCLUSIONS: Organ preservation has become the standard approach to low-stage penile cancer, whereas in lymphatic disease, it is recognised that multimodal treatment with radical inguinal node surgery and adjuvant chemotherapy improves outcome. PATIENT SUMMARY: Approximately 80% of penile cancer patients of all stages can be cured. With increasing experience in the management of penile cancer, it is recognized that organ-preserving treatment allows for better quality of life and sexual function and should be offered to all patients whenever feasible. Referral to centres with experience is recommended. PMID- 25457022 TI - Mitochondrial DNA haplogroup B5 confers genetic susceptibility to Alzheimer's disease in Han Chinese. AB - Mitochondrial dysfunction has been widely reported in psychiatric and neurodegenerative diseases. We aimed to investigate the association between matrilineal structures of Han Chinese populations and Alzheimer's disease (AD) by a 2-stage case-control study: A total of 341 AD patients and 435 normal individuals from Southwest China were analyzed for mitochondrial DNA sequence variations and were classified into respective haplogroups. A total of 371 AD patients and 470 normal individuals from East China, as validation samples, were genotyped for the variants defining the risk haplogroup. Haplogroup B5 had a significantly higher frequency in AD patients (7.33%) than in control subjects (3.68%) from Southwest China, and we found a similar pattern of higher frequency of B5 in patients in the case-control sample from East China. In the combined population, association of haplogroup B5 with AD risk was strengthened (p = 0.02; odds ratio = 1.74; 95% confidence interval = 1.10-2.76). In lymphoblastoid cell lines belonging to haplogroup B5a, we observed significantly increased reactive oxygen species and decreased mitochondrial mass. Hela cells with stable expression of the MT-ATP6 gene with B5-defining variant m.8584G>A also showed a significantly decreased mitochondrial function. Taken together, our results indicated that haplogroup B5 conferred genetic susceptibility to AD in Han Chinese, and this effect was most likely mediated by ancient variant m.8584G>A. The predisposing effect of B5 to AD is consistent with the ancestral susceptibility model of complex diseases. PMID- 25457023 TI - Dipeptide repeat protein toxicity in frontotemporal lobar degeneration and in motor neurone disease associated with expansions in C9ORF72-a cautionary note. PMID- 25457020 TI - Clinical Outcomes of Castration-resistant Prostate Cancer Treatments Administered as Third or Fourth Line Following Failure of Docetaxel and Other Second-line Treatment: Results of an Italian Multicentre Study. AB - BACKGROUND: The availability of new agents (NAs) active in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel treatment (abiraterone acetate, cabazitaxel, and enzalutamide) has led to the possibility of using them sequentially to obtain a cumulative survival benefit. OBJECTIVE: To provide clinical outcome data relating to a large cohort of mCRPC patients who received a third-line NA after the failure of docetaxel and another NA. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively reviewed the clinical records of patients who had received at least two successive NAs after the failure of docetaxel. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The independent prognostic value of a series of pretreatment covariates on the primary outcome measure of overall survival was assessed using Cox regression analysis. RESULTS AND LIMITATIONS: We assessed 260 patients who received one third-line NA between January 2012 and December 2013, including 38 who received a further NA as fourth-line therapy. The median progression-free and overall survival from the start of third-line therapy was, respectively, 4 mo and 11 mo, with no significant differences between the NAs. Performance status, and haemoglobin and alkaline phosphatase levels were the only independent prognostic factors. The limitations of the study are mainly due its retrospective nature and the small number of patients treated with some of the sequences. CONCLUSIONS: We were unable to demonstrate a difference in the clinical outcomes of third-line NAs regardless of previous NA therapy. PATIENT SUMMARY: It is debated which sequence of treatments to adopt after docetaxel. Our data do not support the superiority of any of the three new agents in third-line treatment, regardless of the previously administered new agent. PMID- 25457025 TI - CaMKII-dependent dendrite ramification and spine generation promote spatial training-induced memory improvement in a rat model of sporadic Alzheimer's disease. AB - Participation in cognitively stimulating activities can preserve memory capacities in patients with Alzheimer's disease (AD), but the mechanism is not fully understood. Here, we used a rat model with hyperhomocysteinemia, an independent risk factor of AD, to study whether spatial training could remodel the synaptic and/or dendritic plasticity and the key molecular target(s) involved. We found that spatial training in water maze remarkably improved the subsequent short-term and long-term memory performance in contextual fear conditioning and Barnes maze. The trained rats showed an enhanced dendrite ramification, spine generation and plasticity in dentate gyrus (DG) neurons, and stimulation of long-term potentiation between perforant path and DG circuit. Spatial training also increased the levels of postsynaptic GluA1, GluN2A, GluN2B, and PSD93 with selective activation of calcium/calmodulin-dependent protein kinase II (CaMKII), although inhibition of CaMKII by stereotaxic injection of KN93 into hippocampal DG, abolished the training-induced cognitive improvement, dendrite ramification, and spine generation. We conclude that spatial training can preserve the cognitive function by CaMKII-dependent remodeling of dendritic plasticity in hyperhomocysteinemia-induced sporadic AD-like rats. PMID- 25457024 TI - VCP gene analyses in Japanese patients with sporadic amyotrophic lateral sclerosis identify a new mutation. AB - Accumulating evidence has proven that mutations in the VCP gene encoding valosin containing protein (VCP) cause inclusion body myopathy with Paget disease of the bone and frontotemporal dementia. This gene was later found to be causative for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, occurring typically in elderly persons. We thus sequenced the VCP gene in 75 Japanese patients with sporadic ALS negative for mutations in other genes causative for ALS and found a novel mutation, p.Arg487His, in 1 patient. The newly identified mutant as well as known mutants rendered neuronal cells susceptible to oxidative stress. The presence of the mutation in the Japanese population extends the geographic region for involvement of the VCP gene in sporadic ALS to East Asia. PMID- 25457026 TI - Intermediate-length polyglutamine in ATXN2 is a possible risk factor among Eastern Chinese patients with amyotrophic lateral sclerosis. AB - An effective treatment for amyotrophic lateral sclerosis (ALS) has not yet been found because the pathogenesis of this fatal disease is not well understood. A number of previous studies demonstrated that intermediate-length polyglutamine repeats within the ataxin-2 gene (ATXN2) might be a risk factor among patients with ALS in Western countries. Here, we aim to determine whether this sequence is a risk factor in Eastern Chinese ALS patients. Therefore, 379 unrelated sporadic ALS patients, 15 unrelated familial ALS patients, and 900 neurologically normal controls were studied. The ATXN2 CAG repeats were amplified using polymerase chain reaction. The products were separated on an 8% polyacrylamide gel and confirmed using Sanger sequencing. The results were evaluated using SPSS 17.0. We found that ATXN2 intermediate-length polyglutamine expansions greater than 24 and 27 repeats were associated with sporadic ALS. Our finding supports the hypothesis that ATXN2 plays an important role in the pathogenesis of ALS. PMID- 25457027 TI - Identifying Abeta-specific pathogenic mechanisms using a nematode model of Alzheimer's disease. AB - Multiple gene expression alterations have been linked to Alzheimer's disease (AD), implicating multiple metabolic pathways in its pathogenesis. However, a clear distinction between AD-specific gene expression changes and those resulting from nonspecific responses to toxic aggregating proteins has not been made. We investigated alterations in gene expression induced by human beta-amyloid peptide (Abeta) in a Caenorhabditis elegans AD model. Abeta-induced gene expression alterations were compared with those caused by a synthetic aggregating protein to identify Abeta-specific effects. Both Abeta-specific and nonspecific alterations were observed. Among Abeta-specific genes were those involved in aging, proteasome function, and mitochondrial function. An intriguing observation was the significant overlap between gene expression changes induced by Abeta and those induced by Cry5B, a bacterial pore-forming toxin. This led us to hypothesize that Abeta exerts its toxic effect, at least in part, by causing damage to biological membranes. We provide in vivo evidence consistent with this hypothesis. This study distinguishes between Abeta-specific and nonspecific mechanisms and provides potential targets for therapeutics discovery. PMID- 25457028 TI - RIT2 polymorphism is associated with Parkinson's disease in a Han Chinese population. AB - Recently, a meta-analysis including 5 large genome-wide association studies has identified rs12456492 variant of RIT2 gene as a novel risk locus for Parkinson's disease (PD) in Caucasian populations. However, the association between RIT2 polymorphism and PD risk has not been positively replicated in Asian population yet. We detected the genotypes of rs12456492 in 524 PD patients and 521 control subjects from a Han Chinese population. The allele and genotype distribution of rs12456492 variant were significantly different between PD patients and controls (allele p = 0.001, genotype p = 0.002). Logistic regression analysis showed that the G-carrying genotype (AG + GG) individuals exhibited a nearly 1.4-fold increased risk for PD compared with the AA genotype carriers (OR = 1.390; 95% confidence interval = 1.079-1.791; p = 0.011). Our data support that the carriage of G allele of rs12456492 variant of RIT2 gene significantly increases the risk for PD in Han Chinese population, suggesting a potential role of RIT2 in the etiology of PD. PMID- 25457041 TI - Deconstructing evidence-based practice: progress and ambiguities. PMID- 25457029 TI - Important outcome predictors showed greater baseline heterogeneity than age in two systematic reviews. AB - OBJECTIVES: An unknown number of randomized controlled trials (RCTs) have their treatment allocation subverted. If such trials are included in systematic reviews, biased results may be used to change policy. To assess whether a systematic review contains subverted trials, a meta-analysis of group differences regarding a baseline variable can be undertaken. In this article, the performance of age with another prognostic variable in detecting selection bias within systematic reviews is compared. STUDY DESIGN AND SETTING: Two Cochrane systematic reviews, one of low back pain and one of hip protectors for fracture prevention, were identified. The component RCT texts were obtained, and data were extracted on age, baseline back pain score (low back pain review), and baseline body mass (hip protector review). In this exemplar, we tested for baseline heterogeneity with a fixed-effects meta-analysis. RESULTS: Heterogeneity in age between the intervention and control groups was found. The observed heterogeneity increased with baseline back pain and body mass relative to age in each review. CONCLUSION: We found that covariates predictive of outcome demonstrate greater heterogeneity than age. However, there were fewer missing data relating to age. Reviewers should consider using age and another prognostic covariate in baseline meta analyses to check the validity of their results. PMID- 25457042 TI - Optimizing bi-objective redundancy allocation problem with a mixed redundancy strategy. AB - Redundancy Allocation Problem (RAP) is a challenging subject which has attracted the attention of many authors. Generally, in the RAP there are two strategies for using the redundant components: active and standby. In this paper a new redundancy strategy, called mixed redundancy, is introduced and considered in a multi-objective optimization RAP. Results demonstrate that the new strategy increases the reliability value of the system considerably. This improvement can be very important for system designers, because the reliability of any systems with the structure of redundant components can be increased by changing the redundancy strategy, not by only adding redundant component. Moreover, this improvement dose not increases the cost and other known physical characteristics of the system. PMID- 25457043 TI - Design and real time implementation of single phase boost power factor correction converter. AB - This paper presents a real time implementation of the single-phase power factor correction (PFC) AC-DC boost converter. A combination of higher order sliding mode controller based on super twisting algorithm and predictive control techniques are implemented to improve the performance of the boost converter. Due to the chattering effects, the higher order sliding mode control (HOSMC) is designed. Also, the predictive technique is modified taking into account the large computational delays. The robustness of the controller is verified conducting simulation in MATLAB, the results show good performances in both steady and transient states. An experiment is conducted through a test bench based on dSPACE 1104. The experimental results proved that the proposed controller enhanced the performance of the converter under different parameters variations. PMID- 25457044 TI - Distance estimation using RSSI and particle filter. AB - This paper presents a particle filter algorithm for distance estimation using multiple antennas on the receiver's side and only one transmitter, where a received signal strength indicator (RSSI) of radio frequency was used. Two different placements of antennas were considered (parallel and circular). The physical layer of IEEE standard 802.15.4 was used for communication between transmitter and receiver. The distance was estimated as the hidden state of a stochastic system and therefore a particle filter was implemented. The RSSI acquisitions were used for the computation of important weights within the particle filter algorithm. The weighted particles were re-sampled in order to ensure proper distribution and density. Log-normal and ground reflection propagation models were used for the modeling of a prior distribution within a Bayesian inference. PMID- 25457045 TI - Climate governance as a complex adaptive system: reply to comments on "climate change governance, cooperation and self-organization". PMID- 25457046 TI - Interpersonal struggle or interpersonal bonding? Comment on "personality from a cognitive-biological perspective", by Y. Neuman. PMID- 25457047 TI - The emotional fundamentals of personality and the higher affective polarities of mind: comment on "personality from a cognitive-biological perspective" by Y. Neuman. PMID- 25457048 TI - Avoiding "greedy reductionism" in personality theory: comment on "personality from a cognitive-biological perspective" by Y. Neuman. PMID- 25457049 TI - Who is afraid of reductionism and why reductionism is necessary for understanding the complexity of personality: reply to comments on "personality from a cognitive biological perspective" by Y. Neuman. PMID- 25457050 TI - Early asymmetric cues triggering the dorsal/ventral gene regulatory network of the sea urchin embryo. AB - Dorsal/ventral (DV) patterning of the sea urchin embryo relies on a ventrally localized organizer expressing Nodal, a pivotal regulator of the DV gene regulatory network. However, the inceptive mechanisms imposing the symmetry breaking are incompletely understood. In Paracentrotus lividus, the Hbox12 homeodomain-containing repressor is expressed by prospective dorsal cells, spatially facing and preceding the onset of nodal transcription. We report that Hbox12 misexpression provokes DV abnormalities, attenuating nodal and nodal dependent transcription. Reciprocally, impairing hbox12 function disrupts DV polarity by allowing ectopic expression of nodal. Clonal loss-of-function, inflicted by blastomere transplantation or gene-transfer assays, highlights that DV polarization requires Hbox12 action in dorsal cells. Remarkably, the localized knock-down of nodal restores DV polarity of embryos lacking hbox12 function. Finally, we show that hbox12 is a dorsal-specific negative modulator of the p38 MAPK activity, which is required for nodal expression. Altogether, our results suggest that Hbox12 function is essential for proper positioning of the DV organizer. PMID- 25457052 TI - Thermodynamic evidence for a dual transport mechanism in a POT peptide transporter. AB - Peptide transport plays an important role in cellular homeostasis as a key route for nitrogen acquisition in mammalian cells. PepT1 and PepT2, the mammalian proton coupled peptide transporters (POTs), function to assimilate and retain diet-derived peptides and play important roles in drug pharmacokinetics. A key characteristic of the POT family is the mechanism of peptide selectivity, with members able to recognise and transport >8000 different peptides. In this study, we present thermodynamic evidence that in the bacterial POT family transporter PepTSt, from Streptococcus thermophilus, at least two alternative transport mechanisms operate to move peptides into the cell. Whilst tri-peptides are transported with a proton:peptide stoichiometry of 3:1, di-peptides are co transported with either 4 or 5 protons. This is the first thermodynamic study of proton:peptide stoichiometry in the POT family and reveals that secondary active transporters can evolve different coupling mechanisms to accommodate and transport chemically and physically diverse ligands across the membrane. PMID- 25457054 TI - Corkscrew intravascular channels within chronic common carotid artery occlusions in takayasu arteritis that disappear after angioplasty. PMID- 25457051 TI - Stepwise visualization of membrane pore formation by suilysin, a bacterial cholesterol-dependent cytolysin. AB - Membrane attack complex/perforin/cholesterol-dependent cytolysin (MACPF/CDC) proteins constitute a major superfamily of pore-forming proteins that act as bacterial virulence factors and effectors in immune defence. Upon binding to the membrane, they convert from the soluble monomeric form to oligomeric, membrane inserted pores. Using real-time atomic force microscopy (AFM), electron microscopy (EM), and atomic structure fitting, we have mapped the structure and assembly pathways of a bacterial CDC in unprecedented detail and accuracy, focussing on suilysin from Streptococcus suis. We show that suilysin assembly is a noncooperative process that is terminated before the protein inserts into the membrane. The resulting ring-shaped pores and kinetically trapped arc-shaped assemblies are all seen to perforate the membrane, as also visible by the ejection of its lipids. Membrane insertion requires a concerted conformational change of the monomeric subunits, with a marked expansion in pore diameter due to large changes in subunit structure and packing. PMID- 25457053 TI - Scaffold and edge vascular response following implantation of everolimus-eluting bioresorbable vascular scaffold: a 3-year serial optical coherence tomography study. AB - OBJECTIVES: This study sought to investigate the in-scaffold vascular response (SVR) and edge vascular response (EVR) after implantation of an everolimus eluting bioresorbable scaffold (BRS) using serial optical coherence tomography (OCT) imaging. BACKGROUND: Although studies using intravascular ultrasound have evaluated the EVR in metal stents and BRSs, there is a lack of OCT-based SVR and EVR assessment after BRS implantation. METHODS: In the ABSORB Cohort B (ABSORB Clinical Investigation, Cohort B) study, 23 patients (23 lesions) in Cohort B1 and 17 patients (18 lesions) in Cohort B2 underwent truly serial OCT examinations at 3 different time points (Cohort B1: post-procedure, 6 months, and 2 years; B2: post-procedure, 1 year, and 3 years) after implantation of an 18-mm scaffold. A frame-by-frame OCT analysis was performed at the 5-mm proximal, 5-mm distal edge, and 2-mm in-scaffold margins, whereas the middle 14-mm in-scaffold segment was analyzed at 1-mm intervals. RESULTS: The in-scaffold mean luminal area significantly decreased from baseline to 6 months or 1 year (7.22 +/- 1.24 mm(2) vs. 6.05 +/- 1.38 mm(2) and 7.64 +/- 1.19 mm(2) vs. 5.72 +/- 0.89 mm(2), respectively; both p < 0.01), but remained unchanged from then onward. In Cohort B1, a significant increase in mean luminal area of the distal edge was observed (5.42 +/- 1.81 mm(2) vs. 5.58 +/- 1.53 mm(2); p < 0.01), whereas the mean luminal area of the proximal edge remained unchanged at 6 months. In Cohort B2, the mean luminal areas of the proximal and distal edges were significantly smaller than post-procedure measurements at 3 years. The mean luminal area loss at both edges was significantly less than the mean luminal area loss of the in-scaffold segment at both 6-month and 2-year follow-up in Cohort B1 or at 1 year and 3 years in Cohort B2. CONCLUSIONS: This OCT-based serial EVR and SVR evaluation of the Absorb Bioresorbable Vascular Scaffold (Abbott Vascular, Santa Clara, California) showed less luminal loss at the edges than luminal loss within the scaffold. The luminal reduction of both edges is not a nosologic entity, but an EVR in continuity with the SVR, extending from the in-scaffold margin to both edges. (ABSORB Clinical Investigation, Cohort B [ABSORB B]; NCT00856856). PMID- 25457055 TI - The role of frame geometry assessment during transcatheter aortic valve replacement by rotational angiography. PMID- 25457056 TI - Organized thrombus mimicking spontaneous coronary artery dissection. PMID- 25457057 TI - Left ventricular perforation during ventriculogram using an optitorque tiger catheter. PMID- 25457058 TI - Recanalized thrombus treated with bioresorbable vascular scaffold: insights from optical coherence tomography. PMID- 25457059 TI - Percutaneous treatment of chronic distal aortic occlusion: a viable option. PMID- 25457064 TI - Salivary transforming growth factor alpha in patients with Sjogren's syndrome and reflux laryngitis. AB - INTRODUCTION: Saliva plays a key role in the homeostasis of the digestive tract, through its inorganic components and its protein growth factors. Sjogren's syndrome patients have a higher prevalence of gastroesophageal reflux disease and laryngopharyngeal reflux. Decreased salivary transforming growth factor alpha levels were observed in dyspeptic patients, but there have been no studies in patients with Sjogren's syndrome and laryngopharyngeal reflux. OBJECTIVE: To compare the salivary transforming growth factor alpha levels of patients with Sjogren's syndrome and laryngopharyngeal reflux to those of healthy controls. METHODS: This is a prospective controlled study. Twelve patients with Sjogren's syndrome and laryngopharyngeal reflux and 11 controls were prospectively evaluated. Spontaneous and stimulated saliva samples were obtained to establish salivary transforming growth factor alpha concentrations. RESULTS: The salivary transforming growth factor alpha levels of patients were significantly higher than those of healthy controls. Five patients with laryngopharyngeal reflux also had erosive esophagitis; their salivary transforming growth factor alpha levels were comparable to controls. CONCLUSION: Salivary transforming growth factor alpha level was significantly higher in patients with Sjogren's syndrome and laryngopharyngeal reflux when compared to the control group. PMID- 25457065 TI - Effectiveness of balloon sinuplasty in patients with chronic rhinosinusitis without polyposis. AB - INTRODUCTION: Balloon sinuplasty is a minimally invasive endoscopic procedure, developed with the aim of restoring patency of the paranasal sinuses ostia with minimal damage to the mucosa. OBJECTIVE: To evaluate the effectiveness of balloon sinuplasty in patients with chronic rhinosinusitis. METHODS: This was a prospective cohort study comprising 18 patients with chronic rhinosinusitis without polyposis who underwent balloon sinuplasty. Patients were evaluated for clinical criteria, quality of life (Sino-Nasal Outcome Questionnaire Test-20 [SNOT-20]), and computed tomography of the sinuses (Lund-Mackay staging) preoperatively and three to six months after the procedure. RESULTS: Out of 18 patients assessed, 13 were included, with a mean age of 39.9+/-15.6 years. Ostia sinuplasty was performed in 24 ostia (four sphenoid, ten frontal, and ten maxillary sinus). At the follow-up, 22 (92%) ostia were patent and there was no major complication. There was symptomatic improvement (SNOT-20), with Cronbach coefficients for consistency of the questionnaire items of 0.86 (95% CI: 0.73 0.94) preoperatively and of 0.88 (95% CI: 0.77-0.95) postoperatively, the difference being statistically significant (p<0.001). In addition, there was marked reduction of the computed tomography signs, an average of 4.2 point score (p<0.001). CONCLUSION: Sinuplasty is effective in reducing symptoms and improving quality of life as a treatment option for chronic rhinosinusitis in selected patients. PMID- 25457061 TI - Adipose tissue lipolysis and energy metabolism in early cancer cachexia in mice. AB - Cancer cachexia is a progressive metabolic disorder that results in depletion of adipose tissue and skeletal muscle. A growing body of literature suggests that maintaining adipose tissue mass in cachexia may improve quality-of-life and survival outcomes. Studies of lipid metabolism in cachexia, however, have generally focused on later stages of the disorder when severe loss of adipose tissue has already occurred. Here, we investigated lipid metabolism in adipose, liver and muscle tissues during early stage cachexia - before severe fat loss - in the colon-26 murine model of cachexia. White adipose tissue mass in cachectic mice was moderately reduced (34-42%) and weight loss was less than 10% of initial body weight in this study of early cachexia. In white adipose depots of cachectic mice, we found evidence of enhanced protein kinase A - activated lipolysis which coincided with elevated total energy expenditure and increased expression of markers of brown (but not white) adipose tissue thermogenesis and the acute phase response. Total lipids in liver and muscle were unchanged in early cachexia while markers of fatty oxidation were increased. Many of these initial metabolic responses contrast with reports of lipid metabolism in later stages of cachexia. Our observations suggest intervention studies to preserve fat mass in cachexia should be tailored to the stage of cachexia. Our observations also highlight a need for studies that delineate the contribution of cachexia stage and animal model to altered lipid metabolism in cancer cachexia and identify those that most closely mimic the human condition. PMID- 25457066 TI - Classification of rhinoplasties performed in an otorhinolaryngology referral center in Brazil. AB - INTRODUCTION: Facial plastic and reconstructive surgery involves the use of surgical procedures to achieve esthetic and functional improvement. It can be used for traumatic, congenital, or developmental injuries. Medicine, with an emphasis on facial plastic surgery, has made progress in several areas, including rhinoplasty, providing good long-term results and higher patient satisfaction. OBJECTIVE: To evaluate cases of rhinoplasty and its subtypes in a referral center, and to understand the relevance of teaching rhinoplasty techniques in a service of otolaryngology residency. METHODS: A retrospective study that assessed 325 rhinoplasties performed by third-year medical residents under the supervision of chief residents in charge of the Service of Facial Plastic Surgery in this hospital was conducted from January of 2003 to August of 2012. The Service Protocol included the following subtypes: functional, esthetic, post-traumatic, revision, and reconstructive rhinoseptoplasty. RESULTS: Of the rhinoplasties performed 184 (56.21%) were functional, 59 (18.15%) were post-traumatic, 27 were (8.30%) esthetic, 15 were (4.61%) reconstructive, and 40 (12.30%) were revision procedures. CONCLUSION: Functional rhinoseptoplasties were the most prevalent type, which highlights the relevance of teaching surgical techniques, not only for septoplasty, but also the inclusion of rhinoplasty techniques in teaching centers. PMID- 25457067 TI - Evaluation of the ability of an experimental model to induce bacterial rhinosinusitis in rabbits. AB - INTRODUCTION: For decades, animals have been used in sinonasal experimental models, and the practice has increased substantially in the last few years. This study aimed to assess the pathogenesis of infectious process and medication efficiency to treat rhinosinusitis. OBJECTIVE: To evaluate the efficiency of the proposed experimental model to induce an acute bacterial sinonasal infectious process through histological analysis and sinus secretion cultures. METHODS: This was an experimental study with 22 New Zealand rabbits, divided into: group A (six rabbits), group B (seven rabbits), group C (seven rabbits), and group D (control group with two rabbits). Rhinosinusitis was induced by the insertion of a synthetic sponge into the right nasal cavity of 20 animals (study groups), followed by the instillation of bacterial strains (50% Staphylococcus sp. and 50% Streptococcus sp.). The groups were euthanized within 10 days (group A), 17 days (group B), and 30 days (groups C and D). RESULTS: All the rabbits of the study group developed acute bacterial rhinosinusitis, which was diagnosed through macroscopic evaluation, histological analysis, and sinus secretion culture. CONCLUSION: The proposed model is technically simple to perform, it is similar to the rhinogenic model in human beings, and it is highly efficient to reproduce an acute bacterial sinus infection. PMID- 25457068 TI - New clinical staging for pharyngeal surgery in obstructive sleep apnea patients. AB - INTRODUCTION: The success of pharyngeal surgery in the treatment of obstructive sleep apnea syndrome depends on the appropriate selection of patients. OBJECTIVE: To propose a new staging for indication of pharyngeal surgery in obstructive sleep apnea syndrome. METHODS: A total of 54 patients undergoing extended tonsillectomy were retrospectively included, divided into six stages. Stage I: patients with palatine tonsils grade 3/4 and modified Mallampati index 1/2; stage II: palatine tonsils 3/4 and modified Mallampati index 3/4; stage III: palatine tonsils 1/2 and modified Mallampati index 1/2; stage IV: palatine tonsils 1/2 and modified Mallampati index 3/4; stage V: body mass index >=40 kg/m(2) with palatine tonsils 3/4 and modified Mallampati index 1, 2, 3, or 4. Stage VI: body mass index >=40 with palatine tonsils 1/2 and modified Mallampati index 1, 2, 3, or 4. RESULTS: The surgical success rates were 88.9%, 75.0%, 35.7%, 38.5%, and 100.0% in stages I-V. CONCLUSION: The presence of hypertrophic palatine tonsils was the anatomical factor in common in the most successful stages (I, II, and V), regardless of body mass index. Although the modified Mallampati index classes 3 and 4 reduced the success rate of surgery in patients with hypertrophic tonsils (stage II), the presence of modified Mallampati index classes 1 and 2 did not favor surgical success in patients with normal tonsils (stage III). PMID- 25457069 TI - Psychogenic dysphonia: diversity of clinical and vocal manifestations in a case series. AB - INTRODUCTION: Psychogenic dysphonia is a functional disorder with variable clinical manifestations. OBJECTIVE: To assess the clinical and vocal characteristics of patients with psychogenic dysphonia in a case series. METHODS: The study included 28 adult patients with psychogenic dysphonia, evaluated at a University hospital in the last ten years. Assessed variables included gender, age, occupation, vocal symptoms, vocal characteristics, and videolaryngostroboscopic findings. RESULTS: 28 patients (26 women and 2 men) were assessed. Their occupations included: housekeeper (n=17), teacher (n=4), salesclerk (n=4), nurse (n=1), retired (n=1), and psychologist (n=1). Sudden symptom onset was reported by 16 patients and progressive symptom onset was reported by 12; intermittent evolution was reported by 15; symptom duration longer than three months was reported by 21 patients. Videolaryngostroboscopy showed only functional disorders; no patient had structural lesions or changes in vocal fold mobility. Conversion aphonia, skeletal muscle tension, and intermittent voicing were the most frequent vocal emission manifestation forms. CONCLUSIONS: In this case series of patients with psychogenic dysphonia, the most frequent form of clinical presentation was conversion aphonia, followed by musculoskeletal tension and intermittent voicing. The clinical and vocal aspects of 28 patients with psychogenic dysphonia, as well as the particularities of each case, are discussed. PMID- 25457070 TI - Tissue expression, serum and salivary levels of vascular endothelial growth factor in patients with HNSCC. AB - INTRODUCTION: Vascular endothelial growth factor is thought to be an important angiogenic factor involved in tumor growth, progression, and metastasis. OBJECTIVE: The present study evaluated the relation between tissue expression, serum and salivary levels of vascular endothelial growth factor in head and neck squamous cell carcinomas, and their correlation with clinicopathologic features. METHODS: Samples were collected from 30 patients with head and neck squamous cell carcinomas and 24 healthy volunteers. Immunohistochemical analysis was used for tissue expression and enzyme-linked immunosorbent assay was employed to measure serum and salivary levels. RESULTS: No vascular endothelial growth factor staining was observed in normal tissues, whereas vascular endothelial growth factor expression was seen in 6 patients (20%). Mean serum level of VEGF was 83.7+/-104.47 in patients and 50.04+/-32.94 in controls. Mean salivary level of vascular endothelial growth factor was 174.41+/-115.07 in patients and 149.58+/ 101.88 in controls. No significant difference was found by Mann-Whitney test between controls and patients (p=0.411, p=0.944, respectively). No correlation was found between vascular endothelial growth factor tissue expression and its serum and salivary level. CONCLUSION: Overexpression of vascular endothelial growth factor was found in head and neck squamous cell carcinoma patients, suggesting its role in the pathogenesis of head and neck squamous cell carcinoma, but no relation was found between tissue expression, serum levels, and salivary levels of this marker. PMID- 25457071 TI - Postural control in Parkinson's disease. AB - INTRODUCTION: Postural instability is one of the most disabling features of Parkinson's disease. OBJECTIVE: To evaluate postural balance in Parkinson's disease. METHODS: Thirty patients with Parkinson's disease were compared with controls using TetraxTM interactive balance system posturography. RESULTS: For different positions, patients with Parkinson's disease showed a significantly higher weight distribution index, fall index, Fourier transformation at low medium frequencies (F2-F4), and significantly lower right/left and toe/heel synchronization versus controls. CONCLUSION: Postural imbalance in Parkinson's disease patients is characterized by the abnormalities of weight distribution index, synchronization index, Fourier transformation index, and fall index as measured by TetraxTM posturography. PMID- 25457072 TI - Evaluation of hearing protection used by police officers in the shooting range. AB - INTRODUCTION: Impact noise is characterized by acoustic energy peaks that last less than a second, at intervals of more than 1s. OBJECTIVE: To quantify the levels of impact noise to which police officers are exposed during activities at the shooting range and to evaluate the attenuation of the hearing protector. METHODS: Measurements were performed in the shooting range of a military police department. An SV 102 audiodosimeter (Svantek) was used to measure sound pressure levels. Two microphones were used simultaneously: one external and one insertion type; the firearm used was a 0.40 Taurus(r) rimless pistol. RESULTS: The values obtained with the external microphone were 146 dBC (peak), and a maximum sound level of 129.4 dBC (fast). The results obtained with the insertion microphone were 138.7 dBC (peak), and a maximum sound level of 121.6 dBC (fast). CONCLUSION: The findings showed high levels of sound pressure in the shooting range, which exceeded the maximum recommended noise (120 dBC), even when measured through the insertion microphone. Therefore, alternatives to improve the performance of hearing protection should be considered. PMID- 25457073 TI - Preparation and placement of cartilage island graft in tympanoplasty. AB - INTRODUCTION: Cartilage graft tympanoplasty has a better success rate in the treatment of chronic otitis media if regularly prepared and placed. OBJECTIVE: To prepare cartilage island material and evaluate its effect on the success rate of tympanoplasty. METHODS: The medical records of 87 patients (48 males and 39 females; mean age, 27.3+/-11.2 years; range, 14-43 years) with chronic otitis media without cholesteatoma who underwent intact canal-wall-up tympanoplasty and revision surgery between December of 2007 and October of 2011 were retrospectively evaluated. Surgery was performed under general anesthesia via a retroauricular approach. RESULTS: The overall success rate of this technique was 93% in terms of perforation closure. No graft lateralization or displacement into the middle ear occurred. The overall average preoperative air bone gap was 37.27+/-12.35 dB, and the postoperative air bone gap was 27.58+/-9.84 dB. The mean postoperative follow-up period was 15.3 months (range: 7-21 months). CONCLUSION: If cartilage graft is properly prepared and placed, cartilage graft tympanoplasty appears to provide better success rates and hearing results. PMID- 25457074 TI - Congenital laryngeal anomalies. AB - INTRODUCTION: It is essential for clinicians to understand issues relevant to the airway management of infants and to be cognizant of the fact that infants with congenital laryngeal anomalies are at particular risk for an unstable airway. OBJECTIVES: To familiarize clinicians with issues relevant to the airway management of infants and to present a succinct description of the diagnosis and management of an array of congenital laryngeal anomalies. METHODS: Revision article, in which the main aspects concerning airway management of infants will be analyzed. CONCLUSIONS: It is critical for clinicians to understand issues relevant to the airway management of infants. PMID- 25457075 TI - Lacrimal sac mucocele. PMID- 25457076 TI - Nasopharyngeal Burkitt lymphoma as an early AIDS manifestation. PMID- 25457077 TI - Comparison of two different epidemiological profiles of otorhinolaryngology emergencies. PMID- 25457078 TI - Perioperative parathyroid hormone measurements in thyroid surgery: one stone to hit three birds. PMID- 25457079 TI - Seminars in Fetal & Neonatal Medicine. Update on congenital diaphragmatic hernia. Introduction. PMID- 25457080 TI - Analgesics, sedatives, anticonvulsant drugs, and the cooled brain. AB - Multiple randomized controlled trials have shown that prolonged, moderate cerebral hypothermia initiated within a few hours after severe hypoxia-ischemia and continued until resolution of the acute phase of delayed cell death reduces mortality and improves neurodevelopmental outcome in term infants. The challenge is now to find ways to further improve outcomes. In the present review, we critically examine the evidence that conventional analgesic, sedative, or anticonvulsant agents might improve outcomes, in relation to the known window of opportunity for effective protection with hypothermia. This review strongly indicates that there is insufficient evidence to recommend routine use of these agents during therapeutic hypothermia. Further systematic research into the effects of pain and stress on the injured brain, and their treatment during hypothermia, is essential to guide the rational development of clinical treatment protocols. PMID- 25457081 TI - Prediction of outcome methods assessing short- and long-term outcome after therapeutic hypothermia. AB - Therapeutic hypothermia has significantly changed outcomes for newborns suffering neonatal encephalopathy. Outcome predictors established in the pre-cooling era may not automatically be transferred to the cooling era. This article reviews how the reliability of routinely used outcome predictors has changed. We summarize current knowledge about why this may be the case and when to best obtain and analyze different clinical, biochemical, and imaging outcome markers to predict outcome in cooled asphyxiated newborns. PMID- 25457082 TI - Physiological responses to hypothermia. AB - Therapeutic hypothermia is the only treatment currently recommended for moderate or severe encephalopathy of hypoxic-ischaemic origin in term neonates. Though the effects of hypothermia on human physiology have been explored for many decades, much of the data comes from animal or adult studies; the latter originally after accidental hypothermia, followed by application of controlled hypothermia after cardiac arrest or trauma, or during cardiopulmonary bypass. Though this work is informative, the effects of hypothermia on neonatal physiology after perinatal asphyxia must be considered in the context of a prolonged hypoxic insult that has already induced a number of significant physiological sequelae. This article reviews the effects of therapeutic hypothermia on respiratory, cardiovascular, and metabolic parameters, including glycaemic control and feeding requirements. The potential pitfalls of blood-gas analysis and overtreatment of physiological changes in cardiovascular parameters are also discussed. Finally, the effects of hypothermia on drug metabolism are covered, focusing on how the pharmacokinetics, pharmacodynamics, and dosing requirements of drugs frequently used in neonatal intensive care may change during therapeutic hypothermia. PMID- 25457083 TI - Cooling in a low-resource environment: lost in translation. AB - Although cooling therapy has been the standard of care for neonatal encephalopathy (NE) in high-income countries for more than half a decade, it is still not widely used in low- and middle-income countries (LMIC), which bear 99% of the encephalopathy burden; neither is it listed as a priority research area in global health. Here we explore the major roadblocks that prevent the use of cooling in LMIC, including differences in population comorbidities, suboptimal intensive care, and the lack of affordable servo-controlled cooling devices. The emerging data from LMIC suggest that the incidence of coexisting perinatal infections in NE is no different to that in high-income countries, and that cooling can be effectively provided without tertiary intensive care and ventilatory support; however, the data on safety and efficacy of cooling are limited. Without adequately powered clinical trials, the creeping and uncertain introduction of cooling therapy in LMIC will be plagued by residual safety concerns, and any therapeutic benefit will be even more difficult to translate into widespread clinical use. PMID- 25457084 TI - A case of recurrent encephalopathy with SCN2A missense mutation. AB - Voltage-gated sodium channels regulate neuronal excitability, as well as survival and the patterning of neuronal connectivity during development. Mutations in SCN2A, which encodes the Na(+) channel Nav1.2, cause epilepsy syndromes and predispose children to acute encephalopathy. Here, we report the case of a young male with recurrent acute encephalopathy who carried a novel missense mutation in the SCN2A gene. He was born by normal delivery and developed repetitive apneic episodes at 2days of age. Diffusion-weighted imaging revealed high-intensity areas in diffuse subcortical white matter, bilateral thalami, and basal nuclei. His symptoms improved gradually without any specific treatment, but he exhibited a motor milestone delay after the episode. At the age of 10months, he developed acute cerebellopathy associated with a respiratory syncytial viral infection. He received high-dose intravenous gammaglobulin and methylprednisolone pulse therapy and seemed to have no obvious sequelae after the episode. He then developed severe diffuse encephalopathy associated with gastroenteritis at the age of 14months. He received high-dose intravenous gammaglobulin and methylprednisolone pulse therapy but was left with severe neurological sequelae. PCR-based analysis revealed a novel de novo missense mutation, c.4979T>G (p.Leu1660Trp), in the SCN2A gene. This case suggests that SCN2A mutations might predispose children to repetitive encephalopathy with variable clinical and imaging findings. PMID- 25457085 TI - A Japanese girl with an early-infantile onset vanishing white matter disease resembling Cree leukoencephalopathy. AB - Vanishing white matter disease (VWM)/childhood ataxia with central hypomyelination (CACH) is an autosomal recessive leukoencephalopathy caused by mutations in one of five genes, EIF2B1-5, encoding the 5 subunits of eukaryotic translation initiation factor 2B (eIF2B). The classical phenotype is characterized by early childhood onset and chronic progressive neurological deterioration with cerebellar ataxia, spasticity, optic atrophy and epilepsy. However, the onset of disease varies from antenatal period to adulthood. Cree leukoencephalopathy (CLE) is a severe variant of VWM and caused by a homozygous mutation (R195H) in the EIF2B5 gene. The patient reported in this study developed lethargy, vomiting and seizure 3days after an oral poliovirus vaccination at the age of 4months. She presented with rapid neurological deterioration within a month of onset. Brain MRI showed abnormal white matter intensity. Whole-exome sequencing identified two heterozygous mutations in the EIF2B5 gene: a known mutation, c.584G>A (R195H, which is homozygous in CLE), and a novel mutation, c.1223T>C (I408T, which resides in the "I-patch"). Mutations in the "I-patch" encoded region of eIF2Bepsilon may be related to an early-infantile onset phenotype. This patient exhibits an early-infantile onset and progressive disease course resembling CLE, suggesting a severe functional disruption of eIF2Bepsilon caused by R195H as well as by I408T mutations. PMID- 25457086 TI - A unilateral optic perineuritis in a teenager - A case report. AB - Optic perineuritis is an uncommon inflammatory disorder that involves optic nerve sheath. Numerous case reports have been published on optic perineuritis in adults, the majority of whom had bilateral presentation. There are limited data on optic perineuritis occurring in pediatric patients. We report a teenager who presented with a unilateral sign that mimicked the presentation of optic neuritis. The orbit and brain magnetic resonance imaging confirmed features of unilateral optic perineuritis. She was treated with a high dose of corticosteroids for 2weeks, and her final visual outcome was satisfactory. No signs of relapse were noted during follow-up visits. PMID- 25457087 TI - Comparison of estimated glomerular filtration rate equations for dosing new oral anticoagulants in patients with atrial fibrillation. AB - INTRODUCTION AND OBJECTIVES: New oral anticoagulants require dosing adjustment according to renal function. We aimed to determine discordance in hypothetical recommended dosing of these drugs using different estimated glomerular filtration rate equations in patients with atrial fibrillation. METHODS: Cross-sectional analysis of 910 patients with atrial fibrillation and an indication for oral anticoagulation. The glomerular filtration rate was estimated using the Cockcroft Gault, Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations. For dabigatran, rivaroxaban, and apixaban we identified dose discordance when there was disagreement in the recommended dose based on different equations. RESULTS: Among the overall population, relative to Cockcroft-Gault, discordance in dabigatran dosage was 11.4% for Modification of Diet in Renal Disease and 10% for Chronic Kidney Disease Epidemiology Collaboration, discordance in rivaroxaban dosage was 10% for Modification of Diet in Renal Disease and 8.5% for the Chronic Kidney Disease Epidemiology Collaboration. The lowest discordance was observed for apixaban: 1.4% for Modification of Diet in Renal Disease and 1.5% for the Chronic Kidney Disease Epidemiology Collaboration. In patients with Cockcroft-Gault<60mL/min or elderly patients, discordances in dabigatran and rivaroxaban dosages were higher, ranging from 13.2% to 30.4%. Discordance in apixaban dosage remained<5% in these patients. CONCLUSIONS: Discordance in new oral anticoagulation dosages using different equations is frequent, especially among elderly patients with renal impairment. This discordance was higher in dabigatran and rivaroxaban dosages than in apixaban dosages. Further studies are needed to clarify the clinical importance of these discordances and the optimal anticoagulant dosages depending on the use of different equations to estimate renal function. PMID- 25457088 TI - Endoscopic ultrasound: an alternative to transesophageal echocardiography for patients with esophageal varices during a structural interventional procedure. PMID- 25457089 TI - Optimal medical treatment: is it the worst option in multivessel coronary disease? Response. PMID- 25457090 TI - Compulsive buying tendencies and personal finances. AB - In a community sample of 225 adults, scores on the Compulsive Buying Scale were associated with scores on the subscales of the Executive Personal Finance Scale (rs = -.35 to -.70) and the Money Attitudes Scale (positively with using money for impressing others, and negatively with saving and planning). The results suggested that common tendencies toward compulsive buying may not be pathological, but merely associated with attitudes toward money in general and financial management habits. PMID- 25457092 TI - Motivated behavioral outcomes affect ratings of attractiveness. AB - A relatively new theory of motivation posits that purposeful human behavior may be partly explained by multidimensional individual differences "traits of action" (motives). Its 15 motives can be characterized according to their purpose: individual integrity, competitiveness, and cooperativeness. Existing evidence supports the model on which the motives are based and the reliability and validity of strategies to assess them. This experiment tested whether the hypothetical results of consistent, motivated cooperative and competitive behavior could affect ratings of attractiveness. Male and female participants (N = 98; M age = 18.8, SD = 1.4) were shown 24 opposite-sex facial photos ranging in attractiveness. The photos were paired with one of three conditions representing theoretical outcomes that would result from low, control, and high levels of cooperative and competitive motives. As predicted, outcome descriptions representing high motive strength of six motives statistically significantly affected ratings of attractiveness. This result was independent of sex of participant and consistent with the theory. PMID- 25457093 TI - A note on Cohen's overlapping proportions of normal distributions. AB - Social scientists are often interested in computing the proportion of overlap and nonoverlap between two normal distributions that are separated by some magnitude. In his popular book, Statistical Power Analysis for the Behavioral Sciences (1988, 2nd ed.), Jacob Cohen provided a table (Table 2.2.1) for determining such proportions from common values of separation. Unfortunately, Cohen's proportions are inconsistent with his explication of the popular index of effect size, d; and his proportions are underestimates of distributional overlap and overestimates of nonoverlap. The authors explain how Cohen derived his values and then provide a revised, corrected table of proportions that also match values presented elsewhere. PMID- 25457091 TI - An experimental study of the influence of limited time horizon on positivity effects among young adults using eye-tracking. AB - Compared to younger adults, older adults attend more to positive stimuli, a positivity effect. Older adults have limited time horizons, and they focus on maintaining positive affect, whereas younger adults have unlimited time horizons, and they focus on acquiring knowledge and developing skills. Time horizons were manipulated by asking participants (66 young adults, M age = 20.5 yr., SD = 1.2) to think that their lives would end in three years. Some participants focused on what they would do in these three years (life focus), whereas others focused on the fact that they would die in three years (death focus). Attentional biases to facial expressions of happiness, sadness, fear, anger, and disgust were measured. Participants viewed 20 slides including pairings of a happy face with each of the negative emotions. The dependent measure was the relative attention paid to the faces on each slide. Participants in the experimental conditions exhibited a positivity effect compared to participants in the control condition, although some results suggested that this effect was weaker in the death focus condition than in the life focus condition. PMID- 25457094 TI - Reading anxiety, classroom anxiety, language motivation, reader self-perception, and arabic achievement of Arab-American students learning arabic as a second language. AB - The present study assessed the relations between reading anxiety, classroom anxiety, language motivation, and readers' self-perception for a sample of Arab American students in Arabic classes. The effects of sex, grade, and years studying Arabic on academic achievement were examined as well. Measures were administered to 118 middle school students (56 boys, 62 girls; M age = 13.0 yr., SD = 0.8), and teachers reported academic grades in Arabic. Reading anxiety was significantly correlated with classroom anxiety and reader self-perception. Classroom anxiety scores were significantly correlated with motivation and reader self-perception. Significant positive correlations were found between language motivation and reader self-perception scores, and between years studying Arabic and reader self-perception scores. Boys in the second year of Arabic had significantly lower classroom anxiety than girls, and students in Grade 7 had higher reader self-perception than those in Grade 8. Classroom anxiety, language motivation, and reader self-perception significantly predicted Arabic achievement. Pedagogical implications are discussed. PMID- 25457095 TI - Inducing the concept of love among men and their compliance to a donation request for an association against domestic violence toward women. AB - Previous research found that exposition to the concept of love appeared effective to increase men's helping behavior toward women. However, only direct solicitation was examined. In this study, 40 men were first induced with the idea of love with the help of a dummy survey about love and romantic behavior, and one minute later they were asked to help an association against domestic violence toward women. In the control condition, 40 men were induced using a neutral dummy survey on odd jobs. More men (35.7%) donated to the association in the love inducing condition than in the control condition (17.5%). No statistical difference was found in the amount of money left in the two conditions: 1.40? in the love-inducing condition and 1.12? in the control condition. The results suggest that the love-inducing method does not only activate motivation for romantic relationships with women but also influences men's concerns about a women's cause. PMID- 25457096 TI - Organ donation by suicides: sex and ethnicity. AB - An analysis of 2,034 actual organ donations by suicides for the years 2008-2010 indicated that women were more likely to be donors than were men and Blacks more likely to donate than were Whites. The sex difference was consistent with the responses of men and women to surveys of the general public about their willingness to become organ donors, but the ethnic difference was the reverse of the responses to surveys of the general public about their willingness to be organ donors. Future research should explore the role of the responses, positive vs negative toward organ donation, of the significant others of those dying from different causes of death, and the extent to which people have signed donor cards. PMID- 25457097 TI - Self-esteem and Arab-American elementary students. AB - This study assessed self-esteem and the relation between self-esteem and academic achievement in a sample of Arab-American elementary students who completed the What I Think About Myself Self-esteem Inventory. 123 students' (M age = 8.7 yr., 65 boys and 58 girls) self-esteem scores were associated with their academic achievement. Alpha internal consistency reliability was acceptable (Cronbach's alpha = .85) for the inventory. The results also indicated that the participants tended to have healthy self-esteem. PMID- 25457098 TI - Drinking behavior and drinking refusal self-efficacy in Korean college students. AB - The prevalence of drinking behavior and sex differences were examined. A possible relationship between drinking behavior and drinking refusal self-efficacy (DRSE) also was investigated among a convenience sample of 582 Korean college students (309 men, 273 women). A drinking habit scale (from AUDIT-K) and drinking refusal self-efficacy questionnaire (DRSEQ-R) were administered. Results indicated 74.4% of the students drank alcohol and 80.1% of the students were regular drinkers (> 2 to 4 times per month). There were significant differences in drinking behavior by sex and in the DRSE constructs for current drinking statuses. Drinking behavior was significantly associated with sex and DRSE. The present study offers more information about practical interventions aimed at reasonably controlling the drinking behavior of Korean college students in a university setting. The findings may provide better understanding of Korean students' drinking behavior. PMID- 25457099 TI - Eveningness is associated with higher risk-taking, independent of sex and personality. AB - This study tested the hypotheses that eveningness is associated with higher risk taking propensities across different domains of risk and that this association is not the result of sex differences or confounding covariation with particular personality traits. Study participants were 172 men and women between 20 and 40 years of age. Surveys assessed chronotype, domain-specific risk-taking and risk perception, and Big Five personality dimensions. Eveningness was associated with greater general risk-taking in the specific domains of financial, ethical, and recreational decision making. Although risk-taking was associated with both risk perception and some personality dimensions, eveningness predicted risk-taking independent of these factors. Higher risk-taking propensities among evening types may be causally or functionally linked to their propensities for sensation- and novelty-seeking, impulsivity, and sexual promiscuity. PMID- 25457100 TI - Response to "Framing unauthorized immigrants: the effects of labels on evaluations," by Ommundsen, et al. (2014). AB - Ommundsen, Larsen, van der Veer, and Eilertsen (2014 ) presented evidence that varying how immigrants are described in surveys can lead to differences in how respondents to those surveys change their self-reported orientations toward those immigrants and immigration policy. We argue that the apparent conflict between their findings and those of Knoll, Redlawsk, and Sanborn (2011 ) should be interpreted as complementary rather than contradictory. In particular, differences in samples, timing, and dependent variables limit direct comparisons between the studies. Moreover, because Ommundsen, et al. (2014) do not have a measure of partisanship and did not test for interaction effects between ideology and frames, their broader conclusions are limited given that immigration is such a highly charged political issue that is strongly affected by political ideology and partisan cues. PMID- 25457101 TI - An emetic Bacillus cereus outbreak in a kindergarten: detection and quantification of critical levels of cereulide toxin. AB - A Bacillus cereus-related emetic outbreak was reported in a Belgian kindergarten. High levels of emetic B. cereus (>1.5E+07 colony-forming units/g) were detected in the food leftovers, and the presence of an emetic strain was confirmed in feces. Emetic toxin levels ranging up to 4.2 MUg/g were also quantified in the leftovers by liquid chromatography coupled to tandem mass spectrometry (LC-MS(2)) analysis. Those levels, although moderate in comparison with earlier published intoxications, provoked profuse-vomiting episodes in 20 toddlers aged between 10 and 18 months. Few studies have focused on the levels of emetic toxin implicated in food intoxications. This publication emphasizes the importance of defining toxic doses of emetic toxin among high-risk population groups. PMID- 25457102 TI - Bifidobacterium breve C50 secretes lipoprotein with CHAP domain recognized in aggregated form by TLR2. AB - Extracellular components secreted by Bifidobacterium breve C50 can induce maturation, high IL-10 production and prolonged survival of dendritic cells via a TLR2 pathway. In this study, the components were isolated from the supernatant by gel filtration chromatography. Antibodies raised against the major compounds with molecular weight above 600 kDa (Bb C50BC) also recognized compounds of lower molecular weight (200-600 kDa). TLR2 and TLR6 bound to the components already recognized by the antibodies. Trypsin digestion of Bb C50BC released three major peptides whose sequences displayed close similarities to a putative secreted protein with a CHAP amidase domain from B. breve. The 1300-bp genomic region corresponding to the hypothetical protein was amplified by PCR. The deduced polypeptide started with an N-terminal signal sequence of 45 amino acids, containing the lipobox motif (LAAC) with the cysteine in position 25, and 2 positively charged residues within the first 14 residues of the signal sequence. Lipid detection in Bb C50BC by GC/MS further supported the implication of a lipoprotein. Sugars were also detected in Bb C50BC. Close similarity with the glucan-binding protein B from Bifidobacterium animalis of two released peptides from Bb C50BC protein suggested that glucose moieties, possibly in glucan form, could be bound to the lipoprotein. Finally, heating at 100 degrees C for 5 min led to the breakdown of Bb C50BC in compounds of molecular weight below 67 kDa, which suggested that Bb C50BC was an aggregate. One might assume that a basic unit was formed by the lipoprotein bound putatively to glucan. Besides the other sugars and hexosamines recognized by galectin 1 were localized at the surface of the Bb C50BC aggregate. In conclusion, the extracellular components secreted by B. breve C50 were constituted of a lipoprotein putatively associated with glucose moieties and acting in an aggregating form as an agonist of TLR2/TLR6. PMID- 25457103 TI - Isolation and characterization of four medium-size disintegrins from the venoms of Central American viperid snakes of the genera Atropoides, Bothrops, Cerrophidion and Crotalus. AB - Four disintegrins were isolated from the venoms of the Central American viperid snakes Atropoides mexicanus (atropoimin), Bothrops asper (bothrasperin), Cerrophidion sasai (sasaimin), and Crotalus simus (simusmin). Purifications were performed by reverse-phase HPLC. The four disintegrins have biochemical characteristics, i.e. molecular mass and location of Cys, which allow their classification within the group of medium-size disintegrins. All of them present the canonical RGD sequence, which determines their interaction with integrins in cell membranes. The disintegrins inhibited ADP and collagen-induced human platelet aggregation, with similar IC50s in the nM range. In addition, disintegrins inhibited the adhesion of an endothelial cell line and a melanoma cell line to the extracellular matrix proteins type I collagen, laminin, fibronectin, and vitronectin, albeit showing variable ability to exert this activity. This study expands the inventory of this family of viperid venom proteins, and reports, for the first time, disintegrins from the venoms of species of the genera Atropoides and Cerrophidion. PMID- 25457105 TI - Genipin inhibits MMP-1 and MMP-3 release from TNF-a-stimulated human periodontal ligament cells. AB - Genipin, the aglycon of geniposide found in gardenia fruit has long been considered for treatment of inflammatory diseases in traditional oriental medicine. Genipin has recently been reported to have some pharmacological functions, such as antimicrobial, antitumor, and anti-inflammatory effects. The aim of this study was to examine whether genipin could modify matrix metalloproteinase (MMP)-1 and MMP-3, which are related to the destruction of periodontal tissues in periodontal lesion, expression in tumor necrosis factor (TNF)-alpha-stimulated human periodontal ligament cells (HPDLCs). Genipin prevented TNF-alpha-mediated MMP-1 and MMP-3 productions in HPDLCs. Moreover, genipin could suppress not only extracellular signal-regulated kinase (ERK) and Jun-N-terminal kinase (JNK) phosphorylations but also AMP-activated protein kinase (AMPK) phosphorylation in TNF-alpha-stimulated HPDLCs. Inhibitors of ERK and AMPK could inhibit both MMP-1 and MMP-3 productions. Moreover, we revealed the ERK inhibitor suppressed AMPK phosphorylation in TNF-alpha-stimulated HPDLCs. These data provide a new mechanism through which genipin could be used for the treatment of periodontal disease to prevent MMPs expression in periodontal lesion. PMID- 25457104 TI - Cytotoxic activity of chimeric protein PD-L4UWSCI(tr) does not appear be affected by specificity of inhibition mediated by anti-protease WSCI domain. AB - In a previously study, a type 1 ribosome inactivating protein (PD-L4) and a wheat subtilisin/chymotrypsin inhibitor (WSCI) were engineered into a chimeric protein (PD-L4UWSCI) that presented in addition to the same properties of both domains an intriguing selective cytotoxic action on murine tumor cells. This finding supported the idea that the protection of C-terminal region of PD-L4 could amplify its cytotoxic action by virtue of a greater resistance to proteases. Several authors indeed revealed that the cytotoxicity of RIPs depends not only on the intracellular routing, but also on the intrinsic resistance to proteolysis. In this regard in the present work we have produced a variant of chimeric protein, named PD-L4UWSCI(tr), changing the inhibitory specificity of WSCI domain. The purpose of this approach was to check if the cytotoxicity of the chimeric protein was altered depending on the properties of protease inhibitor domain or by a different fold of whole protein. Data collected supposedly indicate that WSCI domain contributes to cytotoxicity of chimeric protein exclusively from a structural point of view. PMID- 25457106 TI - [Estimate of the needs in renal transplantation in Morocco]. AB - Kidney transplantation is still underdeveloped in Morocco. In order to anticipate needs and discuss a possible reorganization of the provision of care, an estimate of the number of patients who would benefit from kidney transplant was conducted. This study was done in two steps. During the first step, based on the French renal replacement therapy registry (Rein), we develop a prediction score based on the likelihood of being treated by an autonomous dialysis (hemodialysis in self care unit or peritoneal dialysis non-assisted by a nurse) and be registered on the national kidney transplant waiting list. During the second step, we apply this score to the data of the registry Magredial (Moroccan registry of renal replacement therapy, deployed in seven regions). Twelve parameters were related to autonomy and registration on the waiting list. Each of these parameters has been assigned a weight. Each patient was assigned a number of points, sum of different weights. By retaining a threshold of 21 points (80% specificity), 2260 subjects (57%) had a score less than or equal to this threshold in Magredial. With a number of patients on dialysis in Morocco estimated to 13,000 in late 2013, the estimated need for kidney transplant will be of 7410. This estimate should encourage professionals and health authorities of Morocco to engage more effort in the implementation of actions related to the transplant program. PMID- 25457107 TI - The essential of 2012 results from the French Renal Epidemiology and Information Network (REIN) ESRD registry. AB - The French Renal Epidemiology and Information Network (REIN) registry began in 2002 to provide a tool for public health decision support, evaluation and research related to renal replacement therapies (RRT) for end-stage renal disease (ESRD). It is relying on a network of nephrologists, epidemiologists, patients and public health representatives. Continuous registration covers all dialysis and transplanted patients. In 2012, in France, 10,048 patients started a RRT (154 per million inhabitants). Elders provided majority of new patients (median age at RRT start: 70 years old). New patients had a high and age increasing rate of comorbidities, especially diabetes (42% of the new patients) and cardiovascular comorbidities (>50% of the new patients). Like previous years, incidence is stabilized. On December 31, 2012, 73,491 patients were receiving a RRT in France (1127 per million inhabitants, 56% on dialysis and 44% living with a functional renal transplant). More than 50% of patients were undergoing in-center hemodialysis with significant variations among regions. An increase in medical satellite unit hemodialysis but a decrease in self-care unit hemodialysis rates were noticed across the time, whereas peritoneal dialysis remained stable at 7%. Five years after starting RRT, the overall survival rate was 51% but only 16% among patients over 85 years. Mortality rate was highly dependent on treatment and age; transplanted patients aged 60-69 had a 27/1000 patients-year mortality rate versus 133 for a dialysis patient. Patients who started dialysis had a probability of first wait-listing of 4.8% at the start of dialysis (pre-emptive registrations) and 27% at 72 months. Whatever their diabetes status was, patients older than 60 had poor access to the waiting list. Seventeen percent of the patients received a first renal transplant within 15.4 month median time; 3% had received a pre-emptive graft. Ten years after the start of the French ESRD registry, this report provides a comprehensive and nation-wide overview of dialysis and transplantation cares in France, including overseas. PMID- 25457108 TI - [Antiphospholipids antibodies and hemodialysis: a frequent association linked to arteriovenous fistula thrombosis]. AB - Antiphospholipid antibodies (APL) are a heterogeneous family of auto-antibodies that recognize phospholipoproteins bound antigenic epitopes. APL prevalence in patients on chronic hemodialysis ranges from 11 to 37% in the literature. The association of APL with hemodialysis vascular access (VA) thrombosis has already been reported in small studies. In this single center and retrospective study, we defined the APL prevalence and APL risk factors in a large cohort of 192 hemodialysis patients. The association between history of VA thrombosis and APL presence was also analyzed. At least one type of APL was found in 38 patients (19.8%) of which 74% (n=28) had only lupus anticoagulant. Median age of APL positive patients was 68.1years vs. 71.3years in APL negative patients (P=0.02). Smoking history was associated with APL presence: 35.5% of APL positive patients had a smoking history vs only 18.3% of APL negative patients (P=0.04). The multivariate analysis showed an association between the history of VA thrombosis and patient age (HR [IC 95%]=1.04 [1.02-1.06]; P=0.001) or APL presence (HR [IC 95%]=3.03 [1.69-4.42]; P<10(-3)). In conclusion, the prevalence of APL in hemodialysis patients remains high despite hemodialysis techniques improvement: hemodiafiltration, biocompatibility improvements, ultrapure dialysis water. We report that a younger age and past history of smoking are associated with an increased risk of APL presence. The presence of APL, especially lupus anticoagulant, is associated to VA thrombosis in hemodialysis patients. PMID- 25457109 TI - Mitogen-activated protein kinase cascades in signaling plant growth and development. AB - Mitogen-activated protein kinase (MAPK) cascades are ubiquitous signaling modules in eukaryotes. Early research of plant MAPKs has been focused on their functions in immunity and stress responses. Recent studies reveal that they also play essential roles in plant growth and development downstream of receptor-like protein kinases (RLKs). With only a limited number of MAPK components, multiple functional pathways initiated from different receptors often share the same MAPK components or even a complete MAPK cascade. In this review, we discuss how MAPK cascades function as molecular switches in response to spatiotemporal-specific ligand-receptor interactions and the availability of downstream substrates. In addition, we discuss other possible mechanisms governing the functional specificity of plant MAPK cascades, a question central to our understanding of MAPK functions. PMID- 25457111 TI - Only in dying, life: programmed cell death during plant development. AB - Programmed cell death (PCD) is a fundamental process of life. During the evolution of multicellular organisms, the actively controlled demise of cells has been recruited to fulfil a multitude of functions in development, differentiation, tissue homeostasis, and immune systems. In this review we discuss some of the multiple cases of PCD that occur as integral parts of plant development in a remarkable variety of cell types, tissues, and organs. Although research in the last decade has discovered a number of PCD regulators, mediators, and executers, we are still only beginning to understand the mechanistic complexity that tightly controls preparation, initiation, and execution of PCD as a process that is indispensable for successful vegetative and reproductive development of plants. PMID- 25457112 TI - Origin of plant auxin biosynthesis in charophyte algae. PMID- 25457110 TI - Plant innate immunity--sunny side up? AB - Reactive oxygen species (ROS)- and calcium- dependent signaling pathways play well-established roles during plant innate immunity. Chloroplasts host major biosynthetic pathways and have central roles in energy production, redox homeostasis, and retrograde signaling. However, the organelle's importance in immunity has been somehow overlooked. Recent findings suggest that the chloroplast also has an unanticipated function as a hub for ROS- and calcium signaling that affects immunity responses at an early stage after pathogen attack. In this opinion article, we discuss a chloroplastic calcium-ROS signaling branch of plant innate immunity. We propose that this chloroplastic branch acts as a light-dependent rheostat that, through the production of ROS, influences the severity of the immune response. PMID- 25457113 TI - Intensive care unit and hospital mortality in patients with obstructive sleep apnea. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is a common disorder affecting between 5% and 24% of men and women. The prevalence of OSA in the intensive care unit (ICU) population is unknown. This study was undertaken to determine the prevalence of OSA in patients admitted to the ICU and to determine if OSA is an independent predictor of mortality. METHODS: This is a retrospective study using an Acute Physiology and Chronic Health Evaluation III database cross-referenced to a comprehensive clinical database to identify patients with and without OSA admitted to medical, surgical, and mixed ICUs at a large academic medical center. RESULTS: Between January 2003 and December 2005, 15077 patients were admitted to the ICUs; and of these, 1183 (7.8%) had a physician-documented diagnosis of OSA. Eight hundred thirty-five (71%) patients had polysomnographic testing at our institution with a documented apnea-hypopnea index more than 5 per hour. Patients with OSA were younger (59.1 +/- 14.0 vs 62.3 +/- 18.0), male (58.9% vs 53.7%), and had lower Acute Physiology and Chronic Health Evaluation III scores (45.3 +/- 24.1 vs 54.9 +/- 27.7). Predicted mortality (10.3% +/- 16.4% vs 16.3 +/- 21.7), median ICU length of stay (1.13 vs 1.50 days), ICU mortality (2.4% vs 6.2%), and hospital mortality (3.9% vs 11.4%) were all reduced in patients with OSA, P values < .001. When adjusted for the severity of illness, OSA was independently associated with decreased hospital mortality, (0.408; 95% confidence interval, 0.298-0.557). CONCLUSIONS: Obstructive sleep apnea is common in patients admitted to the ICU. Obstructive sleep apnea was associated with a reduction in both ICU and hospital mortality. PMID- 25457116 TI - The effectiveness of an intensive care quick reference checklist manual--a randomized simulation-based trial. AB - PURPOSE: We aimed to test the effectiveness of checklists for emergency procedures on medical staff performance in intensive care crises. MATERIALS AND METHODS: This is a prospective single-center randomized trial in a high-fidelity simulation center modeling an intensive care unit (ICU) in a tertiary care hospital in Germany. Teams consisted of 1 ICU resident and 2 ICU nurses (in total, n = 48). All completed 4 crisis scenarios, in which they were randomized to use checklists or to perform without any aid. In 2 of the scenarios, checklists could be used immediately (type 1 scenarios); and for the remaining, some further steps, for example, confirming diagnosis, were required first (type 2 scenarios). Outcome measurements were number of predefined items and time to completion of more than 50% and more than 75% of steps, respectively. RESULTS: When using checklists, participants initiated items faster and more completely according to appropriate treatment guidelines (9 vs 7 items with and without checklists, P < .05). Benefit of checklists was better in type 2 scenarios than in type 1 scenarios (2 vs 1 additional item, P < .05). In type 2 scenarios, time to complete 50% and 75% of items was faster with the use of checklists (P < .005). CONCLUSIONS: Use of checklists in ICU crises has a benefit on the completion of critical treatment steps. Within the type 2 scenarios, items were fulfilled faster with checklists. The implementation of checklists for intensive care crises is a promising approach that may improve patients' care. PMID- 25457114 TI - Cytomegalovirus reactivation in a general, nonimmunosuppressed intensive care unit population: incidence, risk factors, associations with organ dysfunction, and inflammatory biomarkers. AB - PURPOSE: Cytomegalovirus (CMV) reactivation, a significant cause of morbidity and mortality in immunosuppression, may affect "immunocompetent" seropositive critically ill patients. The aim of this prospective, observational study was to define the incidence, risk factors, and the association with morbidity and mortality of CMV reactivation in a general population of critically ill immunocompetent patients. We also studied the relationship between reactivation and patients' inflammatory response, as expressed by cytokine levels and stress up-regulation by salivary cortisol. METHODS: This study included mechanically ventilated CMV-seropositive patients. A quantitative real-time polymerase chain reaction (PCR) was performed for CMV plasma DNAemia determination, upon intensive care unit (ICU) admission and weekly thereafter until day 28. Cytomegalovirus reactivation was defined as CMV plasma DNAemia greater than or equal to 500 copies/mL. Upon ICU admission, interferon gamma, interleukin (IL) 10, IL-17A, IL 2, IL-6, and tumor necrosis factor alpha were quantified in plasma, and morning saliva was obtained to measure cortisol. Disease severity was assessed by Acute Physiology and Chronic Health Evaluation II score, whereas the degree of organ dysfunction was quantified by Sequential Organ Failure Assessment score. Mortality, duration of mechanical ventilation, and ICU length of stay were recorded. RESULTS: During the study period, 80 (51 men) patients with a median age of 63 years fulfilled the inclusion criteria. Reactivation of CMV occurred in 11 patients (13.75%). Median day of reactivation was day 7 post ICU admission. Total number of red blood cell units transfused (odds ratio [OR], 1.50; confidence interval [CI], 1.06-2.13; P = .02) and C-reactive protein levels upon ICU admission (OR, 1.01; CI, 1.00-1.02; P = .02) were independently associated with CMV reactivation. High IL-10 was marginally related to reactivation (P = .06). Sequential Organ Failure Assessment scores were higher in the group with CMV reactivation compared with patients without reactivation during the entire 28 day observation period (P < .006). Salivary cortisol, mortality, length of ICU stay, and duration of mechanical ventilation were similar in the 2 groups. CONCLUSIONS: Cytomegalovirus reactivation occurred in 13.75% of critically ill, immunocompetent patients. The degree of inflammation and the total number of transfused red blood cells units constituted risk factors. Cytomegalovirus reactivation was associated with more severe of organ dysfunction, but not with a worse clinical outcome. PMID- 25457115 TI - Experience with a hospital policy on not offering cardiopulmonary resuscitation when believed more harmful than beneficial. AB - PURPOSE: This study investigated the impact of age, race, and functional status on decisions not to offer cardiopulmonary resuscitation (CPR) despite patient or surrogate requests that CPR be performed. METHODS: This was a retrospective cohort study of all ethics committee consultations between 2007 and 2013 at a large academic hospital with a not offering CPR policy. RESULTS: There were 134 cases of disagreement over whether to provide CPR. In 45 cases (33.6%), the patient or surrogate agreed to a do-not-resuscitate (DNR) order after initial ethics consultation. In 67 (75.3%) of the remaining 89 cases, the ethics committee recommended not offering CPR. In the other 22 (24.7%) cases, the ethics committee recommended offering CPR. There was no significant relationship between age, race, or functional status and the recommendation not to offer CPR. Patients who were not offered CPR were more likely to be critically ill (61.2% vs 18.2%, P < .001). The 90-day mortality rate among patients who were not offered CPR was 90.2%. CONCLUSIONS: There was no association between age, race, or functional status and the decision not to offer CPR made in consultation with an ethics committee. Orders to withhold CPR were more common among critically ill patients. PMID- 25457117 TI - Incidence, risk factors, and outcome of transfusion-related acute lung injury in critically ill children: a retrospective study. AB - PURPOSE: Acute lung injury (ALI) that develops within 6 hours after transfusion (TRALI) is the leading cause of transfusion-related morbidity and mortality. Both incidence and patient and transfusion-related risk factors are well studied in the adult critically ill patient population. Clinical data on TRALI in the pediatric population are sparse and are mainly limited to case reports and hemovigilance reporting systems. The objective of this study was to determine incidence, risk factors, and outcome of TRALI in critically ill children. MATERIALS AND METHODS: In a retrospective cohort study, all first-time admissions to the pediatric intensive care unit from January 1, 2009, until December 31, 2012, were screened for onset of TRALI using the consensus criteria. RESULTS: Of 2294 admitted patients, 304 were transfused, of whom 21 (6.9%) developed TRALI. Compared with transfused control subjects, risk factors for TRALI were mechanical ventilation (odds ratio, 18.94 [2.38-2452.56]), sepsis (odds ratio, 7.20 [2.69 19.69]), and high Pediatric Risk of Mortality III score (odds ratio, 1.05 [1.01 1.10]). Patients with TRALI had a higher mortality and a longer duration of mechanical ventilation when compared with transfused control subjects. CONCLUSIONS: Transfusion-related ALI is relatively common in critically ill children. The incidence in the pediatric intensive care unit population is similar to that in adult intensive care unit patients. High PRISM score on admission, mechanical ventilation and sepsis were identified as independent risk factors, which may help to assess the risks and benefits of transfusion in critically ill patients. PMID- 25457118 TI - Sympathoadrenal activation and endothelial damage in patients with varying degrees of acute infectious disease: an observational study. AB - PURPOSE: To investigate levels, associations between, and predictive value of plasma catecholamines and biomarkers of endothelial damage in patients with acute infectious illness stratified according to infection type and sepsis severity. MATERIAL AND METHODS: This is a post hoc study of plasma samples collected in prospective studies conducted at a department of internal medicine. Plasma catecholamines, syndecan-1, and thrombomodulin were measured. Registration of biochemistry, physiology, and 28- and 90-day mortality was performed. RESULTS: Patients (n = 321) were stratified into 5 groups: no infection (n = 50), local infection (n = 63), sepsis (n = 95), severe sepsis (n = 100), or septic shock (n = 13). Median Sequential Organ Failure Assessment (SOFA) score in all patients was 2, and 28- and 90-day mortality was 6% and 10%. Syndecan-1 and thrombomodulin increased progressively across groups with increasing disease severity (both P < .001), correlating with SOFA score in all groups (rho = 0.24-0.87, all P < .05). Plasma noradrenaline, syndecan-1, and thrombomodulin were higher in nonsurvivors (P < .05) and by log-rank test, levels above median predicted increased 28-day (noradrenaline and syndecan-1, P < .05) and 90-day (thrombomodulin, P < .05) mortality. CONCLUSIONS: Biomarkers of endothelial glycocalyx and cell damage increased with increasing acute infectious disease severity, correlated with SOFA score, and predicted mortality together with plasma noradrenaline. Sympathoadrenal activation and endothelial damage are linked to disease pathology also in less sick patients. PMID- 25457119 TI - Continuous electroencephalogram patterns are suggestive of eventual neurologic outcomes in post-cardiac arrest patients treated with therapeutic hypothermia. AB - INTRODUCTION: Therapeutic hypothermia (TH) after cardiac arrest (CA) resuscitation is the first therapy proven to increase survival to discharge and neurologic recovery. Methods for neurologic and mortality prognostication after CA resuscitation have been called into question because they were developed based on evidence that was developed prior to the advent of TH. This study examines the relationship between electroencephalogram (EEG) patterns and mortality and neurologic outcomes in post-CA patients undergoing TH. METHODS: Eighty-three of 732 patients who had continuous EEG (cEEG) monitoring during TH were included. Continuous EEG tracings were classified as isoelectric, low voltage, burst suppression, epileptic form, and diffuse slowing. Primary outcomes are survival to discharge and Cerebral Performance Categories (CPCs) at hospital discharge. RESULTS: Among patients with favorable neurologic outcomes (CPC1 and CPC2), the duration cardiopulmonary resuscitation and time until return of spontaneous circulation were shorter than observed in patients with poorer neurologic outcomes (CPC3, CPC4, and CPC5). The time to target temperature was equivalent among neurologic outcome groups (499.5 minutes vs 431.0 minutes, P = .09). Favorable neurologic outcome was associated with initial presentation with ventricular tachycardia or ventricular fibrillation and had cEEG patterns suggestive of diffuse slowing and epileptiform waves. DISCUSSION: The use of cEEG can provide prognostication information otherwise not obtainable by clinical examination. Specific cEEG patterns predicted probability of mortality for patients according to their initial rhythm of CA as a function of cardiopulmonary resuscitation time. PMID- 25457120 TI - Chemical cryptology of cancer's histone code. AB - Somatic mutations in non-Hodgkin's lymphoma frequently activate EZH2, a protein methyltransferase responsible for H3K27 trimethylation. In this issue of Chemistry and Biology, Bradley and coworkers describe a new set of EZH2 inhibitors amenable to probing the targetable role of H3K27 trimethylation in lymphoma. PMID- 25457121 TI - Now playing: farnesol in the biofilm. AB - The evolutionary pathway of specialized metabolism often takes unexpected, perplexing turns. In this issue of Chemistry & Biology, Feng and coworkers provide evidence for a unique phosphatase whose enzymatic product plays a critical role in biofilm formation in Bacillus subtilis. PMID- 25457122 TI - Palliative care as a primary therapeutic approach in advanced dementia: a narrative review. AB - PURPOSE: The goal of this narrative review was to identify and summarize the ways in which palliative care could benefit patients who have advanced dementia. METHODS: This case-based discussion article examines current literature on palliative care for dementia. FINDINGS: Dementia is an incurable, progressive disease that affects millions of subjects. The prevalence has grown in the last decade and is projected to continue on this trajectory. In the later stages of dementia, subjects require increasing levels of care due to severe cognitive and functional impairment. Although the field of palliative medicine focuses on improving the quality of life of patients with life-limiting illnesses, many patients with advanced dementia do not receive palliative care services. IMPLICATIONS: Palliative care has been shown to improve patient and caregiver satisfaction, quality of life, and symptom burden at the end of life. Patients with advanced dementia would benefit from increased access to palliative care. PMID- 25457123 TI - Addressing depression in a long-term care setting: a phase II pilot of problem solving treatment. AB - PURPOSE: This was a Phase II pilot study of a problem-solving treatment (PST) to address subsyndromal depression in residents of long-term care facilities. Our goal was to demonstrate PST implementation feasibility and to identify PST's potential for reducing depressive symptoms in this geriatric health care setting. METHODS: Eligible participants were randomized to receive a PST treatment (six 1 hour sessions) or a social contact comparison (6 "friendly" visits) after an initial baseline assessment. Follow-up assessments occurred 7 weeks later (after treatment) and 2 months posttreatment. The basic analytic approach was based on an intention-to-treat analysis. FINDINGS: We enrolled 21 elderly subjects in the PST group and 16 elderly subjects in the social contact comparison group. The PST group experienced a decline in depression scores compared with the social contact group. Although not statistically significant (likely due to the small sample size), PST was associated with decreased depressive symptom scores for those who were able to complete the intervention. Implementation proved to be difficult in terms of study recruitment and intervention acceptance and adherence. IMPLICATIONS: These study findings point to the potential benefits of an integrated mental health component in long-term care, involving rehabilitation professionals who are already working with the older adults in both postacute/short-stay and long-stay settings. PMID- 25457124 TI - Enhanced resolution of low molecular weight poly(ethylene glycol) in nanopore analysis. AB - A design with conjugation of DNA hairpin structure to the poly(ethylene glycol) molecule was presented to enhance the temporal resolution of low molecular weight poly(ethylene glycol) in nanopore studies. By the virtue of this design, detection of an individual PEG with molecular weight as low as 140 Da was achieved at the single-molecule level in solution, which provides a novel strategy for characterization of an individual small molecule within a nanopore. Furthermore, we found that the current duration time of poly(ethylene glycol) was scaled with the relative molecular weight, which has a potential application in single-molecule detection. PMID- 25457125 TI - 'Click' glycosylation of peptides through cysteine propargylation and CuAAC. AB - 'Click' glycosylation of cysteine-containing peptides were carried out in good yield by Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC). For that peptides were functionalized though direct propargylation of the cysteine residue allowing their use in CuAAC with suitable free or protected azido sugars of gluco, manno and galacto configuration. Among these free and protected glycopeptides a series of 'glycoRGD' peptides were obtained and submitted to in vitro platelet aggregation tests, showing that the pseudoglycosylation of the adhesion sequence lowers the IC50 value and thus could improve the in vivo pharmacokinetic properties. PMID- 25457126 TI - (R)-3-amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan 1-one derivatives as potent inhibitors of dipeptidyl peptidase-4: design, synthesis, biological evaluation, and molecular modeling. AB - A series of (R)-3-amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5 trifluorophenyl)butan-1-one derivatives was designed, synthesized, and evaluated as novel inhibitors of dipeptidyl peptidase-4 (DPP-4) for the treatment of type 2 diabetes. Most of the synthesized compounds demonstrated good inhibition activities against DPP-4. Among these, compounds 3e, 4c, 4l, and 4n exhibited prominent inhibition activities against DPP-4, with IC50s of 0.07, 0.07, 0.14, and 0.17MUM, respectively. The possible binding modes of compounds 3e and 4n with dipeptidyl peptidase-4 were also explored by molecular docking simulation. These potent DPP-4 inhibitors were optimized for the absorption, distribution, metabolism, and excretion (ADME) properties, and compound 4n displayed an attractive pharmacokinetic profile (F=96.3%, t1/2=10.5h). PMID- 25457127 TI - Synthesis of aminoacylated N(6),N(6)-dimethyladenosine solid support for efficient access to hydrolysis-resistant 3'-charged tRNA mimics. AB - RNA-amino acid and RNA-peptide conjugates that mimic charged tRNA 3'-ends are valuable substrates for structural and functional investigations of ribosomal complexes. To obtain such conjugates, most synthetic approaches that are found in the literature make use of puromycin. This well available aminonucleoside antibiotic contains a dimethylamino group at the nucleobase and a methylated tyrosine that is connected via an amide linkage to the ribose moiety. To increase structural diversity, we present the synthesis of a N(6),N(6)-dimethylated 3' azido-3'-deoxyadenosine precursor that can be coupled to any amino acid. Further derivatization results in the solid support that is eligible for the preparation of stable 3'-aminoacyl- or 3'-peptidyl-tRNA termini with an amide instead of the natural ester linkage. The present work expands our previously established route that delivered a broad range of peptidyl-tRNA mimics to the corresponding counterparts with N(6),N(6)-dimethylation pattern of the terminal adenosine (A76). This aspect is of significance to modulate the binding preferences of the mimics for ribosomal A- versus P-site. PMID- 25457128 TI - Cytomegalovirus DNAemia in pregnant women. AB - BACKGROUND: Cytomegalovirus (CMV) transmission from mother to fetus occurs at a much greater rate following primary rather than reactivated infections and CMV dissemination in the mother is considered a key step in the pathogenesis of fetal infection. However, knowledge of CMV DNAemia in CMV-seropositive pregnant women is very limited. OBJECTIVE: Major objective of this study was to assess the prevalence and diagnostic value of CMV DNAemia in a large population of seropositive pregnant women. STUDY DESIGN: Serologic and DNAemia results obtained from 2211 blood samples of 1371 consecutive pregnant women referred to our Institution for suspected CMV infection in the period 2001-2010 were reviewed. RESULTS: DNAemia was detected in 452/597 (75.7%) women with serologic evidence of primary CMV infection and in 4/774 (0.5%) women without evidence of primary infection. CONCLUSION: In pregnant women, CMV DNAemia is detected primarily during primary infection. CMV DNAemia determination may be helpful in the diagnosis of primary infection. PMID- 25457130 TI - Children with Developmental Coordination Disorder are deficient in a visuo-manual tracking task requiring predictive control. AB - The aim of this study was to examine how feedback, or its absence, affects children with Developmental Coordination Disorder (DCD) during a visuo-manual tracking task. This cross-sectional study included 40 children with DCD and 40 typically developing (TD) children between 6 and 10 years old. Participants were required to track a target moving along a circular path presented on a monitor by moving an electronic pen on a digitizing tablet. The task was performed under two visibility conditions (target visible throughout the trajectory and target intermittently occluded) and at two different target velocities (30 degrees and 60 degrees per second). Variables reflecting tracking success and tracking behavior within the target were compared between groups. Results showed that children with DCD were less proficient in tracking a moving target than TD children. Their performance deteriorated even more when the target was occluded and when the target speed increased. The mean tracking speed of the DCD group exceeded the speed at which the target rotated which was attributed to accelerations and decelerations made during tracking. This suggests that children with DCD have significant difficulties in visuo-manual tracking especially when visual feedback is reduced. It appears that their impaired ability to predict together with impairments in fine-tuning arm movements may be responsible for poor performance in the intermittently occluded visuo-manual tracking task. PMID- 25457129 TI - Downregulation of spinal endomorphin-2 correlates with mechanical allodynia in a rat model of tibia cancer. AB - The endogenous tetrapeptide endomorphin-2 (EM2) participates in pain modulation by binding to pre- and/or post-synaptic MU opioid receptor (MOR). In the present study, pathological expression and antinociceptive effects of EM2 at the spinal level were investigated in a rat model of bone cancer pain. The model was established by introducing Walker 256 mammary gland carcinoma cells into the tibia medullary cavity. Immunohistochemical staining for EM2 showed a markedly reduced EM2-immunoreactivity in the ipsilateral spinal dorsal horn on days 6, 12 and 18 post Walker 256 inoculation (p < 0.05). Intrathecal injection (i.t.) of EM2 significantly attenuated cancer-induced mechanical allodynia (p < 0.05) which could be blocked by beta-funaltrexamine (beta-FNA), the MU receptor antagonist (p < 0.05). Furthermore, topical application of EM2 dose-dependently inhibited the electrically evoked C-fiber responses and postdischarge of wide dynamic range (WDR) neurons within the spinal cord (p < 0.05), and pretreatment with beta-FNA abolished the hyperactivity of these neurons. Compared with the antinociception of morphine which took effect from 40 min to 100 min post application, the analgesic action of EM2 was characterized by quick onset and short-lived efficacy (p < 0.05), being most potent at 10 min and lasting about 20 min. These findings indicate that the down-regulated spinal EM2 is an important contributor to the neuropathological process of bone cancer pain and enhancing activation of EM2/MU receptor signaling might provide a therapeutic alternative to optimizing the treatment of cancer-induced bone pain. PMID- 25457131 TI - Editorial. Special issue: SVEPM 2014--supporting decision making on animal health through advanced and multidisciplinary methodologies, 2014 Society of Veterinary Epidemiology and Preventive Medicine conference. PMID- 25457132 TI - Estimation of flock/herd-level true Mycobacterium avium subspecies paratuberculosis prevalence on sheep, beef cattle and deer farms in New Zealand using a novel Bayesian model. AB - The study aimed to estimate the national- and island-level flock/herd true prevalence (HTP) of Mycobacterium avium subsp. paratuberculosis (MAP) infection in pastoral farmed sheep, beef cattle and deer in New Zealand. A random sample of 238 single- or multi-species farms was selected from a postal surveyed population of 1940 farms. The sample included 162 sheep flocks, 116 beef cattle and 99 deer herds from seven of 16 geographical regions. Twenty animals from each species present on farm were randomly selected for blood and faecal sampling. Pooled faecal culture testing was conducted using a single pool (sheep flocks) or two pools (beef cattle/deer herds) of 20 and 10 samples per pool, respectively. To increase flock/herd-level sensitivity, sera from all 20 animals from culture negative flocks/herds were individually tested by Pourquier((r)) ELISA (sheep and cattle) or ParalisaTM (deer). Results were adjusted for sensitivity and specificity of diagnostic tests using a novel Bayesian latent class model. Outcomes were adjusted by their sampling fractions to obtain HTP estimates at national level. For each species, the posterior probability (POPR) of HTP differences between New Zealand North (NI) and South (SI) Islands was obtained. Across all species, 69% of farms had at least one species test positive. Sheep flocks had the highest HTP estimate (76%, posterior probability interval (PPI) 70 81%), followed by deer (46%, PPI 38-55%) and beef herds (42%, PPI 35-50%). Differences were observed between the two main islands of New Zealand, with higher HTP in sheep and beef cattle flocks/herds in the NI. Sheep flock HTP was 80% in the NI compared with 70% (POPR=0.96) in the SI, while the HTP for beef cattle was 44% in the NI and 38% in the SI (POPR=0.80). Conversely, deer HTP was higher in the SI (54%) than the NI (33%, POPR=0.99). Infection with MAP is endemic at high prevalence in sheep, beef cattle and deer flocks/herds across New Zealand. PMID- 25457133 TI - Modeling the impact of vaccination control strategies on a foot and mouth disease outbreak in the Central United States. AB - The central United States (U.S.) has a large livestock population including cattle, swine, sheep and goats. Simulation models were developed to assess the impact of livestock herd types and vaccination on foot and mouth disease (FMD) outbreaks using the North American Animal Disease Spread Model. In this study, potential FMD virus outbreaks in the central region of the U.S. were simulated to compare different vaccination strategies to a depopulation only scenario. Based on data from the U.S. Department of Agriculture National Agricultural Statistics Service, a simulated population of 151,620 livestock operations characterized by latitude and longitude, production type, and herd size was generated. For the simulations, a single 17,000 head feedlot was selected as the initial latently infected herd in an otherwise susceptible population. Direct and indirect contact rates between herds were based on survey data of livestock producers in Kansas and Colorado. Control methods included ring vaccination around infected herds. Feedlots >=3000 head were either the only production type that was vaccinated or were assigned the highest vaccination priority. Simulated vaccination scenarios included low and high vaccine capacity, vaccination zones of 10 km or 50 km around detected infected premises, and vaccination trigger of 10 or 100 detected infected herds. Probability of transmission following indirect contact, movement controls and contact rate parameters were considered uncertain and so were the subjects of sensitivity analysis. All vaccination scenarios decreased number of herds depopulated but not all decreased outbreak duration. Increased size of the vaccination zone during an outbreak decreased the length of the outbreak and number of herds destroyed. Increased size of the vaccination zone primarily resulted in vaccinating feedlots >=3000 head across a larger area. Increasing the vaccination capacity had a smaller impact on the outbreak and may not be feasible if vaccine production and delivery is limited. The ability to vaccinate all the production types surrounding an infected herd did not appear as beneficial as priority vaccination of feedlot production types that have high numbers of indirect contacts. Outbreak duration, number of herds depopulated and the effectiveness of vaccination were sensitive to indirect contact transmission probability and movement restrictions. The results of this study will provide information about the impacts of disease control protocols which may be useful in choosing the optimal control methods to meet the goals of rapid effective control and eradication. PMID- 25457134 TI - Options for managing animal welfare on intensive pig farms confined by movement restrictions during an outbreak of foot and mouth disease. AB - An outbreak of foot and mouth disease in Australia would trigger a major disease control and eradication program that would include restriction of movement of live animals within defined disease control zones. Experiences from outbreaks in other countries show that restrictions that limit the ability to turn off stock can lead to animal welfare compromise on intensively managed farms that are not infected with the disease. Intensive pig farms are considered to be at high risk of developing welfare problems during a control program due to the imposed movement restrictions and limited space available to house growing pigs. This study was designed to investigate strategies that could be used to mitigate animal welfare problems on intensive pig farms during a simulated outbreak of foot and mouth disease in a livestock dense region of Australia. Three strategies for managing farms affected by animal welfare problems were assessed, including on-farm culling of grower and finisher pigs, on-farm culling of finisher pigs only, and permit-based movement of finisher pigs to slaughter at abattoir. Under traditional approaches of giving infected premises (IP) priority over culling of farms with welfare problems (WP), delays of up to 25 days were experienced prior to culling of WPs. Deployment of vaccination did little to reduce the delay to culling of WPs. These delays were sensitive to resources available for control, with reduced resources increasing the time until welfare problems were addressed. Assigning equal priority to all farms requiring culling regardless of status as IP or WP and culling each as they arose reduced the delay to culling of WPs to no more than 4 days without large increases in either the duration or the size of the outbreaks observed. PMID- 25457135 TI - Bridge hosts for avian influenza viruses at the wildlife/domestic interface: an eco-epidemiological framework implemented in southern Africa. AB - Wild terrestrial birds can act as potential local spreaders or bridge hosts for avian influenza viruses (AIVs) between waterfowl (the maintenance hosts of AIVs) and domestic avian populations in which AIVs may cause disease. Few studies have investigated this hypothesis, although it is an important knowledge gap in our understanding of AIV spread within socio-ecosystems. We designed a simple and reproducible approach in an agro-ecosystem in Zimbabwe based on: (1) bird counts at key target sites (i.e., wetlands, villages, intensive poultry production buildings and ostrich farms) to identify which wild birds species co-occur in these different sites and seasons when the risk of AIV transmission through these potential bridge hosts is maximal and (2) targeted sampling and testing for AIV infection in the identified potential bridge hosts. We found that 12 wild bird species represented the vast majority (79%) of co-occurrences in the different sites, whereas 230 bird species were recorded in this ecosystem. Specifically, three species - barn swallow, Hirundo rustica, red-billed quelea, Quelea quelea and cattle egret, Bubulcus ibis - represented the main potential bridge host species (65% of co-occurrences). In two out of these three species (i.e., barn swallow and red-billed quelea), we detected AIV infections, confirming that they can play a bridge function between waterfowl and domestic species in the ecosystem. Our approach can be easily implemented in other ecosystems to identify potential bridge hosts, and our results have implications in terms of surveillance, risk management and control of AIV spread in socio-ecosystems. PMID- 25457136 TI - Evaluation of a behavioral assessment tool for dogs relinquished to shelters. AB - The goal of the present study was to evaluate a shortened, 42-item version of the Canine Behavioral Assessment and Research Questionnaire (C-BARQ((S))) as a behavioral screening tool for dogs relinquished to animal shelters. In contrast to a previous finding, the current study found no consistent evidence that relinquishing owners gave unreliable or biased responses to the questionnaire depending on whether or not they believed that this information would be shared with shelter staff or used to evaluate dogs for adoption. Relinquishing owners' C BARQ((S)) responses for items related to aggression and fear directed toward humans and other dogs correlated with independent subjective assessments of aggressiveness made by shelter staff (generalized linear mixed models, P<0.05, N=84 aggressive dogs, N=156 non-aggressive dogs). In addition, C-BARQ((S)) scores successfully discriminated between dogs based on their eventual outcomes (i.e., adoption or euthanasia; Generalized Linear Mixed Models, P<0.05, N=181 adopted, N=177 euthanized), indicating convergent validity. Follow-up surveys with a subset of adoptive owners (N=53) revealed significant correlations (after correction for multiple comparisons) between relinquishing and adoptive owners' C BARQ((S)) ratings for 3 behavioral traits: stranger-directed aggression (rs=0.494, P<0.001), chewing inappropriate objects (rs=0.402, P<0.01), and urination when left alone (rs=0.421, P<0.01). Overall, the findings confirmed the value of this type of shelter intake survey instrument for screening owner surrendered dogs for the presence of behavior problems. PMID- 25457137 TI - Cardioversion of atrial fibrillation in a dog with structural heart disease using an esophageal-right atrial lead configuration. AB - Atrial fibrillation is a common arrhythmia in dogs with structural cardiac disease and can result in significant clinical signs. Several methods of electrical cardioversion of atrial fibrillation have been described. Biphasic transthoracic cardioversion of atrial fibrillation in dogs with naturally occurring heart disease has been described in veterinary medicine and has been shown to be highly successful. In humans and research animals intracardiac and transesophageal cardioversion of atrial fibrillation has been described as an alternative to transthoracic cardioversion. While transesophageal cardioversion is very successful in humans and research animals, this technique has not been previously described in a clinical patient with naturally occurring heart disease in veterinary medicine. This report describes the use of transesophageal cardioversion in a dog with atrial fibrillation and structural cardiac disease. Cardioversion was unsuccessful using two electrodes positioned within the esophagus. Cardioversion of atrial fibrillation to normal sinus rhythm was successfully achieved and maintained using one electrode positioned within the esophagus and one electrode positioned within the right atrium using a synchronized monophasic shock of 50 J. PMID- 25457138 TI - Robotic catheterization: the importance of evaluation by interventional radiologists. PMID- 25457139 TI - Endovascular repair of a ruptured abdominal aortic aneurysm with arteriovenous fistula and duplication of the inferior vena cava. PMID- 25457140 TI - Covered metallic stents in malignant common bile duct obstruction: to use or not to use--that is the question! PMID- 25457142 TI - Shepherd's hook technique for superselective catheterization of hepatic arteries. AB - From October 2013 to March 2014, the shepherd's hook technique was attempted in 21 patients for superselective catheterization of the hepatic artery. The technique was successful in 18 of 21 patients (86%).The indications for using the shepherd's hook technique were acute angulation < 60 degrees (n = 14), a small feeder artery from a large hepatic artery at a right angle (n = 6), or obtuse angulation from the complex parent artery (n = 1). The shepherd's hook technique is a useful tool in superselective catheterization of hepatic arteries with complex geometry. PMID- 25457141 TI - Intravascular mesenchymal chondrosarcoma. PMID- 25457143 TI - Retrograde popliteal endovascular stent-graft repair for a growing persistent sciatic artery aneurysm (type IIa): case report and review of the literature. PMID- 25457144 TI - Removal of a malpositioned central venous catheter from a direct main pulmonary artery puncture with transthoracic temporary balloon occlusion. PMID- 25457145 TI - Acute severe thrombocytopenia secondary to intraarterial low-osmolar iodinated contrast administered during coronary angiography. PMID- 25457146 TI - Re: "Selective arterial embolization with ethylene-vinyl alcohol copolymer for control of massive lower gastrointestinal bleeding: feasibility and initial experience". PMID- 25457147 TI - Reply to: "Re: 'Selective arterial embolization with ethylene-vinyl alcohol copolymer for control of massive lower gastrointestinal bleeding: feasibility and initial experience' ". PMID- 25457148 TI - Advances in analysis, treatment technologies, and environmental fate of emerging contaminants. PMID- 25457151 TI - When are serum specific IgE levels positive? PMID- 25457150 TI - Basophil expression of diamine oxidase: a novel biomarker of allergen immunotherapy response. AB - BACKGROUND: Immunotherapy inhibits basophil histamine release, but the assay is cumbersome, and no one has studied the effects of immunotherapy withdrawal. OBJECTIVE: Intracellular fluorochrome-labeled diamine oxidase (DAO) was used as a novel functional readout of basophil histamine release after immunotherapy. Results were compared with conventional basophil surface expression of activation markers. METHODS: Subcutaneous immunotherapy (SCIT)-treated patients (n = 14), sublingual immunotherapy (SLIT)-treated patients (n = 12), participants who completed 3 years of treatment with grass pollen sublingual immunotherapy (the SLIT-TOL group; n = 6), patients with untreated seasonal allergic rhinitis (SAR; n = 24), and nonatopic control subjects (n = 12) were studied. Intracellularly labeled DAO(+) and surface expression of CD203c(bright), CD63(+), and CD107a(+) on chemoattractant receptor-homologous molecule expressed on TH2 lymphocytes (CRTh2)-positive basophils were measured by means of flow cytometry. Serum IgG4 levels and serum inhibitory activity for IgE-allergen complex binding to B cells (IgE-FAB) and basophil histamine release were also determined. RESULTS: Proportions of allergen-stimulated DAO(+)CRTh2(+) basophils were higher in participants in the SCIT, SLIT, and SLIT-TOL groups (all P < .0001) compared with those in patients in the SAR group. Similarly, there were lower proportions of CRTh2(+) basophils expressing surface CD203c(bright) (all P < .001), CD63 (all P < .001), and CD107a (all P < .01). Rhinitis symptoms were lower in the SCIT, SLIT, and SLIT-TOL groups (P < .001) compared with those in the SAR group. Serum inhibitory activity for IgE-FAB and basophil histamine release were also significantly greater in all immunotherapy groups (P < .05) compared with the SAR group. CONCLUSION: These results support long-term clinical and immunologic tolerance during and after grass pollen immunotherapy. Intracellularly labeled DAO expression by basophils merits further investigation as a surrogate biomarker for monitoring efficacy and tolerance after immunotherapy. PMID- 25457149 TI - Atopic dermatitis increases the effect of exposure to peanut antigen in dust on peanut sensitization and likely peanut allergy. AB - BACKGROUND: History and severity of atopic dermatitis (AD) are risk factors for peanut allergy. Recent evidence suggests that children can become sensitized to food allergens through an impaired skin barrier. Household peanut consumption, which correlates strongly with peanut protein levels in household dust, is a risk factor for peanut allergy. OBJECTIVE: We sought to assess whether environmental peanut exposure (EPE) is a risk for peanut sensitization and allergy and whether markers of an impaired skin barrier modify this risk. METHODS: Peanut protein in household dust (in micrograms per gram) was assessed in highly atopic children (age, 3-15 months) recruited to the Consortium of Food Allergy Research Observational Study. History and severity of AD, peanut sensitization, and likely allergy (peanut-specific IgE, >=5 kUA/mL) were assessed at recruitment into the Consortium of Food Allergy Research study. RESULTS: There was an exposure response relationship between peanut protein levels in household dust and peanut skin prick test (SPT) sensitization and likely allergy. In the final multivariate model an increase in 4 log2 EPE units increased the odds of peanut SPT sensitization (1.71-fold; 95% CI, 1.13- to 2.59-fold; P = .01) and likely peanut allergy (PA; 2.10-fold; 95% CI, 1.20- to 3.67-fold; P < .01). The effect of EPE on peanut SPT sensitization was augmented in children with a history of AD (OR, 1.97; 95% CI, 1.26-3.09; P < .01) and augmented even further in children with a history of severe AD (OR, 2.41; 95% CI, 1.30-4.47; P < .01); the effect of EPE on PA was also augmented in children with a history of AD (OR, 2.34; 95% CI, 1.31 4.18; P < .01). CONCLUSION: Exposure to peanut antigen in dust through an impaired skin barrier in atopically inflamed skin is a plausible route for peanut SPT sensitization and PA. PMID- 25457152 TI - Respiratory allergy caused by house dust mites: What do we really know? AB - The house dust mite (HDM) is a major perennial allergen source and a significant cause of allergic rhinitis and allergic asthma. However, awareness of the condition remains generally low. This review assesses the links between exposure to HDM, development of the allergic response, and pathologic consequences in patients with respiratory allergic diseases. We investigate the epidemiology of HDM allergy to explore the interaction between mites and human subjects at the population, individual, and molecular levels. Core and recent publications were identified by using "house dust mite" as a key search term to evaluate the current knowledge of HDM epidemiology and pathophysiology. Prevalence data for HDM allergen sensitization vary from 65 to 130 million persons in the general population worldwide to as many as 50% among asthmatic patients. Heterogeneity of populations, terminology, and end points in the literature confound estimates, indicating the need for greater standardization in epidemiologic research. Exposure to allergens depends on multiple ecological strata, including climate and mite microhabitats within the domestic environment, with the latter providing opportunity for intervention measures to reduce allergen load. Inhaled mite aeroallergens are unusually virulent: they are able to activate both the adaptive and innate immune responses, potentially offering new avenues for intervention. The role of HDM allergens is crucial in the development of allergic rhinitis and asthma, but the translation of silent sensitization into symptomatic disease is still incompletely understood. Improved understanding of HDMs, their allergens, and their microhabitats will enable development of more effective outcomes for patients with HDM allergy. PMID- 25457154 TI - Tolerability of aztreonam and carbapenems in patients with IgE-mediated hypersensitivity to penicillins. AB - BACKGROUND: Studies performed on samples larger than 100 subjects with a documented IgE-mediated hypersensitivity to penicillins have demonstrated a cross reactivity rate of approximately 1% between penicillins and both imipenem and meropenem, whereas a single study found a cross-reactivity rate of 6.2% with aztreonam in 16 such subjects. OBJECTIVE: To assess the cross-reactivity and tolerability of aztreonam and 3 carbapenems (imipenem-cilastatin, meropenem, and ertapenem) in patients with documented IgE-mediated hypersensitivity to penicillins. METHODS: A total of 212 consecutive subjects with immediate reactions to penicillins and positive results on skin tests to at least 1 penicillin reagent underwent skin tests with aztreonam and carbapenems; subjects with negative results were challenged with escalating doses of aztreonam and carbapenems. RESULTS: All subjects displayed negative skin test results to both aztreonam and carbapenems; 211 accepted challenges and tolerated them. Challenges were not followed by full therapeutic courses. CONCLUSIONS: These data indicate the tolerability of both aztreonam and carbapenems in penicillin-allergic subjects. In those who especially require these alternative beta-lactams, however, we recommend pretreatment skin tests, both because rare cases of cross reactivity have been reported and because negative results indicate tolerability. PMID- 25457155 TI - Dicer is indispensable for the development of murine mast cells. PMID- 25457153 TI - Hematopoietic stem cell transplantation rescues the immunologic phenotype and prevents vasculopathy in patients with adenosine deaminase 2 deficiency. PMID- 25457156 TI - Reply: To PMID 24794684. PMID- 25457158 TI - Advances in animal ecology from 3D-LiDAR ecosystem mapping. AB - The advent and recent advances of Light Detection and Ranging (LiDAR) have enabled accurate measurement of 3D ecosystem structure. Here, we review insights gained through the application of LiDAR to animal ecology studies, revealing the fundamental importance of structure for animals. Structural heterogeneity is most conducive to increased animal richness and abundance, and increased complexity of vertical vegetation structure is more positively influential compared with traditionally measured canopy cover, which produces mixed results. However, different taxonomic groups interact with a variety of 3D canopy traits and some groups with 3D topography. To develop a better understanding of animal dynamics, future studies will benefit from considering 3D habitat effects in a wider variety of ecosystems and with more taxa. PMID- 25457157 TI - Prognostic significance of promyelocytic leukemia expression in gastrointestinal stromal tumor; integrated proteomic and transcriptomic analysis. AB - Prognostic markers are urgently needed to optimize the postoperative treatment strategies for gastrointestinal stromal tumors (GIST). GIST of the small intestine (I-GIST) show more aggressive behavior than those of the stomach (S GIST), and the molecular background of the malignancy in I-GIST may include potential prognostic biomarkers. We conducted integrated proteomic and transcriptomic analysis to identify genes showing differential expressions according to the tumor site. We generated protein expression profiles for four cases each of surgically resected I-GIST and S-GIST using label-free proteomic analysis. For proteins showing differential expressions, global mRNA expression was compared between 9 I-GIST and 23 S-GIST. Among the 2555 genes analyzed, we found that promyelocytic leukemia (PML), a tumor suppressor gene, was significantly downregulated in I-GIST at both the protein and mRNA levels (P < 0.01; fold difference >=2.0). Immunohistochemistry of 254 additional cases from multiple clinical facilities showed that PML-negative cases were significantly frequent in the I-GIST group (P < 0.001). The 5-year recurrence-free survival rate was significantly lower in the PML-negative than in the PML-positive cases (60.1% vs 91.7%; P < 0.001). Multivariate analysis revealed that downregulation of PML was an independent unfavorable prognostic factor (hazard ratio = 2.739; P = 0.001). Our study indicated that prognostication based on PML expression may have potential for optimizing the treatment strategy for GIST patients. Further validation studies of PML for clinical application, and investigation for the mechanistic significance of PML to clarify the molecular backgrounds of malignancy in GIST are warranted. PMID- 25457159 TI - Self-reported remission of obstructive sleep apnea following bariatric surgery: cohort study. AB - BACKGROUND: Evidence on remission of obstructive sleep apnea (OSA) after bariatric surgery and its relation to weight loss is conflicting. We sought to identify factors associated with successful self-reported OSA remission in a large cohort of bariatric surgery patients. METHODS: We analyzed data from the statewide, prospective clinical registry of the Michigan Bariatric Surgery Collaborative and identified 3,550 patients with OSA who underwent a primary bariatric procedure between June 2006 and October 2011 and had at least 1 year of follow-up data. We used multivariate logistic regression to identify preoperative factors associated with successful self-reported OSA remission, defined as discontinuation of continuous positive airway pressure or bilevel positive airway pressure at 1 year. Our regression model also included procedure type and weight loss at 1 year, divided into equal quintiles, as covariates. RESULTS: The overall 1-year self-reported OSA remission rate was 60%. Significant predictors of remission included age category (per 10 yr) (OR .73, CI .69-.78), body mass index category (per 10 units) (OR .57, CI .54-.62), male gender (OR .58, CI .52-.69), hypertension (OR .83, CI .74-.99), depression (OR .78, CI .69-.88), pulmonary disease (OR .88, CI .78-.98), and baseline Health and Activities Limitations Index score (OR 1.70, CI 1.32-2.23). Relative to gastric banding, the adjusted odds of OSA remission were greater with gastric bypass (OR 2.38, CI 1.89-3.08), sleeve gastrectomy (OR 2.01, CI 1.44-2.55), and duodenal switch (OR 2.57, CI 1.02 7.26). The odds ratio of OSA remission increased stepwise through quintiles of 1 year weight loss. Relative to the lowest quintile, the odds ratios of remission in the 2(nd) through 5(th) quintiles were 1.44 (CI 1.11-1.84), 2.03 (CI 1.48 2.57), 2.47 (1.85-3.40), and 3.53 (CI 2.56-4.85). CONCLUSIONS: Weight loss is an important predictor of self-reported OSA remission after bariatric surgery. However, independent of weight loss, there remain significant differences in the likelihood of remission between gastric banding and other bariatric procedures. This suggests that there may be metabolic, weight-independent effects of procedure type on self-reported OSA remission. PMID- 25457160 TI - Comment on: Replication and evaluation of a proposed two-factor Binge Eating Scale (BES) structure in a sample of bariatric surgery candidates. PMID- 25457161 TI - Comment on: Acid suppression medications are associated with suboptimal weight loss after laparoscopic Roux-en-Y gastric bypass in patients older than 40 years. PMID- 25457162 TI - Segmental splenic ischemia after laparoscopic sleeve gastrectomy. PMID- 25457163 TI - Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. AB - Anophthalmia/microphthalmia (A/M) is a genetically heterogeneous birth defect for which the etiology is unknown in more than 50% of patients. We used exome sequencing with the ACE Exome(TM) (Personalis, Inc; 18 cases) and UCSF Genomics Core (21 cases) to sequence 28 patients with A/M and four patients with varied developmental eye defects. In the 28 patients with A/M, we identified de novo mutations in three patients (OTX2, p.(Gln91His), RARB, p.Arg387Cys and GDF6, p.Ala249Glu) and inherited mutations in STRA6 in two patients. In patients with developmental eye defects, a female with cataracts and cardiomyopathy had a de novo COL4A1 mutation, p.(Gly773Arg), expanding the phenotype associated with COL4A1 to include cardiomyopathy. A male with a chorioretinal defect, microcephaly, seizures and sensorineural deafness had two PNPT1 mutations, p.(Ala507Ser) and c.401-1G>A, and we describe eye defects associated with this gene for the first time. Exome sequencing was efficient for identifying mutations in pathogenic genes for which there is no clinical testing available and for identifying cases that expand phenotypic spectra, such as the PNPT1 and COL4A1 associated disorders described here. PMID- 25457164 TI - The RSC complex localizes to coding sequences to regulate Pol II and histone occupancy. AB - ATP-dependent chromatin remodelers regulate chromatin structure during multiple stages of transcription. We report that RSC, an essential chromatin remodeler, is recruited to the open reading frames (ORFs) of actively transcribed genes genome wide, suggesting a role for RSC in regulating transcription elongation. Consistent with such a role, Pol II occupancy in the ORFs of weakly transcribed genes is drastically reduced upon depletion of the RSC catalytic subunit Sth1. RSC inactivation also reduced histone H3 occupancy across transcribed regions. Remarkably, the strongest effects on Pol II and H3 occupancy were confined to the genes displaying the greatest RSC ORF enrichment. Additionally, RSC recruitment to the ORF requires the activities of the SAGA and NuA4 HAT complexes and is aided by the activities of the Pol II CTD Ser2 kinases Bur1 and Ctk1. Overall, our findings strongly implicate ORF-associated RSC in governing Pol II function and in maintaining chromatin structure over transcribed regions. PMID- 25457167 TI - Redundant mechanisms to form silent chromatin at pericentromeric regions rely on BEND3 and DNA methylation. AB - Constitutive heterochromatin is typically defined by high levels of DNA methylation and H3 lysine 9 trimethylation (H3K9Me3), whereas facultative heterochromatin displays DNA hypomethylation and high H3 lysine 27 trimethylation (H3K27Me3). The two chromatin types generally do not coexist at the same loci, suggesting mutual exclusivity. During development or in cancer, pericentromeric regions can adopt either epigenetic state, but the switching mechanism is unknown. We used a quantitative locus purification method to characterize changes in pericentromeric chromatin-associated proteins in mouse embryonic stem cells deficient for either the methyltransferases required for DNA methylation or H3K9Me3. DNA methylation controls heterochromatin architecture and inhibits Polycomb recruitment. BEND3, a protein enriched on pericentromeric chromatin in the absence of DNA methylation or H3K9Me3, allows Polycomb recruitment and H3K27Me3, resulting in a redundant pathway to generate repressive chromatin. This suggests that BEND3 is a key factor in mediating a switch from constitutive to facultative heterochromatin. PMID- 25457170 TI - Teleost fish scales amongst the toughest collagenous materials. AB - Fish scales from modern teleost fish are high-performance materials made of cross plies of collagen type I fibrils reinforced with hydroxyapatite. Recent studies on this material have demonstrated the remarkable performance of this material in tension and against sharp puncture. Although it is known that teleost fish scales are extremely tough, actual measurements of fracture toughness have so far not been reported because it is simply not possible to propagate a crack in this material using standard fracture testing configurations. Here we present a new fracture test setup where the scale is clamped between two pairs of miniature steel plates. The plates transmit the load uniformly, prevent warping of the scale and ensure a controlled crack propagation. We report a toughness of 15 to 18kJm(-2) (depending on the direction of crack propagation), which confirms teleost fish scales as one of the toughest biological material known. We also tested the individual bony layers, which we found was about four times less tough than the collagen layer because of its higher mineralization. The mechanical response of the scales also depends on the cohesion between fibrils and plies. Delamination tests show that the interface between the collagen fibrils is three orders of magnitude weaker than the scale, which explains the massive delamination and defibrillation observed experimentally. Finally, simple fracture mechanics models showed that process zone toughening is the principal source of toughening for the scales, followed by bridging by delaminated fibrils. These findings can guide the design of cross-ply composites and engineering textiles for high-end applications. This study also hints on the fracture mechanics and performance of collagenous materials with similar microstructures: fish skin, lamellar bone or tendons. PMID- 25457171 TI - A method to characterize average cervical spine ligament response based on raw data sets for implementation into injury biomechanics models. AB - Experimental testing on cervical spine ligaments provides important data for advanced numerical modeling and injury prediction; however, accurate characterization of individual ligament response and determination of average mechanical properties for specific ligaments has not been adequately addressed in the literature. Existing methods are limited by a number of arbitrary choices made during the curve fits that often misrepresent the characteristic shape response of the ligaments, which is important for incorporation into numerical models to produce a biofidelic response. A method was developed to represent the mechanical properties of individual ligaments using a piece-wise curve fit with first derivative continuity between adjacent regions. The method was applied to published data for cervical spine ligaments and preserved the shape response (toe, linear, and traumatic regions) up to failure, for strain rates of 0.5s(-1), 20s(-1), and 150-250s(-1), to determine the average force-displacement curves. Individual ligament coefficients of determination were 0.989 to 1.000 demonstrating excellent fit. This study produced a novel method in which a set of experimental ligament material property data exhibiting scatter was fit using a characteristic curve approach with a toe, linear, and traumatic region, as often observed in ligaments and tendons, and could be applied to other biological material data with a similar characteristic shape. The resultant average cervical spine ligament curves provide an accurate representation of the raw test data and the expected material property effects corresponding to varying deformation rates. PMID- 25457165 TI - RNA targeting by the type III-A CRISPR-Cas Csm complex of Thermus thermophilus. AB - CRISPR-Cas is a prokaryotic adaptive immune system that provides sequence specific defense against foreign nucleic acids. Here we report the structure and function of the effector complex of the Type III-A CRISPR-Cas system of Thermus thermophilus: the Csm complex (TtCsm). TtCsm is composed of five different protein subunits (Csm1-Csm5) with an uneven stoichiometry and a single crRNA of variable size (35-53 nt). The TtCsm crRNA content is similar to the Type III-B Cmr complex, indicating that crRNAs are shared among different subtypes. A negative stain EM structure of the TtCsm complex exhibits the characteristic architecture of Type I and Type III CRISPR-associated ribonucleoprotein complexes. crRNA-protein crosslinking studies show extensive contacts between the Csm3 backbone and the bound crRNA. We show that, like TtCmr, TtCsm cleaves complementary target RNAs at multiple sites. Unlike Type I complexes, interference by TtCsm does not proceed via initial base pairing by a seed sequence. PMID- 25457172 TI - Tracheal bioengineering: the next steps. Proceeds of an International Society of Cell Therapy Pulmonary Cellular Therapy Signature Series Workshop, Paris, France, April 22, 2014. AB - There has been significant and exciting recent progress in the development of bioengineering approaches for generating tracheal tissue that can be used for congenital and acquired tracheal diseases. This includes a growing clinical experience in both pediatric and adult patients with life-threatening tracheal diseases. However, not all of these attempts have been successful, and there is ongoing discussion and debate about the optimal approaches to be used. These include considerations of optimal materials, particularly use of synthetic versus biologic scaffolds, appropriate cellularization of the scaffolds, optimal surgical approaches and optimal measure of both clinical and biologic outcomes. To address these issues, the International Society of Cell Therapy convened a first-ever meeting of the leading clinicians and tracheal biologists, along with experts in regulatory and ethical affairs, to discuss and debate the issues. A series of recommendations are presented for how to best move the field ahead. PMID- 25457173 TI - Efficacy of the transillumination method for appropriate tracheal tube placement in small children: a randomized controlled trial. AB - STUDY OBJECTIVE: To evaluate whether the transillumination method increased the probability of appropriate tracheal tube (TT) placement compared with the main stem method. DESIGN: Prospective, randomized, controlled study. SETTING: Operating room, university hospital. PATIENTS: Eighty children <2 years old scheduled for elective surgery undergoing general anesthesia. INTERVENTIONS: Trachlight was used for the transillumination method. After intubation, patients were randomly assigned to 1 of 2 groups: (1) deliberate bronchial intubation with subsequent withdrawal of the TT to 2 cm above the carina (main-stem group) or (2) transmitted visual signal from a bright light at the TT tip on the skin at the suprasternal notch after inserting the Trachlight into the TT (transillumination group). MEASUREMENTS: The TT tip position was assessed by chest radiograph after the procedure. Appropriate TT placement was defined when the TT tip was located between the sternoclavicular junction and 1 cm above the carina. MAIN RESULTS: Appropriate TT placement was found in 31 (80%) of 39 patients in the transillumination group and 26 (65%) of 40 in the main-stem group. The transillumination method had higher rate of appropriate TT placement than the main-stem method (P = .15; risk ratio, 1.22; 95% confidence interval, 0.93-1.61). Seven patients (18%) had proximal TT placement, and 1 (3%) had distal TT placement in the transillumination group. In the main-stem group, 7 patients (18%) had proximal TT placement, and 7 (18%) had distal TT placement. CONCLUSIONS: The transillumination method was reliable for appropriate TT placement in small children <2 years old undergoing general anesthesia, although the transillumination method was not found to be better compared with the main stem method. PMID- 25457166 TI - PRMT5 protects genomic integrity during global DNA demethylation in primordial germ cells and preimplantation embryos. AB - Primordial germ cells (PGCs) and preimplantation embryos undergo epigenetic reprogramming, which includes comprehensive DNA demethylation. We found that PRMT5, an arginine methyltransferase, translocates from the cytoplasm to the nucleus during this process. Here we show that conditional loss of PRMT5 in early PGCs causes complete male and female sterility, preceded by the upregulation of LINE1 and IAP transposons as well as activation of a DNA damage response. Similarly, loss of maternal-zygotic PRMT5 also leads to IAP upregulation. PRMT5 is necessary for the repressive H2A/H4R3me2s chromatin modification on LINE1 and IAP transposons in PGCs, directly implicating this modification in transposon silencing during DNA hypomethylation. PRMT5 translocates back to the cytoplasm subsequently, to participate in the previously described PIWI-interacting RNA (piRNA) pathway that promotes transposon silencing via de novo DNA remethylation. Thus, PRMT5 is directly involved in genome defense during preimplantation development and in PGCs at the time of global DNA demethylation. PMID- 25457174 TI - Tracheal resection with regional anesthesia. AB - A 52-year-old man underwent tracheal resection during regional anesthesia with sedation. The patient had a prior history of tracheostomy resulting in tracheal stenosis and expiratory wheezing. Awake tracheal resection with spontaneous ventilation was performed. Patient cooperation was essential to identify the lesion and perform the resection safely. PMID- 25457175 TI - Reactivity of C-Amino-1,2,4-triazoles toward Electrophiles: A Combined Computational and Experimental Study of Alkylation by Halogen Alkanes. AB - A combination of computational and experimental methods was used to examine the structure-reactivity relationships in the reactions of C-amino-1H-1,2,4-triazoles with electrophiles. The global nucleophilicity of 3-amino- and 3,5-diamino-1H 1,2,4-triazoles was predicted to be higher than that of 5-amino-1H-1,2,4 triazoles. Fukui functions and molecular electrostatic potential indicate that reactions involving an amino group should occur more easily for the 3-amino- than for the 5-amino-1H-1,2,4-triazoles. Increasing electrophile hardness should increase the probability of attack at the N-4 atom of the triazole ring, whereas increasing softness should enhance the probability of attack at the N-2 atom and 3-NH2 group. Calculated transition state energies of model SN2 reactions and experimental studies showed that quaternization of 1-substituted 3-amino- and 3,5 diamino-1H-1,2,4-triazoles by many alkyl halides proceeds with low selectivity and can involve the N-2 and N-4 atoms as well as the 3-NH2 group as reaction centers. A new method for the selective synthesis of 1,4-disubstituted 3-amino- and 3,5-diamino-1,2,4-triazoles based on quaternization of readily available 1 substituted 3-acetylamino-1,2,4-triazoles with subsequent removal of the acetyl protecting group by acid hydrolysis was developed. PMID- 25457176 TI - 'Check it out!' Decision-making of vulnerable groups about participation in a two stage cardiometabolic health check: a qualitative study. AB - OBJECTIVE: Exploring determinants influencing vulnerable groups regarding (non-) participation in the Dutch two-stage cardiometabolic health check, comprising a health risk assessment (HRA) and prevention consultations (PCs) for high-risk individuals. METHODS: Qualitative study comprising 21 focus groups with non Western (Surinamese, Turkish, Moroccan) immigrants aged 45-70, adult children from one of these descents, native Dutch with a lower socioeconomic status, and healthcare professionals working with these groups. RESULTS: Reasons for not completing the HRA included (flawed) risk perceptions, health negligence, (health) illiteracy, and language barriers. A face-to-face invitation from a reliable source and community outreach to raise awareness were perceived as facilitating participation. Reasons for not attending the PCs overlapped with completing the HRA but additionally included risk denial, fear about the outcome, its potential consequences (lifestyle changes and medication prescription), and disease-related stigma. CONCLUSION: Reasons for not completing the HRA were mainly cognitive, whereas reasons for not attending the PCs were also affective. PRACTICE IMPLICATIONS: When designing a two-stage health check, choice of invitation method seems important, as does training healthcare professionals in techniques to effectively handle patients' (flawed) risk perceptions and attitudinal ambivalence. Focus should be on promoting informed choices by providing accurate information. PMID- 25457177 TI - Physician gender and patient centered communication: the moderating effect of psychosocial and biomedical case characteristics. AB - OBJECTIVE: Female physicians have a more patient-centered communication style than their male counterparts; however, few studies have investigated how the biomedical or psychosocial nature of a patient diagnosis might moderate this relationship. METHODS: Seventy six 3rd year residents (50 male and 26 females) seeking board certification from the Korean Academy of Family Medicine participated in the 2013 Clinical Practice Examination by conducting two simulated patient (SP) interviews, one presenting a largely psychosocial case and the other largely biomedical. The interview recordings were coded with the Roter Interaction Analysis System (RIAS). RESULTS: Female physicians and their SPs engaged in more dialog than male physicians in both cases. Female physicians were more patient-centered than males for the psychosocial case (t = -3.24, P < 0.05), however, their scores did not differ for the biomedical case. In multivariate analysis, a significant interaction between physician gender and case (z = -3.90, P < 0.001) similarly demonstrated greater female patient-centeredness only for the predominantly psychosocial case. CONCLUSION: Case characteristics moderated the association between physician gender and patient-centeredness. PRACTICE IMPLICATIONS: Case characteristics need to be considered in future research on the association of physician gender and the patient-centered communication, as well as in the tailoring of physician communication training. PMID- 25457178 TI - Fertility knowledge and awareness in oocyte donors in Spain. AB - OBJECTIVE: To evaluate motherhood intentions and awareness of the limits of fertility as related to menstrual cycle, female age, and assisted reproductive technologies (ART) in oocyte-donation candidates in Spain. METHODS: Cross sectional study with 229 women seeking information about oocyte donation in March October 2013. Women were interviewed by healthcare professionals. RESULTS: The majority of participants (95.6%) wanted to be mothers in future and 36.7% already had children. Even so, knowledge about female reproduction was low: 48.3% failed to identify the ovulation time, 48.5% missed women's fertility peak before 25, and 27.9% overestimated the age limits for ART. University education does not improve global fertility knowledge and is associated with a later intended age for childbearing (p = 0.001), which results in a twofold risk of childlessness at age of 30 (RR = 1.95, 95% CI 1.11-3.43). CONCLUSION: We conclude that fertility knowledge is insufficient but, encouragingly, nearly 30% of interviewees were proactive in seeking information from the healthcare professionals. PRACTICE IMPLICATIONS: The future fertility of young people should be protected through educational interventions emphasizing the increasing phenomenon of age-related infertility at every point of contact with a women's health professional, for instance, when oocyte-donation candidates attend a fertility center for an information visit. PMID- 25457179 TI - N-terminal ArgD peptides from the classical Staphylococcus aureus Agr system have cytotoxic and proinflammatory activities. AB - AgrD is the precursor for the autoinducing peptide in a quorum-sensing system regulating virulence phenotypes of the preeminent pathogen Staphylococcus aureus. Mass spectrometry-based methods, including molecular networking, identified formylated and nonformylated peptide variants derived from the AgrD N-terminal leader domain in S. aureus cell-free culture supernatants. Functional assessment of these peptides revealed unexpected bioactivities, including human cell-line cytotoxicity, modulation of neutrophil chemotaxis, neutrophil extracellular trap formation, and the aggravation of skin lesions in vivo. PMID- 25457180 TI - EZH2 inhibitor efficacy in non-Hodgkin's lymphoma does not require suppression of H3K27 monomethylation. AB - The histone lysine methyltransferase (MT) Enhancer of Zeste Homolog 2 (EZH2) is considered an oncogenic driver in a subset of germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) and follicular lymphoma due to the presence of recurrent, monoallelic mutations in the EZH2 catalytic domain. These genomic data suggest that targeting the EZH2 MT activity is a valid therapeutic strategy for the treatment of lymphoma patients with EZH2 mutations. Here we report the identification of highly potent and selective EZH2 small molecule inhibitors, their validation by a cellular thermal shift assay, application across a large cell panel representing various non-Hodgkin's lymphoma (NHL) subtypes, and their efficacy in EZH2mutant-containing GCB-DLBCL xenograft models. Surprisingly, our EZH2 inhibitors selectively affect the turnover of trimethylated, but not monomethylated histone H3 lysine 27 at pharmacologically relevant doses. Importantly, we find that these inhibitors are broadly efficacious also in NHL models with wild-type EZH2. PMID- 25457181 TI - Intracellular calcium levels determine differential modulation of allosteric interactions within G protein-coupled receptor heteromers. AB - The pharmacological significance of the adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromer is well established and it is being considered as an important target for the treatment of Parkinson's disease and other neuropsychiatric disorders. However, the physiological factors that control its distinctive biochemical properties are still unknown. We demonstrate that different intracellular Ca2+ levels exert a differential modulation of A2AR-D2R heteromer-mediated adenylyl-cyclase and MAPK signaling in striatal cells. This depends on the ability of low and high Ca2+ levels to promote a selective interaction of the heteromer with the neuronal Ca2+-binding proteins NCS-1 and calneuron-1, respectively. These Ca2+-binding proteins differentially modulate allosteric interactions within the A2AR-D2R heteromer, which constitutes a unique cellular device that integrates extracellular (adenosine and dopamine) and intracellular (Ca+2) signals to produce a specific functional response. PMID- 25457183 TI - Sebaceous neoplasms and the immunoprofile of mismatch-repair proteins as a screening target for syndromic cases. AB - INTRODUCTION: Muir-Torre syndrome (MTS), a subset of Lynch syndrome, is characterized by concurrent or sequential development of sebaceous neoplasms, and internal malignancies, specifically colorectal carcinoma (CRC), and can be related to mismatch-repair (MMR)-protein deficiency. In CRC context, p16 negativity in MLH1-deficient cases may denote methylation rather than mutation. The prime aim of this study was to evaluate the mismatch-repair (MMR)-protein deficiency and the p16 status among sebaceous neoplasms. MATERIAL AND METHOD: From January 1990 through October 2012, 26 sebaceous adenomas (SAs) and 6 sebaceous carcinomas (SCs) were accrued. The expression of MLH1, MSH2, MSH6, and PMS2 was recorded. MLH1-deficient cases were tested for p16 status. RESULTS: Eighteen (56%) of the 32 specimens with SA or SC displayed MMR-protein deficiency, comprising 17 (65.4%) SAs (MSH2/MSH6 loss in 12, MLH1/PMS2 loss in 3, MSH6 loss only in 2 cases) and 1 (16.7%) SC (MLH1/PMS2 loss). All 4 MLH1 deficient cases were p16-positive. CONCLUSION: A substantial proportion of sebaceous neoplasms were MMR-protein deficient and thus likely MTS candidates. Given the low prevalence of sebaceous neoplasms in Denmark, immunohistochemistry for the four MMR-proteins is recommended in the initial diagnostic approach. The addition of p16 was none-informative, but evaluation of its utility in larger series is warranted. PMID- 25457182 TI - Brain region mapping using global metabolomics. AB - Historically, studies of brain metabolism have been based on targeted analyses of a limited number of metabolites. Here we present an untargeted mass spectrometry based metabolomic strategy that has successfully uncovered differences in a broad array of metabolites across anatomical regions of the mouse brain. The NSG immunodeficient mouse model was chosen because of its ability to undergo humanization leading to numerous applications in oncology and infectious disease research. Metabolic phenotyping by hydrophilic interaction liquid chromatography and nanostructure imaging mass spectrometry revealed both water-soluble and lipid metabolite patterns across brain regions. Neurochemical differences in metabolic phenotypes were mainly defined by various phospholipids and several intriguing metabolites including carnosine, cholesterol sulfate, lipoamino acids, uric acid, and sialic acid, whose physiological roles in brain metabolism are poorly understood. This study helps define regional homeostasis for the normal mouse brain to give context to the reaction to pathological events. PMID- 25457184 TI - Pyruvate kinase isoenzyme M2 expression correlates with survival of cardiomyocytes after allogeneic rat heterotopic heart transplantation. AB - The aim of our study was to assess correlations between PKM2 and the survival of cardiomyocytes after heart transplantation in rat. The PKM2, Bcl-xl, active caspase-3 proteins were detected by western blot, and PKM2 was testified by immunohistochemistry and immunofluorescence. At the same time, active caspase-3, alpha-actinin, VCAM-1, and CD4 were detected by immunofluorescence. Compared with rare expression in syngeneic Lewis rat hearts, the PKM2 protein level in allogeneic hearts was detected at various survival times after transplantation, which prominently expressed on day five postoperatively. In addition, we examined the expression of Bcl-xl and active caspase-3 in allogeneic hearts, which has a similar expression pattern with PKM2. Immunohistochemical and immunofluorescent methods displayed that PKM2 was widely expressed in cardiac tissue, and active caspase-3 was also expressed in cardiomyocytes. However, the PKM2 was not expressed in T cells and other immune response cells. These results suggested that PKM2 may regulate the survival of cardiomyocytes in acute rejection after heart transplantation in rat. PMID- 25457185 TI - Clear cell papillary renal cell carcinoma: a chromosomal microarray analysis of two cases using a novel Molecular Inversion Probe (MIP) technology. AB - Chromosomal microarray analysis using novel Molecular Inversion Probe (MIP) technology demonstrated 2,570 kb copy neutral LOH of 10q11.22 in two clear cell papillary renal cell carcinomas. In addition, one of the tumors had a big 29,784 kb deletion of 13q11-q14.2. There were two variants of unknown significance, a 2,509 kb gain of Xp22.33 and a 257 kb homozygous deletion of 8p11.22. The somatic mutation panel containing 74 mutations in nine genes did not reveal any mutations. Besides identification of submicroscopic duplications or deletions, SNP microarrays can reveal abnormal allelic imbalances including LOH and copy neutral LOH, which cannot be recognized by chromosome, FISH, and non-SNP microarray arrays. To the best of our knowledge, this is the first study demonstrating copy neutral LOH of 10q11.22 in clear cell papillary renal cell carcinomas using the new MIP SNP OncoScan FFPE Assay Kit on formalin-fixed paraffin-embedded tumor samples. PMID- 25457186 TI - [Dermatology Days, Paris, 2014]. PMID- 25457187 TI - p53 in metabolism, aging and cancer. PMID- 25457188 TI - Comparison of mean glandular dose values provided by a digital breast tomosynthesis system in Brazil. AB - Studies are needed to determine the radiation dose of patients that are undergoing Digital breast tomosynthesis (DBT) procedures. Mean glandular dose (DG) values were derived from the incident air kerma (Ki) measurements and tabulated conversion coefficients. Ki values were obtained through an ionization chamber positioned in a Hologic Selenia Dimensions system using appropriate exposure parameters. This work contributes to determine the reliable radiation dose received by the patients and compare DG values provided by this DBT system images. PMID- 25457189 TI - Availability of accessible and high-quality information on the Internet for patients regarding the diagnosis and management of rotator cuff tears. AB - BACKGROUND: In the era of informed patient decision-making, educated patients are vital contributors. The Internet provides a vast information source that patients will access. It is imperative that this information be relevant and understandable. Various treatments, each with advantages and disadvantages, are available. We sought to examine the standard of information about the diagnosis and management of rotator cuff tears available to patients on the Internet. METHODS: We identified 125 websites from searching "rotator cuff tear" in the 5 most popular Internet search engines. The websites were examined for readability by measuring the Flesch Reading Ease Score, the Flesch-Kincaid Grade Level, and the Gunning Fog Index. The quality of the websites was measured by the DISCERN instrument, the Journal of the American Medical Association benchmark criteria, and Health on the Net Foundation certification. RESULTS: There were 59 individual URLs analyzed. Overall, the quality was poor, with the average DISCERN score being only 39.47. Furthermore, the mean reading grade level was above 9 (recommended level, 6). Health on the Net Foundation certification did correspond to significantly worse readability scores (P = .004) but did not correlate with improved DISCERN scores. Those that satisfied more of the Journal of the American Medical Association benchmark criteria had significantly better DISCERN scores (P < .001). CONCLUSION: Information about rotator cuff tears is of a low standard and is in many cases written at too high a level for the general population. There are instruments of which we, as surgeons, must be aware to evaluate the resources available and to recommend them to patients to ensure that they understand their condition and treatment options. PMID- 25457190 TI - Reliability and validity in measurement of true humeral retroversion by a three dimensional cylinder fitting method. AB - HYPOTHESIS AND BACKGROUND: Humeral retroversion is defined as the orientation of the humeral head relative to the distal humerus. Because none of the previous methods used to measure humeral retroversion strictly follow this definition, values obtained by these techniques vary and may be biased by morphologic variations of the humerus. The purpose of this study was 2-fold: to validate a method to define the axis of the distal humerus with a virtual cylinder and to establish the reliability of 3-dimensional (3D) measurement of humeral retroversion by this cylinder fitting method. METHODS: Humeral retroversion in 14 baseball players (28 humeri) was measured by the 3D cylinder fitting method. The root mean square error was calculated to compare values obtained by a single tester and by 2 different testers using the embedded coordinate system. To establish the reliability, intraclass correlation coefficient (ICC) and precision (standard error of measurement [SEM]) were calculated. RESULTS: The root mean square errors for the humeral coordinate system were <1.0 mm/1.0 degrees for comparison of all translations/rotations obtained by a single tester and <1.0 mm/2.0 degrees for comparison obtained by 2 different testers. Assessment of reliability and precision of the 3D measurement of retroversion yielded an intratester ICC of 0.99 (SEM, 1.0 degrees ) and intertester ICC of 0.96 (SEM, 2.8 degrees ). DISCUSSION AND CONCLUSION: The error in measurements obtained by a distal humerus cylinder fitting method was small enough not to affect retroversion measurement. The 3D measurement of retroversion by this method provides excellent intratester and intertester reliability. PMID- 25457191 TI - The long-term outcome of displaced mid-third clavicle fractures on scapular and shoulder function: variations between immediate surgery, delayed surgery, and nonsurgical management. AB - BACKGROUND: Conservative management for uncomplicated displaced clavicle fractures is common practice. Delay of surgical fixation may result in less favorable outcomes. METHODS: A retrospective cohort study was conducted of 60 patients with a closed mid-third clavicle fracture that did not meet current operative or nonoperative guidelines; 20 primary (plate fixation <6 weeks), 20 delayed (plate fixation >6 weeks), and 20 matched conservative patients were included. Each patient completed 2 questionnaires, the Disabilities of the Arm, Shoulder, and Hand and the American Shoulder and Elbow Surgeons, as well as visual analog scales for pain, cosmetic satisfaction, and overall satisfaction. In addition, 10 patients from each group underwent clinical review of scapular rotation by the lateral scapular slide test, clinical impingement, range of motion assessment, and radiologic review of clavicle union and length. RESULTS: The American Shoulder and Elbow Surgeons patient self-reported questionnaire demonstrated a median score of 5.5 for the delayed group, 2 for the primary group, and 1 for the conservative group (P = .032). The median Disabilities of the Arm, Shoulder, and Hand score was 7.92 for the delayed group, 3.32 for the primary group, and 1.67 for the conservative group (P = .212). Six patients in the delayed group had scapular malrotation compared with 2 in the primary group and none in the conservative group (P = .008). Flexion and external rotation in 90 degrees abduction were decreased in the conservative group (P = .049 and .041, respectively). CONCLUSION: We support the conservative management of uncomplicated displaced clavicle fractures but recognize that a lower threshold for early surgery should be considered where optimal shoulder function is required. PMID- 25457192 TI - Controllable defect redistribution of ZnO nanopyramids with exposed {1011} facets for enhanced gas sensing performance. AB - ZnO nanopyramids (NPys) with exposed crystal facets of {1011} were synthesized via a one-step solvothermal method, having a uniform size with a hexagonal edge length of ~100 nm and a height of ~200 nm. Technologies of XRD, TEM, HRTEM, Raman, PL, and XPS were used to characterize the morphological and structural properties of the products, while the corresponding gas sensing properties were determined by using ethanol as the target gas. For the overall goal of defect engineering, the effect of aging temperature on the gas sensing performance of the ZnO NPys was studied. The test results showed that, at the aging temperature of 300 degrees C, the gas sensing property has been improved to the best, with the fast response-recovery time and the excellent selectivity, because the ZnO300 has the most electron donors for absorbing the largest content of O(2-). Model of defect redistribution was used to explicate the changing of the surface defects at different aging temperatures. The findings showed that, in addition to VO, Zni was the dominant defect of the {1011} crystal facet. The gas sensing performance of the ZnO NPys was determined by the contents of VO and Zni, with all of the defects redistributed on the surface. All of the results will be noticeable for the improvement of the sensing performance of materials with special crystal facet exposing. PMID- 25457193 TI - Implication of HLA-G 5' upstream regulatory region polymorphisms in idiopathic recurrent spontaneous abortions. AB - The effect of HLA-G 5'-upstream regulatory region (URR) single nucleotide polymorphisms (SNP) in idiopathic recurrent spontaneous abortion (RSA) was evaluated. Parental genotype combination analysis and HLA-G expression at transcriptional level was evaluated for 5'URR SNP, which have shown increased risk for idiopathic RSA. If a fetus were aneuploid, attributing causation to a HLA-G 5'-URR SNP would be illogical; therefore couples with abnormal parental karyotypes and also those with abortus material that revealed chromosomal abnormalities were excluded. One hundred women who had experienced idiopathic RSA, along with their respective male partners and 100 pairs of control couples, were studied. HLA-G 5'-URR SNP were evaluated through sequencing. Quantitative polymerase chain reaction was used for HLA-G expression analysis. An increased risk for idiopathic RSA cases among women carriers of mutant genotypes of 1179G>A(rs1233335), -725C>G/T(rs915670) and -486A>C(rs114252012) SNP. The parental genotype combination analysis revealed a 3.5-fold increased risk for 1179G>A and 4.3-fold increased risk for -725C>G/T SNP among carriers of mutant parental genotypes in couples who have experienced idiopathic RSA. Down regulation in HLA-G expression was seen at transcriptional level for -1179G>A and -725C>G/T SNPs in cases of idiopathic RSA. Transmission of a mutant allele from single carrier parents may, therefore, affect pregnancy outcome. PMID- 25457194 TI - CatSper channel, sperm function and male fertility. AB - A number of physiological events, such as sperm hyperactivation, chemotaxis towards the egg, capacitation and acrosome reaction, are triggered by activation of sperm ion channels in response to a diverse range of chemical cues. Cation channel of sperm (CatSper), a sperm-specific ion channel, is unique in orchestrating the events for fertilization, and seems to be exclusively evolved for sperm function and male fertility. CatSper acts as a polymodal, chemosensory calcium channel and plays a vital role in the regulation of sperm hyperactivation. CatSper knockout models and application of patch clamp recordings have shown that it is indispensable for male fertility, and mutations and deletions in CatSper gene(s) may lead to infertility. In fact, mutations in CatSper1 and 2 have been identified in infertile individuals; however, CatSper3 and 4 have not been explored. Restricted localization and expression of CatSper in sperm offer an added advantage to developing gamete-based safe non-hormonal contraceptives. This review concisely covers identification, structure, function, and mechanism of action of CatSper channels. The functional importance of this complex ion channel in sperm motility and male fertility is highlighted for further research on male fertility, infertility, and contraception. PMID- 25457195 TI - Response to "Comment on Emergence and fate of siloxanes (D4, D5) in municipal waste streams: release mechanisms, partitioning and persistence in air, water, soil and sediments". PMID- 25457196 TI - Effectiveness of different styles of massage therapy in fibromyalgia: a systematic review and meta-analysis. AB - The systematic review aimed to evaluate the effectiveness of massage in fibromyalgia. An electronic search was conducted at MEDLINE, SCiELO, EMBASE, ISI, PEDro, SPORTDiscus, CINAHL, Cochrane CENTRAL and LILACS (Jan 1990-May 2013). Ten randomized and non-randomized controlled trials investigating the effects of massage alone on symptoms and health-related quality of life of adult patients with fibromyalgia were included. Two reviewers independently screened records, examined full-text reports for compliance with the eligibility criteria, and extracted data. Meta-analysis (pooled from 145 participants) shows that myofascial release had large, positive effects on pain and medium effects on anxiety and depression at the end of treatment, in contrast with placebo; effects on pain and depression were maintained in the medium and short term, respectively. Narrative analysis suggests that: myofascial release also improves fatigue, stiffness and quality of life; connective tissue massage improves depression and quality of life; manual lymphatic drainage is superior to connective tissue massage regarding stiffness, depression and quality of life; Shiatsu improves pain, pressure pain threshold, fatigue, sleep and quality of life; and Swedish massage does not improve outcomes. There is moderate evidence that myofascial release is beneficial for fibromyalgia symptoms. Limited evidence supports the application of connective tissue massage and Shiatsu. Manual lymphatic drainage may be superior to connective tissue massage, and Swedish massage may have no effects. Overall, most styles of massage therapy consistently improved the quality of life of fibromyalgia patients. PMID- 25457197 TI - Authors' response to Chin et al. PMID- 25457198 TI - New imaging techniques for liver diseases. AB - Newly developed or advanced methods of ultrasonography and MR imaging provide combined anatomical and quantitative functional information about diffuse and focal liver diseases. Ultrasound elastography has a central role for staging liver fibrosis and an increasing role in grading portal hypertension; dynamic contrast-enhanced ultrasonography may improve tumor characterization. In clinical practice, MR imaging examinations currently include diffusion-weighted and dynamic MR imaging, enhanced with extracellular or hepatobiliary contrast agents. Moreover, quantitative parameters obtained with diffusion-weighted MR imaging, dynamic contrast-enhanced MR imaging and MR elastography have the potential to characterize further diffuse and focal liver diseases, by adding information about tissue cellularity, perfusion, hepatocyte transport function and visco elasticity. The multiparametric capability of ultrasonography and more markedly of MR imaging gives the opportunity for high diagnostic performance by combining imaging biomarkers. However, image acquisition and post-processing methods should be further standardized and validated in multicenter trials. PMID- 25457199 TI - Exploration of skin perfusion in cirrhotic patients with septic shock. AB - BACKGROUND & AIMS: Skin perfusion alterations are early and strong predictors of death in patients with septic shock. Cirrhosis is associated with systemic vasodilation and increases mortality from septic shock. We aimed at assessing whether the mottling score and tissue oxygen saturation (StO2) could be used as early predictors of death in cirrhotic patients with septic shock. METHODS: This observational study included cirrhotic patients with septic shock. Each 6 h during the first 24 h, we collected data reflecting macrocirculation (mean arterial pressure, heart rate, central venous pressure, and cardiac output) and organ perfusion (arterial lactate, urinary output, ScvO2, mottling score, thenar, and knee StO2). Data of 75 non-cirrhotic patients with previously reported septic shock were used as control. RESULTS: 42 cirrhotic patients were included. Mortality at day 14 was 71%. At H6, parameters reflecting macrocirculation were not associated with mortality, whereas higher arterial lactate and mottling score were associated with death. Mottling score was the strongest predictor of mortality (sensitivity=0.63, specificity=1, OR=42.4 (2.3-785.9)). At H6, knee StO2 decreased in non-survivors and predicted death (sensitivity=0.45, specificity=1). In comparison with control, mottling kinetic was different in cirrhotic patients (delayed mottling appearance in non-survivors, earlier mottling disappearance in survivors). Knee StO2 and skin perfusion, assessed by laser-Doppler, were higher in cirrhotic patients. CONCLUSIONS: Mottling score and knee StO2 at H6 were very specific predictors of death in patients with cirrhosis and septic shock. Their sensitivity was lower in cirrhotic patients due to delayed mottling appearance and higher knee StO2 related to higher skin perfusion. PMID- 25457200 TI - Phenotypic and functional analyses show stem cell-derived hepatocyte-like cells better mimic fetal rather than adult hepatocytes. AB - BACKGROUND & AIMS: Hepatocyte-like cells (HLCs), differentiated from pluripotent stem cells by the use of soluble factors, can model human liver function and toxicity. However, at present HLC maturity and whether any deficit represents a true fetal state or aberrant differentiation is unclear and compounded by comparison to potentially deteriorated adult hepatocytes. Therefore, we generated HLCs from multiple lineages, using two different protocols, for direct comparison with fresh fetal and adult hepatocytes. METHODS: Protocols were developed for robust differentiation. Multiple transcript, protein and functional analyses compared HLCs to fresh human fetal and adult hepatocytes. RESULTS: HLCs were comparable to those of other laboratories by multiple parameters. Transcriptional changes during differentiation mimicked human embryogenesis and showed more similarity to pericentral than periportal hepatocytes. Unbiased proteomics demonstrated greater proximity to liver than 30 other human organs or tissues. However, by comparison to fresh material, HLC maturity was proven by transcript, protein and function to be fetal-like and short of the adult phenotype. The expression of 81% phase 1 enzymes in HLCs was significantly upregulated and half were statistically not different from fetal hepatocytes. HLCs secreted albumin and metabolized testosterone (CYP3A) and dextrorphan (CYP2D6) like fetal hepatocytes. In seven bespoke tests, devised by principal components analysis to distinguish fetal from adult hepatocytes, HLCs from two different source laboratories consistently demonstrated fetal characteristics. CONCLUSIONS: HLCs from different sources are broadly comparable with unbiased proteomic evidence for faithful differentiation down the liver lineage. This current phenotype mimics human fetal rather than adult hepatocytes. PMID- 25457201 TI - Genome-wide association study identifies TF as a significant modifier gene of iron metabolism in HFE hemochromatosis. AB - BACKGROUND & AIMS: Hereditary hemochromatosis (HH) is the most common form of genetic iron loading disease. It is mainly related to the homozygous C282Y/C282Y mutation in the HFE gene that is, however, a necessary but not a sufficient condition to develop clinical and even biochemical HH. This suggests that modifier genes are likely involved in the expressivity of the disease. Our aim was to identify such modifier genes. METHODS: We performed a genome-wide association study (GWAS) using DNA collected from 474 unrelated C282Y homozygotes. Associations were examined for both quantitative iron burden indices and clinical outcomes with 534,213 single nucleotide polymorphisms (SNP) genotypes, with replication analyses in an independent sample of 748 C282Y homozygotes from four different European centres. RESULTS: One SNP met genome wide statistical significance for association with transferrin concentration (rs3811647, GWAS p value of 7*10(-9) and replication p value of 5*10(-13)). This SNP, located within intron 11 of the TF gene, had a pleiotropic effect on serum iron (GWAS p value of 4.9*10(-6) and replication p value of 3.2*10(-6)). Both serum transferrin and iron levels were associated with serum ferritin levels, amount of iron removed and global clinical stage (p<0.01). Serum iron levels were also associated with fibrosis stage (p<0.0001). CONCLUSIONS: This GWAS, the largest one performed so far in unselected HFE-associated HH (HFE-HH) patients, identified the rs3811647 polymorphism in the TF gene as the only SNP significantly associated with iron metabolism through serum transferrin and iron levels. Because these two outcomes were clearly associated with the biochemical and clinical expression of the disease, an indirect link between the rs3811647 polymorphism and the phenotypic presentation of HFE-HH is likely. PMID- 25457202 TI - Patient selection based on treatment duration and liver biochemistry increases success rates after treatment withdrawal in autoimmune hepatitis. AB - BACKGROUND & AIMS: In autoimmune hepatitis (AIH), relapse rates as high as 90% have been reported after treatment withdrawal. We therefore investigated, whether longer duration of treatment and proper patient selection could increase the long term success rates after treatment withdrawal. METHODS: Following our previously published experience, treatment withdrawal was considered when biochemical remission was maintained under immunosuppressive monotherapy for at least 2 years. Remission was defined as repeatedly normal serum aminotransferase levels as well as normal IgG levels. RESULTS: Out of 288 patients with well-defined AIH, 28 patients were included. Median duration of treatment was 48.5 months (range 35 179) and a sustained remission was observed for 45 months (range 24-111). All patients were in remission on immunosuppressive monotherapy for a minimum of 2 years before treatment was withdrawn. Using this strict approach, 15 patients (54%) remained in long-term remission after a median of 28 months follow-up (range 17-57) and 13 patients (46%) required reinstitution of treatment. Higher ALT and IgG levels - although within the normal range in all patients--were associated with the time to relapse. All patients who remained in remission had ALT levels less than half the ULN and IgG levels not higher than 12 g/L at the time of treatment withdrawal. CONCLUSIONS: Proper patient selection including a sustained complete biochemical remission on immunosuppressive monotherapy for a minimum of 2 years can markedly improve the success rates of treatment withdrawal. The interpretation of aminotransferase and IgG levels within the normal range could aid in predicting the risk of relapse. PMID- 25457203 TI - S-Adenosylmethionine increases circulating very-low density lipoprotein clearance in non-alcoholic fatty liver disease. AB - BACKGROUND & AIMS: Very-low-density lipoproteins (VLDLs) export lipids from the liver to peripheral tissues and are the precursors of low-density-lipoproteins. Low levels of hepatic S-adenosylmethionine (SAMe) decrease triglyceride (TG) secretion in VLDLs, contributing to hepatosteatosis in methionine adenosyltransferase 1A knockout mice but nothing is known about the effect of SAMe on the circulating VLDL metabolism. We wanted to investigate whether excess SAMe could disrupt VLDL plasma metabolism and unravel the mechanisms involved. METHODS: Glycine N-methyltransferase (GNMT) knockout (KO) mice, GNMT and perilipin-2 (PLIN2) double KO (GNMT-PLIN2-KO) and their respective wild type (WT) controls were used. A high fat diet (HFD) or a methionine deficient diet (MDD) was administrated to exacerbate or recover VLDL metabolism, respectively. Finally, 33 patients with non-alcoholic fatty-liver disease (NAFLD); 11 with hypertriglyceridemia and 22 with normal lipidemia were used in this study. RESULTS: We found that excess SAMe increases the turnover of hepatic TG stores for secretion in VLDL in GNMT-KO mice, a model of NAFLD with high SAMe levels. The disrupted VLDL assembly resulted in the secretion of enlarged, phosphatidylethanolamine-poor, TG- and apoE-enriched VLDL-particles; special features that lead to increased VLDL clearance and decreased serum TG levels. Re establishing normal SAMe levels restored VLDL secretion, features and metabolism. In NAFLD patients, serum TG levels were lower when hepatic GNMT-protein expression was decreased. CONCLUSIONS: Excess hepatic SAMe levels disrupt VLDL assembly and features and increase circulating VLDL clearance, which will cause increased VLDL-lipid supply to tissues and might contribute to the extrahepatic complications of NAFLD. PMID- 25457205 TI - CXCL9 is a prognostic marker in patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt. AB - BACKGROUND & AIMS: Inflammation, collagen deposition and tissue remodelling are involved in the pathogenesis and complications of cirrhosis with portal hypertension. CXCL9 and other chemokines play an important role in these processes and have been associated with liver injury and complications of liver disease in humans. However, their predictive value in patients with cirrhosis and portal hypertension remains to be established. METHODS: 103 patients with liver cirrhosis who had received TIPS (transjugular intrahepatic portosystemic shunt) were included into this study. The TIPS indication was either refractory ascites or recurrent bleeding. Before and after the TIPS procedure portal and hepatic venous blood samples were obtained in 78 patients. In 25 patients blood samples were obtained from the portal vein, hepatic vein, right atrium and cubital vein at TIPS insertion. Serum levels of CXCL9 were measured by cytometric bead array and correlated with clinical parameters and overall outcome. RESULTS: Portal venous levels of CXCL9 decreased after TIPS. Child-Pugh score, refractory ascites, renal dysfunction and alcoholic aetiology of cirrhosis were associated with increased CXCL9 levels. Importantly, low levels of CXCL9 in portal and hepatic vein samples were prognostic factors for the survival of patients receiving TIPS during long-time follow-up. CONCLUSIONS: The CXCR3 ligand CXCL9 affects the liver and/or is released by the liver and thereby might contribute to hepatic and extrahepatic organ dysfunction. Elevated levels of CXCL9 are associated with shorter survival in cirrhotic patients with severe portal hypertension receiving TIPS. This chemokine should be further evaluated as a novel biomarker for the outcome in patients with cirrhosis and portal hypertension and its modulation as a new therapeutic strategy. PMID- 25457204 TI - Complete response of Ctnnb1-mutated tumours to beta-catenin suppression by locked nucleic acid antisense in a mouse hepatocarcinogenesis model. AB - BACKGROUND & AIMS: Hepatocellular cancer (HCC) remains a disease of poor prognosis, highlighting the relevance of elucidating key molecular aberrations that may be targeted for novel therapies. Wnt signalling activation, chiefly due to mutations in CTNNB1, have been identified in a major subset of HCC patients. While several in vitro proof of concept studies show the relevance of suppressing Wnt/beta-catenin signalling in HCC cells or tumour xenograft models, no study has addressed the impact of beta-catenin inhibition in a relevant murine HCC model driven by Ctnnb1 mutations. METHODS: We studied the in vivo impact of beta catenin suppression by locked nucleic acid (LNA) antisense treatment, after establishing Ctnnb1 mutation-driven HCC by diethylnitrosamine and phenobarbital (DEN/PB) administration. RESULTS: The efficacy of LNA directed against beta catenin vs. scrambled on Wnt signalling was demonstrated in vitro in HCC cells and in vivo in normal mice. The DEN/PB model leads to HCC with Ctnnb1 mutations. A complete therapeutic response in the form of abrogation of HCC was observed after ten treatments of tumour-bearing mice with beta-catenin LNA every 48h as compared to the scrambled control. A decrease in beta-catenin activity, cell proliferation and increased cell death was evident after beta-catenin suppression. No effect of beta-catenin suppression was evident in non-Ctnnb1 mutated HCC, observed after DEN-only administration. CONCLUSIONS: Thus, we provide the in vivo proof of concept that beta-catenin suppression in HCC will be of significant therapeutic benefit, provided the tumours display Wnt activation via mechanisms like CTNNB1 mutations. PMID- 25457207 TI - Reducing the neglected burden of viral hepatitis in Africa: strategies for a global approach. AB - The burden of liver disease may dramatically increase in the near future in Africa, where screening and access to care and treatment are hampered by inadequate disease surveillance, lack of high-quality tools to assess chronic liver disease, and underestimated needs for human and financial resources. Chronic hepatitis may be considered as silent and neglected killer, fuelled by many years of global inertia from stakeholders and policy makers alike. However, the global battle against viral hepatitis is facing a new era owing to the advent of highly effective drugs, innovative tools for screening and clinical follow-up, and recent signs that governments, advocacy groups and global health organizations are mobilizing to advocate universal access-to-treatment. This review details the barriers to prevention, screening and treatment of viral hepatitis on the African continent, focuses on the urgent need for operational and research programmes, and suggests integrated ways to tackle the global epidemic. PMID- 25457206 TI - Alcohol directly stimulates epigenetic modifications in hepatic stellate cells. AB - BACKGROUND & AIMS: Alcohol is a primary cause of liver disease and an important co-morbidity factor in other causes of liver disease. A common feature of progressive liver disease is fibrosis, which results from the net deposition of fibril-forming extracellular matrix (ECM). The hepatic stellate cell (HSC) is widely considered to be the major cellular source of fibrotic ECM. We determined if HSCs are responsive to direct stimulation by alcohol. METHODS: HSCs undergoing transdifferentiation were incubated with ethanol and expression of fibrogenic genes and epigenetic regulators was measured. Mechanisms responsible for recorded changes were investigated using ChIP-Seq and bioinformatics analysis. Ethanol induced changes were confirmed using HSCs isolated from a mouse alcohol model and from ALD patient's liver and through precision cut liver slices. RESULTS: HSCs responded to ethanol exposure by increasing profibrogenic and ECM gene expression including elastin. Ethanol induced an altered expression of multiple epigenetic regulators, indicative of a potential to modulate chromatin structure during HSC transdifferentiation. MLL1, a histone 3 lysine 4 (H3K4) methyltransferase, was induced by ethanol and recruited to the elastin gene promoter where it was associated with enriched H3K4me3, a mark of active chromatin. Chromatin immunoprecipitation sequencing (ChIPseq) revealed that ethanol has broad effects on the HSC epigenome and identified 41 gene loci at which both MML1 and its H3K4me3 mark were enriched in response to ethanol. CONCLUSIONS: Ethanol directly influences HSC transdifferentiation by stimulating global changes in chromatin structure, resulting in the increased expression of ECM proteins. The ability of alcohol to remodel the epigenome during HSC transdifferentiation provides mechanisms for it to act as a co-morbidity factor in liver disease. PMID- 25457209 TI - Circulating triacylglycerol signatures and insulin sensitivity in NAFLD associated with the E167K variant in TM6SF2. AB - BACKGROUND & AIMS: The Glu167Lys (E167K) variant in the transmembrane 6 superfamily member 2 protein (TM6SF2) was recently shown to influence liver fat (LFAT) content. We aimed at studying how this variant influences circulating triacylglycerol (TAG) signatures and whether it influences hepatic or adipose tissue insulin sensitivity. METHODS: We genotyped 300 Finnish subjects for the E167K (rs58542926) variant in TM6SF2 and for the I148M (rs738409) variant in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) in whom LFAT was measured using 1H-MRS and circulating lipids by UPLC-MS. We compared the plasma lipidome between E167K carriers (TM6SF2EK/KK) and non-carriers (TM6SF2EE), and between three groups of NAFLD: (i) carriers of the E167K but not of the I148M variant in PNPLA3 ('TM6SF2 NAFLD'), (ii) carriers of the I148M but not of the E167K variant ('PNPLA3 NAFLD'), and (iii) non-carriers of either risk allele ('Non-risk NAFLD'). Hepatic and adipose tissue insulin sensitivities were measured using the euglycemic hyperinsulinemic clamp technique combined with infusion of [3-3H]glucose in 111 subjects. RESULTS: The LFAT content was 34% higher in the TM6SF2EK/KK (13.07+/-1.57%) than in the TM6SF2EE group (9.77+/ 0.58%, p=0.013). The effect of insulin on glucose production and lipolysis were significantly higher in the TM6SF2EK/KK than in the TM6SF2EE group. Comparison of the three NAFLD groups with similar LFATs showed that both the 'TM6SF2 NAFLD' and 'PNPLA3 NAFLD' had significantly lower triglyceride levels and were characterized by lower levels of most common TAGs compared to the 'Non-risk NAFLD' group. CONCLUSIONS: We conclude that the E167K variant in TM6SF2 is associated with a distinct subtype of NAFLD, characterized by preserved insulin sensitivity with regard to lipolysis, hepatic glucose production and lack of hypertriglyceridemia despite a clearly increased LFAT content. PMID- 25457208 TI - Aldehyde dedydrogenase-2 plays a beneficial role in ameliorating chronic alcohol induced hepatic steatosis and inflammation through regulation of autophagy. AB - BACKGROUND & AIMS: Mitochondrial aldehyde dehydrogenase (ALDH2) plays a critical role in the detoxification of the ethanol metabolite acetaldehyde. This study was designed to examine the impact of global ALDH2 overexpression on alcohol-induced hepatic steatosis. METHODS: Wild type Friend virus B (FVB) and ALDH2 transgenic mice were placed on a 4% alcohol or control diet for 12 weeks. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin and cholesterol, hepatic triglyceride, steatosis, fat metabolism-related proteins, pro-inflammatory cytokines, glutathione (GSH), oxidized glutathione (GSSG), autophagy and autophagy signalling were examined. The role of autophagy was evaluated in alcohol dehydrogenase 1 (ADH1)-transfected human hepatocellular liver carcinoma cells (VA-13) treated with or without the autophagy inducer rapamycin and lysosomal inhibitors. RESULTS: Chronic alcohol intake led to elevated AST-, ALT-levels, bilirubin, AST/ALT ratio, cholesterol, hepatic triglycerides and hepatic fat deposition as evidenced by H&E and Oil Red O staining. Hepatic fat deposition was associated with disturbed levels of fat metabolism-related proteins (fatty acid synthase, SCD1), upregulated interleukin 6, TNF-alpha, cyclooxygenase, oxidative stress, and loss of autophagy, effects which were attenuated or ablated by the ALDH2 transgene. Moreover, ethanol (100 mM) and acetaldehyde (100 and 500 MUM) increased levels of IL-6 and IFN-gamma, and suppressed autophagy in VA-13 cells, effects which were markedly alleviated by rapamycin. In addition, lysosomal inhibitors mimicked ethanol-induced p62 accumulation with little additive effect with ethanol. Ethanol significantly suppressed LC3 conversion in the presence of lysosomal inhibitors. CONCLUSIONS: In summary, our results revealed that ALDH2 plays a beneficial role in ameliorating chronic alcohol intake-induced hepatic steatosis and inflammation through regulation of autophagy. PMID- 25457210 TI - Association of diabetes and PNPLA3 genetic variants with disease severity of patients with chronic hepatitis C virus infection. AB - BACKGROUND & AIMS: Genetic variants of patatin-like phospholipase domain containing 3 (PNPLA3) and diabetes are associated with liver disease severity, in patients with chronic hepatitis C (CHC) infection. We aimed at exploring their interaction in determining hepatitis C virus (HCV)-related liver fibrosis. METHODS: The PNPLA3 genetic polymorphism at rs738409 was verified in 1077 biopsy proven CHC patients. Other clinical variables, including diabetes status, were analysed for factors associated with bridging fibrosis. RESULTS: Patients with advanced liver fibrosis had higher proportions of the GG genotype (14.5% vs. 10.4%, p=0.06 in recessive model) and GG/GC genotype carriage (64.0% vs. 56.8%, p=0.03 in dominant model). Stepwise logistic regression analysis revealed that factors predictive of advanced liver fibrosis included age (odds ratio [OR]: 1.02, 95% confidence intervals [CI]: 1.008-1.037, p=0.002), diabetes (OR: 1.81, CI: 1.236-2.653, p=0.002), alpha-fetoprotein (OR: 1.006, CI: 1.001-1.01, p=0.01), platelet counts (OR: 1.009, CI: 1.006-1.012, p<0.001), and PNPLA3 rs738409 CG/GG genotype (OR: 1.34, CI: 1.006-1.785, p=0.046). When patients were grouped according to their diabetes status, the PNPLA3 genetic variants were associated with advanced liver fibrosis in diabetic patients only, but not in non-diabetic patients. The PNPLA3 gene was the most important predictive factor of bridging fibrosis in diabetic patients, using the recessive model (OR: 4.53, CI: 1.356 15.106, p=0.014) or the dominant model (OR: 2.20, CI: 1.026-4.734, p=0.04). Compared to non-diabetic patients, patients with the diabetes/GG genotype were more likely to have advanced liver fibrosis (OR: 8.79, CI: 2.889-26.719, p<0.001), followed by those with diabetes/non-GG genotype (OR: 1.55, CI: 1.048 2.286, p=0.03). CONCLUSIONS: The effect of PNPLA3 genetic variants in HCV-related advanced liver fibrosis was enhanced in diabetic patients. The strong genetic environmental interaction contributed to the high risk of advanced liver disease in CHC patients. PMID- 25457211 TI - Role for the endoplasmic reticulum stress sensor IRE1alpha in liver regenerative responses. AB - BACKGROUND & AIMS: As the main detoxifying organ of the body, the liver possesses a remarkable ability to regenerate after toxic injury, tissue resection or viral infection. A growing number of cellular signaling pathways have been implicated in orchestrating the process of liver regeneration. Here we investigated the role of inositol-requiring enzyme-1alpha (IRE1alpha), a key signal transducer of the unfolded protein response (UPR), in liver regeneration. METHODS: Using mice with hepatocyte-specific deletion of IRE1alpha, we examined the role of IRE1alpha in liver regeneration after challenges with carbon tetrachloride (CCl4) or hepatic surgery. We also investigated if IRE1alpha deficiency could affect the activation state of signal transducer and activator of transcription 3 (STAT3) in hepatocytes. Using co-immunoprecipitation and glutathione S-transferase (GST) pull-down assays, we analyzed whether IRE1alpha could interact with STAT3 to regulate its phosphorylation. RESULTS: We found that in response to CCl4-induced liver damage or after two-thirds partial hepatectomy (PH), abrogation of IRE1alpha caused marked exacerbation of liver injury and impairment in regenerative proliferation of hepatocytes in mice. Furthermore, IRE1alpha deficiency resulted in dampened STAT3 activation, and restoration of IRE1alpha expression led to sustained phosphorylation of STAT3 in IRE1alpha-null hepatocytes. Additionally, IRE1alpha could directly and constitutively associate with STAT3, leading to elevated phosphorylation when stimulated by IL-6. CONCLUSIONS: These results suggest that IRE1alpha may promote liver regeneration through acting as a signaling platform to regulate the STAT3 pathway. PMID- 25457212 TI - Chronic unilateral stimulation of the nucleus accumbens at high or low frequencies attenuates relapse to cocaine seeking in an animal model. AB - BACKGROUND: Deep brain stimulation (DBS), a form of neurosurgical intervention that is used to modulate the electrophysiological activity of specific brain areas, has emerged as a form of therapy for severe cases of treatment-refractory addiction. OBJECTIVE/HYPOTHESIS: Recent research suggests that the nucleus accumbens (NAC) is a promising target area for DBS in addiction. The current experiments were designed to determine optimal parameters of stimulation and long term efficacy of NAC DBS in an animal model of cocaine addiction. METHODS: Rats were implanted with a stimulating electrode in the right NAC and exposed to chronic cocaine self-administration (0.5 mg/kg/infusion). Rats underwent drug seeking tests by exposing them to the self-administration context paired with cocaine challenge (5 mg/kg i.p.) on days 1, 15 and 30 after withdrawal from cocaine self-administration. Low-frequency (LF, 20 Hz) or high-frequency (HF, 160 Hz) DBS was applied for 30 min daily for 14 consecutive days starting one day after drug withdrawal. RESULTS: Rats exhibited robust drug-seeking 1, 15 and 30 days after withdrawal from cocaine self-administration, with responding being highest on day 15. Both LF and HF attenuated cocaine seeking on day 15 post withdrawal by 36 and 48%, respectively. Both forms of stimulation were ineffective on the tests conducted on days 1 and 30. CONCLUSION: The present data showed that unilateral DBS of the NAC effectively attenuated cocaine relapse after 15 days of drug withdrawal, with therapeutic-like effects seemingly diminishing after DBS discontinuation. This evidence provides support for DBS as a promising intervention in intractable cases of stimulant addiction. PMID- 25457214 TI - Heterogeneity in high hypnotic suggestibility and the neurophysiology of hypnosis. PMID- 25457215 TI - [Acute pain transfusion reaction]. PMID- 25457213 TI - Measurement of evoked potentials during thalamic deep brain stimulation. AB - BACKGROUND: Deep brain stimulation (DBS) treats the symptoms of several movement disorders, but optimal selection of stimulation parameters remains a challenge. The evoked compound action potential (ECAP) reflects synchronized neural activation near the DBS lead, and may be useful for feedback control and automatic adjustment of stimulation parameters in closed-loop DBS systems. OBJECTIVES: Determine the feasibility of recording ECAPs in the clinical setting, understand the neural origin of the ECAP and sources of any stimulus artifact, and correlate ECAP characteristics with motor symptoms. METHODS: The ECAP and tremor response were measured simultaneously during intraoperative studies of thalamic DBS, conducted in patients who were either undergoing surgery for initial lead implantation or replacement of their internal pulse generator. RESULTS: There was large subject-to-subject variation in stimulus artifact amplitude, which model-based analysis suggested may have been caused by glial encapsulation of the lead, resulting in imbalances in the tissue impedance between the contacts. ECAP recordings obtained from both acute and chronically implanted electrodes revealed that specific phase characteristics of the signal varied systematically with stimulation parameters. Further, a trend was observed in some patients between the energy of the initial negative and positive ECAP phases, as well as secondary phases, and changes in tremor from baseline. A computational model of thalamic DBS indicated that direct cerebellothalamic fiber activation dominated the clinically measured ECAP, suggesting that excitation of these fibers is critical in DBS therapy. CONCLUSIONS: This work demonstrated that ECAPs can be recorded in the clinical setting and may provide a surrogate feedback control signal for automatic adjustment of stimulation parameters to reduce tremor amplitude. PMID- 25457216 TI - [Pleuro-pericarditis developed under a leflunomide therapy]. AB - Leflunomide is an immunosuppressant drug used in rheumatoid arthritis and psoriatic arthritis. This product may cause rare but serious interstitial lung disease that appear at the beginning of treatment. This is why leflunomide should be prescribed and monitored in hospital. We present the case of a 71 years old woman who presented a pleuro-pericarditis with an increase of CA 125 during a treatment with leflunomide. This is the second case reported in the literature. The outcome was favorable after discontinuation of leflunomide. PMID- 25457217 TI - [Superior vena cava syndrome with malignant causes]. AB - Superior vena cava syndrome comprises various symptoms and signs resulting from the obstruction of the superior vena cava and resulting in reduced blood flow. Superior vena cava may occur secondary to a variety of conditions, but malignant etiologies are the most common. Usually, the diagnosis is based on a quite clear clinical presentation. Patient with acute presentation can develop life threatening complications such as cerebral or laryngeal edema. In the absence of these two conditions, a histologic diagnosis should be obtained before the initiation of any therapy. Management of superior vena cava syndrome requires a multidisciplinary team. Therapeutic approaches include radiotherapy, chemotherapy and endovascular approach, and the choice of therapy will depend on the severity of the symptoms, the type and the stage of the tumor, but also the patient's general condition. PMID- 25457218 TI - [Use of pulmonary function tests and biomarkers studies to diagnose and follow-up interstitial lung disease in systemic sclerosis]. AB - Interstitial lung disease (ILD) is becoming one of the main causes of death of patients with systemic sclerosis (SSc). The prevalence of ILD associated with SSc (SSc-ILD) varies from 33% to 100% according to diagnostic methods. Clinical features such as dyspnea on exertion, dry cough, and chest pains are not specific and usually late-appearing, implying more specific tests in the diagnostic, prognosis, and follow-up of ILD in patients with SSc. High resolution thoracic CT scanner (HRCT) is more sensitive than chest X-ray in the detection of SSc-ILD. Pulmonary function tests (PFT) are non-invasive and periodically used to assess the impacts of SSc on respiratory function. Diagnostic values of bronchoalveolar lavage and histological examination on lung biopsy are controversial. However, these techniques are essential for studying cellular and molecular mechanisms underlying the pathophysiology of SSc-ILD. Several biomarkers such as surfactant A (SP-A), -D (SP-D), mucin-like high molecular weight glycoprotein (KL-6), and chemokine CCL-18 have been implicated in SSc-PID. Serum levels of these proteins are correlated with the severity of SSc-ILD, as assessed by HRCT and/or PFT. Finally, alveolar concentration of exhaled nitric oxide can be used to screen SSc patients with high risk of deterioration of respiratory function, in whom immunosuppressant treatment could be useful in preventing the evolution to irreversible lung fibrosis. PMID- 25457219 TI - [Peripartum cardiomyopathy revealed by multifocal tuberculosis]. PMID- 25457220 TI - [Does antifungal therapy influence postoperative morbidity or long-term survival after surgical resection for pulmonary aspergilloma?]. AB - BACKGROUND: Surgical resection of pulmonary aspergilloma is associated with symptoms control, complications prevention, and improved survival, given that the disease is localized and the patient fit enough to undergo surgery. In these operable forms, the impact of perioperative antifungal therapy remains controversial. The purpose of this study was to analyze the impact of antifungal therapy on postoperative morbidity and overall survival in patients with operable pulmonary aspergilloma. METHODS: The clinical records of 113 patients who underwent thoracic surgery for aspergilloma in our institution from January 1989 to December 2010 were retrospectively reviewed. Of these, 64 patients received antifungal therapy in the perioperative period and were included in group 1, and 49 patients did not receive antifungal therapy and were included in group 2. RESULTS: Postoperative complication rates were 31.2% in group 1 and 20.4% in group 2 (P = 0.30). Univariable analysis showed that immunocompromised status (P < 0.001), past history of cancer (P = 0.50), preoperative purulent sputum (P = 0.024), and pneumonectomy (P < 0.001) were significantly associated with postoperative complications, but that antifungal therapy was not. Five- and 10 year overall survival rates were respectively 78.3% and 57.8% in group 1 vs. 85.9% and 65.7% in group 2 (P = 0.23). Multivariate analysis revealed that age higher than 50, immunocompromised status and pneumonectomy were significantly associated with adverse long-term survival (chi(2) = 6.59, df = 5, P < 0.001), but that antifungal therapy was not. CONCLUSION: Antifungal therapy has no significant impact on postoperative morbidity or long-term survival following surgical resection of pulmonary aspergilloma. Such procedure is associated with acceptable postoperative morbidity and long-term survival. PMID- 25457221 TI - [Squamous cell carcinoma of the trachea: imaging lymph node mapping]. AB - The anatomy of the trachea lymphatics is poorly understood and the only researches date back to more than one century. Tracheal tumors are very rare, miscellaneous and variously lymphophilic. The cancers of the trachea have no TNM and their lymph node metastases are little studied despite their poor prognosis. We observed 2 cases of squamous cell carcinoma, one in the cervical and the other in the intrathoracic trachea. TDM-3D reformats demonstrated metastatic lymph nodes of the right para-tracheal lymph node chain (2R and 4R) in both patients and in the cervical lymph nodes (right recurrent nerve lymph node chain) in the patient with cervical tumor. Right location of the mediastinal metastases may be explained by the anatomy of the lymph node chain drainage of the lung segments, the right para-tracheal chain being the only one to regularly possess lymph nodes at that level. The right recurrent nerve lymph node metastases of the cervical tumor are explained by common lymph drainage of the cervical trachea towards larynx lymph centres. Besides lymph node metastases, cancers prognosis may also depends on its location in the trachea. Thus, the tracheal tumors are complex and constitute quite as many orphan tumors. Multicentric studies are mandatory to better understand their behavior. Means provided by new imaging techniques might permit establishing a veritable TNM lymph node mapping of these tumors. PMID- 25457222 TI - [Lung cancer surgery in a single-lung]. AB - INTRODUCTION: The diagnosis of a second lung cancer in a patient with a previous medical history of lung cancer is no longer a rarity. Also, it is possible to observe a new location in a patient who underwent pneumonectomy in the past. Surgery remains the best treatment. Our objective was to overview this subject. PATIENTS AND METHODS: Among 5611 patients operated in our institution, 186 (3.3%) had metachronous cancer and 17 had previous pneumonectomy (0.7% of pneumonectomies and 0.2% of NSCLC treated in our department). The procedure was diagnostic and therapeutic in 88% of cases (n=15). RESULTS: There were 16 males and 1 female, mean age was 62.5-years. All were smokers (11 were former smokers) and 6 had other medical history. Mean FEV was 52% (range 35-95%). Types of resection were 2 lobectomies, 4 segmentectomies, and 11 wedge resections. There were no postoperative deaths, but two complications. Histological subtype of the first and second cancer was the same in 11 patients. All patients were pN0 after second surgery. The long-term survival (median 33 months) was 35.3% at 5-years and 14.1% at 10-years. Two patients treated with pneumonectomy for their first cancer were pN2. Patients who underwent upper right lobectomy for treatment of their second cancer survived longer than 5-years. CONCLUSION: Surgical resection for lung cancer on single-lung is associated with acceptable morbidity and mortality. Prolonged survival can be achieved in selected patients. PMID- 25457223 TI - [Cardiac tamponade: the pericardium is not always guilty! A case report and review]. PMID- 25457224 TI - CTGF/CCN2 exerts profibrotic action in myoblasts via the up-regulation of sphingosine kinase-1/S1P3 signaling axis: Implications in the action mechanism of TGFbeta. AB - The matricellular protein connective tissue growth factor (CTGF/CCN2) is recognized as key player in the onset of fibrosis in various tissues, including skeletal muscle. In many circumstances, CTGF has been shown to be induced by transforming growth factor beta (TGFbeta) and accounting, at least in part, for its biological action. In this study it was verified that in cultured myoblasts CTGF/CCN2 causes their transdifferentiation into myofibroblasts by up-regulating the expression of fibrosis marker proteins alpha-smooth muscle actin and transgelin. Interestingly, it was also found that the profibrotic effect exerted by CTGF/CCN2 was mediated by the sphingosine kinase (SK)-1/S1P3 signaling axis specifically induced by the treatment with the profibrotic cue. Following CTGF/CCN2-induced up-regulation, S1P3 became the S1P receptor subtype expressed at the highest degree, at least at mRNA level, and was thus capable of readdressing the sphingosine 1-phosphate signaling towards fibrosis rather than myogenic differentiation. Another interesting finding is that CTGF/CCN2 silencing prevented the TGFbeta-dependent up-regulation of SK1/S1P3 signaling axis and strongly reduced the profibrotic effect exerted by TGFbeta, pointing at a crucial role of endogenous CTGF/CCN2 generated following TGFbeta challenge in the transmission of at least part of its profibrotic effect. These results provide new insights into the molecular mechanism by which CTGF/CCN2 drives its biological action and strengthen the concept that SK1/S1P3 axis plays a critical role in the onset of fibrotic cell phenotype. PMID- 25457226 TI - Arundo donax L.: a non-food crop for bioenergy and bio-compound production. AB - Arundo donax L., common name giant cane or giant reed, is a plant that grows spontaneously in different kinds of environments and that it is widespread in temperate and hot areas all over the world. Plant adaptability to different kinds of environment, soils and growing conditions, in combination with the high biomass production and the low input required for its cultivation, give to A. donax many advantages when compared to other energy crops. A. donax can be used in the production of biofuels/bioenergy not only by biological fermentation, i.e. biogas and bio-ethanol, but also, by direct biomass combustion. Both its industrial uses and the extraction of chemical compounds are largely proved, so that A. donax can be proposed as the feedstock to develop a bio-refinery. Nowadays, the use of this non-food plant in both biofuel/bioenergy and bio-based compound production is just beginning, with great possibilities for expanding its cultivation in the future. To this end, this review highlights the potential of using A. donax for energy and bio-compound production, by collecting and critically discussing the data available on these first applications for the crop. PMID- 25457225 TI - Toxicants inhibiting anaerobic digestion: a review. AB - Anaerobic digestion is increasingly being used to treat wastes from many sources because of its manifold advantages over aerobic treatment, e.g. low sludge production and low energy requirements. However, anaerobic digestion is sensitive to toxicants, and a wide range of compounds can inhibit the process and cause upset or failure. Substantial research has been carried out over the years to identify specific inhibitors/toxicants, and their mechanism of toxicity in anaerobic digestion. In this review we present a detailed and critical summary of research on the inhibition of anaerobic processes by specific organic toxicants (e.g., chlorophenols, halogenated aliphatics and long chain fatty acids), inorganic toxicants (e.g., ammonia, sulfide and heavy metals) and in particular, nanomaterials, focusing on the mechanism of their inhibition/toxicity. A better understanding of the fundamental mechanisms behind inhibition/toxicity will enhance the wider application of anaerobic digestion. PMID- 25457227 TI - Attention-deficit/hyperactivity disorder and risk for substance use disorders in relatives. AB - BACKGROUND: Previous research indicates that attention-deficit/hyperactivity disorder (ADHD) is highly associated with substance use disorders (SUD). However, these studies have failed to clarify the nature of the overlap. The main aim of this study was to explore whether the overlap between ADHD and SUD could be explained by shared genetic and environmental factors or by harmful effects of ADHD medication. METHODS: We employed a matched cohort design across different levels of family relatedness recorded from 1973-2009. By linking longitudinal Swedish national registers, 62,015 ADHD probands and first-degree and second degree relatives were identified and matched 1:10 with control subjects without ADHD and their corresponding relatives. Any record of SUD was defined by discharge diagnoses of the International Classification of Diseases or a purchase of any drug used in the treatment of SUD. RESULTS: First-degree relatives of ADHD probands were at elevated risk for SUD (odds ratios 2.2 and 1.8) compared with relatives of control subjects. The corresponding relative risk in second-degree relatives was substantially lower (odd ratios 1.4 and 1.4). The familial aggregation patterns remained similar for first-degree and second-degree relatives after excluding individuals with coexisting disorders such as schizophrenia, bipolar disorder, depression, and conduct disorder. CONCLUSIONS: Our findings suggest that the co-occurrence of ADHD and SUD is due to genetic factors shared between the two disorders, rather than to a general propensity for psychiatric disorders or harmful effects of ADHD medication. PMID- 25457228 TI - Modeling the dynamics of stable isotope tissue-diet enrichment. AB - Reconstructions of dietary composition and trophic level from stable isotope measurements of animal tissue rely on predictable offsets of stable isotope ratios from diet to tissue. Physiological processes associated with metabolism shape tissue stable isotope ratios, and as such the spacing between stable isotope ratios of diet and tissue may be influenced by processes such as growth, nutritional stress, and disease. Here, we develop a model of incorporation stable isotopes in diet to tissues by coupling stable isotope dynamics to a model of macronutrient energy metabolism. We use the model to explore the effect of changes in dietary intake, both composition and amount, and in energy expenditure, on body mass and carbon and nitrogen stable isotope ratios of tissue. PMID- 25457229 TI - Modeling intrinsic heterogeneity and growth of cancer cells. AB - Intratumoral heterogeneity has been found to be a major cause of drug resistance. Cell-to-cell variation increases as a result of cancer-related alterations, which are acquired by stochastic events and further induced by environmental signals. However, most cellular mechanisms include natural fluctuations that are closely regulated, and thus lead to asynchronization of the cells, which causes intrinsic heterogeneity in a given population. Here, we derive two novel mathematical models, a stochastic agent-based model and an integro-differential equation model, each of which describes the growth of cancer cells as a dynamic transition between proliferative and quiescent states. These models are designed to predict variations in growth as a function of the intrinsic heterogeneity emerging from the durations of the cell-cycle and apoptosis, and also include cellular density dependencies. By examining the role all parameters play in the evolution of intrinsic tumor heterogeneity, and the sensitivity of the population growth to parameter values, we show that the cell-cycle length has the most significant effect on the growth dynamics. In addition, we demonstrate that the agent-based model can be approximated well by the more computationally efficient integro differential equations when the number of cells is large. This essential step in cancer growth modeling will allow us to revisit the mechanisms of multidrug resistance by examining spatiotemporal differences of cell growth while administering a drug among the different sub-populations in a single tumor, as well as the evolution of those mechanisms as a function of the resistance level. PMID- 25457230 TI - Synergy of local, regional, and systemic non-specific stressors for host defense against pathogens. AB - The immune brinksmanship conceptual model postulates that many of the non specific stressful components of the acute-phase response (e.g. fever, loss of appetite, iron and zinc sequestration) are host-derived systemic stressors used with the "hope" that pathogens will be harmed relatively more than the host. The concept proposes that pathogens, needing to grow and replicate in order to invade their host, should be relatively more vulnerable to non-specific systemic stress than the host and its cells. However, the conceptual model acknowledges the risk to the host in that the gamble to induce systemic self-harming stress to harm pathogens may not pay off in the end. We developed an agent-based model of a simplified host having a local infection to evaluate the utility of non-specific stress, harming host and pathogen alike, for host defense. With our model, we explore the benefits and risks of self-harming strategies and confirm the immune brinksmanship concept of the potential of systemic stressors to be an effective but costly host defense. Further, we extend the concept by including in our model the effects of local and regional non-specific stressors at sites of infection as additional defenses. These include the locally hostile inflammatory environment and the stress of reduced perfusion in the infected region due to coagulation and vascular leakage. In our model, we found that completely non-specific stressors at the local, regional, and systemic levels can act synergistically in host defense. PMID- 25457232 TI - Management of splenic trauma: a single institution's 8-year experience. AB - BACKGROUND: Management of splenic trauma has evolved, with current practice favoring selective angiographic embolization and non-operative treatment over immediate splenectomy. Defining the optimal selection criteria for the appropriate management strategy remains an important question. METHODS: This retrospective registry review was conducted at a Level I trauma center. The patient population consisted of 20,561 patients in the State Trauma Registry from April 2004 to May 2012. Splenectomy, angiography, splenic embolization, nonoperative, and noninterventional (NI) observation were the management strategies under study. Morbidity and mortality were the outcome measures. Morbidity and mortality by management strategy. RESULTS: During the 8-year study period, 926 (4.5%) patients sustained splenic injury. Observational management increased over time despite the similar distribution of splenic injury grade over the study period: grade I/II (50%), grade III (24.2%), and grade IV/V (25.8%). Mortality rates associated with each management strategy were the following: immediate splenectomy (IS; 25%), splenic embolization (SE; 3.9%), and angiography only or observation, that is, NI (6.5%) management. Injury severity score (ISS) was highest in IS (36.1 +/- 1.3) compared with SE (29.1 +/- 1.0, P = .001) and NI (21.6, P < .001). Splenectomy was required in 5 of the 129 (3.9%) patients managed with SE and 9 of the 677 (1.3%) patients managed by NI. Mortality was significantly lower among those managed by SE (odds ratio .12, 95% confidence interval: .05 to .32) or NI (odds ratio .21, 95% confidence interval: .12 to .35). This survival benefit was explained by the association of IS with systolic blood pressure <90, high ISS, low GCS at presentation, ISS, development of shock, need for transfusion, and multiorgan failure. CONCLUSIONS: In this large 8-year single institution study, we observed an increase in nonoperative management by an increased application of angiography and embolization. An aggressive utilization of SE in patients with appropriate indications will result in low failure rates and improved mortality. PMID- 25457233 TI - Long-term risk of mesenteric ischemia in patients with inflammatory bowel disease: a 13-year nationwide cohort study in an Asian population. AB - BACKGROUND: It is unclear whether patients with inflammatory bowel disease (IBD) have higher risks of developing mesenteric ischemia. METHODS: We enrolled 9,363 patients who had been hospitalized because of IBD between January 1998 and December 2010, along with 37,452 control patients who were matched at a 1:4 proportion for age, sex, and index year. We accounted the cumulative incidences and hazard ratios (HRs) of developing mesenteric ischemia during the 13-year study period. RESULTS: Patients with IBD had a considerably higher incidence rate of subsequent mesenteric ischemia compared with the controls (22.7 vs 3.09 per 10,000 person-years), with adjusted HR of 6.33 (95% confidence interval: 4.75 to 8.43). A multivariate stratified analysis showed that the mesenteric ischemia risk after adjustment for comorbidities is significantly higher in patients of all age groups, particularly in patients younger than 44 years (adjusted HR: 48.0; 95% confidence interval: 11.3 to 203.9). Moreover, patients with IBD were at highest risk of developing mesenteric ischemia within the first year of follow up. CONCLUSIONS: Careful follow-up and effective therapy are necessary to reduce the excessive risk in these patients. PMID- 25457231 TI - Activation of C-H bonds via the merger of photoredox and organocatalysis: a coupling of benzylic ethers with Schiff bases. AB - The photoredox-mediated coupling of benzylic ethers with Schiff bases has been accomplished. Direct benzylic C-H activation by a combination of a thiol catalyst with an iridium photocatalyst and subsequent radical-radical coupling with secondary aldimines affords a variety of beta-amino ether products in good to excellent yields. Mechanistic studies suggest that a reductive quenching pathway of the photocatalyst is operable. PMID- 25457234 TI - Braun enteroenterostomy during pancreaticoduodenectomy decreases postoperative delayed gastric emptying. AB - BACKGROUND: Modified digestive reconstruction during pancreaticoduodenectomy (PD) may affect the postoperative incidence of delayed gastric emptying (DGE). The purpose of this study is to investigate whether Braun enteroenterostomy following PD can reduce the incidence of DGE. METHODS: Four hundred seven patients who received PD with child reconstruction from June 2000 to March 2013 were divided into 2 groups: 206 patients with Braun enteroenterostomy (Child-Braun group) and 201 patients without Braun enteroenterostomy (Child-non-Braun group). Clinical data were retrospectively extracted; univariate and multivariate analyses were performed to investigate the association between Braun enteroenterostomy and DGE. RESULTS: DGE was less frequent in the Child-Braun group than in the Child-non Braun group (6.7% vs. 26.87%, P < .001). The multivariate logistic regression analysis showed that Braun enteroenterostomy was the only significant independent factor associated with the reduced DGE after PD with Child reconstruction, with an odds ratio of 4.485 (95% confidence interval: 2.372 to 8.482, P < .001). CONCLUSION: Braun enteroenterostomy reduces the incidence of postoperative DGE associated with PD. PMID- 25457235 TI - Patient variables impacting hospital costs from 2008 to 2010. AB - BACKGROUND: Studying the variables associated with the increased costs of health care provides valuable insight. METHODS: A review and analysis of the pertinent variables and information collected for 118.3 million hospital admissions recorded as Nationwide Inpatient Samples database was done for the years 2008 to 2010. We used hospital charges as an approximation of costs in the analysis of the patient variables and other factors contributing to hospital costs. RESULTS: The top 5 factors with the most impact on charges were diagnostic category, length of stay, number of procedures, major operating room procedures, and ownership of the hospital. CONCLUSION: The top 5 factors with the most impact on charges were length of stay, number of procedures, major diagnostic category, major operating room procedures, and ownership of the hospital. PMID- 25457236 TI - Prothrombin complex concentrate in trauma patients. AB - BACKGROUND: Despite recent advances, trauma care providers nowadays face a number of coagulopathic patients. Coagulopathy in trauma patients can be secondary to the traumatic insult or therapeutic effect of the anticoagulants including the Vitamin K antagonist. The efficacy of a concentrated product of Vitamin K dependent coagulation factors, prothrombin complex concentrate (PCC), to reverse coagulopathy has been tested mainly in nontrauma setting. DATA SOURCES: Currently available literature on the use of PCC was identified by searches of electronic database. The indications (trauma vs nontrauma) and types of the PCC products (3 vs 4 factors) were also reviewed in each article. CONCLUSIONS: There are small studies that show promising results regarding PCC use to reverse the Vitamin K antagonist-related coagulopathy in trauma patients. It remains unanswered whether PCC can be effective as an adjunct in patients who require massive transfusion. PMID- 25457237 TI - The effect of temporal artery biopsy on the treatment of temporal arteritis. AB - BACKGROUND: Temporal artery biopsy (TAB) is frequently used to guide treatment for suspected temporal arteritis. Our purpose was to determine the influence on subsequent temporal arteritis treatment, particularly the initiation, termination, or continuation of corticosteroids after a histologically negative TAB. METHODS: This is a retrospective analysis from a single regional referral center on all patients undergoing TAB March 2003 through November 2010. Demographic, clinical, and surgical informations were recorded including changes in treatment based on biopsy results. RESULTS: In all, 237 patients had complete documentation for review; the average age was 71 years (range 34 to 94) and 56% were women. Thirty-six patients had 42 positive biopsies; 26 biopsies were bilateral. Positive biopsy results were defined as having marked intimal thickening, transmural inflammation, and "giant cells." Neither length of biopsy specimen nor preoperative steroid use affected pathologic diagnosis (2.41 vs 2.38 cm, P = .46, and 52% vs 50%, P = .8, respectively). Symptoms included new-onset headache (75%), preauricular tenderness and jaw claudication (32%), erythrocyte sedimentation rate greater than 50 mm/h (60%), and a score of 3 or more using the American College of Rheumatology criteria (56%). Among the 56% of patients who met the criteria for the clinical diagnosis of temporal arteritis, 22% demonstrated a positive biopsy. Biopsy results had no significant impact on subsequent treatment in 69% of patients who met clinical diagnostic criteria (P = .7); in the remaining 31%, biopsy results altered subsequent treatment with either corticosteroid initiation or discontinuation. CONCLUSIONS: The pathologic results of the TAB did not significantly affect treatment in most patients. PMID- 25457239 TI - The true relevance of first-case start delays. PMID- 25457238 TI - Patient-specific risk factors are predictive for postoperative adverse events in colorectal surgery: an American College of Surgeons National Surgical Quality Improvement Program-based analysis. AB - BACKGROUND: Pay-for-performance measures incorporate surgical site infection rates into reimbursement algorithms without accounting for patient-specific risk factors predictive for surgical site infections and other adverse postoperative outcomes. METHODS: Using American College of Surgeons National Surgical Quality Improvement Program data of 67,445 colorectal patients, multivariable logistic regression was performed to determine independent risk factors associated with various measures of adverse postoperative outcomes. RESULTS: Notable patient specific factors included (number of models containing predictor variable; range of odds ratios [ORs] from all models): American Society of Anesthesiologists class 3, 4, or 5 (7 of 7 models; OR 1.25 to 1.74), open procedures (7 of 7 models; OR .51 to 4.37), increased body mass index (6 of 7 models; OR 1.15 to 2.19), history of COPD (6 of 7 models; OR 1.19 to 1.64), smoking (6 of 7 models; OR 1.15 to 1.61), wound class 3 or 4 (6 of 7 models; OR 1.22 to 1.56), sepsis (6 of 7 models; OR 1.14 to 1.89), corticosteroid administration (5 of 7 models; OR 1.11 to 2.24), and operation duration more than 3 hours (5 of 7 models; OR 1.41 to 1.76). CONCLUSIONS: These findings may be used to pre-emptively identify colorectal surgery patients at increased risk of experiencing adverse outcomes. PMID- 25457240 TI - Impact of gender and body surface area on outcome after abdominal aortic aneurysm repair. AB - BACKGROUND: A gender-neutral threshold aneurysm diameter (AD) of more than 5.5 cm for surgical intervention in abdominal aortic aneurysms (AAA) ignores the fact that women have a smaller baseline AD. We hypothesized that women have a greater AD relative to body surface area (BSA) at the time of surgery and that this worsens outcome. METHODS: The Vascular Study Group of New England database was queried for elective AAA repairs performed from 2003 to 2011 to compare BSA indexed AD, ie, aortic size index (ASI), between men and women at the time of surgery and the impact of ASI on outcome. RESULTS: Women were older and had higher ASI among both open-repair (n = 1,566) and endovascular repair (n = 2,172) patients (P < .001). Among open-repair patients, mean ASI for men undergoing repair at AD of 5.5 cm (2.75 cm/m2) was used to subdivide women into 2 categories: women with ASI of 2.75 or more were older (P < .001), had a larger aneurysm size (P < .001), and had a higher 1-year mortality (P = .042) than women with ASI less than 2.75. CONCLUSIONS: When indexed to BSA, women have a larger aneurysm size than men at the time of AAA repair. PMID- 25457242 TI - Initial operative treatment of isolated ileal Crohn's disease in adolescents. AB - BACKGROUND: We hypothesize that in children with Crohn's disease (CD) isolated to a single site, resection leads to clinical improvement, decreased medication requirements, and improved growth. METHODS: A retrospective review was conducted of children with CD isolated to the terminal ileum undergoing operative intervention at Children's Hospital Colorado between 2002 and 2013. RESULTS: Twenty-six patients underwent ileocecetomy (mean age at diagnosis 14.1 +/- 2.6 years; mean age at resection 15.7 +/- 2.5 years; median follow-up 2 +/- 1.5 years). Twenty-two (84.6%) patients reported clinical improvement and 17 (65.4%) were able to decrease the number or dosage of medications. Average weight increased from the 29th to the 45th percentile (P = .09) at 1 year and to the 56th percentile (P = .02) at 3 years post resection. Average body mass index increased from the 30th to the 48th and 49th percentile at 1 and 3 years (P < .05 for both), respectively. Height increased from the 39th percentile at the time of resection to the 51st percentile at 3 years (P = nonsignificant). CONCLUSION: Surgical resection of an isolated ileal segment in adolescents with CD allows for catch-up growth and reduction in medication requirements. PMID- 25457241 TI - Acceptability of the decision support for safer surgery tool. AB - BACKGROUND: We examined providers' perceptions of the Decision Support for Safer Surgery (DS3) tool, which provided preoperative patient-level risk estimates of postoperative adverse events. METHODS: The DS3 tool was evaluated at 2 academic medical centers. During the validation study, surgeons provided usefulness ratings of the DS3 tool for each patient before surgery. At the end of the study, providers' perceptions of the DS3 tool were assessed via questionnaire. Data were analyzed using descriptive statistics and independent samples t tests. RESULTS: During the trial, 23 surgeons completed usefulness ratings of the DS3 tool for 1,006 patients. Surgeons rated the tool as "very useful" or "moderately useful" in 251 (25%) of the cases, "neutral" in 469 (46.6%) of the cases, and "moderately unuseful" or "not useful" in 286 (28.4%) cases. At the end of the trial, 32 providers completed the questionnaire; perceptions were relatively neutral, although several aspects were rated quite favorably. CONCLUSION: The DS3 tool may be most useful for achieving particular tasks (eg, training novice surgeons, increasing patient engagement) or encouraging specific processes (eg, team-based care) in surgical care settings. PMID- 25457243 TI - Localization of nonpalpable breast lesions with sonographically visible clip: optimizing tailored resection and clear margins. AB - BACKGROUND: Achieving clear margins with adequate resection volumes is one of the principal goals of breast-conserving surgery. The aim of our study was to compare preoperative localization using 2 different clips, radiopaque or sonographically visible, to reach this goal. METHODS: We reviewed 209 consecutive nonpalpable breast cancers that were treated with lumpectomy: 59 with radiopaque and 150 with sonographically visible clip positioned during biopsy procedure. In the former case, preoperative localization was performed with mammography and in the latter by ultrasonography. RESULTS: Clear margins were achieved in 80.4% of patients: 57.6% in the first and 89.3% in the second group (P < .0001; odds ratio, 7.6; 95% confidence interval, 3.4 to 17.2). By using sonographically visible clips, the re excision rate has decreased from 42.4% to 10.7%, (P < .0001), and resections resulted smaller with average calculated resection ratio of 3.54 vs. 5.08 (P = .03). CONCLUSIONS: Preoperative localization using a sonographically visible clip allows a more tailored breast-conserving surgery and reduces the re-excision rate. PMID- 25457244 TI - Early postoperative small bowel obstruction: open vs laparoscopic. AB - BACKGROUND: The window for safe reoperation in early postoperative (<6 weeks) small bowel obstruction (ESBO) is short and intimately dependent on elapsed time from the initial operation. Laparoscopic procedures create fewer inflammatory changes than open laparotomies. We hypothesize that it is safer to reoperate for ESBO after laparoscopic procedures than open. METHODS: Review of patients who underwent re-exploration for ESBO from 2003 to 2009 was performed. Based on the initial operation, patients were classified as "open" or "laparoscopic." The Revised Accordion Severity Grading System was used to define complications as minor (1 to 2) or severe (3 to 6). RESULTS: There were 189 patients identified (age 55 years, 48% male): 130 open and 59 laparoscopic. Adhesive disease was more common (65% vs 42%, P < .01), while strictures were less frequent (5% vs 14% P = .03), in the open group. The open group had a greater rate of malignancy, days to re-exploration, and severity of complications. There was no difference in the rates of minor complications, enterotomy, and mortality. ESBO after laparoscopic surgery was more commonly caused by a focal source (85% vs 63%). Eighty-three patients (64 open, 19 laparoscopic) underwent re-exploration at or beyond 14 days. Within this subgroup, there were more severe complications (25% vs 5%) after open procedures with equivalent mortality (4% vs 0%). CONCLUSIONS: Laparoscopic approaches confer a lower rate of adhesive disease and severity of complications in early SBO as compared with open surgery even if performed after 2 weeks of index procedure. PMID- 25457245 TI - Factors which affect the use of lumpectomy and mastectomy in an underinsured, safety net hospital population. AB - BACKGROUND: This study was performed to evaluate variables that affect the use of mastectomy and lumpectomy in an underinsured population. METHODS: A retrospective review of all patients who underwent breast cancer operations from July 2001 to February 2011 at a safety net hospital was performed. Univariate and multivariate analyses were performed to identify variables, which were associated with the type of operation. RESULTS: Of the 412 patients, 81% of the patients were underinsured or uninsured. Most patients (58%) presented with clinical stage 2A/B disease. Mastectomy was performed in 37% of patients and lumpectomy in 63%. In multivariate analysis, clinical tumor size (P = .035) and pathologic stage (P = .003) remained associated with mastectomy, while use of preoperative chemotherapy (P = .004) and type of surgeon (P = .001) was associated with lumpectomy. CONCLUSIONS: Most patients underwent lumpectomy despite later stage at presentation. Preoperative chemotherapy was associated with increased likelihood of lumpectomy. PMID- 25457246 TI - Colon cancer surgery following emergency presentation: effects on admission and stage-adjusted outcomes. AB - BACKGROUND: Emergency presentation with colon cancer is intuitively related to advanced disease. We measured its effect on outcomes of surgically treated colon cancer. METHODS: A retrospective cohort of 1,071 surgical colon cancer patients (2004 to 2011), with 102 emergency cases requiring surgery within the index admission, was analyzed. RESULTS: Emergency patients required longer surgeries (median 141 vs 124 minutes; P = .04), longer median admissions (8% vs 5%; P < .001), more readmissions (12.7% vs 7.1%; P = .040), and perioperative mortality (7.8% vs .8%; P < .001). Surgical pathology displayed higher rates of node positive disease (56.6% vs 38.6%; P < .001), extramural vascular invasion (39.6% vs 29.1%; P = .021), and metastatic disease (19.6% vs 8%; P < .001). Consequently, adjusting for staging, emergency presentations had considerably higher mortality (odds ratio = 2.07; P = .003) and shorter disease-free survival (hazard ratio = 1.39; P = .042). CONCLUSIONS: Emergency presentation is a stage independent poor prognostic factor associated with aggressive tumor biology, resulting in longer surgeries and admissions, frequent readmissions, worsening outcomes, and increasing healthcare costs. PMID- 25457247 TI - "Evaluation of the Sendai and 2012 International Consensus Guidelines based on cross-sectional imaging findings performed for the initial triage of mucinous cystic lesions of the pancreas: a single institution experience with 114 surgically treated patients." Or rather "Don Giovanni o sia il convitato di pietra". PMID- 25457248 TI - High oxygen concentration to prevent surgical site infection after rectal cancer surgery. PMID- 25457249 TI - Effects of ascites on outcomes of colorectal surgery in congestive heart failure patients. AB - BACKGROUND: There are limited data regarding the effects of ascites on outcome of patients undergoing colorectal resection. We sought to identify complications related to ascites. METHODS: The National Surgical Quality Improvement Program database was used to evaluate congestive heart failure (CHF) patients who had ascites before colorectal resection between 2005 and 2012. Multivariate regression analysis was performed to identify affected outcomes. RESULTS: We sampled a total of 2,178 patients who suffered CHF and underwent colorectal resection, of which 195 (9%) had preoperative ascites. The mortality rate of patients who had preoperative ascites was 46.2% compared to 25.7% for patients without ascites (adjusted odd ratio [AOR], 3.38; P < .01). Complications affected by ascites include (P < .05) ventilator dependency (AOR, 2.40), acute renal failure (AOR, 2.18), and wound disruption (AOR, 2.44; P < .05). There was no increase in superficial surgical site infection rate in patients with ascites (AOR, 1.01; P = .9). CONCLUSIONS: The presence of ascites in CHF patients is associated with increased mortality in patients undergoing colorectal surgery. There is no correlation between ascites and surgical site infection but wound disruption increases in the presence of ascites. PMID- 25457250 TI - Predictors of the necessity for early tracheostomy in patients with acute cervical spinal cord injury: a 15-year experience. AB - BACKGROUND: The need for mechanical ventilation (MV) after spinal cord injury (SCI) is a risk factor for prolonged critical care. The "purpose" of this study was to identify the level of cervical SCI that requires MV, thereby defining candidates for tracheostomy. METHODS: Patients with cervical SCI over a 15-year period were reviewed. RESULTS: One hundred sixty-three patients sustained cervical SCI. Of 76 complete injuries, 91% required MV for greater than 48 hours. By injury level, MV incidence was 100% for C2-4, 91% for C5, 79% for C6, and 80% for C7. Only one quarter of patients with incomplete SCI required MV for greater than 48 hours; Glascow Coma Score and Injury Severity Score were significantly worse compared with patients not requiring MV. CONCLUSIONS: Factors influencing the decision for tracheostomy in cervical SCI patients include the presence of a complete SCI, anatomic level of injury, Glascow Coma Score, Injury Severity Score, and associated thoracic injury. Patients with complete cervical SCI often require prolonged MV. Conversely, the minority of incomplete SCI required MV; the need for tracheostomy was likely performed for associated injuries. Utilizing identified factors permits a thoughtful approach to tracheostomy in this patient population. PMID- 25457251 TI - A preliminary study on surgery for hepatocellular carcinoma patients with portal hypertension. AB - BACKGROUND: To assess the effects of various operations for hepatocellular carcinoma with portal hypertension (PH). METHODS: Data regarding 78 patients with resectable liver cancer with PH were analyzed. Patients were divided into 3 groups: A (splenic artery ligation), B (in situ splenectomy), and C (in situ splenectomy + pericardial devascularization). RESULTS: White blood cell and platelet counts in the 3 groups increased significantly after surgery. Postoperative portal pressure was not significantly lower than preoperative portal pressure in Group A, while it was significantly lower in B. In Group C, the portal pressure after splenectomy was significantly lower than that before the operation, but not again after pericardial devascularization. The 1-, 2-, and 3-year survival rates of all the patients were 89.7%, 64.1%, and 46.1%, respectively. CONCLUSIONS: PH is not an absolute contraindication to liver resection in Child-Pugh class B cirrhotic patients. The combined surgery for hepatocellular carcinoma patients with PH is a safe choice. PMID- 25457252 TI - Laparoscopic versus open colonic resection for complicated diverticular disease in the emergency setting: a safe choice? A retrospective comparative cohort study. AB - BACKGROUND: We conducted a retrospective cohort study to compare the outcomes of laparoscopic colon resection (LCR) with open colon resection (OCR) for complicated diverticular disease (CDD) during emergent hospital admission. METHODS: Charts from all patients undergoing colon resection for CDD during emergent hospital admission at a single academic institution were reviewed. The primary outcomes were overall 30-day postoperative morbidity and mortality. RESULTS: From 2000 to 2010, 125 cases were retrieved (49 LCR and 86 OCR). Conversion rate was 5.1%. Overall morbidity significantly decreased with laparoscopic surgery compared with OCR. No mortality occurred with LCR. Prolonged ileus was less frequent (12.8% vs. 32.6%; P = .02), time to oral intake shorter (3 vs. 6 days; P < .01), and LOS shorter (5 vs. 8 days; P = .05) for LCR. CONCLUSIONS: In our series, in the patients selected, LCR for CDD during emergent hospital admission appears to be a safe procedure associated with decreased morbidity, time to oral intake, and LOS compared with OCR. PMID- 25457253 TI - The validity of the VA surgical risk tool in predicting postoperative mortality among octogenarians. AB - BACKGROUND: To examine the validity of Veterans Affair-VA risk assessment tool in predicting the perioperative and overall mortality among octogenarians. METHODS: This is a single-institution retrospective observational study, in which the clinical information of 1,618 octogenarians were extracted from the VA Surgical Quality Improvement Program database. VA risk assessment tool and ASA classification were used to predict the probability of postoperative mortality and morbidity. Multiple risk groups were compared for mortality using multiple logistic regressions. RESULTS: There were 570 survivors and 1,048 nonsurvivors. VA risk tool strongly predicted perioperative 30-day mortality in receiver operator characteristic curve analysis (area under the curve: .82 +/- .02). The power of this tool, while acceptable, was less in predicting overall mortality (area under the curve: .68 +/- .01). Age, dialysis, a history of congestive heart failure, functional status, transfusion, and weight loss were also associated with increased rate of death within 30 days. CONCLUSIONS: VA risk tool predicted both perioperative and overall mortality. Relatively strong power of this tool in predicting overall mortality may be unique to this age group because of their advanced age. PMID- 25457257 TI - Additional anatomic information on the aortic root. PMID- 25457258 TI - One step closer to the elimination of primary graft dysfunction. PMID- 25457259 TI - Kinematic parameters of sheep walking on a treadmill. AB - Ovine locomotion studies are rare, despite their relevance for medical research. The aim of this preliminary study was to investigate habituation and temporospatial parameters during treadmill walking of seven Austrian Mountain sheep. Sheep were naive to treadmill exercise. During five treadmill sessions, movement cycle duration (MCD), vertical trunk movement (VTM), stride height (SH), stride length (SL), and percentage of movement cycle at stance (%St) were assessed. Two sheep were excluded from the study because they would not walk on the treadmill. From the end measurement session, MCD (0.95 s) and %St (62%) were similar to reported kinetics of sheep walking over ground, although stride length (1.05 m) was longer in this study. These findings suggest that sheep may require more than five sessions to become habituated to treadmill walking. PMID- 25457260 TI - Skeletal and hepatic changes induced by chronic vitamin A supplementation in cats. AB - The first aim of this study was to determine whether vitamin D supplementation influenced the effects of high vitamin A intake on new bone formation in adult cats. The second aim was to determine whether high vitamin A intake in cats caused liver pathology and, if so, whether the current upper limit for the dietary intake of vitamin A for healthy adult cats would be safe. Twenty-four healthy adult cats were divided into four groups that received a control diet supplemented with peanut oil (control), or peanut oil containing a 100-fold increase in vitamin A (HA), or a 100-fold increase in vitamin A and a fivefold increase in vitamin D (HAMD), or a 100-fold increase in vitamin A and a 65-fold increase in vitamin D (HAHD) over a period of 18 months. Cats did not show abnormal locomotion or clinical signs of liver failure after 18 months of supplementation but did show subtle skeletal changes and liver pathology, suggesting that the current National Research Council (2006) safe upper limit for vitamin A for cats is too high. The addition of vitamin D did not seem to influence bone pathology. While moderately elevated dietary vitamin D levels (HAMD) seemed to protect cats against the liver pathology caused by the consumption of large amounts of vitamin A, higher dietary levels of vitamin D (HAHD) did not seem to be protective. PMID- 25457261 TI - Limited efficacy of topical recombinant feline interferon-omega for treatment of cats with acute upper respiratory viral disease. AB - Despite a lack of controlled studies confirming its efficacy, recombinant feline interferon-omega (rfeIFN-omega) is used in the treatment of feline upper respiratory tract disease (FURTD), which is usually caused by feline calicivirus (FCV) or feline herpesvirus-1 (FHV-1). The aims of the present study were to investigate whether administration of rfeIFN-omega improves clinical signs in cats with acute FURTD and whether this treatment reduces shedding of FCV. Thirty seven cats affected with acute FURTD were recruited into a prospective, randomised, placebo-controlled, double-blinded clinical trial. The presence of FCV and/or FHV-1 was determined by performing quantitative polymerase chain reaction (qPCR) on oropharyngeal and conjunctival swabs. Cats were randomly assigned to treatment groups, receiving either placebo or rfeIFN-omega (2.5 MU/kg) subcutaneously, followed by 0.5 MU topically at 8-h intervals via the conjunctiva, intranasally, and orally for 21 days. All cats received additional treatment with antibiotics, expectorants, and inhalation of nebulised physiological saline with camomile. Clinical signs and FCV shedding were evaluated over 42 days. All cats demonstrated improvement in clinical signs during the course of the study, with no significant difference in any of the assessed variables when comparing the two groups. FCV copy numbers decreased more rapidly in cats receiving rfeIFN-omega. Treatment with rfeIFN-omega was not effective in ameliorating clinical signs of acute viral FURTD compared to placebo, but might accelerate a reduction in FCV load in infected cats. PMID- 25457262 TI - First report of bovine viral diarrhoea virus-2 infection in cattle in Poland. AB - This report describes the first identification in Poland of bovine viral diarrhoea virus (BVDV)-2 in a dairy herd where severe clinical disease with losses of young animals was observed. The virus was readily cultivated in cell culture and a phylogenetic analysis of the nucleotide sequences and secondary structures of the viral genomic 5' untranslated region confirmed virus identity. The economic impact of the infection was significant compared to the previously prevalent BVDV-1 infections confirming that this genotype of BVDV can cause severe sickness in affected herds. The use of BVDV-1 vaccine did not prevent the infection with the BVDV-2 genotype. PMID- 25457263 TI - Seroprevalence and risk factors associated with Babesia caballi and Theileria equi infections in donkeys from Southern Italy. AB - Equine piroplasmosis (EP) has been frequently described in donkeys in subtropical and tropical regions, but published data reflecting large scale surveys are very limited in Europe. The seroprevalence of Babesia caballi and Theileria equi was determined in a donkey population from Campania Region in Southern Italy using a commercial indirect fluorescent antibody test (IFAT), and the risk factors associated with the occurrence of the infection were assessed. Of 203 samples, the overall seroprevalence for EP was 57.1% (116/203), with 35.5% (72/203) for B. caballi and 44.3% (90/203) for T. equi. Co-infection was detected in 46 donkeys (22.6%). The distribution of IFAT antibody titres to B. caballi was: 1:80 (n= 67), 1:160 (n= 2), 1:320 (n= 3); while the distribution of IFAT antibody titres to T. equi was: 1:80 (n= 25), 1:160 (n= 42), 1:320 (n= 12), 1:640 (n= 8), 1:1280 (n= 3). All examined donkeys were asymptomatic, except one adult male (with a titre of 1:640 against T. equi) that showed clinical signs corresponding to the acute stage of EP, reported for the first time in Italy. The unique risk factor associated with a higher B. caballi seroprevalence was the presence of horses in the farms, while risk factors associated with a higher T. equi seroprevalence were poor body condition, presence of ruminants in the farms and milk production. The results indicate a high level of exposure in donkeys living in Southern Italy and suggest that donkeys may be an important reservoir of EP. PMID- 25457264 TI - Variance associated with subject velocity and trial repetition during force platform gait analysis in a heterogeneous population of clinically normal dogs. AB - Factors that contribute to variance in ground reaction forces (GRF) include dog morphology, velocity, and trial repetition. Narrow velocity ranges are recommended to minimize variance. In a heterogeneous population of clinically normal dogs, it was hypothesized that the dog subject effect would account for the majority of variance in peak vertical force (PVF) and vertical impulse (VI) at a trotting gait, and that narrow velocity ranges would be associated with less variance. Data from 20 normal dogs were obtained. Each dog was trotted across a force platform at its habitual velocity, with controlled acceleration (+/-0.5 m/s(2)). Variance effects from 12 trotting velocity ranges were examined using repeated-measures analysis-of-covariance. Significance was set at P <0.05. Mean dog bodyweight was 28.4 +/- 7.4 kg. Individual dog and velocity significantly affected PVF and VI for thoracic and pelvic limbs (P <0.001). Trial number significantly affected thoracic limb PVF (P <0.001). Limb (left or right) significantly affected thoracic limb VI (P = 0.02). The magnitude of variance effects from largest to smallest was dog, velocity, trial repetition, and limb. Velocity ranges of 1.5-2.0 m/s, 1.8-2.2 m/s, and 1.9-2.2 m/s were associated with low variance and no significant effects on thoracic or pelvic limb PVF and VI. A combination of these ranges, 1.5-2.2 m/s, captured a large percentage of trials per dog (84.2 +/- 21.4%) with no significant effects on thoracic or pelvic limb PVF or VI. It was concluded that wider velocity ranges facilitate capture of valid trials with little to no effect on GRF in normal trotting dogs. This concept is important for clinical trial design. PMID- 25457265 TI - Recombinant canine single chain insulin analogues: insulin receptor binding capacity and ability to stimulate glucose uptake. AB - Virtually all diabetic dogs require exogenous insulin therapy to control their hyperglycaemia. In the UK, the only licensed insulin product currently available is a purified porcine insulin preparation. Recombinant insulin is somewhat problematic in terms of its manufacture, since the gene product (preproinsulin) undergoes substantial post-translational modification in pancreatic beta cells before it becomes biologically active. The aim of the present study was to develop recombinant canine single chain insulin (SCI) analogues that could be produced in a prokaryotic expression system and which would require minimal processing. Three recombinant SCI constructs were developed in a prokaryotic expression vector, by replacing the insulin C-peptide sequence with one encoding a synthetic peptide (GGGPGKR), or with one of two insulin-like growth factor (IGF)-2 C-peptide coding sequences (human: SRVSRRSR; canine: SRVTRRSSR). Recombinant proteins were expressed in the periplasmic fraction of Escherichia coli and assessed for their ability to bind to the insulin and IGF-1 receptors, and to stimulate glucose uptake in 3T3-L1 adipocytes. All three recombinant SCI analogues demonstrated preferential binding to the insulin receptor compared to the IGF-1 receptor, with increased binding compared to recombinant canine proinsulin. The recombinant SCI analogues stimulated glucose uptake in 3T3-L1 adipocytes compared to negligible uptake using recombinant canine proinsulin, with the canine insulin/cIGF-2 chimaeric SCI analogue demonstrating the greatest effect. Thus, biologically-active recombinant canine SCI analogues can be produced relatively easily in bacteria, which could potentially be used for treatment of diabetic dogs. PMID- 25457266 TI - A cohort study of epilepsy among 665,000 insured dogs: incidence, mortality and survival after diagnosis. AB - The main objective of this study was to estimate the incidence and mortality rates of epilepsy in a large population of insured dogs and to evaluate the importance of a variety of risk factors. Survival time after a diagnosis of epilepsy was also investigated. The Swedish animal insurance database used in this study has previously been helpful in canine epidemiological investigations. More than 2,000,000 dog-years at-risk (DYAR) were available in the insurance database. In total, 5013 dogs had at least one veterinary care claim for epilepsy, and 2327 dogs were euthanased or died because of epilepsy. Based on veterinary care claims the incidence rate of epilepsy (including both idiopathic and symptomatic cases) was estimated to be 18 per 10,000 DYAR. Dogs were followed up until they were 10 (for life insurance claims) or 12 years of age (veterinary care claims). Among the 35 most common breeds in Sweden, the Boxer was at the highest risk of epilepsy with 60.3 cases per 10,000 DYAR, and also had the highest mortality rate of 46.7 per 10,000 DYAR (based on life insurance claims). Overall, males were at a higher risk than females (1.4:1). Median survival time (including euthanasia and death) after diagnosis was 1.5 years. In general, breeds kept solely for companionship lived longer after diagnosis than those kept for dual-purposes, such as hunting and shepherd and working breeds. The study demonstrates marked breed differences in incidence and mortality rates, which are assumed to reflect genetic predisposition to epilepsy. PMID- 25457267 TI - Stem cell therapies for treating osteoarthritis: prescient or premature? AB - There has been unprecedented interest in recent years in the use of stem cells as therapy for an array of diseases in companion animals. Stem cells have already been deployed therapeutically in a number of clinical settings, in particular the use of mesenchymal stem cells to treat osteoarthritis in horses and dogs. However, an assessment of the scientific literature highlights a marked disparity between the purported benefits of stem cell therapies and their proven abilities as defined by rigorously controlled scientific studies. Although preliminary data generated from clinical trials in human patients are encouraging, therapies currently available to treat animals are supported by very limited clinical evidence, and the commercialisation of these treatments may be premature. This review introduces the three main types of stem cells relevant to veterinary applications, namely, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells, and draws together research findings from in vitro and in vivo studies to give an overview of current stem cell therapies for the treatment of osteoarthritis in animals. Recent advances in tissue engineering, which is proposed as the future direction of stem cell-based therapy for osteoarthritis, are also discussed. PMID- 25457268 TI - Mastitis in dairy heifers: prevalence and risk factors. AB - Poor udder health represents a serious problem in dairy production and has been investigated intensively, but heifers generally have not been the main focus of mastitis control. The aim of this study was to evaluate the prevalence, risk factors and consequences of heifer mastitis in Switzerland. The study included 166,518 heifers of different breeds (Swiss Red Pied, Swiss Brown Cattle and Holstein). Monthly somatic cell counts (SCCs) provided by the main dairy breeding organisations in Switzerland were monitored for 3 years; the prevalence of subclinical mastitis (SCM) was determined on the basis of SCCs >=100,000 cells/mL at the first test date. The probability of having SCM at the first test date during lactation was modelled using logistic regression. Analysed factors included data for the genetic background, morphological traits, geographical region, season of parturition and milk composition. The overall prevalence of SCM in heifers during the period from 2006 to 2010 was 20.6%. Higher frequencies of SCM were present in heifers of the Holstein breed (odds ratio, OR, 1.62), heifers with high fat:protein ratios (OR 1.97) and heifers with low milk urea concentrations combined with high milk protein concentrations (OR 3.97). Traits associated with a low risk of SCM were high set udders, high overall breeding values and low milk breeding values. Heifers with SCM on the first test day had a higher risk of either developing chronic mastitis or leaving the herd prematurely. PMID- 25457269 TI - Acute enlargement of subdural hygroma due to subdural hemorrhage in a victim of child abuse. AB - An 11-month-old female baby was found dead by her mother. Cranial postmortem CT prior to the forensic autopsy showed dilatation of bilateral extra-axial spaces and ventricles. The autopsy revealed a new linear fracture of the left parietal bone and occipital bone, and a healed linear fracture of the right parietal bone and occipital bone like a mirror image of the left one as well. Intracranially, 230ml of subdural fluid were collected, which was mixed with blood. There was a fresh hemorrhage around a bridging vein of the left parietal lobe and the dura mater. Moreover, the outer side of the cerebrum and the inner side of the dura mater were covered by a thin membrane, which mater might have been previously formed because of being positive for Fe-staining and anti-CD68 antibody. A subdural hematoma might have been developed when the right side of the skull was previously fractured, which was transformed into a subdural hygroma. Subsequently, it is likely that, after the left side fracture of the skull occurred, the subdural hygroma rapidly enlarged due to hemorrhaging from the bridging vein, which resulted in intracranial hypertension, because microbleeding was detected in the brain stem. Accordingly, we diagnosed the cause and manner of death as intracranial hypertension due to subdural hemorrhage in subdural hygroma, and homicide, including child abuse, respectively. PMID- 25457270 TI - Response to "MacIntyre et al., 2014: Respiratory protection for healthcare workers treating Ebola virus disease (EVD): are facemasks sufficient to meet occupational health and safety obligations?". PMID- 25457271 TI - Response to Martin-Moreno et al. (2014) Surgical mask or no mask for health workers not a defensible position for Ebola. PMID- 25457272 TI - Implementation challenges in end-of-life research with adults with intellectual and developmental disabilities. AB - Although the 4 million+people in the U.S. with an intellectual or developmental disability (I/DD) experience the same life expectancy as those in the general population, end-of-life research including these individuals is lacking and can be difficult to implement. As will be described in this paper, it is possible to overcome barriers to successfully include people with I/DD in end-of-life research. In this paper, the implementation challenges, feasibility, and implications for successful end-of-life research with individuals with I/DD using focus groups are described. Individuals with I/DD were able to discuss their experiences and views about end-of-life care. However, while people with I/DD made valuable contributions to the focus groups, there were several modifications needed in order to execute this study. In order to gain a complete picture of end of-life care for people with I/DD, it is imperative to include them in research to the best of their ability. By anticipating issues related to recruitment, the consent process, setting, and support needs of participants, focus groups can be successfully implemented. PMID- 25457273 TI - Development and testing of a scale to assess fluid overload symptoms. AB - AIM: This study aimed to develop and test the reliability and validity of a scale about fluid overload symptoms in patients with heart failure. BACKGROUND: Fluid overload symptoms are a common cause of admission of patients with heart failure. An instrument that is quick to complete and easy to use for the measurement of fluid overload symptoms would be beneficial for early intervention and avoidance of hospital admission. METHODS: Fifty-six participants were recruited from cardiology wards. Internal consistency reliability was assessed using Cronbach's alpha coefficient. Validity was assessed using Pearson's correlation coefficient and exploratory factor analysis. RESULTS: This new instrument had a Cronbach's alpha of .81. Exploratory factor analysis revealed two factors (breathing symptoms and body fluid accumulation symptoms) with acceptable criterion validity. CONCLUSIONS: The fluid overload symptoms scale exhibits reliability with construct and criterion validity. It would be more beneficial if further testing is done. PMID- 25457274 TI - Improving umbilical cord blood processing to increase total nucleated cell count yield and reduce cord input wastage by managing the consequences of input variation. AB - BACKGROUND AIMS: With the rising use of umbilical cord blood (UCB) as an alternative source of hematopoietic stem cells, storage inventories of UCB have grown, giving rise to genetically diverse inventories globally. In the absence of reliable markers such as CD34 or counts of colony-forming units, total nucleated cell (TNC) counts are often used as an indicator of potency, and transplant centers worldwide often select units with the largest counts of TNC. As a result, cord blood banks are driven to increase the quality of stored inventories by increasing the TNC count of products stored. However, these banks face challenges in recovering consistent levels of TNC with the use of the standard protocols of automated umbilical cord processing systems, particularly in the presence of input variation both of cord blood volume and TNC count, in which it is currently not possible to process larger but useable UCB units with consequent losses in TNC. METHODS: This report addresses the challenge of recovering consistently high TNC yields in volume reduction by proposing and validating an alternative protocol capable of processing a larger range of units more reliably. RESULTS: This work demonstrates improvements in plastic ware and tubing sets and in the recovery process protocol with consequent productivity gains in TNC yield and a reduction in standard deviation. CONCLUSIONS: This work could pave the way for cord blood banks to improve UCB processing and increase efficiency through higher yields and lower costs. PMID- 25457275 TI - Clinical mesenchymal stromal cell products undergo functional changes in response to freezing. AB - BACKGROUND AIMS: Current methods of mesenchymal stromal cell (MSC) cryopreservation result in variable post-thaw recovery and phenotypic changes caused by freezing. The objective of this investigation was to determine the influence of ex vivo cell expansion on phenotype of MSCs and the response of resulting phenotypes to freezing and thawing. METHODS: Human bone marrow aspirate was used. MSCs were isolated and cells were assessed for total count, viability, apoptosis and senescence over 6 passages (8-10 doublings/passage) in ex vivo culture. One half of cells harvested at each passage were re-plated for continued culture and the other half were frozen at 1 degrees C/min in a controlled-rate freezer. Frozen samples were stored in liquid nitrogen, thawed and reassessed for total cell count, viability and senescence immediately and 48 h after thaw. RESULTS: Viability did not differ significantly between samples before freeze or after thaw. Senescence increased over time in pre-freeze culture and was significantly higher in one sample that had growth arrest both before freeze and after thaw. Freezing resulted in similar initial post-thaw recovery in all samples, but 48-h post-thaw growth arrest was observed in the sample with high senescence only. CONCLUSIONS: High pre-freeze senescence appears to correlate with poor post-thaw function in MSC samples, but additional studies are necessary to obtain a sample sizes large enough to quantify results. PMID- 25457276 TI - Effective modulation of transforming growth factor-beta1 expression through engineered microRNA-based plasmid-loaded nanospheres. AB - BACKGROUND AIMS: Sustained gene delivery could be particularly necessary in modulating gene expression in healing intrasynovial tendons and may be a promising approach for preventing adhesions. METHODS: Polylactic-co-glycolic acid nanospheres were prepared and were then incorporated with plasmids expressing enhanced green fluorescence protein and miRNA for inhibiting the transforming growth factor-beta1 gene expression. RESULTS: We demonstrated that cultured tenocytes could be effectively transfected by means of nanosphere/plasmid. The expression of transforming growth factor-beta1 is significantly downregulated in healing chicken flexor tendon treated with nanosphere/plasmid. Histology analysis did not demonstrate any significant inflammation or necrosis in tendons injected with nanosphere/plasmid after surgery. CONCLUSIONS: Nanosphere/plasmid may be a promising non-viral vector for gene therapy of the injured flexor tendon. PMID- 25457277 TI - Human CD14+ cells loaded with Paclitaxel inhibit in vitro cell proliferation of glioblastoma. AB - BACKGROUND AIMS: In attempting to develop new strategies to circumvent the immunosuppression associated with glioblastoma (GB), novel approaches have been designed using dendritic cell (DC)-based vaccination, which is considered a promising strategy to attack high-grade glioma. In previous studies, we demonstrated that human mesenchymal stromal cells without genetic manipulation but primed with Paclitaxel (PTX) acquire a potent anti-tumor activity, providing an interesting new biological approach for drug delivery. On the basis of these results, we here investigated whether both CD14+ and their derived DCs may behave like mesenchymal stromal cells acquiring anti-tumor activity on priming with PTX. METHODS: Human CD14+ cells were isolated from peripheral blood. Fluorescence activated cell sorter analysis was performed to determine the purity of CD14+ and their differentiation into mature DCs. Cells were primed by incubation with 1 MUg/mL of PTX for 24 h, and the PTX released by cells was assessed by mass spectrometry analysis. Anti-tumor activity was checked by testing the conditioned medium (CM) on the proliferation of U87 MG, a GB cell line. RESULTS: Both CD14+ and DCs were able to incorporate PTX and release the drug in the CM in a time dependent manner (maximal release over 24 h). The addition of CM from CD14+ and DCs loaded with PTX strongly inhibits proliferation of U87 MG cells. CONCLUSIONS: Our results are the first demonstration that peripheral blood-derived CD14+ and DCs, in addition to their application for immunotherapy for GB, could also be used to delivery anti-cancer drugs, such as PTX, to kill GB cells. PMID- 25457278 TI - Phenotypic characterization and anti-tumor effects of cytokine-induced killer cells derived from cord blood. AB - BACKGROUND AIMS: Cytokine-induced killer (CIK) cell therapy represents a feasible immunotherapeutic option for treating malignancies. However, the number of anti tumor lymphocytes cannot be easily obtained from the cancer patients with poor immunity status, and older patients cannot tolerate repeated collection of blood. Cord blood-derived CIK (CB-CIK) cells have shown efficacy in treating the patients with cancer in several clinical trials. This study was conducted to evaluate the biological characteristics and anti-tumor function of CB-CIK cells. METHODS: The immunogenicity, chemokine receptors and proliferation of CB-CIK cells were analyzed by flow cytometry. The CIK cells on day 13 were treated with cisplatin and the anti-apoptosis capacity was analyzed. The function of CB-CIK cells against the human cancer was evaluated both in vitro and in vivo. RESULTS: Compared with peripheral blood-derived CIK (PB-CIK) cells, CB-CIK cells demonstrated lower immunogenicity and increased proliferation rates. CB-CIK cells also had a higher percentage of main functional fraction CD3(+)CD56(+). The anti apoptosis ability of CB-CIK cells after treatment with cisplatin was higher than that of PB-CIK cells. Furthermore, CB-CIK cells were effective for secreting interleukin-2 and interferon-gamma and a higher percentage of chemokine receptors CCR6 and CCR7. In addition, tumor growth was greatly inhibited by CB-CIK treatment in a nude mouse xenograft model. CONCLUSIONS: CB-CIK cells exhibit more efficient anti-tumor activity in in vitro analysis and in the preclinical model and may serve as a potential therapeutic approach for the treatment of cancer. PMID- 25457279 TI - Effect of 17beta-estradiol on mediators involved in mesenchymal stromal cell trafficking in cell therapy of diabetes. AB - BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) have shown great promise for cell therapy of a wide range of diseases such as diabetes. However, insufficient viability of transplanted cells reaching to damaged tissues has limited their potential therapeutic effects. Expression of estrogen receptors on stem cells may suggest a role for 17beta-estradiol (E2) in regulating some functions in these cells. There is evidence that E2 enhances homing of stem cells. Induction of hypoxia-inducible factor-1alpha (HIF-1alpha) by E2 and the profound effect of HIF 1alpha on migration of cells have previously been demonstrated. We investigated the effect of E2 on major mediators involved in trafficking and subsequent homing of MSCs both in vitro and in vivo in diabetic rats. METHODS: E2 has been selected to improve the poor migration capacity of MSCs toward sites of injury. MSCs were incubated with different concentrations of E2 for varying periods of time to investigate whether estradiol treatment could be effective to enhance the efficiency of MSC transplantation. RESULTS: E2 significantly enhanced the viability of the cells that were blocked by ICI 182,780 (estrogen receptor antagonist). E2 also increased HIF-1alpha, CXC chemokine receptor 4 and C-C chemokine receptor 2 protein and messenger RNA levels measured by Western blot and reverse transcription-polymerase chain reaction. The enzymatic activity of matrix metalloproteinase 2 and metalloproteinase 9 was elevated in E2-treated cells through the use of gelatin zymography. Finally, the improved migration capacity of E2-treated MSCs was evaluated with the use of a Boyden chamber and in vivo migration assays. CONCLUSIONS: Our data support that conditioning of MSCs with E2 promotes migration of cells in cultured MSCs in vitro and in a diabetic rat model in vivo through regulation of major mediators of cell trafficking. PMID- 25457280 TI - Human adipose-derived mesenchymal stromal cells increase endogenous neurogenesis in the rat subventricular zone acutely after 6-hydroxydopamine lesioning. AB - BACKGROUND AIMS: In Parkinson's disease (PD), neurogenesis in the subventricular zone (SVZ)-olfactory bulb (OB) axis is affected as the result of the lack of dopaminergic innervations reaching the SVZ. This aberrant network has been related to the hyposmia of PD patients, which is an early diagnostic marker of the disease. Consequently, much interest arose in finding mechanisms to modulate the SVZ-OB axis. Direct modulation of this axis could be achieved by transplantation of mesenchymal stromal cells (MSC), as it has been shown in rat and mouse PD models. However, the neurogenic effect of MSC in PD was thus far only analyzed weeks after transplantation, and little is known about effects immediately after transplantation. METHODS: We assessed the acute neuroprotective and neurogenic effects of adipose-derived MSC transplanted into the rat substantia nigra in the 6-hydroxydopamine model of PD. RESULTS: Three days after transplantation, subventricular neurogenesis was significantly increased in MSC transplanted versus non-transplanted animals. Most MSC were found in the region of the substantia nigra and the surrounding arachnoid mater, expressing S100beta and brain-derived neurotrophic factor, whereas some MSC showed an endothelial phenotype and localized around blood vessels. CONCLUSIONS: The acute neurogenic effects and neurotrophic factor expression of MSC could help to restore the SVZ OB axis in PD. PMID- 25457281 TI - Chelation in metal intoxication--Principles and paradigms. AB - The present review provides an update of the general principles for the investigation and use of chelating agents in the treatment of intoxications by metals. The clinical use of the old chelators EDTA (ethylenediamine tetraacetate) and BAL (2,3-dimercaptopropanol) is now limited due to the inconvenience of parenteral administration, their own toxicity and tendency to increase the neurotoxicity of several metals. The hydrophilic dithiol chelators DMSA (meso-2,3 dimercaptosuccinic acid) and DMPS (2,3-dimercapto-propanesulphonate) are less toxic and more efficient than BAL in the clinical treatment of heavy metal poisoning, and available as capsules for oral use. In copper overload, DMSA appears to be a potent antidote, although d-penicillamine is still widely used. In the chelation of iron, the thiols are inefficient, since iron has higher affinity for ligands with nitrogen and oxygen, but the new oral iron antidotes deferiprone and desferasirox have entered into the clinical arena. Comparisons of these agents and deferoxamine infusions are in progress. General principles for research and development of new chelators are briefly outlined in this review. PMID- 25457282 TI - Cadmium, lead and mercury concentrations and their influence on morphological parameters in blood donors from different age groups from southern Poland. AB - Due to industrial development, environmental contamination with metals increases which leads to higher human exposure via air, water and food. In order to evaluate the level of the present exposition, the concentrations of metals can be measured in such biological materials as human blood. In this study, we assessed the concentrations of cadmium (Cd), mercury (Hg) and lead (Pb) in blood samples from male blood donors from southern Poland (Europe) born in 1994 (n=30) and between 1947 and 1955 (n=30). Higher levels of Pb were seen in the group of older men (4.48 vs 2.48MUg/L), whereas the Hg levels were lower (1.78 vs 4.28MUg/L). Cd concentrations did not differ between age groups (0.56MUg/L). The levels of Cd and Pb in older donors were significantly correlated (Spearman R 0.5135). We also observed a positive correlation between the number of red blood cells (RBC) and Hg concentrations in the older group (Spearman R 0.4271). Additionally, we noted numerous correlations among morphological parameters. Based on our results, we can state that metals influence the blood morphology and their concentrations in blood vary among age groups. PMID- 25457283 TI - Potential neurochemical links between cholesterol and suicidal behavior. AB - The role of cholesterol in psychiatric diseases has aroused the interest of the medical community, particularly in association with violent and suicidal behavior. Herein, we discuss some aspects of brain cholesterol metabolism, exploring possible mechanisms underlying the findings and reviewing the available literature on the possible neurochemical link between suicide and low or reduced levels of serum cholesterol. Most of the current hypotheses suggest a decreased serotonergic activity due to a decrease in cholesterol in the lipid rafts of synaptic membranes. Some aspects and limitations of this assumption are emphasized. In addition to serotonin hypofunction, other mechanisms have been proposed to explain increased impulsivity in suicidal individuals, including steroid modulation and brain-derived neurotrophic factor decrease, which could also be related to changes in lipid rafts. Other putative markers of suicidal behavior (e.g. protein S100B) are discussed in connection with cholesterol metabolism in the brain tissue. PMID- 25457284 TI - Stigma, discrimination and medication adherence in schizophrenia: results from the Swedish COAST study. AB - The aims of this naturalistic non-interventional study were to quantify the level of stigma and discrimination in persons with schizophrenia and to test for potential associations between different types of stigma and adherence to antipsychotics. Antipsychotic medication use was electronically monitored with a Medication Event Monitoring System (MEMS(r)) for 12 months in 111 outpatients with schizophrenia and schizophrenia-like psychosis (DSM-IV). Stigma was assessed at endpoint using the Discrimination and Stigma Scale (DISC). Single DISC items that were most frequently reported included social relationships in making/keeping friends (71%) and in the neighborhood (69%). About half of the patients experienced discrimination by their families, in intimate relationships, regarding employment and by mental health staff. Most patients (88%) wanted to conceal their mental health problems from others; 70% stated that anticipated discrimination resulted in avoidance of close personal relationships. Non adherence (MEMS(r) adherence<=0.80) was observed in 30 (27.3%). When DISC subscale scores (SD) were entered in separate regression models, neither experienced nor anticipated stigma was associated with adherence. Our data do not support an association between stigma and non-adherence. Further studies in other settings are needed as experiences of stigma and levels of adherence and their potential associations might vary by a healthcare system or cultural and sociodemographic contexts. PMID- 25457286 TI - It is all in a name ... and the name brings us new opportunities. PMID- 25457287 TI - Implementing the 'No One Dies Alone program': process and lessons learned. PMID- 25457288 TI - Changes to hospice attending physician rules. PMID- 25457285 TI - The association between unilateral heel-rise performance with static and dynamic balance in community dwelling older adults. AB - As a measure of both strength and muscle endurance of the plantar flexors, the unilateral heel rise (UHR) test has been suggested as a method to evaluate balance capabilities in older adults. Thus, the purpose of this study was to examine the association between UHR performance with biomechanical measures of balance in seniors. Twenty-two older adults completed two testing sessions. The first visit included UHR performance; the second visit included dynamic and static motion analysis. UHR performance was significantly associated with dynamic balance capability as measured by medial-lateral inclination angle during gait. As indicated by an analysis of center of pressure, there were significant associations between UHR performance and measures of static balance. Balance is influenced by plantar flexor performance as measured by the UHR test. We therefore suggest incorporating the UHR test in analyses of balance in seniors. PMID- 25457289 TI - The perfect INTERACTions to reduce hospitalizations. PMID- 25457290 TI - A new class of sedative/hypnotics: dual orexin receptor antagonists. PMID- 25457291 TI - Correlates of wellness among youth with functional disabilities. AB - BACKGROUND: The literature is more informative on the impediments to wellness among youth with functional limitations and less instructive on the state of wellness for this population. OBJECTIVE: To explore overall wellness, and each sub-dimension of wellness, in a national sample of youth with functional limitations and to determine how demographic characteristics are associated with wellness. METHODS: Using a previously validated screening instrument, we identify youth with functional limitations aged 12 to 17 represented in the 2011/12 National Survey of Children's Health. Survey items were coded to operationalize an overall wellness score comprised of four sub-dimensions of wellness (i.e., physical, intellectual, emotional, and social). RESULTS: The mean overall wellness score was 26.7 (out of 40) and had an approximate normal distribution. Mean raw scores for each sub-dimension were as follows: social = 2.79 (out of 4; 69.7%); emotional = 4.09 (out of 6; 68.2%); intellectual = 3.79 (out of 8; 47.4%); and physical = 6.30 (out of 8; 78.7%). Lower wellness scores were associated with older age among youth, increasing number of chronic health conditions, lower income, single mother homes, and youth whose mother reported fair or poor mental health status (all p < 0.05). Higher wellness scores were positively associated with mother's education (p < 0.001). CONCLUSIONS: Program planners should consider interventions that target youth with functional limitations shown to be at particular risk for lower overall wellness and promote family involvement and comprehensive supports, including maternal educational attainment, mental health screening, and referral. PMID- 25457292 TI - Dynamic inversion enables external magnets to concentrate ferromagnetic rods to a central target. AB - The ability to use magnets external to the body to focus therapy to deep tissue targets has remained an elusive goal in magnetic drug targeting. Researchers have hitherto been able to manipulate magnetic nanotherapeutics in vivo with nearby magnets but have remained unable to focus these therapies to targets deep within the body using magnets external to the body. One of the factors that has made focusing of therapy to central targets between magnets challenging is Samuel Earnshaw's theorem as applied to Maxwell's equations. These mathematical formulations imply that external static magnets cannot create a stable potential energy well between them. We posited that fast magnetic pulses could act on ferromagnetic rods before they could realign with the magnetic field. Mathematically, this is equivalent to reversing the sign of the potential energy term in Earnshaw's theorem, thus enabling a quasi-static stable trap between magnets. With in vitro experiments, we demonstrated that quick, shaped magnetic pulses can be successfully used to create inward pointing magnetic forces that, on average, enable external magnets to concentrate ferromagnetic rods to a central location. PMID- 25457294 TI - Medical tourism: new strategies for the health care industry in Taiwan. PMID- 25457293 TI - Leisure activities, apolipoprotein E e4 status, and the risk of dementia. AB - BACKGROUND/PURPOSE: Leisure activities have been associated with a decreased risk of dementia. However, to date, no study has explored how apolipoprotein E (ApoE) e4 status or vascular risk factors modified the association between leisure activities and dementia risks. METHODS: This case-control study recruited patients (age >= 60 years) with Alzheimer's disease (AD; n = 292) and vascular dementia (VaD; n = 144) and healthy controls (n = 506) from three teaching hospitals in Taiwan between 2007 and 2010. Information on patient's leisure activities were obtained through a questionnaire. Conditional logistic regression models were used to assess the association of leisure activities and ApoE e4 status with the risk of dementia. RESULTS: High-frequency physical activity was associated with a decreased risk of AD [adjusted odds ratio (AOR) = 0.45], and the results become more evident among ApoE e4 carriers with AD (AOR = 0.30) and VaD (AOR = 0.26). Similar findings were observed for cognitive (AOR = 0.42) and social activities (AOR = 0.55) for AD. High-frequency physical, cognitive, and social activities were associated with a decreased risk of VaD (AOR = 0.29-0.60). Physical and social activities significantly interacted with each other on the risk of VaD (pinteraction = 0.04). CONCLUSION: Physical activity consistently protects against AD and VaD. Significant interactions were identified across different types of leisure activities in lowering dementia risk. PMID- 25457295 TI - Ovarian Vein Diameter Cannot Be Used as an Indicator of Ovarian Venous Reflux. AB - OBJECTIVES: Previous research into pelvic venous reflux has suggested that the size of the ovarian veins indicates the presence or absence of reflux. It is already known that vessel diameter is not an indicator of reflux in the great saphenous vein. However, to this day, physicians still use vein size to plan treatment of refluxing ovarian veins. The authors aimed to investigate whether or not vessel diameter can be used as an indicator of reflux in the ovarian veins. METHODS: Nineteen female patients (mean 40.2 years, range 29-60) presenting to a specialist vein unit with leg varicose veins underwent duplex ultrasonography (DUS). All were found to have a significant pelvic contribution to their leg reflux on transvaginal duplex ultrasonography (TVS) and were referred to an interventional radiologist for treatment by transjugular coil embolization. During the procedure, the diameter of the ovarian veins was measured using digital subtraction venography. RESULTS: Thirty-four ovarian veins were measured (17 right, 17 left) and of these 18 were found to be non-refluxing while 16 displayed reflux. The mean diameter of the non-refluxing veins was 7.2 mm (range 3-13 mm)and that of the refluxing veins was 8.5 mm (range 4-13 mm). This difference was found to be insignificant at a 95% confidence level (Student t test, p = .204). CONCLUSIONS: There is no significant difference between the diameters of competent and refluxing ovarian veins and, as such, techniques that measure vein diameter may not be suitable for the diagnosis of venous reflux in the ovarian veins. PMID- 25457296 TI - Three-dimensional computed tomographic reconstruction of the carotid artery: identifying high bifurcation. AB - OBJECTIVE: To investigate variability in the level of bifurcation relative to other anatomical landmarks on computed tomography (CT) and to develop an objective and reproducible technique for identifying patients with a high carotid bifurcation who might therefore be at greater risk of operative complications. METHODS: This was a retrospective cross-sectional, imaging study. A series of 86 nonselected consecutive CT carotid angiograms (172 arteries) were analysed. Using three-dimensional reconstructive software, the curved length (CL) of the internal carotid artery (ICA) and the straight-line distance (SLD) from the bifurcation to the base of skull was measured for 140 carotid arteries. The tortuosity index (TI) of each ICA was calculated by dividing CL by SLD. The relationship of the bifurcation to eight anatomical landmarks in the neck was assessed in order to identify a landmark that could act as a surrogate marker of high carotid bifurcation. The landmarks examined were the angle of mandible, greater horn of hyoid, body of hyoid, upper margin of thyroid cartilage, cervical vertebrae, mastoid process, sternoclavicular joint, and sternal notch. RESULTS: The median curved length of the ICA was 80.4 mm (range 58.0-129.0 mm). The median distance of bifurcation from the base of the skull was 72.7 mm (range 58.1-98.1 mm). There was excellent interobserver agreement in measuring SLD, with an intraclass correlation coefficient of 0.993 (p = .00). The median tortuosity index was 1.12 (range 1.01-1.64). Distance from the mastoid process had the greatest correlation with high bifurcation; Pearson's correlation coefficient of 0.894 (two-tailed p = .00). Bifurcations within 5 cm of the mastoid process are likely to be in the highest quartile (82.9% sensitive, 80.1% specific). CONCLUSIONS: Measuring the distance of carotid bifurcation from the base of the skull (SLD), a measure previously not well defined, may be useful in predicting difficult neck dissection and endarterectomy. A distance from mastoid of <= 5 cm may also alert the surgeon to potential difficulties. PMID- 25457297 TI - Response to 'Re. Spontaneous Delayed Sealing in Selected Patients with a Primary Type-Ia Endoleak After Endovascular Aneurysm Repair'. PMID- 25457298 TI - Galectin-3, Carotid Plaque Vulnerability, and Potential Effects of Statin Therapy. AB - OBJECTIVES: Galectin-3, a member of galectines, a family of b-galactoside specific lectins, has been reported to propagate vascular inflammation. The role of galectin-3 in carotid atherosclerosis is controversial. The aim of this study was to investigate the relationship of galectin-3 with plaque vulnerability in patients with high grade carotid stenosis. METHODS: This was a cross sectional study of patients undergoing carotid endarterectomy (CEA). Carotid plaques obtained from 78 consecutive patients (40 symptomatic [SG], 38 asymptomatic [AG]) undergoing CEA were histologically analyzed for galectin-3, macrophages (CD68) and laminin. Pre-operatively the biochemical profile and plaque echogenicity (gray-scale median, GSM) score were determined. RESULTS: There were no significant differences in clinical and demographic parameters between SG and AG(p > .05). The SG had a lower GSM score (44.21 +/- 18.24 vs. 68.79 +/- 28.79, p < .001) and a smaller positive stained area for galectin-3 (4.89 +/- 1.60% vs. 12.01 +/- 5.91%, p < .001) and laminin (0.88 +/- 0.71% vs. 3.46 +/- 2.12%, p < .001) than the AG. On the other hand, intra-plaque macrophage content was increased in SG (p < .001). For the whole cohort, symptomatic status was independently associated with intra-plaque contents of both galectin-3 (OR=0.634, p < .001), and GSM score (OR=0.750, p < .001). Notably, patients on long term statin treatment had elevated galectin-3 and lowered macrophage intra-plaque concentrations compared with those on short term treatment (p < .05). CONCLUSIONS: A low galectin-3 intra-plaque concentration seems to correlate with clinically and ultrasonically defined unstable human carotid plaques. Long term statin treatment may induce increase of intra-plaque galectin-3 concentration mediating plaque stabilization. PMID- 25457300 TI - Beneficial Effects of Pre-operative Exercise Therapy in Patients with an Abdominal Aortic Aneurysm: A Systematic Review. AB - OBJECTIVE/BACKGROUND: The impact of post-operative complications in abdominal aortic aneurysm (AAA) surgery is substantial, and increases with age and concomitant co-morbidities. This systematic review focuses on the possible effects of pre-operative exercise therapy (PET) in patients with AAA on post operative complications,aerobic capacity, physical fitness, and recovery. METHODS: A systematic search on PET prior to AAA surgery was conducted. The methodological quality of the included studies was rated using the Physiotherapy Evidence Database scale. The agreement between the reviewers was assessed with Cohen's kappa. RESULTS: Five studies were included, with a methodological quality ranging from moderate to good. Cohen's kappa was 0.79. Three studies focused on patients with an AAA (without indication for surgical repair) with physical fitness as the outcome measure. One study focused on PET in patients awaiting AAA surgery and one study focused on the effects of PET on post-operative complications, length of stay, and recovery. CONCLUSION: PET has beneficial effects on various physical fitness variables of patients with an AAA. Whether this leads to less complications or faster recovery remains unclear. In view of the large impact of post-operative complications, it is valuable to explore the possible benefits of a PET program in AAA surgery. PMID- 25457299 TI - Detection of Peripheral Arterial Disease Within the Foot Using Vascular Optical Tomographic Imaging: A Clinical Pilot Study. AB - OBJECTIVE: Vascular optical tomographic imaging (VOTI) is a novel imaging modality that is capable of detecting hemoglobin concentrations in tissue. VOTI is non-invasive, non-ionizing and does not require contrast injection. This technology was applied to the diagnosis of peripheral arterial disease (PAD) within lower extremities of diabetic patients with calcified arteries. This could be of substantial benefit as these patients suffer from comorbidities such as arterial incompressibility, which complicates diagnosis and monitoring. METHODS: Forty individuals (10 non-diabetic patients with PAD, 10 diabetic patients with PAD, and 20 healthy volunteers) were enrolled in a diagnostic pilot study using the VOTI system. The patients were imaged during at high pressure cuff occlusion. RESULTS: The VOTI system was capable of quantifying the blood volume changes within the foot during the thigh cuff occlusion and outputting diagnostic parameters, such as change in hemoglobin concentration, enabling the assessment of foot perfusion. This study resulted in a statistically significant difference between the healthy cohort and both the non-diabetic and the diabetic PAD cohorts (p = .006, p = .006). Receiver operating characteristic (ROC) curve analysis showed that PAD diagnosis could be made with over 80% sensitivity or specificity depending on the characteristic cutoff point. In addition, VOTI was capable of providing the locations of under-perfused regions within the foot and evaluating the severity of arterial disease, even within diabetic patients with calcified arteries, who are traditionally difficult to diagnose. CONCLUSION: VOTI can effectively diagnose PAD independently of arterial compressibility, making it very useful for assessing vascular disease in diabetic patients. PMID- 25457301 TI - Middle East respiratory syndrome coronavirus (MERS-CoV): prevention in travelers. AB - Middle East respiratory syndrome coronavirus (MERS-CoV), a novel coronavirus that causes a severe lower respiratory tract infection in humans, emerged in the Middle East in 2012. Since then, MERS-CoV has caused an ongoing epidemic in the Arabian Peninsula with sporadic cases imported in Europe, North Africa, Southeast Asia, and the United States of America. As of 28th May 2014, 636 laboratory confirmed cases of infection with MERS-CoV have been reported to World Health Organization including 14 cases imported by travelers. The epicenter of the current MERS-CoV epidemic is located in Saudi Arabia, where millions of pilgrims travel for two mass gatherings annually. In this review we summarize MERS-CoV cases in relation to travel with focus on the epidemiology and prevention in travelers. It is important to increase awareness of travelers about the risks and appropriate preventive measures and for health professionals to be on alert if a patient with severe respiratory symptoms reports a recent history of travel to the region affected with MERS-CoV. Measures should be taken by local health authorities of the affected countries in order to improve hospital hygiene. Finally, it is crucial to investigate the reasons for travelers' poor compliance with rules and recommendations issued by Saudi officials and to take appropriate measures in order to improve them. PMID- 25457302 TI - An overview: tularemia and travel medicine. AB - Tularemia is a bacterial zoonotic infection. The disease is endemic in most parts of the world, has been reported through the northern hemisphere between 30 and 71 degrees N latitude. Francisella tularensis causes infection in a wide range of vertebrates (rodents, lagomorphs) and invertebrates (ticks, mosquitoes and other arthropods). Humans can acquire this infection through several routes including; a bite from an infected tick, deerfly or mosquito, contact with an infected animal or its dead body. It can also be spread to human by drinking contaminated water or breathing contaminated dirt or aerosol. Clinical manifestation of this disease varies depending on the biotype, inoculum and port of entry. Infection is potentially life threatening, but can effectively be treated with antibiotics. Travelers visiting rural and agricultural areas in endemic countries may be at greater risk. Appropriate clothing and use of insect repellants is essential to prevent tick borne illness. Travelers also should be aware of food and waterborne disease; avoid consuming potentially contaminated water and uncooked meat. Physicians should be aware of any clinical presentation of tularemia in the patients returning from endemic areas. PMID- 25457304 TI - Factors associated with non-use of condoms in an online community of frequent travellers. AB - BACKGROUND: Millions of travellers around the world have gathered together into online communities. The objective is to analyse the factors associated with risky sexual behaviour among travellers. METHODS: Cross-sectional study was conducted within an online community of travellers using an online survey; we included travellers who had engaged in sexual activity while on their last trip. Risky sexual behaviour was defined as inconsistent condom use (<100%), and the factors associated were evaluated using the prevalence ratio (PR). RESULTS: Of the 468 participants, 245 had sex during their last trip. 59.7% did not consistently use condoms, and one out of every four participants reported never using condoms. Having a travel destination of Latin America or the Caribbean was significantly associated with inconsistent condom use. This association was maintained (PR 1.37, CI 95% 1.06-1.77) after adjusting for gender, age, migration, the presence of travel partners, and the use of drugs and alcohol prior to sexual activity. CONCLUSION: An association was observed between travel destination (specifically Latin America or the Caribbean) and risky sexual behaviour. For this reason, tourists should be educated in STI transmission and regional STI and HIV incidences both before and during their travels; public health systems ought to work together with travel agencies, international airports, etc., in order to distribute this information and ensure a responsible travel experience. PMID- 25457303 TI - Brucellar epididymo-orchitis: a retrospective multicenter study of 28 cases and review of the literature. AB - OBJECTIVE: To review retrospectively the clinical symptoms, laboratory findings and treatment outcomes of patients with Brucellar epididymo-orchitis. MATERIAL AND METHOD: Retrospective data of 28 patients with Brucellar epididymo-orchitis who admitted to four medical centers between 2005 and 2013 were retrospectively reviewed. Positive blood culture, positive Rose Bengal test results or high agglutination titres of >= 1/160 with the positive clinical and ultrasonographic findings of orchitis were accepted as the main criteria for Brucellar epididymo orchitis. RESULTS: The mean patient age was 31 +/- 16.9 years. Testicular involvement was on the left side in 16 patients and on the right side in 11 patients, one had bilateral disease. Testicular pain and swelling were the most common symptoms and elevation of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and leucocytosis were the most common laboratory findings. Initial treatment was orchidectomy in six patients due to malignancy suspicion. All but three patients were successfully treated with antibiotic combinations of rifampicin, doxycycline and streptomycin. Two of three treatment resistant patients underwent orchidectomy. CONCLUSION: Brucellosis is a common cause of epididymo-orchitis in endemic regions. Early diagnosis and treatment is crucial in the management and thus it must be kept in mind in endemic and non endemic regions. PMID- 25457305 TI - Chronic illnesses in travelers to developing countries. AB - BACKGROUND: Data regarding travelers with chronic illnesses (TCI) traveling to developing countries is limited. METHODS: A retrospective cohort study of travelers. We analyzed demographics, travel destinations, travel dates and duration, as well as the medical history (chronic illnesses, chronic medications, and allergies) of the travelers. RESULTS: Of 16,681 travelers evaluated, 3046 (18%) were TCI, of who, 2221 (13%) were taking chronic medications. The percentage of TCI ranged from 4% in the first decade of life to 65% in the 8th decade. The highest number of TCI (1085) was among the 20-30 years age group. The median age (IQR) of TCI was 39.0 (23.1-58.2), compared to 24.2 (22.0-32.1) years, of healthy travelers (p < 0.001). The major pre-existing medical conditions among TCI were endocrine/metabolic (38%), cardiovascular (26%) and pulmonary illnesses (16%). Within age groups, no difference was found in itinerary and other travel characteristics. However, 20-30 years old TCI, who were using chronic medications had significantly shorter travel duration (P < 0.001). CONCLUSIONS: TCI form a significant proportion of travelers among all age groups and travel destinations. Chronic illnesses appear to have little impact on travel itinerary and characteristics, but chronic medication use is associated with shorter travel duration to developing countries. PMID- 25457306 TI - Ingestion of oats and barley in patients with celiac disease mobilizes cross reactive T cells activated by avenin peptides and immuno-dominant hordein peptides. AB - Celiac disease (CD) is a common CD4(+) T cell mediated enteropathy driven by gluten in wheat, rye, and barley. Whilst clinical feeding studies generally support the safety of oats ingestion in CD, the avenin protein from oats can stimulate intestinal gluten-reactive T cells isolated from some CD patients in vitro. Our objective was to establish whether ingestion of oats or other grains toxic in CD stimulate an avenin-specific T cell response in vivo. We fed participants a meal of oats (100 g/day over 3 days) to measure the in vivo polyclonal avenin-specific T cell responses to peptides contained within comprehensive avenin peptide libraries in 73 HLA-DQ2.5(+) CD patients. Grain cross-reactivity was investigated using oral challenge with wheat, barley, and rye. Avenin-specific responses were observed in 6/73 HLA-DQ2.5(+) CD patients (8%), against four closely related peptides. Oral barley challenge efficiently induced cross-reactive avenin/hordein-specific T cells in most CD patients, whereas wheat or rye challenge did not. In vitro, immunogenic avenin peptides were susceptible to digestive endopeptidases and showed weak HLA-DQ2.5 binding stability. Our findings indicate that CD patients possess T cells capable of responding to immuno-dominant hordein epitopes and homologous avenin peptides ex vivo, but the frequency and consistency of these T cells in blood is substantially higher after oral challenge with barley compared to oats. The low rates of T cell activation after a substantial oats challenge (100 g/d) suggests that doses of oats commonly consumed are insufficient to cause clinical relapse, and supports the safety of oats demonstrated in long-term feeding studies. PMID- 25457312 TI - Anterior Combined Endopelvic (ACE) approach for the treatment of acetabular and pelvic ring fractures: A new proposal. AB - PURPOSE: We present our experience of using the Anterior Combined Endopelvic (ACE) approach, which consists of a combination of a newly modified Stoppa approach with the lateral approach to the iliac crest. This approach is discussed in terms of fracture reduction and fixation, technical aspects, and the incidence of complications, and as an alternative to the ilioinguinal approach for the treatment of acetabular fractures. METHODS: A consecutive group of 34 adult patients with acetabular fractures treated surgically with the ACE approach was compared with a group of 42 adult patients treated with the ilioinguinal approach between 2010 and 2013. Both approaches were performed by a single surgeon to fix the acetabular fractures with main anterior displacement and the anterior and lateral parts of the pelvis. All the patients were analysed with typical X-ray projections for acetabular fractures and CT-scan. Charts and radiographs were reviewed for fracture pattern. Operative time, blood loss, quality of reduction, functional outcomes and perioperative complications were compared between the two groups of patients. RESULTS: The mean follow-up of patients was 26 months (range 6-49 months), with a median of 24.5 months. The types of acetabular fraction in the study were as follows: 32 anterior and posterior columns, 18 anterior columns, 10 anterior columns with posterior hemitransverse, 10 transverse associated with posterior walls, two transverse; two T-Type transverse and two anterior walls. Average blood loss was 1090 mL in the ACE group and 1200 mL in the ilioinguinal group. Anatomic or satisfactory reduction was achieved in 94% of the acetabular fractures. Two patients (one in each group) had mild symptoms of the lateral femoral cutaneous nerve and improved within 4-6 months; one patient in the ilioinguinal group developed ossification Brooks grade III. CONCLUSION: The ACE approach for the treatment of acetabular fractures is highly recommended when the fracture involves the quadrilateral surface and anterior column. This approach provides a direct good-to-excellent visualisation and access to the entire fracture, which makes reduction and fixation easier. The clinical outcomes were slightly better with ACE compared with the ilioinguinal approach. Complication rate was similar in the two groups. The ACE technique is a viable alternative to the ilioinguinal approach when exposure of the anterior acetabulum is required. PMID- 25457313 TI - A sneaky surgical emergency: Acute compartment syndrome. Retrospective analysis of 66 closed claims, medico-legal pitfalls and damages evaluation. AB - BACKGROUND: Acute compartment syndrome (ACS) is a clinical condition with potentially dramatic consequences, therefore, it is important to recognise and treat it early. Good management of ACS minimises or avoids the sequelae associated with a late diagnosis, and may also reduce the risk of malpractice claims. The aim of this article was to evaluate different errors ascribed to the surgeon and to identify how the damage was evaluated. MATERIALS AND METHODS: A total of 66 completed and closed ACS cases were selected. The following were analysed for each case: clinical management before and after diagnosis of ACS, imputed errors, professional fault, damage evaluation and quantification. Particular attention was paid to distinguishing between impairment because of primary injury and iatrogenic impairment. Statistical analyses were performed using Fisher's exact test and Pearson's correlation. RESULTS: The most common presenting symptom was pain. Delay in the diagnosis, and hence delay in decompression, was common in the study. A total of 48 out of 66 cases resolved with the verdict of iatrogenic damage, which varied from 12% to 75% of global capability of the person. A total of $394,780 out of $574,680 (average payment) derived from a medical error. CONCLUSIONS: ACS is a clinical emergency that requires continuous clinical surveillance from both medical and nursing staff. The related damage should be evaluated in two parts: damage deriving from the trauma, so that it is considered inevitable and independent from the surgeon's conduct, and damage deriving from a surgeon's error, which is eligible for an indemnity payment. PMID- 25457307 TI - Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells. AB - Regulatory T cells (Tregs) expressing FOXP3 are essential for the maintenance of self-tolerance and are deficient in many common autoimmune diseases. Immune tolerance is maintained in part by IL-2 and deficiencies in the IL-2 pathway cause reduced Treg function and an increased risk of autoimmunity. Recent studies expanding Tregs in vivo with low-dose IL-2 achieved major clinical successes highlighting the potential to optimize this pleiotropic cytokine for inflammatory and autoimmune disease indications. Here we compare the clinically approved IL-2 molecule, Proleukin, with two engineered IL-2 molecules with long half-lives owing to their fusion in monovalent and bivalent stoichiometry to a non-FcRgamma binding human IgG1. Using nonhuman primates, we demonstrate that single ultra-low doses of IL-2 fusion proteins induce a prolonged state of in vivo activation that increases Tregs for an extended period of time similar to multiple-dose Proleukin. One of the common pleiotropic effects of high dose IL-2 treatment, eosinophilia, is eliminated at doses of the IL-2 fusion proteins that greatly expand Tregs. The long half-lives of the IL-2 fusion proteins facilitated a detailed characterization of an IL-2 dose response driving Treg expansion that correlates with increasingly sustained, suprathreshold pSTAT5a induction and subsequent sustained increases in the expression of CD25, FOXP3 and Ki-67 with retention of Treg-specific epigenetic signatures at FOXP3 and CTLA4. PMID- 25457314 TI - Is it really necessary to restore radial anatomic parameters after distal radius fractures? AB - Small variations within normal range of radiographic parameters, except ulnar variance and volar tilt, do not influence the final functional outcome in distal radius fractures. INTRODUCTION: There are many reports in the literature on the relationship between radiographic variables and their influence on the final outcome of distal radius fractures. Most authors report that a good functional result depends on anatomical restoration of the articular surface and extra articular alignment. The aim of this study was to verify if it is really necessary to restore anatomic radiographic parameters to obtain satisfactory functional outcome in distal radius fractures treated with volar plate. MATERIALS AND METHODS: We retrospectively evaluated 51 patients treated with volar locked plate for articular unstable distal radius fractures from December 2006 to March 2009. Each fracture was evaluated according to the AO classification. The average follow-up was 40.5 months. Radiological measurements were performed considering radial height, radial inclination, volar tilt and ulnar variance, both preoperatively and postoperatively, to estimate the correction value. We examined range of motion (ROM), grip strength with a Jamar((r)) dynamometer and Disabilities of the Arm, Shoulder and Hand (DASH) score. The tau Student test was performed for statistical analysis. RESULTS: The persistence of articular step off was assessed in 35.3% of patients. Normal radial inclination (21-25 degrees ) was restored in 74.5% of patients (range 15-27.5 degrees ). Normal radial height (10-13 mm) was restored in 66.6% of patients (range 6.8-17.3mm). Normal volar tilt (7-15 degrees ) was achieved in 90.2% of patients (range 3-17 degrees ). Normal ulnar variance (0.7-1.5mm) was restored in 86.3% of patients (range 0.7 4.1mm). There was a statistically significant difference between the preoperative and postoperative radiographic values (p<0.01). The majority of patients showed complete recovery of ROM, with no statistically significant difference (p>0.05) in extension, flexion, supination and pronation compared with the contralateral hand. Eight patients who had postoperative volar tilt and/or ulnar variance out of range had a statistically significant difference (p<0.05) in ROM compared with the non-operated side. At final follow-up, all patients had a statistically significant difference (p<0.05) in grip strength compared with the contralateral side, even with good strength values. The mean DASH score was 12.2 (range 0-61). DISCUSSION AND CONCLUSION: Our experience suggests that ulnar variance and volar tilt are the most important radiographic parameters to be restored to obtain good functional outcome in distal radius fracture. Small variations of other radiographic parameters seem to not affect the final outcome at minimum 3 years' follow-up. PMID- 25457315 TI - Micromotion in the fracture healing of closed distal metaphyseal tibial fractures: A multicentre prospective study. AB - The dynamic locking screw (DLS) in association with minimally invasive plate osteosynthesis (MIPO) in a bridging construct for simple metadiaphyseal long bone fractures enables modulation of the rigidity of the system and facilitates the development of early and triplanar bone callus. Twenty patients affected by distal tibial fracture were treated with MIPO bridging technique and DLS at the proximal side of the fracture. Time of consolidation, quality of the reduction, complications and American Orthopaedic Foot and Ankle Society (AOFAS) score were monitored and the results compared with those from a control group treated with only standard screws on both fracture sides. Student t-test for independent samples was used for the comparison of means between the two groups. Chi-square test was used for the comparison of proportions. A multiple logistic regression model was constructed to assess the possible confounding effects. Performance was considered significant for p<0.05. The mean healing time was 17.6 +/- 2.8 weeks in the group treated with standard screws and 13.5 +/- 1.8 weeks in the group treated with DLS (t=5.5, p<0.0001). The DLS was associated with early healing and triplanar bone callus. PMID- 25457316 TI - Preliminary experience with Piccolo CompositeTM, a radiolucent distal fibula plate, in ankle fractures. AB - The radiolucent plate has many advantageous properties in the treatment of complex ankle fractures, particularly trimalleolar fractures. Surgeons may sometimes have difficulty observing the posterior malleolus after synthesis of lateral malleolus with a traditional plate because common materials of conventional plates are not radiolucent. In this study, the authors highlight the importance of the radiolucent property in the treatment of ankle fractures and describe their preliminary experience with a carbon fibre-reinforced polyetheretherketone distal fibula plate, with good results at 4 months' follow up and no signs of tissue inflammatory reaction. PMID- 25457317 TI - Salter-Harris type III and IV displaced fracture of the hallux in young gymnasts: A series of four cases at 1-year follow-up. AB - The purpose of this study was to describe four exceptional cases of Salter-Harris type III and IV fractures of the proximal phalanx of the hallux in young high level gymnasts. All gymnasts underwent the same mechanism of injury of hyperadduction, which indicates a role of the abductor hallucis muscle in the genesis and displacement of these fractures. An open reduction and internal fixation was performed to achieve an anatomical reduction and avoid chronic disability. At 1-year follow-up, all patients had an excellent American Orthopaedic Foot and Ankle Society (AOFAS) score (100 points), and there was no shortening or angulation of the first ray and no evidence of degenerative joint disease on X-ray. Moreover, all the gymnasts had returned to pre-injury levels of sporting activity. To our knowledge, there are no previous studies that address these types of injuries and how they are handled in gymnasts. PMID- 25457318 TI - Fractures and fracture-dislocations of the proximal humerus: A retrospective analysis of 82 cases treated with the Philos((r)) locking plate. AB - OBJECTIVE: To present the experience in a single institution of the management of 82 consecutive fractures and fracture-dislocations of the proximal humerus treated with the Proximal Humeral Internal Locking System (Philos((r))) plate. MATERIALS AND METHODS: A total of 81 patients with 82 proximal humerus fractures (one patient had bilateral fracture) were treated at our institution with open reduction and internal fixation with Philos((r)) plate from January 2008 to December 2012 and the clinico-radiological outcome was analysed. Twelve of these patients also had a dislocation of the proximal humerus. According to the Neer classification, there were seven two-part fractures, 40 three-part fractures and 35 four-part fractures. All patients received a similar physical therapy programme following internal fixation. Mean final follow-up was 32 months. Functional outcome was evaluated for each patient using the Constant-Murley score; radiographic evaluation was also conducted and complications were recorded. RESULTS: At the end of the follow-up period, the mean Constant-Murley score for the injured side was 75 points (range 42-92); results were graded as excellent for eight patients, good for 52, moderate for 17 and poor for five. Twenty-three patients (28%) had complications during the follow-up period. Reoperation was required in 12 patients. Complications included avascular necrosis of the humeral head in 10 patients (12%), varus positioning of the head in four patients (4.8%), impingement syndrome in three patients (3.6%), secondary screw perforation in three patients (3.6%), non-union of the fracture in two patients (2.4%) and infection in one patient (1.2%). CONCLUSIONS: Open reduction and internal fixation of proximal humeral fractures with the Philos((r)) plate was associated with good clinical outcomes provided the correct surgical technique was used. To better evaluate the real incidence of complications, it is important to follow patients for more than one year after surgery as some complications may arise after this time. PMID- 25457319 TI - Indications and limitations of the fixator TGF "Gex-Fix" in proximal end humeral fractures. AB - The incidence of fractures of the humerus has increased exponentially in recent years. The most used classifications for humerus fracture are morphological (Neer), biological (AO/ASIF) and descriptive (Hertel). The types of surgical treatment for humerus fracture include prosthetic replacement and synthesis using different devices, including the Tension Guide Fixator (TGF), Gex-Fix. External fixation for displaced proximal humeral fractures avoids dissection and soft tissue stripping and has been reported by some authors to be associated with higher union rates, a lower incidence of avascular necrosis, less scarring of the scapulohumeral interface, and faster rehabilitation compared with open reduction and internal fixation. Other authors have reported that external fixation does not ensure acceptable reduction and fracture stability, particularly in patients with osteoporosis. The external fixation technique involves the introduction of Steinmann's pin to keep manual reduction, the introduction of two K-wires in the humeral head, the removal of the Steinmann's pin, and the introduction of two fiches on the humeral shaft. Hub connectors are mounted on the wires and on the chips to connect the outer bar and tensioning system. A total of 84 patients aged 42-84 years with proximal end humeral fractures (66% had two-part fractures) were treated with Fixator TGF in this study from December 2007 to June 2012. The postoperative recovery was earlier and the active-assisted motion was less painful than has been reported with other surgical techniques. The TGF was removed without anaesthesia at the outpatient clinic at a mean of 7 weeks (range 5-8 weeks) after surgery, and there was no loss of reduction or secondary displacement after removal. These results, after five years of experience, confirm that the best indication for this fixator is two- or three-part fractures because the device enables early active mobilisation. The limitations of this fixator are evident in fractures in which closed reduction is not possible and in three-part fractures with varus displacement because the TGF has less stability than other systems, such as the plate or cage. The short learning curve, reduced surgical time and risk, and low cost encourage the use of this technique. PMID- 25457320 TI - Hinged external fixation for complex fracture-dislocation of the elbow in elderly people. AB - The authors report their experience of treating complex elbow fracture dislocations in elderly people, using a minimally-invasive approach with a new articulated external fixator that is associated with minimal internal fixation. The clinical results for 19 patients are presented according to outcome factors, such as range of motion, pain and function, rate and type of complications, and reoperation rate. The results indicate that this treatment strategy should be considered as a good alternative to other treatment options reported in the literature, including conservative treatment, ORIF with angular stable plates and total elbow arthroplasty. PMID- 25457321 TI - Temporary bridging external fixation in distal tibial fracture. AB - Fractures that involve the distal area of the tibia are associated with a high percentage of complications. Soft tissue oedema, swelling, blisters, skin abrasions and open wounds could compromise the outcome of these lesions. The waiting time before surgery with ORIF is mostly due to soft tissue conditions. Early application of a simple joint-spanning external fixator would achieve the initial goal of stability and the respect of soft tissue, thereby decreasing the time necessary for definitive treatment. A total of 40 consecutive patients (22 male and 18 female) with a mean age of 52 years (range 17-82 years) with distal tibial fracture treated between January 2010 and January 2013 were evaluated. Early temporary external fixation was the first treatment step. Twenty patients had pilon fractures, characterised by the intra-articular involvement of the distal tibia with metaphyseal extension, and 20 patients had malleolar fracture dislocation. Patients were divided into two groups, A and B. Group A comprised 10 patients with ankle fracture-dislocation and bone fragmentation, who were treated with a temporary bridging external fixation that was maintained after ORIF to exploit ligamentotaxis during the first phases of bone healing. In Group B (30 patients), the external fixation was removed after ORIF. The results of the study are in line with the recent literature: temporary external fixation in high energy trauma and fracture-dislocation of the ankle enables soft tissue to be restored, which facilitates postoperative assessment of bone fragments by CT scan. The complication rate in this study was 5% in patients with malleolar fractures and 20% in patients with pilon fractures. The maintenance of temporary external fixation after ORIF synthesis during the entire first stage of bone healing seems to be a good method of treatment that has a low rate of soft tissue complications. PMID- 25457322 TI - Heel displaced intra-articular fractures treated with mini-calcaneal external fixator. AB - INTRODUCTION: Treatment of displaced heel fractures is controversial; however, ORIF is widely described in the literature to be the gold-standard. Percutaneous reduction and monolateral external fixation is gaining increasing attention because it provides a good and stable reduction, and minimises soft tissue complications due to open surgery, such as deep infections and delays in wound healing. The aim of this study was to show that the new Orthofix Calcaneal Minifixator (six pins) provides a greater stability than the four-pin version to enable a better and more stable reduction, an earlier weight-bearing (30 days) and improved functional outcomes. METHODS: A series of 69 consecutive closed heel intraarticular displaced fractures treated with the new Orthofix Calcaneal Minifixator were evaluated. Patients were assessed clinically with the Maryland Foot Score and radiologically with standard radiographs. RESULTS: The clinical results at follow-up were excellent in 37 cases (53.6%), good in 27 (39.2%), fair in two (2.9%) and poor in three (4.3%). The mean preoperative Bohler's angle was 5.2 (range 0-18) and the mean postoperative value was 28.5 (range 16-38). CONCLUSION: The excellent functional outcomes were despite some radiological images of imperfect posterior facet anatomical reduction and seemed to correlate with the use of a good and stable minimally-invasive surgical technique. This technique enabled early weight-bearing, minimised complications, respected the delicate biology of this anatomical site and restored the good heel volume and Bohler angle. PMID- 25457324 TI - Paediatric radial neck fractures: One-step percutaneous reduction and fixation. AB - INTRODUCTION: Dislocated radial neck fractures of the third and fourth degree, according to the Judet classification, are rare events in children. These fractures account for 1% of all paediatric fractures. Their relatively low incidence is inversely proportional to the serious morphofuntional alterations that can follow without treatment. MATERIALS AND METHODS: Nine paediatric patients with an average age of 9.1 years (range 6-12 years), with radial neck fractures of the third and fourth degree, according to the Judet classification, were treated between 2010 and 2011. All patients underwent percutaneous reduction and fixation using only one K-wire by the same surgeon in a surgery time of 20 min (range 15-25 min). The average follow-up was 26.6 months (range 12-36 months), with X-rays and clinical evaluations conducted at four time points. The results were assessed radiologically (Metaizeau classification) and clinically (Mayo Clinic Elbow Performance Score). RESULTS: X-ray results (according to Metaizeau) were excellent in eight cases and good in one case. Clinical results were excellent in all cases. There was only one minor complication: a superficial skin infection that was treated with an oral antibiotic. DISCUSSION: The purpose of this study was to evaluate the results achieved in our hospital with a percutaneous reduction and fixation technique using only one K-wire in children with dislocated radial neck fractures of the third and fourth degree. The results obtained indicate that a single percutaneous surgery act that circumvents further operations is the best option for these patients. CONCLUSION: Although the number of patients in the study was small, the results are encouraging and support the continued use of this one-step percutaneous reduction and fixation technique. PMID- 25457323 TI - Balloon-assisted reduction, pin fixation and tricalcium phosphate augmentation for calcanear fracture. AB - Two-thirds of hindfoot fractures involve the calcaneus. The best treatment for intraarticular fractures is still debated. The goal of treatment has been focussed for years on the anatomical reduction of the articular surface. Open reduction and internal fixation enables the surgeon to view the articular surface directly, but it is associated with a high rate of wound breakdown and infection. Therefore, length, width and angular replacement of the great tuberosity are actually the main parameters to consider when treating this type of fracture. This is a report of our experience of 20 patients treated with a minimally invasive technique of reduction using an inflatable bone tamp filled with tricalcium phosphate, with a mean follow-up of 12.25 months (range 7-26 months). Percutaneous K-wires were used to help reduction and to direct balloon inflation. Surgical goals were restoration of the mechanical stability for earlier full weight-bearing and patient mobilisation. PMID- 25457325 TI - Causes of failure in periprosthetic fractures of the hip at 1- to 14-year follow up. AB - INTRODUCTION: The results and causes of failure for 61 patients undergoing surgery for femoral hip periprosthetic fracture are reported. MATERIALS AND METHODS: Fractures were classified according to the Vancouver System. Osteosynthesis was performed in 88% of cases and prosthetic revision in 12% of cases. Clinical and functional outcomes were assessed according to the Harris Hip Score and radiological results were evaluated using Beals and Tower's criteria. RESULTS: At a mean follow-up of 32 months, the Harris Hip Score was 73.1 and the radiological results were excellent-to-good in 72.2% of patients after the first surgery. At the end of treatment, complete healing of the fracture and stability of the prosthesis was found in 87.3% of patients. The most relevant result was the recovery of walking in 73.8% of patients. Mortality after surgery was 1.6% at 3 months and 3.3% at 12 months. A higher mortality rate occurred when surgery was delayed more than 5 days after trauma. CONCLUSIONS: The analysis of our cases shows that in Vancouver type B1 fractures treated with plating osteosynthesis, there were worse outcomes in total hip arthroplasty with cemented stems compared with uncemented stems. In Vancouver type B2 fractures with cementless straight stems, osteosynthesis with a plate can be a valid option. In Vancouver type C fractures, the stability of the stem must be carefully assessed. PMID- 25457326 TI - Validation of the Non-Union Scoring System in 300 long bone non-unions. AB - INTRODUCTION: Non-union of long bones is a significant consequence of fracture treatment. The ideal classification for non-union of long bones would give sufficient significant information to the orthopaedic surgeon to enable good management of the treatment required and to facilitate the creation of comparable study groups for research purposes. The Non-Union Scoring System (NUSS) is a new scoring system to assist surgeons in the choice of the correct treatment in non union surgery. The aim of this study was to determine the evidence supporting the use of the NUSS classification in the treatment of non-unions of long bones and to validate the treatment algorithm suggested by this scoring system. MATERIALS AND METHODS: A total of 300 patients with non-union of the long bones were included in the clinical study. RESULTS: A radiographic and clinical healing was reached in 60 of 69 non-unions (86%) in group 1 (0-25 points), in 102 of 117 non unions (87%) in group 2 (26-50 points), and in 69 of 84 (82%) in group 3 (51-75 points). The mean time to clinical healing was 7.17 +/- 1.85 months in group 1, 7.30 +/- 1.72 months in group 2 and 7.60 +/- 1.49 months in group 3. The mean time to radiographic healing was 8.78 +/- 2.04 months in group 1, 9.02 +/- 1.84 months in group 2 and 9.53 +/- 1.40 months in group 3. DISCUSSION: There are few articles in the scientific literature that examine the classification systems for non-union. CONCLUSIONS: A statistical analysis of the first results we have obtained with the use of NUSS showed significant rates of union in all the evaluated groups. This indicates that NUSS could be an appropriate scoring system to classify and stratify non-unions and to enable the surgeon to choose the correct treatment. PMID- 25457327 TI - Total knee replacement in acute and chronic traumatic events. AB - Total knee replacement (TKR) is a widely used procedure for the treatment of post traumatic arthritis. This type of solution has also been used recently for the treatment of acute fractures around the knee, particularly in joints that were already arthritic before the trauma. The purpose of this paper is to present our experience with TKR in both acute and chronic traumatic events, highlighting the main problems associated with these conditions and focussing on the indications, principles of technique, tips, tricks and pitfalls of this procedure. The main issues related to post-traumatic arthritis and the problem of TKR in acute fractures are discussed, and our case series of both groups of patients is presented. PMID- 25457328 TI - Megaprosthesis in post-traumatic and periprosthetic large bone defects: Issues to consider. AB - INTRODUCTION: The recent evolution of prosthesis technology has enabled the surgeon to replace entire limbs. These special prostheses, or megaprostheses, were developed for the treatment of severe oncological bone loss; however, the indications and applications of these devices have expanded to other orthopaedic and trauma situations. For some years, surgeons have been implanting megaprostheses in non-oncological conditions, such as acute trauma in severe bone loss and poor bone quality; post-traumatic failures, both aseptic and septic (represented by complex non-unions and critical size bone defects); major bone loss in prosthetic revision, both aseptic and septic; periprosthetic fractures with component mobilisation and poor bone stock condition. The purpose of this study was to evaluate retrospectively the complications during and after the implantation of megaprosthesis of the lower limb in post-traumatic and prosthetic bone loss, and to propose tips about how to avoid and manage such complications. MATERIALS AND METHODS: All the complications and difficulties we have encountered during or after the implantation of megaprosthesis in non-oncology patients were evaluated retrospectively. A total of 72 patients were treated with large resection mono-and bi-articular prostheses between January 2008 and January 2014. RESULTS: The main critical problems found in the study were: restoration of the correct length and rotation of the limb; reconstruction of the knee extensor mechanism; trochanteric reconstruction; stability/dislocation of the implant; mobility/range of motion (ROM) of the implant; skin cover; sepsis, and bone quality. CONCLUSION: Megaprosthesis in severe bone loss can be considered as an available solution for the orthopaedic surgeon in extreme, appropriately selected cases. This type of complex surgery must be performed in specialised centres where knowledge and technologies are present. Patients with severe bone loss should not be treated in the same way as oncology patients because life expectancy is definitely longer; therefore, the surgical technique and the system implantation must be extremely rigorous to ensure longevity of the prosthesis. The characteristics of the bone and soft tissue conditions in these patients are very different from those presented by oncology patients, which creates critical problems that the surgeon should be able to manage to avoid serious complications. PMID- 25457330 TI - Incidence of donor site morbidity following harvesting from iliac crest or RIA graft. AB - INTRODUCTION: Clinical management of non-union of long bone fractures and segmental bone defect is a challenge for orthopaedic surgeons. The use of autologous bone graft (ABG) is always considered the gold standard treatment. Traditional techniques for harvesting ABG from iliac crest usually involve several complications, particularly at the donor site. The Reamer-Irrigator Aspirator (RIA) is an intramedullary reaming system that generates a large volume of cancellous bone material in a single-step reaming process; this bone material can be collected and potentially used as an ABG source. Our interest is to compare the complications associated with the standard technique of harvesting from iliac crest with those of the innovative RIA harvesting device. MATERIALS AND METHODS: A database of 70 patients with long bone non-unions was studied. The patients were divided into two groups according to the surgical harvesting technique used: RIA system ABG (35 patients) and iliac crest ABG (35 patients). RESULTS: At the 12-month follow-up, pain at the donor site was reported in no patients in the RIA system ABG group and five of 35 patients (14.28%) in the iliac crest ABG group. Local infections at the donor site were found in no patients in the RIA system ABG group compared with five patients (14.28%) in the iliac crest ABG group. There were no fractures in the RIA system ABG group and one case (2.85%) of anterior superior iliac spine (ASIS) dislocation in the iliac crest ABG group. No systemic infections were detected in either group. DISCUSSION: We analysed the scientific literature on the use of RIA technique to collect ABG for use in patients with anthropic-oligotrophic non-unions, with a focus on the complications associated with this technique. CONCLUSION: RIA bone graft for the treatment of non-unions and segmental bone defect of long bones seems to be a safe and efficient procedure with low donor site morbidity. PMID- 25457329 TI - Masquelet technique for the treatment of a severe acute tibial bone loss. AB - The "induced membrane" technique described by Masquelet has been used successfully for many years for posttraumatic bone defect reconstruction, non unions and osteomyelitis. The main advantages are the two-step surgical procedure that in case of primary infection allows repeated debridement if necessary, in case of internal fixation early weight bearing with decreased malalignment risk and it has a short learning curve. A theoretical application of this procedure is the management of acute severe traumatic bone loss of the limbs despite the lack of this experience in literature. We report on a Gustilo IIIB meta-epiphyseal fracture (AO 43-C3) of the leg with a 6 cm in length bone loss that was treated with the Masquelet technique. PMID- 25457331 TI - Tibial plateau lesions. Surface reconstruction with a biomimetic osteochondral scaffold: Results at 2 years of follow-up. AB - INTRODUCTION: Tibial plateau articular pathology caused by post-traumatic or degenerative lesions is a challenge for the orthopaedic surgeon and can lead to early osteoarthritis. The aim of the present study was to evaluate the results of treatment of these complex defects with implantation of an osteochondral scaffold, which is designed to target the cartilage surface and to reconstruct joint anatomy by addressing the entire osteochondral unit. MATERIALS AND METHODS: Eleven patients (5 female and 6 male) with a mean age of 37.3 +/- 11.0 years and osteochondral lesions of the tibial plateau (mean 5.1 +/- 2.7 cm(2); range 3.0 12.5 cm(2)) were treated with the implantation of an osteochondral biomimetic collagen-hydroxyapatite scaffold (Maioregen((r)), Fin-Ceramica, Faenza, Italy). Comorbidities were addressed taking care to restore the correct limb alignment. Patients were evaluated pre-operatively and prospectively followed-up for 2 years using the International Knee Documentation Committee (IKDC) subjective and objective scores; activity level was documented using the Tegner score. RESULTS: Three patients experienced minor adverse events. No patients required further surgery for treatment failure during the study follow-up period, and 8 patients (72.7%) reported a marked improvement. The IKDC subjective score improved from 42.5 +/- 10.2 before treatment to 69.8 +/- 19.0 at 12 months (p<0.05), with stable results at 24 months. The IKDC objective score increased from 27.3% normal and nearly normal knees before treatment to 85.7% normal and nearly normal knees at 24 months of follow-up. The Tegner score increased from 2.3 +/- 2.1 before treatment to 4.8 +/- 2.4 at 12 months (p<0.05), and was stable at the final follow-up. CONCLUSION: The present study on the implantation of an osteochondral scaffold for the treatment of tibial plateau lesions showed a promising clinical outcome at short-term follow-up, which indicates that this procedure can be considered as a possible treatment option, even in these complex defects, when comorbidities are concomitantly addressed. PMID- 25457332 TI - Autologous fat graft as treatment of post short stature surgical correction scars. AB - INTRODUCTION: Surgical limb lengthening is undertaken to correct pathological short stature. Among the possible complications related to this procedure, painful and retractile scars are a cause for both functional and cosmetic concern. Our team has already shown the efficacy of autologous fat grafting in the treatment of scars with varying aetiology, so we decided to apply this technique to scars related to surgical correction of dwarfism. A prospective study was conducted to evaluate the efficacy of autologous fat grafting in the treatment of post-surgical scars in patients with short-limb dwarfism using durometer measurements and a modified patient and observer scar assessment scale (POSAS), to which was added a parameter to evaluate movement impairment. PATIENTS AND METHODS: Between January 2009 and September 2012, 36 children (28 female and 8 male) who presented retractile and painful post-surgical scars came to our unit and were treated with autologous fat grafting. Preoperative and postoperative mean durometer measurements were analysed using the analysis of variance (ANOVA) test and POSAS parameters were studied using the Wilcoxon rank sum test. RESULTS: There was a statistically significant reduction in all durometer measurements (p value <0.05) and in all but one of the POSAS parameters (p-value <0.05) following treatment with autologous fat grafting. DISCUSSION: Surgical procedures to camouflage scars on lower limbs are not often used as a first approach and non surgical treatments often lead to unsatisfactory results. In contrast, our autologous fat grafting technique in the treatment of post-surgical scars has been shown to be a valuable option in patients with short-limb dwarfism. CONCLUSION: There was a reduction of skin hardness and a clinical improvement of all POSAS parameters in all patients treated. Moreover, the newly introduced POSAS parameter appears to be reliable and we recommend that it is included to give a more complete evaluation of patient perception. PMID- 25457333 TI - Posterior tibial artery perforator flaps for coverage of Achilles region defects. AB - BACKGROUND: Defects of the Achilles tendon region still represent a tricky issue in lower limb surgery. Among the several reconstructive possibilities, local propeller perforator flaps have gained popularity in the last decade. MATERIALS AND METHODS: We report our experience with eight patients affected by small-to moderate soft-tissue defects of the Achilles tendon region, who underwent surgical reconstruction with local flaps based on posterior tibial perforator branches. RESULTS: All patients healed successfully in terms of aesthetic and functional aspect. In only one case a transient venous congestion was observed and this resolved spontaneously. CONCLUSIONS: Although the surgical technique requires much care and skill, including an extremely gentle dissection of perforator vessels, local propeller flaps should be considered the first-line choice for reconstruction in small-to-medium size soft-tissue defects in the Achilles region. PMID- 25457334 TI - Impending fracture: A difficult diagnosis. AB - INTRODUCTION: The concept of impending fracture has been developed to help address this difficult skeletal-related problem. There is no consensus on the subject in the literature and a specific definition of impending fracture has not been outlined. DISCUSSION: There is disagreement in the literature on the best criteria for the diagnosis of impending fracture. A method of discrimination for patients who need preventative treatment for a metastatic lesion has not yet been established. CONCLUSIONS: Current score systems consider variables like size, location and treatment response and are easy to remember. However, these score systems have never been evaluated prospectively and rigorously, their sensitivity is low and they do not take into account potentially relevant factors that can influence patient prognosis. A consistent tool to evaluate impending fractures would be of great value to guide the treatment of metastatic bone disease. PMID- 25457335 TI - How was the Turin Shroud Man crucified? AB - As the literature is not exhaustive with reference to the way the Turin Shroud (TS) Man was crucified, and it is not easy to draw significant information from only a "photograph" of a man on a linen sheet, this study tries to add some detail on this issue based on both image processing of high resolution photos of the TS and on experimental tests on arms and legs of human cadavers. With regard to the TS Man hands, a first hypothesis states that the left hand of the TS Man was nailed twice at two different anatomical sites: the midcarpal joint medially to the pisiform between the lunate/pyramidal and capitate/uncinate bones (Destot's space) and the radiocarpal joint between the radio, lunate and scaphoid; also the right hand would have been nailed twice. A second hypothesis, preferred by the authors, states that the hands were nailed only once in the Destot's space with partial lesion of the ulnar nerve and flexion of the metacarpophalangeal joint of the thumbs. With regard to the TS Man feet, the imprint of the sole of the right foot leads to the conclusion that TS Man suffered a dislocation at the ankle just before the nailing. The entrance hole of the nail on the right foot is a few inches from the ankle, and excludes a double nailing. The nail has been driven between the tarsal bones. The TS Man suffered the following tortures during crucifixion: a very serious and widespread causalgia due to total paralysis of the upper right limb (paradoxical causalgia); a nailing of the left wrist with damage to the ulnar nerve; a similar nailing of the right wrist; and a nailing to both feet using one only nail that injured the plantaris medialis nerves. The respiratory limitation was probably not sufficient to cause death by asphyxiation. Also considering the hypovolemia produced by scourging and the many other tortures detectable on the TS, the principal cause of death can be attributed to a myocardial infarction. PMID- 25457336 TI - Is it safe to use a kinetic therapy bed for care of patients with cervical spine injuries? AB - INTRODUCTION: Bedrest is often used for temporary management, as well as definitive treatment, for many spinal injuries. Under such circumstances patients cannot remain flat for extended periods due to possible skin breakdown, blood clots, or pulmonary complications. Kinetic therapy beds are often used in the critical care setting, although this is felt to be unsafe for turning patients with spine fractures. We sought to evaluate whether a kinetic therapy bed would cause as much spinal motion at an unstable cervical injury as occurs during manual log-rolling on a standard intensive care unit bed. METHODS: Unstable C5-C6 ligamentous injuries were surgically created in 15 fresh, whole cadavers. Sensors were affixed to C5 and C6 posteriorly and electromagnetic motion tracking analysis performed. In all cases a cervical collar was applied by an orthotist after creation of the injury. The amount of angular motion and linear displacement that occurred at this injured level was measured during manual log rolling and patient turning using a kinetic therapy bed. For statistical analysis, the range of motion for angles about each axis and displacement in each direction was analyzed by multivariate analysis of variance with repeated measures. RESULTS: When comparing manual log-rolling and kinetic bed therapy, significantly more angular motion was created by the log-roll manoeuvre in flexion-extension (p=0.03) and lateral bending (p=0.01). There was no significant difference in axial rotation between the two methods (p=0.80). There were no significant differences demonstrated in medial-lateral and anterior-posterior translation. There was almost two times the axial displacement between manual log rolling and the kinetic therapy bed and this reached statistical significance (p=0.05). CONCLUSION: There is less motion at an unstable cervical injury in flexion-extension, lateral bending, and axial displacement when turning a patient using a kinetic therapy bed as opposed to traditional manual log-rolling. It may be preferable to use a kinetic therapy bed rather than manual log-rolling for patients with cervical spine injuries to decrease unwanted spinal motion. In addition, it may be easier and less physically demanding on nursing staff that must regularly turn the patient if manual log-rolling is implemented. PMID- 25457337 TI - Pedicled fibular flap for reconstruction of composite defects in foot. AB - INTRODUCTION: Reconstruction of complex injuries involving bone and soft-tissue in foot remains a tough challenge for surgeons. The free fibular flap is a popular flap for treating these composite defects. However, complications caused by microvascular anastomoses are not uncommon. Herein, we designed a pedicled fibular flap elevated in the ipsilateral leg for reconstruction of multiple defects in foot. METHODS: From July 2005 to April 2013, four patients with composite defects in foot were treated by pedicled fibular flaps. The defects were located in the first metatarsal bone and medial cuneiform bone in two patients, in the fourth metatarsal bone in one patient, and in the second to fourth metatarsal bones in one patient. The size of soft-tissue defects ranged from 10*7 cm to 15*7 cm, and the length of bone defects ranged from 6 to 8 cm. RESULTS: The length of fibular grafts ranged from 7 to 8.5 cm, and the size of skin flaps ranged from 11*8 cm to 16*8 cm. All flaps survived completely. Complications occurred in two patients. One suffered moderate venous congestion and the flap survived without intervention. The other one sustained re-infection. Debridement was performed and the wound healed uneventfully. Follow-up ranged from 8 to 32 months. Bone union occurred at an average of 12 weeks, and the skin flaps showed good cosmetic results. No serous donor-site complications occurred. CONCLUSION: The pedicled fibular flap transfer could avoid anastomosis complications and preserve healthy limb. It is a good option for reconstruction of complex defects in foot. PMID- 25457338 TI - Relationships between posterior ligamentous complex injury and radiographic parameters in patients with thoracolumbar burst fractures. AB - INTRODUCTION: The purpose of this study was to determine whether radiographic findings associated with thoracolumbar burst fractures could also indicate the presence of posterior ligamentous complex (PLC) injuries, which were identified through short-tau inversion-recovery (STIR)-weighted MRI. PATIENTS AND METHOD: Sixty-four patients were surgically treated for thoracolumbar burst fractures between April 2007 and February 2014 at our institution. Twenty-four patients were excluded from this study because of the lack of STIR-weighted MRIs, and therefore 40 patients were included in this study. The patients were divided into two groups based upon the integrity of the PLC, which was evaluated using STIR weighted MRI: a P group with a PLC injury and a C group without such injury. The following radiographic parameters were evaluated: loss of vertebral body height (LOVBH), local kyphosis (LK), vertebral body translation, canal compromise (sagittal transverse ratio, STR), interlaminar distance (ISD), supraspinous distance (SSD) and interspinous distance (ISD). Frankel scale score and total severity score (load sharing and thoracolumbar injury classification systems, respectively) were also evaluated. RESULTS: Preoperative STIR-weighted MRI showed that 25 patients had a PLC injury (P group: 15 men and 10 women), and 15 patients did not have a PLC injury (C group: 8 men and 7 women). More patients in the P group had an LK>20 degrees : 14 patients in the P group and 1 patient in the C group (p<0.01). The % SSD differed between the P and C groups (118.8%+/-53.4% and 88.0%+/-24.3%, respectively; p<0.05). Multivariate logistic analysis showed that an LK>20 degrees was a risk factor for PLC injury in patients with thoracolumbar burst fractures (odds ratio, 55.5 [95% confidence interval, 1.30-2360.1]; p<0.05). CONCLUSIONS: These results demonstrate that while LOVBH, vertebral body translation, and canal compromise do not correlate significantly with the presence of a PLC injury in patients with thoracolumbar fractures, an LK>20 degrees and increased % SSD are associated with a PLC injury. PMID- 25457339 TI - Hip fractures are risky business: an analysis of the NSQIP data. AB - INTRODUCTION: Hip fractures are one of the most common types of orthopaedic injury with high rates of morbidity. Currently, no study has compared risk factors and adverse events following the different types of hip fracture surgeries. The purpose of this paper is to investigate the major and minor adverse events and risk factors for complication development associated with five common surgeries for the treatment of hip fractures using the NSQIP database. METHODS: Using the ACS-NSQIP database, complications for five forms of hip surgeries were selected and categorized into major and minor adverse events. Demographics and clinical variables were collected and an unadjusted bivariate logistic regression analyses was performed to determine significant risk factors for adverse events. Five multivariate regressions were run for each surgery as well as a combined regression analysis. RESULTS: A total of 9640 patients undergoing surgery for hip fracture were identified with an adverse events rate of 25.2% (n=2433). Open reduction and internal fixation of a femoral neck fracture had the greatest percentage of all major events (16.6%) and total adverse events (27.4%), whereas partial hip hemiarthroplasty had the greatest percentage of all minor events (11.6%). Mortality was the most common major adverse event (44.9-50.6%). For minor complications, urinary tract infections were the most common minor adverse event (52.7-62.6%). Significant risk factors for development of any adverse event included age, BMI, gender, race, active smoking status, history of COPD, history of CHF, ASA score, dyspnoea, and functional status, with various combinations of these factors significantly affecting complication development for the individual surgeries. CONCLUSIONS: Hip fractures are associated with significantly high numbers of adverse events. The type of surgery affects the type of complications developed and also has an effect on what risk factors significantly predict the development of a complication. Concerted efforts from orthopaedists should be made to identify higher risk patients and prevent the most common adverse events that occur postoperatively. PMID- 25457340 TI - Reinforcing good practice: Implementation of guidelines at hospital G. Pini. AB - INTRODUCTION: Surgical site infections (SSIs) in orthopaedic surgery are a demanding complication for the patient and in terms of economics. Many guidelines (GLs) are available on antibiotic prophylaxis as an effective preventive measure; however, these GLs are often ignored in practice. A surveillance study of SSIs in arthroplasty, promoted by the Italian Study Group of Hospital Hygiene of the Italian Society of Public Health (SitI), showed a high percentage of non adherence to GLs on antibiotic prophylaxis. OBJECTIVES: The purpose of this study was to review the existing GLs, share them within the hospital and then monitor their implementation. MATERIALS AND METHODS: Information and training are considered to be great tools for implementation and sharing of GLs, which leads to significant improvements in clinical practice. A multidisciplinary team comprising infectious disease specialists, orthopaedic surgeons, nurse epidemiologists and public health specialists was established at the G. Pini Hospital in Milan to revise GLs, and to organise educational events for their implementation, sharing and dissemination. A checklist was devised for monitoring purposes. RESULTS: GLs were presented to orthopaedic surgeons and nurse coordinators during two educational events. Meetings were organised in each unit to present the results of the surveillance of SSIs in arthroplasty and to discuss the reasons why the prophylaxis regimens adopted were not consistent with GLs. It was emphasised that the most important issue, on which there is consensus in the scientific literature, was related to the duration of prophylaxis beyond 24h. The review process for GLs was presented and pocket-sized GLs were given to surgeons. The importance of documenting on medical record any deviations from the GLs was emphasised. CONCLUSIONS: Any changes in behaviour in clinical practice must be monitored and evaluated regularly. The monitoring of GLs in terms of correct choice of drug, timing of administration and duration of prophylaxis is made using a special checklist on a representative sample of medical records. PMID- 25457341 TI - Central acetabular fracture dislocations: are existing classifications comprehensive? PMID- 25457342 TI - Clinical results of acetabular fracture management with the Pararectus approach. AB - INTRODUCTION: To present the accuracy of reduction, complications and results two years after open reduction and internal fixation of displaced acetabular fractures involving the anterior column (AC) through the Pararectus approach. Frequencies for conversion to total hip replacement in the early follow up, the clinical outcome in preserved hips, and the need for an extension of the approach (1st window of the ilioinguinal approach) are compared to the literature about the modified Stoppa approach. METHODS: Forty-eight patients (mean age 62 years, range: 16-98; 41 male) with displaced acetabular fractures involving the AC (AC: n = 9; transverse fracture: n = 2; AC and hemitransverse: n = 24; both column: n = 13) were treated between 12/2009 and 12/2011 using the Pararectus approach. Surgical data and accuracy of reduction (using computed tomography) were assessed. Patients were routinely followed up at eight weeks, 6, 12 and 24 months postoperatively. Failure was defined as the need for total hip arthroplasty. Twenty-four months postoperatively the outcome was rated according to Matta. RESULTS: In four patients there were four intraoperative complications (minor vascular damage in two, small perforations of the peritoneum in two) which were managed intraoperatively. Fracture reduction showed statistically significant decreases (mean +/- SD, pre- vs. postoperative, in mm) in "step-offs": 2.6 +/- 1.9 vs. 0.1 +/- 0.3, p < 0.001 and "gaps": 11.2 +/- 6.8 vs. 0.7 +/- 0.9, p < 0.001. Accuracy of reduction was "anatomical" in 45, "imperfect" in three. Five (13%) from 38 available patients required a total hip arthroplasty. Of 33 patients with a preserved hip the clinical outcome was graded as "excellent" in 13 or "good" in 20; radiographically, 27 were graded as "excellent", four as "good" and two as "fair". An extension of the approach was infrequently used (1st window ilioinguinal approach in 2%, mini-incision at the iliac crest in 21%). CONCLUSION: In the treatment of acetabular fractures involving the anterior column the Pararectus approach allowed for anatomic restoration with minimal access morbidity. Results obtained by means of the Pararectus approach after two years at least parallel those reported after utilisation of the modified Stoppa approach. In contrast to the modified Stoppa approach, a relevant extension of the Pararectus approach was almost not necessary. PMID- 25457343 TI - Pedicle axis view combined by sacral mapping can decrease fluoroscopic shot count in percutaneous iliosacral screw placement. AB - BACKGROUND: Percutaneous iliosacral screw fixation of the posterior pelvic ring is a demanding procedure with high exposure to radiation. The conventional technique includes the use of three classical projections with the C-arm: inlet, outlet, and true lateral views. A projection in the axis of the upper sacral alar pedicles with a 30 degrees cephalad and 30 degrees ventral oblique view would help in obtaining a more accurate visualization of the safe corridor. Two subcutaneously placed K-wires, one placed horizontally and one vertically, may facilitate the starting point and aim changes by offering the surgeon an option for exactly matching the position of the sacrum with the image. The purpose of this study was to detect if the radiation application could be decreased by our new methodology. METHODS: Seventeen patients with pelvic posterior ring disruptions, in which percutaneous iliosacral screw placement was indicated, were included in the study. Group 1 comprised 7 patients in whom conventional projections and technique were used. Group 2 comprised 10 patients in whom 30 degrees -30 degrees projection and sacral mapping technique via two subcutaneous K-wires were applied. Radiation exposure time, total fluoroscopic shot count, fluoroscopic shot count needed for only guide wire and screw placement, radiation dose, and complications were compared between the two groups. RESULTS: The median number of fluoroscopic images for guide and screw placement was 132 (56-220) and 29.5 (19-83) in Groups 1 and 2, respectively, and the difference was statistically significant (p < 0.001). The median total fluoroscopic radiation time was 138 (68-234) and 52 (28-77) s in Groups 1 and 2, respectively, and the difference was significant (p < 0.001). Group 1 had a significantly higher median radiation dose than Group 2 [3020 (1502-6032) vs. 1192 (426-2359); (p = 0.001)]. CONCLUSIONS: Iliosacral screw placement with the help of sacral mapping and a fourth view, "30 degrees -30 degrees ", helps the surgeon to markedly reduce the fluoroscopic shots, radiation time and dose during guide wire and screw placement. LEVEL OF EVIDENCE: Therapeutic, Level II. PMID- 25457344 TI - A randomised prospective study of two different combined internal and external fixation techniques for distal tibia shaft fractures. AB - BACKGROUND: External fixation combined with limited open reduction and internal fixation (EF + LORIF) is a well-accepted and effective method for distal tibia shaft fractures, but it was also related to complications. The objective of this study was to compare external fixation combined with closed reduction and internal fixation (EF + CRIF) with EF + LORIF in the treatment of distal tibia shaft fractures, and explore the benefits and defects of these two techniques. METHODS: Fifty-six patients were randomised to operative stabilisation either by an external fixator combined with two closed titanium elastic nails or by external fixation combined with limited open reduction and internal fixation. Pre operative variables included the patients' age, sex, the affected side, cause of injury, Tscherne classification of soft tissue injury, fracture pattern, and time from injury to surgery. Peri-operative variables were the operating time and the radiation time. Postoperative variables were wound problems and other complications, union time, time of recovery to work, the functional American Orthopaedic Foot and Ankle surgery (AOFAS) score. RESULTS: There was no significant difference in the mean operating time (72.6 +/- 11.5 vs. 78.5 +/- 16.4 min, P = 0.125), the time to union (21.2 +/- 11.0 vs. 22.5 +/- 12.3 weeks, P = 0.678), the time of recovery to work (25.0 +/- 14.5 vs. 26.4 +/- 13.6 weeks, P = 0.711), pin track infection (3/28 vs. 4/28, P = 1.000), delayed union (2/28 vs. 3/28, P = 1.000), pain (38.3 +/- 1.6 vs. 38.7 +/- 1.5, P = 0.339), function (44.4 +/- 6.0 vs. 45.0 +/- 5.5, P = 0.698), and total AOFAS scores (91.5 +/- 7.4 vs. 93.4 +/- 6.8, P = 0.322) between the two groups. However, the mean radiation time was longer in the EF + CRIF group than in the EF + LORIF group (2.0 +/- 1.2 vs. 0.3 +/- 0.1 min, P < 0.01). The EF + CRIF group had no wound complications while the EF + LORIF group had five wound complications, though the difference was not statistically significant (P = 0.052). Acceptable alignment was obtained in 50 patients (22 in EF + CRIF vs. 28 in EF + LORIF, P = 0.023). Two cases with EF + CRIF had a 6 degrees of recurvatum deformity and four had 6-9 degrees of valgus deformity. CONCLUSION: Our results indicated that both EF + CRIF and EF + LORIF were reliable methods in treatment of distal tibia shaft fractures. EF + CRIF had fewer wound complications and broader indications while EF + LORIF had lower radiation exposure and better alignment. PMID- 25457345 TI - Biomechanical study of four kinds of percutaneous screw fixation in two types of unilateral sacroiliac joint dislocation: a finite element analysis. AB - OBJECTIVE: To compare the biomechanical stability of four different kinds of percutaneous screw fixation in two types of unilateral sacroiliac joint dislocation. METHODS: Finite element models of unstable Tile type B and type C pelvic ring injuries were created in this study. Modelling was based on fixation with a single S1 screw (S1-1), single S2 screw (S2-1), two S1 screws (S1-2) and a combination of a single S1 and a single S2 screw (S1-S2). The biomechanical test of two types of pelvic instability (rotational or vertical) with four types of percutaneous fixation were compared. Displacement, flexion and lateral bend (in bilateral stance) were recorded and analyzed. RESULTS: Maximal inferior translation (displacement) was found in the S2-1 group in type B and C dislocations which were 1.58 mm and 1.90 mm, respectively. Maximal flexion was found in the S2-1 group in type B and C dislocations which were 1.55 degrees and 1.95 degrees , respectively. The results show that the flexion from most significant angulation to least is S2-1, S1-1, S1-2, and S1-S2 in type B and C dislocations. All the fixations have minimal lateral bend. CONCLUSION: Our findings suggest single screw S1 fixation should be adequate fixation for a type B dislocation. For type C dislocations, one might consider a two screw construct (S1-S2) to give added biomechanical stability if clinically indicated. PMID- 25457346 TI - Homeostatic reinforcement learning for integrating reward collection and physiological stability. AB - Efficient regulation of internal homeostasis and defending it against perturbations requires adaptive behavioral strategies. However, the computational principles mediating the interaction between homeostatic and associative learning processes remain undefined. Here we use a definition of primary rewards, as outcomes fulfilling physiological needs, to build a normative theory showing how learning motivated behaviors may be modulated by internal states. Within this framework, we mathematically prove that seeking rewards is equivalent to the fundamental objective of physiological stability, defining the notion of physiological rationality of behavior. We further suggest a formal basis for temporal discounting of rewards by showing that discounting motivates animals to follow the shortest path in the space of physiological variables toward the desired setpoint. We also explain how animals learn to act predictively to preclude prospective homeostatic challenges, and several other behavioral patterns. Finally, we suggest a computational role for interaction between hypothalamus and the brain reward system. PMID- 25457347 TI - Simultaneous pancreas and kidney transplantation for liver transplant recipients with diabetes and uremia. AB - BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) has become a critical problem due to immunosuppressant related nephrotoxicity in liver transplant (LTx) recipients, especially in patients with pre-transplant risk factors. LTx recipients with uraemia and diabetes have poor prognosis even when treated with dialysis and insulin. Simultaneous pancreas and kidney transplantation (SPK) has been proven to be an effective treatment for patients with diabetic uraemia, but rarely performed in patients after LTx. Two cases of SPK after LTx were performed in our centre and we present our experience here. PATIENTS AND METHODS: Two patients received LTx because of HBV related liver cirrhosis; both of them had pre-transplant diabetes mellitus (DM), which worsened after the administration of immunosuppressive drugs. These two patients suffered from CKD and developed uraemia due to diabetic nephropathy and immunosuppressive drugs induced renal toxicity years after LTx. They relied on dialysis and insulin injection. SPK were performed years after LTx and the clinical data was retrospectively analyzed. RESULTS: SPK was successfully performed in these two patients. Pancreatic fluid drainage was achieved via a side-to-side duodenojejunostomy into the proximal jejunum. No serious surgical complications, including pancreatitis or pancreatic fistula were observed postoperatively. In both cases, kidney and pancreatic grafts were functioning well as evidenced by euglycemia without the need for insulin injections and normal serum-creatinine level 7days after the operation. One of the patients presented with renal graft impairment 1week after the operation. FK506 was tapered and rapamycin was used when the renal graft biopsy indicated drug toxicity. The patient's kidney graft function recovered gradually after the adjustment. Both patients have good function of liver, kidney and pancreas grafts during a 60-month and 30-month period of follow up. CONCLUSIONS: SPK could serve as an effective option for patients with diabetes and uremia after LTx. Perioperative management, especially the immunosuppressive strategy is crucial to improve the outcome of this procedure. PMID- 25457348 TI - Thrombolysis for hemodynamically stable pulmonary embolism: time to close the book? PMID- 25457350 TI - Disrupting the scaffold, an alternative approach to inhibiting FAK. PMID- 25457349 TI - Inflammation, metabolic dysregulation, and pulmonary function among obese urban adolescents with asthma. AB - RATIONALE: Insulin resistance and low high-density lipoprotein (HDL) are associated with pulmonary morbidity, including asthma, but the underlying mechanisms are not well elucidated. OBJECTIVES: To investigate whether systemic inflammation underlies the association of metabolic abnormalities with pulmonary function among urban adolescents. METHODS: Th-cell responses and monocyte subsets, and their association with serum homeostatic model assessment of insulin resistance (HOMA-IR) and HDL, and pulmonary function were quantified in 168 adolescents, including 42 obese subjects with asthma, 42 normal-weight subjects with asthma, 40 obese subjects without asthma, and 44 healthy control subjects. Th-cell responses (Th1 [CD4(+)IFNgamma(+)] and Th2 [CD4(+)IL4(+)] cells) to stimulation with phytohemagglutinin, leptin, and dust mite, and classical (CD14(+)CD16(-)), resident (CD14(+)CD16(+)), and patrolling (CD14dimCD16(+)) monocytes, and their C-C chemokine receptor type-2 (CCR2) expression were quantified by flow cytometry. MEASUREMENTS AND MAIN RESULTS: Th1/Th2 ratio to all three stimuli was higher in obese subjects with asthma than normal-weight subjects with asthma and directly correlated with HOMA-IR. Classical monocytes inversely associated with Th1/Th2 ratio to phytohemagglutinin (r = -0.43; P = 0.01) and directly with Asthma Control Test score (beta = 1.09; P = 0.04), while patrolling monocytes correlated with Composite Asthma Severity Index score (beta = 1.11; P = 0.04) only among obese subjects with asthma. HDL was inversely associated with patrolling monocytes and directly associated with CCR2 expression on resident monocytes. CCR2 expression on patrolling monocytes predicted residual volume (RV), RV/TLC ratio, and FRC, after adjusting for HDL, but not after adjusting for body mass index. Association of Th1/Th2 ratio with RV, FRC, and inspiratory capacity was attenuated after adjusting for HOMA-IR. CONCLUSIONS: Th1 polarization and monocyte activation among obese subjects with asthma correlates with metabolic abnormalities. Association of monocyte activation with pulmonary function is mediated by body mass index, whereas that of Th1 polarization is mediated by insulin resistance. PMID- 25457351 TI - [From bench to bed side:a splendid route fraught with difficulties]. PMID- 25457353 TI - Caspase crosstalk: integration of apoptotic and innate immune signalling pathways. AB - The caspase family of cysteine proteases has been functionally divided into two groups: those involved in apoptosis and those involved in innate immune signalling. Recent findings have identified 'apoptotic' caspases within inflammasome complexes and revealed that 'inflammatory' caspases are capable of inducing cell death, suggesting that the earlier view of caspase function may have been overly simplistic. Here, I review evidence attributing nonclassical functions to many caspases and propose that caspases serve as critical mediators in the integration of apoptotic and inflammatory pathways, thereby forming an integrated signalling system that regulates cell death and innate immune responses during development, infection, and homeostasis. PMID- 25457352 TI - Prion-like polymerization as a signaling mechanism. AB - The innate immune system uses pattern recognition receptors such as RIG-I and NLRP3 to sense pathogen invasion and other danger signals. Activation of these receptors induces robust signal transduction cascades that trigger the production of cytokines important for host protection. MAVS and ASC are essential adaptor proteins downstream of RIG-I and NLRP3, respectively, and both contain N-terminal domains belonging to the death domain superfamily. Recent studies suggest that both MAVS and ASC form functional prion-like fibers through their respective death domains to propagate downstream signaling. Here, we review these findings, and in this context discuss the emerging concept of prion-like polymerization in signal transduction. We further examine the potential benefits of this signaling strategy, including signal amplification, host evolutionary advantage, and molecular memory. PMID- 25457354 TI - Integration of CTs in acute cancer care: celebrating two UK pioneers. PMID- 25457355 TI - Application of an integrative yoga therapy programme in cases of essential arterial hypertension in public healthcare. AB - OBJECTIVE: To examine the efficacy of an integrative yoga programme as adjuvant treatment of essential arterial hypertension. METHODS: An Integrative yoga programme was conducted during three months in 26 sessions with a group of ten essential arterial hypertension patients at a public health centre. The same number of patients acted as the control group without treatment. The patients were randomly selected and assigned to the groups. All patients filled in the Positive and Negative Affect Schedule (PANAS), the Hospital Anxiety and Depression Scale (HADS) and the Smith Relaxation States Inventory 3 (SRSI3) before and after the treatment. RESULTS: A statistically significant reduction of systolic and diastolic blood pressure, negative affect, symptoms of anxiety and degree of stress could be observed in the study group. CONCLUSIONS: These positive and promising results confirm the effectiveness of these techniques in the treatment of essential arterial hypertension and suggest possible further investigations. PMID- 25457356 TI - [Internal carotid aneurysm of dysphasic origin]. AB - Extracranial carotid aneurysms are rare, but are of significant clinical interest due to the high risk of cerebral embolism. Despite considerable progress in endovascular techniques, surgical treatment of these aneurysms remains the golden standard. We report the case of a 50-year-old man who presented an aneurysm of the left internal carotid artery measuring 46 * 26 mm. Resection of the aneurysm with interposition of a prosthetic graft was performed. The postoperative course was uneventful. Pathology reported that the aneurysmal sac probably had a dysplastic origin. PMID- 25457357 TI - [An abdominal aortic aneurysm revealing Behcet's disease]. AB - Behcet's disease is a vasculitis of unknown origin. Vascular lesions predominantly affect veins. Arterial involvement is rare but usually associated with poor prognosis. Aortic syndromes are usually aneurysmal and occasionally reveal Behcet's disease. We report the case of a 46-year-old man whose Behcet's disease was revealed by a sub-renal abdominal aortic aneurysm in pre-rupture state. The diagnosis of this disease was retained based on clinical, biological and radiological criteria. The surgical procedure consisted in the resection of the aneurysmal sac and the interposition of a prosthetic PTFE tube. PMID- 25457358 TI - Background acetabular aneurysmal bone cyst in a 7 year-old: Presentation of a case. AB - The bone cyst is a rare benign tumor that usually develops in childhood. There are several treatment options, however when it is located within the pelvis treatment is complex. A 7 year-old patient who presented with 3 months of right hip pain and limping. The initial radiograph showed a discrete periostic reaction and acetabulum effacement. The MRI and CT scans suggested the diagnosis of aneurysmal bone cyst and was confirmed by open biopsy. Two serial embolizations were performed with good results, the patient was asymptomatic one year after. PMID- 25457359 TI - Concordance in the radiological diagnosis of thoracolumbar spine fractures. AB - INTRODUCTION: Thoracolumbar spine fractures are frequent and severe. Early diagnosis and appropriate treatment to obtain good clinical results is essential, with many classifications being proposed for this purpose. OBJECTIVE: To determine the external validity of radiographic and computed tomography (CT) measurements for the most used classifications, and decide on the type of treatment required. The working hypothesis is the existence of external validity of radiographic measurements. MATERIAL AND METHOD: A sample of patients with thoracolumbar fracture was selected. Three spine specialists and a resident performed measurements on anteroposterior and lateral radiographic images as well as coronal, sagittal and axial CT slices. Fractures were classified as stable or unstable, evaluating the degree of intra-and interobserver agreement based on a standard observer. Sagittal index of Farcy, lateral wedging, Beck Index, traumatic regional angulation and channel occupancy were studied. RESULTS: All indicators studied, except the lateral wedging, showed a high degree of concordance. CONCLUSIONS: Instability determinants studied with radiographs and CT, which had obtained statistical significance, are reliable and accurate for the classification of thoracolumbar fractures and, therefore, to indicate an appropriate treatment. PMID- 25457360 TI - Intra- and extra-capsular hip fractures in the elderly: Two different pathologies? AB - OBJECTIVES: To compare intracapsular (IC) and extracapsular (EC) hip fractures (HIF) in elderly patients in order to determine if they are different pathologies. SUBJECTS AND METHODS: Longitudinal, observational, descriptive, analytical prospective design, using a non-probabilistic sample from a full sample collection with 647 subjects (male and female), of 60 or more years old, admitted with HIF to the Department of Orthopedics and Traumatology of the Hospital, between January 1, 2010 and December 31, 2012. Follow-up was for 1 year post HIF. Socio-demographic, etiological, developmental, therapeutic and prognostic variables are compared. RESULTS: This is the first study on this subject with Latin American population. EC HIF incidence was superior to IC, contrary to that published in European/American populations. There are significant differences in etiological variables (chi(2)=6.34, p<0.042), with traumatic etiology in EC and non-traumatic in IC. There are also differences in therapeutic interventions performed (osteosynthesis for EC, arthroplasty for IC), with the decision on not to operate being lower in IC (both p<0.0000). The variables associated with the decision on not to perform surgery are age, etiology and postoperative mortality. DISCUSSION: The results are similar to other studies, adding the IC association with non-traumatic origin, in particular the trend of statistical association between IC and non-primary osteoporotic pathology (neoplasms, renal osteodystrophy, primary hyperparathyroidism). A further analysis was performed on the differences between Latin American and European/American populations in the incidence of either type of HIF. There are important etiological and therapeutic differences between IC and EC HIF; therefore it would be advisable to consider them as distinct disease entities. PMID- 25457361 TI - Response to the letter "Spanish arthoplasty register" from M. Fernandez Fairen, R. Llopis and A. Rodriguez. PMID- 25457362 TI - Genetic characterization of hepadnaviruses associated with histopathological changes in the liver of duck and goose embryos. AB - Avian hepadnaviruses are etiological agents of hepatitis B, that has been identified primarily in ducks, and more recently in various avian species. In this paper, 16 hepadnaviruses were detected by polymerase chain reaction (PCR) in the field samples from dead embryos of commercially reared domestic duck and goose. Based on the molecular analysis of the S-protein gene sequences and phylogenetic Neighbor-joining tree, identified viruses were clustered in the same genetic group, indicating no host-related diversity. Both duck and goose-origin hepadnaviruses were grouped within the cluster consisting of "Western-country" and "Chinese" duck hepatitis B (DHBV) isolates, showing more evolutionary distances with other known avian hepadnaviruses. Histopathologically, the lesions observed in the liver tissue from hepadnavirus positive duck and goose embryos varied from low to mild degree of perivascular mononuclear cells and mixed cell infiltrations, followed by mild vacuolar changes. Small focal necrotic changes in the liver parenchyma, and bile ductular proliferation were also found in examined liver samples. Generally, the microscopic findings resemble those described in experimentally infected ducks, while this was the first description of hepadnavirus associated lesions in domestic goose. Although hepadnaviruses are considered to have a very narrow host range, this study showed that domestic ducks and geese are susceptible to infection with genetically almost identical hepadnaviruses, that were likely to produce similar microscopic changes in the liver of both duck and goose embryos. The impact of naturally occurred hepadnavirus infection and possible synergistic interactions with other infectious or non-infectious agents on embryo viability needs further investigation. PMID- 25457363 TI - Enzootic genotype S of H9N2 avian influenza viruses donates internal genes to emerging zoonotic influenza viruses in China. AB - Avian influenza viruses of subtype H9N2 are widely prevalent in poultry in many Asian countries, and the segmented nature of the viral genome results in multiple distinct genotypes via reassortment. In this study, genetic evolution of H9N2 viruses circulating in eastern China during 2007-2013 was analyzed. The results showed that the diversity of the gene constellations generated six distinct genotypes, in which a novel genotype (S) bearing the backbone of A/chicken/Shanghai/F/98-like viruses by acquiring A/quail/Hong Kong/G1/97-like polymerase basic subunit 2 and matrix genes has gradually established its ecological niche and been consistently prevalent in chicken flocks in eastern China since its first detection in 2007. Furthermore, genotype S possessed the peculiarity to donate most of its gene segments to other emerging influenza A viruses in China, including the novel reassortant highly pathogenic avian influenza H5N2, the 2013 novel H7N7, H7N9 and the latest reassortant H10N8 viruses, with potential threat to poultry industry and human health. PMID- 25457364 TI - Multiple amino acid substitutions involved in the adaptation of H6N1 avian influenza virus in mice. AB - H6N1 avian influenza viruses (AIVs) are one of the most abundantly detected avian influenza virus subtype, and a human H6N1 infection case has been reported in 2013. H6N1 AIVs may pose a potential human risk, however, the factors that promote the replication of H6N1 viruses in mammals remain poorly understood. Here, we generated mouse-adapted variants of a H6N1 virus (A/Mallard/SanJiang/275/2007) to identify adaptive changes that confer enhanced virulence to H6N1 viruses in mammals. After eight sequential passages in mice, the mouse lethal doses (MLD50) of the variants were reduced >1000-fold compared to the parental virus. We found that the variants displayed the greatest enhancement of replication in vitro and in vivo, and also were capable of replicating in the brains of infected mice. These observations suggest that enhanced growth characteristics and modified cell tropism may contribute to increased virulence of H6N1 AIVs in mice. Sequencing of the variants revealed amino acid changes in the PB2 (E627K), PA (T97I), and HA (N394T) proteins. Our results suggest that these mutations involved in the enhancement of the ability of H6N1 virus to efficient replicate and cause severe disease in mammals. PMID- 25457365 TI - Effects of the nuclear localization of the N(pro) protein of classical swine fever virus on its virulence in pigs. AB - The N(pro) protein of classical swine fever virus (CSFV) is localized in the cytoplasm and nucleus. However, it is unknown whether the nuclear localization of N(pro) correlates with the virulence of CSFV in the host. Previously, we showed that the N(pro) protein fused with interferon regulatory factor 3 (IRF3) was present only in the cytoplasm. Here, we generated and evaluated a recombinant CSFV vSM-IRF3 harboring the IRF3 gene inserted into the N(pro) gene of the highly virulent CSFV Shimen strain. Compared to the even nuclear and cytoplasmic distribution of the enhanced green fluorescent protein (EGFP)-N(pro) fusion expressed by the recombinant CSFV EGFP-CSFV, vSM-IRF3 expressed an IRF3-N(pro) fusion protein that only was localized in the cytoplasm. vSM-IRF3 was markedly attenuated in vitro and in vivo, and the inoculated pigs were completely protected from lethal CSFV challenge, whereas the parental virus as well as EGFP CSFV exhibited a typical virulent phenotype. Taken together, the nuclear localization of N(pro) plays a significant role in the CSFV replication and virulence. PMID- 25457366 TI - Pestiviral E(rns) blocks TLR-3-dependent IFN synthesis by LL37 complexed RNA. AB - The ribonuclease activity of the soluble glycoprotein E(rns) of pestiviruses represents a unique mechanism to circumvent the host's innate immune system by blocking interferon type-I synthesis in response to extracellularly added single- (ss) and double-stranded (ds) RNA. However, the reason why pestiviruses encode a ribonuclease in addition to the abundant serum RNases remained elusive. Here, we show that the 5' UTR and NS5B regions of various strains of the RNA genome of the pestivirus bovine viral diarrhea virus (BVDV) are resistant to serum RNases and are potent TLR-3 agonists. Inhibitory activity of E(rns) was restricted to cleavable RNA products, and did not extend to the synthetic TLR-7/8 agonist R 848. RNA complexed with the antimicrobial peptide LL37 was protected from degradation by E(rns)in vitro but was fully inhibited by E(rns) in its ability to induce IFN in cell cultures, suggesting that the viral protein is mainly active in cleaving RNA in an intracellular compartment. We propose that secreted E(rns) represents a potent IFN antagonist, which degrades viral RNA that is resistant to the ubiquitous host RNases in the extracellular space. Thus, the viral RNase prevents its own pathogen-associated molecular pattern (PAMP) to inadvertently activate the IFN response that might break innate immunotolerance required for persistent pestivirus infections. PMID- 25457367 TI - GP5 expression in Marc-145 cells inhibits porcine reproductive and respiratory syndrome virus infection by inducing beta interferon activity. AB - The major neutralizing epitope of porcine reproductive and respiratory syndrome virus (PRRSV) is mainly located on virus glycoprotein 5 (GP5). Immunization with exogenous GP5 or exposure to native GP5 by means of DNA immunization can provide some degree of immune protection to PRRSV infection in pigs. However, during PRRSV infection in pigs, the production of neutralization antibodies induced by GP5 is delayed or suppressed. This suggests that the synthesis of GP5 is late than some PRRSV proteins or other PRRSV proteins interfering with the function of GP5 in inducing host responses during virus infection. Here, to exclude the impacts of the other PRRSV proteins and determine the role of GP5 in the replication of PRRSV in vitro, a Marc-145 cell line stably expressing GP5 (Marc 145-GP5(Flag)) was constructed. Cell proliferation and cell apoptosis measurements indicated that the expression of GP5 in Marc-145 cells did not disturb the cells' viability. Following infection with different PRRSV strains PRRSV replication in Marc-145-GP5(Flag) cells was inhibited significantly. Type I interferon assay results showed that beta interferon (IFN-beta) in the Marc-145 GP5(Flag) cells were increased at mRNA and protein levels. When siRNA was introduced into the cells to knock down IFN-beta mRNA, PRRSV infectivity of these cells was recovered. These data suggest that early GP5 expression is not favorable for further infection by PRRSV, because it not only stimulates production of neutralization antibodies in pigs, but also induces IFN-beta production in host cells. Therefore, GP5 is an important protein in the induction of self-protection responses from the host. PMID- 25457368 TI - Proteomic analysis of Lawsonia intracellularis reveals expression of outer membrane proteins during infection. AB - Lawsonia intracellularis is the aetiological agent of the commercially significant porcine disease, proliferative enteropathy. Current understanding of host-pathogen interaction is limited due to the fastidious microaerophilic obligate intracellular nature of the bacterium. In the present study, expression of bacterial proteins during infection was investigated using a mass spectrometry approach. LC-ESI-MS/MS analysis of two isolates of L. intracellularis from heavily-infected epithelial cell cultures and database mining using fully annotated L. intracellularis genome sequences identified 19 proteins. According to the Clusters of Orthologous Groups (COG) functional classification, proteins were identified with roles in cell metabolism, protein synthesis and oxidative stress protection; seven proteins with putative or unknown function were also identified. Detailed bioinformatic analyses of five uncharacterised proteins, which were expressed by both isolates, identified domains and motifs common to other outer membrane-associated proteins with important roles in pathogenesis including adherence and invasion. Analysis of recombinant proteins on Western blots using immune sera from L. intracellularis-infected pigs identified two proteins, LI0841 and LI0902 as antigenic. The detection of five outer membrane proteins expressed during infection, including two antigenic proteins, demonstrates the potential of this approach to interrogate L. intracellularis host-pathogen interactions and identify novel targets which may be exploited in disease control. PMID- 25457370 TI - Whole genomic analysis of porcine G10P[5] rotavirus strain P343 provides evidence for bovine-to-porcine interspecies transmission. AB - Porcine group A rotavirus (RVA) strain P343 (RVA/Pig-tc/THA/P343/1991/G10P[5]) was suggested to have VP7 and VP4 genes of bovine origin. In order to obtain precise information on the exact origin and evolution of this unusual porcine strain, the remaining nine genes (VP6, VP1-3, and NSP1-5) of strain P343 were sequenced and analyzed in the present study. On whole genomic analysis, strain P343 was found to have a bovine RVA-like genotype constellation (G10-P[5]-I2-R2 C2-M2-A3-N2-T6-E2-H3) different from those of typical porcine RVA strains. Furthermore, on phylogenetic analysis, each of the 11 genes of strain P343 appeared to be of bovine origin. Therefore, strain P343 was suggested to be a bovine RVA strain that was transmitted to pigs. PMID- 25457369 TI - Koolpinyah and Yata viruses: two newly recognised ephemeroviruses from tropical regions of Australia and Africa. AB - Koolpinyah virus (KOOLV) isolated from healthy Australian cattle and Yata virus (YATV) isolated from a pool of Mansonia uniformis mosquitoes in the Central African Republic have been tentatively identified as rhabdoviruses. KOOLV was shown previously to be related antigenically to kotonkon virus, an ephemerovirus that has caused an ephemeral fever-like illness in cattle in Nigeria, but YATV failed to react antigenically with any other virus tested. Here we report the complete genome sequences of KOOLV (16,133 nt) and YATV (14,479 nt). Each has a complex genome organisation, with multiple genes, including a second non structural glycoprotein (GNS) gene and a viroporin (alpha1) gene, between the G and L genes as is characteristic of ephemeroviruses. Based on an analysis of genome organisation, sequence identity and cross-neutralisation, we demonstrate that both KOOLV and YATV should be classified as two new species in the genus Ephemerovirus. PMID- 25457372 TI - Objective analysis of voice changes in a hemodialysis session and its correlation with ultrafiltration. AB - INTRODUCTION: The aim of the study is to analyze the voice changes occurring during a hemodialysis session objectively and to investigate the statistical correlation between voice changes and ultrafiltration, blood pressure, dry weight and the other variables of the patients. MATERIALS AND METHODS: A total of 169 patients were included in the study. Electronic voice recordings of the patients were performed with the aim of making objective voice analysis before and after dialysis. Fundamental frequency measurements occurring at the level of the larynx (Fo) and harmonic-to-noise ratio (HNR) were measured from these voice recordings. RESULTS: When the voice recordings obtained from 169 hemodialysis patients before and after dialysis were investigated, it was observed that a significant increase occurred in the Fo (from 164.52+/-43.36 Hz to 193.19+/-47.08 Hz, p<0.01). When the change in HNR was investigated, a significant reduction was determined in the post-dialysis measurements (4.6+/-3.23 dB) compared to the pre-dialysis measurements (16.10+/-4.06 dB, p<0.01). Mean 2.49+/-0.83 L of ultrafiltration was performed and a significant reduction was observed in post-session body weights of the patients (p<0.01). There was a highly statistical significance between the measurements of post-dialysis Fo and post-dialysis body weights. A highly significant correlation was determined between the amount of ultrafiltration performed and a significant increase observed in Fo before and after dialysis. Also a significant correlation was determined between the reduction in the mean post-session blood pressures and the reduction in the HNRs. CONCLUSION: Objective voice analysis is suggesting that it can be a simple and applicable method that can be used to determine the dry weight. PMID- 25457373 TI - Outline of the national mapping projects implemented after the Fukushima accident. AB - The national mapping projects were implemented with the collaboration of many organizations in order to obtain reliable and detailed information on radiological conditions due to the Fukushima Daiichi Nuclear Power Plant accident. In the projects, repeated large-scale environmental monitoring has clarified the distributions of radionuclide deposition densities and air dose rates over wide areas and their time-dependent tendencies. In parallel, migration of radiocesium was investigated in the test sites having different environmental conditions to draw a comprehensive picture on the movement of radiocesium in the environment. It turned out that the migration velocity of radiocesium drastically varies depending on conditions and the variation was reflected in air dose rates. The radiocesium migration was slow in undisturbed fields and forest; while monitoring data in urban and water areas implied fast migration velocity of radiocesium in these areas. It was confirmed that radiocesium movement through rivers plays an essential role in long-distance migration of radiocesium. In order to securely store the obtained environmental data and open them to the public, a database was constructed and has been maintained. In the latter half of the projects, we started construction of a numerical model to predict contamination conditions according to the statistical analysis of accumulated monitoring data, as well as numerical models to simulate migration of radiocesium. PMID- 25457371 TI - Prevalence of Coxiella burnetii in environmental samples collected from cattle farms in Eastern and Central Poland (2011-2012). AB - Coxiella burnetii is the etiologic agent of Q fever. It may occur as two different morphological forms, a large cell variant (LCV) and a small cell variant (SCV). The SCV is characterized by unique resistance to physical and chemical factors and may survive in the environment for many months. The objective of this study was to examine environmental samples for the presence of C. burnetii using real-time PCR in areas where Q fever was previously reported and in randomly selected animal farms where Q fever was not reported. The samples were collected in the following provinces in Poland: Lublin, Subcarpathian and Masovian. Monitoring was performed with real-time PCR and serological methods. Of the 727 environmental samples, 33 (4.54%) contained the multi-copy insertion sequence IS1111, which is specific for C. burnetii. Subsequently, the presence of C. burnetii antibodies was determined using serological tests in selected herds in which positive genetic results were obtained. Serological analyses of 169 serum samples using CFT and ELISA were performed on Polish black-and-white Holstein-Friesian cows and one cow imported from Denmark. Using the CFT method, 11 samples were positive for phase I antibodies and six were positive for phase II antibodies. Moreover, in two cases, the presence of antibodies specific for both phase I and phase II antigens of C. burnetii was detected. However, of the 169 examined serum samples, 20 were positive by ELISA test, of which six were also positive by CFT. Additionally, multi spacer typing (MST) of isolated C. burnetii strains was performed. The MST results identified two new genotypes in Poland, ST3 and ST6. The results indicate that continued research regarding spread of this pathogen within a country is necessary. PMID- 25457374 TI - Genotyping of Salmonella enterica serovar Typhimurium isolates by multilocus variable number of tandem repeat high-resolution melting analysis (MLV-HRMA). AB - Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) is one of the most important virulent foodborne pathogens in industrialized countries. The ability to type bacterial strains is essential for surveillance, investigation of outbreaks, and epidemiological studies. Multilocus variable number tandem repeat combined with high-resolution melting analysis (MLV-HRMA) is a fast, cost efficient, and easy sample genotyping method. In this study, MLV-HRMA and multilocus variable number tandem repeat analysis (MLVA) were used to differentiate between the allelic variants in 5 tandem repeat (TR) loci in 117 Salmonella Typhimurium isolates derived from various farms, slaughterhouses, market, and humans in Thailand. Both MLV-HRMA and MLVA analyses resulted in the identification of a total of 43 different genotypes, but slight differences were observed in cluster analysis results between the 2 methods. The unweighted pair group method with arithmetic mean-based cluster analysis showed the same core clades; some small differences in the placement of sister-clades and subgrouping were observed due to the inability to reliably type the polymorphic STTR3 locus in the MLV-HRMA. The results of this study show that the MLV-HRMA, following the selection of suitable TR loci, is a relatively reliable and rapid screening method capable of differentiating between Salmonella Typhimurium isolates on the basis of allelic diversity at TR loci. As such, MLV-HRMA can be potentially used to investigate and track sources of contamination in order to effectively control Salmonella contamination in the food supply chain. PMID- 25457375 TI - How pregnant women learn about foetal movements: sources and preferences for information. AB - BACKGROUND: Unexplained late gestation stillbirth is a significant health issue. Antenatal information about foetal movements has been demonstrated to reduce the stillbirth rate in women with decreased foetal movements. Midwives are ideally placed to provide this information to women. AIM: To investigate pregnant women's perceptions of information about foetal movements and preferences for receiving information. METHODS: This prospective, descriptive study was conducted in the antenatal clinic of a large metropolitan maternity hospital. FINDINGS: Pregnant women (n=526) at 34 weeks gestation or later were recruited. Only 67% of women reported receiving information about foetal movements. Women reported that midwives (80%), family (57%), friends (48%) and own mother (48%) provided this information. Midwives were the most preferred source of information. Around half (52%) of the women used the internet for information but only 11% nominated the web as their preferred information source. CONCLUSION: Women prefer to be given as much information about foetal movements as possible. Women favour information from health professionals, mainly from a midwife. Midwives are well-placed to partner with pregnant women and give them unbiased and evidenced based information enabling them to make decisions and choices regarding their health and well-being. While the internet is a prevalent information source, women want to be reassured that it is trustworthy and want direction to reliable pregnancy related websites. PMID- 25457377 TI - Reply to Letter: Incidence and outcome of in-hospital cardiac arrest in the United Kingdom Cardiac Arrest Audit--Can we clarify our purpose and shift the paradigm? PMID- 25457376 TI - Listen up! Speech is for thinking during infancy. AB - Infants' exposure to human speech within the first year promotes more than speech processing and language acquisition: new developmental evidence suggests that listening to speech shapes infants' fundamental cognitive and social capacities. Speech streamlines infants' learning, promotes the formation of object categories, signals communicative partners, highlights information in social interactions, and offers insight into the minds of others. These results, which challenge the claim that for infants, speech offers no special cognitive advantages, suggest a new synthesis. Far earlier than researchers had imagined, an intimate and powerful connection between human speech and cognition guides infant development, advancing infants' acquisition of fundamental psychological processes. PMID- 25457378 TI - Where no guideline has gone before: retrospective analysis of resuscitation in the 24th century. AB - AIM OF THE STUDY: Evaluation of the treatment, epidemiology and outcome of cardiac arrest in the television franchise Star Trek. METHODS: Retrospective cohort study of prospective events. Screening of all episodes of Star Trek: The Next Generation, Star Trek: Deep Space Nine and Star Trek: Voyager for cardiac arrest events. Documentation was performed according to the Utstein guidelines for cardiac arrest documentation. All adult, single person cardiac arrests were included. Patients were excluded if cardiac arrest occurred during mass casualties, if the victims were annihilated by energy weapons or were murdered and nobody besides the assassin could provide first aid. Epidemiological data, treatment and outcome of cardiac arrest victims in the 24th century were studied. RESULTS: Ninety-six cardiac arrests were included. Twenty-three individuals were female (24%). Cardiac arrest was witnessed in 91 cases (95%), trauma was the leading cause (n = 38; 40%). Resuscitation was initiated in 17 cases (18%) and 12 patients (13%) had return of spontaneous circulation. Favorable neurological outcome and long-term survival was documented in nine patients (9%). Technically diagnosed cardiac arrest was associated with higher rates of favorable neurological outcome and long-term survival. Neurological outcome and survival did not depend on cardiac arrest location. CONCLUSION: Cardiac arrest remains a critical event in the 24th century. We observed a change of etiology from cardiac toward traumatic origin. Quick access to medical help and new prognostic tools were established to treat cardiac arrest. PMID- 25457379 TI - A novel approach to life support training using "action-linked phrases". AB - BACKGROUND: Observations of cardiopulmonary arrests (CPAs) reveal concerning patterns when clinicians identify a problem, (e.g. loss of pulse) but do not immediately initiate appropriate therapy (e.g. compressions) resulting in delays in life saving therapy. METHODS: We hypothesized that when individuals utilized specific, short, easy-to-state action phrases stating an observation followed by an associated intervention, there would be a higher likelihood that appropriate action would immediately occur. Phase I: A retrospective analysis of residents in simulated CPAs measured what proportion verbalized "There's no pulse", statements and/or actions that followed and whether "Action-Linked Phrases" were associated with faster initiation of compressions. Phase II: Two prospective, quasi experimental studies evaluated if teaching three Action-Linked Phrases for Basic Life Support (BLS) courses or six Action-Linked Phrases for Advanced Cardiovascular Life Support (ACLS) courses was associated with increased use of these phrases. RESULTS: Phase I: 62% (42/68) of residents verbalized "there's no pulse" during initial assessment of a pulseless patient, and only 16/42 (38%) followed that by stating "start compressions". Residents verbalizing this Action Linked Phrase started compressions sooner than others: (30s [IQR:19-42] vs. 150 [IQR:51-242], p < 0.001). Phase II: In BLS courses, the three Action-Linked Phrases were used more frequently in the intervention group: (226/270 [84%] vs. 14/195 [7%]; p < 0.001). In ACLS courses, the six Action-Linked Phrases were uttered more often in the intervention group: (43% [157/368] vs. 23% [46/201], p < 0.001). CONCLUSIONS: Action-Linked Phrases innately used by residents in simulated CPAs were associated with faster initiation of compressions. Action Linked Phrases were verbalized more frequently if taught as part of a regular BLS or ACLS course. This simple, easy to teach, and easy to implement technique holds promise for impacting cardiac arrest teams' performance of key actions. PMID- 25457380 TI - Deep anterior lamellar keratoplasty for keratectasia after laser in situ keratomileusis. AB - PURPOSE: To assess the efficacy of deep anterior lamellar keratoplasty (DALK) for treating post-LASIK keratectasia. SETTING: Poostchi Eye Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. DESIGN: Retrospective interventional cases series. METHODS: The same surgeon performed all DALK procedures using the Melles manual technique. The preoperative and postoperative corrected distance visual acuity (CDVA), spherical equivalent (SE) refraction, keratometry (K) readings, and endothelial cell profiles were compared. RESULTS: The cohort comprised 20 eyes of 18 patients (72% women) with a mean age of 29 years +/- 4 (SD). The mean follow-up was 31.8 +/- 17.0 months (range 6 to 60 months). The mean Snellen CDVA improved significantly from 20/191 before DALK to 20/23 after DALK (P < .001). The mean of the modulus of SE refraction was 11.9 +/ 6.6 diopters (D) and 11.4 +/- 4.3 D, respectively (P = .446). The mean K value was 52.2 +/- 7.0 D before DALK and 46.0 +/- 1.9 D after DALK (P = .001); the mean apical K value, 59.5 +/- 5.1 D and 49.9 +/- 2.8 D, respectively (P < .001); and the mean keratometric astigmatism, 4.3 +/- 2.4 D and 1.9 +/- 1.2 D, respectively (P = .003). The endothelial cell profile did not change significantly, and no major complications related to DALK occurred. Twelve eyes had additional refractive procedures to correct residual ametropia. CONCLUSION: Deep anterior lamellar keratoplasty using the Melles manual technique was effective and safe in restoring CDVA in patients with post-LASIK keratectasia; however, high residual ametropia was a common finding. PMID- 25457382 TI - The use of big data in manual physiotherapy. PMID- 25457381 TI - Implementation of the posterior chamber intraocular lens intrascleral haptic fixation technique (glued intraocular lens) in a United States practice: Outcomes and insights. AB - PURPOSE: To evaluate intrascleral haptic posterior chamber intraocular lens (PC IOL) fixation (glued IOL). SETTING: North American tertiary referral center, private practice. DESIGN: Noncomparative interventional case series. METHODS: A retrospective review of early cases of the technique performed at the same center evaluated outcomes and complications. Based on early experience, 2 modifications were made to the standard technique. The first was to transition to IOLs with more flexible and resilient haptic materials than poly(methyl methacrylate) or polypropylene. Second, the scleral flap was created with a diamond knife and only 2 edges were lifted, leaving the side adjacent to the tunnel uncut. This allowed reliable creation of a scleral tunnel at equal depth to the flap bed and improved ease of subsequent haptic enclavation; it also strengthened the anterior aspect of the tunnel entrance. RESULTS: Fifty PC IOLs were successfully placed with intrascleral haptic fixation by 1 of 3 experienced surgeons to treat a variety of IOL complications or aphakia. Two cases involved the successful placement of iris prostheses. Staged endothelial keratoplasty was performed in 11 cases without complication. No IOL dislocated, decentered, or was unstable. Self-resolving hypotony occurred in 11 eyes (22%). The median visual acuity improved from 20/200 to 20/50. CONCLUSIONS: The glued IOL technique reliably provided secure IOL fixation in the absence of capsule support and successfully treated a variety of IOL complications, aphakia, and aniridia. Minor technique modifications minimized some difficulties associated with this surgery. PMID- 25457383 TI - Visual electrochemiluminescence detection of cancer biomarkers on a closed bipolar electrode array chip. AB - This paper describes a novel electrochemiluminescence (ECL) imaging platform for simultaneous detection of cancer biomarkers based on a closed bipolar electrode (BPE) array. It consists of two separated channel arrays: detection channel array and sensing channel array, which are connected by a group of parallel ITO BPEs on a glass substrate. Besides, two parallel ITO strips are fabricated at the two sides of BPE array and employed as driving electrodes. After Au films are electrochemically deposited on the cathodes of the BPE array, nanobioprobes including biorecognition elements (aptamer or antibody) and a novel electrochemical tag, which is synthesized by doping thionine in silica nanoparticles (Th@SiO2 NPs), are introduced into the cathodes by immunoreaction or DNA hybridization. The Th@SiO2 coupled nanobioprobes as both recognition probes and signal amplification indicators could mediate the ECL signals of Ru(bpy)3(2+)/tripropylamine (TPA) on the anodes of BPE array through faradaic reaction due to the charge neutrality of BPE. Thus, multiplex detection of cancer biomarkers (adenosine triphosphate (ATP), prostate-specific antigen (PSA), alpha fetoprotein (AFP) and thrombin) is realized by forming specific sensing interfaces onto the cathodic poles of BPEs in different sensing channels and reported by the ECL images of the Ru(bpy)3(2+)/TPA system on the anodic poles of BPEs in detection channels. The results demonstrate that this visual ECL platform enables sensitive detection with excellent reproducibility, which may open a new door toward the development of simple, sensitive, cost-effective, and high throughput detection methods on biochips. PMID- 25457384 TI - SCF-mediated gamma-globin gene expression in adult human erythroid cells is associated with KLF1, BCL11A and SOX6 down-regulation. PMID- 25457385 TI - Genetic variant in the BCL11A (rs1427407), but not HBS1-MYB (rs6934903) loci associate with fetal hemoglobin levels in Indian sickle cell disease patients. AB - India along with Nigeria and DRC contribute to 57% of the world sickle cell anemia population. The annual number of newborns in India with SCA was estimated at 44,000 in 2010. Even with this high prevalence there is minimal information about genetic factors that influence the disease course in Indian patients. The current study was conducted on 240 patients with SCD and 60 with sickle cell trait, to determine the association of genetic variants at the BCL11A (rs1427407) and HBS1-MYB (rs6934903) loci with fetal hemoglobin levels (HbF). Both these loci have been implicated with influencing HbF levels, a powerful modulator of the clinical and hematologic features of SCD. Our results indicate the BCL11A rs1427407 G>T variant to be significantly associated with HbF levels {19.12+/ 6.61 (GG), 20.27+/-6.92 (GT) and 24.83+/-2.92 (TT) respectively} contributing to ~23% of the trait variance. Interestingly no association of the HBS1L-MYB rs6934903 with the HbF levels was seen. The present study indicates the BCL11A (rs1427407) but not HMIP (rs6934903) to be associated with elevated HbF levels in Indian patient. Further interrogation of additional variants at both the loci; as also a GWAS which may help uncover new loci controlling HbF levels. PMID- 25457386 TI - In silico approaches for probiotic-derived bioactives. PMID- 25457387 TI - Metabolic variability in bioprocessing: implications of microbial phenotypic heterogeneity. AB - Phenotypic heterogeneity is a major issue in the context of industrial bioprocessing. Stochasticity of gene expression is usually considered to be the main source of heterogeneity among microbial population, but recent evidence demonstrates that metabolic reactions can also be subject to stochasticity without any intervention of gene expression. Although metabolic heterogeneity can be encountered in laboratory-scale cultivation devices, stochasticity at the level of metabolic reactions is perturbed directly by microenvironmental heterogeneities occurring in large-scale bioreactors. Accordingly, analytical tools are needed for the determination of metabolic variability in bioprocessing conditions and for the efficient design of metabolic engineering strategies. In this context, implementation of single cell technologies for bioprocess monitoring would benefit from knowledge acquired in more fundamental studies. PMID- 25457388 TI - Green genes: bioinformatics and systems-biology innovations drive algal biotechnology. AB - Many species of microalgae produce hydrocarbons, polysaccharides, and other valuable products in significant amounts. However, large-scale production of algal products is not yet competitive against non-renewable alternatives from fossil fuel. Metabolic engineering approaches will help to improve productivity, but the exact metabolic pathways and the identities of the majority of the genes involved remain unknown. Recent advances in bioinformatics and systems-biology modeling coupled with increasing numbers of algal genome-sequencing projects are providing the means to address this. A multidisciplinary integration of methods will provide synergy for a systems-level understanding of microalgae, and thereby accelerate the improvement of industrially valuable strains. In this review we highlight recent advances and challenges to microalgal research and discuss future potential. PMID- 25457389 TI - Reactor concepts for bioelectrochemical syntheses and energy conversion. AB - In bioelectrochemical systems (BESs) at least one electrode reaction is catalyzed by microorganisms or isolated enzymes. One of the existing challenges for BESs is shifting the technology towards industrial use and engineering reactor systems at adequate scales. Due to the fact that most BESs are usually deployed in the production of large-volume but low-value products (e.g., energy, fuels, and bulk chemicals), investment and operating costs must be minimized. Recent advances in reactor concepts for different BESs, in particular biofuel cells and electrosynthesis, are summarized in this review including electrode development and first applications on a technical scale. A better understanding of the impact of reactor components on the performance of the reaction system is an important step towards commercialization of BESs. PMID- 25457390 TI - Components of overbite correction in lingual orthodontics: molar extrusion or incisor intrusion? AB - OBJECTIVE: The aim of this study was to evaluate the components of overbite correction with the lingual Incognito((r)) technique. MATERIALS AND METHODS: The study was based on 45 files of patients with overbite treated with the Incognito((r)) technique. The evaluation of overbite correction is assessed by comparing lateral cephalograms before and after treatment using QuickCeph 2000((r)) software. All the statistical calculations were performed using Statview II software for Mac((r)). RESULTS: The results revealed the efficiency of the Incognito((r)) technique in overbite correction despite the absence of bite planes in the majority of cases. The components of this correction are, in order: intrusion of mandibular incisors, extrusion of mandibular molars, weak extrusion of maxillary molars and stability of the maxillary incisors. These were the results commonly found in previous studies on small samples. The study also demonstrated an increase of lower face height in extraction and non-extraction cases. CONCLUSION: The Incognito((r)) technique is very efficient in overbite correction. As the main component of overbite correction is mandibular incisor intrusion, it seems crucial from the esthetic point of view to evaluate the smile line when overbite correction is needed. PMID- 25457391 TI - Orthodontics and enamel demineralization: clinical study of risk factors. AB - The appearance of white spots on the vestibular surface of teeth fitted with brackets has been described as one of the potential iatrogenic effects of orthodontic treatment. These enamel demineralizations, more commonly known as "white spot lesions" (WSL), lead in some rare cases to the creation of true cavities, causing both esthetic and functional problems. The aim of our retrospective clinical study was to evaluate the incidence of the appearance of these WSL in a Moroccan orthodontic population and to determine possible associations with a number of risk factors. PATIENTS AND METHODS: The study was based on intraoral photographs of a pool of 69 patients who underwent orthodontic treatment with or without extractions in the DFO unit of the Rabat CCDT (Center for dental consultation and treatment). Patients with prostheses or WSL before the beginning of the study were excluded. Digital start- and end-of-treatment photos for each patient were compared by a single operator looking for the appearance of WSL on the vestibular surfaces of the incisors, canines, premolars and first molars. WSL were classed according to three degrees of severity: slight, severe and cavitation. Data were processed using SPSS 13.0 software. RESULTS: The results of the study showed that the prevalence of WSL in the sample was 66.7%, with a highly significant predominance of localization in the premolar/molar segment and in patients with poor oral hygiene. CONCLUSION: Poor oral and dental hygiene was identified as the most important risk factor for the development of white spots during multibracket orthodontic treatment. PMID- 25457392 TI - Miniscrews: a simple alternative for complex treatments. AB - The use of mini-implants has already considerably changed the way we plan and perform a large number of orthodontic treatments to the point where, today, we can envisage taking a fresh look at some of our "classical" treatment options. This article will describe a number of clinical cases drawn from several years' experience of working with miniscrews. We present first a brief flashback and an overview of the different indications for micro-implants followed by four case studies presenting treatments which, without miniscrews, would have been treated by much more aggressive approaches. PMID- 25457393 TI - The time needed to refit an orthodontic wire: influence of the attachments. AB - In this prospective clinical study, we assessed the relative speed with which archwires can be changed by comparing self-ligating brackets with classical methods using elastomeric and metal ties, as well as the impact of the stage of orthodontic treatment. The main judgement criterion was the time required to place orthodontic archwires with different cross-sections, alloys and compositions, using two types of brackets, conventional twin-tie and self ligating. Placement time was recorded 10 times for each procedure by three operators experienced in the use of self-ligating bracket clips. The In-Ovation self-ligating bracket in the metal version (In-Ovation R) and its ceramic variant (In-Ovation C) has a shorter implementation (archwire removal and placement) time than a classical system (conventional MicroArch((r)) bracket). Mean ligating time is halved with the In-Ovation self-ligating brackets versus elastomeric ties and is reduced four-fold versus metal ties (with the help of an assistant) and even six-fold versus metal ties placed unassisted. On average, the time-saving was 1.5 minutes per patient for ligating times ranging from 1.5 to 6 minutes. The time saved in this way at each session could be used easily and intelligently to improve patient hygiene, talk with the child about his/her treatment progress and improve communication with parents. PMID- 25457394 TI - Vertical photogrammetric evaluation of the soft tissue profiles of two different racial groups: a comparative study. AB - INTRODUCTION: Facial soft-tissue analyses based on photographic records (photogrammetric analysis of the soft tissues) highlight interracial and interethnic dimorphism. The standards for facial analyses, originally obtained from Caucasian subjects, are not appropriate for the diagnosis and treatment planning of other groups of orthodontic patients. The purpose of this study was to compare the photogrammetric soft tissue profile characteristics in the vertical dimension of Senegalese and Moroccan adults. MATERIALS AND METHODS: A cross-sectional study was performed on a group of Senegalese and Moroccan students in the Faculty of Medicine, Pharmacy and Dentistry of Dakar. Standardized profile photographs were taken for each student in a natural head position, centric relation, and relaxed lip posture. Fourteen linear and ten angular parameters were measured on a paper print using a graduated ruler and a protractor. The mean and standard deviation (SD) were calculated for each variable. In addition an independent samples t-test was performed to detect sexual and racial dimorphism. Results were regarded as significant at P=0.05. RESULTS: Moroccan subjects had a less pronounced nasal bridge and a significantly more open nasolabial angle than the Senegalese, who had significantly greater lip height and a significantly less open inter-labial angle than the Moroccans. CONCLUSION: Further studies including different age groups would enable longitudinal data according to age to be obtained. PMID- 25457395 TI - ER stress: how trypanosomes deal with it. AB - An efficient response to endoplasmic reticulum (ER) stress is essential for the viability of eukaryotic cells. The causative agent of African sleeping sickness, Trypanosoma brucei, responds to such stress by inducing spliced leader RNA silencing (SLS), resulting in shutdown of mRNA biogenesis. A new study elucidates the activation cascade and its molecular components, which are unique to the ER stress response in trypanosomes. PMID- 25457396 TI - Disentangling multiple interactions in the hive ecosystem. AB - The widespread losses of honeybee colonies recorded over the past number of years in the northern hemisphere represent a major concern for the beekeeping industry and, more importantly, may have a severe impact on ecological services and biodiversity. There is now a general consensus about the multifactorial origin of colony losses, but the mechanistic basis of this complex phenomenon still remains largely elusive. In this review, we propose a functional framework for interpreting how different stress agents can interact to adversely affect bee immunity and health. This provides a new background rationale in which to develop an integrated approach to bee protection, as part of a more comprehensive strategy for the conservation of insect pollinators. PMID- 25457397 TI - Polypill opens a path for improving adherence. PMID- 25457398 TI - Short- and long-term cause of death in patients treated with primary PCI for STEMI. AB - BACKGROUND: Short-term mortality has been studied thoroughly in patients undergoing primary percutaneous coronary intervention (PCI), whereas long-term cause of death in patients with ST-segment elevation myocardial infarction (STEMI) remains unknown. OBJECTIVES: The goal of this study was to describe the association between time and cause of death in patients with STEMI undergoing primary PCI. METHODS: A centralized civil registration system, patient files, and public disease and death cause registries with an accurate record linkage were used to trace time and cause of death in 2,804 consecutive patients with STEMI (age 63 +/- 13 years, 72% males) treated with primary PCI. RESULTS: Patients were followed up for a median of 4.7 years. During a total of 13,447 patient-years, 717 patients died. Main causes of death within the first 30 days were cardiogenic shock and anoxic brain injury after cardiac arrest. Age, culprit vessel size and flow, and the presence of heart failure and diabetes were independent predictors of mortality. After 30 days, the annual cardiac mortality rate was <1.5%. Causes of death beyond 30 days were noncardiac in 65% of cases (mainly malignancies and pulmonary diseases). The 30-day, 1-year, and 5-year all-cause (and cardiac) mortality rates were 7.9% (7.3%), 11.4% (8.4%), and 23.3% (13.8%), respectively. CONCLUSIONS: Patients who survive the first month after an STEMI treated with primary PCI have an excellent prognosis, with a <1.5% annual risk of successive cardiac death. Noncardiac causes are responsible for the majority of later deaths in these patients. PMID- 25457399 TI - A long-term perspective on short-term outcomes. PMID- 25457401 TI - Is modest QT interval prolongation in normal adults like the canary in the coal mine? PMID- 25457402 TI - Association of immature platelets with adverse cardiovascular outcomes. AB - BACKGROUND: Immature platelets are less responsive to the effects of antiplatelet drugs and contain messenger ribonucleic acid that is translationally active. They can be measured easily using an automated hematoanalyzer and reported as part of the complete blood count. OBJECTIVES: The purpose of this study was to determine the prognostic significance of elevated immature platelet count (IPC) in patients with coronary artery disease (CAD). METHODS: In this prospective cohort study in patients with CAD, patients underwent IPC measurement and were then followed up for the composite endpoint of major adverse cardiovascular events (MACE), defined as a composite of all-cause mortality, myocardial infarction, unplanned revascularization, or hospitalization for angina. For the purposes of analysis, patients were stratified into tertiles of IPC. RESULTS: Eighty-nine patients were followed up for a median of 31 months. Stratification to the high IPC tertile was associated with higher rates of MACE compared with the intermediate and low tertiles (60% vs. 24% vs. 16%, respectively; p < 0.001). Time-dependent receiver operating characteristic analysis revealed that an IPC level >=7,632 platelets/MUl was 70.7% sensitive and 82.1% specific for MACE. After adjustment for age, admission diagnosis, index revascularization, heart failure, smoking, hematocrit, and baseline platelet count, patients with an IPC level >=7,632 platelets/MUl were more likely to experience a MACE (hazard ratio: 4.65; 95% confidence interval: 1.78 to 12.16; p < 0.002). CONCLUSIONS: IPC is a novel biomarker for MACE risk stratification in patients with CAD. Future studies should focus on the utilization of this marker for individualized antiplatelet therapy. PMID- 25457403 TI - Immature platelet count: part of the cardiologist's complete blood count? PMID- 25457400 TI - The QT interval is associated with incident cardiovascular events: the MESA study. AB - BACKGROUND: Prolonged heart rate-corrected QT interval on electrocardiograms (ECGs) is associated with increased risk of myocardial infarction and cardiovascular disease (CVD)-related deaths in patients with prevalent coronary heart disease. OBJECTIVES: This study sought to examine the prognostic association between the baseline QT interval and incident cardiovascular events in individuals without prior known CVD. METHODS: The corrected baseline 12-lead ECG QT interval duration (QTcorr) was determined by adjustment for age, sex, race/ethnicity, and RR interval duration in 6,273 participants in MESA (Multi Ethnic Study of Atherosclerosis). Cox proportional hazards models adjusting for demographic and clinical risk factors were used to examine the association of baseline QTcorr with incident cardiovascular events. RESULTS: The mean age at enrollment was 61.7 +/- 10 years, and 53.4% of participants were women. Cardiovascular events occurred in 291 participants over a mean follow-up of 8.0 +/- 1.7 years. Each 10-ms increase in the baseline QTcorr was associated with incident heart failure (hazard ratio [HR]: 1.25; 95% CI: 1.14 to 1.37), CVD events (HR: 1.12; 95% CI: 1.05 to 1.20), and stroke (HR: 1.19; 95% CI: 1.07 to 1.32) after adjustment for CVD risk factors and potential confounders. There was no evidence of interaction with sex or ethnicity. CONCLUSIONS: The QT interval was associated with incident cardiovascular events in middle-aged and older adults without prior CVD. PMID- 25457404 TI - Your professional home: the value of American College of Cardiology membership. PMID- 25457405 TI - The push to subspecialize: choosing a career in cardiology. PMID- 25457406 TI - TAVR-associated prosthetic valve infective endocarditis: results of a large, multicenter registry. PMID- 25457407 TI - Coronary myocardial bridges: pathophysiology and clinical relevance. PMID- 25457408 TI - Myocardial bridging. PMID- 25457409 TI - Reply: Myocardial bridging. PMID- 25457410 TI - Reply: MicroRNA-29, a mysterious regulator in myocardial fibrosis and circulating miR-29a as a biomarker. PMID- 25457411 TI - MicroRNA-29, a mysterious regulator in myocardial fibrosis and circulating miR 29a as a biomarker. PMID- 25457413 TI - Decreased expression of nucleophosmin/B23 increases drug sensitivity of adriamycin-resistant Molt-4 leukemia cells through mdr-1 regulation and Akt/mTOR signaling. AB - Nucleophosmin/B23 (NPM) is a nuclear protein with prosurvival and ribosomal RNA processing functions. However, the potential role of NPM involved in drug resistance in leukemia has not been investigated clearly. In this study, we generated an adriamycin (ADM)-resistant lymphoblastic cell line Molt-4/ADR (MAR) by stepwise induction. Cell proliferation, sensitivity to chemotherapy agents and expressions of drug resistance related molecules were assessed. The IC50 of Molt 4 cells were 0.58+/-0.11MUmol/L and MAR cells were 22.56+/-1.94MUmol/L, meaning MAR cells were 38.63 fold resistant to Molt-4 cells. Furthermore, MAR cells gained an expression of mdr-1 (P-gp) and a higher expression of NPM compared to Molt-4 cells. Knockdown of NPM by RNA interference (RNAi) suppressed the viability of both Molt-4 and MAR cells. After NPM RNAi, the IC50 of MAR and Molt 4 cells were 3.83+/-0.38MUmol/L and 0.19+/-0.02MUmol/L respectively. Both of them revealed an increase of drug sensitivity with down-regulation of mdr-1 and Akt/mTOR signaling. Knockdown of mdr-1 could also reverse the drug resistance, with no change in NPM expression. It could be concluded that knockdown of NPM reversed the drug resistance by down-regulating P-gp and Akt/mTOR signal pathway, indicating that NPM may serve as a potential modulator in drug resistance. PMID- 25457412 TI - Microparticles induce multifactorial resistance through oncogenic pathways independently of cancer cell type. AB - Multidrug resistance (MDR) is considered a multifactorial event that favors cancer cells becoming resistant to several chemotherapeutic agents. Numerous mechanisms contribute to MDR, such as P-glycoprotein (Pgp/ABCB1) activity that promotes drug efflux, overexpression of inhibitors of apoptosis proteins (IAP) that contribute to evasion of apoptosis, and oncogenic pathway activation that favors cancer cell survival. MDR molecules have been identified in membrane microparticles (MP) and can be transferred to sensitive cancer cells. By co culturing MP derived from MDR-positive cells with recipient cells, we showed that sensitive cells accumulated Pgp, IAP proteins and mRNA. In addition, MP promoted microRNA transfer and NFkappaB and Yb-1 activation. Therefore, our results indicate that MP can induce a multifactorial phenotype in sensitive cancer cells. PMID- 25457414 TI - Stimulation of the histamine 4 receptor with 4-methylhistamine modulates the effects of chronic stress on the Th1/Th2 cytokine balance. AB - Alterations to the immune system caused by stress have been considered to markedly increase the risk for immune-related diseases such as cancer and autoimmune disorders. We investigated the potential anti-stress effects of the histamine 4 receptor (H4R) agonist, 4-methylhistamine (4-MeH), in a murine stress model. Mice were placed in 50ml conical centrifuge tubes for 12h followed by a 12h rest. The effects of treatment with 4-MeH (30mg/kg, i.p., twice daily) for 2 days were assessed. At 2 days after physical restraint, mice were sacrificed and tissues harvested. We evaluated the effects of 4-MeH treatment on CD4(+) T cell production, and intracellular IFN-gamma and IL-4 expression in these cells. We also assessed IL-1beta, IFN-gamma, TNF-alpha, and IL-4 mRNA expression as well as IFN-gamma, TNF-alpha, GITR, Ox40 and IL-4 protein expression in the spleen. The results showed that 4-MeH treatment of stressed mice results in a substantial increase in the CD4(+) T cells as well as in IFN-gamma production by these cells. Compared to both untreated and stressed controls. In contrast, IL-4 expression decreased significantly following 4-MeH treatment of mice. Moreover, stimulation of the H4R resulted in up-regulated expression of IL-1beta, IFN-gamma and TNF alpha mRNAs and decreased the expression of IL-4. Western blot analysis confirmed decreased protein expression of IFN-gamma, TNF-alpha, GITR, Ox40 and increased IL 4 in the SC group and treatment of mice with 4-MeH reversed these effects. Our results confirm the significant impact of chronic stress on T cell function and production of Th1/Th2 mediators H4R. PMID- 25457416 TI - Effect of arm swing on single-step balance recovery. AB - Balance recovery techniques are useful not only in preventing falls but also in many sports activities. The step strategy plays an important role especially under intense perturbations. However, relatively little is known about the effect of arm swing on stepping balance recovery although considerable arm motions have been observed. The purpose of this study was to examine how the arms influence kinematic and kinetic characteristics in single-step balance recovery. Twelve young male adults were released from three forward-lean angles and asked to regain balance by taking a single step under arm swing (AS) and arm constrained (AC) conditions. It was found that unconstrained arms had initial forward motion and later upward motion causing increased moment of inertia of the body, which decreased falling angular velocity and allowed more time for stepping. The lengthened total balance time included weight transfer and stepping time, although duration increase in the latter was significant only at the largest lean angle. In contrast, step length, step velocity, and vertical ground reaction forces on the stepping foot were unaffected by arm swing. Future studies are required to investigate optimal movement strategies for the arms to coordinate with other body segments in balance recovery and injury reduction. PMID- 25457415 TI - Effects of forefoot bending elasticity of running shoes on gait and running performance. AB - The aim of this study was to investigate the effects of forefoot bending elasticity of running shoes on kinetics and kinematics during walking and running. Twelve healthy male participants wore normal and elastic shoes while walking at 1.5m/s, jogging at 2.5m/s, and running at 3.5m/s. The elastic shoes were designed by modifying the stiffness of flexible shoes with elastic bands added to the forefoot part of the shoe sole. A Kistler force platform and Vicon system were used to collect kinetic and kinematic data during push-off. Electromyography was used to record the muscle activity of the medial gastrocnemius and medial tibialis anterior. A paired dependent t-test was used to compare the various shoes and the level of significance was set at alpha=.05. The range of motion of the ankle joint and the maximal anterior-posterior propulsive force differed significantly between elastic and flexible shoes in walking and jogging. The contact time and medial gastrocnemius muscle activation in the push off phase were significantly lower for the elastic shoes compared with the flexible shoes in walking and jogging. The elastic forefoot region of shoes can alter movement characteristics in walking and jogging. However, for running, the elasticity used in this study was not strong enough to exert a similar effect. PMID- 25457417 TI - Effect of stride length on overarm throwing delivery: A linear momentum response. AB - Changing stride length during overhand throwing delivery is thought to alter total body and throwing arm linear momentums, thereby altering the proportion of throwing arm momentum relative to the total body. Using a randomized cross-over design, nineteen pitchers (15 collegiate and 4 high school) were assigned to pitch two simulated 80-pitch games at +/-25% of their desired stride length. An 8 camera motion capture system (240Hz) integrated with two force plates (960Hz) and radar gun tracked each throw. Segmental linear momentums in each plane of motion were summed yielding throwing arm and total body momentums, from which compensation ratio's (relative contribution between the two) were derived. Pairwise comparisons at hallmark events and phases identified significantly different linear momentum profiles, in particular, anteriorly directed total body, throwing arm, and momentum compensation ratios (P?.05) as a result of manipulating stride length. Pitchers with shorter strides generated lower forward (anterior) momentum before stride foot contact, whereas greater upward and lateral momentum (toward third base) were evident during the acceleration phase. The evidence suggests insufficient total body momentum in the intended throwing direction may potentially influence performance (velocity and accuracy) and perhaps precipitate throwing arm injuries. PMID- 25457419 TI - Deficits of hot executive function in developmental coordination disorder: sensitivity to positive social cues. AB - Recent research shows that children with motor coordination problems (or developmental coordination disorder - DCD) show deficits in not only cool executive function (EF), but also hot EF. We aimed to determine whether this deficit of hot EF is due to heightened sensitivity to rewarding stimuli, specifically, or to a general deficit of cognitive control, like inhibition. Using two versions of a go/no-go task, one with neutral facial expressions and the other with happy and fearful faces, we compared 12 children with DCD with 28 typically-developing children, aged 7-12 years. Like earlier studies, children responded faster to happy faces. Both groups showed comparable accuracy in response to go targets, and also had similar commission errors, except when the no-go stimulus was a happy face. Importantly, the DCD group made significantly more commission errors to happy faces failing to suppress their response on more than half of the no-go trials. These results suggest a heightened sensitivity to emotionally significant distractors in DCD; this type of impulsivity may undermine self-regulation in DCD, with possible implications for adaptive function and emotional well-being. We argue that the interaction of cognitive control and emotion processing networks may be disrupted in DCD or delayed in development. PMID- 25457418 TI - Does SAQ training improve the speed and flexibility of young soccer players? A randomized controlled trial. AB - The aim of this study was to determine the effects of a 12 week speed, agility and quickness (SAQ) training program on speed and flexibility in young soccer players. One hundred and thirty-two soccer players were randomly assigned to experimental (EG; n=66, mean+/-SD: age: 18.5+/-0.4 years (range 17-19 years); body mass: 71.30+/-5.93 kg; stature: 177.2+/-6.5 cm) and control groups (CG; n=66, mean+/-SD: age: 18.6+/-0.6 years (range 17-19 years); body mass: 70.63+/ 4.87 kg; stature: 175.9+/-5.7 cm). The experimental group performed SAQ training whilst the control group undertook straight-line sprint training matched for volume and duration. Sprint performance was assessed using 5 and 10 m sprints and a further test including maximal speed, a 20 m sprint. Flexibility was assessed using sit and reach, V-sit and reach, leg lift from supine position and lateral leg lift while lying on the side tests. Sprints over 5, 10 and 20 m did not differ between groups at baseline, but by week 12, the 5m sprint had significantly improved (P<.05) in the SAQ training group compared to the control group (1.40+/-0.13 vs. 1.46+/-0.12s, respectively) although this improvement had a trivial effect size (ES=0.15). The 10 m sprint time had improved by 3.3% (P<.01) in the SAQ group with a moderate effect size (ES=0.66). No significant differences (P>.05) for all flexibility tests were found between experimental and control group at baseline and after the training programs. Consequently SAQ training was found to be an effective way of improving sprint time for short distances over 5 and 10 m but not over 20 m (where maximum speed was achieved) or flexibility. These results indicate that SAQ training may be more effective for improving sprint performance for some soccer players but more research is required to determine ideal training methods for improving acceleration and flexibility in young soccer players. PMID- 25457420 TI - Use of video observation and motor imagery on jumping performance in national rhythmic gymnastics athletes. AB - The aim of this study was to evaluate whether a mental training protocol could improve gymnastic jumping performance. Seventy-two rhythmic gymnasts were randomly divided into an experimental and control group. At baseline, experimental group completed the Movement Imagery Questionnaire Revised (MIQ-R) to assess the gymnast ability to generate movement imagery. A repeated measures design was used to compare two different types of training aimed at improving jumping performance: (a) video observation and PETTLEP mental training associated with physical practice, for the experimental group, and (b) physical practice alone for the control group. Before and after six weeks of training, their jumping performance was measured using the Hopping Test (HT), Drop Jump (DJ), and Counter Movement Jump (CMJ). Results revealed differences between jumping parameters F(1,71)=11.957; p<.01, and between groups F(1,71)=10.620; p<.01. In the experimental group there were significant correlations between imagery ability and the post-training Flight Time of the HT, r(34)=-.295, p<.05 and the DJ, r(34)=-.297, p<.05. The application of the protocol described herein was shown to improve jumping performance, thereby preserving the elite athlete's energy for other tasks. PMID- 25457421 TI - Small choices can enhance balance learning. AB - The present study examined whether the learning of exercise routines would be enhanced by giving participants an incidental choice (i.e., exercise order). Two groups of participants were asked to perform three balance exercises. After watching a demonstration of each exercise, a choice group was allowed to choose the order of exercises, while yoked control group participants performed them in the same order as their choice group counterparts. To assess learning, a retention test was conducted 1 day later. The choice group had a significantly smaller number of errors (i.e., contacting the ground with the free leg to regain balance) than the control group. This finding indicates that performers' need for autonomy can be supported by giving them small choices--which in turn can positively affect the learning of balance exercises. PMID- 25457422 TI - How perceiving additional targets modifies teams' tactical behavior during football small-sided games. AB - This study aimed to measure how the change on targets information modifies teams' tactical behavior during football small-sided games. 20 male senior professional players divided in 4 teams of 5 players participated in the study. Each team played two small-sided games, one with 2 official targets with goalkeeper and one with 6 small targets. Positional data of each player were recorded using a 15Hz portable GPS. The distance between the centers of gravity (CG) of both team, the stretch index and the relative stretch index were measured and differences accessed via standardized differences, coefficient intervals and meta-analysis procedures. A moderate increase on the distance between the CG of each team and a small decrease on the stretch index and on the relative stretch index from 2 targets to the 6 targets games was observed. It was also identified that pitch location affected the interaction between teams. When the game was played in lateral corridors or defensive sectors, the differences between game conditions increased. Emphasizing the information for attacking team to shoot at goal, by manipulating the number of targets constrained tactical behavior of teams. The amplification of specific information on small-sided games can help coaches to promote players and teams' emergent adapted behaviors. PMID- 25457424 TI - Age-related changes in trunk neuromuscular activation patterns during a controlled functional transfer task include amplitude and temporal synergies. AB - While healthy aging is associated with physiological changes that can impair control of trunk motion, few studies examine how spinal muscle responses change with increasing age. This study examined whether older (over 65 years) compared to younger (20-45 years) adults had higher overall amplitude and altered temporal recruitment patterns of trunk musculature when performing a functional transfer task. Surface electromyograms from twelve bilateral trunk muscle (24) sites were analyzed using principal component analysis, extracting amplitude and temporal features (PCs) from electromyographic waveforms. Two PCs explained 96% of the waveform variance. Three factor ANOVA models tested main effects (group, muscle and reach) and interactions for PC scores. Significant (p<.0125) group interactions were found for all PC scores. Post hoc analysis revealed that relative to younger adults, older adults recruited higher agonist and antagonistic activity, demonstrated continuous activation levels in specific muscle sites despite changing external moments, and had altered temporal synergies within abdominal and back musculature. In summary both older and younger adults recruit highly organized activation patterns in response to changing external moments. Differences in temporal trunk musculature recruitment patterns suggest that older adults experience different dynamic spinal stiffness and loading compared to younger adults during a functional lifting task. PMID- 25457423 TI - The effects of heavy upper-body strength training on ice sledge hockey sprint abilities in world class players. AB - The current study investigated the effects of 6 weeks of heavy upper-body strength training on maximal strength and sprint abilities in eight world class ice sledge hockey players. Before and after the strength training intervention, all subjects performed a 30-m maximal sprint on ice (where time for each 10 m section was measured) and 1 repetition maximal (1RM) strength test in the bench pull (BP), pull-down (PD), pull over (PO) and front pull (FP) exercises. Three weekly sessions with 3*6-8RM for these strength exercises were added during the intervention period. From pre- to post-test, 1RM in the strength exercises improved by 4-8%, whereas 30-m sprint time, all 10-m section times and the calculated power output in the 10-m acceleration phase all improved by 2-3% (all P<.05). The pre- to post-test changes in 30-m sprint time and the initial 10-m time correlated significantly with the changes in 1RM for BP (r=0.59 and 0.55) and PD (r=0.60 and 0.68) (all P<.05). In conclusion, the results of this study strongly suggest that heavy upper-body strength training improves upper-body strength and ice sledge hockey sprint abilities, and that the magnitude of improvements in strength correlates with the improvements in sprint abilities. PMID- 25457425 TI - The influence of slope and speed on locomotive power in cross-country skiing. AB - PURPOSE: A model was developed for cross-country skiing where locomotive power depends on speed and slope as variables, and further depends on snow friction, gravitation, mass, air drag, wind, and air density. Model parameters were estimated experimentally. METHODS: Two differential equations were developed for how locomotive power depends on speed and slope. The equations are of the logistic form with a threshold determined by the skier's technique, intensity, mass, metabolic rate, gross efficiency, and lactate threshold. Three parameters were estimated by minimizing the average summed square difference between the simulated speed, using the model, and experimental speed of an elite male skier in a 4218 m track. Distance and height along the track were measured using a measuring wheel and an inclinometer generating 52 datapoints. Research assistants measured time from start at 14 different positions. Parameter values were determined from the literature. RESULTS: We illustrated how speed and slope impact locomotive power. The model was shown to be superior to a model where locomotive power is a function of speed only. The joint dependence of locomotive power on speed and slope is crucial in the non-stationary conditions where the skier passes high and low points along the track where both speed and slope change rapidly. CONCLUSION: The model is useful to predict the impact of altering a subset of the 23 variables and parameters on the remaining variables, for example the impact of changed friction or terrain slope on the skier's speed and thus time to complete a ski race. PMID- 25457426 TI - Vertical adaptation of the center of mass in human running on uneven ground. AB - In running we are frequently confronted with different kinds of disturbances. Some require quick reactions and adaptations while others, like moderate changes in ground level, can be compensated passively. Monitoring the kinematics of the runner's center of mass (CoM) in such situations can reveal what global locomotion control strategies humans use and can help to distinguish between active and passive compensation methods. In this study single and permanent upward steps of 10 cm as well as drops of the same height were used as mechanical disturbances and the adaptations in the vertical oscillation of the runners CoM were analyzed. We found that runners visually perceiving uneven ground ahead substantially adapted their CoM in preparation by lifting it about 50% of step height or lowering it by about 40% of drop height, respectively. After contact on the changed ground level different adaptations depending on the situation occur. For persisting changes the adaptation to the elevated ground is completed after the first step on the new level. For single steps part of the adaptation takes place while returning to the ground. The consistent adaptations for the different situations support the idea that controlling the CoM by adapting leg parameters is a general control principle in running. PMID- 25457427 TI - Body movement distribution with respect to swimmer's glide position in human underwater undulatory swimming. AB - Human swimmers use undulatory motions similar to fish locomotion to attain high speeds. The human body is a non-smooth multi-body linkage system with restricted flexibility and is not primarily adapted to motion in the water. Due to anatomical limitations, the human swimmer is forced to deviate from the symmetric fish-like motion and to adjust his motion to his limited abilities. The goal of this paper is to investigates the movement of ten swimmers during human underwater undulatory in a still water pool and to find out to what extent the human swimmer approaches an ideal undulatory wave which is symmetric with respect to the extended gliding position. Therefore, it is necessary to (i) to ascertain the magnitude of the normalized dorsal, ventral and total amplitudes of the undulatory movements, (ii) to examine the distribution and symmetry/asymmetry of the dorsal, ventral and total amplitudes along the length of the swimming body, and (iii) to compare the differences in amplitude distribution and other indicators between different skill levels. The amplitude distribution of the dorsal and ventral deflection along the body (related to the swimmer's stretched position) is highly asymmetric. Skilled swimmers swim with a more linear body wave and use a smaller range of envelop than less skilled swimmers. The durations of the up and down kicks show only minor differences. The down kick is slightly faster than the up kick. Although the down kick is more powerful than the up kick, the hip marker shows almost the same average swimming speed in both half cycles. PMID- 25457428 TI - Influence of wedges on lower limbs' kinematics and net joint moments during healthy elderly gait using principal component analysis. AB - The elderly are susceptible to many disorders that alter the gait pattern and could lead to falls and reduction of mobility. One of the most applied therapeutical approaches to correct altered gait patterns is the insertion of insoles. Principal Component Analysis (PCA) is a powerful method used to reduce redundant information and it allows the comparison of the complete waveform. The purpose of this study was to verify the influence of wedges on lower limbs' net joint moment and range of motion (ROM) during the gait of healthy elderly participants using PCA. In addition, discrete values of lower limbs' peak net moment and ROM were also evaluated. 20 subjects walked with no wedges (control condition) and wearing six different wedges. The variables analyzed were the Principal Components from joint net moments and ROM in the sagittal plane in the ankle and knee and joint net moments in frontal plane in the knee. The discrete variables were peak joint net moments and ROM in sagittal plane in knee and ankle. The results showed the influence of the wedges to be clearer by analyzing through PCA methods than to use discrete parameters of gait curves, where the differences between conditions could be hidden. PMID- 25457429 TI - Variability of kinematic graphomotor fluency in adults with ADHD. AB - Although graphomotor differences and variability of performance have been observed in children with attention deficit hyperactivity disorder (ADHD), no study has investigated whether this variability manifests in the kinematic graphomotor domain in adults with ADHD. Fourteen ADHD and 20 control participants wrote a novel grapheme and common word on a digitizing tablet 30 times each, with ADHD participants counterbalanced on and off stimulant medication. Variability of graphomotor fluency was significantly greater in ADHD versus control participants only in the novel writing task, both on, F(1,31)=5.988, p=.020, and off stimulant medication, F(1,32)=8.789, p=.006. Results suggest that motor control differences in ADHD are not limited to childhood and extend into adulthood. Given sufficient additional research, variability of kinematic graphomotor fluency may increase the sensitivity/specificity of differential diagnoses and/or represent a biomarker for ADHD. PMID- 25457430 TI - Quantitative comparison between the commercial software STRATOS((r)) by Philips and a homemade software for voxel-dosimetry in radiopeptide therapy. AB - BACKGROUND: Targeted radionuclide therapy is a rapidly growing modality. A few commercial treatment planning systems are entering the market. However, some in house systems are currently developed for a more flexible and customized dosimetry calculation at voxel-level. For this purpose, we developed a novel software, VoxelMed, and performed a comparison with the software STRATOS. METHODS: The validation of both of them was undertaken using radioactive phantoms with different volume inserts. A cohort of 10 patients was also studied after a therapeutic administration of (177)Lu-labelled radiopeptides. The activity, number of disintegrations, absorbed dose and dose-volume histogram (DVH) were calculated for the phantoms and the kidneys in patients, which were the main critical organs at risk in this study. RESULTS: In phantoms the absorbed doses computed with VoxelMed and STRATOS agree within 5%. In patients at the voxel level the absorbed dose to kidneys (VoxelMed: mean 0.66 Gy/GBq) showed a limited difference of 5%, but with a remarkable range (-40%, +60%) between the two software packages. Voxel-dosimetry allows to estimate the dose non-homogeneities in volumes, which may be evaluated through DVHs. CONCLUSION: This study demonstrates that a fully 3D voxel-dosimetry with multiple SPECT images is feasible by using home-made or commercial software package and absorbed dose results obtained are similar. The main difference between the studied tools was observed in the activity integration method (effective vs physical half-time to time activity curve tail). We believe that an effective half-time integration method produces a more accurate approximation of clinical uptake and resultant dosimetry. PMID- 25457432 TI - Can we rely only on ratios of cerebrospinal fluid biomarkers for AD biological diagnosis? PMID- 25457431 TI - The influence of biological and technical factors on quantitative analysis of amyloid PET: Points to consider and recommendations for controlling variability in longitudinal data. AB - In vivo imaging of amyloid burden with positron emission tomography (PET) provides a means for studying the pathophysiology of Alzheimer's and related diseases. Measurement of subtle changes in amyloid burden requires quantitative analysis of image data. Reliable quantitative analysis of amyloid PET scans acquired at multiple sites and over time requires rigorous standardization of acquisition protocols, subject management, tracer administration, image quality control, and image processing and analysis methods. We review critical points in the acquisition and analysis of amyloid PET, identify ways in which technical factors can contribute to measurement variability, and suggest methods for mitigating these sources of noise. Improved quantitative accuracy could reduce the sample size necessary to detect intervention effects when amyloid PET is used as a treatment end point and allow more reliable interpretation of change in amyloid burden and its relationship to clinical course. PMID- 25457433 TI - Diet self-management and readiness to change in underserved adults with type 2 diabetes. AB - AIM: Dietary assessment in diabetes may be enhanced by considering patient centered perspectives and barriers to change within IDF guidelines. Consideration of readiness to change (RTC) diet in underserved samples may guide future interventions in high risk populations. This study assesses the utility of a rapid assessment of RTC diet in a medically underserved sample. METHOD: Participants were 253 Black (43.7%) and White (55.1%) American adults with type 2 diabetes [M age=57.93 (11.52); 60.5% female; 19% below the US poverty threshold]. Participants were recruited at medical clinics and completed validated self report measures assessing diabetes knowledge, self-efficacy and dietary behaviors and barriers by RTC. RESULTS: Stage-based comparisons identified significant differences in diabetes and dietary domains: participants in the Action stage endorsed fewer behavioral dietary barriers (p<.001), more frequent dietary problem-solving (p<.001), and greater diabetes self-efficacy (p<.001) than participants in the Contemplation and Preparation stages. Women were more likely to be in the Preparation stage and beyond (p<.05). CONCLUSIONS: Findings highlight the clinical utility of a brief measure of RTC in understanding patient perspectives toward dietary behaviors in a medically underserved sample. The impact of gender on RTC diet warrants further exploration. PMID- 25457434 TI - Improving the quality and safety of care on the medical ward: A review and synthesis of the evidence base. AB - Despite its place at the heart of inpatient medicine, the evidence base underpinning the effective delivery of medical ward care is highly fragmented. Clinicians familiar with the selection of evidence-supported treatments for specific diseases may be less aware of the evolving literature surrounding the organisation of care on the medical ward. This review is the first synthesis of that disparate literature. An iterative search identified relevant publications, using terms pertaining to medical ward environments, and objective and subjective patient outcomes. Articles (including reviews) were selected on the basis of their focus on medical wards, and their relevance to the quality and safety of ward-based care. Responses to medical ward failings are grouped into five common themes: staffing levels and team composition; interdisciplinary communication and collaboration; standardisation of care; early recognition and treatment of the deteriorating patient; and local safety climate. Interventions in these categories are likely to improve the quality and safety of care in medical wards, although the evidence supporting them is constrained by methodological limitations and inadequate investment in multicentre trials. Nonetheless, with infrequent opportunities to redefine their services, institutions are increasingly adopting multifaceted strategies that encompass groups of these themes. As the literature on the quality of inpatient care moves beyond its initial focus on the intensive care unit and operating theatre, physicians should be mindful of opportunities to incorporate evidence-based practice at a ward level. PMID- 25457435 TI - Fat, epigenome and pancreatic diseases. Interplay and common pathways from a toxic and obesogenic environment. AB - The worldwide obesity epidemic is paralleled by a rise in the incidence of pancreatic disorders ranging from "fatty" pancreas to pancreatitis and cancer. Body fat accumulation and pancreatic dysfunctions have common pathways, mainly acting through insulin resistance and low-grade inflammation, frequently mediated by the epigenome. These mechanisms are affected by lifestyle and by the toxic effects of fat and pollutants. An early origin is common, starting in pediatric age or during the fetal life in response to nutritional factors, endocrine disruptor chemicals (EDCs) or parental exposure to toxics. A "fatty pancreas" is frequent in obese and is able to induce pancreatic damage. The fat is a target of EDCs and of the cytotoxic/mutagenic effects of heavy metals, and is the site of bioaccumulation of lipophilic and persistent pollutants related with insulin resistance and able to promote pancreatic cancer. Increased Body Mass Index (BMI) can act as independent risk factor for a more severe course of acute pancreatitis and obesity is also a well-known risk factor for pancreatic cancer, that is related with BMI, insulin resistance, and duration of exposure to the toxic effects of fat and/or of environmental pollutants. All these mechanisms involve gene-environment interactions through epigenetic factors, and might be manipulated by primary prevention measures. Further studies are needed, pointing to better assess the interplays of modifiable factors on both obesity and pancreatic diseases, and to verify the efficacy of primary prevention strategies involving lifestyle and environmental exposure to toxics. PMID- 25457436 TI - Elevated serum homocysteine is a predictor of accelerated decline in renal function and chronic kidney disease: A historical prospective study. AB - OBJECTIVE: To estimate the effect of elevated serum homocysteine level on renal function decline and on the incidence of chronic kidney disease (CKD) in the general population. METHODS: A historical prospective study on 3602 subjects attending a screening center in Israel between the years 2000 and 2012. Only subjects with normal estimated glomerular filtration rate (eGFR) and without proteinuria were included. Subjects were divided to two groups according to mean total serum homocysteine level (<= 15, >15MUmol/l). Linear mixed effect model was used to estimate the annual eGRF decline in respect to homocysteine group. Cox proportional hazards models were used to estimate hazard ratios for CKD in the normal compared to the elevated homocysteine group. RESULTS: Annual eGFR decline was 25% higher in subjects with elevated versus normal mean homocysteine level (0.90 +/- 0.16 ml/min/1.37 m(2) vs. 0.72 +/- 0.14 ml/min/1.37 m(2), p<0.001). In a median follow up of 7.75 years, 38 subjects developed CKD (1.05%). Elevated mean homocysteine level was highly associated with developing CKD (HR 4.85, 95% CI 2.48-9.49, p<0.001). In a multivariate analysis which adjusted for age, baseline kidney function, HDL cholesterol, BMI, vitamin B12 and folic acid levels, these relationships remained substantially unchanged. CONCLUSIONS: Elevated mean serum homocysteine level is associated with an accelerated decline in renal function in both men and women, and is an independent risk factor for the development of CKD in the general population. Further prospective randomized clinical trials are needed to clarify whether the reduction in serum homocysteine concentrations will result in an improved renal prognosis. PMID- 25457440 TI - Time-Lapse Electrical Geophysical Monitoring of Amendment-Based Biostimulation. AB - Biostimulation is increasingly used to accelerate microbial remediation of recalcitrant groundwater contaminants. Effective application of biostimulation requires successful emplacement of amendment in the contaminant target zone. Verification of remediation performance requires postemplacement assessment and contaminant monitoring. Sampling-based approaches are expensive and provide low density spatial and temporal information. Time-lapse electrical resistivity tomography (ERT) is an effective geophysical method for determining temporal changes in subsurface electrical conductivity. Because remedial amendments and biostimulation-related biogeochemical processes often change subsurface electrical conductivity, ERT can complement and enhance sampling-based approaches for assessing emplacement and monitoring biostimulation-based remediation. Field studies demonstrating the ability of time-lapse ERT to monitor amendment emplacement and behavior were performed during a biostimulation remediation effort conducted at the Department of Defense Reutilization and Marketing Office (DRMO) Yard, in Brandywine, Maryland, United States. Geochemical fluid sampling was used to calibrate a petrophysical relation in order to predict groundwater indicators of amendment distribution. The petrophysical relations were field validated by comparing predictions to sequestered fluid sample results, thus demonstrating the potential of electrical geophysics for quantitative assessment of amendment-related geochemical properties. Crosshole radar zero-offset profile and borehole geophysical logging were also performed to augment the data set and validate interpretation. In addition to delineating amendment transport in the first 10 months after emplacement, the time-lapse ERT results show later changes in bulk electrical properties interpreted as mineral precipitation. Results support the use of more cost-effective surface-based ERT in conjunction with limited field sampling to improve spatial and temporal monitoring of amendment emplacement and remediation performance. PMID- 25457441 TI - alpha-Allenyl Ethers as Starting Materials for Palladium Catalyzed Suzuki-Miyaura Couplings of Allenylphosphine Oxides with Arylboronic Acids. AB - We disclose here the first palladium-catalyzed Suzuki-Miyaura couplings of aryl ethers functionalized allenylphosphine oxides with arylboronic acids. This new methodology with alpha-allenyl ethers as starting materials provides a novel approach to generate phosphinoyl 1,3-butadienes and derivatives with medium to excellent yields. The reaction tolerates a variety of functional groups to afford ranges of structurally diverse substituted phosphionyl 1,3-butadienes. For unsymmetrical allene substrates, high stereospecific additions to give E-isomers are usually observed. On the basis of the known palladium and allene chemistry, a mechanism is proposed. PMID- 25457442 TI - Two meta-analyses of noncontact healing studies. AB - OBJECTIVE: Reviews of empirical work on the efficacy of noncontact healing have found that adopting various practices that incorporate an intention to heal can have some positive effect upon the recipient's wellbeing. However, such reviews focus on 'whole' human participants who might be susceptible to expectancy effects or benefit from the healing intentions of friends, family or their own religious groups. We proposed to address this by reviewing healing studies that involved biological systems other than 'whole' humans (e.g., studies of plants or cell cultures) that were less susceptible to placebo-like effects. Secondly, doubts have been cast concerning the legitimacy of some of the work included in previous reviews so we planned to conduct an updated review that excluded that work. DATA SOURCES: The following databases were searched: Swetswise, ASSIA, Psych-NET, Web of Science, Cochrane Library, British Nursing Index, Cinahl Full Text, and Informaworld. STUDY SELECTION: Only studies in English were eligible for inclusion. All studies must have examined the effects upon a biological system of the explicit intention to improve the wellbeing of that target; 49 non whole human studies from 34 papers and 57 whole human studies across 56 papers were included. DATA SYNTHESIS: The combined weighted effect size for non-whole human studies yielded a highly significant r of .258, but outcomes were heterogeneous and correlated with blind ratings of study quality; 22 studies that met minimum quality thresholds gave a reduced but still significant weighted r of .115. Whole human studies yielded a small but significant effect size of r = .203. Outcomes were again heterogeneous, and correlated with methodological quality ratings; 27 studies that met threshold quality levels gave an increased r = .224. CONCLUSIONS: Results suggest that subjects in the active condition exhibit a significant improvement in wellbeing relative to control subjects under circumstances that do not seem to be susceptible to placebo and expectancy effects. Findings with the whole human database suggests that the effect is not dependent upon the previous inclusion of suspect studies and is robust enough to accommodate some high profile failures to replicate. Both databases show problems with heterogeneity and with study quality and recommendations are made for necessary standards for future replication attempts. PMID- 25457443 TI - The positive emotions that facilitate the fulfillment of needs may not be positive emotions at all: the role of ambivalence. AB - RATIONALE: According to some scholars, if individuals experience over three times as many positive emotions as negative emotions, they are more likely to thrive. We contend, however, that perhaps positive and negative emotions that overlap in time are likely to enhance wellbeing. Specifically, if positive and negative emotions are experienced simultaneously rather than separately-called ambivalent emotions-the fundamental needs of individuals are fulfilled more frequently. EVIDENCE: Considerable evidence supports this perspective. First, many emotions that enhance wellbeing, although classified as positive, also coincide with negative feelings. Second, ambivalent emotions, rather than positive or negative emotions separately, facilitate creativity and resilience. Third, ambivalent emotions activate distinct cognitive systems that enable individuals to form attainable goals, refine their skills, and enhance their relationships. PMID- 25457444 TI - Tongue piercing and chronic abdominal pain with nausea and vomiting--two cases. AB - Chronic upper gastrointestinal (GI) symptoms of unclear etiology are frustrating to patients and physicians alike. The integrative medicine procedures of acupuncture and neural therapy may provide treatment options. Tongue piercing, which is prevalent in 5.6% of the adolescent population, may be a contributing factor in upper gastrointestinal symptoms. The objectives of the study were as follows: (1) To demonstrate the usefulness of an integrative medicine treatment approach in two cases of patients with chronic abdominal pain, nausea, and vomiting of unclear etiology who had failed standard medical management. (2) To identify scars from tongue piercings as a possible contributing factor in chronic upper GI symptoms of unclear etiology. Two retrospective case studies are presented of young adult females who were seen in a private multi-physician integrative medicine practice in the US. The patients were treated with neural therapy and acupuncture. The desired outcome was the cessation or reduction of the frequency of abdominal pain, nausea, and vomiting. Both patients had resolution of their symptoms. From this study, we have concluded the following: (1) Tongue scars from tongue rings may be causes of chronic upper gastrointestinal symptoms. (2) Neural therapy and acupuncture may be helpful in the treatment of chronic upper GI symptoms related to tongue scars. PMID- 25457446 TI - Evaluation of discriminant functions for sexing skulls from visually assessed traits applied in the Rainer Osteological Collection (Bucharest, Romania). AB - The sexing of human skeletal remains based on visual scoring of descriptive traits on the skull is useful for both forensic and bioarchaeological studies, given that many such features preserve well in the field and can be assessed quickly. The goal of our work is to evaluate the accuracy of this method on an age-balanced, known sex, random sample of 360 modern adult crania in the Rainer Osteological Collection. Consistent with Walker (2008), we scored glabella area (G), the mastoid process (Ma), the mental eminence (M), the orbital edge (O) and the nuchal crest (N), on a five-point scale. We generated sex discriminant functions (logistic), selected the most accurate of them, and subsequently applied them to archaeological samples from Romania. Each skull feature showed significant score differences by sex. Eight out of 31 discriminant functions passed criteria of high accuracy (~90%), sex bias (+/-2%), and ease of use (direct calculation of sex). The best estimates were obtained for the 30-60 age groups. Further testing these functions on six archaeological samples showed high percentages of agreement with the sex assessed on the coxal bone. The study also indicated that, although easy to learn by novices, the method of visually scoring the skull traits depends on prior experience with human osteology. The accuracy of the method may be influenced by geographical and historical differences which are bound to exist between populations. PMID- 25457445 TI - Loving-kindness meditation's effects on nitric oxide and perceived well-being: a pilot study in experienced and inexperienced meditators. AB - BACKGROUND: Meditation is associated with lower blood pressure, but little is known about how loving-kindness meditation affects nitric oxide (NO) metabolism, a key mediator of cardiovascular physiology associated with vasodilation. METHODS: We studied seven inexperienced and five experienced healthy meditators at one study visit, after they refrained from eating nitrate-rich foods for at least 12h. Participants completed questionnaires on demographics and meditation practices. We measured nitrite and nitrate and self-reported stress at baseline, after a neutral reading period (prior to meditation), immediately after, and 10 min following a standardized 20-min loving-kindness meditation. RESULTS: The 12 subjects had a mean age of 51 years, and two were male. Stress was significantly lower at baseline in the experienced group (15 vs. 49 on 100 point scale, P < .05) as was heart rate (HR) [68.1 +/- 0.5 beats per minute (bpm) vs. 73.4 +/- 0.7 bpm, P < .05]. Stress levels fell significantly with meditation (52 vs. 11, P < .05), while relaxation increased (55 vs. 89, P < .05) in the inexperienced group. Plasma nitrite levels were not significantly higher, but nitrate levels were more than twice as high (P < .05) for experienced vs. inexperienced meditators before and after loving-kindness meditation. CONCLUSION: Loving-kindness meditation is associated with stress reduction in inexperienced meditators. Experienced meditators had higher nitrate levels, trended toward having higher nitrite levels, and had significantly lower stress levels than inexperienced meditators. Nitric oxide metabolism may be involved in the cardiovascular effects of persistent meditation practice. Larger longitudinal studies would be fruitful to better understand the mechanisms involved. PMID- 25457447 TI - The dorsal tangential X-ray view to determine dorsal screw penetration during volar plating of distal radius fractures. AB - PURPOSE: To evaluate whether the dorsal tangential view (DTV) allows for reliable and valid in vivo measurement of the distance between screw tips and the dorsal radial cortex (STCD) during volar plating of distal radius fractures. METHODS: Subjects included 22 patients with displaced distal radius fractures who had volar plate osteosynthesis. We performed standardized DTV images intraoperatively. After surgery, we performed computed tomography (CT) scans with reconstructions parallel to the distal screws. Three independent observers blinded to the study protocol measured the STCD on the basis of the DTV images and CT reconstructions. We calculated inter- and intraobserver reliability and the correlation between STCD values measured with DTV images and CT scans. RESULTS: Eleven screws were changed intraoperatively. We observed no cases of postoperative screw perforations. Inter- and intraobserver reliability of STCD measurement was good when measured with DTV images and excellent when measured on the basis of CT reconstructions. Statistical analysis showed a good correlation between mean STCD values measured with DTV and CT. CONCLUSIONS: The DTV allowed in vivo evaluation of the dorsal radial cortex and enabled reliable assessment of the distance between the screw tip and the dorsal cortex. It may allow detection of dorsal screw perforation during volar plating of distal radial fractures. PMID- 25457448 TI - Role of the gluten-free diet on neurological-EEG findings and sleep disordered breathing in children with celiac disease. AB - PURPOSE: To determine whether celiac children are at risk for EEG-neurological features and sleep disordered breathing (SDB), and whether an appropriate gluten free diet (GFD) influences these disorders. METHODS: We consecutively enrolled 19 children with a new biopsy-proven celiac disease (CD) diagnosis. At CD diagnosis and after 6 months of GFD, each patient underwent a general and neurological examination, an electroencephalogram, a questionnaire about neurological features, and a validated questionnaire about SDB: OSA (obstructive sleep apnea) scores<0 predict normality; values>0 predict OSA. RESULTS: At CD diagnosis, 37% of patients complained headache that affected daily activities and 32% showed positive OSA score. The EEG examinations revealed abnormal finding in 48% of children. After 6 months of GFD headache disappeared in 72% of children and EEG abnormalities in 78%; all children showed negative OSA score. CONCLUSION: According to our preliminary data, in the presence of unexplained EEG abnormalities and/or other neurological disorders/SDB an atypical or silent CD should also be taken into account. PMID- 25457449 TI - Memory in children with epilepsy: a systematic review. AB - PURPOSE: Research suggests an increased risk for cognitive impairment in childhood epilepsy with memory being one area of cognition most likely to be affected. Understanding the prevalence and predictors of memory difficulties may help improve awareness of the difficulties and allow efficacious supports to be put in place. METHOD: A systematic review was carried out using the search terms 'memory', 'children' and 'epilepsy' in the database PUBMED. Eighty-eight studies met inclusion criteria. The review focuses on comparisons of memory scores of children with epilepsy and controls, and comparison of memory scores of children with epilepsy to normative scores. Predictors of memory impairment and the effect of surgery on memory functioning are also reviewed. RESULTS: The majority (78%) of studies reviewed revealed that children with epilepsy scored lower than controls and normative scores on measures of memory. Post-surgery, memory scores were reported to improve in 50% of studies. Predictors of memory impairment included a greater number of AEDs used, younger age of onset, increased seizure frequency and longer duration of epilepsy. CONCLUSION: Children with epilepsy have a high frequency of memory impairments. However, the exact prevalence of difficulties is not clear due to the lack of population-based data. Most studies have not controlled for IQ and thus it is unclear if difficulties are always related to global cognitive difficulties. There is need for future population based studies and studies focussing on the neurobiology of memory problems in children with epilepsy. PMID- 25457450 TI - Encephalopathy with status epilepticus during sleep: unusual EEG patterns. AB - PURPOSE: To retrospectively analyze the electroclinical characteristics, etiology, treatment, and prognosis of patients with epileptic encephalopathy with status epilepticus during sleep (ESES) with unusual EEG features and to corroborate if this series of patients is part of the ESES syndrome. METHOD: Charts of 17 patients with typical clinical manifestations of the ESES syndrome with focal ESES of non-REM sleep at onset and during the focal ESES phase, or bilateral synchronic and asynchronic ESES with a symmetric or asymmetric morphology, continuous or subcontinuous and sometimes multifocal paroxysms with or without slow-wave activity during slow sleep seen between 2000 and 2012 were analyzed. RESULTS: Mean patient follow-up from onset was 7.5 years. An idiopathic cause was found in seven patients, a structural cause in eight, and etiology was unknown in the remaining two. The median age at onset of the unusual ESES syndrome was 7 years. During the ESES phase, 15 children developed new seizure types, negative myoclonus was observed in seven patients, positive myoclonus in five, and absences in nine. Six patients had motor impairment, two had auditory verbal agnosia, and two had motor speech impairment. Attention deficit hyperactivity disorder was observed in four, aggressiveness in six, memory deficit in two, and impaired temporospatial orientation in four. The patients with focal ESES in the frontal region showed behavioral disturbances and/or motor deterioration, and in those with temporo-occipital involvement the dominant clinical manifestations were language and/or behavioral disturbances. CONCLUSION: Our patients with typical clinical manifestations of ESES syndrome but with unusual EEG patterns may be variants of this syndrome. PMID- 25457451 TI - The dilemma of treating young women with generalized epilepsy with sodium valproate and how to get out of it. PMID- 25457452 TI - Epilepsy research methods update: Understanding the causes of epileptic seizures and identifying new treatments using non-mammalian model organisms. AB - This narrative review is intended to introduce clinicians treating epilepsy and researchers familiar with mammalian models of epilepsy to experimentally tractable, non-mammalian research models used in epilepsy research, ranging from unicellular eukaryotes to more complex multicellular organisms. The review focuses on four model organisms: the social amoeba Dictyostelium discoideum, the roundworm Caenorhabditis elegans, the fruit fly Drosophila melanogaster and the zebrafish Danio rerio. We consider recent discoveries made with each model organism and discuss the importance of these advances for the understanding and treatment of epilepsy in humans. The relative ease with which mutations in genes of interest can be produced and studied quickly and cheaply in these organisms, together with their anatomical and physiological simplicity in comparison to mammalian species, are major advantages when researchers are trying to unravel complex disease mechanisms. The short generation times of most of these model organisms also mean that they lend themselves particularly conveniently to the investigation of drug effects or epileptogenic processes across the lifecourse. PMID- 25457453 TI - Does intellectual disability increase sudden unexpected death in epilepsy (SUDEP) risk? AB - PURPOSE: An estimated 1.4 million people in the United Kingdom (UK) have intellectual disability (ID) with 210,000 having severe or profound ID. Of these, approximately 125,000 have epilepsy, representing one quarter of all patients with epilepsy in the UK. For those with full scale intellectual quotients (FSIQs) of less than 50, half have epilepsy, with half of these having treatment resistant epilepsy. One of the two major causes of mortality within this population is sudden unexpected death in epilepsy (SUDEP). METHODS: We performed a literature review exploring the extent to which ID was considered as a risk factor for SUDEP. We also considered whether there was any relationship between the types of health care system in which the studies were conducted and whether ID was considered in studies of SUDEP. RESULTS: We identified 49 studies which had explored risk factors for SUDEP, of which, approximately 50% (n=23) considered ID in the planning stages. Of these studies 60% (n=14) found ID was a risk factor for SUDEP. 60% of all the studies were conducted in countries where the health care system was publicly funded. CONCLUSIONS: Overall we found ID definitions and specified standardized mortality rates and impact of institutionalization to be quite poorly presented. PMID- 25457455 TI - Biological evaluation of (177)Lu-labeled DOTA-Ala(SO3H)-Aminooctanoyl-Gln-Trp-Ala Val-N methyl Gly-His-Statine-Leu-NH2 for gastrin-releasing peptide receptor positive prostate tumor targeting. AB - Bombesin binds with selectivity and high affinity to a Gastrin-releasing peptide receptor (GRPR), which is highly overexpressed in prostate cancer cells. The present study describes the in vitro and in vivo biological characteristics of DOTA-Ala(SO3H)-Aminooctanoyl-Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH2 (DOTA-sBBNA), an antagonist analogue of bombesin peptide for the targeting of GRPR. DOTA-sBBNA was synthesized and labeled with (177)Lu as previously published. A saturation assay on PC-3 human prostate cancer cells revealed that the Kd value of the radiolabeled peptide was 1.88 nM with a maximum binding capacity (Bmax) of 289.3 fmol/10(6) cells. The radio-peptide slowly internalized, and 24.4+/-0.5% of the total binding was internalized in 4hr. Biodistribution studies were conducted in healthy and PC-3 xenografted balb/c mice, which showed high uptake and retention of tumor-associated radioactivity in PC-3 xenografted mice. The tumor-to-blood ratio was 126.02+/-9.36 at 1.5hr p.i., and was increased to 216.33+/-61.58 at 24hr p.i., which means that the radiolabeled peptide was highly accumulated in a tumor and rapidly cleared from the blood pool. The GRPR is also over-expressed in Korean prostate cancer patients. These results suggest that this (177)Lu-labeled peptide has promising characteristics for application in nuclear medicine, namely for the diagnosis and treatment of GRPR over expressing prostate tumors. PMID- 25457456 TI - Radiofluorinated probe for PET imaging of fatty acid binding protein 4 in cancer. AB - INTRODUCTION: Cancer-associated adipocytes metabolically interact with adjacent cancer cells to promote tumor proliferation and metastasis. Fatty acid binding protein 4 (FABP4) participates in this interaction, and is gathering attention as a therapeutic and diagnostic target. Positron emission tomography (PET) is a useful diagnostic method that enables noninvasive in vivo quantitative imaging of biofunctional molecules with probes labeled with positron-emitting radioisotopes. Here a novel (18)F labeled probe for PET FABP4 imaging developed through dedicated drug design from a radioiodinated probe we recently reported is evaluated in vitro and in vivo. METHODS: We designed the [(18)F]-labeled FTAP1 and FTAP3 probe, composed of a single or triple oxyethylene linker and a triazolopyrimidine scaffold derived from an FABP4 inhibitor. FABP4 binding affinities for chemically synthesized FTAP1 and FTAP3 were measured using FABP4 and 8-anilino-1-naphthalene sulfonic acid. Cell membrane permeability was measured using a commercially available plate assay system. After radiosynthesis, [(18)F]FTAP1 affinity and selectivity were evaluated using immobilized FABP3, FABP4, and FABP5. Cell uptake was investigated using differentiated adipocytes expressing FABP4 with inhibitor treatment. Following biodistribution studies in C6 glioblastoma-bearing mice, ex vivo autoradiography and immunohistochemistry were performed using thin sliced tumor sections. PET/CT imaging was then performed on C6 tumor bearing mice. RESULTS: FTAP1 showed high FABP4 affinity (Ki=68+/-8.9 nM) and adequate cell permeability. [(18)F]FTAP1 with >=98% radiochemical purity was shown to selectively bind to FABP4 (16.3- and 9.3-fold higher than for FABP3 and FABP5, respectively). [(18)F]FTAP1 was taken up by FABP4 expressing cells, and this uptake could be blocked by an inhibitor, indicating very low non-specific cell binding. [(18)F]FTAP1 showed high tumor accumulation, which demonstrates its potential use for in vivo tumor PET imaging, and the intratumoral radioactivity distribution corresponded to the FABP4 expression profile. CONCLUSION: [(18)F]FTAP1 is a promising PET probe to target FABP4. PMID- 25457454 TI - The standardization debate: A conflation trap in critical care electroencephalography. AB - PURPOSE: Persistent uncertainty over the clinical significance of various pathological continuous electroencephalography (cEEG) findings in the intensive care unit (ICU) has prompted efforts to standardize ICU cEEG terminology and an ensuing debate. We set out to understand the reasons for, and a satisfactory resolution to, this debate. METHOD: We review the positions for and against standardization, and examine their deeper philosophical basis. RESULTS: We find that the positions for and against standardization are not fundamentally irreconcilable. Rather, both positions stem from conflating the three cardinal steps in the classic approach to EEG, which we term "description", "interpretation", and "prescription". Using real-world examples we show how this conflation yields muddled clinical reasoning and unproductive debate among electroencephalographers that is translated into confusion among treating clinicians. We propose a middle way that judiciously uses both standardized terminology and clinical reasoning to disentangle these critical steps and apply them in proper sequence. CONCLUSION: The systematic approach to ICU cEEG findings presented herein not only resolves the standardization debate but also clarifies clinical reasoning by helping electroencephalographers assign appropriate weights to cEEG findings in the face of uncertainty. PMID- 25457457 TI - Target-based screen against a periplasmic serine protease that regulates intrabacterial pH homeostasis in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb) maintains its intrabacterial pH (pHIB) near neutrality in the acidic environment of phagosomes within activated macrophages. A previously reported genetic screen revealed that Mtb loses this ability when the mycobacterial acid resistance protease (marP) gene is disrupted. In the present study, a high throughput screen (HTS) of compounds against the protease domain of MarP identified benzoxazinones as inhibitors of MarP. A potent benzoxazinone, BO43 (6-chloro-2-(2'-methylphenyl)-4H-1,3-benzoxazin-4-one), acylated MarP and lowered Mtb's pHIB and survival during incubation at pH 4.5. BO43 had similar effects on MarP-deficient Mtb, suggesting the existence of additional target(s). Reaction of an alkynyl-benzoxazinone, BO43T, with Mycobacterium bovis variant bacille Calmette-Guerin (BCG) followed by click chemistry with azido-biotin identified both the MarP homologue and the high temperature requirement A1 (HtrA1) homologue, an essential protein. Thus, the chemical probe identified through a target-based screen not only reacted with its intended target in the intact cells but also implicated an additional enzyme that had eluded a genetic screen biased against essential genes. PMID- 25457458 TI - Lower extremity weakness after endovascular aneurysm repair with multibranched thoracoabdominal stent grafts. AB - OBJECTIVE: We conducted our study to describe the incidence, presentation, management, risk factors, and outcomes of lower extremity weakness (LEW) after elective endovascular aneurysm repair with multibranched thoracoabdominal stent grafts. METHODS: Excluding symptomatic patients and those with aortic dissection, between July 2005 and October 2013, 116 patients with aortic aneurysms were treated in a prospective, single-center trial of multibranched endovascular aneurysm repair. LEW that resolved within 30 days of operation was classified as transient. Persistent LEW was defined as inability to walk or stand 30 days after surgery. Perioperative spinal cord protection measures included bypass as needed to maintain flow to the subclavian and internal iliac arteries, cerebrospinal fluid drainage, and permissive hypertension. RESULTS: Postoperative LEW occurred in 24 of 116 patients (20.6%). In 15 (12.9%), LEW was transient with full recovery. Nine patients (7.7%) had persistent LEW, three with paraparesis and six with paraplegia. Five of 24 patients (21%) awoke from anesthesia with LEW. Symptoms of LEW developed within 72 hours of operation in 14 of 24 (58%). Late onset LEW (>=72 hours postoperatively) always occurred in the presence of a precipitating hypotensive event (5 of 24; 21%). Univariate analysis showed no association between LEW and Crawford type, staged repair, aneurysm extent, or postoperative endoleak. Baseline glomerular filtration rate <30 mL/min/1.73 m(2) (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.2-14.6; P = .03), fluoroscopy time >190 minutes (OR, 3.6; 95% CI, 1.0-12.7; P = .04), and sustained hypotension (OR, 2.9; 95% CI, 1.1-7.7; P = .04) were identified as independent risk factors for LEW in multivariate analysis. CONCLUSIONS: Most episodes of LEW after multibranched endovascular aneurysm repair are transient and do not occur in the operating room. Adjunctive strategies to maintain spinal perfusion, including cerebrospinal fluid drainage and permissive hypertension, may help prevent permanent LEW. PMID- 25457459 TI - Durability and survival are similar after elective endovascular and open repair of abdominal aortic aneurysms in younger patients. AB - OBJECTIVE: The role of endovascular repair (EVAR) of aortic aneurysms in young patients is controversial. The purpose of this study was to determine the long term outcomes and reintervention rates in patients 60 years of age or younger who underwent elective open or endovascular repair of an abdominal aortic aneurysm. METHODS: Retrospective review of a prospectively collected vascular surgery database at a university-affiliated medical center was performed to identify all patients who underwent elective repair of an abdominal aortic aneurysm between 2000 and 2013 and were 60 years of age or younger at the time of the repair. Preoperative anatomic measurements were performed and compared with instructions for use (IFU) criteria for the endografts. RESULTS: The study cohort comprised 169 patients 60 years of age or younger (mean age, 56.7 +/- 2.8 years) who underwent elective repair (119 open repair, 50 EVAR). Patients treated with open repair and EVAR had similar comorbidities, except that EVAR patients were more likely to have hypertension (P = .03) and poor left ventricular function (P = .04). The open repair group had significantly larger suprarenal (P = .004) and infrarenal (P = .005) neck angles, shorter neck lengths (P < .001), and larger maximum aneurysm diameter (P = .02) compared with the EVAR group. Only five patients (13%) in the EVAR group did not meet all IFU criteria. The overall in hospital mortality rate was 1.8% (0% EVAR, 2.5% open repair; P = .56). Overall mean life expectancy was 11.5 years (9.8 years EVAR, 11.9 years open repair; P = .09). The 1-year (98% EVAR, 96% open repair), 5-year (86% EVAR, 88% open repair), and 10-year (54% EVAR, 75% open repair) survival did not differ between EVAR and open repair (P = .16). Long-term survival (78% EVAR, 85% open repair; P = .09) and reintervention rates (12% EVAR, 16% open repair; P = .80) did not differ. No late aneurysm rupture or aneurysm-related deaths were observed. The most common causes of long-term mortality were malignant disease and cardiovascular events. Reinterventions in the open repair group were exclusively laparotomy related (incisional hernia repairs), whereas all reinterventions in the EVAR group were aortic related, including one conversion to open repair. CONCLUSIONS: After elective aneurysm repair, younger patients have a moderate life expectancy related to malignant disease and cardiovascular health. EVAR offers durability and long-term survival similar to those with open repair in these younger patients as long as aneurysm anatomy and IFU are adhered to. PMID- 25457460 TI - Peer victimization as a mediator of the relationship between disability status and psychosocial distress. AB - BACKGROUND: Youth with disabilities experience greater levels of peer victimization and psychosocial distress than non-disabled youth. However, the extent to which exposure to peer victimization mediates the relationship between disability status and psychosocial distress is unknown. OBJECTIVE: To determine whether the relationship between disability status and psychological distress was mediated by exposure to peer victimization, and if so, whether the mediation effects of peer victimization on psychosocial distress was moderated by sex. METHODS: This cross-sectional study involved a series of regressions to test for mediation and moderated mediation using complex survey data from 6664 Oregon 11th graders. RESULTS: Peer victimization partially mediated the relationship between disability status and psychosocial distress. Sex, however, did not significantly moderate the mediating effects of peer victimization on psychosocial distress. CONCLUSION: Exposure to peer victimization mediated the relationship between disability status and psychosocial distress; there was little support for sex as a moderator. PMID- 25457461 TI - Increased serum mannose binding lectin levels are associated with diabetic retinopathy. AB - BACKGROUND: Mannose-binding lectin (MBL) may be implicated in the pathogenesis of diabetic retinopathy (DR) complications. We investigated serum MBL levels in type 2 diabetic patients with and without DR. METHOD: Serum MBL levels were determined in 184 type 2 diabetic patients with DR and 189 type 2 diabetic patients without DR matched for age, sex, and duration of diabetes. Multivariate analyses were performed using logistic regression models. The diagnostic value of MBL was compared with the HbA1c, Hs-CRP and with other known markers. RESULTS: We found that serum MBL levels were significantly higher in diabetes with DR as compared to without-DR [3456 (IQR, 3128-3800) ug/l and 2432 (IQR, 2100-2670) ug/l, respectively; P<0.0001]. In multivariate logistic regression analysis, after adjusting for all other significant factors, MBL remained can be seen as an independent DR marker with an adjusted OR of 1.002 (95% CI, 1.001-1.003; P<0.0001). Based on the ROC curve, the optimal cutoff value of serum MBL levels as an indicator for diagnosis of DR was projected to be 3050 ug/L, which yielded a sensitivity of 82.5% and a specificity of 88.0%, with the area under the curve at 0.907 (95% CI, 0.876-0.938). CONCLUSION: In type 2 diabetic patients, evaluated serum levels of MBL can be seen as an independent marker of DR even after correcting for possible confounding factors. PMID- 25457462 TI - A clinical screening score for diabetic polyneuropathy: KORA F4 and AusDiab studies. AB - AIMS: Since screening for distal sensorimotor polyneuropathy (DSPN) in individuals with diabetes is being underused, our aim was to develop a clinical screening score for identifying individuals with DSPN. METHODS: All participants with type 2 diabetes and aged 61-82 years from the German population-based KORA F4 Study (n=177) and the Australian population-based AusDiab Study (n=244) were combined into one study sample. Risk indicators of DSPN were identified and entered into a stepwise model-selection procedure, constructing two consecutive scores with increasing complexity (a base and clinical model). RESULTS: The prevalence of DSPN was 18.2% (95% confidence interval (CI): 14.7-22.3). The base model comprised age (years), height (cm), weight (kg), pain or discomfort in the feet and/or legs (yes/no), and duration of diabetes (years), yielding an area under the receiver operating characteristics curve (AUC) of 0.80 (95% CI: 0.76 0.85). The clinical model additionally included diastolic blood pressure (mmHg) and serum creatinine levels (mmol/l). The AUC increased only marginally to 0.82 (0.77-0.87) (p for AUC comparison=0.188). The internal validation of the scores produced similar AUCs. CONCLUSIONS: The screening scores developed in this study are a simple tool to differentiate between a high and low likelihood of having DSPN among individuals with type 2 diabetes. PMID- 25457463 TI - Intraoperative condyle positioning by sonographic monitoring in orthognathic surgery verified by MRI. AB - OBJECTIVE: Repositioning of the jaw in orthognathic surgery must produce precise and stable long-term results; an effective and practical method of intraoperative condyle positioning is required to achieve this. Most traditional methods, such as manual positioning or positioning plates do not permit intraoperative monitoring of the temporomandibular joint (TMJ) position. This study evaluates the results of intraoperative, sonographically-monitored joint positioning, comparing preoperative and postoperative MRI scans. PATIENTS AND METHODS: Of the 97 patients who were originally assessed (53 female, average age 29 +/- 10.93; and 44 male, average age 28 +/- 9.25), 21 had incomplete data sets and were excluded, leaving 76 evaluable patients. MRIs were performed preoperatively between 2 days and 100 weeks (median 30.5 days), and postoperatively between 12 and 96 weeks (median 150 days). Condyle positioning, intercondylar distance, and disc degeneration and dislocation were compared in preoperative and postoperative MRIs, and differentiated by Angle class on horizontal, axial and sagittal scans. Condyle to fossa distances were measured on parasagittal images from 0 degrees (the vertical sagittal plane), 45 degrees anteriorly and 45 degrees posteriorly. The intercondylar distances between the condylar head midpoints were measured on axial sections. Two-sided t-tests (alpha < 0.05) were used for comparisons within classes; the interclass correlation was performed using univariate ANOVA and linear correlation for paired sample correlation settings. RESULTS: In 27 Angle class II cases, the anterior distance of both condyles increased on average 0.3 +/- 1.0 mm, the posterior position decreased 0.1 +/- 1.2 mm, and the vertical position decreased 0.2 +/- 1.1 mm postoperatively. In 47 Angle class III cases the anterior distance of both condyles increased on average 0.3 +/- 0.8 mm, the posterior 0.1 +/- 0.8 mm and the vertical distance 0.1 +/- 0.8 mm postoperatively. All alterations of the condyle-fossa relation were non significant except for the anterior distance in Angle class III (p = 0.02). Alterations of the disc position and disc degeneration were non-significant in class II. In class III, the disc degeneration deteriorated slightly on the left side (p = 0.02). Intercondylar distance increased 1 +/- 5.5 mm in class II and decreased by 1 +/- 5.5 mm in class III postoperatively, alterations were non significant. CONCLUSION: Sonography is a non-invasive, comfortable, fast, economical and effective intraoperative method of condyle positioning. The results of the present study support this statement because the degree of disc degeneration and luxation remained unaltered and the condyle position did not change significantly. Prospective randomized comparison to manual positioning is in preparation and will be conducted in the near future. PMID- 25457464 TI - Is mandibular asymmetry more frequent and severe with unilateral disc displacement? AB - PURPOSE: To investigate the prevalence of mandibular asymmetry (MA) within the symptomatic unilateral anterior disc displacement (ADD) patients, and analyze the influence TMJ factors of the MA severity. METHODS: Patients aged under 20 years old with symptomatic unilateral ADD and asymptomatic volunteers with normal disc condyle relationship diagnosed by magnetic resonance imaging (MRI) were included in this study. Posteroanterior cephalometric radiographs were taken to measure MA. Condylar height, disc length and disc displacement were measured by MRI. The prevalence and severity of MA were compared between the ADD and the control groups. The correlation between the severity of MA with the amount of condylar height shortage, disc deformity and distance of disc displacement were also evaluated within the ADD group. RESULTS: There were 165 cases in the unilateral ADD group, and 156 cases in the control group. One hundred and nineteen cases had MA which accounted 72.12% (119/165) in the ADD group; while in the control group, only 25.64% (40/156) exhibited MA. The mean horizontal menton deviation and condylar height shortage in the unilateral ADD group were significantly larger than that in the control group (5.62 mm vs. 4.19 mm; 3.14 mm vs. 1.32 mm, p < 0.01). The severity of MA was significantly correlated with the amount of disc displacement, disc deformity and condylar height shortage (correlation coefficient: 0.80, 0.70, and 0.82). CONCLUSION: MA is much more common and severe in young unilateral ADD patients. The severity of MA is correlated with the height of condyle and the status of the disc. PMID- 25457466 TI - Clinical and radiological characteristics of Graves' orbitopathy patients showing spontaneous decompression. AB - OBJECTIVE: To investigate clinical implications and radiological characteristics of spontaneous decompression in patients with Graves' orbitopathy (GO). METHODS: The medical records and images of GO patients showing spontaneous decompression in computed tomography (CT) scans without any other cause, such as orbital surgery or trauma were retrospectively reviewed. Clinical parameters, including clinical activity score (CAS), modified NOSPECS score, exophthalmometry results, extraocular muscle involvement, and the presence of optic nerve compression were evaluated. Paired orbit analyses of maximum recti muscle diameters, area of lamina papyracea, and number of ethmoid air cell septa were determined quantitatively in the unilaterally decompressed group. RESULTS: 77 orbits of 55 patients were found to present spontaneous decompression, which was observed only in the medial orbital wall in all cases. In the paired orbit comparison, maximal diameters of medial (P = 0.009) and lateral recti muscles (P = 0.023) were significantly larger in decompressed orbits than in non-decompressed orbits. However, the incidence of optic neuropathy was not significantly different (P = 0.500). There was no difference in anatomic features of lamina papyracea or ethmoid air cells between decompressed and non-decompressed orbits. CONCLUSIONS: Spontaneous decompression occurred in the medial wall, associated with enlarged horizontal recti muscles, but not with structures of lamina papyracea or the ethmoidal sinus. Orbital bone remodeling by spontaneous decompression by lowering intraorbital pressure, might have provided a protective effect against the development of optic neuropathy. PMID- 25457465 TI - European Maxillofacial Trauma (EURMAT) project: a multicentre and prospective study. AB - The purpose of this study was to analyse the demographics, causes and characteristics of maxillofacial fractures managed at several European departments of oral and maxillofacial surgery over one year. The following data were recorded: gender, age, aetiology, site of facial fractures, facial injury severity score, timing of intervention, length of hospital stay. Data for a total of 3396 patients (2655 males and 741 females) with 4155 fractures were recorded. The mean age differed from country to country, ranging between 29.9 and 43.9 years. Overall, the most frequent cause of injury was assault, which accounted for the injuries of 1309 patients; assaults and falls alternated as the most important aetiological factor in the various centres. The most frequently observed fracture involved the mandible with 1743 fractures, followed by orbital zygomatic-maxillary (OZM) fractures. Condylar fractures were the most commonly observed mandibular fracture. The results of the EURMAT collaboration confirm the changing trend in maxillofacial trauma epidemiology in Europe, with trauma cases caused by assaults and falls now outnumbering those due to road traffic accidents. The progressive ageing of the European population, in addition to strict road and work legislation may have been responsible for this change. Men are still the most frequent victims of maxillofacial injuries. PMID- 25457467 TI - Internal fixation of mandibular angle fractures using one miniplate in Greek children: a 5-year retrospective study. AB - Treatment modalities of mandibular angle fractures (MAFs) have been analyzed in several studies mainly referring to adult populations. AIM: The aim of this study was to retrospectively present and discuss our experience and literature findings regarding the treatment of MAFs in children. PATIENTS AND METHODS: Data were retrieved from the files of the Oral and Maxillofacial department, at the Children's Hospital ''P. & A. Kyriakou'' of Athens, during a 5 years period (2009 2013). Demographic features, treatment methods, outcome and follow-up of all patients with mandibular angle fractures were recorded. RESULTS: 6 boys, 5-14 years old (mean age 10 years), were included in the study. They were all treated intraorally with open reduction and fixation via one monocortical titanium plate osteosynthesis at the external oblique line of the mandible, followed by 1 week of intermaxillary fixation (IMF). Plates were removed 3-12 months post operatively. Follow-up period ranged from 12 to 18 months (mean 14.7 months). All fractures healed uneventfully and the patients tolerated well both the operation and the post-operative period. CONCLUSION: Osteosynthesis via intraoral approach combined with short duration IMF is adequate in treating MAFs in children. PMID- 25457468 TI - Influence of different palate repair protocols on facial growth in unilateral complete cleft lip and palate. AB - OBJECTIVE: To address the question of whether one- or two-stage palatal treatment protocol has fewer detrimental effects on craniofacial growth in patients aged 5 years with unilateral complete cleft lip and palate. MATERIALS AND METHODS: Forty patients with non-syndromic unilateral complete cleft lip and palate (UCCLPs) who had received primary cleft lip repair at age 6-12 months and cleft palate repair at age 18-30 months were selected in this study. Eighteen UCCLP patients who received two-stage palate repair were selected as group 1, and 22 UCCLP patients who received one-stage palate repair were selected as group 2. The control group consisted of 20 patients with unilateral incomplete cleft lip (UICL patients) whose age and gender matched with UCCLP patients. A one-sample Kolmogorov-Smirnov test was used to analyze the nature of data distribution. Bonferroni test and Kruskal-Wallis H tests were used for multiple comparisons. RESULTS: Both case groups showed reduced maxillary sagittal length (ANS-PMP, A-PM, p < 0.05) and retrusion of the maxilla (S-Ptm, p < 0.05), A point and ANS point (Ba-N-A, Ba-N ANS, p < 0.05). Patients treated with two-stage palate repair had a reduced posterior maxillary vertical height (R-PMP, p < 0.05). CONCLUSIONS: Our results indicated that maxillary sagittal length and position could be perturbed by both one- and two-stage palate repair. Vomer flap repair inhibited maxilla vertical growth. Delayed hard palate repair showed less detrimental effects on maxillary growth compared to early hard palate repair in UCCLP patients aged 5 years. PMID- 25457469 TI - Bone marrow mesenchymal stem cells slow intervertebral disc degeneration through the NF-kappaB pathway. AB - BACKGROUND CONTEXT: Previous studies have demonstrated the use of bone marrow mesenchymal stem cells (BMSCs) in tissue-engineering treatments to slow or reverse diseased intervertebral discs. Several approaches have successfully used the coculturing of stem cells with disc-native nucleus pulposus cells (NPCs) with the evidence of transformed BMSCs into NP-like cells, increased activity and matrix production by NPCs, or elements of both. The influence of the cytokine transforming growth factor-beta (TGF-beta) in the differentiation of BMSCs into NP-like cells and its upregulation in coculture to increase matrix production are well established. However, the role of the inflammatory signaling molecule nuclear factor kappa B (NF-kappaB) in intervertebral disc degeneration is far less clear, although there is some existing evidence suggesting its role in the pathogenesis and progression of disc disease. A limited number of studies in other pathologies have alluded to the antagonistic relationship between both proteins. To date, there is no such investigation of their dynamic role in coculture of BMSCs and NPCs. PURPOSE: The purpose of this study was to investigate the relationship of the regenerative effects of BMSCs cocultured with NPCs. The authors hypothesized that as levels of TGF-beta increase in the coculture, the levels of NF-kappaB will concomitantly decrease. This would in turn be reflected by an increase in the expression of messenger RNA markers of the nucleus pulposus matrix that includes aggrecan, Type II collagen (CII), and SOX-9 and an increase in the cellular proliferation. STUDY DESIGN/SETTING: This study is based on a coculture with the contact of rabbit NPCs and BMSCs. METHODS: Bone marrow mesenchymal stem cells were cocultured with NPCs at a ratio of 1:1 and compared with BMSC and NPC controls cultured alone. Cell proliferation was evaluated by Cell Counting Kit-8 from 3 to 9 days. Gene expressions of aggrecan, CII, and SOX-9 was assayed by reverse transcription-polymerase chain reaction from 5 to 14 days. Detection of TGF-betal and NF-kappaB was determined by enzyme linked immunosorbent assay, and immunohistochemical staining was carried out to evaluate CII synthesis. RESULTS: After 3 days, cellular proliferation of the cocultured group exceeded that of controls. After 11 days, the expression of SOX 9 in the cocultured group had also exceeded controls. Furthermore, after 14 days, expressions of aggrecan and CII significantly exceeded controls. Immunohistochemical stains of CII in the NPC control group were positive at each point in time and demonstrated strongest expression at 14 days. Coculturing BMSCs with NPCs, therefore, seems to have resulted in the promotion of aggrecan, CII, and SOX-9 gene expressions. Finally, after 11 days, TGF-betal content of the cocultured group significantly exceeded control levels, whereas NF-kappaB content had significantly lowered. CONCLUSIONS: Coculture of BMSCs may be able to delay NPC matrix degeneration potentially through the concomitant upregulation of TGF beta and the downregulation of NF-kappaB pathway. PMID- 25457470 TI - Preliminary investigation of high-dose tranexamic acid for controlling intraoperative blood loss in patients undergoing spine correction surgery. AB - BACKGROUND CONTEXT: With a significant increase in the number and complexity of spinal deformity corrective surgeries, blood loss, often requiring massive intraoperative transfusions, becomes a major limiting factor during surgery. This scenario is particularly during posterior vertebral column resection (PVCR), where extensive intraoperative blood loss may pose a major risk to the patient, preventing smooth execution of the procedure. Tranexamic Acid (TXA) has been used in cardiac and orthopedic surgeries, including major spinal surgeries, to reduce blood loss and transfusion requirements for decades. PURPOSE: To assess the efficacy and safety of high doses of TXA in posterior spinal deformity corrective surgery, including PVCR procedures. STUDY DESIGN: A retrospective study from a single institution. PATIENT SAMPLE: Fifty-nine patients (age range 7 to 46 years old) with spinal deformities undergoing spinal corrective surgeries were included. The patients were divided into two groups: the TXA group (total of 26 patients, including 8 PVCR patients) and the control group (total of 33 patients, including 9 PVCR patients). OUTCOME MEASURES: The analyzed outcome measures included estimated intraoperative blood loss, real blood loss (RBL; blood loss/blood volume*100%), blood transfusion requirements, coagulation parameters, complete blood count, liver function, and renal function. Lower limb vein thrombus, symptomatic pulmonary embolism, symptomatic myocardial infarction, seizures, and acute renal failure were also recorded. METHODS: Before skin incision, the patients in the TXA group received an intravenous loading dose of 100 mg/Kg over a 20-minute period, followed by a maintenance infusion of 10 mg/Kg/h until skin closure was completed. The patients in the control group received saline infusion of a similar volume. Statistics included estimated intraoperative blood loss, RBL, blood transfusion requirements, coagulation parameters, complete blood count, liver function, and renal function. All patients in this study were also carefully monitored for consciousness level, breathing status, chest tightness or pain, and urine output after surgery. These were done to detect the presence or absence of pulmonary embolism, myocardial infarction, seizures, and acute renal failure. Patients treated with TXA were examined via vascular ultrasound before and after surgery. RESULTS: There were no significant differences in the demographic or surgical traits between the two groups. The blood loss of the patients in the TXA group was 2,441+/-1,666 mL, whereas that of the control group patients was 4,789+/-4,719 mL. The difference was statistically significant (p<.05). The average RBL of the patients in the TXA group was 80.6%+/-49.6% versus 160.8%+/-163.1% in the control group (p<.05). The blood transfusion requirements for the patients in the TXA group were significantly less than that in the control group (p<.05). Blood loss, RBL, and blood transfusion requirements were all significantly lower in the TXA group, compared with the control group among both PVCR patients and non-PVCR patients. In the TXA group, there was an average of 57.4% reduced blood loss in patients who received PVCR and 39.8% in patients not receiving PVCR. There were no differences in liver and renal functions between the TXA and control groups. There was no lower limb vein thrombus, symptomatic myocardial infarction, symptomatic pulmonary embolism, seizures, or acute renal failure reported in the TXA group. CONCLUSIONS: In our study, high doses of TXA have been shown to effectively control blood loss and reduce the transfusion requirement. This effect was more apparent in patients receiving PVCR. No adverse drug reaction was recorded in the study. In the future, prospective randomized controlled trials to validate our results will be necessary. Future studies conducted on older patient cohort may also be necessary to confirm the safety of extending the use of TXA to the older patients. PMID- 25457471 TI - The Internet as a communication tool for orthopedic spine fellowships in the United States. AB - BACKGROUND CONTEXT: Orthopedic residents seeking additional training in spine surgery commonly use the Internet to manage their fellowship applications. Although studies have assessed the accessibility and content of Web sites in other medical specialties, none have looked at orthopedic spine fellowship Web sites (SFWs). PURPOSE: The purpose of this study was to evaluate the accessibility of information from commonly used databases and assess the content of SFWs. STUDY DESIGN: This was a Web site accessibility and content evaluation study. METHODS: A comprehensive list of available orthopedic spine fellowship programs was compiled by accessing program lists from the SF Match, North American Spine Society, Fellowship and Residency Electronic Interactive Database (FREIDA), and Orthopaedicsone.com (Ortho1). These databases were assessed for accessibility of information including viable links to SFWs and responsive program contacts. A Google search was used to identify SFWs not readily available on these national databases. SFWs were evaluated based on online education and recruitment content. RESULTS: Evaluators found 45 SFWs of 63 active programs (71%). Available SFWs were often not readily accessible from national program lists, and no program afforded a direct link to their SFW from SF Match. Approximately half of all programs responded via e-mail. Although many programs described surgical experience (91%) and research requirements (87%) during the fellowship, less than half mentioned didactic instruction (46%), journal clubs (41%), and national meetings or courses attended (28%). Evaluators found an average 45% of fellow recruitment content. Comparison of SFWs by program characteristics revealed three significant differences. Programs with greater than one fellowship position had greater online education content than programs with a single fellow (p=.022). Spine fellowships affiliated with an orthopedic residency program maintained greater education (p=.006) and recruitment (p=.046) content on their SFWs. CONCLUSIONS: Most orthopedic spine surgery programs underuse the Internet for fellow education and recruitment. The inaccessibility of information and paucity of content on SFWs allow for future opportunity to optimize these resources. PMID- 25457472 TI - Liraglutide in whole-pancreas transplant patients with impaired glucose homoeostasis: A case series. AB - Hyperglycaemia may develop after whole-pancreas transplantation (PTX) in patients with type 1 diabetes mellitus (T1DM), but the efficacy and tolerability of GLP-1 receptor agonists have not been assessed in this population. This report is a 6 month prospective follow-up of six T1DM recipients of PTX (mean time after PTX: 68.8 +/- 45.7 months), all of whom had an HbA1c>6.5% (48 mmol/mol) [mean: 7.1% (54 mmol/mol)] after initiation of liraglutide alone at 0.6 mg once daily titrated to 1.2mg once daily at week 1. Gastrointestinal disorders were reported in three of the six patients, with discontinuation of liraglutide in only one patient. HbA1c improved in the five remaining patients, with a median decrease of 0.8% (0.0-2.7%) at 6 months, and the median decrease in body weight was 2.0 kg. Immunosuppressive treatments remained unchanged with liraglutide. Thus, liraglutide appears to be an effective and well-tolerated option in PTX patients with impaired glucose homoeostasis, regardless of the cause. PMID- 25457473 TI - Efficacy of vildagliptin and sitagliptin in lowering fasting plasma glucose: Results of a randomized controlled trial. AB - AIM: This study compared the efficacy of vildagliptin and sitagliptin in lowering fasting plasma glucose (FPG) as single-pill combinations (SPCs) with metformin. METHODS: The randomized crossover, open-label, active-controlled study design assessed the FPG-lowering abilities of a vildagliptin/metformin (50/1000 mg twice daily) SPC compared with a sitagliptin/metformin (50/1000 mg twice daily) SPC after 2 weeks of treatment in 99 type 2 diabetes patients uncontrolled by stable metformin therapy (1000-2000 mg/day). RESULTS: The change in FPG from baseline to day 14 was significantly greater (P < 0.02, Wilcoxon) with vildagliptin [-21.9 mg/dL (SD 27.0)] than with sitagliptin [-14.5 mg/dL (SD 23.0)]. After 14 days of treatment, the mean FPG was 137.8 mg/dL (SD 28.5) with vildagliptin and 140.1mg/dL (SD 26.5) with sitagliptin (P < 0.05, Wilcoxon). CONCLUSION: Both of these DPP-4 inhibitors, given as SPCs twice daily with metformin, lowered FPG after 14 days of treatment. However, vildagliptin produced a significantly greater reduction in FPG vs baseline compared with sitagliptin, which may translate into clinical relevance. PMID- 25457474 TI - The impact of hyperfiltration on the diabetic kidney. AB - More than two decades ago, hyperfiltration (HF) in diabetes was postulated to be a maladaptive response observed early in the course of diabetic kidney disease (DKD), which may eventually predispose to irreversible damage to nephrons and development of progressive renal disease. Despite this, the potential mechanisms leading to renal HF in diabetes are not fully understood, although several hypotheses have been proposed, including alterations in glomerular haemodynamic function and tubulo-glomerular feedback. Furthermore, the role of HF as a causative factor in renal disease progression is still unclear and warrants further prospective longer-term studies. Although HF has been entrenched as the first stage in the classic albuminuric pathway to end-stage renal disease in DKD, and HF has been shown to predict the progression of albuminuria in many, but not all studies, the concept that HF predisposes to the development of chronic kidney disease (CKD) stage 3, that is, glomerular filtration rate (GFR) decline to<60mL/min/1.73m(2), remains to be proved. Further long-term studies of GFR gradients therefore are required to establish whether HF ultimately leads to decreased kidney function, after adjustment for glycaemic control and other confounders. Whether reversal of HF with therapeutic agents is protective against reducing the risk of development of albuminuria and renal impairment is also worth investigating in prospective randomized trials. PMID- 25457475 TI - The dawn phenomenon in type 2 diabetes: how to assess it in clinical practice? AB - AIM: The study was aimed at determining whether the dawn phenomenon in type 2 diabetes (T2D) can be predicted and quantified using simple and easily accessible glucose determinations. METHODS: A total of 210 non-insulin-treated persons with T2D underwent continuous glucose monitoring (CGM). The dawn phenomenon was quantified as the absolute increment from the nocturnal glucose nadir to the pre breakfast value (Deltadawn, mg/dL). Pre-lunch (preL) and pre-dinner (preD) glucose, and their averaged values (preLD), were compared with the nocturnal nadir. These pre-meal values were subtracted from the pre-breakfast values. The differences obtained (Deltapre-mealL, Deltapre-meal D and Deltapre-meal LD) were correlated with Deltadawn values. The receiver operating characteristic (ROC) curve was used to select the optimal Deltapre-meal value that best predicted a dawn phenomenon, set at a threshold of 20mg/dL. RESULTS: All pre-meal glucose levels and differences from pre-breakfast values (Deltapre-meal) significantly correlated (P<0.0001) with the nocturnal nadir and Deltadawn values, respectively. The strongest correlations were observed for the parameters averaged at preL and preD time points: r=0.83 for preLD and r=0.58 for Deltapre meal LD. ROC curve analysis indicated that the dawn phenomenon at a threshold of 20mg/dL can be significantly predicted by a Deltapre-meal LD cut off value of 10mg/dL. The relationship between Deltadawn (Y, mg/dL) and Deltapre-meal LD (X, mg/dL) was Y=0.49 X+15. CONCLUSION: The self-monitoring of preprandial glucose values at the three main mealtimes can predict the presence/absence of the dawn phenomenon, and permits reliable assessment of its magnitude without requiring continuous overnight glucose monitoring. PMID- 25457476 TI - Cardiac resynchronization therapy in patients with atrial fibrillation: a meta analysis. AB - BACKGROUND AND OBJECTIVE: To combine the results of the best scientific evidence in order to compare the effects of cardiac resynchronization therapy (CRT) in heart failure patients with atrial fibrillation (AF) and in sinus rhythm (SR) and to determine the effect of atrioventricular nodal ablation in AF patients. METHODS: The electronic databases PubMed, B-On and Cochrane CENTRAL were searched, and manual searches were performed, for randomized controlled trials and cohort studies up to November 2012. The endpoints analyzed were all-cause and cardiovascular mortality and response to CRT. RESULTS: We included 19 studies involving 5324 patients: 1399 in AF and 3925 in SR. All-cause mortality was more likely in patients with AF compared to patients in SR (OR = 1.69; 95% CI: 1.20 2.37; p = 0.002). There were no statistically significant differences in cardiovascular mortality (OR = 1.36; 95% CI: 0.92-2.01; p = 0.12). AF was associated with an increased likelihood of lack of response to CRT (OR = 1.41; 95% CI: 1.15-1.73; p = 0.001). Among subjects with AF, ablation of the atrioventricular node was associated with a reduction in all-cause mortality (OR = 0.42; 95% CI: 0.22-0.80; p = 0.008), cardiovascular death (OR = 0.39; 95% CI: 0.20-0.75; p = 0.005) and the number of non-responders to CRT (OR = 0.30; 95% CI: 0.10-0.90; p = 0.03). CONCLUSIONS: The presence of AF is associated with increased likelihood of all-cause death and non-response to CRT, compared to patients in SR. However, many patients with AF benefit from CRT. Atrioventricular nodal ablation appears to increase the benefits of CRT in patients with AF. PMID- 25457477 TI - National practice patterns of treatment of erectile dysfunction with penile prosthesis implantation. AB - PURPOSE: The increase in medical options to manage erectile dysfunction has changed how urologists approach erectile dysfunction. We reviewed contemporary trends in penile prosthesis implantation in the United States with an emphasis on practice patterns, demographics and temporal changes. MATERIALS AND METHODS: Annualized case log data of penile prosthesis surgeries from certifying and recertifying urologists from 2003 to 2012 were obtained from the American Board of Urology. CPT code 54400 was used to identify malleable prosthesis surgeries and CPT codes 54401 and 54405 were used to identify inflatable prosthesis surgeries. To evaluate the association between surgeon characteristics and practice patterns we used the chi-square test. RESULTS: The surgical cohort included 6,615 urologists who placed a total of 9,558 penile prostheses during the study period. Only 23.9% of urologists reported performing a penile prosthesis operation. Of the prostheses 75% were placed by surgeons who completed 4 or fewer such operations per year. Of urologists who recorded logs 1.5% considered themselves to be specialists in andrology and yet they were responsible for a disproportionate 10% of all prostheses implanted (OR 5.9, p <0.0001). The proportion of inflatable penile prostheses compared to malleable prostheses increased twelvefold in 10 years. The number of logged prosthesis surgeries was skewed toward more implants placed by the most experienced urologists than by new urologists (OR 1.92, p <0.0001). CONCLUSIONS: Although specialists and high volume surgeons perform a disproportionate number of implant surgeries, low volume surgeons place most penile prostheses in the United States. Additional research is needed to determine best practices to achieve optimal patient outcomes in penile prosthesis surgery. PMID- 25457478 TI - The clinical impact of hip joint centre regression equation error on kinematics and kinetics during paediatric gait. AB - Regression equations based on pelvic anatomy are routinely used to estimate the hip joint centre during gait analysis. While the associated errors have been well documented, the clinical significance of these errors has not been reported. This study investigated the clinical agreement of three commonly used regression equation sets (Bell et al., Davis et al. and Orthotrak software) against the equations of Harrington et al. Full 3-dimensional gait analysis was performed on 18 healthy paediatric subjects. Kinematic and kinetic data were calculated using each set of regression equations and compared to Harrington et al. In addition, the Gait Profile Score and GDI-Kinetic were used to assess clinical significance. Bell et al. was the best performing set with differences in Gait Profile Score (0.13 degrees ) and GDI-Kinetic (0.84 points) falling below the clinical significance threshold. Small deviations were present for the Orthotrak set for hip abduction moment (0.1 Nm/kg), however differences in Gait Profile Score (0.27 degrees ) and GDI-Kinetic (2.26 points) remained below the clinical threshold. Davis et al. showed least agreement with a clinically significant difference in GDI-Kinetic score (4.36 points). It is proposed that Harrington et al. or Bell et al. regression equation sets are used during gait analysis especially where inverse dynamic data are calculated. Orthotrak is a clinically acceptable alternative however clinicians must be aware of the effects of error on hip abduction moment. The Davis et al. set should be used with caution for inverse dynamic analysis as error could be considered clinically meaningful. PMID- 25457479 TI - Slow changing postural cues cancel visual field dependence on self-tilt detection. AB - Interindividual differences influence the multisensory integration process involved in spatial perception. Here, we assessed the effect of visual field dependence on self-tilt detection relative to upright, as a function of static vs. slow changing visual or postural cues. To that aim, we manipulated slow rotations (i.e., 0.05 degrees s(-1)) of the body and/or the visual scene in pitch. Participants had to indicate whether they felt being tilted forward at successive angles. Results show that thresholds for self-tilt detection substantially differed between visual field dependent/independent subjects, when only the visual scene was rotated. This difference was no longer present when the body was actually rotated, whatever the visual scene condition (i.e., absent, static or rotated relative to the observer). These results suggest that the cancellation of visual field dependence by dynamic postural cues may rely on a multisensory reweighting process, where slow changing vestibular/somatosensory inputs may prevail over visual inputs. PMID- 25457480 TI - Gait characteristics of adults with Down syndrome explain their greater metabolic rate during walking. AB - The altered gait patterns of adults with Down syndrome (DS) may contribute to their higher net metabolic rate (net-MR) during walking than adults without DS, leading to mobility limitations. This study examined the extent to which gait characteristics explain differences in net-MR during walking between adults with and without DS. Fifteen adults with DS (27 +/- 8 years) and 15 adults without DS (28 +/- 6 years) completed two testing sessions in which expiratory gases and kinematic data were collected, respectively, during treadmill walking. Participants walked at six, randomly-presented dimensionless speeds, ranging from slow to fast. Hierarchical and stepwise regressions were used to determine the proportion of the variance in net-MR explained by gait variables that differed between groups, after controlling for variance due to walking speed. Positive work rate, the range of the body center of mass (COM) mediolateral position and its square, variability in the time-course of COM anteroposterior velocity, and the variability of step length, step width, and step time significantly predicted net-MR (p < .05). These variables collectively explained 73.9% of the variance in net-MR that was explained by DS but not by walking speed. After accounting for shared variance among predictors, step length variability made the greatest unique contribution (10.6%) to the higher net-MR in adults with DS, followed by the range of COM mediolateral motion (6.3%), step width variability (2.8%), and variability in COM anteroposterior velocity (0.7%). Therefore, the gait characteristics of adults with DS appear to largely explain their higher net-MR during walking. PMID- 25457481 TI - Anticipatory changes in control of swing foot and lower limb joints when walking onto a moving surface traveling at constant speed. AB - Adapting to a predictable moving surface such as an escalator is a crucial part of daily locomotor tasks in modern cities. However, the associated biomechanics have remained unexplored. In a gait laboratory, fifteen young adults walked from the ground onto a moving or a static surface while their kinematic and kinetic data were obtained for calculating foot and pelvis motions, as well as the angles and moments of the lower limb joints. Between-surface-condition comparisons were performed using a paired t-test (alpha = 0.05). The results showed that anticipatory locomotor adjustments occurred at least a stride before successfully walking onto the moving surface, including increasing step length and speed in the trailing step (p < 0.05), but the opposite in the leading step (p < 0.05). These modifications reduced the plantarflexor moment of the trailing ankle needed for stabilizing the body, while placing increased demand on the knee extensors of the trailing stance limb. For a smooth landing and to reduce the risk of instability, the subjects adopted a flat foot contact pattern with reduced leading toe-clearance (p < 0.05) at an instantaneous speed matching that of the moving surface (p > 0.05), mainly through reduced extension of the trailing hip but increased pelvic anterior tilt and leading swing ankle plantarflexion (p < 0.05). The current results provide baseline data for future studies on other populations, which will contribute to the design and development of strategies to address falls while transferring onto moving surfaces such as escalators. PMID- 25457482 TI - Non-uniform in vivo deformations of the human Achilles tendon during walking. AB - The free Achilles tendon (AT) consists of distinct fascicles arising from each of the triceps surae muscles that may give rise to non-uniform behavior during functional tasks such as walking. Here, we estimated in vivo deformations of the human AT during walking using simultaneous ultrasound and motion capture measurements. Ten subjects walked at three speeds (0.75, 1.00, and 1.25 m/s) on a force-measuring treadmill. A custom orthotic secured a linear array transducer in two locations: (1) the distal lateral gastrocnemius muscle-tendon junction and (2) the free AT, on average centered 6 cm superior to calcaneal insertion. We used motion capture to record lower extremity kinematics and the position and orientation of the ultrasound transducer. A 2D ultrasound elastography algorithm tracked superficial and deep tissue displacements within the free AT. We estimated AT elongation (i.e., change in length) relative to the calcaneal insertion by transforming the orthotic, transducer, and calcaneus kinematics into a common reference frame. Superficial and deep regions of the free AT underwent significantly different longitudinal displacements and elongations during walking. For example, we found that the superficial AT exhibited 16-29% greater peak elongation than the deep AT during the stance phase of walking (p < 0.01). Moreover, superficial-deep AT tissue deformations became less uniform with faster walking speed (p < 0.01). Non-uniform deformations of the free AT, which could reflect inter-fascicle sliding, may enable the gastrocnemius and soleus muscles to transmit their forces independently while allowing unique kinematic behavior at the muscle fiber level. PMID- 25457483 TI - Anti-inflammatory activity on mice of extract of Ganoderma lucidum grown on rice via modulation of MAPK and NF-kappaB pathways. AB - Ganoderma lucidum is a popular medicinal mushroom with anti-inflammatory potential. In the present study, the aim was to determine the anti-inflammatory effect and mode of action of G. lucidum grown on germinated brown rice (GLBR) in a mouse model of colitis. It was shown that GLBR suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS) stimulated macrophages and decreased the expression of COX-2, TNF-alpha, iNOS, IL 1beta, IL-6, and IL-10 mRNAs. GLBR also inhibited activation of p38, ERK, JNK, MAPKs, and nuclear factor kappa-B (NF-kappaB). In a mouse model of colitis, colonic mucosal injury was evaluated using macroscopic, biochemical, and histopathological testing. Disease activity index (DAI), macroscopic score, and histological score significantly decreased upon GLBR treatment. Moreover, immunofluorescence studies indicated that DSS activates nuclear translocation of NF-kappaB in colon tissue, which is attenuated by GLBR extract. These findings suggest that GLBR is protective against colitis via inhibition of MAPK phosphorylation and NF-kappaB activation. PMID- 25457484 TI - Molecular defense response of oil palm to Ganoderma infection. AB - Basal stem rot (BSR) of oil palm roots is due to the invasion of fungal mycelia of Ganoderma species which spreads to the bole of the stem. In addition to root contact, BSR can also spread by airborne basidiospores. These fungi are able to break down cell wall components including lignin. BSR not only decreases oil yield, it also causes the stands to collapse thus causing severe economic loss to the oil palm industry. The transmission and mode of action of Ganoderma, its interactions with oil palm as a hemibiotroph, and the molecular defence responses of oil palm to the infection of Ganoderma boninense in BSR are reviewed, based on the transcript profiles of infected oil palms. The knowledge gaps that need to be filled in oil palm-Ganoderma molecular interactions i.e. the associations of hypersensitive reaction (HR)-induced cell death and reactive oxygen species (ROS) kinetics to the susceptibility of oil palm to Ganoderma spp., the interactions of phytohormones (salicylate, jasmonate and ethylene) at early and late stages of BSR, and cell wall strengthening through increased production of guaiacyl (G) type lignin, are also discussed. PMID- 25457485 TI - Lanostane triterpenoids from Ganoderma hainanense J. D. Zhao. AB - Chemical investigation of the fruiting bodies of Ganoderma hainanense resulted in isolation of fourteen lanostane triterpenoids, including nine ganoderma acids and five ganoderma alcohols, together with five known compounds. Structural elucidation was determined using extensive spectroscopic technologies, Mosher's method and X-ray single crystal diffraction. Three of the compounds showed inhibitory activities against HL-60, SMMC-7721, A-549 and MCF-7 cells with IC50 values of 15.0-40.0 MUM. PMID- 25457487 TI - Chemical features of Ganoderma polysaccharides with antioxidant, antitumor and antimicrobial activities. AB - Ganoderma genus comprises one of the most commonly studied species worldwide, Ganoderma lucidum. However, other Ganoderma species have been also reported as important sources of bioactive compounds. Polysaccharides are important contributors to the medicinal properties reported for Ganoderma species, as demonstrated by the numerous publications, including reviews, on this matter. Yet, what are the chemical features of Ganoderma polysaccharides that have bioactivity? In the present manuscript, the chemical features of Ganoderma polysaccharides with reported antioxidant, antitumor and antimicrobial activities (the most studied worldwide) are analyzed in detail. The composition of sugars (homo- versus hetero-glucans and other polysaccharides), type of glycosidic linkages, branching patterns, and linkage to proteins are discussed. Methods for extraction, isolation and identification are evaluated and, finally, the bioactivity of polysaccharidic extracts and purified compounds are discussed. The integration of data allows deduction of structure-activity relationships and gives clues to the chemical aspects involved in Ganoderma bioactivity. PMID- 25457486 TI - Accessing biological actions of Ganoderma secondary metabolites by in silico profiling. AB - The species complex around the medicinal fungus Ganoderma lucidum Karst. (Ganodermataceae) is widely known in traditional medicines, as well as in modern applications such as functional food or nutraceuticals. A considerable number of publications reflects its abundance and variety in biological actions either provoked by primary metabolites, such as polysaccharides, or secondary metabolites, such as lanostane-type triterpenes. However, due to this remarkable amount of information, a rationalization of the individual Ganoderma constituents to biological actions on a molecular level is quite challenging. To overcome this issue, a database was generated containing meta-information, i.e., chemical structures and biological actions of hitherto identified Ganoderma constituents (279). This was followed by a computational approach subjecting this 3D multi conformational molecular dataset to in silico parallel screening against an in house collection of validated structure- and ligand-based 3D pharmacophore models. The predictive power of the evaluated in silico tools and hints from traditional application fields served as criteria for the model selection. Thus, the focus was laid on representative druggable targets in the field of viral infections (5) and diseases related to the metabolic syndrome (22). The results obtained from this in silico approach were compared to bioactivity data available from the literature. 89 and 197 Ganoderma compounds were predicted as ligands of at least one of the selected pharmacological targets in the antiviral and the metabolic syndrome screening, respectively. Among them only a minority of individual compounds (around 10%) has ever been investigated on these targets or for the associated biological activity. Accordingly, this study discloses putative ligand target interactions for a plethora of Ganoderma constituents in the empirically manifested field of viral diseases and metabolic syndrome which serve as a basis for future applications to access yet undiscovered biological actions of Ganoderma secondary metabolites on a molecular level. PMID- 25457489 TI - Fatty acid profiles from the plasma membrane and detergent resistant membranes of two plant species. AB - It is essential to establish the composition of the plant plasma membrane in order to understand its organization and behavior under continually changing environments. Knowledge of the lipid phase, in particular the fatty acid (FA) complex repertoire, is important since FAs determine many of the physical chemical membrane properties. FAs are constituents of the membrane glycerolipid and sphingolipid backbones and can also be linked to some sterols. In addition, FAs are components of complex lipids that can constitute membrane micro-domains, and the use of detergent-resistant membranes is a common approach to study their composition. The diversity and cellular allocation of the membrane lipids containing FAs are very diverse and the approaches to analyze them provide only general information. In this work, a detailed FA analysis was performed using highly purified plasma membranes from bean leaves and germinating maize embryos and their respective detergent-resistant membrane preparations. The analyses showed the presence of a significant amount of very long chain FAs (containing 28C, 30C and 32C), in both plasma membrane preparations from bean and maize, that have not been previously reported. Herein is demonstrated that a significant enrichment of very long chain saturated FAs and saturated FAs can occur in detergent-resistant membrane preparations, as compared to the plasma membranes from both plant species. Considering that a thorough analysis of FAs is rarely performed in purified plasma membranes and detergent-resistant membranes, this work provides qualitative and quantitative evidence on the contributions of the length and saturation of FAs to the organization of the plant plasma membrane and detergent-resistant membranes. PMID- 25457488 TI - Non-host disease resistance response in pea (Pisum sativum) pods: Biochemical function of DRR206 and phytoalexin pathway localization. AB - Continually exposed to potential pathogens, vascular plants have evolved intricate defense mechanisms to recognize encroaching threats and defend themselves. They do so by inducing a set of defense responses that can help defeat and/or limit effects of invading pathogens, of which the non-host disease resistance response is the most common. In this regard, pea (Pisum sativum) pod tissue, when exposed to Fusarium solani f. sp. phaseoli spores, undergoes an inducible transcriptional activation of pathogenesis-related genes, and also produces (+)-pisatin, its major phytoalexin. One of the inducible pathogenesis related genes is Disease Resistance Response-206 (DRR206), whose role in vivo was unknown. DRR206 is, however, related to the dirigent protein (DP) family. In this study, its biochemical function was investigated in planta, with the metabolite associated with its gene induction being pinoresinol monoglucoside. Interestingly, both pinoresinol monoglucoside and (+)-pisatin were co-localized in pea pod endocarp epidermal cells, as demonstrated using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging. In addition, endocarp epidermal cells are also the site for both chalcone synthase and DRR206 gene expression. Taken together, these data indicate that both (+)-pisatin and pinoresinol monoglucoside function in the overall phytoalexin responses. PMID- 25457490 TI - Unusual cycloartane triterpenoids from Kadsura ananosma. AB - Five 3,4-seco-cycloartane triterpenoids were isolated from the stems of Kadsura ananosma, two of which had rearranged 5/6 consecutive carbocycle rings C/D (trivially named ananosins A (1) and B (2)), one had a migrated CH3-18 (named ananosins C (3)), and two were analogs, ananosins D (4) and E (5). Their structures were characterized by comprehensive spectroscopic analysis, especially using 2D NMR spectra. A biogenetic pathway to 1 was proposed. These 5 compounds, together with 5 known analogs isolated from the same origin, were evaluated for their cytotoxicity against HL-60, SMMC-7721, A-549, PANC-1, and SK-BR-3 human cancer cells, but were inactive. PMID- 25457491 TI - Quinolone and indole alkaloids from the fruits of Euodia rutaecarpa and their cytotoxicity against two human cancer cell lines. AB - Four quinolone alkaloids (1-4) and three indole alkaloids (20-22), together with 30 known alkaloids (5-19, 23-37), were isolated from the fruits of Euodia rutaecarpa. Their structures were established by spectroscopic analyses. The in vitro cytotoxic activities of these alkaloids against leukaemia HL-60 and prostate cancer PC-3 cell lines were evaluated. PMID- 25457492 TI - Diels-Alder adducts with PTP1B inhibition from Morus notabilis. AB - Eight Diels-Alder adducts, morbilisins A-H (1-8), a known analogue, chalcomoracin (9), together with eleven known flavonoids and 2-arylbenzofurans, were isolated from the leaves of Morus notabilis. Their structures were elucidated by extensive spectroscopic analysis, including 1D, 2D NMR, MS, and ECD data. Compounds 1, 5, and 7-9 showed inhibition against PTP1B phosphatase activity in vitro. PMID- 25457493 TI - Withanolides from Physalis coztomatl. AB - Six withanolides (1-6), as well as two known withanolides (physachenolide D 7 and withanoside VI 8), were isolated from the aerial parts of Physalis coztomatl (Solanaceae). Structural elucidations of 1-6 were achieved through 2D NMR and other spectroscopic techniques, while the structure of 1 was confirmed by X-ray crystallographic analysis. In addition, the stereochemical orientation of the 17 hydroxy group in withanolides was discussed in relation to (13)C NMR shifts of C 12, 13, 14 and 16. Such analysis established that coagulansin A contains a 17alpha-hydroxy moiety rather than the reported 17beta-hydroxy functionality, and has been revised accordingly. PMID- 25457494 TI - Radical prostatectomy versus radiation therapy: can pretreatment nomograms be used to select the appropriate prostate cancer treatment? PMID- 25457495 TI - Risk Stratification in Hormone-sensitive Metastatic Prostate Cancer: More Questions than Answers. PMID- 25457496 TI - Differences in Treatment and Outcome After Treatment with Curative Intent in the Screening and Control Arms of the ERSPC Rotterdam. AB - Screening for prostate cancer (PCa) results in a favorable stage shift. However, even if screening did not result in a clinically apparent lower stage or grade, it might still lead to less disease recurrence after treatment with curative intent (radical prostatectomy [RP] and radiation therapy [RT]) because the tumor had less time to develop outside the prostate. The outcome after treatment could also differ because of variations in treatment quality (eg, radiation dosage/adjuvant hormonal therapy). To test these hypotheses, we compared differences in the treatment quality of the screening and control arms of the European Randomized Study of Screening for Prostate Cancer (ERSPC) Rotterdam and disease-free survival (DFS) after curative treatment in PCa patients with similar stage and grade. A total of 2595 men were initially treated with RP or RT. In the control arm, RT was more often combined with hormonal therapy; treatment dosage was often >=69Gy. This most likely resulted from changes over time in treatment that coincided with the later detection in the control arm. DFS was higher in the screening arm in all risk groups. After correction for lead time, these differences were minimal, however. We concluded that treatment quality differed between the screening and control arms of the ERSPC Rotterdam. RT quality was especially superior in the control arm with higher dosages and more often RT in combination with hormonal therapy. Despite these differences favoring the control arm, DFS differences were minimal. PATIENT SUMMARY: We looked at differences in prostate cancer (PCa) treatment and outcome after PCa treatment in men diagnosed after screening and men diagnosed after normal clinical practice. Treatment differed with superior treatment given to men diagnosed in normal clinical practice. We propose a likely explanation for this apparently counterintuitive finding (progressive insight combined with, on average, a later detection of tumors in unscreened men). Although unscreened men received better treatment, this advantage seemed to be outweighed by the advantage associated with the earlier detection, on average, of the tumor in screened men. TRIAL REGISTRATION: ISRCTN49127736. PMID- 25457498 TI - Making trials work in practice: please mind the gap. PMID- 25457497 TI - A randomised phase 2 trial of dexamethasone versus prednisolone in castration resistant prostate cancer. AB - BACKGROUND: Prednisolone is widely used as secondary hormonal treatment for castration-resistant prostate cancer (CRPC). We hypothesised that dexamethasone, another corticosteroid, is more active. OBJECTIVE: To compare the activity of prednisolone and dexamethasone in CRPC. DESIGN, SETTING, AND PARTICIPANTS: This single-centre, randomised, phase 2 trial was performed in 82 men with chemotherapy-naive CRPC enrolled from 2006 to 2010. INTERVENTION: Prednisolone 5mg twice daily versus dexamethasone 0.5mg once daily versus intermittent dexamethasone 8mg twice daily on days 1-3 every 3 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The main end point was prostate-specific antigen (PSA) response rate. Secondary end points included time to PSA progression, radiologic response rate using Response Evaluation Criteria In Solid Tumors (RECIST), and safety. RESULTS AND LIMITATIONS: The intermittent dexamethasone arm was dropped after no response was seen in seven patients. By intention to treat, confirmed PSA response was seen in 41% versus 22% for daily dexamethasone versus prednisolone, respectively (p=0.08). In evaluable patients, the PSA response rates were 47% versus 24% for dexamethasone and prednisolone, respectively (p=0.05). Median time to PSA progression was 9.7 mo on dexamethasone versus 5.1 mo on prednisolone (hazard ratio: 1.6; 95% confidence interval, 0.9-2.8). In 43 patients with measurable disease, the response rate by RECIST was 15% and 6% for dexamethasone and prednisolone, respectively (p=0.6). Of 23 patients who crossed over at PSA progression on prednisolone, 7 of the 19 evaluable (37%) had a confirmed PSA response to dexamethasone. Clinically significant toxicities were rare. CONCLUSIONS: Dexamethasone may be more active than prednisolone in CRPC. In the absence of more definitive trials, dexamethasone should be used in preference to prednisolone. PATIENT SUMMARY: We compared two different steroids used for treating men with advanced prostate cancer. Our results suggest that dexamethasone may be more effective than prednisolone and that both are well tolerated. CLINICAL TRIAL REGISTRY: EUDRAC 2005-006018-16. PMID- 25457499 TI - The crucial role of Phi- and K-segments in the in vitro functionality of Vitis vinifera dehydrin DHN1a. AB - Dehydrins (DHNs), group II LEA (Late Embryogenesis Abundant) proteins, are among the most commonly observed proteins which accumulate in plants in response to cold and any other environmental factors, causing the dehydration of cells. In previous studies, we isolated a YSK2-type VvcDHN1a gene from table grapes (Vitis vinifera cv. Cardinal) which presented two spliced variants (the spliced, DHN1a_s and the unspliced, DHN1a_u). Their expression was induced by low temperature storage and CO2, although with different accumulation patterns. DHN1a_u codifies for a truncated YS protein lacking F- and K-segments, which might affect its functionality. In this work, we expressed both DHN1a_s and DHN1a_u recombinant proteins in Escherichia coli. We carried out a number of in vitro assays to analyze the implications that F- and K-segments have in the protective role of VvcDHN1 against different abiotic stresses and their antifungal activity against the fungal pathogen Botrytis cinerea. Our results showed that unlike DHN1a_u, DHN1a_s has a potent cryoprotective effect on lactate dehydrogenase activity, protects malate dehydrogenase against dehydration and partially inhibits B. cinerea growth. Moreover, the DHN1a promoter presented cis-regulatory elements related to cold and drought, as well as biotic stress-related elements. We also observed that both spliced variants interact weakly with DNA, suggesting that K segments are not involved in DNA binding. Overall, this work highlights the crucial role of F- and K-segments in DHNs function in plant response to abiotic stress showing for the first time, the potential role of the V. vinifera DHN1a_s in the protection against freezing and dehydration as well as inhibiting B. cinerea growth. PMID- 25457500 TI - Profiling of secondary metabolites in root exudates of Arabidopsis thaliana. AB - To explore the chemical composition of root exudates of the model plant Arabidopsis thaliana a workflow for nontargeted metabolite profiling of the semipolar fraction of root exudates was developed. It comprises hydroponic plant cultivation and sampling of root exudates under sterile conditions, sample preparation by solid-phase extraction and analysis by reversed-phase UPLC/ESI QTOFMS. Following the established workflow, root exudates of six-week-old plants were profiled and a set of reproducibly occurring molecular features was compiled. To structurally elucidate the corresponding metabolites, accurate mass tandem mass spectrometry and on-line hydrogen/deuterium exchange were applied. Currently, a total of 103 compounds were detected and annotated by elemental composition of which more than 90 were structurally characterized or classified. Among them, 42 compounds were rigorously identified using an authenticated standard. The compounds identified so far include nucleosides, deoxynucleosides, aromatic amino acids, anabolites and catabolites of glucosinolates, dipeptides, indolics, salicylic and jasmonic acid catabolites, coumarins, mono-, di- and trilignols, hydroxycinnamic acid derivatives and oxylipins and exemplify the high chemical diversity of plant root exudates. PMID- 25457501 TI - Retention time prediction for dereplication of natural products (CxHyOz) in LC-MS metabolite profiling. AB - The detection and early identification of natural products (NPs) for dereplication purposes require efficient, high-resolution methods for the profiling of crude natural extracts. This task is difficult because of the high number of NPs in these complex biological matrices and because of their very high chemical diversity. Metabolite profiling using ultra-high pressure liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HR-MS) is very efficient for the separation of complex mixtures and provides molecular formula information as a first step in dereplication. This structural information alone or even combined with chemotaxonomic information is often not sufficient for unambiguous metabolite identification. In this study, a representative set of 260 NPs containing C, H, and O atoms only was analysed in generic UHPLC-HR-MS profiling conditions. Two easy to use quantitative structure retention relationship (QSRR) models were built based on the measured retention time and on eight simple physicochemical parameters calculated from the structures. First, an original approach using several partial least square (PLS) regressions according to the phytochemical classes provided satisfactory results with an easy calculation. Secondly, a unique artificial neural network (ANN) model provided similar results on the whole set of NPs but required dedicated software. The retention prediction methods described in this study were found to improve the level of confidence of the identification of given analytes among putative isomeric structures. Its applicability was verified for the dereplication of NPs in model plant extracts. PMID- 25457502 TI - An integrated approach using UHPLC-PDA-HRMS and 2D HSQC NMR for the metabolic profiling of the red alga Laurencia: dereplication and tracing of natural products. AB - The global metabolic profile of Laurencia crude red algal extracts was addressed by applying high-throughput analytical techniques, namely UHPLC-PDA-HRMS and 2D HSQC NMR. An integrated platform including software tools and databases, such as Xcalibur, ToxID, ACD/Labs and MarinLit, has been developed to mine the complex analytical data towards the accelerated identification of known metabolites and the detection of new natural products at the early stages of phytochemical analysis. In parallel, a searchable 'in-house' Laurencia-focused NMR database incorporating chemical structures, NMR spectroscopic data and reported biological activities has been generated. The screening strategy has been developed as a tool to prioritize the crude extracts to be further subjected to phytochemical analysis by tracing the presence of new natural products among the pool of known compounds. The successful application of this integrated methodology in the crude extract of Laurencia chondrioides led to the rapid detection of two new C15 bromoallene acetogenins (1 and 2), which were subsequently isolated and characterized. PMID- 25457503 TI - Further iridoid glucosides in the genus Manulea (Scrophulariaceae). AB - From Manulea altissima (Scrophulariaceae) were isolated five known secoiridoid glucosides sweroside, eustomoside, eustoside, secoxyloganin and secologanoside as well as the 4"-O-rhamnopyranosyl-feruloyl ester of adoxosidic acid, named altissimoside. Also, the caffeoyl phenylethanoid glycoside verbascoside was isolated. In addition two previously unknown terpenoid esters of 6beta-hydroxy 8 epi-boschnaloside, named manucoside A and B were isolated from a formerly obtained fraction from the work-up of Manulea corymbosa. The distribution of iridoid glucosides in the Scrophulariaceae is discussed. PMID- 25457508 TI - Cognitive function in children with primary dystonia before and after deep brain stimulation. AB - BACKGROUND: Dystonia is characterised by involuntary movements (twisting, writhing and jerking) and postures. The effects of deep brain stimulation (DBS) surgery on the motor aspect of primary dystonias have been well reported, however, there is a paucity of research investigating its impact on cognitive function, particularly in childhood dystonia. We performed a follow-up of cognitive function in children with primary dystonia following DBS pallidal surgery. METHODS: Cognitive function was measured in a cohort of 13 children with primary or primary plus dystonia who had undergone DBS surgery using a retrospective case series design. Baseline pre-DBS neuropsychological measures were compared to scores obtained at least one year following DBS. Cognitive function was assessed using standardised measures of intellectual ability and memory. RESULTS: All children demonstrated improvements with regard to dystonia reduction, as measured by the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). Overall, cognition remained stable following DBS in the majority of the cohort. Individual case analysis revealed improvements in some domains of cognitive function in eight members of the cohort and a deterioration of certain domains in four. CONCLUSION: Cognition largely remained stable in children with primary/primary plus dystonia following DBS surgery, although further research with a larger sample is necessary to explore this statistically. Notwithstanding the limitations of a small size, this preliminary data has potentially positive implications for the impact of DBS on cognitive functioning within a paediatric population. PMID- 25457509 TI - Pediatric intramedullary spinal cord tumors: a single center experience. AB - AIM: To evaluate clinical and radiological findings, pathological features and treatment modalities in pediatric patients with intramedullary spinal cord tumors. PATIENTS AND METHODS: The medical records of 36 patients with intramedullary spinal tumors were reviewed for clinical, radiological and histopathological data, chemotherapy, radiotherapy, surgical resection, treatment responses, events, and final outcome. Survival analyses were performed. RESULTS: The median age was 7.9 years (range: 1-16 years; male/female ratio:1.4). Majority of the tumors were histopathologically diagnosed as astrocytomas (n = 16, 44.4%) and ependymomas (n = 19, 52.8%); whereas one was unclassified glioma. Overall, 94% of the astrocytomas and 84% of the ependymomas were low-grade, only three tumors were high-grade. In one patient with ependymoma, histopathological grade was undetermined. The primary tumor was commonly located in thoracic (47%) and cervical segments (28%). All patients had undergone surgery (gross-total resection, 33%; subtotal resection, 45%; biopsy, 22%). Radiotherapy was administered to 26 patients (72%) and chemotherapy to 15 patients (42%). The 3-, 5- and 10-year overall survival rates were 72%, 63% and 56%, respectively; and event-free survival rates were 43%, 40% and 40%. Survival did not significantly differ with gender, age groups, lag-time, neurologic status, histopathological tumor type, tumor location, extent of resection, treatment, or treatment responses in univariate survival analyses. Survival rates were significantly higher in patients with low-grade tumors and in ependymoma patients with resected tumors. CONCLUSIONS: Patients with low-grade tumors and those who underwent gross total tumor resection had better prognosis. Surgery remains the main treatment in intramedullary spinal tumors. The role of radiotherapy and chemotherapy is limited and even controversial in low-grade tumors. PMID- 25457510 TI - Pregnancy and neurodevelopmental outcomes with in-utero antiepileptic agent exposure. A pilot study. AB - OBJECTIVE: To assess pregnancy outcomes on women exposed to monotherapy with antiepileptic agents. METHODS: Questionnaires were sent to women with epilepsy in our practice who were pregnant between 2006 and 2011. 62/86 patients (72%) who responded were on monotherapy. 24 fetuses (63%) were exposed to lamotrigine, 11 (28%) to levetiracetam, 2 (5.2%) to topiramate, 1 (2.6%) to gabapentin, 17 (27%) to carbamazepine, 5 to phenytoin and 2 to valproate. RESULTS: There were 55 (88%) live births and 7 unsuccessful pregnancies (miscarriages/stillbirths). Unsuccessful pregnancies were reported in 2/24 gestations exposed to lamotrigine, 2/11 to levetiracetam and 3/17 to carbamazepine. Delayed motor development or speech delay requiring therapy and special programming was noted in 2/24 children prenatally exposed to lamotrigine, 3/17 exposed to carbamazepine and 1/2 children exposed to valproate. CONCLUSION: Our pilot study of children exposed to antiepileptic drug monotherapy in-utero demonstrated a favorable trend for successful pregnancy outcomes and developmental trajectory. PMID- 25457511 TI - Effectiveness of the ketogenic diet used to treat resistant childhood epilepsy in Scandinavia. AB - BACKGROUND: This Scandinavian collaborative retrospective study of children treated with ketogenic diet (KD) highlights indications and effectiveness over two years follow-up. METHODS: Five centres specialised in KD collected data retrospectively on 315 patients started on KD from 1999 to 2009. Twenty-five patients who stopped the diet within four weeks because of compliance-problems and minor side-effects were excluded. Seizure-type(s), seizure-frequency, anti epileptic drugs and other treatments, mental retardation, autism-spectrum disorder and motor-dysfunction were identified and treatment-response was evaluated. RESULTS: An intention-to-treat analysis was used. Responders (>50% seizure-frequency reduction) at 6, 12 and 24 months were 50%, 46% and 28% respectively, seizure-free were 16%, 13% and 10%. Still on the diet were 80%, 64% and 41% after 6, 12 and 24 months. No child had an increased seizure-frequency. The best seizure outcome was seen in the group with not-daily seizures at baseline (n = 22), where 45%, 41% and 32% became seizure-free at 6, 12 and 24 months A significant improvement in seizure-frequency was seen in atonic seizures at three months and secondary generalised seizures at three and six months. Side effects were noted in 29 subjects; most could be treated and only two stopped due to hyperlipidaemia and two due to kidney-stones. In 167 patients treated with potassium-citrate, one developed kidney-stones, compared with six of 123 without potassium-citrate treatment (relative risk = 8.1). CONCLUSIONS: As the first study of implementing KD in children in the Scandinavian countries, our survey of 290 children showed that KD is effective and well tolerated, even in such severe patients with therapy-resistant epilepsy, more than daily seizures and intellectual disability in the majority of patients. Long-term efficacy of KD was comparable or even better than reported in newer AEDs. Addition of potassium citrate reduced risk of kidney-stones. Our data indicate that the response might be predicted by seizure-frequency before initiation of the diet but not by age, seizure-type or aetiology. PMID- 25457512 TI - Mixed treatment comparison meta-analysis of porcine circovirus type 2 (PCV2) vaccines used in piglets. AB - Porcine circovirus type 2 (PCV2) vaccination is globally one of the most commonly used intervention strategies in growing pigs since several products became commercially available in 2006. While multiple trials have described the efficacy of individual PCV2 vaccines relative to non-vaccination, few studies provide product-to-product comparisons of efficacy. Given the well-documented efficacy of PCV2 vaccines, information about the comparative efficacy of available vaccines is more relevant to producers and veterinarians than comparison to non vaccination. The objective of this study was to provide comparative estimates of changes in average daily gain effect associated with the use of the commercially available PCV2 vaccines. PubMed, CAB Abstracts, AGRICOLA, the USA Department of Agriculture Center for Veterinary Biologics database of licenses and provisions, and the proceedings of the Annual Meeting of the American Association of Swine Veterinarians, the Allen D. Leman Swine Conference, the Iowa State University Swine Disease Conference for Swine Practitioners, and the International Pig Veterinary Society Congress were used as the sources of information. Trials of licensed PCV2 vaccines administered according to manufacturers' specifications to intensively raised piglets with a known herd porcine reproductive and respiratory syndrome virus (PRRSV) status were considered relevant to the meta-analysis. Relevant studies had to report average daily gain (ADG) from weaning to finish and PCV2 infection had to be naturally occurring. PMID- 25457513 TI - Efficiency of dairy farms participating and not participating in veterinary herd health management programs. AB - This paper compares farm efficiencies between dairies who were participating in a veterinary herd health management (VHHM) program with dairies not participating in such a program, to determine whether participation has an association with farm efficiency. In 2011, 572 dairy farmers received a questionnaire concerning the participation and execution of a VHHM program on their farms. Data from the questionnaire were combined with farm accountancy data from 2008 through 2012 from farms that used calendar year accounting periods, and were analyzed using Stochastic Frontier Analysis (SFA). Two separate models were specified: model 1 was the basic stochastic frontier model (output: total revenue; input: feed costs, land costs, cattle costs, non-operational costs), without explanatory variables embedded into the efficiency component of the error term. Model 2 was an expansion of model 1 which included explanatory variables (number of FTE; total kg milk delivered; price of concentrate; milk per hectare; cows per FTE; nutritional yield per hectare) inserted into the efficiency component of the joint error term. Both models were estimated with the financial parameters expressed per 100 kg fat and protein corrected milk and per cow. Land costs, cattle costs, feed costs and non-operational costs were statistically significant and positive in all models (P<0.01). Frequency distributions of the efficiency scores for the VHHM dairies and the non-VHHM dairies were plotted in a kernel density plot, and differences were tested using the Kolmogorov-Smirnov two-sample test. VHHM dairies had higher total revenue per cow, but not per 100 kg milk. For all SFA models, the difference in distribution was not statistically different between VHHM dairies and non-VHHM dairies (P values 0.94, 0.35, 0.95 and 0.89 for the basic and complete model per 100 kg fat and protein corrected milk and per cow respectively). Therefore we conclude that with our data farm participation in VHHM is not related to overall farm efficiency. PMID- 25457514 TI - Risk factors for H7 and H9 infection in commercial poultry farm workers in provinces within Pakistan. AB - A cross sectional survey was conducted involving 354 farm poultry workers on 85 randomly selected commercial poultry farms in high density poultry farm areas in Pakistan to estimate the sero-prevalence of H5, H7 and H9 and to identify the potential risk factors for infection with the avian influenza virus. A haemagglutination inhibition test titre at 1:160 dilution was considered positive, based on WHO guidelines. The estimated sero-prevalence was 0% for H5, 21.2% for H7 and 47.8% for H9. Based on a generalized linear mixed model, the significant risk factors for H7 infection were area, type of farm and age of poultry worker. Risk of infection increased with the age of poultry workers. Compared with broiler farms, breeder farms presented a greater risk of infection (odds ratio [OR]=3.8, 95% confidence interval [CI]: 1.4, 10.1). Compared with the combined Khyber Pakhtunkhwa Province and Federal area, North Punjab had higher observed biosecurity measures and presented a lesser risk of infection (OR=0.3, 95% CI 0.1, 0.9). Biosecurity should therefore be enhanced (especially in breeder farms) to reduce the occupational risks in poultry farm workers and to decrease the risk of emergent human-adapted strains of AI H7 and H9 viruses. PMID- 25457515 TI - Pretreatment of garlic powder using sweep frequency ultrasound and single frequency countercurrent ultrasound: optimization and comparison for ACE inhibitory activities. AB - The sweep frequency ultrasound (SFU) and single frequency countercurrent ultrasound (SFCU) pretreatments were modeled and compared based on production of angiotensin I-converting enzyme (ACE) inhibitory peptides from garlic hydrolysates. Two mathematical models were developed to show the effect of each variable and their combinatorial interactions on ACE inhibitory activity. The optimum levels of the parameters in SFU were determined using uniform design, which revealed these as follows: total ultrasonic time 1.5 h, on-time of pulse 18 s and off-time of pulse 3 s. Under optimized conditions, the experimental values of SFU and SFCU were 65.88% and 67.78%, which agreed closely with the predicted values of 63.44% and 67.33%. The SFU and SFCU pretreatments both resulted in higher ACE inhibitory activity compared with untreated garlic (p<0.05). However, there were no significant differences in the ACE inhibitory activities and IC50 values obtained from SFCU and SFU pretreatments under optimum conditions (p>0.05). PMID- 25457516 TI - Synthesis of titanium dioxide by ultrasound assisted sol-gel technique: effect of calcination and sonication time. AB - Nanostructured titanium dioxide has been synthesized using both conventional and ultrasound assisted sol-gel technique with an objective of understanding the role of cavitational effects in the synthesis process. The experiments were conducted at a constant calcination temperature of 750 degrees C and the calcination time was varied from 30 min to 3 h to study the effect of calcination time on the properties of the synthesized TiO2. The TiO2 specimens were characterized using X ray diffraction (XRD) and scanning electron microscopy (SEM). The influence of the sonication time on the phase transformation process from anatase to rutile and also on the crystallite size and percentage crystallinity of the synthesized TiO2 has also been investigated. It was observed that 100% phase transformation occurred after 3 h of calcination for the ultrasound assisted sol-gel synthesized TiO2. The study on the phase transformation via variation of sonication time yielded interesting results. It was observed that as the sonication time increased, an initial increase in the rutile content is obtained and beyond optimum sonication time, the rutile content decreased. In general, the ultrasound assisted process results in synthesis of TiO2 material with higher rutile content as compared to the conventional sol-gel process. PMID- 25457517 TI - Comparison of response surface methodology and artificial neural network approach towards efficient ultrasound-assisted biodiesel production from muskmelon oil. AB - The present study is to evaluate and compare the prediction and simulating efficiencies of response surface methodology (RSM) and artificial neural network (ANN) based models on fatty acid methyl esters (FAME) yield achieved from muskmelon oil (MMO) under ultrasonication by two step in situ process. In first in situ process, free fatty acid content of MMO was reduced from 6.43% to 0.91% using H2SO4 as acid catalyst and organic phase in the first step was subjected to second reaction by adding KOH in methanol as basic catalyst. The influence of process variables (methanol to oil molar ratio, catalyst concentration, reaction temperature and reaction time) on conversion of FAME (second step) was investigated by central composite rotatable design (CCRD) of RSM and Multi-Layer Perceptron (MLP) neural network with the topology of 4-7-1. Both (RSM and ANN) were statistically compared by the coefficient of determination, root mean square error and absolute average deviation, based on the validation data set. The coefficient of determination (R(2)) calculated from the validation data for RSM and ANN models were 0.869 and 0.991 respectively. While both models showed good predictions in this study. But, the ANN model was more precise compared to the RSM model and it showed that, ANN is to be a powerful tool for modeling and optimizing FAME production. PMID- 25457518 TI - High rate CNP removal from a milk processing wastewater in a single ultrasound augmented up-flow anaerobic/aerobic/anoxic bioreactor. AB - Simultaneous removal of carbon, nitrogen and phosphorus (CNP) in a single bioreactor is of high significance in terms of reactor volume and energy consumption. Therefore, in this study, an innovative up-flow anaerobic/aerobic/anoxic bioreactor (UAAASB) augmented by ultrasound was developed as a high rate single bioreactor for the simultaneous removal of nutrients from a milk processing wastewater. The ultrasonic irradiation used in this work was in the range of high frequency (1.7 MHz). The central composite design (CCD) and response surface methodology (RSM) were applied to design the experimental conditions, model obtained data, and optimize the process. The effects of three independent variables, i.e. hydraulic retention time (HRT), aeration mode and mixed liquor suspended solid (MLSS) concentration on 10 process responses were investigated. The results prove that the ultrasonic irradiation has a positive effect on the sludge settling velocity and effluent turbidity. The optimum conditions were determined as 12-15 h, 4000-5000 mg/l and 1.5-2 for HRT, MLSS concentration and aeration mode, respectively, based on removal efficiency of sCOD ? 90%, TN and TP ? 50%. PMID- 25457519 TI - Evaluation of diffusion-weighted MR imaging in the diagnosis of mild acute pancreatitis. AB - The goal of our study was to determine the diagnostic value of diffusion-weighted magnetic resonance imaging in the identification of acute mild pancreatitis with low Ranson scores. The study group included 22 healthy subjects and 40 patients with mild acute pancreatitis. Patients with Ranson scores of 1-3 were included in the present study. There was a significant reduction in mean pancreatic apparent diffusion coefficient among the acute pancreatitis patients (1.46+/-2.80*10( 3)mm(2)/s) relative to the healthy subjects (1.69+/-2.26*10(-3)mm(2)/s). Diffusion-weighted imaging improves diagnosis of mild acute pancreatitis and enables the differentiation of acute pancreatitis from other diseases involving abdominal pain and other nonspecific findings. PMID- 25457520 TI - Apparent diffusion coefficient (ADC) value to evaluate BI-RADS 4 breast lesions: correlation with pathological findings. AB - Diffusion-weighted imaging and apparent diffusion coefficient (ADC) of 36 breast lesions previously categorized as 4 according to the Breast Imaging Reporting and Data System (BI-RADS) were prospectively studied. The pathological results were 21 benign lesions and 15 malignant. The ADC of malignant lesions was significantly lower than that of the benign ones (0.87 +/- 0.12 * 10(-3) mm(2)/s vs. 1.41 +/- 0.22 * 10(-3) mm(2)/s, respectively) (P<.001). Using a threshold ADC value of 1.08 * 10(-3) mm(2)/s, a sensitivity of 95% and specificity of 100% were obtained. PMID- 25457521 TI - Spontaneous regression of primary renal cell carcinoma following image-guided percutaneous biopsy. AB - Spontaneous regression of metastatic renal cell carcinoma (RCC) is a rare but well-described clinical phenomenon; spontaneous regression of nonmetastatic RCC has been reported far less frequently. We present three cases of primary RCC that regressed spontaneously following the image-guided biopsy that established their diagnosis. We briefly review the literature describing spontaneous regression of both primary and metastatic RCC and emphasize how knowledge of this phenomenon may be useful for abdominal imagers that perform renal biopsy or interpret postbiopsy follow-up studies. PMID- 25457522 TI - Alterations in pituitary gland volume in polycystic ovary syndrome: a structural magnetic resonance imaging study. AB - The purpose of this prospectively designed cross-sectional observational study was to evaluate the effect of polycystic ovary syndrome (PCOS) on pituitary gland volume (PGV) under the hypothesis that endocrinologic changes may lead to morphologic changes of the pituitary gland. Twenty-six PCOS patients and 31 control subjects underwent magnetic resonance imaging (MRI) of the pituitary. Informed consent was obtained from all subjects. PGV was significantly larger in PCOS patients than in control subjects. Luteinizing hormone/follicle-stimulating hormone ratio was the only predictor of PGV. The association between pituitary gland enlargement and PCOS should be kept in mind when pituitary hypertrophy is detected on MRI. PMID- 25457523 TI - Plicae palmatae: an anatomical uterine cervix variation to be considered on magnetic resonance images. AB - OBJECTIVE: The aim of this study was to research the frequency and distribution of plicae palmatae in women in different age groups. METHODS: Data of 409 female patients' magnetic resonance images were evaluated. RESULTS: We found a frequency of plicae palmatae variations in the study population of 44.5%. It was statistically most frequent in the fourth decade. The presence of plicae palmatae variations in the period after menopause was significantly lower than that during the reproductive period. CONCLUSIONS: Identification of plicae palmatae may be misdiagnosed as uterine septum and more awareness of this situation is required to prevent unnecessary surgery. PMID- 25457524 TI - CT and MR findings in 16 cases of primary neuroendocrine carcinoma in the otolaryngeal region. AB - Primary neuroendocrine carcinoma (NEC) is a rare malignancy in the otolaryngeal region. Computed tomography and magnetic resonance imaging findings in 16 patients with primary otolaryngeal NECs were summarized. Most of tumors occurred in the sinonasal cavity (n=9; 56.3%), then supraglottis (n=3; 18.8%). All sinonasal and one hard palate tumors were ill defined, and the other tumors were well defined. All lesions showed moderate to marked enhancement, but homogeneously in well-differentiated tumors while heterogeneously in most of poorly differentiated tumors. Most sinonasal tumors were poorly differentiated and invaded adjacent bones. Primary otolaryngeal NECs might have some distinct features related to their origin and differentiation. PMID- 25457525 TI - Accuracy of prostate measurements on MRI with and without an endorectal coil. AB - PURPOSE: To assess accuracy of prostate measurements with and without endorectal coil (ERC). MATERIALS AND METHODS: Anteroposterior (AP), transverse (TX) and craniocaudal (CC) measurements were recorded from 49 prostate magnetic resonance images (MRIs) done both with and without ERC. Prostate weight was calculated as follows: AP*TX*CC*pi/6. Prostate dimensions and weight were obtained from radical prostatectomy pathology report. RESULTS: After ERC placement, AP decreased by 0.71 cm [95% confidence interval (CI) 0.80-0.61], TX and CC increased by 0.26 cm (95% CI 0.18-0.33) and 0.25 cm (95% CI 0.16-0.35), respectively. Agreement between weight on pathology and MR was excellent: intraclass correlation coefficient (ICC) without ERC=0.96, ICC with ERC=0.90. CONCLUSION: Although ERC distorts measurements and despite a tendency to underestimate the prostate weight, absolute agreement between prostate weight on pathology and MRI is excellent, both with and without ERC. PMID- 25457526 TI - Tuberculosis of the manubriosternal joint and concurrent asymptomatic active pulmonary tuberculosis in a patient presenting with a chest wall mass. AB - A 62-year-old woman presented to our hospital with an anterior chest wall swelling. Computed tomography (CT) and magnetic resonance imaging showed findings consistent with an infectious arthritis of the manubriosternal joint, and CT images also demonstrated multiple centrilobular nodules in both lungs, suggesting an infectious bronchiolitis. A CT-guided fine needle aspiration of a presternal mass yielded growth of Mycobacterium tuberculosis. Bronchoalveolar lavage confirmed an active pulmonary tuberculosis. Septic arthritis of the manubriosternal joint is exceedingly rare. PMID- 25457527 TI - F-18 Choline PET angiography of the pelvic arteries: evaluation of image quality and comparison with contrast-enhanced CT. AB - PURPOSE: The purpose was to show the feasibility of F-18 choline positron emission tomography (PET) angiography for the evaluation of abdominal and iliac arteries. METHODS: Thirty-five patients were examined and image quality was scored. Findings were correlated with contrast-enhanced computed tomography. RESULTS: Image quality was best in the aorta and common iliac arteries (100% and 93% of vessels). Negative predictive values of PET angiography were excellent (100%), and positive predictive values were impaired by disease overestimation. CONCLUSION: PET angiography is technically feasible and of good image quality in large arteries. In selected cases, it may become an alternative to established angiographic methods. PMID- 25457528 TI - Association between changes in suspicious prostate lesions on serial MRI examinations and follow-up biopsy results. AB - We assessed changes in prostate lesions on serial magnetic resonance imaging (MRI) examinations in predicting biopsy results. Fifty-five men undergoing two prostate MRI examinations >=6 months apart, followed by targeted biopsy, were included. Two radiologists assessed dominant lesions for an increase in size or suspicion score. Progression on MRI had lower sensitivity (23.5%-35.3%) and higher specificity (76.2%-90.5%) than prostate-specific antigen (PSA) velocity (sensitivity 70.6%, specificity 52.4%) for predicting positive biopsy. Highest accuracy was achieved by PSA velocity (63.6%) for positive biopsy, and by MRI (65.5%-72.7%) for Gleason >6 tumor. Findings support lesion progression on MRI serving as a basis for performing subsequent targeted biopsy. PMID- 25457529 TI - Intraosseous schwannoma of the ilium. AB - We presented a 27-year-old male diagnosed with intraosseous schwannoma of the ilium. Computed tomographic images revealed a well-demarcated, lobulated, expansile, osteolytic lesion in the right supraacetabular region of the ilium. In addition, an intratumoral punctate calcification and a sclerotic rim were observed. T2-weighted magnetic resonance (MR) images demonstrated a heterogeneously hyperintense lesion with a hypointense rim. Major parts of the lesion, excluding some central areas, were enhanced on gadolinium-enhanced MR images. Pathological examination revealed an intraosseous schwannoma. Our findings indicate that intraosseous schwannoma should be considered when images demonstrate a well-demarcated, lobulated, expansile, osteolytic lesion with a sclerotic rim. PMID- 25457530 TI - Automated small bowel motility measurements in MRI using 2D coronal slices - does the intrasegmental location matter? A pilot study. AB - INTRODUCTION: To evaluate if small bowel motility analyses are influenced by the positioning of the 2D-cross-section measurement point within the lumen. MATERIALS AND METHODS: Forty-four small-bowel motility measurements were included in this institutional review board-approved, prospective study. Motility sequences (Dixon dynFFE; Temporal-resolution 1s, breath-hold) of the ileocecal region were acquired using magnetic resonance imaging (3.0-Tesla; Ingenia-Philips). Motility was analyzed in three different compartments of the small bowel lumen (ventral, central, dorsal). Curve characteristics were statistically compared. RESULTS: Mean luminal diameter, contraction amplitudes (P>.05) and the extent of luminal occlusion during contraction (P=.11) did not differ significantly between the compartments (ventral/central/dorsal) of the bowel lumen. CONCLUSION: Quantitative motility parameters are not substantially influenced by the choice of cross sections on coronal planes as long as the segment is visible throughout the measurement. PMID- 25457531 TI - The relation between apparent diffusion coefficient and clinical stage of clear cell renal cell carcinoma. AB - PURPOSE: The utility of the apparent diffusion coefficient (ADC) in patients with clear-cell renal cell carcinoma (RCC) for distinguishing between the four clinical stages was assessed. METHODS: Forty-nine patients with pathologically proven RCCs (I, II, III, IV; 27, 5, 10, 7) were included. The ADC was compared between each stage. RESULTS: The difference of ADC between stage I and the more advanced stages (III and IV) was statistically significant. CONCLUSIONS: When ADC in primary tumor site of clear-cell RCC would be higher than the cutoff level, the stage might not be an advanced stage (III or IV). PMID- 25457532 TI - Intradiverticular bladder cancer: CT imaging features and their association with clinical outcomes. AB - OBJECTIVES: To evaluate if computed tomographic (CT) features of intradiverticular bladder cancer can predict clinical outcome. METHODS: Retrospective study of 34 patients with intradiverticular bladder cancer. Two radiologists independently evaluated all CT exams. RESULTS: CT tumor length and width were significantly associated with survival for both readers [hazard ratios (HRs) 1.31-1.62, P<.001-.043]. No other tumor features were significantly associated with survival. The interreader agreement for the assessment of CT features was fair to substantial (k=0.34-0.78, concordance correlation coefficient=0.56-0.66). There was no association between transurethral resection pathology stage and survival (HR 2.10, P=.21). CONCLUSIONS: In patients with intradiverticular bladder cancer, the tumor length and width measured on the pretreatment CT predicted survival. PMID- 25457533 TI - Hepatobiliary phase of gadoxetic acid-enhanced MR in patients suspected of having gallbladder dyskinesia: comparison with hepatobiliary scintigraphy. AB - OBJECTIVE: To compare hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance (HMR) and hepatobiliary scintigraphy (HBS) for evaluation of cystic duct patency and gallbladder contractility in patients suspected of having gallbladder dyskinesia. MATERIALS AND METHODS: Eighteen patients underwent HMR and HBS. Cystic duct patency and gallbladder ejection fraction (GBEF) were compared to determine a significant difference between HMR and HBS. RESULTS: HMR and HBS had 15 concordant and 3 discordant results for cystic duct patency. GBEF in eight patients showed no significant difference between both modalities. CONCLUSION: HMR may be an alternative to HBS for the functional evaluation of cystic duct patency and GBEF. PMID- 25457534 TI - Renal cell carcinoma subtype differentiation using single-phase corticomedullary contrast-enhanced CT. AB - OBJECTIVE: To compare multiphase and single-phase corticomedullary contrast enhanced computed tomographic (CT) imaging in the differentiation of renal cell carcinoma (RCC) subtype. MATERIAL AND METHODS: Pathology records were reviewed from January 2008 to March 2013. The final cohort consisted of 79 patients (57 men, 22 women; mean age: 64+/-13). Quantitative tumor percentage enhancement (TE), cortical enhancement, and tumor-to-cortex enhancement (TCI) indexes were calculated. RESULTS: Single-phase evaluations showed significantly lower mean TE and TCI for papillary tumors when compared with clear cell and cromophobe tumors (P<.01). Comparison of receiver operating characteristic curve analyses did not show significant differences between both evaluation methods. CONCLUSION: Accuracy of RCC subtype differentiation with single-phase corticomedullary contrast-enhanced CT is comparable to multiphasic imaging. PMID- 25457535 TI - Characterization of renal cell carcinoma, oncocytoma, and lipid-poor angiomyolipoma by unenhanced, nephrographic, and delayed phase contrast-enhanced computed tomography. AB - The purpose of this study was to assess the characterization of renal cell carcinoma (RCC) and benign renal tumors by unenhanced, nephrographic, and delayed phase computed tomography (CT). The study group consisted of 129 renal tumors including 79 clear cell RCCs, 17 papillary RCCs, 6 chromophobe RCCs, 21 oncocytoma, and 6 lipid-poor angiomyolipomas (AMLs). CT studies were retrospectively reviewed. Our results suggested that it was possible to discriminate clear cell RCC from papillary RCC, chromophobe RCC, and lipid-poor AML. CT findings of oncocytoma overlapped with both clear cell and non-clear cell RCCs, although oncocytoma more commonly became homogeneous in the delayed phase. PMID- 25457536 TI - Successful catheter-directed thrombolysis of a massive pulmonary embolism in a patient after recent pneumonectomy. AB - Massive pulmonary embolism (PE) after major thoracic surgery is an uncommon but life-threatening event that is challenging to manage. At present, the treatment of acute PE is either anticoagulation with or without systemic thrombolytic therapy. We report a case of a 65-year-old female with recent left pneumonectomy who developed a massive PE. The patient was successfully and safely treated with catheter-directed thrombolysis. To our knowledge, this is the first patient treated in this fashion. PMID- 25457537 TI - CT angiography of cervical anterior spinal artery and anterior radicular artery: preliminary study on technology and its clinical application. AB - Spinal cord ischemia significantly threatens patient health. Cervical spinal cord ischemia is mainly caused by anterior spinal artery (ASA) or anterior radicular artery (ARA) injury. Because of the complex hemodynamics in cervical spinal cord arteries, conventional CT angiography (CTA) does not satisfactorily show the ASA and ARA. In this study, cervical cord CTA was done to 20 patients suspected of cervical spinal cord ischemia with an increased dose of contrast medium and an extra 6-s delay from the peak time determined on the test bolus. The visualization quality of ASA and ARA in the cervical cord CTA was compared with conventional craniocervical CTA using a four-grade visual analogue scale, and injuries to ASA and ARA were evaluated. Our initial experience indicated that cervical cord CTA can efficiently display the anatomical features and comprehensively evaluate injury of the ASA and ARA. PMID- 25457538 TI - Multidetector computed tomography (MDCT): simple CT protocol for trauma patient. AB - The purpose of this retrospective monocenter study was to evaluate a monophasic multidetector computed tomography (MDCT) protocol with a fixed delay for patients with polytrauma. A total of 2086 patients were evaluated retrospectively. For the intravenous contrast media, we used a fixed protocol with an injection for an adult patient of 120 mL at a rate of 2 mL/s. In the venous phase, we detected injuries of parenchyma and localized ongoing bleedings in regard to the clinical follow-up, with regard to the easy feasibility and the quickness with only one scan. Monophasic venous injection protocol can detect all injuries in the whole body MDCT for patients with polytrauma. PMID- 25457539 TI - Assessment of 3D T2-weighted high-sampling-efficiency technique (SPACE) for detection of cerebellar tonsillar motion: new useful sign for Chiari I malformation. AB - OBJECTIVE: To describe tonsillar blackout sign (TBS) on three-dimensional (3D) SPACE, evaluate its performance in identifying Chiari malformation (CM1) as diagnostic marker, and investigate its role in differentiation of symptomatic and asymptomatic CM1. METHODS: One-hundred fifty-six patients were divided into two groups based on caudal displacement of cerebellar tonsils: CM1 (Group I) and non CM1 (Group II). Group I was subclassified as symptomatic and asymptomatic by a neurosurgeon. Two radiologists evaluated TBS and cerebrospinal fluid flow abnormality. RESULTS: All subjects presenting TBS had CM1. Difference in presence of TBS between Group I and Group II was highly significant (P<.001).Grading of TBS in symptomatic patients was significantly higher than that in asymptomatic patients (P<.001). CONCLUSION: TBS is highly suggestive of CM1 and potentially useful in differentiation of symptomatic and asymptomatic CM1. PMID- 25457540 TI - Pheochromocytoma supporting blood pressure in the setting of cardiogenic shock. AB - Sixty-seven-year-old male presented with abdominal pain, nausea, vomiting, and decreasing level of consciousness. He was tachycardic but not hypotensive. Computed tomography scan revealed a peripherally enhancing adrenal mass and evidence of low cardiac output state. He was admitted to the intensive care unit but expired within 12 h. Autopsy determined the cause of death as acute coronary insufficiency and identified the adrenal mass as a pheochromocytoma. The pheochromocytoma may have maintained blood pressure in the setting of cardiogenic shock and delayed diagnosis of myocardial infarction. PMID- 25457541 TI - Rare isolated trigeminal nerve sarcoidosis mimicking schwannoma. AB - Sarcoidosis is a granulomatous disorder of unknown etiology involving multiple organ systems. Isolated neurosarcoidosis is exceedingly rare. This case report presents isolated trigeminal nerve sarcoidosis mimicking schwannoma in a patient presenting with symptoms of trigeminal neuralgia. Neuroimaging revealed a mass associated with trigeminal nerve which prospectively thought to represent schwannoma. However, surgical pathology was consistent with sarcoidosis. Given great overlap in imaging characteristic of tumors in the Meckel's cave intraoperative frozen section biopsy may be considered to rule out an inflammatory lesion. PMID- 25457542 TI - Delayed intravenous contrast-enhanced 3D FLAIR MRI in Meniere's disease: correlation of quantitative measures of endolymphatic hydrops with hearing. AB - OBJECTIVE: Using three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging (3D-FLAIR MRI), our goal was to correlate quantifiable measures of endolymphatic hydrops (EH) with auditory function in the setting of Meniere's disease (MD). MATERIALS AND METHODS: Forty-one ears were analyzed in 21 subjects (12 ears with MD, 29 without MD). Vestibular endolymphatic space size measurements obtained with two different techniques were referenced against clinical data. RESULTS: EH was better evaluated on 3D maximum intensity projections (MIPs) than on two-dimensional (2D) images. Using MIPs, quantitative assessments EH correlated with severity of hearing impairment. CONCLUSION: 3D MIPs were superior to 2D images for evaluating EH in the setting of MD. PMID- 25457543 TI - Invasive lung cancer staging: influence of CT-guided core needle biopsy on onset of pleural carcinomatosis. AB - In lung cancer patients with single peripheral lesions, CT-guided needle biopsies (CTNBs) are common for histological sampling. Recently published studies showed conflicting results for the influence of CTNB on the onset of pleural carcinomatosis (PC). In order to estimate the influence of CTNB on pleural tumor spread, 146 histologically confirmed cases of lung cancer diagnosed by CTNB were retrospectively compared to 112 control lung cancer patients diagnosed by non CTNB. CTNB was not associated with an earlier onset of PC, identifying CTNB as a safe procedure for minimally invasive lung cancer staging. PMID- 25457544 TI - Use of CT perfusion to discriminate between brain metastases from different primaries. AB - Thirty-six metastases in 22 patients were studied prospectively using computed tomography perfusion. Regions of interests were drawn around: the enhancing part of the tumor, necrotic central part, periphery, peritumoral edema, and normal white matter. Cerebral blood volume, cerebral blood flow, and mean transit time were calculated for each zone. The enhancing part of the tumor significantly differed from the other zones in 11 of 12. Metastases of different primaries can be differentiated from one another with statistically significance (P<.05) by at least one perfusion parameter in 57% of cases. PMID- 25457545 TI - A few considerations on "Ultrasound elastography in the early diagnosis of plantar fasciitis". PMID- 25457546 TI - The benefit of docosahexaenoic acid for the adult brain in aging and dementia. AB - A brief overview of the evidence for omega-3 fatty acids and, in particular, of docosahexaenoic acid (DHA), involvement in cognition and in dementia is given. Two studies are presented in this regard in which the key intervention is a DHA supplement. The fist, the MIDAS Study demonstrated that DHA can be of benefit for episodic memory in healthy adults with a mild memory complaint. The second, the ADCS AD trial found no benefit of DHA in the primary outcomes but found an intriguing benefit for cognitive score in ApoE4 negative allele patients. This leads to a consideration of the mechanisms of action and role of ApoE and its modulation by DHA. Given the fundamental role of ApoE in cellular lipid transport and metabolism in the brain and periphery, it is no surprise that ApoE affects n 3 PUFA brain function as well. It remains to be seen to what extent ApoE4 deleterious effect in AD is associated with n-3 PUFA-related cellular mechanisms in the brain and, more specifically, whether ApoE4 directly impairs the transport of DHA into the brain, as has been suggested. PMID- 25457547 TI - Swine Leukocyte Antigen (SLA) class I allele typing of Danish swine herds and identification of commonly occurring haplotypes using sequence specific low and high resolution primers. AB - The swine major histocompatibility complex (MHC) genomic region (SLA) is extremely polymorphic comprising high numbers of different alleles, many encoding a distinct MHC class I molecule, which binds and presents endogenous peptides to circulating T cells of the immune system. Upon recognition of such peptide-MHC complexes (pMHC) naive T cells can become activated and respond to a given pathogen leading to its elimination and the generation of memory cells. Hence SLA plays a crucial role in maintaining overall adaptive immunologic resistance to pathogens. Knowing which SLA alleles that are commonly occurring can be of great importance in regard to future vaccine development and the establishment of immune protection in swine through broad coverage, highly specific, subunit based vaccination against viruses such as swine influenza, porcine reproductive and respiratory syndrome virus, vesicular stomatitis virus, foot-and-mouth-disease virus and others. Here we present the use of low- and high-resolution PCR-based typing methods to identify individual and commonly occurring SLA class I alleles in Danish swine. A total of 101 animals from seven different herds were tested, and by low resolution typing the top four most frequent SLA class I alleles were those of the allele groups SLA-3*04XX, SLA-1*08XX, SLA-2*02XX, and SLA-1*07XX, respectively. Customised high resolution primers were used to identify specific alleles within the above mentioned allele groups as well as within the SLA-2*05XX allele group. Our studies also suggest the most common haplotype in Danish pigs to be Lr-4.0 expressing the SLA-1*04XX, SLA-2*04XX, and SLA-3*04XX allele combination. PMID- 25457548 TI - Two carboxypeptidase counterparts from rock bream (Oplegnathus fasciatus): molecular characterization, genomic arrangement and immune responses upon pathogenic stresses. AB - Carboxypeptidases (CPs) are proteases that hydrolyze C-terminal peptide bonds. They are involved in regulating the complement system of the immune system. Here, we report the molecular characterization and immune response of two carboxypeptidases, named carboxypeptidase A (Rb-CPA) and carboxypeptidase N1 (Rb CPN1), from rock bream. The genomic sequence of Rb-CPA contains 12 exons interrupted by 11 introns, while the genomic sequence of Rb-CPN1 has 9 exons and 8 introns. The cDNA sequence of Rb-CPA encodes a 421-amino-acid (AA) polypeptide (48kDa), and the cDNA of Rb-CPN1 encodes a 448-AA polypeptide (51kDa). The amino acid sequences of Rb-CPA and Rb-CPN1 were found to harbor two characteristic Zn binding signature domains and a peptidase-M14 Zn carboxypeptidase site. Pairwise analysis revealed that Rb-CPA and Rb-CPN1 had the highest identity with the corresponding proteins from Anoplopoma fimbria (87.6%) and Dicentrarchus labrax (96.9%), respectively. qPCR results indicated that Rb-CPA and Rb-CPN1 were constitutively expressed mainly in the kidney, heart, liver, and head kidney. Both genes were transcriptionally regulated in the liver upon challenge with pathogenic bacteria (Streptococcus iniae, Edwardsiella tarda), rock bream iridovirus (RBIV), and the immune modulators polyinosinic:polycytidylic acid and lipopolysaccharide. Taken together, our findings suggest that Rb-CPA and Rb-CPN1 have immune-related functions in rock bream. PMID- 25457549 TI - Modulation of AD neuropathology and memory impairments by the isoprostane F2alpha is mediated by the thromboxane receptor. AB - Beside amyloid-beta plaques and neurofibrillary tangles, brain oxidative damage has been constantly implicated in Alzheimer's disease (AD) pathogenesis. Numerous studies demonstrated that F2-isoprostanes, markers of in vivo lipid peroxidation, are elevated in AD patients and mouse models of the disease. Previously, we showed that the 8-isoprostaneF2alpha, (8ISO) increases brain amyloid-beta levels and deposition in the Tg2576 mice. However, no data are available on its effects on behavior and tau metabolism. To this end, we characterize the behavioral, biochemical, and neuropathologic effects of 8ISO in the triple transgenic mouse model. Compared with controls, mice receiving 8ISO showed significant memory deficits, increase in tau phosphorylation, activation of the cyclin kinase 5 pathway, and neuroinflammation. All these effects were blocked by pharmacologic blockade of the thromboxane receptor. Our findings establish the novel functional role that oxidative stress via the formation of this isoprostane plays in the development of cognitive impairments and AD-related tau neuropathology. It provides important preclinical support to the neurobiological importance of the thromboxane receptor as an active player in the pathogenesis of AD. PMID- 25457551 TI - Abeta induces PUMA activation: a new mechanism for Abeta-mediated neuronal apoptosis. AB - p53 upregulated modulator of apoptosis (PUMA) is a promising tumor therapy target because it elicits apoptosis and profound sensitivity to radiation and chemotherapy. However, inhibition of PUMA may be beneficial for curbing excessive apoptosis associated with neurodegenerative disorders. Alzheimer's disease (AD) is a representative neurodegenerative disease in which amyloid-beta (Abeta) deposition causes neurotoxicity. The regulation of PUMA during Abeta-induced neuronal apoptosis remains poorly understood. Here, we reported that PUMA expression was significantly increased in the hippocampus of transgenic mice models of AD and hippocampal neurons in response to Abeta. PUMA knockdown protected the neurons against Abeta-induced apoptosis. Furthermore, besides p53, PUMA transactivation was also regulated by forkhead box O3a through p53 independent manner following Abeta treatment. Notably, PUMA contributed to neuronal apoptosis through competitive binding of apoptosis repressor with caspase recruitment domain to activate caspase-8 that cleaved Bid into tBid to accelerate Bax mitochondrial translocation, revealing a novel pathway of Bax activation by PUMA to mediate Abeta-induced neuronal apoptosis. Together, we demonstrated that PUMA activation involved in Abeta-induced apoptosis, representing a drug target to antagonize AD progression. PMID- 25457550 TI - N-terminal region of myelin basic protein reduces fibrillar amyloid-beta deposition in Tg-5xFAD mice. AB - Alzheimer's disease is a progressive neurodegenerative disorder that is characterized by extensive deposition of fibrillar amyloid-beta (Abeta) in the brain. Previously, myelin basic protein (MBP) was identified to be a potent inhibitor to Abeta fibril formation, and this inhibitory activity was localized to the N-terminal residues 1-64, a fragment designated MBP1. Here, we show that the modest neuronal expression of a fusion protein of the biologically active MBP1 fragment and the enhanced green fluorescent protein (MBP1-EGFP) significantly improved the performance of spatial learning memory in Tg-5xFAD mice, a model of pathologic Abeta accumulation in brain. The levels of insoluble Abeta and fibrillar amyloid were significantly reduced in bigenic Tg-5xFAD/Tg MBP1-EGFP mice. Quantitative stereological analysis revealed that the reduction in amyloid was because of a reduction in the size of fibrillar plaques rather than a decrease in plaque numbers. The current findings support previous studies showing that MBP1 inhibits Abeta fibril formation in vitro and demonstrate the ability of MBP1 to reduce Abeta pathology and improve behavioral performance. PMID- 25457552 TI - Silencing phosphodiesterase 7B gene by lentiviral-shRNA interference attenuates neurodegeneration and motor deficits in hemiparkinsonian mice. AB - Different studies have suggested that the nucleotide cyclic adenosine 3', 5' monophosphate can actively play an important role as a neuroprotective and anti inflammatory agent after a brain injury. The phosphodiesterase 7 (PDE7) enzyme is one of the enzymes responsible for controlling specifically the intracellular levels of cyclic adenosine 3', 5'-monophosphate in the immune and central nervous systems. Therefore, this enzyme could play an important role in brain inflammation and neurodegeneration. In this regard, using different chemical inhibitors of PDE7 we have demonstrated their neuroprotective and anti inflammatory activity in different models of neurodegenerative disorders, including Parkinson's disease (PD). In the present study, we have used the toxin 6-hydroxydopamine and lipopolysaccharide to model PD and explore the protective effects of PDE7B deficiency in dopaminergic neurons cell death. Lentivirus mediated PDE7B deprivation conferred marked in vitro and in vivo neuroprotection against 6-hydroxydopamine and lipopolysaccharide toxicity in dopaminergic neurons and preserved motor function involving the dopamine system in mouse. Our results substantiate previous data and provide a validation of PDE7B enzyme as a valuable new target for therapeutic development in the treatment of PD. PMID- 25457553 TI - Changes in TDP-43 expression in development, aging, and in the neurofilament light protein knockout mouse. AB - The transactive response DNA-binding protein 43 (TDP-43) has been identified as a neurofilament light (NF-L) messenger RNA (mRNA)-binding protein. Abnormally increased levels of TDP-43 are detected in patients with amyotrophic lateral sclerosis and a downregulation of NF-L mRNA. However, links between NF-L and TDP 43 expressions are unclear. In this study, we investigated whether the deficiency of NF-L protein can result in alterations in TDP-43 localization or protein expression and whether this is altered with aging. There was a significant increase in TDP-43 protein levels in the cortex and lumbar spinal cord in 12 month-old NF-L knockout (NF-L KO) mice, compared with wild-type (WT) C57BL/6 mice. However, there was no difference in either the phosphorylation of TDP-43 between WT and NF-L KO mice or the abnormal mislocalization of TDP-43 to the cytoplasm in NF-L KO animals. Our findings suggest that NF-L protein or mRNA may negatively affect the expression of TDP-43 in the central nervous system. However, altered phosphorylation of TDP-43 may be more highly associated with aging than the levels of TDP-43 expression. PMID- 25457554 TI - Systemic administration of fibroblast growth factor-2 (FGF2) reduces BACE1 expression and amyloid pathology in APP23 mice. AB - There is an emerging evidence that growth factors may have a potential beneficial use in the treatment of Alzheimer's disease (AD) because of their neuroprotective properties and effects on neuronal proliferation. Basic fibroblast growth factor or fibroblast growth factor-2 (FGF2) is an anti-inflammatory, angiogenic, and neurotrophic factor that is expressed in many cell types, including neurons and glial cells. Here, we explored whether subcutaneous administration of FGF2 could have therapeutic effects in the APP 23 transgenic mouse, a model of amyloid pathology. FGF2 treatment attenuated spatial memory deficits, reduced amyloid beta (Abeta) and tau pathologies, decreased inducible nitric oxide synthase expression, and increased the number of astrocytes in the dentate gyrus in APP 23 mice compared with the vehicle-treated controls. The decrease in Abeta deposition was associated with a reduction in the expression of BACE1, the main enzyme responsible for Abeta generation. These results were confirmed in a neuroblastoma cell line, which demonstrated that incubation with FGF2 regulates BACE1 transcription. In addition, and in contrast with what has been previously published, the levels of FGF2 were reduced in postmortem brains from AD patients compared with controls. These data, therefore, suggest that systemic administration of FGF2 could have a potential therapeutic application in AD. PMID- 25457556 TI - Accumulation of carboxy-terminal fragments of APP increases phosphodiesterase 8B. AB - The long-standing "amyloid hypothesis" that Alzheimer's disease is caused by the production and aggregation of amyloid-beta faces serious challenges by data recently obtained from neuroimaging studies and amyloid-beta amyloid-focused clinical trials. Meanwhile, accumulation of carboxy-terminal fragments (CTFs) of the amyloid precursor protein (APP) may be neurotoxic and may impair synaptic plasticity and long-term memory in Alzheimer's disease, as suggested in murine models. To clarify these issues, we carried out a proteomic analysis of Chinese hamster ovary cells expressing APP CTFs and found that APP-CTF accumulation induced an increase in the level of phosphodiesterase 8B, suggesting that the hydrolysis of cyclic AMP was enhanced. PMID- 25457555 TI - White matter hyperintensities and normal-appearing white matter integrity in the aging brain. AB - White matter hyperintensities (WMH) of presumed vascular origin are a common finding in brain magnetic resonance imaging of older individuals and contribute to cognitive and functional decline. It is unknown how WMH form, although white matter degeneration is characterized pathologically by demyelination, axonal loss, and rarefaction, often attributed to ischemia. Changes within normal appearing white matter (NAWM) in subjects with WMH have also been reported but have not yet been fully characterized. Here, we describe the in vivo imaging signatures of both NAWM and WMH in a large group of community-dwelling older people of similar age using biomarkers derived from magnetic resonance imaging that collectively reflect white matter integrity, myelination, and brain water content. Fractional anisotropy (FA) and magnetization transfer ratio (MTR) were significantly lower, whereas mean diffusivity (MD) and longitudinal relaxation time (T1) were significantly higher, in WMH than NAWM (p < 0.0001), with MD providing the largest difference between NAWM and WMH. Receiver operating characteristic analysis on each biomarker showed that MD differentiated best between NAWM and WMH, identifying 94.6% of the lesions using a threshold of 0.747 * 10(-9) m(2)s(-1) (area under curve, 0.982; 95% CI, 0.975-0.989). Furthermore, the level of deterioration of NAWM was strongly associated with the severity of WMH, with MD and T1 increasing and FA and MTR decreasing in NAWM with increasing WMH score, a relationship that was sustained regardless of distance from the WMH. These multimodal imaging data indicate that WMH have reduced structural integrity compared with surrounding NAWM, and MD provides the best discriminator between the 2 tissue classes even within the mild range of WMH severity, whereas FA, MTR, and T1 only start reflecting significant changes in tissue microstructure as WMH become more severe. PMID- 25457557 TI - De novo FUS mutations in 2 Korean patients with sporadic amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder. Approximately 5% of ALS patients are familial (fALS) cases, and the remaining 95% are apparently sporadic (sALS) cases. To date, a number of genes have been discovered as associated with ALS, but the genetic background of sALS is not yet fully understood. The occurrence of de novo mutations in ALS genes might be an explanation for sALS, but reduced penetrance could be an alternative theory. Previously, we screened mutations in 5 ALS genes including SOD1 and FUS in 9 fALS and 249 sALS patients and found a total of 15 patients with either SOD1 (7 fALS and 3 sALS) or FUS (1 fALS and 4 sALS) mutations. Interestingly, only 1 fALS patient had the FUS mutation, whereas 4 sALS patients had mutations in this gene. To determine if the FUS mutations in sALS were de novo, we performed genetic analysis on 2 sALS patients with living parents. Genetic analysis confirmed that 2 FUS mutations, including the c.1483C>T (p.Arg495*) and the c.1509_1510delAG (p.Gly504Trpfs*12) mutations, were found only in the patients and not in their parents, confirming the de novo occurrence of these mutations. These findings support the notion that de novo mutations are responsible for a certain proportion of sALS. PMID- 25457559 TI - gamma-Hydroxybutyrate (Xyrem) ameliorates clinical symptoms and neuropathology in a mouse model of Alzheimer's disease. AB - The chronic decrease of brain amyloid-beta (Abeta) peptides is an emerging therapeutic for Alzheimer's disease, but no such treatment has achieved clinical validation yet. In vivo, some brain proteases, including neprilysin, possess the ability of degrading Abeta and experimental data suggest their exploitation in strategies to reduce cerebral Abeta concentration. Previous studies have shown that pharmacologic doses of gamma-hydroxybutyrate (sodium oxybate or Xyrem) induce histone deacetylases (HDACs) inhibition and neprilysin gene expression. Here, we demonstrate that brain neprilysin overexpression induced in vivo by repeated gamma-hydroxybutyrate autoadministration reduces cerebral Abeta contents and prevents cognitive deficits in APPSWE mice. Oral gamma-hydroxybutyrate also counteracted phosphoramidon-induced brain neprilysin inhibition and Abeta accumulation. HDACs activities in SH-SY5Y cells were inhibited by gamma hydroxybutyrate which did not affect amyloid peptide precursor intracellular domain. Together, our results suggest that gamma-hydroxybutyrate, acting via HDAC inhibition, upregulates neprilysin to reduce Abeta level and related memory deficits. Because gamma-hydroxybutyrate doses used herein are clinically relevant, our data suggest that chronic oral administration of gamma hydroxybutyrate or its analogs may be considered for strategies against presymptomatic or established Alzheimer's disease. PMID- 25457558 TI - Recombinant adenoassociated virus 2/5-mediated gene transfer is reduced in the aged rat midbrain. AB - Clinical trials are examining the efficacy of viral vector-mediated gene delivery for treating Parkinson's disease. Although viral vector strategies have been successful in preclinical studies, to date clinical trials have disappointed. This may be because of the fact that preclinical studies fail to account for aging. Aging is the single greatest risk factor for developing Parkinson's disease and age alters cellular processes utilized by viral vectors. We hypothesized that the aged brain would be relatively resistant to transduction when compared with the young adult. We examined recombinant adeno-associated virus 2/5-mediated green fluorescent protein (rAAV2/5 GFP) expression in the young adult and aged rat nigrostriatal system. GFP overexpression was produced in both age groups. However, following rAAV2/5 GFP injection to the substantia nigra aged rats displayed 40%-60% less GFP protein in the striatum, regardless of rat strain or duration of expression. Furthermore, aged rats exhibited 40% fewer cells expressing GFP and 4-fold less GFP messenger RNA. rAAV2/5-mediated gene transfer is compromised in the aged rat midbrain, with deficiencies in early steps of transduction leading to significantly less messenger RNA and protein expression. PMID- 25457560 TI - Cross-talk between Abeta and endothelial SSAO/VAP-1 accelerates vascular damage and Abeta aggregation related to CAA-AD. AB - An association between semicarbazide-sensitive amine oxidase (SSAO) and cerebral amyloid angiopathy (CAA) related to Alzheimer's disease (AD) has been largely postulated. Increased SSAO activity and expression have been detected in cerebrovascular tissue and plasma of AD patients, colocalizing with cerebrovascular amyloid-beta (Abeta) deposits. As an enzyme, SSAO metabolizes primary amines generating hydrogen peroxide, ammonia, and aldehydes. The ability of these products to generate oxidative stress, to enhance the advanced glycation end-product generation, to promote the Abeta aggregation in vitro, and to induce apoptosis supports its role in CAA-related vascular pathology. However, whether the SSAO increase constitutes a cause or it is a consequence of the pathologic process has not been elucidated so far. To set up the nature of this relationship, vascular cell models expressing SSAO were treated with different Abeta forms, simulating the CAA conditions in vitro. It was found that the presence of the vasculotropic Dutch-mutated Abeta1-40 increases (Abeta1-40 D) the SSAO-dependent toxicity, which is accompanied by an increase of SSAO protein availability in endothelial cell membranes. In addition, SSAO enhances Abeta1-40 D and Abeta1-42 deposition on vascular cells by both activity-dependent and independent mechanisms. Thus, we provide evidences indicating that Abeta itself could be one of the factors inducing SSAO increase in AD, enhancing its toxic effect, and inducing the vascular dysfunction and, in turn, that SSAO stimulates Abeta deposition on the vascular walls, thereby contributing to the CAA-AD progression. Therefore, molecules inhibiting SSAO could provide an alternative treatment for preventing/delaying the progress of CAA-AD-associated vasculopathy. PMID- 25457561 TI - Dielectric screening in atomically thin boron nitride nanosheets. AB - Two-dimensional (2D) hexagonal boron nitride (BN) nanosheets are excellent dielectric substrate for graphene, molybdenum disulfide, and many other 2D nanomaterial-based electronic and photonic devices. To optimize the performance of these 2D devices, it is essential to understand the dielectric screening properties of BN nanosheets as a function of the thickness. Here, electric force microscopy along with theoretical calculations based on both state-of-the-art first-principles calculations with van der Waals interactions under consideration, and nonlinear Thomas-Fermi theory models are used to investigate the dielectric screening in high-quality BN nanosheets of different thicknesses. It is found that atomically thin BN nanosheets are less effective in electric field screening, but the screening capability of BN shows a relatively weak dependence on the layer thickness. PMID- 25457562 TI - Serum citrulline as a diagnostic marker of sepsis-induced intestinal dysfunction. AB - OBJECTIVE: To investigate the use of citrulline as an indicator for diagnosing septic acute intestinal dysfunction (SAID) in a rat model. METHODS: SD rats were divided into three groups: a normal group (A), a model group (B), and a glutamine group (C). Group B was divided into a 36-h group (B1) and a 72-h feeding group (B2). The concentrations of serum citrulline, intestinal fatty acid-binding protein (I-FABP) and intestinal glutamine and histopathological changes were measured. RESULTS: The lengths of the villus and thicknesses of the mucosal layer in groups B1, B2 and C were significantly different from those in group A. Citrulline concentrations in groups B1, B2 and C were lower than in group A; the serum concentrations in group C were significantly greater than in groups B1 and B2. The I-FABP levels of groups B1, B2 and C were higher than group A; I-FABP levels of groups B1 and B2 were higher than group C. Intestinal glutamine levels of groups B1 and B2 were lower than groups A and C. The serum citrulline of group C was negatively correlated with I-FABP and Chiu's score. CONCLUSIONS: Serum citrulline could be used as the diagnostic indicator of SAID. PMID- 25457563 TI - NICeSim: an open-source simulator based on machine learning techniques to support medical research on prenatal and perinatal care decision making. AB - OBJECTIVE: This paper describes NICeSim, an open-source simulator that uses machine learning (ML) techniques to aid health professionals to better understand the treatment and prognosis of premature newborns. METHODS: The application was developed and tested using data collected in a Brazilian hospital. The available data were used to feed an ML pipeline that was designed to create a simulator capable of predicting the outcome (death probability) for newborns admitted to neonatal intensive care units. However, unlike previous scoring systems, our computational tool is not intended to be used at the patients bedside, although it is possible. Our primary goal is to deliver a computational system to aid medical research in understanding the correlation of key variables with the studied outcome so that new standards can be established for future clinical decisions. In the implemented simulation environment, the values of key attributes can be changed using a user-friendly interface, where the impact of each change on the outcome is immediately reported, allowing a quantitative analysis, in addition to a qualitative investigation, and delivering a totally interactive computational tool that facilitates hypothesis construction and testing. RESULTS: Our statistical experiments showed that the resulting model for death prediction could achieve an accuracy of 86.7% and an area under the receiver operating characteristic curve of 0.84 for the positive class. Using this model, three physicians and a neonatal nutritionist performed simulations with key variables correlated with chance of death. The results indicated important tendencies for the effect of each variable and the combination of variables on prognosis. We could also observe values of gestational age and birth weight for which a low Apgar score and the occurrence of respiratory distress syndrome (RDS) could be less or more severe. For instance, we have noticed that for a newborn with 2000 g or more the occurrence of RDS is far less problematic than for neonates weighing less. CONCLUSIONS: The significant accuracy demonstrated by our predictive model shows that NICeSim might be used for hypothesis testing to minimize in vivo experiments. We observed that the model delivers predictions that are in very good agreement with the literature, demonstrating that NICeSim might be an important tool for supporting decision making in medical practice. Other very important characteristics of NICeSim are its flexibility and dynamism. NICeSim is flexible because it allows the inclusion and deletion of variables according to the requirements of a particular study. It is also dynamic because it trains a just-in-time model. Therefore, the system is improved as data from new patients become available. Finally, NICeSim can be extended in a cooperative manner because it is an open-source system. PMID- 25457564 TI - Promoting healthful behaviour changes in people affected by diabetes. PMID- 25457565 TI - Outcomes of transurethral resection (TUR) of intravesical mesh after suburethral slings in the treatment of urinary stress incontinence. AB - OBJECTIVE: The objective of this study was to determine the efficacy as well as the complications associated with transurethral removal (TUR) of intravesical mesh after suburethral sling, transobturator tape-TOT (MonarcTM) or "minisling" (MiniArc((r))), in the treatment of female urinary stress incontinence (USI). MATERIAL AND METHODS: retrospective and consecutive study on 9 women with bladder perforation after midurethral slings (3 MonarcTM and 6 MiniArc(r)) placement for urinary stress incontinence. To remove the mesh, transurethral resection with an electrode loop (TUR-E) was used. The technique included: location and total removal of mesh with bipolar resectoscope up to healthy tissue. RESULTS: The median age was 61 years (49-70 years). The median time between midurethral sling placement and onset the sympltoms was 13 months (1-79 months). and between sling placement and mesh removal was 16 months (1-91 months). Five women (55.5%) developed bladder stones. Mean operating time was 29.4 +/- 10.4 minutes and mean length of hospital stay was 2.6 +/- 0.5 days. The median follow-up after mesh removal was 38 months (range, 14 to 109 months). No complications were found. CONCLUSIONS: The use of transurethral resection of intravesical mesh after suburethral slings is easy and the results obtained by our surgical team are excellent. PMID- 25457566 TI - Comment to "Residency in urology and training in Kidney transplantion. Result of a national survey". PMID- 25457567 TI - Impact of 3D vision on mental workload and laparoscopic performance in inexperienced subjects. AB - OBJECTIVE: To assess the effect of vision in three dimensions (3D) versus two dimensions (2D) on mental workload and laparoscopic performance during simulation based training. MATERIALS AND METHODS: A prospective, randomized crossover study on inexperienced students in operative laparoscopy was conducted. Forty-six candidates executed five standardized exercises on a pelvitrainer with both vision systems (3D and 2D). Laparoscopy performance was assessed using the total time (in seconds) and the number of failed attempts. For workload assessment, the validated NASA-TLX questionnaire was administered. RESULTS: 3D vision improves the performance reducing the time (3D = 1006.08 +/- 315.94 vs. 2D = 1309.17 +/- 300.28; P < .001) and the total number of failed attempts (3D = .84 +/- 1.26 vs. 2D = 1.86 +/- 1.60; P < .001). For each exercise, 3D vision also shows better performance times: "transfer objects" (P = .001), "single knot" (P < .001), "clip and cut" (P < .05), and "needle guidance" (P < .001). Besides, according to the NASA-TLX results, less mental workload is experienced with the use of 3D (P < .001). However, 3D vision was associated with greater visual impairment (P < .01) and headaches (P < .05). CONCLUSION: The incorporation of 3D systems in laparoscopic training programs would facilitate the acquisition of laparoscopic skills, because they reduce mental workload and improve the performance on inexperienced surgeons. However, some undesirable effects such as visual discomfort or headache are identified initially. PMID- 25457568 TI - The use of ACR Appropriateness Criteria: a survey of radiology residents and program directors. AB - PURPOSE: Assess the utilization of American College of Radiology Appropriateness Criteria (ACR-AC) among radiology residency program directors (PDs) and residents. METHODS: Radiology PD and resident survey. RESULTS: Seventy-four percent (46/62) of PDs promote ACR-AC in education (P<.05), and 84% (317/376) of residents have read at least a few (P<.05). Seventy-four percent (74/100) of first-year residents compared to 56.8% (157/276) of second- to fourth-year residents report at least occasional faculty reference of ACR-AC (P<.05). ACR-AC are well regarded (P<.05), but 40% believe that they are perplexing. CONCLUSION: There is widespread resident awareness of ACR-AC and integration into resident training. However, faculty are only beginning to teach with them, and radiologists are not citing them with clinicians. PMID- 25457569 TI - Diagnostic imaging of posterior fossa anomalies in the fetus and neonate: part 2, Posterior fossa disorders. AB - This second portion of a two-part review illustrates examples of posterior fossa disorders detectable on prenatal ultrasound and MRI, with postnatal or pathology correlation where available. These disorders are discussed in the context of an anatomic classification scheme described in Part 1 of this posterior fossa anomaly review. Assessment of the size and formation of the cerebellar hemispheres and vermis is critical. Diagnoses discussed here include arachnoid cyst, Blake's pouch cyst, Dandy-Walker malformation, vermian agenesis, Joubert syndrome, rhombencephalosynapsis, Chiari II malformation, ischemia, and tumors. PMID- 25457570 TI - Feasibility of ultra-low radiation dose reduction for renal stone CT using model based iterative reconstruction: prospective pilot study. AB - PURPOSE: To compare dose, reader assessments, and noise between ultra-low-dose (ULD) and low-dose (LD) renal stone computed tomography (CT) using multiple reconstruction methods. MATERIALS AND METHODS: Prospective study of 19 patients having noncontrast LD and ULD renal stone CT reconstructed using filtered back projection, adaptive statistical iterative reconstruction (ASIR), and model-based iterative reconstruction (MBIR). Dose, noise measurements, and subjective image assessments were recorded. RESULTS: ULD volume CT dose index was 61% less. Noise was 50% less with ULD MBIR than with LD ASIR (P<.001); no other significant differences existed. CONCLUSION: ULD MBIR is comparable to our standard of care, LD ASIR, with 61% lower dose and 50% less noise. PMID- 25457571 TI - Solitary spinal extradural plasmacytoma: MR imaging findings in seven cases. AB - PURPOSE: The aim of this study was to retrospectively review the magnetic resonance (MR) imaging presentation of solitary spinal extradural plasmacytoma (SSEP), which originates from the dura and extends into the extradural space. MATERIALS AND METHODS: MR imaging features of seven patients with SSEP were analyzed. RESULTS: All the tumors were spindle shaped, well defined, and located in the extradural dorsal spinal canal. Most lesions occurred in the thoracic regions with homogeneous enhancement. No bone erosion or exophytic paraspinal mass was noted. CONCLUSION: SSEP should be considered if a well-circumscribed mass has homogeneous enhancement without bone erosion in the dorsal spinal canal. PMID- 25457572 TI - Pearls and pitfalls in first-trimester obstetric sonography. AB - Ultrasound is the primary imaging modality used in the evaluation of first trimester vaginal bleeding and pelvic pain. This article will summarize the ultrasound findings in normal first-trimester pregnancy, failed pregnancy, ectopic pregnancy, subchorionic hemorrhage, retained products of conception, and gestational trophoblastic disease. Mastery of the spectrum of sonographic findings in the normal and abnormal first-trimester pregnancy allows the radiologist to make accurate diagnoses and helps to appropriately guide patient management. PMID- 25457573 TI - Diagnostic imaging of posterior fossa anomalies in the fetus and neonate: part 1, normal anatomy and classification of anomalies. AB - This article is the first portion of a two-part review that illustrates the normal appearance of the cerebellum and posterior fossa on prenatal ultrasound and MRI and on postnatal diagnostic imaging studies. Classification and terminology of posterior fossa abnormalities in the literature are confusing due to evolution of concepts and sometimes lack of consensus. Accurate classification of posterior fossa anomalies is important for predicting fetal outcome and for appropriate counseling. In Part 1 of this review, prenatal and postnatal imaging techniques for assessing the posterior fossa will be discussed, followed by a discussion of how cerebellar malformations may be classified. PMID- 25457574 TI - Vaginal shape at resting pelvic MRI: predictor of pelvic floor weakness? AB - OBJECTIVE: The objective was to determine if alteration in vaginal shape seen on nonstraining pelvic magnetic resonance (MR) scans is associated with pelvic floor weakness. METHODS: Two readers classified the shape of the middle third of the vagina on resting T2-weighted axial images as normal or abnormal for 76 women with and without pelvic floor weakness. RESULTS: The sensitivity and specificity for diagnosing pelvic floor dysfunction were 84% and 68% for reader A and 41% and 91% for reader B. Interobserver agreement was fair (kappa=0.39). CONCLUSIONS: Architectural distortion of vaginal shape on routine pelvic MR imaging may suggest pelvic floor dysfunction but is not diagnostic. PMID- 25457575 TI - Two cases of sclerosing angiomatoid nodular transformation of the spleen with gradual growth: usefulness of diffusion-weighted imaging. AB - Sclerosing angiomatoid nodular transformation (SANT) is a recently recognized and rare, nonneoplastic lesion of the spleen. Some papers have reported an increased SANT diameter during the follow-up period. We present two cases of SANT whose size increased during the follow-up period. Diffusion-weighted magnetic resonance imaging (DWI) findings correlated well with the pathological findings of SANT, the multinodular high-intensity area as the angiomatoid nodules and the peripheral low-intensity area as fibrous tissues. Therefore, DWI may be a useful imaging tool. PMID- 25457583 TI - Efficacy and safety of anticoagulant therapy for the treatment of acute cancer associated thrombosis: a systematic review and meta-analysis. AB - BACKGROUND: Current clinical practice guidelines all recommend the use of therapeutic doses of low molecular weight heparins (LMWH) for the initial and long-term treatment of cancer-related thrombosis. The use of vitamin-K antagonists (VKA) is acceptable if LMWH is not available. Direct oral anticoagulants (DOACs) have been shown to be comparable to conventional therapy for the acute treatment of VTE but their efficacy and safety in cancer patients remains uncertain. METHODS: A systematic literature search strategy was conducted using MEDLINE, EMBASE, and the EBM reviews. Randomized controlled trials (RCTs) reporting rates of recurrent VTE and major bleeding in cancer patients were included. Relative risks (RR) (95% confidence intervals (CI)) for these outcomes were generated. RESULTS: A total of 9 RCTs (2310 patients) were included in our analysis. In comparison to VKA, LMWH showed a significant reduction in recurrent VTE events (RR: 0.52; 95% CI: 0.36 to 0.74) whereas DOACs did not (RR: 0.66; 95% CI: 0.39 to 1.11). LMWH was associated with a non significant increase in the risk of major bleeding (RR: 1.06; 95% CI: 0.5 to 2.23) whereas DOACs showed a non significant reduction (RR: 0.78; 95% CI: 0.42 to 1.44). Annualized risks of recurrent VTE and major bleeding among patients randomized to VKA were higher in the LMWH studies as compared to the studies assessing DOACs suggesting that a higher risk cancer population were enrolled in the LMWH studies. CONCLUSIONS: LMWH should be used for the treatment of acute cancer-associated thrombosis. The use DOACs cannot be supported until trials comparing them to LMWH are conducted. PMID- 25457584 TI - A meta-analysis of phase III randomized controlled trials with novel oral anticoagulants in atrial fibrillation: comparisons between direct thrombin inhibitors vs. factor Xa inhibitors and different dosing regimens. AB - AIMS: Previous studies evaluating the ability of novel oral anticoagulants (NOAC) to prevent thromboembolism in patients with non-valvular atrial fibrillation (AF) have identified differences between the efficacy and safety of the drugs tested. Whether these differences reflect differences in direct thrombin or Xa inhibition, different dosing regimens or specific aspects of each agent or trial has not yet been explored. METHODS: A search was performed on MEDLINE, EMBASE and COCHRANE, and ongoing studies were tracked on clinicaltrials.gov. Phase III randomized controlled trials of direct thrombin inhibitors (DTI) and factor Xa inhibitors (FXaI) vs. warfarin in patients with AF were eligible. Data were pooled using random-effects, according to the Mantel-Haenszel model. Sensitivity analyses were performed on DTI, FXaI, once-daily and twice-daily regimens. RESULTS: Seven studies were pooled, including a total of 80,290 patients. Both DTI and FXaI outperformed warfarin regarding stroke or systemic embolism, intracranial bleeding, total and cardiovascular mortality. No significant differences were found between DTI and FXaI or between once-daily and twice-daily regimens. Some drugs performed worse than warfarin regarding some secondary endpoints, including: edoxaban 30 mg bid on ischaemic stroke, dabigatran on acute myocardial infarction, dabigatran 150 mg bid and rivaroxaban 20mgod on gastrointestinal bleeding. CONCLUSION: Our pooled data do not support the hypothesis of a significant class-effect of DTI or FXaI, nor the benefit of once daily vs. twice-daily dosing in the setting of AF, reinforcing that the choice of NOAC should be adapted to the specific patient and focused on the agent itself, rather than the pharmacological class or dosing regimen. PMID- 25457585 TI - Thrombolysis in hemodynamically stable patients with acute pulmonary embolism: a meta-analysis. AB - INTRODUCTION: The role of thrombolysis in hemodynamically stable patients with acute pulmonary embolism (PE) remains controversial. We performed a meta-analysis of randomized trials to assess the effect of thrombolysis in these patients. MATERIALS AND METHODS: We searched MEDLINE and EMBASE for randomized studies comparing thrombolysis and heparin for the initial treatment of hemodynamically stable PE patients. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated. NNH to cause a major bleeding (MB) or an intracranial hemorrhage (ICH) and NNT to avoid one death were also calculated. RESULTS: Eleven studies (1833 patients) were included seven with rt-PA, three with tenecteplase and one with urokinase. Patients randomized to thrombolysis had a significant increased risk for MB (5.9% vs 1.9%; OR 2.83, 95% CI 1.68-4.76, I2 18.7%) and an increased risk for ICH (1.74% versus 0.6%; OR 2.36, 95% CI 0.98-5.71, I2 0%) and for fatal bleeding (1.3% versus 0.54%; OR 1.84, 95% CI 0.73-4.61, I2 0%). A not-significant reduction for all-cause death (1.74% vs 2.51%; OR 0.68, 95% CI 0.37-1.26, I2 0%) and a significant reduction for recurrent PE (1.1% vs 2.5%; OR 0.44, 95% CI 0.21 0.92, I2 0%) in favor of thrombolysis compared with heparin was found. NNH to cause a MB or an ICH were 27 and 91 patients, respectively. NNT to avoid one death was 125 patients. CONCLUSIONS: Due to increased risk for MB and ICH with no evidence of reduction in mortality, thrombolysis should not be used for most normotensive PE patients. PMID- 25457586 TI - VASP phosphorylation and genetic polymorphism for clopidogrel resistance in Chinese patients with non-cardioembolic ischemic stroke. AB - BACKGROUND: Clopidogrel resistance(CR)is found in non-cardioembolic ischemic stroke (NCIS) patients. However, it is still largely unknown how to identify CR in NCIS patients by laboratory and genetic characteristics. METHODS: A total of 95 patients with acute NCIS were recruited. Phosphorylation of the vasodilator stimulated phosphoprotein (VASP) was detected using flow cytometry, and genes(CYP2C19,CYP3A4) were detected using the Sanger method. The baseline of platelet reactivity index (BPRI) before clopidogrel treatment and the platelet reactivity index with clopidogrel treatment (CPRI) for 7 days were measured. Laboratory clopidogrel resistance (LCR) was defined as CPRI of >= 50%. Clinical clopidogrel resistance (CCR) was defined as the presence of progressive stroke during hospitalization, stroke recurrence or occurrence of other ischemic vascular events within 6 months. RESULTS: The incidence of LCR was 41.05% and 18.95% developed CCR. The incidence of LCR was significantly higher in GA/AA patients with CYP2C19 (681G > A) (chi2 = 11.16, P = 0.001) and CYP2C19 (636G > A) (chi2 = 4.829, P = 0.028) than in wildtype GG patients. CYP2C19 (681G > A) (OR 6.272, 95%CI 2.162,18.199,P = 0.001) and CYP2C19 (636G > A) (OR: 5.625,95%CI 1.439, 21.583,P = 0.013) were risk factors for LCR. patients with LCR were more likely to develop CCR (chi2 = 6.021, P = 0.014). The probability of CCR was markedly increased in GA/AA patients with CYP2C19 (681G > A) (chi2 = 10.341, P = 0.001). We identified CYP2C19 (681G > A) (OR 7.814, 95%CI 1.816, 33.618 P = 0.006), Essen score (OR 8.351, 95%CI 1.848, 37.745 P = 0.006), and LCR (OR 5.881, 95%CI 1.373, 25.192, P = 0.017) as risk factors for CCR. CONCLUSION: In clinical practice,LCR and CYP2C19 gene polymorphism should be assessed in NCIS patients receiving clopidogrel treatment. PMID- 25457587 TI - FCGR2A rs1801274 polymorphism is associated with risk of childhood-onset idiopathic (immune) thrombocytopenic purpura: evidence from a meta-analysis. AB - INTRODUCTION: Previous studies have evaluated the association between FCGR2A H131R (rs1801274) polymorphism and idiopathic (immune) thrombocytopenic purpura (ITP), but results remain inconsistent. This meta-analysis was conducted to clarify these controversies. METHODS: Literatures on PubMed/ Medline, Embase and CENTRAL databases up to September 2013 were searched by two investigators. The distributions of alleles and genotypes between cases and controls were compared by using odds ratios (ORs) and 95% confidence intervals (95% CIs). Fixed or Random-effects models were used when appropriate. RESULTS: 10 studies involving 553 patients and 1088 controls were available for this study, including 7 studies of Caucasian descendents, 2 studies of Asian descendents, and 1 study contained diverse ethnicity. In this studied overall population, we didn't found any significant association between the FCGR H131R polymorphism and the risk of ITP for all genetic models. But in the subgroup analysis, a significant association between FCGR H131R polymorphism and ITP susceptibility was observed in Caucasian population of childhood-onset group for H vs. R (OR = 1.246, 95% CI 1.021-1.522, p = 0.031), HH vs. HR + RR (OR = 1.562, 95% CI 1.145-2.129, p = 0.005), HH vs. HR (OR = 1.598, 95% CI 1.146-2.228, p = 0.006), HH vs. RR (OR = 1.484, 95% CI 1.005 2.191, p = 0.047). No significantly between-study heterogeneity was observed for all genotype models in Caucasian childhood-onset ITP subtype analysis. However, this association was not stable after sensitivity analysis. CONCLUSION: Our present meta-analysis indicated that FCGR H131R polymorphism might not be associated with risk of ITP in overall population. However, in Caucasian childhood-onset subgroup, there might be an association between FCGR2A H131R polymorphism and ITP risk, which is not robust and should be explained with caution. PMID- 25457588 TI - Early versus delayed oral feeding for patients after cesarean. AB - BACKGROUND: Early oral feeding (EOF) after cesarean delivery is still controversial. OBJECTIVES: To assess whether EOF is superior to delayed oral feeding (DOF) after cesarean in terms of safety and effectiveness. SEARCH STRATEGY: PubMed, Embase, and the Cochrane Library were searched for reports related to early feeding and cesarean published in English before June 30, 2014. SELECTION CRITERIA: Randomized controlled trials comparing at least one of six outcomes after EOF (<=12 hours after surgery) and DOF (after return of bowel sounds/movement or >12 hours) after cesarean delivery were included. DATA COLLECTION AND ANALYSIS: Data were extracted using a predesigned extraction form. Risk ratios or mean differences were calculated. MAIN RESULTS: A total of 20 studies were included, including 4584 women who had undergone cesarean. No significant differences were identified in patient satisfaction and frequency of postoperative complications. Compared with DOF, EOF promoted a quicker return of bowel sounds, flatus, bowel movement, and regular diet (P<0.001 for all). Significant reductions were also noted in duration and amount of intravenous fluids, length of hospital stay, and time to first breastfeeding (P<0.001 for all). CONCLUSIONS: There are no obvious advantages in withholding fluid and food after cesarean. Indeed, EOF offers some short-term benefits. PMID- 25457589 TI - "The famous zenith sector" at Greenwich. PMID- 25457592 TI - Modeling sheep pox disease from the 1994-1998 epidemic in Evros Prefecture, Greece. AB - Sheep pox is a highly transmissible disease which can cause serious loss of livestock and can therefore have major economic impact. We present data from sheep pox epidemics which occurred between 1994 and 1998. The data include weekly records of infected farms as well as a number of covariates. We implement Bayesian stochastic regression models which, in addition to various explanatory variables like seasonal and environmental/meteorological factors, also contain serial correlation structure based on variants of the Ornstein-Uhlenbeck process. We take a predictive view in model selection by utilizing deviance-based measures. The results indicate that seasonality and the number of infected farms are important predictors for sheep pox incidence. PMID- 25457593 TI - Spatial prevalence and associations among respiratory diseases in Maine. AB - Chronic respiratory diseases rank among the leading global disease burdens. Maine's respiratory disease prevalence exceeds the US average, despite limited urbanization/industrialization. To provide insight into potential etiologic factors among this unique, rural population, we analyzed the spatial distributions of, and potential associations among asthma, COPD, pneumonia, and URI adult outpatient data (n=47,099) from all outpatient transactions (n=5,052,900) in 2009 for Maine hospitals and affiliate clinics, using spatial scan statistic, geographic weighted regression (GWR), and a Delaunay graph algorithm. Non-random high prevalence regions were identified, the majority of which (84% of the population underlying all regions) exhibited clusters for all four respiratory diseases. GWR provided further evidence of spatial correlation (R(2)=0.991) between the communicable and noncommunicable diseases under investigation, suggesting spatial interdependence in risk. Sensitivity analyses of known respiratory disease risks did not fully explain our results. Prospective epidemiology studies are needed to clarify all contributors to risk. PMID- 25457594 TI - Geographic access to healthy and unhealthy food sources for children in neighbourhoods and from elementary schools in a mid-sized Canadian city. AB - We examined location-related accessibility to healthy and unhealthy food sources for school going children in Saskatoon, Saskatchewan. We compared proximity to food sources from school sites and from small clusters of homes (i.e., dissemination blocks) as a proxy for home location. We found that (1) unhealthy food sources are more prevalent near schools in lower income than higher income neighbourhoods; (2) unhealthy compared to healthy food sources are more accessible from schools as well as from places of residence; and (3) while some characteristics of neighbourhood low socio-economic status are associated with less accessibility to healthy food sources, there is no consistent pattern of access. Greater access to unhealthy food sources from schools in low-income neighbourhoods is likely a reflection of the greater degree of commercialization. Our spatial examination provides a more nuanced understanding of accessibility through our approach of comparing place of residence and school access to food sources. PMID- 25457596 TI - Spatio-temporal epidemiology of highly pathogenic avian influenza (subtype H5N1) in poultry in eastern India. AB - In India, majority outbreaks of highly pathogenic avian influenza (HPAI) H5N1 have occurred in eastern states of West Bengal, Assam and Tripura. This study aimed to identify disease clusters and risk factors of HPAI H5N1 in these states, for targeted surveillance and disease control. A spatial scan statistic identified two significant disease clusters in West Bengal and Assam, occurring during January and November-December 2008, respectively. Key risk factors were identified at sub-district level using bootstrapped logistic regression and boosted regression trees model. With both methods, HPAI H5N1 outbreaks in backyard poultry were associated with accessibility in terms of time taken to access a city with >50,000 persons, human population density and duck density (P<0.005). In addition, areas at lower elevation were also identified as high risk by BRT model. It is recommended that risk-based surveillance should be implemented in high duck density areas and all live-bird markets in high throughput locations. PMID- 25457595 TI - The use of sampling weights in Bayesian hierarchical models for small area estimation. AB - Hierarchical modeling has been used extensively for small area estimation. However, design weights that are required to reflect complex surveys are rarely considered in these models. We develop computationally efficient, Bayesian spatial smoothing models that acknowledge the design weights. Computation is carried out using the integrated nested Laplace approximation, which is fast. An extensive simulation study is presented that considers the effects of non response and non-random selection of individuals, allowing examination of the impact of ignoring the design weights and the benefits of spatial smoothing. The results show that, when compared with standard approaches, mean squared error can be greatly reduced with the proposed methods. Bias reduction occurs through the inclusion of the design weights, with variance reduction being achieved through hierarchical smoothing. We analyze data from the Washington State 2006 Behavioral Risk Factor Surveillance System. The models are easily and quickly fitted within the R environment, using existing packages. PMID- 25457597 TI - Supervised learning and prediction of spatial epidemics. AB - Parameter estimation for mechanistic models of infectious disease can be computationally intensive. Nsoesie et al. (2011) introduced an approach for inference on infectious disease data based on the idea of supervised learning. Their method involves simulating epidemics from various infectious disease models, and using classifiers built from the epidemic curve data to predict which model were most likely to have generated observed epidemic curves. They showed that the classification approach could fairly identify underlying characteristics of the disease system, without fitting various transmission models via, say, Bayesian Markov chain Monte Carlo. We extend this work to the case where the underlying infectious disease model is inherently spatial. Our goal is to compare the use of global epidemic curves for building the classifier, with the use of spatially stratified epidemic curves. We demonstrate these methods on simulated data and apply the method to analyze a tomato spotted wilt virus epidemic dataset. PMID- 25457598 TI - A multivariate CAR model for mismatched lattices. AB - In this paper, we develop a multivariate Gaussian conditional autoregressive model for use on mismatched lattices. Most current multivariate CAR models are designed for each multivariate outcome to utilize the same lattice structure. In many applications, a change of basis will allow different lattices to be utilized, but this is not always the case, because a change of basis is not always desirable or even possible. Our multivariate CAR model allows each outcome to have a different neighborhood structure which can utilize different lattices for each structure. The model is applied in two real data analysis. The first is a Bayesian learning example in mapping the 2006 Iowa Mumps epidemic, which demonstrates the importance of utilizing multiple channels of infection flow in mapping infectious diseases. The second is a multivariate analysis of poverty levels and educational attainment in the American Community Survey. PMID- 25457599 TI - Estimation of district-level under-5 mortality in Zambia using birth history data, 1980-2010. AB - Birth history data-the primary source of data on under-5 mortality in developing countries-are infrequently used for subnational estimates due to concerns over small sample sizes. In this study we consider different methods for analyzing birth history data in combination with various small area models. We construct a simulation environment to assess the performance of different combinations of birth history methods and small area models in terms of bias, efficiency, and coverage. We find that performance is highly dependent on the birth history method applied and how temporal trends are accounted for. We estimated trends in district-level under-5 mortality in Zambia from 1980 to 2010 using the best performing model. We find that under-5 mortality is highly variable within Zambia: there was a 1.8-fold difference between the lowest and highest levels in 2010, and declines over the period 1980 to 2010 ranged from less than 5% to more than 50%. PMID- 25457600 TI - Neighborhood geographic disparities in heart attack and stroke mortality: comparison of global and local modeling approaches. AB - This study investigated neighborhood geographic disparities in myocardial infarction (MI) and stroke mortality risks in middle Tennessee and identified determinants of observed disparities. Descriptive and spatial analyses were performed on MI and stroke mortality data covering the time period 1999-2007. Besag, York and Mollie (BYM) model was used to investigate spatial patterns. Global (BYM) and local models [Poisson Geographically Weighted Generalized Linear Models (GWGLM)] were used to investigate determinants of the identified spatial patterns. Significant (p<0.05) differences in mortality risks by sex, race, age and education were observed. Rural census tracts (CT) and those with higher proportions of the older populations were associated with high MI and stroke mortality risks. Additionally, CTs with high proportions of widows had significantly higher mortality risks for stroke. There was evidence of geographical variability of all regression coefficients implying that local models complement the findings of the global models and provide useful information to guide local and regional disease control decisions and resource allocation. Identification of high risk CTs is essential for targeting resources and will aid the development of more needs-based prevention programs. PMID- 25457601 TI - Using exceedance probabilities to detect anomalies in routinely recorded animal health data, with particular reference to foot-and-mouth disease in Viet Nam. AB - The widespread availability of computer hardware and software for recording and storing disease event information means that, in theory, we have the necessary information to carry out detailed analyses of factors influencing the spatial distribution of disease in animal populations. However, the reliability of such analyses depends on data quality, with anomalous records having the potential to introduce significant bias and lead to inappropriate decision making. In this paper we promote the use of exceedance probabilities as a tool for detecting anomalies when applying hierarchical spatio-temporal models to animal health data. We illustrate this methodology through a case study data on outbreaks of foot-and-mouth disease (FMD) in Viet Nam for the period 2006-2008. A flexible binomial logistic regression was employed to model the number of FMD infected communes within each province of the country. Standard analyses of the residuals from this model failed to identify problems, but exceedance probabilities identified provinces in which the number of reported FMD outbreaks was unexpectedly low. This finding is interesting given that these provinces are on major cattle movement pathways through Viet Nam. PMID- 25457603 TI - Spatial and statistical methodologies to determine the distribution of dengue in Brazilian municipalities and relate incidence with the Health Vulnerability Index. AB - Dengue fever is among the most important emerging infectious diseases in the world, and in recent years it has been a source of public concern for the public health control systems of many tropical and subtropical countries. Thus, the purpose of this study was to apply spatial and statistical methodologies to analyze the geographic distribution of dengue and to relate its incidence to the Health Vulnerability Index (HVI), an indicator that integrates different socioeconomic variables to estimate the degree of health vulnerability in different Brazilian cities. The cases of dengue, incidence rates and Bayesian incidence rates were determined using census tracts covering a period of 3 years in a city with socioeconomic and administrative characteristics typical of Brazilian municipalities. Distribution plots, descriptive statistics, kernel density maps, test of global and local spatial autocorrelation and Spearman correlation were used. No association was found between the incidence of dengue and the HVI. Conversely, statistically significant high-incidence clusters were found over the 3 years in an area identified as having lower health vulnerability. The finding that HVI was not a good indicator of dengue in the city studied may be explained by the complexity of the disease. Administrative and financial problems in the municipalities, environmental factors, cultural changes and the emergence of new serotypes are other factors that hinder the understanding and control of the disease. However, the spatial and statistical methodologies used here are suitable and useful tools for the accurate understanding of dengue and other infectious epidemiological processes. PMID- 25457602 TI - Spatio-temporal modeling of the African swine fever epidemic in the Russian Federation, 2007-2012. AB - In 2007 African swine fever (ASF) entered Georgia and in the same year the disease entered the Russian Federation. From 2007 to 2012 ASF spread throughout the southern region of the Russian Federation. At the same time several cases of ASF were detected in the central and northern regions of the Russian Federation, forming a northern cluster of outbreaks in 2011. This northern cluster is of concern because of its proximity to mainland Europe. The aim of this study was to use details of recorded ASF outbreaks and human and swine population details to estimate the spatial distribution of ASF risk in the southern region of the European part of the Russian Federation. Our model of ASF risk was comprised of two components. The first was an estimate of ASF suitability scores calculated using maximum entropy methods. The second was an estimate of ASF risk as a function of Euclidean distance from index cases. An exponential distribution fitted to a frequency histogram of the Euclidean distance between consecutive ASF cases had a mean value of 156 km, a distance greater than the surveillance zone radius of 100-150 km stated in the ASF control regulations for the Russian Federation. We show that the spatial and temporal risk of ASF expansion is related to the suitability of the area of potential expansion, which is in turn a function of socio-economic and geographic variables. We propose that the methodology presented in this paper provides a useful tool to optimize surveillance for ASF in affected areas. PMID- 25457604 TI - Optimal vaccination strategies against vector-borne diseases. AB - Using a process oriented semi-agent based model, we simulated the spread of Bluetongue virus by Culicoides, biting midges, between cattle in Denmark. We evaluated the minimum vaccination cover and minimum cost for eight different preventive vaccination strategies in Denmark. The simulation model replicates both a passive and active flight of midges between cattle distributed on pastures and cattle farms in Denmark. A seasonal abundance of midges and temperature dependence of biological processes were included in the model. The eight vaccination strategies were investigated under four different grazing conditions. Furthermore, scenarios were tested with three different index locations stratified for cattle density. The cheapest way to vaccinate cattle with a medium risk profile (less than 1000 total affected cattle) was to vaccinate cattle on pasture. Regional vaccination displayed better results when index cases were in the vaccinated areas. However, given that the long-range spread of midge borne disease is still poorly quantified, more robust national vaccination schemes seem preferable. PMID- 25457605 TI - The rubber plantation environment and Lassa fever epidemics in Liberia, 2008 2012: a spatial regression. AB - As Lassa fever continues to be a public health challenge in West Africa, it is critical to produce good maps of its risk pattern for use in active surveillance and control intervention. We identified eight spatial features related to the rubber plantation environment and used them as explanatory variables for Lassa fever (LF) outbreaks on the Uniroyal Liberian Agricultural Company (LAC) rubber plantation environment in Grand Bassa County, Liberia. We computed classical and spatial lag regression models on all spatial features, including proximity of residential camp to rubber tree-edge, main road in the plantation, LAC hospital, rice farmland, household refuse dump, human population density, post-harvest storage density of rice and density of rodent deterrent on rice storage. We found significant (p=0.0024) spatial autocorrelation between LF cases and the spatial features we have considered. We concluded that the rubber plantation environment influenced Mastomys species' breeding and transmission of Lassa virus along spatial scale to humans. The risk factors identified in this study offered a baseline for more effective surveillance and control of LF in the post-civil conflict Liberia. PMID- 25457606 TI - Synthesis, characterization, and in vitro evaluation of artesunate-beta cyclodextrin conjugates as novel anti-cancer prodrugs. AB - A novel series of artesunate-beta-cyclodextrin (ATS-beta-CD) conjugates, in which artesunate (ATS) was coupled covalently to one of the primary hydroxyl groups of beta-cyclodextrin (beta-CD) through amino bond formation, were synthesized and characterized by (1)H NMR, HRMS, 2D NMR (ROESY), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). The results showed that the aqueous solubility of ATS-beta-CD conjugates was 26-45 times better than that of free ATS. The cytotoxicity of the ATS-beta-CD conjugates was evaluated on human colon cancer cell lines HCT116, LOVO, SW480, and HT-29, and the results indicated that ATS 2NbetaCD exhibited a very high cytotoxicity against HCT116, LOVO, and HT-29 with IC50 values of 0.58, 1.62, and 5.18MUmol/L, respectively. In addition, the supposition of better cytotoxicity was further supported by the control experiment of fluorescent cyclodextrin. PMID- 25457607 TI - Structural determination of Streptococcus pneumoniae repeat units in serotype 41A and 41F capsular polysaccharides to probe gene functions in the corresponding capsular biosynthetic loci. AB - We report the repeating unit structures of the native capsular polysaccharides of Streptococcus pneumoniae serotypes 41A and 41F. Structural determinations yielded six carbohydrate units in the doubly branched repeating unit to give the following structure for serotype 41A: The structure determinations were motivated (1) by an ambition to help close the remaining gaps in S. pneumoniae capsular polysaccharide structures, and (2) by the attempt to derive functional annotations of carbohydrate active enzymes in the biosynthesis of bacterial polysaccharides from the determined structures. An activity present in 41F but not 41A is identified as an acetyltransferase acting on the rhamnopyranosyl sidechain E. The genes encoding the formation of the six glycosidic bonds in serogroup 41 were determined from the capsular polysaccharide structures of serotype 41A, 41F, and genetically related serotypes, in conjunction with corresponding genomic information and computational homology searches. In combination with complementary information, NMR spectroscopy considerably simplifies the functional annotation of carbohydrate active enzymes in the biosynthesis of bacterial polysaccharides. PMID- 25457608 TI - Susceptibility of enoxaparin reducing end amino sugars to periodate oxidation. AB - There is a growing interest on glycol-split low-molecular weight heparins (gs LMWHs), obtained by periodate oxidation of LMWHs, optionally followed by borohydride reduction, as potential anticancer and anti-inflammatory drugs. However, their structural characterization is still a challenging task, mainly because of the high microheterogeneity of the starting material. In addition, susceptibility to oxidation of some end-groups of LMWHs induces additional heterogeneity, making analysis of gs-LMWHs more complex. In our previous study we showed that 1,6-anhydro-d-mannosamine N-sulfate was affected by periodate, while its epimer 1,6-anhydro-d-glucosamine N-sulfate was resistant. In order to understand the apparently anomalous behavior of terminal 1,6-anhydro-d mannosamine N-sulfate residues, in the present work we have studied by NMR spectroscopy and LC/MS the behavior of the reducing end amino sugar residues of the tetrasaccharides, isolated from the LMWH enoxaparin, in the presence of periodate. Their molecular mechanics conformational characterization has been also performed. We have shown that the C(2)-C(3) bond of the 1,6-anhydro-d mannosamine residue can be split by periodate despite the N-substitution. Moreover, we have found that both terminal d-mannosamine N-sulfate and d glucosamine N-sulfate, lacking the 1,6-anhydro-bridge, can be also oxidized by periodate but with a significantly lower rate. The present results suggest that the cis-e-/a-position of OH and NHSO3(-) groups of N-sulfated 1,6-anhydro-d mannosamine is not the only factor that makes these end residues susceptible to the oxidation. The 1,6-anhydro-bridge that 'blocks' the ring conformation appears another crucial factor for oxidation to occur. Moreover, we have shown that controlling the reaction time could permit to selectively split non-sulfated iduronic acids of enoxaparin chains without oxidizing terminal amino sugar residues, a finding that may be useful to obtain more structurally homogeneous gs LMHWs. PMID- 25457610 TI - The role of PPK26 in Drosophila larval mechanical nociception. AB - In Drosophila larvae, the class IV dendritic arborization (da) neurons are polymodal nociceptors. Here, we show that ppk26 (CG8546) plays an important role in mechanical nociception in class IV da neurons. Our immunohistochemical and functional results demonstrate that ppk26 is specifically expressed in class IV da neurons. Larvae with mutant ppk26 showed severe behavioral defects in a mechanical nociception behavioral test but responded to noxious heat stimuli comparably to wild-type larvae. In addition, functional studies suggest that ppk26 and ppk (also called ppk1) function in the same pathway, whereas piezo functions in a parallel pathway. Consistent with these functional results, we found that PPK and PPK26 are interdependent on each other for their cell surface localization. Our work indicates that PPK26 and PPK might form heteromeric DEG/ENaC channels that are essential for mechanotransduction in class IV da neurons. PMID- 25457609 TI - Synthesis of a heparin-related GlcN-IdoA sulfation-site variable disaccharide library and analysis by Raman and ROA spectroscopy. AB - Synthesis of an array of differentially sulfated GlcN-IdoA disaccharides, accessible on good scale, directly from l-iduronate components is described. These are specifically directed to provide the sulfation variability at the key most common biologically relevant sulfation-variable l-IdoA O-2 and d-GlcN O-6 and amino sites of this heparin disaccharide. This sulfation-varied matrix has allowed the first evaluation of using Raman/ROA spectroscopy to characterize changes in spectra as a function of both site and level of sulfation with pure, defined heparin-related disaccharide species. This provides analysis of both similarities and differences to digest native heparin and this shows evidence of different types of changes in conformations and conformational freedom as a function of some specific sulfation changes at the disaccharide level. It is anticipated that this data set will open the way for applications to further site specific sulfated saccharides and demonstrates the capability offered by Raman ROA towards fingerprinting sulfation in heparin fragments. PMID- 25457611 TI - Trim25 Is an RNA-Specific Activator of Lin28a/TuT4-Mediated Uridylation. AB - RNA binding proteins have thousands of cellular RNA targets and often exhibit opposite or passive molecular functions. Lin28a is a conserved RNA binding protein involved in pluripotency and tumorigenesis that was previously shown to trigger TuT4-mediated pre-let-7 uridylation, inhibiting its processing and targeting it for degradation. Surprisingly, despite binding to other pre microRNAs (pre-miRNAs), only pre-let-7 is efficiently uridylated by TuT4. Thus, we hypothesized the existence of substrate-specific cofactors that stimulate Lin28a-mediated pre-let-7 uridylation or restrict its functionality on non-let-7 pre-miRNAs. Through RNA pull-downs coupled with quantitative mass spectrometry, we identified the E3 ligase Trim25 as an RNA-specific cofactor for Lin28a/TuT4 mediated uridylation. We show that Trim25 binds to the conserved terminal loop (CTL) of pre-let-7 and activates TuT4, allowing for more efficient Lin28a mediated uridylation. These findings reveal that protein-modifying enzymes, only recently shown to bind RNA, can guide the function of canonical ribonucleoprotein (RNP) complexes in cis, thereby providing an additional level of specificity. PMID- 25457612 TI - Sestrins inhibit mTORC1 kinase activation through the GATOR complex. AB - The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a sensor of different environmental conditions and regulator of cell growth, metabolism, and autophagy. mTORC1 is activated by Rag GTPases, working as RagA:RagB and RagC:RagD heterodimers. Rags control mTORC1 activity by tethering mTORC1 to the lysosomes where it is activated by Rheb GTPase. RagA:RagB, active in its GTP-bound form, is inhibited by GATOR1 complex, a GTPase-activating protein, and GATOR1 is in turn negatively regulated by GATOR2 complex. Sestrins are stress-responsive proteins that inhibit mTORC1 via activation of AMP-activated protein kinase (AMPK) and tuberous sclerosis complex. Here we report an AMPK-independent mechanism of mTORC1 inhibition by Sestrins mediated by their interaction with GATOR2. As a result of this interaction, the Sestrins suppress mTOR lysosomal localization in a Rag-dependent manner. This mechanism is potentially involved in mTORC1 regulation by amino acids, rotenone, and tunicamycin, connecting stress response with mTORC1 inhibition. PMID- 25457614 TI - Antioxidant properties and efficacies of synthesized alkyl caffeates, ferulates, and coumarates. AB - Caffeic, ferulic, and coumaric acids were lipophilized with saturated fatty alcohols (C1-C20). The antioxidant properties of these hydroxycinnamic acids and their alkyl esters were evaluated in various assays. Furthermore, the antioxidant efficiency of the compounds was evaluated in a simple o/w microemulsion using the conjugated autoxidizable triene (CAT) assay. All evaluated phenolipids had radical scavenging, reducing power, and metal chelating properties. Only caffeic acid and caffeates were able to form a complex with iron via their catechol group in the phenolic ring. In the o/w emulsion, the medium chain phenolipids of the three homologues series were most efficient. The antioxidant properties and efficacies were dependent upon functional groups substituted to the ring structure and were in the following order: caffeic acid and caffeates > ferulic acid and ferulates > coumaric acid and coumarates. Moreover, the results demonstrated that the test system has an impact on the antioxidative properties measured. PMID- 25457613 TI - Rescuing dicer defects via inhibition of an anti-dicing nuclease. AB - Genetic defects in the microRNA (miRNA) generating enzyme, dicer, are increasingly linked to disease. Loss of miRNA in dicer deficiency is thought to be due to loss of miRNA-generating activity. Here, we demonstrate a catabolic mechanism driving miRNA depletion in dicer deficiency. We developed a Dicer antagonist assay revealing a pre-miRNA degrading enzyme that competes with pre miRNA processing. We purified this pre-miRNA degrading activity using an unbiased chromatographic procedure and identified the ribonuclease complex Translin/Trax (TN/TX). In wild-type dicer backgrounds, pre-miRNA processing was dominant. However, in dicer-deficient contexts, TN/TX broadly suppressed miRNA. These findings indicate that miRNA depletion in dicer deficiency is due to the combined loss of miRNA-generating activity and catabolic function of TN/TX. Importantly, inhibition of TN/TX mitigated loss of both miRNA and tumor suppression with dicer haploinsufficiency. These studies reveal a potentially druggable target for restoring miRNA function in cancers and emerging dicer deficiencies. PMID- 25457615 TI - Cell-intrinsic TLR2/MyD88 pathway in breast and colon cancer. PMID- 25457618 TI - Regulation of T cell trafficking by the T cell immunoglobulin and mucin domain 1 glycoprotein. AB - Leukocyte trafficking is generally considered the initial stage of any immune response, and it involves a multistep intravascular process including capture, rolling, activation, arrest, crawling, and transmigration. Both capture and rolling are predominantly mediated by selectins, which allow circulating leukocytes to sense activating signals on the endothelium and adhere to vessel walls. In this review, we discuss recent data showing that the T cell immunoglobulin and mucin domain 1 (TIM-1) protein is a major ligand for endothelial P-selectin, mediating T helper (Th) cell Th1 and Th17 trafficking in inflamed tissues. We highlight structural and functional features showing that TIM-1 can be included in the restricted group of major adhesion receptors involved in leukocyte trafficking with a pathophysiological role in inflammation and autoimmunity. PMID- 25457617 TI - Seeing through VEGF: innate and adaptive immunity in pathological angiogenesis in the eye. AB - The central role of vascular endothelial growth factor (VEGF) signaling in regulating normal vascular development and pathological angiogenesis has been documented in multiple studies. Ocular anti-VEGF therapy is highly effective for treating a subset of patients with blinding eye disorders such as diabetic retinopathy and neovascular age-related macular degeneration (AMD). However, chronic VEGF suppression can lead to adverse effects associated with poor visual outcomes due to the loss of prosurvival and neurotrophic capacities of VEGF. In this review, we discuss emerging evidence for immune-related mechanisms that regulate ocular angiogenesis in a VEGF-independent manner. These novel molecular and cellular pathways may provide potential therapeutic avenues for a multitarget strategy, preserving the neuroprotective functions of VEGF in those patients whose disease is unresponsive to VEGF neutralization. PMID- 25457620 TI - miRNAs as biomarkers of myocardial infarction: a step forward towards personalized medicine? AB - miRNAs are small noncoding RNAs known to post-transcriptionally regulate gene expression. miRNAs are expressed in the heart where they regulate multiple pathophysiological processes. The discovery of stable cardiac miRNAs in the bloodstream has also motivated the investigation of their potential as biomarkers. This review gathers the current knowledge on the use of miRNAs as novel biomarkers to improve risk stratification, diagnosis, and prognosis of patients with myocardial infarction. In the rapidly evolving era of biomarkers, the potential of miRNAs as promising tools to move personalized medicine a step forward is discussed. PMID- 25457621 TI - A study exploring the association of attitude and treatment satisfaction with glycaemic level among gestational diabetes mellitus patients. AB - AIMS: The aim of this study was to evaluate attitude and treatment satisfaction of women suffering from GDM and their association with glycaemic level. METHODS: A cross sectional study was conducted in antenatal clinic of Hospital Pulau Pinang, Malaysia from June to December 2013 on the sample of 175 patients. Data was collected through modified version of Diabetes Integration Scale (ATT-19) and Diabetes Treatment Satisfaction Questionnaires (DSTQs). Glycaemic level was evaluated in terms of Fasting Plasma Glucose (FPG). Three most recent values of FPG (mmol/l) were taken from patients medical profiles and their mean was calculated. Descriptive and inferential statistics were used for data analysis. RESULTS: A total of 166 patients were included in final analysis. Only 35 (21.1%) patients had positive attitude and 122 (73.5%) of patients had adequate treatment satisfaction. There was no significant association of total mean ATT-19 score with age, ethnicity, educational level, occupational status, family history and type of therapy. For treatment satisfaction statistically significant association was present only between total mean treatment satisfaction score and educational level. Patients with negative attitude and inadequate treatment satisfaction had higher mean glycaemic level. CONCLUSIONS: It is concluded that more than two folds of patients were satisfied with their ongoing treatment but majority of the patients were feeling difficulty in active coping measures for the management of GDM. PMID- 25457619 TI - Clock genes, pancreatic function, and diabetes. AB - Circadian physiology is responsible for the temporal regulation of metabolism to optimize energy homeostasis throughout the day. Disturbances in the light/dark cycle, sleep/wake schedule, or feeding/activity behavior can affect the circadian function of the clocks located in the brain and peripheral tissues. These alterations have been associated with impaired glucose tolerance and type 2 diabetes. Animal models with molecular manipulation of clock genes and genetic studies in humans also support these links. It has been demonstrated that the endocrine pancreas has an intrinsic self-sustained clock, and recent studies have revealed an important role of clock genes in pancreatic beta cells, glucose homeostasis, and diabetes. PMID- 25457623 TI - [Evaluation of grip strength in normal and obese Wistar rats submitted to swimming with overload after median nerve compression]. AB - OBJECTIVE: To verify the functionality through muscle grip strength in animals with obesity induced by monosodium glutamate (MSG) and in control animals, which suffered compression of the right median nerve, and treated with swimming with overload. METHODS: During the first five days of life, neonatal Wistar rats received subcutaneous injections of MSG. The control group received a hypertonic saline solution. Forty-eight rats were divided into six groups: G1 (control); G2 (control + injury); G3 (control + injury + swimming); G4 (obese); G5 (obese + injury); G6 (obese + injury + swimming). The animals in groups G2, G3, G5 and G6 were submitted to compression of the median nerve and G3 and G6 groups were treated, after injury, with swimming exercise with load for three weeks. The swimming exercise had a progressive duration, according to the week, of 20, 30 and 40minutes. Muscle strength was assessed using a grip strength meter preoperatively and on the 3rd, 7th, 14th and 21st days after surgery. The results were expressed and analyzed using descriptive and inferential statistics. RESULTS: When the grip strength was compared among assessments regardless of group, in the second assessment the animals exhibited lower grip strength. G1 and G4 groups had greater grip strength, compared to G2, G3, G4 and G6. CONCLUSION: The swimming exercise with overload has not been effective in promoting improvement in muscle grip strength after compression injury of the right median nerve in control and in obese-MSG rats. PMID- 25457624 TI - Commentary on "Kindergarten classroom functioning of extremely preterm/extremely low birth weight children" or "Leaving no child behind: promoting educational success for preterm survivors". AB - OBJECTIVE: Our purpose was to discuss the supports required at school entry for children with extreme prematurity. METHODS: We commented on the kindergarten classroom functioning and the importance of providing structure and supports to ensure school-entry learning success. RESULTS: Kindergarten readiness is a multidimensional construct that integrates physical, developmental, behavioral, social-emotional, and adaptive skills necessary for learning in groups. Key components that predict classroom functioning include attention and executive function skills. CONCLUSIONS: Extremely preterm survivors as well as other critically ill neonates require proactive supports by informed educators. PMID- 25457625 TI - Narrating narcolepsy--centering a side effect. AB - The mass-vaccination with Pandemrix was the most important preventive measure in Sweden during the A(H1N1) influenza pandemic of 2009-2010, and covered 60% of the population. From 2010, an increased incidence of the neurological disease narcolepsy was reported, and an association with Pandemrix was affirmed for more than 200 children and young adults. The parental experience of this side effect provided a starting point for a collectively shaped critical narrative to be acted out in public, but also personalized narratives of continual learning about the disease and its consequences. This didactic functionality resulted in active meaning-making practices about how to handle the aftermath--using dark humor, cognitive tricks, and making themselves and their children's bodies both objects and subjects of knowledge. Using material from interviews with parents, this mixing of knowledge work and political work, and the potential for reflective consciousness, is discussed. PMID- 25457626 TI - Antioxidant capacity of synovial fluid in the temporomandibular joint correlated with radiological morphology of temporomandibular disorders. AB - We investigated the correlation between the antioxidant capacity of synovial fluid and radiological findings of intra-articular structures in patients with disorders of the temporomandibular joint (TMJ). We recruited 21 patients (9 men and 12 women, aged 18-84 years of age) with such disorders, excluding myofascial pain and dysfunction syndrome, or other muscular disorders. The clinical variables recorded included age, sex, interincisal distance, and visual analogue pain scores (VAS). Radiological findings were obtained from diagnostic arthrogram and cone-beam computed tomography (CT). The antioxidant capacity of the synovial fluid was measured by chemiluminescence. Eleven patients were radiologically diagnosed with closed lock, and the remaining 10 with no closed lock. An anchored intra-articular disc was most often seen on cone-beam CT (n=19) followed by perforated disc (n=7), osteoarthrosis (n=7), and anterior disc displacement without reduction (n=5). Although there were no significant differences between antioxidant capacity and age, sex, VAS, or any findings on cone-beam CT, antioxidant capacity was significantly decreased in the patients with closed lock compared with those who did not have closed lock (p=0.02). The results suggest an association between the oxidative stress of the synovial fluid and closed-lock in disorders of the TMJ. PMID- 25457627 TI - Tumours of the salivary glands in northeastern China: a retrospective study of 2508 patients. AB - Little information has been published in English about the epidemiology of tumours of the salivary glands in northeastern China. From August 2004 to March 2014, 2508 cases of primary epithelial salivary gland tumours were diagnosed in the Department of Oral and Maxillofacial Surgery, the Affiliated Stomatology Hospital of China Medical University. Tumours were analysed according to their histological type and site, and the age and sex of the patients. Ages ranged from 5 to 98 years, with a slight propensity in favour of men. The peak incidence was in the sixth decade for both sexes. The mean (SD) ages were 48 (16) years when the tumour was benign and 51 (15) years when it was malignant. The parotid gland and palate were the sites most commonly affected. There were 1934 (77.1%) benign and 574 (22.9%) malignant tumours, with the most common histological types being pleomorphic adenomas and mucoepidermoid carcinomas. A lesion that arises from the floor of the mouth (92.8%) or the tongue (86.2%) is more likely to be malignant than those from other minor salivary glands. PMID- 25457628 TI - Mini-scleral lenses in the visual rehabilitation of patients after penetrating keratoplasty and deep lamellar anterior keratoplasty. AB - OBJECTIVE: To evaluate fitting feasibility, efficacy, and safety of mini scleral contact lenses in correcting post corneal graft vision. METHODS: Prospective interventional case series, 56 visually unsatisfied post corneal graft eyes of 45 patients were fitted with miniscleral lenses (15.8 mm). Keratometric values, UCVA and BSCVA, fit, best corrected vision with the lens, decision to order lens, comfortable daily wearing time (CDWT), contact lens handling issues, and contact lens related complications were documented. RESULTS: The mean age was 34.6 years (SD: 10.9), ranging from 8 to 63 years. Forty-three eyes had history of full thickness corneal graft, 12 eyes had deep anterior lamellar graft (DALK) and 1 eye had the rotational graft. The mean UCVA was 1.05 logMar (SD: 0.54), ranging from 0.30 to 2.52 logMar. The mean BSCVA was 0.73 logMar (SD: 0.50) ranging from 0.09 to 2.00 which improved to 0.17 logMar (SD: 0.19) with the miniscleral lens. All eyes had ideal (40 eyes) or acceptable (16 eyes) fits. Nineteen patients (23 eyes) ordered their lenses of whom 11 (14 eyes) continued using the lens with a mean follow up time of 21.92 months (SD: 6.8). These patients reported a mean CDWT of 9.62 h/day (SD: 4.5). Five eyes of 4 patients discontinued the lens. Four eyes were lost to follow-up. The main reported barriers for ordering the lenses were economic and handling concerns. CONCLUSION: Miniscleral contact lenses can be considered helpful in the visual management of post corneal graft patients. Other factors may influence the acceptance of the lenses. PMID- 25457629 TI - Portuguese mitochondrial DNA genetic diversity-An update and a phylogenetic revision. AB - In recent years a large amount of mitochondrial population data for forensic purposes has been produced. Current efforts are focused at increasing the number of studied populations while generating updated genetic information of forensic quality. However, complete mitochondrial control region sequences are still scarce for most populations and even more so for complete mitochondrial genomes. In the case of Portugal, previous population genetics studies have already revealed the general portrait of HVS-I and HVS-II mitochondrial diversity, becoming now important to update and expand the mitochondrial region analysed. Accordingly, a total of 292 complete control region sequences from continental Portugal were obtained, under a stringent experimental design to ensure the quality of data through double sequencing of each target region. Furthermore, H specific coding region SNPs were examined to detail haplogroup classification and complete mitogenomes were obtained for all sequences belonging to haplogroups U4 and U5. In general, a typical Western European haplogroup composition was found in mainland Portugal, associated to high level of mitochondrial genetic diversity. Within the country, no signs of substructure were detected. The typing of extra coding region SNPs has provided the refinement or confirmation of the previous classification obtained with EMMA tool in 96% of the cases. Finally, it was also possible to enlarge haplogroup U phylogeny with 28 new U4 and U5 mitogenomes. PMID- 25457630 TI - Development of an Italian RM Y-STR haplotype database: Results of the 2013 GEFI collaborative exercise. AB - Recently introduced rapidly mutating Y-chromosomal short tandem repeat (RM Y-STR) loci, displaying a multiple-fold higher mutation rate relative to any other Y STRs, including those conventionally used in forensic casework, have been demonstrated to improve the resolution of male lineage differentiation and to allow male relative separation usually impossible with standard Y-STRs. However, large and geographically-detailed frequency haplotype databases are required to estimate the statistical weight of RM Y-STR haplotype matches if observed in forensic casework. With this in mind, the Italian Working Group (GEFI) of the International Society for Forensic Genetics launched a collaborative exercise aimed at generating an Italian quality controlled forensic RM Y-STR haplotype database. Overall 1509 male individuals from 13 regional populations covering northern, central and southern areas of the Italian peninsula plus Sicily were collected, including both "rural" and "urban" samples classified according to population density in the sampling area. A subset of individuals was additionally genotyped for Y-STR loci included in the Yfiler and PowerPlex Y23 (PPY23) systems (75% and 62%, respectively), allowing the comparison of RM and conventional Y STRs. Considering the whole set of 13 RM Y-STRs, 1501 unique haplotypes were observed among the 1509 sampled Italian men with a haplotype diversity of 0.999996, largely superior to Yfiler and PPY23 with 0.999914 and 0.999950, respectively. AMOVA indicated that 99.996% of the haplotype variation was within populations, confirming that genetic-geographic structure is almost undetected by RM Y-STRs. Haplotype sharing among regional Italian populations was not observed at all with the complete set of 13 RM Y-STRs. Haplotype sharing within Italian populations was very rare (0.27% non-unique haplotypes), and lower in urban (0.22%) than rural (0.29%) areas. Additionally, 422 father-son pairs were investigated, and 20.1% of them could be discriminated by the whole set of 13 RM Y-STRs, which was very close to the theoretically expected estimate of 19.5% given the mutation rates of the markers used. Results obtained from a high coverage Italian haplotype dataset confirm on the regional scale the exceptional ability of RM Y-STRs to resolve male lineages previously observed globally, and attest the unsurpassed value of RM Y-STRs for male-relative differentiation purposes. PMID- 25457631 TI - Forensic massively parallel sequencing data analysis tool: Implementation of MyFLq as a standalone web- and Illumina BaseSpace((r))-application. AB - Routine use of massively parallel sequencing (MPS) for forensic genomics is on the horizon. The last few years, several algorithms and workflows have been developed to analyze forensic MPS data. However, none have yet been tailored to the needs of the forensic analyst who does not possess an extensive bioinformatics background. We developed our previously published forensic MPS data analysis framework MyFLq (My-Forensic-Loci-queries) into an open-source, user-friendly, web-based application. It can be installed as a standalone web application, or run directly from the Illumina BaseSpace environment. In the former, laboratories can keep their data on-site, while in the latter, data from forensic samples that are sequenced on an Illumina sequencer can be uploaded to Basespace during acquisition, and can subsequently be analyzed using the published MyFLq BaseSpace application. Additional features were implemented such as an interactive graphical report of the results, an interactive threshold selection bar, and an allele length-based analysis in addition to the sequenced based analysis. Practical use of the application is demonstrated through the analysis of four 16-plex short tandem repeat (STR) samples, showing the complementarity between the sequence- and length-based analysis of the same MPS data. PMID- 25457632 TI - Forensic botany II, DNA barcode for land plants: Which markers after the international agreement? AB - The ambitious idea of using a short piece of DNA for large-scale species identification (DNA barcoding) is already a powerful tool for scientists and the application of this standard technique seems promising in a range of fields including forensic genetics. While DNA barcoding enjoyed a remarkable success for animal identification through cytochrome c oxidase I (COI) analysis, the attempts to identify a single barcode for plants remained a vain hope for a longtime. From the beginning, the Consortium for the Barcode of Life (CBOL) showed a lack of agreement on a core plant barcode, reflecting the diversity of viewpoints. Different research groups advocated various markers with divergent set of criteria until the recent publication by the CBOL-Plant Working Group. After a four-year effort, in 2009 the International Team concluded to agree on standard markers promoting a multilocus solution (rbcL and matK), with 70-75% of discrimination to the species level. In 2009 our group firstly proposed the broad application of DNA barcoding principles as a tool for identification of trace botanical evidence through the analysis of two chloroplast loci (trnH-psbA and trnL-trnF) in plant species belonging to local flora. Difficulties and drawbacks that were encountered included a poor coverage of species in specific databases and the lack of authenticated reference sequences for the selected markers. Successful preliminary results were obtained providing an approach to progressively identify unknown plant specimens to a given taxonomic rank, usable by any non-specialist botanist or in case of a shortage of taxonomic expertise. Now we considered mandatory to update and to compare our previous findings with the new selected plastid markers (matK+rbcL), taking into account forensic requirements. Features of all the four loci (the two previously analyzed trnH psbA+trnL-trnF and matK+rbcL) were compared singly and in multilocus solutions to assess the most suitable combination for forensic botany. Based on obtained results, we recommend the adoption of a two-locus combination with rbcL+trnH-psbA plastid markers, which currently best satisfies forensic needs for botanical species identification. PMID- 25457633 TI - Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma. AB - BACKGROUND: Second-line treatment options for patients with advanced urothelial carcinoma (UC) are limited. Fibroblast growth factor receptor 3 (FGFR3) is dysregulated in UC by activating mutations or protein overexpression in non mutant tumours. In this study, the efficacy, pharmacodynamics and safety of dovitinib-a broad-targeted inhibitor of tyrosine kinases, including FGFR3-were evaluated in patients with previously treated advanced UC with and without FGFR3 mutations. METHODS: Forty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant (FGFR3(MUT); n=12), wild-type (FGFR3(WT); n=31), or unknown (n=1) FGFR3 status. Patients received 500 mg dovitinib once daily on a 5 days-on/2-days-off schedule. The primary end-point of this two-stage study was the investigator-assessed overall response rate (ORR). RESULTS: Most of the patients were men (75%) and over half of the patients were aged ?65 years (61%). All patients had received ?1 prior antineoplastic therapy for UC. The study was terminated at the end of stage 1, when it was determined by investigator review that the ORR of both the FGFR3(MUT) (0%; 95% confidence interval [CI], 0.0-26.5) and FGFR3(WT) (3.2%; 95% CI, 0.1-16.7) groups did not meet the criteria to continue to stage 2. The most common grade 3/4 adverse events, suspected to be study-drug related, included thrombocytopenia (9%), fatigue (9%), and asthenia (9%). CONCLUSION: Although generally well tolerated, dovitinib has very limited single-agent activity in patients with previously treated advanced UC, regardless of FGFR3 mutation status. clinicaltrials.gov NCT00790426. PMID- 25457634 TI - Long telomere length and a TERT-CLPTM1 locus polymorphism association with melanoma risk. AB - Telomere length has been associated with the development of cancer. Studies have shown that shorter telomere length may be related to a decreased risk of cutaneous melanoma. Furthermore, deregulation of the telomere-maintaining gene complexes, has been related to this oncogenic process. Some variants in these genes seem to be correlated with a change in telomerase expression. We examined the effect of 10 single nucleotide polymorphisms (SNPs) in the TERT gene (encoding telomerase), one SNP in the related TERT-CLPTM1L locus and one SNP in the TRF1 gene with telomere length, and its influence on melanoma risk in 970 Spanish cases and 733 Spanish controls. Genotypes were determined using KASP technology, and telomere length was measured by quantitative polymerase chain reaction (PCR) on DNA extracted from peripheral blood leucocytes. Our results demonstrate that shorter telomere length is associated with a decreased risk of melanoma in our population (global p-value, 2.69*10(-11)), which may be caused by a diminution of proliferative potential of nevi (melanoma precursor cells). We also obtained significant results when we tested the association between rs401681 variant (TERT-CLPTM1L locus) with melanoma risk (Odds ratio, OR; 95% confidence interval, CI=1.24 (1.08-1.43); p-value, 3*10(-3)). This is the largest telomere related study undertaken in a Spanish population to date. Furthermore, this study represents a comprehensive analysis of some of the most relevant telomere pathway genes in relation to cutaneous melanoma susceptibility. PMID- 25457635 TI - PTEN/PIK3CA genes are frequently mutated in spontaneous and medroxyprogesterone acetate-accelerated 7,12-dimethylbenz(a)anthracene-induced mammary tumours of tree shrews. AB - Tree shrew has increasingly become an attractive experimental animal model for human diseases, particularly for breast cancer due to spontaneous breast tumours and their close relationship to primates and by extension to humans. However, neither normal mammary glands nor breast tumours have been well characterised in the Chinese tree shrew (Tupaia belangeri chinensis). In this study, normal mammary glands from four different developmental stages and 18 spontaneous breast tumours were analysed. Haematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) showed that normal mammary gland morphology and structures of tree shrews were quite similar to those found in humans. Spontaneous breast tumours of tree shrews were identified as being intraductal papilloma, papillary carcinoma, and invasive ductal carcinoma with or without lung metastasis. To further analyse breast cancer tumours among tree shrews, 40 3 4 month-old female tree shrews were orally administrated 20 mg 7,12 dimethylbenz(a)anthracene (DMBA) or peanut oil thrice, and then, 15 of these DMBA administrated tree shrews were implanted with medroxyprogesterone acetate (MPA) pellets. DMBA was shown to induce breast tumours (12%) while the addition of MPA increased the tumour incidence (50%). Of these, three induced breast tumours were intraductal papillary carcinomas and one was invasive ductal carcinoma (IDC). The PTEN/PIK3CA (phosphatase and tensin homologue/phosphatidylinositol-4,5 bisphosphate 3-kinase catalytic subunit alpha), but not TP53 and GATA3, genes are frequently mutated in breast tumours, and the PTEN/PIK3CA gene mutation status correlated with the expression of pAKT in tree shrew breast tumours. These results suggest that tree shrews may be a promising animal model for a subset of human breast cancers with PTEN/PIK3CA gene mutations. PMID- 25457636 TI - Mind your thoughts: associations between self-generated thoughts and stress induced and baseline levels of cortisol and alpha-amylase. AB - Stress is a major health burden in today's society. Research shows that negative cognitive styles are associated with increased stress reactivity, low mood and accelerated cellular aging. Our study sought to unravel the relationship between the content of self-generated thoughts and psychosocial stress measured in terms of hypothalamic-pituitary-adrenal axis and sympathetic activity. Features of self generated thoughts were assessed using thought sampling while participants performed cognitive tasks following a stress induction or in a baseline condition. More negatively toned emotional thoughts and more social temporal thoughts with a past focus were associated with increased cortisol and alpha amylase levels, both after stress and at baseline. More social temporal thoughts with a future focus, on the other hand, had an overall attenuating effect on the levels of both stress markers. Our results indicate a fundamental link between the thoughts and stress levels we experience. Understanding the mechanisms governing this mind-body association may have important implications for understanding and counteracting the high incidence of stress-related disorders in today's society. PMID- 25457638 TI - A functional polymorphism in the HTR2C gene associated with stress responses: a validation study. AB - Previously we have shown that a functional nonsynonymous single nucleotide polymorphism (SNP), rs6318 on the HTR2C gene located on the X-chromosome, is associated with hypothalamic-pituitary-adrenal axis response to a laboratory stress recall task. The present paper reports a validation of the cortisol response to stress in a second, independent sample. The study population consisted of 60 adult participants (73.3% males). Consistent with our prior findings, compared to Cys23 G allele carriers, persons homozygous for the Ser23C allele had a significantly greater average cortisol response (p=0.007) and area under the curve (p=0.021) over the course of an emotional stress recall protocol. Also parallel to our prior report, the change in cortisol from baseline to the average during the stress protocol was roughly twice as large among Ser23C homozygotes than among persons with Cys23 G. These findings validate our initial observation of association between rs6318 and cortisol response to an acute stressor, and extend the results to include females. PMID- 25457639 TI - Individual differences in heart rate variability are associated with the avoidance of negative emotional events. AB - Although the emotional outcome of a choice generally affects subsequent decisions, humans can inhibit the influence of emotion. Heart rate variability (HRV) has emerged as an objective measure of individual differences in the capacity for inhibitory control. In the present study, we investigated how individual differences in HRV at rest are associated with the emotional effects of the outcome of a choice on subsequent decision making using a decision-making task in which emotional pictures appeared as decision outcomes. We used a reinforcement learning model to characterize the observed behaviors according to several parameters, namely, the learning rate and the motivational value of positive and negative pictures. Consequently, we found that individuals with a lower resting HRV exhibited a greater negative motivational value in response to negative pictures, suggesting that these individuals tend to avoid negative pictures compared with individuals with a higher resting HRV. PMID- 25457637 TI - Perceived appearance judgments moderate the biological stress effects of social exchanges. AB - Social relationships are generally thought of as beneficial. However, the present study set out to test the hypothesis that for individuals who perceive others to judge their appearance negatively, daily social interactions can also be a source of stress. Indeed when assessing 38 young adults, we found that both more incidences of negative exchanges reported during the past month as well as perceived negative appearance judgments by others were associated with more self reported stress. Interestingly, however, for individuals with low attribution body esteem, higher numbers of positive social exchanges during the past month were related to health-relevant changes in biological markers of chronic stress as well. The same was true for individuals with high attribution body esteem who reported to experience only very few positive exchanges. As such, these findings go beyond the initial focus on low body esteem and negative social exchanges and introduce high body esteem as well as daily positive exchanges as potential health risk factors. PMID- 25457641 TI - Pediatric neurology far from home: globalization, guidelines, and standards of care. PMID- 25457640 TI - Psychophysiological support of increasing attentional reserve during the development of a motor skill. AB - The aim of this study was to determine the relationship between motor skill and attentional reserve. Participants practiced a reaching task with the dominant upper extremity, to which a distortion of the visual feedback was applied, while a control group performed the same task without distortion. Event-related brain potentials (ERPs), elicited by auditory stimuli were recorded throughout practice. Performance, as measured by initial directional error, was initially worse relative to controls and improved over trials. Analyses of the ERPs revealed that exogenous components, N1 and P2, were undifferentiated between the groups and did not change with practice. Notably, amplitude of the novelty P3 component, an index of the involuntary orienting of attention, was initially attenuated relative to controls, but progressively increased in amplitude over trials in the learning group only. The results provide psychophysiological evidence that attentional reserve increases as a function of motor skill acquisition. PMID- 25457642 TI - Can a revolution hide another one? Charles Darwin and the Scientific Revolution. PMID- 25457643 TI - Was there a Darwinian Revolution? Yes, no, and maybe! AB - Was there a Darwinian Revolution and was it but part of the Scientific Revolution? Before Thomas Kuhn's Structure of Scientific Revolutions in 1962, most people thought that there was a Darwinian Revolution, that it was in some sense connected to the Scientific Revolution, but that neither question nor answer was terribly interesting. Then revolutions in science became a matter of intense debate, not so much about their very existence but about their nature. Was there a switch in world-views? Did the facts change? What was the importance of social groups? And so forth. Recently however some students of the history of science have started to argue that the very questions are misconceived and that there cannot have been a Darwinian Revolution and its relationship to the Scientific Revolution is imaginary because there are no such revolutions in science! This paper takes a sympathetic look at these issues, concluding that there is still life in the revolution-in-science issue, that Kuhn's book was seminal and still has things of importance to say, but that matters are more complex and more interesting than we thought back then. PMID- 25457645 TI - A brief, but imperfect, historical sketch of a 'considerable revolution'. PMID- 25457644 TI - On Darwin's science and its contexts. AB - The notions of 'the Darwinian revolution' and of 'the scientific Revolution' are no longer unproblematic; so this paper does not construe its task as relating these two items to each other. There can be big-picture and long-run history even when that task is declined. Such history has to be done pluralistically. Relating Darwin's science to Newton's science is one kind of historiographical challenge; relating Darwin's science to seventeenth-century finance capitalism is another kind. Relating Darwin's science to long-run traditions and transitions is a different kind of task from relating his science to the immediate short-run contexts. PMID- 25457646 TI - Darwin and the geological controversies over the steady-state worldview in the 1830s. AB - In the first part of this paper, I will show that although Darwin's geological works only covered the first years of his scientific career, these played a non negligible role in the earth sciences of the mid-nineteenth century. His intellectual proximity with Charles Lyell often made him his disciple. This is indeed the case with respect to debates over 'gradual' soil movements and 'catastrophic' soil movements, and for 'steady-state' cycles as opposed to 'directionalistic' ones. This being said, it is also true that in South America Darwin saw geological processes which were incompatible with Lyell's explanations. It must therefore be recognized that Darwin held a middle-of-the road position between uniformitarianism (Lyell) and catastrophism (Humbolt and von Buch), at least as far as some geological questions were concerned. In the second part of the paper, debates on geological issues during Darwin's active years will be put in the methodological context of the Scientific Revolution of the seventeenth century. PMID- 25457647 TI - Evolution in a fully constituted world: Charles Darwin's debts towards a static world in the Origin of Species (1859). AB - The Transformist Revolution was a long intellectual quest that has expanded from the 18th century to today. One area of inquiry after another has confronted the necessity of recasting its object of study under an evolutionary view: human history, geology, biology, astronomy, etc. No single scholar fully managed to make the transition from a static worldview to an evolutionary one during his or her own lifetime; Charles Darwin is no exception. Many versions of evolutionism were proposed during this revolution, versions offering all sorts of compromises between old and new views. Not sufficiently acknowledged in the historiography is the profoundness of Darwin's debts towards the old static view. As a dual child of the Scientific Revolution and natural theology, Darwin inherited key concepts such as stability, completeness, timelessness, unity, permanence, and uniformity. Darwin took these concepts into consideration while erecting his theory of biological evolution. Unsurprisingly, this theory was ill-equipped to embrace the directionality, historicity, and novelty that came along with a new evolutionary world. This paper analyses a fundamental idea at the heart of Darwin's Origins of Species (1859) inherited from a static, stable, and machine-like conception of the world: the notion of a fully constituted world. Although in principle antithetical to the very idea of evolution itself, Darwin found a way to 'loosen up' this notion so as to retain it in a way that allows for some kind of evolutionary change. PMID- 25457648 TI - Laws of variation: Darwin's failed Newtonian program? PMID- 25457649 TI - [The invisible radiologist]. PMID- 25457650 TI - A heating-superfusion platform technology for the investigation of protein function in single cells. AB - Here, we report on a novel approach for the study of single-cell intracellular enzyme activity at various temperatures, utilizing a localized laser heating probe in combination with a freely positionable microfluidic perfusion device. Through directed exposure of individual cells to the pore-forming agent alpha hemolysin, we have controlled the membrane permeability, enabling targeted delivery of the substrate. Mildly permeabilized cells were exposed to fluorogenic substrates to monitor the activity of intracellular enzymes, while adjusting the local temperature surrounding the target cells, using an infrared laser heating system. We generated quantitative estimates for the intracellular alkaline phosphatase activity at five different temperatures in different cell lines, constructing temperature-response curves of enzymatic activity at the single-cell level. Enzymatic activity was determined rapidly after cell permeation, generating five-point temperature-response curves within just 200 s. PMID- 25457651 TI - Focal cortical dysplasia alters electrophysiological cortical hubs in the resting state. AB - OBJECTIVE: To test the hypothesis that epilepsy patients with focal cortical dysplasia (FCD) have different electrophysiological functional cortical hubs from those of healthy controls. METHODS: Resting-state functional networks in the theta, alpha, beta and gamma frequency bands were evaluated in 35 epilepsy patients with histopathologically verified FCD as a single pathology and in 46 age-matched healthy controls. Using magnetoencephalography (MEG), we investigated the network differences between the two groups by comparing the nodal efficiency (Enodal) and betweenness centrality (BC) values at the source level. RESULTS: The FCD patients had significant Enodal increases in the functional cortical hubs in the left anterior, middle, and posterior cortices and the medial orbital superior frontal cortex in the beta band. The left posterior cingulate cortex showed significant BC increases in the theta, alpha, and beta bands. There was a negative correlation between Enodal and age at seizure onset. CONCLUSIONS: Cortical dysplasia alters whole brain functional cortical hubs compared to healthy controls. The age at seizure onset was negatively correlated with Enodal in the beta band in FCD patients. SIGNIFICANCE: Our study for the first time investigated the functional cortical hubs and their alteration in the resting state functional network in epilepsy patients with FCD using noninvasive MEG signals. PMID- 25457652 TI - Microneurographic recording from unmyelinated nerve fibers in neurological disorders: an update. AB - Microneurography is a unique neurophysiological technique allowing direct recording of unmyelinated postganglionic sympathetic or afferent nociceptive fibers by tungsten needles inserted into a peripheral nerve fascicle. In recent years, microneurography has been used to ascertain autonomic impairments in central neurological disorders such as sleep disorders, Parkinson's disease, amyotrophic lateral sclerosis, or vasovagal syncope. Abnormal resting muscle sympathetic nerve activity (MSNA) and skin sympathetic nerve activity (SSNA) or the abnormal sympathetic response to arousal have been described in these disorders, thereby clarifying important pathophysiological aspects of the underlying impairment. In addition, microneurography was also recently used to demonstrate absent or decreased sympathetic outflow in diseases affecting the peripheral nervous system such as Ross syndrome, pure autonomic failure, and small-fiber neuropathy. Microneurography has also been used to study nociceptor outflow in pain disorders affecting the peripheral nervous system such as small fiber neuropathy, diabetic neuropathy, erythromelalgia, complex regional pain syndrome, and fibromyalgia. In these disorders, microneurography mainly documented mechano-insensitive C-nociceptor hyperexcitability that might account for the ongoing pain. PMID- 25457653 TI - Comparison of DOTA and NODAGA as chelators for (64)Cu-labeled immunoconjugates. AB - INTRODUCTION: Bifunctional chelators have been shown to impact the biodistribution of monoclonal antibody (mAb)-based imaging agents. Recently, radiolabeled 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) peptide complexes have demonstrated improved in vivo stability and performance compared to their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) counterparts. Here, we investigated if similar utility could be achieved with mAbs and compared (64)Cu-labeled DOTA and NODAGA-immunoconjugates for the detection of epithelial cell adhesion molecule (EpCAM) in a prostate cancer model. METHODS: DOTA and NODAGA-immunoconjugates of an EpCAM targeting mAb (mAb7) were synthesized and radiolabeled with (64)Cu (DOTA: 40 degrees C for 1hr; NODAGA: 25 degrees C for 1hr). The average number of chelators per mAb was quantified by isotopic dilution, and the biological activity of the immunoconjugates was evaluated by flow cytometry and ELISA. Radioligand assays were performed to compare cellular uptake and determine the dissociation constant (Kd) and maximum number of binding sites (Bmax) for the immunoconjugates using DsRed-transfected PC3-cells. A PC3-DsRed xenograft tumor model was established in nude mice and used to perform biodistribution studies to compare organ uptake and pharmacokinetics. RESULTS: (64)Cu-DOTA-mAb7 and (64)Cu-NODAGA-mAb7 were prepared with chelator/protein ratios of 2-3 and obtained in comparable radiochemical yields ranging from 59 to 71%. Similar immunoreactivity was observed with both agents, and mock labeling studies indicated that incubation at room temperature or 40 degrees C did not affect potency. (64)Cu-NODAGA-mAb7 demonstrated higher in vitro cellular uptake while (64)Cu-DOTA-mAb7 had higher Kd and Bmax values. From the biodistribution data, we found similar tumor uptake (13.44+/-1.21%ID/g and 13.24+/-4.86%ID/g for (64)Cu-DOTA-mAb7 and (64)Cu-NODAGA-mAb7, respectively) for both agents at 24hr, although normal prostate tissue was significantly lower for (64)Cu-NODAGA-mAb7. (64)Cu-NODAGA-mAb7 also had less accumulation in the liver, suggesting excellent retention of the chelation complex in vivo. This was further confirmed by the higher blood activity of (64)Cu-NODAGA-mAb7, which corresponds to increased bioavailability afforded by the enhanced in vivo stability of the agent. Although tumor/muscle ratios were comparable, tumor/prostate ratios were >2-fold and 1.5-fold higher for (64)Cu-NODAGA-mAb7 at 24 and 48hr, respectively, and suggest better ability to discriminate tumor tissue with (64)Cu-NODAGA-mAb7 in our prostate cancer model. CONCLUSIONS: To the best of our knowledge, this study represents the first comparison of (64)Cu-labeled DOTA and NODAGA immunoconjugates in vivo. Our results show favorable in vivo performance for (64)Cu-NODAGA-mAb7 which builds upon previous data on our hybrid mAb7 imaging agent by increasing the detection sensitivity for metastatic prostate tumors, as well as for other types of cancer that express EpCAM. PMID- 25457654 TI - Speech perception with interaction-compensated simultaneous stimulation and long pulse durations in cochlear implant users. AB - Early multi-channel designs in the history of cochlear implant development were based on a vocoder-type processing of frequency channels and presented bands of compressed analog stimulus waveforms simultaneously on multiple tonotopically arranged electrodes. The realization that the direct summation of electrical fields as a result of simultaneous electrode stimulation exacerbates interactions among the stimulation channels and limits cochlear implant outcome led to the breakthrough in the development of cochlear implants, the continuous interleaved (CIS) sampling coding strategy. By interleaving stimulation pulses across electrodes, CIS activates only a single electrode at each point in time, preventing a direct summation of electrical fields and hence the primary component of channel interactions. In this paper we show that a previously presented approach of simultaneous stimulation with channel interaction compensation (CIC) may also ameliorate the deleterious effects of simultaneous channel interaction on speech perception. In an acute study conducted in eleven experienced MED-EL implant users, configurations involving simultaneous stimulation with CIC and doubled pulse phase durations have been investigated. As pairs of electrodes were activated simultaneously and pulse durations were doubled, carrier rates remained the same. Comparison conditions involved both CIS and fine structure (FS) strategies, either with strictly sequential or paired simultaneous stimulation. Results showed no statistical difference in the perception of sentences in noise and monosyllables for sequential and paired simultaneous stimulation with doubled phase durations. This suggests that CIC can largely compensate for the effects of simultaneous channel interaction, for both CIS and FS coding strategies. A simultaneous stimulation paradigm has a number of potential advantages over a traditional sequential interleaved design. The flexibility gained when dropping the requirement of interleaving pulses across electrodes may be instrumental in designing coding strategies for a more accurate transmission of stimulus features such as temporal fine structure or interaural time delays to the auditory nerve. Also, longer pulse phase durations may be implemented while maintaining relatively high stimulation pulse rates. Utilizing longer pulse durations may relax requirements on implant compliance and facilitate the design of more energy-efficient implant receivers for a longer battery lifetime or a reduction in implant size. This article is part of a Special Issue entitled . PMID- 25457656 TI - Posterior ankle and hind foot arthroscopy - how do you responsibly learn this new technique? AB - Posterior ankle and hind foot arthroscopy has become an important diagnostic and therapeutic tool when dealing with ankle pathology. Although not yet widely adopted it is gaining popularity and there have been various descriptions of the technique [1] and its outcomes [2,3]. With posterior arthroscopy there are well documented risks of injury to the sural nerve and medial neurovascular bundle in particular [7-9]. These risks need to be carefully considered, particularly by surgeons early in the learning curve of what is undoubtedly a challenging technique. In an ideal world there should be scope for regular simulation to be integrated into a consultant's working week and this would allow them to be prepared for untoward incidences and also learn new techniques such as hind-foot arthroscopy in a safe environment prior to introduction into clinical practice. PMID- 25457655 TI - Localization training results in individuals with unilateral severe to profound hearing loss. AB - Adults with unilateral hearing loss often demonstrate decreased sound localization ability and report that situations requiring spatial hearing are especially challenging. Few studies have evaluated localization abilities combined with training in this population. The present pilot study examined whether localization of two sound types would improve after training, and explored the relation between localization ability or training benefit and demographic factors. Eleven participants with unilateral severe to profound hearing loss attended five training sessions; localization cues gradually decreased across sessions. Localization ability was assessed pre- and post training. Assessment stimuli were monosyllabic words and spectral and temporal random spectrogram sounds. Root mean square errors for each participant and stimulus type were used in group and correlation analyses; individual data were examined with ordinary least squares regression. Mean pre-to post-training test results were significantly different for all stimulus types. Among the participants, eight significantly improved following training on at least one localization measure, whereas three did not. Participants with the poorest localization ability improved the most and likewise, those with the best pre training ability showed the least training benefit. Correlation results suggested that test age, age at onset of severe to profound hearing loss and better ear high frequency audibility may contribute to localization ability. Results support the need for continued investigation of localization training efficacy and consideration of localization training within rehabilitation protocols for individuals with unilateral severe to profound hearing loss. PMID- 25457657 TI - Lateral ankle and hindfoot instability: a new clinical based classification. AB - Ankle sprains are one of the most common soft tissue injuries accounting for nearly 40% of sports injuries. There are large number of procedures for its treatment reported in the literature with largely good results. The ankle forms a functional unit with the subtalar joint. We present a new classification for peritalar lateral instability. There are two intents of this classification. Firstly, the classification demonstrates an assessment and treatment guideline for the many causes of peritalar lateral instability. The second use of the classification is for research purposes so that cohorts of patients can be accurately described and the efficacy of different operations in different groups can be properly assessed. PMID- 25457658 TI - Frequency and trends in foot and ankle injuries within an English Premier League Football Club using a new impact factor of injury to identify a focus for injury prevention. AB - BACKGROUND: Foot and ankle injuries are common in football. Prevention strategies exist in order to decrease the incidence of such injuries and minimize the number of days that a player is unavailable for selection. METHODS: Injuries were recorded over a 4-season period while the team was playing in the English Premier League (EPL). We present the epidemiology of foot and ankle injuries within a professional football club and offer a calculation that may be of use in the future to identify areas of injury prevention. RESULTS: Anterior Talo-Fibular Ligament (ATFL) injuries and fifth metatarsal fractures were of high impact as they were both common and resulted in significant time periods where the player was unavailable. CONCLUSIONS: This is the first time an EPL club has been prepared to publish data regarding injury. Our findings may be used by others to focus their prevention strategies on the injuries with the highest impact. PMID- 25457659 TI - The impact of ankle osteoarthritis. The difference of opinion between patient and orthopedic surgeon. AB - BACKGROUND: Outcome measures for ankle osteoarthritis (OA) are created by physicians with little input of the target patient group. The aim of this study was to determine the difference in opinion between patients and orthopedic surgeons concerning the importance of specific symptoms of ankle OA and its impact on daily life and function. METHODS: A modified Delphi method was applied, consisting of structured interviews with patient focus groups and experts, followed by a poll using 32 statements. The difference in opinion between patients and orthopedic surgeons was evaluated. RESULTS: Forty patients and forty orthopedic surgeons responded to the 32 statements. Statistically significant differences in opinion on symptoms, function and the impact of ankle OA on daily life were found. CONCLUSIONS: This study demonstrates a significant difference in opinion between patients and orthopedic surgeons concerning specific symptoms of ankle OA. These results advocate incorporating the needs and demands of the individual patient for new outcome measures. PMID- 25457660 TI - Endoscopic curettage and bone grafting of huge talar bone cyst with preservation of cartilaginous surfaces: surgical planning. AB - Open curettage and bone grafting of the huge talar cysts may need extensive soft tissue dissection or even different types of malleolar osteotomy to access the lesion. Arthroscopic approach can minimize soft tissue dissection or the need for malleolar osteotomy. Careful pre-operative planning of the portal sites allows endoscopic curettage and bone grafting of the lesions with preservation of the articular surfaces. PMID- 25457661 TI - Hypertrophy of the flexor hallucis longus muscle after tendon transfer in patients with chronic Achilles tendon rupture. AB - BACKGROUND: Flexor hallucis longus tendon (FHLT) transfer has become a popular method for reconstructing a chronic Achilles tendon rupture (ATR). The purpose of this study was to evaluate the clinical outcomes and possible hypertrophy of the FHL muscle after FHLT transfer in patients with chronic ATR. METHODS: Seven patients with chronic ATR underwent an FHLT transfer to heel through single incision. The patients were clinically evaluated 27 (16-39) months after the surgery. The patient satisfaction was assessed with Achilles Tendon Total Rupture Scale (ATRS). Isokinetic strength was measured from both legs. The FHL muscle hypertrophy was evaluated from MRI of both legs. All subjects also performed a gait analysis with an instrumented walkway system (GAITRite((r))). RESULTS: The plantar flexion strength was 16.1% (-45, 7-2, 4%) weaker in the operated leg. ATRS scores averaged 70.3. Marked hypertrophy, +52% (9-104%) of the FHL muscle was seen in the operated leg compared to the non-operated leg. The gait analysis did not show any marked pathology in any of the patients. CONCLUSIONS: A mean hypertrophy of 52% of the FHL muscle was found after FHLT transfer for the chronic ATR. This indicates strong adaptation capacity of this muscle after FLHT transfer in situation where the function of the gastro-soleus complex was severely impaired preoperatively. The reconstruction of chronic ATR with FHLT transfer provided a good functional outcome and excellent patient satisfaction. PMID- 25457662 TI - Does the IOFIX improve compression in ankle fusion? AB - BACKGROUND: The new IOFIX is an intra-osseous fixation device comprising an "X post" through which a lag screw passes to apparently improve force distribution across an arthrodesis. We conducted a novel human cadaveric study. Our null hypothesis was no difference in force exists in an ankle arthrodesis model stabilized with the IOFIX or a conventional single lag screw. METHOD: In ten cadaver ankles a pressure transducer was compressed as an IOFIX and standard single lag screws were alternately compared. RESULTS: The median average force created by the IOFIX was 3.95kg and 2.4kg for the single conventional lag screw (p?0.01). The IOFIX improved contact area across the arthrodesis with a median average of 3.41cm(2) compared with 2.42cm(2) in the lag screw group (p?0.03). CONCLUSION: Our results suggest an IOFIX improves force distribution across an ankle arthrodesis compared with a single conventional lag screw. PMID- 25457663 TI - A novel modification of the Stainsby procedure: surgical technique and clinical outcome. AB - BACKGROUND: The 'Stainsby procedure' is an effective salvage procedure for correction of fixed claw toe deformity. A novel approach is described involving the extensor tenotomy step of the procedure, which is easier, faster and safer to perform. METHODS: A retrospective single surgeon review was performed to assess this modification. 37 patients (92 lesser toes in 42 feet) underwent the modified Stainsby procedure. Mean follow-up was 17 months. Patients were interviewed and examined at a dedicated review clinic. American Orthopaedic Foot and Ankle Society (AOFAS) forefoot scores and Foot and Ankle Outcome (FAO) scores were calculated. RESULTS: Significant improvements in end-points including metatarsalgia, callosity and requirement for insoles or chiropody were noted. Median AOFAS and FAOS scores following the modified Stainsby procedure are reported and compare favourably to previously reported scores. Median FAOS scores were as follows: 92 for the category of pain, 84 for symptoms and stiffness, 96 for activities of daily living, 100 for sports and recreation and 81 for quality of life. Median AOFAS forefoot score was 80. There was a low rate of wound infection of 2.7% (n=1). CONCLUSION: We describe a novel technical modification to the Stainsby procedure and our results support the use of this modification, following assessment of patient outcome. However, limitations to this study were noted in terms of the length of follow-up, the absence of pre-operative clinical scores for comparative purposes, and the variety of surgical procedures performed concomitantly on the 1st ray. PMID- 25457664 TI - Complications of tibio-talar-calcaneal fusion using intramedullary nails. AB - BACKGROUND: Hindfoot nails are being increasingly used, however significant complications can occur. The purpose of this study was to assess the complications following the use of hindfoot nails at our institution. METHODS: We identified patients from a retrospective database. All underwent hindfoot nailing under the care of the senior author. Details of complications were recorded. RESULTS: We identified 52 patients undergoing 55 procedures. Mean follow up was 44.8 months (18-69). Forty patients achieved ankle fusion and 36 subtalar joint fusion. Complications included prominent metalwork in 13 patients, CRPS in five and one peri-prosthetic fracture. Nine developed deep infection, and of these limb salvage was achieved in six patients by removal of metalwork, debridement and insertion of antibiotic loaded cement beads. The remaining three patients underwent below knee amputation. CONCLUSION: Significant complications can occur, although limb preservation was possible in most cases of deep infection. Hindfoot nailing should be reserved as salvage procedure. PMID- 25457665 TI - Results after gastrocnemius recession in 73 patients. AB - BACKGROUND: Very few studies describe the clinical results and complications following the surgical procedure of gastrocnemius recession. PURPOSE: To survey the patient reported outcomes in patients operated with gastrocnemius recession as single procedure for various foot conditions. MATERIAL AND METHODS: 93 patients operated with gastrocnemius recession as single procedure between 2006 and 2011 were detected in the database. 73 patients responded to the invitation for study participation. Questionnaires containing patient reported satisfaction, complications, plantar flexion power and visual analog pain score were used for evaluation of the postoperative result. RESULTS: 45/73 (62%) patients reported a good or excellent result. 8/73 (11%) patients reported a significant postoperative complication. 16/73 (22%) patients noted reduced or severely reduced plantar flexion power after surgery. VAS pain score significantly decreased from 7.0 before surgery to 1.8 (p=0.015) after surgery for patients with plantar fasciitis (n=18) and from 5.6 to 2.3 (p<0.01) for patients with metatarsalgia (n=28). CONCLUSION: Patients treated with gastrocnemius recession for plantar fasciitis demonstrated good clinical results. The complication rate was higher than reported by others. PMID- 25457666 TI - The association between medial malleolar fracture geometry, injury mechanism, and syndesmotic disruption. AB - BACKGROUND: Precise correlations between medial malleolar fracture geometry and fracture mechanism have not been thoroughly described. This study sought to determine the prevalence of different medial malleolar fracture types and to elucidate the association between fracture geometry and fracture mechanism. METHODS: The records of 112 medial malleolar ankle fractures were reviewed. For each fracture, the direction of the fracture line in the medial malleolus (transverse, oblique, vertical, or comminuted), the Lauge-Hansen classification, and the presence or absence of syndesmotic injury was recorded. Bivariate correlation analysis was performed to determine if correlations existed. RESULTS: Transverse fractures were the most prevalent type of medial malleolar fracture [n=64 (57%)], and they correlated with supination-external rotation injuries. These were followed by oblique fractures [29 (26)], which correlated with pronation-external rotation injuries [29 (26)], and vertical fractures [7 (6)], which correlated with supination-adduction injuries [9 (8)]. Comminuted fractures [12 (11)] and pronation-abduction injuries [22 (20)] did not correlate with any other categories. Syndesmotic injuries were correlated with transverse fractures, bimalleolar fractures, and pronation-external rotation injuries. CONCLUSION: Medial malleolar fractures can be divided into four fracture types: transverse fractures, which correlated with supination-external rotation injuries; oblique fractures, which correlated with pronation-external rotation injuries; vertical fractures, which correlated with supination-adduction injuries; and comminuted fractures, which did not correlate with a particular type of injury. Syndesmotic injury was positively correlated with transverse fractures of the medial malleolus, bimalleolar fractures, and pronation-external rotation injuries. These findings suggest that medial malleolar fracture geometry can provide valuable information for the clinician when classifying and managing ankle fractures. PMID- 25457667 TI - Ligamentous advancement for the treatment of subacute syndesmotic injuries. Report of a new technique in 5 cases. AB - BACKGROUND: Integrity and optimum functioning of the syndesmotic ligament complex is of paramount importance for stability of the ankle joint during various ankle movements. Persistent widening and chronic isolated instability of the distal tibio-fibular syndesmosis leads to poor functional outcome and the development of osteoarthritis. In subacute total ruptures the focus of treatment is to restore the normal anatomy by repair of the ruptured ligament and to protect the reconstruction for a period of time. Various techniques have been previously reported with good results but associated with donor site morbidity and multiple incisions. METHOD: Ligamentous advancement allows repair of the syndesmosis when the AITFL is dysfunctional but intact. The lax AITFL was mobilised with periosteum from the tibia leaving the fibular side intact. The Syndesmosis was cleared, reduced with a clamp, and held with two syndesmotic screws inserted transversely between the distal fibular and tibial shafts. The tibial surface was roughened to receive the new attachment of AITFL. The sleeve of tissue was then secured to the roughened tibial surface under tension using suture anchors with the ankle in neutral position. The repair was protected with a two hole plate and screws. RESULTS: The functional outcome scores showed excellent outcome at the end of 6 months. CONCLUSION: Ligamentous advancement technique obviates the need of any bony procedure and does not involve the use of any material which will lead to any sort of foreign body reaction or donor site morbidity while providing anatomical reconstruction of the syndesmosis with excellent functional outcome. PMID- 25457668 TI - Short-term and mid-term outcome of total ankle replacement in haemophilic patients. AB - BACKGROUND: Ankle arthropathy is very frequent in haemophilic patients. Prostheses are valuable alternatives to arthrodesis in non-haemophilic patients. We report the experience of a single centre in France on the use of prostheses in haemophilic patients. METHODS: Retrospective study of 21 patients with haemarthropathy who underwent ankle arthroplasty (32 ankles), with additional surgery, if needed, from July 2002 to September 2009 (mean follow-up 4.4+/-1.7 years). The American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale was used to evaluate pain, function, ankle mobility and alignment. RESULTS: The overall AOFAS score improved from 40.2+/-19.4 (pre-surgery) to 85.3+/-11.4 (post-surgery). The function score increased from 23.6+/-7.7 to 35.9+/-6.7 and dorsiflexion from 0.3 degrees +/-5.0 degrees to 10.3 degrees +/-4.4 degrees . Two patients underwent further ankle arthrodesis. On X-ray, both tibial and talar components were stable and correctly placed in all ankles. Alignment was good. CONCLUSION: Ankle arthroplasty is a promising alternative to arthrodesis in haemophilic patients. PMID- 25457669 TI - The "Lollypop" technique for polyethylene exchange in total ankle replacement. AB - We describe a simple technique for the removal of the polyethylene meniscus bearing surface in patients undergoing re-operation and meniscus bearing exchange following a previous total ankle replacement. LEVEL OF EVIDENCE: Level V. PMID- 25457670 TI - Technical tips: reconstruction of deep and superficial deltoid ligaments by peroneus longus tendon in stage 4 posterior tibial tendon dysfunction. AB - The deltoid ligament is composed of the superficial and deep layers. Disruption of the deltoid ligament can occur in rotational ankle fracture, chronic ankle instability, or stage 4 posterior tibial tendon dysfunction. Correcting valgus tilt at the time of flatfoot reconstruction in case of stage 4 posterior tibial tendon dysfunction may prevent future collapse and the need for ankle arthrodesis or possibly ankle arthroplasty. We describe a technique of reconstruction of both the superficial and deep deltoid ligaments by peroneus longus tendon. PMID- 25457671 TI - Valgus toe deformity of fourth proximal phalanx due to osteochondroma treated with closing wedge osteotomy. AB - Osteochondroma is the most common benign tumor of all benign and primary bone tumors. It rarely occurs in the proximal phalanx of the lesser toe. The treatment of osteochondroma usually consists of simple resection. However, if other deformities remain, added procedures may be considered. We report a case of a valgus toe deformity of the fourth proximal phalanx due to osteochondroma. The patient was a 21-year-old man who noticed a valgus deformity of his fourth toe over 10 years earlier. He began to experience pain in his fifth toe because of crossover of the fourth toe when wearing formal shoes. Although resection of osteochondroma was performed, the valgus deformity was not sufficiently corrected. Therefore, closing wedge osteotomy of the proximal phalanx was performed at the same time. A good outcome was achieved for this patient. PMID- 25457672 TI - Bilateral anterior tarsal tunnel syndrome variant secondary to extensor hallucis brevis muscle hypertrophy in a ballet dancer: a case report. AB - We present a case of bilateral anterior tarsal tunnel syndrome secondary EHB hypertrophy in a dancer, with successful treatment with bilateral EHB muscle excisions for decompression. The bilateral presentation of this case with the treatment of EHB muscle excision is the first of its type reported in the literature. PMID- 25457673 TI - An atraumatic case of extensive Achilles tendon ossification. AB - BACKGROUND: Ossification of the Achilles tendon is rare with most cases of ossification or calcification consisting of small, focal lesions. This pathology is usually predisposed by surgery, trauma, or other factors. CASE DESCRIPTION: A case of extensive Achilles ossification and calcification, without prior surgery or trauma, is reported. Following removal of one of the largest ossific masses reported in the literature, measuring 11.0cm*2.5cm*2.0cm with additional 6.5cm calcifications, surgical reconstruction was required. PURPOSE AND CLINICAL RELEVANCE: The objective of this report was to describe an unusual case of Achilles tendon ossification and calcification that occurred without the presence of predisposing factors. When a large gap is present after removal of the ossification, direct repair may be impossible and V-Y lengthening plus flexor hallucis longus (FHL) transfer is a viable option for pain relief and return to function. PMID- 25457674 TI - Short-term muscle disuse atrophy is not associated with increased intramuscular lipid deposition or a decline in the maximal activity of key mitochondrial enzymes in young and older males. AB - Aging is generally accompanied by a progressive loss of skeletal muscle mass and impairments in metabolic function. Even a few days of muscle disuse (such as that occurring during injury or illness) leads to considerable loss of muscle mass and strength. It has been speculated that short, successive periods of muscle disuse throughout the lifespan may be largely responsible for the age-related loss of muscle mass. However, it remains unknown whether such short periods of disuse also induce impairments in metabolic function within skeletal muscle. Here, we investigated the effects of a five day period of muscle disuse on intramyocellular triacylglycerol (IMTG) content, muscle oxidative capacity, and the expression of key genes that regulate oxidative metabolism in healthy young and elderly men. Muscle biopsies were collected from healthy, young (n=12; 23+/ 1y) and elderly (n=12; 70+/-1y) men prior to and immediately after a five day period of one-legged knee immobilization by way of a full leg cast. At baseline, elderly men had a greater IMTG content when compared with the young (56.2+/-5.1 and 34.8+/-7.3MUmol.g(-1), respectively; P<0.05) with no changes in either group following immobilization (53.4+/-5.0 and 35.7+/-5.0MUmol.g(-1), respectively; P>0.05). In line, five days of disuse did not lower citrate synthase, beta-HAD or cytochrome C oxidase activity in skeletal muscle tissue. Pyruvate dehydrogenase activity increased following immobilization in the older subjects only, from 0.39+/-0.06 to 0.55 0.05MUmol.g(-1).min(-1) (71+/-33%; P<0.01). The skeletal muscle mRNA expression of PGC1alpha and citrate synthase both declined following immobilization in both the young and elderly subjects. We conclude that five days of muscle disuse does not increase intramuscular lipid deposition or reduce the maximal activity of key mitochondrial enzymes within the skeletal muscle of young or older men. PMID- 25457675 TI - Tumor necrosis factor-alpha-accelerated degradation of type I collagen in human skin is associated with elevated matrix metalloproteinase (MMP)-1 and MMP-3 ex vivo. AB - Tumor necrosis factor (TNF)-alpha induces matrix metalloproteinases (MMPs) that may disrupt skin integrity. We have investigated the effects and mechanisms of exogenous TNF-alpha on collagen degradation by incubating human skin explants in defined serum-free media with or without TNF-alpha (10ng/ml) in the absence or presence of the nonselective MMP inhibitor GM6001 for 8 days. The basal culture conditions promoted type I collagen catabolism that was accelerated by TNF-alpha (p<0.005) and accomplished by MMPs (p<0.005). Levels of the collagenases MMP-8 and MMP-13 were insignificant and neither MMP-2 nor MMP-14 were associated with increased collagen degradation. TNF-alpha increased secretion of MMP-1 (p<0.01) but had no impact on MMP-1 quantities in the tissue. Immunohistochemical analysis confirmed similar tissue MMP-1 expression with or without TNF-alpha with epidermis being the major source of MMP-1. Increased tissue-derived collagenolytic activity with TNF-alpha exposure was blocked by neutralizing MMP-1 monoclonal antibody and was not due to down-regulation of tissue inhibitor of metalloproteinase-1. TNF-alpha increased production (p<0.01), tissue levels (p<0.005) and catalytic activity of the endogenous MMP-1 activator MMP-3. Type I collagen degradation correlated with MMP-3 tissue levels (rs=0.68, p<0.05) and was attenuated with selective MMP-3 inhibitor. Type I collagen formation was down regulated in cultured compared with native skin explants but was not reduced further by TNF-alpha. TNF-alpha had no significant effect on epidermal apoptosis. Our data indicate that TNF-alpha augments collagenolytic activity of MMP-1, possibly through up-regulation of MMP-3 leading to gradual loss of type I collagen in human skin. PMID- 25457676 TI - Assembly of fission yeast eisosomes in the plasma membrane of budding yeast: import of foreign membrane microdomains. AB - Eisosomes are plasma membrane-associated protein complexes organizing the membrane compartment of Can1 (MCC), a membrane microdomain of specific structure and function in ascomycetous fungi. By heterologous expression of specific components of Schizosaccharomyces pombe eisosomes in Saccharomyces cerevisiae we reconstitute structures exhibiting the composition and morphology of S. pombe eisosome in the host plasma membrane. We show S. pombe protein Pil1 (SpPil1) to substitute the function of its S. cerevisiae homologue in building plasma membrane-associated assemblies recognized by inherent MCC/eisosome constituents Sur7 and Seg1. Our data indicate that binding of SpPil1 to the plasma membrane of S. cerevisiae also induces formation of furrow-like invaginations characteristic for MCC. To the best of our knowledge, this is the first report of interspecies transfer of a functional plasma membrane microdomain. In the described system, we identify a striking difference between eisosome stabilizer proteins Seg1 and SpSle1. While Seg1 recruits both Pil1 and SpPil1 to the plasma membrane, SpSle1 recognizes only its natural counterpart, SpPil1. In the presence of Pil1, SpSle1 is segregated outside the Pil1-organized eisosomes and forms independent microdomains in the host membrane. PMID- 25457678 TI - Conversion of intraovarian patterns from preovulation to postovulation based on location of dominant follicle and corpus luteum in heifers. AB - The conversion of preovulatory intraovarian patterns based on location of the preovulatory follicle (PF) and the associated corpus luteum (cl) to postovulatory patterns based on location of the future and established dominant follicle (DF) and corpus luteum (CL) was studied daily in 26 heifers from Days -5 to 6 (Day 0 = ovulation). The two ipsilateral preovulatory patterns were PF-cl and devoid (neither PF nor cl), and the two contralateral patterns were PF and cl. The postovulatory patterns were DF-CL, devoid, DF, and CL. For the contralateral preovulatory relationships, a conversion from PF to DF-CL and the accompanying conversion from cl to devoid occurred most frequently (17 of 18 conversions, 94%). For the ipsilateral preovulatory relationships, a conversion from PF-cl to CL and from devoid to DF occurred most frequently (6 of 8, 75%). Number of 2-mm follicles during preovulation was greatest (P < 0.05) for the devoid and PF patterns, and number of 6-mm follicles during postovulation was greatest (P < 0.05) for the DF-CL and DF patterns. Blood flow resistance at a color Doppler signal in the ovarian pedicle indicated increasing ovarian perfusion over days in the PF to DF-CL and devoid to DF conversions and decreasing perfusion in the PF cl to CL and cl to devoid conversions. In addition to formation of the CL from the PF, it was interpreted that the conversion of patterns involved number of newly emerging 2-mm follicles per ovary before ovulation and a continuation of the preovulatory angioarchitecture into postovulation. Results supported the novel hypothesis that the four preovulatory intraovarian patterns determine the frequency of the four postovulatory patterns. PMID- 25457679 TI - Wee1B depletion promotes nuclear maturation of canine oocytes. AB - Most mammalian oocytes are arrested at the germinal vesicle stage by activation of Wee1B. Meiotic resumption is regulated by inactivation of Wee1B and activation of cell division cycle 25B. The aim of this study was to determine whether treatment with Wee1B-targeting small interfering RNA (Wee1B-siRNA) promotes nuclear maturation of canine oocytes from germinal vesicle stage to metaphase II (MII) stage. In experiment 1, the percentage of canine oocytes that matured to MII stage was higher (P < 0.05) among oocytes cultured in vitro for 72 hours than among those cultured for 24 and 48 hours (5.4 +/- 2.5% vs. 0.0 +/- 0.0% and 1.4 +/- 1.0%, respectively). Furthermore, the percentage of oocytes that matured to metaphase I (MI) stage was higher (P < 0.05) among oocytes cultured for 48 and 72 hours than among those cultured for 24 hours (14.9 +/- 10.0% and 22.4 +/- 8.1%, respectively, vs. 5.7 +/- 6.0%). In experiment 2, canine oocytes were intracytoplasmically microinjected with Wee1B-siRNA (50 MUM) at various culture time points (0, 24, 48, or 72 hours). The nuclear configuration of the exception of oocytes in the 72-hour group was examined after 84 hours of culture. The percentage of oocytes that matured to the MII stage was higher (P < 0.05) among those treated with Wee1B-siRNA at 0 hours than among control oocytes and those injected at 72 hours (18.0 +/- 1.7% vs. 2.1 +/- 2.8% and 0.0 +/- 0.0%, respectively). Moreover, the percentage of oocytes that matured to the MI stage was higher (P < 0.05) among those injected at 0 hours than among control oocytes and those injected at 24 and 72 hours (45.9 +/- 6.8% vs. 22.1 +/- 3.5%, 22.8 +/- 10.0%, and 10.0 +/- 4.4%, respectively). In experiment 3, oocytes were intracytoplasmically microinjected with Wee1B-siRNA at 0 hours of IVM and cultured for 0, 24, 48, or 72 hours. Thereafter, maturation-related gene expression was analyzed by quantitative real-time polymerase chain reaction. Messenger RNA expression of cAMP and cell division cycle 25B was lower (P < 0.05) in oocytes injected at 48 hours than in the other groups. Messenger RNA expression of cAMP was lower (P < 0.05) in oocytes injected at 0 hours than in control oocytes and those injected at 72 hours. Messenger RNA expression of mitogen-activated protein kinase 1 and mitogen-activated protein kinase 3 was higher (P < 0.05) in oocytes injected at 72 hours than in the other groups. In conclusion, we confirmed that Wee1B-siRNA microinjection enhances the percentages of canine oocytes that reach the MI and MII stages. These data suggest that Wee1B siRNA microinjection could be a useful strategy to obtain mature canine oocytes for research and assisted canine reproduction. PMID- 25457677 TI - Invadosomes in their natural habitat. AB - Podosomes and invadopodia (collectively known as invadosomes) are small, F-actin rich protrusions that are located at points of cell-ECM contacts and endow cells with invasive capabilities. So far, they have been identified in human or murine immune (myelomonocytic), vascular and cancer cells. The overarching reason for studying invadosomes is their connection to human disease. For example, macrophages and osteoclasts lacking Wiskott-Aldrich syndrome protein (WASp) are not able to form podosomes, and this leads to altered macrophage chemotaxis and defective bone resorption by osteoclasts. In contrast, the ability of cancer cells to form invadopodia is associated with high invasive and metastatic potentials. While invadosome composition, dynamics and signaling cascades leading to their assembly can be followed easily in in vitro assays, studying their contribution to pathophysiological processes in situ remains challenging. A number of recent papers have started to address this issue and describe invadosomes in situ in mouse models of cancer, cardiovascular disease and angiogenesis. In addition, in vivo invadosome homologs have been reported in developmental model systems such as C. elegans, zebrafish and sea squirt. Comparative analyses among different invasion mechanisms as they happen in their natural habitats, i.e., in situ, may provide an outline of the invadosome evolutionary history, and guide our understanding of the roles of the invasion process in pathophysiology versus development. PMID- 25457680 TI - Expression of factors associated with apoptosis in the porcine corpus luteum throughout the luteal phase of the estrous cycle and early pregnancy: their possible involvement in acquisition of luteolytic sensitivity. AB - The studies on the acquisition of luteolytic sensitivity have been focused mainly on molecular changes induced in the luteal tissue after treatment with exogenous PGF2alpha or on physiological changes occurring during the estrous cycle. The comparison of changes leading to the acquisition of luteolytic sensitivity after Day 12 of the estrous cycle and corresponding days of pregnancy has not been investigated in the pig. The present study was undertaken to evaluate (1) apoptosis measured as the proportions of early apoptotic, late apoptotic, and viable cells; (2) expression of factors involved in the extrinsic (TNFA/TNFalpha, TNFRSF1A/TNFR1, TNFRSF1B/TNFR2, FAS/Fas, and FASLG/FasL) and intrinsic (CASP3/Casp3, TP53/p-53, BAX/Bax, and BCL2/Bcl-2) apoptotic pathways, with two components of the activating protein-1 complex, i.e., FOS/Fos and JUN/Jun and IFNG/IFNgamma; and (3) concentrations of luteal and blood plasma progesterone (P4) throughout the luteal phase of the estrous cycle and early pregnancy. Corpora lutea (CL) were collected postmortem on Days 8, 10, 12, and 14 of the estrous cycle and the corresponding days of pregnancy. The luteal tissue was subjected to RNA and/or protein isolation and disaggregation of CL cells followed by flow cytometry analysis aimed to determine apoptotic changes. Luteal and blood plasma P4 concentrations decreased on Day 14 of the estrous cycle versus pregnancy (P < 0.05 and P < 0.001, respectively). A significant increase in the number of early apoptotic cells and a decrease in the number of viable cells were observed on Day 14 of the estrous cycle (P < 0.001 and P < 0.05, respectively). Increase (P < 0.05) of TNFA messenger RNA (mRNA) level coincided with that of IFNG on Day 12 of the estrous cycle but not on the corresponding day of pregnancy. The content of FAS mRNA and protein increased on Day 14 of the estrous cycle versus pregnancy (P < 0.05). The mRNA expression of CASP3, BCL-2 and BAX was unchanged in cyclic and pregnant CL, while level of TP53 increased (P < 0.05) on Day 12 of the estrous cycle versus Day 8. The level of FOS and JUN mRNA increased (P < 0.05) on Day 14 of the estrous cycle versus the remaining days. The level of FOS and JUN mRNA was significantly higher (P < 0.001 and P < 0.05, respectively) on Day 14 of the estrous cycle than that on the corresponding day of pregnancy. In summary, the simultaneous increase of TNFA and IFNG transcript in cyclic CL suggests the crucial role of both cytokines in sensitization of porcine CL to further luteolytic action of PGF2alpha. The upregulated expression of FAS, FOS, and JUN mRNA in the late luteal phase in cyclic CL can indicate their involvement in structural luteolysis. The increased viability of luteal cells and elevated P4 concentrations in pregnant CL confirm the protective role of luteal P4 against apoptosis. PMID- 25457682 TI - Meeting the challenges of training for interdisciplinary care. PMID- 25457681 TI - Poly-S-nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide. AB - Autophagy is one of the major causes of drug resistance. For example, the angiogenesis inhibitor bevacizumab shows only transient and short-term therapeutic effects, whereas long-term therapeutic benefits are rarely observed, probably due to hypoxia-induced autophagy. Nitric oxide (NO) is an important molecule with multiple functions, and it has recently been reported to function as a regulator of autophagy. Therefore, a reasonable therapeutic strategy for overcoming drug resistance by NO would involve it being directly delivered to the tumor. Here, we investigated the inhibitory effect of NO on autophagy by using a macromolecular NO donor S-nitrosated human serum albumin (SNO-HSA) with a high degree of NO loading and tumor targeting potential. In colon 26 (C26) cells, SNO HSA significantly suppressed hypoxia-induced autophagy by inhibiting the phosphorylation of JNK1 and the expression of its downstream molecule Beclin1. The effect of SNO-HSA was also confirmed in vivo by combining it with Bev. In C26 bearing mice, significant suppression of tumor growth as well as lung metastasis was achieved in the combination group compared to the SNO-HSA or bevacizumab alone group. Similar to the in vitro experiments, the immunostaining of tumor tissues clearly showed that SNO-HSA inhibited the autophagy of tumor cells induced by bevacizumab treatment. In addition to other known antitumor effects of SNO-HSA, that is, the induction of apoptosis and the inhibition of multidrug efflux pumps, these data may open alternate strategies for cancer chemotherapy by taking advantage of the ability of SNO-HSA to suppress autophagy-mediated drug resistance and enhance the efficacy of chemotherapy. PMID- 25457683 TI - Reflections from Dutch advanced nursing practice students on psychiatric mental healthcare in the United States. AB - BACKGROUND: An international clinical learning experience is a unique opportunity to witness another nursing and healthcare system. The Master of Advanced Nursing Practice (MANP) program at Rotterdam University of Applied Sciences in the Netherlands, mandates an international experience. METHODS: Semi-structured qualitative interviews, a focus group session and written reflections were used for data collection with 6 Dutch MANP nursing students who specialized in psychiatric mental healthcare. RESULTS: Five major themes were revealed from the data. The themes identified were as follows: (1) pride and passion for mental health profession (2) role diversity within psychiatric mental health nursing (3) nursing leadership at the organization level (4) comparable Westernized approaches to mental healthcare and (5) differences in access to care. IMPLICATIONS FOR NURSING PRACTICE: Incorporating a mandatory international clinical experience is a beneficial tool to promote a global understanding of the unique advanced practice nursing student's academic and professional development. CONCLUSIONS: The international clinical learning experience is considered a highlight of the 2-year MANP program. The students are able to gain a new and broader vision of the APN role and a greater appreciation for the Dutch healthcare system. PMID- 25457684 TI - Vitamin d, depression and coping self-efficacy in young women: longitudinal study. AB - Depression is a significant health issue in young women with few assessment strategies for early detection. It has been suggested that self-efficacy and vitamin D levels can predict and prevent depression. The authors examined the relationship between vitamin D levels, coping self-efficacy and depression in 77 college age women over three seasons. The results of the repeated measures analysis showed that a strong, inverse relationship existed between self-efficacy and depression but not vitamin D levels. These findings were consistent across the three data collection points. The results implied that strengthening perceived coping self-efficacy may be useful in order to maintain the mental health of young college age women. PMID- 25457685 TI - A survey on 465 patients with post-stroke depression in China. AB - The incidence of PSD patients is very high. To analyze the related factors and incidence of post-stroke depression (PSD). A total of 465 stroke patients were evaluated by a self-designed questionnaire, Self-Rating Depression Scale (SDS) and Hamilton Depression Rating Scale (HAMD). The neurologic deficit score was tested using the National Institute of Health stroke scale (NIHSS). A multiple factor analysis with the logistic regression method was carried out to analyze related factors of PSD. A total of 146 cases (31.4%) were identified as suffering from PSD. In addition the stepwise regression analysis showed that important risk factors of PSD included of sex, lesion location, the course of post-stroke and degree of neurological deficit score (all P<0.05). Above mentioned factors about the patients of PSD are very significant and may provide reference for further treating. PMID- 25457686 TI - The perception of drug users about their human rights. AB - The objective was to understand how illegal drug users monitored at a psychosocial care center for alcohol and drug users perceive and experience their human rights. The data were collected through semistructured interviews with 17 users and analyzed through content analysis. The results demonstrated the difficulty the users perceive to express what their human rights are, as if rights were something extraneous to their own life, particularly in function of the prejudice and stigma related to illegal drugs use in Brazil. PMID- 25457687 TI - Potential long-term effects of a mind-body intervention for women with major depressive disorder: sustained mental health improvements with a pilot yoga intervention. AB - Despite pharmacologic and psychotherapeutic advances over the past decades, many individuals with major depressive disorder (MDD) experience recurrent depressive episodes and persistent depressive symptoms despite treatment with the usual care. Yoga is a mind-body therapeutic modality that has received attention in both the lay and research literature as a possible adjunctive therapy for depression. Although promising, recent findings about the positive mental health effects of yoga are limited because few studies have used standardized outcome measures and none of them have involved long-term follow-up beyond a few months after the intervention period. The goal of our research study was to evaluate the feasibility, acceptability, and effects of a yoga intervention for women with MDD using standardized outcome measures and a long follow-up period (1year after the intervention). The key finding is that previous yoga practice has long-term positive effects, as revealed in both qualitative reports of participants' experiences and in the quantitative data about depression and rumination scores over time. Although generalizability of the study findings is limited because of a very small sample size at the 1-year follow-up assessment, the trends in the data suggest that exposure to yoga may convey a sustained positive effect on depression, ruminations, stress, anxiety, and health-related quality of life. Whether an individual continues with yoga practice, simple exposure to a yoga intervention appears to provide sustained benefits to the individual. This is important because it is rare that any intervention, pharmacologic or non pharmacologic, for depression conveys such sustained effects for individuals with MDD, particularly after the treatment is discontinued. PMID- 25457688 TI - Theoretical approaches to maternal-infant interaction: which approach best discriminates between mothers with and without postpartum depression? AB - OBJECTIVE: The purpose of this study was to determine which of the four common approaches to coding maternal-infant interaction best discriminates between mothers with and without postpartum depression. METHODS: After extensive training, four research assistants coded 83 three minute videotapes of maternal infant interaction at 12month postpartum visits. Four theoretical approaches to coding (Maternal Behavior Q-Sort, the Dyadic Mini Code, Ainsworth Maternal Sensitivity Scale, and the Child-Caregiver Mutual Regulation Scale) were used. Twelve month data were chosen to allow the maximum possible exposure of the infant to maternal depression during the first postpartum year. The videotapes were created in a laboratory with standard procedures. Inter-rater reliabilities for each coding method ranged from .7 to .9. The coders were blind to depression status of the mother. RESULTS: Twenty-seven of the women had major depressive disorder during the 12month postpartum period. Receiver operating characteristics analysis indicated that none of the four methods of analyzing maternal infant interaction discriminated between mothers with and without major depressive disorder. CONCLUSION: Limitations of the study include the cross-sectional design and the low number of women with major depressive disorder. Further analysis should include data from videotapes at earlier postpartum time periods, and alternative coding approaches should be considered. Nurses should continue to examine culturally appropriate ways in which new mothers can be supported in how to best nurture their babies. PMID- 25457689 TI - The use of restrictive measures in an acute inpatient child and adolescent mental health service. AB - There are significant issues associated with the use of restrictive measures, such as seclusion and restraint, in child and adolescent mental health care. Greater understanding of how restrictive measures are used is important for informing strategies to reduce their use. In this brief report we present a 12 month audit (1/1/2010-31/12/2011) of the use of restrictive measures (seclusion, physical restraint) in one child and adolescent acute inpatient mental health unit in Australia. The study highlights the need for continued efforts to reduce the use of restrictive measures in child and adolescent mental health services. PMID- 25457690 TI - Effects of a family-to-family support program on the mental health and coping strategies of caregivers of adults with mental illness: a randomized controlled study. AB - This randomized, controlled intervention study was carried out to investigate the effects of a Family-to-Family Support (FFS) program on the coping strategies and mental health status of caregivers of schizophrenia patients. Data were collected via a General Health Questionnaire (GHQ) and the Ways of Coping with Stress Scale (WCSS). During the first phase of the study, the FFS program was developed, followed by a second phase in which the participants of the study were identified and trained. In the third phase, trained caregivers trained other caregivers. The study sample consisted of 46 caregivers. We determined statistically significant differences in the mean GHQ scores of the FFS group over four measurements. In the WCSS subscales, the self-confident approach, optimistic approach and seeking social support approach scores of caregivers participating in the FFS program were high, while their helpless approach score was low. The FFS program had a positive impact on the coping strategies and mental health status of caregivers of schizophrenia patients. PMID- 25457691 TI - Chronic conditions in elders in assisted living facilities: associations with daily functioning, self-assessed health, and depressive symptoms. AB - BACKGROUND: The increasing life expectancy of older adults has prompted an increase in chronic conditions that may interfere with their daily living and impact physical and mental health. OBJECTIVES: This study examined associations between commonly reported chronic conditions, daily functioning, self-assessed health, and depressive symptoms of elders. METHODS/DESIGN: A secondary analysis of existing data from 314 elderly residents of 29 facilities was conducted. RESULTS: The most frequently reported conditions were arthritis (64%), hypertension (47%), and heart problems (35%). Elders who reported having all three of these most frequently reported conditions differed significantly from those who reported none or one of the three conditions (p<.001) on their perception of interference with daily functioning and self-assessed health. Although differences on depressive symptoms were found between groups defined by number and combinations of conditions, specific trends in the data were not detected. Elder's rating of interference of their chronic conditions on daily functioning was moderately associated with their self-assessed health (r=-.50, p<.001) and depressive symptoms (r=.41, p<.001). CONCLUSION: While chronic conditions may be unavoidable, assessing their comorbidity in elders is important for developing interventions to preserve their daily functioning and promote their optimal health. PMID- 25457692 TI - Illness perception in Turkish schizophrenia patients: a qualitative explorative study. AB - BACKGROUND: Schizophrenia is a serious mental illness that is highly complex and not fully understood. Individuals with serious mental illnesses like schizophrenia experience difficulty trying to access mental health services. Few have the opportunity to receive the most optimal evidence-based treatment and only half of those who do actually adhere to the recommended treatment. Understanding what it is like to have this illness would help in our approaches to treatment. METHODS: In-depth interviews were conducted on nine Turkish patients with schizophrenia in order to explore the illness from the perspective of patients in remission. RESULTS: Five themes emerged from the patients' descriptions of schizophrenia: schizophrenia is a complicated illness, a mystery, a lost life, a dynamic journey towards recovery, and a developmental process of recovery. CONCLUSION: This study has identified areas of concern about reflecting the patients' perspectives on their experiences thoroughly, which should help improve healthcare provision and guide future research. PMID- 25457693 TI - Describing brain activity of persons with AD and depressive symptoms. AB - The purpose of this retrospective pilot study was to characterize depression of AD using electrophysiological changes in the brain activity of persons with AD and depressive symptoms. Participants had a mean age of 70.12+/-12.68. Participants manifested an increase in absolute/relative theta activity (p=.000) over entire brain when compared to normative population-based database. Electrophysiological changes did not differ by age or gender except for increased absolute theta activity in the right lateral frontal areas (t-test=-2.31 to 2.39, p=.04) in females. An increased theta activity suggests that depressive symptoms may be part of AD symptomatology, not a co-morbid feature. PMID- 25457694 TI - Profiling frequent presenters to the emergency department for mental health complaints: socio-demographic, clinical, and service use characteristics. AB - BACKGROUND: A small subset of individuals makes a disproportionate number of ED visits for mental health complaints. STUDY OBJECTIVES: To explore the population profile and associated socio-demographic, clinical, and service use factors of individuals who make frequent visits (5+ annually) to hospital EDs for mental health complaints. METHODS: Case-control study using electronic health record data. RESULTS: Frequent presenters represented 3% of mental health ED patients and accounted for 18% of visits. Several factors were significantly associated with frequent ED use, including limited social support, documented personality disorder/traits, regular antipsychotic use, self-reported alcohol use, and having multiple referral sources. PMID- 25457695 TI - [Intraobserver reliability and internal consistency of the Behavioral Pain Scale in mechanically-ventilated patients]. AB - BACKGROUND: The Behavioral Pain Scale (BPS) is a tool of pain assessment that often gives contradictory results when used by different raters. OBJECTIVE: To assess internal consistency and interrater reliability of BPS scale in the pain assessment performed by intensives care nurses. METHODS: A prospective observational study in 34 mechanically-ventilated patients, carried out in an Intensive Care Unit from April to June 2012. Variables analyzed included demographic characteristics, diagnosis of referral, clinical status, pain and sedation level. Pain was assessed by two nurses independently at rest (T1) and during a mobilization procedure (T2) using the BPS scale. Internal consistency was calculated by Cronbach's alpha, and intraobserver reliability was determined with the intraclass correlation coefficient (ICC), with a confidence interval (CI) of 95%. This study was approved by the Ethical Committee for Clinical Research. RESULTS: One-hundred and twenty-eight pain assessments were performed. The Cronbach's alpha of total BPS score at rest was 0.66 (95%CI: 0.33 to 0.83) and during mobilization of 0.73 (95%CI: 0.47 to 0.87). The CCI of total BPS score was 0.50 (95%CI: 0.19 to 0.71) at rest and 0.58 (95%CI: 0.31 to 0.77) during mobilization. CONCLUSIONS: The level of internal consistency of the scale is appropriate and moderate interrater agreement. For the BPS useful in clinical practice, it is imperative that nurses have prior experience with a regulated use of this tool. PMID- 25457697 TI - [Hyperglycemia in critically ill patients. Sample of choice, controls and values: literature review]. AB - The hyperglycemia is one of the most common problems in the critically ill patient, hence the importance of a good control of it in the ICUs. OBJECTIVES: To identify the sample of choice for glycemic control in the critically ill patient; To distinguish the necessary controls to ensure the correct levels of glucose in the critically ill patient; To determine the range of blood glucose values suitable for the critically ill patient. METHODS: This review was made in different databases: MEDLINE with the assistance of specific search PubMed and ProQuest, CUIDEN-PLUS and ELSEVIER Publishing website. RESULTS: 24 articles were collected: descriptive, analytic and cohort studies, and also literature reviews. The golden sample for the glucose determination in this patient is the arterial one, and can be also used the venous one, excluding the capillary sample. The analysis should be carried out in a clinical laboratory. However, glucometers can be used to provide instantaneous measurements. Blood glucose controls in the critically ill patient are initially set each hour until their stabilization, and then, they are spaced to periods of two-three hours. The glycemic index is moderate, with values between 140-180 mg/dl. CONCLUSIONS: The arterial sample is the chosen one for glucose determination in this patient. Blood glucose controls should be initially set each hour, until their stabilization, and then they are spaced to periods of two-three hours. The glycemia in the critically ill patient should be included in a index of 140-180 mg/dl, which is considered a moderate control. PMID- 25457696 TI - [Nursing perception of communication with intensive care unit patients family members]. AB - INTRODUCTION: Communication is referred as one of the most important needs by the families of intensive care unit patients. AIM OF THE STUDY: To analyze nursing perception of the communication process with the family members of an intensive care unit patient. MATERIALS AND METHODS: Transversal study (December 2012) with a questionnaire Nurse Activities for Communicating with Families (NACF), cross culturally adapted by Santana Cabrera et al. Participants: intensive care unit nurses from a third level university hospital. Descriptive analysis of variables and inferential statistics with Chi-square and Kruskal-Wallis, statistic program SPSS 17.0; significant P < .05. RESULTS: Complementation was of 80% (132 out of 166 nurses). The average experience was of 9.6 +/- 7.95 years. 55.9% sometimes explain to families the treatment and equipment of the patient and a 37% almost always. Nurses talk to the families about the disease and the treatment given to the patient always/almost always in 59% of the cases and sometimes in a 35.38%. 54,6% talk to the family about their feelings sometimes and a 28.46% almost always. A 47.8% notify always/almost always changes on the care plan. 87.9% ensure patient comfort always/almost always. There is no relation between years of experience in ICU and the outcomes of the questionnaire. There is a relation between the different kinds of ICUs and the information given about disease and treatment. DISCUSSION: Nurses tend to inform more about technical aspects than feelings related to the families. Patient comfort is the most referred item regardless of years of experience and the kind of intensive care unit. PMID- 25457698 TI - [Satisfaction of relatives of the patients admitted to an intensive careunit: Perceptions of relatives and professionals]. AB - OBJECTIVES: To estimate the satisfaction of relatives of critical care patients with regard to the environment, relationship with professionals and visitation and compare it to the perception of professionals. METHODOLOGY: A descriptive study in two phases. In the first phase validated telephone survey within 15 days of discharge to the relatives of the patients was performed. In the second phase, the same modified questionnaire was self-administered to the professionals. The same variables were studied in both populations. RESULTS: We interviewed 78 family members and 44 professionals. 95% of professionals vs 67% of the families claimed not to know the name of the nurses (P < .001). Over 70% of professionals and families agreed that the visit protocol is correct and that the information was adequate income. 70% of professionals felt that the information received at admission is not understood by the family although 97% of households claimed to have understood themselves. Statistically significant differences were observed in relation to the location of the unit assessment, the waiting, the aspects of information and comfort, always being the professionals who felt greater dissatisfaction (P < .05). CONCLUSIONS: The perceptions of relatives and professionals were mostly uneven, making it necessary to continue exploring the differences through qualitative and participatory methodologies. PMID- 25457699 TI - Rapid tests for detection of carbapenemase producers in P. aeruginosa; what do we really need? PMID- 25457700 TI - Footnotes, acknowledgments, and authorship: toward greater responsibility, accountability, and transparency. PMID- 25457701 TI - Balancing the cost and benefit of developing new glaucoma surgical devices. PMID- 25457702 TI - Reply: To PMID 24881836. PMID- 25457703 TI - Acute retinal arterial ischemia: an emergency often ignored. PMID- 25457704 TI - Factors influencing long-term regression after posterior chamber phakic intraocular lens implantation for moderate to high myopia. PMID- 25457705 TI - Reply: To PMID 24699155. PMID- 25457706 TI - Tattoo-associated uveitis. PMID- 25457707 TI - Wavefront-guided versus wavefront-optimized laser in situ keratomileusis for patients with myopia: a prospective randomized contralateral eye study. PMID- 25457708 TI - Reply: To PMID 24875002. PMID- 25457709 TI - Reply: To PMID 24560995. PMID- 25457710 TI - Association between the percent tissue altered and post-laser in situ keratomileusis ectasia in eyes with normal preoperative topography. PMID- 25457711 TI - Reply: To PMID 24727263. PMID- 25457712 TI - Complications in the first 5 years following cataract surgery in infants with and without intraocular lens implantation in the infant aphakia treatment study. PMID- 25457713 TI - Reply: To PMID 25077835. PMID- 25457714 TI - Reply: To PMID 24875000. PMID- 25457715 TI - Long-term increase in subfoveal choroidal thickness after surgery for senile cataracts. PMID- 25457716 TI - Reply: To PMID 24879946. PMID- 25457717 TI - The association of blood pressure and primary open-angle glaucoma: a meta analysis. PMID- 25457718 TI - Cephalometric study of the upper airways and dentoalveolar height in open bite patients. AB - Open bite is related to various etiological factors and, in many cases, is difficult to diagnose. The present study is aimed at evaluating, through cephalometric analysis, the dimensions of the upper airways and dentoalveolar heights in open bite (OB) patients versus normal overbite patients. The relationship between the width of the upper airways and the lack of overbite is also studied, in order to differentiate between dental open bite (DOB) and skeletal open bite (SOB). MATERIALS AND METHODS: Eighty X-rays were selected from files of orthodontic patients to form the control sample (n=40) and open bite sample (n=40). Dimensions of the upper airways and dentoalveolar heights were measured in both samples, using 16 linear measurements, two angle values and one ratio. RESULTS: In OB patients, anteroposterior narrowing of the upper airways, mainly in the nasopharynx and oropharynx, was observed, together with forward displacement of the hyoid bone and increased maxillary and mandibular dentoalveolar heights, and anterior facial height. In SOB, the overbite was more negative and facial growth was more clockwise-oriented than in DOB. Greater narrowing of the airways in the anteroposterior orientation was also noted. In DOB, there was evidence of muscular adaptation, as shown by increased values of the hyoid bone displacement to a more anterior and lower position, and increased values of the vertical dimensions of the airways. An increase in posterior facial height was also observed allowing anterior rotation of the mandible. CONCLUSION: The results suggest that the airway's dimensions reflect a tendency to open bite. The variable vertical airway length (Val) and the position of the hyoid bone allow the adaptive potential of these individuals to be determined and make the treatment of open bites more predictable. PMID- 25457719 TI - Reliability of skeletal maturity analysis using the cervical vertebrae maturation method on dedicated software. AB - OBJECTIVES: The aim of this study was to assess the feasibility of skeletal maturation analysis using the Cervical Vertebrae Maturation (CVM) method by means of dedicated software, developed in collaboration with Outside Format (Paullo Milan), as compared with manual analysis. MATERIALS AND METHODS: From a sample of patients aged 7-21 years, we gathered 100 lateral cephalograms, 20 for each of the five CVM stages. For each cephalogram, we traced cervical vertebrae C2, C3 and C4 by hand using a lead pencil and an acetate sheet and dedicated software. All the tracings were made by an experienced operator (a dentofacial orthopedics resident) and by an inexperienced operator (a student in dental surgery). Each operator recorded the time needed to make each tracing in order to demonstrate differences in the times taken. RESULTS: Concordance between the manual analysis and the analysis performed using the dedicated software was 94% for the resident and 93% for the student. Interobserver concordance was 99%. The hand-tracing was quicker than that performed by means of the software (28 seconds more on average). CONCLUSIONS: The cervical vertebrae analysis software offers excellent clinical performance, even if the method takes longer than the manual technique. PMID- 25457720 TI - The relationship between molar bite force and incisor inclination: a prospective cross-sectional study. AB - OBJECTIVE: To examine the relationship between molar bite force (MBF) and both the upper and lower axis inclination of the incisors. MATERIALS AND METHODS: The sample consisted of 51 participants aged between 18-27 years (mean age: 21.04+/ 2.03), with normal occlusion and a skeletal Class I relationship, no sign of temporomandibular disorders, and no previous orthodontic treatment. Lateral cephalograms were taken and traced and the following measurements were identified: upper incisor angle (U1:SN), lower incisor angle (L1:GoMe), and the interincisal angle (U1:L1). Three sets of groups were established according to the three previously mentioned measurements (G1: decreased; G2: normal; and G3: increased). MBF was measured using a specific sensor that is sensitive to the pressure. Patients were asked to bite in the central occlusion, chew, then swallow the saliva. The mean values and standard deviation of MBF were obtained in each position and in every group then compared between related groups using the independent sample t-test. RESULTS: MBF values were significantly lower in the decreased upper incisor angle group during chewing at each side than in the normal (P=0.02 right, 0.01 left) and increased (P=0.03 right, 0.02 left) groups,while higher in the increased lower incisor group compared with the normal group (P=0.01) during chewing at the right side. In addition, there was a significant positive correlation between the upper incisor axis and MBF values both in central maximum clenching and chewing. Moreover, there was a positive correlation between the MBF and lower incisor axis during chewing, whereas a negative correlation between the MBF and interincisal angle was detected during chewing and swallowing. CONCLUSIONS: There was a linear relationship between the MBF and incisor axis. The MBF was higher when both the upper and lower inclination of incisors increased. PMID- 25457725 TI - Editorial overview: neuromodulation: tuning the properties of neurons, networks and behavior. PMID- 25457726 TI - Sexual size dimorphism in three North Sea gadoids. AB - Existing biological data on whiting Merlangius merlangus, cod Gadus morhua and haddock Melanogrammus aeglefinus from a long-term international survey were analysed to address sexual size dimorphism (SSD) and its effect on their ecology and management. Results show that SSD, with larger females of the same age as males, is a result of higher growth rates in females. A direct consequence of SSD is the pronounced length-dependent female ratio that was found in all three gadoids in the North Sea. Female ratios of the three species changed from equality to female dominance at specific dominance transition lengths of c. 30, 35 and 60 cm for M. merlangus, G. morhua and M. aeglefinus, respectively. An analysis by area for M. merlangus also revealed length dependence of female ratios. SSD and length-dependent female ratios under most circumstances are inseparable. Higher overall energy demand as well as a higher energy uptake rate must result from the observed SSD and dimorphism in growth rates. Potential processes related to feeding, locomotion and physiology are proposed that could balance the increased energy investment of females. Potential consequences of SSD and length dependency of female ratios are the reduction of the reproductive potential of a stock due to size-selective fishing and biased assessment of the true size of the female spawning stock that could distort decisions in fisheries management. PMID- 25457727 TI - Introduction to special issue "Non-homeostatic control of respiration". PMID- 25457724 TI - Intercellular adhesion molecule 1 and progression of percent emphysema: the MESA Lung Study. AB - BACKGROUND: Endothelial intercellular adhesion molecule (ICAM) 1 binds neutrophils and facilitates their transmigration into the lung; E-selectin facilitates leukocyte rolling. As neutrophils contribute to tissue destruction in emphysema and chronic obstructive pulmonary disease, we hypothesized that soluble ICAM-1 (sICAM-1) and E-selectin (sE-selectin) would be associated with longitudinal progression of emphysema and lung function decline. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants 45-84 years old without clinical cardiovascular disease in 2000-02. The MESA Lung Study assessed percent emphysema (<-950 Hounsfield units) on cardiac (2000-07) and full lung CT scans (2010-12), and spirometry was assessed twice over five years. sICAM 1 and sE-selectin were measured at baseline. Mixed-effect models adjusted for demographics, anthropometry, smoking, C-reactive protein, sphingomyelin and scanner factors. RESULTS: Among 1865 MESA Lung participants with measurement of sICAM-1 and percent emphysema the mean log-sICAM-1 was 5.5 +/- 0.3 ng/mL and percent emphysema increased 0.73 percentage points (95% CI: 0.34, 1.12; P < 0.001) over ten years. A one SD increase in sICAM-1 was associated with an accelerated increase in percent emphysema of 0.23 percentage points over ten years (95% CI: 0.06, 0.39; P = 0.007). No significant association was found for sE-selectin, or between any adhesion molecule and lung function. CONCLUSIONS: Higher levels of sICAM-1 were independently associated with progression of percent emphysema in a general population sample. PMID- 25457731 TI - Nutritional comparison of packed and school lunches in pre-kindergarten and kindergarten children following the implementation of the 2012-2013 National School Lunch Program standards. AB - OBJECTIVE: Approximately 40% of children bring a packed lunch to school. Little is known about the quality of these lunches. This study examined the nutritional quality of packed lunches compared with school lunches for pre-kindergarten and kindergarten children after the implementation of 2012-2013 National School Lunch Program standards. METHODS: The researchers collected observational data for packed and school lunches from 3 schools in rural Virginia for 5 consecutive school days and analyzed them for macro and micro nutrients. RESULTS: Of the 1,314 observations collected; 42.8% were packed lunches (n = 562) and 57.2% were school lunches (n = 752). Energy, fat, saturated fat, sugar, vitamin C, and iron were significantly higher whereas protein, sodium, fiber, vitamin A, and calcium were significantly lower for packed lunches than school lunches. CONCLUSIONS AND IMPLICATIONS: Packed lunches were of less nutritional quality than school lunches. Additional research is needed to explore factors related to choosing packed over school lunches. PMID- 25457730 TI - Influence of behavioral theory on fruit and vegetable intervention effectiveness among children: a meta-analysis. AB - OBJECTIVE: To test the hypotheses that interventions clearly based on theory, multiple theories, or a formal intervention planning process will be more effective in changing fruit and vegetable consumption among children than interventions with no behavioral theoretical foundation. DESIGN: Systematic review and meta-analysis. SETTING: Identification of articles in PubMed, PsycInfo, Medline, Cochrane Collaborative database, and existing literature reviews and meta-analyses. PARTICIPANTS: Children aged 2-18 years. INTERVENTIONS: Change in fruit and/or vegetable consumption in dietary change interventions. METHODS: Meta-analysis, meta-regression analysis, and summary reporting for articles. CONCLUSIONS AND IMPLICATIONS: Predicating an intervention on behavioral theory had a small to moderate enhancement (P < .001) of outcome effectiveness. Differences in mean Hedges' g effect sizes between theory and non-theory interventions were 0.232 for fruit, 0.043 for vegetables, and 0.333 for fruit and vegetables combined. There was mixed support, however, for enhanced dietary change with multiple theories or a formal planning process. After controlling for study quality, theory use was related only to vegetable consumption (beta = 0.373; P < .001). More research is needed on theory's influences on dietary behaviors to guide future interventions among children. More research is also needed to identify what may be effective practical- or experience-based procedures that complement theory, to incorporate into interventions. PMID- 25457732 TI - The Shaping Healthy Choices Program: design and implementation methodologies for a multicomponent, school-based nutrition education intervention. AB - OBJECTIVE: To provide a framework for implementation of multicomponent, school based nutrition interventions. This article describes the research methods for the Shaping Healthy Choices Program, a model to improve nutrition and health related knowledge and behaviors among school-aged children. DESIGN: Longitudinal, pretest/posttest, randomized, controlled intervention. SETTING: Four elementary schools in California. PARTICIPANTS: Fourth-grade students at intervention (n = 252) and control (n = 238) schools and their parents and teachers. Power analyses demonstrate that a minimum of 159 students per group will be needed to achieve sufficient power. The sample size was determined using the variables of nutrition knowledge, vegetable preference score, and body mass index percentile. INTERVENTION: A multicomponent school-based nutrition education intervention over 1 academic year, followed by activities to support sustainability of the program. MAIN OUTCOME MEASURES: Dietary and nutrition knowledge and behavior, critical thinking skills, healthy food preferences and consumption, and physical activity will be measured using a nutrition knowledge questionnaire, a food frequency questionnaire, a vegetable preferences assessment tool, the Test of Basic Science Process Skills, digital photography of plate waste, PolarActive accelerometers, anthropometrics, a parent questionnaire, and the School and Community Actions for Nutrition survey. ANALYSIS: Evaluation will include quantitative and qualitative measures. Quantitative data will use paired t, chi-square, and Mann-Whitney U tests and regression modeling using P = .05 to determine statistical significance. PMID- 25457734 TI - Synthesis of 2-Oxazolines by in Situ Desilylation and Cyclodehydration of beta Hydroxyamides. AB - A powerful method for the synthesis of 2-oxazolines from silyl-protected beta hydroxyamides is reported. Using diethylaminosulfur trifluoride (DAST) or its tetrafluoroborate salt (XtalFluor-E), silyl-protected beta-amidoalcohols can be in situ deprotected and dehydrated to give 2-oxazolines in good yields. The utility of this approach was demonstrated by preparing the first reported oligomer of [2,4']-coupled 2-oxazoline units. By tuning the stability of the silyl protecting groups (ex. IPDMS < TES < TBS, etc.), the deprotection rate can be optimized so that all reaction intermediates remain soluble, allowing cyclodehydration to occur at all potential sites of ring closure. N-Terminal Ser residues containing an Fmoc carbamate are converted into 2-(9' fluorenylmethyloxy)-2-oxazoline in high yield, thereby providing a new pathway for the synthesis of peptides capped with an N-terminal 2-alkoxy-2-oxazoline or 2 oxazolidinone unit. PMID- 25457733 TI - The effects of Young Adults Eating and Active for Health (YEAH): a theory-based Web-delivered intervention. AB - OBJECTIVE: To assess the effectiveness of a tailored theory-based, Web-delivered intervention (Young Adults Eating and Active for Health) developed using community-based participatory research process. DESIGN: A 15-month (10-week intensive intervention with a 12-month follow-up) randomized, controlled trial delivered via Internet and e-mail. SETTING: Thirteen college campuses. PARTICIPANTS: A total of 1,639 college students. INTERVENTION: Twenty-one mini educational lessons and e-mail messages (called nudges) developed with the non diet approach and focusing on eating behavior, physical activity, stress management, and healthy weight management. Nudges were short, frequent, entertaining, and stage-tailored to each behavior, and reinforced lesson content. MAIN OUTCOME MEASURE: All participants were assessed at baseline, postintervention (3 months from baseline), and follow-up (15 months from baseline) for primary outcomes of weight, body mass index (BMI), fruit and vegetable intake (FVI), physical activity (PA), and perceived stress; and secondary outcomes of waist circumference, percent dietary fat, energy from sugar sweetened beverages, servings of whole grains, self-instruction and regulation for mealtime behavior, hours of sleep, and stage of readiness for change for consuming 5 cups of FVI, completing 150 minutes of PA/wk, and managing stress on most days of the week. Demographics were collected at baseline. ANALYSIS: Chi square analysis and mixed-models repeated measures analysis were performed to determine differences between experimental and control outcomes. RESULTS: There were no differences between experimental and control participants in BMI, weight, and waist circumference. There were small improvements in FVI (P = .001), vigorous PA in females (P = .05), fat intake (P = .002), self-instruction (P = .001), and regulation (P = .004) for mealtime behavior, and hours of sleep (P = .05) at postintervention, but improvements were not maintained at follow-up. At postintervention, a greater proportion of experimental participants were in the action/maintenance stages for FVI (P = .019) and PA (P = .002) than control. CONCLUSIONS AND IMPLICATIONS: Young Adults Eating and Active for Health is one of the first studies to use the community-based participatory research process of PRECEDE-PROCEED to develop a non-diet approach intervention. Although there were no differences between experimental and control participants in weight change or BMI, the intervention supported positive change in behaviors that may mediate excessive weight gain, such as increasing FVI and more healthful self-regulation mealtime behaviors immediately postintervention. Additional strategies to maintain the behavior changes need to be explored. PMID- 25457735 TI - Low-concentration contrast medium for 128-slice dual-source CT coronary angiography at a very low radiation dose using prospectively ECG-triggered high pitch spiral acquisition. AB - RATIONALE AND OBJECTIVES: To assess the impact of low-concentration contrast medium on vascular enhancement, image quality, and radiation dose of coronary computed tomography (CT) angiography (CCTA) by using prospectively electrocardiography (ECG)-triggered high-pitch spiral acquisition with low tube voltage in combination with iterative reconstruction. MATERIALS AND METHODS: One hundred patients (body mass index <= 25 kg/m(2), heart rate <= 65 beats per minute) were prospectively randomized to two groups, with 50 patients each, which were differed by contrast medium. All patients underwent prospectively ECG triggered high-pitch spiral acquisition CCTA (2 * 128 * 0.6 mm, 300 mAs). Group A patients received iopromide 370 (370 mg I/mL), were scanned using 100 kVp, and reconstructed with filtered back projection. Group B patients received Iodixanol 270 (270 mg I/mL), were scanned using low tube voltage of 80 kVp, and reconstructed with iterative reconstruction techniques (IRT). CT attenuation was measured in coronary artery and other anatomic regions. Image quality score, noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and radiation dose were calculated and compared. RESULTS: The iodixanol 270 group showed no significant difference in image quality score (1.61 +/- 0.69 vs 1.57 +/- 0.66; P > .05), CT attenuation (P > .05), noise (P > .05), SNR (47.89 +/- 14.03 vs 44.37 +/- 12.79; P > .05), and CNR (42.38 +/- 12.67 vs 38.13 +/- 11.38; P > .05) in comparison to the iopromide 370 group but at a significantly lower radiation dose (0.26 +/- 0.05 vs 0.57 +/- 0.10; P < .001), which reflects dose saving of 54.4%. CONCLUSIONS: Combining IRT with high-pitch spiral acquisition mode and low-tube voltage technique, a low-concentration contrast medium of 270 mg I/mL can still maintain the contrast enhancement in coronary arteries without impairing image quality and significantly lower the radiation dose. PMID- 25457736 TI - Non-fragile robust synchronization for Markovian jumping chaotic neural networks of neutral-type with randomly occurring uncertainties and mode-dependent time varying delays. AB - This paper deals with the problem of robust synchronization for uncertain chaotic neutral-type Markovian jumping neural networks with randomly occurring uncertainties and randomly occurring control gain fluctuations. Then, a sufficient condition is proposed for the existence of non-fragile output controller in terms of linear matrix inequalities (LMIs). Uncertainty terms are separately taken into consideration. This network involves both mode dependent discrete and mode dependent distributed time-varying delays. Based on the Lyapunov-Krasovskii functional (LKF) with new triple integral terms, convex combination technique and free-weighting matrices method, delay-dependent sufficient conditions for the solvability of these problems are established in terms of LMIs. Furthermore, the problem of non-fragile robust synchronization is reduced to the optimization problem involving LMIs, and the detailed algorithm for solving the restricted LMIs is given. Numerical examples are provided to show the effectiveness of the proposed theoretical results. PMID- 25457737 TI - Characterizing white matter changes in cigarette smokers via diffusion tensor imaging. AB - BACKGROUND: Tobacco use remains the most preventable cause of death; however, its effects on the brain, and particularly white matter, remain elusive. Previous diffusion tensor imaging (DTI) studies have failed to yield consistent findings, with some reporting elevated measures of fractional anisotropy (FA) and others reporting lowered FA. METHODS: In our study, we sought to elucidate the effects of tobacco on white matter by using enhanced imaging acquisition parameters and multiple analysis methods, including tract-based spatial statistics (TBSS) with crossing fiber measures and probabilistic tractography. RESULTS: Our TBSS results revealed that chronic cigarette smokers have decreased FA in corpus callosum and bilateral anterior internal capsule, as well as specific reduced anisotropy in the two major fiber directions in a crossing fiber model. Further, our tractography results indicated that smokers have decreased FA in tracts projecting to the frontal cortex from (1) nucleus accumbens, (2) habenula, and (3) motor cortex. We also observed that smokers have greater disruptions in those regions when they had recently smoked compared to when they abstained from smoking for 24h. Our results also support previous evidence showing hemispheric asymmetry, with greater damage to the left side compared to the right. CONCLUSIONS: These findings provide more conclusive evidence of white matter disruptions caused by nicotine use. By better understanding the neural disruptions correlating with cigarette smoking we can elucidate the addictive course and explore targeted treatment regimens for nicotine dependence. PMID- 25457738 TI - It is not just memory: propositional thinking influences performance on the autobiographical IAT. AB - INTRODUCTION: The autobiographical Implicit Association Test (aIAT) is a variant of the Implicit Association Test reportedly capable of detecting an individual's concealed autobiographical event with very high accuracy. A previous attempt to utilize this measurement technique for the identification of cocaine users rendered an alarming rate of false positives. In this study, we aimed to explore the potential reasons behind the measurement's inaccuracy. METHODS: Two versions of the cocaine aIAT were devised with different category labels (descriptive 'guilty/innocent' and self-referenced 'as if you were/were not'). Forty-one cocaine abstinent participants (43.9% male; mean age = 28.17 +/- 7.36) were randomly assigned to one of the two conditions. Self-declared cocaine abstinence was confirmed for the 12-month period preceding data collection through hair analysis. Participants were also administered bespoke implicit and explicit cocaine user attitude measures, the self-esteem IAT and the Rosenberg self-esteem scale. RESULTS: The category labels which elicited self-referenced knowledge showed low accuracy (19%) compared to the 65% of the 'guilty/innocent' labels proposed by original authors. The self-referenced aIAT version significantly correlated with the self-concept measures. The aIAT outcomes were independent from attitudes toward cocaine users. CONCLUSIONS: Category labels play an influential role in determining the test's accuracy, demonstrating that participants' propositional knowledge and self-concept are involved during test performance. The aIAT does not appear to tap directly into an individual's implicit memory when relevant memory is not available. Although the test cannot be recommended for detecting drug use, further research should investigate underlying mechanisms and other potentials of the technique. PMID- 25457740 TI - DRD4 and susceptibility to peer influence on alcohol use from adolescence to adulthood. AB - BACKGROUND: The long allele of DRD4 is associated with greater susceptibility to peer influences on alcohol use in young adulthood, but it is unclear whether this increased susceptibility extends to other developmental periods. This study examined the interactive effects of DRD4 polymorphism and friends' alcohol use from adolescence to adulthood. METHODS: Participants (N = 340; 59% female; 98% White) reported on their own and their friends' alcohol use at four time points between mean ages 17 and 33. Autoregressive cross-lagged models evaluated reciprocal relationships between friends' alcohol use and participants' own alcohol use and frequency of heavy drinking over time. Multigroup modeling tested differences in model paths and covariances across high vs. low risk DRD4 polymorphisms. RESULTS: Alcohol use at age 33 was predicted by previous friends' alcohol use and correlated with current friends' alcohol use only for carriers of the DRD4 long allele. Regardless of DRD4 genotype, friends' alcohol use at age 17 predicted greater alcohol use and more frequent heavy drinking at age 23. Alcohol use and/or heavy drinking predicted greater friends' alcohol use at later time points for both genotype groups across adolescence and adulthood. CONCLUSIONS: The long allele of DRD4 is associated with increased susceptibility to peer influences on alcohol use in young adulthood, but not earlier in development. Adults with the long allele of DRD4 may benefit from interventions educating them about this risk and equipping them with strategies to reduce affiliations with and influence of drinking friends. PMID- 25457739 TI - Gender differences in clinical outcomes for cocaine dependence: randomized clinical trials of behavioral therapy and disulfiram. AB - BACKGROUND: Despite extensive research on gender differences in addiction, there are relatively few published reports comparing treatment outcomes for women versus men based on evidence-based treatments evaluated in randomized clinical trials. METHODS: An aggregate sample comprised of data from five randomized clinical trials of treatment for cocaine dependence (N = 434) was evaluated for gender differences in clinical outcomes. Secondary analyses compared gender differences in outcome by medication condition (disulfiram versus no medication) and across multiple behavioral treatment conditions. RESULTS: Women, compared with men, had poorer treatment outcomes on multiple measures of cocaine use during treatment and at post-treatment follow-up. These results appear to be primarily accounted for by disulfiram being less effective in women compared with men. There was no evidence of meaningful gender differences in outcome as a function of the behavioral therapies evaluated. CONCLUSIONS: These findings suggest that women and men may benefit to similar degrees from some empirically validated behavioral treatments for addiction. Conversely, some addiction pharmacotherapies, such as disulfiram, may be associated with poorer outcomes among women relative to men and point to the need for careful assessment of pharmacological treatments in both sexes prior to widespread clinical implementation. PMID- 25457741 TI - Nonvascular transport distraction osteogenesis in bone formation and regeneration. Is it an accidental phenomenon? AB - PURPOSE: To explore the osteogenic mechanism of nonvascular transport distraction osteogenesis (NTDO) by constructing mandibular defects in dogs. METHODS: Sixty adult dogs were randomly divided into three groups with 20 dogs in each group. Canine mandibular defect models of NTDO were constructed. Animals were euthanized 1, 4 and 12 weeks after distraction, and the transport disc and surrounding tissue were collected and fixed. Histochemical staining using hematoxylin and eosin (H&E) and electron microscopic observations were used to examine bone regeneration. RESULTS: Distraction bone regeneration was observed in the distraction gap and around the transport disc, and osseous connections had formed between new bone and the transport disc after one week. Osteoclasts gathered around the transport disc, and bone absorption pit formation could be seen. After 4 weeks of distraction, the new bone around the transport disc was close to maturity with thick sclerostin on the middle of the transport disc. After 12 weeks the new bone and the transport disc were fully integrated, and were difficult to distinguish by H&E staining and electron microscopy. CONCLUSIONS: Canine mandibular defects were successfully repaired by NTDO resulting in ideal new bone formation and fully recovered mandibular physiological function. The surrounding tissues, including musculoskeletal tissues, the periosteum and other soft tissues and the nonvascular transport disc, together contribute to bone regeneration and neovascularization in NTDO. PMID- 25457742 TI - Reasons for plate removal after treatment of orbitozygomatic complex fractures. AB - PURPOSE: The purpose of this study was to assess numbers of patients that required removal of miniplates after open reduction and internal fixation of the orbitozygomatic complex over a six-year period, and review the reasons for removal. PATIENTS AND METHODS: This was a retrospective study from February 2007 to December 2013. All patients who had open reduction and internal fixation for traumatic orbitozygomatic complex fractures were included and those who returned to theatre for plate removal were identified. RESULTS: 307 plates were placed in 216 patients. Eight plates were removed from six patients giving a 2.6% incidence of plate removal (2.78% of patients). Infection or exposure occurred within the first year in five out of six patients, accounting for the seven buttress plates, which were in situ for an average of 180 days. The infraorbital plate was in situ for 972 days. The majority of plates used were buttress plates as single point fixation. CONCLUSIONS: In our experience placement of buttress plates for one point fixation of traumatic orbitozygomatic complex fractures seems to be a safe and effective method with a low rate of complication. Complications seem to occur within a year, which is similar to previous studies. PMID- 25457743 TI - Acoustic analysis of vowel sounds before and after orthognathic surgery. AB - The purpose of this study was to compare the articular structures and vowel sounds of patients with mandibular prognathism before and after bilateral sagittal split ramus osteotomy (BSSRO). Eight patients who underwent BSSRO to correct mandibular prognathism were selected for inclusion in this study. All patients were asked to read short words (vowels), and these sounds were recorded. Every utterance was repeated twice in four different sessions before the operation and at 6 weeks, 3 months, and 6 months after the operation. The data were analysed using Praat (ver. 5.1.31), and the formant frequencies (F1, F2) of the eight vowels were extracted. PlotFormant (ver. 1.0) was used to draw formant diagrams. The F1 and F2 of front-low vowels were reduced after BSSRO, and the articulating positions of the patients shifted in a posterior-superior direction after the procedure. Additionally, the area of vowel articulation was dramatically reduced after BSSRO but increased slowly over time. PMID- 25457744 TI - Treatment of condylar fractures with an intraoral approach using an angulated screwdriver: results of a multicentre study. AB - BACKGROUND: This multicentre study aimed to investigate long-term radiographic and functional results following the treatment of condylar fractures using an angulated screwdriver system and open rigid internal fixation with an intraoral surgical approach. METHODS: Twenty-nine patients with a total of 32 condylar fractures were evaluated. The patients were investigated prospectively based on the following variables: age, sex, aetiology, side, location and classification of the fracture, degree of displacement, associated fractures, surgical approach, oral health status, type of osteosynthesis plate, duration of surgery, mouth opening, complications, and duration of follow-up. RESULTS: The fractures were classified as subcondylar (n = 25) or condylar neck (n = 7). Mean patient age was 36.38 +/- 16.60 years. The median duration of postoperative follow-up was 24.39 +/- 13.94 months. No joint noise, weakness of the facial nerve, joint pain, or muscle pain was observed. An additional retromandibular approach was necessary to enable the treatment of one subcondylar fracture with medial displacement. CONCLUSION: Subcondylar or condylar neck fractures with medial or lateral displacement can be treated using an intraoral approach with satisfactory results with the advantages of the absence of visible scarring, the avoidance of facial nerve injury, and the ability to obtain rapid access to the fracture. PMID- 25457746 TI - Neocortical development and evolution. PMID- 25457748 TI - Guest editorial "remembering the past personal life time leaders". PMID- 25457745 TI - Detection of tumor-associated glycopeptides by lectins: the peptide context modulates carbohydrate recognition. AB - Tn antigen (alpha-O-GalNAc-Ser/Thr) is a convenient cancer biomarker that is recognized by antibodies and lectins. This work yields remarkable results for two plant lectins in terms of epitope recognition and reveals that these receptors show higher affinity for Tn antigen when it is incorporated in the Pro-Asp-Thr Arg (PDTR) peptide region of mucin MUC1. In contrast, a significant affinity loss is observed when Tn antigen is located in the Ala-His-Gly-Val-Thr-Ser-Ala (AHGVTSA) or Ala-Pro-Gly-Ser-Thr-Ala-Pro (APGSTAP) fragments. Our data indicate that the charged residues, Arg and Asp, present in the PDTR sequence establish noteworthy fundamental interactions with the lectin surface as well as fix the conformation of the peptide backbone, favoring the presentation of the sugar moiety toward the lectin. These results may help to better understand glycopeptide-lectin interactions and may contribute to engineer new binding sites, allowing novel glycosensors for Tn antigen detection to be designed. PMID- 25457747 TI - Patients treated with therapeutic plasma exchange: a single center experience. AB - INTRODUCTION: Therapeutic Plasma Exchange (TPE) is a therapeutic procedure that is used to remove high molecular weight substances from plasma. We analyzed data of patients who received TPE during the last 7 years, and focused on the efficiency of TPE in various disease groups. MATERIAL AND METHODS: We studied 110 patients treated with TPE by membrane plasma separation technique from 2007 to 2013. We examined the demographic data, underlying disease, biochemical parameters, volume and type of replacement fluid, complications, concomitant treatment, the need for hemodialysis and number of TPE sessions. RESULTS: One hundred ten patients, 58 male, 52 female were included. The mean age was 47.3 +/- 17.6 years. A total of 734 TPE sessions were performed and the mean number of TPE sessions per patient was 6.6 +/- 4.3. The underlying disease was renal transplantation in 26 patients, ANCA-associated vasculitis in 18, rapidly progressive glomerulonephritis in 17, hemolytic uremic syndrome in 11, thrombotic thrombocytopenic purpura in 9, autoimmunic hemolytic anemia in 6, focal segmental glomerulosclerosis in 6 and other diseases. Partial and complete remission was obtained in 65 (59.1%) and 24 patients (21.8%) respectively, while 14 (12.7%) patients had no response and 7 (6.4%) patients died. Complications were muscle cramps (6.4%), allergic reactions (4.5%), severe hypotension (3.6%), fever (1.8%), unconsciousness (0.9%), leukopenia (0.9%) and catheter related hematoma (0.9%). CONCLUSION: According to our 7 years of experience in TPE, we can say that therapeutic plasma exchange by membrane separation technique is a useful, easy, available and effective life-saving therapeutic treatment. PMID- 25457749 TI - Storage and handling of blood components - perspectives. AB - The storage and handling conditions of cellular blood components and plasma are often rigorous, which is causing extensive discard of components that may be of acceptable quality as the rules for "out of optimal storage conditions" seem to be based more on tradition than scientific investigations. This short review summarizes some of the key papers indicating that it should be time for reconsideration of these rules, and some new suggestions are carefully indicated. Red cell concentrates, platelet concentrates and FFP are considered;lyophilized plasma and never-frozen liquid plasma are not included in this paper. PMID- 25457750 TI - "Go no Go" in plasma fractionation in the world's emerging economies: still a question asked 70 years after the COHN process was developed! AB - In the late 1980s, following the human immunodeficiency virus (HIV) epidemic and transfusion-transmitted infections from plasma-derived coagulation factor concentrates to hemophiliacs, many "advanced thinkers" claimed that plasma derived products would be completely replaced by the year 2000 by safe recombinant products in most developed countries. However, things have not turned out that way, due to both the continual progress witnessed in plasma fractionation and viral-reduction technologies and technical difficulties still being encountered in developing more cost-effective non-immunogenic, fully active recombinant therapeutic proteins. Accordingly, plasma fractionation remains a reasonably healthy industry worldwide, with an ever-increasing volume of plasma fractionated each year to meet the demands for safe and effective plasma-derived medicines at the global level. While high-income countries currently have generally good access to a panel of plasma-derived and recombinant products, desperate shortages of fractionated plasma products remain in developing economies,and patients still have to be treated inadequately. The steady development of the collection of whole blood in developing economies, to gradually cover the recognized needs for red blood cell concentrates, generates an increasing volume of recovered plasma that is currently wasted. Incentives are therefore high for those countries to consider fractionating such plasma as a means of enhancing their supply of products to treat patients, thereby also decreasing the level of dependence on imported products. Challenges of local plasma fractionation in developing economies are high, in a context where the technological and regulatory sophistication of the plasma fractionation industry is often underestimated, and the blood supply may be exposed to emerging infectious agents. In parallel, plasma product quality requirements and drivers are evolving in developed economies as is the awareness of clinicians to newer uses of products such as intravenous immunoglobulins, somewhat deviating from what currently remain the basic needs of developing countries in terms of affordable safe plasma products. Global market trends for plasma-derived products, through plasma fractionation, are still increasing, despite increasing use of recombinant products, and attention is being focused on the five Ws of the fractionation field: which products; where; when; what and how much; and who will be the main suppliers? PMID- 25457751 TI - Ebola virus convalescent blood products: where we are now and where we may need to go. AB - The world is regularly exposed to emerging infections with the potential to burst into a pandemic. One possible way to treat patients, when no other treatment is yet developed,is passive immunization performed by transfusing blood, plasma or plasma immunoglobul infractions obtained from convalescent donors who have recovered from the disease and have developed protective antibodies. The most recent on-going epidemic is caused by the Ebola virus, a filovirus responsible for Ebola virus disease, a severe, often lethal, hemorrhagic fever. Recently, the use of convalescent blood products was proposed by the WHO as one early option for treating patients with Ebola virus disease. This publication provides an overview of the various convalescent blood products and technological options that could theoretically be considered when there is a need to rely on this therapeutic approach.In countries without access to advanced blood-processing technologies, the choice may initially be restricted to convalescent whole blood or plasma. In technologically advanced countries, additional options for convalescent blood products are available, including virally inactivated plasma and fractionated immunoglobulins. The preparation of minipool immunoglobulins is also a realistic option to consider. PMID- 25457752 TI - Analytical model for calculating indeterminate results interval of screening tests, the effect on seroconversion window period: a brief evaluation of the impact of uncertain results on the blood establishment budget. AB - The evaluation of measurement uncertainty is not required by the European Union regulation or blood establishments' laboratory tests. However, it is required for tests accredited by ISO 15189. Also, the forthcoming ISO 9001 edition requires "risk based thinking" with risk described as "the effect of uncertainty on an expected result". ISO recommends GUM models for determination of measurement uncertainty, but their application is not intended for ordinal value measurements, such as what happens with screening test binary results. This article reviews, discusses and proposes concepts intended for measurement uncertainty of screening test results. The precision model focuses on cutoff level allowing the evaluation of the indeterminate interval using analytical sources of variance. The intervalis considered in the estimation of the seroconversion window period. The delta-value of patients and healthy subjects' samples allows ranking two tests according to the probability of the two classes of indeterminate results: chance of false negative results and chance of false positive results (waste on budget). PMID- 25457754 TI - Value of CT in patients undergoing self-expandable TAVR to assess outcomes of concomitant mitral regurgitation. PMID- 25457755 TI - Mechanical dispersion by strain echocardiography: a predictor of ventricular arrhythmias in subjects with lamin A/C mutations. PMID- 25457756 TI - FDG-PET imaging for oxidized LDL in stable atherosclerotic disease: a phase II study of safety, tolerability, and anti-inflammatory activity. PMID- 25457757 TI - A soft computing-based B-line analysis for objective classification of severity of pulmonary edema and fibrosis. PMID- 25457753 TI - Assessing ethanol's actions in the suprachiasmatic circadian clock using in vivo and in vitro approaches. AB - Research over the past decade has demonstrated substantial interactions between the circadian system and the processes through which alcohol affects behavior and physiology. Here we summarize the results of our collaborative efforts focused on this intersection. Using a combination of in vivo and in vitro approaches, we have shown that ethanol affects many aspects of the mammalian circadian system, both acutely as well as after chronic administration. Conversely, we have shown circadian influences on ethanol consumption. Importantly, we are beginning to delve into the cellular mechanisms associated with these effects. We are also starting to form a picture of the neuroanatomical bases for many of these actions. Finally, we put our current findings into perspective by suggesting new avenues of inquiry for our future efforts. PMID- 25457758 TI - Linking pediatric obesity to subclinical alterations in cardiac structure and function. PMID- 25457759 TI - High-Intensity Plaques on Noncontrast T1-Weighted Imaging as a Predictor of Periprocedural Myocardial Injury. PMID- 25457760 TI - Accurate conductance-based post-dilation balloon catheter sizing. PMID- 25457762 TI - Relation between the SYNTAX score and culprit vessel vulnerability in non-ST segment elevation acute coronary syndrome. PMID- 25457761 TI - A novel approach to neonatal management of tetralogy of Fallot, with pulmonary atresia, and multiple aortopulmonary collaterals. PMID- 25457763 TI - Early Reperfusion Can Reduce Infarction Size but not Salvaged Myocardial Size in Acute Myocardial Infarction Rats. PMID- 25457764 TI - Prevalence and Prognostic Significance of Lipomatous Metaplasia in Patients With Prior Myocardial Infarction. PMID- 25457765 TI - Two-Year Follow-Up OCT Images of 2 Bifurcation Lesions Treated With Bioresorbable Vascular Scaffolds. PMID- 25457766 TI - Disagreement Between Different Definitions of Coronary Artery Calcium Progression. PMID- 25457767 TI - Spectrum of Biventricular Involvement on CMR Among Carriers of ARVD/C-Associated Mutations. PMID- 25457768 TI - Abnormal myocardial perfusion in Kawasaki disease convalescence. PMID- 25457769 TI - Noninvasive evaluation of bone-forming activity within the calcified atherosclerotic lesions by Tc 99m HMDP scintigraphy. PMID- 25457770 TI - Three-dimensional printing of mitral valve using echocardiographic data. PMID- 25457773 TI - The role of Clofarabine in the treatment of adults with acute myeloid leukemia. AB - The therapeutic scenario available for adult patients with acute myeloid leukemia (AML) has shown only partial progresses over the last few years. This is especially true for refractory and relapsed AML whose outcome is still extremely disappointing. In this context Clofarabine has offered new promising perspectives within first and second line protocols. This review will firstly describe the initial development in monotherapy, considering then the different potential combination strategies which include both polichemotherapeutic regimens and less conventional approaches with new generation drugs. The potential use of Clofarabine as induction treatment for patients candidate to stem cell transplantation and within conditioning regimens will be finally evaluated. PMID- 25457772 TI - Yeast DNA ligase IV mutations reveal a nonhomologous end joining function of BRCT1 distinct from XRCC4/Lif1 binding. AB - LIG4/Dnl4 is the DNA ligase that (re)joins DNA double-strand breaks (DSBs) via nonhomologous end joining (NHEJ), an activity supported by binding of its tandem BRCT domains to the ligase accessory protein XRCC4/Lif1. We screened a panel of 88 distinct ligase mutants to explore the structure-function relationships of the yeast Dnl4 BRCT domains and inter-BRCT linker in NHEJ. Screen results suggested two distinct classes of BRCT mutations with differential effects on Lif1 interaction as compared to NHEJ completion. Validated constructs confirmed that D800K and GG(868:869)AA mutations, which target the Lif1 binding interface, showed a severely defective Dnl4-Lif1 interaction but a less consistent and often small decrease in NHEJ activity in some assays, as well as nearly normal levels of Dnl4 accumulation at DSBs. In contrast, mutants K742A and KTT(742:744)ATA, which target the beta3-alpha2 region of the first BRCT domain, substantially decreased NHEJ function commensurate with a large defect in Dnl4 recruitment to DSBs, despite a comparatively greater preservation of the Lif1 interaction. Together, these separation-of-function mutants indicate that Dnl4 BRCT1 supports DSB recruitment and NHEJ in a manner distinct from Lif1 binding and reveal a complexity of Dnl4 BRCT domain functions in support of stable DSB association. PMID- 25457771 TI - Exo1 phosphorylation status controls the hydroxyurea sensitivity of cells lacking the Pol32 subunit of DNA polymerases delta and zeta. AB - Exo1 belongs to the Rad2 family of structure-specific nucleases and possesses 5' 3' exonuclease activity on double-stranded DNA substrates. Exo1 interacts physically with the DNA mismatch repair (MMR) proteins Msh2 and Mlh1 and is involved in the excision of the mispaired nucleotide. Independent of its role in MMR, Exo1 contributes to long-range resection of DNA double-strand break (DSB) ends to facilitate their repair by homologous recombination (HR), and was recently identified as a component of error-free DNA damage tolerance pathways. Here, we show that Exo1 activity increases the hydroxyurea sensitivity of cells lacking Pol32, a subunit of DNA polymerases delta and zeta. Both, phospho mimicking and dephospho-mimicking exo1 mutants act as hypermorphs, as evidenced by an increase in HU sensitivity of pol32Delta cells, suggesting that they are trapped in an active form and that phosphorylation of Exo1 at residues S372, S567, S587, S692 is necessary, but insufficient, for the accurate regulation of Exo1 activity at stalled replication forks. In contrast, neither phosphorylation status is important for Exo1's role in MMR or in the suppression of genome instability in cells lacking Sgs1 helicase. This ability of an EXO1 deletion to suppress the HU hypersensitivity of pol32Delta cells is in contrast to the negative genetic interaction between deletions of EXO1 and POL32 in MMS-treated cells as well as the role of EXO1 in DNA-damage treated rad53 and mec1 mutants. PMID- 25457774 TI - Hepatitis C virus and lymphoma. AB - Hepatitis C virus (HCV) is a hepatotrophic and lymphotrophic virus and is a global health problem. Cirrhosis and hepatocellular cancer are the most common complications of HCV. Association between HCV and B cell non-Hodgkin lymphomas (B NHL) has been shown in epidemiological studies in the last 20 years. High prevalence of HCV infection among patients with NHL has been reported in the early 1990s by Ferri in Italy and this association has been confirmed in later studies. Geographically, HCV related NHL is highly variable and chronic rather than cleared HCV infection is required for lymphomagenesis. Although anti-HCV antibody test is the most commonly used technique in epidemiological studies, HCV RNA is more useful test to detect the association between HCV and NHL. The optimal management of HCV related NHL is not clear. However, anti-viral treatment may be sufficient for cases with low grade and/or asymptomatic lymphomas, while immuno-chemotherapy is necessary, in spite of probable hepatic toxicity, in cases with high grade lymphomas. PMID- 25457775 TI - Influence of attachment strategy on the thermal stability of hybridized DNA on gold surfaces. AB - The thermal stabilities of double-stranded DNA hybrids immobilized on gold surfaces are shown to be significantly affected by the conformation of the hybrid. To analyze this behavior, DNA probes were immobilized using attachment strategies where the nucleotides within the strand had varying levels of interactions with the gold substrate. The abilities of these probes to form double-stranded hybrids with solution DNA targets were evaluated by surface plasmon resonance (SPR) over a temperature range 25-60 degrees C. The measurements were used to construct thermal stability profiles for hybrids in each conformation. We observe that DNA hybrids formed with probe strands that interact extensively with the gold surface have stability profiles that are shifted lower by 5-10 degrees C compared to hybrids formed with end-tethered probes that have fewer interactions with the surface. The results provide an understanding of the experimental conditions in which these weaker DNA hybrids can form and show the additional complexity of evaluating denaturation profiles generated from DNA on surfaces. PMID- 25457776 TI - The effect of radial head implant shape on radiocapitellar kinematics during in vitro forearm rotation. AB - BACKGROUND: A number of radial head implants are in clinical use for the management of radial head fractures and their sequelae. However, the optimal shape of a radial head implant to ensure proper tracking relative to the capitellum has not been established. This in vitro biomechanical study compared radiocapitellar joint kinematics for 3 radial head implant designs as well as the native head. METHODS: Eight cadaveric upper extremities were tested using a forearm rotation simulator with the elbow at 90 degrees of flexion. Motion of the radius relative to the capitellum was optically tracked. A stem was navigated into a predetermined location and cemented in place. Three unipolar implant shapes were tested: axisymmetric, reverse-engineered patient-specific, and population-based quasi-anatomic. The patient-specific and quasi-anatomic implants were derived from measurements performed on computed tomography models. RESULTS: Medial-lateral and anterior-posterior translation of the radial head with respect to the capitellum varied with forearm rotation and radial head condition. A significant difference in medial-lateral (P = .03) and anterior-posterior (P = .03) translation was found between the native radial head and the 3 implants. No differences were observed among the radial head conditions except for a difference in medial-lateral translation between the axisymmetric and patient specific implants (P = .04). CONCLUSIONS: Radiocapitellar kinematics of the tested radial head implants were similar in all but one comparison, and all had different kinematics from the native radial head. Patient-specific radial head implants did not prove advantageous relative to conventional implant designs. The shape of the fixed stem unipolar radial head implants had little influence on radiocapitellar kinematics when optimally positioned in this testing model. PMID- 25457777 TI - Four-dimensional computed tomography scans facilitate preoperative planning in snapping scapula syndrome. AB - HYPOTHESIS: Because a 4-dimensional CT scan (4D CT) is able to provide a moving 3 dimensional (3D) image in real time in patients with snapping scapula syndrome, a 4D CT scan should be able to demonstrate bony impingement of the scapula on the posterior thorax. This study was performed to determine if 4D CT scans aid the clinician in defining the size and location of the scapular bone causing impingement in patients with snapping scapula syndrome. MATERIALS AND METHODS: Between October 2009 and August 2013, 12 patients (median age, 26.5 years; range 15-55 years) with snapping scapula syndrome were investigated with 4D CT. The images formed produced a dynamic volume-rendered reconstruction of the scapulothoracic joint that displayed its movements and any dynamic area of impingement of the scapula on surrounding bony structures. Asymmetry between symptomatic and asymptomatic scapulae was used to determine the radiologic cause of the patient's symptoms. After the failure of conservative management, 8 patients underwent surgery for their condition. RESULTS: Five patients demonstrated bony contact of the scapula on the posterior thoracic ribs. Four patients demonstrated no bony contact but close apposition of the scapula to the posterior thoracic ribs. Three patients demonstrated no bony impingement but abnormal movement of the second and third rib caused by a soft-tissue tethering structure. CONCLUSION: The 4D CT scan images defined pathology well in patients with snapping scapula syndrome and improved assessment of the amount and location of the scapular bone and soft tissue causing symptoms. PMID- 25457778 TI - Risk of arthropathy after the Bristow-Latarjet repair: a radiologic and clinical thirty-three to thirty-five years of follow-up of thirty-one shoulders. AB - BACKGROUND: Transfer of the coracoid (Bristow-Latarjet [B-L]) is used to stabilize anterior shoulder instability. We report the long-term results of our first 31 operations with this method. MATERIALS AND METHODS: Thirty-six patients (mean age, 26.7 years) had a B-L repair from 1977 to 1979. Five patients died, and during 2012 to 2013, the remaining 31 shoulders had a follow-up with questionnaire, physical examination, Western Ontario Shoulder Instability Index, Subjective Shoulder Value, Subjective Assessment of Shoulder Function, subjective assessment of loss of motion, and radiologic imaging. RESULTS: One patient required revision surgery because of recurrence and another because of repeat dislocation. Six patients reported subluxations. Eighteen patients (58%) were very satisfied, and 13 (42%) were satisfied. The mean Western Ontario Shoulder Instability Index score (100 possible) was 85, and the median score was 93. According to Samilson-Prieto classification of arthropathy of the shoulder, 39% were classified as normal, 27% as mild, 23% as moderate, and 11% as severe. The classification of arthropathy varied with observers and radiologic views. Age younger than 22 years at the primary dislocation meant less arthropathy at follow up (P = .045). CONCLUSION: The degree of arthropathy 33 to 35 years after the B-L repair seems to follow the natural history of shoulder dislocation with respect to arthropathic joint degeneration. Postoperative restriction of external rotation does not increase later arthropathy. PMID- 25457779 TI - Effects of the humeral tray component positioning for onlay reverse shoulder arthroplasty design: a biomechanical analysis. AB - BACKGROUND: Recent shoulder prostheses have introduced a concept of a universal humeral stem component platform that has an onlay humeral tray for the reverse total shoulder arthroplasty (RTSA). No studies have reported how humeral tray positioning can affect the biomechanics of RTSA. MATERIALS AND METHODS: The Newcastle Shoulder Model was used to investigate the biomechanical effect of humeral tray positioning in the Biomet Comprehensive Total Shoulder System (Biomet, Warsaw, IN, USA) RTSA. Five humeral tray configuration positions were tested: no offset, and 5 mm offset in the anterior, posterior, medial, and lateral positions. Superior and inferior impingement were evaluated for abduction, scapular plane elevation, forward flexion, and external/internal rotation with the elbow at the side (adduction) and at 90 degrees of shoulder abduction. Muscle lengths and moment arms (elevating and rotational) were calculated for the deltoid, the infraspinatus, the teres minor, and the subscapularis. RESULTS: Inferior impingement was not affected by the humeral tray position. There was less superior impingement during abduction, scapular plane elevation, and rotation with the shoulder when the tray was placed laterally or posteriorly. The subscapularis rotational moment arm was increased with a posterior offset, whereas infraspinatus and teres minor rotational moment arms were increased with an anterior offset. Very little change was observed for the deltoid elevating moment arm or for its muscle length. CONCLUSION: Positioning the humeral tray with posterior offset offers a biomechanical advantage for patients needing RTSA by decreasing superior impingement and increasing the internal rotational moment arm of the subscapularis, without creating inferior impingement. PMID- 25457780 TI - Angular stable fixation of displaced distal-third clavicle fractures with superior precontoured locking plates. AB - HYPOTHESIS: We reviewed the outcome of angular stable plates in addressing displaced lateral-third clavicle fractures. We investigated union, shoulder function, request for implant removal, and return to sport. Our hypothesis was that these implants provide predictable union and return to sports without the negative consequence of leaving plates in situ, reducing the requirement for a second surgery. METHODS: We undertook a retrospective review of a consecutive series of patients who underwent this surgery between 2007 and 2010. Nineteen patients with a mean follow-up of 25 months were included. Postoperative follow up was performed at 2 weeks and monthly thereafter until union was assessed as achieved clinically and radiographically. Two telephone interviews at a mean of 7 months and 25 months postoperatively assessed shoulder function by Oxford Shoulder Score, presence of any plate or scar discomfort, need for implant removal, and return to sport. RESULTS: Nineteen patients achieved union by 4 months (median, 12 weeks; range, 6-16 weeks). The mean Oxford Shoulder Score was 46 (range, 41-48) at a mean of 7 months (range, 3-18 months) and 47 (range, 44 48) at 25 months (range, 18-48 months). Initially, 2 patients requested implant removal; later, however, both declined surgery. No plates have been removed. Four patients complained of mild plate discomfort but did not wish removal. All patients had returned to sporting activities. CONCLUSION: Angular stable plate fixation of Neer group II, type II clavicle fractures resulted in a 100% union rate with excellent return of function with no mandatory need for removal. PMID- 25457781 TI - A comparison of debridement with and without anconeus muscle flap for treatment of refractory lateral epicondylitis. AB - BACKGROUND: Lateral epicondylitis is a common condition encountered by orthopedic surgeons. Whereas the majority of patients improve with conservative management, a small percentage will require surgery. The purpose of this study was to compare the clinical outcomes of surgical debridement of the common extensor origin alone with debridement combined with rotation of an anconeus muscle flap in patients who failed to respond to conservative management of chronic lateral epicondylitis. METHODS: Fifty-seven patients who failed to respond to a minimum of 5 months of conservative treatment for lateral epicondylitis were retrospectively reviewed. Patients in group 1 were treated with open debridement of the common extensor origin. Patients in group 2 were treated with open debridement combined with rotation of an anconeus muscle flap. Outcome measures included elbow range of motion, grip strength, visual analog scale (VAS) for pain score, and Disabilities of the Arm, Shoulder, and Hand (DASH) score. Statistical analyses were performed by Student's t test with 95% confidence intervals. RESULTS: At final follow-up, average DASH scores were significantly lower in group 2. There were no significant differences between the groups with regard to elbow range of motion or grip strength. VAS pain scores were significantly reduced in both groups. Preoperative VAS pain scores were significantly greater in group 2; however, at final follow-up, there was no significant difference between groups. There were no apparent complications in either group. CONCLUSIONS: In addition to debridement of the common extensor origin, the rotation of an anconeus muscle flap may improve outcomes in cases of lateral epicondylitis that require operative intervention. PMID- 25457782 TI - Delaminated rotator cuff tear: extension of delamination and cuff integrity after arthroscopic rotator cuff repair. AB - BACKGROUND: The purpose of this study was to evaluate the extension of delamination and the cuff integrity after arthroscopic repair of delaminated rotator cuff tears. METHODS: Sixty-five patients with delaminated rotator cuff tears were retrospectively reviewed. The delaminated tears were divided into full thickness delaminated tears and partial-thickness delaminated tears. To evaluate the medial extension, we calculated the coronal size of the delaminated portion. To evaluate the posterior extension, we checked the tendon involved. Cuff integrity was evaluated by computed tomography arthrography. RESULTS: The mean medial extension in the full-thickness and partial-thickness delaminated tears was 18.1 +/- 6.0 mm and 22.7 +/- 6.3 mm, respectively (P = .0084). The posterior extension into the supraspinatus and the infraspinatus was 36.9% and 32.3%, respectively, in the full-thickness delaminated tears, and it was 27.7% and 3.1%, respectively, in the partial-thickness delaminated tears (P = .0043). With regard to cuff integrity, 35 cases of anatomic healing, 10 cases of partial healing defects, and 17 cases of retear were detected. Among the patients with retear and partial healing of the defect, all the partially healed defects showed delamination. Three retear patients showed delamination, and 14 retear patients did not show delamination; the difference was statistically significant (P = .0001). CONCLUSION: The full-thickness delaminated tears showed less medial extension and more posterior extension than the partial-thickness delaminated tears. Delamination did not develop in retear patients, but delamination was common in the patients with partially healed defects. PMID- 25457783 TI - Reconstruction of rotator cuff tears in wheelchair-bound paraplegic patients. AB - BACKGROUND: Rotator cuff surgery in wheelchair-bound patients is challenging, and clinical data on this condition are limited. We hypothesized that rotator cuff repair in these patients might improve functional outcomes. METHODS: In a retrospective study, data on 13 paraplegic patients (8 men and 5 women; 16 shoulders) who underwent rotator cuff repair were analyzed. The average age at the time of surgery was 48.7 years. The causes of paraplegia were poliomyelitis in 9 patients, spinal fracture in 4, and cerebral infarction in 2. Open rotator cuff repair was performed in 11 patients and arthroscopic repair in 2 patients. No wheelchair propulsion was allowed until 6 months postoperatively to protect the repaired cuffs. American Shoulder and Elbow Surgeons (ASES) score and Constant score were used for functional evaluation. To assess tendon integrity, magnetic resonance imaging or ultrasonography was used at an average of 31.2 months postoperatively. RESULTS: ASES scores improved from 53 to 85, and Constant scores improved from 48 to 75. Radiographic evaluation revealed healing in 88% of the cases and retear in 12%. In the retear group, functional scores improved. CONCLUSION: Rotator cuff repair surgery for paraplegic wheelchair-bound patients provides satisfactory functional outcomes. Careful postoperative management can help in obtaining positive functional outcomes. PMID- 25457784 TI - Effect of shoulder abduction on the fixation of humeral greater tuberosity fractures: a biomechanical study for three types of fixation constructs. AB - BACKGROUND: An abduction brace and abduction exercises are commonly employed after humeral greater tuberosity fracture repair. However, the effects of glenohumeral abduction on the biomechanical strength have seldom been elucidated. METHOD: We studied 24 pairs of female fresh frozen porcine shoulders randomly divided into 3 groups. After creation of a greater tuberosity fracture on each shoulder, 3 fixation techniques were used for the 3 groups: double-row suture anchor fixation (DR), suture bridge technique (SB), and 2-screw fixation (TS). This biomechanical study was conducted to compare the forces that create 3- and 5 mm displacements and the ultimate failure load at the simulated shoulder abduction angles of 0 degrees and 45 degrees among the 3 groups. RESULTS: In the DR group, the mean forces to create 3- and 5-mm displacements and the failure load at 0 degrees were higher than those at 45 degrees (P = .036, P = .012, P = .027). By contrast, in the SB group, the mean forces to create 3- and 5-mm displacements at 45 degrees were greater than those at 0 degrees (P = .012, P = .012). There were no significant differences in the forces to create 3- and 5-mm displacements and construct failure between 0 degrees and 45 degrees in the TS group (P = .575, .327, .478). CONCLUSION: The DR group had greatest initial fixation strength at a low abduction angle, whereas the SB group had the highest initial fixation strength at a high abduction angle. The TS group appeared unaffected by the abduction angle. PMID- 25457785 TI - The ability of massive osteochondral allografts from the medial tibial plateau to reproduce normal joint contact pressures after glenoid resurfacing: the effect of computed tomography matching. AB - BACKGROUND: Current techniques for resurfacing of the glenoid in the treatment of arthritis are unpredictable. Computed tomography (CT) studies have demonstrated that the medial tibial plateau has close similarity to the glenoid. The purpose of this study was to assess contact pressures of transplanted massive tibial osteochondral allografts to resurface the glenoid without and with CT matching. METHODS: Ten unmatched cadaveric tibiae were used to resurface 10 cadaveric glenoids with osteochondral allografts. Five cadaveric tibiae and glenoids were CT matched and studied. An internal control group of 4 matched pairs of glenoids, with the contralateral glenoid transplanted to the opposite glenoid, was also included as a best-case scenario to measure the effects of the surgical technique. All glenoids were tested before and after grafting at different abduction and rotation angles, with recording of peak contact pressures. RESULTS: Peak contact pressures were not different from the intact state in the autografted group but were increased in both allografted groups. CT-matched tibial grafts had lower peak pressures than unmatched grafts. Peak pressures were on average 24.8% (range [18.3%, 29.6%]) greater than in the native glenoids for unmatched allografts, 21.8% ([17.0%, 25.5%]) greater for the matched allografts, and 4.9% ([3.8%, 5.5%]) greater for matched autografts. CONCLUSION: Osteochondral grafting from the medial tibial plateau to the glenoid is feasible but results in increased peak contact pressures. The technique is reproducible as defined by the autografted group. Contact pressures between native and allografted glenoids were significantly different. The clinical significance remains unknown. Peak pressures experienced by the glenoid seem highly sensitive to deviations from the native glenoid shape. PMID- 25457787 TI - The anatomy and histology of the bicipital tunnel of the shoulder. AB - BACKGROUND: The bicipital tunnel is the extra-articular, fibro-osseous structure that encloses the long head of the biceps tendon. METHODS: Twelve cadaveric shoulder specimens underwent in situ casting of the bicipital tunnel with methyl methacrylate cement to demonstrate structural competence (n = 6) and en bloc harvest with gross and histologic evaluation (n = 6). The percentage of empty tunnel was calculated histologically by subtracting the proportion of cross sectional area of the long head of the biceps tendon from that of the bicipital tunnel for each zone. RESULTS: Cement casting demonstrated that the bicipital tunnel was a closed space. Zone 1 extended from the articular margin to the distal margin of the subscapularis tendon. Zone 2 extended from the distal margin of the subscapularis tendon to the proximal margin of the pectoralis major tendon. Zone 3 was the subpectoral region. Zones 1 and 2 were both enclosed by a dense connective tissue sheath and demonstrated the presence of synovium. Zone 3 had significantly greater percentage of empty tunnel than zones 1 and 2 did (P < .01). CONCLUSION: The bicipital tunnel is a closed space with 3 distinct zones. Zones 1 and 2 have similar features, including the presence of synovium, but differ from zone 3. A significant bottleneck occurs between zone 2 and zone 3, most likely at the proximal margin of the pectoralis major tendon. The bicipital tunnel is a closed space where space-occupying lesions may produce a bicipital tunnel syndrome. Careful consideration should be given to surgical techniques that decompress both zones 1 and 2 of the bicipital tunnel. PMID- 25457788 TI - Sixty-nine-year follow-up of a McKee radial head arthroplasty. PMID- 25457786 TI - Iliac bone grafting of the intact glenoid improves shoulder stability with optimal graft positioning. AB - BACKGROUND: Bone grafting procedures are increasingly popular for the treatment of anterior shoulder instability. In patients with a high risk of recurrence, open coracoid transplantation is preferred but can be technically demanding. Free bone graft glenoid augmentation may be an alternative strategy for high-risk patients without significant glenoid bone loss. This biomechanical cadaveric study assessed the stabilizing effect of free iliac crest bone grafting of the intact glenoid and the importance of sagittal graft position. METHODS: Eight fresh frozen cadaveric shoulders were tested. The bone graft was fixed on the glenoid neck at 3 sagittal positions (50%, 75%, and 100% below the glenoid equator). Displacement and reaction force were monitored with a custom device while translating the humeral head over the glenoid surface in both anterior and anteroinferior direction. RESULTS: Peak force (PF) increased significantly from the standard labral repair to the grafted conditions in both anterior (14.7 +/- 5.5 N vs 27.3 +/- 6.9 N) and anteroinferior translation (22.0 +/- 5.3 N vs 29.3 +/- 6.9 N). PF was significantly higher for the grafts at the 50% and 75% positions compared with the grafts 100% below the equator with anterior translation. Anteroinferior translation resulted in significantly higher values for the 100% and 75% positions compared with the 50% position. CONCLUSIONS: This biomechanical study confirms improved anterior glenohumeral stability after iliac crest bone graft augmentation of the anterior glenoid. The results also demonstrate the importance of bone graft position in the sagittal plane, with the ideal position determined by the direction of dislocation. PMID- 25457789 TI - [Thermoplastic mask in radiotherapy: a source of anxiety for the patient?]. AB - PURPOSE: The thermoplastic mask often used to immobilize patients in radiotherapy can cause varying levels of stress and anxiety. This study aimed at evaluating the anxiety related to the use of radiotherapy masks and the coping strategies adopted by patients. PATIENTS AND METHODS: Nineteen patients treated with radiotherapy mask for head and neck cancer, a brain tumour or a lymphoma, were met twice by a psychologist, either after the making of the mask and the first course of radiotherapy, or in the middle and at the end of treatment. Thirty-four semi-structured interviews were treated using a thematic content analysis and 13 patients answered to anxiety (STAI-YB) and coping (WCC) scales. RESULTS: The STAI YB anxiety scores related to wearing the masks were low during the radiotherapy treatment period, and were confirmed by the remarks of patients recorded during the semi-structured interviews. Most patients had a positive perception of the mask, and considered it as a friend or protection. Twelve out of the 13 patients admitting to anxiety benefited from problem focused coping strategies. CONCLUSIONS: Thermoplastic mask-related anxiety is low and possibly lies in the positive representation patients have about the mask. The explanations provided by health professionals on the radiotherapy mask possibly have a very positive effect on this perception. PMID- 25457790 TI - [Sexual functions after treatment for rectal cancer: impact of doses in autonomic pelvic nerves]. AB - PURPOSE: Prospective evaluation of sexual function after treatment of rectal cancer and identification of predictive factors. PATIENTS AND METHODS: Thirty three patients were treated with curative intent by chemoradiation and surgery for localized rectal adenocarcinoma. Sexual toxicity was assessed four times (before treatment and at 2, 6 and 12 months) using validated questionnaires: QLQ C30 and EORTC CR38 for all, simplified IIEF for men and FSFI for women. A correlation was sought between the toxicity and clinical and dosimetric parameters by Fisher and Mann-Whitney tests. RESULTS: In men, erections and sexual satisfaction decreased significantly from the acute phase and then stabilized (respective scores of 84.5 and 86/100 in the initial phase, 66 and 70.4 at the end of radiotherapy, 70 and 70 at 6 months and 68.5 and 70 at 12 months). For women, the changes were not significant. This study confirms some risk factors for sexual toxicity already mentioned (original function, age, tumor volume) and highlights new (dose to the seminal vesicles and above all, doses to pelvic autonomic plexus). CONCLUSION: Sexual effects of combined treatment of rectal cancer have only recently been described but remain undervalued and poorly understood. The impact of the autonomic pelvic plexus doses is a completely new data that could be extended in the development of intensity-modulated radiotherapy. PMID- 25457791 TI - Elevated carcinoembryonic antigen tumour marker caused by head and neck cancer: a case report and literature study. AB - Carcinoembryonic antigen is a tumour marker commonly increased in gastrointestinal and pulmonary cancers. We report a case of a 46-year-old man with a mucoepidermoid carcinoma of the base of tongue with an elevated and traceable serum carcinoembryonic antigen level. This antigen proved to be a valuable marker in the treatment follow-up. When a raised carcinoembryonic antigen level is found, salivary gland malignancies should be taken into the differential diagnosis and clinical examination of the head and neck region should not be overlooked. PMID- 25457792 TI - Design of VA Cooperative Study #591: CERV-PTSD, comparative effectiveness research in veterans with PTSD. AB - CERV-PTSD is a randomized controlled trial of two of the most effective treatments for PTSD, Prolonged Exposure (PE) and Cognitive Processing Therapy (CPT). Despite solid evidence that both treatments are effective, there is limited evidence about their effectiveness relative to one another. The primary objective is to compare the effectiveness of PE and CPT for reducing PTSD symptom severity in a healthcare system that offers both treatments. The secondary objective is to compare the effectiveness of PE and CPT for reducing the severity of comorbid mental health problems and service utilization as well as improving functioning and quality of life. The tertiary objective is to examine whether discrepancy between patient preferences and treatment assignment reduces the effectiveness of each treatment. Exploratory analyses will examine whether demographic and clinical characteristics predict differential response to PE and CPT. The study is designed to randomize 900 male and female veterans with PTSD due to any traumatic military event to receive PE or CPT. The standard dose of treatment is 12 weekly sessions but veterans who improve more rapidly may finish in fewer sessions and veterans who improve more slowly may have additional sessions. The primary outcome is improvement in PTSD symptoms, measured during and after treatment and then 3 and 6 months later. As a large multi-site trial with men and women, CERV-PTSD is designed to advance the delivery of care for PTSD by providing conclusive information about whether one treatment is better than the other, overall, and for different types of patients. PMID- 25457793 TI - Rationale and design of a comparative effectiveness trial to prevent type 2 diabetes in mothers and children: the ENCOURAGE healthy families study. AB - The number of youth with type 2 diabetes (T2D) is expected to quadruple over 4 decades. Gestational diabetes mellitus (GDM) is also increasing and is linked with development of T2D in women, and greater risk for T2D in adolescents exposed to GDM. Despite the increasing prevalence of T2D, approaches to prevent diabetes in high-risk youth and families are rare. To address this, we are conducting the Encourage Health Families Study (ENCOURAGE). This is a randomized trial evaluating the comparative effectiveness and costs of an adaptation of the Diabetes Prevention Program (DPP) directed at mothers who had GDM or prediabetes and their children. The intervention is a group-based lifestyle program which we developed and implemented in partnership with the YMCA. We are comparing the ENCOURAGE intervention targeted to 1) mothers who have had GDM or prediabetes, and 2) mothers who have had GDM or prediabetes along with their school-aged children. This manuscript provides 1) the rationale for a targeted approach to preventing T2D and the interventions, 2) description of the translation of the DPP curriculum, and 3) the study design and methodology. The primary aims are to determine if participation leads to 1) weight loss in high-risk mothers, and 2) youth having healthier weights and lifestyle habits. We will also evaluate costs associated with each approach. These data are essential to build a translation model of T2D prevention that is both realistic and feasible to address this growing problem in both youth and adults. PMID- 25457794 TI - In vitro and in vivo antifungal activity of Cassia surattensis flower against Aspergillus niger. AB - Invasive aspergillosis (IA) in immunocompromised host is a major infectious disease leading to reduce the survival rate of world population. Aspergillus niger is a causative agent causing IA. Cassia surattensis plant is commonly used in rural areas to treat various types of disease. C. surattensis flower extract was evaluated against the systemic aspergillosis model in this study. Qualitative measurement of fungal burden suggested a reduction pattern in the colony forming unit (CFU) of lung, liver, spleen and kidney for the extract treated group. Galactomannan assay assessment showed a decrease of fungal load in the treatment and positive control group with galactomannan index (GMI) value of 1.27 and 0.25 on day 28 but the negative control group showed high level of galactomannan in the serum with GMI value of 3.58. Histopathology examinations of the tissues featured major architecture modifications in the tissues of negative control group. Tissue reparation and recovery from infection were detected in extract treated and positive control group. Time killing fungicidal study of A. niger revealed dependence of the concentration of C. surattensis flower extract. PMID- 25457795 TI - Antibacterial activity of antagonistic bacterium Bacillus subtilis DJM-51 against phytopathogenic Clavibacter michiganense subsp. michiganense ATCC 7429 in vitro. AB - To investigate antibacterial activity against the tomato pathogen Clavibacter michiganense subsp. michiganense ATCC 7429 (Cmm ATCC 7429), Bacillus subtilis DJM 51 was isolated from rhizosphere soil. For isolation of bacteria, samples were taken from rhizosphere soil. The isolate, DJA-51, had strong antagonistic ability against Tomato pathogen Cmm ATCC 7429 on nutrient-broth yeast extract agar (NBYA) as indicated by inhibition zones around colonies. On the basis of the nucleotide sequence of a conserved segment of the 16S rRNA gene, the bacterium has been identified as B. subtilis DJM-51. The growth of Cmm ATCC 7429 on NBYA plates was inhibited by culture broth of B. subtilis DJM-51 including cells, by the supernatant of culture broth of B. subtilis DJM-51, and by the liquid material resulting from butanol extract of bacterial cultures. The OD value in co-culture mixture was lower than the control throughout the entire incubation period. Antibiotics obtained from B. subtilis DJM-51 inhibited the growth of Tomato pathogen Cmm ATCC 7429. These results provide potentially information about the protection of tomato from pathogen Cmm ATCC 7429 under greenhouse conditions in Quebec. PMID- 25457796 TI - Modulation of the inflammatory response of bovine mammary epithelial cells by cholecalciferol (vitamin D) during Staphylococcus aureus internalization. AB - Vitamin D is an immunomodulator that exerts anti-inflammatory effects. In this work, the effects of cholecalciferol, a vitamin D precursor, on the inflammatory response of bovine mammary epithelial cells (bMECs) during the internalization of Staphylococcus aureus were analyzed. Cholecalciferol and S. aureus inhibited TLR2 mRNA expression, but cholecalciferol differentially modulated the TLR2 membrane abundance. In fact, 50 nM cholecalciferol inhibited the TLR2 membrane abundance in bMECs infected with S. aureus, and this concentration also exerted the highest inhibitory effect on internalization. Cholecalciferol down-regulated the mRNA expression of TNF-alpha and IL-1beta and up-regulated that of RANTES and IL-10 but did not modify IL-6 and IL-8 expression. S. aureus strongly induced the mRNA expression of TNF-alpha, RANTES and IL-10 and inhibited IL-8 expression. Interestingly, cholecalciferol pre-treatments inhibited the bacterial-induced expression of TNF-alpha, IL-1beta, RANTES and IL-10. In conclusion, cholecalciferol differentially regulates the inflammatory response of bMECs during S. aureus internalization and may be an effective innate immunity modulator in mammary gland tissues. PMID- 25457797 TI - Relationship between growth factors and its implication in the pathogenesis of leprosy. AB - Leprosy is a chronic infectious disease caused by Mycobacterium leprae which affects the skin and peripheral nervous system. The immune response of the host determines the clinical course of the disease. The tuberculoid form is the result of high cell-mediated immunity characterized by a Th1 response, whereas the lepromatous form is characterized by low cell-mediated immunity and a Th2 humoral response. The neural damage established produces marked changes in the expression of growth factors such as nerve growth factor (NGF) and its receptors (NGF-R). The expression of NGF, associated with the expression of Th1 and Th2 cytokines, might be involved in the tissue damage caused by the bacillus. Therefore, the objective of this study was to correlate the immunoexpression patterns of NGF and NGF-R in the different clinical forms of leprosy, and to associate the findings with the in situ expression of TGF-beta and clinical classification of the disease. TGF-beta, NGF and NGF-R immunoexpression was analyzed by immunohistochemistry in paraffin-embedded material. Most patients were males with a mean age of 40.7 years. TGF-beta levels were significantly higher in the lepromatous forms. No significant difference in the immunoexpression of NGF or NGF-R was observed between the clinical forms, but expression tended to be higher at the lepromatous pole. There was a significant positive correlation between NGF and NGF-R in the different clinical forms of leprosy. A significant positive correlation was observed between NGF, NGF-R and TGF-beta. It can be concluded that, even existing evidence on the role of these molecules in the clinical spectrum of leprosy. PMID- 25457798 TI - Sortase A: an ideal target for anti-virulence drug development. AB - Sortase A is a membrane enzyme responsible for the anchoring of surface-exposed proteins to the cell wall envelope of Gram-positive bacteria. As a well-studied member of the sortase subfamily catalysing the cell wall anchoring of important virulence factors to the surface of staphylococci, enterococci and streptococci, sortase A plays a critical role in Gram-positive bacterial pathogenesis. It is thus considered a promising target for the development of new anti-infective drugs that aim to interfere with important Gram-positive virulence mechanisms, such as adhesion to host tissues, evasion of host defences, and biofilm formation. The additional properties of sortase A as an enzyme that is not required for Gram-positive bacterial growth or viability and is conveniently located on the cell membrane making it more accessible to inhibitor targeting, constitute additional reasons reinforcing the view that sortase A is an ideal target for anti-virulence drug development. Many inhibitors of sortase A have been identified to date using high-throughput or in silico screening of compound libraries (synthetic or natural), and while many have proved useful tools for probing the action model of the enzyme, several are also promising candidates for the development into potent inhibitors. This review is focused on the most promising sortase A inhibitor compounds that are currently in development as leads towards a new class of anti-infective drugs that are urgently needed to help combat the alarming increase in antimicrobial resistance. PMID- 25457799 TI - Analyzing the quality robustness of chemotherapy plans with respect to model uncertainties. AB - Mathematical models of chemotherapy planning problems contain various biomedical parameters, whose values are difficult to quantify and thus subject to some uncertainty. This uncertainty propagates into the therapy plans computed on these models, which poses the question of robustness to the expected therapy quality. This work introduces a combined approach for analyzing the quality robustness of plans in terms of dosing levels with respect to model uncertainties in chemotherapy planning. It uses concepts from multi-criteria decision making for studying parameters related to the balancing between the different therapy goals, and concepts from sensitivity analysis for the examination of parameters describing the underlying biomedical processes and their interplay. This approach allows for a profound assessment of a therapy plan, how stable its quality is with respect to parametric changes in the used mathematical model. PMID- 25457800 TI - An actinide metallacyclopropene complex: synthesis, structure, reactivity, and computational studies. AB - The synthesis, structure, and reactivity of an actinide metallacyclopropene were comprehensively studied. The reduction of [eta(5)-1,2,4-(Me3C)3C5H2]2ThCl2 (1) with potassium graphite (KC8) in the presence of diphenylacetylene (PhC=CPh) yields the first stable actinide metallacyclopropene [eta(5)-1,2,4 (Me3C)3C5H2]2Th(eta(2)-C2Ph2) (2). The magnetic susceptibility data show that 2 is indeed a diamagnetic Th(IV) complex, and density functional theory (DFT) studies suggest that the 5f orbitals contribute to the bonding of the metallacyclopropene Th-(eta(2)-C?C) moiety. Complex 2 shows no reactivity toward alkynes, but it reacts with a variety of heterounsaturated molecules such as aldehyde, ketone, carbodiimide, nitrile, organic azide, and diazoalkane derivatives. DFT studies complement the experimental observations and provide additional insights. Furthermore, a comparison between Th and group 4 metals reveals that Th(4+) shows unique reactivity patterns. PMID- 25457802 TI - Global health challenges facing bureaucracy: democratization or revolution? PMID- 25457801 TI - Race and health profiles in the United States: an examination of the social gradient through the 2009 CHIS adult survey. AB - OBJECTIVE: To examine the role of the social gradient on multiple health outcomes and behaviors. It was predicted that higher levels of SES, measured by educational attainment and family income, would be associated with positive health behaviors (i.e., smoking, drinking, physical activity, and diet) and health status (i.e., limited physical activity due to chronic condition, blood pressure, obesity, diabetes, BMI, and perceived health condition). The study also examined the differential effects of the social gradient in health among different racial/ethnic groups (i.e., non-Hispanic Whites, Blacks, Asian, Hispanics, and American Indians). STUDY DESIGN: Cross-sectional study. METHODS: The data were from the adult 2009 California Health Interview Survey (CHIS). Weighted multivariable linear and logistic regression models were conducted to examine trends found between SES and health conditions and health behaviors. Polynomial trends were examined for all linear and logistic models to test for the possible effects (linear, quadratic, and cubic) of the social gradient on health behaviors and outcomes stratified by race/ethnicity. RESULTS: Findings indicated that, in general, Whites had more favorable health profiles in comparison to other racial/ethnic groups with the exception of Asians who were likely to be as healthy as or healthier than Whites. Predicted marginals indicated that Asians in the upper two strata of social class display the healthiest outcomes of health status among all other racial/ethnic groups. Also, the social gradient was differentially associated with health outcomes across race/ethnicity groups. While the social gradient was most consistently observed for Whites, education did not have the same protective effect on health among Blacks and American Indians. Also, compared to other minority groups, Hispanics and Asians were more likely to display curvilinear trends of the social gradient: an initial increase from low SES to mid-level SES was associated with worse health outcomes and behaviors; however, continued increase from mid-SES to high SES saw returns to healthy outcomes and behaviors. CONCLUSION: The study contributes to the literature by illustrating unique patterns and trends of the social gradient across various racial/ethnic populations in a nationally representative sample. Future studies should further explore temporal trends to track the impact of the social gradient for different racial and ethnic populations in tandem with indices of national income inequalities. PMID- 25457803 TI - Factors influencing the propensity of nurses to counsel patients for eye donation: a pilot study in a tertiary care hospital in north India. PMID- 25457804 TI - Further research required to determine unique factors associated with dental care access among deprived populations. PMID- 25457809 TI - New insights on the role of sea ice in intercepting atmospheric pollutants using (129)I. AB - Measurements of (129)I carried out on sea ice samples collected in the central Arctic Ocean in 2007 revealed relatively high levels in the range of 100 1400*10(7) at L(-1) that are comparable to levels measured in the surface mixed layer of the ocean at the same time. The (129)I/(127)I ratio in sea ice is much greater than that in the underlying water, indicating that the (129)I inventory in sea ice cannot be supported by direct uptake from seawater or by iodine volatilization from proximal (nearby) oceanic regimes. Instead, it is proposed that most of the (129)I inventory in the sea ice is derived from direct atmospheric transport from European nuclear fuel reprocessing plants at Sellafield and Cap La Hague. This hypothesis is supported by back trajectory simulations indicating that volume elements of air originating in the Sellafield/La Hague regions would have been present at arctic sampling stations coincident with sampling collection. PMID- 25457810 TI - Bioremediation potential of microorganisms derived from petroleum reservoirs. AB - Bacterial strains and metagenomic clones, both obtained from petroleum reservoirs, were evaluated for petroleum degradation abilities either individually or in pools using seawater microcosms for 21 days. Gas Chromatography-Flame Ionization Detector (GC-FID) and Gas Chromatography-Mass Spectrometry (GC-MS) analyses were carried out to evaluate crude oil degradation. The results showed that metagenomic clones 1A and 2B were able to biodegrade n alkanes (C14 to C33) and isoprenoids (phytane and pristane), with rates ranging from 31% to 47%, respectively. The bacteria Dietzia maris CBMAI 705 and Micrococcus sp. CBMAI 636 showed higher rates reaching 99% after 21 days. The metagenomic clone pool biodegraded these compounds at rates ranging from 11% to 45%. Regarding aromatic compound biodegradation, metagenomic clones 2B and 10A were able to biodegrade up to 94% of phenanthrene and methylphenanthrenes (3-MP, 2-MP, 9-MP and 1-MP) with rates ranging from 55% to 70% after 21 days, while the bacteria Dietzia maris CBMAI 705 and Micrococcus sp. CBMAI 636 were able to biodegrade 63% and up to 99% of phenanthrene, respectively, and methylphenanthrenes (3-MP, 2-MP, 9-MP and 1-MP) with rates ranging from 23% to 99% after 21 days. In this work, isolated strains as well as metagenomic clones were capable of degrading several petroleum compounds, revealing an innovative strategy and a great potential for further biotechnological and bioremediation applications. PMID- 25457811 TI - Metal contamination of estuarine intertidal sediments of Moreton Bay, Australia. AB - Trace element concentrations in surface intertidal sediments were analyzed to assess the level of contamination along the western side of Moreton Bay (Australia). The environmental risks posed by metals were evaluated using sediment quality guidelines, the Risk Assessment Code (RAC) and enrichment relative to background levels. Chromium, Ni, and Cu are the main contributors to sediment pollution. Sediments are also enriched in Zn, Cd and Pb by 1.5-3 times the regional background. Zinc, Cd and Co may pose high to very high risk to the aquatic biota due to their potential bioavailability, while Ni, As, Cu, Pb and Cr may pose medium risk at some of the investigated sites. Results emphasize the importance of using different methods for the assessment of sediment pollution at an estuarine site. PMID- 25457812 TI - Trace metal concentrations in Spartina densiflora and associated soil from a Patagonian salt marsh. AB - The objectives of this study were to (i) assess in situ trace metal concentrations in soil and in Spartina densiflora in a Patagonian salt marsh (Rawson, Chubut, Argentina) and (ii) investigate the relationship between trace metal concentrations in soils and in plants to improve our knowledge regarding the ability of S. densiflora to take up and accumulate trace metals from the soil within its native region. Our results indicate that the soil and S. densiflora exhibit low metal concentrations in the Rawson salt marsh. S. densiflora accumulates Zn in below- and above-ground plant structures and Cr in below-ground parts. These results suggest at the time of this study there is scarce human impact associated with metals in the Rawson salt marsh. PMID- 25457813 TI - Metabolic engineering as a tool for enhanced lactic acid production. AB - Metabolic engineering is a powerful biotechnological tool that finds, among others, increased use in constructing microbial strains for higher lactic acid productivity, lower costs and reduced pollution. Engineering the metabolic pathways has concentrated on improving the lactic acid fermentation parameters, enhancing the acid tolerance of production organisms and their abilities to utilize a broad range of substrates, including fermentable biomass-derived sugars. Recent efforts have focused on metabolic engineering of lactic acid bacteria as they produce high yields and have a small genome size that facilitates their genetic manipulation. We summarize here the current trends in metabolic engineering techniques and strategies for manipulating lactic acid producing organisms developed to address and overcome major challenges in the lactic acid production process. PMID- 25457814 TI - Cancer risks among the users of ergot-derived dopamine agonists for Parkinson's disease, a nationwide population-based survey. AB - BACKGROUND: Factors of cancer occurrence among Parkinson disease patients are still not well known, although genetic predilection has been investigated. The aim of this study is to evaluate the medication effect of dopamine agonists of Parkinson disease on incidence of cancers from the Taiwan National Health Insurance Research Database. METHODS: We conducted a population-based nested case control study by using the resources of the Taiwanese National Health Insurance from 1996 to 2000 and analyzed the prevalence of cancer among patients with Parkinson disease. A nested analysis was then implemented among those patients with both Parkinson disease and cancer, focusing separately on the use of ergot- and nonergot-derived-dopamine agonists. RESULTS: We reviewed 6211 patients with Parkinson's disease and found 329 patients with cancer. The ergot-derived dopamine agonists users were associated with an increased odds ratio for cancer, compared with nonergot-derived dopamine agonist users, with an adjusted odds ratio of 2.16 (95% confidence interval, 1.55-2.99). Among all the cancer types, we observed the higher occurrence of liver cancer among the ergot-derived dopamine agonist users. CONCLUSION: The association of ergot-derived-dopamine agonist use and cancers, especially the liver cancers, has provided us the information to further understand the drug-cancer interaction. We hope this result would prompt further investigations on the risk and benefit of the dopamine agonists use among the Parkinson's disease patients. PMID- 25457815 TI - Predictors of the psychosocial impact of being a carer of people living with Parkinson's disease: a systematic review. AB - INTRODUCTION: Caring for a person with Parkinson's disease (PwP) can have a variety of negative consequences that may challenge their ability to continue their caring role. It is still unknown why some individuals adapt better than others in response to such burdens. This review is the first to synthesize and evaluate the evidence on the predictive factors of psychosocial outcomes in PwP carers. METHODS: Studies which identified predictors of psychosocial outcomes for unpaid carers were included. PsychINFO, EMBASE, AMED, BNI and CINAHL databases were searched, supplemented by scanning of references lists of included studies and relevant journals from 2008 onwards. Quality was assessed using the NICE methodology checklist for prognostic studies. RESULTS: Twenty-nine studies were included in the review, providing a low-level of evidence. Carer burden was investigated in 18 studies and mental health and quality of life (QoL) in seven studies each. PwP non-motor symptoms and QoL and carer depression were consistently identified as predictors for at least one psychosocial outcome. Demographics and disease factors were consistently found not to be predictors. Carer involvement and protective factors (e.g. social support, personality) demonstrated promising findings but studies were too few or factors measured inconsistently. CONCLUSION: Confident conclusions could not be drawn regarding the most important predictors that should be targeted in psychosocial interventions due to methodological weaknesses and lack of theoretical testing across the current literature. Future research should build upon psychological theory to gain a better understanding of the mechanisms that explain how carers adapt to caregiving. PMID- 25457816 TI - Peripheral nervous system involvement in Parkinson's disease: evidence and controversies. AB - BACKGROUND: In recent years, non-motor features of Parkinson's disease (PD) have received increasing attention and PD is currently considered a systemic rather than a pure basal ganglia disorder. Among the systemic features, peripheral neuropathy (PN) is a recent acquisition since the first case-control study reporting increased frequency of PN in PD dates back to 2008. METHODS: We reviewed available literature on peripheral nervous system (PNS) involvement in PD. RESULTS: Evidence of alpha-synuclein deposition in the PNS and small nerve fiber deterioration in both drug-naive and treated PD patients is becoming stronger. In addition, several recent reports documented a significant role of levodopa exposure together with group B vitamin deficiency in facilitating the development of PN and case reports suggested that treatment with continuous levodopa intestinal infusion may increase the risk of acute PN compared to both oral levodopa and other dopaminergic treatments. CONCLUSION: It is currently debated whether PN is an intrinsic disease-related feature, a consequence of levodopa treatment or both. In this review, we will discuss the different hypotheses, as well as our perspective on open issues and controversies. PMID- 25457817 TI - PRRT2 truncated mutations lead to nonsense-mediated mRNA decay in Paroxysmal Kinesigenic Dyskinesia. AB - BACKGROUND AND PURPOSE: Paroxysmal Kinesigenic Dyskinesia (PKD) is an episodic involuntary movement disorder characterized by recurrent and brief involuntary movements. Proline-rich transmembrane protein 2 (PRRT2) has been identified as the causative gene for PKD, Benign familial infantile convulsions (BFIC) and Infantile convulsions with choreoathetosis (ICCA). As well, PRRT2 mutations have been detected in patients with PED or PNKD. To date, most of the mutations have been found to be nonsense. METHOD: We used inhibitors of nonsense-mediated mRNA decay (NMD) pathway --emetine dihydrochloride hydrate and cycloheximide and silencing regulator of nonsense transcripts 1(UPF1) with immortalized lymphoblasts to detect whether the truncated mutations lead to NMD, a type of mRNA surveillance in every eukaryotic cell proved so far and that generally degrades mRNA containing premature translation termination codons (PTCs). In addition, we transfected the SH-SY5Y cells with wild-type and mutant PRRT2 plasmids to identify the PRRT2 protein's subcellular localization. RESULTS: We detected, low expression of truncated PRRT2 and was further rescued by applying the inhibitor of NMD pathway, suggesting that NMD plays an important role in the pathogenesis of PKD by haplo-insufficiency. Moreover, for the small portion of undegraded mutant PRRT2 that was translated into truncated proteins, their cellular localization changed from membrane to cytoplasm and nuclear, which might lead to a functional loss. CONCLUSION: We suggest that the NMD of truncated mutation of PRRT2 and altered cellular localization of undegraded of PRRT2, might lead to PKD. PMID- 25457818 TI - Structural MRI correlates of the MMSE and pentagon copying test in Parkinson's disease. AB - BACKGROUND: Cognitive impairment in Parkinson's disease (PD) is common and recent studies have focused on addressing the most suitable screening tool for its assessment. MMSE is commonly used in clinical practice and longitudinal studies found a relationship between the MMSE pentagon copying item and progression to dementia, but its neuroanatomical correlates have been poorly investigated. The aim of this study is to investigate the MRI structural correlates of the global MMSE and the pentagon item scores in PD patients in the absence of dementia. METHODS: We selected a sample of 92 PD patients and 36 controls. MMSE was used as a global measure of cognitive status, and the pentagon copying test as a measure of visuospatial performance. FreeSurfer software was used to assess intergroup differences in cortical thickness (CTh) and global atrophy measures, as well as their relationship with cognitive performance. RESULTS: Compared to controls, patients showed significant differences in measures of global atrophy, which correlated with performance on MMSE and the pentagon item. Regional differences in CTh were seen between PD patients and controls bilaterally in the temporo parietal-occipital region. Patients with impaired performance compared with those of normal performance also showed CTh reductions in these regions. CONCLUSION: Our results suggest MMSE and the pentagon item reflect brain changes which at a regional level involve mainly posterior regions. Correlates of the pentagon item were seen in the same regions where PD patients exhibited significant thinning, and involved more areas and bigger cluster sizes than the correlates of MMSE global scores. PMID- 25457819 TI - Outcomes, management, and potential mechanisms of interleaving deep brain stimulation settings. AB - INTRODUCTION: DBS is a therapeutic option for patients with Parkinson disease (PD), tremor and dystonia. In patients who experience suboptimal clinical results with conventional programming (monopolar, double monopolar or bipolar settings), interleaved pulses can sometimes be used to provide differential therapeutic benefits with the possibility of fewer side effects. Interleaving allows a clinician to define two "programs" that automatically alternate. The goal of this paper is to 1) present clinical scenarios where DBS interleaving was used across two clinics to provide improved symptom control in three patients with suboptimal results from conventional programming; 2) address the potential mechanisms of interleaving; and 3) provide practical tips on the use of interleaving. METHODS: Three patients were formally compared for therapeutic benefit on interleaved and conventional parameter settings. RESULTS: Interleaving is most likely to be useful in two clinical scenarios: 1) different contacts are beneficial for specific symptoms, but each at a different stimulation amplitude; or 2) symptoms are resolved incompletely, and further voltage increase is limited by side effects. The factors underpinning the differences in outcomes with interleaving are unknown but may be highly dependent on specific symptoms and to electrode positioning. Interleaving is a relatively new programming platform and there is no data to demonstrate long-term benefits. CONCLUSIONS: Interleaving is a tool that may augment outcomes, and possibly obviate the need for surgical revisions, although in our experience across two large centers it has been effective for only a small number of patients. PMID- 25457820 TI - Bilateral sagittal split osteotomy versus distraction osteogenesis of the mandible: a randomized clinical trial. AB - A randomized clinical trial was performed to evaluate differences in postoperative neurosensory disturbance (NSD) between two methods of mandibular advancement surgery. A total of 66 non-syndromal class II patients with mandibular hypoplasia were randomized for either distraction osteogenesis (DO) or bilateral sagittal split osteotomy (BSSO). Twenty-nine patients in the BSSO group and 34 patients in the DO group were available for evaluation. Objective assessment was performed by Semmes-Weinstein (SW) monofilament testing preoperatively and at least 1 year after surgery. Six of the 34 patients (17.6%) in the DO group experienced objective NSD, compared to 5/29 patients (17.2%) in the BSSO group. In the evaluation of nerve function by individual nerves, 8/68 nerves (11.8%) revealed objective NSD in the DO group, compared to 7/58 nerves (12.1%) in the BSSO group. A subjective NSD was reported in 11/34 patients (32.4%) in the DO group, compared to 9/29 patients (31.0%) in the BSSO group. In the evaluation of nerve function by individual nerves, a subjective NSD was reported for 13/68 nerves (19.1%) in the DO group, compared to 13/58 nerves (22.4%) in the BSSO group. None of the differences was significant. No differences in neurosensory disturbance could be found between the two study groups. Objective WS monofilament testing appeared to underestimate NSD compared to subjective patient report. PMID- 25457821 TI - Survival rate of osseointegrated implants in atrophic maxillae grafted with calvarial bone: a retrospective study. AB - The aim of this study was to evaluate the clinical survival rate of osseointegrated implants placed in the atrophic maxilla that has been reconstructed by means of autogenous bone grafts harvested from a cranial calvarial site. Further, we sought to analyse the level of peri-implant bone after prosthetic rehabilitation and to determine subjective patient satisfaction with the treatment performed. This study conformed to the STROBE guidelines regarding retrospective studies. Twenty-five patients who had received osseointegrated implants with late loading in the reconstructed atrophic maxilla were included in the study. The survival rate and level of peri-implant bone loss were evaluated. A questionnaire related to the surgical and prosthetic procedures was completed. The observed implant survival rate was 92.35%. The mean bone loss recorded was 1.76mm in the maxilla and 1.54mm in the mandible. The results of the questionnaire indicated a high level of patient satisfaction, little surgical discomfort, and that the patients would recommend the procedure and would undergo the treatment again. From the results obtained, it is concluded that the cranial calvarial site is an excellent donor area; calvarial grafts provided stability and maintenance of bone volume over the course of up to 11 years. PMID- 25457822 TI - QKI-5 suppresses cyclin D1 expression and proliferation of oral squamous cell carcinoma cells via MAPK signalling pathway. AB - Oral squamous cell carcinoma (OSCC) is one of the most frequently occurring malignancies in the world. The RNA-binding protein quaking (QKI) is a newly identified tumour suppressor in multiple cancers, but its role in OSCC is currently unknown. The purpose of the present study was to clarify the relationship between QKI expression and OSCC development. We found QKI-5 expression to be significantly decreased in the oral cancer cell line CAL-27. QKI 5 overexpression also reduced the proliferation of CAL-27 cells, which correlated with cyclin D1. This regulative function of QKI-5 occurs by modulating the phosphorylation level of the mitogen-activated protein kinase (MAPK) pathway. Therefore this study shows that underexpression of tumour suppressor QKI-5 could activate the MAPK pathway and contribute to uncontrolled cyclin D1 expression, thus resulting in increased proliferation of oral cancer cells. PMID- 25457823 TI - The effect of human amniotic fluid on mandibular distraction osteogenesis. AB - The aim of this study was to evaluate the effects of local administration of human amniotic fluid (HAF) on newly formed bone obtained by mandibular distraction osteogenesis (DO) with histomorphometry. A unilateral mandibular osteotomy at the left corpus was performed in 32 adult male rabbits. After a 5 day latency period, the left mandibles were lengthened by mandibular DO over 5 days, at a rate of 1mm/day, via a custom-made distractor. After the distraction, the rabbits were divided randomly into four groups: 0.3 ml HAF was injected into the distraction gap followed by 21 (group 1) or 45 (group 2) days of consolidation; or 0.3 ml normal saline (NS) was administered followed by 21 (group 3) or 45 (group 4) days of consolidation. Mandibles were removed at the end of the consolidation period and investigated histomorphometrically. The newly formed bone area (NFBA) and number of fibroblasts increased significantly in the HAF groups compared to the NS groups (NFBA: group 1 vs. group 3, P<0.05; group 2 vs. group 4, P<0.01; fibroblasts: group 1 vs. group 3, and group 2 vs. group 4, P<0.05), and also in both 45-day consolidation groups compared to the 21-day consolidation groups (NFBA: group 1 vs. group 2, and group 3 vs. group 4, P<0.001; fibroblasts: group 1 vs. group 2, and group 3 vs. group 4, P<0.01). Additionally, the numbers of osteoblasts and capillaries were increased significantly at 45 days of consolidation compared to 21 days in both the HAF and NS groups (osteoblasts: group 1 vs. group 2, P<0.01; group 3 vs. group 4, P<0.05; capillaries: group 1 vs. group 2, and group 3 vs. group 4, P<0.01). Histomorphometric analysis demonstrated that local HAF administration effectively accelerated bone formation. Thus, a HAF injection procedure could improve new bone formation around the bone in maxillofacial operations such as DO. PMID- 25457824 TI - Changes in expression of Slit1 and its receptor Robo2 in trigeminal ganglion and inferior alveolar nerve following inferior alveolar nerve axotomy in adult rats: a pilot study. AB - The objective of this study was to analyze changes in expression pattern of Slit1 and Robo2, and to clarify the relationship between these changes and functional recovery of the axotomized inferior alveolar nerve (IAN) without repair using a rat IAN axotomy model. Slit1 and Robo2 were weakly expressed in samples taken from trigeminal ganglion (TG) and IAN of sham surgery rats. In axotomized rats, expression levels increased significantly from day 2 to day 28 post-axotomy, with peaks on days 14 (Slit1) and 7 (Robo2) after axotomy (relative to sham: Slit1 in TG P<0.0005, Slit1 in IAN P = 0.003, Robo2 in TG P<0.0005, and Robo2 in IAN P<0.0005). Over-expressed Slit1 and Robo2 in both the TG and IANs of axotomized rats did not return to sham levels during the 28-day observation period of this study. The regeneration and functional recovery of axotomized IAN was evaluated by jaw opening reflex (JOR) recorded before and after axotomy. JOR occurrence (0% on day 7, 35% on day 14, and 85% on day 28) increased gradually, and the relative threshold of electrical stimulation eliciting JOR decreased gradually (1000.0 +/- 0.0% on day 7, 854.3 +/- 132.5% on day 14, and 302.6 +/- 92.3% on day 28). On day 28 after axotomy, JOR occurrence and the relative JOR threshold had almost returned to those of sham rats. These findings suggest that Slit1 and Robo2 are involved in the regeneration and functional recovery of the axotomized IAN. PMID- 25457825 TI - Non-infectious myositis of the lateral pterygoid muscle: a report of four cases. AB - Non-infectious myositis is a condition characterized by chronic localized myalgia originating from central nervous system effects. It is also known as centrally mediated myalgia associated with neurogenic inflammation. When this condition occurs in the lateral pterygoid muscle, clinical evaluation is difficult due to its inaccessible anatomic location. In order to diagnose this rare condition, careful clinical examination and advanced imaging are necessary. The authors report herein four cases of non-infectious myositis of the lateral pterygoid muscle diagnosed by magnetic resonance or enhanced computed tomography imaging. The patients reported prolonged parafunctional habits and chronic jaw pain. In each case, clinical signs suggested the diagnosis of anterior disc displacement without reduction, but the progressive history of internal derangement did not fit this diagnosis. Limited lateral excursion was observed, and patients reported pain in the temporomandibular joint (TMJ) area without tenderness to palpation of the TMJ. Advanced imaging, including axial views, provided valuable information for accurate diagnosis and appropriate management. PMID- 25457826 TI - Usefulness of mandibular third molar coronectomy assessed through clinical evaluation over three years of follow-up. AB - The aim of this study was to investigate the 3-year morbidity of coronectomy of the lower third molar and to monitor the behaviour and migration pattern of the retained roots postoperatively. A total of 92 patients (111 teeth) who had undergone a coronectomy between October 2005 and July 2009 were investigated. Patients were followed up at 3 months and 1, 2, and 3 years for clinical evaluation and dental computed tomography imaging of the coronectomy sites. In total, 10 cases (9%) required tooth root extraction within the 3 years after coronectomy. In seven of them, the distal pocket of the lower second molars remained connected to the roots within the first year. Of the cases in whom a pocket did not remain at an early stage, none showed peri-apical lesions on transmission images of the retained roots in the apical area, which usually result from necrosis of the pulp. Root migration increased in the first 2 years after coronectomy but stabilized between the second and third years. In addition, a significant difference was noted in root migration between patients of different ages and sex. Retained roots after coronectomy in the lower third molars led to no complications in terms of infection or the development of pathologies within the first 3 years postoperatively. PMID- 25457827 TI - Surgical versus non-surgical treatment of mandibular condylar fractures: a meta analysis. AB - The aim of the present study was to test whether there is a significant difference in the clinical outcomes between surgical and non-surgical treatment of mandibular condylar fractures. An electronic search was undertaken in February 2014. Eligibility criteria included clinical human studies, either randomized or not. The search strategy resulted in 36 publications. The estimates of an intervention were expressed as the risk ratio (RR) and mean difference (MD) in millimetres. A statistically significant effect was observed for the outcome of post-treatment malocclusion (RR 0.46, P<0.00001), lateral deviation during maximum inter-incisal opening (RR 0.56, P=0.0001, dichotomous; MD -0.75, P=0.002, continuous), protrusion (MD 0.68, P=0.01), and laterotrusion (MD 0.53, P=0.03) favouring surgical treatment, and for infection (RR 3.43, P=0.03) favouring non surgical treatment. There was no statistically significant effect on temporomandibular joint pain (RR 0.81, P=0.46) or noise (RR 1.44, P=0.24), or maximum inter-incisal opening (MD 2.24, P=0.14). The test for overall effect showed that the difference between the procedures significantly affected the incidence of post-treatment complications, favouring surgical treatment, when all dichotomous and continuous outcomes were analysed (RR 0.70, P=0.006 and MD 1.17, P=0.0006, respectively). PMID- 25457828 TI - Diagnostic investigation of parotid neoplasms: a 16-year experience of freehand fine needle aspiration cytology and ultrasound-guided core needle biopsy. AB - This study aimed to examine the diagnostic yield of fine needle aspiration cytology (FNAC) and ultrasound-guided core needle biopsy (USCB) in the diagnosis of parotid neoplasia. A 16-year retrospective analysis was performed of patients entered into our pathology database with a final diagnosis of parotid neoplasia. FNAC and USCB data were compared to surgical excision where available. One hundred and twenty FNAC, 313 USCB, and 259 surgical specimens were analyzed from 397 patients. Fifty-six percent of FNAC and 4% of USCB were non-diagnostic. One hundred and thirty-two (33%) patients had a final diagnosis made by USCB and did not undergo surgery. Surgery was performed in 257 (65%) patients, 226 (88%) of whom had a preoperative biopsy. Most lesions were benign, but there were 62 parotid and 13 haematological malignancies diagnosed; false-negative results were obtained in three FNAC and two USCB samples. The sensitivity and specificity of FNAC were 70% and 89%, respectively, and for USCB were 93% and 100%, respectively. This study represents the largest series of patients with a parotid neoplasm undergoing USCB for diagnosis. USCB is highly accurate with a low non diagnostic rate and should be considered an integral part of parotid assessment. PMID- 25457829 TI - A simple novel prognostic model for early stage oral tongue cancer. AB - The prognostication of patient outcome is one of the greatest challenges in the management of early stage oral tongue squamous cell carcinoma (OTSCC). This study introduces a simple histopathological model for the prognostication of survival in patients with early OTSCC. A total of 311 cases (from Finland and Brazil) with clinically evaluated early stage OTSCC (cT1-T2cN0cM0) were included in this multicentre retrospective study. Tumour budding (B) and depth of invasion (D) were scored on haematoxylin-eosin-stained cancer slides. The cut-off point for tumour budding was set at 5 buds (low <5; high >=5) and for depth of invasion at 4mm (low <4mm; high >=4mm). The scores of B and D were combined into one model: the BD predictive model. On multivariate analysis, a high risk score (BD score 2) correlated significantly with loco-regional recurrence (P=0.033) and death due to OTSCC (P<0.001) in early stage OTSCC. The new BD model is a promising prognostic tool to identify those patients with aggressive cases of early stage OTSCC who might benefit from multimodality treatment. PMID- 25457831 TI - Electrical activity of the orbicularis muscles before and after installation of ocular prostheses. AB - This study examined the electrical activity of the superior (SO) and inferior (IO) orbicularis oculi muscles before and after installing ocular prostheses in patients who had undergone unilateral enucleation. Twelve volunteers requiring prostheses were selected. Their electrical activity was monitored at rest and during normal opening and closing of the eyelids, rapid opening and closing of the eyelids, and squeezing. Data were recorded before and 7, 30, and 60 days after the ocular prosthesis was installed. Two-way analysis of variance was performed to verify whether there were any significant differences between the muscles and periods, and means were compared by Tukey-Kramer honestly significant difference (HSD) tests (P < 0.05). Results from the initial period differed significantly from those after prosthesis installation in all clinical situations. The SO had significantly higher electrical activity levels than the IO in all clinical situations but squeezing. The authors observed the same values during the initial period for the condition of rest (SO 8.42/IO 5.93) and the highest values for the condition of squeezing after 60 days (SO 131.50/IO 117.12). Rehabilitative treatment promoted an increase in the electrical activity of the orbicularis oculi muscles, restoring part of the muscle tone and motor function to muscles of the affected area. PMID- 25457830 TI - Positional cranial deformity--the parents' point of view. AB - The parents' point of view regarding positional cranial deformities and helmet therapy has not been the subject of scientific interest yet. However, carer acceptance is a key factor for therapeutic success. We therefore investigated parental perception. The parents of 218 infants were included in a telephone survey; 122 children had undergone helmet therapy and 96 had not. Satisfaction with the outcome, treatment-associated problems, and parental stress were investigated using a structured questionnaire. The great majority (90.8%) of caregivers were satisfied with the outcome, regardless of whether or not helmet therapy was used. Retrospectively, 76% of the parents of infants who had not undergone helmet therapy would decide against helmet therapy again. Therapy was either temporarily stopped (27.0%) or terminated (4.9%) in 31.9% of infants treated with a helmet. Major problems were sweating (51.1%) and skin lacerations (30.9%). The parents indicated minor (54.9%) or even great (25.4%) personal strain. Conflict with others (38.5%), stress for the child (30.3%), and a financial burden (36.9%) were mentioned most frequently. There appear to be more parental problems than expected associated with helmet therapy. Medical experts should take this into consideration. The indication for a helmet should be evaluated critically and the potential parental burdens should be addressed during counselling. PMID- 25457832 TI - Prognostic impact of perineural invasion and lymphovascular invasion in advanced stage oral squamous cell carcinoma. AB - Perineural invasion (PNI) and lymphovascular invasion (LVI) have been associated with the risk of local recurrences and lymph node metastasis. The aim of this study was to evaluate the prognostic impact of PNI and LVI in patients with advanced stage squamous cell carcinoma of the tongue and floor of the mouth. One hundred and forty-two patients without previous treatment were selected. These patients underwent radical surgery with neck dissection and adjuvant treatment. Clinicopathological data were retrieved from the medical charts, including histopathology and surgery reports. Univariate analysis was performed to assess the impact of studied variables on survival. Overall survival was negatively influenced by six tumour-related factors: increasing T stage (P = 0.003), more than two clinically positive nodes (P = 0.002), extracapsular spread of lymph node metastasis (P < 0.001), tumour thickness (P = 0.04), PNI (P < 0.001), and LVI (P = 0.012). Disease-free survival was influenced by PNI (P = 0.04), extracapsular spread of lymph node metastasis (P = 0.008), and N stage (P = 0.006). Multivariate analysis showed PNI to be an independent predictor for overall survival (P = 0.01) and disease-free survival (P = 0.03). Thus the presence of PNI in oral carcinoma surgical specimens has a significant impact on survival outcomes in patients with advanced stage tumours submitted to radical surgery and adjuvant radiotherapy/radiochemotherapy. PMID- 25457833 TI - Trichophytic brow lift: a modification. AB - Trichophytic brow lifting is a popular method of repositioning the brows/upper lid complex. The procedure has traditionally been described in a subcutaneous plane of dissection. An equally effective, yet safer modification of the trichophytic brow lift, performed in the deeper, subgaleal plane, is described herein. This modification significantly improves the vascularity of the forehead flap. PMID- 25457834 TI - Monckeberg's arteriosclerosis: vascular calcification complicating microvascular surgery. AB - Monckeberg's arteriosclerosis is often an incidental finding, identified either clinically or on plain radiography. It can occasionally be associated with diabetes mellitus or chronic kidney disease. It differs from the more common atherosclerosis in that the tunica intima remains largely unaffected and the diameter of the vessel lumen is preserved. Despite such vessels appearing hard and pulseless throughout their affected length, they deliver relatively normal distal perfusion, indeed there is often a bounding pulse at the end of the calcified zone. They appear unremarkable on magnetic resonance angiography but visibly calcified on plain radiography. Monckeberg's arteriosclerosis has a prevalence of < 1% of the population, but when it does occur it can cause consternation at the prospect of using these vessels for microvascular anastamosis. We report our experience of deliberately using these vessels in an osseocutaneous radial forearm free flap reconstruction. Although there are some technical considerations to bear in mind, we would suggest that unlike vessels affected by atherosclerosis, anastomosis of arteries affected by Monckeberg's arteriosclerosis has little or no impact on free flap survival. PMID- 25457835 TI - An inverse-to-anticipated relationship of Lp-PLA2 activity in diabetes: reflection of underlying autoimmune activation. PMID- 25457836 TI - Improving Acute Kidney Injury (AKI) outcomes through the use of automated electronic alerts. PMID- 25457837 TI - Exclusion criteria for sarcoidosis: A novel approach for an ancient disease? PMID- 25457838 TI - TCR signal quantity and quality in CD4+ T cell differentiation. AB - The adaptive immune system protects its host from a myriad of pathogens. This ability stems from a vast set of lymphocytes, each with a different antigen receptor, a small number of which will bind to antigens derived from a given pathogen. Although the cells within any antigen-specific population appear to be relatively homogenous before antigenic encounter, recent work on T cells indicates that individual cells within the population differentiate in very different ways after exposure to the antigen. We focus here on studies of CD4+ T cells and review evidence indicating that variable differentiation of effector cells from single naive cells is caused by both cell-extrinsic stochastic factors and cell-intrinsic factors related to T cell antigen receptor (TCR) signal quantity and quality. PMID- 25457839 TI - Pregnancy level of estrogen attenuates experimental autoimmune encephalomyelitis in both ovariectomized and pregnant C57BL/6 mice through expansion of Treg and Th2 cells. AB - Pregnancy suppressive effect on autoimmune diseases including Multiple Sclerosis and Rheumatoid Arthritis may result from high levels of sex steroids such as estrogen and estriol. This study was designed to reveal the molecular and cellular mechanisms underlying the effect of estrogen on MS alleviation. Female C57BL/6 mice were immunized with MOG35-55. Clinical scores and other relevant parameters were monitored daily. Brain and spinal cord histology was performed to measure lymphocyte infiltration and central nervous system demyelination. Th1/Th2/Th17 and Treg cell profiles were determined through ELISA, flow cytometry, and real-time PCR. Transcription factor expression levels in the CNS were assessed by real-time PCR and T cell differentiation was explored through flow cytometry examination. Pregnancy and pregnancy level of estrogen alleviated clinical manifestations in EAE induced mice, reduced CNS demyelination and cell infiltration, suppressed spleen T cell proliferation, enhanced production of anti inflammatory cytokines in splenocytes and increased the percentage of Th2 and Treg cells. Furthermore, the results of real-time PCR for transcription factors and related cytokines of Th1/Th2/Th17 and Treg cells in CNS showed reduced expression levels of Th1 and Th17 transcription factors, including T-bet and ROR gammat, and decreased Th1 and Th17 cytokines including IFN-gamma, TNF-alpha, IL 17 and IL-23. These results are the first to indicate that pregnancy and pregnancy level of estrogen ameliorate the EAE condition by favoring Treg and Th2 differentiation through induced expression of Foxp3 and GATA3 in the CNS. Moreover, pregnancy and pregnancy level of estrogen decreased mRNA levels of T bet and ROR-gammat in the CNS. PMID- 25457840 TI - Inhibition of adenosine kinase attenuates inflammation and neurotoxicity in traumatic optic neuropathy. AB - Traumatic optic neuropathy (TON) is associated with apoptosis of retinal ganglion cells. Local productions of reactive oxygen species and inflammatory mediators from activated microglial cells have been hypothesized to underlie apoptotic processes. We previously demonstrated that the anti-inflammatory effect of adenosine, through A2A receptor activation had profound protective influence against retinal injury in traumatic optic neuropathy. This protective effect is limited due to rapid cellular re-uptake of adenosine by equilibrative nucleotside transporter-1 (ENT1) or break down by adenosine kinase (AK), the key enzyme in adenosine clearance pathway. Further, the use of adenosine receptors agonists are limited by systemic side effects. Therefore, we seek to investigate the potential role of amplifying the endogenous ambient level of adenosine by pharmacological inhibition of AK. We tested our hypothesis by comparing TON-induced retinal injury in mice with and without ABT-702 treatment, a selective AK inhibitor (AKI). The retinal-protective effect of ABT-702 was demonstrated by significant reduction of Iba-1, ENT1, TNF-alpha, IL-6, and iNOS/nNOS protein or mRNA expression in TON as revealed by western blot and real time PCR. TON-induced superoxide anion generation and nitrotyrosine expression were reduced in ABT-702 treated mice retinal sections as determined by immunoflourescence. In addition, ABT-702 attenuated p-ERK1/2 and p-P38 activation in LPS induced activated mouse microglia cells. The results of the present investigation suggested that ABT-702 had a protective role against marked TON-induced retinal inflammation and damage by augmenting the endogenous therapeutic effects of site- and event-specific accumulation of extracellular adenosine. PMID- 25457841 TI - The cerebrospinal fluid cytokine signature of multiple sclerosis: a homogenous response that does not conform to the Th1/Th2/Th17 convention. AB - In this cross-sectional study, we wanted to identify key cytokines characteristic of different stages of multiple sclerosis (MS). To this end, cerebrospinal fluid from patients with MS was investigated with a multiplexed fluorescent bead-based immunoassay. In total 43 cytokines were assessed and related to clinical and imaging data. Increased levels of CCL22, CXCL10 and sCD40L characterized relapsing-remitting MS patients with the presence of gadolinium-enhancing lesions; decreased CCL2 and increased CXCL1 and CCL5 were typical of relapsing remitting MS patients irrespectively of the presence of gadolinium-enhancing lesions. These homogenous patterns of cytokine activation do not conform to conventional Th1/Th2/Th17 responses. PMID- 25457843 TI - A challenging cause of chronic diarrhea. PMID- 25457844 TI - New questionnaire for eosinophilic esophagitis: will it measure what we want? PMID- 25457842 TI - Preliminary evidence of a blunted anti-inflammatory response to exhaustive exercise in fibromyalgia. AB - Exercise intolerance, as evidenced by a worsening of pain, fatigue, and stiffness after novel exertion, is a key feature of fibromyalgia (FM). In this pilot study, we investigate whether; insufficient muscle repair processes and impaired anti inflammatory mechanisms result in an exaggerated pro-inflammatory cytokine response to exhaustive exercise, and consequently a worsening of muscle pain, stiffness and fatigue in the days post-exercise. We measured changes in muscle pain and tenderness, fatigue, stiffness, and serum levels of neuroendocrine and inflammatory cytokine markers in 20 women with FM and 16 healthy controls (HCs) before and after exhaustive treadmill exercise. Compared to HCs, FM participants failed to mount the expected anti-inflammatory response to exercise and experienced a worsening of symptoms post-exercise. However, changes in post exertional symptoms were not mediated by post-exertional changes in pro inflammatory cytokine levels. Implications of these findings are discussed. PMID- 25457845 TI - Treating constipation with prucalopride: one size does not fit all. PMID- 25457846 TI - Microbial therapy in liver disease: probiotics probe the microbiome-gut-liver brain axis. PMID- 25457847 TI - Reply. "radiofrequency ablation for Barrett's esophagus with low-grade dysplasia: a hammer looking for a nail,". PMID- 25457848 TI - Macrophage heterogeneity in liver injury: you are now leaving Kupffertown. PMID- 25457849 TI - Reply: To PMID 24481979. PMID- 25457851 TI - Etrolizumab in ulcerative colitis: tightening leukocyte traffic control in the inflamed mucosa. PMID- 25457852 TI - Is antiviral drug-induced hepatitis B surface antigen loss durable? PMID- 25457853 TI - Atomic structure of epitaxial graphene sidewall nanoribbons: flat graphene, miniribbons, and the confinement gap. AB - Graphene nanoribbons grown on sidewall facets of SiC have demonstrated exceptional quantized ballistic transport up to 15 MUm at room temperature. Angular-resolved photoemission spectroscopy (ARPES) has shown that the ribbons have the band structure of charge neutral graphene, while bent regions of the ribbon develop a bandgap. We present scanning tunneling microscopy and transmission electron microscopy of armchair nanoribbons grown on recrystallized sidewall trenches etched in SiC. We show that the nanoribbons consist of a single graphene layer essentially decoupled from the facet surface. The nanoribbons are bordered by 1-2 nm wide bent miniribbons at both the top and bottom edges of the nanoribbons. We establish that nanoscale confinement in the graphene miniribbons is the origin of the local large band gap observed in ARPES. The structural results presented here show how this gap is formed and provide a framework to help understand ballistic transport in sidewall graphene. PMID- 25457854 TI - The inheritance of obesity. AB - Syndromic adiposity appears to have a predisposition to run in families suggesting a hereditary element in its transmission. Purely genetic defects and DNA sequence variants have been directly associated with the development of adiposity; however, these account for a very small proportion of cases. A stronger association has been made between the intrauterine and early childhood nutritional environment of the foetus and young child and the predisposition of childhood and subsequent adulthood obesity. The nutritional environments include both a situation of nutritional deprivation or excess working through the interplay of epigenetic changes, and pancreatic and hypothalamic development. This is further compounded by the nutritional and lifestyle attitudes of the particular at-risk family. Adiposity prevention measures must include reenforced intervention strategies stating with lifestyle education schemes during pregnancy followed through until infancy and early childhood especially in those families/individuals identified as being at a risk of developing significant adiposity. PMID- 25457855 TI - Obesity and stillbirth. AB - Recent years have witnessed a rise in maternal obesity, which is independently associated with an increased risk of stillbirth. The pathophysiology is unclear, but it is likely related to abnormal placental function, and inflammatory, metabolic and hormonal imbalances in the mother. Obesity is associated with conditions such as diabetes, which can also cause stillbirth. In order to reduce the risk of obesity-associated stillbirth, women of reproductive age should be actively encouraged to optimise their pre-pregnancy weight as the safety of weight loss interventions during pregnancy is unproven. Obese and extremely obese women should be treated as high-risk obstetric patients, with increased antenatal surveillance and specialist input. The postnatal period may be a useful time to provide weight management advice to women to prevent interpregnancy weight gain and reduce the risk of stillbirth in subsequent pregnancies. PMID- 25457856 TI - Obesity and the challenges of caesarean delivery: prevention and management of wound complications. AB - Caesarean section in obese patients is associated with an increased risk of surgical wound complications, including haematoma, seroma, abscess and dehiscence. This review focusses on the available strategies to decrease wound complications in this population, and on the clinical management of these situations. Appropriate dose of prophylactic antibiotics, closure of the subcutaneous tissue, and avoidance of subcutaneous drains reduce the incidence of wound complications associated with caesarean section in obese patients. For treatment of superficial wound infection associated with dehiscence, there are data from general surgery patients to suggest that the use of vacuum-assisted devices leads to faster healing and that surgical reclosure is preferable to healing by secondary intention, when there are no signs of ongoing infection. There is a need for stronger evidence regarding the prevention and management of wound complications for caesarean section in obese women. PMID- 25457857 TI - Deep venous thrombosis and pulmonary embolism in obese women. AB - Obesity increases the risk of venous thromboembolism, and pregnancy also increases the risk, particularly around delivery and in the puerperium. Pregnancy complications, which often involve bed rest in hospital, increase the risk still further. This chapter reviews recent studies aimed at quantifying these risks and discusses the mechanisms linking obesity, pregnancy and thromboembolism. It is now apparent that obesity is a proinflammatory condition that creates a prothrombotic milieu, but as yet little is known about how this interacts with pregnancy. Awareness of interacting risk factors has led to guidelines for risk assessment in pregnancy, and implementation of thromboprophylaxis guidelines has been followed by a dramatic fall in deaths from thromboembolism, which was for many years the leading cause of direct maternal deaths in the UK. This chapter summarises the guidelines on the prevention, diagnosis and treatment of thromboembolism in pregnancy and discusses the next steps to further reduce mortality. PMID- 25457858 TI - Screening and management of gestational diabetes. AB - Gestational diabetes (GDM) is a frequent medical condition during pregnancy. It is associated with an increased risk of complications for both the mother and the baby during pregnancy and post partum. The International Association of Diabetes and Pregnancy Study Groups (IADPSG) has proposed a new screening strategy for overt diabetes in pregnancy and screening for GDM. However, there is still a lack of international uniformity in the approach to the screening and diagnosis of GDM. Controversies include universal versus selective screening, the optimal time for screening, appropriate tests and cutoff values, and whether testing should be conducted in one or two steps. This review gives an update on screening for GDM and overt diabetes during pregnancy. We also give an overview on the medical and obstetrical management of GDM. PMID- 25457859 TI - Placental dysfunction in obese women and antenatal surveillance strategies. AB - This review is aimed at discussing placental dysfunction in obesity and its clinical implication in pregnancy as well as an antenatal surveillance strategy for these women. Maternal obesity is associated with adverse perinatal outcome. Obesity is an independent risk factor for fetal hyperinsulinaemia, birthweight and newborn adiposity. Maternal obesity is associated with childhood obesity and obesity in adult life. Obesity induces a low-grade inflammatory response in placenta, which results in short- and long-term programming of obesity in fetal life. Preconception and antenatal counselling on obstetrics risk in pregnancy, on diet and lifestyle in pregnancy and on gestational weight gain is associated with a better outcome. Fetal growth velocity is closely associated with maternal weight and gestational weight gain. Careful monitoring of gestational weight gain and fetal growth, and screening and management of obstetrical complications such as gestational diabetes and pre-eclampsia, improves perinatal outcome. The use of metformin in non-diabetic obese women is under investigation; further evidence is required before recommending it. PMID- 25457860 TI - Obesity and the challenges of ultrasound fetal abnormality diagnosis. AB - Prenatal ultrasound has become an essential clinical tool for aneuploidy screening, detection of fetal congenital anomalies, and assessment of fetal growth and well-being. Maternal obesity, an increasing global problem, has been shown to decrease the accuracy of ultrasound examination in high-risk pregnancy. The purpose of this review is to provide an evidenced-based perspective on the challenges of performing fetal ultrasound in obese women and to provide a practical guide on how to care for these patients in the ultrasound suite. PMID- 25457861 TI - Reducing morbidity and mortality among pregnant obese. AB - Obesity is increasing; in the UK, almost 20% of pregnant women have a body mass index (BMI) of >=30 kg/m(2). Obese mothers have increased risks of pregnancy complications including miscarriage, congenital anomaly, gestational diabetes, pre-eclampsia, macrosomia, induction of labour, caesarean section, anaesthetic and surgical complications, post-partum haemorrhage, infection and venous thromboembolism. Complications tend to be greater in those with the highest BMIs. In recent triennia, obesity (27-29%) was over-represented in maternal mortality figures. Strategies to reduce morbidity and mortality include calculating BMI at booking visit to identify obese mothers and plan their antenatal care and delivery. This should include nutritional and lifestyle advice, screening for gestational diabetes and pre-eclampsia, thromboembolism risk assessment, antenatal anaesthetic review if BMI is >= 40 kg/m(2), ensuring availability of robust theatre tables and other equipment and involving senior doctors, especially in the labour ward. Afterwards, continuing weight reduction should be encouraged to reduce future pregnancy and health risks. PMID- 25457862 TI - Measurement of aeroallergens from furnace filters. AB - BACKGROUND: Exposure assessment is an important component of allergic disease diagnosis and management. Analysis for allergen content in vacuumed dust has been used traditionally. OBJECTIVE: To study allergen levels of dust taken from high efficiency furnace filters in Midwestern homes. METHODS: Furnace filters used were FQT12 1-inch disposable filters with high-efficiency media placed in homes enrolled in the Kansas City Safe and Healthy Homes Project. Dust was removed from the filters by vacuuming. Fungal culture was used to obtain counts of viable spores. Aeroallergens Fel d1, Can f1, Mus m1, Der f1, Der p1, and Bla g2 and antigenic material from Alternaria, Aspergillus, Cladosporium, and Penicillium species were measured using commercially available immunoassay materials. RESULTS: Sixty filters were recovered from 56 homes after an average 135 days in situ. Mean weight of dust recovered was 2.43 g and correlated well with the time the filter was in place. Viable spore counts ranged to 4.8 * 10(7) per gram of dust. Mean fungal antigenic material ranged to 42 MUg per gram for Cladosporium species. Mean aeroallergen material ranged to 7 MUg per gram for Fel d1. Aeroallergen measurements were above the level of detection in 100% of houses for Fel d1 and 89% of houses for Bla g2. Levels of Fel d1 and Can f1 were strongly positively correlated. CONCLUSION: Allergens from 5 common aeroallergen species and antigenic material from 4 common fungal taxa can be measured in dust taken from high-efficiency furnace filters. PMID- 25457863 TI - Misuse of medical devices: a persistent problem in self-management of asthma and allergic disease. PMID- 25457864 TI - Benefits of hydroxychloroquine in the treatment of a patient with angioedema due to acquired C1 inhibitor deficiency. PMID- 25457865 TI - Uncertainty and the ethics of allergy care. PMID- 25457866 TI - Longitudinal trends in asthma health care use in Southern Nevada. PMID- 25457867 TI - Anaphylaxis due to topical pramoxine. PMID- 25457868 TI - Grazax sublingual immunotherapy in pre-co-seasonal and continuous treatment regimens: is there a difference in clinical efficacy? PMID- 25457869 TI - Diagnostic challenge in a patient with severe pruritic rash. PMID- 25457870 TI - [Cardiovascular risk factors and metabolic syndrome in the young adult population]. PMID- 25457871 TI - Comparison between three-dimensional and standard miniplates in the management of mandibular angle fractures: a prospective, randomized, double-blind, controlled clinical study. AB - The aim of this study was to compare the clinical and radiological outcomes of mandibular angle fractures (MAFs) managed with three-dimensional (3D) miniplates and standard miniplates (according to Champy's principles). A prospective, randomized, controlled clinical study was carried out on 20 patients with MAFs, divided into two groups. Group A patients were treated with a single 1-mm 3D titanium miniplate; group B patients were treated with a single 2.0-mm standard titanium miniplate. Patients were followed for 6 months for infection, wound dehiscence, segmental mobility, malocclusion, mouth opening, hardware failure, hardware palpability, paraesthesia, and malunion/non-union. A densitometry analysis was performed using DIGORA software on digital panoramic radiographs to evaluate bone healing. Six complications occurred, representing a total rate of 30%. Three complications occurred in group A and three in group B, with identical complication rates of 30%. No major difference in terms of the radiographic assessment was observed between the two systems. The 3D curved strut plate is an effective treatment modality for the management of MAFs, with a complication rate comparable to that found with the standard miniplate. This trial is registered at ClinicalTrials.gov, number NCT01939015. PMID- 25457874 TI - beta-Caryophyllene, a natural sesquiterpene, modulates carbohydrate metabolism in streptozotocin-induced diabetic rats. AB - The study was designed to evaluate the antihyperglycemic effects of beta caryophyllene (BCP), a natural sesquiterpene from spices on streptozotocin (STZ) induced diabetic rats. Diabetes mellitus was induced by a single intraperitoneal injection of STZ (40 mg/kg b.w.) in adult male Wistar rats. Diabetic rats exhibited an increase in glucose and HbA1c with a significant fall in insulin and hemoglobin levels. Aberrations in carbohydrate metabolic enzymes were noticed in liver, kidney and skeletal muscle of diabetic rats. A fall in liver and skeletal muscle glycogen with alterations in glycogen synthase and phosphorylase activities was also observed. Oral administration of BCP in dose dependent manner and glibenclamide (600 MUg/kg b.w.), a standard oral hypoglycemic drug to diabetic rats for 45 days significantly decreased glucose with increased plasma insulin levels and ameliorated the altered activities of carbohydrate metabolic enzymes to near normal. The insulinotropic effect of BCP was supported by immunohistochemical studies. BCP at a dose of 200mg/kg b.w. exerted significant antidiabetic effects than other two doses (100 and 400mg/kg b.w.). We conclude that administration of BCP has beneficial effects in glucose homeostasis in diabetic rats. PMID- 25457875 TI - Racial and ethnic minority nurses' job satisfaction in the U.S. AB - BACKGROUND: Understanding minority nurses' job satisfaction is a critical first step to inform strategies designed to retain minority nurses and improve institutional climate to ensure sustained diversity. Yet, empirical evidence is limited in this regard, especially comparisons across racial and ethnic groups in a national sample in the U.S. OBJECTIVES: To determine minority nurses' job satisfaction across racial and ethnic groups relative to White nurses using a national representative sample. METHODS: A retrospective cross-sectional analysis was conducted using the 2008 National Sample Survey of Registered Nurses. The sample includes registered nurses who were primarily employed in nursing in the U.S. Job satisfaction was measured by a single survey item. Racial and ethnic minority status was defined as self-identified membership in a group other than White non-Hispanic, including Hispanic and non-Hispanic Black, Asian, Native Hawaiian/Pacific Islander, American Indian/Alaska Native, and Multiracial. Multinomial logistic regression was performed to compare job satisfaction across racial and ethnic groups while adjusting for individual and job-related characteristics. RESULTS: The majority of nurses were satisfied with their job. The nurse group that had the highest proportion of being satisfied with their job was Native Hawaiian/Pacific Islander (88.8%), followed by White (81.6%), Asian (81%), Hispanic (78.9%), Black (76%), Multiracial (75.7%), and American Indian/Alaska Native (74.3%). Adjusting for individual and job-related characteristics, evidence indicated the potential for lower job satisfaction among Black, American Indian/Alaska Native, and Multiracial nurses compared to White nurses. Asian nurses reported the highest levels of neutral (versus dissatisfaction) compared to White nurses. There was no evidence indicating a clear difference in job satisfaction between Hispanic, Native Hawaiian/Pacific Islander, and White nurses. CONCLUSIONS: Moderate differences in job satisfaction were observed across racial and ethnic groups. More research is needed to understand factors underlying these differences, so that nursing and hospital administrators can develop effective strategies to improve job satisfaction and retain minority nurses. PMID- 25457876 TI - On self-compassion and self-care in nursing: selfish or essential for compassionate care? PMID- 25457877 TI - Contrasting stories of life-threatening illness: a narrative inquiry. AB - BACKGROUND: Advances in science and technology have resulted in longer lives for people with life-threatening illnesses. However, little research compares the stories of people with different life-threatening illnesses. OBJECTIVES: The objectives of this study were to explore and contrast how people story and re story life-threatening illness specifically cancer, chronic kidney disease (CKD) and HIV. DESIGN: Narrative inquiry within a social constructionist perspective was used. METHODS: A total of 113 in-depth interviews were conducted with 32 participants over a period of three years. PARTICIPANTS: Study participants included 32 people: 10 with cancer, 14 with CKD and 8 with HIV/AIDS. Participants varied in age (37-83 years old, mean=61.2 years), gender (17 men and 14 women), location (urban and rural), time post-diagnosis (median=8 years), intensity or invasiveness of treatment, and prognosis (continuous treatment, remission, cure, palliative). RESULTS: Participants described living with a life-threatening illness as a delicate balance. They focused on living their lives yet were fully and acutely aware of their own mortality. There was an undercurrent of sustained uncertainty that permeated their lives. Stories of life-threatening illness differed across the three illness groups and shifted over time as disease trajectories changed. Each disease brought specific challenges. With cancer, turning points and uncertainty were prominent. With CKD, a stealthy beginning to life-extending treatment through dialysis or transplant was evident, and with HIV, a shift from a perceived death sentence to a focus on hope and living was notable. CONCLUSIONS: Findings revealed that trajectories of illness for participants living with cancer, CKD and HIV are complex and differ markedly across the groups. Narratives shifted across all of the illness groups as participants navigated and re-storied the terrains of their life-threatening illness. Findings illuminated the need for health care providers to focus on person specific and contextualized aspects of the illness experience. PMID- 25457878 TI - The equine immune responses to infectious and allergic disease: a model for humans? AB - The modern horse, Equus caballus has historically made important contributions to the field of immunology, dating back to Emil von Behring's description of curative antibodies in equine serum over a century ago. While the horse continues to play an important role in human serotherapy, the mouse has replaced the horse as the predominant experimental animal in immunology research. Nevertheless, continuing efforts have led to an improved understanding of the equine immune response in a variety of infectious and non-infectious diseases. Based on this information, we can begin to identify specific situations where the horse may provide a unique immunological model for certain human diseases. PMID- 25457879 TI - MicroRNAs are implicated in the suppression of CD4+CD25- conventional T cell proliferation by CD4+CD25+ regulatory T cells. AB - CD4+CD25+ regulatory T cells (Tregs) are critical for sustaining immunological homeostasis. CD4+CD25- conventional T cells (Tcons) are the progenitors of populations including Th1, Th2, Th17, Tfh, and Treg cells. Suppression of Tcons proliferation by Tregs requires cell-cell contact and/or is mediated by immunosuppressive soluble factors. However, upon receiving suppressive signals from Tregs, the exact molecular responses in Tcons remain elusive. Here, by using microRNA (miRNA) microarray preliminary screening and quantitative RT-PCR (qRT PCR) validation, we showed that paralleled with the suppression of the Tcons proliferation, miR-146a was induced but miR-106b and miR-21 were reduced in Tcons upon receiving suppressive signals from Tregs. Moreover, our results showed that either increase of miR-146a or decrease of miR-106b and miR-21 by using miRNA mimics or inhibitors in Tcons significantly enhanced the suppression triggered by Tregs. However, decrease of miR-146a or increase of miR-106b and miR-21 in Tcons impaired the suppression triggered by Tregs. Collectively, our findings demonstrate the roles of miR-146a, miR-106b and miR-21 in Tcons in regulating Treg-triggered immune-suppression. PMID- 25457880 TI - The tag SNP rs10746463 in decay-accelerating factor is associated with the susceptibility to gastric cancer. AB - BACKGROUND: Complement activation involved in the innate immunity and adaptive immunity and further contributed to the development of tumor growth. This study aimed to investigate the association of genetic variants in complement 3 (C3) and decay-accelerating factor (DAF) genes with the risk of gastric cancer. METHODS: This case-control study included 500 gastric cancer patients and 500 cancer-free controls. Based on the Chinese population data from HapMap database, we used Haploview 4.2 program to select candidate tag SNPs. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression to evaluate the association of each genetic variant with the risk of gastric cancer. RESULTS: Among 12 tag SNPs of C3, no correlation was observed between C3 genetic variants and risk of gastric cancer. For tag SNPS of DAF, logistic regression analysis revealed that the carriers with DAF rs10746463 AA genotype had a significantly increased risk for developing gastric cancer (OR = 1.46, 95% CI = 1.01-2.10) when compared with GG genotype, but those carrying with rs10746463 AG genotype didn't (OR = 1.31, 95% CI = 0.98-1.75). When stratified by smoking status, we found that the risk of gastric cancer was associated with rs10746463 GA or AA genotype carriers among smoker with OR (95% CI) of 1.64 (1.06-2.54), but not among non smoker (OR = 1.37, 95% CI = 0.97-1.94). CONCLUSION: DAF rs10746463 polymorphism effects on the risk of developing gastric cancer in Chinese population. PMID- 25457883 TI - "Over my dead body": the future of oral (and maxillofacial) surgery. PMID- 25457882 TI - Porphyromonas gingivalis HSP60 peptides have distinct roles in the development of atherosclerosis. AB - Different epitope peptides of bacterial heat shock proteins may function as effector or regulatory molecules in autoimmune responses in infection-triggered atherosclerosis. We investigated the mechanisms for the distinct roles of two epitope peptides from Porphyromonas gingivalis heat shock protein 60 (HSP60) in atherogenesis with regard to peptide-specific T cell polarization relevant to (1) phenotype and cytokine profiles, (2) expression of transcription factors, and (3) role of antigen presenting dendritic cell subsets.Apolipoprotein E-knockout (ApoE KO) mice were immunized with peptide 14 or peptide 19 from P. gingivalis HSP60 prior to induction of atherosclerosis by infection with P. gingivalis plus a Western diet. Significant reductions in plaque/lipid droplet area and plasma cholesterol levels were observed in mice immunized with peptide 14, whereas the opposite phenomenon was evident in mice immunized with peptide 19. CD4+ T-cells polarized to the regulatory T-cell type in peptide 14-immunized group, whereas they polarized to the Th1 cells in peptide 19-immunized group; this observation was supported by the cytokine profiles characteristic to each T-cell phenotype.Significantly higher expression of Nr4a1 and Nr4a2 mRNA, transcriptional factors for regulatory T-cell type, were observed in peptide 14 immunized group. In contrast, the expression level of IFN-gamma and T-bet mRNA, signaling molecules for Th1 cells, was higher in peptide 19-immunized group than in PBS-immunized group.In non-immunized wild mice, BMDC-derived CD11c+ dendritic cells have shown to stimulate Tregs significantly in antigen-nonspecific manner. However, each peptide antigen demonstrated a unique mode of preferential adoption of dendritic cell subsets.In conclusion, peptide 14 or peptide 19 from P. gingivalis HSP60, respectively, may play either an anti- or pro-atherogenic role in the ApoE KO mouse model of infection-triggered atherosclerosis through distinct mechanisms operating in the polarization of T cells. PMID- 25457881 TI - A new mouse anti-mouse complement receptor type 2 and 1 (CR2/CR1) monoclonal antibody as a tool to study receptor involvement in chronic models of immune responses and disease. AB - Although reagents are available to block mouse complement receptor type 2 and/or type 1 (CR2/CR1, CD21/CD35) function in acute or short term models of human disease, a mouse anti-rat antibody response limits their use in chronic models. We have addressed this problem by generating in Cr2-/- mice a mouse monoclonal antibody (mAb 4B2) to mouse CR2/CR1. The binding of murine mAb 4B2 to CR2/CR1 directly blocked C3dg (C3d) ligand binding. In vivo injection of mAb 4B2 induced substantial down regulation of CR2 and CR1 from the B cell surface, an effect that lasted six weeks after a single injection of 2 mg of mAb. The 4B2 mAb was studied in vivo for the capability to affect immunological responses to model antigens. Pre-injection of mAb 4B2 before immunization of C57BL/6 mice reduced the IgG1 antibody response to the T-dependent antigen sheep red blood cells (SRBC) to a level comparable to that found in Cr2-/- mice. We also used the collagen-induced arthritis (CIA) model, a CR2/CR1-dependent autoimmune disease model, and found that mice pre-injected with mAb 4B2 demonstrated substantially reduced levels of pathogenic IgG2a antibodies to both the bovine type II collagen (CII) used to induce arthritis and to endogenous mouse CII. Consistent with this result, mice pre-injected with mAb 4B2 demonstrated only very mild arthritis. This reduction in disease, together with published data in CII-immunized Cr2-/- mice, confirm both that the arthritis development depends on CR2/CR1 receptors and that mAb 4B2 can be used to induce biologically relevant receptor blockade. Thus mAb 4B2 is an excellent candidate for use in chronic murine models to determine how receptor blockage at different points modifies disease activity and autoantibody responses. PMID- 25457884 TI - Risk factors for and consequences of inadequate surgical margins in oral squamous cell carcinoma. AB - OBJECTIVE: The purpose of this study was to examine which factors are associated with inadequate surgical margins and to assess the postoperative consequences. STUDY DESIGN: A retrospective cohort of 110 patients with oral squamous cell carcinoma treated with surgery during a 2-year period was examined. Clinical, histopathologic, and operative variables were related to the surgical margin status. Furthermore postoperative treatment data were compared with margin status. RESULTS: Univariate statistically significant associations were found between the tumor site in the floor of mouth, more advanced T-stage, increasing tumor thickness, and inadequate margins. Of the patients with involved margins, 87% were treated with postoperative radiotherapy or re-resection, but among patients with close margins, only 35% received either radiotherapy or re resection. CONCLUSIONS: Clinical and histopathologic factors were associated with the inadequate margin. Postoperative treatment for patients with close margins is controversial, and more studies are needed to define clear guidelines. PMID- 25457885 TI - Local delivery of imiquimod in hamsters using mucoadhesive films and their residence time in human patients. AB - OBJECTIVE: To investigate the ability of mucoadhesive films to locally deliver an immune response modifier (imiquimod) to oral mucosa. STUDY DESIGN: After determining the residence time of films in hamster cheek pouches, drug-loaded films and commercially available imiquimod cream were tested for localization of drug in mucosal tissue. The residence time of drug-free films at different locations was also tested in humans. RESULTS: Mucoadhesive films delivered imiquimod to the buccal mucosa with no measureable amounts in blood. In contrast, although the cream formulation resulted in higher tissue levels, it also led to significant systemic distribution of imiquimod. In humans, the films resided on tissue for up to 4 hours, increasing in the order of tongue < cheek < gingiva. CONCLUSION: Preclinical findings of localized imiquimod delivery in animals and residence in humans support future investigations of the mucoadhesive system in controlled clinical trials for treating oral precancerous lesions. PMID- 25457887 TI - p16(INK4) expression is not associated with human papillomavirus in oral lichen planus. AB - OBJECTIVE: Frequencies as high as 60% of overexpressed p16(INK4) were recently reported in lichen planus (LP). Because p16(INK4) overexpression may be a feature of human papilloma virus (HPV)-induced cancer, it has been postulated that LP may be somehow related to HPV. The present study is the first to evaluate both high p16(INK4) expression and HPV in patients with LP. STUDY DESIGN: Thirty-five consecutive biopsy specimens from patients with LP constituted the basis of the present study. Level of p16(INK4A) expression was evaluated in each sample by immunohistochemical analysis, and the presence of HPV DNA was tested by real-time polymerase chain reaction (PCR). RESULTS: p16(INK4) expression was detected in 26 specimens, whereas HPV was found in 4 lesions: 3 low-risk HPV and 1 high-risk HPV. All HPV-positive lesions also indicated p16(INK4A) overexpression, whereas 22 cases of overexpressed p16(INK4A) were HPV negative (Chi square 2.6; ns). CONCLUSIONS: p16(INK4) overexpression is not correlated with HPV in patients with LP. PMID- 25457886 TI - Chemoprevention of oral cancer by topical application of black raspberries on high at-risk mucosa. AB - OBJECTIVE: To evaluate the preclinical efficacy of topical administration of freeze-dried black raspberries (BRBs) to inhibit the progression of premalignant oral lesions and modulate biomarkers of cancer development in high at-risk mucosa (HARM). STUDY DESIGN: Hamster cheek pouches (HCPs) were treated with carcinogen for 6 weeks to initiate a HARM microenvironment. Subsequently, right HCPs were topically administered a BRB suspension in short-term or long-term studies. After 12 weeks, squamous cell carcinoma (SCC) multiplicity, SCC incidence, and cell proliferation rates were evaluated. mRNA expression was measured in short-term treated pouches for selected oral cancer biomarkers. RESULTS: SCC multiplicity ( 41.3%), tumor incidence (-37.1%), and proliferation rate (-6.9%) were reduced in HCPs receiving BRBs. Topical BRBs correlated with an increase in RB1 expression in developing oral lesions. CONCLUSIONS: Topical BRBs inhibit SCC development when targeted to HARM tissues. These results support the translational role of BRBs to prevent oral cancer development in humans. PMID- 25457888 TI - Small cell carcinoma in the parotid harboring Merkel cell polyomavirus. AB - OBJECTIVE: This study aimed to document three new cases of primary small cell carcinoma (SmCC) of the parotid and examine immunohistochemical and quantitative real-time polymerase chain reaction (qPCR) data of the recently developed Merkel cell polyomavirus (MCPyV) within these tumors. STUDY DESIGN: Immunohistochemistry for neuroendocrine markers (chromogranin A, CD56, CD57, neuron-specific enolase [NSE], thyroid transcription factor 1 [TTF-1]), epithelial markers (CK20, CK7, CAM 5.2), and MCPyV large T antigen (LTAg) were examined. qPCR and Sanger sequencing were performed to confirm the presence of the MCPyV LTAg gene. RESULTS: Two males and one female, average age 76 years, presented with left parotid masses. Clinical examinations, histories, and imaging studies were negative for cutaneous Merkel cell carcinoma (MCC), pulmonary and extrapulmonary SmCC, or any other malignancy. Immunohistochemical analysis demonstrated positive immunoreactivity for CK20 in a perinuclear dotlike pattern (3/3), CAM 5.2 (3/3), (2/3), NSE (3/3), CD56 (2/3), and CD57 (3/3). Two cases stained positive for MCPyV, showing moderate to strong, diffuse positivity, confirmed with qPCR. PCR Sanger sequencing of LTAg exon 2 showed greater than 97% similarity to the MCPyV reference genome in both cases. CONCLUSION: Our findings expand the number of reported cases classified as primary parotid SmCC that harbors MCPyV and underscore the similarity between cutaneous MCC and parotid SmCC. Further investigation is needed to determine whether immune-based therapeutic strategies targeting MCPyV in MCC are also effective in the setting of parotid SmCC harboring MCPyV. PMID- 25457889 TI - Keratosis of unknown significance and leukoplakia: a preliminary study. AB - OBJECTIVE: The objectives were to (1) determine the frequency of specific diagnoses in a series of white lesions, and (2) describe the nature of keratotic lesions that are neither reactive nor dysplastic. STUDY DESIGN: White lesions were analyzed and diagnosed as reactive keratoses, dysplastic/malignant, or keratoses of unknown significance (KUS). RESULTS: Of the 1251 specimens that were evaluated, 703 met criteria for inclusion, and approximately 75% were reactive, 10% dysplastic/malignant, and 14% KUS. Excluding reactive keratoses, 43% were dysplastic/malignant and 57% were KUS. CONCLUSIONS: Reactive keratoses were the most common white lesions followed by lichen planus. Dysplastic/malignant lesions constituted almost 50% of all true leukoplakias. KUS constituted the remaining cases and do not show typical reactive histopathology as well as clear dysplasia. They may represent evolving or devolving reactive keratoses but may also represent the very earliest dysplasia phenotype. Clinical findings may be helpful in differentiating the two. PMID- 25457890 TI - Soft tissue image reconstruction using cone-beam computed tomography combined with laser scanning: a novel method to evaluate the masticatory mucosa. AB - OBJECTIVE: To construct a 3-D model of the masticatory mucosa to measure the thickness of the facial/lingual gingiva and palatal mucosa. STUDY DESIGN: Maxillofacial regions of 8 volunteers were scanned using cone-beam computed tomography to generate 3-D maxillary and mandibular models. Digital models were obtained by laser scanning of the impressions. Models were constructed using global data registration and Boolean subtraction. Accuracy was assessed by comparison against control patients with a periodontal pack around their gingival boundaries. Inter- and intra-observer variability were determined. RESULTS: Masticatory mucosa models (in stereolithography format) showed the gingival and mucosal contours. The gingival thickness of the 3-D models and controls were not significantly different (P > .05). The interclass correlation coefficient and Kappa values indicated good intra-observer and inter-observer agreement, respectively. CONCLUSIONS: Cone-beam computed tomography combined with laser scanning can be reliable for visualizing and measuring the thickness of the masticatory mucosa. PMID- 25457891 TI - Psammomatoid and trabecular juvenile ossifying fibroma: two distinct radiologic entities. AB - OBJECTIVE: Evaluate and compare the radiologic features of psammomatoid versus trabecular variants of juvenile ossifying fibromas. STUDY DESIGN: Twelve of fifteen cases of juvenile ossifying fibroma of the craniofacial bones, retrieved from our pathology archives for the period between 2002 and 2013, had available preoperative computed tomography (CT) scans. The radiologic features of each case were analyzed and compared by two neuroradiologists and one oral and maxillofacial radiologist, each blinded to the histopathologic diagnosis. RESULTS: Juvenile psammomatoid ossifying fibroma (JPOF) exhibited a ground-glass pattern, as an outer mantle with central radiolucency, a single mural nodule, or a solid homogeneous mass. The trabecular variant presented as a radiolucent lesion with irregular, scattered calcifications. Both variants displayed a well defined border. CONCLUSION: This study demonstrates that psammomatoid and trabecular juvenile ossifying fibromas exhibit unique radiologic features that allow for distinction between the two variants on CT studies. PMID- 25457892 TI - The correlation of carotid artery calcification on panoramic radiographs and determination of carotid artery atherosclerosis with ultrasonography. AB - OBJECTIVES: To investigate the association of carotid artery calcification (CAC) on panoramic radiographs and determine carotid artery atherosclerosis with ultrasonography. STUDY DESIGN: The study included 4050 subjects aged 50 years and older. Panoramic radiographs for the presence of CAC were interpreted. Common carotid artery intima-media thickness (CCA-IMT), carotid bulb IMT (CB-IMT), carotid plaques, and the diameter of the common carotid artery (CCA-diameter) were measured by using ultrasonography. RESULTS: CB-IMT was significantly greater in male subjects with CAC than in those without CAC. CCA-diameter was significantly greater in subjects with CAC than in those without CAC in both genders. However, there was no significant difference in CCA-IMT. CAC was associated with carotid plaque (for men, odds ratio [OR] 2.14; 95% confidence interval [CI] 1.01-3.36; for women, OR 1.19; 95% CI 0.84-1.67). CONCLUSION: CAC on panoramic radiographs was positively associated with IMT and plaque in men and positively associated with carotid diameter in both sexes. CAC on panoramic radiographs was positively associated with carotid atherosclerosis. PMID- 25457893 TI - Atypical temporomandibular joint pain: a case report. AB - Atypical temporomandibular joint (TMJ) pain can consist of an unusual intensity, location or set of pain descriptors that do not match what is traditionally observed for TMJ capsular pain, disc displacements or arthritic conditions. Presented in this case report is an atypical pain report regarding a unilateral TMJ pain as the chief complaint. An overview of typical vs atypical TMJ pain is also reviewed to highlight unusual signs and symptoms so that the clinician can identify these atypical presentations and pursue further diagnostic approaches. PMID- 25457894 TI - Oral ulcerations as a sequela of tacrolimus and mycophenolate mofetil therapy. AB - Medication-induced ulcerative stomatitis can be a complication of immunosuppressive therapy in a post-transplant patient. A 54-year-old African American female patient presented with significant, recalcitrant oral ulcers 5 months after renal transplant as a result of mucosal toxicity and severe leucopenia caused by her immunosuppressive maintenance regimen of tacrolimus (US Pharmacopeia, Rockville, MD) and mycophenolate mofetil (Santa Cruz Biotechnology, Santa Cruz, CA). The patient was also prescribed fluconazole as an antifungal, which likely contributed to the patient's increase in tacrolimus blood levels. Altering the medication dosages ultimately reduced blood tacrolimus levels, allowing for resolution of her oral ulcers. This report indicates that medication induced oral ulcerations are a potential sequela of post-transplant immunosuppressive therapy. PMID- 25457895 TI - Clinical importance of incidental findings reported on small-volume dental cone beam computed tomography scans focused on impacted maxillary canine teeth. AB - OBJECTIVE: To investigate the clinical importance of incidental findings reported for small-volume cone beam computed tomography (CBCT) scans of impacted maxillary canine teeth. STUDY DESIGN: Radiology reports of CBCT examinations performed as part of diagnosis and treatment planning for impacted or ectopically erupting maxillary canine teeth for 183 consecutive patients were assessed retrospectively. The scans were obtained with a small-volume unit (3 D Accuitomo 80) with a field of view that was either 40 * 40 or 60 * 60 mm. The findings were graded according to their clinical importance as low, intermediate, or high. RESULTS: Three hundred and forty incidental findings were reported. One of the incidental findings was of high importance (0.3%), 97 were of intermediate importance (28.5%), and 242 were of low importance or anatomic variant (71.1%). CONCLUSIONS: Incidental findings reported on small-dimension CBCT scans of impacted maxillary canine teeth rarely require immediate attention; nonetheless, 28.8% would require follow-up. PMID- 25457896 TI - Cone beam computed tomography imaging of ponticulus posticus: prevalence, characteristics, and a review of the literature. AB - OBJECTIVE: The aim of this study was to investigate the frequency of ponticulus posticus (PP) using cone beam computed tomography (CBCT) and to describe the radiologic characteristics of the detected cases. STUDY DESIGN: The presence and types of PP were investigated on 730 CBCT images. RESULTS: PP was found in 17.4% (127) of the 730 CBCT scans. Of these 127 patients, 79 (10.8%) had bilateral PP and 48 (6.6%) had unilateral PP. Male predominance was found with a prevalence of 19.5% (54 of 277) and female prevalence was 16.1% (73 of 453). The prevalence of PP increased with age; the highest prevalence of PP was seen in those who were 49 to 81 years of age. CONCLUSIONS: This study shows that PP is not an uncommon anatomic variation and is a natural incidental finding on CBCT. PMID- 25457903 TI - Improving air quality starts at home. PMID- 25457902 TI - Effect of macitentan on hospitalizations: results from the SERAPHIN trial. AB - OBJECTIVES: This study sought to evaluate the effect of macitentan on hospitalization of patients with symptomatic pulmonary arterial hypertension (PAH). BACKGROUND: PAH is a progressive, life-threatening disease often requiring hospitalization. METHODS: In the multicenter, double-blind, randomized, event driven, phase III SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) trial, patients with symptomatic PAH were randomized (1:1:1) to receive placebo or 3 mg or 10 mg of macitentan. Effects of macitentan on the risk, rate, and number of hospital days for all-cause and PAH-related hospitalizations were compared with those for placebo. Risk and causes of hospitalizations unrelated to PAH were investigated. RESULTS: Of 742 randomized patients, 250 received placebo, 250 received 3 mg of macitentan, and 242 received 10 mg of macitentan; the overall median duration of treatment was 115 weeks. Risk of all-cause hospitalization was reduced by 18.9% (p = 0.1208) and 32.3% (p = 0.0051) in the macitentan 3-mg and 10-mg arm, respectively. Rates of all-cause hospitalizations and numbers of hospital days were reduced by 20.5% (p = 0.0378) and 30.6% (p = 0.0278), respectively, with 3 mg of macitentan and by 33.1% (p = 0.0005) and 31.0% (p = 0.0336), respectively, with 10 mg of macitentan. Risk of PAH-related hospitalizations were reduced by 42.7% (p = 0.0015) and 51.6% (p < 0.0001) in the macitentan 3-mg and 10-mg arms, respectively. Rate of PAH-related hospitalizations and numbers of hospital days were reduced by 44.5% (p = 0.0004) and 53.3% (p = 0.0001), respectively, with 3 mg of macitentan, and reduced by 49.8% (p < 0.0001) and 52.3% (p = 0.0003), respectively, with 10 mg of macitentan. Risk of non-PAH-related hospitalization was similar between treatment arms. CONCLUSIONS: Macitentan 10 mg significantly reduced the risk and rate of all-cause hospitalization, which was driven by reductions in the risk and rate of PAH-related hospitalization. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension; NCT00660179). PMID- 25457904 TI - Drowning: a largely preventable cause of death. PMID- 25457905 TI - Principles to guide type 2 diabetes care in the USA. PMID- 25457906 TI - Acting on the Pacific crisis in non-communicable diseases. PMID- 25457909 TI - Hubbub: troubling rest through experimental entanglements. PMID- 25457910 TI - Compassionate use of experimental drugs in the Ebola outbreak - Authors' reply. PMID- 25457911 TI - Postmastectomy radiotherapy in patients with breast cancer. PMID- 25457912 TI - Postmastectomy radiotherapy in patients with breast cancer. PMID- 25457913 TI - Postmastectomy radiotherapy in patients with breast cancer - Authors' reply. PMID- 25457914 TI - Postmastectomy radiotherapy in patients with breast cancer. PMID- 25457915 TI - EMA's transparency seems to be opaque. PMID- 25457916 TI - Overdiagnosis and screening for thyroid cancer in Korea. PMID- 25457917 TI - A pregnant woman with chronic meningococcaemia from Neisseria meningitidis with lpxL1-mutations. PMID- 25457918 TI - Straightforward method to quantify GSH, GSSG, GRP, and hydroxycinnamic acids in wines by UPLC-MRM-MS. AB - A novel, robust and fast ultrahigh performance liquid chromatography-multiple reaction monitoring mass spectrometry method has been developed for the simultaneous quantification of reduced glutathione (GSH), oxidized glutathione (GSSG), grape reaction product (GRP) and hydroxycinnamic acids in wine. The method was evaluated in terms of linearity, precision, accuracy, limits of detection and quantification, stability and matrix effects. Quantitative recovery (74-110%) and satisfactory interday precision (RSD <14%) were achieved for all target compounds. No significant matrix-dependent suppression/enhancement effects were observed. To demonstrate the method applicability, white, rose and red wine samples with different levels of oxidation were analyzed. Levels of GSH and GSSG varied from 1.63 to 9.91 mg/L and from 0.32 to 3.33 mg/L, respectively. Levels of caftaric acid ranged from 2.57 to 293.07 mg/L. Levels of GRP were between 28.35 and 114.20 mg/L. PMID- 25457919 TI - Holocentric plant meiosis: first sisters, then homologues. AB - Meiosis is a crucial process of sexual reproduction by forming haploid gametes from diploid precursor cells. It involves 2 subsequent divisions (meiosis I and meiosis II) after one initial round of DNA replication. Homologous monocentric chromosomes are separated during the first and sister chromatids during the second meiotic division. The faithful segregation of monocentric chromosomes is realized by mono-orientation of fused sister kinetochores at metaphase I and by bi-orientation of sister kinetochores at metaphase II. Conventionally this depends on a 2-step loss of cohesion, along chromosome arms during meiosis I and at sister centromeres during meiosis II. PMID- 25457920 TI - Experiences of women of color with a nurse patient navigation program for linkage and engagement in HIV care. AB - Patient navigation, a patient-centered model of care coordination focused on reducing barriers to care, is an emerging strategy for linking patients to and retaining them in HIV care. The Guide to Healing Program (G2H), implemented at the Infectious Diseases Clinic at UNC Chapel Hill, provided patient navigation to women of color (WOC) new to or re-engaging in HIV care through a 'nurse guide' with mental health training and experience. The purpose of this study was to qualitatively explore patients' experiences working with the nurse guide. Twenty one semi-structured telephone interviews with G2H participants were conducted. Interviews were transcribed and thematic analysis was utilized to identify patterns and themes in the data. Women's experiences with the nurse guide were overwhelmingly positive. They described the nurse guide teaching them critical information and skills, facilitating access to resources, and conveying authentic kindness and concern. The findings suggest that a properly trained nurse in this role can provide critical medical and psychosocial support in order to eliminate barriers to engagement in HIV care, and successfully facilitate patient HIV self management. The nurse guide model represents a promising approach to patient navigation for WOC living with HIV. PMID- 25457922 TI - Family homelessness: a deepening crisis in urban communities. PMID- 25457923 TI - Delinquency, depression, and psychosis among adolescents in foster care: what holds three heads together? PMID- 25457924 TI - Web-based interventions for youth internalizing problems: a systematic review. AB - OBJECTIVE: To review published reports on Web-based treatment and prevention programs for depression, anxiety, and suicide prevention in children, adolescents, and emerging adults. METHOD: A systematic search of the PsycINFO, PubMed, Medline, and Web of Science databases was conducted in December 2013. Programs were classified according to evidence-base level (Well-Established, Probably Efficacious, Possibly Efficacious, Experimental, and Of Questionable Efficacy). RESULTS: Of the 14,001 citations initially identified, 25 articles met inclusion criteria for Web-based interventions. These described 9 programs, of which 8 were Internet based and 1 was a mobile application. No Web-based interventions for suicide prevention were identified. Of the randomized controlled trials (n = 14) and open trials (n = 3) identified, 10 reported significant postintervention reductions in symptoms of depression and/or anxiety or improvements in diagnostic ratings, with small to large effect sizes. Many of these studies also reported significant improvements at follow-up. The methodological quality of the studies varied. Many programs were limited by their small sample sizes and use of waitlist or no-treatment control groups. CONCLUSION: There is limited evidence for the effectiveness of Web-based interventions for youth depression and anxiety. Additional research and program development are needed to fill the current gaps in the literature. PMID- 25457925 TI - How gay-straight alliance groups mitigate the relationship between gay-bias victimization and adolescent suicide attempts. AB - OBJECTIVE: We examined the relationships between victimization from being bullied, suicide, hopelessness, and the presence of a Gay-Straight Alliance (GSA) on a school campus. METHOD: We analyzed data from the California Healthy Kids Survey from 2005 to 2007 using hierarchical modeling. RESULTS: We found that gay bias (versus non-gay-bias) victimization is meaningfully connected with the inwardly destructive behavior of attempted suicide among adolescents. We also found that hopelessness helps explain associations between gay-bias victimization and suicide attempts and that the presence of a GSA club on a school's campus attenuates significant connections between gay-bias victimization and suicide attempts by reducing hopelessness. CONCLUSION: Gay-bias victims are more likely than other victims to attempt suicide while also feeling more hopeless. The presence of a GSA on campus may help to reduce the attempted suicide and hopelessness associated with gay-bias victimization. PMID- 25457926 TI - Effects of multidimensional treatment foster care on psychotic symptoms in girls. AB - OBJECTIVE: Neurodevelopmental theories of psychosis highlight the potential benefits of early intervention, prevention, and/or preemption. How early intervention should take place has not been established, nor whether interventions based on social learning principles can have preemptive effects. The objective was to test whether a comprehensive psychosocial intervention can significantly alter psychotic symptom trajectories during adolescence-a period of heightened risk for a wide range of psychopathology. METHOD: This study was a randomized controlled trial (RCT) of Multidimensional Treatment Foster Care (MTFC) for delinquent adolescent girls. Assessment of psychotic symptoms took place at baseline and then 6, 12, 18, and 24 months post-baseline using a standardized self-report instrument (Brief Symptom Inventory). A second source of information about psychotic symptoms was obtained at baseline or 12 months, and again at 24 months using a structured diagnostic interview (the Diagnostic Interview Schedule for Children [DISC]). RESULTS: Significant benefits for MTFC over treatment as usual for psychosis symptoms were observed over a 24-month period. Findings were replicated across both measures. Effects were independent of substance use and initial symptom severity and persisted beyond the initial intervention period. CONCLUSION: Ameliorating nonclinical psychotic symptoms trajectories beginning in mid-adolescence via a multifaceted psychosocial intervention is possible. Developmental research on nonclinical psychotic symptoms and their prognostic value should be complemented by more psychosocial intervention research aimed at modifying these symptom trajectories early in their natural history. Clinical trial registration information-Juvenile Justice Girls Randomized Control Trial: Young Adult Follow-up; http://clinicaltrials.gov; NCT01341626. PMID- 25457927 TI - A behavioral intervention for war-affected youth in Sierra Leone: a randomized controlled trial. AB - OBJECTIVE: Youth in war-affected regions are at risk for poor psychological, social, and educational outcomes. Effective interventions are needed to improve mental health, social behavior, and school functioning. This randomized controlled trial tested the effectiveness of a 10-session cognitive-behavioral therapy (CBT)-based group mental health intervention for multisymptomatic war affected youth (aged 15-24 years) in Sierra Leone. METHOD: War-affected youth identified by elevated distress and impairment via community screening were randomized (stratified by sex and age) to the Youth Readiness Intervention (YRI) (n = 222) or to a control condition (n = 214). After treatment, youth were again randomized and offered an education subsidy immediately (n = 220) or waitlisted (n = 216). Emotion regulation, psychological distress, prosocial attitudes/behaviors, social support, functional impairment, and posttraumatic stress disorder (PTSD) symptoms were assessed at pre- and postintervention and at 6-month follow-up. For youth in school, enrollment, attendance, and classroom performance were assessed after 8 months. Linear mixed-effects regressions evaluated outcomes. RESULTS: The YRI showed significant postintervention effects on emotion regulation, prosocial attitudes/behaviors, social support, and reduced functional impairment, and significant follow-up effects on school enrollment, school attendance, and classroom behavior. In contrast, education subsidy was associated with better attendance but had no effect on mental health or functioning, school retention, or classroom behavior. Interactions between education subsidy and YRI were not significant. CONCLUSION: YRI produced acute improvements in mental health and functioning as well as longer-term effects on school engagement and behavior, suggesting potential to prepare war-affected youth for educational and other opportunities. Clinical trial registration information-Trial of the Youth Readiness Intervention (YRI); http://clinicaltrials.gov; NCT01684488. PMID- 25457928 TI - Telephone cognitive-behavioral therapy for adolescents with obsessive-compulsive disorder: a randomized controlled non-inferiority trial. AB - OBJECTIVE: Many adolescents with obsessive-compulsive disorder (OCD) do not have access to evidence-based treatment. A randomized controlled non-inferiority trial was conducted in a specialist OCD clinic to evaluate the effectiveness of telephone cognitive-behavioral therapy (TCBT) for adolescents with OCD compared to standard clinic-based, face-to-face CBT. METHOD: Seventy-two adolescents, aged 11 through 18 years with primary OCD, and their parents were randomized to receive specialist TCBT or CBT. The intervention provided differed only in the method of treatment delivery. All participants received up to 14 sessions of CBT, incorporating exposure with response prevention (E/RP), provided by experienced therapists. The primary outcome measure was the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Blind assessor ratings were obtained at midtreatment, posttreatment, 3-month, 6-month, and 12-month follow-up. RESULTS: Intent-to-treat analyses indicated that TCBT was not inferior to face-to-face CBT at posttreatment, 3-month, and 6-month follow-up. At 12-month follow-up, there were no significant between-group differences on the CY-BOCS, but the confidence intervals exceeded the non-inferiority threshold. All secondary measures confirmed non-inferiority at all assessment points. Improvements made during treatment were maintained through to 12-month follow-up. Participants in each condition reported high levels of satisfaction with the intervention received. CONCLUSION: TCBT is an effective treatment and is not inferior to standard clinic based CBT, at least in the midterm. This approach provides a means of making a specialized treatment more accessible to many adolescents with OCD. Clinical trial registration information-Evaluation of telephone-administered cognitive behaviour therapy (CBT) for young people with obsessive-compulsive disorder (OCD); http://www.controlled-trials.com; ISRCTN27070832. PMID- 25457929 TI - Tic-related obsessive-compulsive disorder (OCD): phenomenology and treatment outcome in the Pediatric OCD Treatment Study II. AB - OBJECTIVE: Prior research has shown that youth with co-occurring tic disorders and obsessive-compulsive disorder (OCD) may differ from those with non-tic related OCD in terms of clinical characteristics and treatment responsiveness. A broad definition of "tic-related" was used to examine whether children with tics in the Pediatric OCD Treatment Study II differed from those without tics in terms of demographic and phenomenological characteristics and acute treatment outcomes. METHOD: Participants were 124 youth aged 7 to 17 years, inclusive, with a primary diagnosis of OCD who were partial responders to an adequate serotonin reuptake inhibitor (SRI) trial. Participants were randomized to medication management, medication management plus instructions in cognitive-behavioral therapy (CBT), or medication management plus full CBT. Tic status was based on the presence of motor and/or vocal tics on the Yale Global Tic Severity Scale. RESULTS: Tics were identified in 53% of the sample. Those with tic-related OCD did not differ from those with non-tic-related OCD in terms of age, family history of tics, OCD severity, OCD-related impairment, or comorbidity. Those with tics responded equally in all treatment conditions. CONCLUSION: Tic-related OCD was very prevalent using a broad definition of tic status. Results suggest that youth with this broad definition of tic-related OCD do not have increased OCD severity or inference, higher comorbidity rates or severity, or worsened functioning, and support the use of CBT in this population. This highlights the importance of not making broad assumptions about OCD symptoms most likely to occur in an individual with comorbid tics. Clinical trial registration information-Treatment of Pediatric OCD for SRI Partial Responders; http://clinicaltrials.gov; NCT00074815. PMID- 25457931 TI - Neural response to social rejection in children with early separation experiences. AB - OBJECTIVE: Nonhuman and human studies have documented the adverse effects of early life stress (ELS) on emotion regulation and underlying neural circuitry. Less is known about how these experiences shape social processes and neural circuitry. In this study, we thus investigated how ELS affects children's perception of, and neural response to, negative social experiences in a social exclusion paradigm (Cyberball). METHOD: Twenty-five foster or adopted children with ELS (age 10.6 +/- 1.8 years, 13 male and 12 female) and 26 matched nonseparated controls (age 10.38 +/- 1.7 years, 12 male and 14 female) took part in a Cyberball paradigm during functional magnetic resonance imaging (fMRI). RESULTS: During peer rejection, children with ELS reported significantly more feelings of exclusion and frustration than nonseparated controls. On the neural level, children with ELS showed reduced activation in the dorsal anterior cingulate cortex (dACC) and dorsolateral prefrontal cortex (dlPFC), and reduced connectivity between dlPFC-dACC, areas previously implicated in affect regulation. Conversely, children with ELS showed increased neural activation in brain regions involved in memory, arousal, and threat-related processing (middle temporal gyrus, thalamus, ventral tegmental area) relative to controls during social exclusion. The number of separation experiences before entering the permanent family predicted reductions in fronto-cingulate recruitment. The relationship between early separations and self-reported exclusion was mediated by dlPFC activity. CONCLUSION: The findings suggest that ELS leads to alterations in neural circuitry implicated in the regulation of socioemotional processes. This neural signature may underlie foster children's differential reactivity to rejection in everyday life and could increase risk for developing affective disorders. PMID- 25457930 TI - 18-month predictors of later outcomes in younger siblings of children with autism spectrum disorder: a baby siblings research consortium study. AB - OBJECTIVE: Younger siblings of children with autism spectrum disorder (ASD) are at high risk (HR) for developing ASD as well as features of the broader autism phenotype. Although this complicates early diagnostic considerations in this cohort, it also provides an opportunity to examine patterns of behavior associated specifically with ASD compared to other developmental outcomes. METHOD: We applied Classification and Regression Trees (CART) analysis to individual items of the Autism Diagnostic Observation Schedule (ADOS) in 719 HR siblings to identify behavioral features at 18 months that were predictive of diagnostic outcomes (ASD, atypical development, and typical development) at 36 months. RESULTS: Three distinct combinations of features at 18 months were predictive of ASD outcome: poor eye contact combined with lack of communicative gestures and giving; poor eye contact combined with a lack of imaginative play; and lack of giving and presence of repetitive behaviors, but with intact eye contact. These 18-month behavioral profiles predicted ASD versus non-ASD status at 36 months with 82.7% accuracy in an initial test sample and 77.3% accuracy in a validation sample. Clinical features at age 3 years among children with ASD varied as a function of their 18-month symptom profiles. Children with ASD who were misclassified at 18 months were higher functioning, and their autism symptoms increased between 18 and 36 months. CONCLUSION: These findings suggest the presence of different developmental pathways to ASD in HR siblings. Understanding such pathways will provide clearer targets for neural and genetic research and identification of developmentally specific treatments for ASD. PMID- 25457932 TI - Reply to "Adolescents are like adults (sort of)". PMID- 25457933 TI - In reply. PMID- 25457935 TI - Signed off and signing on: editor's annual report--volume 53, 2014. PMID- 25457938 TI - Exacerbations of COPD and radiological condensation: three controversial questions. PMID- 25457939 TI - The discovery of ivermectin. PMID- 25457940 TI - Malaria parasites prepare for flight. AB - Life in seasonal environments often means facing extreme environmental fluctuations. Many multicellular organisms have evolved strategies to cope with this lifestyle. Single-celled malaria parasites are no different. An elegant experiment reveals that they respond to the availability of mosquitoes to make the most of seasonal transmission opportunities. PMID- 25457942 TI - Archaeorhizomyces borealis sp. nov. and a sequence-based classification of related soil fungal species. AB - The class Archaeorhizomycetes (Taphrinomycotina, Ascomycota) was introduced to accommodate an ancient lineage of soil-inhabiting fungi found in association with plant roots. Based on environmental sequencing data Archaeorhizomycetes may comprise a significant proportion of the total fungal community in soils. Yet the only species described and cultivated in this class is Archaeorhizomyces finlayi. In this paper, we describe a second species from a pure culture, Archaeorhizomyces borealis NS99-600(T) (=CBS138755(ExT)) based on morphological, physiological, and multi-locus molecular characterization. Archaeorhizomyces borealis was isolated from a root tip of a Pinus sylvestris seedling grown in a forest nursery in Lithuania. Analysis of Archaeorhizomycete species from environmental samples shows that it has a Eurasian distribution and is the most commonly observed species. Archaeorhizomyces borealis shows slow growth in culture and forms yellowish creamy colonies, characteristics that distinguish A. borealis from its closest relative A. finlayi. Here we also propose a sequence based taxonomic classification of Archaeorhizomycetes and predict that approximately 500 species in this class remain to be isolated and described. PMID- 25457941 TI - Career plans and perceptions in readiness to practice of graduating general surgery residents in Canada. AB - INTRODUCTION: Overall, 25% of American general surgery residents identified as not feeling confident operating independently at graduation, which may contribute to 70% pursuing further training. This study was undertaken to identify intended career plans of general surgery graduates in Canada on a national level, and perceived strengths and weaknesses of training that would affect transition to early practice. METHODS: Questionnaires were distributed to graduating general surgery residents at a Canadian national review course in 2012 and 2013. Data were analyzed for overall trends. RESULTS: Overall, 75% (78/104) of graduating residents responded in 2012 and 53% (50/95) in 2013. Greater than 60% of respondents were entering a fellowship program upon graduation (49/78 in 2012 and 37/50 in 2013); the most common fellowship choices were minimally invasive surgery (24% in 2012 and 39% in 2013) or surgical oncology (16% in 2012). Most residents reported that they were completing subspecialty training to meet career goals (64/85 overall) rather than feeling unprepared for practice (0/85 overall). Most residents planned on practicing in urban centers (54%) and academic hospitals (73%). Residents perceived a need for assistance for laparoscopic adrenalectomy, neck dissection, laparoscopic splenectomy, laparoscopic low anterior resection, groin dissection, and thyroidectomy. CONCLUSIONS: An overwhelming majority of general surgery graduates plan to pursue fellowship training to meet career goals of working in urban, academic centers, rather than a perceived lack of competence. It is vital to describe operative competency expectations for residents and to promote a variety of practice opportunities following graduation. PMID- 25457943 TI - Three common bryophilous fungi with meristematic anamorphs and phylogenetic alliance to Teratosphaeriaceae, Capnodiales. AB - Bryophilous ascomycetes are an overlooked and poorly known fungal group. In this study, the extreme and small-sized niche of Polytrichum piliferum hyaline leaf tips was screened for the presence of these fungi in Finland. Three closely related species were found. Bryochiton perpusillus and Bryochiton monascus were identified from several samples, and DNA isolations revealed a third closely related species, Bryochiton sp. In addition, melanised hyphae, typical to the Bryochiton species, were present in all the samples. According to phylogenetic analyses consisting of combined small subunit (SSU), large subunit (LSU), and 5.8S rDNA sequences, and internal transcribed spacer (ITS) rDNA sequences, the species showed affinity with Teratosphaeriaceae within Capnodiales, and especially with black, meristematic species often inhabiting rock substrate in extreme environments. The connection was supported by meristematic growth of the Bryochiton species in culture. Bryochiton is the second sexual genus associated within the family Teratosphaeriaceae, and B. perpusillus, and B. monascus constitute examples of teleomorphs within a group of meristematic anamorphs. These findings emphasize the multiform diversity underlying poorly researched fungal groups, such as the bryophilous fungi. PMID- 25457944 TI - Phylogeny of ambrosia beetle symbionts in the genus Raffaelea. AB - The genus Raffaelea was established in 1965 when the type species, Raffaelea ambrosia, a symbiont of Platypus ambrosia beetles was described. Since then, many additional ambrosia beetle symbionts have been added to the genus, including the important tree pathogens Raffaelea quercivora, Raffaelea quercus-mongolicae, and Raffaelea lauricola, causal agents of Japanese and Korean oak wilt and laurel wilt, respectively. The discovery of new and the dispersal of described species of Raffaelea to new areas, where they can become invasive, presents challenges for diagnosticians as well as plant protection and quarantine efforts. In this paper, we present the first comprehensive multigene phylogenetic analysis of Raffaelea. As it is currently defined, the genus was found to not be monophyletic. On the basis of this work, Raffaelea sensu stricto is defined and the affinities of undescribed isolates are considered. PMID- 25457945 TI - Reactive oxygen species regulate lovastatin biosynthesis in Aspergillus terreus during submerged and solid-state fermentations. AB - In a previous work we detected an important increase in reactive oxygen species (ROS) concentrations during idiophase in lovastatin fermentations. Hence, the objective of the present work was to determine if ROS contributes to the regulation of lovastatin biosynthesis. Exogenous antioxidants were used to reduce ROS accumulation. The addition of N-Acetyl-L-cysteine (NAC) decreased ROS accumulation and concurrent lovastatin production. In solid-state fermentation (SSF), the addition of 100 mM of NAC lowered ROS accumulation by 53%, together with a 79% decrease in lovastatin biosynthesis. A similarly, situation was observed in submerged fermentation (SmF). Decreased lovastatin production was due to a lower expression of the regulatory gene lovE, and gene lovF. Moreover, the addition of H2O2 to the culture caused precocious gene expression and lovastatin biosynthesis. These results indicate that ROS accumulation in idiophase contributes to the regulation of the biosynthetic genes. It was considered that Yap1 (Atyap1) could be a transcription factor linking ROS with lovastatin biosynthesis. In a Northern analysis, Aspergillus terreus yap1 gene (Atyap1) was highly expressed during trophophase but down regulated during idiophase. Conversely, expression pattern of srrA gene, suggested that SrrA could positively control lovastatin biosynthesis, and also explaining the characteristics of the biosynthesis in SSF. PMID- 25457946 TI - Responsiveness of entomopathogenic fungi to menadione-induced oxidative stress. AB - Entomopathogenic fungi are predisposed to ROS induced by heat and UV-A radiation when outside the insect host. When inside the host, they are subject to phagocytic cells that generate ROS to eliminate invading pathogens. The oxidative stress tolerance of the entomopathogenic fungi Aschersonia aleyrodis (ARSEF 430 and 10276), Aschersonia placenta (ARSEF 7637), Beauveria bassiana (ARSEF 252), Isaria fumosorosea (ARSEF 3889), Lecanicillium aphanocladii (ARSEF 6433), Metarhizium acridum (ARSEF 324), Metarhizium anisopliae (ARSEF 5749), Metarhizium brunneum (ARSEF 1187 and ARSEF 5626), Metarhizium robertsii (ARSEF 2575), Tolypocladium cylindrosporum (ARSEF 3392), Tolypocladium inflatum (ARSEF 4877), and Simplicillium lanosoniveum (ARSEF 6430 and ARSEF 6651) was studied based on conidial germination on a medium supplemented with menadione. Conidial germination was evaluated 24 h after inoculation on potato dextrose agar (PDA) (control) or PDA supplemented with menadione. The two Aschersonia species (ARSEF 430, 7637, and 10276) were the most susceptible fungi, followed by the two Tolypocladium species (ARSEF 3392 and 4877) and the M. acridum (ARSEF 324). Metarhizium brunneum (ARSEF 5626) and M. anisopliae (ARSEF 5749) were the most tolerant isolates with MIC 0.28 mM. All fungal isolates, except ARSEF 5626 and ARSEF 5749, were not able to germinate at 0.20 mM. PMID- 25457947 TI - Hydro- and thermotimes for conidial germination kinetics of the ochratoxigenic species Aspergillus carbonarius in vitro, on grape skin and grape flesh. AB - The objective was to compare the ability of spores of Aspergillus carbonarius to germinate in vitro, in situ on grape skin and grape flesh in relation to temperature (15-40 degrees C) and different relative humidities (100-85% RH). Spores were inoculated as a spore suspension (10(6) spores ml(-1)) onto the surface of white organic grapes and directly onto cut grape flesh. For comparison, spores were spread plate onto a synthetic grape juice medium (SGM) modified to the equivalent water activity (a(w)) range of 0.995-0.85. This showed that conidia germinated more rapidly on grape flesh (6 h) followed by that on the SGM medium (9 h) and then grape skin (24 h) under optimal condition of 30-35 degrees C and 100 % RH. At marginal conditions, such as 15 degrees C and 85-90% RH, germination was very slow. The time to 5% germination was significantly shorter on grape flesh than in vitro on grape medium and slowest on grape skin. This suggests that damaged grapes provide the main method of infection and contamination of grapes and grape products with ochratoxin A (OTA). The combined effect of temperature and RH on conidial germination of A. carbonarius on SGM and grape skin was described by combining Beta and polynomial equations. The equations developed in this work provided a good fit of the biological processes; they could be integrated in a predictive model for infection and OTA prediction in ripening grapes. PMID- 25457948 TI - Diversity of Clonostachys species assessed by molecular phylogenetics and MALDI TOF mass spectrometry. AB - We assessed the species diversity among 45 strains of Clonostachys from different substrates and localities in Brazil using molecular phylogenetics, and compared the results with the phenotypic classification of strains obtained from matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Phylogenetic analyses were based on beta tubulin (Tub), ITS-LSU rDNA, and a combined Tub-ITS DNA dataset. MALDI-TOF MS analyses were performed using intact conidia and conidiophores of strains cultivated on oatmeal agar and 4% malt extract agar. Six known species were identified: Clonostachys byssicola, Clonostachys candelabrum, Clonostachys pseudochroleuca, Clonostachys rhizophaga, Clonostachys rogersoniana, and Clonostachys rosea. Two clades and two singleton lineages did not correspond to known species represented in the reference DNA dataset and were identified as Clonostachys sp. 1-4. Multivariate cluster analyses of MALDI-TOF MS data classified the strains into eight clusters and three singletons, corresponding to the ten identified species plus one additional cluster containing two strains of C. rogersoniana that split from the other co specific strains. The consistent results of MALDI-TOF MS supported the identification of strains assigned to C. byssicola and C. pseudochroleuca, which did not form well supported clades in all phylogenetic analyses, but formed distinct clusters in the MALDI-TOF dendrograms. PMID- 25457950 TI - Welcome to the World Stem Cell Report. PMID- 25457949 TI - Evidence for amphithallism and broad geographical hybridization potential among Agaricus subrufescens isolates from Brazil, France, and Thailand. AB - Agaricus subrufescens is a cultivated edible and medicinal mushroom. Its known geographical distribution encompasses the Americas, Europe, Oceania, and Asia. The objective of this study was to assess mating compatibility and interfertility of strains originating from Brazil, France, and Thailand. Progeny of each strain were analyed with codominant molecular markers. Multilocus genotype tests revealed that the three strains were amphithallic with percentages of heterokaryotic single spore progenies of 75% for the Thai strain and around 40% for the Brazilian and French strains. In mating tests A. subrufescens had a multiallelic unifactorial system of sexual incompatibility. The three parent strains were interfertile based on experimental pairings of single-spore isolates, the recovery of hybrid heterokaryons from compatible matings, and the ability of hybrids to produce mushrooms and fertile spores. This biological approach supports the inclusion of the European strains within the species and the extension of the geographical distribution range to Asia. Our data should help to develop breeding strategies and to better manage and exploit the diversity existing in A. subrufescens. PMID- 25457952 TI - An interview with Katie Jackson. PMID- 25457951 TI - An interview with Norio Nakatsuji. PMID- 25457953 TI - An interview with Marion Riggs on the Student Society for Stem Cell Research. PMID- 25457954 TI - Stem cell research and regenerative medicine at King Abdullah International Medical Research Center. AB - Translation of stem cell research from bench to bedside opens up exciting new therapeutic options for patients. Although stem cell research has progressed rapidly, its clinical applications have not kept pace. We report on the establishment of a stem cell research and regenerative medicine program at King Abdullah International Medical Research Center (KAIMRC). The purpose of this unit is to coordinate advanced stem cell research and translational outcomes with the goal of treating chronic human diseases, such as cancer, diabetes, cardiovascular, neurological, immunological, and liver diseases. Our first step in achieving this goal was to integrate the stem cells and regenerative medicine unit with our umbilical cord blood bank and bone marrow registry. This organizational structure will provide different sources for stem cells for research and clinical purposes, and facilitate our stem cell research and stem cell transplantation program. We are at an early and exciting stage in our program, but we believe that our progress to the international stage will be rapid and have a significant impact. PMID- 25457955 TI - Current status of stem cells and regenerative medicine research in Argentina. AB - Since Takahashi and Yamanaka demonstrated for the first time that fully differentiated somatic cells can be reprogrammed to a pluripotent state with a small group of transcription factors a revolution erupted in the regenerative medicine field. New advances showing direct differentiation of mature cells increased the excitement of the field. This work describes the present situation of the field in Argentina and the efforts implemented by science authorities to strengthen and push the field forward. PMID- 25457956 TI - The current state of research with human pluripotent stem cells in Brazil. AB - This article provides a brief overview of research with human pluripotent stem cells in Brazil, the federal funding supporting this research, and the legislation that allows the isolation of human embryonic stem cells. PMID- 25457957 TI - CellCAN: a unique enabler of regenerative medicine and cell therapy in Canada. AB - Regenerative Medicine and Cell Therapy (RMCT) is paving the way for the most innovative and promising medical breakthroughs of the 21st century. Indeed, its curative potential is immense and builds on the already proven benefits of stem cell transplantation. Successful and broad clinical implementation of RMCT, as well as reaping of its full social and economic benefits, is contingent on the resolution of a range of issues. The CellCAN network, a not-for-profit corporation, was created to tackle these challenges, gathering the key forces of the numerous Canadian organizations involved in basic research, assay development, manufacturing, clinical research, clinical trials, legal and ethical regulations, and policies, all working to move RMCT forward. CellCAN creates a national enterprise by bringing together a community of renowned researchers, industries, clinicians, funders and regulators, and aligning it with cell handling facilities involved in processing cell products and other products for cell therapy clinical trials to ensure capacity and know-how for stem cell research and efficient execution of cell therapy clinical trials. CellCAN is uniquely positioned to accelerate the implementation of RMCT in Canada and disseminate novel developments and findings, thus significantly contributing to the world's knowledge in cellular therapeutics. As such, the CellCAN model could also serve as a useful benchmark to accelerate RMCT implementation in other countries. PMID- 25457958 TI - The Netherlands advancing to the forefront of regenerative medicine. AB - The country, and especially Limburg, the most southern province, is making major leaps forward in the commercialization of regenerative medicine. Chemelot Campus, a major business park, is making a massive commitment with the creation of "Regeneration Street"; 50,000 m2 of world leading research, development, manufacturing and innovation in regenerative medicine. PMID- 25457959 TI - Regulatory loophole enables unproven autologous cell therapies to thrive in Australia. AB - As in many jurisdictions around the world, there are a growing number of doctors in Australia who are offering autologous cell therapies outside of a clinical trial setting and in the absence of sound and convincing evidence of safety or efficacy. Such interventions, often marketed as "stem cell" treatments, involve the administration of the patient's own cells-or products derived from them-for a wide range of conditions at considerable financial cost to patients. At present, Australian regulations treat autologous cell treatments as medical practice, exempt from the regulatory framework for cell and gene therapy and biologicals. As a consequence, Australia risks becoming the destination of choice for those practitioners seeking to capitalize on community demand for "stem cell" therapies. PMID- 25457960 TI - The European Court of Human Rights' ruling on unproven stem cell therapies: a missed opportunity? AB - On May 6th 2014, the European Court of Human Rights added yet a new element to the judicial history of stem cells as it ruled in Durisotto v. Italy [appeal n. 62804/13]. The ruling rejected a patient claim to access an unproven cell therapy an outcome that is certainly to be welcomed. However, this ruling is a missed occasion to clarify and reaffirm some important legal distinctions that could have greatly benefited the whole field of regenerative medicine. We claim that the ethical and political assumptions that sustain the regulation of expanded access programs to new therapies should be carefully scrutinized, with particular attention to the justifications for the risks connected to unconventional therapies. A clear legal definition of what counts as compassionate cure as distinct from unregulated and untested therapies cannot be provided unless those points are previously addressed. PMID- 25457961 TI - Legal and regulatory news from Europe. AB - An opinion presented to the Court of Justice of the European Union on the patentability of parthenotes challenges the court's own competence in a notorious case on human embryonic stem cells. PMID- 25457962 TI - Better safe than sorry: ethics review in European Union-funded health research. AB - Public scrutiny and the increasing number of projects addressing later stages of the research and innovation process announced the need for an enhanced attention to be paid to identify and address ethics concerns. Ex-ante ethics review as implemented in EU-funded health research and a proactive ethics management are a genuinely useful exercise and ensures top-quality research, from the lab to the patient. PMID- 25457964 TI - No patent-no therapy: a matter of moral and legal consistency within the European Union regarding the use of human embryonic stem cells. AB - In the aftermath of the European Court of Justice's decision case of Brustle v Greenpeace of October 2011 that patent claims encompassing human embryonic stem cells were patent-ineligible in the European Union on public order and morality grounds, a rash of stories has appeared predicting the destruction or exodus of human embryonic stem cells research. Irrespective of whether these predictions are justified, amazingly it has not been examined so far whether this decision has an implication on the justification of human embryonic stem cell-based therapies. Therefore, this article presents considerations about the logical link between that patent ruling and the justification of therapies based on human embryonic stem cells. PMID- 25457963 TI - Regulatory insight into the European human pluripotent stem cell registry. AB - The European pluripotent stem cell registry aims at listing qualified pluripotent stem cell (PSC) lines that are available globally together with relevant information for each cell line. Specific emphasis is being put on documenting ethical procurement of the cells and providing evidence of pluripotency. The report discusses the tasks and challenges for a global PSC registry as an instrument to develop collaboration, to access cells from diverse resources and banks, and to implement standards, and as a means to follow up usage of cells and support adherence to regulatory and scientific standards and transparency for stakeholders. PMID- 25457965 TI - U.S. National Football League athletes seeking unproven stem cell treatments. AB - From professionals to weekend warriors, many athletes seek unproven stem cell (SC) treatments in an effort to heal injuries nonsurgically and/or to accelerate recovery times after surgery. Among the elite athletes opting for these treatments are high-profile U.S. National Football League (NFL) players. Over the past 5 years, several NFL players have publicly advocated for SC types of treatments and credit them as a major reason they could continue their careers after injuries. In this article, we describe the current problems associated with unproven SC treatments, focusing on treatments without U.S. Food and Drug Administration approval undertaken by NFL players in the past 5 years. Specifically, we highlight the types of treatments obtained and how the clinics advertise specifically to athletes. We also review the intended and unintended consequences of high-profile players receiving and advocating for these types of therapies. Our findings suggest that NFL players increasingly seek out unproven SC therapies to help accelerate recoveries from injuries. While most seem to receive treatment within the United States, several have traveled abroad for therapies unavailable domestically. PMID- 25457966 TI - Can we assure quality without stifling innovation? AB - The emergence of regenerative medicine raises new questions about the best ways to ensure the safety and efficacy of stem cell therapies for patients. The Foundation for the Accreditation of Cellular Therapy (FACT) believes minimum requirements for cellular therapy for regenerative medicine will promote patient safety, protect the research environment, and aid in the swift advancement of regenerative therapies from bench to bedside. The standards development process has demonstrated that consensus on minimum requirements advances the field. FACT's accreditation process and newly established "Common Standards for Cellular Therapies" can help meet unmet needs in regenerative medicine that will drive commercialization of new cell therapies. PMID- 25457967 TI - Scientific innovation's two Valleys of Death: how blood and tissue banks can help to bridge the gap. AB - Most biomedical basic research in the United States takes place at universities and research institutes and is funded by federal grants. Basic research is awarded billions of federal dollars every year, enabling new discoveries and greater understanding of the fundamental science that makes new innovations and therapies possible. However, when basic research yields an invention of practical use and the research evolves from basic to applied, the playing field changes. Pre-technology licensing federal dollars all but disappear, and innovations rely predominantly on private funding to support the full path from bench to bedside. It is along this path that the scientific advance faces two Valleys of Death. These sometimes insurmountable development stages are the product of the innovation's inherent financial, business and investment risks. Well-planned and executed in vivo studies using quality biological materials demonstrating proof of-concept is often the key to bridging these gaps, and blood and tissue banks offer unique services and resources to enable this process. PMID- 25457969 TI - Bioprinting is changing regenerative medicine forever. AB - 3D printing, or solid freeform fabrication, applied to regenerative medicine brings technologies from several industries together to help solve unique challenges in both basic science and tissue engineering. By more finely organizing cells and supporting structures precisely in 3D space, we will gain critical knowledge of cell-cell communications and cell-environment interactions. As we increase the scale, we will move toward complex tissue and organ structures where several cell phenotypes will functionally and structurally interact, thus recapitulating the form and function of native tissues and organs. PMID- 25457968 TI - Stem cell health and tissue regeneration in microgravity. AB - Exposure to microgravity causes significant mechanical unloading of mammalian tissues, resulting in rapid alterations of their physiology, which poses a significant risk for long-duration manned spaceflight. The immediate degenerative effects of spaceflight we understand best are those studied during short-term low Earth-orbit experiments, and include rapid microgravity-adaptive bone and muscle loss, loss of cardiovascular capacity, defects in wound and bone fracture healing, and impaired immune function. Over the long-term, exposure to microgravity may cause severe deficits in mammalian stem cell-based tissue regenerative health, including, osteogenesis, hematopoiesis, and lymphopoeisis, as well as cause significant stem cell-based tissue degeneration in amphibian tail and lens regeneration. To address the needs for stem cell and other cell science research on the International Space Station (ISS), NASA has developed the new Bioculture System that will allow investigators to initiate and conduct on orbit experiments that astronauts will be able to monitor and interact with during the course of cell cultures. This cell culture capability combined with advanced technologies for molecular biology and on-orbit measurement of gene expression (WetLab2) and other tools that are now coming online bring the ISS National Laboratory a step closer to becoming a fully functional space laboratory for advancing space biological sciences. PMID- 25457970 TI - Nonhuman primate models in translational regenerative medicine. AB - Humans and nonhuman primates (NHPs) are similar in size, behavior, physiology, biochemistry, structure and function of organs, and complexity of the immune system. Research on NHPs generates complementary data that bridge translational research from small animal models to humans. NHP models of human disease offer unique opportunities to develop stem cell-based therapeutic interventions that directly address relevant and challenging translational aspects of cell transplantation therapy. These include the use of autologous induced pluripotent stem cell-derived cellular products, issues related to the immune response in autologous and allogeneic setting, pros and cons of delivery techniques in a clinical setting, as well as the safety and efficacy of candidate cell lines. The NHP model allows the assessment of complex physiological, biochemical, behavioral, and imaging end points, with direct relevance to human conditions. At the same time, the value of using primates in scientific research must be carefully evaluated and timed due to expense and the necessity for specialized equipment and highly trained personnel. Often it is more efficient and useful to perform initial proof-of-concept studies for new therapeutics in rodents and/or other species before the pivotal studies in NHPs that may eventually lead to first-in-human trials. In this report, we present how the Southwest National Primate Research Center, one of seven NIH-funded National Primate Research Centers, may help the global community in translating promising technologies to the clinical arena. PMID- 25457971 TI - Clinical validity of prototype personality disorder ratings in adolescents. AB - A growing body of research shows that personality pathology in adolescents is clinically distinctive and frequently stable into adulthood. A reliable and useful method for rating personality pathology in adolescent patients has the potential to enhance conceptualization, dissemination, and treatment effectiveness. The aim of this study is to examine the clinical validity of a prototype matching approach (derived from the Shedler Westen Assessment Procedure Adolescent Version) for quantifying personality pathology in an adolescent inpatient sample. Sixty-six adolescent inpatients and their parents or legal guardians completed forms of the Child Behavior Checklist (CBCL) assessing emotional and behavioral problems. Clinical criterion variables including suicide history, substance use, and fights with peers were also assessed. Patients' individual and group therapists on the inpatient unit completed personality prototype ratings. Prototype diagnoses demonstrated substantial reliability (median intraclass correlation coefficient =.75) across independent ratings from individual and group therapists. Personality prototype ratings correlated with the CBCL scales and clinical criterion variables in anticipated and meaningful ways. As seen in prior research with adult samples, prototype personality ratings show clinical validity across independent clinician raters previously unfamiliar with the approach, and they are meaningfully related to clinical symptoms, behavioral problems, and adaptive functioning. PMID- 25457972 TI - Effect of therapeutic insoles on the medial longitudinal arch in patients with flatfoot deformity: a three-dimensional loading computed tomography study. AB - BACKGROUND: Insoles are frequently used in orthotic therapy as the standard conservative treatment for symptomatic flatfoot deformity to rebuild the arch and stabilize the foot. However, the effectiveness of therapeutic insoles remains unclear. In this study, we assessed the effectiveness of therapeutic insoles for flatfoot deformity using subject-based three-dimensional (3D) computed tomography (CT) models by evaluating the load responses of the bones in the medial longitudinal arch in vivo in 3D. METHODS: We studied eight individuals (16 feet) with mild flatfoot deformity. CT scans were performed on both feet under non loaded and full-body-loaded conditions, first with accessory insoles and then with therapeutic insoles under the same conditions. Three-dimensional CT models were constructed for the tibia and the tarsal and metatarsal bones of the medial longitudinal arch (i.e., first metatarsal bone, cuneiforms, navicular, talus, and calcaneus). The rotational angles between the tarsal bones were calculated under loading with accessory insoles or therapeutic insoles and compared. FINDINGS: Compared with the accessory insoles, the therapeutic insoles significantly suppressed the eversion of the talocalcaneal joint. INTERPRETATION: This is the first study to precisely verify the usefulness of therapeutic insoles (arch support and inner wedges) in vivo. PMID- 25457973 TI - Quantifying strain in the vertebral artery with simultaneous motion analysis of the head and neck: a preliminary investigation. AB - BACKGROUND: Spontaneous vertebral artery dissection has significant mortality and morbidity among young adults. Unfortunately, causal mechanisms remain unclear. The purpose of this study was to quantify mechanical strain in the vertebral artery while simultaneously capturing motion analysis data during passive movements of the head and neck relative to the trunk during spinal manipulation and cardinal planes of motion. METHODS: Eight piezoelectric crystals (four per vertebral artery) were sutured into the lumen of the left and right vertebral arteries of 3 cadaveric specimens. Strain was then calculated as changes in length between neighboring crystals from a neutral head/neck reference position using ultrasound pulses. Simultaneously, passive motion of the head and neck on the trunk was captured using eight infrared cameras. The instantaneous strain arising in the vertebral artery was correlated with the relative changes in head position. FINDINGS: Strain in the contralateral vertebral artery during passive flexion-rotation compared to that of extension-rotation is variable ([df=32]: 0.6160% in islets and reduced cytokine induced apoptotic cell death in vitro significantly. The delivery of siRNA-iNOS and E2 simultaneously using E2-loaded R3V6 peptide micelles improved the diabetes reversal rate of marginal mass islet transplantation into the renal subcapsular space of diabetic syngeneic mice significantly compared with the siRNA-iNOS and E2 alone treatment control groups. Our results demonstrated that the co-delivery of siRNA and a cytoprotective drug within a single non-toxic carrier, R3V6 peptide micelles, provides a novel rational strategy for combined ex vivo islet therapy to improve the outcome of islet transplantation. PMID- 25457985 TI - Direct ionization of solid-phase microextraction fibers for quantitative drug bioanalysis: from peripheral circulation to mass spectrometry detection. AB - A novel approach is described for the quantitative bioanalysis of drugs in blood samples by ionization of the analytes collected on solid-phase microextraction (SPME) fibers by mass spectrometry (MS). The technique combines the attractive features of SPME microsampling using minimal sample volumes with the speed, selectivity, and sensitivity capabilities of MS detection. The method reported in this study involved generating gas-phase ions directly from SPME fibers without the need for any additional sample preparation or chromatographic separation; the entire process was completed within 5 min. Traditionally, analytes extracted by SPME fibers are desorbed by washing with suitable solvents followed by a transfer into a sample vial and subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to quantify the amount of analyte extracted and thereby determining the analyte concentration in the matrix. These sample preparation steps are completely eliminated by inserting the SPME fiber directly into the MS. Physiologically relevant concentrations of metoprolol and propranolol in blood samples were measured over several orders of magnitude down to concentration levels of 10 ng/mL. This preliminary assessment of direct SPME-MS showed high sensitivity (ng/mL), acceptable reproducibility (<30%), and lack of carryover. This novel approach simplifies current bioanalytical procedures providing time and cost savings. It demonstrates considerable potential for qualitative and quantitative pharmaceutical bioanalysis as well as other areas of challenging environmental and food analysis. PMID- 25457983 TI - Nanovaccine loaded with poly I:C and STAT3 siRNA robustly elicits anti-tumor immune responses through modulating tumor-associated dendritic cells in vivo. AB - Although cancer vaccine-based immunotherapy holds great potential for cancer treatment, tumor-induced dendritic cell (DC) dysfunction remains to be the major obstacle for developing effective vaccines. Compared with normal DCs, tumor associated DCs (TADCs) are less matured with poor responsiveness to Toll-like receptor (TLR) stimulation, which has been related with STAT3 hyperactivity. In the present study, Poly I:C (PIC, a TLR3 agonist), STAT3 siRNA and OVA antigen were co-encapsulated by poly (ethylene glycol)-b-poly (L-lysine)-b-poly (L leucine) (PEG-PLL-PLLeu) polypeptide micelles to generate PMP/OVA/siRNA nanovaccine, which was aimed to effectively overcome DC dysfunction in vivo by deleting STAT3 gene in situ. The results showed that PMP/OVA/siRNA simultaneously facilitated the cellular uptake of OVA antigen and siRNA about 3-200 folds, and decreased STAT3 expression in TADCs over 50% both in vitro and in vivo. PMP/OVA/siRNA also elevated CD86 and CD40 expression as well as IL-12 production by TADCs more effectively than PMP/OVA did, indicating its strong potency of inducing TADC maturation and activation. Moreover, the immunization of PMP/OVA/siRNA rather than PMP/OVA effectively abrogated immunosuppression in the tumor microenvironment by increasing mature DCs and decreasing immunosuppressive cells in tumor-draining lymph nodes, which thereby led to potent anti-tumor immune responses and dramatic tumor regression with prolonged survival. Hence, in vivo co-delivery of immunopotentiator (PIC) and immunosuppressive gene silencer (STAT3 siRNA) by nanovaccines are expected to be a promising strategy to improve the therapeutic efficacy of cancer vaccines by modulating TADCs and overcoming tumor immunosupression. PMID- 25457984 TI - Enhanced BBB permeability of osmotically active poly(mannitol-co-PEI) modified with rabies virus glycoprotein via selective stimulation of caveolar endocytosis for RNAi therapeutics in Alzheimer's disease. AB - RNA interference (RNAi) holds one of the promising tools for Alzheimer's disease (AD) treatment by directly arresting the causative genes. For successful RNAi therapeutics for AD, limited access of therapeutic genes to the brain needs to be overcome by developing siRNA delivery system that could cross the blood-brain barrier (BBB). Here, we report a non-viral vector, rabies virus glycoprotein (RVG)-modified poly(mannitol-co-PEI) gene transporter (PMT), R-PEG-PMT. The RVG ligand directed the PMT/siRNA complexes toward the brain through binding to nicotinic acetylcholine receptors expressed on BBB. In mechanistic study using in vitro BBB model, we observed that osmotically-active PMT enhanced the receptor mediated transcytosis by stimulating the caveolar endocytosis. The potential of RNAi therapeutics for AD using R-PEG-PMT/siBACE1 complexes was demonstrated in vitro and in vivo. Our results suggest that R-PEG-PMT is a powerful gene carrier system for brain targeted RNAi therapeutics with synergistic effect of RVG ligand and PMT on well-modulated receptor-mediated transcytosis through BBB. PMID- 25457986 TI - Antidiabetic plants used among the ethnic communities of Unakoti district of Tripura, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: A large group of ethnic communities living in Unakoti district of Tripura, India is still dependent on traditional herbal remedies for treatment of diabetes. Valuable information collected from these communities in the present investigation is important in maintaining their indigenous knowledge of folklore medicine. METHODS: Systematic and extensive field surveys were conducted during 2011-2013 among the ethnic inhabitants of Unokati district, Tripura, India covering all the seasons to collect information on their traditional herbal medication system for treatment of diabetes. Obtained data were analysed through fidelity level (FL), use value (UV) and relative frequency of citation (RFC) to authenticate the uniqueness of the species being used for diabetes treatment. RESULTS: In this current study a total of 39 medicinal plant species belonging to 37 genera and 28 families were presented, used by the traditional healers of Unakoti district, Tripura, India for diabetes treatment. FL, UV and RFC values of collected plants for the selected study area ranges between 06% and 100%, 0.07% and 2.64% and 0.02% and 0.51% respectively. Out of 39 collected plants, 11, 5 and 3 plant species have showed significant (<50%) FL, UV and RFC values respectively. CONCLUSION: Like many other ethnic communities of the world, inhabitants of Unakoti district depend on a traditional medication system to treat diabetes. Documented floras are locally available and need proper further pharmacological validation to endorse their traditional use in a modern health care system. This will help in the development of effective herbal antidiabetic medicines in near future. PMID- 25457988 TI - Useful Brazilian plants listed in the manuscripts and publications of the Scottish medic and naturalist George Gardner (1812-1849). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Information regarding the beneficial use of native Brazilian plants was compiled by a number of European naturalists in the 19th century. The Scottish surgeon botanist George Gardner (1812-1849) was one such naturalist; however, the useful plants recorded in his manuscripts have not yet been studied in depth. AIM OF THE STUDY: To present data recorded by Gardner in his manuscript Catalogue of Brazilian Plants regarding the use of native plants by Brazilian people and evaluate the extent to which they have been explored. MATERIALS AND METHODS: Data on useful plants were obtained from Gardner's manuscript Catalogue of Brazilian Plants deposited in the Archives of the Royal Botanic Gardens, Kew, UK. The identification of each plant was determined and/or updated by consulting the preserved botanical collections of Gardner deposited in the Herbarium of the Royal Botanic Gardens, Kew (hereafter K), and expert determinations in other herbaria where duplicates are held. Correlated pharmacological studies for each plant were obtained from the PubMed database. Information recorded in Gardner's diary and previously published elsewhere complemented these data. RESULTS: A total of 63 useful plants was recorded from the Catalogue and a further 30 from Gardner's book Travels in the Interior of Brazil (Gardner, 1846). Of the recorded names in the Catalogue, 46 (73%) could be identified to species by consulting specimens collected by Gardner and held at Kew. Thirty-six different traditional uses were registered for the identified plants, the most common being as febrifuges, to treat venereal complaints and as purgatives. Fewer than 50% of these species have been the focus of published pharmacological studies, yet for those which have been thus investigated, the efficacies reported by Gardner were confirmed. CONCLUSION: The data recorded by Gardner represent a rich, relatively unexplored source of information regarding the traditional uses of Brazilian plants which merits further investigation. PMID- 25457987 TI - Illite improves memory impairment and reduces Abeta level in the Tg-APPswe/PS1dE9 mouse model of Alzheimer's disease through Akt/CREB and GSK-3beta phosphorylation in the brain. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The use of illite in Korean medicine has a long history as a therapeutic agent for various cerebrovascular diseases. According to Dongui Bogam, illite can be used for Qi-tonifying, phlegm dispersing and activation of blood circulation which is an important principle for the treatment of brain-associated diseases. AIM OF THE STUDY: This study was undertaken to evaluate beneficial effects of illite on the neurodegenerative diseases such as Alzheimer's disease (AD). MATERIAL AND METHODS: The transgenic mice of AD, Tg APPswe/PS1dE9, were fed with 1% or 3% of illite for 3 months. Behavioral, immunological and ELISA analyses were used to assess memory impairment with additional measurement of Abeta accumulation and plaque deposition in the brain. Other in vitro studies were performed to examine whether illite inhibits the Abeta-induced neurotoxicity in human neuroblastoma cell line, SH-SY5Y cells. RESULTS: Illite treatment rescued Abeta-induced neurotoxicity on SH-SY5Y cells, which was dependent on the PI3K/Akt activation. Intake of illite improved the Abeta-induced memory impairment and suppressed Abeta levels and plaque deposition in the brain of Tg-APPswe/PS1dE9 mice. Illite increased CREB, Akt, and GSK-3beta phosphorylation and suppressed tau phosphorylation in the AD-like brains. Moreover, 1% of illite reduced weight gain and suppressed glucose level in the blood. CONCLUSION: The present study suggests that illite has the potential to be a useful adjunct as a therapeutic drug for the treatment of AD. PMID- 25457989 TI - Substrate specificity of beta-glucosidase from Gordonia terrae for ginsenosides and its application in the production of ginsenosides Rg3, Rg2, and Rh1 from ginseng root extract. AB - A beta-glucosidase from Gordonia terrae was cloned and expressed in Escherichia coli. The recombinant enzyme with a specific activity of 16.4 U/mg for ginsenoside Rb1 was purified using His-trap chromatography. The purified enzyme specifically hydrolyzed the glucopyranosides at the C-20 position in protopanaxadiol (PPD)-type ginsenosides and hydrolyzed the glucopyranoside at the C-6 or C-20 position in protopanaxatriol (PPT)-type ginsenosides. The reaction conditions for the high-level production of Rg3 from Rb1 by the enzyme were pH 6.5, 30 degrees C, 20 mg/ml enzyme, and 4 mg/ml Rb1. Under these conditions, G. terrae beta-glucosidase completely converted Rb1 and Re to Rg3 and Rg2, respectively, after 2.5 and 8 h, respectively. Moreover, the enzyme converted Rg1 to Rh1 at 1 h with a molar conversion yield of 82%. The enzyme at 10 mg/ml produced 1.16 mg/ml Rg3, 1.47 mg/ml Rg2, and 1.17 mg/ml Rh1 from Rb1, Re, and Rg1, respectively, in 10% (w/v) ginseng root extract at pH 6.5 and 30 degrees C after 33 h with molar conversion yields of 100%, 100%, and 77%, respectively. The combined molar conversion yield of Rg2, Rg3, and Rh1 from total ginsenosides in 10% (w/v) ginseng root extract was 68%. These above results suggest that this enzyme is useful for the production of ginsenosides Rg3, Rg2, and Rh1. PMID- 25457990 TI - Improving breast cancer therapy with CDK4/6 inhibitors. PMID- 25457991 TI - A good drug made better: the fulvestrant dose-response story. AB - Sequential use of endocrine therapies remains the cornerstone of treatment for hormone receptor-positive advanced breast cancer, before the use of cytotoxic chemotherapy for unresponsive disease. Fulvestrant is an estrogen receptor (ER) antagonist approved for the treatment of postmenopausal women with ER+ advanced breast cancer after failure of prior antiestrogen therapy. Initially approved at a monthly dose of 250 mg, the recommended fulvestrant dose was revised to 500 mg (500 mg/mo plus 500 mg on day 14 of month 1) after demonstration of improved progression-free survival versus fulvestrant 250 mg. We have reviewed the dose dependent effects of fulvestrant, both from a retrospective combined analysis of dose-dependent reduction of tumor biomarkers in the presurgical setting (3 previously reported studies: Study 18, Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors, and Trial 57) and from a review of clinical studies for advanced breast cancer in postmenopausal women. Analysis of presurgical data revealed a consistent dose-dependent effect for fulvestrant on tumor biomarkers, with increasing fulvestrant dose resulting in greater reductions in ER, progesterone receptor, and Ki67 labeling index. The dose dependent biological effect corresponds with the dose-dependent clinical efficacy observed in the treatment of advanced breast cancer after failure of prior antiestrogen therapy. Although it remains to be determined in a phase III trial, cross-trial comparisons suggest a dose-dependent relationship for fulvestrant as first-line treatment for advanced breast cancer. Overall, biological and clinical data demonstrate a strong dose-dependent relationship for fulvestrant, supporting the efficacy benefit seen with fulvestrant 500 mg over the 250 mg dose. PMID- 25457993 TI - [Preventing chronic kidney disease in France: advantages, feasibility and concerns]. AB - Chronic kidney disease concerns 10 to 14 % of Western populations, and these people are at increased risk of mortality. Treating those patients who reach end stage renal disease is socially and financially costly and requires considerable medical efforts. While the number of nephrologists per inhabitant in France seems to be preserved over time, the increasing prevalence of end-stage renal disease and improvement in early referral of chronic kidney disease patients results in increased workload for renal physicians. In order to reduce the consequences of chronic kidney disease at both, individual and societal levels, promoting primary prevention (elimination of risk factors), secondary prevention (early management of patients) or tertiary prevention (optimal treatment of functional disabilities related to chronic kidney disease) seems relevant. Some of these actions could narrow the gap between current medical practices and recommendations or prevent new end-stage renal disease cases with an acceptable cost-effectiveness ratio. New approaches might be necessary to better control the disease and overcome current limitations such as resistance to treatments. PMID- 25457994 TI - [Pregnancies in hemodialysis and in patients with end-stage chronic kidney disease : epidemiology, management and prognosis]. AB - Pregnancy in patients presenting end-stage renal disease is rare and there are currently no recommendations for the management of these patients. In hemodialysis patients, reduced fertility and medical reluctance limit the frequency of pregnancies. Although the prognosis has significantly improved, a significant risk for unfavorable maternal (pre-eclampsia, eclampsia) and fetal (pre-term birth, intrauterine growth restriction, still death) outcome still remains. Increasing dialysis dose with the initiation of daily dialysis sessions, early adaptation of medications to limit teratogenicity and management of chronic kidney disease complications (anemia, hypertension) are required. A tight coordination between nephrologists and obstetricians remains the central pillar of the care. In peritoneal dialysis, pregnancy is also possible with modification of the exchange protocol and reducing volumes. PMID- 25457995 TI - Bilateral nephrectomy for uncontrolled hypertension in hemodialysis patient: a forgotten option? AB - Resistant arterial hypertension in chronic hemodialysis patients is still a therapeutical challenge despite the development of modern antihypertensive drugs and dialysis procedures. Bilateral nephrectomy seems to be a forgotten option, although it has given good results. We present a case of a 39-year-old female chronic hemodialysis patient, in whom the problem of uncontrolled renal parenchymal hypertension remained despite multiple drug therapy and the ultrafiltration intensification. The problem was solved by bilateral nephrectomy. We discuss the role of bilateral nephrectomy for arterial hypertension control in chronic hemodialysis patients and the surgical and non-surgical options of nephrectomy. PMID- 25457996 TI - Hypersensitivity reactions to racemic calcium folinate (leucovorin) during FOLFOX and FOLFIRI chemotherapy administrations. PMID- 25457997 TI - Facilitated dissociation of IgE versus cell replacement. PMID- 25457998 TI - Serum free light chains in the differential diagnosis and prognosis of primary and secondary hypogammaglobulinemia. PMID- 25457999 TI - Vitamin D enhances production of soluble ST2, inhibiting the action of IL-33. PMID- 25458001 TI - Is there a risk using hypoallergenic cosmetic pediatric products in the United States? PMID- 25458000 TI - "Default" versus "pre-atopic" IgG responses to foodborne and airborne pathogenesis-related group 10 protein molecules in birch-sensitized and nonatopic children. AB - BACKGROUND: The route and dose of exposure are believed to be relevant factors in the sensitization process. Pathogenesis-related group 10 protein (PR-10) molecules are a family of allergenic proteins shared by many pollens (eg, birch and alder) and foods (eg, apple, peach, and soy). Children are exposed to both pollen-derived (inhaled) and food-derived (ingested) PR-10 molecules. OBJECTIVE: We sought to investigate the role of route and dose of exposure in the evolution of IgG and IgE responses to recombinant PR-10 molecules. METHODS: The German Multicentre Allergy Study examined a birth cohort born in 1990. Blood samples were collected at the ages of 1, 2, 3, 5, 6, 7, 10, and 13 years. Participants were included in the present analysis if they had (1) at least 1 serum sample at each of the 4 age periods or time points (1-3 years, 5-7 years, 10 years, and 13 years) and (2) IgE responses to birch (children with birch atopy) or no IgE response at all to 9 common aeroallergens and food allergens (nonatopic children). Therefore serum IgE antibodies to a panel of 4 airborne and 5 foodborne extracts, as well as to Bet v 1, were measured in singleplex assays, whereas IgG and IgE antibodies to a panel of 3 airborne PR-10 molecules (rBet v 1, rAln g 1, and rCor a 1.0101) and 7 foodborne PR-10 molecules (rCor a 1.0401, rMal d 1, rPru p 1, rGly m 4, rAra h 8, rApi g 1, and rDau c 1) were tested by using a multiplex microarray. RESULTS: In the present analyses we included 28 children with birch atopy and randomly selected 28 nonatopic children from the 190 children fulfilling the inclusion criteria. Two different patterns of IgG responses to PR-10 molecules were identified. Among nonatopic subjects, a "default" IgG response was directed mostly against foodborne PR-10, started often before age 2 years, stayed weak, and was mostly transient. Among all atopic subjects, the default IgG response at age 1 year was overwhelmed after age 2 years by an "pre-atopic" IgG response, which started with or shortly before the IgE response and was intense and persistent. This atopic IgG response, as well as the IgE response, involved progressively more foodborne PR-10 proteins with frequencies and levels related to their homology with Bet v 1. CONCLUSIONS: The results suggest that children have a default antibody response to PR-10 molecules, which is early, weak, and transient; does not involve IgE; and is initiated by foodborne PR-10. By contrast, an atopic antibody response to PR-10 molecules is delayed, strong, and persistent; involves both IgG and IgE; and is initiated by airborne PR-10. PMID- 25458002 TI - IL36RN mutations define a severe autoinflammatory phenotype of generalized pustular psoriasis. PMID- 25458004 TI - Credibility and reproducibility. PMID- 25458005 TI - chinmo Mutant fly testis stem cells switching sex farewell to maleness. AB - Maintaining cellular identity is crucial for homeostasis, and sexual fates of vertebrate testis and ovary cells require continual reinforcement. In this issue of Developmental Cell, Ma et al. (2014) provide insights into stem cell fate maintenance in Drosophila, finding that the JAK/STAT target chinmo prevents transformation of testis somatic stem cells into their ovarian counterparts. PMID- 25458003 TI - Symptom dynamics during repeated serial allergen challenge chamber exposures to house dust mite. PMID- 25458006 TI - Arrested detachment: a DEPDC1B-mediated de-adhesion mitotic checkpoint. AB - Mitotic cell rounding is accompanied by changes in the actin cytoskeleton, de adhesion, and an increase in cortical rigidity. In this issue, Marchesi et al. (2014) describe an adhesion-dependent mitotic checkpoint and identify DEPDC1B as the factor responsible for coordinating de-adhesion with the ability of cells to enter mitosis. PMID- 25458007 TI - HORMA domains at the heart of meiotic chromosome dynamics. AB - HORMA domain proteins are required for the careful orchestration of chromosomal organization during meiosis. Kim et al. (2014) and Silva et al. (2014) now provide structural and functional insights into the roles of C. elegans HORMA proteins, revealing parallels to the function of the HORMA protein MAD2 in mitotic checkpoint signaling. PMID- 25458008 TI - A longer life for yeast with good memory. AB - Cell polarity establishment has been studied in great detail, but much less is known about mechanisms that prevent polarization. Reporting recently in Cell, Meitinger et al. (2014) identify an elaborate mechanism in yeast cells that efficiently inhibits Cdc42 activation in cytokinesis remnants. Failure of this "anti-polarization" memory increases replicative aging. PMID- 25458009 TI - RanBP1 governs spindle assembly by defining mitotic Ran-GTP production. AB - Accurate control of the Ras-related nuclear protein (Ran) GTPase cycle depends on the regulated activity of regulator of chromosome condensation 1 (RCC1), Ran's nucleotide exchange factor. RanBP1 has been characterized as a coactivator of the Ran GTPase-activating protein RanGAP1. RanBP1 can also form a stable complex with Ran and RCC1, although the dynamics and function of this complex remain poorly understood. Here, we show that formation of the heterotrimeric RCC1/Ran/RanBP1 complex in M phase Xenopus egg extracts controls both RCC1's enzymatic activity and partitioning between the chromatin-bound and soluble pools of RCC1. This mechanism is critical for spatial control of Ran-guanosine triphosphate (GTP) gradients that guide mitotic spindle assembly. Moreover, phosphorylation of RanBP1 drives changes in the dynamics of chromatin-bound RCC1 pools at the metaphase-anaphase transition. Our findings reveal an important mitotic role for RanBP1, controlling the spatial distribution and magnitude of mitotic Ran-GTP production and thereby ensuring accurate execution of Ran-dependent mitotic events. PMID- 25458010 TI - DEPDC1B coordinates de-adhesion events and cell-cycle progression at mitosis. AB - Cells entering mitosis become rounded, lose attachment to the substrate, and increase their cortical rigidity. Pivotal to these events is the dismantling of focal adhesions (FAs). How mitotic reshaping is linked to commitment to divide is unclear. Here, we show that DEPDC1B, a protein that accumulates in G2, coordinates de-adhesion events and cell-cycle progression at mitosis. DEPDC1B functions as an inhibitor of a RhoA-based signaling complex, which assembles on the FA-associated protein tyrosine phosphatase, receptor type, F (PTPRF) and mediates the integrity of FAs. By competing with RhoA for the interaction with PTPRF, DEPDC1B promotes the dismantling of FAs, which is necessary for the morphological changes preceding mitosis. The circuitry is relevant in whole organisms, as shown by the control exerted by the DEPDC1B/RhoA/PTPRF axis on mitotic dynamics during zebrafish development. Our results uncover an adhesion dependent signaling mechanism that coordinates adhesion events with the control of cell-cycle progression. PMID- 25458012 TI - A predictive model of bifunctional transcription factor signaling during embryonic tissue patterning. AB - Hedgehog signaling controls pattern formation in many vertebrate tissues. The downstream effectors of the pathway are the bifunctional Gli transcription factors, which, depending on hedgehog concentration, act as either transcriptional activators or repressors. Quantitatively understanding the interplay between Gli activator and repressor forms for patterning complex tissues is an open challenge. Here, we describe a reductionist mathematical model for how Gli activators and repressors are integrated in space and time to regulate transcriptional outputs of hedgehog signaling, using the pathway readouts Gli1 and Ptch1 as a model system. Spatially resolved measurements of absolute transcript numbers for these genes allow us to infer spatiotemporal variations of Gli activator and repressor levels. We validate our model by successfully predicting expression changes of Gli1 and Ptch1 in mutants at different developmental stages and in different tissues. Our results provide a starting point for understanding gene regulation by bifunctional transcription factors during mammalian development. PMID- 25458011 TI - Eya1 interacts with Six2 and Myc to regulate expansion of the nephron progenitor pool during nephrogenesis. AB - Self-renewal and proliferation of nephron progenitor cells and the decision to initiate nephrogenesis are crucial events directing kidney development. Despite recent advancements in defining lineage and regulators for the progenitors, fundamental questions about mechanisms driving expansion of the progenitors remain unanswered. Here we show that Eya1 interacts with Six2 and Myc to control self-renewing cell activity. Cell fate tracing reveals a developmental restriction of the Eya1(+) population within the intermediate mesoderm to nephron forming cell fates and a common origin shared between caudal mesonephric and metanephric nephrons. Conditional inactivation of Eya1 leads to loss of Six2 expression and premature epithelialization of the progenitors. Six2 mediates translocation of Eya1 to the nucleus, where Eya1 uses its threonine phosphatase activity to control Myc phosphorylation/dephosphorylation and function in the progenitor cells. Our results reveal a functional link between Eya1, Six2, and Myc in driving the expansion and maintenance of the multipotent progenitors during nephrogenesis. PMID- 25458013 TI - The PI3K class III complex promotes axon pruning by downregulating a Ptc-derived signal via endosome-lysosomal degradation. AB - Developmental axon pruning is essential for wiring the mature nervous system, but its regulation remains poorly understood. Here we show that the endosomal lysosomal pathway regulates developmental pruning of Drosophila mushroom body gamma neurons. We demonstrate that the UV radiation resistance-associated gene (UVRAG) functions together with all core components of the phosphatidylinositol 3 kinase class III (PI3K-cIII) complex to promote pruning via the endocytic pathway. By studying several PI(3)P binding proteins, we found that Hrs, a subunit of the ESCRT-0 complex, required for multivesicular body (MVB) maturation, is essential for normal pruning progression. Thus, we hypothesized the existence of an inhibitory signal that needs to be downregulated. Finally, our data suggest that the Hedgehog receptor, Patched, is the source of this inhibitory signal likely functioning in a Smo-independent manner. Taken together, our in vivo study demonstrates that the PI3K-cIII complex is essential for downregulating Patched via the endosomal-lysosomal pathway to execute axon pruning. PMID- 25458014 TI - Assessment of patients' awareness and factors influencing patients' demands for sedation in endodontics. AB - INTRODUCTION: Endodontic therapy is perceived by many as a procedure to be feared. Many studies have reported that fear and anxiety are major deterrents to seeking dental care in general, but only a few deal with the use of sedation in endodontic therapies. The purpose of this study was to assess patients' awareness of and factors influencing the potential demand for sedation in endodontics. We hypothesized that there is an association between demographic factors and the demand for sedation in endodontics. METHODS: A survey consisting of 24 questions was given to patients 18 years and older who presented to the graduate endodontic clinic. Results were collected and statistically analyzed. RESULTS: Thirty-six percent of patients reported that their perception of sedation was being put to sleep, and 27% perceived it as related to or reducing pain. Concerns associated with endodontic therapy were the fear of pain (35%), fear of needles (16%), difficulty getting numb (10%), and anxiety (7%). The 2 major demographic factors that influenced the demand for sedation were cost and the level of anxiety (P < .05). Fifty-one percent showed a positive interest in sedation for endodontic therapy if the option of sedation was available. CONCLUSIONS: The demand for sedation in endodontics is high. Patients' understanding of sedation varies. More patients would consider having endodontic procedures if sedation was available. The provision of sedation by endodontists could result in more patients accepting endodontic therapies. PMID- 25458016 TI - Tanning lamps: health effects and reclassification by the Food and Drug Administration. AB - Tanning lamps have long been considered a class I medical device under regulation by the Food and Drug Administration (FDA). A growing body of research has repeatedly documented the association between elective indoor tanning and several negative health consequences. These accepted findings have prompted action by the FDA to officially reclassify tanning lamps as a class II medical device. The main purpose of this review is to update practitioners on the current state of tanning lamp classification and highlight the practical implications of this recent change. This information can be used by clinicians to easily reference this important action, and empower patients with a better understanding of the risks associated with indoor tanning. PMID- 25458017 TI - Shared medical appointments for the preoperative consultation visit of Mohs micrographic surgery. AB - BACKGROUND: Shared medical appointments (SMAs) allow patients with similar diagnoses to be simultaneously educated and cared for by 1 provider. SMAs appear well suited for Mohs micrographic surgery because all patients receive similar information about skin cancer pathophysiology, prognosis, prevention, treatment, reconstructive options, and wound care. OBJECTIVE: We sought to create a SMA for the preoperative consultation visit of Mohs micrographic surgery and to evaluate patient satisfaction with this model. METHODS: A pilot SMA was implemented. Patient satisfaction was assessed via a 13-question survey over a 6-month period. RESULTS: In all, 149 patients were seen in our SMAs. The survey response rate was 65.8%. Respondents answered Likert scale questions with a mean value of 4.29 +/- 0.09 (on a 1-5 scale, where 5 is the best). Patients found the SMA model useful (84.7%) and would attend another SMA in the future (80.6%). LIMITATIONS: Limitations include the sample size of the study, relatively homogenous patient population, possible response bias, and a potential selection bias (as all participants in the SMA chose this type of appointment rather than a conventional one). CONCLUSIONS: SMA can be successfully used for the Mohs preoperative consultation visit with high patient satisfaction. PMID- 25458015 TI - Sunitinib impedes brain tumor progression and reduces tumor-induced neurodegeneration in the microenvironment. AB - Malignant gliomas can be counted to the most devastating tumors in humans. Novel therapies do not achieve significant prolonged survival rates. The cancer cells have an impact on the surrounding vital tissue and form tumor zones, which make up the tumor microenvironment. We investigated the effects of sunitinib, a small molecule multitargeted receptor tyrosine kinase inhibitor, on constituents of the tumor microenvironment such as gliomas, astrocytes, endothelial cells, and neurons. Sunitinib has a known anti-angiogenic effect. We found that sunitinib normalizes the aberrant tumor-derived vasculature and reduces tumor vessel pathologies (i.e. auto-loops). Sunitinib has only minor effects on the normal, physiological, non-proliferating vasculature. We found that neurons and astrocytes are protected by sunitinib against glutamate-induced cell death, whereas sunitinib acts as a toxin towards proliferating endothelial cells and tumor vessels. Moreover, sunitinib is effective in inducing glioma cell death. We determined the underlying pathways by which sunitinib operates as a toxin on gliomas and found vascular endothelial growth factor receptor 2 (VEGFR2, KDR/Flk1) as the main target to execute gliomatoxicity. The apoptosis-inducing effect of sunitinib can be mimicked by inhibition of VEGFR2. Knockdown of VEGFR2 can, in part, foster the resistance of glioma cells to receptor tyrosine kinase inhibitors. Furthermore, sunitinib alleviates tumor-induced neurodegeneration. Hence, we tested whether temozolomide treatment could be potentiated by sunitinib application. Here we show that sunitinib can amplify the effects of temozolomide in glioma cells. Thus, our data indicate that combined treatment with temozolomide does not abrogate the effects of sunitinib. In conclusion, we found that sunitinib acts as a gliomatoxic agent and at the same time carries out neuroprotective effects, reducing tumor-induced neurodegeneration. Thus, this report uncovered sunitinib's actions on the brain tumor microenvironment, revealing novel aspects for adjuvant approaches and new clinical assessment criteria when applied to brain tumor patients. PMID- 25458018 TI - Tanning accelerators: prevalence, predictors of use, and adverse effects. AB - BACKGROUND: Tanning accelerators are topical products used by indoor tanners to augment and hasten the tanning process. These products contain tyrosine, psoralens, and/or other chemicals. OBJECTIVE: We sought to better define the population using accelerators, identify predictors of their use, and describe any related adverse effects. METHODS: This cross-sectional study surveyed 200 indoor tanners about their tanning practices and accelerator use. Primary analysis compared accelerator users with nonusers with respect to questionnaire variables. Descriptive statistics and chi(2) contingency tables were applied to identify statistically significant variables. RESULTS: Of respondents, 53% used accelerators; 97% were female and 3% were male with a median age of 22 years (range: 19-67). Users were more likely to spray tan, tan frequently, and be addicted to tanning. Acne and rashes were more common in accelerator users. Adverse reactions to accelerators prevented their further use 31% of the time. LIMITATIONS: A limited adult population was evaluated; exact accelerator ingredients were not examined. CONCLUSIONS: Tanning accelerator users are high risk indoor tanners who tan more frequently and who are more likely addicted to tanning. Acne and rashes are more common with these products and act as only mild deterrents to continued use. Additional research should investigate accelerators' longer-term health effects. PMID- 25458019 TI - Clinical characteristics, prognostic factors, and survival of 393 patients with mycosis fungoides and Sezary syndrome in the southeastern United States: a single institution cohort. AB - BACKGROUND: Limited data exist on patients with mycosis fungoides (MF) and Sezary syndrome (SS) from the southeastern United States, a region with a high proportion of African Americans (AA). OBJECTIVES: We sought to determine clinical characteristics, prognostic factors, and survival of patients with MF/SS in a southeastern US cohort, compare with other cohorts, and validate proposed revisions in MF/SS staging. METHODS: This was a retrospective chart review of patients from an academic dermatology referral center (Atlanta, GA) from 1998 to 2013. Kaplan-Meier estimates were calculated for overall survival, disease specific survival, and progression; univariate and multivariate Cox proportional hazard models were used for assessment of prognostic variables. RESULTS: Of 393 patients, 55.2% were white, 43.3% AA, and 1.5% other; 52.7% were male and 47.3% female (ratio 1.1:1). Mean age was 53.6 years; mean age among AA was 48.9 years. In all, 19.6% died of disease; 21.9% experienced disease progression. Advanced TNMB classification, presence of a circulating clone without phenotypic evidence of blood involvement, and older age were predictors of poor disease-specific survival in the multivariate analysis, whereas AA race was not. LIMITATIONS: This study was from a single academic center. CONCLUSIONS: Outcomes of our patients generally paralleled those of other geographic regions. MF/SS may affect younger patients and more women than previously recognized, particularly among AA. Survival among AA may be more favorable than that observed in prior reports. Our data support the validity of the staging criteria revisions for MF/SS. PMID- 25458020 TI - [Quality of individual health history in in-patient electronic medical records]. PMID- 25458021 TI - The efficacy of excimer laser pretreatment for calcified nodule in acute coronary syndrome. AB - Stent underexpansion is known as a major cause of restenosis and stent thrombosis in calcified coronary lesions. We report a case of calcified nodule pretreated with excimer laser coronary angioplasty (ELCA) in acute coronary syndrome (ACS). Excimer laser use altered underlying lesion morphology such as calcified nodule and accompanied plaque and thrombus. Pretreatment of ELCA may be a useful tool to get a full expansion of the deployed stent without distal embolism for calcified nodule in ACS. PMID- 25458022 TI - [Translation, cultural adaptation, validity and reliability of the shoulder rating questionnaire for use in Brazil]. AB - OBJECTIVE: To translate and culturally adapt the Shoulder Rating Questionnaire (SRQ) to the Brazilian Portuguese language, and to determine its validity, reliability and sensitivity to change in patients with functional impairment of the shoulder. METHODS: After translation and back-translation of the original version by four independent translators, the instrument was reviewed by a committee of experts and subsequently applied to eight patients with shoulder injury (target audience) to produce the Portuguese version. Then, this version was applied to 102 patients selected from four reference centers for functional treatment of the shoulder, who had a variety of clinical diagnoses, educational levels, socioeconomic, and cultural backgrounds. The evaluation was performed twice with an interval of four weeks between each application. RESULTS: The Brazilian version of SRQ was equivalent in terms of semantics and showed good levels of reliability (Cronbach's Alpha=0.89 and ICC=0.83). The reproducibility was high (Spearman Correlation Coefficient=0.82) and validity of the items that ranged from 0.54 to 0.99 was considered excellent. The Cohen's d and T test for repeated measures showed that the instrument is able to monitor and track improvements in shoulder function. CONCLUSION: Psychometric criteria were found, which justify the applicability of the Brazilian version of SRQ in individuals with shoulder functional impairments. PMID- 25458024 TI - [Acupuncture in fibromyalgia: a randomized, controlled study addressing the immediate pain response]. AB - OBJECTIVE: To evaluate the efficacy of acupuncture in the treatment of fibromyalgia, considering the immediate response of the visual analogue pain scale (VAS) as its primary outcome. METHODS: Randomized, controlled, double-blind study including 36 patients with fibromyalgia (ACR 1990) selected from the outpatient rheumatology clinic, Santa Casa de Misericordia, Ponta Grossa, PR. Twenty-one patients underwent an acupuncture session, under the principles of the traditional Chinese medicine, and 15 patients underwent a placebo procedure (sham acupuncture). For pain assessment, the subjects completed a Visual Analogue Scale (VAS) before and immediately after the proposed procedure. The mean change in VAS was compared among groups. RESULTS: The variation between the final and initial VAS values was -4.36+/-3.23 (P=0.0001) in the treatment group and -1.70+/-1.55 in the control group (P=0.06). The difference in terms of amplitude of variation of VAS (initial - final VAS) among groups favored the actual procedure (P=0.005). The effect size (ES) for the treatment group was d=1.7, which is considered a large effect. Although small, the statistical power of the sample for these results was very relevant (94.8%). CONCLUSION: Acupuncture has proven effective in the immediate pain reduction in patients with fibromyalgia, with a quite significant effect size. PMID- 25458023 TI - [Epidemiologic profile of juvenile-onset compared to adult-onset spondyloarthritis in a large Brazilian cohort]. AB - OBJECTIVE: To analyze the clinical and epidemiologic characteristics of juvenile onset spondyloarthritis (SpA) (< 16 years) and compare them with a group of adult onset (>= 16 years) SpA patients. PATIENTS AND METHODS: Prospective, observational and multicentric cohort with 1,424 patients with the diagnosis of SpA according to the European Spondyloarthropathy Study Group (ESSG) submitted to a common protocol of investigation and recruited in 29 reference centers participants of the Brazilian Registry of Spondyloarthritis (RBE - Registro Brasileiro de Espondiloartrites). Patients were divided in two groups: age at onset<16 years (JOSpA group) and age at onset >= 16 years (AOSpA group). RESULTS: Among the 1,424 patients, 235 presented disease onset before 16 years (16.5%). The clinical and epidemiologic variables associated with JOSpA were male gender (p<0.001), lower limb arthritis (p=0.001), enthesitis (p=0.008), anterior uveitis (p=0.041) and positive HLA-B27 (p=0.017), associated with lower scores of disease activity (Bath Ankylosing Spondylitis Disease Activity Index - BASDAI; p=0.007) and functionality (Bath Ankylosing Spondylitis Functional Index - BASFI; p=0.036). Cutaneous psoriasis (p<0.001), inflammatory bowel disease (p=0.023), dactylitis (p=0.024) and nail involvement (p=0.004) were more frequent in patients with adult-onset SpA. CONCLUSIONS: Patients with JOSpA in this large Brazilian cohort were characterized predominantly by male gender, peripheral involvement (arthritis and enthesitis), positive HLA-B27 and lower disease scores. PMID- 25458025 TI - [The relationship between hemoglobin level and disease activity in patients with rheumatoid arthritis]. AB - OBJECTIVES: This study aims to investigate the relationship of hemoglobin level with disease activity in patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: The hemoglobin level, the 66/68 joint count, the Disease Activity Score 28 joints (DAS28), the Health Assessment Questionnaire (HAQ), the Visual Analog Scales (VAS), the Modified Sharp Score (MSS), and the disease duration in 89 patients with RA were used to analyze the possible relationship. The World Health Organization (WHO) criteria for anemia uses a hemoglobin threshold of<120g/L for women and<130g/L for men. Pregnant or breastfeeding patients, patients with a history of other inflammatory or no inflammatory arthritis, malignancies, chronic infectious and inflammatory diseases and other diseases in the stage of decompensation were excluded from the study. RESULTS: Anemia was observed in 64% of the patients (1(st) group); the other group (2(nd) group) had normal levels of hemoglobin. There was a statistically significant negative correlation between hemoglobin level and swollen and tender joints' count, DAS28, HAQ score, VAS, MSS, and disease duration (p<0.001). DAS28, HAQ score, VAS, MSS, swollen and tender joints' count and disease duration were significantly (p<0.001) higher in 1(st) versus 2(nd) group. CONCLUSION: In conclusion, we determined that low hemoglobin level was significantly related to disability and impairment, disease activity, articular damage, pain and disease duration in RA patients in our study. We believe that by keeping disease activity under control, therefore preventing articular damage, the disability in RA patients can be lessened or possibly even eliminated. PMID- 25458026 TI - [Influence of gait speed on plantar pressure in subjects with unilateral knee osteoarthritis]. AB - OBJECTIVE: Changing gait speed is a common strategy to manipulate exercise intensity during physical exercise, but may elicit higher impact forces and consequent joint loading. Here we analyzed the effects of increasing walking velocity on plantar pressure and asymmetries in elderly with knee osteoarthritis (OA). Our hypothesis was that the contralateral limb could receive higher loading compared to the OA limb in the different walking speeds tested. METHODS: Twelve elderly with unilateral knee OA walked at different self-selected speeds along a 10 m pass way stepping on an instrumented mat for measurement of plantar pressure at preferred, slow and fast gait speeds. Five steps were recorded for each speed. Plantar pressure data were compared between the speeds and legs. RESULTS: speeds were significantly different between them (p<0.05). Mean and peak plantar pressure increased when speed changed from slow to fast (p<0.05). Velocity of the center of pressure increased and the single stance time decreased when walk speed was increased (p<0.05). Any asymmetries were observed. CONCLUSION: Increasing gait speed from slow to fast in subjects with unilateral knee OA significantly affected variables of plantar pressure, but asymmetries between committed and contralateral leg were not detected. PMID- 25458027 TI - [Oral N-acetylcysteine in the treatment of Raynaud's phenomenon secondary to systemic sclerosis: a randomized, double-blind, placebo-controlled clinical trial]. AB - OBJECTIVE: To evaluate the safety and efficacy of N-acetylcysteine (NAC) orally on digital microcirculation blood flow in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc). METHODS: This was a randomized, double blind, placebo-controlled trial in which 42 patients with SSc received oral NAC at a dose of 600mg tid (21 patients, mean age 45.6+/-9.5 years) or placebo (21 patients, mean age 45.0+/-12.7 years) for four weeks. The primary endpoint was the change in cutaneous microcirculation blood flow before and after cold stimulation measured by laser Doppler imaging (LDI) at weeks 0 and 4. The frequency and severity of RP and the number of digital ulcers were also measured at weeks 0 and 4. The adverse events were recorded in the fourth week. RESULTS: There was no significant change in digital blood flow assessed by LDI before or after cold stimulus after four weeks of NAC or placebo. Both groups showed significant improvement in the frequency and severity of RP attacks, with no difference between the two groups. At the end of the study, the placebo group had three digital ulcers, while the NAC group showed no ulcers. NAC was well tolerated and no patient discontinued the treatment. CONCLUSIONS: NAC orally at a dose of 1800mg/day showed no vasodilator effect on hands' microcirculation after four weeks of treatment in patients with RP secondary to SSc. PMID- 25458028 TI - [Influence of physical activity on quality of life in postmenopausal women with osteoporosis]. AB - The present study aimed to conduct a review on the association between exercise and quality of life in postmenopausal women with osteoporosis. A search was performed in PubMed, SciELO, SpringerLink and Sport Discus databases to identify relevant articles that addressed this association. We used the following descriptors in the English and Portuguese languages: osteoporosis, exercise, menopause, women, physical activity, quality of life/osteoporose, exercicio fisico, menopausa, mulheres, atividade fisica, qualidade de vida. Regarding quality of life and physical aspects like muscle strength and balance, with the exception of two studies, all others have reported improvement in quality of life and in physical domain of participants. Intervention with exercise has proved essential to improving the quality of life of women with postmenopausal osteoporosis. Activities that aim at the improvement of muscle strength and balance are essential to prevent falls, and consequently to reduce the incidence of fractures in this population. PMID- 25458029 TI - [Positron emission tomography with (18)F-FDG in the evaluation of patients with rheumatoid arthritis--a systematic review]. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a disease characterized by inflammation of the synovial membrane. Several authors have investigated the role of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose ((18)F FDG) in RA. OBJECTIVES: To systematically review the current literature on the role of (18)F-FDG PET in the diagnosis, determination of disease activity and assessment of treatment response in patients with RA. METHODS: Searches were conducted in Medline, Cochrane Library, Lilacs, Pubmed and Scopus in Portuguese, English and Spanish languages, using the keywords "rheumatoid arthritis", "synovitis", "FDG", "PET", "glycolytic metabolism" and "disease activity". RESULTS: 142o articles were initially identified, of which only 40 were related directly to the subject. Twelve original articles and three case reports that met the inclusion criteria were selected. DISCUSSION: The presence of activated macrophages and fibroblasts in pannus are responsible for the intense periarticular uptake of (18)F-FDG. The uptake patterns do not allow the differential diagnosis with other arthritides. The uptake intensity and the number of joints involved are metabolic parameters of disease activity that correlate well with the composite indices. Longitudinal studies of PET have proven useful in assessing the response to treatment with anti-TNF. When performed early, PET can predict the therapeutic response. CONCLUSION: Although the actual role of this new technique for the investigation of RA is not yet established, (18)F-FDG PET is a promising tool in determining the activity and prediction of response to treatment of patients with RA. PMID- 25458030 TI - [Colonic perforation due to invasive amebic colitis during anti-TNF therapy for spondyloarthritis]. AB - TNF blockade has been successful in the treatment of some rheumatic diseases such as spondyloarthritis. Many infectious complications have been reported with anti TNF therapy, mainly bacterial, mycobacterial, viral and fungal infections. Entamoeba histolytica is an extracellular protozoan parasite that mainly causes colitis and hepatic abscess; bowel perforation is an uncommon complication with high mortality. TNF is considered the principal mediator of cell immunity against amebiasis. Initially, it is chemotactic to E. histolytica, enhancing its adherence to enterocyte via galactose inhibitable lectin, and then activating macrophages to kill ameba though the release of NO, so that TNF blocking could be harmful, increasing amebic virulence. We describe the case of a 46-year-old woman with spondyloarthritis who presented a colonic perforation due to invasive amebic colitis during anti-TNF use. PMID- 25458041 TI - Taking a break from the lab: can it really be done? AB - Scientists are by nature a determined, dedicated breed and do not give up easily even when confronted with seemingly insurmountable obstacles. So why would anyone who has embarked along this career path choose to take a break from it, and can one really return to a successful academic career after this break? PMID- 25458042 TI - A novel segmentation approach for noisy medical images using intuitionistic fuzzy divergence with neighbourhood-based membership function. AB - Medical image segmentation demands higher segmentation accuracy especially when the images are affected by noise. This paper proposes a novel technique to segment medical images efficiently using an intuitionistic fuzzy divergence-based thresholding. A neighbourhood-based membership function is defined here. The intuitionistic fuzzy divergence-based image thresholding technique using the neighbourhood-based membership functions yield lesser degradation of segmentation performance in noisy environment. Its ability in handling noisy images has been validated. The algorithm is independent of any parameter selection. Moreover, it provides robustness to both additive and multiplicative noise. The proposed scheme has been applied on three types of medical image datasets in order to establish its novelty and generality. The performance of the proposed algorithm has been compared with other standard algorithms viz. Otsu's method, fuzzy C means clustering, and fuzzy divergence-based thresholding with respect to (1) noise-free images and (2) ground truth images labelled by experts/clinicians. Experiments show that the proposed methodology is effective, more accurate and efficient for segmenting noisy images. PMID- 25458043 TI - The cutoff level of free/total prostate specific antigen (f/t PSA) ratios in the diagnosis of prostate cancer: a validation study on a Turkish patient population in different age categories. AB - We investigated an optimal cutoff level of free/total PSA ratios (f/t PSA) in predicting prostate cancer in different age groups, focusing on the avoidance of unnecessary prostate biopsies. A total of 4955 men were enrolled into the study. Serum tPSA, fPSA, and f/t PSA ratios were determined for the study population. All males who had suspicious digital rectal examination and tPSA > 4 ng/mL underwent transrectal ultrasonography-guided prostate biopsy. Receiver operating characteristic (ROC) curves for each group were generated by plotting the sensitivity versus 1-specificity for the f/t PSA ratio. The sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were obtained using various f/t PSA ratio cutoffs for different age groups. There were 657 patients with a PSA level of 4-10 ng/mL. According to sensitivity and specificity f/t% PSA cutoff points were determined to be 10%, 15%, 15%, and 10% in 50-59 years, 60-69 years, >70 years, and all ages categories, respectively, in patients with initial PSA level of 4-10 ng/mL. f/t PSA ratio had an area under the curve (AUC) value of 0.81 (95% confidence level: 0.80-0.82) for all age groups in detecting prostate cancer. f/t PSA ratio has an AUC value of 0.669 (0.632-0.705) in detecting prostate cancer among patients with a PSA level of 4 10 ng/mL. Ten percent of f/t PSA ratio had the highest specificity with PLR and 30% f/t PSA ratio had the highest sensitivity with lower NLR in the all-age categories. The current study shows that the use of f/t PSA ratio in patients with PSA levels of 4-10 ng/mL should enhance the specificity of PSA screening and decrease the number of unnecessary biopsies. The age-related changes warrant further investigation in a large, multicentric, and multinational population to improve the clinical use of f/t PSA cutoffs. PMID- 25458044 TI - Role of cytokine gene (interferon-gamma, transforming growth factor-beta1, tumor necrosis factor-alpha, interleukin-6, and interleukin-10) polymorphisms in the risk of oral precancerous lesions in Taiwanese. AB - Oral squamous cell carcinoma can be preceded by some benign oral lesions with malignant potential, including leukoplakia, erythroplakia, oral lichen planus, and oral submucous fibrosis. There are different degrees of inflammatory cells infiltration in histopathology. Inflammatory cytokines may play a pathogenic role in the development of oral precancerous lesions (OPCLs). Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. We hypothesized that the risk of OPCLs might be associated with cytokine gene polymorphisms of interferon (IFN)-gamma, transforming growth factor (TGF)-beta1, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-10. In the present study, 42 OPCL patients and 128 controls were analyzed for eight polymorphisms in five different cytokine genes [IFN-gamma (+874 T/A), TGF-beta1 (codons 10 T/C and 25 G/C), TNF-alpha (-308 G/A), IL-6 (-174 G/C), and IL-10 (-1082 A/G, -819 T/C, and -592 A/C)]. Cytokine genotyping was determined by the polymerase chain reaction sequence-specific primer technique using commercial primers. Allele and genotype data were analyzed for significance of differences between cases and controls using the Chi-square (chi(2)) test. Two-sided p < 0.05 were considered to be statistically significant. A series of multivariate logistic regression models, adjusted for age, sex, betel quid chewing, alcohol consumption, and smoking, was constructed in order to access the contribution of homozygous or heterozygous variant genotypes of polymorphisms. The TNF-alpha (-308) polymorphism was significantly associated with OPCLs. There were significant differences in the distribution of AA, GA, and GG genotypes between OPCL patients and controls (p = 0.0004). Patients with the AA or GA genotype had a 3.63-fold increased risk of OPCLs. The TGF-beta1 (codon 10 and 25) polymorphism was also significantly associated with OPCLs (p < 0.001). The IL-6 polymorphism was significantly associated with OPCLs. There are significant differences in the distribution of CC, GC, and GG genotypes between OPCL patients and controls (p < 0.001). Patients with the CC or GC genotype had a 35- or 20.59-fold increased risk of OPCLs. There were no significant differences in the distribution of IL-10 and IFN-gamma genotypes between different groups of control individuals and OPCL patients. The IL-6, TGF-beta1, and TNF-alpha gene polymorphisms may have a significant association with the development of OPCLs. PMID- 25458045 TI - The impact of general anesthesia on radiofrequency ablation of hepatocellular carcinoma. AB - This study investigates the impact of general anesthesia (GA) on percutaneous radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). A total of 118 treatment-naive HCC patients in Barcelona Clinic Liver Cancer curative stage were enrolled. Patients who underwent RFA with GA were designated as the GA group, and the others were identified as the non-GA group. All the percutaneous RFA procedures were performed by the same hepatologist. The GA group comprised 42 (44.1%) patients with 71 tumors (mean size, 2.53 cm) and the non-GA group had 66 patients (55.9%) with 90 tumors (mean size, 2.35 cm). Complete tumor ablation was achieved after one session in 92.3% of the 52 GA patients, and after one to three sessions in 92.4% of 66 non-GA patients. The GA group required significantly fewer RFA sessions to obtain a similar treatment effect (p < 0.001) and the duration of hospitalization was also shortened among the GA patients (4.4 +/- 0.9 days vs. 5.1 +/- 1.9 days, p = 0.044). The 2-year overall survival and recurrence free survival rates were not significantly different between the two groups. Overall, performing RFA with GA can decrease the number of sessions required to achieve complete tumor ablation in early stage HCC patients and shorten the hospitalization duration. PMID- 25458046 TI - The effect of intravenous paracetamol for the prevention of rocuronium injection pain. AB - Rocuronium is a nondepolarizing neuromuscular blocking agent used in anesthesia induction and is associated with considerable discomfort and burning pain during injection, which is reported to occur in 50-80% of patients. This study was carried out to investigate the effectiveness of intravenous paracetamol pretreatment compared with lidocaine and normal saline to prevent rocuronium injection pain. The study included 150 ASA I-II patients undergoing elective orthopedic, gastrointestinal, and gynecological procedures under general anesthesia. They were allocated into three groups according to pretreatment drugs: lidocaine (40 mg) (n = 50), paracetamol (n = 50), and normal saline group (n = 50). Before anesthesia induction with propofol, all patients were pretreated with rocuronium. The pain caused by the injection was evaluated. Local signs were assessed on the arm at the end of the injection, as well as 24 hours after recovery from anesthesia. There were no patients with blurred speech or vision and there was no respiratory depression in any group after pretreatment with the study drug. The level of pain on injection was statistically lower in those who had received paracetamol compared to normal saline (p = 0.009). There were more patients in the saline group with severe pain (p < 0.001). Paracetamol relieved the rocuronium injection pain better than normal saline but lidocaine was the best of the three drugs (p < 0.001). PMID- 25458047 TI - Does the etiology affect the outcome and satisfaction rates of penile prosthesis implantation surgery? AB - Our aim was to compare the outcomes and satisfaction rates of men undergoing penile prostheses implantation (PPI) secondary to radical prostatectomy (RP) and other causes of vasculogenic erectile dysfunction (ED). A total of 142 patients, of whom 60 underwent PPI due to ED following RP (Group 1) and 82 underwent PPI due to ED with other vasculogenic causes (Group 2) were included in this study. The preoperative erectile status was evaluated with the International Index of Erectile Function (IIEF). The satisfaction of patients and partners were evaluated by a telephone interview using Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire and Erectile Dysfunction Inventory of Treatment Satisfaction Partner Survey. Preoperative mean IIEF scores were significantly lower in Group 1 (17.5 +/- 6.4 vs. 24.2 +/- 5.1, p = 0.01). For Groups 1 and 2, the mean EDITS scores of the patients were 58 +/- 10 and 71 +/- 8, respectively, and that for the partners were 46 +/- 8 and 65 +/- 7, respectively. Group 1 had significantly lower scores both for the EDITS and the EDITS Partner Survey (p = 0.03, p = 0.01, respectively). Patients who had undergone RP and their partners were found to have lower satisfaction rates compared to patients with other causes of vasculogenic ED who had penile implant surgery. From this point of view, it is important to know the patient's expectations about the treatment outcomes and a preoperative psychological and sexual counseling should be managed for possible treatment alternatives after RP. PMID- 25458048 TI - Single bolus parecoxib attenuates sore throat after laryngeal microsurgery: a randomized double-blind control study. AB - Laryngeal microsurgery is performed to assess disorders of the larynx. Parecoxib is the only parenterally administered selective cyclooxygenase (COX)-2 inhibitor widely used in acute pain control. The purpose of this study is to assess the analgesic effects of parecoxib compared with morphine for postoperative sore throat in patients undergoing laryngeal microsurgery. Fifty patients were randomly allocated to receive either parecoxib 0.5 mg/kg or morphine 50 MUg/kg prior to anesthesia induction. General anesthesia was maintained with sevoflurane 2-4%. Postoperative sore throat and other outcomes were measured at a postanesthesia care unit (PACU) 4 hours and 24 hours postoperatively. The severity of postoperative sore throat was assessed by sore throat score as follows: none (0) = no pharyngeal or laryngeal discomfort; mild (1) = no pain at rest, but swallowing induced mild pain or discomfort; moderate (2) = constant pain without swallowing exacerbation; and severe (3) = constant pain with swallowing or respiratory exacerbation. The incidences of postoperative side effects (nausea, vomiting, itching, dizziness, and somnolence) were also recorded. Demographic data from the parecoxib (n = 25) and morphine (n = 25) groups did not differ significantly. The parecoxib group depicted similar sore throat scores as the morphine group at three measured postoperative time points. Patients requiring postoperative analgesics were comparable between the parecoxib group and morphine group (2/25, 8% vs. 3/25, 12%, p = 0.64). Overall postoperative adverse events were fewer in the parecoxib group than the morphine group (3/25, 12% vs. 9/25, 36%, p = 0.047). Both parecoxib and morphine are effective to attenuate postoperative sore throat after laryngeal microsurgery. Parecoxib may be an effective and well-tolerated injectable analgesic to manage postoperative sore throat after laryngeal microsurgery. PMID- 25458049 TI - The metabolic syndrome and risk of coronary artery disease in patients with chronic schizophrenia or schizoaffective disorder in a chronic mental institute. AB - The prevalence rate of metabolic syndrome (MS) and coronary artery disease (CAD) has been found to be high in patients with chronic schizophrenia. Current evidence shows that CAD is underdiagnosed in this group. Our study evaluated the prevalence of MS and the risk of CAD in patients with chronic schizophrenia in a chronic care mental hospital in southern Taiwan. We included all patients with the diagnosis of schizophrenia or schizoaffective disorder. We collected all laboratory, physical examination, psychiatric interview, and chart review data. We also evaluated the risk of CAD in these patients using the Framingham point system. There was no significant age difference in the MS prevalence rate in these patients. The young patients with schizophrenia in our study tended to have a higher prevalence of MS than the general population. In addition, female patients had a higher prevalence rate of MS than males. Based on the Framingham point system, we found the 10-year risk of CAD to be higher among the patients with schizophrenia than in the general population. Our study highlights the importance of the high risk of MS in both younger and older patients with schizophrenia, without a significant relationship to the use of antipsychotics. More complete cohort studies are needed to confirm these findings. Psychiatrists may want to establish more specific and detailed clinical guidelines for patients with chronic schizophrenia with comorbid physical diseases, especially MS and CAD. PMID- 25458050 TI - Primary cutaneous mucinous carcinoma of the breast. PMID- 25458051 TI - Recurrent local advanced hypopharyngeal squamous cell carcinoma with isolated quadriceps femoralis metastasis. PMID- 25458052 TI - Ureteral calculi combined with xanthogranulomatous pyelonephritis mimicking renal tuberculosis in a male child. PMID- 25458055 TI - Construction of 2-Pyrone Skeleton via Domino Sequence between 2-Acyl-1 Chlorocyclopropanecarboxylate and Amines. AB - A base-promoted domino reaction of 2-acyl-1-chlorocyclopropaneformic esters with amines is described. In the presence of inorganic bases like Cs2CO3 or Mg(OEt)2, the reaction proceeded smoothly in acetonitrile to afford 2-pyrone derivatives in modest to excellent yields (up to 97%). This reaction provides a straightforward and transition metal-free protocol to efficiently construct 2-pyrone skeleton. A possible mechanistic process involving 1,2-elimination of hydrogen chloride, aza Michael addition, ring-opening, and intramolecular lactonization was suggested to rationalize the formation of the target 2-pyrone derivatives. PMID- 25458053 TI - A novel strategy for targeted killing of tumor cells: Induction of multipolar acentrosomal mitotic spindles with a quinazolinone derivative mdivi-1. AB - Traditional antimitotic drugs for cancer chemotherapy often have undesired toxicities to healthy tissues, limiting their clinical application. Developing novel agents that specifically target tumor cell mitosis is needed to minimize the toxicity and improve the efficacy of this class of anticancer drugs. We discovered that mdivi-1 (mitochondrial division inhibitor-1), which was originally reported as an inhibitor of mitochondrial fission protein Drp1, specifically disrupts M phase cell cycle progression only in human tumor cells, but not in non-transformed fibroblasts or epithelial cells. The antimitotic effect of mdivi-1 is Drp1 independent, as mdivi-1 induces M phase abnormalities in both Drp1 wild-type and Drp1 knockout SV40-immortalized/transformed MEF cells. We also identified that the tumor transformation process required for the antimitotic effect of mdivi-1 is downstream of SV40 large T and small t antigens, but not hTERT-mediated immortalization. Mdivi-1 induces multipolar mitotic spindles in tumor cells regardless of their centrosome numbers. Acentrosomal spindle poles, which do not contain the bona-fide centrosome components gamma tubulin and centrin-2, were found to contribute to the spindle multipolarity induced by mdivi-1. Gene expression profiling revealed that the genes involved in oocyte meiosis and assembly of acentrosomal microtubules are highly expressed in tumor cells. We further identified that tumor cells have enhanced activity in the nucleation and assembly of acentrosomal kinetochore-attaching microtubules. Mdivi 1 inhibited the integration of acentrosomal microtubule-organizing centers into centrosomal asters, resulting in the development of acentrosomal mitotic spindles preferentially in tumor cells. The formation of multipolar acentrosomal spindles leads to gross genome instability and Bax/Bak-dependent apoptosis. Taken together, our studies indicate that inducing multipolar spindles composing of acentrosomal poles in mitosis could achieve tumor-specific antimitotic effect, and mdivi-1 thus represents a novel class of compounds as acentrosomal spindle inducers (ASI). PMID- 25458054 TI - Biomarker validation and testing. AB - A tumor biomarker is a molecular or process-based change that reflects the status of an underlying malignancy. A tumor biomarker may be identified and measured by one or more assays, or tests, for the biomarker. Increasingly, tumor biomarker tests are being used to drive patient management, either by identifying patients who do not require any, or any further, treatment, or by identifying patients whose tumors are so unlikely to respond to a given type of treatment that it will cause more harm than good. A tumor biomarker assay should only be used to guide management if it has analytical validity, meaning that it is accurate, reproducible, and reliable, and if it has been shown to have clinical utility. The latter implies that high levels of evidence are available that demonstrate that application of the tumor biomarker test for a given use context results in better outcomes, or similar outcomes with less cost, than if the assay were not applied. Use contexts include risk categorization, screening, differential diagnosis, prognosis, prediction of therapeutic activity or monitoring disease course. Very few tumor biomarker tests have passed these high bars for routine clinical application. However, if tumor biomarker tests are going to be used to drive patient care, than an understanding, and careful assessment, of these concepts are essential, since "A Bad Tumor Biomarker Test Is as Bad as a Bad Drug." PMID- 25458057 TI - Profunda femoris injury following lesser trochanter displacement: complications following intramedullary femoral nailing. AB - Iatrogenic vascular complications following intramedullary nailing of hip fractures is a rare occurrence. We describe a case report of injury to the profunda femoris artery due to a displaced lesser trochanteric fragment following ambulation. We discuss the mechanism of arterial injury and associated signs in addition to possible preventative strategies. PMID- 25458056 TI - Modified tension band fixation and coracoclavicular stabilisation for unstable distal clavicle fracture. AB - BACKGROUND: The purpose of this study was to report a new surgical technique for the treatment of unstable distal clavicle fracture with modified tension band fixation (MTBF) and coracoclavicular (CC) stabilisation, and evaluate the radiologic and clinical outcome of these patients. MATERIAL AND METHODS: Thirteen patients who had a fracture of the distal clavicle (Neer classification type IIb) were treated with MTBF and CC stabilisation. After the CC stabilisation was performed with a suture anchor or flip button, internal fixation using MTBF was carried out. Each patient was followed up for a minimum of 12 months and their clinical and radiological results were analysed. RESULTS: The mean period required for fracture union was 12.6 (range, 8-24) weeks and union was successfully completed in all cases. The mean Constant score at the final follow up was 94.7 (88-100); the modified University of California, Los Angeles (UCLA) shoulder rating scale was 31.3 points (range, 22-35). All patients returned to normal daily activities at an average of 3.7 months postoperatively (range, 3-5 months). One patient had a new fracture around drilled holes for CC stabilisation by inappropriate tunnelling. CONCLUSION: MTBF and CC stabilisation is a useful technique for treating an unstable distal clavicle fracture. This procedure provides minimal incision and stable fixation without causing any further acromioclavicular joint injury to those with distal clavicle fractures. PMID- 25458058 TI - Is body temperature an independent predictor of mortality in hip fracture patients? AB - INTRODUCTION: Admission body temperature is a critical parameter in all trauma patients. Low admission temperature is strongly associated with adverse outcomes. We have previously shown, in a prospective study that low admission body temperature is common and associated with high mortality in hip fracture patients (Uzoigwe et al., 2014). However, no previous studies have evaluated whether admission temperature is an independent predictor of mortality in hip fracture patients after adjustment for the 7 recognised independent prognostic indicators (Maxwell et al., 2008). METHODS: We retrospectively collated data on all patients presenting to our institution between June 2011 and February 2013 with a hip fracture. This included patients involved in the original prospective study (Uzoigwe et al., 2014). Admission tympanic temperature, measured on initial presentation at triage, was recorded. The prognosticators of age, gender, source of admission, abbreviated mental test score, haemoglobin, co-morbid disease and the presence or absence of malignancy were also recorded. Using multiple logistic regression, adjustment was made for these potentially confounding prognostic indicators of 30-day mortality, to determine if admission low body temperature were independently linked to mortality. RESULTS: 1066 patients were included. 781 patients, involved in the original prospective study (Uzoigwe et al., 2014), presented in the relevant time frame and were included in the retrospective study. The mean age was 81. There were 273 (26%) men and 793 (74%) women. 407 (38%) had low body temperature (<36.5 degrees C). Adjustment was made for age, gender, source of admission, abbreviated mental test score, haemoglobin, co morbid disease and the presence or absence of malignancy. Those with low body temperature had an adjusted odds ratio of 30-day mortality that was 2.1 times that of the euthermic (36.5-37.5 degrees C). CONCLUSIONS: Low body temperature is strongly and independently associated with 30-day mortality in hip fracture patients. PMID- 25458059 TI - The inpatient fracture neck of femur: an important subgroup of patients. AB - Fractured neck of femur (FNOF) is an increasing problem for the National Health Service (NHS) with 61,508 recorded on the National Hip Fracture Database (NHFD) in 2012-2013 and treatment of such patients is estimated to cost the NHS L1.5 billion per year. Inpatients falling in hospital and sustain a FNOF have rarely been studied as a separate group of patients to assess standards of patient care, time to operative management, and patient mortality. Of 694 patients sustaining an acute FNOF at a single trust between January 2012 and June 2013, 40 patients (5.8%) sustained an inpatient FNOF. 19 patients (47.5%) were male and 15 patients (37.5%) had an ASA grade of 4 or 5, compared to 153 patients (23.4%) and 127 patients (19.4%) respectively of "community" FNOF. 39 of 40 patients received operative management. Patients with an "inpatient" FNOF were less likely to be admitted to an orthopaedic ward within 4 h (30%) and receive operative management within 48 h (65%) according to "Blue Book" standards. Results according to best practice tariff (BPT) were also significantly reduced for the "inpatient" FNOF group, with 23 patients (57.5%) receiving operative management within 36 h and only 19 patients (47.5%) achieving BPT compared to 76.5% and 72.5% respectively for "community" FNOF patients. Mortality among inpatients reached 40% at 120 days and 50% at 1 year, significantly higher than community FNOF patients after multivariate analysis. Patients sustaining an "inpatient" FNOF are more likely to have significant medical co-morbidity and require aggressive medical and surgical management, especially due to their increased risk of mortality post-operatively. Such injuries have direct and indirect financial implications to a health care trust, which can be minimised by prompt management of these patients. This study highlights the need for a standardised protocol of management of this important subgroup of patients and for further work on falls prevention strategies within the National Health Service. PMID- 25458060 TI - Pertrochanteric fractures (AO/OTA 31-A1 and A2) not amenable to closed reduction: causes of irreducibility. AB - PURPOSE: To define the unique radiographic features, operative treatment, and complications of pertrochanteric fractures (AO/OTA 31-A1 and A2) which are not amenable to the usual closed reduction manoeuvres. METHODS: During a 2-year period (from August 2011 until December 2013), 212 patients with pertrochanteric fractures were treated at our level I trauma centre. A retrospective review was undertaken to determine which of these fractures were not reducible via the routine closed reduction manoeuvres and required some form of open reduction. These fractures were assessed for radiographic markers of irreducibility, surgical findings, reduction techniques, and perioperative complications. RESULTS: Twenty-four patients had fractures, which were not amenable to closed reduction and underwent open reduction. These fractures could be grouped into four patterns. A preoperative CT scan was available for at least two cases of each pattern, which provided further insights into the cause of irreducibility by closed means. These included a variant where the proximal fragment is locked underneath the shaft fragment (3 cases), bisected lesser trochanter with a locked proximal fragment (3 cases), irreducibility due to entrapped posteromedial fragment at the fracture site (6 cases) and a variant where the proximal fragment is flexed passively by the underlying lesser trochanter (12 cases). CONCLUSIONS: Pertrochanteric fractures, which are not amenable to closed reduction, are uncommon, but are heralded by unique radiographic features. These patients warrant special consideration in terms of recognition and management. The specific radiographic markers should alert the surgeon to this injury pattern and its related difficulty encountered during closed reduction. Once reduction is achieved, however, these fractures follow an uneventful course. PMID- 25458061 TI - Radiological assessment of the safe zone for medial minimally invasive plate osteosynthesis in the distal femur with computed tomography angiography. AB - INTRODUCTION: Surgical treatment options for distal femur fractures include intramedullary nailing or plating using a lateral or lateral parapatellar approach. However, medial plating is required for additional stability in some fractures such as severely comminuted fractures and periprosthetic fractures, and in those for which use of a lateral plate or nail is not appropriate. This study aimed to explore the safe zone for medial minimally invasive plate osteosynthesis of the distal femur with computed tomography angiography. MATERIAL AND METHODS: In a series of 30 patients, the region of interest between the lesser trochanter (LT) to the adductor tubercle (AT) was divided into six levels (I to VI), and the distance from the femur to the femoral artery (FA) was measured. At each level, the medial half of the femur was divided into eight sections that were assigned 'A to H' from anteromedial to posteromedial, and the position of the FA and the deep femoral artery (DFA) was recorded. RESULTS: The average length from the LT to AT was 295.0 mm. The average distance to FA was 38.0 mm, 29.9 mm, 26.9 mm, 27.0 mm, 21.8 mm, and 12.2 mm from level I to VI, respectively. The FA was positioned posteromedially below level IV and positioned at C-H below level II, which was out of the anterior aspect of the femur. The DFA was in the same location as the FA between levels II and III. CONCLUSION: The anteromedial aspect of the distal half of the femur is the safe zone, and a long plate can be positioned safely in this zone at the anterior aspect up to the level of 8 cm below the LT. PMID- 25458062 TI - Management of comminuted patellar fracture with non-absorbable suture cerclage and Nitinol patellar concentrator. AB - PURPOSE: To evaluate the effectiveness and safety of a fixation technique for comminuted patellar fracture using non-absorbable suture cerclage and nickel titanium patellar concentrator (Ni-Ti PC). METHODS: Twenty-nine consecutive patients with displaced comminuted patellar fractures accepted internal fixation procedure using Ni-Ti PC augmented with different types of non-absorbable suture cerclage. During follow-up, the clinical grading scales of Bostman, including range of movement, pain, work, atrophy, assistance in walking, effusion, giving way, and stair-climbing, were used to evaluate the clinical results. Complications including implant loosening, fragment displacement, bone nonunion, infection, breakage of the implants, painful hardware, and post-traumatic osteoarthritis were also assessed. RESULTS: Patients were followed up for a mean period of 27 months. The bone union radiographically occurred approximately 2.5 months without implant loosening and fragment displacement. According to Bostman method, satisfactory results were obtained, and the mean score at final follow-up was 28 (range 20-30) points. Twenty-two patients with excellent results had mean score of 29.8 +/- 0.5 (range 28-30) and seven patients with good results had mean score of 22.7 +/- 3.14 (range 20-27). No postoperative complications, such as infection, dislocation, breakage of the implants, painful hardware, and post traumatic osteoarthritis, were observed. CONCLUSION: Ni-Ti PC fixation with non absorbable suture cerclage is a feasible approach for comminuted patellar fractures. Firm fixation with this technique resulted in satisfactory outcomes without obvious complications. PMID- 25458063 TI - Functional outcomes of bicondylar tibial plateau fractures treated with dual buttress plates and risk factors: a case series. AB - OBJECTIVE: Although there are different ways to treat bicondylar tibial plateau fractures, treatment remains as a challenge to most orthopaedic surgeons. The purpose of this study was to assess the outcomes of dual buttress plates fixation in treatment of bicondylar tibial plateau fractures and to determine risk factors for outcome. METHODS: Clinical data for 74 patients with bicondylar tibial plateau fracture were retrospectively reviewed. Dual buttress plates were placed through two incisions. All patients were evaluated both radiographically and clinically according to Rasmussen scores and Hospital for Special Surgery (HSS) scores during the follow-up period. The data were analyzed using univariate analysis and multivariate logistic regression analysis to identify independent risk factors for functional outcome (Rasmussen functional score). RESULTS: Rasmussen anatomic score was excellent in 34, good in 23, and fair in 17 patients. Sixty-nine patients were followed for a mean of 27 months. Functional results of excellent and good were obtained in 56(81.2%) patients by Rasmussen functional score and in 57 (82.6%) patients by HSS score. Univariate analysis showed Arbeitsgemeinschaft fur Osteosynthesefragen (AO) fracture type and reduction quality were significantly related to functional results. Multivariate analysis showed that AO fracture type and reduction quality were independent risk factors for outcome. CONCLUSION: Dual buttress plates technique provided a favourable quality of fracture reduction and satisfactory clinical function. Appropriate selection for operation chance, limited soft tissue stripping and filling of osseous defects may lessen or prevent serious complications. Fracture reduction quality and AO fracture type were independent risk factors for clinical function. PMID- 25458064 TI - Are bilateral tibial shaft fractures associated with an increased risk for adverse outcome? AB - INTRODUCTION: Long bone fractures are assumed to be an independent risk factor for systemic complications and death after trauma. Multiple studies have identified an increased risk for mortality and morbidity in patients with bilateral femoral fractures. Data about bilateral tibial shaft fractures is rare. The aim of our study was to analyze if patients with bilateral tibial shaft fractures are at higher risk for systemic complications. METHODS: We performed a retrospective analysis of the TraumaRegister DGU(r) from 1993 to 2008. Inclusion criteria were unilateral or bilateral tibial shaft fractures and an age >=16. Additionally to the overall collective we analyzed different subgroups (divided into different injury severities and treatment periods). RESULTS: 1899 patients with unilateral and 175 patients with bilateral tibial shaft fractures were included. Age, gender and mean ISS (25.8 vs. 26.2, p = 0.51) in the two groups were comparable. Regarding the entire study population, patients with bilateral tibial shaft fractures showed no significant higher incidence of respiratory organ failure (29.5% vs. 23.1%, p = 0.076) or mortality (20.0% vs. 16.3%, p = 0.203). However, subgroup analysis showed a significant higher rate of pulmonary organ failure for bilateral tibial shaft fractures as compared to unilateral tibial shaft fractures in the group ISS < 25 (20.7% vs. 11.7%, p = 0.023). Multivariate regression analysis identified the additional tibial shaft fracture as an independent risk factor for pulmonary organ failure (OR = 1.56) but not for mortality. DISCUSSION: The additional tibial shaft fracture is an independent risk factor for pulmonary organ failure but not for multiple organ failure or mortality. The impact of the additional tibial shaft fracture is especially pronounced in less severely injured patients (ISS < 25). These findings are comparable to results of bilateral femoral fracture studies and we therefore suggest to treat patients with bilateral tibial shaft fractures with the same caution as those with bilateral femoral fractures. PMID- 25458065 TI - The short musculoskeletal functional assessment (SMFA) score amongst surgical patients with reconstructive lower limb injuries in war wounded civilians. AB - BACKGROUND/OBJECTIVES: The MSF programme in Jordan provides specialized reconstructive surgical care to war-wounded civilians in the region. The short musculoskeletal functional assessment score (SMFA) provides a method for quantitatively assessing functional status following orthopaedic trauma. In June 2010 the Amman team established SMFA as the standard for measuring patients' functional status. The objective of this retrospective study is to evaluate whether the SMFA scores can be useful for patients with chronic war injuries. METHODS: All patients with lower limb injuries requiring reconstruction were enrolled in the study. Each patient's SMFA was assessed at admission, at discharge from Amman and during follow-up in home country. In the analysis we compared patients with infected versus non-infected injuries as well as with both high and low admissions dysfunctional index (ADI). RESULTS: Among infected patients, higher ADI correlated with more surgeries and longer hospital stay. Infected patients with ADI >50 required an average of 2.7 surgeries while those with ADI <50, averaged 1.7 operations (p = 0.0809). Non-infected patients with ADI >50 required an average of 1.6 operations compared to 1.5 for those with ADI <50 (p = 0.4168). CONCLUSIONS: The ADI score in our sample appeared to be useful in two areas: (1) hospital course in patients with infection, where a high ADI score correlated with longer hospital stays and more surgeries, and (2) prognosis, which was better for non-infected patients who had high ADI scores. A scoring system that predicts functional outcome following surgical reconstruction of lower limb injuries would be enormously useful. PMID- 25458066 TI - Flap reconstruction for soft-tissue defects with exposed hardware following deep infection after internal fixation of ankle fractures. AB - The aim of the present study was to determine the outcome for patients treated with flap reconstruction following deep ankle fracture infection with exposed hardware. Out of 3041 consecutive ankle fracture operations in 3030 patients from 2006 to 2011, we identified 56 patients requiring flap reconstruction following deep infection. Thirty-two of these patients could be examined at a follow-up visit. Olerud-Molander Ankle (OMA) score, 15D score, Numeric Rating Scale (NRS), and clinical examination were used to assess the outcome. A total of 58 flap reconstructions were performed in 56 patients with a mean age of 57 years (range 25-93 years) and mean follow-up time of 52 months. The most commonly used reconstruction was a distally based peroneus brevis muscle flap with a split thickness skin graft. A microvascular free flap was required in only one patient. 22 (39%) patients required subsequent surgical interventions because of a flap related complication. With flap reconstruction, hardware could eventually be salvaged in 53% of patients with a non-consolidated fracture. The mean OMA score was fair or poor in 53% of the patients, and only 56% had recovered their pre injury level of function. Half of the patients had shoe wear limitations. The 15D score showed a significantly poorer health-related quality of life compared to an age-standardised sample of the general population. The mean pain NRS was 2.1 (range 0-6), and the mean satisfaction NRS was 6.6 (range 0-10). Our study showed that successful treatment of a soft-tissue defect with exposed hardware following ankle fracture infections can be achieved with local flaps. Despite eventual reconstructive success, complications are common. Patients perceive a poorer health-related quality of life, have shoe wear limitations, and only half of them achieve their pre-injury level of function. PMID- 25458067 TI - Increased osteogenic capacity of Reamer/Irrigator/Aspirator derived mesenchymal stem cells. AB - INTRODUCTION: Donor-site morbidity, complications and availability remain concerns in autologous bone grafting today. The Reamer/Irrigator/Aspirator system (RIA) provides an alternative method to overcome these problems. According to literature, RIA graft possesses a higher osteogenic potency. This study compares iliac crest and RIA graft performance by determining their in vitro osteogenic capacity in a porcine model. METHODS: Osteogenic capacity and cell content was determined in RIA and iliac crest bone grafts harvested from six female domestic white pigs. Cells initially washed off, and cells harvested with collagenase were analysed separately and in combination. Alkaline phosphatase expression (ALP) and cell numbers were evaluated after 7 and 14 days of culture. Matrix mineralisation was quantified after 14 days. RESULTS: Cell cultures showed a significant increase of matrix mineralisation by RIA-derived cells compared to iliac crest bone graft (p = 0.0313). The yield of collagenase derived cells was increased in the RIA group and a synergy between washed off and collagenase derived cells was observed. Cell proliferation was similar in both groups. DISCUSSION: The osteogenic differentiation capacity of cell populations isolated from the RIA derived bone graft surpasses that of iliac crest derived cells. It is proposed that the observed effect can be attributed to the origin of the cells and to the specific action of the RIA system. This study provides further evidence indicating that RIA bone graft provides superior osteogenic properties compared to iliac crest bone graft. PMID- 25458068 TI - The burden of trauma in four rural district hospitals in Malawi: a retrospective review of medical records. AB - BACKGROUND: Few injury surveillance systems collect data in sub-Saharan Africa. This medical record review of four rural hospitals provides baseline data on the burden of trauma in Malawi. METHODS: We reviewed all outpatient, inpatient, and mortuary records for one full year at four of the 28 district hospitals in Malawi: Dedza in central Malawi, Mangochi in the east, Nkhata Bay in the north, and Thyolo in the south. We used descriptive and comparative statistics to examine characteristics of patients and the data file. RESULTS: During 2012, 18,735 trauma patients were treated at the four district hospitals. Trauma cases accounted for 3.5% of the 541,170 patient visits. In total, 60.8% of trauma patients were male; 39.1% were 0-14 years old and 50.4% were 15-49 years old. The logbooks were missing information about the primary type of injury for 44.9% of patients and about injury cause for 82.7%. Of the recorded trauma diagnoses, the most common injuries were soft tissue injuries, fractures, and sprains. The most commonly reported causes of injuries were animal bites (mostly dog bites), road traffic injuries, assaults, burns, and falls. CONCLUSIONS: The development and implementation of improved methods for acquiring more complete, accurate, and useful trauma data in Malawi and other low-income countries requires addressing difficulties that might result in missing data. Increased injury surveillance is critical for improving trauma care and meeting the emerging global demand for burden of disease data. PMID- 25458069 TI - The extent and application of patient diaries in Australian intensive care units: a national survey. AB - BACKGROUND: Critical illness can be a psychological stressor for patients and family members. Scandinavian studies have portrayed patient diaries as a supporting catalyst for patients and their families through a process of reflection and fact presentation. However, the small number of randomisation trials exhibits theoretical and methodological limitations. Given the increased interest amongst Australian Critical Care Nurses, further understanding of nurses' perceptions and use of patient diaries was warranted. OBJECTIVES: To identify nurses' perceptions of patient diary use and to describe their application within Australian ICUs. METHOD: A descriptive, exploratory study design using an online survey of the Australian College of Critical Care Nurses was used. Descriptive statistics illustrated participant responses and textual data were subjected to content analysis for emergent themes. RESULTS: Out of the 194 participants, 19% (n=37) reported patient diary use in their unit, with nine indicating some form of evaluation. Fifty (70%) of the non-diary users, who responded, indicated hesitancy to introduce them. Respondents noted a lack of guiding policies and potential medico-legal ambiguity. Content analysis revealed three themes, considering diaries as: communication tool, patient recovery tool and a family centred care strategy. CONCLUSION: Patient diary use appears to be in its infancy in Australia with a lack of guiding policy for format and processes including evaluation. Nurses using diaries were enthusiastic about the initiative, holding optimistic perceptions about the potential positive impact of diaries on patient and family outcomes. Further research on their efficacy is required. PMID- 25458070 TI - Age adjusted nationwide trends in the incidence of all cause and ST elevation myocardial infarction associated cardiogenic shock based on gender and race in the United States. AB - BACKGROUND: Recent improvement in the care of patients with myocardial infarction should lead to better outcome. The goal of this study was to evaluate the incidence of all cause cardiogenic shock (CS) and CS occurring in the setting of ST elevation myocardial infarction (STEMI) in the United States. METHOD: The Nationwide Inpatient Sample (NIS) database was utilized to calculate the age adjusted incident rate of CS from 1996 to 2006 based on ICD-9 coding in the setting of STEMI. Furthermore, we evaluated this trend based on race and gender. RESULTS: A total population of 52,784,917 patients was available between 1996 and 2006. We found that the incidence of all cause CS has not changed over time. However, in the setting of STEMI, CS has been declining slowly over the last 10 years. The age-adjusted rate for CS was 4.3 per 100,000 in 1996 which remained steady with an incidence of 3.1 per 100.000 in 2006 (p<0.01). This decline was persistent across different race or gender. However, African Americans and female gender had persistently lower rate of CS. CONCLUSION: Advancement in the treatment of acute STEMI has led to gradual reduction in the incidence of STEMI related cardiogenic shock irrespective of ethnicities or gender suggesting improving outcome of patients presenting with STEMI in recent years. PMID- 25458071 TI - Medical devices: US medical device regulation. AB - Medical devices are regulated by the US Food and Drug Administration (FDA) within the Center for Devices and Radiological Health. Center for Devices and Radiological Health is responsible for protecting and promoting the public health by ensuring the safety, effectiveness, and quality of medical devices, ensuring the safety of radiation-emitting products, fostering innovation, and providing the public with accurate, science-based information about the products we oversee, throughout the total product life cycle. The FDA was granted the authority to regulate the manufacturing and marketing of medical devices in 1976. It does not regulate the practice of medicine. Devices are classified based on complexity and level of risk, and "pre-1976" devices were allowed to remain on the market after being classified without FDA review. Post-1976 devices of lower complexity and risk that are substantially equivalent to a marketed "predicate" device may be cleared through the 510(k) premarket notification process. Clinical data are typically not needed for 510(k) clearance. In contrast, higher-risk devices typically require premarket approval. Premarket approval applications must contain data demonstrating reasonable assurance of safety and efficacy, and this information typically includes clinical data. For novel devices that are not high risk, the de novo process allows FDA to simultaneously review and classify new devices. Devices that are not legally marketed are permitted to be used for clinical investigation purposes in the United States under the Investigational Device Exemptions regulation. PMID- 25458072 TI - Impaired working memory in geriatric depression: an FMRI study. AB - OBJECTIVE: Older adults with major depressive disorder (MDD) experience poor cognitive and behavioral outcomes as MDD occurs in the context of other age related brain changes. Patients with depression often have impairments on measures of frontal lobe functioning such as working memory. Understanding the effects of depression on cognitive functioning in older adults is important for the development of treatment strategies that focus on cognitive changes as well as mood. METHODS: Eleven older adults with current MDD and 12 nondepressed comparison participants (all aged 60 years and older) performed the N-back test of working memory during fMRI. RESULTS: Depressed older adults performed worse than nondepressed participants on the N-back task. Depressed older adults had decreased lateral frontal and parietal activation during the most difficult working memory load condition on the N-back compared with nondepressed older adults. CONCLUSION: Cognitive dysfunction in geriatric depression may be related to reorganization of brain networks involved in working memory. PMID- 25458074 TI - Rabies vaccination among migrant workers in Thailand. PMID- 25458075 TI - Eradicating leprosy in Saudi Arabia: outcome of a ten-year surveillance (2003 2012). AB - BACKGROUND: The Kingdom of Saudi Arabia (KSA) has a sentinel surveillance system on leprosy for effective monitoring of the disease. METHODS: A retrospective epidemiological analysis of all cases of leprosy captured by the surveillance system between 2003 and 2012 was conducted. RESULTS: Over the 10-year period, there were 242 reported cases of leprosy in KSA, 67% of which were in those aged between 15 and 44 years of age. Males accounted for over 77% of all cases and non Saudi nationals, dominated by Indians, and represented 57.4% of the total cases. Just over half of the cases were paucibacillary leprosy, and 9% were grade 2 disability. Makkah region accounted for nearly 42% of all cases. Annual trends showed an overall decline in the yearly cases and prevalence of the disease from 41 cases (0.018 per 10,000 population) in 2003 to 15 cases (0.005 per 10,000 population) in 2012. CONCLUSION: KSA needs to strengthen the leprosy surveillance systems, as well as health care and community education about the disease which will help effective monitoring, early detection and treatment of the disease. Moreover, the role or migrants in the importation of the disease needs to be addressed to achieve and maintain eradication. PMID- 25458073 TI - Functional manipulation of dendritic cells by photoswitchable generation of intracellular reactive oxygen species. AB - Reactive oxygen species (ROS) play an important role in cellular signaling as second messengers. However, studying the role of ROS in physiological redox signaling has been hampered by technical difficulties in controlling their generation within cells. Here, we utilize two inert components, a photosensitizer and light, to finely manipulate the generation of intracellular ROS and examine their specific role in activating dendritic cells (DCs). Photoswitchable generation of intracellular ROS rapidly induced cytosolic mobilization of Ca(2+), differential activation of mitogen-activated protein kinases, and nuclear translocation of NF-kappaB. Moreover, a transient intracellular ROS surge could activate immature DCs to mature and potently enhance migration in vitro and in vivo. Finally, we observed that intracellular ROS-stimulated DCs enhanced antigen specific T-cell responses in vitro and in vivo, which led to delayed tumor growth and prolonged survival of tumor-bearing mice when immunized with a specific tumor antigen. Therefore, a transient intracellular ROS surge alone, if properly manipulated, can cause immature DCs to differentiate into a motile state and mature forms that are sufficient to initiate adaptive T cell responses in vivo. PMID- 25458076 TI - Which soft lens power is better for piggyback in keratoconus? Part II. AB - PURPOSE: To evaluate how soft lens power affects rigid gas-permeable (RGP) lens power and visual acuity (VA) in piggyback fittings for keratoconus. METHODS: Sixteen keratoconus subjects (30 eyes) were included in the study. Piggyback contact lens fittings combining Senofilcon-A soft lenses of -6.00, -3.00, +3.00 and +6.00 D with Rose K2 RGP contact lenses were performed. Corneal topography was taken on the naked eye and over each soft contact lens before fitting RGP lenses. Mean central keratometry, over-refraction, RGP back optic zone radius (BOZR) and estimated final power as well as VA were recorded and analyzed. RESULTS: In comparison to the naked eye, the mean central keratometry flattened with both negative lens powers (p<0.05 in all cases), did not change with the +3.00 soft lens power (p=1.0); and steepened with the +6.00 soft lens power (p=0.02). Rigid gas-permeable over-refraction did not change significantly between different soft lens powers (all p>0.05). RGP's BOZR decreased significantly with both positive in comparison with both negative soft lens powers (all p<0.001), but no significant differences were found among negative- or positive-powers separately (both p>0.05). Estimated RGP's final power increased significantly with positive in comparison with negative lens powers (all p<0.001), but no significant differences were found among negative or positive lens powers separately (both p>0.05). Visual acuity did not change significantly between the different soft lens powers assessed (all p>0.05). CONCLUSION: The use of negative-powered soft lenses in piggyback fitting reduces RGP lens power without impacting VA in keratoconus subjects. PMID- 25458077 TI - Cosmetic iris implantation complicated by secondary angle closure. PMID- 25458078 TI - Simultaneous use of an (125)I-seed to guide tumour excision and (99m)Tc nanocolloid for sentinel node biopsy in non-palpable breast-conserving surgery. AB - PURPOSE: In the present study we describe patients with non-palpable breast lesions, in which an Iodine-125 ((125)I)-marker (or "seed") for excision of the primary tumour and Technetium-99m nanocolloid ((99m)Tc-nanocolloid) for sentinel node biopsy (SNB) are used simultaneously. The purpose was to investigate any interference between (125)I-seeds and (99m)Tc-nanocolloid by an in vitro and in vivo analysis. METHODS: Contrast/interference-ratios between (125)I and (99m)Tc count-rates were determined in vitro using a realistic simulation model. Measurements were performed with 3 gamma-probes with different crystal materials. In 25 consecutive patients (99m)Tc-nanocolloid was intratumourally administered at the site of a previously implanted (125)I-seed. Respectively, the (125)I setting and (99m)Tc-setting of the gamma-probe guided the wide local excision and SNB and maximum counts-per-second (cps) were measured. RESULTS: In vitro the different probes varied in (125)I- and (99m)Tc-sensitivity. The contrast-ratio between (125)I and (99m)Tc in the (125)I-channel was 4.6 for a 3-month-old (125)I seed using the most appropriate gamma-probe. In vivo the gamma-probe in the (125)I-setting measured a median of 16,300 cps at the tumour site compared to 4820 cps using the (99m)Tc-setting. The (125)I-seed could be well distinguished from the (99m)Tc-nanocolloid in 92% of the patients and 96% required a single operation. The SNB was successful in all patients. CONCLUSIONS: Simultaneous use of (125)I-seeds and (99m)Tc-nanocolloid is possible under well-standardised conditions. Non-palpable breast lesions can be safely excised using the (125)I seed in combination with a SN procedure. Use of (125)I-seeds is a next step within fine-tuning breast-conserving surgery that should lead to further investigation to confirm its value. PMID- 25458079 TI - Immune reconstitution inflammatory syndrome-associated Burkitt lymphoma after combination antiretroviral therapy in HIV-infected patients. PMID- 25458080 TI - Immunohistochemical expression of mTOR in germinal center and nongerminal center group of diffuse large B-cell lymphoma: a clinicopathological study. AB - BACKGROUND: The mammalian target of rapamycin (mTOR) pathway regulates many major cellular processes and is implicated in an increasing number of neoplasms, including lymphoma. PATIENTS AND METHODS: We correlated immunohistochemical expression of mTOR with germinal center and nongerminal center phenotype, B cell lymphoma-2 (bcl-2) and cellular homolog of the retroviral v-myconcogene (c-myc) expression, and International Prognostic Index (IPI) score in 31 patients with diffuse large B-cell lymphoma (DLBCL). RESULTS: Virtually all patients in our study with high mTOR scores had a germinal center phenotype. Furthermore within the germinal center subgroup, patients with high mTOR scores were associated with higher IPI scores (P < .001). CONCLUSION: Based on our results we propose that within the category of germinal center phenotype of DLBCL, mTOR expression might help identify a subset of patients with potentially more aggressive tumors who might benefit from use of targeted therapy using mTOR inhibitors. PMID- 25458082 TI - Optimizing the treatment of patients with multiple myeloma and renal impairment. AB - Renal impairment is a common complication of multiple myeloma. It is found in about 20% to 25% of patients at diagnosis and in <= 50% at some point during the disease course. The presence of renal insufficiency diminishes patients' quality of life and has been associated with increased mortality, although the outcomes of patients after successful induction therapy have been comparable to those with normal renal function. Therefore, the treatment of patients with multiple myeloma and renal impairment is a major challenge and should aim to achieve remission in a large proportion of patients. New drugs introduced to treat multiple myeloma during the past decade have an established place in the treatment of patients with renal failure. Bortezomib appears to be most beneficial in this setting and, combined with other drugs, provides a chance for rapid remission and related improvement of renal function. Immunomodulatory drugs such as thalidomide and lenalidomide have also been used successfully in patients with renal insufficiency, although for the latter drug appropriate dose adjustments are necessary. The presence of renal failure is not a contraindication to autologous bone marrow transplantation in patients eligible for this procedure. Among the classic cytotoxic agents, bendamustine, in particular, should be considered for patients with renal insufficiency. Appropriate supportive care is also extremely important in the treatment of patients with multiple myeloma and renal failure. It can include plasmapheresis and removal of free light chains with high cut-off hemodialysis, adapted dosages of bisphosphonates, and avoidance of drugs and conditions that can impair renal function. PMID- 25458081 TI - Modified EBMT Pretransplant Risk Score Can Identify Favorable-risk Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for AML, Not Identified by the HCT-CI Score. AB - INTRODUCTION: Risk scores have been developed for allogeneic hematopoietic cell transplantation (HCT) outcomes, such as the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and the modified European Group for Blood and Marrow Transplantation risk score (mEBMT) for acute leukemia. We investigated the influence of these scores for 350 patients who underwent transplantation for acute myeloid leukemia (AML). PATIENTS AND METHODS: The HCT-CI scores were grouped as 0 to 2 and >= 3 (231 and 119 patients, respectively) and the mEBMT scores as 0 to 2 and >= 3 (166 and 184 patients, respectively). RESULTS: Univariate analysis showed a significant association between the HCT-CI score and overall survival (OS) (P = .01), as did the mEBMT score (P = .002). The 5-year OS rate was 50% and 34% for a mEBMT score of 0 to 2 and >= 3, respectively. A subgroup of patients with a mEBMT score of 0 to 1 (n = 32) demonstrated a favorable OS of 75% at 5 years. This subgroup was younger (median age, 31 years), in first remission at transplantation, and had related donors. For the HCT-CI, the 5-year OS was 46% and 34% for a score of 0 to 2 and >= 3, respectively. Patients with an HCT-CI score of 0 (n = 94) had a 5-year OS of 44%. Multivariable analysis confirmed both the HCT-CI score and the mEBMT score, as previously grouped, as independent prognostic variables for both OS (P = .02 and P = .001, respectively) and nonrelapse mortality (NRM) (P = .01 and P = .003, respectively). CONCLUSION: The results of the present study have demonstrated that the HCT-CI and mEBMT are both prognostic for OS and NRM in our cohort. However, the mEBMT score can identify a favorable-risk subgroup of patients not identifiable using the HCT-CI. PMID- 25458083 TI - Long-Term Complete Responses to Combination Therapies and Allogeneic Stem Cell Transplants in Patients With Sezary Syndrome. AB - INTRODUCTION: Sezary syndrome (SS) is a rare leukemic variant of cutaneous T-cell lymphoma (CTCL). It presents with 80% erythroderma of the body, the presence of > 1000 Sezary cells in the peripheral blood, lymphadenopathy, and pruritus. Complete remission or response (CR) is rare in patients with SS. PATIENTS AND METHODS: An analysis of a prospective database identified 217 patients with SS (14%), whose long-term CRs (> 1 years) are reported. RESULTS: Of 217 patients with SS, 18 (8.3%) achieved a CR (14 Caucasians, 2 African Americans, and 2 Hispanics; 9 women and 9 men). The median age at diagnosis was 53.5 years (range, 21-80 years). The stage at the initial diagnosis was IB in 1, III in 2, IVA in 4, and IVB in 11. The median duration of CR was 6.25 years (range, 1-13 years). The average interval between the diagnosis and CR was 2 years (range, 1-11 years). Three CRs were achieved with immunomodulatory therapy (extracorporeal photopheresis, interferon-alpha, and/or retinoids), antibiotics, and topical steroids. One CR was achieved with alemtuzumab and another with mogamulizumab. The other 13 CRs were achieved after allogeneic stem cell transplantation (SCT). Seven patients achieved a durable response (DR) with a 5.1-year disease-free interval. Three patients with a DR after SCT died of sepsis after 2 years with relapse. Of the remaining 4 patients, 3 achieved a DR from medical therapy alone and were alive with stable disease at the last follow-up visit. The fourth patient died of sepsis 1 year after relapse. CONCLUSION: SS is a rare and aggressive type of CTCL that is refractory to current therapies. We report that CRs can be achieved in 3 methods: combined immunomodulatory therapy, targeted biologic agents, or total skin electron beams followed by nonablative allogeneic SCT. PMID- 25458084 TI - Effectiveness of homoharringtonine (omacetaxine mepesuccinate) for treatment of acute myeloid leukemia: a meta-analysis of Chinese studies. AB - The present meta-analysis provides an overview on the effectiveness of homoharringtonine (HHT) combination regimens to treat acute myeloid leukemia (AML). Because most of these studies were performed in China, Chinese published clinical studies were used for the analysis. A search for studies from 2006 to 2013 of regimens containing HHT for AML treatment was performed using published studies and Chinese databases in Mandarin. The complete response (CR) and overall response (OR) rates were analyzed, and the fixed effects model and random effects model (REM) were calculated. The heterogeneity of the studies was calculated using Q homogeneity statistics. The meta-analysis included 21 studies (n = 1310, n = 229 pediatric, and n = 216 elderly). HHT was given in combination with cytarabine, daunorubicin, idarubicin, aclacinomycin, mitoxantrone, or granulocyte colony-stimulating factor. Heterogeneity was seen in all analyzed pools, but it was most pronounced in retrospective studies. Overall, the REM showed a CR rate of 65.2%. However, in studies in which HHT-containing regimens were compared to regimens without HHT, the CR rates were 69.1% in randomized trials and 62.8% in retrospective studies. Additionally, in studies with exclusively elderly patients, the CR rate was considerably lower than it was for the studies with mixed age populations (47.5% vs. 65.2%). Higher overall CR rates for HHT containing regimens in AML treatment in the Chinese studies suggest that HHT could be an active agent in the management of AML. Additional clinical trials are warranted to evaluate the efficacy of HHT in AML treatment. PMID- 25458085 TI - Small-angle neutron scattering studies of mineralization on BSA coated citrate capped gold nanoparticles used as a model surface for membrane scaling in RO wastewater desalination. AB - Bovine serum albumin (BSA) coated on citrate capped gold nanoparticles (BSA-GNPs) was exposed to a simulated wastewater effluent (SSE) in order to study the mineralization and thereby mimic scaling at biofouled membranes of reverse osmosis (RO) wastewater desalination plants. RO is a leading technology of achieving freshwater quality as it has the capability of removing both dissolved inorganic salts and organic contaminants from tertiary wastewater effluents. The aim was to better understand one of the major problems facing this technology which is fouling of the membranes, mainly biofouling and scaling by calcium phosphate. The experiments were performed using the small-angle neutron scattering (SANS) technique. The nanoparticles, GNPs, stabilized by the citrate groups showed 30 A large particles having a homogeneous distribution of gold and citrate with a gold volume fraction of the order of 1%. On the average two BSA monomers are grafted at 2.4 GNPs. The exposed BSA-GNPs to SSE solution led to immediate mineralization of stable composite particles of the order of 0.2 MUm diameter and a mineral volume fraction between 50% and 80%. The volume fraction of the mineral was of the order of 10(-5), which is roughly 3 times larger but an order of magnitude smaller than the maximum possible contents of respectively calcium phosphate and calcium carbonate in the SSE solution. Considering the extreme low solubility product of calcium phosphate, we suggest total calcium phosphate and partially (5-10%) calcium carbonate formation in the presence of BSA-GNPs. PMID- 25458086 TI - Systematic characterization of cell cycle phase-dependent protein dynamics and pathway activities by high-content microscopy-assisted cell cycle phenotyping. AB - Cell cycle progression is coordinated with metabolism, signaling and other complex cellular functions. The investigation of cellular processes in a cell cycle stage-dependent manner is often the subject of modern molecular and cell biological research. Cell cycle synchronization and immunostaining of cell cycle markers facilitate such analysis, but are limited in use due to unphysiological experimental stress, cell type dependence and often low flexibility. Here, we describe high-content microscopy-assisted cell cycle phenotyping (hiMAC), which integrates high-resolution cell cycle profiling of asynchronous cell populations with immunofluorescence microscopy. hiMAC is compatible with cell types from any species and allows for statistically powerful, unbiased, simultaneous analysis of protein interactions, modifications and subcellular localization at all cell cycle stages within a single sample. For illustration, we provide a hiMAC analysis pipeline tailored to study DNA damage response and genomic instability using a 3-4-day protocol, which can be adjusted to any other cell cycle stage dependent analysis. PMID- 25458087 TI - Does the study design really compare apples to apples? PMID- 25458088 TI - Reply to letter to editor 'Does the study design really compare apples to apples?'. PMID- 25458089 TI - In reply. PMID- 25458090 TI - Diabetes mellitus, hyperglycemia, hemoglobin A1C and the risk of prosthetic joint infections in total hip and knee arthroplasty. AB - Diabetes mellitus is an established risk factor for infections but evidence is conflicting to what extent perioperative hyperglycemia, glycemic control and treatment around the time of surgery modify the risk of prosthetic joint infections (PJIs). In a cohort of 20,171 total hip and knee arthroplasty procedures, we observed a significantly higher risk of PJIs among patients with a diagnosis of diabetes mellitus (hazard ratio [HR] 1.55, 95% CI 1.11, 2.16), patients using diabetes medications (HR 1.56, 95% CI 1.08, 2.25) and patients with perioperative hyperglycemia (HR 1.59, 95% CI 1.07, 2.35), but the effects were attenuated after adjusting for body mass index, type of surgery, ASA score and operative time. Although data were limited, there was no association between hemoglobin A1c values and PJIs. PMID- 25458091 TI - Does intramedullary canal irrigation reduce fat emboli? A randomized clinical trial with transesophageal echocardiography. AB - The effect of medullary cavity irrigation on fat emboli during total knee arthroplasty (TKA) was evaluated. Thirty female patients with osteoarthritis were randomly assigned to undergo conventional TKA without irrigation (conventional group) or with medullary canal saline irrigation (irrigation group). The four chamber view was monitored by transesophageal echocardiography (TEE) and echogenic reflections of fat emboli were observed. The grey-scale score and area ratio of fat emboli were calculated during TKA. Hemodynamic parameters were simultaneously monitored and showed no obvious change between two groups (P>0.05). The average grey-scale score (P=0.016) and area ratio (P=0.033) of emboli were significantly decreased in irrigation group. Removal of medullary contents by irrigation could significantly reduce the formation of fat emboli during TKA. PMID- 25458092 TI - Topical versus intravenous tranexamic acid in total knee arthroplasty. AB - The objective of this study is to compare the effectiveness of intravenous versus topical application of tranexamic acid in patients undergoing knee arthroplasty. All patients who underwent primary knee arthroplasty at our total joint center over a 12-month period were included in the study. One surgeon utilized 1 g of IV TXA at time of incision in all patients (n=373) except those with a documented history of venous thromboembolism (VTE). Two surgeons utilized a topical application of TXA for all patients without exception (n=198) in which the joint was injected after capsular closure with 3 g TXA/100 mL saline. The transfusion rate was 0% in the topical group vs. 2.4% in the IV group and this was statistically significant (P<0.05). PMID- 25458094 TI - In response to "Is continuous adductor canal block better than continuous femoral nerve block after total knee arthroplasty? Effect on ambulation ability, early functional recovery and pain control: a randomized controlled trial". PMID- 25458093 TI - Transfusion cost savings with tranexamic acid in primary total knee arthroplasty from 2009 to 2012. AB - Tranexamic acid (TXA) has proven to be very advantageous to the total knee arthroplasty (TKA) population. With TXA, the need for allogeneic blood transfusion is reduced and thus hospital costs are reduced. In our hospital system, before TXA was used, facility cost was an estimated $84.90/TKA for blood transfusion and required 0.13 man-hours/TKA (transfusion rate 6.5%); after incorporating intravenous TXA, cost was $82.59/TKA for blood transfusion and TXA medication and 0.007 man-hours/TKA (transfusion rate 0.3%). There were no transfusions when TXA was applied topically, and the facility cost was $39.14/TKA and no employee hours consumed. Topical TXA has the potential to significantly reduce blood transfusions and decrease hospital man-hours/TKA as well as achieve larger cost saving. PMID- 25458095 TI - Co-morbidities and outcome of childhood psychogenic non-epileptic seizures--an observational study. AB - PURPOSE: To assess the psychiatric diagnoses and outcome in children with psychogenic non-epileptic seizures (PNES). METHODOLOGY: This hospital based observational study was performed on 44 children aged <16 years, who suspected to have psychogenic non-epileptic seizures based on video-EEG, from August 2005 to August 2012. The parameters noted were the psychiatric diagnosis, co-morbidities, management assessment and interventions (pharmacological and psychosocial), number and duration of follow-up visits, symptoms at follow-up, functioning as reflected by involvement in the social and scholastic work. RESULTS: All forty four children completed the evaluation. Thirty four children were diagnosed as having PNES and the underlying psychiatric diagnosis was conversion disorder (n=34, 77.3%). Co-morbid psychiatric disorders were present in 17 children (50%). The common co-morbidities were intellectual disability (n=8, 23.5%), specific learning disorder (n=5, 14.7%), and depression (n=5, 14.7%). Co-morbid epilepsy was present in 8 (23.5%) children and family history of epilepsy was present in 10 (29.4%) cases. About 17 of 34 (50.0%) patients had a minimum follow-up of 6 months (13.9 +/- 4.8 months). Twenty six children (76.5%) remained symptom free at the follow-up of 9.8 +/- 7 months. The remaining 10 children (22.7%) had non epileptic seizures with underlying diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), gratification disorder and other physiological conditions. CONCLUSIONS: Conversion disorder is a common diagnosis underlying psychogenic non epileptic seizures. Outcome was good in 76.5% children with PNES. A multidisciplinary approach is needed in the diagnosis and management of PNES. PMID- 25458096 TI - Epilepsy and mortality in Latin America. AB - PURPOSE: To assess the mortality related to epilepsy in Latin America. METHODS: We searched MEDLINE, EMBASE, and LILACS from inception to December 2013 for articles evaluating mortality in patients with epilepsy in Latin America. Studies were included if they evaluated any mortality outcome, included a population of subjects with recurrent seizures or epilepsy, and contained original data analysis. RESULTS: The search strategy yielded 177 publications in MEDLINE and EMBASE, and 59 publications in LILACS; of which 18 met inclusion criteria for our overall review of epilepsy and mortality in Latin America. Most excluded studies did not report the mortality or lacked original data. We also included two references obtained from 2 non-systematic reviews fulfilling our inclusion criteria, and able to provide data for our analyses. Five studies reported Standardized Mortality Ratio (SMR), and demonstrated that people with epilepsy had a higher risk of death than the general population. The SMRs reported in two community-based studies were 1.34 and 2.45. CONCLUSION: The information about mortality in epilepsy in Latin America is very scarce. Comparisons cannot be made among studies due to methodological differences. More studies are needed. PMID- 25458098 TI - Association of insulin receptor H1085H C>T, insulin receptor substrate 1 G972R and insulin receptor substrate 2 1057G/A polymorphisms with refractory temporal lobe epilepsy in Han Chinese. AB - PURPOSE: Insulin/insulin receptor (INSR) signaling plays diverse roles in the central nervous system, including regulation of blood glucose, synaptic plasticity, dendritic growth, modulation of electrophysiological activity, proliferation of astrocytes and neuronal apoptosis. Interestingly, many of these and/or related processes represent biological mechanisms associated with temporal lobe epilepsy (TLE). Thus, insulin signaling may play a role in the development of TLE and its therapeutic responses. We hypothesized that functional polymorphisms in the insulin pathway genes INSR, insulin receptor substrate 1 (IRS1), and IRS2 may be associated with the therapeutic responses of TLE. Therefore, in this study we analyzed the association of three single nucleotide polymorphisms (SNPs) showing a risk for TLE drug resistance using a hospital based case-control design. METHOD: Two hundred and one patients with refractory TLE and one hundred and seventy-five drug-responsive TLE patients were recruited for the study. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the genotypes of INSR His1085His, IRS1 G972R and IRS2 1057G/A. RESULTS: No significant differences between refractory and drug-responsive TLE patients were observed for the IRS1 G972R and IRS2 1057G/A polymorphisms (P>0.05), but a significant association was found for the INSR His1085His polymorphism for both genotypes (P=0.035) and alleles (P=0.011). IRS2 1057G/A combined with the INSR His 1085 His polymorphism increased the odds ratio of drug resistance in TLE (P=0.011, OR=2.263, 95% CI: 1.208-4.239). CONCLUSION: These results suggest that a genetic variation in the insulin signaling pathway genes may affect the therapeutic response of TLE. PMID- 25458097 TI - Development and validation of a seizure prediction model in critically ill children. AB - PURPOSE: Electrographic seizures are common in encephalopathic critically ill children, but identification requires continuous EEG monitoring (CEEG). Development of a seizure prediction model would enable more efficient use of limited CEEG resources. We aimed to develop and validate a seizure prediction model for use among encephalopathic critically ill children. METHOD: We developed a seizure prediction model using a retrospectively acquired multi-center database of children with acute encephalopathy without an epilepsy diagnosis, who underwent clinically indicated CEEG. We performed model validation using a separate prospectively acquired single center database. Predictor variables were chosen to be readily available to clinicians prior to the onset of CEEG and included: age, etiology category, clinical seizures prior to CEEG, initial EEG background category, and inter-ictal discharge category. RESULTS: The model has fair to good discrimination ability and overall performance. At the optimal cut off point in the validation dataset, the model has a sensitivity of 59% and a specificity of 81%. Varied cut-off points could be chosen to optimize sensitivity or specificity depending on available CEEG resources. CONCLUSION: Despite inherent variability between centers, a model developed using multi-center CEEG data and few readily available variables could guide the use of limited CEEG resources when applied at a single center. Depending on CEEG resources, centers could choose lower cut-off points to maximize identification of all patients with seizures (but with more patients monitored) or higher cut-off points to reduce resource utilization by reducing monitoring of lower risk patients (but with failure to identify some patients with seizures). PMID- 25458099 TI - Polymorphism of the multidrug resistance 1 gene MDR1/ABCB1 C3435T and response to antiepileptic drug treatment in temporal lobe epilepsy. AB - PURPOSE: A synonymous C to T variant at position 3435 (c.3435C>T) is one common polymorphism of the multidrug resistant 1 (MDR1) gene, which encodes the major transmembrane efflux transporter P-glycoprotein. It has been suggested that this polymorphism, and more specifically the 3435CC genotype, may be associated with the response to antiepileptic drug treatment. Here we wished to examine the role of such a candidate variant in a cohort of 175 patients (98 women and 76 men; mean +/- SD age: 47.90 +/- 17.64) with temporal lobe epilepsy (TLE). METHODS: Patients were classified according to whether they had drug-responsive (n=134) or drug-resistant (n=41) epilepsy. We also enrolled 175 healthy controls (93 women and 82 men; mean +/- SD age: 72.5 +/- 6.8), matched for sex and ethnicity. RESULTS: Patients and controls were genotyped for detection of the 3435C>T polymorphism, but the analysis showed no significant association between the CC genotype and the risk of drug-resistant epilepsy. CONCLUSION: These findings rule out the MDR1 c.3435C>T polymorphism having a major role or increasing the risk of drug-resistance suggesting a revision is required to determine the contribution of this polymorphism in predicting drug response in epilepsy. PMID- 25458100 TI - The impact of conveying the diagnosis when using a biopsychosocial approach: A qualitative study among adolescents and young adults with NES (non-epileptic seizures). AB - PURPOSE: This qualitative study explored the impact of using a biopsychosocial approach to explain the diagnosis of non-epileptic seizures (NES). METHODS: Semi structured interviews of eleven adolescents and young adults who had participated in an inpatient follow-up stay of the diagnosis were used. The interviews were taped, transcribed, and analysed using systematic text condensation. RESULTS: Three key themes were identified:1."Threatened self-image": Patients initially perceived their diagnosis as being purely psychological. As they did not accept that they had mental disorders, they interpreted this as frightening and threatening, and resisted the diagnosis.2."Being believed and belief in oneself": Participants had many experiences of being suspected by healthcare providers of staging their seizures. Some had even begun to have doubts themselves as to whether the attacks were voluntary or not. Explaining that unconscious processes are involved in NES contributed towards increasing patients' feelings of being believed, and thereby acceptance of the diagnosis.3."Getting an explanation that makes sense": Some participants identified connections between their personal histories and their seizures and became seizure-free. Others found that the explanatory models gave personal meaning, but did not become seizure-free, while a few continued to doubt whether NES was the correct diagnosis. CONCLUSION: Being believed was the most elemental factor for coping with the condition. Using a biopsychosocial approach to explain the diagnosis may facilitate identification with the explanatory models, and thus acceptance of the diagnosis. PMID- 25458101 TI - Adult nonconvulsive status epilepticus in a clinical setting: Semiology, aetiology, treatment and outcome. AB - PURPOSE: Our objective was to study the semiology, aetiology, treatment and outcome of nonconvulsive status epilepticus (NCSE) in adults. METHODS: All NCSE episodes in an unselected hospital cohort in the period 2004-2009 were identified, and the files reviewed. STESS (Status Epilepticus Severity Scale) was conducted retrospectively and correlated to outcome. Follow-up was undertaken after >2 years. RESULTS: 48 NCSEs in 39 patients, 22 men and 17 women, were found. Mean age was 63 years. 23/39 (59%) patients had established epilepsy. The underlying cause of NCSE was cerebrovascular disease in 17/39 (44%). 37/48 (77%) NCSEs were complex focal status epilepticus. 3/48 NCSEs (6.3%) lead to death, whereas 8.5% lead to severe sequelae. Cognitive sequelae were found after 14.9% of NCSEs. The outcome was worst in the group with no prior epilepsy (p=0.013). STESS had a negative predictive value of 96% (cut-off value of 3) for severe sequelae and death combined (p<0.002). CONCLUSIONS: NCSE has a potential for severe sequelae and represents an emergency in need of intensive treatment. The major determinant of outcome is the underlying cause. The outcome was worse in patients without epilepsy than in patients with epilepsy. STESS is of value in predicting outcome. Cognitive sequelae following NCSE can occur, but need further investigation with prospective, systematic studies. PMID- 25458102 TI - Appearance of post ictal psychosis after radiosurgical damage in the temporal lobe. PMID- 25458103 TI - Treatment of refractory generalized convulsive status epilepticus with enteral topiramate in resource limited settings. AB - PURPOSE: To explore the feasibility, safety and efficacy of enterally administered topiramate (TPM) as an adjunctive treatment for adult patients with refractory generalized convulsive status epilepticus (RGCSE). METHODS: This prospective open-label non-randomized clinical trial was performed at Namazee hospital, Shiraz University of Medical Sciences, Shiraz, Iran from January 2013 through February 2014. Patients 18 years of age and older with RGCSE were enrolled. Topiramate was used, in case of failure of at least two standard anti epileptic drugs in patients in whom the standard third or fourth line therapies were not available. Topiramate tablets were crushed and administered through the nasogastric tube; 400mg stat and then 200mg Bid. Status epilepticus response to TPM was categorized as successful (termination of SE within 24h following TPM introduction, without modification of concomitant AEDs), possible (SE termination associated with the introduction of TPM, concomitantly with other medications) or unsuccessful. RESULTS: Twenty patients were studied. Topiramate was successful in terminating SE in five (25%) patients; possibly successful in 11 (55%); and not successful in four (20%). No clinically significant adverse effects related to TPM administration were observed. Eleven (55%) patients returned to their baseline clinical condition at the time of discharge from the hospital, but two (10%) patients did not. CONCLUSION: Treatment with enterally administered topiramate could potentially be efficacious in some patients and appeared to be tolerated well in patients with RGCSE. Low cost and feasibility makes TPM a potentially useful agent in treating patients with RGCSE, especially in resource limited settings. PMID- 25458104 TI - Epilepsy and physical exercise. AB - Epilepsy is one of the commonest neurologic diseases and has always been associated with stigma. In the interest of safety, the activities of persons with epilepsy (PWE) are often restricted. In keeping with this, physical exercise has often been discouraged. The precise nature of a person's seizures (or whether seizures were provoked or unprovoked) may not have been considered. Although there has been a change in attitude over the last few decades, the exact role of exercise in inducing seizures or aggravating epilepsy still remains a matter of discussion among experts in the field. Based mainly on retrospective, but also on prospective, population and animal-based research, the hypothesis that physical exercise is prejudicial has been slowly replaced by the realization that physical exercise might actually be beneficial for PWE. The benefits are related to improvement of physical and mental health parameters and social integration and reduction in markers of stress, epileptiform activity and the number of seizures. Nowadays, the general consensus is that there should be no restrictions to the practice of physical exercise in people with controlled epilepsy, except for scuba diving, skydiving and other sports at heights. Whilst broader restrictions apply for patients with uncontrolled epilepsy, individual risk assessments taking into account the seizure types, frequency, patterns or triggers may allow PWE to enjoy a wide range of physical activities. PMID- 25458106 TI - Becoming the Parent of a Child With Life-Threatening Food Allergies. AB - Food induced anaphylaxis (FIA) is a serious medical event and managing it can place tremendous mental, emotional and financial burdens on parents of children with FIA. Using grounded theory methods, the experiences of parents caring for a child with FIA and the adjustments and strategies used to effectively manage a child's diagnosis were examined. Findings revealed once a child is diagnosed with FIA, parental competency is often severely challenged, calling into question parents' ability to succeed in the parenting role. To regain parental competency, parents engage in a 3 phase process to learn how to parent a child with FIA. PMID- 25458105 TI - Children with chronic conditions: perspectives on condition management. AB - This qualitative study described children's (8-13 years old) perspectives of their chronic health conditions (e.g., asthma, diabetes, cystic fibrosis): how they perceived their condition, its management, and its implications for their future. The study used the family management style framework (FMSF) to examine child perspectives on the joint venture of condition management between the child and family. Children within this age group viewed condition management in ways similar to their parents and have developed their own routines around condition management. Future studies of this phenomenon comparing child and parent perspectives would further our understanding of the influence of family management. PMID- 25458107 TI - Pulse Oximetry Screening for Critical Congenital Heart Disease: Bringing Evidence Into Practice. AB - Congenital heart disease is the most common and serious type of infant birth defect. Pulse oximetry screening has been supported in the literature as a valuable tool to aid in the prompt detection of critical defects. Pulse oximetry is easily accessible, inexpensive, and noninvasive, and can be readily performed by clinical nurses at the infant's bedside; however, it remains a technology that is underutilized in newborns. Nurses can be leaders in addressing the need to translate knowledge into practice to improve the morbidity and mortality rates in the newborn population. PMID- 25458108 TI - The perspective of siblings of children with chronic illness: a literature review. AB - This review gives an overview about the existing research concerning siblings' perspective within the familial experiences of childhood chronic illness. Besides attaining a conception of their world, it was intended to identify the unacknowledged issues concerning siblings' experience. Four databases were systematically searched. The analysis was concentrated on nine literature reviews. As a result, we identified a map of dimensions of experiences-well elaborated as well as fragmentary. Many of the studies were conducted by a proxy and not from the sole siblings' perspective. Further research should concentrate on the sole siblings' perspective, in order to make siblings' voices audible. PMID- 25458109 TI - Improving pediatric emergencies one rural hospital at a time. PMID- 25458110 TI - Pediatric concussions: can technology detect the impact? PMID- 25458111 TI - Pick your poison: what's new in poison control for the preschooler. AB - Accidental childhood poisonings are a major public health concern despite many efforts to alleviate this problem. While the rate of pediatric fatalities due to poisonings have decreased over the last two decades, poison control centers around the US have collectively fielded over one million calls with regard to toxic exposures in the preschool age group. According to the American Association of Poison Control Centers nearly half of all human exposures reported last year involved children under six. By focusing poison prevention efforts on the preschooler, we can attempt to decrease morbidity and mortality in the most vulnerable age group affected. Although the subject is still prevalent, current discussion on this topic is limited. Newer literature discusses past initiatives such as child resistant packaging and sticker deterrent programs and addresses their efficacy. This article revisits older mechanisms of prevention as well as the science behind the human motivation to change one's own practice and behavior. PMID- 25458112 TI - Involving parents in managing their child's long-term condition-a concept synthesis of family-centered care and partnership-in-care. AB - BACKGROUNG: Fostering effective engagement, collaboration and empowerment are central to supporting parents caring for children with long-term conditions. METHODS: A concept synthesis was undertaken to identify the shared antecedents and attributes underpinning models of family-centered care and partnership-in care. RESULTS: Thirty studies were reviewed; antecedents of models related to unclear roles, entrenched professional practices, and lack of guidelines supporting their implementation; with central attributes being building trust, listening to parent concerns and valuing parents' knowledge of their child. CONCLUSION: The key attributes are outlined in a practical framework of involvement which may promote parent-professional collaboration for families of children with long-term conditions. PMID- 25458114 TI - Emerging structural insights into biased GPCR signaling. AB - The discovery of biased signaling at G protein-coupled receptors (GPCRs), the largest class of cell surface receptors and primary drug targets for numerous human diseases, has redefined the classical concepts of receptor pharmacology. It not only highlights the depth of signaling diversity within the GPCR system, but also offers possibilities for novel and more-effective therapeutics. Here, we highlight the recent biophysical and structural advances in our understanding of ligand-receptor interactions and conformational changes in the receptors, which provide novel mechanistic insights into biased GPCR signaling. We also underline key aspects of GPCR-biased signaling that remain to be investigated in greater detail to develop a complete molecular understanding of this process and overall GPCR signaling. PMID- 25458115 TI - Digital health interventions: widening access or widening inequalities? PMID- 25458113 TI - Activation of 5-HT2a receptors in the basolateral amygdala promotes defeat induced anxiety and the acquisition of conditioned defeat in Syrian hamsters. AB - Conditioned defeat is a model in Syrian hamsters (Mesocricetus auratus) in which normal territorial aggression is replaced by increased submissive and defensive behavior following acute social defeat. The conditioned defeat response involves both a fear-related memory for a specific opponent as well as anxiety-like behavior indicated by avoidance of novel conspecifics. We have previously shown that systemic injection of a 5-HT2a receptor antagonist reduces the acquisition of conditioned defeat. Because neural activity in the basolateral amygdala (BLA) is critical for the acquisition of conditioned defeat and BLA 5-HT2a receptors can modulate anxiety but have a limited effect on emotional memories, we investigated whether 5-HT2a receptor modulation alters defeat-induced anxiety but not defeat-related memories. We injected the 5-HT2a receptor antagonist MDL 11,939 (0 mM, 1.7 mM or 17 mM) or the 5-HT2a receptor agonist TCB-2 (0 mM, 8 mM or 80 mM) into the BLA prior to social defeat. We found that injection of MDL 11,939 into the BLA impaired acquisition of the conditioned defeat response and blocked defeat-induced anxiety in the open field, but did not significantly impair avoidance of former opponents in the Y-maze. Furthermore, we found that injection of TCB-2 into the BLA increased the acquisition of conditioned defeat and increased anxiety-like behavior in the open field, but did not alter avoidance of former opponents. Our data suggest that 5-HT2a receptor signaling in the BLA is both necessary and sufficient for the development of conditioned defeat, likely via modulation of defeat-induced anxiety. PMID- 25458116 TI - Why do local authorities undertake controlled evaluations of health impact? A qualitative case study of interventions in housing. AB - OBJECTIVES: A significant amount of literature documents the challenges of undertaking evaluative research on the public health impacts of interventions in the non-health sector. However, few studies have investigated why such studies are undertaken despite the undoubted challenges. Taking housing as a case study, the authors aimed to identify the factors contributing to successful evaluative research in the non-health sector. STUDY DESIGN: Qualitative interview study. METHODS: Semi-structured interviews with 16 investigators involved in seven successful experimental studies of housing interventions across the UK, analysed using thematic content analysis. RESULTS: Intervention studies were undertaken when existing collaborative links enabled 'windows of opportunity' to be exploited. Although different 'cultures of evidence' were reported across the collaborating teams, these did not necessarily map onto the public health research/non-academic divide, and did not undermine collaborative work when all parties could gain from taking part in the research. CONCLUSIONS: Focussing on success, rather than failure, suggests that to encourage the uptake of evaluative evidence in the non-health sector, efforts might be better directed at fostering opportunities for partnership building rather than simply on educating non-health partners in the principles of academic research. PMID- 25458117 TI - Evidence for repeated gene duplications in Tritrichomonas foetus supported by EST analysis and comparison with the Trichomonas vaginalis genome. AB - Tritrichomonas foetus causes a venereal infection in cattle; the disease has mild or no clinical manifestation in bulls, while cows may present vaginitis, placentitis, pyometra and abortion in the more severe cases. T. foetus has one of the largest known genomes among trichomonads. However molecular data are fragmentary and have minimally contributed to the understanding of the biology and pathogenesis of this protozoan. In a search of new T. foetus genes, a detailed exploration was performed using recently available expressed sequences. Genes involved in the central carbon metabolism (phosphoenol pyruvate carboxykinase, glyceraldehyde-3-phosphate dehydrogenase, fructose-1,6 bisphosphate aldolase, thioredoxin peroxidase, alpha and beta chains of succinyl CoA synthetase, malate dehydrogenase, malate oxidoreductase and enolase) as well as in cell structure and motility (actin, alpha-tubulin and beta-tubulin) were found duplicated and, in many cases, repeatedly duplicated. Homology analysis suggested that massive expansions might have occurred in the T. foetus genome in a similar way it was also predicted for Trichomonas vaginalis, while conservation assessment showed that duplications have been acquired after differentiation of the two species. Therefore, gene duplications might be common among these parasitic protozoans. PMID- 25458118 TI - Efficacy of oxyclozanide against adult Paramphistomum leydeni in naturally infected sheep. AB - The aim of the current study was to assess oxyclozanide (OCZ) efficacy against Paramphistomum leydeni in naturally infected adult sheep. OCZ concentrations in blood stream and gastrointestinal fluids collected from treated animals were also measured. Fifteen P. leydeni naturally infected sheep were randomly divided into two groups: untreated control (n=5) and treated (n=10). The treated group was orally drenched with OCZ (20mg/kg, day 0). A second dose was administered 72 h later. Faecal samples were taken at days 0, +3 and +5. Five sheep from both groups were slaughtered at day +5. At necropsies, rumen, abomasum and small intestine were examined for adult and immature flukes. All recovered flukes were counted and the treatment efficacy was estimated. Additionally, serum and gastrointestinal fluid content (ruminal, abomasal and small intestine) samples, obtained from five treated animals at day +5, were analyzed by HPLC to measure OCZ concentrations. OCZ showed high efficacy (99%) against mature P. leydeni. The post-treatment egg reduction was also high after the first dose with values ranging from 98.4% (day +3) to 99.5% (day +5). The highest OCZ concentrations were measured in serum (20.7 +/- 11.5 MUg/mL) followed by the small intestinal fluid (6.00 +/- 4.50 MUg/mL). Very low OCZ concentrations (ranging between 0.05 and 0.02 MUg/mL) were measured in ruminal and abomasal fluids. OCZ administered to sheep twice (20mg/kg) by the oral route was highly efficacious against mature stages of P. leydeni in naturally infected sheep. Despite a high drug concentration at the intestinal fluid, OCZ efficacy against immature stages could not be assessed. OCZ efficacy and assessment of its concentration profiles in different tissues are considered a contribution to the scarce information available on this ruminant fluke. PMID- 25458120 TI - Effects of intravenous and subcutaneous heartworm homogenate from doxycycline treated and untreated donor dogs on bronchial reactivity and lung in cats. AB - A controlled, blind research study was conducted to define the innate response of lungs in specific pathogen free (SPF) cats to intravenous (n=10) or subcutaneous (n=4) administration of homogenate of adult Dirofilaria immitis from donor dogs compared with lung response in control cats (n=6). There was no difference in cats that received heartworm homogenate IV for 18 days from donor dogs treated with doxycycline for 1 month compared with cats given heartworm homogenate from untreated donor dogs. Cats did not develop clinical signs, and no radiographic changes were noted. Cats given SC heartworm homogenate at lower concentration than IV groups did not develop histologic changes. Cats that received IV heartworm homogenate for 18 days developed mild interstitial and peribronchial myofibrocyte proliferation and smooth muscle proliferation of the pulmonary arteries. Bronchial ring contractility in vitro was blunted in the IV homogenate cats to the agonists acetylcholine and 5-hydroxytryptamine. Cats in the SC group had increased sensitivity to histamine at high concentrations but normal contractility and relaxation responses to other agonists. No increase in mast cells was noted in lung tissues of cats given homogenate. In the absence of bronchial wall remodeling, cats given IV homogenate had blunted responses to bronchial constriction, but normal relaxation to nitroprusside and substance P and increased sensitivity to histamine. In the absence adult heartworms, the homogenate of adult heartworms in the circulation of SPF cats induced a direct effect on lung parenchyma and altered bronchial ring reactivity. PMID- 25458119 TI - Apoptotic effects of antimalarial artemisinin on the second generation merozoites of Eimeria tenella and parasitized host cells. AB - Artemisinin (ART) is a sesquiterpene lactone isolated from Artemesia annua L., and well-known for the antimalarial treatment. Recently many reports show the effectiveness of ART in the control of poultry coccidiosis, but the mechanism remains unclear. In this study, we found that ART could effectively improve the pathological alterations in chicken ceca infected by E. tenella with decreased number of second generation merozoites (SGM). In addition, ART significantly reduced mitochondrial membrane potential by 47.4% and notably increased apoptotic rate by 61.9% in SGM. Morphological analysis showed that SGM with ART treatment represented some apoptotic features such as the condensability of chromatin, increase of cytoplasmic density and the marginalization of heterochromatin. We also found that ART treatment significantly increased caspase-3 activity whereas reduced Bcl-2 activity in cecum tissues compared with the infection group by immunohistochemical analysis. These results suggest the anticoccidial effects of ART are closely related to facilitate apoptosis in both merozoites and the infected host cells. This study makes a better understanding of ART against poultry coccidiosis. PMID- 25458121 TI - Effects of doxycycline on heartworm embryogenesis, transmission, circulating microfilaria, and adult worms in microfilaremic dogs. AB - Tetracycline treatment of animals or humans infected with filariae that harbor Wolbachia endosymbionts blocks further embryogenesis, and existing microfilariae gradually die. This treatment also kills developing larvae and has a slow-kill effect on adult filariae, all presumably due to elimination of the Wolbachia. Also, Dirofilaria immitis microfilariae in blood collected from dogs up to 25 days after the last dose of doxycycline developed to infective L3 that were normal in appearance and motility in mosquitoes but did not continue to develop or migrate normally after subcutaneous (SC) injection into dogs. The present study was designed to determine whether heartworm microfilariae collected at later times after treatment would regain the ability to continue normal development in a dog. The study also was expected to yield valuable data on the effects of treatment on microfilariae and antigen levels and adult worms. The study was conducted in 16 dogs as two separate replicates at different times. A total of five dogs (two in Replicate A and three in Replicate B) infected either by SC injection of L3 or intravenous transplantation of adult heartworms were given doxycycline orally at 10mg/kg twice daily for 30 days, with three untreated controls. Microfilarial counts in the five treated dogs gradually declined during the 12-13 months after treatment initiation. Two dogs were amicrofilaremic before necropsy and three had 13 or fewer microfilariae/ml. Only one treated dog was negative for heartworm antigen before necropsy. Overall, treated dogs generally had fewer live adult heartworms than controls, and most of their live worms were moribund. All three control dogs remained positive for microfilariae and antigen and had many live worms. L3 from mosquitoes fed on blood collected 73-77 or 161 164 days after initiation of doxycycline treatments were injected SC into five dogs. None of the dogs injected with L3 from mosquitoes fed on blood from doxycycline-treated dogs were ever positive for microfilariae or antigen, and none had worms at necropsy; three control dogs were positive for microfilariae and antigen and had many live worms. These data indicate that doxycycline treatment of microfilaremic dogs gradually reduces numbers of microfilariae and blocks further transmission of heartworms. This latter effect should be highly effective in reducing the rate of selection of heartworms with genes that confer resistance to macrocyclic lactone preventives and microfilaricides. The data also suggest that doxycycline has a slow-kill effect on adult heartworms. PMID- 25458122 TI - Intestinal malrotation--volvulus: imaging findings. AB - Radiologists must be able to recognize the imaging signs of intestinal malrotation because this condition can lead to potentially lethal complications such as midgut volvulus. The correct diagnosis depends on both high clinical suspicion and the radiologist's ability to recognize the specific signs of malrotation and the normal variants that can lead to the wrong diagnosis. Although the location of the third portion of the duodenum outside the retroperitoneal area on ultrasonography, CT, or MRI seems to be a reliable sign of malrotation, the gold standard for determining whether the duodenojejunal flexure is in an abnormal location continues to be the upper gastrointestinal series. In this article, we review the most important imaging signs of malrotation and emphasize the role of ultrasonography in diagnosing midgut volvulus. PMID- 25458123 TI - [Introduction to critical reading of articles: study design and biases]. AB - The critical evaluation of an article enables professionals to make good use of the new information and therefore has direct repercussions for the benefit of our patients. Before undertaking a detailed critical reading of the chosen article, we need to consider whether the study used the most appropriate design for the question it aimed to answer (i.e., whether the level of evidence is adequate). To do this, we need to know how to classify studies in function of their design (descriptive or analytical; prospective or retrospective; cross-sectional or longitudinal) as well as their correlation with the levels of evidence. In critical reading it is also important to know the main systematic errors or biases that can affect a study. Biases can appear in any phase of a study; they can affect the sample, the development of the study, or the measurement of the results. PMID- 25458126 TI - Risk factors for recurrent spontaneous epistaxis. AB - OBJECTIVE: To identify risk factors associated with spontaneous recurrent epistaxis. PATIENTS AND METHODS: This was a retrospective cohort study assessing patients in the Marshfield Clinic system diagnosed as having epistaxis between January 1, 1991, and January 1, 2011. There were 461 cases with at least 2 episodes of spontaneous epistaxis within 3 years and 912 controls with only 1 episode in the same time frame. More than 50 potential risk factors were investigated, including demographic features, substance use, nasal anatomical abnormalities, nasal infectious and inflammatory processes, medical comorbidities, medications, and laboratory values. A Cox proportional hazards regression modeling approach was used to calculate hazard ratios of epistaxis recurrence. RESULTS: Traditional risk factors for epistaxis, including nasal perforation, nasal septum deviation, rhinitis, sinusitis, and upper respiratory tract infection, did not increase the risk of recurrence. Significant risk factors for recurrent epistaxis included congestive heart failure, diabetes mellitus, hypertension, and a history of anemia. Warfarin use increased the risk of recurrence, independent of international normalized ratio. Aspirin and clopidogrel were not found to increase the risk of recurrence. Few major adverse cardiovascular events were observed within 30 days of the first epistaxis event. CONCLUSION: Congestive heart failure is an underappreciated risk factor for recurrent epistaxis. Hypertension and diabetes mellitus may induce atherosclerotic changes in the nasal vessels, making them friable and more at risk for bleeding. Patients with recurrent epistaxis may also be more susceptible to developing anemia. Physicians should promote antiplatelet and antithrombotic medication adherence despite an increased propensity for recurrent epistaxis to prevent major adverse cardiovascular events. PMID- 25458127 TI - Delineation of the IGF-II C domain elements involved in binding and activation of the IR-A, IR-B and IGF-IR. AB - OBJECTIVE: Human insulin-like growth factor-I and -II (IGF-I and -II) ligands share a high degree of sequence and structural homology. Despite their similarities, IGF-I and IGF-II exhibit differential receptor binding and activation characteristics. The C domains of IGF-I and IGF-II are the primary determinants of binding specificity to the insulin-like growth factor I receptor (IGF-IR), insulin receptor exon 11- (IR-A) and exon 11+ (IR-B) isoforms. DESIGN: Three IGF-II analogues were generated in order to delineate the C domain residues that confer the differential receptor binding affinity and activation properties of the IGFs. Chimeric IGF-II analogues IGF-IICI(N) and IGF-IICI(C) contained partial IGF-I C domain substitutions (IGF-I residues underlined) GYGSSSRRSR and SRVSRRAPQT, respectively. RESULTS: The IGF-IICI(N) analogue bound the IR-A and IGF-IR with high affinity but bound the IR-B with a relatively lower affinity than IGF-II, suggesting a negative interaction between the exon-11 encoded peptide in the IR-B and the C-domain. The ability of IGF-IICI(N) to activate receptors and elicit cell viability responses was generally proportional to its relative receptor binding affinity but appeared to act as a partial agonist equivalent to IGF-I when binding and activating the IGF-IR. In contrast, IGF IICI(C) bound IGF-IR with high affinity but elicited lower receptor activation and cell viability responses. Analogue IGF-IICI(S) contained a truncated IGF-I C domain (GSSSRRAT) and generally displayed a relatively poor ability to bind, activate and elicit viability responses via each receptor. CONCLUSIONS: Together, the IGF analogues demonstrate that both flanks of the IGF-II C domain play important roles in the greater ability of IGF-II to bind and activate IR receptors than IGF-I. PMID- 25458129 TI - Independent brachytherapy plan verification software: improving efficacy and efficiency. AB - BACKGROUND AND PURPOSE: To compare the pre-treatment brachytherapy plan verification by a physicist assisted by custom plan verification software (SAV) with those performed manually (MV). MATERIALS AND METHODS: All HDR brachytherapy plans used for treatment in 2013, verified using either SAV or MV, were retrospectively reviewed. Error rate (number of errors/number of plans) was measured and verification time calculated. All HDR brachytherapy safety events recorded between 2010 and 2013 were identified. The rate of patient-related safety events (number of events/number of fractions treated) and the impact of SAV on the underlying errors were assessed. RESULTS: Three/106 errors (2.8%) were found in the SAV group and 24/273 (8.8%) in the MV group (p=0.046). The mean +/-1 standard deviation plan verification time was 8.4+/-4.0min for SAV and 11.6+/-5.3 for MV (p=0.006). Seven safety events out of 4729 fractions delivered (0.15%) were identified. Four events (57%) were associated with plan verification and could have been detected by SAV. CONCLUSIONS: We found a safety event rate in HDR brachytherapy of 0.15%. SAV significantly reduced the number of undetected errors in HDR treatment plans compared to MV, and reduced the time required for plan verification. PMID- 25458130 TI - Evidence synthesis and its role in evidence-based health care. AB - The central role of evidence synthesis (or the systematic review of evidence) in evidence-based health care is often poorly understood. There are numerous examples in the literature of poorly conceived and/or executed systematic reviews and of a lack of awareness of the international standards developed by the international leaders in systematic reviews. The Cochrane Collaboration has played a critical global role in developing and refining systematic review methods in relation to evidence of effects and of diagnostic accuracy. PMID- 25458128 TI - Creating a data exchange strategy for radiotherapy research: towards federated databases and anonymised public datasets. AB - Disconnected cancer research data management and lack of information exchange about planned and ongoing research are complicating the utilisation of internationally collected medical information for improving cancer patient care. Rapidly collecting/pooling data can accelerate translational research in radiation therapy and oncology. The exchange of study data is one of the fundamental principles behind data aggregation and data mining. The possibilities of reproducing the original study results, performing further analyses on existing research data to generate new hypotheses or developing computational models to support medical decisions (e.g. risk/benefit analysis of treatment options) represent just a fraction of the potential benefits of medical data pooling. Distributed machine learning and knowledge exchange from federated databases can be considered as one beyond other attractive approaches for knowledge generation within "Big Data". Data interoperability between research institutions should be the major concern behind a wider collaboration. Information captured in electronic patient records (EPRs) and study case report forms (eCRFs), linked together with medical imaging and treatment planning data, are deemed to be fundamental elements for large multi-centre studies in the field of radiation therapy and oncology. To fully utilise the captured medical information, the study data have to be more than just an electronic version of a traditional (un-modifiable) paper CRF. Challenges that have to be addressed are data interoperability, utilisation of standards, data quality and privacy concerns, data ownership, rights to publish, data pooling architecture and storage. This paper discusses a framework for conceptual packages of ideas focused on a strategic development for international research data exchange in the field of radiation therapy and oncology. PMID- 25458131 TI - The systematic review of health care evidence: methods, issues, and trends. AB - The systematic review is a key component to the evidence based health care cycle. There are two main types of systematic reviews: qualitative and quantitative. Systematic reviews bring together large amounts of information that can help support individual patient decision, inform guidelines, policy and primary research. The basic steps for each type of systematic review are the same; however, differences occur in the tools used to appraise the included studies and the method of synthesis. Over the years, many different systems have been used to grade the quality (level) of evidence and the strength of recommendations, which has meant that the same evidence and recommendation could be graded differently according to the system used at the time. PMID- 25458133 TI - Evidence in perioperative care. AB - Perioperative care is comprised of preoperative, intraoperative, and postoperative care. Given the vulnerable status of the perioperative patient, coupled with the complex nature of these areas, evidence-based practice and clinical decision-making must be rooted in high-quality evidence for safe and effective patient and family care. Evidence-based practice is comprised of patient and family preferences, clinical expertise, and best available evidence. This article showcases systematic reviews that have focused on clinical issues within the preoperative, intraoperative, and postoperative care areas. A case study presents the importance of applying best available evidence to solve a thorny clinical problem and improve patient outcomes. PMID- 25458132 TI - Developing a robust evidence base for nursing. AB - Systematic reviews provide robust evidence for nursing practice because of the exhaustiveness of search, the critical appraisal methods to determine the risks of bias, and synthesis methods that pool evidence to increase the power of statistical estimates or credibility of aggregated metasynthesis of qualitative findings. More consistency in publication standards will enhance the rigor of available evidence and allow nursing to live up to the promise of best available evidence. PMID- 25458134 TI - Evidence-based health care in pediatrics. AB - This article examines current trends in the type and quality of systematic reviews underpinning the evidence base for pediatric health care. A case study is used to highlight the quality standards for the conduct and publication of systematic reviews and the processes being used to transition the evidence produced from systematic reviews into the everyday systems and processes of care. PMID- 25458135 TI - Finding and using best evidence for rehabilitation. AB - With the demands for improved experiences of care, improved outcomes, and greater efficiency/lower costs, the need for an evidence-based approach to care in rehabilitation settings has never been more urgent. This article guides practitioners in how to find the best available evidence for rehabilitation settings. It then discusses the use of evidence from systematic reviews through a high-impact case study: delirium in patients with postoperative hip fracture. PMID- 25458136 TI - Evidence in mental health. AB - Health practitioners wishing to positively improve health outcomes for their clients have access to a unique set of collated tools to guide their practice. Systematic reviews provide guidance in the form of synthesized evidence that can form the basis of decision making as they provide care for their clients. This article describes systematic reviews as a basis for informed decision making by mental health practitioners. The process of systematic review is discussed, examples of existing systematic review topics relevant to mental health are presented, a sample systematic review is described, and gaps and emerging topics for mental health systematic reviews are addressed. PMID- 25458137 TI - Evidence in public health: steps to make it real. AB - This study addresses the methodological trends in the development of systematic reviews in public health, and examines the reviews of the Cochrane Public Health Group in order to exemplify syntheses of evidence in public health and its implementation and impact on practice and research. PMID- 25458138 TI - Impact of evidence and health policy on nursing practice. AB - The story of evidence-based practice in nursing is long, with many successes, contributors, leaders, scientists, and enthusiasts. Nurse educators have great advantages offered from a wide variety of educational resources for evidence based practice. These resources offer students the opportunity to connect their emerging competencies with clinical needs for best practices in clinical and microsystem changes. PMID- 25458139 TI - Translating evidence into policy and practice. AB - This paper uses a published case study to illustrate the practical application of a translational model for the implementation of evidence into practice. The paper examines a translational approach to moving knowledge from robust methods for systematic review into guidance for clinical practice, and then in to action followed by evaluation of its impact on practice and health care outcomes. The conceptual model for evidence-based health care reported in this paper provides the theoretic framework for practice change. PMID- 25458140 TI - The utilization of evidenced-based practice in nursing: some important considerations. PMID- 25458141 TI - Evidence-based nursing: synthesizing the best available evidence to translate into action in policy and practice. PMID- 25458142 TI - What do physical therapists think about evidence-based practice? A systematic review. AB - Evidence-Based Practice (EBP) has been widely implemented in different health related areas. Several studies investigated important characteristics in EBP by physiotherapists and systematic review is needed. Therefore the aim of this study is to describe the current evidence on EBP knowledge, skills, behaviour, opinions and barriers by physiotherapists. Searches were conducted on MEDLINE, EMBASE, CINAHL, PSYCINFO, LILACS, and SciELO in September 2014. We retrieved quantitative cross-sectional studies that investigated EBP knowledge, skills, behaviour, opinions, and barriers in physiotherapy. Risk of bias was assessed using a scale to evaluate representativeness of the sample, response rate, the accuracy of the data, evidence of power calculation and the instrument used. The search yielded 12,392 potentially eligible studies. Of these, 12 studies were included in the review (pooled sample = 6411 participants). In 3 studies that analysed knowledge, approximately 21-82% of respondents claimed to have received prior information on EBP. In 2 studies that reported skills and behaviour, nearly half of the sample had used databases to support clinical decision-making. In 6 studies that investigated opinions, the majority of the samples considered EBP necessary or important. The barriers most frequently reported were: lack of time, inability to understand statistics, lack of support from employer, lack of resources, lack of interest and lack of generalisation of results. Although the majority of physiotherapists have a positive opinion about EBP, they consider that they need to improve their knowledge, skills and behaviour towards EBP. They also faced barriers that might hinder the implementation of EBP. PMID- 25458143 TI - Comparison of shoulder rotation range of motion in professional tennis players with and without history of shoulder pain. AB - A glenohumeral internal rotation deficit of the dominant shoulder relative to the non-dominant shoulder (GIRD) is considered a risk factor for shoulder injury in overhead athletes. The aim of this study was to investigate whether professional tennis players with a history of self-reported shoulder pain show differences in rotation range of motion (ROM) of the dominant and non-dominant shoulder compared to asymptomatic controls. Forty-seven professional tennis players belonging to the Association of Tennis Professionals World Tour took part in the study: 19 with shoulder pain history and 28 without. Passive shoulder ROM was measured using a process of photography and software calculation of angles. The dominant shoulder had reduced internal rotation (IR) ROM and total rotation ROM, and increased external rotation (ER) ROM compared to the non-dominant side. These differences did not correlate significantly with years of tennis practice, years of professional play, nor the players' age. However, glenohumeral rotation ROMs correlated negatively with the duration of tennis practice and players' age. Although tennis players with shoulder pain history showed less IR ROM in both shoulders compared with the no-pain group, no significant differences between groups were found for ER ROM, side-to-side ROM asymmetries, years of tennis practice or years of professional play. In professional tennis players, limited IR ROM rather than a GIRD, seems to be associated with shoulder pain history, duration of tennis practice and the players' age, when compared to a similar cohort with no history of shoulder pain. PMID- 25458144 TI - Acceleration of clinician hand movements during spinal manipulative therapy. AB - This study used an observational design to examine the kinematics of spinal manipulative therapy (SMT) by determining the acceleration characteristics of the manipulative input at the cervical, thoracic, and lumbar spinal regions. Studies of SMT have been restricted to measuring the forces that result from the manipulative input. Several studies have indicated the rate of force development is a key parameter of clinically delivered SMT. Despite this, the movement strategies employed during SMT, including acceleration, have not been directly measured. Participants (n = 29) were recruited from a private practice chiropractic clinic. A wireless accelerometer attached to the clinician's hand was used to characterize the thrust phase of the SMT treatments. Significant differences were found across each spinal region for acceleration amplitude parameters (p < 0.0001). Post-hoc analysis indicated that amplitudes significantly increased in order from thoracic to cervical to lumbar regions (p < 0.0001). Spinal level was also a significant factor in determining the temporal parameters of hand acceleration during SMT (p < 0.0005). This study provides a description of the acceleration properties of clinically delivered SMT. Consistent with that reported for SMT forces, acceleration amplitudes varied significantly across spinal regions with relatively little differences in acceleration latencies. Notably, acceleration amplitudes and latencies were not associated with each other within spinal regions. These findings indicate that changes in acceleration amplitude, rather than latency, are used to tailor SMT to individuals. PMID- 25458145 TI - Dextran-gated, multifunctional mesoporous nanoparticle for glucose-responsive and targeted drug delivery. AB - Design of drug delivery nanocarrier having targeted recognition followed by bioresponsive controlled release, especially via glucose-responsive release, is a challenging issue. Here, we report magnetic mesoporous silica (MMS)-based drug delivery nanocarrier that can target specific cell and release drug via glucose responsive gate. The design involves synthesis of MMS functionalized with phenylboronic acid and folate. After drug loading inside the pores of MMS, outside of the pores are closed by dextran via binding with phenylboronic acid. Dextran-gated pores are opened for drug release in the presence of glucose that competes binding with phenylboronic acid. We found that tolbutamide and camptothecin loaded MMS can target beta cells and cancer cells, respectively, release drugs depending on bulk glucose concentration and offers glucose concentration dependent cytotoxicity. Developed functional MMS can be used for advanced drug delivery applications for diabetes and cancers with more efficient therapy. PMID- 25458146 TI - Mechanical instability of normal and aneurysmal arteries. AB - Tortuous arteries associated with aneurysms have been observed in aged patients with atherosclerosis and hypertension. However, the underlying mechanism is poorly understood. The objective of this study was to determine the effect of aneurysms on arterial buckling instability and the effect of buckling on aneurysm wall stress. We investigated the mechanical buckling and post-buckling behavior of normal and aneurysmal carotid arteries and aorta's using computational simulations and experimental measurements to elucidate the interrelationship between artery buckling and aneurysms. Buckling tests were done in porcine carotid arteries with small aneurysms created using elastase treatment. Parametric studies were done for model aneurysms with orthotropic nonlinear elastic walls using finite element simulations. Our results demonstrated that arteries buckled at a critical buckling pressure and the post-buckling deflection increased nonlinearly with increasing pressure. The presence of an aneurysm can reduce the critical buckling pressure of arteries, although the effect depends on the aneurysm's dimensions. Buckled aneurysms demonstrated a higher peak wall stress compared to unbuckled aneurysms under the same lumen pressure. We conclude that aneurysmal arteries are vulnerable to mechanical buckling and mechanical buckling could lead to high stresses in the aneurysm wall. Buckling could be a possible mechanism for the development of tortuous aneurysmal arteries such as in the Loeys-Dietz syndrome. PMID- 25458147 TI - Fluid shear stress induces calcium transients in osteoblasts through depolarization of osteoblastic membrane. AB - Intracellular calcium transient ([Ca(2+)]i transient) induced by fluid shear stress (FSS) plays an important role in osteoblastic mechanotransduction. Changes of membrane potential usually affect [Ca(2+)]i level. Here, we sought to determine whether there was a relationship between membrane potential and FSS induced [Ca(2+)]i transient in osteoblasts. Fluorescent dyes DiBAC4(3) and fura 2AM were respectively used to detect membrane potential and [Ca(2+)]i. Our results showed that FSS firstly induced depolarization of membrane potential and then a transient rising of [Ca(2+)]i in osteoblasts. There was a same threshold for FSS to induce depolarization of membrane potential and [Ca(2+)]i transients. Replacing extracellular Na(+) with tetraethylammonium or blocking stretch activated channels (SACs) with gadolinium both effectively inhibited FSS-induced membrane depolarization and [Ca(2+)]i transients. However, voltage-activated K(+) channel inhibitor, 4-Aminopyridine, did not affect these responses. Removing extracellular Ca(2+) or blocking of L-type voltage-sensitive Ca(2+) channels (L VSCCs) with nifedipine inhibited FSS-induced [Ca(2+)]i transients in osteoblasts too. Quantifying membrane potential with patch clamp showed that the resting potential of osteoblasts was -43.3mV and the depolarization induced by FSS was about 44mV. Voltage clamp indicated that this depolarization was enough to activated L-VSCCs in osteoblasts. These results suggested a time line of Ca(2+) mobilization wherein FSS activated SACs to promote Na(+) entry to depolarize membrane that, in turn, activated L-VSCCs and Ca(2+) influx though L-VSCCs switched on [Ca(2+)]i response in osteoblasts. PMID- 25458149 TI - Subject-specific finite element analysis to characterize the influence of geometry and material properties in Achilles tendon rupture. AB - Achilles tendon injuries including rupture are one of the most frequent musculoskeletal injuries, but the mechanisms for these injuries are still not fully understood. Previous in vivo and experimental studies suggest that tendon rupture mainly occurs in the tendon mid-section and predominantly more in men than women due to reasons yet to be identified. Therefore we aimed to investigate possible mechanisms for tendon rupture using finite element (FE) analysis. Specifically, we have developed a framework for generating subject-specific FE models of human Achilles tendon. A total of ten 3D FE models of human Achilles tendon were generated. Subject-specific geometries were obtained using ultrasound images and a mesh morphing technique called Free Form Deformation. Tendon material properties were obtained by performing material optimization that compared and minimized difference in uniaxial tension experimental results with model predictions. Our results showed that both tendon geometry and material properties are highly subject-specific. This subject-specificity was also evident in our rupture predictions as the locations and loads of tendon ruptures were different in all specimens tested. A parametric study was performed to characterize the influence of geometries and material properties on tendon rupture. Our results showed that tendon rupture locations were dependent largely on geometry while rupture loads were more influenced by tendon material properties. Future work will investigate the role of microstructural properties of the tissue on tendon rupture and degeneration by using advanced material descriptions. PMID- 25458148 TI - Can stability really predict an impending slip-related fall among older adults? AB - The primary purpose of this study was to systematically evaluate and compare the predictive power of falls for a battery of stability indices, obtained during normal walking among community-dwelling older adults. One hundred and eighty seven community-dwelling older adults participated in the study. After walking regularly for 20 strides on a walkway, participants were subjected to an unannounced slip during gait under the protection of a safety harness. Full body kinematics and kinetics were monitored during walking using a motion capture system synchronized with force plates. Stability variables, including feasible stability-region measurement, margin of stability, the maximum Floquet multiplier, the Lyapunov exponents (short- and long-term), and the variability of gait parameters (including the step length, step width, and step time), were calculated for each subject. Sensitivity of predicting slip outcome (fall vs. recovery) was examined for each stability variable using logistic regression. Results showed that the feasible-stability-region measurement predicted fall incidence among these subjects with the highest sensitivity (68.4%). Except for the step width (with an sensitivity of 60.2%), no other stability variables could differentiate fallers from those who did not fall for the sample included in this study. The findings from the present study could provide guidance to identify individuals at increased risk of falling using the feasible-stability-region measurement or variability of the step width. PMID- 25458151 TI - Hybrid neuromusculoskeletal modeling to best track joint moments using a balance between muscle excitations derived from electromyograms and optimization. AB - Current electromyography (EMG)-driven musculoskeletal models are used to estimate joint moments measured from an individual's extremities during dynamic movement with varying levels of accuracy. The main benefit is the underlying musculoskeletal dynamics is simulated as a function of realistic, subject specific, neural-excitation patterns provided by the EMG data. The main disadvantage is surface EMG cannot provide information on deeply located muscles. Furthermore, EMG data may be affected by cross-talk, recording and post processing artifacts that could adversely influence the EMG's information content. This limits the EMG-driven model's ability to calculate the multi-muscle dynamics and the resulting joint moments about multiple degrees of freedom. We present a hybrid neuromusculoskeletal model that combines calibration, subject specificity, EMG-driven and static optimization methods together. In this, the joint moment tracking errors are minimized by balancing the information content extracted from the experimental EMG data and from that generated by a static optimization method. Using movement data from five healthy male subjects during walking and running we explored the hybrid model's best configuration to minimally adjust recorded EMGs and predict missing EMGs while attaining the best tracking of joint moments. Minimally adjusted and predicted excitations substantially improved the experimental joint moment tracking accuracy than current EMG-driven models. The ability of the hybrid model to predict missing muscle EMGs was also examined. The proposed hybrid model enables muscle-driven simulations of human movement while enforcing physiological constraints on muscle excitation patterns. This might have important implications for studying pathological movement for which EMG recordings are limited. PMID- 25458150 TI - The effects of tensile-compressive loading mode and microarchitecture on microdamage in human vertebral cancellous bone. AB - The amount of microdamage in bone tissue impairs mechanical performance and may act as a stimulus for bone remodeling. Here we determine how loading mode (tension vs. compression) and microstructure (trabecular microarchitecture, local trabecular thickness, and presence of resorption cavities) influence the number and volume of microdamage sites generated in cancellous bone following a single overload. Twenty paired cylindrical specimens of human vertebral cancellous bone from 10 donors (47-78 years) were mechanically loaded to apparent yield in either compression or tension, and imaged in three dimensions for microarchitecture and microdamage (voxel size 0.7*0.7*5.0 MUm3). We found that the overall proportion of damaged tissue was greater (p=0.01) for apparent tension loading (3.9+/-2.4%, mean+/-SD) than for apparent compression loading (1.9+/-1.3%). Individual microdamage sites generated in tension were larger in volume (p<0.001) but not more numerous (p=0.64) than sites in compression. For both loading modes, the proportion of damaged tissue varied more across donors than with bone volume fraction, traditional measures of microarchitecture (trabecular thickness, trabecular separation, etc.), apparent Young's modulus, or strength. Microdamage tended to occur in regions of greater trabecular thickness but not near observable resorption cavities. Taken together, these findings indicate that, regardless of loading mode, accumulation of microdamage in cancellous bone after monotonic loading to yield is influenced by donor characteristics other than traditional measures of microarchitecture, suggesting a possible role for tissue material properties. PMID- 25458152 TI - Temporal phosphoproteomics to investigate the mechanotransduction of vascular smooth muscle cells in response to cyclic stretch. AB - Vascular smooth muscle cells (VSMCs) are exposed to mechanical cyclic stretch in vivo, which play important roles in maintenance of vascular homeostasis and regulation of pathological vascular remodeling. Reversible protein phosphorylation is crucial for intracellular signaling transduction. However, the dynamic phosphorylated profile induced by cyclic stretch in VSMCs is still unclear. Using the stable isotope labeling by amino acid in cell culture, VSMCs were labeled and exposed to 10% physiological cyclic stretch in vitro at 1.25 Hz for 0 min, 15 min, 30 min, 1 h and 6 h, respectively. Using TiO2 beads and liquid chromatography tandem mass spectrometry, the temporal phosphoproteomic profiles in response to cyclic stretch were then detected. Bioinformatics analysis including fuzzy c-means clustering, functional classifications, and Ingenuity Pathway Analysis were applied to further reveal the potential mechanotranduction networks. The results indicated that protein kinase C (PKCs) family, Rho associated coiled-coil containing protein kinase 1 (ROCK1) and Akt may participate in cyclic-stretch induced VSMC functions. Cyclic stretch repressed the expression of ROCK1, while it had no significant effect on the phosphorylation of PKCalpha/betaII, PKCzeta/lambda and PKCdelta/theta. PKCtheta was activated first at short time-phase (15 min and 30 min), and again at long time-phase (6 h, 12 h and 24 h). The activation of p-PKCMU was immediate and short-term, similar to p-Akt. Our present in vitro work hence revealed that cyclic stretch activates complex mechanotransduction networks, suggesting that novel mechanoresponsive molecules, i.e., PKCtheta, PKCMU, and ROCK1, may participate in the mechanotransduction and modulation VSMC functions. PMID- 25458153 TI - Finite element modeling of superelastic nickel-titanium orthodontic wires. AB - Thanks to its good corrosion resistance and biocompatibility, superelastic Ni-Ti wire alloys have been successfully used in orthodontic treatment. Therefore, it is important to quantify and evaluate the level of orthodontic force applied to the bracket and teeth in order to achieve tooth movement. In this study, three dimensional finite element models with a Gibbs-potential-based-formulation and thermodynamic principles were used. The aim was to evaluate the influence of possible intraoral temperature differences on the forces exerted by NiTi orthodontic arch wires with different cross sectional shapes and sizes. The prediction made by this phenomenological model, for superelastic tensile and bending tests, shows good agreement with the experimental data. A bending test is simulated to study the force variation of an orthodontic NiTi arch wire when it loaded up to the deflection of 3 mm, for this task one half of the arch wire and the 3 adjacent brackets were modeled. The results showed that the stress required for the martensite transformation increases with the increase of cross-sectional dimensions and temperature. Associated with this increase in stress, the plateau of this transformation becomes steeper. In addition, the area of the mechanical hysteresis, measured as the difference between the forces of the upper and lower plateau, increases. PMID- 25458155 TI - Simultaneous Postural Adjustments (SPA) scrutinized using the Lissajous method. AB - The goal of this research was to study the postural adjustments that occur during the course of a voluntary movement (Simultaneous Postural Adjustments: SPA). A pointing task performed at maximal velocity was considered and upper limb kinematics and body kinetics were recorded. A 2-DOF model was elaborated that distinguishes between the body segments that are mobilized in order to perform the pointing movement. These segments are the right upper limb (termed the "focal" component) and the rest of the body (termed the "postural" component). This model allowed for the calculation of both sub-systems' kinetics and a comparison of the resultant reaction (RoSh) with the corresponding action (AoSh) at the shoulder level. The analysis was based on the ellipsoidal shape of their relationship. The ellipse computation ("Lissajous ellipse") allowed the time lag to be estimated. The results showed that the kinetics of the postural component preceded that of the focal ones and that the time lag during the SPA was not statistically different from the APA duration (dAPA). In addition, the kinetics of the postural component were found to be opposed to the perturbation induced by the pointing movement, but only during part of the SPA time interval. It was concluded that the postural component plays a dual role during the movement, which consists of postural stabilization and propulsive action, with one prevailing over the other depending on the time-instant of movement evolution. This new evidence in healthy subjects is helpful to further specify differences associated with motor impairments. PMID- 25458154 TI - Do patients with diabetic neuropathy use a higher proportion of their maximum strength when walking? AB - Diabetic patients have an altered gait strategy during walking and are known to be at high risk of falling, especially when diabetic peripheral neuropathy is present. This study investigated alterations to lower limb joint torques during walking and related these torques to maximum strength in an attempt to elucidate why diabetic patients are more likely to fall. 20 diabetic patients with moderate/severe peripheral neuropathy (DPN), 33 diabetic patients without peripheral neuropathy (DM), and 27 non-diabetic controls (Ctrl) underwent gait analysis using a motion analysis system and force plates to measure kinetic parameters. Lower limb peak joint torques and joint work done (energy expenditure) were calculated during walking. The ratio of peak joint torques and individual maximum joint strengths (measured on a dynamometer) was then calculated for 59 of the 80 participants to yield the 'operating strength' for those participants. During walking DM and DPN patients showed significantly reduced peak torques at the ankle and knee. Maximum joint strengths at the knee were significantly less in both DM and DPN groups than Ctrls, and for the DPN group at the ankle. Operating strengths were significantly higher at the ankle in the DPN group compared to the Ctrls. These findings show that diabetic patients walk with reduced lower limb joint torques; however due to a decrement in their maximum ability at the ankle and knee, their operating strengths are higher. This allows less reserve strength if responding to a perturbation in balance, potentially increasing their risk of falling. PMID- 25458156 TI - Mosaic aneuploidy in Leishmania: the perspective of whole genome sequencing. PMID- 25458157 TI - Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial. AB - BACKGROUND: Combinations of inhaled long-acting bronchodilator therapies such as muscarinic antagonists and beta2-agonists may be more effective than monotherapy in the treatment of chronic obstructive pulmonary disease (COPD). METHODS: This study was a 24-week, Phase III, multicenter, randomized, blinded, double-dummy, parallel-group study of the once-daily, inhaled, fixed-dose combination of the long-acting muscarinic antagonist umeclidinium bromide and the long-acting beta2 agonist vilanterol (UMEC/VI 62.5/25 mcg) versus tiotropium (TIO, 18 mcg). The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at Day 169. The secondary endpoint was weighted mean FEV1 over 0-6 h post-dose at Day 168. For key endpoints, a step-down closed testing hierarchy was applied to account for multiplicity. Other efficacy and safety endpoints were assessed. RESULTS: Statistically significant improvements in trough FEV1 at Day 169 (0.112 L, 95% confidence interval [CI]: 0.081, 0.144; p < 0.001) and weighted mean FEV1 over 0 6 h post-dose at Day 168 (0.105 L, 95% CI: 0.071, 0.140; p < 0.001) were observed for UMEC/VI versus TIO. In addition UMEC/VI improved health-related quality of life, and reduced requirement for the use of rescue medication compared with TIO. The incidence of adverse events was similar between treatment groups. CONCLUSIONS: UMEC/VI was associated with statistically significant and clinically meaningful improvements in lung function versus TIO. UMEC/VI was well tolerated. UMEC/VI 62.5/25 mcg could provide an effective new treatment option for patients with moderate-to-very severe COPD. PMID- 25458158 TI - How to count coughs? Counting by ear, the effect of visual data and the evaluation of an automated cough monitor. AB - BACKGROUND: Cough causes morbidity and transmits disease yet has been under researched. The best method for recognising and counting coughs remains unclear. We tested the accuracy of the human ear and measured the influence of visual data on cough counting. We also evaluated PulmoTrack(r), a potentially fully-automated cough monitor. METHODS: Consistency amongst listeners and the effect of visual data: Three 14-22-min sequences containing 45-79 coughs were played to 15 respiratory physicians on at least two occasions. Only sound was played on the first occasions but on the final occasion a simultaneous display of audio activity was included. Counts of cough sounds across methods and listeners were compared. Evaluation of PulmoTrack(r): 20-h recordings were made from 10 patients with cough. Automated counts were compared with assessment by one investigator. RESULTS: Agreement among listeners was high. The intraclass correlation coefficient (ICC) for cough counts by ear alone was 0.89 (95% CI, 0.65-1.00). With a concurrent visual display of sound amplitude it was 0.94 (0.80-1.00). 4.8% (0.6-9.5) fewer coughs were counted using visual data than by listening alone (mean [SD] total coughs: 190.2 [3.4] vs 200.7 [14.6]; p = 0.04). Cough frequencies reported by PulmoTrack(r) and the researcher differed substantially (ICC 0.23, -0.51 to 0.34, p = 0.87); PulmoTrack(r) had a sensitivity of 26% for detecting coughs identified by ear. CONCLUSION: Coughs are well recognised by different listeners. The method used to count coughs should be clearly described as visual information has a significant influence. Non-automated cough counting remains the gold standard method of quantifying cough. PMID- 25458159 TI - Middle ear inflammation of rat induced by urban particles. AB - OBJECTIVE: The aim of this study was to evaluate the histologic change of middle ear mucosa and the expression levels of epithelial sodium channel (ENaC) subunits and mucin production genes, after the injection of urban particulate matter (UPM) into the middle ear cavity of rats. METHODS: Fifty pathogen-free, male Sprague Dawley rats were assigned to the study. Transtympanic injection of UPM solution (300MUg/ml, 50MUl) was made into the middle ear cavity of rats. Rats were sacrificed at day 1 (group1); day 3 (group2); day 5 (group3); and day 14 (group4) after the procedure. The expression levels of ENaC subunits (alpha, beta and gamma) and mucin producing genes (MUC5AC and MUC5B) were analyzed using semi quantitative real-time reverse transcriptase-polymerase chain reaction. Thickness of middle ear mucosa was measured and analyzed. RESULT: After transtympanic injection, the thickness of middle ear mucosa increased significantly on day 1, 3 and 5 (p<0.05) and was normalized on day 14, compared to the control group. Inflammatory changes observed in the middle ear mucosa were subepithelial widening, inflammatory cell infiltration and vascular space widening on day 1, 3 and 5. These changes had reverted to normal on day 14. The level of ENaC-alpha expression decreased 0.60 fold on day 1 (p<0.05), but was normalized thereafter. The level of ENaC-beta and gamma decreased 0.39 and 0.27 fold, respectively, on day 1, was normalized on days 3 and 5, and increased 2.30 and 2.47 fold on day 14, respectively (p<0.05). The level of MUC5AC expression increased 1.97-fold on day 1 (p<0.05) and 2.58-fold on day 5 (p<0.05), but was normalized on day 14. The level of MUC5B expression increased 5.4-fold on day 1, 3.14-fold on day 3, 3.85 fold on day 5, and 2.46-fold on day 14, respectively (p<0.05). CONCLUSION: Transtympanic injection of UPM solution into the middle ear cavity of rat induced a characteristic inflammatory response and altered gene expression related with inflammation and mucin production. These findings provide a useful clue for the understanding of how air pollutants, particularly UPM, contribute to the development of otitis media. PMID- 25458160 TI - Effects of caffeic acid on cisplatin-induced hair cell damage in HEI-OC1 auditory cells. AB - INTRODUCTION: Cisplatin is a widely used anticancer chemotherapeutic agent. However, it is notorious for its ototoxicity and nephrotoxicity due to induction of reactive oxygen species (ROS). Caffeic acid is a naturally occurring polyphenol present in honey that is known to reduce the generation of oxygen derived free radicals. The objective of the present study was to evaluate the protective effects and mechanism underlying the effect of caffeic acid on cisplatin-induced ototoxicity in HEI-OC1 auditory cell lines. METHODS: Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Apoptosis was determined by Hoechst 33258 staining and Annexin V-fluorescein isothiocyanate/propidium iodide double staining. Cell cycle stages were analyzed by flow cytometry. The radical scavenging activity of caffeic acid was assessed using the 1,1-diphenyl-2 picrylhydrazyl (DPPH) assay. The expression levels of caspase-3, -8, and -9, as well as the activity of caspase-3, were evaluated. RESULTS: Caffeic acid showed a protective effect against cisplatin-induced HEI-OC1 cell damage as demonstrated by the MTT assay. Caffeic acid decreased cell death by apoptosis and necrosis. Caffeic acid showed strong scavenging activity against the radical DPPH and decreased intracellular ROS production. Caffeic acid decreased the expression of caspase-3 and -8 and increased the activity of caspase-3. CONCLUSIONS: Caffeic acid attenuated cisplatin-induced hair cell loss in HEI-OC1 cell lines; these effects were mediated by its radical scavenging activity and inhibition of apoptosis. PMID- 25458161 TI - Open vs closed type congenital cholesteatoma of the middle ear: two distinct entities or two aspects of the same phenomenon? AB - OBJECTIVE: The clinical features and surgical results of "closed type" versus "open type" congenital cholesteatoma were compared in order to analyse the differences between the two forms; whether the morphology of the disease may have a role in the staging systems has been also evaluated. PATIENTS AND METHODS: We reviewed retrospectively 95 patients (96 ears) who underwent surgery for congenital cholesteatoma over a 15-year period focusing on the clinical differences between open and closed type congenital cholesteatoma. RESULTS: Seventy-one patients (74%) had a closed-type and 25 (26%) an open type congenital cholesteatoma. Our study confirmed the higher prevalence of the closed type, as well as, a younger age at initial diagnosis compared with the open type congenital cholesteatoma. Other differences between the two forms were: modality of diagnosis (pathognomonic otoscopy in 100% of the closed type and in 40% of the open type), positive history for otitis media with effusion (51.4% in closed type vs 20% in open type), involvement of the tympanic membrane quadrants (anterior quadrants were more frequently involved in the closed forms, whereas posterior quadrants were more frequently involved in the open forms), disease extension and aggressiveness. A residual cholesteatoma was found in 6 out of the 71 patients (8.4%) with a closed type congenital cholesteatoma and in 10 out of the 25 patients (40%) with an open type congenital cholesteatoma. After adjusting for potential confounders, open-type congenital cholesteatoma was significantly associated with residual cholesteatoma compared to the closed-type (odds ratio [OR] 7.39, 95% confidence interval [CI] 1.10-49.77, p=0.03). CONCLUSION: This study confirmed that the open congenital cholesteatoma has global clinical features that are uniquely different from the classical closed form. These differences could reflect a distinct pathogenesis, but there is no proof of this to date. The classification of the congenital cholesteatoma could be further refined by adding the morphologic type of the disease. PMID- 25458162 TI - Does parental experience of the diagnosis and intervention process differ for children with auditory neuropathy? AB - OBJECTIVES: This study compared parental experience of the audiological diagnosis and intervention process in children with auditory neuropathy spectrum disorder and sensory neural hearing loss. METHODS: A matched group survey was used with parents of children with auditory neuropathy spectrum disorder (ANSD) matched with a control group of parents and children with sensorineural hearing loss (SNHL). The two groups were matched in terms of the child's gender, age, amplifications used, social background and utilisation of private or public health care sectors. An interview questionnaire, consisting of 45 questions in six categories (1. biographic information, 2. experiences of audiological diagnosis, 3. hearing aid benefit, 4. parental experience of the rehabilitation decision making process, 5. parental needs for emotional support and 6. parental needs for information) using a 5-point Likert scale for categories 2-7, was administered by the same audiologist. RESULTS: Children with ANSD experienced a significantly longer waiting period from diagnosis to hearing aid fitting (p=0.025) and/or cochlear implantation (p=0.036). Parents of children with ANSD reported significantly different experiences of the diagnostic process (p=0.001) with poorer understanding of the diagnosis and reporting insufficient time allowed for asking questions. During the rehabilitation decision-making process 47% of parents with ANSD children (vs. 0% of parents with SNHL children) reported receiving conflicting information. Parents of children with ANSD were also less likely to recommend hearing aids to other parents. Information needs were similar between groups. CONCLUSIONS: Parents of children with ANSD have different experiences and greater uncertainty during the diagnostic and rehabilitation process. Providing regular consultation and structured timelines through the diagnostic process and decision-making process may facilitate this process with less uncertainty. PMID- 25458163 TI - Autosomal recessive non-syndromic hearing loss is caused by novel compound heterozygous mutations in TMC1 from a Tibetan Chinese family. AB - OBJECTIVES: Hearing loss is the most common sensory disorder worldwide. Biallelic mutations in 42 different genes have been identified as associated with autosomal recessive non-syndromic hearing loss (ARNSHL). One of the common genes responsible for ARNSHL is TMC1. TMC1 mutations have been reported to cause non syndromic hearing loss in a variety of populations. The current study is designed to investigate mutations prevalent among Chinese ethnic groups with ARNSHL. METHODS: Targeted exome sequencing (TES) was employed to study the genetic causes of two siblings with ARNSHL in a Tibetan Chinese family. Variants identified by TES were further confirmed by Sanger sequencing. RESULTS: We identified two distinct variants in the TMC1 gene in two deaf siblings of one Tibetan Chinese family using TES. Both siblings inherited a paternal allele containing a deletion of c.1396_1398AAC (p.Asn466del) and a maternal allele containing an insertion of c.2210_2211insCT (p.Glu737HisfsX2). The former disrupts a highly conserved residue in the large intracellular loop domain adjacent to the fourth transmembrane domain, and the latter causes a truncation of a portion of the C terminal domain. These variants were compound heterzygous and segregated with the hearing impairment in this family. CONCLUSION: The novel compound heterozygous mutant alleles of TMC1 identified in this study were responsible for the ARNSHL in this Tibetan Chinese family. Although compound heterozygous mutations in TMC1 occurring in different TMC1 domains have been previously described in Han Chinese; this result suggests that the TMC1 variants contributing to hereditary deafness in Chinese populations may be more complex than initially assumed and that sequence-based diagnostics will be required for a comprehensive evaluation of ARNSHL. PMID- 25458164 TI - Mucosal trauma induced apoptosis in guinea pig middle ear: comparision of hemostatic agents. AB - OBJECTIVE: The aim of this study is to compare the effects of the absorbable gelatin sponge (AGS), microporous polysaccharide hemospheres (MPH), and Ankaferd on wound healing after middle ear trauma and to evaluate their ototoxicity in an experimental guinea pig model. METHODS: Middle ear mucosal trauma was created in 21 healthy adult guinea pigs. MPH, Ankaferd, and AGS were applied into the right tympanic bulla of the guinea pigs (7 ears for each treatment modality). The left ears of the seven animals were used as the sham group. At the fourth postoperative week (28-30 days), the guinea pigs were decapitated. Apoptosis was investigated, and the expression of Bcl-xl, Apaf, p53, cytochrome 3, and caspase 3 were evaluated. RESULTS: The Ankaferd and AGS groups demonstrated significantly lower epithelial thickness, inflammation, and capillary dilatation than did the control group (p<0.001, <0.001, /0.001, <0.001/, 0.005, and 0.005, respectively). A statistically significant decrease in Bcl-xl staining was observed in the middle ears of animals treated with MPH (p=0.003). There was significantly higher caspase 3 expression in the Ankaferd and AGS groups than in the control group (p<0.001 and p=0.002, respectively). CONCLUSION: Light microscopy indicates that Ankaferd and AGS create less inflammation and increased caspase expression, which seems to induce inflammatory cell apoptosis. Ankaferd seems to be a promising hemostatic agent in otology. PMID- 25458165 TI - Improving outcomes in a high-output pediatric otolaryngology practice. AB - OBJECTIVES: To identify factors associated with efficient operating room work flow on high volume pediatric otolaryngology days and the effects on provider and perceived parent satisfaction. METHODS: Retrospective review was performed of a sample of 20 days with greater than 10 cases per day performed by a pediatric otolaryngologist operating in 2 rooms. Turnover time and complications were the main outcome measures. Providers from otolaryngology and anesthesia that participated in these days were surveyed regarding efficiency, safety, and satisfaction. RESULTS: 223 cases were performed over 20 operative days. The average turnover time was significantly longer in "major" surgeries (p=0.03), cases with multispecialty involvement (p=0.01), cases requiring intubation (p<0.001), and in cases where a fellowship trained pediatric anesthesiologist (p=0.01) or CRNA was present (p<0.001). When comparing "fast" (<25min average turnover) operative days vs. "slow" (>25min average turnover) days, presence of a non-fellowship trained anesthesiologist (p<0.001), and the presence of an anesthesiology resident (p=0.03) were significantly associated with "fast" days, while the presence of a CRNA was associated with "slow" days (p<0.001). A significantly greater proportion of patients required intubation on "slow" turnover days vs. "fast" days (p=0.13). Only one complication was observed (0.4%). 48 providers were surveyed with a 63% response rate. Reported satisfaction amongst providers was significantly greater on days with at least 10 cases (p=0.047) and on days with turnover times of 25min or less (p<0.001). Pre operative nursing evaluation/preparation of the patient, inter-provider communication and delays in room cleaning/setup were identified most often as causative factors responsible for delays in turnover. CONCLUSIONS: High-operative volume operating days are common in pediatric otolaryngology and can be safely performed in an efficient manner. Appropriate scheduling and high-level communication between providers is needed to ensure success on these days. Identified areas of potential inefficiency can be a starting point for work flow optimization practices. PMID- 25458166 TI - Difference in maxillary sinus volumes of patients with cleft lip and palate. AB - BACKGROUND AND OBJECTIVE: Sinus disease is noted to be common in patients with cleft lip and palate. Many have wondered if anatomic differences are a cause or at least a contributor of this. In this sense, comparisons of sinus volumes of patients with different craniofacial clefts may be helpful to determine possible differences from normal. Thus, the present study aimed to evaluate and compare the maxillary sinus volume of patients with unilateral (UCLP) and bilateral (BCLP) cleft lip and palate to control, i.e. non-cleft patients, using cone beam computed tomography (CBCT) images. METHODS: The sample consisted of 30 subjects with UCLP, 15 with BCLP and 15 control individuals (non-cleft). Each maxillary sinus was assessed three-dimensionally, segmented and its volume was calculated. The comparison between right and left sinus was performed by Student t-test, and the differences between the control and cleft groups were calculated using ANOVA. RESULTS: No statistical differences were found when the sides were compared (p>0.05). In relation to the assessment among groups, all comparisons had statistically significant differences (p<0.05), with the UCLP group presenting the lowest sinus volume. CONCLUSION: UCLP individuals present maxillary sinuses with smaller volumes, without differences found between the cleft and non-cleft side. BCLP subjects also present a reduction in the volume when compared to a control sample, but the average sinus volume is larger than in UCLP patients. PMID- 25458167 TI - Bardet-Biedl syndrome and a large concha bullosa pyocele. AB - Bardet-Biedl syndrome is a rare disease involving rode cone dystrophy, polydactyly, obesity, learning disabilities, hypogonadism and renal anomalies, symptoms caused by immotile cilia dysfunction. We report the first case of this syndrome in a teenager with an endonasal mass secondary to pyocele of a concha bullosa. The patient was treated successfully with endoscopic sinus surgery. Nasal obstruction secondary to a middle turbinate pyocele in Bardet-Biedl syndrome has not been described before. The pediatrician and the rhinologist should take this entity into consideration when investigating patients with Bardet-Biedl syndrome and sinonasal symptoms. PMID- 25458168 TI - Tunable carrier multiplication and cooling in graphene. AB - Time- and angle-resolved photoemission measurements on two doped graphene samples displaying different doping levels reveal remarkable differences in the ultrafast dynamics of the hot carriers in the Dirac cone. In the more strongly (n-)doped graphene, we observe larger carrier multiplication factors (>3) and a significantly faster phonon-mediated cooling of the carriers back to equilibrium compared to in the less (p-)doped graphene. These results suggest that a careful tuning of the doping level allows for an effective manipulation of graphene's dynamical response to a photoexcitation. PMID- 25458169 TI - Early diagnosis of Danon disease: Flow cytometric detection of lysosome associated membrane protein-2-negative leukocytes. AB - INTRODUCTION: Danon disease is an extremely rare X-linked dominant disorder characterized by progressive cardiomyopathy, muscle weakness, and mild mental retardation. Most cases harbor nonsense, frameshift, or splice-site mutations in LAMP2 that result in lysosome-associated membrane protein-2 (LAMP-2) deficiency and lysosomal defects. The identification of LAMP2 mutations makes it possible to detect female carriers with significant cardiomyopathy. Therefore, it is of paramount importance to develop useful carrier detection methods. METHODS: To screen for diminished LAMP-2 expression among female patients with progressive cardiomyopathy, we developed a flow cytometric method to detect LAMP-2-deficient leukocytes. RESULTS: In healthy controls, all circulating leukocyte populations, including granulocytes, monocytes, and lymphocytes, expressed significant levels of LAMP-2. In contrast, cells from a male patient with Danon disease lacked detectable LAMP-2. His younger twin sisters showed reduced levels of LAMP-2 expression with characteristic bimodal fluorescence intensity patterns. The percentage of LAMP-2-negative cells in the asymptomatic sibling was nearly the same as that in the symptomatic sibling. CONCLUSION: We developed a flow cytometric assay for LAMP-2 expression that can serve as a rapid primary screening method to detect carriers of LAMP-2 deficiencies. This assay will narrow the target population before subjecting patients to more laborious and expensive gene mutation analysis. PMID- 25458171 TI - Tonsil metastasis as initial presentation of clear cell renal carcinoma. PMID- 25458170 TI - Association between smoking habits and the first-time appearance of atrial fibrillation in Japanese patients: Evidence from the Shinken Database. AB - BACKGROUND: We previously reported a cross-sectional analysis regarding the relationship between smoking and atrial fibrillation (AF) in a single hospital based cohort with Japanese patients, but the effect of cessation of smoking and/or total tobacco consumption were unclear. METHODS AND RESULTS: We used data from the Shinken Database 2004-2011 (men/women, n=10,714/6803, respectively), which included all new patients attending the Cardiovascular Institute between June 2004 and March 2012. After excluding those previously diagnosed with AF (n=2296), 15,221 patients (men/women, n=9016/6205) were analyzed. During the follow-up period of 2.0+/-2.1 years (range 0.0-8.1), the incidence rates of new AF in smokers and non-smokers were 9.0 and 5.0 per 1000 patient-years, respectively. In adjusted models with Cox regression analysis, smokers were independently associated with new AF [hazard ratio (HR) 1.47, 95% confidence interval (CI) 1.09-2.00]. Also, current smokers (HR 1.81, 95% CI 1.17-2.79) and smokers with Brinkman index >=800 (HR 1.69, 95% CI 1.05-2.70) were independently associated with new AF. However, in current smokers, the HRs were not different by Brinkman index (Brinkman index <800/>=800; HR 1.81/1.82, 95% CI 1.07-3.05/0.94 3.51, respectively). CONCLUSIONS: Smoking was independently associated with the first-appearance of AF in patients in sinus rhythm, especially when the patients continued their smoking habit. However, in patients who continued smoking, difference by total tobacco consumption was not observed, suggesting the significance of cessation of smoking for preventing AF. Our data are limited because of a single hospital-based nature and a relatively short observation period. PMID- 25458172 TI - Assessing adaptability and reactive scope: Introducing a new measure and illustrating its use through a case study of environmental stress in forest living baboons. AB - In order to maintain regulatory processes, animals are expected to be adapted to the range of environmental stressors usually encountered in their environmental niche. The available capacity of their stress responses is termed their reactive scope, which is utilised to a greater or lesser extent to deal with different stressors. Typically, non-invasive hormone assessment is used to measure the physiological stress responses of wild animals, but, for methodological reasons, such measurements are not directly comparable across studies, limiting interpretation. To overcome this constraint, we propose a new measure of the relative strength of stress responses, 'demonstrated reactive scope', and illustrate its use in a study of ecological correlates (climate, food availability) of faecal glucocorticoid (fGC) levels in two forest-living troops of baboons. Results suggest the wild-feeding troop experiences both thermoregulatory and nutritional stress, while the crop-raiding troop experiences only thermoregulatory stress. This difference, together with the crop-raiding troop's lower overall physiological stress levels and lower demonstrated fGC reactive scope, may reflect nutritional stress-buffering in this troop. The relatively high demonstrated fGC reactive scope levels of both troops compared with other baboons and primate species, may reflect their extreme habitat, on the edge of the geographic range for baboons. Demonstrated reactive scope provides a means of gauging the relative strengths of stress responses of individuals, populations, or species under different conditions, enhancing the interpretive capacity of non-invasive studies of stress hormone levels in wild populations, e.g. in terms of animals' adaptive flexibility, the magnitude of their response to anthropogenic change, or the severity of impact of environmental conditions. PMID- 25458173 TI - Biomarkers, mineralocorticoid receptor antagonism, and cardiorenal remodeling. PMID- 25458174 TI - The impact of galectin-3 inhibition on aldosterone-induced cardiac and renal injuries. AB - OBJECTIVES: This study investigated whether galectin (Gal)-3 inhibition could block aldosterone-induced cardiac and renal fibrosis and improve cardiorenal dysfunction. BACKGROUND: Aldosterone is involved in cardiac and renal fibrosis that is associated with the development of cardiorenal injury. However, the mechanisms of these interactions remain unclear. Gal-3, a beta-galactoside binding lectin, is increased in heart failure and kidney injury. METHODS: Rats were treated with aldosterone-salt combined with spironolactone (a mineralocorticoid receptor antagonist) or modified citrus pectin (a Gal-3 inhibitor), for 3 weeks. Wild-type and Gal-3 knockout mice were treated with aldosterone for 3 weeks. Hemodynamic, cardiac, and renal parameters were analyzed. RESULTS: Hypertensive aldosterone-salt-treated rats presented cardiac and renal hypertrophy (at morphometric, cellular, and molecular levels) and dysfunction. Cardiac and renal expressions of Gal-3 as well as levels of molecular markers attesting fibrosis were also augmented by aldosterone-salt treatment. Spironolactone or modified citrus pectin treatment reversed all of these effects. In wild-type mice, aldosterone did not alter blood pressure levels but increased cardiac and renal Gal-3 expression, fibrosis, and renal epithelial mesenchymal transition. Gal-3 knockout mice were resistant to aldosterone effects. CONCLUSIONS: In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac and renal fibrosis and dysfunction but was prevented by pharmacological inhibition (modified citrus pectin) or genetic disruption of Gal-3. These data suggest a key role for Gal-3 in cardiorenal remodeling and dysfunction induced by aldosterone. Gal-3 could be used as a new biotarget for specific pharmacological interventions. PMID- 25458175 TI - Mineralocorticoid receptor antagonists modulate galectin-3 and interleukin-33/ST2 signaling in left ventricular systolic dysfunction after acute myocardial infarction. AB - OBJECTIVES: This study aimed to evaluate the specific role of the 2 available mineralocorticoid receptor antagonists (MRAs), eplerenone and spironolactone, on the modulation of galectin-3 (Gal-3) and interleukin (IL)-33/ST2 signaling in an experimental model of left ventricular systolic dysfunction after acute myocardial infarction (MI). BACKGROUND: The molecular mechanisms of benefits of MRAs in patients with left ventricular systolic dysfunction after MI not well understood. METHODS: MI and left ventricular systolic dysfunction were induced by permanent ligation of the anterior coronary artery in 45 male Wistar rats, randomly assigned to no therapy (MI group, n = 15) or to receive MRAs (100 mg/kg/day) for 4 weeks; either eplerenone (n = 15) or spironolactone (n = 15) was used. A sham group was used as a control (n = 8). Elements of the pathway for Gal 3 including transforming growth factor (TGF)-beta and SMAD3, as well as that for IL-33/ST2 (including IL-33 and soluble ST2 [sST2]) were analyzed in the infarcted and noninfarcted myocardium by quantitative real-time reverse transcription polymerase chain reaction. Expression of markers of fibrosis (collagen types I and III, tissue inhibitor of metalloproteinase-1) and inflammation (IL-6, tumor necrosis factor-alpha, monocyte chemotactic protein-1) was also examined. RESULTS: In the infarcted myocardium, compared with sham animals, the MI group had higher concentrations of Gal-3, TGF-beta, SMAD3, IL-33, and sST2, as well as higher concentrations of markers of fibrosis and inflammation. Treatment with MRAs down-regulated Gal-3, TGF-beta, and SMAD3 and enhanced IL-33/ST2 signaling with lower expression of sST2; protective IL-33 up-regulation was unaffected by MRAs. Modulation of Gal-3 and IL-33/ST2 signaling induced by MRAs correlated with lower expression levels of fibrosis and inflammatory markers. No differences were found between eplerenone and spironolactone. In the noninfarcted myocardium, compared with sham animals, the MI group exhibited a higher expression of Gal-3 and IL-33, but no signs of inflammation or fibrosis were observed; in the presence of MRAs, IL-33 expression was significantly up-regulated, but Gal-3 was unaffected. CONCLUSIONS: MRAs play a pivotal role in the Gal-3 and IL-33/ST2 modulation in post-MI cardiac remodeling. PMID- 25458176 TI - Natural history and prognostic factors in alcoholic cardiomyopathy. AB - OBJECTIVES: This study sought to determine the natural history of contemporary alcoholic cardiomyopathy (ACM), to compare it with that of idiopathic dilated cardiomyopathy (IDCM), and to identify risk factors for poor outcome. BACKGROUND: ACM is a common cause of dilated cardiomyopathy (DCM), but little is known about its natural history or the effect of reducing alcohol intake on disease progression. METHODS: We studied the clinical characteristics and outcomes of 94 consecutive patients with ACM and 188 with IDCM, evaluated over the period between 1993 and 2011. RESULTS: After a median follow-up of 59 months (interquartile range: 25 to 107 months), 14 ACM patients (15%) had died from cardiovascular causes (6 from heart failure and 8 from sudden cardiac death), 14 (15%) underwent heart transplantation, 35 (37%) experienced recovery in left ventricular function, and 31 (33%) remained clinically stable without improvement in systolic function. Transplantation-free survival was higher in ACM patients than in IDCM patients (p = 0.002), and ACM was associated with a favorable outcome on multiple analysis of the entire cohort (odds ratio [OR]: 0.4; 95% confidence interval [CI]: 0.2 to 0.8; p = 0.01). Independent predictors of death or heart transplantation in ACM identified by multiple logistic regression analysis were atrial fibrillation (OR: 9.7; 95% CI: 2.56 to 36.79; p = 0.001); QRS duration >120 ms (OR: 7.2; 95% CI: 2.02 to 26; p = 0.002), and lack of beta blocker therapy (OR: 4.4; 95% CI: 1.35 to 14.49; p = 0.014). ACM patients who reduced their alcohol intake to moderate levels exhibited similar survival (p = 0.22) and cardiac function recovery (p = 0.8) as abstainers. CONCLUSIONS: ACM has a better prognosis than IDCM. Atrial fibrillation, QRS width >120 ms, and the absence of beta-blocker therapy identify patients with a poor outcome. Alcohol abstainers and those who reduce intake to a moderate degree show similar clinical outcomes. PMID- 25458177 TI - The science prior to the crime--August Hirt's career before 1941. AB - August Hirt (1898-1945) has achieved macabre renown for atrocities perpetrated during his years as professor of anatomy at the Reichsuniversitat Strabetaburg 1941-1945. Little, however, is known about his preceding scientific career. To fill this gap and to scrutinise whether he really was a mediocre scientist during his early years, as some have purported, we perused relevant historical archives and the available literature. In 1921, after medical school, Hirt started to research and teach at the Institute of Anatomy in Heidelberg, forging a steady career until becoming interim chair in 1935. He then became director of anatomical institutes in Greifswald 1936 and Frankfurt 1938 before going to Strabetaburg in 1941. Hirt seems to have been well-established in the community of anatomists. Some of his career advancements after 1933 were nevertheless facilitated by Nazi support. His main scientific fields were the autonomic nervous system, in which he produced a relevant contribution to anatomical knowledge, and fluorescence microscopy. His development of a special "luminescence microscope", in cooperation with pharmacologist Ellinger, was an important advancement in the history of microscopic technique. His early research was funded by national and international sponsoring bodies and was neither unethical nor racist. As Hirt did not publish anything after 1940, those who only knew his publications might think of him as a "good" scientist. To simply dismiss Hirt as a "pseudoscientist" would avoid the question-still difficult to answer-of how he could develop from an accepted, successful anatomist to a criminal "in the name of science". PMID- 25458178 TI - Developmental covariation of human vault and base throughout postnatal ontogeny. AB - In the present study, we analyzed postnatal ontogenetic integration among morphological traits of the human neurocranium. Particularly, the covariation between the vault and the base during postnatal life was assessed. Since the association between these regions may depend on the generalized change produced by allometry, we tested its effect on their covariation. On a sample of adults and subadults ranging from 0 to 31 years, 3D coordinates of neurocranial landmarks and semilandmarks were digitized and geometric morphometric technics were applied. Main aspects of shape variation were examined using Principal Components analysis. Covariation between the vault and the base was examined by Partial Least Squares analysis. According to our results, the vault and the base covary strongly during postnatal ontogeny and their relation depends largely on allometry. Two size variables were studied: centroid size, which was obtained from the recorded morphometric points, and endocranial volume, taken as an estimation of brain size. Although growing brain was found to be a developmental process that contributes to covariation among neurocranial traits, there would be other factors that exert their influence during ontogeny. These results lead to reconsider cranial morphological evolution taking into account the developmental constraints given by ontogenetic patterns of integration and reinforcing the idea that in human evolution a suite of relevant characters may be fuelled by few developmental processes. PMID- 25458179 TI - Occlusal load distribution through the cortical and trabecular bone of the human mid-facial skeleton in natural dentition: a three-dimensional finite element study. AB - Understanding of the occlusal load distribution through the mid-facial skeleton in natural dentition is essential because alterations in magnitude and/or direction of occlusal forces may cause remarkable changes in cortical and trabecular bone structure. Previous analyses by strain gauge technique, photoelastic and, more recently, finite element (FE) methods provided no direct evidence for occlusal load distribution through the cortical and trabecular bone compartments individually. Therefore, we developed an improved three-dimensional FE model of the human skull in order to clarify the distribution of occlusal forces through the cortical and trabecular bone during habitual masticatory activities. Particular focus was placed on the load transfer through the anterior and posterior maxilla. The results were presented in von Mises stress (VMS) and the maximum principal stress, and compared to the reported FE and strain gauge data. Our qualitative stress analysis indicates that occlusal forces distribute through the mid-facial skeleton along five vertical and two horizontal buttresses. We demonstrated that cortical bone has a priority in the transfer of occlusal load in the anterior maxilla, whereas both cortical and trabecular bone in the posterior maxilla are equally involved in performing this task. Observed site dependence of the occlusal load distribution may help clinicians in creating strategies for implantology and orthodontic treatments. Additionally, the magnitude of VMS in our model was significantly lower in comparison to previous FE models composed only of cortical bone. This finding suggests that both cortical and trabecular bone should be modeled whenever stress will be quantitatively analyzed. PMID- 25458180 TI - Infundibular dilatation of the posterior communicating artery in a defined population. AB - Unusual widening of the posterior communicating artery (PCoA) at its beginning from the cerebral portion of the internal carotid artery (ICA) was described as its infundibular dilatation (ID). A possibility of ID rupture or progression to aneurysm was the reason for an investigation of its frequency and morphologic features in specimens of the Serbian population. Cerebral arteries on the brain base of 267 adult cadavers of both genders and varying age and causes of death were dissected. The images of the PCoA in 190 fetuses were also reviewed. ID of the PCoA was defined as a funnel shaped beginning of different width from ICA, wherein PCoA continues from ID apex to the posterior cerebral artery. There were no cases of ID in fetuses. ID and aneurysms of the PCoA were found in 6/267 or 2.2% and 3/267 or 1.12% of adults, respectively. Unilaterally, they existed on the left side and, frequently, in male cases aging 70 years and older, that had died without cerebral cause. Bilaterally, ID was found in 2/6 cases. There was only one case of ID and aneurysm of the PCoA, but from the ID. We are of the opinion that ID of the PCoA only develops postnatally and probably is due to the influence of hemodynamic factors or hypertension. PMID- 25458181 TI - Pyramidal lobe of the thyroid gland and the thyroglossal duct remnant: a study using human fetal sections. AB - To investigate developmental changes in the thyroglossal duct, we observed serial sagittal sections of eight embryos (crown-rump length (CRL) 6-12 mm; approximately 5-6 weeks of gestation) as well as serial horizontal or cross sections of 70 embryos and fetuses (CRL 15-110 mm; 6-15 weeks). In the sagittal sections, the thyroglossal duct was identified as a small sheet or mass of relatively large cells with vacuolization anterior, superior or inferior to the fourth pharyngeal arch artery. However, we found no continuous duct-like structure that reached the thyroid gland. Thus, previous classical schemes might have overestimated the continuity of the duct. Among cross-sections of 70 specimens, we found the thyroglossal duct remnant in only two specimens (CRL 15 mm and 100 mm), in contrast to the pyramidal lobe, which was seen in one-third of the specimens. The duct remnant ran downward along the lateral edge of the hyoid body to reach the anterior aspect of the thyroid cartilage. However, the connection between the pyramidal lobe and the duct remnant was interrupted by the anterior cervical muscles. Therefore, it was unlikely that the thyroglossal duct remnant would more frequently be evident in fetuses than in adults. The highly tortuous course of the duct along the lingual aspect of the hyoid body, which has been reported previously, appeared to become established near term. Descent of the thyroid gland was not evident after the CRL 20 mm stage (6 weeks): the gland appeared to retain its position at the level of the third-sixth cervical vertebrae. PMID- 25458182 TI - Cell-based peptide screening to access the undruggable target space. AB - Only 20-30% of drug target proteins can be accessed by common drug classes, like small molecules or therapeutic antibodies. The vast majority of the remaining proteins are considered "undruggable" and include drug target proteins, like transcription factors, scaffold or adapter proteins, which play important roles in disease. However over the last years innovative compound classes including nucleotide derived drugs (e.g. siRNA, antisense), macrocyclic compounds and cell permeable peptides matured significantly and hold now the potential to modulate these hard to access target proteins for therapeutic use. This article will focus on the discovery of cell-permeable peptides and discuss intracellular screening systems for peptides, which yield highly relevant peptides, because peptide selection takes place in eukaryotic cells, under conditions, which are very similar to the later therapeutic use. PMID- 25458184 TI - Introduction to the "15th anniversary issue" of Epilepsy & behavior. PMID- 25458183 TI - Design of inhibitors of thymidylate kinase from Variola virus as new selective drugs against smallpox. AB - Recently we constructed a homology model of the enzyme thymidylate kinase from Variola virus (VarTMPK) and proposed it as a new target to the drug design against smallpox. In the present work, we used the antivirals cidofovir and acyclovir as reference compounds to choose eleven compounds as leads to the drug design of inhibitors for VarTMPK. Docking and molecular dynamics (MD) studies of the interactions of these compounds inside VarTMPK and human TMPK (HssTMPK) suggest that they compete for the binding region of the substrate and were used to propose the structures of ten new inhibitors for VarTMPK. Further docking and MD simulations of these compounds, inside VarTMPK and HssTMPK, suggest that nine among ten are potential selective inhibitors of VarTMPK. PMID- 25458185 TI - Comments on Hughes JR. A review of recent reports on autism: 1000 studies published in 2007. Epilepsy & behavior 2008;13:425-437 and Hughes JR. Update on autism: a review of 1300 reports published in 2008. Epilepsy & behavior 2009;16:569-589. PMID- 25458186 TI - Comments on Devinsky O, Lai G. Spirituality and religion in epilepsy. Epilepsy & behavior 2008;12:636-643. PMID- 25458187 TI - A letter to the editor-in-chief congratulating him on fifteen years of hard work on one of the most relevant clinical neuroscience journals in publication. PMID- 25458188 TI - Numerical correction of anti-symmetric aberrations in single HRTEM images of weakly scattering 2D-objects. AB - Here, we present a numerical post-processing method for removing the effect of anti-symmetric residual aberrations in high-resolution transmission electron microscopy (HRTEM) images of weakly scattering 2D-objects. The method is based on applying the same aberrations with the opposite phase to the Fourier transform of the recorded image intensity and subsequently inverting the Fourier transform. We present the theoretical justification of the method, and its verification based on simulated images in the case of low-order anti-symmetric aberrations. Ultimately the method is applied to experimental hardware aberration-corrected HRTEM images of single-layer graphene and MoSe2 resulting in images with strongly reduced residual low-order aberrations, and consequently improved interpretability. Alternatively, this method can be used to estimate by trial and error the residual anti-symmetric aberrations in HRTEM images of weakly scattering objects. PMID- 25458189 TI - Efficient phase contrast imaging in STEM using a pixelated detector. Part 1: experimental demonstration at atomic resolution. AB - We demonstrate a method to achieve high efficiency phase contrast imaging in aberration corrected scanning transmission electron microscopy (STEM) with a pixelated detector. The pixelated detector is used to record the Ronchigram as a function of probe position which is then analyzed with ptychography. Ptychography has previously been used to provide super-resolution beyond the diffraction limit of the optics, alongside numerically correcting for spherical aberration. Here we rely on a hardware aberration corrector to eliminate aberrations, but use the pixelated detector data set to utilize the largest possible volume of Fourier space to create high efficiency phase contrast images. The use of ptychography to diagnose the effects of chromatic aberration is also demonstrated. Finally, the four dimensional dataset is used to compare different bright field detector configurations from the same scan for a sample of bilayer graphene. Our method of high efficiency ptychography produces the clearest images, while annular bright field produces almost no contrast for an in-focus aberration-corrected probe. PMID- 25458190 TI - Catadioptric aberration correction in cathode lens microscopy. AB - In this paper I briefly review the use of electrostatic electron mirrors to correct the aberrations of the cathode lens objective lens in low energy electron microscope (LEEM) and photo electron emission microscope (PEEM) instruments. These catadioptric systems, combining electrostatic lens elements with a reflecting mirror, offer a compact solution, allowing simultaneous and independent correction of both spherical and chromatic aberrations. A comparison with catadioptric systems in light optics informs our understanding of the working principles behind aberration correction with electron mirrors, and may point the way to further improvements in the latter. With additional developments in detector technology, 1 nm spatial resolution in LEEM appears to be within reach. PMID- 25458191 TI - Arterial stiffness in patients after Kawasaki disease without coronary artery involvement: Assessment by performing brachial ankle pulse wave velocity and cardio-ankle vascular index. AB - BACKGROUND: It remains unclear whether systemic arterial beds other than the coronary arteries are truly healthy in patients without coronary artery lesions (CAL) after Kawasaki disease (KD). We tested the hypothesis that patients with KD without echocardiographic evidence of CAL during the acute phase of the disease have abnormal mechanical properties in systemic arteries later. METHODS AND RESULTS: We studied 201 consecutive patients with KD (age 2-23 years, mean 10+/-4 years; 109 male, 92 female) without CAL during the acute phase. Data were compared with those in 129 control subjects (age 2-25 years, mean 10+/-4 years; 73 male, 56 female; control group). We examined arterial stiffness by using the brachial-ankle pulse wave velocity (baPWV) and the cardio-ankle vascular index (CAVI). The baPWV in the KD group was significantly higher than that in the control group (913+/-121cm/s vs. 886+/-135cm/s, p=0.04). In contrast, there was no significant difference in CAVI (4.0+/-1.0 vs. 4.2+/-1.0, p=0.9) between the two groups. Multivariate analysis indicated a highly significant difference in baPWV (higher baPWV in patients with KD than in controls, p=0.004), after controlling for age, gender, body height and weight, and systolic and diastolic blood pressure, but no difference in CAVI between the groups. CONCLUSION: Years after KD occurs in patients without apparent CAL during the acute phase, there is a small but significant change in systemic arterial properties, characterized by increased wall stiffness. The clinical importance of these findings must be clarified by performing long-term follow-up studies. PMID- 25458192 TI - Increased extent of myocardial fibrosis in genotyped hypertrophic cardiomyopathy with ventricular tachyarrhythmias. AB - BACKGROUND: Occurrence of malignant ventricular tachyarrhythmias such as ventricular tachycardia and fibrillation (VT/VF) in hypertrophic cardiomyopathy (HCM) can be related to the extent of myocardial fibrosis. Although late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) imaging has been used to detect myocardial fibrosis, few data exist regarding relationships between CMR-determined myocardial fibrosis and VT/VF in genotyped HCM populations. OBJECTIVE: We retrospectively investigated whether the extent of LGE can be increased in HCM patients with VT/VF compared to those without VT/VF in the genotyped HCM population. METHODS AND RESULTS: We studied 35 HCM patients harboring sarcomere gene mutations (TNNI3=22, MYBPC3=12, MYH7=1) who underwent both CMR imaging and 24-h ambulatory electrocardiographic monitoring. VT/VF were identified in 6 patients (2 men, mean age 55.0 years). The extent of LGE was significantly increased in patients with VT/VF (n=6) compared with those without VT/VF (n=29) (18.6+/-14.4% vs. 8.3+/-11.4%, p=0.04), although the LGE extent was not an independent predictor for the occurrence of VT/VF. Applying a cut-off point >=3.25%, episodes of VT/VF were identified with a sensitivity of 100%, specificity of 51.7%, positive predictive value of 30%, negative predictive value of 100%, and the area under the curve of 0.767 (95% confidence interval: 0.590 0.944). CONCLUSION: These results demonstrate that myocardial fibrosis determined by CMR imaging may be increased in genotyped HCM patients with episodes of VT/VF. A further prospective study will be needed to clarify the association between the LGE extent and arrhythmic events in HCM patients harboring sarcomere gene mutations. PMID- 25458193 TI - Rectal swab culture-directed antimicrobial prophylaxis for prostate biopsy and risk of postprocedure infection: a cohort study. AB - OBJECTIVE: To examine the effect of rectal swab culture-directed prophylaxis on the incidence of prostate biopsy-associated infections. Secondary objectives were to determine the rate of fluoroquinolone resistance and extended-spectrum beta lactamase production in local rectal flora. METHODS: All men receiving prostate biopsies from February 2013 to February 2014 were included in a retrospective institutional review board-approved study. All received either a preprocedural rectal swab and culture-directed antimicrobial prophylaxis or routine fluoroquinolone antibiotics. Clinical information was collected on infectious complications treated within 30 days of biopsy. Chi-square test, Fisher exact test, and Welch t test were used for statistical analysis. Confounding variables were included in a multivariate logistic regression model. RESULTS: Of 487 total patients, 314 received preprocedure rectal cultures and 173 did not. Average ages were 62.7 and 64.1 years, respectively (P = .07). There was no difference in mean prostate-specific antigen value (P = .9), Charlson comorbidity score (P = .8), or ethnicity (P = .1). The rectal swab group was more likely to receive supplemental gentamicin (P < .001) and had fewer infectious complications (1.9% vs 2.9%; P = .5). On multivariate analysis, decreased odds of infection was associated with culture-directed antibiotics (odds ratio, 0.70; 95% confidence interval, 0.20 2.50; P = .6). However, the study was only powered to detect a 97% reduction in infections. The incidence of fluoroquinolone resistance and extended-spectrum beta-lactamase production was 12.1% and 0.64%, respectively. CONCLUSION: Our study was underpowered but suggests that there are lower odds of infection with rectal swab-directed antimicrobial prophylaxis. The local incidence of fluoroquinolone resistance is high. A prospective, randomized, controlled trial is warranted to further evaluate this intervention. PMID- 25458195 TI - Ultrastructure of the posterior corneal stroma. AB - PURPOSE: To reinvestigate the ultrastructure of the posterior stroma of the human cornea and to correlate the findings with the stromal behavior after big-bubble creation. DESIGN: Observational consecutive 3-center case series. SPECIMENS: Fresh corneoscleral buttons from human donors (n = 19) and organ-cultured corneoscleral buttons (n = 10) obtained after Descemet's membrane endothelial keratoplasty. METHODS: Corneal specimens were divided into central (3 mm), mid peripheral (8 mm), and peripheral parts by trephination and processed for transmission electron microscopic and immunohistochemical analyses. A big bubble was created by air injection into the stroma of organ-cultured corneas before fixation. MAIN OUTCOME MEASURES: The distance of keratocytes to Descemet's membrane, number of collagen lamellae between keratocytes and Descemet's membrane, diameter and arrangement of collagen fibrils, thickness of stromal lamella created by air injection, and immunopositivity for collagen types III, IV, and VI. RESULTS: Stromal keratocytes were observed at variable distances from Descemet's membrane, increasing from 1.5 to 12 MUm (mean, 4.97+/-2.19 MUm) in the central, 3.5 to 14 MUm (mean, 8.03+/-2.47 MUm) in the midperipheral, and 4.5 to 18 MUm (mean, 9.77+/-2.90 MUm) in the peripheral regions. The differences in mean distances were significant (P < 0.0001). The number of collagen lamellae between Descemet's membrane and most posterior keratocytes varied from 2 to 10 and the diameter of collagen fibrils averaged 23.5+/-1.8 nm and corresponded with that of the remaining stroma. A thin layer (0.5-1.0 MUm thick) of randomly arranged, unaligned collagen fibers, which was positive for collagen types III and VI, was observed at the Descemet-stroma interface. The residual stromal sheet separated by air injection in 8 of 10 donor corneas varied in thickness from 4.5 to 27.5 MUm, even within individual corneas (<=3-fold), and was composed of 5 to 11 collagen lamellae that revealed keratocytes on their anterior surface and in between. CONCLUSIONS: Barring an anchoring zone of interwoven collagen fibers at the Descemet-stroma interface, the findings did not provide any evidence for the existence of a distinctive acellular pre-Descemet's stromal layer in the human cornea. The intrastromal cleavage plane after pneumodissection seems to be nonreproducibly determined by the intraindividually and interindividually variable distances of keratocytes to Descemet's membrane. PMID- 25458196 TI - Ocular nutritional supplements: are their ingredients and manufacturers' claims evidence-based? AB - PURPOSE: To compare ingredients contained in top-selling brands of ocular nutritional supplements with the Age-Related Eye Disease Study (AREDS) and AREDS2 formulae and investigate the validity of claims made by manufacturers of leading brands of ocular nutritional supplements. DESIGN: Descriptive. PARTICIPANTS: None. METHODS: We examined the 5 top-selling brands of ocular nutritional supplements in the United States according to dollar sales tracked by SymphonyIRI (Waltham, MA) from June 2011 to June 2012. We reviewed the ingredients and manufacturer claims of 11 ocular nutritional supplements on the companies' consumer information websites; the ingredients were compared with those contained in the AREDS and AREDS2 formulae. MAIN OUTCOME MEASURES: Proportion of ocular nutritional supplements that contained the same ingredients, in the same doses, as the AREDS or AREDS2 formula; proportion of nutritional supplements with unsubstantiated claims made by the manufacturer. RESULTS: All of the ocular nutritional supplements contained the ingredients from the AREDS or AREDS2 formula; 36% (4/11) of the supplements contained equivalent doses of AREDS or AREDS2 ingredients; 55% (6/11) included some information about the AREDS on their consumer information websites. Product descriptions from 4 of the 11 supplements (36%) stated that the supplements were important to maintain general eye health; none of these supplements duplicated the AREDS or AREDS2 formula. All the individual supplements claimed to "support," "protect," "help," or "promote" vision and eye health, but none specified that there is no proven benefit in using nutritional supplements for primary prevention of eye disease. CONCLUSIONS: The majority of top-selling ocular nutritional supplements did not contain the identical ingredient dosages of the AREDS or AREDS2 formula and had product description claims that lacked level 1 evidence, underscoring the importance of ophthalmologists educating their patients on the evidence-based role of nutritional supplements in the management of eye health. PMID- 25458197 TI - Time to initial clinician-reported inactivation of neovascular age-related macular degeneration treated primarily with ranibizumab. AB - PURPOSE: To characterize in more detail routine treatment patterns of intravitreal ranibizumab for neovascular age-related macular degeneration (nAMD), we analyzed the length of time and the number of injections required until lesions with choroidal neovascularization (CNV) were first graded inactive. DESIGN: Database observational study. PARTICIPANTS: Treatment-naive eyes receiving predominantly ranibizumab for nAMD in routine clinical practice that were tracked in the Fight Retinal Blindness! observational registry. METHODS: Eyes treated with ranibizumab were followed until CNV was first reported to be "inactive" (i.e., absence of intraretinal fluid and hemorrhages). MAIN OUTCOME MEASURES: The length of time until lesion inactivation occurred and the number of injections required. RESULTS: A total of 1096 eyes (65.8% from women) were included in the study. The median number of weeks until a lesion was graded as inactive after beginning treatment was 15 weeks. One to 3 injections were sufficient to inactivate the lesion in 61.1% of eyes. A mean change in visual acuity of +5.5 logarithm of the minimum angle of resolution letters (95% confidence interval, 4.8-6.3) was found from treatment initiation to the time that eyes were reported as inactive. In eyes with a mean treatment frequency less than every 5.3 weeks, a median of only 3 injections (mean=3.7) were required before lesions with CNV were graded as inactive, but if the mean treatment interval extended beyond 5.3 weeks, the median number of injections required increased sharply to 6 injections (mean, 7 injections). Occult lesions became inactive more slowly than classic lesions. CONCLUSIONS: Most lesions with CNV became inactive with 3 injections of ranibizumab, but a small proportion remained active for more than 12 months. Injection frequency and lesion type were the main factors that predicted the time and number of injections required to render lesions inactive. PMID- 25458199 TI - Microbial dysbiosis in bronchiectasis. PMID- 25458200 TI - The effect of long-term macrolide treatment on respiratory microbiota composition in non-cystic fibrosis bronchiectasis: an analysis from the randomised, double blind, placebo-controlled BLESS trial. AB - BACKGROUND: Long-term macrolide treatment has proven benefit in inflammatory airways diseases, but whether it leads to changes in the composition of respiratory microbiota is unknown. We aimed to assess whether long-term, low-dose erythromycin treatment changes the composition of respiratory microbiota in people with non-cystic fibrosis bronchiectasis. METHODS: Microbiota composition was determined by 16S rRNA gene sequencing of sputum samples from participants in the BLESS trial, a 12-month, double-blind, placebo-controlled trial of twice daily erythromycin ethylsuccinate (400 mg) in adult patients with non-cystic fibrosis bronchiectasis and at least two infective exacerbations in the preceding year. The primary outcome was within-patient change in respiratory microbiota composition (assessed by Bray-Curtis index) between baseline and week 48, comparing erythromycin with placebo. The BLESS trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12608000460303. FINDINGS: The BLESS trial took place between Oct 15, 2008, and Dec 14, 2011. Paired sputum samples were available from 86 randomly assigned patients, 42 in the placebo group and 44 in the erythromycin group. The change in microbiota composition between baseline and week 48 was significantly greater with erythromycin than with placebo (median Bray-Curtis score 0.52 [IQR 0.14-0.78] vs 0.68 [0.46-0.93]; median difference 0.16, 95% CI 0.01-0.33; p=0.03). In patients with baseline airway infection dominated by Pseudomonas aeruginosa, erythromycin did not change microbiota composition significantly. In those with infection dominated by organisms other than P. aeruginosa, erythromycin caused a significant change in microbiota composition (p=0.03 [by analysis of similarity]), representing a reduced relative abundance of Haemophilus influenzae (35.3% [5.5-91.6] vs 6.7% [0.8-74.8]; median difference 12.6%, 95% CI 0.4-28.3; p=0.04; interaction p=0.02) and an increased relative abundance of P aeruginosa (0.02% [0.00-0.33] vs 0.13% [0.01-39.58]; median difference 6.6%, 95% CI 0.1 37.1; p=0.002; interaction p=0.45). Compared with placebo, erythromycin reduced the rate of pulmonary exacerbations over the 48 weeks of the study in patients with P. aeruginosa-dominated infection (median 1 [IQR 0-3] vs 3 [2-5]; median difference -2, 95% CI -4 to -1; p=0.01), but not in those without P. aeruginosa dominated infection (1 [0-2] vs 1 [0-3]; median difference 0, -1 to 0; p=0.41; interaction p=0.04). INTERPRETATION: Long-term erythromycin treatment changes the composition of respiratory microbiota in patients with bronchiectasis. In patients without P. aeruginosa airway infection, erythromycin did not significantly reduce exacerbations and promoted displacement of H. influenzae by more macrolide-tolerant pathogens including P. aeruginosa. These findings argue for a cautious approach to chronic macrolide use in patients without P. aeruginosa airway infection. FUNDING: Mater Adult Respiratory Research Trust Fund. PMID- 25458202 TI - Inertial compensation for belt acceleration in an instrumented treadmill. AB - Instrumented treadmills provide a convenient means for applying horizontal perturbations during gait or standing. However, varying the treadmill belt speed introduces inertial artifacts in the sagittal plane moment component of the ground reaction force. Here we present a compensation method based on a second order dynamic model that predicts inertial pitch moment from belt acceleration. The method was tested experimentally on an unloaded treadmill at a slow belt speed with small random variations (1.20+/-0.10m/s) and at a faster belt speed with large random variations (2.00+/-0.50m/s). Inertial artifacts of up to 12Nm (root-mean-square, RMS) and 30Nm (peak) were observed. Coefficients of the model were calibrated on one trial and then used to predict and compensate the pitch moment of another trial with different random variations. Coefficients of determination (R(2)) were 72.08% and 96.75% for the slow and fast conditions, respectively. After compensation, the root-mean-square (RMS) of the inertial artifact was reduced by 47.37% for the slow speed and 81.98% for fast speed, leaving only 1.5Nm and 2.1Nm of artifact uncorrected, respectively. It was concluded that the compensation technique reduced inertial errors substantially, thereby improving the accuracy in joint moment calculations on an instrumented treadmill with varying belt speed. PMID- 25458201 TI - Differences in muscle activity between natural forefoot and rearfoot strikers during running. AB - Running research has focused on reducing injuries by changing running technique. One proposed method is to change from rearfoot striking (RFS) to forefoot striking (FFS) because FFS is thought to be a more natural running pattern that may reduce loading and injury risk. Muscle activity affects loading and influences running patterns; however, the differences in muscle activity between natural FFS runners and natural RFS runners are unknown. The purpose of this study was to measure muscle activity in natural FFS runners and natural RFS runners. We tested the hypotheses that tibialis anterior activity would be significantly lower while activity of the plantarflexors would be significantly greater in FFS runners, compared to RFS runners, during late swing phase and early stance phase. Gait kinematics, ground reaction forces and electromyographic patterns of ten muscles were collected from twelve natural RFS runners and ten natural FFS runners. The root mean square (RMS) of each muscle's activity was calculated during terminal swing phase and early stance phase. We found significantly lower RMS activity in the tibialis anterior in FFS runners during terminal swing phase, compared to RFS runners. In contrast, the medial and lateral gastrocnemius showed significantly greater RMS activity in terminal swing phase in FFS runners. No significant differences were found during early stance phase for the tibialis anterior or the plantarflexors. Recognizing the differences in muscle activity between FFS and RFS runners is an important step toward understanding how foot strike patterns may contribute to different types of injury. PMID- 25458203 TI - A novel disease connection for TRPM2 channels. PMID- 25458204 TI - Photodegradation of imidacloprid insecticide by Ag-deposited titanate nanotubes: a study of intermediates and their reaction pathways. AB - The present work demonstrates the influence of Ag-loading (0.2-1.0 wt %) onto sodium titanate nanotubes (TNT) for complete photomineralization of the neurotoxic imidacloprid (IMI) insecticide under UV light illumination. It has been observed that degradation of IMI follows pseudo-first-order kinetics, where 0.5 wt % Ag-loaded TNT exhibited highest apparent rate constant (2.2 * 10(-2) min(-1)) and corresponding least half-life (t1/2) of 31 min for IMI relative to bare P25-TiO2 (3.4 * 10(-3) min(-1), t1/2 = 230 min). The mineralization of IMI intermediates to CO2 during its photooxidation has been described by time course GC-MS and GC analysis and has been correlated with the kinetic analysis. The investigation for the role and quantitative estimation of the fate of heteroatoms (N, O, and Cl) present in IMI revealed an increase in the amount of nitrate, nitrite, and chloride ions with time during its photooxidation. On the basis of these results a mechanistic pathway for photomineralization of IMI is proposed. PMID- 25458213 TI - Diel vertical migration. AB - In this Quick Guide, Brierley provides a brief overview of a pervasive aspect of aquatic ecosystems, the daily movement of organisms up and down the water column. PMID- 25458214 TI - Synaptogenesis. AB - Synapses are specialized asymmetric cell-cell connections permitting the controlled transfer of an electrical or chemical signal between a presynaptic neuronal cell and a postsynaptic target cell (e.g. neuron or muscle). Adequate synapse function is an essential prerequisite of all neuronal processing, including higher cognitive functions, such as learning and memory. At synapses, neurotransmitters (e.g. amino acids, amines, peptides, and acetylcholine) are released from synaptic vesicles into the synaptic cleft in response to action potentials. The Nobel Prize for Physiology and Medicine in 2013 was awarded to James E. Rothman, Randy W. Schekman and Thomas C. Sudhof "for their discoveries of the machinery regulating vesicle traffic, a major transport system in our cells". This included crucial revelations, such as the identification of the core machinery of synaptic vesicle fusion. However, in contrast to the advances concerning the organization of the core functions of the synapse, our current understanding of the processes of synapse formation and maintenance--i.e. 'synaptogenesis'--is still somewhat fragmentary. Here, we will outline the current status and future directions of the field of synaptogenesis, primarily from the perspective of the presynaptic release site. PMID- 25458205 TI - Factors associated with retention and viral suppression among a cohort of HIV+ women of color. AB - Access to sustained HIV medical care is critical to achieving viral suppression. However, a variety of factors may impede or facilitate retention in care or becoming virally suppressed. Though retention and suppression are often treated separately, this study examined both in a cohort of 921 HIV+ women of color who participated in eight demonstration programs across the US. For women who met the inclusion criteria, 83% (n = 587) were retained and 73% (n = 357) were virally suppressed. Average age of women retained was 40.9, and 41.9 for those virally suppressed. The majority were African American/Black or Hispanic/Latina, single, and had no children less than 18 years of age, had health insurance, a high school degree or higher, were stably housed, and unemployed. Some factors associated with retention in care were indecision about seeking HIV medical care (AOR = 0.42) and having children under the age of 18 (AOR = 0.59). Some factors associated with being virally suppressed were living with others (AOR = 0.58), current substance abuse (AOR = 0.38), and fair/poor health (AOR = 0.40). The findings suggest different processes and social mechanisms may influence retention and viral suppression. Interventions seeking to improve retention in care may require tailored program components and strategies that focus on improving viral suppression. PMID- 25458215 TI - Single-cell transcriptomics for microbial eukaryotes. AB - One of the greatest hindrances to a comprehensive understanding of microbial genomics, cell biology, ecology, and evolution is that most microbial life is not in culture. Solutions to this problem have mainly focused on whole-community surveys like metagenomics, but these analyses inevitably loose information and present particular challenges for eukaryotes, which are relatively rare and possess large, gene-sparse genomes. Single-cell analyses present an alternative solution that allows for specific species to be targeted, while retaining information on cellular identity, morphology, and partitioning of activities within microbial communities. Single-cell transcriptomics, pioneered in medical research, offers particular potential advantages for uncultivated eukaryotes, but the efficiency and biases have not been tested. Here we describe a simple and reproducible method for single-cell transcriptomics using manually isolated cells from five model ciliate species; we examine impacts of amplification bias and contamination, and compare the efficacy of gene discovery to traditional culture based transcriptomics. Gene discovery using single-cell transcriptomes was found to be comparable to mass-culture methods, suggesting single-cell transcriptomics is an efficient entry point into genomic data from the vast majority of eukaryotic biodiversity. PMID- 25458216 TI - Convergent evolution: the genetics of queen number in ants. AB - Large, non-recombining genomic regions underlie the polymorphism in colony queen number in two distantly related ant species. This illustrates that convergence in complex phenotypes can arise via convergence in general genomic architecture, rather than convergent changes in specific genes. PMID- 25458217 TI - Self-awareness: the neural signature of disturbed self-monitoring. AB - A new study reveals that the illusion of feeling another person close by results from a misperception of the source and identity of sensorimotor signals of one's own body. PMID- 25458218 TI - Plant development: small RNAs and the metamorphosis of leaves. AB - In many plant species, the degree of serration and complexity in successive leaves increases. A new study suggests that small-RNA-mediated licensing of competitive interactions between transcription factors links the developmental clock regulating vegetative phase change with leaf morphology. PMID- 25458219 TI - Neurobiology: Reelin mediates form and function. AB - Reelin choreographs neuronal migration to establish laminar structures during brain formation. A recent paper uncovers a new function for Reelin signaling in specifying dendritic compartmentalization. Reelin-induced tyrosine phosphorylation is responsible for enrichment of ion channels in dendritic tufts. PMID- 25458220 TI - Sleep: a neuropeptidergic wake-up call for flies. AB - Endogenous circadian rhythms exert strong effects on sleep, but the neuronal mechanisms that produce these effects have remained obscure. New work implicates neuropeptidergic signaling in a subset of circadian clock cells in the regulation of sleep late at night. PMID- 25458221 TI - Speciation: frog mimics prefer their own. AB - Ranitomeya poison frogs in the Peruvian Amazon are a rare example of Mullerian mimicry in vertebrates. These frogs also prefer to court same-coloured mimics. This suggests that divergence in mimicry plays a role in reproductive isolation. PMID- 25458222 TI - Vision: efficient adaptive coding. AB - Recent studies show that perception is driven not only by the stimuli currently impinging on our senses, but also by the immediate past history. The influence of recent perceptual history on the present reflects the action of efficient mechanisms that exploit temporal redundancies in natural scenes. PMID- 25458223 TI - Deciphering the evolutionary history of open and closed mitosis. AB - The origin of the nucleus at the prokaryote-to-eukaryote transition represents one of the most important events in the evolution of cellular organization. The nuclear envelope encircles the chromosomes in interphase and is a selectively permeable barrier between the nucleoplasm and cytoplasm and an organizational scaffold for the nucleus. It remains intact in the 'closed' mitosis of some yeasts, but loses its integrity in the 'open' mitosis of mammals. Instances of both types of mitosis within two evolutionary clades indicate multiple evolutionary transitions between open and closed mitosis, although the underlying genetic changes that influenced these transitions remain unknown. A survey of the diversity of mitotic nuclei that fall between these extremes is the starting point from which to determine the physiologically relevant characteristics distinguishing open from closed mitosis and to understand how they evolved and why they are retained in present-day organisms. The field is now poised to begin addressing these issues by defining and documenting patterns of mitotic nuclear variation within and among species and mapping them onto a phylogenic tree. Deciphering the evolutionary history of open and closed mitosis will complement cell biological and genetic approaches aimed at deciphering the fundamental organizational principles of the nucleus. PMID- 25458225 TI - Ultra-low dose abdominal MDCT: using a knowledge-based Iterative Model Reconstruction technique for substantial dose reduction in a prospective clinical study. AB - PURPOSE: To assess lesion detection and image quality parameters of a knowledge based Iterative Model Reconstruction (IMR) in reduced dose (RD) abdominal CT examinations. MATERIALS AND METHODS: This IRB-approved prospective study included 82 abdominal CT examinations performed for 41 consecutive patients (mean age, 62 +/- 12 years; F:M 28:13) who underwent a RD CT (SSDE, 1.5 mGy +/- 0.4 [~ 0.9 mSv] at 120 kV with 17-20 mAs/slice) immediately after their standard dose (SD) CT exam (10 mGy +/- 3 [~ 6 mSv] at 120 kV with automatic exposure control) on 256 MDCT (iCT, Philips Healthcare). SD data were reconstructed using filtered back projection (FBP). RD data were reconstructed with FBP and IMR. Four radiologists used a five-point scale (1=image quality better than SD CT to 5=image quality unacceptable) to assess both subjective image quality and artifacts. Lesions were first detected on RD FBP images. RD IMR and RD FBP images were then compared side by-side to SD-FBP images in an independent, randomized and blinded fashion. Friedman's test and intraclass correlation coefficient were used for data analysis. Objective measurements included image noise and attenuation as well as noise spectral density (NSD) curves to assess the noise in frequency domain were obtained. In addition, a low-contrast phantom study was performed. RESULTS: All true lesions (ranging from 32 to 55) on SD FBP images were detected on RD IMR images across all patients. RD FBP images were unacceptable for subjective image quality. Subjective ratings showed acceptable image quality for IMR for organ margins, soft-tissue structures, and retroperitoneal lymphadenopathy, compared to RD FBP in patients with a BMI <= 25 kg/m(2) (median-range, 2-3). Irrespective of patient BMI, subjective ratings for hepatic/renal cysts, stones and colonic diverticula were significantly better with RD IMR images (P<0.01). Objective image noise for RD FBP was 57-66% higher, and for RD IMR was 8-56% lower than that for SD-FBP (P<0.01). NSD showed significantly lower noise in the frequency domain with IMR in all patients compared to FBP. CONCLUSION: IMR considerably improved both objective and subjective image quality parameters of RD abdominal CT images compared to FBP in patients with BMI less than or equal to 25 kg/m(2). PMID- 25458226 TI - Ultrasound screening of contralateral breast after surgery for breast cancer. AB - OBJECTIVE: To determine whether supplemental screening ultrasound (US) to mammography could improve cancer detection rate of the contralateral breast in patients with a personal history of breast cancer and dense breasts. MATERIALS AND METHODS: During a one-year study period, 1314 screening patients with a personal history of breast cancer and dense breasts simultaneously underwent mammography and breast US. BI-RADS categories were given for mammography or US detected lesions in the contralateral breast. The reference standard was histology and/or 1-year imaging follow-up, and the cancer rate according to BI RADS categories and cancer detection rate and positive biopsy rate according to detection modality were analyzed. RESULTS: Of 1314 patients, 84 patients (6.4%) were categorized as category 3 with one interval cancer and one cancer which was upgraded to category 4A after 6-month follow-up US (2.5% cancer rate, 95% CIs 1.5 9.1%). Fifteen patients (1.1%) had category 4A or 4B lesions in the contralateral breast. Four lesions were detected on mammography (two lesions were also visible on US) and 11 lesions were detected on US and 5 cancers were confirmed (33.3%, 95% CIs 15.0-58.5%). Six patients (0.5%) had category 4C lesions, 2 detected on mammography and 4 on US and 4 cancers were confirmed (66.7%, 95% CIs 29.6-90.8%). No lesions were categorized as category 5 in the contralateral breast. Cancer detection rate by mammography was 3.3 per 1000 patients and that by US was 5.0 per 1000 patients, therefore overall cancer detection rate by mammography plus US was 8.3 per 1000 patients. Positive biopsy rate of mammography-detected lesions was 66.7% (4 of 6) and that of US-detected lesions was 40.0% (6 of 15). CONCLUSION: US can be helpful to detect mammographically occult breast cancer in the contralateral breast with high positive biopsy rate and low category 3 rate in patients with a previous history of breast cancer and dense breasts. PMID- 25458228 TI - [TTP or HUS? About a case revealing an IgA nephropathy]. AB - Thrombotic microangiopathy includes a set of conditions characterized by the association of mechanical hemolytic anemia, thrombocytopenia and organ failure which accurate diagnosis is sometimes difficult. We report the case of a patient who presented a thrombotic microangiopathy (TMA) due to an atypical hemolytic and uremic syndrome (HUS) associated with an immunoglobulin A (IgA) nephropathy with a favorable outcome under corticosteroid. PMID- 25458227 TI - Noninvasive nodal restaging in clinically node positive breast cancer patients after neoadjuvant systemic therapy: a systematic review. AB - OBJECTIVE: To provide a systematic review of studies comparing the diagnostic performance of noninvasive techniques and axillary lymph node dissection in the identification of initially node positive patients with pathological complete response of axillary lymph nodes to neoadjuvant systemic therapy. METHODS: PubMed and Embase databases were searched until May 21st, 2014. First, duplicate studies were eliminated. Next, study abstracts were read by two readers to assess eligibility. Studies were selected based on predefined inclusion criteria. Of these, data extraction was performed by two readers independently. RESULTS: Of the 987 abstracts that were considered for inclusion, four were eligible for final analysis, which included a total of 572 patients. The diagnostic performance of clinical examination, axillary ultrasound, breast MRI, whole body (18)F-FDG PET-CT, and a prediction model to identify patients with pathological complete response were investigated. Studies were often limited by small sample size. Furthermore, systemic therapy regimens and definitions of clinical and pathological complete response were variable, refraining further pooling of data. The reported positive predictive value of different techniques to identify patients with axillary pathological complete response after neoadjuvant systemic therapy varied between 40% and 100%. CONCLUSION: At present, there is no accurate noninvasive restaging technique able to identify patients with complete axillary response after neoadjuvant systemic therapy. PMID- 25458229 TI - The effects of using problem-based learning in the clinical nursing education on the students' outcomes in Iran: a quasi-experimental study. AB - There are some strategies including problem based learning (PBL) that could enhance the learning experience. This quasi-experimental design was conducted to compare the effects of PBL with traditional clinical education that is commonly used for nursing students. The effects were observed by monitoring differences in their special and general competencies, performance and attitudes towards learning experiences. In 2010, 70, undergraduate nursing students were assigned into two groups as either PBL (n = 34) or Control group (n = 36) at Hamadan University of Medical Sciences in Iran. The research tools used in this study were: the "students' competency self-evaluation" and the "students' attitudes toward their learning experiences" questionnaires, and also a "Coding system of performance" checklist. The groups were similar in most demographic characteristics. The PBL students' general and special competencies improved in the post-test significantly more than those of the control students (P < .001). The PBL students' attitude was significantly better than the control group (P < .01) as well. There was also an incredible enhancement only in the PBL students' performance (P < .01). Therefore the Problem-based learning fostered nursing students' competency, attitude, and performance. PMID- 25458230 TI - Qualitative evaluation of a standardized patient clinical simulation for nurse practitioner and pharmacy students. AB - This article describes a qualitative evaluation of an interprofessional educational experience for nurse practitioner and pharmacy students using standardized patients and physicians role-playing physicians in clinical scenarios. This experience included the development of two clinical scenarios; training of standardized patients, providers, and faculty facilitators; pre briefing preparation; partial facilitator prompting simulations; and facilitated debriefings. Forty-six students participated in the formative simulation. Small groups of students and faculty facilitators worked through two clinical scenarios that were based on the expected emergence of the patient-centered medical homes. The scenarios incorporated different interprofessional communication modes, including in-person, telephonic, and video-conferencing. Time-in/time-out debriefings were incorporated to provide guidance to students about how to engage in interprofessional collaboration. After completion of the scenarios, facilitated group debriefings allowed for reflection on communication strategies and roles. Immediately following the learning activity, 30 volunteer focus group participants provided comments anonymously in a semi-structured format. Conventional content analysis was used to identify overarching themes. Participants expressed improved understanding of individual roles, increased confidence, and a better sense of interprofessional support. The educational experience themes included the benefits of a realistic nature of the simulation and the need for improved student orientation to roles and expectations prior to the clinical simulations. PMID- 25458231 TI - Psychometric testing of the Norwegian version of the questionnaire, student satisfaction and self-confidence in learning, used in simulation. AB - Simulation is increasingly being used as an approach to learning in nurse education. There is a need for frameworks and valid evaluation tools to help guide educators in implementing the method. The questionnaire, Student Satisfaction and Self-Confidence in Learning, which consists of two subscales, has been developed by the National League for Nursing in the US for evaluating simulation used in nurse education. The aim of the present study was to test the questionnaire, Student Satisfaction and Self-Confidence in Learning, for psychometric properties in a Norwegian nurse education context. A sample consisting of 130 nursing students participated in a simulation situation, and 123 responded. When the questionnaire was tested in its entirety, psychometric testing conducted with a principal component analysis did not reveal a stable factor solution. The two subscales were then tested separately. The analysis for Satisfaction with Current Learning suggested a one-component solution, thereby explaining 62.8% of the variance, and the internal reliability was 0.84. With regard to Self-Confidence in Learning, no stable solution was achieved, and an alpha value of 0.64 was shown. To further validate the questionnaire, Student Satisfaction and Self-Confidence in Learning, more studies by various nursing programmes in different cultural contexts are recommended. PMID- 25458233 TI - Underestimated PTCH1 mutation rate in sporadic keratocystic odontogenic tumors. AB - OBJECTIVES: Keratocystic odontogenic tumors (KCOTs) are benign cystic lesions of the jaws that occur sporadically in isolation or in association with nevoid basal cell carcinoma syndrome (NBCCS). The protein patched homolog 1 gene (PTCH1) is associated with NBCCS development and tumor genesis associated with this syndrome. However, previous studies have revealed that more than 85% of syndromic KCOTs and less than 30% of sporadic KCOTs harbor PTCH1 mutations. The significantly lower PTCH1 mutation rates observed in sporadic KCOTs suggest that they serve a minor role in pathogenesis. We aimed to discern the importance of PTCH1 mutations in sporadic KCOTs. MATERIALS AND METHODS: PTCH1 mutational analysis was performed with 19 new sporadic KCOT cases by direct sequencing of epithelial lining samples separated from fibrous capsules. Using this approach, we further reexamined 9 sporadic KCOTs that were previously reported to lack PTCH1 mutations by our group. RESULTS: Nineteen PTCH1 mutations were detected in patient samples from 16/19 new cases (84%) all these mutations were absent in fibrous tissues and peripheral blood specimens from the same patients. We also identified four PTCH1 mutations in 3/9 patients (33%) that were previously undetected. DISCUSSION: These data indicated that PTCH1 mutations occur in sporadic KCOTs at a higher rate than previously suspected, owing to the masking effects of the attached stromal tissues in the test samples. These results suggest that the PTCH1 gene plays a significant role in the pathogenesis of sporadic KCOTs, which is comparable to that observed in NBCCS patients. PMID- 25458232 TI - The learning experiences of senior student nurses who take on the role of standardised patient: a focus group study. AB - The use of clinical simulation involving standardised patients is increasing in nursing education programmes. In this study, we sought to identify whether participation in simulation through taking on the role of standardised patients benefited student nurses in terms of knowledge and skill development, and if so, how. Data was collected in two focus group interviews with fifteen senior undergraduate nursing students in 2011 and subjected to processes of thematic analysis. Four main themes were identified--seeing the nurse through the eyes of the patient, using observation skills, using reflection and evaluation. Being in the standardised patients role provided students with the opportunity to apply the clinical skills of observation, reflection and evaluation to gain new insights into their own practice, particularly their communication skills. Although there were unique learning opportunities for senior student nurses offered by their experience as standardised patient, more research is need to determine how well this knowledge is translated into practice as they take on the role of registered nurses in the future. PMID- 25458234 TI - RNA interference in oral cancer. PMID- 25458235 TI - Oral squamous cell carcinoma prone disorders/individuals. PMID- 25458236 TI - Preemptive thoracic drainage to eradicate postoperative pulmonary complications after living donor liver transplantation. AB - BACKGROUND: Thoracic fluid retention after living donor liver transplantation (LDLT) has various negative consequences, including atelectasis, pneumonia, and respiratory distress or failure. STUDY DESIGN: We analyzed the clinical impact of preemptive thoracic drainage in 177 patients undergoing adult-to-adult LDLT for chronic liver diseases at a single center. Recipients were divided into 2 time periods. The earlier cohort (n = 120) was analyzed for risk factors for postoperative atelectasis retrospectively; the later cohort (n = 57), with a risk factor for postoperative atelectasis, underwent preemptive thoracic drainage prospectively. The incidence of postoperative pulmonary complications was compared between these 2 cohorts. RESULTS: Independent risk factors for atelectasis in earlier cohort were body mass index >=27 kg/m(2) (p < 0.001), performance status >=3 (p = 0.003) and model for end-stage liver disease score >=23 (p = 0.005). The rates of atelectasis (21.1% vs 42.5%, p = 0.005) and pneumonia (1.8% vs 10.0%, p = 0.049) were significantly lower in later than in earlier cohort. Moreover, the mean durations of ICU stay (3.6 +/- 0.2 days vs 5.7 +/- 0.6 days, p = 0.038) and postoperative oxygen support (5.1 +/- 0.8 days vs 7.1 +/- 0.5 days, p = 0.037) were significantly shorter in the later than in the earlier cohort. There were no significant differences in the incidence of adverse events associated with thoracic drainages between these 2 cohorts. CONCLUSIONS: Preemptive thoracic drainage for transplant recipients at high risk of postoperative atelectasis could decrease morbidities after LDLT. PMID- 25458237 TI - Early diagnosis of clinically significant hyperfibrinolysis using thrombelastography velocity curves. AB - BACKGROUND: Clot lysis values (LY30) determined by rapid thrombelastography (rTEG) predict postinjury transfusion needs and mortality risk. However, the first derivative velocity curve values generated by rTEG measuring lysis-maximum rate of lysis (MRL) and total lysis (TL)-have not been evaluated. Although recent data support use of antifibrinolytics in trauma, the population that would benefit remains poorly defined. The purpose of this study was to determine if velocity curves more accurately predict large volume transfusions and early mortality than conventional rTEG values. STUDY DESIGN: Conventional and velocity curve admission rTEG values of adult trauma patients were retrospectively evaluated for their ability to predict early transfusion of RBC and plasma, substantial bleeding, massive transfusion, and mortality. Patient outcomes were compared according to hyperfibrinolysis diagnosed by velocity curve values and the conventional LY30 cutoff. RESULTS: There were 1,625 patients included. Clot lysis values predicted early transfusion of RBC (p = 0.003), but not plasma (p = 0.298), within 3 hours of arrival. With respect to velocity curves, MRL and TL predicted both early RBC and plasma transfusion (p < 0.05). All 3 parameters predicted massive transfusion, but only MRL and TL predicted substantial bleeding (odds ratio [OR] 3.1 and 2.9, respectively). In addition, MRL was a stronger predictor of 24-hour and 30-day mortality (p < 0.001) and was also available earlier after arrival than LY30 (p < 0.001). CONCLUSIONS: Velocity curve measures of fibrinolysis are stronger predictors of early transfusion of blood components, bleeding, and mortality after trauma compared with conventional rTEG values. In addition, the MRL is more rapidly available after arrival, which may facilitate earlier diagnosis and treatment of clinically significant hyperfibrinolysis. PMID- 25458238 TI - How do administrative data compare with a clinical registry for identifying 30 day postoperative complications? PMID- 25458239 TI - Evaluating the effects of earlier palliative surgical interventions on post-liver transplant: in reply to Zamora-Valdes and colleagues. PMID- 25458240 TI - Liver transplantation for polycystic liver disease. PMID- 25458241 TI - Angiography and embolization for blunt splenic injuries. PMID- 25458242 TI - Clarification on angiography and embolization for blunt splenic injuries: in reply to Livingston and colleagues. PMID- 25458243 TI - Liver volumetry in virtual hepatectomy must account for vascular territories. PMID- 25458244 TI - Hepatic resection planning in the modern era: in reply to Mise and colleagues. PMID- 25458245 TI - Is it time for liver hanging under full visual control? PMID- 25458246 TI - Saline injection method: in reply to Julianov. PMID- 25458248 TI - Pine bark extract prevents low-density lipoprotein oxidation and regulates monocytic expression of antioxidant enzymes. AB - Polyphenols are widely distributed in leaves, seeds, bark, and flowers and considered to have beneficial effects on cardiovascular health. We hypothesized that the potent antioxidant properties of pine bark extract (PBE) are exerted by its ability to scavenge free radicals and induce antioxidant enzymes. Therefore, we investigated the effects of PBE on low-density lipoprotein (LDL) oxidation and the antioxidant defense system in monocytes. Oxidative susceptibility of LDL was determined by lag time assay in vitro and by using a human umbilical vein endothelial cell-mediated oxidation model. THP-1 monocytic cells were treated with PBE, and the expression of antioxidant enzymes was measured by real-time polymerase chain reaction and Western blot. Pine bark extract showed radical scavenging ability and significantly inhibited free radical-induced and endothelial cell-mediated LDL oxidation in vitro. Pine bark extract treatment resulted in increases in the expressions of antioxidant enzymes, glutathione peroxidase-1, catalase, and heme oxygenase-1 in THP-1 cells. In addition, PBE induced nuclear factor-erythroid-2-related factor 2 activation, which was accompanied by the activation of extracellular signal-regulated kinase and Akt despite a down-regulation of reactive oxygen species. After the monocyte investigations, we further examined the antioxidant effect after the intake of PBE by 10 healthy male volunteers. Pine bark extract significantly prolonged the lag time of LDL oxidation. Based on our findings, it appears that PBE enhances the antioxidant defense capacity of LDL and monocytes and may play a preventive role in atherosclerosis progression. PMID- 25458249 TI - Mass isotopomer analysis of nucleosides isolated from RNA and DNA using GC/MS. AB - Nucleosides are biosynthesized from metabolites that are at key nodes of intermediary metabolism. Therefore, (13)C labeling patterns in nucleosides from ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) in suitably designed isotopic tracer studies provide information on metabolic flux distributions of proliferating cells. Here, we present a gas chromatography (GC)-mass spectrometry (MS)-based approach that permits one to exploit that potential. In order to elucidate positional isotopomers of nucleosides from RNA and DNA, we screened the fragmentation spectra of their trimethylsilyl derivatives. We identified the molecular ion moieties retained in the respective fragment ions, focusing particularly on the carbon backbone. Nucleosides fragmented at the N-glycosidic bond provide nucleobase and/or ribose or 2'-deoxyribose fragment ions and fragments thereof. Nucleoside fragments composed of the nucleobase plus some carbons of the ribose ring were also observed. In total, we unequivocally assigned 31 fragments. The mass-isotopic distribution of the assigned fragments provides valuable information for later (13)C metabolic flux analysis as indicated by a labeling experiment applying [1-(13)C]glucose in a yeast culture. PMID- 25458250 TI - Insomnia in the elderly: the role of age-related changes in sleep homeostasis. PMID- 25458251 TI - Clinical and practical considerations in the pharmacologic management of narcolepsy. AB - Despite published treatment recommendations and the availability of approved and off-label pharmacologic therapies for narcolepsy, the clinical management of this incurable, chronic neurologic disorder remains challenging. While treatment is generally symptomatically driven, decisions regarding which drug(s) to use need to take into account a variety of factors that may affect adherence, efficacy, and tolerability. Type 1 narcolepsy (predominantly excessive daytime sleepiness with cataplexy) or type 2 narcolepsy (excessive daytime sleepiness without cataplexy) may drive treatment decisions, with consideration given either to a single drug that targets multiple symptoms or to multiple drugs that each treat a specific symptom. Other drug-related characteristics that affect drug choice are dosing regimens, tolerability, and potential drug-drug interactions. Additionally, the patient should be an active participant in treatment decisions, and the main symptomatic complaints, treatment goals, psychosocial setting, and use of lifestyle substances (ie, alcohol, nicotine, caffeine, and cannabis) need to be discussed with respect to treatment decisions. Although there is a lack of narcolepsy-specific instruments for monitoring therapeutic effects, clinically relevant subjective and objective measures of daytime sleepiness (eg, Epworth Sleepiness Scale and Maintenance of Wakefulness Test) can be used to provide guidance on whether treatment goals are being met. These considerations are discussed with the objective of providing clinically relevant recommendations for making treatment decisions that can enhance the effective management of patients with narcolepsy. PMID- 25458252 TI - Retroviral vectors: from cancer viruses to therapeutic tools. PMID- 25458253 TI - P300 in individuals with sensorineural hearing loss. AB - INTRODUCTION: Behavioral and electrophysiological auditory evaluations contribute to the understanding of the auditory system and of the process of intervention. OBJECTIVE: To study P300 in subjects with severe or profound sensorineural hearing loss. METHODS: This was a descriptive cross-sectional prospective study. It included 29 individuals of both genders with severe or profound sensorineural hearing loss without other type of disorders, aged 11 to 42 years; all were assessed by behavioral audiological evaluation and auditory evoked potentials. RESULTS: A recording of the P3 wave was obtained in 17 individuals, with a mean latency of 326.97ms and mean amplitude of 3.76V. There were significant differences in latency in relation to age and in amplitude according to degree of hearing loss. There was a statistically significant association of the P300 results with the degrees of hearing loss (p=0.04), with the predominant auditory communication channels (p<0.0001), and with time of hearing loss. CONCLUSIONS: P300 can be recorded in individuals with severe and profound congenital sensorineural hearing loss; it may contribute to the understanding of cortical development and is a good predictor of the early intervention outcome. PMID- 25458255 TI - Auditory and language skills of children using hearing aids. AB - INTRODUCTION: Hearing loss may impair the development of a child. The rehabilitation process for individuals with hearing loss depends on effective interventions. OBJECTIVE: To describe the linguistic profile and the hearing skills of children using hearing aids, to characterize the rehabilitation process and to analyze its association with the children's degree of hearing loss. METHODS: Cross-sectional study with a non-probabilistic sample of 110 children using hearing aids (6-10 years of age) for mild to profound hearing loss. Tests of language, speech perception, phonemic discrimination, and school performance were performed. The associations were verified by the following tests: chi squared for linear trend and Kruskal-Wallis. RESULTS: About 65% of the children had altered vocabulary, whereas 89% and 94% had altered phonology and inferior school performance, respectively. The degree of hearing loss was associated with differences in the median age of diagnosis; the age at which the hearing aids were adapted and at which speech therapy was started; and the performance on auditory tests and the type of communication used. CONCLUSION: The diagnosis of hearing loss and the clinical interventions occurred late, contributing to impairments in auditory and language development. PMID- 25458254 TI - Brainstem auditory evoked potentials in children with lead exposure. AB - INTRODUCTION: Earlier studies have demonstrated an auditory effect of lead exposure in children, but information on the effects of low chronic exposures needs to be further elucidated. OBJECTIVE: To investigate the effect of low chronic exposures of the auditory system in children with a history of low blood lead levels, using an auditory electrophysiological test. METHODS: Contemporary cross-sectional cohort. Study participants underwent tympanometry, pure tone and speech audiometry, transient evoked otoacoustic emissions, and brainstem auditory evoked potentials, with blood lead monitoring over a period of 35.5 months. The study included 130 children, with ages ranging from 18 months to 14 years, 5 months (mean age 6 years, 8 months +/- 3 years, 2 months). RESULTS: The mean time integrated cumulative blood lead index was 12 MUg/dL (SD +/- 5.7, range: 2.433). All participants had hearing thresholds equal to or below 20 dBHL and normal amplitudes of transient evoked otoacoustic emissions. No association was found between the absolute latencies of waves I, III, and V, the interpeak latencies I III, III-V, and I-V, and the cumulative lead values. CONCLUSION: No evidence of toxic effects from chronic low lead exposures was observed on the auditory function of children living in a lead contaminated area. PMID- 25458256 TI - Hearing rehabilitation in cerebral palsy: development of language and hearing after cochlear implantation. AB - INTRODUCTION: Auditory rehabilitation in children with bilateral severe-to profound sensorineural hearing loss with cochlear implant has been developed in recent decades; however, the rehabilitation of children with cerebral palsy still remains a challenge to otolaryngology and speech therapy professionals. OBJECTIVE: To verify the effectiveness of cochlear implants in the development of auditory and language skills in children with cerebral palsy. METHODS: A prospective analytical study. The evaluation of auditory responses to speech test was applied to the children in this study at regular intervals following implantation. Standardized tests that assess and quantify the development of auditory and language skills were administered and speech therapy video records and speech therapy files were analyzed. All children went through individually tailored intensive audiological rehabilitation programs following cochlear implantation. RESULTS: Two participants had gradual auditory and language development when compared to other participants who reached advanced levels in hearing and oral language classifications. CONCLUSION: The use of the Cochlear implant enabled participants to reach advanced stages of hearing and language skills in three of the five participants with cerebral palsy in this study. This electronic device is a viable therapeutic option for children with cerebral palsy to help them achieve complex levels of auditory and language skills. PMID- 25458257 TI - Oral cancer preventive campaigns: are we reaching the real target? AB - INTRODUCTION: Oral cavity malignant neoplasms have a high mortality rate. For this reason, preventive campaigns have been developed, both to educate the population and to diagnose lesions at an early stage. However, there are studies that contest the validity of these endeavors, principally because the target audience of the campaigns may not conform to the group at highest risk for oral malignancy. OBJECTIVE: To describe the profile of patients who avail themselves of the preventive campaign, identify the presence of oral lesions in that population, and compare that data with the epidemiological profile of patients with oral cancer. METHODS: Cross-sectional historical cohort study performed by analysis of epidemiological data of the campaign "Abra a Boca para a Saude" collected in the years from 2008 to 2013. RESULTS: In the years analyzed, 11,965 people were treated and 859 lesions were diagnosed, all benign. There was a female predominance (52.7%), with mean age of 44 years (+/-15.4 years); 26% were smokers and 29% reported alcohol consumption. It is known that the group at highest risk to develop oral cancer is 60- to 70-year-old men, who are alcoholic smokers. CONCLUSION: The population that seeks preventive campaigns is not the main risk group for the disease. This fact explains the low number of lesions and the lack of cancer detection. PMID- 25458258 TI - Papillary thyroid carcinoma: does the association with Hashimoto's thyroiditis affect the clinicopathological characteristics of the disease? AB - INTRODUCTION: Papillary carcinoma is the most common malignant thyroid neoplasm. The effect of the concurrent presence of Hashimoto's thyroiditis and papillary thyroid carcinoma remains controversial. OBJECTIVE: To evaluate the association between Hashimoto's thyroiditis and clinicopathological parameters in thyroid papillary carcinoma cases, based on an historical institutional cohort analysis. METHODS: Cross-sectional study obtained from a historical cohort, including all cases submitted to thyroidectomy for papillary thyroid carcinoma in a single institution during an 11-year period study. RESULTS: A total of 417 patients with papillary thyroid carcinoma were enrolled; 148 (35.4%) also had Hashimoto's thyroiditis. A female predominance among cases associated to Hashimoto's thyroiditis was observed. The thyroid tumor, in cases associated with Hashimoto's thyroiditis, had a smaller mean diameter, lower frequency of extra-thyroid extension, and earlier clinicopathological staging. CONCLUSIONS: A high proportion of papillary thyroid carcinoma cases are associated with Hashimoto's thyroiditis. There are associations among these cases with several histopathological factors already recognized for their prognostic value, which by themselves could impact outcomes. PMID- 25458260 TI - Work-related voice disorder. AB - INTRODUCTION: Dysphonia is the main symptom of the disorders of oral communication. However, voice disorders also present with other symptoms such as difficulty in maintaining the voice (asthenia), vocal fatigue, variation in habitual vocal fundamental frequency, hoarseness, lack of vocal volume and projection, loss of vocal efficiency, and weakness when speaking. There are several proposals for the etiologic classification of dysphonia: functional, organofunctional, organic, and work-related voice disorder (WRVD). OBJECTIVE: To conduct a literature review on WRVD and on the current Brazilian labor legislation. METHODS: This was a review article with bibliographical research conducted on the PubMed and Bireme databases, using the terms "work-related voice disorder", "occupational dysphonia", "dysphonia and labor legislation", and a review of labor and social security relevant laws. CONCLUSION: WRVD is a situation that frequently is listed as a reason for work absenteeism, functional rehabilitation, or for prolonged absence from work. Currently, forensic physicians have no comparative parameters to help with the analysis of vocal disorders. In certain situations WRVD may cause, work disability. This disorder may be labor-related, or be an adjuvant factor to work-related diseases. PMID- 25458259 TI - Quantitative evaluation of taste in childhood populations: a systematic review. AB - INTRODUCTION: Taste is of great importance for the feeding process. Seen in this light, it is essential to investigate this sense in children as developing human beings. However, despite little variation in the use of tests that measure the gustatory capacity, there are still questions about the applicability and effective use of tools for quantitative assessment in children. OBJECTIVE: To search the literature on quantitative instruments used for the evaluation of taste used in studies with children. METHODS: A search was conducted in the PUBMED and Web of Science platforms, and subsequently, the identified articles were selected and reviewed. The descriptors and terms used were "taste," "child," "assessment," "diagnosis," and "dysgeusia". Original articles related to the theme in English, restricted to children and with no year limitation, were selected. Studies conducted in other stages of human development, exclusively or concurrently with the pediatric population; animal studies; literature review articles; dissertations and book chapters; and case studies and editorials were excluded. The data analysis was performed through a cataloging protocol created for this study, including the following points: author, research department, year, location, population/sample, age, purpose of the study, methods, and primary results. RESULTS: 5613 items were found. 5307 were excluded based on title, 248 by abstract analysis, and 43 by full text evaluation. Fifteen articles were selected for analysis; of these, six were repeated articles, and thus nine articles were selected for review. CONCLUSION: The tests aiming at evaluation of taste were judiciously used, ensuring reliability for future research, which may employ methods similar to previous studies. PMID- 25458261 TI - Gradual approach to refinement of the nasal tip: surgical results. AB - INTRODUCTION: The complexity of the nasal tip structures and the impact of surgical maneuvers make the prediction of the final outcome very difficult. Therefore, no single technique is enough to correct the several anatomical presentations, and adequate preoperative planning represents the basis of rhinoplasty. OBJECTIVE: To present results of rhinoplasty, through the gradual surgical approach to nasal tip definition based on anatomical features, and to evaluate the degree of patient satisfaction after the surgical procedure. METHODS: Longitudinal retrospective cohort study of the medical charts of 533 patients of both genders who underwent rhinoplasty from January of 2005 to January of 2012 was performed. Cases were allocated into seven groups: (1) no surgery on nasal tip; (2) interdomal breakup; (3) cephalic trim; (4) domal suture; (5) shield-shaped graft; (6) vertical dome division; (7) replacement of lower lateral cartilages. RESULTS: Group 4 was the most prevalent. The satisfaction rate was 96% and revision surgery occurred in 4% of cases. CONCLUSION: The protocol used allowed the implementation of a gradual surgical approach to nasal tip definition with the nasal anatomical characteristics, high rate of patient satisfaction with the surgical outcome, and low rate of revision. PMID- 25458262 TI - Oral changes in individuals undergoing hematopoietic stem cell transplantation. AB - INTRODUCTION: Patients undergoing hematopoietic stem cell transplantation receive high doses of chemotherapy and radiotherapy, which cause severe immunosuppression. OBJECTIVE: To report an oral disease management protocol before and after hematopoietic stem cell transplantation. METHODS: A prospective study was carried out with 65 patients aged>18 years, with hematological diseases, who were allocated into two groups: A (allogeneic transplant, 34 patients); B (autologous transplant, 31 patients). A total of three dental status assessments were performed: in the pre-transplantation period (moment 1), one week after stem cell infusion (moment 2), and 100 days after transplantation (moment 3). In each moment, oral changes were assigned scores and classified as mild, moderate, and severe risks. RESULTS: The most frequent pathological conditions were gingivitis, pericoronitis in the third molar region, and ulcers at the third moment assessments. However, at moments 2 and 3, the most common disease was mucositis associated with toxicity from the drugs used in the immunosuppression. CONCLUSION: Mucositis accounted for the increased score and potential risk of clinical complications. Gingivitis, ulcers, and pericoronitis were other changes identified as potential risk factors for clinical complications. PMID- 25458263 TI - Performance of hearing skills in children with auditory neuropathy spectrum disorder using cochlear implant: a systematic review. AB - INTRODUCTION: Currently, there are no doubts about the benefits of cochlear implants for the development of children with severe or profound hearing loss. However, there is still no consensus among researchers and professionals regarding the benefits for the improvement of hearing skills in children with auditory neuropathy spectrum disorder using cochlear implants. OBJECTIVE: Review the available evidence in the literature to answer the following: "What is the performance of hearing skills in children with auditory neuropathy spectrum disorder using cochlear implants?" METHODS: Systematic review of the literature through electronic database consultation, considering publications in the period 2002-2013. RESULTS: Twenty-two studies met the criteria and were included in the systematic review. CONCLUSION: The analyzed studies demonstrated that after cochlear implant surgery, individuals with auditory neuropathy spectrum disorder improved their performance of hearing skills and had similar performance to that of children with sensorineural hearing loss using cochlear implant. PMID- 25458264 TI - Reevaluation of McCulloch-Pitts-von Neumann's clock. AB - In neuroscience research, a firing pattern expression, called a firing snapshot, defined by firing counts of multiple neurons in discrete time-bin is frequently used. However, the firing pattern expression over multiple neurons requires synchronization commonly known as a "central clock" in computation circuits to externally control or observe multi-neuron firing. Since it is not appropriate to hypothesize the central clock in the brain, we have to reconsider the synchronization assumption. We found the historical origins of central clock synchronization in the works of McCulloch, Pitts and von Neumann and propose an alternative perspective to study neural processing without the central clock. In the "First draft of a report on the EDVAC" known as the first proposal of store program type computer, von Neumann incorporated McCulloch and Pitts' arbitrary assumption of constant synaptic delay into the logical circuit modeling. He introduced a constant pulse delay stabilized by a central clock to synchronize multiple pulse lines. This constant delay carried over to automaton theory by von Neumann and then theoretical neuroscience as an integral part of distributed representation and firing pattern analysis. Instead, we propose a rethinking of neuronal processing by focusing on a variable synaptic delay. We review neuron type dependent differences and point out that the maximum inter-stimulus interval which can affect the last stimulus response is longer than the minimum inter spike interval, indicating the possibility of asynchronous input summation without a firing rate level clock. This fundamental baseline contributes to the investigation of time consuming processes: e.g., the compression of appositional synaptic inputs with duration into a single firing. PMID- 25458265 TI - 3rd EPNOE international polysaccharide conference (EPNOE 2013). PMID- 25458267 TI - Green synthesis of the silver nanoparticles mediated by pullulan and 6 carboxypullulan. AB - Unoxidized and carboxylated pullulan (obtained by pullulan oxidation using TEMPO sodium hypochlorite-sodium bromide system) have been used as mediators for the silver nanoparticles formation (AgNPs), under environment-friendly conditions: using aqueous solutions, room temperature and notably, by using both mediators as reducing and stabilizing agents. The formation of AgNPs was first screened by measuring the surface plasmon resonance peak in the range of 380-440 nm using UV vis spectroscopy. The morphology of the synthesized silver nanoparticles was determined by TEM, which indicated that the AgNPs differ on shape and thickness of the polymer shell by varying the silver nitrate concentration, different size and shape of AgNPs was achieved. The presence of elemental silver and the crystalline structure of the AgNPs were confirmed by EDX and XRD analyses. Moreover, the possible functional groups of pullulan (oxidized pullulan) responsible for the reduction and stabilization of AgNPs were evaluated using FT IR. The results showed that both, pullulan and 6-carboxypullulan could be successfully used as reducing as well as capping agents for the AgNPs synthesis which shows potential antimicrobial activity against Gram positive and Gram negative bacteria. PMID- 25458266 TI - New supramolecular metallo-terpyridine carboxymethyl cellulose derivatives with antimicrobial properties. AB - Preparation of a new water-soluble, cellulose derivative via a supramolecular route is presented. In a one-step procedure, carboxymethyl cellulose (CMC) was reacted with the Cu(BF4)2 complex of 4'-chloro[2,2':6',2"]terpyridine to generate the desired CMC-Cu(II)-terpyridine derivative. This polymeric salt was characterized by elemental analysis, ultraviolet-visible spectroscopy (UV visible), Fourier transform infrared (FTIR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), rheological properties measurements, thermogravimetric analysis (TGA), dynamic mechanical thermal analysis (DMTA), and tensile strength properties testing. In addition, antimicrobial properties were demonstrated against Gram-positive bacteria (Staphylococcus aureus and Streptococcus thermophilus), Gram-negative bacteria (Escherichia coli), and yeast (Saccharomyces cervisiae). The minimum inhibitory concentration of the prepared metallo-terpyridine CMC derivative against the studied microorganisms ranged from 6 to 8 mg/L to achieve >=90% of microbial growth inhibition. PMID- 25458268 TI - Monosaccharide production in an acid sulfite process: kinetic modeling. AB - Spent sulfite liquor is a lignocellulosic waste obtained after the sulfite pulping process. It is mainly formed by sugars and lignosulfonates which are isolated from the pulp during the cooking process. The current work investigates the kinetic modeling of the sulfite process from a biorefinery point of view since monosaccharides present in the spent liquor can be used as a raw material in further biorefinery processes to produce other value-added products. Kinetic parameters of carbohydrate degradation have been determined following sugar and inhibitors from wood to spent liquor, using laboratory scale reactors and different temperatures, 130, 140 and 150 degrees C. Three types of reaction schemes were developed. Kinetic parameters were obtained for each one using first and n order reactions, using Aspen Custom Modeler. Results show that the best temperature to be used in the process is 130 degrees C, giving the maximum sugar conversion, 33.91 mol% and obtaining 13.81 mol% of decomposition products. PMID- 25458269 TI - Amphiphilic derivatives of chitosan using microwave irradiation. Toward an eco friendly process to chitosan derivatives. AB - Conventional heating and microwave irradiation have been compared for the synthesis of chitosans grafted with alkyl chains. Reaction time (1-60 min), temperature (25 and 40 degrees C) and chitosan molar mass have been studied onto the yield of alkylation. The irradiation mode has been scrupulously controlled to highlight the effect of the use of microwaves. The chemical structure of modified polymers (degree of alkylation) is determined from NMR. In relation to the rheological behavior and surface tension measurements, the evolution of hydrophobic interactions is studied as a function of the yield of alkylation. A maximum of intrinsic viscosity and hydrodynamic diameter was observed for a degree of alkylation of around 10%. All the results tend to prove that microwave assisted synthesis is a powerful method to obtain modified chitosan under extremely low reaction time without any degradation and/or property modifications. PMID- 25458271 TI - Optimized triazine-mediated amidation for efficient and controlled functionalization of hyaluronic acid. AB - Triazine-based coupling agents have the potential to replace carbodiimides in the functionalization of hyaluronic acid (HA) giving derivatives with high degrees of substitution (DS) under mild conditions with excellent efficiency. Kinetics of the triazine-mediated amidation of HA in aqueous solution were investigated to understand the reaction mechanism and the role of the amine reagent. The DS decreased with increasing basicity of the amine. The water soluble coupling agent was stable under the reaction conditions (t1/2=10 days) in the absence of amines. The activation of HA proceeded quantitatively. The stoichiometry of amine was the limiting factor in the substitution. Functional HA derivatives with DS up to 55% were obtained by the triazine-mediated amidation. They were used successfully to prepare well-defined HA conjugates via the maleimide-thiol and the azide-alkyne "click" reactions. PMID- 25458270 TI - Antioxidant activities of a polyglucuronic acid sodium salt obtained from TEMPO mediated oxidation of xanthan. AB - A xanthouronic acid sodium salt called xanthouronan was produced from xanthan by regioselective oxidation with NaOCl/NaBr using 2,2,6,6-tetramethylpiperidine-1 oxy radical (TEMPO) as catalyst. The efficiency of the one pot TEMPO-mediated oxidation was confirmed by HPAEC-PAD, (13)C NMR, and FT-IR. The oxidation degree was close to 98% and the mass yield of this new polyglucuronic acid was higher than 90% (w/w). The macromolecular characterization of xanthouronan using SEC MALLS showed a molecular size reduced by a third due to the oxidation treatment and the degree of polymerization (DP) of the xanthouronan form was about 665. The evaluation of the enzymatic degradation of this C-6 carboxylated xanthan by various polysaccharide hydrolases and one polysaccharide lyase showed its high resistant to biodegradation. The antioxidant activity of xanthouronan was also tested by using the 2,2'-diphenyl-1-picrylhydrazyle (DPPH) and hydroxyl radical procedures. At 1 g/L, xanthouronan presented 75% of the ascorbic acid antioxidant activity. PMID- 25458272 TI - Synthesis of new cellulose ethers using Suzuki-Miyaura reactions. AB - Cellulose ethers are functionalized biopolymers that are industrially produced through drastic conditions employing gaseous reactants with a high risk of industrial accident. The cellulose ethers that are commercially available generally bear short carbon-chains. In this work, an alternative method using non gaseous chemicals is proposed. It relies on the use of the Suzuki-Miyaura reaction employing mild, moisture- and air-stable conditions. Relatively innocuous reagents are used for this step, which allows the formation of a wide range of cellulose ethers bearing various functional groups with different chain length. PMID- 25458273 TI - Amination and thiolation of chloroacetyl cellulose through reactive dissolution in N,N-dimethylformamide. AB - The synthesis and characterization of aminoacetyl cellulose and thioacetyl cellulose is presented in this paper. Cellulose was first chemically modified with chloroacetyl chloride using N,N-dimethylformamide (DMF) as reaction medium. The maximum substitution of hydroxyl groups of cellulose was achieved reacting in the presence of 6 equiv. of chloroacetyl chloride over 24 h at 60 degrees C. DMF were then recovered by fractional distillation of the media. In the next step, chloroacetyl cellulose was reacted with either secondary amines or thiols. The reactions were initially heterogeneous in hot DMF. As the reactions proceeded, homogenous mixtures were obtained. Highly substituted cellulose derivatives were achieved via this method. The success of the reactions was confirmed by ATR-IR and NMR spectroscopy. Various pulps were used as cellulose source. The resulting products were found to be thermally stable and have glass transition temperatures around 120 degrees C. Gel permeation chromatography (GPC) indicated that degradation of the cellulose backbone had occurred. The cellulose derivatives were then processed into films. Their potential, as packaging films, was then studied from the view-point of their moisture and oxygen barrier properties, as well as their tensile properties. PMID- 25458274 TI - Polysaccharide purification from Haemophilus influenzae type b through tangential microfiltration. AB - Haemophilus influenzae type b (Hib) is a human pathogen that causes meningitis in infants worldwide. Capsular polysaccharide linked to a protein has been used as an efficient vaccine, and this approach has reduced the incidence of Hib disease since its inclusion in national immunisation campaigns. The traditional polysaccharide downstream process is based on several ethanol precipitations, treatment with detergents and centrifugation. The aim of this study was to introduce tangential microfiltration (TMF) in the place of centrifugation to simplify handling and to scale up the process. The purity of the polysaccharide was RPNA=1747.2 and RPPrt=196.1 for nucleic acid and protein, respectively, meeting the quality requirements for this polysaccharide. Moreover, the polysaccharide was recognised by at specific antibody, and the ribose and phosphate contents were within the expected limits. Thus, we established a process for the purification of capsular polysaccharide produced by H. influenzae type b that is effective, robust and feasible to be scaling up. PMID- 25458275 TI - Introduction of aldehyde vs. carboxylic groups to cellulose nanofibers using laccase/TEMPO mediated oxidation. AB - The chemo-enzymatic modification of cellulose nanofibers (CNFs) using laccase as biocatalysts and TEMPO or 4-Amino-TEMPO as mediators under mild aqueous conditions (pH 5, 30 degrees C) has been investigated to introduce surface active aldehyde groups. 4-Amino TEMPO turned out to be kinetically 0.5-times (50%) more active mediator, resulting to oxoammonium cation intermediacy generated and its in situ regeneration during the modification of CNFs. Accordingly, beside of around 750 mmol/kg terminally-located aldehydes, originated during CNFs isolation, the reaction resulted to about 140% increase of C6-located aldehydes at optimal conditions, without reducing CNFs crystallinity. While only the C6-aldehydes were wholly transformed into the carboxyls after additional post-treatment using NaOH according to the Cannizzaro reaction, the post-oxidation with air-oxygen in EtOH/water medium or NaClO2 resulted to no- or very small amounts of carboxyls created, respectively, at a simultaneous loss of all C6- and some terminal-aldehydes in the latter due to the formation of highly resistant hemiacetal covalent linkages with available cellulose hydroxyls. The results indicated a new way of preparing and stabilizing highly reactive C6 aldehydes on cellulose, and their exploitation in the development of new nanocellulose-based materials. PMID- 25458276 TI - Comparison of different twin-screw extraction conditions for the production of arabinoxylans. AB - The aim of this article is to compare two different sets of optimal conditions for twin-screw extraction of xylans and define their influence on the purification steps, combining ultrafiltration and industrial chromatography. Two xylan extracts were obtained by twin-screw extrusion of straw and bran. Condition 1 used a high straw/bran ratio (equal to 6) and high sodium hydroxide content, and condition 2 used a lower straw/bran ratio (equal to 2) and low sodium hydroxide content. Arabinoxylan extraction yields are slightly higher for conditions with low straw content (5.1% versus 4.4%). Nevertheless, these recovery yields remain between 9% and 10%. Ultrafiltration is as efficient as evaporation for polysaccharide concentration, with lower energy consumption, but also demineralizes the solution. The combination of ultrafiltration and chromatography gives partial purification of the extract with a final arabinoxylan purity ranging from 16% to 26%. This is slightly higher than by direct precipitation, but limited because all the large molecules such as proteins and lignins were retained by ultrafiltration. PMID- 25458277 TI - Miscibility and dynamical properties of cellulose acetate/plasticizer systems. AB - Due to its biodegradability and renewability, a great interest has been devoted to investigating cellulose acetate in order to expand its potential applications. In addition, secondary cellulose acetate (CDA) could also be considered as a model system for strongly polar polymer system. The dynamical behavior of CDA is supposed to be governed by H-bonding and dipolar interaction network. Due to their high glass transition temperature, cellulose acetate-based systems are processed when blended with plasticizers. It is thus of utmost importance to study the miscibility and plasticizing effects of various molecules. We prepared CDA films via solvent casting method with diethyl phthalate as the plasticizer. Miscibility diagrams were established by calorimetry and thermo-mechanical (DMTA) experiments. Dynamical properties were analyzed by DMTA and broadband dielectric spectroscopy. We could identify the alpha-relaxation of these CDA-plasticizer systems in the frequency range from 0.06 Hz to 10(6)Hz, which allowed for describing the dynamics in the so-called Williams-Landel-Ferry/Vogel-Fulcher Tammann regime. PMID- 25458278 TI - Effect of granule organisation on the behaviour of starches in the NMMO (N-methyl morpholine N-oxide) solvent system. AB - The response of starches of different botanical origin to heating in 78% N-methyl morpholine N-oxide (NMMO) is compared with their behaviour in water. For all starches studied an exothermic transition is obtained in the NMMO system rather than the endothermic transition in water. In NMMO the transition temperatures are lower for A-type starches (wheat, rice and tapioca) than the C-type starches (sago and pea) and also potato which has a B-type polymorph. Observations using a hot stage microscope show two different types of initial behaviour in NMMO; erosion of the granule from the surface or disruption into fragments. In both cases the final outcome is dissolution but for the most resistant C-type starches (pea and sago) some intact granules could be seen following heating at 95 degrees C in 78% NMMO and subsequent precipitation in ethanol. The results are discussed in terms of what is known from previous structural studies on these six starches and the behaviour of maize starch in NMMO and ionic liquids. The work is relevant to the co-dissolution of starch and cellulose to form novel polysaccharide based materials. PMID- 25458279 TI - Film formation of omega-aminoalkylcellulose carbamates--a quartz crystal microbalance (QCM) study. AB - The film formation of novel omega-aminoalkylcellulose carbamates on gold surface was studied by means of quartz crystal microbalance with dissipation monitoring (QCM-D) and atomic force microscopy (AFM). The influence of the pH value of the buffer solution, the concentration, the degree of polymerization, and the structure (spacer length) of the polymers on the coating was investigated. The layer formation was explained based on the pKa value and the degree of substitution of the omega-aminoalkylcellulose carbamates determined by potentiometric titration. This work provides novel supporting materials that might be applied in field of immobilization of biomolecules. PMID- 25458280 TI - Rheological study of reinforcement of agarose hydrogels by cellulose nanowhiskers. AB - The influence of the addition of tunicate cellulose nanowhiskers on the structural and rheological properties of an agarose hydrogel matrix has been studied, with the objective to design innovative green material, with good mechanical properties. The cellulose nanowhiskers were characterized using transmission electron microscopy, and their charge surface density was determined by a titration method. Oscillatory shear and stress relaxation tests were performed in order to characterize the rheological properties of the agarose matrix, and of the agarose hydrogels filled by nanowhiskers at volume fractions below 0.2%. The results show a significant reinforcement effect due to the addition of nanowhiskers, and suggest changes in the matrix network structure induced by the cellulose nanoparticles. PMID- 25458281 TI - Aqueous thiocyanate-urea solution as a powerful non-alkaline swelling agent for cellulose fibres. AB - For many applications cellulose fibres are treated with concentrated solutions of swelling agents to increase reactivity and to achieve reorganisation of fibre structure. Representative examples are caustic soda, potassium hydroxide solution or liquid ammonia. These highly concentrated media bear considerable safety hazards during the technical handling thus alternative swelling agents are of interest. The thiocyanate-urea system investigated in this work offers high swelling potential for regenerated cellulose fibres. Experiments with different cations of M(+) in M(+) SCN(-) demonstrate the significant influence of the cation on the degree of fibre swelling. In concentrated NaSCN/urea solutions, at 80 degrees C, lyocell fibres expand the diameter from 12-14 to 100 MUm. The treatment in the swelling agent also led to a significant increase in the water retention value which was accompanied by a strength loss of 20-40% of the initial value. FTIR analysis of treated fibres did not indicate substantial changes in structure of the cellulose polymer. Limited weight loss of up to 20% was observed despite the high expansion of the fibre. PMID- 25458282 TI - Complexes of xylan and synthetic polyelectrolytes. Characterization and adsorption onto high quality unbleached fibres. AB - In this work, polyelectrolyte complexes (PECs) were formed by adding polyacrylic acid (PAA) or 4-O-methylglucuronoxylan (Xyl) on poly(allylamine hydrochloride) (PAH) solutions, at different ionic strength and neutral pH. Turbidity curves, charge densities of the cationic complexes determined by polyelectrolyte titration method, and z-potential values showed clear differences between both complexes. Stirring favourably reverses the effects of sedimentation of Xyl/PAH complexes, as demonstrated by colloidal stability tests. Adsorption studies on silica surfaces, performed by Quartz Crystal Microbalance with Dissipation (QCM D) showed that PAA/PAH adsorbed complexes layers were rigid, while the corresponding Xyl/PAH layers were viscoelastic. Despite the different conformations, both complexes were adsorbed as spherical particles, as observed by Atomic Force Microscopy (AFM). Adsorption isotherms performed on fibre suspensions showed that the ionic strength of the liquid medium determines the amount of PEC retained. Finally, it was found that the papermaking properties were significantly increased due to the addition of these PECs. PMID- 25458283 TI - Impact of cultivation of Mastocarpus stellatus in IMTA on the seaweeds chemistry and hybrid carrageenan properties. AB - The biomass yield potential of Mastocarpus stellatus, a commercially attractive carrageenophyte for foods and pharmaceutics, was investigated by cultivating the seaweeds in the nutrient-rich outflow of a commercial fish farm. Results from two consecutive 4 weeks experiments indicate that the cultivation of this seaweed produces a mean biomass of 21 to 40.6 gDW m(-2) day(-1) depending on the time of the experiment. DRIFT and CP-MAS NMR analyses of seaweeds indicate that cultivation during May affected quantitatively the seaweeds chemistry, and thus the chemical and gelling properties of native extracts of kappa/iota-hybrid carrageenan (KI). Overall, algal growth leads to the production of more sulphated KI, the percentage increase varying between 27% and 44% for the two experiments. However, alkali treatment of seaweeds before extraction reduces the variations in gelling properties of KI induced by the algal growth. This study demonstrates the capacity of growing M. stellatus in an integrated multi-trophic aquaculture system for the sustainable production of high value polysaccharides. PMID- 25458284 TI - Antifouling coating of cellulose acetate thin films with polysaccharide multilayers. AB - In this investigation, partially deacetylated cellulose acetate (DCA) thin films were prepared and modified with hydrophilic polysaccharides with the layer-by layer (LbL) technique. As polysaccharides, chitosan (CHI) and carboxymethyl cellulose (CMC) were used. DCA thin films were manufactured by exposing spin coated cellulose acetate to potassium hydroxide solutions for various times. The deacetylation process was monitored by attenuated total reflectance-infrared spectroscopy, film thickness and static water contact angle measurements. A maximum of three bilayers was created from the alternating deposition of CHI and CMC on the DCA films under two different conditions namely constant ionic strengths and varying pH values of the CMC solutions. Precoatings of CMC at pH 2 were used as a base layer. The sequential deposition of CMC and CHI was investigated with a quartz crystal microbalance with dissipation, film thickness, static water contact angle and atomic force microscopy (AFM) measurements. The versatility and applicability of the developed functional coatings was shown by removing the multilayers by rinsing with mixtures containing HCl/NaCl. The developed LbL coatings are used for studying the fouling behavior of bovine serum albumin (BSA). PMID- 25458285 TI - Characterization and biological effects of two polysaccharides isolated from Acanthopanax sciadophylloides. AB - Two polysaccharides abbreviated ANP and AAP were isolated from the young buds of Acanthopanax sciadophylloides. ANP consisted of L-arabinose, D-mannose, D-glucose and D-galactose in a ratio of ca 1.0:2.6:2.5:1.4 and its weight average molecular weight (Mw) was 1.07*10(4). AAP consisted of L-arabinose, D-galactose and 4-O methyl-D-glucuronic acid in a ratio of ca 5:10:1, and its Mw was estimated to be 8.40*10(4). ANP was suggested to be an acetylated heteropolysaccharide, whereas AAP was speculated to be a type II arabinogalactan on the basis of structural analysis data. Both polysaccharides were found to stimulate NO production and induce the expression of cytokine mRNAs including IL-1beta, IL-6, IL-10 and TNF alpha on RAW264.7 cells. They also induced NF-kappaB activation in RAW-Blue cells. NO production and NF-kappaB activation by both polysaccharides were decreased by pretreatment with neutralizing anti-TLR-4 and anti-CD14 antibodies but not with anti-TLR-2, anti-SR-A, anti-CD11c, and anti-Dectin-1 antibodies. Therefore, these immunostimulating effects of ANP and AAP were suggested to be promoted by the interaction through the membrane receptors, TLR-4 and CD14. In addition to immunomodulating effects, ANP showed anti-HSV-2 effects in vitro. PMID- 25458286 TI - Study of the chemical stability of the capsular polysaccharide produced by Haemophilus influenzae type b. AB - Haemophilus influenzae type b (Hib) is a human pathogen that causes severe infections such as pneumonia, sepsis and meningitis. Vaccines for Hib infections are based on its capsular polysaccharide conjugated to a protein. This conjugated Hib antigen is included as one of the components of polyvalent vaccines and accounts for more than 50% of the total cost of the formulations. The instability of the polysaccharide is responsible for the high cost of the vaccine. In this study, the factors affecting the spontaneous degradation of the polysaccharide from Hib were evaluated based on the decrease in its molecular mass, as measured by size-exclusion chromatography. Temperature and pH were found to be the most significant variables, and the results showed that the conditions of bacterial cell growth (37 degrees C and pH 7.5) are favourable for depolymerization. An increase in the concentration of sodium ions up to 200 mM intensified the effect of pH, allowing higher rates of depolymerization at lower pH values, whereas the presence of magnesium ions showed no effects. PMID- 25458287 TI - Characterization of purified bacterial cellulose focused on its use on paper restoration. AB - Bacterial cellulose (BC) synthesized by Gluconacetobacter sucrofermentans CECT 7291 seems to be a good option for the restoration of degraded paper. In this work BC layers are cultivated and purified by two different methods: an alkaline treatment when the culture media contains ethanol and a thermal treatment if the media is free from ethanol. The main goal of these tests was the characterization of BC layers measured in terms of tear and burst indexes, optical properties, SEM, X-ray diffraction, FTIR, degree of polymerization, static and dynamic contact angles, and mercury intrusion porosimetry. The BC layers were also evaluated in the same terms after an aging treatment. Results showed that BC has got high crystallinity index, low internal porosity, good mechanical properties and high stability over time, especially when purified by the alkaline treatment. These features make BC an adequate candidate for degraded paper reinforcement. PMID- 25458289 TI - Microfluidics assisted generation of innovative polysaccharide hydrogel microparticles. AB - Capillary flow-based approach such as microfluidic devices offer a number of advantages over conventional flow control technology because they ensure highly versatile geometry and can be used to produce monodisperse spherical and non spherical polymeric microparticles. Based on the principle of a flow-focusing device to emulsify the coflow of aqueous solutions in an organic phase, we were able to produce the following innovative polysaccharide hydrogel microparticles: Janus hydrogel microparticles made of pectin-pectin (homo Janus) and pectin alginate (hetero Janus) were produced. The efficiency of separation of the two hemispheres was investigated by confocal scanning laser microscopy (CSLM) of previously labelled biopolymers. The Janus structure was confirmed by subjecting each microparticle hemisphere to specific enzymatic degradation. As a proof of concept, free BSA or BSA grafted with dextran, were encapsulated in each hemisphere of the hetero Janus hydrogel microparticles. While BSA, free or grafted with dextran, was always confined in the alginate hemisphere, a fraction of BSA diffused from the pectin to the alginate hemisphere. Methoxy groups along the pectin chain will be responsible of the decrease of the number of attractive electrostatic interactions occurring between amino groups of BSA and carboxylic groups of pectin. - Pectin hydrogel microparticles of complex shapes were successfully produced by combining on-chip the phenomenon of gelation and water diffusion induced self-assembly, using dimethyl carbonate as continuous phase, or by deformation of the pre-gelled droplets off-chip at a fluid-fluid interface. Sphere, oblate ellipsoid, torus or mushroom-type morphologies were thus obtained. Moreover, it was established that after crossing the interface during their collect, mushroom-type microparticles did not migrate in the calcium or DMC phase but stayed at the liquid-liquid interface. These new and original hydrogel microparticles will open up opportunities for studying relationships between combined enzymatic hydrolysis and active release for Janus particles and relationships between shape and swelling behaviour for anisotropic pectin microparticles. PMID- 25458288 TI - Effect of a small amount of sodium carbonate on konjac glucomannan-induced changes in wheat starch gel. AB - Wheat starch gels were produced with konjac glucomannan (KGM) and low concentrations of Na2CO3 (0.1-0.2 wt% of starch) using a rapid viscosity analyzer (RVA). The gelling properties of wheat starch in varying ratios of KGM and Na2CO3 were characterized by differential scanning calorimetry (DSC), rheometry and confocal laser scanning microscopy (CLSM). A small amount of Na2CO3 resulted in gels with increased elasticity whereas structural ordering during retrogradation was insignificantly affected. Comparison of CLSM images of composite gels revealed that Na2CO3 at 0.2 wt% of starch allowed the formation of fiber-like extensions around scattered swollen granules by KGM and amylose interaction, making swollen granules disperse within the micro phase, which was not typical in CLSM images of gels in the absence of Na2CO3. Dynamic storage modulus and dynamic power law exponent were substantially higher than those observed for the same concentration of KGM in the presence of Na2CO3, supporting the hypothesis that Na2CO3 could promote strong interchain associations between KGM and starch components. PMID- 25458290 TI - Influence of the extraction time on macromolecular parameters of galactomannans. AB - This study evaluated the aqueous extraction of galactomannans from the seeds of Mimosa scabrella (GM), Stryphnodendron adstringens (GS) and Schizolobium parahybae (GG) for 1, 2, 3, 4, 6, 24 and 48 h. The efficiency of extraction processes was assessed in terms of yield, carbohydrate and protein content. The extraction process, as well as the source of the galactomananns generated molecules with differences in molar mass, viscosity and rigidity analyzed by HPSEC-MALLS/RI/VIS. The extraction time results for each species, based on minimum extraction time and HPSEC-MALLS/RI/VIS results, were 4 h (GM4h), 6 h (GS6h) and 2 h (GG2h) for GM, GS and GG, respectively. In most cases, the apparent persistence length, as determined by viscometry, indicated that aggregates remained in galactomannans after centrifugation and filtration. Results suggest an effective extraction time for each plant source of galactomannan based on its performance and its macromolecular behavior in solution. PMID- 25458291 TI - Cholesterol and fat lowering with hydrophobic polysaccharide derivatives. AB - Hydrophobic derivatives of highly methylated citrus pectin, chitosan and cellulose were prepared and tested as potential cholesterol lowering agents. Elemental analysis and spectroscopic methods confirmed high substitution degree for all of them. Substitution with long alkyl/acyl groups led to significant changes in physical and thermal properties of modified polysaccharides. Sorption of cholate and cholesterol by these polysaccharide-based sorbents was estimated in comparison with the synthetic drug cholestyramine. It was found that modified polysaccharides have high affinity to cholesterol. By contrast, cholestyramine was effective only in cholate sorption. PMID- 25458292 TI - Valuation of brewers spent yeast polysaccharides: a structural characterization approach. AB - Brewers spent yeast (BSY) is a by-product from beer industry that can be exploited as source of glucans and mannoproteins, with potential biological activities. In order to solubilize these carbohydrate-rich polymeric materials, a sequential extraction with hot water and alkaline solutions (0.1-8 M KOH) was performed. Mannoproteins were mainly (85%) extracted with 4 M KOH whereas glucans were extracted with 8 M KOH and in an amount that accounted only for 34% of total glucose. Final residue still accounted for 34% of the initial glucans and contained 98% of glucose. Cellulase and alpha-amylase treatments showed the presence of both alpha- and beta-(1->4)-Glc linkages. To promote total solubilization of these insoluble glucans, the final residue was submitted to a partial acid hydrolysis. This work is the first report showing that the most abundant polysaccharides in BSY are polymers that contain structural features similar to cellulose, thus justifying their resistance to alkaline extractions, acid hydrolysis, and insolubility in water. PMID- 25458293 TI - Nanocellulose-alginate hydrogel for cell encapsulation. AB - TEMPO-oxidized bacterial cellulose (TOBC)-sodium alginate (SA) composites were prepared to improve the properties of hydrogel for cell encapsulation. TOBC fibers were obtained using a TEMPO/NaBr/NaClO system at pH 10 and room temperature. The fibrillated TOBCs mixed with SA were cross-linked in the presence of Ca(2+) solution to form hydrogel composites. The compression strength and chemical stability of the TOBC/SA composites were increased compared with the SA hydrogel, which indicated that TOBC performed an important function in enhancing the structural, mechanical and chemical stability of the composites. Cells were successfully encapsulated in the TOBC/SA composites, and the viability of cells was investigated. TOBC/SA composites can be a potential candidate for cell encapsulation engineering. PMID- 25458294 TI - Topical curcumin-loaded hydrogels obtained using galactomannan from Schizolobium parahybae and xanthan. AB - The curcumin (CUR)-loaded binary hydrogel was formulated using xanthan and galactomannan from Schizolobium parahybae (guapuruvu). The binary hydrogels presented gel characteristics, stable pH values and mechanical stress resistance even after 45 days of heat exposure (45 degrees C). The CUR-loaded hydrogel content was 98.6% for XGMC (xanthan and galactomannan with CUR-microemulsion) after the stability test. The in vitro cytotoxicity analysis suggested non cutaneous membrane irritation, and the in vitro skin permeation analysis indicated 2.15 to 2.50 MUg mL(-1) CUR at the stratum corneum, epidermal and dermal levels. The XGEC (xanthan and galactomannan with CUR solubilized in ethanol) and XGMC hydrogels presented 76.8 and 63.2% inhibition of topical inflammation, respectively. Chemical stability and non-cytotoxicity analysis confirm the safety of prolonged exposure of the skin during the topical treatment, offering long-lasting XGEC and XGMC action. PMID- 25458295 TI - Chitosan films and blends for packaging material. AB - An increased interest for hygiene in everyday life as well as in food, feed and medical issues lead to a strong interest in films and blends to prevent the growth and accumulation of harmful bacteria. A growing trend is to use synthetic and natural antimicrobial polymers, to provide non-migratory and non-depleting protection agents for application in films, coatings and packaging. In food packaging, antimicrobial effects add up to the barrier properties of the materials, to increase the shelf life and product quality. Chitosan is a natural bioactive polysaccharide with intrinsic antimicrobial activity and, due to its exceptional physicochemical properties imparted by the polysaccharide backbone, has been recognized as a natural alternative to chemically synthesized antimicrobial polymers. This, associated with the increasing preference for biofunctional materials from renewable resources, resulted in a significant interest on the potential for application of chitosan in packaging materials. In this review we describe the latest developments of chitosan films and blends as packaging material. PMID- 25458297 TI - Evaluation of thermally crosslinkable chitosan-based nanofibrous mats for the removal of metal ions. AB - Environmentally sensitive composite nanofibrous mats capable of metal ion adsorption were successfully prepared via electrospinning. The composite nanofibers were fabricated with different ratios of chitosan to thermo-responsive polymer, poly(N-isopropylacrylamide-co-N-methylolacrylamide) (poly(NIPAAm-co NMA), PNN). NMA provided the function of thermal crosslinking of the nanofibrous mats to form water-stable nanofibers in aqueous solution. Subsequently, glutaraldehyde was used as a secondary crosslinking agent to increase the gel fraction of the nanofibrous mats. The morphology changes of the nanofibers in different environments were studied. Comparing the nanofibrous mats and films of the same material, the fibrous mats showed significantly increased adsorption of Cu(II). The adsorption amount of Cu(II) on the chitosan/PNN (50/50) nanofibrous mats could reach 79+/-2 mg/g-mats, and its desorption was relatively effective. The incorporation of poly(NIPAAm-co-NMA) significantly improved the desorption of Cu(II) from the nanofibrous mats. The chitosan/PNN fibrous mats maintained the capacity of Cu(II) adsorption for 4-time regeneration. PMID- 25458298 TI - Influences of saltwater immersion on properties of wood-cellulosic paper. AB - The saltwater immersion method was developed to inhibit mould growth on flood- or tsunami-damaged paper. Commercially available fine paper used for printing and writing showed decreased tensile indices after saltwater immersion. The salt remaining in the paper tended to increase the moisture content because of the salt deliquescence and moisture in the air. The tensile index was restored by removing salt from the paper. Crystallization and distribution of salt in interfibre pores were also considered to influence interfibre rebonding. The difference in the fibre responses to saltwater depended on the relationship between nano-scaled pores in the fibre walls, osmotic pressure, and the degree of sizing, which resulted in low water retention values. More of the starch applied as a surface sizing agent was dissolved or dispersed during distilled water immersion than saltwater immersion. This loosened the fibre network, which was a factor that decreased the sizing degree of the paper. PMID- 25458296 TI - Influence of ionic strength on membrane selectivity during the ultrafiltration of sulfated pentasaccharides. AB - Due to their numerous biological properties, natural sulfated polysaccharides have attracted the interest of the food and pharmaceutical industries. Membrane processes were thought to be especially suitable for their production at industrial scale. The aim of this study was to evaluate the effect of sodium chloride, often used as a preservative and a precipitation adjuvant, on the ultrafiltration of sulfated pentasaccharides. In pure water, results showed a complete retention of the polymers on membranes with molecular weight cut-off up to eight times the molecular weight of the studied pentasaccharides. When NaCl was added to a concentration of 0.5 mol L(-1), retention rates decreased significantly (~-50%). As no relevant modification of the molecules size was observed through hydrodynamic radius measurements, these variations of selectivity were fully attributed to the screening of membrane surface charges by the electrolyte. Therefore, optimising the ultrafiltration of charged molecules need absolutely exammining electrostatic interactions. PMID- 25458300 TI - Polysaccharide-based strategies for heart tissue engineering. AB - Polysaccharides are abundant biomolecules in nature presenting important roles in a wide variety of living systems processes. Considering the structural and biological functions of polysaccharides, their properties have raised interest for tissue engineering. Herein, we described the latest advances in cardiac tissue engineering mediated by polysaccharides. We reviewed the data already obtained in vitro and in vivo in this field with several types of polysaccharides. Cardiac injection, intramyocardial in situ polymerization strategies, and scaffold-based approaches involving polysaccharides for heart tissue engineering are thus discussed. PMID- 25458301 TI - Kinetic and structural analysis of fluorescent peptides on cotton cellulose nanocrystals as elastase sensors. AB - Human neutrophil elastase (HNE) and porcine pancreatic elastase (PPE) are serine proteases with destructive proteolytic activity. Because of this activity, there is considerable interest in elastase sensors. Herein we report the synthesis, characterization, and kinetic profiles of tri- and tetrapeptide substrates of elastase as glycine-esterified fluorescent analogs of cotton cellulose nanocrystals (CCN). The degree of substitution of peptide incorporated in CCN was 3-4 peptides per 100 anhydroglucose units. Glycine and peptide-cellulose nanocrystals revealed crystallinity indices of 79 and 76%, respectively, and a crystallite size of 58.5 A. A crystallite model of the peptide-cellulose conjugate is shown. The tripeptide conjugate of CCN demonstrated five-fold greater efficiency in HNE than the tripeptide in solution judged by its kcat/Km of 33,515. The sensor limits of detection at 2mg of the tri- and tetrapeptide CCN conjugates over a 10 min reaction time course were 0.03 U/mL PPE and 0.05 U/mL HNE, respectively. PMID- 25458299 TI - Photoreductive generation of amorphous bismuth nanoparticles using polysaccharides--bismuth-cellulose nanocomposites. AB - A simple and highly reproducible synthesis of amorphous bismuth nanoparticles incorporated into a polysaccharide matrix using a photoreduction process is presented. As precursor for the generation of the Bi nanoparticles, organosoluble triphenylbismuth is used. The precursor is dissolved in toluene and mixed with a hydrophobic organosoluble polysaccharide, namely trimethylsilyl cellulose (TMSC) with high DSSi. The solution is subjected to UV exposure, which induces the homolytic cleavage of the bismuth-carbon bond in BiPh3 resulting in the formation of Bi(0) and phenyl radicals. The aggregation of the Bi atoms can be controlled in the TMSC matrix and yields nanoparticles of around 20 nm size as proven by TEM. The phenyl radicals undergo recombination to form small organic molecules like benzene and biphenyl, which can be removed from the nanocomposite after lyophilization and exposure to high vacuum. Finally, the TMSC matrix is converted to cellulose after exposure to HCl vapors, which remove the trimethylsilyl groups from the TMSC derivative. Although TMSC is converted to cellulose, the formed TMS OH is not leaving the nanocomposite but reacts instead with surface oxide layer of the Bi nanoparticles to form silylated Bi nanoparticles as proven by TEM/EDX. PMID- 25458302 TI - Processing of alpha-chitin nanofibers by dynamic high pressure homogenization: characterization and antifungal activity against A. niger. AB - Chitin nano-objects become more interesting and attractive material than native chitin because of their usable form, low density, high surface area and promising mechanical properties. This work suggests a straightforward and environmentally friendly method for processing chitin nanofibers using dynamic high pressure homogenization. This technique proved to be a remarkably simple way to get alpha chitin into alpha-chitin nanofibers from yellow lobster wastes with a uniform width (bellow 100 nm) and high aspect ratio; and may contributes to a major breakthrough in chitin applications. Moreover, the resulting alpha-chitin nanofibers were characterized and compared with native alpha-chitin in terms of chemical and crystal structure, thermal degradation and antifungal activity. The biological assays highlighted that the nano nature of chitin nanofibers plays an important role in the antifungal activity against Aspergillus niger. PMID- 25458303 TI - Production of microparticles with gelatin and chitosan. AB - In the past few decades, the textile industry has significantly increased investment in research to develop functional fabrics, with a special focus on those aggregating values. Such fabrics can exploit microparticles inferior to 100 MUm, such as those made by complex coacervation in their creation. The antimicrobial properties of chitosan can be attributed to these microparticles. Developing particles with uniform structure and properties would facilitate the control for the eventual release of the core material. Thus, a complex coacervation between gelatin and chitosan was studied, and the optimal conditions were replicated in the encapsulation of limonene. Spherical particles formed had an average diameter (D3,2) of 30 MUm and were prepared with 89.7% efficiency. Cross-linking of these microparticles using glutaraldehyde and tripolyphosphate was carried out before spray drying. After drying, microparticles cross-linked with glutaraldehyde were oxidized and clustered and those that were cross-linked with tripolyphosphate resisted drying and presented a high yield. PMID- 25458304 TI - Structure of an arabinogalactan from the edible tropical fruit tamarillo (Solanum betaceum) and its antinociceptive activity. AB - A structural characterization of polysaccharides obtained by aqueous extraction of ripe pulp of the edible exotic tropical fruit named tamarillo (Solanum betaceum) was carried out. After fractionation by freeze-thaw and alpha-amylase treatments, a fraction containing a mixture of highly-methoxylated homogalacturonan and of arabinogalactan was obtained. A degree of methylesterification (DE) of 71% and a degree of acetylation (DA) of 1.3% was determined by (1)H NMR spectroscopy and spectrophotometric quantification, respectively. A type I arabinogalactan was purified via Fehling precipitation and ultrafiltration through 50 kDa (cut-off) membrane. Its chemical structure was performed by sugar composition, HPSEC, methylation, carboxy-reduction and (13)C NMR spectroscopy analysis. Intraperitoneal administration of the arabinogalactan did not reduce the nociception induced by intraplantar injection of 2.5% formalin in mice, but significantly reduced the number of abdominal constrictions induced by 0.6% acetic acid, indicating that fraction has an antinociceptive effect on the visceral inflammatory pain model. PMID- 25458306 TI - Why a woodpecker? PMID- 25458305 TI - Shape memory starch-clay bionanocomposites. AB - 1-10% starch/clay bionanocomposites with shape memory properties were obtained by melt processing. X-ray diffraction (XRD) and TEM evidenced the presence of a major fraction of clay tactoids, consisting of 4-5 stacked crystalline layers, with a thickness of 6.8 nm. A significant orientation of the nanoparticles induced by extrusion was also observed. Tensile tests performed above the glass transition of the materials showed that the presence of clay nanoparticles leads to higher elastic modulus and maximum stress, without significant loss in elongation at break which typically reached 100%. Samples submitted to a 50% elongation and cooled below the glass transition showed shape memory behavior. Like unreinforced starch, the bionanocomposites showed complete shape recovery in unconstrained conditions. In mechanically constrained conditions, the maximum recovered stress was significantly improved for the bionanocomposites compared to unreinforced starch, opening promising perspectives for the design of sensors and actuators. PMID- 25458307 TI - Editorial. PMID- 25458309 TI - Assessing cognition and function in Alzheimer's disease clinical trials: do we have the right tools? AB - Several lines of evidence from Alzheimer's disease (AD) research continue to support the notion that the biological changes associated with AD are occurring possibly several decades before an individual will experience the cognitive and functional changes associated with the disease. The National Institute on Aging Alzheimer's Association revised criteria for AD provided a framework for this new thinking. As a result of this growing understanding, several research efforts have launched or will be launching large secondary prevention trials in AD. These and other efforts have clearly demonstrated a need for better measures of cognitive and functional change in people with the earliest changes associated with AD. Recent draft guidance from the US Food and Drug Administration further elevated the importance of cognitive and functional assessments in early stage clinical trials by proposing that even in the pre-symptomatic stages of the disease, approval will be contingent on demonstrating clinical meaningfulness. The Alzheimer's Association's Research Roundtable addressed these issues at its fall meeting October 28-29, 2013, in Washington, D.C. The focus of the discussion included the need for improved cognitive and functional outcome measures for clinical of participants with preclinical AD and those diagnosed with Mild Cognitive Impairment due to AD. PMID- 25458310 TI - The TNFalpha converting enzyme (TACE) from ayu (Plecoglossus altivelis) exhibits TNFalpha shedding activity. AB - TNFalpha converting enzyme (TACE) is responsible for converting membrane-anchored TNFalpha to its soluble form in mammalian. However, the function and characteristics of TACE in teleosts is unclear. In this study, we report the cloning of a cDNA sequence of the PaTACE from ayu, Plecoglossus altivelis. PaTACE encodes an 865-aa polypeptide, which is closest to the TACE gene found in pufferfish (Takifugu rubripes). PaTACE mRNA was detected in all the tissues tested, although it was considerably higher in liver, spleen, and brain tissues following infection with Listonella anguillarum. The recombinant region including the PaTACE catalytic domain was used to produce anti-PaTACE IgG. Western blot results revealed two bands for PaTACE from monocytes/macrophages. PNGase F digestion confirmed that the high molecular mass of PaTACE was caused by glycosylation. TACE activity in cell homogenates from ayu monocytes/macrophages increased following L. anguillarum infection. Moreover, PaTACE neutralization led to downregulation of TNFalpha expression in the supernatant of ayu monocyte/macrophages. Anti-PaTACE IgG also decreased respiratory burst in monocytes/macrophages. In conclusion, we report for the first time the TNFalpha converting activity of TACE from a teleost. More investigation is needed to illustrate PaTACE-shedding activity in other immune regulators. PMID- 25458311 TI - Characterization and genotyping of the DRB1 gene of the major histocompatibility complex (MHC) in the Marmota monax, animal model of hepatitis B. AB - The major histocompatibility complex (MHC)-containing genes are among the most polymorphic in vertebrates. MHC genes code for proteins that are critical in the immune system response. In this study, the polymorphism of the second exon of the MHC class II DRB gene was characterized in the Eastern woodchuck (Marmota monax). Woodchucks chronically infected with the woodchuck hepatitis virus (WHV) represent the best available animal model for the study of chronic hepatitis B infection in humans. In the genotyped animals we found fifteen alleles, which were expressed in two independent loci and that were named DRB1A and DRB1B in this work. The 15 alleles investigated showed an elevated divergence. A significant excess of non-synonymous substitutions was detected, which could indicate that a historical positive selection is acting in the woodchuck DRB1 genes. This hypothesis was confirmed in our study by the high variability in or near the antigen binding sites (ABS) and by the results obtained in sequence variability analyses. This analysis identified the presence of a microsatellite sequence that is located at the start of the second intron, which could further allow the development of a fast and cheap semiautomatic sequencing method. PMID- 25458308 TI - Independent comparison of CogState computerized testing and a standard cognitive battery with neuroimaging. AB - BACKGROUND: Inexpensive, non-invasive tools for assessing Alzheimer-type pathophysiologies are needed. Computerized cognitive assessments are prime candidates. METHODS: Cognitively normal participants, aged 51-71, with magnetic resonance imaging, fluorodeoxyglucose-positron emission tomography (FDG-PET), amyloid PET, CogState computerized cognitive assessment, and standard neuropsychological tests were included. We first examined the association between the CogState battery and neuroimaging measures. We then compared that association to the one between standard neuropsychological z-scores and neuroimaging. RESULTS: Slower reaction times for CogState Identification and One Back, and lower memory and attention z-scores, were associated (P < .05) with FDG-PET hypometabolism. Slower time on the Groton Maze Learning Task and worse One Card Learning accuracy were associated (P < .05) with smaller hippocampal volumes. There were no associations with amyloid PET. Associations of CogState and neuropsychological Z-scores with neuroimaging were small and of a similar magnitude. CONCLUSIONS: CogState subtests were cross-sectionally comparable to standard neuropsychological tests in their relatively weak associations with neurodegeneration imaging markers. PMID- 25458312 TI - Generation of a chickenized catalytic anti-nucleic acid antibody by complementarity-determining region grafting. AB - In contrast to a number of studies on the humanization of non-human antibodies, the reshaping of a non-human antibody into a chicken antibody has never been attempted. Therefore, nothing is known about the animal species-dependent compatibility of the framework regions (FRs) that sustain the appropriate conformation of the complementarity-determining regions (CDRs). In this study, we attempted the reshaping of the variable domains of the mouse catalytic anti nucleic acid antibody 3D8 (m3D8) into the FRs of a chicken antibody ("chickenization") by CDR grafting, which is a common method for the humanization of antibodies. CDRs of the acceptor chicken antibody that showed a high homology to the FRs of m3D8 were replaced with those of m3D8, resulting in the chickenized antibody (ck3D8). ck3D8 retained the biochemical properties (DNA binding, DNA hydrolysis, and cellular internalizing activities) and three-dimensional structure of m3D8 and showed reduced immunogenicity in chickens. Our study demonstrates that CDR grafting can be applied to the chickenization of a mouse antibody, probably due to the interspecies compatibility of the FRs. PMID- 25458313 TI - Increased inflammasome related gene expression profile in PBMC may facilitate T helper 17 cell induction in multiple sclerosis. AB - The NLRP3 inflammasome is a macromolecular complex importantly involved in IL 1beta processing. A role for this has been described in multiple sclerosis (MS). One mechanism by which IL-1beta might be involved in MS is by inducing pathogenic Th17 cells, i.e. GM-CSF+ Th17 cells. In the present study, we show that expression of the inflammasome related genes, NLRP3, caspase-1, IL-1beta and the IL-1beta/IL-1Ra ratio, was increased in PBMC from MS patients compared to healthy controls (HC). However, in an in vitro inflammasome activity assay with PBMC, IL 1beta protein secretion and the IL-1beta/IL-1Ra protein ratio were similar in MS patients and HC. Th cells cultured in the presence of supernatant derived from LPS/ATP inflammasome activated PBMC showed increased Th17 and GM-CSF+ Th17 cell frequencies in HC and MS patients and decreased anti-inflammatory IL-10+Th cell frequency in HC compared to Th cells cultured in the presence of control supernatant. Moreover, addition of the immune modulator calcitriol to the former condition resulted in reduced frequencies of Th17 and GM-CSF+Th17 cells, and also of IL-10+ Th cells. Evidently, our data indicate that inflammasome activity can skew the Th cell population toward a more pro-inflammatory composition, an effect that might be inhibited by vitamin D, and that might be importantly involved in inflammation within the central nervous system. PMID- 25458314 TI - Phenylbutyrate induces cathelicidin expression via the vitamin D receptor: Linkage to inflammatory and growth factor cytokines pathways. AB - Antimicrobial peptides (AMPs) constitute an indispensable arm of innate immunity against infectious microbes in humans. Induction of endogenous AMPs may become an alternative therapy against infections. Our previous studies have demonstrated phenylbutyrate (PBA) as a novel inducer of the AMPs cathelicidin (encoded by the CAMP gene) and human beta-defensin-1 in the human bronchial epithelial cell line VA10. In this work, we have continued by studying molecular mechanisms of PBA mediated induction of LL-37 expression and associated pathways in the human bronchial epithelial cell line VA10. In this study we demonstrate vitamin D receptor (VDR) as a key transcription factor required for PBA mediated up regulation of the CAMP gene expression. PBA also increases mRNA expression of the vitamin D3 regulated genes CYP24A1 and CD14. The siRNA knockdown of VDR reduced PBA mediated increase in CAMP, CYP24A1 and CD14 expression. Furthermore, we demonstrate that PBA enhances Toll-Like Receptor 5 ligand flagellin regulated mRNA expression of the inflammatory cytokine TNFalpha and chemokine CXCL8. PBA also up-regulates the expression of the genes encoding the growth factor cytokines transforming growth factor (TGF) alpha, TGFbeta1 and TGFbeta2. Our results indicate that TGFbeta type I receptor and epidermal growth factor receptor are involved in PBA mediated CAMP regulation. Finally, we show that co treatment with PBA and vitamin D3 reduces Pseudomonas aeruginosa growth in vitro. PMID- 25458315 TI - Adenosine A2A receptor, a potential valuable target for controlling reoxygenated DCs-triggered inflammation. AB - Dendritic cells (DCs) exposed to various oxygen tensions under physiopathological conditions are the critical immune cells linking innate and adaptive immunity. We have previously demonstrated that reoxygenation of hypoxia-differentiated DCs triggers complete DCs activation and inflammatory responses, so restraining the activation of reoxygenated DCs is important to suppress inflammatory responses in diseases caused by oxygen redelivery such as ischemia-reperfusion injury. In the current study, we showed that reoxygenation of hypoxia-differentiated DCs led to predominant expression of high levels of adenosine receptor A2AR on reoxygenated DCs as compared to those on hypoxic or normoxic DCs. Agonist CGS21680 targeting A2AR could effectively inhibit the maturation and activation of reoxygenated DCs through downregulating the expression of MHC class II molecules and CD86. In response to CGS21680 treatment, reoxygenated DCs exhibited a decrease in proinflammatory cytokines IL-1beta, IL-6 and TNF-alpha, and an increase in immune regulatory cytokine TGF-beta. These data suggest the critical role of A2AR signaling pathway in inhibiting the maturation and proinflammatory function of reoxygenated DCs, thereby proposing A2AR as a potential valuable target for controlling reoxygenated DCs-triggered inflammation. PMID- 25458316 TI - FAS/FASL-mediated cell death in the bovine endometrium. AB - In many mammals, endometrial cells are remodeled by apoptosis and cell proliferation throughout the estrous cycle. Although apoptosis is known to be induced by various factors involving two major apoptotic pathways (the death receptor- and mitochondria-mediated pathways), how it is regulated in the bovine endometrium is unclear. We examined (1) the cyclic expressions of apoptosis related factors, FAS, DcR3, BCL2 and BAX, in the bovine endometrium and (2) the effect of death ligands on the viability of, and FAS mRNA expression in, cultured bovine endometrial epithelial and stromal cells. FAS expression did not change during the estrous cycle, whereas DcR3 expression was higher at the mid and late luteal stages than at the early luteal and follicular stages. BCL2 expression was higher at the late luteal stage than at the early luteal and follicular stages, and the BAX/BCL2 ratio was higher at the early luteal stage than at the late luteal stage. Treatment or pretreatment with tumor necrosis factor-alpha (TNF)+interferon gamma (IFNG) in combination with FAS ligand significantly reduced the viability of both epithelial and stromal cells. Furthermore, TNF+IFNG treatment significantly increased the expression of FAS mRNA in both types of endometrial cells. The overall results suggest that both extrinsic and intrinsic pathways are involved in remodeling the bovine endometrium throughout the estrous cycle, and that the death ligands produced by immune cells and the endometrium play important roles in inducing cyclic endometrial cell death. PMID- 25458317 TI - Seasonal changes in some oxidant and antioxidant parameters during folliculogenesis in Egyptian buffalo. AB - Knowledge regarding oxidant and antioxidant status in follicular fluid remains limited and its studying in vivo should enhance our understanding of the impact of them on fertility and contribute to optimization of in vitro maturation conditions. The present study was conducted on follicular fluid and serum samples obtained from 708 buffaloes. They were examined for Malondialdehyde (MDA) as indicator of lipid peroxidation as well as superoxide dismutase (SOD) and total antioxidant capacity (TAC) as antioxidant markers. The obtained results revealed that MDA levels and SOD activity in follicular fluid decreased significantly as follicle size increased, while TAC increased significantly with the increase in follicular size. Whereas MDA level was significantly higher in summer, the TAC was significantly higher in spring. Moreover, MDA levels and SOD activities were significantly higher in the follicular fluid from different size follicles during the luteal phase than follicular phase. MDA levels in medium follicles in luteal phase and small follicles in follicular and luteal phases were significantly higher in summer than other seasons. Serum MDA levels were significantly increased in summer. In addition, MDA levels, SOD activities and TAC in serum were significantly higher during luteal phase than follicular phase in summer. TAC levels were significantly higher in follicular fluid than serum, while MDA was significantly lower in follicular fluid than serum. In conclusion, the present study revealed that oxidants/antioxidants balance may play a role in normal follicular development and oxidative stress that occur in summer could be related to reproductive seasonality in buffalo. PMID- 25458318 TI - Refrigerated storage of ram sperm in presence of Trolox and GSH antioxidants: effect of temperature, extender and storage time. AB - Antioxidants have a potential to improve the quality and fertility of refrigerated-stored ram semen. Reduced glutathione (GSH) and Trolox (0.2, 1 and 5mM) were evaluated in ram semen preserved at 15 and 5 degrees C up to 48 and 96h, respectively. Extenders were also evaluated (15 degrees C: Tris-citrate fructose, TCF, without lipids, and TES-Tris-fructose 10% egg yolk, TTF-EY; 5 degrees C: TTF-EY and 3.5% soybean lecithin, TTF-SL; INRA96 at both temperatures). Storage at 5 degrees C resulted in poorer quality than 15 degrees C up to 48h, while allowing acceptable quality at 96h. Antioxidants had few effects on sperm quality, with use of Trolox resulting in reduced motility and viability in TCF. Storage at 15 degrees C in the TCF extender resulted in decreased motility, viability and mitochondrial activity compared with use of TTF EY. Sperm quality when storage was at 5 degrees C was similar, but storage in TTF SL resulted in decreased motility and mitochondrial activity. Acrosomal status was only slightly affected by extender and antioxidant. Mitochondrial activity was improved by antioxidants in TTF-SL, and GSH at 5mM when semen was stored at 5 degrees C in TTF-EY. A preliminary artificial insemination trial indicated that supplementation with GSH has the potential for improving lambing (P<0.1). In conclusion, use of antioxidants resulted in lesser effects than extender composition or storage time on quality of ram semen. Use of Trolox negatively impacted sperm quality and GSH had some positive impacts. The use of soybean lecithin requires further research to assess its impact on mitochondria. PMID- 25458319 TI - Relationships among body composition, circulating concentrations of leptin and follistatin, and the onset of puberty and fertility in young female sheep. AB - The onset of puberty depends on the attainment of critical body mass, so should also be affected by increases in the rate of accumulation of muscle and adipose tissue. Adipose tissue and reproduction are linked by leptin. For muscle, a link has not yet been identified, although one possibility is follistatin. We assessed the relationships among circulating concentrations of follistatin and leptin and the rates of growth and accumulation of muscle and fat during pubertal development in female sheep. We used 326 animals with known phenotypic values for live weight (LW), depths of eye muscle (EMD) and fat (FAT), and known breeding values at post-weaning age for body mass (PWT) and depths of eye muscle (PEMD) and fat (PFAT). Leptin concentration was positively correlated with values for EMD, PEMD, FAT, PFAT, LW and PWT (P<0.001), whereas follistatin concentration was negatively correlated with values for EMD and PWT (P<0.001), and PEMD (P<0.01) and FAT (P<0.05). Leptin concentration was negatively related to age and positively related to live weight at first oestrus and the proportion of females that attained puberty (P<=0.05), and to fertility and reproductive rate (P<0.01). Follistatin concentration was negatively related to live weight at first oestrus and to fertility (P<0.01) and reproductive rate (P<0.05). There were positive correlations (P<0.001) between muscle accumulation and leptin concentration, and between muscle accumulation and reproductive performance. We conclude that leptin and follistatin are probably both involved in effects of accelerated accumulation of muscle and adipose tissues on the onset of puberty. PMID- 25458320 TI - Feed restriction ameliorates metabolic dysregulation and improves reproductive performance of meat-type country chickens. AB - Restricted feed intake improves egg production in Cornish*Plymouth Rock (broiler) hens. Red-feather (RF) and Black-feather (BF) chickens are 2 local strains of non broiler meat-type chickens whose egg production has declined with continued selection for meat yield, and which are unstudied regarding restricted feeding and egg-laying improvement. Sixteen week old RF and BF pullets were either fed ad libitum (AL) or restricted to 85% AL intake (R). At 35wk and 50wk R-hens showed improved egg production and less abnormal ovarian morphology than AL-hens. Obesity, hepatic steatosis, lipotoxic change to plasma lipids, and systemic inflammation induced by AL feeding in RF and BF hens were similar to those observed previously in AL-broiler hens. Egg production was negatively correlated to body weight, fractional abdominal fat weight and plasma NEFA concentrations in AL hens (P<0.05). AL-hen hierarchical follicles accumulated ceramide and increased interleukin-1beta production (P<0.05) in conjunction with increased granulosa cell apoptosis, follicle atresia, ovarian regression, and reduced plasma 17beta-estradiol concentrations (P<0.05). The present outcomes from non broiler but nevertheless meat-type country chicken strains indicate that selection for rapid growth and increased meat yield fundamentally changes energy metabolism in a way that renders hens highly susceptible to reproductive impairment from lipid dysregulation and pro-inflammatory signaling rather than impaired resource allocation per se. PMID- 25458321 TI - Effects of dietary supplementation of organic chromium (picolinate) on physical and biochemical characteristics of semen and carcass traits of male turkeys. AB - This experiment investigated the effect of dietary chromium (Cr as picolinate) on physical and biochemical characteristics of semen and carcass traits of adult male turkey. Seventy-two (72) male turkeys (16 weeks old) were randomly distributed into four dietary treatment groups (4*3*6) for a period of 24 weeks. Three experimental diets were supplemented with 250, 500 and 750MUg Cr/kg (T2, T3 and T4 respectively) in basal diet (T1 considered as control). Semen physical characteristics viz. sperm concentration, progressive motility, live and dead count of spermatozoa and fertility differed significantly (P<0.05). Sperm concentration, progressive motility and fertility were higher and dead count was lower in T4 (750MUg) group than control (T1) or other dietary treatments (T2 or T3) group. Semen biochemical parameters like creatinine, acid phosphatase (ACP) and alkaline phosphatase (ALP) concentration did not differ significantly among the dietary treatment groups, whereas, total protein, glucose, malondialdehyde (MAD) and cholesterol concentration differed significantly (P<0.05) amongst the treatment groups. Protein and MAD were higher while glucose and cholesterol concentrations were lower in T3 and T4 group than control or T1 group. The shrinkage loss, eviscerated yield, relative weight (as percent of body weight) of breast, thigh and liver improved on supplementation of Cr leading to significantly higher in T4 group in comparison to control. From this study, it could be concluded that supplementation of chromium as chromium picolinate, at 750MUg/kg level in diet was beneficial for improving physical characteristics of semen, carcass yield and breast yield of adult male turkeys. However, Cr levels of 500 or 750MUg/kg in diet were beneficial for semen biochemical parameters of adult male turkeys. PMID- 25458322 TI - Storage of Steindachneridion parahybae oocytes at different temperatures. AB - The objective of this study was to assess the influence of temperature and time on the storage of fresh Steindachneridion parahybae oocytes. Two experiments were carried out: (1) the fertilization rates of oocytes exposed to temperatures of 5, 15, 28 (room temperature) and 35 degrees C were assessed 15min (control), 115, 235 and 355min after release; (2) the fertilization and hatching rates, as well as the percentage of normal larvae of oocytes exposed to 14, 17 or 20 degrees C, 20min (control) were assessed 50, 80 and 110min after stripping. In the first experiment, the highest fertilization rates (P<0.05) were obtained in the control treatment (15min, 28 degrees C), with 74.34+/-5.48% oocytes showing loss of viability over time. In the second experiment, there was a reduction (P<0.05) in the fertilization rates at the temperatures and times tested. The artificial fertilization of S. parahybae oocytes is recommended immediately after collection, and if storage is necessary, it should be conducted at temperatures between 17 and 20 degrees C. PMID- 25458323 TI - Temporal summation of muscle pain evoked by very fast pressure sequences and rotation. AB - BACKGROUND: Pressure evoked temporal summation of pain has been described with slow repetitions (<0.5 Hz) relative to what is recommended originally for assessing temporal pain summation (>1 Hz). This study examined temporal summation of pain by repeated computer-controlled pressure stimulation at high repetition rates with and without simultaneous active probe rotations for potential better efficiency. METHODS: In 15 healthy subjects, 15 pressure stimuli (300 and 500 ms durations) were delivered at the pressure pain threshold intensity with and without rotation of a rounded probe (1 cm(2)) at three repetition frequencies (1.5, 1, 0.5 Hz). The pressure pain intensity was continuously rated on a visual analogue scale (VAS) and scores after each stimulus were extracted and normalized to the first score. RESULTS: The peak VAS score was larger for rotational (p < 0.001), longer stimulus duration (p < 0.02), and lower frequencies (p < 0.05) compared with non-rotational, shorter stimulus duration, and higher frequencies, respectively. VAS scores progressively increased from the first to the fifteenth stimulus (p < 0.01). The sum of VAS scores was higher after 1 Hz stimulation compared with 0.5 and 1.5 Hz stimulations (p < 0.01). Finally, the VAS sum was higher after rotational as well as longer stimulus duration compared with non rotational and shorter stimulus duration paradigms (p < 0.01). CONCLUSIONS: An optimum of 500 ms repeated pressure stimulation at 1 Hz produced the most apparent temporal summation of pain sensation which further was enhanced during probe rotation. These findings suggest an optimized and novel method to improve the current procedures for assessing temporal summation of pressure-induced pain. PMID- 25458324 TI - Pre-diabetes and the risk of contrast induced nephropathy in patients undergoing coronary angiography or percutaneous intervention. AB - BACKGROUND: Contrast induced nephropathy (CIN) is a complication of coronary angiography/percutaneous intervention (PCI). It is known that diabetes is an independent risk factor for CIN, but we have no data regarding the association between CIN and glycemic levels in patients without diabetes. Aim of our study was to evaluate whether high level of glycated-haemoglobin in patients without diabetes is associated with an increased risk of CIN. METHODS: A total of 1324 patients without diabetes, undergoing elective/urgent coronary angiography/angioplasty were divided according to quartiles of baseline glycated haemoglobin. CIN was defined as an absolute >= 0.5mg/dL or a relative >= 25% increase in creatinine level at 24-48 h after the procedure. RESULTS: Patients with elevated glycated-haemoglobin were older, with hypertension, metabolic syndromes, previous history of AMI, PCI and CABG. They had higher gycaemia, fasting-glycaemia and triglycerides but lower HDL-cholesterol. Patients with higher glycated-haemoglobin were more often on therapy with statins, diuretics and calcium-antagonist at admission, had higher basal, 24 and 48 h creatinine, lower creatinine clearance and lower ejection fraction. They had the highest incidence of PCI and contrast volume-eGFR rate. CIN occurred in 10.6% of patients with a linear association with glycated-haemoglobin (p=0.001). No relationship was found between glycaemia/fasting glycaemia at admission and CIN. The multivariate analysis confirmed the association between elevated glycated haemoglobin (above the median value 5.7%) and the risk of CIN after adjustment for baseline confounding factors (Adjusted OR [95% CI]=1.69 [1.14-2.51], p=0.009). In fact, the results were consistent in major high-risk subgroups. CONCLUSION: This is the first study showing that among patients without diabetes undergoing coronary angiography/PCI elevated glycated-haemoglobin but not glucose levels is independently associated with the risk of CIN. PMID- 25458325 TI - Association of sleep quality and quality of life in type 2 diabetes mellitus: a cross-sectional study in China. AB - OBJECTIVE: The aim of this study is to investigate sleep quality and quality of life, and to assess the relationship between sleep quality and quality of life in Chinese patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: 944 patients with T2DM were enrolled in our study. General characteristics and laboratory testing such as glycosylated hemoglobin A1c (HbA1c) were measured. Each patient completed a Chinese version of the Pittsburgh sleep quality index (PSQI) and the diabetes specificity quality of life scale (DSQL) questionnaires. A PSQI global score >7 was defined as poor sleep quality. A global DSQL score <40 was defined as a good quality of life. Multiple logistic regression analysis was used to examine the relationships between PSQI and DSQL. RESULTS: Poor quality of life in participants was associated with a longer duration of diabetes, a greater number of diabetes complications, no alcohol drinking, poor glycemic control and having depression and anxiety (all P<0.001). Of the participants, 33.6% of them were poor sleepers according to their PSQI. Poor sleepers had significantly lower DSQL (P<001). After adjustment for confounders, poor sleep quality was positively associated with a lower health related quality of life (OR: 3.67, 95% CI: 1.30-10.33, P<0.001). CONCLUSIONS: Our results suggest that poor sleep is prevalent in T2DM and inversely associated with quality of life. It is necessary for primary health-care workers to include sleep related knowledge in diabetes self-management programs to improve sleep quality in diabetes patients. PMID- 25458327 TI - Uncomplicated human type 2 diabetes is associated with meal-induced blood pressure lowering and cardiac output increase. AB - AIMS: Since many type 2 diabetes patients experience postprandial hypotension, the aim of this study was to unravel meal-related changes in systemic hemodynamics and autonomic nervous system (ANS)-balance. METHODS: Forty-two age matched males (15 type 2 diabetes; 12 metabolic syndrome; 15 controls) without overt autonomic neuropathy received a standardized high-fat mixed meal after an overnight fast. Hemodynamic variables were measured by finger plethysmography. Fourier analysis was used to calculate the low-/high-frequency (LF/HF)-ratio, a marker of autonomic nervous system-balance, and baroreceptor reflex sensitivity (BRS). RESULTS: Following the meal, diastolic blood pressure (DBP) decreased in type 2 diabetes patients only, paralleled by a significant decrement in systemic vascular resistance (SVR) and an increase in cardiac index. All groups showed an increase in postprandial heart rate. Controls, but not metabolic syndrome or type 2 diabetes patients, showed a meal-related increase in LF/HF-ratio. When combining all study subjects, homeostatic model assessment-insulin resistance (HOMA-IR) was inversely correlated with changes in DBP, SVR, LF/HF-ratio and BRS. CONCLUSIONS: Based on these data, we hypothesize that in patients with uncomplicated type 2 diabetes, insulin resistance hampers adequate meal-induced sympathetic activation, leading to a decrease in SVR and resulting in a postprandial drop in DBP. PMID- 25458326 TI - Improvement in diet habits, independent of physical activity helps to reduce incident diabetes among prediabetic Asian Indian men. AB - AIMS: To assess the beneficial effects of the components of lifestyle intervention in reducing incidence of diabetes in Asian Indian men with impaired glucose tolerance (IGT) in India. METHODS: This analysis was based on a 2 year prospective, randomized controlled primary prevention trial in a cohort of Asian Indian men with IGT (n=537) (Clinical Trial No: NCT00819455). Intervention and control groups were given standard care advice at baseline. Additionally, the intervention group received frequent, mobile phone based text message reminders on healthy lifestyle principles. Dietary intake and physical activity habits were recorded by validated questionnaires. The lifestyle goals were: reductions in consumption of carbohydrates, oil, portion size and body mass index of at least 1 unit (1 kg/m(2)) from baseline and maintenance of good physical activity. The association between diabetes and lifestyle goals achieved was assessed using multiple logistic regression analyses. Changes in insulin sensitivity (Matsuda's insulin sensitivity index) and oral disposition index during the follow-up were assessed. RESULTS: At the end of the study, 123 (23.8%) participants developed diabetes. The mean lifestyle score was higher in the intervention group compared with control (2.59 +/- 1.13 vs. 2.28 +/- 1.17; P=0.002). Among the 5 lifestyle variables, significant improvements in the 3 dietary goal were seen with intervention. Concomitant improvement in insulin sensitivity and oral disposition index was noted. Higher lifestyle score was associated with lower risk of developing diabetes (odds ratio: 0.54 [95% CI: 0.44-0.70]; P<0.0001). CONCLUSIONS: Beneficial effects of intervention were associated with increased compliance to lifestyle goals. The plausible mechanism is through improvement in insulin sensitivity and beta cell preservation. PMID- 25458328 TI - Glucose control in Rwandan youth with type 1 diabetes following establishment of systematic, HbA1c based, care and education. AB - AIMS: To assess change in glycemic control concurrent with increased clinic visits, HbA1c testing, and education. Rates of complications were also examined. METHODS: A 1-2 year follow-up of 214 members of the Rwanda Life for a Child program (aged <26 years) with a first HbA1c between June 2009 and November 2010 was conducted. Data were analyzed for the entire cohort and by age (<18 years, >=18 years). Trajectory analysis was performed to identify trends in HbA1c. RESULTS: Mean overall HbA1c decreased significantly from baseline (11.2 +/- 2.7%; 99 +/- 30 mmol/mol) to one- (10.2 +/- 2.6%; 88 +/- 28 mmol/mol) and two- (9.8 +/- 26%; 84 +/- 25 mmol/mol) year follow up visits. The prevalence of microalbuminuria did not significantly change (21.0%, 18.8%, and 19.6%), nor did nephropathy (4.7%, 7.8%, and 5.4%). However, rates of hypertension (31.8%, 44.9%, and 40.3%) were higher than expected. Five HbA1c groups were identified by trajectory analysis, and those with the worst control monitored their glucose significantly fewer times per week. CONCLUSIONS: The establishment of regular care, HbA1c testing, and increased education is associated with significant improvements in glycemic control in youth with type 1 diabetes (T1D) in sub Saharan Africa, but the high prevalence of hypertension is of concern. PMID- 25458329 TI - Evaluation of exenatide versus insulin glargine for the impact on endothelial functions and cardiovascular risk markers. AB - AIMS: To demonstrate the efficacy of exenatide versus insulin glargine on endothelial functions and cardiovascular risk markers. METHODS: Thirty-four insulin and incretin-naive patients with type 2 diabetes mellitus (body mass index 25-45 kg/m(2)) who received metformin for at least two months were randomized to exenatide or insulin glargine treatment arms and followed-up for 26 weeks. Measurements of endothelial functions were done by ultrasonography, cardiovascular risk markers by serum enzyme-linked immunosorbent assay, and total body fat mass by bioimpedance. RESULTS: Levels of high sensitivity-C-reactive protein and endothelin-1 decreased (27.5% and 18.75%, respectively) in the exenatide arm. However, in the insulin glargine arm, fibrinogen, monocyte chemoattractant protein-1, leptin and endothelin-1 levels (13.4, 30.2, 47.5, and 80%, respectively) increased. Post-treatment flow mediated dilatation and endothelium independent vascular responses were significantly higher in both arms (p=0.0001, p=0.0001). Positive correlation was observed between the changes in body weight and endothelium-independent vasodilatation, leptin, plasminogen activator inhibitor type 1 and endothelin-1 in both arms (r=0.376, r=0.507, r=0.490, r=0.362, respectively). CONCLUSIONS: Insulin glargine improved endothelial functions, without leading to positive changes in cardiovascular risk markers. Exenatide treatment of 26 weeks resulted in reduced body weight and improvement in certain cardiovascular risk markers and endothelial functions. PMID- 25458331 TI - The effects of pitavastatin on glucose metabolism in patients with type 2 diabetes with hypercholesterolemia. AB - BACKGROUND: Although there have been several reports that statins cause insulin resistance that leads to the occurrence of type 2 diabetes in Caucasians, there has been no Japanese prospective studies investigating the effects of statins on the glucose metabolism system. MATERIALS AND METHODS: Our subjects were 86 Japanese patients with type 2 diabetes with hypercholesterolemia. Pitavastatin 2mg/day was administered for 12 months and the lipid-related values, glucose metabolism values, and the presence/absence of side effects were investigated. RESULTS: None of these factors was found to differ between before and after administration of pitavastatin in overall analysis of all subjects. In subgroup analysis, fasting blood glucose showed a decrease in the BMI >= 25 group and there was a significant difference between the BMI<25 and BMI >=2 5 groups (P values: 0.021 and 0.0036). Although HbA1c showed an increase both in the group switched to pitavastatin and the BMI<25 group (P-values: 0.035 and 0.033) and HOMA-beta showed a decrease in the BMI<25 group (P-values: 0.044), there were no significant differences in changes between each divided group and their counterparts. CONCLUSION: In the Japanese obese group with BMI >= 25, pitavastatin elicited a significant decrease in fasting blood glucose. It is not clear whether or not this is due to improved insulin resistance as a direct effect of pitavastatin, but in contrast to findings in Caucasians pitavastatin does not worsen insulin resistance in Japanese patients with type 2 diabetes complicated by hypercholesterolemia. PMID- 25458330 TI - Metformin in combination with various insulin secretagogues in type 2 diabetes and associated risk of cardiovascular morbidity and mortality--a retrospective nationwide study. AB - AIMS: Metformin is the first-line treatment for most patients with type 2 diabetes but many patients need additional treatment with insulin secretagogues (IS) to achieve glycemic control. We aimed to compare mortality and cardiovascular risk among users of metformin in combination with pharmacologically different ISs. METHODS: Using nationwide administrative Danish registries, we followed all individuals without prior stroke or myocardial infarction who initiated metformin and an IS from 1997 through 2009. Rate ratios (RR) of all-cause mortality, cardiovascular death, and a composite of myocardial infarction, stroke, or cardiovascular death were compared between user groups using time-dependent multivariable Poisson regression models. The most common combination, glimepiride+metformin, was used as reference. RESULTS: A total of 56,827 patients were included, 56% male, the mean age was 61 +/- 12.5 years, and median duration of prior monotherapy was 2.2 (inter quartile range 0.5-4.5) years. Crude incidence rates of mortality for combinations of ISs with metformin were; 15.4 (repaglinide), 28.1 (glipizide), 23.7 (glibenclamide), 21.1 (gliclazide), 20.7 (glimepiride), 27.7 (tolbutamide) deaths per 1000 person years. In adjusted analysis, the associated mortality risk was similar for users of gliclazide+metformin (RR=1.01 [0.88-1.15]), repaglinide+metformin (RR=0.81 [0.62-1.05]), glibenclamide+metformin (RR=0.98 [0.87-1.10]), and tolbutamide+metformin (RR=1.04 [0.85-1.28]). Users of glipizide+metformin was associated with increased all-cause mortality (RR=1.16 [1.02-1.32], p=0.02), cardiovascular death (RR=1.21 [1.01-1.46], p=0.04), and the combined endpoint (RR=1.20 [1.06-1.36, p=0.005). CONCLUSION: Most ISs in combination with metformin were associated with similar mortality and cardiovascular risk. Whether glipizide is associated with increased risk compared with other ISs when used in combinations with metformin warrants further study. PMID- 25458332 TI - Identification of patient-centered outcomes among African American women with type 2 diabetes. AB - AIMS: African American women carry a disproportionate diabetes burden, yet there is limited information on strategies to identify outcomes women perceive as important intervention outcomes (patient-centered outcomes). This study presents a brief strategy to solicit these outcomes and to describe outcomes identified using the highlighted strategy. METHODS: Thirty-four African-American women with type 2 diabetes were enrolled in group-based, diabetes/weight management interventions. A diabetes educator asked participants to write down their intervention expectations followed by verbal sharing of responses. Expectation related themes were identified using an iterative, qualitative, team analytic approach based on audio-recorded responses. RESULTS: The majority of the expectation-related themes (6 of 10) were reflective of self-care education/management and weight loss-related patient-centered outcomes. The remaining themes were associated with desires to help others prevent or manage diabetes, reduce negative diabetes-related emotions, get rid of diabetes, and stop taking diabetes medications. CONCLUSION: This study adds to a limited body of knowledge regarding patient-centered outcomes among a group that experiences a disproportionate diabetes burden. Future work could include integrating outcomes that are less commonly addressed in diabetes-related lifestyle interventions (e.g., diabetes-related negative emotions), along with more commonly addressed outcomes (e.g., weight loss), to increase the patient-centeredness of the interventions. PMID- 25458334 TI - Clinical implications of linear immunofluorescent staining for immunoglobulin G in patients with diabetic nephropathy. AB - AIMS: The kidneys of patients with diabetes mellitus usually exhibit a characteristic pattern of linear immunofluorescent staining for immunoglobulin G (IgG) along the glomerular and tubular basement membranes. However, the association between linear IgG staining and the renal prognosis remains unclear. METHODS: Among 223 patients with diabetes who underwent renal biopsy from 1985 to 2010 and were confirmed to have pure diabetic nephropathy according to the classification of Tervaert et al., 165 patients (glomerular classes I to III) were enrolled in this study. Immunofluorescent staining was classified into three categories according to its intensity (0=none, 1=weakly positive, and 2=positive). Cox proportional hazards regression analysis was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for death-censored renal death, with each regression analysis employing four levels of multivariate adjustment. RESULTS: After adjustment for important clinical factors at the time of renal biopsy, the HR for death-censored renal death in patients with an IgG staining score of 1 or 2 was, respectively, 3.01 (95% CI: 1.05-8.68) and 4.68 (1.67-13.1) compared with patients who had a staining score of 0. Even after adjustment for clinical variables and pathological findings, the HR for IgG score of 1 or 2 was higher than that for an IgG score of 0, and it was, respectively, 2.22 (0.71-7.00) and 3.76 (1.27-11.2). CONCLUSIONS: More intense linear IgG staining is associated with a higher HR for renal death, which suggests that linear immunofluorescent staining for IgG may be a prognostic indicator in patients with diabetic nephropathy. PMID- 25458335 TI - Predictors of response to liraglutide in Japanese type 2 diabetes. AB - AIM: In Japan, liraglutide is approved for use alone or in combination with sulfonylureas, and the approved maximum dosage is 0.9 mg/day. This restriction could limit the glucose-lowering effect of liraglutide in Japanese patients with type 2 diabetes mellitus (T2DM). This study was designed to identify predictors of response to liraglutide therapy at the approved dosage. METHODS: This observational retrospective study included 380 patients with T2DM who were treated with liraglutide alone or in combination with sulfonylureas at Diabetes Centers located in four geographically different areas of Japan. Binary logistic regression analysis was used to identify patient characteristics associated with discontinuation of liraglutide, while multiple regression and decision tree analyses were used to identify predictors of response to liraglutide therapy. RESULTS: Factors associated with discontinuation of liraglutide included high BMI, long duration of diabetes, and prior insulin therapy. Predictors of response to liraglutide therapy in patients who did not use insulin previously included previous use of few oral glucose-lowering agents and high baseline HbA1c level. CONCLUSION: The results suggest greater efficacy of liraglutide monotherapy or liraglutide-sulfonylurea combination therapy in patients with short duration of diabetes, non-insulin therapy, and low BMI and high HbA1c level at baseline. PMID- 25458333 TI - Real-time continuous glucose monitoring versus internet-based blood glucose monitoring in adults with type 2 diabetes: a study of treatment satisfaction. AB - AIMS: To compare treatment satisfaction between real-time continuous glucose monitoring (RT-CGM) and internet-blood glucose monitoring (IBGM) in adults with type 2 diabetes treated with insulin. METHODS: This study recruited 40 patients who completed a parallel randomized controlled trial comparing a RT-CGM to an IBGM. Patients in the RT-CGM group monitored their blood-glucose levels bi-weekly and emailed results to their endocrinologist. Patients in the IBGM group also monitored their blood-glucose levels bi-weekly, but entered their data into an IBGM. Both groups used a secure website to submit blood-glucose readings and to receive feedback from their endocrinologist. Feedback included changes in therapy, suggestions on testing frequency, lifestyle modifications and/or encouragement to continue with no changes. At the end of 6 months, treatment satisfaction was measured using the 8-item Diabetes Treatment Satisfaction Questionnaire. In this study, "treatment" refers to the blood glucose monitoring system to which patients were randomized. RESULTS: Thirty-two of the 40 patients completed the treatment satisfaction questionnaire (80%). Compared to the RT-CGM group, the IBGM group reported a significantly higher level of overall treatment satisfaction (24.80 vs. 33.41, p<0.000). Ratings of individual satisfaction components including convenience, flexibility, likelihood of recommending treatment to others, and willingness to continue with treatment were also found to be significantly higher in the IBGM group. CONCLUSION: Patients using IBGM are more satisfied with their blood glucose monitoring system compared to those using RT-CGM. PMID- 25458336 TI - Exercise patterns and behaviour in Asian Indians: data from the baseline survey of the Diabetes Community Lifestyle Improvement Program (D-CLIP). AB - AIMS: This paper attempts to describe the patterns of exercise and the perceived benefits and barriers to exercise in an urban south Indian population. METHODS: Study participants were recruited from the baseline survey of the D-CLIP (Diabetes Community Lifestyle Improvement Program). Frequency, duration, type and location of exercise were assessed using a questionnaire, while a Likert type scale was used to assess perceived benefits of and barriers to exercise. Quality of life was measured using the EQ-5D. RESULTS: Out of 1281 participants (63.7% males), 24.1% reported doing >=150min of exercise/week ("exercisers") compared to 75.9% "non-exercisers". Exercisers were significantly older (47 vs. 43 years), better educated (68.8% vs. 60%), had a higher monthly income (41% vs. 29.2%), consumed more fruits (38.2% vs. 25.6%) and vegetables (84.1% vs. 77.7%) and had better perceived state of health (81.1% vs. 76.8%), compared to non-exercisers. Exercisers had significantly lower HOMA-IR, higher Matsuda index and lower prevalence of low HDL cholesterol compared to non-exercisers. However, there were no significant differences in cardio-metabolic risk factors like diabetes, hypertension and obesity between the two groups. Walking was the most common type of exercise. Both exercisers and non-exercisers perceived the benefits of exercising, but barriers weighed more heavily on exercise behaviour. CONCLUSIONS: Urgent steps are needed to improve overall exercise levels in India by addressing barriers and improving the quality of exercise performed so as to enhance overall metabolic health. PMID- 25458337 TI - Changes in markers of oxidative stress and DNA damage in human visceral adipose tissue from subjects with obesity and type 2 diabetes. AB - AIMS: In the past 30 years, prevalence of obesity has almost trebled resulting in an increased incidence of type 2 diabetes mellitus and other co-morbidities. Visceral adipose tissue is believed to play a vital role, but underlying mechanisms remain unclear. Our aim was to investigate changes in markers of oxidative damage in human visceral adipose tissue to determine levels of oxidative burden that may be attributed to obesity and/or diabetes. METHODS: Visceral adipose tissue samples from 61 subjects undergoing abdominal surgery grouped as lean, obese and obese with type 2 diabetes mellitus, were examined using 3 different markers of oxidative stress. Malondialdehyde (MDA) concentration was measured as a marker of lipid peroxidation, telomere length and Comet assay as markers of oxidative DNA damage. RESULTS: No significant difference in MDA concentration, telomere length and DNA damage was observed between groups, although longer telomere lengths were seen in the obese with diabetes group compared to the obese group (P<0.05). Lower MDA concentration and longer telomere length were seen in subjects with diabetes compared to those without (P<0.05). DNA damage, analysed via Comet assay, was significantly lower in subjects with diabetes compared to those without (P<0.05). CONCLUSION: A paradoxical decrease in oxidative stress and DNA damage was observed in samples from subjects with type 2 diabetes mellitus. Further work is required to investigate this further, however this phenomenon may be due to an up regulation of antioxidant defences in adipose tissue. PMID- 25458338 TI - Late successful weight reduction and maintenance among overweight and obese adults--a two-year retrospective study. AB - AIMS: Our purpose was to identify those factors associated with successful late weight reduction and maintenance among overweight and obese adults who failed to achieve initial weight reduction success. METHODS: Medical computerized files of 5254 participants, who failed to achieve >= 5% weight reduction after an initial 6-month period, were retrospectively analyzed to identify predictors associated with late successful weight reduction and maintenance (>= 5% during the first and second years, respectively). Over 40 independent variables were analyzed. The main outcome was the percentage of weight change. RESULTS: Significant predictors of late success in weight reduction were as follows: more visits to a dietitian, higher baseline BMI, and any initial weight reduction (0-5%) (OR=3.69, compared with participants who initially gained weight). The use of insulin (OR=0.499) and the presence of hypertension (OR=0.75) were significantly correlated with failure to reduce weight. Predictors of late maintenance were as follows: more visits to a dietitian, higher baseline BMI, any initial weight reduction, a younger age, not being treated with insulin (OR=0.316), and more weighings (OR=1.68). CONCLUSIONS: A substantial sub-group of obese and overweight patients was able to reduce their weight at a slower rate than the defined successful time of 6 months. Significant specific predictors were identified. Diabetic and hypertensive patients are at a significantly higher risk of failure to reduce and maintain weight. Using regression models, we calculated the probability of successful late weight reduction. This calculation could serve as a clinical tool for a professional team. PMID- 25458339 TI - Effects of cilnidipine on sympathetic nerve activity and cardiorenal function in hypertensive patients with type 2 diabetes mellitus: association with BNP and aldosterone levels. AB - AIMS: Hypertension stimulates the sympathetic nervous system and this phenomenon is exacerbated by diabetes mellitus. We investigated the effects of cilnidipine, an N/L-type calcium channel blocker, on aspects of this system in patients with type 2 diabetes mellitus. METHODS: In 33 hypertensive patients with type 2 diabetes mellitus treated with a calcium channel blocker other than cilnidipine, we evaluated the influence of switching to cilnidipine on blood pressure, heart rate, catecholamine, plasma renin and aldosterone concentration, brain natriuretic peptide, urine liver-type fatty acid binding protein, and urinary albumin excretion ratio in the same patients by a cross-over design. Other biochemical parameters were also evaluated. RESULTS: Switching to cilnidipine did not change blood pressure but caused reduction in catecholamine concentrations in blood and urine and plasma aldosterone concentration, accompanied by significant reduction in brain natriuretic peptide, urine liver-type fatty acid binding protein, and albumin excretion ratio. These parameters other than brain natriuretic peptide were significantly increased after cilnidipine was changed to the original calcium channel blocker. CONCLUSIONS: In 33 hypertensive patients with type 2 diabetes mellitus, compared to other calcium channel blockers, cilnidipine suppressed sympathetic nerve activity and aldosterone, and significantly improved markers of cardiorenal disorders. Therefore, cilnidipine may be an important calcium channel blocker for use in combination with renin angiotensin-aldosterone system inhibitors when dealing with hypertension complicated with diabetes mellitus. PMID- 25458340 TI - Social network and development of prediabetes and type 2 diabetes in middle-aged Swedish women and men. AB - AIM: Explore if social network affects development of prediabetes and type 2 diabetes. METHODS: Individuals with normal glucose tolerance at baseline, 2924 women and 2039 men, aged 35-56 years, were followed-up 8-10 years later by an oral glucose tolerance test. Prediabetes and type 2 diabetes was then evident in 168 and 50 women and in 236 and 93 men, respectively. Measures of social network (AVSI-index (availability of social integration), civil status and participation in social activities), recorded by questionnaire at baseline, were evaluated by logistic regression. RESULTS: Having AVSI scores in the highest tertile was associated with a decreased risk to develop type 2 diabetes in women (age adjusted odds ratio 0.41 [95% CI: 0.19-0.88]) less significant after full adjustment (0.50 [0.22-1.16]). Contrary, in men AVSI was associated with an increased risk to develop type 2 diabetes (1.93 [1.03-3.60]) after full adjustment. Participation in social activities decreased the risk to develop prediabetes and type 2 diabetes in women, (age-adjusted 0.65 [0.46-0.91] and 0.43 [0.24-0.77], respectively), less significant when adjusted for confounders (0.78 [0.54-1.12] and 0.59 [0.31-1.13]). In men a decreased risk was observed for prediabetes (0.59 [0.43-0.82] multi-adjusted model). Being married or living with a partner decreased type 2 diabetes risk only in men (0.57 [0.33-0.97] and 0.61 [0.34-1.08] age- and multi-adjusted models, respectively). CONCLUSIONS: Individuals having a social network seemed less likely to develop abnormal glucose regulation. Contradictory to an overall protective pattern of having a social network, high AVSI-index in men increased the risk to develop type 2 diabetes. PMID- 25458341 TI - Vitamin B status in patients with type 2 diabetes mellitus with and without incipient nephropathy. AB - AIM: To investigate the vitamin B status, with particular focus on vitamin B6, in adults with and without incipient nephropathy secondary to type 2 diabetes mellitus. METHODS: Plasma and/or urine concentrations of vitamins B6, B1, B12, related vitamers and biomarkers (including total homocysteine, methylmalonic acid) were measured in 120 adults with type 2 diabetes (including 46 patients with microalbuminuria) and 52 non-diabetic control subjects. RESULTS: Plasma concentrations of pyridoxal 5'-phosphate (PLP) were significantly lower in patients with type 2 diabetes than in control subjects (median: 22.7 nmol/L, diabetes with microalbuminuria; 26.8 nmol/L, diabetes without microalbuminuria; 39.5 nmol/L, non-diabetic control; p<0.0001). The prevalence of low PLP (<30 nmol/L) was 63%, 58%, and 25% in the diabetes groups with and without microalbuminuria and the control group, respectively. Plasma levels of pyridoxine and pyridoxal were also lower (p<0.0001), but levels of pyridoxamine, pyridoxamine 5'-phosphate, and pyridoxic acid were higher in both groups with diabetes compared to the control group (p<0.001). Thiamine deficiency was highly prevalent in all groups, whereas low vitamin B12 and elevated methylmalonic acid were rare. Increased levels of C-reactive protein and soluble vascular cell adhesion molecule-1 were observed in the groups with diabetes (p<0.05, versus healthy control). CONCLUSIONS: Deficiency of vitamin B6 (PLP, pyridoxine, pyridoxal) and vitamin B1 (thiamine) was prevalent in type 2 diabetes. Incipient nephropathy was associated with more pronounced alterations in vitamin B6 metabolism and stronger indications of endothelial dysfunction and inflammation. PMID- 25458342 TI - Determinants of fructosamine levels in a multi-ethnic Sub-Saharan African population. AB - BACKGROUND AND PURPOSE: Fructosamine provides an estimate of diabetes control over a shorter period than HbA1c, and has been proposed as a suitable parameter to monitor glycemic control in low-income countries. The aim of this study was to investigate determinants of fructosamine levels in an urban non-diabetic population of Cameroon. METHODS: This was a cross-sectional study including 437 healthy adults with no known history of diabetes mellitus, aged 40 years and above, recruited from the ten administrative regions, representing major ethnic groups in the country. Plasma glucose and fructosamine were measured after an overnight fasting. Univariable and multivariable analyses were used to investigate the factors associated with fructosamine measurements. RESULTS: Fructosamine levels ranged from 68.2 to 940.8 MUmol/l with a mean (standard deviation) of 294.4 (131.3) MUmol/l. These levels varied significantly across regions and were higher in men than in women (p=0.001) and in those with screen detected diabetes than in those with normoglycemia (p<0.0001). There was a negative correlation between fructosamine and body mass index (r=-0.15, p=0.009), and a positive correlation with fasting plasma glucose (FPG) (r=0.37, p<0.0001) and total bilirubinemia (r=0.21, p<0.0001). In multivariable model, sex, BMI, FPG, total bilirubine and screen-detected diabetes were no longer associated with fructosamine levels. CONCLUSION: Fructosamine was not independently associated with age, sex, ethnicity, and the glycemic status. Further studies need to be carried out to better elucidate all the factors determining the measurement of fructosamine in order to accurately interpret its values in diabetic populations. PMID- 25458343 TI - Upper eyelid platinum chain placement for treating paralytic lagophthalmos. AB - For the definitive treatment of lagophthalmos and satisfactory rehabilitation of the affected eye, different surgical strategies have been proposed, including static or dynamic procedures. Although some of these can have good results, lid loading is now the most common technique for treating paralytic long-term lagophthalmos. Among the different types of loading, the use of a platinum chain is preferred to the use of a standard gold weight because platinum has a higher density than gold and is also more biocompatible. In this paper authors retrospectively analyzed 43 patients with regards to functional and cosmetic results. Questionnaires were also employed to assess changes and improvements in the patients' quality of life. Analysis of the excellent results achieved confirmed that platinum chain lid loading should be considered as a first-line treatment for paralytic lagophthalmos rehabilitation. It is a simple, reliable, and effective technique that significantly improves the health-related quality of life of patients. PMID- 25458344 TI - Frontal sinus fractures with suspected outflow tract obstruction: a new approach for sinus preservation. AB - OBJECTIVE: The description of a new approach for the management of patients with frontal sinus fractures and associated obstruction of the frontal outflow tract to, restore sinus function and avoiding sinus obliteration. SUBJECTS AND METHODS: In a prospective study, 21 patients with anterior wall frontal sinus fractures associated with potential obstruction of the frontal outflow tract, underwent rigid internal fixation and intraoperative guarded nasal endoscopic debridement of any bony spicules and lacerated mucosa to clear the frontal recess. Patients were followed up clinically and radiologically by CT to assess the status of the frontal sinus and to detect any manifestations of frontal sinusitis or any other complications. RESULTS: Seventeen patients completed the postoperative follow-up while four patients were excluded from the study. Postoperative follow-up ranged from 6 to 34 months with a mean of 20 months. All patients had associated craniofacial fractures. Follow-up CT scans showed complete restoration of frontal sinus ventilation and mucociliary clearance for 13 patients. Four patients showed frontal sinus mild mucosal thickening without signs of chronic sinusitis. CONCLUSION: Patients with anterior wall frontal sinus fractures associated with frontal sinus outflow tract obstruction could be successfully managed with rigid internal fixation and intraoperative guarded endoscopic debridement of any bony spicules and lacerated mucosa to clear the frontal recess. This type of management could increase the chance of frontal sinus preservation and decrease the need for frontal sinus obliteration for similar patients. PMID- 25458345 TI - Optimizing the osteogenic differentiation of human mesenchymal stromal cells by the synergistic action of growth factors. AB - A variety of different growth factors, most notably bone morphogenetic proteins (BMPs), have been shown to stimulate the osteogenic differentiation of mesenchymal stromal cells (MSCs) in vitro. Yet, due to the lack of comparative studies it remains unclear which protocol is the most effective in the induction of osteogenesis in MSC cultures. The aim of this study was to compare the most potent growth factors in regard to their osteoinductive potential. Human MSCs were cultured for 10 days in the presence of BMP-2, BMP-6, BMP-9 + IGF-2 and BMP 2, -6, -9 (day 1 + 2: 50 ng/ml; days 3-6: 100 ng/ml; days 7-10: 200 ng/ml). The formation of the osteoblast phenotype was assessed by quantification of osteoblast-related marker genes using reverse transcription polymerase chain reaction (RT-PCR) and alkaline phosphatase (ALP) staining. Matrix mineralization was assessed by alizarin red S and von Kossa staining. Statistical analysis was carried out using the one-way analysis of variance (ANOVA) followed by Scheffe's post hoc procedure. Among the tested growth factors the combination of BMP-2 + BMP-6 + BMP-9 most effectively induced the upregulation of collagen type I, collagen type V, osteocalcin, alkaline phosphatase, RUNX2, BMP-2, osteonectin and DLX5 (p < 0.01) and resulted in a consistent matrix mineralization. The findings suggest the combined addition of BMP-2, BMP-6 and BMP-9 to the osteoinductive culture medium containing dexamethasone, beta-glycerophosphate and ascorbate-2 phosphate produces more potent osteoblast differentiation of human MSCs in vitro. PMID- 25458346 TI - Double anterior (anterolateral and anteromedial) thigh flap for oral perforated defect reconstruction. AB - OBJECTIVE: The purpose of this study was to assess the therapeutic efficacy of oral perforated defect reconstruction with a double anterior (anterolateral and anteromedial) thigh flap through the modified lateral lip-submandibular approach. MATERIALS AND METHODS: From July 2010 to August 2013, eight patients with oral perforated defects secondary to oral cancer ablation involving the superior partial mandible or the posterior partial maxilla, with immediate reconstruction by double anterior (anterolateral and anteromedial) thigh flaps, were retrospectively enrolled into this study. RESULTS: All double anterior flaps were musculocutaneous flaps. Seven double flaps resulted in good functional and aesthetic outcomes with complete flap survival. One patient required operative exploration in the postoperative period due to thrombosis in the external jugular vein. After the salvage, one of the double flaps in the intraoral region resulted in partial failure of the superficial skin of the flap. No functional impairment at the donor sites occurred in any of the cases. CONCLUSION: The double anterior (anterolateral and anteromedial) thigh flap is a feasible and acceptable technique for reconstruction of an oral perforated defect involving the mandible or the maxilla through the modified lateral lip-submandibular approach. It presents a very acceptable aesthetic and functional result with the additional advantage of low morbidity at the donor site. PMID- 25458347 TI - The influence of unilateral disc displacement on stress in the contralateral joint with a normally positioned disc in a human temporomandibular joint: an analytic approach using the finite element method. AB - OBJECTIVES: To investigate the influence of unilateral disc displacement (DD) in the temporomandibular joint (TMJ) on the stress in the contralateral joint, with a normally-positioned disc, during clenching. STUDY DESIGN: A finite element model of the TMJ was constructed based on MRI and 3D-CT of a single patient with a unilateral DD. A second model with bilateral normally-positioned discs served as a reference. The differences in stress distribution in various TMJ components during clenching were predicted with these models. RESULTS: In the unaffected joint of the unilateral DD model, the largest von Mises stress at the start of clenching was predicted in the inferior surface of the disc and increased by 30% during clenching. In the connective tissue the largest stress (1.16 MPa) did not reduce during clenching, in contrast to the (unaffected) joints of the reference model. In the affected joint, the largest stress was predicted in the temporal cartilage throughout clenching. In the surrounding connective tissue, the largest stress (1.42 MPa) hardly changed during clenching indicating no, or negligible, stress relaxation. CONCLUSIONS: This suggested that a unilateral DD could affect the stresses in the unaffected (contralateral) joint during clenching, where it may lead to weakening of the tissues that keep the disc on the top of the condyle. The results may be helpful in counseling worried patients, since they give insight into possible future developments of the disorder. PMID- 25458348 TI - Virtual surgery simulation in orbital wall reconstruction: integration of surgical navigation and stereolithographic models. AB - PURPOSE: Correction of post traumatic orbital and zygomatic deformity is a challenge for maxillofacial surgeons. Integration of different technologies, such as software planning, surgical navigation and stereolithographic models, opens new horizons in terms of the surgeons' ability to tailor reconstruction to individual patients. The purpose of this study was to analyze surgical results, in order to verify the suitability, effectiveness and reproducibility of this new protocol. METHODS: Eleven patients were included in the study. Inclusion criteria were: unilateral orbital pathology; associated diplopia and enophthalmos or exophthalmos, and zygomatic deformities. Syndromic patients were excluded. Pre surgical planning was performed with iPlan 3.0 CMF software and we used Vector Vision II (BrainLab, Feldkirchen, Germany) for surgical navigation. We used 1:1 skull stereolithographic models for all the patients. Orbital reconstructions were performed with a titanium orbital mesh. The results refer to: correction of the deformities, exophthalmos, enophthalmos and diplopia; correspondence between reconstruction mesh positioning and preoperative planning mirroring; and the difference between the reconstructed orbital volume and the healthy orbital volume. RESULTS: Correspondence between the post-operative reconstruction mesh position and the presurgical virtual planning has an average margin of error of less than 1.3 mm. In terms of en- and exophthalmos corrections, we have always had an adequate clinical outcome with a significant change in the projection of the eyeball. In all cases treated, there was a complete resolution of diplopia. The calculation of orbital volume highlighted that the volume of the reconstructed orbit, in most cases, was equal to the healthy orbital volume, with a positive or negative variation of less than 1 cm(3). CONCLUSION: The proposed protocol incorporates all the latest technologies to plan the virtual reconstruction surgery in detail. The results obtained from our experience are very encouraging and lead us to pursue this path. PMID- 25458349 TI - A single cervical lymph node metastasis of malignant ameloblastoma. AB - INTRODUCTION: Cervical node metastasis of malignant ameloblastoma is extremely rare. Because of its rarity, there is no standard treatment modality in a single lymph node metastasis in malignant ameloblastoma. MATERIALS AND METHODS: Eleven patients of malignant ameloblastoma involving a single cervical lymph node metastasis and one new case were reviewed. Neck treatment was classified into neck dissection and simple excision. Local nodal recurrence, distant metastasis and follow-up periods were investigated. RESULTS: Eight patients were treated with neck dissection (group A) and four patients underwent a simple node excision (group B). Two patients in group A experienced multiple organ metastases such as liver and lung seven months and 13 years after neck dissection respectively. The other patients showed no recurrence and metastasis. In group B, there was no report of a regional neck recurrence and distant metastasis during follow-up of 1 7 years. CONCLUSION: Multiple nodes metastasis requires a radical neck dissection; however, simple excision with close follow-up may be used in a single node metastasis in malignant ameloblastoma. PMID- 25458350 TI - An integrated orthognathic surgery system for virtual planning and image-guided transfer without intermediate splint. AB - Accurate surgical planning and transfer of the planning in orthognathic surgery are very important in achieving a successful surgical outcome with appropriate improvement. Conventionally, the paper surgery is performed based on a 2D cephalometric radiograph, and the results are expressed using cast models and an articulator. We developed an integrated orthognathic surgery system with 3D virtual planning and image-guided transfer. The maxillary surgery of orthognathic patients was planned virtually, and the planning results were transferred to the cast model by image guidance. During virtual planning, the displacement of the reference points was confirmed by the displacement from conventional paper surgery at each procedure. The results of virtual surgery were transferred to the physical cast models directly through image guidance. The root mean square (RMS) difference between virtual surgery and conventional model surgery was 0.75 +/- 0.51 mm for 12 patients. The RMS difference between virtual surgery and image guidance results was 0.78 +/- 0.52 mm, which showed no significant difference from the difference of conventional model surgery. The image-guided orthognathic surgery system integrated with virtual planning will replace physical model surgical planning and enable transfer of the virtual planning directly without the need for an intermediate splint. PMID- 25458351 TI - Mechanical properties, surface morphology and stability of a modified commercially pure high strength titanium alloy for dental implants. AB - OBJECTIVE: Commercially pure titanium (cp Ti) and Ti-6Al-4V (Ti G5) alloy have limitations for biomedical application, due to lower mechanical strength and the possibility of ion release, respectively. The purpose of this work was to compare the properties of a modified cp Ti grade 4 (Ti G4 Hard) with those of available cp Ti and Ti G5 alloys. METHODS: Bars, discs and dental implants made with Ti G2, G4, G5 and G4 Hard were used. Mechanical tests (tension, compression, hardness and torque) and roughness measurements were performed. Clinical trials were used to evaluate the biological behavior of dental implants made with Ti G4 Hard and Ti G4. RESULTS: The results of the mechanical tests showed that the mechanical strength of modified Ti G4 is higher than that of Ti G2, G4 and G5. Scanning electron microscopy analysis showed that modified Ti G4 after etching has better surface morphological features than conventional cp Ti and Ti G5. The clinical performances of Ti G4 and Ti G4 Hard were similar. SIGNIFICANCE: The improvement of the mechanical properties of modified Ti G4 means that Ti G5 can be safely replaced by Ti G4 Hard without compromising the fracture resistance, with the advantage of not releasing toxic ions. PMID- 25458353 TI - Type-3 copper proteins: recent advances on polyphenol oxidases. AB - Recent investigations in the study of plant, fungal, and bacterial type-3 copper proteins are reviewed. Focus is given to three enzymes: catechol oxidases (CO), tyrosinases, and aureusidin synthase. CO were mostly found in plants, however, in 2010 the first fungal CO was published. The first plant-originated tyrosinase was published in 2014, before tyrosinases were only reported in fungi, bacteria, and human. Aureusidin synthase from yellow snapdragon (Antirrhinum majus) was first published in 2000, as part of yellow flower coloration pathway. In the last years, many important results on type-3 copper enzymes originated from X-ray crystallographic investigations. In addition, studies on site-directed mutagenesis of amino acids around the active site were performed to identify the regions determining monophenolase and/or diphenolase activity. Although X-ray crystallographic structures of CO and tyrosinases are available, many questions like the response for the activation via proteases, sequence-based or structural based differences between CO, as well as the physiological roles of many polyphenol oxidases still remain to be addressed. PMID- 25458352 TI - Mechanical properties of dental resin/composite containing urchin-like hydroxyapatite. AB - OBJECTIVES: To investigate the reinforcing effect of urchin-like hydroxyapatite (UHA) in bisphenol A glycidyl methacrylate (Bis-GMA)/triethylene glycol dimethacrylate (TEGDMA) dental resin (without silica nanoparticles) and dental composites (with silica nanoparticles), and explore the effect of HA filler morphologies and loadings on the mechanical properties. METHODS: UHA was synthesized by a facile method of microwave irradiation and studied by X-ray diffraction (XRD), scanning electron microscope (SEM), and thermogravimetric analysis (TGA). Mechanical properties of the dental resin composites containing silanized UHA were tested by a universal mechanical testing machine. Analysis of variance was used for the statistical analysis of the acquired data. The fracture morphologies of tested composites were observed by SEM. Composites with silanized irregular particulate hydroxyapatite (IPHA) and hydroxyapatite whisker (HW) were prepared for comparative studies. RESULTS: Impregnation of lower loadings (5 wt% and 10 wt%) of silanized UHA into dental resin (without silica nanoparticles) substantially improved the mechanical properties; higher UHA loadings (20 wt% and 30 wt%) of impregnation continuously improved the flexural modulus and microhardness, while the strength would no longer be increased. Compared with silanized IPHA and HW, silanized UHA consisting of rods extending radially from center were embedded into the matrix closely and well dispersed in the composite, increasing filler-matrix interfacial contact area and combination. At higher filler loadings, UHA interlaced together tightly without affecting the mobility of monomer inside, which might bear higher loads during fracture of the composite, leading to higher strengths than those of dental resins with IPHA and HW. Besides, impregnation of silanized UHA into dental composites (with silica nanoparticles) significantly improved the strength and modulus. SIGNIFICANCE: UHA could serve as novel reinforcing HA filler to improve the mechanical properties of dental resin and dental composite. PMID- 25458354 TI - Biophysical studies of matrix metalloproteinase/triple-helix complexes. AB - Several members of the zinc-dependent matrix metalloproteinase (MMP) family catalyze collagen degradation. The structures of MMPs, in solution and solid state and in the presence and absence of triple-helical collagen models, have been assessed by NMR spectroscopy, small-angle X-ray scattering, and X-ray crystallography. Structures observed in solution exhibit flexibility between the MMP catalytic (CAT) and hemopexin-like (HPX) domains, while solid-state structures are relatively compact. Evaluation of the maximum occurrence (MO) of MMP-1 conformations in solution found that, for all the high MO conformations, the CAT and HPX domains are not in tight contact, and the residues of the HPX domain reported to be responsible for the binding to the collagen triple-helix are solvent exposed. A mechanism for collagenolysis has been developed based on analysis of MMP solution structures. Information obtained from solid-state structures has proven valuable for analyzing specific contacts between MMPs and the collagen triple-helix. PMID- 25458355 TI - Catalytic mechanisms of metallohydrolases containing two metal ions. AB - At least one-third of enzymes contain metal ions as cofactors necessary for a diverse range of catalytic activities. In the case of polymetallic enzymes (i.e., two or more metal ions involved in catalysis), the presence of two (or more) closely spaced metal ions gives an additional advantage in terms of (i) charge delocalisation, (ii) smaller activation barriers, (iii) the ability to bind larger substrates, (iv) enhanced electrostatic activation of substrates, and (v) decreased transition-state energies. Among this group of proteins, enzymes that catalyze the hydrolysis of ester and amide bonds form a very prominent family, the metallohydrolases. These enzymes are involved in a multitude of biological functions, and an increasing number of them gain attention for translational research in medicine and biotechnology. Their functional versatility and catalytic proficiency are largely due to the presence of metal ions in their active sites. In this chapter, we thus discuss and compare the reaction mechanisms of several closely related enzymes with a view to highlighting the functional diversity bestowed upon them by their metal ion cofactors. PMID- 25458357 TI - Monitoring the biomolecular interactions and the activity of Zn-containing enzymes involved in conformational diseases: experimental methods for therapeutic purposes. AB - Zinc metalloproteases (ZnMPs) participate in diverse biological reactions, encompassing the synthesis and degradation of all the major metabolites in living organisms. In particular, ZnMPs have been recognized to play a very important role in controlling the concentration level of several peptides and/or proteins whose homeostasis has to be finely regulated for the correct physiology of cells. Dyshomeostasis of aggregation-prone proteins causes pathological conditions and the development of several different diseases. For this reason, in recent years, many analytical approaches have been applied for studying the interaction between ZnMPs and their substrates/inhibitors and how environmental factors can affect enzyme activities. In this scenario, nuclear magnetic resonance, X-ray diffraction, mass spectrometric (MS), and optical methods occupy a very important role in elucidating different aspects of the ZnMPs-substrates/inhibitors interaction, ranging from identification of cleavage sites to quantitation of kinetic parameters and inhibition constants. Here, an overview of all the main achievements in the application of different experimental approaches with special attention to MS methods to the investigation of ZnMPs-substrates/inhibitors interaction is given. A general MS experimental protocol which has been proved to be useful to study such interactions is also described. PMID- 25458358 TI - Metal-containing enzymes. Preface. PMID- 25458356 TI - Applications of quantum mechanical/molecular mechanical methods to the chemical insertion step of DNA and RNA polymerization. AB - We review theoretical attempts to model the chemical insertion reactions of nucleoside triphosphates catalyzed by the nucleic acid polymerases using combined quantum mechanical/molecular mechanical methodology. Due to an existing excellent database of high-resolution X-ray crystal structures, the DNA polymerase beta system serves as a useful template for discussion and comparison. The convergence of structures of high-quality complexes and continued developments of theoretical techniques suggest a bright future for understanding the global features of nucleic acid polymerization. PMID- 25458360 TI - [Onychomycosis, what is new in 2014?]. PMID- 25458359 TI - Multitargeting strategy using lenvatinib and golvatinib: maximizing anti angiogenesis activity in a preclinical cancer model. AB - Almost all cancers show intrinsic and/or evasive resistance to vascular endothelial growth factor (VEGF) inhibitors by multiple mechanisms. Serum angiopoietin-2 (Ang2) level has been proposed as a potential biomarker of VEGF inhibitor response in several cancers. From these clinical observations, the Ang2 and Tie2 (its receptor) axis has been focused on as a promising target. Here, we show a novel strategy to circumvent the resistance by combining multi-tyrosine kinase inhibitors lenvatinib (VEGF receptor, fibroblast growth factor receptor, and RET inhibitor) and golvatinib (E7050; c-Met, Tie2, and EphB4 inhibitor). Tie2 identifies a highly pro-angiogenic macrophage subset, Tie2-expressing macrophages (TEM). Angi-Tie2 and EphB4-EphrinB2 signaling plays critical roles in pericyte mediated vessel stabilization. In vitro analyses suggested that golvatinib combined with lenvatinib inhibited pericyte-mediated vessel stabilization and TEM differentiation. In thyroid and endometrial cancer models, golvatinib and lenvatinib inhibited pericyte network development and TEM infiltration, resulting in severe perfusion disorder and massive apoptosis. Body weight loss was tolerable, and no macroscopic change was observed. These preclinical studies suggest that modulation of the tumor microenvironment by a strategic and well tolerated combination of multi-targeting tyrosine kinase inhibitors may sensitize cancer to VEGF inhibitors. PMID- 25458361 TI - [New clinical classification for onychomycoses]. AB - We have updated our clinical classification on onychomycosis (2011) to render it of more practical value for the clinician. It should provide a better understanding of onychomycosis and facilitate an improved approach to treatment, taking into account, for example, the link between the proximal subungual variety and some superficial forms emerging from beneath the cuticle. PMID- 25458362 TI - [Onychomycoses due to molds]. AB - Onychomycoses represent about 30% of superficial mycosis that are encountered in Dermatology consults. Fungi such as dermatophytes, which are mainly found on the feet nails, cause nearly 50% of these onychopathies. Yeasts are predominantly present on hands, whereas non-dermatophytic moulds are very seldom involved in both foot and hand nails infections. According to literature, these moulds are responsible for 2 to 17% of onychomycoses. Nevertheless, we have to differentiate between onychomycoses due to pseudodermatophytes such as Neoscytalidium (ex Scytalidium) and Onychocola canadensis, which present a high affinity for keratin, and onychomycoses due to filamentous fungi such as Aspergillus, Fusarium, Scopulariopsis, Acremonium... These saprophytic moulds are indeed most of the time considered as colonizers rather than real pathogens agents. Mycology and histopathology laboratories play an important role. They allow to identify the species that is involved in nail infection, but also to confirm parasitism by the fungus in the infected nails. Indeed, before attributing any pathogenic role to non-dermatophytic moulds, it is essential to precisely evaluate their pathogenicity through samples and accurate mycological and/or histological analysis. The treatment of onychomycoses due to non-dermatophytic moulds is difficult, as there is today no consensus. The choice of an antifungal agent will first depend on the species that is involved in the infection, but also on the severity of nail lesions and on the patient himself. In most cases, the onychomycosis will be cured with chemical or mechanical removing of the infected tissues, followed by a local antifungal treatment. In some cases, a systemic therapy will be discussed. PMID- 25458363 TI - [Mycological diagnosis of onychomycosis]. AB - Onychomycosis represents about 50% of ungueal pathology. Dermatophytes (especially Trichophyton rubrum and Trichophyton interdigitale) are the main species involved in tinea pedis. Yeasts of the Candida (Candida albicans, Candida parapsilosis,...) genus are predominant on hands and very often associated with ungueal disease and perionyxis. Fungi other than the classic dermatophytes and yeasts can be rarely isolated from nail diseases. Among them, species belonging to Scopulariopsis, Aspergillus and Fusarium genus are mainly found, but their involvement in the disease must be proved. Other fungi, presenting a special affinity to keratin (pseudodermatophytes), such as Neoscytalidium dimidiatum (ex Scytalidium dimidiatum) from tropical and subtropical areas and Onychocola canadensis from Northern America and Europe, are considered as real pathogens in nail diseases. A multidisciplinary approach, including clinicians and biologists, is required to confirm the mycosis. This comparative review emphasizes the importance of histological examination, as well as molecular approaches, which are very contributive to the diagnosis of onychomycosis. The role of the laboratory is to identify at the species level the fungus isolated from nail scrapings and to show its involvement in the ungueal lesions. PMID- 25458365 TI - Molecular diagnosis of onychomycosis. AB - Onychomycosis is a frequent cause of nail infections due to dermatophytes. Molds and yeast may also be responsible of these pathologies. Antifungal treatments are frequently given without a mycological diagnosis, partly because of the requisite time for obtaining the biological results. The mycological diagnosis requires a direct microscopic examination and a culture in order to accurately identify the fungal genus and species. Nevertheless, this conventional diagnosis is often time consuming due to the delay of fungal cultures and presents disadvantages that make it not sufficient enough to give a precise and confident response to the clinicians. Therefore additional tests have been developed to help distinguish onychomycosis from other nail disorders. Among them, molecular biology techniques offer modern and rapid tools to improve traditional microbiological diagnosis. In this review, we first present the conventional diagnosis methods for onychomycosis and then we describe the main molecular biology tools and the currently available commercial kits that allow a rapid detection of the pathology. PMID- 25458364 TI - A non-polyenic antifungal produced by a Streptomyces yatensis strain isolated from Mellah Lake in El Kala, North-East of Algeria. AB - OBJECTIVE: This study aimed at describing one actinomycete strain E65 that was isolated from the water of Mellah Lake in El Kala, North-East of Algeria that produces a non-polyenic antifungal. MATERIALS AND METHODS: Actinomycetes were isolated from Mellah Lake water and screened for antimicrobial activity. Antimicrobial assays were performed on ISP2 agar. The taxonomic position of the strain E65 was determined regarding phenotypic and 16S DNA sequences features. Time course of antifungal metabolites production was evaluated against Candida albicans on ISP2, ISP1 and GYEA broth. The active antifungal compound was extracted using dichloromethane and revealed by a thin layer of chromatography, chemical reagents, UV-visible and infrared spectroscopy. RESULTS: A total of 104 actinomycetes were isolated and screened for antimicrobial activity; 21 strains were active against Staphylococcus aureus, Escherichia coli and Candida albicans. The strain E65 showed a high in vitro activity against S. aureus and C. albicans and a good antifungal activity against a clinical C. albicans strain resistant to 5-fluorocytosine. Its 16S rRNA sequence shared 99% similarity with the Streptomyces yatensis type strain within the Streptomyces violaceusniger subclade of the Streptomyces hygroscopicus clade. It produced a non-polyenic antifungal, the IR spectrum of the antifungal extract corresponded to none of the antimicrobials compounds known to be produced by actinomycete of the S. hygroscopicus clade. CONCLUSION: The wetlands of El Kala, Algeria are a potential source of bioactive actinomycete that deserves to be explored and exploited. The Streptomyces yatensis E65 strain isolated from Mellah Lake brackish water produces a remarkable antifungal compound which original non-polyenic structure warrants further characterization. PMID- 25458366 TI - [Treatment of onychomycosis]. AB - A positive mycological examination is required before discussion of treatment of onychomycosis. Onychomycosis is most commonly due to dermatophytes in association with tinea pedis and/or tinea manuum. It is a catched infection. Candida onychomycosis is a rare opportunistic infection and onychomycosis due to non dermatophytic moulds is very rare as a "chance mishap". The treatment of dermatophyte onychomycosis takes each infected part of the nail into account. Topical antifungal agents should be reserved for mild to moderate onychomycosis. Systemic antifungal agents are required to severe onychomycosis. In all cases, removal of infected nail parts is useful to facilitate the penetration of antifungal drugs and eradication of reinfection sites may be done to prevent recurrences and relapses. In primary, Candida onychomycosis treatment with topical antifungal drugs may be effective but in case of treatment failure, a systemic therapy is required. Suppression predisposing factors is useful. The treatment of non-dermatophytic moulds onychomycosis is still a challenge. Except Neoscytalidium spp., which mimic a dermatophytosis, non-dermatophytic moulds may be isolated from dystrophic nails and it is always difficult to specify their role as a primary pathogen or as a colonizer of nails. The available topical and systemic antifungal drugs are not effective against these non-dermatophytic moulds except itraconazole for onychomycosis due to Aspergillus spp. New therapy such as light and laser therapy are in evaluation. PMID- 25458367 TI - [Pulmonary infection by Geotrichum capitatum about a case and review of the literature]. AB - Pulmonary geotrichosis is a rare mycosis caused by an arthrospore filamentous fungi of the genus Geotrichum. It is an opportunistic infection that develops when underlying conditions are present, particularly immunosuppression including neutropenia. Pulmonary mycoses in non-neutropenic patients affect two main populations: the solid organ transplanted patients and patients whose local pulmonary defenses are altered by a chronic underlying lung pathology. We report a case of pulmonary infection Geotrichum capitatum in an old tuberculosis patient. PMID- 25458368 TI - [Biological diagnosis of onychomycoses. Direct examination after simplified technique of PAS staining]. AB - Confirmation of fungal origin of onychopathy by mycological examination is essential. For that purpose, in parallel to the cultivation of biological samples, achieving a sensitive and informative direct examination of nail fragments and subungual material is primordial. Among the direct examination techniques, and inspired from a technique of reference in histo-pathology (the "periodic acid-Schiff reagent" reaction), the simplified technique of PAS staining according to Hotchkiss and MacManus is the technique of choice. Easy to implement and very sensitive, it can immediately and formally confirm the diagnosis of onychomycosis, mention the type of fungus (yeast, dermatophyte, Hyphomycete opportunistic) and suspect a possible multiple involvement. PMID- 25458369 TI - What is the optimal management of Gleason score 7 prostate cancer at biopsy? A comparison of disease control for prostatectomy versus radiotherapy. AB - OBJECTIVES: To compare outcomes between radical prostatectomy (RP) or radiotherapy (RT) approaches for Gleason 7 (GS7) prostate cancer. METHODS: Patients were retrospectively identified for inclusion by clinically localized disease, GS7, prostate-specific antigen (PSA) < 30 ng/mL at diagnosis, and follow up with PSA at > 12 months. Comparison of demographic, tumor, staging, and outcome variables was performed. Disease recurrence was defined as per contemporary society guidelines. The Kaplan-Meier method was used for disease control estimates. RESULTS: Between 2003 and 2010, a total of 253 patients were diagnosed with GS7 prostate cancer, of whom 207 were eligible for the current analysis (120 RP, 87 RT). Excepting older age for RT patients (median 73 vs. 62 years), the groups were well balanced. For RP patients, 82 patients (60%) had at least 1 high-risk feature, 4 (5%) of whom received adjuvant RT. For RT patients, 71 patients (82%) received hormone therapy (median duration 6 months). At a median follow-up of 62.2 months (range 13.1-136.6 months, with no difference between treatment groups), 64 patients had PSA relapse (51 RP, 13 RT), and 15 had died (5 of or with disease). PSA relapse-free survival was inferior for RP versus RT (P < .0001), with 5-year rates of 55.4% versus 82.6%, respectively. CONCLUSION: For GS7 prostate cancer patients, RT is associated with superior disease-free survival at 5 years compared to RP alone, without difference in disease-specific survival. Whether this difference remains in the setting of appropriately used adjuvant RT after RP, and the effect of possible delay in testosterone recovery for older RT patients remain to be determined. PMID- 25458370 TI - Complete response as an intermediate end point in patients receiving salvage systemic therapy for urothelial carcinoma. AB - BACKGROUND: The complete remission (CR) rate with salvage systemic therapy for urothelial carcinoma (UC) is unclear, and its value as an intermediate end point and association with survival are unknown. MATERIALS AND METHODS: Data from phase II trials of salvage chemotherapy and/or biologic agents were pooled. Data regarding response, overall survival (OS), progression-free survival (PFS), time from prior chemotherapy, hemoglobin, performance status, and liver metastasis status were collected. Cox proportional hazards regression was used to evaluate the association of CR and other prognostic factors with outcomes. RESULTS: A total of 789 of 818 patients enrolled in 12 phase II trials had evaluable data. CR and partial response were seen in 14 (1.8%) and 109 (13.8%) patients. Median (95% confidence interval) OS for those with a CR was 21.5 (14.2-34.3) months, compared with 6.7 (6.0-7.0) months in those without a CR (P < .001). Median (95% confidence interval) PFS for those with a CR was 15.7 (8.2-27.1) months, compared with 2.6 (2.4-2.8) months for those without a CR (P < .001). Prior cisplatin and time from prior chemotherapy of >= 3 months were associated with CR (P < .05). The presence of poor prognostic factors and suboptimal response to prior therapy did not preclude CR. CONCLUSION: CR occurs in 1.8% of patients receiving salvage therapy for advanced UC and is strongly associated with durable OS and PFS. CR warrants validation as an intermediate end point and may help select agents for further investigation and tumors for molecular interrogation. PMID- 25458371 TI - Characteristics of long-term and short-term survivors of metastatic renal cell carcinoma treated with targeted therapies: results from the International mRCC Database Consortium. AB - BACKGROUND: Targeted therapies improve survival in metastatic renal cell carcinoma (mRCC). However, survival patterns can be divergent, and patients at the 2 extremes of the survival spectrum need to be characterized. PATIENTS AND METHODS: Data from 2161 patients included in the International mRCC Database Consortium (IMDC) were analyzed. We identified patients on the basis of their duration of survival. Long-term survival (LTS) was defined as overall survival (OS) of >= 4 years, and short-term survival (STS) was defined as OS of <= 6 months from the start of targeted therapy. Baseline characteristics, including demographic, clinicopathologic, and laboratory data, were compared between LTS and STS. Treatment response by the RECIST criteria was summarized for the 2 survival groups. RESULTS: A total of 152 patients experienced LTS and 218 experienced STS. Adverse clinical and laboratory prognostic factors previously described in the IMDC prognostic model were significantly more frequent in the STS group (P < .0001). In the LTS group, 138 patients (91%) had nonprogressive disease (non-PD) as best response to first-line targeted therapy, and 56 (60%) of 94 patients who received second-line therapy had non-PD. In the STS group, only 51 patients (23%) had non-PD on first-line therapy. None of 21 the patients who received second-line therapy had non-PD as best response. In LTS, the median duration of therapy was 23.6 months (range 0.4 to 81.8+ months) for first-line therapy and 11.5 months (range 0.6 to 45.7 months) for second-line therapy, compared to 2.0 and 0.8 months for the STS group, respectively. CONCLUSION: Baseline prognostic criteria and absence of PD after first and second-line targeted therapy may characterize long-term survival. PMID- 25458372 TI - Effect of vagotomy during Roux-en-Y gastric bypass surgery on weight loss outcomes. AB - BACKGROUND: During Roux-en-Y gastric bypasses (RYGB), some surgeons elect to perform a vagotomy to reduce symptoms of gastro-oesophageal reflux (GER). Routine vagotomy during RYGB may independently affect weight loss and metabolic outcomes following bariatric surgery. We aimed to determine whether vagotomy augments percent excess weight loss in obese patients after RYGB. METHODS: We examined the effect of vagotomy in 1278 patients undergoing RYGB at our institution from 2003 to 2009. Weight and percent excess weight loss (%EWL) were modelled at three months and annually up to five years using a longitudinal linear mixed model controlling for differences in age, gender, initial body mass index (BMI), ideal body weight, and presence of vagotomy. RESULTS: Vagotomy was performed on 40.3% of our cohort. Vagotomy patients had significantly lower initial BMI (46.4+/-6.2 vs. 48.3+/-7.7kg/m(2), p<0.001), but there were no other significant differences at baseline. The strongest predictor of %EWL over time was initial BMI, with lower BMI patients exhibiting greater %EWL (p<0.001). Age and gender effects were also significant, with younger patients (p<0.04) and males (p<0.002) attaining greater %EWL. Vagotomy had no effect on %EWL in either simple or multiple regression models. CONCLUSION: Our series suggest that vagotomy does not augment %EWL when performed with RYGB. PMID- 25458373 TI - Can our residents carry the weight of the obesity crisis? A mixed methods study. AB - BACKGROUND: Obesity is a worldwide problem and has reached epidemic proportions in the Middle East. Although physicians are in a unique position to counsel and treat their obese patients, little is known about healthcare provider management of obesity in this region of the world. The purpose of this study is to assess resident physician diagnosis and management of obese patients, and barriers to obesity management in the United Arab Emirates. METHODS: We conducted a retrospective medical records review of an internal medicine resident clinic in an academic medical centre in the UAE. A focus group was then held with a convenience sample of 20 Internal Medicine residents. Questions were aimed at understanding barriers to obesity diagnosis and management. Focus group discussions were analysed using qualitative thematic analysis. RESULTS: Of 155 patients seen in resident clinic in 2012 and 2013 (representing 766 patient encounters), 50 (32%) met the criteria for overweight, and 102 (66%) met the criteria for obesity. Despite the high prevalence, only 9% had documentation of BMI or obesity in their medical record. Six percent were offered diet or exercise advice, and 6% were referred to a dietician. Focus group results indicated residents had sufficient knowledge, but lacked training in obesity management and adequate time for counselling. Weight biases and feelings of incompetence may exist among our trainees. CONCLUSION: Obesity is under-recognised and under treated by our residents. The findings confirm that a significant gap exists between optimal obesity management recommendations and the current practices of our trainees. PMID- 25458374 TI - Identification of new Presenilin-1 phosphosites: implication for gamma-secretase activity and Abeta production. AB - An important pathological hallmark of Alzheimer's disease (AD) is the deposition of amyloid-beta (Abeta) peptides in the brain parenchyma, leading to neuronal death and impaired learning and memory. The protease gamma-secretase is responsible for the intramembrane proteolysis of the amyloid-beta precursor protein (APP), which leads to the production of the toxic Abeta peptides. Thus, an attractive therapeutic strategy to treat AD is the modulation of the gamma secretase activity, to reduce Abeta42 production. Because phosphorylation of proteins is a post-translational modification known to modulate the activity of many different enzymes, we used electrospray (LC-MS/MS) mass spectrometry to identify new phosphosites on highly purified human gamma-secretase. We identified 11 new single or double phosphosites in two well-defined domains of Presenilin-1 (PS1), the catalytic subunit of the gamma-secretase complex. Next, mutagenesis and biochemical approaches were used to investigate the role of each phosphosite in the maturation and activity of gamma-secretase. Together, our results suggest that the newly identified phosphorylation sites in PS1 do not modulate gamma secretase activity and the production of the Alzheimer's Abeta peptides. Individual PS1 phosphosites shall probably not be considered therapeutic targets for reducing cerebral Abeta plaque formation in AD. In this study, we identified 11 new phosphosites in Presenilin-1 (PS1), the catalytic subunit of the Alzheimer's gamma-secretase complex. By combining a mutagenesis approach with cell-based and cell-free gamma-secretase assays, we demonstrate that the new phosphosites do not modulate the maturation and activity of gamma-secretase. Individual PS1 phosphosites shall thus not be considered therapeutic targets for reducing cerebral Abeta plaque formation in Alzheimer's Disease. Abeta, amyloid beta. PMID- 25458394 TI - [Research in health care professions - value for care delivery as the focus]. PMID- 25458395 TI - [Analysis of potential for research on giving birth in an upright position in German hospitals]. AB - HEALTH PROBLEM: In German hospitals, three quarters of all low-risk pregnant women give birth in the supine position, despite the fact that German, British and WHO guidelines do not recommend a supine birthing position which is associated with a higher risk to the health of both mother and fetus. CORPUS OF EVIDENCE: Based on 22 RCTs with 7,280 participants, a systematic Cochrane review (Gupta et al., 2012) revealed that an upright position - compared with a supine or lithotomy position - (1) has a positive impact on fetal heart rate patterns, (2) reduces the requirement for analgesic or anaesthetic medications in the second stage of labour, and (3) results in fewer episiotomies and (4) fewer instrumental deliveries. There is a lack of evidence regarding perceived maternal autonomy, self-efficacy and anxiety when giving birth. Furthermore, evidence on long-term effects is absent. Some studies indicate that the choice of an upright birthing position might be boosted by a supporting physical and social environment and by specially trained midwives. IMPLICATION FOR RESEARCH: There is a need for a feasibility study and a subsequent cluster RCT in the German healthcare context in order to investigate the effects of the upright posture for birthing on perceived maternal autonomy, self-efficacy and anxiety, on the reduction of perinatal complications and on long-term complaints. The complex experimental intervention consists of (1) evidence-based and user-friendly information for women and their partners, (2) facilitating the choice for an upright labour position by special training for midwives and (3) providing a supportive physical and social environment. Within the first study phase, the exploration of feasibility in terms of access to the target group and acceptance of the intervention by pregnant women, their partners and midwives is recommended. Thereby, the implementation of guidelines for upright labour and birth, the documentation and collection of outcome and cost data could be evaluated. Non-German instruments for measuring benefits, harms and long-term effects could be adapted to and validated for the German context. PMID- 25458396 TI - [Potential analysis for research on physiotherapy-led treadmill training in Parkinson's disease]. AB - HEALTH PROBLEM: Parkinson's disease is one of the major neurodegenerative disorders with prevalence rates between 0.1 and 0.2 % in the global population and 1.8 % in people aged 64 years and over. Future incidence rates are estimated to increase within aging societies. The progressive course of Parkinson's disease is clinically characterised by bradykinesia, rigidity and tremor. These limitations in motor functioning reduce the capacity to work, social participation and the clients' quality of life. Parkinson's disease causes incapacity to work and a large number of days off from work. The benefits clients expect from physiotherapy-led treatment include an improvement of gait, a better speed of motion and the decrease of fatigue and rigidity. CORPUS OF EVIDENCE: A recent Cochrane review (Mehrholz et al., 2010) analysed seven randomised comparisons with 153 participants and found that treadmill training compared with no treatment improved gait speed (SMD 0.50; 95 % confidence interval [0.17 to 0.84]). A lack of evidence exists on how to reduce fatigue and rigidity. There is also need to evaluate long-term effects and cost-effectiveness. Furthermore, an updated meta-analysis should include eleven new randomised trials on treadmill training after 2009. Physiotherapy-led treadmill training can easily be transferred into the German healthcare context since the environmental and educational preconditions are met by German physiotherapeutic care. IMPLICATION FOR RESEARCH: Within the German context, there is need to prepare a randomised clinical trial evaluating the impact of physiotherapy-led treadmill training on motor functioning, quality of life, costs, adverse events und long-term effects. Prior to this, a feasibility study should explore the acceptance and intensity of treadmill training as well as the access of private physiotherapy practices to people suffering from early- to mid-stage Parkinson's disease. PMID- 25458397 TI - [Potential analyses for research on occupational therapy-led training of activities of daily living in stroke patients]. AB - HEALTH PROBLEM: Every year about 200,000 people in Germany suffer from a first stroke and 65,000 persons from a recurrent stroke. Stroke is one of the major causes of acquired life-long disability. It is associated with multiple limitations in functioning, activities of daily living and social participation. People with stroke must develop and apply considerable coping and adaptation strategies to manage the consequences of disabilities in daily life. Insufficient adaptations may result in social isolation, depressive disorders, need for medical and nursing care and subsequently lead to increasing costs for care. Thus occupational therapy-led treatment addressing social participation as well as skills training, adaptation strategies and assistive technology for activities of daily living is essential for stroke patients after hospital discharge. CORPUS OF EVIDENCE: Based on nine randomised comparisons, a Cochrane review from 2006 revealed that occupational therapy-led training after stroke had positive effects on personal activities of daily living (8 studies; 961 participants; 0.18 SMD; 95 % CI [0.04 to 0.32]), on extended activities of daily living (6 studies; 847 participants; 0.21 SMD; 95 % CI [0.03 to 0.39]), and on poor outcome (7 studies; 1,065 participants; odds ratio 0.67; 95 % CI [0.51 to 0.87]). However, direct implementation into the German healthcare context is not recommendable due to (1) different settings and heterogeneity within the primary studies, (2) lack of manualisation of treatment programmes and (3) insufficient evaluation of client oriented outcomes. IMPLICATION FOR RESEARCH: It is recommended to manualise client-centred standardised modules of a stage-specific occupational therapy-led training of activities of daily living and to pilot-test this intervention programme in a feasibility study. If this trial results in a set of reliable and valid client-oriented outcome measurements applicable within the German care context and in a feasible treatment programme well accepted by stroke patients and their treating occupational therapists, a large-scaled randomised clinical trial in terms of comparative effectiveness research may follow. PMID- 25458398 TI - [Potentials for research and innovations in allied health professions in Germany]. AB - In order to address the increasing complexity and continuously changing needs and demands in the German healthcare system, there is a need to strengthen knowledge translation, evidence-based practice and the conduct of clinical trials in the field of allied health professions. An interdisciplinary working group representing the fields of nursing, midwifery, physiotherapy, occupational therapy and speech therapy developed a guide and a concept for seminars to provide potential analyses for research and innovations in the allied health professions in Germany. These potential analyses compare the current state of health care delivery for specific health problems and the corpus of evidence for the effectiveness of related interventions. Thus innovations can be identified which might improve client-centred healthcare in Germany. The introductory paper briefly reports the activities and results of the working group, describes the international context of transferring research into practice and outlines possibilities for the future development of coordinated research strategies in Germany. The following papers consist of five potential analyses: (1) Advanced Practice Nursing (APN) in long-term care; (2) giving birth in an upright position; (3) treadmill training for patients with Parkinson's disease; (4) training of everyday activities after stroke; and (5) communication training for patients with aphasia. PMID- 25458399 TI - [Potential analysis of research on speech therapy-led communication training in aphasia following stroke]. AB - HEALTH PROBLEM: In Germany, about 100,000 people currently suffer from aphasia. This speech disorder occurs as a result of neurologic events such as stroke or traumatic brain injury. Aphasia causes major limitations in social participation and quality of life and can be associated with unemployability and social isolation. For affected persons, it is essential to regain and maintain autonomy in daily life, both at work and with family and friends. The loss of autonomy is perceived much more dramatically than the loss of speech. Clients wish to minimise this loss of autonomy in daily life. As full recovery is not achievable in chronic aphasia, treatment must focus on improved compensatory approaches and on supporting the clients' coping strategies. EVIDENCE BASE: Based on eight randomised comparisons including 347 participants, a recent Cochrane review (Brady et al., 2012) revealed that speech therapy - as compared with no treatment - had positive effects on functional communication in clients suffering from aphasia (0.30 SMD; 95% CI[0.08 to 0.52]). There was no evidence suggesting that one type of training was superior to the others. However, quality of life and social participation were not evaluated as outcomes. Recent studies found that speech therapy-led training for communication and self-efficacy and the integration of communication partners may have a positive impact on these client centred outcomes. IMPLICATION FOR RESEARCH: Speech therapy-led training for communication within a group setting should be manualised and pilot-tested with respect to feasibility and acceptance in a German sample of people with aphasia and their communication partners. Instruments measuring quality of life and social participation can be validated within the scope of this feasibility study. These research efforts are necessary to prepare a large-scale comparative effectiveness research trial comparing the effects of both usual speech therapy and speech therapy-led group communication training on quality of life and social participation. PMID- 25458400 TI - [Potential analysis for research on Advanced Practice Nursing (APN) for persons with dementia living in long-term care facilities]. AB - HEALTH PROBLEM: The nursing Minimum Data Set 3.0 (MDS 3.0) and other nursing quality indices summarise relevant health and nursing outcomes for long-term care that are recommended as quality measures. These are measures like "Percent of High-Risk Residents with Pressure Ulcers", "Percent of Low-Risk Residents Who Lose Control of Their Bowels or Bladder", "Percent of Residents Experiencing One or More Falls with Major Injury", "Percent of Residents Who Lose Too Much Weight" etc. Analyses of healthcare data in Germany showed a substantial higher risk for negative outcomes in the long-term care setting in persons with dementia compared to persons without dementia. There already exist evidence-based guidelines and recommendations for most of the quality measures and underlying health problems (e.g., the German "Expertenstandards in der Pflege"). Implementation and translation of evidence have not been systematically researched yet, and there is uncertainty about structures and processes that support implementation and eventually lead to improved nursing outcomes in people with dementia in long-term care. CORPUS OF EVIDENCE: Studies showed a potential benefit of master-level geriatric advanced practice nurses (GAPNs) concerning the implementation of evidence-based guidelines. This corresponds to the expectation that academic nursing staff positively influences research utilisation in practice. A systematic review identified four controlled trials that evaluated the effectiveness of GAPN on select quality measures. Both the internal and external validity of the trials require a thorough investigation into the intervention before translation and effectiveness research in Germany can be recommended. IMPLICATION FOR RESEARCH: In accordance with national and international recommendations on the development and clinical evaluation of complex interventions, we recommend a multistage model. Such a model comprises the conceptualisation and adaptation of the original intervention. In this way, the original concept of a GAPN has to be translated into the context of the German healthcare system. Furthermore, feasibility of the intervention in general has to be investigated. This includes acceptance of GAPNs in practice and the necessary prerequisites, especially concerning a comprehensive commitment of one APN to more than one long-term care facility. PMID- 25458401 TI - Macrophage migration inhibitory factor in obese and non obese women with polycystic ovary syndrome. AB - OBJECTIVE: To measure macrophage migration inhibitory factor (MIF) concentrations in obese and non-obese women diagnosed with polycystic ovary syndrome (PCOS). METHODS: Women diagnosed with PCOS and age-matched healthy controls with regular menses and normal ovaries on ultrasound examination were selected and divided into 4 groups (group A, PCOS and obese; group B, PCOS and non-obese; group C, obese controls; and group D, non-obese controls) based on body mass index (obese >30 kg/m2 and non-obese <25 kg/m2). Luteinizing hormone, follicle-stimulating hormone, androstenedione, testosterone, sex hormone-binding globulin, serum glucose, insulin and MIF levels were measured. RESULTS: Obese and non-obese women with PCOS had higher luteinizing hormone, follicle-stimulating hormone, androstenedione, testosterone, and insulin levels as compared to the obese and non-obese control groups, respectively (P < .0001). Women with PCOS had significantly higher MIF levels (group A, 48.6 +/- 9.9 mg/ml; group B, 35.2 +/- 6.0 ng/ml) as compared to controls (group C, 13.5 +/- 6.0 ng/ml; group D, 12.0 +/ 4.3 ng/dl; P < .0001). A weak, positive and significant correlation was seen between fasting blood glucose and insulin levels in women with PCOS (P < .05). CONCLUSION: Significant differences exist in plasma MIF levels between obese and non-obese women with and without PCOS. PMID- 25458402 TI - The relationship between xerostomia and diabetes mellitus: a little known complication. PMID- 25458403 TI - Urban vs. rural differences in prescription opioid misuse among adults in the United States: informing region specific drug policies and interventions. AB - BACKGROUND: In the United States, prescription opioid misuse (POM) has increased dramatically over the past two decades. However, there are still questions regarding whether rural/urban differences in adult POM exist, and more important, which factors might be driving these differences. METHODS: Using data from the 2011 and 2012 National Survey on Drug Use and Health, we conducted unadjusted and adjusted binary logistic regression analyses to determine the association between metropolitan status and POM. RESULTS: We found that urban adults were more likely to engage in POM compared to rural adults because of their higher use of other substances, including alcohol, cannabis, and other illicit and prescription drugs, and because of their greater use of these substances as children. CONCLUSION: This study fills an important gap in the literature by not only identifying urban/rural differences in POM, but by also pointing out factors that mediate those differences. Because patterns and predictors of POM can be unique to geographic region, this research is critical to informing tailored interventions and drug policy decisions. Specifically, these findings suggest that interventions should be aimed at urban illicit drug users and adults in manual labor occupations. PMID- 25458404 TI - Asymmetric Carbamoyl Anion Additions to Chiral N-Phosphonyl Imines via the GAP Chemistry Process and Stereoselectivity Enrichments. AB - Carbamoyl anions were found to smoothly react with chiral N-phosphonyl imines in toluene at -78 degrees C to r.t. using LiHMDS as the base. Group-assisted purification (GAP) has been utilized to give the pure amides without using column chromatography or recrystallization. The asymmetric reaction resulted in chiral N phosphonyl amino amides with good to excellent yields (71-99%) and good crude diastereoselectivities (dr 84:16-95:5). In this GAP procedure, the crude solids are washed with diethyl ether to afford the pure products, as revealed by (1)H NMR analysis; GAP washing consistently increases the diastereopurity of the products, resulting in excellent diastereoselectivities, often with final dr > 99:1. Interestingly, the diastereoenriched products can be obtained either in the ether solution or as the suspended solid, depending on the substrate. PMID- 25458407 TI - Ethical considerations on the health consequences of child or adolescent marriage. PMID- 25458406 TI - The IJGO welcomes a new editor. PMID- 25458405 TI - Historical trend of racial and ethnic disparities in meeting Medicare medication therapy management eligibility in non-Medicare population. AB - BACKGROUND: Prior research examining racial and ethnic disparities in meeting Medicare medication therapy management (MTM) eligibility criteria among the non Medicare population suggests minorities have lower likelihood of being eligible than non-Hispanic Whites (Whites). However, such research has not examined trends in disparities and whether these disparities may be expected to decrease over time based on historical data. OBJECTIVES: To examine trends in MTM eligibility disparities among the non-Medicare population from 1996-1997 to 2009-2010. METHODS: This retrospective observational analysis used Medical Expenditure Panel Survey data from the two study periods. The MTM eligibility criteria used by health insurance plans in 2008 and 2010 were analyzed. Trends in disparities were examined by including interaction terms between dummy variables for 2009-2010 and non-Hispanic Blacks (Blacks)/Hispanics in a logistic regression. Interaction effects were estimated on both the multiplicative and additive terms. Main and sensitivity analyses were conducted to represent the ranges of the Medicare MTM eligibility thresholds used by health insurance plans. RESULTS: According to the main analysis, Blacks and Hispanics were less likely to be eligible than Whites for both sets of eligibility criteria in 1996-1997 and in 2009-2010. Trend analysis for both sets of criteria found that on the multiplicative term, there were generally no significant changes in disparities between Whites and Blacks/Hispanics from 1996-1997 to 2009-2010. Interaction on the additive term found evidence that disparities between Whites and Blacks/Hispanics may have increased from 1996-1997 to 2009-2010 (e.g., in the main analysis between Whites and Hispanics for 2010 eligibility criteria: difference in odds = -0.03, 95% CI: [-0.03]-[-0.02]). CONCLUSIONS: Racial and ethnic minorities in the non-Medicare population experience persistent and often increasing disparities in meeting MTM eligibility criteria. Drug benefit plans should take caution when using elements of Medicare MTM eligibility criteria. PMID- 25458408 TI - Ethical considerations regarding requests and offering of cosmetic genital surgery. PMID- 25458409 TI - Ethical guidance on healthcare professionals' responses to violence against women. PMID- 25458410 TI - Ethical guidelines on conscientious objection in training. PMID- 25458412 TI - Ethical issues after sexual assault. PMID- 25458411 TI - Awareness of female condoms and failures reported with two different types in China. AB - OBJECTIVE: To explore knowledge and use of female condoms in China, and to compare four modes of failure between the Phoenurse female condom (PFC) and the second-generation Femidom female condom (FC2). METHODS: In a randomized, crossover trial, sexually active women aged 20-49years who attended a family planning service in Qingdao, China, were recruited between April and October, 2013. A computer-generated randomized sequence was used to assign participants (1:1) to group A (used 10 PFCs followed by 10 FC2s) or group B (used 10 FC2s followed by 10 PFCs). Study investigators and participants were masked to allocation. Participants completed questionnaires at baseline and after using the two types of FCs. They also kept coital logs. RESULTS: At baseline, 30 (10.3%) of 290 participants understood female condoms, but only 1 (0.3%) had ever used one. Total failure rates were 3.6% (420/11 578) and 2.3% (265/11 594) for PFC and FC2, respectively (P<0.001). Slippage was the most common form of failure, affecting 6.9% of PFC uses and 5.0% of FC2 uses. Breakage, misdirection, and slippage were significantly more common with the PFC than with the FC2 (P<=0.002). CONCLUSION: Understanding of female condoms is poor in China. Failure is more common with the PFC than with the FC2. PMID- 25458413 TI - Ethical issues in women's post-reproductive lives. PMID- 25458414 TI - Patients' refusal of recommended treatment. PMID- 25458415 TI - Recommendations on conflict of interest, including relationships with industry. PMID- 25458417 TI - Ethical issues in adolescent pregnancies. PMID- 25458416 TI - Examining negative effects of early life experiences on reproductive and sexual health among female sex workers in Tijuana, Mexico. AB - OBJECTIVE: To explore experiences during childhood and adolescence that influenced reproductive and sexual health among women who had entered the sex industry in adolescence. METHODS: A qualitative study was conducted using information provided by 25 female sex workers (FSWs) from Tijuana, Mexico, who reported entering the sex industry when younger than 18 years. In-depth, semi structured interviews were conducted with all participants between January 31, 2011, and July 8, 2011. RESULTS: Four interrelated themes that shaped health experiences-early sexual abuse, early illicit drug use, ongoing violence, and limited access to reproductive and sexual health care-were identified. Participants reporting these experiences were at risk of unintended teenaged pregnancy, spontaneous abortion or stillbirth, and untreated sexually transmitted infections. CONCLUSION: Programs and policies that address social, structural, and individual vulnerabilities during adolescence and adulthood are required to promote reproductive and sexual health among FSWs in Tijuana, Mexico. PMID- 25458419 TI - Engineering the PRRS virus genome: updates and perspectives. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is endemic in most pig producing countries worldwide and causes enormous economic losses to the pork industry. Infectious clones for PRRSV have been constructed, and so far at least 14 different infectious clones are available representing both genotypes I and II. Two strategies have been taken for progeny reconstitution: RNA transfection and DNA transfection. Mutations, insertions, deletions, and replacements of the viral genome have been employed to study the structure function relationship, foreign gene expression, functional complementation, and virulence determinants. Essential regions and non-essential regions for viral replication have been identified in both the coding regions and non-encoding regions. Foreign sequences have successfully been inserted into the nsp2 and N regions and in the space between ORF1b and ORF2a. Chimeras between member viruses in the family Arteriviridae have also been constructed and utilized to study cell tropism and functional complementation. This review discusses the advances and utilization of PRRSV reverse genetics and its potential for future research. PMID- 25458418 TI - Cholesterol and breast cancer pathophysiology. AB - Cholesterol is a risk factor for breast cancer although the mechanisms by which this occurs are not well understood. One hypothesis is that dyslipidemia results in increased cholesterol content in cell membranes, thus impacting upon membrane fluidity and subsequent signaling. In addition, studies demonstrate that the metabolite, 27-hydroxycholesterol (27HC), can function as an estrogen, increasing the proliferation of estrogen receptor (ER)-positive breast cancer cells. This was unexpected because 27HC and other oxysterols activate the liver X receptors (LXR), resulting in a reduction of intracellular cholesterol. Resolution of this paradox will require dissection of the molecular mechanisms by which ER and LXR converge in breast cancer cells. Regardless, the observation that 27HC influences breast cancer provides a rationale for strategies that target cholesterol metabolism. PMID- 25458420 TI - Study of the virulence of serotypes 4 and 9 of African horse sickness virus in IFNAR(-/-), Balb/C and 129 Sv/Ev mice. AB - African horse sickness virus (AHSV) is a double-stranded RNA virus which belongs to the family Reoviridae, genus Orbivirus. Recent studies have focused on the interferon-alpha/beta receptor knock-out mice (IFNAR(-/-)) as a small animal laboratory for the development of AHSV vaccines. The aim of this work was to study in vivo the virulence of two strains of AHSV and to compare the outcome of the infection of three mouse strains. To address this, AHSV serotypes 4 (AHSV-4) and 9 (AHSV-9) were inoculated subcutaneously (SC) and intranasally (IN) in two immunocompetent mouse strains (Balb/C and 129 Sv/Ev (129 WT)) as well as IFNAR(-/ ) mice (on 129 Sv/Ev genetic background). In IFNAR(-/-) mice, fatality up to 50% was measured and significantly more clinical signs were observed in comparison with SC inoculated immunocompetent mice. The observed clinical signs were significantly more severe after AHSV-4 infection, in particular in immunocompetent mice inoculated by IN route. Considering RNAemia, significantly higher viral loads were measured following AHSV-4 infection. In the organs of 129 WT inoculated by IN route, significantly higher viral loads were detected after AHSV-4 infection. Together the results support a higher virulence for AHSV-4 compared to AHSV-9 and a higher clinical impact following infections in IN inoculated mice, at least in the investigated strains. The study also brought indirect evidences for type I IFN involvement in the control of AHSV infection. PMID- 25458421 TI - Characterization of plasmids encoding CTX-M beta-lactamase and their addiction systems in Escherichia coli isolates from animals. AB - This study was focused on characterization of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolates from chickens and CTX-M associated plasmid addiction systems (PASs) in E. coli from animals using molecular methods. In total, E. coli from nine (9.0%) of the 100 chicken samples examined produced CTX-M type ESBL namely CTX-M-14 (n=4), CTX-M-15 (n=4), and CTX-M-1 (n=1). All of them harbored an additional blaTEM-1 gene. Transfer of blaCTX-M gene was observed in eight out of the nine blaCTX-M-positive isolates by conjugation. Plasmid profiling of blaCTX-M-positive transconjugants revealed a high-molecular weight (95-165 kb) plasmid. Pulsed-field gel electrophoresis showed that most CTX-M producing chicken isolates were genetically diverse. Furthermore, investigation of 92 conjugation-positive E. coli strains carrying blaCTX-M genes from pigs (n=76), chickens (n=8), and dogs (n=8) identified 230 PASs in the parental strains and 118 in their transconjugants. Among them, hok-sok, pemKI, and pndAC were the most frequently represented PASs in both the parental strains and the transconjugants. Moreover, the hok-sok and pemKI systems were strongly associated to IncF plasmids and the pndAC system to IncI1-Igamma plasmids. Our results suggest that the rapid spread of CTX-M genes in E. coli isolates among the animals could be attributed to the presence of multiple PASs in the CTX-M plasmids. To our knowledge, this is the first report of characterization of CTX-M associated PASs in E. coli isolates from pigs, chickens, and dogs. In addition, CTX-M-1 was detected for the first time in Korea. PMID- 25458422 TI - Prevalence of Clostridium perfringens, Clostridium perfringens enterotoxin and dysbiosis in fecal samples of dogs with diarrhea. AB - Clostridium perfringens has been suspected as an enteropathogen in dogs. However, its exact role in gastrointestinal (GI) disorders in dogs remains unknown. Recent studies suggest the importance of an altered intestinal microbiota in the activation of virulence factors of enteropathogens. The aim of this study was to evaluate the relationship between diarrhea, dysbiosis, and the presence of C. perfringens and its enterotoxin (CPE). Fecal samples were collected prospectively from 95 healthy control dogs and 104 dogs with GI disease and assessed for bacterial abundances and the presence of CPE using quantitative PCR and ELISA, respectively. C. perfringens was detected in all dogs. Potentially enterotoxigenic C. perfringens were detected in 33.7% (32/95) of healthy control dogs and 48.1% (50/104) diseased dogs, respectively. CPE was detected by ELISA in 1.0% (1/95) of control dogs and 16.3% (17/104) of diseased dogs. Abundances of Fusobacteria, Ruminococcaceae, Blautia, and Faecalibacterium were significantly decreased in diseased dogs, while abundances of Bifidobacterium, Lactobacillus, and Escherichia coli were significantly increased compared to control dogs. The microbial dysbiosis was independent of the presence of the enterotoxigenic C. perfringens or CPE. In conclusion, the presence of CPE as well as fecal dysbiosis was associated with GI disease. However, the presence of C. perfringens was not indicative of GI disease in all cases of diarrhea, and the observed increased abundance of enterotoxigenic C. perfringens may be part of intestinal dysbiosis occurring in GI disease. The significance of an intestinal dysbiosis in dogs with GI disease deserves further attention. PMID- 25458423 TI - Autonomic responses to exercise: group III/IV muscle afferents and fatigue. AB - Group III and IV muscle afferents originating in exercising limb muscle play a significant role in the development of fatigue during exercise in humans. Feedback from these sensory neurons to the central nervous system (CNS) reflexively increases ventilation and central (cardiac output) and peripheral (limb blood flow) hemodynamic responses during exercise and thereby assures adequate muscle blood flow and O2 delivery. This response depicts a key factor in minimizing the rate of development of peripheral fatigue and in optimizing aerobic exercise capacity. On the other hand, the central projection of group III/IV muscle afferents impairs performance and limits the exercising human via its diminishing effect on the output from spinal motoneurons which decreases voluntary muscle activation (i.e. facilitates central fatigue). Accumulating evidence from recent animal studies suggests the existence of two subtypes of group III/IV muscle afferents. While one subtype only responds to physiological and innocuous levels of endogenous intramuscular metabolites (lactate, ATP, protons) associated with 'normal', predominantly aerobic exercise, the other subtype only responds to higher and concurrently noxious levels of metabolites present in muscle during ischemic contractions or following, for example, hypertonic saline infusions. This review discusses the mechanisms through which group III/IV muscle afferent feedback mediates both central and peripheral fatigue in exercising humans. We also briefly summarize the accumulating evidence from recent animal and human studies documenting the existence of two subtypes of group III/IV muscle afferents and the relevance of this discovery to the interpretation of previous work and the design of future studies. PMID- 25458425 TI - Sympathetic neural adaptations to exercise training in humans. AB - Physiological adaptations to exercise training are well recognized and contribute importantly to health and fitness. Cardiovascular diseases, such as hypertension and heart failure, are often associated with elevated activity of the sympathetic nervous system. This review aims to provide comprehensive overview on the role of exercise training on muscle sympathetic nerve activity (MSNA) regulation in humans, with a focus on recent advances in at-risk populations. Collectively, these studies converge to demonstrate that aerobic exercise training reduces resting MSNA in populations at heightened cardiovascular risk, but do not appear to alter resting MSNA in healthy adults. We provide directions for future research which might address gaps in our knowledge regarding sympathoneural adaptations to exercise training. PMID- 25458424 TI - Functional sympatholysis in hypertension. AB - Sympathetic vasoconstriction is normally attenuated in exercising muscle by local changes in muscle metabolites and other substances that reduce vascular responsiveness to alpha-adrenergic receptor activation. Termed functional sympatholysis, this protective mechanism is thought to optimize muscle blood flow distribution to match perfusion with metabolic demand. Emerging evidence from both animal and human studies indicate that functional sympatholysis is impaired in hypertension and may constitute an important underlying cause of skeletal muscle malperfusion during exercise in this common cardiovascular condition. Findings from studies of animal models of hypertension and patients with essential hypertension will be integrated in this review to provide insight into the underlying mechanisms responsible for inappropriate sympathetic vasoconstriction in exercising muscle and the treatment options that may restore functional sympatholysis and improve muscle perfusion during exercise. PMID- 25458426 TI - Autonomic responses to exercise: cortical and subcortical responses during post exercise ischaemia and muscle pain. AB - Sustained isometric contraction of skeletal muscle causes an increase in blood pressure, due to an increase in cardiac output and an increase in total peripheral resistance-brought about by an increase in sympathetically-mediated vasoconstriction. Both central command and reflex inputs from metaboreceptors in the contracting muscles have been shown to contribute to this sympathetically mediated increase in blood pressure. Occluding the blood supply and trapping the metabolites in the contracted muscle (post-exercise ischaemia) has shown that, while heart rate returns to baseline following exercise, the increase in MSNA and blood pressure persists in the absence of central command-sustained by peripheral inputs. Post-exercise ischaemia activates group III and IV muscle afferents, which are also activated during noxious stimulation. Indeed, post-exercise ischaemia is painful, so what is the role of pain in the increase in blood pressure? Intramuscular injection of hypertonic saline causes a deep dull ache, not unlike that produced by post-exercise ischaemia, and we have shown that this can cause a sustained increase in MSNA and blood pressure. We have used functional Magnetic Resonance Imaging (fMRI) of the brain to identify the cortical and subcortical sites involved in the sensory processing of muscle pain, and in the generation of the autonomic responses to muscle pain, produced either by post-exercise ischaemia or intramuscular injection of hypertonic saline. During static hand-grip exercise there were parallel increases in signal intensity in the contralateral primary motor cortex, deep cerebellar nuclei and cerebellar cortex that ceased at the end of the exercise, reflecting the start and end of central command. Progressive increases during the contraction phase occurred in the contralateral insula, as well as the contralateral primary somatosensory cortex, and continued during the period of post-exercise ischaemia. Decreases in signal intensity occurred in the perigenual anterior cingulate cortex during the contraction phase; these too were sustained during post exercise ischaemia. That similar changes occurred with intramuscular injection of hypertonic saline suggests that much of the cortical and subcortical changes seen during post-exercise ischaemia reflect the sensory and affective attributes of the muscle pain, rather than in furnishing the cardiovascular responses per se. PMID- 25458428 TI - Autonomic responses to exercise: where is central command? AB - A central command is thought to involve a signal arising in a central area of the brain eliciting a parallel activation of the autonomic nervous system and skeletal muscle contraction during exercise. Although much of the neural circuitry involved in autonomic control has been identified, defining the specific higher brain region(s) serving in a central command capacity has proven more challenging. Investigators have been faced with redundancies in regulatory systems, feedback mechanisms and the complexities ofhuman neural connectivity. Several studies have attempted to address these issues and provide more definitive neuroanatomical information. However, none have clearly answered the question, "where is central command?" PMID- 25458429 TI - Autonomic responses to exercise: deconditioning/inactivity. AB - Experimental models of physical inactivity associated with a sedentary lifestyle or extreme forms of inactivity with bed rest or spaceflight affect the balance between parasympathetic and sympathetic nervous system regulation of the cardiovascular system. Deconditioning effects are rapidly seen in the regulation of heart rate to compensate for physical modifications in blood volume and cardiac function. Reflex regulation of cardiovascular control during exercise by metaboreflex and baroreflex is altered by bed rest and spaceflight. These models of extreme inactivity provide a reference to guide physical activity requirements for optimal cardiovascular health. PMID- 25458427 TI - Central mechanisms for exercise training-induced reduction in sympatho-excitation in chronic heart failure. AB - The control of sympathetic outflow in the chronic heart failure (CHF) state is markedly abnormal. Patients with heart failure present with increased plasma norepinephrine and increased sympathetic nerve activity. The mechanism for this sympatho-excitation is multiple and varied. Both depression in negative feedback sensory control mechanisms and augmentation of excitatory reflexes contribute to this sympatho-excitation. These include the arterial baroreflex, cardiac reflexes, arterial chemoreflexes and cardiac sympathetic afferent reflexes. In addition, abnormalities in central signaling in autonomic pathways have been implicated in the sympatho-excitatory process in CHF. These mechanisms include increases in central Angiotensin II and the Type 1 receptor, increased in reactive oxygen stress, upregulation in glutamate signaling and NR1 (N-methyl-D aspartate subtype 1) receptors and others. Exercise training in the CHF state has been shown to reduce sympathetic outflow and result in increased survival and reduced cardiac events. Exercise training has been shown to reduce central Angiotensin II signaling including the Type 1 receptor and reduce oxidative stress by lowering the expression of many of the subunits of NADPH oxidase. In addition, there are profound effects on the central generation of nitric oxide and nitric oxide synthase in sympatho-regulatory areas of the brain. Recent studies have pointed to the balance between Angiotensin Converting Enzyme (ACE) and ACE2, translating into Angiotensin II and Angiotensin 1-7 as important regulators of sympathetic outflow. These enzymes appear to be normalized following exercise training in CHF. Understanding the precise molecular mechanisms by which exercise training is sympatho-inhibitory will uncover new targets for therapy. PMID- 25458430 TI - Abnormal neurocirculatory control during exercise in humans with chronic renal failure. AB - Abnormal neurocirculatory control during exercise is one important mechanism leading to exercise intolerance in patients with both end-stage renal disease (ESRD) and earlier stages of chronic kidney disease (CKD). This review will provide an overview of mechanisms underlying abnormal neurocirculatory and hemodynamic responses to exercise in patients with kidney disease. Recent studies have shown that ESRD and CKD patients have an exaggerated increase in blood pressure (BP) during both isometric and rhythmic exercise. Subsequent studies examining the role of the exercise pressor reflex in the augmented pressor response revealed that muscle sympathetic nerve activity (MSNA) was not augmented during exercise in these patients, and metaboreflex-mediated increases in MSNA were blunted, while mechanoreflex-mediated increases were preserved under basal conditions. However, normalizing the augmented BP response during exercise via infusion of nitroprusside (NTP), and thereby equalizing baroreflex-mediated suppression of MSNA, an important modulator of the final hemodynamic response to exercise, revealed that CKD patients had an exaggerated increase in MSNA during isometric and rhythmic exercise. In addition, mechanoreflex-mediated control was augmented, and metaboreceptor blunting was no longer apparent in CKD patients with baroreflex normalization. Factors leading to mechanoreceptor sensitization, and other mechanisms underlying the exaggerated exercise pressor response, such as impaired functional sympatholysis, should be investigated in future studies. PMID- 25458431 TI - The exercise pressor reflex and peripheral artery disease. AB - The exercise pressor reflex contributes to increases in cardiovascular and ventilatory function during exercise. These reflexive increases are caused by both mechanical stimulation and metabolic stimulation of group III and IV afferents with endings in contracting skeletal muscle. Patients with peripheral artery disease (PAD) have an augmented exercise pressor reflex. Recently, an animal model of PAD was established which allows further investigation of possible mechanisms involved in this augmented reflex. Earlier studies have identified ASIC3 channels, bradykinin receptors, P2X receptors, endoperoxide receptors, and thromboxane receptors as playing a role in evoking the exercise pressor reflex in healthy rats. This review focuses on recent studies using a rat model of PAD in order to determine possible mechanisms contributing to the exaggerated exercise pressor reflex seen in patients with this disease. PMID- 25458433 TI - Forebrain organization for autonomic cardiovascular control. AB - This brief review discusses the current state of knowledge regarding the cortical circuitry associated with autonomic cardiovascular responses to volitional exercise in conscious humans. Studies to date have emphasized the autonomic nervous system adjustments that occur through top-down central command features as well as bottom-up signals arising from skeletal muscle. While in its infancy, the pattern of cortical circuitry associated with exercise seem to depend on the nature of the exercise but with common patterns arising in the insula cortex, dorsal anterior cingulate cortex, medial prefrontal cortex, and hippocampus. PMID- 25458432 TI - Autonomic dysfunction in multiple sclerosis: implications for exercise. AB - Multiple sclerosis (MS), a progressive neurological disease, can result in autonomic dysfunction. Impairments in the autonomic control of cardiovascular and thermoregulatory function during exercise have been observed in MS. Attenuated elevations in blood pressure during exercise in MS patients can negatively impact blood flow to skeletal muscle. Diminished sweating during exercise may impair heat dissipation likely limiting the exercise intensity that can be performed before detrimental core temperatures are reached. Further understanding the physiologic mechanisms of autonomic dysfunction during exercise in MS may lead to the development of novel therapeutic strategies targeted at improving quality of life in individuals with this disease. PMID- 25458434 TI - Acute effects of arterial baroreflex on sympathetic nerve activity and plasma norepinephrine concentration. AB - Arterial pressure (AP) elevates as a logarithmic function of exogenously administered dose of norepinephrine (NE). In contrast, AP is nearly linearly correlated with efferent sympathetic nerve activity (SNA) during acute baroreflex intervention. The present study aimed at quantifying the relationship between SNA and plasma NE concentration during acute baroreflex intervention. Carotid sinus regions were isolated from systemic circulation in five Wistar Kyoto rats, and carotid sinus pressure was changed among 60, 100, 120, 140, and 180 mm Hg every 2 min. Arterial blood (0.2 ml) was obtained at each pressure level for plasma NE measurement. Maximum AP and minimum AP were 153.34 +/- 6.28 and 67.31 +/- 4.92 mm Hg, respectively, in response to pressure perturbation. Plasma NE correlated linearly with SNA for individual animal data (slope: 0.957 +/- 0.090 pg . ml(-1) . %(-1), intercept: 46.57 +/- 7.22 pg/ml, r(2): ranged from 0.923 to 0.992) and also for group averaged data (NE = 0.956 * SNA + 47.97, r(2 )= 0.982). Blockade of neuronal NE uptake by intravenous desipramine (1 mg/kg) administration increased the slope (2.966 +/- 0.686 pg . ml(-1) . %(-1), P < 0.05) and the intercept (168.73 +/- 28.53 pg/ml, P < 0.01) of the plasma NE-SNA relationship. These results indicate that the relationship between SNA and plasma NE concentration was nearly linear within the normal physiological range of acute baroreflex control of AP. While plasma NE concentration can reflect changes in SNA, it may also overestimate the sympathetic outflow from the central nervous system when neuronal NE uptake is impaired systemically. PMID- 25458436 TI - Variability of Origin of Splanchnic and Renal Vessels From the Thoracoabdominal Aorta. AB - OBJECTIVE: To analyze the variability of origin of the celiac trunk (CT), the superior mesenteric artery (SMA), the right renal artery (RRA), and the left renal artery (LRA) in terms of mutual distances, angle from the sagittal aortic axis (clock position), and ostial diameters on computed tomography angiographies (CTAs) in three groups of patients. METHODS: One hundred and fifty CTAs of 50 patients with a non-dilated thoracoabdominal aorta (group A), 50 with thoracoabdominal aneurysm (B), and 50 with infrarenal aneurysm (C) were reviewed. The measurements performed on CTAs, as well as the patients' age, sex, and body surface area, were analyzed. p values <.05 were considered statistically significant. RESULTS: The clock position of the CT and the SMA, the diameters of all vessels, and the distance of the CTeSMA followed a Gaussian distribution. In contrast, the clock position of the renal vessels did not follow a normal distribution, and nor did the distances of the SMA-RRA, SMA-LRA, RRA-LRA or the distances between the renal arteries and the aortic bifurcation. The same values did not differ significantly among the three groups, with the exception of the distances between the renal arteries and the aortic bifurcation, significantly greater in group C. The clock position of the LRA and the distances of the SMA LRA, SMA-RRA, RRA-LRA and between both renal arteries and the aortic bifurcation showed a significant correlation with the increase of aortic diameter. CONCLUSION: The anatomic variability of the origin of both the CT and the SMA in terms of clock position and mutual distances followed a Gaussian distribution, regardless of group. The same applies to the ostial diameters of renal and visceral vessels. In contrast, the origin of the renal vessels had a statistically significant heterogeneity that seemed to be correlated with the increase of aortic diameter in the mesenteric and renal aortic region. PMID- 25458435 TI - Risk factors for proximal neck complications after endovascular aneurysm repair using the endurant stentgraft. AB - OBJECTIVE: To assess the incidence and risk factors for proximal aneurysm neck related complications with a late generation device for endovascular abdominal aneurysm repair (EVAR). METHODS: Data were retrieved from a prospective registry (Endurant Stent Graft Natural Selection Global Postmarket Registry) involving 79 institutions worldwide. The risk factors tested were age, gender, surgical risk profile, proximal neck length (<10 mm), diameter (>30 mm), supra- and infrarenal angulation (>60 degrees and 75 degrees ), mural thrombus/calcification (>50%) and taper (>10%), and AAA diameter (>65 mm). Two neck related composite endpoints were used, for intra-operative (type-1a endoleak, conversion, deployment/retrieval complication or unintentional renal coverage) and post operative (type-1a endoleak or migration) adverse events. Independent risk factors were identified using multivariable backwards modeling. RESULTS: The study included 1263 patients (mean age 73, 10.3% female) from March 2009 to May 2011. Twenty three (1.8%) intra-operative adverse events occurred. Neck length <10 mm (OR 4.9, 95% CI 1.1-22.6) and neck thrombus/calcification >50% (OR 4.8, 95% CI 1.7-13.5) were risk factors for intra-operative events. The planned 1 year follow up visit was reached for the entire cohort, and the 2 year visit for 431 patients. During this time, 99 (7.8%) events occurred. Female gender (HR 1.9, 95% CI 1.1-3.2), aneurysm diameter >65 mm (HR 2.8, 95% CI 1.9-4.2), and neck length <10 mm (HR 2.8, 95% CI 1.1-6.9) were significant post-operative risk factors. Neck angulation, neck taper, large diameter neck, and presence of thrombus/calcification were not predictors of adverse outcome in this study. CONCLUSION: These results support the adequacy of this device in the face of adverse neck anatomy, and confirm neck length as the most relevant anatomical limitation for EVAR. Additionally, the study confirms the decline in early to mid term intervention rates with a newer generation device in a large patient sample. Lastly, it suggests that neck related risk factors affect outcome and impact on prognosis in varying degrees. PMID- 25458437 TI - Re: 'Type II Endoleak: Conservative Management Is a Safe Strategy'. PMID- 25458438 TI - Re: 'Type II Endoleak: Conservative Management Is a Safe Strategy'. PMID- 25458439 TI - Open Dislocation of the High Ankle Joint After Fibular Graft Harvesting. AB - The free microvascular fibula and soft tissue transfer has become a widely used method for reconstruction of different regions. Donor site morbidity for free fibula microvascular flaps has generally been reported to be low, or at least acceptable. We describe the case of a patient who underwent vascularized free fibula graft harvest for mandibular reconstruction. After 21 months, he had sustained an open dislocation of the left high ankle joint during recreational sports activity. We did not found such case in the published data. PMID- 25458440 TI - Osteochondroma of the Talar Neck: A Case Report and Literature Review. AB - Osteochondroma occurs most frequently in the long bones such as the proximal humerus, tibia, and distal femur. It is rare for it to originate in the talar neck. In the present case report, we describe a case of osteochondroma arising from the talar neck. Furthermore, a review of the published studies of talar osteochondroma was performed to obtain a better understanding of the symptoms, diagnosis, and treatment of this unusual entity. PMID- 25458441 TI - A Clinical Evaluation of the Pirani and Dimeglio Idiopathic Clubfoot Classifications. AB - The clubfoot classifications described by Pirani and by Dimeglio are in widespread use today in foot and ankle surgical practice and are used to differentiate between lesions and compare treatment results. The aim of the present study was to determine whether in an independent center, one or both classification systems can be implemented practically and in a reproducible manner. From January 2004 to January 2014, we conducted a prospective study concerning the classification systems for clubfoot. The study group included 280 children (411 feet). The mean Dimeglio score noted by the 2 examiners was 10.3 +/ 0.69 and 10.6 +/- 0.81 points for the 411 feet, respectively. The mean difference in the Dimeglio scoring system was 1.11 +/- 0.43 points (95% confidence interval 1.5 points). The Pearson correlation coefficient was 0.85. The corresponding mean Pirani scores were 5.1 +/- 0.23 and 5.3 +/- 0.17 points for the 411 feet. The mean difference in the Pirani score was 0.65 points (95% confidence interval 0.45 points). The Pearson correlation coefficient was 0.89. The good correlation coefficient for the Dimeglio and Pirani systems recommends their simultaneous use in clubfoot examinations, because the aspects under investigation (reducibility and foot aspect) are both different and complementary. PMID- 25458442 TI - Unconventional, chemically stable, and soluble two-dimensional angular polycyclic aromatic hydrocarbons: from molecular design to device applications. AB - Polycyclic aromatic hydrocarbons (PAHs), consisting of laterally fused benzene rings, are among the most widely studied small-molecule organic semiconductors, with potential applications in organic field-effect transistors (OFETs) and organic photovoltaics (OPVs). Linear acenes, including tetracene, pentacene, and their derivatives, have received particular attention due to the synthetic flexibility in tuning their chemical structure and properties and to their high device performance. Unfortunately, longer acenes, which could exhibit even better performance, are susceptible to oxidation, photodegradation, and, in solar cells which contain fullerenes, Diels-Alder reactions. This Account highlights recent advances in the molecular design of two-dimensional (2-D) PAHs that combine device performance with environmental stability. New synthetic techniques have been developed to create stable PAHs that extend conjugation in two dimensions. The stability of these novel compounds is consistent with Clar's sextet rule as the 2-D PAHs have greater numbers of sextets in their ground-state configuration than their linear analogues. The ionization potentials (IPs) of nonlinear acenes decrease more slowly with annellation in comparison to their linear counterparts. As a result, 2-D bistetracene derivatives that are composed of eight fused benzene rings are measured to be about 200 times more stable in chlorinated organic solvents than pentacene derivatives with only five fused rings. Single crystals of the bistetracene derivatives have hole mobilities, measured in OFET configuration, up to 6.1 cm(2) V(-1) s(-1), with remarkable Ion/Ioff ratios of 10(7). The density functional theory (DFT) calculations can provide insight into the electronic structures at both molecular and material levels and to evaluate the main charge-transport parameters. The 2-D acenes with large aspect ratios and appropriate substituents have the potential to provide favorable interstack electronic interactions, and correspondingly high carrier mobilities. In stark contrast to the 1-D acenes that form mono- and bis-adducts with fullerenes, 2-D PAHs show less reactivity with fullerenes. The geometry of 2-D PAHs plays a crucial role in determining both the barrier and the adduct stability. The reactivity and stability of the 2-D PAHs with regard to Diels-Alder reactions at different reactive sites were explained via DFT calculations of the reaction kinetics and of thermodynamics of reactions and simple Huckel molecular orbital considerations. Also, because of their increased stability in the presence of fullerenes, these compounds have been successfully used in OPVs. The small molecule semiconductors highlighted in this Account exhibit good charge-transport properties, comparable to those of traditional linear acenes, while being much more environmentally stable. These features have made these 2-D PAHs excellent molecules for fundamental research and device applications. PMID- 25458443 TI - Is education all that's needed to reduce inappropriate drugs in long-term care? PMID- 25458444 TI - Antibiotic prescribing in Dutch nursing homes: how appropriate is it? AB - OBJECTIVE: To investigate the appropriateness of decisions to prescribe or withhold antibiotics for nursing home (NH) residents with infections of the urinary tract (UTI), respiratory tract (RTI), and skin (SI). DESIGN: Prospective study. SETTING: Ten NHs in the central-west region of the Netherlands. PARTICIPANTS: Physicians providing medical care to NH residents. MEASUREMENTS: Physicians completed a registration form for any suspected infection over an 8 month period, including patient characteristics, signs and symptoms, and treatment decisions. An algorithm, developed by an expert panel and based on national and international guidelines, was used to evaluate treatment decisions for appropriateness of initiating or withholding antibiotics. RESULTS: Appropriateness of 598 treatment decisions was assessed. Overall, 76% were appropriate, with cases that were prescribed antibiotics judged less frequently "appropriate" (74%) compared with cases in which antibiotics were withheld (90%) (P = .003). Decisions around UTI were least often appropriate (68%, compared with 87% for RTI and 94% for SI [P < .001]). The most common situations in which antibiotic prescribing was considered inappropriate were those indicative of asymptomatic bacteriuria or viral RTI. CONCLUSION: Although the rate of appropriate antibiotic prescribing in Dutch NHs is relatively high compared with previous studies in other countries, our results suggest that antibiotic consumption can be reduced by improving appropriateness of treatment decisions, especially for UTI. Given the current antibiotic resistance developments in long term care facilities, interventions reducing antibiotic use for asymptomatic bacteriuria and viral RTI are warranted. PMID- 25458445 TI - Incidence and predictors of sarcopenia onset in community-dwelling elderly Japanese women: 4-year follow-up study. AB - OBJECTIVES: Several studies have explored the prevalence and risk factors of sarcopenia, but they have been based on cross-sectional data. The objective of this study was to determine the incidence and predictors of the onset of sarcopenia over 4 years in community-dwelling elderly women. DESIGN: Four-year longitudinal follow-up study. SETTING: Urban community in Tokyo, Japan. PARTICIPANTS: A total of 538 nonsarcopenic women older than 75 years. MEASUREMENTS: Body composition was determined by bioelectrical impedance analysis. Functional fitness measurements, including grip strength, usual walking speed, timed up and go (TUG), and interview surveys were conducted at baseline and 4-year follow-up. Blood samples were obtained to analyze serum albumin and hemoglobin A1c, and kidney function was analyzed using serum creatinine and cystatin C. Sarcopenia was defined based on the criteria suggested by the European Working Group on Sarcopenia in Older People, and the development of all stages, that is, presarcopenia, sarcopenia, and severe sarcopenia as well as the components of sarcopenia skeletal muscle index (SMI), grip strength, and walking speed, were analyzed. RESULTS: The incidence of total sarcopenia was 39.6% (presarcopenia 23.8%, sarcopenia 11.2%, severe sarcopenia 4.6%). Older age was significantly predictive of the development of presarcopenia and severe sarcopenia. Body mass index (BMI) lower than 21.0 kg/m(2) was significantly predictive of the development of all stages of sarcopenia, as well as declines in SMI, grip strength, and walking speed. Slow TUG was a predictor of the development of presarcopenia and severe sarcopenia. Increased calf circumference showed protective effects from the development of all stages of sarcopenia. Greater albumin levels also showed lower risk of declines in SMI, walking speed, and development of presarcopenia. Cystatin C was positively associated with the development of severe sarcopenia (odds ratio 1.83, 95% confidence interval 1.08 3.12). Heart disease and hyperlipidemia history were associated with presarcopenia and sarcopenia, respectively. CONCLUSION: Age, BMI, calf circumference, and TUG were consistent predictors of the various stages and components of sarcopenia. The data also suggest that cystatin C was associated with higher odds of incident severe sarcopenia, and further study into kidney function and onset of sarcopenia in large populations is needed. PMID- 25458446 TI - Ultrasound and electrical stimulator-guided obturator nerve block with phenol in the treatment of hip adductor spasticity in long-term care patients: a randomized, triple blind, placebo controlled study. AB - OBJECTIVE: To evaluate the effectiveness of ultrasound-guided phenol nerve block in the treatment of severe hip adductor spasticity in long-term care patients. METHODS: Double-blind placebo-controlled trial with a 9-month follow-up period. SETTING: A 250-bed long-term care hospital and the infirmary units of 5 regional hospitals. PARTICIPANTS: Twenty-six long-term care patients with bilateral severe chronic hip adductor spasticity affecting perineal hygiene and nursing care. INTERVENTIONS: Patients were randomized to 2 groups that received ultrasound and electrical stimulator guided obturator nerve block using either 5% phenol in aqueous solution or saline. MAIN OUTCOME MEASURES: The primary outcome measure was the Modified Ashworth Scale, which reflected the severity of hip adductor spasticity. Secondary outcomes included Goal Attainment Scale (GAS), hygiene score, distances between the knees during fast and slow passive hip abductions; passive range of movement for hip extension and knee extension. Pain was assessed using the Pain Assessment in Advanced Dementia Scale. RESULTS: Twenty-six patients (7 males; mean age = 77, standard deviation = 14) were recruited. At week 6 post-injection, 12/16 (75%) patients in the treatment group vs 1/10 (10%) patients in the control group had at least 1-point reduction of Modified Ashworth Scale (P = .001) on both hip adductors. There was also significant improvement in the GAS, as well as the hygiene score, resting position, and distances between the knees during fast and slow passive hip abductions in the treatment group, which persisted until week 36. No significant difference in the Pain Assessment in Advanced Dementia Scale was found between the 2 groups. No serious phenol nerve block related adverse effects were reported. CONCLUSIONS: Obturator neurolysis with 5% aqueous phenol as guided by both ultrasound and electrical stimulation can safely and effectively reduce hip adductor spasticity, thus, improving hygiene scores and patient-centered outcomes measured by the GAS in affected long-term care residents. PMID- 25458447 TI - The effect of music therapy on cognitive functioning among older adults: a systematic review and meta-analysis. AB - OBJECTIVES: To conduct a systematic review and a meta-analysis of current studies to determine whether music therapy affects the cognitive function of older people. DESIGN: The databases surveyed include PsycINFO, PsycARTICLES, PubMed, MEDLINE, CINAHL, AgeLine, Cochrane Library, and the Chinese Electronic Periodical Services (CEPS) as well as the reference lists of the included studies. The Consolidated Standards of Reporting Trials (CONSORT) extension checklist for nonpharmacologic treatment was used to evaluate the literature. SETTING: Music therapy intervention offered in nursing homes, hospitals, or communities. PARTICIPANTS: A total of 234 participants from 5 studies were assessed in the meta-analysis, with a mean age per study of 71.4 to 82.0 years. MEASUREMENTS: Cognitive outcome domains were analyzed in a systematic review. The short-term effects of music therapy in Mini-Mental State Examination data for meta-analysis were compiled. A forest plot was constructed using a fixed effect model to obtain a pooled mean difference. RESULTS: Active music therapy comprising singing and other musical activities was generally determined to effect a significant improvement in the Mini-Mental State Examination according to individual retrieval studies. However, this study showed no significant improvement in the short-term effects of music therapy when all related studies in meta-analysis were combined. The pooled mean difference was 0.73 (95% confidence interval -0.07 to 1.54; Z = 1.79; P = .07) for using music therapy overall and 0.74 (95% confidence interval -0.08 to 1.56; Z = 1.76; P = .08) for using active music therapy. CONCLUSIONS: The findings of the meta-analysis indicate that the short term effects of music therapy do not improve the cognitive function of older people. Future studies that utilize a good quality methodology with a long-term design and diversified active music therapy are recommended. PMID- 25458448 TI - The Effect of Stone Composition on the Efficacy of Retrograde Intrarenal Surgery: Kidney Stones 1 - 3 cm in Diameter. AB - PURPOSE: The goal of this study was to analyze the effect of stone composition on the efficacy of retrograde intrarenal surgery (RIRS) with kidney stones of 1-3 cm, 1-2 cm, and 2-3 cm in diameter. METHODS: We undertook a retrospective analysis of 74 patients with kidney stones who underwent RIRS. The patients were divided into two groups based on stone composition: Group I (n=47) (calcium oxalate monohydrate and calcium phosphate) was the hard to fragment stone group and group II (n=27) (calcium oxalate dihydrate, magnesium ammonium phosphate, and uric acid) was the easy to fragment stone group. Forty-six patients with kidney stones 1 to 2 cm in diameter were divided into group A (n=30) (smaller than 20 mm, hard to fragment stones) and group B (n=16) (smaller than 20 mm, easy to fragment stones). Twenty-eight patients with stones 2 to 3 cm in diameter were divided into group C (n=17) (larger than 20 mm, hard to fragment stones) and group D (n=11) (larger than 20 mm, easy-to-crush stones). RESULTS: The stone clearance rates of group I and group II were 66.0% and 88.9%, respectively (P<0.05). The stone clearance rates of group A and group B were 73.3% and 100% (P<0.05). The stone clearance rates of group C and group D were 52.9% and 72.7%, respectively. CONCLUSION: Stone composition has a significant impact on the efficacy of RIRS in the management of 1 to 3 cm kidney stones. For 2-3 cm calcium oxalate dihydrate stones, uric acid stones, and magnesium ammonium phosphate stones, the outcome of RIRS treatment was relatively good, and RIRS is recommended. PMID- 25458449 TI - [Organ procurement under Maastricht 3 condition: the unknowable sets the limits in ethics]. PMID- 25458450 TI - [The new ESA guidelines for clinical practice would optimize the therapeutics of the postpartum hemorrhage by the different teams of motherhood?]. PMID- 25458451 TI - [This is just a goodbye]. PMID- 25458452 TI - [Decree of anaesthesia of 1994, day surgery and medical responsibility: necessary reflections on the inevitable conciliation between regulations and recommendations]. AB - Day surgery is often considered as a marker of the necessity of reorganizing the hospital to take care globally and so better meet the expectations of improvement of the management of patients. But the actual deployment of day surgery can also act as a real revelation of the stakes of conciliation between the regulations, which supervise professional practices and organization, and the functioning of hospitals. Between the regulations supervising hospitals and professional practices and the place of the recommendations, between the general legal framework of the medical activity and specific legal framework (decree of anesthesia of 1994) and the Evidence-Based Medicine, the pretext of the improvement of the patient flow in day surgery, recommended by several institutions (Sfar, ANAP, HAS), questions about the legal obligation of the passage of all the patients in the postanesthesia care unit (PACU). Seen under the angle of a legal action against a medical doctor, the study of the French jurisprudence reveals that every practitioner has to respect the recommendations and the Evidence-Based Medicine, and this in the standardized frame of the MD's activity and the respect for a very strict legal environment. The question of an obvious conciliation between all these measures arises today clearly. In the case of a potential conflict, the key of resolution, based only on legal standards (constitution, laws, decrees), is not enough for arbitrating. Applying that the only respect for the decree of anesthesia would be enough for exempting itself from any contentious risk does not satisfy more. There is a real difficulty defining the legal precise nature of the recommendations, so best practices as better organization, which are more and more frequently. Even if these recommendations originally had not their place in the hierarchy of the legal standards, they are brought in there today. There is a real brake in the deployment of the day surgery because the strict respect for the decree of 94 on the systematic passage in PACU can be paradoxical with a better quality of the care. Twenty years after the publication of the decree of anesthesia, it seems essential to ask at first if it's possible to fast-track discharge without any stay in the PACU and thus of the inevitable conciliation between all these measures. Secondly it's necessary of modifying this decree to impulse the deployment of the day surgery. PMID- 25458453 TI - [Law on anesthesia safety in France: 20 years after]. PMID- 25458454 TI - [Prevention of hypotension during spinal anesthesia for elective caesarean section: coloading with HAE 130/0.4 vs normal saline solution]. AB - OBJECTIVE: The aim of this study was to compare the efficacy of HES 130/0.4 coloading compared to normal saline solution for prevention of hypotension during spinal anesthesia for elective caesarean section. STUDY DESIGN: Prospective, randomized. PATIENTS AND METHODS: One hundred and twenty ASA I and II patients scheduled for elective caesarean section were recruited. Patients were randomized to receive either 500mL of HES 130/0.4 (Voluven((r))) coloading (GroupV) or 500mL of normal saline solution coloading (GroupC). Spinal anesthesia technique and ephedrine administration were standardized in both groups. The primary endpoint was the incidence of maternal hypotension during spinal anesthesia for elective caesarean section. RESULTS: Hypotension occurred in 43 patients in group C and 24 patients in group V (p=0.001). Ephedrine consumption was significantly lower in group V (P=0.005). Nausea, vomiting and headache incidence was higher in group C (p=0.006). Apgar scores and umbilical blood gazes were comparable between groups. CONCLUSION: HES 130/0.4 coload was more effective than normal saline solution to prevent hypotension following spinal anesthesia for elective cesarean section. HES 130/0.4 coload reduced the incidence, the duration of longest hypotension, the need for ephedrine and the adverse maternal effects. PMID- 25458455 TI - [Necrotizing fasciitis: results of a survey on management practices in French speaking intensive care units]. AB - OBJECTIVES: Necrotizing fasciitis (NF) are rare and severe soft tissue infections associated with a high mortality rate. In order to assess the management of NF in French-speaking intensive care units (ICUs), we conducted a survey endorsed by the French Society of Anesthesia and Intensive Care (SFAR). STUDY DESIGN: Online self-administered survey. METHODS: A link to an online survey was sent by email to 4620 anesthesiologists and/or intensivists and was available online from January to February 2014. RESULTS: One hundred and seventy-five physicians (3.8%) who worked in 135 ICUs filled out the online survey. Among respondents, 42% reported having managed up to two patients with NF during the previous year; 59% and 72% of respondents reported not having a surgical and a medical specialist consultant, respectively. A delayed access to the operating room (OR) of more than 6hours was reported in 31% of cases and access to the OR was reported not to be routinely considered as a priority in 13% of cases. Only 17% of respondents reported that time to transfer to the OR was never a cause for delayed surgery. The main causes for delayed surgery were: delayed diagnosis (45%), delayed validation of surgical intervention (37%), and difficulty of access to the OR (8%). Finally, 83% of respondents estimated that creating dedicated multidisciplinary teams for managing NFs could lead to improving outcomes. CONCLUSION: This survey illustrates the heterogeneous management of NF in French speaking ICUs and points out several logistical aspects that should be improved to reduce the time to the first surgical debridement. PMID- 25458456 TI - [Fulminant hepatitis and multiorgan failure induced by HHV-6 infection in an immunocompetent 24-year-old woman]. PMID- 25458457 TI - [Specific anaesthetic procedures for nasal and sinus surgery]. AB - In nasal and sinus surgery, the anaesthetist must share the operating field with the surgeon and take into account some patients' specific pathologies. Bleeding must be avoided by different means but the accurate gesture of the surgeon, added to the properties of the new anaesthetic drugs, may reduce the risk of this functional surgery. PMID- 25458458 TI - [Impact of a program designed to improve continuous renal replacement therapy stability]. AB - OBJECTIVES: During continuous renal replacement therapy (CRRT), circuit clotting increases nursing workload, cost of the therapy and blood loss. The aim of this study was to assess the impact of a program designed to improve CRRT stability on unexpected circuit clotting. STUDY DESIGN: Retrospective and observational study. PATIENTS AND METHODS: In January 2011, several changes have been adopted regarding CRRT management. Regional citrate anticoagulation, continuous hemodialysis using super high-flux membranes and a specific training for intensive care unit nurses were implemented. CRRT sessions before (year 2009 and 2010, "Before group") and after (year 2011 and 2012, "After group") were analyzed. The primary endpoint was the incidence of unexpected CRRT session end. RESULTS: During the study period, 401 sessions performed in 152 patients were analyzed. Sixty-three unexpected session's end (40%) occurred before and 43 (17%) after the implementation of the program (P<0.0001). Median filter life time was 33 (13-48) hours before and 55 (27-67) hours after (P<0.0001). CONCLUSION: Our program designed to improve CRRT stability reduced filter losses by reducing unexpected circuit clotting. PMID- 25458459 TI - [Acute respiratory distress syndrome complicating an acute chest syndrome: potential benefit of early combination of exchange transfusion and prone positioning]. AB - We report the case of an 8-year-old sickle cell anemia child admitted for acute respiratory failure complicating acute chest syndrome. Because of threatening respiratory failure, tracheal intubation was performed immediately after ICU admission. The patient met the criteria for ARDS with a PaO2/FiO2 ratio of 94mmHg. An exchange transfusion was performed immediately after admission. HbS fraction failed from 69 % to 30 %. Fluid resuscitation with crystalloids and continuous norepinephrine infusion was needed because of arterial hypotension. Due to persistent severe hypoxemia with PaO2/FiO2 ratio below 100, the patient was placed in prone positioning 16hours after admission, for a total duration of 14hours. A second 12-hour session of prone positioning was performed 41h after admission and PaO2/FiO2 ratio reached 300mmHg after. Treatment also included transfusion of two red-cell pack on day 1 and 2 after admission in order to maintain hemoglobin level above 8g/dL, and a daily folic acid supplementation. The control of hyperthermia was achieved by a systematic parenteral administration of paracetamol. Cefotaxime and erythromycine were continued until day 7 despite the negative results of all bacteriological samples. The outcome was favorable from day 3 and the patient met the criteria for extubation on day 5. A first attempt of extubation was performed on day 5, but re-intubation was required because of laryngeal edema. Steroids were given for 48h and the patient was successfully extubated on day 7. She was discharged from the ICU on day 8, and from the hospital on day 12. We discuss the various treatments available for the management of acute chest syndrome and their actual relevance in acute respiratory distress syndrome in the absence of strong evidence-based guidelines in pediatric ARDS. PMID- 25458461 TI - Nanoniobia modification of CdS photoanode for an efficient and stable photoelectrochemical cell. AB - Herein we report the surface modification of a CdS film by niobia nanoparticles via thioglycerol as an organic linker and thus fabricate an efficient and a stable photoanode for a photoelectrochemical (PEC) cell. We have synthesized three differenly sized (~3, ~6 ,and ~9 nm) niobia nanoparticles by a hydrothermal synthesis approach and have further investigated the particle-size-dependent PEC performance of the nanoparticle-modified CdS photoanode. Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) confirm the formation of Nb2O5 nanoparticles that are prepared via decomposition of the niobium peroxo complex during the hydrothermal reaction and reveal the presence of surface OH(-) groups over niobia nanoparticles that impart a high catalytic property to a material. The nano-Nb2O5-modified photoanode displayed a 23-fold higher power conversion efficiency compared to that of CdS. This modified structure increases the open circuit voltage (OCV) from 0.65 to 0.77 V, which is attributed to the nano-Nb2O5-induced surface passivation effect over bare CdS. Linking of nanoparticles on the CdS surface improves the photocorrosion stability of the CdS photoanode for even longer than 4 h in contrast to the tens of minutes for the base CdS surface. The uniform coverage of the CdS photoanode surface by niobia nanoparticles is thus found to be the controlling parameter for achieving a higher PEC performance and stability of the photoanode. This finding directed us to design an improved CdS photoanode for efficient and prolonged PEC hydrogen generation from a PEC cell. PMID- 25458460 TI - A novel cryptic insertion of CBFB into MYH11: importance of FISH probe design. PMID- 25458462 TI - Genotyping of Pseudomonas aeruginosa reveals high diversity, stability over time and good outcome of eradication. AB - BACKGROUND: Genotyping of Pseudomonas aeruginosa (P.a) is used for surveillance at our CF clinic. METHODS: P.a from 1999 to 2012 were analysed, using pulsed field gel electrophoresis (PFGE) and multiple-locus variable number of tandem repeats analysis (MLVA). RESULTS: Among 232 isolates from 104 patients, we identified 78 unique strains, of which 56 were isolated from individual patients. The B-clone was isolated from 13 patients and the camp transmission clone J strains from 8 patients at the start of the study. There was no indication of transmission within the clinic. PFGE and MLVA clone identification was in 91% agreement. For patients who provided more than 2 P.a isolates, similar strains were identified over time for 45/49 chronically- and for 6/16 intermittently colonized patients despite, periods of no detectable P.a after eradication therapy. CONCLUSIONS: Analyses revealed high genotypic diversity, acceptable outcome of eradication therapy and no indication of cross-infection at the CF centre. PMID- 25458463 TI - Randomized, single blind, controlled trial of inhaled glutathione vs placebo in patients with cystic fibrosis. AB - BACKGROUND: In cystic fibrosis (CF) the defective CF transmembrane conductance regulator protein may be responsible for the impaired transport of glutathione (GSH), the first line defense of the lung against oxidative stress. The aim of this single-blind, randomized, placebo-controlled trial was to evaluate the effect of inhaled GSH in patients with CF. METHODS: 54 adult and 51 pediatric patients were randomized to receive inhaled GSH or placebo twice daily for 12 months. RESULTS: Twelve month treatment with inhaled GSH did not achieve our predetermined primary outcome measure of 15% improvement in FEV1%. Only in patients with moderate lung disease, 3, 6 and 9 months therapy with GSH resulted in a statistically significant increase of FEV1 values from the baseline. Moreover GSH therapy improved 6-minute walking test in pediatric population. GSH was well tolerated by all patients. CONCLUSIONS: Inhaled GSH has slight positive effects in CF patients with moderate lung disease warranting further study. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01450267; URL: www.clinicaltrialsgov. PMID- 25458465 TI - Chronic ivacaftor treatment: getting F508del-CFTR into more trouble? PMID- 25458464 TI - The effect of short-term, high-dose oral N-acetylcysteine treatment on oxidative stress markers in cystic fibrosis patients with chronic P. aeruginosa infection - a pilot study. AB - BACKGROUND: Patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa lung infection have increased oxidative stress as a result of an imbalance between the production of reactive oxygen species caused by inflammation and their inactivation by the impaired antioxidant systems. Supplementation with anti oxidants is potentially beneficial for CF patients. METHODS: The effect of 4 weeks of oral N-acetylcysteine (NAC) treatment (2400 mg/day divided into two doses) on biochemical parameters of oxidative stress was investigated in an open label, controlled, randomized trial on 21 patients; 11 patients in the NAC group and 10 in the control group. Biochemical parameters of oxidative burden and plasma levels of antioxidants were assessed at the end of the study and compared to the baseline values in the two groups. RESULTS: A significant increase in the plasma levels of the antioxidant ascorbic acid (p=0.037) and a significant decrease in the levels of the oxidized form of ascorbic acid (dehydroascorbate) (p=0.004) compared to baseline were achieved after NAC treatment. No significant differences were observed in the control group. The parameters of oxidative burden did not change significantly compared to baseline in either of the groups. A better lung function was observed in the NAC treated group with a mean (SD) change compared to baseline of FEV1% predicted of 2.11 (4.6), while a decrease was observed in the control group (change -1.4 (4.6)), though not statistically significant. CONCLUSION: Treatment with N-acetylcysteine 1200 mg*2/day for 30 days significantly decreased the level of oxidized vitamin C and increased the level of vitamin C (primary end-points) and a not statistically significant improvement of lung function was observed in this group of patients. PMID- 25458466 TI - Structure-based constitutive model can accurately predict planar biaxial properties of aortic wall tissue. AB - Structure-based constitutive models might help in exploring mechanisms by which arterial wall histology is linked to wall mechanics. This study aims to validate a recently proposed structure-based constitutive model. Specifically, the model's ability to predict mechanical biaxial response of porcine aortic tissue with predefined collagen structure was tested. Histological slices from porcine thoracic aorta wall (n=9) were automatically processed to quantify the collagen fiber organization, and mechanical testing identified the non-linear properties of the wall samples (n=18) over a wide range of biaxial stretches. Histological and mechanical experimental data were used to identify the model parameters of a recently proposed multi-scale constitutive description for arterial layers. The model predictive capability was tested with respect to interpolation and extrapolation. Collagen in the media was predominantly aligned in circumferential direction (planar von Mises distribution with concentration parameter bM=1.03 +/- 0.23), and its coherence decreased gradually from the luminal to the abluminal tissue layers (inner media, b=1.54 +/- 0.40; outer media, b=0.72 +/- 0.20). In contrast, the collagen in the adventitia was aligned almost isotropically (bA=0.27 +/- 0.11), and no features, such as families of coherent fibers, were identified. The applied constitutive model captured the aorta biaxial properties accurately (coefficient of determination R(2)=0.95 +/- 0.03) over the entire range of biaxial deformations and with physically meaningful model parameters. Good predictive properties, well outside the parameter identification space, were observed (R(2)=0.92 +/- 0.04). Multi-scale constitutive models equipped with realistic micro-histological data can predict macroscopic non-linear aorta wall properties. Collagen largely defines already low strain properties of media, which explains the origin of wall anisotropy seen at this strain level. The structure and mechanical properties of adventitia are well designed to protect the media from axial and circumferential overloads. PMID- 25458467 TI - Multiple adjustable vascular clamp prototype: feasibility study on an experimental model of end-to-side microsurgical vascular anastomosis. AB - The aim of this study was to establish the feasibility of microsurgical end-to side vascular anastomosis with a multiclamp adjustable vascular clamp prototype in an inert experimental model. Our method consisted of performing an end-to-side microsurgical anastomosis with 10/0 suture on a 2-mm diameter segment. In group 1, the end-to-side segment was held in place by a double clamp and a single end clamp. In group 2, the segment was held in place with a single multiclamp adjustable clamp. The average time for performing the anastomosis was shorter in group 2. The average number of sutures was the same in both groups. No leak was found and permeability was always positive in both groups. Our results show that performing end-to-side anastomosis with a multiclamp adjustable vascular clamp is feasible in an inert experimental model. Feasibility in a live animal model has to be demonstrated before clinical use. PMID- 25458468 TI - Comparison of results after surgical repair of acute and chronic ulnar collateral ligament injury of the thumb. AB - This study sought to demonstrate that successful outcomes can be achieved with the new technique presented here for chronic ulnar collateral ligament (UCL) injury of the thumb metacarpophalangeal (MCP) joint, as well as with K-wire pinning for acute UCL injury. We followed 19 patients who suffered an UCL rupture (mean follow-up: 14.26+/-4.65 months) and 32 patients who presented with UCL avulsion fracture (mean follow-up: 16.81+/-7.54 months). We used a free tendon graft for UCL reconstruction in the UCL rupture group. Both ends of the graft were stabilized with bioabsorbable suture anchors, which were used as biotenodesis interference screws. Closed reduction and K-wire fixation was used in UCL avulsion fracture group. There were no statistically significant differences between operated and contralateral healthy thumb MCP joint in both groups in the grip strength, tip pinch strength, flexion, extension, ulnar deviation, and radial deviation movements at final follow-up. Grip strength, tip pinch strength, ulnar deviation and radial deviation were significantly better in the avulsion group than the rupture group. All patients regained full stability at the MCP joint in avulsion group; 16 patients regained full stability and 3 patients presented with mild laxity (less than 10 degrees laxity) in rupture group. Glickel grading scale used as a functional score was excellent for 30 patients and good for 2 patients in avulsion group; it was excellent for 17 patients and good for 2 patients in rupture group. Our study shows that closed reduction and percutaneous K-wire fixation of acute displaced large UCL avulsion fracture is a simple technique and achieves adequate stability of UCL. For UCL rupture, free tendon reconstruction with bioabsorbable suture anchors provides adequate stability and stable fixation within the tunnels. PMID- 25458469 TI - Total distal radioulnar joint prosthesis as salvage surgery in multioperated patients. AB - The purpose of this study was to report the results following implantation of a total distal radioulnar joint prosthesis in five multioperated patients with posttraumatic or Essex-Lopresti injury. The range of motion (ROM) for flexion and extension, radial deviation and ulnar deviation of the wrist, and pronation and supination of the forearm, grip strength, pain intensity through a visual analog scale (VAS), surgical complications and ability to return to work, were recorded. Subjective and objective functions were assessed using the quick DASH questionnaire and the modified Mayo wrist score, respectively. The mean postoperative follow-up was 4.3 years. Average postoperative increase in ROM was 28.8 degrees for flexion-extension; 2.2 degrees for radial and ulnar deviation, and 18 degrees for pronation-supination, reaching 85.8%, 85% and 80.8% of the contralateral hand function, respectively. Grip strength increased by 6.8kg, with recovery of 78% of the strength of the unaffected hand. VAS score decreased to a mean of 6.2 postoperatively. There were complications in two cases. All five patients showed no signs of implant loosening or movement. The quick DASH score decreased from a mean of 85 preoperatively to 38.6 postoperatively. The modified Mayo wrist score increased from a mean of 24 preoperatively to 73 at final follow up. Four patients recovered their professional and daily activities without restriction and were satisfied with the procedure; one patient with heterotopic bone formation at the distal tip of the ulnar stem did not want any further surgery and agreed to job modifications. PMID- 25458470 TI - [Rehabilitation following primary repair of flexor tendons in adults]. AB - Rehabilitation after primary repair of flexor tendons, particularly in the early phase, has changed due to more solid suture repairs. The objectives of this article are to outline the general principles surrounding this rehabilitation, set out the indications for various early mobilization techniques and describe in detail the physiotherapy protocol used by the Physical Medicine and Rehabilitation Department of the Regional Institute of Rehabilitation in collaboration with the Plastic and Reconstructive Surgery Department of the Emile Galle Surgical Center in Nancy, France. This protocol is mainly used for adult patients and carried out in four stages over a 12-week period. If there are no contraindications, the patient learns protected early active self-rehabilitation during the first four postoperative weeks. The protocol includes standardized multidisciplinary follow-up until the social and occupational rehabilitation phase to ensure the best chance of functional recovery. PMID- 25458471 TI - [Rehabilitation after secondary surgery of the flexor tendons of fingers and thumb]. AB - The repair of the finger flexor tendons can be complicated by the appearance of ruptures and peritendinous adhesions. Ruptures are often treated with tendon grafts. Peritendinous adhesions can require tenolysis. Following these two surgical procedures, there is a risk of new adhesions and rupture. Rehabilitation after this secondary surgery consists of a tailored, closely supervised protocol. Protocols used by the team at the Physical Medicine and Rehabilitation Department of the Regional Rehabilitation Institute and the team at the Plastic and Reconstructive Surgery Department of the Emile-Galle Surgical Center of Nancy (France) are described. A close collaboration between these teams of surgeons and physical therapists is essential. After tendon grafting, protected early motion helps to move the transplant immediately while still protecting it. After tenolysis, immediate (several times a day) and extended rehabilitation ensures that the mobility obtained intraoperatively is maintained. It is performed in a specialized rehabilitation center during the first three postoperative weeks. The goal is to prevent new adhesions from forming while taking into account tendon's fragility. PMID- 25458472 TI - Indirect ELISA using recombinant nonstructural protein 3D to detect foot and mouth disease virus infection associated antibodies. AB - Foot-and-mouth disease (FMD) is a highly infectious disease of transboundary importance. Routine biannual vaccination along with surveillance activities is seen as the principal to control FMD in India. Non-structural protein (NSP) based immunoassays are the test of choice for the differentiation between infected and vaccinated population. In this study, 3D protein of FMD virus was expressed in Escherichia coli and an indirect ELISA (I-ELISA) was developed to detect 3D antibodies in the infected bovines. 3D I-ELISA demonstrated comparable diagnostic sensitivity (97.6%) but lower specificity (80.8%) as compared to the in-house r3AB3 I-ELISA. However, the specificity values varied significantly for naive and vaccinated samples and were observed to be 98.42% and 76.93%, respectively. A moderate degree of concordance (88.5%) was observed between the overall results of two ELISAs. 3D I-ELISA displayed a considerably lower specificity in uninfected vaccinated samples, thereby suggesting against its application for serosurveillance in intensively vaccinated population. However by virtue of its high diagnostic sensitivity and longer duration of persistence of 3D-antibody post-infection, 3D I-ELISA could be adopted for seroepidemiological investigations in regions not practicing vaccination and could be extended to susceptible species which are generally not covered by vaccination. PMID- 25458473 TI - Correlation between ToBI test and in vivo titration for diphtheria and tetanus. AB - Alternatives to animal testing for quality control of biologicals have been a goal since 1959. Instituto Butantan has been developing such methods for quality control of biologicals for human use (vaccines and hyperimmune equine sera) for the last 13 years. In this paper we compare the modified ToBI test and the in vivo seroneutralization test to assess immunogenicity of diphtheria and tetanus vaccines and hyperimmune sera. Data from the last 10 years were statistically analyzed to compare the results for in vivo and in vitro titrations (diphtheria, n = 525 and tetanus, n = 455). The agreement between the tests depended on the serum titer range. For both diphtheria and tetanus components, the correlation and concordance coefficient was higher as the serum titer increased. Overall, the in vitro/in vivo titer ratio did not vary systematically over the range of measurements. These results indicate that although the in vitro ToBI test is not completely able to replace the in vivo serum titration, it is a useful tool to guide the tests during the production process, which can reduce the number of animals used for lot release. PMID- 25458474 TI - Purification of equine whole IgG snake antivenom by using an aqueous two phase system as a primary purification step. AB - There is a need to introduce innovations in the manufacture of snake antivenoms to increase the supply of these products worldwide. In this work, the fractionation of equine hyperimmune plasma with a new methodology that includes an aqueous two phase system (ATPS) as a primary purification step was compared with the traditional method of caprylic acid precipitation. Hyperimmune plasma from horses immunized with the venoms of three snakes from sub-Saharan Africa was used as starting material for the production of both formulations. After being adjusted to the same lethal neutralizing activity, both antivenoms were compared in terms of their immunoreactivity, neutralization of in vitro venom activities, physicochemical characteristics, and stability. Their performance in terms of yield and purity was also assessed. The neutralization profile of in vitro enzymatic activities and the immunoreactivity, analyzed by ELISA and antivenomic approaches, were very similar for both preparations. Likewise, they behaved similarly in stability studies. However, ATPS-fractionated antivenom showed improved physicochemical profile and immunochemical purity and yield, mainly owing to its lower protein content. Additionally, this methodology allowed the recovery of albumin as a byproduct. ATPS purification constitutes a promising technology for antivenom production and should be further evaluated at preclinical and clinical levels. PMID- 25458475 TI - Influence of intraocular lens implantation on anterior capsule contraction and posterior capsule opacification. AB - PURPOSE: To evaluate whether and how intraocular lens (IOL) implantation influences the development of anterior capsule contraction and posterior capsule opacification (PCO). SETTING: Department of Ophthalmology, Dokkyo Medical University, Mibu, Tochigi, Japan. DESIGN: Experimental study. METHODS: Phacoemulsification was performed in 8-week-old white rabbits. A hydrophobic acrylate IOL (12.5 mm) (YA-60BBR) was implanted in 1 eye and no IOL was implanted in the fellow eye. Slitlamp microscopy and anterior segment analysis were performed to evaluate anterior capsule contraction after the surgery. Four weeks postoperatively, sections of the eyes were made, and the thickness of the proliferated lens epithelial cell (LEC) layer at the posterior capsule was measured to assess the PCO. In addition, LECs from white rabbits were cultured in medium containing 50% aqueous humor or in medium containing 50% saline to determine the influence of the aqueous humor on LECs and to compare the degree of LEC proliferation. RESULTS: Starting 2 weeks after surgery, anterior capsule contraction progressed more significantly in the IOL group than in the group without IOLs. Four weeks postoperatively, LEC thickness at the posterior capsule was significantly less in the group without IOLs than in the IOL group. In the culture study, LEC proliferation was more inhibited in the aqueous humor group than in the saline group. CONCLUSIONS: Progression of anterior capsule contraction and PCO is less likely in aphakic eyes than in IOL-implanted eyes. The mechanism of prevention may involve aqueous humor-induced inhibition of LEC proliferation. PMID- 25458477 TI - Anomalous self-experience and childhood trauma in first-episode schizophrenia. AB - BACKGROUND: Anomalous self-experiences (ASEs) are viewed as core features of schizophrenia. Childhood trauma (CT) has been postulated as a risk factor for developing schizophrenia. AIM: The aim of this study is to investigate the relationships between CT, depression and ASEs in schizophrenia. METHOD: ASEs were assessed in 55 patients in the early treated phases of schizophrenia using the Examination of Anomalous Self-Experience (EASE) instrument. Data on CT were collected using the Childhood Trauma Questionnaire, short form (CTQ-SF). This consists of 5 subscales: physical abuse, sexual abuse, emotional abuse, emotional neglect, and physical neglect. Assessment of depression was based on the Calgary Depression Scale for Schizophrenia (CDSS). RESULTS: We found significant associations between EASE total score and CTQ total score and between EASE total score and emotional neglect subscore in women, but not men. We also found significant associations between CDSS total score and CTQ total score and between CDSS total score and emotional abuse, emotional neglect, and physical neglect subscores in women, but not men. In men we did not find any significant associations between EASE total score, CDSS total score and any CTQ scores. CONCLUSION: CT was significantly associated with higher levels of ASEs in women in the early treated phases of schizophrenia, but not in men. This again associated with an increase in depressive symptoms. PMID- 25458478 TI - Development of a structure-validated Sexual Dream Experience Questionnaire (SDEQ) in Chinese university students. AB - BACKGROUND: Sexual dreams reflect the waking-day life, social problems and ethical concerns. The related experience includes different people and settings, and brings various feelings, but there is no systematic measure available to date. METHODS: We have developed a statement-matrix measuring the sexual dream experience and trialed it in a sample of 390 young Chinese university students who had a life-long sexual dream. RESULTS: After both exploratory and confirmatory factor analyses, we have established a satisfactory model of four factor (32 items). Together with an item measuring the sexual dream frequency, we developed a Sexual Dream Experience Questionnaire (SDEQ) based on the 32 items, and subsequently named four factors (scales) as joyfulness, aversion, familiarity and bizarreness. No gender differences were found on the four scale scores, and no correlations were found between the four scales and the sexual dream frequency or the sexual experience in real life. CONCLUSION: The SDEQ might help to characterize the sexual dreams in the healthy people and psychiatric patients. PMID- 25458479 TI - Psychometric properties of the French translation of the Behavioral Activation for Depression Scale-Short Form (BADS-SF) in non-clinical adults. AB - A decrease in the level of engagement in activities ("behavioral activation") is usually observed in major depressive disorder. Because behavioral treatments of depression aim to counteract that mechanism, assessing changes in behavioral activation during treatment is of great interest. Therefore, Manos et al. (2011) developed a scale that assesses these changes, which was called the Behavioral Activation for Depression Scale-Short Form (BADS-SF). The aim of this study is to present a French version of this scale and to discuss its psychometric properties. The BADS-SF was translated into French, and 504 non-clinical adults completed an online survey that was composed of that scale and convergent measures. Exploratory and confirmatory factor analyses were performed in two independent samples, and a two-factor solution was recommended, which references two functions of the engagement in activities (i.e., "activation" and "avoidance"). The results showed high levels of internal consistency and satisfying scores in terms of skewness and kurtosis. Moreover, relationships with measures of depression and behavioral systems indicated a good convergent validity. Therefore, the French BADS-SF can be seen as a reliable and valid instrument. PMID- 25458480 TI - Negative symptoms are associated with lower autonomous motivation towards physical activity in people with schizophrenia. AB - OBJECTIVE: This cross-sectional study examined the association between psychiatric symptoms and motivation for physical activity within the self determination theory (SDT) framework in people with schizophrenia. METHOD: Over a 4-month period, 55 (17?) inpatients with a DSM-V diagnosis of schizophrenia were assessed with the Psychosis Evaluation tool for Common use by Caregivers (PECC) and the Behavioural Regulation in Exercise Questionnaire (BREQ-2), that provided separate scores for amotivation, external, introjected and autonomous regulation. Spearman correlation coefficients were examined between these motivation scores and symptom ratings. RESULTS: The BREQ-2 score for autonomous regulations (2.6+/ 1.1) was significantly correlated with the PECC negative symptoms score (10.3+/ 4.1) (r=-0.34, p=0.011). No other significant correlations between BREQ-2 and PECC scores were found. The BREQ-2 score for external regulations (0.7+/-0.9) was associated with older age (35.2+/-11.3years) (r=-0.30, p=0.024). CONCLUSIONS: These findings provide evidence that negative symptoms are associated with lower autonomous motivation towards physical activity in inpatients with schizophrenia. Future longitudinal research should confirm the current findings. Such research will guide physical activity approaches aimed at facilitating enhanced physical and mental health outcomes in individuals with schizophrenia. PMID- 25458481 TI - Occipital cortical thickness in very low birth weight born adolescents predicts altered neural specialization of visual semantic category related neural networks. AB - Very low birth weight (VLBW) premature born infants have a high risk to develop visual perceptual and learning deficits as well as widespread functional and structural brain abnormalities during infancy and childhood. Whether and how prematurity alters neural specialization within visual neural networks is still unknown. We used functional and structural brain imaging to examine the visual semantic system of VLBW born (<1250 g, gestational age 25-32 weeks) adolescents (13-15 years, n = 11, 3 males) and matched term born control participants (13-15 years, n = 11, 3 males). Neurocognitive assessment revealed no group differences except for lower scores on an adaptive visuomotor integration test. All adolescents were scanned while viewing pictures of animals and tools and scrambled versions of these pictures. Both groups demonstrated animal and tool category related neural networks. Term born adolescents showed tool category related neural activity, i.e. tool pictures elicited more activity than animal pictures, in temporal and parietal brain areas. Animal category related activity was found in the occipital, temporal and frontal cortex. VLBW born adolescents showed reduced tool category related activity in the dorsal visual stream compared with controls, specifically the left anterior intraparietal sulcus, and enhanced animal category related activity in the left middle occipital gyrus and right lingual gyrus. Lower birth weight of VLBW adolescents correlated with larger thickness of the pericalcarine gyrus in the occipital cortex and smaller surface area of the superior temporal gyrus in the lateral temporal cortex. Moreover, larger thickness of the pericalcarine gyrus and smaller surface area of the superior temporal gyrus correlated with reduced tool category related activity in the parietal cortex. Together, our data suggest that very low birth weight predicts alterations of higher order visual semantic networks, particularly in the dorsal stream. The differences in neural specialization may be associated with aberrant cortical development of areas in the visual system that develop early in childhood. PMID- 25458482 TI - Predictability of in vitro dermal assays when evaluating fatty amine derivatives. AB - It is widely accepted that skin assays based on reconstructed human epidermis (RhE) models can be used in place of in vivo testing to accurately predict corrosivity and/or irritancy of commodity chemicals. Due to REACH legislation, substances from various categories of fatty amines derivatives have been evaluated for dermal corrosion applying either the EpiDermTM (EPI-200) or EpiSkinTM assay. Available data and practical experience indicated that these substances are corrosive to the skin. The substances tested are cationic surfactants which dermal effects are characterized by a delayed severe inflammatory reaction. The mechanism is thought to be related to disruption of the cellular membrane following diffusion of the long apolar tails of the molecules into the lipid bilayers. However, unexpectedly almost all obtained study results indicated that these substances are NOT corrosive in these in vitro RhE test systems. Since these results did not align with the experiences on such substances, limited in vivo rabbit studies were employed additionally. These studies confirmed that after some delay full skin tissue destruction occurs, requiring classification as Corrosive Cat.1B or 1C for GHS. The results obtained for various fatty amine derivatives shows that RhE assays do not always predict corrosivity correctly. PMID- 25458483 TI - Antibiotics delay in vitro human stem cell regrowth. AB - Stem cell line from human limbal area was established to study in vitro cell growth and response to the toxic effects of antibiotics used in ophthalmology in terms of cell migration rates and structure of interphase chromatin. Recovery from cellular damages caused by ophthalmologic antibiotics was mimicked by an in vitro scratch model and followed by time-lapse microscopy, scanning electronmicroscopy and chromatin image analysis. Experiments revealed that broad spectrum antibiotics, chloramphenicol (0.5-1.0mg/ml) and rifampicin (0.1 0.2mg/ml), corresponding to concentrations in common clinical practice, slowed down the regeneration process. Results show that nuclei of naturally occurring limbal cells contain the same intermediates of chromatin condensation as seen in mammalian tumor cells and follow the common pathway of chromosome condensation. These intermediates included decondensed veil-like chromatin, fibrillary chromatin, supercoiled ribbon, chromatin bodies, early linear forms and metaphase chromosomes. Upon chloramphenicol and rifampicin treatment characteristic distorsions took place in the intermediates of chromosome condensation. Damaging effects in limbal stem cells in the presence of chloramphenicol or rifampicin indicate that ophthalmologic treatment with antibiotics should be used cautiously. PMID- 25458484 TI - Biokinetics of chlorpromazine in primary rat and human hepatocytes and human HepaRG cells after repeated exposure. AB - Since drug induced liver injury is difficult to predict in animal models, more representative tests are needed to better evaluate these effects in humans. Existing in vitro systems hold great potential to detect hepatotoxicity of pharmaceuticals. In this study, the in vitro biokinetics of the model hepatotoxicant chlorpromazine (CPZ) were evaluated in three different liver cell systems after repeated exposure in order to incorporate repeated-dose testing into an in vitro assay. Primary rat and human hepatocytes, cultured in sandwich configuration and the human HepaRG cell line were treated daily with CPZ for 14 days. Samples were taken from medium, cells and well plastic at specific time points after the first and last exposure. The samples were analysed by HPLC-UV to determine the amount of CPZ in these samples. Based on cytotoxicity assays, the three models were tested at 1-2 MUM CPZ, while the primary rat hepatocytes and the HepaRG cell line were in addition exposed to a higher concentration of 15-20 MUM. Overall, the mass balance of CPZ decreased in the course of 24 h, indicating the metabolism of the compound within the cells. The largest decrease in parent compound was seen in the primary cultures; in the HepaRG cell cultures the mass balance only decreased to 50%. CPZ accumulated in the cells during the 14-day repeated exposure. Possible explanations for the accumulation of CPZ are a decrease in metabolism over time, inhibition of efflux transporters or binding to phospholipids. The biokinetics of CPZ differed between the three liver cell models and were influenced by specific cell properties as well as culture conditions. These results support the conclusion that in vitro biokinetics data are necessary to better interpret chemical-induced cytotoxicity data. PMID- 25458485 TI - Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors. AB - Besides their role in the elucidation of pathogenic processes of medical and pharmacological nature, biomarkers can also be used to document specific toxicological events. Hepatic cells generated from human skin-derived precursors (hSKP-HPC) were previously shown to be a promising in vitro tool for the evaluation of drug-induced hepatotoxicity. In this study, their capacity to identify potential liver-specific biomarkers at the gene expression level was investigated with particular emphasis on acute liver failure (ALF). To this end, a set of potential ALF-specific biomarkers was established using clinically relevant liver samples obtained from patients suffering from hepatitis B associated ALF. Subsequently, this data was compared to data obtained from primary human hepatocyte cultures and hSKP-HPC, both exposed to the ALF-inducing reference compound acetaminophen. It was found that both in vitro systems revealed a set of molecules that was previously identified in the ALF liver samples. Yet, only a limited number of molecules was common between both in vitro systems and the ALF liver samples. Each of the in vitro systems could be used independently to identify potential toxicity biomarkers related to ALF. It seems therefore more appropriate to combine primary human hepatocyte cultures with complementary in vitro models to efficiently screen out potential hepatotoxic compounds. PMID- 25458486 TI - Innate stimulatory capacity of high molecular weight transition metals Au (gold) and Hg (mercury). AB - Nickel, cobalt and palladium ions can induce an innate immune response by triggering Toll-like receptor (TLR)-4 which is present on dendritic cells (DC). Here we studied mechanisms of action for DC immunotoxicity to gold and mercury. Next to gold (Na3Au (S2O3)2?2H2O) and mercury (HgCl2), nickel (NiCl2) was included as a positive control. MoDC activation was assessed by release of the pro-inflammatory mediator IL-8. Also PBMC were studied, and THP-1 cells were used as a substitution for DC for evaluation of cytokines and chemokines, as well as phenotypic, alterations in response to gold and mercury. Our results showed that both Na3Au (S2O3)2?2H2O and HgCl2 induce substantial release of IL-8, but not IL 6, CCL2 or IL-10, from MoDc, PBMC, or THP-1 cells. Also gold and, to a lesser extent mercury, caused modest dendritic cell maturation as detected by increased membrane expression of CD40 and CD80. Both metals thus show innate immune response capacities, although to a lower extent than reported earlier for NiCl2, CoCl2 and Na2 [PdCl4]. Importantly, the gold-induced response could be ascribed to TLR3 rather than TLR4 triggering, whereas the nature of the innate mercury response remains to be clarified. In conclusion both gold and mercury can induce innate immune responses, which for gold could be ascribed to TLR3 dependent signalling. These responses are likely to contribute to adaptive immune responses to these metals, as reflected by skin and mucosal allergies. PMID- 25458487 TI - Influence of dispersive agent on nanomaterial agglomeration and implications for biological effects in vivo or in vitro. AB - Comparing the dispersing properties of the porcine lung surfactant Curosurf((r)) to bovine serum albumin (BSA), the present study investigated how a more close simulation of the in vivo situation influences nanomaterial dispersion and hence the proportion of the administered dose that will reach the in vitro test system, i.e. the 'effective dose'. Dispersions of 16 OECD reference nanomaterials (ZnO, Ag, TiO(2), CeO(2), SiO(2), and multi-walled carbon nanotubes (MWCNTs) were assessed. Overall, the NMs were better dispersed in the BSA-supplemented medium. BSA-addition combined with ultrasonication proved most effective in deagglomerating MWCNTs, but also reduced agglomeration for most metal oxidenanomaterials as compared to the Curosurf((r)) dispersions. However, all materials were at least partially agglomerated in either dispersing agent. For the different nanomaterials, the calculated effective dosage upon 12- or 24-h test substance incubation differed considerably (and to different extents) depending on the applied dispersing agent. When testing nanomaterial effects in vitro, selection of the type of cell culture medium and its additives should take into account what the system is intended to mimic. Study protocols should address whether they aim at best-possible dispersion of the nanomaterials or at simulating more realistically in vivo tissue uptake and distribution. PMID- 25458488 TI - Citrate-stabilized gold nanoparticles as negative controls for measurements of neurite outgrowth. AB - Gold nanoparticles (AuNPs) are promising candidates for medical diagnostics and therapeutics, due to their chemical stability, optical properties, and ease of functionalization. Citrate-stabilized reference materials also have potential as negative controls in toxicology studies of other nanoparticles. Here we examine the impact of 30 nm particles on the in vitro development of rat-cortex neural progenitor cells (NPCs), which mimic aspects of the developing neurological environment. AuNPs dispersed in a low serum culture medium initially agglomerated, but then remained stable during a three day incubation period, and agglomerated only slightly during a ten day incubation period, as determined by dynamic light scattering. Transmission electron microscopy indicated the presence of individual nanoparticles at all time points examined. Fixed cells were cross sectioned by ion milling and imaged by scanning electronmicroscopy and helium-ion microscopy to evaluate particle incorporation. Individual nanoparticles could be resolved inside cross-sectioned cells. AuNPs were incubated with developing NPCs for ten days at concentrations of 0.5 MUg/mL Au, 0.1 MUg/mL Au, or 0.05 MUg/mL Au. Adenosine triphosphate levels, as determined by bioluminescence measurements sensitive to low cell numbers, were not affected by AuNPs and the particles did not interfere with the assay. Multiple endpoints of neurite outgrowth were not altered by AuNPs, in particular, total neurite outgrowth per cell, a sensitive measure of neuronal development. Slide-level comparisons demonstrated the consistent response of NPCs to gold nanoparticles and a positive control chemical, neuroactive lithium. These results indicate that 30 nm citrate stabilized AuNPs could serve as negative-control reference materials for in vitro measurements of neurite outgrowth. PMID- 25458490 TI - Morphologic and immunohistochemical features of Merkel cells in the dog. AB - Merkel cells (MCs) are specialized skin receptors characterized by their particular location and close association with nerve terminals. They also are cells with a presumptive neuroendocrine function and are considered as part of the diffuse neuroendocrine system. By using commercially available monoclonal and polyclonal antibodies in samples of dog skin, MCs were properly distinguished from other clear cell types in the epidermis. They expressed cytokeratins 7, 8, 20, EpCAM, NSE, CGA, SYN, S100 protein, and NF, presented diverse cytological features and arrangements depending on the location considered, and showed pronounced heterogeneity with markedly different expression and distribution patterns for antibodies used. Anti-CK20 presented as the most reliable and specific antibody for their identification. The present study increases our knowledge of MCs and establishes a basis for future studies of the role(s) of the MCs in diseased tissues of the dog skin, including the cutaneous neuroendocrine (Merkel cell) tumour. PMID- 25458489 TI - Influence of physicochemical properties of silver nanoparticles on mast cell activation and degranulation. AB - Silver nanoparticles (AgNPs) are increasingly being incorporated into products for their antimicrobial properties. This has resulted in increased human exposures and the possibility of adverse health effects. Mast cells orchestrate allergic immune responses through degranulation and release of pre-formed mediators. Little data exists on understanding interactions of AgNPs with mast cells and the properties that influence activation and degranulation. Using bone marrow-derived mast cells and AgNPs of varying physicochemical properties we tested the hypothesis that AgNP physicochemical properties influence mast cell degranulation and osteopontin production. AgNPs evaluated included spherical 20 nm and 110 nm suspended in either polyvinylpyrrolidone (PVP) or citrate, Ag plates suspended in PVP of diameters between 40-60 nm or 100-130 nm, and Ag nanowires suspended in PVP with thicknesses <100 nm and length up to 2 MUm. Mast cell responses were found to be dependent on the physicochemical properties of the AgNP. Further, we determined a role for scavenger receptor B1 in AgNP-induced mast cell responses. Mast cell degranulation was not dependent on AgNP dissolution but was prevented by tyrosine kinase inhibitor pretreatment. This study suggests that exposure to AgNPs may elicit adverse mast cell responses that could contribute to the initiation or exacerbation of allergic disease. PMID- 25458491 TI - Hormonal composition of follicular fluid from abnormal follicular structures in mares. AB - The objective was to characterise the hormonal composition of follicular fluid from mares with distinct anovulatory-cystic follicles. Follicular fluid was aspirated from six mares that presented with cystic follicles and from pre ovulatory follicles of five normal mares (controls). Differences in progesterone, oestradiol, testosterone, IGF-I and IGF binding were analysed using Fisher's exact test. There were greater (P < 0.03) follicular fluid oestradiol concentrations in normal follicles and the testosterone concentration of the cystic fluid was greater (P < 0.05) than that of the normal fluid. There also was a greater (P < 0.03) percentage of IGF-I binding and lower (P < 0.02) IGF-I concentrations in the fluid collected from the cystic structures compared with the fluid from normal follicles. Despite the limited number of animals, the fact that fluid aspirated from cystic follicles had higher testosterone and lower oestradiol concentrations could be of diagnostic value when a practitioner wants to distinguish between a cystic and non-cystic persistent follicle. The research reported here also indicates a likely role for the IGF system in the pathogenesis of the development and maintenance of anovulatory follicular structures in mare ovaries. PMID- 25458492 TI - Evaluation of the immune response to Anaplasma marginale MSP5 protein using a HSV 1 amplicon vector system or recombinant protein. AB - Anaplasma marginale is an intraerythrocytic vector-borne infectious agent of cattle. Immunization with the current vaccine, based on parasitized erythrocytes with live Anaplasma centrale, shows some constraints and confers partial protection, suggesting the feasibility for the development of new generation of vaccines. The aim of the present study was to assess the effect of sequential immunization of BALB/c mice, with herpesvirus amplicon vector-based vaccines combined with protein-based vaccines, on the quality of the immune response against the major surface protein 5 of A. marginale. The highest antibody titers against MSP5 were elicited in mice that received two doses of adjuvanted recombinant protein (p < 0.0001). Mice treated with a heterologous prime-boost strategy generated sustained antibody titers at least up to 200 days, and a higher specific cellular response. The results presented here showed that sequential immunization with HSV-based vectors and purified antigen enhances the quality of the immune response against A. marginale. PMID- 25458493 TI - Detection of the new emerging rabbit haemorrhagic disease type 2 virus (RHDV2) in Sicily from rabbit (Oryctolagus cuniculus) and Italian hare (Lepus corsicanus). AB - Rabbit haemorrhagic disease virus (RHDV), a member of the genus Lagovirus, causes rabbit haemorrhagic disease (RHD), a fatal hepatitis of rabbits, not previously reported in hares. Recently, a new RHDV-related virus emerged, called RHDV2. This lagovirus can cause RHD in rabbits and disease and mortality in Lepus capensis (Cape hare). Here we describe a case of RHDV2 infection in another hare species, Lepus corsicanus, during a concurrent RHD outbreak in a group of wild rabbits. The same RHDV2 strain infected rabbits and a hare, also causing a RHD-like syndrome in the latter. Our findings confirmed the capability of RHDV2 to infect hosts other than rabbits and improve the knowledge about the epidemiology and the host range of this new lagovirus. PMID- 25458498 TI - Synthesis, GluN2B affinity and selectivity of benzo[7]annulen-7-amines. AB - Due to their beneficial side effect profile, NMDA receptor antagonists interacting selectively with the allosteric ifenprodil binding site of the GluN2B subunit are of major interest for the treatment of neurological and neurodegenerative disorders. A series of benzo[7]annulen-7-amines 6 was designed by conformational restriction of ifenprodil (1). At first the benzo[7]annulen-7 one 11 was prepared in a three-step synthesis comprising of a double Knoevenagel condensation of phthalaldehyde (7) with dimethyl 3-oxoglutarate (8), hydrogenation of 9 and saponification/decarboxylation of 10. Reductive amination of the ketone 11 with primary amines and NaBH(OAc)3 led to the secondary amines 6a-d, cis-6h and trans-6i. The tertiary amines 6e-g were obtained by SN2 substitution of the nosylate 13. Although H-bond forming substituents in 2- and 5 position are missing, the amines 6 exhibit high affinity towards GluN2B containing NMDA receptors. A distance of four to five bond lengths between the basic amino moiety and the phenyl ring in the side chain appears to be optimal for high GluN2B affinity. The phenylcyclohexylamine cis-6h and the 4 benzylpiperidine 6g show the highest GluN2B affinities (Ki=2.3nM and 2.9nM, respectively). With respect to selectivity against the PCP binding site, sigma1 and sigma2 receptors the phenylpiperazine 6f is the most promising GluN2B antagonist. PMID- 25458499 TI - Rational design of novel CYP2A6 inhibitors. AB - Inhibition of CYP2A6-mediated nicotine metabolism can reduce cigarette smoking. We sought potent and selective CYP2A6 inhibitors to be used as leads for drugs useful in smoking reduction therapy, by evaluating CYP2A6 inhibitory effect of novel formyl, alkyl amine or carbonitrile substituted aromatic core structures. The most potent CYP2A6 inhibitors were thienopyridine-2-carbaldehyde, benzothienophene-3-ylmethanamine, benzofuran-5-carbaldehyde and indole-5 carbaldehyde, with IC50 values below 0.5 MUM for coumarin 7-hydroxylation. Nicotine oxidation was effectively inhibited in vitro by two alkyl amine compounds and benzofuran-5-carbonitrile. Some of these molecules could serve as potential lead molecules when designing CYP2A6 inhibitory drugs for smoking reduction therapy. PMID- 25458500 TI - Synthesis and antiviral evaluation of 2-amino-6-carbamoylpurine dioxolane nucleoside derivatives and their phosphoramidates prodrugs. AB - The synthesis of 9-(beta-d-1,3-dioxolan-4-yl)2,6-diaminopurine nucleoside phosphoramidate prodrugs as well as various 2-amino-6-carbamoylpurine dioxolane derivatives and their phosphoramidates prodrugs is reported. Their ability to block HIV and HBV replication along with their cytotoxicity toward HepG2, human lymphocyte, CEM and Vero cells was also assessed. PMID- 25458501 TI - A comparison of BiobraneTM and cadaveric allograft for temporizing the acute burn wound: Cost and procedural time. AB - INTRODUCTION: In many circumstances early burn excision and autografting is unsafe or even impossible. In these situations, skin substitute dressings can be utilized for temporary wound coverage. Two commonly used dressings for this purpose are cadaveric allograft and BiobraneTM. MATERIALS AND METHODS: Five year retrospective cohort study evaluating upper extremity burns treated with temporary wound coverage (BiobraneTM or allograft). The primary outcome was to determine the impact choice of wound coverage had on operative time and cost. The secondary outcome was the need for revision of upper extremity debridement prior to definitive autografting. RESULTS: 45 patients were included in this study: 15 treated with cadaveric allograft and 30 treated with BiobraneTM skin substitute. BiobraneTM had a significantly lower procedure time (21.12 vs. 54.78 min per %TBSA excised, p=0.02) and cost (1.30 vs. 2.35 dollars per minute per %TBSA excised, p=0.002). Both techniques resulted in 2 revisions due to complications. CONCLUSION: BiobraneTM is superior to cadaveric allograft as a temporizing skin substitute in the acute burn wound, both in terms of procedure time and associated cost. We believe that this is largely due to the relative ease of application of BiobraneTM. Furthermore, given its unique characteristics, BiobraneTM may serve as a triage and transport option for severe burns in the military and mass casualty settings. PMID- 25458502 TI - Biobrane for burns of the ear--a novel technique. PMID- 25458503 TI - The toxic effects of melamine on spleen lymphocytes with or without cyanuric acid in mice. AB - Melamine is an organic nitrogenous compound whose acute toxicity was generally thought to be low in animals. In the present work, we investigated the potential cytotoxic effects of melamine on spleen lymphocytes in mice. In the treated group, morphological changes were observed in cultured lymphocytes in vitro. The co-administration of melamine and cyanuric acid caused a declining tendency in stimulation index of spleen lymphocyte. All treated groups had lower ratios of CD4+/CD8+. Both early apoptotic and late apoptotic/necrotic rates of lymphocyte were significantly higher in the co-administration high groups of melamine and cyanuric acid. Melamine-related toxicity promoted the expression of Bax mRNA, and suppressed the expression of Bcl-2 mRNA in spleen of the treated mice. These results provided useful information for assessing the toxicity of melamine on immune system of mammals, and contributed to the existing toxic profile of melamine. PMID- 25458504 TI - Clastogenic effects of Trypanosoma brucei brucei and Trypanosoma evansi mixed infection in bone marrow of Wistar rats. AB - The clastogenic effect of mixed infection of Trypanosoma evansi and Trypanosoma brucei brucei in the bone marrow (BM) cells of Wistar albino rats was investigated. Clastogenic effects were observed in the BM cells using the micronucleus assay. The findings indicate that T. evansi, T. b. brucei and mixed infection with both parasites induced the formation of micronucleated polychromatic erythrocyte (MN-PCEs) in the BM cells significantly (P < 0.05) by 60, 63 and 81 micronuclei/1000 PCE respectively. Mixed infection induced formation of MN-PCEs increase by about 1.33 fold when compared with single infections of T. b. brucei and T. evansi. These data give a preliminary evidence of possible genotoxic effects in trypanosomiasis. PMID- 25458505 TI - Matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and transforming growth factor-beta (TGF-beta) in advanced canine myxomatous mitral valve disease. AB - This study investigated mitral valve and myocardial protein and gene expression of matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and transforming growth factor-beta (TGF-beta) and plasma MMP and TGF-beta concentrations in age-matched dog groups euthanized due to either advanced myxomatous mitral valve disease (MMVD) or other reasons. Furthermore, echocardiographic data and lumen/area ratio were correlated with tissue and plasma levels of MMPs, TIMPs and TGF-betas. Mitral valve and myocardial gene expression of MMP2, MMP14, TGF-beta1 and TGF-beta2 were increased and plasma MMP9 was decreased in advanced MMVD dogs. Myocardial gene expression of TIMP2 and TIMP3 were increased in advanced MMVD. All affected markers correlated to echocardiographic parameters. Significantly narrowed lumen/area ratio was associated with increased myocardial expression of MMP2, MMP14, TIMP2 and TIMP3. No differences in tissue protein expression were recorded. MMP2, MMP14, TIMP2, TIMP3, TGF-beta1 and TGF-beta2 appear to play a local role in the development of advanced MMVD. PMID- 25458506 TI - Comparison between invasive blood pressure and a non-invasive blood pressure monitor in anesthetized sheep. AB - Monitoring blood pressure under general anesthesia in animals is important to prevent hypotension and poor tissue perfusion. Thirteen sheep were enrolled to evaluate the accuracy of the petMAP, a portable non-invasive blood pressure (NIBP) monitor. Animals were anesthetized with midazolam, fentanyl, ketamine, propofol and maintained with isoflurane in oxygen for ovariectomy. Invasive and non-invasive (petMAP) blood pressure measurements were recorded simultaneously every 5 minutes. Agreement between IBP and NIBP was assessed by evaluation of bias and 95% limits of agreement (LOA) using the Bland-Altman method and correlation coefficient. None of the measurements met the criteria for good agreement between invasive and non-invasive readings established by the Association for the Advancement of Medical Instrumentation. Systolic blood pressure readings obtained at the left thoracic limb site and mean blood pressure at the right pelvic limb site met the bias and LOA criteria established by the American College of Veterinary Internal Medicine. PMID- 25458507 TI - [Hb Burgos (alpha1 CD64(E13)(Asp->Asn)): a new hemoglobin variant detected during follow-up of diabetic patients]. AB - BACKGROUND AND OBJECTIVE: The glycated hemoglobin (HbA1c) test by high performance liquid chromatography is a useful tool for the follow-up of diabetes mellitus patients. Some structural hemoglobin (Hb) variants are known to cause interference in the analytical measurement of HbA1c. PATIENTS AND METHODS: In this study, it has been characterized a new Hb variant in 4 patients during their regular control of HbA1c. RESULTS: Selective alpha1 gene sequencing showed a mutation GAC>AAC at codon 64 within exon 2. This produces a change of aspartic acid (Asp) by asparagine (Asn) that does not produce any functional alteration so the resultant molecule behaves as a silent hemoglobinopathy. CONCLUSION: The structural Hb variants can be detected during the analysis of HbA1c and may alter its values. Though rare, this occurrence signals the need to being aware when measuring HbA1c. PMID- 25458508 TI - [Computed tomography as a tool to detect potential brain-dead donors]. AB - BACKGROUND AND OBJECTIVE: To assess the ability of urgent head computed tomography (CT) scan screening to detect patients who can evolve to brain death (BD). PATIENTS AND METHOD: Patients who underwent urgent head CT scan and meet the following criteria: midline shift greater than 5mm and/or decrease or absence of basal cisterns. A follow-up for 28 days of each patient was made. Epidemiological data (sex, age, cause of brain injury), clinical data (level of consciousness, severity index in the CT) and patient outcomes (death, BD, discharge or transfer) were recorded. This was a prospective observational study. RESULTS: One hundred and sixty-six patients were selected for study, with mean age 60.08 (SD 21.8) years. A percentage of 49.4 were men and the rest women. In the follow-up, 20,5% (n=34) had BD. In univariate analysis, intracerebral hemorrhage, Glasgow Coma Scale score less than 8 and alteration of basal cisterns were statistically significant in predicting BD (P<.05). Multivariate analysis showed that patients with compression of basal cisterns were 20 (95% confidence interval [95% CI] 2.61 to 153.78; P=.004] times more likely to progress to brain death, while the absence there of 62.6 (95% CI 13.1 to 738.8; P<.001] times more. CONCLUSIONS: Our work shows that data as easy to interpret as compression/absence of basal cisterns can be a powerful tool for screening patients at risk for progression to BD. PMID- 25458509 TI - [Amyloidosis complicating spondyloarthropathies: Study of 15 cases]. AB - BACKGROUND AND OBJECTIVE: Secondary amyloidosis (AA) is a rare complication of rheumatic diseases. OBJECTIVE: The aim of this study was to determine the frequency of symptomatic amyloidosis AA in patients with spondyloarthropathy. PATIENTS AND METHOD: Retrospective study (1984-2013). We reviewed the medical records of patients with spondyloarthropathy who had a histological diagnosis of amyloidosis AA (15 patients). RESULTS: We identified 1.125 patients with spondyloarthropathies. Fifteen (1.3%) patients with amyloidosis AA were recruited. It was suspected in 14 patients (93.3%) because of nephrotic syndrome in most of them: 14 were symptomatic (93.3%): 5 (33.3%) ankylosing spondylitis (AS), 5 (33.3%) spondylitis associated with inflammatory bowel diseases (IBD), 4 (26.7%) psoriatic arthritis, and one (6.7%) reactive arthritis. The mean disease duration was 23.9 years. Mortality after one and 5 years of follow-up was 30 and 50% respectively. CONCLUSIONS: The frequency of clinical amyloidosis AA in our patients was 1.3%. There was a marked male predominance, with AS or IBD. Clinical amyloidosis was diagnosed at a relatively late stage in spondyloarthropathy. PMID- 25458510 TI - [Selection criteria for search for germ mutations in colorectal cancer hereditary nonpolyposis]. PMID- 25458511 TI - [Levothyroxine malabsortion]. PMID- 25458512 TI - [Interferon beta, nephrotic syndrome and thrombotic microangiopathy]. PMID- 25458513 TI - Prognostic value of metabolic syndrome for the development of cardiovascular disease in a cohort of premenopausal women with systemic lupus erythematosus. AB - BACKGROUND AND OBJECTIVE: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease of unknown etiology. In lupus patients there is an increased cardiovascular risk due to an accelerated atherogenesis. Furthermore, Metabolic Syndrome (MS) adds an independent risk for developing Cardiovascular Disease (CVD) in the population. Therefore, it is important to determine whether lupus patients have an increased risk of developing Cardiovascular Disease in the presence of MS. To estimate the prognostic value of MS in the incidence of cardiovascular events in a cohort of premenopausal patients with SLE. METHODOLOGY: Cohort study in 238 patients was carried out. Clinical, biochemical, dietetic and anthropometric evaluations were performed. Patients were classified according to the prevalence of MS in 2001. There was a patient follow-up from 2001 to 2008. In 2008, after studying the records, we obtained the "cases" (patients with CVD) and the "no cases" (patients without CVD). RESULTS: The basal prevalence of MS in the cohort was of 21.8% (ATPIII). The MS component with the highest prevalence in the population studied in 2001 was low HDL-Cholesterol (<50mg/dL) with a prevalence of 55.0%. The cumulative incidence of CVD in the group with MS was 17.3% and in the group without MS it was 7.0% with a Relative Risk (RR) of 2.48 (1.12-5.46) and p<0.05. In the multivariable analysis it was noted that MS is a predictive factor of CVD. CONCLUSIONS: We observed the prognostic value of MS for an increased risk of cardiovascular damage in premenopausal patients with lupus. PMID- 25458514 TI - [Pulmonary hemorrhage in patients with systemic lupus erythematosus. Clinical manifestations and prognosis]. AB - BACKGROUND AND OBJECTIVE: Pulmonary hemorrhage (PH) in systemic lupus erythematosus (SLE) is a rare but potentially fatal complication that occurs most frequently in the context of active lupus with involvement of other organs. The objective of this study is to report the clinical features and prognosis of patients with SLE who had PH. METHODS: Patients with SLE (1982 American College of Rheumatology criteria) and PH under monitoring between June 1999 and November 2011 were studied. Demographic, clinical, laboratory, treatment and prognosis data related to PH were analyzed. RESULTS: Eleven patients with SLE developed 14 episodes of PH. PH was the first manifestation of SLE in 2 patients. The most frequent symptoms and clinical signs were dyspnea, fever and cough, which occurred in 12 (85%), 11 (77%) and 7 (50%) patients, respectively. Hemoptysis was also observed in 5 (35%) episodes, tachycardia in 2 (14%), pallor in one (7%) and chest pain in one (7%). All patients had other concomitant organ involvement, and were treated with glucocorticoids. In addition, intravenous cyclophosphamide was indicated in 12 episodes and plasma exchange in 4. Overall mortality was 64%. Factors associated with mortality were infection, mechanical ventilation and dialysis. CONCLUSIONS: PH continues to be a rare and severe complication of SLE. Its suspected presence forces us to quickly study these patients, since early diagnosis and aggressive treatment have been shown to improve survival in them. PMID- 25458516 TI - [Ebola ad portas]. PMID- 25458515 TI - [Activity and results of liver transplantation in Spain during 1984-2012. Analysis of the Spanish Liver Transplant Registry]. AB - BACKGROUND AND OBJECTIVE: Liver transplantation (LT) is a proven effective treatment of severe liver disease. The aim of this paper is to analyze the results of LT in Spain during the period 1984-2012. PATIENTS AND METHOD: We analyze the results of the database of Spanish Liver Transplant Registry. RESULTS: A total of 20,288 transplants were performed in 18,568 patients. The median age of the donor and recipient increased during the analysis period: 25 years (95% confidence interval [95% CI] 18-40) and 47 years (95% CI 34-55), respectively, in the period 1984-1994 compared to 59 years (95% CI 33-65; P<.05) and 55 years (95% CI 48-61; P<.01), respectively, in the period 2010-2012. The most frequent indications were liver cirrhosis (63.18%) and hepatocellular carcinoma (19.62%). The overall patient and graft survival was respectively 85.1 and 77.8% in the first year, 72.6 and 63.5% the fifth year and 62 and 52.6% in the tenth year. First year patients and graft survival increased respectively from 77.8 and 66.3% in the period 1984-1994 to 88.5 and 83% in 2010-2012 (P<.01). Donor and recipient age, etiology of underlying disease, and hepatitis C virus serological status, were factors associated with decreased survival in univariate and multivariate analysis. CONCLUSIONS: Results of LT improved significantly over the review period, despite a progressive increase in donor and recipient age. PMID- 25458517 TI - [The African tragedy of Ebola]. PMID- 25458518 TI - Strategies for treating mitochondrial disorders: an update. AB - Mitochondrial diseases are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory chain due to both nuclear and mitochondrial DNA mutations. The wide heterogeneity of biochemical dysfunctions and pathogenic mechanisms typical of this group of diseases has hindered therapy trials; therefore, available treatment options remain limited. Therapeutic strategies aimed at increasing mitochondrial functions (by enhancing biogenesis and electron transport chain function), improving the removal of reactive oxygen species and noxious metabolites, modulating aberrant calcium homeostasis and repopulating mitochondrial DNA could potentially restore the respiratory chain dysfunction. The challenge that lies ahead is the translation of some promising laboratory results into safe and effective therapies for patients. In this review we briefly update and discuss the most feasible therapeutic approaches for mitochondrial diseases. PMID- 25458519 TI - A straightforward, quantitative ultra-performance liquid chromatography-tandem mass spectrometric method for heparan sulfate, dermatan sulfate and chondroitin sulfate in urine: an improved clinical screening test for the mucopolysaccharidoses. AB - Mucopolysaccharidoses (MPS) are complex storage disorders that result in the accumulation of glycosaminoglycans (GAGs) in urine, blood, brain and other tissues. Symptomatic patients are typically screened for MPS by analysis of GAG in urine. Current screening methods used in clinical laboratories are based on colorimetric assays that lack the sensitivity and specificity to reliably detect mild GAG elevations that occur in some patients with MPS. We have developed a straightforward, reliable method to quantify chondroitin sulfate (CS), dermatan sulfate (DS) and heparan sulfate (HS) in urine by stable isotope dilution tandem mass spectrometry. The GAGs were methanolyzed to uronic acid-N-acetylhexosamine or iduronic acid-N-glucosamine dimers and mixed with stable isotope labeled internal standards derived from deuteriomethanolysis of GAG standards. Specific dimers derived from HS, DS and CS were separated by ultra-performance liquid chromatography and analyzed by electrospray ionization tandem mass spectrometry using selected reaction monitoring for each targeted GAG product and its corresponding internal standard. The method was robust with a mean inaccuracy from 1 to 15%, imprecision below 11%, and a lower limit of quantification of 0.4mg/L for CS, DS and HS. We demonstrate that the method has the required sensitivity and specificity to discriminate patients with MPS III, MPS IVA and MPS VI from those with MPS I or MPS II and can detect mildly elevated GAG species relative to age-specific reference intervals. This assay may also be used for the monitoring of patients following therapeutic intervention. Patients with MPS IVB are, however, not detectable by this method. PMID- 25458520 TI - Duchenne or Meryon muscular dystrophy? PMID- 25458522 TI - Identification of multifunctional graphene-gold nanocomposite for environment friendly enriching, separating, and detecting Hg2+ simultaneously. AB - By virtue of the specific amalgam of mercury with gold and high specific area of a graphene scaffold, an environment-friendly multifunctional graphene-gold nanocomposite (G-AuNPs) has been identified and prepared by a simple one-pot redox reaction. The resultant G-AuNPs can reversibly enrich about 94% of Hg(2+) in water samples, which can be further separated by only a simple filtration. Importantly, the color of the G-AuNPs suspension exclusively changes from purple red to light brown upon the addition of Hg(2+) in the presence of ascorbic acid, which can be applied for colorimetric detection of Hg(2+) with a detection limit (3sigma, n = 20) of 1.6 * 10(-8) mol.L(-1). Furthermore, using ascorbic acid as reducing agents, both the preparation process and the resultant nanocomposite are nontoxic. To the best of our knowledge, this is the first report to enrich, separate and detect Hg(2+) contaminant simultaneously without causing any secondary pollution. PMID- 25458521 TI - Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: a treatable neurological disorder caused by TPK1 mutations. AB - Thiamine pyrophosphokinase (TPK) produces thiamine pyrophosphate, a cofactor for a number of enzymes, including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase. Episodic encephalopathy type thiamine metabolism dysfunction (OMIM 614458) due to TPK1 mutations is a recently described rare disorder. The mechanism of the disease, its phenotype and treatment are not entirely clear. We present two patients with novel homozygous TPK1 mutations (Patient 1 with p.Ser160Leu and Patient 2 with p.Asp222His). Unlike the previously described phenotype, Patient 2 presented with a Leigh syndrome like non-episodic early onset global developmental delay, thus extending the phenotypic spectrum of the disorder. We, therefore, propose that TPK deficiency may be a better name for the condition. The two cases help to further refine the neuroradiological features of TPK deficiency and show that MRI changes can be either fleeting or progressive and can affect either white or gray matter. We also show that in some cases lactic acidosis can be absent and 2-ketoglutaric aciduria may be the only biochemical marker. Furthermore, we have established the assays for TPK enzyme activity measurement and thiamine pyrophosphate quantification in frozen muscle and blood. These tests will help to diagnose or confirm the diagnosis of TPK deficiency in a clinical setting. Early thiamine supplementation prevented encephalopathic episodes and improved developmental progression of Patient 1, emphasizing the importance of early diagnosis and treatment of TPK deficiency. We present evidence suggesting that thiamine supplementation may rescue TPK enzyme activity. Lastly, in silico protein structural analysis shows that the p.Ser160Leu mutation is predicted to interfere with TPK dimerization, which may be a novel mechanism for the disease. PMID- 25458524 TI - Multiple headspace extraction for gas detection in ionic liquids. AB - In this study multiple headspace extraction was used for the first time to measure the saturation concentration of carbon monoxide and oxygen in various ionic liquids (ILs). Many processes in ILs involve the reaction of gases so that the reactant solubility is not a mere characteristical parameter, but understanding the solubility of gases in ILs is required for assessing the feasibility of possible applications. Multiple headspace extraction has proofed to be a powerful tool to obtain solubilities in good accordance with literature data. The measured saturation concentration for carbon monoxide and oxygen in ILs based on rarely researched tetracyanoborates and other anions was in the range of 1.5-6.5mmol/L. The great advantage of multiple headspace extraction is that it is a nonexpensive method that can be realised in most analytical laboratories by combination of a simple gas chromatograph and an eligible headspace injector. PMID- 25458523 TI - Non-thermal atmospheric plasma brush induces HEMA grafting onto dentin collagen. AB - OBJECTIVE: Non-thermal atmospheric plasma (NTAP) brush has been regarded as a promising technique to enhance dental interfacial bonding. However, the principal enhancement mechanisms have not been well identified. In this study, the effect of non-thermal plasmas on grafting of HEMA, a typical dental monomer, onto dentin collagen thin films was investigated. METHODS: Human dentin was sectioned into 10 MUm-thick films. After total demineralization in 0.5M EDTA solution for 30min, the dentin collagen films were water-rinsed, air-dried, treated with 35wt% HEMA aqueous solution. The films were then subject to plasma-exposure under a NTAP brush with different time (1-8min)/input power (5-15W). For comparison, the dentin collagen films were also treated with the above HEMA solution containing photo-initiators, then subject to light-curing. After plasma-exposure or light curing, the HEMA-collagen films were rinsed in deionized water, and then examined by FTIR spectroscopy and TEM. RESULTS: The FITR results indicated that plasma exposure could induce significant HEMA grafting onto dentin collagen thin films. In contrast, light-curing led to no detectable interaction of HEMA with dentin collagen. Quantitative IR spectral analysis (i.e., 1720/3075 or 749/3075, HEMA/collagen ratios) further suggested that the grafting efficacy of HEMA onto the plasma-exposed collagen thin films strongly depended on the treatment time and input power of plasmas. TEM results indicated that plasma treatment did not alter collagen's banding structure. SIGNIFICANCE: The current study provides deeper insight into the mechanism of dental adhesion enhancement induced by non thermal plasmas treatment. The NTAP brush could be a promising method to create chemical bond between resin monomers and dentin collagen. PMID- 25458525 TI - Comparison of the kinetic performance and retentivity of sub-2 MUm core-shell, hybrid and conventional bare silica phases in hydrophilic interaction. AB - The separation performance and retention properties of four sub-2MUm underivatised silica materials were evaluated in the hydrophilic interaction chromatography (HILIC) mode. These included an organic/inorganic hybrid silica, conventional silica, narrow particle size distribution silica and a core-shell silica. Van Deemter characterisation was performed using conditions to give high retention factors (k=5.5-6.0) with 10cm columns to limit the contribution of extra-column dispersion. The core-shell 1.6MUm bare silica (Cortecs) was shown to be kinetically superior to fully porous particle types. Little column-to-column variation in the reduced b-coefficient was observed for the test analytes as corroborated by arrested elution experiments. However, the reduced b-coefficient was shown to be different between analytes, e.g. cytosine versus nortriptyline. It is speculated that the nature of the retention mechanism (hydrophilic versus ionic retention) and solute physiochemical properties perhaps influence the b coefficient. Maxwell-Effective Medium Theory (EMT) applied to results for a wider range of solutes indicated that the intra-particle diffusion (Dpart) behaviour for individual compounds is broadly similar irrespective of the particle morphology in HILIC. Finally, the impact of varying buffer concentration for a test mix showed that retention and peak shape varied considerably between different silicas. High efficiency separations can be achieved for hydrophilic and basic solutes using a combination of sub-2MUm core shell bare silica particles and appropriate buffer concentrations. PMID- 25458526 TI - Off-line two dimensional isoelectrofocusing-liquid chromatography/mass spectrometry (time of flight) for the determination of the bioactive peptide lunasin. AB - Progress in liquid chromatography and mass spectrometry technologies offers a great opportunity for the determination of bioactive peptides. Nevertheless, in many cases, the direct application of this technology does not enable the detection of the investigated peptides due to serious signal suppression. This is the case of lunasin, a cancer preventive, anti-inflammatory, and cholesterol reducing peptide originally isolated from soybean and later found in some cereals. Most methods applied for the quantitation of this peptide were immunological and based on the detection of just a fragment of the lunasin sequence. At this regard, there is a peptide commercially available with a sequence similar to lunasin but differing in just one amino acid that has been wrongly used for the quantitation of lunasin. The use of high resolution mass spectrometry has enabled to be aware of this issue and of the need for new methods enabling the reliable identification and determination of lunasin. However, when different approaches were evaluated in this work for the reduction of the interferences originating signal suppression, such as matrix dilution, previous lunasin purification by reversed-phase or ion-exchange solid-phase extraction, and use of different chromatographic columns, no one resulted successful in the case of soybean. Just a one-dimensional separation of the soybean extract by isoelectrofocusing followed by a second dimension separation by reversed-phase liquid chromatography enabled a significant reduction of matrix interferences and the detection of lunasin in soybean products by high resolution mass spectrometry with a time of flight (TOF) analyzer. After method optimization, selectivity, linearity, accuracy, precision, and limits of detection and quantitation were evaluated, being possible to quantitate as low as 25ng/mL (1.5MUg lunasin/g protein). Concentration of lunasin in the analyzed soybean flour and textured soybean ranged from 14.0 to 22.5mg lunasin/g protein. PMID- 25458527 TI - Benchtop isolation and characterization of functional exosomes by sequential filtration. AB - Early and minimally invasive detection of malignant events or other pathologies is of utmost importance in the pursuit of improved patient care and outcomes. Recent evidence indicates that exosomes and extracellular vesicles in serum and body fluids can contain nucleic acid, protein, and other biomarkers. Accordingly, there is great interest in applying these clinically as prognostic, predictive, pharmacodynamic, and early detection indicators. Nevertheless, existing exosome isolation methods can be time-consuming, require specialized equipment, and/or present other inefficiencies regarding purity, reproducibility and assay cost. We have developed a straightforward, three-step protocol for exosome isolation of cell culture supernatants or large volumes of biofluid based on sequential steps of dead-end pre-filtration, tangential flow filtration (TFF), and low-pressure track-etched membrane filtration that we introduce here. Our approach yields exosome preparations of high purity and defined size distribution and facilitates depletion of free protein and other low-molecular-weight species, extracellular vesicles larger than 100nm, and cell debris. Samples of exosomes prepared using the approach were verified morphologically by nanoparticle tracking analysis and electron microscopy, and mass spectrometry analyses confirmed the presence of previously reported exosome-associated proteins. In addition to being easy-to implement, sequential filtration yields exosomes of high purity and, importantly, functional integrity as a result of the relatively low-magnitude manipulation forces employed during isolation. This answers an unmet need for preparation of minimally manipulated exosomes for investigations into exosome function and basic biology. Further, the strategy is amenable to translation for clinical exosome isolations because of its speed, automatability, scalability, and specificity for isolating exosomes from complex biological samples. PMID- 25458528 TI - Epigenetic regulation of inflammatory gene expression in macrophages by selenium. AB - Acetylation of histone and non-histone proteins by histone acetyltransferases plays a pivotal role in the expression of proinflammatory genes. Given the importance of dietary selenium in mitigating inflammation, we hypothesized that selenium supplementation may regulate inflammatory gene expression at the epigenetic level. The effect of selenium towards histone acetylation was examined in both in vitro and in vivo models of inflammation by chromatin immunoprecipitation assays and immunoblotting. Our results indicated that selenium supplementation, as selenite, decreased acetylation of histone H4 at K12 and K16 in COX-2 and TNFalpha promoters, and of the p65 subunit of the redox sensitive transcription factor NFkappaB in primary and immortalized macrophages. On the other hand, selenomethionine had a much weaker effect. Selenite treatment of HIV-1-infected human monocytes also significantly decreased the acetylation of H4 at K12 and K16 on the HIV-1 promoter, supporting the down-regulation of proviral expression by selenium. A similar decrease in histone acetylation was also seen in the colonic extracts of mice treated with dextran sodium sulfate that correlated well with the levels of selenium in the diet. Bone-marrow-derived macrophages from Trsp(fl/fl)Cre(LysM) mice that lack expression of selenoproteins in macrophages confirmed the important role of selenoproteins in the inhibition of histone H4 acetylation. Our studies suggest that the ability of selenoproteins to skew the metabolism of arachidonic acid contributes, in part, to their ability to inhibit histone acetylation. In summary, our studies suggest a new role for selenoproteins in the epigenetic modulation of proinflammatory genes. PMID- 25458529 TI - Trans-10,cis-12-conjugated linoleic acid worsens renal pathology and alters cyclooxygenase derived oxylipins in obesity-associated nephropathy. AB - Dietary conjugated linoleic acid (CLA) reduces indicators of early renal disease progression and the associated elevated cyclooxygenase (COX) levels in young obese rats with obesity-associated nephropathy (OAN). Therefore, renal function and injury and COX and its metabolites were assessed in obese fa/fa Zucker rats with more advanced renal disease. Obese rats at 16 weeks of age were provided with either cis(c)9, trans(t)11 (fa/fa-9,11) or t10,c12 (fa/fa-10,12) CLA for 8 weeks, and compared to lean (lean-CTL) and obese (fa/fa-CTL) rats provided the control diet without CLA. Obese rats displayed significantly reduced renal function and increased renal injury compared to lean rats. In the obese rat groups, glomerular hypertrophy was reduced in both CLA-supplemented groups. While all other measures of renal function or injury were not different in fa/fa-9,11 compared to fa/fa-CTL rats, the fa/fa-10,12 rats had greater renal hypertrophy, glomerular fibrosis, fibrosis, tubular casts and macrophage infiltration compared to the fa/fa-CTL and fa/fa-9,11 groups. The fa/fa-10,12 group also had elevated levels of renal COX1, which was associated with increased levels of two oxylipins produced by this enzyme, 6-keto-prostaglandin F(1alpha), and thromboxane B2. Renal linoleic acid and its lipoxygenase products also were lower in obese compared to lean rats, but CLA supplementation had no effect on these or any other lipoxygenase oxylipins. In summary, supplementation with c9,t11 CLA did not improve more advanced OAN and t10,c12 CLA worsened the renal pathology. Altered production of select COX1 derived oxylipins was associated with the detrimental effect of the t10,c12 isomer. PMID- 25458531 TI - Pollution of soil and groundwater by heavy metals. PMID- 25458530 TI - Ellagic acid modulates lipid accumulation in primary human adipocytes and human hepatoma Huh7 cells via discrete mechanisms. AB - Previously, we have reported that consumption of a muscadine grape phytochemical powder (MGP) decreased lipid accumulation in high-fat fed mice. The aim of this study was to identify the responsible polyphenolic constituents and elucidate the underlying mechanisms. In mice, MGP supplementation significantly reduced visceral fat mass as well as adipocyte size. To determine whether MGP affects adipogenesis or hypertrophic lipid accumulation, we used a human adipogenic stem cell (hASCs) model. Among the MGP, ellagic acid (EA) was identified as a potent negative regulator of adipogenesis of hASCs. In addition, EA substantially decreased the conversion of [(3)H]-acetyl CoA into fatty acids (FAs), suggesting that EA inhibits de novo synthesis of FA in mature adipocytes. Similarly, MGP supplementation significantly decreased hepatic triglyceride (TG) levels. The TG lowering effects of EA were confirmed in human hepatoma Huh7 cells. EA reduced [(3)H]-oleic acid esterification into [(3)H]-TG as well as the de novo synthesis of FA from [(3)H]-acetyl CoA in Huh7 cells. Intriguingly, EA also increased oxygen consumption rate and beta-oxidation-related gene expression. Taken together, EA attenuated new fat cell formation and FA biosynthesis in adipose tissue, while it reduced the synthesis of TG and FA and increased FA oxidation in the liver. These results suggest that EA exerts unique lipid-lowering effects both in adipose tissue and liver via discrete mechanisms. PMID- 25458532 TI - Educational environment and approaches to learning of undergraduate nursing students in an Indonesian school of nursing. AB - The aims of this study were to assess students' perceptions of their educational environment and approaches to learning, and determine if perceptions of learning environment associates with approaches to learning. A survey was conducted to collect data from a regional private university in Indonesia. A total of 232 nursing students completed two questionnaires that measured their perceptions of educational environment and approaches to learning. The measurement was based on Dundee Ready Education Environment Measurement (DREEM) and Approaches and Study Skills Inventory for Students (ASSIST). Five learning environments dimensions and three learning approaches dimensions from two measures were measured. The overall score of DREEM was 131.03/200 (SD 17.04), it was in the range considered to be favourable. The overall score is different significantly between years of study (p value = 0.01). This study indicated that the majority of undergraduate nursing students' adopt strategic approach (n = 139. 59.9%). The finding showed that perceived educational environment significantly associated with approaches to learning. This study implicated the need to maintain conducive learning environment. There is also a need to improve the management of learning activities that reflect the use of student-centered learning. PMID- 25458533 TI - Adiabatically tapered hyperbolic metamaterials for dispersion control of high-k waves. AB - Hyperbolic metamaterials (HMMs) have shown great promise in the optical and quantum communities due to their extremely large, broadband photonic density of states. This feature is a direct consequence of supporting photonic modes with unbounded k-vectors. While these materials support such high-k waves, they are intrinsically confined inside the HMM and cannot propagate into the far-field, rendering them impractical for many applications. Here, we demonstrate how the magnitude of k-vectors can be engineered as the propagating radiation passes through media of differing dispersion relations (including type II HMMs and dielectrics) in the in-plane direction. The total outcoupling efficiency of waves in the in-plane direction is shown to be on average 2 orders of magnitude better than standard out-of-plane outcoupling methods. In addition, the outcoupling can be further enhanced using a proposed tapered HMM waveguide that is fabricated using a shadowed glancing angle deposition technique; thereby proving the feasibility of the proposed device. Applications for this technique include converting high-k waves to low-k waves that can be out-coupled into free-space and creating extremely high-k waves that are quickly quenched. Most importantly, this method of in-plane outcoupling acts as a bridge through which waves can cross between the regimes of low-k waves in classical dielectric materials and the high-k waves in HMMs with strongly reduced reflective losses. PMID- 25458534 TI - Role of CB2 receptors and cGMP pathway on the cannabinoid-dependent antiepileptic effects in an in vivo model of partial epilepsy. AB - This study aimed at providing an insight on the possible role of cannabinoid (CB) type 2 receptors (CB2R) and cGMP pathway in the antiepileptic activity of WIN 55,212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de] 1,4-benzoxazin-6-Yl]-1-naphthalenylmethanone, a non-selective CB agonist, in the maximal dentate activation (MDA) model of partial epilepsy in adult male rats. We evaluated the activity of a CB2 antagonist/inverse agonist AM630, [6-iodo-2 methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone or 6 iodopravadoline, alone or in co-administration with WIN 55,212-2. Also, in the MDA model it was investigated the co-treatment of WIN 55,212-2 and 1H [1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one (ODQ), a specific inhibitor of the nitric oxide (NO)-activated soluble guanylyl cyclase (sGC), the cGMP producing enzyme. The WIN 55,212-2-dependent (21mg/kg) antiepileptic effects were significantly increased by the co-administration with AM630 and by the co treatment with ODQ (10mg/kg). Whereas, the administration of AM630 (2mg/kg), alone exerts no effects on hippocampal hyperexcitability. Our data show that pharmacological blockade of CB2 receptors and of sGC seems to cooperate with WIN in its antiepileptic action. These findings shed light on CB signaling mechanisms, hinting that the modulation of the effects of CB agonist in the hyperexcitability phenomena may be exerted both by targeting CB receptors and their possible downstream effectors, such as nitrergic-dependent cGMP pathway. PMID- 25458535 TI - Low doses of ethanol markedly potentiate the anti-seizure effect of diazepam in a mouse model of difficult-to-treat focal seizures. AB - Ethanol is commonly used as a solvent in injectable formulations of poorly water soluble drugs. The concentrations of ethanol in such formulations are generally considered reasonably safe. It is long known that ethanol can potentiate central effects of sedatives and tranquillizers, particularly the benzodiazepines, most likely as a result of a synergistic interaction at the GABAA receptor. However, whether this occurs at the low systemic doses of ethanol resulting from its use as solvent in parenteral formulations of benzodiazepines is not known. In the present study we evaluated whether a commercial ethanol-containing aqueous solution of diazepam exerts more potent anti-seizure effects than an aqueous solution of diazepam hydrochloride or an aqueous emulsion of this drug in the intrahippocampal kainate model of temporal lobe epilepsy in mice. Spontaneous epileptic seizures in this model are known to be resistant to major antiepileptic drugs. Administration of the ethanol-containing formulation of diazepam caused an almost complete suppression of seizures. This was not seen when the same dose (5 mg/kg) of diazepam was administered as aqueous solution or emulsion, although all three diazepam formulations resulted in similar drug and metabolite concentrations in plasma. Our data demonstrate that ethanol-containing solutions of diazepam are superior to block difficult-to-treat seizures to other formulations of diazepam. To our knowledge, this has not been demonstrated before and, if this finding can be translated to humans, may have important consequences for emergency treatment of acute seizures, series of seizures, and initial treatment of status epilepticus in patients. PMID- 25458536 TI - Influence of WIN 55,212-2 on the anticonvulsant and acute neurotoxic potential of clobazam and lacosamide in the maximal electroshock-induced seizure model and chimney test in mice. AB - The influence of WIN 55,212-2 mesylate (WIN) on the anticonvulsant activity and acute neurotoxic potential of clobazam (CLB) and lacosamide (LCM) was studied in the maximal electroshock-induced seizure (MES) model and chimney test in mice. RESULTS: indicate that WIN administered intraperitoneally, at doses of 2.5 and 5 mg/kg significantly enhanced the anticonvulsant action of CLB in the MES test by reducing its median effective dose (ED50) from 20.80 mg/kg to 12.05 mg/kg (P<0.05), and 8.22 mg/kg (P<0.001), respectively. In contrast, WIN (1.25 mg/kg) did not significantly potentiate the anticonvulsant activity of CLB against MES induced seizures. Similarly, WIN at doses of 1.25, 2.5 and 5 mg/kg had no significant impact on the anticonvulsant action of LCM in the MES test. On the other hand, WIN (5 mg/kg) had no impact on the acute neurotoxic effects of CLB and LCM in the chimney test and the median toxic doses (TD50) for CLB and LCM were almost unchanged. Thus, WIN (5 mg/kg) elevated the protective index values for CLB (from 1.41 to 3.07) and LCM (from 3.60 to 4.91). In conclusion, WIN potentiates suppression of tonic-clonic seizures produced by CLB in the mouse MES model, without affecting acute neurotoxic adverse effects of CLB in the chimney test in mice, which is favorable from a preclinical point of view. PMID- 25458537 TI - What would be the observable consequences if phospholipid bilayer diffusion of drugs into cells is negligible? AB - For drug transport across (i.e., through) an intact biological membrane, two main routes are possible: drugs may cross (i) through the phospholipid bilayer portion of the membrane, and/or (ii) via proteinaceous pores or transporters. Perhaps surprisingly, there is in fact no direct scientific evidence that the first of these takes place at any significant rate because, in the experiments performed to date, it has neither been varied as an independent variable nor measured directly as a dependent variable. Using a standard hypothetico-deductive framework, I assess the intellectual and observable consequences of assuming that, for drugs, phospholipid bilayer diffusion is negligible - 'PBIN' - (i.e., may be neglected, relative to transporter-mediated transmembrane fluxes). Predictions and postdictions of the PBIN hypothesis are not refuted by available experimental evidence. PMID- 25458538 TI - Novel targets for pharmacological intervention in age-related diseases. PMID- 25458539 TI - Engineering TGF-beta superfamily ligands for clinical applications. AB - TGF-beta superfamily ligands govern normal tissue development and homeostasis, and their dysfunction is a hallmark of many diseases. These ligands are also well defined both structurally and functionally. This review focuses on TGF-beta superfamily ligand engineering for therapeutic purposes, in particular for regenerative medicine and musculoskeletal disorders. We describe the key discovery that structure-guided mutation of receptor-binding epitopes, especially swapping of these epitopes between ligands, results in new ligands with unique functional properties that can be harnessed clinically. Given the promising results with prototypical engineered TGF-beta superfamily ligands, and the vast number of such molecules that remain to be produced and tested, this strategy is likely to hold great promise for the development of new biologics. PMID- 25458540 TI - Computational studies to predict or explain G protein coupled receptor polypharmacology. AB - Since G protein-coupled receptors (GPCRs) belong to a very large superfamily of evolutionarily related receptors (>800 members in humans), and due to the rapid progress on their structural biology, they are ideal candidates for polypharmacology studies. Broad screening and bioinformatics/chemoinformatics have been applied to understanding off-target effects of GPCR ligands. It is now feasible to approach the question of GPCR polypharmacology using molecular modeling and the available X-ray GPCR structures. As an example, large and sterically constrained adenosine derivatives (potent adenosine receptor ligands with low conformational freedom and multiple extended substituents) were screened for binding at diverse receptors. Unanticipated off-target interactions, including at biogenic amine receptors, were then modeled using a structure-based approach to provide a consistent understanding of recognition. A conserved Asp in TM3 changed its role from counterion for biogenic amines to characteristic H bonding to adenosine. The same systematic approach could potentially be applied to many GPCRs or other receptors using other sets of congeneric ligands. PMID- 25458543 TI - [Mesalazine-induced acute hepatitis]. PMID- 25458541 TI - Resistance-resistant antibiotics. AB - New antibiotics are needed because drug resistance is increasing while the introduction of new antibiotics is decreasing. We discuss here six possible approaches to develop 'resistance-resistant' antibiotics. First, multitarget inhibitors in which a single compound inhibits more than one target may be easier to develop than conventional combination therapies with two new drugs. Second, inhibiting multiple targets in the same metabolic pathway is expected to be an effective strategy owing to synergy. Third, discovering multiple-target inhibitors should be possible by using sequential virtual screening. Fourth, repurposing existing drugs can lead to combinations of multitarget therapeutics. Fifth, targets need not be proteins. Sixth, inhibiting virulence factor formation and boosting innate immunity may also lead to decreased susceptibility to resistance. Although it is not possible to eliminate resistance, the approaches reviewed here offer several possibilities for reducing the effects of mutations and, in some cases, suggest that sensitivity to existing antibiotics may be restored in otherwise drug-resistant organisms. PMID- 25458542 TI - Ascorbic acid PEG-2L is superior for early morning colonoscopies in colorectal cancer screening programs: a prospective non-randomized controlled trial. AB - BACKGROUND: The quality of colon cleansing and the tolerability of anterograde preparation are essential to the success of colorectal cancer screening. AIM: To compare the tolerability and efficacy of low-volume preparations vs the standard regimen in individuals scheduled for an early morning colonoscopy. STUDY: Participants in a population-based colorectal cancer screening program using the fecal immunochemical test who were scheduled for a colonoscopy from 09:00 a.m. to 10:20 a.m. were prospectively included and assigned to: (1) control group (PEG ELS 4L): PEG 4L and electrolytes; (2) group AscPEG-2L: a combination of PEG and ascorbic acid 2L; and (3) group PiMg: sodium picosulfate and magnesium citrate 500 mL plus 2L of clear fluids. Tolerability was evaluated with a questionnaire and the quality of bowel preparation with the Boston Bowel Preparation Scale. RESULTS: A total of 292 participants were included: 98 in the PEG-ELS 4L control group, 96 in the AscPEG-2L study group and 98 in the PiMg study group. Low-volume treatments were better tolerated than the standard solution (AscPEG-2L 94.8% and PiMg 93.9% vs PEG-ELS 4L 75.5%; p < 0.0001). The effectiveness of AscPEG-2L was superior to that of PEG-ELS 4L and PiMg (p = 0.011 and p = 0.032, respectively). Patient acceptance was higher for single-dose than for split-dose administration but efficacy was higher with the split dose than with other doses. CONCLUSIONS: In early morning colonoscopies, ascPEG-2L appears to be the best option, especially when administered in a split-dose. PMID- 25458544 TI - [Assessment and treatment of acute pancreatitis. Position document of the Catalan Society of Gastroenterology, Catalan Society of Surgery and Catalan Society of the Pancreas]. AB - The incidence of acute pancreatitis (AP) is increasing. AP is one of the gastrointestinal diseases that most frequently requires hospital admission in affected individuals. In the last few years, considerable scientific evidence has led to substantial changes in the medical and surgical treatment of this disease. New knowledge of the physiopathology of AP indicates that its severity is influenced by its systemic effects (organ failure), especially if the disease is persistent, and also by local complications (fluid collections or necrosis), especially if these become infected. Treatment should be personalized and depends on the patient's clinical status, the location of the necrosis, and disease stage. PMID- 25458545 TI - [Ataxia and frontal syndrome in a young woman resolved with a gluten-free diet]. PMID- 25458546 TI - [The diet low in fermentable carbohydrates short chain and polyols improves symptoms in patients with functional gastrointestinal disorders in Spain]. AB - BACKGROUND AND AIMS: Successful treatment of patients with irritable bowel syndrome (IBS) often remains elusive. Recent studies in Australia, the United Kingdom and New Zealand have suggested the efficacy of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) in the management of these patients. The aims of this study were to determine whether a diet low in FODMAPs improves symptoms in patients with functional gastrointestinal disorders (FGID) in Spain and to analyze the predictors of a good response. PATIENTS AND METHODS: A prospective study was carried out in consecutive patients with FGID type IBS and functioanl abdominal bloating. At inclusion all patients underwent an assessment through a baseline demographic questionnaire of symptoms of anxiety and depression and quality of life. A hydrogen breath test with lactose and fructose was performed and a low FODMAPs diet was indicated for 2 months by expert dietitians. These tests were taken as a reference. A positive response was defined as an improvement of at least 5 points out of a possible 10 in the symptom questionnaire. RESULTS: We included 30 patients (24 women, 39 [12] years). The response to the low FODMAPs diet was positive in controlling overall symptoms and specific symptoms such as functioanl abdominal bloating, abdominal pain, diarrhea, flatulence, nausea and fatigue in more than 70% of patients (P<.05). By contrast, constipation was controlled in only 48% of patients (P>.05). Adherence to the diet was good in 87% of patients and was a predictor of positive response in the univariate analysis. CONCLUSIONS: A diet low in FODMAPs is associated with symptom improvement in patients with IBS and functioanl abdominal bloating. Adherence to the diet was a determining factor. PMID- 25458548 TI - Epigastric hernia with gastric antrum incarceration. PMID- 25458547 TI - [Capsule endoscopy and obscure gastrointestinal bleeding: does the form of presentation matter?]. AB - INTRODUCTION: Obscure gastrointestinal bleeding (OGIB) is defined as bleeding from the gastrointestinal tract with no obvious cause after assessment with upper and lower gastrointestinal endoscopy. In these cases, the source is suspected to be in the small bowel. Obscure bleeding can be occult or overt. The aim of this study was to analyze the clinical and analytical characteristics and findings on capsule endoscopy in patients with OGIB and to determine the factors related to the detection of lesions in both forms of presentation. METHODS: We performed a retrospective study of capsule endoscopies carried out between November 2009 and November 2012 for OGIB. RESULTS: We analyzed 284 capsule endoscopies in 272 patients. Initially, 12 procedures could not be evaluated and were repeated. A total of 272 procedures were finally included in the analysis. The results of 114 (41.9%) capsule endoscopies were normal. Compared with patients with occult OGIB, those with overt OGIB were significantly older (70.2 vs. 67.5 years; p = 0.04), consumed more NSAID (24.2% vs. 11.9%; p = 0.01), had higher hemoglobin levels (9.3 vs. 10.4; p < 0,001) and more frequently required transfusion (64.5% vs 32.2%; p < 0.001). No differences were found between the two forms of presentation in the detection of canker sores-ulcers and polyps-masses. Vascular lesions were more frequently detected in overt than in occult OGIB (40.3% vs. 25.7%, respectively), (p < 0.05). When the total number of diagnoses carried out by capsule endoscopy was analyzed, no differences were found in diagnostic yield between overt OGIB (57%) and occult OGIB (54%), (p = 0.6). In overt OGIB, multivariate analysis showed that the variables that significantly predicted the detection of lesions on capsule endoscopy were consumption of medication NSAID (OR 2.75; p = 0.01), antiplatelets and anticoagulants (OR 2.64; p = 0.03) and analytical data hemoglobin (OR 3.23; p < 0.001) and INR (OR 1.8; p = 0.02). In occult OGIB, multivariate analysis showed that the factors significantly related to the detection of lesions on endoscopy were age (OR 1.9; p = 0.04) and NSAID consumption (OR 2.1; p = 0.01). CONCLUSIONS: Capsule endoscopy is essential in the assessment of OGIB. Although the diagnostic yield was similar in both forms of presentation, vascular lesions were more frequently detected in overt OGIB. The diagnostic yield of capsule endoscopy could be optimized by taking into account the form of presentation (overt vs. occult) and certain clinical and analytic data (age, drug consumption, hemoglobin). PMID- 25458549 TI - Predictive factors of insulin resistance resolution with adjustable gastric band surgery. AB - INTRODUCTION: The aim of the study was to evaluate preoperative factors associated with remission of diabetes and weight loss after laparoscopic gastric band surgery. MATERIAL AND METHODS: A retrospective cohort of 95 patients who had an adjustable gastric band placed were included. A preliminary descriptive study of prognostic factors was performed using the logistic regression model with SPSS 17.0. The independent variables were age, sex, body mass index (BMI), diabetes status and degree of obesity; dependent variables were the proportion of weight loss, change in diabetes status score and percent changes in fasting sugar and glycosylated hemoglobin. RESULTS: The variables that were significantly associated with the percentage of changes in fasting blood sugar and glycated hemoglobin were: the degree of obesity in the first year; preoperative and diabetes status respectively. The analysis of the need for antidiabetic treatment using the modified diabetes status score showed preoperative BMI, age and gender as significant predictors. CONCLUSIONS: In patients undergoing gastric band surgery, weight loss is the fundamental mechanism by which insulin sensitivity increases. This improvement in glucose metabolism is influenced by factors such as sex, age, insulin treatment, duration of diabetes and degree of preoperative obesity. PMID- 25458550 TI - Endoscopic treatment with biologic glue of chronic presacral sinus after low anterior resection. PMID- 25458551 TI - [Treatment of recurrent temporomandibular dislocation by displacement of the zygomatic arch: a modification of Gosserez and Dautrey's technique]. AB - INTRODUCTION: Many methods have been reported for the surgical treatment of recurrent anterior temporomandibular dislocation. Most of these techniques are designed to limit the forward migration of the condylar head. The great number of surgical techniques experimented illustrates the difficulty to find a satisfactory method for the treatment of these recurrent dislocations. TECHNICAL NOTE: We present a modification of Gosserez and Dautrey's surgical technique for the treatment of recurrent anterior temporomandibular joint dislocation. DISCUSSION: The surgical technique is described and its indications are discussed. PMID- 25458552 TI - [67 cases of face and neck cellulitis managed at the Brazzaville Teaching Hospital]. AB - INTRODUCTION: Face and neck cellulitis is an infection of cellular adipose tissues of the head and neck. These are common complications but true diagnostic and therapeutic emergencies. We had for aim to analyze the diagnostic and therapeutic aspects of these infections treated under local anesthesia at the Brazzaville teaching hospital. MATERIEL AND METHODS: We conducted a retrospective study from January 1, 1999 to December 31, 2008 on 67 cases of patients admitted to the ENT and Stomatology units of the Brazzaville teaching hospital. RESULTS: We included 47 male (70%) and 20 female (30%) patients (sex ratio 2.35) with a mean age 21 years (range 14-69 years of age). The cause of infection was dental in 75% of cases, lymph nodes in 24% of cases, and otologic in 1% of cases. The treatment was medical and surgical. DISCUSSION: Cervico-facial cellulitis more frequently concerns young adults. Neglect, poor oral hygiene, and ignorance contribute to the occurrence of these complications. The main portal of entry is dental. The authors recommend the antibiotic and corticosteroid therapy associated with incision and drainage. PMID- 25458553 TI - [A case of malignant amygdaloid cyst]. AB - INTRODUCTION: An amygdaloid cyst is a rare high laterocervical cystic tumor arising from the second branchial cleft. It accounts for 2% of laterocervical tumors and up to 85% of second branchial cleft abnormalities [1]. The incidence of intracystic squamous cell carcinoma ranges from 4 to 22% [2]. The diagnosis of primary carcinoma or intracystic metastasis is a controversial issue. We report a rare case of degenerate amygdaloid cyst meeting the diagnostic criteria for intracystic squamous cell carcinoma determined by Martin and Khafif. OBSERVATION: A 73-year-old female patient consulted for a left cervical swelling in 2010; the diagnosis was an amygdaloid cyst. She had a history of squamous cell carcinoma of the hard palate (T1NoMo) surgery and radiation therapy in 2009, without recurrence. Three years later, the swelling increased to a large size without any cervical node involvement. An exploratory cervicotomy with histological study revealed intracystic squamous cell degeneration. DISCUSSION: Primary squamous cell carcinoma location in the wall of an amygdaloid cyst is extremely rare and a highly controversial issue. The challenge is to be able to discriminate between a cystic metastasis of squamous cell carcinoma of the aerodigestive tract and a primary squamous cell carcinoma located in the wall of an amygdaloid cyst. Martin and Khafif defined specific criteria to confirm the diagnosis of primary branchiogenic carcinoma. PMID- 25458554 TI - Development of a high-efficiency gene knockout system for Pochonia chlamydosporia. AB - The nematophagous fungus Pochonia chlamydosporia, which belongs to the family Clavicipitaceae (Ascomycota: Pezizomycotina: Sordariomycetes: Hypocreales), is a promising biological control agent for root-knot and cyst nematodes. Its biocontrol effect has been confirmed by pot and field trials. The genome sequence of the fungus was completed recently; therefore, genome-wide functional analyses will identify its infection-associated genes. Gene knockout techniques are useful molecular tools to study gene functions. However, cultures of P. chlamydosporia are resistant to high levels of a range of fungal inhibitors, which makes the gene knockout technique difficult in this fungus. Fortunately, we found that the wild P. chlamydosporia strain PC-170 could not grow on medium containing 150MUgml(-1) G418 sulfate, representing a new selectable marker for P. chlamydosporia. The neomycin-resistance gene (neo), which was amplified from the plasmid pKOV21, conferred G418-resistance on the fungus; therefore, it was chosen as the marker gene. We subsequently developed a gene knockout system for P. chlamydosporia using split-marker homologous recombination cassettes with resistance selection and protoplast transformation. The split-marker cassettes were developed using fusion PCR, and involved only two rounds of PCR. The final products comprised two linear constructs. Each construct contained a flanking region of the target gene and two thirds of the neo gene. Alkaline serine protease and chitinase were confirmed to be produced by P. chlamydosporia during infection of nematode eggs and could participate in lysis of the eggshell of nematode eggs. Here, we knocked out one chitinase gene, VFPPC_01099, and two protease genes (VFPPC_10088, VFPPC_06535). We obtained approximately 100 suspected mutants after each transformation. After screening by PCR, the average rate of gene knockout was 13%: 11% (VFPPC_01099), 13% (VFPPC_10088) and 15% (VFPPC_06535). This efficient and convenient technique will accelerate functional genomic studies in P. chlamydosporia. PMID- 25458555 TI - Methods of isolation and purification of outer membrane vesicles from gram negative bacteria. AB - Outer membrane vesicles secreted by gram-negative bacteria play an important role in bacterial physiology as well as in virulence and host-pathogen interaction. Isolated vesicles of some bacteria have also been studied for their immunomodulatory potential in the vaccine development. However, the production of vesicles in sufficient amount, purity and reproducibility remains a critical challenge for subsequent analyses in most bacteria. In the present review methods of production, isolation, purification and quantification of outer membrane vesicles are summarized and discussed. PMID- 25458556 TI - Interplay of Coil-Globule Transition and Surface Adsorption of a Lattice HP Protein Model. AB - An end-grafted hydrophobic-polar (HP) model protein chain with alternating H and P monomers is studied to examine interactions between the critical adsorption transition due to surface attraction and the collapse transition due to pairwise attractive H-H interactions. We find that the critical adsorption phenomenon can always be observed; however, the critical adsorption temperature T(CAP) is influenced by the attractive H-H interactions in some cases. When the collapse temperature T(c) is lower than T(CAP), the critical adsorption of the HP chain is similar to that of a homopolymer without intrachain attractions and T(CAP) remains unchanged, whereas the collapse transition is suppressed by the adsorption. In contrast, for cases where T(c) is close to or higher than T(CAP), T(CAP) of the HP chain is increased, indicating that a collapsed chain is more easily adsorbed on the surface. The strength of the H-H attraction also influences the statistical size and shape of the polymer, with strong H-H attractions resulting in adsorbed and collapsed chains adopting two-dimensional, circular conformations. PMID- 25458557 TI - [Standard protocol for fetal or perinatal autopsy. Haute Autorite de sante ]. PMID- 25458558 TI - An open-label, multicenter, randomized phase Ib/II study of eribulin mesylate administered in combination with pemetrexed versus pemetrexed alone as second line therapy in patients with advanced nonsquamous non-small-cell lung cancer. AB - INTRODUCTION: New treatment options are needed for second-line therapy in patients with NSCLC. PATIENTS AND METHODS: This was a phase Ib/II study in patients with nonsquamous NSCLC in whom 1 previous platinum-based chemotherapy regimen had failed. Fifteen patients were enrolled in a dose escalation of eribulin mesylate in combination with pemetrexed (E+P). In phase II (n = 80), E+P at the maximum tolerated dose was compared with P. RESULTS: In phase Ib, the maximum tolerated dose of E+P was defined as eribulin 0.9 mg/m(2) with pemetrexed (500 mg/m(2)) each on day 1 of a 21-day cycle. In phase II, adverse events were comparable between groups. PFS and OS were similar between treatment groups. Median PFS was 21.4 weeks for E+P (n = 26; 95% confidence interval [CI], 12.7 39.6) and 23.4 weeks for P (n = 29; 95% CI, 17.1-29.9), with a hazard ratio of 1.0 (95% CI, 0.6-1.7). CONCLUSION: During phase Ib, E+P was tolerated only at a markedly lower dosing intensity relative to the eribulin monotherapy regimen approved for breast cancer and used in phase II studies of NSCLC. At the selected phase II dosing regimen, E+P was generally safe and well tolerated but provided no therapeutic advantage for the second-line treatment of locally advanced or metastatic nonsquamous NSCLC. PMID- 25458559 TI - Ceritinib (LDK378): a potent alternative to crizotinib for ALK-rearranged non small-cell lung cancer. AB - The success in identifying the chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) as an oncogenic driver has thoroughly changed the treatment of non-small-cell lung cancer. In the past decade, targeted drugs have emerged as an efficient personalized strategy for ALK-rearranged non-small cell lung cancer. The accelerated approval of potent ALK inhibitors, such as crizotinib and more recently ceritinib (LDK378), based on the well designed phase I/II trials has been a landmark success in clinical cancer research and contributes a new era of oncogenic targeted therapy characterized by elegant clinical trial design. In this review, we aim to present the current knowledge on acquired resistance of crizotinib known as a first-in-class ALK inhibitor and potential solutions to improve the cost-effectiveness, and to review the difference between ceritinib and crizotinib; preclinical data and results of the elegant early clinical trial of ceritinib which promoted its accelerated approval, pharmacokinetics, safety profile, and tolerability, the updated results (eg, efficacy on brain metastases), and robust design of ongoing phase II/III trials, and future directions of ceritinib to be a potent alternative to crizotinib for ALK-rearranged non-small-cell lung cancer are also presented. PMID- 25458560 TI - Lung cancer hormesis in high impact states where nuclear testing occurred. AB - BACKGROUND: Hormesis is a favorable biological response to low toxin exposure. In the case of radiation, large doses are carcinogenic, but low doses might be protective. In the current study, we analyzed lung cancer incidence in high impact radiation states where nuclear testing occurred and compared it with lung cancer incidence in the remaining normal-impact radiation states and the District of Columbia. MATERIALS AND METHODS: Lung cancer incidence data were from the American Cancer Society. Tobacco use 2012 data were from the Centers for Disease Control and Prevention. The distribution of states grouped according to lung cancer incidence interval was from the Centers for Disease Control and Prevention. Total background radiation measurements (terrestrial + cosmic + radon) were from Assessment of Variations in Radiation Exposure in the United States (2005). Data on high- and normal-impact states were from the National Radiation Exposure Screening & Education Program (RESEP). Congress passed the Radiation Exposure Compensation Act Amendments of 2000, creating RESEP, to help thousands of people diagnosed with cancer and other diseases caused by exposure to nuclear fallout or radioactive materials such as uranium. These people live in 12 high-impact states where nuclear testing had occurred. High-impact states were not designated according to measurements of background radiation. RESULTS: Lung cancer incidence is significantly lower in high-impact states in men (t = 5.4 for unequal variance; P < .001) and women (t = 3.0; P < .001). The clustering of the 12 high-impact states in the 2 lowest lung cancer incidence intervals (26.8-56.9 and 57.0-63.2) is statistically significant (P < .001, Fisher exact test, 2 tailed). Because cigarette smoking is ordinarily the most powerful risk factor for lung cancer, multivariate linear regression analysis of the effect of U.S. state group (normal-impact, high-impact, or extra high-impact for Nevada, Utah, and Arizona) on lung cancer incidence in men and women was performed. (In Nevada, Utah, and Arizona, men and women would have been downwind.) The U.S. state group impact was significant (P < .001 for men; P = .015 for women). The effect of percentage of smokers in the population was significant (P < .001 for men; P < .001 for women). The effect of total background radiation was significant (P = .029 for men; P < .029 for women); like the state group impact, more background radiation exposure was associated with less lung cancer. CONCLUSION: Hormesis is still mired in controversy. Yet, it is of vital medical importance because of the continuing debate over whether the low-level radiation doses from diagnostic x ray procedures, such as computed tomography scans, are harmful. Our analysis adds to the body of evidence suggesting that the linear no threshold model of radiation carcinogenicity in lung cancer might not be correct. Low-level radiation exposure might protect against lung cancer rather than cause it. PMID- 25458561 TI - Comparative efficacy of diclazuril (Vecoxan(r)) and toltrazuril (Baycox bovis(r)) against natural infections of Eimeria bovis and Eimeria zuernii in French calves. AB - A blinded, randomized, controlled, multi-centric field study was conducted on French dairy farms (n = 9) to evaluate the long term efficacy of metaphylactic, single oral treatments with either 1 mg/kg body weight (BW) of diclazuril (Vecoxan(r)), or 15 mg/kg BW of toltrazuril (Baycox(r)) against natural infections with Eimeria zuernii and/or Eimeria bovis, compared to untreated control animals. A total of 199 calves from nine commercial farms aged between 21 and 55 days old at the start of study were included and randomly allocated to one of three groups. Calves on all farms were observed for a period of 78 days post treatment, using both parasitological (oocyst excretion), and clinical parameters (faecal score and body weight). The assessment of efficacy was based on both control of oocyst excretion, and on the average daily weight gains throughout the study. During the whole study period, the mean number of days with diarrhoea (>= 2) was similar (0.7 days) between treated groups. Excretion in the untreated group peaked at 21 days after treatment. In both the diclazuril and toltrazuril treated groups, mean oocyst excretion decreased dramatically in the five days following treatment. Thereafter, particularly towards the end of the study period, oocyst counts and percentage levels of E. zuernii were highest in the toltrazuril-treated group. In pooled data from all trial sites, the average daily weight gain was significantly (p = 0.01) higher (+ 0.057 kg/day) in the diclazuril group when compared to the toltrazuril group, and the average body weight gain of the diclazuril treated group was 4.4 kg higher than the toltrazuril group. On eight of the nine trial sites, the average daily gain was greater in the diclazuril group than in the toltrazuril group. This study demonstrates that, over an extended observation period of 78 days, metaphylactic treatment with both diclazuril and toltrazuril reduces the impact of coccidiosis, but greater performance benefits based on average daily weight gains, were achieved following the use of diclazuril. PMID- 25458562 TI - Significant increase of Echinococcus multilocularis prevalence in foxes, but no increased predicted risk for humans. AB - The emergence of the zoonotic tapeworm Echinococcus multilocularis, causative agent of alveolar echinococcosis (AE), poses a public health risk. A previously designed risk map model predicted a spread of E. multilocularis and increasing numbers of alveolar echinococcosis patients in the province of Limburg, The Netherlands. This study was designed to determine trends in the prevalence and worm burden of E. multilocularis in foxes in a popular recreational area in the southern part of Limburg to assess the risk of infection for humans and to study the prevalence of E. multilocularis in dogs in the adjacent city of Maastricht. Thirty-seven hunted red foxes were tested by the intestinal scraping technique and nested PCR on colon content. Additionally, 142 fecal samples of domestic dogs from Maastricht were analyzed by qPCR for the presence of E. multilocularis. In foxes, a significantly increased prevalence of 59% (95% confidence interval 43 74%) was found, compared to the prevalence of 11% (95% CI 7-18%) in 2005-2006. Average worm burden increased to 37 worms per fox, the highest since the first detection, but consistent with the prediction about the parasite population for this region. Updated prediction on the number of AE cases did not lead to an increase in previous estimates of human AE cases up to 2018. No dogs in the city of Maastricht tested positive, but results of questionnaires showed that deworming schemes were inadequate, especially in dogs that were considered at risk for infection. PMID- 25458563 TI - Comparison of Toxocara eggs in hair and faecal samples from owned dogs and cats collected in Ankara, Turkey. AB - This study was undertaken to determine the prevalence of Toxocara eggs on hair and in faeces of healthy owned cats and dogs and to make comparisons between data (sex, age, host factor, etc.) collected from dogs and cats. Toxocara eggs were found on the hair of 14% of 100 dogs and 22% of 100 cats. In total, 58 and 136 eggs were recovered from the hair samples of examined cats and dogs, respectively. Of the total number of eggs, 2 were classified as embryonated in cats. One of the eggs recovered was embryonating in dogs. The maximum number of eggs was found in the tail bottom of cats (28 eggs) and dogs (58 eggs). As well as finding Toxocara eggs in dogs and cats hair, we also found eggs of some helminthic parasites; such as Dicrocoelium sp., Fasciola sp., Taenia sp., Dipylidium caninum and Toxascaris leonina. In addition, faecal samples of same dogs and cats were also examined by two techniques (centrifugal flotation and sedimentation): Toxocara eggs were found in 5% and 13% of dogs and cats faeces, respectively. But, 14% of the dogs and 22% of the cats were positive for Toxocara eggs on hair. The prevalence of eggs in faecal samples was lower than those detected from hair samples (P < 0.05). Two techniques for recovering Toxocara eggs from faecal samples were tested for efficiency and suitability for routine use. The results were expressed as the percentage rate of recovery of Toxocara eggs in positive faecal samples. The recovery rate was better with the method of sedimentation than with the method of flotation (P < 0.05). This study indicates that dogs and cats without internal infections were shown to have eggs on their hair and so uninfected animals also pose a threat in terms of the eggs present on their hair, albeit a small risk. PMID- 25458564 TI - Eucoleus boehmi infection in red fox (Vulpes vulpes) from Italy. AB - In the last decade an increase of the number of red foxes in anthropized habitats across European countries, including Italy, has been observed. This pones implications in terms of disease transmission between wildlife and domestic animals; in fact, there are evidences of the role of foxes as reservoirs and amplifiers of a broad spectrum of parasites infecting pets. The present study evaluated the prevalence of Eucoleus boehmi, an emerging extra-intestinal nematodes of the Capillariinae subfamily, in red foxes. The nasal passages and sinuses of 179 red foxes culled from several areas of northern and central Italy were inspected and the mucosal surfaces were scrapped and examined for adult nematodes and eggs, microscopically and genetically identified. Overall 55 foxes (30.7%) were found to be infected with E. boehmi, i.e. 27 on inspection of the nasal passages and sinuses and 28 on mucosal flush and scraping. The occurrence of E. boehmi was significantly (p < 0.05) correlated to the sampling location, the age and gender of the animals examined; the higher rates of prevalence were observed in animals culled in Piedmont (43.3%) and in female (60.6%) and adult (38.1%) subjects. A total of 184 adult parasites were recovered, with a mean intensity of infection of 3.34, and a more frequent localization of E. boehmi in the nasal passages rather than in the sinuses. A significant (p < 0.05) relationship was found between the parasite burden and body condition and age of the animals; the intensity of infection was significantly higher in juveniles (mean: 6.3 specimens) and in animals showing poor fox body condition (mean: 7.8 specimens). These results show that E. boehmi is highly prevalent in the red fox populations of certain areas of Italy. Epidemiological implications are discussed, with a special focus on the role that this wild canid may have in the increasing transmission of nasal eucoleosis to domestic dogs. PMID- 25458565 TI - Cylicocyclus species predominate during shortened egg reappearance period in horses after treatment with ivermectin and moxidectin. AB - The normal time interval between treatment of horses with a macrocyclic lactone (ML) and reappearance of strongyle eggs in the feces, or 'Egg Reappearance Period (ERP)', is at its shortest 8 weeks for ivermectin (IVM) and 12 weeks for moxidectin (MOX). Nowadays, it is not uncommon to find shorter ERPs, potentially indicating the beginning of the development of drug resistance. Whether all cyathostomin species contribute equally to a shortened ERP is not known. In the present study a Reverse Line Blot (RLB) on individual infective larvae was used to compare species composition before and after ML-treatment in horses with either a normal or a shortened ERP. Species composition was determined for a total of 21 horses on 4 farms and was based on differentiation of approximately 40 larvae per horse per sampling day. After IVM treatment the shortest ERP was found to be 28-42 days. After MOX treatment the shortest ERP was found to be 42 56 days. The RLB showed that early egg shedding was dominated by species of the genus Cylicocyclus (Cyc.) (Cyc. ashworthi, Cyc. insigne, Cyc. leptostomum and Cyc. nassatus). Before treatment, species composition was generally more diverse with species from several other genera also present. Interestingly, on the farm with the overall shortest ERP and where all horses showed a shortened ERP, more species/genera were present during early egg excretion than on other farms. Results suggest that cyathostomin species within the genus Cylicocyclus contribute to a shortened ERP more than species from other genera. However, if shortening of ERP overall becomes more pronounced and widespread within a farm, species from other genera will also be present during early egg shedding. PMID- 25458566 TI - Arrested development of experimental Cyathostominae infections in ponies in Czech republic. AB - Nine ponies, aged 12 months at the time of infection, were randomly allocated to one of three groups. Each pony was infected with 30,000 infective cyathostome larvae stored 4 weeks under the natural environmental conditions of the Czech Republic. Horses of Group A were infected with larvae conditioned from August 16 to September 12 (the first phase of the experiment). Horses of Group B were inoculated with larvae conditioned from October 10 to November 4 (the second phase of the experiment). In the third phase, horses from Group C received larvae stored under natural conditions (from 8.11 to 18.11.2011). The larvae were then kept under laboratory conditions (5 degrees C, the light reduction according to the nature condition). In the first and second phase of the experiment, 98.57% and 95.48% of adult nematodes were found, respectively. However, only 29.07% of adults were found in the third phase of experiment, and the proportion of arrested larvae (EL3) was 67.73%. The share of these larvae in the cecum during last phase of the experiment comprised 92.59% of all cyathostomes. PMID- 25458567 TI - Searching human brain for mechanisms of psychiatric disorders. Implications for studies on schizophrenia. AB - In the past 25years, research on the human brain has been providing a clear path toward understanding the pathophysiology of psychiatric illnesses. The successes that have been accrued are matched by significant difficulties identifying and controlling a large number of potential confounding variables. By systematically and effectively accounting for unwanted variance in data from imaging and postmortem human brain studies, meaningful and reliable information regarding the pathophysiology of human brain disorders can be obtained. This perspective paper focuses on postmortem investigations to discuss some of the most challenging sources of variance, including diagnosis, comorbidity, substance abuse and pharmacological treatment, which confound investigations of the human brain. PMID- 25458569 TI - The prevalence and moderators of clinical pain in people with schizophrenia: a systematic review and large scale meta-analysis. AB - BACKGROUND: People with schizophrenia frequently have physical comorbidities that can cause pain. Experimental studies report reduced pain sensitivity among schizophrenia patients, but it remains unclear if clinically relevant pain is less prevalent in schizophrenia. METHOD: We systematically searched major electronic databases from inception till 03/2014. Articles were included that reported the prevalence of clinical pain in people with schizophrenia. Two independent authors conducted searches, completed methodological quality assessment and extracted data. A random effects relative risks (RR) meta-analysis was conducted to determine the prevalence of all-cause and specific pain in schizophrenia, and the relative prevalence compared to the general population, and to assess moderators. RESULTS: Altogether, 14 studies were included encompassing 242,703 individuals with schizophrenia (30.2-55.8 years) and 4,259,221 controls. Different types of pain were considered. The overall pooled prevalence of clinical pain in people with schizophrenia was 34.7% (95% CI=23.6 46.6). In the comparative analysis involving 7 studies with controls, the RR was 0.99 (95% CI=0.83-1.19). The pooled prevalence of headache among 94,043 individuals with schizophrenia was 29.9% (95% CI=3-69%) and the RR compared to 4,248,284 controls was 1.32 (95% CI=0.85-2.07). In moderator analyses, neither age, sex, study quality or pain assessment method influenced pain prevalence. CONCLUSION: Clinical pain affects a third of people with schizophrenia and levels are similar with age- and sex-comparable controls. Future research is needed to determine if similar clinical pain prevalences in schizophrenia occur despite having more painful conditions, resulting from under-reporting, higher pain thresholds or lower help seeking behaviours. PMID- 25458570 TI - Factors associated with violence among Japanese patients with schizophrenia prior to psychiatric emergency hospitalization: a case-controlled study. AB - BACKGROUND: Numerous studies have examined a wide range of risk factors associated with violence among patients with schizophrenia. However, risk factors linked to different socio-cultural backgrounds remain unclear. OBJECTIVE: The objectives were to investigate factors associated with violence among Japanese patients with schizophrenia prior to emergency hospitalizations and to compare them with factors found in studies on other populations. METHODS: We recruited 420 Japanese patients with schizophrenia who had committed violent acts immediately prior to emergency admission to a psychiatric hospital in Tokyo, during the period 1986 to 2005. Cases were compared with controls (non violent hospitalized patients with schizophrenia) matched for gender, age and admission year. All medical records were reviewed retrospectively. Inter-rater reliability tests of assessment were performed. Conditional logistic regression analysis was used to identify factors associated with violence. RESULTS: The symptoms of gross excitement, prior violence, auditory hallucinations, systematization of delusions, incoherence of speech, delusions of reference, TCO symptoms, living with others and long duration of illness were found to be associated with violence. In contrast, antisocial traits such as substance abuse and antisocial episodes were not recognized as significant violence-associated factors. CONCLUSION: Violence among Japanese patients with schizophrenia was strongly associated with elements of schizophrenia itself, rather than antisocial traits. This study highlighted associated factors for violence among Japanese patients with schizophrenia which differ distinctly from associated factors in other countries. This result demonstrates that future studies assessing the risk of violence among patients with schizophrenia need to consider cultural and racial differences in cohorts. PMID- 25458568 TI - Transcriptional regulation of GAD1 GABA synthesis gene in the prefrontal cortex of subjects with schizophrenia. AB - Expression of GAD1 GABA synthesis enzyme is highly regulated by neuronal activity and reaches mature levels in the prefrontal cortex not before adolescence. A significant portion of cases diagnosed with schizophrenia show deficits in GAD1 RNA and protein levels in multiple areas of adult cerebral cortex, possibly reflecting molecular or cellular defects in subtypes of GABAergic interneurons essential for network synchronization and cognition. Here, we review 20years of progress towards a better understanding of disease-related regulation of GAD1 gene expression. For example, deficits in cortical GAD1 RNA in some cases of schizophrenia are associated with changes in the epigenetic architecture of the promoter, affecting DNA methylation patterns and nucleosomal histone modifications. These localized chromatin defects at the 5' end of GAD1 are superimposed by disordered locus-specific chromosomal conformations, including weakening of long-range promoter-enhancer loopings and physical disconnection of GAD1 core promoter sequences from cis-regulatory elements positioned 50 kilobases further upstream. Studies on the 3-dimensional architecture of the GAD1 locus in neurons, including developmentally regulated higher order chromatin compromised by the disease process, together with exploration of locus-specific epigenetic interventions in animal models, could pave the way for future treatments of psychosis and schizophrenia. PMID- 25458572 TI - A rating scale for the assessment of objective and subjective formal Thought and Language Disorder (TALD). AB - Formal thought disorder (FTD) is a core syndrome of schizophrenia. However, patients with other diagnoses, such as mania and depression amongst others, also present with FTD. We introduce a novel, comprehensive clinical rating scale, capturing the full variety of FTD phenomenology including subjective experiences. The 30-item Thought and Language Disorder (TALD) scale is based on a detailed review of the literature, encompassing all formal thought disorder symptoms reported from the early 20th century onwards. Objectively observable symptoms as well as subjective phenomena were included. Two hundred and ten participants (146 patients ICD-10 diagnoses: depression n=63, schizophrenia n=63, mania n=20; 64 healthy control subjects) were interviewed and symptoms rated with the TALD, TLC, HAMD, YMRS and SAPS/SANS. A principal component analyses was performed for the TALD to differentiate sub-syndromes. The principal component analysis revealed four FTD factors; objective and subjective as well as positive and negative factor dimensions. The correlation analyses with the TLC and the SAPS/SANS FTD sub-scores demonstrated the factor validity for the objective factors. The different diagnoses showed a distinct pattern of symptom severity in each of the factors, with mania patients exhibiting the highest value in the positive, objective dimension. The scale showed good psychometric results, which makes it a practicable, nosologically-open instrument for the detailed assessment of all FTD dimensions. The results strengthen the importance of subjective symptom assessment reported by the patient. PMID- 25458573 TI - Less is more. PMID- 25458571 TI - Impaired insight into illness and cognitive insight in schizophrenia spectrum disorders: resting state functional connectivity. AB - BACKGROUND: Impaired insight into illness (clinical insight) in schizophrenia has negative effects on treatment adherence and clinical outcomes. Schizophrenia is described as a disorder of disrupted brain connectivity. In line with this concept, resting state networks (RSNs) appear differentially affected in persons with schizophrenia. Therefore, impaired clinical, or the related construct of cognitive insight (which posits that impaired clinical insight is a function of metacognitive deficits), may reflect alterations in RSN functional connectivity (fc). Based on our previous research, which showed that impaired insight into illness was associated with increased left hemisphere volume relative to right, we hypothesized that impaired clinical insight would be associated with increased connectivity in the DMN with specific left hemisphere brain regions. METHODS: Resting state MRI scans were acquired for participants with schizophrenia or schizoaffective disorder (n=20). Seed-to-voxel and ROI-to-ROI fc analyses were performed using the CONN-fMRI fc toolbox v13 for established RSNs. Clinical and cognitive insight were measured with the Schedule for the Assessment of Insight Expanded Version and Beck Cognitive Insight Scale, respectively, and included as the regressors in fc analyses. RESULTS: As hypothesized, impaired clinical insight was associated with increased connectivity in the default mode network (DMN) with the left angular gyrus, and also in the self-referential network (SRN) with the left insula. Cognitive insight was associated with increased connectivity in the dorsal attention network (DAN) with the right inferior frontal cortex (IFC) and left anterior cingulate cortex (ACC). CONCLUSION: Increased connectivity in DMN and SRN with the left angular gyrus and insula, respectively, may represent neural correlates of impaired clinical insight in schizophrenia spectrum disorders, and is consistent with the literature attributing impaired insight to left hemisphere dominance. Increased connectivity in the DAN with the IFC and ACC in relation to cognitive insight may facilitate enhanced mental flexibility in this sample. PMID- 25458575 TI - Risk of schizophrenia spectrum and affective disorders associated with small for gestational age birth and height in adulthood. PMID- 25458574 TI - An integrated eye movement score as a neurophysiological marker of schizophrenia. PMID- 25458576 TI - Two-way ANOVA for scalar trajectories, with experimental evidence of non-phasic interactions. AB - Kinematic and force trajectories are often normalized in time, with mean and variance summary statistic trajectories reported. It has been shown elsewhere, for simple one-factor experiments, that statistical testing can be conducted directly on those summary statistic trajectories using Random Field Theory (RFT). This technical note describes how RFT extends to two-factor designs, and how bizarre "non-phasic interactions" can occur in multi-factor experiments. We reanalyzed a public dataset detailing stance phase knee flexion during walking in (a) patellofemoral pain vs. controls, and (b) females vs. males using both a full model (with interaction effect) and a main-effects-only model. In both models the main effect of PAIN failed to reach significance at alpha=0.05. The main effect of GENDER reached significance over 5-40% stance (p=0.0005), but only for the full model. The interaction effect (in the full model) reached significance over 0-15% of stance (p=0.030), and resulted from greater flexion in females but decreased flexion in males in PFP vs. controls. Thus there was a non-phasic interaction in which a non-significant interaction (over 20-40% stance) suppressed the main effect of GENDER. Similarly, if we had only analyzed 20-40% stance, we would have committed Type II error by failing to reject the null PAIN GENDER interaction hypothesis. The possible presence of non-phasic interactions implies that trajectory analyses must be conducted at the whole-trajectory level, because a failure to do so will generally miss non-phasic interactions if present. PMID- 25458577 TI - Mechanical effects of the surface ectoderm on optic vesicle morphogenesis in the chick embryo. AB - Precise shaping of the eye is crucial for proper vision. Here, we use experiments on chick embryos along with computational models to examine the mechanical factors involved in the formation of the optic vesicles (OVs), which grow outward from the forebrain of the early embryo. First, mechanical dissections were used to remove the surface ectoderm (SE), a membrane that contacts the outer surfaces of the OVs. Principal components analysis of OV shapes suggests that the SE exerts asymmetric loads that cause the OVs to flatten and shear caudally during the earliest stages of eye development and later to bend in the caudal and dorsal directions. These deformations cause the initially spherical OVs to become pear shaped. Exposure to the myosin II inhibitor blebbistatin reduced these effects, suggesting that cytoskeletal contraction controls OV shape by regulating tension in the SE. To test the physical plausibility of these interpretations, we developed 2-D finite-element models for frontal and transverse cross-sections of the forebrain, including frictionless contact between the SE and OVs. With geometric data used to specify differential growth in the OVs, these models were used to simulate each experiment (control, SE removed, no contraction). For each case, the predicted shape of the OV agrees reasonably well with experiments. The results of this study indicate that differential growth in the OV and external pressure exerted by the SE are sufficient to cause the global changes in OV shape observed during the earliest stages of eye development. PMID- 25458578 TI - Single-cell force spectroscopy as a technique to quantify human red blood cell adhesion to subendothelial laminin. AB - Single-cell force spectroscopy (SCFS), an atomic force microscopy (AFM)-based assay, enables quantitative study of cell adhesion while maintaining the native state of surface receptors in physiological conditions. Human healthy and pathological red blood cells (RBCs) express a large number of surface proteins which mediate cell-cell interactions, or cell adhesion to the extracellular matrix. In particular, RBCs adhere with high affinity to subendothelial matrix laminin via the basal cell adhesion molecule and Lutheran protein (BCAM/Lu). Here, we established SCFS as an in vitro technique to study human RBC adhesion at baseline and following biochemical treatment. Using blood obtained from healthy human subjects, we recorded adhesion forces from single RBCs attached to AFM cantilevers as the cell was pulled-off of substrates coated with laminin protein. We found that an increase in the overall cell adhesion measured via SCFS is correlated with an increase in the resultant total force measured on 1 um(2) areas of the RBC membrane. Further, we showed that SCFS can detect significant changes in the adhesive response of RBCs to modulation of the cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) pathway. Lastly, we identified variability in the RBC adhesion force to laminin amongst the human subjects, suggesting that RBCs maintain diverse levels of active BCAM/Lu adhesion receptors. By using single-cell measurements, we established a powerful new method for the quantitative measurement of single RBC adhesion with specific receptor-mediated binding. PMID- 25458580 TI - Modela-r as a Froude and Strouhal dimensionless numbers combination for dynamic similarity in running. AB - The aim of this study was to test the hypothesis that running at fixed fractions of Froude (Nfr) and Strouhal (Str) dimensionless numbers combinations induce dynamic similarity between humans of different sizes. Nineteen subjects ran in three experimental conditions, (i) constant speed, (ii) similar speed (Nfr) and (iii) similar speed and similar step frequency (Nfr and Str combination). In addition to anthropometric data, temporal, kinematic and kinetic parameters were assessed at each stage to measure dynamic similarity informed by dimensional scale factors and by the decrease of dimensionless mechanical parameter variability. Over a total of 54 dynamic parameters, dynamic similarity from scale factors was met for 16 (mean r=0.51), 32 (mean r=0.49) and 52 (mean r=0.60) parameters in the first, the second and the third experimental conditions, respectively. The variability of the dimensionless preceding parameters was lower in the third condition than in the others. This study shows that the combination of Nfr and Str, computed from the dimensionless energy ratio at the center of gravity (Modela-r) ensures dynamic similarity between different-sized subjects. The relevance of using similar experimental conditions to compare mechanical dimensionless parameters is also proved and will highlight the study of running techniques, or equipment, and will allow the identification of abnormal and pathogenic running patterns. Modela-r may be adapted to study other abilities requiring bounces in human or animal locomotion or to conduct investigations in comparative biomechanics. PMID- 25458579 TI - Nutrient channels and stirring enhanced the composition and stiffness of large cartilage constructs. AB - A significant challenge in cartilage tissue engineering is to successfully culture functional tissues that are sufficiently large to treat osteoarthritic joints. Transport limitations due to nutrient consumption by peripheral cells produce heterogeneous constructs with matrix-deficient centers. Incorporation of nutrient channels into large constructs is a promising technique for alleviating transport limitations, in conjunction with simple yet effective methods for enhancing media flow through channels. Cultivation of cylindrical channeled constructs flat in culture dishes, with or without orbital shaking, produced asymmetric constructs with poor tissue properties. We therefore explored a method for exposing the entire construct surface to the culture media, while promoting flow through the channels. To this end, chondrocyte-seeded agarose constructs (?10mm, 2.34mm thick), with zero or three nutrient channels (?1mm), were suspended on their sides in custom culture racks and subjected to three media stirring modes for 56 days: uniaxial rocking, orbital shaking, or static control. Orbital shaking led to the highest construct EY, sulfated glycosaminoglycan (sGAG), and collagen contents, whereas rocking had detrimental effects on sGAG and collagen versus static control. Nutrient channels increased EY as well as sGAG homogeneity, and the beneficial effects of channels were most marked in orbitally shaken samples. Under these conditions, the constructs developed symmetrically and reached or exceeded native levels of EY (~400kPa) and sGAG (~9%/ww). These results suggest that the cultivation of channeled constructs in culture racks with orbital shaking is a promising method for engineering mechanically competent large cartilage constructs. PMID- 25458587 TI - Flavodiiron nitric oxide reductases: Recent developments in the mechanistic study and model chemistry for the catalytic reduction of NO. AB - Inducible NO synthase in mammals helps to produce up to micromolar concentration of nitric oxide (NO) which acts as a key immune defense agent to kill invading pathogens. In order to counter the toxic effects of NO, the pathogens have expressed flavodiiron nitric oxide reductases (FNORs). The FNORs reduce the toxic NO into much less toxic N2O and thus help the pathogens to survive under nitrosative stress. As a consequence, these pathogens proliferate in the human body and cause harmful infections. An appreciable amount of research work has been performed to discover the true mechanism of the FNORs. Different mechanisms involving both mononitrosyl and dinitrosyl diiron complexes as key intermediates are proposed. Evidences for the involvement of new intermediates and more and more experimental evidences for existing ones in the proposed catalytic cycle of FNORs are coming up. These interesting biochemical events have recently boosted the biomimetic chemistry of the FNOR activity as well. This article discusses the importance and the currently understood mechanistic aspects of FNORs. Structural and functional models for the active site of FNORs are discussed along with their success and limitations. Possible future prospects of the modeling chemistry are also suggested. PMID- 25458590 TI - Palatal swelling. PMID- 25458588 TI - Cancer-related and treatment-related fatigue. AB - Fatigue is a distressing and persistent symptom for patients with gynecological cancer and for survivors. Debilitating cancer-related fatigue (CRF) is produced by both the disease and its treatment. Although awareness and study of CRF have grown in recent years, consistent assessment has not been a priority in routine medical practice. The pathophysiological mechanisms that induce CRF remain unclear, and effective pharmacological interventions have yet to be established. Based on the literature and our own research results, this review focuses on recent progress toward understanding the nature and causes of CRF and on several promising treatment modalities. Given the prevalence and severity of CRF in the gynecological cancer patient population, establishing standardized fatigue measurement and management methods in routine clinical oncology care is of utmost importance. Whether CRF has an underlying inflammatory cause is still hypothetical, however, and no mechanism-driven symptom intervention is currently in clinical use, even though the development of such interventions would provide patients with greater symptom control. Advancing translational and clinical fatigue research will require anatomical pathway studies and well-designed clinical investigations that focus on the development of mechanism-driven interventions based on physiological-behavioral fatigue research, implementation of guidelines for experimental designs, and discovery of biomarkers identifying individuals at high risk for CRF. Validated patient-reported outcomes measures are an essential component of such clinical studies. Because numerous subscales, unidimensional measures, and multidimensional measures exist, clinicians and researchers should consider individual circumstances, good clinical practice, and research goals as guides for choosing the most appropriate fatigue measurement tool. Additionally, education about CRF should be made available to all patients and their caregivers, as accurate and age-appropriate information about conditions like CRF can alleviate much of the stress and anxiety brought on by poor communication about this distressing condition. PMID- 25458591 TI - [Screening for psychiatric risk factors in a facial trauma patients. Validating a questionnaire]. AB - INTRODUCTION: We recorded similarities between patients managed in the psychiatry department and in the maxillo-facial surgical unit. Our hypothesis was that some psychiatric conditions act as risk factors for facial trauma. We had for aim to test our hypothesis and to validate a simple and efficient questionnaire to identify these psychiatric disorders. MATERIALS AND METHODS: Fifty-eight consenting patients with facial trauma, recruited prospectively in the 3 maxillo facial surgery departments of the Marseille area during 3 months (December 2012 March 2013) completed a self-questionnaire based on the French version of 3 validated screening tests (Self Reported Psychopathy test, Rapid Alcohol Problem Screening test quantity-frequency, and Personal Health Questionnaire). RESULTS: This preliminary study confirmed that psychiatric conditions detected by our questionnaire, namely alcohol abuse and dependence, substance abuse, and depression, were risk factors for facial trauma. DISCUSSION: Maxillo-facial surgeons are often unaware of psychiatric disorders that may be the cause of facial trauma. The self-screening test we propose allows documenting the psychiatric history of patients and implementing earlier psychiatric care. PMID- 25458592 TI - [Chondroma of the tongue: about a case]. PMID- 25458593 TI - A pathognomonic CT of the parotid gland. PMID- 25458594 TI - [Oropharyngeal toothbrush perforation in an infant]. AB - INTRODUCTION: Oral impalement injuries are common in children. We report a case of severe pharyngeal toothbrush perforation in a 15-month-old infant. OBSERVATION: A 15-month-old child was admitted for a penetrating oral injury caused by a toothbrush. There was no hemorrhagic or neurological complication. A CT scan showed the toothbrush in the right parapharyngeal region with its extremity in the mastoid region. Exploration and extraction of the toothbrush was performed under general anesthesia. The outcome was uneventful. DISCUSSION: Penetrating oral cavity wounds caused by a toothbrush in children may be severe and must be explored in the operating room. A preoperative CT scan must be performed to complete the assessment of lesions. The risk of infection is high and an antibiotic prophylaxis is recommended. Neurological and vascular complications may occur but they are rare. PMID- 25458595 TI - [Soft palate chronic lymphocytic leukemia]. AB - INTRODUCTION: Forty percent of non-Hodgkin lymphoma (NHL) are located in extranodal sites. The palatal location of chronic lymphocytic leukemia (CLL) is usually observed at a late stage of the disease. CASE: We report the case of a 62 year-old male patient managed for 8 years for CLL, having presented with a soft palatal tumor in the last 2 years. The diagnosis of CLL was made by immunohistochemistry. The patient was given 6 courses of chemotherapy combining fludarabine, cyclophosphamide, and rituximab. DISCUSSION: The diagnosis of CLL requires immunohistochemistry. Chemotherapy is the first line treatment. The complication may be an aggressive lymphoma (Richter). PMID- 25458597 TI - [Diffuse enlargement of salivary glands]. PMID- 25458596 TI - [Retrospective study on bleeding and thromboembolic complications related to tooth extraction, in 93 patients usually treated by antithrombotic therapy]. AB - INTRODUCTION: Tooth extraction for patients treated by AVK and/or platelet aggregation inhibitor is performed according to local habits rather than to a consensus. We had for objective to assess hemorrhagic and thromboembolic risks for patients for whom treatment with AVK and/or platelet aggregation inhibitor was modified before tooth extraction. MATERIALS AND METHODS: Ninety-three patient files were examined retrospectively. The following data was collected: epidemiological data, ASA score, nature and changes of antithrombotic therapy, preoperative INR, number teeth extracted, postoperative complications (bleeding and thromboembolic events). RESULTS: Thirty-seven patients were treated with oral anticoagulants, 41 by a platelet aggregation inhibitor, 10 by double platelet aggregation inhibitor therapy, and 5 by an AVK-platelet aggregation inhibitor combination. At D0, the mean INR was decreased to 1.4, 4 patients with high thromboembolic risk had received heparin relay treatment; the treatment was stopped for 9 of the 56 patients on monotherapy with antiplatelet therapy, 4 were switched from clopidogrel to lysine acetylate; clopidogrel was stopped for 7 patients under combination therapy. Seven hundred and twenty-six avulsions (mean 8.1 per patient) were performed, 41 patients presented with mild/moderate bleeding, easily resolved. A patient presented with delayed hemorrhage at D6 (AVK overdose). No thromboembolic complication was reported. DISCUSSION: The modification of antithrombotic treatment, as for surgery at high risk of bleeding, seems to limit the risk of bleeding without increasing thromboembolic risk. PMID- 25458598 TI - [Outcome of endoscopically assisted surgical treatment of mandibular condyle fractures: a retrospective study of 22 patients]. AB - INTRODUCTION: The condylar region is a frequent localization of mandibular fractures; there are various types of management. Mini-invasive endoscopic surgery is an alternative to open reduction. We had as goal to evaluate the outcome of this technique. MATERIAL AND METHODS: We performed a monocentric retrospective study of patients consecutively operated for a condylar fracture (type II to V in the Spiessl and Schroll classification) with intraoral route and endoscopic assistance, during 30 months. We assessed the functional and radiological outcomes, and the complications. RESULTS: Twenty-two patients (25 fractures) were included. Seventeen patients (19 fractures) could be followed (mean follow-up: 16.7 months). The mean values were: interincisal opening, 45mm (+/-8.4); protrusion, 8.3mm (+/-1.9); ipsilateral excursion of the jaw: 8.6mm (+/ 2); contralateral excursion: 8.7mm (+/-4). Three routes were used combined with a preauricular approach. The fracture reduction was good for 10 of the 19 fractures and poor for 3. The complications were: 3 cases of infection, 1 case of fixation failure with good consolidation; for combined approaches: 2 cases of temporary facial palsy and 2 cases of Frey syndrome. DISCUSSION: Endoscopic assistance for the surgical management of the fracture of mandibular condyle is a reliable technique, with a good functional outcome, and a low rate of specific complications, especially for facial nerve lesion or esthetic outcome. PMID- 25458599 TI - [New protocol combining orthodontics and implant therapy for partially edentulous adult patients. Part I: Description of the Decker protocol]. AB - INTRODUCTION: The treatment of adult malocclusion is usually complex and pluridisciplinary. Its prognosis is not reliable. We present a new clinical protocol to improve the management and final result. TECHNICAL NOTE: We use a specific software (Simplant(r), OMS(r), Materialise Dental) and its accessory modules. It allows visualization of the expected final clinical result of the orthodontic treatment. Combined with guided-surgery, it allows placing implants at the beginning of treatment in a position that is compatible with the final position. The implants serve as absolute anchorage for dental motions during the orthodontic step; it is also used to support the final prosthesis. The treatment is thus optimized and its prognosis is improved. Finally, the reversed surgical sequences shorten the treatment thus promoting the compliance of patients. PMID- 25458600 TI - Meeting report VLPNPV: Session 6: Development and characterization. PMID- 25458601 TI - Discovery of potent KIFC1 inhibitors using a method of integrated high-throughput synthesis and screening. AB - KIFC1 (HSET), a member of the kinesin-14 family of motor proteins, plays an essential role in centrosomal bundling in cancer cells, but its function is not required for normal diploid cell division. To explore the potential of KIFC1 as a therapeutic target for human cancers, a series of potent KIFC1 inhibitors featuring a phenylalanine scaffold was developed from hits identified through high-throughput screening (HTS). Optimization of the initial hits combined both design-synthesis-test cycles and an integrated high-throughput synthesis and biochemical screening method. An important aspect of this integrated method was the utilization of DMSO stock solutions of compounds registered in the corporate compound collection as synthetic reactants. Using this method, over 1500 compounds selected for structural diversity were quickly assembled in assay-ready 384-well plates and were directly tested after the necessary dilutions. Our efforts led to the discovery of a potent KIFC1 inhibitor, AZ82, which demonstrated the desired centrosome declustering mode of action in cell studies. PMID- 25458602 TI - The special projects of national significance women of color initiative. PMID- 25458603 TI - The role of DNA repair pathways in cisplatin resistant lung cancer. AB - Platinum chemotherapeutic agents such as cisplatin are currently used in the treatment of various malignancies such as lung cancer. However, their efficacy is significantly hindered by the development of resistance during treatment. While a number of factors have been reported that contribute to the onset of this resistance phenotype, alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating this phenomenon. The mode of action of cisplatin has been linked to its ability to crosslink purine bases on the DNA, thereby interfering with DNA repair mechanisms and inducing DNA damage. Following DNA damage, cells respond by activating a DNA-damage response that either leads to repair of the lesion by the cell thereby promoting resistance to the drug, or cell death via activation of the apoptotic response. Therefore, DNA repair is a vital target to improving cancer therapy and reduce the resistance of tumour cells to DNA damaging agents currently used in the treatment of cancer patients. To date, despite the numerous findings that differential expression of components of the various DNA repair pathways correlate with response to cisplatin, translation of such findings in the clinical setting are still warranted. The identification of alterations in specific proteins and pathways that contribute to these unique DNA repair pathways in cisplatin resistant cancer cells may potentially lead to a renewed interest in the development of rational novel therapies for cisplatin resistant cancers, in particular, lung cancer. PMID- 25458604 TI - Navigating later lines of treatment for advanced colorectal cancer - optimizing targeted biological therapies to improve outcomes. AB - Colorectal cancer (CRC) is the third most commonly diagnosed cancer among males and second among females worldwide. The treatment landscape for advanced CRC (aCRC) is rapidly evolving and there are now a number of randomized trials assessing treatment of aCRC beyond first-line, prompting important questions about how to optimize therapy and maximize benefit. The availability of targeted agents has increased the complexity of post-progression treatment of aCRC. Targeted biological agents with varying modes of action are now approved for use in second-line and beyond, including the VEGF-inhibitors bevacizumab and aflibercept, the VEGFR/multikinase-inhibitor regorafenib, and the EGFR-inhibitors cetuximab and panitumumab. This article provides a systematic overview of the available phase III trial data, discusses biomarkers predictive of response to treatment, addresses safety concerns associated with specific agents, and provides practical, evidence-based recommendations for the later lines of treatment for patients with unresectable aCRC. PMID- 25458605 TI - The genetic variants underlying breast cancer treatment-induced chronic and late toxicities: a systematic review. AB - A systematic review was performed to describe the findings from 19 genetic association studies that have examined the genetic variants underlying four common treatment-induced chronic and late toxicities in breast cancer patients, and to evaluate the quality of reporting. Three out of 5 studies found an association between HER2 lle655Val polymorphisms and trastuzumab-induced cardiotoxicity. Two studies found a positive association between cognitive impairment and the Val allele of the COMT gene and the epsilon4 allele of the apolipoprotein E gene. Genetic associations were established between fatigue and the G/G genotype of IL6-174 and TNF-308, and the Met allele of the COMT gene in 4 studies. Among studies (N=8) that evaluated the genetic associations underlying peripheral neuropathy, CYP2C8*3 variant is commonly reported as the associated gene. Most studies failed to conform to the major criteria listed in the STREGA guidelines, with a lack of transparent reporting of methods and results. PMID- 25458606 TI - Nothing to lose: why early career scientists make ideal entrepreneurs. AB - An entrepreneurial movement within science strives to invert the classical trajectory of academic research careers by positioning trainees at the apex of burgeoning industries. Young scientists today have nothing to lose and everything to gain by pursuing this 'third road', and academic institutes and established companies only stand to benefit from supporting this emerging movement of discovery research with economic purpose. PMID- 25458607 TI - Sensing the enemy within: how macrophages detect intracellular Gram-negative bacteria. AB - Caspase-11 contributes to host defense against Gram-negative bacterial pathogens by inducing an inflammatory form of programmed cell death in infected cells. Lipopolysaccharides (LPS) have been identified as the microbial agents that stimulate caspase-11 activation; however, the mechanism of LPS detection has been unknown. In a recent study, Shao and colleagues demonstrate that caspase-11 and its human homologues, caspases -4 and -5, unexpectedly act as direct sensors of cytosolic LPS. PMID- 25458608 TI - Clone-based comparative sequence analysis of 16S rRNA genes retrieved from biodeteriorating brick buildings of the former Auschwitz II-Birkenau concentration and extermination camp. AB - The aim of this work was to analyze the bacterial communities in four samples of historical materials (plaster, brick, and wood) derived from buildings located in the former Auschwitz II-Birkenau concentration and extermination camp in Brzezinka, Poland. For this purpose a molecular strategy based on the construction of 16S rRNA clone libraries was used. In total, 138 partial 16S rRNA gene sequences (~600bp) were obtained and compared. The clones belonged to phyla Proteobacteria (classes: Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria), Actinobacteria, Firmicutes, and Bacteroidetes. The plaster samples predominantly contained clones closely related to Actinobacteria and Alphaproteobacteria, brick samples contained Gammaproteobacteria, while wood samples had Actinobacteria clones. Interestingly, the historic plaster and brick samples contained the following bacteria with known and described biodeterioration potential: chemoorganotrophic Streptomyces sp. and Pseudonocardia sp., halotolerant or halophilic Rubrobacter sp., Salinisphaera sp. and Halomonas sp. Principal component analysis (PCA) showed that amongst the bacterial species detected and identified none occurred on all the tested historical materials. The 16S rRNA clone library construction method was successfully used for the detection and diversity determination of bacterial communities inhabiting brick barracks located in the former Auschwitz II-Birkenau concentration and extermination camp in Brzezinka. PMID- 25458609 TI - Phylogenetic multilocus sequence analysis of native rhizobia nodulating faba bean (Vicia faba L.) in Egypt. AB - The taxonomic diversity of forty-two Rhizobium strains, isolated from nodules of faba bean grown in Egypt, was studied using 16S rRNA sequencing, multilocus sequence analyses (MLSA) of three chromosomal housekeeping loci and one nodulation gene (nodA). Based on the 16S rRNA gene sequences, most of the strains were related to Rhizobium leguminosarum, Rhizobium etli, and Rhizobium radiobacter (syn. Agrobacterium tumefaciens). A maximum likelihood (ML) tree built from the concatenated sequences of housekeeping proteins encoded by glnA, gyrB and recA, revealed the existence of three distinct genospecies (I, II and III) affiliated to the defined species within the genus Rhizobium/Agrobacterium. Seventeen strains in genospecies I could be classified as R. leguminosarum sv. viciae. Whereas, a single strain of genospecies II was linked to R. etli. Interestingly, twenty-four strains of genospecies III were identified as A. tumefaciens. Strains of R. etli and A. tumefaciens have been shown to harbor the nodA gene and formed effective symbioses with faba bean plants in Leonard jar assemblies. In the nodA tree, strains belonging to the putative genospecies were closely related to each other and were clustered tightly to R. leguminosarum sv. viciae, supporting the hypothesis that symbiotic and core genome of the species have different evolutionary histories and indicative of horizontal gene transfer among these rhizobia. PMID- 25458611 TI - "Relinquish the reins": persuasion and consensus in the discourse of pregnancy and childbirth advice literature. AB - BACKGROUND: Popular pregnancy and childbirth advice books constitute an important source of information for pregnant women. These texts shape women's perceptions of pregnancy, childbirth and the medical care they will receive during this time. AIMS: This article reports on a study of the enactment of power relations between pregnant women and their medical caregivers in the discourse of pregnancy and childbirth advice literature and its implications for practice. METHODS: The study focuses on the discursive positioning of women in relation to medical personnel through a critical discourse analysis of two popular advice books, one in English and one in French. FINDINGS: The article suggests that through the use of a number of key discursive strategies, pregnant women are constructed as under the control of the medical institution in these texts. However, this control is not achieved by an overt oppressive discourse, instead it is achieved through persuasion and consensus by generating the consent of pregnant women to comply with medical norms. CONCLUSIONS: The medical institution is represented in these texts as a dominant force while women are constructed as powerless recipients of medical care. Medical professionals should firstly consider whether the power relations represented in these texts correspond to those enacted in clinics and delivery rooms. Secondly, caregivers should be cautious about recommending popular pregnancy and childbirth advice books to women as the relationship between pregnant women and their caregivers may be undermined by the negative power asymmetry enacted in these texts. PMID- 25458610 TI - A retrospective, descriptive study of maternal and neonatal transfers, and clinical outcomes of a Primary Maternity Unit in rural Queensland, 2009-2011. AB - BACKGROUND: A widely held view in maternity services in rural Australia is they require 24-h on-site surgical and anaesthetic capability to be considered safe. This study aimed to provide a detailed description of three years of activity (2009-2011) of a rural maternity unit approximately 1h from the nearest surgical service. We describe the reasons for transfer to and from the unit, transfer times and the clinical health outcomes of all women (all risk status) and their babies. METHODS: This retrospective study utilised contemporaneously, purposefully collected audit data, routinely collected data and medical chart review. Data were analysed based on the model of care that women were allocated to at the time of booking. RESULTS: The PMU provided care to twice as many young women (13.3% MDH vs. 5.1% QLD) and almost five times as many Aboriginal and/or Torres Strait Islander women (27.5% MDH vs. 5.7% QLD). A total of 506 women booked to receive care through a midwifery group practice (MGP), and 377 (74.5%) gave birth at the local facility as planned. Clinical outcomes for women and babies birthing both at the PMU and those transferred were comparable or better than other published data. CONCLUSION: The results challenge the notion that birthing services can only be offered in rural areas with onsite surgical capability. More PMUs should be made available in rural areas, in line with national and state policy and international evidence. PMID- 25458612 TI - Vaginal births after caesarean: what does Google think about it? AB - AIM: Vaginal birth after caesarean (VBAC) is a relatively safe alternative to repeat caesarean birth in the proper context. This important decision to undergo an elective caesarean versus VBAC is ultimately a decision of the mother. The purpose of our study was to assess the quality of online information in relation to VBAC collected using the most common search engine: Google. METHODS: The 10 most common hit sites for the keywords "VBAC" and "Vaginal birth after caesarean" were evaluated using the search engine Google. The quality of websites was rated based on the Silberg scale for accountability, the modified Abbott's criteria for presentation and the SMOG index for readability. The content of each website was compared to the Society of Obstetricians and Gynecologists of Canada (SOGC) guidelines for VBAC. FINDINGS: 13 out of 20 identified websites met the adequate criteria for accountability, with 85% of the websites indicating authorship. 11 websites were deemed aesthetically agreeable. The target audience, assessed by the readability score, was notably above the non-medical population with an average SMOG index score of 14.75. Only half of the websites contained recommendations, as detailed by the SOGC guidelines. CONCLUSION: Almost all sites target a higher academic level, making it beyond the comprehension of the general population. Woman-friendly web-assessment tools should be provided to enable pregnant women to take an active role in their decision making. PMID- 25458613 TI - The present and future of tuberculosis vaccinations. AB - The clinical, social, and economic burden of tuberculosis (TB) remains high worldwide, thereby highlighting the importance of TB prevention. The bacilli Calmette-Guerin (BCG) vaccine that is currently available can protect younger children but is less effective in adults, the major source of TB transmission. In addition, the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains and the high prevalence of HIV infection have significantly complicated TB prognosis and treatment. Together, these data highlight the need for new and more effective vaccines. Recently, several vaccines containing multiple antigens, including some of those specific for dormant Mtb strains, have been developed. These vaccines appear to be the best approach for satisfactory Mtb prevention. However, until a new vaccine is proven more effective and safe than BCG, BCG should remain part of the immunization schedules for neonates and children at risk for TB as a fundamental prophylactic measure. PMID- 25458614 TI - Complete annotated genome sequence of Mycobacterium tuberculosis (Zopf) Lehmann and Neumann (ATCC35812) (Kurono). AB - We report the completely annotated genome sequence of Mycobacterium tuberculosis (Zopf) Lehmann and Neumann (ATCC35812) (Kurono), which is a used for virulence and/or immunization studies. The complete genome sequence of M. tuberculosis Kurono was determined with a length of 4,415,078 bp and a G+C content of 65.60%. The chromosome was shown to contain a total of 4,340 protein-coding genes, 53 tRNA genes, one transfer messenger RNA for all amino acids, and 1 rrn operon. Lineage analysis based on large sequence polymorphisms indicated that M. tuberculosis Kurono belongs to the Euro-American lineage (lineage 4). Phylogenetic analysis using whole genome sequences of M. tuberculosis Kurono in addition to 22 M. tuberculosis complex strains indicated that H37Rv is the closest relative of Kurono based on the results of phylogenetic analysis. These findings provide a basis for research using M. tuberculosis Kurono, especially in animal models. PMID- 25458616 TI - Introduction: Beyond bulk semen parameters. AB - What can the analysis of semen reveal about the fertility potential of sperm? A series of articles reviews the current status and limitations of basic and advanced semen testing. PMID- 25458615 TI - Future target-based drug discovery for tuberculosis? AB - New drugs that retain potency against multidrug/extensively drug-resistant strains of Mycobacterium tuberculosis, with the additional benefit of a shortened treatment duration and ease of administration, are urgently needed by tuberculosis (TB) control programs. Efforts to develop this new generation of treatment interventions have been plagued with numerous problems, the most significant being our insufficient understanding of mycobacterial metabolism during disease. This, combined with limited chemical diversity and poor entry of small molecules into the cell, has limited the number of new bioactive agents that result from drug screening efforts. The biochemical, target-driven approach to drug development has been largely abandoned in the TB field, to be replaced by whole-cell or target-based whole-cell screening approaches. In this context, the properties of a good drug target are unclear, since these are directly determined by the ability to find compounds, using current screening algorithms, which are able to kill M. tuberculosis. In this review, we discuss issues related to the identification and validation of drug targets and highlight some key properties for promising targets. Some of these include essentiality for growth, vulnerability, druggability, reduced propensity to evolve drug resistance and target location to facilitate ready access to drugs during chemotherapy. We present these in the context of recent drugs that have emerged through various approaches with the aim of consolidating the knowledge gained from these experiences to inform future efforts. PMID- 25458618 TI - Male infertility testing: reactive oxygen species and antioxidant capacity. AB - Reactive oxygen species (ROS) are an integral component of sperm developmental physiology, capacitation, and function. Elevated ROS levels, from processes such as infection or inflammation, can be associated with aberrations of sperm development, function, and fertilizing capacity. We review the impact of ROS on sperm physiology, its place in infertility evaluation, the implications for reproductive outcomes, and antioxidant therapy. Our systematic review of PubMed literature from the last 3 decades focuses on the physiology and etiology of ROS and oxidative stress (OS), evaluation of ROS, and antioxidants. ROS is normally produced physiologically and is used to maintain cellular processes such as sperm maturation, capacitation, and sperm-oocyte interaction. When ROS production exceeds the buffering capacity of antioxidants, OS occurs and can have a negative impact on sperm and fertility. ROS and antioxidant capacity testing can potentially add additional prognostic information to standard laboratory testing for the infertile male, although its role as standard part of an evaluation has yet to be determined. Elevated ROS levels have been implicated with abnormal semen parameters and male infertility, but the impact of ROS on fertilization rates and pregnancy is controversial. This is partly because of the lack of consensus on what type of patients may be suitable for ROS testing and assay standardization. Routine ROS testing for the infertile male is not currently recommended. PMID- 25458619 TI - Mild approaches in assisted reproduction--better for the future? AB - Mild approaches in assisted reproduction are aimed at achieving quality and not quantity of gametes, embryos, and endometrium with a view to protecting the long term health and welfare of women and children at an affordable cost. The true success of IVF is in creating children who are full term and normal for gestational age without compromising the health of their mothers. Equal access to IVF treatment can only be achieved by reducing the cost and complications. The state and the society should not suffer as a consequence of IVF treatment. This is the time for change. PMID- 25458617 TI - Limitations of semen analysis as a test of male fertility and anticipated needs from newer tests. AB - Semen analysis is the first step to identify male factor infertility. Standardized methods of semen analysis are available allowing accurate assessment of sperm quality and comparison among laboratories. Population-based reference ranges are available for standard semen and sperm parameters. Sperm numbers and morphology are associated with time to natural pregnancy, whereas sperm motility may be less predictive. Routine semen analysis does not measure the fertilizing potential of spermatozoa and the complex changes that occur in the female reproductive tract before fertilization. Whether assisted reproduction technology (ART) is required depends not only on male factors but female fecundity. Newer tests should predict the success of fertilization in vitro and the outcome of the progeny. PMID- 25458620 TI - Report on varicocele and infertility: a committee opinion. AB - This document discusses the evaluation and management of varicoceles in the male partners of infertile couples, and presents the controversies and recommendations regarding this condition. This document replaces the ASRM Practice Committee document titled "Report on Varicocele and Infertility," last published in 2008, and was developed in conjunction with the Society for Male Reproduction and Urology (Fertil Steril 2008;90:S247-9). PMID- 25458621 TI - How do we decide how many embryos are safe for transfer? PMID- 25458623 TI - The value of systematic review: guest editorial. PMID- 25458622 TI - In vitro safety assessment of food ingredients in canine renal proximal tubule cells. AB - In vitro models are useful tools to initially assess the toxicological safety hazards of food ingredients. Toxicities of cinnamaldehyde (CINA), cinnamon bark oil, lemongrass oil (LGO), thymol, thyme oil (TO), clove leaf oil, eugenol, ginger root extract (GRE), citric acid, guanosine monophosphate, inosine monophosphate and sorbose (SORB) were assessed in canine renal proximal tubule cells (CPTC) using viability assay and renal injury markers. At LC50, CINA was the most toxic (0.012mg/ml), while SORB the least toxic (>100mg/ml). Toxicities (LC50) of positive controls were as follows: 4-aminophenol (0.15mg/ml in CPTC and 0.083mg/ml in human PTC), neomycin (28.6mg/ml in CPTC and 27.1mg/ml in human PTC). XYL displayed lowest cytotoxic potency (LC50=82.7mg/ml in CPTC). In vivo renal injury markers in CPTC were not significantly different from controls. The LGO toxicity mechanism was analyzed using qPCR and electron microscopy. Out of 370 genes, 57 genes (15.4%) were significantly up (34, 9.1%) or down (23, 6.2%) regulated, with the most upregulated gene gsta3 (~200-fold) and the most affected pathway being oxidative stress. LGO induced damage of mitochondria, phospholipid accumulation and lack of a brush border. Viability assays along with mechanistic studies in the CPTC model may serve as a valuable in vitro toxicity screening tool. PMID- 25458624 TI - An overview of systematic review. AB - Systematic review is an invaluable tool for the practicing clinician. A well designed systematic review represents the latest and most complete information available on a particular topic or intervention. This article highlights the key elements of systematic review, what it is and is not, and provides an overview of several reputable organizations supporting the methodological development and conduct of systematic review. Important aspects for evaluating the quality of a systematic review are also included. PMID- 25458625 TI - A systematic review of the effectiveness of intravenous tranexamic acid administration in managing perioperative blood loss in patients undergoing spine surgery. AB - This systematic review aimed to identify the effectiveness of intravenous tranexamic acid (TXA) administration in managing perioperative blood loss in patients undergoing spine surgery. The study design was a systematic review and meta-analysis. Quantitative articles were pooled in a statistical meta-analysis using the Joanna Briggs Institute Meta-Analysis of Statistical Assessment and Review Instrument. Twelve studies totaling 934 participants carried out between 1960 and 2013 were included in the review. Intraoperative blood loss showed statistically significant (P < .0001) blood loss in the control group compared with that in the treatment group. Perioperative blood loss was approaching significance for blood loss in the control group with an overall P = .067. TXA helps reduce perioperative blood loss for patients undergoing spine surgery. TXA should be administered to patients undergoing spine surgery when significant blood loss is anticipated. PMID- 25458626 TI - Is dexmedetomidine more effective than remifentanil for neurologic outcomes in patients undergoing CEA surgery using regional anesthesia? AB - Carotid endarterectomy (CEA) surgery is performed using regional anesthesia and intravenous/sedative drugs, such as dexmedetomidine and remifentanil. It is unclear which drug provides the least amount of hemodynamic variability, sedation, and respiratory depression so cognitive function can be continuously monitored intraoperatively. A search of the literature was conducted to identify the evidence of the effects of dexmedetomidine and remifentanil in patients undergoing awake CEA surgery with regional anesthesia. A literature search was conducted using Google Scholar, Cumulative Index to Nursing and Allied Health Literature, PubMed, MEDLINE, and the Cochrane Systematic Review databases. Four randomized control studies and a retrospective study were critically appraised to evaluate the evidence on the effectiveness of dexmedetomidine compared with remifentanil during CEA surgery, using regional anesthesia and dexmedetomidine or remifentanil from 2004 to 2009. These studies found that dexmedetomidine provides adequate sedation with less respiratory depression than remifentanil when used in adjunct with regional anesthesia, allowing the provider to monitor hemodynamic stability and neurologic status continuously during the intraoperative period. Dexmedetomidine was evaluated as the primary agent of choice for sedation when performing an awake CEA with regional anesthesia. PMID- 25458627 TI - Intraoperative brain activity monitoring and postanesthesia care unit length of stay: results of a systematic review. AB - A systematic review represents the highest level of evidence to inform clinical practice and research. The results of this systematic review report on the impact of intraoperative brain activity monitoring on postanesthesia care unit length of stay. If used to guide anesthesia practice, the intraoperative brain activity monitor will have a statistically insignificant impact on reducing postanesthesia care unit length of stay. Clinicians should be aware, however, that there is a clinically useful reduction in postanesthesia care unit length of stay resulting in potential cost savings. PMID- 25458628 TI - Using systematic reviews to guide decision making about family-witnessed resuscitation. AB - Family-witnessed resuscitation (FWR) allows family members to be present while emergency cardiac life support measures are applied. This article describes the use of systematic reviews to inform best clinical policy on FWR. The authors searched Medline and CINAHL for relevant systematic reviews and retrieved four. The reviews were then tested for rigor and validity using the open source Critical Appraisal Skills Programme from the Institute of Health Science, University of Oxford. The reviews were assessed to be of acceptable quality and therefore good sources of evidence to guide practice and policy development. Two reviews examined FWR of adult patients, one examined FWR of children and adults, and one examined FWR of children. Together, the four reviews covered 83 studies that describe the perspectives of more than 15,000 health care providers; 2,000 family members; and 2,000 patients. The systematic reviews provide clear evidence that both patients and family members want the option to be present during FWR. In contrast, there is significant variability among health care providers, with those in favor ranging from 7% to 96%. This wide range is related to (worldwide) geography and to provider status (e.g., Registered Nurse and Medical Doctor). Generally, patients, family, and providers agreed on the benefits of FWR. Barriers to FWR include perceptions of possible performance anxiety and family interruption of care. The authors conclude that institutional settings need to develop a rational policy on FWR, have family support personnel present during FWR, and develop training programs for students and staff on family presence. PMID- 25458629 TI - The effects of amino acid infusions on core body temperature during the perioperative period: a systematic review. AB - The aim of this systematic review was to determine the effect of amino acid infusions on core body temperature and shivering. We searched the PubMed, EMBASE, CINAHL, and Cochrane Register of Controlled Trials databases to identify randomized controlled trials that met the inclusion criteria. A total of 11 eligible trials involving 506 participants were identified. Amino acid infusions were associated with shorter periods of mechanical ventilation and hospitalization and less perioperative shivering, mechanical intubation, and hospitalization in surgical patients without hepatic, renal, or severe metabolic disorders. It is recommended that infusions are warmed before administration to avoid further decrease in core body temperature. PMID- 25458630 TI - Daily sedation interruption: current state of the science. PMID- 25458632 TI - Aviation tools to improve patient safety. PMID- 25458631 TI - Leaders get results! PMID- 25458633 TI - Happiness in the work of nursing. PMID- 25458634 TI - Antiemetics: focus on pharmacology. PMID- 25458635 TI - Perianesthesia nurse-sensitive indicators. PMID- 25458636 TI - Ebola--a crisis. PMID- 25458637 TI - A randomized case-controlled study of recombinant human granulocyte colony stimulating factor for the treatment of sepsis in preterm neutropenic infants. AB - BACKGROUND: To investigate the efficacy and safety of recombinant human granulocyte colony-stimulating factor, recombinant human granulocyte-macrophage colony-stimulating factor (rhG-CSF) to treat sepsis in neutropenic preterm infants. METHODS: Fifty-six neutropenic preterm infants with suspected or culture proven sepsis hospitalized in Zeynep Kamil Maternity and Children's Educational and Training Hospital, Kozyatagi/Istanbul, Turkey between January 2008 and January 2010 were enrolled. Patients were randomized either to receive rhG-CSF plus empirical antibiotics (Group I) or empirical antibiotics alone (Group II). Clinical features were recorded. Daily complete blood count was performed until neutropenia subsided. Data were analyzed using SPSS version 11.5. RESULTS: Thirty three infants received rhG-CSF plus antibiotic treatment and 23 infants received antibiotic treatment. No drug-related adverse event was recorded. Absolute neutrophil count values were significantly higher on the 2(nd) study day and 3(rd) study day in Group I. Short-term mortality did not differ between the groups. CONCLUSION: Treatment with rhG-CSF resulted in a more rapid recovery of ANC in neutropenic preterm infants. However, no reduction in short-term mortality was documented. PMID- 25458638 TI - Infantile Systemic Hyalinosis Complicated with Right Atrial Thrombus and Pericardial Effusion in an Infant. AB - Infantile systemic hyalinosis (ISH) is a rare multisystem fatal autosomal recessive disorder that involves widespread deposition of hyaline on connective tissues and certain internal organs. The major manifestations include painful articular contractures, hyperpigmentation, subcutaneous nodules, gingival hypertrophy, failure to thrive secondary to protein-losing enteropathy, and osteolytic bone lesions. In this paper, we report a 12-month-old girl with ISH presenting with recurrent diarrhea, failure to thrive, and refractory infections. A molecular study identified a homozygous missense mutation, c.134T > C; p.L45P, in exon 1 of the anthrax toxin receptor 2 (ANTRX2) gene. Our patient passed through an eventful course that included septic shock, central line infections, right atrial thrombosis, and pericardial effusion. She incurred acute bronchiolitis due to respiratory syncytial virus infection, which led to her death. In conclusion, this case report highlights that severe and life threatening morbidities and complications can be encountered in ISH, to which some management options can be applied. PMID- 25458639 TI - A case of child nasopharyngeal carcinoma admitted with cervical lymphadenitis responsive to antibiotic therapy. PMID- 25458640 TI - Nonocclusive Mesenteric Ischemia after Chemotherapy in an Adolescent Patient with a History of Three Allogeneic Hematopoietic Stem Cell Transplantations for Acute Lymphoblastic Leukemia. AB - Nonocclusive mesenteric ischemia (NOMI) is induced by intestinal vasospasm without thromboembolic occlusion and is associated with high morbidity and mortality. The estimated overall incidence of autopsy-verified fatal NOMI is 2.0 cases/100,000 person-years; however, no pediatric or adolescent cases have yet been reported. An 18-year-old female was diagnosed with B-cell precursor acute lymphoblastic leukemia at the age of 10 years. Our patient received three allogeneic hematopoietic stem cell transplantations but experienced hematological relapse after each. She received combination therapy of prednisolone, L asparaginase, vincristine, and bortezomib after the third relapse. On Day 16 after the initiation of chemotherapy, she developed NOMI; therefore, we performed a right-sided hemicolectomy on Day 27. Nonocclusive mesenteric ischemia should be considered during the differential diagnosis of intestinal complications after chemotherapy, even in pediatric and adolescent patients. PMID- 25458641 TI - Gallbladder teratoma and a review of the literature. PMID- 25458642 TI - Reducing the burden of disease and death from familial hypercholesterolemia: a call to action. AB - Familial hypercholesterolemia (FH) is a genetic disease characterized by substantial elevations of low-density lipoprotein cholesterol, unrelated to diet or lifestyle. Untreated FH patients have 20 times the risk of developing coronary artery disease, compared with the general population. Estimates indicate that as many as 1 in 500 people of all ethnicities and 1 in 250 people of Northern European descent may have FH; nevertheless, the condition remains largely undiagnosed. In the United States alone, perhaps as little as 1% of FH patients have been diagnosed. Consequently, there are potentially millions of children and adults worldwide who are unaware that they have a life-threatening condition. In countries like the Netherlands, the United Kingdom, and Spain, cascade screening programs have led to dramatic improvements in FH case identification. Given that there are currently no systematic approaches in the United States to identify FH patients or affected relatives, the patient-centric nonprofit FH Foundation convened a national FH Summit in 2013, where participants issued a "call to action" to health care providers, professional organizations, public health programs, patient advocacy groups, and FH experts, in order to bring greater attention to this potentially deadly, but (with proper diagnosis) eminently treatable, condition. PMID- 25458645 TI - Multidisciplinary rehabilitation program in recently hospitalized patients with heart failure and preserved ejection fraction: rationale and design of a randomized controlled trial. AB - BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) comprises a large portion of heart failure patients and portends poor prognosis with similar outcome to heart failure with reduced ejection fraction (HFrEF). Thus far, no medical therapy has been shown to improve clinical outcome in this common condition. TRIAL DESIGN: The study is a randomized-controlled, multicenter clinical trial aimed to determine whether early posthospitalization comprehensive cardiac rehabilitation (CR) including exercise training (ET) in recently hospitalized HFpEF patients reduces the composite end point of all-cause mortality and hospitalizations in comparison with usual care (UC). After undergoing baseline evaluation, patients are randomized to either UC or to ambulatory comprehensive CR program. Patients in the CR arm will participate in a 6-month biweekly ET program according to a predefined protocol, in addition to a complementary home exercise prescribed by a specialist in CR. Exercise training will include endurance and low-intensity resistance training. Patients in the UC arm will be followed up at the outpatient clinic, with management according to current heart failure guidelines. Physician follow-up visits will be conducted at 3, 6, and 12 months for assessment of adherence to therapy and ET, functional status, quality of life, and clinical events. Secondary end points will include quality-of-life questionnaire, economic end points, blood pressure, and hemoglobin A1C levels. CONCLUSIONS: Cardiac rehabilitation and ET are relatively inexpensive and accessible and can be beneficial in HFpEF patients. Our trial is designed to evaluate the impact of early posthospitalization comprehensive rehabilitation program on clinical end points of mortality, hospitalization, and quality of life in HFpEF patients. PMID- 25458643 TI - Metal pollutants and cardiovascular disease: mechanisms and consequences of exposure. AB - INTRODUCTION: There is epidemiological evidence that metal contaminants may play a role in the development of atherosclerosis and its complications. Moreover, a recent clinical trial of a metal chelator had a surprisingly positive result in reducing cardiovascular events in a secondary prevention population, strengthening the link between metal exposure and cardiovascular disease (CVD). This is, therefore, an opportune moment to review evidence that exposure to metal pollutants, such as arsenic, lead, cadmium, and mercury, is a significant risk factor for CVD. METHODS: We reviewed the English-speaking medical literature to assess and present the epidemiological evidence that 4 metals having no role in the human body (xenobiotic), mercury, lead, cadmium, and arsenic, have epidemiologic and mechanistic links to atherosclerosis and CVD. Moreover, we briefly review how the results of the Trial to Assess Chelation Therapy (TACT) strengthen the link between atherosclerosis and xenobiotic metal contamination in humans. CONCLUSIONS: There is strong evidence that xenobiotic metal contamination is linked to atherosclerotic disease and is a modifiable risk factor. PMID- 25458644 TI - Pioglitazone for secondary prevention after ischemic stroke and transient ischemic attack: rationale and design of the Insulin Resistance Intervention after Stroke Trial. AB - BACKGROUND: Recurrent vascular events remain a major source of morbidity and mortality after stroke or transient ischemic attack (TIA). The IRIS Trial is evaluating an approach to secondary prevention based on the established association between insulin resistance and increased risk for ischemic vascular events. Specifically, IRIS will test the effectiveness of pioglitazone, an insulin-sensitizing drug of the thiazolidinedione class, for reducing the risk for stroke and myocardial infarction (MI) among insulin resistant, nondiabetic patients with a recent ischemic stroke or TIA. DESIGN: Eligible patients for IRIS must have had insulin resistance defined by a Homeostasis Model Assessment Insulin Resistance > 3.0 without meeting criteria for diabetes. Within 6 months of the index stroke or TIA, patients were randomly assigned to pioglitazone (titrated from 15 to 45 mg/d) or matching placebo and followed for up to 5 years. The primary outcome is time to stroke or MI. Secondary outcomes include time to stroke alone, acute coronary syndrome, diabetes, cognitive decline, and all-cause mortality. Enrollment of 3,876 participants from 179 sites in 7 countries was completed in January 2013. Participant follow-up will continue until July 2015. SUMMARY: The IRIS Trial will determine whether treatment with pioglitazone improves cardiovascular outcomes of nondiabetic, insulin-resistant patients with stroke or TIA. Results are expected in early 2016. PMID- 25458647 TI - Prevalence and clinical outcome of phrenic nerve injury during superior vena cava isolation and circumferential pulmonary vein antrum isolation using radiofrequency energy. AB - BACKGROUND: Phrenic nerve injury (PNI) is recognized as an important complication during atrial fibrillation ablation. This study aimed to investigate the incidence and outcome of PNI during superior vena cava isolation (SVCI) and circumferential pulmonary vein isolation (CPVI) using radiofrequency (RF) energy and the factors associated with its occurrence. METHODS AND RESULTS: Five hundred sixty-seven consecutive patients who underwent SVCI after CPVI without substrate modification who completed a 12-month follow-up were retrospectively analyzed. Point-by-point RF applications were applied with maximum energy settings of 35 W and 30 seconds for the SVCI. In the former 210 patients, sites where pacing captured the PN were avoided whenever possible; however, the maximum power was 35 W. In the latter 357 patients, RF energy was delivered regardless of PN capture; however, the power at PN capture sites was limited to 10 W during continuous diaphragmatic movement monitoring on fluoroscopy. Circumferential pulmonary vein isolation and SVCI were successfully achieved in all. Twelve patients (2.1%) had PNI during SVCI but not during CPVI. Phrenic nerve injury completely recovered in all patients a median of 8.0 months after the procedure. The prevalence was higher in the former period (3.8% vs 1.1%; P = .03). A multivariate logistic regression analysis revealed that the study period (odds ratio 3.546; 95% CI 1.051-11.965; P = .041) was the sole independent predictor for identifying patients with PNI during SVCI. CONCLUSIONS: Phrenic nerve injury occurred in 2.1% of the patients. All occurred during SVCI but not during contemporary CPVI. Energy titration and continuous diaphragmatic movement monitoring significantly decreased the incidence during SVCI. PMID- 25458648 TI - Appropriateness of coronary interventions in Japan by the US and Japanese standards. AB - BACKGROUND: Appropriateness use criteria (AUC) are widely used to assess quality of care. American professional organizations and Japanese experts have both developed original AUC for percutaneous coronary intervention (PCI). However, rating discrepancies have not been investigated. METHODS: Patients registered in the Japanese multicenter PCI registry were analyzed. We assessed the appropriateness of PCI based on both the US and Japanese criteria and compared the ratings. A logistic regression analysis was performed to identify clinical predictors of inappropriate ratings under both standards. RESULTS: From a total of 4,950 nonacute, consecutive PCIs, 1,982 and 2,077 procedures could be successfully rated using the US and Japanese criteria, respectively. The major difference between the 2 criteria was the rating of "asymptomatic, low- or intermediate-risk patients, no lesion in the proximal left anterior descending coronary artery (PLAD)"; this scenario was deemed appropriate in the Japanese but not in the US criteria. As a consequence, the rate of inappropriate PCI using the Japanese criteria (5.2%) was substantially lower when compared with the rating using the US criteria (15%). Common clinical variables associated with "inappropriate" PCI were male, multivessel diseases, and lesions in the non-PLAD. Suboptimal antianginal medication was also a significant predictor of inappropriate PCI under the US but not under the Japanese criteria. CONCLUSIONS: Significant and clinically relevant rating discrepancies were observed between the US and Japanese criteria-based assessments, owing largely to the ratings of asymptomatic, non-PLAD-related, low- or intermediate-risk cases. PMID- 25458649 TI - Impact of inhospital stent thrombosis and cerebrovascular accidents on long-term prognosis after percutaneous coronary intervention. AB - BACKGROUND: Inhospital stent thrombosis (ST) and cerebrovascular accidents (CVA) are rare but serious adverse events after percutaneous coronary intervention (PCI). The association of ST or CVA with long-term outcome after PCI remains poorly investigated. METHODS: The study included 18,334 consecutive patients who underwent PCI. Patients were divided into 3 groups: the group with ST, the group with CVA, and the group without these events. The primary outcome was all-cause mortality at 3-year follow-up. RESULTS: Inhospital ST or CVA occurred in 59 patients (0.32%) and in 90 patients (0. 49%), respectively. There were 2,149 deaths (11.7%) during the follow-up: 26 deaths among patients with ST, 32 deaths among patients with CVA, and 2,091 deaths among patients without ST or CVA (Kaplan-Meier estimates of 3-year mortality 45.3%, 38.0%, and 12.9%, odds ratio 6.1, 95% CI 3.6-10.2, P < .001 for ST group vs the group without ST or CVA and odds ratio 4.2 [2.7-6.6], P < .001 for CVA group vs the group without ST or CVA). There was no significant difference in the 3-year mortality between CVA and ST groups (P = .29). The Cox proportional hazards model showed that ST (adjusted hazard ratio 4.97, 95% CI 2.58-9.56, P < .001) and CVA (adjusted hazard ratio 2.25 [1.25-4.04], P = .006) were independently associated with the increased risk of 3-year mortality. CONCLUSION: Inhospital ST and CVA after PCI are associated with the increased risk of 3-year mortality. Both events seem to have a similar impact on long-term survival. PMID- 25458646 TI - Design and rationale for the Minimizing Adverse haemorrhagic events by TRansradial access site and systemic Implementation of angioX program. AB - BACKGROUND: Transradial intervention (TRI) and bivalirudin infusion compared with transfemoral coronary intervention or unfractionated heparin plus glycoprotein IIb/IIIa inhibitors decrease bleeding complications in patients with acute coronary syndromes (ACS). Although bleeding is thought to be associated with worse outcomes, it remains unclear whether TRI and bivalirudin both independently lower ischemic or combined ischemic and bleeding complications in ACS patients undergoing contemporary invasive management. HYPOTHESES: The primary objectives of the MATRIX program are to assess whether TRI or bivalirudin as compared, respectively, with transfemoral coronary intervention (MATRIX access site) or unfractionated heparin plus provisional glycoprotein IIb/IIIa inhibitors, (MATRIX antithrombin) decrease the 30-day incidence of an ischemic (ie, death, myocardial infarction or stroke) or an ischemic and bleeding composite end point across the whole spectrum of ACS patients, including clarifying the optimal duration of bivalirudin infusion after percutaneous coronary intervention (MATRIX treatment duration). STUDY DESIGN: The MATRIX (NCT01433627) study, which incorporates 3 randomized comparisons in a nonfactorial manner and primary end points at 30 days and clinical follow-up <= 1 year, is a large-scale, multicenter study with blind event adjudication conducted at approximately 100 European sites. With 8,200 patients in the randomized comparison of access sites and 6,800 individuals participating in the randomized comparison of antithrombin regimens, this study will have >= 85% power for the primary end points. SUMMARY: The MATRIX program aims at conclusively ascertaining the role of TRI and bivalirudin infusion in the whole spectrum of ACS patients undergoing contemporary invasive management. PMID- 25458650 TI - Vorapaxar with or without clopidogrel after non-ST-segment elevation acute coronary syndromes: results from the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome trial. AB - BACKGROUND: Protease-activated receptor 1 antagonism with vorapaxar represents a novel strategy for platelet inhibition. In TRACER, vorapaxar was compared with placebo plus standard of care among 12,944 patients with non-ST-segment elevation acute coronary syndromes. We anticipated that most patients would have received clopidogrel as part of standard care. We investigated the modification of vorapaxar's effect associated with clopidogrel use over time. METHODS: The marginal structural model method was used to estimate causal modification of vorapaxar effect by use of clopidogrel over time. The primary outcomes were the composite of cardiovascular death, myocardial infarction, or stroke and Global Use of Strategies to Open Occluded Coronary Arteries moderate or severe bleeding. The event accrual period excluded the time during which clopidogrel was clinically warranted. RESULTS: Among 12,887 patients who received study medication, 11,117 (86.3%) received clopidogrel before randomization, of whom 38.5% stopped later in the trial (median time to stoppage 200 days with placebo; interquartile range [IQR] 14-367) (186 days with vorapaxar; IQR 17-366). In total, 1,770 (13.7%) patients were not on clopidogrel at randomization, of whom 47.8% started afterward (median time to start 2 days; IQR 2-4). During the period of event accrual, vorapaxar was associated with a 26% reduction in the composite of cardiovascular death, myocardial infarction, or stroke when used with clopidogrel (hazard ratio [HR] 0.74; 95% CI 0.60-0.91) and a 24% reduction when used without clopidogrel (HR 0.76; 95% CI 0.56-1.02) (interaction; P = .89). The hazard of Global Use of Strategies to Open Occluded Coronary Arteries bleeding with vorapaxar was not significantly different without clopidogrel (HR 1.33; 95% CI 0.81-2.20) or with clopidogrel (HR 1.09; 95% CI 0.76-1.56) (interaction; P = .53). CONCLUSIONS: We observed no interaction between vorapaxar and clopidogrel after non-ST-segment elevation acute coronary syndromes on efficacy or safety outcomes, supporting a complementary role of protease-activated receptor 1 and P2Y12 antagonism. PMID- 25458651 TI - Long-term risk of cardiovascular events across a spectrum of adverse major plasma lipid combinations in the Framingham Heart Study. AB - BACKGROUND: Blood levels of high low-density lipoprotein cholesterol (LDL-C), high triglycerides (TG), and low high-density lipoprotein cholesterol (HDL-C) have been associated with increased risk of cardiovascular disease (CVD). The long-term comparative CVD risk associated with these 3 major lipid classes in various combinations is, however, unknown. METHODS: A total of 3,501 participants of the Framingham Offspring Study (mean age 51 +/- 10 years, 56% women) without CVD at baseline were followed up for incident CVD between 1987 and 2011. Participants were grouped according to baseline lipid values into 8 distinct categories to compare the prognostic significance of values within an optimal range to Third Report of the National Cholesterol Educational Program-defined high LDL-C (> 130 mg/dL), high TG (> 150 mg/dL), and/or low HDL-C (< 40 mg/dL) in various combinations using multivariable-adjusted Cox regression models. RESULTS: On follow-up (median 20.2 years), 724 (21%) had new-onset CVD. Adjusted for confounders and compared with the group with optimal lipid values, hazards ratios and population-attributable risks (PARs) were as follows: isolated low HDL-C, 1.93 (95% CI 1.37-2.71), PAR = 3.1%; isolated high LDL-C, 1.28 (1.03-1.59), PAR 6.4%; isolated high TG, 1.35 (0.91-1.98), PAR = 1.1% (not significant); low HDL-C and high LDL-C, 1.82 (1.33-2.49), PAR = 3.9%; low HDL-C and high TG, 1.74 (1.28 2.37), PAR = 3.9%; high LDL-C and high TG, 1.52 (1.12-2.07), PAR = 6.4%; and high LDL-C, high TG and low HDL-C 2.28 (1.73-3.02), PAR = 7.5%. CONCLUSIONS: Aside from isolated hypertriglyceridemia, low levels of HDL-C, high levels of LDL-C, and high levels of TG in any combination were associated with increased risk of CVD. PMID- 25458652 TI - Incidence, angiographic features and outcomes of patients presenting with subtle ST-elevation myocardial infarction. AB - BACKGROUND: Borderline electrocardiograms represent a challenge in ST-segment elevation myocardial infarction (STEMI) management and are associated with inappropriate discharges and delays to intervention. OBJECTIVES: To assess angiographic characteristics and outcomes of patients presenting with subtle ST elevation (STE) myocardial infarction. METHODS: A total of 504 consecutive patients with suspected STEMI treated by systematic primary percutaneous coronary intervention were prospectively included. Subtle STE was defined as a maximal preinterventional STE of 0.1 to 1 mm. Angiograms were interpreted by investigators unaware of the electrocardiographic data. RESULTS: The proportion of patients with subtle STE was 18.3%, 86% of them presented with Thrombolysis In Myocardial Infarction flow grade 0/1 and 91% underwent percutaneous coronary intervention. Despite having smaller infarcts, subtle STE patients associated more frequent multivessel disease (57% vs 44%, P = .02) and larger delays to reperfusion. During a follow-up of 19.0 +/- 4.9 months, the rates of death or reinfarction were similar among groups (10.0% vs 12.6%, P = .467). Subtle STE was not associated with better outcomes neither in univariate nor after adjustment in a multivariate analysis (adjusted hazard ratio 0.79, 95% CI 0.37-1.69, P = .546). CONCLUSIONS: Subtle STEMI is frequent in clinical practice and is usually associated with acute total coronary occlusion. Therefore, it should be diagnosed and treated in the same expeditiously manner as marked STEMI. PMID- 25458653 TI - Transient and persistent worsening renal function during hospitalization for acute heart failure. AB - BACKGROUND: Transient and persistent worsening renal function (WRF) may be associated with different risks during hospitalization for acute heart failure. We compared outcomes of patients hospitalized for acute heart failure with transient, persistent, or no WRF. METHODS: We identified patients 65 years or older hospitalized with acute heart failure from a clinical registry linked to Medicare claims data. We defined WRF as an increase in serum creatinine of >= 0.3 mg/dL after admission. We further classified patients with WRF by the difference between admission and last recorded serum creatinine levels into transient WRF (< 0.3 mg/dL) or persistent WRF (>= 0.3 mg/dL). We examined unadjusted rates and adjusted associations between 90-day outcomes and WRF status. RESULTS: Among 27,309 patients, 18,568 (68.0%) had no WRF, 3,205 (11.7%) had transient WRF, and 5,536 (20.3%) had persistent WRF. Patients with WRF had higher observed rates of 90-day postdischarge all-cause readmission and 90-day postadmission mortality (P < .001). After multivariable adjustment, transient WRF (hazard ratio [HR] 1.19, 99% CI 1.05-1.35) and persistent WRF (HR 1.73, 99% CI 1.57-1.91) were associated with higher risks of 90-day postadmission mortality (P < .001 for both). Compared with transient WRF, persistent WRF was associated with a higher risk of 90-day postadmission mortality (HR 1.46, 99% CI 1.28-1.66, P < .001). CONCLUSIONS: Transient and persistent WRF during hospitalization for acute heart failure were associated with higher adjusted risks for 90-day all-cause postadmission mortality. Patients with persistent WRF had worse outcomes. PMID- 25458654 TI - Emergency department visits for heart failure and subsequent hospitalization or observation unit admission. AB - BACKGROUND: Treatment of acute heart failure in the emergency department (ED) or observation unit is an alternative to hospitalization. Both ED management and observation unit management have been associated with reduced costs and may be used to avoid penalties related to rehospitalizations. The purpose of this study was to examine trends in ED visits for heart failure and disposition following such visits. METHODS: We used the National Hospital Ambulatory Medical Care Survey, a representative sample of ED visits in the United States, to estimate rates and characteristics of ED visits for heart failure between 2002 and 2010. The primary outcome was the discharge disposition from the ED. Regression models were fit to estimate trends and predictors of hospitalization and admission to an observation unit. RESULTS: The number of ED visits for heart failure remained stable over the period, from 914,739 in 2002 to 848,634 in 2010 (annual change 0.7%, 95% CI -3.7% to +2.5%). Of these visits, 74.2% led to hospitalization, wheras 3.1% led to observation unit admission. The likelihood of hospitalization did not change during the period (adjusted prevalence ratio 1.00, 95% CI 0.99 1.01 for each additional year), whereas admission to the observation unit increased annually (adjusted prevalence ratio 1.12, 95% CI 1.01-1.25). We observed significant regional differences in likelihood of hospitalization and observation admission. CONCLUSIONS: The number of ED visits for heart failure and the high proportion of ED visits with subsequent inpatient hospitalization have not changed in the last decade. Opportunities may exist to reduce hospitalizations by increasing short-term management of heart failure in the ED or observation unit. PMID- 25458655 TI - Is mechanical dyssynchrony a therapeutic target in heart failure with preserved ejection fraction? AB - BACKGROUND: Previous studies have found a high frequency of mechanical dyssynchrony in patients with heart failure (HF) with preserved ejection fraction (HFpEF), hence suggesting that cardiac resynchronization therapy (CRT) may be considered in HFpEF. The present study was designed to compare the amount of mechanical dyssynchrony between HFpEF patients and (1) HF with reduced EF (HFrEF) patients with an indication for CRT (HFrEF-CRT(+)) group, (2) HFrEF patients with QRS duration < 120 ms (HFrEF-QRS < 120 ms) group, and (3) hypertensive controls (HTN). METHODS: Electrical (ECG) and mechanical dyssynchrony (atrio-ventricular dyssynchrony, interventricular dyssynchrony, intraventricular dyssynchrony) were assessed using conventional, tissue Doppler, and Speckle Tracking strain echocardiography in 40 HFpEF patients, 40 age- and sex-matched HTN controls, 40 HFrEF-QRS < 120 ms patients, and 40 HFrEF-CRT(+) patients. RESULTS: The frequency of left bundle branch block was low in HFpEF patients (5%) and similar to HTN controls (5%, P = 0.85). Indices of dyssynchrony were similar between HFpEF and HTN patients or HFrEF-QRS < 120 ms patients. In contrast, most indices of dyssynchrony differed between HFpEF and HFrEF-CRT(+) patients. The principal components analysis on the entire cohort of 160 patients yielded 2 homogeneous groups of patients in terms of dyssynchrony, the first comprising HFrEF-CRT(+) patients and the second comprising HTN, HFrEF-QRS < 120 ms and HFpEF patients. CONCLUSIONS: Mechanical dyssynchrony in HFpEF does not differ from that of patients with HTN or patients with HFrEF and a narrow QRS. This data raises concerns regarding the role of dyssynchrony in the pathophysiology of HFpEF and thereby the potential usage of CRT in HFpEF. PMID- 25458657 TI - Case management reduces global vascular risk after stroke: secondary results from the The preventing recurrent vascular events and neurological worsening through intensive organized case-management randomized controlled trial. AB - BACKGROUND: Survivors of ischemic stroke/transient ischemic attack (TIA) are at high risk for other vascular events. We evaluated the impact of 2 types of case management (hard touch with pharmacist or soft touch with nurse) added to usual care on global vascular risk. METHODS: This is a prespecified secondary analysis of a 6-month trial conducted in outpatients with recent stroke/TIA who received usual care and were randomized to additional monthly visits with either nurse case managers (who counseled patients, monitored risk factors, and communicated results to primary care physicians) or pharmacist case managers (who were also able to independently prescribe according to treatment algorithms). The Framingham Risk Score [FRS]) and the Cardiovascular Disease Life Expectancy Model (CDLEM) were used to estimate 10-year risk of any vascular event at baseline, 6 months (trial conclusion), and 12 months (6 months after last trial visit). RESULTS: Mean age of the 275 evaluable patients was 67.6 years. Both study arms were well balanced at baseline and exhibited reductions in absolute global vascular risk estimates at 6 months: median 4.8% (Interquartile range (IQR) 0.3% 11.3%) for the pharmacist arm versus 5.1% (IQR 1.9%-12.5%) for the nurse arm on the FRS (P = .44 between arms) and median 10.0% (0.1%-31.6%) versus 12.5% (2.1% 30.5%) on the CDLEM (P = .37). These reductions persisted at 12 months: median 6.4% (1.2%-11.6%) versus 5.5% (2.0%-12.0%) for the FRS (P = .83) and median 8.4% (0.1%-28.3%) versus 13.1% (1.6%-31.6%) on the CDLEM (P = .20). CONCLUSIONS: Case management by nonphysician providers is associated with improved global vascular risk in patients with recent stroke/TIA. Reductions achieved during the active phase of the trial persisted after trial conclusion. PMID- 25458656 TI - Cognitive status in patients hospitalized with acute decompensated heart failure. AB - BACKGROUND: Cognitive impairment is highly prevalent in patients with heart failure and is associated with adverse outcomes. However, whether specific cognitive abilities (eg, memory vs executive function) are impaired in heart failure has not been fully examined. We investigated the prevalence of impairment in 3 cognitive domains in patients hospitalized with acute decompensated heart failure (ADHF) and the associations of impairment with demographic and clinical characteristics. METHODS: The sample included 744 patients hospitalized with ADHF (mean age 72 years, 46% female) at 5 medical centers. Impairment was assessed in 3 cognitive domains (memory, processing speed, executive function) using standardized measures. Demographic and clinical characteristics were obtained from a structured interview and medical record review. RESULTS: A total of 593 (80%) of 744 patients were impaired in at least 1 cognitive domain; 32%, 31%, and 17% of patients were impaired in 1, 2, or all 3 cognitive domains, respectively. Patients impaired in more than 1 cognitive domain were significantly older, had less formal education, and had more noncardiac comorbidities (all P values < .05). In multivariable adjusted analyses, patients with older age and lower education had higher odds of impairment in 2 or more cognitive domains. Depressed patients had twice the odds of being impaired in all 3 cognitive domains (odds ratio 1.98, 95% CI 1.08-3.64). CONCLUSION: Impairments in executive function, processing speed, and memory are common among patients hospitalized for ADHF. Recognition of these prevalent cognitive deficits is critical for the clinical management of these high-risk patients. PMID- 25458659 TI - Impact of diabetes mellitus and metabolic syndrome on acute and chronic on clopidogrel platelet reactivity in patients with stable coronary artery disease undergoing drug-eluting stent placement. AB - BACKGROUND: Previous studies, which compared the prevalence of high on clopidogrel platelet reactivity (HCPR) in type 2 diabetes mellitus (T2DM) versus non-T2DM and obese versus nonobese patients provided conflicting results. METHODS: We compared the prevalence of HCPR in patients with T2DM, metabolic syndrome (MS), or neither T2DM nor MS undergoing drug-eluting stent implantation for stable coronary artery disease. Platelet functions were measured after a 600 mg clopidogrel loading dose and after 4 months on clopidogrel 75 mg/d. RESULTS: The prevalence of HCPR was significantly higher in 63 T2DM and 50 MS patients than in 43 patients with neither T2DM nor MS (46.0% and 52.0% vs 20.9%) after clopidogrel loading dose, whereas, at 4 months, only T2DM patients had a significantly higher prevalence of HCPR (50.8% and 31.3% vs 23.8%). By multivariable analysis, T2DM (odds ratio [OR] 3.62, 95% CI, 1.34-9.80, P = .011), MS (OR 4.00, 95% CI 1.39-11.46, P = .010), and previous chronic treatment with clopidogrel (OR 0.22, 95% CI 0.09-0.49; P < .001) were the main independent predictors of HCPR after clopidogrel loading dose, whereas only T2DM (OR 2.98, 95% CI 1.20-7.41, P = .017) was an important independent predictor of HCPR at 4 months. CONCLUSIONS: Both MS and T2DM were independent predictors of HCPR after clopidogrel loading dose. On clopidogrel maintenance therapy, only T2DM remained an independent predictor. This observation may be clinically relevant in the current era of antiplatelet therapy. PMID- 25458658 TI - Associations of N-terminal pro-B-type natriuretic peptide with kidney function decline in persons without clinical heart failure in the Heart and Soul Study. AB - BACKGROUND: Subclinical volume overload in the absence of diagnosed heart failure (HF) may be an underrecognized contributor to kidney function decline in coronary artery disease (CAD) patients. We evaluated associations of circulating N terminal pro-B-type natriuretic peptide (NT-proBNP), a marker of ventricular stretch, with change in estimated glomerular filtration rate (eGFR). METHODS: We evaluated 535 patients with stable CAD and no history of HF, who were enrolled in the Heart and Soul Study and followed for 5 years. N-terminal pro-B-type natriuretic peptide was measured at baseline. We evaluated the associations of NT proBNP with change in kidney function over 5 years: (a) annual percent change in eGFR, (b) rapid kidney function loss (> 3% per year for 5 years), and (c) incident eGFR < 60 mL/min per 1.73 m2. In multivariable models, we adjusted for demographics, comorbid conditions, echocardiographic parameters, medications, and baseline kidney function. RESULTS: Among 535 participants, median NT-proBNP was 130.6 (interquartile range 61.8-280.9) pg/mL, and median B-type natriuretic peptide (BNP) was 32.5 (14.4-75.9) pg/mL. Individuals with NT-proBNP levels in the highest quartile (> 280.9 pg/mL) had a greater odds of rapid kidney function loss after full adjustment (odds ratio 2.95; 95% CI 1-8.65; P = .0492). Associations with incident eGFR < 60 mL/min per 1.73 m2 were also significant (adjusted odds ratio 4.23; 95% CI 1.05-16.98; P = .0422). Results were similar when analyzed using BNP as the predictor. CONCLUSIONS: N-terminal pro-B-type natriuretic peptide and BNP are strongly and independently associated with accelerated kidney function loss, even in the absence of clinical HF. These findings suggest that subclinical cardiovascular dysfunction may contribute to elevated kidney disease risk in persons with CAD. PMID- 25458660 TI - Inpatient admissions and costs of congenital heart disease from adolescence to young adulthood. AB - BACKGROUND: Health care utilization patterns and associated costs of congenital heart disease (CHD) in young adulthood are not well understood. METHODS: California State Inpatient Databases 2005 to 2009 were used to conduct a retrospective study on inpatient admissions of CHD patients 10 to 29 years old (n = 7,419) and of all patients of the same age (n = 1,195,233). RESULTS: Compared with all patients, annual admission costs of CHD patients monotonically decreased, from $13.9 million at age 10 to 14 years to $7.2 million at age 25 to 29 years, which were due to lower costs per admission and somewhat fewer annual hospitalizations. Admissions from the emergency department in CHD patients increased with age regardless of insurance status: at age 25 to 29 years, 62% of admissions with public insurance, 43% with private insurance, and 78% with no insurance were admitted from the emergency department. Cardiac surgery, catheterization, and electrophysiologic study admissions decreased with age in CHD patients, whereas admissions due to arrhythmia and congestive heart failures became more prevalent. Results from multivariate linear regression in CHD patients showed that cardiac surgery was the most costly factor, associated with $29,543 more in costs per admission, followed by the use of a children's hospital, at $10,533. Factors predicting lower costs included female gender, low complexity CHD, and shorter stay, all P < .001. CONCLUSIONS: Compared with adolescents, young adults with CHD use fewer resources because the natural history of CHD results in fewer surgical admissions and more frequent but less expensive medical admissions. PMID- 25458661 TI - Birth prevalence of congenital heart defects in Norway 1994-2009--a nationwide study. AB - BACKGROUND: The reasons for decreasing birth prevalence of congenital heart defects (CHDs) in several European countries and Canada are not fully understood. We present CHD prevalence among live births, stillbirths, and terminated pregnancies in an entire nation over a period of 16 years. METHODS: Information on all births in the Medical Birth Registry of Norway, 1994-2009, was updated with information on CHD from the hospitals' Patient Administrative Systems, the National Hospital's clinical database for children with heart disease, and the Cause of Death Registry. Individuals with heart defects were assigned specific cardiac phenotypes. RESULTS: Among 954,413 births, 13,081 received a diagnosis of CHD (137.1 per 10,000 births, 133.2 per 10,000 live births). The prevalence per 10,000 births was as follows: heterotaxia, 1.6; conotruncal defects, 11.6; atrioventricular septal defects, 5.6; anomalous pulmonary venous return, 1.1; left outflow obstructions, 8.7; right outflow obstructions, 5.6; septal defects, 65.5; isolated patent ductus arteriosus, 24.6; and other specified or unspecified CHD, 12.7. Excluding preterm patent ductus arteriosus, the CHD prevalence was 123.4 per 10,000; per year, the prevalence increased with 3.5% (95% CI 2.5-4.4) in 1994-2005 and declined with 9.8% (-16.7 to -2.4) from 2005 onwards. Severe CHD prevalence was 30.7 per 10,000; per-year increase was 2.3% (1.1-3.5) in 1994 2004, and per-year decrease was 3.4% (-6.6 to -0.0) in 2004-2009. Numbers included severe CHD in stillbirths and terminated pregnancies. CONCLUSIONS: The birth prevalence of CHD declined from around 2005. Specifically, the prevalence of severe CHD was reduced by 3.4% per year from 2004 through 2009. PMID- 25458662 TI - Exercise training in CKD: efficacy, adherence, and safety. AB - BACKGROUND: Exercise training increasingly is recommended as an important part of the management of cardiovascular disease. However, few studies have evaluated the effectiveness of exercise training in patients with chronic kidney disease (CKD), and those that have included very selective populations. STUDY DESIGN: Analysis of secondary outcomes of a randomized controlled trial, with participants randomly assigned to either lifestyle intervention or usual care (control). SETTING & PARTICIPANTS: Patients with CKD stages 3 to 4 and one or more uncontrolled cardiovascular risk factor were recruited from an outpatient clinic at a large tertiary hospital. INTERVENTION: Lifestyle intervention included access to multidisciplinary care through a nurse practitioner-led CKD clinic, exercise training, and a lifestyle program. The exercise training was a 2-phased program in which participants received 8 weeks of supervised training before commencing 10 months of home-based training. OUTCOMES & MEASUREMENTS: Efficacy, as assessed by metabolic equivalent tasks (METs), 6-minute walk distance, Timed Get-Up-and-Go test, grip strength, and anthropomorphic measures; adherence, as assessed by self-reported physical activity; and safety, as assessed by reported serious adverse events, were recorded. RESULTS: 83 patients were randomly assigned and 72 patients completed follow-up testing (intervention, n=36; control, n=36). The intervention resulted in a significant improvement in METs (pre, 7.2+/-3.3; post, 9.7+/-3.6), 6-minute walk distance (pre, 485+/-110m; post, 539+/-82m), and body mass index (pre, 32.5+/-6.7kg/m(2); post, 31.9+/ 7.3kg/m(2)). Reported physical activity levels significantly increased in the intervention group at 6 months, but decreased at 12 months. There were no serious adverse events related to the exercise training. LIMITATIONS: This study was not powered to evaluate the safety of exercise training on serious adverse events. CONCLUSIONS: The findings from the present study suggest that an exercise program that includes a supervised and home-based training phase is effective, adhered to, and safe in patients with CKD. PMID- 25458664 TI - Bariatric surgery, kidney function, insulin resistance, and adipokines in patients with decreased GFR: a cohort study. PMID- 25458665 TI - Imaging mass spectrometry on the nanoscale with cluster ion beams. AB - Imaging with cluster secondary ion mass spectrometry (SIMS) is reaching a mature level of development. Using a variety of molecular ion projectiles to stimulate desorption, 3-dimensional imaging with the selectivity of mass spectrometry can now be achieved with submicrometer spatial resolution and <10 nm depth resolution. In this Perspective, stock is taken regarding what it will require to routinely achieve these remarkable properties. Issues include the chemical nature of the projectile, topography formation, differential erosion rates, and perhaps most importantly, ionization efficiency. Shortcomings of existing instrumentation are also noted. Speculation about how to successfully resolve these issues is a key part of the discussion. PMID- 25458666 TI - Emergence of multidrug resistant infection in patients with severe acute pancreatitis. AB - BACKGROUND/OBJECTIVES: Infection is the most important risk factor contributing to death in severe acute pancreatitis. Multidrug resistant (MDR) bacterial infections are an emerging problem in severe acute pancreatitis. METHODS: From January 2009 to December 2011 the medical records of 46 patients with infected severe acute pancreatitis were reviewed retrospectively to identify risk factors for the development of MDR bacterial infection and assess the related outcomes. RESULTS: The mean age of the 46 patients was 55 years; 38 were males. Thirty-six patients (78.3%) had necrotizing pancreatitis and all of enrolled 46 patients had suspected or proven pancreatic infection. MDR microorganisms was found in 29 (63%) of the 46 patients. A total of 51 episodes of MDR infection were collected from 11 cases of infected pancreatic pseudocysts, 36 cases of infected necrosis/infected walled-off necrosis and 4 cases of bacteremia. The most frequent MDR bacteria was methicillin-resistant Staphylococcus aureus (n = 15). Transferred patients had a higher incidence of MDR infections than primarily admitted patients (72% vs. 35%, P = .015). The mean intensive care unit stay was significantly longer in patients with MDR bacterial infections (20 vs. 2 days, P = .001). Mortality was not significantly different in the patients with MDR infections vs. those without it (14% vs. 6%, P = .411). CONCLUSIONS: Clinicians should be aware of the high incidence of MDR bacterial infections in patients with severe acute pancreatitis, especially referred patients. Empiric therapy directed at these pathogens may be used in patients where severe sepsis persists, until definitive culture results are obtained. PMID- 25458663 TI - Healthy lifestyle and risk of kidney disease progression, atherosclerotic events, and death in CKD: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study. AB - BACKGROUND: In general populations, healthy lifestyle is associated with fewer adverse outcomes. We estimated the degree to which adherence to a healthy lifestyle decreases the risk of renal and cardiovascular events among adults with chronic kidney disease (CKD). STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 3,006 adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. PREDICTORS: 4 lifestyle factors (regular physical activity, body mass index [BMI] of 20-<25kg/m(2), nonsmoking, and "healthy diet"), individually and in combination. OUTCOMES: CKD progression (50% decrease in estimated glomerular filtration rate or end-stage renal disease), atherosclerotic events (myocardial infarction, stroke, or peripheral arterial disease), and all-cause mortality. MEASUREMENTS: Multivariable-adjusted Cox proportional hazards. RESULTS: During a median follow-up of 4 years, we observed 726 CKD progression events, 355 atherosclerotic events, and 437 deaths. BMI>=25kg/m(2) and nonsmoking were associated with reduced risk of CKD progression (HRs of 0.75 [95% CI, 0.58 0.97] and 0.61 [95% CI, 0.45-0.82] for BMIs of 25 to <30 and >=30kg/m(2), respectively, versus 20 to <25kg/m(2); HR for nonsmoking of 0.68 [95% CI, 0.55 0.84] compared to the current smoker reference group) and reduced risk of atherosclerotic events (HRs of 0.67 [95% CI, 0.46-0.96] for BMI of 25-<30 vs 20 <25kg/m(2) and 0.55 [95% CI, 0.40-0.75] vs current smoker). Factors associated with reduced all-cause mortality were regular physical activity (HR, 0.64 [95% CI, 0.52-0.79] vs inactive), BMI>=30kg/m(2) (HR, 0.64 [95% CI, 0.43-0.96] vs 20 <25kg/m(2)), and nonsmoking (HR, 0.45 [95% CI, 0.34-0.60] vs current smoker). BMI<20kg/m(2) was associated with increased all-cause mortality risk (HR, 2.11 [95% CI, 1.13-3.93] vs 20-<25kg/m(2)). Adherence to all 4 lifestyle factors was associated with a 68% lower risk of all-cause mortality compared to adherence to no lifestyle factors (HR, 0.32; 95% CI, 0.11-0.89). LIMITATIONS: Lifestyle factors were measured only once. CONCLUSIONS: Regular physical activity, nonsmoking, and BMI>=25kg/m(2) were associated with lower risk of adverse outcomes in this cohort of individuals with CKD. PMID- 25458667 TI - Association between probiotics and enteral nutrition in an experimental acute pancreatitis model in rats. AB - BACKGROUND/OBJECTIVES: Recently, a randomized controlled trial showed that probiotic prophylaxis was associated with an increased mortality in enterally fed patients with predicted severe pancreatitis. In a rat model for acute pancreatitis, we investigated whether an association between probiotic prophylaxis and enteral nutrition contributed to the higher mortality rate. METHODS: Male Sprague-Dawley rats were allocated to four groups: 1) acute pancreatitis (n = 9), 2) acute pancreatitis and probiotic prophylaxis (n = 10), 3) acute pancreatitis and enteral nutrition (n = 10), and 4) acute pancreatitis, probiotic prophylaxis and enteral nutrition (n = 11). Acute pancreatitis was induced by intraductal glycodeoxycholate and intravenous cerulein infusion. Enteral nutrition, saline, probiotics and placebo were administered through a permanent jejunal feeding. Probiotics or placebo were administered starting 4 days before induction of pancreatitis and enteral nutrition 1 day before start until the end of the experiment, 6 days after induction of pancreatitis. Tissue samples and body fluids were collected for microbiological and histological examination. RESULTS: In all animals, serum amylase was increased six hours after induction of pancreatitis. After fulfilling the experiment, no differences between groups were found in histological severity of pancreatitis, degree of discomfort, weight loss, histological examination of small bowel and bacterial translocation (all p > 0.05). Overall mortality was 10% without differences between groups (p = 0.54). CONCLUSION: No negative association was found between prophylactic probiotics and enteral nutrition in acute pancreatitis. No new clues for a potential mechanism responsible for the higher mortality and bowel ischaemia in the PROPATRIA study were found. PMID- 25458668 TI - Combination of cyst fluid CEA and CA 125 is an accurate diagnostic tool for differentiating mucinous cystic neoplasms from intraductal papillary mucinous neoplasms. AB - BACKGROUND/OBJECTIVES: Despite advances in imaging techniques, diagnosis and management of pancreatic cystic lesions still remains challenging. The objective of this study was to determine the utility of cyst fluid analysis (CEA, CA 19-9, CA 125, amylase, and cytology) in categorizing pancreatic cystic lesions, and in differentiating malignant from benign cystic lesions. METHODS: A retrospective analysis of 68 patients with histologically and clinically confirmed cystic lesions was performed. Cyst fluid was obtained by surgical resection (n = 45) or endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) (n = 23). Cyst fluid tumor markers and amylase were measured and compared between the cyst types. RESULTS: Receiver operating characteristic (ROC) curve analysis of the tumor markers demonstrated that cyst fluid CEA provided the greatest area under ROC curve (AUC) (0.884) for differentiating mucinous versus non-mucinous cystic lesions. When a CEA cutoff value was set at 67.3 ng/ml, the sensitivity, specificity and accuracy for diagnosing mucinous cysts were 89.2%, 77.8%, and 84.4%, respectively. The combination of cyst fluid CEA content >67.3 ng/ml and cyst fluid CA 125 content >10.0 U/ml segregated 77.8% (14/18) of mucinous cystic neoplasms (MCNs) from other cyst subtypes. On the other hand, no fluid marker was useful for differentiating malignant versus benign cystic lesions. Although cytology (accuracy 83.3%) more accurately diagnosed malignant cysts than CEA (accuracy 65.6%), it lacked sensitivity (35.3%). CONCLUSIONS: Our results demonstrate that cyst fluid CEA can be a helpful marker in differentiating mucinous from non-mucinous, but not malignant from benign cystic lesions. A combined CEA and CA 125 approach may help segregate MCNs from IPMNs. PMID- 25458670 TI - Review of the progress in preparing nano TiO2: an important environmental engineering material. AB - TiO2 nanomaterial is promising with its high potential and outstanding performance in photocatalytic environmental applications, such as CO2 conversion, water treatment, and air quality control. For many of these applications, the particle size, crystal structure and phase, porosity, and surface area influence the activity of TiO2 dramatically. TiO2 nanomaterials with special structures and morphologies, such as nanospheres, nanowires, nanotubes, nanorods, and nanoflowers are thus synthesized due to their desired characteristics. With an emphasis on the different morphologies of TiO2 and the influence factors in the synthesis, this review summarizes fourteen TiO2 preparation methods, such as the sol-gel method, solvothermal method, and reverse micelle method. The TiO2 formation mechanisms, the advantages and disadvantages of the preparation methods, and the photocatalytic environmental application examples are proposed as well. PMID- 25458669 TI - Efficacy and tolerance of a diabetes specific formula in patients with type 2 diabetes mellitus: An open label, randomized, crossover study. AB - AIM: This study evaluated the effect of a diabetes specific formula on acute glucose, insulin, and triglyceride responses in patients with type 2 diabetes mellitus (T2DM). METHODS: This open-label, randomized, crossover, pilot single center study had two phases (pre-treatment and treatment). After screening, the patients entered run-in period and were counseled on diet and exercise regime. They were then randomly allocated to receive either diabetes specific formula (Nutren Diabetes, Nestle Health Science, Switzerland; Group A) or isocaloric meal (Cornflakes and milk; Group B). Blood samples were collected to estimate blood glucose, insulin and triglyceride levels (Baseline at 0 min and post-meal at 30, 60, 120, and 180 min). RESULTS: Area under curve for blood glucose post-meal at 30 min, 60 min, 120 min, and 180 min was significantly lower for Group A as compared with Group B (p=0.003, 0.0001, 0.0001, 0.0001, respectively). Increase in serum insulin levels from baseline was also lower for Group A post-meal at 120 and 180 min, respectively, as compared to Group B (p=0.0001 and 0.0002, respectively). CONCLUSION: The Diabetes specific formula tested in this study showed lower post-meal blood glucose and insulin levels as compared with isocaloric meal. Thus, diabetes specific formula may be an option for diabetic and hyperglycemic patients in need of nutritional support. PMID- 25458671 TI - Utilization of plant-based natural coagulants as future alternatives towards sustainable water clarification. AB - Rapid industrial developments coupled with surging population growth have complicated issues dealing with water scarcity as the quest for clean and sanitized water intensifies globally. Existing fresh water supplies could be contaminated with organic, inorganic and biological matters that have potential harm to the society. Turbidity in general is a measure of water cloudiness induced by such colloidal and suspended matters and is also one of the major criteria in raw water monitoring to meet the stipulated water quality guidelines. Turbidity reduction is often accomplished using chemical coagulants such as alum. The use of alum is widely associated with potential development of health issues and generation of voluminous sludge. Natural coagulants that are available in abundance can certainly be considered in addressing the drawbacks associated with the use of chemical coagulants. Twenty one types of plant-based natural coagulants categorized as fruit waste and others are identified and presented collectively with their research summary in this review. The barriers and prospects of commercialization of natural coagulants in near future are also discussed. PMID- 25458672 TI - Effect of different molecular weight organic components on the increase of microbial growth potential of secondary effluent by ozonation. AB - Ozonation has been widely applied in advanced wastewater treatment. In this study, the effect of ozonation on assimilable organic carbon (AOC) levels in secondary effluents was investigated, and AOC variation of different molecular weight (MW) organic components was analyzed. Although the removal efficiencies were 47%-76% and 94%-100% for UV254 and color at ozone dosage of 10mg/L, dissolved organic carbon (DOC) in secondary effluents was hardly removed by ozonation. The AOC levels increased by 70%-780% at an ozone dosage range of 1 10mg/L. AOC increased significantly in the instantaneous ozone demand phase, and the increase in AOC was correlated to the decrease in UV254 during ozonation. The results of MW distribution showed that, ozonation led to the transformation of larger molecules into smaller ones, but the increase in low MW (<1kDa) fraction did not contribute much to AOC production. The change of high MW (>100kDa and 10 100kDa) fractions itself during ozonation was the main reason for the increase of AOC levels. Furthermore, the oxidation of organic matters with high MWs (>100kDa and 10-100kDa) resulted in more AOC production than those with low MWs (1-10kDa and <1kDa). The results indicated that removing large molecules in secondary effluents could limit the increase of AOC during ozonation. PMID- 25458673 TI - Perfluoroalkyl substances and organochlorine pesticides in sediments from Huaihe watershed in China. AB - Twelve perfluoroalkyl substances (PFASs) and nine organochlorine pesticides (OCPs) were quantified in surface sediments from the Huaihe River, China, along which there are intensive industrial and agricultural activities. Concentrations of PFASs ranged from 0.06 to 0.46ng/g dry weight (dw), and concentrations of OCPs ranged from 1.48 to 32.65ng/gdw. Compared with other areas in China, concentrations of PFASs were lesser than the national mean value, while concentrations of OCPs were moderate. Concentrations of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) ranged from n.d. (not detected) to 0.03 and n.d. to 0.10ng/gdw, respectively. Among the three groups of OCPs, mean concentrations of hexachlorocyclohexane and its isomers (HCHs), dichlorodiphenyltrichloroethane and its metabolites (DDTs) and hexachlorobenzene (HCB) were 5.62+/-4.35, 2.43+/-3.12 and 1.55+/-4.17ng/gdw, respectively. Concentrations of HCHs and DDTs decreased from upstream to downstream along the mainstream of the Huaihe River. When compared to sediment quality guidelines (SQGs), concentrations of HCHs, DDTs and HCB would pose adverse biological effects. In general, contamination by PFASs in the upstream of the Huaihe River was more severe than that in the downstream, which was mainly caused by interception from dams, locks and industrial emissions. And OCPs from tributaries, especially the Yinghe River and Wohe River, were higher than those from Huaihe mainstream, and primarily came from historical inputs. PMID- 25458674 TI - Effects of pH on photochemical decomposition of perfluorooctanoic acid in different atmospheres by 185nm vacuum ultraviolet. AB - Perfluorooctanoic acid (PFOA), a persistent organic pollutant, receives increasing concerns due to its worldwide occurrence and resistance to most conventional treatment processes. The photochemical decomposition by 185nm vacuum ultraviolet (VUV) is one of the efficient methods for PFOA decomposition. The effects of pH on PFOA decomposition in nitrogen atmosphere or oxygen atmosphere were investigated. At its original pH (4.5) of PFOA aqueous solution, PFOA decomposed efficiently both in nitrogen and in oxygen atmosphere. However, when the pH increased to 12.0, PFOA decomposition was greatly inhibited in oxygen atmosphere, while it was greatly accelerated in nitrogen atmosphere with a very short half-life time (9min). Furthermore, fluorine atoms originally contained in PFOA molecules were almost completely transformed into fluoride ions. Two decomposition pathways have been proposed to explain the PFOA decomposition under different conditions. In acidic and neutral solutions, PFOA predominantly decomposes via the direct photolysis in both atmospheres; while in the alkaline solution and in the absence of oxygen, the decomposition of PFOA is mainly induced by hydrated electrons. PMID- 25458675 TI - Aerobic granules cultivated and operated in continuous-flow bioreactor under particle-size selective pressure. AB - A novel method based on the selective pressure of particle size (particle-size cultivation method, PSCM) was developed for the cultivation and operation of aerobic granular sludge in a continuous-flow reactor, and compared with the conventional method based on the selective pressure of settling velocity (settling-velocity cultivation method, SVCM). Results indicated that aerobic granules could be cultivated in continuous operation mode by this developed method within 14days. Although in the granulation process, under particle-size selective pressure, mixed liquor suspended solids (MLSS) in the reactor fluctuated greatly and filamentous bacteria dominated the sludge system during the initial operation days, no obvious difference in profile was found between the aerobic granules cultivated by PSCM and SVCM. Moreover, aerobic granules cultivated by PSCM presented larger diameter, lower water content and higher specific rates of nitrification, denitrification and phosphorus removal, but lower settling velocity. Under long term operation of more than 30days, aerobic granules in the continuous-flow reactor could remain stable and obtain good chemical oxygen demand (COD), NH4(+)-N, total nitrogen (TN) and total phosphorus (TP) removal. The results indicate that PSCM was dependent on the cultivation and maintenance of the stability of aerobic granules in continuous-flow bioreactors. PMID- 25458676 TI - Attenuation of arsenic in a karst subterranean stream and correlation with geochemical factors: a case study at Lihu, South China. AB - Arsenic (As) pollutants generated by human activities in karst areas flow into subterranean streams and contaminate groundwater easily because of the unique hydrogeological characteristics of karst areas. To elucidate the reaction mechanisms of arsenic in karst subterranean streams, physical-chemical analysis was conducted by an inductively coupled plasma mass spectrometer and an X-ray fluorescence spectrometer. The results show that inorganic species account for most of the total arsenic, whereas organic arsenic is not detected or occurs in infinitesimal amounts. As(III) accounts for 51.0%+/-9.9% of the total inorganic arsenic. Arsenic attenuation occurs and the attenuation rates of total As, As(III) and As(V) in the Lihu subterranean stream are 51%, 36% and 59%, respectively. To fully explain the main geochemical factors influencing arsenic attenuation, SPSS 13.0 and CANOCO 4.5 bundled with CanoDraw for Windows were used for simple statistical analysis and redundancy analysis (RDA). Eight main factors, i.e., sediment iron (SFe), sediment aluminum (SAl), sediment calcium (SCa), sediment organic matter (SOM), sediment manganese (SMn), water calcium (WCa(2+)), water magnesium (WMg(2+)), and water bicarbonate ion (WHCO3(-)) were extracted from thirteen indicators. Their impacts on arsenic content rank as: SFe>SCa>WCa(2+)>SAl>WHCO3(-)>SMn>SOM>WMg(2+). Of these factors, SFe, SAl, SCa, SOM, SMn, WMg(2+) and WCa(2+) promote arsenic attenuation, whereas WHCO3(-) inhibits it. Further investigation revealed that the redox potential (Eh) and pH are adverse to arsenic removal. The dramatic distinction between karst and non karst terrain is that calcium and bicarbonate are the primary factors influencing arsenic migration in karst areas due to the high calcium concentration and alkalinity of karst water. PMID- 25458677 TI - Nitrogen removal from coal gasification wastewater by activated carbon technologies combined with short-cut nitrogen removal process. AB - A system combining granular activated carbon and powdered activated carbon technologies along with shortcut biological nitrogen removal (GAC-PACT-SBNR) was developed to enhance total nitrogen (TN) removal for anaerobically treated coal gasification wastewater with less need for external carbon resources. The TN removal efficiency in SBNR was significantly improved by introducing the effluent from the GAC process into SBNR during the anoxic stage, with removal percentage increasing from 43.8%-49.6% to 68.8%-75.8%. However, the TN removal rate decreased with the progressive deterioration of GAC adsorption. After adding activated sludge to the GAC compartment, the granular carbon had a longer service life and the demand for external carbon resources became lower. Eventually, the TN removal rate in SBNR was almost constant at approx. 43.3%, as compared to approx. 20.0% before seeding with sludge. In addition, the production of some alkalinity during the denitrification resulted in a net savings in alkalinity requirements for the nitrification reaction and refractory chemical oxygen demand (COD) degradation by autotrophic bacteria in SBNR under oxic conditions. PACT showed excellent resilience to increasing organic loadings. The microbial community analysis revealed that the PACT had a greater variety of bacterial taxons and the dominant species associated with the three compartments were in good agreement with the removal of typical pollutants. The study demonstrated that pre-adsorption by the GAC-sludge process could be a technically and economically feasible method to enhance TN removal in coal gasification wastewater (CGW). PMID- 25458678 TI - Evaluating the emission status of light-duty gasoline vehicles and motorcycles in Macao with real-world remote sensing measurement. AB - Roadside remote sensing measurement was used to explore the real-world emission status of light duty gasoline vehicles (LDGVs) and motorcycles in Macao. Both fuel-based and distance-based emission factors were derived using the mass balance method. The emission concentration profile of LDGVs illustrated the benefits of tightening emission standards at the source country or region of import. The distance-based emission factors for CO, HC and NOx of LDGVs registered before 2000 were 8.00, 1.04 and 1.36g/km, respectively. The distance based emission factors for CO, HC and NOx of LDGVs registered in or after 2000 were 1.16, 0.15 and 0.18g/km, respectively. The fuel-based CO emission factors of light duty motorcycles (LDMCs) and heavy duty motorcycles (HDMCs) registered before 2000 were about 10 times higher than those of LDGVs of the same age group. As the emissions of LDGVs decreased more quickly after 2000, the gap widens for newer vehicles. The distance-based HC emission factors of LDMCs and HDMCs registered before 2000 were 4.81 and 2.91g/km, respectively. The distance-based HC emission factors of LDMCs and HDMCs registered in or after 2000 were 3.52 and 0.93g/km, respectively. The poor emission performance of motorcycles and their larger share in the traffic flow will cause them to be the major contributor to traffic CO and HC emissions. LDMCs, especially two-stroke models, should be the priority for vehicle emission control efforts in Macao. PMID- 25458679 TI - Experimental study of NO2 reduction in N2/Ar and O2/Ar mixtures by pulsed corona discharge. AB - Non-thermal plasma technology has been regarded as a promising alternative technology for NOx removal. The understanding of NO2 reduction characteristics is extremely important since NO2 reduction could lower the total NO oxidation rate in the plasma atmosphere. In this study, NO2 reduction was experimentally investigated using a non-thermal plasma reactor driven by a pulsed power supply for different simulated gas compositions and operating parameters. The NO2 reduction was promoted by increasing the specific energy density (SED), and the highest conversion rates were 33.7%, 42.1% and 25.7% for Ar, N2/Ar and O2/Ar, respectively. For a given SED, the NO2 conversion rate had the order N2/Ar>Ar>O2/Ar. The highest energy yield of 3.31g/kWh was obtained in N2/Ar plasma and decreased with increasing SED; the same trends were also found in the other two gas compositions. The conversion rate decreased with increasing initial NO2 concentration. Furthermore, the presence of N2 or O2 led to different reaction pathways for NO2 conversion due to the formation of different dominating reactive radicals. PMID- 25458680 TI - Absorption characteristics of elemental mercury in mercury chloride solutions. AB - Elemental mercury (Hg(0)) in flue gases can be efficiently captured by mercury chloride (HgCl2) solution. However, the absorption behaviors and the influencing effects are still poorly understood. The mechanism of Hg(0) absorption by HgCl2 and the factors that control the removal were studied in this paper. It was found that when the mole ratio of Cl(-) to HgCl2 is 10:1, the Hg(0) removal efficiency is the highest. Among the main mercury chloride species, HgCl3(-) is the most efficient ion for Hg(0) removal in the HgCl2 absorption system when moderate concentrations of chloride ions exist. The Hg(0) absorption reactions in the aqueous phase were investigated computationally using Moller-Plesset perturbation theory. The calculated Gibbs free energies and energy barriers are in excellent agreement with the results obtained from experiments. In the presence of SO3(2-) and SO2, Hg(2+) reduction occurred and Hg(0) removal efficiency decreased. The reduced Hg(0) removal can be controlled through increased chloride concentration to some degree. Low pH value in HgCl2 solution enhanced the Hg(0) removal efficiency, and the effect was more significant in dilute HgCl2 solutions. The presence of SO4(2-) and NO3(-) did not affect Hg(0) removal by HgCl2. PMID- 25458681 TI - Variations in stable hydrogen and oxygen isotopes in atmospheric water vapor in the marine boundary layer across a wide latitude range. AB - The newly-developed cavity ring-down laser absorption spectroscopy analyzer with special calibration protocols has enabled the direct measurement of atmospheric vapor isotopes at high spatial and temporal resolution. This paper presents real time hydrogen and oxygen stable isotope data for atmospheric water vapor above the sea surface, over a wide range of latitudes spanning from 38 degrees N to 69 degrees S. Our results showed relatively higher values of delta(18)O and delta(2)H in the subtropical regions than those in the tropical and high latitude regions, and also a notable decreasing trend in the Antarctic coastal region. By combining the hydrogen and oxygen isotope data with meteoric water line and backward trajectory model analysis, we explored the kinetic fractionation caused by subsiding air masses and related saturated vapor pressure in the subtropics, and the evaporation-driven kinetic fractionation in the Antarctic region. Simultaneous observations of meteorological and marine variables were used to interpret the isotopic composition characteristics and influential factors, indicating that d-excess is negatively correlated with humidity across a wide range of latitudes and weather conditions worldwide. Coincident with previous studies, d-excess is also positively correlated with sea surface temperature and air temperature (Tair), with greater sensitivity to Tair. Thus, atmospheric vapor isotopes measured with high accuracy and good spatial-temporal resolution could act as informative tracers for exploring the water cycle at different regional scales. Such monitoring efforts should be undertaken over a longer time period and in different regions of the world. PMID- 25458682 TI - Effect of ammonium sulfate and urea on PCDD/F formation from active carbon and possible mechanism of inhibition. AB - The effect of ammonium sulfate ((NH4)2SO4) and urea (CO(NH2)2) on polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDD/F) formation from active carbon was investigated in this study. Both additives could significantly inhibit PCDD/F formation, and PCDD/F (TEQ) generation was reduced to 98.5% (98%) or 64.5% (77.2%) after 5% (NH4)2SO4 or CO(NH2)2 was added into model ash, respectively. The inhibition efficiency of PCDDs was higher than the value of PCDFs, however, the reduction of PCDD/F yield was mainly from PCDFs decreasing. In addition, the solid-phase products were reduced more than the gas-phase compounds by inhibitors. By the measurement of chlorine emission in the phase of ion (Cl[Cl( )]) and molecule gas (Cl[Cl2]), it was observed that both Cl[Cl(-)] and Cl[Cl2] were reduced after inhibitors were added into ash. Cl[Cl2] was reduced to 51.0% by urea addition, which was supposed as one possible mechanism of PCDD/F inhibition. PMID- 25458684 TI - An assessment of the effectiveness and impact of electrokinetic remediation for pyrene-contaminated soil. AB - The effectiveness of electrokinetic remediation for pyrene-contaminated soil was investigated by an anode-cathode separated system using a salt bridge. The applied constant voltage was 24 V and the electrode gap was 24 cm. Two types of soil (sandy soil and loam soil) were selected because of their different conductive capabilities. The initial concentrations of pyrene in these soil samples were 261.3mg/kg sandy soil and 259.8 mg/kg loam soil. After treatment of the sandy soil and loam soil for seven days, 56.8% and 20.1% of the pyrene had been removed respectively. Under the same power supply voltage, the removal of the pollutant from the sandy soil was greater than that from the loam soil, due to the higher current and lower pH. Further analysis revealed that the effectiveness of electrokinetic remediation was affected by the energy expenditure, and was associated with changes in soil properties. PMID- 25458683 TI - Theoretical study on the degradation reaction of octachlorinated dibenzo-p-dioxin with atomic oxygen O((3)P) in dielectric barrier discharge reactor. AB - Dielectric barrier discharges (DBD) have been used in the degradation of dioxins due to the large number of excimers and free radicals produced in discharge process. In this article, the density functional theory (DFT) is used to study the degradation mechanism of octachlorinated dibenzo-p-dioxin (OCDD) with the atomic oxygen O((3)P) in DBD reactor. The reactants, intermediates, transition states and products are optimized at the MPWB1K/6-31+G(d,p) level. The vibrational frequencies have been calculated at the same level. The reaction pathways and mechanisms are analyzed in detail. The effect of removing the chlorine atom on environment also has been discussed. PMID- 25458685 TI - Effect of surfactant on phenanthrene metabolic kinetics by Citrobacter sp. SA01. AB - To attain a better understanding of the effects of surfactants on the metabolic kinetics of hydrophobic organic compounds, the biodegradation of phenanthrene by Citrobacter sp. SA01 was investigated in a batch experiment containing Tween 80, sodium dodecyl benzene sulfonate and liquid mineral salt medium. The Monod model was modified to effectively describe the partition, phenanthrene biodegradation and biopolymer production. The results showed that Tween 80 and sodium dodecyl benzene sulfonate (each at 50mg/L) enhanced phenanthrene metabolism and poly-beta hydroxybutyrate production as indicated by the increasing amounts of intermediates (by 17.2% to 47.9%), and percentages of poly-beta-hydroxybutyrate (by 107.3% and 33.1%) within the cell dry weight when compared to their absence. The modified Monod model was capable of predicting microbial growth, phenanthrene depletion and biopolymer production. Furthermore, the Monod kinetic coefficients were largely determined by the surfactant-enhanced partition, suggesting that partitioning is a critical process in surfactant-enhanced bioremediation of hydrophobic organic compounds. PMID- 25458686 TI - Cytochrome P450 BM3 of Bacillus megaterium - a possible endosulfan biotransforming gene. AB - Computing chemistry was applied to understand biotransformation mechanism of an organochlorine pesticide, endosulfan. The stereo specific metabolic activity of human CYP-2B6 (cytochrome P450) on endosulfan has been well demonstrated. Sequence and structural similarity search revealed that the bacterium Bacillus megaterium encodes CYP-BM3, which is similar to CYP-2B6. The functional similarity was studied at organism level by batch-scale studies and it was proved that B. megaterium could metabolize endosulfan to endosulfan sulfate, as CYP-2B6 does in human system. The gene expression analyses also confirmed the possible role of CYP-BM3 in endosulfan metabolism. Thus, our results show that the protein structure based in-silico approach can help us to understand and identify microbes for remediation strategy development. To the best of our knowledge this is the first report which has extrapolated the bacterial gene for endosulfan biotransformation through in silico prediction approach for metabolic gene identification. PMID- 25458687 TI - Phosphatase activity and culture conditions of the yeast Candida mycoderma sp. and analysis of organic phosphorus hydrolysis ability. AB - Orthophosphate is an essential but limiting macronutrient for plant growth. About 67% cropland in China lacks sufficient phosphorus, especially that with red soil. Extensive soil phosphorus reserves exist in the form of organic phosphorus, which is unavailable for root uptake unless hydrolyzed by secretory acid phosphatases. Thus, many microorganisms with the ability to produce phosphatase have been exploited. In this work, the activity of an extracellular acid phosphatase and yeast biomass from Candida mycoderma was measured under different culture conditions, such as pH, temperature, and carbon source. A maximal phosphatase activity of 8.47*10(5)+/-0.11*10(5)U/g was achieved by C. Mycoderma in 36 hr under the optimal conditions. The extracellular acid phosphatase has high activity over a wide pH tolerance range from 2.5 to 5.0 (optimum pH3.5). The effects of different phosphorus compounds on the acid phosphatase production were also studied. The presence of phytin, lecithin or calcium phosphate reduced the phosphatase activity and biomass yield significantly. In addition, the pH of the culture medium was reduced significantly by lecithin. The efficiency of the strain in releasing orthophosphate from organic phosphorus was studied in red soil (used in planting trees) and rice soil (originating as red soil). The available phosphorus content was increased by 230% after inoculating 20 days in rice soil and decreased by 50% after inoculating 10 days in red soil. This work indicates that the yeast strain C. mycoderma has potential application for enhancing phosphorus utilization in plants that grow in rice soil. PMID- 25458688 TI - Microencapsulated chlorpyrifos: degradation in soil and influence on soil microbial community structures. AB - Degradation kinetics of microencapsulated chlorpyrifos (CPF-MC) in soil and its influence on soil microbial community structures were investigated by comparing with emulsifiable concentration of chlorpyrifos (CPF-EC) in laboratory. The residual periods of CPF-MC with fortification levels of 5 and 20mg/kg reached 120 days in soil, both of the degradation curves did not fit the first-order model, and out-capsule residues of chlorpyrifos in soil were maintained at 1.76 (+/ 0.33) and 5.92 (+/-1.20) mg/kg in the period between 15 and 60 days, respectively. The degradation kinetics of CPF-EC fit the first-order model, and the residual periods of 5 and 20mg/kg treatments were 60 days. Bacterial community structures in soil treated with two concentrations of CPF-MC showed similarity to those of the control during the test period, as seen in the band number and relative intensities of the individual band on DGGE gels (p>0.05). Fungal community structures were slightly affected in the 5mg/kg treatments and returned to the control levels after 30 days, but initially differed significantly from control in the 20mg/kg treatments (p<0.05) and did not recover to control levels until 90 days later. The CPF-EC significantly altered microbial community structures (p<0.05) and effects did not disappear until 240 days later. The results indicated that the microcapsule technology prolonged the residue periods of chlorpyrifos in soil whereas it decreased its side-effects on soil microbes as compared with the emulsifiable concentration formulation. PMID- 25458689 TI - Molecular characterization and mRNA expression of ribosomal protein L8 in Rana nigromaculata during development and under exposure to hormones. AB - Like Xenopus laevis, some species of the Rana genus are also used to study endocrine disrupting chemicals (EDCs). Although ribosomal protein L8 (rpl8) is the most-used reference gene for analyzing gene expression by quantitative reverse transcription polymerase chain reaction in Rana, its suitability as the reference gene has never been validated in any species of the Rana genus. We characterized rpl8 cDNA in Rana nigromaculata, a promising native species in East Asia for assaying endocrine disrupting effects. We found that the rpl8 cDNA consisted of 919bp and encoded 257 amino acids, exhibiting high identities of amino acid sequence with known rpl8 in other Rana species. Then, we examined the stability of mRNA expression during development. Compared with elongation factor 1 alpha 1, another common housekeeping gene, neither stage-specific nor tissue specific expression of the rpl8 gene was found in all tissues examined (brain, liver, intestine, tail, testis and ovary) during R. nigromaculata development. Finally, we investigated rpl8 expression under exposure to hormones. No change in rpl8 mRNA expression was found under exposure to thyroid hormone (T4) and estrogen (estradiol), whereas expression of the corresponding biomarker genes was induced. Our results show that rpl8 is an appropriate reference gene for analyzing gene expression by quantitative reverse transcription polymerase chain reaction for assaying EDCs using R. nigromaculata, and might also provide support for using rpl8 as a reference gene in other Rana species due to the high conservation of rpl8 among the Rana genus. PMID- 25458690 TI - Spatial-temporal distribution and potential ecological risk assessment of nonylphenol and octylphenol in riverine outlets of Pearl River Delta, China. AB - The aquatic environments of the Pearl River Delta in Southern China are subjected to contamination with various industrial chemicals from local industries. In this paper, the occurrence, seasonal variation and spatial distribution of alkylphenol octylphenol (OP) and nonylphenol (NP) in river surface water and sediments in the runoff outlets of the Pearl River Delta were investigated. NP and OP were detected in all water and sediment samples and their mean concentrations in surface water during the dry season ranged from 810 to 3366 ng/L and 85.5 to 581 ng/L, respectively, and those in sediments ranged from 14.2 to 95.2 ng/g dw and 0.4 to 3.0 ng/g dw, respectively. In surface water, much higher concentrations were detected in the dry season than those in the wet season. In sediments, the concentrations in the dry season were also mostly higher. High concentrations of NP and OP were found in Humen outlet, likely due to high levels of domestic and industrial wastewater discharges. An ecological risk assessment with the use of hazard quotient (HQ) was also carried out and the HQ values ranged from 3.6*10( 5) to 35 and 64% of samples gave a HQ>1, indicating that the current levels of NP and OP pose a significant risk to the relevant aquatic organisms in the region. PMID- 25458691 TI - Synthesis and characterisation of potassium polytitanate for photocatalytic degradation of crystal violet. AB - Potassium titanate nanostructures were synthesised by hydrothermal treatment of TiO2 (P25) in KOH and H2O2. As-produced powders were characterised by scanning electron microscopy, energy-dispersive X-ray spectroscopy, transmission electron microscopy, X-ray diffraction, and nitrogen adsorption-desorption methods. Longitudinally-oriented-wire-like structures with a length up to several micrometres and diameters ranging from 10 to 30 nm were obtained. Larger size fibrous nanowires resulting from the hydrothermal treatment showed high affinity in adsorbing crystal violet (CV), which was mainly due to their high surface area. The photocatalytic bleaching of CV solution revealed that the wires are photoactive under ultraviolet light irradiation. Macroporous nanowires are considered as effective adsorbents of CV, capable of photocatalytic degradation, and they can be easily separated from the solution by settling. PMID- 25458692 TI - Ultrasonic preparation of nano-nickel/activated carbon composite using spent electroless nickel plating bath and application in degradation of 2,6 dichlorophenol. AB - Ni was effectively recovered from spent electroless nickel (EN) plating baths by forming a nano-nickel coated activated carbon composite. With the aid of ultrasonication, melamine-formaldehyde-tetraoxalyl-ethylenediamine chelating resins were grafted on activated carbon (MFT/AC). PdCl2 sol was adsorbed on MFT/AC, which was then immersed in spent electroless nickel plating bath; then nano-nickel could be reduced by ascorbic acid to form a nano-nickel coating on the activated carbon composite (Ni/AC) in situ. The materials present were carefully examined by Fourier transform infrared spectroscopy, X-ray diffraction, field emission scanning electron microscopy, X-ray photoelectron spectroscopy and electrochemistry techniques. The resins were well distributed on the inside and outside surfaces of activated carbon with a size of 120 +/- 30 nm in MFT/AC, and a great deal of nano-nickel particles were evenly deposited with a size of 3.8 +/ 1.1 nm in Ni/MFT. Moreover, Ni/AC was successfully used as a catalyst for ultrasonic degradation of 2,6-dichlorophenol. PMID- 25458693 TI - Photocatalytic degradation of endocrine disruptor Bisphenol-A in the presence of prepared CexZn1-xO nanocomposites under irradiation of sunlight. AB - Photocatalytic degradation of Bisphenol A (BPA), a representative endocrine disruptor chemical, was carried out under irradiation of sunlight in the presence of CexZn1-xO nanophotocatalyst. Cerium (Ce) ions were successfully incorporated into the bulk lattice of ZnO by simple co-precipitation process. The CexZn1-xO composite nanostructures exhibited higher photocatalytic efficiency than pure ZnO in the degradation of BPA under sunlight irradiation and nearly complete mineralization of BPA was achieved. The degradation rate was strongly dependent on factors such as the size and structure of catalyst, doping material concentration, BPA concentration, catalyst load, irradiation time and pH levels. This work suggested that the CexZn1-xO assisted photocatalytic degradation is a versatile, economic, environmentally benign and efficient method for BPA removal in the aqueous environment. PMID- 25458694 TI - Regulating life or death: potential role of microRNA in rescue of the corpus luteum. AB - The role of miRNA in tissue biology has added a new level of understanding of gene regulation and function. The corpus luteum (CL) is a transitory endocrine gland; the dynamic nature of the CL makes it a candidate for regulation by miRNA. Rescue of the CL from luteolysis is essential for the maintenance of pregnancy in all eutherian mammals. Using next generation sequencing, we profiled miRNA expression in the bovine CL during maternal recognition of pregnancy. We identified 590 luteal miRNA, of which 544 were known and 46 were novel miRNAs. Fifteen (including 3 novel) miRNAs were differentially expressed between CL of pregnant vs. cyclic animals. Target analysis of the differentially expressed miRNA resulted in genes involved in regulating apoptosis and immune response, providing evidence that miRNAs regulate the intracellular pathways that lead to either luteal regression or survival. PMID- 25458696 TI - Omega 3 and omega 6 fatty acids in human and animal health: an African perspective. AB - Lipids are essential for plant and animal development, growth and nutrition and play critical roles in health and reproduction. The dramatic increase in the human population has put increasing pressure on human food sources, especially of those sources of food which contain adequate levels of polyunsaturated fatty acids (PUFAs) and more importantly, sources of food which have favorable ratios of the n-3 (18-carbon, alpha-linolenic acid, ALA) to n-6 (18-carbon linoleic acid, LA) PUFAs. Recent studies have demonstrated the beneficial effects of the n 3 PUFAs in diets as well as potentially negative effects of excessive levels of n 6 PUFAs in diets. This review discusses these human health issues relating to changes in diets based on environmental and industrial changes as well as strategies in East Africa for improving lipid composition of food using indigenous sources. PMID- 25458695 TI - 3beta-Hydroxysteroid dehydrogenase isoforms in human aldosterone-producing adenoma. AB - It has become important to evaluate the possible involvement of 3beta hydroxysteroid dehydrogenase type 1 (HSD3B1) and 2 (HSD3B2) isoforms in aldosterone-producing adenoma (APA). In this study, we studied 67 and 100 APA cases using real-time quantitative PCR (qPCR) and immunohistochemistry, respectively. Results of qPCR analysis demonstrated that HSD3B2 mRNA was significantly more abundant than HSD3B1 mRNA (P < 0.0001), but only HSD3B1 mRNA significantly correlated with CYP11B2 (aldosterone synthase) mRNA (P <0.0001) and plasma aldosterone concentration (PAC) of the patients (P <0.0001). Results of immunohistochemistry subsequently revealed that HSD3B2 immunoreactivity was detected in the great majority of APA but a significant correlation was also detected between HSD3B1 and CYP11B2 (P <0.0001). In KCNJ5 mutated APA, CYP11B2 mRNA (P <0.0001) and HSD3B1 mRNA (P = 0.011) were significantly higher than those of wild type APA. These results suggest that HSD3B1 is involved in aldosterone production, despite its lower levels of expression compared with HSD3B2, and also possibly associated with KCNJ5 mutation in APA. PMID- 25458697 TI - Steroid responsive regulation of IFNgamma2 alternative splicing and its possible role in germ cell proliferation in medaka. AB - Interferon gamma (IFNgamma) is an active player in estrogen dependent immuno regulation of fish. The present work was aimed to characterize the alternatively spliced isoforms of IFNgamma2 in the gonadal sex development in medaka. Phylogenetic analysis demonstrated that IFNgamma2a and 2b were clustered with fish specific interferon gamma. Our in vitro promoter and mini-genome analysis data confirmed that alternative splicing of IFNgamma2 is regulated by estrogens and androgens. Tissue distribution, quantitative PCR and ISH data demonstrated ubiquitous expression of IFNgamma2a, while IFNgamma2b was only expressed predominantly in female germ cells than males. This was further confirmed by germ cell specific GFP signals in the IFNgamma2b-GFP over-expressed embryos and specific induction of IFNgamma2b expression in the BrdU positive cells. All together our data suggest that steroid responsive alternatively spliced IFNgamma2b isoforms might have some indirect roles in germ cell proliferation and thus can be an important candidate for immuno-reproductive interaction studies. PMID- 25458698 TI - Regulation of FGF23 expression in IDG-SW3 osteocytes and human bone by pro inflammatory stimuli. AB - Fibroblast growth factor-23 (FGF23), produced by osteocytes, is the key physiological regulator of phosphate homeostasis. Sepsis patients often experience transient hypophosphataemia, suggesting the regulation of FGF23 levels by pro-inflammatory factors. Here, we used the osteocyte-like cell line IDG-SW3 to investigate the effect of pro-inflammatory stimuli on FGF23 production. In differentiated IDG-SW3 cultures, basal Fgf23 mRNA was dose-dependently up regulated by pro-inflammatory cytokines TNF, IL-1beta and TWEAK, and bacterial LPS. Similar effects were observed in human bone samples. TNF- and IL-1beta induced Fgf23 expression was NF-kappaB-dependent. Conversely, mRNA encoding negative regulators of FGF23, Phex, Dmp1 and Enpp1, were suppressed by TNF, IL 1beta, TWEAK and LPS, independent of NF-kappabeta signalling. Galnt3, the protein product of which protects intact FGF23 protein from furin/furin-like proprotein convertase cleavage, increased in response to these treatments. C-terminal FGF23 and intact FGF23 protein levels also increased, the latter only in the presence of Furin inhibitors, suggesting that enzymatic cleavage exerts critical control of active FGF23 secretion by osteocytes. Our results demonstrate in principle that pro-inflammatory stimuli are capable of increasing osteocyte secretion of FGF23, which may contribute to hypophosphataemia during sepsis and possibly other inflammatory conditions. PMID- 25458699 TI - Variants in IRAK1-MECP2 region confer susceptibility to autoimmune thyroid diseases. AB - Our objective was to investigate whether interleukin-1 receptor-associated kinase (IRAK1) and methyl-CpG-binding protein 2 (MECP2) are associated with autoimmune thyroid diseases (AITDs). We selected four single nucleotide polymorphisms (SNPs), rs3027898, rs1059703 in IRAK1 and rs2075596, rs2239464 in MECP2, for genotyping using PCR-based ligase detection reaction (LDR) method in 1042 AITDs patients and 897 controls. Minor alleles in the four SNPs were strongly associated with AITDs, and similar associations were found in Graves' disease (GD). In Hashimoto's thyroiditis (HT) patients, a significantly increased risk of T allele in rs1059703 was found. There were obvious differences in allele and genotype distributions in female AITDs, GD and HT patients. Moreover, the haplotypes CCAA and ATGG were the associated variants for AITDs and GD. Besides, these two haplotypes showed similar associations with AITDs and GD in female patients. Our results firstly indicated that IRAK1 and MECP2 genes are crucial risk factors for AITDs. PMID- 25458700 TI - Differential expression of vitelline membrane outer layer protein 1: hormonal regulation of expression in the oviduct and in ovarian carcinomas from laying hens. AB - Vitelline membrane outer layer protein 1 (VMO1), a basic protein present in the outer layer of the vitelline membrane of eggs, plays essential roles in separating the yolk from the egg white and preventing infection from bacteria by forming a barrier of fibrous layers in avian eggs. Although VMO1 is expressed in the oviduct of hens, little is known about endocrine regulation of transcription of VMO1 in the oviduct and its expression in cancerous ovaries of laying hens. Results of present study indicated that expression of VMO1 mRNA increased in the chick oviduct in response to diethylstilbestrol (DES, a synthetic non-steroidal estrogen). VMO1 mRNA and protein were particularly abundant in the glandular epithelium (GE) and luminal epithelium (LE) of the magnum of the oviducts of chicks treated with DES. Also, during the regression and recrudescence phases of the oviduct during induced molting with zinc feeding, VMO1 expression decreased as the oviduct regressed and increased with remodeling and recrudescence of the oviduct in laying hens. In addition, changes in relative expression of specific microRNAs (miR-1623, miR-1552-3p, miR-1573, miR-22-3p, miR-124a and miR-1764) regulating VMO1 gene were detected in the oviducts during the molting period. Moreover, abundant expression of VMO1 was found in GE of cancerous, but not normal ovaries of laying hens. Results of the present study suggest that VMO1 is regulated by estrogen and target microRNAs in the chicken oviduct and that it is a potential diagnostic marker of ovarian cancer in laying hens. PMID- 25458701 TI - Osteoclast formation elicited by interleukin-33 stimulation is dependent upon the type of osteoclast progenitor. AB - Osteoclasts are bone resorbing multinucleated cells (MNCs) derived from macrophage progenitors. IL-33 has been reported to drive osteoclastogenesis independently of receptor activator of NFkappaB ligand (RANKL) but this remains controversial as later studies did not confirm this. We found IL-33 clearly elicited functional dentine-resorbing osteoclast formation from human adult monocytes. However, monocytes from only 3 of 12 donors responded this way, while all responded to RANKL. Human cord blood-derived progenitors and murine bone marrow macrophages lacked an osteoclastogenic response to IL-33. In RAW264.7 cells, IL-33 elicited NFkappaB and p38 responses but not NFATc1 signals (suggesting poor osteoclastogenic responses) and formed only mononuclear tartrate resistant acid phosphatase positive (TRAP(+)) cells. Since TGFbeta boosts osteoclastogenesis in RAW264.7 cells we employed an IL-33/TGFbeta co-treatment, which resulted in small numbers of MNCs expressing key osteoclast markers TRAP and calcitonin receptors. Thus, IL-33 possesses weak osteoclastogenic activity suggesting pathological significance and, perhaps, explaining previous conflicting reports. PMID- 25458702 TI - Grass carp prolactin: molecular cloning, tissue expression, intrapituitary autoregulation by prolactin and paracrine regulation by growth hormone and luteinizing hormone. AB - Prolactin (PRL), a pituitary hormone with diverse functions, is well-documented to be under the control of both hypothalamic and peripheral signals. Intrapituitary modulation of PRL expression via autocrine/paracrine mechanisms has also been reported, but similar information is still lacking in lower vertebrates. To shed light on autocrine/paracrine regulation of PRL in fish model, grass carp PRL was cloned and its expression in the carp pituitary has been confirmed. In grass carp pituitary cells, local secretion of PRL could suppress PRL release with concurrent rises in PRL production and mRNA levels. Paracrine stimulation by growth hormone (GH) was found to up- regulate PRL secretion, PRL production and PRL transcript expression, whereas the opposite was true for the local actions of luteinizing hormone (LH). Apparently, local interactions of PRL, GH and LH via autocrine/paracrine mechanisms could modify PRL production in carp pituitary cells through differential regulation of PRL mRNA stability and gene transcription. PMID- 25458703 TI - Dietary phytoestrogens present in soy dramatically increase cardiotoxicity in male mice receiving a chemotherapeutic tyrosine kinase inhibitor. AB - Use of soy supplements to inhibit cancer cell growth is increasing among patients due to the perception that phytoestrogens in soy inhibit carcinogenesis via induction of apoptosis. Genistein, the most prevalent phytoestrogen in soy, is a potent endocrine disruptor and tyrosine kinase inhibitor (TKI) that causes apoptosis in many cells types. Chemotherapeutic TKIs limit cancer cell growth via the same mechanisms. However, TKIs such as Sunitinib cause cardiotoxicity in a significant number of patients. Molecular interactions between Sunitinib and dietary TKIs like genistein have not been examined in cardiomyocytes. Significant lethality occurred in mice treated with Sunitinib and fed a phytoestrogen supplemented diet. Isolated cardiomyocytes co-treated with genistein and Sunitinib exhibited additive inhibition of signaling molecules important for normal cardiac function and increased apoptosis compared with Sunitinib alone. Thus, dietary soy supplementation should be avoided during administration of Sunitinib due to exacerbated cardiotoxicity, despite evidence for positive effects in cancer. PMID- 25458704 TI - IRE1 impairs insulin signaling transduction of fructose-fed mice via JNK independent of excess lipid. AB - The unfolded protein response (UPR) pathways have been implicated in the development of hepatic insulin resistance during high fructose (HFru) feeding. The present study investigated their roles in initiating impaired insulin signaling transduction in the liver induced by HFru feeding in mice. HFru feeding resulted in hepatic steatosis, increased de novo lipogenesis and activation of two arms of the UPR pathways (IRE1/XBP1 and PERK/eIF2alpha) in similar patterns from 3days to 8weeks. In order to identify the earliest trigger of impaired insulin signaling in the liver, we fed mice a HFru diet for one day and revealed that only the IRE1 branch was activated (by 2-fold) and insulin-mediated Akt phosphorylation was blunted (~25%) in the liver. There were significant increases in phosphorylation of JNK (~50%) and IRS at serine site (~50%), protein content of ACC and FAS (up to 2.5-fold) and triglyceride level (2-fold) in liver (but not in muscle or fat). Blocking IRE1 activity abolished increases in JNK activity, IRS serine phosphorylation and protected insulin-stimulated Akt phosphorylation without altering hepatic steatosis or PKCepsilon activity, a key link between lipids and insulin resistance. Our findings together suggest that activation of IRE1-JNK pathway is a key linker of impaired hepatic insulin signaling transduction induced by HFru feeding. PMID- 25458705 TI - Participatory assessment of animal health and husbandry practices in smallholder pig production systems in three high poverty districts in Uganda. AB - While animal health constraints have been identified as a major limiting factor in smallholder pig production in Uganda, researchers and policy makers lack information on the relative incidence of diseases and their impacts on pig production. This study aimed to assess animal health and management practices, constraints and opportunities for intervention in smallholder pig value chains in three high poverty districts of Uganda. Semi-qualitative interview checklists through Focus Group Discussions (FGDs) were administered to 340 pig farmers in 35 villages in Masaka, Kamuli and Mukono districts. Quantitative data was obtained during the exercise through group consensus. Results of FGDs were further triangulated with secondary data and information obtained from key informant interviews. Findings show that pig keeping systems are dominated by tethering and scavenging in rural areas. In peri-urban and urban areas, intensive production systems are more practiced, with pigs confined in pens. The main constraints identified by farmers include high disease burden such as African swine fever (ASF) and parasites, poor housing and feeding practices, poor veterinary services, ineffective drugs and a general lack of knowledge on piggery management. According to farmers, ASF is the primary cause of pig mortality with epidemics occurring mainly during the dry season. Worms and ectoparasites namely; mange, lice and flies are endemic leading to stunted growth which reduces the market value of pigs. Diarrhoea and malnutrition are common in piglets. Ninety three percent of farmers say they practice deworming, 37% practice ectoparasite spraying and 77% castrate their boars. Indigenous curative treatments include the application of human urine and concoctions of local herbs for ASF control and use of old engine oil or tobacco extracts to control ectoparasites. There is a need for better technical services to assist farmers with these problems. PMID- 25458706 TI - Cost assessment of the movement restriction policy in France during the 2006 bluetongue virus episode (BTV-8). AB - This study aims at evaluating the costs of the movement restriction policy (MRP) during the 2006 BTV-8 epidemic in France for the producers of 6-9 month old Charolais beef weaned calves (BWC), an important sector that was severely affected by the restrictions imposed. This study estimates the change in the number of BWC sold that was due to the movement restrictions, and evaluates the economic effect of the MRP. The change in BWC sold by producers located inside the restriction zone (RZ) was analyzed for 2006 by using a multivariate matching approach to control for any internal validity threat. The economic evaluation of the MRP was based on several scenarios that describe farms' capacity constraints, feeding prices, and the animal's selling price. Results show that the average farmer experienced a 21% decrease in animals sold due to the MRP. The economic evaluation of the MRP shows a potential gain during the movement standstill period in the case of no capacity constraint faced by the farm and food self sufficiency. This gain remains limited and close to zero in case of a low selling price and when animals are held until they no longer fit the BWC market so that they cannot be sold as an intermediate product. Capacity constraints represent a tremendous challenge to farmers facing movement restrictions and the fattening profit becomes negative under such conditions. The timing and length of the movement standstill period significantly affect the profitability of the strategy employed by the farmer: for a 5.5 month-long standstill period with 3.5 months of cold weather, farmers with capacity constraints have stronger incentives to leave their animals outside during the whole period and face higher mortality and morbidity rates than paying for a boarding facility for the cold months. This is not necessarily true for a shorter standstill period. Strategies are also sensitive to the feed costs and to the food self-sufficiency of the farm. Altogether, the present work shows the farmer's vulnerability to animal movement restrictions and quantifies the costs of the standstill. These results should assist decision-makers who seek to calculate adequate subsidies/aid or to efficiently allocate resources to prevent future outbreaks. PMID- 25458707 TI - Dry eye disease after refractive surgery: comparative outcomes of small incision lenticule extraction versus LASIK. AB - PURPOSE: To compare small incision lenticule extraction (SMILE) versus LASIK for post-refractive dry eye disease. DESIGN: Prospective, comparative, nonrandomized clinical study. PARTICIPANTS: Thirty patients scheduled for bilateral myopic SMILE and 30 age-, sex-, and refraction-matched patients scheduled for bilateral myopic LASIK were enrolled and followed for 6 months after the surgery. METHODS: Complete evaluation of dry eye disease was performed at 1 and 6 months postoperatively, which included vision-related quality of life (Ocular Surface Disease Index [OSDI]), clinical examinations (tear film breakup time [TBUT], Schirmer I test, corneal staining), and tear osmolarity measurements, together with an overall severity score. Function and morphology of the corneal innervation were evaluated by corneal esthesiometry and subbasal nerve imaging using in vivo confocal microscopy (IVCM). MAIN OUTCOME MEASURES: Overall analysis of dry eye disease and corneal innervation. RESULTS: High incidence of mild to moderate dry eye disease was observed in both groups 1 month postoperatively, which remained significantly higher in the LASIK group than in the SMILE group 6 months after surgery (overall severity score [0-4]: 1.2+/-1.1 vs. 0.2+/-0.4, respectively, P < 0.01), leading to more frequent use of tear substitutes over the long term. Corneal sensitivity was better in SMILE than in LASIK eyes 1 month postoperatively (3.5+/-1.79 vs. 2.45+/-2.48, respectively, P < 0.01) and then recovered to statistically similar values at 6 months. Corneal nerve density, number of long fibers, and branchings as assessed by IVCM were significantly higher in the SMILE group compared with the LASIK group 1 and 6 months after surgery. Corneal sensitivity was negatively correlated with dry eye-related corneal damage (R2 = 0.48, P < 0.01), and the long fiber nerve density was independently correlated with the OSDI score (R2 = 0.50, P < 0.01) and the Schirmer test (R2 = 0.21, P < 0.01) 6 months postoperatively. CONCLUSIONS: The SMILE procedure has a less pronounced impact on the ocular surface and corneal innervation compared with LASIK, further reducing the incidence of dry eye disease and subsequent degradation in quality of life after refractive surgery. PMID- 25458709 TI - Cognitive-behavioral, behavioral, and mindfulness-based therapies for menopausal depression: a review. AB - Menopause is a natural transition that all women go through in their lives that is often accompanied by a number of physical and emotional symptoms. Upwards of 40% of women report depression symptoms associated with menopause (Timur & Sahin, 2010) [1]. Treatments for menopausal depression include pharmacological agents such as antidepressants and hormone therapy (HT) as well as psychological approaches. This paper provides a review of cognitive-behavioral, behavioral, and mindfulness based (CBBMB) therapies in treating depression during the menopausal transition. After conducting an electronic database search, only two studies specifically using CBBMB methods were found, both had positive results. Since so few studies existed that specifically evaluated CBBMB treatments for menopausal depression (n=2), a larger net was cast. Studies that assessed depression symptoms as an outcome measure in an evaluation of CBBMB treatments for hot flashes or menopausal symptoms more broadly, were included. The review revealed that interventions targeting hot flashes or menopausal symptoms using CBBMB methods mostly proved to have had a positive impact on depression symptoms in the mild range of severity. Directions for future research are discussed including the need for more CBBMB interventions targeting depression during the menopausal transition to establish their efficacy. PMID- 25458710 TI - Correlates of dependence and beliefs about the use of hypnotics among zolpidem and zopiclone users. AB - BACKGROUND: Zolpidem and zopiclone are the two most commonly prescribed Z-drugs approved to treat insomnia. OBJECTIVES: To examine the demographic and clinical correlates of dependence and beliefs about hypnotic use among long-term zolpidem and zopiclone users in psychiatric treatment for insomnia. METHODS: A total of 392 psychiatric outpatients who received zolpidem or zopiclone treatment for at least 3 months for insomnia were studied. Participants' severity of hypnotic dependence and beliefs about the use of hypnotics to treat sleep problems were assessed. The correlation of dependence and beliefs about zolpidem and zopiclone treatment with demographic characteristics, hypnotic-using behaviors, co-use of addictive substances, and depressive symptoms were analyzed using multiple regression analysis models. RESULTS: Zolpidem users reported more severe dependence and a lower level of necessity regarding the use of hypnotics than zopiclone users did. High equivalent doses of hypnotics and long duration of use were significantly associated with severe dependence and a low level of necessity. Severe depressive symptoms were signiciantly associated with severe dependence, a low level of necessity, and a low level of concern. Educational level was also associated with the levels of concern and necessity. Conclusions/Importance: There were differences in the level of dependence and belief about hypnotic use between zolpidem and zopiclone users. The correlates of dependence and belief identified in this study can serve as the basis for prevention and intervention programs. PMID- 25458708 TI - The association between uncarboxylated matrix Gla protein and lipoprotein associated phospholipase A2. AB - BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is independently associated with cardiovascular risk, probably via inflammatory activity in sclerotic plaque. We speculated whether Lp-PLA2 has a role in the aetiology of vascular calcifications, estimated from circulating uncarboxylated matrix Gla protein (MGP) species and whether we could find a potential interaction of Lp PLA2 and MGP in terms of mortality. MATERIALS AND METHODS: We examined 798 patients (mean age 65.1 years) with stable vascular disease and followed them in a prospective study. Both, desphospho-uncarboxylated and total MGP (dp-ucMGP or t ucMGP) were quantified by pre-commercial ELISA assays, developed by VitaK (Maastricht, The Netherland) RESULTS: Lp-PLA2 activity was independently positively associated with desphospho-uncarboxylated MGP (dp-ucMGP) [beta coeff = 0.098, p=0.006]. 1SD of Lp-PLA2 activity was associated with 37% increased risk (p=0.001) of elevated dp-ucMGP (>=977 pmol/L, top quartile). In the Cox proportional hazard model adjusted for conventional risk factors, the patients in the highest quartile of dp-ucMGP or lowest quintile of total-uncarboxylated ucMGP (<2660 nmol/L) had higher risk of all-cause mortality [HRR 2.79 (95% CI 1.97 3.94) and HRR 1.69 (95% CI 1.18-2.42), respectively]. We observed no effect of high Lp-PLA2 activity (>=195 nmol/min/mL) on total mortality. CONCLUSIONS: We assume that Lp-PLA2 is involved in vascular calcification and that dp-ucMGP is a more appropriate biomarker of residual risk than Lp-PLA2 itself. PMID- 25458711 TI - Is There a Link Between Physical Activity and Alcohol use? AB - Physical activity (PA) is discussed as a protective factor as well as a risk factor for alcohol consumption. Therefore, this study aimed at exploring a potential relationship between these behaviors. In a population-based cross sectional study of 15,474 people living in Austria physical activity, alcohol consumption and demographic variables were assessed. Regression analysis including age and gender revealed no significant relationship between PA and alcohol consumption for the total sample. More alcohol consumption was found in men with low PA-levels. Focusing on a part of the population who consumed alcohol the weekend before, men with high PA-levels reported more alcohol consumption in comparison to men with moderate PA-levels. This study does not support a common alcohol-physical activity relationship. Prevention programs to increase PA levels from low to moderate combined with a reduction of alcohol intake in men who regularly drink alcohol should be considered. PMID- 25458712 TI - Immediate and late modulation of interhemipheric imbalance with bilateral transcranial direct current stimulation in acute stroke. AB - BACKGROUND: Significant changes in neurophysiological and clinical outcomes in chronic stroke had been reported after tDCS; but there is a paucity of data in acute stroke. OBJECTIVE: We aimed to evaluate whether a tDCS-induced modulation of primary motor cortex excitability in patients with acute stroke enhances motor recovery associated with rehabilitation and induces differential neuroplasticity. METHODS: We conducted two experiments in acute stroke patients. In experiment 1 (14 patients), we tested the immediate effects of bilateral tDCS alone as compared to sham tDCS on recovery. Experiment 2 (20 patients) was designed to assess effects of bilateral tDCS delivered together with constraint-induced movement therapy (CIMT). In this experiment, we included a longer follow-up (3 months) and measured, in addition to the same clinical outcomes of experiment 1, changes of motor cortex excitability and the amount of promoted LTP-like activity. RESULTS: Despite the expected improvement at 1 week, none of the clinical measures showed any different modulation in dependence of CIMT and tDCS. On the neurophysiological assessments, on the other hand, the Real_tDCS group, compared to Sham_tDCS group, showed a reduction of inter-hemispheric imbalance when considering the differences of motor evoked potential between both 3-month and 1 week follow up (P = 0.007) and three month and baseline (P = 0.015). CONCLUSIONS: Despite the lack of additional clinical changes, real bilateral tDCS, together with CIMT, significantly reduces inter-hemispheric imbalance between affected and unaffected hemispheres. These findings may shed light on plasticity changes in acute stroke and its potential impact in chronic phases. PMID- 25458713 TI - Minimum-energy coils for transcranial magnetic stimulation: application to focal stimulation. AB - BACKGROUND: In transcranial magnetic stimulation (TMS), the stimulation-coil current is typically increased from 0 to over 5000 A in less than 100 MUs. At the peak current, the energy stored in the magnetic field is over 300 J. Thus, the average power during a pulse exceeds 3 MW; the stimulator needs to be built from high-power electronics. The power requirements often limit the duration and frequency of repetitive TMS, for example, via coil heating. OBJECTIVE: We introduce a method for finding the minimum-energy solution for a TMS coil with given focality constraints. METHODS: This optimization is performed by using a spherically symmetric head model and by expressing the coil as a continuous surface current density, which is eventually discretized to form the coil windings. For the optimization, we defined TMS focality separately for the directions parallel and perpendicular to the field direction at the maximum of induced electric field. RESULTS: The computational model used for optimization was verified by manufacturing a prototype coil and measuring the electric field it induces in a spherically symmetric conductor. The optimized coil design requires significantly less power than existing TMS coil designs (a 73% reduction compared to an existing TMS coil with similar focality). CONCLUSION: The described method allows for more efficient, more focal TMS coils, which may reduce coil heating and the coil click. PMID- 25458714 TI - The influence of age and weight status on cardiac autonomic control in healthy children: a review. AB - Heart rate variability (HRV) analyses can provide a non-invasive evaluation of cardiac autonomic activity. How autonomic control normally develops in childhood and how this is affected by obesity remain incompletely understood. In this review we examine the evidence that childhood age and weight status influence autonomic control of the heart as assessed using HRV. Electronic databases (Pubmed, EMBASE and Cochrane Library) were searched for studies examining HRV in healthy children from birth to 18 years who adhered to the Task Force (1996) guidelines. Twenty-four studies met our inclusion criteria. Seven examined childhood age and HRV. A reduction in 24-hour LF:HF was reported from birth to infancy (1 year), while overall HRV (SDNN) showed a marked and progressive increase. From infancy to early-to-late childhood (from 12 months to 15 years) LF:HF ratio was reported to decline further albeit at a slower rate, while RMSSD and SDNN increased. Twenty studies examined the effects of weight status and body composition on HRV. In a majority of studies, obese children exhibited reductions in RMSSD (n = 8/13), pNN50% (n = 7/9) and HF power (n = 14/18), no difference was reported for LF (n = 10/18), while LF:HF ratio was elevated (n = 10/15). HRV changes during childhood are consistent with a marked and progressive increase in cardiac parasympathetic activity relative to sympathetic activity. Obesity disrupts the normal maturation of cardiac autonomic control. PMID- 25458715 TI - Overcoming social segregation in health care in Latin America. AB - Latin America continues to segregate different social groups into separate health system segments, including two separate public sector blocks: a well resourced social security for salaried workers and their families and a Ministry of Health serving poor and vulnerable people with low standards of quality and needing a frequently impoverishing payment at point of service. This segregation shows Latin America's longstanding economic and social inequality, cemented by an economic framework that predicted that economic growth would lead to rapid formalisation of the economy. Today, the institutional setup that organises the social segregation in health care is perceived, despite improved life expectancy and other advances, as a barrier to fulfilling the right to health, embodied in the legislation of many Latin American countries. This Series paper outlines four phases in the history of Latin American countries that explain the roots of segmentation in health care and describe three paths taken by countries seeking to overcome it: unification of the funds used to finance both social security and Ministry of Health services (one public payer); free choice of provider or insurer; and expansion of services to poor people and the non-salaried population by making explicit the health-care benefits to which all citizens are entitled. PMID- 25458717 TI - Health protection as a citizen's right. PMID- 25458716 TI - Social determinants of health, universal health coverage, and sustainable development: case studies from Latin American countries. AB - Many intrinsically related determinants of health and disease exist, including social and economic status, education, employment, housing, and physical and environmental exposures. These factors interact to cumulatively affect health and disease burden of individuals and populations, and to establish health inequities and disparities across and within countries. Biomedical models of health care decrease adverse consequences of disease, but are not enough to effectively improve individual and population health and advance health equity. Social determinants of health are especially important in Latin American countries, which are characterised by adverse colonial legacies, tremendous social injustice, huge socioeconomic disparities, and wide health inequities. Poverty and inequality worsened substantially in the 1980s, 1990s, and early 2000s in these countries. Many Latin American countries have introduced public policies that integrate health, social, and economic actions, and have sought to develop health systems that incorporate multisectoral interventions when introducing universal health coverage to improve health and its upstream determinants. We present case studies from four Latin American countries to show the design and implementation of health programmes underpinned by intersectoral action and social participation that have reached national scale to effectively address social determinants of health, improve health outcomes, and reduce health inequities. Investment in managerial and political capacity, strong political and managerial commitment, and state programmes, not just time-limited government actions, have been crucial in underpinning the success of these policies. PMID- 25458718 TI - Leading the way towards universal health coverage: a call to action. AB - Policy innovations and lessons associated with the quest for universal health coverage in Latin America are the result of a complex epidemiological transition, an extended process of democratisation, and high economic growth in recent times that has facilitated additional investments in health. The goal of universal health coverage is part of a third generation of health-system reforms, which implies a comprehensive scope of policy interventions, including the introduction of explicit ethical frameworks, the enhanced attention to financial arrangements, and the transformation of major dimensions of the organisation of health systems. The call for action emphasises the next steps that could help reach the goal of universal health coverage both in the Latin American region and the rest of the developing world. PMID- 25458719 TI - Conditional cash transfers and health in Latin America. PMID- 25458720 TI - Latin America: priorities for universal health coverage. PMID- 25458721 TI - The right to health: what model for Latin America? PMID- 25458722 TI - Human-rights-based approaches to health in Latin America. PMID- 25458723 TI - Achieving universal health coverage is a moral imperative. PMID- 25458724 TI - Universal health coverage: not why, what, or when--but how? PMID- 25458725 TI - Health-system reform and universal health coverage in Latin America. AB - Starting in the late 1980s, many Latin American countries began social sector reforms to alleviate poverty, reduce socioeconomic inequalities, improve health outcomes, and provide financial risk protection. In particular, starting in the 1990s, reforms aimed at strengthening health systems to reduce inequalities in health access and outcomes focused on expansion of universal health coverage, especially for poor citizens. In Latin America, health-system reforms have produced a distinct approach to universal health coverage, underpinned by the principles of equity, solidarity, and collective action to overcome social inequalities. In most of the countries studied, government financing enabled the introduction of supply-side interventions to expand insurance coverage for uninsured citizens--with defined and enlarged benefits packages--and to scale up delivery of health services. Countries such as Brazil and Cuba introduced tax financed universal health systems. These changes were combined with demand-side interventions aimed at alleviating poverty (targeting many social determinants of health) and improving access of the most disadvantaged populations. Hence, the distinguishing features of health-system strengthening for universal health coverage and lessons from the Latin American experience are relevant for countries advancing universal health coverage. PMID- 25458727 TI - Human stem cell-derived retinal cells for macular diseases. PMID- 25458726 TI - A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster randomised trial. AB - BACKGROUND: Antenatal corticosteroids for pregnant women at risk of preterm birth are among the most effective hospital-based interventions to reduce neonatal mortality. We aimed to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of antenatal corticosteroids at all levels of health care in low-income and middle-income countries. METHODS: In this 18-month, cluster-randomised trial, we randomly assigned (1:1) rural and semi-urban clusters within six countries (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia) to standard care or a multifaceted intervention including components to improve identification of women at risk of preterm birth and to facilitate appropriate use of antenatal corticosteroids. The primary outcome was 28-day neonatal mortality among infants less than the 5th percentile for birthweight (a proxy for preterm birth) across the clusters. Use of antenatal corticosteroids and suspected maternal infection were additional main outcomes. This trial is registered with ClinicalTrials.gov, number NCT01084096. FINDINGS: The ACT trial took place between October, 2011, and March, 2014 (start dates varied by site). 51 intervention clusters with 47,394 livebirths (2520 [5%] less than 5th percentile for birthweight) and 50 control clusters with 50,743 livebirths (2258 [4%] less than 5th percentile) completed follow-up. 1052 (45%) of 2327 women in intervention clusters who delivered less than-5th-percentile infants received antenatal corticosteroids, compared with 215 (10%) of 2062 in control clusters (p<0.0001). Among the less-than-5th-percentile infants, 28-day neonatal mortality was 225 per 1000 livebirths for the intervention group and 232 per 1000 livebirths for the control group (relative risk [RR] 0.96, 95% CI 0.87-1.06, p=0.65) and suspected maternal infection was reported in 236 (10%) of 2361 women in the intervention group and 133 (6%) of 2094 in the control group (odds ratio [OR] 1.67, 1.33-2.09, p<0.0001). Among the whole population, 28-day neonatal mortality was 27.4 per 1000 livebirths for the intervention group and 23.9 per 1000 livebirths for the control group (RR 1.12, 1.02-1.22, p=0.0127) and suspected maternal infection was reported in 1207 (3%) of 48,219 women in the intervention group and 867 (2%) of 51,523 in the control group (OR 1.45, 1.33-1.58, p<0.0001). INTERPRETATION: Despite increased use of antenatal corticosteroids in low-birthweight infants in the intervention groups, neonatal mortality did not decrease in this group, and increased in the population overall. For every 1000 women exposed to this strategy, an excess of 3.5 neonatal deaths occurred, and the risk of maternal infection seems to have been increased. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development. PMID- 25458729 TI - Scaling up antenatal corticosteroids in low-resource settings? PMID- 25458728 TI - Human embryonic stem cell-derived retinal pigment epithelium in patients with age related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies. AB - BACKGROUND: Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients. METHODS: In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardt's macular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dose cohorts (50,000, 100,000, and 150,000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardt's macular dystrophy) and NCT01344993 (age-related macular degeneration). FINDINGS: There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16-25 points 3-12 months after transplantation in patients with atrophic age-related macular degeneration and 8-20 points in patients with Stargardt's macular dystrophy. INTERPRETATION: The results of this study provide the first evidence of the medium-term to long term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement. FUNDING: Advanced Cell Technology. PMID- 25458730 TI - Ebola: worldwide dissemination risk and response priorities. PMID- 25458731 TI - Typhoid fever. AB - Control of typhoid fever relies on clinical information, diagnosis, and an understanding for the epidemiology of the disease. Despite the breadth of work done so far, much is not known about the biology of this human-adapted bacterial pathogen and the complexity of the disease in endemic areas, especially those in Africa. The main barriers to control are vaccines that are not immunogenic in very young children and the development of multidrug resistance, which threatens efficacy of antimicrobial chemotherapy. Clinicians, microbiologists, and epidemiologists worldwide need to be familiar with shifting trends in enteric fever. This knowledge is crucial, both to control the disease and to manage cases. Additionally, salmonella serovars that cause human infection can change over time and location. In areas of Asia, multidrug-resistant Salmonella enterica serovar Typhi (S Typhi) has been the main cause of enteric fever, but now S Typhi is being displaced by infections with drug-resistant S enterica serovar Paratyphi A. New conjugate vaccines are imminent and new treatments have been promised, but the engagement of local medical and public health institutions in endemic areas is needed to allow surveillance and to implement control measures. PMID- 25458733 TI - Towards universal health coverage: applying a gender lens. PMID- 25458732 TI - Assessment of the potential for international dissemination of Ebola virus via commercial air travel during the 2014 west African outbreak. AB - BACKGROUND: The WHO declared the 2014 west African Ebola epidemic a public health emergency of international concern in view of its potential for further international spread. Decision makers worldwide are in need of empirical data to inform and implement emergency response measures. Our aim was to assess the potential for Ebola virus to spread across international borders via commercial air travel and assess the relative efficiency of exit versus entry screening of travellers at commercial airports. METHODS: We analysed International Air Transport Association data for worldwide flight schedules between Sept 1, 2014, and Dec 31, 2014, and historic traveller flight itinerary data from 2013 to describe expected global population movements via commercial air travel out of Guinea, Liberia, and Sierra Leone. Coupled with Ebola virus surveillance data, we modelled the expected number of internationally exported Ebola virus infections, the potential effect of air travel restrictions, and the efficiency of airport based traveller screening at international ports of entry and exit. We deemed individuals initiating travel from any domestic or international airport within these three countries to have possible exposure to Ebola virus. We deemed all other travellers to have no significant risk of exposure to Ebola virus. FINDINGS: Based on epidemic conditions and international flight restrictions to and from Guinea, Liberia, and Sierra Leone as of Sept 1, 2014 (reductions in passenger seats by 51% for Liberia, 66% for Guinea, and 85% for Sierra Leone), our model projects 2.8 travellers infected with Ebola virus departing the above three countries via commercial flights, on average, every month. 91,547 (64%) of all air travellers departing Guinea, Liberia, and Sierra Leone had expected destinations in low-income and lower-middle-income countries. Screening international travellers departing three airports would enable health assessments of all travellers at highest risk of exposure to Ebola virus infection. INTERPRETATION: Decision makers must carefully balance the potential harms from travel restrictions imposed on countries that have Ebola virus activity against any potential reductions in risk from Ebola virus importations. Exit screening of travellers at airports in Guinea, Liberia, and Sierra Leone would be the most efficient frontier at which to assess the health status of travellers at risk of Ebola virus exposure, however, this intervention might require international support to implement effectively. FUNDING: Canadian Institutes of Health Research. PMID- 25458734 TI - Universal health coverage in Latin American countries: how to improve solidarity based schemes. AB - In this Health Policy we examine the association between the financing structure of health systems and universal health coverage. Latin American health systems encompass a wide range of financial sources, which translate into different solidarity-based schemes that combine contributory (payroll taxes) and non contributory (general taxes) sources of financing. To move towards universal health coverage, solidarity-based schemes must heavily rely on countries' capacity to increase public expenditure in health. Improvement of solidarity based schemes will need the expansion of mandatory universal insurance systems and strengthening of the public sector including increased fiscal expenditure. These actions demand a new model to integrate different sources of health-sector financing, including general tax revenue, social security contributions, and private expenditure. The extent of integration achieved among these sources will be the main determinant of solidarity and universal health coverage. The basic challenges for improvement of universal health coverage are not only to spend more on health, but also to reduce the proportion of out-of-pocket spending, which will need increased fiscal resources. PMID- 25458735 TI - Pharmacokinetics and safety of plasma-derived factor XIII concentrate (human) in patients with congenital factor XIII deficiency. AB - Congenital factor XIII (FXIII) deficiency is a rare condition with substantial risk for life-threatening bleeding. Replacement of deficient FXIII with plasma derived FXIII concentrate is a treatment option. The current 12-week study evaluated the steady-state pharmacokinetic (PK) and safety profile of prophylactic infusions of FXIII concentrate (human) in patients with congenital FXIII deficiency. Patients received FXIII concentrate (human) 40 IU kg(-1) on Days 0, 28, and 56. FXIII levels were assessed before and after each infusion; steady-state PK parameters were assessed up to 28 days after the infusion on Day 56. Treatment effectiveness in maintaining trough FXIII activity levels >= 5% over 28 days and safety parameters were also assessed. Fourteen patients received FXIII concentrate (human) and 13 completed the study. Post-infusion, FXIII activity levels increased to within the range found in patients without congenital FXIII deficiency without reaching supra-therapeutic levels. Non baseline-adjusted trough FXIII activity levels were maintained at or above 10% at all post-baseline visits in all patients. Steady-state PK parameters were baseline-adjusted; maximum FXIII activity was 87.7% at 1.72 h post-infusion, subsequently declining to a minimum of 5.0%. The half-life was 6.6 days. FXIII concentrate (human) was generally well tolerated. Two patients had possibly treatment-related adverse events. There were no reports of thromboembolism, viral transmission, bleeding events or treatment-related hypersensitivity. These findings support use of FXIII concentrate (human) 40 IU kg(-1) every 28 days as an appropriate regimen for routine, long-term prophylaxis in children and adults with congenital FXIII deficiency. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov/ct2/show/NCT00883090. PMID- 25458736 TI - Totally laparoscopic total gastrectomy for gastric cancer: literature review and comparison of the procedure of esophagojejunostomy. AB - There has been a recent increase in the use of totally laparoscopic total gastrectomy (TLTG) for gastric cancer. However, there is no scientific evidence to determine which esophagojejunostomy (EJS) technique is the best. In addition, both short- and long-term oncological results of TLTG are inconsistent. We reviewed 25 articles about TLTG for gastric cancer in which at least 10 cases were included. We analyzed the short-term results, relationships between EJS techniques and complications, long-term oncological results, and comparative study results of TLTG. TLTG was performed in a total of 1170 patients. The mortality rate was 0.7%, and the short-term results were satisfactory. Regarding EJS techniques and complications, circular staplers (CSs) methods were significantly associated with leakage (4.7% vs. 1.1%, p < 0.001) and stenosis (8.3% vs. 1.8%, p < 0.001) of the EJS as compared with the linear stapler method. The long-term oncological prognosis was acceptable in patients with early gastric cancers and without metastases to lymph nodes. Although TLTG tended to increase surgical time compared with open total gastrectomy and laparoscopy-assisted total gastrectomy, it reduced intraoperative blood loss and was expected to shorten postoperative hospital stay. TLTG is found to be safer and more feasible than open total gastrectomy and laparoscopy-assisted total gastrectomy. At present, there is no evidence to encourage performing TLTG for patients with advanced gastric cancer from the viewpoint of long-term oncological prognosis. Although the current major EJS techniques are CS and linear stapler methods, in this review, CS methods are significantly associated with leakage and stenosis of the EJS. PMID- 25458738 TI - [SIFUD-PP, a scientific society of the past... or the future?]. PMID- 25458737 TI - A propensity-matched comparison of perioperative complications and of chronic kidney disease between robot-assisted laparoscopic partial nephrectomy and radiofrequency ablative therapy. AB - OBJECTIVE: The study presents a matched-pair analysis of robot-assisted laparoscopic partial nephrectomy (RALPN) versus radiofrequency ablation (RFA) to compare the perioperative incidence of complications and chronic kidney disease (CKD). METHODS: All 46 RFA and 206 RALPN cases from June 2005 to December 2011 were retrospectively reviewed from the medical records and were matched 1:1 based on propensity scores by sex, tumor size, tumor laterality of kidney, tumor location within the kidney, and clinical T stage. Hilar vessel clamping was performed in all RALPN patients. The estimated glomerular filtration rate was used to define the CKD of < 60 mL/minute/1.73 m(2) by the Modification of Diet in Renal Disease equation. All patients with baseline CKD or solitary kidney were excluded prior to the matching analysis. The complication was noted with modified Clavien grades >= 3. Statistical analysis was performed to compare the perioperative incidence of complications and CKD. RESULTS: A total of 27 matched pairs of RFA and RALPN patients were enrolled for analyzing CKD and perioperative complications. The better general conditions, higher estimated blood loss and transfusion rates, and longer operative time and hospital stay were observed significantly in RALPN patients (p < 0.05). Matched analysis demonstrated that the incidences of both perioperative complications (p = 0.434) and of CKD (p = 0.500) were not significantly different. No complication higher than Grade 4 was detected in either group. CONCLUSION: Despite the intraoperative renal ischemia and invasiveness of the procedure associated with RALPN, the incidence of perioperative complication and of CKD developing rates were statistically similar. PMID- 25458739 TI - [Urethral meatus deformities and urethra hypospadias in women: prevalence, problems and definitions. Study of 12,739 patients]. AB - The difficulty to access to the urethral meatus is found in women in relation to morphological abnormalities of urogenital or ectopic locations meatus, whether acquired (urethral meatus buried [UMB]) or congenital reality (urethra hypospadias [UH]). The pathophysiology is not unequivocal with lack of clear and specific studies. PURPOSE: Verify the existence of specific functional problems, assess the prevalence and identify the anatomical features of UMB and UH. MATERIALS: UMB and UH were sought in a computerized database listing the patients attending a neurourology department between 2000 and 2014 for a pelvic-perineal disease. Each case was analysed for specific reached leaks, urinary tract infections and difficulties catheterization. RESULTS: Of the 12,739, 131 patients (1%) met the inclusion criteria, including 18 UH and 113 UMB. Ninety-one patients consulted for urinary disorders of neurological origin. The circumstances of UMB and UH discovery were: perineal systematic review in 63 cases (48%); difficulties of urethral catheterization in 65 cases (49%); urinary incontinence for 3 patients (3%). Urinary tract infections have not led to the discovery of UMB or UH. Difficulties locating the urethral meatus were congenital (UH) in 18 cases (13%). In 113 cases (87%), it was an acquired abnormality (UMB) overweight for 16 patients (12%), troublesome spasticity of the adductor muscles in 18 cases (14%), vulvovaginal atrophy in 5 cases (4%) and a patient (1%) with a pelvic organ prolapse. No details were given for the remaining 72 patients (54%). CONCLUSION: The urethral meatus difficult access due to MUE or UH can be met in a specialized service but the exact concept of MUE be defined. It can be considered as urethral meatus difficult to access and the cause is acquired. Functional impairment may be particularly important in patients requiring catheterization for bladder emptying. LEVEL OF EVIDENCE: 4. PMID- 25458740 TI - [Highlights of the 14th joint IUGA and AUGS meeting in Washington 2014]. PMID- 25458741 TI - Universal treatment success among healthcare workers diagnosed with occupationally acquired acute hepatitis C. AB - Healthcare workers (HCWs) are at risk of occupationally acquired hepatitis C. In the UK, 17 HCWs were diagnosed with occupationally acquired acute hepatitis C between 2002 and 2011. All 17 cases involved percutaneous injuries from hollowbore needles, 16 known to be contaminated with blood. Of these 17 HCWs, 15 received antiviral therapy and 14 are known to have achieved viral clearance. Treatment success was irrespective of genotype. The successful treatment of HCWs emphasizes the need for UK guidelines on the management of occupationally acquired acute hepatitis C. PMID- 25458742 TI - Closed vs open systems: when should short peripheral intravenous catheters be the first choice? PMID- 25458743 TI - Value of an active surveillance policy to document clearance of meticillin resistant Staphylococcus aureus and vancomycin-resistant enterococci amongst inpatients with prolonged admissions. AB - This article reports the impact of an active surveillance policy to identify clearance of meticillin-resistant Staphylococcus aureus (MRSA) or vancomycin resistant enterococci (VRE) in known colonized inpatients with prolonged admissions in order to discontinue isolation precautions. Amongst 365 colonized patients with hospital admissions exceeding 30 days, clearance rates of 11% for MRSA and 18% for VRE were found after a median of 23 days and 26.5 days, respectively, resulting in a saving of 2152 patient-days of contact precautions over one year. This has proven to be a cost-beneficial policy. PMID- 25458744 TI - Highlights in basic autonomic neurosciences: Diet-induced enteric, vagal and brainstem dysfunction. PMID- 25458746 TI - Solving our patients' nutrition problems. PMID- 25458747 TI - Registered dietitian takes the wheel at center for nutrition policy and promotion. PMID- 25458745 TI - Immune and inflammatory role of hydroxyethyl starch 130/0.4 and fluid gelatin in patients undergoing coronary surgery. AB - OBJECTIVES: Compare the effects on inflammatory (TNF-alpha, IL-6, IL-8 and IL-10) and immunologic (CD3(+), CD4(+), CD8(+), CD11b(+), CD16(+)/56(+) T cells and total lymphocyte concentration) variables of hydroxyethyl starch 130/0.4, 4% modified fluid gelatin, or crystalloid when used as volume replacement fluids for acute normovolemic hemodilution (a blood conservation technique) in coronary artery bypass graft patients. METHODS: Thirty patients undergoing coronary artery bypass graft surgery were randomized to receive Isolyte S(r) (Group ISO), 6% hydroxyethyl starch 130/0.4 (Group HES) or 4% modified gelatin solution (Group GEL) for acute normovolemic hemodilution. Blood samples were taken immediately after induction of anaesthesia (T0), and 2 h (T1), 12 h (T2), 24 h (T3), and 48 h (T4) after separation from cardiopulmonary bypass. TNF-alpha, IL-6, IL-8 and IL 10 levels were determined with commercially available ELISA kits. CD3(+) (mature T cells), CD4(+) (T helper cells), CD8(+) (suppressor cytotoxic T cells), CD16(+)/56(+) (natural killer lymphocytes), and CD11b(+) (Mac-1, adhesion receptor) levels were measured using flow-cytometry reagents. The CD4(+):CD8(+) ratio was calculated. RESULTS: Between-group comparisons showed significantly higher levels of TNF-alpha at T1 (2 h after weaning from cardiopulmonary bypass) in Group HES compared to Group ISO (p=0.003). IL-8 was significantly lower in Group HES than Group GEL at T1 (p=0.0005). IL-10 was significantly higher in Group HES than in Group GEL at T1 (p=0.0001). The CD4(+):CD8(+) ratio in Group ISO was significantly lower than that in Group HES at T2 (p=0.003). CD11b(+) levels in Group HES were also higher than those in Group GEL and group ISO at T2, but not significantly. CD16/56(+) levels in Group HES were higher than those in Group GEL at T2 (p<0.003). No excessive hemorrhage occurred in any patient. Mediastinal drainage during the first 24 h after surgery in Group HES (347+/-207 mL) was not significantly different from that of Group GEL (272+/-177 mL) or Group ISO (247+/-109) (p>0.05). CONCLUSION: Hydroxyethyl starch 130/0.4 reduced pro-inflammatory responses and increased anti-inflammatory responses to a greater degree than gelatin solution and isolyte S(r). The use of hydroxyethyl starch, compared to gelatin solution and isolyte S(r), resulted in less decrease in the CD4(+):CD8(+) ratio, suggesting less immunosuppression. PMID- 25458748 TI - Consensus statement of the Academy of Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition: indicators recommended for the identification and documentation of pediatric malnutrition (undernutrition). AB - The Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition, utilizing an evidence-informed, consensus-derived process, recommend that a standardized set of diagnostic indicators be used to identify and document pediatric malnutrition (undernutrition) in routine clinical practice. The recommended indicators include z scores for weight for height/length, body mass index for age, length/height for age, or mid-upper arm circumference when a single data point is available. When two or more data points are available, indicators may also include weight-gain velocity (younger than 2 years of age), weight loss (2 to 20 years of age), deceleration in weight for length/height z score, and inadequate nutrient intake. The purpose of this consensus statement is to identify a basic set of indicators that can be used to diagnose and document undernutrition in the pediatric population (ages 1 month to 18 years). The indicators are intended for use in multiple settings, such as acute, ambulatory care/outpatient, residential care, etc. Several screening tools have been developed for use in hospitalized children. However, identifying criteria for use in screening for nutritional risk is not the purpose of this paper. Clinicians should use as many data points as available to identify and document the presence of malnutrition. The universal use of a single set of diagnostic parameters will expedite the recognition of pediatric undernutrition, lead to the development of more accurate estimates of its prevalence and incidence, direct interventions, and promote improved outcomes. A standardized diagnostic approach will also inform the prediction of the human and financial responsibilities and costs associated with the prevention and treatment of undernutrition in this vulnerable population, and help to further ensure the provision of high-quality, cost-effective, nutrition care. PMID- 25458749 TI - Development and pilot testing of a human subjects protection training course unique to registered dietitian nutritionists. PMID- 25458750 TI - Registered dietitian nutritionists bring value to emerging health care delivery models. AB - Health care in the United States is the most expensive in the world; however, most citizens do not receive quality care that is comprehensive and coordinated. To address this gap, the Institute for Healthcare Improvement developed the Triple Aim (ie, improving population health, improving the patient experience, and reducing costs), which has been adopted by patient-centered medical homes and accountable care organizations. The patient-centered medical home and other population health models focus on improving the care for all people, particularly those with multiple morbidities. The Joint Principles of the Patient-Centered Medical Home, developed by the major primary care physician organizations in 2007, recognizes the key role of the multidisciplinary team in meeting the challenge of caring for these individuals. Registered dietitian nutritionists (RDNs) bring value to this multidisciplinary team by providing care coordination, evidence-based care, and quality-improvement leadership. RDNs have demonstrated efficacy for improvements in outcomes for patients with a wide variety of medical conditions. Primary care physicians, as well as several patient-centered medical home and population health demonstration projects, have reported the benefits of RDNs as part of the integrated primary care team. One of the most significant barriers to integrating RDNs into primary care has been an insufficient reimbursement model. Newer innovative payment models provide the opportunity to overcome this barrier. In order to achieve this integration, the Academy of Nutrition and Dietetics and RDNs must fully understand and embrace the opportunities and challenges that the new health care delivery and payment models present, and be prepared and empowered to lead the necessary changes. All stakeholders within the health care system need to more fully recognize and embrace the value and multidimensional role of the RDN on the multidisciplinary team. The Academy's Patient-Centered Medical Home/Accountable Care Organizations Workgroup Report provides a framework for the Academy, its members, and key partners to use to achieve this goal. PMID- 25458751 TI - The academy's military roots visualized. PMID- 25458752 TI - What impact does water consumption have on weight loss or weight loss maintenance? PMID- 25458753 TI - Effect of vitamin E and selenium separately and in combination on biochemical, immunological and histological changes induced by sodium azide in male mice. AB - Sodium azide (SA) is used as an active ingredient to control a broad spectrum of soil borne pathogens including insects, weeds, nematodes, fungi, and bacteria. The purpose of this study was to evaluate the ameliorator property of vitamin E (Vit E) or/and selenium (Se) against SA-induced injury in male mice at the biochemical, immunological and histological levels. The mice were divided into nine groups (10/group). The first three groups were served as control, Vit E and Se while, the second three groups were treated with three different doses of SA. The last three groups were treated with high dose of SA with Vit E or Se or Vit E and Se and all animals were treated for a period of 30 days. Exposure to SA at the three doses to mice led to an alternation of liver and kidney functions, decrease the testosterone concentration, decreased IgG and IgM levels as well as the increasing the TNF-alpha. The effects of SA on the biochemical parameters of mice were dose-dependent. Administration of Se or/and Vit E to SA-treated mice attenuates the toxicity of this compound, objectified by biochemical and histological improvement of liver, kidney and testis. But, the alleviation is more pronounced with the both antioxidants. Thus, the synergistic effect of Se and Vit E is most powerful in reducing the toxicity induced by SA and improving the humoral immune response of mice. PMID- 25458754 TI - Survival of Shiga toxin-producing Escherichia coli in broth as influenced by pH, water activity and temperature. AB - This study examined the effects of and interactions between pH, aw and temperature on the survival of the top six non-O157 STECs and Escherichia coli O157:H7. All variables significantly affected the survival of all STEC serotypes. However, aw bore the most significant effect, followed by temperature and then pH. Examination of the effect of the interaction between these variables revealed that the interaction between aw and temperature was the most significant followed by the interaction between pH and temperature and then aw and pH. Decrease in aw resulted in population reduction of all serotypes studied. This reduction in population was significantly increased with the increase in temperature and was further significantly enhanced with decreasing pH. Examination of the differences in the survival among the individual serotypes revealed that the response of each serotype to aw or temperature changes was significantly different, while their response to pH changes was similar. Analysis of the relative survival of individual non-O157 STECs to O157:H7 revealed that the survival of O121 and O45 was not significantly different to O157:H7 while O103, O111, O145 and O26 showed less tolerance to the combined treatments, and their survival was significantly different from O157:H7. SIGNIFICANCE AND IMPACT OF THE STUDY: Results of this study estimate the interaction between pH, aw and temperature on the survival of the top six non-O157 STECs relative to Escherichia coli O157:H7 and provide important growth and no-growth condition which will offer risk assessors a means of estimating the likelihood of these pathogens, if present, would grow in response to the interaction between the three variables assessed. PMID- 25458755 TI - Biointerfaces: global Perspectives. Preface. PMID- 25458756 TI - Australian and New Zealand Indigenous mothers' report respect for smoking bans in homes. AB - BACKGROUND: There is limited data about the reasons behind residential rules to reduce environmental tobacco smoke (ETS) exposure or the establishment or enforcement of such rules in Indigenous populations. AIM: We aimed to gain an understanding of smokefree rules around Australian and New Zealand (NZ) Indigenous infants. METHOD: This was a qualitative study nested within a randomised controlled trial that aimed to test the efficacy of a family-centred tobacco control programme about environmental tobacco smoke (ETS) to improve the respiratory health of Indigenous infants in Australia and New Zealand. Qualitative semi-structured interviews were conducted with 26 Indigenous mothers of infants in Australia (n=7) and NZ (n=19). We asked about the presence of smokefree rules, who set the rules, how the rules were set and enforced, and presence of smokefree rules in participants' wider social circle. Interviews were audiotaped, transcribed, and inductively analysed to identify key themes. FINDINGS: Sixty-nine percent of mothers had partners, 77% smoked and all reported some presence of smokefree rules for house and car. Three main themes were identified: strategies to minimise exposure to ETS, establishing smokefree rules in homes and cars, and, adherence and enforcement of smokefree rules. Several strategies were identified to limit children's exposure to ETS, including rules to limit exposure to third-hand smoke. Mothers extended their smokefree rules to apply to other people's houses or cars, and reported that their family and social circles also had smokefree rules. The main reason for having smokefree rules was for the health of their children. Rules were most commonly set by the mother, often jointly with their partner. Few mothers reported challenges or problems with other people adhering to the smokefree rules. CONCLUSION: Women tried very hard to, and believed that they were effective in, protecting their children from the harmful effects of ETS exposure. In this context, health professionals need to emphasise smoking cessation in parents, so that children are maximally protected from ETS exposure. PMID- 25458757 TI - JCF - 2014 and beyond. PMID- 25458758 TI - Electrochemically induced ring-opening/Friedel-Crafts arylation of chalcone epoxides catalyzed by a triarylimidazole redox mediator. AB - The indirect anodic oxidation of chalcone epoxides in the presence of electron rich heteroarenes mediated by a triarylimidazole (Med) was investigated by cyclic voltammetry (CV) and controlled potential electrolysis. The CV results indicate that a homogeneous electron transfer between Med*+ and chalcone epoxides is facilitated by an electron-rich heteroarene that serves as an arylation reagent. The preparative scale electrolysis generated epoxide-ring-opened/Friedel-Crafts arylation products in moderate to good yields. The fact that only a catalytic amount of charge was required suggests that Med*+ initiates a chain reaction. In addition, overoxidation of the products is avoided even though their oxidation potential is less than that of the starting chalcone epoxides. PMID- 25458759 TI - Evaluation of resource recovery from waste incineration residues--the case of zinc. AB - Solid residues generated at European Waste to Energy plants contain altogether about 69,000 t/a of Zn, of which more than 50% accumulates in air pollution control residues, mainly boiler and filter ashes. Intensive research activities aiming at Zn recovery from such residues recently resulted in a technical scale Zn recovery plant at a Swiss waste incinerator. By acidic leaching and subsequent electrolysis this technology (FLUREC) allows generating metallic Zn of purity>99.9%. In the present paper the economic viability of the FLUREC technology with respect to Zn recovery from different solid residues of waste incineration has been investigated and subsequently been categorised according to the mineral resource classification scheme of McKelvey. The results of the analysis demonstrate that recovery costs for Zn are highly dependent on the costs for current fly ash disposal (e.g. cost for subsurface landfilling). Assuming current disposal practice costs of 220?/ton fly ash, resulting recovery costs for Zn are generally higher than its current market price of 1.6?/kg Zn. With respect to the resource classification this outcome indicates that none of the identified Zn resources present in incineration residues can be economically extracted and thus cannot be classified as a reserve. Only for about 4800 t/a of Zn an extraction would be marginally economic, meaning that recovery costs are only slightly (less than 20%) higher than the current market price for Zn. For the remaining Zn resources production costs are between 1.5 and 4 times (7900 t/a Zn) and 10-80 times (55,300 t/a Zn) higher than the current market value. The economic potential for Zn recovery from waste incineration residues is highest for filter ashes generated at grate incinerators equipped with wet air pollution control. PMID- 25458760 TI - Performance evaluation of a hybrid-passive landfill leachate treatment system using multivariate statistical techniques. AB - A pilot-scale hybrid-passive treatment system operated at the Merrick Landfill in North Bay, Ontario, Canada, treats municipal landfill leachate and provides for subsequent natural attenuation. Collected leachate is directed to a hybrid passive treatment system, followed by controlled release to a natural attenuation zone before entering the nearby Little Sturgeon River. The study presents a comprehensive evaluation of the performance of the system using multivariate statistical techniques to determine the interactions between parameters, major pollutants in the leachate, and the biological and chemical processes occurring in the system. Five parameters (ammonia, alkalinity, chemical oxygen demand (COD), "heavy" metals of interest, with atomic weights above calcium, and iron) were set as criteria for the evaluation of system performance based on their toxicity to aquatic ecosystems and importance in treatment with respect to discharge regulations. System data for a full range of water quality parameters over a 21-month period were analyzed using principal components analysis (PCA), as well as principal components (PC) and partial least squares (PLS) regressions. PCA indicated a high degree of association for most parameters with the first PC, which explained a high percentage (>40%) of the variation in the data, suggesting strong statistical relationships among most of the parameters in the system. Regression analyses identified 8 parameters (set as independent variables) that were most frequently retained for modeling the five criteria parameters (set as dependent variables), on a statistically significant level: conductivity, dissolved oxygen (DO), nitrite (NO2(-)), organic nitrogen (N), oxidation reduction potential (ORP), pH, sulfate and total volatile solids (TVS). The criteria parameters and the significant explanatory parameters were most important in modeling the dynamics of the passive treatment system during the study period. Such techniques and procedures were found to be highly valuable and could be applied to other sites to determine parameters of interest in similar naturalized engineered systems. PMID- 25458761 TI - Kinetic modelling of anaerobic hydrolysis of solid wastes, including disintegration processes. AB - A methodology to estimate disintegration and hydrolysis kinetic parameters of solid wastes and validate an ADM1-based anaerobic co-digestion model is presented. Kinetic parameters of the model were calibrated from batch reactor experiments treating individually fruit and vegetable wastes (among other residues) following a new protocol for batch tests. In addition, decoupled disintegration kinetics for readily and slowly biodegradable fractions of solid wastes was considered. Calibrated parameters from batch assays of individual substrates were used to validate the model for a semi-continuous co-digestion operation treating simultaneously 5 fruit and vegetable wastes. The semi continuous experiment was carried out in a lab-scale CSTR reactor for 15 weeks at organic loading rate ranging between 2.0 and 4.7 gVS/Ld. The model (built in Matlab/Simulink) fit to a large extent the experimental results in both batch and semi-continuous mode and served as a powerful tool to simulate the digestion or co-digestion of solid wastes. PMID- 25458762 TI - Application of Anaerobic Digestion Model No. 1 for simulating anaerobic mesophilic sludge digestion. AB - Improving anaerobic digestion of sewage sludge by monitoring common indicators such as volatile fatty acids (VFAs), gas composition and pH is a suitable solution for better sludge management. Modeling is an important tool to assess and to predict process performance. The present study focuses on the application of the Anaerobic Digestion Model No. 1 (ADM1) to simulate the dynamic behavior of a reactor fed with sewage sludge under mesophilic conditions. Parametric sensitivity analysis is used to select the most sensitive ADM1 parameters for estimation using a numerical procedure while other parameters are applied without any modification to the original values presented in the ADM1 report. The results indicate that the ADM1 model after parameter estimation was able to predict the experimental results of effluent acetate, propionate, composites and biogas flows and pH with reasonable accuracy. The simulation of the effect of organic shock loading clearly showed that an organic shock loading rate above of 35kg/m(3) day affects the performance of the reactor. The results demonstrate that simulations can be helpful to support decisions on predicting the anaerobic digestion process of sewage sludge. PMID- 25458763 TI - Mercury leaching from hazardous industrial wastes stabilized by sulfur polymer encapsulation. AB - European Directive 2013/39/EU records mercury as a priority hazardous substance. Regulation n degrees 2008/1102/EC banned the exportation of mercury and required the safe storage of any remaining mercury compounds. The present work describes the encapsulation of three wastes containing combinations of HgS, HgSe, HgCl2, HgO2, Hg3Se2Cl2, HgO and Hg(0), according to patent of Spanish National Research Council WO2011/029970A2. The materials obtained were subjected to leaching tests according to standards UNE-EN-12457 and CEN/TS 14405:2004. The results are compared with the criteria established in the Council Decision 2003/33/EC for the acceptance of waste at landfills. The Hg concentrations of all leachates were <0.01mgHg/kg for a liquid/solid ratio of 10l/kg. All three encapsulated materials therefore meet the requirements for storage in inert waste landfills. PMID- 25458764 TI - Upgrading of PVC rich wastes by magnetic density separation and hyperspectral imaging quality control. AB - Polyvinylchloride (PVC) is one of the most produced polymers in Europe, with a share of 11% in terms of mass (8 milliontons) of total polymer consumption, but in 2010 only 5% of the total PVC production came from recycled materials, where other polymer recycling achieves a level of 15% on average. In order to find an innovative process to extract PVC from window frames waste, a combination of two innovative technologies was tested: magnetic density separation (MDS) and hyperspectral imaging (HSI). By its nature, MDS is a flexible high precision density separation technology that is applicable to any mixture of polymers and contaminants with non-overlapping densities. As PVC has a very distinctive high density, this technology was tested to obtain high-grade PVC pre-concentrates from window frame waste. HSI was used to perform a quality control of the products obtained by MDS showing that PVC was clearly discriminated from unwanted rubber particles of different colors. The results showed that the combined application of MDS and HSI techniques allowed to separate and to check the purity of PVC from window frame waste. PMID- 25458765 TI - Nitrous oxide and methane emissions and nitrous oxide isotopic composition from waste incineration in Switzerland. AB - Solid waste incineration accounts for a growing proportion of waste disposal in both developed and developing countries, therefore it is important to constrain emissions of greenhouse gases from these facilities. At five Swiss waste incineration facilities with grate firing, emission factors for N2O and CH4 were determined based on measurements of representative flue gas samples, which were collected in Tedlar bags over a one year period (September 2010-August 2011) and analysed with FTIR spectroscopy. All five plants burn a mixture of household and industrial waste, and two of the plants employ NOx removal through selective non catalytic reduction (SNCR) while three plants use selective catalytic reduction (SCR) for NOx removal. N2O emissions from incineration plants with NOx removal through selective catalytic reduction were 4.3 +/- 4.0g N2O tonne(-1) waste (wet) (hereafter abbreviated as t(-1)) (0.4 +/- 0.4 g N2O GJ(-1)), ten times lower than from plants with selective non-catalytic reduction (51.5 +/- 10.6g N2O t(-1); 4.5 +/- 0.9g N2O GJ(-1)). These emission factors, which are much lower than the value of 120g N2O t(-1) (10.4g N2O GJ(-1)) used in the 2013 Swiss national greenhouse gas emission inventory, have been implemented in the most recent Swiss emission inventory. In addition, the isotopic composition of N2O emitted from the two plants with SNCR, which had considerable N2O emissions, was measured using quantum cascade laser spectroscopy. The isotopic site preference of N2O - the enrichment of (14)N(15)NO relative to (15)N(14)NO - was found to be 17.6 +/- 0.80/00, with no significant difference between the two plants. Comparison to previous studies suggests SP of 17-190/00 may be characteristic for N2O produced from SNCR. Methane emissions were found to be insignificant, with a maximum emission factor of 2.5 +/- 5.6g CH4 t(-1) (0.2 +/- 0.5g CH4 GJ(-1)), which is expected due to high incinerator temperatures and efficient combustion. PMID- 25458766 TI - An innovative recycling process to obtain pure polyethylene and polypropylene from household waste. AB - An innovative recycling process, based on magnetic density separation (MDS) and hyperspectral imaging (HSI), to obtain high quality polypropylene and polyethylene as secondary raw materials, is presented. More in details, MDS was applied to two different polyolefin mixtures coming from household waste. The quality of the two separated PP and PE streams, in terms of purity, was evaluated by a classification procedure based on HSI working in the near infrared range (1000-1700 nm). The classification model was built using known PE and PP samples as training set. The results obtained by HSI were compared with those obtained by classical density analysis carried in laboratory on the same polymers. The results obtained by MDS and the quality assessment of the plastic products by HSI showed that the combined action of these two technologies is a valid solution that can be implemented at industrial level. PMID- 25458767 TI - Composting of the solid fraction of digestate derived from pig slurry: Biological processes and compost properties. AB - The aim of this paper was to assess the characteristics of the solid fractions (SF) obtained by mechanical separation of digestate, their compostability and compost quality. To do so, the SF of digestates obtained from anaerobic digestion of pig slurry, energy crops and agro-industrial residues were sampled in five plants located in Northern Italy. Results obtained indicated that anaerobic digestion by itself promoted the high biological stability of biomasses with a Potential Dynamic Respiration Index (PDRI) close to 1000 mgO2 kg V S(-1)h(-1). Subsequent composting of digestates, with an added bulking agent, did not give remarkably different results, and led only to a slight modification of the characteristics of the initial non-composted mixtures; the composts obtained fully respected the legal limits for high quality compost. Chemical studies of organic matter composition of the biomasses by using CP MAS (13)C NMR, indicated that the compost was composed of a high relative content of O-alkyl-C (71.47% of total C) (cellulose and hemicelluloses) and a low alkyl-C (12.42%) (i.e. volatile fatty acids, steroid-like molecules, aliphatic biopolymers and proteins). PMID- 25458773 TI - The impact of the new antiviral regimens on patient reported outcomes and health economics of patients with chronic hepatitis C. AB - Hepatitis C is an important cause of chronic liver disease worldwide with an estimated 170 million people infected. Hepatitis C virus (HCV)-infected patients are physically and mentally impacted by fatigue, depression and anxiety causing an impairment of health related quality of life (HRQOL), lower worker productivity and other patient reported outcomes (PROs). Although anti-HCV regimens containing first generation direct acting antiviral agents (DAAs) were associated with significant side effects, the second generation DAAs, sofosbuvir (SOF) and simeprevir (SMV), are associated with fewer side effects, better tolerability and high cure rates. Despite these advantages, key stakeholders are currently trying to find ways to best integrate these new therapeutic regimens into the management of patients with chronic hepatitis C for the benefit of all. The purpose of this article is to offer insight into the other key and equally important outcomes (PRO's, HRQOL and cost) which should be considered when assessing the applicability of these new regimens for the care of patients infected with HCV. Our review provides evidence that the new treatment regimens for HCV not only have high efficacy rates but are also associated with better patient reported outcomes and cost per case of HCV cured. Additionally, compared to other medical interventions, these new regimens are cost-effective from a societal perspective. PMID- 25458774 TI - Bone as a foreign body. PMID- 25458772 TI - Sleep, sleep disturbance, and fertility in women. AB - Sleep and sleep disturbances are increasingly recognized as determinants of women's health and well-being, particularly in the context of the menstrual cycle, pregnancy, and menopause. At present, however, little is known about whether fertility is affected by sleep quantity and quality. That is, to what degree, and by what mechanisms, do sleep and/or its disturbances affect fertility? The purpose of this review is to synthesize what is known about sleep disturbances in relation to reproductive capacity. A model is provided, whereby stress, sleep dysregulation, and circadian misalignment are delineated for their potential relevance to infertility. Ultimately, if it is the case that sleep disturbance is associated with infertility, new avenues for clinical intervention may be possible. PMID- 25458775 TI - Prevalence of benign gastric polyps in a large pathology database. AB - AIMS: The aim of the study was to utilize a large national histopathology database for the analysis of the clinical epidemiology of gastric polyps. METHODS: In a case-control study, 71,575 case subjects with gastric polyps were compared to 741,351 control subjects without gastric polyps. RESULTS: Of all patients, 7.72% harboured fundic gland polyps, 1.79% gastric hyperplastic polyps, 0.09% gastric adenomas, and 0.06% type I neuroendocrine tumours. All types showed a clear-cut age-dependent rise. Reflux disease was significantly more common in patients with fundic gland polyps and significantly less common in patients with gastric adenomas or neuroendocrine tumours. Anaemia was more common in patients with gastric hyperplastic polyps, gastric adenomas, or neuroendocrine tumours. Helicobacter pylori was found significantly less frequently in all subjects with gastric polyps than in controls. Intestinal metaplasia and gastric atrophy were both more common in gastric adenoma and neuroendocrine tumours and less common in fundic gland polyps than in controls. Different polyp types tended to coincide in the same patients. CONCLUSIONS: Gastric hyperplastic polyps appeared to mark the beginning of a progression from chronic gastritis to intestinal metaplasia and gastric atrophy, which leads to diminished gastric acid output and increased gastrin secretion. Gastric adenoma and neuroendocrine tumours reflect later stages of this process. PMID- 25458776 TI - Extrahepatic manifestations of chronic hepatitis C virus infection. AB - Hepatitis C virus (HCV) infected patients are known to be at risk of developing liver complications i.e. cirrhosis and liver cancer. However, the risks of morbidity and mortality are underestimated because they do not take into account non-liver consequences of chronic hepatitis C virus infection. Numerous extrahepatic manifestations have been reported in up to 74% of patients, from perceived to disabling conditions. The majority of data concern hepatitis C virus related autoimmune and/or lymphoproliferative disorders, from mixed cryoglobulinaemia vasculitis to frank lymphomas. More recently, other hepatitis C virus-associated disorders have been reported including cardiovascular, renal, metabolic, and central nervous system diseases. This review aims to outline most of the extrahepatic manifestations that are currently being investigated, including some of autoimmune and/or lymphoproliferative nature, and others in which the role of immune mechanisms appears less clear. Beyond the liver, hepatitis C virus chronic infection should be analyzed as a multifaceted systemic disease leading to heavy direct and indirect costs. The accurate consideration of extrahepatic consequences of such a systemic infection significantly increases the weight of its pathological burden. The need for effective viral eradication measures is underlined. PMID- 25458777 TI - The evolution of the therapeutic strategy in hepatitis C: features of sofosbuvir and indications. AB - The treatment of chronic hepatitis C virus infection is rapidly evolving with the entry into the therapeutic armamentarium of a series of new and highly effective direct antiviral agents, targeted to the different virus structures involved in hepatitis C virus replication and assembly. Sofosbuvir is considered, without controversies, the most promising single direct antiviral agent in the current scenario. The pharmacological properties of sofosbuvir allow a single oral daily administration and ensure a favourable drug-drug interaction profile, compared to other direct antiviral agents. Clinical development of sofosbuvir has been conducted with the strategy of positioning it as the backbone drug of several combination regimes, including triple therapy with pegylated interferon and ribavirin, but also IFN-free regimen with ribavirin alone as well as with complementary direct antiviral agents directed against other virus targets. Based on available data and International guidelines sofosbuvir is indicated in combination with pegylated interferon and ribavirin in patients infected with hepatitis C virus 1 to 6 that can take interferon, and this regimen is particularly efficacious in those who have not received any previous antiviral treatment. The pangenotypic activity, excellent safety (even in advanced liver disease) make sofosbuvir the ideal backbone for combination therapy in all hepatitis C virus patients subgroups, the limiting factors being safety and tolerability of the combined direct antiviral agent rather than those of sofosbuvir itself. PMID- 25458778 TI - The prevalence of oesophagitis in "silent" gastro-oesophageal reflux disease: higher than expected? PMID- 25458779 TI - Usefulness of low- and high-volume multiple rapid swallowing during high resolution manometry. AB - BACKGROUND: It has been suggested that multiple rapid swallowing should be added to oesophageal manometry. AIM: To prospectively evaluate whether 10 and 200 mL multiple rapid swallowing provide different information concerning motor function. METHODS: 30 consecutive patients with oesophageal symptoms, 13 achalasia patients after successful pneumatic dilation and 19 healthy subjects performed eight 5 mL single swallows, two 10 mL and one 200 mL multiple rapid swallowing. RESULTS: Almost all of the healthy subjects and two-thirds of the patients with oesophageal symptoms showed motor inhibition during both 10 and 200 mL multiple rapid swallowing. The oesophago-gastric pressure gradient was significantly higher during 200 mL multiple rapid swallowing within each group (p < 0.01), and significantly higher in the achalasia patients than in the other two groups (p < 0.0001). Presence of a contraction and increased contraction strength in comparison with single swallows were both more frequent after 10 mL than after 200 mL multiple rapid swallowing in the healthy subjects and the patients (p<0.05). CONCLUSION: Motor inhibition could be similarly evaluated by means of 10 and 200 mL multiple rapid swallowing; 10 mL evaluated the after-contraction, whereas 200 mL multiple rapid swallowing was more valuable in identifying increased resistance to outflow. PMID- 25458780 TI - Overall efficacy and safety results of sofosbuvir-based therapies in phase II and III studies. AB - The uridine nucleotide analogue sofosbuvir is a selective hepatitis C virus NS5B polymerase inhibitor, active regardless of genotype. We analyzed data on efficacy and safety of sofosbuvir, either in combination with pegylated interferon alfa-2a and ribavirin, or in combination with ribavirin alone as part of an interferon free regimen in more than 1300 patients. Treatment with sofosbuvir for 12 weeks in combination with P/R, in naive genotype 1 patients was mainly studied in Neutrino. The efficacy of sofosbuvir as part of an all-oral combination including ribavirin alone, was explored in 555 naive, ineligible and previous treatment failure genotype 2/3 patients. Rates of Sustained Viral Response in genotype 1 and 2 were higher than 85%. For genotype 3 and 4, a European study, Valence, and a US study on patients of Egyptian origin showed that naive patients are cured at high rates by the all-oral combination given for 24 weeks. The efficacy of sofosbuvir plus P/R for 12 weeks in previous treatment failure genotype 3 has also been demonstrated. Sofosbuvir-based combinations are safe and well tolerated without side effects directly related to the drug. A large body of evidence suggests that sofosbuvir marks a revolution in HCV treatment. PMID- 25458781 TI - Efficacy of sofosbuvir-based therapies in HIV/HCV infected patients and persons who inject drugs. AB - In the era of Directly Acting anti HCV Antivirals treatment of hepatitis C is successful in the majority of persons treated. However, treatment of persons with HIV or who inject drugs remains challenging because of special issues: drug-drug interactions with antiretroviral, psychiatric and drug substitution therapies, treatment adherence, impact of treatment on HIV disease course or on risk of bacterial infections. Sofosbuvir induced sustained virologic response in 91% of 23 HIV/HCV coinfected persons treated in combination with ribavirin and pegylated interferon, in 83% of 497 treated in combination with ribavirin and in all 50 patients infected with HCV GT1 treated in combination with ledipasvir and ribavirin. The rates of efficacy in HCV-HIV coinfected were almost the same as those observed in HCV monoinfected suggesting that the efficacy of sofosbuvir is not reduced by HIV coinfection. There are no data on the efficacy of sofosbuvir in injection drugs users. The pangenotypic activity, the high barrier to resistance, the modest potential for drug-drug interactions makes sofosbuvir a reference drug for the treatment of these two special populations. PMID- 25458782 TI - Efficacy of new direct acting antivirals in transplant recipients and patients with advanced disease. AB - The development of new direct acting antivirals constitutes a clinical revolution in the field of hepatitis C therapy and, most probably, in the history of Hepatology. Difficult-to-treat patients, such as cirrhotics or patients in the peri-transplant setting, will clearly benefit from these therapies, particularly from interferon-free all-oral combinations. However, despite the substantial improvement of the hepatitis C drug market, access to these therapies will likely be different around the world due to economic restrictions. This review aims to clarify the current stage of different antiviral strategies (with or without interferon) in these difficult populations by analysing specific efficacy and safety results in patients with cirrhosis, patients on the waiting list for liver transplantation and recipients with hepatitis C recurrence after liver transplantation. Hitherto, some important challenges still remain unanswered in these patients and will need to be assessed in clinical practice, such as the evaluation of safety and efficacy in advanced cirrhotic patients with portal hypertension, the impact (if any) of viral clearance on clinical outcomes in patients with decompensated liver disease, the role of ribavirin in all-oral combinations, the relevance of the development of multi-drug viral resistant strains and the drug-drug interaction profiles of these drugs, especially after liver transplantation. PMID- 25458784 TI - Tunable aggregation by competing biomolecular interactions. AB - Measurements and models are reported for Concanavalin A (ConA) mediated aggregation of dextran coated colloids that is tunable via a competing ConA glucose interaction. Video and confocal scanning laser microscopy were used to characterize ConA adsorption to dextran colloids and quasi-2D dextran coated colloid aggregation kinetics vs [ConA] and [glucose]. ConA adsorption to, and aggregation rates of, dextran coated colloids increased from negligible values to high coverage and rapid rates for increasing [ConA] in the range 0.1-10 mM and decreasing [glucose] in the range 1-100 mM, consistent with dissociation constant estimates. Analysis of colloidal aggregation kinetics indicates ConA bridge formation is the rate-limiting step controlling the transition from slow to rapid aggregation. Our findings reveal a mechanism for tuning colloidal interactions and aggregation kinetics through specific, competitive biomolecular interactions, which lends insights into aggregation phenomena in mixed synthetic-biomaterial and biological systems. PMID- 25458783 TI - On the spread and control of MDR-TB epidemics: an examination of trends in anti tuberculosis drug resistance surveillance data. AB - BACKGROUND: Multidrug resistant tuberculosis (MDR-TB) poses serious challenges for tuberculosis control in many settings, but trends of MDR-TB have been difficult to measure. METHODS: We analyzed surveillance and population representative survey data collected worldwide by the World Health Organization between 1993 and 2012. We examined setting-specific patterns associated with linear trends in the estimated per capita rate of MDR-TB among new notified TB cases to generate hypotheses about factors associated with trends in the transmission of highly drug resistant tuberculosis. RESULTS: 59 countries and 39 sub-national settings had at least three years of data, but less than 10% of the population in the WHO-designated 27-high MDR-TB burden settings were in areas with sufficient data to track trends. Among settings in which the majority of MDR TB was autochthonous, we found 10 settings with statistically significant linear trends in per capita rates of MDR-TB among new notified TB cases. Five of these settings had declining trends (Estonia, Latvia, Macao, Hong Kong, and Portugal) ranging from decreases of 3% to 14% annually, while five had increasing trends (four individual oblasts of the Russian Federation and Botswana) ranging from 14% to 20% annually. In unadjusted analysis, better surveillance indicators and higher GDP per capita were associated with declining MDR-TB, while a higher existing absolute burden of MDR-TB was associated with an increasing trend. CONCLUSIONS: Only a small fraction of countries in which the burden of MDR-TB is concentrated currently have sufficient surveillance data to estimate trends in drug-resistant TB. Where trend analysis was possible, smaller absolute burdens of MDR-TB and more robust surveillance systems were associated with declining per capita rates of MDR-TB among new notified cases. PMID- 25458785 TI - Quinoline: a promising antitubercular target. AB - Tuberculosis (TB) remains a global public health problem in recent years. TB originated mainly from various strains of Mycobacterium tuberculosis, is a highly infectious and chronic disease with high infection rate since ancient times. Since the last 50 years, the same long-duration, multidrug treatment plan is being followed for the treatment of tuberculosis. Due to the development of resistance to conventional antibiotics there is a need for new therapeutic strategies to combat M. tuberculosis. Subsequently, there is an urgent need for the development of new drug molecules with newer targets and with an alternative mechanism of action. Among hetrocyclic compounds, quinoline compounds are important privileged structure in medicinal chemistry, are widely used as "parental" compounds to synthesize molecules with medical benefits, especially with anti-malarial and anti-microbial activities. Certain, quinoline-based compounds, also show effective anti-TB activity. This broad spectrum of biological and biochemical activities has been further facilitated by the synthetic versatility of quinoline, which allows the generation of a large number of structurally diverse derivatives. To pave the way for future research, there is a need to collect the latest information in this promising area. In the present review, we have collated published reports on this versatile core to provide an insight so that its full therapeutic potential can be utilized for the treatment tuberculosis. It is hoped that, this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic quinoline-based anti-TB drugs. PMID- 25458786 TI - Omega-3 fatty acids improve postprandial lipemia and associated endothelial dysfunction in healthy individuals - a randomized cross-over trial. AB - BACKGROUND: Postprandial elevation of triglycerides impairs endothelial function and contributes to the development of atherosclerosis. We investigated the effects of omega-3 fatty acids on postprandial endothelial function and lipid profiles. METHODS: Healthy volunteers [10] were given supplementation at 4g/day omega-3 fatty acids (or were not treated) for 4 weeks in a randomised crossover study. Postprandial levels of various lipids were monitored and endothelial function assessed by brachial artery flow-mediated dilation during fasting and after a standard cookie test. RESULTS: Omega-3 fatty acids reduced postprandial endothelial dysfunction compared with the control diet (flow-mediated dilation at 4h=-0.5+/-1.2 vs. -2.0+/-1.6%, P=0.03). Postprandial levels of triglycerides, apolipoprotein B-48, and remnant lipoprotein-cholesterol increased in untreated subjects, peaked at 2-4h, and returned to baseline at 8h, whereas low-density lipoprotein-cholesterol levels did not change. Supplementation with omega-3 fatty acids significantly suppressed postprandial elevation of triglycerides (incremental area under the curve=220+/-209 vs. 374+/-216mg/h/dL, P=0.04) and remnant lipoprotein-cholesterol (incremental area under the curve=21.7+/-13.8 vs. 13.3+/-12.9mg/h/dL, P=0.04). Supplementation with omega-3 fatty acids significantly suppressed the increase in triglyceride content in chylomicrons as well as in very-low-density lipoproteins from baseline to 4h after the cookie test. CONCLUSION: Omega-3 fatty acids significantly decreased postprandial triglyceride elevation and postprandial endothelial dysfunction, suggesting that omega-3 fatty acids may have vascular protective effects in postprandial state. PMID- 25458787 TI - Development of poly (I:C) modified doxorubicin loaded magnetic dendrimer nanoparticles for targeted combination therapy. AB - The objective of this study was to develop and evaluate the anticancer activity and the safety of a combinational drug delivery system using polyamidoamine (PAMAM) dendrimer-coated iron oxide nanoparticles for doxorubicin and poly I:C delivery in vitro. Dendrimer-coated magnetic nanoparticles (DcMNPs) are suitable for drug delivery system as nanocarriers with their following properties, such as surface functional groups, symmetry perfection, internal cavities, nano-size and magnetization. These nanoparticles could be targeted to the tumor site under a magnetic field since they have a magnetic core. DcMNPs were found as a convenient vehicle for targeted doxorubicin delivery in cancer therapy. Poly (I:C) binding on doxorubicin loaded DcMNPs (DcMNPs-Dox) was reported for the first time in the literature. It was also demonstrated that loading of doxorubicin into the cavities of DcMNPs increases the binding efficiency of poly (I:C) to the surface functional groups of dendrimer up to 10 times. When we compare the in vitro cytotoxic properties of doxorubicin, poly (I:C) and poly (I:C) bound doxorubicin loaded DcMNPs (PIC-DcMNPs-Dox), it was observed that PIC-DcMNPs-Dox show the highest cytotoxic effect by passing the cell resistance mechanisms on doxorubicin resistant MCF7 (MCF7/Dox) cells. Results demonstrated that applying PIC-DcMNPs Dox would improve the efficacy by increasing the biocompatibility of system in blood stream and the toxicity inside tumor cells. These results provide invaluable information and new insight for the design and optimization of a novel combinational drug delivery system for targeted cancer therapy. PMID- 25458788 TI - Coated dextrin microcapsules of amlodipine incorporable into orally disintegrating tablets for geriatric patients. AB - To improve oral absorption and patient compliance when using amlodipine, novel coated dextrin microcapsules incorporable into orally disintegrating tablets (ODT's) were investigated. Amlodipine-loaded dextrin microcapsules (ADM) were prepared by spray-drying a mixture of amlodipine free base dissolved in ethanol and aqueous dextrin solution. The ADM were suspended in Eudragit((r)) EPO solution in ethanol and subsequently spray-dried to collect coated ADM (CADM). The ADM or CADM were blended with ODT excipients and then directly compressed into ODTs. The ADM and CADM used were both spherical with smooth surfaces and had mean particle sizes of 13.3 and 18.5MUm, respectively. Amlodipine was dispersed in an amorphous state and was readily encapsulated within ADM or CADM. Unlike the ADM, the tableted CADM remained intact without rupture during tableting, which was consistent with no loss of ethanol (0.82%) entrapped in the ODTs containing the CADM (ODTs-CADM). The amlodipine content appeared to be uniformly maintained as designed in all the dextrin microcapsules and ODTs. The ODTs-CADM compressed with 3kp of hardness showed acceptable ODT characteristics: fast disintegration time (29.8s) and low friability (0.1%). Drug dissolution from the ODTs-CADM was much faster than that of amlodipine free base itself at both pH 1.2 and 6.8 over the tested time. CADM demonstrated significantly higher plasma concentrations (2.7 fold in AUC0-24h and 2.5 fold in Cmax) in SD rats than did amlodipine free base. These results indicate that CADM substantially increased the oral absorption of amlodipine and can be incorporated into ODTs while maintaining their original physicochemical features. The dextrin microcapsules coated using Eudragit((r)) EPO may be applied to the development of an amlodipine ODT formulation for improving geriatric patient compliance. PMID- 25458789 TI - Colon cancer: cancer stem cells markers, drug resistance and treatment. AB - Malignant tumours consist of heterogeneous populations of tumour cells. Cancer stem cells (CSC) represent a population of cells within a tumour with highly tumorigenic and chemoresistant properties. These cells may be identified by the expression of CSC markers. There are several key stem cells markers specified for colon cancer: CD133, CD44, ALDH1, ALCAM. These days, a major obstacle to effective cancer management is development of a multidrug resistance (MDR). The principal mechanism responsible for development of MDR phenotype is the over expression of ABC transporters. Tumours and relapsing tumours after therapy are drived by subpopulations of tumour cells with aggressive phenotype resistant to chemotherapeutics. These cells are called CSC or tumour-initiating cells (TIC). Here we outline recent information about MDR of colon cancer and CSC markers. We have focused on novel therapeutic strategies which have been developed to prevent or overcome MDR. One such strategy is a combination of chemotherapy and modulators of MDR pumps or chemotherapy and monoclonal antibodies against vascular endothelial growth factor VEGF. Colon cancer is characterized by the presence of colon CSC expressing specific stem cell markers. The divergent presence of these markers can help to adjust personalized therapy. The review provides a detailed overview of resistance of colon cancer cells and discusses how the presence of CSC markers can influence therapy and prognosis of patients. PMID- 25458790 TI - The flavonoid quercetin: possible solution for anthracycline-induced cardiotoxicity and multidrug resistance. AB - Anthracycline chemotherapy is often used in the treatment of various malignancies. Its application, however, encounters several limitations due to development of serious side effects, mainly cardiotoxicity and may be ineffective due to multidrug resistance (MDR). Many different compounds have been evaluated as poorly effective in the protection against anthracycline side effects and in the prevention from MDR. Thus, continuous investigational efforts are necessary to find valuable protectants and the flavonoid quercetin (Q) seems to be a promising candidate. It is present in relatively high amounts in a human diet and the lack of its toxicity, including genotoxicity has been confirmed. The structure of Q favours its high antioxidant activity, the potential to inhibit the activity of oxidative enzymes and to interact with membrane transporter proteins responsible for development of MDR, e.g. P-glycoprotein. Furthermore, Q can influence cellular signalling and gene expression, and thus, alter response to exogenous genotoxicants and oxidative stress in normal cells. It accounts for its chemopreventive and anticancer properties. Overall, these properties might indicate the possibility of application of Q as cardioprotectant during anthracycline chemotherapy. Moreover, numerous biological properties displayed by Q might possibly result in the reversal of MDR in tumour cells and improve the efficacy of chemotherapy. However, these beneficial effects towards anthracycline induced complications of chemotherapy have to be further explored and confirmed both in animal and clinical studies. Concurrently, investigations aimed at improvement of the bioavailability of Q and further elucidation of its metabolism after application in combination with anthracyclines are needed. PMID- 25458791 TI - Novel role of Sarco/endoplasmic reticulum calcium ATPase 2 in development of colorectal cancer and its regulation by F36, a curcumin analog. AB - Sarco/endoplasmic reticulum calcium ATPase (SERCA) enzymes play important roles in several signal transduction pathways that control proliferation, differentiation and apoptosis. Here, we reported that SERCA2 expression was positively correlated with tumor node metastasis (TNM) stages (n=75, P=0.0251) and grades (n=63, P=0.0146) of patients with colorectal cancer. The animal experiments demonstrated that SERCA2 expression was consistent with PCNA staining of intestinal tissues of male C57BL/6J-Apc(Min/)JNju mice. Besides, SERCA2 expression was also increased in undifferentiated HT-29 cells as compared with that in differentiated HT-29gal cells. Moreover, SERCA2 overexpression promoted proliferation and migration of SW480 cells via activating MAPK and AKT signaling pathways, while silence of SERCA2 inhibited the proliferation and migration of SW480 cells. In addition, we identified that a curcumin analog, F36, exhibited more potent inhibitory effect in colorectal cancer cells than curcumin through inhibiting SERCA2 expression. Taken together, our findings indicate that SERCA2 is involved in the malignant progress of colorectal cancer and maybe a therapeutic target for colorectal cancer treatment. Curcumin analog F36 shows enhanced anti-cancer activity in colorectal cancer cells by targeting SERCA2. PMID- 25458792 TI - Prognostic role of high Bmi-1 expression in Asian and Caucasian patients with solid tumors: a meta-analysis. AB - Recently, many studies have shown that the B-cell-specific moloney leukemia virus insertion site 1 (Bmi-1) exhibits altered expression in various cancers and may serve as prognostic biomarkers. We performed a meta-analysis to evaluate the prognostic role of Bmi-1 expression in solid cancers. Studies were recruited by searching PubMed, Embase and the Cochrane Library. Thirty-nine articles including 40 studies were involved in this meta-analysis. Our results indicated that the Bmi-1 showed the opposite prognostic effect in Asian and Caucasian populations. High Bmi-1 expression as a negative predictor for overall survival (OS) in Asian patients (HR=1.96, 95% CI 1.62-2.36), but a positive predictor in Caucasian populations (HR=0.77, 95% CI 0.63-0.93). Furthermore, we took a further subgroup analysis based on tumor type in these two populations, respectively. In Asian cases, high expression of Bmi-1 was associated with poor OS in oesophageal carcinoma (HR=1.93, 95% CI 1.52-2.46), gastric cancer (HR=1.50, 95% CI 1.22 1.85), lung cancer (HR=1.73, 95% CI 1.05-2.85), cervical cancer (HR=2.80, 95% CI 2.26-3.47) and colorectal cancer (HR=3.36, 95% CI 2.19-5.15), rather than in breast cancer and HCC. In Caucasian populations, high expression of Bmi-1 was associated with better OS in breast cancer (HR=0.70, 95% CI 0.51-0.97), but it showed no significance in oesophageal carcinoma. In conclusion, high Bmi-1 expression was significantly associated with poor survival in Asian patients with oesophageal carcinoma, gastric cancer, lung cancer, colorectal cancer and cervical carcinoma, whereas high level of Bmi-1 can predict better prognosis in Caucasian patients with breast cancer. PMID- 25458794 TI - Enhancement of the antibiotic activity of aminoglycosides by alpha-tocopherol and other cholesterol derivates. AB - Alpha-tocopherol, one of the most abundant isoforms of vitamin E, is a biologically active liposoluble vitamin and potent antioxidant. It occurs naturally in foods of plant and animal origin. Because of its lipophilic character, it can cause perturbations in the bacterial cell membrane, resulting in damage to components essential for the integrity of the membrane, thereby allowing an increase in permeability. This is the first report of the modulatory effect of alpha-tocopherol in multiresistant bacteria. We evaluated alpha tocopherol against multiresistant strains of Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli, and determined if there was any similarity with the mechanism of modulatory action of cholesterol and ergosterol. When combined with aminoglycosides in a microdilution broth assay, alpha-tocopherol possibly acted through a lipophilic action on the cell envelope, modulating more effectively P. aeruginosa and E. coli, when compared with S. aureus. PMID- 25458793 TI - Novel tetrahydroacridine derivatives inhibit human lung adenocarcinoma cell growth by inducing G1 phase cell cycle arrest and apoptosis. AB - Lung cancer is not only the most commonly diagnosed cancers worldwide but it is still the leading cause of cancer-related death. Acridine derivatives are a class of anticancer agents with the ability to intercalate DNA and inhibit topoisomerases. The aim of this study was to evaluate the effect of sixteen new tetrahydroacridine derivatives on the viability and growth of human lung adenocarcinoma cells. We compared anticancer activity of a series of eight compounds with 4-fluorobenzoic acid and eight compounds with 6-hydrazinonicotnic acid differed from each other in length of the aliphatic chain containing from 2 to 9 carbon atoms. Interestingly, tetrahydroacridine with 4-fluorobenzoic acid (compounds 9-16) showed higher anticancer activity than derivatives with 6 hydrazinonicotnic acid (compounds 1-8) and their efficacy was correlated with increasing number of carbon atoms in the aliphatic chain. The results showed that inhibition of cancer cell growth by the most effective compounds 15 and 16 was associated with induction of G1 phase cell cycle arrest followed by caspase-3 dependent apoptosis. Our findings suggest that tetrahydroacridine with 4 fluorobenzoic acid containing 8 and 9 carbon atoms may be potential candidate for treatment of lung cancer. PMID- 25458795 TI - Inhaled corticosteroids in children with persistent asthma: is there a dose response impact on growth? An overview of Cochrane reviews. PMID- 25458796 TI - Pulmonary complications of abdominal wall defects. AB - The abdominal wall is an integral component of the chest wall. Defects in the ventral abdominal wall alter respiratory mechanics and can impair diaphragm function. Congenital abdominal wall defects also are associated with abnormalities in lung growth and development that lead to pulmonary hypoplasia, pulmonary hypertension, and alterations in thoracic cage formation. Although infants with ventral abdominal wall defects can experience life-threatening pulmonary complications, older children typically experience a more benign respiratory course. Studies of lung and chest wall function in older children and adolescents with congenital abdominal wall defects are few; such investigations could provide strategies for improved respiratory performance, avoidance of respiratory morbidity, and enhanced exercise ability for these children. PMID- 25458797 TI - Personalized medicine in children with asthma. AB - Personalized medicine for children with asthma aims to provide a tailored management of asthma, which leads to faster and better asthma control, has less adverse events and may be cost saving. Several patient characteristics, lung function parameters and biomarkers have been shown useful in predicting treatment response or predicting successful reduction of asthma medication. As treatment response to the main asthma therapies is partly genetically determined, pharmacogenetics may open the way for personalized medicine in children with asthma. However, the number of genes identified for the various asthma drug response phenotypes remains small and randomized controlled trials are lacking. Biomarkers in exhaled breath or breath condensate remain promising but did not find their way from bench to bedside yet, except for the fraction of exhaled nitric oxide. E-health will most likely find its way to clinical practice and most interventions are at least non-inferior to usual care. More studies are needed on which interventions will benefit most individual children. PMID- 25458798 TI - Follow-up after gastric electrical stimulation for gastroparesis. AB - BACKGROUND: Gastric electrical stimulation (GES) is used to treat medically refractory gastroparesis. However, there are few large series with outcomes beyond 12 months. This study reports surgical outcomes of GES for patients up to 8 years receiving treatment from a single institution. STUDY DESIGN: A prospective database was reviewed from 2003 to 2013 for patients undergoing GES. Baseline patient characteristics were recorded, including age, sex, cause of gastroparesis, gastric emptying, and Hgb A1C. Outcomes variables included nutrition supplementation, additional operations, 30-day morbidity, and mortality. Pre- and postoperative pain and function scores are analyzed over time using generalized estimating equations. Patient outcomes in terms of reoperation rates and types of operations are also reviewed. RESULTS: Seventy-nine patients underwent GES with a mean +/- SD age of 43 +/- 11 years and a BMI of 27 +/- 8 kg/m(2). Symptom scores were available for 60 patients: 60 patients at baseline, 52 patients at 1 year, 14 patients during years 2 to 3, and 18 patients during years 4 to 8. Symptom scores decreased considerably in all categories. At 1-year follow-up, 44% and 31% of patients had at least a 25% reduction in symptom distress for functional and pain symptoms, respectively. Preoperatively, 9 patients required nutrition supplementation. After implantation, 34 (43%) patients underwent additional operations, with a mean of 2.15 operations per patient. Generator-related causes were the most common indication for reoperation, including battery exchanges and relocation. Other operations included 8 gastrectomies and 7 median arcuate ligament releases. Postoperatively, 4 patients required supplemental nutrition. There were no 30-day mortalities, but 11 patients died during the study period. CONCLUSIONS: Gastric electrical stimulation was significantly associated with reductions in both functional and pain-related symptoms of gastroparesis. Patients who undergo GES have a high likelihood of additional surgery. PMID- 25458799 TI - Implementing a standardized safe surgery program reduces serious reportable events. AB - BACKGROUND: Patient safety in the perioperative period is essential for delivery of quality patient care. Mainstream quality organizations have implemented safe surgery recommended practices for ensuring patient safety. Effectively implementing safe surgery practices should result in a reduction in serious reportable event (SRE) rates. STUDY DESIGN: This retrospective cohort study compared results before and after implementation of a standardized safe surgery program across a large health care system. Observational audits were performed to assure adoption of the new process. Serious reportable event rates (retained surgical item, wrong site, wrong patient, and wrong procedure) were tracked. Statistical analyses were performed on the SRE rate and days between SREs. RESULTS: A total of 683,193 cases in the operating room and labor and delivery were evaluated over a 4-year period. The SRE rate before implementation was 0.075/1,000 cases and after implementation was 0.037/1,000 cases. There was a 52% reduction in the SRE rate (p < 0.05). The mean time between SREs increased from 27.4 days to 60.6 days (p < 0.05). Robotic and nonrobotic cases were affected equally; however, a significant difference in SRE rate persisted between robotic and non-robotic cases (p < 0.05). Robotic cases are 7 times more likely to incur an SRE. Audits demonstrated that the compliance rates for the program improved to 96% after complete system implementation. CONCLUSIONS: An effectively implemented standardized safe surgery program results in a significant reduction in SREs. Robotic cases are at high risk for an SRE. PMID- 25458800 TI - Impact of deceased organ donor demographics and critical care end points on liver transplantation and graft survival rates. AB - BACKGROUND: The criteria for organ acceptance remain inconsistent, which limits the ability to standardize critical care practices. We sought to examine predictors of liver graft use and survival to better guide the selection and management of potential organ donors. STUDY DESIGN: A prospective observational study of all donors managed by the 8 organ procurement organizations in United Network for Organ Sharing Region 5 was conducted from July 2008 to March 2011. Critical care end points that reflect the normal hemodynamic, acid-base, respiratory, endocrine, and renal status of the donor were collected at 3 time points. Critical care and demographic data associated with liver transplantation and graft survival rates were first determined using univariate analyses, and then logistic regression was used to identify independent predictors of these two outcomes. RESULTS: From 961 donors, 730 (76%) livers were transplanted and 694 (95%) were functioning after 74 +/- 73 days of follow-up. After regression analysis, donor BMI (odds ratio [OR] = 0.94), male sex (OR = 1.89), glucose <150 mg/dL (OR = 1.97), lower dopamine dose (OR = 0.95), vasopressin use (OR = 1.95), and ejection fraction >50% (OR = 1.77) remained as independent predictors of liver use. Graft survival was associated with lower donor BMI (OR = 0.91) and sodium levels (OR = 0.95). CONCLUSIONS: After controlling for donor age, sex, and BMI, both hemodynamic and endocrine critical care end points were associated with increased liver graft use. Both donor BMI and lower sodium levels during the course of donor management were independently predictive of improved graft survival. These results may help guide the management and selection of potential organ donors after neurologic determination of death. PMID- 25458801 TI - The FINISH-3 trial: a phase 3, international, randomized, single-blind, controlled trial of topical fibrocaps in intraoperative surgical hemostasis. AB - BACKGROUND: This Phase 3, international, randomized, single-blind, controlled trial (FINISH-3) compared the efficacy and safety of Fibrocaps, a ready-to-use, dry-powder fibrin sealant containing human plasma-derived thrombin and fibrinogen, vs gelatin sponge alone for use as a hemostat for surgical bleeding in 4 indications (ie, spinal, hepatic, vascular, soft tissue dissection). STUDY DESIGN: Adults with mild to moderate surgical bleeding (randomized 2:1; Fibrocaps vs gelatin sponge) were treated at a single bleeding site (day 1). Time to hemostasis (TTH) during 5 minutes was compared (log-rank statistic) within each indication. Safety follow-up continued to day 29. RESULTS: Patients were treated (Fibrocaps, n = 480; gelatin sponge, n = 239) when undergoing spinal (n = 183), vascular (n = 175), hepatic (n = 180), or soft-tissue (n = 181) procedures. Fibrocaps was applied by spray device in 53% of all procedures (94% of hepatic and soft-tissue procedures). Fibrocaps significantly reduced TTH compared with gelatin sponge; estimated hazard ratios were 3.3, 2.1, 2.3, and 3.4 for the 4 surgical indications, respectively (each p < 0.001; primary end point). Fibrocaps significantly reduced median TTH for each indication (p < 0.001) and was superior for secondary efficacy end points of restricted mean TTH (p < 0.001) and probability of hemostasis at 3 (p < 0.001) and 5 (p <= 0.002) minutes. Adverse event incidences were generally similar between treatment arms. Non-neutralizing, anti-thrombin antibodies developed in 2% of Fibrocaps-treated and 3% of gelatin sponge-treated patients. CONCLUSIONS: Fibrocaps was well tolerated and significantly reduced TTH relative to gelatin sponge alone in all 4 surgical indications. These findings demonstrate the broad utility of Fibrocaps as a hemostatic agent for mild to moderate surgical bleeding. PMID- 25458802 TI - Leadership education, certification and resident outcomes in US nursing homes: cross-sectional secondary data analysis. AB - BACKGROUND: Leadership is a key consideration in improving nursing home care quality. Previous research found nursing homes with more credentialed leaders had lower rates of care deficiencies than nursing homes with less credentialed leaders. Evidence that nursing home administrator (NHA) and director of nursing (DON) education and certification is related to resident outcomes is limited. OBJECTIVES: To examine associations of education and certification among NHAs and DONs with resident outcomes. DESIGN: Cross-sectional secondary data analysis. SETTINGS: This study used National Nursing Home Survey data on leadership education and certification and Nursing Home Compare quality outcomes (e.g. pain, catheter use). PARTICIPANTS: 1142 nursing homes in the survey which represented 16628 nursing homes in the US. METHODS: Leadership education and certification were assessed separately for NHAs and DONs. Nursing home resident outcomes were measured using facility-level nursing home quality indicator rates selected from the Minimum Data Set. Facility-level quality indicators were regressed onto leadership variables in models that also held constant facility size and ownership status. RESULTS: Nursing homes led by NHAs with both Master's degrees or higher and certification had significantly better outcomes for pain. Nursing homes led by DONs with Bachelor's degrees or higher plus certification also had significantly lower pain and catheter use. Whereas pressure ulcer rates were higher in facilities led by DONs with more education. CONCLUSIONS: Selected outcomes for nursing home residents might be improved by increasing the education and certification requirements for NHAs and DONs. Additional research is needed to clarify these relationships. PMID- 25458803 TI - Nurses' perspectives regarding the disclosure of errors to patients: A qualitative study. AB - BACKGROUND: There is often a mismatch between patients' desire to be informed about errors and clinical reality. In closing the "disclosure gap" an understanding of the views of all members of the healthcare team regarding errors and their disclosure to patients is needed. However, international research on nurses' views regarding this issue is currently limited. OBJECTIVES: Explore nurses' attitudes and experiences concerning disclosing errors to patients and perceived barriers to disclosure. DESIGN: Inductive, exploratory study employing semi-structured interviews with participants, followed by conventional content analysis in which investigators read and discussed transcribed data to identify important themes. SETTINGS: Nursing departments from hospitals in two German speaking cantons in Switzerland. PARTICIPANTS: Purposive sample of 18 nurses from a range of fields, positions in organisational hierarchy, work experience, hospitals, and religious perspectives. METHODS: Data were collected via individual, face-to-face interviews using a researcher-developed semi-structured interview guide. Interviews were transcribed in German and analysed using the qualitative data analysis software package Atlas-Ti (Berlin) and conventional content analysis. The most illustrative quotes were translated into English. RESULTS: Nurses generally thought that patients should be informed about every error, but only a very few nurses actually reported disclosing errors in practice. Indeed, many nurses reported that most errors are not disclosed to the patient. Nurses identified a number of barriers to error disclosure that have already been reported in the literature among all clinicians, such as legal consequences and the fear of losing patients' trust. However, nurses in this study more frequently reported personal characteristics and a lack of guidance from the organisation as barriers to disclosure. Both issues suggest the need for a systematic institutional approach to error disclosure in which the decision to inform the patient stems from within the organisation and is not shouldered by individual nurses alone. CONCLUSIONS: Our study suggests that hospitals need to do more to support and train nurses in relation to error disclosure. Such measures as hospitals establishing a disclosure support system, providing background disclosure education, ensuring that disclosure coaching is available at all times, and providing emotional support for all parties involved, would likely go a long way to address the barriers identified by nurses. PMID- 25458804 TI - Coming to grips with challenging behaviour: a cluster randomised controlled trial on the effects of a new care programme for challenging behaviour on burnout, job satisfaction and job demands of care staff on dementia special care units. AB - BACKGROUND: Caring for people with dementia in dementia special care units is a demanding job. Challenging behaviour is one of the factors influencing the job satisfaction and burnout of care staff. A care programme for the challenging behaviour of nursing home residents with dementia might, next to diminishing the challenging behaviour of residents, improve job satisfaction and reduce the care staff's feelings of burnout. OBJECTIVES: To determine the effects of a care programme for the challenging behaviour of nursing home residents with dementia on the burnout, job satisfaction and job demands of care staff. DESIGN: The care programme was implemented according to a stepped wedge design in which care units were randomly divided over five groups with different time points of starting with implementation. SETTING: 17 Dutch dementia special care units. PARTICIPANTS: Care staff members of the 17 units. INTERVENTION: The care programme consists of an education package and of various structured assessment tools that guide professionals through the multidisciplinary detection, analysis, treatment and evaluation of treatment of challenging behaviour. METHODS: Burnout, job satisfaction and job demands were measured before implementation, halfway through the implementation process and after all the care units had implemented the care programme. Burnout was measured with the Dutch version of the Maslach burnout inventory (UBOS-C, three subscales); job satisfaction and job demands were measured with subscales of the Leiden Quality of Work Questionnaire. Mixed model analyses were used to determine effects. Care staff could not be blinded for the intervention. RESULTS: Of the 1441 questionnaires, 645 were returned (response 45%, 318 control measurements, 327 intervention measurements) by 380 unique care staff members. Significant effects were found on job satisfaction (0.93, 95% CI 0.48-1.38). On the other outcomes, no significant changes in the scores were found. CONCLUSION: Positive effects of using the Grip on Challenging behaviour care programme were found on job satisfaction, without an increase in job demands. PMID- 25458805 TI - [Elastography of cervix to predict delay from induction to delivery]. AB - OBJECTIVE: Induction of labor for medical indications has become a routine practice. To date, the Bishop score remains as the standard method to predict the duration of induced labor. Elastography is an objective method of assessing the relative consistency of tissues. Therefore, we sought to assess strain elastography of cervix to predict delay from induction to delivery in pregnant women with a low Bishop score. PATIENTS AND METHODS: Ultrasound elastography was immediately performed before induction of labor for medical indications among patients with a singleton pregnancy at>36 weeks of gestation and a Bishop score<6. Patients received 50 MUg of misoprostol intravaginally, repeated 6 hours later if regular painful uterine contractions had not started. A second ultrasound elastography was also performed 6 hours after starting the induction before the second dose of misoprostol if regular painful uterine contractions had not started. At each examination, a color map from blue (hardest tissue) to red (softest tissue) was produced. The cervical elastography was considered as positive if at least one part of its anterior wall was red. We assessed the predictive value of elastography on vaginal delivery within 24 hours. Patients delivering by cesarean section were excluded from this study. RESULTS: Elastography was initially performed in 48 patients. Twelve patients delivering by cesarean section after induction of labor were excluded, leading to 36 patients evaluated in this study. Among these 36 patients with elastography performed before induction of labor, 20 had a second elastography before the second dose of misoprostol. Sensibility, specificity, positive predictive value (PPV) and negative predictive value (NPV) of elastography performed before induction of labor on vaginal delivery within 24 hours were 40%, 27.3%, 55.6%, and 16.7%, respectively. Sensibility, specificity, PPV and NPV of elastography performed before the second dose of misoprostol were 64.3%, 16.7%, 64.3% and 16.7%, respectively. Among the 8 patients with red color occurring on the second cervical color map, sensibility, specificity, PPV and NPV were 83.3%, 0%, 62.5%, and 0%. DISCUSSION AND CONCLUSION: Qualitative cervical elastography is a poor predictor for delay from induction to delivery in pregnant women with a low Bishop score. PMID- 25458806 TI - [Association of mifepristone and misoprostol for the medical management of early pregnancy failure]. AB - OBJECTIVES: A retrospective monocentric clinical trial was performed to evaluate the efficacy of the association of mifepristone and misoprostol for the management of early pregnancy failure. PATIENTS AND METHODS: Ninety-two women with early pregnancy failure or anembryonic pregnancy were first treated with 600 mg of mifepristone and 48 hours later with 400 MUg of misoprostol by oral administration. Successful treatment, defined as an empty uterus, was searched at day 3, with the association of misoprostol-mifepristone alone or with complementary medical treatment, prostaglandins or ocytocine. RESULTS: The overall treatment success was 82% (75 of 92 women) with 69 successful cases at day 3 (75%). Six of 92 women (7%) needed a second-line medical treatment. For the last 17 women (18%), the failure of the associated tested medical treatment lead to a secondary surgery. No prognostic factor for the successful medical treatment has been highlighted. DISCUSSION AND CONCLUSION: A high efficacy for the management of early pregnancy failure is demonstrated for the mifepristone and misoprostol medical treatment. The specific contribution of mifepristone, although proven in the cases of termination of evolutive pregnancies, should be further evaluated in the future for the specific management of early pregnancy failure. Nevertheless, no prognostic factor for the success of the propose treatment can be determined, as the amount of patients enrolled in this study was not sufficient. PMID- 25458808 TI - [The pains of medically assisted procreation: what place for psychic suffering?]. AB - Human fertility is very sensible to emotional motions. Some unconscious representations infiltrate the child's project, they can make it fail, and are sometimes in conflict with the consciously declared child's desire. In a not exceptionally way, professionals are faced with requests for termination of pregnancy, even though the child was very expected, and the pregnancy obtained after a long period of medically assisted procreation. The author offers some ideas to explore the psychological clinic for infertility, before to centre himself more specifically on the issues raised by situations of egg donation, and conclude by therapeutic proposals on a joint collaboration between gynecologists and child psychiatrists. PMID- 25458807 TI - [Practical guide to the examination and interpretation of genital lesions of minor female victims of sexual assault]. AB - Through a comprehensive review of the literature on sexual assault, the authors propose to clarify the different stages of the exam and help the practitioner to the forensic interpretation of lesions. The authors describe the basic principles that make consensus in how to interview victims in order to increase the reliability of the information collected. The various medical data that must be collected allowing to guide diagnosis (urogenital symptoms, sexual behaviour disorder) or facilitate the interpretation of lesions (age of puberty, use of tampons...) are specified as well as the different positions of examination and their association to other complementary techniques (Foley catheter, colposcopy, toluidine blue). The authors present a simple decision tree that can help the practitioner to interpret the laceration of the hymen. They detail the description and forensic interpretation of all genital lesions that may be encountered as a result of sexual assault, and the pitfalls to avoid. Finally, two main problems in the interpretation of lesions are described, the absence of injury after penetration and the accidental genital lesions. PMID- 25458809 TI - [Controversy in ART: should we cryopreserve oocytes or embryos? Do prefer embryos]. PMID- 25458810 TI - Apathy in older patients with type 2 diabetes. AB - OBJECTIVE: To determine the prevalence, incidence, persistence, likely causes, and consequences of apathy in patients with Type 2 diabetes and to compare the prevalence with a healthy control sample. DESIGN: Cross-sectional comparison of diabetic and nondiabetic samples; longitudinal follow-up of diabetic sample. SETTING: Academic research department. PARTICIPANTS: Non-demented, older patients with long-standing Type 2 diabetes (N = 122) recruited from a community-based cohort study and 69 healthy volunteers. MEASUREMENTS: Clinical assessments of apathy and potential causative conditions, repeated in the diabetic sample after 16.7 +/- 2.5 months. Informant rated symptoms from the 14-item Apathy Scale were used to generate apathy diagnoses based on standardized criteria. Cognition was assessed by Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). RESULTS: The diabetic and comparison samples had the same age and MMSE scores, but the diabetic sample had a higher frequency of depression, cerebrovascular history, and cognitive deficits. Apathy was more prevalent in diabetes (diabetic 13.9% versus control sample 1.4%, p = 0.005) and was independently associated with CDR 0.5 status (OR [95% CI]: 3.66 [1.25-19.70]) and depression (8.48 [2.74-26.21]). In 108 diabetic patients who were followed up, incident apathy occurred in 7.4% of cases, and persisted in 50% of those with baseline apathy. Baseline apathy was independently associated with lnHbA1c levels (beta: 0.20, t = 2.29, df = 119, p = 0.024; model R(2) = 0.10) and incident/persistent apathy was associated with greater risk of cognitive decline (6.72 [1.19-37.87]). CONCLUSION: Apathy is a frequent neuropsychiatric syndrome in older patients with Type 2 diabetes, and is associated with poor glycaemic control and cognitive decline. PMID- 25458811 TI - Finding splitting lines for touching cell nuclei with a shortest path algorithm. AB - A shortest path-based algorithm is proposed in this paper to find splitting lines for touching cell nuclei. First, an initial splitting line is obtained through the distance transform of a marker image and the watershed algorithm. The initial splitting line is then separated into different line segments as necessary, and the endpoint positions of these line segments are adjusted to the concave points on the contour. Finally, a shortest path algorithm is used to find the accurate splitting line between the starting-point and the end-point, and the final split can be achieved by the contour of the touching cell nuclei and the splitting lines. Comparisons of experimental results show that the proposed algorithm is effective for segmentation of different types of touching cell nuclei. PMID- 25458813 TI - Histological and ultrastructural characteristics of the testis of the invasive suckermouth sailfin catfish Pterygoplichthys disjunctivus (Siluriformes: loricariidae) from Marikina River, Philippines. AB - The histological and ultrastructural features of the testis of the invasive suckermouth sailfin catfish Pterygoplichthys disjunctivus rapidly proliferating in Marikina River, Philippines were characterized during the fish's 2010-2011 reproductive season. The germinal compartment of the testes was composed of anastomosing tubules with cysts undergoing synchronous development. Spermatogenic cells were along the length of the testes indicate it to be of the unrestricted spermatogonial type. The spermatozoon is classified as type 1 ect aquasperm devoid of acrosome, has rounded nucleus, and a long flagellum - characteristics necessary for external fertilization. Male P. disjunctivus was reproductively active during half of the year-long study with peak spawning during the most rainy months (June-August) and prolonged recrudescence during the dry months (February-May). Results from this study form a histological baseline to describe the gonad dynamics and reproduction of this invasive fish species as well as provide possible means of mechanical control to curb the population of the fish in this river. PMID- 25458812 TI - LocFuse: human protein-protein interaction prediction via classifier fusion using protein localization information. AB - Protein-protein interaction (PPI) detection is one of the central goals of functional genomics and systems biology. Knowledge about the nature of PPIs can help fill the widening gap between sequence information and functional annotations. Although experimental methods have produced valuable PPI data, they also suffer from significant limitations. Computational PPI prediction methods have attracted tremendous attentions. Despite considerable efforts, PPI prediction is still in its infancy in complex multicellular organisms such as humans. Here, we propose a novel ensemble learning method, LocFuse, which is useful in human PPI prediction. This method uses eight different genomic and proteomic features along with four types of different classifiers. The prediction performance of this classifier selection method was found to be considerably better than methods employed hitherto. This confirms the complex nature of the PPI prediction problem and also the necessity of using biological information for classifier fusion. The LocFuse is available at: http://lbb.ut.ac.ir/Download/LBBsoft/LocFuse. BIOLOGICAL SIGNIFICANCE: The results revealed that if we divide proteome space according to the cellular localization of proteins, then the utility of some classifiers in PPI prediction can be improved. Therefore, to predict the interaction for any given protein pair, we can select the most accurate classifier with regard to the cellular localization information. Based on the results, we can say that the importance of different features for PPI prediction varies between differently localized proteins; however in general, our novel features, which were extracted from position-specific scoring matrices (PSSMs), are the most important ones and the Random Forest (RF) classifier performs best in most cases. LocFuse was developed with a user-friendly graphic interface and it is freely available for Linux, Mac OSX and MS Windows operating systems. PMID- 25458814 TI - Amylin-like immunoreactivity in pancreatic X cells of the black-spotted frog Rana (Pelophylax) nigromaculata. AB - tIn this study, we investigated the presence of ovoid or ellipsoidal amylin immunoreactive cells of the pancreatic islets of the black-spotted frog Rana (Pelophylax) nigromaculata. Using double immunofluorescent staining, all amylin immunoreactive cells were shown to be immuno-negative for insulin, glucagon, and somatostatin, and they were often observed in peripheral regions of clusters of insulin-immunoreactive cells. Under immunoelectron microscopy, amylin immunoreactive signals were detected on the secretory granules in a specific type of endocrine cells. From our results, we conclude that the amylin-immunoreactive cells correspond to X cells among the 4 distinct types of endocrine cells (B, A/PP, D, and X) previously identified in the frog. Amylin secreted from X cells may regulate the hormone secretion from A/PP cells and/or B cells through a paracrine mechanism. PMID- 25458815 TI - Recent developments in a computational theory of visual attention (TVA). AB - This article reviews the foundations of the theory of visual attention (TVA) and describes recent developments in the theory. TVA is based on the principle of biased competition: All possible visual categorizations ascribing features to objects compete (race) to become encoded into visual short-term memory before it is filled up. Each of the possible categorizations is supported by sensory evidence, but the competition is biased by multiplication with attentional weights (high weights on important objects) and perceptual biases (toward use of important categories). The way sensory evidence and attentional biases interact is specified in the rate and weight equations of TVA, so TVA represents a mathematical formalization of the biased competition principle. In addition to describing TVA as a psychological theory, we present the neural interpretation of TVA, NTVA. PMID- 25458830 TI - Comparison of a carbohydrate-free diet vs. fasting on plasma glucose, insulin and glucagon in type 2 diabetes. AB - OBJECTIVE: Hyperglycemia improves when patients with type 2 diabetes are placed on a weight-loss diet. Improvement typically occurs soon after diet implementation. This rapid response could result from low fuel supply (calories), lower carbohydrate content of the weight-loss diet, and/or weight loss per se. To differentiate these effects, glucose, insulin, C-peptide and glucagon were determined during the last 24 h of a 3-day period without food (severe calorie restriction) and a calorie-sufficient, carbohydrate-free diet. RESEARCH DESIGN: Seven subjects with untreated type 2 diabetes were studied. A randomized crossover design with a 4-week washout period between arms was used. METHODS: Results from both the calorie-sufficient, carbohydrate-free diet and the 3-day fast were compared with the initial standard diet consisting of 55% carbohydrate, 15% protein and 30% fat. RESULTS: The overnight fasting glucose concentration decreased from 196 (standard diet) to 160 (carbohydrate-free diet) to 127 mg/dl (fasting). The 24 h glucose and insulin area responses decreased by 35% and 48% on day 3 of the carbohydrate-free diet, and by 49% and 69% after fasting. Overnight basal insulin and glucagon remained unchanged. CONCLUSIONS: Short-term fasting dramatically lowered overnight fasting and 24 h integrated glucose concentrations. Carbohydrate restriction per se could account for 71% of the reduction. Insulin could not entirely explain the glucose responses. In the absence of carbohydrate, the net insulin response was 28% of the standard diet. Glucagon did not contribute to the metabolic adaptations observed. PMID- 25458829 TI - The addition of medium-chain triglycerides to a purified fish oil-based diet alters inflammatory profiles in mice. AB - OBJECTIVE: Parenteral nutrition associated liver disease (PNALD) is a deadly complication of long term parenteral nutrition (PN) use in infants. Fish oil based lipid emulsion has been shown in recent years to effectively treat PNALD. Alternative fat sources free of essential fatty acids have recently been investigated for health benefits related to decreased inflammatory response. We hypothesized that the addition of medium-chain triglycerides (MCT) to a purified fish oil-based diet would decrease the response to inflammatory challenge in mice, while allowing for sufficient growth and development. MATERIALS/METHODS: Six groups of ten adult male C57/Bl6 mice were pair-fed different dietary treatments for a period of twelve weeks, varying only in fat source (percent calories by weight): 10.84% soybean oil (SOY), 10% coconut oil (HCO), 10% medium chain triglycerides (MCT), 3% purified fish oil (PFO), 3% purified fish oil with 3% medium-chain triglycerides (50:50 MCT:PFO) and 3% purified fish oil with 7.59% medium-chain triglycerides (70:30 MCT:PFO). An endotoxin challenge was administered to half of the animals in each group at the completion of dietary treatment. RESULTS: All groups demonstrated normal growth throughout the study period. Groups fed MCT and HCO diets demonstrated biochemical essential fatty acid deficiency and decreased IL-6 and TNF-alpha response to endotoxin challenge. Groups containing PFO had increased inflammatory response to endotoxin challenge, and the addition of MCT to PFO mitigated this inflammatory response. CONCLUSION: These results suggest that the addition of MCT to PFO formulations may decrease the host response to inflammatory challenge, which may pose potential for optimized PN formulations. Inclusion of MCT in lipid emulsions given with PN formulations may be of use in therapeutic interventions for disease states resulting from chronic inflammation. PMID- 25458831 TI - Obesity and asthma: beyond T(H)2 inflammation. AB - Obesity is a major risk factor for asthma. Likewise, obesity is known to increase disease severity in asthmatic subjects and also to impair the efficacy of first line treatment medications for asthma, worsening asthma control in obese patients. This concept is in agreement with the current understanding that some asthma phenotypes are not accompanied by detectable inflammation, and may not be ameliorated by classical anti-inflammatory therapy. There are growing evidences suggesting that the obesity-related asthma phenotype does not necessarily involve the classical T(H)2-dependent inflammatory process. Hormones involved in glucose homeostasis and in the pathogeneses of obesity likely directly or indirectly link obesity and asthma through inflammatory and non-inflammatory pathways. Furthermore, the endocrine regulation of the airway-related pre-ganglionic nerves likely contributes to airway hyperreactivity (AHR) in obese states. In this review, we focused our efforts on understanding the mechanism underlying obesity related asthma by exploring the T(H)2-independent mechanisms leading to this disease. PMID- 25458832 TI - Leptin and adiponectin during the first week after kidney transplantation: biomarkers of graft dysfunction? AB - CONTEXT AND OBJECTIVE: Based on evidence that leptin and adiponectin are removed from circulation primarily by the kidney, we designed a study to examine the longitudinal changes of these adipokines during the first week after kidney transplantation (KTx) and to test the hypothesis that higher levels of leptin and/or adiponectin could be early biomarkers of delayed graft function (DGF=dialysis requirement during the first post-transplant week) and acute rejection. STUDY DESIGN: Repeated-measures prospective study. MATERIAL AND METHODS: Forty consecutive adult patients with end-stage renal disease who were undergoing KTx. Leptin and adiponectin were measured in blood samples that were collected before (day-0) and after KTx (days-1, 2, 4 and 7). Linear mixed-models, receiver operating characteristic and area under curve (AUC-ROC) were used. RESULTS: At post-transplant day-1, leptinemia and adiponectinemia declined 43% and 47%, respectively. At all times studied after KTx, the median leptin levels were significantly higher in patients developing DGF (n=18), but not adiponectin levels. Shortly after KTx (day-1), leptin values were significantly higher in DGF recipients in contrast to patients with promptly functioning kidneys, approximately two times higher when controlling for gender and BMI. The leptin reduction rate between pre-tranplant and one-day after KTx moderately predicted DGF (AUC=0.73). On day-1, serum leptin predicted DGF (AUC-ROC=0.76) with a performance slightly better than serum creatinine (AUC-ROC=0.72), even after correcting for BMI (AUC-ROC=0.73). Separating this analysis by gender showed that the performance of leptin in predicting DGF for male gender (AUC-ROC=0.86) improved. CONCLUSIONS: Kidney graft function is an independent determinant of leptin levels, but not of adiponectin. Leptin levels at day-1 slightly outperformed serum creatinine in predicting the occurrence of DGF, and more accurately in male gender. No significant association was detected with acute rejection. PMID- 25458833 TI - Association between methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and essential hypertension: a systematic review and meta-analysis. AB - OBJECTIVE: Many studies have investigated the role of 5,10 methylenetetrahydrofolate reductase gene (MTHFR) C677T/A1298C polymorphisms in essential hypertension (EH), but results are inconclusive. The purpose of this meta-analysis was to clarify the effects of MTHFR C677T/A1298C polymorphisms on the risk of EH. METHODS: Electronic databases were searched to identify relevant studies published until January 2014. Data were extracted by two independent authors. Odds ratios (ORs) with 95%confidence intervals (CIs) were used to assess the association between MTHFR C677T/A1298C polymorphisms and the risk of EH using random effect models or fixed effect models. Finally,30 studies with 5207 cases and 5383 controls were included for C677T polymorphism and 6 studies with 1009 cases and 994 controls were included for A1298C polymorphism. RESULTS: Meta analysis results indicated that MTHFR C677T polymorphism contributed to an increased risk of EH (for T vs. C: OR=1.30, 95%CI=1.18-1.43; for TT+CT vs. CC: OR=1.34, 95%CI=1.24-1.46; for TT vs. CC: OR=1.62, 95%CI=1.32-1.99; for TT vs. CT+CC: OR=1.41, 95%CI=1.26-1.59). However, no significant association was detected between MTHFR A1298C polymorphism and the risk of EH. CONCLUSION: This meta-analysis supports that MTHFR C677T polymorphism plays a role in developing EH. MTHFR A1298C polymorphism may not be associated with an increased risk of EH. Further large and well-designed studies are warranted to confirm these findings. PMID- 25458834 TI - A platform of C-type lectin-like receptor CLEC-2 for binding O-glycosylated podoplanin and nonglycosylated rhodocytin. AB - Podoplanin is a transmembrane O-glycoprotein that binds to C-type lectin-like receptor 2 (CLEC-2). The O-glycan-dependent interaction seems to play crucial roles in various biological processes, such as platelet aggregation. Rhodocytin, a snake venom, also binds to CLEC-2 and aggregates platelets in a glycan independent manner. To elucidate the structural basis of the glycan-dependent and independent interactions, we performed comparative crystallographic studies of podoplanin and rhodocytin in complex with CLEC-2. Both podoplanin and rhodocytin bind to the noncanonical "side" face of CLEC-2. There is a common interaction mode between consecutive acidic residues on the ligands and the same arginine residues on CLEC-2. Other interactions are ligand-specific. Carboxyl groups from the sialic acid residue on podoplanin and from the C terminus of the rhodocytin alpha subunit interact differently at this "second" binding site on CLEC-2. The unique and versatile binding modes open a way to understand the functional consequences of CLEC-2-ligand interactions. PMID- 25458835 TI - Structural and dynamics aspects of ASC speck assembly. AB - Activation of the inflammasome is accompanied by rapid formation of a micrometer sized perinuclear structure called the ASC speck, a platform for caspase-1 activity. The ASC speck is often referred to as an aggregate and shares certain features with aggresomes. It is thus an open question whether the ASC speck formation takes place via nonspecific aggregation of hydrophobic patches or specific interactions of its domains; PYD and CARD, which belong to the death fold superfamily. Bringing together structure and dynamics studies using the Gaussian network model of PYD and CARD, and molecular dynamics simulations of the wild-type and in silico mutated PYD, with the mutational analysis on the ASC structure and its separate domains in human cells, we show that the ASC speck is an organized structure with at least two levels of distinct compaction mechanisms based on the specific interactions of PYD and CARD. PMID- 25458837 TI - [Effect of head rotation on intraocular pressure in prone position: randomized study]. PMID- 25458838 TI - [Allergic reaction to patent blue dye in breast surgery - case report]. AB - We present a case of allergic reaction to patent blue in a patient who underwent excision of sentinel lymph node associated with segmental breast resection. About 20minutes after the dye injection, the patient developed hypotension (BP=70*30mmHg) associated with increased heart frequency. The patient was treated successfully with decreased inspired fraction of inhaled anesthetic and fluid replacement. At the end of the procedure, she presented with bluish urticarial - like plaques on the head, neck, upper limbs, and trunk; hydrocortisone was then used. The patient recovered uneventfully and was discharged from the PACU two hours after the end of surgery without skin changes, and was discharged from hospital on the morning after surgery. The incidence of allergic reactions with the use of patent blue is far superior to the hypersensitivity reactions seen with anesthetic and adjuvant drugs. Therefore, the anesthesiologist must be aware of cardiovascular instability associated with skin changes during the use of patent blue, for early diagnosis and appropriate treatment of this hypersensitivity reaction to this dye. PMID- 25458836 TI - Synchronous opening and closing motions are essential for cAMP-dependent protein kinase A signaling. AB - Conformational fluctuations play a central role in enzymatic catalysis. However, it is not clear how the rates and the coordination of the motions affect the different catalytic steps. Here, we used NMR spectroscopy to analyze the conformational fluctuations of the catalytic subunit of the cAMP-dependent protein kinase (PKA-C), a ubiquitous enzyme involved in a myriad of cell signaling events. We found that the wild-type enzyme undergoes synchronous motions involving several structural elements located in the small lobe of the kinase, which is responsible for nucleotide binding and release. In contrast, a mutation (Y204A) located far from the active site desynchronizes the opening and closing of the active cleft without changing the enzyme's structure, rendering it catalytically inefficient. Since the opening and closing motions govern the rate determining product release, we conclude that optimal and coherent conformational fluctuations are necessary for efficient turnover of protein kinases. PMID- 25458839 TI - [Anatomical basis for sciatic nerve block at the knee level]. AB - BACKGROUND AND OBJECTIVES: Recently, administration of sciatic nerve block has been revised due to the potential benefit for postoperative analgesia and patient satisfaction after the advent of ultrasound. The aim of this study was to describe the anatomical relations of the sciatic nerve in the popliteal fossa to determine the optimal distance the needle must be positioned in order to realize the sciatic nerve block anterior to its bifurcation into the tibial and common fibular nerve. METHOD: The study was conducted by dissection of human cadavers' popliteal fossa, fixed in 10% formalin, from the Laboratory of Human Anatomy and Morphology Departments of the Universidade Federal de Alagoas and Universidade de Ciencias da Saude de Alagoas. Access to the sciatic nerve was obtained. RESULTS: 44 popliteal fossa were analyzed. The bifurcation of the sciatic nerve in relation to the apex of the fossa was observed. There was bifurcation in: 67.96% below the apex, 15.90% above the apex, 11.36% near the apex, and 4.78% in the gluteal region. CONCLUSIONS: The sciatic nerve bifurcation to its branches occurs at various levels, and the chance to succeed when the needle is placed between 5 and 7 cm above the popliteal is 95.22%. PMID- 25458840 TI - Hydrogen ion supercapacitor: a new hybrid configuration of highly dispersed MnO2 in porous carbon coupled with nitrogen-doped highly ordered mesoporous carbon with enhanced H-insertion. AB - A new configuration of hydrogen ion supercapacitors was reported. A positive electrode composed of pseudocapacitive MnO2, highly dispersed into active porous carbon through an impregnation method, was combined with a nitrogen-doped highly ordered mesoporous carbon with enhanced electrochemical hydrogen insertion capacity as a negative electrode. During the operation, hydrogen ion shuttled between MnO2 and carbon electrodes. The MnO2 was formed on the surface of nanostructured carbon through a spontaneous redox reaction. Operating in an aqueous neutral solution, the hybrid device demonstrated an extended working voltage to ~2.1 V with good cycle life. PMID- 25458841 TI - A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. AB - Cancer cells are typically subject to profound metabolic alterations, including the Warburg effect wherein cancer cells oxidize a decreased fraction of the pyruvate generated from glycolysis. We show herein that the mitochondrial pyruvate carrier (MPC), composed of the products of the MPC1 and MPC2 genes, modulates fractional pyruvate oxidation. MPC1 is deleted or underexpressed in multiple cancers and correlates with poor prognosis. Cancer cells re-expressing MPC1 and MPC2 display increased mitochondrial pyruvate oxidation, with no changes in cell growth in adherent culture. MPC re-expression exerted profound effects in anchorage-independent growth conditions, however, including impaired colony formation in soft agar, spheroid formation, and xenograft growth. We also observed a decrease in markers of stemness and traced the growth effects of MPC expression to the stem cell compartment. We propose that reduced MPC activity is an important aspect of cancer metabolism, perhaps through altering the maintenance and fate of stem cells. PMID- 25458842 TI - Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. AB - Alternative modes of metabolism enable cells to resist metabolic stress. Inhibiting these compensatory pathways may produce synthetic lethality. We previously demonstrated that glucose deprivation stimulated a pathway in which acetyl-CoA was formed from glutamine downstream of glutamate dehydrogenase (GDH). Here we show that import of pyruvate into the mitochondria suppresses GDH and glutamine-dependent acetyl-CoA formation. Inhibiting the mitochondrial pyruvate carrier (MPC) activates GDH and reroutes glutamine metabolism to generate both oxaloacetate and acetyl-CoA, enabling persistent tricarboxylic acid (TCA) cycle function. Pharmacological blockade of GDH elicited largely cytostatic effects in culture, but these effects became cytotoxic when combined with MPC inhibition. Concomitant administration of MPC and GDH inhibitors significantly impaired tumor growth compared to either inhibitor used as a single agent. Together, the data define a mechanism to induce glutaminolysis and uncover a survival pathway engaged during compromised supply of pyruvate to the mitochondria. PMID- 25458843 TI - Regulation of substrate utilization by the mitochondrial pyruvate carrier. AB - Pyruvate lies at a central biochemical node connecting carbohydrate, amino acid, and fatty acid metabolism, and the regulation of pyruvate flux into mitochondria represents a critical step in intermediary metabolism impacting numerous diseases. To characterize changes in mitochondrial substrate utilization in the context of compromised mitochondrial pyruvate transport, we applied (13)C metabolic flux analysis (MFA) to cells after transcriptional or pharmacological inhibition of the mitochondrial pyruvate carrier (MPC). Despite profound suppression of both glucose and pyruvate oxidation, cell growth, oxygen consumption, and tricarboxylic acid (TCA) metabolism were surprisingly maintained. Oxidative TCA flux was achieved through enhanced reliance on glutaminolysis through malic enzyme and pyruvate dehydrogenase (PDH) as well as fatty acid and branched-chain amino acid oxidation. Thus, in contrast to inhibition of complex I or PDH, suppression of pyruvate transport induces a form of metabolic flexibility associated with the use of lipids and amino acids as catabolic and anabolic fuels. PMID- 25458844 TI - Structural model of active Bax at the membrane. AB - Bax plays a central role in the mitochondrial pathway of apoptosis. Upon activation, cytosolic Bax monomers oligomerize on the surface of mitochondria and change conformation concertedly to punch holes into the outer membrane. The subsequent release of cytochrome c initiates cell death. However, the structure of membrane-inserted Bax and its mechanism of action remain largely unknown. Here, we propose a 3D model of active Bax at the membrane based on double electron-electron resonance (DEER) spectroscopy in liposomes and isolated mitochondria. We show that active Bax is organized at the membrane as assemblies of dimers. In addition to a stable dimerization domain, each monomer contains a more flexible piercing domain involved in interdimer interactions and pore formation. The most important structural change during Bax activation is the opening of the hairpin formed by helices 5 and 6, which adopts a clamp-like conformation central to the mechanism of mitochondrial permeabilization. PMID- 25458845 TI - Programmable RNA shredding by the type III-A CRISPR-Cas system of Streptococcus thermophilus. AB - Immunity against viruses and plasmids provided by CRISPR-Cas systems relies on a ribonucleoprotein effector complex that triggers the degradation of invasive nucleic acids (NA). Effector complexes of type I (Cascade) and II (Cas9-dual RNA) target foreign DNA. Intriguingly, the genetic evidence suggests that the type III A Csm complex targets DNA, whereas biochemical data show that the type III-B Cmr complex cleaves RNA. Here we aimed to investigate NA specificity and mechanism of CRISPR interference for the Streptococcus thermophilus Csm (III-A) complex (StCsm). When expressed in Escherichia coli, two complexes of different stoichiometry copurified with 40 and 72 nt crRNA species, respectively. Both complexes targeted RNA and generated multiple cuts at 6 nt intervals. The Csm3 protein, present in multiple copies in both Csm complexes, acts as endoribonuclease. In the heterologous E. coli host, StCsm restricts MS2 RNA phage in a Csm3 nuclease-dependent manner. Thus, our results demonstrate that the type III-A StCsm complex guided by crRNA targets RNA and not DNA. PMID- 25458847 TI - Origin of plant auxin biosynthesis in charophyte algae: a reply to Wang et al. PMID- 25458848 TI - Auxin--a novel regulator of stomata differentiation. AB - Three recent publications identify the phytohormone auxin as a novel regulator of stomata development and distribution. We discuss how auxin signaling and polar auxin transport blend in with the established signaling network that controls cell division and differentiation within the stomatal cell lineage. PMID- 25458846 TI - SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer. AB - Oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), occur with high frequency in breast cancer. The protein kinase Akt is considered to be the primary effector of PIK3CA, although mechanisms by which PI3K mediates Akt-independent tumorigenic signals remain obscure. We show that serum and glucocorticoid-regulated kinase 3 (SGK3) is amplified in breast cancer and activated downstream of PIK3CA in a manner dependent on the phosphoinositide phosphatase INPP4B. Expression of INPP4B leads to enhanced SGK3 activation and suppression of Akt phosphorylation. Activation of SGK3 downstream of PIK3CA and INPP4B is required for 3D proliferation, invasive migration, and tumorigenesis in vivo. We further show that SGK3 targets the metastasis suppressor NDRG1 for degradation by Fbw7. We propose a model in which breast cancers harboring oncogenic PIK3CA activate SGK3 signaling while suppressing Akt, indicative of oncogenic functions for both INPP4B and SGK3 in these tumors. PMID- 25458849 TI - Synthesis of a tetrahydronaphthyridine spiropyrimidinetrione DNA gyrase inhibiting antibacterial agent--differential substitution at all five carbon atoms of pyridine. AB - The synthesis of (-)-1, a potent antibacterial agent, was achieved stereoselectively in nine steps from readily available starting materials. Directed metalations were developed to assemble a pentasubstituted pyridine with appropriately positioned aldehyde and dimethylmorpholine substituents for a key tertiary amino effect reaction (T-reaction) that led to the spirocylic architecture. Ultimately, (-)-1 was isolated as the thermodynamically most favored stereoisomer. PMID- 25458850 TI - N-acetylcysteine improves function and follicular survival in mice ovarian grafts through inhibition of oxidative stress. AB - The effect of N-acetylcysteine (NAC) on mouse ovary heterotopic autotransplantation was investigated. Mice (age 4-5 weeks) were divided into the following groups: control; autograft plus NAC (150 mg/kg daily intraperitoneal injection) and autograft plus saline (n = 6 per group). Groups were treated from 1 day before until 7 days after transplantation. After 28 days, ovary compartments were estimated stereologically. Plasma malondialdehyde, progesterone, oestradiol concentrations and the percentage of apoptotic follicles were measured to evaluate the rate of oxidative stress and ovarian graft function. The mean total volume of ovary, cortex and the number of follicles was significantly higher (all P < 0.001) in the autografts plus NAC group compared with the saline group. In the autografts plus NAC group, the mean percentage of apoptotic follicles (P < 0.001) and malondialdehyde concentration (P < 0.001 day 7; P < 0.05 day 28) were significantly lower, whereas oestradiol concentration was significantly higher (P < 0.05) compared with the saline group. Although NAC cannot compensate the above parameters to the control level, it considerably improves follicular survival and development and also the structure and function of transplanted ovaries, through reducing oxidative stress and apoptosis. PMID- 25458851 TI - The relationship between sperm head retardance using polarized light microscopy and clinical outcomes. AB - In human sperm head, birefringence can be seen under polarized light resulting from highly ordered structures within the acrosome and nucleus. Selecting sperm with partial head birefringence improves success of clinical pregnancies in patients with severe male factor infertility. The aim of this study was to establish a range of retardance in sperm heads using polarized light microscopy to select an optimum sperm for intracytoplasmic sperm injection (ICSI). Sperm heads of 63 couples undergoing ICSI in women aged 38 years or younger were imaged at the time of ICSI and later analysed for retardance blinded to embryo and cycle outcomes. Sperm head retardance was similar irrespective of whether fertilization occurred. Quality of embryos on day 3 and day 5 were higher when sperm were selected with head retardance ranging from 0.56 nm or greater to 0.91 nm or less. Selection of sperm with head retardance ranging from 0.56 nm or greater to 0.91 nm or less was associated with higher clinical pregnancy rates (OR 3.74 95% CI 1.43 to 9.77). Optimum sperm for selection at the time of ICSI was with head retardance within the range 0.56 nm or greater to 0.91 nm or less. PMID- 25458852 TI - No evidence of association between blastocyst aneuploidy and morphokinetic assessment in a selected population of poor-prognosis patients: a longitudinal cohort study. AB - Recent studies involving a limited number of patients have indicated a correlation between aneuploidy and various morphokinetic parameters during preimplantation development. The results among different groups, however, have been inconsistent in identifying the parameters that are able to predict chromosomal abnormalities. The aim of this study was to investigate whether aneuploidy of human blastocysts was detectable by specific morphokinetic parameters in patients at increased risk of aneuploidy because of advanced maternal age, history of unsuccessful IVF treatments, or both. A longitudinal cohort study was conducted using 455 blastocysts from 138 patients. Morphokinetic features of preimplantation development were detected in a timelapse incubator. Blastocysts were subjected to trophectodermal biopsy and comprehensive chromosomal screening. Analyses were conducted by means of logistic mixed-effects models, with a subject-specific intercept. No statistical correlation between 16 commonly detected morphokinetic characteristics of in-vitro embryo development and aneuploidy was found. Results suggest that morphokinetic characteristics cannot be used to select euploid blastocysts in poor-prognosis patients regarded as candidates for pre-implantation genetic screening. PMID- 25458853 TI - Housefly maggot-treated composting as sustainable option for pig manure management. AB - In traditional composting, large amounts of bulking agents must be added to reduce the moisture of pig manure, which increases the cost of composting and dilutes the N, P and K content in organic fertilizers. In this study, maggot treatment was used in composting instead of bulking agents. In experiment of selecting an optimal inoculum level for composting, the treatment of 0.5% maggot inoculum resulted in the maximum yield of late instar maggots, 11.6% (maggots weight/manure weight). The manure residue became noticeably granular by day 6 and its moisture content was below 60%, which was suitable for further composting without bulking agents. Moreover, in composting experiment with a natural compost without maggot inoculum and maggot-treated compost at 0.5% inoculum level, there were no significant differences in nutrient content between the two organic fertilizers from the two treatments (paired Student's t15=1.0032, P=0.3317). Therefore, maggot culturing did not affect the characteristics of the organic fertilizer. The content of TNPK (total nitrogen+total phosphorus+total potassium) in organic fertilizer from maggot treatment was 10.72% (dry weight), which was far more than that of organic fertilizer made by conventional composting with bulking agents (about 8.0%). Dried maggots as feed meet the national standard (GB/T19164-2003) for commercial fish meal in China, which contained 55.32 +/- 1.09% protein; 1.34 +/- 0.02% methionine; 4.15 +/- 0.10% lysine. This study highlights housefly maggot-treated composting can be considered sustainable alternatives for pig manure management to achieve high-quality organic fertilizer and maggots as feed without bulking agents. PMID- 25458854 TI - Optimizing and developing a continuous separation system for the wet process separation of aluminum and polyethylene in aseptic composite packaging waste. AB - The consumption of milk in China is increasing as living standards rapidly improve, and huge amounts of aseptic composite milk packaging waste are being generated. Aseptic composite packaging is composed of paper, polyethylene, and aluminum. It is difficult to separate the polyethylene and aluminum, so most of the waste is currently sent to landfill or incinerated with other municipal solid waste, meaning that enormous amounts of resources are wasted. A wet process technique for separating the aluminum and polyethylene from the composite materials after the paper had been removed from the original packaging waste was studied. The separation efficiency achieved using different separation reagents was compared, different separation mechanisms were explored, and the impacts of a range of parameters, such as the reagent concentration, temperature, and liquid solid ratio, on the separation time and aluminum loss ratio were studied. Methanoic acid was found to be the optimal separation reagent, and the suitable conditions were a reagent concentration of 2-4 mol/L, a temperature of 60-80 degrees C, and a liquid-solid ratio of 30 L/kg. These conditions allowed aluminum and polyethylene to be separated in less than 30 min, with an aluminum loss ratio of less than 3%. A mass balance was produced for the aluminum-polyethylene separation system, and control technique was developed to keep the ion concentrations in the reaction system stable. This allowed a continuous industrial-scale process for separating aluminum and polyethylene to be developed, and a demonstration facility with a capacity of 50t/d was built. The demonstration facility gave polyethylene and aluminum recovery rates of more than 98% and more than 72%, respectively. Separating 1t of aluminum-polyethylene composite packaging material gave a profit of 1769 Yuan, meaning that an effective method for recycling aseptic composite packaging waste was achieved. PMID- 25458855 TI - 'Wasteaware' benchmark indicators for integrated sustainable waste management in cities. AB - This paper addresses a major problem in international solid waste management, which is twofold: a lack of data, and a lack of consistent data to allow comparison between cities. The paper presents an indicator set for integrated sustainable waste management (ISWM) in cities both North and South, to allow benchmarking of a city's performance, comparing cities and monitoring developments over time. It builds on pioneering work for UN-Habitat's solid waste management in the World's cities. The comprehensive analytical framework of a city's solid waste management system is divided into two overlapping 'triangles' one comprising the three physical components, i.e. collection, recycling, and disposal, and the other comprising three governance aspects, i.e. inclusivity; financial sustainability; and sound institutions and proactive policies. The indicator set includes essential quantitative indicators as well as qualitative composite indicators. This updated and revised 'Wasteaware' set of ISWM benchmark indicators is the cumulative result of testing various prototypes in more than 50 cities around the world. This experience confirms the utility of indicators in allowing comprehensive performance measurement and comparison of both 'hard' physical components and 'soft' governance aspects; and in prioritising 'next steps' in developing a city's solid waste management system, by identifying both local strengths that can be built on and weak points to be addressed. The Wasteaware ISWM indicators are applicable to a broad range of cities with very different levels of income and solid waste management practices. Their wide application as a standard methodology will help to fill the historical data gap. PMID- 25458858 TI - Altered default mode network functional connectivity in schizotypal personality disorder. AB - The default mode network (DMN) has been identified to play a critical role in many mental disorders, but such abnormalities have not yet been determined in patients with schizotypal personality disorder (SPD). The purpose of this study was to analyze the alteration of the DMN functional connectivity in subjects with (SPD) and compared it to healthy control subjects. Eighteen DSM-IV diagnosed SPD subjects (all male, average age: 19.7+/-0.9) from a pool of 3000 first year college students, and eighteen age and gender matched healthy control subjects were recruited (all male, average age: 20.3+/-0.9). Independent component analysis (ICA) was used to analyze the DMN functional connectivity alteration. Compared to the healthy control group, SPD subjects had significantly decreased functional connectivity in the frontal areas, including the superior and medial frontal gyrus, and greater functional connectivity in the bilateral superior temporal gyrus and sub-lobar regions, including the bilateral putamen and caudate. Compared to subjects with SPD, the healthy control group showed decreased functional connectivity in the bilateral posterior cingulate gyrus, but showed greater functional connectivity in the right transverse temporal gyrus and left middle temporal gyrus. The healthy control group also showed greater activation in the cerebellum compared to the SPD group. These findings suggest that DMN functional connectivity, particularly that involving cognitive or emotional regulation, is altered in SPD subjects, and thus may be helpful in studying schizophrenia. PMID- 25458856 TI - GABA abnormalities in schizophrenia: a methodological review of in vivo studies. AB - Abnormalities of GABAergic interneurons are some of the most consistent findings from post-mortem studies of schizophrenia. However, linking these molecular deficits with in vivo observations in patients - a critical goal in order to evaluate interventions that would target GABAergic deficits - presents a challenge. Explanatory models have been developed based on animal work and the emerging experimental literature in schizophrenia patients. This literature includes: neuroimaging ligands to GABA receptors, magnetic resonance spectroscopy (MRS) of GABA concentration, transcranial magnetic stimulation of cortical inhibitory circuits and pharmacologic probes of GABA receptors to dynamically challenge the GABA system, usually in combination with neuroimaging studies. Pharmacologic challenges have elicited behavioral changes, and preliminary studies of therapeutic GABAergic interventions have been conducted. This article critically reviews the evidence for GABAergic dysfunction from each of these areas. These methods remain indirect measures of GABAergic function, and a broad array of dysfunction is linked with the putative GABAergic measures, including positive symptoms, cognition, emotion, motor processing and sensory processing, covering diverse brain areas. Measures of receptor binding have not shown replicable group differences in binding, and MRS assays of GABA concentration have yielded equivocal evidence of large-scale alteration in GABA concentration. Overall, the experimental base remains sparse, and much remains to be learned about the role of GABAergic interneurons in healthy brains. Challenges with pharmacologic and functional probes show promise, and may yet enable a better characterization of GABAergic deficits in schizophrenia. PMID- 25458857 TI - Anti-NMDA receptor encephalitis, autoimmunity, and psychosis. AB - Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a recently-discovered synaptic autoimmune disorder in which auto-antibodies target NMDARs in the brain, leading to their removal from the synapse. Patients manifest with prominent psychiatric symptoms - and in particular psychosis - early in the disease course. This presentation converges with long-standing evidence on multiple fronts supporting the glutamatergic model of schizophrenia. We review mechanisms underlying disease in anti-NMDAR encephalitis, and discuss its role in furthering our understanding of neural circuit dysfunction in schizophrenia. PMID- 25458859 TI - Both volumetry and functional connectivity of Heschl's gyrus are associated with auditory P300 in first episode schizophrenia. AB - BACKGROUND: Reduced gray matter volume in left superior temporal gyrus (STG) is considered to be associated with auditory P300 amplitude in schizophrenia. Little is known about possible pathological circuits regarding sub-regions of STG that contribute to auditory P300 abnormality in schizophrenia. The current study investigated gray matter volume in STG and functional connectivity of Heschl's gyrus in first-episode schizophrenia (FESZ), as well as their correlations with P300 amplitude. METHODS: Nineteen FESZ patients and 19 healthy controls contributed MRI scans. Eighteen patients and 17 controls underwent auditory P300 test within 1 week after MRI scanning. STG structural abnormalities were analyzed using voxel-based morphometry (VBM) analysis. Bilateral Heschl's gyri (HG) were selected as seeds for FC analysis in resting MRI data. Correlations of P300 amplitude with gray matter alterations in STG and HG-based FC were analyzed using Pearson correlation analysis within each group. RESULTS: Compared to healthy controls, FESZ patients showed reduced gray matter in left STG and P300 amplitude. Gray matter volume of left Heschl's gyrus was positively correlated with P300 amplitude in FESZ patients. HG-based FC of resting fMRI was decreased in the inferior frontal gyrus (IFG), medial frontal gyrus (MFG), anterior cingulate cortex (ACC), and left temporal pole, whereas the same metric was increased in the lingual gyrus, precuneus and cerebellar tonsil among FESZ patients. FC between bilateral HG and precuneus was inversely correlated with P300 amplitude among healthy controls, and was absent among FES patients. CONCLUSIONS: The findings point towards both decreased volume of Heschl's gyrus and its altered functional pathways may contribute to auditory P300 abnormality in schizophrenia. PMID- 25458860 TI - Self-reported attenuated psychotic-like experiences in help-seeking adolescents and their association with age, functioning and psychopathology. AB - OBJECTIVE: Self-rated attenuated psychotic-like experiences (APLEs) are increasingly used to screen for ultra-high-risk (UHR) across all ages. However, self-rated psychotic-like experiences (PLEs), in particular perception-related ones, were more frequent in children and adolescents, in which they possessed less clinical significance. We therefore explored the prevalence of different factors of APLEs in help-seeking adolescents, and their relationship with age, functioning and psychopathology. METHOD: As a part of the "Liberiamo il Futuro" project, help-seeking adolescents (N=171; 11-18 years, 53% male) were screened with the 92-item Prodromal Questionnaire (PQ-92). A factor analysis was performed on the PQ-92 positive items (i.e., APLEs) to identify different APLE-factors. These were assessed for their association with age, functioning and psychopathology using regression analyses. RESULTS: APLEs were very common in help-seeking adolescents, and formed four factors: "Conceptual Disorganization and Suspiciousness", "Perceptual Abnormalities", "Bizarre Experiences", and "Magical Ideation". Associations with age and functioning but not psychopathology were found for "Perceptual Abnormalities" that was significantly more severe in 11-12-year-olds, while "Conceptual Disorganization and Suspiciousness" was significantly related to psychopathology. CONCLUSION: In line with findings on PLEs, prevalence and clinical significance of APLEs, especially perception related ones, might depend on age and thus neurodevelopmental stage, and may fall within the normal spectrum of experience during childhood. This should be considered when screening for UHR status in younger age groups. PMID- 25458861 TI - Prolonged cortical silent period among drug-naive subjects at ultra-high risk of psychosis. AB - BACKGROUND: Deficits in gamma-aminobutyric acid (GABA) inhibitory neurotransmission have been associated with pathophysiological mechanisms underlying schizophrenia. However, little is known about whether these deficits occur before or after the onset of psychosis. METHOD: We recruited 16 drug-naive subjects at ultra-high risk of psychosis (UHR), 17 schizophrenia patients and 28 healthy controls. Cortical inhibition was determined using transcranial magnetic stimulation (TMS) over the left primary motor cortex. TMS markers such as short interval cortical inhibition (SICI), cortical silent period (CSP) and intracortical facilitation (ICF) were obtained from each subject. While SICI can reflect GABA type A (GABAA) mediated inhibition, CSP is thought to indicate GABA type B (GABAB) mediated inhibitory circuits. RESULTS: As compared with healthy controls, UHR subjects showed a prolonged CSP with no change in SICI, whereas schizophrenia patients demonstrated both a prolonged CSP and a reduced SICI. No group differences were found for ICF. CSP in schizophrenia patients also had a positive correlation with positive symptom score of the positive and negative symptom scale (PANSS). CONCLUSIONS: Cortical inhibitory deficits among UHR subjects were relatively limited compared to those among schizophrenia patients. Alterations might occur in some subgroup of GABA-mediated neurotransmitter systems before the onset of psychosis, while alterations in both GABAA and GABAB networks might contribute to full-blown psychosis. PMID- 25458863 TI - Re: Less is more. PMID- 25458862 TI - Forming first impressions of others in schizophrenia: impairments in fast processing and in use of spatial frequency information. AB - Individuals form first impressions of others all the time, which affects their social functioning. Typical adults form threat impressions in faces with neutral expressions quickly, requiring less than 40 ms. These impressions appear to be mediated by low spatial frequency (LSF) content in the images. Little is known, however, about mechanisms of first impression formation in schizophrenia. The current study investigated how quickly individuals with schizophrenia can form consistent impressions of threat compared with controls and explored the mechanisms involved. Patients and controls were presented intact, LSF- or high spatial frequency (HSF)-filtered faces with durations that varied from 39 to 1703 ms and were asked to rate how threatening each face was on a scale from 1 to 5. In order to assess the speed of impression formation for intact faces, correlations were calculated for ratings made at each duration compared to a reference duration of 1703 ms for each group. Controls demonstrated a significant relation for intact faces presented for 39 ms, whereas patients required 390 ms to demonstrate a significant relation with the reference duration. For controls, LSFs primarily contributed to the formation of consistent threat impressions at 39 ms, whereas patients showed a trend for utilizing both LSF and HSF information to form consistent threat impressions at 390 ms. Results indicate that individuals with schizophrenia require a greater integration time to form a stable "first impression" of threat, which may be related to the need to utilize compensatory mechanisms such as HSF, as well as LSF, information. PMID- 25458864 TI - Cortico-accumbens circuitry in schizophrenia: merely a "reward system"? PMID- 25458865 TI - [CXCL4: a new biomarker of diagnosis and severity in systemic sclerosis?]. PMID- 25458866 TI - [Cutaneous adverse drug reactions]. AB - Cutaneous adverse drug reactions (CADR) represent a heterogeneous field including various clinical patterns without specific features suggesting drug causality. Exanthematous eruptions, urticaria and vasculitis are the most common forms of CADR. Fixed eruption is uncommon in western countries. Serious reactions (fatal outcome, sequelae) represent 2% of CADR: bullous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), DRESS (drug reaction with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome) and acute generalized exanthematous pustulosis (AGEP). These forms must be quickly diagnosed to guide their management. The main risk factors are immunosuppression, autoimmunity and some HLA alleles in bullous reactions and DRESS. Most systemic drugs may induce cutaneous adverse reactions, especially antibiotics, anticonvulsivants, antineoplastic drugs, non-steroidal anti-inflammatory drugs, allopurinol and contrast media. Pathogenesis includes immediate or delayed immunologic mechanism, usually not related to dose, and pharmacologic/toxic mechanism, commonly dose-dependent or time-dependent. In case of immunologic mechanism, allergologic exploration is possible to clarify drug causality, with a variable sensitivity according to the drug and to the CADR type. It includes epicutaneous patch testing, prick test and intradermal test. However, no in vivo or in vitro test can confirm the drug causality. To determine the cause of the eruption, a logical approach based on clinical characteristics, chronologic factors and elimination of differential diagnosis is required, completed with a literature search. A reporting to pharmacovigilance network is essential in case of a serious CADR whatever the suspected drug and in any case if the involved drug is a newly marketed one or unusually related to cutaneous reactions. PMID- 25458867 TI - [Assessment of clinical observation skills of last year medical students]. AB - PURPOSE: Clinical examination skills are poorly evaluated by theoretical tests. We observed the clinical examination of real patients by 6th year medical students. METHODS: Four internists involved in teaching activities defined 11 clinical examination items, with two objective performance criteria each. The students were evaluated in two internal medicine departments during the rotation preceding or following their national graduation test. Scores by item and by criterion and an overall score were calculated and correlated with their rank at the national graduation test. RESULTS: Thirty-two students were evaluated in one department and 18 in the other; each evaluation lasted approximately 30 minutes. The results were similar in both departments. Only 2 items got a score over 75% in this students' sample (acute respiratory failure, peripheral pulses); 4 items were satisfied at less than 50% (lymph nodes, right heart failure, liver failure, and attention). The mean overall score was 6.5/11 (standard deviation 1.5). National rankings were good (median 1605/8001, interquartile 453-3036) but uncorrelated with the global score (Spearman coefficient -0.13; P=0.39). CONCLUSION: Bedside evaluation of the students reveals substantial deficiencies, a few months or weeks before taking their position as residents. Several elementary skills are mastered by a minority of them (search for an asterixis, distended jugular veins, deep tendon reflexes), even among those successful at the national graduation test. Bedside evaluation of clinical examination skills should be more systematically performed. PMID- 25458868 TI - Vertically-aligned sandwich nanowires enhance the photoelectrochemical reduction of hydrogen peroxide: hierarchical formation on carbon nanotubes of cadmium sulfide quantum dots and Prussian blue nanocoatings. AB - We describe a vertically-aligned array of sandwiched nanowires comprising Prussian blue (PB) nanocoating-carbon nanotube (CNT) core-shell structures with CdS particles positioning at the core/shell interface, viz. PB/CdS/CNT. The PB/CdS/CNT electrode thus constructed are noticeable in synchronically harvesting photon-, ionic-, and chemical-energies, respectively, from visible light radiation, K(+) uptaking and releasing, and the reduction of H2O2. In 0.2 M K2SO4 aqueous solution, the photoelectrocatalytic reduction of 1.5 mM H2O2 at PB/CdS/CNT delivered the current density as high as 1.91 mA/cm(2) at reduced overpotential, that is, three times that at the Pt/C. This superb performance is causally linked to the judicious choice of materials and their assembly into defining sandwich nanostructures wherein the three components closely cooperate with each other in the photoelectrocatalytic reduction of H2O2, including photo induced charge separation in CdS, spontaneous electron injection into PB due to its relatively low Fermi level, and the electrocatalytic reduction of H2O2 by PB via an electrochemical-chemical-electrochemical reaction mechanism. The structural alignment of PB/CdS/CNT ensures the simplest pathway for the mass diffusion and electron shuttle, and a high surface area accessible to the chemical and electrochemical reactions, so as to minimize the concentration- and electrochemical-polarization and thus ensure the fast overall kinetics of the electrode reaction. PMID- 25458870 TI - A valedictory editorial. PMID- 25458869 TI - Antipruritic mechanisms of topical E6005, a phosphodiesterase 4 inhibitor: inhibition of responses to proteinase-activated receptor 2 stimulation mediated by increase in intracellular cyclic AMP. AB - BACKGROUND: Phosphodiesterase 4 (PDE4), which catalyses the conversion of cyclic adenosine 3',5'-monophosphate (cAMP) to 5'-AMP, plays a critical role in the pathogenesis of inflammatory disorders. Pruritus is the main symptom of dermatitides, such as atopic dermatitis, and is very difficult to control. Recent studies have shown that the activation of proteinase-activated receptor 2 (PAR2) is involved in pruritus in dermatoses in humans and rodents. OBJECTIVE: To investigate the inhibitory effect of E6005, a topically effective PDE4 inhibitor, on PAR2-associated itching in mice. METHODS: Mice were given an intradermal injection of SLIGRL-NH2 (100 nmol/site), a PAR2 agonist peptide, into the rostral part of the back. E6005 and 8-bromo-cAMP were applied topically and injected intradermally, respectively, to the same site. Scratching bouts were observed as an itch-related behavior, and firing activity of the cutaneous nerve was electrophysiologically recorded. Keratinocytes were isolated from the skin of neonatal mice and cultured for in vitro experiments. The concentrations of cAMP and leukotriene B4 (LTB4) were measured by enzyme immunoassay. The distribution of PDE4 subtypes in the skin was investigated by immunostaining. RESULTS: Topical E6005 and intradermal 8-bromo-cAMP significantly inhibited SLIGRL-NH2-induced scratching and cutaneous nerve firing. Topical E6005 increased cutaneous cAMP content. Topical E6005 and intradermal 8-bromo-cAMP inhibited cutaneous LTB4 production induced by SLIGRL-NH2, which has been shown to elicit LTB4-mediated scratching. E6005 and 8-bromo-cAMP inhibited SLIGRL-NH2-induced LTB4 production in the cultured murine keratinocytes also. PDE4 subtypes were mainly expressed in keratinocytes and mast cells in the skin. CONCLUSIONS: The results suggest that topical E6005 treatment inhibits PAR2-associated itching. Inhibition of LTB4 production mediated by an increase in cAMP may be partly involved in the antipruritic action of E6005. PMID- 25458871 TI - [Half a century of Spanish journal of geriatrics and gerontology]. PMID- 25458872 TI - Protective effects of human milk antimicrobial peptides against bacterial infection. PMID- 25458873 TI - Metabolic syndrome in children and adolescents with phenylketonuria. AB - OBJECTIVE: This study aimed to identify markers of metabolic syndrome (MS) in patients with phenylketonuria (PKU). METHODS: This was a cross-sectional study consisting of 58 PKU patients (ages of 4-15 years): 29 patients with excess weight, and 29 with normal weight. The biochemical variables assessed were phenylalanine (phe), total cholesterol, HDL-c, triglycerides, glucose, and basal insulin. The patients had Homeostasis Model Assessment (HOMA) and waist circumference assessed. RESULTS: No inter-group difference was found for phe. Overweight patients had higher levels of triglycerides, basal insulin, and HOMA, but lower concentrations of HDL-cholesterol, when compared to the eutrophic patients. Total cholesterol/HDL-c was significantly higher in the overweight group. A positive correlation between basal insulin level and HOMA with waist circumference was found only in the overweight group. CONCLUSION: The results of this study suggest that patients with PKU and excess weight are potentially vulnerable to the development of metabolic syndrome. Therefore, it is necessary to conduct clinical and laboratory monitoring, aiming to prevent metabolic changes, as well as excessive weight gain and its consequences, particularly cardiovascular risk. PMID- 25458874 TI - Probiotics: an update. AB - OBJECTIVE: Triggered by the growing knowledge on the link between the intestinal microbiome and human health, the interest in probiotics is ever increasing. The authors aimed to review the recent literature on probiotics, from definitions to clinical benefits, with emphasis on children. SOURCES: Relevant literature from searches of PubMed, CINAHL, and recent consensus statements were reviewed. SUMMARY OF THE FINDINGS: While a balanced microbiome is related to health, an imbalanced microbiome or dysbiosis is related to many health problems both within the gastro-intestinal tract, such as diarrhea and inflammatory bowel disease, and outside the gastro-intestinal tract such as obesity and allergy. In this context, a strict regulation of probiotics with health claims is urgent, because the vast majority of these products are commercialized as food (supplements), claiming health benefits that are often not substantiated with clinically relevant evidence. The major indications of probiotics are in the area of the prevention and treatment of gastro-intestinal related disorders, but more data has become available on extra-intestinal indications. At least two published randomized controlled trials with the commercialized probiotic product in the claimed indication are a minimal condition before a claim can be sustained. Today, Lactobacillus rhamnosus GG and Saccharomyces boulardii are the best-studied strains. Although adverse effects have sporadically been reported, these probiotics can be considered as safe. CONCLUSIONS: Although regulation is improving, more stringent definitions are still required. Evidence of clinical benefit is accumulating, although still missing in many areas. Misuse and use of products that have not been validated constitute potential drawbacks. PMID- 25458875 TI - Brazilian adaptation of the Functioning after Pediatric Cochlear Implantation (FAPCI): comparison between normal hearing and cochlear implanted children. AB - OBJECTIVE: Enabling development of the ability to communicate effectively is the principal objective of cochlear implantation (CI) in children. However, objective and effective metrics of communication for cochlear-implanted Brazilian children are lacking. The Functioning after Pediatric Cochlear Implantation (FAPCI), a parent/caregiver reporting instrument developed in the United States, is the first communicative performance scale for evaluation of real-world verbal communicative performance of 2-5-year-old children with cochlear implants. The primary aim was to cross-culturally adapt and validate the Brazilian-Portuguese version of the FAPCI. The secondary aim was to conduct a trial of the adapted Brazilian-Portuguese FAPCI (FAPCI-BP) in normal hearing (NH) and CI children. METHODS: The American-English FAPCI was translated by a rigorous forward-backward process. The FAPCI-BP was then applied to the parents of children with NH (n=131) and CI (n=13), 2-9 years of age. Test-retest reliability was verified. RESULTS: The FAPCI-BP was confirmed to have excellent internal consistency (Cronbach's alpha > 0.90). The CI group had lower FAPCI scores (58.38 +/- 22.6) than the NH group (100.38 +/- 15.2; p<0.001, Wilcoxon test). CONCLUSION: The present results indicate that the FAPCI-BP is a reliable instrument. It can be used to evaluate verbal communicative performance in children with and without CI. The FAPCI is currently the only psychometrically-validated instrument that allows such measures in cochlear-implanted children. PMID- 25458876 TI - Chromosomal microarrays testing in children with developmental disabilities and congenital anomalies. AB - OBJECTIVES: Clinical use of microarray-based techniques for the analysis of many developmental disorders has emerged during the last decade. Thus, chromosomal microarray has been positioned as a first-tier test. This study reports the first experience in a Chilean cohort. METHODS: Chilean patients with developmental disabilities and congenital anomalies were studied with a high-density microarray (CytoScanTM HD Array, Affymetrix, Inc., Santa Clara, CA, USA). Patients had previous cytogenetic studies with either a normal result or a poorly characterized anomaly. RESULTS: This study tested 40 patients selected by two or more criteria, including: major congenital anomalies, facial dysmorphism, developmental delay, and intellectual disability. Copy number variants (CNVs) were found in 72.5% of patients, while a pathogenic CNV was found in 25% of patients and a CNV of uncertain clinical significance was found in 2.5% of patients. CONCLUSION: Chromosomal microarray analysis is a useful and powerful tool for diagnosis of developmental diseases, by allowing accurate diagnosis, improving the diagnosis rate, and discovering new etiologies. The higher cost is a limitation for widespread use in this setting. PMID- 25458877 TI - Poor diet quality among Brazilian adolescents with HIV/AIDS. AB - OBJECTIVE: This study aimed to assess diet quality among adolescents with HIV/AIDS. METHOD: A cross-sectional study was conducted involving patients with HIV/AIDS treated in a referral hospital in Sao Paulo, Brazil. Eighty-eight adolescents (10-19 years of age) participated in the study. Information on disease history and use of medication were obtained from medical records. The participants responded to two 24-hour diet recalls. Diet quality was assessed by means of the Healthy Eating Index-2005 (HEI-2005) adapted to the Brazilian population. Pearson's correlation coefficients were calculated. Mean HEI-2005 scores were compared according to the independent variables using either the Student's t-test or the Mann-Whitney test. RESULTS: The mean HEI-2005 score was 51.90 (SE=0.90). The components with the lowest means were whole grains and sodium. Components with highest means were total grains and oils. No correlations were found between the independent variables and HEI score. Adolescents living in foster homes had higher means for total fruit and lower means for meat and beans in comparison to adolescents living with their families. Girls had higher means for milk and lower means for calories from solid fats, alcoholic beverages, and added sugars in comparison to boys. CONCLUSIONS: Adolescents with HIV/AIDS exhibited a similar eating pattern to that of adolescents in the general population: high consumption of added sugar, saturated fat, and sodium, and insufficient ingestion of whole grains and fruits. Special attention should be paid to the diet of adolescents with HIV/AIDS, who are at greater risk of developing cardiovascular and other chronic diseases. PMID- 25458878 TI - Preventing childhood overweight and obesity. PMID- 25458879 TI - The effect of anesthesia with propofol and sedation with butorphanol on quantitative contrast-enhanced ultrasonography of the healthy feline kidney. AB - Contrast-enhanced ultrasonography of the left kidney was performed using a commercial contrast agent in six healthy adult purpose-bred cats. A cross-over design was used to compare three protocols: (1) awake, (2) butorphanol (0.4 mg/kg IM), and (3) propofol (3.5-7.7 mg/kg IV boluses to effect). Time-intensity curves were created from two regions-of-interest drawn in the renal cortex. The curves were analyzed for blood flow parameters representing blood volume (base intensity, peak intensity, area-under-curve) and blood velocity (arrival time, time-to-peak, wash-in/out). There was no difference in the subjective enhancement pattern between the three protocols. No significant effect of butorphanol was observed in any of the perfusion parameters (P > 0.05). Propofol did not influence the most important perfusion parameter, area-under-the-curve, and is adequate for use in contrast-enhanced ultrasound studies. PMID- 25458880 TI - Increased leptin mRNA expression in the blood of dogs naturally infected by Leishmania infantum. AB - Canine leishmaniosis (CL) is a severe and potentially fatal zoonosis caused by the protozoan Leishmania infantum. Severe forms of CL are commonly associated with a non-protective, humoral immune-response and high parasitic loads. Leptin, a 16 kD hormone mainly secreted by adipocytes, regulates both the innate and adaptive immunity. The goal of this study was to evaluate leptin mRNA expression levels in blood samples from privately owned dogs with CL (n = 11) and healthy controls (n = 10) using quantitative, real-time polymerase chain reaction. Blood samples from dogs with CL expressed significantly higher leptin mRNA levels (two fold) compared to healthy controls (P = 0.018). The results suggest a possible involvement of leptin in the pathophysiology of Leishmania infection in dogs and the possible use of leptin as a biomarker for CL. Future studies investigating the immunological role of leptin in dogs with CL are warranted. PMID- 25458881 TI - Multi-species visit rates to farmyards: implications for biosecurity. AB - Disease transmission dynamics between wildlife and livestock are likely to be affected by contacts between the two populations. In this study, rates of visitation of rodents, badgers, red foxes and cats to 11 farmyards were quantified from July 2012 to August 2013. There was variation in rates of visitation between different species and between farmyards. Rates of visitation were 60.3% (n = 2374) for cats, 19.1% (n = 751) for rodents, 16.7% (n = 657) for red foxes and 3.9% (n = 153) for badgers. Multi-species visits are relevant to disease transmission, highlighting the need for increased biosecurity on farms. PMID- 25458882 TI - Frequencies of regulatory T cells in the peripheral blood of dogs with primary immune-mediated thrombocytopenia and chronic enteropathy: a pilot study. AB - Regulatory T (Treg) cells are specialized immune cells with a pivotal role in the maintenance of immune homeostasis and control of inflammation. However, relatively little is known about immune regulation in the peripheral blood of dogs with primary immune-mediated thrombocytopenia or chronic enteropathy. Using flow cytometry this study investigated Treg responses in the peripheral blood of dogs with respective autoimmune or chronic intestinal diseases and demonstrated that a reduction of Treg frequencies is observed in dogs with clinical signs compared to dogs undergoing remission and healthy dogs. These findings suggest that reduced frequencies of Treg cells in peripheral blood might be causally associated with the onset and/or progression of autoimmune and chronic intestinal diseases in dogs and that measurement of regulatory T cells might represent a useful tool in the monitoring of treatment response and disease progression. PMID- 25458883 TI - Osteoarthritis of the temporo-mandibular joint in free-living Soay sheep on St Kilda. AB - Osteoarthritis (OA) is a common degenerative disease of synovial joints with the potential to cause pathology and welfare issues in both domestic and wild ruminants. Previous work has identified OA of the elbow joint in domestic sheep, but the prevalence of OA of the jaw and in particular the temporomandibular joint (TMJ) has not been previously reported. Following up a previous report of a single case of TMJ OA in a free-living population of Soay sheep on St Kilda in the Outer Hebrides, an archive of 2736 jaw bones collected from this population between 1985 and 2010 was surveyed. Evidence of TMJ OA was found in 35 sheep. Of these, 15 cases were unilateral (11 right side, 4 left side) and the remaining 20 were bilateral. TMJ pathology was much more common in females than males: only 3/35 cases were in males, with overall prevalence at 2.3% for females and 0.2% in males. Radiographic examination of TMJ with OA revealed extensive bone re modelling with osteophytosis, particularly of the condyle of the mandible. There was a highly significant age-dependence in TMJ OA incidence among age classes: 30/35 cases occurred in geriatric sheep (aged 7 years or more; 11.1% prevalence within this age class), four in adults (2-6 years old; 0.9% prevalence), one in yearlings (0.3% prevalence) and none in lambs. The low incidence in males was confounded by sex differences in longevity: while 18% of females sampled died in the geriatric age class, only 2% of males did so. Although the low prevalence of the pathology limited the ability to test its association with other traits, it was possible to examine relationships with reproductive performance measures amongst geriatric females with and without TMJ OA. Although there were trends towards lower fecundity and lower lamb birth weight in the breeding season prior to death, these were not statistically significant. PMID- 25458884 TI - Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney function biomarkers in healthy geriatric cats fed reduced protein foods enriched with fish oil, L-carnitine, and medium-chain triglycerides. AB - The purpose of this study was to determine whether feeding cats reduced protein and phosphorus foods with added fish oil, L-carnitine, and medium-chain triglycerides (MCT) altered serum biomarkers of renal function. Thirty-two healthy cats, mean age 14.0 (8.3-19.6) years, were fed control food or one of two experimental foods for 6 months. All foods had similar concentrations of moisture, protein, and fat (approximately 8.0%, 26.5%, and 20.0%, respectively). Both experimental foods contained added fish oil (1.5%) and L-carnitine (500 mg/kg). Experimental-food 2 also contained increased MCT (10.5% from coconut oil), 1.5% added corn oil, and reduced animal fat. Glomerular filtration rate (GFR), serum biochemistries, renal function biomarkers including serum creatinine (sCr) and symmetrical dimethylarginine (SDMA), and plasma metabolomic profiles were measured at baseline, and at 1.5, 3, and 6 months. Body composition was determined by dual-energy X-ray absorptiometry. Although both experimental foods altered plasma fatty acids, carnitine and related metabolites, and lysophospholipid concentrations, there were no changes in renal function biomarkers. There was, however, a benefit in using SDMA versus sCr to assess renal function in older cats with less total lean mass. Compared with cats <12 years, those >15 years had lower total lean mass (P < 0.01), lower GFR (P = 0.04), and lower sCr concentrations (P < 0.01). However, SDMA concentrations (P < 0.01) were higher in older cats. This study shows that in cats, serum SDMA concentration is more highly correlated with GFR than sCr concentration, and, unlike sCr, which declines with age because of muscle wasting, SDMA increases as GFR declines with age. PMID- 25458885 TI - Use of water troughs by badgers and cattle. AB - The frequency of visits by badgers and cattle to five water troughs was examined using motion-activated infra-red cameras in a farming landscape in Northern Ireland between May and July 2013. Cattle visit rates varied significantly across troughs, were greatest during daylight periods, and more frequent during dry weather. Badgers were recorded visiting only one of the five water troughs. These visits were recorded on 14 different nights between midnight and 0300 h and were mainly by individual badgers. Water troughs were not used concurrently by badgers and cattle and the minimum period between badger and cattle use was 3 days. Although badgers used water troughs rarely during the study there remains the potential for indirect transmission of a bacterium such as Mycobacterium bovis that may merit further investigation. PMID- 25458886 TI - Comparison of the effects of enteral psyllium, magnesium sulphate and their combination for removal of sand from the large colon of horses. AB - Prospective studies documenting the efficacy and side effects of medical treatment for colonic sand accumulation in horses are limited. The purpose of the study was to compare the effect of enteral administration of magnesium sulphate (MgSO4), psyllium mucilloid (psyllium), and a combination of MgSO4 and psyllium on the evacuation of large accumulations of sand in the large colon of adult horses. Thirty-four horses with naturally acquired, large sand accumulations (>5 cm * 15 cm) identified on abdominal radiography were randomly allocated to one of three treatment groups: (1) 1 g/kg psyllium (n = 12); (2) 1 g/kg MgSO4 (n = 10), or (3) their combination (n = 12). Treatments were administered once a day via nasogastric intubation and continued for a total of 4 days. Lateral radiographs of the ventral abdomen were repeated on day 4 of treatment. If the area of sand in the radiographic image was <25 cm(2) on day 4, the sand accumulation was considered resolved. Of 12 horses treated with a combination of psyllium and MgSO4, nine evacuated the sand from the ventral colon within 4 days. In comparison, only 3/12 horses treated with psyllium and 2/10 horses treated with MgSO4 resolved (both significantly different from the combination; P <0.05). Large accumulations of sand in the large colon of horses can be treated medically. Administering a combination of psyllium and MgSO4 via nasogastric intubation once daily for a total of 4 days was a more effective treatment than either constituent alone. PMID- 25458887 TI - Validation study of an interpolation method for calculating whole lung volumes and masses from reduced numbers of CT-images in ponies. AB - Quantitative computer tomographic analysis (qCTA) is an accurate but time intensive method used to quantify volume, mass and aeration of the lungs. The aim of this study was to validate a time efficient interpolation technique for application of qCTA in ponies. Forty-one thoracic computer tomographic (CT) scans obtained from eight anaesthetised ponies positioned in dorsal recumbency were included. Total lung volume and mass and their distribution into four compartments (non-aerated, poorly aerated, normally aerated and hyperaerated; defined based on the attenuation in Hounsfield Units) were determined for the entire lung from all 5 mm thick CT-images, 59 (55-66) per animal. An interpolation technique validated for use in humans was then applied to calculate qCTA results for lung volumes and masses from only 10, 12, and 14 selected CT images per scan. The time required for both procedures was recorded. Results were compared statistically using the Bland-Altman approach. The bias +/- 2 SD for total lung volume calculated from interpolation of 10, 12, and 14 CT-images was 1.2 +/- 5.8%, 0.1 +/- 3.5%, and 0.0 +/- 2.5%, respectively. The corresponding results for total lung mass were -1.1 +/- 5.9%, 0.0 +/- 3.5%, and 0.0 +/- 3.0%. The average time for analysis of one thoracic CT-scan using the interpolation method was 1.5-2 h compared to 8 h for analysis of all images of one complete thoracic CT-scan. The calculation of pulmonary qCTA data by interpolation from 12 CT-images was applicable for equine lung CT-scans and reduced the time required for analysis by 75%. PMID- 25458888 TI - Molecular typing of Streptococcus suis isolates from Iberian pigs: a comparison with isolates from common intensively-reared commercial pig breeds. AB - The Iberian pig (IP) is a traditional Spanish breed variety of the domestic pig (Sus scrofa domesticus) with high economic importance because of the value of the dry-cured products in national and international markets. The genetic characteristics of tonsillar and clinical Streptococcus suis isolates from the IP maintained under extensive or intensive management conditions were investigated. S. suis isolates from IP pigs were compared with S. suis isolates from intensively-farmed pigs of common breeds (CBP). S. suis was isolated from 48.4% of the IP tonsils examined, indicating wide distribution among IP pigs. Serotypes 1 (9.4%), 2 (8.6%) and 9 (7%) were the most commonly found, although a high percentage of S. suis isolates were not typeable by coagglutination testing. No significant differences in carrier rates or serotype diversity were observed between management systems, indicating that intensive farming does not influence S. suis colonisation. Both pulsed-field gel electrophoresis and multiple-locus variable number tandem repeat analysis showed a serotype-based distribution of S. suis IP isolates. Serotypes 1 and 2 S. suis isolates were grouped in the same cluster, whereas isolates of serotypes 9 and 7 were assigned to another cluster. All clinical and most tonsillar serotype 2 IP isolates were assigned to sequence type 1 (ST1) and exhibited the virulence genotype mrp+/epf+/sly+, indicating a high distribution of this genetic lineage among IP as well as a population of serotype 2 common to IPs and CBPs. The only clinical isolate of serotype 9 from IP was assigned to ST123, a sequence type associated with clinical isolates in CBPs in Spain. PMID- 25458889 TI - The amino-terminal region of the neuraminidase protein from avian H5N1 influenza virus is important for its biosynthetic transport to the host cell surface. AB - Influenza virus neuraminidase (NA) is a major viral envelope glycoprotein, which plays a critical role in viral infection. Although NA functional domains have been determined previously, the precise role of the amino acids located at the N terminus of avian H5N1 NA for protein expression and intracellular transport to the host plasma membrane is not fully understood. In the present study, a series of N-terminal truncation or deletion mutants of H5N1 NA were generated and their expression and intracellular trafficking were investigated. Protein expression from mutants NADelta20, NADelta35, NADelta40, NADelta7-20 and NADelta7-35 was undetectable by immunoblotting and by performing NA activity assays. Mutants NADelta6, NADelta11 and NADelta15-20 showed a marked decreased in protein expression, whereas mutants NADelta7-15 and NADelta15 displayed a slight increase in protein expression, compared with that of the native NA protein. These data suggest that amino acid residues 16-20 are vital for NA protein expression, while amino acids 7-15 might suppress NA protein expression. In deletion mutants NADelta7-15 and NADelta15 there was an accumulation of NA protein at the juxta nuclear region, with reduced expression of NA at the cell surface. Although active Cdc42 could promote transport of wild-type NA to the host cell surface, this member of the Rho family of GTPases failed to regulate transport of mutants NADelta7-15 and NADelta15. The results of the study reveal that amino acid residues 7-15 of H5N1 NA are critical for its biosynthetic transport to the host cell surface. PMID- 25458890 TI - Special Issue dedicated to Karl-Erich Jaeger on the occasion of his 60th birthday. PMID- 25458891 TI - Endogenous WNT signaling regulates hPSC-derived neural progenitor cell heterogeneity and specifies their regional identity. AB - Neural progenitor cells (NPCs) derived from human pluripotent stem cells (hPSCs) are a multipotent cell population that is capable of nearly indefinite expansion and subsequent differentiation into the various neuronal and supporting cell types that comprise the CNS. However, current protocols for differentiating NPCs toward neuronal lineages result in a mixture of neurons from various regions of the CNS. In this study, we determined that endogenous WNT signaling is a primary contributor to the heterogeneity observed in NPC cultures and neuronal differentiation. Furthermore, exogenous manipulation of WNT signaling during neural differentiation, through either activation or inhibition, reduces this heterogeneity in NPC cultures, thereby promoting the formation of regionally homogeneous NPC and neuronal cultures. The ability to manipulate WNT signaling to generate regionally specific NPCs and neurons will be useful for studying human neural development and will greatly enhance the translational potential of hPSCs for neural-related therapies. PMID- 25458892 TI - p19 INK4d controls hematopoietic stem cells in a cell-autonomous manner during genotoxic stress and through the microenvironment during aging. AB - Hematopoietic stem cells (HSCs) are characterized by the capacity for self renewal and the ability to reconstitute the entire hematopoietic compartment. Thrombopoietin maintains adult HSCs in a quiescent state through the induction of cell cycle inhibitors p57(Kip2) and p19(INK4d). Using the p19(INK4d-/-) mouse model, we investigated the role of p19(INK4d) in basal and stress-induced hematopoiesis. We demonstrate that p19(INK4d) is involved in the regulation of HSC quiescence by inhibition of the G0/G1 cell cycle transition. Under genotoxic stress conditions, the absence of p19(INK4d) in HSCs leads to accelerated cell cycle exit, accumulation of DNA double-strand breaks, and apoptosis when cells progress to the S/G2-M stages of the cell cycle. Moreover, p19(INK4d) controls the HSC microenvironment through negative regulation of megakaryopoiesis. Deletion of p19(INK4d) results in megakaryocyte hyperproliferation and increased transforming growth factor beta1 secretion. This leads to fibrosis in the bone marrow and spleen, followed by loss of HSCs during aging. PMID- 25458893 TI - Characterization of Cre recombinase activity for in vivo targeting of adipocyte precursor cells. AB - The increased incidence of obesity and metabolic disease underscores the importance of elucidating the biology of adipose tissue development. The recent discovery of cell surface markers for prospective identification of adipose precursor cells (APCs) in vivo will greatly facilitate these studies, yet tools for specifically targeting these cells in vivo have not been identified. Here, we survey three transgenic mouse lines, Fabp4-Cre, PdgfRalpha-Cre, and Prx1-Cre, precisely assessing Cre-mediated recombination in adipose stromal populations and mature tissues. Our data provide key insights into the utility of these tools to modulate gene expression in adipose tissues. In particular, Fabp4-Cre is not effective to target APCs, nor is its activity restricted to these cells. PdgfRalpha-Cre directs recombination in the vast majority of APCs, but also targets other populations. In contrast, adipose expression of Prx1-Cre is chiefly limited to subcutaneous inguinal APCs, which will be valuable for dissection of APC functions among adipose depots. PMID- 25458894 TI - Fast and efficient neural conversion of human hematopoietic cells. AB - Neurons obtained directly from human somatic cells hold great promise for disease modeling and drug screening. Available protocols rely on overexpression of transcription factors using integrative vectors and are often slow, complex, and inefficient. We report a fast and efficient approach for generating induced neural cells (iNCs) directly from human hematopoietic cells using Sendai virus. Upon SOX2 and c-MYC expression, CD133-positive cord blood cells rapidly adopt a neuroepithelial morphology and exhibit high expansion capacity. Under defined neurogenic culture conditions, they express mature neuronal markers and fire spontaneous action potentials that can be modulated with neurotransmitters. SOX2 and c-MYC are also sufficient to convert peripheral blood mononuclear cells into iNCs. However, the conversion process is less efficient and resulting iNCs have limited expansion capacity and electrophysiological activity upon differentiation. Our study demonstrates rapid and efficient generation of iNCs from hematopoietic cells while underscoring the impact of target cells on conversion efficiency. PMID- 25458895 TI - Sox2-mediated conversion of NG2 glia into induced neurons in the injured adult cerebral cortex. AB - The adult cerebral cortex lacks the capacity to replace degenerated neurons following traumatic injury. Conversion of nonneuronal cells into induced neurons has been proposed as an innovative strategy toward brain repair. Here, we show that retrovirus-mediated expression of the transcription factors Sox2 and Ascl1, but strikingly also Sox2 alone, can induce the conversion of genetically fate mapped NG2 glia into induced doublecortin (DCX)(+) neurons in the adult mouse cerebral cortex following stab wound injury in vivo. In contrast, lentiviral expression of Sox2 in the unlesioned cortex failed to convert oligodendroglial and astroglial cells into DCX(+) cells. Neurons induced following injury mature morphologically and some acquire NeuN while losing DCX. Patch-clamp recording of slices containing Sox2- and/or Ascl1-transduced cells revealed that a substantial fraction of these cells receive synaptic inputs from neurons neighboring the injury site. Thus, NG2 glia represent a potential target for reprogramming strategies toward cortical repair. PMID- 25458896 TI - An expandable, inducible hemangioblast state regulated by fibroblast growth factor. AB - During development, the hematopoietic and vascular lineages are thought to descend from common mesodermal progenitors called hemangioblasts. Here we identify six transcription factors, Gata2, Lmo2, Mycn, Pitx2, Sox17, and Tal1, that "trap" murine cells in a proliferative state and endow them with a hemangioblast potential. These "expandable" hemangioblasts (eHBs) are capable, once released from the control of the ectopic factors, to give rise to functional endothelial cells, multilineage hematopoietic cells, and smooth muscle cells. The eHBs can be derived from embryonic stem cells, from fetal liver cells, or poorly from fibroblasts. The eHBs reveal a central role for fibroblast growth factor, which not only promotes their expansion, but also facilitates their ability to give rise to endothelial cells and leukocytes, but not erythrocytes. This study serves as a demonstration that ephemeral progenitor states can be harnessed in vitro, enabling the creation of tractable progenitor cell lines. PMID- 25458899 TI - Determining the fatty acid composition in plasma and tissues as fatty acid methyl esters using gas chromatography - a comparison of different derivatization and extraction procedures. AB - Analysis of the fatty acid (FA) composition in biological samples is commonly carried out using gas liquid chromatography (GC) after transesterification to volatile FA methyl esters (FAME). We compared the efficacy of six frequently used protocols for derivatization of different lipid classes as well as for plasma and tissue samples. Transesterification with trimethylsulfonium hydroxide (TMSH) led to insufficient derivatization efficacies for polyunsaturated FAs (PUFA, <50%). Derivatization in presence of potassium hydroxide (KOH) failed at derivatizing free FAs (FFAs). Boron trifluoride (BF3) 7% in hexane/MeOH (1:1) was insufficient for the transesterification of cholesterol ester (CE) as well as triacylglycerols (TGs). In contrast, methanolic hydrochloric acid (HCl) as well as a combination of BF3 with methanolic sodium hydroxide (NaOH+BF3) were suitable for the derivatization of FFAs, polar lipids, TGs, and CEs (derivatization rate >80% for all tested lipids). Regarding plasma samples, all methods led to an overall similar relative FA pattern. However, significant differences were observed, for example, for the relative amount of EPA+DHA (n3-index). Absolute FA plasma concentrations differed considerably among the methods, with low yields for KOH and BF3. We also demonstrate that lipid extraction with tert-butyl methyl ether/methanol (MTBE/MeOH) is as efficient as the classical method according to Bligh and Dyer, making it possible to replace (environmentally) toxic chloroform.We conclude that HCl-catalyzed derivatization in combination with MeOH/MTBE extraction is the most appropriate among the methods tested for the analysis of FA concentrations and FA pattern in small biological samples. A detailed protocol for the analysis of plasma and tissues is included in this article. PMID- 25458898 TI - Enterocyte fatty acid-binding proteins (FABPs): different functions of liver and intestinal FABPs in the intestine. AB - Fatty acid-binding proteins (FABP) are highly abundant cytosolic proteins that are expressed in most mammalian tissues. In the intestinal enterocyte, both liver (LFABP; FABP1) and intestinal FABPs (IFABP; FABP2) are expressed. These proteins display high-affinity binding for long-chain fatty acids (FA) and other hydrophobic ligands; thus, they are believed to be involved with uptake and trafficking of lipids in the intestine. In vitro studies have identified differences in ligand-binding stoichiometry and specificity, and in mechanisms of FA transfer to membranes, and it has been hypothesized that LFABP and IFABP have different functions in the enterocyte. Studies directly comparing LFABP- and IFABP-null mice have revealed markedly different phenotypes, indicating that these proteins indeed have different functions in intestinal lipid metabolism and whole body energy homeostasis. In this review, we discuss the evolving knowledge of the functions of LFABP and IFABP in the intestinal enterocyte. PMID- 25458900 TI - Wound healing effects of new 15-hydroxyprostaglandin dehydrogenase inhibitors. AB - Previously, we reported that the antidiabetic drug ciglitazone and its analogs were potent inhibitors of 15-hydroxyprostaglandin dehydrogenase (15-PGDH). In continuing attempts to develop highly potent 15-PGDH inhibitors, a series of thiazolidinedione analogs were synthesized and tested. Compound 17 exhibited IC50 of 45 nM. This compound also significantly increased levels of prostaglandin E2 (PGE2) in A549 cells by approximately eight-fold that in the control. Much experimental data suggests that PGE2 plays a role in the prevention of excessive scarring. However, it has a very short half-life in blood, its oxidization to 15 ketoprostaglandins is catalyzed by 15-PGDH. Therefore, 15-PGDH inhibitors may have utility for the therapeutic management of diseases requiring elevated PGE2 levels. Scratch wounds were analyzed in confluent monolayers of HaCaT cells. Cells exposed to compound 17 showed significantly improved wound healing with respect to a control. PMID- 25458897 TI - A miR-590/Acvr2a/Rad51b axis regulates DNA damage repair during mESC proliferation. AB - Embryonic stem cells (ESCs) enable rapid proliferation that also causes DNA damage. To maintain genomic stabilization during rapid proliferation, ESCs must have an efficient system to repress genotoxic stress. Here, we show that withdrawal of leukemia inhibitory factor (LIF), which maintains the self-renewal capability of mouse ESCs (mESCs), significantly inhibits the cell proliferation and DNA damage of mESCs and upregulates the expression of miR-590. miR-590 promotes single-strand break (SSB) and double-strand break (DSB) damage repair, thus slowing proliferation of mESCs without influencing stemness. miR-590 directly targets Activin receptor type 2a (Acvr2a) to mediate Activin signaling. We identified the homologous recombination-mediated repair (HRR) gene, Rad51b, as a downstream molecule of the miR-590/Acvr2a pathway regulating the SSB and DSB damage repair and cell cycle. Our study shows that a miR-590/Acvr2a/Rad51b signaling axis ensures the stabilization of mESCs by balancing DNA damage repair and rapid proliferation during self-renewal. PMID- 25458903 TI - Implementation of a simple electronic transfusion alert system decreases inappropriate ordering of packed red blood cells and plasma in a multi-hospital health care system. AB - BACKGROUND AND OBJECTIVES: Prescriber adherence to institutional blood component ordering guidelines can be low. The goal of this study was to decrease red blood cell (RBC) and plasma orders that did not meet institutional transfusion guidelines by using data within the laboratory information system to trigger alerts in the computerized order entry (CPOE) system at the time of order entry. METHODS: At 10 hospitals within a regional health care system, discernment rules were created for RBC and plasma orders utilizing transfusion triggers of hemoglobin <8 gm/dl and INR >1.6, respectively, with subsequent alert generation that appears within the CPOE system when a prescriber attempts to order RBCs or plasma on a patient whose antecedent laboratory values do not suggest that a transfusion is indicated. Orders and subsequent alerts were tracked for RBCs and plasma over evaluation periods of 15 and 10 months, respectively, along with the hospital credentials of the ordering health care providers (physician or nurse). RESULTS: Alerts triggered which were heeded remained steady and averaged 11.3% for RBCs and 19.6% for plasma over the evaluation periods. Overall, nurses and physicians canceled statistically identical percentages of alerted RBC (10.9% vs. 11.5%; p = 0.78) and plasma (21.3% vs. 18.7%; p = 0.22) orders. CONCLUSIONS: Implementing a simple evidence-based transfusion alert system at the time of order entry decreased non-evidence based transfusion orders by both nurse and physician providers. PMID- 25458904 TI - Transfusion-related acute lung injury in paediatric surgical patients: a retrospective study. AB - BACKGROUND: Little is known about the occurrence of transfusion-related acute lung injury(TRALI) in Chinese paediatric patients. As such, a retrospective review of medical records from January 2008 to December 2011 was undertaken. OBJECTIVE: To determine the incidence of TRALI and its risk factors in children (age <14 years). STUDY DESIGN AND METHODS: All medical records of Sheng Jing Hospital from January 2008 to December 2011 were reviewed retrospectively using the hospital's record system. Paediatric surgical patients who had been diagnosed clinically with acute lung injury were included. Transfusion data were collected, together with risk factors such as sepsis and aspiration. RESULTS: In total, 1495 patients were involved in the study. Thirty-five cases were analysed further as they had acute lung injury, pulmonary oedema and respiratory distress. TRALI was confirmed in two of these cases. The average duration of transfusion was found to be significantly longer in patients with TRALI compared with controls, and the percentage of female donors was significantly higher for patients with TRALI. CONCLUSION: The incidence of TRALI was found to be lower than reported previously, but TRALI is under-recognised, under-reported and undertreated. PMID- 25458905 TI - Quality innovation network quality improvement organizations' (QIN-QIOs') benefits to skilled nursing facilities and physicians. PMID- 25458901 TI - Microfluidics-to-mass spectrometry: a review of coupling methods and applications. AB - Microfluidic devices offer great advantages in integrating sample processes, minimizing sample and reagent volumes, and increasing analysis speed, while mass spectrometry detection provides high information content, is sensitive, and can be used in quantitative analyses. The coupling of microfluidic devices to mass spectrometers is becoming more common with the strengths of both systems being combined to analyze precious and complex samples. This review summarizes select achievements published between 2010 and July 2014 in novel coupling between microfluidic devices and mass spectrometers. The review is subdivided by the types of ionization sources employed, and the different microfluidic systems used. PMID- 25458906 TI - The use of critical reflection in clinical practice and health profession education. PMID- 25458907 TI - Nursing home telepsychiatry. PMID- 25458908 TI - Introduction to innate sensing and response to pathogens (part 2). PMID- 25458909 TI - High-efficiency multiplex genome editing of Streptomyces species using an engineered CRISPR/Cas system. AB - Actinobacteria, particularly those of genus Streptomyces, remain invaluable hosts for the discovery and engineering of natural products and their cognate biosynthetic pathways. However, genetic manipulation of these bacteria is often labor and time intensive. Here, we present an engineered CRISPR/Cas system for rapid multiplex genome editing of Streptomyces strains, demonstrating targeted chromosomal deletions in three different Streptomyces species and of various sizes (ranging from 20 bp to 30 kb) with efficiency ranging from 70 to 100%. The designed pCRISPomyces plasmids are amenable to assembly of spacers and editing templates via Golden Gate assembly and isothermal assembly (or traditional digestion/ligation), respectively, allowing rapid plasmid construction to target any genomic locus of interest. As such, the pCRISPomyces system represents a powerful new tool for genome editing in Streptomyces. PMID- 25458911 TI - Histone deacetylase 6 inhibition impairs effector CD8 T-cell functions during skin inflammation. AB - BACKGROUND: Broad-spectrum histone deacetylase (HDAC) inhibitors are useful in the treatment of allergic and autoimmune diseases and malignancy. However, use of more specific HDAC inhibitors might limit the toxicities caused by HDAC inhibition. HDAC6, a member of the HDAC family, is highly expressed on CD8 T cells and has been shown to regulate immune responses through interactions between T cells and antigen-presenting cells. However, the mechanism by which HDAC6 inhibition affects the activation and functions of CD8 T cells is unclear. OBJECTIVES: We investigated the role or roles of HDAC6 in CD8 T-cell activation and functions during skin inflammation in vitro and in vivo and examined the mechanism by which HDAC6 inhibition modifies T-cell receptor signaling in vitro. METHODS: We assessed the clinical and biological effects of ACY-1215, an HDAC6 specific inhibitor, by using murine CD8 T cell-related skin disease models, including contact hypersensitivity (CHS) and experimental graft-versus-host disease (GVHD)-like disease. RESULTS: ACY-1215, an HDAC6 inhibitor, prevented the development of CHS and GVHD-like disease in vivo by modulating CD8 T-cell activation and functions; abrogated the induction of effector T cells from naive CD8 T cells by means of anti-CD3/CD28 antibody- or antigen-specific stimulation in vitro; and enhanced the binding of acetylated heat shock protein 90 to lymphocyte-specific protein tyrosine kinase in vitro, disrupting lymphocyte specific protein tyrosine kinase phosphorylation and leading to impairment of the mitogen-activated protein kinase pathway. CONCLUSION: HDAC6, a key modifier of T cell receptor signaling, might represent a novel target for the treatment of CD8 T cell-related skin diseases, including CHS and GVHD. PMID- 25458910 TI - Randomized trial to evaluate azithromycin's effects on serum and upper airway IL 8 levels and recurrent wheezing in infants with respiratory syncytial virus bronchiolitis. AB - BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis in infancy is a major risk factor for recurrent wheezing and asthma. Because azithromycin attenuated neutrophilic airway inflammation in a murine viral bronchiolitis model, demonstration of similar effects in human subjects might provide a strategy for the prevention of postbronchiolitis recurrent wheezing. OBJECTIVES: We sought to investigate whether azithromycin treatment during RSV bronchiolitis reduces serum and nasal lavage IL-8 levels and the occurrence of postbronchiolitis recurrent wheezing. METHOD: We performed a randomized, double-masked, placebo-controlled proof-of-concept trial in 40 otherwise healthy infants hospitalized with RSV bronchiolitis who were treated with azithromycin or placebo for 14 days. IL-8 levels were measured in nasal lavage fluid and serum on randomization, day 8, and day 15 (nasal lavage only). The occurrence of wheezing episodes was assessed monthly over the ensuing 50 weeks. RESULTS: Compared with placebo, azithromycin treatment did not reduce serum IL-8 levels at day 8 (P = .6) but resulted in a greater decrease in nasal lavage fluid IL-8 levels by day 15 (P = .03). Twenty two percent of azithromycin-treated participants experienced at least 3 wheezing episodes compared with 50% of participants in the placebo group (P = .07). Azithromycin treatment resulted in prolonged time to the third wheezing episode (P = .048) and in fewer days with respiratory symptoms over the subsequent year in comparison with placebo (36.7 vs 70.1 days, P = .01). CONCLUSION: In this proof-of-concept study azithromycin treatment during RSV bronchiolitis reduced upper airway IL-8 levels, prolonged the time to the third wheezing episode, and reduced overall respiratory morbidity over the subsequent year. PMID- 25458912 TI - Whole-exome sequencing in patients with ichthyosis reveals modifiers associated with increased IgE levels and allergic sensitizations. PMID- 25458913 TI - Immunologic basis for allopurinol-induced severe cutaneous adverse reactions: HLA B*58:01-restricted activation of drug-specific T cells and molecular interaction. PMID- 25458914 TI - Meeting report VLPNPV: Session 10: Virus-like particle and nano-particle vaccines. AB - Session 10 of the Virus-like Particle and Nano-Particle Vaccines meeting 2014 focused on new methods in vaccine technology to accelerate process development, manufacturing and quality control. The session presented new ways of quantifying and characterizing particle samples. In addition platform approaches for production and purification of virus-like particle (VLP) vaccines were highlighted. PMID- 25458915 TI - Tetracycline improved the efficiency of other antimicrobials against Gram negative multidrug-resistant bacteria. AB - Treatment of infectious diseases with antimicrobials constituted a great achievement in the history of medicine. Unfortunately, the emergence of resistant strains of bacteria to all classes of antimicrobials limited their efficacy. The present study was aimed at evaluating the effect of combinations of antibiotics on multi-drug resistant Gram-negative (MDRGN) bacteria. A liquid micro-broth dilution method was used to evaluate the antibacterial activity of 10 different classes of antimicrobials on 20 bacterial strains belonging to six different species. The antimicrobials were associated with phenylalanine beta-naphthylamide (PAbetaN), an efflux pump inhibitor, and with other antimicrobials at their sub inhibitory concentrations. The effectiveness of each combination was monitored using the minimal inhibitory concentration (MIC) and the fractional inhibitory concentration (FIC). Most of the antimicrobials tested showed low antibacterial activity with a MIC value of 128 mg/L on a majority of the bacterial strains, justifying their multidrug-resistant (MDR) profile. Synergistic effects were mostly observed (FIC<=0.5) when ampicillin (AMP), cloxacillin (CLX), erythromycin (ERY), chloramphenicol (CHL), kanamycin (KAN) and streptomycin (STR) were combined with tetracycline (TET) at the sub-inhibitory concentration of MIC/5 or MIC/10. The results of the present work suggest that the association of several antimicrobials with TET could improve the fight against MDRGN bacterial species. PMID- 25458916 TI - Molecular investigation of Staphylococcus aureus isolated from the patients, personnel, air and environment of an ICU in a hospital in Tehran. AB - BACKGROUND: The aim of this study was to determine the prevalence and characteristics of Staphylococcus aureus isolates from the patients, staff, air and environments of an ICU in a hospital in Tehran. MATERIALS AND METHODS: During this study, 37 S. aureus isolates were collected and analyzed via the spa typing method. RESULTS: Of the 37 S. aureus isolates, 35 (94%) were methicillin resistant (MRSA), 28 (76%) were identified as SCCmec types III or IIIA, four (10%) were identified as SCCmec types I or IA and three (8%) were identified a SCCmec type IV. All of the MRSA isolates were resistant to oxacillin and contained mecA. The isolates were all spa typed and found to comprise 11 spa types, including t7688, t7689, and t7789, which have not previously been reported. The spa type t7688 was isolated from the hands of two ICU personnel. The spa type t7689 was observed among five isolates from the air and the environment. The spa type t7789 was observed among three isolates from the patients, ventilators and the air. The majority of the isolates (43%) belonged to spa types t030 and t037. CONCLUSION: Our results revealed that MRSA strains that were isolated from the air, the environment of the ICU and the patients who were colonized or infected with MRSA often exhibited the same spa and SCCmec types. These results also reveal that the isolates from the patients and environment were usually indistinguishable. PMID- 25458918 TI - Disparities in viral load and CD4 count trends among HIV-infected adults in South Carolina. AB - On a population level, trends in viral load (VL) and CD4 cell counts can provide a marker of infectivity and an indirect measure of retention in care. Thus, observing the trend of CD4/VL over time can provide useful information on disparities in populations across the HIV care continuum when stratified by demography. South Carolina (SC) maintains electronic records of all CD4 cell counts and HIV VL measurements reported to the state health department. We examined temporal trends in individual HIV VLs reported in SC between January 1, 2005 and December 31, 2012 by using mixed effects models adjusting for gender, race/ethnicity, age, baseline CD4 count, HIV risk category, and residence. Overall VL levels gradually decreased over the observation period. There were significant differences in the VL decline by gender, age groups, rural/urban residence, and HIV risk exposure group. There were significant differences in CD4 increases by race/ethnicity, age groups, and HIV risk exposure group. However, the population VL declines were slower among individuals aged 13-19 years compared to older age groups (p<0.0001), among men compared to women (p=0.002), and among people living with HIV/AIDS (PLWHA) with CD4 count <=200 cell/mm(3) compared to those with higher CD4 counts (p<0.0001). Significant disparities were observed in VL decline by gender, age, and CD4 counts among PLWHA in SC. Population based data such as these can help streamline and better target local resources to facilitate retention in care and adherence to medications among PLWHA. PMID- 25458919 TI - Personal day-time exposure to ultrafine particles in different microenvironments. AB - In order to assess the personal exposure to ultrafine particles (UFP) during individual day-time activities and to investigate the impact of different microenvironments on exposure, we measured personal exposure to particle number concentrations (PNC), a surrogate for UFP, among 112 non-smoking participants in Augsburg, Germany over a nearly two-year period from March 2007 to December 2008. We obtained 337 personal PNC measurements from 112 participants together with dairies of their activities and locations. The measurements lasted on average 5.5h and contained on average 330 observations. In addition, ambient PNC were measured at an urban background stationary monitoring site. Personal PNC were highly variable between measurements (IQR of mean: 11780-24650cm(-3)) and also within a single measurement. Outdoor personal PNC in traffic environments were about two times higher than in non-traffic environments. Higher indoor personal PNC were associated with activities like cooking, being in a bistro or exposure to passive smoking. Overall, personal and stationary PNC were weakly to moderately correlated (r<0.41). Personal PNC were much higher than stationary PNC in traffic (ratio: 1.5), when shopping (ratio: 2.4), and indoors with water vapor (ratio: 2.5). Additive mixed models were applied to predict personal PNC by participants' activities and locations. Traffic microenvironments were significant determinants for outdoor personal PNC. Being in a bistro, passive smoking, and cooking contributed significantly to an increased indoor personal PNC. PMID- 25458921 TI - Ionic Dynamics in [C4mim]NTf2 in the Glassy and Liquid States: Results from 13C and 1H NMR Spectroscopy. AB - The ionic dynamics of the room temperature ionic liquid 1-butyl-3 methylimdiazolium bis((trifluoromethyl)sulfonyl)amide ([C(4)mim]NTf(2)) is studied using (13)C and (1)H nuclear magnetic resonance (NMR) spectroscopy over a wide temperature range encompassing the glassy and liquid states. The temperature dependence of the (13)C spin-lattice relaxation time is analyzed with four different models to derive the rotational dynamics of the RTIL in the nano to picosecond range. It was found that the extended model-free approach bridges the data obtained from the BPP and DC models, and describes ion dynamics of the RTIL well. Three different motions are observed based on the approach: an overall ion rotation, a slow and a fast local rotational motion. The time scale of the slow local rotational motion, particularly of the imidazolium ring carbons, is strongly coupled to the time scale of the overall ion rotation, above the melting point. Below the melting point these two time scales show strong decoupling and the local rotation displays nanosecond dynamics in the glassy state. The analyses of the second moment (M(2)) of the (1)H and (13)C nuclides indicate that, in addition to the axial rotations of the two methyl groups (cation) and the CF(3) group (anion), all (13)C sites including the imidazolium ring carbon and CF(3) show evidence of mobility, even in the glassy state. PMID- 25458922 TI - [SemFYC preparing for Horizon 2020]. PMID- 25458923 TI - [The conciliation and electronic prescription]. PMID- 25458917 TI - Dual roles of NRF2 in tumor prevention and progression: possible implications in cancer treatment. AB - The cap'n'collar (CNC) family serves as cellular sensors of oxidative and electrophilic stresses and shares structural similarities including basic leucine zipper (bZIP) and CNC domains. They form heterodimers with small MAF proteins to regulate antioxidant and phase II enzymes through antioxidant response element (ARE)-mediated transactivation. Among the CNC family members, NRF2 is required for systemic protection against redox-mediated injury and carcinogenesis. On the other hand, NRF2 is activated by oncogenic pathways, metabolism, and hypoxia. Constitutive NRF2 activation is observed in a variety of human cancers and it is highly correlated with tumor progression and aggressiveness. In this review, we will discuss how NRF2 plays dual roles in cancer prevention and progression depending on the cellular context and environment. Therefore, a better understanding of NRF2 will be necessary to exploit this complex network of balancing antioxidant pathways to inhibit tumor progression. PMID- 25458924 TI - No shortcut solution to the problem of Y-STR match probability calculation. AB - Match probability calculation is deemed much more intricate for lineage genetic markers, including Y-chromosomal short tandem repeats (Y-STRs), than for autosomal markers. This is because, owing to the lack of recombination, strong interdependence between markers is likely, which implies that haplotype frequency estimates cannot simply be obtained through the multiplication of allele frequency estimates. As yet, however, the practical relevance of this problem has not been studied in much detail using real data. In fact, such scrutiny appears well warranted because the high mutation rates of Y-STRs and the possibility of backward mutation should have worked against the statistical association of Y STRs. We examined haplotype data of 21 markers included in the PowerPlex((r))Y23 set (PPY23, Promega Corporation, Madison, WI) originating from six different populations (four European and two Asian). Assessing the conditional entropies of the markers, given different subsets of markers from the same panel, we demonstrate that the PowerPlex((r))Y23 set cannot be decomposed into smaller marker subsets that would be (conditionally) independent. Nevertheless, in all six populations, >94% of the joint entropy of the 21 markers is explained by the seven most rapidly mutating markers. Although this result might render a reduction in marker number a sensible option for practical casework, the partial haplotypes would still be almost as diverse as the full haplotypes. Therefore, match probability calculation remains difficult and calls for the improvement of currently available methods of haplotype frequency estimation. PMID- 25458925 TI - Amelogenin test abnormalities revealed in Belarusian population during forensic DNA analysis. AB - Study of gender markers is a part of routine forensic genetic examination of crime scene and reference samples, paternity testing and personal identification. Amelogenin locus as a gender marker is included in majority of forensic STR kits of different manufacturers. In current study we report 11 cases of amelogenin abnormalities identified in males of Belarusian origin: 9 cases of AMELY dropout and 2 cases of AMELX dropout. Cases were obtained from forensic casework (n=9) and paternity testing (n=2) groups. In 4 out of 9 AMELY-negative cases deletion of AMELY was associated with the loss of DYS458 marker. In addition, we identified 3 males with SRY-positive XX male syndrome. Deletion of the long arm of the Y-chromosome was detected in two XX males. Loss of the major part of the Y chromosome was identified in the third XX male. The presence of two X-chromosomes in XX males was confirmed with the use of Mentype((r)) Argus X-8 PCR Amplification Kit. AMELY null allele observed in 2 out of 9 cases with AMELY dropout can be caused by mutation in the primer-binding site of AMELY allele. Primer-binding site mutations of AMELX can result in AMELX dropout identified in 2 cases with amplification failure of AMELX. Our study represents the first report and molecular genetic investigation of amelogenin abnormalities in the Belarusian population. PMID- 25458926 TI - Y-STR analysis of digital and/or penile penetration cases with no detected spermatozoa. AB - This forensic casework trial involved Yfiler((r)) testing samples from 47 digital and/or penile penetration cases where the medical examination had occurred within 48h of the alleged incident and no spermatozoa had been detected following Sperm Elution((c)). 30% of these cases yielded at least one Y-STR profile comprising three or more alleles per profile and 21% yielded at least one Y-STR profile of ten or more alleles per profile. This trial further investigated the persistence of male DNA in different case types, the location of samples submitted for testing and whether samples from different locations benefit from being combined prior to testing. The data supports the use of Y-STR profiling to provide scientific evidence to investigate whether the alleged sexual activity had occurred as well as to obtain probative evidence in spermatozoa negative penetration cases. PMID- 25458920 TI - Hypothalamic microinflammation: a common basis of metabolic syndrome and aging. AB - Chronic microinflammation is a hallmark of many aging-related neurodegenerative diseases as well as metabolic syndrome-driven diseases. Recent research indicates that chronic caloric excess can lead to hypothalamic microinflammation, which in turn participates in the development and progression of metabolic syndrome disorders such as obesity, glucose intolerance, and hypertension. Additionally, it was recently shown that increasing age after young adulthood can cause hypothalamic microinflammation independently of nutritional status, mediating a central mechanism of systemic aging. Taken together, these findings suggest that the hypothalamus has a fundamental role, via hypothalamic microinflammation, in translating overnutrition and aging into complex outcomes. Here we summarize recent work and suggest a conceptual model in which hypothalamic microinflammation is a common mediator of metabolic syndrome and aging. PMID- 25458927 TI - Genetic profile of 17 Y-chromosome STR haplotypes in East of Iran. PMID- 25458939 TI - Francis Galton's saltationism and the ambiguities of selection. PMID- 25458947 TI - Implementation of a novel track-based pediatric residency training program. PMID- 25458948 TI - 50 years ago in the Journal of Pediatrics: The effect of alkali and glucose infusion on permanent brain damage in rhesus monkeys asphyxiated at birth. PMID- 25458949 TI - 50 years ago in the Journal of Pediatrics: The epidemiology of prematurity. PMID- 25458950 TI - 50 years ago in the Journal of Pediatrics: Familial extrahepatic biliary atresia? PMID- 25458951 TI - Learning across borders: Advocacy of pediatricians in public health response during a recent wild poliovirus transmission in Israel. PMID- 25458952 TI - MicroRNA-320b promotes colorectal cancer proliferation and invasion by competing with its homologous microRNA-320a. AB - Colorectal cancer metastasis is believed to be associated with microRNA dysregulation. However, little is known as to how microRNAs regulate colorectal cancer proliferation, invasion and metastasis. In the present study, we compared the microRNA expression profiles between patients of colorectal cancer at diagnosis with and without liver metastasis. MicroRNA-320b was found to be among those up-regulated in the patient group with metastasis. We subsequently found that microRNA-320b, opposite of its homolog, microRNA-320a that differs by only a single nucleotide, functions in promoting colorectal cancer cell proliferation and invasion. Moreover, we found that overexpression of exogenous microRNA-320b can up-regulate the target genes of microRNA-320a including beta-catenin, Neuropilin-1 and Rac-1, which are all known to promote tumor proliferation, invasion and metastasis. These results suggest that microRNA-320b may function in competing with microRNA-320a. Thus, our study has proposed one novel mechanism for controlling colorectal cancer proliferation and invasion through homologous competition between microRNAs. This mechanism may be important for colorectal cancer metastasis. PMID- 25458953 TI - CIP2A cooperates with H-Ras to promote epithelial-mesenchymal transition in cervical-cancer progression. AB - The oncoprotein Cancerous Inhibitor of PP2A (CIP2A) has been reported to interact with Protein phosphatase 2 (PP2A) to stabilize c-Myc and prevent its degradation, and high expression levels of CIP2A have been proved to be related to poor clinical outcomes in multiple cancers. Here, we not only proved that the expression of CIP2A is positively correlated with lymph-node metastasis and cervical-cancer progression, but also revealed a close correlation between the protein's expression and the expression levels of two core epithelial-to mesenchymal transition (EMT) markers, Vimentin and Snail. In addition, we manipulated CIP2A expression to regulate EMT conversion and employed a pull-down assay, mass-spectrometric (MS) peptide sequencing, as well as bilateral co immunoprecipitation to identify potentially interacting proteins in cervical cancer cells. In this study, we proposed and successfully proved, for the first time, that CIP2A physically associates with H-Ras, which leads to the activation of the MEK/ERK signaling pathway and promotes EMT and cervical-cancer progression. Based on our observations and prior findings that CIP2A participates in c-Myc regulation, we conjecture that CIP2A may be a potentially promising molecular target for the adoptive therapy of human cancer. PMID- 25458955 TI - Guidelines for diagnostics and treatment of aromatase inhibitor-induced bone loss in women with breast cancer: a consensus of Lithuanian medical oncologists, radiation oncologists, endocrinologists, and family medicine physicians. AB - The aim of this article is to inform about cancer treatment-induced bone loss, to identify patients at risk and those that can benefit from bone targeted treatment as well as highlight the importance of the multidisciplinary approach in the bone health in cancer care. Patients with breast cancer treated or intended to be treated with aromatase inhibitors belong to a high-risk group because their fracture risk increases up to 30% due to a significant decrease in bone mineral density within 6-12 months after the start of hormonal treatment. To evaluate bone status and predict risk for fractures, lateral thoracic and lumbar spine X ray imaging, bone mineral density measurement by dual energy X-ray absorptiometry at the lumbar spine L1-L4 vertebrae and/or hip and fracture risk factors assessment are mandatory tests prior to hormonal treatment. Morbidity and mortality associated with bone loss can be prevented with appropriate screening, lifestyle interventions, and therapy. Algorithm for the management of bone health in breast cancer patients was established in Lithuania to screen patients with increased risk for bone loss and to provide adequate specific osteoporosis treatment. PMID- 25458954 TI - Synergistic antitumor interactions between MK-1775 and panobinostat in preclinical models of pancreatic cancer. AB - Pancreatic cancer remains a clinical challenge, thus new therapies are urgently needed. The selective Wee1 inhibitor MK-1775 has demonstrated promising results when combined with DNA damaging agents, and more recently with CHK1 inhibitors in various malignancies. We have previously demonstrated that treatment with the pan histone deacetylase inhibitor panobinostat (LBH589) can cause down-regulation of CHK1. Accordingly, we investigated using panobinostat to down-regulate CHK1 in combination with MK-1775 to enhance cell death in preclinical pancreatic cancer models. We demonstrate that MK-1775 treatment results in increased H2AX phosphorylation, indicating increased DNA double-strand breaks, and activation of CHK1, which are both dependent on CDK activity. Combination of MK-1775 and panobinostat resulted in synergistic antitumor activity in six pancreatic cancer cell lines. Finally, our in vivo study using a pancreatic xenograft model reveals promising cooperative antitumor activity between MK-1775 and panobinostat. Our study provides compelling evidence that the combination of MK-1775 and panobinostat has antitumor activity in preclinical models of pancreatic cancer and supports the clinical development of panobinostat in combination with MK-1775 for the treatment of this deadly disease. PMID- 25458956 TI - Significance of blood serum catalase activity and malondialdehyde level for survival prognosis of ovarian cancer patients. AB - BACKGROUND AND OBJECTIVE: Several markers were found to be potential prognostic factors in ovarian cancer. Among markers resembling systemic changes in the host's organism are markers of the oxidative stress. In this study we attempted to analyze the oxidant and antioxidant parameters of ovarian cancer patients. MATERIALS AND METHODS: A total of 42 patients with newly diagnosed stages I-IV primary ovary cancer were examined. Level of malondialdehyde (MDA) and catalytic activity catalase (CAT) were determined spectrophotometrically. RESULTS: Significantly lower CAT (28.2+/-15.5 vs. 36.1+/-14.6nmol/L/min, P=0.019) activity and higher MDA levels (8.7+/-3.0 vs. 6.7+/-2.7nmol/L, P=0.002) were observed in cancer patients compared with healthy volunteers. Both variables were not confirmed as prognostic factors according to Kaplan-Meier survival estimates. CONCLUSIONS: MDA and CAT demonstrate oxidative stress in cancer patients: CAT activity was significantly lower and MDA levels higher in cancer patients compared to healthy controls. These variables were not confirmed to be prognostic factors in ovarian cancer, possibly due to small size of the study group. PMID- 25458957 TI - Nevomelanocytic atypia detection by in vivo reflectance confocal microscopy. AB - BACKGROUND AND OBJECTIVE: In vivo reflectance confocal microscopy (RCM) is a promising novel technology for non-invasive early diagnostics of cutaneous melanoma. However, the possibility to detect melanocytic atypia in nevi by means of in vivo RCM remains unknown. The aim of the study was to evaluate the significance of in vivo RCM features of melanocytic atypia for the diagnosis of melanocytic nevi, dysplastic nevi and cutaneous melanoma. MATERIALS AND METHODS: A total of 138 melanocytic skin lesions comprising 25 melanocytic nevi, 69 dysplastic nevi and 44 melanomas were analyzed by means of dermoscopy, in vivo RCM and routine histopathology. In vivo RCM images were analyzed for the arrangement of keratinocytes in epidermis, pagetoid cells and junctional melanocytic nests and correlated refractivity aspects of nests with histopathology. RESULTS: Separately and all together taken the in vivo RCM features of melanocytic atypia were significant in differential diagnosis of benign and malignant melanocytic skin lesions, though none of the features was significant in discriminating nevi without cytologic atypia of dysplastic nevi. In vivo RCM feature of dense cell clusters corresponded with melanin containing nevomelanocytes on histopathology though exact correspondence of non-homogeneous and atypical sparse cell clusters remained questionable. CONCLUSIONS: Nevus with histopathologically confirmed nevomelanocytic atypia (dysplastic nevus) could not be distinguished from nevus without atypia using analyzed in vivo RCM features of melanocytic atypia. More accurate diagnostics by means of in vivo RCM needs further investigation on reflectance of single and nested cutaneous melanocytes in benign and malignant skin lesions. PMID- 25458958 TI - Impact of microsatellite instability on survival of endometrial cancer patients. AB - BACKGROUND AND OBJECTIVE: Endometrial cancer (EC) is the most commonly diagnosed gynecologic malignancy among women worldwide and may be classified on the basis of different molecular, pathologic and genetic alterations, including microsatellite instability (MSI). Although MSI is associated with a more favorable outcome in colorectal cancer, its relationship with prognosis in EC cancer is not yet clear. The aim of our study is to identify whether MSI correlates with survival of patients in EC. MATERIALS AND METHODS: We examined MSI status and survival of 109 women. MSI was detected by employing the Promega MSI Analysis System, which used 5 mononucleotides markers (BAT-25, BAT-26, NR-21, NR-24, and MONO-27) to identify MSI in a tumor and normal tissue DNA and 2 pentanucleotide markers (Penta C and Penta D) for specimen identification. Median follow-up of patients was 40.4 months (range 5.2-47.9). Survival was estimated by the Kaplan-Meier method and Cox regression analysis was used to assess the effects of different variables on patient survival. RESULTS: MSI-high was detected in 15.6% EC cases, all of which were associated with endometrioid type histology. Kaplan-Meier survival analysis showed no statistically significant differences between patients with MSI-high and MSI stable tumors (P=0.4) and multivariate analysis concluded that MSI status remained insignificant after stage, histology and tumor grade adjustment (P=0.5). CONCLUSIONS: Our study showed no statistically significant relationship between MSI-high and survival of endometrial cancer patients. PMID- 25458960 TI - Postmastectomy internal mammary nodal irradiation: a long-term outcome. AB - BACKGROUND AND OBJECTIVE: The internal mammary lymph nodes (IMN) have been recognized as a potential site of regional breast cancer spread. The aim of this study was to evaluate the impact of internal mammary node radiotherapy (RT) to on clinical outcomes in breast cancer patients treated with mastectomy and postoperative radiation therapy. MATERIALS AND METHODS: This cohort study included 588 patients with breast cancers located in the central and medial quadrants. IMN RT was applied to 320 patients and 268 patients did not receive it IMN RT. Inside the IMN RT group, 165 patients received external beam IMN irradiation (IMN-EB). Mastectomy combined with using Californium-252 neutron source implantation was applied to 155 patients (IMN-BT). Cox proportional hazards modeling was used to determine the influence of IMN RT on clinical outcome. Age, tumor size, lymph nodal status, adjuvant radiotherapy, chemotherapy and hormonal therapy were assessed. RESULTS: IMN-EB resulted in a significant improvement of distant metastasis-free survival, breast cancer-specific survival and overall survival (P=0.033, P=0.037 and P=0.011, respectively). The IMN-EB radiotherapy has a significant impact on event-free survival (HR, 0.67; 95% CI, 0.46-0.91; P=0.043) and breast cancer-specific survival (HR, 0.64; 95% CI, 45 0.91; P=0.013) in patients with moderate-risk (stage T1-2N1). There was no association between IMN RT and clinical outcomes of patients with high-risk disease (stage T3-4N2-3) in any of the study end points. CONCLUSIONS: The effects of IMN-EB radiotherapy on event-free survival and breast cancer-specific survival were benefit for women with moderate-risk breast cancer. PMID- 25458959 TI - The significance of reduced glutathione and glutathione S-transferase during chemoradiotherapy of locally advanced cervical cancer. AB - BACKGROUND AND OBJECTIVE: To determine changes in reduced glutathione (GSH) and glutathione S-transferase (GST) during neoadjuvant chemotherapy followed by concurrent chemoradiation for patients with stage IIB-IIIB cervical cancer, and to evaluate their significance to the efficacy of the treatment. MATERIALS AND METHODS: According to the prospective phase II study protocol, 36 patients with stage IIB-IIIB cervical cancer were enrolled. A short course of intensive weekly neoadjuvant cisplatin and gemcitabine chemotherapy followed by concurrent weekly cisplatin and gemcitabine-based chemoradiation was administered. Blood samples for GSH, GST analysis were collected and analyzed before the start of the treatment, after neoadjuvant chemotherapy, and after the end of the chemoradiation. RESULTS: A statistically significant increase in the concentration of GSH after neoadjuvant chemotherapy was identified. After chemoradiation, values of this rate significantly decreased in contrast with GSH concentration after neoadjuvant chemotherapy in cases of stage IIB, regional metastases negative patients group, patients with a positive response to treatment, and patients who had no progression of the disease during the first 2 years after treatment. Statistically significant changes in GST during the treatment were not identified; the GST concentration after chemoradiation showed a statistically significant difference in GST concentrations in terms of the progression of the disease and disease without progression. CONCLUSIONS: The results suggest that changes in the concentration of GSH during the treatment of locally advanced cervical cancer might be important for the prediction of the efficacy of the treatment. Statistically significant changes in GST concentration levels during the treatment were not observed. PMID- 25458961 TI - Accumulation and biological effects of cobalt ferrite nanoparticles in human pancreatic and ovarian cancer cells. AB - BACKGROUND AND OBJECTIVE: Superparamagnetic iron oxide nanoparticles (SPIONs) emerge as a promising tool for early cancer diagnostics and targeted therapy. However, both toxicity and biological activity of SPIONs should be evaluated in detail. The aim of this study was to synthesize superparamagnetic cobalt ferrite nanoparticles (Co-SPIONs), and to investigate their uptake, toxicity and effects on cancer stem-like properties in human pancreatic cancer cell line MiaPaCa2 and human ovarian cancer cell line A2780. MATERIALS AND METHODS: Co-SPIONs were produced by Massart's co-precipitation method. The cells were treated with Co SPIONs at three different concentrations (0.095, 0.48, and 0.95MUg/mL) for 24 and 48h. Cell viability and proliferation were analyzed after treatment. The stem like properties of cells were assessed by investigating the cell clonogenicity and expression of cancer stem cell-associated markers, including CD24/ESA in A2780 cell line and CD44/ALDH1 in MiaPaCa2 cell line. Magnetically activated cell sorting was used for the separation of magnetically labeled and unlabeled cells. RESULTS: Both cancer cell lines accumulated Co-SPIONs, however differences in response to nanoparticles were observed between MiaPaCa2 and A2780 cell. In particular, A2780 cells were more sensitive to exposition to Co-SPIONs than MiaPaCa2 cells, indicating that a safe concentration of nanoparticles must be estimated individually for a particular cell type. Higher doses of Co-SPIONs decreased both the clonogenicity and ESA marker expression in A2780 cells. CONCLUSIONS: Co-SPIONs are not cytotoxic to cancer cells, at least when used at a concentration of up to 0.95MUg/mL. Co-SPIONs have a dose-dependent effect on the clonogenic potential and ESA marker expression in A2780 cells. Magnetic detection of low concentrations of Co-SPIONS in cancer cells is a promising tool for further applications of these nanoparticles in cancer diagnosis and treatment; however, extensive research in this field is needed. PMID- 25458962 TI - Early prediction of response to cetuximab and radiotherapy by FDG-PET/CT for the treatment of a locoregionally advanced squamous cell carcinoma of the hypopharynx. AB - Cetuximab (CTX) is used for the concurrent treatment with radiotherapy (RT) in squamous cell carcinoma of head and neck (HNSCC). There are no reliable clinical predictive markers of effectiveness of CTX at yet. We describe the clinical case of patient who received a CTX/RT to cure locoregionally advanced hypopharyngeal SCC. 2-Deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography and computed tomography ((18)FDG-PET/CT) was performed before the treatment and repeated 10 days after CTX induction dose. A repeated (18)FDG-PET/CT scan showed dramatic decrease of metabolic parameters. Patient had a complete response after treatment and is still alive and cured after 5 years. PMID- 25458963 TI - Sacral insufficiency fracture after pelvic radiotherapy: a diagnostic challenge for a radiologist. AB - Sacral insufficiency fractures can occur as a complication after pelvic radiotherapy. Despite several recent studies showing high incidence of sacral insufficiency fractures in elderly women after pelvic radiotherapy this condition still remains underdiagnosed. We present a case of sudden onset of low back pain in a female patient with a history of cervical cancer radiotherapy. Initial diagnostic imaging misinterpreted SIF for metastasis. Bone scan and single-photon emission-computed tomography with low-dose computed tomography revealed the correct diagnosis. Due to the reasons that sacral insufficiency fractures still remain underdiagnosed this report is important to practical routine work of oncologists and radiologists. PMID- 25458964 TI - Our bodies, our choices: Australian law on foetal personhood. AB - The debate revolving around foetal vs maternal rights has been philosophised for years. It has captured attention internationally with the European Court of Human Rights struggling for over five decades to define personhood, and is still yet to reach a definite formulation. A proposed Law Crimes Amendment Bill (Zoe's Law, 2) is currently fuelling public debate about women's reproductive choices in New South Wales, Australia. The proposed legal bill attempts to redefine a 'person' or 'human being' by placing a marker on when 'personhood begins' namely at 20 weeks or weighing a minimum of 400g. Similar laws recognising personhood at foetal viability have come into force in the United States of America that clearly show the broader consequences of this kind of legislation as American women now face county-by-county, state-by-state anti-choice legislative activism. Midwives work closely with women and their families giving them the authority to formulate opinions on issues of maternal-foetal conflict. If a law such as this is allowed to pass a number of legal and ethical issues will arise for Australian midwives that could potentially have far reaching implications for them and for the women and families that they provide women-centred care for. PMID- 25458966 TI - Term and preterm labour are associated with distinct microbial community structures in placental membranes which are independent of mode of delivery. AB - Infection is considered a possible trigger for preterm labour, supported by evidence showing the presence of bacteria in the placenta and placental membranes from preterm births. In this study, 16S rDNA pyrosequencing was used to identify bacteria in placental membranes. Caesarean sections and vaginal deliveries at term were found to harbour common genera. Mycoplasma hominis, Aerococcus christensenii, Gardnerella vaginalis and Fusobacterium nucleatum were either only present in preterm membranes or in greater abundance than at term. These data support previous studies that used either targeted qPCR or broad-range 16S rDNA PCR and cloning but not a recent microbiome analysis of placental tissue using high-throughput sequencing. PMID- 25458965 TI - Comparison of placental findings in type 1 and type 2 diabetic pregnancies. AB - INTRODUCTION: The aim of this study is to compare placental pathology and related clinical parameters between gravidas with type 1 and type 2 pregestational diabetes. METHODS: This is a retrospective cohort study of women with singleton gestations and pregestational diabetes who delivered at Women and Infants Hospital from 2003 to 2011. Pathology reports, maternal and neonatal outcomes were extracted and compared between the two groups. RESULTS: In our cohort, 293 pregnancies were studied, including 117 with type 1 diabetes and 176 with type 2 diabetes. Women with type 1 diabetes had worse glycemic control during pregnancy, as characterized by higher HbA1c values and average fasting and postprandial blood sugars. More infants from the type 1 group were admitted to Neonatal ICU. Pregestational diabetes led to small for gestational age (SGA) placentas in nearly 20% pregnancies and large for gestational age (LGA) placentas in 30% of cases. Both groups shared similar incidences of preeclampsia and significant placental pathology related to uteroplacental (maternal) and fetal circulatory disorders; however, maternal decidual vasculopathy and placentas with insufficiency (fetal-to-placental weight ratio < 10th %tile) were more commonly found in placentas from women with type 2 diabetes. DISCUSSION: Both types of pregestational diabetes have significant impact on placental growth and development. The comparison between the two groups suggests different pathogenetic mechanisms and may be helpful for better management of diabetic pregnancy. PMID- 25458967 TI - Pathophysiological mechanisms regulated by cytokines in gliomas. AB - Glioma, a neuroglia originated malignancy, consists of one of the most aggressive primary tumors of the central nervous system with poor prognosis and lack of efficient treatment strategy. Cytokines have been implicated in several stages of glioma progression, participating in tumor onset, growth enhancement, angiogenesis and aggressiveness. Interestingly, cytokines have also the ability to inhibit glioma growth upon specific regulation or interplay with other molecules. This review addresses the dual role of major cytokines implicated in glioma pathology, pointing toward promising therapeutic approaches. PMID- 25458969 TI - Abdominal visceral adiposity influences CD4+ T cell cytokine production in pregnancy. AB - Women with pre-gravid obesity are at risk for pregnancy complications. While the macrophage response of obese pregnant women categorized by body mass index (BMI) has been documented, the relationship between the peripheral CD4(+) T cell cytokine profile and body fat compartments during pregnancy is unknown. In this study, third trimester peripheral CD4(+) T cell cytokine profiles were measured in healthy pregnant women [n=35; pre-pregnancy BMI: 18.5-40]. CD4(+) T cells were isolated from peripheral blood mononuclear cells and stimulated to examine their capacity to generate cytokines. Between 1 and 3weeks postpartum, total body fat was determined by dual-energy X-ray absorptiometry and abdominal subcutaneous and visceral fat masses were determined by magnetic resonance imaging. Pearson's correlation was performed to assess relationships between cytokines and fat mass. Results showed that greater abdominal visceral fat mass was associated with a decrease in stimulated CD4(+) T cell cytokine expression. IFN-gamma, TNF-alpha, IL-12p70, IL-10 and IL-17A were inversely related to visceral fat mass. Chemokines CCL3 and IL-8 and growth factors G-CSF and FLT-3L were also inversely correlated. Additionally, total body fat mass was inversely correlated with FGF-2 while abdominal subcutaneous fat mass and BMI were unrelated to any CD4(+) T cell cytokine. In conclusion, lower responsiveness of CD4(+) T cell cytokines associated with abdominal visceral fat mass is a novel finding late in gestation. PMID- 25458971 TI - Impact of a pay for performance programme on French GPs' consultation length. AB - BACKGROUND: In 2009, a voluntary-based pay for performance scheme targeting general practitioners (GPs) was introduced in France through the 'Contract for Improving Individual Practices' (CAPI). OBJECTIVE: To study the impact of the CAPI on French GPs' consultation length. METHODS: Univariate analysis, and multilevel regression analyses were performed to disentangle the different sources of the consultation length variability (intra and inter physician). The dependant variable was the logarithm of the consultation length. Independent variables included patient's sociodemographics as well as the characteristics of GPs and their medical activity. RESULTS: Between November 2011 and April 2012, 128 physicians were recruited throughout France and generated 20,779 consultations timed by residents. The average consultation length in the sample was 16.8 min. After adjusting for patients' characteristics only, the consultation length of CAPI signatories was 14.1% lower than that observed for non signatories (p<0.001). After adjusting for GPs' characteristics and the case mix, the CAPI was no longer a significant predictor of the consultation length. The results did not change significantly from one type of consultation to another. CONCLUSION: Although the CAPI was extended to all GPs in 2012, our results provide a cautionary message to regulators about its ability to generate higher quality of care. PMID- 25458970 TI - A regulatory governance perspective on health technology assessment (HTA) in France: the contextual mediation of common functional pressures. AB - The new regulatory governance perspective has introduced several insights to the study of health technology assessment (HTA): it has broadened the scope for the analysis of HTA; it has provided a more sophisticated account of national diversity and the potential for cross-border policy learning; and, it has dissolved the distinction between HTA assessment and appraisal processes. In this paper, we undertake a qualitative study of the French process for HTA with a view to introducing a fourth insight: that the emergence and continuing function of national agencies for HTA follows a broadly evolutionary pattern in which contextual factors play an important mediating role. We demonstrate that the French process for HTA is characterised by distinctive institutions, processes and evidential requirements. Consistent with the mediating role of this divergent policy context, we argue that even initiatives for the harmonisation of national approaches to HTA are likely to meet with divergent national policy responses. PMID- 25458972 TI - First- and fifth-year medical students' intention for emigration and practice abroad: a case study of Serbia. AB - Health worker migration is causing profound health, safety, social, economic and political challenges to countries without special policies for health professionals' mobility. This study describes the prevalence of migration intentions among medical undergraduates, identifies underlying factors related to migration intention and describes subsequent actions in Serbia. Data were captured by survey of 938 medical students from Belgrade University (94% response rate), representing two thirds of matching students in Serbia stated their intentions, reasons and obstacles regarding work abroad. Statistical analyses included descriptive statistics and a sequential multivariate logistic regression. Based on descriptive and inferential statistics we were able to predict the profile of first and fifth year medical students who intend or have plans to work abroad. This study contributes to our understanding of the causes and correlates of intent to migrate and could serve to raise awareness and point to the valuable policy options to manage migration. PMID- 25458973 TI - Patient-centered communication strategies for patients with aphasia: discrepancies between what patients want and what physicians do. AB - BACKGROUND: Communication during clinical encounters can be challenging with patients with communication disabilities. Physicians have the potential to positively affect the encounter by using communication strategies that engage the patient in patient-centered communication. OBJECTIVE: We engaged patients and their physicians in defining their preferences for patient-centered communication strategies, then evaluated the use of the identified strategies during observed clinical encounters. METHODS: We video-recorded 25 clinical encounters with persons with aphasia. All encounters were previously scheduled with community physicians and a companion was present. Following each encounter, physicians completed a brief questionnaire and the person with aphasia and his or her companion participated in a video elicitation interview. RESULTS: While many of the communication strategies identified and described by physicians, patients and companions were similar, patients and companions identified three additional key communication strategies. These strategies included (1) using visual aids, (2) writing down key words while speaking, and (3) using gestures. In the video recorded clinical encounters, no physicians wrote down key words while speaking and only one used a visual aid during the clinical encounter. The frequency with which physicians used gestures varied greatly, even within the same patient, suggesting the use of gestures was independent of patient or companion characteristics. CONCLUSIONS: To maximize patient-centered communication with patients with communication disabilities, physicians should use "disability specific" communication strategies. Our study suggests that physicians should routinely ask patients and companions about communication preferences and then incorporate identified communication strategies into their communication style. PMID- 25458974 TI - The occurrence of the cervical pain syndromes in parents of children with physical disability in the population of Poland. AB - BACKGROUND: Pain in the cervical spine area is one of the main health problems of inhabitants of Western Europe. The necessity of parents' taking care of a child with physical disability is connected with parents' exposure to the factors affecting the risk of occurrence of pain in the cervical spine. OBJECTIVE: The objective of this study was to analyze whether there are differences in the occurrence of cervical spine pain between the group of parents of children with physical disability and parents of children without a disability. METHOD: The research included a group of parents of school-aged children with physical disability (n = 47) and a group of parents of children without disability (n = 69), aged between 29 and 60 years from the Silesian Voivodeship (Poland). The people taking part in the research were asked to complete two questionnaires: Visual Analogue Scale (VAS) for the cervical spine and Neck Disability Index (NDI) questionnaire. Means, standard deviations, and ranges to compare scores across groups were calculated. RESULTS: The mean VAS score among parents of children with physical disability was 4.22 (SD = 3.23) compared to 2.16 (SD = 2.31; p < .001) among parents of children without physical disability. Similarly, mean NDI scores were 19.6 (SD = 15.12) and 9.68 (SD = 8.84; p < .001), respectively. CONCLUSIONS: The parents of children with physical disability are to a greater extent exposed to the occurrence of cervical spine pain. Therefore, suitable training as regards ergonomics, especially during lifting, transferring and transporting children might be beneficial to these parents. PMID- 25458968 TI - T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. AB - CD4(+) T helper (Th) cells are critical for proper immune cell homeostasis and host defense, but are also major contributors to pathology of autoimmune and inflammatory diseases. Since the discovery of the Th1/Th2 dichotomy, many additional Th subsets were discovered, each with a unique cytokine profile, functional properties, and presumed role in autoimmune tissue pathology. This includes Th1, Th2, Th17, Th22, Th9, and Treg cells which are characterized by specific cytokine profiles. Cytokines produced by these Th subsets play a critical role in immune cell differentiation, effector subset commitment, and in directing the effector response. Cytokines are often categorized into proinflammatory and anti-inflammatory cytokines and linked to Th subsets expressing them. This article reviews the different Th subsets in terms of cytokine profiles, how these cytokines influence and shape the immune response, and their relative roles in promoting pathology in autoimmune and inflammatory diseases. Furthermore, we will discuss whether Th cell pathogenicity can be defined solely based on their cytokine profiles and whether rigid definition of a Th cell subset by its cytokine profile is helpful. PMID- 25458975 TI - Increased risk of unintentional injuries in adults with disabilities: a systematic review and meta-analysis. AB - BACKGROUND: An increased risk of unintentional injuries among individuals with disability has been reported in many studies, yet quantitative syntheses of findings from previous studies have not been done. OBJECTIVES: We conducted a systematic review and meta-analysis to characterize the relationship between pre existing disability and unintentional injuries. METHODS: We searched 14 electronic databases to identify original research published between Jan 1, 1990 and Feb 28, 2013. Included studies reported the odds ratio (OR) or relative risk (RR) of unintentional injuries in adults 18+ years of age with pre-existing disabilities compared with adults without disabilities. Twenty six eligible studies were included covering 54,586 individuals with disabilities. We conducted quality assessments and then analyzed the pooled effects using random-effect models. RESULTS: The pooled OR of unintentional injuries was 1.77 (95% CI 1.51 2.07) for all studies in individuals with disabilities compared with individuals without disabilities. The pooled ORs were 1.87 (95% CI 1.52-2.30) for overall unintentional injuries, 1.64 (95% CI 1.39-1.94) for falls-related injuries, 1.62 (95% CI 1.24-2.13) for occupational injuries, and 1.91 (95% CI 1.59-2.30) for non occupational injuries. CONCLUSIONS: Compared with adults without disabilities, individuals with disabilities are at a significantly higher risk of unintentional injuries. Evidence about the association between cognitive disabilities and unintentional injuries is weak. Future researchers are encouraged to use International Classification of Functioning, Disability and Health (ICF) to classify disability and use rigorous evaluation methods to assess and implement the most appropriate injury prevention efforts to mitigate the risks identified. PMID- 25458976 TI - Disability and unmet health care needs in Canada: a longitudinal analysis. AB - BACKGROUND: The rate of unmet health care needs is quite high for the general population in Canada; however, the rate is even higher for the subset of people with disabilities. To date, there is a gap in the research utilizing longitudinal data to measure the unmet health care needs of Canadians. OBJECTIVE/HYPOTHESIS: The purpose of this research is to compare the rate of unmet health care needs of people with disabilities to people without disabilities over 15 years. METHODS: Longitudinal data from waves 1 to 8 (1994/95 to 2008/09) of the National Population Health Survey in Canada (NPHS) were analyzed using a growth curve modeling approach. RESULTS: Respondents with disabilities have two to three times the rate of unmet health care needs compared to respondents without disabilities. Unmet health care needs increase over time, and at a faster rate for all disability types except work-related disability. Personal reasons for unmet health care needs decrease over time and there is no significant difference between respondents with disabilities and respondents without disabilities. The opposite was found for structural reasons, which increase over time, and, people with disabilities have higher rates of structural-based unmet health care needs (45% higher) at baseline. CONCLUSIONS: The incidence of disability in the population increases over time while at the same time the rate of unmet health care needs are higher for people with disabilities. The combination of these factors suggests that, in the absence of intervention, Canadians can expect more unmet health care needs in the future. PMID- 25458978 TI - Sport participation among individuals with acquired physical disabilities: group differences on demographic, disability, and Health Action Process Approach constructs. AB - BACKGROUND: Despite numerous physical, social, and mental health benefits of engaging in moderate and vigorous intensity physical activities (e.g., sport), few individuals with acquired physical disabilities currently participate in adapted sport. Theory-based sport promotion interventions are one possible way to increase the amount of individuals who engage in sport. OBJECTIVES: The primary objective of this study was to examine the profiles of three different sport participation groups with respect to demographic, injury, and Health Action Process Approach (HAPA) constructs. METHODS: ANOVAs and Chi-square tests were used to determine group differences on demographic and disability-related constructs. A MANCOVA was conducted to determine differences between three sport participation groups (non-intenders, intenders, and actors) with age, years post injury, mode of mobility, and sex included as covariates. RESULTS: A cohort of 201 individuals was recruited; 56 (27.9%) were non-intenders, 21 (10.4%) were intenders, and 124 (61.7%) were actors. The MANCOVA revealed significant differences between groups on the HAPA constructs, F(22,370) = 9.02, p < .0001, Pillai's trace = .70, demonstrating that individuals with acquired physical disabilities will rate important health behavior constructs differently based on their sport intentions. CONCLUSION: These results provide an important framework that adapted sport organizations can use to tailor their sport promotion programs. PMID- 25458977 TI - The relationship between body composition and femoral neck osteoporosis or osteopenia in adults with previous poliomyelitis. AB - BACKGROUND: Articles in the literature describing the association between body composition and osteoporosis in subjects with poliomyelitis are scarce. OBJECTIVE: To assess the relationship between body composition and femoral neck osteoporosis or osteopenia in adults with previous polio. METHOD: After excluding postmenopausal women, 44 polio (mean age +/- standard deviation, 46.1 +/- 3.3 years) and 44 able-bodied control volunteers (47.0 +/- 4.0 years) participated in the study. Each participant's femoral neck bone mineral density (FNBMD) and whole body composition were measured using dual-energy X-ray absorptiometry. With local reference BMD values of normal young adults installed in the instrument, we obtained T-score values that depended on each FNBMD value. A T-score value of <= 1.0 indicated decreased T-score, including osteoporosis (T-score <= -2.5) and osteopenia (-1.0 to -2.5). This study conducted logistic regression analyses to find factors associated with osteoporosis and osteopenia. RESULTS: Based on the FNBMD T-score values, 60.0% of middle-aged men with polio had osteoporosis. In adjusted logistic regression analyses, total lean tissue mass (Adjusted odds ratio [95% confidence interval], 0.74 [0.56-0.99], P < 0.05) and male gender (947.16 [6.02-148,926.16], P < 0.01) were important factors associated with decreased T-score in polio group. CONCLUSIONS: Osteoporosis or osteopenia is a common medical problem for middle-aged men with polio. Reduced total lean tissue mass seems to be one of the important factors associated with osteoporosis or osteopenia among subjects with polio. Further research for a clinical tool to assess lean tissue mass for subjects with polio is needed. PMID- 25458979 TI - Transfusion for shock in US military war casualties with and without tourniquet use. AB - STUDY OBJECTIVE: We assess whether emergency tourniquet use for transfused war casualties admitted to military hospitals is associated with survival. METHODS: A retrospective review of trauma registry data was made of US casualties in Afghanistan and Iraq. Patients with major limb trauma, transfusion, and tourniquet use were compared with similar patients who did not receive tourniquet use. A propensity-matching analysis was performed by stratifying for injury type and severity by tourniquet-use status. Additionally, direct comparison without propensity matching was made between tourniquet use and no-tourniquet use groups. RESULTS: There were 720 casualties in the tourniquet use and 693 in the no tourniquet use groups. Of the 1,413 casualties, 66% (928) also had nonextremity injury. Casualties with tourniquet use had worse signs of hemorrhagic shock (admission base deficit, admission hemoglobin, admission pulse, and transfusion units required) than those without. Survival rates were similar between the 2 groups (1% difference; 95% confidence interval -2.5% to 4.2%), but casualties who received tourniquets had worse shock and received more blood products. In propensity-matched casualties, survival rates were not different (2% difference; 95% confidence interval -6.7% to 2.7%) between the 2 groups. CONCLUSION: Tourniquet use was associated with worse shock and more transfusion requirements among hospital-admitted casualties, yet those who received tourniquets had survival rates similar to those of comparable, transfused casualties who did not receive tourniquets. PMID- 25458980 TI - A randomized trial on subject tolerance and the adverse effects associated with higher- versus lower-flow oxygen through a standard nasal cannula. AB - STUDY OBJECTIVE: Experts advocate the use of a standard nasal cannula to provide oxygen at flow rates of up to 15 L/minute during emergency intubation. However, because of concerns about potential patient discomfort, some providers avoid providing nasal cannula oxygen at flow rates greater than 6 L/minute. This trial is designed to determine the participants' ability to tolerate 10 minutes of nasal cannula oxygen at higher flow rates. METHODS: This was a prospective, randomized, crossover trial of healthy volunteers at an emergency department in New Zealand. Participants were randomized to first receive either higher-flow (15 L/minute) or lower-flow (6 L/minute) nasal cannula oxygen for 10 minutes. After a 1-hour washout period, they received the alternate flow rate for 10 minutes. The primary outcome was the ability to tolerate 10 minutes of the nasal cannula oxygen at each flow rate. The secondary outcome was the difference in discomfort between the flow rates as measured on a 100-mm visual analog scale. RESULTS: All 77 of the participants (100%) were able to tolerate 10 minutes at both flow rates. Participants rated the higher-flow nasal cannula oxygen as a mean of 25 mm (SD 20 mm) more uncomfortable than the lower-flow nasal cannula oxygen. One minute after the oxygen was discontinued, the mean difference in discomfort between the flow rates was a clinically insignificant 9.8 mm (SD 17 mm) more uncomfortable. There were no adverse events. CONCLUSION: Participants were able to tolerate higher-flow nasal cannula oxygen for 10 minutes without difficulty. Higher-flow nasal cannula oxygen at 15 L/minute was associated with some discomfort, but the discomfort quickly dissipated and caused no adverse events. PMID- 25458981 TI - Repeated emergency department visits among children admitted with meningitis or septicemia: a population-based study. AB - STUDY OBJECTIVE: Early diagnosis of children with meningitis or septicemia remains a significant challenge in emergency medicine. We seek to describe the frequency of repeated emergency department (ED) visits among children admitted with meningitis or septicemia in Ontario, Canada. METHODS: In this retrospective cohort study, using health administrative data, we included all children aged 30 days to 5 years who were hospitalized with a final diagnosis of meningitis or septicemia in Ontario between 2005 and 2010. ED visits at any hospital in the preceding 5 days were identified as potential repeated ED visits. We used generalized estimating equations to model the association of sex, age, triage score, immunocompromised state, visit timing, type of ED, and annual patient volume on the risk of repeated ED visits. RESULTS: Of 521 children, 114 (21.9%) had repeated ED visits before admission. Children admitted on initial visit and those with repeated visits had similar median lengths of stay (13 versus 12 days), critical care use (21.1% versus 16.7%), and mortality (mean 2.9%). One in 3 children repeating visits returned to a different hospital. Repeated visits were associated with older age, a less acute triage score, and initial visit to a community hospital without available pediatric consultation. CONCLUSION: In this cohort, repeated ED visits among children with meningitis or septicemia were common, yet they had health outcomes similar to those of children admitted on initial visit. One in 3 returned to a different ED, making it unlikely that EDs and clinicians can learn from these critical events without a regionalized reporting system. PMID- 25458982 TI - Continuous infusion of recombinant factor VIII formulated with sucrose in surgery: non-interventional, observational study in patients with severe haemophilia A. AB - In haemophilia A, continuous infusion (CI) of FVIII perioperatively provides a more constant FVIII level than conventional bolus injections, avoiding low trough levels that could increase bleeding risk. Due to the low number of surgical cases in clinical trials, especially in haemophilia, more information on the clinical practice of CI from observational studies is helpful. We aimed to evaluate the effectiveness and safety of CI with recombinant factor VIII formulated with sucrose (rFVIII-FS) in a typical surgery practice setting. This was a non interventional study in 12 centres. Patients with severe haemophilia A who received rFVIII-FS by CI during and after surgery were included in this study if they had more than 150 exposure days (EDs) to any FVIII product and had no history of inhibitors before CI. Patients were observed during the entire course of CI, with monitoring up to 3 months thereafter. Twenty-five patients with 28 surgeries were included in the analysis. Median age was 51.7 (range 10-75). Most (75%; 21/25) patients underwent orthopaedic surgeries. The median dose of rFVIII FS consumed during CI was 376 IU kg(-1) (range 157.9-3605.6 IU kg(-1)) with a greater median dose for orthopaedic surgeries (424.0 IU kg(-1)) compared to non orthopaedic surgeries (278.5 IU kg(-1)). 95% of all FVIII measurements (214/224) were on target. Efficacy and tolerability were rated as good/excellent in 89.3% (25/28) of surgeries. No inhibitors were observed during or after surgery. This study demonstrates the effectiveness of CI with rFVIII-FS during surgery in patients with severe haemophilia A in a clinical practice setting. PMID- 25458983 TI - Seroprevalency of transfusion-transmitted infections in first-time volunteer and replacement donors in Tunisia. AB - BACKGROUND: Replacement donors are considered as having a major risk of transmission of infections to recipients mainly by the World Health Organisation. STUDY DESIGN AND METHODS: Seroprevalency of HBV, HCV, HIV and syphilis were determined in 19,783 whole blood donations collected in the Tunisian National Blood Transfusion Centre during the year 2010 (12,968 [65.55%] replacement donations and 6815 [34.44%] voluntary blood donations). For HBV, HCV and syphilis, we performed a univariate analysis to determine whether age, sex and type of donation were risk factors, then multivariate logistic regression, to see if these factors were independent. RESULTS: Mean age of donors was 30.1 years (replacement donors 34.5 years, first time non-remunerated donors 34.5 years, P<0.001). The predominant age group was 30-39 years (35.51%) in replacement donors and 20-29 years (54.15%) in first time non-remunerated donors. Male gender was significantly predominant (73.00% men vs 27.00% women, P<10(-6)). There were significantly more men among replacement donors (82.27% vs 55.38%, P<10(-3)). There were more women in the age groups 18-19 and 20-29 years. Only one HIV seropositive donation was noted in a male first time non-remunerated donor aged 18. Replacement type of donation, male sex and age were three independent risk factors for the HBs Ag carriage. For anti-HCV antibodies and TPHA, only replacement type of donation and age were found out to be risk factors and only age was independent. CONCLUSION: In Tunisia, replacement blood donors were at higher risk of infection transmission, but only for hepatitis B. PMID- 25458984 TI - [Clinico-biological and immunohaematological profile of patients with beta thalassemia in Tunisia: about 26 cases]. AB - AIM OF THE STUDY: To study the clinical and biological profile of beta thalassemic patients in our region, reflecting the quality of their care. PATIENTS AND METHODS: A retrospective study (2010-2011) on 26 beta-thalassemic patients followed in the pediatrics service at CHU Farhat Hached Sousse, Tunisia. Epidemiological, clinical and biological data were collected from medical records and transfusion files of patients. The transfusion protocol adopted was to maintain a hemoglobin level>10g/dL by regular transfusions every 3-4 weeks. Iron chelation therapy, in order to maintain serum ferritin<1500ng/mL, was introduced when serum ferritin exceeded 800-1000ng/mL. RESULTS: The mean age of patients at diagnosis was 15 months. The clinical impact of anemia had resulted in failure to thrive in 54% of patients and facial dysmorphism in 23%. The average transfusion requirement was estimated at 311.02mL/kg/year with 6 cases of hyperconsumption. The immunohaematological monitoring showed the appearance of anti-RBC alloimmunization in one patient and 4 cases of autoimmunization. Poor adherence of chelation therapy was 62% and causing 5 cases of cardiac complications, 4 cases of liver injury and 14 cases of endocrine complications. CONCLUSION: Improving the therapeutic care of beta-thalassemic children requires better monitoring of transfusion recovery and improved adherence to chelation therapy. PMID- 25458985 TI - RHD positive among C/E+ and D-negative blood donors in Tunisia. AB - PURPOSE OF THE STUDY: The aim of this study was to investigate RHD alleles among Tunisian blood donors with D-negative phenotype and positive for C and/or E antigen. PATIENTS AND METHODS: A total of 100 D-negative and C/E+ samples were analyzed by RHD genotyping using an initial test for RHD exon 10. In case of a positive reaction, further molecular investigations including real time quantitative PCR, allele specific PCR and nucleotide sequencing were done to elucidate the RHD involved mechanisms. RESULTS: Seventy-five percent of the studied samples lacked the RHD gene. Twenty-three percent carried the hybrid RHD CE-D alleles (16 RHD-CE(3-7)-D, 5 RHD-CE(4-7)-D, 1 RHD-CE(4-8)-D, 1 RHD-CE(3-8) D) and 2% were weak D (1 weak D type 1 and 1 weak D type 5). CONCLUSION: Our study proved the high frequency of RHD gene among serologically D-negative samples, positive for C and/or E antigen. Thus achieving systematically RHCE phenotyping in all transfusion centers on the Tunisian territory and considering blood donated from D-negative C/E+ persons as D-positive will be recommended to reduce anti-D allo-immunization. PMID- 25458986 TI - [Assessment of transfusion practice: assessing nurses' knowledge in transfusion medicine at Mohamed VI Hematology and Oncology Center of Marrakesh, Morocco]. AB - Blood transfusion is a complex activity, involving many actors. It is a high-risk activity which could not be controlled without the use of specific methods. Health care workers beliefs and organizational factors are two major issues for the blood transfusion safety. PURPOSE: In our medical center, transfusion medicine care practices were evaluated by testing the nursing staff with a list of questions. We carried out a cross-sectional study. The information was gathered by using an anonymous questionnaire. The latter was developed by foreign teams and adapted to the local context. Forty-two nurses have participated to study. Only 25% have appropriate knowledge and practice with no negative consequences for the patient safety. In our sample, poor knowledge and practice concerned mainly (1) pre-transfusion compatibility check when receiving blood units (30%); (2) delay in preservation of blood unit in the ward (65%); and (3) recognition of abnormal reactions after transfusion (40%). These results showed on which topics the teaching program should emphasize so as to improve the quality of blood transfusion in the medical centers according to legal obligations. PMID- 25458987 TI - [Anti-erythrocyte and anti-HLA immunization in hemoglobinopathies]. AB - AIM: Evaluate the anti-erythrocyte and anti-HLA immunization rates in hemoglobinopathies. PATIENTS AND METHODS: Cross-sectional study (October 2009 March 2010) on 83 patients followed for hemoglobinopathies. The irregular antibodies research is realized by two techniques: indirect Coombs and enzymatic technique on gel cards. The search for anti-HLA class I antibodies is done by complement dependent lymphocytotoxicity. RESULTS: The mean age was 30 years (14 64 years), the sex ratio M/F is 0.84. Our series included 42 cases of sickle cell disease (29 homozygous sickle cell anemia and 13 sickle-thalassemia) and 41 cases of thalassemia syndromes (26 major and 15 intermediate). The anti-erythrocyte alloimmunization rate is 10.84% without difference between thalassemia syndromes and sickle cell disease. The autoimmunization rate (22.89%) is higher in thalassemia syndromes (41.46%) than in the sickle cell disease (7.14%) (P<0.001). The anti-HLA immunization rate is 31.6% without difference between thalassemia syndromes and sickle cell disease. The young age, transfusion at a young age and the total number of transfusions are the factors that increase the risk of anti erythrocyte autoimmunization. No clinicobiological parameter does influence the anti-erythrocyte and anti-HLA alloimmunization. There is no significant association between anti-erythrocyte and anti-HLA immunization. CONCLUSION: The erythrocyte and anti-HLA anti-immunization rates are high in our series. Preventive strategy is needed to ensure optimal blood safety. PMID- 25458988 TI - The knowledge gap: a different type of nerve gap. PMID- 25458989 TI - SOCS3 and STAT3, major controllers of the outcome of infection with Mycobacterium tuberculosis. AB - In our review, we address the role of signal transducer and activator of transcription-3 (STAT3) and suppressor of cytokine signaling-3 (SOCS3) in the outcome of Mycobacterium tuberculosis infection, focusing on functions of these molecules in regulating the biology of myeloid and lymphoid cells. The STAT3 transcription factor has paradoxical roles: mainly activating an anti inflammatory program in myeloid cells while promoting the differentiation and activation of inflammatory T cells. STAT3 is a major player in all phases of T cell responses, including T cell subset differentiation, T cell activation, and generation of memory. We review the roles of cytokines that activate, or are activated by, STAT3 during the infection with M. tuberculosis. SOCS3 inhibits STAT3 activation, by some but not all STAT3-activating cytokine receptors. Infection with M. tuberculosis also stimulates SOCS3 expression in phagocytes. Studies in different mouse models have proven the critical importance of SOCS3 in restraining inflammation and allowing optimal levels of protective immune responses against the infection. The accumulated data presented here suggest a relevant program coordinated by SOCS3 in different cell populations, which results in improved control of infection with M. tuberculosis. STAT3 and SOCS3 may thus be targeted to improve the control of infection with M. tuberculosis or the efficiency of vaccination. PMID- 25458991 TI - Primary cutaneous CD8+ cytotoxic T-cell lymphoma involving the epidermis and subcutis in a young child. AB - CD8+ cytotoxic T-cell lymphoma involving the skin represents a heterogeneous group of diseases that include subcutaneous panniculitis-like T-cell lymphoma, primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, and 'type D' lymphomatoid papulosis. In this report, we describe a case of CD8+ cytotoxic T-cell lymphoma involving both the epidermis and subcutis. The patient was a 6-year-old girl who presented with a 3-year history of multiple plaques on her trunk and legs. The lesions had relapsed twice but responded well to prednisone. Histopathologic examination showed the proliferation of atypical lymphocytes in the epidermis, dermis and subcutaneous tissue. On immunohistochemical analysis, the atypical lymphocytes were positive for betaF1, CD3, CD8, perforin, granzyme B and TIA-1, but negative for T-cell receptor (TCR) gamma, CD4, CD30 and CD56. It was difficult to classify this tumor in terms of the known types of cutaneous lymphoma, and this case should be differentiated with subcutaneous panniculitis-like T-cell lymphoma and primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. PMID- 25458992 TI - Nutrient intake, diet quality, and weight/adiposity parameters in breakfast patterns compared with no breakfast in adults: National Health and Nutrition Examination Survey 2001-2008. AB - BACKGROUND: The effect of different breakfast consumption patterns on nutrient intake, diet quality, and weight/adiposity status is unknown. OBJECTIVE: To compare nutrient intake, diet quality, and weight/adiposity measures of consumers assigned to different breakfast patterns with breakfast skippers. DESIGN AND PARTICIPANTS: These associations were assessed in adults 19+ years (N=18,988) participating in the 2001-2008 National Health and Nutrition Examination Survey. Intake was determined from 1-day 24-hour dietary recall. Diet quality was quantified using the Healthy Eating Index-2005. Body mass index (calculated as kg/m(2)) and waist circumferences were determined. Twelve patterns (including No Breakfast [approximately 19% of population]), explaining 58% of the variance in energy from the breakfast meal, were examined. Covariate adjusted general linear models were used to compare nutrient intakes, Healthy Eating Index-2005 scores, and body mass index/waist circumference of consumers of different patterns with breakfast skippers. The P value was Bonferroni corrected (<0.05/12 breakfast patterns <0.0042). RESULTS: Consumers of the Grain/100% Fruit Juice and Presweetened Ready-to-Eat Cereal (RTEC)/Lower-Fat Milk patterns had lower daily intakes of nutrients to limit (added sugars, saturated fatty acids, solid fats, cholesterol, and sodium) than breakfast skippers. Consumers of the Grain/100% Fruit Juice; Presweetened RTEC/Lower-Fat Milk; and RTEC/Lower-Fat Milk/Whole Fruit/100% Fruit Juice patterns had higher daily intakes of all shortfall nutrients examined (dietary fiber; vitamins A, D, and C; calcium, potassium, folate, iron, and magnesium) than breakfast skippers. Consumers of the Grain/100% Fruit Juice; Grain; Presweetened RTEC/Lower-Fat Milk; RTEC/Lower-Fat Milk/Whole Fruit/100% Fruit Juice; Cooked Cereal; Lower-Fat Milk/Whole Fruit; and Whole Fruit patterns had higher Healthy Eating Index-2005 scores than breakfast skippers. Consumers of the Grain/100% Fruit Juice; Presweetened RTEC/Lower-Fat Milk; RTEC/Lower-Fat Milk/Whole Fruit/100% Fruit Juice; and Cooked Cereal patterns had lower body mass indexes and waist circumferences than breakfast skippers. CONCLUSIONS: Results suggest dietary and weight advantages of consuming breakfast, especially ones that include grains, cereals, lower-fat milk, and whole fruit/100% fruit juice, in contrast to the potential adverse effects of skipping breakfast. PMID- 25458993 TI - Defining nutritious breakfasts and their benefits. PMID- 25458994 TI - The role of breakfast in health: definition and criteria for a quality breakfast. PMID- 25458990 TI - The role of B cells and humoral immunity in Mycobacterium tuberculosis infection. AB - Mycobacterium tuberculosis remains a major public health burden. It is generally thought that while B cell- and antibody-mediated immunity plays an important role in host defense against extracellular pathogens, the primary control of intracellular microbes derives from cellular immune mechanisms. Studies on the immune regulatory mechanisms during infection with M. tuberculosis, a facultative intracellular organism, has established the importance of cell-mediated immunity in host defense during tuberculous infection. Emerging evidence suggest a role for B cell and humoral immunity in the control of intracellular pathogens, including obligatory species, through interactions with the cell-mediated immune compartment. Recent studies have shown that B cells and antibodies can significantly impact on the development of immune responses to the tubercle bacillus. In this review, we present experimental evidence supporting the notion that the importance of humoral and cellular immunity in host defense may not be entirely determined by the niche of the pathogen. A comprehensive approach that examines both humoral and cellular immunity could lead to better understanding of the immune response to M. tuberculosis. PMID- 25458995 TI - Genetics of immune-mediated disorders: from genome-wide association to molecular mechanism. AB - Genetic association studies have identified not only hundreds of susceptibility loci to immune-mediated diseases but also pinpointed causal amino-acid variants of HLA genes that contribute to many autoimmune reactions. Majority of non-HLA genetic variants are located within non-coding regulatory region. Expression QTL studies have shown that these variants affect disease mainly by regulating gene expression. We discuss recent findings on shared genetic loci between infectious and immune-mediated diseases and provide potential clues to explore genetic associations in the context of these infectious agents. We propose that the interdisciplinary studies (genetics-genomics-immunology-infection-bioinformatics) are the future post-GWAS approaches to advance our understanding of the pathogenesis of immune-mediated diseases. PMID- 25458996 TI - I-L-C-2 it: type 2 immunity and group 2 innate lymphoid cells in homeostasis. AB - Innate type 2 immune cells are activated in response to helminths, allergens, and certain types of proteases and particulates. Recently, innate type 2 immune pathways have also been implicated in protective host responses to homeostatic perturbations, such as metabolic dysfunction, atherosclerosis, and tissue injury. In this context, innate type 2 cytokines stimulate local tissues, recruit eosinophils, and alternatively activate macrophages to restore homeostasis. As the major source of innate interleukin (IL)-5 and IL-13, group 2 innate lymphoid cells are positioned to initiate and maintain homeostatic type 2 responses. The absence of exogenous stimuli in these processes implicates endogenous pathways in the activation of type 2 immunity and suggests an alternative evolutionary trajectory for type 2 immunity, apart from its role in response to helminths and allergens. PMID- 25458998 TI - Cellular and molecular pathways through which commensal bacteria modulate sensitization to dietary antigens. AB - Food allergies are a growing public health concern. The rapidly increasing prevalence of allergic disease cannot be explained by genetic variation alone, suggesting a role for gene-by-environment interactions. The bacteria that colonize barrier surfaces, often referred to as the commensal microbiota, are dramatically affected by environmental factors and have a major impact on host health and homeostasis. Increasing evidence suggests that alterations in the composition of the microbiota, caused by factors such as antibiotic use and diet, are contributing to increased sensitization to dietary antigens. This review will discuss the cellular and molecular pathways activated by commensal bacteria to protect against allergic sensitization. By understanding the interplay between the environment, the microbiota, and the host, we may uncover novel therapeutic targets that will allow us to control the allergy epidemic. PMID- 25458999 TI - Genetics of systemic lupus erythematosus: immune responses and end organ resistance to damage. AB - Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disorder. Considerable progress has been made to delineate the genetic control of this complex disorder. In this review, selected aspects of human and mouse genetics related to SLE are reviewed with emphasis on genes that contribute to both innate and adaptive immunity and to genes that contribute directly to susceptibility to end organ damage. It is concluded that the interactions among these two major pathways will provide further insight into the pathogenesis of SLE. An interactive model of the two major pathways is proposed without emphasis on the importance of breaking tolerance to autoantigens. PMID- 25458997 TI - The contribution of natural selection to present-day susceptibility to chronic inflammatory and autoimmune disease. AB - Chronic inflammatory and autoimmune diseases have been the focus of many genome wide association studies (GWAS) because they represent a significant cause of illness and morbidity, and many are heritable. Almost a decade of GWAS studies suggests that the pathological inflammation associated with these diseases is controlled by a limited number of networked immune system genes. Chronic inflammatory and autoimmune diseases are enigmatic from an evolutionary perspective because they exert a negative affect on reproductive fitness. The persistence of these conditions may be partially explained by the important roles the implicated immune genes play in pathogen defense and other functions thought to be under strong natural selection in humans. The evolutionary reasons for chronic inflammatory and autoimmune disease persistence and uneven distribution across populations are the focus of this review. PMID- 25459002 TI - Dermal group 2 innate lymphoid cells in atopic dermatitis and allergy. AB - Type 2 immune responses in the skin cause a variety of pathologies, including urticaria and atopic dermatitis. Traditionally, CD4(+) helper T cells have been implicated in the pathogenesis of these conditions. However, recently a new player, the group 2 innate lymphoid (ILC2) cell, has emerged as an important contributor to skin allergies. In this review, we summarize our current knowledge of the role ILC2 cells play in the physiology and pathology of mouse and human skin. PMID- 25459000 TI - Immunodeficiency and immune dysregulation associated with proximal defects of T cell receptor signaling. AB - Engagement of the TCR/CD3 complex triggers a cascade of events that result in T lymphocyte activation and promote positive and negative selection of thymocytes, T lymphocyte migration and effector functions, development and activation of regulatory T cells. Gene mutations that abrogate early TCR signaling are associated with profound abnormalities of T lymphocyte development and function both in humans and in mice, causing susceptibility to severe infections since early in life. In recent years, a growing number of genetic defects have been discovered that reduce, but do not completely abrogate proximal TCR signaling. These defects result in complex phenotypic manifestations that are not limited to immunodeficiency, but also include immune dysregulation. The identification of these conditions may also prompt development of novel therapeutic strategies for autoimmune disorders. PMID- 25459001 TI - Role of viruses and bacteria-virus interactions in autoimmunity. AB - A potential role for viral and bacterial-viral interactions in the pathogenesis of autoimmune disease has been long recognized. Recently, intensive investigation has begun to decipher interactions between specific microbes with the host that contribute toward autoimmunity. This work has primarily focused on known viral and bacterial pathogens. A major challenge is to determine the role of bacteria that are typically considered as commensals as well as chronic viruses. Furthermore, equally challenging is to prove causality given the potential complexity of microbe-microbe interactions. Important initial contributions to this field have shown that specific interactions of microbes with hosts that contain a background of genetic susceptibility can play a role in autoimmune pathogenesis. In this review, we describe principles of immune tolerance with a focus on its breakdown during pathogenic as well as commensal relationships between the host and the microbial world. PMID- 25459003 TI - The role of ILC2 in pathology of type 2 inflammatory diseases. AB - Group 2 innate lymphoid cells (ILC2) which are strategically interspersed throughout barrier surfaces are important regulators of type 2 immune reactions, particularly against helminthic parasites. ILC2 are also involved in tissue homeostasis and repair. Studies in a variety of animal models have demonstrated that when dysregulated or chronically activated, ILC2 can contribute to the pathology of allergic inflammatory diseases such as allergic asthma and atopic dermatitis. Here we discuss new findings of the cross talk of ILC2 with other hematopoietic cells, in particular T cells, and review recent information on the role of ILC2 in type 2 inflammatory diseases. PMID- 25459004 TI - Self-DNA, STING-dependent signaling and the origins of autoinflammatory disease. AB - Self-DNA has long been considered a key cause of inflammatory and autoimmune disease, although the exact origin and general mechanisms of action have remained to be elucidated. Recently, new insight has been gained into our understanding of those innate immune pathways and sensors that are responsible for instigating self-DNA triggered autoinflammatory events in the cell. One such sensor referred to as STING (for stimulator of interferon genes) has been found to be seminal for controlling cytosolic-DNA induced cytokine production, and may be responsible for a wide variety of inflammatory diseases including systemic lupus erythematosus (SLE), Aicardi-Goutieres syndrome (AGS) and STING-associated vasculopathy with onset of infancy (SAVI). STING may also be involved with augmenting certain types of carcinogen induced cancer. Aside from generating valuable information into mechanisms underlining innate immune gene regulation, these findings offer new opportunities to generate innovative therapeutics which may help treat such diseases. PMID- 25459005 TI - Seminars in Pediatric Surgery. Neonatal surgery. Preface. PMID- 25459006 TI - Prenatal counselling and the role of the paediatric surgeon. AB - With the development of prenatal ultrasound and of foetal medicine, the paediatric surgeon has extended his knowledge of the natural history of surgical malformations. He is a part of the prenatal team and parents should always be referred to him when a surgical malformation is suspected, even when termination of pregnancy is planned because of an expected poor prognosis. Direct contact between the prenatal medicine specialist and the paediatric surgeon is also highly recommended to ensure continuity in the messages delivered to the parents. Postnatal counselling does not compare with prenatal counselling, and the paediatric surgeon has learned from the obstetrician to modulate his talk by including other conditions that might affect the outcome of the foetus, especially genetically determined syndromes. When the foetal malformation is diagnosed very early, especially in the first trimester, it therefore seems important for the consultation with the paediatric surgeon to be scheduled when the complementary exams required by the anomalies diagnosed are done, in order to avoid later contradictory messages. Repeated consultations should be favoured as they allow provision of more precise information regarding changes in ultrasound and/or MRI images and so decrease parents' anxiety and help them to take their decision. Foetal surgery, which has reached various stages of development in different countries, requires paediatric surgeons and obstetricians to join forces to optimise procedures and evaluate their benefit/risk ratio. Since 2004, the National Rare Disease Plan in France has allowed the creation of Rare Disease Centres, which deal with congenital malformations and produce recommendations for the health care pathway of these patients by means of a multidisciplinary approach. This greatly enhances interdisciplinary communication and ensures that best care is provided to the parents-to-be and to their child. PMID- 25459007 TI - Progress in anesthesia and management of the newborn surgical patient. AB - Ongoing advances in the perioperative management of the newborn have undoubtedly decreased the incidence of morbidity and mortality of this vulnerable patient group. The introduction of new surgical techniques and more comprehensive understanding of the effects of varied anesthetic drugs and techniques on the surgical newborn present many challenges for pediatric surgeons and anesthesiologists. Thorough preoperative evaluation and open communication between members of the health care team are important. A basic understanding of age-dependent variables and the interaction of anesthetic and surgical procedures is essential in minimizing perioperative morbidity and mortality. PMID- 25459008 TI - Minimal invasive surgery in the newborn: current status and evidence. AB - The evolution of minimally invasive surgery (MIS) in the newborn has been delayed due to the limited working space and the unique physiology. With the development of smaller instruments and advanced surgical skills, many of the initial obstacles have been overcome. MIS is currently used in specialized centers around the world with excellent feasibility. Obvious advantages include better cosmesis, less trauma, and better postoperative musculoskeletal function, in particular after thoracic procedures. However, the aim of academic studies has shifted from proving feasibility to a critical evaluation of outcome. Prospective randomized trials and high-level evidence for the benefit of endoscopic surgery are still scarce. Questions to be answered in the upcoming years will therefore include both advantages and potential disadvantages of MIS, especially in neonates. This review summarizes recent developments of MIS in neonates and the evidence for its use. PMID- 25459009 TI - Management of congenital tracheal anomalies and laryngotracheoesophageal clefts. AB - Congenital obstructions and anomalies of the pediatric airway are rare problems that may be associated with mild symptoms or critical stenoses that may be life threatening in the first few days of life. This review provides an overview of the embryologic development of the airway, different congenital anomalies associated with airway development, and surgical correction that may be associated with good long-term outcome. PMID- 25459010 TI - Difficult esophageal atresia: trick and treat. AB - Although most patients with esophageal atresia (EA) and tracheo-esophageal fistula (TEF) may benefit from "standard" management, which is deferred emergency surgery, some may present unexpected elements that change this paradigm. Birth weight, associated anomalies, and long gap can influence the therapeutic schedule of the patients with EA/TEF and can make their treatment tricky. As a consequence, detailed information on these aspects gives the power to develop a decision-making process as correct as possible. In this article, we will review the most important factors influencing the treatment of patients with EA/TEF and will share our experience on the diagnostic and therapeutic tips that may provide pivotal help in the management of such patients. PMID- 25459011 TI - Congenital lung malformations: informing best practice. AB - The management of congenital lung malformations is controversial both in the prenatal and postnatal periods. This article attempts to inform best practice by reviewing the level of evidence with regard to prenatal diagnosis, prognosis, and management and postnatal management, including imaging, surgical indication, surgical approach, and risk of malignancy. We present a series of clinically relevant statements along those topics and analyze the evidence for each. In the end, we make a plea for an adequate description of the lesions, both before and after birth, which will allow future comparisons between management options and the initiation of prospective registries. PMID- 25459012 TI - Congenital diaphragmatic hernia: where and what is the evidence? AB - Congenital diaphragmatic hernia (CDH) retains high mortality and morbidity due to lung hypoplasia, pulmonary hypertension and severe co-existent anomalies. This article offers a comprehensive state-of-the-art review for the paediatric surgeon whilst also describing key contributions from the basic sciences in the search to uncover the cause of the birth defect together with efforts to develop new and better therapies for CDH. PMID- 25459013 TI - Abdominal wall defects: prenatal diagnosis, newborn management, and long-term outcomes. AB - Omphalocele and gastroschisis represent the most frequent congenital abdominal wall defects a pediatric surgeon is called to treat. There has been an increased reported incidence in the past 10 years mainly due to the diffuse use of prenatal ultrasound. The early detection of these malformations, and related associated anomalies, allows a multidisciplinary counseling and planning of delivery in a center equipped with high-risk pregnancy assistance, pediatric surgery, and neonatology. At present times, closure of defects, even in multiple stages, is always possible as well as management of most of cardiac-, urinary-, and gastrointestinal-associated malformations. The progress, herein discussed, in the care of newborns with abdominal wall defects assures most of them survive and reach adulthood. Some aspects of transition of medical care will also be considered, including fertility and cosmesis. PMID- 25459014 TI - Short bowel syndrome in children: surgical and medical perspectives. AB - The main cause of intestinal failure in children is due to short bowel syndrome (SBS) resulting from congenital or acquired intestinal lesions. From the first lengthening procedure introduced by Bianchi, the last three decades have seen lengthening procedures established as fundamental components of multidisciplinary intestinal rehabilitation programs. Debate on indications and timing of the procedures is still open leaving SBS surgical treatment a great challenge. However, enteral autonomy is possible only with an individualized approach remembering that each SBS patient is unique. Current literature on autologous gastrointestinal reconstruction technique was reviewed aiming to assess a comprehensive pathway in SBS non-transplant management. PMID- 25459015 TI - Chylothorax and chylous ascites: management and pitfalls. AB - Leakage of lymph from the lymphatic ducts causes chylothorax (CT) or chylous ascitis (CA). This may happen for unknown reasons during fetal life or after birth and may also be caused by trauma after thoracic surgery or by other conditions. Fetal CT and CA may be lethal particularly in cases with fetal hydrops that sometimes benefit of intra-uterine instrumentation. After birth, symptoms are related to the amount of accumulated fluid. Sometimes, severe cardio respiratory compromise prompts active therapy. Most patients with CT or CA benefit from observation, rest, and supportive measures alone. Drainage of the fluid may be necessary, but then loss of protein, fat, and lymphoid cells introduce new risks and require careful replacement. Low-fat diets with MCT and parenteral nutrition decrease fluid production while allowing adequate nutritional input. If lymph leakage does not stop, secretion inhibitors like somatostatin or octreotide are prescribed, although there is only weak evidence of their benefits. Imaging of the lymphatic system is indicated when the leaks persist, but this is technically demanding in children. Shunting of the lymph from one body space to another by means of valved catheters, embolization of the thoracic duct, and/or ligation of the major lymphatics may occasionally be indicated in cases refractory to all other treatments. PMID- 25459016 TI - Neonatal surgery: towards evidence-based practice and management. AB - Like all modern medical therapy, neonatal surgery is founded on clinical research, well-tried clinical practice and basic scientific research. Likewise, modern neonatal surgery strives increasingly for evidence-based management and practice. The very nature of neonatal and pediatric surgery renders associated research challenging because of the rarity and small numbers of surgical disorders and varying resources in different countries and institutions and consequently only a few well-designed trials on truly important issues in neonatal surgical treatment have been performed. This article highlights the research methods by which valid evidence-based research data is obtained in observational studies, randomized controlled trials, and meta-analyses. The problem of small numbers of patients may be overcome by multi-center trials, meta analyses, and networking. Consideration is also given on the quality and the validity of the study data as well as ethical issues in neonatal surgical research. PMID- 25459017 TI - Ethical aspects of care in the newborn surgical patient. AB - This article places focus on three main subjects that are all related to the ethical aspects of care of newborns undergoing major surgical interventions. The first concerns the communication between the surgeon, as a representative of the treatment team, and the parents. The second is the way to handle new developments in neonatal surgery. The third issue covers several aspects of the ethical decision-making process with regard to forgoing life support in surgical neonates. These issues will be discussed on the basis of two clinical case reports. PMID- 25459018 TI - Organ bioengineering for the newborn. AB - Regenerative medicine has recently been established as an emerging interdisciplinary field focused on the repair; replacement or regeneration of cells, tissues and organs. It involves various disciplines, which are focused on different aspects of the regeneration process such as cell biology, gene therapy, bioengineering, material science and pharmacology. In this article, we will outline progress on tissue engineering of specific tissues and organs relevant to paediatric surgery. PMID- 25459023 TI - Temporal leakage of Cu,Zn superoxide dismutase and loss of two low-molecular weight forms of glutathione peroxidase-1 from buffalo (Bubalus bubalis) sperm after freezing and thawing. AB - The postthaw motility and fertility of frozen-thawed buffalo spermatozoa are substantially low as compared with those of cattle sperm. The sperm motility and fertility have been positively correlated with the antioxidant enzyme activities of human and canine sperm. However, the extent of antioxidant enzyme loss during cryopreservation, although reported for human and cattle sperm, is still not clear for buffalo sperm. Thus, in the present study, an attempt was made to determine the activities of various antioxidant enzymes in buffalo spermatozoa cryopreserved for various durations (0, 30, and 60 days) and the mechanism of antioxidant enzyme loss, if any, during the process. Total superoxide dismutase (SOD) activity of cryopreserved sperm decreased and that of extended seminal plasma increased progressively with the increase in duration of cryopreservation indicating the possible time-dependent leakage of these enzymes from cryopreserved sperm into the extended seminal plasmas. The catalase and glutathione peroxidase (GPx) enzyme activities could not be detected in buffalo sperm but could be detected in fresh and extended seminal plasmas. Total GPx activities of extended seminal plasma decreased progressively with the increase in duration of cryopreservation. To confirm the presence of these enzymes at protein levels, specific antioxidant enzymes such as Cu,Zn SOD of 16 kDa and three molecular weight forms (57.7, 40.9, and 26.05 kDa) of GPx-1 were detected in buffalo sperm by Western blot. Furthermore, the intensities of 16-kDa Cu,Zn SOD in 60-day cryopreserved sperm and those of two low-molecular-weight forms of GPx-1 (40.9 and 26.05 kDa) in 30-day cryopreserved sperm decreased significantly (P < 0.05) as compared with those of noncryopreserved (0-day cryopreserved) sperm indicating selective and temporal leakage of only low-molecular-weight antioxidant proteins in the initial phase. However, all the mentioned GPx-1 forms disappeared in 60-day-old cryopreserved sperm. Immunocytochemistry experiment also revealed that Cu,Zn SOD proteins are distributed over the acrosomal region of noncryopreserved buffalo spermatozoa, and the fluorescence signal decreased substantially in 60-day cryopreserved sperm. Thus, the present study reported that there is temporal leakage of Cu,Zn SOD and loss of two low-molecular-weight forms of GPx-1 from the cryopreserved buffalo spermatozoa after freezing and thawing. PMID- 25459024 TI - Comparative transcript profiling of gene expression of fresh and frozen-thawed bull sperm. AB - Although frozen semen is widely used commercially in the cattle breeding industry, the resultant pregnancy rate is lower than that produced using fresh semen. Cryodamage is a major problem in semen cryopreservation; it causes changes to sperm transcripts that may influence sperm function and motility. We used suppression subtractive hybridization technology to establish a complementary DNA subtractive library, and combined microarray technology and sequence homology analysis to screen and analyze differentially expressed genes in the library, comparing fresh sperm with the frozen-thawed sperm of nine bulls. Overall, 19 positive differentially expressed unigenes were identified using microarray data and Significance Analysis of Microarrays software (|score (d)| >= 2, fold change > 1, and false discovery rate < 0.05). Of 15 differentially expressed unigenes exhibited high sequence homology (E-value <= 1 * 10(-3)), 12 were upregulated in frozen-thawed sperm, the remaining 3 were upregulated in fresh sperm, and 4 other clones were identified as unknown because of incomplete sequences or because there was no significant sequence homology (E-value > 1E(-03)) and were considered novel genes. The expression of five of these genes-RPL31, PRKCE, PAPSS2, PLP1, and R1G7-was verified by quantitative real-time reverse transcription-polymerase chain reaction. There was a significant differential expression of the RPL31 gene (P < 0.05). Our preliminary results provide an overview of differentially expressed transcripts between fresh and frozen-thawed sperm of Holstein bulls. PMID- 25459025 TI - Color Doppler provides a reliable and rapid means of monitoring luteolysis in female donkeys. AB - When artificial reproduction technologies designed for use with horses are used with donkeys, success is dependent on awareness of the physiological differences between these species, yet little information is available on many aspects of donkey reproduction. The present work examines the activity of the CL in Catalonian jennies after induced luteolysis. Plasma progesterone concentration, luteal blood flow (determined by color Doppler), and CL cross-sectional area (CL CSA; determined by B-mode ultrasound examination) were assessed after a single dose (5 mg intramuscular) of dinoprost thromethamine (DT, a PGF2alpha analog) on Day 10 after ovulation in two experiments. In experiment 1, a preliminary experiment, data were collected daily for 4 days after DT administration. Values for all the measured variables decreased over this period. In experiment 2, data were collected during the first 24 hours after DT administration because in experiment 1, most luteolytic activity occurred during this time. An increase in luteal blood flow was seen between 0 and 3 hours, followed by a progressive reduction, whereas the values for plasma progesterone and CL-CSA gradually decreased from 0 hours onward. In both studies, negative correlations were seen between all variables and the time of sampling. In contrast, positive correlations were seen between plasma progesterone, CL-CSA, uterine tone, and luteal blood flow. Indeed, a strong correlation was recorded between plasma progesterone and luteal blood flow (r = 0.70; P < 0.0001). In conclusion, plasma progesterone and CL-CSA both become reduced after induced luteolysis in Catalonian jennies. Unlike in mares, an increase in luteal blood flow occurs soon after induced luteolysis, rather like that seen in the cow. The luteal blood flow, as evaluated here by color Doppler, was also closely related to the plasma progesterone concentration. Color Doppler would appear therefore to offer a rapid and easy means of examining the state of luteolysis. PMID- 25459026 TI - Ultrasound monitoring of blood flow and echotexture of the corpus luteum and uterus during early pregnancy of beef heifers. AB - The aim was to characterize changes in the ultrasound characteristics of the CL and uterus in pregnant, inseminated nonpregnant, and cyclic beef heifers and to correlate findings with systemic progesterone (P4) concentrations with the intention of identifying possible markers for early identification of pregnancy. Heifers were randomly selected for artificial insemination after estrus synchronization. Ultrasound examinations of the CL and uterus were carried out by transrectal ultrasonography using a high-resolution ultrasound scanner equipped with a 12 MHz linear array probe on Days 7, 11, 14, 16, and 18 after artificial insemination (Day 0; i.e., estrus). Cross-sectional B-mode images of the CL were captured for calculation of CL tissue area and echotexture. Images of the CL and associated blood flow were captured and stored for analysis of luteal blood flow area and ratio. Longitudinal B-mode images of the uterine horns were captured just beyond the bifurcation of the uterine horns and stored for analysis of contrast and homogeneity (MaZda v4.6; Technical University of Lodz, Institute of Electronics, Poland). A total of three images were captured for each structure of interest. Serum concentrations of P4 were determined from blood samples collected at each ultrasound examination. After pregnancy diagnosis by ultrasound, heifers were retrospectively allocated as being pregnant (embryonic heartbeat on Day 28; n = 14) or nonpregnant (interestrous interval 18-21 days; n = 8) and their data were compared with noninseminated cyclic heifers (n = 10). Corpus luteum tissue area did not appear to change between pregnant, nonpregnant, or cyclic control groups between Days 7 and 18 (P > 0.05). No significant differences in CL echotexture characteristics were found between groups at any time point. There were no significant differences between pregnant, nonpregnant, and cyclic control groups for CL blood flow area (P > 0.05). However, CL blood flow ratio decreased significantly (P < 0.05) in both inseminated nonpregnant and cyclic heifers between Days 14 and 18, whereas it remained unchanged in pregnant heifers (P > 0.05). Uterine homogeneity was not significantly different between groups at any time point (P > 0.05). However, uterine contrast was significantly greater (P < 0.05) in pregnant compared with cyclic control heifers on Days 16 and 18. Concentrations of P4 were lower (P < 0.05) in nonpregnant and control heifers than in pregnant heifers from Days 16 to 18. In conclusion, there were differences between nonpregnant and cyclic heifers compared with pregnant heifers in P4 concentrations from Day 16. On Day 18, the CL and uterine characteristics were different between the nonpregnant and pregnant heifers. Ultrasound measures of CL blood flow and uterine echotexture may be useful to establish pregnancy status. Further investigation is required to identify if pregnancy diagnosis can be made on Day 18 or at a later day postpartum. PMID- 25459027 TI - Reproductive performance of backcross Holstein * Brown Swiss and their Holstein contemporaries under subtropical environmental conditions. AB - The objective of this study was to evaluate the reproductive performance of the Holstein (HO) and their backcross HO * Brown Swiss (BS) under Egyptian subtropical conditions. The backcrosses were HBH (HO sires crossed with F1 BS * HO cows) and HHB (HO sires crossed with F1 HO * BS cows). Several reproductive indices and health traits for different genotypes were measured, and the effect of temperature-humidity index level (THI) on reproductive performance was investigated. Reproductive indices of the HHB backcross were better than those of the HO. The conception (30.1%) and pregnancy (28.9%) rates of the HHB backcross were significantly higher than those of the HO (28.1% and 22.6%, respectively). The calving interval and the days open of the HHB backcross were significantly shorter than those of the HO. The fertility of the HHB backcross was not affected by the level of the THI. The conception and the pregnancy rate of the HO decreased from 35.8% and 29.4%, respectively, at low THI to 16.1% and 12.1%, respectively, at high THI. The HHB backcross had the significant lowest incidence of retained placenta and metritis (9.6 and 16.9, respectively). In conclusion, despite their high milk production efficiency, pure HO had retarded reproductive performance and adaptability. On the other hand, the HHB backcross had a better adaptability and fertility under Egyptian conditions. PMID- 25459028 TI - Double-Ovsynch, compared with presynch with or without GnRH, improves fertility in heat-stressed lactating dairy cows. AB - The objective was to compare 3 timed artificial insemination (TAI) protocols in lactating dairy cows during heat stress. Multiparous Holstein cows yielding (mean +/- SEM) 29.4 +/- 0.3 kg of milk/d randomly were assigned to 1 of 3 TAI protocols at 34 +/- 5.1 days in milk: 1) double-Ovsynch (DO; n = 486): the cows received GnRH-7d-2alpha-3d-GnRH and Ovsynch56 (GnRH-7d-PGF2alpha-56h-GnRH-16h-AI) was initiated 7 days later; 2) Presynch-GnRH-Ovsynch (PGO; n = 453): the cows received PGF2alpha-14d-PGF2alpha-2d-GnRH and Ovsynch56 was initiated 7 days later; and 3) presynch-Ovsynch (PO; n = 435): the cows received PGF2alpha-14d PGF2alpha and Ovsynch56 was initiated 12 days later. The ovulatory response to the first GnRH of Ovsynch56 was higher in DO (65.0%) compared to PGO (53.2%) and PO (45.5%). Luteolytic response to PGF2alpha of Ovsynch was similar among TAI protocols (90.1%, 87.1%, and 86.2% for DO, PGO, and PO, respectively). Synchronization rate was greater in DO (86.2%) than in PGO (78.1%) and PO (72.1%) protocols. Irrespective of the TAI protocol, cows that ovulated in response to first GnRH had greater response to PGF2alpha (92.7 vs. 77.1%). Mean (+/-SEM) diameter (mm) of ovulatory follicle at TAI was larger in DO (16.1 +/- 0.3) than PGO (15.6 +/- 0.21) and PO (15.2 +/- 0.12). Cows subjected to DO had greater P/AI at 32 days and at 60 days after TAI (26.6 and 24.4%) compared with those in PGO (21.4 and 20.0%) and PO (17.2 and 15.9%). However, TAI protocol had no significant effect on the incidence of pregnancy loss (6.1%, 6.6%, and 7.4% for DO, GO, and PO, respectively). In summary, cows in the DO protocol had a greater ovulation rate to the first GnRH and a greater synchronization rate, larger ovulatory follicles and greater P/AI. Of the 3 protocols used, DO yield the best reproductive performance in heat-stressed, lactating dairy cows. PMID- 25459029 TI - Effects of crossbreeding on endocrine patterns determined in pregnant beef/dairy cows naturally infected with Neospora caninum. AB - Neospora caninum is an intracellular coccidian parasite causing abortion worldwide in dairy cattle. Studies have shown that N caninum infection modifies endocrine patterns and that beef cows or cows with a crossbreed pregnancy, especially for a greater maternal-paternal genetic distance, show a reduced risk of abortion when naturally infected compared with pure-breed Holstein Friesian (HF) pregnancies. This study examined the effects of crossbreeding on plasma progesterone (P4), pregnancy-associated glycoprotein (PAG)-1 and -2, and prolactin patterns produced during gestation in N caninum-infected beef/dairy cows. We analyzed 74 pregnancies in nonaborting cows carrying a single fetus established in 26 lactating HF cows bred with Holstein bulls (H-H), 13 HF cows bred with Limousin bulls (H-L), 12 HF cows used as recipients of transferred in vivo-produced frozen-thawed Rubia Gallega (beef breed; RG) embryos (H-RG-ET), and 23 RG suckling cows bred with RG bulls (RG-RG). Of the cows, 29 (39%) were seropositive for N caninum. Blood samples for hormone and placental protein determinations were collected on Days 30, 60, 90, 120, 150, and 180 of gestation. Procedures of repeated measures analysis of variance throughout gestation revealed higher PAG-1 levels in the H-L and H-RG-ET groups compared with H-H and RG-RG. Higher prolactin levels were detected in RG-RG than in the remaining groups. N caninum seropositivity and fetal genotype had a significant effect on PAG-2 concentrations, such that highest levels of PAG-2 occurred in RG-RG seropositive cows and lowest in H-H seropositive cows, whereas Neospora seropositive cows showed lower P4 concentrations than their seronegative partners. In conclusion, chronic N caninum infection modifies endocrine patterns of PAG-2 and P4 during pregnancy, whereas PAG-1 and prolactin concentrations are affected by breed and fetal genotype, irrespective of Neospora infection status. PMID- 25459030 TI - LH secretion around induced ovulation during early and late diestrus and its effect on the appearance of short estrous cycles in cyclic dairy heifers. AB - The aim of this study was to investigate the effect of the stage of the estrus cycle (early vs. late diestrus) on the LH secretion after induced ovulation and on the incidence of short estrous cycles in dairy heifers. Cyclic heifers were presynchronized with dexcloprostenol and divided into Groups D7 (n = 6) and D14 (n = 6). On Day 7 (D7) or Day 14 (D14) after ovulation (Day 0), all animals were treated with dexcloprostenol followed by 0.1 mg of gonadorelin (GnRH) 24 hours later. Blood samples were taken daily for progesterone (P4) analysis and for LH analysis every 10 minutes for 3 hours on Days 1, 3, and 5 and every 30 minutes for 6 hours starting just before GnRH administration. In a control group, Group C (n = 7), estrus was synchronized with an intravaginal progesterone-releasing device (CIDR) inserted for 9 days. Blood for P4 analysis was taken daily for 16 days and for LH analysis every 30 minutes for 31 hours starting 30 hours after CIDR removal (unmanipulated LH peak) and every 10 minutes for 3 hours on Days 1, 3, and 5 after ovulation. In all groups, ovarian structures and ovulation were detected via daily transrectal ultrasound examination around first and second ovulation. In D7, all cycles (6/6) were shorter than normal (range 7-9 days). In D14, 2 of the 6 animals had a short cycle (both 7 days) whereas 4 had a cycle of normal length. All cycles were of normal length in C. Animals in D7 and D14 were divided according to their cycle length into short (SC) and normal (NC) cycle groups. The mean size of the ovulatory follicle during the 3 days before ovulation was significantly different between D7 and D14 and on 3 days and 1 day before ovulation between SC and NC. Secretion of LH during the 6 hours after GnRH administration did not differ between D7 and D14, or SC and NC. The mean basal LH secretion in D7 and D14 on Days 1, 3, and 5 was significantly different. No difference on those days was noted between SC and NC. In conclusion, when ovulation is induced with GnRH 24 hours after giving dexcloprostenol, short estrous cycles can occur during both early and late diestrus. The preovulatory LH surge did not differ between D7 and D14, or SC and NC. Also, basal LH secretion on Days 1, 3, and 5 was similar in SC and NC, and lower basal LH concentration coincided with higher P4 concentration. PMID- 25459031 TI - Effect of photoperiod on endocrine profiles and vitellogenin expression in European eels Anguilla anguilla during artificially induced ovarian development. AB - The aim of this work was to determine the effects of dark and light conditions on the E2, testosterone and thyroid hormones levels and on the gene expression levels (vitellogenin 1, vitellogenin 2, and estradiol receptor one) in European eels (Anguilla anguilla) during ovarian development induced by increasing doses of carp pituitary extracts (CPEs). The subjects were divided into 2 groups: 14 hour light:10-hour dark (Light Group) and 24-hour darkness (Dark Group). All the eels received intramuscular injections with CPE at a dosage of 10 mg/kg body weight (BW) once a week for the first 3 weeks, 20 mg/kg BW fourth-sixth week, 30 mg/kg BW seventh-ninth week, and 40 mg/kg up to the end of the experiment (13th week). Vitellogenin and estradiol receptor expression levels did not show significant differences between the two housing conditions whereas in both groups vitellogenin mRNA increased starting from first CPE injection. Testosterone and 17-beta estradiol plasma levels were significantly greater in the Dark Group compared with the Light Group starting from the ninth and the 13th week, respectively. These results suggest that darkness could be a useful variable for standardizing gonadal maturation in eels kept in captivity. PMID- 25459032 TI - Quantitative characteristics of Atlantic halibut (Hippoglossus hippoglossus L.) egg quality throughout the reproductive season. AB - Assessment of egg quality is an important aspect in finfish hatchery management, but guidelines for such assessment are scarce, especially for marine fish production. In the present work, potential indicators of egg and larval quality were measured in 39 batches of eggs of Atlantic halibut (Hippoglossus hippoglossus L.) throughout the reproductive season. The paternal influence on offspring was minimized by using the same cryopreserved semen for all fertilizations; consequently, maternal effects were emphasized. The progression of the spawning season and ovarian fluid parameters, including pH, electrical conductivity (EC), osmolality, and the amount of fluid were registered. The behavior of the broodfish at egg collection was registered and the eggs were analyzed for cortisol content. Fertilization and hatching rates as well as larvae survival were calculated, and larval standard length and myotome height were measured. Furthermore, the occurrence of major types of larval deformities was registered. The myotome height was significantly (P < 0.05) affected by the spawning season progress. Cortisol content in the eggs was decreasing with the progressing spawning season and correlated positively with the occurrence of yolk sac edema. The ovarian fluid pH and EC were significantly related to fertilization and hatching rates. High fertilization and hatching success was associated with pH greater than 7.9 and EC less than 2.5 mS/cm. Low fertilization rates (< 50%) resulted in further low hatchability from such egg batches. Ovarian fluid EC was significantly and positively related to increased occurrence of yolk sac edema. High quantity of ovarian fluid in egg batches was associated with reduced egg quality in terms of fertilization and hatching rates and occurrence of yolk-sac edema. A cumulative effect of ovarian fluid pH, EC, osmolality, and quantity explained up to 62% of the total variation in fertilization rates. The findings from the present study indicate that parameters measurable at the initial phase of production, in particular ovarian fluid pH and EC, might have a potential for future use as egg quality indicators in hatchery management. PMID- 25459033 TI - Fertility and flow cytometric evaluations of frozen-thawed rooster semen in cryopreservation medium containing low-density lipoprotein. AB - Frozen-thawed rooster semen is not reliable for use in artificial insemination in commercial stocks. Low-density lipoprotein (LDL) has been assessed for effectiveness as a cryoprotectant in the extender to improve the quality of frozen-thawed rooster semen. Although LDL has been evaluated in a few studies in other species for semen cryopreservation, so far no study has been conducted to examine this cryoprotectant for cryopreservation of fowl semen. Thus, this study aims to analyze the effects of different concentrations of LDL (0%, 2%, 4%, 6%, and 8%) in a Beltsville extender for cryopreservation of rooster spermatozoa. In experiment 1, motion parameters, membrane integrity, acrosome integrity, apoptosis status, and mitochondria activity were assessed after freeze-thawing. The highest quality frozen-thawed semen was selected to be used for evaluation of the fertility rate in experiment 2. Semen was collected from six roosters, twice weekly, then extended in a Beltsville extender that contained different concentrations of LDL as follows: 0% (control), 1% (Beltsville plus 1% LDL [BLDL1]), 2% (BLDL2), 4% (BLDL4), 6% (BLDL6), and 8% (BLDL8). Supplementation of the Beltsville extender with 4% LDL produced the most significant percentage of motility (43.1 +/- 1.3), membrane integrity (59.4 +/- 2.1),mitochondria activity (49.1 +/- 1.19), and viable spermatozoa (45 +/- 2.28) compared with the control treatment with the results of 22.7 +/- 1.3 (motility), 38.4 +/- 2.1 (membrane integrity), 40.25 +/- 1.19 (mitochondrial activity), and 37.8 +/- 2.28 (viability). In experiment 2, a significantly higher percentage of fertility rate was observed for frozen-thawed semen in the extender supplemented with 4% LDL (49.5 +/- 1.6) compared with the control (29.2 +/- 2.9). Progressive motility and acrosome integrity were not affected by LDL levels in the extenders. The results revealed that supplementation of the Beltsville extender with 4% LDL resulted in higher quality of frozen-thawed rooster sperm. PMID- 25459034 TI - Haplotype and mutation analysis for newly suggested Y-STRs in Korean father-son pairs. AB - In this study, 363 Korean father-son haplotype transfers in 351 families were analyzed using an in-house multiplex PCR system for 14 Y-STRs (DYS385a/b, DYF387S1, DYS391, DYS449, DYS460, DYS481, DYS518, DYS533, DYS549, DYS570, DYS576, DYS627 and DYS643), that included 11 loci newly added to the PowerPlex Y23 system or the Yfiler Plus system. The Y-STRs showed gene diversity values ranging from 0.2499 to 0.9612; the multicopy Y-STR loci DYS385 and DYF387S1 had high gene diversity of 0.9612 and 0.9457, respectively. In addition, DYF387S1, which has two copies, showed three alleles in seven individuals, and micro-variant alleles were observed in 14 individuals at four loci (DYS448, DYS518, DYS570 and DYS627). Among 351 haplotypes for the 11 newly added Y-STRs, 350 different haplotypes were observed, with an overall haplotype diversity of 0.9999 and discrimination capacity of 99.72%. In 363 haplotype transfers from 351 pedigrees, 29 single-step mutations were observed at 11 Y-STRs. Locus-specific mutation rate estimates varied from 0.0 to 1.93*10(-2), with an average estimated mutation rate of 6.66*10(-3). Two father-son pairs had mutations at two different loci in 11 Y STRs. The number of pairs with mutations at multiple loci increased to five when the mutation event was investigated for haplotype transfer at 28 Y-STRs including 17 Yfiler loci and 11 Y-STRs examined in this study: four father-son pairs had mutations at two loci, and one pair had mutations at three loci. Overall, mutations were frequently observed at DYS449, DYS576 and DYS627 loci, which are known to be rapidly mutating Y-STRs. Mutation rate estimates at most loci were not significantly different from rates in other populations, but estimates for DYF387S1, DYS518 and DYS570 were considerably lower in the Korean population than in other populations. PMID- 25459035 TI - Percutaneous left atrial appendage closure: procedural techniques and outcomes. AB - Percutaneous left atrial appendage closure technology for stroke prevention in patients with atrial fibrillation has significantly advanced in the past 2 decades. Several devices are under clinical investigation, and a few have already received Conformite Europeene (CE)-mark approval and are available in many countries. The WATCHMAN device (Boston Scientific, Natick, Massachusetts) has the most supportive data and is under evaluation by the U.S. Food and Drug Administration for warfarin-eligible patients. The Amplatzer Cardiac Plug (St. Jude Medical, Plymouth, Minnesota) has a large real-world experience over the past 5 years, and a randomized trial comparing Amplatzer Cardiac Plug with the WATCHMAN device is anticipated in the near future. The Lariat procedure (SentreHEART Inc., Redwood City, California) has also gained interest lately, but early studies were concerning for high rates of serious pericardial effusion and major bleeding. The current real-world experience predominantly involves patients who are not long-term anticoagulation candidates or who are perceived to have high bleeding risks. This pattern of practice is expected to change when the U.S. Food and Drug Administration approves the WATCHMAN device for warfarin-eligible patients. This paper reviews in depth the procedural techniques, safety, and outcomes of the current leading devices. PMID- 25459037 TI - Outcomes after transfemoral transcatheter aortic valve replacement. PMID- 25459036 TI - Outcomes after transfemoral transcatheter aortic valve replacement: a comparison of the randomized PARTNER (Placement of AoRTic TraNscathetER Valves) trial with the NRCA (Nonrandomized Continued Access) registry. AB - OBJECTIVES: This study sought to determine whether outcomes for transfemoral (TF) transcatheter aortic valve replacement (TAVR) differ between the randomized controlled trial (RCT) and the subsequent NRCA (Nonrandomized Continued Access) registry of the PARTNER (Placement of AoRTic TraNscathetER Valves) trial. BACKGROUND: The PARTNER RCT demonstrated that TAVR with the Edwards Sapien valve (Edwards Lifesciences, Irvine, California) is noninferior to surgery in high-risk patients and superior to standard therapy for inoperable patients. METHODS: The inclusion and exclusion criteria, data collection, monitoring, and core laboratories were the same for the RCT and NRCA registry. Baseline characteristics, procedural results, and 1-year outcomes were compared between patients undergoing TF-TAVR as part of the RCT and as part of the NRCA registry. RESULTS: In the RCT, 415 patients underwent TF-TAVR, whereas in the NRCA, 1,023 patients did. At 30 days, death, cardiac death, stroke, and transient ischemic attacks were not different in the NRCA registry than in the RCT. Major vascular complications (8.0% vs. 15.7%, p < 0.0001) and major bleeding (6.8% vs. 15.3%, p < 0.0001) were significantly lower in the NRCA registry. At 1 year, death rates were significantly lower in the NRCA cohort (19.0% vs. 25.3%, p = 0.009) and cardiac death tended to be lower (8.4% vs. 11.1%, p = 0.12). Stroke or transient ischemic attack (6.2% vs. 8.7%, p = 0.10) and stroke alone (5.0% vs. 7.1%, p = 0.13) also tended to be lower. CONCLUSIONS: The large NRCA registry demonstrates further improvement in procedural and longer-term outcomes after TF-TAVR when compared with the favorable results from the PARTNER RCT. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894). PMID- 25459038 TI - One-year follow-up of the Melody transcatheter pulmonary valve multicenter post approval study. AB - OBJECTIVES: This study sought to confirm that the short-term hemodynamic effectiveness of the Melody transcatheter pulmonary valve (TPV) (Medtronic, Inc., Minneapolis, Minnesota) achieved by real-world providers is equivalent to the historical results established in the initial 5-center Investigational Device Exemption trial. BACKGROUND: TPV replacement has been used to treat right ventricular outflow tract (RVOT) conduit dysfunction for >10 years. The Melody TPV received U.S. Food and Drug Administration approval in 2010 as a Humanitarian Use Device. METHODS: Patients with dysfunctional RVOT conduits were entered in this prospective, nonrandomized study at 10 centers. The primary endpoint was acceptable hemodynamic function at 6 months post-implantation, defined as a composite of RVOT echocardiographic mean gradient <=30 mm Hg, pulmonary regurgitation less than moderate as measured by echocardiography, and freedom from conduit reintervention and reoperation. RESULTS: Cardiac catheterization was performed in 120 patients for potential implantation of the Melody TPV; of these, 100 patients were implanted, with a 98.0% procedural success rate. There were no procedure-related deaths. Acceptable hemodynamic function at 6 months was achieved in 96.7% of patients with evaluable data (87.9% of the entire implanted cohort), with results maintained through 1 year. No patient had moderate or severe pulmonary regurgitation after implantation. No patient required catheter reintervention in the first year after implantation, and 2 patients required reoperation for conduit replacement. The rate of freedom from TPV dysfunction was 96.9% at 1 year. CONCLUSIONS: This first prospective, real-world experience with the Melody TPV in the United States demonstrates continued high procedural success, excellent short-term TPV function, and low reintervention and reoperation rates at 1 year. (Melody Transcatheter Pulmonary Valve Post-Approval Study; NCT01186692). PMID- 25459039 TI - Transcatheter pulmonary valve implants: the unchained Melody. PMID- 25459041 TI - Hybrid coronary revascularization: a new treatment paradigm for selected patients with multivessel coronary artery disease. PMID- 25459040 TI - Hybrid revascularization for multivessel coronary artery disease. AB - OBJECTIVES: The aim of this study was to assess the feasibility of hybrid coronary revascularization (HCR) in patients with multivessel coronary artery disease (MVCAD) referred for standard coronary artery bypass grafting (CABG). BACKGROUND: Conventional CABG is still the treatment of choice in patients with MVCAD. However, the limitations of standard CABG and the unsatisfactory long-term patency of saphenous grafts are commonly known. METHODS: A total of 200 patients with MVCAD involving the left anterior descending artery (LAD) and a critical (>70%) lesion in at least 1 major epicardial vessel (except the LAD) amenable to both PCI and CABG and referred for conventional surgical revascularization were randomly assigned to undergo HCR or CABG (in a 1:1 ratio). The primary endpoint was the evaluation of the safety of HCR. The feasibility was defined by the percent of patients with a complete HCR procedure and the percent of patients with conversions to standard CABG. The occurrence of major adverse cardiac events such as death, myocardial infarction, stroke, repeated revascularization, and major bleeding within the 12-month period after randomization was also assessed. RESULTS: Most of the pre-procedural characteristics were similar in the 2 groups. Of the patients in the hybrid group, 93.9% had complete HCR and 6.1% patients were converted to standard CABG. At 12 months, the rates of death (2.0% vs. 2.9 %, p = NS), myocardial infarction (6.1% vs. 3.9%, p = NS), major bleeding (2% vs. 2%, p = NS), and repeat revascularization (2% vs. 0%, p = NS) were similar in the 2 groups. In both groups, no cerebrovascular incidents were observed. CONCLUSIONS: HCR is feasible in select patients with MVCAD referred for conventional CABG. (Safety and Efficacy Study of Hybrid Revascularization in Multivessel Coronary Artery Disease [POL-MIDES]; NCT01035567). PMID- 25459042 TI - The imperative of reducing contrast dose in percutaneous coronary intervention. PMID- 25459043 TI - Pressure-wire-guided percutaneous transluminal pulmonary angioplasty: a breakthrough in catheter-interventional therapy for chronic thromboembolic pulmonary hypertension. AB - OBJECTIVES: This study sought to prove the safety and effectiveness of pressure wire-guided percutaneous transluminal pulmonary angioplasty (PTPA). BACKGROUND: PTPA has been demonstrated to be effective for treatment of chronic thromboembolic pulmonary hypertension. However, a major and occasionally fatal complication after PTPA is reperfusion pulmonary edema. To avoid this, we developed the PEPSI (Pulmonary Edema Predictive Scoring Index). The pressure wire has been used to detect insufficiency of flow in a vessel. METHODS: We included 350 consecutive PTPA sessions in 103 patients with chronic thromboembolic pulmonary hypertension from January 1, 2009 to December 31, 2013. During these 5 years, 140 PTPA sessions were performed without guidance, 65 with guidance of PEPSI alone, and 145 with both PEPSI and pressure-wire guidance. Each PTPA session was finished after achieving PEPSI scores of <35.4 with PEPSI guidance and each target lesion achieving distal mean pulmonary arterial pressure <35 mm Hg with pressure-wire guidance. RESULTS: The occurrence of clinically critical reperfusion pulmonary edema and vessel injuries were lowest in the group using the guidance of both pressure wire and PEPSI (0% and 6.9%, respectively). Furthermore, the group guided by pressure wire and PEPSI accomplished the same hemodynamic improvements with fewer numbers of target lesions treated and sessions performed. CONCLUSIONS: The combined approach using pressure wire and PEPSI produced more efficient clinical results and greatly reduced reperfusion pulmonary edema and vessel complications. This is further evidence that PTPA is an alternative strategy for treating chronic thromboembolic pulmonary hypertension. PMID- 25459044 TI - Acute artery occlusion during transcatheter aortic valve replacement in a patient with an anomalous origin of the circumflex artery. PMID- 25459046 TI - Ruptured neoatherosclerosis presenting as a large intrastent neointimal dissection. PMID- 25459045 TI - PCSK9: is it fluoride for cardiology? PMID- 25459048 TI - Kounis syndrome manifesting as coronary aneurysm and very late coronary stent thrombosis. PMID- 25459047 TI - Pacemaker lead entrapment complicating transcatheter closure of a patent foramen ovale. PMID- 25459049 TI - Transseptal closure of left ventricular pseudoaneurysm post-transapical transcatheter aortic valve replacement. PMID- 25459052 TI - Iridium-catalyzed borylation of pyrene: irreversibility and the influence of ligand on selectivity. AB - The iridium-catalyzed borylation of pyrene, using 4,4'-dimethyl-2,2'-bipyridine as the ligand, in the presence of t-BuOK, gave a mixture of 2,4,7,9 tetrakis(Bpin)pyrene (c4) and its 2,4,7,10-isomer (m4) in a 2.2:1 ratio, and the selectivity of the Ir-catalyzed borylation of pyrene is kinetically determined and can be influenced to some extent by the nature of the ligand. PMID- 25459053 TI - Low-cost telemedicine device performing cell and particle size measurement based on lens-free shadow imaging technology. AB - Recent advances in lens-free shadow imaging technology have enabled a new class of cell imaging platform, which is a suitable candidate for point-of-care facilities. In this paper, we firstly demonstrate a compact and low-cost telemedicine device providing automated cell and particle size measurement based on lens-free shadow imaging technology. Using the generated shadow (or diffraction) patterns, the proposed approach can detect and measure the sizes of more than several hundreds of micro-objects simultaneously within a single digital image frame. In practical experiments, we defined four types of shadow parameters extracted from each micro-object shadow pattern, and found that a specific shadow parameter (peak-to-peak distance, PPD) demonstrated a linear relationship with the actual micro-object sizes. By using this information, a new algorithm suitable for operation on both a personal computer (PC) and a cell phone was also developed, providing automated size detection of poly-styrenemicro beads and biological cells such as red blood cells, MCF-7, HepG2, and HeLa. Results from the proposed device were compared with those of a conventional optical microscope, demonstrating good agreement between two approaches. In contrast to other existing cell and particle size measurement approaches, such as Coulter counter, flow-cytometer, particle-size analyzer, and optical microscope, this device can provide accurate cell and particle size information with a 2 um maximum resolution, at almost no cost (less than 100 USD), within a compact instrumentation size (9.3*9.0*9.0 cm(3)), and in a rapid manner (within 1 min). The proposed lens-free automated particle and cell size measurement device, based on shadow imaging technology, can be utilized as a powerful tool for many cell and particle handling procedures, including environmental, pharmaceutical, biological, and clinical applications. PMID- 25459054 TI - In vivo continuous and simultaneous monitoring of brain energy substrates with a multiplex amperometric enzyme-based biosensor device. AB - Enzyme-based amperometric biosensors are widely used for monitoring key biomarkers. In experimental neuroscience there is a growing interest in in vivo continuous and simultaneous monitoring of metabolism-related biomarkers, like glucose, lactate and pyruvate. The use of multiplex biosensors will provide better understanding of brain energy metabolism and its role in neuropathologies such as diabetes, ischemia, and epilepsy. We have developed and characterized an implantable multiplex microbiosensor device (MBD) for simultaneous and continuous in vivo monitoring of glucose, lactate, and pyruvate. First, we developed and characterized amperometric microbiosensors for monitoring lactate and pyruvate. In vitro evaluation allowed us to choose the most suitable biosensors for incorporation into the MBD, along with glucose and background biosensors. Fully assembled MBDs were characterized in vitro. The calculated performance parameters (LOD, LR, LRS, IMAX and appKM) showed that the multiplex MBD was highly selective and sensitive (LRS>=100 nA/mM) for each analyte and within an adequate range for in vivo application. Finally, MBDs were implanted in the mPFC of anesthetized adult male Wistar rats for in vivo evaluation. Following an equilibration period, baseline brain levels of glucose (1.3+/-0.2 mM), lactate (1.5+/-0.4 mM) and pyruvate (0.3+/-0.1 mM) were established. Subsequently, the MBDs recorded the responses of the animals when submitted to hyperglycemic (40% glucose i.v.) and hypoglycemic (5 U/kg insulin i.v.) challenges. Afterwards, MBDs were recalibrated to convert electrochemical readings into accurate substrate concentrations and to assess biofouling. The presented MBD can monitor simultaneously multiple biomarkers in vivo. PMID- 25459055 TI - Magnetic bead droplet immunoassay of oligomer amyloid beta for the diagnosis of Alzheimer's disease using micro-pillars to enhance the stability of the oil-water interface. AB - Despite scientific progress in the study of Alzheimer's disease (AD), it is still challenging to develop a robust and sensitive methodology for the early diagnosis of AD due to the lack of a decisive biomarker in blood. Recent reports on the oligomer amyloid beta (Abeta) as a biomarker demonstrated its possibility for identifying early onset of AD in patients, but its low concentration in blood requires highly reliable detection techniques. To overcome the low reliability and labor-intensive procedures of conventional enzyme-linked immunosorbent assay (ELISA), we present a magnetic bead-droplet immunoassay platform for simple and highly sensitive detection of oligomer Abeta for the diagnosis of AD. This microchip consists of chambers that contain water-based reagents or oil for consecutive assay procedures, and there are arrays of micro-pillars fabricated between the two adjacent chambers to form robust water-oil interfaces. With the aid of these micro-pillars, magnetic beads can stably pass through each chamber by linearly actuating a magnet along the microchip. The robust water-oil interface and simple procedures of the assay make it possible to obtain reliable results from this microchip. The intensity of the fluorescence at the read-out chamber increased quantitatively and linearly, depending on the amount of serially-diluted standard Abeta solution. The results of the assay indicated that the limit of detection was about 10 pg/mL even though it was done with manual manipulation of the magnet. This platform simplified the complicated ELISA procedure and achieved high sensitivity that was no lower than that of the conventional magnetic bead immunoassay. The magnetic bead-droplet platform reduced the assay time to 45 min, and it also reduced the amount of antibody usage in a single diagnosis significantly (10-30 ng of antibody per single assay). Consequently, this microfluidic chip has strong potential as a feasible system for use in the diagnosis of AD with a fast and easy immunoassay process, since the suggested platform can be automated with ease for point-of-care testing as well as high-throughput diagnostic equipment. PMID- 25459056 TI - Sensitive biosensor based on recombinant PP1alpha for microcystin detection. AB - A novel electrochemical microcystin-LR (MC-LR) biosensor based on the inhibition of recombinant protein phosphate type 1 (PP1alpha) is reported in this work. The use of innovative recombinant enzyme led to investigate new commercially available substrate, electrochemically active after their dephosphorylation by PP1alpha. Only two of selected substrates, 1-naphylphosphate and phosphoparacetamol, showed a good affinity toward PP1alpha. Kinetic parameters were performed by classical colorimetric assays and revealed that phosphoparacetamol is an excellent synthetic substrate with a Km value of 1.2 mM. The reported biosensor is constructed by entrapment of the enzyme in Polyvinyl Alcohol (azid unit) on Cobalt-Phtalocyanine (CoPC) modified screen printed electrode. Electrocatalytic mediator demonstrated a significant improvement in the electrochemical detection of dephosphorylated substrate. The standard inhibition curve has provided a limit of detection at 0.93 ug/L and a broad dynamic range from 0.93 to 40.32 MUg/L for MC-LR, demonstrating the improved analytical performance. PMID- 25459057 TI - Antithyroid drug detection using an enzyme cascade blocking in a nanoparticle based lab-on-a-chip system. AB - A methimazole (MT) biosensor based on a nanocomposite of magnetic nanoparticles (MNPs) functionalized with iridium oxide nanoparticles (IrOx NPs) and tyrosinase (Tyr) immobilized onto screen printed electrode (SPE) by using a permanent magnet is presented. This system is evaluated in batch mode via chelating copper at the active site of tyrosinase and in flow mode by thioquinone formation. The MT detection in flow mode is achieved using a hybrid polydimethylsiloxane/polyester amperometric lab-on-a-chip (LOC) microsystem with an integrated SPE. Both systems are very sensitive with low limit of detection (LOD): 0.006 MUM and 0.004 MUM for batch and flow modes, respectively. Nevertheless, the flow mode has advantages such as its reusability, automation, low sample volume (6 MUL), and fast response (20 s). Optimization and validation parameters such as enzyme-substrate amount, flow rate, inhibition conditions, repeatability and reproducibility of the biosensor have been performed. The proposed methods have been applied in MT detection in spiked human serum and pharmaceutical dosage forms. PMID- 25459058 TI - Detection and classification of natural odors with an in vivo bioelectronic nose. AB - The mammalian olfactory system is recognized as one of the most effective chemosensing systems. We thus investigated the potential of utilizing the rat's olfactory system to detect odors. By chronically coupling multiple microelectrodes to olfactory bulb of behaving rats, we extract an array of mitral/tufted cells (M/Ts) which could generate odor-specific temporal patterns of neural discharge. We performed multidimensional analysis of recorded M/Ts, finding that natural odors released from different fruit lead to distinct odor response patterns. Thus an array of M/Ts carried sufficient information to discriminate odors. This novel brain-machine interface using rat's olfaction presents a promising method for odor detection and discrimination, and it is the first step towards in vivo bioelectronic nose equipped with biological olfaction and artificial devices. PMID- 25459059 TI - Detection of the cyanobacterial toxin, microcystin-LR, using a novel recombinant antibody-based optical-planar waveguide platform. AB - Microcystins are a major group of cyanobacterial heptapeptide toxins found in freshwater and brackish environments. There is currently an urgent requirement for highly-sensitive, rapid and in-expensive detection methodologies for these toxins. A novel single chain fragment variable (scFv) fragment was generated and is the first known report of a recombinant anti-microcystin avian antibody. In a surface plasmon resonance-based immunoassay, the antibody fragment displayed cross-reactivity with seven microcystin congeners (microcystin-leucine-arginine (MC-LR) 100%, microcystin-tyrosine-arginine (MC-YR) 79.7%, microcystin-leucine alanine (MC-LA) 74.8%, microcystin-leucine-phenylalanine (MC-LF) 67.5%, microcystin-leucine-tryptophan (MC-LW) 63.7%, microcystin-arginine-arginine (MC RR) 60.1% and nodularin (Nod) 69.3%, % cross reactivity). Following directed molecular evolution of the parental clone the resultant affinity-enhanced antibody fragment was applied in an optimized fluorescence immunoassay on a planar waveguide detection system. This novel immuno-sensing format can detect free microcystin-LR with a functional limit of detection of 0.19 ng mL(-1)and a detection range of 0.21-5.9 ng mL(-1). The assay is highly reproducible (displaying percentage coefficients of variance below 8% for intra-day assays and below 11% for inter-day assays), utilizes an inexpensive cartridge system with low reagent volumes and can be completed in less than twenty minutes. PMID- 25459060 TI - A reusable robust radio frequency biosensor using microwave resonator by integrated passive device technology for quantitative detection of glucose level. AB - A reusable robust radio frequency (RF) biosensor with a rectangular meandered line (RML) resonator on a gallium arsenide substrate by integrated passive device (IPD) technology was designed, fabricated and tested to enable the real-time identification of the glucose level in human serum. The air-bridge structure fabricated by an IPD technology was applied to the RML resonator to improve its sensitivity by increasing the magnitude of the return loss (S21). The resonance behaviour, based on S21 characteristics of the biosensor, was analysed at 9.20 GHz with human serum containing different glucose concentration ranging from 148 268 mg dl(-1), 105-225 mg dl(-1) and at a deionised (D) water glucose concentration in the range of 25- 500 mg dl(-1) for seven different samples. A calibration analysis was performed for the human serum from two different subjects and for D-glucose at a response time of 60 s; the reproducibility, the minimum shift in resonance frequency and the long-term stability of the signal were investigated. The feature characteristics based on the resonance concept after the use of serum as an analyte are modelled as an inductor, capacitor and resistor. The findings support the development of resonance-based sensing with an excellent sensitivity of 1.08 MHz per 1 mg dl(-1), a detection limit of 8.01 mg dl(-1), and a limit of quantisation of 24.30 mg dl(-1). PMID- 25459061 TI - Biosensors: Fundamentals and applications - Historic book now open access. PMID- 25459062 TI - Reply to "The symbolic value of prostheses in maxillofacial rehabilitation". PMID- 25459064 TI - Influence of electrodes on the effective electromechanical coupling coefficient distributions of high-overtone bulk acoustic resonator. AB - In this paper, the influence of the electrodes on effective electromechanical coupling coefficient k(2)eff distribution of high-overtone bulk acoustic resonators (HBAR) is investigated using the four-layer thickness extension mode composite resonator model. The k(2)eff distributions and the spacing of the parallel resonance frequency (SPRF) distributions are calculated for HBARs with different electrode and substrate materials. The frequency of first peak fM in k(2)eff distribution curve is close to the frequency of first valley in SPRF distribution curve, which has the maximum deviation of about 20%. The fM ratio of Al0.1MUm-ZnO0.6MUm-Au0.1MUm-Sapphire400MUm to Au0.1MUm-ZnO0.6MUm-Al0.1MUm Sapphire400MUm is 1.91 which indicated that the k(2)eff distribution of HBAR is affected significantly by different electrode materials. We discuss for the first time the influence of the acoustic impedance ratio of the electrodes to substrate to the k(2)eff distribution, which is independent on the thickness ratio of the electrodes to piezoelectric film. It is found that for the pure-hard and pure soft substrate HBARs, the resonator frequency of piezoelectric sandwich structure can be used to estimate the resonator frequency fM of the first peak of k(2)eff curve, which has the maximum deviation of 7%. The fabricated HBAR(I) Al-ZnO-Al Sapphire and HBAR(II) Al-ZnO-Au-Sapphire shows identical outlines of k(2)eff and SPRF curves with the simulations, which have fMs of about 2GHz and 3GHz. The k(2)t of ZnO films are extracted from the first peak of the k(2)eff curve. The ZnO film deposited on Al and Au electrodes have k(2)t of 0.0597 and 0.0615, respectively. PMID- 25459063 TI - Trends in epidemiology and treatment and outcome for head and neck cancer: a population-based long-term analysis from 1996 to 2011 of the Thuringian cancer registry. AB - INTRODUCTION: The objective of this study was to examine patterns of care and survival in a population-based sample of patients with head neck cancer (HNC) who were treated in Thuringia, a federal state in Germany, between 1996 and 2011. METHODS: Data of 6291 patients with primary HNC from the Thuringian cancer registry were used to evaluate for patient's characteristics, tumor stage, incidence, and trends in treatment and overall survival (OS). RESULTS: The distribution between stages I-IV did not change significantly during the observation period. Crude incidences of HNC increased significantly between 1996 and 2011 from 13.77 to 20.39 (relative risk [RR]=1.34; 95% confidence interval [CI]=1.25-1.45). This increase was mainly driven by a significant increase of oropharynx cancer (from 3.29 to 5.85; RR=1.67; 95%CI=1.49-1.88) and cancer of the oral cavity (3.41-5.90; RR=1.5; 95%CI=1.33-1.69). The relative frequency of multimodal therapy increased (RR=1.42; 95%CI=1.3-1.55). The use of cetuximab increased (RR=473.32; 95%CI=51.57-4344.51). The 5-year and 10-year OS for the entire cohort was 49.1% and 34.1%, respectively. The multivariable analysis has proven that male gender, age ?60years, therapy without surgery, and TNM stage were independent significant negative risk factors for OS (all p<0.0001). CONCLUSIONS: OS did not improve during the study period. Incidence of oral cancer is significantly increasing. Although modern treatment strategies have been included in routine HNC care over the time, outcome has not improved significantly. PMID- 25459065 TI - Robust Suzuki-Miyaura cross-coupling on DNA-linked substrates. AB - The Suzuki-Miyaura cross-coupling is one of the most widely employed reactions in medicinal chemistry. To apply this reaction to DNA-encoded library technology (ELT), an alternative approach in the discovery of small molecule hits and leads, we explored the Suzuki-Miyaura cross-coupling on DNA-linked aryl halides. Pd(PPh3)4 was demonstrated to be an effective catalyst for cross-coupling with on DNA halide substrates under aqueous conditions. It efficiently catalyzes the coupling of phenyl halides (iodide or bromide) and pyridinyl bromides with various boronic acids/esters, including challenging heterocyclic boronic acids/esters. PMID- 25459066 TI - Simple surface treatment of cell-culture scaffolds with ultrafine bubble water. AB - We propose a novel method to treat polymeric scaffold surfaces for cell culture with water containing nanobubbles, called ultrafine bubbles (UFBs), with typical diameters less than 1 MUm. A thin film of polystyrene (PS) prepared on a solid substrate was exposed to UFB water for 2 days at room temperature. The PS surface was characterized by X-ray photoelectron spectroscopy (XPS), static contact angle measurements in water, and atomic force microscopy (AFM). The surface chemical composition and wettability of PS films remained unchanged after treatment, so that aggregation states of PS at film surfaces remained unaltered by UFB water. On the other hand, after treatment, many UFBs were adsorbed on hydrophobic PS surfaces. To study the effect of UFBs on scaffold properties, the adsorption behavior of fibronectin, which is a typical extracellular matrix protein involved in cell adhesion and proliferation, was examined. While the effect on the adsorption was unclear, the structural denaturation of fibronectin was enhanced after UFB treatment, so that the proliferation of fibroblast cells on PS surfaces was promoted. PMID- 25459067 TI - [Management of resistant hypertension. Expert consensus statement from the French Society of Hypertension, an affiliate of the French Society of Cardiology]. AB - To improve the management of resistant hypertension, the French Society of Hypertension, an affiliate of the French Society of Cardiology, has published a set of eleven recommendations. The primary objective is to provide the most up-to date information, based on the strongest scientific rationale and which is easily applicable to daily clinical practice for health professionals working within the French health system. Resistant hypertension is defined as uncontrolled blood pressure (BP) both on office measurements and confirmed by out-of-office measurements despite a therapeutic strategy comprising appropriate lifestyle and dietary measures and the concurrent use of three antihypertensive agents including a thiazide diuretic, a renin-angiotensin system blocker (ARB or ACEI) and a calcium channel blocker, for at least four weeks, at optimal doses. Treatment compliance must be closely monitored, as most factors that are likely to affect treatment resistance (excessive dietary salt intake, alcohol, depression and drug interactions, or vasopressors). If the diagnosis of resistant hypertension is confirmed, the patient should be referred to a hypertension specialist to screen for potential target organ damage and secondary causes of hypertension. The recommended treatment regimen is a combination therapy comprising four treatment classes, including spironolactone (12.5 to 25mg/day). In the event of a contraindication or a non-response to spironolactone, or if adverse effects occur, a beta-blocker, an alpha-blocker, or a centrally acting antihypertensive drug should be prescribed. Because renal denervation is still undergoing assessment for the treatment of hypertension, this technique should only be prescribed by a specialist hypertension clinic. PMID- 25459068 TI - Modified simultaneous integrated boost radiotherapy for unresectable locally advanced breast cancer: preliminary results of a prospective clinical trial. AB - BACKGROUND: The purpose of this study was to evaluate the effect of modified simultaneous integrated boost (SIB) radiotherapy for patients with extensive breast cancer. PATIENTS AND METHODS: Patients with macroscopic tumor and histologically proven adenocarcinoma of the breast were enrolled in the study. Patients were included whether they had or did not have previous surgery, chemotherapy, hormone therapy, or molecular targeted therapy; patients with past history of thoracic radiotherapy were excluded. Under conditions of not exceeding the tolerance dose for normal tissue, irradiation to the tumor was increased to the maximum possible extent using the modified SIB technique. RESULTS: Three breast cancer patients were treated with the modified SIB technique. All patients were diagnosed as T4b (median maximum diameter of the tumor: 16 cm; range, 15.5 22 cm), and all patients exhibited symptoms because of the extremely large tumor. The median total dose to the part of tumor tissue was 128.8 Gy (range, 110-140 Gy). Total dose to normal tissue was < 72 Gy in all patients. Although large tumors were radio-resistant, it was macroscopically confirmed that all tumors eventually disappeared. Although skin defects persisted because of tumor disappearance, there were no Grade >= 3 toxicities due to radiotherapy. CONCLUSION: Although much care is required in delivering extremely high doses of radiotherapy to the tumor, modified SIB radiotherapy was shown to be effective against extremely large tumors that could not be controlled using conventional radiotherapy. In future, an increase in the number of study patients and establishment of the technique will be required. PMID- 25459069 TI - Unique characteristics and failure patterns of metaplastic breast cancer in contrast to invasive ductal carcinoma: a retrospective multicenter case-control study (KROG 13-07). AB - BACKGROUND: This retrospective study was performed to investigate the need for management modification in MBC according to evaluation of characteristics and failure patterns compared with IDC. PATIENTS AND METHODS: We performed this multicenter study taking MBC and randomly assigned IDC cases matched for age (+/- 3 years), pathologic stage (T and N), locoregional treatment methods (surgery with or without radiation therapy), and period of treatment (+/- 6 months) that occurred from January 1999 to November 2011 in the 6 institutions of the Korean Radiation Oncology Group. RESULTS: A total of 144 female MBC patients were enrolled. The median follow-up was 51 months (range, 1-186 months). The rates of positivity for estrogen receptor (P < .001), progesterone receptor (P < .001), and HER2 (P = .007) were significantly lower in MBC patients. During follow-up, recurrence developed in 22 (15.3%) MBC and 6 (4.2%) IDC patients (P = .002). The median time to recurrence of MBC and IDC was 15 months and 24 months, respectively. Most instances of recurrence in MBC developed in the triple negative (TN) subgroup (TN-MBC). In particular, locoregional recurrence developed exclusively in the TN-MBC subgroup. In the TN-MBC subgroup, the number of risk factors (pT2-3, N1-3) was related to significant differences in overall survival (P = .001) and recurrence-free survival (P < .001). CONCLUSION: The MBC patients had a higher rate of TN, poorer differentiation, and a higher recurrence rate than did the IDC patients. Considering the unique characteristics and failure patterns, it is necessary to modify the current management guidelines for MBC. PMID- 25459070 TI - Disease-free survival according to the use of postmastectomy radiation therapy after neoadjuvant chemotherapy. AB - INTRODUCTION: The purpose of the study was to determine predictors of recurrence for patients treated with neoadjuvant chemotherapy (NAC) and mastectomy according to the use of postmastectomy radiation therapy (PMRT). PATIENTS AND METHODS: An analysis of 161 clinically staged T1 to T3/N0 to N3 patients treated with NAC and mastectomy with and without PMRT at our institution from 2003 to 2010 was conducted. The Kaplan-Meier product limit method was used to estimate survival and time to recurrence rates and the log-rank test was used to compare groups. A Cox proportional hazard regression analysis was carried out for time to recurrence, radiation therapy, and their interaction in the model. RESULTS: The median follow-up period was 48 months and 18 patients developed a recurrence. The 5-year recurrence rate and overall survival was 16.1% (95% confidence interval [CI], 9.6%-26.3%) and 93.6% (95% CI, 88.2%-97.0%), respectively. Patients who underwent PMRT had a decreased risk of recurrence compared with patients who did not (hazard ratio [HR], 0.25; 95% CI, 0.097-0.661; P < .005). The 5-year disease free survival (DFS) rate for those who received PMRT was 91.3% (95% CI, 82.8% 95.7%) and 64.8% (95% CI, 37.8%-82.4%) for those who did not (P = .0126). Among all clinicopathologic factors examined, pathologic T stage (ypT) and pathological N stage (ypN) significantly correlated with the risk of recurrence (P < .05). Patients with any pathological nodal disease had an increased risk of recurrence compared with patients who were pathologically node-negative (HR, 7.196; 95% CI, 2.05-25.264; P < .002). CONCLUSION: Patients treated with NAC and mastectomy, but without PMRT had a higher risk recurrence with increasing ypT and ypN stages. PMRT might increase DFS. PMID- 25459071 TI - Student-Assisted Services (SAS): an innovative clinical education model that prepares graduates for the future, contributes to health service delivery, and addresses internship shortages. PMID- 25459072 TI - A matter of location: influence of G-quadruplexes on Escherichia coli gene expression. AB - We provide important insights into secondary-structure-mediated regulation of gene expression in Escherichia coli. In a comprehensive survey, we show that the strand orientation and the exact position of a G-quadruplex sequence strongly influence its effect on transcription and translation. We generated a series of reporter gene constructs that contained systematically varied positions of quadruplexes and respective control sequences inserted into several positions within the promoter, 50-UTR, and 30-UTR regions. G-rich sequences at specific locations in the promoter and also in proximity to the ribosome-binding site (RBS) showed pronounced inhibitory effects. Additionally, we rationally designed a system where quadruplex formation showed a gene-activating behavior. Moreover, we characterized quadruplexes in proximity to the RBS that occur naturally in E. coli genes, demonstrating that some of these quadruplexes exert significant modulation of gene expression. Taken together, our data show strong position dependent effects of quadruplex secondary structures on bacterial gene expression. PMID- 25459073 TI - A novel murine model of established Staphylococcal bone infection in the presence of a fracture fixation plate to study therapies utilizing antibiotic-laden spacers after revision surgery. AB - Mice are the small animal model of choice in biomedical research due to the low cost and availability of genetically engineered lines. However, the devices utilized in current mouse models of implant-associated bone infection have been limited to intramedullary or trans-cortical pins, which are not amenable to treatments involving extensive debridement of a full-thickness bone loss and placement of a segmental antibiotic spacer. To overcome these limitations, we developed a clinically faithful model that utilizes a locking fracture fixation plate to enable debridement of an infected segmental bone defect (full-thickness osteotomy) during a revision surgery, and investigated the therapeutic effects of placing an antibiotic-laden spacer in the segmental bone defect. To first determine the ideal time point for revision following infection, a 0.7 mm osteotomy in the femoral mid-shaft was stabilized with a radiolucent PEEK fixation plate. The defect was inoculated with bioluminescent Staphylococcus aureus, and the infection was monitored over 14 days by bioluminescent imaging (BLI). Osteolysis and reactive bone formation were assessed by X-ray and micro computed tomography (micro-CT). The active bacterial infection peaked by 5 days post-inoculation, however the stability of the implant fixation became compromised by 10-14 days post-inoculation due to osteolysis around the screws. Thus, day 7 was defined as the ideal time point to perform the revision surgery. During the revision surgery, the infected tissue was debrided and the osteotomy was widened to 3mm to place a poly-methyl methacrylate spacer, with or without vancomycin. Half of the groups also received systemic vancomycin for the remaining 21 days of the study. The viable bacteria remaining at the end of the study were measured using colony forming unit assays. Volumetric bone changes (osteolysis and reactive bone formation) were directly measured using micro-CT image analysis. Mice that were treated with local or systemic vancomycin did not display gross pathology at the end of the study. While localized vancomycin delivery alone tended to decrease the bacterial burden and osteolysis, these effects were only significant when combined with systemic antibiotic therapy. This novel mouse model replicates key features of implant-associated osteomyelitis that make treatment extremely difficult, such as biofilm formation and osteolysis, and imitates the clinical practice of placing an antibiotic-laden spacer after infected tissue debridement. In addition, the model demonstrates the limitations of current PMMA spacers and could be an invaluable tool for evaluating alternative antimicrobial treatments for implant-associated bone infection. PMID- 25459074 TI - National Institutes of Health State of the Science Symposium in Therapeutic Apheresis: scientific opportunities in extracorporeal photopheresis. AB - The clinical use of extracorporeal photopheresis (ECP) for accepted indications such as graft-versus-host disease, transplant rejection, and cutaneous T-cell lymphoma continues to increase. Expanded applications for ECP, such as the treatment of select autoimmune diseases, are being explored. Extracorporeal photopheresis's capacity to both immunotolerize in the autoreactive setting, while immunizing against a lymphoma is unusual and suggestive of a unique mechanism. It is likely that ECP's induction of dendritic cells is key to its efficacy in both of these settings, but exactly how ECP impacts other immune components and their interactions is not fully understood. Further basic science research is necessary to elucidate how these dissimilar cellular activities are functionally integrated. On the clinical side, collaborative multicenter trials designed to recognize the principal variables controlling therapeutic responses and improve prognostic indicators may enable tailoring devices, treatment schedules, and doses to the needs of the individual patients or diseases. This review describes our current understanding of how ECP influences the immune system, reviews the existing clinical applications of ECP, and explores areas for future basic science and clinical research as presented at the National Institutes of Health State of the Science Symposium in Therapeutic Apheresis in November 2012. PMID- 25459075 TI - Superovulatory response and embryo development in ewes treated with two doses of bovine somatotropin. AB - This study evaluated whether the administration of 50 and 100mg bovine somatotropin (bST) at the start of synchronization and at the time of natural mating in ewes improves the ovulation rate, embryonic development and pregnancy rate of transferred embryos. Forty-eight donors were assigned to three treatments: the bST-100 treatment (n=15) received 100mg bST at the start of synchronization and at natural mating, the bST-50 treatment (n=15) received 50mg bST on the same schedule as the previous group, and the control (n=18) did not receive any bST. Two embryos were transferred to each recipient (n=121): 35 received embryos from bST-100; 50 received embryos from bST-50, and 36 received embryos from the control. The superovulatory rate, percentage of recovered structures, cleavage rate, percentage of transferable embryos, embryo quality and development and pregnancy rate were analyzed using the GENMOD procedure of SAS. The number of corpora lutea and the cell number were analyzed using the GLM procedure of SAS. The insulin and IGF-1 concentrations were analyzed with ANOVA for repeated measures. The bST application did not affect the superovulatory rate, number of corpora lutea and recovered structures (P>0.05). The numbers of transferable embryos and embryos reaching the blastocyst were higher (P<=0.01) in the bST-50 (96.4+/-3.6% and 69.0+/-7.8%) than the bST-100 (93.0+/-4.5% and 27.2+/ 38.9%) and control (87.7+/-5.4% and 50.4+/-6.4%) groups. The insulin and IGF-1 concentrations were higher (P<0.05) in the bST-treated groups, but the insulin concentration was higher (P<0.05) in the bST-100 group than in the bST-50 group. The pregnancy rate was similar (P=0.21) in ewes receiving embryos from the two treatments [bST-50, (70.0%); bST-100, (62.5%), and control, (56.6%)]. The administration of 50mg bST at the start of synchronization and at natural mating in superovulated ewes was concluded to enhance the proportion and development of transferable embryos. However, bST did not affect the pregnancy rate of transferred embryos. PMID- 25459077 TI - Role of body condition score and body weight in the control of seasonal reproduction in Blanca Andaluza goats. AB - The reproductive activity of 84 female Blanca Andaluza goats was monitored over 17 months to determine the role of body condition score (BCS) and body weight (BW) in its control. Following a 3*2 factorial experimental design, the animals were allocated to three groups: low BCS (<=2.50, n=24), medium BCS (BCS=2.75 3.00, n=31) and high BCS (>=3.25, n=29). The same animals, irrespective of the BCS group categorization, were also divided into two groups depending on BW: low BW (<=40kg, n=44) and high BW (>40kg, n=40). Oestrus was evaluated daily using vasectomised males. The ovulation rate was assessed by trans-rectal ultrasonography after the identification of oestrus. Ovulations were determined by monitoring the plasma progesterone concentration weekly. The BCS and BW were recorded once a week and nutritional status adjusted to maintain the initial differences in BW and BCS between the groups. Both BCS and BW had a significant (at least P<0.05) influence on the onset, the end, and the duration of the breeding season, with longer periods of reproductive activity recorded in does with a BCS of >=2.75 and BW of >40kg. No significant interaction between these variables was observed. Some (11.7%) of the does in the groups with animals of BCS>=2.75 had ovulations during seasonal anoestrus. None of the does with a BCS of <=2.5 had ovulations during seasonal anoestrus. The ovulation rate of the first and last oestrus was influenced by BW (P<0.01). These results demonstrate that Blanca Andaluza goats show marked reproductive seasonality that is clearly and independently modulated by BCS and BW. PMID- 25459076 TI - Prostaglandin receptors (EP2 and EP4) and angiotensin receptor (AGTR2) mRNA expression increases in the oviducts of Nelore cows submitted to ovarian superstimulation. AB - Many peptides are responsible for the coordination of muscle contraction, secretion and ciliary beating of the oviduct epithelium to allow the transport of gametes and embryos, including vascular endothelial growth factors (VEGF), prostaglandins (PGs), endotelin-1 (ET-1) and angiotensin II (Ang II). The effect of reproductive biotechnologies used to improve embryo yield on oviduct gene expression is poorly understood. Thus, the aim of the present study was to evaluate the effect of ovarian superstimulation on the mRNA expression of the genes encoding the major peptides involved in oviduct contraction in bovine. Therefore, Nelore cows were submitted to P-36 (n=5) or P-36/eCG (n=5) ovarian superstimulatory protocols and a control group of cows was not submitted to any superstimulatory protocol (n=5). The relative expression of VEGF (VEGF, Flk1, Flt1), Ang II (AGTR2, ACE1), ET1 (ET1, ECE1) and PG pathway members (PGES, EP2, EP4, COX1, COX2) was analyzed using real time RT-PCR in each of oviduct segment (infundibulum, ampulla and isthmus). All target genes were expressed in the three segments of the bovine oviduct; however, specific genes were regulated by ovarian superstimulation: EP2 and EP4 receptors mRNA was affected by P-36/eCG protocol, in the ampulla and infundibulum, respectively; and AGTR2 mRNA was up-regulated by both the P-36/eCG and P-36 protocols in the isthmus. The upregulation of EP2, EP4 and AGTR2 expression in the superstimulated cows suggests a suitable effect of FSH and eCG on bovine oviduct physiology, coordinating the contraction in Nelore cows. PMID- 25459078 TI - Enzymatic scavengers in the epididymal fluid: comparison between pony and miniature breed stallions. AB - The use of stallion semen collected from cauda epididymis for AI has increased due to the new protocols available for cryopreservation. Preserving the genetic material from valuable males that suffer sudden death or other events that prematurely end the stallion's reproductive life is an important strategy for Stud breeding management. While protecting spermatozoa from oxidative stress and infectious agents, the epididymis promotes the enhancement of sperm cell morphology and changes in membrane protein profile, increasing its fertility potential. The epididymal fluid must be a balanced redox environment to allow sperm preservation and protein-protein and protein-lipids interactions to quantify. The aim of this study was quantify the enzymatic ROS scavengers in epididymal fluid of pony and miniature breed stallions. Epididymides from 8 pony stallions and 12 miniature breed stallions were dissected and fluid from caput, corpus and cauda epididymis collected. Spermatozoa were separated of epididymal fluid by 2-step centrifugation. The activities of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) were measured and compared between stallion groups and epididymal regions. The three enzymes were present in all epididymal regions tested, with higher activities of catalase and SOD in cauda epididymis in miniature breed stallions (P<0.05). GPx activity was higher in caput epididymis in pony stallions (P<0.05), however with no difference to fluid from cauda epididymis of both breeds. These results show a difference in antioxidant enzymatic scavengers between pony and miniature breed stallions. Also, our data confirm the protective role of cauda epididymis, preserving spermatozoa integrity from oxidative damage. As glutathione peroxidase is involved in several signaling pathways, its constant activity during epididymal transit corroborates the importance of this enzyme for spermatozoa maturation. PMID- 25459079 TI - A genome-wide association study reveals a novel candidate gene for sperm motility in pigs. AB - Sperm motility is one of the most widely used parameters in order to evaluate boar semen quality. However, this trait can only be measured after puberty. Thus, the use of genomic information appears as an appealing alternative to evaluate and improve selection for boar fertility traits earlier in life. With this study we aimed to identify SNPs with significant association with sperm motility in two different commercial pig populations and to identify possible candidate genes within the identified QTL regions. We performed a single-SNP genome-wide association study using genotyped animals from a Landrace-based (L1) and a Large White-based (L2) pig populations. For L1, a total of 602 animals genotyped for 42,551 SNPs were used in the association analysis. For L2, a total of 525 animals genotyped for 40,890 SNPs were available. After the association analysis, a false discovery rate q-value <=0.05 was used as the threshold for significant association. No SNPs were significantly associated with sperm motility in L1, while six SNPs on Sus scrofa chromosome 1 (position 117.26-119.56Mb) were significant in L2. The mitochondrial methionyl-tRNA formyltransferase (MTFMT) gene, which affects translation efficiency of proteins in sperm cells, was identified as a putative candidate gene. The significant markers identified in this study may be useful to enhance the genetic improvement of sperm motility by selection of boars at an earlier age under a marker assisted selection strategy. PMID- 25459080 TI - Characterization and cardiac differentiation of chicken spermatogonial stem cells. AB - Spermatogonial stem cells (SSCs), a unique population of germline stem cells in adult testis, have the capability to self-renew and produce daughter cells destined to differentiate into spermatozoa throughout the life of the bird. Chicken SSCs were successfully isolated from testicular cells and subsequent analysis was performed to identify pluripotent cells by investigation with cytochemical reagents including Periodic acid-Schiff (PAS), alkaline phosphatase (AP), and antibodies to germline cell specific (DAZL or VASA) and stage-specific embryonic antigens (Oct4, SSEA1, SSEA3, SSEA4, TRA-1-60, and TRA-1-81). Results confirmed these as germline cells with the expression of DAZL (Deleted in Azoospermia-Like) and VASA genes in isolated cells. Immunochemistry results showed that multipotent germline stem cells (mGSCs) expressed these gene markers related to embryonic stem cells (ESCs) and could spontaneously differentiate into three embryonic germ (EG) layers in vitro. The mGSC-derived cardiomyocytes expressed cardiac-specific markers such as sarcomeric alpha actinin, alpha cardiac actinin; conexin-43, the major protein of gap junctions which are thought to have an important role in the synchronized contraction of the heart and in embryonic development; and cardiac troponin T, the tropomyosin binding subunit of the troponin complex which regulates muscle contraction. Furthermore, reverse transcription polymerase chain reaction (RT-PCR) results indicated that the genes related to cardiac transcription factors were expressed following differentiation. Results of the present study strongly contribute to the information related to the ability of chicken mGSCs to differentiate into cells such as contraction cardiomyocytes similar to ESCs and may provide a new source of cardiomyocytes for basic research and potential therapeutic application in various cardiac degenerative diseases of birds and other animals. PMID- 25459081 TI - Effect of butylated hydroxytoluene (BHT) on the cryopreservation of common carp (Cyprinus carpio) spermatozoa. AB - The aim of the present study was to test the effects of butylated hydroxytoluene (BHT) on the cryopreservation of common carp spermatozoa. BHT is widely used in the cryopreservation of the spermatozoa of different animal species and successfully sustains the characteristics of spermatozoa during freezing and thawing, but it has not previously been used with fish. After sampling, common carp spermatozoa were diluted with an extender composed of modified Kurokura's extender, 10% DMSO, and 10% egg yolk containing 0.0001, 0.001, 0.01, 0.1, 1, 2.5, 5, or 10mM BHT and subsequently frozen in liquid nitrogen. The post-thaw spermatozoa characteristics (i.e., progressive motility percentage (%), duration of progressive motility (s), fertilization rate (%), and eyed-eggs rate (%)) were evaluated and compared with those of the control group. There were significant increases in the percentage of progressive motility and the duration of progressive motility at the concentrations of 0.1 and 0.001mM BHT (P<0.05). The duration of post-thawed spermatozoa progressive motility at 0.001mM BHT was significantly greater than that of the other groups (39.6+/-0.4s, P<0.05), and the fertilization rates and eyed-eggs rates were also higher following the 0.1 and 1mM BHT treatments. BHT at concentrations of more than 1mM caused sperm immobility during the preparatory stages of the sperm freezing. We concluded that 0.001-0.1mM BHT can be beneficial for the cryopreservation of common spermatozoa. PMID- 25459083 TI - Aryne polymerization enabling straightforward synthesis of elusive poly(ortho arylene)s. AB - Herein we present the first straightforward aryne polymerization that successively connects aromatic rings at their ortho-positions, directly giving poly(ortho-phenylene)s of up to ca. 100-mer size. The polymerization proceeds smoothly in a chain-growth fashion in the presence of a monovalent copper reagent. Direct synthesis of poly(ortho-arylene)s has been a "missing piece" of aromatic chemistry for a long time (although the discovery of arynes dates back to 1902), in contrast to the well-investigated para- and meta-linked polyarylenes. Our achievement reported here is expected to open up new areas of nanocarbon and materials science. PMID- 25459082 TI - Travel-related leptospirosis in Japan: a report on a series of five imported cases diagnosed at the National Center for Global Health and Medicine. AB - Leptospirosis is one of the most common travel-related infections. We report 5 cases of travel-related leptospirosis who presented at our clinic between January 2008 and December 2013. Patients were included in the study if they presented with a clinical profile that was compatible with the disease within 21 days of their return from traveling, which were laboratory-diagnosed as leptospirosis by blood culture, rise in antibody titers in paired sera using the microscopic agglutination test (MAT), and/or DNA detection using flaB-nested PCR. Five leptospirosis cases were evaluated, all of which contracted the disease after exposure to fresh water in Southeast Asian countries. All of the cases had fevers, headaches, conjunctival injections, and relative bradycardia. The pertinent laboratory findings included elevated C-reactive protein levels, elevated creatinine levels, and sterile pyuria. All 5 cases had serum MAT titers that increased by >= 4 times in the interval between specimens taken during the acute phase and those taken during the convalescence phase, and leptospiral DNA was detected in plasma and/or urine specimens in 4 cases. Leptospira interrogans was isolated from one patient's blood sample. Patients were treated with penicillin G, minocycline, or doxycycline. One case was cured without antibiotics. A diagnosis of leptospirosis should be considered for febrile travelers who return from Southeast Asian countries to Japan after being exposed to freshwater while traveling. PMID- 25459084 TI - Mervyn Susser, the last of the three American classical epidemiology tenors. PMID- 25459085 TI - Correlates of prediabetes and type II diabetes in US South Asians: findings from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study. AB - PURPOSE: In this study, we aim to elucidate the role of sociodemographic, lifestyle, and cultural factors in prediabetes and diabetes in South Asian immigrants to the United States, a population at high risk of type II diabetes. METHODS: We performed a cross-sectional analysis of a community-based cohort of 899 South Asians without known cardiovascular disease from the Mediators of Atherosclerosis in South Asians Living in America study. Glycemic status was determined by fasting glucose, 2-hour postchallenge glucose, and use of diabetes medication. We used multinomial logistic regression models to estimate the independent associations of sociodemographic, lifestyle, and cultural factors with prediabetes and diabetes, adjusting for confounders identified using directed acyclic graphs. RESULTS: Approximately 33% of participants had prediabetes and 25% had diabetes. In multivariate analyses, an independent correlate of prediabetes was low exercise. Additional covariates associated with diabetes included lower family income, less education, high chronic psychological burden score, and greater time spent watching television; and fasting monthly or annually was inversely associated with diabetes prevalence. CONCLUSIONS: We found several modifiable risk factors associated with prediabetes and diabetes that may help guide diabetes prevention interventions for South Asian immigrants to the United States. PMID- 25459087 TI - Antegrade-retrograde opposing lag screws for internal fixation of simple displaced talar neck fractures. AB - The talar neck is deviated medially with reference to the long axis of the body of the talus. In addition, it deviates plantarward. The talar neck fracture line is sometimes observed to be oriented obliquely (not perpendicular to the long axis of the talar neck). This occurs when the medially deviated talar neck strikes the horizontally oriented anterior lower tibial edge. Internal fixation of a simple displaced talar neck fracture usually requires 2 lag screws. Because the fracture line is obliquely oriented, a better method for positioning the screws perpendicular to the fracture line is to place them in a reversed direction to provide maximum interfragmentary compression at the fracture site, which could increase the likelihood of absolute stability with subsequent improvement in the incidence of fracture union and a reduction of complications, such as avascular necrosis of the body of the talus. Two lag screws are used, with the first inserted from posteriorly to anteriorly (perpendicular to the fracture line) using a medial approach after medial malleolar chevron osteotomy. The second screw is inserted from anteriorly to posteriorly (perpendicular to the fracture line) using an anterolateral approach. Both screw heads should be countersunk. A series of 8 patients underwent this form of internal fixation for talar neck fracture repair, with satisfactory functional outcomes. In conclusion, the use of antegrade-retrograde opposing lag screws is a reasonable method of internal fixation for simple displaced talar neck fractures. PMID- 25459086 TI - Preterm birth and long-term maternal cardiovascular health. AB - PURPOSE: To investigate whether preterm birth (PTB) is associated with greater cardiovascular disease (CVD) risk in a longitudinal cohort. METHODS: We examined differences in systolic blood pressure (SBP), diastolic blood pressure, insulin resistance (Homeostatic model assessment of insulin resistance), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein, triglycerides, C-reactive protein, and interleukin 6 at 3 years postpartum between women who delivered preterm (gestation <37 weeks; n = 54) versus term (>=37 weeks; n = 751) using multivariable linear regression. We also assessed relations with body mass index, weight change from prepregnancy, and waist circumference at 3 and 7 years postpartum. RESULTS: Median age at enrollment was 33.9 years (range: 16.4-44.9). After adjusting for age, race, prepregnancy body mass index, parity, marital status, education, and SBP during early pregnancy, women with PTB had 3.99 mm Hg (95% confidence interval, 0.82-7.16) higher SBP and 7.01 mg/dL (1.54-12.50) lower HDL than those who delivered at term. The association with SBP was attenuated after accounting for hypertension before or during pregnancy (2.78 mm Hg [-0.30 to 5.87]). PTB was not related to other postpartum outcomes. CONCLUSIONS: PTB is related to greater CVD risk by 3 years postpartum as indicated by higher SBP and lower HDL. Although these associations may be due to preexisting conditions exacerbated during pregnancy, PTB may flag high-risk women for more vigilant CVD monitoring and lifestyle interventions. PMID- 25459088 TI - Posterior Tibial Labrum Injury in a Professional Soccer Player: A Case Report. AB - Ankle ligament injuries are one of the most frequent lesions identified in professional soccer players. In most cases, the ligaments involved are the anterior talofibular ligament and the calcaneal fibular ligament. In the present report, we describe a professional soccer player who sustained an ankle sprain that did not respond to initial therapy. The findings from radiographic and magnetic resonance images were inconclusive. Ultimately, rupture of the posterior, transverse ligament with avulsion of the tibial labrum was identified as the cause of his ongoing ankle pain. Confirmation of the pathologic findings and successful treatment were performed arthroscopically. PMID- 25459089 TI - Retrograde Percutaneous Drilling for Osteochondritis Dissecans of the Head of the Talus: Case Report and Review of the Literature. AB - Osteochondral lesions of the talus might be a more common cause of pain than previously recognized, especially among those involved in athletic activities. However, the location of an osteochondral lesion on the talar head is much less common than such lesions localized to the dome of the talus and can pose diagnostic difficulties. We present the case of a 14-year-old soccer player who complained of longstanding pain in his left foot. After unsuccessful conservative treatment consisting of rest and bracing, he was ultimately treated with retrograde percutaneous drilling of the talar head performed by a medial approach. This was followed by casting and non-weightbearing for 6 weeks, after which physical therapy was undertaken. He was able to return to full activity and remained asymptomatic during a 5-year observation period. Although rare, osteochondritis dissecans of the talar head should be considered in young athletes with persistent foot pain that is unresponsive to reasonable therapy. PMID- 25459090 TI - Selecting Residents in Podiatric Medicine and Surgery. AB - Limited information exists to guide students of podiatric medicine and residency directors through the resident selection process. The present study aimed to evaluate the podiatric medicine and surgery resident selection process using an online survey. Residency directors of podiatric medicine and surgery programs across the United States and fourth-year students across all 9 colleges of podiatric medicine were contacted for participation. Two separate surveys were created, one for the directors and one for the students. The directors and students were asked the relative importance of 21 items considered in resident selection on a 7-point importance scale. Subsequent questions covered an array of related topics. The directors, compared with the students, identified the following items as more important (p < .05): previous disciplinary actions against the student, number of classes failed during school, undergraduate experiences and activities, number of Part I board attempts, class rank, involvement in research, and grade point average during podiatric medical school. The manual dexterity portion of the residency interview was considered significantly more important by the students than the directors. The directors more satisfied with their residents placed greater importance on the following items (p < .05): opinions of current residents, opinions of other attending physicians, and letters of recommendation. Additional trends and differences were also discovered. The results of the present study provide baseline data on the selection of podiatric medicine and surgery residents. PMID- 25459091 TI - Reconstruction of Traumatic Composite Tissue Defect of Medial Longitudinal Arch With Free Osteocutaneous Fibular Graft. AB - A 34-year-old male sustained a crush injury resulting in bone and soft tissue loss along the medial longitudinal arch of his left foot. Specifically, the injury resulted in loss of first metatarsal without injury to the medial cuneiform or proximal phalanx, fracture of the third metatarsal, and a 5-cm * 9 cm soft tissue defect overlying the dorsomedial aspect of the right foot. After debridement and daily wound care, the defect was subsequently reconstructed using a free osteocutaneous fibular graft. Approximately 6 months after reconstructive surgery, the patient returned to his job without pain, and his pedogram showed almost equal weightbearing distribution on both feet. PMID- 25459092 TI - Periarticular osteoid osteoma of the ankle: a report of nine arthroscopically treated patients. AB - Periarticular osteoid osteoma often presents with unspecific clinical symptoms, mimicking other clinical conditions. This can lead a clinician to a ''diagnostic side path'' and a delayed or missed diagnosis compared with extra-articular osteoid osteoma. We report the cases of 9 patients with a mean age of 22 (range 14 to 32) years who were diagnosed with periarticular osteoid osteoma of the ankle and were surgically treated in our department during a 12-year period. The diagnostic difficulties associated with periarticular osteoid osteoma must be resolved by obtaining a detailed patient history and performing a thorough physical examination. Computed tomography is the ultimate imaging method to confirm the suspicion of osteoid osteoma. Arthroscopic removal of the osteoid osteoma was performed in all 9 patients in the present case series, with synovectomy performed when indicated. Under arthroscopic visualization, a specimen was obtained for histopathologic analysis to confirm the diagnosis, followed by tumor excision. All the patients were pain free at the final follow up visit after a mean duration of 6 years (range 6 months to 12.7 years) postoperatively. We suggest arthroscopic removal of periarticular osteoid osteomas of the ankle as an effective treatment method, because it allows complete tumor excision, synovectomy when needed, a short postoperative rehabilitation period, and satisfactory functional results. PMID- 25459093 TI - Single Oblique Posterolateral Approach for Open Reduction and Internal Fixation of Posterior Malleolar Fractures With an Associated Lateral Malleolar Fracture. AB - The purpose of the present retrospective study was to describe the single oblique posterolateral approach for open reduction and internal fixation of large, displaced, posterior malleolar fractures with an associated lateral malleolar fracture. A single oblique posterolateral approach was used for osteosynthesis of the posterior and lateral malleolus in 50 consecutive patients (23 females [46%], 27 males [54%]; mean age, 47.44 +/- 16.13 years; mean follow-up duration, 26.32 +/- 5.15 months). The mean interval to surgery was 4.3 +/- 1.9 days after the inciting trauma. During the follow-up period, the surgery was complicated by skin necrosis around the incision in 2 (4%) patients and sural nerve damage in 2 (4%) patients. We found that the single oblique posterolateral approach to large, displaced, posterior malleolar fractures with an associated lateral malleolar fracture provided easy exposure of the posterior and lateral malleoli and had the potential to decrease the incidence of sural nerve injury because of the smaller incision size. PMID- 25459094 TI - Simultaneous use of lateral calcaneal ostectomy and subtalar arthroscopic debridement for residual pain after a calcaneal fracture. AB - Inadequate primary treatment of calcaneal fractures frequently results in persistent, residual pain. This can be caused by subtalar arthritis, an increased calcaneal width, and/or calcaneal fibular impingement of the peroneal tendons. Many patients experience multiple disorders simultaneously, requiring a combination of procedures to treat the injury. The purpose of the present study was to evaluate the clinical outcomes of arthroscopic debridement with lateral calcaneal ostectomy for residual pain after a calcaneal fracture. Four feet (4 patients) were treated with arthroscopic debridement and lateral calcaneal ostectomy. The patients were 3 males and 1 female, with a mean age of 55.3 +/- 14.1 years. The mean follow-up duration was 33.5 +/- 10.5 months postoperatively. Three patients received worker's compensation as a result of their condition. The patients were examined for improvement in pain levels using the numeric pain intensity scale and healing was assessed using the Japanese Society of Surgery of the Foot score. The mean Japanese Society of Surgery of the Foot score improved from 64.5 +/- 13.8 preoperatively to 82.5 +/- 7.1 postoperatively. The mean postoperative numeric pain intensity scale score was 2.3 +/- 1.9. No complications, such as deep infection or problems with wound healing, were observed in any of the patients. The simultaneous use of arthroscopic subtalar debridement and lateral calcaneal ostectomy is a valuable intervention for the treatment of residual pain after a calcaneal fracture in patients who present with increased calcaneal width and mild or no degenerative changes in the subtalar joint. PMID- 25459095 TI - Young adults' sources of contraceptive information: variations based on demographic characteristics and sexual risk behaviors. AB - OBJECTIVES: Sexual information sources used by young adults can influence their contraceptive knowledge and behaviors, yet little is known about sources most frequently used by young adults, especially by groups with histories of sexual risk involvement. STUDY DESIGN: Nationally representative data from 1800 unmarried young adults, aged 18-29 years, were analyzed to (1) examine the sources of contraceptive information most frequently used by young adults and (2) assess variations (if any) in source use based on demographic characteristics and sexual risk history (determined based on past sexual behaviors). RESULTS: "Doctors/nurses" was the most frequently used contraceptive information source reported by young adults. Significant variations existed in source use based on demographic characteristics and sexual risk history. Females were more likely to obtain contraceptive information from health care professionals, whereas males were more likely to report friends, partners, internet and television/radio as their frequently used source. Young adults with a sexual risk history were more likely to rely on doctors/nurses and less likely to report friends and internet as their frequently used source than those without a sexual risk history. Receiving contraceptive information from doctors/nurses was associated with greater accuracy in knowledge about contraceptive use and efficacy as compared to all other sources. CONCLUSIONS: Young adults' use of specific contraceptive information sources can vary based on their demographic characteristics and sexual risk involvement. Future research should identify better strategies to connect young adults, especially young males, with sexual risk histories to more reliable sources of information. PMID- 25459096 TI - Nitrous oxide for pain management of first trimester surgical abortion -- a randomized controlled pilot study. AB - OBJECTIVE: The objective was to determine feasibility of a study comparing mean pain scores between women randomized to nitrous oxide/oxygen (NO) versus oxygen+oral analgesics for trimester surgical abortion. STUDY DESIGN: Pilot randomized controlled trial comparing NO (n=10) versus oxygen+oral analgesics (n=10). Feasibility of subject recruitment, and pain and satisfaction scores on a visual analog scale were evaluated. RESULTS: Fifty-seven percent of eligible women participated. Mean pain scores were similar between groups, and mean satisfaction scores were higher for the NO group (77.5 vs. 46.7, P=.048). CONCLUSIONS: The majority of eligible women agreed to participate in this study evaluating an uncommon pain control intervention. PMID- 25459097 TI - Sino-implant (II)(r) continuation and effect of concomitant tenofovir disoproxil fumarate-emtricitabine use on plasma levonorgestrel concentrations among women in Bondo, Kenya. AB - OBJECTIVE: The objective was to assess associations between tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) exposure and levonorgestrel (LNG) concentrations among Kenyan HIV prevention trial participants using Sino-implant (II) LNG implants for contraception. METHODS: Women were offered implants among other contraceptive methods, were randomized to daily TDF-FTC or placebo, and followed monthly up to 56weeks. Associations between TDF-FTC exposure and mean LNG values were analyzed with linear mixed models. RESULTS: Of 739 women, 29 (3.9%) received implants with no incident pregnancies and one discontinuation. Mean LNG concentrations over 56weeks among 28 women contributing data ranged between 214.0 and 659.8pg/mL with no significant difference between TDF-FTC and placebo arms or between variable levels of TDF-FTC adherence. CONCLUSION: Concomitant TDF-FTC use was not associated with a significant change in plasma LNG concentrations among women using Sino-implant (II) in the first year of use. PMID- 25459098 TI - Randomized comparison of bleeding patterns in women using a combined contraceptive vaginal ring or a low-dose combined oral contraceptive on a menstrually signaled regimen. AB - OBJECTIVES: To compare bleeding patterns for 12 months continuous use of a contraceptive ring [contraceptive vaginal ring (CVR)] and pill [combined oral contraceptive (COC)] on a menstrually signaled regimen and the effectiveness of 4 days "treatment withdrawal" to stop bleeding. STUDY DESIGN: Women, 66 to each group, were randomized to continuous use of a CVR (15 mcg ethinyl estradiol/150 mcg etonogestrel) or a low-dose pill (20 mcg ethinyl estradiol/100 mcg levonorgestrel) for 360 days on a menstrually signaled regimen. Bleeding/spotting days, daily use of ring or pill, was recorded. Endpoint was the total number of bleeding/spotting days for each method over four 90-day reference periods (RP) plus the analysis of bleeding patterns using modified World Health Organization criteria. RESULTS: There was a reduction in the mean (+/-S.D.) number of bleeding/spotting days from RP1 (CVR 14.2+/-10; pill 16.6+/-10.9) to RP4 (CVR 8.8+/-9.6; pill 8.8+/-9.1). Fifteen percent of CVR and 4% COC users experienced amenorrhea or infrequent bleeding throughout the study. Amenorrhea increased over time (RP1 vs. RP4: CVR 10% vs. 21% and COC 2% vs. 30%). Compliance with the menstrually signaled regimen was poor. Ceasing hormones for 4 days stopped a bleeding episode within 5 days in the majority of episodes and many stopped spontaneously. CONCLUSION: Bleeding patterns with continuous use of the CVR and COC are similar and improve over 1 year of use. The unpredictability, but short duration, of bleeding episodes should be stressed during counseling. IMPLICATION: This information for clinicians and women about breakthrough bleeding patterns with use of a CVR or combined pill over 12 months using a menstrually signaled regimen will give women an indication of what to expect with continuous use. PMID- 25459099 TI - Letter to the editor re: article: "a systematic review of the safety, efficacy and acceptability of task sharing tubal sterilization to mid-level providers" by Rodriguez and Gordon-Maclean (Epub). PMID- 25459100 TI - The role of material, psychosocial and behavioral factors in mediating the association between socioeconomic position and allostatic load (measured by cardiovascular, metabolic and inflammatory markers). AB - Lower socioeconomic position (SEP), both accumulated across the life course and at different life-stages, has been found to be associated with higher cumulative physiological burden, as measured by allostatic load. This study aimed to identify what factors mediate the association between SEP and allostatic load, as measured through combining cardiovascular, metabolic and inflammatory markers. We explored the role of material, psychological and behavioral factors, accumulated across two periods in time, in mediating the association between SEP and allostatic load. Data are from the West of Scotland Twenty-07 Study, with respondents followed over five waves of data collection from ages 35 to 55 (n=999). Allostatic load was measured by summing nine binary biomarker scores ('1'=in the highest-risk quartile) measured when respondents were 55years old (wave 5). SEP was measured by a person's accumulated social class over two periods All mediators and SEP were measured at baseline in 1987 and 20years later and combined to form accumulated measures of risk. Material mediators included car and home ownership, and having low income. The General Health Questionnaire (GHQ-12) was used as the psychosocial mediator. Behavioral mediators included smoking, alcohol consumption, physical activity and diet. Path analysis using linear regressions adjusting for sex were performed for each of the potential mediators to assess evidence of attenuation in the association between lower SEP and higher allostatic load. Analyses by mediator type revealed that renting one's home (approximately 78% attenuation) and having low income (approx. 62% attenuation) largely attenuated the SEP-allostatic load association. GHQ did not attenuate the association. Smoking had the strongest attenuating effect of all health behaviors (by 33%) with no other health behaviors attenuating the association substantially. Material factors, namely home tenure and income status, and smoking have important roles in explaining socioeconomic disparities in allostatic load, particularly when accumulated over time. PMID- 25459102 TI - beta2-Adrenergic receptors in immunity and inflammation: stressing NF-kappaB. AB - beta2-Adrenergic receptors (beta2-ARs) transduce the effects of (nor)epinephrine on a variety of cell types and act as key mediators of the body's reaction to stress. beta2-ARs are also expressed on immune cells and there is ample evidence for their role in immunomodulation. A key regulator of the immune response and a target for regulation by stress-induced signals is the transcription factor Nuclear Factor-kappaB (NF-kappaB). NF-kappaB shapes the course of both innate and adaptive immune responses and plays an important role in susceptibility to disease. In this review, we summarise the literature that has been accumulated in the past 20years on adrenergic modulation of NF-kappaB function. We here focus on the molecular basis of the reported interactions and show that both physiological and pharmacological triggers of beta2-ARs intersect with the NF-kappaB signalling cascade at different levels. Importantly, the action of beta2-AR-derived signals on NF-kappaB activity appears to be highly cell type specific and gene selective, providing opportunities for the development of selective NF-kappaB modulators. PMID- 25459101 TI - The role of the ventral striatum in inflammatory-induced approach toward support figures. AB - Although considerable research has shown that inflammation leads to social withdrawal more generally, it is also possible that inflammation leads to social approach when it comes to close others. Whereas it may be adaptive to withdraw from strangers when sick, it may be beneficial to seek out close others for assistance, protection, or care when sick. However, this possibility has never been explored in humans nor have the neural substrates of these behavioral changes. Based on the role of the ventral striatum (VS) in responding to: (1) the anticipation of and motivation to approach rewarding outcomes and (2) viewing social support figures, the VS may also be involved in sickness-induced approach toward support figures. Thus, the goal of the present study was to examine whether inflammation leads to a greater desire to approach support figures and greater VS activity to viewing support figures. To examine this, 63 participants received either placebo or low-dose endotoxin, which safely triggers an inflammatory response. Participants reported how much they desired to be around a self-identified support figure, and viewed pictures of that support figure while undergoing an fMRI scan to assess reward-related neural activity. In line with hypotheses, endotoxin (vs. placebo) led participants to report a greater desire to be around their support figure. In addition, endotoxin (vs. placebo) led to greater VS activity to images of support figures (vs. strangers), and greater increases in inflammation (IL-6 levels) were associated with greater increases in VS activity. Together, these results reveal a possible neural mechanism important for sickness-induced social approach and highlight the need for a more nuanced view of changes in social behavior during sickness. PMID- 25459103 TI - Comparison of centrally injected tryptophan-related substances inducing sedation in acute isolation stress-induced neonatal chicks. AB - In the present study, we first focused on the function of l-tryptophan (TRP) metabolites which are synthesized in different metabolic pathways, namely, the kynurenine (KYN) pathway and serotonin (5-HT) pathway during an acute isolation stress. When l-TRP metabolites were intracerebroventricularly injected on an equimolar basis (100 nmol), 5-HT induced a sedative effect in neonatal chicks. Additionally, plasma corticosterone, dopamine, 5-HT, and its metabolite 5 hydroxyindoleacetic acid concentrations were increased in the diencephalon of the 5-HT treated group compared with other groups. Second, the two doses (400 or 800 nmol) of l- and d-TRP were compared under a corticotrophin-releasing hormone augmented social isolation stress. When comparing the efficacy between l- and d TRP against stress behavior, both amino acids had a similar effect and quickly suppressed distress vocalizations. Finally, d-amino acid levels in the diencephalon and telencephalon were measured but d-TRP was not found. These results indicate that l- and d-TRP induce the same effect in attenuating stress but the mode of action of TRP derivatives, namely 5-HT differs during an acute isolation stress in neonatal chick. The absence of d-TRP in the diencephalon further suggests that instead of being an endogenous factor it may play role as a pharmacological factor. PMID- 25459104 TI - Naltrexone and bupropion, alone or combined, do not alter the reinforcing effects of intranasal methamphetamine. AB - Naltrexone and bupropion, when administered alone in clinical trials, modestly reduce amphetamine use. Whether combining these drugs would result in greater reductions in methamphetamine taking relative to either drug alone is undetermined. This study examined the influence of naltrexone, bupropion and a naltrexone-bupropion combination on methamphetamine self-administration in humans. Seven subjects reporting recent illicit stimulant use completed a placebo controlled, crossover, double-blind study in which the reinforcing, subject-rated and physiological effects of intranasal methamphetamine (0, 10 and 30 mg) were assessed during maintenance on placebo, naltrexone (50 mg), bupropion (300 mg/day), and naltrexone combined with bupropion. Methamphetamine maintained responding and produced prototypic subjective and physiological effects (e.g., increased ratings of good effects, elevated systolic blood pressure). Maintenance doses were well tolerated and generally devoid of effects. No maintenance condition reduced methamphetamine self-administration or systematically altered the subject-rated effects of methamphetamine. These outcomes demonstrate the robust behavioral effects of methamphetamine that could make it resistant to pharmacological manipulation. Although these outcomes indicate that this combination may be ineffective for managing methamphetamine use disorder, future work should evaluate longer maintenance dosing, individuals with different levels of amphetamine use, adding this combination to a behavioral platform and other pharmacotherapy combinations for reducing methamphetamine use. PMID- 25459105 TI - Proficient motor impulse control in Parkinson disease patients with impulsive and compulsive behaviors. AB - BACKGROUND: Parkinson disease (PD) patients treated with dopamine agonist therapy can develop maladaptive reward-driven behaviors, known as impulse control disorder (ICD). In this study, we assessed if ICD patients have evidence of motor impulsivity. METHODS: We used the stop-signal task in a cohort of patients with and without active symptoms of ICD to evaluate motor-impulsivity. Of those with PD, 12 were diagnosed with ICD symptoms (PD-ICD) and were assessed before clinical reduction of dopamine agonist medication; 12 were without symptoms of ICD [PD-control] and taking equivalent dosages of dopamine agonist. Levodopa, if present, was maintained in both settings. Groups were similar in age, duration, and severity of motor symptoms, levodopa co-therapy, and total levodopa daily dose. All were tested in the dopamine agonist medicated and acutely withdrawn (24 h) state, in a counterbalanced manner. Primary outcome measures were mean reaction time to correct go trials (go reaction time), and mean stop-signal reaction time (SSRT). RESULTS: ICD patients produce faster SSRT than both Healthy Controls, and PD-Controls. Faster SSRT in ICD patients is apparent in both dopamine agonist medication states. Also, we show unique dopamine medication effects on Go Reaction time (GoRT). In dopamine agonist monotherapy patients, dopamine agonist administration speeds GoRT. Conversely, in those with levodopa co-therapy, dopamine agonist administration slows. DISCUSSION: PD patients with active ICD symptoms are significantly faster at stopping initiated motor actions, and this is not altered by acute dopamine agonist withdrawal. In addition, the effect of dopamine agonist on GoRT is strongly influenced by the presence or absence of levodopa, even though levodopa co-therapy does not appear to influence SSRT. We discuss these findings as they pertain to the multifaceted definition of 'impulsivity,' the lack of evidence for motor-impulsivity in PD-ICD, and dopamine effects on motor-control in PD. PMID- 25459109 TI - Preclinical pharmacokinetics, biodistribution, radiation dosimetry and acute toxicity studies required for regulatory approval of a Clinical Trial Application for a Phase I/II clinical trial of (111)In-BzDTPA-pertuzumab. AB - INTRODUCTION: (111)In-BzDTPA-pertuzumab is a novel imaging probe for detecting changes in HER2 expression in breast cancer (BC) caused by treatment with trastuzumab (Herceptin). Our aim was to evaluate the pharmacokinetics, normal tissue biodistribution, radiation dosimetry and acute toxicity of (111)In-BzDTPA pertuzumab in non-tumor bearing mice in order to obtain regulatory approval to advance this agent to a first-in-humans Phase I/II clinical trial. METHODS: Biodistribution and pharmacokinetic studies were performed in non-tumor bearing Balb/c mice injected i.v. with (111)In-BzDTPA-pertuzumab (2.5MBq; 2MUg). The cumulative number of disintegrations per source organ derived from the biodistribution data was used to predict the radiation absorbed doses in humans using OLINDA/EXM software. Acute toxicity was studied at two weeks post-injection of (111)In-BzDTPA-pertuzumab (1.0MBq, 20MUg) with comparison to control mice injected with unlabeled BzDTPA-pertuzumab (20MUg) or Sodium Chloride Injection USP. The dose of (111)In-BzDTPA-pertuzumab corresponded to 23-times the human radioactivity dose and 10-times the protein dose on a MBq/kg and mg/kg basis, respectively. Toxicity was assessed by monitoring body mass, complete blood cell count (CBC), hematocrit (Hct), hemoglobin (Hb), serum creatinine (SCr) and alanine aminotransferease (ALT) and by histopathological examination of tissues at necropsy. RESULTS: (111)In-BzDTPA-pertuzumab exhibited a biphasic elimination from the blood with a distribution half-life (t1/2alpha) of 3.8h and an elimination half-life (t1/2beta) of 228.2h. The radiopharmaceutical was distributed mainly in the blood, heart, lungs, liver, kidneys and spleen. The projected whole-body radiation absorbed dose in humans was 0.05mSv/MBq corresponding to a total of 16.8mSv for three separate administrations of (111)In BzDTPA-pertuzumab (111MBq) planned for the Phase I/II trial. There were slight changes in Hb and SCr levels associated with administration of multiples of the human dose in healthy Balb/c mice but no histopathological abnormalities were noted in any tissues. There were no significant differences in body mass between mice injected with (111)In-BzDTPA-pertuzumab or control mice. CONCLUSION: Preclinical studies predicted that (111)In-BzDTPA-pertuzumab is safe to administer to humans at a dose of 111MBq (5mg). The radiopharmaceutical exhibited preclinical pharmacokinetic, biodistribution and radiation dosimetry properties suitable for advancement to a first-in-humans clinical trial. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: The results of these studies supported the regulatory approval by Health Canada of (111)In-BzDTPA-pertuzumab for a Phase I/II clinical trial of for imaging the response of patients with metastatic BC to treatment with trastuzumab combined with chemotherapy (PETRA trial; ClinicalTrials.gov identifier: NCT01805908). PMID- 25459111 TI - Comparison of biological properties of (111)In-labeled dimeric cyclic RGD peptides. AB - INTRODUCTION: In this study two (111)In-labeled dimeric cyclic RGD peptides, (111)In(DOTA-Galacto-RGD2) and (111)In(DOTA-3P-RGD2), were evaluated as radiotracers for breast tumor imaging. The objective was to evaluate the impact of SAA, PEG2 and 1,2,3-triazole linkers as compare to PEG4 on the tumor uptake and excretion kinetics of (111)In radiotracers. METHODS: DOTA-Galacto-RGD2 was prepared by conjugation of Galacto-RGD2 with DOTA-OSu in the presence of diisopropylethylamine. Its integrin alphavbeta3 binding affinity was determined using a whole-cell displacement assay against (125)I-echistatin bound to U87MG glioma cells, and was compared with those of c(RGDfK), DOTA-3P-RGD2 and DOTA-3P RGK2 (a nonsense peptide conjugate with "scrambled" RGK sequences). (111)In(DOTA Galacto-RGD2) and (111)In(DOTA-3P-RGD2) were prepared and evaluated for their tumor-targeting capability and biodistribution properties in athymic nude mice bearing MDA-MB-435 breast tumor xenografts. Planar imaging studies were performed to demonstrate the utility of (111)In(DOTA-Galacto-RGD2) and (111)In(DOTA-3P RGD2) for breast tumor imaging. RESULTS: IC50 values of DOTA-Galacto-RGD2, DOTA 3P-RGD2, and DOTA-3P-RGK2 were calculated to be 27+/-2, 29+/-4, 596+/-48nM, respectively. The tumor uptake values of (111)In(DOTA-Galacto-RGD2) (6.79+/-0.98, 6.56+/-0.56, 4.17+/-0.61 and 1.09+/-0.13 %ID/g at 1, 4, 24 and 72hours p.i., respectively) were almost identical to those of (111)In(DOTA-3P-RGD2) (6.17+/ 1.65, 5.94+/-0.84, 3.40+/-0.50 and 0.99+/-0.20 %ID/g, respectively). (111)In(DOTA Galacto-RGD2) had a faster clearance from blood and muscle than (111)In(DOTA-3P RGD2), leading to higher tumor/blood and tumor/muscle ratios. (111)In(DOTA-3P RGD2) had lower liver uptake and better tumor/liver ratios than (111)In(DOTA Galacto-RGD2). The tumor uptake of (111)In(DOTA-Galacto-RGD2) and (111)In(DOTA-3P RGD2) was both integrin alphavbeta3 and RGD-specific. Imaging data suggest that (111)In(DOTA-Galacto-RGD2) and (111)In(DOTA-3P-RGD2) are useful as radiotracers for imaging integrin alphavbeta3-positive breast tumors. CONCLUSION: The results from this study suggest that replacing PEG4 linkers between two RGD moieties with a pair of SAA, PEG2 and 1,2,3-triazole groups has little impact on integrin alphavbeta3 binding affinity and tumor uptake of (111)In-labeled dimeric cyclic RGD peptides. Despite the subtle differences in their excretion kinetics from noncancerous tissues, (111)In(DOTA-Galacto-RGD2) and (111)In(DOTA-3P-RGD2) are useful radiotracers for imaging integrin alphavbeta3-positive breast tumors. PMID- 25459110 TI - [(68)Ga]FSC-(RGD)3 a trimeric RGD peptide for imaging alphavbeta3 integrin expression based on a novel siderophore derived chelating scaffold-synthesis and evaluation. AB - Over the last years Gallium-68 ((68)Ga) has received tremendous attention for labeling of radiopharmaceuticals for positron emission tomography (PET). (68)Ga labeling of biomolecules is currently based on bifunctional chelators containing aminocarboxylates (mainly DOTA and NOTA). We have recently shown that cyclic peptide siderophores have very good complexing properties for (68)Ga resulting in high specific activities and excellent metabolic stabilities, in particular triacetylfusarinine-C (TAFC). We postulated, that, starting from its deacetylated form (Fusarinine-C (FSC)) trimeric bioconjugates are directly accessible to develop novel targeting peptide based (68)Ga labeled radiopharmaceuticals. As proof of principle we report on the synthesis and (68)Ga-radiolabeling of a trimeric FSC-RGD conjugate, [(68)Ga]FSC-(RGD)3, targeting alphavbeta3 integrin, which is highly expressed during tumor-induced angiogenesis. Synthesis of the RGD peptide was carried out applying solid phase peptide synthesis (SPPS), followed by the coupling to the siderophore [Fe]FSC via in situ activation using HATU/HOAt and DIPEA. Subsequent demetalation allowed radiolabeling of FSC-(RGD)3 with (68)Ga. The radiolabeling procedure was optimized regarding peptide amount, reaction time, temperature as well buffer systems. For in vitro evaluation partition coefficient, protein binding, serum stability, alphavbeta3 integrin binding affinity, and tumor cell uptake were determined. For in vitro tests as well as for the biodistribution studies alphavbeta3 positive human melanoma M21 and alphavbeta3 negative M21-L cells were used. [(68)Ga]FSC-(RGD)3 was prepared with high radiochemical yield (>98%). Distribution coefficient was -3.6 revealing a hydrophilic character, and an IC50 value of 1.8+/-0.6 nM was determined indicating a high binding affinity for alphavbeta3 integrin. [(68)Ga]FSC-(RGD)3 was stable in PBS (pH7.4), FeCl3- and DTPA-solution as well as in fresh human serum at 37 degrees C for 2hours. Biodistribution assay confirmed the receptor specific uptake found in vitro. Uptake in the alphavbeta3 positive tumor was 4.3% ID/g 60min p.i. which was 3-fold higher than the monomeric [(68)Ga]NODAGA-RGD. Tumor to blood ratio of approx. 8 and tumor to muscle ratio of approx. 7 were observed. [(68)Ga]FSC-(RGD)3 serves as an example for the feasibility of a novel class of bifunctional chelators based on cyclic peptide siderophores and shows excellent targeting properties for alphavbeta3 integrin in vivo for imaging tumor induced neovascularization. PMID- 25459113 TI - Characterization and evaluation of DOTA-conjugated Bombesin/RGD-antagonists for prostate cancer tumor imaging and therapy. AB - INTRODUCTION: Here we present the metallation, characterization, in vivo and in vitro evaluations of dual-targeting, peptide-based radiopharmaceuticals with utility for imaging and potentially treating prostate tumors by virtue of their ability to target the alphaVbeta3 integrin or the gastrin releasing peptide receptor (GRPr). METHODS: [RGD-Glu-6Ahx-RM2] (RGD: Arg-Gly-Asp; Glu: glutamic acid; 6-Ahx: 6-amino hexanoic acid; RM2: (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu NH2)) was conjugated to a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid) bifunctional chelator (BFCA) purified via reversed-phase high performance liquid chromatography (RP-HPLC), characterized by electrospray ionization-mass spectrometry (ESI-MS), and radiolabeled with (111)In or (177)Lu. Natural-metallated compounds were assessed for binding affinity for the alphaVbeta3 integrin or GRPr in human glioblastoma U87-MG and prostate PC-3 cell lines and stability prior to in vivo evaluation in normal CF-1 mice and SCID mice xenografted with PC-3 cells. RESULTS: Competitive displacement binding assays with PC-3 and U87-MG cells revealed high to moderate binding affinity for the GRPr or the alphaVbeta3 integrin (IC50 range of 5.39+/-1.37 nM to 9.26+/-0.00 nM in PC-3 cells, and a range of 255+/-47 nM to 321+/-85 nM in U87-MG cells). Biodistribution studies indicated high tumor uptake in PC-3 tumor-bearing mice (average of 7.40+/-0.53% ID/g at 1h post-intravenous injection) and prolonged retention of tracer (mean of 4.41+/-0.91% ID/g at 24h post-intravenous injection). Blocking assays corroborated the specificity of radioconjugates for each target. Micro-single photon emission computed tomography (microSPECT) confirmed favorable radiouptake profiles in xenografted mice at 20h post injection. CONCLUSIONS: [RGD-Glu-[(111)In-DO3A]-6-Ahx-RM2] and [RGD-Glu-[(177)Lu- DO3A]-6-Ahx-RM2] show favorable pharmacokinetic and radiouptake profiles, meriting continued evaluation for molecular imaging in murine U87-MG/PC-3 xenograft models and radiotherapy studies with (177)Lu and (90)Y conjugates. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: These heterovalent, peptide-targeting ligands perform comparably with many mono- and multivalent conjugates with the potential benefit of increased sensitivity for detecting cancer cells exhibiting differential expression of target receptors. PMID- 25459112 TI - (68)Ga-AMBA and (18)F-FDG for preclinical PET imaging of breast cancer: effect of tamoxifen treatment on tracer uptake by tumor. AB - INTRODUCTION: AMBA is a bombesin analogue that binds to GRPr. In a mouse model of estrogen-dependent human breast cancer, we tested whether (68)Ga-AMBA can be used for PET detection of GRPr-expressing tumors and could be more accurate than (18)F FDG to monitor tumor response to hormone therapy. METHODS: The radiolabeling of (68)Ga-AMBA was automated using a R&D Synchrom module. ZR75-1, a breast cancer cell line, was xenografted in nude mice. (68)Ga-AMBA tumor uptake was compared with that of (18)F-FDG before and after treatment with tamoxifen. RESULTS: AMBA was (68)Ga-radiolabelled in 30min with 95.3% yield and purity>=98%. Prior to treatment, (68)Ga-AMBA was highly concentrated into tumors (tumor to non-tumor ratio=2.4 vs. 1.3 with (18)F-FDG). With tamoxifen treatment (n=6) (68)Ga-AMBA uptake plateaued after 1week and decreased after 2weeks, with a significant reduction compared to controls (n=4). In contrast the effect of tamoxifen treatment could not be appreciated using (18)F-FDG. CONCLUSIONS: (68)Ga-AMBA appeared better than (18)F-FDG to visualize and monitor the response to hormone treatment in this breast cancer model. PMID- 25459114 TI - [Atypical neuropathies associated with diabetes]. AB - Diabetes is the leading cause of neuropathy worldwide and, due to the epidemic progression of the affection, prevalence of diabetic neuropathies will increase in the near future. Beside the typical diabetic neuropathy pattern and the common entrapment neuropathies, several unusual clinical forms have been described with either a symmetrical or an asymmetrical pattern. Treatment-induced neuropathy is an acute sensory affection most commonly related to acute glycemic control. Pain is debilitating and associated with vegetative dysfunction. Prevention is important, as resolution is often incomplete. Several patterns or asymmetrical neuropathies of inflammatory and ischemic origin were described long ago in the lower limb. They are debilitating, most often painful and require steroid treatment. Other patterns affecting the thoracolumbar region or the upper limbs or involving a painless motor deficit must be identified as specific treatments are sometimes needed. An association between diabetes and chronic inflammatory demyelinating polyneuropathy has not been demonstrated but diagnosis may be suggested due to the misleading low conduction velocities seen in classical diabetic neuropathy. Like any other patient, the diabetic patient may present a neuropathy unrelated to diabetes. To facilitate patient care, neurologists should be aware of such clinical entities. PMID- 25459115 TI - Biotherapies in stroke. AB - Stroke is the second leading cause of death worldwide and the most common cause of severe disability. Neuroprotection and repair mechanisms supporting endogenous brain plasticity are often insufficient to allow complete recovery. While numerous neuroprotective drugs trials have failed to demonstrate benefits for patients, they have provided interesting translational research lessons related to neurorestorative therapy mechanisms in stroke. Stroke damage is not limited to neurons but involve all brain cell type including the extracellular matrix in a "glio-neurovascular niche". Targeting a range of host brain cells, biotherapies such as growth factors and therapeutic cells, currently hold great promise as a regenerative medical strategy for stroke. These techniques can promote both neuroprotection and delayed neural repair through neuro-synaptogenesis, angiogenesis, oligodendrogliogenesis, axonal sprouting and immunomodulatory effects. Their complex mechanisms of action are interdependent and vary according to the particular growth factor or grafted cell type. For example, while "peripheral" stem or stromal cells can provide paracrine trophic support, neural stem/progenitor cells (NSC) or mature neurons can act as more direct neural replacements. With a wide therapeutic time window after stroke, biotherapies could be used to treat many patients. However, guidelines for selecting the optimal time window, and the best delivery routes and doses are still debated and the answers may depend on the chosen product and its expected mechanism including early neuroprotection, delayed neural repair, trophic systemic transient effects or graft survival and integration. Currently, the great variety of growth factors, cell sources and cell therapy products form a therapeutic arsenal that is available for stroke treatment. Their effective clinical use will require prior careful considerations regarding safety (e.g. tumorgenicity, immunogenicity), potential efficacy, cell characterization, delivery route and in vivo biodistribution. Bone marrow-derived cell populations such as mesenchymal stromal/stem cells (MSC) or mononuclear cells (MNC), umbilical cord stem cells and NSC are most investigated notably in clinical trials. Finally, we discuss perspectives concerning potential novel biotherapies such as combinatorial approaches (growth factor combined with cell therapy, in vitro optimization of cell products, or co-transplantation) and the development of biomaterials, which could be used as injectable hydrogel scaffold matrices that could protect a cell graft or selectively deliver drugs and growth factors into the post-stroke cavity at chronic stages. Considering the remaining questions about the best procedure and the safety cautions, we can hope that future translational research about biotherapies will bring more efficient treatments that will decrease post-stroke disability for many patients. PMID- 25459116 TI - Biotherapies for Parkinson disease. AB - The clinical use of biotherapies in Parkinson disease already has 30 years' history. The transplantation of dopamine fetal cells in the striatum of advanced patients has proved to be relevant in some patients but randomized efficacy trials in the US have provided disappointing results. However, cell therapies might come back on stage with the use of stem cells in the future. Gene therapy is a more recent strategy relying on viral vectors able to transduce genes coding either for the enzymes that can increase neurotransmitters production or genes for trophic factors. Several approaches have been developed in PD and have been experimented in patients. Although, some of the studies have evidenced insufficient clinical benefit, other programs, such as those using dopamine replacement techniques are promising. We find fresh hope in this field that might be the future of PD treatment. It remains however that advanced PD might not be the ideal condition to properly benefit from biotherapies and there is a need of studies at earlier stages of the disease, a time where major change in the disease course might be expected. PMID- 25459117 TI - [Investigating peripheral nerve injuries: what's new in 2013?]. AB - Magnetic resonance imaging (MRI) and ultrasonographic (US) investigations have recently became prominent tools for the investigation of peripheral nerve injuries. MRI is the most valuable for the study of proximal nervous structures, i.e. roots and plexi, whereas US is better suited for the investigation of distal nerves, including entrapment syndromes. However, as nerve conduction studies and electromyographic studies still have a better sensitivity and specificity than MRI and US, they remain the gold standard for the evaluation of the peripheral nervous system. PMID- 25459118 TI - [2013: what's new in inflammatory neuropathies]. AB - Several high-quality publications were published in 2013 and some major trials studies were started. In Guillain-Barre syndrome, events included the launch of IGOS and a better understanding of diagnostic limits, the effect of influenza vaccination, and better care, but uncertainty remains about analgesics. A new mouse model was also described. In chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), diagnostic pitfalls can be recalled. Our knowledge of underlying pathophysiological processes has improved, and the value of monitoring with function and deficit scores has been demonstrated. IVIG can sometimes be effective longer than expected, but CIDP remains sensitive to corticosteroids, particularly with the long-term beneficial effects of megadose dexamethasone. The impact of fingolimod remains to be demonstrated in an ongoing trial. Advances concerning multifocal motor neuropathy, inflammatory plexopathy, and neuropathy with anti -MAG activity are discussed but treatments already recognized as effective should not be changed. Imaging of peripheral nerve progresses. PMID- 25459119 TI - [New insights on the organization of the nodes of Ranvier]. AB - Myelin plays a crucial role in the rapid and saltatory conduction of the nerve impulse along myelinated axons. In addition, myelin closely regulates the organization of the axonal compartments. This organization involves several complex mechanisms including axo-glial contact, diffusion barriers, the cytoskeletal network, and the extracellular matrix. In peripheral nerves, the axo glial contact dictates the formation of the nodes and the clustering of the voltage-gated sodium channels (Nav). The axo-glial contact at nodes implicates adhesion molecules expressed by the Schwann cell (gliomedin and NrCAM), which binds a partner, neurofascin-186, on the axonal side. This complex is essential for the recruitment of ankyrin-G, a cytoskeletal scaffolding protein, which binds and concentrates Nav channels at nodes. The paranodal junctions flanking the nodes also play a complementary function in node formation. These junctions are formed by the association of contactin-1/caspr-1/neurofascin-155 and create a diffusion barrier, which traps proteins at the nodes and dampens their diffusion along the internode. In the central nervous system, the mechanisms of node formation are different and the formation of the paranodal junctions precedes the aggregation of Nav channels at nodes. However, node formation can still happen in absence of paranodal junctions in the CNS. One explanation is that NF186 interacts with components of the extracellular matrix around the node and thereby stabilizes the aggregation of nodal proteins. It is likely that many other proteins are also implicated in the signaling pathways that regulate the differentiation of the axonal compartments. The nature and function of these proteins are yet to be identified. PMID- 25459120 TI - Gene therapy of the central nervous system: general considerations on viral vectors for gene transfer into the brain. AB - The last decade has nourished strong doubts on the beneficial prospects of gene therapy for curing fatal diseases. However, this climate of reservation is currently being transcended by the publication of several successful clinical protocols, restoring confidence in the appropriateness of therapeutic gene transfer. A strong sign of this present enthusiasm for gene therapy by clinicians and industrials is the market approval of the therapeutic viral vector Glybera, the first commercial product in Europe of this class of drug. This new field of medicine is particularly attractive when considering therapies for a number of neurological disorders, most of which are desperately waiting for a satisfactory treatment. The central nervous system is indeed a very compliant organ where gene transfer can be stable and successful if provided through an appropriate strategy. The purpose of this review is to present the characteristics of the most efficient virus-derived vectors used by researchers and clinicians to genetically modify particular cell types or whole regions of the brain. In addition, we discuss major issues regarding side effects, such as genotoxicity and immune response associated to the use of these vectors. PMID- 25459121 TI - Amyloid beta peptide immunotherapy in Alzheimer disease. AB - Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid beta peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid beta peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid beta peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid beta peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation. PMID- 25459122 TI - Biotherapies of neuromuscular disorders. AB - This review focuses on the most recent data on biotherapeutic approaches, using DNA, RNA, recombinant proteins, or cells as therapeutic tools or targets for the treatment of neuromuscular diseases. Many of these novel technologies have now reached the clinical stage and have or are about to move to the market. Others, like genome editing are still in an early stage but hold great promise. PMID- 25459123 TI - Biotherapies in brain diseases: for who, when and how? PMID- 25459124 TI - Regenerative medicine in Huntington's disease: current status on fetal grafts and prospects for the use of pluripotent stem cell. AB - Huntington's disease is currently incurable, but cell therapy is seen as a promising alternative treatment. We analyze the safety and efficacy of the intrastriatal transplantation of human fetal neuroblasts from ganglionic eminences in patients with Huntington's disease. A few rare surgical incidents were reported, but the main difficulty associated with this therapeutic approach is the occurrence of recipient alloimmunization against the graft and the lack of availability, standardization and quality control for the fetus-derived products required for cell therapy. Some patients showed sustained cognitive improvement over periods of more than six years, and motor improvements for more than four years. Grafting outcomes are variable even within individual transplantation centers. The reasons for this variability are poorly understood, highlighting the need for further research in this specific area. With the perspective of additional trials in the future, we review here the development of human pluripotent stem cell-derived cell therapy products for HD, and their advantages and disadvantages with respect to fetal cells. PMID- 25459125 TI - [Painful neuropathies and small fiber involvement]. AB - It is customary to consider that a purely sensory and painful neuropathy accompanied by normal electroneuromyographic examination may be or must be a small fiber neuropathy. This leads to perform specific tests, such as measuring the intra-epidermal nerve fiber density on skin biopsy or neurophysiological tests, such as evoked potentials to noxious stimuli (laser) or quantification of thermal sensory thresholds. However, these tests are only sensitive to the loss of small fibers (A-delta and C), which does not reflect the mechanisms responsible for peripheral neuropathic pain. Selective loss of small sensory fibers inherently generates a sensory deficit that does not necessarily present a painful character. Also, assigning the cause of a painful neuropathy to a small fiber neuropathy has no pathophysiological sense, although there are indirect links between these two conditions. In fact, it is not possible to explain univocally peripheral neuropathic pain, which reflects complex and diverse mechanisms, involving different types of nerve fibers. In this context, the clinical and laboratory approach must be improved to better understand the underlying mechanisms. It is imperative to interpret the data provided by laboratory tests and to correlate these data to the clinical signs and symptoms presented by the patients. Thus, one must go beyond many a priori and misinterpretations that unfortunately exist in this area at present and are not based on any solid pathophysiological basis. PMID- 25459126 TI - Pathophysiology and biomarkers in chronic inflammatory demyelinating polyradiculoneuropathies. AB - Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired dysimmune disorder characterized by strong heterogeneity in terms of clinical manifestations, prognostic and response to treatment. To date, its pathophysiology and potential target antigens are not totally identified despite substantial progress in the understanding of the involved molecular mechanisms. Recent researches in the field have underlined the importance of cell-mediated immunity (lymphocytesT CD4+, CD8+ and macrophages), the breakdown of blood-nerve barrier, a failure of T-cell regulation, and the disruption of nodal and paranodal organization at the node of Ranvier. This last point is possibly mediated by autoantibodies towards axoglial adhesion molecules which may disrupt sodium and potassium voltage-gated channels clustering leading to a failure of saltatory conduction and the apparition of conduction blocks. The purpose of this article is to overview the main pathophysiologic mechanisms and biomarkers identified in CIDP. PMID- 25459127 TI - Biotherapies in multiple sclerosis: a step toward remyelination and neuroprotection? AB - Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS), characterized by CNS-restricted inflammation with subsequent demyelination and neurodegeneration. Current disease-modifying therapies efficiently reduce relapse rate and new lesions appearance, but still fail to impact the progressive course of the disease. There is a great need for the avenue of new therapies aimed at promoting myelin repair or reducing neurodegeneration that should result in the prevention of neurological disability in this chronic disease. This review will focus on the potentials and limitations of biotherapies that are currently developed for the promotion of CNS repair in MS, either monoclonal antibodies targeting axonal growth and remyelination, or cell therapies aimed at replacing the depleted myelinating cells within the CNS. As other researches aimed at promoting neuroprotection or remyelination are following a classical pharmacological approach, they will not be described in this review, which will focus on antibody-based therapies and cell therapies. PMID- 25459128 TI - [Review of the recent literature on hereditary neuropathies]. AB - The recent literature included interesting reports on the pathogenic mechanisms of hereditary neuropathies. The axonal traffic and its abnormalities in some forms of Charcot-Marie-Tooth (CMT) disease were particularly reviewed by Bucci et al. Many genes related to CMT disease code for proteins that are involved directly or not in intracellular traffic. KIF1B controls vesicle motility on microtubules. MTMR2, MTMR13 and FIG4 regulate the metabolism of phosphoinositide at the level of endosomes. The HSPs are involved in the proteasomal degradation. GDAP1 and MFN2 regulate the mitochondrial fission and fusion respectively and the mitochondial transport within the axon. Pareyson et al. reported a review on peripheral neuropathies in mitochondrial disorders. They used the term of "mitochondrial CMT" for the forms of CMT with abnormal mitochondrial dynamic or structure. Among the new entities, we can draw the attention to a proximal form of hereditary motor and sensory neuropathy with autosomal dominant inheritance, which is characterized by motor deficit with cramps and fasciculations predominating in proximal muscles. Distal sensory deficit can be present. The gene TFG on chromosome 3 has been recently identified to be responsible for this form. Another rare form of axonal autosomal recessive neuropathy due to HNT1 gene mutation is characterized by the presence of hands myotonia that appears later than neuropathy but constitute an interesting clinical hallmark to orientate the diagnosis of this form. In terms of differential diagnosis, CMT4J due to FIG4 mutation can present with a rapidly progressive and asymmetric weakness that resembles CIDP. Bouhy et al. made an interesting review on the therapeutic trials, animal models and the future therapeutic strategies to be developed in CMT disease. PMID- 25459129 TI - Do genetic factors protect against Parkinson's disease? What I can learn from my healthy grandma. AB - Parkinson's disease (PD) is a progressive, neurodegenerative disorder and it affects 4-5% of people age 85 years or older. The etiopathogenesis of PD is a consequence of interaction between two factors, environmental pathogens and genetic susceptibility. If an environmental agent such as a toxin or pathogen were to play a major role in the causality of PD, it would need to be something relatively ubiquitous in our environment since we cannot find a specific population at risk. On the other hand, all efforts to implicate specific genetic sequences in risk of PD were futile since the great majority of PD cases are sporadic; however, if the majority of the population is exposed to a culpable environmental factor and only 5% of the population 85 years or older manifest the disorder, this raises an important question: Why and how does vast majority of the population not manifest with PD? It seems that we should investigate the certain genome or epigenetic alterations of the unaffected 95%. This large non affected population might have PD but they are not yet symptomatic and some may not be so for at least another 10 or 20 years. To further address this issue, we should screen and study the population that have been exposed to the environmental factor but with high certainty are not yet affected. Therefore the perfect population would be non-PD subjects who are 90 years or older. We believe the following are the unmet research needs that deserve more attention in PD. (1) More genetic studies. Comparison should be between PD subjects and non-PD control subjects who are 90 years old and above. (2) Study the mechanism of action of the candidate genes, as a subsequent examination of their gene products may lead to the discovery of neuroprotective agents in the disease. PMID- 25459130 TI - Acidic pH derived from cancer cells may induce failed reprogramming of normal differentiated cells adjacent tumor cells and turn them into cancer cells. AB - BACKGROUND: Eelier studies demonstrated the up-regulation of some transcriptional factors such as Oct4, Nanog, Sox2 in undifferentiated cancer cells. These transcriptional regulators are up-regulated in pluripotent cells, as well and are responsible for cell reprogramming in normal cells. It might be said that normal cells adjacent tumor site are undergone of failed cell reprogramming. PRESENTATION OF THE HYPOTHESIS: Extracellular pH of cancer cell is acidic and recent studies reveal the role of acidic environment in cell reprogramming of normal cells. This hypothesis deals with the potential role of acidic pH in malignant tumor development through normal cells adjacent cancer cells. It seems that cancer cells are more intelligent and acid release from these cells is not just a by-product but also and more important reason, is a tool to up-regulate cell reprogramming markers, induce epigenetic modification and tumor progress in normal cells adjacent cancer cells. If this is correct, then it could be expected that with alkaline targeting of tumor environment, failed cell reprogramming, aberrant epigenetic modification will decrease in normal cells adjacent cancer cells and afterward metastasis will decrease. TESTING THE HYPOTHESIS: It is proposed to investigate altered genetic and epigenetic modification (DNA methylation, histone modification) in cancer, early cancer and cells in vicinity of cancer cells at different pH range of 5.8-7.8. This study is performed to determine whether acidic pH induces reprogramming, global hypomethylation and promoter hypermethylation in cancer cells and cells in vicinity of cancer cells at different pH values. IMPLICATIONS OF THE HYPOTHESIS: This hypothesis deal with the ability of acidic pH to convert normal cells adjacent cancer cells to cancerous cells and its inductive potential on genetic and epigenetic modification of normal cells adjacent cancer cells and will further emphasize the important of extracellular acidic targeting in cancer therapy. PMID- 25459131 TI - Potential use of Magnolia officinalis bark polyphenols in the treatment of cannabis dependence. AB - In recent years, epidemiological data confirm that cannabis-related emergencies, cannabis-use disorders and dependence are significantly increased. Cannabis is generally considered a little dangerous substances of abuse, however, chronic consumption has been associated to the development of mental disorders, cognitive deficits, chronic bronchitis, emphysema, increased risk of myocardial infarction in the hour after use, increased mortality after myocardial infarction, liver inflammation and steatosis in patients affected by hepatitis C. In this article we described the pharmacological characteristics of Magnolia officinalis bark active principles suggesting a potential application in the treatment of both cannabis dependence and cannabis-related disorders. PMID- 25459132 TI - Helicobacter pylori and urinary system stones: endoluminal damage as sub hypothesis to support the current stone theory. AB - Helicobacter pylori (H. pylori) is a atypical gram-negative bacteria preferring gastric mucosa which also have bizarre multisystem effects extended to some malignancies, hematologic and vascular disorders through some not well defined pathophysiologic pathways. Our pioneer data was pointing that the urinary system stone existence was seemed to be high in the group of H. pylori+cases. While the explanation of the reason of the coincidence of renal-gall bladder stones, it was previously suggested that there may be a shift mechanism of intestinal microbial flora, from Oxalobacter formigenes that may reduce the risk of renal stone by consuming intestinal oxalate, to H. pylori which is known to induce gallstone by unknown mechanism. This hypothesis is an indirect one and highly controversial for the effect of H. pylori in the renal stone formation because intestinal absorption of oxalate is not significant when it is compared with the endogen oxalate. The present preliminary unique data in connection with our hypothesis claimed that a possible relation between H. pylori and renal stones. We think that this detrimental effect is due to the possible systemic influence such as vascular and/or endoluminal sickness due to the H. pylori other than directs bacteriologic colonization. There is strong evidence that H. pylori have some role in the atherosclerotic procedure. The vascular theory of Randall plaque formation at renal papilla and subsequent calcium oxalate stone development that suggests microvascular injury of renal papilla in an atherosclerotic-like fashion results in calcification near vessel walls that eventually erodes as a calculus format into the urinary system. Briefly, theories of stone and atherosclerosis seemed to be overlap and H. pylori is one of the factor of both processes. In addition to our hypothesis, we claimed that H. pylori might have same detrimental effect on endoluminal surfaces of urinary and genital systems and resulting in some special pathologies as Hunner's ulcers in interstitial cystitis and even posttesticular infertility. The accumulating knowledge about extragastric sequelae of H. pylori may open new aspects on therapeutic and the prevention strategies of urolithiasis and even this progress may reach to chronic pelvic pain syndromes and idiopathic infertility. PMID- 25459133 TI - Assigning appropriate and comprehensive diagnosis for scientific report. AB - The use of currently available guidelines such as the International Classification of Diseases, 10th Revision (ICD-10) and its clinical modification to assign a principal diagnosis to a patient who has multiple principal diagnoses appears unreliable. This is because these guidelines are complex and uses criteria that are highly subjective. Even when one main diagnosis is selected, the comprehensive list of other diseases that the patient has is often not reported such that the overall clinical condition of the patient is obscured. To address these issues, we have proposed: (i) a simple, potentially reliable and stepwise guide that can be used to assign the single most appropriate main principal diagnosis to each patient and illustrated this with case reports (ii) how to simultaneously report the main and other diagnoses in a scientific paper. It is hoped that our proposal (named NJ model for easy referencing) will help standardize how diagnosis is assigned to patients. PMID- 25459134 TI - Activating Na+-K+ ATPase: a potential cardioprotective therapy during early hemorrhagic shock. AB - Cell volume and resting potential are heavily affected by the activity of Na+-K+ ATPase (NKA, Na+-K+ pump), an essential membrane protein that regulates plasma K+ and Na+ levels. It is generally accepted that the ineffective perfusion of body tissues inhibits NKA activity and that NKA activity and heart failure are closely related. Recently, research has proven that the activation of NKA provides significant cardioprotection against ischemic injury. Based on these data, we propose that NKA stimulation could attenuate the development of heart arrhythmia during the early phase of hemorrhagic shock. PMID- 25459135 TI - Human granzymes: related but far apart. AB - Granzymes (GZMs) are a class of serine protease, found in cytoplasmic granules of cytotoxic T cells and natural killer cells. The main function of these proteins has been recognized as wiping out viral infections via inducing the apoptosis. This review will highlight inter and intra species differences of GZMs in terms of their functional and structure. These futures may help to device a strategy for isolation of human specific GZMs, which are needed for understating of their role in immune system and devising an effective immune therapy. PMID- 25459136 TI - Bi-directionally selective bone targeting delivery for anabolic and antiresorptive drugs: a novel combined therapy for osteoporosis? AB - Osteoporosis is a progressive systemic skeletal disease, in which the equilibrium of bone resorption and bone formation is disturbed. The drugs for osteoporosis can be divided into two categories according to their predominant effects: antiresorptive drugs and anabolic drugs. Antiresorptive drugs are designed to inhibit bone resorption and anabolic drugs are aiming to stimulate bone formation. On the other hand, most antiresorptive drugs usually decrease anabolic activities and reduce bone formation, while anabolic drugs can unintendedly increase bone resorption. Furthermore, both types of drugs show no preferential distribution in bone and can locate generally in the areas of both bone formation and bone resorption. Consequently, the non-specific interaction of these drugs with non-targeting area and cells can lead to a compromised efficacy. Combined therapies of antiresorptive and anabolic drugs do not necessarily yield superiority when compared to monotherapy. Here, basing on the targeting cells of these two kinds of drugs and the spatial distribution of osteoblasts and osteoclasts, we propose a novel drug delivery system of bi-directionally selective targeting in order to facilitate the efficacy of antiresorptive and anabolic drugs in combined therapy. In the system, an antiresorptive drug will be linked with a peptide of the eight repeating sequences of aspartate--(Asp)8 that can preferentially guide the drugs to bone resorption zone; while an anabolic drug linked with a peptide of six repeats of the sequence aspartate, serine, serine--(Asp-Ser-Ser)6 that can favorably guide the drugs to bone formation zone. The novel delivery system will improve the specific interaction between the drugs and their targeting cells. Furthermore, the system will reduce the non-specific interaction of the anabolic and antiresorptive drugs with their respective non targeting cells, which will maximally reduce their side-effects. Therefore, we postulate that the new bone targeting drug delivery system will be a blessing for osteoporotic patients. PMID- 25459137 TI - Inhibition of matrix metalloproteinase-2 and 9 by Piroxicam confer neuroprotection in cerebral ischemia: an in silico evaluation of the hypothesis. AB - Matrix metalloproteinases are zinc-containing endopeptidases that are involved in extracellular matrix (ECM) remodeling cascade in many neurological disorders, including cerebral ischemia (CI). Remodeling of the ECM followed by disruption of the blood-brain barrier (BBB) is one of the major factors contributing to the ultimate neurodegeneration in CI. BBB disruption causes a cascade of pathophysiologies that trigger Anoikis-like cell death. While inhibition of MMP-2 and MMP-9 decreases the extent of neuronal damage in CI, MMP-2/9 knock-out mice have reduced infarct volume in experimental animal models of CI. Piroxicam, which is a non-steroidal anti-inflammatory drug (NSAID), has been demonstrated to be protective against aquaporin-4 and acid-sensing ion channel 1a--mediated neurodegeneration in CI. However, no report exists on the inhibitory action of Piroxicam on MMPs. We tested the hypothesis that Piroxicam, with its larger molecular size and more number of interacting pharmacophores, can inhibit MMP-2 and MMP-9. A comparative study on the inhibitory potential of Piroxicam with other reported MMP-inhibitors, viz., Aspirin, Melatonin and Doxycycline, has also been performed. Since the drug has already been reported to be neuroprotective through its inhibitory action in other pathways, it can be the drug of choice in the therapeutic management and prevention of neurodegeneration in CI. PMID- 25459139 TI - Music increase altruism through regulating the secretion of steroid hormones and peptides. AB - Music is well known for its effect on human behavior especially of their bonding and empathy towards others. Music provokes one's emotion and activates mirror neurons and reward system. It also regulates social hormones such as steroid hormones or peptides, and increases empathy, pro-sociality and altruism. As a result, it improves one's reproductive success. PMID- 25459138 TI - Enhancing stem cell survival in an ischemic heart by CRISPR-dCas9-based gene regulation. AB - Ischemic heart disease has remained the number one killer around the world for over the past 20 years. While stem cell therapy has become a promising new frontier to repair the damaged heart, limited stem cell survivability post transplantation has precluded widespread use of this therapy. Strategies to genetically modify stem cells to activate pro-survival and anti-apoptotic and anti-inflammatory pathways, such as Akt and heme oxygenase-1, have been shown to improve the lifespan of transplanted stem cells within the ischemic myocardium, but constitutive overexpression of these pathways at high levels has been shown to have side effects. Therefore, more specific and controlled gene activation would be necessary. Current techniques used for gene regulation include zinc finger and TALE proteins, but there are still disadvantages to each of these methods, such as ease and cost of use. Also, those methods use synthesized promoters to express synthesized cDNA, which lack regulatory elements, including introns and 3' untranslated regions for microRNA mediated post-transcriptional regulation. A new novel technique, the CRISPR/dCas9 system, was recently developed as a simple and efficient method for endogenous gene regulation. With its use of single guide chimeric RNA's (sgRNA's), this system has been shown to provide a high level of specificity and efficiency. When targeting different loci, past studies have found that the CRISPR/dCas9 system can activate gene expression at varying levels. In addition, this system makes use of the genome's endogenous regulatory elements, such as the aforementioned introns and 3' UTR's, which can help provide a safer method of gene activation. If targeted to a gene promoting cellular survival or decreasing cell death, it could potentially improve stem cell longevity in a more efficient and controllable manner. As a result, our hypothesis is to use the CRISPR/dCas9 system to activate expression of an anti-inflammatory and anti-apoptotic gene, such as heme oxygenase-1 (HO-1), to an optimal level to increase transplanted stem cell survival while also mitigating its cytotoxic effects due to lack of internal regulation, thus prolonging its effects within the ischemic myocardium leading to greater therapeutic benefit. PMID- 25459140 TI - M. paratuberculosis and Parkinson's disease--is this a trigger. AB - Genetic linkage studies and genome wide analysis have provided insights into complex medical diseases. Mycobacterium avium ss. paratuberculosis (MAP) causes Johne's disease, an important enteric inflammatory disease mostly studied in ruminant animals. MAP is also the putative cause of Crohn's disease. Moreover, MAP has been linked to other inflammatory diseases: sarcoidosis, Blau syndrome, autoimmune diabetes, autoimmune thyroiditis and multiple sclerosis. Genetic studies reveal an association between Parkinson's disease (PD), leprosy and Crohn's disease and since discovered, these findings have been considered "surprising". Autophagy and ubiquitin-proteosome systems are cellular systems that both fight intracellular pathogens (xenophagy) and maintain cellular protein quality control. PD is a common neurodegenerative disease that manifests clinically as a profound movement disorder. The recognized genetic defects of PD create disruption of cellular homeostasis that result in protein folding abnormalities of PD called Lewy bodies. Those same genetic defects are associated with susceptibility to intracellular pathogens, including mycobacteria. It is now understood that PD Lewy body pathology starts in the enteric nervous system and "spreads" to the brain in a retrograde fashion via the vagus nerve. This is the same process by which prions affect the brain. Lewy body pathology of the enteric nervous system predates the Lewy body pathology of the central nervous system (CNS) by years or even decades. This article proposes that genetic defects associated with PD also result in a permissive environment for MAP infection- ineffective xenophagy. It postulates that beginning as an enteric infection, MAP- via the vagus nerve--initiates a pathologic process that results in a targeted neuroinvasion of the CNS. The article proposes that MAP infection and resultant PD pathology are due, in the genetically at-risk and age dependant, to the consumptive exhaustion of the protein quality control systems. PMID- 25459141 TI - The hierarchical model of stem cell genesis explains the man mouse paradox, Peto's paradox, the red cell paradox and Wright's enigma. AB - The central dogma of carcinogenesis is that deleterious mutations accumulate in regularly cycling stem cells and eventually one of the cells will acquire a specific set of mutations which leads to uncontrolled cell proliferation. Each mutation is rare and the specific set is extremely rare so that even though there are millions of stem cells in a small area of mucosa the specific set of mutations to initiate the process of malignancy will only arise in one stem cell at most; hence neoplasia is clonal. But this model predicts that men, who are 1000 times larger than mice and live 30 times as long, should have a vastly increased risk of cancer compared with mice, but they don't (man-mouse paradox). The model also predicts that the prevalence of cancer in men should rise as power function of age and mutagen dose, the former is correct but not the latter (Peto's paradox). Furthermore there are more mitotic divisions in red cell precursors than in all other stem cells combined and yet erythroleukaemia is rare (red cell paradox). The central dogma is also challenged by Wright's enigma; the observation that some gastro-intestinal neoplasms are polyclonal in origin. The problem with the central dogma is the concept of a regularly cycling stem cell. In fact it is possible to produce all the cells that arise in a human lifetime with fewer than 60 rounds of DNA replication separating the zygote from mature differentiated cells in extreme old age. This hierarchical model of stem cell genesis leads to a very low prevalence of cancer, unless the orderly progression of the hierarchy is disturbed by inflammation, ulceration or trauma. This model explains the paradoxes and Wright's enigma. It is suggested that the number of cell divisions that separate the zygote from stem cells is a key variable in carcinogenesis. PMID- 25459142 TI - The link between oral contraceptive use and prevalence in autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a group of developmental disabilities that include full syndrome autism, Asperger's syndrome, and other pervasive developmental disorders. The identified prevalence of ASD has increased in a short time period across multiple studies causing some to conclude that it has reached epidemic proportions in the U.S. Many possible explanations for the rise in numbers of individuals diagnosed with ASD have been offered and yet, causes and contributing factors for ASD are inadequately understood. Current evidence suggests that both genetics and environment play a part in causing ASD. One possible risk factor for the increase in prevalence has been profoundly overlooked in the existing biomedical and epidemiologic literature. As the prevalence of ASD has risen in the last sixty years, so has the prevalence of the usage of the oral contraceptives and other modern hormonal delivery methods. In 1960 about one million American women were using oral contraceptives, today close to 11 million women in the U.S. use oral contraceptives. Eighty-two percent of sexually active women in the U.S. have used oral contraceptives at some point during their reproductive years. Thus, the growth in use of progesterone/estrogen based contraceptives in the United State has reached near-ubiquitous levels among women in the child-bearing age range. The suppression of ovulation produced by estrogen-progesterone is an indisputable abnormality. It is logical to consider the outcome of the ovum that would have been normally released from the ovary during ovulation. To date there is no comprehensive research into the potential neurodevelopmental effects of oral contraceptive use on progeny. The issue has been only sparsely considered in the biomedical literature. This article hypothesizes that the compounds, estrogen and progesterone, used in oral contraceptives modify the condition of the oocyte and give rise to a potent risk factor that helps explain the recent increase in the prevalence of ASD's. This hypothesis does not propose to delineate the cause of autism. Rather, it attempts to explain the recent dramatic increase in prevalence and point the way for further study that will lead to causal examination. PMID- 25459143 TI - Should we be more cautious about replacement of vitamin B12 in patients with cancer receiving cytotoxic chemotherapy? AB - Vitamin B12 (Cbl) deficiency may cause hematologic and neurologic dysfunction. Replacement therapy is effective in correcting hematologic abnormalities and improving neurologic symptoms. Cbl is known to have antioxidant activity. This antioxidant activity may antagonize the effects of chemotherapeutics (i.e. genotoxic effects of paclitaxel) on tumor DNA. We claim that Cbl replacement should be done more cautiously in patients receiving cytotoxic chemotherapy. PMID- 25459144 TI - Increased left ventricular mass in hypercortisolemic depressed patients: a hypothesis based on a case series. AB - BACKGROUND: Hypercortisolemia in depressed patients is known to be related to changes in body composition, especially increased ectopic fat and lowered bone mineral density. Both hypercortisolemia in patients with Cushing's disease and depression in patients undergoing treatment with hemodialysis have been shown to be associated with increased left ventricular mass. HYPOTHESIS: Increased activity of the hypothalamus-pituitary-adrenal (HPA) system in depressed patients is related to high left ventricular mass. EMPIRICAL DATA: To corroborate our hypothesis, we measured left ventricular mass in 5 depressed patients with clear evidence for HPA system activation (nonsuppression in dexamethasone suppression test [DST]; increased 24 h cortisol excretion) and 27 healthy controls. We found increased left ventricular mass in hypercortisolemic depressed patients compared to healthy controls (343+/-97 vs. 176+/-57 gr; p=0.007). CONCLUSIONS: Depression is known to be related to an increased risk of cardial morbidity and mortality, although the risk architecture is not completely understood. We hypothesize that hypercortisolemic depression is associated with increased left ventricular mass, which is known to be a strong predictor for cardial mortality. Thus, a potential effect of activated stress-responsive systems on heart morphology may contribute to depressed patients' increased cardiovascular risk. PMID- 25459145 TI - Accuracy of pulmonary auscultation to detect abnormal respiratory mechanics: a cross-sectional diagnostic study. AB - Pulmonary auscultation is a method used in clinical practice for the evaluation and detection of abnormalities relating to the respiratory system. This method has limitations, as it depends on the experience and hearing acuity of the examiner to determine adventitious sounds. In this context, it's important to analyze whether there is a correlation between auscultation of lung sounds and the behavior of the respiratory mechanical properties of the respiratory system in patients with immediate postoperative cardiac surgery. PMID- 25459146 TI - Two-slope ascending arm of the early trans-mitral flow velocity Doppler wave in patients with heart failure and preserved ejection fraction. AB - Trans-mitral flow velocity (TMFV) examination is a standard echocardiographic measure for assessing diastolic function of the heart. Typically, the Doppler signal representing the early rapid filling phase of the left ventricle (LV), termed: E wave, is triangular. The ascending arm of the E wave (EWAA) represents blood accelerating into the LV from the left atrium (LA), whereas the descending arm reflects blood decelerating as the LV fills and resists further filling. The slope of EWAA is linear, starting at TMFV of zero cm/s (prior to mitral valve opening) and building to peak E wave value. The physical meaning of a single slope is that blood acceleration is constant with time. Little data exist regarding the significance of the shape of EWAA. It is hypothesized that in heart failure with preserved ejection fraction (HFPEF) the EWAA displays 2 slopes. A first steeper slope followed by a second less steep slope reaching peak E wave. The different slopes represent a change in the composition of driving forces propelling blood from LA to LV. It is hypothesized that the first steeper slope of EWAA represents a set of driving force including a force termed: diastolic suction, whereas in the second slope diastolic suction has already dissipated. This 2-slope phenomenon is not expected in healthy subjects because the assumed underlying mechanism is not operative. PMID- 25459147 TI - Piroxicam inhibits NMDA receptor-mediated excitotoxicity through allosteric inhibition of the GluN2B subunit: an in silico study elucidating a novel mechanism of action of the drug. AB - Hyperactivation of GluN2B subunit containing N-methyl-d-aspartate receptors (NMDARs) significantly contributes to the development of several neurodegenerative diseases through a process called excitotoxicity. NMDARs are voltage-gated Ca2+ channels which when activated lead to excessive influx of Ca2+ into neurons thereby exacerbating several calcium-dependent pathways that cause oxidative stress and apoptosis. Several drugs are presently in use to counter the NMDAR-mediated excitotoxic events among which Ifenprodil and its derivatives are GluN2B selective allosteric antagonists. Certain non-steroidal anti-inflammatory drugs (NSAIDs) have also been reported to inhibit NMDARs and the resultant pathologies. Meanwhile, Piroxicam, which is a NSAID, has been reported to be protective in cerebral ischemia-induced neurodegeneration through various pathways. Since Piroxicam has more number of interacting groups as compared to other NSAIDs and also has structural similarities with Ifenprodil, we thought it prudent that Piroxicam may inhibit NMDARs similar to Ifenprodil. By using molecular docking as a tool, we validated the hypothesis and hereby report for the first time that Piroxicam can inhibit GluN2B containing NMDARs through allosteric mode similar to the well known selective antagonist--Ifenprodil; and thus can be a therapeutic drug for the prevention of excitotoxic neurodegeneration. PMID- 25459148 TI - A role for tissue plasminogen activator in thrombotic thrombocytopenic purpura. AB - Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by generalized microvascular occlusion. TTP has been related to severe deficiency of ADAMTS13, an enzyme that cleaves von Willebrand factor multimers into less adhesive molecules. However, ADAMTS13 deficiency correlates poorly with severity of thrombocytopenia or microangiopathic hemolysis, with the frequency of neurologic complications or the response to plasma exchange. Also, some patients with severe hereditary ADAMTS13 deficiency consistently relapse every few weeks, whereas others remain asymptomatic into their forties. Taken together, these findings suggest that an additional element is missing in the pathophysiology of TTP. We postulate that both low ADAMTS13 activity and low tissue-plasminogen activator activity are required to trigger TTP attacks. Tissue plasminogen activator end product, plasmin, extensively degrades von Willebrand factor, breaking-down the bonds between platelets and the blood vessel wall, so that low tissue-plasminogen activator activity prevents a mechanism similar to that of ADAMTS13. The hypothesis that low tissue-plasminogen activator activity plays an important role in TTP pathogenesis is further substantiated by TTP comorbidity. Problems prevalent in patients with TTP attacks or with long-term TTP remission, including increased body mass index, major depression, cognitive abnormalities, hypertension, and premature death, are somehow associated with low tissue-plasminogen activator activity. PMID- 25459149 TI - Aromatic amides and ureas as novel molecular probes for diagnosing disease. AB - It is firmly established that control over the three-dimensional shape (i.e., the conformation) of aromatic amides and ureas can be achieved using a variety of methods, all of which rely on the addition of a substituent to a central nitrogen atom; exactly which conformation is adopted in solution can be determined using a variety of analytical techniques, such as: fluorescence, NMR and HPLC. We hypothesise that if the central nitrogen atoms were suitably functionalised with enzyme-cleavable groups, then the associated change in shape could be exploited upon the removal of a group, and these compounds could thus be exploited as diagnostic probes for the detection of analytes (i.e., enzymes) in solution or biological samples. The exquisite selectivity of naturally-occurring enzymes therefore makes it possible that the enzyme-cleavable group could be rationally designed and tailored for each enzyme of interest, thus making an analytical toolkit of diagnostic probes for detecting enzymes which are over-expressed in disease. If the sensitivity of such probes was sufficiently low enough, then they could potentially be used to detect the on-set of disease in a non-invasive manner from bodily fluids. PMID- 25459150 TI - Sleep paralysis and "the bedroom intruder": the role of the right superior parietal, phantom pain and body image projection. AB - Sleep paralysis (SP) is a common condition occurring either at sleep onset or sleep offset. During SP the sleeper experiences gross motor paralysis while the sensory system is clear. Hypnogogic and hypnopompic hallucinations are common during SP and may involve seeing, hearing, and sensing the presence of menacing intruders in one's bedroom. This "intruder" is often perceived as a shadowy humanoid figure. Supernatural accounts of this hallucinated intruder are common across cultures. In this paper, we postulate that a functional disturbance of the right parietal cortex explains the shadowy nocturnal bedroom intruder hallucination during SP. This hallucination may arise due to a disturbance in the multisensory processing of body and self at the temporoparietal junction. We specifically propose that this perceived intruder is the result of a hallucinated projection of the genetically "hard-wired" body image (homunculus), in the right parietal region; namely, the same circuits that dictate aesthetic and sexual preference of body morphology. One way to test this hypothesis would be to study clinical populations who may have genetically acquired "irregularities" in their internal hard-wired body image in the right superior parietal lobule (SPL); for example, individuals with apotemnophilia or anorexia nervosa. If such individuals experience SP (e.g., induced in a sleep lab), and they hallucinate this shadowy figure, one would predict that they would see humanoid shadows and shapes with body irregularities, mirroring their own internal body image morphology. If correct, our hypothesis will offer a neurological explanation for this nocturnal bedroom intruder that has been a source of controversy, and striking and implausible cultural interpretations throughout history. Indeed, if our proposed hypothesis is tested and corroborated, dissemination of such findings would provide great relief to SP experiencers worldwide and could potentially be used in a therapeutic context. PMID- 25459151 TI - Exhaustive exercise--a near death experience for skeletal muscle cells? AB - In sports medicine, muscle enzymes in the blood are frequently used as an indicator of muscle damage. It is commonly assumed that mechanical stress disrupts plasma membrane to an extent that allows large molecules, such as enzymes, to leak into the extracellular space. However, this does not appear to fully explain changes in muscle enzyme activity in the blood after exercise. Apart from this mechanically induced membrane damage, we hypothesize that, under critical metabolic conditions, ATP consuming enzymes like creatine kinase (CK) are "volitionally" expulsed by muscle cells in order to prevent cell death. This would put themselves into a situation comparable to that of CK deficient muscle fibers, which have been shown in animal experiments to be virtually infatigable at the expense of muscle strength. Additionally we expand on this hypothesis with the idea that membrane blebbing is a way for the muscle fibers to store CK in fringe areas of the muscle fiber or to expulse CK from the cytosol by detaching the blebs from the plasma membrane. The blebbing has been shown to occur in heart muscle cells under ischaemic conditions and has been speculated to be an alternative pathway for the expulsion of troponin. The blebbing has also been seen skeletal muscle cells when intracellular calcium concentration increases. Cytoskeletal damage, induced by reactive oxygen species (ROS) or by calcium activated proteases in concert with increasing intracellular pressure, seems to provoke this type of membrane reaction. If these hypotheses are confirmed by future investigations, our current understanding of CK as a blood muscle damage marker will be fundamentally affected. PMID- 25459152 TI - Joseph Boruwlaski (1739-1837): a case of Laron syndrome? PMID- 25459153 TI - Neuronal plasticity in depressive or manic states--new assessment of our hypothesis: mania is an extension of depression from the perspective of neuronal plasticity. PMID- 25459154 TI - Pure inorganic separator for lithium ion batteries. AB - Battery safety is critical for many applications including portable electronics, hybrid and electric vehicles, and grid storage. For lithium ion batteries, the conventional polymer based separator is unstable at 120 degrees C and above. In this research, we have developed a pure aluminum oxide nanowire based separator; this separator does not contain any polymer additives or binders; additionally, it is a bendable ceramic. The physical and electrochemical properties of the separator are investigated. The separator has a pore size of about 100 nm, and it shows excellent electrochemical properties under both room and high temperatures. At room temperature, the ceramic separator shows a higher rate capability compared to the conventional Celgard 2500 separator and life cycle performance does not show any degradation. At 120 degrees C, the cell with the ceramic separator showed a much better cycle performance than the conventional Celgard 2500 separator. Therefore, we believe that this research is really an exciting scientific breakthrough for ceramic separators and lithium ion batteries and could be potentially used in the next generation lithium ion batteries requiring high safety and reliability. PMID- 25459155 TI - Thermal printed receipts found to contain bisphenol: a potential carcinogen. PMID- 25459156 TI - Pirfenidone-a ray of hope in oral sub mucous fibrosis. PMID- 25459157 TI - Rationale for combined blockade of PD-1 and CTLA-4 in advanced head and neck squamous cell cancer-review of current data. AB - Targeted immunotherapy promoting anti-tumor T-cell activity has shown improved survival and durable objective responses in advanced melanoma patients. Data is mounting that concurrent use of ipilimumab and nivolumab has a more pronounced effect than either as monotherapy. Although no completed clinical trials exist for their use in head and neck cancer, preclinical data suggests these therapies would be beneficial in head and neck malignancies as well. Their role in head and neck cancer management is an ongoing research effort. PMID- 25459158 TI - DNA content status using brush biopsy with image cytometry correlated with staging of oral leukoplakia: a preliminary study. AB - BACKGROUND: Oral leukoplakia (OL) is the best-known potentially malignant disorder of oral cancer. The hypothesis was tested that DNA content abnormality may contribute to risk prediction of malignant potential of OL. METHODS: All OLs were staged according to a clinicopathologic classification and OL-staging system. DNA content status was investigated in a blinded prospective series of OL using brush biopsy with image cytometry, and examined the correlation of DNA content with the clinicopathologic features and OL-staging system in this preliminary study. RESULTS: Among 65 patients with OL, 27 (41.5%) was identified as DNA content abnormality. The frequency (77.8%) of DNA content abnormality in tongue was higher than that (22.2%) in other oral sites (chi(2) test, P=0.038), and moderate or severe dysplasia had a higher frequency (63.0%) of DNA content abnormality than that (37.0%) of no or mild dysplasia (chi(2) test, P=0.022). Moreover, the odds ratio of DNA content abnormality in high-risk patient group was 5.74-fold (95% confidence interval, 1.81-18.20; P=0.003) increase compared with low-risk patient group. Importantly, the positive correlation between OL staging system and DNA content status was significant (P=0.018, correlation coefficient=0.292). CONCLUSION: Our findings showed that DNA content status correlated with OL-staging system, suggesting that DNA content abnormality in OL as detected by image cytometry was an early event in oral carcinogenesis. The further large-scale prospective studies with clinical endpoints are warranted to validate the value of DNA image cytometry. PMID- 25459160 TI - Increased percentage of IFN-gamma producing CD56+CD3+ cells in active tuberculosis patients upon CFP-10 stimulation of peripheral mononuclear cells. AB - Aiming to identify a possible biomarker that distinguishes immune cellular response of active tuberculosis from latent infection. Peripheral blood mononuclear cells (PBMCs) of pulmonary tuberculosis patients (PTB), tuberculin positive household contacts (TST(+) HHC), and tuberculin negative non-household contacts (TST- Non HHC) were stimulated with PPD or CFP-10 and the percentage of CD69(+) cells, proliferating precursor and IFN-gamma producing CD4(+), CD8(+), CD56(+)CD3(-) and CD56(+)CD3(+) cells were compared. IL-2, IL-12p70, IL-15, IL-18 and IL-10 were measured in culture supernatants. PTB and TST+ HHC presented higher percentages of CD69(+) cells, IFN-gamma(+) and proliferating precursors in all subpopulations studied and higher IL-12p70 levels than TST- Non HHC. The increased percentage of IFN-gamma producing CD56(+)CD3(+) cells in response to CFP-10 in PTB, compared with TST- Non HHC and the ratios between the percentage of CD56(+)CD3(+) cells/CD56(+)CD3(-) and CD8(+) cells producing IFN-gamma suggest that these parameters may distinguish active TB from latently infected individuals. PMID- 25459161 TI - Effect of 1,25-dihydroxy vitamin D3 on cathelicidin expression in patients with and without cavitary tuberculosis. AB - 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) is a potent immuno-modulator which induces LL-37, the active peptide of cathelicidin, and restricts the growth of Mycobacterium tuberculosis (Mtb) in human macrophages. In the present study, we investigated the effect of 1,25(OH)2D3 on cathelicidin antimicrobial peptide (CAMP) expression in healthy controls (HCs) and pulmonary tuberculosis (PTB) patients. Peripheral blood mononuclear cells (PBMCs) from 50 HCs and 35 PTB patients were cultured for 72 h either with Mtb alone or Mtb with 1,25(OH)2D3 at 10(-7) M concentration. 1,25(OH)2D3 significantly up regulated the macrophage phagocytosis, CD14, CAMP gene expression and hCAP18 protein in HCs and PTB patients (p < 0.05). A significant positive correlation was observed between macrophage phagocytosis and CAMP gene expression in both the study groups (p < 0.05). Moreover, 1,25(OH)2D3 up regulated CAMP gene expression was more prominent in PTB patients without lung cavity (less severe form of disease) as compared to patients with cavitary TB (severe form of disease) (p < 0.05). The present study suggests that vitamin D may be used as an adjunct to anti-TB treatment and may be useful for a quicker recovery from less severe forms of TB disease. PMID- 25459162 TI - Assessing humoral immune response of 4 recombinant antigens for serodiagnosis of tuberculosis. AB - Serodiagnostic potential of four recombinant proteins (38 kDa[Rv0934], MPT64[Rv1980c], Adk[Rv0733], and BfrB[Rv3874]) was evaluated in Healthy control subjects (HCS), Healthy household contacts (HHC), Pulmonary tuberculosis patients (PTB), and Human immuno deficiency virus & Tuberculosis co-infected patients (HIV TB). All the antigens tested individually for the detection of serum IgG by indirect ELISA. All the four antigens have a significantly higher antibody response in PTB compared to healthy controls (P < 0.05). The sensitivity of individual antigens ranged from 20% to 52.5% for the prefixed specificity of 95%. When results of all 4 antigens were combined the sensitivity was increased to 75% and specificity was reduced 89% in HCS. In smear- and culture-positive (S+C+) PTB, four antigen combination gives maximum sensitivity (89.6%) with 89% specificity. In smear negative culture negative (S-C+) PTB, three antigen combination (38 kDa with MPT64 and BfrB) gives maximum sensitivity (69.5%) and specificity (91.6%). In HIV-TB, 4 antigen combinations give the maximum sensitivity of 51.2% with 89% specificity. Combining serology (Four antigen combination) with smear was able to increase the sensitivity from 70% to 92.5% in culture positive PTB. So, we propose that this serology test can be used as adjunct test along with smear for rapid diagnosis of PTB. PMID- 25459163 TI - Mycobacterium tuberculosis strains spreading in Hanoi, Vietnam: Beijing sublineages, genotypes, drug susceptibility patterns, and host factors. AB - Beijing genotype strains are divided into two major sublineages, ancient (atypical) and modern (typical) types, but their phenotypic variations remain largely unknown. Mycobacterium tuberculosis (MTB) isolates from Hanoi, Vietnam, were analyzed by single-nucleotide polymorphisms and spoligotyping. Patient information and drug susceptibility patterns were obtained. Genetic clustering was assessed by variable number of tandem repeat (VNTR) locus sets. Multivariate analysis was also performed to investigate factors possibly associated with these sublineages. Of the 465 strains tested, 175 (37.6%) belonged to the ancient Beijing sublineage and 97 (20.9%) were of the modern Beijing sublineage. Patients with the Beijing genotype were significantly younger and more undernourished than those with non-Beijing genotype. The proportion of clustered strains calculated from 15 locus-optimized mycobacterial interspersed repetitive units [optimized (MIRU)15]-, optimized-MIRU24-, optimized-MIRU28-, Japan Anti-Tuberculosis Association (JATA)15-, and JATA18-VNTRs were 55.7%, 49.2%, 33.8%, 44.5%, and 32.0%, respectively. Ancient and modern Beijing genotype strains were more frequently clustered than non-Beijing genotype strains, even when using VNTR sets with high discriminatory power. Isoniazid and streptomycin resistance tended to be more frequently observed in ancient Beijing strains than in modern Beijing strains and others. Our findings may provide insight into area-dependent differences in Beijing family strain characteristics. PMID- 25459164 TI - Editorial overview: pharmaceutical biotechnology: engineering cells for high quality biopharmaceuticals production. PMID- 25459165 TI - Important roles of platelets as immune cells in the skin. AB - Platelets work as immune cells by initiating and modulating inflammatory and immune responses, in addition to having prominent functions in hemostasis and thrombosis. They store a multitude of immune-associated molecules in their granules. Upon activation in response to various factors such as thrombin, chemokines, and microbial toxins, platelets express adhesive and immune receptors such as P-selectin, CD40 ligand, and Toll-like receptors on their surface, and release soluble mediators such as chemokines, cytokines, and antimicrobial peptides. In this way, platelets interact with endothelial cells and leukocytes including dendritic cells, T cells, B cells, neutrophils, monocytes, and natural killer cells, both directly by cell to cell contact and indirectly via secretion of soluble mediators. In cutaneous inflammatory diseases such as atopic dermatitis and psoriasis, platelets circulate in an activated state, and the degree of platelet activation correlates with disease severity. Platelets are closely linked to the pathogenesis of inflammatory skin diseases, including atopic dermatitis, contact dermatitis, and psoriasis, via several pathomechanisms, e.g. increasing leukocyte rolling on the endothelium via formation of platelet-leukocyte complexes, recruiting leukocytes into inflamed skin via release of inflammatory mediators including chemokines, inhibiting monocytic apoptosis, inducing neutrophil phagocytosis, promoting allergic sensitization, provoking pruritus, and regulating inflammation. Platelets can also recognize bacterial pathogens through interactions via Toll-like receptors, leading to subsequent elimination of the bacteria by release of antimicrobial peptides or by aggregation of platelets around the bacteria. Thus, platelets are deeply involved in the innate and acquired immune responses in the skin via interactions with leukocytes and the endothelium. PMID- 25459166 TI - Graduate nursing students' evaluation of EBP courses: a cross-sectional study. AB - BACKGROUND: There is a lack of appropriate tools for assessing the effectiveness of teaching evidence-based practice in nursing. OBJECTIVES: The objective of the study was to develop the instrument evaluating the students' perception of the effectiveness of EBP courses and to verify its psychometric properties. DESIGN: A descriptive cross-sectional study design was used to verify psychometric properties of the questionnaire measuring the students' perception of the effectiveness of EBP courses. PARTICIPANTS: The psychometric properties were evaluated in a group of 129 graduate nursing students who completed EBP courses. METHODS: The instrument for measuring the students' perception of the effectiveness of EBP courses was inspired by Kirkpatrick's evaluation model, which advocates evaluating interventions at four levels - reaction (satisfaction), learning, behavior change (transfer) and results (benefits). A web-based survey was used for data collection. Data was collected from the middle of January 2013 through the end of March 2013. RESULTS: A thirteen item instrument was developed for measuring the students' perception of the effectiveness of EBP courses. The internal consistency of the scale, based on standardized Cronbach's alpha, was .93. The results of factor analysis identified three factors of the instrument. The highest rated items on a scale of 1 (strongly disagree) to 7 (strongly agree) were 'implementation of EBP can improve clinical care' (mean 6.16), 'EBP instructors had a thorough knowledge of EBP' (6.13), 'EBP instructors were enthusiastic about teaching EBP' (5.65), and 'I can use my EBP knowledge and skills in my practice' (5.58). CONCLUSIONS: The results of testing of the psychometric properties of the questionnaire showed at least satisfactory validity and reliability. The majority of students perceived EBP courses as effective. The instrument may be used to assess the students' perception of the effectiveness of EBP courses. PMID- 25459167 TI - Impact of the Bachelor's thesis on the nursing profession. PMID- 25459168 TI - Novice nurses' level of global interdependence identity: a quantitative research study. AB - BACKGROUND: Often, therapeutic relationships are cross-cultural in nature, which places both nurses and patients at risk for stress, depression, and anxiety. OBJECTIVES: The purpose of this investigation was to describe novice nurses' level of global interdependence identity, as manifested by worldminded attitudes, and identify the strongest predictors of worldminded attitudes. DESIGN: Prospective descriptive with multiple regression study. SETTING: The various nursing units of a large hospital in the great Cleveland, OH, area. PARTICIPANTS: The participants were novice nurses up to two years after graduation from nursing school and employed as hospital clinicians. METHODS: Descriptive statistics with the mean and standard deviation of the scores was used for the delineation of the development of the participants. The study relied on a survey instrument, the Scale to Measure Worldminded Attitudes developed by Sampson and Smith (1957). The numerical data was scored and organized on a Microsoft Excel spreadsheet. The Statistical Package for Social Sciences (SPSS) version 21 was the program used to assist with analysis. The assessment of the models created through regression was completed using the model summary and analysis of variance (ANOVA). RESULTS: The nurses' mean level of global interdependence identity was slightly above the neutral point between extreme national-mindedness and full development of global interdependence identity. The best predictors of worldminded attitudes were immigration, patriotism, and war conceptualized under a global frame of reference. CONCLUSION: Novice nurses did not demonstrate an optimum developmental status of global interdependence identity to safeguard cross-cultural encounters with patients. The recommendation is the inclusion of immigration, patriotism, and war in the nursing curriculum and co-curriculum to promote student development and a turnaround improvement in patient experience. PMID- 25459169 TI - Medical memoir: a tool to teach empathy to nursing students. PMID- 25459170 TI - The development and empirical validation of the Q-PDN: a questionnaire measuring continuing professional development of nurses. AB - BACKGROUND: Although separate studies among nurses have been conducted into their continuing professional development (CPD) motives, importance attached to CPD, conditions deemed needed for CPD, and actual CPD activities undertaken, these variables have not yet been investigated at the same time, on the same sample. OBJECTIVES: The aim of this study is to report on the development and initial psychometric testing of the Q-PDN, a questionnaire measuring several aspects of CPD among nurses. METHOD: Based on a survey administered to 1329 nurses in hospitals in the Netherlands, a multi-dimensional instrument for CPD was validated. The constructs 'CPD motives', 'CPD importance', 'CPD conditions', and 'CPD activities undertaken' were established through factor analyses. RESULTS: Reliability analyses showed satisfactory to good Cronbach's alpha scores on all factors, ranging from .70 to .89. CONCLUSION: Using this instrument can stimulate and support CPD of nurses, which has been shown to contribute to increasing the quality of care. Human resource development (HRD) professionals, educators in healthcare, and managers can use this questionnaire to gain insight in the extent to which nurses undertake CPD activities, in the importance they attribute to CPD activities, in the conditions they deem necessary to participate in CPD, and in the motives that they have to engage in CPD. PMID- 25459171 TI - Does a 3-week critical research appraisal course affect how students perceive their appraisal skills and the relevance of research for clinical practice? A repeated cross-sectional survey. AB - BACKGROUND: Research utilisation is essential in developing evidence-based practices; although many students may be generally able to adopt such skills, there are reports of barriers related to critical appraisal skills. OBJECTIVES: To explore how students perceive the relevance of research to future clinical practice and patients, and to what extent they read research (including reading pattern). Additionally, the objective was to explore whether a three-week intensive course in critical appraisal of research could affect these variables. DESIGN: A cross-sectional survey design, with a pre- and post-test. SETTINGS: One large university college in Southeastern Norway. PARTICIPANTS: 196 multidisciplinary healthcare students at baseline and 147 after three weeks. METHODS: A purposely-designed 21 item questionnaire was used to quantify students' attitudes towards using research and critical thinking. The questionnaire was based on themes emerging from prior focus group interviews with 10 nursing and social educator students as well as from the existing literature. RESULTS: At baseline, 6.1% and 7.1% of respondents perceived the research to be of little or very little importance for their future work and patients, respectively. Furthermore, 83.2% reported that they seldom or very seldom read scientific papers. At baseline, 40 different patterns of reading a scientific paper were identified. Additionally, 7.1% of respondents reported to read the introduction, methods and conclusion in combination. Significantly improved scores were found after completing the three-week course related to a) relevance of research for future work (p<0.01), b) self-perceived skills in critical appraisal (p<0.001), c) ability to find scientific papers (p<=0.01), and d) relevance of research for patients and users (p<=0.001). CONCLUSIONS: Teaching students' practical critical appraisal skills improved their view of the relevance of research for patients, future work as well as their own critical appraisal skills. Prospective studies are warranted to explore the effects of such teaching modules in the long-term. PMID- 25459172 TI - Effectiveness of patient simulation in nursing education: meta-analysis. AB - BACKGROUND: The use of simulation as an educational tool is becoming increasingly prevalent in nursing education, and a variety of simulators are utilized. Based on the results of these studies, nursing facilitators must find ways to promote effective learning among students in clinical practice and classrooms. OBJECTIVE: To identify the best available evidence about the effects of patient simulation in nursing education through a meta-analysis. METHODS: This study explores quantitative evidence published in the electronic databases: EBSCO, Medline, ScienceDirect, and ERIC. Using a search strategy, we identified 2503 potentially relevant articles. Twenty studies were included in the final analysis. RESULTS: We found significant post-intervention improvements in various domains for participants who received simulation education compared to the control groups, with a pooled random-effects standardized mean difference of 0.71, which is a medium-to-large effect size. In the subgroup analysis, we found that simulation education in nursing had benefits, in terms of effect sizes, when the effects were evaluated through performance, the evaluation outcome was psychomotor skills, the subject of learning was clinical, learners were clinical nurses and senior undergraduate nursing students, and simulators were high fidelity. CONCLUSIONS: These results indicate that simulation education demonstrated medium to large effect sizes and could guide nurse educators with regard to the conditions under which patient simulation is more effective than traditional learning methods. PMID- 25459173 TI - Teaching skills to resolve conflicts with acute confusional syndrome patients in nursing using the Case Method (CM). AB - OBJECTIVE: This study sets out to design and implement a teaching sequence that offers students the opportunity to acquire the necessary knowledge, skills, attitudes and values to deal with a confrontational patient. When designing the teaching methodology, we chose an active teaching strategy, commonly entitled the Case Method. METHOD: The case was developed during the 2011-2012 academic year and implemented across the curriculum in the 2012-2013 academic year, in the "Relations and Communications in Nursing Care" and "Geriatric Nursing" subject modules, in the second year undergraduate nursing course at the University of the Basque Country. RESULTS: Implementation results indicate that the Case Method is a satisfactory tool to facilitate acquisition of the chosen skills, as well as being a learning method that is well received by students. At the end of the process, 72.8% of them shared the opinion that "this methodology has helped me more or much more than traditional 'chalk and talk' expository methodology". Moreover, 93% of the students successfully achieved at least the minimum learning results required. Nevertheless, students said that they felt overwhelmed on more than one occasion. IMPLICATIONS: The study has provided evidence that the Case Method contributes to acquiring skills that every nurse will need during their career. This should spur us on to continue extending the range of possibilities offered by active methodologies. PMID- 25459174 TI - Transplantation in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is associated with poor outcome mainly because of relapse. The best antileukemic treatment is allogeneic stem cell transplantation. However, the associated significant nonrelapse mortality limits both the application and outcome of the procedure. Recent advances in understanding the genetic landscape of the disease enable educated selection of patients. Improved treatment protocols, supportive therapy, patient selection, and posttransplant manipulations all contribute to a better outcome. PMID- 25459175 TI - Allogeneic hematopoietic cell transplantation in adult patients with acute lymphoblastic leukemia. AB - This review discusses the use of prognostic factors, patient and donor selection, choice of conditioning regimens, and timing of transplant. It also describes the management of Philadelphia-positive acute lymphocytic leukemia (ALL) and central nervous system disease. All aggressively treated adults with ALL should be considered for allogeneic transplantation and tissue typed at diagnosis. We further suggest that eligible patients be entered into clinical trials (that incorporate transplantation); these unselected prospective outcome data are essential to evaluate the true value of allogeneic transplantation in adults with ALL. PMID- 25459176 TI - Transplants in myelodysplastic syndromes. AB - Myelodysplastic syndromes are one of the most common hematological disorders in the elderly. Therefore, an increase in the prevalence of de novo but also of secondary forms after prior chemotherapy or radiotherapy, respectively, is anticipated within the next years. Allogeneic stem cell transplantation is considered the only potentially curable therapy, but many patients are not eligible because of age or comorbidities. Reduced-intensity conditioning regimens have improved early tolerability of the procedure, although late effects remain a challenge in the care of these patients. However, hypomethylating agents have become available as alternative therapeutic approaches with a moderate toxicity profile. PMID- 25459178 TI - Chronic myeloid leukemia-transplantation in the tyrosine kinase era. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) revolutionized the outlook for many patients with chronic myeloid leukemia (CML) in the 1980s. The introduction of the tyrosine kinase inhibitors (TKIs) nearly 15 years ago displaced HSCT as the first-line treatment for most CML patients. However, in the twenty-first century HSCT remains a viable treatment option for many patients with CML. This review focuses on the role of HSCT for CML in the TKI era, paying particular attention to patient selection and transplant outcome. PMID- 25459180 TI - Hematopoietic stem cell transplantation for non-Hodgkin lymphoma. AB - Up-front rituximab-based chemotherapy has improved outcomes in non-Hodgkin lymphoma (NHL); refractory or relapsed NHL still accounts for approximately 18,000 deaths in the United States. Autologous hematopoietic stem cell transplantation (SCT) can improve survival in primary refractory or relapsed aggressive NHL and mantle cell lymphoma and in relapsed follicular or peripheral T-cell lymphoma. Autologous SCT as a consolidation therapy after first complete or partial remission in high-risk aggressive NHL, mantle cell lymphoma, and peripheral T-cell lymphoma may improve progression-free survival. Allogeneic SCT offers a lower relapse rate but a higher nonrelapse mortality resulting in overall survival similar to autologous SCT. PMID- 25459177 TI - Role of hematopoietic stem cell transplantation in patients with myeloproliferative disease. AB - Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell disorders. While some MPN patients have an indolent course, all are at risk of progressing to severe marrow failure or transforming into acute leukemia. Allogeneic hematopoietic cell transplantation (allo-HCT) is the only potential curative therapy. Major pre-transplant risk factors are disease stage of the MPN, the presence of comorbid conditions and the use of HLA non-identical donors. The development of reduced-intensity conditioning regimens has allowed for successful allo-HCT even for older patients and patients with comorbid conditions. The pre transplant use of JAK2 inhibitors, which may be effective in down staging a patient's disease, may improve the outcomes following allo-HCT. PMID- 25459181 TI - Stem cell transplantation in Hodgkin lymphoma. AB - Patients with Hodgkin lymphoma (HL) who relapse following effective front-line therapy are offered salvage second-line chemotherapy regimens followed by high dose therapy and autologous stem cell transplantation (HDT/ASCT). Randomized studies comparing HDT/ASCT with conventional chemotherapy in patients with relapsed refractory HL have shown significant improvement in progression-free survival and freedom from treatment failure but were not powered to show improvements in overall survival. For patients who relapse after salvage HDT/ASCT, novel therapies exist as a bridge to allogeneic SCT. In this article, we review indications and results of autologous and allogeneic SCT in HL. PMID- 25459182 TI - Multiple myeloma. AB - Autologous stem cell transplant (ASCT) remains an integral part of the treatment strategy for many myeloma patients. The role of allogeneic stem cell transplant continues to be defined. There is increasing evidence that posttransplant maintenance therapy can significantly improve outcomes. It is predicted that with more routine use of cytogenetic and gene expression profiling in the future, we will be better able to identify those subgroups of patients who are expected to benefit most from early versus late versus no ASCT and those who will benefit from allogeneic stem cell transplant. PMID- 25459179 TI - Transplantation in chronic lymphocytic leukemia: does it still matter in the era of novel targeted therapies? AB - Allogeneic stem cell transplantation (HSCT) offers the only potentially curative approach in chronic lymphocytic leukemia (CLL). However, this applies only to a minority of patients, and is associated with significant treatment-related mortality and morbidity. HSCT must therefore always be considered in view of other, potentially less toxic therapies. Several new agents demonstrate impressive and durable responses in high-risk patients who might be candidates for HSCT. Therefore the choice of HSCT versus a novel agent is one that must be gauged on a patient-by-patient basis; this will change as data mature on the use of these novel agents in CLL. PMID- 25459183 TI - High dose melphalan and autologous peripheral blood stem cell transplantation in AL amyloidosis. AB - AL amyloidosis is the most common form of systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. It is often difficult to recognize because of its many manifestations. Recent diagnostic and prognostic advances include the serum-free light chain assay, cardiac MRI, and serologic cardiac biomarkers. Treatment strategies that have evolved during the past decade are prolonging survival and preserving organ function. This article outlines the role of high-dose melphalan and stem cell transplantation. This year marks the 20th anniversary for the first patient who underwent successful stem cell transplantation for this disease at Boston Medical Center. PMID- 25459184 TI - Bone marrow transplantation for acquired severe aplastic anemia. AB - This article addresses current transplant options for patients with acquired severe aplastic anemia (SAA). This discussion includes ongoing progress in the use of SAA in the setting of unrelated donor transplants, which now provide outcomes similar, though still not identical, to HLA-identical sibling transplants. Recent data on stem cell source, conditioning regimens, and graft versus-host disease prophylaxis are outlined. Other donor types such as cord blood and haploidentical mismatched family donors are also discussed. PMID- 25459185 TI - Hematopoietic stem cell transplantation for primary immunodeficiencies. AB - Allogeneic hematopoietic stem cell transplantation has been shown to be curative for well-described as well as newly discovered immunodeficiencies. However, it is difficulty to define a universal transplant regimen given the rarity of these disorders and the varied pathophysiology these disorders encompass. This article discusses those primary immunodeficiencies most commonly treated by hematopoietic stem cell transplant and describes the transplant issues specific to these disorders. PMID- 25459187 TI - Allogeneic stem cell transplantation for thalassemia major. AB - Allogeneic stem cell transplant remains the only curative option for beta thalassemia major. In patients with good risk features it is reasonable to anticipate a greater than 90% chance of a successful transplant outcome. The conventional risk stratification system has limitations and alternative systems are being explored to better identify subsets that require innovative approaches. Several novel regimens have been evaluated to reduce treatment-related morbidity and mortality. There remain challenges in improving the clinical outcome of high risk patients. There are limited data on the role of splenectomy before transplantation or optimal posttransplant chelation and care of these patients. PMID- 25459186 TI - Hematopoietic stem cell transplantation for patients with sickle cell disease: progress and future directions. AB - Research has solidified matched sibling marrow, cord blood, or mobilized peripheral blood as the best source for allogeneic hematopoietic stem cell transplantation for patients with sickle cell disease, with low graft rejection and graft-versus-host disease (GVHD) and high disease-free survival rates. Fully allelic matched unrelated donor is an option for transplant-eligible patients without HLA-matched sibling donors. Unrelated cord transplant studies reported high GVHD and low engraftment rates. Haploidentical transplants have less GVHD, but improvements are needed to increase the low engraftment rate. The decision to use unrelated cord blood units or haploidentical donors depends on institutional expertise. PMID- 25459188 TI - Referral to transplant center for hematopoietic cell transplantation. AB - Hematopoietic cell transplantation is a complex and highly specialized medical procedure offered by selected centers with the requisite expertise and resources. Timely referral to a transplant center is among the most important determinants of successful outcomes. Patients, providers, and payors consider several factors in selecting a transplant center, such as center outcomes and accreditation, patient health insurance coverage, geographic location and accessibility, availability of ancillary and support services, and coordination of care after discharge from the transplant center. Ongoing evaluation and research is needed to advise optimal care models for timely referral to a transplant center and transition of care from the transplant center back to the referring physician. PMID- 25459189 TI - Bone marrow transplantation. Preface. PMID- 25459190 TI - Ziconotide-induced psychosis: a case report. AB - Ziconotide is used intrathecally in the management of severe chronic pain that contains a warning against neuropsychiatric adverse events. The definition of psychiatric events is broad and management strategies are vague. This case report describes a 49-year-old female who was admitted to the acute psychiatric unit to address auditory hallucinations and paranoid ideation persisting for 3 weeks. Approximately 3 months ago, an intrathecal pump with ziconotide was implanted to treat pain. Upon hospital admission, the pump was infusing at a rate of 4.9 mcg/24 hours. Because the drug could not be immediately discontinued, risperidone 0.5 mg nightly was initiated and subsequently, the pump was drained of ziconotide, rinsed, and refilled with normal saline. The patient reported no hallucinations or apparent delusions several hours later and was eventually discharged with resolution of psychotic symptoms and continuation of risperidone for 10 days. Despite the identification of neuropsychiatric effects, limited information is available to characterize the presentation and guide specific management aside from recommendations to discontinue the infusion and possible use of psychotropic medications or necessity for hospitalization. This case report characterizes one presentation of hallucinations and paranoia associated with ziconotide intrathecal infusion. Clinicians should be aware of the management strategies to mediate these adverse effects, including expected time to adverse effect resolution, removal of ziconotide from the pump, and role for short-term use of antipsychotics. PMID- 25459191 TI - Clinical usefulness of therapeutic drug monitoring of voriconazole in a university hospital. AB - INTRODUCTION: The aim of this study was to assess the clinical usefulness of therapeutic drug monitoring (TDM) of voriconazole (VOR) in a university hospital. METHODS: A retrospective review was conducted on the clinical records of 52 patients treated with VOR and on whom TDM was performed. Steady-state trough plasma VOR concentration was measured at least 5 days after starting treatment. The therapeutic range of plasma VOR concentration was defined as 1-5.5MUg/mL. RESULTS: The most frequent underlying conditions in the study population were lung transplant (48.1%) and hematological malignancies (26.9%). At the first TDM in each patient, VOR levels were outside the therapeutic range in 16 (30.7%) cases: <1MUg/mL in 10 (19.2%) and >5.5MUg/mL in 6 (11.5%). Eleven patients (21.2%) experienced severe muscle weakness and had considerable difficulty walking. All these patients were receiving concomitant treatment with corticosteroids. Age younger than 30 years (p=.005) and cystic fibrosis as the underlying disease (p=.04) were factors associated with low VOR levels. Almost all patients who had VOR concentrations >1MUg/mL at the first TDM had a successful outcome (96%). CONCLUSIONS: Plasma VOR concentrations were outside the therapeutic range at the first TDM in 30% (16/52) of patients. Age younger than 30 years and cystic fibrosis were factors associated with low VOR levels. The potential interactions between corticosteroids and VOR should be highlighted, as they could be responsible for a high rate of muscle weakness observed in our patients. Prospective trials are needed to investigate VOR TDM and corticosteroid pharmacokinetics. PMID- 25459192 TI - Rectal pre-treatment with ozonized oxygen (O3) aggravates clinic status in septic rats treated with amoxicillin/clavulanate. AB - INTRODUCTION: Despite the advanced antibiotic therapies, sepsis continues being a clinical entity with high morbidity and mortality. The ozone/oxygen mixture (O3/O2) has been reported to exhibit positive effects on immunity. The aim of our study was to analyze whether (O3/O2) combined with amoxicillin/clavulanate has any influence on the morbidity and mortality of septic rats. METHODS: We used 48 Sprague-Dawley rats randomly allocated to 6 groups (n=8): healthy (C), septic (I), healthy+ozone therapy (O3), septic+amoxicillin/clavulanate (AMC), septic+amoxicillin/clavulanate+ozone therapy (AMC/O3) and septic+ozone therapy (I/O3). O3/O2 was administered rectally at increasing O3 concentrations during 10 days prior to the onset of sepsis model (intraperitoneally injection of fecal material) or saline administration in healthy control rats. Later (post inoculation), 3 days per week, O3 was also administered. Vital signs were recorded, and microbiological, hematological and histopathological studies were performed. RESULTS: The number of surviving animal/total was higher in AMC (8/8) than in AMC/O3 (4/8) p=0.077. The percentage of surviving animals with pneumonia was higher in AMC/O3 than in AMC (100% vs 37.5%). In dead animals, AMC/O3 rats had a significantly higher percentage of lesions: Cardiac lesions, pulmonary hemorrhages and pleuritis (100%) and serositis/peritonitis (75%). Only Escherichia coli (2 different biotypes) was isolated from blood and/or peritoneal fluid from all infected groups. A significant decrease in the percentage of band neutrophils from the surviviors belonging to AMC/O3vs AMC was observed (p<0.05). CONCLUSION: Rectal pre-treatment with O3/O2 aggravates clinic status in septic rats treated with amoxicillin/clavulanate. PMID- 25459193 TI - [Incidence and severity of pertussis in infants with a respiratory syncytial virus infection]. AB - INTRODUCTION: Pertussis is a re-emerging disease that mostly affects infants. At this age, the severity can be affected by intercurrent infections such as respiratory syncytial virus (RSV). OBJECTIVES: To estimate the incidence of RSV infection during an epidemic period in patients hospitalized due to pertussis. The impact on the severity was also observed during hospitalization. PATIENTS AND METHOD: A descriptive study of cases diagnosed with pertussis admitted to a tertiary hospital over a 3year period, where the presence of co-infection with RSV was analyzed. The estimate of severity was estimated using the incidence of complications and the level of care required. RESULTS: From a total of 73 infants with pertussis, 34 occurred in a bronchiolitis season epidemic. A co-infection due to RSV was detected in 17 patients. The mean age was not significantly different compared to the non co-infected. The mean stay and the need for intensive care was similar in both groups. The need for oxygen therapy care and nutritional support was higher in the coinfected patients. CONCLUSIONS: Coinfection with RSV in infants hospitalized with pertussis occurred in ono in 2 patients during a RSV epidemic season, in infants of similar age. Severity in terms of stay, presence of apnea and admission to intensive care was similar, but more need for respiratory care and nutritional support was found. PMID- 25459194 TI - Unexpected results in BK virus detection by real-time PCR due to polymorphisms in the T-antigen gene. PMID- 25459195 TI - Nasal carriage of coagulase positive staphylococci in patients of a Primary Healthcare-Center: genetic lineages and resistance and virulence genes. AB - INTRODUCTION: Staphylococcus aureus and Staphylococcus pseudintermedius are highly important due to their capacity for producing diseases in humans and animals, respectively. The aim of the study was to investigate and characterize the coagulase positive Staphylococcus (CoPS) carriage in a Primary Healthcare Center population. METHODS: Nasal swabs were obtained from 281 non-infectious patients. The CoPS isolates recovered were typed, and their resistance phenotype and genotype, as well as their virulence profiles, were analyzed. RESULTS: CoPS isolates were recovered from 56/281 patients (19.9%). Fifty-five were S. aureus (19.6%), 54 were methicillin susceptible (MSSA) and one was methicillin resistant (MRSA). The remaining isolate was S. pseudintermedius (0.4%). A high diversity of spa-types (n=40) was detected, with 6 of them being new ones. The multi-locus sequence-typing of 13 MSSA and one MRSA selected isolates was performed and the STs detected were: ST8, ST15, ST30, ST34, ST121, ST146, ST398, ST554, ST942, ST2499, and ST2500 (the last two STs being new). One MSSA isolate was typed as t1197-ST398-(Clonal complex)CC398. The MRSA isolate was typed as t002-ST146-CC5 SCCmec-IVc, and exhibited a multiresistance phenotype. The detected resistances were: penicillin (76%), macrolides (7%), tetracycline (7%), trimethoprim sulfamethoxazole (7%), quinolones (7%), and lincosamides (5%). Five isolates contained lukF/lukS-PV genes, 17 tst gene, one eta gene, and two etb gene. The S. pseudintermedius isolate presented a new spa-type (t57) (belonging to a new ST180) and the genes lukS/F-I, siet, se-int, and expB. CONCLUSIONS: A high genetic diversity of S. aureus was detected. Mention must be made of the identification of MSSA CC398 and S. pseudintermedius isolates in two patients, one of them with animal contact. The detection of the genes lukF/lukS-PV and tst should be noted. PMID- 25459196 TI - A rare case of schwannomatosis incidentally detected by 18F-FDG PET/CT during metabolic evaluation of a chest wall tumor. PMID- 25459197 TI - Diagnostic confidence and image quality of CT pulmonary angiography at 100 kVp in overweight and obese patients. AB - AIM: To compare image quality and diagnostic confidence of 100 kVp CT pulmonary angiography (CTPA) in patients with body weights (BWs) below and above 100kg. MATERIALS AND METHODS: The present retrospective study comprised 216 patients (BWs of 75-99kg, 114 patients; 100-125kg, 88 patients; >125kg, 14 patients), who received 100 kVp CTPA to exclude pulmonary embolism. The attenuation was measured and the contrast-to-noise ratio (CNR) was calculated in the pulmonary trunk. Size specific dose estimates (SSDEs) were evaluated. Three blinded radiologists rated subjective image quality and diagnostic confidence. Results between the BW groups and between three body mass index (BMI) groups (BMI <25kg/m(2), BMI = 25 29.9kg/m(2), and BMI >=30kg/m(2), i.e., normal weight, overweight, and obese patients) were compared using the Kruskal-Wallis test. RESULTS: Vessel attenuation was higher and SDDE was lower in the 75-99kg group than at higher BWs (p-values between <0.001 and 0.03), with no difference between the 100-125 and >125kg groups (p = 0.892 and 1). Subjective image quality and diagnostic confidence were not different among the BW groups (p = 0.225 and 1). CNR was lower (p < 0.006) in obese patients than in normal weight or overweight subjects. Diagnostic confidence was not different in the BMI groups (p = 0.105). CONCLUSION: CTPA at 100 kVp tube voltage can be used in patients weighing up to 125kg with no significant deterioration of subjective image quality and confidence. The applicability of 100 kVp in the 125-150kg BW range needs further testing in larger collectives. PMID- 25459198 TI - Improving the radiologist-CAD interaction: designing for appropriate trust. AB - Computer-aided diagnosis (CAD) has great potential to improve radiologists' diagnostic performance. However, the reported performance of the radiologist-CAD team is lower than what might be expected based on the performance of the radiologist and the CAD system in isolation. This indicates that the interaction between radiologists and the CAD system is not optimal. An important factor in the interaction between humans and automated aids (such as CAD) is trust. Suboptimal performance of the human-automation team is often caused by an inappropriate level of trust in the automation. In this review, we examine the role of trust in the radiologist-CAD interaction and suggest ways to improve the output of the CAD system so that it allows radiologists to calibrate their trust in the CAD system more effectively. Observer studies of the CAD systems show that radiologists often have an inappropriate level of trust in the CAD system. They sometimes under-trust CAD, thereby reducing its potential benefits, and sometimes over-trust it, leading to diagnostic errors they would not have made without CAD. Based on the literature on trust in human-automation interaction and the results of CAD observer studies, we have identified four ways to improve the output of CAD so that it allows radiologists to form a more appropriate level of trust in CAD. Designing CAD systems for appropriate trust is important and can improve the performance of the radiologist-CAD team. Future CAD research and development should acknowledge the importance of the radiologist-CAD interaction, and specifically the role of trust therein, in order to create the perfect artificial partner for the radiologist. This review focuses on the role of trust in the radiologist-CAD interaction. The aim of the review is to encourage CAD developers to design for appropriate trust and thereby improve the performance of the radiologist-CAD team. PMID- 25459199 TI - Ankylosing spondylitis: correlations between clinical and MRI indices of sacroiliitis activity. AB - AIM: To analyse the correlations between clinical and MRI sacroiliitis activity indices in ankylosing spondylitis (AS). MATERIALS AND METHODS: Sixteen normal volunteers and 52 patients were enrolled. The clinical AS activity indices included the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score, serum high-sensitivity C-reactive protein, and erythrocyte sedimentation rate. The MRI sacroiliitis activity indices included apparent diffusion coefficient (ADC) values of bone and the Spondyloarthritis Research Consortium of Canada (SPARCC) score. RESULTS: The mean SPARCC score of the control group was 0 and of the AS group was 9.9 +/- 9.1 (range 0-36). The mean ADC value of the AS group was statistically significantly higher than that of the control group (49.7 +/- 20.2 * 10(-5)mm(2)/s versus 38.9 +/- 5.3 * 10(-5)mm(2)/s, p < 0.05). The BASDAI score showed a statistically significant correlation with the SPARCC score (r = 0.685, p < 0.05) and with ADC values (r = 0.329, p < 0.05). ADC values correlated with the SPARCC score (r = 0.390, p < 0.05). CONCLUSION: ADC values and the SPARCC index may be useful activity indices in AS. PMID- 25459200 TI - The LEA Grating Test in assessing detection grating acuity in normal infants less than 4 months of age. AB - PURPOSE: To assess binocular detection grating acuity using the LEA GRATINGS test to establish age-related norms in healthy infants during their first 3 months of life. METHOD: In this prospective, longitudinal study of healthy infants with clear red reflex at birth, responses to gratings were measured at 1, 2, and 3 months of age using LEA gratings at a distance of 28 cm. The results were recorded as detection grating acuity values, which were arranged in frequency tables and converted to a one-octave scale for statistical analysis. For the repeated measurements, analysis of variance (ANOVA) was used to compare the detection grating acuity results between ages. RESULTS: A total of 133 infants were included. The binocular responses to gratings showed development toward higher mean values and spatial frequencies, ranging from 0.55 +/- 0.70 cycles per degree (cpd), or 1.74 +/- 0.21 logMAR, in month 1 to 3.11 +/- 0.54 cpd, or 0.98 +/- 0.16 logMAR, in month 3. Repeated ANOVA indicated differences among grating acuity values in the three age groups. CONCLUSIONS: The LEA GRATINGS test allowed assessment of detection grating acuity and its development in a cohort of healthy infants during their first 3 months of life. PMID- 25459201 TI - Results of Ahmed glaucoma valve implantation in primary congenital glaucoma. AB - PURPOSE: To evaluate the outcome of Ahmed glaucoma valve (AGV) implantation in primary congenital glaucoma (PCG). METHODS: The medical records of patients with PCG refractory to trabeculotomy and medical therapy who had undergone AGV implantation with a minimum follow-up of 6 months were retrospectively reviewed. The primary outcome measure was cumulative probability of success, defined as intraocular pressure (IOP) of 6-21 mm Hg, with or without medication, and no serious complications, additional glaucoma surgery, or loss of light perception. RESULTS: A total of 33 eyes of 22 children with a mean age (and standard deviation) of 2.7 +/- 3.1 years were included. The patients had a mean follow-up time of 32.6 +/- 18.3 months. The mean IOP was 32.8 +/- 7.3 mm Hg preoperatively and 16.8 +/- 4.0 mm Hg postoperatively. The number of glaucoma medications was 2.5 +/- 0.7 preoperatively and 2.2 +/- 0.7 postoperatively. The cumulative probability of success (and standard error) was 97% +/- 3.0% in the 1st year, 85% +/- 7.0% in the 2nd year, and 56% +/- 14.8% in the 5th year. When only the first operated eye per patient was included, the cumulative probability of success was 96% +/- 4.4% in the 1st and the 2nd years and 72% +/- 15.3% in the 5th year. Major complications comprised tube-endothelial touch (3 eyes), cataract (2 eyes), shunt extrusion (1 eye), and retinal detachment (1 eye). CONCLUSIONS: AGV implantation in patients with PCG offers moderate success in controlling the IOP with a low rate of complications. Most continued to require medications. PMID- 25459202 TI - Sensitivity of the three-step test in diagnosis of superior oblique palsy. AB - PURPOSE: Although the Parks-Bielschowsky three-step test is the cornerstone of cyclovertical strabismus diagnosis, it has not been validated against an external benchmark. We evaluated the test's sensitivity in clinical diagnosis of superior oblique palsy in patients with unequivocal magnetic resonance imaging (MRI) evidence of superior oblique atrophy. METHODS: A total of 73 strabismic patients were selected from a prospective MRI study because they exhibited superior oblique atrophy indicative of superior oblique denervation and thus confirmatory of superior oblique palsy. Of these, 50 patients who had no confounding factors were included for detailed study. Ocular motility data were evaluated to determine sensitivity of single and combined clinical findings in diagnosis of superior oblique palsy. RESULTS: Maximum mean ipsilesional superior oblique cross section was reduced to 9.6 +/- 0.6 mm(2) (mean +/- standard error) in superior oblique palsy, representing 52% of the 18.5 +/- 0.6 mm(2) contralesional superior oblique maximum cross section and 52% of the 18.4 +/- 0.4 mm(2) control maximum superior oblique cross section (P < 0.001). Of the 50 patients, 35 (70%) with superior oblique atrophy fulfilled the entire three-step test. In 14 (28%) patients two steps were fulfilled; in 1 patient (2%), only one step. Affected superior oblique cross section was similar in orbits that fulfilled the three step test (9.8 +/- 0.9 mm(2)) and those that did not (9.1 +/- 0.7 mm(2); P = 0.58). CONCLUSIONS: The complete three-step test fails to detect 30% of cases of superior oblique atrophy. Often only two of three steps are positive in superior oblique palsy. PMID- 25459203 TI - Education and health knowledge: evidence from UK compulsory schooling reform. AB - We investigate if there is a causal link between education and health knowledge using data from the 1984/85 and 1991/92 waves of the UK Health and Lifestyle Survey (HALS). Uniquely, the survey asks respondents what they think are the main causes of ten common health conditions, and we compare these answers to those given by medical professionals to form an index of health knowledge. For causal identification we use increases in the UK minimum school leaving age in 1947 (from 14 to 15) and 1972 (from 15 to 16) to provide exogenous variation in education. These reforms predominantly induced adolescents who would have left school to stay for one additionally mandated year. OLS estimates suggest that education significantly increases health knowledge, with a one-year increase in schooling increasing the health knowledge index by 15% of a standard deviation. In contrast, estimates from instrumental-variable models show that increased schooling due to the education reforms did not significantly affect health knowledge. This main result is robust to numerous specification tests and alternative formulations of the health knowledge index. Further research is required to determine whether there is also no causal link between higher levels of education - such as post-school qualifications - and health knowledge. PMID- 25459204 TI - The geography of malaria genetics in the Democratic Republic of Congo: A complex and fragmented landscape. AB - Understanding how malaria parasites move between populations is important, particularly given the potential for malaria to be reintroduced into areas where it was previously eliminated. We examine the distribution of malaria genetics across seven sites within the Democratic Republic of Congo (DRC) and two nearby countries, Ghana and Kenya, in order to understand how the relatedness of malaria parasites varies across space, and whether there are barriers to the flow of malaria parasites within the DRC or across borders. Parasite DNA was retrieved from dried blood spots from 7 Demographic and Health Survey sample clusters in the DRC. Malaria genetic characteristics of parasites from Ghana and Kenya were also obtained. For each of 9 geographic sites (7 DRC, 1 Ghana and 1 Kenya), a pair-wise RST statistic was calculated, indicating the genetic distance between malaria parasites found in those locations. Mapping genetics across the spatial extent of the study area indicates a complex genetic landscape, where relatedness between two proximal sites may be relatively high (RST > 0.64) or low (RST < 0.05), and where distal sites also exhibit both high and low genetic similarity. Mantel's tests suggest that malaria genetics differ as geographic distances increase. Principal Coordinate Analysis suggests that genetically related samples are not co-located. Barrier analysis reveals no significant barriers to gene flow between locations. Malaria genetics in the DRC have a complex and fragmented landscape. Limited exchange of genes across space is reflected in greater genetic distance between malaria parasites isolated at greater geographic distances. There is, however, evidence for close genetic ties between distally located sample locations, indicating that movement of malaria parasites and flow of genes is being driven by factors other than distance decay. This research demonstrates the contributions that spatial disease ecology and landscape genetics can make to understanding the evolutionary dynamics of infectious diseases. PMID- 25459207 TI - Reply to: Are stressful childhood experiences relevant in non-monosexual women? PMID- 25459206 TI - Development and validation of the attitudes toward outdoor play scales for children. AB - The natural world has long been associated with health and described as a therapeutic landscape, and a growing body of research demonstrates the benefits of interacting with nature for mental and physical health. However, concern is growing that children have lost connection to the natural world and spend less time outdoors, despite the known health benefits of doing so. It is likely that healthy behaviors related to engagement with nature are mediated by beliefs about the value and safety of play in nature. While the literature abounds with qualitative examinations of children's attitudes toward outdoor play, there exist few instruments to quantitatively measure these attitudes. Informed by health behavior change theories, we describe the development and validation of the Attitudes toward Outdoor Play (ATOP) scales. As part of a community-academic partnership project called More Than a Pretty Place, the development of the ATOP scales unfolded in stages: (1) item generation based on a comprehensive literature review and consensus among the project team, (2) interviews with environmental educators, (3) initial pilot testing, (4) scale refinement, (5) administration during 2012 and 2013 to a sample of school children ages 9-13 (n = 362) in Milwaukee, WI, USA, and (6) quantitative psychometric evaluation. Two distinct scales emerged: ATOP-benefits (alpha = 0.79) and ATOP-fears (alpha = 0.79). Validity analyses found that both scales correlated as expected with measures of engagement in outdoor play, parental support for outdoor play, and sedentary behaviors. The ATOP scales are reliable and valid instruments for measuring attitudes toward outdoor play that may mediate children's outdoor activity in natural settings. The ATOP scales could be useful for evaluating the effects of programming, such as environmental education programming, on improving children's attitudes toward the benefits of nature and reducing their fears, and may predict more distal outcomes including engagement in outdoor activity. PMID- 25459205 TI - A scalable climate health justice assessment model. AB - This paper introduces a scalable "climate health justice" model for assessing and projecting incidence, treatment costs, and sociospatial disparities for diseases with well-documented climate change linkages. The model is designed to employ low cost secondary data, and it is rooted in a perspective that merges normative environmental justice concerns with theoretical grounding in health inequalities. Since the model employs International Classification of Diseases, Ninth Revision Clinical Modification (ICD-9-CM) disease codes, it is transferable to other contexts, appropriate for use across spatial scales, and suitable for comparative analyses. We demonstrate the utility of the model through analysis of 2008-2010 hospitalization discharge data at state and county levels in Texas (USA). We identified several disease categories (i.e., cardiovascular, gastrointestinal, heat-related, and respiratory) associated with climate change, and then selected corresponding ICD-9 codes with the highest hospitalization counts for further analyses. Selected diseases include ischemic heart disease, diarrhea, heat exhaustion/cramps/stroke/syncope, and asthma. Cardiovascular disease ranked first among the general categories of diseases for age-adjusted hospital admission rate (5286.37 per 100,000). In terms of specific selected diseases (per 100,000 population), asthma ranked first (517.51), followed by ischemic heart disease (195.20), diarrhea (75.35), and heat exhaustion/cramps/stroke/syncope (7.81). Charges associated with the selected diseases over the 3-year period amounted to US$5.6 billion. Blacks were disproportionately burdened by the selected diseases in comparison to non-Hispanic whites, while Hispanics were not. Spatial distributions of the selected disease rates revealed geographic zones of disproportionate risk. Based upon a downscaled regional climate-change projection model, we estimate a >5% increase in the incidence and treatment costs of asthma attributable to climate change between the baseline and 2040-2050 in Texas. Additionally, the inequalities described here will be accentuated, with blacks facing amplified health disparities in the future. These predicted trends raise both intergenerational and distributional climate health justice concerns. PMID- 25459208 TI - A meta-analysis of education effects on chronic disease: the causal dynamics of the Population Education Transition Curve. AB - As the Epidemiological Transition progresses worldwide, chronic diseases account for the majority of deaths in developed countries and a rising proportion in developing countries indicating a new global pattern of mortality and health challenges into the future. Attainment of formal education is widely reported to have a negative gradient with risk factors and onset of chronic disease, yet there has not been a formal assessment of this research. A random-effects meta analysis finds that across 414 published effects more education significantly reduces the likelihood of chronic disease, except for neoplastic diseases with substantial genetic causes. Some studies, however, report null effects and other research on infectious disease report positive education gradients. Instead of assuming these contradictory results are spurious, it is suggested that they are part of a predictable systemic interaction between multiple mediating effects of education and the Epidemiological Transition stage of the population; and thus represent one case of the Population Education Transition Curve modeling changes in the association between education and health as dependent on population context. PMID- 25459209 TI - To whom do bureaucrats need to respond? Two faces of civil society in health policy. AB - The South Korean government implemented a law that separates the dispensing and prescribing (SDP) of drugs in July 2000. It was one of the most controversial issues in the Korean healthcare delivery system. Drawing on the conflict-cycle view and stakeholder analysis, which was used to examine how multiple stakeholders influenced this policymaking process, this study examines 1) the role of Korean civil society (i.e., civic and special interest groups) in SDP reform and 2) why SDP reform led to unintended consequences. We argue that bureaucrats in the Ministry of Health and Welfare (MoHW) should have played a central role in accommodating the public interest. Because they failed to do so, civic groups assumed major mediating and moderating roles. Due to the civic groups' lack of technical knowledge and professional experience, however, they played a limited role. In finalizing the proposal, therefore, bureaucrats were captured by strong interest groups, leading to unintended consequences, such as the increased use of non-covered services and higher healthcare expenditures. To ensure that the government serves the authentic public interest rather than special interest groups, bureaucrats should be responsible to the public rather than these interest groups. Moreover, civic groups should be strengthened (in relation to strongly organized interest groups) and included systematically in creating health policy. PMID- 25459210 TI - Weight loss: slow and steady does not win the race. PMID- 25459211 TI - The effect of rate of weight loss on long-term weight management: a randomised controlled trial. AB - BACKGROUND: Guidelines recommend gradual weight loss for the treatment of obesity, indicative of a widely held opinion that weight lost rapidly is more quickly regained. We aimed to investigate the effect of the rate of weight loss on the rate of regain in obese people. METHODS: For this two phase, randomised, non-masked, dietary intervention trial in a Melbourne metropolitan hospital, we enrolled 204 participants (51 men and 153 women) aged 18-70 years with a BMI between 30 and 45 kg/m2. During phase 1, we randomly assigned (1:1) participants with a block design (block sizes of 2, 4, and 6) to account for sex, age, and BMI, to either a 12-week rapid weight loss or a 36-week gradual programme, both aimed at 15% weight loss. We placed participants who lost 12.5% or more weight during phase 1 on a weight maintenance diet for 144 weeks (phase 2). The primary outcome was mean weight loss maintained at week 144 of phase 2. We investigated the primary outcome by both completers only and intention-to-treat analyses. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000190909. FINDINGS: 200 participants were randomly assigned to the gradual weight loss (n=103) or rapid weight loss (n=97) programme between Aug 8, 2008, and March 9, 2010. After phase 1, 51 (50%) participants in the gradual weight loss group and 76 (81%) in the rapid weight loss group achieved 12.5% or more weight loss in the allocated time and started phase 2. At the end of phase 2, both gradual weight loss and rapid weight loss participants who completed the study (n=43 in gradual weight loss and n=61 in rapid weight loss) had regained most of their lost weight (gradual weight loss 71.2% regain, 95% CI 58.1-84.3 vs rapid weight loss 70.5%, 57.8-83.2). Intention-to-treat analysis showed similar results (gradual weight loss 76.3% regain, 95% CI 65.2-87.4 vs rapid weight loss 76.3%, 65.8-86.8). In phase 1, one participant in the rapid weight loss group developed cholecystitis, requiring cholecystectomy. In phase 2, two participants in the rapid weight loss group developed cancer. INTERPRETATION: The rate of weight loss does not affect the proportion of weight regained within 144 weeks. These findings are not consistent with present dietary guidelines which recommend gradual over rapid weight loss, based on the belief that rapid weight loss is more quickly regained. FUNDING: The Australian National Health and Medical Research Council and the Sir Edward Dunlop Medical Research Foundation. PMID- 25459212 TI - People with tuberculosis are associated with a subsequent risk of depression. AB - BACKGROUND: There is some evidence that the prevalence of depression in patients with tuberculosis (TB) is higher than those in the general population. However, the incidence of depression after Mycobacterium tuberculosis infection remains unknown. Our aim was to assess the association between TB and the subsequent risk of depression. METHODS: We conducted a retrospective cohort study using data from the National Health Insurance (NHI) system of Taiwan. The TB cohort included 9020 patients who were newly diagnosed and recruited between 2000 and 2010. Each patient was randomly frequency-matched for age, sex and the year of index date with four people without TB from the general population. The newly diagnosed depression was followed up until the end of 2011. The relative risks of depression were estimated using Cox proportional hazard models after adjusting for age, sex, index year and comorbidities. RESULTS: The overall incidence rate of depression was 1.54-fold higher in the TB cohort as compared with the controlled cohort (8.15 vs. 5.29 per 1000 person-years, 95% confidence interval [CI]=1.45-1.64). Stratified analyses by gender, age group, monthly income and comorbidities revealed that the adjusted hazard ratio (HR) of depression was higher in males as well as individuals older than 65 years with a low monthly income and comorbidities. CONCLUSION: People who have been diagnosed with TB have a significantly higher risk of developing depression compared with those in the general population. We should pay more attention to this group of individuals and ensure that they are offered appropriate support. PMID- 25459213 TI - Causes of protidemia above 100g/L. PMID- 25459214 TI - A predictive rule for mortality of inpatients with Staphylococcus aureus bacteraemia: A classification and regression tree analysis. AB - OBJECTIVE: To create a predictive rule to identify risk factors for mortality among patients with Staphylococcus aureus bacteraemia (SAB). DESIGN, SETTING AND PATIENTS: This was a retrospective cohort study of all adult patients with SAB at a large community hospital in Tokyo, Japan, from April 1, 2004 to March 31, 2011. Baseline data and clinically relevant factors were collected from electronic charts. The primary outcome was in-hospital mortality. All candidate predictors were included in a classification and regression tree (CART) analysis. A receiver operating characteristic (ROC) curve was drawn, and the area under the curve (AUC) was obtained. A cross-validation analysis was performed. MEASUREMENTS AND MAIN RESULTS: A total of 340 patients had SAB during the study period. Of these, 118 (34.7%) patients died in hospital. Among 41 potential variables, the CART analysis revealed that underlying malignancy, serum blood glucose level, methicillin resistance, and low serum albumin were predictors of mortality. The AUC was 0.73 (95% CI: 0.67-0.79). For validation, the estimated risk was 0.26 (+/ SE: 0.02) in the resubstitution analysis and 0.33 (+/- SE: 0.03) in the cross validation analysis. CONCLUSION: We propose a predictive model for the mortality of patients with SAB consisting of four predictors: underlying malignancy, low serum albumin, high glucose, and methicillin resistance. This model may facilitate appropriate preventative management for patients with SAB who are at high risk of mortality. PMID- 25459215 TI - Research and common sense. PMID- 25459216 TI - Chemical burns revisited: What is the most appropriate method of decontamination? AB - The purpose of this study is to investigate the efficacy of decontamination by immediate surgical debridement in the acute management of chemical burns as compared to conventional dilutional approaches by irrigation or wetting. A retrospective review of the medical records of patients admitted to the Burns Centre of the Prince of Wales Hospital, Hong Kong, between 2001 and 2012, was performed. The time to recovery as reflected by the hospital stay for patients who had received immediate debridement, continuous irrigation, and wet packs was calculated and compared. A total of 99 patients were admitted for chemical burns (3.3% of total admissions). There were three mortalities. Immediate surgical debridement failed to achieve a faster recovery than irrigation or wet packs. Continuous water irrigation was better than wet packs in achieving earlier recovery. Continuous water irrigation remains the most preferred method of decontamination in acute chemical burn management. PMID- 25459217 TI - Development and evaluation of a novel smart device-based application for burn assessment and management. AB - We have developed a novel software application that provides a simple and interactive Lund-Browder diagram for automatic calculation of total body surface area (TBSA) burned, fluid formula recommendations, and serial wound photography on a smart device platform. The software was developed for the iPad (Apple, Cupertino, CA) smart device platforms. Ten burns ranging from 5 to 95% TBSA were computer generated on a patient care simulator using Adobe Photoshop CS6 (Adobe, San Jose, CA). Burn clinicians calculated the TBSA first using a paper-based Lund Browder diagram. Following a one-week "washout period", the same clinicians calculated TBSA using the smart device application. Simulated burns were presented in a random fashion and clinicians were timed. Percent TBSA burned calculated by Peregrine vs. the paper-based Lund-Browder were similar (29.53 [25.57] vs. 28.99 [25.01], p=0.22, n=7). On average, Peregrine allowed users to calculate burn size significantly faster than the paper form (58.18 [31.46] vs. 90.22 [60.60]s, p<0.001, n=7). The smart device application also provided 5 megapixel photography capabilities, and acute burn resuscitation fluid calculator. We developed an innovative smart device application that enables accurate and rapid burn size assessment to be cost-effective and widely accessible. PMID- 25459218 TI - Tracheostomy in pediatric burn patients. AB - BACKGROUND: Tracheostomy is often performed in the pediatric burn population to establish secure airways. Tracheostomy is safe in this population, but the duration of tracheostomy may be related to age and extent and severity of burn. We hypothesized that burn related factors and not age determine the time to removal of a tracheostomy in pediatric burn patients. METHODS: A 5-year retrospective review was performed for pediatric burn patients (age <=18 years) who underwent tracheostomy. Patients were divided into three groups by age (group 1: 0 to <=2 years, group 2: >2 to <=12 years, group 3: >12 to <=18 years). Data collected included: age, total body surface area burn injured (TBSA), gender, mechanism of injury, diagnosis of inhalation injury, mortality, time from injury to admission, time from admission to placement of tracheostomy, time of injury to placement of tracheostomy, duration of tracheostomy, days of mechanical ventilation, and tracheostomy related complications. RESULTS: 45 patients were reviewed. There were no differences in TBSA, length of ICU stay, length of hospital stay, and mortality between the three groups. Additionally, there were no differences in ventilator days and duration of tracheostomy. Multivariate linear regression analysis indicated that TBSA and not age independently increased the duration of tracheostomy. CONCLUSION: Tracheostomy duration is dependent on the extent of burn in pediatric burn patients. PMID- 25459219 TI - Low bioaccumulative materials for parahygrophobic nanosheets with sticking behaviour. AB - Here, we report the formation of surface nanosheets by electropolymerization of original 3,4 propylenedioxythiophene (ProDOT) derivatives bearing both a short perfluorobutyl chain (C4F9) and a branched alkyl chain of various lengths in order to reduce the bioaccumulative potential of the obtained materials. The dimension of the nanosheets is dependent on the size of the branched alkyl chain. These nanostructures display parahygrophobic properties (apparent contact angle theta>theta(Y) for various liquid probes, where theta(Y) is the Young angle of the corresponding smooth surface) with an extremely high liquid adhesion. These properties are due to the presence of nanoporosity between the nanosheets, which favours the Cassie-Baxter state but with high adhesion due to an important contact between the nanosheets and the liquids. These results are extremely important also in a theoretical point of view in the aim to study surfaces with high contact angles and high adhesion. Such materials could also be used in water harvesting systems especially in hot environment. PMID- 25459220 TI - The effect of HIV infection on the host response to bacterial sepsis. AB - Bacterial sepsis is an important cause of morbidity and mortality in patients with HIV. HIV causes increased susceptibility to invasive infections and affects sepsis pathogenesis caused by pre-existing activation and exhaustion of the immune system. We review the effect of HIV on different components of immune responses implicated in bacterial sepsis, and possible mechanisms underlying the increased risk of invasive bacterial infections. We focus on pattern recognition receptors and innate cellular responses, cytokines, lymphocytes, coagulation, and the complement system. A combination of factors causes increased susceptibility to infection and can contribute to a disturbed immune response during a septic event in patients with HIV. HIV-induced perturbations of the immune system depend on stage of infection and are only in part restored by combination antiretroviral therapy. Immunomodulatory treatments currently under development for sepsis might be particularly beneficial to patients with HIV co-infection because many pathogenic mechanisms in HIV and sepsis overlap. PMID- 25459222 TI - Ammonia removal in the carbon contactor of a hybrid membrane process. AB - The hybrid membrane process (HMP) coupling powdered activated carbon (PAC) and low-pressure membrane filtration is emerging as a promising new option to remove dissolved contaminants from drinking water. Yet, defining optimal HMP operating conditions has not been confirmed. In this study, ammonia removal occurring in the PAC contactor of an HMP was simulated at lab-scale. Kinetics were monitored using three PAC concentrations (1-5-10 g L(-1)), three PAC ages (0-10-60 days), two temperatures (7-22 degrees C), in ambient influent condition (100 MUg N-NH4 L(-1)) as well as with a simulated peak pollution scenario (1000 MUg N-NH4L(-1)). The following conclusions were drawn: i) Using a colonized PAC in the HMP is essential to reach complete ammonia removal, ii) an older PAC offers a higher resilience to temperature decrease as well as lower operating costs; ii) PAC concentration inside the HMP reactor is not a key operating parameter as under the conditions tested, PAC colonization was not limited by the available surface; iii) ammonia flux limited biomass growth and iv) hydraulic retention time was a critical parameter. In the case of a peak pollution, the process was most probably phosphate-limited but a mixed adsorption/nitrification still allowed reaching a 50% ammonia removal. Finally, a kinetic model based on these experiments is proposed to predict ammonia removal occurring in the PAC reactor of the HMP. The model determines the relative importance of the adsorption and biological oxidation of ammonia on colonized PAC, and demonstrates the combined role of nitrification and residual adsorption capacity of colonized PAC. PMID- 25459221 TI - Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus. AB - In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, clinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymyxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics. PMID- 25459223 TI - GeoChip-based analysis of microbial community of a combined nitritation-anammox reactor treating anaerobic digestion supernatant. AB - A combined nitritation-anammox reactor was established to treat anaerobic digestion supernatant. The reactor achieved a nitrogen loading rate of 0.5 kg N/(m(3).d) and total nitrogen removal efficiency of 85% after 140 days' operation. To examine the microbial community responsible for the process, GeoChip 4.0, a high-throughput, microarray-based metagenomic tool, was adopted to measure microbial functional potential under different percentages of digestion supernatant. Intriguingly, our results showed that microbial community composition in a stably functioning bioreactor were significantly different under varying environmental conditions. Functional gene diversities decreased with increasing percentages of digestion supernatant. Genes involved in organic remediation and metal resistance were highly abundant, revealing new metabolic potentials in addition to nitrogen and carbon removal. Compared to the significant decrease of genes involved in denitrification and nitrification caused by inhibition of the digestion supernatant, relative abundances of genes for anammox remained relatively stable. This could be partially attributed to the protection of biofilm, which was vital for the stable performance of nitrogen removal. In addition, nitrogen compounds, C/N ratio and the operation parameters (pH and temperature) were the key variables shaping the microbial community, contributing to a total of 76.64% of the variance of the reactor. PMID- 25459224 TI - Anaerobic codigestion of sewage sludge and glycerol, focusing on process kinetics, microbial dynamics and sludge dewaterability. AB - Anaerobic codigestion (AcoD) is a proven option to significantly boost biogas production while utilizing existing digesters and infrastructure. The aim of the present research was to conduct an exhaustive study regarding anaerobic codigestion of mixed sewage sludge and crude glycerol considering impacts on organic load, hydraulic load, process performance and microbial community. The methane potential of crude glycerol varied from 370 mL CH4.g(-1) VS to 483 mL CH4.g(-1) VS for different samples tested. The half maximal inhibitory concentration of crude glycerol was 1.01 g VS L(-1), and the primary mechanism of inhibition was through overload from rapid fermentation rather than the presence of toxic compounds in the crude glycerol. In continuous operation over 200 days, feeding glycerol at up to 2% v/v, increased organic load by up to 70% and resulted in a 50% increase in methane production. Glycerol dosing resulted in no change in apparent dewaterability, with both codigestion and control reactors returning values of 22%-24%. Members of the phylum Thermotogae emerged as a niche population during AcoD of sewage sludge and glycerol; however there was no gross change in microbial community structure and only minimal changes in diversity. AcoD did not result in synergisms between sewage sludge and crude glycerol. Actually, at dose rate up to 2% v/v glycerol dosing is still an effective strategy to increase the organic loading rate of continuous anaerobic digesters with minimal impact of the hydraulic retention time. Nonetheless, the dose rate must be managed to: (i) prevent process inhibition and (ii) ensure sufficient degradation time to produce a stable biosolids product. PMID- 25459225 TI - Evaluation of quantitative PCR combined with PMA treatment for molecular assessment of microbial water quality. AB - Microbial water quality assessment currently relies on cultivation-based methods. Nucleic acid-based techniques such as quantitative PCR (qPCR) enable more rapid and specific detection of target organisms and propidium monoazide (PMA) treatment facilitates the exclusion of false positive results caused by DNA from dead cells. Established molecular assays (qPCR and PMA-qPCR) for legally defined microbial quality parameters (Escherichia coli, Enterococcus spp. and Pseudomonas aeruginosa) and indicator organism group of coliforms (implemented on the molecular detection of Enterobacteriaceae) were comparatively evaluated to conventional microbiological methods. The evaluation of an extended set of drinking and process water samples showed that PMA-qPCR for E. coli, Enterococcus spp. and P. aeruginosa resulted in higher specificity because substantial or complete reduction of false positive signals in comparison to qPCR were obtained. Complete compliance to reference method was achieved for E. coli PMA-qPCR and 100% specificity for Enterococcus spp. and P. aeruginosa in the evaluation of process water samples. A major challenge remained in sensitivity of the assays, exhibited through false negative results (7-23%), which is presumably due to insufficient sample preparation (i.e. concentration of bacteria and DNA extraction), rather than the qPCR limit of detection. For the detection of the indicator group of coliforms, the evaluation study revealed that the utilization of alternative molecular assays based on the taxonomic group of Enterobacteriaceae was not adequate. Given the careful optimization of the sensitivity, the highly specific PMA-qPCR could be a valuable tool for rapid detection of hygienic parameters such as E. coli, Enterococcus spp. and P. aeruginosa. PMID- 25459226 TI - Parent-adolescent drug use discussions: studying content and affective processes. PMID- 25459227 TI - Meeting report VLPNPV: Session 7: Respiratory. PMID- 25459228 TI - Time dependent changes in the intestinal Ca2+ absorption in rats with type I diabetes mellitus are associated with alterations in the intestinal redox state. AB - The aim was to determine the intestinal Ca2+ absorption in type I diabetic rats after different times of STZ induction, as well as the gene and protein expression of molecules involved in both the transcellular and paracellular Ca2+ pathways. The redox state and the antioxidant enzymes of the enterocytes were also evaluated in duodenum from either diabetic or insulin-treated diabetic rats as compared to control rats. Male Wistar rats (150-200 g) were divided into two groups: 1) controls and 2) STZ-induced diabetic rats (60 mg/kg b.w.). A group of diabetic rats received insulin for five days. The insulin was adjusted daily to maintain a normal blood glucose level. Five 5 d after STZ injection, there was a reduction in the intestinal Ca2+ absorption, which was maintained for 30 d and disappeared at 60 d. Similar changes occurred in the GSH and ()O(2)(-) levels. The protein expression of molecules involved in the transcellular pathway increased at 5 and 30 d returning to control values at 60 d. Their mRNA levels declined considerably at 60 d. The gene and protein expression of claudin 2 was upregulated at 30 d. Catalase activity increased at 5 and 30 d normalizing at 60 d. To conclude, type I D.m. inhibits the intestinal Ca2+ absorption, which is transient leading to a time dependent adaptation and returning the absorptive process to normal values. The inhibition is accompanied by oxidative stress. When insulin is administered, the duodenal redox state returns to control values and the intestinal Ca2+ absorption normalizes. PMID- 25459229 TI - Graduating Pediatrics Residents' Reports on the Impact of Fatigue Over the Past Decade of Duty Hour Changes. AB - OBJECTIVE: Concern about resident and patient safety has led to changes in Accreditation Council on Graduate Medical Education requirements over the past decade, with duty hour limitations in 2003 and 2011. This study examines pediatric residents' experiences on the impact of fatigue before, during, and after this time. METHODS: An annual survey of graduating pediatrics residents was administered to a national, random sample in 2002, 2004, and 2013. Respondents were asked about the impact of fatigue. Multivariable logistic regression was conducted to compare differences between survey years. RESULTS: The combined response rate for all 3 years was 62.6% (1,251 of 2,000). In multivariable analyses, residents were less likely in both 2004 and 2013 than in 2002 to fall asleep during an educational conference (adjusted odds ratio [aOR] 0.61, 95% confidence interval [CI] 0.41-0.91 and aOR 0.32, 95% CI 0.22-0.45, respectively) and to fall asleep while driving from work (aOR 0.55, 95% CI 0.37-0.81 and 0.43, 95% CI 0.31-0.60, respectively). Residents were less likely in 2004 than in 2002 to report making an error in patient care due to fatigue (aOR 0.46, 95% CI 0.27 0.76); however, in 2013 resident report of making an error in patient care due to fatigue returned to levels similar those reported in 2002. CONCLUSIONS: Surveys of graduating pediatrics residents over the past decade (2002-2013) indicate overall reduced fatigue effects. During this same time frame, however, reports about making patient care errors improved but then returned to a level not significantly different from 2002, a finding warranting further exploration. PMID- 25459230 TI - HIV testing among adults with mental illness in the United States. AB - Nationally representative data from the 2007 National Health Interview Survey (NHIS) were used to compare HIV testing prevalence among US adults with mental illness (schizophrenia spectrum disorder, bipolar disorder, depression, and/or anxiety) to those without, providing an update of prior work using 1999 and 2002 NHIS data. Logistic regression modeling was used to estimate the probability of ever being tested for HIV by mental illness status, adjusting for age, sex, race/ethnicity, marital status, substance abuse, excessive alcohol or tobacco use, and HIV risk factors. Based on data from 21,785 respondents, 15% of adults had a psychiatric disorder and 37% ever had an HIV test. Persons with schizophrenia (64%), bipolar disorder (63%), and depression and/or anxiety (47%) were more likely to report ever being tested for HIV than those without mental illness (35%). In multivariable models, individuals reporting schizophrenia (adjusted prevalence ratio=1.68, 95% confidence interval=1.33-2.13), bipolar disease (1.58, 1.39-1.81), and depression and/or anxiety (1.31, 1.25-1.38) were more likely to be tested for HIV than persons without these diagnoses. Similar to previous analyses, persons with mental illness were more likely to have been tested than those without mental illness. However, the elevated prevalence of HIV in populations with mental illness suggests that high levels of testing along with other prevention efforts are needed. PMID- 25459232 TI - High intensity interval exercise is an effective alternative to moderate intensity exercise for improving glucose tolerance and insulin sensitivity in adolescent boys. AB - OBJECTIVES: High-intensity interval exercise (HIIE) may offer a time efficient means to improve health outcomes compared to moderate-intensity exercise (MIE). This study examined the acute effect of HIIE compared to a work-matched bout of MIE on glucose tolerance, insulin sensitivity (IS), resting fat oxidation and exercise enjoyment in adolescent boys. DESIGN: Within-measures design with counterbalanced experimental conditions. METHODS: Nine boys (14.2 +/- 0.4 years) completed three conditions on separate days in a counterbalanced order: (1) HIIE; (2) work matched MIE, both on a cycle ergometer; and (3) rest (CON). An oral glucose tolerance test (OGTT) was performed after exercise or rest and the area under curve (AUC) responses for plasma [glucose] and [insulin] were calculated, and IS estimated (Cederholm index). Energy expenditure and fat oxidation were measured following the OGTT using indirect calorimetry. Exercise enjoyment was assessed using the Physical Activity Enjoyment Scale. RESULTS: The incremental AUC (iAUC) for plasma [glucose] was reduced following both MIE (-23.9%, P = 0.013, effect size [ES] = -0.64) and HIIE (-28.9%, P=0.008, ES = -0.84) compared to CON. The iAUC for plasma [insulin] was lower for HIIE (-24.2%, P = 0.021, ES = -0.71) and MIE (-29.1%, P = 0.012, ES = -0.79) compared to CON. IS increased by 11.2% after HIIE (P = 0.03, ES = 0.76) and 8.4% after MIE (P = 0.10, ES = 0.58). There was a trend for an increase in fat oxidation following HIIE (P = 0.097, ES = 0.70). Both HIIE and MIE were rated as equally enjoyable (P > 0.05, ES < 0.01). CONCLUSION: A single bout of time efficient HIIE is an effective alternative to MIE for improving glucose tolerance and IS in adolescent boys immediately after exercise. PMID- 25459233 TI - Validation of the SenseWear mini armband in children during semi-structure activity settings. AB - OBJECTIVES: The purpose of the study is to evaluate the validity of different SenseWear software (algorithms v5.2 vs. algorithm v2.2) for estimating energy expenditure (EE) in children. DESIGN: Original research. METHODS: Forty-five children aged 7-13 years performed 12 randomly assigned activities (out of a set of 24) while wearing a SWA with simultaneous monitoring via portable calorimetry (IC). Each activity lasted 5min, with a 1min break between activities. The estimated EE values from the SWA were compared to the measured EE values from the IC using 3-way (Method*Algorithm*Activity) mixed model ANOVA. RESULTS: The analyses revealed a significant method (IC vs. SWA)*Algorithm (v5.2 vs. v2.2) interaction, with significantly smaller errors (IC-SWA) for the newer v5.2 algorithms (0.25+/-0.09kcalmin(-1)) than the older v2.2 algorithms (1.04+/ 0.09kcalmin(-1)). The mean absolute percent error (MAPE) was 17.0+/-12.1% for SWA5.2 algorithm and 31.4+/-11.1% for SWA2.2 algorithm. The v5.2 algorithms yielded non-significant (p>0.5) differences in EE estimates for most of the walking related activities as well as for stationary cycling at moderate intensity (MAPE=14.5%). CONCLUSIONS: The smaller errors in estimated EE with the SenseWear v5.2 algorithms (compared to v2.2) demonstrate continued incremental improvements in estimates of EE for monitoring free-living activities in children. PMID- 25459231 TI - Patient and provider perspectives on HIV and HIV-related stigma in Dutch health care settings. AB - Ensuring that people living with HIV (PLWH) feel accepted in health care settings is imperative. This mixed methods study explored the perspectives of PLWH and health professionals on their interactions. A total of 262 predominantly gay men of Dutch origin participated in a survey study of possible negative interactions with health professionals, and semi-structured interviews were subsequently conducted with 22 PLWH and 14 health professionals. Again, most PLWH were gay men of Dutch origin. All health professionals were Dutch. PLWH reported negative experiences with health professionals including awkward interactions, irrelevant questions, rude treatment, blame, pity, excessive or differential precautions, care refusal, unnecessary referrals, delayed treatment, poor support, and confidentiality breaches. They also reported positive experiences including equal treatment, being valued as a partner in one's health, social support provision, and confidentiality assurances. Health professionals reported having little experience with PLWH and only basic knowledge of HIV. They contended that PLWH are treated equally and that HIV is no longer stigmatized, but also reported fear of occupational infection, resulting in differential precautions. Additionally, they conveyed labeling PLWH's files to warn others, and curiosity regarding how patients acquired HIV. The findings suggest that there is a gap in perception between PLWH and health professionals regarding the extent to which negative interactions occur, and that these interactions should be improved. Implications for stigma reduction and care optimization are discussed. PMID- 25459234 TI - Changes in time-segment specific physical activity between ages 10 and 14 years: A longitudinal observational study. AB - OBJECTIVES: Describe (1) time-segment specific changes in physical activity (PA) into adolescence, (2) differences in change in PA between specific time-segments (weekdays-weekends, in-school-out-of-school, out-of-school-weekends, lesson-time lunch-time), and (3) associations of change in time-segment specific with overall PA. DESIGN: Longitudinal observational study (4-year follow-up). METHODS: Children from the SPEEDY study (n=769, 42% boys) had PA measured by accelerometer for at least three days at ages 10.2+/-0.3, 11.2+/-0.3 and 14.3+/-0.3years. Changes in moderate-to-vigorous PA (DeltaMVPA, minutes >=2000counts/minute [cpm]) and total PA (DeltaTPA, average cpm) during weekdays, weekends, in-school, out-of school, lesson-times and lunch-times, were tested using three level (age, individual, school) mixed-effects linear regression. Differences in DeltaMVPA/DeltaTPA between time-segments were tested using time-segment*age interaction terms. Associations of four-year time-segment specific DeltaMVPA/DeltaTPA with four-year overall DeltaMVPA/DeltaTPA were tested using two level (time-segment specific DeltaMVPA/DeltaTPA, school) mixed-effects linear regression. RESULTS: MVPA and TPA declined in all time-segments, except lesson time MVPA. Annual DeltaMVPA and, for boys only, DeltaTPA was greater on weekends than weekdays (beta+/-SE for interaction term: boys, -3.53+/-0.83min, -29.64+/ 7.64cpm; girls, -2.20+/-0.64min) and out-of-school (boys, -4.36+/-0.79min, 19.36+/-8.46cpm; girls, -2.44+/-0.63min). DeltaMVPA and DeltaTPA during lunch time was greater than during lesson-time (boys, -0.96+/-0.20min, -36.43+/ 6.55cpm; girls, -0.90+/-0.13min, -38.72+/-4.40cpm). DeltaTPA was greater out-of school than in-school (boys, -19.89+/-6.71cpm; girls, -18.46+/-6.51cpm). For all time-segments, four-year DeltaMVPA/DeltaTPA was positively associated with four year overall DeltaMVPA/DeltaTPA (all p<0.042), except for girl's in-school and lunch-time TPA. CONCLUSIONS: Interventions focused on PA maintenance could target all time-segments, but weekends and out-of-school may be particularly advantageous due to the relatively large declines observed. PMID- 25459236 TI - Photoinduced Electron Transfer in 2,5,8,11-Tetrakis-Donor-Substituted Perylene 3,4:9,10-bis(dicarboximides). AB - A series of electron donor-acceptor compounds based on substitution of perylene 3,4:9,10-bis(dicarboximide) (PDI) with four electron donors at the 2,5,8,11 positions were synthesized and characterized using femtosecond transient absorption spectroscopy. The distance between the PDI and the N,N-dimethylaniline or phenothiazine donors was varied using one or two phenyl groups. Photoexcitation of PDI results in rapid charge separation followed by charge recombination with time constants ranging from tens of picoseconds to nanoseconds. The electron transfer time constants are compared with those of the corresponding molecules in which the donor is attached to the PDI through its imide nitrogen atom. The electron transfer reactions through the 2,5,8,11 positions of PDI are generally much faster than those through the imide nitrogen positions, in concert with stronger donor electronic coupling to the PDI acceptor core and in contrast to substituents at the imide positions through which the HOMO and LUMO nodal planes pass. PMID- 25459237 TI - Endovascular stroke intervention in the very young. AB - OBJECT: This study aims to evaluate the use of endovascular therapy to treat very young (<= 35 years) patients with acute ischemic stroke from large vessel occlusion. METHODS: We identified from a prospectively maintained database young patients (<= 35 years) undergoing endovascular intervention for AIS at two cerebrovascular referral centers. The study only included patients with a confirmed large vessel occlusion. Modified Rankin scale (mRS) scores were determined at 90 days during a follow-up visit. RESULTS: A total of 15 patients met the inclusion criteria. Mean age was 27.93 years +/- 6.75 years (range: 9-35 years). On admission, the mean NIHSS score was 14.07 +/- 9.16. Mechanical thrombectomy was performed using the Solitaire FR device in 4 of 15 (26.67%) patients and the Merci/Penumbra systems in 11 (73.33%) patients. Successful recanalization (TICI 2-3) was achieved in all but one patient (14/15; 93.33%). Only one patient (6.67%) had a hemorrhagic conversion following intervention; he later expired. The rate of 90-day favorable outcome (mRS 0-2) was 86.67% (13/15). CONCLUSION: Endovascular treatment in the very young population may be carried out with limited complications and attain remarkably high rate of recanalization and favorable outcome. This study supports the role of aggressive management strategies for very young patients with large vessel occlusion. PMID- 25459235 TI - Comparisons of prediction equations for estimating energy expenditure in youth. AB - OBJECTIVES: The purpose of this study was to compare the validity of Actigraph 2 regression models (2RM) and 1-regression models (1RM) for estimation of EE in children. DESIGN: The study used a cross-sectional design with criterion estimates from a metabolic cart. METHODS: A total of 59 children (7-13yrs) performed 12 activities (randomly selected from a set of 24 activities) for 5min each, while being concurrently measured with an Actigraph GT3X and indirect calorimetry. METRMR (MET considering one's resting metabolic rate) for the GT3X was estimated applying 2RM with vector magnitude (VM2RM) and vertical axis (VA2RM), and four standard 1RMs. The validity of the 2RMs and 1RMs was evaluated using 95% equivalence testing and mean absolute percent error (MAPE). RESULTS: For the group-level comparison, equivalence testing revealed that the 90% confidence intervals for all 2RMs and 1RMs were outside of the equivalence zone (range: 3.63, 4.43) for indirect calorimetry. When comparing the individual activities, VM2RM produced smaller MAPEs (range: 14.5-45.3%) than VA2RM (range, 15.5-58.1%) and 1RMs (range, 14.5-75.1%) for most of the light and moderate activities. CONCLUSIONS: None of the 2RMs and 1RMs were equivalent to indirect calorimetry. The 2RMs showed smaller individual-level errors than the 1RMs. PMID- 25459238 TI - Gender differences and woman-specific trends in acute stroke: results from a hospital-based registry (1986-2009). AB - OBJECTIVE: We assessed gender differences and women-specific secular trends in stroke. METHODS: Data from 2318 women and 2274 men with first-ever stroke collected from the Sagrat Cor Hospital Stroke Registry of Barcelona between 1986 and 2009 were analyzed. RESULTS: Patient's age increased significantly from a mean of 74.5 years in 1986-1992 to 81.2 years in 2004-2009 (P < 0.001). Patients aged >= 85 years increased from 18.5% to 38.5% (P = 0.0001) as were patients with hypertension, atrial fibrillation, and cardioembolic stroke. The in-hospital death decreased from 17.6% to 11% (P = 0.02), median length of hospital from 14 to 9 days (P = 0.0001) and prolonged hospital stay (> 12 days) from 59.7% to 33.7% (P = 0.0001). Lacunar infarction was more frequent in men (21.5% vs. 16.2%, P = 0.0003) and cardioembolic infarction in women (26% vs. 15.6%, P = 0.0001). Acute stroke in women continues to be a severe disease with high risk of death in the immediate post-stroke phase (13.5%) and low probability of early full neurological recovery (13.9% vs. 11.8%, P = 0.029). CONCLUSION: Women differ from men in the distribution of risk factors and stroke subtype, stroke severity, and outcome. An increase in the patient's age, hypertension, atrial fibrillation and cardioembolic infarction, as well as a decrease mortality and length of hospitalization over a 24-year period was recorded. PMID- 25459239 TI - Brain natriuretic peptide level on admission predicts recurrent stroke after discharge in stroke survivors with atrial fibrillation. AB - OBJECTIVE: We investigated whether brain natriuretic peptide (BNP) levels could be used as a marker to predict recurrent stroke in ischemic stroke survivors. METHODS: From April 2007 to March 2011, consecutive patients within 24h of onset of ischemic stroke were prospectively enrolled, and admission plasma BNP levels were measured. Survivors were followed up to 12 months after stroke onset. Patients were divided into two groups: the recurrence group and the non recurrence group. Factors associated with stroke recurrence were investigated by multiple logistic regression analysis. RESULTS: A total of 793 patients who were alive at hospital discharge were included; 42 (5%) patients had recurrent stroke. There were no differences in BNP levels between groups. With respect to 257 patients with atrial fibrillation (AF), BNP levels were significantly higher in the recurrence group than in the non-recurrence group (426.0 vs. 192.0 pg/mL, P = 0.0007). The optimal cutoff level, sensitivity, and specificity of BNP levels to distinguish the recurrence group from the non-recurrence group were 300.0 pg/mL, 80%, and 73%, respectively. After adjustment for age and sex, plasma BNP >= 300.0 pg/mL (OR, 9.2; 95% CI, 1.87-45.01, P = 0.0062) was found to be independently associated with recurrent stroke in stroke survivors with AF. CONCLUSION: Admission BNP levels can predict recurrent stroke in stroke survivors with AF. PMID- 25459241 TI - Vogt-Koyanagi-Harada disease with meningitis-retention syndrome and increased CSF adenosine deaminase levels. PMID- 25459240 TI - Time dependent pattern of cellular characteristics causing ventriculoperitoneal shunt failure in children. AB - BACKGROUND: Ventriculoperitoneal shunt obstruction remains a major problem in pediatric neurosurgery. We analyzed the tissue reaction to ventriculoperitoneal shunts and compared the histology versus time elapsed to shunt failure. METHODS: 85 ventricular catheter tissues samples obtained from 71 patients were reviewed along with time elapsed to shunt revision. Pathology reports of all tissue samples were divided into three categories: inflammatory based on the presence of lymphocytes, macrophages, and microglial cells; reactive based on the presence of fibro-connective tissue, reactive astrocytes, and Rosenthal fibers; and normal brain tissue based on presence of choroid plexus. These categories were then grouped according to time elapsed to shunt revision. Group I had those shunts revised <6 months, group II included shunts revised between 6 months and 3 years, while group III had shunts revised after more than 3 years. RESULTS: The incidence of inflammatory type of histology was 44% (16/36) in group I, 22% (6/27) in group II, and 18% (4/22) in group III. The reactive histology was 42% (15/36) in group I, 67% (18/27) in group II, and 77% (17/22) in group III. There was a clear noted difference of incidence between inflammatory versus reactive histology between early shunt failure compared to late shunt failure. Incidence of normal brain tissue remained high in group I with 8%, 11% in group II, and none in group III. CONCLUSION: Early shunt obstruction arises from pathologies different from those causing late shunt obstructions. PMID- 25459242 TI - Anterocollis and anterocaput. AB - Anterocollis/anterocaput is a subtype of cervical dystonia and the most infrequent of its abnormal head-positions. Anterocollis can be differentiated from anterocaput by the abnormal angle between thoracic and cervical spine or between skull-base and vertebrum-1 in anterocaput. Anterocollis/anterocaput is classified as primary (idiopathic) or secondary (due to identifiable neurological disease) and as pure or complex. Complex anterocollis is most frequently associated with other types of focal dystonia, such as torticollis or laterocollis. Patients complain about impaired head-movement and report to release the fixed head-position occasionally by a "geste antagonistique". Neurological exam shows tonic (contractures with anteflexion) or tremulous head movements and neck-posturing. The diagnosis is based on the clinical presentation, needle-electromyography to identify affected muscles and rule out other conditions, X-ray of the cervical/thoracic spine, and cerebral MRI. Treatment of choice is botulinum toxin. If botulinum toxin is ineffective, drug treatment can be tried. If botulinum toxin and drug treatment fail, deep brain stimulation of the internal pallidal globes should be considered. PMID- 25459243 TI - Association of cognitive impairment and lesion volumes in multiple sclerosis--a MRI study. AB - Cognitive impairment (CI) can be demonstrated in 40-65% of multiple sclerosis (MS) patients, sometimes starting from the early stages of the disease. The objective of this study was a community-based investigation of FLAIR-hyperintense lesion volumes (LV) and their association with CI in patients with relapsing remitting (RR) MS. The neurocognitive assessment was conducted with the brief cognitive screening instrument, MUSIC. Magnetic resonance imaging (MRI) scans were obtained with a 1.5 Tesla Sigma Magnetom MRI scanner. We conducted a stepwise multiple regression analysis to assess the relative contribution of the main clinical, demographic and MRI-variables in predicting cognitive impairment. We recruited 78 patients with RRMS. The mean MUSIC score was 20.6 +/- 5.4. Forty five percent of patients (n = 35, mean score 15.1 +/- 3.3) had CI and 55% (n = 43, mean score 24.4 +/- 2.5) had no sign of CI. In the correlation analysis of the MUSIC subtests only the interference test correlated negatively with the LV (r = -0.23). Multivariate linear regression analysis using MUSIC as the dependent continuous variable revealed LV and disability severity as independent factors associated with MUSIC (p value of the regression model < 0.001; adjusted R-square = 0.11). The results of the present study suggest an association between white matter damage and CI in MS. We could demonstrate an association between attention difficulties and the LV in MS patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01250665 and NCT01250678. PMID- 25459244 TI - Cavernous sinus cavernous hemangioma: imaging features and therapeutic effect of Gamma Knife radiosurgery. AB - OBJECT: To investigate the imaging features of cavernous sinus cavernous hemangioma (CSCH) and evaluate the therapeutic effect of Gamma Knife radiosurgery (GKRS) in treatment of CSCH. METHODS AND MATERIALS: Fifteen patients with CSCH treated by GKRS in our institute, including 6 males and 9 females, age range 20 77 years old, were analyzed retrospectively. Three of them were given craniotomies as the initial therapy. All cases had performed conventional and contrast-enhanced MRI and 5 patients underwent dynamic enhanced MRI preoperatively. In 6 cases, the multi-directional continuous data of axial, coronal and sagittal enhanced MRI were acquired. Three cases performed digital subtraction angiography (DSA) simultaneously. The diagnoses of lesions were determined mainly depending on typical imaging features. In 3 patients, the diagnoses of CSCH were confirmed histopathologically. The radiation dosimetry was done with a goal of conformal and selective coverage of the lesion with a 50% prescription isodose line. The mean marginal dose constituted 13.4 Gy (range 10 16 Gy). After GKRS was performed, all patients were arranged regular clinical and MRI follow-up every 6 months during the first 12 months, and once per year thereafter. RESULTS: On MRI, the lesions were typically demonstrated as iso/hypo intensities on T1WI and remarkable hyper-intensities on T2WI, and apparent homogeneous enhancement. The phenomenon of dynamic enhancement was found in 11 cases. The progressive enhancing process from heterogeneous to uniform was displayed in the 5 patients performed same-slice dynamic MRI, including imaging characteristics of 'edge to center' enhancement in 2 case. In the other 6 cases, the delayed homogeneous enhancement of lesion was observed. Ten patients obtained radiological follow-up results after GKRS. Reviewing the follow-up data of 8 patients during the period of 3-6 months, the lesions were apparently shrunk in 5 patients with shrinkage rate of 20.8-46.8%. In 4 patients with imaging follow-up during the period of 6-12 months, the lesions of 3 patients were remarkably shrunk with shrinkage rate of 53.5-81.7%. Four patients had imaging follow-up data over 12 months, and all their lesion sizes were reduced with shrinkage rate of 19-83.6%. The clinical presentations of all patients after GKRS were followed up during the period of 1-30 months. In 7 of 9 cases with headache, the symptom was improved; in 5 of 6 cases, facial hypesthesia was improved; in 6 of 9 cases with visual impairments, the visions were markedly improved; and in 8 cases with preoperative diplopia, the symptoms were all resolved. CONCLUSION: Although bright hyper-intensities on T2WI and significant homogeneous enhancement on contrast-enhanced T1WI are considered as typical imaging characteristics of CSCH, the dynamic process of progressive delayed enhancement on contrast-enhanced MR is more persuasive in diagnosis. According to our study, GKRS could be chosen as an effective and safe alternative treatment for CSCH. We consider that using relatively low marginal dose may get better effects in tumor shrinkage and protection of cranial nerves. PMID- 25459245 TI - Application of titanium and polyetheretherketone cages in the treatment of pyogenic spondylodiscitis. AB - OBJECTIVE: Surgical treatment of a pyogenic spondylodiscitis (PSD) involves a fixation and debridement of the affected segment combined with a specific antibiotic therapy. To achieve a proper stability and to avoid pseudarthrosis and kyphotic malposition many surgeons favour the interposition of an anterior graft. Besides autologous bone grafts titanium (TTN) cages have gained acceptance in the treatment of PSD. Polyetheretherketone (PEEK) cages have a more favourable modulus of elasticity than TTN. We compared both cage types. Primary endpoints were the rate of reinfection and radiological results. METHODS: From 2004 to 2013 51 patients underwent surgery for PSD with fixation and TTN or PEEK cage implantation. While lumbar patients underwent a partial discectomy by the posterior approach, discs of the cervical and thoracic patients had been totally removed from anterior. Clinical and radiological parameters were assessed in 37 eligible patients after a mean of 20.4 months. 21 patients received a PEEK- and 16 patients a TTN-cage. RESULTS: A reinfection after surgery and 3 months of antibiotic therapy was not observed. Solid arthrodesis was found in 90.5% of the PEEK-group and 100% of the TTN-group. A segmental correction could be achieved in both groups. Nonetheless, a cage subsidence was observed in 70.3% of all cases. Comparison of radiological results revealed no differences between both groups. CONCLUSIONS: A debridement and fixation with anterior column support in combination with an antibiotic therapy appear to be the key points for successful treatment of PSD. The application of TTN- or PEEK-cages does not appear to influence the radiological outcome or risk of reinfection, neither does the extent of disc removal in this clinical subset. PMID- 25459247 TI - Risk factors for failed transverse sinus stenting in pseudotumor cerebri patients. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) when no underlying etiology is found, is a clinical syndrome characterized by elevated intracranial pressure (ICP) (>25 cm H2O), which may lead to headaches and visual symptoms. In patients with IIH who are found to have transverse sinus stenosis, placement of a venous stent across the stenosis has been shown to lower ICP and to resolve the symptoms in several case series, with generally favorable results. In this study, we examine common risk factors associated with failure of transvenous stenting for IIH. If venous sinus stenting fails, CSF diversion should be considered as the next line of treatment. METHODS: We retrospectively reviewed the records of eighteen patients diagnosed with IIH who underwent venous sinus stenting for transverse sinus stenosis with a mean pressure gradient (MPG) of at least 4 mmHg. Fifteen of these patients did not need further treatment. We compared their pre- and post-treatment, neurological and neuro-ophthalmological evaluations to the three patients who went on to have a shunt placement as a second line treatment. RESULTS: Shunting after stent placement patients (n=3) had a mean age of 30 years and a mean body mass index of 36.6 kg/m(2), whereas the group that underwent stent placement alone (n=15) had a mean age of 40.7 years and a mean body mass index of 33.3 kg/m(2). In the shunting after stent placement group, the mean opening pressure on the most recent lumbar puncture obtained prior to any intervention was 50 cm of H2O, whereas the group that underwent stent placement alone had an opening CSF pressure of 37 cm of H2O which was statistically significant (p<0.05). There were no other significant differences in pre- or post intervention factors between the two groups. CONCLUSION: In patients with IIH and documented evidence of venous sinus stenosis with a pressure gradient, venous sinus stenting should be the primary treatment of choice; however, some patients may be refractory to stenting and still require permanent CSF diversion, which can be complicated in these chronically anticoagulated patients. Patients with persistent papilledema post-stenting and highly elevated opening pressure pre stenting should be followed closely as they are at greatest risk of requiring a shunt and failing stenting. PMID- 25459246 TI - REM sleep behaviour disorder: how useful is it for the differential diagnosis of parkinsonism? AB - BACKGROUND: REM sleep behaviour disorder (RBD) is typically linked to synucleinopathies (SP). In this study we analyzed the utility and performance of RBD as a tool for the differential diagnosis of the most common forms of degenerative parkinsonism, including SPs and tauopathies. METHODS: Patients with a syndromic diagnosis of degenerative parkinsonism matched for gender, age, and disease stage were assessed using a structured protocol with demographic and clinical data, including the diagnosis of probable RBD (pRBD), ascertained clinically using established criteria. RESULTS: One hundred cases of Parkinson's disease (PD), 87 with progressive supranuclear palsy (PSP), 72 with the parkinsonian form of multiple system atrophy (MSA), 50 with dementia with Lewy bodies (DLB), and 18 with corticobasal degeneration (CBD) were included. pRBD was found in 58 (58%) of the PD patients, 59 (81.9%) of those with MSA, 37 (74%) with DLB, 32 (36.7%) with PSP, and one (5.5%) with CBD. Among the SPs, pRBD was significantly more common in MSA when compared with PD patients. Differences were also significant individually for all SPs when compared to PSP. The positive predictive value (PPV) of pRBD for a SP was 82.3%, but sensitivity was 69.4% and specificity 68.6%. CONCLUSIONS: In our sample, pRBD was more frequent in SPs than in PSP and CBD, however, its' frequency in PSP was significant. Although pRBD had a good PPV for a SP, all other measurements used for determine diagnostic performance were disappointing. PMID- 25459248 TI - Wide-bore 1.5 T MRI-guided deep brain stimulation surgery: initial experience and technique comparison. AB - OBJECT: We report results of the initial experience with magnetic resonance image (MRI)-guided implantation of subthalamic nucleus (STN) deep brain stimulating (DBS) electrodes at the University of Wisconsin after having employed frame-based stereotaxy with previously available MR imaging techniques and microelectrode recording for STN DBS surgeries. METHODS: Ten patients underwent MRI-guided DBS implantation of 20 electrodes between April 2011 and March 2013. The procedure was performed in a purpose-built intraoperative MRI suite configured specifically to allow MRI-guided DBS, using a wide-bore (70 cm) MRI system. Trajectory guidance was accomplished with commercially available system consisting of an MR visible skull-mounted aiming device and a software guidance system processing intraoperatively acquired iterative MRI scans. RESULTS: A total of 10 patients (5 male, 5 female)-representative of the Parkinson Disease (PD) population-were operated on with standard technique and underwent 20 electrode placements under MRI-guided bilateral STN-targeted DBS placement. All patients completed the procedure with electrodes successfully placed in the STN. Procedure time improved with experience. CONCLUSION: Our initial experience confirms the safety of MRI guided DBS, setting the stage for future investigations combining physiology and MRI guidance. Further follow-up is required to compare the efficacy of the MRI guided surgery cohort to that of traditional frame-based stereotaxy. PMID- 25459249 TI - Relapsing multiple sclerosis patients treated with disease modifying therapy exhibit highly variable disease progression: a predictive model. AB - OBJECTIVE: To describe a "new natural history" of multiple sclerosis (MS), characterizing three patterns of progression in Relapsing MS (RMS) patients during the "treatment era," using newly developed definitions. By utilizing our simple model we intend to predict which patients are most likely to reach an EDSS of 6.0. METHODS: We stratified MS progression into three distinct patterns: aggressive MS (AMS), intermediate MS (IMS) and mild MS (MMS), based on Expanded Disability Status Scale (EDSS) score rate of change. These groups were compared for progression of EDSS before and after reaching these definitions. RESULTS: The three groups remained significantly different in terms of disability throughout their disease courses p <= 0.001; 98% of the patients used disease modifying treatments (DMTs). AMS patients represent a significantly more disabling and aggressive form of MS than the IMS group. CONCLUSIONS: Transition from relatively mild MS to aggressive course may begin at any time in the first 15 years, despite DMTs. Our definition for AMS is unique and identifies a group of patients who become permanently disabled within two years after a variable amount of time in a benign phase, despite treatment with modern DMTs. PMID- 25459250 TI - Non-motor fluctuations in Parkinson's disease: prevalence, characteristics and management in a large cohort of parkinsonian outpatients. AB - OBJECTIVE: To describe demographic and clinical characteristics in a group of Parkinson's disease (PD) patients with non-motor fluctuations (NMF) and to evaluate the management of medications proposed to treat NMF. METHODS: Three hundred and three PD patients (mean age, 66 +/- 10.3 years; mean disease duration, 10.1 +/- 6.5 years) were enrolled. Each patient was interviewed in a non-directed fashion about the main NMF manifestations, i.e. dysautonomic, mental, and sensory symptoms. Both groups of patients with and without NMF were compared. Dysautonomia, motor fluctuations, age, disease duration, and LEDD were included in a multiple regression to determine which were predictive of NMF. RESULTS: NMF were found in 57 (19%) patients, mean age 65 +/- 10.1 years, mean age at onset of PD 53.7 +/- 10.9 years, mean disease duration 12.5 +/- 6.9 years. NMF occurred on average 9.8 +/- 7.7 years after the onset of PD. Fifty patients (86%) with NMF had also MF and 10 (21%) had PDD. Twenty-five (44%) patients suffered from sensory, 28 (49%) from autonomic and 25 (44%) from neuropsychiatric symptoms. Both disease and L-Dopa treatment durations, and LEDD were significantly higher in NMF patient's group. Motor fluctuations (p = 0.0016) and presence of dysautonomia (p = 0.007) were found to be two independent predictors of NMF. CONCLUSION: The development of new instruments to assess NMF is crucial for optimized management of advanced PD. PMID- 25459251 TI - Predictors of deterioration indicating a requirement for surgery in mild to moderate traumatic brain injury. AB - OBJECTIVES: Careful course observation is necessary for cases of mild to moderate traumatic brain injury even when disturbed consciousness is mild on admission. This is because delayed enlargement of hematoma and progression of cerebral swelling may occur and result in an emergency craniotomy. Here, we investigated coagulopathy and abnormal fibrinolysis as a predictive factor of "deterioration requiring surgery" in mild to moderate traumatic brain injury. PATIENTS AND METHODS: Sixty-one patients with mild to moderate (Glasgow Coma Scale (GCS) score 9-15) traumatic brain injury were admitted between June 2009 and October 2010. There were 54 subjects in the study, excluding those treated with oral antiplatelet agents and anticoagulants. Patients were classified into those with deterioration requiring surgery [op(+)] or those without deterioration requiring surgery [op(-)]. This was based on whether surgical treatment was performed for hematoma expansion, and exacerbated consciousness level within 3 days after admission. Age, GCS score on admission and blood test findings (platelet count, PT-INR, APTT, fibrinogen, FDP, and d-dimer) on admission were compared. RESULTS: The op(+) and op(-) groups comprised 7 (13.0%) and 47 patients (87.0%), respectively. Platelet counts (24.8 vs 18.5 * 10(4)/MUl) were decreased, and PT INR (1.0 vs 1.2) was higher in the op(+) group. Specially, APTT (28.6 vs 39.1s), FDP (28.9 vs 112.9 MUg/ml), and D-dimer (17.3 vs 69.6 MUg/ml) values were significantly higher in the op(+) group. CONCLUSIONS: Coagulopathy and abnormal fibrinolysis, which are measurable in routine medical practice, is associated with deterioration requiring surgery in mild to moderate traumatic brain injury, indicating that careful course observation is necessary. PMID- 25459252 TI - Peripheral field stimulation for thoracic post herpetic neuropathic pain. AB - OBJECTIVE: Post herpetic neuralgia is a chronic, debilitating pain with very few management options and is often refractory to treatment. We present our experience with a series of 4 patients who underwent subcutaneous peripheral field stimulation for treatment of thoracic post herpetic neuropathic pain. METHODS: Four patients with intractable thoracic post herpetic neuropathic pain were operated after maximum medical treatment and a neuropsychological evaluation. Multiple percutaneous electrodes were placed in the subcutaneous plane in the region of pain for a 7-day trial. Following a successful trial (more than 50% reduction of pain), the electrodes were then internalized and attached to a pulse generator. Visual analog scores (VAS) were studied during the preoperative, immediate postoperative and last follow-up visits. Long-term treatment results were determined by retrospective review of medical records. Average follow-up period was 28.2 months. RESULTS: All 4 patients showed persistent improvement in their VAS pain scores with an average improvement of more than 75%. There were no treatment failures and no complication requiring re operation was reported. CONCLUSION: Peripheral field stimulation for the treatment of post herpetic neuropathic pain is a safe and effective method for pain relief for an extremely complex problem with very few solutions. Patient selection and proper lead placement is most important for the success of treatment. PMID- 25459253 TI - Reduced neurotoxicity with combined treatment of high-dose methotrexate, cyclophosphamide, doxorubicin, vincristine and prednisolone (M-CHOP) and deferred radiotherapy for primary central nervous system lymphoma. AB - OBJECTIVE: Although high-dose methotrexate and whole-brain radiation therapy (WBRT) is the current standard for primary central nervous system lymphoma (PCNSL), it has a limited response rate and produces radiation-induced neurotoxicity. We report the effect of a combined treatment of high-dose methotrexate, cyclophosphamide, doxorubicin, vincristine and prednisolone (M CHOP) for immunocompetent patients with PCNSL. METHODS: We analyzed 24 patients who had received M-CHOP administered in 28-day cycles with or without WBRT. The response rate to M-CHOP, overall survival (OS), and recurrence-free survival (RFS) were analyzed. RESULTS: Nine patients were treated with M-CHOP plus WBRT and 15 patients were treated with M-CHOP alone. Twenty-one patients achieved a complete response and three patients achieved a partial response to M-CHOP, for a 100% response rate. With a median follow-up of 70 months, the median OS and RFS were 33 and 13 months, respectively. The median OS for patients treated with M CHOP plus WBRT and M-CHOP alone was 33 and 32 months, respectively. Of the 13 patients whose age was above 65 years, the median OS for the M-CHOP plus WBRT group (two patients) and the M-CHOP alone group (11 patients) was 14 and 32 months, respectively. Toxicities related to M-CHOP were mostly hematologic and generally mild to moderate. Two patients whose age was above 65 years in the M CHOP plus WBRT group developed neurotoxicity. CONCLUSION: Combined treatment with M-CHOP was well tolerated and produced a high response rate. Deferring WBRT was associated with reduced neurotoxicity without worsening the prognosis, especially in elderly patients. PMID- 25459254 TI - Impact of body mass index in spinal surgery for degenerative lumbar spine disease. AB - BACKGROUND: Obesity is a factor for degenerative lumbar spine disease (DLSD), with increasing prevalence worldwide. Consequently, patients who are overweight or obese have benefited from surgical treatment for DLSD, despite their anatomical and clinical differences. OBJECTIVES: To analyse the effect of body mass index (BMI) in spinal surgery for degenerative lumbar spine disease (DLSD). PATIENTS AND METHODS: A retrospective analysis of 100 patients who underwent surgery for DLSD was performed. The study time was 13 months (January 2013 January 2014). The patients were first evaluated with regard to their BMI and were subsequently divided into four groups of patients: BMI <25, BMI between 25 and 30, BMI between 30 and 35, and BMI above 35. The same patients were assessed for their results regarding the extent of surgery in four groups: patients undergoing surgery for treatment of one segment, two segments, three segments, and four or more segments of DLS. The aspects evaluated were surgical time, bleeding, surgical complications, surgical site infection (SSI), and re-operation due to failure of the first procedure. RESULTS: A total of 118 surgeries were performed on 100 patients (52 male/48 female), mean age 52.77 years old (52.77 +/ 14.45), range between 26 and 85 years old, and a mean BMI of 29.43 kg/m(2) (29.43 +/- 5.54). The surgical time averaged 258.1 min (258.1 +/- 82.79); the bleeding was 660 millilitres (ml) (660 +/- 509.1); complications that were related to the surgical procedure occurred in 38% of cases; SSI occurred in 5% of cases, and re-operations or SSI due to complications occurred in 12% of cases. After analysis of all variables, it was observed that the groups were homogeneous without statistical variation when divided by the BMI; however, it was also observed that the extent of surgery was the factor responsible for the increased rate of SSI (p=0.05) and increased potential of re-operation due to complications (p=0.003). CONCLUSION: BMI is not a complicating factor for the outcome of patients undergoing surgery for DLSD in terms of SSI, surgical complications, and re-operation rates. Furthermore, the extent of surgery was associated with increased postoperative SSI and the need for a second surgery due to the failure of the first procedure. PMID- 25459255 TI - Ocular motor abnormalities in a patient with phenytoin toxicity--case report and minireview. PMID- 25459256 TI - Atopic myelitis: a case report from India. PMID- 25459257 TI - Epileptic status immediately after initiation of D-penicillamine therapy in a patient with Wilson's disease. PMID- 25459258 TI - Extremely late wound dehiscence following bevazicumab treatment in a long term survival glioblastoma patient. PMID- 25459259 TI - Optimum timing of revascularization for emergent admissions of carotid artery stenosis with infarction. AB - OBJECTIVE: There is debate concerning the optimum timing of revascularization for emergent admissions of carotid artery stenosis with infarction. Our intent was to stratify clinical and economic outcomes based on the timing of revascularization. METHODS: We performed a retrospective cohort study using the Nationwide Inpatient Sample from 2002 to 2011. Patients were included if they were admitted non electively with a primary diagnosis of carotid artery stenosis with infarction and subsequently treated with revascularization. Cases were stratified into four groups based upon the timing of revascularization: (1) within 48-h of admission, (2) between 48-h and day four of hospitalization, (3) between days five and seven, and (4) during the second week of admission. RESULTS: 27,839 cases met our inclusion criteria. The lowest odds of iatrogenic complications (OR=0.643, P<.001) and mortality (OR=0.631, P<.001) coincided with revascularization between days five and seven of hospitalization. Treatment with carotid artery stenting (CAS) and administration of recombinant tissue plasminogen activator (rtPA) increased the odds of complications and death. With regards to economic measures, administration of rtPA and utilization of CAS drove cost and length-of-stay up, while lower co-morbidity burden and earlier time to revascularization drove both measures down. CONCLUSIONS: The present study suggests that the optimum timing of revascularization may be near the end of the first week of hospitalization following acute stroke. However, this study must be cautioned with limitations including its inability to control for critical disease specific variables including symptom severity and degree of stenosis. Prospective examination seems warranted. PMID- 25459260 TI - Occipitocervical fusion: fix to C2 or C3? AB - OBJECTIVE: The objective of this study was to explore the differences in clinical outcome between short-segment fixation (SSF; occiput-C2) and multi-segment fixation (MSF; occiput-C2, 3). METHODS: From January 2008 to January 2012, patients who underwent surgery for instability at the occipitocervical junction were included in the study. Two different groups of surgeons using two different management options completed the surgeries. One group performed SSF, whereas the other group performed MSF. A total of 53 patients met the criteria (33 SSF, 20 MSF). Mean follow-up was 33.9 months (range, 12-62 months). Fusion was demonstrated by plain radiographs and computed tomography imaging. Neurological status, pillow neck pain, operative time, blood loss during operation, and perioperative complications were compared between the SSF and MSF groups. RESULTS: The fusion rate was 97% in the SSF group and 100% in MSF the group. There was no statistically significant difference in the fusion rate between the two groups (P>0.05). One patient (3%) in the SSF group and two patients (10%) in the MSF group experienced perioperative complications. Of the 25 patients who had neurological symptoms, 22 (88%) showed improvement after the operation in the SSF group and 14 (87.5%) of 16 showed improvement in MSF group. In addition, patients who suffered from pillow neck pain achieved varying degrees of improvement after the operation. CONCLUSION: SSF may be the better choice for treating occipitocervical instability when no subaxial instability is present. Overall, modern instrumentation can provide the stability needed for successful clinical fusion. PMID- 25459261 TI - Recurrent myelitis in localized scleroderma. PMID- 25459262 TI - Current practices in vestibular schwannoma management: a survey of American and Canadian neurosurgeons. AB - OBJECTIVES: Comprehensive therapy for vestibular schwannomas has changed dramatically over the past fifty years. Previously, neurosurgeons were most likely to treat these tumors via an independent surgical approach. Currently, many neurosurgeons treat vestibular schwannomas employing an interdisciplinary team approach with neuro-otologists and radiation oncologists. This survey aims to determine the current treatment paradigm for vestibular schwannomas among American and Canadian neurosurgeons, with particular attention to the utilization of a team approach to the surgical resection of these lesions. METHODS: A seventeen part survey questionnaire was sent by electronic mail to residency trained members of the American Association of Neurological Surgeons currently practicing in Canada or the United States. Questions were divided into groups regarding physician background, overall practice history, recent practice history, opinions on treatment paradigms, and experience with an interdisciplinary team approach. RESULTS: Seven hundred and six responses were received. The vast majority of neurosurgeons surgically resect vestibular schwannomas as part of an interdisciplinary team (85.7%). Regional variations were observed in the use of an interdisciplinary team: 52.3% of responding neurosurgeons who surgically treat vestibular schwannomas without neuro otologists currently practice in the South (no other region represented more than 15.4% of this group, p=0.02). Surgeons who have treated >50 vestibular schwannomas show a trend towards more frequent utilization of an interdisciplinary approach than less experienced surgeons, but this did not reach statistical significance. CONCLUSIONS: The majority of neurosurgeons in the United States and Canada surgically resect vestibular schwannomas via an interdisciplinary approach with the participation of a neuro-otologist. Neurosurgeons in the South appear more likely to surgically treat these tumors alone than neurosurgeons in other regions of the U.S. and Canada. PMID- 25459263 TI - A meta-analysis of interlaminar minimally invasive discectomy compared to conventional microdiscectomy for lumbar disk herniation. AB - A meta-analysis was conducted to evaluate the evidence that compared the safety and efficacy of interlaminar minimally invasive discectomy (ILMI) and conventional microdiscectomy (MD) for treating lumbar disk herniation (LDH) patients and to develop GRADE based recommendations for using the procedures to treat LDH. Eleven studies, encompassing 1012 patients, met the inclusion criteria. Overall, the results of the meta-analysis indicated that there were significant differences between the two groups in blood loss (SMD=-0.93, 95% CI 1.84, -0.02; p=0.05), and the number of days stays in hospital (SMD=-0.79, 95% CI -1.55, -0.04; p=0.04). However, there were no significant differences in the short-term back visual analog scale (VAS) scores (SMD=-0.34, 95% CI -0.81, 0.14; p=0.16), the long-term back VAS scores (SMD=0.13, 95% CI -0.04, 0.30; p=0.14), the short-term leg VAS scores (SMD=0.14, 95% CI -0.01, 0.29; p=0.07), the long term leg VAS scores (SMD=0.12, 95% CI -0.05, 0.30; p=0.17), the short-term Oswestry disability index (ODI) scores (SMD=0.01, 95% CI -0.14, 0.15; p=0.92), the long-term ODI scores (SMD=0.11, 95% CI -0.03, 0.25; p=0.14), and the incidence of complications (RR=1.22, 95% CI 0.88, 1.69; p=0.24). The results of this meta-analysis demonstrate that ILMI and MD are both safe and effective surgical procedures for treating LDH. Compared with MD, ILMI can shorten days in hospital, decrease the mounts of blood loss during surgery. However, the overall GRADE evidence quality was very low. Therefore, further validation is required, and medical institutions should conduct high-quality studies. PMID- 25459264 TI - A rare coincidence of torticollis in Familial Mediterranean Fever: atlanto-axial rotatory subluxation. PMID- 25459267 TI - Analytical protocol for the sensitive determination of mannitol, sorbitol and glucose containing powders in pharmaceutical workplaces by ion chromatography using a pulsed amperometric detector. AB - Workers in the pharmaceutical industry can potentially be exposed to airborne dusts and powders that can contain potent active pharmaceutical ingredients (API). Occupational hygienists and health and safety professionals need to assess and ultimately minimise such inhalation and dermal exposure risks. Containment of dusts at source is the first line of defence but the performance of such technologies needs to be verified, for which purpose the good practice guide: assessing the particulate containment performance of pharmaceutical equipment, produced by the International Society for Pharmaceutical Engineering (ISPE), is a widely used reference document. This guide recommends the use of surrogate powders that can be used to challenge the performance of such containment systems. Materials such as lactose and mannitol are recommended as their physical properties (adhesion, compactability, dustiness, flow characteristics and particle sizes) mimic those of API-containing materials typically handled. Furthermore they are safe materials to use, are available in high purity and can be procured at a reasonable cost. The aim of this work was to develop and validate a sensitive ion-chromatography based analytical procedure for the determination of surrogate powders collected on filter samples so as to meet analytical requirements set out in this ISPE guide. PMID- 25459268 TI - Prioritization and analysis of pharmaceuticals for human use contaminating the aquatic ecosystem in Italy. AB - A predictive approach is needed to study pharmaceuticals and their loads in the environment so as to restrict monitoring to the molecules most likely to occur widely. A three steps method has been developed for this purpose. The first step is to establish the Predicted Environmental Concentrations (PECs) following the approach proposed by the European Medicines Agency (EMA); then the list is refined taking account of metabolic rates and excretion of the parent compounds in humans. In the third stage the substances are sorted according to their fate in sewage treatment plants (STPs). Finally, the results are compared with real concentrations of the pharmaceuticals in surface waters analyzed by HPLC-MS/MS techniques. This paper reports results of this predictive approach in 2013 for Italy. PMID- 25459269 TI - Sex determination of the pelvis using Fourier analysis of postmortem CT images. AB - BACKGROUND: The Fourier transform (FT) is an image-processing tool that can be used to analyze space or linear systems. We used the FT to analyze the shape of the subpubic line (SL) and the right greater sciatic notch area line (GSNAL) of the pelvis to identify sexing in computed tomographic (CT) images. METHODS: 120 bodies (60 male, 60 female) were scanned by multislice CT before autopsy. SL and GSNAL images were reconstructed using an image workstation. The range of the SL is between the bottom ends of the bilateral acetabulum, and the range of the right GSNAL is from the posterior superior iliac spine to the ischial tuberosity. Coordinates (x, y) of the bone outline were extracted from CT images and calculated by fast FT. The Mann-Whitney U test comparing the amplitude of each frequency was used to determine significant differences between the two populations. Multiple regression analyses were performed to find statistically significant amplitudes of each frequency. We verified the accuracy of prediction of the regression equation, and a Cohen's kappa coefficient was measured. RESULTS: Statistically significant differences of amplitude were found in the 2nd, 3rd, and 4th frequencies of the SL and the 1st, 3rd, and 4th frequencies of GSNAL. Adjusted R(2) using all amplitudes having a significant difference was 0.772. The accuracy was 0.983. Kappa coefficient was 0.983. CONCLUSION: We could determine sexing from SL and GSNAL of the pelvis using FT with high accuracy. FT is a useful tool to analyze the curved shape of human bone. PMID- 25459270 TI - Soil examination for a forensic trace evidence laboratory - Part 2: Elemental analysis. AB - Laser-induced breakdown spectroscopy (LIBS), X-ray fluorescence spectroscopy (XRF) and scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDX) are compared in terms of their discrimination power when applied to Australian soil specimens. SEM/EDX and XRF are frequently used in forensic laboratories for the elemental analysis of paint and glass, and for miscellaneous examinations. LIBS is an emerging technique for forensic applications, with a number of researchers promoting its use for the elemental profiling of glass fragments. In this study, 29 soil specimens were analysed, with 12 specimens coming from the Canberra area and the remaining 17 specimens from other sites around Australia. As very good discrimination results were obtained for each of the analytical methods, any of these elemental analysis techniques, available in a trace evidence laboratory, could be used as part of a wider examination protocol to differentiate soil specimens. PMID- 25459272 TI - Statistical sex determination from craniometrics: Comparison of linear discriminant analysis, logistic regression, and support vector machines. AB - Accuracy of identification tools in forensic anthropology primarily rely upon the variations inherent in the data upon which they are built. Sex determination methods based on craniometrics are widely used and known to be specific to several factors (e.g. sample distribution, population, age, secular trends, measurement technique, etc.). The goal of this study is to discuss the potential variations linked to the statistical treatment of the data. Traditional craniometrics of four samples extracted from documented osteological collections (from Portugal, France, the U.S.A., and Thailand) were used to test three different classification methods: linear discriminant analysis (LDA), logistic regression (LR), and support vector machines (SVM). The Portuguese sample was set as a training model on which the other samples were applied in order to assess the validity and reliability of the different models. The tests were performed using different parameters: some included the selection of the best predictors; some included a strict decision threshold (sex assessed only if the related posterior probability was high, including the notion of indeterminate result); and some used an unbalanced sex-ratio. Results indicated that LR tends to perform slightly better than the other techniques and offers a better selection of predictors. Also, the use of a decision threshold (i.e. p>0.95) is essential to ensure an acceptable reliability of sex determination methods based on craniometrics. Although the Portuguese, French, and American samples share a similar sexual dimorphism, application of Western models on the Thai sample (that displayed a lower degree of dimorphism) was unsuccessful. PMID- 25459271 TI - Application of Purkait's triangle method on a skeletal population from southern Europe. AB - The existence of sexual dimorphism in individual elements of the human skeleton allows sex determination and significantly enhances the identification of fragmentary skeletal material. Traditionally, the pelvis and the skull are used for an accurate sex determination. Sometimes they are not available and alternative methods have to be used. The aim of this work is to study the sexual dimorphism of the proximal portion of the posterior femur by analyzing the biometric data of the Purkait's triangle. The studied sample comprises 203 individuals (112 males and 91 females) from the Modern Human Skeletal Reference Collection (The Athens Collection) of the Department of Animal & Human Physiology (National & Kapodistrian University of Athens). The biometric data were analyzed by Discriminant Analysis and equations were generated for sex determination, which gave an overall correct classification of 78.3%. For the right and the left femur the percentages of correct classification were 77.8% and 75.9% respectively. These accuracy rates were compared to those of an Indian population and were found to be lower (86.5% for males and 86.3% for females). The study of sexual dimorphism (SD) in Greek, Indian, European-American and African-American populations gave interesting results. The AB diameter in the Greek sample shows the lowest degree of SD while the AC diameter shows the highest. In the other three population samples, the BC diameter shows the highest degree of SD. We assume that the femur anatomy of the Greeks is the major cause that the Purkait method does not give high rates of correct classification. It is therefore advisable that practitioners exercise caution when using this method on skeletal material from Greece, especially in forensic contexts. PMID- 25459273 TI - Assessment of legal adult age of 18 by measurement of open apices of the third molars: Study on the Albanian sample. AB - The third molar tooth is one of the few anatomical structures in development available for estimating the age of individuals in the late adolescence. This study tests the accuracy of Cameriere's cut-off value of the third molar index (I3M) in assessing legal adult age of 18 years in an Albanian sample. For this purpose, a sample of orthopantomograms (OPTs) of 286 living subjects (152 female and 134 male) aged between 15 and 22 years was analyzed. Intra-rater and inter raters agreement of I3M were 0.998 and 0.998, respectively and Cohen Kappa for intra-rater and inter-rater agreement in decision on adult or minor was 1.0 and 1.0, respectively. Age distribution gradually decreases as I3M increases in both males and females. The mean age of females is higher than that of males when I3M is between 0.04 and 0.08. Sensitivity test for males was 94.1%, with a 95% confidence interval (95% CI) 85.6-98.4%, and specificity was 90.9% (95%CI 81.3 96.6%). The proportion of correctly classified individuals was 92.5%, with a 95%CI of (86.7%, 96.4%). For females, the sensitivity test was 75.4%, with a 95%CI of (63.1%, 85.2%) and specificity was 96.6%, with a 95%CI of (90.3%, 99.3%). The proportion of correctly classified individuals was 87.5%, with a 95%CI of (81.2%, 92.3%). The results indicate that Cameriere's cut-off value of the third molar index (I3M=0.08) is useful in discriminating between Albanian adults and juveniles, and encourage us to test its suitability for determining the adult age in individuals from other populations. PMID- 25459274 TI - Ancestry estimation in South Africa using craniometrics and geometric morphometrics. AB - Population history and positive assortative mating directs gene flow in such a way that biological differences are recognized among groups. In turn, forensic anthropologists quantify biological differences to estimate ancestry. Some anthropologists argue that highly admixed population groups, such as South African coloureds, cannot achieve acceptable accuracies because within group variance is too large. Whereas ancestry estimation in South Africa has been limited to craniometric data from South African blacks and whites, the current study integrates craniometric and geometric morphometric data from the three largest South African groups. Crania from 377 South African individuals (black=158, white=112, and coloured=107) comprised the sample. Standard measurements were collected and the coordinate data were subjected to Generalized Procrustes Analysis (GPA), which resulted in size-free shape variables (ProCoords). A principal component analysis was used to combine the shape variation captured in the ProCoords (ProCoords PC). Linear discriminant analysis (LDA), using equal priors, stepwise variable selection and leave-one-out cross validation, was conducted on the ProCoords, the ProCoords PCs, and the traditional craniometric data. The LDA using 18 stepwise selected ProCoords resulted in the highest cross-validated accuracy (89%). Utilization of geometric morphometric data emphasized that the relative location of cranial landmarks was more discriminating than simple linear distances. Regardless of high levels of genetic admixture, South African coloureds are a homogeneous group and morphologically distinct from other contemporaneous South African populations. Furthermore, the present study demonstrated a correspondence between peer reported race and morphological differences in the crania of black, white, and coloured South Africans. PMID- 25459275 TI - Tufted angioma with Kasabach-Merritt syndrome mistaken for child abuse. AB - We report the case of a 2-month-old infant with a single apparently ecchymotic lesion on the shoulder that raised suspicions of abuse. The medicolegal examination concluded that the appearance of the lesion was only mildly suggestive of an ecchymosis. A second, temporally remote examination confirmed this doubt. The evolution of the lesion, notably an increase in its volume, allowed us to rule out a traumatic lesion and was suggestive of a vascular tumor. The histological type of the tumor was a tufted angioma. There was thrombocytopenia and consumptive coagulopathy. All these data confirmed the diagnosis of Kasabach-Merritt syndrome. In contrast to benign infantile hemangiomas, which are frequent and well-known in clinical practice, vascular tumors complicated by Kasabach-Merritt syndrome are rare. They deserve to be widely known because they mandate rapid medical management and because they are one of the only differential diagnoses of ecchymosis, especially in children. When there is doubt about the traumatic nature of a cutaneous lesion, a temporally remote examination is essential. The evolution of the lesion may then suggest a dermatologic origin. PMID- 25459276 TI - Where do those remains come from? AB - Part of the study of skeletal remains or corpses in advance decay located in the field involves determining their origin. They may be the result of criminal activity, accident, unearthed because of erosion, or they may also have originated from a cemetery. The discovery site, condition of the remains, and the associated artifacts, are factors that could be helpful for the forensic anthropologist to identify the origin of the remains. In order to contribute to this recognition, an analysis was made of the exhumations of 168 unclaimed human remains from the cemetery of Terrassa (Catalonia, Spain). This investigation presents a description of artifacts and conditions of remains that could indicate that the human remains may have originated from a cemetery. PMID- 25459278 TI - Drawbacks in the scientification of forensic science. AB - This letter to the Editor comments on the article On the limitations of probability in conceptualizing pattern matches in forensic science by P. T. Jayaprakash (Forensic Science International, [10]). PMID- 25459277 TI - Sudden death due to a cystic lesion in the cerebellum. AB - A middle-aged female patient with a depressive disorder presented to a mental hospital because of a 2-month worsening history of headache, dizziness, and nausea. The next morning, she was observed to be sleeping, but was then found dead 1h later. Postmortem computed tomography and autopsy revealed a large cyst in the right cerebellar hemisphere, hydrocephalus, and transforaminal herniation. Careful observation revealed an approximately 0.4cm*0.8cm slightly grayish discoloration in the cyst wall that was diagnosed as hemangioblastoma based on its histological features. Finally, we concluded that the cause of death in this case was attributable to the brain stem compression, which was caused by obstructive hydrocephalus secondary to the cystic hemangioblastoma in the cerebellum. The symptoms for 2 months before her death had most likely resulted from increased intracranial pressure. Hemangioblastomas usually appear as nodules in the wall of the cyst, but the tumor in our case looked like just a slightly grayish discoloration. Therefore, cystic lesions in the CNS need to be carefully examined. PMID- 25459279 TI - Reliability and validity of selected measures associated with increased fall risk in females over the age of 45 years with distal radius fracture - A pilot study. AB - STUDY DESIGN: Clinical measurement. PURPOSE: This study examined test-retest reliability and convergent/divergent construct validity of selected tests and measures that assess balance impairment, fear of falling (FOF), impaired physical activity (PA), and lower extremity muscle strength (LEMS) in females >45 years of age after the distal radius fracture (DRF) population. METHODS: Twenty one female participants with DRF were assessed on two occasions. Timed Up and Go, Functional Reach, and One Leg Standing tests assessed balance impairment. Shortened Falls Efficacy Scale, Activity-specific Balance Confidence scale, and Fall Risk Perception Questionnaire assessed FOF. International Physical Activity Questionnaire and Rapid Assessment of Physical Activity were administered to assess PA level. Chair stand test and isometric muscle strength testing for hip and knee assessed LEMS. Intraclass correlation coefficients (ICC) examined the test-retest reliability of the measures. Pearson correlation coefficients (r) examined concurrent relationships between the measures. RESULTS: The results demonstrated fair to excellent test-retest reliability (ICC between 0.50 and 0.96) and low to moderate concordance between the measures (low if r <= 0.4; moderate if r = 0.4-0.7). DISCUSSION: The results provide preliminary estimates of test-retest reliability and convergent/divergent construct validity of selected measures associated with increased risk for falling in the females >45 years of age after DRF. Further research directions to advance knowledge regarding fall risk assessment in DRF population have been identified. PMID- 25459280 TI - Chemotherapy-induced peripheral neuropathy: What do we know about mechanisms? AB - Cisplatin, oxaliplatin, paclitaxel, vincristine and bortezomib are some of the most effective drugs successfully employed (alone or in combinations) as first line treatment for common cancers. However they often caused severe peripheral neurotoxicity and neuropathic pain. Structural deficits in Dorsal Root Ganglia and sensory nerves caused symptoms as sensory loss, paresthesia, dysaesthesia and numbness that result in patient' suffering and also limit the life-saving therapy. Several scientists have explored the various mechanisms involved in the onset of chemotherapy-related peripheral neurotoxicity identifying molecular targets useful for the development of selected neuroprotective strategies. Dorsal Root Ganglia sensory neurons, satellite cells, Schwann cells, as well as neuronal and glial cells in the spinal cord, are the preferential sites in which chemotherapy neurotoxicity occurs. DNA damage, alterations in cellular system repairs, mitochondria changes, increased intracellular reactive oxygen species, alterations in ion channels, glutamate signalling, MAP-kinases and nociceptors ectopic activation are among the events that trigger the onset of peripheral neurotoxicity and neuropathic pain. In the present work we review the role of the main players in determining the pathogenesis of anticancer drugs-induced peripheral neuropathy. PMID- 25459281 TI - Informational masking of complex tones in dyslexic children. AB - In complex auditory scenes, perceiving a given target signal is often complicated by the presence of competing maskers. In addition to energetic masking (EM), which arises because of peripheral interferences between target and maskers at the cochlear level, informational masking (IM), which takes place at a more central level, is also responsible for the difficulties encountered in typical ecological auditory environments. While recent research has led to mixed results regarding a potential speech-perception-in-noise deficit in dyslexic children, most of them actually investigated EM situations. The current study aimed at evaluating dyslexic children's sensitivity to pure IM in complex auditory sequences. Performance of the control normally-reading children increased throughout the experiment, reaching a significantly better level than dyslexics' in the last blocks. Our results provide evidence for a general auditory deficit in noise in dyslexic children. Although due to central mechanisms, this deficit does not seem to stem from a mere auditory attention impairment. Further research is needed to examine the precise nature of the auditory difficulty, and its link with reading acquisition in dyslexic children. PMID- 25459282 TI - High-resolution MR imaging of the arterial wall in moyamoya disease. AB - High resolution magnetic resonance imaging (HRMRI) has been developed as an emerging tool for evaluating intracranial arterial disease. We aimed to analyze the progression of diseased arterial walls in moyamoya disease (MMD) and further elucidate differences compared to intracranial atherosclerotic stenosis using HRMRI. The population of this HRMRI study consisted of 21 patients with MMD and 44 patients with atherosclerotic middle cerebral artery (MCA) stenosis. The cross sectional images of the MCA wall on HRMRI were compared between the two groups based on outer diameter, wall thickness, luminal stenotic morphology, signal intensity, collateral vascular structures adjacent to stenotic position. In addition, stage classification based on MRA finding was used to depict the course of moyamoya disease. We compared outer diameter and wall thickness of the MCAs in different MRA stages. As a result, the outer diameter and wall thickness of MCAs were significantly smaller in the MMD group than in the atherosclerosis group (outer diameter: MMD 2.01 +/- 0.31 mm vs. atherosclerosis 3.31 +/- 0.37 mm, p<0.001 and wall thickness: MMD 0.39 +/- 0.19 mm vs. atherosclerosis 1.64 +/- 0.38 mm, p < 0.001). The concentric stenosis (91.4% in MMD vs. 36.9% in atherosclerosis group, p < 0.001), homogeneous signal intensity (85.7% in MMD vs. 32.6% in atherosclerosis group, p < 0.001) and collateral vascular structures (54.3% in MMD vs. 8.7% in atherosclerosis group, p < 0.001) were more common in MMD patients. In addition, the outer diameter of MCAs in MMD was significantly different between MRA stage 1 and MRA stage 3 or 4 (MRA stage 1 vs. MRA stage 3, Nemenyi test p = 0.005 and MRA stage 1 vs. MRA stage 4, Nemenyi test p = 0.009). But the wall thickness of MCAs was no significantly different in different MRA stages (Kruskal-wallis H test, p = 0.074). We conclude that HRMRI may be used to identify different types of middle cerebral artery stenosis. MMD was characterized by concentric stenosis, homogeneous signal intensity, and collateral vascular structures in the affected MCA segments by HRMRI. Pathological shrinkage of MCA was an important phenomenon in MMD progression. PMID- 25459283 TI - Ketamine ameliorates depressive-like behaviors and immune alterations in adult rats following maternal deprivation. AB - A growing body of evidence points toward an association between the glutamatergic system, as well as immune system dysregulation and major depression. So, the present study was aimed at evaluating the behavioral and molecular effects of the ketamine, an antagonist of the N-methyl-D-aspartate (NMDA) receptor of glutamate in maternally deprived adult rats. In deprived rats treated with saline, we observed an increase in the immobility time; however, ketamine treatment reversed this effect, decreasing immobility time. In addition, maternal deprivation induced an increase in cytokines: TNF-alpha and IL-1 in serum, and in IL-6 in serum and cerebrospinal fluid (CSF). Interestingly, ketamine treatment reduced the levels of all the cytokines in deprived rats. In conclusion, these findings further support a relationship between immune activation and depression. Considering the action of ketamine, this study suggested that antagonists of the NMDA receptor, such as ketamine, could exert their effects by modulation of the immune system. PMID- 25459284 TI - Sex differences in spatiotemporal expression of AR, ERalpha, and ERbeta mRNA in the perinatal mouse brain. AB - It has been shown that every masculinized function might be organized by a particular contribution of androgens vs. estrogens in a critical time window. Here, we aimed to investigate the sex differences in brain testosterone levels and in the spatiotemporal dynamics of steroid receptor mRNA expression in perinatal mice, by using enzyme immunoassay and real-time PCR, respectively. We found that testosterone levels in the forebrain transiently increased around birth in male mice. During the perinatal period, levels of androgen receptor mRNA in the hypothalamus (hypo) and prefrontal cortex (PFC) were higher in male mice than in female mice. Estrogen receptor alpha (ERalpha) mRNA levels in the hypo and hippocampus were higher in male mice than in female mice before birth. In contrast, ERbeta mRNA expression in the PFC was higher in female mice immediately after birth. These spatiotemporal sex differences in steroid receptor expression might contribute to organizing sex differences of not only reproductive function, but also anxiety, stress responses, and cognition in mice. PMID- 25459285 TI - Resveratrol-induced SIRT1 activation promotes neuronal differentiation of human bone marrow mesenchymal stem cells. AB - Resveratrol-3,4',5-trihydroxy-trans-stillbene (resveratrol; RSV), a natural non flavonoid polyphenol compound, provides protection against stress injury, excessive sunlight, ultraviolet radiation, infections, and invading fungi. There is increasing evidence that resveratrol, a sirtuin1 activator, plays a pivotal role in neuroprotection and neuronal differentiation. In this study, we investigated whether resveratrol induces neuronal differentiation of human bone marrow-mesenchymal stem cells (hBM-MSCs). Quantitative PCR results showed that resveratrol-treated MSCs (RSV-MSCs) had significantly increased expression of the neuroprogenitor markers Nestin, Musashi, CD133, and GFAP. When RSV-MSCs were differentiated with neuronal induction media (RSV-dMSCs), they exhibited a cell body and dendritic morphology similar to neurons. The number and neurite length of these RSV-dMSCs were significantly increased compared to differentiated MSCs (dMSCs). The RSV-dMSCs and dMSCs had significantly increased expression of the neuronal-specific marker genes Nestin, Musashi, CD133, GFAP, NF-M, MAP-2, and KCNH1. The RSV-dMSCs also showed a higher expression of the neuronal marker proteins, Nestin and NF-M, based on immunocytochemical staining and immunoblot analysis. This effect was abolished by the treatment of sirtuin1 inhibitor EX527. Therefore, we have shown that resveratrol treatment, along with the use of neuronal induction media, effectively stimulates neuronal cell differentiation of hBM-MSCs. PMID- 25459286 TI - Altered trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type glutamate receptors (AMPARs) in the striatum leads to behavioral changes in emotional responses. AB - The striatum receives and integrates multiple inputs from diverse areas in the brain and plays a critical role in the regulation of motor activity. However, whether the striatum is involved in the alteration of behavior in the presence of emotional challenges is unknown. Here, we examined whether alterations in the surface expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type glutamate receptors (AMPARs) in the dorsal striatum would affect anxiety related behaviors. We found that the transient expression of G1CT or G2CT, AMPAR derived peptides, in the dorsomedial striatum led to decreased mobility in high anxiety circumstances; however, the expression of these peptides in the dorsolateral striatum did not affect anxiety-related behavior. These data suggest that excitatory connections within the dorsomedial striatum play important roles in the control of motor actions in the presence of emotional challenges. PMID- 25459287 TI - Projections from the oral pontine reticular nucleus to the spinal cord of the mouse. AB - The present study investigated projections of the mouse oral pontine reticular nucleus (PnO) to the spinal cord by (a) injecting a retrograde tracer fluoro-gold (FG) to the lumbar cord and (b) an anterograde tracer biotinylated dextran amine (BDA) to PnO. We found that PnO projects to the entire spinal cord with an ipsilateral predominance. PnO fibers mainly travel in the ipsilateral ventral funiculus in the entire cord, terminating in laminae 7-10 with a lower density of fibers and boutons in lower segments. A small number of fibers travel in the contralateral ventral funiculus in the cervical cord with a similar terminating pattern to the ipsilateral counterpart. The present study is the first demonstration of PnO fiber terminals in the mouse spinal cord. This pathway might be responsible for muscle atonia during REM sleep, but needs physiological research to confirm this. PMID- 25459288 TI - The role of handedness-dependent sensorimotor experience in the development of mirroring. AB - In daily life, we often try to learn motor actions by imitating others' actions. Motor imitation requires us to simultaneously map an observed action onto a motor program used to perform that action. This sensorimotor associative experience can plastically modulate the mirror property of the human mirror system, which has a role in matching observed actions directly with the observer's motor programs, to enhance the association between observed and performed actions. In the present study, we investigated the effects of handedness on the mirror property. Healthy left- and right-handed individuals performed a motor imitation task. They were required to imitate hand actions with their dominant hand as quickly and accurately as possible in response to pictures of a left and right hand. Reaction times (RTs) for imitating the hand actions were evaluated. Under the condition where the hand pictures were presented as if facing the participant, we found that, in left-handed participants, RTs for imitating right-handed actions were significantly shorter than those for imitating left-handed actions. Under the same conditions in right-handers, similar differences in RTs when presented left- and right-handed actions were not observed. These findings demonstrate that the imitative responses for left- and right-handed actions are differently facilitated depending on the handedness of the observer, indicating an effect of handedness on the development of mirror systems. The mirror property in left- and right-handers is likely modulated in a different manner by different sensorimotor associative experiences throughout their daily lives. PMID- 25459289 TI - Identification of key amino acid differences contributing to neonicotinoid sensitivity between two nAChR alpha subunits from Pardosa pseudoannulata. AB - Chemical insecticides are still primary methods to control rice planthoppers in China, which not only cause environmental pollution, insecticide residue and insecticide resistance, but also have negative effects on natural enemies, such as Pardosa pseudoannulata (the pond wolf spider), an important predatory enemy of rice planthoppers. Neonicotinoids insecticides, such as imidacloprid and thiacloprid, are insect-selective nAChRs agonists that are used extensively in the areas of crop protection and animal health, but have hypotoxicity to P. pseudoannulata. In the present study, two nAChR alpha subunits, Ppalpha1 or Ppalpha8, were found to be successfully expressed with rbeta2 in Xenopus oocytes, but with much different sensitivity to imidacloprid and thiacloprid on two recombinant receptors Ppalpha1/rbeta2 and Ppalpha8/rbeta2. Key amino acid differences were found in and between the important loops for ligand binding. In order to well understand the relationship between the amino acid differences and neonicotinoid sensitivities, different segments in Ppalpha8 or Ppalpha1 with key amino acid differences were introduced into the corresponding regions of Ppalpha1 or Ppalpha8 to construct chimeras and then co-expressed with rbeta2 subunit in Xenopus oocytes. The results from chimeras of both Ppalpha8 and Ppalpha1 showed that segments Delta5, Delta6, and Delta7 contributed to neonicotinoid sensitivities directly between two receptors. Although the segment Delta4 including all loop B region had no direct influences on neonicotinoid sensitivities, it could more remarkably influence neonicotinoid sensitivities when co-introductions with Delta5, Delta6 or Delta7. So, key amino acid differences in these four segments were important to neonicotinoid sensitivities, but the difference in Delta4 was likely ignored because of its indirect effects. PMID- 25459290 TI - Single 5HTR2A-1438 A/G nucleotide polymorphism affects performance in a metacontrast masking task: implications for vulnerability testing and neuromodulation of pyramidal cells. AB - It is known that 5HTR2A (rs6311) receptors have high concentration in the cortical layer-5 pyramidal neurons and that these receptors play an important role in the modulation of neurocognitive functions. For example, layer-5 pyramidal neurons mediate cellular level integrative interaction of primary sensory afferent signals and top-down signals exerting contextual modulatory influence. It is also known that genetic variability of 5HTR2A is implicated in individual differences in mental processes. Interestingly, serotonin selectively enhances the asynchronous type of glutamate release when modulating the activity of cortical layer-5 pyramidal neurons, with a post-stimulation delay of this effect at about 50 ms. There are not many behavioral tasks capable of tapping that small temporal intervals in terms of change of the values of independent variables leading to an observable change in the subjects' behavior. However, in the metacontrast masking vision task stimulus onset asynchronies between target and mask critical for the change in the expression of the masking effect correspond to this small temporal value. Thus we hypothesized that genetic variability in 5HTR2A (rs6311) is likely to be associated with different behavioral effects of metacontrast masking and more specifically, that because A allele carriers typically demonstrate greater promoter activity, target-to-mask asynchrony variations should have stronger impact on the masking effect especially with this group of subjects. We obtained support for this hypothesis, but only when target and mask shapes were mutually incongruent. PMID- 25459291 TI - Reversal of morphine tolerance by a compound with NPFF receptor subtype-selective actions. AB - Neuropeptide FF (NPFF) modulates opiate actions. It has pro-nociceptive effects, primarily through the NPFF receptor 1 subtype, and anti-nociceptive effects, primarily through the NPFFR2 subtype. AC-263093 is a small l, organic, systemically active molecule that was previously shown to functionally activate NPFFR2, but not NPFFR1. It was hypothesized that AC-263093 would attenuate morphine tolerance. Rats were tested for radiant heat tail-flick latency before and after 5 mg/kg morphine sulfate s.c. They were then rendered morphine-tolerant by continuous subcutaneous infusion of 17.52 mg/kg/day morphine sulfate. On the seventh day of infusion, they were retested for analgesia 10 and 20 min after 5mg/kg morphine sulfate s.c. Tolerance was indicated by reduction of morphine analgesia from the pre-infusion test. Fifty minutes prior to morphine challenge, rats received either 10 mg/kg i.p. AC-263093 or injection vehicle alone. AC 2623093-treated rats had far smaller tolerance scores than control rats. This drug effect was significant, p = 0.015. The same dose of AC-263093 had almost no analgesic effect in non-tolerant, saline-infused rats. In vitro experiments revealed that AC-263093 had equal affinity for NPFFR1 and NPFFR2, and functionally inactivated NPFFR1, in addition to its previously shown ability to activate NPFFR2. Thus, altering the balance between activation of NPFF receptor subtypes may provide one approach to reversing opiate tolerance. PMID- 25459292 TI - Effect of the environmental enrichment on the severity of psychological dependence and voluntary methamphetamine consumption in methamphetamine withdrawn rats. AB - Previously results have been shown that chronic methamphetamine causes dependence, withdrawal syndrome and drug craving. Also, environmental enrichment (EE) has been shown protective effects in several animal models of addiction. This study evaluated effect of the EE on the anxiety-depression profile and voluntary METH consumption in METH-dependent rats after abstinence. The rats were chronically treated with bi-daily doses (2 mg/kg, at 12 h intervals) of METH over a period of 14 days. METH dependent rats reared in standard environment (SE) or EE during spontaneous METH withdrawal which lasted 30 days. Then, the rats were tested for anxiety (the elevated plus maze-EPM) and depression (forced swim test FST) and also voluntary consumption of METH using a two-bottle choice paradigm (TBC). The results showed that the EE rats exhibited an increase in EPM open arm time and entries (P < 0.05), lower levels of immobility (P < 0.001) as compared with the SE groups. Preference ratio of METH was less in the METH/EE rats than the SE group during 2 periods of the intake of drug (P < 0.05). Environmental enrichment seems to be one of the strategies in reduction of behavioral deficits and the risk of relapse induced by METH withdrawal. PMID- 25459293 TI - Altered baseline brain activities before food intake in obese men: a resting state fMRI study. AB - Obesity as a chronic disease has become a global epidemic. However, why obese individuals eat more still remains unclear. Recent functional neuroimaging studies have found abnormal brain activations in obese people. In the present study, we used resting state functional MRI to observe spontaneous blood-oxygen level dependent (BOLD) signal fluctuations during both hunger and satiety states in 20 lean and 20 obese men. Using a regional homogeneity (ReHo) analysis method, we measured temporal homogeneity of the regional BOLD signals. We found that, before food intake, obese men had significantly increased synchronicity of activity in the left putamen relative to lean men. Decreased synchronicity of activity was found in the orbitofrontal cortex (OFC) and medial prefrontal cortex(MPFC) in the obese subjects. And, the ratings of hunger of the obese subjects were higher than those of the lean subjects before food intake. After food intake, we did not find the significant differences between the obese men and the lean men. In all participations, synchronicity of activity increased from the fasted to the satiated state in the OFC. The results indicated that OFC plays an important role in feeding behavior, and OFC signaling may be disordered in obesity. Obese men show less inhibitory control during fasting state. This study has provided strong evidence supporting the hypothesis that there is a hypo functioning reward circuitry in obese individuals, in which the frontal cortex may fail to inhibit the striatum, and consequently lead to overeating and obesity. PMID- 25459294 TI - Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-kappaB pathways. AB - Activation of microglia cells in the brain contributes to neurodegenerative processes promoted by many neurotoxic factors such as pro-inflammatory cytokines and nitric oxide (NO). Reactive oxygen species (ROS) actively affect microglia associated neurodegenerative diseases through their role as pro-inflammatory molecules and modulators of pro-inflammatory processes. Although the ROS which involved in microglia activation are thought to be generated primarily by NADPH oxidase (NOX) and involved in the immune response, mitochondrial ROS have also been proposed as important regulators of the inflammatory response in the innate immune system. However, the role of mitochondrial ROS in microglial activation has yet to be fully elucidated. In this study, we demonstrate that inhibition of mitochondrial ROS by treatment with Mito-TEMPO effectively suppressed the level of mitochondrial and intracellular ROS. Mito-TEMPO treatment also significantly prevented LPS-induced increase in the TNF-alpha, IL-1beta, IL-6, iNOS and Cox-2 in BV-2 and primary microglia cells. Furthermore, LPS-induced suppression of mitochondrial ROS generation not only affected LPS-stimulated activation of MAPKs, including ERK, JNK, and p38, but also regulated IkappaB activation and NF kappaB nuclear localization. These results indicate that mitochondria constitute a major source of ROS generation in LPS-mediated activated microglia cells. Additionally, suppression of LPS-induced mitochondrial ROS plays a role in modulating the production of pro-inflammatory mediators by preventing MAPK and NF kappaB activation in microglia cells. Our findings suggest that a potential strategy in the development of therapy for inflammation-associated degenerative neurological diseases involves targeting the regulation of mitochondrial ROS in microglial cells. PMID- 25459295 TI - Electrophysiological correlates related to the conflict adaptation effect in an emotional conflict task. AB - Previous studies have provided some evidence of the neural basis of the emotional conflict adaptation effect. However, the neural time-course is largely unknown. Therefore, a face-word Stroop task was used in the present study to explore the neural dynamics of the emotional conflict control effect, using event-related potentials (ERPs). The behavioral data showed a robust emotional conflict adaptation effect, and there was an interaction between previous trials and current trials for RT. There were two ERP components (N450 and conflict SP) that might be related to trial congruency. The N450 results showed both a main effect of current trial congruency and an interaction between previous trials and current trials, which might be related to successful conflict adaptation. The SP results only showed the main effect of current trial congruency, which might be associated with post-response monitoring. PMID- 25459296 TI - Involvement of dopaminergic and cholinergic pathways in the induction of yawning and genital grooming by the aqueous extract of Saccharum officinarum L. (sugarcane) in rats. AB - Yawning, associated with genital grooming, is a physiological response that may be used for elucidating the mechanism of action of drugs. Preliminary analysis showed that aqueous extract (AE) of Saccharum induced yawns in rats. So, we aimed to quantify these behavioral responses and investigate the pharmacological mechanisms involved in these actions. During 120 min, after AE administration, the yawns and the genital grooming were quantified at 10 min intervals. Since dopaminergic and cholinergic pathways are implied in these responses, AE were evaluated in the presence of haloperidol 0.5 mg/kg and atropine 2 mg/kg. AE 0.5 g/kg increased the yawns, effect that was blocked both by haloperidol and atropine. Genital grooming could only be stimulated by AE 0.5 g/kg when dopaminergic receptors were blocked by haloperidol. However, it was inhibited when atropine was previously administered. So, we demonstrated a central action of Saccharum and it was postulated that neural circuits with the participation of dopaminergic and cholinergic pathways are involved. The fact that AE is comprised of innumerous compounds could justify the extract's distinct responses. Also, we cannot disregard the presence of different neural circuits that count on the participation of dopaminergic and cholinergic pathways and could be activated by the same induction agent. PMID- 25459297 TI - Genetic data on 17 STR autosomal loci for a sample population of the State of Rio de Janeiro, Brazil. PMID- 25459298 TI - Hydrogen sulfide interacts with calcium signaling to enhance the chromium tolerance in Setaria italica. AB - The oscillation of intracellular calcium (Ca(2+)) concentration is a primary event in numerous biological processes in plants, including stress response. Hydrogen sulfide (H2S), an emerging gasotransmitter, was found to have positive effects in plants responding to chromium (Cr(6+)) stress through interacting with Ca(2+) signaling. While Ca(2+) resemblances H2S in mediating biotic and abiotic stresses, crosstalk between the two pathways remains unclear. In this study, Ca(2+) signaling interacted with H2S to produce a complex physiological response, which enhanced the Cr(6+) tolerance in foxtail millet (Setaria italica). Results indicate that Cr(6+) stress activated endogenous H2S synthesis as well as Ca(2+) signaling. Moreover, toxic symptoms caused by Cr(6+) stress were strongly moderated by 50MUM H2S and 20mM Ca(2+). Conversely, treatments with H2S synthesis inhibitor and Ca(2+) chelators prior to Cr(6+)-exposure aggravated these toxic symptoms. Interestingly, Ca(2+) upregulated expression of two important factors in metal metabolism, MT3A and PCS, which participated in the biosynthesis of heavy metal chelators, in a H2S-dependent manner to cope with Cr(6+) stress. These findings also suggest that the H2S dependent pathway is a component of the Ca(2+) activating antioxidant system and H2S partially contributes Ca(2+) activating antioxidant system. PMID- 25459300 TI - TRPV4 channels activity in bovine articular chondrocytes: regulation by obesity associated mediators. AB - Turnover of the cartilage extracellular matrix depends exclusively on chondrocytes and varies in response to load and osmolarity fluctuations. Obesity can affect chondrocyte physiology; adipokines, insulin and proinflammatory cytokines levels are all altered in the obese and are related to matrix turnover impairments and thus to osteoarthritis. TRPV4, a mechanosensitive cation channel, is responsible for reacting to hypotonic variations. In this study, the presence and activity of TRPV4 channels in bovine chondrocytes were evaluated using the whole-cell patch-clamp technique and fluorescence measurements to perform characterisations of these channels and to determine intracellular calcium responses. The expression of TRPV4 was determined by RT-PCR. The TRPV4 regulation by hypotonic shock, insulin and adipokines were analysed. Hypoosmolarity induced a Gd(3+)-, ruthenium red-, and HC-067047-sensitive current, predominantly inward, an intracellular Ca(2+) concentration increase and a membrane depolarisation. The current had a reversal potential of +28+/-4mV and exhibited preferential permeability to Ca(2+); 4alphaPDD, a specific TRPV4 agonist, evoked the same response. TNFalpha, IL-1beta, insulin, and, to a lesser degree, leptin and resistin attenuated the TRPV4-mediated effects; in contrast, adiponectin did not affect them. These results confirm the function of TRPV4 in bovine articular chondrocytes and its regulation by obesity-associated mediators. PMID- 25459301 TI - Pitfalls in the application of gene-set analysis to genetics studies. AB - Gene-set analysis (GSA) ('enrichment') is a popular approach for the interpretation of genome-wide association studies (GWASs). GSA is most commonly applied to the analysis of transcriptomes, but from the outset it has been considered useful for any study that provides rankings or 'hit lists' of genes. The recent review by Mooney et al. [1] is a valuable resource for geneticists wishing to apply GSA to the output of GWASs. Here we describe some additional points of practical importance if the methods are to be applied and interpreted soundly. PMID- 25459299 TI - Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs. AB - The coupling of ER Ca(2+)-sensing STIM proteins and PM Orai Ca(2+) entry channels generates "store-operated" Ca(2+) signals crucial in controlling responses in many cell types. The dimeric derivative of 2-aminoethoxydiphenyl borinate (2 APB), DPB162-AE, blocks functional coupling between STIM1 and Orai1 with an IC50 (200 nM) 100-fold lower than 2-APB. Unlike 2-APB, DPB162-AE does not affect L type or TRPC channels or Ca(2+) pumps at maximal STIM1-Orai1 blocking levels. DPB162-AE blocks STIM1-induced Orai1 or Orai2, but does not block Orai3 or STIM2 mediated effects. We narrowed the DPB162-AE site of action to the STIM-Orai activating region (SOAR) of STIM1. DPB162-AE does not prevent the SOAR-Orai1 interaction but potently blocks SOAR-mediated Orai1 channel activation, yet its action is not as an Orai1 channel pore blocker. Using the SOAR-F394H mutant which prevents both physical and functional coupling to Orai1, we reveal DPB162-AE rapidly restores SOAR-Orai binding but only slowly restores Orai1 channel mediated Ca(2+) entry. With the same SOAR mutant, 2-APB induces rapid physical and functional coupling to Orai1, but channel activation is transient. We infer that the actions of both 2-APB and DPB162-AE are directed toward the STIM1-Orai1 coupling interface. Compared to 2-APB, DPB162-AE is a much more potent and specific STIM1/Orai1 functional uncoupler. DPB162-AE provides an important pharmacological tool and a useful mechanistic probe for the function and coupling between STIM1 and Orai1 channels. PMID- 25459302 TI - 'Pitfalls in the application of gene set analysis to genetics studies': a response. PMID- 25459303 TI - Variability of Tricuspid Annulus Diameter Measurement in Healthy Volunteers. PMID- 25459304 TI - Value of CMR to Differentiate Cardiac Angiosarcoma From Cardiac Lymphoma. PMID- 25459305 TI - Medial Arterial Calcification: Active Reversible Disease in Human Breast Arteries. PMID- 25459306 TI - Dobutamine stress echocardiography for risk stratification of patients with low gradient severe aortic stenosis undergoing TAVR. PMID- 25459307 TI - OCT Visualization of the Structure of Intimal Tissue After Drug-Eluting Balloon Deployment. PMID- 25459308 TI - Can Computational Simulation Quantitatively Determine Mitral Valve Abnormalities? PMID- 25459309 TI - The biological efficacy profile of BAX 855, a PEGylated recombinant factor VIII molecule. AB - Prophylaxis prevents joint and other bleeding episodes in patients with haemophilia A. Development of new factor concentrates with longer circulating half-lives may encourage patients to start, continue or resume prophylaxis. The aim of this study was to compare the pharmacodynamic effect of a PEGylated full length recombinant factor VIII (rFVIII) concentrate with that of an unmodified rFVIII concentrate with respect to the duration of prophylactic efficacy in a murine model of haemophilic joint bleeding. Mice were pretreated with BAX 855 or unmodified rFVIII at specified times before right knee puncture to induce haemarthrosis; left knee joints served as controls. Joint bleeding was evaluated using a combination of visual and histological assessments. Administration of a single dose of unmodified rFVIII before joint puncture prevented haemarthrosis in mice up to 24 h, whereas pretreatment with BAX 855 protected the joint from bleeding up to 48 h. This pharmacodynamic study showed prolonged efficacy of BAX 855 compared to ADVATE in a haemophilia A mouse joint bleeding model. This finding supports the possibility of using BAX 855 to increase FVIII trough levels and/or extend the dosing interval in patients with haemophilia A on prophylaxis, which may potentially improve prophylactic efficacy and long-term adherence. PMID- 25459310 TI - Prognostic factors of head and neck sarcomas. PMID- 25459311 TI - Middle ear pressure during sleep and the effects of continuous positive airway pressure. AB - PURPOSE: Prior studies evaluating Eustachian tube physiology, baseline middle ear pressure (MEP), and the effects of continuous positive airway pressure (CPAP) have been performed on awake patients. No study to date has specifically investigated MEP during sleep despite the fact that the average individual spends a third of their lifetime sleeping. The primary objectives of the current study are to quantify normal physiologic MEP during sleep and to evaluate the effects of escalating CPAP levels. MATERIALS AND METHODS: Prospective observational study at a tertiary academic referral center evaluating serial tympanometry on sleeping adult patients during polysomnography. MEP was recorded awake, at 1-hour intervals during diagnostic polysomnography, and at all CPAP levels during titration. Changes in MEP with duration of sleep and escalating CPAP levels were analyzed. RESULTS: Ten adults were included (4 females; 6 males; mean age 58years). The mean MEP while awake was 3 decapascals (daPa). The mean MEP during sleep without CPAP rose steadily from 14 daPa at 1hour to 41 daPa at 4hours (r=0.52; p<0.001). The mean MEP during sleep at a CPAP level of 5cm of water was 54 daPa. The mean MEP rose steadily with increasing CPAP levels, and was 104 daPa at 10cm of water, (r=0.82; p<0.001). The mean MEP during sleep without CPAP was 26 daPa, which was significantly lower than the mean MEP during sleep with CPAP between 5-10cm H2O (p<0.01). CONCLUSIONS: MEP naturally increases with duration of sleep. CPAP therapy causes a supraphysiologic elevation in MEP that rises with increasing pressure levels. These findings may help guide future studies examining the safety of CPAP following otologic surgery and the potential therapeutic benefit in patients with chronic middle ear disease. PMID- 25459312 TI - Cholesteatoma of the maxillary sinus: a case report and review of the literature. AB - Cholesteatoma is a relatively common disease entity within the middle ear cavity, but it is rarely found in the paranasal sinuses. We describe a rare case of cholesteatoma in the maxillary sinus of an elderly man presenting with recurrent sinus infections and nasal obstruction refractory to medical treatment. The patient was treated using functional endoscopic sinus surgery with successful removal of the cholesteatoma. He has no recurrence of the cholesteotoma at a 13year follow-up. We review the literature and history on maxillary cholesteatomas and discuss the theories on the pathogenesis of cholesteatoma formation. We propose functional endoscopic sinus surgery with maxillary antrostomy and marsupialization of the cholesteatoma as a primary treatment option for a maxillary cholesteatoma. PMID- 25459313 TI - Reconstruction of composite oral cavity defects with temporalis flaps after prior treatment. AB - BACKGROUND: Reconstruction of composite oral cavity defects in the setting of prior surgery and radiotherapy presents a significant challenge. Although free tissue transfer has shown success in such situations, it is not without considerable risk. Regional pedicled flaps may provide a more suitable alternative. In certain patients, however, severe soft tissue fibrosis makes more conventional regional flaps impractical or impossible. In these situations, temporalis flaps (temporalis muscle and temporoparietal fascia flaps) are versatile options for coverage of complex defects. OBJECTIVE: To report our experience using pedicled temporalis flaps for reconstruction of composite oral cavity defects in patients with significant co-morbidities and prior treatment. METHODS: Three patients were identified and their medical records were reviewed. Their clinical courses and functional outcomes are described. We include a discussion of the operative technique and relevant literature. RESULTS: All patients had previously undergone extensive treatment. One patient needed reconstruction after resection of a third head and neck malignancy and two patients presented for treatment of osteoradionecrosis. A temporalis muscle flap was used to reconstruct composite oral cavity defects in two patients and a combined temporalis muscle and temporoparietal fascia flap was used for independent defects in one patient. All flaps survived. Functional status and pain improved or stabilized in all patients. There were no major or minor complications. CONCLUSION: In previously treated fields, where more conventional flaps are impractical, temporalis flaps are a suitable alternative to achieve a stable healing wound and prevent worsening of functional status. PMID- 25459314 TI - Isolated adult lymphadenopathy: a rare presentation of Langerhans cell histiocytosis. AB - INTRO: Langerhans cell histiocytosis (LCH) is a rare disease involving the proliferation of histiocytes in one or more organ systems. The presentation of LCH is more common in the pediatric population and rarely occurs within the adult population. Isolated lymph node involvement is an extremely rare presentation of the disease. The authors present a case of isolated lymph node LCH in an otherwise healthy adult female and discuss management strategies for these unusual findings. METHODS: A case report of a patient at a tertiary care facility in June 2014 is discussed. RESULTS/DISCUSSION: The diagnosis, clinical course, and management strategies for isolated adult LCH are discussed and reviewed. CONCLUSION: Langerhans cell histiocytosis rarely presents with isolated lymph node involvement in adults. Management and surveillance algorithms are discussed in this unusual case of seemingly benign lymphadenopathy. PMID- 25459315 TI - Postoperative radiotherapy for laryngeal carcinoma: the prognostic role of subcellular Maspin expression. AB - PURPOSE: Reported outcomes of postoperative radiotherapy (PORT) for laryngeal squamous cell carcinoma (LSCC) have varied and sometimes been disappointing. The aim of the present preliminary study was to investigate whether a given immunohistochemical pattern of Maspin expression in laryngeal carcinoma cells could be prognostically associated with response to PORT. MATERIALS AND METHODS: Thirty-two consecutive patients treated for LSCC with primary surgery and PORT. The subcellular (nuclear vs non-nuclear) pattern of Maspin expression was assessed immunohistochemically on LSCC surgical specimens and analyzed in relation to recurrence rate (RR) and disease-free survival (DFS). RESULTS: A non nuclear Maspin expression was found in 23 of 32 cases (72%), and all recurrences (17 cases) occurred in this subgroup of patients. A non-nuclear Maspin expression was strongly associated with recurrence [p = 0.0002, hazard ratio (HR) 5.58] and a shorter DFS (p = 0.0004) after PORT for LSCC. Even in N0 patients, a non nuclear Maspin expression was associated with a significantly higher RR (p = 0.04, HR 1.42) and a shorter DFS (p = 0.02). Among the common clinic-pathological parameters considered, only N stage showed a trend toward an association with prognosis in terms of DFS (p = 0.08). CONCLUSION: Assessing subcellular patterns of Maspin expression in LSCC specimens could identify patients less likely to respond to PORT, who might benefit from combined chemo-radiotherapy to improve the efficacy of adjuvant protocols. PMID- 25459316 TI - Endoscopic transcanal removal of symptomatic external auditory canal exostoses. AB - Exostoses are bony outgrowths of the external auditory canal (EAC) that can lead to cerumen entrapment, recurrent infections, and conductive hearing loss. When surgical removal is indicated, a drill or osteotome may be used via a post auricular, endaural, or transcanal approach. Studies suggest that exostoses removed by transcanal osteotome result in decreased morbidity when compared to open, drilled approaches; however, inadvertent injury to the facial nerve or inner ear is a theoretical concern given the restrictive geometry of the EAC and challenges of visualizing the tip of the chisel through the microscope. The endoscope provides superior visualization of the external auditory canal and tympanic membrane compared to the microscope. We sought to demonstrate the efficacy and safety of endoscopic exostosis surgery with an osteotome. We find that the endoscope provides improved wide angled views without blind spots. There were no intraoperative complications. Endoscopic canaloplasty for exostoses may be readily applied. PMID- 25459317 TI - Long-term outcomes of facial nerve schwannomas with favorable facial nerve function: tumor growth rate is correlated with initial tumor size. AB - OBJECTIVE: The study aimed to report long-term outcomes of facial nerve schwannomas (FNS) with favorable facial nerve function by observation, and to discuss about the relationship between initial tumor size and tumor growth. METHODS: 21 facial nerve schwannoma cases with favorable facial nerve function were managed by observation. They were divided into larger size group (size >=10mm) and smaller size group (size <10mm) according to initial tumor size. RESULTS: They were followed up for 6.4+/-1.7years. 18 of 21 cases (85.7%) maintained House-Brackmann Grade III or better. Growth rate of the tumors in larger size group was 72.7%, much higher than 10% in smaller size group (p<0.05). CONCLUSIONS: Observation was feasible for most FNS with favorable facial nerve function, and growth rate of the tumors was associated with tumor size. PMID- 25459318 TI - Giant submandibular gland mucocele as a complication of previous sialolith removal. AB - Mucoceles are common lesions of minor salivary glands. Mucoceles of the major salivary glands including the submandibular gland are extremely rare, but should be considered in the differential diagnosis of submandibular space swellings. We present a rare case of a 25-year old man, who was diagnosed with a submandibular gland mucocele and had a history of sialolithiasis and intraductal sialolith excision, as well as numerous evacuating punctures and needle aspirations of the mass. The cyst was surgically excised and the specimen included the sublingual gland, in order to prevent recurrence. No postoperative complications were noted. PMID- 25459319 TI - Voicing an impact: who does the National Institutes of Health support for voice disorder research? AB - PURPOSE: Interest in a variety of neoplastic, functional, neurological, and age related laryngeal disorders has contributed to the development of laryngology as an established subspecialty. Funding support plays a critical role in facilitating scholarship within the field. Our objectives were to evaluate who is receiving funding from the NIH for topics relevant to voice disorders, and further describe temporal trends in grants awarded. METHODS: The NIH RePORTER database was searched for grants relevant to voice disorders. Data were further organized by PI specialty, academic department, and funding totals. Furthermore, PI scholarly impact, as measured by the h-index, was calculated. RESULTS: A total of 830 funded fiscal years (for 232 unique projects) totaling $203 million have supported projects examining voice disorders. A plurality of projects (32.8%) was awarded to PIs in otolaryngology departments, followed by 17.2% to speech pathology/communication sciences departments. Although year-to-year variation was noted, otolaryngology departments received approximately 15% of funding annually. Funded otolaryngologists had similar scholarly impact values to individuals in other specialties. CONCLUSIONS: The study of voice disorders involves an interdisciplinary approach, as PIs in numerous specialties receive NIH funding support. As they receive a considerable proportion of this funding and had similar h-indices compared to other specialties involved, otolaryngologists have just as much scholarly impact despite being a smaller specialty. As speech and language pathologists also comprised a significant proportion of individuals in this analysis, enhanced cooperation and encouragement of interdisciplinary scholarly initiatives may be beneficial. PMID- 25459320 TI - Postoperative radiotherapy for diffuse pigmented villonodular synovitis of the temporomandibular joint. AB - BACKGROUND: Pigmented villonodular synovitis (PVNS) is a rare/benign condition of the synovial joint lining. It most commonly presents in the knee but has also been reported to occur in the temporomandibular joint (TMJ). Although there are several series reporting the use of postoperative radiotherapy (PORT) for extremity PVNS, there is scant literature on the use of PORT for PVNS of the TMJ. METHODS: We conducted a literature review for case reports related to PVNS of the TMJ and discuss two additional cases treated with surgery and PORT. RESULTS: 71 cases were found in the literature. 89% were the diffuse subtype. 92% had primary surgery and 7% had PORT. 68% were locally controlled. Both patients treated at our institution are locally controlled. CONCLUSIONS: PVNS of the TMJ is a rare entity. Surgery is the mainstay of treatment but PORT may be useful for local control of extensive tumors or positive margins. PMID- 25459321 TI - Acylated-based long-acting insulin analogues: is "misfolding" the problem? Commentary letter on Hamasaki H and Yanai H. The switching from insulin glargine to insulin degludec reduced HbA1c, daily insulin doses and anti-insulin antibody in anti-insulin antibody-positive subjects with type 1 diabetes. PMID- 25459322 TI - Injury biomechanics. PMID- 25459323 TI - Environmental pollution and occupational health in a changing world. PMID- 25459324 TI - International scientific cooperation on asbestos-related disease prevention in Latin America. PMID- 25459325 TI - Global occupational health: current challenges and the need for urgent action. AB - BACKGROUND: Global occupational health and safety (OHS) is strictly linked to the dynamics of economic globalization. As the global market is increasing, the gap between developed and underdeveloped countries, occupational diseases, and injuries affect a vast number of workers worldwide. Global OHS issues also become local in developed countries due to many factors, including untrained migrant workers in the informal sector, construction, and agriculture. OBJECTIVE: To identify the current status and challenges of global occupational health and safety and the needs for preventive action. FINDINGS: Absence of OHS infrastructure amplifies the devastating consequences of infectious outbreaks like the Ebola pandemic and tuberculosis. Interventions in global OHS are urgently needed at various levels: 1. Increased governmental funding is needed for international organizations like the World Health Organization and the International Labor Organization to face the increasing demand for policies, guidance, and training. 2. Regulations to ban and control dangerous products are needed to avoid the transfer of hazardous production to developing countries. 3. The OHS community must address global OHS issues through advocacy, position papers, public statements, technical and ethical guidelines, and by encouraging access of OHS professionals from the developing countries to leadership positions in professional and academic societies. 4. Research, education, and training of OHS professionals, workers, unions and employers are needed to address global OHS issues and their local impact. 5. Consumers also can influence significantly the adoption of OHS practices by demanding the protection of workers who are producing he goods that are sold in the global market. CONCLUSIONS: Following the equation of maximized profits prompted by the inhibition of OHS is an old practice that has proven to cause significant costs to societies in the developed world. It is now an urgent priority to stop this process and promote a harmonized global market where the health of workers is guaranteed in the global perspective. PMID- 25459326 TI - The global spread of asbestos. AB - BACKGROUND: Asbestos continues to be used in large quantities around the world and to be an important commodity in global trade. OBJECTIVE: To assess and quantify current global patterns of asbestos production, export and use; to examine global patterns of asbestos-related disease; and to examine barriers to an asbestos ban. METHOD: Review of the biomedical literature describing patterns of asbestos exposure and disease; review of documents from national governments, UN agencies, and NGOs on asbestos production and use. FINDINGS: Despite widespread knowledge of the hazards of asbestos and bans on any use of asbestos in more than 50 countries, an estimated 2 million tons of asbestos continue to be used around the world each year. Although this amount is significantly less than peak annual consumption of nearly 5 million tons two decades ago, significant amounts of asbestos are still used in India, China, Russia, and some developing countries. This use of asbestos is responsible for disease today and will cause still more asbestos-related disease in the years ahead. Real and artificially manufactured controversies regarding asbestos such as arguments about the relative hazards of different asbestos fiber types and fiber sizes have impeded bans on asbestos. CONCLUSIONS: All forms of asbestos pose grave dangers to human health. All are proven human carcinogens. There is no continued justification for the use of asbestos. Its production and use should be banned worldwide. PMID- 25459327 TI - Occupational burden of asbestos-related cancer in Argentina, Brazil, Colombia, and Mexico. AB - BACKGROUND: An estimate at the national level of the occupational cancer burden brought about by the industrial use of asbestos requires detailed routine information on such uses as well as on vital statistics of good quality. A causal association with asbestos exposure has been established for mesothelioma and cancers of the lung, larynx, and ovary. OBJECTIVES: The aim of this study was to provide estimates of the occupational burden of asbestos-related cancer for the Latin American countries that are or have been the highest asbestos consumers in the region: Argentina, Brazil, Colombia, and Mexico. METHODS: The burden of multifactorial cancers has been estimated through the approach suggested for the World Health Organization using the population attributable fraction. The following data were used: Proportion of workforce employed in each economic sector. Proportion of workers exposed to asbestos in each sector. Occupational turnover. Levels of exposure. Proportion of the population in the workforce. Relative risk for each considered disease for 1 or more levels of exposure. Data on the proportion of workers exposed to asbestos in each sector are not available for Latin American countries; therefore, data from the European CAREX database (carcinogen exposure database) were used. FINDINGS: Using mortality data of the World Health Organization Health Statistics database for the year 2009 and applying the estimated values for population attributable fractions, the number of estimated deaths in 5 years for mesothelioma and for lung, larynx, and ovary cancers attributable to occupational asbestos exposures, were respectively 735, 233, 29, and 14 for Argentina; 340, 611, 68, and 43 for Brazil; 255, 97, 14, and 9 for Colombia, and 1075, 219, 18, and 22 for Mexico. CONCLUSIONS: The limitations in compiling the estimates highlight the need for improvement in the quality of asbestos-related environmental and health data. Nevertheless, the figures are already usable to promote a ban on asbestos use. PMID- 25459328 TI - Blood lead levels in Mexico and pediatric burden of disease implications. AB - BACKGROUND: Although there has been success in reducing lead exposure with the phase-out of leaded gasoline, exposure to lead in Mexico continues to threaten the health of millions, much of which is from lead-based glazes used in pottery that leaches into food. OBJECTIVES: An extensive historical review and analysis of available data on blood lead levels in Mexican populations was conducted. We used a calculated geometric mean to evaluate the effect of lead on the pediatric burden of disease. METHODS: An extensive bibliographic search identified 83 published articles from 1978 to 2010 with blood lead level (BLL) data in Mexican populations representing 150 data points from more than 50,000 study participants. Values from these publications were categorized into various groupings. We then calculated the incidence of disease and disability-adjusted life-years resulting from these BLLs using the World Health Organization's burden of disease spreadsheets for mild mental retardation. RESULTS: Reviewing all relevant studies, the geometric means of Mexican BLLs in urban and rural areas were found to be 8.85 and 22.24 ug/dL, respectively. Since the phase-out of leaded gasoline, the mean in urban areas was found to be 5.36 ug/dL and the average in rural areas is expected to be much higher. The U.S. Centers for Disease Control and Prevention's (CDC) upper limit of blood lead in children under the age of 6 years is 5 ug/dL and the current U.S. average is 1.2 ug/dL. Our results indicate that more than 15% of the population will experience a decrement of more than 5 IQ points from lead exposure. The analysis also leads us to believe that lead is responsible for 820,000 disability-adjusted life-years for lead-induced mild mental retardation for children aged 0 to 4 years. CONCLUSION: Lead continues to threaten the health of millions and remains a significant cause of disability in Mexico. Additional interventions in reducing or managing lead-based ceramic glazes are necessary to protect the public health. PMID- 25459329 TI - A simplified risk-ranking system for prioritizing toxic pollution sites in low- and middle-income countries. AB - BACKGROUND: In low- and middle-income countries (LMICs), chemical exposures in the environment due to hazardous waste sites and toxic pollutants are typically poorly documented and their health impacts insufficiently quantified. Furthermore, there often is only limited understanding of the health and environmental consequences of point source pollution problems, and little consensus on how to assess and rank them. The contributions of toxic environmental exposures to the global burden of disease are not well characterized. OBJECTIVES: The aim of this study was to describe the simple but effective approach taken by Blacksmith Institute's Toxic Sites Identification Program to quantify and rank toxic exposures in LMICs. This system is already in use at more than 3000 sites in 48 countries such as India, Indonesia, China, Ghana, Kenya, Tanzania, Peru, Bolivia, Argentina, Uruguay, Armenia, Azerbaijan, and Ukraine. METHODS: A hazard ranking system formula, the Blacksmith Index (BI), takes into account important factors such as the scale of the pollution source, the size of the population possibly affected, and the exposure pathways, and is designed for use reliably in low-resource settings by local personnel provided with limited training. FINDINGS: Four representative case studies are presented, with varying locations, populations, pollutants, and exposure pathways. The BI was successfully applied to assess the extent and severity of environmental pollution problems at these sites. CONCLUSIONS: The BI is a risk-ranking tool that provides direct and straightforward characterization, quantification, and prioritization of toxic pollution sites in settings where time, money, or resources are limited. It will be an important and useful tool for addressing toxic pollution problems in LMICs. Although the BI does not have the sophistication of the US Environmental Protection Agency's Hazard Ranking System, the case studies presented here document the effectiveness of the BI in the field, especially in low-resource settings. Understanding of the risks posed by toxic pollution sites helps assure better use of resources to manage sites and mitigate risks to public health. Quantification of these hazards is an important input to assessments of the global burden of disease. PMID- 25459330 TI - E-waste: a global hazard. AB - BACKGROUND: Waste from end-of-life electrical and electronic equipment, known as e-waste, is a rapidly growing global problem. E-waste contains valuable materials that have an economic value when recycled. Unfortunately, the majority of e-waste is recycled in the unregulated informal sector and results in significant risk for toxic exposures to the recyclers, who are frequently women and children. OBJECTIVES: The aim of this study was to document the extent of the problems associated with inappropriate e-waste recycling practices. METHODS: This was a narrative review that highlighted where e-waste is generated, where it is recycled, the range of adverse environmental exposures, the range of adverse health consequences, and the policy frameworks that are intended to protect vulnerable populations from inappropriate e-waste recycling practices. FINDINGS: The amount of e-waste being generated is increasing rapidly and is compounded by both illegal exportation and inappropriate donation of electronic equipment, especially computers, from developed to developing countries. As little as 25% of e-waste is recycled in formal recycling centers with adequate worker protection. The health consequences of both direct exposures during recycling and indirect exposures through environmental contamination are potentially severe but poorly studied. Policy frameworks aimed at protecting vulnerable populations exist but are not effectively applied. CONCLUSIONS: E-waste recycling is necessary but it should be conducted in a safe and standardized manor. The acceptable risk thresholds for hazardous, secondary e-waste substances should not be different for developing and developed countries. However, the acceptable thresholds should be different for children and adults given the physical differences and pronounced vulnerabilities of children. Improving occupational conditions for all e-waste workers and striving for the eradication of child labor is non negotiable. PMID- 25459331 TI - Health impact assessments for environmental restoration: the case of Cano Martin Pena. AB - BACKGROUND: Health Impact Assessment (HIA) is a methodology for predicting the effects of a proposed policy or plan on health. A proposed environmental restoration and development plan presented an opportunity for an HIA in an environmental justice community surrounding the Martin Pena channel in San Juan, Puerto Rico. The HIA focused on the dredging of the channel, debris removal, road, sewer, and storm water infrastructure improvements, housing demolition, and resident relocation. OBJECTIVE: The aim of this study was to determine the potential effects of the proposed plan on the community's health to inform the funding decision by the Puerto Rican legislature. As the first HIA in Puerto Rico, a secondary objective was to build HIA capacity in Puerto Rico. METHODS: This HIA used community training, literature reviews, existing local studies, focus groups, interviews, and disease surveillance data to assess baseline health, determine expected effects, and build capacity. FINDINGS: The Martin Pena community is experiencing deteriorating environmental conditions. Flooding and negative environmental exposures, such as mold, limits to physical activity, stress, chemical toxicants, pathogenic bacteria, and pests, are worsening. The higher rates of diseases, such as asthma and diarrhea, in the community compared with elsewhere in Puerto Rico appear to be largely attributable to these factors. Overall, the proposed plan is expected to improve many of these health disparities but the successful implementation depends on continued community acceptance and participation, particularly with the relocation process. Recommendations are for full financing and several mitigation efforts to avoid negative and preserve beneficial health consequences. CONCLUSIONS: As the first HIA in Puerto Rico, this assessment provided specific recommendations to benefit the health of the community affected by an environmental restoration and development plan and also capacity building for a larger audience in Puerto Rico. This approach could be generalized to other Latino environmental justice communities in Puerto Rico and abroad. PMID- 25459332 TI - The developmental neurotoxicity of arsenic: cognitive and behavioral consequences of early life exposure. AB - BACKGROUND: More than 200 million people worldwide are chronically exposed to arsenic. Arsenic is a known human carcinogen, and its carcinogenic and systemic toxicity have been extensively studied. By contrast, the developmental neurotoxicity of arsenic has been less well described. The aim of this review was to provide a comprehensive review of the developmental neurotoxicity of arsenic. METHODS: We reviewed the published epidemiological and toxicological literature on the developmental neurotoxicity of arsenic. RESULTS: Arsenic is able to gain access to the developing brain and cause neurotoxic effects. Animal models link prenatal and early postnatal exposure to reduction in brain weight, reductions in numbers of glia and neurons, and alterations in neurotransmitter systems. Animal and in vitro studies both suggest that oxidative stress may be a mechanism of arsenic neurotoxicity. Fifteen epidemiological studies indicate that early life exposure is associated with deficits in intelligence and memory. These effects may occur at levels of exposure below current safety guidelines, and some neurocognitive consequences may become manifest only later in life. Sex, concomitant exposures, and timing of exposure appear to modify the developmental neurotoxicity of arsenic. Four epidemiological studies failed to show behavioral outcomes of arsenic exposure. CONCLUSIONS: The published literature indicates that arsenic is a human developmental neurotoxicant. Ongoing and future prospective birth cohort studies will allow more precise definition of the developmental consequences of arsenic exposure in early life. PMID- 25459333 TI - Hazards of the health care sector: looking beyond infectious disease. AB - BACKGROUND: Possessing every hazard class, the health care sector poses significant health threats to its workforce in both high-resource settings and low- and middle-income countries (LMICs). OBJECTIVES: The aim of this paper was to examine the applicability of the classical hierarchy of hazard control technologies in resource-constrained health care settings. METHODS: Using a biologic and chemical hazard example, the hazard control hierarchy was applied for risk mitigation. FINDINGS: Even when resource constraints force a reordered selection of hazard control elements, risk reduction can be achieved across a variety of hazard classes. CONCLUSION: For LMICs with limited resources, the hazard control hierarchy can be effectively employed, although the selection of methods may be reordered, to achieve significant hazard control. Such prevention strategies can thereby strengthen and sustain a critical pillar of the health system, its workforce. PMID- 25459334 TI - The response to September 11: a disaster case study. AB - BACKGROUND: The response to 9/11 continues into its 14th year. The World Trade Center Health Program (WTCHP), a long-term monitoring and treatment program now funded by the Zadroga Act of 2010, includes >60,000 World Trade Center (WTC) disaster responders and community members ("survivors"). The aim of this review is to identify several elements that have had a critical impact on the evolution of the WTC response and, directly or indirectly, the health of the WTC-exposed population. It further explores post-disaster monitoring efforts, recent scientific findings from the WTCHP, and some implications of this experience for ongoing and future environmental disaster response. FINDINGS: Transparency and responsiveness, site safety and worker training, assessment of acute and chronic exposure, and development of clinical expertise are interconnected elements determining efficacy of disaster response. CONCLUSION: Even in a relatively well resourced environment, challenges regarding allocation of appropriate attention to vulnerable populations and integration of treatment response to significant medical and mental health comorbidities remain areas of ongoing programmatic development. PMID- 25459338 TI - A 34-year-old woman with heavy vaginal bleeding. PMID- 25459337 TI - Through a glass, only slightly less darkly: advances in measuring the influences of late-life anxiety. PMID- 25459335 TI - When it rains, it pours: future climate extremes and health. AB - BACKGROUND: The accelerating accumulation of greenhouse gases in the Earth's atmosphere is changing global environmental conditions in unprecedented and potentially irreversible ways. Climate change poses a host of challenges to the health of populations through complex direct and indirect mechanisms. The direct effects include an increased frequency of heat waves, rising sea levels that threaten low-lying communities, anticipated extremes in the global hydrologic cycle (droughts, floods, and intense storms), and adverse effects on agricultural production and fisheries due to environmental stressors and changes in land use. Indirectly, climate change is anticipated to threaten health by worsening urban air pollution and increasing rates of infectious (particularly waterborne and vector-borne) disease transmission. OBJECTIVE: To provide a state-of-the-science review on the health consequences of a changing climate. FINDINGS: Environmental public health researchers have concluded that, on balance, adverse health outcomes will dominate under these changed climatic conditions. The number of pathways through which climate change can affect the health of populations makes this environmental health threat one of the largest and most formidable of the new century. Geographic location plays an influential role the potential for adverse health effects caused by climate change, and certain regions and populations are more vulnerable than others to expected health effects. Two kinds of strategies are available for responding to climate change: mitigation policies (which aim to reduce greenhouse gas emissions) and adaptation measures (relating to preparedness for anticipated impacts). CONCLUSIONS: To better understand and address the complex nature of health risks posed by climate change, interdisciplinary collaboration is critical. Efforts to move beyond our current reliance on fossil fuels to cleaner, more sustainable energy sources may offer some of the greatest health opportunities in more than a century and cobenefits beyond the health sector. Because the nations least responsible for climate change are most vulnerable to its effects, the challenge to reduce greenhouse gas emissions is not merely technical, but also moral. PMID- 25459339 TI - Measuring the physiologic response to traumatic injury. PMID- 25459340 TI - Editorial: proteomics technology in Mexican research. PMID- 25459343 TI - Developmental origins and lineage descendants of endogenous adult cardiac progenitor cells. AB - Mammalian hearts carry a number of primitive stem cell-like populations, although the magnitude of their contribution to tissue homeostasis and repair remains controversial. Recent CRE recombinase-based lineage tracing experiments suggest only a minor contribution to the formation of new cardiomyocytes from such cells, albeit one that might be augmented therapeutically. As the field explores clinical translation of cardiac stem cells, it will be important to understand the biology of these cells in great detail. In this review we document the various reported stem and progenitor cell populations in mammalian hearts and discuss the current state of knowledge on their origins and lineage capabilities. PMID- 25459346 TI - Minimal hepatic encephalopathy in patients with liver cirrhosis: magnetic resonance spectroscopic brain findings versus neuropsychological changes. AB - BACKGROUND AND STUDY AIM: Minimal hepatic encephalopathy (MHE) is a subtle complication of cirrhosis that may have a detrimental effect on daily functioning and may progress to overt hepatic encephalopathy (HE). The aims of this study were to identify MHE and assess neuropsychological changes in those patients. PATIENTS AND METHODS: A case-control study was conducted in 35 cirrhotic patients. MHE was identified by brain (hydrogen-1) magnetic resonance spectroscopy ((1)H-MRS). Neuropsychological changes were evaluated using cognitive abilities screening instrument (CASI) test, Hamilton depression scale, and soft neurological sign assessment. RESULTS: Of the patients, 16 (45.7%) had significant brain (1)H-MRS findings suggesting MHE in the form of decreased myo Inositol/creatine (mI/Cr) and choline/creatine (Cho/Cr) ratios and increased glutamine-glutamate/creatine (Glx/Cr) ratios in white and grey matters compared to patients without MHE and healthy controls. Patients with MHE had significantly lower abstract thinking subset and total CASI score in comparison to patients without MHE (p=0.03 and p=0.05, respectively) and controls (p=0.003 and p=0.02, respectively). No statistically significant differences were observed amongst different groups regarding other CASI subsets, depression, and soft neurological assessment in spite of a tendency towards increased values in patients with MHE. CONCLUSION: MHE associated with neurophysiological changes demonstrated by (1)H MRS preceded neuropsychological changes. Thus, (1)H-MRS may be considered as a potential tool for diagnosis of cirrhosis-associated cerebral dysfunction and a promising method for prioritisation of subjects awaiting liver transplantation. PMID- 25459347 TI - Managing the future: the Special Virus Leukemia Program and the acceleration of biomedical research. AB - After the end of the Second World War, cancer virus research experienced a remarkable revival, culminating in the creation in 1964 of the United States National Cancer Institute's Special Virus Leukemia Program (SVLP), an ambitious program of directed biomedical research to accelerate the development of a leukemia vaccine. Studies of cancer viruses soon became the second most highly funded area of research at the Institute, and by far the most generously funded area of biological research. Remarkably, this vast infrastructure for cancer vaccine production came into being before a human leukemia virus was shown to exist. The origins of the SVLP were rooted in as much as shifts in American society as laboratory science. The revival of cancer virus studies was a function of the success advocates and administrators achieved in associating cancer viruses with campaigns against childhood diseases such as polio and leukemia. To address the urgency borne of this new association, the SVLP's architects sought to lessen the power of peer review in favor of centralized Cold War management methods, fashioning viruses as "administrative objects" in order to accelerate the tempo of biomedical research and discovery. PMID- 25459348 TI - The depth and breadth of public health science in the UK. PMID- 25459349 TI - Numerical study of weak polybase brushes grafted on neutral or charged spherical surface by the self-consistent field theory. AB - The self-consistent field theory (SCFT) is employed to numerically study the response of weak polybase type polymer chains grafted on a sphere to electric fields generated by the uniform positive or negative charges on the grafting substrate in the planar polyelectrolyte brush limit. Also the effect of curvature of the grafting sphere on the brush height of weak polybase brushes in the absence of surface charges is investigated. The numerical study reveals interesting and nontrivial dependence of the brush height on the radius of the grafting substrate. Consistent with experimental results, in the parameter range of the surface charge density examined, the brush height is found to be independent of the applied electric field at intermediate and high grafting densities. At relatively low grafting density, the applied negative surface charge which is termed as negative bias in this study results in a reduction of the brush height. At rather low grafting density, the positive bias corresponding to applied positive surface charges can lead to a slight increase in the brush height. The underlining mechanism governing the response of weak polybase brushes to the applied electric field is elucidated. PMID- 25459350 TI - Mining cancer gene expression databases for latent information on intronic microRNAs. AB - Around 50% of all human microRNAs reside within introns of coding genes and are usually co-transcribed. Gene expression datasets, therefore, should contain a wealth of miRNA-relevant latent information, exploitable for many basic and translational research aims. The present study was undertaken to investigate this possibility. We developed an in silico approach to identify intronic-miRNAs relevant to breast cancer, using public gene expression datasets. This led to the identification of a miRNA signature for aggressive breast cancer, and to the characterization of novel roles of selected miRNAs in cancer-related biological phenotypes. Unexpectedly, in a number of cases, expression regulation of the intronic-miRNA was more relevant than the expression of their host gene. These results provide a proof of principle for the validity of our intronic miRNA mining strategy, which we envision can be applied not only to cancer research, but also to other biological and biomedical fields. PMID- 25459352 TI - [Systemic sarcoidosis and membranous glomerulonephritis]. AB - Renal involvement in sarcoidosis is rare and more often related to calcium metabolism disorders or granulomatous interstitial nephritis. Glomerulonephritis is exceptional. There may be a long latency period between the development of active sarcoidosis and glomerular involvement and inversely. We report a case membranous glomerulonephritis revealing systemic sarcoidosis. PMID- 25459351 TI - Development of pharmacodynamic biomarkers for ATR inhibitors. AB - BACKGROUND: ATR, which signals DNA damage to S/G2 cell cycle checkpoints and for repair, is an attractive target in cancer therapy. ATR inhibitors are being developed and a pharmacodynamic assay is needed to support clinical studies. METHODS: Phosphorylation of ATR targets, Chk1 and H2AX, was evaluated in MCF7 and K562 cells, human volunteer PBMCs and whole blood by Western blot, immunofluorescence microscopy and flow cytometry after DNA damage. The effect of cell cycle phase, ATR knockdown and inhibition on these phosphorylation events was determined. RESULTS: Hydroxyurea, UV and 4NQO induced Chk1 and H2AX phosphorylation in MCF7 and K562 cells. UV/4NQO activation of ATR was detectable in non-cycling cells. Chk1 phosphorylation was reduced by ATR knockdown and reflects ATR activity for 3 h, H2AX phosphorylation after UV/4NQO is ATR dependent for 1 h but increasingly ATM and DNA-PK-dependent at later time points. In isolated PBMCs both phospho-targets were detectable after UV/4NQO but in PBMCs from whole blood treated with 4NQO only H2AX was detectable. CONCLUSION: PhosphoChk1 and H2AX are useful biomarkers for ATR inhibition using a variety of immuno-detection methods, but timing may be critical. Importantly, ATR activity is detectable in non-cycling PBMCs allowing them to be used as a surrogate tissue for biomarker measurement. In PBMCs from whole blood treated with 4NQO phosphoH2AX was the most useful biomarker of ATR activity and a clinically viable pharmacodynamic assay for ATR inhibitors has been developed. PMID- 25459353 TI - Fiftieth anniversary of the oral pathology course of Professor William G. Shafer in Brazil. PMID- 25459354 TI - Evaluation of temporomandibular joint disk displacement and its correlation with pain and osseous abnormalities in symptomatic young patients with magnetic resonance imaging. AB - OBJECTIVE: To evaluate the occurrence of temporomandibular joint disk displacement and its correlation with pain and osseous abnormalities using magnetic resonance imaging (MRI) in patients under 21 years of age. STUDY DESIGN: MRI images in open- and closed-mouth positions from 102 patients, under 21 years of age (mean age 17 years), were studied retrospectively. Patients were divided into six groups according to the disk-condyle relationship. Chi-square, Marascuilo procedure, and Cochran-Mantel-Haenszel tests were used to evaluate the relationships among pain, abnormalities, and the groups. RESULTS: There was a statistically significant correlation between bilateral disk displacement without reduction and pain (P = .011), and osseous changes (P < .0001). There was no proven link between pain and osseous abnormality (P = .414). CONCLUSION: Young patients are susceptible to all stages of disk displacement. There was a strong correlation only between each variable (osseous abnormalities and pain) and the most severe stage of disk displacement (bilateral disk displacement without reduction). PMID- 25459355 TI - Impact of the economic recession on the etiology of maxillofacial fractures in Greece. AB - OBJECTIVE: The global economic crisis and the subsequent austerity measures taken in Greece in 2010 have moved the country to the epicenter of a financial storm with negative effects on the national health sector and all aspects of social life. METHODS: Records of patients admitted for treatment of maxillofacial fractures in two different periods of time were used in this study. Data concerning the etiology of fractures from 2006 to 2009 were compared with data from 2010 to 2013 to investigate whether the economic recession has significantly influenced the causality of trauma. RESULTS AND CONCLUSION: Our study demonstrates that the rate of facial fractures caused by motor vehicle accidents before the worsening of the crisis was significantly reduced in the period after 2010 but that the incidence of fractures due to interpersonal violence increased during the period of the severe economic crisis. We discuss the reasons that may have led to these changing patterns of trauma. PMID- 25459356 TI - Neuroendocrine tumor in the mandible: a case report with imaging and histopathologic findings. AB - Neuroendocrine tumors (NETs) arise from neuroendocrine cells and are mostly observed in the gastrointestinal tract, pancreas, and lungs. NETs in the oral and maxillofacial region are extremely rare. We report a case of a 59-year-old woman with an NET in the mandible. The patient did not show any symptoms except for remarkable swelling and bleeding. The lesion appeared as a radiolucent honeycomb abnormality with bone destruction on panoramic radiography. The histopathologic diagnosis following a biopsy was NET. Contrast-enhanced computed tomography (CT), 18F-fluorodeoxyglucose positron emission computed tomography (18F-FDG PET/CT), and adrenal scintigraphy-labeled meta-iodobenylguanidine were the modalities added to identify the primary site. Multiple lesions were confirmed in the gastrointestinal tract. Endoscopy was performed to identify the lesions, and several lesions were observed protruding from the mucous membranes. However, the endoscopy specimens did not yield an accurate diagnosis because adequate samples were not acquired. Blood and urine tests revealed no functional activity caused by the tumors. Although the origin was not histopathologically confirmed with endoscopy, this patient was situationally diagnosed with nonfunctional NET originating from the duodenum, as demonstrated by the metastases in the mandible. PMID- 25459357 TI - Angiogenesis in regenerative dentistry. PMID- 25459358 TI - Contemporary bladder cancer: variant histology may be a significant driver of disease. AB - OBJECTIVES: To evaluate pathologic and survival outcomes among patients with variant histology (VH) urothelial carcinoma of the bladder. METHODS: A retrospective review of an institutional database was performed to identify all patients who underwent radical cystectomy with curative intent for urothelial carcinoma between 2008 and June 2013. VH was assigned by genitourinary pathologists. Descriptive statistics comparing clinicopathologic outcomes were performed using the Pearson chi-square test and analysis of variance. Survival was evaluated using the Kaplan-Meier methodology and the Cox proportional hazards regression. RESULTS: In total, 624 patients were identified. Overall, 26% (n = 162) had VH, with the most common being squamous differentiation (n = 68), micropapillary variant (MPV, n = 28), plasmacytoid variant (PCV, n = 25), and sarcomatoid variant (n = 15); 64% of MPV and 72% of PCV had positive lymph nodes. Compared with 8% of patients with a non VH, 44% of those with VH were categorized as pT4 (P<0.001). MPV and PCV were independently associated with twice the risk of all-cause mortality compared with nonvariant, when adjusting for demographics, American Society of Anesthesiologists class, transurethral resection of bladder tumor stage, cystectomy stage, positive lymph nodes, and reception of chemotherapy (odds ratio = 2.20, 95% CI: 1.28-3.78; P = 0.004; odds ratio = 2.42, 95% CI: 1.33-4.42; P = 0.004, respectively). There was no difference in risk of mortality associated with squamous differentiation or sarcomatoid variant (P>0.05 each). CONCLUSIONS: MPV and PCV are associated with increased risk of mortality. Improved recognition of VH will enable larger cohorts of study and better prognostic understanding of the significance of specific VH involvement. PMID- 25459359 TI - Radical prostatectomy in high-risk and locally advanced prostate cancer: Mayo Clinic perspective. AB - PURPOSE: Men diagnosed with high-risk prostate cancer represent the cohort of prostate cancer patients at greatest risk for subsequent disease-specific mortality. Unfortunately, however, the classification of high-risk tumors remains imprecise and heterogeneous. There has been a historical reluctance to offer such patients aggressive local treatment, and considerable debate exists regarding the optimal management in this setting. METHODS: We present here our institutional experience, as well as data from several other centers, with radical prostatectomy for high-risk tumors. RESULTS: We discuss that surgery affords accurate pathological staging, thereby improving the identification of patients for secondary therapies. Moreover, prostatectomy not only provides durable local disease control but in addition numerous contemporary surgical series in high risk patients have shown radical prostatectomy to be associated with excellent long-term cancer-specific survival. Further, although studies comparing surgical and radiotherapy modalities in high-risk prostate patients have been wrought with methodological challenges, consistently these observational studies have found equivalent to improved oncologic outcomes when surgery is utilized as the primary treatment. CONCLUSIONS: Herein, we review the advantages, long-term outcomes, and technique of surgery for high-risk prostate cancer. PMID- 25459360 TI - Contemporary, age-based trends in the incidence and management of patients with early-stage kidney cancer. AB - PURPOSE: Although kidney cancer incidence and nephrectomy rates have risen in tandem, clinical advances have generated new uncertainty regarding the optimal management of patients with small renal tumors, especially the elderly. To clarify existing practice patterns, we assessed contemporary trends in the incidence and management of patients with early-stage kidney cancer. MATERIALS AND METHODS: Using Surveillance, Epidemiology, and End Results data, we identified adult patients diagnosed with T1aN0M0 kidney cancer from 2000 to 2010. We determined age-adjusted and age-specific incidence and management rates (i.e., nonoperative, ablation, partial nephrectomy [PN], and radical nephrectomy) per 100,000 adults and determined the average annual percent change (AAPC). Finally, we compared management groups using multinomial logistic regression accounting for patient characteristics, cancer information, and county-level measures for health. RESULTS: From 2000 to 2010, we identified 41,645 adults diagnosed with T1aN0M0 kidney cancer. Overall incidence increased from 3.7 to 7.0 per 100,000 adults (AAPC = 7.0%, P<0.001). Over the study interval, rates of PN (AAPC = 13.1%, P<0.001) increased substantially, becoming the most used treatment by 2010. Among the elderly, rates of nonoperative management and ablation approached nephrectomy rates for those aged 75 to 84 years and became the predominant strategy for patients older than 84 years. Adjusting for clinical, oncological, and environmental factors, older patients less frequently underwent PN and more often received ablative or nonoperative management (P<0.001). CONCLUSIONS: As the incidence of early-stage kidney cancer rises, patients are increasingly treated with nonoperative and nephron-sparing strategies, especially among the most elderly. The broader array of treatment options suggests opportunities to better personalize kidney cancer care for seniors. PMID- 25459362 TI - A unique case of adolescent neuroborreliosis presenting with multiple cranial neuritis and cochlear inflammation on magnetic resonance imaging. AB - BACKGROUND: Lyme disease is the most common vector-borne disease in the United States and is caused by infection with the spirochete Borrelia burgdorferi. In children, neuroborreliosis usually presents as peripheral facial nerve palsy and lymphocytic meningitis and only rarely is associated with cranial polyneuritis. PATIENT DESCRIPTION: We present a 15-year-old with tinnitus, hearing loss, and facial nerve palsy in the setting of acute, severe right arm pain and a several week history of malaise and headache. Lumbar puncture was notable for lymphocytic pleocytosis. Serologic testing demonstrated positive Lyme antibody and a positive immunoglobulin M Western blot. Immunofluorescent assay of cerebrospinal fluid was also positive for anti-Lyme immunoglobulin M. Audiologic testing revealed mixed, right-sided hearing loss. Neuroimaging demonstrated cranial polyneuritis and right-sided cochlear inflammation. The patient was treated with parenteral ceftriaxone with resolution of his symptoms at close follow-up. DISCUSSION: Neuroborreliosis with radiculopathy, lymphocytic meningitis, and cranial polyneuritis is a rare presentation of pediatric Lyme disease. Additionally, cochlear inflammation along with cranial nerve VIII inflammation may contribute to hearing loss in patients with neuroborreliosis. PMID- 25459361 TI - The breadth and type of systemic inflammation and the risk of adverse neurological outcomes in extremely low gestation newborns. AB - BACKGROUND: We hypothesized that the risk of brain damage in extremely preterm neonates increases with the breadth and type of systemic inflammation, indexed by the number of elevated inflammation-related proteins and the number of functional categories of inflammation-related proteins exhibiting an elevated concentration. METHODS: In blood from 881 infants born before 28 weeks gestation, we measured the concentrations of 25 inflammation-related proteins, representing six functional categories (cytokines, chemokines, growth factors, adhesion molecules, metalloproteinases, and liver-produced acute phase reactant proteins) on postnatal days 1, 7, and 14. We evaluated associations between the number and type of proteins whose concentrations were elevated on two separate occasions a week apart and the diagnoses of ventriculomegaly as a neonate, and at 2 years, microcephaly, impaired early cognitive functioning, cerebral palsy, and autism risk as assessed with the Modified Checklist for Autism in Toddlers screen, and in a subset of these children from 12 of 14 sites (n = 826), an attention problem identified with the Child Behavior Checklist. RESULTS: The risk of abnormal brain structure and function overall was increased among children who had recurrent and/or persistent elevations of the 25 proteins. The risk for most outcomes did not rise until at least four proteins in at least two functional categories were elevated. When we focused our analysis on 10 proteins previously found to be associated consistently with neurological outcomes, we found the risk of low Mental Development Index on the Bayley Scales of Infant Development-II, microcephaly, and a Child Behavior Checklist-defined attention problem increased with higher numbers of these recurrently and/or persistently elevated proteins. INTERPRETATION: Increasing breadth of early neonatal inflammation, indexed by the number of protein elevations or the number of protein functional classes elevated, is associated with increasing risk of disorders of brain structure and function among infants born extremely preterm. PMID- 25459363 TI - Patterns of cerebral ischemia in children with moyamoya. AB - BACKGROUND: Moyamoya disease is characterized by progressive cerebrovascular stenosis with recurrent cerebral ischemic events. Transient ischemic attacks are often associated with hyperventilation in children with moyamoya, suggesting hypoperfusion rather than thrombotic vaso-occlusion as a prominent mechanism. The patterns of ischemia and severity of steno-occlusive disease in such children may elucidate these mechanisms. METHODS: Children, 1 month to 18 years, with moyamoya, observed over 11 years were analyzed. A study neuroradiologist reviewed all presurgical neuroimaging. Ischemic injury was categorized into cortical, subcortical, and watershed infarction. Angiographic findings were staged using a standardized method. RESULTS: Twenty children, 15 girls, median age 6.4 years, were included. All children had magnetic resonance imaging and angiography, and in 16, conventional angiography was available. All 40 hemispheres, in 20 children, were evaluated. The initial clinical presentation included neurological deficits in 17, recurrent transient ischemic attacks in 7, headache in 8, seizures in 8, and alteration in consciousness in 4 children. Infarcts were bilateral in 13 (65%) children (ischemia alone in 14, ischemic stroke with hemorrhagic transformation in two, and primary hemorrhage in two). Infarcts were cortical and/or subcortical in 13 (65%), both deep and cortical watershed in 11 (55%), and cortical watershed alone in 5 (25%) children. The predominant vascular territory involved was the middle cerebral artery. The internal carotid arterial system was involved in all, with stage IV being the most frequent angiographic stage. CONCLUSIONS: Ischemic injury in deep watershed zones is common in childhood moyamoya and may reflect non-vaso-occlusive ischemic mechanisms. Location and severity of vascular involvement may correlate with various patterns of ischemic infarction in moyamoya disease and requires further study. PMID- 25459365 TI - Muscle quality and relative adiposity are the strongest predictors of lower extremity physical function in older women. AB - OBJECTIVES: The aim of this study was to examine the relative contributions of physical activity, adiposity, lean mass and muscle quality to lower-extremity physical function (LEPF) in older women. STUDY DESIGN: Cross-sectional analysis at a university research laboratory. MAIN OUTCOME MEASURES: Community-dwelling older women (n=96, 73.9 +/- 5.6 years, BMI=26.5 +/- 4.7 kg/m(2)) were assessed for body composition via dual-energy X-ray absorptiometry, leg extension power using the Nottingham power rig, muscle quality (W/kg) as the ratio of leg extension power (W) to lower-body mineral free lean mass (kg) and moderate intensity physical activity via questionnaire. A composite measure of LEPF was calculated by summing Z-scores of the 6-min walk, 8-foot up-and-go and 30-s chair stand tests. RESULTS: Muscle quality and physical activity were associated with all measures of LEPF (all p<0.01). Relative adiposity was related to the 6-min walk and 30-s chair stand (both p<0.01); lower-body mineral-free lean mass was not related to any measure of LEPF (p>0.05). Hierarchical linear regression analyses revealed that muscle quality (standardized beta=0.47, p<0.01) and relative adiposity (beta=-0.33, p<0.01) were the strongest independent predictors of composite LEPF Z-score explaining 24% and 17% of the variance, respectively. CONCLUSIONS: Muscle quality and relative adiposity are the strongest independent predictors of LEPF in older women. These findings suggest that maintaining muscle quality, especially relative to adiposity, may be a critical target for interventions to prevent declines in physical function in older women. PMID- 25459364 TI - Obesity and its relation to depressive symptoms and sedentary lifestyle in middle aged women. AB - BACKGROUND: The prevalence of obesity increases during female mid-life and although many factors have been identified, data from Latin America is lacking. OBJECTIVE: To assess factors related to obesity among middle-aged women and determine the association with depressive symptoms, sedentary lifestyle and other factors. METHODS: A total of 6079 women aged 40-59 years of 11 Latin American countries were asked to fill out the Goldberg Anxiety and Depression Scale, the Menopause Rating Scale, the Athens Insomnia Scale, the Pittsburgh Sleep Quality Index and a general questionnaire containing personal socio-demographic data, anthropometric measures and lifestyle information. Obesity was defined as a body mass index (BMI) >=30 kg/m(2). RESULTS: Obesity was observed in 18.5% and sedentary lifestyle in 63.9%. A 55.5% presented vasomotor symptoms, 12.2% had severe menopausal symptoms and 13.2% used hormone therapy for the menopause. Prevalence of depressive symptoms was 46.5% and anxiety 59.7%. Our logistic regression model found that significant factors associated to obesity included: arterial hypertension (OR: 1.87), depressive symptoms (OR: 1.57), sedentary lifestyle (OR: 1.50) diabetes mellitus (OR: 1.34), higher number of individuals living at home (OR: 1.31), sleep problems (OR:1.22), anxiety (OR: 1.21), having a stable partner (OR: 1.20), parity (OR: 1.16) and vasomotor symptoms (OR:1.14). A lower risk for obesity was found among women using hormonal contraceptives (OR: 0.69). CONCLUSION: Obesity in middle-aged women is the consequence of the interaction of multiple factors. It was associated to hypertension, depressive symptoms, sedentary lifestyle, climacteric symptoms and other factors. PMID- 25459366 TI - Bangladesh Midlife Women's Health Study (BMWHS): methods, challenges and experiences. AB - OBJECTIVES: To understand the challenges and experiences encountered during data collection for Bangladesh Midlife Women's Health Study (BMWHS) that investigated the low uptake of cervical cancer (CCa) screening barriers, understanding of breast cancer (BCa) knowledge and practices, the prevalence of urinary and fecal incontinence and menopausal symptoms. METHODS: A multistage cluster sampling technique was used to recruit women from the 32 districts of Bangladesh that had offered CCa screening. Female interviewers were trained to undertake structured face-to-face interviews that incorporated both non-validated and several validated questionnaires, such as Question for Urinary Incontinence Diagnosis, Pelvic Organ Prolapse Distress Inventory, Colorectal-Anal Distress Inventory and Menopause-Specific Quality of Life. RESULTS: We completed surveys of 1590 women, estimated age 30-59 years, between September 2013 and March 2014. We implemented several strategies to deal with low literacy and used the temporal relationship between marriage and childbirth, and the average age of onset of menarche, to estimate age. Cultural and religious sensitivities and personal security were managed by engaging community leaders, limiting activities to daylight hours, adopting local codes of dress, such as the wearing of head scarves. Our major challenges and experiences included difficulties in age determination, selection of and access to households, interview privacy, lack of basic and health literacy, transportation, political unrest and security of the interviewers. CONCLUSION: By anticipating challenges, we have been able to comprehensively survey a representative sample of Bangladeshi women. Disseminating information about the field challenges and experiences from the BMWHS should assist other researchers planning to conduct surveys about women's health issues in similar context. PMID- 25459367 TI - Joining of multiple duplex stems at a single quadruplex loop. AB - We report here the formation of stable DNA quadruplex-duplex hybrid complexes harboring multiple duplex stems within the same loop of a quadruplex structure. The folding topology of a two-stem quadruplex-duplex hybrid construct was validated using nuclear magnetic resonance (NMR) spectroscopy. This multi-stem incorporation principle is applicable at different loop positions of the same quadruplex construct and could be extended to three or more duplex stems, giving rise to a diverse range of possible structures. These multi-stem complexes offer new design principles for the assembly of DNA architectures. The potential existence of such complex motifs in genomic sequences could have biological implications and would represent novel targets for drug development. PMID- 25459368 TI - Estimation of stature using hand and foot dimensions in Slovak adults. AB - Hand and foot dimensions used for stature estimation help to formulate a biological profile in the process of personal identification. Morphological variability of hands and feet shows the importance of generating population specific equations to estimate stature. The stature, hand length, hand breadth, foot length and foot breadth of 250 young Slovak males and females, aged 18-24 years, were measured according to standard anthropometric procedures. The data were statistically analyzed using independent t-test for sex and bilateral differences. Pearson correlation coefficient was used for assessing relationship between stature and hand/foot parameters, and subsequently linear regression analysis was used to estimate stature. The results revealed significant sex differences in hand and foot dimensions as well as in stature (p<0.05). There was a positive and statistically significant correlation between stature and all measurements in both sexes (p<0.01). The highest correlation coefficient was found for foot length in males (r=0.71) as well as in females (r=0.63). Regression equations were computed separately for each sex. The accuracy of stature prediction ranged from +/-4.6 to +/-6.1cm. The results of this study indicate that hand and foot dimension can be used to estimate stature for Slovak for the purpose of forensic field. The regression equations can be of use for stature estimation particularly in cases of dismembered bodies. PMID- 25459369 TI - Sequencing the hypervariable regions of human mitochondrial DNA using massively parallel sequencing: Enhanced data acquisition for DNA samples encountered in forensic testing. AB - Mitochondrial DNA testing is a useful tool in the analysis of forensic biological evidence. In cases where nuclear DNA is damaged or limited in quantity, the higher copy number of mitochondrial genomes available in a sample can provide information about the source of a sample. Currently, Sanger-type sequencing (STS) is the primary method to develop mitochondrial DNA profiles. This method is laborious and time consuming. Massively parallel sequencing (MPS) can increase the amount of information obtained from mitochondrial DNA samples while improving turnaround time by decreasing the numbers of manipulations and more so by exploiting high throughput analyses to obtain interpretable results. In this study 18 buccal swabs, three different tissue samples from five individuals, and four bones samples from casework were sequenced at hypervariable regions I and II using STS and MPS. Sample enrichment for STS and MPS was PCR-based. Library preparation for MPS was performed using Nextera(r) XT DNA Sample Preparation Kit and sequencing was performed on the MiSeqTM (Illumina, Inc.). MPS yielded full concordance of base calls with STS results, and the newer methodology was able to resolve length heteroplasmy in homopolymeric regions. This study demonstrates short amplicon MPS of mitochondrial DNA is feasible, can provide information not possible with STS, and lays the groundwork for development of a whole genome sequencing strategy for degraded samples. PMID- 25459370 TI - Impact of evolving epidemiology on treatments for complicated skin and skin structure infections: the surgical perspective. PMID- 25459371 TI - Enhancing laser therapy using PEGylated gold nanoparticles combined with ultrasound and microbubbles. AB - BACKGROUND: Gold nanorod (AuNR) laser therapy (LT) is a non-invasive method of increasing the temperature of a target tissue using near infrared light. In this study, the effects of ultrasound and microbubbles (USMB) with AuNR and LT were investigated on cell viability. METHODS: MDA-MB-231 cells in suspension were treated with three different treatment combinations of AuNR, LT and USMB (Pneg=0.6 or 1.0 MPa): (1) AuNR with USMB followed by LT, (2) AuNR and LT followed by USMB, and (3) USMB followed by AuNR and LT. Cells were also exposed to USMB and LT without AuNR. The USMB conditions were: 500 kHz frequency, 16 cycles, 1kHz pulse repetition frequency for 1 min in the presence of Definity microbubbles (1.7% v/v). AuNR and LT conditions were: mPEG coated AuNR at 3*10(11) np/mL and 1.9 W/cm(2) for 3 min. Following the treatment, cell viability was assessed using propidium iodide (PI) fluorescent marker and flow cytometry (VPI), and colony assay (VCA). Cell viabilities were compared using a non parametric Mann-Whitney U-test and synergism was assessed using the Bliss Independence Model. RESULTS AND DISCUSSION: USMB improved cell death when combined with AuNR and LT. VPI of 17+/-2% (at 0.6 MPa) and 11+/-4% (at 1.0 MPa) were observed with combined treatment of AuNR and USMB followed by LT compared to VPI of 60+/-2% (at 0.6 MPa) and 42+/-3% (at 1.0 MPa) with USMB alone and VPI of 22+/-3% for AuNR and LT. The combined effect of AuNR and LT with USMB was additive regardless of treatment order. VCA results agreed with the additive effect caused by combining AuNR and LT with USMB for all treatment orders. In the absence of AuNR, samples exposed to LT prior to USMB at 0.6 MPa increased VPI by 13% (p<0.01) showing a protective effect. CONCLUSION: Combining AuNR and LT with USMB resulted in an additive effect on cell viability compared to AuNR and LT, or USMB. In addition, cells exposed to low intensity NIR light appear to be protected against USMB exposure. PMID- 25459372 TI - Lunch, recess and nutrition: responding to time incentives in the cafeteria. AB - OBJECTIVES: In this study, we evaluate if moving recess before lunch has an effect on the amount of fruits and vegetables elementary school students eat as part of their school-provided lunch. METHODS: Participants were 1st-6th grade students from three schools that switched recess from after to before lunch and four similar schools that continued to hold recess after lunch. We collected data for an average of 14 days at each school (4 days during spring 2011, May 3 through June 1, 2011 and 9 days during fall 2011, September 19 through November 11, 2011). All of the schools were in Orem, UT. Data was collected for all students receiving a school lunch and was based on observational plate waste data. RESULTS: We find that moving recess before lunch increased consumption of fruits and vegetables by 0.16 servings per child (a 54% increase) and increased the fraction of children eating at least one serving of fruits or vegetables by 10 percentage points (a 45% increase). In contrast, the schools in our control group actually experienced a small reduction in fruit and vegetable consumption during the same time period. CONCLUSIONS: Our results show the benefits of holding recess before lunch and suggest that if more schools implement this policy, there would be significant increases in fruit and vegetable consumption among students who eat school lunch as part of the National School Lunch Program. PMID- 25459375 TI - Costs incurred by applying computer-aided design/computer-aided manufacturing techniques for the reconstruction of maxillofacial defects. AB - This study aims to evaluate the additional costs incurred by using a computer aided design/computer-aided manufacturing (CAD/CAM) technique for reconstructing maxillofacial defects by analyzing typical cases. The medical charts of 11 consecutive patients who were subjected to the CAD/CAM technique were considered, and invoices from the companies providing the CAD/CAM devices were reviewed for every case. The number of devices used was significantly correlated with cost (r = 0.880; p < 0.001). Significant differences in mean costs were found between cases in which prebent reconstruction plates were used (?3346.00 +/- ?29.00) and cases in which they were not (?2534.22 +/- ?264.48; p < 0.001). Significant differences were also obtained between the costs of two, three and four devices, even when ignoring the cost of reconstruction plates. Additional fees provided by statutory health insurance covered a mean of 171.5% +/- 25.6% of the cost of the CAD/CAM devices. Since the additional fees provide financial compensation, we believe that the CAD/CAM technique is suited for wide application and not restricted to complex cases. Where additional fees/funds are not available, the CAD/CAM technique might be unprofitable, so the decision whether or not to use it remains a case-to-case decision with respect to cost versus benefit. PMID- 25459376 TI - Long-term outcomes of endoscopic endonasal conjunctivodacryocystorhinostomy with Jones tube placement: a thirteen-year experience. AB - PURPOSE: To report thirteen years of experience with endoscopic-assisted endonasal primary conjunctivodacryocystorhinostomy (CDCR) and revision with Jones tube placement in Korean patients. METHODS: Thirty-three patients who underwent primary endoscopic endonasal CDCR with a Jones tube and were followed for over 6 months and 22 patients who underwent revision CDCR were retrospectively reviewed. We evaluated the cause of obstruction, operation time, tube length, success rate (at 6, 12 and 24 months), and the cause of failure for primary and revision procedures. RESULTS: The most common cause for operation in primary CDCR was trauma. The mean operation time was 26 min and 24 min in the primary and revision groups. The initial success rate was 87.9% vs. 74.3% at 6 months postoperative and 63.6% vs. 60% at two years after surgery in the primary and revision group. The most common reason for failure in both groups was medial migration of the tube, and the mean onset of these complications was about 10 months postoperative. Other major reasons for failure were inappropriate length of tube insertion in the primary group and inflammation in the revision group. CONCLUSION: Fatal complications which lead to failure may develop many months into the procedure, so long-term follow-up is necessary. The most common cause of failure was medial migration of the Jones tube; however, inappropriate tube insertion in primary surgery and severe inflammation in revision may also be concerns. PMID- 25459377 TI - Reinvestigation of epithelial lining of the genital coelomic sinus in asteroids. An ultrastructural study. AB - Ultrastructural study of gonadal muscles in sea star, Asterina pectinifera, showed that myoepithelial cells were located only in the epithelial lining of the genital coelomic sinus. No myoepithelial cells were found in the visceral peritoneal epithelium or within connective tissue layer of the outer sac. Morphology of the myoepithelial cells in gonads of A. pectinifera varies during the reproductive cycle. During the gametogenic phase of the reproductive cycle, the myoepithelial cells get an elongated, spindle-like shape having a length of 20-30 m. In prespawning gonads, many of the myoepithelial cells form cytoplasmic extensions of 3-5 m in length, filled with myofilaments and penetrating into the underlying connective tissue of the outer sac or haemal sinus. Besides, myoepithelial cells, simultaneously anchored in the inner and outer sacs, were also observed. These changes result in development of more elaborated musculature and increase in contractility of the gonadal wall in prespawning gonads as compared to that during other stages of the reproductive cycle. PMID- 25459378 TI - Force variations in the distal radius and ulna: effect of ulnar variance and forearm motion. AB - PURPOSE: To better define normal wrist joint forces during wrist motion and forearm motion at specific wrist and forearm positions and to see if there is a relationship between these forces and the amount of ulnar variance. A secondary purpose was to determine the relationship between the thickness of the articular disk of the triangular fibrocartilage complex and the amount of force transmitted through the distal ulna. METHODS: Multi-axis load cells were attached to the distal radius and ulna of 9 fresh cadaver forearms. The axial radial and ulnar compressive forces were recorded while each wrist was moved through wrist and forearm motions using a modified wrist joint simulator. During each motion, the tendon forces required to cause each motion were recorded. The ulnar variance and triangular fibrocartilage complex articular disc thickness were measured. RESULTS: The axial force through the distal ulna and the wrist extensor forces were greatest with the forearm in pronation. No relationship was found between the amount of force through the distal ulna and the amount of ulnar variance. A strong inverse relationship was found between the triangular fibrocartilage complex thickness and the ulnar variance. CONCLUSIONS: Wrists with positive ulnar variance have generally been thought to transmit greater loads across the distal ulna, which has been felt to predispose these wrists to the development of ulnar impaction. The results of this study appear to show that all wrists have similar loading across the distal ulna regardless of ulnar variance. By comparison, pronation relatively increases loading across the distal ulna. CLINICAL RELEVANCE: Because these results suggest that within reasonable ranges of ulnar variance loading across the distal ulna is independent of ulnar variance, the clinically observed incidence of ulnar impaction is more likely the result of increased wear on a thinner and less durable triangular fibrocartilage complex than due to increased distal ulna loading in ulnar positive variant wrists. PMID- 25459379 TI - Short-term electrical stimulation to promote nerve repair and functional recovery in a rat model. AB - PURPOSE: To evaluate the effect of duration of electrical stimulation on peripheral nerve regeneration and functional recovery. Based on previous work, we hypothesized that applying 10 minutes of electrical stimulation to a 10-mm rat sciatic nerve defect would significantly improve nerve regeneration and functional recovery compared with the non-electrical stimulation group. METHODS: A silicone tube filled with a collagen gel was used to bridge a 10-mm nerve defect in rats, and either 10 minutes or 60 minutes of electrical stimulation was applied to the nerve during surgery. Controls consisted of a silicone tube with collagen gel and no electrical stimulation or an isograft. We analyzed recovery over a 12-week period, measuring sciatic functional index and extensor postural thrust scores and concluding with histological examination of the nerve. RESULTS: Functional assessment scores at week 12 increased 24% in the 10-minute group as compared to the no stimulation control group. Electrical stimulation of either 10 or 60 minutes improved the number of nerve fibers over no stimulation. Additionally, the electrical stimulation group's histomorphometric analysis was not different from the isograft group. CONCLUSIONS: Several previous studies have demonstrated the effectiveness of 60-minute stimulations on peripheral nerve regeneration. This study demonstrated that an electrical stimulation of 10 minutes enhanced several functional and histomorphometric outcomes of nerve regeneration and was overall similar to a 60-minute stimulation over 12 weeks. CLINICAL RELEVANCE: Decreasing the electrical stimulation time from 60 minutes to 10 minutes provided a potential clinically feasible and safe method to enhance nerve regeneration and functional recovery. PMID- 25459380 TI - Perilunate dislocations. PMID- 25459381 TI - Dorsal distraction plating for highly comminuted distal radius fractures. PMID- 25459382 TI - The effect of intrinsic loading and reconstruction upon grip capacity and finger extension kinematics. AB - PURPOSE: To compare active and passive reconstructive procedures for tetraplegia and their ability to produce a powerful grip and allow appropriate finger extension in a cadaveric model. METHODS: Seventeen fresh-frozen hands were used, which included 5 in intrinsic minus and intrinsic activation conditions, 6 with Zancolli-lasso tenodeses, and 6 with modified House tenodeses to simulate intrinsic function. To test grip, flexor digitorum profundus tendons were powered with a motor. Polyvinyl chloride cylinders of diameters 43, 51, 57, 70, or 89 mm and masses 250, 400, or 550 g were used. Grip was considered successful if the cylinder was grasped and resisted gravity. Finger extension was tested by powering the extensor tendons in the same hands. RESULTS: No successful grasps were recorded in the intrinsic minus hands for larger diameter cylinders (>= 70 mm), whereas multiple successes were seen after intrinsic activation and after Zancolli-lasso and House procedures. Whereas active intrinsic and the House reconstruction reached near full extension, this was not true for the Zancolli lasso group. CONCLUSIONS: These data demonstrated that active and passive intrinsic reconstruction methods improved basic grasp and release kinematics in experimental cadaver hand models. Using our model and based on the more optimal kinematics and full extension of the House procedure, we suggest that this should be the preferred tenodesis-based intrinsic reconstruction method. Nevertheless, both procedures were equally successful at grasping objects of the sizes and masses studied. CLINICAL RELEVANCE: Comparative clinical studies are indicated to corroborate the findings of this cadaveric hand model. PMID- 25459383 TI - Porous polyurea network showing aggregation induced white light emission, applications as biosensor and scaffold for drug delivery. AB - We have designed a urea functionalized novel nanoporous material, POP-PU, which showsaggregation induced white light emission in the presence of suitable polar solvents. This nanomaterial has been explored as a pseudowhite light emitter where the polymeric luminogen moiety can interact with the suitable polar solvent, leading to charge transfer. Thus, solvent assisted rotational freezing of nonrigid polymeric nanoparticles gives radiative emission and the whole solution emits white light with color temperature of 8533 K. This nanoporous material also holds the pockets (donor-donor-acceptor array) for specific biomolecular interaction. Among three pyrimidine based nucleotide bases, only cytosine can amplify the PL emission intensity of POP-PU and the other two bases cannot, suggesting its future potential as a biosensor. Further, this urea functionalized porous organic nanomaterial can be utilized as an efficient drug delivery vehicle for liver cancer diagnostics and therapy based on the specific biomolecular interaction at its surface. PMID- 25459385 TI - [Album of models for qualitative tools in the Family Medicine decision making. Other maps to describe a country]. PMID- 25459384 TI - [Baseline clinical characteristics and management of patients included in IBERICAN study]. AB - AIMS: To determine the prevalence and incidence of cardiovascular risk factors and cardiovascular events in Spain, as well as the quality of the follow-up in clinical practice. In this study the baseline data of the first interim analysis of IBERICAN are shown (n=830). METHODS: IBERICAN is a multicenter, longitudinal and observational population-based study of patients daily attended in primary care setting according to clinical practice in Spain. Subjects between 18 and 85 years daily attended in primary care setting are being included consecutively. Treatment of patients will be performed according only to clinical criteria of investigators. Blood pressure control was defined according to 2013 European guidelines of hypertension; LDL-cholesterol control was defined according to 2012 European guidelines of cardiovascular prevention; diabetes control was defined as HbA1c<7%. RESULTS: Mean age was 57.9+/-14.1 years. 54.1% of patients had dyslipidemia, 47.5% hypertension, 17.7% diabetes, and 10.8% history of ischemic heart disease. Regarding drugs, despite 55% of hypertensive patients were taking>=2 antihypertensive agents, only 59.9% achieved blood pressure targets; 65.7% of patients with dyslipidemia were taking statins, but only 35.6% attained LDL-cholesterol goals. Only 51.4% of diabetics achieved HbA1c goals. CONCLUSIONS: Subjects attended in primary care showed a high prevalence of cardiovascular risk factors with a poor control. PMID- 25459386 TI - Creation through immobilization: a new family of high performance heterogeneous bifunctional iminophosphorane (BIMP) superbase organocatalysts. AB - An immobilized chiral bifunctional iminophosphorane superbase organocatalyst has been developed and applied in a range of challenging enantioselective reactions. A unique feature of this novel catalytic system is that the final step creation of the iminophosphorane occurs at the point of immobilization. The utility of the immobilized catalyst system was demonstrated in the nitro-Mannich reaction of ketimines as well as the conjugate addition of high pKa 1,3-dicarbonyl pro nucleophiles to nitrostyrene. Catalyst recycling was also demonstrated. PMID- 25459387 TI - Examining trends in the treatment of ureterocele yields no definitive solution. AB - INTRODUCTION: The surgical management of ureteroceles is extremely variable. Some have hypothesized that if these patients were treated with 'definitive' staged surgical intervention, the need for further revision surgery would be eliminated. OBJECTIVE: The present study sought to determine if the rate of revision surgery differed among patients who have undergone different surgical approaches for the ureterocele complex. STUDY DESIGN: A large retrospective chart review was conducted, identifying all patients having undergone ureterocele surgery at a single institution over the past 41 years. The cohort was divided into four groups based on surgical approach: upper tract approach (UTA), lower tract reconstruction (LTR), simultaneous upper and lower tract approach (ULTA), and staged lower tract reconstruction (SLTR). Demographics, the presence of preoperative/postoperative VUR, postoperative morbidity and the need for revision surgery were compared using the Chi- squared test, Fisher's exact test, Kruskal Wallis test, Mann-Whitney U test (Bonferroni correction), logistic regression modeling and survival analyses (Kaplan-Meier and Cox proportional Hazards regression with unplanned revision operation as the outcome event). RESULTS: Between 1969 and 2010, 180 patients were identified as having undergone surgical management of ureteroceles, of which 120 had complete demographic data available for analysis. The median age at the time of initial surgical intervention was 5.8 months and the majority of patients (83.3%) were female. The median follow-up was 33.1 months. Surgical management was as follows: 18 (15.0%) patients underwent UTA, 47 (39.2%) underwent LTR, 23 (19.2%) underwent ULTA, and 32 (26.6%) underwent SLTR. Among these groups, the only difference in median age was between the LTR and SLTR groups (6.3 months vs 3.7 months, P=0.012). Additional revision surgery was required in: nine (50.0%) of UTA, ten (21.3%) of LTR, four (17.4%) of ULTA, and three (9.4%) of SLTR. The only statistically significant difference in unplanned revision surgery was noted in the UTA group versus each of the other groups with VUR as the predominant indication (88.9%). The likelihood of requiring revision surgery in comparison to the SLTR group was significantly increased in the UTA group (OR 9.67, CI 2.15-43.56), but not in the LTR (OR 2.61, CI 0.66-10.37) or the ULTA group (OR 2.04, CI 0.41-10.13). Obstruction, recurring UTIs and VUR were the main indications for revision surgery overall. DISCUSSION: There is a large body of literature examining the surgical management of ureteroceles. It most recently primarily focuses on an endoscopic approach to the lower tract. The present retrospective review examined the need for re-operative intervention by comparing four different surgical approaches, and found that there is no panacea. Although heminephrectomy (UTA) was a definitive procedure in some patients without reflux at presentation, many who underwent heminephrectomy, went on to require later bladder surgery for either recurrent UTI or persistent reflux. The present study has multiple limitations. Although VUR was an indication for revision surgery in the early part of the series, the current treatment of VUR is not necessarily as stringent. In addition, no distinction was made between an orthotopic or ectopic ureterocele, although some authors have reported differing outcomes in these two groups. However, it is felt that given the large data set of a relatively uncommon condition, the lack of superiority of one approach is apparent. CONCLUSION: There is no definitive surgical repair for the ureterocele complex. All groups except UTA had statistically similar rates of revision surgery. The widespread variability in current management echoes the lack of one superior approach found in this comprehensive series. PMID- 25459388 TI - Laparoendoscopic single-site surgery (LESS) for the treatment of different urologic pathologies in pediatrics: single-center single-surgeon experience. AB - INTRODUCTION: Recently LESS has been reported as a valid minimally option for treatment of some urologic pathologies in pediatrics. However, the initial reports of pediatric LESS are still limited to case reports and initial case series. This may be due to the inherent technical difficulty of LESS and the currently available LESS instruments. In this report, we present the largest case series of pediatric LESS for treatment of different urologic pathologies in pediatrics. MATERIALS AND METHODS: Included in this study are children who had LESS during the period of January 2011 to June 2013. Both Olympus TriPort (Olympus, New York, USA and Advance Surgical Concept, Wicklow, Ireland) and Covedien SILS access port (Covedien, Chicopec, Massachusetts, USA) were used and were inserted through the umbilicus. Exclusion criteria included children less than 3 years old, history of previous transperitoneal abdominal surgery, malignant indications, and complex urogenital congenital anomalies. All LESS procedures were done by a single experienced laparoscopist and data were reviewed retrospectively. RESULTS: Twenty-two children had 39 LESS procedures without conversion to conventional laparoscopy or open surgery. No intraoperative or postoperative complications were reported and no extra-port was added in any of the patients. The following table shows the mean age, operative time, hospital stay, VAS as well as the overall mean of different LESS procedures. In all patients the umbilical scar was invisible and all patients and their parents had high wound satisfaction. At a mean follow up of 18.6 +/- 6.4 months, all patients with UPJO had successful repair. DISCUSSION: Our study included 13 boys with undescended testis who were managed in different ways according to the length of spermatic vessels and the size of the testis. One of the arguments against LESS management of undescended testis is that it requires a 2.5-cm incision, which is collectively larger than a 5-mm camera and two 3-mm working ports of conventional laparoscopy. However, the Triport access can be inserted through a 12-15-mm single umbilical incision without any additional openings in the abdomen as required with conventional laparoscopy which may increase the risk of internal organ injury and other port-related complications. Our results of five LESS varicocelectomies correlate with reports in the literature; regarding the operative time and hospital stay. LESS pediatric nephrectomy has been reported by many authors and our results correlates with that have been published. Compared with conventional laparoscopic nephrectomy, LESS nephrectomy seems to have shorter operative time and hospital stay. Although both cases of LESS nephrectomy were on the right side, we did not add any extra-ports which could be related to technical modifications during the surgery as well as the experience of the surgeon. To date, few data are available about LESS pyeloplasty in pediatrics. Our study included three patients who had left LESS pyeloplasties. In these patients, no extra-port was added. Despite of the technical difficulty of intracorporeal suturing during LESS, LESS pyeloplasty seems to be feasible with adequate training. Our patients had short hospital stay, low VAS at discharge, received a low dose of NSAID as postoperative analgesic and in all cases there was high wound satisfaction. One of the limitations of the current study could be the selection criteria of the patients, with children younger than 3 years and children who may be more technically difficult, being excluded. Furthermore, the number of patients in some indications is small and more patients are required to give solid conclusions and detect possible complications. CONCLUSIONS: Our study demonstrates the technical feasibility and safety of LESS for both ablative and reconstructive pathologies in pediatrics. However, more applications including a larger scale of pediatric patients as well as prospective comparative studies with conventional laparoscopy, are necessary. PMID- 25459389 TI - The "flowerpot" sign: inference of poor renal function in high grade vesicoureteral reflux by calyceal orientation. AB - INTRODUCTION/OBJECTIVE: Modern radiographic advances have allowed for detailed and accurate imaging of not only urologic anatomy but also urologic function. The art of observational inference of subtle anatomic features and function from a static radiograph is being traded for new, more precise, and more expensive modalities. While the superiority of these methods cannot be denied, the total information provided in simpler tests should not be ignored. The relationship between high grade vesicoureteral reflux with the dilated calyces arranged cephalad to a dilated funnel-shaped renal pelvis on VCUG and reduced differential renal function has not been previously described, but has been anecdotally designated a "flowerpot" sign by our clinicians. We hypothesize that the appearance of a "flowerpot" kidney as described herein is an indicator of poor renal function in the setting of high grade VUR. STUDY DESIGN: IRB approval was obtained and 315 patients were identified from system-wide VCUG reports from 2004 2012 with diagnosed "high grade" or "severe" vesicoureteral reflux. Inclusion into the study required grade IV or V VUR on initial VCUG and an initial radionuclide study for determination of differential function. Patients with a solitary kidney, posterior urethral valve, multicystic dysplastic kidney, renal ectopia, or duplex collecting systems were excluded. Grade of reflux, angle of the inferior-superior calyceal axis relative to the lumbar spine, and differential uptake were recorded along with presence of the new "flowerpot" sign. Variables were analyzed using the Mann-Whitney U test to determine statistical significance. RESULTS: Fifty seven patients met inclusion criteria with 11 being designated as "flowerpot" kidneys. These "flowerpot" kidneys could be objectively differentiated from other kidneys with grade IV and/or grade V VUR both by inferior-superior calyceal axis (median angle, 52 degrees [37-66] vs. 13 degrees [2-37], respectively p < 0.001) and by differential renal uptake (median, 23% [5-49] vs. 45% [15-81], respectively p < 0.001). Likewise, there was no difference between either calyceal axis (median angle, 13 degrees [3-20] vs. 13 degrees [2-37]) or differential function (median, 48% [24-81] vs. 40% [15 66], p = 0.129) when comparing kidneys with grade IV and grade V VUR, respectively, that did not demonstrate the "flowerpot" sign. DISCUSSION/CONCLUSION: Grading of VUR is used to provide a common language for scientific discussion and determine prognosis for children with similar attributes. The dysmorphic calyceal system in the "flowerpot" kidneys supports the theory of abnormal renal blastema induction associated with abnormal differentiation of the ureteral bud. Even in the absence of urinary tract infections and/or pyelonephritis, renal abnormalities and decreased differential function can be observed on renal scintigraphy. This study also confirms the male predominance and functional similarities between grade 4 and 5 refluxing renal units. Recognizing this is a limited observational study based on imaging alone, the "flowerpot" sign is an indicator of the most severe form of grade 5 VUR but is only one factor in predicting long term overall renal prognosis. However, 14% (8/57) of our cohort had a relative uptake of less than 20% with 5 of these exhibiting the "flowerpot" sign. The "flowerpot" sign on VCUG can be used as indirect evidence of poor differential renal function and, therefore, useful in guiding parental expectations prior to formal functional imaging. PMID- 25459390 TI - Identification of subjects at risk of proximal advanced neoplasia for colorectal cancer screening. AB - Flexible sigmoidoscopy (FS) and colonoscopy are two commonly used screening tools for colorectal cancer (CRC), and FS mainly detects distal lesions. Colonoscopy resource is limited, yet there is no definite evidence on when flexible sigmoidoscopy is suitable as a screening alternative. This study evaluated the optimal cut-off score from a validated risk stratification system which best predicts proximal advanced neoplasia (PAN) by comparing the sensitivity, specificity and relative risk of PAN according to various cut-off scores. 5819 asymptomatic subjects aged between 50 and 70years (average age 57.7years, standard deviation (SD) 4.9) received colonoscopy between 2008 and 2014 in Hong Kong. Their prevalence of PAN was evaluated according to a prediction tool for colorectal neoplasia based on age, gender, smoking status, family history of CRC, body mass index (BMI) and diabetes (ranging from 0 to 6). One binary logistic regression model was performed with PAN as the outcome variable and the risk score as the variable tested for association. In multivariate regression analysis, risk score ?3 was associated with significantly higher risk of PAN (3.4 9.1%; AOR=3.18-8.09, p<0.001) when compared with those scoring 0. Risk scores 0-2 were associated with either insignificant or lower risks of PAN compared to the overall risk. Applying FS for screening those who scored 0-2 and colonoscopy for those who scored ?3 led to a very small proportion of PAN being missed (1.60%), whilst maintaining a high level of specificity (81.9%). Clinicians may use this scoring system to inform subjects and facilitate their choice between colonoscopy and FS. PMID- 25459391 TI - Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2. AB - AIM: To investigate the efficacy and safety of gemcitabine and platinum salt, with or without trastuzumab, in patients with locally advanced or metastatic urothelial carcinoma overexpressing Her2. METHODS: The main eligibility criterion was Her2 overexpression on immunohistochemistry (IHC 2+ or 3+) of primary tumour tissue confirmed by fluorescence in situ hybridisation (FISH). Patients were randomised to Arm A: gemcitabine 1000mg/m(2) (days 1 and 8) plus either cisplatin (70mg/m(2)) or carboplatin (AUC=5) (day 1 every 3 weeks) or Arm B: added trastuzumab (8mg/kg loading dose, then 6 mg/kg every 21 days until progression). The primary end-point was progression-free survival (PFS). RESULTS: Among 563 screened patients, 75 (13.3%) were Her2 positive (IHC 2+/3+ and FISH+) and 61 met all eligibility criteria (median age, 64 years; 54/61 males; 50/61 baseline ECOG PS 0-1; 11 locally advanced and 50 metastatic). There was no significant difference between Arms A and B in median PFS (10.2 versus 8.2 months, respectively, p=0.689), objective response rate (65.5% versus 53.2%, p=0.39), and median overall survival (15.7 versus 14.1 months, respectively, p=0.684). In an exploratory analysis, trastuzumab-treated patients receiving cisplatin rather than carboplatin-based chemotherapy fared better (PFS: 10.6 versus 8.0; OS: 33.1 versus 9.5 months). Myelosuppression was the main grade 3/4 toxicity. A case of grade 3 cardiotoxicity and one death from febrile neutropenia occurred in arm B. CONCLUSION: The unexpectedly low incidence of Her2 overexpression precluded the detection of a significant difference in efficacy on addition of trastuzumab to platinum-based chemotherapy with gemcitabine. However, the satisfactory tolerance of the combination warrants further studies, especially of the cisplatin-based combination, in well-defined patient subsets. PMID- 25459392 TI - A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action. METHODS: A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000mg/m(2) d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2) d1+8 and sunitinib 50mg p.o. d1-14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR). RESULTS: The confirmatory analysis of PFS was based on the intend-to treat (ITT) population (N=106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4-18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0-18.0 weeks; p=0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7-20.2%) for GEM and for 7.1% (95%-CI: 0.9-23.5%) for SUNGEM (p=0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4-22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3-19.3 weeks) for SUNGEM (p=0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6-49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1-37.6 weeks) for the SUNGEM (p=0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p=0.045, two sided log rank). CONCLUSIONS: The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity. PMID- 25459393 TI - Paclitaxel and bevacizumab with or without capecitabine as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a multicentre, open-label, randomised phase 2 trial. AB - BACKGROUND: The addition of bevacizumab to paclitaxel or capecitabine has demonstrated improved progression-free survival (PFS) and objective response rate (ORR) as compared with chemotherapy alone in patients with HER2-negative locally recurrent or metastatic breast cancer (LR/MBC). We evaluated the efficacy and safety of first-line therapy of paclitaxel and bevacizumab with or without capecitabine in patients with HER2-negative LR/MBC. METHODS: In this multicentre, open-label, randomised phase II trial, women with HER2-negative LR/MBC were randomly assigned in a 1:1 ratio to paclitaxel (90 mg/m2 intravenously [IV] on days 1, 8, and 15) and bevacizumab (10 mg/kg IV on days 1 and 15) every 4 weeks for six cycles, followed by bevacizumab (15 mg/kg IV on day 1) every 3 weeks (AT) or to paclitaxel (90 mg/m2 IV on days 1 and 8), bevacizumab (15 mg/kg IV on day 1) and capecitabine (825 mg/m2 orally twice daily on days 1-14) every 3 weeks for eight cycles, followed by bevacizumab and capecitabine at the same doses every 3 weeks (ATX). The primary end-point was investigator-assessed PFS. Secondary end points included ORR, duration of response, overall survival (OS) and safety. Exploratory analyses were conducted to evaluate the impact of capecitabine on OS and to validate a novel prognostic model. This trial is registered with EudraCT, number 2006-006058-83. FINDINGS: Median PFS was significantly longer in ATX as compared with AT (11.2 months versus 8.4 months; stratified hazard ratio (HR), 0.52; 95% confidence interval (CI), 0.41-0.67; p < 0.0001). The ORR in ATX patients with measurable disease (n = 268) was higher than that in AT (69% versus 51%; p = 0.01). The median duration of response was 6.8 versus 5.4 months for, respectively, ATX and AT (p < 0.0001). Median OS was 24.2 months for ATX and 23.1 months for AT (p = 0.53). The increased rate of grade 3-4 adverse events related to the addition of capecitabine, being hand-foot syndrome (34% versus 0% for AT) and neutropenia (20% versus 12% for AT), generally did not preclude continuation of treatment. Exploratory analyses indicated that (1) patients receiving capecitabine at some line for treatment have significantly improved OS and (2) a prognostic model can classify patients into three risk groups associated with OS. INTERPRETATION: In patients with HER2-negative LR/MBC, addition of capecitabine to paclitaxel and bevacizumab significantly improved PFS, ORR and response duration. This combination was reasonably well tolerated and may be considered of use as first-line treatment in rapidly progressive disease. FUNDING: F. Hoffmann La Roche Ltd, the Netherlands. PMID- 25459394 TI - Outcome of 3-day bleomycin, etoposide and cisplatin chemotherapeutic regimen for patients with malignant ovarian germ cell tumours: a Taiwanese Gynecologic Oncology Group study. AB - BACKGROUND: The combination of bleomycin, etoposide and cisplatin (BEP) is currently the most widely used treatment for malignant ovarian germ cell tumours (MOGCTs). The aim of this study was to evaluate the efficacy and adverse effects of the 3-day BEP regimen in Taiwan. The prognostic factors of the MOGCT patients were also analysed. PATIENTS AND METHODS: Two hundred and thirty-nine cases of MOGCTs were identified from the Taiwanese Gynecologic Oncology Group database, and 204 of those who received postoperative BEP chemotherapy were then analysed. RESULTS: The estimated rate of no evidence of disease was 94.0% for 204 patients with adjuvant BEP regimen. Seven grade 3/4 haematological adverse effects including four subjects with neutropenia, one with pancytopenia and two with neutropenic fever were recorded in the 853 total courses of chemotherapeutic cycles. The rates of haematological and non-haematological adverse effects were 0.82% and 2.3%, respectively. No treatment-related mortality was noted. In the analysis of prognostic factors, only tumour stage had a significant impact on disease recurrence (95% confidence interval (CI), 4.2-94.4, p < 0.001) and disease-related mortality (95% CI, 2.2-163.9, p = 0.007). CONCLUSIONS: The current 3-day adjuvant BEP regimen was effective and safe for patients with MOGCTs. PMID- 25459395 TI - First-line anthracycline-based chemotherapy for angiosarcoma and other soft tissue sarcoma subtypes: pooled analysis of eleven European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials. AB - BACKGROUND: Angiosarcoma is a rare subtype of soft tissue sarcoma (STS). Doxorubicinis the standard first-line chemotherapy for advanced STS. It is not known whether angiosarcoma response to anthracycline-based chemotherapy is different to other STS subtypes. METHODS: Pooled data were analysed from 11 prospective randomised and non-randomized European Organisation for Research and Treatment of Cancer (EORTC) clinical trials of first-line anthracycline-based chemotherapy for advanced STS. Baseline patient characteristics, chemotherapy response, progression free survival (PFS) and overall survival (OS) of angiosarcoma patients were compared with other STS patients. Analysis was performed to identify factors prognostic for angiosarcoma response to chemotherapy, PFS and OS. RESULTS: With a median follow-up of 4.2 years, data from 108 locally advanced and metastatic angiosarcoma patients and 2557 patients with other STS histologies were analysed. 25% of angiosarcoma patients had a complete or partial response to chemotherapy compared to 21% for other STS histotypes. The median PFS was 4.9 months and OS 9.9 months, which were not significantly different from other STS histotypes. In univariate analysis, bone metastases were an adverse prognostic factor for OS (hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.03-2.67; p = 0.036). Tumour grade was as an adverse prognostic factor for PFS (HR 1.72, 95% CI 1.01-2.92; p = 0.044) and OS (HR 2.03; 95% CI 1.16-3.56; p = 0.011). Compared to single agent anthracyclines, doxorubicin + ifosfamide was associated with improved PFS (HR 0.53, 95% CI 0.33 0.86; p = 0.010) and OS (HR 0.53, 95% CI 0.32-0.90; p = 0.018). CONCLUSIONS: Angiosarcoma response and survival following first-line anthracycline-based chemotherapy was similar to other STS histotypes. Our analysis provides a useful measure of angiosarcoma response to chemotherapy for comparison with future clinical trials. PMID- 25459396 TI - Growth deceleration in children treated with imatinib for chronic myeloid leukaemia. AB - PURPOSE: The aim is to study statural growth in a large cohort of children with chronic myeloid leukaemia (CML) treated with front-line imatinib. METHODS: Retrospective data from 81 children less than 18 years of age with CML identified in the French pediatric registry were analysed. Height was expressed as standard deviation score (SDS). RESULTS: A gradual decrease in height SDS was observed over time since starting imatinib. The height SDS was significantly lower 12 months and 24 months after the start of imatinib overall (p < 10(-4)) irrespective of gender and pubertal age. The height SDS was significantly (p < 10(-4)) lower 12 months after the start of imatinib in boys and girls, and in the prepubertal age group as well as in the postpubertal age group, respectively. A similar finding was observed in the subgroups of boys and girls starting imatinib at a prepubertal or postpubertal age. Loss in height SDS 12 months after the start of imatinib was of the same range in boys when compared to girls and in patients who started imatinib at a prepubertal age compared to those who started at a postpubertal age. CONCLUSION: Growth velocity was altered during the first years of imatinib treatment in boys as well as in girls and in prepubertal age patients as well as in adolescents. PMID- 25459397 TI - A comparison of function after limb salvage with non-invasive expandable or modular prostheses in children. AB - BACKGROUND: Modular and non-invasive expandable prostheses have been developed to provide a functional knee joint that allows future expansion as growth occurs in the contralateral extremity in children with bone sarcomas that require removal of the growth plate. This study aimed to evaluate the functional outcomes of paediatric patients who received either a non-invasive expandable or modular prosthesis for bone sarcomas arising around the knee. METHODS: We evaluated clinician-reported, patient-reported and measured function in 42 paediatric patients at least one year (median age at assessment 19.1 years) after limb salvage surgery, and compared patients who received modular system prostheses (N = 29, median age 15.5), who did not require lengthening procedures to those who received non-invasive expandable prostheses (N = 13, median age 11.1) requiring lengthening procedures (median 5). RESULTS: The number of revisions and time to first revision did not differ between the two groups. There were no differences between the two groups in total scores on the Enneking Musculoskeletal Tumor Society Scale, the Toronto Extremity Salvage Scale, and the Functional Mobility Assessment. Children with non-invasive expandable prostheses climbed stairs (11.93 +/- 4.83 versus 16.73 +/- 7.24 s, p = 0.02) in less time than those with modular prostheses. CONCLUSION: Our results suggest that the non-invasive expandable prosthesis produces similar functional results to the more traditional modular prosthesis. PMID- 25459398 TI - No change in lymph node positivity rate despite increased lymph node yield and improved survival in colon cancer. AB - AIM: To analyse trends over time in the number of lymph nodes evaluated and in the proportion of node positivity and to investigate the impact on survival for patients with colon cancer. PATIENTS AND METHODS: 8616 patients resected for M0 colon cancer diagnosed in the southern Netherlands between 2000 and 2011 were included in this study. Trends in nodal evaluation and node positivity were analysed. Multivariable logistic regressions were used to assess the influence of period of diagnosis on adequate nodal evaluation (P12 lymph nodes) and no depositivity after adjusting for patient and tumour characteristics. Crude 5-year relative survival was used as an estimate for disease-specific survival. RESULTS: Overall, the proportion adequate nodal evaluation increased from 13% in 2000-2002 to 59% in 2009-2011 (p < 0.0001), whereas the proportion node positivity remained similar across study periods (approximately 35%). Patients diagnosed in later periods were more likely to have received adequate nodal yield (adjusted Odds ratio (OR) 2009-2011 versus 2000-2002 9.8, 95% Confidence interval (CI) 8.3 11.6). However, the adjusted odds of having node positive disease did not differ between periods of diagnosis. Relative excess risk of dying was independently correlated with the number of lymph nodes evaluated (1-8 LNs versus P12 LNs, N0: 2.2, 95% CI 1.7-2.9; N+: 1.7, 95% CI 1.4-2.0) and period of diagnosis (2009-2011 versus 2000-2002, N+ only: 0.8, 95% CI 0.6-1.0). CONCLUSION: The reason for improved survival with increased nodal yield is different from simple understaging as the proportion of lymph node positivity remained constant. PMID- 25459399 TI - Going underground: root traits as drivers of ecosystem processes. AB - Ecologists are increasingly adopting trait-based approaches to understand how community change influences ecosystem processes. However, most of this research has focussed on aboveground plant traits, whereas it is becoming clear that root traits are important drivers of many ecosystem processes, such as carbon (C) and nutrient cycling, and the formation and structural stability of soil. Here, we synthesise emerging evidence that illustrates how root traits impact ecosystem processes, and propose a pathway to unravel the complex roles of root traits in driving ecosystem processes and their response to global change. Finally, we identify research challenges and novel technologies to address them. PMID- 25459400 TI - Alterations of gut barrier and gut microbiota in food restriction, food deprivation and protein-energy wasting. AB - Increasing evidence shows that gut microbiota composition is related to changes of gut barrier function including gut permeability and immune function. Gut microbiota is different in obese compared to lean subjects, suggesting that gut microbes are also involved in energy metabolism and subsequent nutritional state. While research on gut microbiota and gut barrier has presently mostly focused on intestinal inflammatory bowel diseases and more recently on obesity and type 2 diabetes, this review aims at summarizing the present knowledge regarding the impact, in vivo, of depleted nutritional states on structure and function of the gut epithelium, the gut-associated lymphoid tissue (GALT), the gut microbiota and the enteric nervous system. It highlights the complex interactions between the components of gut barrier in depleted states due to food deprivation, food restriction and protein energy wasting and shows that these interactions are multidirectional, implying the existence of feedbacks. PMID- 25459402 TI - Optimal loading regimen and achievement of trough concentrations for teicoplanin using Japanese population parameters. PMID- 25459403 TI - Wiring mechanisms for olfaction and vision--not completely different after all. AB - Gradients of repulsive EphrinAs in the target were thought to repel temporal retinal ganglion cell axons expressing high levels of EphA receptors. Now, in this issue of Neuron, Suetterlin and Drescher (2014) show that EphrinA expressed on nasal axons contributes to the repulsion of temporal axons. PMID- 25459401 TI - Evaluation of the efficiency of cefoxitin/cefepime combination against Enterobacteriaceae resistant to expanded-spectrum cephalosporins. PMID- 25459404 TI - Learn to forget: regulation of age-related memory impairment by neuronal-glial crosstalk. AB - Dementia is among the most feared complications of aging in the U.S. In this issue of Neuron, Yamazaki et al. (2014) present a tour de force mechanistic analysis of a "hit" from a proteomic screen carried out using a Drosophila mutation that affects memory. PMID- 25459405 TI - TRPV1 channels: not so inactive on the ER. AB - In this issue of Neuron, Wong et al. (2014) report a remarkable evolutionarily conserved role for the Drosophila TRPV1 homolog Inactive controlling synaptic growth at larval neuromuscular junctions by facilitating Ca(2+) release from the endoplasmic reticulum. PMID- 25459406 TI - When is the time for a change? Decomposing dynamic learning rates. AB - Humans flexibly weight incoming evidence when updating beliefs and adjusting behavior. In the current issue of Neuron, McGuire et al. (2014) show how distinct neuronal correlates of main factors underlying this weighting converge on a common mechanism driving belief updates. PMID- 25459407 TI - Combining decoder design and neural adaptation in brain-machine interfaces. AB - Brain-machine interfaces (BMIs) aim to help people with paralysis by decoding movement-related neural signals into control signals for guiding computer cursors, prosthetic arms, and other assistive devices. Despite compelling laboratory experiments and ongoing FDA pilot clinical trials, system performance, robustness, and generalization remain challenges. We provide a perspective on how two complementary lines of investigation, that have focused on decoder design and neural adaptation largely separately, could be brought together to advance BMIs. This BMI paradigm should also yield new scientific insights into the function and dysfunction of the nervous system. PMID- 25459410 TI - [Representation of women in health-related scientific societies in Spain in 2014]. AB - OBJECTIVE: To describe the presence of women in the governance of health-related scientific societies in Spain today. METHODS: Spanish scientific societies were identified by vising the websites of the Ministry of Health, Social Services and Equality, and Fisterra. The sex of the president, executive officers and the board of directors was identified. Data were analyzed according to the overall percentage of women and by profession and setting. RESULTS: Of 173 scientific societies in July 2014, 41 had a female president (22.53%). Women held 35.45% of executive positions and accounted for 36.32% of the boards of directors. Only 16.07% of medical societies had a female president compared with 76.92% of nursing societies. Primary care societies had more women in executive positions (54.55%) than societies in which the professional activity of members involved both primary and secondary care (35.74%) and societies related to hospital care (27.93%). CONCLUSION: There is a lack of parity, which is greater in nursing and primary care societies than in medical and hospital-related societies. Parity decreases as the level of responsibility rises. PMID- 25459409 TI - Functionally dissociable influences on learning rate in a dynamic environment. AB - Maintaining accurate beliefs in a changing environment requires dynamically adapting the rate at which one learns from new experiences. Beliefs should be stable in the face of noisy data but malleable in periods of change or uncertainty. Here we used computational modeling, psychophysics, and fMRI to show that adaptive learning is not a unitary phenomenon in the brain. Rather, it can be decomposed into three computationally and neuroanatomically distinct factors that were evident in human subjects performing a spatial-prediction task: (1) surprise-driven belief updating, related to BOLD activity in visual cortex; (2) uncertainty-driven belief updating, related to anterior prefrontal and parietal activity; and (3) reward-driven belief updating, a context-inappropriate behavioral tendency related to activity in ventral striatum. These distinct factors converged in a core system governing adaptive learning. This system, which included dorsomedial frontal cortex, responded to all three factors and predicted belief updating both across trials and across individuals. PMID- 25459411 TI - Adjusting the focus of transoral robotic surgery. PMID- 25459408 TI - Studying brain organization via spontaneous fMRI signal. AB - In recent years, some substantial advances in understanding human (and nonhuman) brain organization have emerged from a relatively unusual approach: the observation of spontaneous activity, and correlated patterns in spontaneous activity, in the "resting" brain. Most commonly, spontaneous neural activity is measured indirectly via fMRI signal in subjects who are lying quietly in the scanner, the so-called "resting state." This Primer introduces the fMRI-based study of spontaneous brain activity, some of the methodological issues active in the field, and some ways in which resting-state fMRI has been used to delineate aspects of area-level and supra-areal brain organization. PMID- 25459412 TI - Chondroid hamartoma of the larynx: An exceptional case. PMID- 25459414 TI - Is it possible to shorten examination time in posture control studies? AB - INTRODUCTION AND OBJECTIVES: The sensory organization test (SOT) is the gold standard test for the study of postural control with posturographic platforms. Three registers of Conditions 3, 4, 5 and 6 are conducted to find an arithmetic mean of the 3, with the time that this entails. The aim of this study was to determine whether a single record for each SOT condition would give us the same information as the arithmetic mean of the 3 recordings used until now. MATERIALS AND METHODS: 100 healthy individuals who performed a sensory organisation test in the Smart Balance Master((r)) Neurocom platform. For the statistical analysis we used the Wilcoxon test for nonparametric variables and dependent t-student for paired samples for parametric variables (P<.05). RESULTS: When comparing the scores on the first record with the average of the 3 records, we found statistically significant differences for the 4 conditions (P<0.05). Comparing the first record to the second record also yielded statistically significant differences in the 4 conditions (P<.05). Upon comparing the second record with the third, however, we found differences in only Condition 5, with the significance being borderline (P=.04). Finally, comparing the average of the first and second record with the average of the 3 records, we also found statistically significant differences for the 4 conditions (P<.05). CONCLUSION: Using only 1 or 2 records from each of the conditions on the SOT does not give us the same information as the arithmetic average of the 3 records used until now. PMID- 25459413 TI - Our experience with facial nerve monitoring in vestibular schwannoma surgery under partial neuromuscular blockade. AB - INTRODUCTION AND OBJECTIVES: Facial nerve monitoring is fundamental in the preservation of the facial nerve in vestibular schwannoma surgery. Our objective was to analyse the usefulness of facial nerve monitoring under partial neuromuscular blockade. METHODS: This was a retrospective analysis of 69 patients operated in a tertiary hospital. RESULTS: We monitored 100% of the cases. In 75% of the cases, we could measure an electromyographic response after tumour resection. In 17 cases, there was an absence of electromyographic response. Fifteen of them had an anatomic lesion with loss of continuity of the facial nerve and, in 2 cases, there was a lesion with preservation of the nerve. Preoperative facial palsy (29% 7%; P=.0349), large tumour size (88 vs. 38%; P=.0276), and a non-functional audition (88 vs. 51%; P=.0276) were significantly related with an absence of electromyographic response. CONCLUSIONS: Facial nerve monitoring under neuromuscular blockade is possible and safe in patients without previous facial palsy. If the patient had an electromyographic response after tumour excision, they developed better facial function in the postoperative period and after a year of follow up. PMID- 25459415 TI - Pneumolabyrinth: An atypical complication in a cochlear implant. PMID- 25459416 TI - Perspectives for the treatment of sensorineural hearing loss by cellular regeneration of the inner ear. AB - Sensorineural hearing loss is a caused by the loss of the cochlear hair cells with the consequent deafferentation of spiral ganglion neurons. Humans do not show endogenous cellular regeneration in the inner ear and there is no exogenous therapy that allows the replacement of the damaged hair cells. Currently, treatment is based on the use of hearing aids and cochlear implants that present different outcomes, some difficulties in auditory discrimination and a limited useful life. More advanced technology is hindered by the functional capacity of the remaining spiral ganglion neurons. The latest advances with stem cell therapy and cellular reprogramming have developed several possibilities to induce endogenous regeneration or stem cell transplantation to replace damaged inner ear hair cells and restore hearing function. With further knowledge of the cellular and molecular biology of the inner ear and its embryonic development, it will be possible to use induced stem cells as in vitro models of disease and as replacement cellular therapy. Investigation in this area is focused on generating cellular therapy with clinical use for the treatment of profound sensorineural hearing loss. PMID- 25459417 TI - Association between defense mechanisms and psychiatric symptoms in North Korean Refugees. AB - OBJECTIVE: Defense mechanism may contribute to psychiatric symptoms. Refugees are vulnerable to various psychiatric symptoms, such as depression, anxiety, somatization, and those associated with post-traumatic stress disorder (PTSD), due to their traumatic or stressful experiences. We aimed to investigate the mediating role of each defense mechanism in the occurrence of specific psychiatric symptoms in North Korean refugees. METHOD: Among 213 North Korean refugees initially recruited, 201 completed the following questionnaires: the Defense Style Questionnaire, the Center for Epidemiological Studies-Depression Scale (CES-D), the State-Trait Anxiety Inventory-State (STAI-S), the somatization subscale of Symptom Check-List-90-Revised (SCL-90-R), and the Impact of Event Scale-Revised (IES-R). Stepwise regression analysis was performed to determine the defense mechanisms more predominantly associated with specific psychiatric symptoms after controlling for age, sex, number of traumatic experiences, and other psychiatric symptoms (depressive symptoms and/or anxiety). RESULTS: Higher levels of depression were independently predicted by greater use of resignation. More use of acting out and less use of humor and sublimation independently predicted higher levels of anxiety. Somatization was independently predicted by more use of inhibition. PTSD symptoms were independently predicted by more use of undoing and isolation. CONCLUSIONS: Specific psychiatric symptoms were associated with specific defense mechanisms in North Korean refugees. Our findings suggest that the manifest psychiatric symptoms of refugees may be mediated by their dominant defense mechanism. PMID- 25459418 TI - Self-perceived cognitive functioning and its relationship with objective performance in first-episode schizophrenia: the Subjective Cognitive Impairment Scale. AB - BACKGROUND: Self-perceived cognitive dysfunction is under-recognized in clinical practice and under-studied in schizophrenia, particularly in the early illness stage. Findings on the relationship between subjective and objective cognitive measures were inconsistent. This study aimed to examine psychometric properties of a newly developed scale, Subjective Cognitive Impairment Scale (SCIS) and to investigate the relationship of self-reported ratings with objective test performance in first-episode schizophrenia. METHODS: One hundred one Chinese patients aged 18 to 64years presenting with first episode schizophrenia-spectrum disorder were studied. A comprehensive set of assessments examining objective cognitive functioning, clinical and treatment characteristic were administered. Internal consistency, factor structure and construct validity of SCIS were evaluated. Correlations of scale score with objective cognitive measures, clinical and treatment variables were examined. RESULTS: A single-factor underlying the structure of SCIS items was demonstrated by principal components analysis. Cronbach's alpha coefficient for the scale was 0.92. SCIS score was positively correlated with depression and anxiety symptom severity, and duration of untreated psychosis. SCIS score was not associated with other symptom dimensions, insight and chlorpromazine equivalents. No significant correlations were observed between SCIS score and objective cognitive measures with the exception of letter-number span test. CONCLUSION: Our results provided preliminary evidence in support of reliability and validity of SCIS in evaluating patient's cognitive complaints. A lack of correspondence between subjective and objective cognitive functioning suggested that they may represent two distinct constructs with potentially differential therapeutic implications. Further research is warranted to examine ecological validity and clinical utility of the scale. PMID- 25459419 TI - Age-related differences in suicidality between young people and older adults with depression: data from a nationwide depression cohort study in Korea (the CRESCEND study). AB - This study compared young people and older adults with depression to identify differences in suicidality between these groups. A total of 1003 patients with moderate to severe depression (Hamilton Depression Rating Scale [HDRS] score >=14) were recruited from a national sample of 18 hospitals. Of the patients included in this study, 103 (10.3%) were placed in the younger group (age <25years) and 900 (89.7%) were placed in the older group (age >=25years). Suicide related variables and predictive factors associated with significant suicidal ideation were compared between the two groups. Regardless of the severity of depression, subjects in the younger group were more likely than were those in the older group to report significant suicidal ideation (scores >=6 on the Beck Scale for Suicide Ideation [SSI-B], 79.6 vs. 53.7%, respectively; p<0.001), have had a suicide attempt at the current episode (4.9 vs. 1.6%, respectively; p=0.037), and have a history of suicide attempts (43.7 vs. 19.4%, respectively; p<0.001). Logistic regression models revealed that, in contrast to the predictive factors in the older group, subjects in the younger group were more affected by their history of suicide attempts (OR [95% CI]: 12.4, [1.5-99.1]; p=0.018) and depressive episodes (OR [95% CI]: 13.0, [1.6-104.0]; p=0.016). Also in contrast to the older group, an increase in HDRS score was not identified as a possible precipitating factor of significant suicidal ideation in younger subjects. The present findings demonstrate that suicidality in depressed young people was more severe than in older adults, but that suicidality was not correlated with the severity of depression. These data suggest that close attention should be paid to young people even in mild or moderate depression. PMID- 25459420 TI - Sex addiction and gambling disorder: similarities and differences. AB - OBJECTIVE: Recently, the DSM-5 has developed a new diagnostic category named "Substance-related and Addictive Disorders". This category includes gambling disorder (GD) as the sole behavioral addiction, but does not include sex addiction (SA). The aim of this study is to investigate whether SA should be classified more closely to other behavioral addictions, via a comparison of the personality characteristics and comorbid psychopathology of individuals with SA with those of individuals with GD, which comes under the category of addiction and related disorders. METHOD: The sample included 59 patients diagnosed with SA, who were compared to 2190 individuals diagnosed with GD and to 93 healthy controls. Assessment measures included the Diagnostic Questionnaire for Pathological Gambling, the South Oaks Gambling Screen, the Symptom CheckList-90 Items-Revised and the Temperament and Character Inventory-Revised. RESULTS: No statistically significant differences were found between the two clinical groups, except for socio-economic status. Although statistically significant differences were found between both clinical groups and controls for all scales on the SCL 90, no differences were found between the two clinical groups. The results were different for personality characteristics: logistic regression models showed that sex addictive behavior was predicted by a higher education level and by lower scores for TCI-R novelty-seeking, harm avoidance, persistence and self transcendence. Being employed and lower scores in cooperativeness also tended to predict the presence of sex addiction. CONCLUSIONS: While SA and GD share some psychopathological and personality traits that are not present in healthy controls, there are also some diagnostic-specific characteristics that differentiate between the two clinical groups. These findings may help to increase our knowledge of phenotypes existing in behavioral addictions. PMID- 25459421 TI - Bulls grazing Kentucky 31 tall fescue exhibit impaired growth, semen quality, and decreased semen freezing potential. AB - Serum prolactin (PRL) and testosterone concentrations, body weight, body composition, semen quality, and semen freezing potential for bulls grazing the toxic tall fescue (Lolium arundinaceum [Schreb.] Darbysh. = Schedonorous arundinaceum [Schreb.] Dumort.) cultivar Kentucky 31 (E+) compared with a novel endophyte cultivar lacking ergot alkaloids (E-) were evaluated. Angus bulls were allotted to treatment (Day 0) and grazed E+ or E- for 155 days. Treatment-by-day interaction was significant (P < 0.05) for serum PRL concentrations with E+treated bulls exhibiting reduced PRL values compared with E- control bulls, but no differences were observed for serum testosterone concentrations (P > 0.05). Further, bulls on the E+ treatment exhibited decreased total gain, average daily gain, and body weight by Day 140 (P < 0.05) compared with the E- bulls. Rump muscle depth was lower because the treatment in bulls grazing E+ compared with E- (P < 0.05) and intramuscular fat in the E- bulls compared with the E+ group was higher by Day 155 (P < 0.05). Analysis of ejaculates showed significant treatment * day effects for sperm concentration with lower values observed for bulls on the E+ treatment (P < 0.05). The percent normal morphology was reduced in ejaculates from E+ bulls compared with E- bulls (P < 0.05), and the difference was due to an increase in abnormal sperm present in the E+ ejaculates from Day 84 to 140 (P < 0.05). In addition, spermatozoa motility and progressive motility were decreased on thawing in semen samples from E+ bulls compared with E- bulls (P < 0.05). PMID- 25459422 TI - Combining reduced glutathione and ascorbic acid has supplementary beneficial effects on boar sperm cryotolerance. AB - The main aim of this work was to evaluate how supplementing freezing and thawing media with reduced glutathione (GSH) and l-ascorbic acid (AA) affected the quality parameters of frozen-thawed boar spermatozoa. With this purpose, semen samples of 12 ejaculates coming from 12 boars were used. Each ejaculate was split into seven aliquots to which 5 mM of GSH and 100 MUM of AA were added separately or together at two different steps of freeze-thawing. Various sperm parameters (levels of free cysteine residues in sperm nucleoproteins, sperm viability, acrosome membrane integrity, intracellular peroxide and superoxide levels [ROS], and total and progressive motility) were evaluated before freezing and at 30 and 240 minutes after thawing. Both GSH and AA significantly improved boar sperm cryotolerance when they were separately added to freezing and thawing media. However, the highest improvement was recorded when both freezing and thawing media were supplemented with 5 mM of GSH plus 100 MUM of AA. This improvement was observed in sperm viability and acrosome integrity, sperm motility, and nucleoprotein structure. Although ROS levels were not much increased by freeze thawing procedures, the addition of GSH and AA to both freezing and thawing extenders significantly decreased intracellular peroxide levels and had no impact on superoxide levels. According to our results, we can conclude that supplementation of freezing and thawing media with both GSH and AA has a combined, beneficial effect on frozen-thawed boar sperm, which is greater than that obtained with the separate addition of either GSH or AA. PMID- 25459423 TI - Blastocele fluid from in vitro- and in vivo-produced equine embryos contains nuclear DNA. AB - Normal mammalian early embryonic development involves apoptosis of blastomeres as a remodeling process during differentiation, starting at the blastocyst stage. Genomic DNA has been recently detected in the blastocele fluid of human embryos and has been amplified by real-time polymerase chain reaction (PCR) to diagnose the sex of in vitro-produced human embryos. This new approach varies from conventional preimplantation genetic diagnosis in that no cells are extracted from the embryo and only the blastocele fluid is aspirated and used as a DNA sample for diagnosis. In the present work, we investigated whether the blastocele fluid of equine preimplantation embryos contains nuclear DNA and whether this DNA could be used to diagnose the sex of the embryos by conventional PCR, using specific primers that target the TSPY and AMEL equine genes. The sex of 11 of 13 in vivo-produced embryos and of four of five in vitro-produced embryos was successfully diagnosed. The PCR amplification product was analyzed using genetic sequencing reporting that the DNA present in blastocele fluid was genomic. Additionally, after polyacrylamide gel electrophoresis and silver staining, the blastocele fluid from three different embryos produced a ladder pattern characteristic of DNA fragmented during apoptosis. Therefore, the results presented in this work report that blastocele fluid from in vivo- and in vitro produced equine embryos contains nuclear DNA which is probably originated by apoptosis of embryonic cells, and this DNA could be used to diagnose the sex of preimlpantation embryos by conventional PCR. PMID- 25459424 TI - Analysis of hygienic critical control points in boar semen production. AB - The present study addresses the microbiological results of a quality control audit in artificial insemination (AI) boar studs in Germany and Austria. The raw and processed semen of 344 boars in 24 AI boar studs were analyzed. Bacteria were found in 26% (88 of 344) of the extended ejaculates and 66.7% (18 of 24) of the boar studs. The bacterial species found in the AI dose were not cultured from the respective raw semen in 95.5% (84 of 88) of the positive samples. These data, together with the fact that in most cases all the samples from one stud were contaminated with identical bacteria (species and resistance profile), indicate contamination during processing. Microbiological investigations of the equipment and the laboratory environment during semen processing in 21 AI boar studs revealed nine hygienic critical control points (HCCP), which were addressed after the first audit. On the basis of the analysis of the contamination rates of the ejaculate samples, improvements in the hygiene status were already present in the second audit (P = 0.0343, F-test). Significant differences were observed for heating cabinets (improvement, P = 0.0388) and manual operating elements (improvement, P = 0.0002). The odds ratio of finding contaminated ejaculates in the first and second audit was 1.68 (with the 95% confidence interval ranging from 1.04 to 2.69). Furthermore, an overall good hygienic status was shown for extenders, the inner face of dilution tank lids, dyes, and ultrapure water treatment plants. Among the nine HCCP considered, the most heavily contaminated samples, as assessed by the median scores throughout all the studs, were found in the sinks and/or drains. High numbers (>10(3) colony-forming units/cm(2)) of bacteria were found in the heating cabinets, ejaculate transfer, manual operating elements, and laboratory surfaces. In conclusion, the present study emphasizes the need for both training of the laboratory staff in monitoring HCCP in routine semen production and audits in such AI centers for the external control of hygiene parameters. PMID- 25459425 TI - Localization and functional modification of L-type voltage-gated calcium channels in equine spermatozoa from fresh and frozen semen. AB - It is well known that insemination of cryopreserved semen always results in lower fertility when compared with fresh semen, but there is an increased interest and demand for frozen equine semen by the major breeder associations because of the utility arising from semen already "on hand" at breeding time. In this article, we report that equine sperm cells express L-type voltage-gated calcium channels; their localization is restricted to sperm neck and to the principal piece of the tail in both fresh and frozen-thawed spermatozoa. We also studied the causes of cryoinjury at the membrane level focusing on the function of L-type calcium channels. We report that in cryopreserved spermatozoa the mean basal value of [Ca(2+)]i is higher than that of spermatozoa from fresh semen (447.130 vs. 288.3 nM; P < 0.001) and L-type channels function differently in response to their agonist and antagonist in relation to semen condition (fresh or frozen-thawed). We found that on addition of agonist to the culture medium, the increase in intracellular calcium concentrations ([Ca(2+)]i) was greater in frozen semen than in fresh semen (Delta[Ca(2+)]i = 124.59 vs. 16.04 nM; P < 0.001), whereas after the addition of antagonist the decrease in [Ca(2+)]i was lower in frozen semen than in fresh semen (Delta[Ca(2+)]i = 32.5 vs. 82.5 nM; P < 0.001). In this article, we also discuss the impact of cryopreservation on sperm physiology. PMID- 25459426 TI - Differential expression of microRNAs in sexually immature and mature canine testes. AB - Mammalian testis exhibits spatiotemporal gene expression patterns that are essential for successful and continuous spermatogenesis. Although microRNAs (miRNAs) modify gene expression through translational repression and degradation of target messenger RNAs, the precise molecular mechanisms of these regulatory processes are unclear. We used canine miScript miRNA polymerase chain reaction (PCR) Array technology to elucidate the repertoire of canine testis miRNAs and compared their expression patterns between sexually immature (prepubertal) and mature (adult) dog testes. Eighty-four well-characterized canine miRNAs were customized in this study. The data were analyzed by RT(2) Profiler PCR Array Data Analysis (version 3.5). Results identified upregulation of 32 and considerable downregulation of 12 miRNAs in adult dog testis. In conclusion, the two developmental stages had significantly different miRNAs expression patterns. The finding provides fundamental information of miRNAs which may help to elucidate their role in spermatogenesis and male infertility in this species. To the best of our knowledge, this study is the first to offer comparative profile of the miRNA transcriptome in prepubertal and adult canine testes using miRNA PCR array approach. PMID- 25459427 TI - Immunotherapeutic vitamin E nanoemulsion synergies the antiproliferative activity of paclitaxel in breast cancer cells via modulating Th1 and Th2 immune response. AB - Paclitaxel (PTX) is used as first line treatment for metastatic breast cancer but the relief comes at a heavy cost in terms of accompanying adverse effects. The pharmaceutical credentials of PTX are further dampened by the intrinsically low aqueous solubility. In order to sideline such insidious tendencies, PTX was incorporated in a vitamin E nanoemulsion using high pressure homogenization. The encapsulation efficiency of PTX in nanoemulsion was 97.81+/-2.7% and a sustained drug release profile was obtained. PTX loaded nanoemulsion exhibited higher cytotoxicity in breast cancer cell line (MCF-7) when compared to free PTX and marketed formulation (Taxol). Cell cycle arrest study depicted that MCF-7 cells treated with PTX loaded nanoemulsion showed high arrest in G2-M phase. Moreover blank nanoemulsion induced additional apoptosis in breast cancer cells through G1 S arrest by disrupting mitochondrial membrane potential. Cytokine estimation study in macrophages showed that both PTX loaded nanoemulsion and blank nanoemulsion enhanced secretion of IL-12 and downregulated secretion of IL-4 and IL-10. Results suggest that inclusion of vitamin E in nanoemulsion opened multiple complementary molecular effects which not only magnified the principle antiproliferative activity of PTX but also independently showcased potential in restoring the proactive nature of the breast cancer slackened chronic immune response. In-vivo anticancer activity showed significantly improved efficacy of PTX loaded nanoemlsion compare to Taxol and free PTX. The list of plausible advantages of PTX nanoemulsification was further substantiated by acceptable haemolytic potential, reduced in-vivo toxicity and conveniently modified pharmacokinetic profile in which the AUC and MRT were extended considerably. Overall, there were strong evidences that developed formulation can serve as a viable alternative to currently available PTX options. PMID- 25459428 TI - Drug delivery in aortic valve tissue engineering. AB - Over the last 50 years medicine and technology have progressed to the point where it has become commonplace to safely replace damaged or diseased heart valves with mechanical and biological prostheses. Despite the advancements in technology current valve substitutes continue to have significant limitations with regards to thrombogenicity, durability, and inability to grow or remodel. In an attempt to overcome the limitations of currently available valve prosthesis, heart valve tissue engineering has emerged as a promising technique to produce biological valve substitutes. Currently, the field of tissue engineering is focused on delivering complex matrices which include scaffolds and cells separately or together to the damaged site. Additional functional enhancement of the matrices by exposing encoded biological signals to their residing cells in a controlled manner has the potential to augment the tissue engineering approach. This review provides an overview of the delivery of biological reagents to guide and regulate heart valve tissue engineering. PMID- 25459429 TI - Rabies--an important zoonotic threat for travelers. PMID- 25459431 TI - Transfusion transmitted leishmaniasis. What to do with blood donors from endemic areas? AB - Leishmaniasis clinical spectrum ranges from cryptic infection to fatal visceral leishmaniasis. Cryptic infection can be found in blood donors from areas endemic for leishmaniasis all over the world. Although leishmaniasis is a classic vector borne disease, cases of transfusion transmitted leishmaniasis have been reported especially in nonendemic areas. Most of these cases regarded infants or children. This paper reviews the literature on this specific feature and the impact of leishmaniasis on transfusion medicine. Relevant literature was found through PubMed. The reference lists of selected articles identified further sources. CONCLUSIONS: Blood donations by emigrants or travelers from endemic areas require special attention. Routine diagnostic methods should be implemented in blood banks to exclude donors that are positive for Leishmania, and individuals who suffered from visceral leishmaniasis should be prohibited from donating blood. The use of leukodepletion filters at the time of collection should be recommended in at-risk areas especially for high-risk recipients. PMID- 25459430 TI - Ebola and travel--management of imported cases. PMID- 25459433 TI - Severe sandfly virus infection following domestic travel to the Negev desert. PMID- 25459432 TI - Rabies in Greece; historical perspectives in view of the current re-emergence in wild and domestic animals. AB - Greece has been rabies free since 1987 while no human cases have been seen since 1970. The re-emergence of rabies in Northern Greece during 2012-2013 in wild and domestic animals prompted a systematic review of historical evidence of the presence of the disease in the country from ancient years till the present. Historical data is presented along with efforts to prevent disease in animals and humans especially during the high prevalent periods in the country in the mid 20th century. These efforts serve as a guide to current extensive efforts to prevent spread especially in the wild and domestic animal populations. PMID- 25459434 TI - Effectiveness of pre-travel consultation in the prevention of travel-related diseases: a retrospective cohort study. AB - BACKGROUND: This study aims to evaluate the effectiveness of pre-travel counselling carried out in Travel Clinics. METHODS: This is a retrospective cohort. Three hundred international travellers were enrolled; 150 people were from users of Bari Travel Clinic, 150 were users of a travel agency. Enrolled subjects were interviewed using a questionnaire. RESULTS: The average age of the enrolled subjects was 37.5 +/- 13.9, without statistically significant differences between the two groups. 86% of cases and 19.3% of the controls reported the use of anti-malaria prophylaxis (p < 0.0001). Vaccination against cholera was given to 62% of cases and 7.3% of the controls (p < 0.001). Travel Clinic users, 6% reported diarrhoea and these figures were 27% in the control group (p < 0.0001). The proportion of those interviewed who reported fever (3.7) or insomnia (1.3) did not differ between the two groups. Mosquito bites were reported by 8% of cases and 20% of the controls (p = 0.003). Three cases of malaria were reported among the controls but no cases were detected among the cases (chi-square = 3.03; p = 0.08). CONCLUSIONS: Our study demonstrated the effectiveness of pre-travel counselling; in the future, new studies must investigate the cost-effectiveness of pre-travel prevention measures. PMID- 25459435 TI - This edition of Seminars in Pediatric Surgery focuses on diseases of the peritoneal cavity. Preface. PMID- 25459436 TI - Anatomy and physiology of the peritoneum. AB - The peritoneum is commonly encountered in abdominal surgery. The development and rotation of the primitive gut tube lead to the normal adult arrangement of the peritoneal cavity, which forms bloodless planes allowing the retroperitoneal portions of the bowel to be safely mobilised. The arrangement of the peritoneum also forms spaces in which infected fluid or pus can collect. The microcirculation of peritoneal fluid is now well understood, and the large absorptive surface of the peritoneum can be exploited in peritoneal dialysis. The absorption of gas by the peritoneum following abdominal surgery is faster in neonates than in older children, and understanding this process contributes to the interpretation of post-operative radiographs. PMID- 25459437 TI - Response to pathological processes in the peritoneal cavity--sepsis, tumours, adhesions, and ascites. AB - The peritoneum is one of the commonest sites for pathological processes in pediatric surgery. Its response to pathological processes is characterized by an inflammatory reaction with specific pathways depending on the type of injury or peritoneal process involved. This review discusses the current understanding of peritoneal inflammation, adhesion formation, intra-abdominal sepsis, peritoneal metastasis, and ascites and briefly reviews new therapeutic strategies to treat or prevent these pathological entities. Recent studies have improved the understanding of peritoneal responses, resulting in possible new targets for prevention and therapy. PMID- 25459438 TI - The biology of adhesion formation in the peritoneal cavity. AB - Intraperitoneal adhesions are frequently encountered and present significant challenges to the practicing surgeon, including increased operating time, bowel obstruction, pelvic pain, and infertility. Until recently, however, our knowledge of the biology of adhesion formation within the peritoneal cavity has been limited, which in turn limits prevention and treatment strategies for surgical patients. Extensive research has now led to an increased understanding of adhesion formation, with hypoxia playing a central role. Hypoxia stimulates a cascade that leads to oxidative stress, anaerobic metabolism, formation of free radicals, and ultimately the adhesion phenotype. By understanding the precipitants to adhesion development, we may begin to develop prevention and treatment therapies that will provide clinically significant improvement over the currently available approaches to limit postoperative adhesions. PMID- 25459439 TI - Epidemiology of adhesions in infants and children following open surgery. AB - Adhesions following intra-abdominal surgery are a major cause of small bowel obstruction. The nature of surgical interventions in children (especially neonates) increases the risk of adhesion-related complications. Following laparotomy in neonates, the collective literature reveals an aggregate mean incidence of adhesive small bowel obstruction (ASBO) of 6.2%; malrotation, 14.2%; gastroschisis, 12.6%; necrotising enterocolitis, 10.4%; exomphalos, 8.6%; Hirschsprung's disease, 8.1%; congenital diaphragmatic hernia, 6.3% and intestinal atresia, 5.7%. In children beyond the neonatal period, the aggregate mean incidence was 4.7%; colorectal surgery, 14%; open fundoplication, 8.2%; small bowel surgery, 5.7%; cancer surgery, 5.5%; choledochal cyst, 3.1%; appendicectomy, 1.4% and pyloromyotomy, 0.1%. PMID- 25459440 TI - Adhesive small bowel obstruction--acute management and treatment in children. AB - Adhesive small bowel obstruction is a significant cause of short- and long-term morbidity in infants and children. Unfortunately, the majority of scientific literature relative to adhesive obstructions continues to be dominated by adult studies. In this article, the existing literature for infant and pediatric adhesive obstructions is reviewed, with relevant comparisons to the available adult data. In addition, general guidelines for the management of infant and pediatric adhesive obstructions are recommended, based on the best available evidence. PMID- 25459441 TI - Role of laparoscopy in the prevention and in the treatment of adhesions. AB - The formation of adhesions after abdominal surgery can lead to increased morbidity in children, increases the incidence of readmission, and may pose a significant challenge to subsequent surgical care over their lifetime. As the pathophysiology of peritoneal adhesion formation has been better understood, preventive strategies that minimize surgical trauma and contamination have been sought. Laparoscopy, over the past few decades, has become an increasingly utilized approach for many pediatric surgical problems and intuitively should have an advantage over open surgery in reducing adhesion formation. In this review, we examine the utility of laparoscopy in both the prevention and the treatment of intraabdominal adhesive disease in children. PMID- 25459442 TI - Intra-abdominal sepsis--epidemiology, aetiology and management. AB - Peritonitis is a progressive disease leading inexorably from local peritoneal irritation to overwhelming sepsis and death unless this trajectory is interrupted by timely and effective therapy. In children peritonitis is usually secondary to intraperitoneal disease, the nature of which varies around the world. In rich countries, appendicitis is the principal cause whilst in poor countries diseases such as typhoid must be considered in the differential diagnosis. Where resources are limited, the clinical diagnosis of peritonitis mandates laparotomy for diagnosis and source control. In regions with unlimited resources, radiological investigation, ultrasound, CT scan or MRI may be used to select patients for non operative management. For patients with appendicitis, laparoscopic surgery has achieved results comparable to open operation; however, in many centres open operation remains the standard. In complicated peritonitis "damage control surgery" may be appropriate wherein source control is undertaken as an emergency with definitive repair or reconstruction awaiting improvement in the patient's general condition. Awareness of abdominal compartment syndrome is essential. Primary peritonitis in rich countries is seen in high-risk groups, such as steroid-dependent nephrotic syndrome patients, whilst in poor countries the at risk population is less well defined and the diagnosis is often made at surgery. PMID- 25459443 TI - Miscellaneous conditions of the peritoneal cavity--peritoneal tumors, pseudomyxoma, mesothelioma, fibroblastic reaction, cocoon, cystic lymphatic malformations, blue-bleb, and chylous ascites. AB - The peritoneum is subject to both primary neoplasia and secondary malignancy from direct, trans-coelomic, or hematogenous spread from any cancer. The knowledge base in the pediatric age group is very limited due to the rarity of peritoneal conditions in children, and much of the information is extrapolated from adult literature. There have been few reports in the pediatric population on the diagnosis and management of peritoneal conditions including peritoneal malignancy. In this article, we aim to highlight some of these conditions and the treatments available with a special emphasis on the evolving role of cytoreduction surgery and hyperthermic intraperitoneal chemotherapy in the treatment of certain peritoneal malignancies in children. PMID- 25459445 TI - Response to the letter from Gozzetti et al. entitled: "Oral low-dose fludarabine and cyclophosphamide with rituximab as initial treatment for elderly patients with chronic lymphoproliferative disorders". PMID- 25459444 TI - Lymphocyte/monocyte ratio and cycles of rituximab-containing therapy are risk factors for hepatitis B virus reactivation in patients with diffuse large B-cell lymphoma and resolved hepatitis B. AB - Reactivation of hepatitis B virus (HBV) following rituximab (R)-containing chemotherapy for lymphoma is a major concern, and risk factors remain to be defined. We enrolled 190 patients diagnosed with diffuse large B-cell lymphoma (DLBCL) and resolved hepatitis B, receiving first-line R-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone)-based regimens. Twenty-seven patients (14.2%) developed HBV reactivation during a median follow-up of 23.6 months. Two independent risk factors were identified: cycles of rituximab>8 (hazard ratio [HR], 2.797; 95% confidence interval [CI], 1.184-6.612) and lymphocyte/monocyte ratio (LMR)<2.50 (HR, 2.733; 95% CI, 1.122-6.657). Two-year overall survival in patients with or without HBV reactivation was 53.8% vs. 77.6% (p=0.025). Regarding the negative impact on clinical outcome, patients at "super high risk" of HBV reactivation, including those receiving more than eight cycles of R and having low LMR at diagnosis, may warrant first priority for antiviral prophylaxis. PMID- 25459446 TI - Spontaneous remission in a patient with follicular lymphoma carrying T cell-rich neoplastic follicles and a new complex variant translocation of t(14;18): t(5;14;18)(p15;q32;q21.3). PMID- 25459447 TI - Reconstituted mother tinctures of Gelsemium sempervirens L. improve memory and cognitive impairment in mice scopolamine-induced dementia model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gelsemium sempervirens (L.) J.St.-Hil is a herb used for the treatment of various neuroses in both homeopathic and Ayurvedic systems. The present study examines whether Gelsemium reconstituted tincture can protect against scopolamine induced cognitive discrepancies in amnesic mouse model. In order to investigate the protective mechanism of Gelsemium against dementia, in vitro acetyl cholinesterase and beta-secretase enzyme inhibition and estimation of glutathione level in mouse brain were carried out. MATERIALS AND METHODS: The inhibition study on acetyl cholinesterase and beta-secretase enzyme was conducted on brain homogenate supernatant spectrophotometrically using specific substrate. Cognitive enhancement activity was assessed by elevated plus maze and passive avoidance study in scopolamine induced dementia mouse model. Glutathione, an anti-oxidant, was measured spectrophotometrically from scopolamine induced amnesic mice brain supernatant using 5,5'-dithiobis 2 nitrobenzoic acid in the presence and absence of Gelsemium tincture. RESULTS: Significant inhibition was found with Gelsemium on AChE and beta-secretase enzyme with an IC50 of 9.25 and 16.25 ug/ml, respectively, followed by increasing glutathione levels in comparison to the untreated dementia group. The effect of Gelsemium of scopolamine-induced cognitive deficits was determined by measuring the behavioral parameters and the antioxidant status of the brain after scopolamine (1mg/kg i.p.) injected amnesic mice. Gelsemium significantly demonstrated in vivo anti-dementia activity (60% protection) and increased exploratory behavior. CONCLUSION: Our investigations indicated that alkaloid, iridoids and coumarin enriched reconstituted Gelsemium tincture extract displays promising cognitive enhancement in adult mice after short-term oral treatment. Hence, Gelsemium can be a promising anti-dementia agent, mediating the protection against amnesia, attention disorders and learning dysfunctions through dual inhibition of both acetyl cholinesterases (no false positive effect was shown), beta-secretase and antioxidant activity. PMID- 25459448 TI - Identification and characterization of novel protein-derived arginine-rich cell penetrating peptides. AB - Cell-penetrating peptides (CPPs) have proven their potential as an efficient delivery system due to their intrinsic ability to traverse biological membranes and transport various cargoes into the cells. In the present study, we have identified novel natural protein-derived CPPs using an integrated (in silico and experimental) approach. First, using bioinformatics approach, arginine-rich peptide segments were extracted from SwissProt proteins and their cell penetrating properties were predicted. Finally, eight peptides were selected and their internalization was validated using experimental techniques. Laser scanning confocal microscopy and flow cytometry confirmed that seven out of eight peptides were internalized into live cells with varying efficiencies without significant cytotoxicity. Three peptides have shown higher internalization efficacy than TAT peptide, the most widely used CPP. Among these three peptides, one peptide (P8), derived from voltage-dependent L-type calcium channel subunit alpha-1D, was able to accumulate inside in a variety of cell types very efficiently through a rapid dose-dependent process. Further, experiments involving inhibition with various endocytic inhibitors along with co-localization studies indicate that the uptake mechanism of P8 is macropinocytosis, a fluid-phase endocytosis process. In addition, competitive inhibition with heparin revealed the involvement of cell surface proteoglycans in P8 uptake. In summary, the present study provides evidence that an integrated in silico and experimental approach is an effective strategy for the identification of novel CPPs and CPPs identified in the present study have promising perspectives for future drug delivery applications. PMID- 25459449 TI - Clinical characteristics and airway inflammation profile of COPD persistent sputum producers. AB - BACKGROUND: COPD patients with chronic bronchitis include a subgroup with persistent sputum production on most or every day. We hypothesized that COPD patients with persistent sputum production have a different profile of airway inflammation, and more severe clinical characteristics. OBJECTIVE: To compare the airway inflammation profile and clinical characteristics of COPD persistent and non-persistent sputum producers. METHODS: COPD persistent sputum producers (n = 26) and non-persistent sputum producers (n = 26) underwent sputum induction and pulmonary function tests. Exacerbation history was recorded; the St. George's Respiratory Questionnaire, Modified Medical Research Council Dyspnoea scale and COPD Assessment Tool were completed. 33 COPD patients provided sputum for bacteriology. RESULTS: Persistent sputum producers had lower post-bronchodilator FEV1% predicted (p = 0.01), diffusion capacity (p = 0.04), 6 min walk test distance (p = 0.05), and higher closing volume (p = 0.01), BODE index (p = 0.01), rate of bacterial colonization (p = 0.004) and exacerbations (p = 0.03) compared to non-persistent sputum producers. The mean SGRQ and CAT scores were higher in persistent sputum producers (p = 0.01 and 0.03 respectively). Sputum neutrophil and eosinophil total cell counts were higher in persistent sputum producers (p = 0.02 and 0.05 respectively). Sputum levels of eotaxin (p = 0.02), MCP-1 (p = 0.02), TNF-alpha (p = 0.03) and IL-6 (p = 0.05) were higher in persistent sputum producers. CONCLUSION: COPD persistent sputum producers have more severe clinical characteristics and increased concentrations of some inflammatory mediators in the airways. PMID- 25459450 TI - COPD care programme can reduce readmissions and in-patient bed days. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common disease worldwide with significant morbidity and mortality. AIM: To investigate the effect of a comprehensive COPD management programme in decreasing COPD readmissions 1 year before and 1 year after the programme. METHOD: 185 (166 males) patients admitted for acute exacerbation of COPD (AECOPD) were recruited between September 2010 and December 2012. COPD care team provided crisis support and maintenance therapy for the COPD patients for a total of 16 weeks. The protocol included COPD clinic run by respiratory physicians, COPD education and nurse clinics by respiratory nurses, out-patient pulmonary rehabilitation programme by physiotherapists, fast track doctor's clinic, telephone hotline for patients and nurse telephone calls to patients. Readmissions over a period of 1 year were assessed. RESULTS: The mean (SD) age of the subjects and FEV1 % predicted normal were 76.9 +/- 7.37 yrs and 44.4 +/- 20.7% respectively. 40 (21.6%) patients required non-invasive positive pressure ventilation during the recruitment admission. Admissions for AECOPD decreased from 2.39 +/- 2.05 one year before programme to 1.65 +/- 2.1 one year after programme (mean difference 0.75 +/- 2.11 episodes, p < 0.001). The length of hospital stay was reduced from 12.17 +/- 9.14 days one year before programme to 9.09 +/- 12.1 days one year after the programme (mean difference 3.09 +/- 12.1 days, p < 0.001). The FEV1 percentage predicted and quality of life measured by St George's Respiratory Questionnaire showed no significant improvement at 16 weeks after recruitment into the programme as compared to at 6 weeks. CONCLUSION: COPD care programme is effective in decreasing readmissions and length of hospital day for COPD patients. PMID- 25459451 TI - Semiquantitative cough strength score and associated outcomes in noninvasive positive pressure ventilation patients with acute exacerbation of chronic obstructive pulmonary disease. AB - BACKGROUND: Weak cough may result in the failure of noninvasive positive pressure ventilation (NPPV) in patients with AECOPD. However, no detailed descriptions have yet been published for the measurement of cough strength and associated outcomes in AECOPD patients. METHODS: This study prospectively enrolled 261 AECOPD patients who received NPPV. Semiquantitative cough strength score (SCSS, ranging from 0 = weak to 5 = strong) was recorded before NPPV. Patients who required intubation were defined as NPPV failures. RESULTS: NPPV failed in 55 patients (21.1%). Weak cough (SCSS <=3, OR = 8.1), high disease severity (APACHE II score >19, OR = 3.8), and malnutrition (total proteins <=58 g/L, OR = 2.8) were independent risk factors for NPPV failure. Patients with 1, 2, and 3 risk factors were 4.7, 13.6, and 21.6 times more likely, respectively, to experience NPPV failure compared with patients with no risk factors. The NPPV failure rates were 80%, 40%, and 10.2% in patients with SCSS of 0-1, 2-3, and 4-5, respectively (p < 0.001). Compared with NPPV success patients, NPPV failure patients stayed longer in ICU (10.1 +/- 7.9 days vs. 6.5 +/- 4.6 days, p < 0.001), and they had higher ICU costs (?2986 +/- 1906 vs. ?5680 +/- 3,604, p < 0.001), higher hospital costs (? 6714 +/- 7025 vs. ?10,399 +/- 9,509, p = 0.009), and higher hospital mortality (72.7% vs. 4.4%, p < 0.001). Moderate accuracy to distinguish NPPV failure by APACHE II score, SCSS, and total proteins was evidenced by ROC curves, with areas under the curve of 0.71, 0.78, and 0.67, respectively. A combination of all three factors reached good accuracy, with an area under the curve of 0.86. CONCLUSION: AECOPD patients with weak cough had a high risk of NPPV failure. SCSS, APACHE II scores, and total proteins were predictors of NPPV failure. Combined, these factors increased the power to predict NPPV failure. PMID- 25459452 TI - Results of angular-stable locked intramedullary nails in the treatment of distal tibia fractures. AB - INTRODUCTION: Intramedullary nailing in distal tibial fracture is controversial because of a lack of stability. The present study sought to assess radiological and clinical results for a new "angular-stable" locking system in difficult indications for intramedullary nailing. MATERIAL AND METHOD: A prospective study recruited 41 patients (41 tibias) with distal tibial fracture consecutively managed using angular-stable locked intramedullary nails. Radiologic assessment comprised AP and lateral lower-limb views, taken postoperatively and through to last follow-up. The mean distance was measured between fracture and joint line. Fusion, with or without malunion, primary reduction defect, non-union and secondary displacement were recorded, as were all complications. RESULTS: Mean follow-up was 18 +/- 5 months; 3 patients were lost to follow-up. Mean fracture distance from the joint line was 63 +/- 25 mm. Fusion was achieved within 3 months in 29 cases (76%); delayed fusion in 7 patients (18%) required secondary dynamization at a mean 3 months, with favorable evolution. Revision surgery was required in 2 cases: 1 for secondary displacement exceeding 10 degrees , and 1 for non-union at 7 months. Other complications mainly comprised 4 malunions of less than 10 degrees due to primary reduction defect. CONCLUSION: Angular-stable locked lower-limb intramedullary nailing provided a very satisfactory fusion rate, with few complications. It is, however, a demanding procedure, especially as regards fracture reduction and nail positioning in the distal fragment. PROSPECTIVE COHORT STUDY: level IV. PMID- 25459453 TI - Soft-tissue coverage of olecranon with musculocutaneous flexor carpi ulnaris flap. AB - Coverage of the olecranon area is always challenging in traumatology. Because of the superficial situation of the bone, the absence of muscle, the thinness of the skin and the subcutaneous tissue locally, skin defects are not uncommon and can lead to exposure of hardware or prostheses. We report an original surgical technique using a musculocutaneous flap from the flexor carpi ulnaris (FCU) with a proximal pedicle to cover the olecranon area, detailing its limits and indications. The FCU flap has become our first-choice procedure to cover olecranon skin defects because of its low morbidity, its reliability, and its straightforward procedure, obviating the need for any microsurgery technique. Furthermore, it allows moving the elbow, immediately decreasing the risk of elbow stiffness. PMID- 25459454 TI - Bone scan as a screening test for missed fractures in severely injured patients. AB - BACKGROUND: In many cases, patients with severe blunt trauma have multiple fractures throughout the body. These fractures are not often detectable by history or physical examination, and their diagnosis can be delayed or even missed. Thus, screening test fractures of the whole body is required after initial management. We performed this study to evaluate the reliability of bone scans for detecting missed fractures in patients with multiple severe traumas and we analyzed the causes of missed fractures by using bone scan. HYPOTHESIS: A bone scan is useful as a screening test for fractures of the entire body of severe trauma patients who are passed the acute phase. MATERIAL AND METHODS: We reviewed the electronic medical records of severe trauma patients who underwent a bone scan from September 2009 to December 2010. Demographic and medical data were compared and statistically analyzed to determine whether missed fractures were detected after bone scan in the two groups. RESULTS: A total of 382 patients who had an injury severity score [ISS] greater than 16 points with multiple traumas visited the emergency room. One hundred and thirty-one patients underwent bone scan and 81 patients were identified with missed fractures by bone scan. The most frequent location for missed fractures was the rib area (55 cases, 41.98%), followed by the extremities (42 cases, 32.06%). The missed fractures that required surgery or splint were most common in extremities (11 cases). In univariate analysis, higher ISS scores and mechanism of injury were related with the probability that missed fractures would be found with a bone scan. The ISS score was statistically significant in multivariate analysis. DISCUSSION: Bone scan is an effective method of detecting missed fractures among patients with multiple severe traumas. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 25459455 TI - Real-time dosimetry reduces radiation exposure of orthopaedic surgeons. AB - BACKGROUND: Cancer prevalence of orthopaedic surgeons is elevated and chronic exposure to occupational ionizing radiation is seen as one reason. HYPOTHESIS: Use of a new dosimeter enabling radiation dose monitoring in real-time may reduce radiation exposure of orthopaedic surgeons. MATERIALS AND METHODS: Over a period of four months, the surgeon and the C-arm operator were equipped with a novel dosimeter called DoseAware((r)) (DA) while using the C-arm fluoroscope intraoperatively. Data of 68 patients DA were retrospectively compared using matched-pair analysis with 68 controls without DA. Both groups were assessed regarding fluoroscopic time (FT) and radiation dose (RD). Seven types of operative procedures were performed: internal fixation of subcapital humerus fractures, midshaft clavicular fractures, distal radius fractures, pertrochanteric femoral fractures, ankle fractures, traumatic vertebral fractures and osteoporotic vertebral fractures. RESULTS: Concerning the FT, use of DoseAware((r)) led to a significant reduction for all evaluated operation types except for internal fixation of distal radius fractures (P=0.0511). Regarding the RD, use of DoseAware((r)) led to a significant reduction for all evaluated operation types except trochanteric femoral fractures with a PFNA((r)) (P=0.0841). CONCLUSION: DoseAware((r)) allowing real-time radiation dose monitoring reduces radiation exposure of the orthopaedic surgeon and instantly demonstrates the effects of dose-reduction techniques. LEVEL OF EVIDENCE: Level III retrospective case control study. PMID- 25459456 TI - Detorsion night-time bracing for the treatment of early onset idiopathic scoliosis. AB - BACKGROUND: Management for early onset scoliosis has recently changed, with the development of new surgical procedures. However, multiple surgeries are often required and high complication rates are still reported. Conservative management remains an alternative, serial casting achieving excellent results in young children. Better compliance and improvement over natural history have been reported with night-time bracing in adolescent idiopathic scoliosis (AIS), but this treatment has never been reported in early onset idiopathic scoliosis (EIOS). METHODS: All patients treated for progressive EOIS by detorsion night time bracing (DNB), and meeting the Scoliosis Research Society (SRS) criteria for brace studies were reviewed. Recommendations were given to wear the DNB 8h/night and no restriction was given regarding sports activities. Radiological parameters were compared between referral and latest follow-up. Based on the SRS criteria defined for AIS, a similar classification was used as follows to analyze the course of the curves: success group: patients with a progression of 5 degrees or less; unsuccess group (progression or failure): patients with a progression>5 degrees , patients with curves exceeding 45 degrees at maturity, or who have had recommendation for/undergone surgery, or patients who changed orthopaedic treatment, or who were lost to follow-up. RESULTS: Thirty-three patients were included (21 girls and 12 boys), with a median Cobb angle of 31 degrees (Q1-Q3: 22-40). Age at brace initiation averaged 50months (Q1-Q3: 25-60). Median follow up was 102-months (Q1-Q3: 63-125). Fifteen patients (45.5%) had reached skeletal maturity at last follow-up. The success rate was 67% (22 patients), with a median Cobb angle reduction of 15 degrees (P<0.001). Four patients stopped DNB due to an important regression. Eleven patients were in the unsuccessful group (33%). Only one had surgery. All patients remained balanced in the frontal plane and normokyphotic. Initial curve magnitude and age at brace initiation appeared to be important prognostic factors. CONCLUSIONS: DNB is an effective conservative treatment, which can be considered a delaying tactic in the management of EOIS. This brace offers potential psychosocial and compliance benefits, and allows unconstrained spinal and chest wall growth, resulting in normokyphosis at maturity. LEVEL OF EVIDENCE: Therapeutic study (retrospective consecutive case series): Level IV. PMID- 25459457 TI - DXA-based variables and osteoporotic fractures in Lebanese postmenopausal women. AB - INTRODUCTION: The aim of this study was to assess DXA-based variables (bone mineral density, bone mineral apparent density, compressive strength index of the femoral neck and trabecular bone score) in Lebanese postmenopausal women having presented a previous fracture. MATERIALS AND METHODS: One thousand Lebanese postmenopausal women between 45 and 89 years participated in this study. The women were recruited by advertisements offering bone mineral density measurements at a reduced cost. Subjects with previous history of radiotherapy or chemotherapy were excluded. Informed written consent was obtained from all the participants. RESULTS: Femoral neck compressive strength index (FN CSI) was significantly (P<0.001) associated with the presence of fracture using a simple logistic regression (odds ratio=0.51 [0.385-0.653]). When a multivariate logistic regression analysis was performed with the presence of fracture as a dependent variable and each of age, FN BMD and FN CSI as independent variables, only FN BMD (P=0.005) and FN CSI (P=0.004) were found to be associated with the presence of fracture. CONCLUSION: This study suggests that FN CSI is associated with history of osteoporotic fractures in postmenopausal women. The use of FN CSI in clinical practice may help to identify patients with high risk of fracture. LEVEL OF EVIDENCE: Epidemiological study, level IV. PMID- 25459458 TI - MR Imaging with T2*- mapping for improved acetabular cartilage assessment in FAI a case report with arthroscopic correlation. AB - Articular cartilage assessment in femoroacetabular impingement (FAI) is challenging. Recent studies on T2* relaxation time mapping suggest the technique may be useful in diagnosing cartilage damage. The purpose of this case report is to describe how quantitative T2*-mapping may improve cartilage assessment of the acetabulum in patients with FAI. MR arthrography was performed at 3 Tesla (T) using intra-articular Gadolinium and a T2* mapping protocol. Data from the acetabular cartilage was separated from femoral head cartilage data and then superimposed on a flattened, map projection representation of the patient's acetabulum. The areas of unhealthy cartilage observed at the time of arthroscopy including debonding and delamination - were seen preoperatively at the same anatomic locations as areas of decreased T2* values. T2* mapping values provided a non-invasive assessment of the acetabular articular cartilage. A flattened acetabular map projection allowed for anatomic visualization of areas of unhealthy cartilage. LEVEL OF EVIDENCE: Level IV. PMID- 25459461 TI - IEP goals for school-age children with speech sound disorders. AB - PURPOSE: The purpose of the current study was to describe the current state of practice for writing Individualized Education Program (IEP) goals for children with speech sound disorders (SSDs). METHOD: IEP goals for 146 children receiving services for SSDs within public school systems across two states were coded for their dominant theoretical framework and overall quality. A dichotomous scheme was used for theoretical framework coding: cognitive-linguistic or sensory-motor. Goal quality was determined by examining 7 specific indicators outlined by an empirically tested rating tool. In total, 147 long-term and 490 short-term goals were coded. RESULTS: The results revealed no dominant theoretical framework for long-term goals, whereas short-term goals largely reflected a sensory-motor framework. In terms of quality, the majority of speech production goals were functional and generalizable in nature, but were not able to be easily targeted during common daily tasks or by other members of the IEP team. Short-term goals were consistently rated higher in quality domains when compared to long-term goals. CONCLUSIONS: The current state of practice for writing IEP goals for children with SSDs indicates that theoretical framework may be eclectic in nature and likely written to support the individual needs of children with speech sound disorders. Further investigation is warranted to determine the relations between goal quality and child outcomes. LEARNING OUTCOMES: (1) Identify two predominant theoretical frameworks and discuss how they apply to IEP goal writing. (2) Discuss quality indicators as they relate to IEP goals for children with speech sound disorders. (3) Discuss the relationship between long-term goals level of quality and related theoretical frameworks. (4) Identify the areas in which business-as-usual IEP goals exhibit strong quality. PMID- 25459462 TI - Systemic therapies for diabetic retinopathy: the accord eye study. PMID- 25459460 TI - The effect of increased vocal intensity on interarticulator timing in speakers with Parkinson's disease: a preliminary analysis. AB - PURPOSE: The purpose of the current study was to investigate the effect of increased vocal intensity on interarticulator timing in individuals with Parkinson's disease (PD). METHODS: Ten individuals with mild to moderate hypophonia, secondary to PD, were selected for study. Over an 8-week treatment period, multi-talker babble noise was presented monaurally to the individuals with PD during everyday communication contexts to elicit increased vocal intensity (Lombard effect). Outcome measures included sound pressure level (SPL), voice onset time (VOT), VOT ratio, percent voicing, and speech intelligibility. RESULTS: Group and individual participant responses to the treatment are reported and discussed. Speakers with PD were shown to significantly increase SPL in response to treatment. Six of the 10 speakers showed improved temporal coordination between the laryngeal and supralaryngeal mechanisms (interarticulator timing) in response to treatment. Four of the 10 speakers, however, showed reduced laryngeal-supralaryngeal timing at the end of treatment. Group speech intelligibility scores were significantly higher post-treatment as compared to pre-treatment. CONCLUSIONS: Voice treatment during everyday communication resulted in improved temporal coordination across the laryngeal and supralaryngeal mechanisms for the majority of speakers with PD and made them easier to understand. Further investigations are planned to explore individual differences in response to treatment. The identification of speaker-specific voicing and devoicing strategies is consistent with the heterogeneous nature of PD. LEARNING OUTCOMES: Readers will be able to: 1. Describe the speech and voice characteristics of individuals with Parkinson's disease. 2. Define the Lombard effect. 3. Describe acoustic measures of voice onset time and percent voicing. 4. Describe the effect of voice treatment on voice onset time and percent voicing in individuals with Parkinson's disease. PMID- 25459463 TI - Footnotes, acknowledgments, and authorship: toward greater responsibility, accountability, and transparency. PMID- 25459464 TI - Re: Nanji et al.: Surgical versus medical treatment of ocular surface squamous neoplasia: a comparison of recurrences and complications (Ophthalmology 2014;121:994-1000). PMID- 25459465 TI - Author reply: To PMID 24411578. PMID- 25459466 TI - Re: Said et al.: Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting (Ophthalmology 2014;121:1377-82). PMID- 25459467 TI - Re: Pakravan et al.: Effect of early treatment with aqueous suppressants on Ahmed glaucoma valve implantation outcomes (Ophthalmology 2014;121:1693-8). PMID- 25459468 TI - Author reply: To PMID 24819857. PMID- 25459470 TI - Author reply: To PMID 24893767. PMID- 25459469 TI - Re: Albert et al.: A proposal to improve ophthalmic education in medical schools (Ophthalmology 2014;121:1157-9). PMID- 25459472 TI - AVMA releases new economic analyses. PMID- 25459473 TI - What is your diagnosis? Coccidioidomycosis. PMID- 25459475 TI - Diagnostic imaging in veterinary dental practice. Primary endodontic lesion with secondary periodontal involvement. PMID- 25459476 TI - Pathology in practice. A equuli septicemia in a neonatal foal. PMID- 25459477 TI - Pathology in practice. Hepatic hematoma with subcapsular rupture in a dog. PMID- 25459480 TI - Vaginal impedometry for detection of optimal breeding time in bitches. AB - OBJECTIVE: To compare the efficacy of canine vaginal impedometry in identifying the preovulatory luteinizing hormone (LH) peak to that of currently used methods (serum progesterone concentration measurement, vaginal cytologic evaluation, and vaginoscopy). DESIGN: Prospective study. ANIMALS: 12 sexually intact female dogs. PROCEDURES: 12 mature postpubertal Beagle (n = 3), Beagle-cross (2), and hound cross (7) bitches ranging from 7.5 to 27.5 kg (16.5 to 60.6 lb) were enrolled in the study. After the onset of spontaneous proestrus, determined on the basis of appearance of serosanguineous vaginal discharge, serum progesterone assays, vaginoscopy, vaginal cytologic evaluation, and vaginal impedometry were performed daily until approximately 4 days after peak LH concentration (day 0) as measured by radioimmunoassay. Vaginal impedometry was compared against serum progesterone concentration measurement, vaginal cytologic evaluation, and vaginoscopy as a method for accurately identifying the LH peak and therefore the optimal breeding time. Ten of 12 bitches were bred with subsequent assessment of embryos. RESULTS: Vaginal impedometry accurately predicted the preovulatory LH peak in 5 of 11 bitches. One bitch was removed from the study because data were not collected. Of the remaining 11 bitches, 6 had their LH peak on the day serum progesterone concentration first exceeded 2 ng/mL. Crenulation scores reached 1 (mean, 1.3; 95% confidence interval, 0.8 to 1.7) on day 0 as expected; however, these scores were not significantly different from those on days -1 or 1. Vaginal epithelial cell populations did not change noticeably on day 0. Nine of the 10 bitches that were bred produced viable embryos. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that daily use of vaginal impedometry in bitches was unreliable as a method for monitoring periovulatory events. All techniques evaluated (ie vaginal impedometry, serum progesterone concentration assays, vaginoscopy and vaginal cytologic evaluation) frequently produced inaccurate results when used individually. Multiple methods should be used to identify optimal breeding time in dogs. PMID- 25459481 TI - Comparison of peak flow velocity through the left ventricular outflow tract and effective orifice area indexed to body surface area in Golden Retriever puppies to predict development of subaortic stenosis in adult dogs. AB - OBJECTIVE: To evaluate the usefulness of Doppler-derived peak flow velocity through the left ventricular outflow tract (LVOT Vmax) and effective orifice area indexed to body surface area (EOAi) in puppies to predict development of subaortic stenosis (SAS) in the same dogs as adults. DESIGN: Prospective, longitudinal, observational study. ANIMALS: 38 Golden Retrievers. PROCEDURES: Cardiac auscultation and echocardiography were performed on 2- to 6-month-old puppies, then repeated at 12 to 18 months. Subaortic stenosis was diagnosed when LVOT Vmax was >= 2.3 m/s in adult dogs with left basilar systolic murmurs. RESULTS: All puppies with EOAi < 1.46 cm(2)/m(2) had SAS as adults. All adults with EOAi < 1.29 cm(2)/m(2) had SAS. An LVOT Vmax > 2.3 m/s in puppyhood was 63% sensitive and 100% specific for SAS in adulthood. In puppies, LVOT Vmax was more strongly associated with a future diagnosis of SAS (area under the curve [AUC], 0.89) than was EOAi (AUC, 0.80). In puppies, the combination of LVOT Vmax and EOAi yielded slightly higher sensitivity (69%) and specificity (100%) for adult SAS than did LVOT Vmax alone. In unaffected and affected dogs, LVOT Vmax increased significantly from puppyhood to adulthood but EOAi did not. CONCLUSIONS AND CLINICAL RELEVANCE: In Golden Retriever puppies, LVOT Vmax > 2.3 m/s and EOAi < 1.46 cm(2)/m(2) were both associated with a diagnosis of SAS at adulthood. The combination of these 2 criteria may result in higher sensitivity for SAS screening. Unlike LVOT Vmax, EOAi did not change during growth in either unaffected Golden Retrievers or those with SAS. PMID- 25459483 TI - Risk factors for perioperative death in dogs undergoing splenectomy for splenic masses: 539 cases (2001-2012). AB - OBJECTIVE: To determine the perioperative mortality rate, causes of death, and risk factors for perioperative death in dogs undergoing splenectomy for splenic mass lesions. DESIGN: Retrospective case series. ANIMALS: 539 dogs. PROCEDURES: Medical records of dogs that underwent splenectomy for known splenic masses were reviewed. Perioperative mortality rate and causes of death were determined. Associations between potential prognostic factors and perioperative death were evaluated by multivariable logistic regression analysis. RESULTS: 41 of 539 (7.6%) dogs died during the perioperative period. Thrombotic and coagulopathic syndromes and uncontrolled bleeding from metastatic lesions were the most common causes of death. Of the variables selected for multivariable analysis, platelet count at admission, whether PCV at admission was < 30%, and development of ventricular arrhythmias during surgery were significantly associated with outcome. For each decrease in platelet count of 10,000 platelets/MUL, odds of death increased by approximately 6%. For dogs with PCV < 30%, odds of death were approximately twice those for dogs with PCV >= 30%, and for dogs that developed intraoperative arrhythmias, odds of death were approximately twice those for dogs that did not. CONCLUSIONS AND CLINICAL RELEVANCE: Marked preoperative thrombocytopenia or anemia and development of intraoperative ventricular arrhythmias were identified as risk factors for perioperative death in dogs with splenic masses. The risk of death may be limited by efforts to prevent thrombotic and coagulopathic syndromes and to control all sources of intra-abdominal hemorrhage. PMID- 25459482 TI - Comparison of carprofen and tramadol for postoperative analgesia in dogs undergoing enucleation. AB - OBJECTIVE: To compare analgesia provided by carprofen and tramadol in dogs after enucleation. DESIGN: Randomized, masked clinical trial. ANIMALS: 43 dogs. PROCEDURES: Client-owned dogs admitted for routine enucleation were randomly assigned to receive either carprofen or tramadol orally 2 hours prior to surgery and 12 hours after the first dose. Dogs were scored for signs of pain at baseline (ie, before carprofen or tramadol administration) and at 0.25, 0.5, 1, 2, 4, 6, 8, 24, and 30 hours after extubation. Dogs received identical premedication and inhalation anesthesia regimens, including premedication with hydromorphone. If the total pain score was >= 9 (maximum possible score of 20), there was a score >= 3 in any of 5 behavioral categories (highest score possible per category was 3 or 4), or the visual analog scale (VAS) score was >= 35 (maximum possible score of 100) combined with a palpation score > 0, rescue analgesia (hydromorphone) was administered and treatment failure was recorded. RESULTS: No differences were found in age, sex, or baseline pain scores between groups. Significantly more dogs receiving tramadol required rescue analgesia (6/21), compared with dogs receiving carprofen (1/22). Pain and VAS scores decreased linearly over time. No significant differences were found in pain or VAS scores between groups at any time point (dogs were excluded from analysis after rescue). CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study suggested that carprofen, with opioid premedication, may provide more effective postoperative analgesia than tramadol in dogs undergoing enucleation. PMID- 25459484 TI - Diagnosis and treatment of chronic lymphocytic leukemia in a bat-eared fox (Otocyon megalotis). AB - CASE DESCRIPTION: Severe lymphocytosis and leukocytosis were detected during examination of a 10-year-old sexually intact male bat-eared fox (Otocyon megalotis) with regionally extensive alopecia. CLINICAL FINDINGS: A CBC revealed severe leukocytosis (39,100 leukocytes/MUL) and marked lymphocytosis (90%). A blood smear consisted predominantly of intermediate-sized lymphocytes and few large lymphocytes, with mild to moderate nuclear atypia. These findings were highly suggestive of chronic lymphocytic leukemia (CLL). Cytologic evaluation of bone marrow aspirates revealed no evidence of overt malignancy, with 10% of all cells identified as small to intermediate-sized mature lymphocytes. TREATMENT AND OUTCOME: Treatment with chlorambucil and prednisone administered orally over a 1.8-year period decreased the leukocyte and lymphocyte counts to within reference intervals with no adverse effects. Although repeated flow cytometry revealed evidence of residual disease, the fox remained free of clinical disease, and WBC counts were within reference intervals for this species. At 22 months after initial evaluation, the fox was euthanized because of debilitating arthritis. No evidence of CLL was detected grossly or histologically during necropsy. CLINICAL RELEVANCE: To the authors' knowledge, this was the first report of CLL in a bat eared fox and first successful treatment in a nondomestic carnivore. Treatment in accordance with a chemotherapeutic protocol successfully resolved the leukocytosis and lymphocytosis with no serious adverse effects. Description of this fox and the treatment protocol should provide a valuable reference for future cases in this and other nondomestic canine species. PMID- 25459485 TI - A strategy for translating evidence into policy and practice to close the gap - developing essential service standards for Aboriginal and Torres Strait Islander cardiovascular care. AB - The development and application of essential standards for cardiovascular care for Aboriginal and Torres Strait Islander people creates a strategic platform on which to systematically close the gap in the health outcomes and life expectancy between Aboriginal and Torres Strait Islander and non-Indigenous people in Australia. We outline six developmental stages that can be used to enhance the effective translation of evidence into practice that reduces life expectancy differentials. Focussing efforts where the biggest gain can be made; considering how to make a policy-relevant difference with an emphasis on translation into policy and practice; establishing a foundation for action by engaging with stakeholders throughout the process; developing a framework to guide action; drafting policy-relevant and framework-appropriate essential service standards; and defining standards that help policy decision makers achieve current priority policy targets. PMID- 25459486 TI - Cardio-protective signalling by glyceryl trinitrate and cariporide in a model of donor heart preservation. AB - BACKGROUND: Storage of donor hearts in cardioplegic solutions supplemented with agents that mimic the ischaemic preconditioning response enhanced their post reperfusion function. The present study examines the minimisation of cell death and activation of pro-survival signalling directed towards maintenance of mitochondrial homeostasis in hearts arrested and stored in two such agents, glyceryl-trinitrate, a nitric oxide donor and cariporide, (a sodium-hydrogen exchange inhibitor). METHODS: After baseline functional measurement, isolated working rat hearts were arrested and stored for 6h at 4 degrees C in either Celsior((r)), Celsior((r)) containing 0.1mg/ml glyceryl-trinitrate, 10MUM cariporide or both agents. After reperfusion, function was remeasured. Hearts were then processed for immunoblotting or histology. RESULTS: Necrotic and apoptotic markers present in the Celsior((r)) group post-reperfusion were abolished by glyceryl-trinitrate, cariporide or both. Increased phosphorylation of ERK and Bcl2, after reperfusion in groups stored in glyceryl-trinitrate, cariporide or both along with increased phospho-STAT3 levels in the glyceryl trinitrate/cariporide group correlated with functional recovery. Inhibition of STAT3 phosphorylation blocked recovery. No phospho-Akt increase was seen in any treatment. CONCLUSIONS: Activation of signalling pathways that favour mitophagy activation (ERK and Bcl2 phosphorylation) and maintenance of mitochondrial transition pore closure after reperfusion (STAT3 and ERK phosphorylation) were crucial for functional recovery of the donor heart. PMID- 25459487 TI - Essential service standards for equitable national cardiovascular care for Aboriginal and Torres Strait Islander people. AB - Cardiovascular diseases (CVD) constitute the largest cause of death for Aboriginal and Torres Strait Islander people and remain the primary contributor to life expectancy differentials between Aboriginal and Torres Strait Islander and non-Indigenous Australians. As such, CVD remains the most critical target for reducing the life expectancy gap. The Essential Service Standards for Equitable National Cardiovascular Care for Aboriginal and Torres Strait Islander people (ESSENCE) outline elements of care that are necessary to reduce disparity in access and outcomes for five critical cardiovascular conditions. The ESSENCE approach builds a foundation on which the gap in life expectancy between Aboriginal and Torres Strait Islander and non-Indigenous Australians can be reduced. The standards purposefully focus on the prevention and management of CVD extending across the continuum of risk and disease. Each of the agreed essential service standards are presented alongside the most critical targets for policy development and health system reform aimed at mitigating population disparity in CVD and related conditions. PMID- 25459488 TI - Ciclovia participation and impacts in San Diego, CA: the first CicloSDias. AB - OBJECTIVE: Ciclovia or Open Streets initiatives support physical activity through cycling/rolling, and walking/running. We evaluated San Diego's first Open Streets event, CicloSDias, to document attendance, reach and marketing, and effects on social cohesion, businesses, and physical activity. METHODS: The comprehensive evaluation consisted of a city-wide survey 1 week before and after the event (n=805), counts of event attendees, and surveys of event attendees (n=713) and businesses (n=26). RESULTS: An estimated 8311 people attended the event. Attendees had an average of 144 min (SD=85) of physical activity, 97% met the 30 min/day guideline, and 39% met the 150 min/week guideline during the event. 27% of attendees would have been inactive without the event. Awareness of the event was 10% before and 26% after the event. When comparing event attendees to San Diego residents, Latinos and non-White race/ethnicities were under-represented. Restaurants/pubs, services, and most retail stores excluding liquor stores and food markets reported positive or neutral impacts on business. CONCLUSION: Open Street initiatives are promising ways to promote physical activity and are desired by the community. Positive effects were observed for physical activity, social cohesion, and businesses, though reach should be expanded to include more underserved community members. Evaluating Open Streets is important for sustaining and improving these efforts. PMID- 25459489 TI - Initial recall and understanding of a multimedia communication campaign to promote physical activity among tweens: a process evaluation study. AB - OBJECTIVE: To examine the degree of awareness and understanding of a multimedia communication campaign (WIXX) aimed at promoting physical activity among tweens (9-13years old) during the early phases of campaign implementation. METHODS: This study adopted a repeated posttest-only design. Two cross-sectional web-based surveys were conducted in Quebec, Canada, among tweens three (T1; N=400) and nine (T2; N=403) months after the launch of the campaign in 2012. The activities of the WIXX campaign included website development, community events and paid advertisements. Recall, recognition and understanding of the campaign were the three outcomes. Logistic regression analyses were conducted to examine factors associated with the assessed outcomes. RESULTS: The likelihood of having unaided/aided recall (OR=0.7; 95%CI: 0.5, 0.9) rather than no recall decreased between T1 and T2. A significant sex*survey period interaction effect was observed for recall (p=.04). Tweens were also less likely to recognize the WIXX advertisements at T2 (OR=0.6; 95%CI: 0.5, 0.9) and a significant school grade*survey period interaction was observed for recognition (p=.002). CONCLUSIONS: The likelihood of recall and recognition decreased across survey periods. Girls were generally more likely to be aware of the WIXX multimedia campaign. Further efforts are required to maintain and increase awareness of WIXX among tweens. PMID- 25459490 TI - Prediction of Phospholipid-Water Partition Coefficients of Ionic Organic Chemicals Using the Mechanistic Model COSMOmic. AB - The partition coefficient of chemicals from water to phospholipid membrane, K(lipw), is of central importance for various fields. For neutral organic molecules, log K(lipw) correlates with the log of bulk solvent-water partition coefficients such as the octanol-water partition coefficient. However, this is not the case for charged compounds, for which a mechanistic modeling approach is highly necessary. In this work, we extend the model COSMOmic, which adapts the COSMO-RS theory for anisotropic phases and has been shown to reliably predict K(lipw) for neutral compounds, to the use of ionic compounds. To make the COSMOmic model applicable for ionic solutes, we implemented the internal membrane dipole potential in COSMOmic. We empirically optimized the potential with experimental K(lipw) data of 161 neutral and 75 ionic compounds, yielding potential shapes that agree well with experimentally determined potentials from the literature. This model refinement has no negative effect on the prediction accuracy of neutral compounds (root-mean-square error, RMSE = 0.62 log units), while it highly improves the prediction of ions (RMSE = 0.70 log units). The refined COSMOmic is, to our knowledge, the first mechanistic model that predicts K(lipw) of both ionic and neutral species with accuracies better than 1 log unit. PMID- 25459491 TI - Comparison of acute lobar nephronia and acute pyelonephritis in children: a single-center clinical analysis in southern taiwan. AB - BACKGROUND: Patients with acute lobar nephronia (ALN) require a longer duration of antimicrobial treatment than those with acute pyelonephritis (APN), and ALN is associated with renal scarring. The aim of this study was to provide an understanding of ALN by comparing the clinical features of pediatric patients with ALN and APN. METHODS: We enrolled all of the patients with ALN (confirmed by computed tomography) admitted to our hospital from 1999 to 2012 in the ALN group. In addition, each patient diagnosed with APN who was matched for sex, age, and admission date to each ALN patient was enrolled in the APN group. The medical charts of patients in these two groups were retrospectively reviewed and analyzed for comparison. RESULTS: The fever duration after hospitalization in the ALN group and the APN group were 4.85 +/- 2.33 days and 2.30 +/- 1.47 days respectively. The microbiological distributions and the majority of susceptibilities were similar in the ALN and APN groups. The majority of clinical manifestations are nonspecific and unreliable for the differentiation of ALN and APN. The patients with ALN were febrile for longer after antimicrobial treatment, had more nausea/vomiting symptoms, higher neutrophil count, bandemia, and C reactive protein (CRP) levels, and lower platelet count (all p < 0.05). In multivariate analysis, initial CRP levels, nausea/vomiting symptoms, and fever duration after admission were independent variables with statistical significance to predict ALN. Severe nephromegaly occurred significantly more in the ALN group than in the APN group (p = 0.022). CONCLUSION: The majority of clinical manifestations, laboratory findings, and microbiological features are similar between patients with ALN and APN. Clinicians should keep a high index of suspicion regarding ALN, particularly for those with ultrasonographic nephromegaly, initial higher CRP, nausea/vomiting, and fever for > 5 days after antimicrobial treatment. PMID- 25459495 TI - When should automatic Auditory Brainstem Response test be used for newborn hearing screening? AB - OBJECTIVES: The aim of this study was to investigate the referral rate and when automatic Auditory Brainstem Response (aABR) should be used for newborn hearing screening. METHODS: The present study enrolled 2933 healthy full-term infants and 176 infants with perinatal risk factors. Hearing screening using Transient Evoked Otoacoustic Emissions (TEOAEs) was performed in newborns for the first time 5 days after birth except perinatal risk factors infants. The TEOAE was repeated to neonates failing to pass at the 15th day after birth. Neonates failing to pass the second TEOAE, repeated the test again at the 30th day after birth. Neonates failing to pass the third TEOAE were referred for the second stage screening using aABR. In addition, neonates with risk factors were tested with aABR directly. RESULTS: In this research, 85 (2.9%) infants who could not pass the TEOAE and 176 infants exposed to perinatal risk factors, underwent the aABR test. In the aABR, 14 (7.9%) of 176 infants exposed to perinatal risk factors and 10 (11.7%) of 85 infants who could not pass the TEOAE failed to pass. As a result, hearing loss was detected in only 10 (0.34%) of 2933 healthy full-term infants. CONCLUSION: TEOAE should be performed at least twice in healthy full-term infants before aABR, because aABR is to be performed by specially trained personnel and takes a long time. In view of these results, it is our opinion that infants without perinatal risk factors should undergo TEOAE screening test and infants who did not pass control screening tests and have perinatal risk factors should absolutely undergo aABR test. But it should be remembered that TEOAE can cause a problem to miss auditory neuropathy in infants without perinatal risk factors. PMID- 25459494 TI - Salvage surgery after local recurrence in patients with head and neck carcinoma treated with chemoradiotherapy or bioradiotherapy. AB - OBJECTIVE: To analyze the oncologic outcomes and surgical complications after salvage surgery for recurrence following chemoradiotherapy or bioradiotherapy for advanced head and neck squamous cell carcinoma. METHODS: From 2007 to 2011, 187 patients were treated with chemoradiotherapy (n=154) or bioradiotherapy (n=33). Patients treated with bioradiotherapy were older and showed a tendency to poorer general condition. During the follow-up, 43 patients treated with chemoradiotherapy (27.9%) and 13 patients treated with bioradiotherapy (39.3%) had a local recurrence of the tumor. We analyzed the patient candidates to salvage surgery, and the associated complications and outcome of these surgeries. RESULTS: Sixteen patients treated with chemoradiotherapy (37.2%) and eight treated with bioradiotherapy (61.5%) had salvage surgery. Multivariate analysis showed that the variable most strongly related to salvage surgery after local recurrence of the tumor was the type of initial treatment. The frequency of postoperative complications was higher in patients who received chemoradiotherapy (62.5% versus 12.5%, P=0.03). Five-year adjusted-survival after salvage surgery was 26.0% for patients receiving chemoradiotherapy and 70.0% for patients undergoing bioradiotherapy (P=0.156). CONCLUSION: Patients who presented recurrence after bioradiotherapy were more likely candidates to salvage surgery than those who had chemoradiotherapy. Patients undergoing salvage surgery had fewer postoperative complications and better adjusted survival after bioradiotherapy than after chemoradiotherapy. PMID- 25459496 TI - Efficacy of three-dimensional endoscopy in endonasal surgery. AB - OBJECTIVE: To examine the efficacy of a three-dimensional (3D) endoscope for endoscopic sinus and skull base surgery. METHODS: The study design was a retrospective case series and qualitative research. The clinical efficacy of 3D endoscopes was examined on five cadavers. We performed conventional endoscopic sinus surgery (ESS) in five cases and hypophysectomy in two cases using a 3D endoscope. The educational advantages of the 3D endoscope were assessed using questionnaires given to the participants of cadaver dissection courses. RESULTS: In the posterior portion of the nasal cavity, images captured via 3D endoscopy provided a superior perception of depth of information than those via two dimensional (2D) endoscopy. All endonasal surgeries were completed in clinical settings using a 3D endoscope without perioperative complications. In terms of the operative time and amount of bleeding, the results of 3D endoscopic surgeries were not inferior to those of 2D endoscopic surgeries. Fatigue from 3D viewing through polarized glasses did not adversely affect performance of the surgery. Moreover, questionnaires for the evaluation of educational efficacy were completed by 73 surgeons. Of the respondents, 89% agreed that 3D endoscopy provided a better understanding of the surgical anatomy than did 2D endoscopy. As for the site where 3D endoscopy would be the most useful for understanding surgical anatomy, 40% of the respondents named the skull base; 29%, the posterior ethmoid sinuses; and 26%, the sphenoid sinus; and 9%, the ethmoid bulla and middle turbinate. CONCLUSION: The 3D endoscope contributes to a more precise anatomical understanding of the posterior structures of the sinuses and skull base and ensures a more precise operation of the instruments. Thus, 3D endoscopes will likely become a standard device for endonasal surgery in the near future. PMID- 25459497 TI - Sphenoid esthesioneuroblastoma arising from the hindmost olfactory filament. AB - Esthesioneuroblastoma (ENB), or olfactory neuroblastoma, is a rare malignant neoplasm arising from the olfactory neuroepithelium. Typically, ENBs are found in the olfactory cleft with extension to the ethmoid sinuses or anterior skull base. Here we report a case of ENB located in the sphenoid sinus, which had been considered as an ectopic ENB. However, endoscopic resection revealed the continuity of the tumor with the hindmost olfactory filament. The present case suggests that an ENB in the sphenoid sinus was not ectopic, but arose from the normal olfactory neuroepithelium. This continuity of the ENB with this filament indicated that the tumor was not ectopic, and that there was possible tumor invasion into the olfactory neuroepithelium in the cribriform niche. Therefore, pathological examination of the olfactory neuroepithelium in the cribriform niche may be necessary in case of sphenoid ENBs. PMID- 25459498 TI - Anti-anaerobic coverage is not necessary for Klebsiella pneumoniae liver abscess: a propensity score-matched cohort study. AB - Although most Klebsiella pneumoniae liver abscesses have been reported to be monomicrobial, clinical outcomes have not been compared between antimicrobial therapy with and without anti-anaerobic coverage. A propensity score-matched cohort study was conducted using the 731 cases of K. pneumoniae liver abscess. Clinical outcomes were compared between a group discontinuing anti-anaerobic agents after K. pneumoniae identification and a group continuing. A total of 170 cases were matched at a 1:1 ratio using their propensity to discontinue anti anaerobic agents. The McNemar's test showed no difference in mortality rates (1.8% for discontinuation versus 2.3% for continuation; P = 1.00) or relapse (1.8% versus 2.9%; P = 0.73) between groups. Early discontinuation of anti anaerobic agents had no association with treatment failure by means of the generalized estimating equation model (odds ratio 0.48; P = 0.14) and the Kaplan Meier method (P = 0.85) in matched groups. Early discontinuation of anti anaerobic agents does not affect the clinical outcomes of patients with K. pneumoniae liver abscess. PMID- 25459499 TI - Comparison of resting and exercise echocardiographic parameters as indicators of outcomes in hypertrophic cardiomyopathy. AB - BACKGROUND: Both resting echocardiography and exercise echocardiography produce variables predictive of outcomes in patients with hypertrophic cardiomyopathy (HCM). The aim of the present study was to compare the respective value of resting and exercise echocardiographic parameters as indicators of clinical outcomes in patients with HCM. METHODS: Resting and exercise echocardiography was performed prospectively in patients with HCM evaluated at the HCM Competence Center of Bordeaux and followed up every 6 months. A composite cardiac event was defined. RESULTS: One hundred fifteen patients (mean age, 51.9 +/- 15.2 years; 66% men) were evaluated by echocardiography and followed for a mean period of 19 +/- 11 months. Eighteen patients (16%) reached the composite end point, including 10 progressions to New York Heart Association functional class III or IV. On rest echocardiography, in patients with cardiac events during follow-up, left atrial volume index was significantly more increased, as were lateral E/E' ratio and left ventricular outflow tract (LVOT) gradient, whereas mean global longitudinal strain (GLS) expressed in magnitude (14.0 +/- 2.6% vs 17.0 +/- 3.6%, P < .001) and peak velocities at the lateral annulus by Doppler tissue imaging were significantly reduced compared with patients without events. At peak exercise, patients who developed cardiac events were characterized by lower ejection fractions and greater LVOT gradients (76 +/- 55 mm Hg vs 40 +/- 40 mm Hg, P < .002). A Cox backward-entry selection model revealed that GLS <= 15% at rest and LVOT gradient >= 50 mm Hg at peak exercise were independently associated with an increased risk for poor outcomes in patients with HCM (hazard ratios, 3.8 [P = .017] and 3.3 [P = .028], respectively). On Kaplan-Meier survival analyses, peak exercise LVOT gradient evaluation showed additive value to predict outcomes, particularly in patients with rest GLS > 15% (log-rank P = .001) and despite a resting LVOT gradient >= 30 mm Hg (log-rank P = .001). CONCLUSION: This study supports the value of resting GLS and of peak LVOT gradient, measured during exercise echocardiography, in identifying patients with HCM at increased risk for adverse events during follow-up. PMID- 25459500 TI - Exercise echocardiography demonstrates biventricular systolic dysfunction and reveals decreased left ventricular contractile reserve in children after tetralogy of Fallot repair. AB - BACKGROUND: Long-term biventricular systolic performance is a key determinant of clinical outcomes late after tetralogy of Fallot (TOF) repair. A need exists for early indices of both left ventricular (LV) and right ventricular (RV) compromise in this population. METHODS: Twenty-nine children (age range, 5-18 years) with repaired TOF and 44 healthy controls were prospectively evaluated. M-mode and tissue Doppler data were obtained for each ventricle and the RV outflow tract at rest and during semisupine bicycle exercise. By making measurements of myocardial acceleration during isovolumic contraction during exercise, at increasing heart rates, LV force-frequency curves were constructed. Patients also underwent cardiac magnetic resonance imaging, cardiopulmonary exercise testing, and measurement of serum neurohormonal markers. RESULTS: Children with repaired TOF had dilated right ventricles (RV end-diastolic volume index = 153 +/- 37.3 mL/m(2)) but normal ejection fractions as measured on magnetic resonance imaging (LV ejection fraction = 59.3 +/- 6.2%, RV ejection fraction = 50.2 +/- 8.5%) and normal serum neurohormonal markers. Detailed resting echocardiography detected abnormal ventricular function, worst in the right ventricle and RV outflow tract. Exercise exacerbated these findings and provoked significant decline in LV indices. The LV force-frequency curves of patients were attenuated, with an early plateau and inadequate increase of isovolumic contraction. Correlations were seen between peak exercise LV isovolumic contraction and percentage predicted peak oxygen uptake (r = 0.51, P = .02), LV and RV ejection fractions (r = 0.41, P = .03), and RV and LV long-axis fractional shortening (r = 0.44, P = .02). CONCLUSIONS: The postsurgical pathophysiology of TOF begins early after repair. At a time when clinically well and while routine indices of heart function remain normal, children with repaired TOF exhibit RV dilatation and subtle, interlinked biventricular abnormalities on resting echocardiography. Exercise echocardiography provides additional information and reveals abnormal LV excitation-contractile coupling that may be linked to impaired exercise capacity. PMID- 25459501 TI - Carotid artery intima-media thickness measurements in the youth: reproducibility and technical considerations. AB - BACKGROUND: Carotid artery intima-media thickness (CIMT), a marker of atherosclerosis, is increased in youth at risk for future cardiovascular disease. Some pediatric studies have used CIMT as a primary outcome in clinical trials, yet data are limited on the standardization of methodology in children. The goal of this study was to evaluate reproducibility of CIMT measurements using two different measurement techniques. METHODS: Carotid artery ultrasound studies of children and adolescents obtained as a component of a research study in Kawasaki syndrome were retrospectively analyzed. The CIMTs of both common carotid arteries (CCAs) were measured by one of two sonographers at the time in the cardiac cycle when resolution subjectively was determined to be optimal (Opt-CIMT). These sonographers blindly remeasured a random sample of studies of their own and each other's, using the same method. Another observer made CIMT measurements using exclusively frames on the R wave (R-CIMT). A fourth observer independently measured a random sample of studies twice with the R-CIMT method. RESULTS: Carotid artery images from 184 subjects (mean age, 14.7 +/- 2.2 years) were analyzed. The intraclass correlation coefficient for interobserver variability was 0.86 (95% confidence interval [CI], 0.69-0.94) compared with 0.85 (95% CI, 0.65-0.93) for the right and 0.86 (95% CI, 0.67-0.94) versus 0.95 (95% CI, 0.87 0.98) for the left CCA for Opt-CIMT and R-CIMT, respectively. R-CIMT was significantly thicker than Opt-CIMT (right CCA, 0.439 +/- 0.030 vs 0.428 +/- 0.024 mm, P < .001; left CCA, 0.446 +/- 0.030 vs 0.434 +/- 0.025 mm, P < .001). CONCLUSION: Pediatric CIMT measurements have excellent reproducibility when the same methodology is applied but vary significantly throughout the cardiac cycle. This report highlights the need to standardize CIMT measurements in the youth and supports the use of electrocardiographic timing, as recommended in adults, in pediatric longitudinal studies. PMID- 25459502 TI - RETRACTED: Facile, eco-friendly and template free photosynthesis of cauliflower like ZnO nanoparticles using leaf extract of Tamarindus indica (L.) and its biological evolution of antibacterial and antifungal activities. AB - In the present investigation, we chose the very simple and eco-friendly chemical method for synthesis of zinc oxide nanoparticles from leaf extract of Tamarindus indica (L.) (T. indica) and developed the new green route for synthesis of nanoparticles. Formed product has been studied by UV-vis absorption spectroscopy, Photoluminescence (PL) spectroscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Field emission scanning electron microscopy (FE SEM) and with corresponding energy dispersive X-ray analysis (EDX). Mainly, the present results depicted that the synthesized nanoproducts are moderately stable, hexagonal phase, roughly spherical with maximum particles in size range within 19 37 nm in diameter. The antibacterial and fungal activities of aqueous extracts of T. indica were ended with corresponding disk diffusion and Minimum Inhibitory Concentration (MIC). The highest mean zones of inhibition were observed in the ZnO NPs (200 MUg/mL) against Staphylococcus aureus (13.1+/-0.28). Finally, it can be concluded that microbial activity of ZnO NPs has more susceptible S. aureus than the other micro organisms. Further, the present investigation suggests that ZnO NPs has the potential applications for various medical and industrial fields. PMID- 25459503 TI - 2-Pyridinium propanol hydrogen squarate: experimental and computational study of a nonlinear optical material. AB - The experimental and theoretical investigation of a novel organic nonlinear optical (NLO) squarate salt of 2-pyridinium propanol hydrogen squarate (1), C8H12ON(+).C4HO4(-), were reported in this study. The crystal structure of the title compound was found to crystallize in the triclinic P-1 space group. In the asymmetric unit each squaric acid molecules have donated one H atom to the pyridines N1 and N2 atoms of a 2-pyridine propanol molecule, forming the salt (1). The X-ray analysis clearly indicated that the crystal packing has shown the hydrogen bonding ring pattern of D2(2)(10) (alpha-dimer) through N-H?O interactions. The structural and vibrational properties of the compound were also studied by computational methods of ab initio performed on the compound at DFT/B3LYP/6-31++G(d,p) (2) and HF/6-31++G(d,p) (3) level of theory. The calculation results on the basis of two models for both the optimized molecular structure and vibrational properties for the 1 are presented and compared with the X-ray analysis result. The molecular electrostatic potential (MEP), electronic absorption spectra, frontier molecular orbitals (FMOs), conformational flexibility and non-linear optical properties (NLO) of the title compound were also studied at the 2 level and the results are reported. In order to evaluate the suitability for NLO applications thermal analysis (TG, DTA and DTG) data of 1 were also obtained. PMID- 25459504 TI - Application of ultrasonic radiation for simultaneous removal of auramine O and safranine O by copper sulfide nanoparticles: experimental design. AB - In this study, copper sulfide nanoparticles loaded on activated carbon (CuS-NP AC) were synthesized by novel, low cost and green approach and characterized using SEM and XRD. The application of this material for the simulations removal of auramine O (AO) and safranine O (SO) from aqueous solutions was investigated. The dependency of removal percentages to variables such as pH, initial dyes concentration, adsorbent dosage, sonication time and sonication temperature were studied with response surface methodology (RSM) by considering the desirability function (DF). The quadratic model between the dependent and the independent variables was built. The proposed method showed good agreement between the experimental data and predictive value, and it has been successfully employed to removal of AO and SO in aqueous media. The studied adsorbent (0.06 g of CuS-NP AC) was capable of high percentage removal (99.8% and 99.5%) of 18 mg mL(-1) AO and SO in short time (7.0 min). PMID- 25459505 TI - Exploiting external reflection FTIR spectroscopy for the in-situ identification of pigments and binders in illuminated manuscripts. Brochantite and posnjakite as a case study. AB - In the present work, the use of portable instrumentation allowing in-situ reflection FTIR analyses is exploited to identify the coloring matters of northern-Italian illuminations dating to the XVI century. In order to build a database of spectra, reference paint samples were prepared spreading the pigments on parchment with two different binders, i.e. gum arabic and egg white, used in antiquity. Pigments for the database were chosen considering their use in the Middle Ages and in the Renaissance and their response in the mid- and near-IR region. The reflection FTIR spectra obtained resulted to be dominated by the specular reflection component, allowing the use of the Kramers-Kronig transform to convert them to the more conventional absorbance FTIR spectra. Several pigments could thus be identified in ancient illuminations, even if some green details showed a spectral pattern different with respect to the most common commercial green pigments of the database. Therefore, in addition, basic copper sulfates brochantite and posnjakite were synthesized and characterized. In three green details, posnjakite was identified, both as a pure compound and together with malachite. PMID- 25459506 TI - Molecular structure, spectroscopic properties, NLO, HOMO-LUMO and NBO analyses of 6-hydroxy-3(2H)-pyridazinone. AB - The molecular structure and relative stabilities of the six possible isomers of 6 hydroxy-3(2H)-pyridazinone (DHP) in the gas phase and in solutions of different polarities are predicted using the B3LYP/6-311++G(d,p) method. The oxo-hydroxo isomer is the most stable form in the gas phase and in solution. These results agree with our reported X-ray structure. The effect of solvents on the spectroscopic properties of the most stable isomer has been studied using the polarized continuum method (PCM) at the same level of theory. The vibrational spectra of the compound studied are calculated and compared with the experimentally measured FTIR spectra. The electronic spectra in gas phase and in solution were calculated using the TD-DFT method. The most intense absorption band is predicted at 312.4 nm and belongs mainly to a pi->pi(*) transition. In polar solvents, this spectral band undergoes a hypsochromic shift. Two stable dimer forms were calculated at same level of theory. Dimer A is more stable than dimer B, by 6.66 kcal mol(-1). The former is stabilized by stronger O-H?O H-bonds compared to the weaker N-H?O interactions in the latter. The effect of these H bonding interactions on the molecular structure and vibrational spectra of these compounds are predicted. NBO analyses were carried out to investigate the stabilization energy of various inter- and intramolecular charge transfer interactions within the systems studied. PMID- 25459507 TI - Synthesis, characterization, DNA binding and in vitro antimicrobial studies of a novel tetra-substituted N-isopropyl-N-(4-ferrocenylphenyl)-N'-(2,6-diethylphenyl) N"-benzoylguanidine: crystallographic structure and quantum chemical computations. AB - A novel tetra-substituted guanidine, N-isopropyl-N-(4-ferrocenylphenyl)-N'-(2,6 diethylphenyl)-N"-benzoylguanidine (1), [(CH3)2CH)(C5H5FeC5H4C6H4)NC(NHCOC6H5)(NHC6H3(CH2CH3)2] has been synthesized and characterized by elemental analysis, FT-IR, multinuclear ((1)H, (13)C) NMR spectroscopy, single crystal X-rays diffraction analysis and density functional theory based quantum chemical calculations. The torsion angles indicating that the guanidine moiety and carbonyl group are almost co-planar, due to the pseudo hexagonal ring formed by intramolecular N-H?O hydrogen bonds. The DNA interaction studies performed by cyclic voltammetry and UV-visible spectroscopy are in close agreement with the binding constants (K) 1.4*10(4) and 1.2*10(4) respectively. The shift in peak potential, current and absorption maxima of the studied ferrocenyl guanidine in the presence of DNA discovered that CV coupled with UV vis spectroscopy could provide an opportunity to elaborate DNA interaction mechanism, a prerequisite for the design of new drug like agents and understanding the molecular basis of their action. The synthesized compound (1) has also been screened for their antibacterial and antifungal. PMID- 25459509 TI - A mononuclear zinc(II) complex with piroxicam: crystal structure, DNA- and BSA binding studies; in vitro cell cytotoxicity and molecular modeling of oxicam complexes. AB - A new mononuclear Zn(II) complex, trans-[Zn(Pir)2(DMSO)2], where Pir(-) is 4 hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (piroxicam), has been synthesized and characterized. The crystal structure of the complex was obtained by the single crystal X-ray diffraction technique. The interaction of the complex with DNA and BSA was investigated. The complex interacts with FS-DNA by two binding modes, viz., electrostatic and groove binding (major and minor). The microenvironment and the secondary structure of BSA are changed in the presence of the complex. The anticancer effects of the seven complexes of oxicam family were also determined on the human K562 cell lines and the results showed reasonable cytotoxicities. The interactions of the oxicam complexes with BSA and DNA were modeled by molecular docking and molecular dynamic simulation methods. PMID- 25459508 TI - Study on conformational stability, molecular structure, vibrational spectra, NBO, TD-DFT, HOMO and LUMO analysis of 3,5-dinitrosalicylic acid by DFT techniques. AB - In this work we analyzed the vibrational spectra of 3,5-dinitrosalicylic acid (3,5DNSA) molecule. The total energy of eight possible conformers can be calculated by Density Functional Theory with 6-31G(d,p) as basis set to find the most stable conformer. Computational result identify the most stable conformer of 3,5DNSA is C6. The assignments of the vibrational spectra have been carried out by computing Total Energy Distribution (TED). The molecular geometry, second order perturbation energies and Electron Density (ED) transfer from filled lone pairs of Lewis base to unfilled Lewis acid sites for 3,5-DNSA molecular analyzed on the basis of Natural Bond Orbital (NBO) analysis. The formation of inter and intramolecular hydrogen bonding between OH and COOH group gave the evidence for the formation of dimer formation for 3,5-DNSA molecule. The energy and oscillator strength calculated by Time-Dependent Density Functional Theory (TD-DFT) complements with the experimental findings. The simulated spectra satisfactorily coincides with the experimental spectra. PMID- 25459510 TI - Molecular structure, vibrational spectra, natural bond orbital and thermodynamic analysis of 3,6-dichloro-4-methylpyridazine and 3,6-dichloropyridazine-4 carboxylic acid by dft approach. AB - Vibrational spectral analysis of the molecules 3,6-dichloro-4-methylpyridazine (DMP) and 3,6-dichloropyridazine-4-carboxylic acid (DPC) was carried out using FT IR and FT-Raman spectroscopic techniques. The molecular structure and vibrational spectra of DMP and DPC were obtained by the density functional theory (DFT) method, using B3LYP functional, with 6-311++G(d,p) basis set. A detailed interpretation of the Infrared and Raman spectra of the two molecules were reported based on potential energy distribution (PED). The theoretically predicted FTIR and FT-Raman spectra of the titled molecules have been simulated and were compared with the experimental spectra. Determination of electric dipole moment (MU) and hyperpolarizability beta0 helps to study the non-linear optical (NLO) behavior of DMP and DPC. Stability of the molecules arising from hyperconjugative interactions, charge delocalization have been analyzed using natural bond orbital (NBO) analysis. (13)C and (1)H NMR spectra were recorded and (13)C and (1)H NMR chemical shifts of the molecules were calculated using the gauge independent atomic orbital (GIAO) method. UV-visible spectrum of the compounds was also recorded in the region 200-1100 nm and electronic properties, HOMO (Highest Occupied Molecular Orbitals) and LUMO (Lowest Unoccupied Molecular Orbitals) energies were measured by time-dependent TD-DFT approach. Charge density distribution and site of chemical reactivity of the molecule have been studied by mapping electron density isosurface with molecular electrostatic potential (MESP). PMID- 25459511 TI - Spectroscopic, structural and theoretical investigation of bis(4 trimethylammoniumbenzoate) hydroiodide hydrate. AB - The structure of bis(4-trimethylammoniumbenzoate) hydroiodide hydrate 1 has been studied by X-ray diffraction, B3LYP/6-311G(d,p) calculations, FTIR, Raman and NMR spectroscopic techniques. The crystal is polar in monoclinic space group Cc. Two 4-trimethylammoniumbenzoate moieties are joined by a short and asymmetric hydrogen bond of 2.45(2) A. Water molecules are gradually released from the structure, causing shifts in the position of iodine anions, which induces their disorder. The water molecule interacts with 4-trimethylammoniumbenzoate moiety and iodide anion via two O(3)-H(1)?O(1) and O(3)-H(2)?I(1) hydrogen bonds of lengths 2.70(3) and 3.51(1) A. Hydrogen bonds in theoretically predicted structures of 2 and 3 (in vacuum), and 4, 5 (in DMSO) optimized by the B3LYP/6 311G(d,p) approach are slightly longer than in crystal 1. The FTIR spectrum of 1 shows a broad and intense absorption in the 1500-400 cm(-1) region, typical of short hydrogen bonds assigned to the nuas(OHO)+gamma(OHO) vibrations. The correlations between the experimental (13)C and (1)H chemical shifts (deltaexp) of the investigated compound in DMSO and the GIAO/B3LYP/6-311G(d,p) magnetic isotropic shielding constants (sigmacalc) calculated by using the screening solvation model (COSMO) are linear, deltaexp=a+b sigmacalc, and they well reproduce the experimental chemical shifts. PMID- 25459512 TI - Selenium compounds as therapeutic agents in cancer. AB - BACKGROUND: With cancer cells encompassing consistently higher production of reactive oxygen species (ROS) and with an induced antioxidant defense to counteract the increased basal ROS production, tumors have a limited reserve capacity resulting in an increased vulnerability of some cancer cells to ROS. Based on this, oxidative stress has been recognized as a tumor-specific target for the rational design of new anticancer agents. Among redox modulating compounds, selenium compounds have gained substantial attention due to their promising chemotherapeutic potential. SCOPE OF REVIEW: This review aims in summarizing and providing the recent developments of our understanding of the molecular mechanisms that underlie the potential anticancer effects of selenium compounds. MAJOR CONCLUSIONS: It is well established that selenium at higher doses readily can turn into a prooxidant and thereby exert its potential anticancer properties. However, the biological activity of selenium compounds and the mechanism behind these effects are highly dependent on its speciation and the specific metabolic pathways of cells and tissues. Conversely, the chemical properties and the main molecular mechanisms of the most relevant inorganic and organic selenium compounds as well as selenium-based nanoparticles must be taken into account and are discussed herein. GENERAL SIGNIFICANCE: Elucidating and deepening our mechanistic knowledge of selenium compounds will help in designing and optimizing compounds with more specific antitumor properties for possible future application of selenium compounds in the treatment of cancer. This article is part of a Special Issue entitled Redox regulation of differentiation and de differentiation. PMID- 25459513 TI - Magainin-AM2 improves glucose homeostasis and beta cell function in high-fat fed mice. AB - BACKGROUND: Magainin-AM2, a previously described amphibian host-defense peptide, stimulates insulin- and glucagon-like peptide-1-release in vitro. This study investigated anti-diabetic effects of the peptide in mice with diet-induced obesity and glucose intolerance. METHODS: Male National Institute of Health Swiss mice were maintained on a high-fat diet for 12-weeks prior to the daily treatment with magainin-AM2. Various indices of glucose tolerance were monitored together with insulin secretory responsiveness of islets at conclusion of study. RESULTS: Following twice daily treatment with magainin-AM2 for 15 days, no significant difference in body weight and food intake was observed compared with saline treated high fat control animals. However, non-fasting blood glucose was significantly (P<0.05) decreased while plasma insulin concentrations were significantly (P<0.05) increased. Oral and intraperitoneal glucose tolerance and insulin secretion following glucose administration via both routes were significantly (P<0.05) enhanced. The peptide significantly (P<0.001) improved insulin sensitivity as well as the beta cell responses of islets isolated from treated mice to a range of insulin secretagogues. Oxygen consumption, CO2production, respiratory exchange ratio and energy expenditure were not significantly altered by sub-chronic administration of magainin-AM2 but a significant (P<0.05) reduction in fat deposition was observed. CONCLUSION: These results indicate that magainin-AM2 improves glucose tolerance, insulin sensitivity and islet beta cells secretory responsiveness in mice with obesity diabetes. GENERAL SIGNIFICANCE: The activity of magainin-AM2 suggests the possibility of exploiting this peptide for treatment of type 2 diabetes. PMID- 25459514 TI - Mitochondrial proteases act on STARD3 to activate progesterone synthesis in human syncytiotrophoblast. AB - BACKGROUND: STARD1 transports cholesterol into mitochondria of acutely regulated steroidogenic tissue. It has been suggested that STARD3 transports cholesterol in the human placenta, which does not express STARD1. STARD1 is proteolytically activated into a 30-kDa protein. However, the role of proteases in STARD3 modification in the human placenta has not been studied. METHODS: Progesterone determination and Western blot using anti-STARD3 antibodies showed that mitochondrial proteases cleave STARD3 into a 28-kDa fragment that stimulates progesterone synthesis in isolated syncytiotrophoblast mitochondria. Protease inhibitors decrease STARD3 transformation and steroidogenesis. RESULTS: STARD3 remained tightly bound to isolated syncytiotrophoblast mitochondria. Simultaneous to the increase in progesterone synthesis, STARD3 was proteolytically processed into four proteins, of which a 28-kDa protein was the most abundant. This protein stimulated mitochondrial progesterone production similarly to truncated-STARD3. Maximum levels of protease activity were observed at pH7.5 and were sensitive to 1,10-phenanthroline, which inhibited steroidogenesis and STARD3 proteolytic cleavage. Addition of 22(R)-hydroxycholesterol increased progesterone synthesis, even in the presence of 1,10-phenanthroline, suggesting that proteolytic products might be involved in mitochondrial cholesterol transport. CONCLUSION: Metalloproteases from human placental mitochondria are involved in steroidogenesis through the proteolytic activation of STARD3. 1,10-Phenanthroline inhibits STARD3 proteolytic cleavage. The 28-kDa protein and the amino terminal truncated-STARD3 stimulate steroidogenesis in a comparable rate, suggesting that both proteins share similar properties, probably the START domain that is involved in cholesterol binding. GENERAL SIGNIFICANCE: Mitochondrial proteases are involved in syncytiotrophoblast-cell steroidogenesis regulation. Understanding STARD3 activation and its role in progesterone synthesis is crucial to getting insight into its action mechanism in healthy and diseased syncytiotrophoblast cells. PMID- 25459515 TI - Potential biological role of laccase from the sponge Suberites domuncula as an antibacterial defense component. AB - BACKGROUND: Laccases are copper-containing enzymes that catalyze the oxidation of a wide variety of phenolic substrates. METHODS: We describe the first poriferan laccase from the marine demosponge Suberites domuncula. RESULTS: This enzyme comprises three characteristic multicopper oxidase homologous domains. Immunohistological studies revealed that the highest expression of the laccase is in the surface zone of the animals. The expression level of the laccase gene is strongly upregulated after exposure of the animals to the bacterial endotoxin lipopolysaccharide. To allow the binding of the recombinant enzyme to ferromagnetic nanoparticles, a recombinant laccase was prepared which contained in addition to the His-tag, a Glu-tag at the N-terminus of the enzyme. The recombinant laccase was enzymatically active. The apparent Michaelis constant of the enzyme is 114 MUM, using syringaldazine as substrate. Exposure of E. coli to the nanoparticles, coated with Glu-tagged laccase, and to the mediator 2,2'-azino bis(3-ethylbenzothiazoline-6-sulfonic acid) in the presence of lignin, as the oxidizable substrate, resulted in an almost complete inhibition of colony formation. Quantitative studies of the effect of the laccase-coated iron oxide nanoparticles were performed using E. coli grown in suspension in reaction tubes within a magnetic nanoparticle separator. CONCLUSIONS: This newly designed magnetic nanoparticle separator allowed a removal of the nanoparticles after terminating the reaction. Using this system, a strong dose-dependent inhibition of the growth of E. coli by the laccase iron oxide nanoparticles was determined. GENERAL SIGNIFICANCE: From our data we conclude that the sponge laccase is involved in the anti-bacterial defense of the sponge organism. PMID- 25459516 TI - Mitochondrial proteolysis: its emerging roles in stress responses. AB - BACKGROUND: Mitochondria are multifunctional organelles that not only serve as cellular energy stores but are also actively involved in several cellular stress responses, including apoptosis. In addition, mitochondria themselves are also continuously challenged by stresses such as reactive oxygen species (ROS), an inevitable by-product of oxidative phosphorylation. To exert various functions against these stresses, mitochondria must be equipped with appropriate stress responses that monitor and maintain their quality. SCOPE OF REVIEW: Interestingly, increasing evidence indicates that mitochondrial proteolysis has important roles in mitochondrial and cellular stress responses. In this review, we summarize current advances in mitochondrial proteolysis-mediated stress responses. MAJOR CONCLUSIONS: Mitochondrial proteases do not only function as surveillance systems of protein quality control by degrading unfolded proteins but also regulate mitochondrial stress responses by processing specific mitochondrial proteins. GENERAL SIGNIFICANCE: Studies on the regulation of mitochondrial proteolysis-mediated stress responses will provide the novel mechanistic insights into the stress response research fields. PMID- 25459517 TI - Thiophene-based fluorescent probes with low cytotoxicity and high photostability for lysosomes in living cells. AB - BACKGROUND: Selective imaging of lysosomes by fluorescence microscopy using specific fluorescent probes allows the study of biological processes and it is potentially useful also for diagnosis. Lysosomes are involved in numerous physiological processes, such as bone and tissue remodeling, plasma membrane repair, and cholesterol homeostasis, along with cell death and cell signaling. Despite the great number of dyes available today on the market, the search for new fluorescent dyes easily up-taken by cells, biocompatible and bearing bright and long-lasting fluorescence is still a priority. METHODS: Two thiophene-based fluorescent dyes, TC1 and TC2, were synthetized as lysosome-specific probes. RESULTS: The new dyes showed high selectivity for fluorescent staining and imaging of lysosomes and disclosed high photostability, low toxicity and pH insensitivity in the range 2-10. CONCLUSIONS: The TC dyes exhibited high co localization coefficients (>95%) and moderate quantum yields. They showed high biocompatibility and long-term retention, important features for biological applications. GENERAL SIGNIFICANCE: The results of the present work disclose a new class of organic dyes with potential wide applications as specific and efficient lysosome probes in the study of various biological processes. PMID- 25459518 TI - Introduction to the special issue on heart regeneration and rejuvenation. AB - Despite therapeutic advances that slow its progression, heart disease remains the world's leading cause of death. Until recently, the "Holy Grail" of cardiac biology, to regenerate the damaged heart, appeared to be a fantastical and quixotic quest. However, recent studies showing that the mammalian heart possesses an innate, albeit limited, regenerative capacity offer hope that effective cardiac regeneration may be an attainable goal. This Special Issue of Stem Cell Research reviews the remarkable progress that has been made in this field in the last few years. PMID- 25459520 TI - Endotoxemia-induced muscle wasting is associated with the change of hypothalamic neuropeptides in rats. AB - In critical patients, sepsis-induced muscle wasting is considered to be an important contributor to complications and mortality. Previous work mainly focuses on the peripheral molecular mechanism of muscle degradation, however little evidence exists for the role of central nervous system in the process. In the present study, we, for the first time, characterized the relationship between muscle wasting and central neuropeptide changes in a septic model. Thirty-six adult male Sprague-Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) or saline. Twelve, 24 and 48 hrs after injection, skeletal muscle and hypothalamus tissues were harvested. Muscle wasting was measured by the mRNA expression of two E3 ubiquitin ligases, muscle ring finger 1 (MuRF-1) and muscle atrophy F-box (MAFbx), as well as 3-methyl-histidine (3-MH) and tyrosine release. Hypothalamic neuropeptides and inflammatory marker expressions were also measured in three time points. LPS injection caused an increase expression of MuRF-1 and MAFbx, and a significant higher release of 3-MH and tyrosine. Hypothalamic neuropeptides, proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), agouti-related protein (AgRP) and neuropeptide Y (NPY) presented a dynamic change after LPS injection. Also, hypothalamic inflammatory markers, interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) increased substantially after LPS administration. Importantly, the expressions of POMC, AgRP and CART were well correlated with muscle atrophy gene, MuRF-1 expression. These findings suggest hypothalamic peptides and inflammation may participate in the sepsis-induced muscle wasting, but the exact mechanism needs further study. PMID- 25459521 TI - Psychological online consultation service attracts men: a new approach to close the gap between being ill and being treated. AB - BACKGROUND: Since 1999, the University Hospital Zurich (Zurich, Switzerland) has offered an e-mail-based consultation service for individual health concerns where anonymous questions can be asked to an online doctor. This study aimed at the characterization of the user profile, the content of the question, and the answers given specific in the field of psychiatry. MATERIALS AND METHODS: In total, 3,148 questions were asked from 2008 to 2010. Of these, 209 (6.6%) requests were selected by International Classification of Diseases-10 and International Classification of Primary Care codes relevant for psychiatry and included in the retrospective qualitative study. The content analysis of the requests was supported by means of the Mayring inductive category system using a professional text analysis program (MAXQDA). RESULTS: Of the users, 45.9% were female, and 46.9% were male. The mean age was 37.4 years. The main topics of the request were somatoform, somatization, and hypochondriac disorders in 18.4%, behavioral syndromes in 17.9%, and mood disorders in 15.4%. The reason stated most frequently for using the service was looking for a second opinion. The doctors responded with detailed information about disease and treatment and in 70.8% recommended consultation of a physician. CONCLUSIONS: Telemedicine is suggested to empower patients by developing health literacy with professional advice. The gender ratio of the users is almost equal, although the prevalence of psychological diseases in the general population is higher in women than in men. Psychological online consultation may potentially reach mentally ill individuals who do not have or did not seek professional help yet, and it seems to be especially attractive for men. PMID- 25459519 TI - Environmental stressors influence limited-access ethanol consumption by C57BL/6J mice in a sex-dependent manner. AB - Exposure to stress contributes to ethanol consumption in humans, but it produces inconsistent effects on ethanol drinking in rodent models. Therefore, the present study examined the influence of different stressors (restraint, tail suspension, predator odor, foot shock, and tail pinch) on 2-h access to water and 10% ethanol by male and female C57BL/6J mice and determined whether there were sex-dependent differences in response to stress. Plasma corticosterone (CORT) and allopregnanolone (ALLO) were assessed as indexes of hypothalamic-pituitary adrenal axis activity and of endogenous neurosteroid levels, respectively, following restraint, tail suspension, and predator odor. These stressors increased plasma CORT and ALLO levels, and produced a greater increase in CORT and ALLO levels in females versus males. Ethanol intake was decreased following restraint, tail suspension, foot shock, and tail pinch in both sexes, with stressor-related differences in the duration of the suppression. Predator odor significantly increased ethanol intake on the following two days in females and on the second day after stress in males. Notably, there was a significant positive correlation between CORT levels immediately after predator odor stress and ethanol intake on the following day. In summary, the type of stressor influenced ethanol consumption, with subtle sex differences in the magnitude and persistence of the effect. These findings are the first to demonstrate that a single, acute exposure to restraint, tail suspension, and predator odor stress increased plasma CORT and ALLO levels in animals with a history of ethanol consumption and that female mice were more responsive than males to the ability of stress to increase CORT and ALLO levels as well as to increase ethanol intake following predator odor stress. Because predator odor stress is a model of post traumatic stress disorder (PTSD), the present sex differences have important implications for preclinical studies modeling the comorbidity of PTSD and alcohol use disorders. PMID- 25459522 TI - Introduction. PMID- 25459523 TI - Individualized model discovery: the case of anemia patients. AB - The universal sequel to chronic kidney condition (CKD) is anemia. Patients of anemia have kidneys that are incapable of performing certain basic functions such as sensing of oxygen levels to secrete erythropoietin when red blood cell counts are low. Under such conditions, external administration of human recombinant erythropoietin (EPO) is administered as alternative to improve conditions of CKD patients by increasing their hemoglobin (Hb) levels to a given therapeutic range. Presently, EPO dosing strategies extensively depend on packet inserts and on "average" responses to the medication from previous patients. Clearly dosage strategies based on these approaches are, at best, nonoptimal to EPO medication and potentially dangerous to patients that do not adhere to the notion of expected "average" response. In this work, a technique called semi-blind robust identification is provided to uniquely identify models of the individual patients of anemia based on their actual Hb responses and EPO administration. Using the a priori information and the measured input-output data of the individual patients, the procedure identifies a unique model consisting of a nominal model and the associated model uncertainty for the patients. By incorporating the effects of unknown system initial conditions, considerably small measurement samples can be used in the modeling process. PMID- 25459524 TI - The design and evaluation of a peripheral device for use with a computer game intended for children with motor disabilities. AB - Many children with motor impairments cannot participate in games and jokes that contribute to their formation. Currently, commercial computer games there are few options of software and sufficiently flexible access devices to meet the needs of this group of children. In this study, a peripheral access device and a 3D computerized game that do not require the actions of dragging, clicking, or activating various keys at the same time were developed. The peripheral access device consists of a webcam and a supervisory system that processes the images. This method provides a field of action that can be adjusted to various types of motor impairments. To analyze the sensitivity of the commands, a virtual course was developed using the scenario of a path of straight lines and curves. A volunteer with good ability in virtual games performed a short training with the virtual course and, after 15min of training, obtained similar results with a standard keyboard and the adapted peripheral device. A 3D game in the Amazon forest was developed using the Blender 3D tool. This free software was used to model the characters and scenarios. To evaluate the usability of the 3D game, the game was tested by 20 volunteers without motor impairments (group A) and 13 volunteers with severe motor limitations of the upper limbs (group B). All the volunteers (group A and B) could easily execute all the actions of the game using the adapted peripheral device. The majority positively evaluated the questions of usability and expressed their satisfaction. The computerized game coupled to the adapted device will offer the option of leisure and learning to people with severe motor impairments who previously lacked this possibility. It also provided equality in this activity to all the users. PMID- 25459525 TI - Monte-Carlo simulations of clinically realistic respiratory gated (18)F-FDG PET: application to lesion detectability and volume measurements. AB - In PET/CT thoracic imaging, respiratory motion reduces image quality. A solution consists in performing respiratory gated PET acquisitions. The aim of this study was to generate clinically realistic Monte-Carlo respiratory PET data, obtained using the 4D-NCAT numerical phantom and the GATE simulation tool, to assess the impact of respiratory motion and respiratory-motion compensation in PET on lesion detection and volume measurement. To obtain reconstructed images as close as possible to those obtained in clinical conditions, a particular attention was paid to apply to the simulated data the same correction and reconstruction processes as those applied to real clinical data. The simulations required 140,000h (CPU) generating 1.5 To of data (98 respiratory gated and 49 ungated scans). Calibration phantom and patient reconstructed images from the simulated data were visually and quantitatively very similar to those obtained in clinical studies. The lesion detectability was higher when the better trade-off between lesion movement limitation (compared to ungated acquisitions) and image statistic preservation is considered (respiratory cycle sampling in 3 frames). We then compared the lesion volumes measured on conventional PET acquisitions versus respiratory gated acquisitions, using an automatic segmentation method and a 40% threshold approach. A time consuming initial manual exclusion of noisy structures needed with the 40%-threshold was not necessary when the automatic method was used. The lesion detectability along with the accuracy of tumor volume estimates was largely improved with the gated compared to ungated PET images. PMID- 25459526 TI - Pre-angioplasty instantaneous wave-free ratio pullback provides virtual intervention and predicts hemodynamic outcome for serial lesions and diffuse coronary artery disease. AB - OBJECTIVES: The aim of this study was to perform hemodynamic mapping of the entire vessel using motorized pullback of a pressure guidewire with continuous instantaneous wave-free ratio (iFR) measurement. BACKGROUND: Serial stenoses or diffuse vessel narrowing hamper pressure wire-guided management of coronary stenoses. Characterization of functional relevance of individual stenoses or narrowed segments constitutes an unmet need in ischemia-driven percutaneous revascularization. METHODS: The study was performed in 32 coronary arteries with tandem and/or diffusely diseased vessels. An automated iFR physiological map, integrating pullback speed and physiological information, was built using dedicated software to calculate physiological stenosis severity, length, and intensity (DeltaiFR/mm). This map was used to predict the best-case post percutaneous coronary intervention (PCI) iFR (iFRexp) according to the stented location, and this was compared with the observed iFR post-PCI (iFRobs). RESULTS: After successful PCI, the mean difference between iFRexp and iFRobs was small (mean difference: 0.016 +/- 0.004) with a strong relationship between DeltaiFRexp and DeltaiFRobs (r = 0.97, p < 0.001). By identifying differing iFR intensities, it was possible to identify functional stenosis length and quantify the contribution of each individual stenosis or narrowed segment to overall vessel stenotic burden. Physiological lesion length was shorter than anatomic length (12.6 +/- 1.5 vs. 23.3 +/- 1.3, p < 0.001), and targeting regions with the highest iFR intensity predicted significant improvement post-PCI (r = 0.86, p < 0.001). CONCLUSIONS: iFR measurements during continuous resting pressure wire pullback provide a physiological map of the entire coronary vessel. Before a PCI, the iFR pullback can predict the hemodynamic consequences of stenting specific stenoses and thereby may facilitate the intervention and stenting strategy. PMID- 25459527 TI - Outcomes after percutaneous coronary intervention with stents in patients treated with thoracic external beam radiation for cancer. AB - OBJECTIVES: The aim of this study was to assess outcomes after percutaneous coronary intervention (PCI) with stents in patients treated with thoracic external beam radiation therapy (EBRT). BACKGROUND: Thoracic EBRT for cancer is associated with long-term cardiotoxic sequelae. The impact of EBRT on patients requiring coronary stents is unclear. METHODS: We analyzed outcomes after PCI in cancer survivors treated with curative thoracic EBRT before and after stenting between 1998 and 2012. Reference groups were propensity-matched cohorts with stenting but no EBRT. Primary endpoint was target lesion revascularization (TLR), a clinical surrogate for restenosis. Secondary endpoints included myocardial infarction (MI) and cardiac and overall mortality. RESULTS: We identified 115 patients treated with EBRT a median 3.6 years after stenting (group A) and 45 patients treated with EBRT a median 2.2 years before stenting (group B). Long term mean TLR rates in group A (3.2 vs. 6.6%; hazard ratio: 0.6; 95% confidence interval: 0.2 to 1.6; p = 0.31) and group B (9.2 vs. 9.7%; hazard ratio: 1.2; 95% confidence interval: 0.4 to 3.4; p = 0.79) were similar to rates in corresponding control patients (group A: 1,390 control patients; group B: 439 control patients). Three years post-PCI, group A had higher overall mortality (48.6% vs. 13.9%; p < 0.001) but not MI (4.8% vs. 4.3%; p = 0.93) or cardiac mortality (2.3% vs. 3.6%; p = 0.66) rates versus control patients. There were no significant differences in MI, cardiac, or overall mortality rates in group B. CONCLUSIONS: Thoracic EBRT is not associated with increased stent failure rates when used before or after PCI. A history of PCI should not preclude the use of curative thoracic EBRT in cancer patients or vice versa. Optimal treatment of cancer should be the goal. PMID- 25459528 TI - Pre-angioplasty instantaneous wave-free ratio pullback and virtual revascularization: the pressure wire as a crystal ball. PMID- 25459529 TI - On the BCS biowaivers of orally disintegrating tablets. AB - A recent paper in this journal by Ono and Sugano (2014) suggests BCS-based biowaivers can be applied to assess the bioequivalence of orally disintegrating tablets (ODTs) with immediate release formulations for Class III drugs. The assertion made by the paper is a concern for us for reasons including the following: the supposition has not been tested with products that have differing bioavailabilities, the most common posology for administration of ODTs does not appear to have been considered, and there is a risk of differences in bioavailability between ODTs taken without water and immediate release products because of differences in gastric emptying. PMID- 25459530 TI - The effect of multidrug resistance modulator HZ08 on pharmacodynamics and pharmacokinetics of adriamycin in xenograft-nude mice. AB - To overcome MDR (multidrug resistance) of cancer mediated by P-gp (P glycoprotein) has become a key strategy to improve the survival rate in clinic. Therefore, it is imperative to develop advanced modulators that have no side effects or interactions with cytotoxic drugs. HZ08, which acts as a P-gp inhibitor, shows a notable reverse effect with low cytotoxicity in vitro. Based on the previous results, the goal of this experiment is to elucidate the effect of HZ08 on pharmacodynamics and pharmacokinetics of adriamycin in tumor-bearing nude mice. Several criterions and methods, such as tumor weight and volume, in vivo imaging, western blot, immunohistochemistry as well as ATPase hydrolysis assay were selected to evaluate the reversing activity and mechanism of HZ08 on MDR; Furthermore, fluorescence detection assay was applied to determine the distribution of adriamycin in the blood and tissues. This study revealed that HZ08 potentiated the anti-tumor activity of adriamycin but with little effect on the expression of P-gp in vivo. Adriamycin accumulation in tumor was enhanced by HZ08 via ATPase activity inhibition. In addition, HZ08 did not alter the pharmacokinetic characteristic of adriamycin in plasma or tissues. In conclusion, HZ08 showed dramatic MDR reversing activity and had no influence on the pharmacokinetics of adriamycin. PMID- 25459531 TI - Enhanced pulmonary immunization with aerosolized inactivated influenza vaccine containing delta inulin adjuvant. AB - Vaccination is the primary intervention to contain influenza virus spread during seasonal and pandemic outbreaks. Pulmonary vaccination is gaining increasing attention for its ability to induce both local mucosal and systemic immune responses without the need for invasive injections. However, pulmonary administration of whole inactivated influenza virus (WIV) vaccine induces a Th2 dominant systemic immune response while a more balanced Th1/Th2 vaccine response may be preferred and only induces modest nasal immunity. This study evaluated immunity elicited by pulmonary versus intramuscular (i.m.) delivery of WIV, and tested whether the immune response could be improved by co-administration of delta (delta)-inulin, a novel carbohydrate-based particulate adjuvant. After pulmonary administration both unadjuvanted and delta-inulin adjuvanted WIV induced a potent systemic immune response, inducing higher serum anti-influenza IgG titers and nasal IgA titers than i.m. administration. Moreover, the addition of delta-inulin induced a more balanced Th1/Th2 response and induced higher nasal IgA titers versus pulmonary WIV alone. Pulmonary WIV alone or with delta-inulin induced hemagglutination inhibition (HI) titers>40, titers which are considered protective against influenza virus. In conclusion, in this study we have shown that delta-inulin adjuvanted WIV induces a better immune response after pulmonary administration than vaccine alone. PMID- 25459533 TI - Crop-destroying fungal and oomycete pathogens challenge food security. AB - Of the various crop pests and pathogens which blight our harvests, it is the fungi and oomycetes which are the most widely-dispersed groups and which lead the global invasion of agriculture. Here, we highlight the rapid growth in fungal and oomycete disease incidence and spread across the globe. We draw attention to the need for improved disease surveillance and for more sustainable agricultural intensification and consider the economic and humanitarian costs of fungal and oomycete diseases. PMID- 25459532 TI - Intravenous administration of Factor VIII-O-Phospho-L-Serine (OPLS) complex reduces immunogenicity and preserves pharmacokinetics of the therapeutic protein. AB - Hemophilia A is a bleeding disorder caused by the deficiency of an important coagulation factor; Factor VIII (FVIII). Replacement therapy using exogenously administered recombinant FVIII is the most commonly used method of treatment. However, approximately 30% of Hemophilia A patients develop neutralizing antibodies (Nabs) against the recombinant protein. Nabs abolish FVIII activity and drastically influence efficacy of the protein. The immunogenic epitopes of FVIII reside predominantly in the C2 domain of FVIII. However, the C2 domain also contains a lipid binding region. O-Phospho-L-Serine (OPLS) which is the head group moiety of phosphatidylserine, interacts with the lipid binding region of FVIII. Previous studies have shown that FVIII complexed with OPLS lowered Nab development against FVIII following subcutaneous administration. In dendritic cell-T-cell co-culture studies, OPLS treatment increased the secretion of immunosuppressive cytokines (Transforming Growth Factor-beta and Interleukin-10), and simultaneously decreased pro-inflammatory IL-17 cytokine. Here, we investigated FVIII immune response and pharmacokinetics upon intravenous administration of FVIII-OPLS complex. We studied the effect of FVIII-OPLS complex on the interaction between a professional antigen presenting cell; dendritic cell and T-cell, and T-cell clonal expansion. Pharmacokinetics parameters were estimated following intravenous administration of FVIII and FVIII-OPLS. The results suggest that OPLS lowers FVIII immune response following intravenous administration. OPLS also hinders FVIII-specific T-cell clonal proliferation and preserves FVIII PK profile. Thus, the ease of protein-lipid complexation, preservation of FVIII activity and in vivo behavior, and improved in vitro FVIII stability, makes OPLS an attractive excipient in the preparation of next generation or biosimilar FVIII products with improved safety profile. PMID- 25459534 TI - Kinesin-3 in the basidiomycete Ustilago maydis transports organelles along the entire microtubule array. AB - The molecular motor kinesin-3 transports early endosomes along microtubules in filamentous fungi. It was reported that kinesin-3 from the ascomycete fungi Aspergillus nidulans and Neurospora crassa use a subset of post-translationally modified and more stable microtubules. Here, I show that kinesin-3 from the basidiomycete Ustilago maydis moves along all hyphal microtubules. This difference is likely due to variation in cell cycle control and associated organization of the microtubule array. PMID- 25459535 TI - Defining the genome-wide role of CRE1 during carbon catabolite repression in Trichoderma reesei using RNA-Seq analysis. AB - The ascomycete Trichoderma reesei is one of the most well-studied cellulolytic fungi and is widely used by the biotechnology industry in the production of second generation bioethanol. The carbon catabolite repression (CCR) mechanism adopted by T. reesei is mediated by the transcription factor CRE1. CCR represses genes related to cellulase production when a carbon source is readily available in the medium. Using RNA sequencing, we investigated CCR during the synthesis of cellulases, comparing the T. reesei Deltacre1 mutant strain with its parental strain, QM9414. Of 9129 genes in the T. reesei genome, 268 genes were upregulated and 85 were downregulated in the presence of cellulose (Avicel). In addition, 251 genes were upregulated and 230 were downregulated in the presence of a high concentration of glucose. Genes encoding cellulolytic enzymes and transcription factors and genes related to the transport of nutrients and oxidative metabolism were also targets of CCR, mediated by CRE1 in a carbon source-dependent manner. Our results also suggested that CRE1 regulates the expression of genes related to the use of copper and iron as final electron acceptors or as cofactors of enzymes that participate in biomass degradation. As a result, the final effect of CRE1 mediated transcriptional regulation is to modulate the access of cellulolytic enzymes to cellulose polymers or blocks the entry of cellulase inducers into the cell, depending on the glucose content in the medium. These results will contribute to a better understanding of the mechanism of carbon catabolite repression in T. reesei, thereby enhancing its application in several biotechnology fields. PMID- 25459536 TI - Gene expression associated with intersterility in Heterobasidion. AB - Intersterility (IS) is thought to prevent mating compatibility between homokaryons that belong to different species. Although IS in Heterobasidion is regulated by the genes located at the IS loci, it is not yet known how the IS genes influence sexual compatibility and heterokaryon formation. To increase our understanding of the molecular events underlying IS, we studied mRNA abundance changes during IS compatible and incompatible interactions over time. The clustering of the transcripts into expression profiles, followed by the application of Gene Ontology (GO) enrichment pathway analysis of each of the clusters, allowed inference of biological processes participating in IS. These analyses identified events involved in mating and sexual development (i.e., linked with IS compatibility), which included processes associated with cell-cell adhesion and recognition, cell cycle control and signal transduction. We also identified events potentially involved in overriding mating between individuals belonging to different species (i.e., linked with IS incompatibility), which included reactive oxygen species (ROS) production, responses to stress (especially to oxidative stress), signal transduction and metabolic biosynthesis. Our findings thus enabled detection and characterization of gene expression changes associated with IS in Heterobasidion, as well as identification of important processes and pathways associated with this phenomenon. Overall, the results of this study increase current knowledge regarding the molecular mechanisms underpinning IS in Heterobasidion and allowed for the establishment of a vital baseline for further studies. PMID- 25459537 TI - The role of AtfA and HOG MAPK pathway in stress tolerance in conidia of Aspergillus fumigatus. AB - Aspergillus fumigatus is a life-threatening pathogenic fungus, whose conidium is the infectious agent of aspergillosis. To better understand the mechanism underlying the long-term viability of conidia, we characterized a bZip transcription factor, AtfA, with special reference to stress-tolerance in conidia. The atfA deletion mutant conidia showed significant sensitivity to high temperature and oxidative stress. The trehalose content that accumulated in conidia was reduced in the mutant conidia. Transcriptome analysis revealed that AtfA regulated several stress-protection-related genes such as catA, dprA, scf1, and conJ at the conidiation stage. The upstream high-osmolarity glycerol pathway was also involved in conferring stress tolerance in conidia because DeltapbsB showed stress sensitivity and reduced trehalose in conidia. However, a mutant lacking the SakA mitogen-activated protein kinase (MAPK) produced normal conidia. We investigated another MAPK, MpkC, in relation with SakA, and the double deletion mutant, DeltasakA,mpkC, was defective in conidia stress tolerance. We concluded that MpkC is able to bypass SakA, and the two MAPKs redundantly regulate the conidia-related function of AtfA in A. fumigatus. PMID- 25459538 TI - Changing demographics of the American population. AB - Since 1950, the United States has been in the midst of a profound demographic change: the rapid aging of the population. The baby boom generation began turning 65 in 2011 and is now driving growth at the older ages of the population. This article highlights geriatric demographic changes and illustrates how these and future trends will have wide ranging implications for the US health care system. PMID- 25459539 TI - Health care: economic impact of caring for geriatric patients. AB - National health care expenditures constitute a continuously expanding component of the US economy. Health care resources are distributed unequally among the population, and geriatric patients are disproportionately represented. Characterizing this group of individuals that accounts for the largest percentage of US health spending may facilitate the introduction of targeted interventions in key high-impact areas. Changing demographics, an increasing incidence of chronic disease and progressive disability, rapid technological advances, and systemic market failures in the health care sector combine to drive cost. A multidisciplinary approach will become increasingly necessary to balance the delicate relationship between our constrained supply and increasing demand. PMID- 25459540 TI - Effect of aging on cardiac function plus monitoring and support. AB - Cardiovascular disease is the most prevalent and influential comorbidity affecting outcomes in geriatric surgical patients. The unique physiology of the aging cardiovascular system and the impact of these changes during the stress of surgery is presented in this article. The necessary response to these changes is discussed with attention to methods of monitoring and recommendations for providing supportive care. PMID- 25459541 TI - Effect of aging on the vascular system plus monitoring and support. AB - Cardiovascular diseases have become a major cause of morbidity and mortality and are likely to only increase as the geriatric population continues to grow. Much is already known about the basic risk factors associated with vascular aging, but there is a new direction of investigation into the health and viability of the endothelium at a biochemical level. As we continue to shift much of our health care focus into prevention tactics and techniques, slowing or reversing the aging process of the vascular system could have a profound impact on our aging population. PMID- 25459542 TI - The effect of aging on pulmonary function: implications for monitoring and support of the surgical and trauma patient. AB - Age-related anatomic, physiologic, and immunologic changes to the pulmonary system, as well as a high prevalence of chronic pulmonary diseases, puts the geriatric patient at an especially high risk for postoperative pulmonary complications. Successful perioperative respiratory care of the geriatric patient relies on careful risk assessment and optimization of pulmonary function and support. The success of such efforts aimed at preventing and/or mitigating pulmonary complications in the geriatric patient depends on a thorough, individualized, yet standardized and evidence-based approach to the care of every patient. PMID- 25459543 TI - Effect of aging on renal function plus monitoring and support. AB - Several anatomic changes and physiologic alterations occur in the aging kidney, awareness of which is essential for the early recognition of acute kidney injury (AKI) to improve outcomes in hospitalized geriatric patients. There are no unique diagnostic methods or treatment modalities in the care of the geriatric patient with AKI. Therapy is mainly supportive, and the full spectrum of treatment options, including renal replacement therapy (RRT), should not be withheld from a patient based on age. More studies need to be performed to determine the optimal timing, intensity, and modality of RRT in the geriatric population. PMID- 25459544 TI - Management of the gastrointestinal tract and nutrition in the geriatric surgical patient. AB - Aging is associated with physiological changes in the gut and with physical and psychosocial risk factors that predispose to malnutrition, particularly in the presence of disease states. The geriatric faction of the surgical population is increasing, and malnourished, critically ill geriatric surgical patients have worse outcomes. The authors discuss the assessment of nutritional risk, recognition of risk factors, statement of dietary goals, and appropriate nutritional interventions in critically ill geriatric surgical patients. PMID- 25459545 TI - Management of the skin and soft tissue in the geriatric surgical patient. AB - Aging has significant effects on the healing ability of the geriatric population. When the elderly suffer injuries, they have a decreased metabolic reserve to handle the stress required to recover. Diseases of the elderly, such as malnutrition, diabetes mellitus, treatment of malignancies, and vascular disease, all impair tissue repair. The geriatric population is more prone to pressure ulcers, venous stasis ulcers, and other chronic wounds. This review discusses how changes in the elderly lead to impaired healing or chronic wounds. Prevention of these problems and their treatment are also discussed. PMID- 25459546 TI - Management of fractures in a geriatric surgical patient. AB - Trauma is an increasingly common problem in geriatric patients; fractures are frequent among the elderly. Life expectancy continues to rise. Advances in medical care allow people to live longer and better lives. Medications, surgical advances (treatment for coronary artery disease, coronary bypass grafting), and joint replacement surgery can be safely performed in elderly patients. Thus, geriatric patients are no longer confined to a life of inactivity. They are out of their homes and interacting in the community, exercising and leading active lives. Thus, they are more likely to become injured and present to trauma centers for care. PMID- 25459548 TI - Pharmacology for the geriatric surgical patient. AB - Alterations in pharmacokinetics and pharmacodynamics place geriatric patients at an increased risk of experiencing an adverse drug event. The incidence of medication-related adverse events can be decreased with careful selection of agents and appropriate dosage adjustments. PMID- 25459547 TI - Hematologic issues in the geriatric surgical patient. AB - Geriatric patients are at higher risk for hemorrhagic complications after surgery and traumatic injuries. The geriatric population is more likely to take anticoagulant or antiplatelet medications. Chronic disease, autoimmune disease, and nutritional deficiencies can lead to coagulation factor and platelet disorders. One must be familiar with the current anticoagulant and antiplatelet medications, their mechanism of action, and reversal agents to properly care for this group of patients. The new oral anticoagulants do not have Food and Drug Administration (FDA) approved reversal agents, but known procoagulant agents with other FDA indications may be effective. PMID- 25459549 TI - Operative risk stratification in the older adult. AB - As the population ages, the health care system must to adapt to the needs of the older population. Hospitalization risks are particularly significant in the frail geriatric patients, with costly and morbid consequences. Appropriate preoperative assessment can identify sources of increased risk and enable the surgical team to manage this risk, through "prehabilitation," intraoperative modification, and postoperative care. Geriatric preoperative assessment expands usual risk stratification and careful medication review to include screening for functional disability, cognitive impairment, nutritional deficiency, and frailty. The information gathered can also equip the surgeon to develop a patient-centered and realistic treatment plan. PMID- 25459550 TI - Rehabilitation of the geriatric surgical patient: predicting needs and optimizing outcomes. AB - Geriatric surgical and trauma patients often require institutionalization following acute hospitalization, generally related to frailty. The potential need for rehabilitation can be assessed using various tools. Once the likelihood of rehabilitation needs is established, early involvement of the rehabilitation team is warranted. Rehabilitation interventions can be initiated during acute hospitalization, and even in the intensive care unit. The rehabilitation team addresses a tremendous spectrum of issues, and targeted interventions are carried out by various team members. There are many gaps in current knowledge of the benefits of rehabilitation interventions. Understanding common standardized assessment tools is important to assess the literature and advance the field. PMID- 25459551 TI - End-of-life care of the geriatric surgical patient. AB - Providing end-of-life care is a necessity for nearly all health care providers and especially those in surgical fields. Most surgical practices will involve caring for geriatric patients and those with life-threatening or terminal illnesses where discussions about end-of-life decision making and goals of care are essential. Understanding the differences between do not resuscitate (DNR), palliative care, hospice care, and symptom management in patients at the end of life is a critical skill set. PMID- 25459552 TI - Caring for geriatric surgical patients. PMID- 25459553 TI - Caring for the geriatric surgical patient. PMID- 25459554 TI - Migration and invasion of oral squamous carcinoma cells is promoted by WNT5A, a regulator of cancer progression. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) constitutes 90% of all cancers in the oral cavity, and the prognosis for patients diagnosed with OSCC is still poor. The identification of novel therapeutic targets and prognostic markers for OSCC is therefore essential. Previous studies of OSCC revealed an increased expression of WNT5A in the tumor tissue. However, no functional studies of WNT5A induced effects in OSCC have been performed. METHODS: Two different OSCC cell lines were used for analysis of WNT5A expression by Western blot, whereas WNT5A induced responses were analyzed by measuring calcium (Ca2+) signaling, PKC activation, migration and invasion. RESULTS: Despite the lack of WNT5A expression, both cell lines responded to recombinant WNT5A (rWNT5A) with activation of the non-canonical WNT/Ca2+ /PKC pathway. This effect was ascertained to be mediated by WNT5A by use of the WNT5A antagonist, Box5. To investigate how WNT5A affects tumor progression, rWNT5A-induced alterations in BrdU absorbance (reflecting the number of tumor cells) were analyzed. rWNT5A had no effect on BrdU absorbance but instead promoted tumor cell migration and invasion. These results were confirmed by the use of the WNT5A-mimicking peptide Foxy5, while the rWNT5A-induced migration was blocked by secreted Frizzled related protein 1 (SFRP1), protein kinase C inhibitors or the intracellular Ca2+ chelator, MAPT. CONCLUSIONS: These novel data clearly show that WNT5A activates the non-canonical WNT/Ca2+ /PKC pathway and increases migration and invasion of OSCC cells. This may indicate how an increased WNT5A expression in the tumor tissue is likely to promote progression of OSCC. PMID- 25459555 TI - Portal vein thrombosis is not associated with increased mortality among patients with cirrhosis. AB - BACKGROUND & AIMS: Portal vein thrombosis (PVT) is common in patients with cirrhosis and may have adverse clinical consequences. We investigated whether PVT is associated with survival in patients with cirrhosis. METHODS: Using the United Network for Organ Sharing registries from 2002 through 2013, we followed a cohort of transplant-naive adults with cirrhosis without hepatocellular carcinoma (N = 66,506) from the time of transplant listing until the time of liver transplantation or death before transplantation. We used Cox proportional hazards analysis and competing risks analysis to compare patients who had PVT at the time of listing (n = 2207) with those who did not (n = 64,299) with regard to the risk of transplantation or death before transplantation, after adjusting for important baseline characteristics. RESULTS: During a mean follow-up period of 1.78 years, 17,757 (27%) patients died before liver transplantation, 29,179 (44%) patients underwent transplantation, and 19,570 (29%) patients were still alive without having undergone transplantation. Compared with patients who did not have PVT, patients with PVT had lower mortality (adjusted hazard ratio [AHR], 0.88; 95% confidence interval [CI], 0.81-0.96), a similar risk of transplantation (AHR, 0.95; 95% CI, 0.89-1.02), and a lower risk of the combined outcome of death or transplantation (AHR, 0.92; 95% CI, 0.88-0.97). Similar results were found by competing risks analyses. Independent predictors of mortality included age, model for end-stage liver disease score, serum albumin level, ascites, encephalopathy, diabetes, hepatitis C virus infection, and low body mass index (<24.4 kg/m(2)). CONCLUSIONS: Among patients with cirrhosis on liver transplant waiting lists, patients with PVT have lower mortality than patients without PVT. PMID- 25459556 TI - No evidence for efficacy of radiofrequency ablation for treatment of gastroesophageal reflux disease: a systematic review and meta-analysis. AB - BACKGROUND & AIMS: A radiofrequency ablation technique known as Stretta was recommended by the Society of American Gastrointestinal and Endoscopic Surgeons as an alternative treatment for gastroesophageal reflux disease (GERD). However, randomized controlled trials of the efficacy of Stretta have produced conflicting findings, and those from previous systematic reviews were compromised as a result of deficiencies in study conduct and reporting of findings. We performed a systematic review to evaluate all evidence on the efficacy of Stretta for the management of GERD. METHODS: We searched MEDLINE and the Cochrane Central Register of Controlled Trials (The Cochrane Library) from inception until February 28, 2014, along with other databases, for randomized controlled trials of Stretta in patients with GERD. Primary outcomes were physiologic parameters of GERD, including normalization of esophageal pH values and augmentation of lower esophageal sphincter pressure (LESP). Secondary outcomes were health-related quality of life (HRQOL) and ability to stop the use of proton pump inhibitors (PPIs). For quality assurance purposes, 2 investigators were involved throughout the study. Data were pooled under a random-effects model. The systematic review was performed as per the standards of the Cochrane collaboration. RESULTS: We collected data from 4 trials and a total of 165 patients (153 patients were analyzed). Three trials compared Stretta vs sham, and 1 trial compared Stretta with PPI therapy. The overall quality of evidence was very low. The pooled results showed no difference between Stretta and sham or management with PPI in patients with GERD for the outcomes of mean (%) time the pH was less than 4 over a 24-hour time course, LESP, ability to stop PPIs, or HRQOL. CONCLUSIONS: In a meta-analysis of trials, we found that Stretta for patients with GERD does not produce significant changes, compared with sham therapy, in physiologic parameters, including time spent at a pH less than 4, LESP, ability to stop PPIs, or HRQOL. PMID- 25459557 TI - Perinatal risk factors for development of celiac disease in children, based on the prospective Norwegian Mother and Child Cohort Study. AB - BACKGROUND & AIMS: There have been inconsistent reports of prenatal and perinatal factors that affect risk for development of celiac disease. We assessed the association of fetal growth, birth weight, and mode of delivery with development of celiac disease within the Norwegian Mother and Child (MoBa) Cohort Study. METHODS: The MoBa cohort contains pregnancy information on 95,200 women and data on their 114,500 children, which were collected in Norway from 1999 through 2008; it is linked to the Medical Birth Registry. Women and children with celiac disease were identified from the National Patient Registry and from women's responses to MoBa questionnaires. We calculated odds ratios (ORs) for celiac disease by using a multivariable logistic regression model, adjusting for maternal celiac disease, sex of children, and children's age (model 1); in a second model, we adjusted for age of gluten introduction and duration of breastfeeding (model 2). RESULTS: We identified 650 children with celiac disease and 107,828 controls in the MoBa database. We found no association between birth weight or height with celiac disease (born small for gestational age was not associated). Celiac disease was not associated with mode of delivery (cesarean section, model 1: OR, 0.84; 95% confidence interval [CI], 0.65-1.09, and model 2: OR, 0.83; 95% CI, 0.63-1.09). Maternal celiac disease, adjusted for age and sex of the children (OR, 12.45; 95% CI, 8.29-18.71) and type 1 diabetes (model 1: OR, 2.58; 95% CI, 1.19-5.53, and model 2: OR, 2.61; 95% CI, 1.14-5.98) were associated with development of celiac disease in children, whereas maternal type 2 diabetes and gestational diabetes were not. CONCLUSIONS: On the basis of analysis of the Norwegian MoBa cohort, development of celiac disease in children is significantly associated with sex of the child, maternal celiac disease, and type 1 diabetes but not with intrauterine growth. PMID- 25459559 TI - The CROWN initiative: journal editors invite researchers to develop core outcomes in women's health. PMID- 25459558 TI - Nonalcoholic fatty liver disease increases the risk of hepatocellular carcinoma in patients with alcohol-associated cirrhosis awaiting liver transplants. AB - BACKGROUND & AIMS: Many patients with alcohol-associated cirrhosis also have diabetes, obesity, or insulin resistance-mediated steatosis, but little is known about how these disorders affect the severity of liver disease. We analyzed the prevalence and prognostic implications of metabolic risk factors (MRFs) such as overweight, diabetes, dyslipidemia, and hypertension in patients with alcohol associated cirrhosis awaiting liver transplants. METHODS: We performed a retrospective study of 110 patients with alcohol-associated cirrhosis (77% male; mean age, 55 y; 71% with >6 mo of abstinence) who received liver transplants at a single center in Paris, France, from 2000 through 2013. We collected data on previous exposure to MRFs, steatosis (>10% in the explant), and histologically confirmed hepatocellular carcinoma (HCC). RESULTS: HCC was detected in explants from 29 patients (26%). Steatosis was detected in explants from 47 patients (70% were abstinent for >=6 mo); 50% had a history of overweight or type 2 diabetes. Fifty-two patients (47%) had a history of MRFs and therefore were at risk for nonalcoholic fatty liver disease. A higher proportion of patients with MRF had HCC than those without MRF (46% vs 9%; P < .001). A previous history of overweight or type 2 diabetes significantly increased the risk for HCC (odds ratio, 6.23; 95% confidence interval [CI], 2.47-15.76, and odds ratio, 4.63; 95% CI, 1.87-11.47, respectively; P < .001). MRF, but not steatosis, was associated with the development of HCC (odds ratio, 11.76; 95% CI, 2.60-53; P = .001) independent of age, sex, amount of alcohol intake, or severity of liver disease. CONCLUSIONS: Patients with alcohol-associated cirrhosis who received transplants frequently also had nonalcoholic fatty liver disease. MRFs, particularly overweight, obesity, and type 2 diabetes, significantly increase the risk of HCC. PMID- 25459560 TI - Noninvasive prenatal testing: need for informed enthusiasm. PMID- 25459561 TI - State-based maternal death reviews: assessing opportunities to alter outcomes. PMID- 25459562 TI - Molecular epidemiology of Aspergillus collected from cystic fibrosis patients. AB - BACKGROUND: Aspergillus respiratory infection is a common complication in cystic fibrosis (CF) and is associated with loss of pulmonary function and allergic disease. METHODS: Fifty-three Aspergillus isolates recovered from CF patients were identified to species by Internal Transcribed Spacer Region (ITS), beta tubulin, and calmodulin sequencing. RESULTS: Three species complexes (Terrei, Nigri, and Fumigati) were found. Identification to species level gave a single Aspergillus terreus sensu stricto, one Aspergillus niger sensu stricto and 51 Aspergillus fumigatus sensu stricto isolates. No cryptic species were found. CONCLUSIONS: To our knowledge, this is the first prospective study of Aspergillus species in CF using molecular methods. The paucity of non-A. fumigatus and of cryptic species of A. fumigatus suggests a special association of A. fumigatus sensu stricto with CF airways, indicating it likely displays unique characteristics making it suitable for chronic residence in that milieu. These findings could refine an epidemiologic and therapeutic approach geared to this pathogen. PMID- 25459563 TI - Implications of multiple freeze-thawing on respiratory samples for culture independent analyses. AB - BACKGROUND: Best practice when performing culture-independent microbiological analysis of sputum samples involves their rapid freezing and storage at -80 degrees C. However, accessing biobanked collections can mean that material has been passed through repeated freeze-thaw cycles. The aim of this study was to determine the impact of these cycles on microbial community profiles. METHODS: Sputum was collected from eight adults with cystic fibrosis, and each sample was subjected to six freeze-thaw cycles. Following each cycle, an aliquot was removed and treated with propidium monoazide (PMA) prior to DNA extraction and 16S rRNA gene pyrosequencing. RESULTS: The impact of freeze-thaw cycles was greatest on rare members of the microbiota, with variation beyond that detected with within sample repeat analysis observed after three cycles. CONCLUSION: Four or more freeze thaw cycles result in a significant distortion of microbiota profiles from CF sputum. PMID- 25459564 TI - Opportunities for cystic fibrosis care teams to support treatment adherence. AB - BACKGROUND: The purpose of this study was to identify the extent to which pediatric and adult cystic fibrosis (CF) care teams implement best practices in adherence assessment and counseling. METHODS: All US CF Foundation accredited programs were invited to participate in a web-based survey; 80% (92/115) of pediatric and 40% (38/95) of adult centers participated. Health care providers reported on current approaches and barriers to implementing adherence promotion practices. RESULTS: 64% discussed adherence at every clinic visit while only 8% used an objective assessment of adherence. Most centers reported frequent use of strategies to increase knowledge; behavioral and support strategies were used less regularly. Several barriers to adherence promotion were reported. CONCLUSIONS: Many opportunities exist for care teams to improve consistency in adherence practices and integrate a greater repertoire of effective counseling strategies into clinic visits. Adherence promotion practices should be considered for quality improvement (QI) projects. PMID- 25459565 TI - Hypothermia slows sequential and parallel steps initiated during caerulein pancreatitis. AB - BACKGROUND AND OBJECTIVES: Multiple deleterious signaling cascades are simultaneously activated in acute pancreatitis (AP), which may limit the success of pharmacologic approaches targeting a single step. We explored whether cooling acinar cells slows distinct steps initiated from a stimulus causing pancreatitis simultaneously, and the temperature range over which inhibition of such deleterious signaling occurs. METHODS: Caerulein (100 nM) induced trypsinogen activation (TGA), CXCL1, CXCL2 mRNA levels, cell injury were studied at 37 degrees C, 34 degrees C, 31 degrees C, 29 degrees C and 25 degrees C in acinar cells. Trypsin, cathepsin B activities and cathepsin B mediated TGA were studied at 37 degrees C, 23 degrees C and 4 degrees C. RESULTS: There was >80% reduction in TGA, CXCL1 and CXCL2 mRNA levels at 29 degrees C, and in cell injury at 34 degrees C, compared to those at 37 degrees C. Trypsin activity, cathepsin B activity and cathepsin B mediated TGA at 23 degrees C were respectively, 53%, 64% and 26% of that at 37 degrees C. Acinar cooling to 31 degrees C reduced LDH leakage even when cooling was initiated an hour after caerulein stimulation at 37 degrees C. CONCLUSIONS: Hypothermia synergistically and simultaneously slows parallel and distinct signaling steps initiated by caerulein, thereby reducing TGA, upregulation of inflammatory mediators and acinar injury. PMID- 25459566 TI - Management of a metastasized high grade insulinoma (G3) with refractory hypoglycemia: case report and review of the literature. AB - Insulinomas represent the most common functional neuroendocrine tumor of the pancreas. They are usually solitary, benign, well differentiated (G1/G2) and curable by surgery. We describe the case of a 45 year old male Caucasian with a unique malignant, metastasized pancreatic insulinoma (Ki 67 of 70%, G3). To control excessive insulin production emanating in refractory hypoglycemia and growth of the highly proliferating tumor a multimodal therapeutic approach including the consecutive use of tumor debulking surgery, chemotherapy, TACE, SIRT, PRRT as well as a drug therapy with diazoxide, somatostatin analogs and everolimus was employed. Chemotherapy with carboplatin/etoposide plus everolimus provided the longest normoglycemic period. After progress chemotherapy with dacarbazine had the most positive effect, while debulking approaches such as surgery and liver directed therapies, as well as PRRT were less efficient with only transient success. PMID- 25459567 TI - Laparoscopic pylorus preserving pancreaticoduodenectomy in paediatric age for solid pseudopapillary neoplasm of head of the pancreas - case report. AB - Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare tumour commonly seen in young women without significant clinical features. SPN is usually a lowgrade malignant neoplasm which warrants resection. Recurrence and metastasis is seen rarely after complete resection. Pancreaticoduodenectomy is indicated for SPN situated in head of the pancreas which is generally performed by open approach. Laparoscopic pancreaticoduodenectomy (LPD) is difficult to perform for this condition because of smaller size of pancreatic and hepatic ducts more so in paediatric population. We report a case of 12 years old girl having SPN arising from head of the pancreas. She underwent laparoscopic pylorus preserving pancreaticoduodenectomy. Post-operative period was uneventful. Histological examination of resected specimen confirmed diagnosis of SPN. At 6 months follow up, she was doing well without any recurrence. To best of our knowledge, no case of LPD in paediatric patients is reported in literature available to us. PMID- 25459568 TI - Do metal post-retained restorations result in more root fractures than fiber post retained restorations? A systematic review and meta-analysis. AB - INTRODUCTION: Teeth requiring endodontic treatment commonly have compromised a coronal tooth structure that often requires the use of an intraradicular post to retain the coronal restoration. Although usually successful, catastrophic failures requiring extraction have been reported in the literature. The aim of this systematic review was to analyze clinical trials and cohort studies that evaluated the incidence rate of root fractures in post-retained restorations. The hypothesis was that the incidence rate related to the use of metal posts was higher than that of fiber posts. METHODS: A MEDLINE search for clinical studies reporting the incidence of root fractures of restorations retained with fiber posts or metal posts of endodontically treated teeth with a more than 5-year follow-up was conducted from inception to January 2014. Seven randomized clinical trials and 7 cohort studies were included. RESULTS: The pooled survival rate was 90% (95% confidence interval, 85.5-93.3) for metal-based posts and 83.9% (95% confidence interval, 67.6-92.8) for fiber-reinforced posts. The overall incidence rate of root fractures (catastrophic failures) was similar between metal and fiber posts. Prefabricated metal posts and carbon fiber posts had a 2-fold increase in the incidence rate of root fractures compared with cast metal posts and glass fiber posts, respectively. CONCLUSIONS: The results of this study did not show significant differences for root fracture incidence between metal- and fiber posts. However, the studies included in this review presented a high risk of bias, and further well-designed clinical studies are required to confirm these findings. PMID- 25459569 TI - Perforating internal root resorption repaired with mineral trioxide aggregate caused complete resolution of odontogenic sinus mucositis: a case report. AB - INTRODUCTION: An extensive perforating internal root resorption accompanied by apical periodontitis and odontogenic sinus mucositis was detected on preoperative cone-beam computed tomographic scans in a first maxillary molar. METHODS: After the chemomechanical debridement of the root canals, calcium hydroxide was placed as a temporary dressing for 7 days. Mineral trioxide aggregate was used to fill the perforation site with the aid of a surgical microscope. At the next visit, the root with the resorption defect was filled with warm vertical compaction of gutta-percha. RESULTS: A control cone-beam computed tomographic scan acquired 6 months after the endodontic treatment revealed complete resolution of the sinus retention cyst. Moreover, the patient's frequent otolaryngologic disturbances ceased. The tooth was functional with satisfactory clinical and radiographic results after 12 months. CONCLUSIONS: Based on the results of this case, successful repair of an extensive, perforating internal resorption with mineral trioxide aggregate may lead to complete resolution of apical periodontitis and maxillary sinus retention cyst. PMID- 25459570 TI - Effect of a combination of torsional and cyclic fatigue preloading on the fracture behavior of K3 and K3XF instruments. AB - INTRODUCTION: The purpose of this study was to evaluate the effect of various degrees of cyclic fatigue on torsional failure and torsional preloading on the cyclic fatigue life of heat-treated K3XF nickel-titanium (NiTi) instruments (SybronEndo, Orange, CA). METHODS: The mean number of cycles until failure (Nf) of K3XF and K3 NiTi instruments was examined in a 3-point bending apparatus with a 7-mm radius and 45 degrees curve. Torque and distortion angles at failure of new instruments and instruments stressed to 25%, 50%, and 75% of the Nf were measured according to ISO 3630-1. Other new files were preloaded at 25%, 50%, and 75% of the mean distortion angles before the fatigue test. After torsional preloading, the Nf was examined. The fracture surface of each fragment was examined with a scanning electron microscope. RESULTS: The fatigue resistance of K3XF instruments was 2 times higher than that of K3 instruments (P < .05). The torque and angle of rotation at fracture of K3XF instruments were similar to those of K3 instruments. The 25%, 50%, and 75% torsional preloading significantly lowered the Nf of both K3 and K3XF instruments (P < .05). In the fatigue prestressed groups, K3 instruments with 75% preloading had significantly lower torque and distortion angles than unused K3 instruments (P < .05). The fractographic patterns corresponded to the pattern defined by the last stage test. CONCLUSIONS: A low amount of torsional preloading reduced the fatigue resistance of K3 and K3XF instruments. A high amount of precycling fatigue significantly reduced the torsional resistance of K3 instruments. The torsional resistance of K3XF instruments was less affected by previous load cycling even after extensive precycling. PMID- 25459571 TI - Efficacy of platelet-rich plasma as a scaffold in regenerative endodontic treatment. AB - INTRODUCTION: Current research is concerned with discovering better scaffolds for use in regenerative endodontic treatment. This study aimed to clinically and radiographically evaluate the efficacy of platelet-rich plasma (PRP) used as a scaffold in regenerative endodontic treatment and compare it with that of a conventional blood clot (BC) scaffold. METHODS: A total of 20 necrotic, single rooted immature teeth were randomly distributed into 2 groups. After disinfecting the root canal space with triple antibiotic paste (1:1:1 ciprofloxacin, metronidazole, and cefaclor), a tissue scaffold was created by using either PRP or BC and covered with white mineral trioxide aggregate. Clinical and radiographic follow-up examinations were performed once every 3 months during an 18-month period. Differences in root area were calculated from preoperative and postoperative radiographs. Fisher exact and Mann-Whitney U tests were used to evaluate differences between groups, with P value <.05 considered to be statistically significant. RESULTS: All 20 teeth were clinically asymptomatic during 18-month follow-up period; however, 1 tooth in the BC group exhibited periapical pathosis and was judged radiographically unsuccessful. Complete apical closure was observed in a mean of 8.1 months in the PRP group compared with 9 months in the BC group. The PRP group exhibited 9.86% increase in root area, compared with 12.6% increase in the BC group. The difference in success rates between the groups was not statistically significant (P > .05). CONCLUSIONS: PRP successfully created a scaffold for regenerative endodontic treatment; however, treatment outcomes did not differ significantly between PRP and conventional BC scaffold. PMID- 25459572 TI - Comparison of Quick-Set and mineral trioxide aggregate root-end fillings for the regeneration of apical tissues in dogs. AB - INTRODUCTION: Quick-Set (Avalon Biomed Inc, Bradenton, FL) is a calcium aluminosilicate cement that is a potential alternative to mineral trioxide aggregate (MTA) with greater acid resistance and faster setting. The purpose of this study was to compare the regeneration of apical tissues after root-end surgery when the apical tissues were exposed to Quick-Set or White ProRoot MTA (Dentsply Tulsa Dental Specialties, Tulsa, OK) by root-end resection. METHODS: The root canals of 42 mandibular premolars in 7 beagle dogs were accessed, cleaned and shaped, and obturated with Quick-Set or white MTA. Osteotomies and root-end resections were performed immediately. The dogs were sacrificed at 90 days, and the teeth and surrounding tissues were removed and prepared for histologic analysis. The sections of the apical areas were scored for inflammation, new cementum formation, periodontal ligament formation, and bone quality. RESULTS: At 90 days, both materials supported some degree of cementum formation on the surface of the material, periodontal ligament regeneration, and excellent bone quality. The only significant difference was greater inflammation found in the Quick-Set group. CONCLUSIONS: Quick-Set and White ProRoot MTA had a similar effect on bone quality, cementum formation, and periodontal ligament formation after root-end surgery in dogs. Quick-Set was associated with greater inflammation. PMID- 25459573 TI - FOXP3 DNA methylation levels as a potential biomarker in the development of periapical lesions. AB - INTRODUCTION: Epigenetic mechanisms, such as DNA methylation, can modify gene expression patterns without changing the DNA sequence, comprising a tool that cells use to lock genes in the "off" position. Variations in the methylation profile have been correlated to a variety of human diseases. Here, we hypothesize that DNA methylation in immune response-related genes may contribute to the development of periapical lesions. METHODS: The DNA methylation patterns of 22 immune response-related gene promoters were evaluated in 137 human periapical granulomas, 8 apical cysts, and 31 healthy gingival tissues from 2 independent cohorts using a pathway-specific real-time polymerase chain reaction array (EpiTect Methyl II; Qiagen Inc, Valencia, CA). Messenger RNA expression analysis by qualitative polymerase chain reaction was also performed. SABiosciences's hierarchical clustering and methylation (Qiagen, Valencia, CA) and Prism6 software (GraphPad Software, Inc, La Jolla, CA) were used for data analysis. RESULTS: FOXP3 gene promoter showed the highest level of methylation in both periapical granulomas and apical cysts (P < .001), and methylation levels were inversely correlated with FOXP3 messenger RNA expression in the lesions. Furthermore, FOXP3 expression was prevalent in inactive lesions and was positively correlated with interleukin-10 and transforming growth factor beta levels. CONCLUSIONS: Our results suggest that FOXP3 acts as a master switch governing the development and function of T-regulatory cells, whose functions include the inhibition of immune responses and temper inflammation. The observed differential methylation patterns of FOXP3 in periapical lesions may be crucial in determining its suppressive activity and may be involved in periapical lesion development. PMID- 25459574 TI - The role of the early-life environment in the development of allergic disease. AB - A consensus has been reached that the development of allergic disorders is strongly influenced by early life exposures. An overview of several prenatal and early life factors that have been investigated for their associations with development of childhood allergy is presented. Delivery mode, the gut microbiome, vitamin D, folate, breastfeeding, pets, antibiotics, environmental tobacco smoke, and airborne traffic pollutants are discussed. Although many studies suggest an effect, overall, no risk factors clearly increase or reduce the risk of allergic outcomes. PMID- 25459578 TI - Potential treatments for food allergy. AB - This article presents an overview of potential treatments of food allergy, with an emphasis on various forms of immunotherapy (including oral immunotherapy, sublingual immunotherapy, epicutaneous immunotherapy, immunotherapy with modified food antigens, and immunotherapy with a recombinant peanut vaccine). Allergen nonspecific treatments, such as Chinese herbal formulas, probiotics/prebiotics, helminths, monoclonal antibodies, and toll-like receptor agonists, are also summarized. PMID- 25459577 TI - Optimizing the diagnosis of food allergy. AB - Accurately diagnosing a patient with a possible food allergy is important to avoid unnecessary dietary restrictions and prevent life-threatening reactions. Routine testing modalities have limited accuracy, and an oral food challenge is often required to make a definitive diagnosis. Given that they are labor intensive and risk inducing an allergic reaction, several alternative diagnostic modalities have been investigated. Testing for IgE antibodies to particular protein components in foods has shown promise to improve diagnostics and has entered clinical practice. Additional modalities show potential, including epitope binding, T-cell studies, and basophil activation. PMID- 25459580 TI - Asthma: the interplay between viral infections and allergic diseases. AB - Respiratory viruses and allergens synergistically contribute to disease pathogenesis in asthma. Potential mechanisms underlying this clinically relevant association are the subject of intense investigation. This review summarizes current knowledge and recent advances in this area, with an emphasis on potential mechanisms involving immunoglobulin E, type I interferon antiviral responses, epithelial factors, and the role of dendritic cells and other antigen-presenting cells in linking viral and allergic inflammatory responses relevant to asthmatic disease. PMID- 25459576 TI - Food allergy: epidemiology and natural history. AB - The prevalence of food allergy is rising for unclear reasons, with prevalence estimates in the developed world approaching 10%. Knowledge regarding the natural course of food allergies is important because it can aid the clinician in diagnosing food allergies and in determining when to consider evaluation for food allergy resolution. Many food allergies with onset in early childhood are outgrown later in childhood, although a minority of food allergy persists into adolescence and even adulthood. More research is needed to improve food allergy diagnosis, treatment, and prevention. PMID- 25459579 TI - Inner city asthma. AB - The inner city has long been recognized as an area of high asthma morbidity and mortality. A wide range of factors interact to create this environment. These factors include well-recognized asthma risk factors that are not specific to the inner city, the structure and delivery of health care, the location and function of the urban environment, and social inequities. In this article, these facets are reviewed, and successful and unsuccessful interventions are discussed, to understand what is needed to solve this problem. PMID- 25459575 TI - Genetics of allergic diseases. AB - Genome-wide association studies (GWAS) have been employed in the field of allergic disease, and significant associations have been published for nearly 100 asthma genes/loci. An outcome of GWAS in allergic disease has been the formation of national and international collaborations leading to consortia meta-analyses, and an appreciation for the specificity of genetic associations to sub-phenotypes of allergic disease. Molecular genetics has undergone a technological revolution, leading to next-generation sequencing strategies that are increasingly employed to hone in on the causal variants associated with allergic diseases. Unmet needs include the inclusion of diverse cohorts and strategies for managing big data. PMID- 25459582 TI - Eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is a clinicopathologic disease of increasing prevalence. Because EoE is a chronic disease, its prevalence will continue to increase. Antigen triggers, including food and aeroallergens, drive eosinophilic and T helper cell type 2 inflammation, resulting in subepithelial fibrosis; this esophageal remodeling is the likely underlying pathogenesis for complications of narrowing, rigidity, and food impactions. Management includes dietary antigen elimination and topical corticosteroids. Long-term therapy and repeated endoscopy are often needed; consideration must be given to maintenance regimens and side effects. This review describes the clinical features, treatment options, epidemiology, and pathogenesis of EoE. PMID- 25459581 TI - Pediatric asthma: guidelines-based care, omalizumab, and other potential biologic agents. AB - Over the past several decades, the evidence supporting rational pediatric asthma management has grown considerably. As more is learned about the various phenotypes of asthma, the complexity of management will continue to grow. This article focuses on the evidence supporting the current guidelines-based pediatric asthma management and explores the future of asthma management with respect to phenotypic heterogeneity and biologics. PMID- 25459585 TI - Anaphylaxis and urticaria. AB - Anaphylaxis and urticaria are common presenting allergic complaints. Affecting up to 2% of the population, anaphylaxis is a serious, life-threatening allergic reaction. Although not life-threatening, urticaria is a rash of transient, erythematous, pruritic wheals that can be bothersome and affects up to 25% of the population. All cases of anaphylaxis warrant thorough clinical evaluation by the allergist-immunologist, although most cases of urticaria are self-limited and do not require specialist referral. This article offers an overview of our current knowledge on the epidemiology, pathogenesis, triggers, diagnosis, and treatment of anaphylaxis and urticaria. PMID- 25459584 TI - Pediatric allergic rhinitis. AB - Allergic rhinitis is a common pediatric problem with significant comorbidities and potential complications. This article is an overview of the epidemiology, pathophysiology, and current therapeutic strategies. Allergic rhinitis management in a specific child is age dependent and influenced by the severity and frequency of the symptoms and the presence of any concurrent conditions. Current strategies permit symptomatic control and improved quality of life for most patients. PMID- 25459586 TI - Drug and vaccine allergy. AB - Most children with a history of penicillin allergy are labeled allergic and denied treatment with penicillin and sometimes other beta-lactam antibiotics. Most of these children never were or are no longer allergic to penicillin. Penicillin skin testing and oral challenge can identify patients who are not currently allergic, allowing them to be treated with penicillin. Children with egg allergy are often denied influenza vaccination, because the vaccine contains a small amount of egg protein. However, recent studies have demonstrated that children with even severe egg allergy can safely receive the vaccine, reducing their risk of the morbidity and mortality associated with influenza. PMID- 25459587 TI - Pediatric allergy. PMID- 25459583 TI - Atopic dermatitis in children: clinical features, pathophysiology, and treatment. AB - Atopic dermatitis (AD) is a chronic, relapsing, highly pruritic skin condition resulting from disruption of the epithelial barrier and associated immune dysregulation in the skin of genetically predisposed hosts. AD generally develops in early childhood, has a characteristic age-dependent distribution and is commonly associated with elevated IgE, peripheral eosinophilia, and other allergic diseases. Medications such as antihistamines have demonstrated poor efficacy in controlling AD-associated itch. Education of patients regarding the primary underlying defects and provision of a comprehensive skin care plan is essential for disease maintenance and management of flares. PMID- 25459588 TI - Is cardiac hypertrophy good or bad? The answer, of course, is yes. PMID- 25459589 TI - Prognostic value of RV function before and after lung transplantation. AB - OBJECTIVES: We investigated the effects of lung transplantation on right ventricular (RV) function as well as the prognostic value of pre- and post transplantation RV function. BACKGROUND: Although lung transplantation success has improved over recent decades, outcomes remain a challenge. Identifying predictors of mortality in lung transplant recipients may lead to improved long term outcomes after lung transplantation. METHODS: Eighty-nine (age 60 +/- 6 years, 58 men) consecutive patients who underwent single or double lung transplantation and had pre- and post-transplantation echocardiograms between July 2001 and August 2012 were evaluated. Echocardiographic measurements were performed before and after lung transplantation. Left ventricular (LV) and RV longitudinal strains were analyzed using velocity vector imaging. Cox proportional prognostic hazard models predicting all-cause death were built. RESULTS: There were 46 all-cause (52%) and 17 cardiac (19%) deaths during 43 +/- 33 months of follow-up. After lung transplantation, echocardiography showed improved systolic pulmonary artery pressure (SPAP) (50 +/- 19 mm Hg to 40 +/- 13 mm Hg) and RV strain (-17 +/- 5% to -18 +/- 4%). No pre-transplantation RV parameter predicted all-cause mortality. After adjustment for age, sex, surgery type, and etiology of lung disease in a Cox proportional hazards model, both post transplantation RV strain (hazard ratio: 1.13, 95% confidence interval: 1.04 to 1.23, p = 0.005), and post-transplantation SPAP (hazard ratio: 1.03, 95% confidence interval: 1.01 to 1.05, p = 0.011) were independent predictors of all cause mortality. When post-transplantation RV strain and post-transplantation SPAP were added the clinical predictive model based on age, sex, surgery type, and etiology, the C-statistic improves from 0.60 to 0.80 (p = 0.002). CONCLUSIONS: Alterations of RV function and pulmonary artery pressure normalize, and post-transplantation RV function may provide prognostic data in patients after lung transplantation. Our study is based on a highly and retrospectively selected group. We believe that larger prospective studies are warranted to confirm this result. PMID- 25459590 TI - RV dysfunction after lung transplantation: a new prognostic marker or mainly a correlate of lung allograft function? PMID- 25459591 TI - The dawn of perfusion CMR: taking over from FFR in suspected coronary artery disease? PMID- 25459593 TI - Indexes of subclinical atherosclerosis: signposts on the highway to disease. PMID- 25459594 TI - How close is close enough? PMID- 25459592 TI - Coronary artery calcium and incident cerebrovascular events in an asymptomatic cohort. The MESA Study. AB - OBJECTIVES: This study assessed the predictive value of coronary artery calcium (CAC) score for cerebrovascular events (CVE) in an asymptomatic multiethnic cohort. BACKGROUND: The CAC score, a measure of atherosclerotic burden, has been shown to improve prediction of coronary heart disease events. However, the predictive value of CAC for CVE is unclear. METHODS: CAC was measured at baseline examination of participants (N = 6,779) of MESA (Multi-Ethnic Study of Atherosclerosis) and then followed for an average of 9.5 +/- 2.4 years for the diagnosis of incident CVE, defined as all strokes or transient ischemic attacks. RESULTS: During the follow-up, 234 (3.5%) adjudicated CVE occurred. In Kaplan Meier analysis, the presence of CAC was associated with a lower CVE event-free survival versus the absence of CAC (log-rank chi-square: 59.8, p < 0.0001). Log transformed CAC was associated with increased risk for CVE after adjusting for age, sex, race/ethnicity, body mass index, systolic and diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, cigarette smoking status, blood pressure medication use, statin use, and interim atrial fibrillation (hazard ratio [HR]: 1.13 [95% confidence interval (CI): 1.07 to 1.20], p < 0.0001). The American College of Cardiology/American Heart Association recommended CAC cutoff was also an independent predictor of CVE and strokes (HR: 1.70 [95% CI: 1.24 to 2.35], p = 0.001, and HR: 1.59 [95% CI: 1.11 to 2.27], p = 0.01, respectively). CAC was an independent predictor of CVE when analysis was stratified by sex or race/ethnicity and improved discrimination for CVE when added to the full model (c-statistic: 0.744 vs. 0.755). CAC also improved the discriminative ability of the Framingham stroke risk score for CVE. CONCLUSIONS: CAC is an independent predictor of CVE and improves the discrimination afforded by current stroke risk factors or the Framingham stroke risk score for incident CVE in an initially asymptomatic multiethnic adult cohort. PMID- 25459595 TI - Assessing bioresorbable coronary devices: methods and parameters. AB - Bioresorbable vascular scaffolds (BRS) represent a novel approach to provide transient vessel support to drug-delivery capability without the long-term limitations of metallic drug-eluting stents (DES). The technology has the potential to overcome many of the safety concerns associated with metallic DES and possibly even convey further clinical benefit. In particular, the BRS are designed to provide short-term lumen support, and after being completely bioresorbed, eliminate the permanent caging typical of metallic DES. However, this technology has required new imaging modalities and methodologies for its assessment because the design, degradation rate, loss of mechanical property, and drug deliverability may affect its safety and efficacy. We provide an overview of all existing methods for assessing bioresorbable devices, from noninvasive to invasive, from light to sound based, and from morphological to functional parameters. PMID- 25459596 TI - Bioresorbable coronary devices: advances illuminated by imaging. PMID- 25459597 TI - LV mechanics in mitral and aortic valve diseases: value of functional assessment beyond ejection fraction. AB - The assessment of myocardial function in the context of valvular heart disease remains highly challenging. The myocardium deforms simultaneously in 3 dimensions, and global left ventricular (LV) function parameters such as volume and ejection fraction may remain compensated despite the changes in myocardial deformation properties. Current guidelines recommend valve replacement/repair in the presence of symptoms or reduced LV ejection fraction, but the resolution of symptoms or recovery of LV function post-surgery may not be reliably predicted. A wealth of evidence currently suggests that LV dysfunction is frequently subclinical despite normal ejection fraction. It may precede the onset of symptoms and portend a poor outcome due to progressive myocardial remodeling and dysfunction during the post-operative period. The advent of novel tissue-tracking echocardiography techniques has unleashed new opportunities for the clinical identification of early abnormalities in LV function. This review gathers and summarizes current evidence regarding the use of these techniques to assess myocardial deformation in patients with valvular heart disease. PMID- 25459598 TI - Planning transcaval access using CT for large transcatheter implants. PMID- 25459599 TI - Multiple simultaneous plaque erosion in 3 coronary arteries. PMID- 25459600 TI - Flare spots in intravascular optical coherence tomography images of bioabsorbable stents. PMID- 25459601 TI - Cardiac steatosis and left ventricular dysfunction in HIV-infected patients treated with highly active antiretroviral therapy. PMID- 25459602 TI - A comprehensive evaluation of left atrial performance using volumetric analysis, strain, and strain rate imaging. PMID- 25459603 TI - Reply: A comprehensive evaluation of left atrial performance using volumetric analysis, strain, and strain rate imaging. PMID- 25459604 TI - Publishing the most impactful imaging papers. PMID- 25459606 TI - Third-order nonlinear optical investigations of meso-tetrakis(2,3,5,6-tetrafluoro N,N-dimethyl-4-anilinyl)porphyrin and its metal complexes. AB - We report here the experimental investigation on third-order nonlinear optical parameters of 5,10,15,20-tetrakis(2,3,5,6-tetrafluoro-N,N-dimethyl-4 anilinyl)porphyrin and its various metal complexes, using Z-scan technique at 532 nm. The third-order nonlinear optical susceptibilities (chi(3)) were of the order 10(-12) esu and are compared through degenerate four wave mixing (DFWM). The operating mechanism is reverse saturable absorption (RSA) as the effective excited-state absorption cross-section was found higher than ground state absorption cross-section as well as the magnitude of nonlinear absorption coefficient was found decreasing with on-axis input intensity. The compounds found to exhibit good optical limiting at 532 nm, 7 ns excitation steering applications in laser safety. PMID- 25459605 TI - Synthesis, DNA binding and complex formation reactions of 3-amino-5,6-dimethyl 1,2,4-triazine with Pd(II) and some selected biorelevant ligands. AB - With the purpose of studying the binding behavior of Pd(II) complexes with DNA as the main biological target, and their ability to penetrate reasonably into tumour cells and destroy their replication ability, Pd(ADT)Cl2 complex was synthesized and characterized, where ADT is 3-amino-5,6-dimethyl-1,2,4-triazine. Stoichiometry and stability constants of the complexes formed between various biologically relevant ligands (amino acids, amides, DNA constituents, and dicarboxylic acids) and [Pd(ADT)(H2O)2](2+) were investigated at 25 degrees C and at constant 0.1moldm(-3) ionic strength. The concentration distribution diagrams of the various species formed are evaluated. Further investigation of the binding properties of the diaqua complex [Pd(ADT)(H2O)2](2+) with calf thymus DNA (CT DNA) was investigated by UV-vis spectroscopy. The intrinsic binding constants (Kb) calculated from UV-vis absorption studies was calculated to be 2.00*10(3)moldm(-3). The calculated (Kb) value was found to be of lower magnitude than that of the classical intercalator EB (Ethidium bromide) (Kb=1.23(+/ 0.07)*10(5)moldm(-3)) suggesting an electrostatic and/or groove binding mode for the interaction with CT-DNA. Thermal denaturation has been systematically studied by spectrophotometric method and the calculated DeltaTm was nearly 5 degrees C, supporting the electrostatic and/or groove binding mode for the interaction between the complex and CT-DNA. PMID- 25459607 TI - Two dinuclear Ru(II) polypyridyl complexes with different photophysical and cation recognition properties. AB - Two dinuclear Ru(II) polypyridyl complexes functionalized with vacant coordination sites have been designed and synthesized. Their photophysical properties and interactions with various metal ions have been investigated at room temperature. The two complexes exhibit different UV/Vis absorption and emission intensities. When titrated with various metal ions, complex [{Ru(bpy)2}2(MU2-L(1))](4+) exhibits a notable fluorescence quenching in the presence of Cu(2+) in H2O-CH3CN media (1:1, v/v); its analogous complex [{Ru(bpy)2}2(MU2-L(2))](4+) exhibits no cation selectivity, the fluorescence intensity of complex [{Ru(bpy)2}2(MU2-L(2))](4+) has been enhanced by several transition metal ions due to prevention of the photo-induced electron transfer process. The fluorescence titration spectra and Benesi-Hildebrand expression reveal the formation of a 1:1 bonding mode between [{Ru(bpy)2}2(MU2-L(1))](4+) and Cu(2+) ion with the association constant of 5.50*10(4) M(-1). PMID- 25459608 TI - Spectroscopic and quantum chemical analysis of Isonicotinic acid methyl ester. AB - In this present study, an organic compound Isonicotinic acid methyl ester (INAME) was structurally characterized by FTIR, FT-Raman, and NMR and UV spectroscopy. The optimized geometrical parameters and energies of all different and possible conformers of INAME are obtained from Density Functional Theory (DFT) by B3LYP/6 311++G(d,p) method. There are three conformers (SI, SII-1, and SII-2) for this molecule (ground state). The most stable conformer of INAME is SI conformer. The molecular geometry and vibrational frequencies of INAME in the ground state have been calculated by using HF and density functional method (B3LYP) 6-311++G (d,p) basis set. Detailed vibrational spectral analysis has been carried out and assignments of the observed fundamental bands have been proposed on the basis of peak positions and relative intensities. The computed vibrational frequencies were compared with the experimental frequencies, which yield good agreement between observed and calculated frequencies. A study on the electronic properties, such as HOMO and LUMO energies were performed by time independent DFT approach. Besides, molecular electrostatic potential (MEP) and thermodynamic properties were performed. The electric dipole moment (MU) and first hyper polarizability (beta) values of the investigated molecule were computed using ab initio quantum mechanical calculations. The calculated results show that the INAME molecule may have microscopic nonlinear optical (NLO) behavior with non zero values. The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by gauge independent atomic orbital (GIAO) method. PMID- 25459609 TI - Green synthesis of ZnO nanoparticles using Solanum nigrum leaf extract and their antibacterial activity. AB - In the present investigation, we have described the green biosynthesis of ZnO nanoparticles (NPs) by using Solanum nigrum as capping agent. The functionalization of ZnO particles through S. nigrum leaf extract mediated bioreduction of ZnO was investigated through UV-Vis DRS, photoluminescence (PL), X-ray diffraction (XRD), Fourier Transform Infrared (FTIR) spectroscopy, Field Emission Scanning Electron Microscopy (FE-SEM), Transmission Electron Microscopy (TEM), thermal gravimetric-differential thermal analysis (TG-DTA), X-ray photoelectron spectroscopy (XPS) and antibacterial activities. UV-Vis-DRS studies revealed that the indirect band gap 3.38 eV and photoluminescence study reveals the blue emission at 402, 447, 469 and 483 nm and the green emission at 529 nm respectively. In addition, the synthesized NPs are wurtzite hexagonal structure with an average grain size lies between 20 and 30 nm were found from XRD analysis. Further, FT-IR spectra revealed the functional groups and the presence of protein as the stabilizing agent for surrounding the ZnO NPs. The diameter of the NPs in the range of 20-30 nm was found from FE-SEM study. TEM analysis was investigated the ZnO NPs as a quasi-spherical in shape and their diameter at around 29.79 nm. Finally, the current study has clearly demonstrated that the particle size variations and surface area to volume ratios of ZnO NPs are responsible for significant higher antibacterial activities. Further, the present investigation suggests that ZnO NPs has the potential applications for various medical and industrial fields so, that the investigation is so useful and helpful to the scientific communities. PMID- 25459610 TI - A selective fluorescent and colorimetric dual-responses chemosensor for streptomycin based on polythiophene derivative. AB - A colorimetric and fluorescent dual-responses chemosensor (PT3, a water-soluble polythiophene) for streptomycin was designed and synthesized. The structure of PT3 was characterized by using infrared spectroscopy, (1)H NMR and gel-permeation chromatography analyses. The conformational change of PT3 induced by streptomycin resulted in the red shift of absorption spectra and fluorescent quenching. Moreover, PT3 showed excellent selectivity for streptomycin over other antibiotics and biomolecules. PT3 could quantificationally detect streptomycin in the range of 2-70 MUM with a detection limit of 0.2 MUM (116 ppb), which is lower than the maximum residue limit defined by World Health Organization (200 ppb). PMID- 25459611 TI - Nanostructures formed by cyclodextrin covered procainamide through supramolecular self assembly--spectral and molecular modeling study. AB - Inclusion complexation behavior of procainamide (PCA) with two cyclodextrins (alpha-CD and beta-CD) were analyzed by absorption, fluorescence, scanning electron microscope (SEM), transmission electron microscope (TEM), Raman image, FT-IR, differential scanning colorimeter (DSC), Powder X ray diffraction (XRD) and (1)H NMR. Blue shift was observed in beta-CD whereas no significant spectral shift observed in alpha-CD. The inclusion complex formation results suggest that water molecules also present in the inside of the CD cavity. The present study revealed that the phenyl ring of the PCA drug is entrapped in the CD cavity. Cyclodextrin studies show that PCA forms 1:2 inclusion complex with alpha-CD and beta-CD. PCA:alpha-CD complex form nano-sized particles (46 nm) and PCA:beta-CD complex form self-assembled to micro-sized tubular structures. The shape-shifting of 2D nanosheets into 1D microtubes by simple rolling mechanism were analysed by micro-Raman and TEM images. Thermodynamic parameters (DeltaH, DeltaG and DeltaS) of inclusion process were determined from semiempirical PM3 calculations. PMID- 25459612 TI - Fourier transform infrared spectroscopy quantitative analysis of SF6 partial discharge decomposition components. AB - Gas-insulated switchgear (GIS) internal SF6 gas produces specific decomposition components under partial discharge (PD). By detecting these characteristic decomposition components, such information as the type and level of GIS internal insulation deterioration can be obtained effectively, and the status of GIS internal insulation can be evaluated. SF6 was selected as the background gas for Fourier transform infrared spectroscopy (FTIR) detection in this study. SOF2, SO2F2, SO2, and CO were selected as the characteristic decomposition components for system analysis. The standard infrared absorption spectroscopy of the four characteristic components was measured, the optimal absorption peaks were recorded and the corresponding absorption coefficient was calculated. Quantitative detection experiments on the four characteristic components were conducted. The volume fraction variation trend of four characteristic components at different PD time were analyzed. And under five different PD quantity, the quantitative relationships among gas production rate, PD time, and PD quantity were studied. PMID- 25459613 TI - Spectroscopic (FTIR, FT-Raman), molecular electrostatic potential, NBO and HOMO LUMO analysis of P-bromobenzene sulfonyl chloride based on DFT calculations. AB - The FTIR and FT-Raman spectra of P-bromobenzene sulfonyl chloride (P-BBSC) have been recorded in the regions 4000-400 cm(-1) and 3500-50 cm(-1), respectively. Utilizing the observed FTIR and FT-Raman data, a complete vibrational assignment and analysis of the fundamental modes of the compound were carried out. The optimum molecular geometry, harmonic vibrational frequencies, infrared intensities and Raman scattering activities, were calculated by density functional theory (DFT/B3LYP) method. A good agreement between experimental and calculated normal modes of vibrations has been observed. A detailed interpretation of the infrared and Raman spectra of P-BBSC is also reported based on total energy distribution (TED). Stability of the molecule arising from hyperconjugative interactions, charge delocalization have been analyzed using natural bond orbital (NBO) analysis. The MEP map shows the negative potential sites are on oxygen atoms as well as the positive potential sites are around the hydrogen atoms. The UV-vis spectral analysis of P-BBSC has also been done which confirms the charge transfer of the molecule. PMID- 25459614 TI - beta-Carboline-functionalized dithioacetal as Hg2+-selective fluorescence probe in water. AB - A novel sensing system based on the beta-carboline core has been designed and synthesized for Hg(2+) detection in water. We have demonstrated that a straight forward methodology can provide rapid, sensitive and selective recognition (cross contamination experiments) for Hg(2+) over a wide pH range. The vivid fluorescence change from blue to colorless can be clearly discriminated by the naked eye. Furthermore, there is a good negative correlation between the fluorescent intensity and the concentration of Hg(2+) in the range 1.0*10(-6) M 7.0*10(-6) M. beta-Carboline as a fluorophore synthesized via this route also provides a new strategy for the design of novel fluorescence probes and fluorochromes. PMID- 25459615 TI - HRMS studies on the fragmentation pathways of metallapentalyne. AB - The electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR MS) using collision-induced dissociation (CID) method was applied to investigate the characteristic fragment ions of metalla-aromatic complexes for the first time. The fragmentation process of osmapentalyne, which contained metal-carbon triple bond in a five-membered ring, was discussed in detail. The ESI FT-ICR MS CID experimental results at high resolution mass spectra (HRMS) demonstrated the elemental composition of fragment ions unambiguously, thus a reasonable fragmentation pathway of osmapentalyne was proposed. In addition, the characteristic fragment ions have been investigated, which were specific and useful for the identification of some osmapentalynes complexes. These characteristic fragmentation pathways were helpful to analyze and interpret the stability and property of the parent ion. Also, this method could be used for the characterization of other organometallic complexes, especially containing characteristic isotopic peaks. PMID- 25459616 TI - SEM, EDX and vibrational spectroscopic study of the mineral tunisite NaCa2Al4(CO3)4Cl(OH)8. AB - The mineral tunisite has been studied by using a combination of scanning electron microscopy with energy dispersive X-ray fluorescence and vibrational spectroscopy. Chemical analysis shows the presence of Na, Ca, Al and Cl. SEM shows a pure single phase. An intense Raman band at 1127 cm(-1) is assigned to the carbonate nu1 symmetric stretching vibration and the Raman band at 1522 cm( 1) is assigned to the nu3 carbonate antisymmetric stretching vibration. Infrared bands are observed in similar positions. Multiple carbonate bending modes are found. Raman bands attributable to AlO stretching and bending vibrations are observed. Two Raman bands at 3419 and 3482 cm(-1) are assigned to the OH stretching vibrations of the OH units. Vibrational spectroscopy enables aspects of the molecular structure of the carbonate mineral tunisite to be assessed. PMID- 25459617 TI - SEM, EDS and vibrational spectroscopic study of dawsonite NaAl(CO3)(OH)2. AB - In this work we have studied the mineral dawsonite by using a combination of scanning electron microscopy with EDS and vibrational spectroscopy. Single crystals show an acicular habitus forming aggregates with a rosette shape. The chemical analysis shows a phase composed of C, Al, and Na. Two distinct Raman bands at 1091 and 1068 cm(-1) are assigned to the CO3(2-) nu1 symmetric stretching mode. Multiple bands are observed in both the Raman and infrared spectra in the antisymmetric stretching and bending regions showing that the symmetry of the carbonate anion is reduced and in all probability the carbonate anions are not equivalent in the dawsonite structure. Multiple OH deformation vibrations centred upon 950 cm(-1) in both the Raman and infrared spectra show that the OH units in the dawsonite structure are non-equivalent. Raman bands observed at 3250, 3283 and 3295 cm(-1) are assigned to OH stretching vibrations. The position of these bands indicates strong hydrogen bonding of the OH units in the dawsonite structure. The formation of the mineral dawsonite has the potential to offer a mechanism for the geosequestration of greenhouse gases. PMID- 25459618 TI - Antibacterial and cytotoxic potential of silver nanoparticles synthesized using latex of Calotropis gigantea L. AB - The present study aimed to synthesis silver nanoparticles (AgNPs) in a greener route using aqueous latex extract of Calotropis gigantea L. toward biomedical applications. Initially, synthesis of AgNPs was confirmed through UV-Vis spectroscopy which shows the surface plasmonic resonance peak (SPR) at 420 nm. Fourier transform infrared spectroscopy (FTIR) analysis provides clear evidence that protein fractions present in the latex extract act as reducing and stabilizing bio agents. Energy dispersive X-ray (EDAX) spectroscopy confirms the presence of silver as a major constituent element. X-ray diffractograms displays that the synthesized AgNPs were biphasic crystalline nature. Electron microscopic studies such as Field emission scanning electron microscopic (Fe-SEM) and Transmission electron microscope (TEM) reveals that synthesized AgNPs are spherical in shape with the size range between 5 and 30 nm. Further, crude latex aqueous extract and synthesized AgNPs were evaluated against different bacterial pathogens such as Bacillus cereus, Enterococci sp, Shigella sp, Pseudomonas aeruginosa, Klebsiella pneumonia, Staphylococcus aureus and Escherichia coli. Compared to the crude latex aqueous extract, biosynthesized AgNPs exhibits a remarkable antimicrobial activity. Likewise in vitro anticancer study manifests the cytotoxicity value of synthesized AgNPs against tested HeLa cells. The output of this study clearly suggesting that biosynthesized AgNPs using latex of C. gigantea can be used as promising nanomaterial for therapeutic application in context with nanodrug formulation. PMID- 25459619 TI - chi(3) Measurement and optical power limiting behavior of manganese doped lithium tetraborate nanoparticles. AB - Manganese doped Li2B4O7 nano crystallites were prepared by chemical method and characterized by XRD, FTIR, UV and fluorescence spectra. FESEM reveals that the particles are coagulated and the particle size is in the range of 50-107 nm. Bands appear at 682-769 cm(-1) corresponds to the bending of B-O linkage in borate network. Nonradiative energy transfer process is observed from fluorescence spectrum. UV-Vis studies show the samples are completely transparent in the visible region and having absorption peaks (234 and 276 nm) in UV regime. The measured second harmonic generation values are 0.9 times KDP. The nonlinear optical parameters such as nonlinear refractive index, n2 (10(-8) cm(2)/W), nonlinear absorption, beta (10(-2) cm/W) and nonlinear optical susceptibility, chi(3) (10(-5) esu) are estimated using a Nd:YAG laser (532 nm, 50 mW). PMID- 25459620 TI - A comparative study of novel spectrophotometric resolution techniques applied for pharmaceutical mixtures with partially or severely overlapped spectra. AB - Simultaneous determination of mixtures of lidocaine hydrochloride (LH), flucortolone pivalate (FCP), in presence of chlorquinaldol (CQ) without prior separation steps was applied using either successive or progressive resolution techniques. According to the concentration of CQ the extent of overlapping changed so it can be eliminated from the mixture to get the binary mixture of LH and FCP using ratio subtraction method for partially overlapped spectra or constant value via amplitude difference followed by ratio subtraction or constant center followed by spectrum subtraction spectrum subtraction for severely overlapped spectra. Successive ratio subtraction was coupled with extended ratio subtraction, constant multiplication, derivative subtraction coupled constant multiplication, and spectrum subtraction can be applied for the analysis of partially overlapped spectra. On the other hand severely overlapped spectra can be analyzed by constant center and the novel methods namely differential dual wavelength (D(1) DWL) for CQ, ratio difference and differential derivative ratio (D(1) DR) for FCP, while LH was determined by applying constant value via amplitude difference followed by successive ratio subtraction, and successive derivative subtraction. The spectra of the cited drugs can be resolved and their concentrations are determined progressively from the same ratio spectrum using amplitude modulation method. The specificity of the developed methods was investigated by analyzing laboratory prepared mixtures and were successfully applied for the analysis of pharmaceutical formulations containing the cited drugs with no interference from additives. The proposed methods were validated according to the ICH guidelines. The obtained results were statistically compared with those of the official or reported methods; using student t-test, F-test, and one way ANOVA, showing no significant difference with respect to accuracy and precision. PMID- 25459621 TI - Biogenic synthesis of multi-applicative silver nanoparticles by using Ziziphus Jujuba leaf extract. AB - Herein, we are reporting for the first time one step biogenic synthesis of silver nanoparticles (AgNPs) at room temperature by using Ziziphus Jujuba leaf extract as a reducing and stabilizing agent. The process of nanoparticles preparation is green, rapid, environmentally benign and cost effective. The synthesized AgNPs were characterized by means of UV-Vis., XRD, FT-IR, TEM, DLS and Zeta potential. The absorption band centered at lambdamax 434 nm in UV-Vis. reflects surface plasmon resonance (SPR) of AgNPs. XRD analysis revealed, that biosynthesized AgNPs are crystalline in nature with the face centered cubic structure. FT-IR analysis indicates that nanoparticles were capped with the leaf extract. TEM images shows the synthesized nanoparticles are having different shapes with 20-30 nm size. The data obtained from DLS that support the hydrodynamic size of 28 nm. Zeta potential of -26.4 mV indicates that the nanoparticles were highly stable in colloidal state. The effect of pH, quantity of leaf extract and concentrations of AgNO3 were also studied to attend control over the particle size and stability. The synthesized AgNPs shows highly efficient catalytic activity towards the reduction of anthropogenic pollutant 4-nitrophenol (4-NP) and Methylene Blue (MB) for environmental protection. Synthesized AgNPs also exhibited good antimicrobial activity against Escherichia coli. PMID- 25459622 TI - FTIR, FT-Raman, UV-Visible spectra and quantum chemical calculations of allantoin molecule and its hydrogen bonded dimers. AB - FTIR, FT-Raman and electronic spectra of allantoin molecule are recorded and investigated using DFT and MP2 methods with 6-311++G(d,p) basis set. The molecular structure, anharmonic vibrational spectra, natural atomic charges, non linear optical properties, etc. have been computed for the ground state of allantoin. The anharmonic vibrational frequencies are calculated using PT2 algorithm (Barone method) as well as VSCF and CC-VSCF methods. These methods yield results that are in remarkable agreement with the experiment. The coupling strengths between pairs of modes are also calculated using coupling integral based on 2MR-QFF approximation. The simulations on allantoin dimers have been also performed at B3LYP/6-311++G(d,p) level of theory to investigate the effect of the intermolecular interactions on the molecular structure and vibrational frequencies of the monomer. Vibrational assignments are made with the great accuracy using PED calculations and animated modes. The combination and overtone bands have been also identified in the FTIR spectrum with the help of anharmonic computations. The electronic spectra are simulated in gas and solution at TD B3LYP/6-311++G(d,p) level of theory. The important global quantities such as electro-negativity, electronic chemical potential, electrophilicity index, chemical hardness and softness based on HOMO, LUMO energy eigenvalues are also computed. NBO analysis has been performed for monomer and dimers of allantoin at B3LYP/6-311++G(d,p) level of theory. PMID- 25459623 TI - Adsorption study of antibiotics on silver nanoparticle surfaces by surface enhanced Raman scattering spectroscopy. AB - In this work the adsorption of the antibiotics levofloxacin (LV), tetracycline (TC) and benzylpenicillin (BP) on the surface of silver nanoparticles (AgNP) have been investigated through both surface-enhanced Raman scattering (SERS) and UV VIS-NIR spectroscopies. The SERS spectra were obtained using 1064 nm exciting radiation. Theoretical models for the antibiotic molecules were obtained from DFT calculations, and used in the vibrational assignment. The adsorption geometries were proposed based on the changes in the spectral patterns. The LV compound adsorbs through carboxylate group, TC compound interacts with silver atoms through carbonyl from intermediate ring, and BP compound adsorbs by carbonyl moieties from carboxylate and acyclic amide. PMID- 25459624 TI - Dye-sensitized solar cell based on spray deposited ZnO thin film: performance analysis through DFT approach. AB - A dye-sensitized solar cell based on a spray deposited zinc oxide (ZnO) photoanode with Evans blue as a sensitizer was fabricated. Structural analysis confirms the hexagonal wurtzite phase of the ZnO photoanode with c-axis orientation. Surface morphology of the ZnO photoanode shows uniform distribution of spherically-shaped grains, ranging from 18 nm to 25 nm. The power conversion efficiency of the device was measured as 0.1%. Density functional theory was adopted to study the observed photovoltaic performance of the fabricated device. The analysis of the electronic properties of Evans blue dye showed that it has a pronounced effect on the observed device performance. PMID- 25459625 TI - Spectroscopic and structural studies of the Schiff base 3-methoxy-N-salicylidene o-amino phenol complexes with some transition metal ions and their antibacterial, antifungal activities. AB - Spectroscopic (IR, Raman, NMR, UV-visible, and ESR), and structural studies of the ligand 3-methoxy-N-salicylidene-o-amino phenol (H2L) and its synthesized complexes with some transition metal ions (Mn(II), Co(II), Ni(II)), Cu(II) and Zn(II)) were recorded and analyzed. The magnetic properties and thermal gravimetric analysis (TGA and DTA) were also measured for the complexes. The metal complexes were found to have The structural formula ML?H2O and the metal ions Mn(II), Co(II), Ni(II)) and Zn(II) were found to form tetrahedral complexes with the ligand whereas Cu(II) formed a square planar one. Antimicrobial activity of the ligand and its complexes were also investigated and discussed. PMID- 25459626 TI - Structure-performance relationship for a family of disperse azo dyes having the same D-pi-A 4-nitro-4'-amino-azobenzene skeleton: structures, solvatochromism and DFT computations. AB - A combinational study of structural chemistry and dyestuff chemistry has been carried out to reveal the structure-performance relationship for eight disperse azo dyes by comparing their structures, electronic spectra, solvatochromism and theoretic computations. All eight structural analogues have the same 4-nitro-4' amino-azobenzene donor-pi-acceptor skeleton but different substituted groups, namely, R1 and R2 in ring A, R3, R4 and R5 in Ring B. X-ray single-crystal diffraction analyses indicate that four azo dyes have severely twisted aminoazobenzene structures because of the steric hindrance of ortho dichloro/dibromo radicals of 4-nitrobenzene moiety, while the other four dyes show essentially planar conformation due to the ortho monosubstituted 4 nitrobenzene amine and 4'-amino-azobenzene units. It is noted that the electronic spectra are closely related to their molecular structures, where the presence of different auxochrome groups and the spatial crowding effects in the aminoazobenzene backbone lead to significant alterations of the bathochromic and hypsochromic shifts. PMID- 25459627 TI - Synthesis, characterization of (3E)-1-(6-chloro-2-methyl-4-phenyl quinolin-3-Yl) 3-aryl prop-2-en-1-ones through IR, NMR, single crystal X-ray diffraction and insights into their electronic structure using DFT calculations. AB - 3E-1-(6-Chloro-2-methyl-4-phenylquinolin-3-yl)-3-arylprop-2-en-1-ones were synthesized and characterized by FTIR, (1)H NMR, (13)C NMR, HSQC, DEPT-135. In addition the compound 3E-1-(6-chloro-2-methyl-4-phenylquinolin-3-yl)-3-(2,5 dimethoxyphenyl)prop-2-en-1-one was subjected to the single crystal X-ray diffraction studies. Density functional theory calculations were carried out for this chalcone and its derivatives to investigate into their electronic structure, chemical reactivity, linear and non-linear optical properties. The structure predicted from DFT for chalcone is in good agreement with the structure from XRD measurement. PMID- 25459628 TI - Tuning band structure and electronic transport properties of ZrN nanotube--a first-principles investigation. AB - The band structure and electronic transport properties of pristine ZrN nanotube, oxygen, fluorine and niobium substituted ZrN are successfully optimized using density functional theory. The transport properties of ZrN nanotube are studied in terms of band structure, density of states, electron density and transmission spectrum of ZrN nanotube. The band structure reveals that the nanostructures show metallic nature due to orbital overlapping of zirconium and nitrogen atoms. The density of states gives the information of localization of charges in energy intervals. The major contribution in density of states arises from p and d orbitals of zirconium and nitrogen atoms. The electron density is observed more in nitrogen sites for pristine and impurity substituted ZrN nanotube. The electrons near the Fermi level contributes more to the transmission, the impact in the transmission is seen due to substitution impurity and position of the defect in the ZrN nanotube. The results of the present work focus light to tailor ZrN nanotube with enhanced electronic properties in nanoelectronics applications. PMID- 25459629 TI - Calotropis procera mediated combustion synthesis of ZnAl2O4:Cr(3+) nanophosphors: structural and luminescence studies. AB - ZnAl2O4:Cr(3+) nanophosphors were synthesized for the first time by a simple and environment friendly route using Calotropis procera milk latex as fuel. The structural and surface morphological studies were carried out using powder X-ray diffraction (PXRD), scanning electron microscopy and transmission electron microscopy techniques. The photoluminescence (PL) properties of ZnAl2O4:Cr(3+) as a function of dopant concentration and calcination temperature was studied in detail. The PXRD patterns and Rietveld confinement confirmed the cubic crystal system with space group Fd-3m. The crystallite size estimated from Scherrer's and W-H plots was found to be in the range of 16-26 nm. The PL spectrum shows an intense peak at ~688 and ~699 nm assigned to spin-forbidden (2)Eg->(4)A2g transition of Cr(3+) ions. The PL measurements for two excitations (~410 and 527 nm) and with respect to calcination temperature indicated no significant change in the shape and position of emission peak except PL intensity. The CIE chromaticity coordinates lies well within the white region. Thermoluminescence (TL) studies revealed well resolved glow peak at ~212 degrees C with a small shoulder at 188 and 233 degrees C. The glow peak intensity at ~212 degrees C increases linearly with gamma-dose which suggest ZnAl2O4:Cr(3+) is suitable candidate for radiation dosimetric applications. The activation energy (E in eV), order of kinetics (b) and Frequency factor (s) were estimated using glow peak shape method. PMID- 25459630 TI - Conservation of Moroccan manuscript papers aged 150, 200 and 800 years. Analysis by infrared spectroscopy (ATR-FTIR), X-ray diffraction (XRD), and scanning electron microscopy energy dispersive spectrometry (SEM-EDS). AB - The preservation of manuscripts and archive materials is a serious problem for librarians and restorers. Paper manuscript is subjected to numerous degradation factors affecting their conservation state. This research represents an attempt to evaluate the conservation restoration process applied in Moroccan libraries, especially the alkaline treatment for strengthening weakened paper. In this study, we focused on six samples of degraded and restored paper taken from three different Moroccan manuscripts aged 150, 200 and 800 years. In addition, the Japanese paper used in restoration has been characterized. A modern paper was also analyzed as reference. A three-step analytical methodology based on infrared spectroscopy (ATR-FTIR), X-ray diffraction (XRD) and scanning electron microscopy coupled to energy dispersive spectrometry (SEM-EDS) analysis was developed before and after restoration in order to determine the effect of the consolidation treatment on the paper structure. The results obtained by XRD and ATR-FTIR disclosed the presence of barium sulfate (BaSO4) in all restored paper manuscripts. The presence of calcium carbonate (CaCO3) in all considered samples was confirmed by FTIR spectroscopy. The application of de-acidification treatment causes significant changes connected with the increase of intensity mostly in the region 1426 cm(-1), assigned to the asymmetric and symmetric CO stretching mode of calcite, indicating the effectiveness of de-acidification procedure proved by the rise of the alkaline reserve content allowing the long term preservation of paper. Observations performed by SEM magnify the typical paper morphology and the structure of fibbers, highlighting the effect of the restoration process, manifested by the reduction of impurities. PMID- 25459631 TI - A colorimetric and fluorescent cyanide chemosensor based on dicyanovinyl derivatives: utilization of the mechanism of intramolecular charge transfer blocking. AB - Chemosensor (CS1) was designed and synthesized by simple green chemistry procedure. CS1 exhibited both colorimetric and fluorescence turn-off responses for cyanide (CN(-)) ion in aqueous solution. The probe showed an immediate visible color changes from yellow to colorless and green fluorescence disappearance when CN(-) was added. The mechanism of chemosensor reaction with CN(-) was studied using (1)HH NMR and (13)C NMR spectroscopies and mass spectrometry. Moreover, test strips based on the sensor were fabricated, which served as convenient and efficient CN(-) test kits. PMID- 25459633 TI - Double channel emission from a redox active single component quantum dot complex. AB - Herein we report the generation and control of double channel emission from a single component system following a facile complexation reaction between a Mn(2+) doped ZnS colloidal quantum dot (Qdot) and an organic ligand (8-hydroxy quinoline; HQ). The double channel emission of the complexed quantum dot-called the quantum dot complex (QDC)-originates from two independent pathways: one from the complex (ZnQ2) formed on the surface of the Qdot and the other from the dopant Mn(2+) ions of the Qdot. Importantly, reaction of ZnQ2.2H2O with the Qdot resulted in the same QDC formation. The emission at 500 nm with an excitation maximum at 364 nm is assigned to the surface complex involving ZnQ2 and a dangling sulfide bond. On the other hand, the emission at 588 nm-with an excitation maximum at 330 nm-which is redox tunable, is ascribed to Mn(2+) dopant. The ZnQ2 complex while present in QDC has superior thermal stability in comparison to the bare complex. Interestingly, while the emission of Mn(2+) was quenched by an electron quencher (benzoquinone), that due to the surface complex remained unaffected. Further, excitation wavelength dependent tunability in chromaticity color coordinates makes the QDC a potential candidate for fabricating a light emitting device of desired color output. PMID- 25459632 TI - Combinatorial discovery of cosolvent systems for production of narrow dispersion thiolate-protected gold nanoparticles. AB - The effect of aqueous solvent concentration in the synthesis of water-soluble thiolate-protected gold nanoparticles (AuNPs) was investigated for 13 water miscible solvents and three thiolate ligands (p-mercaptobenzoic acid, thiomalic acid, and glutathione). The results were analyzed by construction of heat maps that rank each reaction result for polydispersity. When solvents were organized in the heat map according to their Dimroth-Reichardt ET parameter (an approximate measure of polarity), two "hot spots" become apparent that are independent of the ligand used. We speculate that one hot spot may arise in part from the metal chelation or coordination ability of solvents that include diglyme, 1,2 dimethoxyethane, 1,4-dioxane, and tetrahydrofuran. The second hot spot arises at concentrations of alcohols including 2-propanol and 1-butanol that appear to selectively precipitate a growing product, presumably stopping its growth at a certain size. We observe some tightly dispersed products that appear novel. Overall, this study expands the number of tightly dispersed water-soluble AuNPs that can be directly synthesized. PMID- 25459634 TI - Leiomyosarcoma of the inferior vena cava in a patient with Budd-Chiari syndrome. PMID- 25459635 TI - B-cell lymphoma of the heart: A rare diagnosis. AB - We present a case of a primary cardiac lymphoma in a 60-year-old woman. The clinical presentation was non-specific and the diagnosis was suggested by its appearance on multidetector computed tomography. The final diagnosis was achieved by histopathological study and was corroborated by a decrease in tumor volume after targeted chemotherapy. A brief review of the appearance of primary cardiac lymphomas in imaging studies is presented. PMID- 25459636 TI - Levosimendan: The current situation and new prospects. AB - Levosimendan is a pyridazinone-dinitrile derivative with positive inotropic and vasodilatory effects that has beneficial effects on myocardial performance. In previous randomized studies levosimendan improved hemodynamics and clinical course, but its effect on prognosis is still unclear. This important issue has limited its use. Although primarily used in the management of acute heart failure syndromes, this new inotropic agent may play a role in other clinical conditions. This review aims to summarize current knowledge on levosimendan and to present future prospects for the use of this drug. PMID- 25459637 TI - Acute aortic dissection complicated by aorto-right ventricular fistula. PMID- 25459638 TI - Abdominal aortic aneurysm - Characterization by three-dimensional computed tomography angiography. PMID- 25459639 TI - A radio-resistant perforin-expressing lymphoid population controls allogeneic T cell engraftment, activation, and onset of graft-versus-host disease in mice. AB - Immunosuppressive pretransplantation conditioning is essential for donor cell engraftment in allogeneic bone marrow transplantation (BMT). The role of residual postconditioning recipient immunity in determining engraftment is poorly understood. We examined the role of recipient perforin in the kinetics of donor cell engraftment. MHC-mismatched BMT mouse models demonstrated that both the rate and proportion of donor lymphoid cell engraftment and expansion of effector memory donor T cells in both spleen and BM were significantly increased within 5 to 7 days post-BMT in perforin-deficient (pfn(-/-)) recipients, compared with wild-type. In wild-type recipients, depletion of natural killer (NK) cells before BMT enhanced donor lymphoid cell engraftment to that seen in pfn(-/-) recipients. This demonstrated that a perforin-dependent, NK-mediated, host-versus-graft (HVG) effect limits the rate of donor engraftment and T cell activation. Radiation resistant natural killer T (NKT) cells survived in the BM of lethally irradiated mice and may drive NK cell activation, resulting in the HVG effect. Furthermore, reduced pretransplant irradiation doses in pfn(-/-) recipients permitted long term donor lymphoid cell engraftment. These findings suggest that suppression of perforin activity or selective depletion of recipient NK cells before BMT could be used to improve donor stem cell engraftment, in turn allowing for the reduction of pretransplant conditioning. PMID- 25459641 TI - Thymoglobulin and an unexpected outbreak of Epstein-Barr virus. PMID- 25459640 TI - Feasible outcomes of T cell-replete haploidentical stem cell transplantation with reduced-intensity conditioning in patients with myelodysplastic syndrome. AB - Even with the recent optimization of haploidentical stem cell transplantation (SCT), its role for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia evolving from MDS (sAML) should be validated. We analyzed the outcomes of consecutive 60 patients with MDS or sAML who received T cell-replete haploidentical SCT after reduced-intensity conditioning with fludarabine, busulfan, and rabbit antithymocyte globuline +/- 800 cGy total body irradiation. Patients achieved a rapid neutrophil engraftment after a median of 12 days (range, 8 to 23) and an early immune reconstitution without high incidences of acute graft-versus-host disease (GVHD) II to IV and chronic GVHD (36.7% and 48.3%, respectively). After a median follow-up of 4 years, incidence of relapse and nonrelapse mortality and rate of overall survival and disease-free survival was 34.8%, 23.3%, 46.8%, and 41.9%, respectively. In multivariate analysis, the disease status at peak was a significant predictor for relapse (lower-risk MDS versus higher-risk MDS or sAML; hazard ratio [HR], 5.69; 95% confidence interval [CI], 1.45 to 22.29; P = .013) and disease-free survival (HR, 4.44; 95% CI, 1.14 to 17.34; P = .032). Chronic GVHD was an additional significant predictor for relapse (no versus yes; HR, 2.87; 95% CI, 1.03 to 7.51; P = .043). Our T cell replete haploidentical SCT may be a feasible option for patients with MDS and sAML without conventional donors. PMID- 25459642 TI - A reduced-toxicity regimen is associated with durable engraftment and clinical cure of nonmalignant genetic diseases among children undergoing blood and marrow transplantation with an HLA-matched related donor. AB - Blood and marrow transplantation (BMT) is a standard curative therapy for patients with nonmalignant genetic diseases. Myeloablative conditioning has been associated with significant regimen-related toxicity (RRT), whereas reduced intensity conditioning regimens have been associated with graft failure. In this prospective pilot trial conducted at 2 centers between 2006 and 2013, we report the outcome of 22 patients with nonmalignant genetic diseases who were conditioned with a novel reduced-toxicity regimen: i.v. busulfan (16 mg/kg), alemtuzumab (52 mg/m(2)), fludarabine (140 mg/m(2)), and cyclophosphamide (105 mg/kg). The median age of the study population was 3.5 years (range, 5 months to 26 years). No cases of sinusoidal obstruction syndrome, severe or chronic graft versus-host disease (GVHD), or primary graft failure were reported. Median time to neutrophil engraftment (>500 cells/MUL) and platelet engraftment (>20K cells/MUL) were 19 (range, 12 to 50) and 23.5 (range, 14 to 134) days, respectively. The median length of follow-up was 3 years (range, .2 to 6.3). The overall survival rates were 95% at 100 days (95% confidence interval, .72 to .99) and 90% at 6 years (95% confidence interval, .68 to .98). RRT and chronic GVHD are significant barriers to BMT for patients with nonmalignant genetic diseases. This alemtuzumab-based reduced-toxicity regimen appears to be promising with durable engraftment, effective cure of clinical disease, low rates of RRT, and no observed chronic GVHD. PMID- 25459645 TI - High-performance liquid chromatography on glass chips using precisely defined porous polymer monoliths as particle retaining elements. AB - A stable and permanent integration of miniature packed bed separation columns into microfluidic systems is a major issue in nano liquid chromatography. Various approaches like differently shaped retaining elements or the use of key stone effect have been investigated. We show a flexible integration of miniature packed bed separation columns into microfluidic chips utilising common HPLC material achieved by laser-assisted generation of narrow, photopolymerised frits. The generated retaining elements serve as an in- and outlet frits for the columns. An optimised pre-polymeric solution, consisting of butyl acrylates and a porogen, allows a precise fabrication of frit-type structures with lengths of less than 100 m and the capability to withstand common slurry packing pressures of more than 250 bar. The separation of seven polycyclic aromatic hydrocarbons by pressure-driven, reversed-phase chromatography proves the high quality of the created chromatographic column inside a glass chip. Plate heights down to 2.9 were achieved and extremely fast separations with sub-second peak widths were performed in isocratic and gradient elution modes on very short columns (<= 25 mm). PMID- 25459646 TI - Liquid chromatography combined with atomic and molecular mass spectrometry for speciation of arsenic in chicken liver. AB - Human exposure to high concentrations of arsenic from water and food is an important health concern. Although 3-nitro-4-hydroxyphenylarsonic acid (Roxarsone) was used for more than 60 years as a feed additive to feed chickens, little is known about the metabolism of this arsenic species in chicken. Determination of potential arsenic metabolites present at trace concentrations is an analytical challenge, requiring efficient separation and sensitive detection. The primary objective of this research is to develop a method that enables the identification and quantification of various arsenic species in chicken liver. This report describes a method of high performance liquid chromatography (HPLC) separation with both inductively coupled plasma mass spectrometry (ICPMS) and electrospray ionization tandem mass spectrometry (ESI-MS/MS) detection. Anion exchange HPLC enabled the separation of Roxarsone and other arsenic species within 12 min. Detection with both ICPMS and ESI-MS/MS allowed for identification and quantification of eight arsenic species in chicken livers, including arsenobetaine, inorganic arsenite, dimethylarsinic acid, monomethylarsonic acid, inorganic arsenate, 3-amino-4-hydroxyphenylarsonic acid, N-acetyl-4 hydroxyphenylarsonic acid (N-AHPAA), and Roxarsone. The concentrations of these arsenic species, with the exception of arsenobetaine, are significantly higher in the Roxarsone-fed chickens than in the control chickens. The simultaneous detection by both ICPMS and ESIMS from the same HPLC separation allowed for comparison of peaks in both ICPMS and ESIMS chromatograms. This is advantageous over two separate analyses, particularly when HPLC retention times might fluctuate due to sample matrix effect. HPLC separation with the complementary atomic and molecular mass spectrometry detection prevented misidentification of co-eluting compounds, as demonstrated by the determination of two possible metabolites of Roxarsone, N-AHPAA and 4-amino-phenylarsonic acid (4-APAA). N AHPAA was confirmed by HPLC separation with simultaneous arsenic-specific detection by ICPMS and multiple reaction monitoring by ESIMS. Although an arsenic containing compound had identical retention time as 4-APAA in the HPLC-ICPMS chromatogram, it was ruled out as 4-APAA from the simultaneous detection by ESIMS. The identification and quantitation of trace arsenic species present in complex samples demonstrate the potential of HPLC separation with simultaneous ICPMS and ESIMS detection for other speciation applications. PMID- 25459647 TI - Evaluation of preparative hydrodynamic chromatography of silica stationary phase supports. AB - Reducing the particle size distribution (PSD) of sub-2 MUm chromatographic packing materials can improve the performance of capillary UHPLC columns, but several size refinement methods are only partially effective in this size range. To this end, a preparative scale hydrodynamic chromatography (HDC) method was developed to size-refine C18 functionalized sub-2 MUm particles, but suffered from poor reproducibility and particle aggregation issues. Presented here are improvements based on the use of an ammonium hydroxide as the mobile phase. This mobile phase makes the method reproducible, decreases column conditioning requirements, and focuses on the preparation of bare silica material which allows for a wider variety of stationary phase bondings. Additionally, particle recovery for both non-porous silica size standards and bridged-ethyl hybrid (BEH) particles are detailed to highlight the advantages of this method. The data presented demonstrates the capability of this method to reduce the relative standard deviation (RSD) of the PSD of BEH particles by 33% in under 2 h with sufficient yield to pack several capillary columns. PMID- 25459644 TI - Treatment of dyslipidemia in allogeneic hematopoietic stem cell transplant patients. AB - As survival rates in allogeneic hematopoietic stem cell transplantation (HSCT) continue to improve, attention to long-term complications, including cardiovascular disease, becomes a major concern. Cardiovascular disease and dyslipidemia are a common, yet often overlooked occurrence post-HSCT that results in significant morbidity and mortality. Also, increasing evidence shows that several anti-hyperlipidemia medications, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in particular, may have a role in modulating graft-versus host disease (GVHD). However, factors such as drug-drug interactions, adverse effect profiles, and the relative efficacy in lowering cholesterol and triglyceride levels must be taken into account when choosing safe and effective lipid-lowering therapy in this setting. This review seeks to provide guidance to the clinician in the management of dyslipidemia in the allogeneic HSCT population, taking into account the recently published American College of Cardiology/American Heart Association guidelines on hyperlipidemia management, special considerations in this challenging population, and the evidence for each agent's potential role in modulating GVHD. PMID- 25459643 TI - Strategies for the identification of T cell-recognized tumor antigens in hematological malignancies for improved graft-versus-tumor responses after allogeneic blood and marrow transplantation. AB - Allogeneic blood and marrow transplantation (allo-BMT) is an effective immunotherapeutic treatment that can provide partial or complete remission for patients with hematological malignancies. Mature donor T cells in the donor inoculum play a central role in mediating graft-versus-tumor (GVT) responses by destroying residual tumor cells that persist after conditioning regimens. Alloreactivity towards minor histocompatibility antigens (miHA), which are varied tissue-related self-peptides presented in the context of major histocompatibility complex (MHC) molecules on recipient cells, some of which may be shared on tumor cells, is a dominant factor for the development of GVT. Potentially, GVT can also be directed to tumor-associated antigens or tumor-specific antigens that are more specific to the tumor cells themselves. The full exploitation of allo-BMT, however, is greatly limited by the development of graft-versus-host disease (GVHD), which is mediated by the donor T cell response against the miHA expressed in the recipient's cells of the intestine, skin, and liver. Because of the significance of GVT and GVHD responses in determining the clinical outcome of patients, miHA and tumor antigens have been intensively studied, and one active immunotherapeutic approach to separate these two responses has been cancer vaccination after allo-BMT. The combination of these two strategies has an advantage over vaccination of the patient without allo-BMT because his or her immune system has already been exposed and rendered unresponsive to the tumor antigens. The conditioning for allo-BMT eliminates the patient's existing immune system, including regulatory elements, and provides a more permissive environment for the newly developing donor immune compartment to selectively target the malignant cells. Utilizing recent technological advances, the identities of many human miHA and tumor antigenic peptides have been defined and are currently being evaluated in clinical and basic immunological studies for their ability to produce effective T cell responses. The first step towards this goal is the identification of targetable tumor antigens. In this review, we will highlight some of the technologies currently used to identify tumor antigens and anti-tumor T cell clones in hematological malignancies. PMID- 25459649 TI - Effects of the surface concentration of fixed charges in C18-bonded stationary phases on the adsorption process and on the preparative chromatography of small ionizable compounds. AB - The effects of the surface concentration of positive charges attached to the surface of research BEH-C18 hybrid particles on the overloaded band profiles and the adsorption isotherms of a neutral (caffeine) and a positively charged (nortryptilinium hydrochloride) compounds were measured and investigated. The inverse method (IM) of chromatography was used to determine the isotherm parameters. Three columns were packed with endcapped BEH-C18 particles doped with three different charge densities on their surfaces (LOW, MEDIUM and HIGH). Two other columns packed with unbonded, non-endcapped, and endcapped BEH-C18 particles served as standard reference materials. Minor disturbance method (MDM) experiments were conducted with acetonitrile/water mixtures in order to assess qualitatively the surface densities of the fixed positive charges. A more quantitative approach based on the solution of the linearized Poisson-Boltzmann equation and the decrease of the experimental Henry constant was also applied. The results show that the surface concentrations of the fixed charges in the LOW, MEDIUM and HIGH columns were 0.029, 0.050, and 0.064MUmol/m2, e.g., close to two orders of magnitude smaller than the surface density of bonded C18 chains (2.1MUmol/m2). The adsorption isotherm of the ionizable compound nortryptilinium onto the BEH-C18 columns is consistent with a two-sites adsorption model. The density of the high energy sites correlates directly to the total amount of the fixed charges and isolated silanols amidst the C18-bonded chains. The amount of low energy sites reflects the specific surface area of the adsorbent. The binding constants on the high- and low-energy adsorption sites are respectively ten and two times lower on the HIGH column than on the reference endcapped column. The active sites are closer to the adsorbent surface than the weak adsorption sites. Finally, a higher production rate of ionizable compounds can be achieved in preparative chromatography with the charge doped than with the reference RPLC-C18 columns. For the same analysis time, larger recovery yields are observed despite a slight loss in selectivity due to non-selective repulsive electrostatic interactions. PMID- 25459648 TI - Instrument parameters controlling retention precision in gradient elution reversed-phase liquid. AB - The precision of retention time in RPLC is important for compound identification, for setting peak integration time windows and in fundamental studies of retention. In this work, we studied the effect of temperature (T), initial (phio) and final mobile phase (phif) composition, gradient time (tG), and flow rate (F) on the retention time precision under gradient elution conditions for various types of low MW solutes. We determined the retention factor in pure water ( [Formula: see text] ) and the solute-dependent solvent strength (S) parameters of Snyder's linear solvent strength theory (LSST) as a function of temperature for three different groups of solutes. The effect of small changes in the chromatographic variables (T, phio, phif, tG and F) by use of the LSST gradient retention equation were estimated. Peaks at different positions in the chromatogram have different sensitivities to changes in these instrument parameters. In general, absolute fluctuations in retention time are larger at longer gradient times. Drugs showed less sensitivity to changes in temperature compared to relatively less polar solutes, non-ionogenic solutes. Surprisingly we observed that fluctuations in temperature, mobile phase composition and flow rate had less effect on retention time under gradient conditions as compared to isocratic conditions. Overall temperature and the initial mobile phase composition are the most important variables affecting retention reproducibility in gradient elution chromatography. PMID- 25459650 TI - Mechanisms of endothelial cell protection by hydroxycinnamic acids. AB - An endothelial dysfunction generates a proatherogenic environment characterized by stimulating thrombus formation. Epidemiological studies have provided evidence of a protective role of healthy diets in the prevention of cardiovascular diseases. Hydroxycinnamic acids constitute abundant polyphenols in our diets as they are present in high levels in many widely consumed foods, such as fruit, vegetables and beverages. Therefore, it can be established that due to the hydroxycinnamic acid content (caffeic, chlorogenic, feluric and p-coumaric acids), fruit, vegetables and beverages contribute to endothelial protection (attenuates oxidative stress, improved nitric oxide bioavailability and decreased E-selectin, ICAM-1 and VCAM-1 expression, among others). In this article, we systematically examine the mechanisms of endothelium protection of hydroxycinnamic acids. PMID- 25459651 TI - The virtual bodily self: Mentalisation of the body as revealed in anosognosia for hemiplegia. AB - Despite the coherence and seeming directness of our bodily experience, our perception of the world, including that of our own body, may constitute an inference based on ambiguous sensory data and prior expectations. In this article, I apply a 'psychologised' version of the recently proposed free energy framework to the understanding of certain disorders of neurological unawareness in order to examine how inferential processes may determine our body perception. I specifically consider three facets of body perception in such disorders: namely, the 'external body' as inferred on the basis of exteroceptive signals and related predictions; the 'internal body' as inferred on the basis of proprioceptive and interoceptive signals and related predictions; and lastly the 'impersonalised body' as inferred on the basis of signals from social and third person perspectives on the body and related predictions. Several conclusions will be drawn from these considerations: (a) there is a deep interdependency of prior beliefs and sensory data; as the brain uses sensory data to update its virtual model of the world, lack or imprecision of sensory prediction errors may lead to aberrant inferences influenced disproportionally by outdated, premorbid predictions; (b) interoception and interoceptive salience have a unique role in our inferences about body awareness and (c) social, 'objectified' prior beliefs about the body may have a silent but potent role in our bodily self-awareness. Finally, the article emphasizes that our learned, virtual model of the body is depended on the nature and thus integrity of the very body that allowed the model to be formed in the first place. PMID- 25459652 TI - The epistemic innocence of motivated delusions. AB - Delusions are defined as irrational beliefs that compromise good functioning. However, in the empirical literature, delusions have been found to have some psychological benefits. One proposal is that some delusions defuse negative emotions and protect one from low self-esteem by allowing motivational influences on belief formation. In this paper I focus on delusions that have been construed as playing a defensive function (motivated delusions) and argue that some of their psychological benefits can convert into epistemic ones. Notwithstanding their epistemic costs, motivated delusions also have potential epistemic benefits for agents who have faced adversities, undergone physical or psychological trauma, or are subject to negative emotions and low self-esteem. To account for the epistemic status of motivated delusions, costly and beneficial at the same time, I introduce the notion of epistemic innocence. A delusion is epistemically innocent when adopting it delivers a significant epistemic benefit, and the benefit could not be attained if the delusion were not adopted. The analysis leads to a novel account of the status of delusions by inviting a reflection on the relationship between psychological and epistemic benefits. PMID- 25459653 TI - Evaluating use of the Siebens Domain Management Model during inpatient rehabilitation to increase functional independence and discharge rate to home in stroke patients. AB - OBJECTIVE: To evaluate use of the Siebens Domain Management Model (SDMM) during stroke inpatient rehabilitation (IR) to increase functional independence and rate of discharge to home. DESIGN: Before and after study. SETTING: IR facility. PARTICIPANTS: Before the intervention: 154 patients with ischemic/hemorrhagic strokes who were admitted to an IR facility in 2010; on average, they were admitted 9.1 days after receiving acute care. After the intervention: 151 patients with ischemic/hemorrhagic strokes who were admitted to an IR facility in 2012; on average they were admitted 7.3 days after receiving acute care. The comorbidity tier severity and prestroke living setting and living support appeared to be similar in both the preintervention and postintervention groups. INTERVENTION: Use of the SDMM involving weekly adjustments of IR care focused on potential barriers to discharge home including medical/surgical issues, cognitive/emotional coping issues, physical function, and living environment/community re-entry needs. MAIN OUTCOME MEASURES: Use of Functional Independence Measure (FIM) score change during IR length of stay (LOS; FIM-LOS efficiency) and rates of discharge to community/home, acute care, and long-term care (LTC) to compare 2010/preintervention data with postintervention data from 2012, along with comparison of facility data to national aggregate data from the Uniform Data System for Medical Rehabilitation (UDSMR) for both years. RESULTS: Preintervention 2010 FIM-LOS efficiency was 1.44 compared with a 2012 postintervention FIM-LOS efficiency of 2.24, which was significant (t = 4.3; P < .0001). Comparison of the UDSMR 2012 national FIM-LOS efficiency score (1.72) to the 2012 postintervention score of 2.24 reached significance (t = 2.6; P < .01). In addition, a significant difference was found between groups for discharge location: In the preintervention group, 57.8% were discharged to home/community, 14.9% to LTC, and 27.3% back to acute care compared with the postintervention group, in which 81.2% were discharged to home/community, 9.4% to LTC, and 9.4% back to acute care (chi(2) = 8.98; P < .001). Also significant was comparison between the 2012 postintervention group and the 2012 national UDSMR data for the same 3 discharge locations (chi(2) = 3.94; P < .05). Comparison of 2010 to 2012 facility data then shows a 23.4% increase in discharge to the community compared with an increase of 5.8% for the UDSMR 2010 to 2012 data, representing a community discharge rate that is 4 times greater for the 2012 facility postintervention group (chi(2) = 83.596; P < .0001). CONCLUSIONS: Use of the SDMM during stroke IR may convey improvement in functional independence and is associated with an increased discharge rate to home/community and a reduction in institutionalization and acute-care transfers. PMID- 25459654 TI - Managing upper extremity clonus with intramuscular botulinum toxin-A injections in a patient poststroke. AB - Spasticity and clonus are common clinical signs of upper motor neuron lesions poststroke. Intramuscular botulinum toxin-A injections have been shown to reduce spasticity and to improve quality of life. Upper extremity clonus can have a significant impact upon activities of daily living and can pose challenges to comfort, self-care, hygiene, and appearance. Although less common than in the ankle, it is important to understand how upper extremity clonus management may be beneficial to patients presenting with this finding. The majority of previous reports have focused on management of clonus in the lower extremity, but very few have addressed the management of upper extremity clonus. We present a case of poststroke upper extremity clonus with marked improvements following intramuscular botulinum toxin-A injections. PMID- 25459655 TI - Comparison of the thickness of lateral abdominal muscles between pregnant women with and without low back pain. AB - OBJECTIVES: To compare the thickness of the external oblique, internal oblique, and transversus abdominis muscles in pregnant subjects with and without low back pain (LBP) by the use of ultrasound to measure thickness. DESIGN: A case-control study. SETTING: An academic and tertiary care referral spine and sports medicine center. PARTICIPANTS: Fifty pregnant women with LBP during pregnancy and 54 pregnant control subjects. METHODS: Case and control subjects were matched for body mass index, gestational age, and number of previous pregnancies. A multiple linear regression model with adjustment for the gestational age of the subjects, as the potential confounder of the primary outcomes, was used to evaluate the association between LBP appearance and abdominal muscles thickness of the subjects. MAIN OUTCOME MEASURES: The thickness of lateral abdominal muscles was measured by ultrasound with the subject in a hook-lying position on the examination table. RESULTS: We found that there was no significant difference between pregnant subjects with and without LBP in terms of the thickness of external oblique, internal oblique, and transversus abdominis muscles. CONCLUSION: These findings suggest that other factors rather than the thickness of core stabilizing muscles are influential in the etiology of LBP during pregnancy. We hypothesize that enlargement of uterus during pregnancy might influence the thickness of the lateral abdominal muscles. PMID- 25459656 TI - Botulinum toxin a injection to facial and cervical paraspinal muscles in a patient with stiff person syndrome: a case report. AB - Stiff person syndrome (SPS) is a rare neurologic disorder of unknown etiology characterized by increased resting muscle tone, progressive rigidity, and stiffness of the axial musculature. We present a case of a 48-year-old male patient with SPS who experienced facial and neck muscle spasms that were uncontrolled with oral medications and the use of an intrathecal baclofen pump. Botulinum toxin A injections into the bilateral masseter and neck paraspinal muscles provided pain relief and spasm control, illustrating the use of botulinum toxin A injections in the small muscles of face and neck in patients with SPS. PMID- 25459657 TI - Ultrasound imaging of a partial flexor digitorum profundus tear due to a bony spur. PMID- 25459658 TI - CSN maintains the germline cellular microenvironment and controls the level of stem cell genes via distinct CRLs in testes of Drosophila melanogaster. AB - Stem cells and their daughters are often associated with and depend on cues from their cellular microenvironment. In Drosophila testes, each Germline Stem Cell (GSC) contacts apical hub cells and is enclosed by cytoplasmic extensions from two Cyst Stem Cells (CySCs). Each GSC daughter becomes enclosed by cytoplasmic extensions from two CySC daughters, called cyst cells. CySC fate depends on an Unpaired (Upd) signal from the hub cells, which activates the Janus Kinase and Signal Transducer and Activator of Transcription (Jak/STAT) pathway in the stem cells. Germline enclosure depends on Epidermal Growth Factor (EGF) signals from the germline to the somatic support cells. Expression of RNA-hairpins against subunits of the COnstitutively Photomorphogenic-9- (COP9-) signalosome (CSN) in somatic support cells disrupted germline enclosure. Furthermore, CSN-depleted somatic support cells in the CySC position next to the hub had reduced levels of the Jak/STAT effectors Zinc finger homeotic-1 (Zfh-1) and Chronologically inappropriate morphogenesis (Chinmo). Knockdown of CSN in the somatic support cells does not disrupt EGF and Upd signal transduction as downstream signal transducers, phosphorylated STAT (pSTAT) and phosphorylated Mitogen Activated Protein Kinase (pMAPK), were still localized to the somatic support cell nuclei. The CSN modifies fully formed Cullin RING ubiquitin ligase (CRL) complexes to regulate selective proteolysis. Reducing cullin2 (cul2) from the somatic support cells disrupted germline enclosure, while reducing cullin1 (cul1) from the somatic support cells led to a low level of Chinmo. We propose that different CRLs enable the responses of somatic support cells to Upd and EGF. PMID- 25459659 TI - Stochasticity and stereotypy in the Ciona notochord. AB - Fate mapping with single cell resolution has typically been confined to embryos with completely stereotyped development. The lineages giving rise to the 40 cells of the Ciona notochord are invariant, but the intercalation of those cells into a single-file column is not. Here we use genetic labeling methods to fate map the Ciona notochord with both high resolution and large sample sizes. We find that the ordering of notochord cells into a single column is not random, but instead shows a distinctive signature characteristic of mediolaterally-biased intercalation. We find that patterns of cell intercalation in the notochord are somewhat stochastic but far more stereotyped than previously believed. Cell behaviors vary by lineage, with the secondary notochord lineage being much more constrained than the primary lineage. Within the primary lineage, patterns of intercalation reflect the geometry of the intercalating tissue. We identify the latest point at which notochord morphogenesis is largely stereotyped, which is shortly before the onset of mediolateral intercalation and immediately after the final cell divisions in the primary lineage. These divisions are consistently oriented along the AP axis. Our results indicate that the interplay between stereotyped and stochastic cell behaviors in morphogenesis can only be assessed by fate mapping experiments that have both cellular resolution and large sample sizes. PMID- 25459660 TI - Identification of a potent antiandrogen that targets the BF3 site of the androgen receptor and inhibits enzalutamide-resistant prostate cancer. AB - There has been a resurgence of interest in the development of androgen receptor (AR) inhibitors with alternative modes of action to overcome the development of resistance to current therapies. We demonstrated previously that one promising strategy for combatting mutation-driven drug resistance is to target the Binding Function 3 (BF3) pocket of the receptor. Here we report the development of a potent BF3 inhibitor, 3-(2,3-dihydro-1H-indol-2-yl)-1H-indole, which demonstrates excellent antiandrogen potency and anti-PSA activity and abrogates the androgen induced proliferation of androgen-sensitive (LNCaP) and enzalutamide-resistant (MR49F) PCa cell lines. Moreover, this compound effectively reduces the expression of AR-dependent genes in PCa cells and effectively inhibits tumor growth in vivo in both LNCaP and MR49F xenograft models. These findings provide evidence that targeting the AR BF3 pocket represents a viable therapeutic approach to treat patients with advanced and/or resistant prostate cancer. PMID- 25459661 TI - Inhibition of AMP deaminase activity does not improve glucose control in rodent models of insulin resistance or diabetes. AB - Inhibition of AMP deaminase (AMPD) holds the potential to elevate intracellular adenosine and AMP levels and, therefore, to augment adenosine signaling and activation of AMP-activated protein kinase (AMPK). To test the latter hypothesis, novel AMPD pan inhibitors were synthesized and explored using a panel of in vitro, ex vivo, and in vivo models focusing on confirming AMPD inhibitory potency and the potential of AMPD inhibition to improve glucose control in vivo. Repeated dosing of selected inhibitors did not improve glucose control in insulin resistant or diabetic rodent disease models. Mice with genetic deletion of the muscle-specific isoform Ampd1 did not showany favorable metabolic phenotype despite being challenged with high-fat diet feeding. Therefore, these results do not support the development of AMPD inhibitors for the treatment of type 2 diabetes. PMID- 25459662 TI - Effects of pharmacological AMP deaminase inhibition and Ampd1 deletion on nucleotide levels and AMPK activation in contracting skeletal muscle. AB - AMP-activated protein kinase (AMPK) plays a central role in regulating metabolism and energy homeostasis. It achieves its function by sensing fluctuations in the AMP:ATP ratio. AMP deaminase (AMPD) converts AMP into IMP, and the AMPD1 isoenzyme is expressed in skeletal muscles. Here, effects of pharmacological inhibition and genetic deletion of AMPD were examined in contracting skeletal muscles. Pharmacological AMPD inhibition potentiated rises in AMP, AMP:ATP ratio, AMPK Thr172, and acetyl-CoA carboxylase (ACC) Ser218 phosphorylation induced by electrical stimulation, without affecting glucose transport. In incubated extensor digitorum longus and soleus muscles from Ampd1 knockout mice, increases in AMP levels and AMP:ATP ratio by electrical stimulation were potentiated considerably compared with muscles from wild-type mice, whereas enhanced AMPK activation was moderate and only observed in soleus, suggesting control by factors other than changes in adenine nucleotides. AMPD inhibitors could be useful tools for enhancing AMPK activation in cells and tissues during ATP depletion. PMID- 25459663 TI - Birdsong memory and the brain: in search of the template. AB - In his pioneering research on the neural mechanisms of filial imprinting, Gabriel Horn has gone a long way to fulfilling Karl Lashley's dream of finding the 'engram' or memory trace in the brain. Here we review recent research into the engram(s) of song learning in songbirds, particularly zebra finches. When juvenile songbirds learn their songs from a tutor, they form and alter a central representation of the tutor song, known as the 'template'. Secondary auditory regions in the caudal medial pallium are likely to contain the neural substrate for the representation of tutor song, but the roles of the different regions remain to be elucidated. Female zebra finches do not sing, but nevertheless form an auditory memory of their father's song, for which the neural substrate is located in the caudomedial pallium. In males that are learning their songs, there is continual interaction between the secondary auditory regions and sensorimotor regions, similar to the interaction between Broca's and Wernicke's areas in human infants acquiring speech and language. PMID- 25459664 TI - Saffold virus respiratory infection in children and immunocompromised patients in Spain. PMID- 25459665 TI - Predictive and prognostic value of circulating tumor cell detection in lung cancer: a clinician's perspective. AB - There is increasing evidence for the use of circulating tumor cells (CTCs) as a "liquid biopsy" for early detection of lung cancer recurrence, prognosticating disease and monitoring treatment response. Further, CTC molecular analysis and interrogation of single cells hold significant potential in providing insights into tumor biology and the metastatic process. Ongoing research will likely see the translation of CTCs as a prognostic and predictive biomarker in both small cell, and non-small cell, lung cancer to routine clinical practice. PMID- 25459666 TI - Evaluation of serum-based cancer biomarkers: a brief review from a clinical and computational viewpoint. AB - Biomarkers are vital to detect diseases in various clinical stages. A variety of cancer serum biomarkers are already known, while for more accurate cancer-type detection, there required more rigorous evaluation manners, especially computational evaluation measures, for biomarkers. In this review, we first show three typical pitfalls in finding biomarkers and their examples, after briefly presenting standard five clinical biomarker screening phases by National Cancer Institute. We then introduce current computational biomarker evaluation measures, including current, standard methods with their intrinsic features. We further show an up-to-date list of existing cancer serum biomarkers, pointing out several issues, being caused by the limitations of current biomarker evaluation approaches. Finally we discuss the current attempts to develop new, statistically robust, computational serum-based biomarker measures in terms of specificity to each of various cancer types. PMID- 25459667 TI - Combination of androgen deprivation therapy and radiotherapy for localized prostate cancer in the contemporary era. AB - Currently, androgen deprivation therapy (ADT) has a well-defined role when administered together with radiotherapy (RT): neo-adjuvant and concurrent combination for intermediate risk-disease and adjuvant therapy for high risk disease. Evidence of this association was generated by randomized trials designed and led approximately 30 years ago; thus the question which arises is how relevant and portable are these data in our current clinical practice? In the present review, we examine the pitfalls of these published randomized controlled trials, their relevance to present daily clinics, where high-dose external beam RT or brachytherapy is applied, as well as the adoption of ADT in patients with concomitant cardiovascular disorders. PMID- 25459668 TI - Angiogenic factors in chronic lymphocytic leukaemia (CLL): Where do we stand? AB - The role of angiogenesis in haematological malignancies such as chronic lymphocytic leukaemia (CLL) is difficult to envision, because leukaemia cells are not dependent on a network of blood vessels to support basic physiological requirements. Regardless, CLL cells secrete high levels of major angiogenic factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor (PDGF). Nonetheless, it remains unclear how most angiogenic factors regulate accumulation and delayed apoptosis of CLL cells. Angiogenic factors such as leptin, granulocyte colony stimulating factor (G-CSF), follistatin, angiopoietin-1 (Ang1), angiogenin (ANG), midkine (MK), pleiotrophin (PTN), progranulin (PGRN), proliferin (PLF), placental growth factor (PIGF), and endothelial locus-1 (Del-1), represent novel therapeutic targets of future CLL research but have remained widely overlooked. This review aims to outline our current understanding of angiogenic growth factors and their relationship with CLL, a still uncured haematopoietic malignancy. PMID- 25459669 TI - The prevalent KRAS exon 2 c.35 G>A mutation in metastatic colorectal cancer patients: A biomarker of worse prognosis and potential benefit of bevacizumab containing intensive regimens? AB - Bevacizumab-containing chemotherapy differently predict increased efficacy in KRAS exon 2 mutant and wild-type metastatic colorectal cancer (MCRC) patients. Mutant compared to wild-type status did not significantly affect progression-free survival (PFS) and overall survival (OS) in patients fit for first line bevacizumab-containing FIr-B/FOx regimen, and after progression. In patients unfit for intensive regimens, mutant status significantly affected PFS, while not OS. Codon 12 KRAS mutations differentially affect GTPase function, and confer worse clinical behaviour. Prognostic relevance of the prevalent c.35 G>A KRAS mutation was retrospectively evaluated. Fit c.35 G>A mutant patients showed significantly worse OS compared to wild-type and to other mutant. After progression and in unfit patients, c.35 G>A mutation affected significantly worse PFS and OS. c.35 G>A mutant status does not significantly affect worse PFS in patients fit for first line FIr-B/FOx, and it may depend upon effectiveness of anti-VEGF-containing intensive regimen. PMID- 25459670 TI - Mismatch repair gone awry: Management of Lynch syndrome. AB - The hallmark of Lynch syndrome involves germline mutations of genes important in DNA mismatch repair. Affected family kindreds will have multiple associated malignancies, the most common of which is colorectal adenocarcinoma. Recently, evidence has shown that clinical diagnostic criteria provided by the Amsterdam Criteria and the Bethesda Guidelines must be linked with microsatellite instability testing to correctly diagnose Lynch syndrome. We present a case of metachronous colorectal adenocarcinomas in a patient less than 50 years of age, followed by a discussion of Lynch syndrome, with an emphasis on surveillance and prevention of malignancies. PMID- 25459671 TI - A review of relative dose intensity and survival in patients with metastatic solid tumors. AB - Studies have shown that in the curative setting patients with cancer receiving chemotherapy at higher relative dose intensity (RDI) had better clinical outcomes than those receiving treatment at lower RDI. However, the impact of RDI in advanced/metastatic disease remains unclear. A review of the literature was performed to evaluate the relationship between RDI and survival in patients with metastatic lung, breast, or ovarian cancer receiving chemotherapy. Few studies attempted to specifically associate RDI with survival in a systematic way. Findings from studies that analyzed overall survival with a prespecified RDI threshold support the emerging perception that maintaining an RDI>=85% has a favorable impact on survival. Nonetheless, these studies were limited by their retrospective nature. More studies are needed to further evaluate the impact of maintaining planned chemotherapy dose intensity on outcomes in metastatic solid tumors. PMID- 25459672 TI - Inflammatory breast cancer: an overview. AB - Inflammatory breast cancer (IBC) is the most aggressive entity of breast cancer. Management involves coordination of multidisciplinary management and usually includes neoadjuvant chemotherapy, ablative surgery if a tumor-free resection margin is expected and locoregional radiotherapy. This multimodal therapeutic approach has significantly improved patient survival. However, the median overall survival among women with IBC is still poor. By elucidating the biologic characteristics of IBC, new treatment options may become available. We performed a comprehensive review of the English-language literature on IBC through computerized literature searches. The objective of the current review is to present an overview of the literature related to the biology, imaging and multidisciplinary treatment of inflammatory breast cancer. PMID- 25459673 TI - Value of 18F-FDG PET/CT in detecting viable tumour and predicting prognosis of hepatocellular carcinoma after TACE. AB - AIM: To evaluate the efficacy of combined PET/CT in the detection of viable tumour in patients with hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). The correlation between 2-[(18)F]-fluoro-2 deoxy-d-glucose (FDG) uptake during PET and prognosis was evaluated. MATERIALS AND METHODS: Seventy-three patients with 91 HCCs who had undergone TACE with lipiodol before (18)F-FDG PET/CT were retrospectively reviewed. The pattern of lipiodol deposition in the tumour was divided into three groups: grade I, lipiodol remaining in >=60% of the tumour; grade II, 20-60%; and grade III, <=20%. The performance of (18)F-FDG PET/CT in evaluating the viability of HCC was assessed and compared with that of contrast-enhanced CT (CECT). The predictive value of maximal tumoural standardized uptake value (SUV) to mean liver SUV (TSUVmax/LSUVmean) ratio was tested. RESULTS: Comparing the receiver-operating characteristic area, (18)F-FDG-PET/CT was found to be superior to CECT for the detection of viable tumour in patients with HCC after TACE (p = 0.04). A high SUV ratio (TSUVmax/LSUVmean >=1.65) correlated significantly with tumour size (p = 0.0096), the grade of lipiodol deposition (p = 0.0387) and serum alpha foetoprotein (AFP) level (p = 0.0142), but did not correlate with pathological grade (p = 0.2626). The overall survival rate was significantly higher in the low SUV ratio (TSUVmax/LSUVmean<1.65) group (p = 0.024). CONCLUSION: (18)F-FDG-PET/CT is efficient in assessing the viability of HCC after TACE and is superior to CECT in grades I and II, and similar in grade III. It provides valuable information for prediction of prognosis and may aid decisions regarding treatment strategy. PMID- 25459674 TI - Antibiotics in interventional radiology. AB - The range and number of interventional procedures is rapidly increasing each year. A major complication associated with many procedures is infection, which can result in serious adverse outcomes for the patient. Consequently, antibiotics are amongst the most common pharmaceuticals used by the interventionist, particularly for non-vascular procedures, yet almost no randomized controlled trial data exist to inform our decision when formulating appropriate antibiotic prophylaxis regimens. The purpose of this review is to provide an update on the utilization of antibiotics for common interventional radiology procedures, focusing on timing and duration of antibiotic prophylaxis. PMID- 25459675 TI - The detection of beta-amyloid plaques in an Alzheimer's disease rat model with DDNP-SPIO. AB - AIM: To detect the beta-amyloid plaques (Abeta) in a rat model of Alzheimer's disease (AD) using superparamagnetic iron oxide nanoparticles coated with 1,1 dicyano-2-[6-(dimethylamino)-naphthalene-2-yl] propene carboxyl derivative (DDNP SPIO). MATERIALS AND METHODS: DDNP-SPIO was prepared in a previous trial. The binding affinity of DDNP-SPIO to Abeta was tested using fluorescence spectrophotometry in vitro. In vivo, five AD rats and five non-AD rats were intravenously injected with DDNP-SPIO at a dose of 76 MUmol Fe/kg. Coronal T2* weighted images were collected at baseline and repeated at 10, 30, and 60 min post-injection. Enhancement features of the two groups were analysed. After imaging, brain specimens were resected for Congo red and Prussian blue staining to assess the binding of DDNP-SPIO to Abeta deposits. RESULTS: In vitro experiments indicated that the DDNP-SPIO nanoparticles displayed high binding affinities towards Abeta with a Kd value of 29.4 nmol/l. A significant decrease in SI was detected in the hippocampal area of AD rats after intravenous injection of the nanoparticles, but not in non-AD rats. The measurement of the percentage signal loss decreased to 52% in AD rats. In non-AD rats, only 10% signal loss was observed. There was a significant difference between the two groups (t = 4.533, p < 0.05). The signal decrease resulted from the binding of the DDNP-SPIO nanoparticles to the Abeta plaques, which was identified with Congo red and Prussian blue staining. CONCLUSION: The DDNP-SPIO nanoparticles could potentially be used for visualizing Abeta plaques, which may be helpful for diagnosing the early stages of AD and monitoring the effects of drug therapy. PMID- 25459676 TI - Utility of barium studies for patients with recurrent weight gain after Roux-en-Y gastric bypass. AB - AIM: To determine the utility of barium studies for detecting abnormalities responsible for recurrent weight gain after gastric bypass surgery. METHODS: A computerized search identified 42 patients who had undergone barium studies for recurrent weight gain after gastric bypass and 42 controls. The images were reviewed to determine the frequency of staple-line breakdown and measure the length/width of the pouch and gastrojejunal anastomosis. A large pouch exceeded 6 cm in length or 5 cm in width and a wide anastomosis exceeded 2 cm. Records were reviewed for the amount of recurrent weight gain and subsequent weight loss after additional treatment. RESULTS: Staple-line breakdown was present in 6/42 patients (14%) with recurrent weight gain. When measurements were obtained, 13/35 patients (37%) with recurrent weight gain had a large pouch, three (9%) had a wide anastomosis, and four (11%) had both, whereas 22/42 controls (52%) had a large pouch, one (2%) had a wide anastomosis, and two (5%) had both. Ten patients (24%) with recurrent weight gain underwent staple-line repair (n = 3) or pouch/anastomosis revision (n = 7). These 10 patients had a mean weight loss of 38.1 lbs versus a mean loss of 8.6 lbs in 19 patients managed medically. CONCLUSION: Only 14% of patients with recurrent weight gain after gastric bypass had staple-line breakdown, whereas 57% had a large pouch, wide anastomosis, or both. Not all patients with abnormal anatomy had recurrent weight gain, but those who did were more likely to benefit from surgical intervention than from medical management. PMID- 25459677 TI - Kerion celsi of the vulva: an unusual location. PMID- 25459678 TI - Vitamin D binding protein polymorphism protects against development of blastomycosis. AB - Blastomycosis is an uncommon endemic fungal infection. It is presumed that in the endemic regions, the number of exposed individuals is significantly greater than those in whom clinical manifestations develop. We conducted a case-control study of individuals with clinical blastomycosis and controls with similar exposure but who did not develop disease. A genetic association was observed between the Gc-2 allele of vitamin D binding protein and reduced susceptibility to blastomycosis in a Canadian cohort. The Gc-2 allele can affect increased antimicrobial activity of macrophages. It may be possible to mimic this mechanism of protection by vitamin D supplementation. PMID- 25459679 TI - Melatonin inhibits biofilm formation in Candida parapsilosis. PMID- 25459680 TI - Micafungin alone and in combination therapy with deferasirox against Pythium insidiosum. AB - This study evaluated the in vitro and in vivo activity of micafungin alone and in combination with the iron chelator deferasirox against Pythium insidiosum. Micafungin showed a poor in vitro activity when it was used alone, but synergistic interactions were observed for 88.2% of the strains when the drug was combined with deferasirox. Smaller lesions were observed in infected rabbits receiving the combination therapy, although it favored disease dissemination to the lungs. The present results show that micafungin alone is ineffective against P. insidiosum, and the combination micafungin-deferasirox might have deleterious effects for the host. PMID- 25459681 TI - Modulation of the mitochondrial voltage dependent anion channel (VDAC) by curcumin. AB - Voltage dependent anion channel (VDAC) of mitochondria plays a crucial role in apoptosis. Human VDAC-1, reconstituted in planar lipid bilayer showed reduced conductance when treated with curcumin. Curcumin interacts with residues in the alpha helical N-terminus of VDAC and in the channel wall, as revealed by molecular docking, followed by mutational analysis. N-terminus mimicking peptide showed conformational changes in circular dichroism, upon curcumin treatment. We propose that the interaction of curcumin with amino acids in N-terminus and in channel wall fixes the alpha helix in closed conformation. This restricts its movement which is required for the opening of the channel. PMID- 25459682 TI - [Off-label use of intravitreal bevacizumab for severe retinopathy of prematurity]. AB - OBJECTIVE: To examine the quality of evidence and the variability in the off label use of intravitreal bevacizumab for retinopathy of prematurity (ROP). METHODS: A wide review of the literature was performed using Pubmed, Medline, and Cochrane database, using the words vascular endothelial growth factor (VEGF), retinopathy of prematurity, treatment and bevacizumab. RESULTS: Case reports, case series, reviews, one sistematic review and one randomized controlled trial were found on the use of intravitreal bevacizumab in severe ROP, as monotherapy or combined with laser and/or vitrectomy. CONCLUSIONS: The results shown on the use of intravitreal bevacizumab in ROP stage 3+ in zone I or in aggressive posterior ROP are promising. However, uncertainty remains regarding its maximum tolerable dose in the neonatal group, its ocular and systemic safety profile, or its efficacy and bioactivity in a developing child. This report found no significant differences in the recurrence rates of ROP stage 3+ in zone II in patients treated with intravitreal bevacizumab monotherapy in comparison to laser, although the latter is the best option due to long-term safety and efficacy. The use of intravitreal bevacizumab is not indicated in stages 1 and 2 of ROP as the risk of severe visual loss is low and VEFG is necessary for normal retinal vessel development. On the other hand, the use of intravitreal bevacizumab would be contraindicated in stages 4 and 5 because the retinal detachment is accelerated. PMID- 25459684 TI - [Intravitreal injections: Satisfaction and preference]. PMID- 25459683 TI - Guidelines for treatment of chronic primary angle-closure glaucoma. AB - OBJECTIVE: To present a clinical practice guideline update on the medical, laser, and surgical treatment of primary angle closure glaucoma (PACG) in adults. METHODS: Following the formulation of key questions using the PICO scheme (Patient/Problem, Intervention, Comparison, Outcome), a systematic review was performed on the literature published to date, including international clinical practice guidelines. The AMSTAR and Risk of Bias tools were used for evaluating the quality of the information. The level of evidence and grade of recommendation was established following the Scottish Intercollegiate Guidelines Network (SIGN) system. RESULTS: Following the above methodology, recommendations of medical, laser and surgical treatment in adult PACG and levels of evidence are presented. CONCLUSIONS: Although the level of scientific evidence for many of the questions raised is not very high, a review is presented on updated treatment recommendations for adult PACG. Among the limitations for the implementation of these recommendations is that most studies have been conducted in Asian populations, and that the effectiveness is measured almost exclusively in terms of reducing intraocular pressure, and does not include visual function, quality of life or cost-effectiveness parameters. PMID- 25459685 TI - Exaggerated inflammation and monocytosis associate with diastolic dysfunction in heart failure with preserved ejection fraction: evidence of M2 macrophage activation in disease pathogenesis. AB - BACKGROUND: Heart failure with preserved ejection fraction (HFPEF) is a major health problem associated with myocardial leukocyte infiltration, inflammation, and fibrosis. Monocyte and macrophage subsets play a role in HFPEF but have not been studied. We analyzed peripheral blood monocyte phenotype and plasma markers of monocyte activation in patients with HFPEF, asymptomatic LV diastolic dysfunction (aLVDD), and asymptomatic hypertension (aHTN). METHODS AND RESULTS: Peripheral blood was collected from 23 aHTN, 30 aLVDD, and 30 HFPEF patients. Peripheral cytokines of classic/pro-inflammatory (tumor necrosis factor alpha, interleukin (IL) 12, IL-6, monocyte chemoattractant protein 1, C-X-C motif chemokine 10) and alternative/anti-inflammatory monocytes (chemokine-C-C motif ligand (CCL) 17, CCL-18, soluble CD163) were increased in aLVDD and HFPEF. Peripheral blood mononuclear cells and monocytes were purified and surface stained for CD14, CD16, CD163, and CD206. Peripheral monocyte percentage was increased in aLVDD and HFPEF and correlated with echocardiographic LVDD indices. Classic/pro-inflammatory monocyte numbers were increased in aLVDD and HFPEF, and alternative/anti-inflammatory monocyte numbers were increased in HFPEF. CD163 M2 macrophage receptor was reduced in HFPEF. Culture of healthy donor monocytes (n = 3) with HFPEF patient-derived sera (n = 6) promoted M2 macrophage features as evidenced by altered morphology and genes (CD206, IL-10). CONCLUSIONS: Increased peripheral inflammation, monocytosis, and monocyte differentiation to anti inflammatory/profibrotic M2 macrophages likely associate with HFPEF and its precedent asymptomatic LVDD phase. PMID- 25459687 TI - Intracoronary transplantation of CD34(+) cells is associated with improved myocardial perfusion in patients with nonischemic dilated cardiomyopathy. AB - BACKGROUND: We investigated the effects of intracoronary transplantation of CD34(+) cells on myocardial perfusion in patients with nonischemic dilated cardiomyopathy (DCM). METHODS AND RESULTS: We enrolled 21 patients with DCM (left ventricular ejection fraction [LVEF] <40%, New York Heart Association functional class III) who underwent peripheral stem cell mobilization with granulocyte colony stimulating factor (G-CSF). CD34(+) cells were collected by means of apheresis. Patients underwent myocardial perfusion imaging, and CD34(+) cells were injected in the coronary artery supplying viable segments with reduced myocardial perfusion and regional dysfunction. Myocardial perfusion imaging was repeated 6 months later. Clinical response to stem cell therapy was predefined as a change in LVEF >5%. The majority of patients were men (81%) with an overall mean age 53 +/- 9 years, LVEF 25 +/- 5%, and 6-minute walking distance 354 +/- 71 m. Myocardial perfusion defects at rest were observed in 86% of patients and were more common in the left anterior descending territory (50%). At 6 months' follow up, there was a significant improvement in rest myocardial perfusion scores (6.3 +/- 5.8 vs 3.1 +/- 4.3; P < .001), LVEF (25 +/- 7% vs 29 +/- 8%; P = .005), and 6 minute walking distance (354 +/- 71 m vs 404 +/- 91 m; P < .001). Responders to stem cell therapy had lower summed rest perfusion score at both baseline (3.2 +/- 3.0 vs 9.1 +/- 6.3; P = .015) and follow-up (1.0 +/- 1.5 vs 5.0 +/- 5.1; P = .028). CONCLUSIONS: CD34(+) cell transplantation may lead to improved myocardial perfusion in patients with nonischemic DCM. Patients with less severe myocardial perfusion defects at baseline may have an increased likelihood to respond to intracoronary CD34(+) cell transplantation. PMID- 25459686 TI - Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. AB - BACKGROUND: Trimethylamine-N-oxide (TMAO) has been linked to increased cardiovascular risk. We aimed to determine the prognostic value of TMAO and its dietary precursors, choline and betaine, in heart failure (HF). METHODS AND RESULTS: In 112 patients with chronic systolic HF with comprehensive echocardiographic evaluation, we measured plasma TMAO, choline, and betaine by mass spectrometry. Median (interquartile range) TMAO levels, choline, and betaine levels were 5.8 (3.6-12.1) MUmol/L, 10.9 (8.4-14.0) MUmol/L, and 43.8 (37.1-53.0) MUmol/L, respectively, and were correlated with each other (all P < .0001 for both). TMAO levels were significantly higher in patients with diabetes mellitus (9.4 [4.9-13.2] vs 4.8 [3.4-9.8] MUmol/L; P = .005) and in subjects with New York Heart Association functional class III or greater (7.0 [4.7-14.8] vs 4.7 [3.4 11.3] MUmol/L; P = .02). Elevated TMAO, choline, and betaine levels were each associated with higher plasma N-terminal pro-B-type natriuretic peptide (NT proBNP) levels and more advanced left ventricular diastolic dysfunction, but not systolic dysfunction or inflammatory and endothelial biomarkers. Higher choline (hazard ratio [HR] 1.64, 95% CI 1.22-2.20; P = .001), betaine (HR 1.51, 95% CI 1.10-2.08; P = .01), and TMAO (HR 1.48, 95% CI 1.10-1.96; P = .01) predicted increased risk for 5-year adverse clinical events (death/transplantation). Only higher TMAO levels predicted incident adverse clinical events independently from age, estimated glomerular filtration rate, mitral E/septal Ea, and NT-proBNP levels (HR 1.46, 95% CI 1.03-2.14; P = .03). CONCLUSION: Elevated plasma TMAO, choline, and betaine levels are each associated with more advanced left ventricular diastolic dysfunction and portend poorer long-term adverse clinical outcomes in chronic systolic HF. However, only higher plasma TMAO was associated with poor prognosis after adjustment for cardiorenal indices. PMID- 25459688 TI - Effects of prenatal cocaine exposure on early postnatal rodent brain structure and diffusion properties. AB - Prenatal cocaine exposure has been associated with numerous behavioral phenotypes in clinical populations, including impulsivity, reduced attention, alterations in social behaviors, and delayed language and sensory-motor development. Detecting associated changes in brain structure in these populations has proven difficult, and results have been inconclusive and inconsistent. Due to their more controlled designs, animal models may shed light on the neuroanatomical changes caused by prenatal cocaine; however, to maximize clinical relevance, data must be carefully collected using translational methods. The goal of this study was two-fold: (1) to determine if prenatal cocaine alters developmental neuroanatomy using methods that are available to human researchers, specifically structural MRI and diffusion tensor imaging, and (2) to determine the feasibility of rodent in vivo neuroimaging for usage in longitudinal studies of developmental disorders. Cocaine-exposed (prenatal days 1-20, 30mg/kg/day) rat pups were sedated and imaged live using diffusion tensor imaging and postmortem (fixed) using magnetic resonance histology on postnatal day 14. Volume and diffusion properties in whole brain as well as specific regions of interest were then assessed from the resulting images. Whole brain analyses revealed that cocaine-exposed animals showed no change in whole brain volume. Additionally, we found alterations in fractional anisotropy across regions associated with reward processing and emotional regulation, especially in the thalamus and globus pallidus, as well as sex-dependent effects of cocaine in the right cortex. Reductions in fractional anisotropy were paired with reductions only in axial diffusivity, which preliminarily suggests that the changes observed here may be due to axonal damage, as opposed to reductions in myelination of the affected regions/pathways. Our data indicate that prenatal cocaine may target a number of developing brain structures but does not result in overt changes to brain volumes. These results highlight not only the brain alterations that result from prenatal cocaine but also the advancements in live imaging that allow longitudinal study designs in other models. PMID- 25459690 TI - Chemically tunable ultrathin silsesquiazane interlayer for n-type and p-type organic transistors on flexible plastic. AB - In organic field-effect transistors (OFETs), surface modification of the gate dielectric is a critical technique for enhancing the electrical properties of the device. Here, we report a simple and versatile method for fabricating an ultrathin cross-linked interlayer (thickness ~3 nm) on an oxide gate dielectric by using polymeric silsesquiazane (SSQZ). The fabricated siloxane film exhibited an ultrasmooth surface with minimal hydroxyl groups; the properties of the surface were chemically tuned by introducing phenyl and phenyl/fluorine pendent groups into the SSQZ. The growth characteristics of two semiconductors-pentacene (p-type) and N,N'-ditridecyl-3,4,9,10-perylene tetracarboxylic diimide (PTCDI C13, n-type)-on this ultrathin film were systematically investigated according to the type of pendent groups in the SSQZ-treated gate dielectric. Pentacene films on phenyl/fluorine groups exhibited large grains and excellent crystalline homogeneity. By contrast, PTCDI-C13 films exhibited greater crystalline order and perfectness when deposited on phenyl groups rather than on phenyl/fluorine groups. These microstructural characteristics of the organic semiconductors, as well as the dipole moment of the pendent groups, determined the electrical properties of FETs based on pentacene or PTCDI-C13. Importantly, compared to FETs in which the gate dielectric was treated with a silane-coupling agent (a commonly used surface treatment), the FETs fabricated using the tunable SSQZ treatment showed much higher field-effect mobilities. Finally, surface treatment with an ultrathin SSQZ layer was also utilized to fabricate flexible OFETs on a plastic substrate. This was facilitated by the facile SSQZ deposition process and the compatibility of SSQZ with the plastic substrate. PMID- 25459691 TI - Structural, spectroscopic, magnetic and electrochemical studies of monomer N substituted-sulfanilamide copper (II) complex with 2,2'-bipyridine. AB - A novel copper (II) complex of sulfamethazine (4-amino-N-[4,6-dimethyl-2 pyrimidinyl] benzene sulfonamide, Hsmz) ([Cu(smz)2bipy]?0.8H2O; bipy: 2,2' bipyridine) has been synthesized and characterized by single crystal X-ray diffraction, EPR, IR, UV-vis and electrochemical methods. The single crystal X ray analysis indicated that the compound crystallizes in the monoclinic space group P21/c with Z=4. The central copper (II) ion is coordinated by two bidentate sulfamethazine anions through the nitrogen atoms together with one bidentate 2,2' bipyridine ligand forming the octahedral geometry. The characteristic vibration bands support the X-ray analysis results. The EPR spectral analysis has led to that the ground state wave function of the unpaired electron of copper ion is [Formula: see text] ((2)B1g state) and also indicated that the metal ions are located in distorted octahedral sites (D4h) elongated along the z-axis. The electrochemical studies of the complex were also carried out to determine the active sites of the ligands. The cyclic and square wave voltammetric techniques have been used to determine the complex. PMID- 25459692 TI - Vibrational analysis using FT-IR, FT-Raman spectra and HF-DFT methods and NBO, NLO, NMR, HOMO-LUMO, UV and electronic transitions studies on 2,2,4-trimethyl pentane. AB - In this work, the vibrational spectral analysis was carried out by using Raman and infrared spectroscopy in the range 100-4000cm(-1)and 50-4000cm(-1), respectively, for 2,2,4-Trimethyl Pentane, TMP (C8H18) molecule. The molecular structure, fundamental vibrational frequencies and intensity of the vibrational bands are interpreted with the aid of structure optimizations and geometrical parameter calculations based on Hartree Fock (HF) and density functional theory (DFT) method with 6-311++G(d,p) basis set. The scaled B3LYP/6-311++G(d,p) results shows the best agreement with the experimental values over the other method. The calculated HOMO and LUMO energies shows that charge transfer within the molecule. The physical reactions of single bond hydrocarbon TMP were investigated. The results of the calculations were applied to simulate spectra of the title compound, which shows the excellent agreement with observed spectra. Besides, Mulliken atomic charges, UV, frontier molecular orbital (FMO), MEP, NLO activity, Natural Bond-Orbital (NBO) analysis, NMR and thermodynamic properties of title molecule were also performed. PMID- 25459693 TI - Encapsulation of 4-hydroxy-3-methoxy benzoic acid and 4-hydroxy-3,5-dimethoxy benzoic acid with native and modified cyclodextrins. AB - Inclusion complex formation of 4-hydroxy-3-methoxybenzoic acid (HMBA) and 4 hydroxy-3,5-dimethoxybenzoic acid (HDMBA) with alpha-CD, beta-CD, HP-alpha-CD and HP-beta-CD were studied by absorption, steady state fluorescence, time resolved fluorescence, FT-IR, (1)H NMR and molecular modeling methods. The effect of the CDs with HMBA and HDMBA were studied in pH~1, pH~7 and pH~10 buffer solutions. The study revealed that both hydroxybenzoic acids formed 1:1 complex with the four CDs. The theoretical values suggest that both guests are partially encapsulated into the CDs cavity. The hydroxy group is present in the interior part of the CD cavity and carboxyl group is present in the hydrophilic part of the CD cavity. Molecular modeling studies proved that (i) the negative Gibbs energy and enthalpy changes for the inclusion complexes indicated that the formation of these complexes were spontaneous and exothermic, (ii) hydrogen bonding interactions played a major role in the inclusion process, (iii) the dipole moment values for guests increased when they entered into the CDs cavities which is an indication of the increase of the polarity and the formation of complex and (iv) differences in binding energy and enthalpy change suggest that the beta-CD formed more stable complex than alpha-CD. PMID- 25459689 TI - Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development. AB - The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11beta hydroxysteroid dehydrogenase enzymes (11beta-HSD1 and 11beta-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11beta-HSD1, while 11beta-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11beta-HSD1 and 11beta HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11beta-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of arsenic results in altered fetal programming of the glucocorticoid system. PMID- 25459694 TI - A detailed experimental and theoretical study of two novel substituted trifluoromethylchromones. The influence of the bulky bromine atom on the crystal packing. AB - The new 3-methyl-2-trifluoromethylchromone (1) and 3-bromomethyl-2 trifluoromethylchromone (2) compounds were synthesized and characterized by vibrational (IR, Raman), UV-Vis and NMR ((1)H, (13)C and (19)F) spectroscopy and MS spectrometry. The crystal structures of 1 and 2 were determined by X-ray diffraction methods. Both compounds crystallize in the monoclinic P21/c space group with Z=4 molecules per unit cell. The structures were solved from 1423 (1) and 1856 (2) reflections with I>2sigma (I) and refined by full-matrix least squares to agreement R1-values of 0.0403 (1) and 0.0554 (2). Because of pi bonding delocalization, the organic molecular skeletons are planar and the molecular bonding structures can be described by formally single, double and resonant bonds. In 2, the CF3 group revealed a strong rotational disorder around the CCF3 bond, which could be explained in terms of four split positions with about uniform angular distribution. The vibrational, electronic and NMR, spectra were discussed and assigned with the assistance of DFT calculations. PMID- 25459695 TI - Microwave assisted facile green synthesis of silver and gold nanocatalysts using the leaf extract of Aerva lanata. AB - Herein, we report a simple microwave assisted method for the green synthesis of silver and gold nanoparticles by the reduction of aqueous metal salt solutions using leaf extract of the medicinal plant Aerva lanata. UV-vis., FTIR, XRD, and HR-TEM studies were conducted to assure the formation of nanoparticles. XRD studies clearly confirmed the crystalline nature of the synthesized nanoparticles. From the HR-TEM images, the silver nanoparticles (AgNPs) were found to be more or less spherical and gold nanoparticles (AuNPs) were observed to be of different morphology with an average diameter of 18.62nm for silver and 17.97nm for gold nanoparticles. In order to evaluate the effect of microwave heating upon rate of formation, the synthesis was also conducted under ambient condition without the assistance of microwave radiation and the former method was found to be much faster than the later. The synthesized nanoparticles were used as nanocatalysts in the reduction of 4-nitrophenol to 4-aminophenol by NaBH4. PMID- 25459696 TI - Simultaneous determination of triple therapy for Helicobacter pylori in human plasma by reversed phase chromatography with online wavelength switching. AB - The infection of gastric mucosa by Helicobacter pylori (HP) is an essential cofactor in the aetiology of gastroduodenal ulcer and gastric carcinoma. Because of the bacterial resistance, combination therapy containing omeprazole (OME), tinidazole (TNZ) and clarithromycin (CLA) is commonly used for eradication of HP. However, the simultaneous determination of the triple therapy in human plasma was not reported. A simple, reproducible, and selective HPLC method was developed for the simultaneous determination of the triple therapy mixture used for management of HP infections in human plasma. An HPLC procedure based on a liquid-liquid extraction, enrichment of the analytes and subsequent reversed-phase chromatography with UV detection was used. To enable sensitive and selective detection, the method involved the use of online wavelength switching detection, with two different detection wavelengths; 280nm for detection of OME and TNZ and 210nm for detection of CLA. Separations were performed on C18 analytical column with acetonitrile-10mM phosphate buffer of pH=3.0 at flow rate of 1.0mLmin(-1). The linear ranges in human plasma were 0.05-10MUgmL(-1) with correlation coefficients >0.9990. The detection limits in human plasma were 0.02-0.07MUgmL( 1). Validation parameters were assessed in compliance with US-FDA guidelines. The method proved to be valuable for the therapeutic drug monitoring after oral administration of triple therapy tablets. PMID- 25459697 TI - A novel Schiff base: Synthesis, structural characterisation and comparative sensor studies for metal ion detections. AB - A novel Schiff base ligand was synthesized by the condensation reaction of 2,6 diformylpyridine and 4-aminoantipyrine in MeOH and characterised by its melting point, elemental analysis, FT-IR, (1)H, (13)C NMR and mass spectroscopic studies. Molecular structure of the ligand was determined by single crystal X-ray diffraction technique. The electrochemical properties of the Schiff base ligand were studied in different solvents at various scan rates. Sensor ability of the Schiff base ligand was investigated by colorimetric and fluorometric methods. Visual colour change of the ligand was investigated in MeOH solvent in presence of various metal ions Na(+), Mg(2+), Al(3+), K(+), Cr(3+), Mn(2+), Fe(3+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+) and Pb(2+). Upon addition of Al(3+) ion into a MeOH solution of the ligand, an orange colour developed which is detectable by naked eye. Fluorescence emission studies showed that the ligand showed single emission band at 630-665nm upon excitation at 560nm. Addition of metal ions Na(+), Mg(2+), K(+), Cr(3+), Mn(2+), Fe(3+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+) and Pb(2+) (1:1M ratio) cause fluorescence quenching, however addition of Al(+3) resulted in an increase in fluorescence intensity. No significant variation was observed in the fluorescence intensity caused by Al(3+) in presence of other metal ions. Therefore, the Schiff base ligand can be used for selective detection of Al(3+) ions in the presence of the other metal ions studied. PMID- 25459698 TI - Composition and (in)homogeneity of carotenoid crystals in carrot cells revealed by high resolution Raman imaging. AB - Three categories of roots differing in both beta/alpha-carotene ratio and in total carotenoid content were selected based on HPLC measurements: high alpha- and beta-carotene (HalphaHbeta), low alpha- and high beta-carotene (LalphaHbeta), and low alpha- and low beta-carotene (LalphaLbeta). Single carotenoid crystals present in the root cells were directly measured using high resolution Raman imaging technique with 532nm and 488nm lasers without compound extraction. Crystals of the HalphaHbeta root had complex composition and consisted of beta carotene accompanied by alpha-carotene. In the LalphaHbeta and LalphaLbeta roots, measurements using 532nm laser indicated the presence of beta-carotene only, but measurements using 488nm laser confirmed co-occurrence of xanthophylls, presumably lutein. Thus the results show that independently on carotenoid composition in the root, carotenoid crystals are composed of more than one compound. Individual spectra extracted from Raman maps every 0.2-1.0MUm had similar shapes in the 1500-1550cm(-1) region indicating that different carotenoid molecules were homogeneously distributed in the whole crystal volume. Additionally, amorphous carotenoids were identified and determined as composed of beta-carotene molecules but they had a shifted the nu1 band probably due to the effect of bonding of other plant constituents like proteins or lipids. PMID- 25459699 TI - Theoretical searches and spectral computations of preferred conformations of various absolute configurations for a cyclodipeptide, cordycedipeptide A from the culture liquid of Cordyceps sinensis. AB - A cyclic dipeptide often has the multiple configurations and the abundant conformations. The density functional theory (DFT) method is used to search the preferred conformation of the most probable configuration for cordycedipeptide A isolated from the culture liquid of Cordyceps sinensis. The time-dependent DFT approach is exploited to describe the profile of electronic circular dichroism (CD). The calculated results show that the most probable configuration is 3S6R7S, whose preferred conformation has a negative optical rotation and a positive lowest energy electronic CD band. PMID- 25459700 TI - An investigation on the effect of high partial pressure of hydrogen on the nanocrystalline structure of silicon carbide thin films prepared by radio frequency magnetron sputtering. AB - The aim of the study reported in this paper is to investigate the role of the high partial pressure of hydrogen introduced during the growth of nanocrystalline silicon carbide thin films (nc-SiC:H). For this purpose, we report the preparation as well as spectroscopic studies of four series of nc-SiC:H obtained by radio-frequency magnetron sputtering at high partial pressure of hydrogen by varying the percentage of H2 in the gas mixture from 70% to 100% at common substrate temperature (TS=500 degrees C). The effects of the dilution on the structural changes and the chemical bonding of the different series have been studied using Fourier transform infrared and Raman spectroscopy. For this range of hydrogen dilution, two groups of films were obtained. The first group is characterized by the dominance of the crystalline phase and the second by a dominance of the amorphous phase. This result confirms the multiphase structure of the grown nc-SiC:H thin films by the coexistence of the SiC network, carbon like and silicon-like clusters. Furthermore, infrared results show that the SiC bond is the dominant absorption peak and the carbon atom is preferentially bonded to silicon. The maximum value obtained of the crystalline fraction is about 77%, which is relatively important compared to other results obtained by other techniques. In addition, the concentration of CHn bonds was found to be lower than that of SiHn for all series. Raman measurements revealed that the crystallization occurs in all series even at 100% H2 dilution suggesting that high partial pressure of hydrogen favors the formation of silicon nanocrystallites (nc-Si). The absence of both the longitudinal acoustic band and the transverse optical band indicate that the crystalline phase is dominant. PMID- 25459701 TI - DNA cleavage, antimicrobial studies and a DFT-based QSAR study of new antimony(III) complexes as glutathione reductase inhibitor. AB - New antimony(III) complexes, [Sb(2-aminopyridine)2Cl3] (1a), [Sb(2 aminopyridine)2Br3] (1b), [Sb(5-methyl-2-aminopyridine)2Cl3] (2a), [Sb(5-methyl-2 aminopyridine)2Br3] (2b), [Sb(2-aminopyrimidine)2Cl3] (3a), [Sb(2 aminopyrimidine)2Br3] (3b), [Sb(4,6-dimethoxy-2-aminopyrimidine)2Cl3] (4a), [Sb(4,6-dimethoxy-2-aminopyrimidine)2Br3] (4b), [Sb(2-amino-1,3,5-triazine)2Cl3] (5a), [Sb(2-amino-1,3,5-triazine)2Br3] (5b), [Sb(2-guanidinobenzimidazole) Cl3] (6a), [Sb(2-guanidinobenzimidazole)Br3] (6b) [Sb(2- benzyl-2 thiopseudeourea)2Cl3] (7a) and [Sb(2- benzyl-2-thiopseudeourea)2Br3] (7b) were synthesized. Their structures were characterized by elemental analysis, molecular conductivity, FT-IR, (1)H NMR, LC-MS techniques. Glutathione reductase inhibitor activity, antimicrobial activity and DNA cleavage studies of the complexes were determined. The geometrical structures of the complexes were optimized by DFT/B3LYP method with LANL2DZ as basis set. Calculation results indicated that the equilibrium geometries of all complexes have square pyramidal shape. About 350 molecular descriptors (constitutional, topological, geometrical, electrostatic and quantum chemical parameters) of the complexes were calculated by DFT/B3LYP/LANL2DZ method with CODESSA software. Calculated molecular parameters were correlated to glutathione reductase inhibitory activity values (pIC50) of all complexes by Best Multi-Linear Regression (BMLR) method. Obtained two-parameter QSAR equation shows that increase in "maximum partial charge for a H atom" and decrease in HOMO-LUMO gap would be favorable for the glutathione reductase inhibitory activity. PMID- 25459702 TI - Binding interaction between 2-(naphthalen-1-yl)-1-p-tolyl-1H-phenanthro[9,10 d]imidazole and semiconductor nanomaterials. AB - The binding interaction of bioactive phenanthrimidazole with nanoparticulate WO3, Fe2O3, Fe3O4, CuO, ZrO2 and Al2O3 has been studied by electronic and life time spectral studies. The phenanthrimidazole adsorbs strongly on the surface of nanosemiconductor, the apparent binding constants have been determined from the fluorescence quenching. In the case of nanocrystalline insulator, fluorescence quenching through electron transfer from the excited state of the phenanthrimidazole to alumina is not possible, but it is due to energy transfer process. PMID- 25459703 TI - Extracellular synthesis of silver nanoparticles by novel Pseudomonas veronii AS41G inhabiting Annona squamosa L. and their bactericidal activity. AB - In present investigation extracellular synthesis of silver nanoparticles were synthesized using cell free supernatant of Pseudomonas veronii AS41G isolated from Annona squamosa L. The bacterium significantly reduced silver nitrate to generate silver nanoparticles which was characterized with hyphenated techniques. Synthesis of silver nanoparticles preliminary confirmed by UV-Visible spectrophotometry with the intense peak at 410nm, Further FTIR analysis revealed the possible role of biomolecules in the supernatant responsible for mediating the nanoparticles formation. The XRD spectra exhibited the characteristic Bragg peaks of 100, 111, 200, and 220 facets of the face centred cubic symmetry of nanoparticles suggesting that these nanoparticles were crystalline in nature. TEM microgram showed polydispersity of nanoparticles with size ranging from 5 to 50nm. Synthesized silver nanoparticles showed antibacterial activity against human and environmental pathogens including MRSA. The study enlightens the role of biosynthesized silver nanoparticles as an emerging alternative for drug resistant microorganisms. The obtained results are promising enough to pave the environmentally benign nanoparticle synthesis processes without use of any toxic chemicals and also envision the emerging role of endophytes towards synthesis of nanoparticles. With scanty reports available on P.veronii species, a new role has been reported in this study which will be very valuable for future researchers working on it. PMID- 25459704 TI - Comparison of nickel doped Zinc Sulfide and/or palladium nanoparticle loaded on activated carbon as efficient adsorbents for kinetic and equilibrium study of removal of Congo Red dye. AB - In this study, the efficiency of nickel doped Zinc Sulfide nanoparticle loaded on activated carbon (Ni-ZnS-NP-AC) and palladium nanoparticles loaded on activated carbon (Pd-NP-AC) for the removal of Congo Red (CR) from aqueous solution was investigated. These materials were fully identified and characterized in term of structure, surface area and pore volume with different techniques such XRD, FE SEM and TEM analysis. The dependency of CR removal percentage to variables such as pH, contact time, amount of adsorbents, CR concentration was examined and optimum values were set as: 0.03g Ni-ZnS-NP-AC and 0.04g of Pd-NP-AC at pH of 3 and 2 after mixing for 22 and 26min for Ni-ZnS-NP-AC and Pd-NP-AC, respectively. Subsequently, it was revealed that isotherm data efficiency can be correlated Langmuir with maximum monolayer adsorption capacities of 286 and 126.6mgg(-1) at room temperature for Ni-ZnS-NP-AC and Pd-NP-AC, respectively. Investigation of correlation between time and rate of adsorption reveal that the CR adsorption onto both adsorbents followed pseudo second order and interparticle diffusion simultaneously. PMID- 25459705 TI - Functional biocompatible magnetite-cellulose nanocomposite fibrous networks: Characterization by fourier transformed infrared spectroscopy, X-ray powder diffraction and field emission scanning electron microscopy analysis. AB - The preparation and characterization of functional biocompatible magnetite cellulose nano-composite fibrous material is described. Magnetite-cellulose nano composite was prepared by a combination of the solution-based formation of magnetic nano-particles and subsequent coating with amino celluloses. Characterization was accomplished using X-ray powder diffraction (XRD), fourier transformed infrared (FTIR) and field emission scanning electron microscopy (FESEM) analysis. The peaks of Fe3O4 in the XRD pattern of nanocomposite confirm existence of the nanoparticles in the amino cellulose matrix. Magnetite-cellulose particles exhibit an average diameter of roughly 33nm as demonstrated by field emission scanning electron microscopy. Magnetite nanoparticles were irregular spheres dispersed in the cellulose matrix. The vibration corresponding to the NCH3 functional group about 2850cm(-1) is assigned in the FTIR spectra. Functionalized magnetite-cellulose nano-composite polymers have a potential range of application as targeted drug delivery system in biomedical field. PMID- 25459706 TI - Spectroscopic and molecular docking studies on the interaction of the drug olanzapine with calf thymus DNA. AB - The present study investigated the binding interaction between olanzapine and calf thymus DNA (ct-DNA) using emission, absorption, circular dichroism, viscosity measurements and molecular modeling. Thermodynamic parameters (DeltaH<0 and DeltaS<0) indicated that hydrogen bond and van der Waals play main roles in the binding of the drug to ct-DNA. Spectrophotometric studies of the interaction of olanzapine with DNA have shown that it could bind to ct-DNA (Kb=2*10(3)M(-1)). The binding constant is comparable to standard groove binding drugs. Competitive fluorimetric studies with Hoechst 33258 have shown that olanzapine exhibits the ability to displace the DNA-bound Hoechst 33258 indicating that binds strongly in minor groove of DNA helix. Furthermore, the drug induces detectable changes in the CD spectrum of ct-DNA as well as changes in its viscosity. All of the experimental results prove that the groove binding must be predominant. The results obtained from experimental data were in good agreement with molecular modeling studies. PMID- 25459707 TI - Photovoltaic performance of TiO2 electrode adsorbed with gardenia yellow purified by nonionic polymeric sorbent in dye-sensitized solar cells. AB - To improve the photovoltaic conversion efficiency in dye-sensitized solar cells (DSSCs), TiO2 electrode adsorbed with gardenia yellow purified by nonionic polymeric sorbent was successfully formulated on nanoporous TiO2 surface. Adsorption and desorption properties of crude gardenia yellow solution on a macroporous resin, XAD-1600, were investigated to purify gardenia yellow because of its strong adsorption and desorption abilities as well as high selectivity. To this end, adsorption equilibrium and kinetic data were measured and fitted using adsorption isotherms and kinetic models. Adsorption and desorption breakthrough curves in a column packed with XAD-1600 resin was obtained to optimize the separation process of gardenia yellow. The photovoltaic performance of the photo electrode adsorbed with the crude and purified gardenia yellow in DSSCs was compared from current-voltage measurements. The results showed that the photovoltaic conversion efficiency was highly dependent on how to separate and purify gardenia yellow as a photosensitizer. PMID- 25459708 TI - EGCG assisted green synthesis of ZnO nanopowders: Photodegradative, antimicrobial and antioxidant activities. AB - Zinc oxide nanopowders were synthesized by solution combustion method using Epigallocatechin gallate (EGCG) a tea catechin as fuel. The structure and morphology of the product was characterized by Powder X-ray Diffraction, Scanning Electron Microscopy, photoluminescence and UV-Visible spectroscopy. The nanopowders (Nps) were subjected to photocatalytic and biological activities such as antimicrobial and antioxidant studies. PXRD patterns demonstrate that the formed product belongs to hexagonal wurtzite system. SEM images show that the particles are agglomerated to form sponge like structure and the average crystallite sizes were found to be ~10-20nm. PL spectra exhibit broad and strong peak at 590nm due to the Zn-vacancies, and O-vacancies. The prepared ZnO Nps exhibit excellent photocatalytic activity for the photodegradation of malachite green (MG) and methylene blue (MB) indicating that the ZnO NPs are potential photocatalytic semiconductor materials. ZnO NPs exhibit significant bactericidal activity against Klebsiella aerogenes, Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus using the agar well diffusion method. Furthermore, the ZnO nano powders show good antioxidant activity by potentially scavenging DPPH radicals. The study successfully demonstrates synthesis of ZnO NPs by simple ecofriendly route employing EGCG as fuel that exhibit superior photodegradative, antibacterial and antioxidant activities. PMID- 25459709 TI - Photophysical characteristics of biologically active 4-aryloxymethyl coumarins 4PTMBC and 1IPMBC. AB - The absorption and fluorescence characteristics of biologically active coumarin derivatives 4-p-tolyloxymethyl-benzo[h]coumarin (4PTMBC) and 1-(4-iodo phenoxymethyl)-benzo[f]coumarin (1IPMBC) are studied at room temperature in a series of organic solvents and 1,4-dioxane - acetonitrile solvent mixture. The effect of pure solvents on the spectral properties are analyzed using Lippert Mataga polarity function, Reichardt's microscopic solvent polarity parameter, Kamlet's and Catalan's multiple linear regression approaches. Both general solute - solvent interactions and hydrogen bonding interactions are operative in these systems. However, the contribution of hydrogen bonding interactions is less compared to general solute-solvent interactions. The solvatochromic correlations are used to estimate excited state dipole moment using experimentally determined ground state dipole moment. The bathochromic shift of the emission spectra and the increase in excited state dipole moment indicate the intramolecular charge transfer (ICT) character in the emitting singlet state. The solvation studies in 1,4-dioxane - acetonitrile solvent mixture suggest that these dyes are preferentially solvated by 1,4-dioxane. PMID- 25459710 TI - Pyrazolo[4,3-a]quinindoline as a new highly fluorescent heterocyclic system: Design, synthesis, spectroscopic characterization and DFT calculations. AB - After obtaining the desired precursors in several reactions, new N-alkyl substituted heterocyclic system pyrazolo[4,3-a]quinindolines (pyrazolo[4,3-f] indolo[2,3-b]quinolines) were synthesized by one-pot reaction of 1-alkyl-5-nitro 1H-indazole with 2-(1-alkyl-1H-3-indolyl)acetonitrile in MeOH/KOH solution via the nucleophilic substitution of hydrogen in excellent yields. Spectral (UV-Vis, FT-IR, NMR and fluorescence) and analytical data allowed the structures of the synthesized compounds to be established. The values of absorption and fluorescence maxima, extinction coefficients and fluorescence quantum yield of these new heterocyclic fluorophores were obtained and they show highlighting interesting photophysical properties. Density functional theory (DFT) calculations of one structure by using the B3LYP hybrid functional and the 6 311+G(d,p) basis set were performed to provide the optimized geometry, relevant frontier orbitals and the prediction of (1)H NMR chemical shifts. Calculated electronic absorption spectrum of one structure was also obtained by time dependent density functional theory (TD-DFT) method. Solvatochromic properties of these dyes have been discussed and the results showed that the absorption and emission bands in polar solvents undergo a modest red shift. PMID- 25459711 TI - A novel strategy for chromogenic chemosensors highly selective toward cyanide based on its reaction with 4-(2,4-dinitrobenzylideneamino)benzenes or 2,4 dinitrostilbenes. AB - N-(2,4-dinitrobenzylidene)-4-methoxyaniline (1), 4-(N,N-dimethylamine)-N-(2,4 dinitrobenzylidene)aniline (2), 2,4-dinitro-4'-methoxystilbene (3), and 2,4 dinitro-4'-(dimethylamino)stilbene (4) were synthesized and studied in dimethyl sulfoxide in a novel strategy as anionic chromogenic chemosensors. The color of the solutions of these compounds changed only in the presence of cyanide. The kinetic studies were performed with compounds 1-3 in an excess of cyanide. Higher second-order rate constant values were obtained for the compounds containing a methoxy group in relation to the compounds with a dimethylamino substituent, since the methoxy group donates electronic density to the 2,4-dinitrophenyl electron-accepting group less easily compared with the dimethylamino group. Stilbenes generally have greater structural rigidity than imines, facilitating the action of the substituents through the mesomeric effect. The data obtained indicate that the anion acts as a nucleophile, being responsible for CN bond breaking. The CC bridge is not broken in the stilbene dyes, but cyanide performs a nucleophilic attack on the 2,4-dinitrophenyl group. PMID- 25459712 TI - Quantum chemical studies on structural, vibrational, NBO and hyperpolarizability of N-(1,1-Dimethyl-2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid. AB - The FTIR and FT-Raman spectra of N-(1,1-Dimethyl-2-hydroxyethyl)-3-amino-2 hydroxypropanesulfonic acid were recorded in the regions 4000-400cm(-1) and 4000 50cm(-1) respectively. The structural and spectroscopic data of the molecule in the ground state were calculated using Hartee-Fock and density functional method (B3LYP) with the correlation consistent-polarized valence double zeta (cc-pVDZ) basis set. The most stable conformer was optimized and the structural and vibrational parameters were determined based on this. With the observed FTIR and FT-Raman data, a complete vibrational assignment and analysis of the fundamental modes of the compound were carried out. Thermodynamic properties and Mulliken charges were calculated using both Hartee-Fock and density functional method using the cc-pVDZ basis set and compared. The calculated HOMO-LUMO energy gap revealed that charge transfer occurs within the molecule. (1)H and (13)C NMR chemical shifts of the molecule were calculated using Gauge Including Atomic Orbital (GIAO) method and were compared with experimental results. Stability of the molecule arising from hyperconjugative interactions and charge delocalization has been analyzed using Natural Bond Orbital (NBO) analysis. The first order hyperpolarizability (beta) and Molecular Electrostatic Potential (MEP) of the molecule was computed using DFT calculations. The electron density based local reactivity descriptor such as Fukui functions were calculated to explain the chemical reactivity site in the molecule. PMID- 25459713 TI - Vibrations and reorientations of NH3 molecules in [Mn(NH3)6](ClO4)2 studied by infrared spectroscopy and theoretical (DFT) calculations. AB - The vibrational and reorientational motions of NH3 ligands and ClO4(-) anions were investigated by Fourier transform middle-infrared spectroscopy (FT-IR) in the high- and low-temperature phases of [Mn(NH3)6](ClO4)2. The temperature dependencies of full width at half maximum (FWHM) of the infrared bands at: 591 and 3385cm(-1), associated with: rhor(NH3) and nuas(N-H) modes, respectively, indicate that there exist fast (correlation times tauR~10(-12)-10(-13)s) reorientational motions of NH3 ligands, with a mean values of activation energies: 7.8 and 4.5kJmol(-1), in the phase I and II, respectively. These reorientational motions of NH3 ligands are only slightly disturbed in the phase transition region and do not significantly contribute to the phase transition mechanism. Fourier transform far-infrared and middle-infrared spectra with decreasing of temperature indicated characteristic changes at the vicinity of PT at TC(c)=137.6K (on cooling), which suggested lowering of the crystal structure symmetry. Infrared spectra of [Mn(NH3)6](ClO4)2 were recorded and interpreted by comparison with respective theoretical spectra calculated using DFT method (B3LYP functional, LANL2DZ ECP basis set (on Mn atom) and 6-311+G(d,p) basis set (on H, N, Cl, O atoms) for the isolated equilibrium two models (Model 1 - separate isolated [Mn(NH3)6](2+) cation and ClO4(-) anion and Model 2 - [Mn(NH3)6(ClO4)2] complex system). Calculated optical spectra show a good agreement with the experimental infrared spectra (FT-FIR and FT-MIR) for the both models. PMID- 25459714 TI - The QSAR and docking calculations of fullerene derivatives as HIV-1 protease inhibitors. AB - The inhibition of HIV-1 protease is considered as one of the most important targets for drug design and the deactivation of HIV-1. In the present work, the fullerene surface (C60) is modified by adding oxygen atoms as well as hydroxymethylcarbonyl (HMC) groups to form 6 investigated fullerene derivative compounds. These compounds have one, two, three, four or five O atoms+HMC groups at different positions on phenyl ring. The effect of the repeating of these groups on the ability of suggested compounds to inhibit the HIV protease is studied by calculating both Quantitative Structure Activity Relationship (QSAR) properties and docking simulation. Based on the QSAR descriptors, the solubility and the hydrophilicity of studied fullerene derivatives increased with increasing the number of oxygen atoms+HMC groups in the compound. While docking calculations indicate that, the compound with two oxygen atoms+HMC groups could interact and binds with HIV-1 protease active site. This is could be attributed to the active site residues of HIV-1 protease are hydrophobic except the two aspartic acids. So that, the increase in the hydrophilicity and polarity of the compound is preventing and/or decreasing the hydrophobic interaction between the compound and HIV-1 protease active site. PMID- 25459715 TI - Vibrational spectroscopic investigations of 4,4-dimethyl-2-oxazoline: A density functional theory approach. AB - The spectroscopic properties were investigated by FT-IR, FT-Raman and (1)H and (13)C nuclear magnetic resonance (NMR) techniques. The FT-IR (4000-400cm(-1)) and FT-Raman (3500-100cm(-1)) spectra in the liquid phase were recorded for 4,4 dimethyl-2-oxazoline (abbreviated as DMOZ). The (1)H and (13)C NMR spectra were recorded and chemical shifts were calculated by using the gauge independent atomic orbital (GIAO) technique with DFT/B3LYP/6-311++G(d,p) basis set and compared with experimental results. The structure of the compound was optimized and quantum chemical calculations of energies, geometric parameters (bond lengths and bond angles) and vibrational wavenumbers of DMOZ were carried out using DFT/B3LYP method with 6-311++G(d,p) basis set. Temperature dependence thermodynamic parameters and magnetic properties of the title compound have been analyzed. The dipole moment (MU), polarizability (alpha-), anisotropy polarizability (gamma(2)) and hyperpolarizability (betatot) of the molecule have been reported. Stability of the molecule arising from hyper conjugative interactions and charge delocalization has been analyzed using natural bond orbital (NBO) analysis. The energy and oscillator strength were calculated using absorption spectra (UV-Vis spectrum), this spectral analysis confirms the charge transfer of the molecule. A study on the electronic properties, such as HOMO and LUMO energies, molecular electrostatic potential (MEP) were also performed. PMID- 25459716 TI - Spectroscopic (FT-IR, FT-Raman and UV) investigation, NLO, NBO, molecular orbital and MESP analysis of 2-{2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid. AB - In this work, FT-IR and FT-Raman spectra of 2-{2-[(2,6 dichlorophenyl)amino]phenyl}acetic acid (abbreviated as 2DCPAPAA) have been reported in the regions 4000-450cm(-1) and 4000-50cm(-1), respectively. The molecular structure, geometry optimization, intensities, vibrational frequencies were obtained by the ab initio and DFT levels of theory B3LYP with 6-311++G(d,p) standard basis set and a different scaling of the calculated wave numbers. The complete vibrational assignments were performed on the basis of the potential energy distribution (PED) of the vibrational modes calculated using vibrational energy distribution analysis (VEDA 4) program. The harmonic frequencies were calculated and the scaled values were compared with experimental FT-IR and FT Raman data. The observed and the calculated frequencies are found to be in good agreement. Stability of the molecule arising from hyper conjugative interactions, charge delocalization has been analyzed using natural bond orbital (NBO) analysis. The thermodynamic properties of the title compound at different temperature reveal the correlations between standard heat capacities (C) standard entropies (S) standard enthalpy changes (DeltaH). The important non-linear optical properties such as electric dipole momentum, polarizability and first hyperpolarizability of 2DCPAPAA have been computed using B3LYP/6-311++G(d,p) quantum chemical calculations. The Natural charges, HOMO, LUMO, chemical hardness (eta), chemical potential (MU), Electro negativity (chi) and electrophilicity values (omega) are calculated and reported. The oscillator's strength, wave length, and energy calculated by TD-DFT and 2DCPAPAA is approach complement with the experimental findings. The molecular electrostatic potential (MESP) surfaces of the molecule were constructed. PMID- 25459717 TI - Spectroscopic (FT-IR, FT-Raman and UV-Visible) investigations, NMR chemical shielding anisotropy (CSA) parameters of 2,6-Diamino-4-chloropyrimidine for dye sensitized solar cells using density functional theory. AB - The molecular structure, geometry optimization, vibrational frequencies of organic dye sensitizer 2,6-Diamino-4-chloropyrimidine (DACP) were studied based on Hartree-Fock (HF) and density functional theory (DFT) using B3LYP methods with 6-311++G(d,p) basis set. Ultraviolet-Visible (UV-Vis) spectrum was investigated by time dependent DFT (TD-DFT). Features of the electronic absorption spectrum in the UV-Visible regions were assigned based on TD-DFT calculation. The absorption bands are assigned to transitions. The interfacial electron transfer between semiconductor TiO2 electrode and dye sensitizer DACP is due to an electron injection process from excited dye to the semiconductor's conduction band. The observed and the calculated frequencies are found to be in good agreement. The energies of the frontier molecular orbitals (FMOS) have also been determined. The chemical shielding anisotropic (CSA) parameters are calculated from the NMR analysis, Stability of the molecule arising from hyperconjugative interactions and charge delocalization has been analyzed using natural bond orbital (NBO) analysis. PMID- 25459718 TI - A study of the molecular, vibrational, electronic and quantum chemical investigation of 2-methyl-1-vinylimidazole. AB - The spectroscopic properties of 2-methyl-1-vinylimidazole (abbreviated as 2M1VIM) were examined by FT-IR, FT-Raman and NMR techniques. FT-IR and FT-Raman spectra were recorded in the region 4000-400cm(-1) and 3500-50cm(-1), respectively. The (1)H and (13)C NMR spectra were recorded in CDCl3. The structural and spectroscopic data of the molecule in the ground state were calculated by using density functional theory (DFT) employing B3LYP and LSDA methods with 6 311++G(d,p) basis set. The geometry of the molecule was fully optimized, vibrational spectra were calculated and fundamental vibration were assigned on the basis of potential energy distribution (PED) of the vibrational modes calculated with scaled quantum mechanical (SQM) method. The optimized structure of the compound was interpreted and compared with the reported experimental values. The observed vibrational ware numbers, absorption wavelengths and chemical shifts were compared with calculated values. The calculated HOMO and LUMO energies show that charge transfer occur within the molecule. As a result, the optimized geometry, and calculated spectroscopic data show a good agreement with the experimental results. PMID- 25459719 TI - Immobilization of cobalt(III) Schiff base complexes onto Montmorillonite-K10: Synthesis, experimental and theoretical structural determination. AB - The [Co(naphophen)(PPh3)(OH2)]ClO4 and [Co(naphophen)(PBu3)(OH2)]BF4 (where naphophen=bis(naphthaldehyde)1,2-phenylenediimine) complexes were synthesized and chracterized by FT-IR, UV-Vis, (1)H NMR, (13)C NMR spectroscopy and elemental analysis techniques. The coordination geometry of the synthesized complexes were determined by X-ray crystallography. Cobalt (III) complexes have six-coordinated pseudo-octahedral geometry in which the O(1), O(2), N(1) and N(2) atoms of the Schiff base forms the equatorial plane. These complexes showed a dimeric structure via hydrogen bonding between the phenolate oxygen and the hydrogens of the coordinated H2O molecule. The theoretical calculations were also performed to optimize the structure of the complexes in the gas phase to confirm the structures proposed by X-ray crystallography. In addition, UV-Visible and IR spectra of complexes were calculated and compared with the corresponding experimental spectra to complete the experimental structural identification. The synthesized complexes were incorporated onto the Montmorillonite-K10 nanoclay via simple ion-exchange reaction. The structure and morphology of the obtained nanohybrids were identified by FT-IR, XRD, TGA/DTA, SEM and TEM techniques. Based on the XRD results of the new nanohybrid materials, the Schiff base complexes were intercalated in the interlayer spaces of clay. SEM and TEM micrographs of the clay/complex shows that the resulting hybrid nanomaterials has layer structures. PMID- 25459720 TI - Surface-enhanced Raman scattering of perchlorate on cationic-modified silver nanofilms - Effect of inorganic anions. AB - Surface-enhanced Raman scattering (SERS) has emerged as one of the most sensitive spectroscopic analysis methods for the detection of environmental contaminants in water, including perchlorate (ClO4(-)). However, as with other commonly used analytical techniques, analysis of realistic environmental samples by SERS presents a challenge due to complex chemical components coexisting in the samples. In this work, we investigated the influence of inorganic anions (particularly oxyanions) on SERS spectra of ClO4(-) using a cationic thiol modified silver nanofilm substrate (Cys-Ag/rCu). The results show that the anions present in the samples did not shift the ClO4(-) characteristic band positions, but did decrease signal intensities due to their competitive binding with the NH3(+) groups of cationic thiol molecules immobilized on the substrates. The pH changes caused by both the dissociation of H2PO4(-) and the hydrolysis of HCO3(-) may also play a non-negligible role. The selectivity of the Cys-Ag/rCu substrate towards these anions was determined to be in the following order: ClO4(-)>SO4(2 )>HCO3(-), NO3(-)>Cl(-)>H2PO4(-), indicating preferential adsorption of ClO4(-) ions. In the solutions with multiple anions present, the ClO4(-) SERS spectra were affected simultaneously by all the coexisting anions. Calibration curves with very good linear relationships were successfully obtained, demonstrating the great potential of quantitative detection of aqueous ClO4(-) in the matrix. PMID- 25459721 TI - A simple protocol for the visual discrimination of natural cyclodextrins in aqueous solution using perichromic probes. AB - Three synthesized compounds, 4-(4-nitrostyryl)phenol, 2,6-dibromo-4-(2,4 dinitrobenzylideneamino)phenol and 2,6-dichloro-4-(2,4 dinitrobenzylideneamino)phenol, were deprotonated to generate the perichromic dyes 2b, 3b and 4b, respectively. These dyes were used as probes to investigate the micropolarity of natural cyclodextrins (CyDs) and it was observed that they interact differently with the CyDs according to the molecular structure of the dye and the diameter of the CyD. The solvatochromic bands of the dyes that interacted with the CyDs were bathochromically shifted, suggesting that the probes were transferred to the hydrophobic interior of the CyD in aqueous solution. Dyes 2b and 4b were found to be very selective for alpha-CyD and gamma CyD, respectively, while beta- and gamma-CyD changed the color of the solution of compound 3b. These dyes were then successfully used in a simple assay that allows the naked-eye discrimination of natural CyDs in aqueous solution, without the need for expensive techniques. PMID- 25459722 TI - Fluorescent reversible regulation based on the interactions of topotecan hydrochloride, neutral red and quantum dots. AB - The interactions of topotecan hydrochloride (THC), neutral red (NR) and thioglycolic acid (TGA) capped CdTe/CdS quantum dots (QDs) built a solid base for the controlling of the fluorescent reversible regulation of the system. This study was developed by means of ultraviolet-visible (UV-vis) absorption, fluorescence (FL), resonance Rayleigh scattering (RRS) spectroscopy and transmission electron microscopy (TEM). Corresponding experimental results revealed that the fluorescence of TGA-CdTe/CdS QDs could be effectively quenched by NR, while the RRS of the QDs enhanced gradually with the each increment of NR concentration. After the addition of THC, the strong covalent conjugation between NR and THC which was in carboxylate state enabled NR to be dissociated from the surface of TGA-CdTe/CdS QDs to form more stable complex with THC, thereby enhancing the fluorescence of the TGA-CdTe/CdS QDs-NR system. What is more, through analyzing the optical properties and experimental data of the reaction between TGA-CdTe/CdS QDs and NR, the possible reaction mechanism of the whole system was discussed. This combination of multiple spectroscopic techniques could contribute to the investigation for the fluorescent reversible regulation of QDs and a method could also be established to research the interactions between camptothecin drugs and dyes. PMID- 25459723 TI - Insights into the interaction between CH2F2 and titanium dioxide: DRIFT spectroscopy and DFT analysis of the adsorption energetics. AB - Difluoromethane (CH2F2, HFC-32) has been proposed as a valid replacement for both CFCs and HCFCs (in particular HCFC-22), and nowadays it is widely used in refrigerant mixtures. Due to its commercial use, in the last years, the atmospheric concentration of HFC-32 has increased significantly. However, this molecule presents strong absorptions within the 8-12MUm atmospheric window, and hence it is a greenhouse gas which contributes to global warming. Heterogeneous photocatalysis over TiO2 surface is an interesting technology for removing atmospheric pollutants since it leads to the decomposition of organic compounds into simpler molecules. In the present work, the adsorbate-substrate interaction between CH2F2 and TiO2 is investigated by coupling experimental measurements using DRIFT spectroscopy to first-principle simulations at DFT/B3LYP level. The experimental results confirm that CH2F2 interacts with the TiO2 surface (~80% rutile, 20% anatase) through both F and H atoms and show that the DRIFT technique is well suited to study the adsorption of halogenated methanes over semiconductor surfaces. DFT calculations are carried out by considering different periodicities and surface coverages, according to a structure involving an acid-base interaction between the F and Ti(4+) atoms as well as an H-bond between the CH2 group and an O(2-) ion. Lateral effects and energetics are analyzed in the limit of low coverage according to a procedure taking into account the binding, interaction, and distortion energies. The simulation at the different surface coverages and periodicities suggests similar decomposition pathways for the different investigated ensemble configurations. PMID- 25459724 TI - Discrimination of Rhizoma Gastrodiae (Tianma) using 3D synchronous fluorescence spectroscopy coupled with principal component analysis. AB - Rhizoma Gastrodiae (Tianma) of different variants and different geographical origins has vital difference in quality and physiological efficacy. This paper focused on the classification and identification of Tianma of six types (two variants from three different geographical origins) using three dimensional synchronous fluorescence spectroscopy (3D-SFS) coupled with principal component analysis (PCA). 3D-SF spectra of aqueous extracts, which were obtained from Tianma of the six types, were measured by a LS-50B luminescence spectrofluorometer. The experimental results showed that the characteristic fluorescent spectral regions of the 3D-SF spectra were similar, while the intensities of characteristic regions are different significantly. Coupled these differences in peak intensities with PCA, Tianma of six types could be discriminated successfully. In conclusion, 3D-SFS coupled with PCA, which has such advantages as effective, specific, rapid, non-polluting, has an edge for discrimination of the similar Chinese herbal medicine. And the proposed methodology is a useful tool to classify and identify Tianma of different variants and different geographical origins. PMID- 25459725 TI - Synthetic, spectral, thermal and powder X-ray diffraction studies of bis(O alkyldithiocarbonato-S,S') antimony(III) dialkyldithiocarbamates. AB - Compounds of antimony(III) with mixed sulfur donor ligands of the type [(ROCS2)2SbS2CNR'2] (where, R=C2H5, and (i)C3H7; R'=CH3, C2H5, and CH2CH2) have been synthesized using anhydrous acetone as a solvent by the one pot reaction of antimony(III) tris(O-alkyldithiocarbonato-S,S'), antimony(III) chloride and sodium/ammonium salt of dialkyldithiocarbamate in 2:1:3molar ratios. These compounds have been characterized by physicochemical [melting points, molecular weight determinations, elemental analyses (C, H, N, S, and Sb)], spectral [UV, IR, Far-IR and NMR ((1)H and (13)C)] studies. In IR spectra strong band was observed at 1028-1051cm(-1) which indicates anisobidentate mode of bonding of both the ligands with antimony metal. NMR spectral data of these compounds show expected proton resonance due to corresponding moieties. The powder XRD, ESI-Mass and thermal (TG and DTA) studies have also been performed to get the information about geometrical parameters, fragmentation pattern and last thermal decomposition product, respectively. The powder XRD studies lead to the structural properties of the synthesized compounds and show the nanorange crystallite size and monoclinic crystal system. Thermal data of these compounds indicate the formation of antimony sulfide (Sb2S3) as a final thermal degradation product which is used in a number of ways like switching devices television cameras and microwave devices. PMID- 25459726 TI - Label-free fluorescent aptasensor for potassium ion using structure-switching aptamers and berberine. AB - A simple, rapid and label-free fluorescent aptasensor was fabricated for the detection of potassium ion (K(+) ion) in aqueous solution using K(+) ion stabilized single stranded DNA (ssDNA) with G-rich sequence as the recognition element and a fluorescent dye, berberine, as the fluorescence probe. In the presence of K(+) ion, the G-rich ssDNA is promoted to form the aptamer-target complex with a G-quadruplex conformation, and berberine binding to the G quadruplex structure results in the enhancement of its fluorescence. The fluorescence intensity of the sensing system displayed a calibration response for K(+) ion in the range of 0-1600MUM with a detection limit of 31nM (S/N=3) and a relative standard deviation (RSD) of 0.45%. This label-free fluorescence aptasensor is conveniently and effectively applicable for analysis of K(+) ion in blood serum samples with the recovery range of 81.7-105.3%. The assay for detection of potassium ion is easy, economical, robust, and stable in rough conditions. PMID- 25459727 TI - Vibrational spectroscopy and density functional theory study of ninhydrin. AB - In this paper, ninhydrin was designed as a model molecule for theoretical and experimental studies of the molecule structure. Density functional theory (DFT) calculations have been performed to predict the IR and Raman spectra for the molecule. In addition, Fourier transform infrared (FTIR) and Raman spectra of the compound have been obtained experimentally. Based on the modeling results obtained at the B3LYP/6-311++G** level, all FTIR and Raman bands of the compound obtained experimentally were assigned. Our calculated vibrational frequencies are in good agreement with the experimental values. The molecular electrostatic potential surface calculation was performed and the result suggested that the ninhydrin had two potential hydrogen bond donors and four potential hydrogen bond acceptors. HOMO-LUMO gap was also obtained theoretically at B3LYP/6-311++G** level. PMID- 25459728 TI - Dual-channel detection of Cu(2+) and F(-) with a simple Schiff-based colorimetric and fluorescent sensor. AB - A simple and easily synthesized colorimetric and fluorescent receptor 1, based on 4-diethylaminosalicylaldehyde moieties as a binding and signaling unit, has been synthesized and characterized. The receptor 1 has a selective colorimetric sensing ability for copper (II) ion by changing color from colorless to yellow in aqueous solution, and could be utilized to monitor Cu(II) over a wide pH range of 4-11. In addition, the detection limit (12MUM) of 1 for Cu(2+) is much lower than that (30MUM) recommended by WHO in drinking water, and its copper complex could be reversible simply through treatment with a proper reagent such as EDTA. Moreover, receptor 1 exhibited both a color change from colorless to yellow and fluorescence enhancement with a red shift upon addition to F(-) in DMSO. The recognition mechanism was attributed to the intermolecular proton transfer between the hydroxyl group of the receptor and the fluoride. PMID- 25459729 TI - Substitutional group dependent colori/fluorimetric sensing of Mn(2+), Fe(3+) and Zn(2+) ions by simple Schiff base chemosensor. AB - Schiff base is one of the easiest synthesizable chemosensor and exhibit strong coordination with metal ions; the property that has been vastly exploited for metal ions sensing. Simple Schiff base chemosensors (1a-d and 2a-d) were synthesized and demonstrated substitutional group dependent colorimetric sensing of metal ions. Chemosensor without (1a, 2a) and OCH3 substitution (1b, 2b) did not show any significant colour change for metal ions. However, a highly selective colorimetric change (colourless to pink) for Mn(2+) ions (10(-6)M) was observed with diethylamine substituted 1c, 2c. Hydroxyl substitution (1d, 2d) leads to selective colorimetric sensing (colourless to orange) of Fe(3+) ions (10(-6)M). PVA thin films of 2c/2d were fabricated and demonstrated selective colorimetric sensing of Mn(2+) and Fe(3+) ions. The practical applicability of the synthesized chemosensors were also demonstrated by performing selective colorimetric sensing of Mn(2+) and Fe(3+) ions in real samples such as tap, ground, pond and river water. Effect of substitution on the fluorescence selectivity of Zn(2+) has also been investigated. PMID- 25459730 TI - Studies on the interaction of apigenin with calf thymus DNA by spectroscopic methods. AB - The interaction between apigenin and calf thymus deoxyribonucleic acid (ctDNA) in a pH 7.4 Tris-HCl buffer solution was investigated by UV-Vis spectroscopy, fluorescence spectroscopy, DNA melting techniques, and viscosity measurements. It was found that apigenin molecules could intercalate into the base pairs of DNA, forming a apigenin-DNA complex with a binding constant of K310K=6.4*10(4)Lmol( 1). The thermodynamic parameters enthalpy change (DeltaH), entropy change (DeltaS) and Gibbs free energy (DeltaG) were calculated to be 7.36*10(4)Jmol(-1), 329JK(-1)mol(-1) and -2.84*10(4)Jmol(-1) at 310K, respectively. Hydrophobic interaction was the predominant intermolecular force in stabilizing the apigenin DNA complex. Thermal denaturation study suggested that the stabilization of the ctDNA helix was increased when the apigenin binding to ctDNA as indicated by the increase in thermal denaturation temperature of ctDNA at around 5.0 degrees C in the presence of apigenin. Spectroscopic techniques together with melting techniques and viscosity determination provided evidences of intercalation mode of binding for the interaction between apigenin and ctDNA. PMID- 25459731 TI - Dye-sensitized solar cell using sprayed ZnO nanocrystalline thin films on ITO as photoanode. AB - ZnO thin films had been successfully prepared by spray pyrolysis (SP) technique on ITO/Glass substrates at different substrate temperature in the range 250-400 degrees C using Zinc acetylacetonate as precursor. The X-ray diffraction studies confirmed the hexagonal wurtzite structure with preferred orientation along (002) plane at substrate temperature 350 degrees C and the crystallite size was found to vary from 18 to 47nm. The morphology of the films revealed the porous nature with the roughness value of 8-13nm. The transmittance value was found to vary from 60% to 85% in the visible region depending upon the substrate temperature and the band gap value for the film deposited at 350 degrees C was 3.2eV. The obtained results revealed that the structures and properties of the films were greatly affected by substrate temperature. The near band edge emission observed at 398nm in PL spectra showed better crystallinity. The measured electrical resistivity for ZnO film was ~3.5*10(-4)Omegacm at the optimized temperature 350 degrees C and was of n-type semiconductor. The obtained porous nature with increased surface roughness of the film and good light absorbing nature of the dye paved way for implementation of quality ZnO in DSSCs fabrication. DSSC were assembled using the prepared ZnO film on ITO coated glass substrate as photoanode and its photocurrent - voltage performance was investigated. PMID- 25459732 TI - A novel Schiff-base as a Cu(II) ion fluorescent sensor in aqueous solution. AB - A new fluorescent Cu(II) sensor (L) obtained from the Schiff base of 5,5' methylene-bis-salicylaldehyde with amidol (2,4-diaminophenol) was synthesized and characterized by FT-IR, MS, (1)H NMR, (13)C NMR techniques. In the presence of pH 6.5 (KHPO4-Na2HPO4) buffer solutions, copper reacted with L to form a stable 2:1 complex. Fluorescence spectroscopic study showed that Schiff base is highly sensitive towards Cu(II) over other metal ions (K(+), Na(+), Al(3+), Ni(2+), Co(2+), Fe(3+), Zn(2+), Pb(2+)) in DMSO/H2O (30%, v/v). The sensor L was successfully applied to the determination of copper in standard reference material. The structural properties and molecular orbitals of the complex formed between L and Cu(2+) ions were also investigated using quantum chemical computations. PMID- 25459733 TI - Spectroscopic and energy transfer behavior of Dy(3+) ions in B2O3TeO2PbOPbF2Bi2O3CdO glasses for laser and WLED applications. AB - A new series of white light emitting Dy(3+) doped Lead tellurofluoroborate glasses have been prepared and their spectroscopic and energy transfer behavior were explored through analyzing XRD, FTIR, Raman, SEM, EDAX, optical absorption, photoluminescence and lifetime measurements. The fundamental stretching of the various borate and tellurite networks were identified using FTIR and Raman spectral analysis. The bonding parameter studies reveal the ionic nature of the DyO bond in the present glasses. The Judd-Ofelt (JO) intensity parameters determined from the absorption spectra have been used to investigate the nature of bonding and symmetry orientation of the Dy-ligand field environment. The luminescence intensity increases with increasing Dy(3+) ion concentration up to 0.5wt%, beyond that luminescence quenching is observed. The JO parameters have been used to determine the transition probability (A), stimulated emission cross section (sigmaP(E)), radiative lifetime (tauR) and branching ratios (betaR) for the different emission transitions from the (4)F9/2 excited level. The higher sigmaP(E) and betaR values of the (4)F9/2->(6)H15/2 and (4)F9/2->(6)H13/2 transitions suggest the possible laser action in the visible region. The Y/B ratio, CIE chromaticity color coordinates (x, y) and Color correlated temperature (CCT) were also estimated from the luminescence spectra for different concentration as well as pumping wavelengths. The x, y chromaticity color coordinates fall within the white light region and the white light can be tuned by varying the excitation wavelengths. The lifetime of the (4)F9/2 excited state were measured and is found to decrease with increasing Dy(3+) ion content. The non-exponential behavior is predominant in higher Dy(3+) ion content glasses and is due to the efficient energy transfer between Dy(3+)Dy(3+) ions. The decay curves were fitted to the Inokuti-Hirayama (IH) model to understand the nature of energy transfer. Among the prepared glasses, 0.5DPTFB glass possesses higher A,betaR,sigmaP(E),eta values and is suggested for lasers and WLED applications. PMID- 25459734 TI - Has the National Health Insurance improved the inequality in the use of tertiary care hospitals in Korea? AB - BACKGROUND: To improve financial protection against catastrophic illness, the Korean government expanded the benefit coverage of the National Health Insurance (NHI) for cancer patients in 2005. This paper examined whether the policy has reduced income-inequality in the use of tertiary care hospitals. METHODS: We evaluated the effect of the policy on income-inequalities in outpatient visits and inpatient admissions to tertiary care hospitals, based on triple difference estimators. Using nationwide claims data of the NHI from 2002 to 2010, we compared cancer patients as a treatment group with liver disease and cardio cerebrovascular disease as control groups and the lower-income with the highest income group. RESULTS: Before the introduction of the policy, lower-income cancer patients utilized less inpatient and outpatient services in tertiary care hospitals than high-income patients did. After the benefit coverage was expanded, while the incidence and total number of inpatient admissions to tertiary care hospitals increased among cancer patients compared with liver diseases, lower income cancer patients experienced a greater increase than those of higher-income did compared with both diseases. The use of outpatient services increased more in cancer patients than those of both diseases; however, the gap between the highest and the lowest-income rarely decreased, except the incidence of visits when compared to liver disease. CONCLUSION: Our findings indicated that the expanded NHI benefits coverage partially improved income-related inequalities in inpatient admissions to tertiary-care hospital, but not in outpatient visits. PMID- 25459735 TI - Context analysis for epidemic control in the Netherlands. AB - When epidemics occur, experts advise the Ministries on effective control measures. There is uncertainty in the translation of epidemiological evidence into effective outbreak management interventions, due to contradicatory problem perspectives, diverse interests and time pressure. Several models have been developed that aim to integrate societal context information in risk assessment to improve the feasibility and the implementation of adviced measures. The current study explored the views of relevant public officials on this issue using the Rapid Risk Assessment of Acute Public Health Events model of the World Health Organization. Eighteen public officials involved in infectious disease risk assessment and policy making in the Netherlands participated in semi-structured qualitative interviews. Their experiences, expectations and expert opinions on the use of societal context information for infectious disease outbreak control were explored. Most interviewees consider information on societal context necessary for infectious disease risk management. However, different perspectives exist on which information is relevant, and how, when, why and by whom it should be obtained. We conclude that outbreak control could benefit from systematically gathered information on the societal context. This requires identifying which information is beneficial and selecting or designing methods to obtain it. Explicit stakeholder assessment seems a first step. PMID- 25459736 TI - Value-based purchasing and hospital acquired conditions: are we seeing improvement? AB - OBJECTIVE: To determine if the Value-Based Purchasing Performance Scoring system correlates with hospital acquired condition quality indicators. DATA SOURCES/STUDY SETTING: This study utilizes the following secondary data sources: the American Hospital Association (AHA) annual survey and the Centers for Medicare and Medicaid (CMS) Value-Based Purchasing and Hospital Acquired Conditions databases. STUDY DESIGN: Zero-inflated negative binomial regression was used to examine the effect of CMS total performance score on counts of hospital acquired conditions. Hospital structure variables including size, ownership, teaching status, payer mix, case mix, and location were utilized as control variables. DATA COLLECTION: The secondary data sources were merged into a single database using Stata 10. PRINCIPAL FINDINGS: Total performance scores, which are used to determine if hospitals should receive incentive money, do not correlate well with quality outcome in the form of hospital acquired conditions. CONCLUSIONS: Value-based purchasing does not appear to correlate with improved quality and patient safety as indicated by Hospital Acquired Condition (HAC) scores. This leads us to believe that either the total performance score does not measure what it should, or the quality outcome measurements do not reflect the quality of the total performance scores measure. PMID- 25459737 TI - In vitro synergistic activity of clofazimine and other antituberculous drugs against multidrug-resistant Mycobacterium tuberculosis isolates. AB - Clofazimine (CLO) is a promising candidate drug for use in the management of multidrug-resistant tuberculosis (MDR-TB) patients. In this study, the minimum inhibitory concentration (MIC) method was used to investigate drug susceptibility to CLO as well as potential synergies between CLO and other antituberculous drugs, including ethambutol (EMB), levofloxacin (LEV), moxifloxacin (MOX), amikacin (AMK) and capreomycin (CAP), among MDR-TB isolates from China. A total of 195 MDR-TB isolates were collected from the national drug resistance survey conducted in China. Of the 195 MDR-TB isolates, 54 (27.7%) were classified as CLO resistant, whilst 141 (72.3%) were CLO-susceptible with MICs of <= 1 MUg/mL. In addition, the prevalence of CLO-resistant isolates among the extensively drug resistant (XDR)-TB group was 61.5% (8/13), which was significantly higher than that of the MDR-TB group (23.0%) (P = 0.006). When fractional inhibitory concentration indexes (FICIs) were calculated for 24 isolates, synergy was found in 11 isolates (45.8%) against the CLO/EMB combination, 6 (25.0%) against the CLO/LEV combination, 8 (33.3%) against the CLO/MOX combination, 4 (16.7%) against the CLO/AMK combination and 5 (20.8%) against the CLO/CAP combination. In addition, <15% of MDR-TB isolates showed antagonistic effects against these five combinations. In conclusion, these findings demonstrate that the combination of CLO and EMB shows better synergism than the other combinations containing CLO. The CLO/MOX combination is more likely to show synergy against MDR-TB isolates than the CLO/LEV combination. Taken together, we suggest that CLO, in combination with EMB or MOX, may be a promising drug regimen for the treatment of MDR-TB. PMID- 25459738 TI - In vitro bactericidal activity of aminoglycosides, including the next-generation drug plazomicin, against Brucella spp. AB - Plazomicin is a next-generation aminoglycoside with a potentially unique set of clinical characteristics compared with other aminoglycosides. This study assessed the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of plazomicin against 15 clinical isolates as well as three reference strains representing Brucella abortus, Brucella melitensis and Brucella suis. These data were compared with those obtained for six other aminoglycosides and two aminocyclitols. Plazomicin and gentamicin were the only drugs demonstrating bactericidal activity towards two of the three Brucella spp., whilst plazomicin was the only drug exhibiting bactericidal activity against B. suis. This is the first study to assess the bactericidal nature of plazomicin against Brucella spp. in vitro. PMID- 25459739 TI - Inhaled colistimethate sodium in ventilator-associated tracheobronchitis due to multidrug-resistant Gram-negative bacteria. PMID- 25459741 TI - Pott disease. PMID- 25459740 TI - Drug resistance characteristics of Mycobacterium tuberculosis isolates to four first-line antituberculous drugs from tuberculosis patients with AIDS in Beijing, China. AB - The objective of this study was to investigate the drug resistance characteristics of Mycobacterium tuberculosis isolates to four first-line antituberculous drugs (ATDs) from tuberculosis (TB) patients with AIDS in Beijing, China. All M. tuberculosis strains were isolated from specimens from TB patients with AIDS hospitalised between April 2010 and October 2012. Isolates were cultured by mycobacterial culture methods and were identified by multilocus PCR. Drug sensitivity testing was performed by the proportion method with the following first-line ATDs: isoniazid; rifampicin; streptomycin; and ethambutol. Results were compared with the drug resistance status of M. tuberculosis strains isolated from TB patients without HIV infection in Beijing. Among 41 M. tuberculosis isolates from TB patients with AIDS, the rates of total drug resistance (58.5%), initial drug resistance (46.7%) and acquired drug resistance (90.9%) were significantly higher than in TB patients without HIV infection (34.1%, 24.5% and 48.5%, respectively; P<0.05). In TB patients with AIDS, the rates of acquired drug resistance (90.9%) and acquired multidrug-resistant TB (MDR-TB) (54.5%) were significantly higher than the rates of initial drug resistance (46.7%) and initial MDR-TB (10.0%) (P<0.05). In patients with TB without HIV infection, the rate of acquired drug resistance (48.5%) was significantly higher than the rate of initial drug resistance (24.5%) (P<0.05). M. tuberculosis drug resistance in TB patients with AIDS is significantly more serious than in TB patients without HIV infection. These results showed that more attention should be paid to M. tuberculosis drug resistance in AIDS patients. PMID- 25459742 TI - Three cases of hemiplegia after cervical paraspinal muscle needling. AB - BACKGROUND CONTEXT: Muscle needling therapy is common for chronic pain management, but the development of unusual complications such as hemiplegia is not well understood. PURPOSE: We report on three cases with hemiplegia after cervical paraspinal muscle needling and propose possible explanations for these unusual complications. STUDY DESIGN: Case report. METHODS: The authors retrospectively reviewed the medical charts from a decade (2002-2013) at Korea University Hospital. The records were systematically searched, and the cases with hemiplegia (grade<3) after needing therapy were collected. No conflict of interest reported. No funding received. RESULTS: A 54-year-old woman, a 38-year old woman, and a 60-year-old man with hemiplegia by cervical subdural or epidural hematoma after cervical posterior paraspinal muscle needling without direct invasion (intramuscular stimulation, acupuncture, or intramuscular lidocaine) were observed. All patients were taken for emergent decompressive laminectomy, and their postoperative motor function improved substantially. CONCLUSION: Spinal hematoma after muscle needling is unusual but was thought to result after a rupture of the epidural or subarachnoid veins by a sharp increase in blood pressure delivered in the intraabdominal or intrathoracic areas after needling therapy. PMID- 25459743 TI - Migration of bone marrow-derived cells for endogenous repair in a new tail looping disc degeneration model in the mouse: a pilot study. AB - BACKGROUND CONTEXT: Mobilization and homing of bone marrow-derived cells (BMCs) play a pivotal role in healing and regeneration of various tissues. However, the cellular response of BMCs in avascular tissue such as the intervertebral disc (IVD) has not been studied in detail. One of the main obstacles to this is a lack of a suitable mouse disc degeneration model. PURPOSE: The purpose of this study was to establish a reproducible disc degeneration mouse model suitable for analyzing the cellular response of the disc microenvironment and to determine whether BMCs are recruited into the IVD. STUDY DESIGN: An experimental animal study of disc degeneration investigating the potential of BMCs in an endogenous repair of the IVD. METHODS: We transplanted whole bone marrow cells from mice ubiquitously expressing enhanced green fluorescent protein into lethally irradiated mice. Intervertebral disc degeneration was induced through uneven loading by creating a loop in the tail of these mice. The vertebral bone-disc vertebral bone units were harvested, and BMCs were identified by immunohistochemistry. RESULTS: A new disc degeneration model was established in the mouse. Applying this model in the bone marrow chimeric mice increased the number of BMCs in the peripheral bone marrow and vascular canals in the endplate, and some were found in the IVD. The migration of BMCs was related to the severity of IVD degeneration. CONCLUSIONS: Although providing a new disc degeneration model in mice, the present study provides evidence to suggest that although BMCs are recruited during disc degeneration, only a limited number of BMCs migrate to the IVD, presumably because of its avascular nature. This fact provides important elements for developing new treatments as many growth factors and compounds are being tested, both in investigational levels and clinical trials to nourish resident endogenous cells during the degenerative process. PMID- 25459744 TI - Improvised interbody fusion cage in an austere medical environment. PMID- 25459745 TI - A delayed spinocutaneous fistula after anterior cervical discectomy and fusion. PMID- 25459746 TI - Sciatic perineural edema treated by Botulinum toxin injection on piriformis muscle. PMID- 25459747 TI - Spinal cord infarction as a complication of hemodialysis. PMID- 25459748 TI - Discography with epidural contrast extravasation along an exiting nerve root. PMID- 25459749 TI - Tissue specific expression of SG2NA is regulated by differential splicing, RNA editing and differential polyadenylation. AB - SG2NA belongs to a three member Striatin subfamily of WD-40 repeat superfamily. It has multiple protein-protein interaction domains that are involved in the assembly of supra-molecular signaling complexes. Earlier we had demonstrated that there are at least five variants of SG2NA, generated by alternative splicing. We now demonstrate that a 52kDa novel variant is generated by the editing of the transcript for the 82kDa isoform. The 52kDa protein is abundant in mouse tissues but it is barely present in immortalized cells, suggesting its role in cell differentiation. Besides splicing and editing, expression of SG2NAs in tissues is also regulated by differential polyadenylation and mRNA/protein stability. Further, the longer UTR is seen only in the brain mRNA from 1month old mouse and 8-10day old chick embryo. Like alternative splicing, differential polyadenylation of Sg2na transcripts is also conserved in evolution. Taken together, these results suggest a highly versatile and dynamic mode of regulation of SG2NA with potential implications in tissue development. PMID- 25459750 TI - Activity and specificity of the human SUV39H2 protein lysine methyltransferase. AB - The SUV39H1 and SUV39H2 enzymes introduce H3K9me3, which is essential for the viability of mammalian cells. It was the aim of the present work to investigate the substrate specificity and product pattern of SUV39H2. Methylation of peptide SPOT arrays showed that SUV39H2 recognizes a long motif on H3 comprising T6-K14, with highly specific readout of R8, S10, T11 and G12 and partial specificity at T6, A7, G13 and K14. Modification of R8 and phosphorylation of S10 or T11 lead to a reduction or loss of SUV39H2 activity towards H3K9. The specificity of SUV39H2 differs from other H3K9 PKMTs, like Dim-5 or G9a, and these biochemical differences can be explained by the structures of the corresponding enzymes. Based on the specificity profile we identified additional non-histone candidate substrates in human proteins, but all of them were only weakly methylated by SUV39H2 at the peptide level. We conclude that SUV39H2 displays a high preference for the methylation of H3. Using the catalytic SET domain we show here that the enzyme prefers H3K9me0 as a substrate over H3K9me1 and H3K9me2 and it introduces the first two methyl groups into H3K9me0 in a processive reaction. SUV39H2 can transfer up to three methyl groups to lysine 9 of histone H3 but the last methylation reaction is much slower than the first two steps. We also demonstrate that the N324K mutant in the SET domain of SUV39H2 that has been shown to cause an inherited nasal skin disease in Labrador Retrievers renders SUV39H2 inactive. Differences in the circular dichroism spectra of wild type and mutant proteins indicated that the mutation causes slight structural changes. PMID- 25459751 TI - Alteration of Scn3a expression is mediated via CpG methylation and MBD2 in mouse hippocampus during postnatal development and seizure condition. AB - Increased expression of sodium channel SCN3A, an embryonic-expressed gene, has been identified in epileptic tissues, which is believed to contribute to the development of epilepsy. However, the regulatory mechanism of SCN3A expression under epileptic condition is still unknown. Here we showed a high level of Scn3a mRNA expression in mouse embryonic hippocampus with gradually decreasing to a low level during the postnatal development and a methylation of a specific CpG site ( 39C) in the Scn3a promoter was increased in hippocampus during postnatal development, corresponding to the downregulation of Scn3a expression. Furthermore, in vitro methylation and -39C>T mutation of the Scn3a promoter decreased the reporter gene expression, suggesting an important role of the -39C site in regulating gene expression. We then demonstrated that the sequence containing -39C was a MBD2-binding motif and the CpG methylation of the promoter region increased the capability of MBD2's binding to the motif. Knockdown of MBD2 in mouse N1E-115 cells led to the -39C methylation and the downregulation of Scn3a transcription by decreasing the Scn3a promoter activity. In the hippocampus of seizure mice, the expressions of Scn3a and Mbd2 were upregulated after 10-day KA treatment. At the same time point, the -39C site was demethylated and the capability of MBD2's binding to the Scn3a promoter motif was decreased. Taken together, these findings suggest that CpG methylation and MBD2 are involved in altering Scn3a expression during postnatal development and seizure condition. PMID- 25459752 TI - N2O and CH4 emissions from a fallow-wheat rotation with low N input in conservation and conventional tillage under a Mediterranean agroecosystem. AB - Conservation agriculture that includes no tillage (NT) or minimum tillage (MT) and crop rotation is an effective practice to increase soil organic matter in Mediterranean semiarid agrosystems. But the impact of these agricultural practices on greenhouse gases (GHGs), such as nitrous oxide (N2O) and methane (CH4), is variable depending mainly on soil structure and short/long-term tillage. The main objective of this study was to assess the long-term effect of three tillage systems (NT, MT and conventional tillage (CT)) and land-covers (fallow/wheat) on the emissions of N2O and CH4 in a low N input agricultural system during one year. This was achieved by measuring crop yields, soil mineral N and dissolved organic C contents, and fluxes of N2O and CH4. Total cumulative N2O emissions were not significantly different (P>0.05) among the tillage systems or between fallow and wheat. The only difference was produced in spring, when N2O emissions were significantly higher (P<0.05) in fallow than in wheat subplots, and NT reduced N2O emissions (P<0.05) compared with MT and CT. Taking into account the water filled pore space (WFPS), both nitrification and denitrification could have occurred during the experimental period. Denitrification capacity in March was similar in all tillage systems, in spite of the higher DOC content maintained in the topsoil of NT. This could be due to the similar denitrifier densities, targeted by nirK copy numbers at that time. Cumulative CH4 fluxes resulted in small net uptake for all treatments, and no significant differences were found among tillage systems or between fallow and wheat land-covers. These results suggest that under a coarse-textured soil in low N agricultural systems, the impact of tillage on GHG is very low and that the fallow cycle within a crop rotation is not a useful strategy to reduce GHG emissions. PMID- 25459753 TI - Declining trends of PCDD/Fs in lichens over a decade in a Mediterranean area with multiple pollution sources. AB - Lichens are one of the most useful environmental biomonitors, due to their ability to clearly reflect atmospheric deposition of pollutants. Dioxin and furan (PCDD/F) emissions have been reported to be decreasing in North European countries as a consequence of European regulations. This reduction has been perceptible across several environmental matrices, but it hasn't yet been shown in lichens as typical biomonitors of atmospheric pollution. In this work we compared concentrations of PCDD/Fs in two lichen species collected in a Mediterranean area with mixed land-uses, encompassing urban, industrial and natural areas, in 2009 and 2011 with the ones obtained in the same species collected in the same region in 2000. We found that PCDD/F concentrations in both lichen species have decreased approximately 70% since 2000 whereas industrial emissions have only decreased 25% for the same period. This substantial greater reduction observed in lichens may be due to several causes; after excluding fires as a possible explanation, we point out that possible causes could not only be the overall decrease in industrial emissions but also other causes such as traffic reduction and/or increase efficiency in the use of fuels. Capsule: PCDD/F concentrations in lichens have decreased 70% over the last decade, whereas industrial emissions have only decreased 25%. PMID- 25459754 TI - Development and validation of method for TH588 and TH287, potent MTH1 inhibitors and new anti-cancer agents, for pharmacokinetic studies in mice plasma. AB - MTH1 is a protein that is required for cancer cell survival and is overexpressed in cancer cells. TH588 and TH287 are two new compounds that inhibit the MTH1 protein. The inhibitors were tested in pharmacokinetic studies on mice. A bioanalytical method was developed and validated for determination in mice plasma. The method was based on protein precipitation followed by LC-MS/MS analysis. The separation was performed on an Ascentis Express RP-Amide C18 column. The mass spectrometer was operated in positive electrospray ionization mode and the analytes were determined with multiple reaction monitoring (MRM). Abundant monoisotopic fragments were used for quantification. Two additional fragments were used for conformational analysis. The recovery of the compounds in plasma varied between 61 and 91% and the matrix effects were low and ranged between -3% and +2%. The method showed to be selective, linear, accurate and precise, and applicable for preclinical pharmacokinetic studies of TH588 and TH287 in mouse plasma. Half-life (T1/2) was <=3.5h and maximum concentration (Cmax) ranged between 0.82 and 338MUM for the different administration routes and compounds. PMID- 25459755 TI - Simple and rapid high performance liquid chromatography method for the determination of polidocanol as bulk product and in pharmaceutical polymer matrices using charged aerosol detection. AB - Currently, neither the European nor the United States Pharmacopoeia provide a method for the determination of polidocanol (PD) content despite the fact that PD, besides being an excipient, is also used as an active pharmaceutical ingredient. We therefore developed a method where the PD content was determined using a Kinetex C18 column operated at 40 degrees C with water-acetonitrile (15:85, v/v) as mobile phase. A Corona((r)) charged aerosol detector was employed for the detection of PD that is lacking a suitable UV chromophore. The method was fully validated. Additionally, the method was applied for the determination of PD release from a pharmaceutical polymer matrix consisting of poly-E-caprolactone and poly(lactic-co-glycolic acid) and PD. PMID- 25459756 TI - Chemical profiling with HPLC-FTMS of exogenous and endogenous chemicals susceptible to the administration of chotosan in an animal model of type 2 diabetes-induced dementia. AB - In our previous study, the daily administration of chotosan (CTS), a Kampo formula consisting of Uncaria and other 10 different crude drugs, ameliorated cognitive deficits in several animal models of dementia including type 2 diabetic db/db mice in a similar manner to tacrine, an acetylcholinesterase inhibitor. The present study investigated the metabonomics of CTS in db/db mice, a type 2 diabetes model, and m/m mice, a non-diabetes control strain, to identify the exogenous and endogenous chemicals susceptible to the administration of CTS using high performance liquid chromatography equipped with an orbitrap hybrid Fourier transform mass spectrometer. The results obtained revealed that the systemic administration of CTS for 20 days led to the distribution of Uncalia plant derived alkaloids such as rhynchophylline, hirsuteine, and corynoxeine in the plasma and brains of db/db and m/m mice and induced alterations in four major metabolic pathways; i.e., (1) purine, (2) tryptophan, (3) cysteine and methionine, (4) glycerophospholipids in db/db mice. Moreover, glycerophosphocholine (GPC) levels in the plasma and brain were significantly higher in CTS-treated db/db mice than in vehicle-treated control animals. The results of the in vitro experiment using organotypic hippocampal slice cultures demonstrated that GPC (10-30 MUM), as well as tacrine, protected hippocampal cells from N-methyl-d-aspartate-induced excitotoxicity in a manner that was reversible with the muscarinic receptor antagonist scopolamine, whereas GPC had no effect on the activity of acetylcholinesterase in vitro. Our results demonstrated that some CTS constituents with neuropharmacological activity were distributed in the plasma and brain tissue following the systemic administration of CTS and may subsequently have affected some metabolic pathways including glycerophospholipid metabolism and cognitive function in db/db mice. Moreover, the present metabonomic analysis suggested that GPC is a putative endogenous chemical that may be involved in the tacrine-like actions of CTS in the present diabetic animal model. PMID- 25459757 TI - Structural elucidation of in vivo metabolites of isobavachalcone in rat by LC-ESI MS(n) and LC-NMR. AB - Isobavachalcone (IBC) is a prenylated chalcone and belongs to the class of flavonoids, which is an active component isolated from Psoralea corylifolia L. IBC showed a range of significant pharmacological activities, including antibacterial, anticancer, anti-reverse transcriptase and antioxidant actions. In this research, the mass spectral fragmentation pattern of IBC was investigated to predict the in vivo metabolites, and five phase I metabolites and ten phase II metabolites of IBC in rat bile were elucidated and identified after oral administration using novel LC-ESI-MS(n) and LC-NMR method. The molecular structures of these metabolites were proposed on the basis of the characteristics of their precursor ions, product ions, MS/MS fragment behaviors and chromatographic retention time. The phase I metabolites were mainly biotransformed via the hydroxylation, reduction, cyclization and oxidative cleavage reactions. The phase II metabolites were mainly identified as the glucuronide conjugates and sulfated conjugates. All these findings were reported for the first time and would contribute to a further understanding of the in vivo intermediate processes and metabolic mechanism of isobavachalcone and its analogs. PMID- 25459758 TI - [Tetanus risk assessment in the older outpatients: Usefulness of the "Tetanos Quick Stick (r)"?]. AB - INTRODUCTION: Tetanus is a serious disease, which could be potentially lethal. All cases are observed in patients inadequately immunized. The immunochromatographic tests (including Tetanos quick Stick((r)) [TQS]) have demonstrated their efficiency in emergency setting. The aim of our study was to assess the usefulness of these tests in elderly outpatients seen in ambulatory settings. MATERIALS: This prospective study included patients aged 65 years and over who presented to the outpatients' clinic of the Gerontologic Departmental Center (Marseille). A TQS and a self-administered questionnaire to assess risk factors for tetanus were performed. RESULTS: One hundred and twenty-two patients were studied. The prevalence of positive TQS was 66%. Patients have an average of 2.5 risk factors for tetanus. Negative TQS was observed in 35% of patients who had seen their general practitioner for a wound during the previous year. CONCLUSION: Elderly patients accumulate several risk factors regardless of age and lifestyle. While physicians are familiar with the vaccine recommendations, they are often faced with the difficulty of assessing patient's status based only on the patient's interview, which is frequently not reliable. The implementation of immunochromatographic tests in general practice could help physicians in the management of patients at risk for tetanus. PMID- 25459759 TI - Interactions of small gold clusters, Aun (n=1-3), with graphyne: theoretical investigation. AB - The interactions of gold atom and clusters (Au2 and Au3) with the active sites of graphyne (GY) have been investigated using density functional theory (PBE, PBE D3, and B3LYP-D3). In order to compare performance of DFT functional (BP86, PBE, TPSSh, B3LYP, PBE-D3, TPSSh-D3, and B3LYP-D3), the interactions of Au2 with various functional groups such as -sp, -sp(2) and aromatic sp(2) carbon atoms, sp, -sp(2) and aromatic sp(2)-bonds have been investigated and also compared with the ab initio MP2 results. Additionally, the nature of interactions for graphyne Au2 complexes are interpreted by means of the natural bond orbital (NBO), the quantum theory of atoms in molecules (QTAIM) and energy decomposition analysis (EDA) and compared with those of related graphene-Au2. This study suggests that graphyne shows complex behavior in comparison to those of graphene and could also be useful in modeling of the next generation electronic devices. PMID- 25459760 TI - Effects of protein flexibility on the site of metabolism prediction for CYP2A6 substrates. AB - Structure-based prediction for the site of metabolism (SOM) of a compound metabolized by human cytochrome P450s (CYPs) is highly beneficial in drug discovery and development. However, the flexibility of the CYPs' active site remains a huge challenge for accurate SOM prediction. Compared with other CYPs, the active site of CYP2A6 is relatively small and rigid. To address the impact of the flexibility of CYP2A6 active site residues on the SOM prediction for substrates, in this work, molecular dynamics (MD) simulations and molecular docking were used to predict the SOM of 96 CYP2A6 substrates. Substrates with known SOM were docked into the snapshot structures from MD simulations and the crystal structures of CYP2A6. Compared to the crystal structures, the protein structures obtained from MD simulations showed more accurate prediction for SOM. Our results indicated that the flexibility of the active site of CYP2A6 significantly affects the SOM prediction results. Further analysis for the 40 substrates with definite Km values showed that the prediction accuracy for the low Km substrates is comparable to that by ligand-based methods. PMID- 25459761 TI - Investigation of the rescue mechanism catalyzed by a nucleophile mutant of rice BGlu1. AB - In the present study, the quantum mechanical/molecular mechanical (QM/MM) method was used to investigate the rescue mechanism of an E386G mutant as well as the glycosylation mechanism of the wild rice beta-D-glucosidase. E386G mutant experiences an asynchronous collaborative process to glycosylate the anionic formate with an energy barrier of 22.6 kcal/mol, while the energy barrier is 25.9 kcal/mol for the wild complex. The low energy barrier of the mutated complex suggests that anionic formate might be a good nucleophile to attack the anomeric carbon atom. Both energy barriers can be lowered when the leaving departure releases from the active site, suggesting that the product release, rather than chemistry, contributes to the rate limiting in BGlu1 mutants. Structure analyses also indicate that the external nucleophile has little steric hindrance with pocket residues and adjusts freely to proceed the rescue mechanism of the mutated complex. Our calculations provide a guide for the selectivity of exogenous nucleophiles in the future study of beta-glucosidase. PMID- 25459762 TI - Lessons from molecular modeling human alpha-L-iduronidase. AB - Human alpha-L-iduronidase (IDUA) is a member of glycoside hydrolase family and is involved in the catabolism of glycosaminoglycans (GAGs), heparan sulfate (HS) and dermatan sulfate (DS). Mutations in this enzyme are responsible for mucopolysaccharidosis I (MPS I), an inherited lysosomal storage disorder. Despite great interest in determining and studying this enzyme structure, the lack of a high identity to templates and other technical issues have challenged both bioinformaticians and crystallographers, until the recent publication of an IDUA crystal structure (PDB: 4JXP). In the present work, four alternative IDUA models, generated and evaluated prior to crystallographic determination, were compared to the 4JXP structure. A combined analysis using several viability assessment tools and molecular dynamics simulations highlights the strengths and limitations of different comparative modeling protocols, all of which are based on the same low identity template (only 22%). Incorrect alignment between the target and template was confirmed to be a major bottleneck in homology modeling, regardless of the modeling software used. Moreover, secondary structure analysis during a 50ns simulation seems to be useful for indicating alignment errors and structural instabilities. The best model was achieved through the combined use of Phyre 2 and Modeller, suggesting the use of this protocol for the modeling of other proteins that still lack high identity templates. PMID- 25459763 TI - Hierarchical particle swarm optimizer for minimizing the non-convex potential energy of molecular structure. AB - The stable conformation of a molecule is greatly important to uncover the secret of its properties and functions. Generally, the conformation of a molecule will be the most stable when it is of the minimum potential energy. Accordingly, the determination of the conformation can be solved in the optimization framework. It is, however, not an easy task to achieve the only conformation with the lowest energy among all the potential ones because of the high complexity of the energy landscape and the exponential computation increasing with molecular size. In this paper, we develop a hierarchical and heterogeneous particle swarm optimizer (HHPSO) to deal with the problem in the minimization of the potential energy. The proposed method is evaluated over a scalable simplified molecular potential energy function with up to 200 degrees of freedom and a realistic energy function of pseudo-ethane molecule. The experimental results are compared with other six PSO variants and four genetic algorithms. The results show HHPSO is significantly better than the compared PSOs with p-value less than 0.01277 over molecular potential energy function. PMID- 25459765 TI - Reaction mechanism and free energy profile for acylation of Candida Antarctica lipase B with methylcaprylate and acetylcholine: density functional theory calculations. AB - Candida Antarctica lipase B (CALB), a specific enzyme to catalyze the hydrolysis of esters, can be a good candidate for acetylcholine (ACh) hydrolysis instead of acetylcholinesterase. The catalytic mechanism of the CALB acylation, as the first stage in the hydrolysis reaction, with ACh and methylcaprylate (MEC) has been examined by using density functional theory technique. The significant emphasis of this article is on the free energy barriers for the acylation step of hydrolysis reactions. Computed free energy barriers of the first step are 9.2 and 15.9 kcal mol(-1), but for the second step are 7.9 and 11.6 kcal mol(-1) for MEC and ACh respectively. Activation free energies are in the comparable and acceptable range and imply both of two reactions are theoretically possible. The stability role of the adjacent amino acids was examined by using two applied tools. It is exposed that the oxyanion hole residues decrease energy barriers by stabilizing the transition state structures. PMID- 25459764 TI - Homology modeling, molecular dynamics, and site-directed mutagenesis study of AlkB human homolog 1 (ALKBH1). AB - The ability to repair DNA is important for the conservation of genetic information of living organisms. Cells have a number of ways to restore damaged DNA, such as direct DNA repair, base excision repair, and nucleotide excision repair. One of the proteins that can perform direct repair of DNA bases is Escherichia coli AlkB. In humans, there are 9 identified AlkB homologs, including AlkB homolog 1 (ALKBH1). Many of these proteins catalyze the direct oxidative dealkylation of DNA and RNA bases and, as such, have an important role in repairing DNA from damage induced by alkylating agents. In addition to the dealkylase activity, ALKBH1 can also function as an apyrimidinic/apurinic lyase and was proposed to have a distinct lyase active site. To our knowledge, no crystal structure or complete homology model of ALKBH1 protein is available. In this study, we have used homology modeling to predict the structure of ALKBH1 based on AlkB and Duffy-binding-like domain crystal structures as templates. Molecular dynamics simulations were subsequently performed on the predicted structure of ALKBH1. The positions of two disulfide bonds or a zinc-finger motif and a disulfide bond were predicted and the importance of these features was tested by mutagenesis. Possible locations for the lyase active site are proposed based on the analysis of our predicted structures and previous experimental results. PMID- 25459766 TI - Evaluating membrane affinity by integrating protein orientations. AB - Energetic interactions of a protein with lipid bilayers determine its propensity to reside in the membrane. Here we seek to evaluate the membrane interactions for EMAPII, a protein found to be released from the cell by unknown mechanisms, as well as several other proteins. Using a knowledge-based coarse-grained membrane potential, we calculate the free energy profiles for these proteins by integrating out the orientation degrees of freedom. Due to the invariance of energy under in-plane rotations about the membrane normal, the orientation space can be reduced to two dimensions and mapped onto the surface of a unit sphere, thus making visualization, sampling and integration more convenient. The integrated free energy profiles determine the relative probabilities along the membrane normal for the proteins regardless of their orientations, and display distinctive characteristics for membrane proteins and water-soluble proteins. The membrane interactions for EMAPII exhibit typical features of a water-soluble protein, with a high energetic barrier to enter or cross the membrane. Our results thus suggest that similar to the non-classical export of FGF1, the release of EMAPII would involve more complicated mechanisms than simple passive diffusion across the membrane. PMID- 25459767 TI - DFT study on X-.(H2O)(n=1-10) (X=OH, NO2, NO3, CO3) anionic water cluster. AB - A theoretical study to understand the interaction between anion and the water molecules through the hydration (X(-).(H2O)n (X=OH, NO2, NO3, CO3), where n=1 10), using the density functional theory method with B3LYP functional and 6 311++G(d,p) basis set has been carried out systematically. In these hydrated clusters we notice three different cases of bond arrangements, namely, symmetrical double hydrogen bond, single hydrogen bond and inter-water hydrogen bond. All the complexes are dominated by the O-H?O hydrogen bond, in which the anion act as a proton acceptor, while the water molecule act as a proton donor. A linear correlation is obtained between the solvent stabilization energy and the size (n) of the hydrated cluster for all the anions. The weighted average interaction energy values, shows that the water molecules strongly bind with the OH(-) anion. Besides, the solvation of the OH(-) anion requires less number of water molecules when compared with the other anions. Energy decomposition analysis (EDA) shows the strong dominance of the electrostatic energy component within the interaction energy. The total NPA charges on the anions indicate an increase in the solvation due to hydration. From AIM analysis, excellent linear inverse correlation is observed for both the electron density and Laplacian of the electron density with respect to the hydrogen bond length. Natural bonding orbital analysis (NBO) predicts large charge transfer between the OH(-) anion and the water molecules. PMID- 25459768 TI - Probing the binding site characteristics of HSA: a combined molecular dynamics and cheminformatics investigation. AB - Human serum albumin is a remarkable protein found in high concentrations in the body. It contains at least seven distinct fatty acid binding sites and two principle sites for drugs. Its primary function is to act as a fatty acid transport system, but it also shows the capacity to bind a diverse range of acidic, neutral and zwitterionic drug molecules. In this paper we investigate the ligand binding selectivity of HSA using cheminformatics analyses and molecular dynamics simulations. We compare and contrast the known ligand binding specificities as obtained from X-ray structural data using PCA, with additional direct analyses of the seven key binding pockets using analyses derived from molecular simulations. We assess both the fatted and defatted states of HSA using 100 ns simulations of the APO and HOLO forms, as well as structures containing one, three and seven myristic acid molecules. We find that differences in fatty acid binding can have a dramatic effect on the flexibility of the protein and also the pocket characteristics. We discuss how the remarkable selectivity of the HSA pockets towards both endogenous fatty acids and exogenous drug molecules is not simply controlled by bulk property effects such as ionization state and lipophilicity. PMID- 25459769 TI - Multi-generational pharmacophore modeling for ligands to the cholane steroid recognition site in the beta1 modulatory subunit of the BKCa channel. AB - Large conductance, voltage- and Ca(2+)-gated K(+) (BKCa) channels play a critical role in smooth muscle contractility and thus represent an emerging therapeutic target for drug development to treat vascular disease, gastrointestinal, bladder and uterine disorders. Several compounds are known to target the ubiquitously expressed BKCa channel-forming alpha subunit. In contrast, just a few are known to target the BKCa modulatory beta1 subunit, which is highly expressed in smooth muscle and scarce in most other tissues. Lack of available high-resolution structural data makes structure-based pharmacophore modeling of beta1 subunit dependent BKCa channel activators a major challenge. Following recent discoveries of novel BKCa channel activators that act via beta1 subunit recognition, we performed ligand-based pharmacophore modeling that led to the successful creation and fine-tuning of a pharmacophore over several generations. Initial models were developed using physiologically active cholane steroids (bile acids) as template. However, as more compounds that act on BKCa beta1 have been discovered, our model has been refined to improve accuracy. Database searching with our best-performing model has uncovered several novel compounds as candidate BKCa beta1 subunit ligands. Eight of the identified compounds were experimentally screened and two proved to be activators of recombinant BKCa beta1 complexes. One of these activators, sobetirome, differs substantially in structure from any previously reported activator. PMID- 25459770 TI - Identifying potential selective fluorescent probes for cancer-associated protein carbonic anhydrase IX using a computational approach. AB - Carbonic anhydrase IX (CAIX) is a biomarker for tumor hypoxia. Fluorescent inhibitors of CAIX have been used to study hypoxic tumor cell lines. However, these inhibitor-based fluorescent probes may have a therapeutic effect that is not appropriate for monitoring treatment efficacy. In the search for novel fluorescent probes that are not based on known inhibitors, a database of 20,860 fluorescent compounds was virtually screened against CAIX using hierarchical virtual ligand screening (HierVLS). The screening database contained 14,862 compounds tagged with the ATTO680 fluorophore plus an additional 5998 intrinsically fluorescent compounds. Overall ranking of compounds to identify hit molecular probe candidates utilized a principal component analysis (PCA) approach. Four potential binding sites, including the catalytic site, were identified within the structure of the protein and targeted for virtual screening. Available sequence information for 23 carbonic anhydrase isoforms was used to prioritize the four sites based on the estimated "uniqueness" of each site in CAIX relative to the other isoforms. A database of 32 known inhibitors and 478 decoy compounds was used to validate the methodology. A receiver operating characteristic (ROC) analysis using the first principal component (PC1) as predictive score for the validation database yielded an area under the curve (AUC) of 0.92. AUC is interpreted as the probability that a binder will have a better score than a non-binder. The use of first component analysis of binding energies for multiple sites is a novel approach for hit selection. The very high prediction power for this approach increases confidence in the outcome from the fluorescent library screening. Ten of the top scoring candidates for isoform selective putative binding sites are suggested for future testing as fluorescent molecular probe candidates. PMID- 25459771 TI - 3D-MoRSE descriptors explained. AB - 3D-MoRSE is a very flexible 3D structure encoding framework for chemoinformatics and QSAR purposes due to the range of scattering parameter values and variety of weighting schemes used. While arising in many QSAR studies, up to this time they were considered as hardly interpreted and were treated like a "black box". This study is intended to lift the veil of mystery, providing a comprehensible way to the interpretation of 3D-MoRSE descriptors in QSAR/QSPR studies. The values of these descriptors are calculated with rather simple equation, but may vary when using differing starting geometries as optimization input. This variation increases with scattering parameter and also is higher for electronegativity weighted and unweighted descriptors. Though each 3D-MoRSE descriptor incorporates the information about the whole molecule structure, its final value is derived mostly from short-distance (up to 3A) atomic pairs. And, if a QSAR study covers structurally similar set of compounds, then the role of 3D-MoRSE descriptor in a model can be interpreted using just several pairs of neighbor atoms. The guide to interpretation process is discussed and illustrated with a case study. Realizing the mathematical concept behind 3D-descriptors and knowing their properties it is easy not only to interpret, but also to predict the importance of 3D-MoRSE descriptors in a QSAR study. The process of prediction is described on the practical example and its accuracy is confirmed with further QSAR modeling. PMID- 25459772 TI - Global challenges, efforts, and controversies in neonatal care. AB - Simple low-cost, evidence-based interventions such as clean delivery practices, immediate warming, umbilical cord care, and neonatal resuscitation could prevent 40% to 70% of newborn deaths globally, but many obstacles preclude the provision of those basic interventions for all newborns, particularly in low-resource regions. Global efforts have led to widespread development of neonatal clinical practice guidelines, training programs, and policies. Because of a shortage of health care resources, standards of care have been redefined to meet the needs of underserved populations. This article provides an overview of the challenges, efforts, and controversies surrounding neonatal health in low-resource settings. PMID- 25459773 TI - Prevention of preterm birth in modern obstetrics. AB - Spontaneous preterm labor is a complex process characterized by the interplay of multiple different pathways. Prevention of preterm labor and delivery is also complicated. The most effective interventions for prevention of preterm birth (PTB) are progestin prophylaxis and lifestyle modifications, with cerclage placement also playing a role in selected populations. Interventions such as activity modification, home tocometry, and routine antibiotic use have fallen out of favor because of lack of effectiveness and possibility of harm. The solution to the problem of PTB remains elusive, and researchers and clinicians must collaborate to find a cure for preterm labor. PMID- 25459774 TI - Challenges and controversies in fetal diagnosis and treatment: hypoplastic left heart syndrome. AB - Today, almost 70% of babies with hypoplastic left heart syndrome (HLHS) will survive into adulthood, although significant long-term morbidity and mortality still exists. Prenatal diagnosis of HLHS is increasingly common, allowing improved counseling, and the potential for fetal intervention if indicated. Exciting progress continues to be made in the area of fetal diagnosis and intervention, specifically catheter intervention for intact atrial septum or severe aortic stenosis. Pediatric cardiologists should be keenly aware of the flaws of staged palliation for the treatment of HLHS, and need to keep abreast of the emerging data regarding fetal diagnosis and intervention. PMID- 25459775 TI - Borderline viability: controversies in caring for the extremely premature infant. AB - Controversy surrounding the decision to resuscitate at the limits or borderline of viability has been at the center of neonatal ethical debate for decades. This debate has led to numerous reports from individual institutions, councils, and advisory committees that all have remarkable consistency in the development of gestational age-based guidelines. This article reviews legal or regulatory concerns that may contradict ethical discussion and guidelines, discriminatory and scientific basis concerns with consensus guidelines, and personal controversy about how to determine best interest. Guidelines are a reasonable place to start in helping determine parental authority and autonomy. The article also addresses controversies raised in counseling and costs. PMID- 25459776 TI - Fetal programming, epigenetics, and adult onset disease. AB - How early life events program adult disease is undergoing a transition from the broad field of maternal malnutrition to the current relevant issues of food deserts and prematurity. Although many adult diseases and morbidities associate with various early life events and programming, the morbidities of insulin resistance, cardiovascular disease, and obesity seem to be common end points of many early life events despite potential confounders. PMID- 25459777 TI - Comparative effectiveness and practice variation in neonatal care. AB - Comparative effectiveness research (CER) is a relatively new term for clinical research that directly assists patients, clinicians, and policymakers in making informed decisions to improve health care. In neonatology, there are similarities and differences between CER and existing clinical research and quality improvement literature. This article uses existing examples in neonatal literature to describe CER methodology and list some future directions and challenges in neonatal CER. PMID- 25459778 TI - Conquering racial disparities in perinatal outcomes. AB - Infant mortality rate (IMR) is a reference indicator for societal health status. Trend analysis of IMR highlights 2 challenges to overcome in the United States: (1) US IMR is higher than most industrialized countries and (2) there are persistent racial/ethnic disparities in birth outcomes, especially for blacks. Racial/ethnic infant mortality disparities result from the complex interplay of adverse social, economic, and environmental exposures. In this article, racial/ethnic disparities are discussed, highlighting trends, the role of epigenetics in understanding mechanisms, key domains of community action planning, and programs and policies addressing the racial gaps in adverse birth outcomes. PMID- 25459779 TI - It's not your mother's marijuana: effects on maternal-fetal health and the developing child. AB - Pro-marijuana advocacy efforts exemplified by the "medical" marijuana movement, coupled with the absence of conspicuous public health messages about the potential dangers of marijuana use during pregnancy, could lead to greater use of today's more potent marijuana, which could have significant short- and long-term consequences. This article reviews the current literature regarding the effects of prenatal marijuana use on the pregnant woman and her offspring. PMID- 25459781 TI - Vascular endothelial growth factor antagonist therapy for retinopathy of prematurity. AB - In this article, the growing problem of retinopathy of prematurity (ROP) worldwide, treatments for severe ROP including standard-of-care laser treatment, and the need for new treatments are discussed. Also discussed are the reasons to consider inhibiting the vascular endothelial growth factor (VEGF) signaling pathway in severe ROP and the concerns about broad VEGF inhibition. Finally, the potential role of VEGF in ROP based on studies in animal models of oxygen-induced retinopathy, the effects of anti-VEGF based on basic research data, and the clinical relevance of these data are covered. PMID- 25459782 TI - Preventing herpes simplex virus in the newborn. AB - Genital herpes simplex virus (HSV) infections are very common worldwide. Approximately 22% of pregnant women are infected genitally with HSV, and most of them are unaware of this. The most devastating consequence of maternal genital herpes is HSV disease in the newborn. Although neonatal HSV infections remain uncommon, due to the significant morbidity and mortality associated with the infection, HSV infection in the newborn is often considered in the differential diagnosis of ill neonates. This review summarizes the epidemiology and management of neonatal HSV infections and discusses strategies to prevent HSV infection in the newborn. PMID- 25459783 TI - Use of cell-free fetal DNA in maternal plasma for noninvasive prenatal screening. AB - Noninvasive prenatal testing (NIPT) using cell-free fetal (cfDNA) offers potential as a screening tool for fetal anomalies. All pregnant women should be offered prenatal screening and diagnostic testing based on current guidelines. Adoption of NIPT in high-risk pregnancies suggests a change in the standard of care for genetic screening; there are advantages to an accurate test with results available early in pregnancy. This accuracy decreases the overall number of invasive tests needed for diagnosis, subjecting fewer pregnancies to the risks of invasive procedures. Women undergoing NIPT need informed consent before testing and accurate, sensitive counseling after results are available. PMID- 25459785 TI - Informing and educating parents about the risks and outcomes of prematurity. AB - The current process of educating and informing parents of the concerns and outcomes of premature infants is suboptimal, mostly because of modifiable factors. Proven methods to improve the transference of information are underused. In most institutions, the task to inform and educate parents is left to individual providers. Effective parent-clinician communication depends collectively on parents, clinicians, and the health care systems. Efforts must focus on improving communication and not on decreasing information provided to parents. If done successfully, we might find new and worthy allies in the trenches of the NICU. PMID- 25459786 TI - Ethical issues in DNA sequencing in the neonate. AB - With the recognition of genetic disorders in the newborn, there is the potential to offer new lifesaving therapies. For other conditions such as hypothyroidism in Down syndrome or hypercalemia in the 22q11 microdeltion syndrome, the early identification of an untreatable condition permits prompt screening for potential comorbid conditions. DNA testing for disorders and DNA-based screening are rapidly evolving. With new more powerful tests, there is an increasing ability to see into a potential future and change the outcome for newborns. However, there remain significant ethical and structural issues to be considered before routine implementation of DNA testing. PMID- 25459784 TI - Probiotics and necrotizing enterocolitis. AB - One of the most controversial areas in neonatology is whether probiotics should be provided routinely to preterm infants to prevent necrotizing enterocolitis (NEC). This review provides the reader with a brief overview of NEC and current concepts of its pathophysiology, discusses the microbial ecology of the intestine in preterm infants and factors that may lead to a "dysbiosis", summarizes studies of probiotics in preterm infants, elaborates on the need for regulation in this area, and discusses alternatives to probiotics and what is the future for the prevention of NEC. PMID- 25459788 TI - Pulse oximetry in very low birth weight infants. AB - Pulse oximetry has become ubiquitous and is used routinely during neonatal care. Emerging evidence highlights the continued uncertainty regarding definition of the optimal range to target pulse oximetry oxygen saturation levels in very low birth weight infants. Furthermore, maintaining optimal oxygen saturation targets is a demanding and tedious task because of the frequency with which oxygenation changes, especially in these small infants receiving prolonged respiratory support. This article addresses the historical perspective, basic physiologic principles behind pulse oximetry operation, and the use of pulse oximetry in targeting different oxygen ranges at various time-points throughout the neonatal period. PMID- 25459787 TI - Screening for and treatments of congenital immunodeficiency diseases. AB - Although newborn screening (NBS) for inborn errors of metabolism has been successfully utilized in the US for decades, only recently has this screening program expanded to include disorders of immunity. Severe combined immunodeficiency (SCID) became the first disorder of immunity to be screened on a population wide basis in 2008. While NBS for SCID has been successful, the implementation of population-based screening programs is not without controversy, and there remain barriers to the nationwide implementation of this test. In addition, as the program has progressed we have learned of new challenges in the management of newborns that fail this screen. PMID- 25459789 TI - Preface. Current controversies in perinatology. PMID- 25459790 TI - Foreword. Current controversies in perinatology: why they don't go away. PMID- 25459780 TI - Pain management in newborns. AB - As a standard of care for preterm/term newborns effective pain management may improve their clinical and neurodevelopmental outcomes. Neonatal pain is assessed using context-specific, validated, and objective pain methods, despite the limitations of currently available tools. Therapeutic approaches reducing invasive procedures and using pharmacologic, behavioral, or environmental measures are used to manage neonatal pain. Nonpharmacologic approaches like kangaroo care, facilitated tucking, non-nutritive sucking, sucrose, and others can be used for procedural pain or adjunctive therapy. Local/topical anesthetics, opioids, NSAIDs/acetaminophen and other sedative/anesthetic agents can be incorporated into NICU protocols for managing moderate/severe pain or distress in all newborns. PMID- 25459791 TI - Outcome producing potential influences twelve-month-olds' interpretation of a novel action as goal-directed. AB - Learning about a novel, goal-directed action is a complex process. It requires identifying the outcome of the action and linking the action to its outcome for later use in new situations to predict the action or to anticipate its outcome. We investigated the hypothesis that linking a novel action to a salient change in the environment is critical for infants to assign a goal to the novel action. We report a study in which we show that 12-month-old infants, who were provided with prior experience with a novel action accompanied with a salient visible outcome in one context, can interpret the same action as goal-directed even in the absence of the outcome in another context. Our control condition shows that prior experience with the action, but without the salient effect, does not lead to goal directed interpretation of the novel action. We also found that, for the case of 9-month-olds infants, prior experience with the outcome producing potential of the novel action does not facilitate a goal-directed interpretation of the action. However, this failure was possibly due to difficulties with generalizing the learnt association to another context rather than with linking the action to its outcome. PMID- 25459793 TI - The effects of exposure to dynamic expressions of affect on 5-month-olds' memory. AB - The purpose of this study was to examine the behavioral effects of adults' communicated affect on 5-month-olds' visual recognition memory. Five-month-olds were exposed to a dynamic and bimodal happy, angry, or neutral affective (face voice) expression while familiarized to a novel geometric image. After familiarization to the geometric image and exposure to the affective expression, 5-month-olds received either a 5-min or 1-day retention interval. Following the 5 min retention interval, infants exposed to the happy affective expressions showed a reliable preference for a novel geometric image compared to the recently familiarized image. Infants exposed to the neutral or angry affective expression failed to show a reliable preference following a 5-min delay. Following the 1-day retention interval, however, infants exposed to the neutral expression showed a reliable preference for the novel geometric image. These results are the first to demonstrate that 5-month-olds' visual recognition memory is affected by the presentation of affective information at the time of encoding. PMID- 25459792 TI - Perinatal depression influences on infant negative affectivity: timing, severity, and co-morbid anxiety. AB - Accumulating evidence suggests that antenatal depression predicts infants' negative affectivity, albeit with variable effect sizes. With a prospective longitudinal design, we sought to explain that variability by addressing questions about timing of the depression across pregnancy and the early postpartum, the role of high symptom levels relative to diagnosed depression, comorbidity with anxiety, and the potential mediating role of neuroendocrine functioning. Primiparous women (n=77) with histories of depression prior to pregnancy were assessed for cortisol levels monthly beginning by mid-pregnancy. Depression symptom levels and diagnostic status were similarly assessed monthly in pregnancy and also until infants reached three months of age, when mothers completed the Infant Behavior Questionnaire-Revised to measure infant negative affectivity. Antenatal depression symptoms and infant negative affectivity were positively associated (r=.39). Controlling for depression symptom levels in other trimesters, only second trimester depression symptoms predicted higher infant negative affectivity (beta=.44). With postpartum depression symptom levels in the model, only antenatal depression symptoms predicted infant negative affectivity (beta=.45). In the context of depression, neither antenatal anxiety symptoms nor anxiety disorder diagnosis were associated with infant NA scores. The hypothesized role of elevated maternal cortisol as a mechanism for the association between antenatal depression and infant NA was not supported. Our findings contribute to efforts to more precisely identify infants of perinatally depressed mothers who are at greater risk for elevated negative affectivity, suggesting a window of vulnerability in mid pregnancy and the need for further study of potential mechanisms. PMID- 25459794 TI - Consistency of maternal cognitions and principles across the first five months following preterm and term deliveries. AB - The aims of this study were to examine and compare the development of parenting cognitions and principles in mothers following preterm and term deliveries. Parenting cognitions about child development, including thinking that is restricted to single causes and single outcomes (categorical thinking) and thinking that takes into account multiple perspectives (perspectivist thinking), have been shown to relate to child outcomes. Parenting principles about using routines (structure) or infant cues (attunement) to guide daily caregiving have been shown to relate to caregiving practices. We investigated the continuity and stability of parenting cognitions and principles in the days following birth to 5 months postpartum for mothers of infants born term and preterm. All parenting cognitions were stable across time. Categorical thinking increased at a group level across time in mothers of preterm, but not term, infants. Perspectivist thinking increased at a group level for first-time mothers (regardless of birth status) and tended to be lower in mothers of preterm infants. Structure at birth did not predict later structure (and so was unstable) in mothers of preterm, but not term, infants and neither group changed in mean level across time. Attunement was consistent across time in both groups of mothers. These results indicate that prematurity has multiple, diverse effects on parenting beliefs, which may in turn influence maternal behavior and child outcomes. PMID- 25459795 TI - Patterns of mother-infant interaction from 3 to 12 months among dyads with substance abuse and psychiatric problems. AB - The aim of this study was to investigate the development of mother-infant interaction patterns from 3 to 12 months among three groups of mother-baby pairs recruited during pregnancy: one group from residential substance abuse treatment (n=28), a second group from psychiatric outpatient treatment (n=22), and a third group from well-baby clinics (n=30). The mother-infant interaction at 3 and 12 months was assessed by the Parent-Child Early Relational Assessment (PCERA), which consists of maternal, child and dyadic subscales (Clark, 2006). Linear mixed effects models were used to analyze group differences and the changes in mother-infant interaction from 3 to 12 months. At 3 months, pairwise comparisons showed that the group with psychiatric problems had significantly more difficulties in the mother-infant interaction than the two other groups. The group with substance abuse problems was not significantly different from the two other groups. At 12 months, the mother-infant pairs in the substance abuse group showed significantly more relational disturbances than the non-clinical pairs, as well as a poorer affective quality of interaction than the dyads in the group with psychiatric problems. Analysis of change from 3 to 12 months showed that difficulties in the interaction increased among the mother-baby pairs in the substance abuse group, while improvements were displayed in the two other groups. These results underline that mother-infant pairs at double risk due to maternal substance abuse and other non-optimal factors, are in need for long-term follow up in order to prevent the development of negative interactional patterns. PMID- 25459796 TI - Infant characteristics and parental engagement at the transition to parenthood. AB - Positive engagement activities support children's adaptive development and new parents are encouraged to be highly engaged with infants. Yet, fathers' engagement is widely understudied and maternal engagement quantity is frequently overlooked. Our study contributes to growing knowledge on associations between infant temperament and parental engagement by testing transactional and moderation models in a recent sample of first-time parents when infants were 3, 6, and 9 months old. Stringent longitudinal, reciprocal structural equation models partially confirmed an engagement "benefit". Mothers' engagement marginally contributed to their children's gains in effortful control from 3 to 6 months regardless of child gender. Further, mothers' engagement reduced infant negative affect from 6 to 9 months regardless of child gender. Mothers' ratings of infant negative affect were gendered; mothers' ratings of infant negative affect increases more from 3 to 6 months for boys. Fathers' engagement was contextually sensitive; child gender moderated the link between negative affect and engagement from 6 to 9 months, such that fathers became more engaged with boys whom they rated higher on negative affect; there was no effect for daughters. Finally, we found that effortful control moderated associations between negative affect and maternal engagement; mothers' engagement increases from 3 to 6 months were greater for children initially rated lower in effortful control. Implications for future research and parenting education and support services are discussed. PMID- 25459797 TI - Mineralization of reactive azo dyes present in simulated textile waste water using down flow microaerophilic fixed film bioreactor. AB - The present research emphasizes on degradation of azo dyes from simulated textile wastewater using down flow microaerophilic fixed film reactor. Degradation of simulated textile wastewater (COD 7200mg/L and dye concentration 300mg/L) was studied in a microaerophilic fixed film reactor using pumice stone as a support material under varying hydraulic retention time (HRT) and organic loading rate (OLR). The intense metabolic activity of the inoculated bacterial consortium in the reactor led to 97.5% COD reduction and 99.5% decolorization of simulated wastewater operated under OLR of 7.2kgCODm(3)/d and 24h of HRT. FTIR, (1)H NMR and GC-MS studies revealed the formation of lower molecular weight aliphatic compounds under 24h of HRT, leading to complete mineralization of simulated wastewater. The detection of oxido-reductive enzyme activities suggested the enzymatic reduction of azo bonds prior to mineralization. Toxicity studies indicated that microbial treatment favors detoxification of simulated wastewater. PMID- 25459798 TI - Upflow anaerobic solid-state (UASS) digestion of horse manure: Thermophilic vs. mesophilic performance. AB - Energetic use of complex lignocellulosic wastes has gained global interest. Thermophilic digestion of horse manure based on straw was investigated using the upflow anaerobic solid-state (UASS) process. Increasing the organic loading rate from 2.5 to 5.5gvsL(-)(1)d(-)(1) enhanced the average methane production rate from 0.387 to 0.687LCH4L(-)(1)d(-)(1), whereas the yield decreased from 154.8 to 124.8LCH4kgvs(-)(1). A single-stage and two-stage process design showed almost the same performance. Compared to prior experiments at mesophilic conditions, thermophilic conditions showed a significantly higher efficiency with an increase of 59.8% in methane yield and 58.1% in methane production rate. Additional biochemical methane potential (BMP) tests with two types of horse manure and four different bedding materials showed that wheat straw obtained the highest BMP. The results show that the thermophilic UASS process can be the key to an efficient energy recovery from straw-based manures. PMID- 25459799 TI - Pilot scale conversion of wheat straw to ethanol via simultaneous saccharification and fermentation. AB - The production of ethanol from wheat straw (WS) by dilute acid pretreatment, bioabatement of fermentation inhibitors by a fungal strain, and simultaneous saccharification and fermentation (SSF) of the bio-abated WS to ethanol using an ethanologenic recombinant bacterium was studied at a pilot scale without sterilization. WS (124.2g/L) was pretreated with dilute H2SO4 in two parallel tube reactors at 160 degrees C. The inhibitors were bio-abated by growing the fungus aerobically. The maximum ethanol produced by SSF of the bio-abated WS by the recombinant Escherichia coli FBR5 at pH 6.0 and 35 degrees C was 36.0g/L in 83h with a productivity of 0.43gL(-1)h(-1). This value corresponds to an ethanol yield of 0.29g/g of WS which is 86% of the theoretical ethanol yield from WS. This is the first report on the production of ethanol by the recombinant bacterium from a lignocellulosic biomass at a pilot scale. PMID- 25459800 TI - Influence of organic loading rate and solid retention time on polyhydroxybutyrate production from hybrid poplar hydrolysates using mixed microbial cultures. AB - The aim of this study was to investigate the potential of using wood hydrolysates (enzymatically hydrolyzed from hybrid poplar) as substrate to produce polyhydroxybutyrate (PHB) using mixed microbial cultures. The optimal operational conditions for fed-batch bioreactors were 4d solid retention time with an organic loading rate of 2.5g/Ld. The maximum PHB accumulated was 27% of cell dry weight with a yield of 0.32g/g (g PHB produced per g sugars consumed). Microbial community analysis was done at the genus level by 16S rRNA sequencing on an Illumina system and community evolution was observed among different samples and initial seed. Actinobacteria, Alpha- and Beta-proteobacteria were found to be the dominant groups in all the bioreactors. Several PHB-storing microorganisms were characterized belonging to Alpha- and Beta-proteobacteria. PMID- 25459801 TI - Synergetic effects and flocculation behavior of anionic polyacrylamide and extracellular polymeric substrates extracted from Klebsiella sp. J1 on improving soluble cadmium removal. AB - The performance and flocs properties in removing soluble cadmium of the dual flocculant APAM-MFX (anionic polyacrylamide APAM used in combination with extracellular polymeric substrates extracted from Klebsiella sp. J1 MFX) were studied compared with the performance of using bioflocculant alone. In addition, adsorption isotherms and kinetic process for Cd(II) adsorption onto APAM-MFX were investigated. APAM-MFX synergistically improved the Cd(II) removal percentage by 82.68%. Characteristic flocs formed by APAM-MFX indicated the synergetic effects resulted from additional bridging bonds between APAM and MFX. Adsorption process was best described by the Freundlich isotherm and pseudo-second order kinetic model. The mean free energy E (8.39-8.57kJmol(-1)) and activation energy Ea (45.09kJmol(-1)) were determined. Based on the results, the main mechanism of Cd(II) removal by APAM-MFX could be chemical ion exchange, and the liquid-film diffusion step was the rate-limiting step. PMID- 25459802 TI - Design and application of a novel ionic liquid with the property of strengthening coenzyme regeneration for whole-cell bioreduction in an ionic liquid-distilled water medium. AB - Focusing on the task-specific properties of ionic liquids (ILs), a novel IL was designed by combining the quaternary ammonium cationic surfactant, [N1,1,1,1](+), with benign amino acid anion ([Cys](-)), and was successfully employed in whole cell-catalyzed bioreduction by Trichodermaasperellum ZJPH0810 using an ionic liquid-distilled water medium. As expected, based on better understanding about the effects of ILs' characteristics of cations and anions on T. asperellum ZJPH0810-catalyzed bioreduction and the optimization of reaction parameters, the developed tetramethylammonium cysteine ([N1,1,1,1][Cys])-containing system is more efficient for the asymmetric reduction of 3,5-bis(trifluoromethyl) acetophenone to (R)-[3,5-bis(trifluoromethyl)phenyl] ethanol by whole-cell catalysis in contrast to that in monophasic aqueous system. Herein, a new biotechnological application for designed type of ILs is proposed due to its novel property of strengthening coenzyme regeneration during the bioreduction process. The designed IL [N1,1,1,1][Cys] was also evaluated in Candidatropicalis 104-catalyzed bioreduction to board its application, with remarkable success. PMID- 25459803 TI - Co-gasification of biosolids with biomass: Thermogravimetric analysis and pilot scale study in a bubbling fluidized bed reactor. AB - This work studied the feasibility of co-gasification of biosolids with biomass as a means of disposal with energy recovery. The kinetics study at 800 degrees C showed that biomass, such as switchgrass, could catalyze the reactions because switchgrass ash contained a high proportion of potassium, an excellent catalyst for gasification. However, biosolids could also inhibit gasification due to interaction between biomass alkali/alkaline earth metals and biosolids clay minerals. In the pilot scale experiments, increasing the proportion of biosolids in the feedstock affected gasification performance negatively. Syngas yield and char conversion decreased from 1.38 to 0.47m(3)/kg and 82-36% respectively as the biosolids proportion in the fuel increased from 0% to 100%. Over the same range, the tar content increased from 10.3 to 200g/m(3), while the ammonia concentration increased from 1660 to 19,200ppmv. No more than 25% biosolids in the fuel feed is recommended to maintain a reasonable gasification. PMID- 25459804 TI - Effects of hydrophilicity/hydrophobicity of membrane on membrane fouling in a submerged membrane bioreactor. AB - The interfacial interactions between sludge foulants and four different types of membranes were assessed based on a new combined calculation method. Effects of membrane surface hydrophilicity/hydrophobicity on the interfacial interactions were investigated. It was found that, membrane surface hydrophilicity/hydrophobicity was not directly relevant to the interfacial interactions with sludge particles. Increasing membrane surface zeta potential could significantly increase the strength of the electrostatic double layer (EL) interaction and the energy barrier. For membrane with a surface roughness of 300nm, the total interaction was continuously repulsive in the separation distance coverage of 0-4nm in this study. The results suggest that, under conditions in this study, designing membranes with a high zeta potential and certain roughness can significantly mitigate membrane fouling, whereas, the strategy of improving membrane surface hydrophilicity cannot alleviate sludge adhesion in the membrane bioreactor. PMID- 25459805 TI - Characterization of methane production and microbial community shifts during waste activated sludge degradation in microbial electrolysis cells. AB - Microbial electrolysis cell (MECs) were investigated as a promising technology to manage waste activated sludge (WAS) reduction and bio-methane generation. The effect of WAS concentration on the MECs performance was discussed. At the optimal concentration of 15gCOD/L, maximum methane yield of MECs fed with alkaline pretreated WAS (A-WAS) were achieved with the value of 77.13+/-2.52LCH4/kg-COD on Day 3, which had been improved by 1.5-fold compared with MECs fed with raw WAS (R WAS), while that was negligible in open circuit controls. Efficient sludge reduction was also obtained in terms of TCOD, total protein, TSS and VSS removal. Pyrosequencing revealed the dominance of exoelectrogen Geobacter and hydrogen producing bacteria Petrimonas in MECs fed with WAS. Methanocorpusculum with the capacity of methane generation using CO2 and H2 also showed overwhelming dominance (96.01%). The large proportions of Petrimonas and Methanocorpusculum indicated the occurrence of hydrogenotrophic methanogenesis in our methane producing MECs. PMID- 25459806 TI - Effects of different pre-extractions combining with chemi-thermomechanical treatments on the enzymatic hydrolysis of wheat straw. AB - Three different pre-extraction methods (i.e., acetic acid, sulfuric acid and sodium hydroxide) were used for the pretreatment followed by chemi thermomechanical treatments and then enzymatic hydrolysis of wheat straw to produce fermentable sugars. The performance of enzymatic hydrolysis by the synergistic effect of pre-extractions and chemi-thermomechanical treatments was remarkable. Results showed that the pre-extraction combining with the chemi thermomechanical treatments shorten the enzymatic hydrolysis time and improved the glucose yield at the same enzyme loadings. The chemical components, swelling ability, and crystallinity, as well as the surface morphology of the substrates were changed obviously. All of these changes can affect the accessibility of enzymes to cellulose in the substrates to a certain extent. PMID- 25459807 TI - Hydrogen production by Rhodobacter sphaeroides DSM 158 under intense irradiation. AB - To identify optimal hydrogen production conditions using growing cultures of Rhodobacter sphaeroides DSM 158 the effects of varying the reactor's volumetric power input (0.01-1.4kWm(-3)) and irradiation intensity (5-2500Wm(-2)) were investigated in batch and continuous production modes. Irradiation intensity had a greater effect on hydrogen production than volumetric power input. Hydrogen production and photofermentative biomass formation were maximized by irradiation at 2250Wm(-2) with a volumetric power input of 0.55kWm(-3). The bacterial dry weight (2.64gL(-1)) and rate of hydrogen production (195mLL(-1)h(-1)) achieved under these conditions were greater than any that have previously been reported for batch-mode hydrogen production by R. sphaeroides. Continuous mode experiments (D=0.1h(-1)) yielded a bacterial dry weight, hydrogen production rate, productivity and hydrogen yield of 2.35+/-0.18gL(-1), 165+/-6.2mLL(-1)h(-1), 3.96LL(-1)d(-1) and 36.6%, respectively. PMID- 25459808 TI - Recycling microbial lipid production wastes to cultivate oleaginous yeasts. AB - To reduce wastes and the costs of microbial lipid production, it is imperative to recycle resources, including spent cell mass, mineral nutrients and water. In the present study, lipid production by the oleaginous yeast Rhodosporidium toruloides was used as a model system to demonstrate resources recycling. It was found that the hydrolysates of spent cell mass were good media to support cell growth of various oleaginous yeasts. When serial repitching experiments were performed using 70g/L glucose and the hydrolysates alone as nutrients, it produced 16.6, 14.6 and 12.9g/L lipids, for three successive cycles, while lipid titre remained almost constant when spent water was also recycled. The cell mass hydrolysates could be used as equivalents to the mixture of yeast extract and peptone to support lipid production from corn stalk hydrolysates. Our results showed efficient recycling of lipid production wastes and should be helpful to advance microbial lipid technology. PMID- 25459809 TI - Production of medium-chain volatile fatty acids by mixed ruminal microorganisms is enhanced by ethanol in co-culture with Clostridium kluyveri. AB - Mixed bacterial communities from the rumen ferment cellulosic biomass primarily to C2-C4 volatile fatty acids, and perform only limited chain extension to produce C5 (valeric) and C6 (caproic) acids. The aim of this study was to increase production of caproate and valerate in short-term in vitro incubations. Co-culture of mixed ruminal microbes with a rumen-derived strain of the bacterium Clostridium kluyveri converted cellulosic biomass (alfalfa stems or switchgrass herbage) plus ethanol to VFA mixtures that include valeric and caproic acids as the major fermentation products over a 48-72h run time. Concentrations of caproate reached 6.1gL(-1), similar to or greater than those reported in most conventional carboxylate fermentations that employ substantially longer run times. PMID- 25459810 TI - Comparison and evaluation of concurrent saccharification and anaerobic digestion of Napier grass after pretreatment by three microbial consortia. AB - Napier grass is potentially a viable feedstock for biofuel production. The present study investigated biological pretreatment of Napier grass by three microbial consortia followed by saccharification and anaerobic digestion. The pretreatment efficiencies of three microbial consortia were compared in terms of degradation ability, saccharide and biogas yield. The lignocellulose loss rates of Napier grass varied largely. The biomass pretreated by the consortium WSD-5 gave 43.4% and 66.2% total sugar yield under low and moderate loadings of commercial enzyme mixtures, while the highest yield was 83.2% pretreated by the consortium MC1 under a high enzyme loading. The maximum methane yield of pretreated samples by the consortia MC1, WSD-5 and XDC-2 were 259, 279, 247ml/g VS, respectively, which were 1.39, 1.49 and 1.32times greater than the values of the untreated controls. This study showed that pretreatments by MC1, WSD-5 and XDC-2 were capable of significantly enhancing both the saccharide and methane yields from Napier grass. PMID- 25459811 TI - Microbial community related to lysozyme digestion process for boosting waste activated sludge biodegradability. AB - Waste activated sludge from a lab-scale sequencing batch reactor was used to investigate the potential relation of microbial community with lysozyme digestion process for sludge solubilization. The results showed the microbial community shifted conspicuously as sludge suffered lysozyme digestion. Soluble protein and polysaccharide kept an increasing trend in solution followed with succession of microbial community. The rise of lysozyme dosage augmented the dissimilarity among communities in various digested sludge. A negative relationship presented between community diversity and lysozyme digestion process under various lysozyme/TS from 0 to 240min (correlation coefficient R(2) exceeded 0.9). Pareto Lorenz curves demonstrated that microbial community tended to be even with sludge disintegration process by lysozyme. Finally, with diversity (H) decrease and community distribution getting even, the SCOD/TCOD increased steadily in solution which suggested the sludge with high community diversity and uneven population distribution might have tremendous potential for improving their biodegradability by lysozyme digestion. PMID- 25459812 TI - Disinhibition of excessive volatile fatty acids to improve the efficiency of autothermal thermophilic aerobic sludge digestion by chemical approach. AB - In this study, we explored a chemical approach to eliminate inhibition of excessive volatile fatty acids (VFAs) in autothermal thermophilic aerobic digestion (ATAD). Ferric nitrate, ferric chloride, potassium nitrate and potassium chloride were employed to demonstrate the combined action of ferric ion and nitrate ion. Supplementation of ferric nitrate in the sludge digestion system resulted in reducing the concentration of Total VFAs (TVFA) by round 5000mg/L and more than 2000mg/L of acetic acid at the end of digestion. Lower TVFA concentration contributed to faster sludge stabilization rate and the VS removal of ferric nitrate dosed digester achieved 38.18% after 12days digestion which was 9days in advance compared with the stabilization time of sludge in digester without chemicals addition. Lower concentrations of NH4(+)-N and SCOD in supernatant while higher content of TP in digestion sludge were obtained in digester with ferric nitrate added. PMID- 25459813 TI - Efficient approach for bioethanol production from red seaweed Gelidium amansii. AB - Gelidium amansii (GA), a red seaweed species, is a popular source of food and chemicals due to its high galactose and glucose content. In this study, we investigated the potential of bioethanol production from autoclave-treated GA (ATGA). The proposed method involved autoclaving GA for 60min for hydrolysis to glucose. Separate hydrolysis and fermentation processing (SHF) achieved a maximum ethanol concentration of 3.33mg/mL, with a conversion yield of 74.7% after 6h (2% substrate loading, w/v). In contrast, simultaneous saccharification and fermentation (SSF) produced an ethanol concentration of 3.78mg/mL, with an ethanol conversion yield of 84.9% after 12h. We also recorded an ethanol concentration of 25.7mg/mL from SSF processing of 15% (w/v) dry matter from ATGA after 24h. These results indicate that autoclaving can improve the glucose and ethanol conversion yield of GA, and that SSF is superior to SHF for ethanol production. PMID- 25459814 TI - Absorption degree analysis on biogas separation with ionic liquid systems. AB - For biogas upgrading, present work mainly focuses on either thermodynamics or mass transfer properties. A systematical study on these two aspects is important for developing a new biogas separation process. In this work, a new criterion "absorption degree", which combines both thermodynamics and mass transfer properties, was proposed for the first time to comprehensively evaluate the absorption performance. Henry's law constants of CO2 and CH4 in ionic liquids polyethylene glycol dimethyl ethers mixtures were investigated. The liquid-side mass transfer coefficients (kL) were determined. The results indicate that IL-NHD mixtures exhibit not only a high CO2/CH4 selectivity, but also a fast kL for CO2 absorption. The [bmim][NO3]+NHD mixtures present a high absorption degree value for CO2 but a low value for CH4. For presenting a highest relative absorption degree value, the 50wt% [bmim][NO3]+50wt% NHD mixture is recommended for biogas upgrading. PMID- 25459815 TI - A closed loop for municipal organic solid waste by lactic acid fermentation. AB - In order to investigate the feasibility of producing lactic acid from municipal organic solid waste different pH values (4-7) and temperatures (37 degrees C and 55 degrees C) were tested. For the evaluation of fermentation conditions the chemical, physical, and microbial characters were monitored over a period of 7days. Quantitative real time PCR, PCR-DGGE, and next generation sequencing of a 16S rRNA gene library were applied to identify the key players of the lactic acid production and their association. Lactobacillus acidophilus and its closest relatives were found to be efficient lactic acid producers (>300mM) under most suitable fermentation conditions tested in this study: 37 degrees C with either uncontrolled pH or at a pH of 5. These data provide the first step in the realization of the idea "reuse, reduce, and recycle" of municipal organic solid waste. PMID- 25459816 TI - Effects of furan derivatives on biohydrogen fermentation from wet steam-exploded cornstalk and its microbial community. AB - Understanding the role of furan derivatives, furfural (FUR) and 5-hydroxymethyl furfural (HMF), is important for biofuel production from lignocellulosic biomass. In this study, the effects of furan derivatives on hydrogen fermentation from wet steam-exploded cornstalk were investigated. The control experiments with only seed sludge indicated that HMF addition of up to 1g/L stimulated hydrogen production. Similar results were obtained using steam-exploded cornstalk as the feedstock. Hydrogen productivity was increased by up to 40% with the addition of HMF. In addition, over 90% of furan derivatives with an initial concentration below 1g/L were degraded. Pyosequencing showed that the addition of HMF and FUR resulted in different microbial communities. HMF led to a higher proportion of the genera Clostridium and Ruminococcaceae, supporting the increased hydrogen production. This study suggested that hydrogen fermentation could be a detoxifying step for steam-exploded cornstalk, and HMF and FUR exhibited different functions for hydrogen fermentation. PMID- 25459817 TI - Production of validamycin A from hemicellulose hydrolysate by Streptomyces hygroscopicus 5008. AB - Validamycin A (VAL-A) is an important agricultural antibiotic produced by Streptomyces hygroscopicus 5008, which uses starch as carbon source occupying about 20% of total production cost. To reduce the medium cost, corncob hydrolysate - a hemicellulose hydrolysate was applied as a low-cost substrate to VAL-A fermentation. It was found that three major sugars in corncob hydrolysate including d-glucose, d-xylose and l-arabinose could all be utilized by S. hygroscopicus 5008 to produce VAL-A while d-xylose was the main contributor. A higher VAL-A production titer from d-xylose was achieved by using a genetically engineered strain TC03 derived from S. hygroscopicus 5008, which resulted in 1.27 fold improvement of VAL-A production from the medium containing 13% (v/v) corncob hydrolysate compared to that by its original strain. A medium cost analysis was done and compared with previous reports. This work indicates a great potential of the hemicellulose hydrolysate as substrate for antibiotic fermentation. PMID- 25459818 TI - Promoting anaerobic biogasification of corn stover through biological pretreatment by liquid fraction of digestate (LFD). AB - A new biological pretreatment method by using liquid fraction of digestate (LFD) was advanced for promoting anaerobic biogasification efficiency of corn stover. 17.6% TS content and ambient temperature was appropriate for pretreatment. The results showed that C/N ratio decreased to about 30, while total lignin, cellulose, and hemicellulose (LCH) contents were reduced by 8.1-19.4% after pretreatment. 3-days pretreatment was considered to be optimal, resulting in 70.4% more biogas production, 66.3% more biomethane yield and 41.7% shorter technical digestion time compared with the untreated stover. The reductions on VS, cellulose, and hemicellulose were increased by 22.1-35.9%, 22.3-35.4%, and 19.8-27.2% for LFD-treated stovers. The promoted anaerobic biogasification efficiency was mainly attributed to the improved biodegradability due to the pre decomposition role of the bacteria in LFD. The method proved to be an efficient and low cost approach for producing bioenergy from corn stover, meanwhile, reducing LFD discharge and minimizing its potential pollution. PMID- 25459819 TI - Thermogravimetric investigation on characteristic of biomass combustion under the effect of organic calcium compounds. AB - Experiments were conducted in a thermogravimetric analyzer to investigate thermal behavior of different organic calcium compounds (OCCs) and its blended fuels with three kinds of biomass. The effectiveness of synthesized method for OCC was assessed by the pyrolysis test. Effect of the mole ratio of calcium to sulfur on co-combustion characteristics was studied. Results indicated that preparation method of modified calcium acetate (MCA) had high precision and accuracy. Co combustion characteristic of OCCs blended with biomass was controlled by OCCs' additive amount and the content of volatile matter which is mainly composed of small hydrocarbon molecules. Combustion performance indexes for peanut shell and wheat straw impregnated by OCCs were improved, however, an inverse trend was found for rice husk because of lower additive amount of OCCs. The blended fuel show higher combustion performance indexes compared with combustion of individual biomass, and these indexes decrease with increases of Ca/S ratio. PMID- 25459820 TI - Making lignin accessible for anaerobic digestion by wet-explosion pretreatment. AB - Lignin is a major part of the recalcitrant fraction of lignocellulose and in nature its degradation occurs through oxidative enzymes along with microbes mediated oxidative chemical actions. Oxygen assisted wet-explosion pretreatment promotes lignin solubility and leads to an increase biodegradation of lignin during anaerobic digestion processes. The pretreatment of feedlot manure was performed in a 10L reactor at 170 degrees C for 25min using 4bars oxygen and the material was fed to a continuous stirred tank reactor operated at 55 degrees C for anaerobic digestion. Methane yield of untreated and pretreated material was 70+/-27 and 320+/-36L/kg-VS/Day, respectively, or 4.5 times higher yield as a result of the pretreatment. Aliphatic acids formed during the pretreatment were utilized by microbes. 44.4% lignin in pretreated material was actually converted in the anaerobic digestion process compared to 12.6% for untreated material indicating the oxygen assisted explosion promoted lignin degradation. PMID- 25459821 TI - Stability and nitrite-oxidizing bacteria community structure in different high rate CANON reactors. AB - In completely autotrophic nitrogen removal over nitrite (CANON) process, the bioactivity of nitrite-oxidizing bacteria (NOB) should be effectively inhibited. In this study, the stability of four high-rate CANON reactors and the effect of free ammonia (FA) and organic material on NOB community structure were investigated using DGGE. Results suggested that with the increasing of FA, the ratio of total nitrogen removal to nitrate production went up gradually, while the biodiversity of Nitrobacter-like NOB and Nitrospira-like NOB both decreased. When the CANON reactor was transformed to simultaneous partial nitrification, anammox and denitrification (SNAD) reactor by introducing organic material, the denitrifiers and aerobic heterotrophic bacteria would compete nitrite or oxygen with NOB, which then led to the biodiversity decreasing of both Nitrobacter-like NOB and Nitrospira-like NOB. The distribution of Nitrobacter-like NOB and Nitrospira-like NOB were evaluated, and finally effective strategies for suppressing NOB in CANON reactors were proposed. PMID- 25459822 TI - Enzymatic hydrolysis of steam-exploded sugarcane bagasse using high total solids and low enzyme loadings. AB - Hydrolysis of phosphoric acid-impregnated steam-treated sugarcane bagasse was pre optimized using a face-centered central composite design in which the process variables were the substrate total solids (TS, %), agitation intensity (AI, rpm) and enzyme loading (EL, gg(-1)). Pretreatment was carried out at 180 degrees C for 10min using cane bagasse with 50wt% moisture content containing 9.5mg of H3PO4 per gram of dry biomass. Hydrolyses were performed for 96h at 50 degrees C using Cellic CTec2(r) and water-washed steam-treated substrates. The highest amount of fermentable sugars was obtained with 20wt% TS, producing 76.8gL(-1) of glucose equivalents, which corresponded to a total glucan conversion of 69.2wt% and to a theoretical net increase of 39% in ethanol production from the same sugarcane tonnage without considering the use of leaves, tops and the additional yields from C5 sugars. PMID- 25459823 TI - The thermophilic (55 degrees C) microaerobic pretreatment of corn straw for anaerobic digestion. AB - Microaerobic process has been proven to be an alternative pretreatment for the anaerobic digestion (AD) process in several studies. In this study, the effect of thermophilic microaerobic pretreatment (TMP) on the AD of corn straw was investigated. Results indicated that TMP process obviously improved the methane yield. The maximum methane yield was obtained at the oxygen loads of 5ml/g VSsubstrate, which was 16.24% higher than that of untreated group. The modified first order equation analysis showed the TMP process not only accelerated the hydrolysis rates but also reduced the lag-phase time of AD process. The structural characterization analysis showed cellulosic structures of corn straw were partly disrupted during TMP process. The crystallinity indexes were also decreased. In addition, large or destroyed pores and substantial structural disruption were observed after pretreatment. The results showed that TMP is an efficient pretreatment method for the AD of corn straw. PMID- 25459824 TI - Unraveling the effects of laccase treatment on enzymatic hydrolysis of steam exploded wheat straw. AB - Laccase enzymes are promising detoxifying agents during lignocellulosic bioethanol production from wheat straw. However, they affect the enzymatic hydrolysis of this material by lowering the glucose recovery yields. This work aimed at explaining the negative effects of laccase on enzymatic hydrolysis. Relative glucose recovery in presence of laccase (10IU/g substrate) with model cellulosic substrate (Sigmacell) at 10% (w/v) was almost 10% points lower (P<0.01) than in the absence of laccase. This fact could be due to an increase in the competition of cellulose binding sites between the enzymes and a slight inhibition of beta-glucosidase activity. However, enzymatic hydrolysis and infrared spectra of laccase-treated and untreated wheat straw filtered pretreated residue (WS-FPR), revealed that a grafting process of phenoxy radicals onto the lignin fiber could be the cause of diminished accessibility of cellulases to cellulose in pretreated wheat straw. PMID- 25459825 TI - Effect of trace hydrazine addition on the functional bacterial community of a sequencing batch reactor performing completely autotrophic nitrogen removal over nitrite. AB - A sequencing batch reactor (SBR) was conducted to perform completely autotrophic nitrogen removal over nitrite (CANON). The effect of long-term trace N2H4 addition on ammonium oxidizing bacteria (AOB) and anaerobic AOB (AnAOB) in the CANON system was investigated. AOB and AnAOB primarily related to Nitrosococcus, Nitrosomonas and Candidatus scalindua, respectively. Before and after trace N2H4 addition, the estimates of AOB population decreased from 1.03*10(7) to 6.25*10(4)copies/g (dry sludge), but that of AnAOB increased from 3.14*10(9) to 5.86*10(10)copies/g (dry sludge). Despite there was a partially negative impact on AOB growth, the trace N2H4 addition exerted a stronger inhibition on nitrite oxidizing bacteria (NOB) and promoted AnAOB growth, which improved the nitrogen removal of the CANON system. Sludge granules enriched under long-term trace N2H4 addition were spherical and ellipsoidal, and the aerobic AOB were mainly located on the outer layers while AnAOB occupied most of the interior parts. PMID- 25459826 TI - Control of nitrogen behaviour by phosphate concentration during microalgal bacterial cultivation using digestate. AB - The cultivation of microalgae with digestate supernatant is a promising process for the recovery of mineralized nutrients (P, N) from anaerobic digestion. Nevertheless, the variability of phosphorus concentration in the influent could limit this process. The impact of initial N:P ratios between 3 and 76gNgP(-1) was studied and proved no growth limitation over 14-day batch experiments even when P was depleted. Nitrogen assimilation was not affected by phosphorus concentrations and reached 10.1mgNL(-1)d(-1) whereas phosphorus removal ranged from 0.6 to 2.0mgPL(-1)d(-1). The biomass N:P ratio was found to be a function of the influent N:P ratio. Phosphorus storage by microalgae was thus confirmed. Nitrification was found to be highly dependent on the initial phosphorus concentration. The evolution of microalgae communities was also monitored and revealed the advantage of Scenedesmus over Chlorella when the media was phosphorus-depleted. PMID- 25459827 TI - Effect of saponins on n-hexane removal in biotrickling filters. AB - Saponins was applied to enhance the removal of n-hexane in a biotrickling filter (BTF) in this study. Comparison experiments were carried out to examine the effect of saponins on n-hexane removal in two BTFs at various saponins concentrations, n-hexane loading rates (LRs) and gas empty bed contact times (EBCTs). Results show that the optimum concentration of saponins in nutrient feed was 50.0mgL(-1). When organic LR of n-hexane increased from 47.8 to 120.0gm(-3)h( 1), the removal efficiency (RE) for BTF1 (with saponins) and BTF2 (without saponins) decreased from 91.3% to 83.3% and from 62.8% to 56.8%, respectively. As gas EBCT decreased from 30.0 to 7.5s, the RE declined from 88.4% to 64.5% for BTF1 and from 61.4% to 38.3% for BTF2. Saponins could also decrease the biomass accumulation rate within the medium bed. These results could be referred in the design and operation of BTFs for hydrophobic VOC removal. PMID- 25459828 TI - Enhanced removal of nitrate using starch/PCL blends as solid carbon source in a constructed wetland. AB - Cornstarch/polycaprolactone (SPCL) blends were prepared and used as external carbon source for biological denitrification in a constructed wetland. The denitrification performances, components of dissolved organic matter (DOM) and microbial diversity were investigated. The results showed that nitrate was removed mainly in the layer filled with SPCL, and the average denitrification rate was 0.069kg/m(3)d (nitrate removal efficiency was 98.23%). The major component of DOM was polysaccharides which mainly consisted of reducing sugar. Besides, the concentrations of polysaccharides and reducing sugar decreased along the height of the constructed wetland. Therefore, the dissolved organic carbon (DOC) of effluent decreased to 6.54mg/L. Denitrifying bacteria Bacillus (24.25%) and Thauera (9.36%) were the most abundant genera in the biofilm attached on the surface of SPCL. PMID- 25459829 TI - Thermal analysis and 454 pyrosequencing to evaluate the performance and mechanisms for deep stabilization and reduction of high-solid anaerobically digested sludge using biodrying process. AB - Biodrying was firstly used for post-treatment of anaerobically digested sludge (ADS) with wheat residues (WR) as bulking agents to improve its quality and reduce its amount. After 18days of biodrying, water was removed at a rate of 664.4gkg(-1) initial water at the typical ratio of ADS/WR. A separate aerobic incubation test showed that 8.11-14.84% of volatile solid (VS) was degraded in the ADS. The degradation of C- and H-containing materials (e.g., carboxylic acid) accounted for oxygen consumption and VS loss. The WR also showed strong biodegradability, and contributed approximately 86.01% of biogenerated heat during the process. Thermal balance analysis showed that the produced heat was primarily consumed through water evaporation and conductive transfer. 454 pyrosequencing implied the obvious succession from the anaerobic to aerobic microorganisms during the process. Some dominant Firmicutes, such as Clostridium and Bacillales, seemed to relate with organic matter degradation of the substrates. PMID- 25459830 TI - Economics evaluation for on-site pyrolysis of kraft lignin to value-added chemicals. AB - This work is part of a series of investigations on pyrolysis of lignin. After obtaining the necessary information regarding the quantity and quality of the obtained products, a first step economics evaluation for converting lignin into chemicals was essential. To accomplish this aim, a pyrolysis plant with a 50t/d capacity was designed, and the total capital investment and operating costs were estimated. Next, the minimal selling price of the obtained dry oil was calculated and the effect of crucial variables on the estimated price was examined. The key result indicates the estimated selling price would not compete with the price of the chemicals that are fossil fuel based, which is primarily due to the high cost of the feedstock. To overcome this challenge, different scenarios for reducing the selling price of the obtained oil, which consequently is helping by taking a place among the fossil fuel based chemicals, were discussed. PMID- 25459831 TI - Integrated campus sewage treatment and biomass production by Scenedesmus quadricauda SDEC-13. AB - The notion of wastewater treatment combined with biomass production is potential and prospective. Campus sewage was utilized twice in procession to cultivate the newly isolated microalgae Scenedesmus quadricauda SDEC-13. Nutrients was efficiently removed with the phosphorus and nitrogen removal efficiency nearly 100% and more than 70% respectively in twice use of campus sewage. Ammonium was consumed rapidly within five days in 1st use. There was no significant difference in the lipid and protein content but distinct difference in their respective productivity which is ascribed to the lower biomass productivity caused by limited nutrients in 2nd use. The diverse nutrient concentration in twice use of campus sewage and BG-11 had effects on the composition of fatty acids and amino acids. SDEC-13 performed better biodiesel quality compared with BG-11 medium and produced high quality protein when cultivated in campus sewage. Finally, the campus sewage after twice use reached the corresponding discharge standard. PMID- 25459832 TI - Biochar supported nanoscale zerovalent iron composite used as persulfate activator for removing trichloroethylene. AB - Biochar (BC) supported nanoscale zerovalent iron (nZVI) composite was synthesized and used as an activator for persulfate to enhance the trichloroethylene (TCE) removal in aqueous solutions. The degradation efficiency of TCE (0.15mmolL(-1)) was 99.4% in the presence of nZVI/BC (4.5mmolL(-1), nZVI to BC mass ratio was 1:5) and persulfate (4.5mmolL(-1)) within 5min, which was significantly higher than that (56.6%) in nZVI-persulfate system under the same conditions. Owing to large specific surface area and oxygen-containing functional groups of BC, nZVI/BC enhanced the SO4(-) generation and accelerated TCE degradation. On the basis of the characterization and analysis data, possible activation mechanisms of the Fe(2+)/Fe(3+) (Fe(II)/Fe(III)) redox action and the electron-transfer mediator of the BC oxygen functional groups promoting the generation of SO4(-) in nZVI/BC-persulfate system were clarified. PMID- 25459833 TI - Prediction of product distribution in fine biomass pyrolysis in fluidized beds based on proximate analysis. AB - A predictive model was satisfactorily developed to describe the general trends of product distribution in fluidized beds of lignocellulosic biomass pyrolysis. The model was made of mass balance based on proximate analysis and an empirical relationship with operating parameters including fluidization hydrodynamics. The empirical relationships between product yields and fluidization conditions in fluidized bed pyrolyzers were derived from the data of this study and literature. The gas and char yields showed strong functions of temperature and vapor residence time in the pyrolyzer. The yields showed a good correlation with fluidization variables related with hydrodynamics and bed mixing. The predicted product yields based on the model well accorded well with the experimental data. PMID- 25459834 TI - Effects of composting process on the dissipation of extractable sulfonamides in swine manure. AB - Effects of composting on the fate of sulfonamides (SAs) in the manure-straw mixture were explored through a simulation of aerobic composting process. Additionally, factors of temperature and coexistence of heavy metal Cu that might influence the removal efficiency were particularly investigated. As shown in the results, the extractable SAs dissipated rapidly during the composting process. The coexistence of Cu in the composting process might have delayed the decline of SAs, but the drugs could still be completely removed by the end of the composting. In contrast to the thermophilic aerobic composting, extractable SAs in air-temperature-placed mixture dissipated much slower and 1.12-1.56mg/kg could be detected after 35days of incubation. The results confirmed that temperature could influence the dissipation of SAs, which was identified as a more important factor than Cu-coexistence. Hence, thermophilic aerobic composting is an effective process to eliminate VAs before manure land application. PMID- 25459835 TI - Biohydrogen production from a novel alkalophilic isolate Clostridium sp. IODB-O3. AB - Hydrogen producing bacteria IODB-O3 was isolated from sludge and identified as Clostridium sp. by 16S rDNA gene analysis. In this study, biohydrogen production process was developed using low-cost agro-waste. Maximum H2 was produced at 37 degrees C and pH 8.5. Maximum H2 yield was obtained 2.54+/-0.2mol-H2/mol-reducing sugar from wheat straw pre-hydrolysate (WSPH) and 2.61+/-0.1mol-H2/mol-reducing sugar from pre-treated wheat straw enzymatic-hydrolysate (WSEH). The cumulative H2 production (ml/L), 3680+/-105 and 3270+/-100, H2 production rate (ml/L/h), 153+/-5 and 136+/-5, and specific H2 production (ml/g/h), 511+/-5 and 681+/-10 with WSPH and WSEH were obtained, respectively. Biomass pre-treatment via steam explosion generates ample amount of WSPH which remains unutilized for bioethanol production due to non-availability of efficient C5-fermenting microorganisms. This study shows that Clostridium sp. IODB-O3 is capable of utilizing WSPH efficiently for biohydrogen production. This would lead to reduced economic constrain on the overall cellulosic ethanol process and also establish a sustainable biohydrogen production process. PMID- 25459836 TI - Improvement of anaerobic digestion of sewage sludge in a wastewater treatment plant by means of mechanical and thermal pre-treatments: Performance, energy and economical assessment. AB - Performances of mechanical and low-temperature (<100 degrees C) thermal pre treatments were investigated to improve the present efficiency of anaerobic digestion (AD) carried out on waste activated sludge (WAS) in the largest Italian wastewater treatment plant (2,300,000p.e.). Thermal pre-treatments returned disintegration rates of one order of magnitude higher than mechanical ones (about 25% vs. 1.5%). The methane specific production increased by 21% and 31%, with respect to untreated samples, for treatment conditions of respectively 70 and 90 degrees C, 3h. Thermal pre-treatments also decreased WAS viscosity. Preliminary energy and economic assessments demonstrated that a WAS final total solid content of 5% was enough to avoid the employment of auxiliary methane for the pre treatment at 90 degrees C and the subsequent AD process, provided that all the heat generated was transferred to WAS through heat exchangers. Moreover, the total revenues from sale of the electricity produced from biogas increased by 10% with respect to the present scenario. PMID- 25459837 TI - Graphene oxide as electron shuttle for increased redox conversion of contaminants under methanogenic and sulfate-reducing conditions. AB - Graphene oxide (GO) is reported for the first time as electron shuttle to increase the redox conversion of the azo compound, reactive red 2 (RR2, 0.5mM), and the nitroaromatic, 3-chloronitrobenzene (3CNB, 0.5mM). GO (5mgL(-1)) increased 10-fold and 7.6-fold the reduction rate of RR2 and 3CNB, respectively, in abiotic incubations with sulfide (2.6mM) as electron donor. GO also increased by 2-fold and 3.6-fold, the microbial reduction rate of RR2 by anaerobic sludge under methanogenic and sulfate-reducing conditions, respectively. Deep characterization of GO showed that it has a proper size distribution (predominantly between 450 and 700nm) and redox potential (+50.8mV) to promote the reduction of RR2 and 3CNB. Further analysis revealed that biogenic sulfide plays a major role on the GO-mediated reduction of RR2. GO is proposed as an electron shuttle to accelerate the redox conversion of recalcitrant pollutants, such as nitro-benzenes and azo dyes. PMID- 25459838 TI - Enhancement of simultaneous gold and copper extraction from computer printed circuit boards using Bacillus megaterium. AB - In this research simultaneous gold and copper recovery from computer printed circuit boards (CPCBs) was evaluated using central composite design of response surface methodology (CCD-RSM). To maximize simultaneous metals' extraction from CPCB waste four factors which affected bioleaching were selected to be optimized. A pure culture of Bacillus megaterium, a cyanogenic bacterium, was used to produce cyanide as a leaching agent. Initial pH 10, pulp density 2g/l, particle mesh#100 and glycine concentration 0.5g/l were obtained as optimal conditions. Gold and copper were extracted simultaneously at about 36.81 and 13.26% under optimum conditions, respectively. To decrease the copper effect as an interference agent in the leaching solution, a pretreatment strategy was examined. For this purpose firstly using Acidithiobacillus ferrooxidans copper in the CPCB powder was totally extracted, then the residual sediment was subjected to further experiments for gold recovery by B. megaterium. Using pretreated sample under optimal conditions 63.8% gold was extracted. PMID- 25459839 TI - Effect of intracellular P content on phosphate removal in Scenedesmus sp. Experimental study and kinetic expression. AB - The present work determines the effect of phosphorus content on phosphate uptake rate in a mixed culture of Chlorophyceae in which the genus Scenedesmus dominates. Phosphate uptake rate was determined in eighteen laboratory batch experiments, with samples taken from a progressively more P-starved culture in which a minimum P content of 0.11% (w/w) was achieved. The results obtained showed that the higher the internal biomass P content, the lower the phosphate removal rate. The highest specific phosphate removal rate was 6.5mgPO4-PgTSS( 1)h(-1). Microalgae with a P content around 1% (w/w) attained 10% of this highest removal rate, whereas those with a P content of 0.6% (w/w) presented 50% of the maximum removal rate. Different kinetic expressions were used to reproduce the experimental data. Best simulation results for the phosphate uptake process were obtained combining Steele equation and Hill function to represent the effect of light and intracellular phosphorus content, respectively. PMID- 25459840 TI - Comparative study on pyrolysis of lignocellulosic and algal biomass using a thermogravimetric and a fixed-bed reactor. AB - Pyrolysis characteristics of four algal and lignocellulosic biomass samples were studied by using a thermogravimetric analyzer (TGA) and a fixed-bed reactor. The effects of pyrolysis temperature and biomass type on the yield and composition of pyrolysis products were investigated. The average activation energy for pyrolysis of biomass samples by FWO and KAS methods in this study were in the range of 211.09-291.19kJ/mol. CO2 was the main gas component in the early stage of pyrolysis, whereas H2 and CH4 concentrations increased with increasing pyrolysis temperature. Bio-oil from Chlorellavulgaris showed higher content of nitrogen containing compounds compared to lignocellulosic biomass. The concentration of aromatic organic compounds such as phenol and its derivatives were increased with increasing pyrolysis temperature up to 700 degrees C. FTIR analysis results showed that with increasing pyrolysis temperature, the concentration of OH, CH, CO, OCH3, and CO functional groups in char decreased sharply. PMID- 25459841 TI - Use of fermentative metabolites for heterotrophic microalgae growth: Yields and kinetics. AB - The growth of two lipid-producing Chlorella species on fermentative end-products acetate, butyrate and lactate, was investigated using a kinetic modeling approach. Chlorella sorokiniana and Auxenochlorella protothecoides were grown on synthetic media with various (acetate:butyrate:lactate) ratios. Both species assimilated efficiently acetate and butyrate with yields between 0.4 and 0.5g carbon of biomass/g carbon of substrate, but did not use lactate. The highest growth rate on acetate, 2.23d(-1), was observed for C. sorokiniana, and on butyrate, 0.22d(-1), for A. protothecoides. Butyrate removal started after complete acetate exhaustion (diauxic effect). However, butyrate consumption may be favored by the increase of biomass concentration induced by the initial use of acetate. A model combining Monod and Haldane functions was then built and fitted the experimental data well for both species. Butyrate concentration and (acetate:butyrate) ratios were identified as key parameters for heterotrophic growth of microalgae on fermentative metabolites. PMID- 25459842 TI - Pilot scale study on steam explosion and mass balance for higher sugar recovery from rice straw. AB - Pretreatment of rice straw on pilot scale steam explosion has been attempted to achieve maximum sugar recovery. Three different reaction media viz. water, sulfuric acid and phosphoric acid (0.5%, w/w) were explored for pretreatment by varying operating temperature (160, 180 and 200 degrees C) and reaction time (5 and 10min). Using water and 0.5% SA showed almost similar sugar recovery (~87%) at 200 and 180 degrees C respectively. However, detailed studies showed that the former caused higher production of oligomeric sugars (13.56g/L) than the later (3.34g/L). Monomeric sugar, followed the reverse trend (7.83 and 11.62g/L respectively). Higher oligomers have a pronounced effect in reducing enzymatic sugar yield as observed in case of water. Mass balance studies for water and SA assisted SE gave total saccharification yield as 81.8% and 77.1% respectively. However, techno-economical viability will have a trade-off between these advantages and disadvantages offered by the pretreatment medium. PMID- 25459843 TI - Bioprocess development for the production of sonorensin by Bacillus sonorensis MT93 and its application as a food preservative. AB - Media composition and environmental conditions were optimized using statistical tools, Plackett Burman design and response surface methodology, to maximize the yield of a bacteriocin, named as sonorensin, from a new marine isolate Bacillus sonorensis MT93 showing broad spectrum of antimicrobial activity. Under optimized conditions, MT93 produced 15-fold higher yield of sonorensin compared to that under initial fermentation conditions. As oxygen supply is a critical parameter controlling growth and product formation in aerobic bioprocesses and used as a parameter for bioprocess scale up, the effects of oxygen transfer, in terms of volumetric oxygen transfer coefficient (kLa), on production of sonorensin was investigated using optimized medium composition in a bioreactor. Studies on effectiveness of sonorensin against Staphylococcus aureus and Listeria monocytogenes in fruit juice and as a preservative in pasteurized milk demonstrated its potential as a biopreservative in fruit products and shelf life extender of the pasteurized milk. PMID- 25459844 TI - Volatile fatty acids productions by mesophilic and thermophilic sludge fermentation: Biological responses to fermentation temperature. AB - The volatile fatty acids (VFAs) productions, as well as hydrolases activities, microbial communities, and homoacetogens, of mesophilic and thermophilic sludge anaerobic fermentation were investigated to reveal the microbial responses to different fermentation temperatures. Thermophilic fermentation led to 10-fold more accumulation of VFAs compared to mesophilic fermentation. alpha-glucosidase and protease had much higher activities in thermophilic reactor, especially protease. Illumina sequencing manifested that raising fermentation temperature increased the abundances of Clostridiaceae, Microthrixaceae and Thermotogaceae, which could facilitate either hydrolysis or acidification. Real-time PCR analysis demonstrated that under thermophilic condition the relative abundance of homoacetogens increased in batch tests and reached higher level at stable fermentation, whereas under mesophilic condition it only increased slightly in batch tests. Therefore, higher fermentation temperature increased the activities of key hydrolases, raised the proportions of bacteria involved in hydrolysis and acidification, and promoted the relative abundance of homoacetogens, which all resulted in higher VFAs production. PMID- 25459845 TI - Effects of carbon dioxide on cell growth and propionic acid production from glycerol and glucose by Propionibacterium acidipropionici. AB - The effects of CO2 on propionic acid production and cell growth in glycerol or glucose fermentation were investigated in this study. In glycerol fermentation, the volumetric productivity of propionic acid with CO2 supplementation reached 2.94g/L/day, compared to 1.56g/L/day without CO2. The cell growth using glycerol was also significantly enhanced with CO2. In addition, the yield and productivity of succinate, the main intermediate in Wood-Werkman cycle, increased 81% and 280%, respectively; consistent with the increased activities of pyruvate carboxylase and propionyl CoA transferase, two key enzymes in the Wood-Werkman cycle. However, in glucose fermentation CO2 had minimal effect on propionic acid production and cell growth. The carbon flux distributions using glycerol or glucose were also analyzed using a stoichiometric metabolic model. The calculated maintenance coefficient (mATP) increased 100%, which may explain the increase in the productivity of propionic acid in glycerol fermentation with CO2 supplement. PMID- 25459846 TI - Biochemical methane potential prediction of plant biomasses: Comparing chemical composition versus near infrared methods and linear versus non-linear models. AB - The reliability of different models to predict the biochemical methane potential (BMP) of various plant biomasses using a multispecies dataset was compared. The most reliable prediction models of the BMP were those based on the near infrared (NIR) spectrum compared to those based on the chemical composition. The NIR predictions of local (specific regression and non-linear) models were able to estimate quantitatively, rapidly, cheaply and easily the BMP. Such a model could be further used for biomethanation plant management and optimization. The predictions of non-linear models were more reliable compared to those of linear models. The presentation form (green-dried, silage-dried and silage-wet form) of biomasses to the NIR spectrometer did not influence the performances of the NIR prediction models. The accuracy of the BMP method should be improved to enhance further the BMP prediction models. PMID- 25459847 TI - Removal of arsenic by magnetic biochar prepared from pinewood and natural hematite. AB - There is a need for the development of low-cost adsorbents to removal arsenic (As) from aqueous solutions. In this work, a magnetic biochar was synthesized by pyrolyzing a mixture of naturally-occurring hematite mineral and pinewood biomass. The resulting biochar composite was characterized with X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and energy-dispersive X-ray analysis (EDS). In comparison to the unmodified biochar, the hematite modified biochar not only had stronger magnetic property but also showed much greater ability to remove As from aqueous solution, likely because the gamma-Fe2O3 particles on the carbon surface served as sorption sites through electrostatic interactions. Because the magnetized biochar can be easily isolated and removed with external magnets, it can be used in various As contaminant removal applications. PMID- 25459848 TI - Accelerating the sludge disintegration potential of a novel bacterial strain Planococcus jake 01 by CaCl2 induced deflocculation. AB - The present study investigates the impacts of phase separated disintegration through CaCl2 (calcium chloride) mediated biosurfactant producing bacterial pretreatment. In the initial phase of the study, the flocs were disintegrated (deflocculation) with 0.06g/gSS of CaCl2. In the subsequent phase, the sludge biomass was disintegrated (cell disintegration) through potent biosurfactant producing new novel bacteria, Planococcus jake 01. The pretreatment showed that suspended solids reduction and chemical oxygen demand solubilization for deflocculated - bacterially pretreated sludge was found to be 17.14% and 14.14% which were comparatively higher than flocculated sludge (treated with bacteria alone). The biogas yield potential of deflocculated - bacterially pretreated, flocculated, and control sludges were observed to be 0.322(L/gVS), 0.225(L/gVS) and 0.145(L/gVS) respectively. To our knowledge, this is the first study to present the thorough knowledge of biogas production potential through a novel phase separated biosurfactant bacterial pretreatment. PMID- 25459849 TI - Dynamics of bacterial microbiota during lignocellulosic waste composting: Studies upon its structure, functionality and biodiversity. AB - An intensive isolation program carried out in three replicated composting piles allowed the identification of the resident and transient components of the composting microbiome. More than 4000 bacterial strains were isolated, enzymatically characterized and identified by partial sequencing of their 16S rRNA gene. While microorganisms isolated under mesophilic conditions were prominent throughout the process, thermophilic stages gathered the highest total counts and spore-forming bacteria prevailed at the bio-oxidative phase of composting. Enzymatic capabilities related to the degradation of polymeric materials were exhibited by most of the isolates and as a result of these activities, more soluble compounds could be made available to the entire composting microbiota. A high proportion of isolates showed to be thermotolerant as they were detected at mesophilic and thermophilic phases. Isolated strains belonged to 187 bacterial species. Biodiversity was greater at the central stages of composting and mesophilic, thermophilic and cooling phases shared 50% of species. PMID- 25459850 TI - Assessment of bioethanol yield by S. cerevisiae grown on oil palm residues: Monte Carlo simulation and sensitivity analysis. AB - Oil palm trunk (OPT) sap was utilized for growth and bioethanol production by Saccharomycescerevisiae with addition of palm oil mill effluent (POME) as nutrients supplier. Maximum yield (YP/S) was attained at 0.464g bioethanol/g glucose presence in the OPT sap-POME-based media. However, OPT sap and POME are heterogeneous in properties and fermentation performance might change if it is repeated. Contribution of parametric uncertainty analysis on bioethanol fermentation performance was then assessed using Monte Carlo simulation (stochastic variable) to determine probability distributions due to fluctuation and variation of kinetic model parameters. Results showed that based on 100,000 samples tested, the yield (YP/S) ranged 0.423-0.501g/g. Sensitivity analysis was also done to evaluate the impact of each kinetic parameter on the fermentation performance. It is found that bioethanol fermentation highly depend on growth of the tested yeast. PMID- 25459851 TI - Catalytic conversion of cellulosic biomass to ethylene glycol: Effects of inorganic impurities in biomass. AB - The effects of typical inorganic impurities on the catalytic conversion of cellulose to ethylene glycol (EG) were investigated, and the mechanism of catalyst deactivation by certain impurities were clarified. It was found that most impurities did not affect the EG yield, but some non-neutral impurities or Ca and Fe ions greatly decreased the EG yield. Conditional experiments and catalyst characterization showed that some impurities changed the pH of the reaction solution and affected the cellulose hydrolysis rate; Ca and Fe cations reacted with tungstate ions and suppressed the retro-aldol condensation. To obtain a high EG yield, the pH of the reaction solution and the concentration of tungstate ions should be respectively adjusted to 5.0-6.0 and higher than 187ppm. For raw biomass conversion, negative effects were eliminated by suitable pretreatments, and high EG yields comparable to those from pure cellulose were obtained. PMID- 25459852 TI - Comparison of premixing methods for solid-state anaerobic digestion of corn stover. AB - The development of solid-state anaerobic digestion (SS-AD) has prompted studies to resolve practical challenges such as mixing of feedstock and inoculum. This study compared the performance of SS-AD using three premixing methods. Results showed that at feedstock to inoculum (F/I) ratios of 4 and 6, the two-layer partial premixing method obtained the highest methane yield, followed by one layer partial premixing and complete premixing methods. Partial premixing methods also showed wider daily methane yield peaks than the complete premixing method. The volatile fatty acid (VFA) concentration was affected by the premixing method, and was highly correlated to methane yield; while the concentration of remaining holocellulose was correlated to pH and alkalinity. SS-AD digesters failed at an F/I ratio of 8, regardless of the premixing method. Adding extra inoculum to the top of failed digesters resulted in recovery of methane production. PMID- 25459853 TI - Recovery of volatile fatty acids from fermentation of sewage sludge in municipal wastewater treatment plants. AB - This work investigated the pilot scale production of short chain fatty acids (SCFAs) from sewage sludge through alkaline fermentation and the subsequent membrane filtration. Furthermore, the impact of the fermentation liquid on nutrient bioremoval was examined. The addition of wollastonite in the fermenter to buffer the pH affected the composition of the carbon source produced during fermentation, resulting in higher COD/NH4-N and COD/PO4-P ratios in the liquid phase and higher content of propionic acid. The addition of wollastonite decreased the capillary suction time (CST) and the time to filter (TTF), resulting in favorable dewatering characteristics. The sludge dewatering characteristics and the separation process were adversely affected from the use of caustic soda. When wollastonite was added, the permeate flux increased by 32%, compared to the use of caustic soda. When fermentation liquid was added as carbon source for nutrient removal, higher removal rates were obtained compared to the use of acetic acid. PMID- 25459854 TI - Improving the performance of a biofuel cell cathode with laccase-containing culture supernatant from Pycnoporus sanguineus. AB - Laccases are multicopper oxidoreductases that can be used in biofuel cells to improve cathode performance by cathodic oxygen reduction. Here we present a laccase from the ligninolytic white-rot fungus Pycnoporus sanguineus that, in contrast to the Trametes versicolor laccase, can be produced in the absence of inducers in a standard culture medium. After 7days of cultivation the activity of this laccase in culture supernatant reached 2.5U/ml, which is high enough for direct application of the supernatant in biofuel cells. The highest current density of 115.0+/-3.5MUA/cm(2) at 400mV vs. SCE was obtained at pH 5 with a buckypaper cathode with a laccase-containing culture supernatant. The enzyme also showed electrocatalytic activity at pH 6 and 7. These results not only present a new cost-efficient laccase for improving cathode performance, but also show that new laccases with different catalytic properties can be suitable for biofuel cells. PMID- 25459855 TI - Investigation on thermal and trace element characteristics during co-combustion biomass with coal gangue. AB - The thermochemical behaviors during co-combustion of coal gangue (CG), soybean stalk (SS), sawdust (SD) and their blends prepared at different ratios have been determined via thermogravimetric analysis. The simulate experiments in a fixed bed reactor were performed to investigate the partition behaviors of trace elements during co-combustion. The combustion profiles of biomass was more complicated than that of coal gangue. Ignition property and thermal reactivity of coal gangue could be enhanced by the addition of biomass. No interactions were observed between coal gangue and biomass during co-combustion. The volatilization ratios of trace elements decrease with the increasing proportions of biomass in the blends during co-combustion. Based on the results of heating value, activation energy, base/acid ratio and gaseous pollutant emissions, the blending ratio of 20-30% biomass content is regarded as optimum composition for blending and could be applied directly at current combustion application with few modifications. PMID- 25459856 TI - Assessment of the factors contributing to the variations in microcystins biodegradability of the biofilms on a practical biological treatment facility. AB - This study revealed the biotic and abiotic parameters driving the variations in microcystins (MCs) biodegradability of a practical biological treatment facility (BTF). Results showed that similar trends of seasonal variation were seen for microcystin-LR (MCLR) biodegradability of biofilms on the BTF and indigenous MCLR degrader population, where both peaks co-occurred in October, following the peaks of natural MCLR concentration and water temperature observed in August. The lag period might be required for accumulation of MCLR-degraders and MCLR-degrading enzyme activity. The MCLR-degrader population was correlated to temperature, MCLR and chlorophyll-a concentration in water where the biofilms submerged, indicating that these abiotic and biotic parameters exerted direct and/or indirect influences on seasonal variation in MCLR-biodegradability. In comparison, no effect of other co-existing MCs on biodegradation of one MC was observed. However, proliferation of MC-degraders along biodegradation processes positively responded to total amount of MCs, suggesting that multiple MCs contributed additively to MC-degrader proliferation. PMID- 25459857 TI - Assessment of integrated process based on hydrothermal and alkaline treatments for enzymatic saccharification of sweet sorghum stems. AB - In this study, sweet sorghum stem was subjected to hydrothermal pretreatment (HTP) and alkaline post-treatment to enhance its saccharification ratio by reducing its recalcitrance. The results showed that the HTP (110-210 degrees C, 0.5-2.0h) significantly degraded hemicelluloses, and the pretreatment at the temperature higher than 190 degrees C led to the partial degradation of the cellulose. As compared to the sole HTP, the integrated process removed most of lignin and hemicelluloses, which incurred a higher cellulose saccharification ratio. Under an optimum condition evaluated (HTP at 170 degrees C for 0.5h and subsequent 2% NaOH treatment), 77.5% saccharification ratio was achieved, which was 1.8, 2.0 and 5.5 times as compared to the only HTP pretreated substrates, alkaline treated substrates alone and the raw material without pretreatment, respectively. Clearly, the integrated process can be considered as a promising approach to achieve an efficient conversion of lignocellulose to fermentable glucose. PMID- 25459858 TI - Optimization of biogas production from Sargassum sp. using a design of experiments to assess the co-digestion with glycerol and waste frying oil. AB - A design of experiments was adopted to assess the optimal conditions for methane production from the macroalgae Sargassum sp. co-digested with glycerol (Gly) and waste frying oil (WFO). Three variables were tested: % total solids of algae (%TSSargassumsp.), co-substrate concentration (gGly/WFOL(-1)), and co-substrate type (Gly or WFO). The biochemical methane potential (BMP) of Sargassum sp. was 181+/-1L CH4kg(-1) COD. The co-digestion with Gly and WFO increased the BMP by 56% and 46%, respectively. The methane production rate (k), showed similar behaviour as the BMP, increasing 38% and 19% with Gly and WFO, respectively. The higher BMP (283+/-18L CH4kg(-1) COD) and k (65.9+/-2.1L CH4kg(-1) CODd(-1)) was obtained in the assay with 0.5% TS and 3.0gGlyL(-1). Co-digestion with glycerol or WFO is a promising process to enhance the BMP from the macroalgae Sargassum sp. PMID- 25459859 TI - Contribution of precipitates formed in fermentation liquor to the enhanced biogasification of ammonia-rich swine manure by wheat-rice-stone addition. AB - This study investigated the effect of wheat-rice-stone (WRS) addition on mesophilic anaerobic fermentation for methane production from swine manure under high ammonia nitrogen level (5145mg-N/L) in addition to exploring its possible mechanisms involved. Results show that addition of WRS could not only effectively increase methane production by 72% from 82.8 (control) to 142.7ml/g-VS but also remarkably shorten the effective biogasification period from 40 (control) to 20days. In addition, WRS addition could promote the degradation of n-HBu and slow down the accumulation of other volatile fatty acids (VFAs) species, achieving much faster VFAs utilization rate and better pH maintaining capability. More specifically, the existing and released ions especially Ca(2+), Mg(2+), and Fe(3+/2+) were supposed to form precipitates (like struvite and Fe-precipitates) with NH4(+) and PO4(3-) rich in the fermentation liquor, probably contributing a lot to the decreased ammonia concentration and enhanced biogasification under WRS addition. PMID- 25459860 TI - Photocatalytic degradation of lignin on synthesized Ag-AgCl/ZnO nanorods under solar light and preliminary trials for methane fermentation. AB - New photocatalysts, Ag-AgCl/ZnO nanorods, were successfully synthesized in this study by using microwave assisted chemical precipitation and deposition precipitation-photoreduction methods. The optimal preparation condition was determined as pH 9 in distilled water and 40min for UV light photoreduction of Ag (i.e. Ag40-AgCl/ZnO) by degradation of methyl orange. This work investigated the feasibility of using Ag40-AgCl/ZnO to degrade lignin under natural solar light and then subsequent methane production with influencing factors like solution pH, dosage of catalyst and initial lignin concentration being considered. OH radicals were found to play the most important role in the photocatalytic process, and the new prepared catalyst possessed stable photocatalytic activity after 7 cycles' utilization. During the subsequent biogasification, the degraded lignin obtained from 120min photocatalysis yielded 184ml methane and 325ml biogas for per gram of removed total organic carbon, increased by 10.9% and 23.1%, respectively compared to the control. PMID- 25459861 TI - Uncertainty analysis and global sensitivity analysis of techno-economic assessments for biodiesel production. AB - There are various uncertain parameters in the techno-economic assessments (TEAs) of biodiesel production, including capital cost, interest rate, feedstock price, maintenance rate, biodiesel conversion efficiency, glycerol price and operating cost. However, fewer studies focus on the influence of these parameters on TEAs. This paper investigated the effects of these parameters on the life cycle cost (LCC) and the unit cost (UC) in the TEAs of biodiesel production. The results show that LCC and UC exhibit variations when involving uncertain parameters. Based on the uncertainty analysis, three global sensitivity analysis (GSA) methods are utilized to quantify the contribution of an individual uncertain parameter to LCC and UC. The GSA results reveal that the feedstock price and the interest rate produce considerable effects on the TEAs. These results can provide a useful guide for entrepreneurs when they plan plants. PMID- 25459863 TI - Technoeconomic analysis of large scale production of pre-emergent Pseudomonas fluorescens microbial bioherbicide in Canada. AB - The study presents an ex ante technoeconomic analysis of commercial production of Pseudomonas fluorescens BRG100 bioherbicide in Canada. An engineering economic model is designed in SuperPro Designer(r) to investigate capital investment scaling and profitability. Total capital investment for a stand-alone BRG100 fermentation plant at baseline capacity (two 33,000L fermenters; 3602tonnesannum( 1)) is $17.55million. Total annual operating cost is $14.76million. Raw materials account for 50% of operating cost. The fermentation plant is profitable over wide operating scale, evaluated over a range of BRG100 prices and costs of capital. Smaller plants require higher NPV breakeven prices. However, larger plants are more sensitive to changes in the cost of capital. Unit production costs decrease as plant capacity increases, indicating scale economies. A plant operating for less than one year approaches positive NPV for periods as low as 2months. These findings can support bioherbicide R&D investment and commercialization strategies. PMID- 25459862 TI - Freezing/thawing pretreatment coupled with biological process of thermophilic Geobacillus sp. G1: Acceleration on waste activated sludge hydrolysis and acidification. AB - A novel pretreatment method combining freezing/thawing with Geobacillus sp. G1 was employed to pretreat waste activated sludge (WAS) for enhancing the WAS hydrolysis and subsequent short-chain fatty acids (SCFAs) production. Results showed that freezing/thawing combined with Geobacillus sp. G1 pretreatment achieved the maximal concentrations of soluble protein from 40+/-6mg COD/L (non pretreated) to 1226+/-24mg COD/L (pretreated), and accumulated SCFAs concentration increased from 248+/-81mg COD/L to 3032+/-53mg COD/L. Excitation emission matrix (EEM) fluorescence spectroscopy revealed the highest fluorescence intensity (FI) of protein-like substances, which was the dominant fluorescent organic matters, indicating the synergistic effect of freezing/thawing and Geobacillus sp. G1 pretreatment on organics hydrolysis. High-throughput pyrosequencing analysis investigated that the abundance of bacteria responsible for WAS hydrolysis (such as Clostridium and Caloramator) and SCFAs production (such as Parabacteroides and Bacterodies) was greatly enhanced due to the novel pretreatment method used. PMID- 25459864 TI - Comparison of aqueous ammonia and dilute acid pretreatment of bamboo fractions: Structure properties and enzymatic hydrolysis. AB - The effect of two pretreatments methods, aqueous ammonia (SAA) and dilute acid (DA), on the chemical compositions, cellulose crystallinity, morphologic change, and enzymatic hydrolysis of bamboo fractions (bamboo yellow, timber, green, and knot) was compared. Bamboo fractions with SAA pretreatment had better hydrolysability than those with DA pretreatment. High crystallinity index resulted in low hydrolysis yield in the conversion of SAA pretreated bamboo fractions, not DA pretreated fractions. The increase of cellulase loading had modestly positive effect in the hydrolysis of both SAA and DA pretreated bamboo fractions, while supplement of xylanase significantly increased the hydrolysis of the pretreated bamboo fractions, especially after SAA pretreatment. The results indicated that SAA pretreatment was more effective than DA pretreatment in conversion of bamboo fractions, and supplementation of xylanase was necessary in effective conversion of the SAA pretreated fractions into fermentable sugars. PMID- 25459865 TI - Lipid production combined with biosorption and bioaccumulation of cadmium, copper, manganese and zinc by oleaginous microalgae Chlorella minutissima UTEX2341. AB - Algae lipid production combined with heavy metal removal is a cost-effective and environment-friendly method for algae biofuel production and hazardous waste treatment. Chlorella minutissima UTEX 2341 had strong resistance to cadmium, copper, manganese and zinc ions under heterotrophic culture condition and could efficiently remove them through intracellular accumulation and extracellular immobilization. Meanwhile, lipid accumulation was not inhibited by heavy metals. Instead, the algae lipid content significantly increased by 21.07% and 93.90%, respectively with the addition of cadmium and copper. Furthermore, the heavy metal residue in lipid was within MUg range and satisfied the commercial standard. This artificial wastewater-algae biofuel-heavy-metal integrated utilization technology offered a new alternative solution to the problems of energy shortage and environmental pollution. PMID- 25459866 TI - Study on anaerobic ammonium oxidation process coupled with denitrification microbial fuel cells (MFCs) and its microbial community analysis. AB - Denitrifying MFC was successfully coupled with anaerobic ammonium oxidation process in this study. With the help of cathode electrons, the stoichiometry relationship Delta(-)NH3-N:Delta(-)NO2(-)-N:Delta(+)NO3(-)-N was approximate 1:1.37:0.03 during the stable operation, which demonstrated its further nitrite and nitrate reduction. According to microbial community analysis, Candidatus Brocadia sinica was the main anammox community, and Rhodopseudomonas palustris with electrochemical driven denitrifying ability, especially enriched in biofilm. Higher abundance of nirK genes in biofilm (compare to the control) and invariable amx genes in suspended sludge were responsible for its better nitrogen removal. The sludge and biofilm performed their own duties on anammox and denitrification, respectively, according to genes quantification. Under the totally autotrophic system, electron donors were "concentrated supplied" and easy to control, which avoided the suppression of anammox growth, making this autotrophic coupling process appears to be more promising. PMID- 25459867 TI - Anaerobic mesophilic co-digestion of ensiled sorghum, cheese whey and liquid cow manure in a two-stage CSTR system: Effect of hydraulic retention time. AB - The aim of this study was to investigate the effect of hydraulic retention time (HRT) on hydrogen and methane production using a two-stage anaerobic process. Two continuously stirred tank reactors (CSTRs) were used under mesophilic conditions (37 degrees C) in order to enhance acidogenesis and methanogenesis. A mixture of pretreated ensiled sorghum, cheese whey and liquid cow manure (55:40:5, v/v/v) was used. The acidogenic reactor was operated at six different HRTs of 5, 3, 2, 1, 0.75 and 0.5d, under controlled pH5.5, whereas the methanogenic reactor was operated at three HRTs of 24, 16 and 12d. The maximum H2 productivity (2.14L/LRd) and maximum H2 yield (0.70mol H2/mol carbohydrates consumed) were observed at 0.5d HRT. On the other hand, the maximum CH4 production rate of 0.90L/LRd was achieved at HRT of 16d, whereas at lower HRT the process appeared to be inhibited and/or overloaded. PMID- 25459868 TI - Aerobic biodegradation of odorous dimethyl disulfide in aqueous medium by isolated Bacillus cereus GIGAN2 and identification of transformation intermediates. AB - A novel, flagellated, rod-shape, Gram-positive facultative aerobe, was isolated and identified as Bacillus cereus GIGAN2. It can effectively remove model odorous organics dimethyl disulfide (DMDS) in aqueous solution under aerobic conditions. Initial concentration, pH value and temperature played important role in DMDS biodegradation, and up to 100% of 10mgL(-1) of DMDS could be removed within 96h under the optimum conditions (30 degrees C, pH 7.0 and 200rpm) with a maximum biodegradation rate constant of 0.0330h(-1) and minimum half-life of 21.0h, respectively. Three main intermediates were identified using gas chromatography mass spectrometry during this biodegradation process. Further, a reaction scheme is also proposed to explain the possible DMDS biodegradation mechanism by GIGAN2 based on the above-identified intermediates. Overall, this is the first report to demonstrate a newly isolated strain using high concentrated DMDS as the sole carbon and energy source with high efficiency. PMID- 25459869 TI - Apparent kinetics of high temperature oxidative decomposition of microalgal biomass. AB - The oxidative thermal characteristics of two microalgae species biomass Nannochloropsis oculta and Chlorella vulgaris have been investigated. The apparent kinetic parameters for the microalgal biomass oxidation process are estimated by fitting the experimental data to the nth order rate model. Also, the iso-conversional methods Kissinger-Akahira-Sunose (KAS) and Flynn-Wall-Ozawa (FWO) were used to evaluate the apparent activation energy. The results indicate that biomass of different microalgae strains exhibit different thermal behavior and characteristics. In addition, growth parameters and medium composition can affect the biomass productivity and composition. This would have significant impact on the thermal decomposition trend of the biomass. The kinetic modeling of the oxidation reaction with direct model fitting method shows good prediction to the experimental data. The apparent activation energies estimated by KAS and FWO methods for N. oculta were 149.2 and 151.8kJ/mol, respectively, while for C. vulgaris were 214.4 and 213.4kJ/mol, respectively. PMID- 25459870 TI - Enhancing microalgal biomass productivity by engineering a microalgal-bacterial community. AB - This study demonstrates that ecologically engineered bacterial consortium could enhance microalgal biomass and lipid productivities through carbon exchange. Phycosphere bacterial diversity analysis in xenic Chlorella vulgaris (XCV) confirmed the presence of growth enhancing and inhibiting microorganisms. Co cultivation of axenic C. vulgaris (ACV) with four different growth enhancing bacteria revealed a symbiotic relationship with each bacterium. An artificial microalgal-bacterial consortium (AMBC) constituting these four bacteria and ACV showed that the bacterial consortium exerted a statistically significant (P<0.05) growth enhancement on ACV. Moreover, AMBC had superior flocculation efficiency, lipid content and quality. Studies on carbon exchange revealed that bacteria in AMBC might utilize fixed organic carbon released by microalgae, and in return, supply inorganic and low molecular weight (LMW) organic carbon influencing algal growth and metabolism. Such exchanges, although species specific, have enormous significance in carbon cycle and can be exploitated by microalgal biotechnology industry. PMID- 25459871 TI - Production of a lignocellulolytic enzyme system for simultaneous bio delignification and saccharification of corn stover employing co-culture of fungi. AB - Aiming at improving the efficiency of transferring corn stover into sugars, an efficient lignocellulolytic enzyme system was developed and investigated by co cultivation of the Coprinus comatus with Trichoderma reesei in a single bioreactor. The results showed that the lignocellulolytic enzyme activities of the co-culture exceeded that of the monoculture, suggesting synergistic interaction between two fungi. The highest laccase activity from the co-culture was 2.6-fold increase over that of the C. comatus monoculture and reached a peak 3days earlier. The maximum delignification obtained was 66.5% and about 82% of the original polysaccharides were converted into fermentable sugars by simultaneous bio-delignification and saccharification process. Correlation analysis showed that sugar yields were directly proportional to the lignin degradation. Our results suggested that co-fungi cultivation was a valuable technique for corn stover bioconversion, which could produce high efficiency of lignocellulolytic enzyme system as a cheaper alternative to commercial enzymes for industrial utilization. PMID- 25459872 TI - Growth hormone replacement therapy in Costello syndrome. AB - Costello syndrome (CS) is considered an overgrowth disorder given the macrosomia that is present at birth .However, shortly after birth the weight drops dramatically and the patients are usually referred for failure to thrive. Subsequently, affected patients develop the distinctive coarse facial appearance and are at risk for cardiac anomalies and solid tumor malignancies. Various endocrine disorders, although not very often, have been reported in patients with CS, including growth hormone deficiency, hypoglycemia, ACTH deficiency, cryptorchidism and hypothyroidism. We report a case of Costello syndrome with hypothyroidism, cryptorchidism and growth hormone deficiency and we evaluate the long-term safety and efficacy of growth hormone replacement therapy. The index patient is a paradigm of successful and safe treatment with growth hormone for almost 7 years. Since patients with CS are at increased risk for cardiac myopathy and tumor development they deserve close monitoring during treatment. PMID- 25459873 TI - Developmental changes in fact and source recall: contributions from executive function and brain electrical activity. AB - Source memory involves recollecting the contextual details surrounding a memory episode. When source information is bound together, it makes a memory episodic in nature. Unfortunately, very little is known about the factors that contribute to its formation in early development. This study examined the development of source memory in middle childhood. Measures of executive function were examined as potential sources of variation in fact and source recall. Continuous electroencephalogram (EEG) measures were collected during baseline and fact and source retrieval in order to examine memory-related changes in EEG power. Six and 8-year-old children were taught 10 novel facts from two different sources and recall for fact and source information was later tested. Older children were better on fact recall, but both ages were comparable on source recall. However, source recall performance was poor at both ages, suggesting that this ability continues to develop beyond middle childhood. Regression analyses revealed that executive function uniquely predicted variance in source recall performance. Task related increases in theta power were observed at frontal, temporal and parietal electrode sites during fact and source retrieval. This investigation contributes to our understanding of age-related differences in source memory processing in middle childhood. PMID- 25459876 TI - Credibility and reproducibility. PMID- 25459877 TI - Pores of no return. AB - In this issue, Bleicken et al. (2014) use double electron-electron resonance (DEER) spectroscopy to propose a new model for the active form of Bax at membranes that differs significantly from those previously proposed. PMID- 25459875 TI - Frequency of spontaneous BOLD signal shifts during infancy and correlates with cognitive performance. AB - Numerous studies have been conducted to delineate the early development of different functional networks, based on measuring the temporal synchronization of spontaneous blood oxygenation level-dependent (BOLD) signals acquired using resting state functional MRI (rsfMRI). However, little attention has been paid to the change of the frequency properties of these signals during early brain development. Such frequency properties may reflect important physiological changes and potentially have significant cognitive consequences. In this study, leveraging a large (N=86 subjects), longitudinal sample of human infants scanned during the first two years of life, we aimed to specifically delineate the developmental changes of the frequency characteristics of spontaneous BOLD signals. Both whole-brain and network-level examinations were carried out and the frequency-behavior relationship was explored. Our results revealed a clear right ward shift of BOLD signal frequency during the first year of life. Moreover, the power at the peak-frequency for sensorimotor and lateral visual networks correlates with domain-specific Mullen Scales in 1-year-olds, suggesting the behavioral significance of the BOLD signal frequency during infancy. Findings from this study shed light into early functional brain development and provide a new perspective for future searches for functional developmental abnormalities. PMID- 25459878 TI - More division of labor at the eukaryotic replication fork. AB - Our understanding of the dynamics of replication fork-associated protein strand specificity is based largely on genetic or in vitro approaches. Yu et al. (2014) present eSPAN, a ChIP approach that reveals differences between protein abundance on nascent leading and lagging strands. PMID- 25459874 TI - The potential of infant fMRI research and the study of early life stress as a promising exemplar. AB - Functional magnetic resonance imaging (fMRI) research with infants and toddlers has increased rapidly over the past decade, and provided a unique window into early brain development. In the current report, we review the state of the literature, which has established the feasibility and utility of task-based fMRI and resting state functional connectivity MRI (rs-fcMRI) during early periods of brain maturation. These methodologies have been successfully applied beginning in the neonatal period to increase understanding of how the brain both responds to environmental stimuli, and becomes organized into large-scale functional systems that support complex behaviors. We discuss the methodological challenges posed by this promising area of research. We also highlight that despite these challenges, early work indicates a strong potential for these methods to influence multiple research domains. As an example, we focus on the study of early life stress and its influence on brain development and mental health outcomes. We illustrate the promise of these methodologies for building on, and making important contributions to, the existing literature in this field. PMID- 25459879 TI - The two faces of receptor interacting protein kinase-1. AB - Receptor Interacting Protein Kinase-1 (RIPK1), a key player in inflammation and cell death, assumes opposite functions depending on the cellular context and its posttranslational modifications. Genetic evidence supported by biochemical and cellular biology approaches sheds light on the circumstances in which RIPK1 promotes or inhibits these processes. PMID- 25459881 TI - Zero-field nuclear magnetic resonance spectroscopy of viscous liquids. AB - We report zero-field NMR measurements of a viscous organic liquid, ethylene glycol. Zero-field spectra were taken showing resolved scalar spin-spin coupling (J-coupling) for ethylene glycol at different temperatures and water contents. Molecular dynamics strongly affects the resonance linewidth, which closely follows viscosity. Quantum chemical calculations have been used to obtain the relative stability and coupling constants of all ethylene glycol conformers. The results show the potential of zero-field NMR as a probe of molecular structure and dynamics in a wide range of environments, including viscous fluids. PMID- 25459882 TI - Simultaneous Gaussian and exponential inversion for improved analysis of shales by NMR relaxometry. AB - Nuclear magnetic resonance (NMR) relaxometry is commonly used to provide lithology-independent porosity and pore-size estimates for petroleum resource evaluation based on fluid-phase signals. However in shales, substantial hydrogen content is associated with solid and fluid signals and both may be detected. Depending on the motional regime, the signal from the solids may be best described using either exponential or Gaussian decay functions. When the inverse Laplace transform, the standard method for analysis of NMR relaxometry results, is applied to data containing Gaussian decays, this can lead to physically unrealistic responses such as signal or porosity overcall and relaxation times that are too short to be determined using the applied instrument settings. We apply a new simultaneous Gaussian-Exponential (SGE) inversion method to simulated data and measured results obtained on a variety of oil shale samples. The SGE inversion produces more physically realistic results than the inverse Laplace transform and displays more consistent relaxation behavior at high magnetic field strengths. Residuals for the SGE inversion are consistently lower than for the inverse Laplace method and signal overcall at short T2 times is mitigated. Beyond geological samples, the method can also be applied in other fields where the sample relaxation consists of both Gaussian and exponential decays, for example in material, medical and food sciences. PMID- 25459883 TI - Mapping B(1)-induced eddy current effects near metallic structures in MR images: a comparison of simulation and experiment. AB - Magnetic resonance imaging (MRI) in the presence of metallic structures is very common in medical and non-medical fields. Metallic structures cause MRI image distortions by three mechanisms: (1) static field distortion through magnetic susceptibility mismatch, (2) eddy currents induced by switched magnetic field gradients and (3) radio frequency (RF) induced eddy currents. Single point ramped imaging with T1 enhancement (SPRITE) MRI measurements are largely immune to susceptibility and gradient induced eddy current artifacts. As a result, one can isolate the effects of metal objects on the RF field. The RF field affects both the excitation and detection of the magnetic resonance (MR) signal. This is challenging with conventional MRI methods, which cannot readily separate the three effects. RF induced MRI artifacts were investigated experimentally at 2.4 T by analyzing image distortions surrounding two geometrically identical metallic strips of aluminum and lead. The strips were immersed in agar gel doped with contrast agent and imaged employing the conical SPRITE sequence. B1 mapping with pure phase encode SPRITE was employed to measure the B1 field around the strips of metal. The strip geometry was chosen to mimic metal electrodes employed in electrochemistry studies. Simulations are employed to investigate the RF field induced eddy currents in the two metallic strips. The RF simulation results are in good agreement with experimental results. Experimental and simulation results show that the metal has a pronounced effect on the B1 distribution and B1 amplitude in the surrounding space. The electrical conductivity of the metal has a minimal effect. PMID- 25459880 TI - RIP3 induces apoptosis independent of pronecrotic kinase activity. AB - Receptor-interacting protein kinase 3 (RIP3 or RIPK3) has emerged as a central player in necroptosis and a potential target to control inflammatory disease. Here, three selective small-molecule compounds are shown to inhibit RIP3 kinase dependent necroptosis, although their therapeutic value is undermined by a surprising, concentration-dependent induction of apoptosis. These compounds interact with RIP3 to activate caspase 8 (Casp8) via RHIM-driven recruitment of RIP1 (RIPK1) to assemble a Casp8-FADD-cFLIP complex completely independent of pronecrotic kinase activities and MLKL. RIP3 kinase-dead D161N mutant induces spontaneous apoptosis independent of compound, whereas D161G, D143N, and K51A mutants, like wild-type, only trigger apoptosis when compound is present. Accordingly, RIP3-K51A mutant mice (Rip3(K51A/K51A)) are viable and fertile, in stark contrast to the perinatal lethality of Rip3(D161N/D161N) mice. RIP3 therefore holds both necroptosis and apoptosis in balance through a Ripoptosome like platform. This work highlights a common mechanism unveiling RHIM-driven apoptosis by therapeutic or genetic perturbation of RIP3. PMID- 25459884 TI - Type of fatty acids in maternal diets during pregnancy and/or lactation and metabolic consequences of the offspring. AB - During pregnancy and/or lactation, maternal nutrition is related to the adequate development of the fetus, newborn and future adult, likely by modifications in fetal programming and epigenetic regulation. Fetal programming is characterized by adaptive responses to specific environmental conditions during early life stages, which may alter gene expression and permanently affect the structure and function of several organs and tissues, thus influencing the susceptibility to metabolic disorders. Regarding lipid metabolism during the first two trimesters of pregnancy, the maternal body accumulates fat, whereas in late pregnancy, the lipolytic activity in the maternal adipose tissue is increased. However, an excess or deficiency of certain fatty acids may lead to adverse consequences to the fetuses and newborns. Fetal exposure to trans fatty acids appears to promote early deleterious effects in the offspring's health, thereby increasing the individual risk for developing metabolic diseases throughout life. Similarly, the maternal intake of saturated fatty acids seems to trigger alterations in the liver and adipose tissue function associated with insulin resistance and diabetes. The polyunsaturated fatty acids (PUFAs), particularly long-chain PUFAs (long-chain PUFA-arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid), play an important and beneficial physiologic role in the offspring who receive this fatty acid during critical periods of development. Therefore, the maternal nutritional condition and fatty acid intake during pregnancy and/or lactation are critical factors that are strongly associated with normal fetal and postnatal development, which influence the modifications in fetal programming and in the individual risk for developing metabolic diseases throughout life. PMID- 25459885 TI - Activity of the dietary flavonoid, apigenin, against multidrug-resistant tumor cells as determined by pharmacogenomics and molecular docking. AB - Apigenin is a common dietary flavonoid with considerable cytotoxic activity in vitro and in vivo. Despite many mechanistic studies, less is known about resistance factors hampering apigenin's activity. We investigated the ATP-binding cassette (ABC) transporters BCRP/ABCG2, P-glycoprotein/ABCB1 and its close relative ABCB5. Multidrug-resistant cells overexpressing these ABC transporters were not cross-resistant toward apigenin. Moreover, apigenin inhibited not only P glycoprotein but also BCRP by increasing cellular uptake of doxorubicin and synergistic inhibition of cell viability in combination with doxorubicin or docetaxel in multidrug-resistant cells. To perform in silico molecular docking studies, we first generated homology models for human P-glycoprotein and ABCB5 based on the crystal structure of murine P-glycoprotein. Their nucleotide binding domains (NDBs) revealed the highest degrees of sequence homologies (89%-100%), indicating that ATP binding and cleavage is of crucial importance for ABC transporters. Molecular docking of apigenin bound to the NDBs of P-glycoprotein and ABCB5 in molecular docking studies. Hence, apigenin may compete with ATP for NDB-binding leading to energy depletion to fuel the transport of ABC transporter substrates. Furthermore, we performed COMPARE and hierarchical cluster analyses of transcriptome-wide mRNA expression profiles of the National Cancer Institute tumor cell line panel. Microarray-based mRNA expressions of genes of diverse biological functions (signal transduction, transcriptional regulation, ubiquitination, autophagy, metabolic activity, xenobiotic detoxification and microtubule formation) significantly predicted responsiveness of tumor cells to apigenin. In conclusion, apigenin's activity is not hampered by classical mechanisms of multidrug resistance and the inhibition of ABC transporters by apigenin indicates that apigenin may overcome multidrug resistance in otherwise refractory tumors. PMID- 25459886 TI - High-protein diet differently modifies intestinal goblet cell characteristics and mucosal cytokine expression in ileum and colon. AB - We have previously shown that high-protein (HP) diet ingestion causes marked changes in the luminal environment of the colonic epithelium. This study aimed to evaluate the impact of such modifications on small intestinal and colonic mucosa, two segments with different transit time and physiological functions. Rats were fed with either normal protein (NP; 14% protein) or HP (53% protein) isocaloric diet for 2 weeks, and parameters related to intestinal mucous-secreting cells and to several innate/adaptive immune characteristics (myeloperoxidase activity, cytokine and epithelial TLR expression, proportion of immune cells in gut associated lymphoid tissues) were measured in the ileum and colon. In ileum from HP animals, we observed hyperplasia of mucus-producing cells concomitant with an increased expression of Muc2 at both gene and protein levels, reduction of mucosal myeloperoxidase activity, down-regulation of Tlr4 gene expression in enterocytes and down-regulation of mucosal Th cytokines associated with CD4+ lymphocyte reduction in mesenteric lymph nodes. These changes coincided with an increased amount of acetate in the ileal luminal content. In colon, HP diet ingestion resulted in a lower number of goblet cells at the epithelial surface but increased goblet cell number in colonic crypts together with an increased Muc3 and a slight reduction of Il-6 gene expression. Our data suggest that HP diet modifies the goblet cell distribution in colon and, in ileum, increases goblet cell activity and decreases parameters related to basal gut inflammatory status. The impact of HP diet on intestinal mucosa in terms of beneficial or deleterious effects is discussed. PMID- 25459887 TI - Chronic consumption of dietary proanthocyanidins modulates peripheral clocks in healthy and obese rats. AB - Circadian rhythm plays an important role in maintaining homeostasis, and its disruption increases the risk of developing metabolic syndrome. Circadian rhythm is maintained by a central clock in the hypothalamus that is entrained by light, but circadian clocks are also present in peripheral tissues. These peripheral clocks are trained by other cues, such as diet. The aim of this study was to determine whether proanthocyanidins, the most abundant polyphenols in the human diet, modulate the expression of clock and clock-controlled genes in the liver, gut and mesenteric white adipose tissue (mWAT) in healthy and obese rats. Grape seed proanthocyanidin extracts (GSPEs) were administered for 21 days at 5, 25 or 50 mg GSPE/kg body weight in healthy rats and 25 mg GSPE/kg body weight in rats with diet-induced obesity. In healthy animals, GSPE administration led to the overexpression of core clock genes in a positive dose-dependent manner. Moreover, the acetylated BMAL1 protein ratio increased with the same pattern in the liver and mWAT. With regards to clock-controlled genes, Per2 was also overexpressed, whereas Rev-erbalpha and RORalpha were repressed in a negative dose-dependent manner. Diet-induced obesity always resulted in the overexpression of some core clock and clock-related genes, although the particular gene affected was tissue specific. GSPE administration counteracted disturbances in the clock genes in the liver and gut but was less effective in normalizing the clock gene disruption in WAT. In conclusion, proanthocyanidins have the capacity to modulate peripheral molecular clocks in both healthy and obese states. PMID- 25459888 TI - Hippocampal gene expression induced by cold swim stress depends on sex and handling. AB - Stress-related disorders such as PTSD and depression are more prevalent in women than men. One reason for such discordance may be that brain regions involved in stress responses are more sensitive to stress in females. Here, we compared the effects of acute stress on gene transcription in the hippocampus of female and male mice, and also examined the involvement of two key stress-related hormones, corticosterone and corticotropin releasing hormone (Crh). Using quantitative reverse transcription polymerase chain reaction (RT-qPCR), we measured gene expression of Fos, Per1 and Sgk1 45 min after exposure to brief cold swim stress. Stress induced a stronger increase in Fos and Per1 expression in females than males. The handling control procedure increased Fos in both sexes, but occluded the effects of stress in males. Further, handling increased Per1 only in males. Sgk1 was insensitive to handling, and increased in response to stress similarly in males and females. The transcriptional changes observed after swim stress were not mimicked by corticosterone injections, and the stress-induced increase in Fos, Per1 and Sgk1 could neither be prevented by pharmacologically blocking glucocorticoid receptor (GR) nor by blocking Crh receptor 1 (Crhr1) before stress exposure. Finally, we demonstrate that the effects are stressor-specific, as the expression of target genes could not be increased by brief restraint stress in either sex. In summary, we find strong effects of acute swim stress on hippocampal gene expression, complex interactions between handling and sex, and a remarkably unique response pattern for each gene. Overall, females respond to a cold swim challenge with stronger hippocampal gene transcription than males, independent of two classic mediators of the stress response, corticosterone and Crh. These findings may have important implications for understanding the higher vulnerability of women to certain stress-related neuropsychiatric diseases. PMID- 25459889 TI - Effects of early childhood trauma on hypothalamic-pituitary-adrenal (HPA) axis function in patients with Chronic Fatigue Syndrome. AB - BACKGROUND: There is a paucity of studies that have investigated the assumption that early childhood trauma is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction in Chronic Fatigue Syndrome (CFS). The current study is the first to simultaneously investigate relationships among early childhood trauma, cortisol activity, and cortisol stress reactivity to psychosocial stress in a sample of well-screened CFS patients. We also examined whether self-critical perfectionism (SCP) plays a mediating role in the potential relationship between early trauma and neurobiological stress responses. METHODS: A total of 40 female patients diagnosed with CFS were asked to provide morning saliva cortisol samples (after awakening, 30min later, and 1h later) for seven consecutive days as a measure of cortisol activity. In addition, patients were exposed to the Trier Social Stress Test, a well-validated stress test, to investigate the relationship between early childhood trauma and cortisol stress reactivity. Before the start of the study, patients completed the Childhood Trauma Questionnaire-Short form (CTQ-SF) as a measure of early childhood trauma (i.e. sexual, physical and emotional traumatic experiences). SCP was measured with the Depressive Experiences Questionnaire (DEQ). Data were analyzed by calculating several indices of cortisol secretion (i.e. Cortisol Awakening Response and Area Under the Curve). RESULTS: There was no association between early childhood trauma and cortisol as measured over the 7-day period. However, emotional neglect was significantly negatively related to cortisol reactivity in the TSST. SCP did not significantly mediate this association. CONCLUSION: Findings of this study suggest that emotional neglect is associated with blunted HPA axis reactivity, congruent with the assumption that CFS may reflect loss of adaptability of the neuroendocrine stress response system in at least a subgroup of patients. PMID- 25459890 TI - Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans. AB - Allopregnanolone (AP) is an endogenous neurosteroid. It modulates the effect of gamma-amino-butyric acid (GABA) on the GABA type A (GABAA) receptor, which leads to increased receptor activity. Since the GABA-system is mainly inhibitory, increased AP activity leads to modulation of neuronal activity. In vitro studies of GABAA receptor activity and in vivo animal studies of sedation have shown that AP-induced effects can be inhibited by another endogenous steroid, namely isoallopregnanolone (ISO). In this study we investigated if ISO can antagonize AP induced effects in healthy female volunteers, via measurements of saccadic eye velocity (SEV) and self-rated sedation. With a single-blind cross-over design, 12 women were studied on three separate occasions; given AP alone or AP in combination with one of two ISO doses. Congruent with previous reports, AP administration decreased SEV and induced sedation and these effects were diminished by simultaneous ISO administration. Also, the ISO effect modulation was seemingly stronger for SEV than for sedation. These effects were observed already at an ISO dose exposure that was approximately half of that of AP. In conclusion, ISO antagonized AP-induced decrease in SEV and self-reported sedation, probably in a non-competitive manner. PMID- 25459891 TI - Examining the joint contribution of placental NR3C1 and HSD11B2 methylation for infant neurobehavior. AB - Infant neurobehavior, a potential sentinel of future mental and behavioral morbidity characterized in part by reflex symmetry, excitability and habituation to stimuli, is influenced by aspects of the intrauterine environment partially through epigenetic alterations of genes involved in the stress response. DNA methylation of two related cortisol response genes, the glucocorticoid receptor (NR3C1), a nuclear receptor to which cortisol binds, and 11-beta hydroxysteroid dehydrogenase (HSD11B2), the enzyme responsible for conversion of cortisol into inactive cortisone, independently associate with infant neurobehavior. Although these factors are part of a common cortisol regulation pathway, the combined effect of DNA methylation of these factors on infant neurobehavior has not been characterized. Therefore, we conducted an examination of the joint contribution of NR3C1 and HSD11B2 DNA methylation on infant neurobehavior. Among 372 healthy term newborns, we tested the interaction between placental NR3C1 and HSD11B2 DNA methylation in association with neurobehavior as assessed with the validated NICU Network Neurobehavioral Scales. Controlling for confounders, interactions between DNA methylation of these genes were detected for distinct domains of neurobehavior (habituation, excitability, asymmetrical reflexes). Moreover, different patterns of DNA methylation across the cortisol regulation pathway associated with different neurobehavioral phenotypes. Those with low NR3C1 methylation but high HSD11B2 methylation had lower excitability scores; those with high NR3C1 methylation but low HSD11B2 methylation had more asymmetrical reflexes; those with high DNA methylation across the entire pathway had higher habituation scores. These results suggest that epigenetic alterations across the cortisol regulation pathway may contribute to different neurobehavioral phenotypes, likely though varying degrees of glucocorticoid exposure during gestation. While the postnatal environment may continue to affect neurobehavioral risk, this study provides novel insights into the molecular basis for fetal origins of mental conditions. PMID- 25459892 TI - A role for synapsin in FKBP51 modulation of stress responsiveness: Convergent evidence from animal and human studies. AB - Both the molecular co-chaperone FKBP51 and the presynaptic vesicle protein synapsin (alternatively spliced from SYN1-3) are intensively discussed players in the still insufficiently explored pathobiology of psychiatric disorders such as major depression, schizophrenia and posttraumatic stress disorder (PTSD). To address their still unknown interaction, we compared the expression levels of synapsin and five other neurostructural and HPA axis related marker proteins in the prefrontal cortex (PFC) and the hippocampus of restrained-stressed and unstressed Fkbp5 knockout mice and corresponding wild-type littermates. In addition, we compared and correlated the gene expression levels of SYN1, SYN2 and FKBP5 in three different online datasets comprising expression data of human healthy subjects as well as of predominantly medicated patients with different psychiatric disorders. In summary, we found that Fkbp5 deletion, which we previously demonstrated to improve stress-coping behavior in mice, prevents the stress-induced decline in prefrontal cortical (pc), but not in hippocampal synapsin expression. Accordingly, pc, but not hippocampal, synapsin protein levels correlated positively with a more active mouse stress coping behavior. Searching for an underlying mechanism, we found evidence that deletion of Fkbp5 might prevent stress-induced pc synapsin loss, at least in part, through improvement of pc Akt kinase activity. These results, together with our finding that FKBP5 and SYN1 mRNA levels were regulated in opposite directions in the PFC of schizophrenic patients, who are known for exhibiting an altered stress-coping behavior, provide the first evidence of a role for pc synapsin in FKBP51 modulation of stress responsiveness. This role might extend to other tissues, as we found FKBP5 and SYN1 levels to correlate inversely not only in human PFC samples but also in other expression sites. The main limitation of this study is the small number of individuals included in the correlation analyses. Future studies will have to verify the here-postulated role of the FKBP51-Akt kinase synapsin pathway in stress responsiveness. PMID- 25459893 TI - Sex differences in acute hormonal and subjective response to naltrexone: The impact of menstrual cycle phase. AB - Women often exhibit larger hormonal and subjective responses to opioid receptor antagonists than men, but the biological mechanisms mediating this effect remain unclear. Among women, fluctuations in estradiol (E2) and progesterone (P4) across the menstrual cycle (MC) affect the endogenous opioid system. Therefore, the goal of the current study was to compare acute naltrexone response between women in the early follicular phase of the MC (low E2 and P4), women in the luteal phase of the MC (high E2 and P4), and men. Seventy healthy controls (n=46 women) participated in two morning sessions in which they received 50mg naltrexone or placebo in a randomized, counterbalanced order. Women were randomized to complete both sessions in either the early follicular (n=23) or luteal phase of the MC. Serum cortisol, salivary cortisol, prolactin, luteinizing hormone (LH), and subjective response were assessed upon arrival to the laboratory and at regular intervals after pill administration. In luteal and early follicular women but not men, naltrexone (vs. placebo) increased serum cortisol and prolactin levels from baseline; however, the naltrexone-induced increases in these hormones were significantly greater in luteal women than early follicular women. Additionally, only luteal women demonstrated an increase from baseline in salivary cortisol levels and the severity of adverse drug effects in response to naltrexone. In sum, the results indicate that luteal phase women are more sensitive to acute hormonal and subjective effects of naltrexone than early follicular women and men. These findings may have important implications for the use of naltrexone in women. PMID- 25459896 TI - The brain mineralocorticoid receptor and stress resilience. AB - Stress exposure activates the HPA-axis and results in the release of corticosteroids which bind to two receptor types in the brain: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). While the role of the GR in stress reactivity has been extensively studied, the MR has received less attention. Nevertheless, pioneering in-depth studies over the past two decades have shown the importance of the brain MR in the processing of stressful information. Moreover, a membrane-bound MR mediating the rapid effects of cortisol was recently discovered. This review summarizes how the MR may play a role in stress resilience. Both preclinical and clinical studies suggest that the MR is an important stress modulator and influences basal as well as stress induced HPA-axis activity, stress appraisal, and fear-related memories. These MR effects are mediated by both genomic and non-genomic MRs and appear to be at least partially sex-dependent. Moreover, the majority of studies indicate that high MR functionality or expression may confer resilience to traumatic stress. This has direct clinical implications. First, increasing activity or expression of brain MRs may prevent or reverse symptoms of stress-related depression. Second, individuals with a relatively low MR functionality may possess an increased stress susceptibility for depression. Nevertheless, the number of clinical MR studies is currently limited. In conclusion, the recent emergence of the MR as a putative stress resilience factor is important and may open up new avenues for the prevention and treatment of psychiatric disorders. PMID- 25459895 TI - Effect of current and lifetime posttraumatic stress disorder on 24-h urinary catecholamines and cortisol: results from the Mind Your Heart Study. AB - Posttraumatic stress disorder (PTSD) is associated with an increased risk of cardiovascular disease and several other chronic illnesses. Alterations in the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis in PTSD might contribute to these associations but findings regarding SNS and HPA activity in PTSD are heterogeneous. We measured 24-h urinary catecholamines and cortisol in a large cohort of adult outpatients recruited from 2 Veterans Affairs medical centers. 24-h urinary norepinephrine, epinephrine, dopamine and cortisol were measured by tandem mass spectrometry. Lifetime and current PTSD were assessed with the Clinician Administered PTSD Scale using DSM IV-TR criteria. Out of 613 participants, 199 (32.5%) had current PTSD, 100 (16.3%) had lifetime but not current PTSD, and 314 (51.2%) never had PTSD. Patients with current PTSD had significantly higher norepinephrine secretion compared to those without PTSD. Patients in the lifetime PTSD group exhibited lower cortisol values compared to those without PTSD. Participants who never had PTSD showed the lowest norepinephrine and the highest cortisol values. All results remained stable when controlling for potentially confounding variables. This study provides evidence for increased norepinephrine secretion and decreased cortisol in PTSD. Future longitudinal studies are needed to determine whether these changes contribute to adverse health outcomes in patients with PTSD. PMID- 25459894 TI - Personality and gene expression: Do individual differences exist in the leukocyte transcriptome? AB - BACKGROUND: The temporal and situational stability of personality has led generations of researchers to hypothesize that personality may have enduring effects on health, but the biological mechanisms of such relationships remain poorly understood. In the present study, we utilized a functional genomics approach to examine the relationship between the 5 major dimensions of personality and patterns of gene expression as predicted by 'behavioural immune response' theory. We specifically focussed on two sets of genes previously linked to stress, threat, and adverse socio-environmental conditions: pro-inflammatory genes and genes involved in Type I interferon and antibody responses. METHODS: An opportunity sample of 121 healthy individuals was recruited (86 females; mean age 24 years). Individuals completed a validated measure of personality; questions relating to current health behaviours; and provided a 5ml sample of peripheral blood for gene expression analysis. RESULTS: Extraversion was associated with increased expression of pro-inflammatory genes and Conscientiousness was associated with reduced expression of pro-inflammatory genes. Both associations were independent of health behaviours, negative affect, and leukocyte subset distributions. Antiviral and antibody-related gene expression was not associated with any personality dimension. CONCLUSIONS: The present data shed new light on the long-observed epidemiological associations between personality, physical health, and human longevity. Further research is required to elucidate the biological mechanisms underlying these associations. PMID- 25459897 TI - Reduced frontal white matter volume in children with early onset of adrenarche. AB - While there is growing evidence that puberty affects brain development, very little is known about the structural brain changes associated with dehydroepiandrosterone (DHEA), an adrenal hormone that exhibits dramatic increases during adrenarche, the earliest phase of puberty. Moreover, no research has investigated whether relatively early exposure to DHEA (i.e., early adrenarche) during this period is associated with differences in brain structure. We ran a whole-brain voxel-based morphometry analysis on T1-weighted magnetic resonance imaging brain scans to compare gray (GMV) and white matter volumes (WMV) between children experiencing relatively early (n=41) vs. relatively late (n=44) adrenarche. We also investigated the correlations between GMV or WMV and DHEA levels, and finally, tested for sex differences in group and correlation analyses. We observed reduced frontal WMV in a cluster located on the left corona radiata in children experiencing earlier adrenarche. In addition, WMV in this area was negatively correlated with DHEA levels. We did not observe any effect of gender in both the group and the correlation analyses. Early onset of adrenarche (as defined by relatively early exposure to DHEA) may be associated with differences in the development of frontal white matter tracts. PMID- 25459898 TI - The influence of stress on social cognition in patients with borderline personality disorder. AB - BACKGROUND: Borderline personality disorder (BPD) is characterized by severe difficulties in interpersonal relationships and emotional functioning. Theories of BPD suggest that individuals with BPD have heightened emotional sensitivity, increased stress reactivity, and problems in making sense of intentions of others. In this study we investigated stress reactivity in BPD and its interference with social cognition, and tested whether any differences are specific for BPD or are inherent to personality disorders in general. METHODS: We investigated 22 patients with BPD, 23 patients with Cluster C personality disorder (CPD), and 24 nonpatients on facial emotion recognition and social evaluation before and after stress induction based on the Trier Social Stress Test (TSST). RESULTS: The results show that stress increased subjective negative emotions in the BPD group to a larger extent than in the other groups, whereas physiological responses were attenuated. Importantly stress induction increased negative evaluations about others, but surprisingly to a similar extent in the BPD and CPD groups as in the nonpatient control group. In addition facial emotion recognition performance was higher after than before stress, but no significant group differences were observed. CONCLUSION: These results suggest that heightened psychological reactivity in BPD co-occurs with attenuated physiological responses to psychosocial stress and that stress affects social cognition to a similar extent in BPD as in others. PMID- 25459899 TI - Mapping the developmental trajectory of stress effects: pubescence as the risk window. AB - The exposure to stress at different developmental time points has long been postulated to have a crucial impact on various brain structures involved in mental disorders. The long-term specific effects seem to emerge as a function of timing and duration of the exposure to stress, as well as the characteristics of the stressor. Previous studies have addressed this issue with an effort to describe a single "hyper-sensitive" time point, and have led to disagreement on a particular sensitive period for stress exposure. The primary aim of our study was to investigate the hypothesis that indeed there is a developmental stress risk window in male Wistar rats. We conducted a systematic mapping of the long-term effects of an acute stress protocol, applied both prenatal (gestational days 14 16) and postnatal (days 9-151), overall at 11 different time-points during development. Stress protocol consists of 3 days of either maternal separation (for rats at postnatal days 9-19) or exposure to the stressors forced swim, elevated plus maze and restraint (for both dams and males at postnatal days 24 151). Consequences in adulthood were measured by investigating the animals' behavior in both the open field and startle box, together with the physiological measure of corticosterone. We found both behaviorally and physiologically that the pubescence time points are the most vulnerable to stress compared to all other tested time points along the developmental trajectory. Carefully considering the comparison between rat and human age, our findings may imply the importance of childhood-to-adulthood transition, as a sensitive time-point which may exacerbate a predisposition for the development of stress-induced psychopathologies. PMID- 25459900 TI - Ghrelin in psychiatric disorders - A review. AB - Ghrelin is a 28-amino-acid peptide hormone, first described in 1999 and broadly expressed in the organism. As the only known orexigenic hormone secreted in the periphery, it increases hunger and appetite, promoting food intake. Ghrelin has also been shown to be involved in various physiological processes being regulated in the central nervous system such as sleep, mood, memory and reward. Accordingly, it has been implicated in a series of psychiatric disorders, making it subject of increasing investigation, with knowledge rapidly accumulating. This review aims at providing a concise yet comprehensive overview of the role of ghrelin in psychiatric disorders. Ghrelin was consistently shown to exert neuroprotective and memory-enhancing effects and alleviated psychopathology in animal models of dementia. Few human studies show a disruption of the ghrelin system in dementia. It was also shown to play a crucial role in the pathophysiology of addictive disorders, promoting drug reward, enhancing drug seeking behavior and increasing craving in both animals and humans. Ghrelin's exact role in depression and anxiety is still being debated, as it was shown to both promote and alleviate depressive and anxiety-behavior in animal studies, with an overweight of evidence suggesting antidepressant effects. Not surprisingly, the ghrelin system is also implicated in eating disorders, however its exact role remains to be elucidated. Its widespread involvement has made the ghrelin system a promising target for future therapies, with encouraging findings in recent literature. PMID- 25459901 TI - Associations between fear-avoidance and endurance responses to pain and salivary cortisol in the context of experimental pain induction. AB - Recent clinical studies in patients with lower back pain indicate that maladaptive fear-avoidance- and endurance-related pain responses (FAR and ER) have an influence on pain-induced physiological stress levels. The aim of the present study was to follow-up these results under well-controlled laboratory conditions. For this purpose, 30 healthy adults were asked to indicate their usual responses to pain, and were then confronted with an experimental pain stimulus (cold pressor test). Cortisol served as a measure of physiological stress. The results reveal positive associations between cortisol and FAR patterns, and negative associations between cortisol and behavioral ER. Conceivably, FAR contribute to long-lasting elevated stress levels in patients with stress-related musculoskeletal pain. In contrast, short-term, stress lowering effects of ER might even be considered an advantage in coping with pain. PMID- 25459902 TI - Stability of fatty acid composition after thermal, high pressure, and microwave processing of cow milk as affected by polyunsaturated fatty acid concentration. AB - Interest has been increasing to enhance the contents of healthy polyunsaturated fatty acid (PUFA) in milk. However, trans fatty acids and conjugated linoleic acid (CLA) can be altered after thermal processing and high pressures disrupt the milk fat globule membrane, exposing the lipid core and helping its oxidation. The objective of the present research was to study whether processing can alter the fatty acid composition of milk and if these changes are affected by PUFA concentration as previous studies suggest. Two cow milk batches (500 L each), one naturally enriched in PUFA, were processed to obtain pasteurized; high temperature, short time; UHT; high pressure; and microwave pasteurized samples. The detailed fatty acid composition was analyzed with special attention to trans fatty acids and CLA isomers. Results showed that after high temperature, short time processing, total CLA content increased in both milk batches, whereas sterilization resulted in a sigmatropic rearrangement of C18:2 cis-9,trans-11 to C18:2 trans-9,trans-11. The extent of these effects was greater in milks naturally enriched in PUFA. PMID- 25459903 TI - Powder X-ray diffraction can differentiate between enantiomeric variants of calcium lactate pentahydrate crystal in cheese. AB - Powder X-ray diffraction has been used for decades to identify crystals of calcium lactate pentahydrate in Cheddar cheese. According to this method, diffraction patterns are generated from a powdered sample of the crystals and compared with reference cards within a database that contains the diffraction patterns of known crystals. During a preliminary study of crystals harvested from various Cheddar cheese samples, we observed 2 slightly different but distinct diffraction patterns that suggested that calcium lactate pentahydrate may be present in 2 different crystalline forms. We hypothesized that the 2 diffraction patterns corresponded to 2 enantiomeric forms of calcium lactate pentahydrate (L- and DL-) that are believed to occur in Cheddar cheese, based on previous studies involving enzymatic analyses of the lactate enantiomers in crystals obtained from Cheddar cheeses. However, the powder X-ray diffraction database currently contains only one reference diffraction card under the title "calcium lactate pentahydrate." To resolve this apparent gap in the powder X-ray diffraction database, we generated diffraction patterns from reagent-grade calcium l-lactate pentahydrate and laboratory-synthesized calcium dl-lactate pentahydrate. From the resulting diffraction patterns we determined that the existing reference diffraction card corresponds to calcium dl-lactate pentahydrate and that the other form of calcium lactate pentahydrate observed in cheese crystals corresponds to calcium l-lactate pentahydrate. Therefore, this report presents detailed data from the 2 diffraction patterns, which may be used to prepare 2 reference diffraction cards that differentiate calcium l-lactate pentahydrate from calcium dl-lactate pentahydrate. Furthermore, we collected crystals from the exteriors and interiors of Cheddar cheeses to demonstrate the ability of powder X ray diffraction to differentiate between the 2 forms of calcium lactate pentahydrate crystals in Cheddar cheeses. Powder X-ray diffraction results were validated using enzymatic assays for lactate enantiomers. These results demonstrated that powder X-ray diffraction can be used as a diagnostic tool to quickly identify different forms of calcium lactate pentahydrate that may occur in Cheddar cheese. PMID- 25459904 TI - Changes in the physical properties, solubility, and heat stability of milk protein concentrates prepared from partially acidified milk. AB - A limiting factor in using milk protein concentrates (MPC) as a high-quality protein source for different food applications is their poor reconstitutability. Solubilization of colloidal calcium phosphate (CCP) from casein micelles during membrane filtration (e.g., through acidification) may affect the structural organization of these protein particles and consequently the rehydration and functional properties of the resulting MPC powder. The main objective of this study was to investigate the effects of acidification of milk by glucono-delta lactone (GDL) before ultrafiltration (UF) on the composition, physical properties, solubility, and thermal stability (after reconstitution) of MPC powders. The MPC samples were manufactured in duplicate, either by UF (65% protein, MPC65) or by UF followed by diafiltration (80% protein, MPC80), using pasteurized skim milk, at either the native milk pH (~pH 6.6) or at pH 6.0 after addition of GDL, followed by spray drying. Samples of different treatments were reconstituted at 5% (wt/wt) protein to compare their solubility and thermal stability. Powders were tested in duplicate for basic composition, calcium content, reconstitutability, particle size, particle density, and microstructure. Acidification of milk did not have any significant effect on the proximate composition, particle size, particle density, or surface morphology of the MPC powders; however, the total calcium content of MPC80 decreased significantly with acidification (from 1.84 +/- 0.03 to 1.59 +/- 0.03 g/100 g of powder). Calcium depleted MPC80 powders were also more soluble than the control powders. Diafiltered dispersions were significantly less heat stable (at 120 degrees C) than UF samples when dissolved at 5% solids. The present work contributes to a better understanding of the differences in MPC commonly observed during processing. PMID- 25459905 TI - Effect of cooling during the dry period on immune response after Streptococcus uberis intramammary infection challenge of dairy cows. AB - Heat stress in the dry period affects the immune status of dairy cows in the subsequent lactation. We hypothesized that cooling during the dry period improves immune response to postpartum intramammary infection (IMI) by environmental pathogens such as Streptococcus uberis. Cows were dried off 46 d before expected calving and assigned to cooling (CL, n = 15) or heat stress (HT, n = 15). Cooled cows were housed with sprinklers, fans, and shade, whereas the HT group had only shade. All cows were cooled postpartum. Rectal temperature (RT) and respiration rate (RR) were recorded thrice weekly during the dry period. From -46 to 42 d relative to calving, dry matter intake was recorded daily, and both body weight (BW) and body condition score (BCS) weekly. Milk yield and composition were recorded daily after calving. Streptococcus uberis IMI was induced at 5 d postpartum in a subset of cows (CL, n = 5; HT, n = 5). Blood was collected at 0, 12, 18, 24, and 36 h after IMI. Hematological analysis was performed, and neutrophils isolated for RNA extraction. Immune response genes (TLR2, IL1-beta, IL6, IL8, IL10, and TNFalpha) were assessed by real-time, reverse transcription PCR. Relative to HT cows, CL cows had lower RT and RR during the dry period. The CL cows also consumed more feed prepartum but not postpartum, gained more BW prepartum but lost more BW in lactation, and had higher BCS score prepartum and a lower BCS postpartum. During 40 wk of lactation, CL cows produced more milk (33.8 vs. 30.0 kg/d) than HT cows but milk composition was not affected. Cows in the CL group had greater white blood cell counts and more neutrophils than HT cows during IMI. From 0 to 36 h post-IMI, TNFalpha mRNA expression decreased, whereas that of IL6 and IL8 increased in both treatments. Additionally, CL cows had lower IL10 mRNA expression at 18 h post-IMI. Expression of TLR2 mRNA decreased over time in both treatments. However, CL cows had greater overall TLR2 mRNA expression than HT. No differences were detected for mRNA expression of IL1-beta, IL6, IL8, or TNFalpha. Cooling cows during the dry period alters immune function and neutrophil response to IMI in early lactation. PMID- 25459906 TI - Clinical outcomes and molecular genotyping of Staphylococcus aureus isolated from milk samples of dairy primiparous Mediterranean buffaloes (Bubalus bubalis). AB - Staphylococcus aureus is one of the most important pathogens causing mastitis in dairy cows and in Mediterranean buffaloes. Genotype B (GTB) is contagious in dairy cows and may occur in up to 87% of cows of a dairy herd. It was the aim of this study to evaluate genotypes present, clinical outcomes, and prevalence of Staph. aureus in milk samples of primiparous Mediterranean dairy buffaloes. Two hundred composite milk samples originating from 40 primiparous buffaloes were collected from May to June 2012, at d 10, 30, 60, 90, and 150 d in milk (DIM) to perform somatic cell counts and bacteriological cultures. Daily milk yields were recorded. Before parturition until 40 to 50 DIM, all primiparous animals were housed separated from the pluriparous animals. Milking was performed in the same milking parlor, but the primiparous animals were milked first. After 50 DIM, the primiparous were mixed with the pluriparous animals, including the milking procedure. Individual quarter samples were collected from each animal, and aliquots of 1 mL were mixed and used for molecular identification and genotyping of Staph. aureus. The identification of Staph. aureus was performed verifying the presence of nuc gene by nuc gene PCR. All the nuc-positive isolates were subjected to genotype analysis by means of PCR amplification of the 16S-23S rRNA intergenic spacer region and analyzed by a miniaturized electrophoresis system. Of all 200 composite samples, 41 (20.5%) were positive for Staph. aureus, and no genotype other than GTB was identified. The prevalence of samples positive for Staph. aureus was 0% at 10 DIM and increased to a maximum of 22/40 (55%) at 90 DIM. During the period of interest, 14 buffaloes tested positive for Staph. aureus once, 6 were positive twice, and 5 were positive 3 times, whereas 15 animals were negative at every sampling. At 90 and 150 DIM, 7 (17.5%) and 3 buffaloes (7.5%), respectively, showed clinical mastitis (CM), and only 1 (2.5%) showed CM at both samplings. At 60, 90, and 150 DIM, 1 buffalo was found with subclinical mastitis at each sampling. At 30, 60, 90, and 150 DIM, 2.5 (1/40), 22.5 (9/40), 35 (14/40), and 10% (4/40) were considered affected by intramammary infection, respectively. Buffaloes with CM caused by Staph. aureus had statistically significantly higher mean somatic cell count values (6.06 +/- 0.29, Log10 cells/mL +/- standard deviation) and statistically significantly lower mean daily milk yields (7.15 +/- 1.49, liters/animal per day) than healthy animals (4.69 +/- 0.23 and 13.87 +/- 2.64, respectively), buffaloes with IMI (4.82 +/- 0.23 and 11.16 +/- 1.80, respectively), or with subclinical mastitis (5.47 +/- 0.10 and 10.33 +/- 0.68, respectively). Based on our knowledge, this is the first time that Staph. aureus GTB has been identified in milk samples of dairy Mediterranean buffaloes. PMID- 25459907 TI - Evaluation of the systemic innate immune response and metabolic alterations of nonlactating cows with diet-induced subacute ruminal acidosis. AB - Subacute ruminal acidosis (SARA) increases lipopolysaccharide endotoxin in the rumen, which might translocate into the systemic circulation, triggering a cascade of clinical and immunological alterations. The objective of this study was to characterize the clinical immune and metabolic responses to ruminal derived lipopolysaccharide in nonlactating cows induced with SARA using 2 challenges, a grain-based SARA challenge (GBSC) or an alfalfa-pellet SARA challenge (APSC). Six dry, nonlactating Holstein cows were used in a 3 * 3 Latin square arrangement of treatments with 4-wk experimental cycles. All cows received the control diet containing 70% forage and 30% mixed concentrates (dry matter basis) for 3 wk. In wk 4, cows received a control diet, GBSC (38% wheat-barley pellets, 32% other mixed concentrate, and 30% forages), or APSC (45% mixed concentrate, 32% alfalfa pellets, and 23% other forages). Total plasma proteins and immunology-related proteins, acute phase proteins, blood cells, serum chemistry, mRNA gene expression of peripheral blood cell surface markers, and selected proinflammatory cytokines were evaluated. Ruminal pH was lower in both groups with induced SARA compared with a control group. Ruminal endotoxins were higher in GBSC; however, plasma endotoxin was not detected in any study group. No significant differences in feed intake, rectal temperature, white blood cell counts, or differentials were found between control and SARA challenge groups; changes in glucose, urea, Ca, and Mg were observed in SARA groups. Total plasma proteins were lower in both SARA groups, and acute phase proteins were higher in GBSC. The expression of CD14, MD2, and TLR4 mRNA in peripheral blood leukocytes was not affected by SARA induction. The induction of SARA as a result of GBSC or APSC challenge was successful; however, LPS was not detected in plasma. Changes in clinical, metabolic, and inflammatory responses were not observed in the SARA challenged cows, suggesting that, in this study, SARA was not associated with a systemic response to inflammation. PMID- 25459908 TI - Effect of dietary starch level and high rumen-undegradable protein on endocrine metabolic status, milk yield, and milk composition in dairy cows during early and late lactation. AB - Diet composition defines the amount and type of nutrients absorbed by dairy cows. Endocrine-metabolic interactions can influence these parameters, and so nutrient availability for the mammary gland can significantly vary and affect milk yield and its composition. Six dairy cows in early and then late lactation received, for 28 d in a changeover design, 2 diets designed to provide, within the same stage of lactation, similar amounts of rumen fermentable material but either high starch plus sugar (HS) content or low starch plus sugar content (LS). All diets had similar dietary crude protein and calculated supply of essential amino acids. Dry matter intake within each stage of lactation was similar between groups. Milk yield was similar between groups in early lactation, whereas a higher milk yield was observed in late lactation when feeding HS. At the metabolic level, the main difference observed between the diets in both stages of lactation was lower blood glucose in cows fed LS. The lower glucose availability during consumption of LS caused substantial modifications in the circulating and postprandial pattern of metabolic hormones. Feeding LS versus HS resulted in an increase in the ratio of bovine somatotropin to insulin. This increased mobilization of lipid reserves resulted in higher blood concentrations of nonesterified fatty acids and beta hydroxybutyrate, which contributed to the higher milk fat content in both stages of lactation in the LS group. This greater recourse to body fat stores was confirmed by the greater loss of body weight during early lactation and the slower recovery of body weight in late lactation in cows fed LS. The lower insulin to glucagon ratio observed in cows fed LS in early and late lactation likely caused an increase in hepatic uptake and catabolism of amino acids, as confirmed by the higher blood urea concentrations. Despite the higher catabolism of amino acids in LS in early lactation, similar milk protein output was observed for both diets, suggesting similar availability of amino acids for peripheral tissue and mammary gland. The latter could be the result of sparing of amino acids at the gut level due to starch that escaped from the rumen, and to the balanced amino acid profile of digestible protein. This last aspect appears worthy of further research, with the aim to enhance the efficiency of protein metabolism of dairy cows, reducing environmental nitrogen pollution without affecting milk yield potential. PMID- 25459909 TI - Use of dry citrus pulp or soybean hulls as a replacement for corn grain in energy and nitrogen partitioning, methane emissions, and milk performance in lactating Murciano-Granadina goats. AB - The aim of this study was to assess the effect of substitution of dietary corn grain by dry citrus pulp or soybean hulls on energy and nitrogen partitioning, substrate oxidation, methane emission, and milk performance in dairy goats during midlactation. Twelve multiparous Murciano-Granadina goats of similar body weight (41.7 +/- 2.8 kg) were split in 3 groups in an incomplete crossover design. One group of 4 goats was fed a mixed ration with 605 g/kg of dry matter of corn grain (CRG), another group replaced corn grain with dry citrus pulp (CTP), and the last with soybean hulls (SYH). The goats were allocated to individual metabolism cages. After 14 d of adaptation, feed intake, total fecal and urine output, and milk yield were recorded daily over a 5-d period. Then, gas exchange measurements were recorded by a mobile open-circuit indirect calorimetry system using a head box. Dry matter intake was similar for all 3 groups (1.53 kg/d, on average). Total replacement of the concentrate with fibrous by-products increased fiber apparent digestibility. The metabolizable energy intake was significantly greater for diet CRG than SYH (1,193 vs. 1,079 kJ/kg of BW0.75, respectively), CTP showed an intermediate value. The heat production was higher for the fiber diet than starchy diet (908 vs. 843 kJ/kg of BW0.75 for SYH and CRG, respectively). The efficiency of use of metabolizable energy for milk production obtained by regression was 0.59. Goats fed CTP and SYH diets produced similar CH4 emissions (34.8 g/d, on average), significantly higher compared with goats fed the CRG diet (24.7 g/d). Goats of the 3 treatments were in negative energy balance, so the oxidation of fat was greater than for carbohydrates. No significant differences were observed for milk production (1.72 kg/d), and milk fat was significantly greater for a more fibrous diet compared with a starchy diet (6.57 vs. 4.95% in SYH and CRG, respectively). PMID- 25459910 TI - Associations between CXCR1 polymorphisms and pathogen-specific incidence rate of clinical mastitis, test-day somatic cell count, and test-day milk yield. AB - The CXCR1 gene plays an important role in the innate immunity of the bovine mammary gland. Associations between single nucleotide polymorphisms (SNP) CXCR1c.735C>G and c.980A>G and udder health have been identified before in small populations. A fluorescent multiprobe PCR assay was designed specifically and validated to genotype both SNP simultaneously in a reliable and cost-effective manner. In total, 3,106 cows from 50 commercial Flemish dairy herds were genotyped using this assay. Associations between genotype and detailed phenotypic data, including pathogen-specific incidence rate of clinical mastitis (IRCM), test-day somatic cell count, and test-day milk yield (MY) were analyzed. Staphylococcus aureus IRCM tended to associate with SNP c.735C>G. Cows with genotype c.735GG had lower Staph. aureus IRCM compared with cows with genotype c.735CC (rate ratio = 0.35, 95% confidence interval = 0.14-0.90). Additionally, a parity-specific association between Staph. aureus IRCM and SNP c.980A>G was detected. Heifers with genotype c.980GG had a lower Staph. aureus IRCM compared with heifers with genotype c.980AG (rate ratio = 0.15, 95% confidence interval = 0.04-0.56). Differences were less pronounced in multiparous cows. Associations between CXCR1 genotype and somatic cell count were not detected. However, MY was associated with SNP c.735C>G. Cows with genotype c.735GG out-produced cows with genotype c.735CC by 0.8 kg of milk/d. Results provide a basis for further research on the relation between CXCR1 polymorphism and pathogen-specific mastitis resistance and MY. PMID- 25459911 TI - Genotype-specific differences in the tumor metabolite profile of pheochromocytoma and paraganglioma using untargeted and targeted metabolomics. AB - CONTEXT AND OBJECTIVE: Pheochromocytomas and paragangliomas (PGLs) are neuroendocrine tumors of sympathetic or parasympathetic paraganglia. Nearly 40% of PGLs are caused by germline mutations. The present study investigated the effect of genetic alterations on metabolic networks in PGLs. DESIGN: Homogenates of 32 sporadic PGLs and 48 PGLs from patients with mutations in SDHB, SDHD, SDHAF 2, VHL, RET, and NF-1 were subjected to proton ((1)H) nuclear magnetic resonance (NMR) spectroscopy at 500 MHz for untargeted and HPLC tandem mass spectrometry for targeted metabolite profiling. RESULTS: (1)H NMR spectroscopy identified 28 metabolites in PGLs of which 12 showed genotype-specific differences. Part of these results published earlier reported low complex II activity (P < .0001) and low ATP/ADP/AMP content (P < .001) in SDH-related PGLs compared with sporadics and PGLs of other genotypes. Extending these results, low levels of N acetylaspartic acid (NAA; P < .05) in SDH tumors and creatine (P < .05) in VHL tumors were observed compared with sporadics and other genotypes. Positive correlation was observed between NAA and ATP/ADP/AMP content (P < .001) and NAA and complex II activity (P < .0001) of PGLs. Targeted purine analysis in PGLs showed low adenine in cluster 1 compared with cluster 2 tumors (SDH P < .0001; VHL P < .05) whereas lower levels (P < .05) of guanosine and hypoxanthine were observed in RET tumors compared with SDH tumors. Principal component analysis (PCA) of metabolites could distinguish PGLs of different genotypes. CONCLUSIONS: The present study gives a comprehensive picture of alterations in energy metabolism in SDH- and VHL-related PGLs and establishes the interrelationship of energy metabolism and amino acid and purine metabolism in PGLs. PMID- 25459912 TI - Associations of advanced glycation end-products with cognitive functions in individuals with and without type 2 diabetes: the maastricht study. AB - CONTEXT: Advanced glycation end-products (AGEs) are thought to be involved in the pathogenesis of Alzheimer's disease. AGEs are products resulting from nonenzymatic chemical reactions between reduced sugars and proteins, which accumulate during natural aging, and their accumulation is accelerated in hyperglycemic conditions such as type 2 diabetes mellitus. OBJECTIVE: The objective of the study was to examine associations between AGEs and cognitive functions. DESIGN, SETTING, AND PARTICIPANTS: This study was performed as part of the Maastricht Study, a population-based cohort study in which, by design, 215 participants (28.1%) had type 2 diabetes mellitus. MAIN OUTCOME MEASURES: We examined associations of skin autofluorescence (SAF) (n = 764), an overall estimate of skin AGEs, and specific plasma protein-bound AGEs (n = 781) with performance on tests for global cognitive functioning, information processing speed, verbal memory (immediate and delayed word recall), and response inhibition. RESULTS: After adjustment for demographics, diabetes, smoking, alcohol, waist circumference, total cholesterol/high-density lipoprotein cholesterol ratio, triglycerides, and lipid-lowering medication use, higher SAF was significantly associated with worse delayed word recall (regression coefficient, b = -0.44; P = .04), and response inhibition (b = 0.03; P = .04). After further adjustment for systolic blood pressure, cardiovascular disease, estimated glomerular filtration rate, and depression, associations were attenuated (delayed word recall, b = -0.38, P = .07; response inhibition, b = 0.02, P = .07). Higher pentosidine levels were associated with worse global cognitive functioning (b = -0.61; P = .04) after full adjustment, but other plasma AGEs were not. Associations did not differ between individuals with and without diabetes. CONCLUSION: We found inverse associations of SAF (a noninvasive marker for tissue AGEs) with cognitive performance, which were attenuated after adjustment for vascular risk factors and depression. PMID- 25459913 TI - Increased serum and bone matrix levels of the secreted Wnt antagonist DKK-1 in patients with growth hormone deficiency in response to growth hormone treatment. AB - CONTEXT: Growth hormone (GH) substitution of adult-onset growth hormone deficiency (aoGHD) patients partially reverses unfavorable body composition profile. Wnt signaling pathway has being acknowledged as an important modulator of bone mass and of energy metabolism in adipose tissue and in beta-cells. OBJECTIVE: To assess the role of selected Wnt antagonists in bone and glucose metabolism before and after GH replacement in aoGHD. PATIENTS AND METHODS: Patients from two randomized placebo-controlled studies of GH replacement in aoGHD were used. In study 1, 39 patients received GH or placebo for 9 months with 4 months wash-out. In study 2, iliac bone biopsies were obtained before and after GH or placebo (n = 10 each) for 12 months. Body composition and serum (study 1) and bone matrix (study 2) levels of Wnt antagonists (DKK-1, sFRP-3, WIF-1, and SOST) were quantified before and after GH. In vitro effect of GH and IGF-1 on DKK 1 secretion and expression of Wnt signaling modulators was assessed in human osteoblasts and mature adipocytes. RESULTS: GH replacement increased circulating and bone matrix levels of DKK-1, but not sFRP-3, WIF-1, and SOST. Furthermore, DKK-1 secretion increased in human osteoblasts stimulated by GH in vitro, with no effects on other cells. At baseline and after treatment, circulating DKK-1 was negatively associated with bone mass, but not fat mass or measures of insulin resistance, in aoGHD patients. CONCLUSIONS: An increase in DKK-1 may limit the effects of GH on bone mass, but does not seem to impact the increase in insulin resistance following GH substitution. PMID- 25459914 TI - NNT pseudoexon activation as a novel mechanism for disease in two siblings with familial glucocorticoid deficiency. AB - CONTEXT: Intronic DNA frequently encodes potential exonic sequences called pseudoexons. In recent years, mutations resulting in aberrant pseudoexon inclusion have been increasingly recognized to cause disease. OBJECTIVES: To find the genetic cause of familial glucocorticoid deficiency (FGD) in two siblings. PATIENTS: The proband and his affected sibling, from nonconsanguineous parents of East Asian and South African origin, were diagnosed with FGD at the ages of 21 and 8 months, respectively. DESIGN: Whole exome sequencing was performed on genomic DNA (gDNA) of the siblings. Variants in genes known to cause FGD were assessed for causality. Further analysis of gDNA and cDNA was performed by PCR/RT PCR followed by automated Sanger sequencing. RESULTS: Whole exome sequencing identified a single, novel heterozygous variant (p.Arg71*) in nicotinamide nucleotide transhydrogenase (NNT) in both affected individuals. Follow-up cDNA analysis in the proband identified a 69-bp pseudoexon inclusion event, and Sanger sequencing of his gDNA identified a 4-bp duplication responsible for its activation. The variants segregated with the disease: p.Arg71* was inherited from the mother, the pseudoexon change was inherited from the father, and an unaffected sibling had inherited only the p.Arg71* variant. CONCLUSIONS: FGD in these siblings is caused by compound heterozygous mutations in NNT; one causing pseudoexon inclusion in combination with another leading to Arg71*. Discovery of this pseudoexon activation mutation highlights the importance of identifying sequence changes in introns by cDNA analysis. The clinical implications of these findings include: facilitation of antenatal genetic diagnosis, early institution of potentially lifesaving therapy, and the possibility of preventative or curative intervention. PMID- 25459915 TI - Coxsackie and adenovirus receptor is increased in adipose tissue of obese subjects: a role for adenovirus infection? AB - CONTEXT: The coxsackie and adenovirus receptor (CAR) was originally identified as a common receptor for coxsackie B viruses and type C adenoviruses. OBJECTIVE: The objective was to investigate CAR gene expression in human adipose tissue to explore its associations with adipocyte physiology. DESIGN AND SETTING: This was an ex vivo study in 91 visceral adipose tissue (VAT) and 109 sc adipose tissue (SAT) human samples (61 paired) obtained during elective surgical procedures. PATIENTS: Patients were recruited at the Endocrinology Service of the Hospital Universitari Dr Josep Trueta. MAIN OUTCOME MEASURE: CAR mRNA was measured in human adipose tissue samples and confirmed at the protein level and in adipose tissue fractions. The effects of inflammatory stimuli on CAR gene expression were also evaluated. RESULTS: In paired samples, CAR was 46-fold higher in VAT vs SAT (P < .0001), being higher also at the protein level (P = .04). CAR was predominantly found in stromal vascular cell fractions (SVFs) in both fat depots. CAR mRNA (P = .006) and protein levels (P = .01) in VAT were significantly increased in obese vs nonobese subjects. In fact, CAR mRNA levels in SAT were positively associated with body mass index (r = 0.26; P = .008) and percentage fat mass (r = 0.28; P = .004). In VAT, MGLL, FSP27, AKAP, omentin, TKT, S14, and FABP contributed independently to CAR mRNA variation after adjusting for age and body mass index. Macrophage-conditioned medium led to increased CAR gene expression in mature adipocytes in vitro. CONCLUSIONS: The increased expression of CAR in adipose tissue from obese subjects, mainly in SVFs, suggests that CAR might play a role in adipose tissue dysfunction, given its dual associations with adipogenic and inflammatory genes. PMID- 25459916 TI - Overall Quality of Life (OQoL) questionnaire in frail elderly: a study of reproducibility and responsiveness of the Depression List (DL). AB - INTRODUCTION: The DL is a generic interview-based questionnaire and previously validated in measuring OQoL in nursing home residents. Our aim was to examine its reproducibility and responsiveness in the frail elderly. MATERIALS AND METHODS: The design was three repeated DL-measures 10, 30 and 365 days on consecutively recruited hip fracture patients with residence in nursing homes and sheltered housing facilities and with a Mini Mental State Examination (MMSE) score of 5 or more. The DL-questionnaire consists of 15 questions covering emotional well being, social relationship, life-satisfaction, comfort, functional competence and autonomy. The scale ranges from 0 (=best OQoL) to score 30 (=worst OQoL). A trained occupational therapist did face-to-face interviews for measuring intra rater reliability with 20 days interval, and 365 days after hip fracture surgery measuring responsiveness after recovery. Inter-rater reliability was evaluated by two raters in a subgroup. RESULTS: 130 residents were eligible and completed the test-retest (86%). The systematic difference was 0.49 points (95% confidence interval: -0.25; 1.23). Standard Error of Measurement (SEM) was 3.02 points, and the Minimal Detectable Change (MDC) was 8.37 points. Intra-class Correlation Coefficient (ICC) was 70%. Evaluating responsiveness, 89 patients (87%) were alive and completed the third interview. The DL improved over time (p<0.001) and was associated with improved physical recovery after hip fracture. The inter rater reliability was high (ICC=97%). CONCLUSIONS: The DL-questionnaire is easy to use in the frail elderly. It has an acceptable reproducibility, and is able to detect a clinically relevant change over time. PMID- 25459917 TI - Compensating for memory losses throughout aging: validation and normalization of the memory compensation questionnaire (MCQ) for non-clinical French populations. AB - AIM: The MCQ is a seven-factor scale that measures individual differences in the tendency to select particular strategies and to overcome perceived or real memory losses. Our aim was to establish a French version of the MCQ and to evaluate its psychometric properties in a lifespan perspective. We first tested the underlying factor structure of the MCQ in a large sample of 749 adults from aged from 18 to 92 years. RESULTS: The results showed that the factor structure of the French version corresponded well with the one obtained in English-, Dutch- and Spanish speaking samples, supporting the cross-national robustness of the MCQ. We confirmed a seven-factor order model that supports the construct validity of the questionnaire. The reliabilities of the scales were good (alpha>.70) to acceptable (alpha=.66 and .62). Criterion validity was verified by means of significant correlations between health composites and MCQ subscales. Gender and Age affected most of the MCQ subscales but not the Level of Education (LE). CONCLUSION: The MCQ revealed to be a heuristic tool for assessing daily compensatory behaviors that are developed in order to achieve successful aging. Thus, regression-based normative data and a user-friendly computer program were provided to facilitate scoring and norming by clinicians and researchers who need to assess daily compensatory behaviors. PMID- 25459918 TI - Abnormal retinal nerve fiber layer thickness and macula lutea in patients with mild cognitive impairment and Alzheimer's disease. AB - OBJECTIVE: We investigated possible abnormalities in the retinal nerve fiber layer (RNFL) and macula lutea of patients diagnosed with Alzheimer's disease (AD) and mild cognitive impairment (MCI) and tested for any correlation with the severity of dementia. METHODS: A total of 72 subjects, comprising 25 AD patients, 26 MCI patients and 21 healthy individuals (controls) were enrolled in this study. The thickness of the RNFL and volume of the macula lutea was determined using optical coherence tomography (OCT). RESULTS: When compared with controls, we found statistically significant thinning of the RNFL in AD patients at all clock-hour positions except 12:00, and nasal quadrant, 2:00, 3:00 and 4:00. After adjusting several risk factors, the average thickness of the RNFL was reduced in MCI patients compared to AD patients, with specific reductions at inferior quadrant, 5:00 and 6:00. Compared to controls, MCI patients showed a significant decrease in RNFL thickness only in the temporal quadrant, 8:00, 9:00 and 10:00. We found significant reduction in the volume of the macula lutea both in AD and MCI patients. Finally, we could not establish any correlation between patient Mini-Mental State Examination (MMSE) scores (an estimation of the severity of cognitive impairment) and any OCT parameter. CONCLUSION: Retinal degeneration in AD and MCI patients results in decreased thickness of the RNFL, and reduced macular volume in AD and MCI patients. However, there seems to be no correlation between these changes and the severity of dementia. PMID- 25459919 TI - Paraoxonase 1 activity and level of antibodies directed against oxidized low density lipoproteins in a group of an elderly population in Poland - PolSenior study. AB - The aim of this study was to assess two factors influencing the amount of oxidized LDL-paraoxonase 1 (PON1) activity and the level of anti-oxidized LDL antibodies (anti-ox LDL) in a large group of elderly individuals in Poland. The effects of cognitive status, hypertension and metabolic syndrome and of selected serum lipids and inflammation indicators on PON1 activity and anti-ox LDL level were also examined. The investigated population consisted of 3154 individuals aged 65 and more - participants of the population-based PolSenior project. PON1 arylesterase activity was determined spectrophotometrically, anti-ox-LDL antibodies using ELISA method. PON1 activity significantly decreased with advancing age, was lower in males than in females and decreased in persons with impaired cognition. Individuals with hypertension and high lipid levels showed higher PON1 activity. Lower PON1 activity was related to higher level of inflammation indicators - hsCRP and IL-6. The significant association of PON1 activity with age, HDL-C, LDL-C, sex and IL-6 was confirmed in multivariate analysis. Anti-ox LDL antibodies level was significantly higher in the two oldest subgroups of males. It was significantly lower in males than in females. It was decreased in persons with higher serum triglycerides. No relationship of anti-ox LDL level with cognition, hypertension, metabolic syndrome, inflammation indicators and serum lipid levels was observed. In some persons very high levels of anti-ox LDL were stated, most frequently in the oldest persons, particularly in men. CONCLUSION: Both investigated antioxidant factors - PON1 activity and anti-ox LDL level, could play an important role in aging. PMID- 25459922 TI - Development and validation of a new stability indicating reversed phase liquid chromatographic method for the determination of prednisolone acetate and impurities in an ophthalmic suspension. AB - A new stability indicating reversed phase high performance liquid chromatography (RP-HPLC) method was developed and validated under current International Conference of Harmonisation (ICH) guidance for the determination of prednisolone acetate (PAC) and impurities in an ophthalmic suspension. The developed method is presented as an alternative to a modified version of the current RP-HPLC method described in the USP monograph for the assay of PAC in an ophthalmic suspension. Along with the assay of PAC, the new method is also capable of identifying and quantifying eight selected PAC impurities and degradation products in an ophthalmic suspension. Using an Agilent Poroshell 120 EC-C18 100 mm * 4.6mm (dp: 2.7 MUm) column set to 60 degrees C with step gradient elution generated using mobile phase A: acetonitrile/water (10:90) (v/v) and mobile phase B: acetonitrile delivered at 1.2 mL min(-1), all peaks of interest are eluted in 33 min with resolution of 1.5 between the critical pairs. The developed method was validated for PAC and impurities to ICH recommendations for accuracy, linearity, precision (repeatability), limit of detection, limit of quantitation, robustness and specificity. PMID- 25459921 TI - Development and validation of liquid chromatography tandem mass spectrometry method for simultaneous quantification of first line tuberculosis drugs and metabolites in human plasma and its application in clinical study. AB - Rifampicin (RIF) and isoniazid (INH), first line drugs for the treatment of tuberculosis, are known to cause hepatotoxicity as a serious adverse side effect. To further understand the pharmacokinetic parameters of these two drugs, we have developed and validated a rapid, sensitive and selective LC-MS/MS method for simultaneous quantification of RIF, INH and their metabolites 25 desacetylrifampicin (DRIF), acetylisoniazid (AcINH) and isonicotinic acid (INA). Analytes were extracted from 20 MUl of plasma using solid-phase extraction (SPE) followed by chromatographic separation on Zorbax SB-Aq column (50 mm * 4.6mm, particle size 5 MUm) using stepwise gradient elution of 5mM ammonium acetate and 90% acetonitrile with 0.1% formic acid. Separation of all analytes was achieved in the total run time of 6 min. The analytes were detected under positive ionization mode by multiple reaction monitoring (MRM) and quantification of analytes was performed by using deuterium-labelled internal standard. Excellent linearity (r(2) >= 0.995) was achieved for the analytes at different concentration ranges. The method was accurate (90-115%), precise (CV %<14) and specific. Matrix effect was in the range of 93-111% except for INA (40-42%) while recovery from SPE was reproducible (CV %<7.4) in the range of 60-86%. Post preparative stability (48 h, 6 degrees C autosampler) and freeze-thaw stability (3 cycles) were assessed with mean recovered concentration of >85%. The method was successfully applied to a clinical study of 33 healthy subjects to evaluate the effect of concomitant of INH on the pharmacokinetic parameters of RIF as well as the segregation of the subjects into slow or fast acetylators of INH. PMID- 25459920 TI - Effects on healthcare utilization of case management for frail older people: a randomized controlled trial (RCT). AB - OBJECTIVES: Various healthcare interventions have been launched targeting the growing population of older people. The objective of this study was to investigate the of a case management intervention for frail old people (aged 65+ years) effects on healthcare utilization. MATERIALS AND METHODS: The study was conducted in a municipality in southern Sweden and included people aged 65+ years who lived in their ordinary homes, were dependent in two or more activities of daily living (ADL), and had at least two hospital admissions, or four physician visits, in the previous year. One-hundred-fifty-three participants were randomly assigned to either an intervention (n=80) or a control group (n=73). The one-year intervention comprised home visits, at least once a month, by case managers. Group differences were investigated 6-12 and 0-6 months before, and 0-6 and 6-12 months after, baseline. RESULTS: The intervention group had, compared to the control group, significant lower mean number (0.08 vs. 0.37, p=0.041) and proportion (17.4 vs. 46.9%, p=0.016) of ED visits not leading to hospitalization 6-12 months after baseline. The intervention group also had a significantly lower mean number of visits to physicians in outpatient care 6-12 months after baseline (4.09 vs. 5.29, p=0.047). CONCLUSION: The effect on ED visits not leading to hospitalization meant that those in the control group were more likely to visit the ED for reasons that did not require hospitalization, suggesting that they may have been less monitored than the intervention group. The intervention has the potential to reduce the burden on outpatient care and ED. PMID- 25459923 TI - Flow-through enzyme immobilized amperometric detector for the rapid screening of acetylcholinesterase inhibitors by flow injection analysis. AB - A commercially available thin-layer flow-through amperometric detector, with the sensing block customized in an original design, was applied to the screening of drug compounds known as acetylcholinesterase (AChE) inhibitors. AChE from electric eel was covalently immobilized onto a cysteamine modified gold disk adjacent to a silver disk working electrode. On-line studies were performed by flow injection analysis (FIA) in PBS buffer pH 7.4. Seven commercially available AChE inhibitors used in the medical field, namely neostigmine, eserine, tacrine, donepezil, rivastigmine, pyridostigmine and galantamine as well as two natural compounds, quercetin and berberine, were investigated. The same trend of inhibitory potency as described in the literature was observed. Of particular interest and in addition to the determination of the IC50 values, this flow through system allowed the study of both, the stability of the enzyme-inhibitor complex and the kinetic of the enzyme activity recovery. PMID- 25459925 TI - Method development for the separation of monoclonal antibody charge variants in cation exchange chromatography, Part II: pH gradient approach. AB - The cation exhange pH gradient approach was evaluated for the characterization of 10 model monoclonal antibodies including panitumumab, natalizumab, cetuximab, bevacizumab, trastuzumab, rituximab, palivizumab, adalimumab, denosumab and ofatumumab. This work shows that retention and resolution can be modelled in cation exchange pH gradient mode, based on only four initial runs (i.e. two gradient times and two mobile phase temperature). Only 6h were required for a complete method optimization when using a 100 mm * 4.6 mm strong cation exchange column. The accuracy of the predictions was excellent, with an average difference between predicted and experimental retention times of about 1%. The 10 model antibodies were successfully eluted in both pH and salt gradient modes, proving that both modes of elution can be considered as multi-product charge sensitive separation methods. For most of the compounds, the variants were better resolved in the salt gradient mode and the peak capacities were also higher in the salt gradient approach. These observations confirm that pH gradient approach may be of lower interest than salt gradient cation exchange chromatography for antibody characterization. PMID- 25459924 TI - Bioassay-guided preparative separation of angiotensin-converting enzyme inhibitory C-flavone glycosides from Desmodium styracifolium by recycling complexation high-speed counter-current chromatography. AB - A new strategy of the convergence of high-speed counter-current chromatography (HSCCC) and bioactive assay technique was developed for rapidly screening and separating the angiotensin-converting enzyme (ACE) inhibitors from the aerial parts of Desmodium styracifolium. Bioactivity-guided fractionation of the crude extract was first established to target the bioactive fractions based on HSCCC coupled with in vitro ACE inhibitory assay. Subsequently, the bioactive fractions were further separated by the recycling complexation HSCCC respectively, using 0.10 mol/L copper sulfate in the lower phase of two-phase solvent system composed of n-butanol/water (1:1, v/v). Five C-glycosylflavones, vicenin 2 (1), carlinoside (2), vicenin 1 (3), schaftoside (4) and vicenin 3 (5), were successfully obtained. Their chemical structures were identified using ESI-MS and NMR. All the isolates showed in vitro ACE inhibitory activity with the IC50 values between 33.62 and 58.37 MUM. The results demonstrated that the established method was proposed as an excellent strategy to systematically screen and purify active compounds from traditional Chinese medicines. PMID- 25459926 TI - Generic on-line solid phase extraction sample preparation strategies for the analysis of drugs in biological matrices by LC-MS/MS. AB - In the present work we investigate the integration of a single hardware platform (Prospekt-2) allowing on-line SPE with pre-/post-trapping dilution and direct injection of plasma extracts, and also compare the benefits and challenges of the different approaches for pharmaceutical drugs with heterogeneous physicochemical properties. In the first part, the generic use of on-line SPE with direct plasma injection or after protein precipitation was investigated for the quantitative analysis of talinolol. In the second part, pre-trapping and post-trapping dilution for on-line SPE is discussed for generic method development on an oxadiazole and its major metabolite. Finally, the difference of performance between direct plasma injection vs. off-line liquid-liquid extraction is also described for the quantification of buprenorphine and naltrexone down to 50 and 100 pg/ml using a 0.25 ml plasma aliquot. All assays were in human plasma and detection was performed by mass spectrometry detection either on simple or triple stage quadrupoles. Regardless of the tested strategy, assays were found linear, with precision and accuracy with <15% for all quality controls samples and <20% for lower limit of quantitation. PMID- 25459927 TI - Enantiospecific determination of arotinolol in rat plasma by LC-MS/MS: application to a stereoselective pharmacokinetic study. AB - A highly sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and fully validated for quantification of arotinolol enantiomers in rat plasma using haloperidol as the internal standard. After solid phase extraction of 50.0 MUL rat plasma in 96 well plate, a baseline resolution of arotinolol enantiomers was achieved on a CHIRALPAK AD-H column using the mobile phase of n-hexane and ethanol in 0.02% diethylamine (20:80, v/v) at a flow rate of 0.550 mL/min within 11.0 min. Acquisition of mass spectrometric data was performed on a triple-quadrupole mass spectrometer in multiple-reaction monitoring (MRM) mode with an ESI source using the transition m/z 372.1 -> 316.1 for (+/-)-arotinolol and m/z 376.1 -> 165.1 for haloperidol. The calibration curves of both enantiomers were linear over the range of 1.00-200.0 ng/mL (r(2)>0.992) and the lower limit of quantification was 1.00 ng/mL. Intra- and inter-day precision ranged from 5.6% to 8.9% for R-(-)-arotinolol and 4.6-7.4% for S-(+)-arotinolol. Accuracy varied from 0.0% to 7.0% for R-(-)-arotinolol and 5.0-10.0% for S-(+)-arotinolol. For R-(-)-arotinolol, the recovery ranged from 87.2% to 99.2% and the matrix factor was 1.03-1.09; for S-(+)-arotinolol, the recovery ranged from 88.0% to 92.4% and the matrix factor was 0.84-0.95, both were not concentration dependent. The method was demonstrated with acceptable accuracy, precision and specificity for the determination of arotinolol enantiomers and has been successfully applied to a stereoselective pharmacokinetic study. PMID- 25459928 TI - Difluprednate: more than meets the eye. AB - Difluprednate, a FDA approved topical corticosteroid indicated for the treatment of inflammation and pain associated with ocular surgery, affords three polymorphic crystal forms (one hexagonal, sg. P65, and two distinct orthorhombic, both sg.'s P212121, phases), whose preparation, thermal stability ranges, crystal structures and stereochemical preferences are here reported. Using DSC, single crystal structural analysis and less conventional ab-initio X-ray powder diffraction methods, the rich structural and thermal behavior of three difluprednate polymorphs have been clarified, and the validity of previous complex and sometimes contradicting literature reports has been challenged. Complementary solution state NMR provided (1)H, (13)C and (19)F chemical shifts full assignment of the corresponding signals. These results allow us to precisely describe the selective isolation pathways toward three distinct crystal phases, and to define their structural and analytical data necessary for identification and easy and accurate quantification, by modern Rietveld analysis, of complex difluprednate polymorphic mixtures, often obtained as a result of poorly controlled (co)-precipitation methods. PMID- 25459929 TI - Chaotropic salts in liquid chromatographic method development for the determination of pramipexole and its impurities following quality-by-design principles. AB - The aim of this paper is to present a development of liquid chromatographic method when chaotropic salts are used as mobile phase additives following the QbD principles. The effect of critical process parameters (column chemistry, salt nature and concentration, acetonitrile content and column temperature) on the critical quality attributes (retention of the first and last eluting peak and separation of the critical peak pairs) was studied applying the design of experiments-design space methodology (DoE-DS). D-optimal design is chosen in order to simultaneously examine both categorical and numerical factors in minimal number of experiments. Two ways for the achievement of quality assurance were performed and compared. Namely, the uncertainty originating from the models was assessed by Monte Carlo simulations propagating the error equal to the variance of the model residuals and propagating the error originating from the model coefficients' calculation. The baseline separation of pramipexole and its five impurities is achieved fulfilling all the required criteria while the method validation proved its reliability. PMID- 25459930 TI - Development and validation of a supercritical fluid chromatography method for the direct determination of enantiomeric purity of provitamin B5 in cosmetic formulations with mass spectrometric detection. AB - A rapid and efficient chiral supercritical fluid chromatography (SFC) method has been developed for the quantitative determination of panthenol enantiomers in cosmetic formulations (cream, lotion, wipe, and exfoliant). Indeed, the pharmacological effect only depends on the D form (Dexpanthenol) thus accurate measurement of its enantiomeric purity in formulated cosmetic products is of interest. The samples were prepared with liquid-liquid extraction followed by solid-phase extraction on Adsorbex amino cartridges. After testing several enantioselective columns in an attempt at reversing the elution order to have the minor enantiomer eluted first, the best separation of enantiomers and internal standard (N-acetyl-L-alanine) was achieved on a 3 MUm-amylose-type immobilized polysaccharide chiral stationary phase (Chiralpak IA) in less than 6 min with a simple mobile phase comprising carbon dioxide and 11% methanol pumped at 2.3 mL/min, 25 degrees C and 150 bar backpressure. Supercritical fluid chromatography coupled to both an optical diode-array detector and a user-friendly single quadrupole mass spectrometer (Waters QDa) equipped with electrospray ionization source has been used. The on-line coupling ensures the technique to be more informative and improves detection sensitivity, as underivatized panthenol has a poor UV absorption. The limit of quantification (LOQ) achieved with single-ion recording was 0.5 MUg/mL. The method was validated in terms of linearity, precision and accuracy and satisfactory results were obtained. PMID- 25459931 TI - Identification of a new isomer from a reversible isomerization of ceftriaxone in aqueous solution. AB - A reversible isomerization of ceftriaxone in aqueous solution was observed, and the structure of the isomer was determined by mass spectrometry and various 1D and 2D NMR techniques. The mechanism of isomerization was also discussed. Finally, molecular docking simulations were performed and the antimicrobial activities of the isomers were measured. This showed that the biological activity of ceftriaxone was stronger than that of its isomer. The results reported in this article may be important to quality control requirements and to the stability of ceftriaxone products. PMID- 25459932 TI - GC/MS technique and AMDIS software application in identification of hydrophobic compounds of grasshoppers' abdominal secretion (Chorthippus spp.). AB - The automated mass spectral deconvolution and identification system (AMDIS) is a modern analytical tool, mostly used as a data processing method in environmental studies. The most attractive feature of that software is a fast, automatic data processing, which includes removal of interferences from the overlapping peaks and purification of the obtained mass spectra. The identification of analytes is based on their retention time and retention index and on comparison of the spectra obtained in GC/MS analysis with the spectra from the library of the National Institute of Standards and Technology (NIST). The main aim of the study reported was to elaborate and test a new data processing method with the use of AMDIS software for identification of lipidomic compounds present in the grasshopper's abdominal secretion. For the first time to the best of our knowledge, we have demonstrated the usage of AMDIS in a lipidomic study concerning a complex insect matrix. The samples processed with AMDIS software were analyzed with the use of GC/MS in order to determine the main fatty components of grasshoppers' abdominal secretion. The purification, concentration and fractionation of compounds present in a complex insect matrix were investigated with the use of liquid-liquid extraction as a pretreatment procedure. Moreover, a double-step derivatization process was carried out in order to obtain more volatile and stable derivatives of polar, non-volatile components of insects' secretion. This process, necessary for GC/MS analysis, was performed with the use of methoxyamine hydrochloride dissolved in pyridine and a mixture of bis-N-O-trimethylsilyl trifluoroacetamide (BSTFA) and chlorotrimethylsilane (TMCS). As a result, we obtained a fast, automatic method based on the use of AMDIS software, which enabled identification of 28 analytes, mainly fatty compounds. Moreover, 10 compounds out of 28 were determined to appear with 100% frequency in the tested samples, namely: seven fatty acids, one sterol, one organic acid and one alkaloid. The last part of our study was statistical analysis of average intensities of signals of compounds identified in grasshopper's abdominal secretion in order to differentiate insects collected at two distant locations in Poland: Starogard Gdanski and Lubianka meadows. PMID- 25459933 TI - Chemical fingerprinting of silicone-based breast implants. AB - With millions of women worldwide carrying them, silicone-based breast implants represent a large market. Even though silicone breast implants already have a history of use of more than 50 years, the discussion on their safety has not yet come to an end. To improve safety assessment, regulatory authorities should have the availability of a set of tests to be able to determine parameters of implant identity and quality. Therefore, the gels and envelopes of various brands and types of silicone-based breast implants have been subjected to infrared, Raman and NMR spectroscopy. We show that by using a combination of complementary spectroscopic techniques breast implants of various origins can be distinguished on typical chemical hallmarks. It was found that typical silicone-based implants display a surplus of vinyl signals in the gel, cyclosiloxane impurities are tolerable at low levels only and a barrier layer is present in the implant envelope. The techniques presented here and the results obtained offer a good starting point for market surveillance studies. PMID- 25459934 TI - Development of a method to quantify clindamycin in vitreous humor of rabbits' eyes by UPLC-MS/MS: application to a comparative pharmacokinetic study and in vivo ocular biocompatibility evaluation. AB - Ocular toxoplasmosis may result in uveitis in the posterior segment of the eye, leading to severe visual complications. Clindamycin-loaded poly(lactide-co glycolide) (PLGA) implants could be applied to treat the ocular toxoplasmosis. In this study, the pharmacokinetic profiles of the drug administrated by PLGA implants and by intravitreal injections in rabbits' eyes were evaluated. The implant released the drug for 6 weeks while the drug administrated by intravitreal injections remained in the vitreous cavity for 2 weeks. Compared to the injected drug, the implants containing clindamycin had higher values of area under the curve (AUC) (39.2 vs 716.7 ng week mL(-1)) and maximum vitreous concentration (Cmax) (8.7 vs 13.83 ng mL(-1)). The implants prolonged the delivery of clindamycin and increased the contact of the drug with the eyes' tissues. Moreover, the in vivo ocular biocompatibility of the clindamycin-loaded PLGA implants was evaluated regarding to the clinical examination of the eyes and the measurement of the intraocular pressure (IOP) during 6 weeks. The implantable devices caused no ocular inflammatory process and induced the increase of the IOP in the fourth week of the study. The IOP augmentation could be related to the maximum concentration of clindamycin released from the implants. In conclusion, the PLGA implants based on clindamycin may be a therapeutic alternative to treat ocular toxoplasmosis. PMID- 25459935 TI - Identification of hydrolytic and isomeric N-oxide degradants of vilazodone by on line LC-ESI-MS/MS and APCI-MS. AB - The present study reports the degradation behavior of a new antidepressant drug, vilazodone, under various stress conditions as per International Conference on Harmonization guidelines (ICH, Q1A(R2). The investigation involved monitoring decomposition of the drug under hydrolytic (acidic, basic and neutral), oxidative, photolytic and thermal stress conditions and identifying degradation products. A rapid, precise, accurate and robust ultra high performance liquid chromatography (UPLC) method has been developed on a Waters CSH Phenyl-Hexyl column (100 mm * 2.1 mm, 1.7 MUm) using gradient elution of 10mM ammonium acetate buffer (pH 5.0) and acetonitrile as mobile phase. The drug was found to be degraded in hydrolytic (acidic and basic) and oxidative conditions, whereas it was stable under neutral hydrolytic, photolytic and thermal stress conditions. The method was extended to quadrupole time-of-flight mass spectrometry (QTOF-MS) for the structural characterization of degradation products. It has been observed that isomeric N-oxide degradation products were formed under oxidative stress condition. The exact location of N-oxidation in the drug was investigated using atmospheric pressure chemical ionization (APCI) due to the formation of characteristic fragment ions. These fragment ions resulted from Meisenheimer rearrangement owing to thermal energy activation at the vaporizer of APCI source. All degradation products were comprehensively characterized by UPLC-ESI-MS/MS and UPLC-APCI-MS experiments. The most probable mechanisms for the formation of degradation products have also been proposed. The method was validated in terms of specificity, linearity, accuracy, precision, and robustness as per ICH guidelines. PMID- 25459936 TI - Constituent analysis and quality control of Lamiophlomis rotata by LC-TOF/MS and HPLC-UV. AB - In the present study, chemical profile analysis for Lamiophlomis rotata, a classic Tibetan folk medicine, was illustrated by an ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (LC-TOF/MS) method, which provided evidence for the certain identification of the main constituents, including iridoids, flavonoids and phenylethanoid glycosides. Among these compounds, nine of them were regarded as marker compounds for the quantitative evaluation of L. rotata, using a simple and reliable method by HPLC with ultraviolet, in combination of chromatographic fingerprint analysis. Separation was achieved on a Waters SunFire C18 analytical column with linear gradient elution of acetonitrile and 0.1% formic acid aqueous solution. The validated method was successfully applied to evaluate twelve batches of L. rotata. Assay results showed that nine compounds did not vary significantly from the aerial parts and the whole plant for each batch, and was consistent with the fingerprint analysis, which confirmed the medicine parts alteration in Chinese Pharmacopoeia from the perspective of chemical components. PMID- 25459937 TI - Quantitative LC-MS/MS determination of flupirtine, its N-acetylated and two mercapturic acid derivatives in man. AB - The non-opiate analgesic drug flupirtine was shown in vitro to undergo hydrolysis followed by N-acetylation to form D13223, glucuronidation and conjugation with glutathione to form the stable mercapturic acid derivatives M-424 and M-466. To quantify flupirtine and its metabolites in samples obtained in a clinical study in healthy subjects selected on their genotype of NAT2, UGT1A1 and GSTP1, two LC MS/MS methods were developed. The validation range for flupirtine and D-13223 in serum was 0.5-500 ng/ml. For urine and feces, the validation ranges for flupirtine and D-13223 were 20-5000 ng/ml and 5.0-5000 ng/ml, respectively. M-424 and M-466 could be quantified in urine between 5.0 and 5000 ng/ml. Free flupirtine and D-13223 were separated from serum, urine and feces with liquid liquid extraction. For flupirtine and D-13223, the chromatography was performed on a XTerra C18 column isocratically with a mobile phase consisting of ammonium formate buffer (pH 3.5mM) and acetonitrile (50:50; v/v), for M-466 and M-424 a Synergi((r)) Fusion-RP column was used and a linear gradient method with water/HCOOH (pH 3) and acetonitrile. The mass spectrometer operated both with electro spray ionization in positive multiple reaction monitoring mode. The developed methods fulfilled the current FDA criteria on bioanalytical method validation for accuracy (error: -16.9 to 11.2%), precision (1.2-13.4%), recovery, stability and matrix effects over the observed analytical range. Thus, the methods were suitable to quantify flupirtine absorption and metabolic disposition in man after single intravenous and oral dosing (100mg) and repeated oral administration (400mg once daily). PMID- 25459938 TI - Plasma protein binding, pharmacokinetics, tissue distribution and CYP450 biotransformation studies of fidarestat by ultra high performance liquid chromatography-high resolution mass spectrometry. AB - Fidarestat, an aldose reductase inhibitor, has been used for the treatment of the diabetic associated complications such as retinopathy, neuropathy and nephropathy. To better understand the metabolism and pharmacokinetics of fidarestat, we have evaluated plasma protein binding, pharmacokinetics, tissue distribution of the drug and its conjugated metabolites and CYP450 biotransformation by liquid chromatography-high resolution mass spectrometry. Effective chromatographic separation of fidarestat and hydrochlorothiazide (IS) in rat plasma and tissues was achieved on Hypersil gold C-18 column in an isocratic elution mode. For detection, a high-resolution Orbitrap mass spectrometer with heated electrospray ionization inlet in the negative ion mode was used. High-resolution extracted ion chromatograms for each analyte were obtained by processing the full-scan MS mode with 5 ppm mass tolerance. The impact of plasma protein binding with the drug and conjugated metabolites of the drug on pharmacokinetics has been determined. The study indicated that 9.5% of free form of fidarestat may be pharmacologically active and the Cmax for free fidarestat was found to be 80.30 +/- 6.78 ng/mL. The AUC0-t and AUC0-infinity were found to be 185.46 +/- 32 and 195.92 +/- 15.06 ng h/mL, respectively. Among tissues, the maximum observed distribution was found to be in kidney followed by liver and heart. Docking experiments and in vitro CYP450 reaction phenotyping revealed that two CYP1A2 and CYP2D6 are involved in the phase I metabolism of fidarestat. Oxidative deamination and N/O glucuronidation are the major phase I and phase II metabolites, respectively. In vitro CYP450 inhibition assay of fidarestat for drug-drug interaction showed weak inhibition and may not alter pharmacokinetics, distribution or clearance of other co-administered drug. PMID- 25459939 TI - A simple and rapid method to identify and quantitatively analyze triterpenoid saponins in Ardisia crenata using ultrafast liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry. AB - Ardisia plant species have been used in traditional medicines, and their bioactive constituents of 13,28-epoxy triterpenoid saponins have excellent biological activities for new drug development. In this study, a fast and simple method based on ultrafast liquid chromatography coupled to electrospray ionization mass spectrometry (UFLC-MS) was developed to simultaneously identify and quantitatively analyze triterpenoid saponins in Ardisia crenata extracts. In total, 22 triterpenoid saponins, including two new compounds, were identified from A. crenata. The method exhibited good linearity, precision and recovery for the quantitative analysis of eight marker saponins. A relative quantitative method was also developed using one major saponin (ardisiacrispin B) as the standard to break through the choke-point of the lack of standards in phytochemical analysis. The method was successfully applied to quantitatively analyze saponins in commercially available plant samples. This study describes the first systematic analysis of 13,28-epoxy-oleanane-type triterpenoid saponins in the genus Ardisia using LC-ESI-MS. The results can provide the chemical support for further biological studies, phytochemotaxonomical studies and quality control of triterpenoid saponins in medicinal plants of the genus Ardisia. PMID- 25459940 TI - Determination of the lipophilicity (log P o/w) of organic compounds by microemulsion liquid chromatography. AB - Four microemulsion liquid chromatography (MELC) systems and one micellar liquid chromatography (MLC) system have been evaluated as potential high-throughput screening platforms capable of modeling the partitioning behaviors of drug compounds in an n-octanol/water system and predicting their lipophilicity (i.e., log P values). The microemulsion mobile phases is consisted of sodium dodecyl sulfate (SDS), butanol, octane, heptanes, octanol and water. A linear solvation energy relationship (LSER)-based method was used to compare the MELC and MLC systems, as well as several other biochemical systems, and to identify the optimal system by comparing their Euclidean distances with the LSER coefficients. The most effective MELC system had a mobile phase consisting of 3.0% (w/w) SDS, 6.0% (w/w) butanol, 0.8% (w/w) octanol, and 90.2% (w/w) water (pH 6.4). The results showed that it gave superior results to the other chromatographic systems in terms of its ability to predict the log P values of drug compounds. PMID- 25459941 TI - Pharmacokinetic properties of MH84, a gamma-secretase modulator with PPARgamma agonistic activity. AB - Alzheimer's disease (AD) is the most common cause of dementia. Since no causative treatment is available, new therapeutic options are utmost needed. Several pirinixic acid derivatives, including MH84 (2-((4,6-bis(4 (trifluoromethyl)phenethoxy)pyrimidin-2-yl)thio)hexanoic acid), have shown promising in vitro results as gamma-secretase modulators as well as PPARgamma activators as potential pharmacological compounds against AD. Using a newly developed and validated sensitive LC-MS (APCI-qTOF mass analyzer) method, the pharmacokinetic and long-term accumulating properties as well as the blood-brain barrier permeability of MH84 were evaluated in a preclinical animal study. MH84 was administered to mice by oral gavage with a dose of 12 mg/kg. Nine time points from 0.5 to 48 h with 6 animals per point were investigated. Additionally 6 animals were fed daily, for 21 days with an identical dose to determine possible long-term accumulation in plasma and brain tissue. The sample preparation was performed by a liquid-liquid extraction on Extrelut((r)) columns whereas the LC separation was operated on a MulthoHigh 100 RP 18-5 MU column (125 * 4 mm) using an isocratic mobile phase of formic acid (0.1% (v/v))-methanol mixture (11:89 (v/v)) at a flow rate of 1 ml/min. The validation confirmed the new LC-MS method to be precise, accurate and reliable. After oral application, Cmax and Tmax of unmetabolized MH84 was determined to be 10.90 MUg/ml and 3h in plasma. In brain tissue a constant level of 300 to maximum 320.64 ng/g was found after 1.5-6h. Daily gavage for 21 days did not lead to a long-term drug accumulation in the brain. The efficacy of the obtained MH84 levels needs to be investigated in further preclinical pharmacodynamic animal studies. PMID- 25459942 TI - Metabolomic screening of regional brain alterations in the APP/PS1 transgenic model of Alzheimer's disease by direct infusion mass spectrometry. AB - The identification of pathological mechanisms underlying to Alzheimer's disease is of great importance for the discovery of potential markers for diagnosis and disease monitoring. In this study, we investigated regional metabolic alterations in brain from the APP/PS1 mice, a transgenic model that reproduces well some of the neuropathological and cognitive deficits observed in human Alzheimer's disease. For this purpose, hippocampus, cortex, cerebellum and olfactory bulbs were analyzed using a high-throughput metabolomic approach based on direct infusion mass spectrometry. Metabolic fingerprints showed significant differences between transgenic and wild-type mice in all brain tissues, being hippocampus and cortex the most affected regions. Alterations in numerous metabolites were detected including phospholipids, fatty acids, purine and pyrimidine metabolites, acylcarnitines, sterols and amino acids, among others. Furthermore, metabolic pathway analysis revealed important alterations in homeostasis of lipids, energy management, and metabolism of amino acids and nucleotides. Therefore, these findings demonstrate the potential of metabolomic screening and the use of transgenic models for understanding pathogenesis of Alzheimer's disease. PMID- 25459943 TI - GC-FID coupled with chemometrics for quantitative and chemical fingerprinting analysis of Alpinia oxyphylla oil. AB - Analytical methods for quantitative analysis and chemical fingerprinting of volatile oils from Alpinia oxyphylla were established. The volatile oils were prepared by hydrodistillation, and the yields were between 0.82% and 1.33%. The developed gas chromatography-flame ionization detection (GC-FID) method showed good specificity, linearity, reproducibility, stability and recovery, and could be used satisfactorily for quantitative analysis. The results showed that the volatile oils contained 2.31-77.30 MUL/mL p-cymene and 12.38-99.34 mg/mL nootkatone. A GC-FID fingerprinting method was established, and the profiles were analyzed using chemometrics. GC-MS was used to identify the principal compounds in the GC-FID profiles. The profiles of almost all the samples were consistent and stable. The harvesting time and source were major factors that affected the profile, while the volatile oil yield and the nootkatone content had minor secondary effects. PMID- 25459944 TI - Characterization, HPLC method development and impurity identification for 3,4,3 LI(1,2-HOPO), a potent actinide chelator for radionuclide decorporation. AB - 3,4,3-LI(1,2-HOPO), 1,5,10,14-tetra(1-hydroxy-2-pyridon-6-oyl)-1,5,10,14 tetraazatetradecane), is a potent octadentate chelator of actinides. It is being developed as a decorporation treatment for internal contamination with radionuclides. Conventional HPLC methods exhibited speciation peaks and bridging, likely attributable to the agent's complexation with residual metallic ions in the HPLC system. Derivatization of the target ligand in situ with Fe(III) chloride, however, provided a single homogeneous iron-complex that can readily be detected and analyzed by HPLC. The HPLC method used an Agilent Eclipse XDB-C18 column (150 mm * 4.6mm, 5 MUm) at 25 degrees C with UV detection at 280 nm. A gradient elution, with acetonitrile (11% to 100%)/buffer mobile phase, was developed for impurity profiling. The buffer consisted of 0.02% formic acid and 10mM ammonium formate at pH 4.6. An Agilent 1200 LC-6530 Q-TOF/MS system was employed to characterize the [Fe(III)-3,4,3-LI(1,2-HOPO)] derivative and impurities. The proposed HPLC method was validated for specificity, linearity (concentration range 0.13-0.35 mg/mL, r = 0.9999), accuracy (recovery 98.3 103.3%), precision (RSD <= 1.6%) and sensitivity (LOD 0.08 MUg/mL). The LC/HRMS revealed that the derivative was a complex consisting of one 3,4,3-LI(1,2-HOPO) molecule, one hydroxide ligand, and two iron atoms. Impurities were also identified with LC/HRMS. The validated HPLC method was used in shelf-life evaluation studies which showed that the API remained unchanged for one year at 25 degrees C/60% RH. PMID- 25459945 TI - Tramadol chronic abuse: an evidence from hair analysis by LC tandem MS. AB - Hair analysis, as complementary matrix, has expanded across the spectrum of toxicological investigations for misuse drug monitoring. Hair has become an important matrix for drug analysis, owing to the possibility to detect target analytes for long time periods, depending on hair length. A liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been developed for the quantitation of tramadol, a widely used centrally acting analgesic, and its main metabolites in hair (ODMT, NDMT, NOT). Hair samples were decontaminated and incubated overnight in diluted hydrochloric acid; the extracts were purified by mixed-mode solid phase cartridges and analyzed by LC-MS/MS in positive ionization mode monitoring two transitions per analyte. The procedure was fully validated in terms of linearity, limit of detection and lower limit of quantitation (LLOQ), accuracy, precision, recovery, matrix effect and selectivity. The linear regression analysis was calibrated by deuterated internal standards; for all analytes, responses were linear over the range 0.04-40.00 ng/mg hair, with R(2) values of at least 0.995. The method offered satisfactory precision (RSD < 10%), accuracy (90-110%) and recovery (> 90%) values. The found LLOQ values for tramadol and metabolites were in the range 0.010-0.030 ng/mg hair. The proposed procedure was successfully applied to quantify tramadol and metabolites in real hair samples submitted to our laboratory: three cases of tramadol assumption within the therapeutic dosage (3 * 2 segments) and one case of tramadol abuse in a binge pattern (8 segments). The ranges found for TRAM, ODMT, NDMT and NOT were markedly higher in the abuse case (63.42-107.30, 3.76-6.26, 24.88-45.66, 0.22 1.18 ng/mg hair, respectively) compared to the other case reports (3.29-20.12, 0.28-1.87, 0.45-4.32, 0.07-0.80 ng/mg, respectively); also the values of NMDT/ODMT ratio differed significantly. According to the obtained data, we hypothesized that the binge pattern may influence the metabolites' to parent drug concentration ratios; therefore this parameter could represent a target assessment tool to monitor abuse cases. PMID- 25459946 TI - An immunodepletion procedure advances free angiopoietin-2 determination in human plasma samples during anti-cancer therapy with bispecific anti-Ang2/VEGF CrossMab. AB - Bispecific monoclonal IgG antibodies offer increased efficacy by antagonizing two different targets. Assessing drug mechanisms, target engagement and biomarker features, the quantification of free target levels is essential. The anti Ang2/VEGF-CrossMab (anti-A2V) recognizes soluble vascular endothelial growth factor-A (VEGF-A) and soluble angiopoietin-2 (Ang2). However, an assay for reliable free Ang2 determination is missing. Here, we describe an immunodepletion procedure that allows for selective quantification of free Ang2 target levels by taking into advantage the bispecificity of the therapeutic antibody. The specificity for VEGF was utilized to efficiently eliminate drug-bound Ang2 from plasma samples prior to an established Ang2 measurement. The magnetic bead-based depletion procedure used an anti-idiotypic monoclonal antibody (mAb) specific for the VEGF binding site of anti-A2V (anti-Id-anti-VEGF mAb) to capture the drug along with drug-bound Ang2. High efficiencies of 99.9% were obtained for anti-A2V depletion (concentration range 300 ng/mL to 10(6)ng/mL) reflecting a 1000-fold reduction of drug-bound Ang2. A significant impact of the interaction of anti-Id anti-VEGF mAb with anti-A2V on the Ang2 binding could be excluded. Moreover, reliable quantification of free Ang2 concentrations in plasma samples was assured by interference testing. Performing advanced free Ang2 determination including the immunodepletion step in parallel to established Ang2 measurement without immunodepletion, we compared free with total Ang2 concentrations in human plasma samples obtained from an anti-A2V Phase 1 clinical study. Samples from untreated patients displayed rather low and equal values for both free and total Ang2. In contrast, samples from drug-treated patients showed a significant reduction of free Ang2 accompanied by an accumulation in total Ang2. These results underline the value of the novel immunodepletion procedure for reliable discrimination of free vs. total target quantification with particular importance for pre-clinical and clinical development of anti-A2V. Moreover, this approach may serve as universal concept for the determination of free target levels of bispecific therapeutic antibodies. PMID- 25459947 TI - UHPLC-UV method for the determination of flavonoids in dietary supplements and for evaluation of their antioxidant activities. AB - A simple and rapid ultra-high performance liquid chromatographic (UHPLC) method coupled with an ultraviolet detector (UV) has been developed and validated for the separation and determination of 14 major flavonoids ((+/-)-catechin, (-) epicatechin, glycitin, (-)-epicatechin gallate, rutin, quercitrin, hesperidine, neohesperidine, daidzein, glycitein, quercetin, genistein, hesperetin, and biochanin A) in herbal dietary supplements. The flavonoids have been separated on a Chromolith Fast Gradient Monolithic RP-18e column utilizing a mobile phase composed of 0.05% trifluoroacetic acid in water and acetonitrile in gradient elution mode. Under these conditions, flavonoids were separated in a 5 min run. The selectivity of the developed UHPLC-UV method was confirmed by comparison with ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC MS/MS) analysis. The validation parameters such as linearity, sensitivity, precision, and accuracy were found to be highly satisfactory. The optimized method was applied to determination of flavonoids in different dietary supplements. Additionally, the developed HPLC-UV method combined with 2,2 diphenyl-1-picrylhydrazyl radical (DPPH) assay was used in the evaluation of antioxidant activity of the selected flavonoids. PMID- 25459948 TI - Detection, identification and quantification by 1H NMR of adulterants in 150 herbal dietary supplements marketed for improving sexual performance. AB - One hundred and fifty dietary supplements (DS) marketed to increase sexual performance were analyzed. All these formulations were claimed to contain only natural compounds, plant extracts and/or vitamins. (1)H NMR spectroscopy was used for detecting the presence of adulterants and for their identification and quantification. Mass spectrometry was used as a complementary method for confirming the chemical structures. 61% of DS were adulterated with phosphodiesterase-5 inhibitors (PDE-5i) (27% with the PDE-5i medicines sildenafil, tadalafil and vardenafil, and 34% with their structurally modified analogues). Among them, 64% contained only one PDE-5i and 36% mixtures of two, three and even four. The amounts of PDE-5i medicines were higher than the maximum recommended dose in 25% of DS tainted with these drugs. Additional 5.5% DS included other drugs for the treatment of sexual dysfunction (yohimbine, flibanserin, phentolamine, dehydroepiandrosterone or testosterone). Some DS (2.5%) contained products (osthole, icariin) extracted from plants known to improve sexual performance. Only 31% of the samples could be considered as true herbal/natural products. A follow-up over time of several DS revealed that manufacturers make changes in the chemical composition of the formulations. Lack of quality or consistent manufacture (contamination possibly due to inadequate cleaning of the manufacturing chain, presence of impurities or degradation products, various compositions of a given DS with the same batch number, inadequate labelling) indicated poor manufacturing practices. In conclusion, this paper demonstrates the power of (1)H NMR spectroscopy as a first-line method for the detection of adulterated herbal/natural DS and the need for more effective quality control of purported herbal DS. PMID- 25459949 TI - Development and validation of a liquid-chromatography tandem mass spectrometry method to determine in vitro and in vivo histamine release. AB - Histamine is an important biogenic amine involved in regulating numerous physiological and pathophysiological processes in humans and animals. To date, there have been very few studies focused on developing and validating sensitive liquid-chromatography-tandem mass spectrometric (LC-MS/MS) assays capable of quantitative trace level histamine analysis in biological matrices. In the present study, a rapid and sensitive LC-MS/MS assay, amenable to high throughput analysis was developed and validated to characterize in vitro and in vivo histamine release. The LC-MS/MS procedure incorporating deuterium labeled internal standards provides rapid resolution of histamine with excellent sensitivity, precision, and accuracy. Histamine eluted at 1.5 min and was well separated from endogenous plasma peaks. The total run time of the assay was 8.0 min. A linear (r(2) >= 0.99) instrument response over the entire concentration range of 1.0-1000 ng/mL was observed. Excellent accuracy (error +/- 3.4%) and precision (CV +/- 10%) of the assay was demonstrated, with the lower limit of quantitation (LLOQ) at 15.6 ng/mL. The validated LC-MS/MS assay was applied to determine histamine release in both in vitro and in vivo models. Peritoneal mast cells treated with prototypical degranulating agents (Compound 48/80 and Teicoplanin) showed that the two chemicals caused approximately 40% histamine release. In rats, using this assay, basal histamine plasma levels were typically under 100 ng/mL. Treatment with an agent suspected of causing anaphylactic type reactions resulted in plasma histamine levels to increase above 3000 ng/mL. The LC-MS/MS assay presented in this study can be applied to further characterize the physiological and pathophysiological role of histamine release in complex in vitro and in vivo models. Importantly, the LC-MS/MS assay may be useful in assessing active pharmaceutical ingredient-mediated degranulation and anaphylaxis as part of either a pre-market or a post-market assessment of drug products. PMID- 25459950 TI - A transcription/translation-based gene signature predicts resistance to chemotherapy in breast cancer. AB - Although chemotherapy is widely used to treat human cancers, most chemotherapeutic agents only benefit a small fraction of patients because of the heterogeneity of cancers. Therefore, identifying of the sensitivity of cancers toward various chemotherapies would be important for choosing of chemotherapeutic regime. In this study, a 23-gene chemoresistance signature was developed from chemoresistant breast cancers. Functions of the genes in the signature were related with transcription and translation. The signature was indicative of chemoresistance and associated with poor prognosis in multiple chemotherapeutic agents and cancer types. Furthermore, by applying computational approaches, we identified several compounds that might specifically affect the chemoresistant signature. Decitabine (DAC) was the compound most likely to target the signature. In vitro and clinical analysis confirmed effect of DAC toward both breast cancer cell lines and ovarian cancers respectively. In conclusion, our study identified a chemoresistant signature that is both predictive and prognostic, and the signature-related chemoresistance could be suppressed by DAC treatment. PMID- 25459951 TI - Effect of lithium salts addition on the ionic liquid based extraction of essential oil from Farfarae Flos. AB - In this study, an ionic liquids (ILs) based extraction approach has been successfully applied to the extraction of essential oil from Farfarae Flos, and the effect of lithium chloride was also investigated. The results indicated that the oil yields can be increased by the ILs, and the extraction time can be reduced significantly (from 4h to 2h), compared with the conventional water distillation. The addition of lithium chloride showed different effect according to the structures of ILs, and the oil yields may be related with the structure of cation, while the chemical compositions of essential oil may be related with the anion. The reduction of extraction time and remarkable higher efficiency (5.41 62.17% improved) by combination of lithium salt and proper ILs supports the suitability of the proposed approach. PMID- 25459952 TI - Investigation of antibody disulfide reduction and re-oxidation and impact to biological activities. AB - Disulfide reduction in therapeutic monoclonal antibodies can occur during cell harvest operations as a result of cell breakage. Understanding these product quality changes and manufacturers' ability to control them would likely be of concern to regulatory bodies. To study the biological impact of disulfide reduction, mAbs, including IgG2kappa, IgG2lambda, IgG1kappa, and IgG1lambda forms, were partially reduced with dithiothreitol (DTT). Samples generated had approximately 10% or 50% intact molecules as determined by nrCE-SDS. Similar to the type of partial reduction obtained during uncontrolled harvest operations, DTT reduced antibodies were free from sulfur-linked adduct, such as attached cysteine. These partially reduced materials were incubated under physiological (blood-mimicking) redox conditions in vitro to follow the fate of the interchain cysteines. Within 8h, the original disulfide bonds reformed. For mAbA, an IgG2kappa, the initial re-oxidized state favored the IgG2-A disulfide isoform, which then underwent conversion over time to other isoforms. Reduced material was fully active. Results suggest that the type of disulfide reduction would have minimal impact to safety or efficacy. Antibody re-oxidation rates were found to be in the order of IgG2kappaA; p.E1211K) was identified in exon 21 of SCN2A gene. This mutation has been reported previously only in a Japanese patient with IS. CONCLUSION: This is the first case of SCN2A mutation identified in Chinese. Similarity of our case and one Japanese case of infantile spasm indicated that this E1211K mutation is important as possible etiology of IS. Trial of Modified Atkins Diet for other cases of infantile spasm with similar SCN2A mutations is worthwhile pursuing. PMID- 25459970 TI - Trinucleotide insertion in the SMN2 promoter may not be related to the clinical phenotype of SMA. AB - BACKGROUND: More than 90% of spinal muscular atrophy (SMA) patients show homozygous deletion of SMN1 (survival motor neuron 1). They retain SMN2, a highly homologous gene to SMN1, which may partially compensate for deletion of SMN1. Although the promoter sequences of these two genes are almost identical, a GCC insertion polymorphism has been identified at c.-320_-321 in the SMN1 promoter. We have also found this insertion polymorphism in an SMN2 promoter in an SMA patient (Patient A) who has SMA type 2/3. PURPOSE: The aims of this study were to determine the frequency of the GCC insertion polymorphism in SMA patients, and to evaluate its effect on SMN transcription efficiency. PATIENTS AND METHODS: Fifty one SMA patients, including Patient A, were involved in this study. SMN2 transcript levels in white blood cells were measured by real-time polymerase chain reaction. Screening of the GCC insertion polymorphism was performed using denaturing high-pressure liquid chromatography. The transcription efficiency of the promoter with the insertion mutation was evaluated using a reporter-gene assay. RESULTS: All SMA patients in this study were homozygous for SMN1 deletion. Patient A retained two copies of SMN2, and showed only a small amount of SMN2 transcript in white blood cells. We detected a GCC insertion polymorphism at c. 320_-321 only in Patient A, and not in 50 other SMA patients. The polymorphism had a slight but significant negative effect on transcription efficiency. DISCUSSION AND CONCLUSION: Patient A was judged to be an exceptional case of SMA, because the GCC insertion polymorphism rarely exists in SMN1-deleted SMA patients. The GCC insertion polymorphism did not enhance the transcriptional efficiency of SMN2. Thus, this GCC insertion polymorphism in the SMN2 promoter may not be associated with the milder phenotype of the patient. Patient A suggests that there are other unknown factors modifying the clinical phenotype of SMA. PMID- 25459971 TI - Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study. AB - INTRODUCTION: Patau syndrome, trisomy 13, is the third commonest autosomal trisomy. It is associated with a 25-50% prevalence of epilepsy, but detailed electroclinical descriptions are rare. The occurrence of early-onset photosensitivity has recently been reported in single patients. MATERIALS/PATIENTS: We collected electroclinical data on 8 infants (age range from 2 months to 3 years and 9 months, median: 17 months) with Patau syndrome referred for an EEG in our Clinical Neurophysiology Department between 1991 and 2011. METHODS: All EEGs, case-notes, cytogenetic diagnosis and neuroimaging when available were reviewed; data on the occurrence of seizures, epileptiform discharges, photoparoxysmal response and their characteristics in terms of positive frequencies, latencies, grade and duration were noted and analysed. RESULTS: Two patients had been previously diagnosed with epilepsy (one with tonic spasms and one with multiple seizure types). We found 3 patients with photosensitive myoclonic epilepsy (37.5%), and one with non-photosensitive myoclonic epilepsy. We also recorded non-epileptic myoclonic jerks in one patient known to suffer from epileptic spasms. Among photosensitive patients we found self-limited, Waltz's grade 2-4, spike-wave/polyspike-wave discharges in low, medium and high frequency ranges in two patients and in the high frequency range in the third patient, with latencies and duration from less than 1s to a maximum of 9s. CONCLUSIONS: In our cohort of Patau syndrome patients, we found a high prevalence of spasms and photic-induced myoclonic jerks. Photosensitivity shows an unusual early age of onset. PMID- 25459972 TI - Carnitine-acylcarnitine translocase deficiency: Two neonatal cases with common splicing mutation and in vitro bezafibrate response. AB - BACKGROUND: Mitochondrial fatty acid oxidation (FAO) disorders are among the causes of acute encephalopathy- or myopathy-like illness. Carnitine-acylcarnitine translocase (CACT) deficiency is a rare FAO disorder, which represent an energy production insufficiency during prolonged fasting, febrile illness, or increased muscular activity. CACT deficiency is caused by mutations of the SLC25A20 gene. Most patients developed severe metabolic decompensation in the neonatal period and died in infancy despite aggressive treatment. PATIENTS AND METHODS: We herein report the clinical findings of two unrelated cases of CACT deficiency with mutation confirmation, and in vitro bezafibrate responses using in vitro probe acylcarnitine (IVP) assay. Patients 1 and 2 are products of nonconsanguineous parents. Both patients developed cardiac arrest at day 3 of life but survived the initial events. Their blood chemistry revealed hypoglycemia and metabolic acidosis. The acylcarnitine profiles in both patients demonstrated increased long chain acylcarnitines, suggesting CACT or carnitine palmitoyltransferase-2 (CPT2) deficiency. RESULTS: The mutation analysis identified homozygous IVS2-10T>G in the SLC25A20 gene in both patients, confirming the diagnosis of CACT deficiency. The IVP assay revealed increased C16, C16:1, but decreased C2 with improvement by bezafibrate in the cultured fibroblasts. The short-term clinical trial of bezafibrate in Patient 1 did not show clinical improvement, and died after starting the trial for 6 months. CONCLUSION: This splicing mutation has been identified in other Asian populations indicating a possible founder effect. IVP assay of cultured fibroblasts could determine a response to bezafibrate treatment. A long-term clinical trial of more enrolled patients is required for evaluation of this therapy. PMID- 25459973 TI - Exercise training in patients with heart disease: review of beneficial effects and clinical recommendations. AB - Over the last decades exercise training has evolved into an established evidence based therapeutic strategy with prognostic benefits in many cardiovascular diseases (CVDs): In stable coronary artery disease (CAD) exercise training attenuates disease progression by beneficially influencing CVD risk factors (i.e., hyperlipidemia, hypertension) and coronary endothelial function. In heart failure (HF) with reduced ejection fraction (HFrEF) training prevents the progressive loss of exercise capacity by antagonizing peripheral skeletal muscle wasting and by promoting left ventricular reverse remodeling with reduction in cardiomegaly and improvement of ejection fraction. Novel areas for exercise training interventions include HF with preserved ejection fraction (HFpEF), pulmonary hypertension, and valvular heart disease. In HFpEF, randomized studies indicate a lusitropic effect of training on left ventricular diastolic function associated with symptomatic improvement of exercise capacity. In pulmonary hypertension, reductions in pulmonary artery pressure were observed following endurance exercise training. Recently, innovative training methods such as high intensity interval training, resistance training and others have been introduced. Although their prognostic value still needs to be determined, these approaches may achieve superior improvements in aerobic exercise capacity and gain in muscle mass, respectively. In this review, we give an overview of the prognostic and symptomatic benefits of exercise training in the most common cardiac disease entities. Additionally, key guideline recommendations for the initiation of training programs are summarized. PMID- 25459975 TI - Strategies for promoting physical activity in clinical practice. AB - The time has come for healthcare systems to take an active role in the promotion of physical activity (PA). The connection between PA and health has been clearly established and exercise should be viewed as a cost effective medication that is universally prescribed as a first line treatment for virtually every chronic disease. While there are potential risks associated with exercise, these can be minimized with a proper approach and are far outweighed by the benefits. Key to promoting PA in the clinical setting is the use of a PA Vital Sign in which every patient's exercise habits are assessed and recorded in their medical record. Those not meeting the recommended 150min per week of moderate intensity PA should be encouraged to increase their PA levels with a proper exercise prescription. We can improve compliance by assessing our patient's barriers to being more active and employing new and evolving technology like accelerometers and smart phones applications, along with various websites and programs that have proven efficacy. PMID- 25459976 TI - Changing the endpoints for determining effective obesity management. AB - Health authorities worldwide recommend weight loss as a primary endpoint for effective obesity management. Despite a growing public awareness of the importance of weight loss and the spending of billions of dollars by Americans in attempts to lose weight, obesity prevalence continues to rise. In this report we argue that effective obesity management in today's environment will require a shift in focus from weight loss as the primary endpoint, to improvements in the causal behaviors; diet and exercise/physical activity (PA). We reason that increases in PA combined with a balanced diet are associated with improvement in many of the intermediate risk factors including cardiorespiratory fitness (CRF) associated with obesity despite minimal or no weight loss. Consistent with this notion, we suggest that a focus on healthy behaviors for the prevention of additional weight gain may be an effective way of managing obesity in the short term. PMID- 25459977 TI - Joint hypermobility and the heritable disorders of connective tissue: clinical and empirical evidence of links with psychiatry. AB - OBJECTIVE: The heritable disorders of connective tissue (HDCTs) are a group of genetic disorders affecting connective tissue matrix proteins. Fragility, laxity of tissues and joint hypermobility (JH) are commons features of HDCT for which the prognosis may range from benign to life threatening. JH and HDCTs, especially joint hypermobility syndrome, Ehlers-Danlos syndromes and Marfan syndrome, have been associated with psychiatric symptomatology. We explored the existing knowledge concerning this association in order to provide an overview of mental disorders linked to JH/HDCT, as well as the hypotheses proposed to explain such association. METHOD: A comprehensive search of scientific online databases and references lists was conducted, encompassing publications based on quantitative and qualitative research, including case reports. RESULTS: Psychiatric conditions in which there is some evidence of an association with JH/HDCT are anxiety disorders, depression, schizophrenia, neurodevelopmental disorders (autism, attention deficit/hyperactivity disorder, and developmental coordination disorder), eating disorders, personality disorders and substance use/misuse. CONCLUSION: Despite the need of more research, the available data highlight the importance of examining psychiatric symptoms in those affected by JH/HDCT and the importance of providing interventions with a multidisciplinary approach. The relationship between JH/HDCT and mental disorders merits further attention in order to improve current knowledge and clarify a possible common etiology. PMID- 25459974 TI - Treating coronary disease and the impact of endothelial dysfunction. AB - Ischemic heart disease is the leading cause of morbidity and mortality throughout the world. Many clinical trials have suggested that lifestyle and pharmacologic interventions are effective in attenuating atherosclerotic disease progression and events development. However, an individualized approach with careful consideration to comprehensive vascular health is necessary to perform successful intervention strategies. Endothelial dysfunction plays a pivotal role in the early stage of atherosclerosis and is also associated with plaque progression and occurrence of atherosclerotic complications. The assessment of endothelial function provides us with important information about individual patient risk, progress and vulnerability of disease, and guidance of therapy. Thus, the application of endothelial function assessment might enable clinicians to innovate ideal individualized medicine. In this review, we summarize the current knowledge on the impact of pharmacological therapies for atherosclerotic cardiovascular disease on endothelial dysfunction, and argue for the utility of non-invasive assessment of endothelial function aiming at individualized medicine. PMID- 25459978 TI - Neuropsychiatric features associated with nutritional and metabolic status in a gastric bypass patient. AB - Bariatric patients may present for psychiatric evaluation due to exacerbation of preexisting psychiatric disorders, new onset psychiatric disorders and/or neuropsychiatric complications associated with abnormal nutritional and metabolic states following the surgical procedure. These neuropsychiatric complications can be insidious, and clinical manifestations may vary, possibly due to the individual central nervous system (CNS) vulnerability to nutritional decline. Lack of awareness of these complications and their symptoms can result in delays in diagnosis and treatment. Identifying and correcting underlying pathophysiologic processes that lead to such neuropsychiatric syndromes can be challenging. We report a case of a patient who developed a protracted course of mood and cognitive disorder after gastric bypass surgery, which illustrates some of the complexities encountered in diagnosing and managing these patients. PMID- 25459980 TI - Staged decision making was an attractive alternative to a plenary approach in panel diagnosis as reference standard. AB - OBJECTIVES: To assess differences between three different decision-making approaches in the method of panel diagnosis as reference standard in diagnostic research. STUDY DESIGN AND SETTING: Within a diagnostic study, the prevalence of heart failure (HF) and chronic obstructive pulmonary disease (COPD) was compared using three approaches of decision making in panel diagnosis. These were (1) a plenary discussion among experts followed by a consensus decision (plenary); (2) a predefined decision rule based on final diagnoses made by each member individually (individual); and (3) a staged procedure in which first the final diagnosis per individual member is generated followed by a plenary discussion of those cases with disagreement (staged). RESULTS: Prevalence of HF and COPD according to plenary approach was 46% and 28%, respectively. Individual approach diagnosed 28% of patients with HF and 31% with COPD and revealed 28 and 8 discordant diagnoses, respectively, compared with plenary approach. Staged approach revealed a prevalence of 43% and 28% for HF and COPD, respectively, with eight discordant diagnoses for HF and none for COPD. CONCLUSION: The staged approach is an attractive choice as it produces very similar results to the full plenary approach, while having the advantage of being less time consuming. Additionally, it provides insights into the decision-making process of the panel, and the "difficult-to-diagnose" patients can easily be identified. PMID- 25459981 TI - Diagnostic accuracy of self-reported arthritis in the general adult population is acceptable. AB - OBJECTIVE: To summarize the diagnostic accuracy of self-reported osteoarthritis (OA), rheumatoid arthritis (RA), and arthritis (i.e., unspecified) in the general adult population. STUDY DESIGN AND SETTING: A systematic literature search identified studies reporting diagnostic data on self-reported diagnosis of OA, RA, or arthritis in adults in population-based or primary care samples. Index tests included any form of participant-reported presence of the condition. Reference tests included rheumatologist, physician, or health professional examination; medical record review; physician interview; laboratory tests; or radiography. Relevant articles were scored using the QUADAS tool. Diagnostic values were summarized using pooled estimates for sensitivity and specificity. RESULTS: The search strategy identified 16 articles: 11 for OA, 5 for RA, and 4 for arthritis. Four of 16 articles scored high on quality. The pooled sensitivity and specificity were 0.75 [95% confidence interval (CI): 0.56, 0.88] and 0.89 (95% CI: 0.77, 0.95) for OA, 0.88 (95% CI: 0.59, 0.97) and 0.93 (95% CI: 0.66, 0.99) for RA, and 0.71 (95% CI: 0.59, 0.80) and 0.79 (95% CI: 0.65, 0.89) for arthritis. There were not enough studies to conduct meta-analyses for joint specific OA. CONCLUSION: The accuracy of self-reported OA and RA is acceptable for large-scale studies in which rheumatologist examination is not feasible. More high-quality studies are required to confirm the accuracy of self-reported arthritis and joint-specific OA. PMID- 25459982 TI - Evaluation of nystatin containing chitosan hydrogels as potential dual action bio active restorative materials: in vitro approach. AB - Healing is a specific biological process related to the general phenomenon of growth and tissue regeneration and is a process generally affected by several systemic conditions or as detrimental side-effects of chemotherapy- and radiotherapy-induced inflammation of the oral mucosa. The objectives of this study is to evaluate the novel chitosan based functional drug delivery systems, which can be successfully incorporated into "dual action bioactive restorative materials", capable of inducing in vitro improved wound healing prototype and containing an antibiotic, such as nystatin, krill oil as an antioxidant and hydroxyapatite as a molecular bone scaffold, which is naturally present in bone and is reported to be successfully used in promoting bone integration when implanted as well as promoting healing. The hydrogels were prepared using a protocol as previously reported by us. The physico-chemical features, including surface morphology (SEM), release behaviors, stability of the therapeutic agent antioxidant-chitosan, were measured and compared to the earlier reported chitosan antioxidant containing hydrogels. Structural investigations of the reactive surface of the hydrogel are reported. Release of nystatin was investigated for all newly prepared hydrogels. Bio-adhesive studies were performed in order to assess the suitability of these designer materials. Free radical defense capacity of the biomaterials was evaluated using established in vitro model. The bio adhesive capacity of the materials in the in vitro system was tested and quantified. It was found that the favorable synergistic effect of free radical built-in defense mechanism of the new functional materials increased sustainable bio-adhesion and therefore acted as a functional multi-dimensional restorative material with potential application in wound healing in vitro. PMID- 25459983 TI - Electrokinetic and hemostatic profiles of nonwoven cellulosic/synthetic fiber blends with unbleached cotton. AB - Greige cotton contains waxes and pectin on the outer surface of the fiber that are removed when bleached, but these components present potential wound dressing functionality. Cotton nonwovens blended with hydrophobic and hydrophilic fibers including viscose, polyester, and polypropylene were assessed for clotting activity with thromboelastography (TEG) and thrombin production. Clotting was evaluated based on TEG measurements: R (time to initiation of clot formation), K (time from end of R to a 20 mm clot), alpha (rate of clot formation according to the angle tangent to the curve as K is reached), and MA (clot strength). TEG values correlate to material surface polarity as measured with electrokinetic parameters (zetaplateau, Deltazeta and swell ratio). The material surface polarity (zetaplateau) varied from -22 to -61 mV. K values and thrombin concentrations were found to be inversely proportional to zetaplateau with an increase in material hydrophobicity. An increase in the swell ratios of the materials correlated with decreased K values suggesting that clotting rates following fibrin formation increase with increasing material surface area due to swelling. Clot strength (MA) also increased with material hydrophobicity. Structure/function implications from the observed clotting physiology induced by the materials are discussed. PMID- 25459985 TI - The interactive effect of maltreatment in the family and unstable institutional caregiving in predicting behavior problems in toddlers. AB - The current study extends research on the effects of institutionalization, most notably by examining whether-and how-both pre-institutional maltreatment in the family and the stability and consistency of institutional care interact to shape emotional and behavioral development. Fifty Portuguese children, placed in residential institutions when 8 days to 26 months of age, were evaluated using the Child Behavior Checklist when aged 18-31 months. Caregiver-rated internalizing and externalizing behavior problems proved to be unrelated to both early family and institutional experiences, as main effects, but the interaction of these factors significantly predicted externalizing problems: a history of maltreatment in the family coupled with unstable institutional caregiving arrangements predicted especially elevated levels of externalizing problems. Results are discussed in terms of the importance of more distal and proximate developmental experiences. PMID- 25459984 TI - Maternal abuse history and self-regulation difficulties in preadolescence. AB - Although poor parenting is known to be closely linked to self-regulation difficulties in early childhood, comparatively little is understood about the role of other risk factors in the early caregiving environment (such as a parent's own experiences of childhood abuse) in developmental pathways of self regulation into adolescence. Using a longitudinal design, this study aimed to examine how a mother's history of abuse in childhood relates to her offspring's self-regulation difficulties in preadolescence. Maternal controlling parenting and exposure to intimate partner aggression in the child's first 24-36 months were examined as important early social and environmental influences that may explain the proposed connection between maternal abuse history and preadolescent self-regulation. An ethnically diverse sample of mothers (N=488) who were identified as at-risk for child maltreatment was recruited at the time of their children's birth. Mothers and their children were assessed annually from the child's birth through 36 months, and at age 9-11 years. Structural equation modeling and bootstrap tests of indirect effects were conducted to address the study aims. Findings indicated that maternal abuse history indirectly predicted their children's self-regulation difficulties in preadolescence mainly through maternal controlling parenting in early childhood, but not through maternal exposure to aggression by an intimate partner. Maternal history of childhood abuse and maternal controlling parenting in her child's early life may have long term developmental implications for child self-regulation. PMID- 25459986 TI - Mothers' self-reported violence toward their children: a multifaceted risk analysis. AB - The universal aim of decreasing parental violence against children requires the detection of risk factors associated with violent behavior among parents. Although research has identified a number of such risk factors, these findings are scattered and a comprehensive picture is lacking. In the present study, 20 child-, parent- and family-related factors have been included in a combined analysis to assess which of these may pose as risk factors for mothers' severe violent behavior toward their children. The study is based on a representative sample of 2,716 Finnish mothers with 0-12-year-old children and was conducted as an anonymous survey. Analyses were carried out using logistic regression models. 6% of the mothers had committed severe violent acts, i.e. slapped, hit, punched (with a fist), kicked, bit, hit/try to hit the child with an object or shook (under 2 year old) child at least once during the 12 months preceding the survey. Corporal punishment experienced by the mother as a child (OR 2.45, CI 1.55-3.88) or used by the mother as a method of discipline (OR 11.14, CI 5.95-20.87), strongly increased the likelihood of severe violent acts. Additionally, work- or family-related stress (OR 1.83, CI 1.24-2.73) and lack of help in dealing with parenting problems (OR 2.55, CI 1.66-3.90) were detected as risk factors for severe violent acts toward one's own child. The findings suggest that prevention of corporal punishment may be an important hinder to the transmission of experiences of violence from one generation to another, and that contextual and situational factors may overlap the influence of individual-related risk factors. PMID- 25459987 TI - Body mass index and anxiety/depression as mediators of the effects of child sexual and physical abuse on physical health disorders in women. AB - The relation between childhood sexual abuse (CSA) and physical health disorders in adulthood, and what factors may serve as mediators, remains poorly understood. Using data from the 2007 Adult Psychiatric Morbidity Survey (N=3,486), we tested whether CSA was associated with physical health disorders in adult women and if mediated effects via body mass index (BMI), anxiety/depression, alcohol dependence, and smoking were present. Compared to women with no CSA, women who had experienced CSA involving intercourse had more than twice the odds of being obese, more than 3 times the odds of experiencing mental health disorders, more than 4 times the odds of being alcohol dependent, more than 5 times the odds of being drug dependent, and more than 6 times the odds of attempting suicide. Those experiencing both CSA and child physical abuse (CPA) were on average over 11kg heavier than those with neither CSA nor CPA. After controlling for demographics, CPA, and childhood bullying, CSA was associated with the majority of physical health disorders studied (typically 50-100% increases in odds). Evidence was found consistent with mediation by BMI (typically accounting for 5-20% increases in odds) and anxiety/depression (typically accounting for 8-40% increases in odds), in a dose-response manner, for the majority of physical health disorders. Bidirectional relations among these mediators and physical health disorders, and residual confounding, may have led to overestimation of mediation through BMI and anxiety/depression and underestimation of mediation through alcohol/smoking. Relations between both CPA and childhood bullying and physical health disorders in adulthood were also found. Longitudinal studies employing more sensitive measures of potential mediators are now required. PMID- 25459988 TI - Protective factors associated with resilient functioning in young adulthood after childhood exposure to violence. AB - Children may be subjected to many forms of violence and a significant number will experience multiple victimizations. These children are at high risk for developing psychological and emotional difficulties that may last into adulthood. Despite the increased risk for psychopathology, a substantial percentage of young adults exhibit resilient functioning following a history of childhood violence. This study examines the role of social support, spirituality, and emotional intelligence in promoting resilience during emerging adulthood. Participants included 321 young adult American college students, age 18-24, who experienced childhood violence, including community violence, interpersonal aggression, child maltreatment, peer/sibling victimization, and/or sexual assault. Findings revealed that this sample was highly victimized, with an average of 9 violent experiences reported during childhood. Hierarchical multiple regression analyses indicated that after controlling for exposure to childhood victimization, other potentially traumatic events, and current depression and anxiety symptoms, higher resilience during emerging adulthood was associated with greater spirituality, greater emotional intelligence, and support from friends (but not from family). Findings suggest that the potency of protective factors outweighs that of adversity and psychopathology when predicting resilient functioning. By identifying variables that can enhance resilience, this study offers unique insight into how functioning may be improved by both individual and environmental factors. PMID- 25459989 TI - Do early care and education services improve language development for maltreated children? Evidence from a national child welfare sample. AB - Young children under 6 years old are over-represented in the U.S. child welfare system (CWS). Due to their exposure to early deprivation and trauma, they are also highly vulnerable to developmental problems, including language delays. High quality early care and education (ECE) programs (e.g. preschool, Head Start) can improve children's development and so policymakers have begun calling for increased enrollment of CWS-supervised children in these programs. However, it is not a given that ECE will benefit all children who experience maltreatment. Some types of maltreatment may result in trauma-related learning and behavior challenges or developmental deficits that cause children to respond to ECE settings differently. The current study uses data from a nationally representative survey of children in the U.S. child welfare system, the National Survey of Child and Adolescent Well-Being II, to assess whether young CWS supervised children (N=1,652) who were enrolled in ECE had better language development outcomes 18 months later than those not enrolled in ECE. We also explore whether the type of maltreatment that brought children to the CWS' attention moderates the relationship between ECE and children's language development. After controlling for children's initial scores on the Preschool Language Scale (PLS-3), type(s) of maltreatment experienced, and child and caregiver demographics, we found that ECE participation predicted better PLS-3 scores at follow-up, with a positive interaction between ECE participation and supervisory neglect. ECE seems to be beneficial for CWS-involved children's early language development, especially for children referred to the CWS because they lack appropriate parent supervision at home. PMID- 25459990 TI - Domestic violence and immigration status among Latina mothers in the child welfare system: findings from the National Survey of Child and Adolescent Well being II (NSCAW II). AB - Many children involved with the child welfare system witness parental domestic violence. The association between children's domestic violence exposure and child welfare involvement may be influenced by certain socio-cultural factors; however, minimal research has examined this relationship. The current study compares domestic violence experiences and case outcomes among Latinas who are legal immigrants (n=39), unauthorized immigrants (n=77), naturalized citizens (n=30), and US-born citizen mothers (n=383) reported for child maltreatment. This analysis used data from the second round of the National Survey of Child and Adolescent Well-being. Mothers were asked about whether they experienced domestic violence during the past year. In addition, data were collected to assess if (a) domestic violence was the primary abuse type reported and, if so, (b) the maltreatment allegation was substantiated. Results show that naturalized citizens, legal residents, and unauthorized immigrants did not differ from US born citizens in self-reports of domestic violence; approximately 33% of mothers reported experiences of domestic violence within the past year. Yet, unauthorized immigrants were 3.76 times more likely than US-born citizens to have cases with allegations of domestic violence as the primary abuse type. Despite higher rates of alleged domestic violence, unauthorized citizens were not more likely than US born citizens to have these cases substantiated for domestic violence (F(2.26, 153.99)=0.709, p=.510). Findings highlight that domestic violence is not accurately accounted for in families with unauthorized immigrant mothers. We recommend child welfare workers are trained to properly assess and fulfill the needs of immigrant families, particularly as it relates to domestic violence. PMID- 25459991 TI - Acute hepatitis C virus infection among HIV-positive men having sex with men, southeastern France. PMID- 25459992 TI - Coffee consumption and risk of gastric cancer: an updated meta-analysis. AB - OBJECTIVES: The aim of this study was to perform an updated review to evaluate the effect of coffee consumption on the risk of gastric cancer. METHODS: We searched the PubMed and Embase database up to October 14th, 2013. Risk ratio (RR) and corresponding 95% confidence intervals (CIs) for the risk of gastric cancer were used as effect sizes. Overall effect sizes were derived using a fixed effects model or a random-effects model when appropriate. Then in subgroup analyses, the data were reanalyzed, which were stratified by gender, area and follow-up time. RESULTS: A total of 8 separate studies, including 312,993 volunteers (among them 1429 were diagnosed with gastric cancer in 10-18 years' follow-up), were considered in the meta-analysis. The overall estimate of coffee consumption on the risk of gastric cancer showed a pooled RR of 1.24 (95% CI: 1.03-1.49; P=0.026). In subgroup analyses, the pooled RR of gastric cancer was 1.36 (95% CI: 1.06-1.75) for USA volunteers and 1.29 (95% CI: 1.05-1.59) for people with more than 15-year follow-up time. The sensitivity analysis proved the stability and credibility of our results, and there was no significant bias (Begg's test P=0.640, Egger's test P=0.600) among the studies. CONCLUSIONS: It indicated that coffee consumption was associated with the development of gastric cancer. More coffee drinking could result in the increased risk of gastric cancer. PMID- 25459993 TI - E-cadherin, guardian of liver physiology. AB - E-cadherin is a cell-to-cell adhesion molecule involved in epithelial cell behavior, tissue formation and cancer suppression. In the liver, E-cadherin is expressed by hepatocytes and biliary epithelial cells. However, the exact role of E-cadherin in hepatic pathophysiology remains largely unknown. Recently, specific loss of E-cadherin in liver epithelial cells has been shown to favor periportal fibrosis, periportal inflammation and liver cancer progression, suggesting that E cadherin is a central liver protector. PMID- 25459994 TI - Protective effects of ursolic acid in an experimental model of liver fibrosis through Nrf2/ARE pathway. AB - AIM: Liver fibrosis is a reversible wound-healing response that occurs following liver injury. In this study, we aimed to investigate the possible protective effects of ursolic acid in liver fibrosis induced by carbon tetrachloride (CCl4). METHODS: ICR mice were randomly divided into six groups (Group 1: normal; Group 2: CCl4-treated group; Group 3: CCl4 plus ursolic acid 25mg/kg group; Group 4: CCl4 plus ursolic acid 50mg/kg group; Group 5: CCl4 plus colchicine 1mg/kg group; Group 6: ursolic acid 50mg/kg group). Mice were administered with CCl4 (2 mL of CCl4 in olive oil (1:1, v/v) per kg body weight twice weekly) by intraperitoneal injection and oral injection of colchicine (1mg/kg) or ursolic acid (25, 50mg/kg) daily. After six weeks, serum aminotransferase activity, hepatic reactive oxygen species (ROS) production, thiobarbituric acid reactive substances (TBARS), antioxidase (SOD, CAT, GPx) activity and histopathological analysis were performed. The levels of nuclear factor E2-related factor 2 (Nrf2), NAD(P)H: quinone oxidoreductase-1 (NQO1), glutathione S-transferase (GST) and heme oxygenase-1 (HO-1), tumor necrosis factor-alpha (TNF-alpha), prostaglandin E2 (PGE2) and inducible nitric oxide synthase (iNOS), Bcl-2 and caspase-3 were measured. RESULTS: Ursolic acid significantly prevented CCl4-induced hepatotoxicity and fibrosis, indicated by both diagnostic indicators and histopathological analysis. CCl4-induced profound elevations of oxidative stress, inflammation and apoptosis in liver were suppressed by ursolic acid. CONCLUSIONS: These results suggest that ursolic acid has the hepatoprotective actions. The inhibition of CCl4-induced liver fibrosis, inflammation and apoptosis by ursolic acid is due at least in part to its ability to modulate the Nrf2/ARE signalling pathway. PMID- 25459996 TI - H2S2014 in Kyoto: the 3rd International Conference on H2S in Biology and Medicine. AB - About 20 years ago, a pungent gas was found to be the physiological mediator of cognitive function and vascular tone. Since then, studies on hydrogen sulfide (H2S) have uncovered its numerous physiological roles such as protecting various tissues/organs from ischemia and regulating inflammation, cell growth, oxygen sensing, and senescence. These effects of H2S were extensively studied, and some of the corresponding mechanisms were also studied in detail. Previous studies on the synergistic interaction between H2S and nitric oxide (NO) have led to the discovery of several potential signaling molecules. Polysulfides are considerably potent and are one of the most active forms of H2S. H2S has a significant therapeutic potential, which is evident from the large number of novel H2S donating compounds and substances developed for manipulating endogenous levels of H2S. The Third International Conference on H2S was held in Kyoto in June 2014. One hundred and sixty participants from 21 countries convened in Kyoto to report new advances, discuss conflicting findings, and make plans for future research. This article summarizes each oral presentation presented at the conference. PMID- 25459995 TI - Probiotic bacteria, B. longum and L. acidophilus inhibit infection by rotavirus in vitro and decrease the duration of diarrhea in pediatric patients. AB - BACKGROUND AND OBJECTIVES: Evidence suggests that specific probiotics may be antagonistic to enteric pathogens and enhance immunity, and thus, provide a means of preventing or treating diarrheal diseases. In the present study, we aimed to evaluate the efficacy of probiotic strains isolated from Koreans for the treatment of viral gastroenteritis in young children and against rotavirus in vitro. METHODS: In vitro antiviral activities of probiotic isolates on rotavirus infection were investigated in the Vero cell using a plaque reduction assay. Then several probiotic strains with the high antiviral activity were chosen for further clinical trials. Twenty-nine pediatric patients who presented with symptoms of viral gastroenteritis were enrolled in a double-blind trial and randomly assigned at admission to receive six probiotic strains (Bifidobacterium longum, B. lactis, Lactobacillus acidophilus, L. rhamnosus, L. plantarum, and Pediococcus pentosaceus) at a dose of 10(9) colony forming units/g or a comparable placebo twice daily for 1 week. RESULTS AND CONCLUSIONS: Of the tested probiotic strains, B. longum isolated from an infant showed the greatest inhibitory effect and L. acidophilus showed the second-highest inhibitory effect. These probiotics significantly shortened the duration of diarrhea as compared with a placebo (6.1 +/- 0.5 vs 7.2 +/- 1.9, P = 0.030) and did not induce any adverse effects. Our findings suggest that the probiotic strains selected in the present study may be useful for the treatment of acute rotaviral gastroenteritis or as an alternative therapy without adverse effects. PMID- 25459997 TI - Sodium thiosulfate attenuates angiotensin II-induced hypertension, proteinuria and renal damage. AB - Hypertension and proteinuria are important mediators of renal damage. Despite therapeutic interventions, the number of patients with end stage renal disease steadily increases. Hydrogen sulfide (H(2)S) is an endogenously produced gasotransmitter with vasodilatory, anti-inflammatory and antioxidant properties. These beneficial characteristics make H(2)S an attractive candidate for pharmacological use in hypertensive renal disease. We investigated the protective properties of H(2)S in angiotensin II (Ang II)-induced hypertensive renal disease in rats. Treatment with the H(2)S donor NaHS and major H(2)S metabolite sodium thiosulfate (STS) during three weeks of Ang II infusion reduced hypertension, proteinuria, oxidative stress and renal functional and structural deterioration. In an ex vivo isolated perfused kidney setup, NaHS, but not STS, reduced intrarenal pressure. The effect of NaHS could partially be explained by its activation of the ATP-sensitive potassium channels. In conclusion, treatment with H(2)S attenuates Ang II-associated functional and structural renal deterioration, suggesting that intervention in H(2)S production pathways has potential therapeutic benefit and might be a valuable addition to the already existing antihypertensive and renoprotective therapies. PMID- 25459998 TI - Application of positron annihilation lifetime spectroscopy (PALS) to study the nanostructure in amphiphile self-assembly materials: phytantriol cubosomes and hexosomes. AB - Self-assembled amphiphile nanostructures of colloidal dimensions such as cubosomes and hexosomes are of interest as delivery vectors in pharmaceutical and nanomedicine applications. Translation would be assisted through a better of understanding of the effects of drug loading on the internal nanostructure, and the relationship between this nanostructure and drug release profile. Positron annihilation lifetime spectroscopy (PALS) is sensitive to local microviscosity and is used as an in situ molecular probe to examine the Q2 (cubosome) -> H2 (hexosome) -> L2 phase transitions of the pharmaceutically relevant phytantriol water system in the presence of a model hydrophobic drug, vitamin E acetate (VitEA). It is shown that the ortho-positronium lifetime (tau) is sensitive to molecular packing and mobility and this has been correlated with the rheological properties of individual lyotropic liquid crystalline mesophases. Characteristic PALS lifetimes for L2 (tau4~ 4 ns) ~ H2 (tau4~ 4 ns) > Q(2 Pn3m) (tau4~ 2.2 ns) are observed for the phytantriol-water system, with the addition of VitEA yielding a gradual increase in tau from tau~ 2.2 ns for cubosomes to tau~ 3.5 ns for hexosomes. The dynamic chain packing at higher temperatures and in the L2 and H2 phases is qualitatively less "viscous", consistent with rheological measurements. This information offers increased understanding of the relationship between internal nanostructure and species permeability. PMID- 25459999 TI - Device explantation following overdiagnosed and overtreated Jervell and Lange Nielsen syndrome. PMID- 25460000 TI - Efficient Bayesian estimates for discrimination among topologically different systems biology models. AB - A major effort in systems biology is the development of mathematical models that describe complex biological systems at multiple scales and levels of abstraction. Determining the topology-the set of interactions-of a biological system from observations of the system's behavior is an important and difficult problem. Here we present and demonstrate new methodology for efficiently computing the probability distribution over a set of topologies based on consistency with existing measurements. Key features of the new approach include derivation in a Bayesian framework, incorporation of prior probability distributions of topologies and parameters, and use of an analytically integrable linearization based on the Fisher information matrix that is responsible for large gains in efficiency. The new method was demonstrated on a collection of four biological topologies representing a kinase and phosphatase that operate in opposition to each other with either processive or distributive kinetics, giving 8-12 parameters for each topology. The linearization produced an approximate result very rapidly (CPU minutes) that was highly accurate on its own, as compared to a Monte Carlo method guaranteed to converge to the correct answer but at greater cost (CPU weeks). The Monte Carlo method developed and applied here used the linearization method as a starting point and importance sampling to approach the Bayesian answer in acceptable time. Other inexpensive methods to estimate probabilities produced poor approximations for this system, with likelihood estimation showing its well-known bias toward topologies with more parameters and the Akaike and Schwarz Information Criteria showing a strong bias toward topologies with fewer parameters. These results suggest that this linear approximation may be an effective compromise, providing an answer whose accuracy is near the true Bayesian answer, but at a cost near the common heuristics. PMID- 25460001 TI - Grant application review: the case of transparency. PMID- 25460002 TI - Canonical Wnt signaling activity in early stages of chick lung development. AB - Wnt signaling pathway is an essential player during vertebrate embryonic development which has been associated with several developmental processes such as gastrulation, body axis formation and morphogenesis of numerous organs, namely the lung. Wnt proteins act through specific transmembrane receptors, which activate intracellular pathways that regulate cellular processes such as cell proliferation, differentiation and death. Morphogenesis of the fetal lung depends on epithelial-mesenchymal interactions that are governed by several growth and transcription factors that regulate cell proliferation, fate, migration and differentiation. This process is controlled by different signaling pathways such as FGF, Shh and Wnt among others. Wnt signaling is recognized as a key molecular player in mammalian pulmonary development but little is known about its function in avian lung development. The present work characterizes, for the first time, the expression pattern of several Wnt signaling members, such as wnt-1, wnt-2b, wnt-3a, wnt-5a, wnt-7b, wnt-8b, wnt-9a, lrp5, lrp6, sfrp1, dkk1, beta-catenin and axin2 at early stages of chick lung development. In general, their expression is similar to their mammalian counterparts. By assessing protein expression levels of active/total beta-catenin and phospho-LRP6/LRP6 it is revealed that canonical Wnt signaling is active in this embryonic tissue. In vitro inhibition studies were performed in order to evaluate the function of Wnt signaling pathway in lung branching. Lung explants treated with canonical Wnt signaling inhibitors (FH535 and PK115-584) presented an impairment of secondary branch formation after 48 h of culture along with a decrease in axin2 expression levels. Branching analysis confirmed this inhibition. Wnt-FGF crosstalk assessment revealed that this interaction is preserved in the chick lung. This study demonstrates that Wnt signaling is crucial for precise chick lung branching and further supports the avian lung as a good model for branching studies since it recapitulates early mammalian pulmonary development. PMID- 25460003 TI - Phosphoinositide 3-kinase alpha-dependent regulation of branching morphogenesis in murine embryonic lung: evidence for a role in determining morphogenic properties of FGF7. AB - Branching morphogenesis is a critical step in the development of many epithelial organs. The phosphoinositide-3-kinase (PI3K) pathway has been identified as a central component of this process but the precise role has not been fully established. Herein we sought to determine the role of PI3K in murine lung branching using a series of pharmacological inhibitors directed at this pathway. The pan-class I PI3K inhibitor ZSTK474 greatly enhanced the branching potential of whole murine lung explants as measured by an increase in the number of terminal branches compared with controls over 48 hours. This enhancement of branching was also observed following inhibition of the downstream signalling components of PI3K, Akt and mTOR. Isoform selective inhibitors of PI3K identified that the alpha isoform of PI3K is a key driver in branching morphogenesis. To determine if the effect of PI3K inhibition on branching was specific to the lung epithelium or secondary to an effect on the mesenchyme we assessed the impact of PI3K inhibition in cultures of mesenchyme-free lung epithelium. Isolated lung epithelium cultured with FGF7 formed large cyst-like structures, whereas co culture with FGF7 and ZSTK474 induced the formation of defined branches with an intact lumen. Together these data suggest a novel role for PI3K in the branching program of the murine embryonic lung contradictory to that reported in other branching organs. Our observations also point towards PI3K acting as a morphogenic switch for FGF7 signalling. PMID- 25460004 TI - Probing the target-specific inhibition of sensitized protein tyrosine phosphatases with biarsenical probes. AB - Selective control of enzyme activity is critical for elucidating the roles of specific proteins in signaling pathways. One potential means for developing truly target-specific inhibitors involves the use of protein engineering to sensitize a target enzyme to inhibition by a small molecule that does not inhibit homologous wild-type enzymes. Previously, it has been shown that protein tyrosine phosphatases (PTPs) can be sensitized to inhibition by a biarsenical probe, FlAsH EDT2, which inhibits PTP activity by specifically binding to cysteine residues that have been introduced into catalytically important regions. In the present study, we developed an array of biarsenical probes, some newly synthesized and some previously reported, to investigate for the first time the structure activity relationships for PTP inhibition by biarsenicals. Our data show that biarsenical probes which contain substitutions at the 2' and 7' positions are more effective than FlAsH-EDT2 at inhibiting sensitized PTPs. The increased potency of 2',7'-substituted probes was observed when PTPs were assayed with both para-nitrophenylphosphate and phosphopeptide PTP substrates and at multiple probe concentrations. The data further indicate that the enhanced inhibitory properties are the result of increased binding affinity between the 2',7'-substituted biarsenical probes and sensitized PTPs. In addition we provide previously unknown physicochemical and stability data for various biarsenical probes. PMID- 25460006 TI - Intervention for diagnosis of deep vein thrombosis in acute stroke patients: a hospital-based study. AB - BACKGROUND: Immobile stroke patients are at high risk of deep vein thrombosis (DVT). Demographic studies suggest a low incidence of DVT in Asian patients, but that might be underestimated. OBJECTIVE: Intervention by in-hospital case management for diagnosis of DVT in patients with acute stroke. PATIENTS AND METHODS: Intervention was defined as: recommendation of D-dimer test for patients who are immobile by day 4 after stroke onset and compression ultrasonography if the level of D-dimer is >=500 ng/ml. Treating physicians were notified by case managers before they failed to do so for qualified patients. Data of patients hospitalized 12 months before and 8 months after the intervention, including basic demographics, Glasgow Coma Scale score, National Institute of Health Stroke Scale (NIHSS) score, laboratory results, and examination reports, was retrieved from electronic medical records for analysis by code searches for acute stroke. RESULTS: A total of 2523 patients were identified. 1528 were before and 995 after intervention. More patients after intervention had D-dimer test and ultrasound examination than that before intervention (22.1% vs 8.6%, P<0.001 and 15.1% vs 1.2%, P<0.001, respectively). Ultrasound diagnosis of DVT was significantly more after than before intervention (2.0% vs 0.3%, P<0.001). DVT was 55.7 per 1000 in patients with a NIHSS score?18. Male sex (Odds ratio 0.33, 95% confidence intervals: 0.11-0.98), NIHSS score (Odds ratio 1.05, 95% confidence intervals: 1.00-1.09), and intervention (Odds ratio 5.39, 95% confidence intervals: 1.88 15.44) were independent predictors of ultrasound diagnosis of DVT. CONCLUSIONS: Intervention by in-hospital case management may be an effective strategy for improvement of under-diagnosis of DVT in acute stroke patients. PMID- 25460005 TI - Allogeneic cardiospheres delivered via percutaneous transendocardial injection increase viable myocardium, decrease scar size, and attenuate cardiac dilatation in porcine ischemic cardiomyopathy. AB - BACKGROUND: Epicardial injection of heart-derived cell products is safe and effective post-myocardial infarction (MI), but clinically-translatable transendocardial injection has never been evaluated. We sought to assess the feasibility, safety and efficacy of percutaneous transendocardial injection of heart-derived cells in porcine chronic ischemic cardiomyopathy. METHODS AND RESULTS: We studied a total of 89 minipigs; 63 completed the specified protocols. After NOGA-guided transendocardial injection, we quantified engraftment of escalating doses of allogeneic cardiospheres or cardiosphere-derived cells in minipigs (n = 22) post-MI. Next, a dose-ranging, blinded, randomized, placebo controlled ("dose optimization") study of transendocardial injection of the better-engrafting product was performed in infarcted minipigs (n = 16). Finally, the superior product and dose (150 million cardiospheres) were tested in a blinded, randomized, placebo-controlled ("pivotal") study (n = 22). Contrast enhanced cardiac MRI revealed that all cardiosphere doses preserved systolic function and attenuated remodeling. The maximum feasible dose (150 million cells) was most effective in reducing scar size, increasing viable myocardium and improving ejection fraction. In the pivotal study, eight weeks post-injection, histopathology demonstrated no excess inflammation, and no myocyte hypertrophy, in treated minipigs versus controls. No alloreactive donor-specific antibodies developed over time. MRI showed reduced scar size, increased viable mass, and attenuation of cardiac dilatation with no effect on ejection fraction in the treated group compared to placebo. CONCLUSIONS: Dose-optimized injection of allogeneic cardiospheres is safe, decreases scar size, increases viable myocardium, and attenuates cardiac dilatation in porcine chronic ischemic cardiomyopathy. The decreases in scar size, mirrored by increases in viable myocardium, are consistent with therapeutic regeneration. PMID- 25460007 TI - Where do the rural poor deliver when high coverage of health facility delivery is achieved? Findings from a community and hospital survey in Tanzania. AB - INTRODUCTION: As part of maternal mortality reducing strategies, coverage of delivery care among sub-Saharan African rural poor will improve, with a range of facilities providing services. Whether high coverage will benefit all socio economic groups is unknown. Iringa rural District, Southern Tanzania, with high facility delivery coverage, offers a paradigm to address this question. Delivery services are available in first-line facilities (dispensaries, health centres) and one hospital. We assessed whether all socio-economic groups access the only comprehensive emergency obstetric care facility equally, and surveyed existing delivery services. METHODS: District population characteristics were obtained from a household community survey (n = 463). A Hospital survey collected data on women who delivered in this facility (n = 1072). Principal component analysis on household assets was used to assess socio-economic status. Hospital population socio-demographic characteristics were compared to District population using multivariable logistic regression. Deliveries' distribution in District facilities and staffing were analysed using routine data. RESULTS: Women from the hospital compared to the District population were more likely to be wealthier. Adjusted odds ratio of hospital delivery increased progressively across socio economic groups, from 1.73 for the poorer (p = 0.0031) to 4.53 (p<0.0001) for the richest. Remarkable dispersion of deliveries and poor staffing were found. In 2012, 5505/7645 (72%) institutional deliveries took place in 68 first-line facilities, the remaining in the hospital. 56/68 (67.6%) first-line facilities reported <=100 deliveries/year, attending 33% of deliveries. Insufficient numbers of skilled birth attendants were found in 42.9% of facilities. DISCUSSION: Poorer women remain disadvantaged in high coverage, as they access lower level facilities and are under-represented where life-saving transfusions and caesarean sections are available. Tackling the challenges posed by low caseloads and staffing on first-line rural care requires confronting a dilemma between coverage and quality. Reducing number of delivery sites is recommended to improve quality and equity of care. PMID- 25460008 TI - Correlation between the beam profile from a curing light and the microhardness of four resins. AB - OBJECTIVE: To demonstrate the effect of localized irradiance and spectral distribution inhomogeneities of one LED-based dental light-curing unit (LCU) on the corresponding microhardness values at the top, and bottom surfaces of four dental resin-based composites (RBCs), which contained either camphorquinone (CQ) alone or a combination of CQ and monoacylphosphine oxide (TPO) as photoinitiators. METHODS: Localized irradiance beam profiles from a polywave LED based LCU were recorded five times using a laser beam analyzer, without and with either a 400 nm or 460 nm narrow bandpass filter placed in front of the camera lens. Five specimens of each of the four RBCs (two containing CQ/TPO and two containing CQ-only) were exposed for 5-, 10-, or 30-s with the light guide directly on the top surface of the RBC. After 24 h, Knoop microhardness values were measured at 45 locations across the top and bottom surfaces of each specimen. Microhardness readings for each RBC surface and exposure time were correlated with localized patterns of the LCU beam profile, measured using the 400 nm and 460 nm bandpass filters. Spearman rank correlation was used to avoid relying on an assumption of a bivariate normal distribution for the KHN and irradiance. RESULTS: The local irradiance and spectral emission values were not uniformly distributed across the light tip. There was a strong significant positive correlation with the irradiance beam profile values from the LCU taken through bandpass filters and the microhardness maps of the RBC surfaces exposed for 5 and 10 s. The strength of this correlation decreased with increasing exposure time for the RBCs containing CQ only, and increased for the RBCs containing both CQ and TPO. CONCLUSIONS: Localized beam and spectral distributions across the tip end of the light guide strongly correlated with corresponding areas of microhardness in both the top and bottom surfaces among four RBCs with different photoinitiator contents. Significance: A light-curing unit with a highly inhomogeneous light output can adversely affect localized microhardness of resin-based composites and this may be a contributing factor for premature failure of a restoration. PMID- 25460011 TI - Postoperative vision-related quality of life in macula-off rhegmatogenous retinal detachment patients and its relation to visual function. AB - OBJECTIVE: To determine the vision-related quality of life (VR-QOL) after surgery for macula-off rhegmatogenous retinal detachment (RRD) in relation to visual acuity, contrast acuity, and color vision. METHODS: In a prospective observational study, we included 55 patients with a macula-off RRD. Best corrected visual acuity (BCVA), color vision (saturated and desaturated color confusion indices (CCI)) and contrast acuity were measured at 12 months postoperatively in both the RRD eye and the fellow control eye, and the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) was filled out. RESULTS: Operated and fellow control eyes differed significantly in mean LogMAR BCVA (P<0.0001), median Log contrast acuity (P<0.0001), saturated CCI (P = 0.009), and desaturated CCI (P = 0.016). Significant correlations were observed between the NEI VFQ-25 overall composite score and postoperative LogMAR BCVA (R = -0.551, P<0.0001), contrast acuity (R = 0.472, P<0.0001), saturated CCI (R = 0.315, P = 0.023), and desaturated CCI (R = -0.283, P = 0.044). CONCLUSIONS: A lower VR-QOL was highly correlated to a worse postoperative BCVA and contrast acuity and to a lesser extent to color vision disturbances. PMID- 25460013 TI - Preventing future infections in cirrhosis: a battle cry for stewardship. PMID- 25460012 TI - Restriction endonucleases from invasive Neisseria gonorrhoeae cause double-strand breaks and distort mitosis in epithelial cells during infection. AB - The host epithelium is both a barrier against, and the target for microbial infections. Maintaining regulated cell growth ensures an intact protective layer towards microbial-induced cellular damage. Neisseria gonorrhoeae infections disrupt host cell cycle regulation machinery and the infection causes DNA double strand breaks that delay progression through the G2/M phase. We show that intracellular gonococci upregulate and release restriction endonucleases that enter the nucleus and damage human chromosomal DNA. Bacterial lysates containing restriction endonucleases were able to fragment genomic DNA as detected by PFGE. Lysates were also microinjected into the cytoplasm of cells in interphase and after 20 h, DNA double strand breaks were identified by 53BP1 staining. In addition, by using live-cell microscopy and NHS-ester stained live gonococci we visualized the subcellular location of the bacteria upon mitosis. Infected cells show dysregulation of the spindle assembly checkpoint proteins MAD1 and MAD2, impaired and prolonged M-phase, nuclear swelling, micronuclei formation and chromosomal instability. These data highlight basic molecular functions of how gonococcal infections affect host cell cycle regulation, cause DNA double strand breaks and predispose cellular malignancies. PMID- 25460014 TI - Necrotizing fasciitis secondary to acute buried bumper syndrome. PMID- 25460015 TI - Computerized Tomography of Patients With Crohn's Disease in the Emergency Department: The More you Look, the Less you See. PMID- 25460016 TI - The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after surgery for Crohn's disease. AB - BACKGROUND & AIMS: Probiotic formulations of single species of bacteria have not been effective in preventing the recurrence of Crohn's disease after surgery. We investigated the ability of VSL#3, a mixture of 8 different bacterial probiotic species, to prevent Crohn's disease recurrence after surgery in a multicenter, randomized, double-blind, placebo-controlled trial. METHODS: Within 30 days of ileocolonic resection and re-anastomosis, patients with Crohn's disease were randomly assigned to groups given 1 sachet of VSL#3 (900 billion viable bacteria, comprising 4 strains of Lactobacillus, 3 strains of Bifidobacterium, and 1 strain of Streptococcus salivarius subspecies thermophilus) (n = 59) or matching placebo (n = 60). Colonoscopy was performed at days 90 and 365 to evaluate the neoterminal ileum for disease recurrence and obtain mucosal biopsies for cytokine analysis. Patients from both groups with either no or mild endoscopic recurrence at day 90 received VSL#3 until day 365. The primary outcome was the proportion of patients with severe endoscopic recurrence at day 90. RESULTS: At day 90, the proportion of patients with severe endoscopic lesions did not differ significantly between VSL#3 (9.3%) and placebo (15.7%, P = .19). The proportions of patients with non-severe lesions at day 90 who had severe endoscopic recurrence at day 365 were 10.0% in the early VSL#3 group (given VSL#3 for the entire 365 days) and 26.7% in the late VSL#3 group (given VSL#3 from days 90 through 365) (P = .09). Aggregate rates of severe recurrence (on days 90 and 365) were not statistically different, 20.5% of subjects in the early VSL#3 group and 42.1% in the late VSL#3 group. Patients receiving VSL#3 had reduced mucosal inflammatory cytokine levels compared with placebo at day 90 (P < .05). Crohn's disease activity index and inflammatory bowel disease quality of life scores were similar in the 2 groups. CONCLUSIONS: There were no statistical differences in endoscopic recurrence rates at day 90 between patients who received VSL#3 and patients who received placebo. Lower mucosal levels of inflammatory cytokines and a lower rate of recurrence among patients who received early VSL#3 (for the entire 365 days) indicate that this probiotic should be further investigated for prevention of Crohn's disease recurrence. Clinical trials.gov number: NCT00175292. PMID- 25460018 TI - Modified positioning of a bariatric surgery stent to manage an atypical staple line leak after sleeve gastrectomy. PMID- 25460017 TI - Low level of hepatitis B virus screening among patients receiving chemotherapy. AB - BACKGROUND & AIMS: Chemotherapy of patients with inactive hepatitis B virus (HBV) infection can lead to viral reactivation and hepatitis flares. We investigated the proportion of patients screened for HBV infection before chemotherapy over time and the outcomes of screened patients. METHODS: In a retrospective study, we collected data from a pharmacy database on patients who underwent cytotoxic chemotherapy for solid or hematologic malignancies at the Mayo Clinic in Rochester, Minnesota, from January 1, 2006, through September 30, 2011. Laboratory data were collected from electronic medical records. Screening was identified based on tests for hepatitis B surface antigen, for any reason at any time before chemotherapy. RESULTS: Of 8005 patients undergoing chemotherapy, 1279 (16%) were screened for HBV infection before chemotherapy, including 668 of 1805 patients with hematologic malignancies (37%). The proportion of patients screened for HBV increased from 14.3% in 2006 to 2008 to 17.7% in 2009 to 2011 (P < .01). This trend was attributed mostly to an increase in the proportion of patients with hematologic malignancies, from 32.7% in 2006 to 2008 to 40.6% in 2009 to 2011 (P < .01). Of 13 patients who tested positive for HBV, 5 did not receive prophylactic antiviral therapy; HBV infection was reactivated in 2 of these patients. None of the 8 patients who received an antiviral agent before chemotherapy experienced HBV reactivation. Of 58 unscreened patients who had increases in their alanine aminotransferase level (>300 U/L), only 1 patient appeared to have an undiagnosed HBV infection. CONCLUSIONS: Only a small percentage of patients receiving chemotherapy are screened for HBV infection. However, a larger proportion of patients was screened during 2009 to 2011 than during 2006 to 2008, especially patients with hematologic malignancies. Strategies are needed to ensure that patients receiving chemotherapy are protected from the consequences of undiagnosed HBV infection. PMID- 25460019 TI - Inflammation, psychiatric symptoms, and opioid use are associated with pain and disability in patients with cirrhosis. AB - BACKGROUND & AIMS: Cirrhosis is associated with significant pain and disability, the etiologies of which are poorly understood. We investigated whether the pain and disability in patients with cirrhosis are associated with systemic inflammation and psychiatric symptoms. METHODS: In a prospective study, we recruited 193 patients with cirrhosis caused by hepatitis C virus infection, nonalcoholic steatohepatitis, or alcohol from the hepatology clinic at the University of Pittsburgh. Patients were assessed using the McGill Pain Questionnaire, the Hospital Anxiety and Depression Scale, the Pittsburgh Sleep Quality Index, and the Pain Disability Index. Serum samples were collected and markers of inflammation were measured using standardized Luminex assays (Milipore, St. Charles, MO). We evaluated factors associated with pain, pain related disability, and chronic opioid use by using multivariable regression models. RESULTS: Pain was reported by 79% of patients, pain-related disability was reported by 75%, and depression and/or anxiety was reported by 47%; the average Model for End-Stage Liver Disease score was 12 +/- 5. Serum samples from 58% percent of patients had increased levels of C-reactive protein. Opioids were prescribed for 30% of patients with pain. In multivariate analysis, factors significantly associated with pain included younger age (odds ratio [OR]/y, 0.93; 95% confidence interval [CI], 0.90-0.99), serum level of interleukin 6 (OR per pg/L, 1.63; 95% CI, 1.09-2.58), Hospital Anxiety and Depression Scale score (OR/point, 1.14; 95% CI, 1.07-1.24), and etiology (hepatitis C virus infection vs alcohol: OR, 3.70; 95% CI, 1.27-11.11). Disability scores were related significantly to psychiatric symptoms (incidence rate ratio [IRR]/point, 1.04; 95% CI, 1.02-1.05), prescription opioid use (IRR, 1.49; 95% CI, 1.14-1.94), Model for End-Stage Liver Disease score (IRR/point, 1.02; 95% CI, 1.0001-1.05), level of C-reactive protein (IRR per mg/dL, 1.13; 95% CI, 1.02-1.24), and pain severity (IRR/point, 1.19; 95% CI, 1.08-1.32). CONCLUSIONS: Pain and disability are common among patients with cirrhosis, and are associated with inflammation, psychiatric symptoms, and opioid use, which potentially are modifiable. Although opioids are used commonly to treat pain, psychiatric symptoms and inflammation also might be treatment targets in this population. PMID- 25460021 TI - Behavioral studies on anxiety and depression in a drug discovery environment: keys to a successful future. AB - The review describes a personal journey through 25 years of animal research with a focus on the contribution of rodent models for anxiety and depression to the development of new medicines in a drug discovery environment. Several classic acute models for mood disorders are briefly described as well as chronic stress and disease-induction models. The paper highlights a variety of factors that influence the quality and consistency of behavioral data in a laboratory setting. The importance of meta-analysis techniques for study validation (tolerance interval) and assay sensitivity (Monte Carlo modeling) are demonstrated by examples that use historic data. It is essential for successful discovery of new potential drugs to maintain a high level of control in animal research and to bridge knowledge across in silico modeling, and in vitro and in vivo assays. Today, drug discovery is a highly dynamic environment in search of new types of treatments and new animal models which should be guided by enhanced two-way translation between bench and bed. Although productivity has been disappointing in the search of new and better medicines in psychiatry over the past decades, there has been and will always be an important role for in vivo models in-between preclinical discovery and clinical development. The right balance between good science and proper judgment versus a decent level of innovation, assay development and two-way translation will open the doors to a very bright future. PMID- 25460022 TI - Dexmedetomidine improves early postoperative cognitive dysfunction in aged mice. AB - Postoperative cognitive dysfunction (POCD) is a frequent complication following major surgery in the elderly. However, the exact pathogenic mechanisms are still unknown. Dexmedetomidine, a selective alpha 2 adrenal receptor agonist, was revealed anesthesia and brain protective role. The present study aimed to examine whether dexmedetomdine protects against POCD induced by major surgical trauma under general anesthesia in aged mice. In the present study, cognitive function was assessed by Y-maze. Proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF-alpha), apoptosis-related factor caspase-3 and Bax were detected by real-time PCR, Western blot or immunohistochemistry. The results showed that anesthesia alone caused weak cognitive dysfunction on the first day after general anesthesia. Cognitive function in mice with splenectomy under general anesthesia was significantly exacerbated at the first and third days after surgery, and was significantly improved by dexmedetomidine administration. Splenectomy increased the expression of IL-1beta, TNF-alpha, Bax and caspase-3 in hippocampus. These changes were significantly inversed by dexmedetomidine. These results suggest that hippocampal inflammatory response and neuronal apoptosis may contribute to POCD, and selective alpha 2 adrenal receptor excitation play a protective role. PMID- 25460023 TI - Evaluation of anti-colitic effect of fluvoxamine against acetic acid-induced colitis in normal and reserpinized depressed rats. AB - High prevalence of psychological comorbidities such as depression and anxiety in patients with inflammatory bowel disease (IBD) supports the premise that adding an anti-depressant drug with known anti-inflammatory effect to the medical treatment have beneficial effect in the course of the underlying disease. Colitis was induced by intracolonic instillation of 2 ml of 4% v/v acetic acid solution in rats. Anti-colitic effect of fluvoxamine was evaluated in two categories: A: normal rats, B: reserpinized (6 mg/kg, i.p.) depressed rats. In group A, fluvoxamine (2.5, 5, 10 mg/kg, i.p.) was administered 2 h after induction of colitis and in group B: reserpine (6 mg/kg, i.p.) was administered 1 h prior to colitis induction and then fluvoxamine (2.5, 5, 10 mg/kg, i.p.) was administered 2 h after colitis induction. Dexamethasone (1 mg/kg) was used as reference drug. All the treatments continued daily for five days. The effect was assessed on the basis of macroscopic score, biochemical (myeloperoxidase) changes and histopathological studies. Results showed that fluvoxamine (2.5 and 5 mg/kg) and dexamethasone treatment markedly reduced disease severity in both reserpinized and non-reserpinized rats as indicated by reduction in macroscopic and microscopic colonic damages while reserpine adversely exacerbated the colitis damage. Myeloperoxidase activity which was increased following colitis induction was also decreased. The findings of this study elucidate the anti-colitic and anti-inflammatory properties of fluvoxamine and so introduced it as a good candidate to treat depressive symptoms in people comorbid to IBD. PMID- 25460024 TI - Inhibition of Ras signalling reduces neutrophil infiltration and tissue damage in severe acute pancreatitis. AB - Neutrophil recruitment is known to be a rate-limiting step in mediating tissue injury in severe acute pancreatitis (AP). However, the signalling mechanisms controlling inflammation and organ damage in AP remain elusive. Herein, we examined the role of Ras signalling in AP. Male C57BL/6 mice were treated with a Ras inhibitor (farnesylthiosalicylic acid, FTS) before infusion of taurocholate into the pancreatic duct. Pancreatic and lung tissues as well as blood were collected 24 h after pancreatitis induction. Pretreatment with FTS decreased serum amylase levels by 82% and significantly attenuated acinar cell necrosis, tissue haemorrhage and oedema formation in taurocholate-induced pancreatitis. Inhibition of Ras signalling reduced myeloperoxidase (MPO) levels in the inflamed pancreas by 42%. In addition, administration of FTS decreased pancreatic levels of CXC chemokines as well as circulating levels of interleukin-6 and high mobility group box 1 in animals exposed to taurocholate. Moreover, treatment with FTS reduced taurocholate-induced MPO levels in the lung. Inhibition of Ras signalling had no effect on neutrophil expression of Mac-1 in mice with pancreatitis. Moreover, FTS had no direct impact on trypsin activation in isolated pancreatic acinar cells. These results indicate that Ras signalling controls CXC chemokine formation, neutrophil recruitment and tissue injury in severe AP. Thus, our findings highlight a new signalling mechanism regulating neutrophil recruitment in the pancreas and suggest that inhibition of Ras signalling might be a useful strategy to attenuate local and systemic inflammation in severe AP. PMID- 25460020 TI - Rodent models of treatment-resistant depression. AB - Major depression is a prevalent and debilitating disorder and a substantial proportion of patients fail to reach remission following standard antidepressant pharmacological treatment. Limited efficacy with currently available antidepressant drugs highlights the need to develop more effective medications for treatment- resistant patients and emphasizes the importance of developing better preclinical models that focus on treatment- resistant populations. This review discusses methods to adapt and refine rodent behavioral models that are predictive of antidepressant efficacy to identify populations that show reduced responsiveness or are resistant to traditional antidepressants. Methods include separating antidepressant responders from non-responders, administering treatments that render animals resistant to traditional pharmacological treatments, and identifying genetic models that show antidepressant resistance. This review also examines pharmacological and non-pharmacological treatments regimes that have been effective in refractory patients and how some of these approaches have been used to validate animal models of treatment-resistant depression. The goals in developing rodent models of treatment-resistant depression are to understand the neurobiological mechanisms involved in antidepressant resistance and to develop valid models to test novel therapies that would be effective in patients that do not respond to traditional monoaminergic antidepressants. PMID- 25460025 TI - The influence of microglia activation on the efficacy of amitriptyline, doxepin, milnacipran, venlafaxine and fluoxetine in a rat model of neuropathic pain. AB - The analgesic properties of antidepressants are often used in the treatment of neuropathy; however their influence on glial cells in maintaining neuropathic pain is unknown. Our studies examined the neuropathic pain-relieving properties after intraperitoneal injection of amitriptyline, doxepin, milnacipran, venlafaxine and fluoxetine 7 days after sciatic nerve injury (CCI) in rats and its influence on microglia/macrophages (IBA-1) and astroglia (GFAP) activation in the spinal cord and dorsal root ganglia (DRG) using Western blot. All tested antidepressants significantly reduced CCI-induced allodynia but hyperalgesia was only antagonised by fluoxetine, doxepine and venlafaxine. The strongest analgesia was observed after fluoxetine administration. Western blot analysis showed the upregulation of the IBA-1 in the lumbar spinal cord and DRG after amitriptyline or milnacipran administration in CCI-exposed rats, whereas after fluoxetine the downregulation was observed. The administration of doxepin did not change the IBA 1 protein level in both studied structures; however venlafaxine decreased the IBA 1 only in the DRG. No changes in the GFAP level in both structures were observed after any of listed above antidepressants administration. Chronic minocycline treatment enhanced amitriptyline and milnacipran, but did not fluoxetine analgesia under neuropathic pain in rats. Our results suggest that nerve injury induced pain is related with the activation of microglia, which is diminished by fluoxetine treatment in the neuropathic pain model. PMID- 25460026 TI - AM404 inhibits NFAT and NF-kappaB signaling pathways and impairs migration and invasiveness of neuroblastoma cells. AB - N-Arachidonoylphenolamine (AM404), a paracetamol lipid metabolite, is a modulator of the endocannabinoid system endowed with pleiotropic activities. AM404 is a dual agonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1) and the Cannabinoid Receptor type 1 (CB1) and inhibits anandamide (AEA) transport and degradation. In addition, it has been shown that AM404 also exerts biological activities through TRPV1- and CB1 -independent pathways. In the present study we have investigated the effect of AM404 in the NFAT and NF-kappaB signaling pathways in SK-N-SH neuroblastoma cells. AM404 inhibited NFAT transcriptional activity through a CB1- and TRPV1-independent mechanism. Moreover, AM404 inhibited both the expression of COX-2 at transcriptional and post transcriptional levels and the synthesis of PGE2. AM404 also inhibited NF-kappaB activation induced by PMA/Ionomycin in SK-N-SH cells by targeting IKKbeta phosphorylation and activation. We found that Cot/Tlp-2 induced NFAT and COX-2 transcriptional activities were inhibited by AM404. NFAT inhibition paralleled with the ability of AM404 to inhibit MMP-1, -3 and -7 expression, cell migration and invasion in a cell-type specific dependent manner. Taken together, these data reveal that paracetamol, the precursor of AM404, can be explored not only as an antipyretic and painkiller drug but also as a co-adjuvant therapy in inflammatory and cancer diseases. PMID- 25460027 TI - Pharmacological and methodological aspects of the separation-induced vocalization test in guinea pig pups; a systematic review and meta-analysis. AB - The separation-induced vocalization test in guinea pig pups is one of many that has been used to screen for anxiolytic-like properties of drugs. The test is based on the cross-species phenomenon that infants emit distress calls when placed in social isolation. Here we report a systematic review and meta-analysis of pharmacological intervention in the separation-induced vocalization test in guinea pig pups. Electronic databases were searched for original research articles, yielding 32 studies that met inclusion criteria. We extracted data on pharmacological intervention, animal and methodological characteristics, and study quality indicators. Meta-analysis showed that the different drug classes in clinical use for the treatment of anxiety disorders, have comparable effects on vocalization behaviour, irrespective of their mechanism of action. Of the experimental drugs, nociception (NOP) receptor agonists proved very effective in this test. Analysis further indicated that the commonly used read-outs total number and total duration of vocalizations are equally valid. With regard to methodological characteristics, repeated testing of pups as well as selecting pups with moderate or high levels of vocalization were associated with larger treatment effects. Finally, reporting of study methodology, randomization and blinding was poor and Egger's test for small study effects showed that publication bias likely occurred. This review illustrates the value of systematic reviews and meta-analyses in improving translational value and methodological aspects of animal models. It further shows the urgent need to implement existing publication guidelines to maximize the output and impact of experimental animal studies. PMID- 25460029 TI - Food restriction does not relieve PTSD-like anxiety. AB - We used the inescapable foot shock paradigm (IFS) in rats as an animal model for post-traumatic stress disorder (PTSD). Previously we showed that exercise reversed the enhanced stress sensitivity induced by IFS. From literature it is known that food restriction has antidepressant and anxiolytic effects. Since both treatments influence energy expenditure, we questioned whether food restriction reduces anxiety in the IFS model via a comparable, NPY dependent mechanism as enrichment. Anxiety of IFS-exposed animals was measured as change in locomotion and freezing after sudden silence in an open field test, before and after two weeks of food restriction. In addition a forced swim test (FST) was performed. Next, using qPCR, the expression of neuropeptide Y (NPY) and the neuropeptide Y1 receptor (Y1 receptor) was measured in the amygdala. Food restriction increased locomotion and decreased freezing behavior both in control and IFS animals. These effects were small. IFS-induced anxiety was not abolished after two weeks of food restriction. IFS did not influence immobility or the duration of swimming in the FST of animals fed ad libitum. However, food restriction increased swimming and decreased the duration of immobility in IFS-exposed animals. Y1 receptor expression in the basolateral amygdala decreased after both IFS and food restriction. Although food restriction seems to induce a general anxiolytic effect, it does not operate via enhanced Y1 receptor expression and has no effect on the more pathogenic anxiety induced by IFS. PMID- 25460028 TI - Effects and underlying mechanisms of human opiorphin on cardiovascular activity in anesthetized rats. AB - The present study was performed to investigate the peripheral cardiovascular effects of opiorphin in anesthetized rats. Intravenous (i.v.) injection of opiorphin (50-500nmol/kg) caused marked dose-dependent increase in blood pressure and heart rate. The pressor and tachycardic responses induced by opiorphin (300nmol/kg, i.v.) were significantly decreased by pretreatment with angiotensin converting enzyme inhibitor captopril or angiotensin II type 1 (AT1) receptor antagonist valsartan, which suggested that endogenous angiotensin may be involved in the response to opiorphin. Pretreatment with alpha-adrenoreceptor antagonist phentolamine and beta-adrenoceptor antagonist propranolol respectively attenuated the pressor response induced by opiorphin. Propranolol, but not phentolamine, inhibited the tachycardic response. Moreover, reserpine blocked both responses to opiorphin. These findings indicated that the effects of opiorphin to increase blood pressure and heart rate might be due to the stimulation of sympathetic ganglia. Additionally, studies with bilaterally adrenalectomized rats showed that adrenal medulla may be involved in the cardiovascular regulation of opiorphin. In addition, pretreatment with nonselective opioid receptor antagonist naloxone did not modify the cardiovascular responses to opiorphin, suggesting that the effects of opiorphin were not related to the opioid system. Furthermore, radioimmunoassay (RIA) showed that opiorphin significantly increased endogenous levels of angiotensin II and angiotensin III. In summary, all the results indicate that the cardiovascular effects induced by opiorphin are mediated through the renin angiotensin system (RAS), the sympathetic ganglia and adrenal medulla, but not the opioid system. PMID- 25460031 TI - Baroreceptor stimulation enhanced nitric oxide vasodilator responsiveness, a new aspect of baroreflex physiology. AB - OBJECTIVE: Increasing evidence suggests that endothelial nitric oxide (NO) deficit and baroreflex dysfunction are associated with a variety of cardiovascular conditions, ranging from arterial hypertension to stroke and coronary heart disease, importantly appearing even in preclinical stages of the disease. To test the hypothesis that the arterial baroreflex has a modulatory effect on NO-dependent vasodilation, sodium nitroprusside (SNP), a spontaneous NO donor, vasodilatory effect was studied in conjunction with sinocarotid baroreceptor magnetic stimulation and potential implementation in NO deficiency states. METHODS: Mean femoral artery blood pressure (MAP), heart rate (HR) and ear lobe skin microcirculatory blood flow, measured by a microphotoelectric plethysmogram (MPPG), were simultaneously recorded in conscious rabbits before and after 40-min sinocarotid baroreceptor exposure to 350 mT static magnetic field (SMF), generated by Nd2-Fe4-B alloy (n=8) or sham magnets (n=8, controls). Arterial baroreflex sensitivity (BRS) was measured by changes in HR and MAP (DeltaHR/DeltaMAP) after intravenous bolus injections of SNP and phenylephrine. RESULTS: The vasodilatory effect of SNP significantly increased after SMF sinocarotid baroreceptor exposure (MPPGbeforeSMF: 2.57 +/- 0.81 V vs. MPPGafterSMF: 7.82 +/- 1.61 V, p<0.0001) and positively correlated with significant increase in BRS (r=0.51, p=0.01). CONCLUSIONS: Baroreflex-mediated increment in vessel sensitivity to NO is suggested to be a new mechanism in baroreflex physiology with potential implementation in cardiovascular conditions where NO deficit and autonomic dysfunction increase the risk of morbidity and mortality substantially. PMID- 25460030 TI - Efficacy of testosterone combined with a PDE5 inhibitor and testosterone combined with a serotonin (1A) receptor agonist in women with SSRI-induced sexual dysfunction. A preliminary study. AB - Selective serotonin reuptake inhibitors (SSRIs) are known to cause sexual dysfunction, such as decreased sexual motivation, desire, arousal, and orgasm difficulties. These SSRI-induced sexual complaints have a high prevalence rate, while there is no approved pharmacological treatment for SSRI-induced sexual dysfunction. It is hypothesized that a polymorphisms in the androgen receptor gene, encoded by the nucleotides cysteine, adenine, and guanine (CAG), influence the effect of testosterone on sexual functioning. In an explorative, randomized, double-blind, placebo-controlled, crossover study we investigated the possible effects of sublingual testosterone combined with a serotonin (5-HT)1A receptor agonist, and of sublingual testosterone combined with a phosphodiesterase type 5 inhibitor (PDE5-i) on sexual functioning in women with SSRI-induced sexual dysfunction. Furthermore, we did an exploratory analysis to assess if the CAG polymorphism influences this effect. 21 pre- and postmenopausal women with SSRI induced sexual dysfunction participated and underwent the following interventions: a combination of testosterone (0.5 mg) sublingually and the PDE5-i sildenafil (50 mg) and a combination of testosterone (0.5 mg) sublingually and the 5-HT1A receptor agonist buspirone (10 mg). The results show that women who use a low dose of SSRI and have relatively long CAG repeats report a marked improvement in sexual function in response to both treatments compared to placebo. This explorative study and preliminary results indicate that in women with SSRI-induced sexual dysfunction, a combination of testosterone sublingually and a PDE5-i or testosterone sublingually and a 5-HT1A receptor agonist might be promising treatments for certain subgroups of women with this condition. PMID- 25460032 TI - Comparison of Cramer classification between Toxtree, the OECD QSAR Toolbox and expert judgment. AB - The Threshold of Toxicological Concern (TTC) is a pragmatic approach in risk assessment. In the absence of data, it sets up levels of human exposure that are considered to have no appreciable risk to human health. The Cramer decision tree is used extensively to determine these exposure thresholds by categorizing non carcinogenic chemicals into three different structural classes. Therefore, assigning an accurate Cramer class to a material is a crucial step to preserve the integrity of the risk assessment. In this study the Cramer class of over 1000 fragrance materials across diverse chemical classes were determined by using Toxtree (TT), the OECD QSAR Toolbox (TB), and expert judgment. Disconcordance was observed between TT and the TB. A total of 165 materials (16%) showed different results from the two programs. The overall concordance for Cramer classification between TT and expert judgment is 83%, while the concordance between the TB and expert judgment is 77%. Amines, lactones and heterocycles have the lowest percent agreement with expert judgment for TT and the TB. For amines, the expert judgment agreement is 45% for TT and 55% for the TB. For heterocycles, the expert judgment agreement is 55% for TT and the TB. For lactones, the expert judgment agreement is 56% for TT and 50% for the TB. Additional analyses were conducted to determine the concordance within various chemical classes. Critical checkpoints in the decision tree are identified. Strategies and guidance on determining the Cramer class for various chemical classes are discussed. PMID- 25460033 TI - Effects of using electronic cigarettes on nicotine delivery and cardiovascular function in comparison with regular cigarettes. AB - The development of electronic cigarettes (e-cigs) has the potential to offer a less harmful alternative for tobacco users. This clinical study was designed to characterize e-cig users' exposure to nicotine, and to investigate the acute effects of e-cigs on the hemodynamic measurements (blood pressure and heart rate) in comparison with the effects of regular smoking. Five e-cigs and one Marlboro(r) cigarette were randomized for twenty-three participants under two exposure scenarios from Day 1 to Day 11: half-hour controlled administration and one hour ad lib use. The nicotine plasma concentrations after 1.5h of product use (C90) were significantly lower in the users of e-cigs than of Marlboro(r) cigarettes. The combination of glycerin and propylene glycol as the vehicle facilitated delivery of more nicotine than glycerin alone. The heart rate, systolic and diastolic blood pressure were significantly elevated after use of Marlboro(r) cigarettes, but the elevation was less after use of most of the e cigs. Use of e-cigs had no impact on the exhaled CO levels, whereas the Marlboro(r) cigarette significantly increased the exhaled CO more than 8 times above the baseline. In conclusion, e-cigs could be a less harmful alternative for tobacco users. PMID- 25460034 TI - Cardioprotective potential of annexin-A1 mimetics in myocardial infarction. AB - Myocardial infarction (MI) and its resultant heart failure remains a major cause of death in the world. The current treatments for patients with MI are revascularization with thrombolytic agents or interventional procedures. These treatments have focused on restoring blood flow to the ischemic tissue to prevent tissue necrosis and preserve organ function. The restoration of blood flow after a period of ischemia, however, may elicit further myocardial damage, called reperfusion injury. Pharmacological interventions, such as antioxidant and Ca(2+) channel blockers, have shown premises in experimental settings; however, clinical studies have shown limited success. Thus, there is a need for the development of novel therapies to treat reperfusion injury. The therapeutic potential of glucocorticoid-regulated anti-inflammatory mediator annexin-A1 (ANX-A1) has recently been recognized in a range of systemic inflammatory disorders. ANX-A1 binds to and activates the family of formyl peptide receptors (G protein-coupled receptor family) to inhibit neutrophil activation, migration and infiltration. Until recently, studies on the cardioprotective actions of ANX-A1 and its peptide mimetics (Ac2-26, CGEN-855A) have largely focused on its anti-inflammatory effects as a mechanism of preserving myocardial viability following I-R injury. Our laboratory provided the first evidence of the direct protective action of ANX A1 on myocardium, independent of inflammatory cells in vitro. We now review the potential for ANX-A1 based therapeutics to be seen as a "triple shield" therapy against myocardial I-R injury, limiting neutrophil infiltration and preserving both cardiomyocyte viability and contractile function. This novel therapy may thus represent a valuable clinical approach to improve outcome after MI. PMID- 25460035 TI - Asthma is not only an airway disease, but also a vascular disease. AB - Multiple studies have identified an expansion and morphological dysregulation of the bronchial vascular network in the airways of asthmatics. Increased number, size and density of blood vessels, as well as vascular leakage and plasma engorgement, have been reported in the airways of patients with all grades of asthma from mild to fatal. This neovascularisation is an increasingly commonly reported feature of airway remodelling; however, the pathophysiological impact of the increased vasculature in the bronchial wall and its significance to pulmonary function in asthma are unrecognised at this time. Multiple factors capable of influencing the development and persistence of the vascular network exist within asthmatic airway tissue. These include structural components of the altered extracellular matrix (ECM), imbalance of proteases and their endogenous inhibitors, release of active matrikines and the dysregulated levels of both soluble and matrix sequestered growth factors. This review will explore the features of the asthmatic airway which influence the development and persistence of the increased vascular network, as well as the effect of enhanced tissue perfusion on chronic inflammation and airway dynamics. The response of cells of the airways to the altered vascular profile and the subsequent influence on the features of airway remodelling will also be highlighted. We will explore the failure of current asthma therapeutics in "normalising" this vascular remodelling. Finally, we will summarize the outcomes of recent clinical trials which provide hope that anti-angiogenic therapies may be a potent asthma resolving class of drugs and provide a new approach to asthma management in the future. PMID- 25460036 TI - Cannabis and adolescent brain development. AB - Heavy cannabis use has been frequently associated with increased rates of mental illness and cognitive impairment, particularly amongst adolescent users. However, the neurobiological processes that underlie these associations are still not well understood. In this review, we discuss the findings of studies examining the acute and chronic effects of cannabis use on the brain, with a particular focus on the impact of commencing use during adolescence. Accumulating evidence from both animal and human studies suggests that regular heavy use during this period is associated with more severe and persistent negative outcomes than use during adulthood, suggesting that the adolescent brain may be particularly vulnerable to the effects of cannabis exposure. As the endocannabinoid system plays an important role in brain development, it is plausible that prolonged use during adolescence results in a disruption in the normative neuromaturational processes that occur during this period. We identify synaptic pruning and white matter development as two processes that may be adversely impacted by cannabis exposure during adolescence. Potentially, alterations in these processes may underlie the cognitive and emotional deficits that have been associated with regular use commencing during adolescence. PMID- 25460037 TI - Postoperative cognitive dysfunction and microglial activation in associated brain regions in old rats. AB - Research indicates that neuroinflammation plays a major role in postoperative cognitive dysfunction (POCD) in older patients. However, studies have mainly focused on hippocampal neuroinflammation and hippocampal-dependent learning and memory, which does not cover the whole spectrum of POCD. We hypothesized that regional differences in postoperative neuroinflammation in the brain may underlie variation in postoperative cognitive impairment. We aimed to investigate this hypothesis in a rat-model for POCD, by analyzing postoperative impairment in behavioral task performance and microglial activation in related brain areas. We subjected 25 months old Wistar rats to surgery and assessed spatial learning and memory, object and location recognition, reversal learning and exploratory behavior in the second postoperative week. The number and morphology of microglia were analyzed in the hippocampus, prefrontal cortex, striatum and amygdala on postoperative day 14. Control groups consisted of 3 and 25 months old rats that did not undergo surgery. We observed age related impairment in learning, memory and behavior, which was aggravated following surgery. Additionally, in old rats surgery was associated with signs of classical microglial activation in brain areas related to the impaired cognitive functions. These outcomes suggest that indeed neuroinflammation may be involved in POCD. Moreover, effects of age and surgery on cognition and microglial morphology seem to be area specific and hence cannot be generalized to the whole brain. This underpins the importance for expanding the research of POCD beyond the hippocampus. PMID- 25460039 TI - Rewarding effects of electrical stimulation of the insular cortex: decayed effectiveness after repeated tests and subsequent increase in vertical behavioral activity and conditioned place aversion after naloxone administration. AB - The insular cortex has been associated with various aversive and rewarding sensory, regulatory, and learning processes. The objective of this study was to examine the characteristics of the reinforcement induced by electrical stimulation of this brain area in rats. Results obtained confirm that electrical stimulation of the insular cortex may induce conditioned place and flavor preferences but the learning acquired is not transferred in a reversal test. Unexpectedly, they also demonstrate that this rewarding effect diminishes after repeated tests. In follow-up experiments, locomotor activity tests revealed an increased number of rearings (a sensitization index) in stimulated animals. Furthermore, in these same animals, administration of low doses of naloxone, an opiate antagonist, developed place aversion toward the maze compartment for which the animals had previously shown preference. These results are interpreted in relation to the effects induced by the repeated administration of natural and artificial rewarding stimuli. PMID- 25460038 TI - Spatio-temporal in vivo recording of dCREB2 dynamics in Drosophila long-term memory processing. AB - CREB (cAMP response element-binding protein) is an evolutionarily conserved transcription factor, playing key roles in synaptic plasticity, intrinsic excitability and long-term memory (LTM) formation. The Drosophila homologue of mammalian CREB, dCREB2, is also important for LTM. However, the spatio-temporal nature of dCREB2 activity during memory consolidation is poorly understood. Using an in vivo reporter system, we examined dCREB2 activity continuously in specific brain regions during LTM processing. Two brain regions that have been shown to be important for Drosophila LTM are the ellipsoid body (EB) and the mushroom body (MB). We found that dCREB2 reporter activity is persistently elevated in EB R2/R4m neurons, but not neighboring R3/R4d neurons, following LTM-inducing training. In multiple subsets of MB neurons, dCREB2 reporter activity is suppressed immediately following LTM-specific training, and elevated during late windows. In addition, we observed heterogeneous responses across different subsets of neurons in MB alphabeta lobe during LTM processing. All of these changes suggest that dCREB2 functions in both the EB and MB for LTM formation, and that this activity contributes to the process of systems consolidation. PMID- 25460040 TI - Post-training cocaine administration facilitates habit learning and requires the infralimbic cortex and dorsolateral striatum. AB - Human drug addiction is a complex disorder, in which exogenous substances are able to recruit and maintain behaviors involved in drug taking. Many drugs that are addictive in humans are able to act on natural brain systems for learning and memory, and while many memory systems may be affected by addictive drugs, work with operant tasks has shown that addictive drugs (e.g. cocaine and alcohol) are particularly effective in recruiting habit learning systems, compared to natural rewards. It is currently unknown if the ability of addictive drugs to facilitate habit learning depends on a direct action on habit learning systems in the brain, versus the rewarding properties of drug administration. To differentiate between these options, rats were trained to perform two actions (lever pressing), each of which was rewarded with a different natural reward. After acquiring the behavior, rats received three training sessions which were followed by post-training injections of saline or cocaine (5 or 10mg/kg, i.p.). Using sensory-specific satiety, extinction tests revealed that lever pressing for actions which were paired with saline were sensitive to devaluation (typical of goal-directed behaviors) while actions which were paired with cocaine were not sensitive to devaluation (typical of habitual behaviors). Lesions of the infralimbic or dorsolateral striatum were able to block the action of post-training cocaine injections. These data indicate that, within individual rats, cocaine injections facilitate the transition of behavior to habitual control for actions that have been recently performed, without a general facilitation of habit learning, and that this action of cocaine requires brain areas that are critical for learning natural habits. PMID- 25460041 TI - Time course of scopolamine effect on memory consolidation and forgetting in rats. AB - The effect of scopolamine on the consolidation and forgetting of emotional memory has not been completely elucidated yet. The aim of the present study was to investigate the time course of scopolamine effect on consolidation and forgetting of passive avoidance response. In a first experiment of the present study, we tested the effect of scopolamine (1mg/kg, i.p., immediately after acquisition), on 24h and 48h retention performance of the step-through passive avoidance task, in adult male Wistar rats. On the 24h retested trial, the latency of the passive avoidance response was significantly lower, while on the 48h retested trial it was significantly higher in scopolamine than in the saline-treated group. In a second experiment, we assessed the 24h time course of scopolamine (1mg/kg) effect on memory consolidation in passive avoidance task. We found that scopolamine administration only within the first six and half hours after acquisition improved memory consolidation in 48h retention performance. Finally, a third experiment was performed on the saline- and scopolamine-treated rats (given immediately after acquisition) that on the 48h retention test did not step through into the dark compartment during the cut-off time. These animals were retested weekly for up to first three months, and after that, every three months until the end of experiment (i.e., 15 months after acquisition). The passive avoidance response in the saline treated group lasted up to 6 weeks after acquisition, while in the scopolamine treated group 50% of animals conserved the initial level of passive avoidance response until the experiment end point. In conclusion, the present data suggest that (1) improving or impairment effect of scopolamine given in post-training periods depends on delay of retention trial, (2) memory consolidation process could be modify by scopolamine within first six and half hours after training and (3) scopolamine could delay forgetting of emotional memory. PMID- 25460042 TI - Insulin induces IRS2-dependent and GRK2-mediated beta2AR internalization to attenuate betaAR signaling in cardiomyocytes. AB - The counter-regulatory effects of insulin and catecholamines on carbohydrate and lipid metabolism are well studied, whereas the details of insulin regulation of beta adrenergic receptor (betaAR) signaling pathway in heart remain unknown. Here, we characterize a novel signaling pathway of insulin receptor (IR) to G protein-coupled receptor kinase 2 (GRK2) in the heart. Insulin stimulates recruitment of GRK2 to beta2AR, which induces beta2AR phosphorylation at the GRK sites of serine 355/356 and subsequently beta2AR internalization. Insulin thereby suppresses betaAR-induced cAMP-PKA activities and contractile response in neonatal and adult mouse cardiomyocytes. Deletion of insulin receptor substrate 2 (IRS2) disrupts the complex of IR and GRK2, which attenuates insulin-mediated beta2AR phosphorylation at the GRK sites and beta2AR internalization, and the counter-regulation effects of insulin on betaAR signaling. These data indicate the requirements of IRS2 and GRK2 for insulin to stimulate counter-regulation of betaAR via beta2AR phosphorylation and internalization in cardiomyocytes. PMID- 25460044 TI - MAPK-induced Gab1 translocation to the plasma membrane depends on a regulated intramolecular switch. AB - The timely orchestration of multiple signalling pathways is crucial for the integrity of an organism and therefore tightly controlled. Gab family proteins coordinate signal transduction at the plasma membrane (PM) by acting as docking platforms for signalling components involved in MAP kinase (MAPK), PI3 kinase (PI3K), phospholipase C (PLC) and Rho family GTPase signalling. The interaction with these components as well as the targeting of the docking platform to the PM underlies complex spatial and temporal regulatory mechanisms. Deregulated Gab1 activation and membrane binding have been observed in some haematopoietic malignancies and solid tumours, thereby contributing, for example, to the development of Philadelphia chromosome-negative myeloproliferative neoplasms and certain lung cancers. Previously, we could demonstrate that the presence of PIP3 in the PM, which is increased in many cancer cells, is not sufficient for constitutive Gab1 membrane recruitment. In addition, MAPK-dependent phosphorylation of Gab1 at serine 552 (Ser552) is vital for Gab1 membrane binding. Here, we confirm our hypothesis that in the absence of MAPK activity an intrinsic part of Gab1 prevents binding to PIP3 at the PM. This epitope of Gab1, which encompasses Ser552, interacts directly with the Gab1 PH domain. Two arginines located in positions +4 and +8 of Ser552 are essential for the interaction with the PH domain, as well as for the inhibition of membrane recruitment of unphosphorylated Gab1. Ser552 phosphorylation is dispensable in respective arginine to alanine mutants of Gab1. Gab1 recruitment to the PM is highly dynamic and continuous PI3K and MAPK activities are both essential for sustained Gab1 membrane localisation. Our data document the existence of a sophisticated and robust control mechanism that prevents Gab1 translocation and signalling complex assembly after the activation of either MAPK or PI3K alone. PMID- 25460043 TI - Regulation of DNA damage responses and cell cycle progression by hMOB2. AB - Mps one binder proteins (MOBs) are conserved regulators of essential signalling pathways. Biochemically, human MOB2 (hMOB2) can inhibit NDR kinases by competing with hMOB1 for binding to NDRs. However, biological roles of hMOB2 have remained enigmatic. Here, we describe novel functions of hMOB2 in the DNA damage response (DDR) and cell cycle regulation. hMOB2 promotes DDR signalling, cell survival and cell cycle arrest after exogenously induced DNA damage. Under normal growth conditions in the absence of exogenously induced DNA damage hMOB2 plays a role in preventing the accumulation of endogenous DNA damage and a subsequent p53/p21 dependent G1/S cell cycle arrest. Unexpectedly, these molecular and cellular phenotypes are not observed upon NDR manipulations, indicating that hMOB2 performs these functions independent of NDR signalling. Thus, to gain mechanistic insight, we screened for novel binding partners of hMOB2, revealing that hMOB2 interacts with RAD50, facilitating the recruitment of the MRE11-RAD50-NBS1 (MRN) DNA damage sensor complex and activated ATM to DNA damaged chromatin. Taken together, we conclude that hMOB2 supports the DDR and cell cycle progression. PMID- 25460045 TI - Thyronamine induces TRPM8 channel activation in human conjunctival epithelial cells. AB - 3-Iodothyronamine (T1AM), an endogenous thyroid hormone (TH) metabolite, induces numerous responses including a spontaneously reversible body temperature decline. As such an effect is associated in the eye with increases in basal tear flow and thermosensitive transient receptor potential melastatin 8 (TRPM8) channel activation, we determined in human conjunctival epithelial cells (IOBA-NHC) if T1AM also acts as a cooling agent to directly affect TRPM8 activation at a constant temperature. RT-PCR and quantitative real-time PCR (qPCR) along with immunocytochemistry probed for TRPM8 gene and protein expression whereas functional activity was evaluated by comparing the effects of T1AM with those of TRPM8 mediators on intracellular Ca(2+) ([Ca(2+)]i) and whole-cell currents. TRPM8 gene and protein expression was evident and icilin (20MUM), a TRPM8 agonist, increased Ca(2+) influx as well as whole-cell currents whereas BCTC (10MUM), a TRPM8 antagonist, suppressed these effects. Similarly, either temperature lowering below 23 degrees C or T1AM (1MUM) induced Ca(2+) transients that were blocked by this antagonist. TRPM8 activation by both 1uM T1AM and 20MUM icilin prevented capsaicin (CAP) (20MUM) from inducing increases in Ca(2+) influx through TRP vanilloid 1 (TRPV1) activation, whereas BCTC did not block this response. CAP (20MUM) induced a 2.5-fold increase in IL-6 release whereas during exposure to 20MUM capsazepine this rise was completely blocked. Similarly, T1AM (1MUM) prevented this response. Taken together, T1AM like icilin is a cooling agent since they both directly elicit TRPM8 activation at a constant temperature. Moreover, there is an inverse association between changes in TRPM8 and TRPV1 activity since these cooling agents blocked both CAP-induced TRPV1 activation and downstream rises in IL-6 release. PMID- 25460046 TI - Effects of ectoine on behavioural, physiological and biochemical parameters of Daphnia magna. AB - Ectoine (ECT) is a compatible solute produced by soil, marine and freshwater bacteria in response to stressful factors. The purpose of our study was to determine the possible toxic influence of ECT on Daphnia magna. We determined the following endpoints: survival rate during exposure and recovery, swimming performance, heart rate, thoracic limb movement determined by image analysis, haemoglobin level by ELISA assay, catalase and nitric oxide species (NOx) by spectrophotometric methods. The results showed 80% survival of daphnids exposed to 50mg/L of ECT after 24h and 10% after 90h, however lower concentrations of ECT were well tolerated. A concentration-dependent reduction of swimming velocity was noted at 24 and 48h of the exposure. ECT (at 2.5 and 4mg/L) induced an increase of heart rate and thoracic limb movement (at 2.5, 4 and 20mg/L) after 24h. After 10h of the exposure to ECT daphnids showed a concentration-dependent increase of haemoglobin level synthesized and accumulated in the epipodite epithelia. After 24h we noted a concentration-dependent decrease of haemoglobin level and its lowest value was found after 48h of the exposure. ECT at a concentration of 20 and 25mg/L slightly stimulated catalase activity after 24h. NOx level was also increased after 10h of the exposure to 20 and 25mg/L of ECT reaching maximal activity after 24h. Our results suggest that ECT possesses some modulatory potential on the behaviour, physiology and biochemical parameters in daphnids. PMID- 25460047 TI - Effects of atrazine and chlorpyrifos on DNA methylation in the brain and gonad of the common carp. AB - DNA methylation is known to play an important role in the regulation of gene expression in animal. The purpose of the present study was to examine the effect of atrazine (ATR), chlorpyrifos (CPF) and combined ATR/CPF exposure on DNA methylation in the brain and gonad of common carp (Cyprinus carpio L.). The carp were sampled after a 40-d exposure to CPF and ATR, individually or in combination, followed by a 40-d recovery to measure the levels of global DNA methylation and the expression of methylation enzymes (DNA methyltransferases (DNMTs) and methylcytosine binding domain 2 (MBD2)) in the brain and gonad tissues. The results revealed that a significant global DNA hypomethylation in the common carp exposed to ATR, CPF and their mixture was observed compared to the control fish. The MBD2 mRNA expression was up-regulated in the brain and gonad of the common carp exposed to ATR, CPF and their mixture, in contrast, the DNMTs mRNA expression was down-regulated. The information regarding the effects of ATR and CPF on DNA methylation status generated in this study is important for pesticides toxicology evaluation. However, the effect of ATR and CPF on the methylation status of specific genes, as well as its detailed mechanism requires further investigation. PMID- 25460048 TI - Intrathecal Fluorescein and Sellar Reconstruction in Pituitary Surgery: What Might Be Truly Useful? PMID- 25460049 TI - Craniopharyngiomas and Visual Loss. PMID- 25460050 TI - Motor-evoked potentials in cerebral aneurysm surgery. PMID- 25460051 TI - Traumatic subarachnoid hemorrhage in developed and developing communities. PMID- 25460052 TI - Diverse pathologies of the jugular foramen. PMID- 25460053 TI - Craniopharyngiomas and visual dysfunction: how to predict the visual outcome. PMID- 25460054 TI - Planum and olfactory groove meningiomas: is it possible to foresee the outcome? PMID- 25460055 TI - Vasospasm in aneurysmal subarachnoid hemorrhage: an evolving knowledge. PMID- 25460056 TI - Season-dependent effects of elevated temperature on stress biomarkers, energy metabolism and gamete development in mussels. AB - In coastal areas, sessile species can be severely affected by thermal stress associated to climate change. Presently, the effect of elevated temperature on metabolic, cellular and tissue-level responses of mussels was determined to assess whether the responses vary seasonally with seawater temperature and reproductive stage. Mussels were collected in fall, winter and summer, and (a) maintained at 16, 12, and 20 degrees C respectively or (b) subject to gradual temperature elevation for 8 days (+1 degrees C per day; from 16 to 24 degrees C in fall, from 12 to 20 degrees C in winter and from 20 to 28 degrees C in summer) and further maintained at 24 degrees C (fall), 20 degrees C (winter) and 28 degrees C (summer) for the following 6 days. Temperature elevation induced membrane destabilization, lysosomal enlargement, and reduced the aerobic scope in fall and summer whereas in winter no significant changes were found. Changes at tissue-level were only evident at 28 degrees C. Gamete development was impaired irrespective of season. Since the threshold of negative effects of warming was close to ambient temperatures in summer (24 degrees C or above) studied mussel populations would be vulnerable to the global climate change. PMID- 25460057 TI - In vitro exposure of haemocytes of the clam Ruditapes philippinarum to titanium dioxide (TiO2) nanoparticles: nanoparticle characterisation, effects on phagocytic activity and internalisation of nanoparticles into haemocytes. AB - The continuous growth of nanotechnology and nano-industries, the considerable increase of products containing nanoparticles (NPs) and the potential release of NPs in aquatic environments suggest a need to study NP effects on aquatic organisms. In this context, in vitro assays are commonly used for evaluating or predicting the negative effects of chemicals and for understanding their mechanisms of action. In this study, a physico-chemical characterisation of titanium dioxide NPs (n-TiO2) was performed, and an in vitro approach was used to investigate the effects of n-TiO2 on haemocytes of the clam Ruditapes philippinarum. In particular, the effects on haemocyte phagocytic activity were evaluated in two different experiments (with and without pre-treatment of haemocytes) by exposing cells to P25 n-TiO2 (0, 1 and 10 MUg/mL). In addition, the capability of n-TiO2 to interact with clam haemocytes was evaluated with a transmission electron microscope (TEM). In this study, n-TiO2 particles showed a mean diameter of approximately 21 nm, and both anatase (70%) and rutile (30%) phases were revealed. In both experiments, n-TiO2 significantly decreased the phagocytic index compared with the control, suggesting that NPs are able to interfere with cell functions. The results of the TEM analysis support this hypothesis. Indeed, we observed that TiO2 NPs interact with cell membranes and enter haemocyte cytoplasm and vacuoles after 60 min of exposure. To the best of our knowledge, this is the first study demonstrating the internalisation of TiO2 NPs into R. philippinarum haemocytes. The present study can contribute to the understanding of the mechanisms of action of TiO2 NPs in bivalve molluscs, at least at the haemocyte level. PMID- 25460058 TI - Trace element seasonality in marine macroalgae of different functional-form groups. AB - Novel information on the seasonality of element accumulation in seaweeds is provided. Seasonal patterns of As, Ba, Cd, Co, Cr, Cu, Mn, Mo, Ni, Pb, Se, Sr, U, V and Zn concentrations in macroalgae belonging to different functional-form groups (Ulva intestinalis, Ulva rigida, Codium fragile, Gracilaria gracilis) from the Thessaloniki Gulf, Aegean Sea were determined and compared. Uni- and multivariate data analyses were applied. Element concentrations generally decreased during spring and/or summer, probably due to the growth effect, but a reverse trend, particularly in Ulva species, was also observed. Most elements (Cd, Co, Cr, Cu, Mo, Ni, Pb, Sr) in Ulva species displayed a comparatively low monthly variability, indicating that the extent of seasonal variation is closely related to thallus morphology and growth strategy. In particular, these data suggest that Cd, Co, Cr, Cu, Mo, Ni, Pb and Sr contents in fast-growing, sheet like macroalgae are less influenced by the season, compared to their contents in coarsely-branched and thick-leathery macroalgae; therefore, sheet-like macroalgae may be more appropriate to be used in biomonitoring of coastal waters. The data presented could be utilized in the development of biomonitoring programmes for the protection of coastal environments. PMID- 25460059 TI - Application of "taxocene surrogation" and "taxonomic sufficiency" concepts to fish farming environmental monitoring. Comparison of BOPA index versus polychaete assemblage structure. AB - "Taxocene surrogation" and "taxonomic sufficiency" concepts were applied to the monitoring of soft bottoms macrobenthic assemblages influenced by fish farming following two approaches. Polychaete assemblage evaluation through multivariate analysis and the benthic index BOPA were compared. Six fish farms along the Spanish Mediterranean coast were monitored. Polychaete assemblage provided a suitable picture of the impact gradient, being correlated with total free sulphides. BOPA did not support the impact gradient described by the polychaete assemblage, providing erroneous categorizations. The inclusion of several polychaete families, which were locally identified as indicative of affection to recalculate BOPA, resulted in an improved diagnosis and correlation with the impact gradient. Nevertheless, frequent misclassifications occurred. These results suggest that the structure of polychaete families, sulphides and granulometry conform an appropriate strategy for fish farming monitoring. Biotic indices need to be specifically designed for concrete activities, and regionally validated, because of the environmental plasticity of benthic invertebrates. PMID- 25460060 TI - Response of intertidal sandy-beach macrofauna to human trampling: An urban vs. natural beach system approach. AB - Sandy beaches are subjected to intense stressors, which are mainly derived from the increasing pattern of beach urbanization. These ecosystems are also a magnet for tourists, who prefer these locations as leisure and holiday destinations, and such activity further increases the factors that have an adverse effect on beaches. In the study reported here the effect of human trampling on macrofauna assemblages that inhabit intertidal areas of sandy beaches was assessed using a BACI design. For this purpose, three contrasting sectors of the same beach were investigated: an urban area with a high level of visitors, a protected sector with a low density of users, and a transitional area with a high level of human occupancy. The physical variables were constant over time in each sector, whereas differences were found in the intensity of human use between sectors. Density variations and changes in the taxonomic structure of the macrofauna with time were shown by PERMANOVA analysis in the urban and transitional locations whereas the protected sector remained constant throughout the study period. The amphipod Bathyporeia pelagica appears sensitive to human trampling pressure and the use of this species as a bioindicator for these types of impact is recommended. PMID- 25460061 TI - Potential impact of mangrove clearance on biomass and biomass size spectra of nematode along the Sudanese Red Sea coast. AB - The potential effect of mangrove clearance on nematode assemblage biomass, biomass size spectra (NBSS) and abundance/biomass curves (ABC) was investigated in three sites representing a varying degree of mangrove clearance as well as in three stations established at each sites representing high-, mid- and low-water levels. Results revealed significant differences in sediment and nematode characteristics between the three sites. Although both the cleared and the intact mangrove had comparable biomass values, clear differences in biomass size spectra and abundance biomass curves were observed. The results suggested that the variation in the silt fraction and the food quality positively affected the total biomass. Mangrove clearance has caused a shift from a unimodal to a bimodal biomass size spectrum at all water levels, owing to an increase in smaller-bodied opportunistic non-selective deposit feeding nematodes. The ABC further confirmed the effect of clearance by classifying the cleared mangrove as moderately to grossly disturbed. PMID- 25460062 TI - Assessing baseline levels of coral health in a newly established marine protected area in a global scuba diving hotspot. AB - While coral reefs are increasingly threatened worldwide, they are also increasingly used for recreational activities. Given the environmental and socio economic significance of coral reefs, understanding the links between human activities and coral health and evaluating the efficacy of marine protected areas (MPAs) as a management regime to prevent further deterioration are critically important. The aim of this study was to quantify indicators of coral health at sites inside and outside a newly rezoned MPA framework in the dive tourism hotspot of Koh Tao, Thailand. We found that patterns in the health and diversity of coral communities one year on did not reflect the protected status conferred by newly zoned MPAs, but instead reflected past history of recreational use around the island. Sites characterised as past high-use sites had lower mean percent cover of hard corals overall and of corals in the typically disease- and disturbance-susceptible family Acroporidae, but higher mean cover of species in the more weedy family Agariciidae. Past high use sites also had higher mean prevalence of infectious diseases and other indicators of compromised health. Sites within the newly established MPAs are currently subjected to higher levels of environmental and anthropogenic pressures, with sedimentation, algal overgrowth, feeding scars from Drupella snails, and breakage particularly prevalent compared to sites in non-MPA areas. Given the greater prevalence of these factors within protected sites, the capacity of the MPA framework to effectively prevent further deterioration of Koh Tao's reefs is unclear. Nevertheless, our study constitutes a strong baseline for future long-term evaluations of the potential of MPAs to maintain coral health and diversity on highly threatened reefs. PMID- 25460063 TI - Twenty-year changes in coral near Muscat, Oman estimated from manta board tow observations. AB - The coastline of Muscat, Oman, contains some of the most extensive and diverse coral reefs in the northeastern Arabian Peninsula. In the past two decades this region has been impacted by expanding coastal development, the largest cyclone ever recorded in the Arabian Sea, and a large-scale harmful algal bloom which resulted in mass mortality of reefs elsewhere in the Gulf of Oman. In 2012 we estimated live and dead coral using manta tow observations on 370 transects at 13 locations along the coastline and nearshore islands of Muscat Oman. We compared these estimates against observations made on 389 transects at the same 13 locations two decades earlier (1993-94) in order to determine long-term changes in benthos along the Muscat coast. Results were mapped and differences in categorical mean values for transect locations were statistically compared between survey years. Live hard and soft coral decreased over the past two decades at most survey sites, and decreases were significant at three exposed coastline sites and one semi-enclosed embayment. One sheltered embayment site showed a significant increase in live hard coral over the study period. Declines in live hard coral were associated with increases in dead coral framework at 8 of the 13 sites, but these changes were non-significant. We attribute these changes primarily to long-term effects of Cyclone Gonu, which struck the Oman coast in June 2007. The study results suggest that the manta tow method can be an effective way to detect long-term changes in coral and other benthic parameters over large areas, despite limitations on its precision. PMID- 25460064 TI - Biochemical biomarkers in barnacles Balanus improvisus: pollution and seasonal effects. AB - Biochemical biomarkers were evaluated in the barnacle Balanus improvisus (Crustacea: Cirripedia) sampled from both polluted and reference sites in the Patos Lagoon Estuary, Southern Brazil. During winter, higher glutathione S transferase (GST) activity was recorded in the barnacles from the polluted sites, indicating environmental exposure to contaminants. Relatively low lipid peroxide levels (LPO) were also observed in barnacles from polluted sites, indicating that oxidative stress by lipid peroxidation was not a major threat in barnacles from those sites. Seasonal differences in the GST and total oxyradical scavenging capacity (TOSC) could have contributed to the low LPO levels in the summer relative to the levels in the winter. Catalase activity and metallothionein levels were not affected by contamination or seasonality. The seasonal changes observed in biomarker responses were paralleled by the differences in temperature, which could have affected physiological responses, including the balance between pro-oxidants and antioxidants. PMID- 25460065 TI - Effects of cadmium and 17beta-estradiol on Mytilus galloprovincialis redox status. Prooxidant-antioxidant balance (PAB) as a novel approach in biomonitoring of marine environments. AB - Cadmium and 17beta-estradiol are rapidly accumulated in mussel tissues, making mussels excellent pollution sentinel organisms. The aim of the present study was to compare the oxidative responses of the mussels after 1, 3 and 7 days of exposure to cadmium with those to 17beta-estradiol and subsequently, to suggest a multi-parametric approach for biomonitoring studies. Our results showed that environmentally relevant concentrations of either cadmium or 17beta-estradiol for 1, 3 and 7 days induced oxidative stress in hemocytes of exposed mussels. The latter was determined by significantly increased ROS levels and apoptosis, by suppression of antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione-S-transferase (GST) expression levels and subsequent increased prooxidant levels, as measured by prooxidant-antioxidant balance (PAB) assay. To our knowledge this is the first time that prooxidant-antioxidant balance is evaluated in invertebrates as an index of oxidative stress. The simultaneous use of the parameters of prooxidant-antioxidant balance and antioxidant enzymes expression patterns, in combination with ROS production levels and apoptosis, in mussel hemocytes is suggested as an approach that may help to better evaluate the impact of environmental pollution on marine organisms and thereupon ecosystems. PMID- 25460066 TI - Duration of maternal undernutrition differentially alters fetal growth and hormone concentrations. AB - To investigate the impact of duration of maternal undernutrition in twin sheep pregnancies, ewes were either fed 100% (C) or 50% of their nutrient requirements from 28 to 78 d gestational age (dGA) and readjusted to 100% beginning at 79 dGA (LC) or continuously restricted from 28 to 135 dGA (LL). Weights of the fetus, empty carcass, brain, and liver were greater in the LC than LL fetuses at 135 dGA (P <= 0.05). Although umbilical vein (UmV) glucose concentrations did not differ, the UmV:umbilical artery (UmA) glucose gradient was smaller (0.26 +/- 0.03 vs 0.38 +/- 0.03 and 0.39 +/- 0.04 mmol L(-1); P <= 0.05) in LL than C and LC fetuses, respectively. Umbilical vein concentrations of IGF-1 were less (46.7 +/- 5.62 vs 74.3 +/- 6.71 ng/mL; P <= 0.05) in LL than LC fetuses. Additionally, LL fetuses tended (P <= 0.10) to have lower UmA concentrations of insulin (0.24 +/- 0.13 vs 0.70 +/- 0.15 ng/mL) and IGF-1 (66.6 +/- 7.51 vs 91.4 +/- 8.97 ng/mL) than LC fetuses. Although most of the observed differences occurred between LC and LL pregnancies, LC fetuses tended (P <= 0.10) to have greater UmV and UmA pCO2 than C fetuses. Furthermore, the UmV:UmA O2 content gradient tended to be greater (5.02 +/- 0.43 vs 3.41 +/- 0.47; P <= 0.10) in C than LL fetuses. UmA placental lactogen also tended to be greater (46.6 +/- 4.40 vs 31.1 +/- 4.69 ng/mL; P <= 0.10) in LL than C fetuses. These data suggest that in twin pregnancies, maternal undernutrition followed by realimentation induces a different fetal outcome compared with continuous nutrient restriction, and both may differ physiologically from control fed pregnancies. PMID- 25460067 TI - Ovariectomy in young prepubertal dairy heifers causes complete suppression of mammary progesterone receptors. AB - Mammary growth and development depends on ovarian steroids and particularly interaction of estrogen and progesterone with their intracellular receptors. The objectives of this study were to determine the effect of ovariectomy on the expression of protein and messenger RNA for estrogen receptor-alpha (ESR1) and progesterone receptor (PGR) and their relation to mammary ductal development and cell proliferation. Prepubertal Holstein heifers 2, 3, or 4 mo of age were randomly assigned to one of 2 treatments, ovariectomized (OVX; n = 8) or sham operated (INT; n = 12). Mammary parenchymal (PAR) tissue samples were harvested 30 d after surgery. Localization and quantitation of ESR1 and PGR in PAR were determined by immunohistochemistry and quantitative multispectral imaging. Relative messenger RNA expression of ESR1 and PGR in PAR was measured by quantitative real time polymerase chain reaction. We observed the complete absence of PGR-positive epithelial cell nuclei and reduced PGR transcript abundance in mammary parenchyma of OVX heifers. The percent of epithelial cells expressing ESR1 did not differ by treatment but was decreased with age. However, average intensity of ESR1 expression per cell was reduced in OVX heifers. The abundance of Ki67 labeled epithelial cells and stromal cells was reduced after ovariectomy. These data suggest that reduced mammary development after ovariectomy may be mediated by loss of PGR expression and reduced ESR1 expression in positive cells. A presumptive relationship with ovarian-derived circulating estradiol remains unresolved, but data suggest other ovarian-derived agents may play a role. Use of specific antagonists to manipulate expression or action of PGR and ESR1 receptors should provide direct evidence for roles of these receptors in prepubertal bovine mammary development. PMID- 25460068 TI - Spatiotemporal phase clusters and phase synchronization patterns derived from high density EEG and ECoG recordings. AB - High density scalp EEG and subdural ECoG recordings provide an opportunity to map the electrical activity of the cortex with high spatial resolution. The spatial power spectral densities conform to a power law distribution with some nonlinear variations. The spatiotemporal patterns of phase derived from these data sets have unique features, such as, amplitude and phase modulation waves and also exhibited formation of spatial phase cluster patterns. These unique features represent different cognitive states and are different between normal and diseased states. Reported results show that the rate of formation of phase cluster patterns derived from the seizure-free interictal EEG data are higher in epileptogenic zones as compared with nearby normal areas of the brain. PMID- 25460071 TI - Single trial analysis of field potentials in perception, learning and memory. AB - The analysis of single trial responses of field potentials is an important tool to study brain signals. Single trial analyses can indeed provide additional information that is obscured or simply not available in the average responses. The importance of studying single trial responses is reinforced by the fact that different brain processes are correlated with trial-by-trial variation of the responses. Here, we review key studies implementing single trial analyses of field potentials-using methods such as single trial latency, amplitude and power changes, spike and LFP relationships, correlations between areas, cross frequency coupling, decoding of the presented stimuli-that bring light into the neural basis of perception, learning and memory. PMID- 25460069 TI - Brain state dependent activity in the cortex and thalamus. AB - Cortical and thalamocortical activity is highly state dependent, varying between patterns that are conducive to accurate sensory-motor processing, to states in which the brain is largely off-line and generating internal rhythms irrespective of the outside world. The generation of rhythmic activity occurs through the interaction of stereotyped patterns of connectivity together with intrinsic membrane and synaptic properties. One common theme in the generation of rhythms is the interaction of a positive feedback loop (e.g., recurrent excitation) with negative feedback control (e.g., inhibition, adaptation, or synaptic depression). The operation of these state-dependent activities has wide ranging effects from enhancing or blocking sensory-motor processing to the generation of pathological rhythms associated with psychiatric or neurological disorders. PMID- 25460070 TI - Olfactory system oscillations across phyla. AB - Neural oscillations are ubiquitous in olfactory systems of mammals, insects and molluscs. Neurophysiological and computational investigations point to common mechanisms for gamma or odor associated oscillations across phyla (40-100Hz in mammals, 20-30Hz in insects, 0.5-1.5Hz in molluscs), engaging the reciprocal dendrodendritic synapse between excitatory principle neurons and inhibitory interneurons in the olfactory bulb (OB), antennal lobe (AL), or procerebrum (PrC). Recent studies suggest important mechanisms that may modulate gamma oscillations, including neuromodulators and centrifugal input to the OB and AL. Beta (20Hz) and theta (2-12Hz) oscillations coordinate activity within and across brain regions. Olfactory beta oscillations are associated with odor learning and depend on centrifugal OB input, while theta oscillations are strongly associated with respiration. PMID- 25460073 TI - The heavy tail of the human brain. AB - Fluctuating oscillations are a ubiquitous feature of neurophysiology. Are the amplitude fluctuations of neural oscillations chance excursions drawn randomly from a normal distribution, or do they tell us more? Recent empirical research suggests that the occurrence of 'anomalous' (high amplitude) oscillations imbues their probability distributions with a heavier tail than the standard normal distribution. However, not all heavy tails are the same. We provide canonical examples of different heavy-tailed distributions in cortical oscillations and discuss the corresponding mechanisms that each suggest, ranging from criticality to multistability, memory, bifurcations, and multiplicative noise. Their existence suggests that the brain is a strongly correlated complex system that employs many different functional mechanisms, and that likewise, we as scientists should refrain from methodological monism. PMID- 25460072 TI - Robust circuit rhythms in small circuits arise from variable circuit components and mechanisms. AB - Small central pattern generating circuits found in invertebrates have significant advantages for the study of the circuit mechanisms that generate brain rhythms. Experimental and computational studies of small oscillatory circuits reveal that similar rhythms can arise from disparate mechanisms. Animal-to-animal variation in the properties of single neurons and synapses may underly robust circuit performance, and can be revealed by perturbations. Neuromodulation can produce altered circuit performance but also ensure reliable circuit function. PMID- 25460074 TI - Communication through coherence with inter-areal delays. AB - The communication-through-coherence (CTC) hypothesis proposes that anatomical connections are dynamically rendered effective or ineffective through the presence or absence of rhythmic synchronization, in particular in the gamma and beta bands. The original CTC statement proposed that uni-directional communication is due to rhythmic entrainment with an inter-areal delay and a resulting non-zero phase relation, whereas bi-directional communication is due to zero-phase synchronization. Recent studies found that inter-areal gamma-band synchronization entails a non-zero phase lag. We therefore modify the CTC hypothesis and propose that bi-directional cortical communication is realized separately for the two directions by uni-directional CTC mechanisms entailing delays in both directions. We review evidence suggesting that inter-areal influences in the feedforward and feedback directions are segregated both anatomically and spectrally. PMID- 25460075 TI - Random graph theory and neuropercolation for modeling brain oscillations at criticality. AB - Mathematical approaches are reviewed to interpret intermittent singular space time dynamics observed in brain imaging experiments. The following aspects of brain dynamics are considered: nonlinear dynamics (chaos), phase transitions, and criticality. Probabilistic cellular automata and random graph models are described, which develop equations for the probability distributions of macroscopic state variables as an alternative to differential equations. The introduced modular neuropercolation model is motivated by the multilayer structure and dynamical properties of the cortex, and it describes critical brain oscillations, including background activity, narrow-band oscillations in excitatory-inhibitory populations, and broadband oscillations in the cortex. Input-induced and spontaneous transitions between states with large-scale synchrony and without synchrony exhibit brief episodes with long-range spatial correlations as observed in experiments. PMID- 25460076 TI - Plant vacuolar trafficking driven by RAB and SNARE proteins. AB - Membrane-bounded organelles are connected to each other by membrane trafficking, which is accomplished by membrane fusion between transport vesicles and target organelles mediated by RAB GTPases and SNARE proteins. Of those trafficking pathways networking plant organelles, the vacuolar trafficking pathway has recently been shown to be uniquely diversified from non-plant systems, most likely reflecting unique functions of plant vacuoles such as the storage of proteins and other organic compounds, generation of turgor pressure, and space filling to enlarge plant bodies. Plant-unique trafficking machineries in addition to evolutionarily conserved molecular components are allocated to this trafficking pathway in distinctive ways. In this review, we summarize recent findings on SNARE proteins and RAB GTPases mediating vacuolar transport in plants, especially focusing on the functions and regulation of two distinct trans SNARE complexes and RAB5 and RAB7 in multiple vacuolar trafficking pathways. PMID- 25460078 TI - Across the great divide: the plant cell surface continuum. AB - The plant cell wall, plasma membrane and cytoskeleton exist as a cell surface continuum. This interconnection of organelles forms the interface between the plant cell and the external environment and is important for detecting the presence of a diverse range of stimuli. A plethora of plasma membrane microdomains with putative roles in membrane localized enzymatic or signalling processes have been described. While regulation of cell wall composition is defined by proteins within the plasma membrane, the cell wall has been shown to have an anchoring role on plasma membrane proteins which affects their lateral mobility. This interplay between plasma membrane and cell wall components is necessary for plasma membrane microdomain function. Actin and microtubule cytoskeletons are also involved in maintenance and function of the cell surface continuum. Investigation of the interactions between organellar components of this mechanism are important if we are to understand how cells respond to external signals. PMID- 25460079 TI - The kinematics and mechanics of leaf expansion: new pieces to the Arabidopsis puzzle. AB - Leaves are the primary organs for photosynthesis, and their angle, size, and timing of deployment determine the light capture efficiency of the canopy. Therefore, leaf development is an important trait in both natural and managed populations. In dicot leaves, the spatial and temporal patterns of cell division and expansion are heterogeneous, and a long-standing challenge has been to understand how subcellular and cellular growth processes can operate across broad spatial scales to influence the macroscopic growth of leaves. This review focuses on recent time-lapse analyses that help to clarify relationships between the polarized growth of individual cells, the growth behaviors of cell clusters, and leaf morphology. PMID- 25460077 TI - Re-constructing our models of cellulose and primary cell wall assembly. AB - The cellulose microfibril has more subtlety than is commonly recognized. Details of its structure may influence how matrix polysaccharides interact with its distinctive hydrophobic and hydrophilic surfaces to form a strong yet extensible structure. Recent advances in this field include the first structures of bacterial and plant cellulose synthases and revised estimates of microfibril structure, reduced from 36 to 18 chains. New results also indicate that cellulose interactions with xyloglucan are more limited than commonly believed, whereas pectin-cellulose interactions are more prevalent. Computational results indicate that xyloglucan binds tightest to the hydrophobic surface of cellulose microfibrils. Wall extensibility may be controlled at limited regions ('biomechanical hotspots') where cellulose-cellulose contacts are made, potentially mediated by trace amounts of xyloglucan. PMID- 25460080 TI - CLASP: a microtubule-based integrator of the hormone-mediated transitions from cell division to elongation. AB - Plants use robust mechanisms to optimize organ size to prevailing conditions. Modulating the transition from cell division to elongation dramatically affects morphology and size. Although it is well established that auxin, cytokinin and brassinosteroid mediate these transitions, recent works show that the cytoskeleton, which is normally thought to act downstream of these hormones, plays a key role in this regulatory process. In particular, the microtubule associated protein CLASP has a dual role in meristem maintenance. CLASP modulates levels of the auxin efflux carrier PIN2 by tethering SNX1 endosomes to cortical microtubules, which in turn fine tunes auxin maxima in the root apical meristem. CLASP is also required for transfacial microtubule bundle formation at the sharp cell edges, a feature strongly associated with maintaining the capacity for further cell division. PMID- 25460081 TI - HPV16 E2 enhances the expression of NF-kappaB and STAT3 target genes and potentiates NF-kappaB activation by inflammatory mediators. AB - HPV-transformed cells exhibit activation of NF-kappaB and STAT3 (mediators of inflammation), but very little is known about their regulation under inflammatory conditions before HPV integration. This study reports that cervical tissues with stromal inflammation and intact HPV16 E2 gene show increased expression of target genes of NF-kappaB and/or STAT3 which can regulate cell survival (cyclin D1, c Myc, survivin and Bcl2) and inflammatory responses (TNF-alpha, IL-1beta, IL-6, IL 8 and CCR2). Increased expression of RelA, p-IkappaBalpha, STAT3, p-STAT3 (Ser727), Pin1 (peptidyl-prolyl cis/trans isomerase) and MCM2 in the squamous epithelia of cervices with stromal inflammation supports early activation of NF kappaB-STAT3. Furthermore, HPV16 E2 potentiated NF-kappaB activation induced by inflammatory mediators, IL-1beta and SDF-1alpha, in HEK293 cells. These results reveal a novel role for E2 in regulating the activities of NF-kappaB and STAT3 that may have implications in carcinogenic progression of HPV16-infected cells under conditions of stromal inflammation. PMID- 25460082 TI - ERDR1 enhances human NK cell cytotoxicity through an actin-regulated degranulation-dependent pathway. AB - Erythroid differentiation regulator 1 (ERDR1), which is a stress-related survival factor, exhibits anti-cancer effects against melanoma. However, the function of ERDR1 on immune cells has not been examined. We investigated whether ERDR1 regulates the cytotoxic ability of human natural killer (NK) cells, which are known as innate effector lymphocytes. In this study, treatment with recombinant ERDR1 resulted in enhanced NK cell cytotoxicity through the secretion of lytic granules. Furthermore, actin modulation was involved in the ERDR1-enhanced NK cell cytotoxicity. ERDR1 stimulated actin accumulation at the immunological synapse, which was induced by the activation of Vav-1 in NK cells. These findings suggest new insight into the function of ERDR1 function in the human immune system. PMID- 25460084 TI - Paradoxical effects of human adipose tissue-derived mesenchymal stem cells on progression of experimental arthritis in SKG mice. AB - We evaluated the therapeutic effect of human adipose tissue-derived mesenchymal stem cells (hAd-MSCs) in a SKG arthritis model, a relevant animal model for human rheumatoid arthritis. hAd-MSCs were administered intraperitoneally into the mice for five consecutive days from on day 12 or 34 after arthritis induction, when the average clinical score was 0.5 or 5, respectively. They remarkably suppressed arthritis when administered on day 12. Disease suppression was correlated with reduction of pro-inflammatory cytokines and with increased levels of TGF-beta and IL-10 from splenocytes. However, when hAd-MSCs were administered on day 34, the clinical scores were not improved, the histopathological scores were aggravated, and cytokine profiles were differed. Thus, hAd-MSCs showed paradoxical effects, according to the disease phase when they were administered. These suggest that the same cells acted differently depending on the disease progress, and cautions should be paid for safe and effective use of MSCs. PMID- 25460083 TI - Distinct kinetics of viral replication, T cell infiltration, and fibrosis in three phases of myocarditis following Theiler's virus infection. AB - We established a novel model of myocarditis induced with Theiler's murine encephalomyelitis virus (TMEV), which has been used as a viral model for multiple sclerosis and seizure/epilepsy. Following TMEV infection, C3H mice developed severe myocarditis with T cell infiltration, while C57BL/6 mice had mild lesions and SJL/J mice had no inflammation in the heart. In C3H mice, myocarditis was divided into three phases: acute viral, subacute immune, and chronic fibrotic phases. Using toll-like receptor (TLR) 4-deficient C3H mice, we found that interleukin (IL)-6, IL-17, TLR4, and anti-viral immune responses were associated with myocarditis susceptibility. PMID- 25460085 TI - Anti-inflammatory effect of chymotrypsin to autoimmune response against CNS is dose-dependent. AB - Multiple sclerosis is an inflammatory autoimmune disease of central nervous system (CNS) in which inflammatory cells release pro-inflammatory cytokines, proteases, and other toxic mediators. Proteases are involved in many aspects of inflammatory process. There are many reports regarding the effect of proteases on inflammation. Chymotrypsin is a serine protease with anti-inflammatory effect. We investigated chymotrypsin effect on experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. Intra-CSF injection with 0.1 mg/ml, 0.2 mg/ml chymotrypsin, or saline was done on day 7 after EAE induction. Our study demonstrated that 0.1 mg/ml chymotrypsin treatment did not decrease clinical signs, but 0.2 mg/ml chymotrypsin ameliorated clinical signs and manipulated immune response in both brain and spinal cord. Administration of 0.1 mg/ml or 0.2 mg/ml chymotrypsin led to decreased IL-17 along with increased IL-4 and FoxP3 in 0.2 mg/ml chymotrypsin-treated animals. Presumably, chymotrypsin acts in a dose-dependent manner and concentrations of chymotrypsin more than 0.2 mg/ml may have more beneficial effect. PMID- 25460086 TI - Application of classification algorithms for analysis of road safety risk factor dependencies. AB - Transportation continues to be an integral part of modern life, and the importance of road traffic safety cannot be overstated. Consequently, recent road traffic safety studies have focused on analysis of risk factors that impact fatality and injury level (severity) of traffic accidents. While some of the risk factors, such as drug use and drinking, are widely known to affect severity, an accurate modeling of their influences is still an open research topic. Furthermore, there are innumerable risk factors that are waiting to be discovered or analyzed. A promising approach is to investigate historical traffic accident data that have been collected in the past decades. This study inspects traffic accident reports that have been accumulated by the California Highway Patrol (CHP) since 1973 for which each accident report contains around 100 data fields. Among them, we investigate 25 fields between 2004 and 2010 that are most relevant to car accidents. Using two classification methods, the Naive Bayes classifier and the decision tree classifier, the relative importance of the data fields, i.e., risk factors, is revealed with respect to the resulting severity level. Performances of the classifiers are compared to each other and a binary logistic regression model is used as the basis for the comparisons. Some of the high ranking risk factors are found to be strongly dependent on each other, and their incremental gains on estimating or modeling severity level are evaluated quantitatively. The analysis shows that only a handful of the risk factors in the data dominate the severity level and that dependency among the top risk factors is an imperative trait to consider for an accurate analysis. PMID- 25460087 TI - Modeling crash spatial heterogeneity: random parameter versus geographically weighting. AB - The widely adopted techniques for regional crash modeling include the negative binomial model (NB) and Bayesian negative binomial model with conditional autoregressive prior (CAR). The outputs from both models consist of a set of fixed global parameter estimates. However, the impacts of predicting variables on crash counts might not be stationary over space. This study intended to quantitatively investigate this spatial heterogeneity in regional safety modeling using two advanced approaches, i.e., random parameter negative binomial model (RPNB) and semi-parametric geographically weighted Poisson regression model (S GWPR). Based on a 3-year data set from the county of Hillsborough, Florida, results revealed that (1) both RPNB and S-GWPR successfully capture the spatially varying relationship, but the two methods yield notably different sets of results; (2) the S-GWPR performs best with the highest value of Rd(2) as well as the lowest mean absolute deviance and Akaike information criterion measures. Whereas the RPNB is comparable to the CAR, in some cases, it provides less accurate predictions; (3) a moderately significant spatial correlation is found in the residuals of RPNB and NB, implying the inadequacy in accounting for the spatial correlation existed across adjacent zones. As crash data are typically collected with reference to location dimension, it is desirable to firstly make use of the geographical component to explore explicitly spatial aspects of the crash data (i.e., the spatial heterogeneity, or the spatially structured varying relationships), then is the unobserved heterogeneity by non-spatial or fuzzy techniques. The S-GWPR is proven to be more appropriate for regional crash modeling as the method outperforms the global models in capturing the spatial heterogeneity occurring in the relationship that is model, and compared with the non-spatial model, it is capable of accounting for the spatial correlation in crash data. PMID- 25460088 TI - Perceived traffic risk for cyclists: the impact of near miss and collision experiences. AB - Though the percentage of people bicycling for transportation rose during the last decade, with an average increase in bicycle commuting of 47% (Flusche, 2012), still only 1% of all U.S. trips are made by bike (Flusche, 2010). Research suggests that people's concern regarding the risk of bicycling near traffic namely the risk of being hit by a car-remain a significant barrier to widespread cycling. However, research has not disaggregated traffic risk to expose its many aspects and how they may affect bicyclists with differing skill levels, experiences, and behaviors. This study begins to address this gap in our understanding. Elaborating on results from an internet survey, this study examined various aspects of traffic risk among 406 potential and current bicyclists in the San Francisco Bay Area. The data indicate that perceived traffic risk negatively influences the decision to bicycle for potential and occasional bicyclists, although the influence decreases with cycling frequency. Additionally, cycling frequency seems to heighten awareness of traffic risk, particularly for cyclists who have experienced "near misses" or collisions. In particular, near misses were found to be (a) much more common than collisions and (b) more strongly associated than collisions with perceived traffic risk. The findings suggest that efforts targeting road user behaviors and roadway designs associated with these near misses could mitigate perceived and actual traffic risk for bicyclists, and thereby eventually help achieve higher cycling ridership. PMID- 25460089 TI - Potential crash reduction benefits of shoulder rumble strips in two-lane rural highways. AB - This paper reports the findings from a study aimed at examining the effectiveness of shoulder rumble strips in reducing run-off-the-road (ROR) crashes on two-lane rural highways using the empirical Bayes (EB) before-and-after analysis method. Specifically, the study analyzed the effects of traffic volume, roadway geometry and paved right shoulder width on the effectiveness of shoulder rumble strips. The results of this study demonstrate the safety benefits of shoulder rumble strips in reducing the ROR crashes on two-lane rural highways using the state of Idaho 2001-2009 crash data. This study revealed a 14% reduction in all ROR crashes after the installation of shoulder rumble strips on 178.63miles of two lane rural highways in Idaho. The results indicate that shoulder rumble strips were most effective on roads with relatively moderate curvature and right paved shoulder width of 3 feet and more. PMID- 25460090 TI - The road user behaviour of school students in Iran. AB - The present study developed a Persian version of the Adolescent Road User Behaviour Questionnaire (ARBQ) and investigated the psychometric properties of the scale in a sample of school students in the province of Tehran (Iran). In total 1111 adolescents completed the Persian version of the ARBQ. Exploratory factor analysis, using the shortened 21-item version of the scale revealed the presence of three reliable factors which were also supported using confirmatory factor analysis. According to this research, engagement in dangerous playing in the road was significantly higher among males, residents of large urban areas, students from private schools, students in the south of Tehran, those who reported relatives or friends had been killed in a road crash and those with a personal history of road accidents. Moreover, older adolescents, those who reported relatives or friends having been killed in a road crash and those with a traffic accident history reported higher involvement in unsafe crossing behaviour. Females, older adolescents, residents of small urban areas, students from schools in small urban areas and those with an accident history also reported less frequent engagement in planned protective behaviours. This study confirms that the ARBQ is a useful framework for investigating adolescents' on road behaviours in Iran. This research also showed that adolescents put themselves at risk by engaging in hazardous behaviours. As is the case in most countries, this study revealed the need for interventions, such as education and enforcement to improve the on-road safety culture amongst Iranian adolescents. PMID- 25460091 TI - Impact of mandating a driving lesson for older drivers at license renewal in Japan. AB - In Japan, a driving lesson consisting of a lecture, a driver aptitude test, on road driving assessment and a discussion session was added to the driving license renewal procedure for drivers aged 75 years or older in 1998 and for drivers aged 70 years or older in 2002. We investigated whether these additions contributed to a reduction in at-fault motor vehicle collisions (MVCs) by examining the trend of the at-fault MVC rates per licensed driver and the rate ratios of the older drivers relative to those aged 65-69 years for the years 1986-2011. All data were derived from nationwide traffic statistics. If the introduction of the lesson was effective in reducing at-fault MVCs of older drivers, the rate ratio should have declined, given that the lesson targeted only the older drivers. We found this was not the case, i.e., there was no declining trend in the at-fault MVC rate ratios of both drivers aged 75 years or older and drivers aged 70 years or older, relative to drivers aged 65-69 years, after the driving lesson at license renewal became mandatory for these older drivers. Therefore, the mandatory lesson for the older drivers at license renewal needs to be reconsidered. PMID- 25460092 TI - Nothing good ever happens after midnight: observed exposure and alcohol use during weekend nights among young male drivers carrying passengers in a late licensing country. AB - Similar to other countries, also in the Netherlands young male drivers (ages between 18 and 24 years) are overrepresented in crashes during weekend nights, thereby fatally injuring one or more of their passengers. This overrepresentation may be due to two contributing factors: (a) a higher exposure-to-risk because of dangerous trip condition, and (b) a higher tendency to take risks. Studies on these factors, mostly carried out in jurisdictions where youngsters are licensed at an earlier age than in Europe, suggest a strong -often negative- influence from peer-aged passengers. Given that in adolescence susceptibility to peer pressure reduces with age, these findings may not be applicable to late licensing countries, such as in Europe. In the Netherlands -a late licensing country- youngsters are licensed after the age of 18 years, followed by a 5 year probation period with a legal alcohol limit of 0.2g/L. Further, designated driver schemes are in place since 2001, alcohol limits are enforced by random breath testing schemes, and no passenger and night time restrictions are in force. Against this background, we examined the incidence of dangerous trip conditions and risk taking among young male drivers and compared those with a reference group with a low passenger fatality rate. To that end, data on trip conditions and risk behavior were obtained from a data base on 18,608 randomly selected drivers during weekend nights in 2010, between 22:00 and 06:00. This data base held information for each randomly selected on breath alcohol concentration (BAC), license status, driver characteristics (age and gender), number of passengers, time of night, and level of urbanization. Binary logistic regression analysis confirmed the overrepresentation of young male drivers in traffic, carrying more frequently passengers than the reference group, especially after midnight. Urbanization level was not a modifying factor, but 'time of night' was, with riskier conditions after midnight in terms of: (a) a higher young male driver presence, (b) young male drivers carrying more frequently multiple passengers and (c) a higher prevalence of illegal BACs. After midnight, no evidence was found for a protective effect of the presence of one passenger on alcohol use. Of the young male drivers, 5% were over the legal limit and 3 in 5 young males who were over the limit carried passengers. However, the indicative result that young male drivers with multiple passengers were less likely to have been drinking than solo drivers or drivers with just one passenger, is suggestive of a protective effect of multiple passengers. These results may guide preventive strategies, including police enforcement and designated driver programmes. PMID- 25460093 TI - Wrong-way driving crashes on French divided roads. AB - CONTEXT: The objective of divided roads is to increase users' safety by posting unidirectional traffic flows. It happens however that drivers proceed in the wrong direction, endangering themselves as well as other users. The crashes caused by wrong-way drivers are generally spotlighted by the media and call for public intervention. OBJECTIVES: This paper proposes a characterization of wrong way driving crashes occurring on French divided road on the 2008-2012 period. The objective is to identify the factors that delineate between wrong-way driving crashes and other crashes. METHOD: Building on the national injury road crash database, 266 crashes involving a wrong-way driver were identified. Their characteristics (related to timing, location, vehicle and driver) are compared to those of the 22,120 other crashes that occurred on the same roads over the same period. The comparison relies on descriptive statistics, completed by a logistic regression. RESULTS: Wrong-way driving crashes are rare but severe. They are more likely to occur during night hours and on non-freeway roads than other crashes. Wrong-way drivers are older, more likely to be intoxicated, to be locals, to drive older vehicles, mainly passenger cars without passengers, than other drivers. PERSPECTIVES: The differences observed across networks can help prioritizing public intervention. Most of the identified WW-driving factors deal with cognitive impairment. Therefore, the specific countermeasures such as alternative road signs should be designed for and tested on cognitively impaired drivers. Nevertheless, WW-driving factors are also risk factors for other types of crashes (e.g. elderly driving, drunk driving and age of the vehicle). This suggests that, instead of (or in addition to) developing WW-driving specific countermeasures, managing these risk factors would help reducing a larger number of crashes. PMID- 25460094 TI - The relationship between the travelling speed and motorcycle styles in urban settings: a case study in Belgrade. AB - This report examines the difference in the distribution of the speeds of different motorcycle styles and the difference in the distribution of speeds of particular motorcycle styles and cars. The relationship between the speed of motorcycles that possess and those that do not possess vehicle registration plates was also explored. The speed was measured at six different locations on main roads in the city of Belgrade, Serbia. The study confirmed that, on average, motorcyclists drive faster than drivers of cars, but extreme speeding is recorded 2.3 times more often by motorcyclists than by car drivers. In this research, the styles of motorcycles were divided into three different groups according to their average speeds. The first group consists of sport motorcycles, which were faster than the other styles. The second group consists of scooter motorcycles, which were slower. The third group consists of conventional, touring, enduro, and chopper motorcycles with speeds that were statistically not significantly different. According to the differences of the mean speed of motorcyclists who use and do not use vehicle registration plates, the use of the registration plates can be considered a significant indicator of traffic safety. By classifying motorcycles in the three different groups, the issue of "generalizing" motorcyclists as a unique group is avoided and can be taken into consideration for future studies of motorcyclist safety. PMID- 25460095 TI - Experimental examination of the effects of televised motor vehicle commercials on risk-positive attitudes, emotions and risky driving inclinations. AB - PURPOSE: This study examined the short-term effects of risky driving motor vehicle television commercials on risk-positive attitudes, emotions and risky driving inclinations in video-simulated critical road traffic situations among males and females, within an experimental design. METHOD: Participants were randomly assigned to one of three televised commercial advertising conditions embedded in a television show: a risky driving motor vehicle commercial condition, a non-risky driving motor vehicle commercial condition and a control non-motor vehicle commercial condition. Participants subsequently completed the Implicit Attitude Test (IAT) to measure risk-positive attitudes, Driver Thrill Seeking Scale (DTSS) to measure risk-positive emotions and the Vienna Risk-Taking Test - Traffic (WRBTV) to measure risky driving inclinations. RESULTS: ANOVA analyses indicated that type of commercial participants watched did not affect their performance on the IAT, DTSS or WRBTV. However, a main effect of heightened risk-positive emotions and risky driving inclinations was found for males. DISCUSSION: Despite public and governmental concern that risky driving motor vehicle commercials may increase the likelihood that people exposed to these commercials engage in risky driving, this experimental study found no immediate effect of brief exposure to a risky driving motor vehicle commercial on risk positive attitudes, emotions or risky driving inclinations. Subsequent research should examine the effects of cumulative exposure to risky driving motor vehicle television commercials and print advertisements. PMID- 25460096 TI - The impact of immediate or delayed feedback on driving behaviour in a simulated Pay-As-You-Drive system. AB - Pay-As-You-Drive (PAYD) insurance links an individual's driving behaviour to the insurance fee that they pay, making car insurance more actuarially accurate. The best known PAYD insurance format is purely mileage based and is estimated to reduce accidents by about 15% (Litman, 2011). However, these benefits could be further enhanced by incorporating a wider range of driving behaviours, such as lateral and longitudinal accelerations and speeding behaviour, thereby stimulating not only a safe but also an eco-friendly driving style. Currently, feedback on rewards and driver behaviour is mostly provided through a web-based interface, which is presented temporally separated from driving. However, providing immediate feedback within the vehicle itself could elicit more effect. To investigate this hypothesis, two groups of 20 participants drove with a behavioural based PAYD system in a driving simulator and were provided with either delayed feedback through a website, or immediate feedback through an in car interface, allowing them to earn up to ?6 extra. To be clear, every participant in the web group did actually view their feedback during the one week between sessions. Results indicate clear driving behaviour improvements for both PAYD groups as compared to baseline rides and an equal sized control group. After both PAYD groups had received feedback, the initial advantage of the in-car group was reduced substantially. Taken together with usability ratings and driving behaviours in specific situations these results show a moderate advantage of using immediate in-car feedback. However, the study also showed that under conditions of feedback certainty, the effectiveness of delayed feedback approaches that of immediate feedback as compared to a naive control group. PMID- 25460097 TI - Modeling anger and aggressive driving behavior in a dynamic choice-latent variable model. AB - This paper develops a hybrid choice-latent variable model combined with a Hidden Markov model in order to analyze the causes of aggressive driving and forecast its manifestations accordingly. The model is grounded in the state-trait anger theory; it treats trait driving anger as a latent variable that is expressed as a function of individual characteristics, or as an agent effect, and state anger as a dynamic latent variable that evolves over time and affects driving behavior, and that is expressed as a function of trait anger, frustrating events, and contextual variables (e.g., geometric roadway features, flow conditions, etc.). This model may be used in order to test measures aimed at reducing aggressive driving behavior and improving road safety, and can be incorporated into micro simulation packages to represent aggressive driving. The paper also presents an application of this model to data obtained from a driving simulator experiment performed at the American University of Beirut. The results derived from this application indicate that state anger at a specific time period is significantly affected by the occurrence of frustrating events, trait anger, and the anger experienced at the previous time period. The proposed model exhibited a better goodness of fit compared to a similar simple joint model where driving behavior and decisions are expressed as a function of the experienced events explicitly and not the dynamic latent variable. PMID- 25460098 TI - Experimental research on the effectiveness and adaptability of speed reduction markings in downhill sections on urban roads: a driving simulation study. AB - The objective of this paper is to test the effectiveness and adaptability of speed reduction markings (SRMs) in downhill sections on urban roads with distinct roadway grades. Empirical data including vehicle speed and acceleration were collected in a driving simulator. Subjective questionnaires were conducted, and two indexes - the relative speed difference and standard deviation of acceleration - were developed to evaluate the effectiveness and adaptability of SRMs. Meanwhile, the effectiveness of driving simulator related to different road alignments and types of SRMs has been validated through a field test. Results of subjective questionnaires showed that the majority of subjects had no feelings of nervousness, but they were affected by SRMs while driving through downhill sections in all four scenarios (i.e., downhill sections with vertical grades of 3, 2, 1.5 and 1%). In terms of vehicle speed and acceleration, the results of the analysis of variance (ANOVA) and the contrast analysis (S-N-K method) indicated that SRMs were significantly effective when roadway grades of downgrade sections were 1.5, 2 and 3%, while transverse speed reduction markings (TSRMs) had significantly worse adaptability (P<0.05). Therefore, this research recommends that TSRMs could be placed in downhill sections with roadway grades of 1.5 or 2%; longitudinal speed reduction markings (LSRMs) could be placed in downhill sections with a roadway grade of 3%. Whether SRMs are placed in downhill sections with a roadway grade of 1% would depend on other factors such as financial issues and crash records, which are not considered in this paper. PMID- 25460099 TI - Exploring motorcycle red-light violation in response to pedestrian green signal countdown device. AB - Literature has suggested that angle/rear-end collisions would arise from the reality that motorists and motorcyclists tended to accelerate aggressively in response to the remaining seconds of green signal countdown device (GSCD). One safety concern, while GSCD has gradually been removed for safety in Taiwan, is pedestrian green signal countdown device (PGSCD) that is used by approaching motorists and motorcyclists that may adopt the information to travel aggressively - an unintended consequence that is detrimental to safety. Research has reported that there appeared no negative effect of PGSCD on motorist behaviours but the effect on motorcyclists' behaviours has been rarely investigated. Using video/speed cameras, the current research investigates motorcyclists' RLV (red light violation) behaviours. The descriptive analyses indicate that the percentage of RLV at PGSCD intersection is higher than that at typical intersection, and the violating motorcycles appear to have higher travelling speeds at PGSCD intersection. Several interaction terms were examined with the binary logit framework, and the results reveal that several factors are associated with RLV, notably male/young riders, moped/large motorcycle users, higher approaching speeds of motorcycles, those with tropical helmets, and lower traffic volume. Similar determinants of early-start behaviours (for those waiting at reds and could view the PGSCDs for the crossing pedestrians at the same time) were identified. Implications of the research findings, the concluding remarks, and recommendations for future research are finally provided. PMID- 25460100 TI - Comparative transcriptomic analysis provides insights into the molecular basis of the metamorphosis and nutrition metabolism change from zoeae to megalopae in Eriocheir sinensis. AB - Within the larval period of Eriocheir sinensis, there is pronounced morphological changes upon the molt from the fifth zoeae (Z5) to megalopae (M), and low survival rate exists during this transition, which is typical in crab species. RNA sequencing was applied to Z5 and M of E. sinensis, resulting in the discovery of 19,186 unigenes and 652 differentially expressed genes (DEGs, 3.40% of the unigenes). The important metabolic pathways that might play roles in the larval development of E. sinensis from Z5 to M were detected to be 'Xenobiotics Biodegradation and Metabolism (8.16%)', 'Metabolism of Cofactors and Vitamins (6.70%)', 'Lipid Metabolism (6.36%)', and 'Amino Acid Metabolism (6.28%)'. Further, 19 DEGs possibly contributing to the morphological and sensory capability changes of the larvae were identified, like multiple copies of cuticle protein genes, retinaldehyde-binding protein 1 (RLBP1), envelope protein (Envelope) and hormone-related gene ecdysteroid-regulated 16kDa protein (ESR16). Moreover, 62 DEGs were identified to be related to carbohydrate, lipid and protein digestion and metabolism, such as glucose dehydrogenases (GDHs), lipases (LIPs) and serine proteases (SPs). Among these DEGs, more genes related to the substance metabolism were found up-regulated in Z5 than M, suggesting that more energy might be essential to be released for Z5 to complete the transition into M. Characterization of the crucial DEGs by real-time quantitative PCR re conformed their expression pattern. This study provides the first genome-wide transcriptomic analysis of E. sinensis Z5 and M for studying the molecular basis of the larvae metamorphosis and nutrition metabolism. PMID- 25460101 TI - Myocardial apoptosis and SIDS. AB - Apoptosis mediates cardiac damage in severe forms of myocarditis. In fatal myocarditis, large amounts of cardiomyocytes show apoptotic DNA fragmentation, while in human controls, few apoptotic cardiomyocytes are found. In the present study the frequency of apoptosis in 88 SIDS cases (category 1b according to the San Diego Classification) and 15 control cases was investigated. In every case myocardial samples from 8 standard locations were collected. Detection of apoptotic cardiomyocytes was performed by TUNEL method. Furthermore the myocardial tissue was stained with HE and immunohistochemical methods (LCA, CD68, CD45-R0). More than 90% of the slides did not contain apoptotic cardiomyocytes at all. The detection rate of apoptotic cardiomyocytes was almost equal in control group (26.7%) and SIDS group (23.86%). A quantification of apoptotic cardiomyocytes per mm(2) revealed no significant difference between both groups either. Altogether there is no evidence for a higher rate of apoptosis in SIDS. PMID- 25460102 TI - The interaction between clothing and air weapon pellets. AB - Comparatively few studies have been carried out on air weapon injuries yet there are significant number of injuries and fatalities caused by these low power weapons because of their availability and the public perception that because they need no licence they are assumed to be safe. In this study ballistic gel was tested by Bloom and rupture tests to check on consistency of production. Two series of tests were carried out firing into unclothed gel blocks and blocks loosely covered by different items of clothing to simulate attire (tee shirt, jeans, fleece, and jacket). The damage to the clothing caused by different shaped pellets when fired at different ranges was examined. The apparent hole size was affected by the shape of pellet (round, pointed, flat and hollow point) and whether damage was predominantly caused by pushing yarn to one side or by laceration of the yarn through cutting or tearing. The study also compared penetration into clothed gel and unclothed gel under identical conditions, and loose clothing greatly reduced penetration. With loose clothing at 9.1 m range clothing reduced penetration to 50-70% of the penetration of unclothed gel but at 18.3m range only 7 out of 36 shots penetrated the gel. This cannot be accounted for by the energy loss at the longer range (3-7% reduction from 9.1 m to 18.3 m range in unclothed gels) and it is suggested that impulse may have a role to play. Shots that did not penetrate the gel were used to estimate the possible stopping time for the pellet (around 75 MUs) and force (1700 N) or stress (100 MPa) required to bring the pellet to a halt. Even with these low energy projectiles, cloth fibres were entrained in the gel showing the potential for penetration of the body and subsequent infection. PMID- 25460103 TI - Assessment of skeletal changes after post-mortem exposure to fire as an indicator of decomposition stage. AB - Forensic anthropologists are tasked with interpreting the sequence of events from death to the discovery of a body. Burned bone often evokes questions as to the timing of burning events. The purpose of this study was to assess the progression of thermal damage on bones with advancement in decomposition. Twenty-five pigs in various stages of decomposition (fresh, early, advanced, early and late skeletonisation) were exposed to fire for 30 min. The scored heat-related features on bone included colour change (unaltered, charred, calcined), brown and heat borders, heat lines, delineation, greasy bone, joint shielding, predictable and minimal cracking, delamination and heat-induced fractures. Colour changes were scored according to a ranked percentage scale (0-3) and the remaining traits as absent or present (0/1). Kappa statistics was used to evaluate intra- and inter-observer error. Transition analysis was used to formulate probability mass functions [P(X=j|i)] to predict decomposition stage from the scored features of thermal destruction. Nine traits displayed potential to predict decomposition stage from burned remains. An increase in calcined and charred bone occurred synchronously with advancement of decomposition with subsequent decrease in unaltered surfaces. Greasy bone appeared more often in the early/fresh stages (fleshed bone). Heat borders, heat lines, delineation, joint shielding, predictable and minimal cracking are associated with advanced decomposition, when bone remains wet but lacks extensive soft tissue protection. Brown burn/borders, delamination and other heat-induced fractures are associated with early and late skeletonisation, showing that organic composition of bone and percentage of flesh present affect the manner in which it burns. No statistically significant difference was noted among observers for the majority of the traits, indicating that they can be scored reliably. Based on the data analysis, the pattern of heat induced changes may assist in estimating decomposition stage from unknown, burned remains. PMID- 25460104 TI - Field detection capability of immunochemical assays during criminal investigations involving the use of TNT. AB - The capability to collect timely information about the substances employed on site at a crime scene is of fundamental importance during scientific investigations in crimes involving the use of explosives. TNT (2,4,6 trinitrotoluene) is one of the most employed explosives in the 20th century. Despite the growing use of improvised explosives, criminal use and access to TNT is not expected to decrease. Immunoassays are simple and selective analytical tests able to detect molecules and their immunoreactions can occur in portable formats for use on-site. This work demonstrates the application of three immunochemical assays capable of detecting TNT to typical forensic samples from experimental tests: an indirect competitive ELISA with chemiluminescent detection (CL-ELISA), a colorimetric lateral flow immunoassay (LFIA) based on colloidal gold nanoparticles label, and a chemiluminescent-LFIA (CL-LFIA). Under optimised working conditions, the LOD of the colorimetric LFIA and CL-LFIA were 1 MUg mL( 1) and 0.05 MUg mL(-1), respectively. The total analysis time for LFIAs was 15 min. ELISA proved to be a very effective laboratory approach, showing very good sensitivity (LOD of 0.4 ng mL(-1)) and good reproducibility (CV value about 7%). Samples tested included various materials involved in controlled explosions of improvised explosive devices (IEDs), as well as hand swabs collected after TNT handling tests. In the first group of tests, targets covered with six different materials (metal, plastic, cardboard, carpet fabric, wood and adhesive tape) were fixed on top of wooden poles (180 cm high). Samples of soil from the explosion area and different materials covering the targets were collected after each explosion and analysed. In the second group of tests, hand swabs were collected with and without hand washing after volunteers simulated the manipulation of small charges of TNT. The small amount of solution required for each assay allows for several analyses. Results of immunoassays confirmed that they were suitable to detect post-blast residues in soil and target materials and post transfer residues on hands, allowing further confirmation by more selective techniques. ELISA and LFIAs results obtained from the same solution were consistently in good agreement, and were confirmed by gas chromatography coupled to mass spectrometry (GC-MS). The reported immunoassays data demonstrates the suitability of LFIAs as on-site rapid and effective assays to detect TNT traces. The CL-ELISA proved useful in obtaining very sensitive detection in forensic investigations and testing, while CL-LFIA had performances in between LFIA and CL-ELISA. PMID- 25460105 TI - The use of magnetic susceptibility as a forensic search tool. AB - There are various techniques available for forensic search teams to employ to successfully detect a buried object. Near-surface geophysical search methods have been dominated by ground penetrating radar but recently other techniques, such as electrical resistivity, have become more common. This paper discusses magnetic susceptibility as a simple surface search tool illustrated by various research studies. These suggest magnetic susceptibility to be a relatively low cost, quick and effective tool, compared to other geophysical methods, to determine disturbed ground above buried objects and burnt surface remains in a variety of soil types. Further research should collect datasets over objects of known burial ages for comparison purposes and used in forensic search cases to validate the technique. PMID- 25460106 TI - The use of methylamphetamine chemical profiling in an intelligence-led perspective and the observation of inhomogeneity within seizures. AB - This study focuses on methylamphetamine (MA) seizures made by the Australian Federal Police (AFP) to investigate the use of chemical profiling in an intelligence perspective. Correlation coefficients were used to obtain a similarity degree between a population of linked samples and a population of unlinked samples. Although it was demonstrated that a general framework can be followed for the use of any forensic case data in an intelligence-led perspective, threshold values have to be re-evaluated for each type of illicit drug investigated. Unlike the results obtained in a previous study on 3,4 methylenedioxymethylamphetamine (MDMA) seizures, chemical profiles of MA samples coming from the same seizure showed relative inhomogeneity, limiting their ability to link seizures. Different hypotheses were investigated to obtain a better understanding of this inhomogeneity although no trend was observed. These findings raise an interesting discussion in regards to the homogeneity and representativeness of illicit drug seizures (for intelligence purposes). Further, it also provides some grounds to discuss the initial hypotheses and assumptions that most forensic science studies are based on. PMID- 25460107 TI - Profiling cocaine by ATR-FTIR. AB - In this article, five hundred and thirteen cocaine seizures of the State of Rio Grande do Sul (Brazil) were analyzed by Fourier transform infrared spectroscopy (FT-IR) in the fingerprint region (1800-650 cm(-1)) to profiling and evaluate the pharmaceutical products used as adulterants. Hierarchical cluster analysis (HCA) and principal component analysis (PCA) were used to identify patterns among the samples whereas partial least square discriminant analysis (PLS-DA) and support vector machines discriminant analysis (SVM-DA) were used to classification the cocaine between base and salt. Spectra of standard solid mixtures of cocaine (salt and base), phenacetin, lidocaine and caffeine were used associated with PCA to predict qualitatively the profile of cocaine seizure. In HCA and PCA, salt and base group were formed correctly. Accordingly with predicted profile of the salt samples, they were majority adulterated with caffeine and lidocaine whereas base cocaine was adulterated only with phenacetin. In the discrimant analysis, all methods have classified the cocaine samples correctly with sensitivity and specificity equal to one between salt and base. PMID- 25460108 TI - Chiral separation and determination of R/S-methamphetamine and its metabolite R/S amphetamine in urine using LC-MS/MS. AB - Methamphetamine (MA) and amphetamine (AM) are widely abused drugs. Differentiation of MA and/or AM abuse from therapeutic ingestion of MA and/or AM or one of their precursor drugs is therefore of relevance in clinical and forensic toxicology. The aim of the study was to develop a simple, rapid, and accurate method for the chiral separation and determination of R/S-MA and R/S-AM in urine using liquid chromatography electrospray ionization tandem mass spectrometry operating in the positive ion multiple-reaction monitoring (MRM) mode. 20 MUL of urine was diluted 500 times and 20 MUL was injected. The chromatographic system consisted of a ChirobioticTM V2 column (2.1 mm * 250 mm, 5 MUm), and the mobile phase was methanol containing 0.1% (v/v) glacial acetic acid and 0.02% (v/v) ammonium hydroxide. The method was fully validated through assessments of its linearity (0.05-50.00 mg/L, r(2)>0.994 for all analytes), and LOQ (0.05 mg/L for all analytes). No matrix effect was observed. The method was successfully applied to 86 urine samples from suspected MA abusers. Only the S isomers of MA and AM were detected in 72 samples. The concentrations of R-MA ranged from below the LOQ to 13.76 mg/L in 14 urine samples with both enantiomers of MA and/or AM. Pure S-MA is the most common found analyte in urine and principally used by abusers. PMID- 25460109 TI - c-Fos induction in mesotelencephalic dopamine pathway projection targets and dorsal striatum following oral intake of sugars and fats in rats. AB - Overconsumption of nutrients high in fats and sugars can lead to obesity. Previous studies indicate that sugar or fat consumption activate individual brain sites using Fos-like immunoreactivity (FLI). Sugars and fats also elicit conditioned flavor preferences (CFP) that are differentially mediated by flavor flavor (orosensory: f/f) and flavor-nutrient (post-ingestive: f/n) processes. Dopamine (DA) signaling in the medial prefrontal cortex (mPFC), the amygdala (AMY) and the nucleus accumbens (NAc), has been implicated in acquisition and expression of fat- and sugar-CFP. The present study examined the effects of acute consumption of fat (corn oil: f/f and f/n), glucose (f/f and f/n), fructose, (f/f only), saccharin, xanthan gum or water upon simultaneous FLI activation of DA mesotelencephalic nuclei (ventral tegmental area (VTA)) and projections (infralimbic and prelimbic mPFC, basolateral and central-cortico-medial AMY, core and shell of NAc as well as the dorsal striatum). Consumption of corn oil solutions, isocaloric to glucose and fructose, significantly increased FLI in all sites except for the NAc shell. Glucose intake significantly increased FLI in both AMY areas, dorsal striatum and NAc core, but not in either mPFC area, VTA or Nac shell. Correspondingly, fructose intake significantly increased FLI in the both AMY areas, the infralimbic mPFC and dorsal striatum, but not the prelimbic mPFC, VTA or either NAc area. Saccharin and xanthan gum intake failed to activate FLI relative to water. When significant FLI activation occurred, highly positive relationships were observed among sites, supporting the idea of activation of a distributed brain network mediating sugar and fat intake. PMID- 25460110 TI - Modelling lamb carcase pH and temperature decline parameters: relationship to shear force and abattoir variation. AB - Carcase pH and temperature decline rates influence lamb tenderness; therefore pH decline parameters are beneficial when modelling tenderness. These include pH at temperature 18 degrees C (pH@Temp18), temperature when pH is 6 (Temp@pH6), and pH at 24 h post-mortem (pH24). This study aimed to establish a relationship between shear force (SF) as a proxy for tenderness and carcase pH decline parameters estimated using both linear and spline estimation models for the m. longissimus lumborum (LL). The study also compared abattoirs regarding their achievement of ideal pH decline, indicative of optimal tenderness. Based on SF measurements of LL and m. semimembranosus collected as part of the Information Nucleus slaughter programme (CRC for Sheep Industry Innovation) this study found significant relationships between tenderness and pH24LL, consistent across the meat cuts and ageing periods examined. Achievement of ideal pH decline was shown not to have significantly differed across abattoirs, although rates of pH decline varied significantly across years within abattoirs. PMID- 25460111 TI - Effect of temperature, high pressure and freezing/thawing of dry-cured ham slices on dielectric time domain reflectometry response. AB - Dielectric Time Domain Reflectometry (TDR) is a useful technique for the characterization and classification of dry-cured ham according to its composition. However, changes in the behavior of dielectric properties may occur depending on environmental factors and processing. The effect of temperature, high pressure (HP) and freezing/thawing of dry-cured ham slices on the obtained TDR curves and on the predictions of salt and water contents when using previously developed predictive models, was evaluated in three independent experiments. The results showed that at temperatures below 20 degrees C there is an increase of the predicted salt content error, being more important in samples with higher water content. HP treatment caused a decrease of the reflected signal intensity due to the major mobility of available ions promoting an increase of the predicted salt content. Freezing/thawing treatment caused an increase of the reflected signal intensity due to the microstructural damages and the loss of water and ions, promoting a decrease of the predicted salt content. PMID- 25460112 TI - Identification of sensory attributes, instrumental and chemical measurements important for consumer acceptability of grilled lamb Longissimus lumborum. AB - In this study, important eating quality attributes that influence consumer liking for grilled lamb loin have been identified using preference mapping techniques. The eating quality attributes identified as driving the consumer liking of lamb loin steaks were "tenderness", "sweet flavour", "meaty aftertaste", "roast lamb flavour" and "roast lamb aftertaste". In contrast, the texture attribute "rubbery" and the flavour attributes "bitter flavour" and "bitter aftertaste" had a negative influence on consumer perceptions. Associations were observed between eating quality and a number of instrumental and chemical measurements. Warner Bratzler Shear Force showed an association with "rubbery" texture and a negative association with "tenderness" and consumer liking scores. The compounds, glucose, glucose-6-phosphate, inosine, inosine monophosphate and adenosine monophosphate were associated with the attributes, "sweet flavour","meaty aftertaste", "roast lamb flavour", "roast lamb aftertaste" and with consumer scores for liking of lamb which is probably caused by the role some of these compounds play as precursors of flavour and as taste compounds. PMID- 25460113 TI - Flavour formation from hydrolysis of pork sarcoplasmic protein extract by a unique LAB culture isolated from Harbin dry sausage. AB - The lactic acid bacteria Pediococcus pentosaceus, Lactobacillus brevis, Lactobacillus curvatus, and Lactobacillus fermentum isolated from Harbin dry sausage were assessed for their protein hydrolysis and flavour development in pork muscle sarcoplasmic protein extracts. Gel electrophoresis indicated that sarcoplasmic proteins were degraded by all of the strains, especially by P. pentosaceus and L. curvatus. Trichloroacetic acid-soluble peptides increased in all of the samples (P < 0.05), especially samples inoculated with P. pentosaceus. Samples inoculated with P. pentosaceus and L. curvatus had higher free amino acid contents than did the other two strains(P < 0.05), and glutamic acid and alanine appeared to be the predominant free amino acids. The volatile compound analysis indicated that the highest aldehydes, alcohols and acid contents were found in the sample with P. pentosaceus followed by L. curvatus. The results revealed that P. pentosaceus could be appropriate for use as a meat starter culture. PMID- 25460114 TI - Pre-slaughter handling and pork quality. AB - Environmental variables, as sound levels, were collected during the pre-slaughter process in 18 different Belgian commercial slaughterhouses. Four pre-slaughter phases were determined: firstly after arrival of the truck at the slaughterhouse and just before unloading, secondly during unloading, thirdly at lairage and finally while moving to the stunner. A total of 8508 pigs was examined during the pre-slaughter process, of which the pH(LT) (M. longissimus thoracis), at 30 min post-mortem was measured. For each pre-slaughter phase, variables which might influence pork quality were determined. Moreover, this study made it possible to infer a checklist to represent and predict PSE traits of pork for all kind of pre slaughter situations. The checklist shows also that the impact on pork quality is more decisive for the variables measured close to the stunning phase. Hence, this information is useful for the industry to optimize handling of pigs, reducing the risk for PSE traits. PMID- 25460115 TI - Application of a check-all-that-apply question for evaluating and characterizing meat products. AB - Four different mortadella samples were technologically characterized by physical/chemical and instrumental analyses and were sensorially characterized by acceptance testing and check-all-that-apply (CATA) questions. Samples were divided into three groups by using a principle component analysis (PCA) of the technological characteristics and by using an internal preference map (IPM) of the sensory attributes from the acceptance test. CATA divided these samples into four different external preference map (EPM) groups because each sample was associated with different sensory attributes. The PCA indicated that there was a relationship between the instrumental color and texture analyses and the CATA attributes, whereby identifying the terms that positively or negatively contributed to sample acceptance. The CATA questions effectively discriminated between the meat products regarding their sensory characteristics. In addition, these attributes were linked to chemical and instrumental quality parameters. Thus, the CATA questions are a potential tool for evaluating and developing novel products. PMID- 25460116 TI - The relationship between pre-harvest stress and the carcass characteristics of beef heifers that qualified for kosher designation. AB - Differences in pre-harvest stress measurements and carcass characteristics between kosher and not-qualified-as-kosher cattle were evaluated. Finished heifers (n=157) were slaughtered by a shochet while held in an upright position using Glatt slaughter procedures. Stress measurements were collected prior to slaughter. Carcass data were collected, and 3.8-cm thick samples were taken from the loin at the 13th rib. Steaks from each sample were evaluated for mechanical tenderness and simulated retail display. Cattle with shorter times from gate to exsanguination and lower vocalization scores were more likely (P < 0.01) to qualify as kosher. Kosher carcasses had larger (P = 0.02) ribeye areas and higher (P < 0.0001) Warner-Bratzler shear values. At each day of simulated retail display, kosher steaks had lower (P < 0.05) L*, a*, and b* values. These data suggest that body composition and pre-harvest stress affect the likelihood of a beef animal qualifying as kosher and quality differences exist between kosher and non-kosher steaks. PMID- 25460117 TI - Pre-rigor temperature control of Chinese yellow cattle carcasses to 12-18 degrees C during chilling improves beef tenderness. AB - This study evaluates the effects of pre-rigor temperature control on quality traits of Chinese yellow cattle M. longissimus lumborum (LL). One stepwise chilling (SC) treatment was used on one half-carcass, involved a fast chilling ( 11 +/- 1 degrees C;0.5 m/s) for 2h, then the refrigeration was stopped to hold a core temperature of 12-18 degrees C until 10h postmortem, followed by a 1 +/- 1 degrees C chilling (0.5 m/s) to 48h postmortem. The other half-carcass was conventional chilled at 1 +/- 1 degrees C (0.5 m/s) until 48h as control chilling (CC). Quality attributes were evaluated at 1, 7 and 14 days. The SC treatment resulted in decreased WBSF and increased myofibril fragmentation index compared with control. SC-treated LL at 7d postmortem had a lower WBSF than those of CC-treated at 14d. This pre-rigor temperature controlled chilling is a realistic alternative for the beef industry in China to ensure adequate tenderness and shorten aging time. PMID- 25460118 TI - Microbial changes in vacuum-packed chilled pork during storage. AB - Microbial composition in vacuum-packed chilled pork was investigated. The number of microbial counts increased during the period of 21 day storage with the deterioration of meat. A total of 28,216 bacterial sequences were obtained for the assessment of microbial diversity from vacuum packed pork during chilled storage. More than 200 bacterial genera belonging to eighteen phyla were observed, and most of them are likely to be associated with contamination via fecal, air and/or water during slaughtering and subsequent meat handling. Microbial populations changed greatly during storage, of which the seventh day was a critical time point for microbial diversity. Micrococcaceae, Flavobacteriaceae, Enterobacteriaceae, Lactobacillaceae and Carnobacteriaceae were the major components that may be associated with the spoilage of meat. Although the potential impact of detected microbes on meat hygiene and/or safety is unknown, effective decontamination of the whole chain is always important for meat industry to guarantee meat safety and to improve shelf-life of fresh meat. PMID- 25460119 TI - Allelic frequencies of NR6A1 and VRTN, two genes that affect vertebrae number in diverse pig breeds: a study of the effects of the VRTN insertion on phenotypic traits of a Duroc * Landrace-Large White cross. AB - A SNP (748 C > T) in the NR6A1 gene and an insertion (g.20311_20312ins291) in the VRTN gene have been shown to affect vertebrae number in the pig. The allelic frequencies of both genes were investigated in six western breeds and the effects of the VRTN insertion on some phenotypic traits in a Duroc * Landrace/Large White cross. The NR6A1 c. 748T allele, associated with higher number of vertebrae, appeared to be fixed in most studied breeds except in Iberians. The VRTN insertion (Ins allele) shows ample variability in all studied breeds although the allelic frequency of Ins seems to be larger in breeds with a greater history of genetic selection. Ins is associated with an increase in weight at slaughter, in loin and rib primal cut proportions, and with modified meat quality properties such as cooking loss, intramuscular fat content or yield after curing. We discuss the usefulness of both gene markers for pig selection. PMID- 25460120 TI - On-line prediction of lamb fatty acid composition by visible near infrared spectroscopy. AB - This study investigated the potential of visible near infrared spectroscopy (Vis NIRS) to quantify the fatty acid(FA) composition of lamb meat under commercial abattoir conditions. Genetic algorithm based partial least squares (PLS) were used to develop regression models for predicting individual FA and FA groups such as saturated FA (SFA), monounsaturated FA (MUFA) and polyunsaturated FA (PUFA). Overall, the majority of the FA(C14:0, C16:0, C16:1, C17:0, C18:1 c9, C18:1 c11, C18:2 n-6, C18:2 c9 t11 and C18:1 t11), intramuscular fat(IMF) and all FA groups were predicted with an R2(CV), the squared correlation between observed and cross validated predicted values,which ranged between 0.60 and 0.74 and ratio prediction to deviation (RPD) values between 1.60 and 2.24. However the results for the remaining FA (C17:1, C18:0, C18:3 n-3, C20:4, C20:5, C22:5, C22:6) were unsatisfactory (R2= 0.35-0.57, RPD= 0.76-1.49). This indicates that Vis-NIRS could be used as an on-line tool to predict a number of FA. PMID- 25460121 TI - Effects of polyethylene film wrap on cooler shrink and the microbial status of beef carcasses. AB - The present study evaluated the use of polyethylene film wrapping of beef half carcasses and its effects on cooler shrink, cooling characteristics and microbial status of the half carcasses. Film wrapping reduced cooler shrink by 55.2%, 43.1%, 36.0% and 30% after 24, 48, 72 and 96 h of cooling, respectively, compared to the unwrapped half carcasses, whereas the surface water activity showed no significant differences among the time periods. The wrapped half carcasses had a lower cooling rate and higher surface and internal temperatures. The highest values of the aerobic mesophiles, Staphylococcus aureus and Enterobacteriaceae were found in the half carcasses wrapped in film. No significant differences were found in the values of Escherichia coli. The polyethylene film was effective in reducing cooler shrink; however, it caused a delay in cooling, thereby enabling greater microbial occurrences and counts and impairing the hygienic and sanitary conditions of the carcasses, which may be an impediment to the practical application of this technology. PMID- 25460122 TI - Estimating the non-thermal inactivation of Listeria monocytogenes in fermented sausages relative to temperature, pH and water activity. AB - Data relative to in situ Listeria monocytogenes inactivation in fermented sausages were collected from 13 individual studies found in the literature. Inactivation rates were extrapolated and used to develop a predictive model to evaluate the relative effects of pH, water activity (a(w)) and temperature on L. monocytogenes fate during fermentation and ripening. Temperature explained ca. 60% of the data variability, while pH and a(w) only a small part. Temperature alone may not be sufficient to cause pathogen's inactivation, but inactivation rate is dominated by temperature when pH and a(w) are in the range which prevent L. monocytogenes growth. A predictive model based on two Arrhenius equations (ln[inactivation rate]=-25.71-[-0.6829 / (8.314 * T)] for fermentation; and ln[inactivation rate]=-44.86-[-1.219/(8.314 * T)] for ripening)was developed. The model can be used to quantify the effect of temperature and/or time changes on fermented sausage safety. The advantages and limitations of the model are discussed. PMID- 25460123 TI - Physicochemical characteristics and quality parameters of a beef product subjected to chemical preservatives and high hydrostatic pressure. AB - The use of high hydrostatic pressure (HHP) on fresh beef causes a deleterious effect on red colour. A beef product subjected to HHP exhibiting acceptable colour and microbiological stability was developed; the process requires as a first step the immersion in a preservative solution containing ascorbic acid, sodium nitrite, and sodium chloride. Desirability functions were used to optimise the composition of this solution in order to maintain the colour attributes minimising the concentration of sodium nitrite. The product was packed in low gas permeability film before HHP treatment. The effect of the applied pressure (300, 600 MPa) on quality parameters (colour,texture) was analysed. The stability of the product during storage at 4 degrees C was determined by microbial counts, colour, texture, and exudate. The combination of treatments provided acceptable colour and microbiological stability during four and six weeks of refrigerated storage after the product has been subjected to 300 and 600 MPa, respectively. PMID- 25460124 TI - Effect of the Programmed Nutrition Beef Program on moisture retention of cooked ground beef patties and enhanced strip loins. AB - This study evaluated the influence of the Programmed Nutrition Beef Program and exogenous growth promotants (ExGP) on water holding capacity characteristics of enhanced beef strip loins. Sixty, frozen strip loins, arranged in a 2 * 2 factorial treatment arrangement with dietary program serving as the first factor and use of ExGP as the second factor, were thawed, injected with an enhancement solution, and stored for 7 days. Loins from ExGP cattle possessed the ability to bind more (P < 0.05) water before pumping and bind less (P < 0.05) water after pumping and storage. Loin pH across treatments was similar (P > 0.10) before injection, but increased post-injection and after storage (P < 0.01). Treatments did not affect loin purge loss, steak cook loss, and expressible moisture (P > 0.10). The Programmed Nutrition Beef Program and use of ExGPs minimally impacted water holding capacity of enhanced frozen/thawed beef strip loins. PMID- 25460125 TI - Meat consumption and breast cancer: a case-control study in women. AB - BACKGROUND: The relationship between meat intake and breast cancer has been inconsistent . OBJECTIVE: The aim of this work was to evaluate the association between meat intake and breast cancer, in women. DESIGN: A case-control study with 250 consecutive, newly diagnosed breast-cancer-female-patients (56 +/- 12 years) and 250, one-to-one age-matched controls was conducted. A standardized, validated questionnaire assessing various socio-demographic, clinical, lifestyle and dietary characteristics was applied through face-to-face interviews. Data on consumption of red, white, processed and grilled meat were also recorded. Overall dietary habits were assessed through the level of adherence to the Mediterranean diet using the MedDietScore (theoretical range 0-55). RESULTS: Processed meat intake, even for 1-2 times/week,was associated with a 2.7-fold (OR= 2.65, 95% CI 1.36, 5.14) (p= 0.004) higher likelihood of having breast cancer, while daily intake increased the likelihood by a 2.8-fold (OR = 2.81, 95% CI 1.13, 6.96) (p = 0.026), after various adjustments made. Red, white and grilled meat intake was not significantly associated with the outcome when the same adjustments were made. CONCLUSIONS: This study suggested that only daily processed-meat intake was consistently associated with increased odds of breast-cancer. PMID- 25460126 TI - Lambmeat colour values (HunterLab CIE and reflectance) are influenced by aperture size (5 mm v. 25 mm). AB - The effect of aperture size on the assessment of lamb meat colour values (L*, a*, b* and R630/580)was investigated. Two experiments using 2 HunterLab MiniScan colorimeters (large [25 mm] and small [5 mm] apertures) were conducted: 1) coloured tiles were measured and 2) unaged lamb (n = 65) m. longissimus lumborum (LL) and m. semimembranosus (SM) muscles were measured over 2.5 d under simulated retail display. For Experiment three, 2 different colorimeters were used on lamb (n = 36) LL aged for 6 weeks before measurement over 4 don simulated retail display. Coloured tile a* and b* values were unaffected by aperture size, but L* values and the R630/580 ratio were influenced by aperture size. The effect of aperture size on lamb meat colour measurements varied with display time and muscle type. The large aperture size generally provided the highest colorimetric values, and is recommended for measuring lamb meat colour. PMID- 25460127 TI - Water holding capacity and collagen profile of bovine m. infraspinatus during postmortem ageing. AB - Changes in the water holding capacity (WHC) and collagen profile in bovine m. infraspinatus during ageing in a vacuum at 3 degrees C up to 20 days were studied. Moisture, expressible water and total collagen content were determined in raw samples and muscles were then subjected to thermal treatment in steam. Moisture, collagen fractions (total, water-soluble, insoluble, acetic acid soluble, total soluble) and cooking loss were determined in the cooked meat. Ageing time did not significantly influence WHC (expressible water content as a % of moisture), moisture content in raw and cooked meat or cooking loss. Between the 5th and 10th day of ageing a significant increase was noted in acetic acid soluble collagen and total soluble collagen content along with a decrease in insoluble collagen content (p b 0.05). A significant negative relationship was found between the expressible water content and the water-soluble collagen. It was concluded that connective tissue ageing of bovine m. infraspinatus might be finished after 10 days. PMID- 25460128 TI - Novel X-ray phase-contrast tomography method for quantitative studies of heat induced structural changes in meat. AB - The objective of this study was to evaluate the use of X-ray phase-contrast tomography combined with 3D image segmentation to investigate the heat induced structural changes in meat. The measurements were performed at the Swiss synchrotron radiation light source using a grating interferometric setup. The non destructive method allowed the same sample to be measured before and after cooking. Heat denaturation resulted in a 36% decrease in the volume of the muscle fibers, while solubilization of the connective tissues increased the volume from 8.4%to 24.9%. The cooking loss was quantified and separated into a water phase and a gel phase formed by the sarcoplasmic proteins in the exudate. The results show that X-ray phase contrast tomography offers unique possibilities in studies both the meat structure and the different meat component such as water, fat, connective tissue and myofibrils in a qualitative and quantitative manner without prior sample preparation as isolation of single muscle components, calibration or histology. PMID- 25460129 TI - Effect of pulsed electric field on the proteolysis of cold boned beef M. Longissimus lumborum and M. Semimembranosus. AB - The effects of pulsed electric field (PEF) and ageing (3, 7, 14 and 21 days) on the shear force, protein profile, and post-mortem proteolysis of beef loins (M. Longissimus lumborum, LL) and topsides (M. Semimembranosus, SM) were investigated using a range of pulsed electric field treatments [voltages (5 and 10 kV) and frequencies (20, 50, and 90 Hz)]. PEF treatment decreased the shear force of beef LL and SM muscles by up to 19%. The reduction in the shear force in the LL was not affected by the treatment intensity whereas the reduction in the SM was dependent on PEF frequency. PEF treated beef loins showed increased proteolysis, both early post-mortem and during subsequent post-mortem storage reflected by increased degradation of troponin-T and desmin. The most prominent troponin-T degradation was found in samples treated with 5 kV-90 Hz, 10 kV-20 Hz at day 3 and day 7 post-treatment in addition to 10 kV-50 Hz in subsequent post-treatment times. The degradation of desmin in PEF treated beef loins increased with ageing time. PMID- 25460130 TI - Pathophysiology of penetrating captive bolt stunning in Alpacas (Vicugna pacos). AB - The aim of this study was to examine the behavioural and cranial/spinal responses of alpacas culled by captive bolt shooting and the resulting pathophysiology of captive bolt injury. Ninety-six alpacas were shot (103 shots) in a range of locations with a penetrating captive bolt gun (CBG). Ten (9.8%) alpacas were incompletely concussed following the first shot. No animals required more than two shots. Incorrectly placed shots accounted for all of the animals that displayed signs of sensibility. Damage to the thalamus, hypothalamus, midbrain, medulla, cerebellum, parietal and occipital lobes were significantly associated with decreasing odds of incomplete concussion. In conclusion, the study confirmed that CBG stunning can induce insensibility in alpacas and suggests that the top of the head (crown) position maximises damage to structures of the thalamus and brainstem. PMID- 25460131 TI - Validation of boar taint detection by sensory quality control: relationship between sample size and uncertainty of performance indicators. AB - To prevent impaired consumer acceptance due to insensitive sensory quality control, it is of primary importance to periodically validate the performance of the assessors. This communication show cases how the uncertainty of sensitivity and specificity estimates is influenced by the total number of assessed samples and the prevalence of positive (here: boar tainted) samples. Furthermore, a statistically sound approach to determining the sample size that is necessary for performance validation is provided. Results show that a small sample size is associated with large uncertainty, i.e., confidence intervals and thus compromising the point estimates for assessor sensitivity. In turn, to reliably identify sensitive assessors with sufficient test power, a large sample size is needed given a certain level of confidence. Easy-to-use tables for sample size estimations are provided. PMID- 25460132 TI - Localization and abundance of early markers of fat cell differentiation in the skeletal muscle of cattle during growth--are DLK1-positive cells the origin of marbling flecks? AB - Localization and abundance of early markers of adipogenic differentiation were investigated in bovine muscle tissue to verify their association with marbling development. Bovine skeletal muscle samples were used for immunohistochemical localization and measurement of mRNA and protein abundance of delta-like homolog 1 (DLK1) and CCAAT/enhancer-binding protein beta (CEBPB). The localization of DLK1-positive cells confirmed the position of small clusters of adipocytes which can be considered as the origin of marbling flecks. The results indicated higher DLK1 expression in the less marbled muscle of Holstein (HS) steers (P < 0.05) and a trend to higher CEBPB expression in Japanese Black (JB) steers (P < 0.1) at slaughter. The number of DLK1-positive cells and fat content were negatively correlated. The lower expression of DLK1 together with higher CEBPB abundance during fattening in JB may have contributed to the development of more adipocytes in the skeletal muscle of JB. PMID- 25460133 TI - Effects of USDA beef quality grade and cooking on fatty acid composition of neutral and polar lipid fractions. AB - The effects of USDA beef quality grade (QG; Prime, Low Choice, and Standard; n=8) and cooking (RC) on fatty acid (FA) concentrations (mg/g dry matter) and percentages of neutral and polar lipid fractions (NL and PL, respectively)from strip steaks were explored. An increase in QG led to an accumulation of most FA, especially in the NL fraction (P < 0.001). Common effects on FA percentages were two-way interactions of either QG or RC with LF (P <= 0.019). Fatty acids were affected differently by QG and RC depending on their originating LF. Monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) percentages of the PL were dependent on QG (P <= 0.014). Cooking and QG had minimal impact on FA percentages of the NL, however, greatly influenced PL MUFA and PUFA percentages (P b 0.001). There was evidence indicating that dry heat cookery affected not only PUFA, as generally thought, but also the MUFA of PL fraction. PMID- 25460134 TI - Effect of including carob pulp in the diet of fattening pigs on the fatty acid composition and oxidative stability of pork. AB - The effect of feeding pigs with carob pulp on meat quality was investigated. Nine pigs were finished on a conventional concentrate-based diet (control), while two groups received a diet comprising of the same ingredients with the inclusion of 8% or 15% carob pulp (Carob 8% and Carob 15%, respectively). Feeding carob containing diets reduced the concentration of saturated fatty acids in the muscle, increased the concentration of monounsaturated fatty acids in meat (P < 0.01) and of n-3 polyunsaturated fatty acids (PUFAs) and reduced the n-6/n-3 PUFA ratio (P < 0.001). The meat underwent slow oxidative deterioration over 9 days of storage. However, the Carob 15% treatment increased meat susceptibility to lipid oxidation across storage (P = 0.03), while the dietary treatment did not affect meat colour stability. In conclusion, feeding pigs with carob pulp could represent a strategy,in the Mediterranean areas, to naturally improve meat nutritional value and to promote the exploitation of this local feed resource. PMID- 25460135 TI - Light backscatter fiber optic sensor: a new tool for predicting the stability of pork emulsions containing antioxidative potato protein hydrolysate. AB - The objective of this study was to determine whether light backscatter response from fresh pork meat emulsions is correlated to final product stability indices. A specially designed fiber optic measurement system was used in combination with a miniature fiber optic spectrometer to determine the intensity of light backscatter within the wavelength range 300-1100 nm (UV/VIS/NIR) at different radial distances (2, 2.5 and 3mm) with respect to the light source in pork meat emulsions with two fat levels (15%, 30%) and two levels (0, 2.5%) of the natural antioxidant hydrolyzed potato protein (HPP). Textural parameters (hardness, deformability, cohesiveness and breaking force), cooking loss, TBARS (1, 2, 3, and 7 days of storage at 4 degrees C) and CIELAB color coordinates of cooked emulsions were measured. The light backscatter was directly correlated with cooking losses, color, breaking force and TBARS. The optical configuration proposed would compensate for the emulsion heterogeneity, maximizing the existing correlation between the optical signal and the emulsion quality metrics. PMID- 25460136 TI - Sound levels above 85 dB pre-slaughter influence pork quality. AB - This study investigates whether sound levels above 85 dB(A), determined in literature as a critical sound level to induce stress in pigs, has also an effect on the pH of pork. Sound levels were recorded during pre-slaughter phases. A measure was taken after the arrival of the truck at the slaughterhouse, during unloading, lairage and just before stunning. The pH of the Longissimus thoracis or lumborum, 30 min after sticking (pH(30LT)) was measured. 8508 pigs were examined and the pH was measured on the carcasses. The results show that the cut off value of 85 dB(A) during the pre-slaughtering phase is not only a threshold to evaluate animal welfare but can also be associated with a slower drop of pH if sound levels are b85 dB(A). Finally a linear mixed model for pH(30LT) was built with the sound level during lairage and the sound level prior to stunning as independent variables, having statistically the highest impact on pH(30LT) of pork. PMID- 25460137 TI - Growth performance, carcass and meat quality of lambs supplemented with increasing levels of a tanniferous bush (Cistus ladanifer L.) and vegetable oils. AB - The effects of dietary inclusion of Cistus ladanifer L. (CL) and a vegetable oil blend were evaluated on growth performance,carcass and meat quality of fifty four lambs that were assigned to 9 diets, corresponding to 3 levels of CL(50, 100 and 200 g/kg DM) and 3 levels of oil inclusion (0, 40 and 80 g/kg DM). Treatments had no effects on growth rate. Oil depressed dry matter intake (P = 0.017), carcass muscle (P = 0.041) and increased (P = 0.016) kidney knob channel fat. Chemical and physical meat quality traits were not affected by treatments. Off-flavour perception was higher for 8% of oil (P b 0.001). The level of 100 g/kg DM of CL inclusion improved meat stability after 7 days of storage. Supplementation with linseed and soybean oils (2:1) was a good approach to improve meat nutritional value from feedlot lambs, increasing total n-3 PUFA. PMID- 25460138 TI - Characterisation and detection of spoilage mould responsible for black spot in dry-cured fermented sausages. AB - Moulds responsible for black spot spoilage of dry-cured fermented sausages were characterised. For this purpose, samples were taken from those dry-cured fermented sausages which showed black spot alteration. Most of the mould strains were first tentatively identified as Penicillium spp. due to their morphological characteristics in different culture conditions, with one strain as Cladosporium sp. The Cladosporium strain was the only one which provoked blackening in culture media. This strain was further characterised by sequencing of ITS1-5.8S-ITS2 rRNA and beta-tubulin genes. This mould strain was able to reproduce black spot formation in dry-cured fermented sausage 'salchichon' throughout the ripening process. In addition, a specific and sensitive real-time PCR method was also developed to detect Cladosporium oxysporum responsible for the black spot formation in sausages. This method could be of great interest for the meat industry to detect samples contaminated with this mould before spoilage of product avoiding economic losses for this sector. PMID- 25460139 TI - Consumer palatability scores and volatile beef flavor compounds of five USDA quality grades and four muscles. AB - Proximate data, consumer palatability scores and volatile compounds were investigated for four beef muscles (Longissimus lumborum, Psoas major, Semimembranosus and Gluteus medius) and five USDA quality grades(Prime, Upper 2/3 Choice, Low Choice, Select, and Standard). Quality grade did not directly affect consumer scores or volatiles but interactions (P < 0.05) between muscle and grade were determined. Consumer scores and volatiles differed (P < 0.05) between muscles. Consumers scored Psoas major highest for tenderness, juiciness, flavor liking and overall liking, followed by Longissimus lumborum, Gluteus medius, and Semimembranosus (P < 0.05). Principal component analysis revealed clustering of compound classes, formed by related mechanisms. Volatile n-aldehydes were inversely related to percent fat. Increases in lipid oxidation compounds were associated with Gluteus medius and Semimembranosus, while greater quantities of sulfur-containing compounds were associated with Psoas major. Relationships between palatability scores and volatile compound classes suggest that differences in the pattern of volatile compounds may play a valuable role in explaining consumer liking. PMID- 25460140 TI - The employment of FTIR spectroscopy in combination with chemometrics for analysis of rat meat in meatball formulation. AB - For Indonesian community, meatball is one of the favorite meat food products. In order to gain economical benefits, the substitution of beef meat with rat meat can happen due to the different prices between rat meat and beef. In this present research, the feasibility of FTIR spectroscopy in combination with multivariate calibration of partial least square (PLS) was used for the quantitative analysis of rat meat in the binary mixture of beef in meatball formulation. Meanwhile, the chemometrics of principal component analysis (PCA) was used for the classification between rat meat and beef meatballs. Some frequency regions in mid infrared region were optimized, and finally, the frequency region of 750-1000 cm( 1) was selected during PLS and PCA modeling.For quantitative analysis, the relationship between actual values (x-axis) and FTIR predicted values (y-axis) of rat meat is described by the equation of y= 0.9417x+ 2.8410 with coefficient of determination (R2) of 0.993, and root mean square error of calibration (RMSEC) of 1.79%. Furthermore, PCA was successfully used for the classification of rat meat meatball and beef meatball. PMID- 25460141 TI - Meat quality and health implications of organic and conventional beef production. AB - Recommendation to reduce fat consumption from ruminant meat does not consider the contribution of nutritionally beneficial fatty acids in lean beef. Here we report effects of production system (organic vs conventional) and finishing season on meat and fat quality of sirloin steaks from retail outlets and simulated fatty acid intakes by consumers. There was little difference in meat quality (pH, shear force and colour), but the fat profiles varied considerably between production systems and season. Meat fat from organic and summer finished cattle contained higher concentrations of conjugated linoleic acid, its precursor vaccenic acid and individual omega-3 fatty acids and had a lower ratio of omega-6 to omega-3 fatty acids compared with non-organic and winter finished cattle respectively. The fat profile from summer finished organic beef aligns better to recommended dietary guideline including those for long chain omega-3 fatty acids compared with that from winter finished, non-organic steak. PMID- 25460142 TI - Validation of the SenseWear Armband as a Measure of Sedentary Behavior and Light Activity. AB - BACKGROUND: This study determined the validity and sensitivity of the SenseWear armband (SWA) during sedentary and light office duties compared with indirect calorimetry (IC). METHODS: Participants (N = 22), 30 to 64 years of age, randomly performed 6 conditions for 5 minutes each (ie, supine, sitting no movement, standing no movement, sitting office work, standing office work, walking at 1.0 mph). Steady state for each activity (ie, average for minutes 4 and 5) was analyzed. RESULTS: Energy expenditure (EE) for the SWA (1.58 kcal/min) and the IC (1.64 kcal/min) were significantly correlated, r(20) = 0.90, P < .001 and ICC = 0.90, 95% CI (0.699, 0.966). Correlation results for each condition varied in strength, r(20) = 0.53 to 0.83 and ICC = 0.49 to 0.81, but were all significant (P < .05). A significant interaction between measurement method and condition existed (P < .001). The SWA under predicted EE during standing with no movement, sitting office work, and standing office work. CONCLUSION: The SWA and IC EE rates were strongly correlated during sedentary and light activity office behaviors. However, the SWA may under predict EE during office work (standing or sitting) and when standing motionless, making it slightly less sensitive than IC. PMID- 25460143 TI - Encapsulated cells for long-term secretion of soluble VEGF receptor 1: Material optimization and simulation of ocular drug response. AB - Anti-angiogenic therapies with vascular endothelial growth factor (VEGF) inhibiting factors are effective treatment options for neovascular diseases of the retina, but these proteins can only be delivered as intravitreal (IVT) injections. To sustain a therapeutic drug level in the retina, VEGF inhibitors have to be delivered frequently, every 4-8weeks, causing inconvenience for the patients and expenses for the healthcare system. The aim of this study was to investigate cell encapsulation as a delivery system for prolonged anti-angiogenic treatment of retinal neovascularization. Genetically engineered ARPE-19 cells secreting soluble vascular endothelial growth factor receptor 1 (sVEGFR1) were encapsulated in a hydrogel of cross-linked collagen and interpenetrating hyaluronic acid (HA). The system was optimized in terms of matrix composition and cell density, and long-term cell viability and protein secretion measurements were performed. sVEGFR1 ARPE-19 cells in the optimized hydrogel remained viable and secreted sVEGFR1 at a constant rate for at least 50days. Based on pharmacokinetic/pharmacodynamic (PK/PD) modeling, delivery of sVEGFR1 from this cell encapsulation system is expected to lead only to modest VEGF inhibition, but improvements of the protein structure and/or secretion rate should result in strong and prolonged therapeutic effect. In conclusion, the hydrogel matrix herein supported the survival and protein secretion from the encapsulated cells. The PK/PD simulation is a convenient approach to predict the efficiency of the cell encapsulation system before in vivo experiments. PMID- 25460144 TI - Comparison between linear and star-like HPMA conjugated pirarubicin (THP) in pharmacokinetics and antitumor activity in tumor bearing mice. AB - Previously we showed that linear poly(N-(2-hydroxypropyl)methacrylamide) conjugates of pirarubicin (THP), LP-THP, with MW about 39 kDa, exhibited far better tumor accumulation and therapeutic effect than that of parental free THP. To improve the pharmacokinetics of LP-THP further, high-MW conjugate of poly(amido amine) (PAMAM) dendrimer grafted with semitelechelic HPMA copolymer (PHPMA) was synthesized [star polymer (SP); 400 kDa] and conjugated with THP via hydrazone bond-containing spacer (SP-THP). THP was conjugated to SP to form SP THP via acid cleavable hydrazone bonding, which responds to acidic milieu of tumor tissue. As a consequence, it would release free THP, by active therapeutic principle. SP-THP exhibits larger hydrodynamic diameter (25.9 nm) in aqueous solution than that of LP-THP (8.2 nm) as observed by light scattering and size exclusion chromatography. Because of the larger size, the tumor AUC5h-72 h of SP THP was 3.3 times higher than that of LP-THP. More importantly, released free THP was retained selectively in the tumor tissue for at least up to 72 h after administration of SP-THP. We found that SP-THP exhibited superior antitumor effect to LP-THP against both S-180 tumor-bearing mice in vivo, and with chemically AOM/DSS-induced colon tumor-bearing mice, most probably due to their different molecular size. In our comparison study of in vitro and in vivo behavior of SP-THP and LP-THP we concluded that SP-THP exhibited enhanced therapeutic efficacy not only in implanted tumor but also in orthotopic/spontaneous tumor despite its higher toxicity compared to LP-THP. Upon these findings further investigation using various tumors including transgenic, and metastatic tumors is going to be conducted soon. PMID- 25460145 TI - Comparison of rheological properties, follicular penetration, drug release, and permeation behavior of a novel topical drug delivery system and a conventional cream. AB - A novel adapalene-loaded solid lipid microparticle (SLMA) dispersion as a topical drug delivery system (TDDS) for follicular penetration has been introduced. The objective of the present study was to investigate the rheological properties, the follicular penetration with differential tape stripping on porcine ear skin, the drug release in sebum and stratum corneum (SC) lipid mixtures, and the permeation behavior across human SC in comparison with a commercially available cream as standard. Physicochemical characterization reveals that adapalene is homogeneously distributed within the SLMA dispersion and chemically stable for at least 24 weeks. The SLMA dispersion shows a lower complex viscosity at 20 degrees C and a higher one at 32 degrees C than the cream, while the phase angle of the dispersion is always larger at both temperatures. Both formulations feature an equivalent potential for follicular penetration and deposition. However, the superiority of the SLMA dispersion is based on the preferential drug release in sebum while there is no or just a slight release in SC lipids and no permeation for both formulations. Due to the similarity of the glyceride matrix of the SLMA to sebum components, a targeted drug delivery into sebum and thereby an increased follicular penetration may be facilitated. PMID- 25460146 TI - Coencapsulation of epirubicin and metformin in PEGylated liposomes inhibits the recurrence of murine sarcoma S180 existing CD133+ cancer stem-like cells. AB - Cancer stem cells (CSCs), also known as tumor-initiating cells, which constitute a subpopulation of tumor cells, are key drivers of tumorigenesis and potential recurrence of cancer. The CSC theory has brought new opportunities as well as challenges to the development of sophisticated drug delivery systems for treating cancer. In the present study, CD133+ cells were sorted from S180 cell lines by magnetic activated cell sorting and a fraction (approximately 1.01%) of CD133+ cells with higher proliferative potential and stronger tumorigenicity in vivo compared with CD133- cells was identified. Furthermore, a procedure for the coencapsulation of epirubicin (EPI) and metformin (MET) was developed with the primary goal of eradicating the bulk population of CD133- cells and the rare population of CD133+ cancer stem-like cells, thus ultimately preventing tumor relapse. The inhibitory effect of free MET was more potent in CD133+cells than in CD133- cells; in addition, EPI- and MET-coencapsulated liposomes exhibited increased cytotoxicity against CD133+ cells compared with liposomal EPI alone. Meanwhile, tumors in KM mice were completely eliminated upon multiple intravenous injections of liposomal EPI and MET, and tumors virtually eliminated in the experimental period, which could be attributed to the arrest of CD133+ cells in the G0/G1 phase. The coencapsulation of an anti-CSC agent with conventional chemotherapy drugs in liposomes may be a promising drug delivery strategy for fighting cancer and eradicating tumor stem cells. PMID- 25460147 TI - A head-to-head multi-parametric high content analysis of a series of medium chain fatty acid intestinal permeation enhancers in Caco-2 cells. AB - There is debate over the narrow safety margin of many oral permeation enhancers. The sodium salts of medium chain fatty acids (MCFAs) are components of selected oral peptide formulations being assessed in advanced clinical studies. The aim of the study was to examine the effects of the C8-C12 series on filter-grown Caco-2 monolayers and cells grown on 96 well plates in order to dissect the relationship between paracellular permeability enhancement (Papp of [14C]mannitol, reduction in TEER), critical micellar concentration (CMC), and sub-lethal cytotoxicity (high content analysis (HCA). There was a high degree of correlation between the EC50 for increasing the Papp with reduction in transepithelial electrical resistance (TEER), and with CMC values. C8 had the highest EC50 and highest CMC value and was the least cytotoxic, while C12 had the reverse, suggesting a close association between increases in chain length with increases in permeability, hydrophobicity and cytotoxicity. HCA revealed further association between MCFA induced intracellular calcium increases and plasma membrane permeability reductions in Caco-2 cells with the EC50 to increase the Papp across monolayers. HCA identified sub-lethal cytotoxicity in a series of MCFA and related cell parameters to physicochemical properties and efficacy as intestinal permeation enhancers. These mild surfactants therefore non-specifically partition into the plasma membrane causing membrane fluidization, which is associated with concentration-dependent increases in permeability. PMID- 25460148 TI - In-line NIR monitoring of key characteristics of enteric coated pellets. AB - We describe the development of an in-line monitoring approach for the fluid-bed drying and coating steps for the production of enteric coated pellets by NIR. Our results show that key pellet characteristics can be monitored in-line. Likewise, the finished product acidic resistance is in excellent agreement to the in-line NIR predictions. Samples were collected at regular intervals and analyzed by several reference methods to characterize both process steps. In-line NIR models for pellets size sieve fractions, residual solvent content, and amount of coating layer have been constructed. Both the pellet coating layer amount and the in vitro enteric performance demonstrate low variability which represents a challenge to the usual chemometric model development approach. To overcome this challenge a hierarchical PLS model for predicting acidic resistance was successfully constructed using time-evolving spectral data from 22 batches. Moreover, a novel multivariate meta-analysis of the PLS loadings of individual in line models and the hierarchical PLS model has identified which pellet characteristics correlate most significantly with the observed enteric performance of the finished product. Additionally, the meta-analysis pointed toward the presence of further mechanisms unrelated to studied characteristics that also significantly influence the acidic resistance. PMID- 25460149 TI - In-line spatial filtering velocimetry for particle size and film thickness determination in fluidized-bed pellet coating processes. AB - A spatial filtering velocimetry (SFV) probe was applied to monitor the increase in particle size during pellet Wurster coating processes in-line. Accuracy of the in-line obtained pellet sizes was proven by at-line performed digital image analysis (DIA). Regarding particle growth, high conformity between both analytical methods (SFV/DIA) was examined for different coating processes. The influence of ring buffer size and the process of filling the buffer were investigated. With buffer sizes of 30,000-50,000 particles best results were obtained in this study. Investigated process parameters, such as inlet air volume and spray rate, had different effects on the impact of the SFV probe. While the particle rate (the number of particles detected by the SVF probe per second) was highly dependent on the inlet air volume, different spray rates of up to ?}1 g/min did not affect the detected particle growth. Artefacts and delays in SFV particle sizing appeared especially at the beginning of the coating processes. The slope of the particle growth during the final spraying period was therefore used to determine coating thickness. PMID- 25460150 TI - Hot-melts in buccoadhesive patches: an approach for bioavailability enhancement of highly-metabolized drugs with short elimination half-life. AB - The present study deals with the inclusion or incorporation of hot-melts into buccoadhesive patches. Our aim is to develop a patient-friendly dosage form that is capable of extending release of short elimination half-life drugs so to decrease dosing frequency and to increase the bioavailability of highly metabolized drugs with the ultimate aim of dose reduction. Tizanidine hydrochloride (TIZ) was used as a model drug.TIZ was incorporated into Compritol based hot-melts, and then further formulated into buccal patches prepared using HPMC, PVA and Polyox. A Central Composite Face-centered Design was employed to statistically optimize the formulation variables; HPMC solution/PVA solution weight ratio, Compritol/TIZ ratio in the hot-melts and percentage Polyox. The optimized formula suggested by the software was successful in controlling drug release, where 85% of TIZ was released after 4 h and the patch showed acceptable mucoadhesion properties. Pharmacokinetic parameters of TIZ from the optimized formula were compared to those of the immediate release tablet, Sirdalud(r), as reference in human volunteers using a randomized crossover design. Significant increase was observed for Cmax, Tmax, AUC(0-12) and AUC(0-1). The increase in relative bioavailability of TIZ from the optimized formula was 2.57 folds. PMID- 25460152 TI - A novel aerosol generator for homogenous distribution of powder over the lungs after pulmonary administration to small laboratory animals. AB - To evaluate powder formulations for pulmonary administration in pre-clinic research, the powder should be administered to the lungs of small laboratory animals. To do so properly, a device is needed that generates particles small enough to reach deep into the lungs. In this study a newly developed aerosol generator was tested for pulmonary administration of powder to the lungs of mice and its performance was compared to the only currently available device, the Penn Century insufflator. Results showed that both devices generated powder particles of approximately the same size distribution, but the fine particle fraction needed for deep lung administration was strongly improved when the aerosol generator was used.Imaging studies in mice showed that powder particles from the aerosol generator deposited into the deep lung, where powder from the Penn Century insufflator did not reach further than the conducting airways.Furthermore, powder administered by using the aerosol generator was more homogenously distributed over the five individual lungs lobes than powder administrated by using the Penn-Century insufflator. PMID- 25460151 TI - Cell permeable peptide conjugated nanoerythrosomes of fasudil prolong pulmonary arterial vasodilation in PAH rats. AB - In this study, we tested the hypothesis that a cell permeable peptide, CARSKNKDC (CAR), conjugated nanoerythrosomes (NERs) containing fasudil, a rho-kinase (ROCK) inhibitor, produces prolonged pulmonary preferential vasodilation. CAR conjugated NERs containing fasudil were prepared by hypotonic lysis and extrusion method, and optimized for various physicochemical properties in-vitro. The formulations were then used to study the hemodynamic efficacy in a monocrotaline-induced rodent model of pulmonary arterial hypertension (PAH). CAR-NERs-Fasudil was spherical in shape with an average vesicle size and entrapment efficiency of 161.3 +/- 1.37 nm and 48.81 +/- 1.96%, respectively. Formulations were stable for ~3 weeks when stored at 4 degrees C and the drug was released in a controlled fashion for >48 h. The uptake of CAR-NERs-Fasudil by TGF-b activated pulmonary arterial smooth muscle cell was ~1.5-fold greater than the uptake of NERs Fasudil. CAR-NERs-Fasudil inhibited ROCK activity and 5-hydroxytryptamine induced cell proliferation. In terms of reduction of pulmonary arterial pressure, intratracheal administration of CAR-NERs-Fasudil was ~2-fold more specific to the lungs compared with plain fasudil. Overall,CAR peptide grafted nanoerythrosomes offers a new platform for improving the therapeutic efficacy ofa rho-kinase inhibitor, fasudil, without affecting peripheral vasodilation. PMID- 25460153 TI - Pulmonary delivered polymeric micelles--pharmacokinetic evaluation and biodistribution studies. AB - Polymeric micelles represent interesting delivery systems for pulmonary sustained release. However, little is known about their in vivo release and translocation profile after delivery to the lungs. In the present study, curcumin acetate (CA), which is an ester prodrug of curcumin, or the mixture of CA and Nile red was encapsulated into PEG-PLGA micelles by a solvent evaporation method. The micellar formulation increased the stability of CA in water and physiologically relevant fluids and led to a sustained drug release in vitro. Following intratracheal (IT) administration to rats, CA loaded micelles achieved not only prolonged pulmonary retention with AUC values almost 400-fold higher than by IV route, but also local sustained release up to 24 h. In addition, IT delivery of micelles appeared to facilitate the uptake into the pulmonary vascular endothelium and efficiently translocate across the air-blood barrier and penetrate into the brain. Co localization of CA and Nile red confirmed that micelles in lung and brain tissue were still intact. This study is the first to demonstrate that aerosolized PEG PLGA micelles are a promising carrier for both pulmonary and non-invasive systemic sustained release of labile drugs. PMID- 25460154 TI - Impact of atomization technique on the stability and transport efficiency of nebulized liposomes harboring different surface characteristics. AB - The objective of this study was to evaluate the impact of nebulization on liposomes with specific surface characteristics by applying three commercially available inhaler systems (air-jet, ultrasonic and vibrating-mesh). Conventional liposome formulations composed of phosphatidylcholine and cholesterol were compared to sterically stabilized PEGylated liposomes and cationic polymer coated liposomes.Liposomes of similar size (between 140 and 165 nm in diameter with polydispersity indices <0.1) were prepared by dry lipid film rehydration followed by size extrusion. Their stability upon nebulization was determined in terms of size, polydispersity index and leakage using a fluorescence quenching system. The transport efficiencies of the nebulizer devices and the influences of both salt and liposomes on the droplet size distribution of the aerosol were investigated. While the droplet size of the aerosol decreased with increasing salt concentration the liposomes had no influence on the droplet size distribution. The output of the nebulizers in terms of liposomal transport efficiencies differed significantly among the nebulizer principles (20-100%, p < 0.05), with the vibrating-mesh nebulizers being the most effective. The integrity of the conventional liposomes was almost unaffected by the atomization process, while polymer coated and especially positively charged liposomes showed enhanced leakage. The release rates for the hydrophilic model drug system were highest for the vibrating-mesh nebulizers regardless of the surface characteristics of the liposomes (increasing from 10% to 20% and 50% for the conventional, PEGylated and positively charged formulations, respectively). In view of surface modified liposomes our data suggest that drug delivery via nebulization necessitates the finding of a compromise between nebulizer efficiency, formulation stability and drug release profile to accomplish the development of tailored formulations suitable for advanced inhalation therapy. PMID- 25460155 TI - Impact of low molecular weight excipient octaacetylmaltose on the liquid crystalline ordering and molecular dynamics in the supercooled liquid and glassy state of itraconazole. AB - Different experimental and theoretical techniques were applied to investigate basic physical properties of very stable and homogeneous solid dispersions formed by itraconazole and octaacetylmaltose. Differential scanning calorimetry as well as semi-empirical calculations have indicated that liquid crystalline ordering in itraconazole was completely suppressed in the binary mixtures. Molecular dynamics studies with the use of broadband dielectric spectroscopy have shown that the width of the structural relaxation process becomes smaller and fragility drops in solid dispersions with respect to the pure itraconazole. Moreover, the dynamics of secondary relaxation processes was affected by acetylated maltose. As demonstrated, beta- and gamma-secondary modes shift to higher and lower frequencies, respectively. On the other hand, aging experiments revealed that isostructural relaxation times in the glassy state become systematically longer with the addition of modified carbohydrate. This is a very important finding in the context of the current discussion on the factors affecting physical stability of easily crystallizing APIs. It seems that beside intermolecular interactions and local reorientation, the global mobility might control the crystallization of amorphous solid dispersions. Finally, we have demonstrated that itraconazole in binary mixtures dissolves faster and to greater extent with respect to the crystalline and amorphous form of this API. PMID- 25460156 TI - Celebrating our 40th year of publication: looking back, moving forward. PMID- 25460157 TI - Going back to the future: what is all the buzz about interprofessional education and collaborative practice? PMID- 25460158 TI - Reasoning back, looking ahead. PMID- 25460159 TI - Student clinical contract struggles: a long history, 1976 to 2015. PMID- 25460160 TI - Will the nursing profession survive? PMID- 25460161 TI - Developing communities of interprofessional practice: using a communities of practice framework for interprofessional education. AB - Development of interprofessional education programs that meet new Interprofessional Education Collaborative competencies is a challenge for faculty and administrators. This article describes a curricular design that places students in learning communities over a 2-year period with a plan for 5 learning sessions. Communities of practice is the theoretical framework of the curricular design, creating interprofessional clinicians capable of effective collaborative practice. PMID- 25460162 TI - Cellular Dynamics Drives the Emergence of Supracellular Structure in the Cyanobacterium, Phormidium sp. KS. AB - Motile filamentous cyanobacteria, such as Oscillatoria, Phormidium and Arthrospira, are ubiquitous in terrestrial and aquatic environments. As noted by Nageli in 1860, many of them form complex three-dimensional or two-dimensional structures, such as biofilm, weed-like thalli, bundles of filaments and spirals, which we call supracellular structures. In all of these structures, individual filaments incessantly move back and forth. The structures are, therefore, macroscopic, dynamic structures that are continuously changing their microscopic arrangement of filaments. In the present study, we analyzed quantitatively the movement of individual filaments of Phormidium sp. KS grown on agar plates. Junctional pores, which have been proposed to drive cell movement by mucilage/slime secretion, were found to align on both sides of each septum. The velocity of movement was highest just after the reversal of direction and, then, attenuated exponentially to a final value before the next reversal of direction. This kinetics is compatible with the "slime gun" model. A higher agar concentration restricts the movement more severely and, thus, resulted in more spiral formation. The spiral is a robust form compatible with non-homogeneous movements of different parts of a long filament. We propose a model of spiral formation based on the microscopic movement of filaments. PMID- 25460163 TI - Comparative analysis of Japanese three-spined stickleback clades reveals the Pacific Ocean lineage has adapted to freshwater environments while the Japan Sea has not. AB - Divergent selection and adaptive divergence can increase phenotypic diversification amongst populations and lineages. Yet adaptive divergence between different environments, habitats or niches does not occur in all lineages. For example, the colonization of freshwater environments by ancestral marine species has triggered adaptive radiation and phenotypic diversification in some taxa but not in others. Studying closely related lineages differing in their ability to diversify is an excellent means of understanding the factors promoting and constraining adaptive evolution. A well-known example of the evolution of increased phenotypic diversification following freshwater colonization is the three-spined stickleback. Two closely related stickleback lineages, the Pacific Ocean and the Japan Sea occur in Japan. However, Japanese freshwater stickleback populations are derived from the Pacific Ocean lineage only, suggesting the Japan Sea lineage is unable to colonize freshwater. Using stable isotope data and trophic morphology, we first show higher rates of phenotypic and ecological diversification between marine and freshwater populations within the Pacific Ocean lineage, confirming adaptive divergence has occurred between the two lineages and within the Pacific Ocean lineage but not in the Japan Sea lineage. We further identified consistent divergence in diet and foraging behaviour between marine forms from each lineage, confirming Pacific Ocean marine sticklebacks, from which all Japanese freshwater populations are derived, are better adapted to freshwater environments than Japan Sea sticklebacks. We suggest adaptive divergence between ancestral marine populations may have played a role in constraining phenotypic diversification and adaptive evolution in Japanese sticklebacks. PMID- 25460164 TI - A matter of timing: identifying significant multi-dose radiotherapy improvements by numerical simulation and genetic algorithm search. AB - Multi-dose radiotherapy protocols (fraction dose and timing) currently used in the clinic are the product of human selection based on habit, received wisdom, physician experience and intra-day patient timetabling. However, due to combinatorial considerations, the potential treatment protocol space for a given total dose or treatment length is enormous, even for relatively coarse search; well beyond the capacity of traditional in-vitro methods. In constrast, high fidelity numerical simulation of tumor development is well suited to the challenge. Building on our previous single-dose numerical simulation model of EMT6/Ro spheroids, a multi-dose irradiation response module is added and calibrated to the effective dose arising from 18 independent multi-dose treatment programs available in the experimental literature. With the developed model a constrained, non-linear, search for better performing cadidate protocols is conducted within the vicinity of two benchmarks by genetic algorithm (GA) techniques. After evaluating less than 0.01% of the potential benchmark protocol space, candidate protocols were identified by the GA which conferred an average of 9.4% (max benefit 16.5%) and 7.1% (13.3%) improvement (reduction) on tumour cell count compared to the two benchmarks, respectively. Noticing that a convergent phenomenon of the top performing protocols was their temporal synchronicity, a further series of numerical experiments was conducted with periodic time-gap protocols (10 h to 23 h), leading to the discovery that the performance of the GA search candidates could be replicated by 17-18 h periodic candidates. Further dynamic irradiation-response cell-phase analysis revealed that such periodicity cohered with latent EMT6/Ro cell-phase temporal patterning. Taken together, this study provides powerful evidence towards the hypothesis that even simple inter-fraction timing variations for a given fractional dose program may present a facile, and highly cost-effecitive means of significantly improving clinical efficacy. PMID- 25460165 TI - Distinct roles for hematopoietic and extra-hematopoietic sphingosine kinase-1 in inflammatory bowel disease. AB - Sphingosine kinase 1 (SK1), one of two SK enzymes, is highly regulated and has been shown to act as a focal point for the action of many growth factors and cytokines. SK1 leads to generation of sphingosine-1-phosphate (S1P) and potentially the activation of S1P receptors to mediate biologic effects. Our previous studies implicated SK1/S1P in the regulation of inflammatory processes, specifically in inflammatory bowel disease (IBD). These studies were conducted using a total body knockout mouse for SK1 and were unable to determine the source of SK1/S1P (hematopoietic or extra-hematopoietic) involved in the inflammatory responses. Therefore, bone marrow transplants were performed with wild-type (WT) and SK1-/- mice and colitis induced with dextran sulfate sodium (DSS). Irrespective of the source of SK1/S1P, bone marrow or tissue, DSS induced colitis in all mice; however, mice lacking SK1 in both hematopoietic and extra hematopoietic compartments exhibited decreased crypt damage. Systemic inflammation was assessed, and mice with WT bone marrow demonstrated significant neutrophilia in response to DSS. In the local inflammatory response, mice lacking SK1/S1P in either bone marrow or tissue exhibited decreased induction of cytokines and less activation of STAT3 (signal transducer and activator of transcription 3). Interestingly, we determined that extra-hematopoietic SK1 is necessary for the induction of cyclooxygenase 2 (COX2) in colon epithelium in response to DSS-induced colitis. Taken together our data suggest that hematopoietic-derived SK1/S1P regulates specific aspects of the systemic inflammatory response, while extra-hematopoietic SK1 in the colon epithelium is necessary for the autocrine induction of COX2 in DSS-induced colitis. PMID- 25460168 TI - Feedback to providers improves evidence-based implantable cardioverter defibrillator programming and reduces shocks. AB - BACKGROUND: Implantable cardioverter-defibrillator (ICD) shocks are associated with increased anxiety, health care utilization, and potentially mortality. OBJECTIVE: The purpose of the Shock-Less Study was to determine if providing feedback reports to physicians on their adherence to evidence-based shock reduction programming could improve their programming behavior and reduce shocks. METHODS: Shock-Less enrolled primary prevention (PP) and secondary prevention (SP) ICD patients between 2009 and 2012 at 118 study centers worldwide and followed patients longitudinally after their ICD implant. Center-specific therapy programming reports (TPRs) were delivered to each center 9 to 12 months after their first enrollment. The reports detailed adherence to evidence-based programming targets: number of intervals to detect ventricular fibrillation (VF NID), longest treatment interval (LTI), supraventricular tachycardia (SVT) discriminators (Wavelet, PR Logic), SVT limit, Lead Integrity Alert (LIA), and antitachycardia pacing (ATP). Clinicians programmed ICDs at their discretion. The primary outcome measure was the change in utilization of evidence-based shock reduction programming before (phase I, n = 2694 patients) and after initiation of the TPR (phase II, n = 1438 patients). RESULTS: Patients implanted after feedback reports (phase II) were up to 20% more likely to have their ICDs programmed in line with evidence-based shock reduction programming (eg, VF NID in PP patients 30/40 in 33.5% vs 18.6%, P < .0001). Patients implanted in phase II had a lower risk of all-cause shock (adjusted hazard ratio 0.72, 95% confidence interval 0.58 0.90, P = .003). CONCLUSION: Providing programming feedback reports improves adherence to evidence-based shock reduction programming and is associated with lower risk of ICD shocks. PMID- 25460166 TI - Neuroprotection by argon ventilation after perinatal asphyxia: a safety study in newborn piglets. AB - Hypothermia is ineffective in 45% of neonates with hypoxic-ischemic encephalopathy. Xenon has additive neuroprotective properties, but is expensive, and its application complicated. Argon gas is cheaper, easier to apply, and also has neuroprotective properties in experimental settings. The aim was to explore the safety of argon ventilation in newborn piglets. METHODS: Eight newborn piglets (weight 1.4-3.0 kg) were used. Heart rate, blood pressure, regional cerebral saturation, and electrocortical brain activity were measured continuously. All experiments had a 30 min. baseline period, followed by three 60 min. periods of argon ventilation alternated with 30 min argon washout periods. Two animals were ventilated with increasing concentrations of argon (1h 30%, 1 h 50%, and 1 h 80%), two were subjected to 60 min. hypoxia (FiO2 0.08) before commencing 50% argon ventilation, and two animals received hypothermia following hypoxia as well as 50% argon ventilation. Two animals served as home cage controls and were terminated immediately. RESULTS: Argon ventilation did not result in a significant change of heart rate (mean +/- s.d. -3.5 +/- 3.6 bpm), blood pressure (-0.60 +/- 1.11 mmHg), cerebral oxygen saturation (0.3 +/- 0.9%), electrocortical brain activity (-0.4 +/- 0.7 uV), or blood gas values. Argon ventilation resulted in elevated argon concentrations compared to the home cage controls (34.5, 25.4, and 22.4 vs. 7.3 ul/ml). CONCLUSION: Ventilation with up to 80% argon during normoxia, and 50% argon after hypoxia did not affect heart rate, blood pressure, cerebral saturation and electrocortical brain activity. Clinical safety studies of argon ventilation in humans seem justified. PMID- 25460167 TI - Signal peptide-binding drug as a selective inhibitor of co-translational protein translocation. AB - In eukaryotic cells, surface expression of most type I transmembrane proteins requires translation and simultaneous insertion of the precursor protein into the endoplasmic reticulum (ER) membrane for subsequent routing to the cell surface. This co-translational translocation pathway is initiated when a hydrophobic N terminal signal peptide (SP) on the nascent protein emerges from the ribosome, binds the cytosolic signal recognition particle (SRP), and targets the ribosome nascent chain complex to the Sec61 translocon, a universally conserved protein conducting channel in the ER-membrane. Despite their common function in Sec61 targeting and ER translocation, SPs have diverse but unique primary sequences. Thus, drugs that recognise SPs could be exploited to inhibit translocation of specific proteins into the ER. Here, through flow cytometric analysis the small molecule macrocycle cyclotriazadisulfonamide (CADA) is identified as a highly selective human CD4 (hCD4) down-modulator. We show that CADA inhibits CD4 biogenesis and that this is due to its ability to inhibit co-translational translocation of CD4 into the lumen of the ER, both in cells as in a cell-free in vitro translation/translocation system. The activity of CADA maps to the cleavable N-terminal SP of hCD4. Moreover, through surface plasmon resonance analysis we were able to show direct binding of CADA to the SP of hCD4 and identify this SP as the target of our drug. Furthermore, CADA locks the SP in the translocon during a post-targeting step, possibly in a folded state, and prevents the translocation of the associated protein into the ER lumen. Instead, the precursor protein is routed to the cytosol for degradation. These findings demonstrate that a synthetic, cell-permeable small-molecule can be developed as a SP-binding drug to selectively inhibit protein translocation and to reversibly regulate the expression of specific target proteins. PMID- 25460169 TI - Electrical connection between ipsilateral pulmonary veins: prevalence and implications for ablation and adenosine testing. AB - BACKGROUND: Anatomic studies have reported the presence of shared myocardial fibers between approximately half of ipsilateral pulmonary veins (IPVs). OBJECTIVE: The purpose of this study was to assess the prevalence of electrical connection between IPVs and the impact of antral isolation with or without carina ablation on IPV connection. METHODS: Thirty consecutive patients undergoing atrial fibrillation (AF) ablation (14 redo) were included. Wide antral pulmonary vein isolation (PVI) was performed with or without carina lesions. For each PV set, IPV electrical connection was assessed before and after PVI by pacing and recording from the ostium of both IPVs using a circular mapping catheter and the ablation catheter. Adenosine was given after PVI to assess for acute PV reconnection. RESULTS: Before PVI without preceding AF ablation procedure, all the PVs had ipsilateral connection albeit frequently via the left atrium. After PVI, 65.6% of the IPVs were connected without carina ablation vs 17.7% if prior carina ablation (P = .001). Left vs right IPVs were connected in 57.1% and 72.2% of the cases without carina ablation, respectively, vs 30% and 0% of cases with carina ablation (P = .19 and P = .001). When transient PV reconnection was demonstrated during adenosine challenge, connected IPVs uniformly demonstrated simultaneous reconnection. CONCLUSION: Electrical connection between IPVs is uniformly demonstrated before any ablation. Two-thirds of the IPVs are connected after antral PVI, and carina ablation decreases IPV connection. Connected IPVs consistently show the same response to adenosine challenge; therefore, a single catheter positioned in either of the IPVs with electrical connection is sufficient to confirm reconnection in both veins. PMID- 25460170 TI - Epicardial leads in adult cardiac resynchronization therapy recipients: a study on lead performance, durability, and safety. AB - BACKGROUND: Transvenous left ventricular (LV) lead placement for cardiac resynchronization therapy-defibrillator (CRT-D) delivery is unsuccessful in 8% to 10% of cases. These patients might benefit from an epicardial lead. However, data on long-term epicardial lead performance are scarce. Furthermore, extracting an epicardial lead requires a rethoracotomy. OBJECTIVE: The purpose of this study was to determine data on almost a decade of experience with epicardial leads and investigate the safety of partially leaving this lead in place after device infection. METHODS: All adult patients receiving an epicardial lead (Medtronic CapSure Epi, model 4968) for CRT-D in the Leiden University Medical Center were included. Leads were implanted during a standalone procedure or in combination with other cardiothoracic procedures. Electrical lead parameters were assessed at implantation and every 6 months thereafter. In case of device infection the epicardial lead was cut off parasternal, just outside the thoracic cavity, leaving the distal part of the lead in place. RESULTS: Two-hundred sixteen patients were included with a median follow-up of 3 years (25th-75th percentile 1.0-5.5). LV pacing threshold decreased within 6 months after implantation [1.1 V (95% confidence interval [CI] 0.9-1.2) vs 0.8 V (95% CI 0.7-0.9), P = .01] and stabilized thereafter. Mean LV electrogram was 15.2 +/- 7.5 mV, and average lead impedance was 633.5 +/- 174.0 Omega. Five-year cumulative incidence was 1.6% for lead failure and 9.6% for device infection. The retained epicardial lead caused skin erosion in 3 patients and fistula formation in 1. CONCLUSION: This study demonstrates that epicardial LV leads have an excellent long-term performance. Partially retaining the lead after device infection was associated with a risk of reinfection with limited long-term clinical implications for the patient. PMID- 25460172 TI - Understanding the microscopic mechanisms for LQT1 needs a global view of the I(Ks) channel. PMID- 25460171 TI - Subcutaneous nerve activity and spontaneous ventricular arrhythmias in ambulatory dogs. AB - BACKGROUND: Stellate ganglion nerve activity (SGNA) is important in ventricular arrhythmogenesis. However, because thoracotomy is needed to access the stellate ganglion, it is difficult to use SGNA for risk stratification. OBJECTIVE: The purpose of this study was to test the hypothesis that subcutaneous nerve activity (SCNA) in canines can be used to estimate SGNA and predict ventricular arrhythmia. METHODS: We implanted radiotransmitters to continuously monitor left stellate ganglion and subcutaneous electrical activities in 7 ambulatory dogs with myocardial infarction, complete heart block, and nerve growth factor infusion to the left stellate ganglion. RESULTS: Spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF) was documented in each dog. SCNA preceded a combined 61 episodes of VT and VF, 61 frequent bigeminy or couplets, and 61 premature ventricular contractions within 15 seconds in 70%, 59%, and 61% of arrhythmias, respectively. Similar incidence of 75%, 69%, and 62% was noted for SGNA. Progressive increase in SCNA [48.9 (95% confidence interval [CI] 39.3-58.5) vs 61.8 (95% CI 45.9-77.6) vs 75.1 (95% CI 57.5-92.7) mV-s] and SGNA [48.6 (95% CI 40.9-56.3) vs 58.5 (95% CI 47.5-69.4) vs 69.0 (95% CI 53.8 84.2) mV-s] integrated over 20-second intervals was demonstrated 60 seconds, 40 seconds, and 20 seconds before VT/VF (P <.05), respectively. The Pearson correlation coefficient for integrated SCNA and SGNA was 0.73 +/- 0.18 (P <.0001 for all dogs, n = 5). Both SCNA and SGNA exhibited circadian variation. CONCLUSION: SCNA can be used as an estimate of SGNA to predict susceptibility to VT and VF in a canine model of ventricular arrhythmia and sudden cardiac death. PMID- 25460173 TI - "Power-on resets" in cardiac implantable electronic devices during magnetic resonance imaging. AB - BACKGROUND: Magnetic resonance imaging (MRI) has been safely performed in some patients with cardiac implantable electronic devices (CIEDs) under careful monitoring and prespecified conditions. Pacemaker-dependent patients are often excluded, partly because of the potential for "power-on reset" (PoR), which can lead to a change from asynchronous to inhibited pacing with consequent inhibition of pacing due to electromagnetic interference during MRI. OBJECTIVE: The purpose of this study was to review risk factors for PoR during MRI. METHODS: A prospective study was performed between January 2008 and May 2013 in patients with CIEDs undergoing clinically indicated MRI. Eligible patients were not pacemaker dependent. Devices were interrogated before and after MRI, programmed to an asynchronous mode or an inhibition mode with tachyarrhythmia therapies turned off, and reprogrammed to their original settings after MRI. RESULTS: MRI scans (n = 256) were performed in 198 patients with non-MRI-conditional CIEDs between 2008 and 2013 (median age 66 years; interquartile range 57-77 years; 59% men). PoR occurred during 9 MRI scans (3.5%) in 8 patients. PoR was more frequent with Medtronic devices than with other generator brands (n = 9/139 vs 0/117 [6% vs 0%]; P = .005). Devices with PoR were all released before 2002 and were implanted from 1999 to 2004. Effects of PoR included a decrease in heart rate during MRI (n = 4) and transient anomalous battery life indication (n = 1). All devices functioned normally after MRI. CONCLUSION: PoR occurs infrequently but can cause deleterious changes in pacing mode and heart rate. MRI should not be performed in pacemaker-dependent patients with older at-risk generators. Continuous monitoring during MRI is essential because unrecognized PoR may inhibit pacing or accelerate battery depletion due to high pacing output. PMID- 25460174 TI - Time-dependent responses to provocative testing with flecainide in the diagnosis of Brugada syndrome. AB - BACKGROUND: Time-dependent variability of electrocardiogram (ECG) in patients with Brugada syndrome could affect the interpretation of provocative testing. OBJECTIVE: The aim of this study was to characterize ECG changes during and after flecainide infusion. METHODS: We studied 59 consecutive patients. The ECG was continuously analyzed during the first 30 minutes of provocative testing, and a single ECG was recorded 60 minutes later. We analyzed CYP2D6 and CYP3A5 variants affecting flecainide metabolism and performed blinded measurements at lead II. RESULTS: At baseline, ECG patterns were classified as follows: type II in 31 patients (53%), type III in 15 (25%), and normal ECG in 13 (22%). Because of induction of type I ECG, the percentage of responders progressively increased with longer recording time periods (6.8% in 10 minutes vs 11.9% in 20-30 minutes vs 18.6% in 90 minutes; P < .01). Four patients displayed a late response, which was evidenced 90 minutes after the initiation of provocative testing. QRS width differentially increased between responders and nonresponders (P < .01), with a maximum QRS width of 110 ms during the first 30 minutes being effective for identifying possible late responders (sensitivity 100%; specificity 85.6%; positive predictive value 88%; negative predictive value 100%). The incidence of CYP2D6 variants was lower in late responders than in early or delayed responders (0% vs 75% vs 100%; P = .04), while a homogeneous distribution of CYP3A5*3/*3 was observed in our population. CONCLUSION: Response to flecainide exhibits time dependent variability of ECG patterns and intervals. Longer periods of ECG recording increase the recognition probability of type I ECG. PMID- 25460175 TI - A tachycardia using a decrementally conducting concealed accessory pathway between the superior caval vein-right atrial junction and the right ventricle. PMID- 25460176 TI - Device complications in adult congenital heart disease. AB - BACKGROUND: Pacemakers and implantable cardioverter-defibrillators (ICDs) are increasingly implanted in adults with congenital heart disease (CHD), but little is known about implant-related complications and mortality. OBJECTIVE: The purpose of this study was to compare pacemaker and ICD implantation complication rates between adults with and those without CHD using a comprehensive, statewide database. METHODS: We used the Healthcare Cost and Utilization Project database to identify initial transvenous pacemaker and ICD implantations and implant related complications in California hospitals from January 1, 2005, to December 31, 2011. We calculated relative risks of implant-related complications by comparing those with and those without CHD using Poisson regression with robust standard errors, adjusting for age and medical comorbidities. RESULTS: We identified 105,852 patients undergoing pacemaker implantation, 1465 with noncomplex CHD and 66 with complex CHD. CHD was not associated with increased risk of pacemaker implant-related complications: adjusted risk ratio (aRR) 0.92, 95% confidence interval (CI) 0.74-1.14, P = .45. We identified 32,948 patients undergoing ICD implantation, 815 with noncomplex CHD and 87 with complex CHD. Patients with CHD had increased risk of ICD implant-related complications: aRR 1.36, 95% CI 1.05-1.76, P = .02. Patients with complex CHD had greater increased risk of ICD implant-related complications: aRR 2.14, 95% CI 1.16-3.95, P = .02. In patients receiving devices, CHD was associated with a trend toward lower 30 day in-hospital mortality after pacemaker (P = .07) and ICD (P = .19) implantation. CONCLUSION: Among adult patients undergoing device implantation in California, CHD was associated with increased risk of ICD implant-related complications, but not pacemaker implant-related complications or higher 30-day in-hospital mortality. PMID- 25460177 TI - Epicardial atrial fat: not quite as idle as it looks. PMID- 25460178 TI - CALM3 mutation associated with long QT syndrome. PMID- 25460180 TI - Histogram analysis of gadoxetic acid-enhanced MRI for quantitative hepatic fibrosis measurement. AB - PURPOSE: The diagnosis and monitoring of liver fibrosis is an important clinical issue; however, this is usually achieved by invasive methods such as biopsy. We aimed to determine whether histogram analysis of hepatobiliary phase images of gadoxetic acid-enhanced magnetic resonance imaging (MRI) can provide non-invasive quantitative measurement of liver fibrosis. METHODS: This retrospective study was approved by the institutional ethics committee, and a waiver of informed consent was obtained. Hepatobiliary phase images of preoperative gadoxetic acid-enhanced MRI studies of 105 patients (69 males, 36 females; age 56.1+/-12.2) with pathologically documented liver fibrosis grades were analyzed. Fibrosis staging was F0/F1/F2/F3/F4 (METAVIR system) for 11/20/13/15/46 patients, respectively. Four regions-of-interest (ROI, each about 2 cm2) were placed on predetermined locations of representative images. The measured signal intensity of pixels in each ROI was used to calculate corrected coefficient of variation (cCV), skewness, and kurtosis. An average value of each parameter was calculated for comparison. Statistical analysis was performed by ANOVA, receiver operating characteristic (ROC) curve analysis, and linear regression. RESULTS: The cCV showed statistically significant differences among pathological fibrosis grades (P<0.001) whereas skewness and kurtosis did not. Univariable linear regression analysis suggested cCV to be a meaningful parameter in predicting the fibrosis grade (P<0.001, beta = 0.40 and standard error = 0.06). For discriminating F0-3 from F4, the area under ROC score was 0.857, standard deviation 0.036, 95% confidence interval 0.785-0.928. CONCLUSION: Histogram analysis of hepatobiliary phase images of gadoxetic acid-enhanced MRI can provide non-invasive quantitative measurements of hepatic fibrosis. PMID- 25460181 TI - Validation of marrow fat assessment using noninvasive imaging with histologic examination of human bone samples. AB - PURPOSE: The marrow composition throughout the body is heterogeneous and changes with age. Due to heterogeneity, invasive biopsies of the iliac crest do not truly represent the complete physiological status, impeding the clinical effectiveness of this method. Therefore, we aim to provide verification for an in vivo imaging technique using co-registered histologic examinations for assessment of marrow adiposity. METHODS: Five recently expired (i.e. <24h) human cadavers were scanned with a dual source CT (DECT) scanner in order to measure marrow fat in the lumbar vertebrae. These donors were also imaged using water-fat MRI (wfMRI) which was used to estimate the fraction of yellow marrow. After imaging, lumbar columns were excised and the superior and inferior aspects of 21 vertebrae were removed. The remaining center section was processed for histological examination to find the ratio of adipocyte volume per tissue volume (AV/TV). RESULTS: Results of DECT and wfMRI had a high correlation (r = 0.88). AV/TV ranged from 0.18 to 0.75 with a mean (SD) of 0.36 (0.18). Inter-evaluator reliability for AV/TV was r > 0.984. There were similar correlations between AV/TV and the imaging modalities, DECT derived MF and wfMRI (r = 0.802 and 0.772, respectively). CONCLUSIONS: A high MF variation was seen among the 25 vertebrae imaged. Both DECT and wfMRI have a good correlation with the histologic adipocyte proportion and can be used to measure MF. This makes longitudinal studies possible without painful, less-effective, invasive biopsies. PMID- 25460182 TI - miR-135a modulates tendon stem/progenitor cell senescence via suppressing ROCK1. AB - Tendon stem/progenitor cell (TSPC) senescence may lead to age-related tendon disorders and impair tendon regeneration and replacement capacity in humans. However, the mechanisms governing TSPC aging and degeneration remain obscure. Recently, it has been reported that Rho-associated coiled-coil protein kinase 1 (ROCK1) might be a key player in TSPC aging process. miRNAs are also involved in cellular senescence. In this study, whether miRNAs modulate senescence of TSPCs through targeting ROCK1 was evaluated. We found that miR-135a, which directly binds to the 3'-untranslated region of ROCK1, is significantly downregulated in aged compared with young TSPCs. Overexpression of miR-135a in young TSPCs suppresses senescence, promotes proliferation, and induces migration and tenogenic differentiation, whereas suppression of miR-135a in aged TSPCs has the opposite effects. By gain-of-function and loss-of-function studies, we confirmed that ROCK1 mediates the effects of miR-135a in TSPCs. Taken together, our data suggest that miR-135a plays an important role in TSPC senescence via targeting ROCK1. PMID- 25460179 TI - Molecular characterization of an intact p53 pathway subtype in high-grade serous ovarian cancer. AB - High-grade serous ovarian cancer (HGSOC) is the most aggressive histological type of epithelial ovarian cancer, which is characterized by a high frequency of somatic TP53 mutations. We performed exome analyses of tumors and matched normal tissues of 34 Japanese patients with HGSOC and observed a substantial number of patients without TP53 mutation (24%, 8/34). Combined with the results of copy number variation analyses, we subdivided the 34 patients with HGSOC into subtypes designated ST1 and ST2. ST1 showed intact p53 pathway and was characterized by fewer somatic mutations and copy number alterations. In contrast, the p53 pathway was impaired in ST2, which is characterized by abundant somatic mutations and copy number alterations. Gene expression profiles combined with analyses using the Gene Ontology resource indicate the involvement of specific biological processes (mitosis and DNA helicase) that are relevant to genomic stability and cancer etiology. In particular we demonstrate the presence of a novel subtype of patients with HGSOC that is characterized by an intact p53 pathway, with limited genomic alterations and specific gene expression profiles. PMID- 25460183 TI - Siglec-15 is a potential therapeutic target for postmenopausal osteoporosis. AB - Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption in association with an immunoreceptor tyrosine-based activation motif (ITAM) adaptor protein, DNAX-activating protein 12kDa (DAP12). Although Siglec-15 has an important role in physiologic bone remodeling by modulating RANKL signaling, it is unclear whether it is involved in pathologic bone loss in which multiple osteoclastogenic factors participate in excessive osteoclastogenesis. Here we demonstrated that Siglec-15 is involved in estrogen deficiency-induced bone loss. WT and Siglec-15(-/-) mice were ovariectomized (Ovx) or sham-operated at 14wk of age and their skeletal phenotype was evaluated at 18 and 22wk of age. Siglec-15( /-) mice showed resistance to estrogen deficiency-induced bone loss compared to WT mice. Although the number of tartrate-resistant acid phosphatase (TRAP) positive osteoclasts increased after ovariectomy in both WT and Siglec-15(-/-) mice, the increase was lower in Siglec-15(-/-) mice than in WT mice. Importantly, osteoclasts in Siglec-15(-/-) mice were small and failed to spread on the bone surface, indicating impaired osteoclast differentiation. Because upregulated production of TNF-alpha as well as RANKL is mainly responsible for estrogen deficiency-induced development of osteoclasts, we examined whether Siglec-15 deficiency affects TNF-alpha-induced osteoclastogenesis in vitro. The TNF-alpha mediated induction of TRAP-positive multinucleated cells was impaired in Siglec 15(-/-) cells, suggesting that Siglec-15 is involved in TNF-alpha induced osteoclastogenesis. We also confirmed that signaling through osteoclast associated receptor/Fc receptor common gamma chain, which is an alternative ITAM adaptor to DAP12, rescues multinucleation but not cytoskeletal organization of TNF-alpha and RANKL-induced Siglec-15(-/-) osteoclasts, indicating that the Siglec-15/DAP12 pathway is especially important for cytoskeletal organization of osteoclasts in both RANKL and TNF-alpha induced osteoclastogenesis. The present findings indicate that Siglec-15 is involved in estrogen deficiency-induced differentiation of osteoclasts and is thus a potential therapeutic target for postmenopausal osteoporosis. PMID- 25460184 TI - Extracellular matrix mineralization in murine MC3T3-E1 osteoblast cultures: an ultrastructural, compositional and comparative analysis with mouse bone. AB - Bone cell culture systems are essential tools for the study of the molecular mechanisms regulating extracellular matrix mineralization. MC3T3-E1 osteoblast cell cultures are the most commonly used in vitro model of bone matrix mineralization. Despite the widespread use of this cell line to study biomineralization, there is as yet no systematic characterization of the mineral phase produced in these cultures. Here we provide a comprehensive, multi technique biophysical characterization of this cell culture mineral and extracellular matrix, and compare it to mouse bone and synthetic apatite mineral standards, to determine the suitability of MC3T3-E1 cultures for biomineralization studies. Elemental compositional analysis by energy-dispersive X-ray spectroscopy (EDS) showed calcium and phosphorus, and trace amounts of sodium and magnesium, in both biological samples. X-ray diffraction (XRD) on resin-embedded intact cultures demonstrated that similar to 1-month-old mouse bone, apatite crystals grew with preferential orientations along the (100), (101) and (111) mineral planes indicative of guided biogenic growth as opposed to dystrophic calcification. XRD of crystals isolated from the cultures revealed that the mineral phase was poorly crystalline hydroxyapatite with 10 to 20nm sized nanocrystallites. Consistent with the XRD observations, electron diffraction patterns indicated that culture mineral had low crystallinity typical of biological apatites. Fourier-transform infrared spectroscopy (FTIR) confirmed apatitic carbonate and phosphate within the biological samples. With all techniques utilized, cell culture mineral and mouse bone mineral were remarkably similar. Scanning (SEM) and transmission (TEM) electron microscopy showed that the cultures had a dense fibrillar collagen matrix with small, 100nm-sized, collagen fibril-associated mineralization foci which coalesced to form larger mineral aggregates, and where mineralized sites showed the accumulation of the mineral-binding protein osteopontin. Light microscopy, confocal microscopy and three-dimensional reconstructions showed that some cells had dendritic processes and became embedded within the mineral in an osteocyte-like manner. In conclusion, we have documented characteristics of the mineral and matrix phases of MC3T3-E1 osteoblast cultures, and have determined that the structural and compositional properties of the mineral are highly similar to that of mouse bone. PMID- 25460185 TI - Diversity of native nicotinic receptor subtypes in mammalian brain. AB - Neuronal nicotinic acetylcholine receptors (nAChRs) are a heterogeneous family of pentameric ligand-gated cation channels that are expressed throughout the brain and involved in a wide range of physiological and pathophysiological processes. The nAChR subtypes share a common basic structure, but their biophysical and pharmacological properties depend on their subunit composition, which is therefore central to understanding their function in the nervous system and discovering new subtype selective drugs. The development of new technologies and the generation of mice carrying deletions or the expression of gain-of-function nAChR subunits, or GFP-tagged receptor genes has allowed the in vivo identification of complex subtypes and to study the role of individual subtypes in specific cells and complex neurobiological systems but much less is known about which native nAChR subtypes are involved in specific physiological functions and pathophysiological conditions in human brain. We briefly review some recent findings concerning the structure and function of native nAChRs, focussing on the subtypes identified in the rodent habenulo-interpeduncular pathway, a pathway involved in nicotine reinforcement and withdrawal. We also discuss recent findings concerning the expression of native subtypes in primate brain. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID- 25460186 TI - Inter-individual variation in the effect of antiepileptic drugs in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice. AB - Despite more than 20 clinically approved antiepileptic drugs (AEDs), there remains a substantial unmet clinical need for patients with refractory (AED resistant) epilepsy. Animal models of refractory epilepsy are needed for at least two goals; (1) better understanding of the mechanisms underlying resistance to AEDs, and (2) development of more efficacious AEDs for patients with refractory seizures. It is only incompletely understood why two patients with seemingly identical types of epilepsy and seizures may respond differently to the same AED. Prompted by this well-known clinical phenomenon, we previously evaluated whether epileptic rats respond differently to AEDs and discovered AED responsive and resistant animals in the same models. In the present study, we used the same approach for the widely used intrahippocampal kainate mouse model of mesial temporal lobe epilepsy. In a first step, we examined anti-seizure effects of 6 AEDs on spontaneous recurrent focal electrographic seizures and secondarily generalized convulsive seizures in epileptic mice, showing that the focal nonconvulsive seizures were resistant to carbamazepine and phenytoin, whereas valproate and levetiracetam exerted moderate and phenobarbital and diazepam marked anti-seizure effects. All AEDs seemed to suppress generalized convulsive seizures. Next we investigated the inter-individual variation in the anti-seizure effects of these AEDs and, in case of focal seizures, found responders and nonresponders to all AEDs except carbamazepine. Most nonresponders were resistant to more than one AED. Our data further validate the intrahippocampal kainate mouse model as a model of difficult-to-treat focal seizures that can be used to investigate the determinants of AED efficacy. PMID- 25460187 TI - Characterizing new fluorescent tools for studying 5-HT3 receptor pharmacology. AB - The pharmacological characterization of ligands depends upon the ability to accurately measure their binding properties. Fluorescence provides an alternative to more traditional approaches such as radioligand binding. Here we describe the binding and spectroscopic properties of eight fluorescent 5-HT3 receptor ligands. These were tested on purified receptors, expressed receptors on live cells, or in vivo. All compounds had nanomolar affinities with fluorescent properties extending from blue to near infra-red emission. A fluorescein-derivative had the highest affinity as measured by fluorescence polarization (FP; 1.14 nM), flow cytometry (FC; 3.23 nM) and radioligand binding (RB; 1.90 nM). Competition binding with unlabeled 5-HT3 receptor agonists (5-HT, mCPBG, quipazine) and antagonists (granisetron, palonosetron, tropisetron) yielded similar affinities in all three assays. When cysteine substitutions were introduced into the 5-HT3 receptor binding site the same changes in binding affinity were seen for both granisetron and the fluorescein-derivative, suggesting that they both adopt orientations that are consistent with co-crystal structures of granisetron with a homologous protein (5HTBP). As expected, in vivo live imaging in anaesthetized mice revealed staining in the abdominal cavity in intestines, but also in salivary glands. The unexpected presence of 5-HT3 receptors in mouse salivary glands was confirmed by Western blots. Overall, these results demonstrate the wide utility of our new high-affinity fluorescently-labeled 5-HT3 receptor probes, ranging from in vitro receptor pharmacology, including FC and FP ligand competition, to live imaging of 5-HT3 expressing tissues. PMID- 25460188 TI - alpha4beta2 Nicotinic receptor stimulation of the GABAergic system within the orbitofrontal cortex ameliorates the severe crossmodal object recognition impairment in ketamine-treated rats: implications for cognitive dysfunction in schizophrenia. AB - Schizophrenia is associated with atypical multisensory integration. Rats treated sub-chronically with NMDA receptor antagonists to model schizophrenia are severely impaired on a tactile-to-visual crossmodal object recognition (CMOR) task, and this deficit is reversed by systemic nicotine. The current study assessed the receptor specificity of the ameliorative effect of nicotine in the CMOR task, as well as the potential for nicotinic receptor (nAChR) interactions with GABA and glutamate. Male Long-Evans rats were treated sub-chronically for 10 days with ketamine or saline and then tested on the CMOR task after a 10-day washout. Systemic nicotine given before the sample phase of the CMOR task reversed the ketamine-induced impairment, but this effect was blocked by co administration of the GABAA receptor antagonist bicuculline at a dosage that itself did not cause impairment. Pre-sample systemic co-administration of the NMDA receptor antagonist MK-801 did not block the remediating effect of nicotine in ketamine-treated rats. The selective alpha7 nAChR agonist GTS-21 and alpha4beta2 nAChR agonist ABT-418 were also tested, with only the latter reversing the ketamine impairment dose-dependently; bicuculline also blocked this effect. Similarly, infusions of nicotine or ABT-418 into the orbitofrontal cortex (OFC) reversed the CMOR impairment in ketamine-treated rats, and systemic bicuculline blocked the effect of intra-OFC ABT-418. These results suggest that nicotine-induced agonism of alpha4beta2 nAChRs within the OFC ameliorates CMOR deficits in ketamine-treated rats via stimulation of the GABAergic system. The findings of this research may have important implications for understanding the nature and potential treatment of cognitive impairment in schizophrenia. PMID- 25460189 TI - Rate-adjusted spike-LFP coherence comparisons from spike-train statistics. AB - Coherence is a fundamental tool in the analysis of neuronal data and for studying multiscale interactions of single and multiunit spikes with local field potentials. However, when the coherence is used to estimate rhythmic synchrony between spiking and any other time series, the magnitude of the coherence is dependent upon the spike rate. This property is not a statistical bias, but a feature of the coherence function. This dependence confounds cross-condition comparisons of spike-field and spike-spike coherence in electrophysiological experiments. Taking inspiration from correction methods that adjust the spike rate of a recording with bootstrapping ('thinning'), we propose a method of estimating a correction factor for the spike-field and spike-spike coherence that adjusts the coherence to account for this rate dependence. We demonstrate that the proposed rate adjustment is accurate under standard assumptions and derive distributional properties of the estimator. The reduced estimation variance serves to provide a more powerful test of cross-condition differences in spike LFP coherence than the thinning method and does not require repeated Monte Carlo trials. We also demonstrate some of the negative consequences of failing to account for rate dependence. The proposed spike-field coherence estimator accurately adjusts the spike-field coherence with respect to rate and has well defined distributional properties that endow the estimator with lower estimation variance than the existing adjustment method. PMID- 25460191 TI - Growth of axial nested P-N heterojunction nanowires for high performance diodes. AB - Heterojunction nanomaterials have attracted the interest of numerous scientists and engineers to explore the fundamental scientific understanding of the formation of heterojunction nanostructures, their special properties with enhanced electrical and optical performance and the relationship between the functionality and the molecular structures. In this work, we synthesized novel axial nested P-N heterojunction nanowires combining the inorganic semiconductor PbS and the organic conjugated polymer polypyrrole (PPy). The nested P-N heterojunction nanowires (NWs) show a higher rectification ratio (exceeding 100), long-term stability and high unilateral conductivity due to the bigger area of junction produced. PMID- 25460192 TI - Methanogenic archaea diversity in hyporheic sediments of a small lowland stream. AB - Abundance and diversity of methanogenic archaea were studied at five localities along a longitudinal profile of a Sitka stream (Czech Republic). Samples of hyporheic sediments were collected from two sediment depths (0-25 cm and 25-50 cm) by freeze-core method. Methanogen community was analyzed by fluorescence in situ hybridization (FISH), denaturing gradient gel electrophoresis (DGGE) and sequencing method. The proportion of methanogens to the DAPI-stained cells varied among all localities and depths with an average value 2.08 * 10(5) per g of dry sediment with the range from 0.37 to 4.96 * 10(5) cells per g of dry sediment. A total of 73 bands were detected at 19 different positions on the DGGE gel and the highest methanogen diversity was found at the downstream located sites. There was no relationship between methanogen diversity and sediment depth. Cluster analysis of DGGE image showed three main clusters consisting of localities that differed in the number and similarity of the DGGE bands. Sequencing analysis of representative DGGE bands revealed phylotypes affiliated with members belonging to the orders Methanosarcinales, Methanomicrobiales and Methanocellales. The knowledge about occurrence and diversity of methanogenic archaea in freshwater ecosystems are essential for methane dynamics in river sediments and can contribute to the understanding of global warming process. PMID- 25460193 TI - Message from the Editor-in-Chief. PMID- 25460190 TI - Proteomics of Fusarium oxysporum race 1 and race 4 reveals enzymes involved in carbohydrate metabolism and ion transport that might play important roles in banana Fusarium wilt. AB - Banana Fusarium wilt is a soil-spread fungal disease caused by Fusarium oxysporum. In China, the main virulence fungi in banana are F. oxysporum race 1 (F1, weak virulence) and race 4 (F4, strong virulence). To date, no proteomic analyses have compared the two races, but the difference in virulence between F1 and F4 might result from their differentially expressed proteins. Here we report the first comparative proteomics of F1 and F4 cultured under various conditions, and finally identify 99 protein species, which represent 59 unique proteins. These proteins are mainly involved in carbohydrate metabolism, post-translational modification, energy production, and inorganic ion transport. Bioinformatics analysis indicated that among the 46 proteins identified from F4 were several enzymes that might be important for virulence. Reverse transcription PCR analysis of the genes for 15 of the 56 proteins revealed that their transcriptional patterns were similar to their protein expression patterns. Taken together, these data suggest that proteins involved in carbohydrate metabolism and ion transport may be important in the pathogenesis of banana Fusarium wilt. Some enzymes such as catalase-peroxidase, galactosidase and chitinase might contribute to the strong virulence of F4. Overexpression or knockout of the genes for the F4 specific proteins will help us to further understand the molecular mechanism of Fusarium-induced banana wilt. PMID- 25460194 TI - In-vitro activity of taurolidine on single species and a multispecies population associated with periodontitis. AB - The antimicrobial activity of taurolidine was compared with minocycline against microbial species associated with periodontitis (four single strains and a 12 species mixture). Minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs), killing as well as activities on established and forming single-species biofilms and a 12-species biofilm were determined. The MICs of taurolidine against single species were always 0.31 mg/ml, the MBCs were 0.64 mg/ml. The used mixed microbiota was less sensitive to taurolidine, MIC and the MBC was 2.5 mg/ml. The strains and the mixture were completely killed by 2.5 mg/ml taurolidine, whereas 256 MUg/ml minocycline reduced the bacterial counts of the mixture by 5 log10 colony forming units (cfu). Coating the surface with 10 mg/ml taurolidine or 256 MUg/ml minocycline prevented completely biofilm formation of Porphyromonas gingivalis ATCC 33277 but not of Aggregatibacter actinomycetemcomitans Y4 and the mixture. On 4.5 d old biofilms, taurolidine acted concentration dependent with a reduction by 5 log10 cfu (P. gingivalis ATCC 33277) and 7 log10 cfu (A. actinomycetemcomitans Y4) when applying 10 mg/ml. Minocycline decreased the cfu counts by 1-2 log10 cfu independent of the used concentration. The reduction of the cfu counts in the 4.5 d old multi-species biofilms was about 3 log10 cfu after application of any minocycline concentration and after using 10 mg/ml taurolidine. Taurolidine is active against species associated with periodontitis, even within biofilms. Nevertheless a complete elimination of complex biofilms by taurolidine seems to be impossible and underlines the importance of a mechanical removal of biofilms prior to application of taurolidine. PMID- 25460195 TI - The occurrence of antibiotic resistance genes in drug resistant Bacteroides fragilis isolates from Groote Schuur Hospital, South Africa. AB - Bacteroides fragilis, an anaerobic gut commensal and opportunistic pathogen, is a leading cause of anaerobic abscesses and bacteraemias. Treatment of infections is complicated by the emergence of resistance to several of the antibiotics used in the clinical setting. Genetic analysis of 23 B. fragilis isolates found that none of the metronidazole resistant strains carried the nimA-J genes, and no cfxA or ermF genes were detected. All of the tetracycline resistant isolates contained the tetQ gene and were sensitive to tigecycline. The cfiA gene was found in 3 of the strains, one of which was imipenem resistant and contained an upstream IS4351 insertion sequence. Another resistant strain had a unique G to A substitution in the promoter region of the cfiA gene, while the third was imipenem sensitive. Thirty percent of the isolates contained at least one plasmid, however, tetQ gene was located on the chromosome and not on any of the plasmids. PMID- 25460196 TI - Detection and molecular typing of Clostridium perfringens isolates from beef, chicken and turkey meats. AB - Here we describe a study investigating the presence of Clostridium perfringens strains in meat samples and the toxin genes in the isolates by PCR. This study, for the first time, demonstrated the presence of C. perfringens type E in turkey meats, while C. perfringens type C strains isolated from chicken meats. PMID- 25460198 TI - Diagnostic histochemistry and clinical-pathological testings as molecular pathways to pathogenesis and treatment of the ageing neuromuscular system: a personal view. AB - Ageing of the neuromuscular system in elderhood ingravescently contributes to slowness, weakness, falling and death, often accompanied by numbness and pain. This article is to put in perspective examples from a half-century of personal and team neuromuscular histochemical-pathological and clinical-pathological research, including a number of lucky and instructive accomplishments identifying new treatments and new diseases. A major focus currently is on some important, still enigmatic, aspects of the ageing neuromuscular system. It is also includes some of the newest references of others on various closely-related aspects of this ageing system. The article may help guide others in their molecular-based endeavors to identify paths leading to discovering new treatments and new pathogenic aspects. These are certainly needed - our ageing and unsteady constituents are steadily increasing. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. PMID- 25460197 TI - NADPH oxidase activation and 4-hydroxy-2-nonenal/aquaporin-4 adducts as possible new players in oxidative neuronal damage presents in drug-resistant epilepsy. AB - A correlation between epilepsy and cellular redox imbalance has been suggested, although the mechanism by which oxidative stress (OS) can be implicated in this disorder is not clear. In the present study several oxidative stress markers and enzymes involved in OS have been determined. In particular, we examined the levels of 4-hydroxy-2-nonenal protein adducts (HNE-PA), a by-product of lipid peroxidation, and the activation of NADPH oxidase 2 (NOX2), as cellular source of superoxide (O(2)(-)), in surgically resected epileptic tissue from drug-resistant patients (N=50). In addition, we investigated whether oxidative-mediated protein damage can affect aquaporin-4 (AQP4), a water channel implicated in brain excitability and epilepsy. Results showed high levels of HNE-PA in epileptic hippocampus, in both neurons and glial cells and cytoplasmic positivity for p47(phox) and p67(phox) suggesting NOX2 activation. Interestingly, in epileptic tissue immunohistochemical localization of AQP4 was identified not only in perivascular astrocytic endfeet, but also in neurons. Nevertheless, negativity for AQP4 was observed in neurons in degeneration. Of note, HNE-mediated post translational modifications of AQP4 were increased in epileptic tissues and double immunofluorescence clearly demonstrated co-localization of AQP4 and HNE-PA in epileptic hippocampal structures. The idea is that sudden, disorderly, and excessive neuronal discharges activates NOX2 with O(2)(-) production, leading to lipid peroxidation. The resulting generation of HNE targets AQP4, affecting water and ion balance. Therefore, we suggest that seizure induces oxidative damage as well as neuronal loss, thereby promoting neuronal hyperexcitability, also affecting water and ion balance by AQP4 modulation, and thus generating a vicious cycle. PMID- 25460200 TI - Potential use of multivariate curve resolution for the analysis of mass spectrometry images. AB - In this work the application of multivariate curve resolution is proposed for the analysis of Mass Spectrometry Imaging (MSI) data. Recently, developments in the ionization of samples have dramatically expanded the number of applications of MSI due to the possibility of collecting the mass spectrum for each pixel of a considered surface in a reasonable time. Using this method, both spatial distribution and spectral information of analyzed samples can be obtained. However, there are major drawbacks inherent to MSI related to the high complexity of the data obtained from real samples and to the extremely huge size of the datasets generated by this technique. Therefore, the potential of chemometrical tools in different steps of the analysis process is unquestionable, from data compression to data resolution of the different components present at each pixel of the image. In this work, this data analysis is carried out by means of the multivariate curve resolution method. The benefits of the application of this method are shown for two examples consisting of a MS image of two platted microbes and a MS image of a mouse lung section. The results show that multivariate curve resolution allows us to obtain distribution maps of different components and their identification from resolved high-resolution mass spectra. PMID- 25460199 TI - Hepatic nerve growth factor induced by iron overload triggers defenestration in liver sinusoidal endothelial cells. AB - The fenestrations of liver sinusoidal endothelial cells (LSECs) play important roles in the exchange of macromolecules, solutes, and fluid between blood and surrounding liver tissues in response to hepatotoxic drugs, toxins, and oxidative stress. As excess iron is a hepatotoxin, LSECs may be affected by excess iron. In this study, we found a novel link between LSEC defenestration and hepatic nerve growth factor (NGF) in iron-overloaded mice. By Western blotting, NGF was highly expressed, whereas VEGF and HGF were not, and hepatic NGF mRNA levels were increased according to digital PCR. Immunohistochemically, NGF staining was localized in hepatocytes, while TrkA, an NGF receptor, was localized in LSECs. Scanning electron microscopy revealed LSEC defenestration in mice overloaded with iron as well as mice treated with recombinant NGF. Treatment with conditioned medium from iron-overloaded primary hepatocytes reduced primary LSEC fenestrations, while treatment with an anti-NGF neutralizing antibody or TrkA inhibitor, K252a, reversed this effect. However, iron-loaded medium itself did not reduce fenestration. In conclusion, iron accumulation induces NGF expression in hepatocytes, which in turn leads to LSEC defenestration via TrkA. This novel link between iron and NGF may aid our understanding of the development of chronic liver disease. PMID- 25460201 TI - Investigation of the Passerini and Ugi reactions in beta-lactam aldehydes. Synthetic applications. AB - Passerini (P-3CR) and Ugi (U-4CR) reactions were investigated in 4-oxoazetidine-2 carboxaldehydes, affording the corresponding Passerini and Ugi adducts with moderate diastereoselectivity in high yields. Fortunately, the obtained mixtures of isomers syn/anti were separated in most cases. The scope of both IMCRs has been studied using a variety of isocyanides, carboxylic acids and amines. Ugi adducts were used for the preparation of unusual 2-azetidinones fused to medium sized rings via RCM. In addition, beta-lactam-diketopiperazine hybrids have also been prepared from the corresponding Ugi adducts. PMID- 25460202 TI - Usability standards meet scenario-based design: challenges and opportunities. AB - The focus of this paper is on the challenges and opportunities presented by developing scenarios of use for interactive medical devices. Scenarios are integral to the international standard for usability engineering of medical devices (IEC 62366:2007), and are also applied to the development of health software (draft standard IEC 82304-1). The 62366 standard lays out a process for mitigating risk during normal use (i.e. use as per the instructions, or accepted medical practice). However, this begs the question of whether "real use" (that which occurs in practice) matches "normal use". In this paper, we present an overview of the product lifecycle and how it impacts on the type of scenario that can be practically applied. We report on the development and testing of a set of scenarios intended to inform the design of infusion pumps based on "real use". The scenarios were validated by researchers and practitioners experienced in clinical practice, and their utility was assessed by developers and practitioners representing different stages of the product lifecycle. These evaluations highlighted previously unreported challenges and opportunities for the use of scenarios in this context. Challenges include: integrating scenario-based design with usability engineering practice; covering the breadth of uses of infusion devices; and managing contradictory evidence. Opportunities included scenario use beyond design to guide marketing, to inform purchasing and as resources for training staff. This study exemplifies one empirically grounded approach to communicating and negotiating the realities of practice. PMID- 25460203 TI - Automatic detection of patients with invasive fungal disease from free-text computed tomography (CT) scans. AB - BACKGROUND: Invasive fungal diseases (IFDs) are associated with considerable health and economic costs. Surveillance of the more diagnostically challenging invasive fungal diseases, specifically of the sino-pulmonary system, is not feasible for many hospitals because case finding is a costly and labour intensive exercise. We developed text classifiers for detecting such IFDs from free-text radiology (CT) reports, using machine-learning techniques. METHOD: We obtained free-text reports of CT scans performed over a specific hospitalisation period (2003-2011), for 264 IFD and 289 control patients from three tertiary hospitals. We analysed IFD evidence at patient, report, and sentence levels. Three infectious disease experts annotated the reports of 73 IFD-positive patients for language suggestive of IFD at sentence level, and graded the sentences as to whether they suggested or excluded the presence of IFD. Reliable agreement between annotators was obtained and this was used as training data for our classifiers. We tested a variety of Machine Learning (ML), rule based, and hybrid systems, with feature types including bags of words, bags of phrases, and bags of concepts, as well as report-level structured features. Evaluation was carried out over a robust framework with separate Development and Held-Out datasets. RESULTS: The best systems (using Support Vector Machines) achieved very high recall at report- and patient-levels over unseen data: 95% and 100% respectively. Precision at report-level over held-out data was 71%; however, most of the associated false positive reports (53%) belonged to patients who had a previous positive report appropriately flagged by the classifier, reducing negative impact in practice. CONCLUSIONS: Our machine learning application holds the potential for developing systematic IFD surveillance systems for hospital populations. PMID- 25460204 TI - Towards probabilistic decision support in public health practice: predicting recent transmission of tuberculosis from patient attributes. AB - OBJECTIVE: Investigating the contacts of a newly diagnosed tuberculosis (TB) case to prevent TB transmission is a core public health activity. In the context of limited resources, it is often necessary to prioritize investigation when multiple cases are reported. Public health personnel currently prioritize contact investigation intuitively based on past experience. Decision-support software using patient attributes to predict the probability of a TB case being involved in recent transmission could aid in this prioritization, but a prediction model is needed to drive such software. METHODS: We developed a logistic regression model using the clinical and demographic information of TB cases reported to Montreal Public Health between 1997 and 2007. The reference standard for transmission was DNA fingerprint analysis. We measured the predictive performance, in terms of sensitivity, specificity, negative predictive value, positive predictive value, the Receiver Operating Characteristic (ROC) curve and the Area Under the ROC (AUC). RESULTS: Among 1552 TB cases enrolled in the study, 314 (20.2%) were involved in recent transmission. The AUC of the model was 0.65 (95% confidence interval: 0.61-0.68), which is significantly better than random prediction. The maximized values of sensitivity and specificity on the ROC were 0.53 and 0.67, respectively. CONCLUSIONS: The characteristics of a TB patient reported to public health can be used to predict whether the newly diagnosed case is associated with recent transmission as opposed to reactivation of latent infection. PMID- 25460206 TI - Prioritization of potential candidate disease genes by topological similarity of protein-protein interaction network and phenotype data. AB - Identifying candidate disease genes is important to improve medical care. However, this task is challenging in the post-genomic era. Several computational approaches have been proposed to prioritize potential candidate genes relying on protein-protein interaction (PPI) networks. However, the experimental PPI network is usually liable to contain a number of spurious interactions. In this paper, we construct a reliable heterogeneous network by fusing multiple networks, a PPI network reconstructed by topological similarity, a phenotype similarity network and known associations between diseases and genes. We then devise a random walk based algorithm on the reliable heterogeneous network called RWRHN to prioritize potential candidate genes for inherited diseases. The results of leave-one-out cross-validation experiments show that the RWRHN algorithm has better performance than the RWRH and CIPHER methods in inferring disease genes. Furthermore, RWRHN is used to predict novel causal genes for 16 diseases, including breast cancer, diabetes mellitus type 2, and prostate cancer, as well as to detect disease related protein complexes. The top predictions are supported by literature evidence. PMID- 25460205 TI - Incorporating temporal EHR data in predictive models for risk stratification of renal function deterioration. AB - Predictive models built using temporal data in electronic health records (EHRs) can potentially play a major role in improving management of chronic diseases. However, these data present a multitude of technical challenges, including irregular sampling of data and varying length of available patient history. In this paper, we describe and evaluate three different approaches that use machine learning to build predictive models using temporal EHR data of a patient. The first approach is a commonly used non-temporal approach that aggregates values of the predictors in the patient's medical history. The other two approaches exploit the temporal dynamics of the data. The two temporal approaches vary in how they model temporal information and handle missing data. Using data from the EHR of Mount Sinai Medical Center, we learned and evaluated the models in the context of predicting loss of estimated glomerular filtration rate (eGFR), the most common assessment of kidney function. Our results show that incorporating temporal information in patient's medical history can lead to better prediction of loss of kidney function. They also demonstrate that exactly how this information is incorporated is important. In particular, our results demonstrate that the relative importance of different predictors varies over time, and that using multi-task learning to account for this is an appropriate way to robustly capture the temporal dynamics in EHR data. Using a case study, we also demonstrate how the multi-task learning based model can yield predictive models with better performance for identifying patients at high risk of short-term loss of kidney function. PMID- 25460207 TI - Exercise therapy for a patient with persistent dyspnea after combined traumatic diaphragmatic rupture and phrenic nerve injury. AB - We present a case report of a patient with a history of diaphragmatic rupture who had persistent dyspnea for 9 months after primary surgical repair of a right diaphragmatic rupture caused by a car accident. A phrenic nerve conduction study was performed, which demonstrated a rare accompanying ipsilateral phrenic nerve injury with resultant hemidiaphragmatic paralysis. Aerobic exercise therapy for the purpose of improving endurance and dietary modification for weight reduction were prescribed and continued for 6 months. The exercise intensity was prescribed based on the percentage of maximum heart rate as confirmed by an exercise tolerance test. The duration of exercise was gradually increased. In this case, the long-persistent dyspnea was successfully alleviated via nonoperative management to the point that the patient could resume regular activities of daily living. PMID- 25460208 TI - Diffuse idiopathic skeletal hyperostosis as a cause of dysphagia in a young patient with metabolic syndrome. PMID- 25460209 TI - Treatment strategies for genu recurvatum in adult patients with hemiparesis: a case series. AB - OBJECTIVE: To report our clinical experience and propose a biomechanical factor based treatment strategy for improvement of genu recurvatum (GR) to reduce the need for knee-ankle-foot orthosis (KAFO) or surgical treatment. DESIGN: Case series. SETTING: Outpatient clinic of a Department of Physical Medicine and Rehabilitation in an academic medical center. SUBJECTS AND INTERVENTIONS: Adult subjects (n = 22) with hemiparesis and GR who received botulinum injections alone or in combination with multiple types of orthotic interventions that included solid ankle-foot orthosis (AFO) +/- heel lift, hinged AFO with an adjustable posterior stop +/- heel lift, AFO with dual-channel ankle joint +/- heel lift, or KAFO with offset knee joint. Biomechanical factors reviewed included muscle strength, modified Ashworth score for spasticity, presence of clonus, posterior capsule laxity, sensory deficits, and proprioception. OUTCOME MEASUREMENTS: Outcome factors were improvement or elimination of GR based on subjective assessment before and after the interventions by the same experienced clinician. RESULTS: More than one biomechanical factor contributed to GR in all patients. Botulinum toxin A injection was used in patients who had significant plantar flexor spasticity and/or clonus. Four types of orthotic interventions were used based on the biomechanical factor: solid AFO in patients with severe ankle dorsiflexion and plantar flexion weakness or clonus; hinged ankle joint with adjustable posterior stop in patients with less severe ankle dorsiflexion weakness in the absence of clonus; AFO with a dual-channel ankle joint for quadriceps weakness or severe proprioceptive deficits; and KAFO with offset knee joints in patients with Achilles tendon contracture or severe proprioceptive deficits. Adjunctive options included the addition of heel lifts and toeplate modifications. Combinatorial interventions of botulinum injection, modified AFOs, and heel lifts improved or eliminated GR and avoided the need for cumbersome orthotics or surgical interventions. CONCLUSIONS: GR in hemiparesis is multifactorial and can be successfully controlled by using a conservative biomechanical factor-based approach and combined medical and orthotic interventions. An algorithmic approach and a prospective study design is proposed to determine a combination of effective interventions to correct GR. PMID- 25460210 TI - Two cases of metallosis from metal-on-polyethylene total hips: an emerging problem. AB - This report describes 2 cases of metallosis from metal-on-polyethylene total hip replacements. Case 1 involved a Stryker rejuvenate implant, which has since been recalled. This patient had minimal symptoms, an elevated cobalt level, and loosening. The patient in case 2 had a Dupuys Pinnacle system, with symptoms of weakness, rash, and hip pain. Abnormal laboratory values include elevated sedimentation rate, C-reactive protein, creatinine, cobalt, and decreased hematocrit. Magnetic resonance imaging revealed synovial thickening and extracapsular edema. Although metallosis is a well-established complication of metal-on-metal implants, emerging data reveal that it also may be a problem in non-metal-on-metal implants such as either metal-on-polyethylene or ceramic-on polyethylene implants, perhaps related to modular corrosion. PMID- 25460211 TI - Comparative effects of multilevel muscle tendon surgery, osteotomies, and dorsal rhizotomy on functional and gait outcome measures for children with cerebral palsy. AB - OBJECTIVE: To compare the impact of common surgical interventions (selective dorsal rhizotomy, muscle-tendon surgery, and osteotomies) for patients with cerebral palsy (CP) on Gross Motor Function Measure and temporal, kinematic, and kinetic gait variables as assessed via 3-dimensional motion analysis. DESIGN: Retrospective cohort study. SETTING: Motion analyses laboratory. PARTICIPANTS: Ninety-four patients with CP, 56 of whom underwent surgery (37, muscle-tendon surgery; 11, osteotomy; and 8, selective dorsal rhizotomy) and 38 of whom did not have surgery; the patients were ages 4-18 years, with a Gross Motor Function Classification System classification of I, II, or III. INTERVENTIONS: Single event, multilevel muscle tendon surgery, selective dorsal rhizotomy, and osteotomy. MAIN OUTCOME MEASURES: Change scores (postintervention - preintervention) in Gross Motor Function Measure and temporal, kinematic, and kinetic gait variables. RESULTS: No statistically significant differences in change scores were found between groups in the Gross Motor Function Measure, velocity, or stride length measures after the observation period. The selective dorsal rhizotomy group had greater improvements in knee extension when compared with the nonsurgical group and greater hip and knee total range of motion during the gait cycle when compared with nonsurgical group and the muscle-tendon surgery and osteotomy cohorts. Lastly, the muscle-tendon surgery group had greater improvements in total knee range of motion compared with the nonsurgical group. CONCLUSIONS: Patients who undergo selective dorsal rhizotomy and, to a lesser extent, muscle tendon procedures demonstrate greater improvements in kinematic gait variables compared with nonsurgical interventions in patients with spasticity resulting from CP. PMID- 25460212 TI - Selectively impaired fasciculus gracilis in cervical spinal cord injury. AB - Selective lesions of the fasciculus gracilis have been reported only in cases of nontraumatic spinal cord disease. We present the case of a 54-year-old man who developed persistent hypesthesia and abnormal vibratory sensation below the T6 segmental level after injuring his cervical spine after a fall. Cervical magnetic resonance imaging (MRI) revealed ossification of the posterior longitudinal ligament, spinal stenosis, and a C3-4 spinal cord injury. A thoracic MRI did not reveal a spinal cord lesion. Lower thoracic dermatomal somatosensory evoked potentials showed delayed latency. The findings in this case indicate selective injury to the fasciculus gracilis at the level of the cervical spinal cord. PMID- 25460213 TI - Lessons learned through leadership. PMID- 25460214 TI - Interactive augmented reality using Scratch 2.0 to improve physical activities for children with developmental disabilities. AB - This study uses a body motion interactive game developed in Scratch 2.0 to enhance the body strength of children with disabilities. Scratch 2.0, using an augmented-reality function on a program platform, creates real world and virtual reality displays at the same time. This study uses a webcam integration that tracks movements and allows participants to interact physically with the project, to enhance the motivation of children with developmental disabilities to perform physical activities. This study follows a single-case research using an ABAB structure, in which A is the baseline and B is the intervention. The experimental period was 2 months. The experimental results demonstrated that the scores for 3 children with developmental disabilities increased considerably during the intervention phrases. The developmental applications of these results are also discussed. PMID- 25460215 TI - Comparison of dosage of intensive upper limb therapy for children with unilateral cerebral palsy: how big should the therapy pill be? AB - This study aimed to compare efficacy of two dosages of modified constraint induced movement therapy (mCIMT) and bimanual therapy on upper limb and individualized outcomes for children with unilateral cerebral palsy. This secondary analysis included two separate randomized trials that compared equal doses (high or low) of mCIMT to bimanual therapy; Study 1 (full dose--60 h) n=64 and; Study 2 (half dose--30 h) n=18 for children aged five to 16 years with unilateral cerebral palsy. Outcomes for both studies included the Melbourne Assessment of Unilateral Upper Limb Function, Assisting Hand Assessment, Jebsen Taylor Test of Hand Function and Canadian Occupational Performance Measure which were administered at baseline, three and 26 weeks. Mixed linear modelling was used to compare between dose (e.g. "full dose" to "half dose" of either mCIMT or bimanual therapy) on outcomes at three and 26 weeks post-intervention. There were no significant differences between groups at baseline, however, on average the half dose mCIMT group was younger with better hand function compared to the other groups. The full compared to half dose mCIMT group achieved greater gains in bimanual performance at three weeks and dexterity and quality of movement at 26 weeks. There were no between group differences for bimanual therapy doses. Half dose groups receiving either mCIMT or bimanual therapy did not make significant within group gains on any upper limb motor outcome, however gains in occupational performance were clinically meaningful. These results suggest that a half dose (30 h) of either mCIMT or bimanual therapy may not be sufficient to impact upper limb outcomes, but made clinically meaningful gains in occupational performance for school aged children with UCP. PMID- 25460216 TI - Comparing the executive attention of adult females with ADHD to that of females with sensory modulation disorder (SMD) under aversive and non-aversive auditory conditions. AB - Certain behavioral expressions of sensory modulation disorder (SMD) such as distractibility, hyperactivity, and impulsivity are often similar to those of attention deficit/hyperactivity disorder (ADHD) in pediatric and adult populations. There is also a high comorbidity rate between these two diagnoses and absence of research regarding the objective neuropsychological differentiation between them. In the present study we employed a factorial design which enabled us to: (a) systematically examine the effects of SMD and ADHD on executive attention in a sample of adult females using a Stroop-like task, and (b) measure the effect of aversive conditions (sounds) on executive attention. The experimental measures used were the Stroop-like Location-Direction Task (SLDT) to assess executive attention and the battery of aversiveness to sounds (BAS), a standardized measure of aversive sounds that was developed for this study and enabled individual customization of aversive auditory sounds. Results revealed, as expected, a specific core deficit in executive attention for the ADHD factor. In addition to that, the present study provides an important, pioneering finding of SMD impairment in a unique combination of a cognitively demanding task with aversive sounds, providing preliminary objective evidence differentiating SMD from ADHD. PMID- 25460217 TI - Evaluating the use of the Child and Adolescent Intellectual Disability Screening Questionnaire (CAIDS-Q) to estimate IQ in children with low intellectual ability. AB - In situations where completing a full intellectual assessment is not possible or desirable the clinician or researcher may require an alternative means of accurately estimating intellectual functioning. There has been limited research in the use of proxy IQ measures in children with an intellectual disability or low IQ. The present study aimed to provide a means of converting total scores from a screening tool (the Child and Adolescent Intellectual Disability Screening Questionnaire: CAIDS-Q) to an estimated IQ. A series of linear regression analyses were conducted on data from 428 children and young people referred to clinical services, where FSIQ was predicted from CAIDS-Q total scores. Analyses were conducted for three age groups between ages 6 and 18 years. The study presents a conversion table for converting CAIDS-Q total scores to estimates of FSIQ, with corresponding 95% prediction intervals to allow the clinician or researcher to estimate FSIQ scores from CAIDS-Q total scores. It is emphasised that, while this conversion may offer a quick means of estimating intellectual functioning in children with a below average IQ, it should be used with caution, especially in children aged between 6 and 8 years old. PMID- 25460218 TI - Exploring spatial working memory performance in individuals with Williams syndrome: the effect of presentation format and configuration. AB - Williams syndrome (WS) is a neurodevelopmental disorder associated with an impaired capacity for visuospatial representation. Individuals with WS have a specific weakness in spatial processing, while visual components are relatively well preserved. This dissociation is apparent in working memory function too. The present study aimed to further investigate spatial working memory performance in individuals with WS, analyzing whether their impaired WM performance regards both simultaneous and sequential spatial formats, and whether presenting configurations differently might reduce their difficulties. These issues were examined by administering simultaneous and sequential spatial tasks, in which the information to be recalled was presented in random or arranged configurations. Our results showed that individuals with WS performed less well than typically developing (TD) children in the spatial-simultaneous task, but not in the spatial sequential one. The presence of a pattern enhanced the performance of both groups, but the difference between the two groups' performance in the spatial simultaneous task remained, albeit to a lesser degree. PMID- 25460219 TI - Sports participation of children with or without developmental delay: prediction from child and family factors. AB - Sports participation is beneficial to health and socioemotional adjustment in youth across development. While there is some evidence indicating lower sports participation for children with developmental delays (DD) as compared with their typically developing (TD) peers, little is known as to the predictors of this differential participation. Given the increased risk of physical and mental health difficulties for children with DD, understanding more about this disparity is important. We examined sports participation in elementary school-aged children with or without DD and examined child and family predictors of three indices of sports participation: number of sports and highest relational sport at ages 6 and 8, and consistent sports from 6 to 8. Children with TD were significantly higher on all three indicators. Mother and child factors related significantly to sports participation indices. The number of sports related positively to mother education and positive perceptions and negatively to mother employment. Relational sports were higher in boys, children with higher social skills, and lower behavior problems. In regression analyses at child age 8 that included these other variables, delay status (DD or TD) did not have a significant effect. Perspectives on varying influences on sports participation and implications for intervention are discussed. PMID- 25460220 TI - Persons with Alzheimer's disease engage in leisure and mild physical activity with the support of technology-aided programs. AB - Three studies were conducted to assess technology-aided programs to promote leisure engagement and mild physical activity in persons with Alzheimer's disease. Specifically, Study I assessed a program aimed at enabling three patients with mild or moderate Alzheimer's disease to choose among different music options and activate the preferred ones. Studies II and III were directed at patients in the low moderate or severe stages of the Alzheimer's disease who were no longer capable of ambulating and spent their time generally inactive, sitting in their wheelchairs. In particular, Study II used a program to help three patients exercise an arm-raising movement. Study III used a program to help three patients exercise a leg-foot movement. Each study was carried out according to a nonconcurrent multiple baseline design across patients. Results were very encouraging. The patients of Study I learned to choose and activate their preferred music pieces. The patients of Studies II and III enhanced their performance of the target movements and increased their indices of positive participation (e.g., smiles and verbalizations) during the sessions. The applicability of the programs in daily contexts and their implications for the patients involved are discussed. PMID- 25460221 TI - A systematic review of sensory-based treatments for children with disabilities. AB - Sensory-based therapies are designed to address sensory processing difficulties by helping to organize and control the regulation of environmental sensory inputs. These treatments are increasingly popular, particularly with children with behavioral and developmental disabilities. However, empirical support for sensory-based treatments is limited. The purpose of this review was to conduct a comprehensive and methodologically sound evaluation of the efficacy of sensory based treatments for children with disabilities. Methods for this review were registered with PROSPERO (CRD42012003243). Thirty studies involving 856 participants met our inclusion criteria and were included in this review. Considerable heterogeneity was noted across studies in implementation, measurement, and study rigor. The research on sensory-based treatments is limited due to insubstantial treatment outcomes, weak experimental designs, or high risk of bias. Although many people use and advocate for the use of sensory-based treatments and there is a substantial empirical literature on sensory-based treatments for children with disabilities, insufficient evidence exists to support their use. PMID- 25460223 TI - Motor imagery for walking: a comparison between cerebral palsy adolescents with hemiplegia and diplegia. AB - The goal of the study was to investigate whether motor imagery (MI) could be observed in cerebral palsy (CP) participants presenting a bilateral affected body side (diplegia) as it has been previously revealed in participants presenting a unilateral body affected sided (hemiplegia). MI capacity for walking was investigated in CP adolescents diagnosed with hemiplegia (n=10) or diplegia (n=10) and in adolescents with typical motor development (n=10). Participants were explicitly asked to imagine walking before and after actually walking toward a target located at 4 m and 8 m. Movement durations for executed and imagined trials were recorded. ANOVA and Pearson's correlation analyses revealed the existence of time invariance between executed and imagined movement durations for the control group and both groups of CP participants. However, results revealed that MI capacity in CP participants was observed for the short distance (4 m) but not for the long distance (8 m). Moreover, even for short distance, CP participants performed worse than typical adolescents. These results are discussed inline of recent researches suggesting that MI in CP participants may not depend on the side of the lesion. PMID- 25460222 TI - Lexical access in children with hearing loss or specific language impairment, using the cross-modal picture-word interference paradigm. AB - In this study we compared lexical access to spoken words in 25 deaf children with cochlear implants (CIs), 13 hard-of-hearing (HoH) children and 20 children with specific language impairment (SLI). Twenty-one age-matched typically developing children served as controls. The children with CIs and the HoH children in the present study had good speech perception abilities. We used a cross-modal picture word interference paradigm to examine lexical access. Results showed that children with SLI revealed overall slower reaction times and produced more errors than the children with CIs, the HoH children, and the control children. Reaction times of children with CIs and the HoH children did not differ from those of the control children. Thus, problems with spoken language processing, as is the case in children with SLI, seem to affect lexical access more than limitations in auditory perception, as is the fundamental problem in children with hearing loss. We recommend that improvement of lexical access in children with SLI deserves specific attention in therapy and education. PMID- 25460224 TI - Predictors of participation change in various areas for preschool children with cerebral palsy: a longitudinal study. AB - This study identifies potential predictors of participation changes in various areas for preschool children with cerebral palsy (CP). Eighty children with CP (2 6 years) were enrolled. Seven potential predictors were identified: age; sex; socioeconomic status, CP subtype; cognitive function, Function Independence Measure for Children (WeeFIM), and motor composite variable from 5 motor factors (gross motor function classification system (GMFCS) level; bimanual fine motor function level; selective motor control score; Modified Ashworth Scale score; and Spinal Alignment and Range of Motion Measure). Outcome was assessed at baseline and at 6-month follow-up using the Assessment of Preschool Children's Participation (APCP) including diversity and intensity scores in the areas of play (PA), skill development (SD), active physical recreation, social activities (SA), and total areas. Dependent variables were change scores of APCP scores at baseline and 6-month follow-up. Regression analyses shows age and sex together predicted for APCP-total, APCP-SD diversity and APCP-total intensity changes (r(2)=0.13-0.25, p<0.001); cognitive function and WeeFIM were negative predictors for APCP-SA and APCP-PA diversity changes, respectively. CP subtype, motor composite variable, and socioeconomic status predicted for APCP changes in some areas. Findings suggest that young boys with poor cognitive function and daily activity predicted most on participation changes. PMID- 25460225 TI - Profiles of visual perceptual functions in Down syndrome. AB - The primary purpose of this study was to investigate the visual perceptual functions measured by the Test of Visual Perceptual Skill-Third Edition (TVPS-3) in Down syndrome (DS). Seventy individuals with DS, seventy with typical development (TD), and forty mental-age-matched participants with intellectual disabilities (ID) were recruited for the assessment session. Significant between group differences in TVPS-3 were observed between either DS or ID and TD groups. There was no significant difference on TVPS-3 between DS and ID groups. Implications for clinical professionals and recommendations for further research are discussed. PMID- 25460226 TI - Predictors for the benefit of selective dorsal rhizotomy. AB - Selective dorsal rhizotomy (SDR) is a spasticity reducing treatment option for children with spastic cerebral palsy. Selection criteria for this procedure are inconclusive to date. Clinical relevance of the achieved functional improvements and side effects like the negative impact on muscle strength are discussed controversially. In this prospective cohort study one and two year results of 54 children with a mean age of 6.9 (+/-2.9) years at the time of SDR are analyzed with regard to gross motor function and factors affecting the functional benefit. Only ambulatory children who were able to perform a gross motor function measure test (GMFM-88) were included in this study. Additionally, the modified Ashworth scale (MAS), a manual muscle strength test (MFT), and the body mass index (BMI) were evaluated as possible outcome predictors. MAS of hip adductors and hamstrings decreased significantly (p<0.001) and stayed reduced after two years, while GMFM improved significantly from 79% to 84% 12 months after SDR (p<0.001) and another 2% between 12 and 24 months (p=0.002). Muscle strength did improve significantly concerning knee extension (p=0.008) and ankle dorsiflexion (p=0.006). The improvement of function correlated moderately with age at surgery and preoperative GMFM and weakly with the standard deviation score of the BMI, the dorsiflexor and plantarflexor strength preoperatively as well as with the reduction of spasticity of the hamstrings and the preoperative spasticity of the adductors and hamstrings. Correctly indicated SDR reduces spasticity and increases motor skills sustainably in children with spastic cerebral palsy corresponding to clinically relevant changes of GMFM without compromising muscular strength. Outcome correlates to GMFM and age rather than to MAS and maximal strength testing. The data of this evaluation suggest that children who benefit the most from SDR are between 4 and 7 years old and have a preoperative GMFM between 65% and 85%. PMID- 25460227 TI - Test driving ToxCast: endocrine profiling for 1858 chemicals included in phase II. AB - Identifying chemicals, beyond those already implicated, to test for potential endocrine disruption is a challenge and high throughput approaches have emerged as a potential tool for this type of screening. This review focused the Environmental Protection Agency's (EPA) ToxCast(TM) high throughput in vitro screening (HTS) program. Utility for identifying compounds was assessed and reviewed by using it to run the recently expanded chemical library (from 309 compounds to 1858) through the ToxPi(TM) prioritization scheme for endocrine disruption. The analysis included metabolic and neuroendocrine targets. This investigative approach simultaneously assessed the utility of ToxCast, and helped identify novel chemicals which may have endocrine activity. Results from this exercise suggest the spectrum of environmental chemicals with potential endocrine activity is much broader than indicated, and that some aspects of endocrine disruption are not fully covered in ToxCast. PMID- 25460229 TI - Phylogeny of five species of Nusuttodinium gen. nov. (Dinophyceae), a genus of unarmoured kleptoplastidic dinoflagellates. AB - Cells of five unarmoured kleptoplastidic dinoflagellates, Amphidinium latum, Amphidinium poecilochroum, Gymnodinium amphidinioides, Gymnodinium acidotum and Gymnodinium aeruginosum were observed under light and/or scanning electron microscopy and subjected to single-cell PCR. The SSU rDNA and the partial LSU rDNA of all the examined species were sequenced, and the SSU rDNA of G. myriopyrenoides was sequenced. Phylogenetic analyses revealed that the unarmoured kleptoplastidic species formed a monophyletic clade within the Gymnodinium-clade sensu Daugbjerg et al. (2000). The sister taxa for this clade were Gymnodinium palustre and Spiniferodinium galeiforme, both of which possess brown-coloured chloroplasts. The results indicated that acquisition of kleptoplastidy in these unarmoured dinoflagellates was a single event and that these unarmoured kleptoplastidic dinoflagellates may have evolved from a form with permanent chloroplasts. Molecular trees suggested that the acquisition of kleptoplastidy took place in a marine habitat and later some species colonized the freshwater habitat. Because these unarmoured kleptoplastidic dinoflagellates are monophyletic and characterized by distinct morphological and cytological features (including the presence of the same type of apical groove, absence of nuclear chambers in the nuclear envelope, absence of genuine chloroplasts, and the possession of kleptochloroplasts), we propose the establishment of a new genus, Nusuttodinium, to accommodate all these dinoflagellates. PMID- 25460228 TI - Transgenerational effects of obesogens and the obesity epidemic. AB - In the last three decades there has been a dramatic, worldwide increase in the incidence of obesity, particularly in Western societies. This trend has required a significant economic investment to treat obesity-related disorders such as type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. There is an urgent need to understand the factors that contribute to this increase in obesity in order to find new tools that will improve quality of life in affected individuals and to avoid the propagation of obesity to future generations. Endocrine disrupting chemicals have become an important piece of the obesity epidemic puzzle but little is known about the mechanism underlying their effects. In this commentary, we highlight recent work showing that the consequences of ancestral exposure to obesogenic chemicals results in the transmission of obesity related phenotypes through at least three generations. PMID- 25460232 TI - Phylogeny, ultrastructure, and flagellar apparatus of a new Marimonad flagellate Abollifer globosa sp. nov. (Imbricatea, Cercozoa). AB - Abollifer is a little-known genus of marine heterotrophic flagellates with no ultrastructural and molecular information, and its taxonomic position remains uncertain. In this study, we report a new species of Abollifer, Abollifer globosa sp. nov., isolated from a seawater sample collected at Tokyo Bay. To reveal the taxonomic position and morphological characteristics of A. globosa, we performed light and electron microscopic observations and a phylogenetic analysis using small subunit ribosomal DNA sequences. A. globosa cells were 29.5 MUm in length and 22.4 MUm in width, oval or ovoid in shape with an apical projection. Two unequal flagella emerged from a deep subapical flagellar pit. The rim of the flagellar pit except for the ventral side was swollen. Electron microscopic observations showed that A. globosa possessed mitochondria with tubular cristae, a Golgi apparatus, microbodies, extrusomes, and many endosymbiotic bacteria. Basal bodies were arranged in parallel. The flagellar apparatus of A. globosa showed affinity with common gliding cercozoan flagellates. Our phylogenetic tree showed that A. globosa branched as the sister position of order Marimonadida (Imbricatea, Cercozoa). On the basis of the morphological and molecular phylogenetic analysis, we conclude that A. globosa is a new member of the order Marimonadida. PMID- 25460230 TI - Formal revision of the Alexandrium tamarense species complex (Dinophyceae) taxonomy: the introduction of five species with emphasis on molecular-based (rDNA) classification. AB - The Alexandrium tamarense species complex is one of the most studied marine dinoflagellate groups due to its ecological, toxicological and economic importance. Several members of this complex produce saxitoxin and its congeners - potent neurotoxins that cause paralytic shellfish poisoning. Isolates from this complex are assigned to A. tamarense, A. fundyense, or A. catenella based on two main morphological characters: the ability to form chains and the presence/absence of a ventral pore between Plates 1' and 4'. However, studies have shown that these characters are not consistent and/or distinctive. Further, phylogenies based on multiple regions in the rDNA operon indicate that the sequences from morphologically indistinguishable isolates partition into five clades. These clades were initially named based on their presumed geographic distribution, but recently were renamed as Groups I-V following the discovery of sympatry among some groups. In this study we present data on morphology, ITS/5.8S genetic distances, ITS2 compensatory base changes, mating incompatibilities, toxicity, the sxtA toxin synthesis gene, and rDNA phylogenies. All results were consistent with each group representing a distinct cryptic species. Accordingly, the groups were assigned species names as follows: Group I, A. fundyense; Group II, A. mediterraneum; Group III, A. tamarense; Group IV, A. pacificum; Group V, A. australiense. PMID- 25460233 TI - Kentomonas gen. n., a new genus of endosymbiont-containing trypanosomatids of Strigomonadinae subfam. n. AB - Compared to their relatives, the diversity of endosymbiont-containing Trypanosomatidae remains under-investigated, with only two new species described in the past 25 years, bringing the total to six. The possible reasons for such a poor representation of this group are either their overall scarcity or susceptibility of their symbionts to antibiotics that are traditionally used for cultivation of flagellates. In this work we describe the isolation, cultivation, as well as morphological and molecular characterization of a novel endosymbiont harboring trypanosomatid species, Kentomonas sorsogonicus sp. n. The newly erected genus Kentomonas gen. n. shares many common features with the genera Angomonas and Strigomonas, such as the presence of an extensive system of peripheral mitochondrial branches distorting the corset of subpellicular microtubules, large and loosely packed kinetoplast, and a rudimentary paraflagellar rod. Here we also propose to unite all endosymbiont-bearing trypanosomatids into the new subfamily Strigomonadinae subfam. n. PMID- 25460234 TI - Genus Gambierdiscus in the Canary Islands (NE Atlantic Ocean) with description of Gambierdiscus silvae sp. nov., a new potentially toxic epiphytic benthic dinoflagellate. AB - Species of the dinoflagellate genus Gambierdiscus are the cause of Ciguatera Fish Poisoning, common in tropical areas. Nevertheless, until recently this syndrome was not reported in the NE Atlantic Ocean. A new photosynthetic dinoflagellate species, Gambierdiscus silvae sp. nov. is described based on samples taken from tide pools on rocky shores of the Canary Islands (NE Atlantic Ocean). Its morphology was studied by light and scanning electron microscopy. The new species is anterioposteriorly compressed, lenticular in shape with an epitheca slightly higher than the hypotheca. It is round in apical view and has a thick smooth theca with many scattered pores. Plate formula is Po, 4', 0a, 6", 6c, 6s?, 5'", 0p, 2"". Plate 2' is hatchet-shaped and Plate 2"" is very wide and the largest of the hypotheca. Phylogenies inferred from the large subunit nuclear rRNA showed that three G. silvae strains clustered in a well supported sister clade to G. polynesiensis, distinct from the other species. G. australes was observed for the first time in the Atlantic, together with G. excentricus already reported from these islands. This work increases the number of Gambierdiscus species described and shows their unexpected diversity in the Canary Islands. PMID- 25460235 TI - Dracomyxa pallida gen. et sp. nov.: a new giant freshwater foraminifer, with remarks on the taxon Reticulomyxidae (emend.). AB - Reticulomyxids are organotrophic freshwater foraminifers typically placed within the radiation of early monothalamous Foraminifera. Though ubiquitous, reticulomyxids are rarely reported, which may be due both to their concealed life style and to inappropriate isolation techniques. Their taxonomic position is largely based on developmental stages of the life cycle. Here, we describe a new freshwater species, Dracomyxa pallida gen. nov. et sp. nov., isolated from submersed plant material. It has two possible life cycles including small cells, large plasmodia and encysted stages. Both types of development occur simultaneously in cultures derived from a single cell as well as in crude cultures. We amplified and sequenced a short sequence fragment of the 18S rRNA gene of the new isolate. Comparative phylogenetic analysis and molecular characterization indicate that it is a new reticulomyxid species, with Reticulomyxa filosa Nauss, Haplomyxa saranae Dellinger and Wobo gigas Hulsmann as the closest relatives. Unique features such as tripodal pediculated cysts and the lack of cleansing process justify the erection of a new genus. PMID- 25460236 TI - EEG manifestations of nondual experiences in meditators. AB - The holistic experiential benefits of meditation among a widely ranging population have been well established within the empirical literature. What remain less clear are the underlying mechanisms of the meditative process. A large impediment to this clarity is attributable to the lack of a unified and comprehensive taxonomy, as well as to the absence of clear differentiation within the literature between method of practice and resulting state. The present study discusses and then attempts to identify within our sample a theoretically universal culminating meditative state known as Nondual Awareness, which is differentiated from the method or practice state. Participants completed an in lab meditation, during which neurological patterns were analyzed using electroencephalography (EEG). Analyses indicated significantly higher EEG power among slower wave frequencies (delta, theta, alpha) during the reported nondual events. These events appear neurologically distinct from meditation sessions as a whole, which interestingly demonstrated significant elevation within the gamma range. PMID- 25460237 TI - The relation between verbal and visuospatial memory and autobiographical memory. AB - The basic-systems approach (Rubin, 2005, 2006) states that autobiographical memory is supported by other cognitive systems and argues that autobiographical memories are constructed from interactions between cognitive systems, such as language, vision and emotion. Although deficiencies in one or more of the basic systems influence the properties of autobiographical memories, little is known about how these cognitive abilities and autobiographical memory are related. To assert whether participants with stronger cognitive abilities also perform better on autobiographical memory tests, participants who completed verbal and visuospatial memory tests also recorded one personal event, which they recalled after a certain interval. Participants who performed well on the verbal memory tests also had better retention for the personal event, providing support for the basic-systems approach to autobiographical memory and preliminary support for the view that people have more memories from adolescence and early adulthood because the memory system works optimally in these lifetime periods. PMID- 25460238 TI - Minding the interpersonal gap: mindfulness-based interventions in the prevention of ostracism. AB - Ostracism is a ubiquitous phenomenon, occurring across a broad range of social contexts and detrimentally impacting personal outcomes. Through enhanced present moment attention and awareness, mindfulness-based interventions may help prevent this harmful behavior. The current research examined the role of state mindfulness in reducing the propensity to commit ostracism. This relationship was investigated in two studies: a field-based quasi-experiment (Study 1, n=51) and a laboratory-based experiment (Study 2, n=100). Both studies supported the utility of brief mindfulness-based interventions in reducing the propensity to ostracize others. The current studies support the relevance of mindfulness in addressing the substantial problem of ostracism. Among other benefits, fostering mindfulness in a variety of contexts may help reduce personal and social costs associated with this type of incivility. This research represents the first known attempt to utilize a personal resource (mindfulness) to decrease the degree to which individuals ostracize others. PMID- 25460239 TI - Unconscious context-specific proportion congruency effect in a stroop-like task. AB - Cognitive control is a central topic of interest in psychology and cognitive neuroscience and has traditionally been associated with consciousness. However, recent research suggests that cognitive control may be unconscious in character. The main purpose of our study was to further explore this area of research focusing on the possibly unconscious nature of the conflict adaptation effect, specifically the context-specific proportion congruency effect (CSPCE), by using a masked Stroop-like task where the proportion of congruency was associated to various masks. We used electrophysiological measures to analyze the neural correlates of the CSPCE. Results showed evidence of an unconscious CSPCE in reaction times (RTs) and the N2 and P3 components. In addition, the P2 component evoked by both target and masks indicated that the proportion of congruency was processed earlier than the congruency between the color word and the ink color of the target. Taken together, our results provided evidence pointing to an unconscious CSPCE. PMID- 25460240 TI - Invisible collinear structures impair search. AB - Visual attention and perceptual grouping both help us from being overloaded by the vast amount of information, and attentional search is delayed when a target overlaps with a snake-like collinear distractor (Jingling & Tseng, 2013). We assessed whether awareness of the collinear distractor is required for this modulation. We first identified that visible long (=9 elements), but not short (=3 elements) collinear distractor slowed observers' detection of an overlapping target. Then we masked part of a long distractor (=9 elements) with continuous flashing color patches (=6 elements) so that the combined dichoptic percept to observers' awareness was a short collinear distractor (=3 elements). We found that the invisible collinear parts, like visible ones, can form a continuous contour to impair search, suggesting that conscious awareness is not a pre requisite for contour integration and its interaction with selective attention. PMID- 25460241 TI - Exploring the boundary conditions of unconscious numerical priming effects with continuous flash suppression. AB - The scope and limits of unconscious processing are a controversial topic of research in experimental psychology. Particularly within the visual domain, a wide range of paradigms have been used to experimentally manipulate perceptual awareness. A recent study reported unconscious numerical processing during continuous flash suppression (CFS), which is a powerful variant of interocular suppression and disrupts the conscious perception of visual stimuli for up to seconds. Since this finding of a distance-dependent priming effect contradicts earlier results showing that interocular suppression abolishes semantic processing, we sought to investigate the boundary conditions of this effect in two experiments. Using statistical analyses and experimental designs that precluded an effect of target numerosity, we found evidence for identity priming, but no conclusive evidence for distance-dependent numerical priming under CFS. Our results suggest that previous conclusions on high-level numerical priming under interocular suppression may have been premature. PMID- 25460242 TI - Beyond visual imagery: how modality-specific is enhanced mental imagery in synesthesia? AB - Synesthesia based in visual modalities has been associated with reports of vivid visual imagery. We extend this finding to consider whether other forms of synesthesia are also associated with enhanced imagery, and whether this enhancement reflects the modality of synesthesia. We used self-report imagery measures across multiple sensory modalities, comparing synesthetes' responses (with a variety of forms of synesthesia) to those of non-synesthete matched controls. Synesthetes reported higher levels of visual, auditory, gustatory, olfactory and tactile imagery and a greater level of imagery use. Furthermore, their reported enhanced imagery is restricted to the modalities involved in the individual's synesthesia. There was also a relationship between the number of forms of synesthesia an individual has, and the reported vividness of their imagery, highlighting the need for future research to consider the impact of multiple forms of synesthesia. We also recommend the use of behavioral measures to validate these self-report findings. PMID- 25460243 TI - Mindfulness meditation and relaxation training increases time sensitivity. AB - Two experiments examined the effect of mindfulness meditation and relaxation on time perception using a temporal bisection task. In Experiment 1, the participants performed a temporal task before and after exercises of mindfulness meditation or relaxation. In Experiment 2, the procedure was similar than that used in Experiment 1, except that the participants were trained to mediate or relax every day over a period of several weeks. The results showed that mindfulness meditation exercises increased sensitivity to time and lengthened perceived time. However, this temporal improvement with meditation exercises was primarily observed in the experienced meditators. Our results also showed the experienced meditators were less anxious than the novice participants, and that the sensitivity to time increased when the level of anxiety decreased. Our results were explained by the practice of mindfulness technique that had developed individuals' abilities in devoting more attention resources to temporal information processing. PMID- 25460244 TI - The pre-reflective experience of "I" as a continuously existing being: the role of temporal functional binding. AB - The present moment is of infinitesimally brief duration. In the brain, however, there are perceptual processes that bind together events occurring at different times, on a time scale of milliseconds, into a coherent and integrated temporal representation. These processes include temporal integration, as in perception of biological motion, synchronisation, and change detection. These processes are also responsible for temporal integration and coherence in inner mental life, such as in mental imagery. I argue that this gives rise to the pre-reflective experience of the self as a continuously existing being. Temporal integration is also a feature of the experience of action-outcome relations, and I argue that this produces a pre-reflective experience of the self, not just as continuously existing, but also as the doer of both physical and mental actions. This is the foundation on which the idea of the self as continuously existing on longer time scales--the narrative self--is built. PMID- 25460245 TI - Can the exploration of left space be induced implicitly in unilateral neglect? AB - The purpose of the present study was to explore the ability of neglect patients to detect and exploit the predictive value of a cue to respond more quickly and accurately to targets on their contralesional side in a Posner spatial cueing task. The majority of the cues (i.e. 80%) were invalid, indicating that the target would appear on the opposite side, although patients were not informed of this bias. Our results demonstrate that some neglect patients were able to extract the cue's predictability and use it to orient faster toward the left. This cueing effect was present even in patients who were subsequently unable to describe the predictive character of the cues, and thus was not modulated by reportable awareness of the cue-target relation. PMID- 25460246 TI - Lmx1a enhances the effect of iNSCs in a PD model. AB - Lmx1a plays a central role in the specification of dopaminergic (DA) neurons, which potentially could be employed as a key factor for trans-differentiation to DA neurons. In our previous study, we have converted somatic cells directly into neural stem cell-like cells, namely induced neural stem cells (iNSCs), which further can be differentiated into subtypes of neurons and glia in vitro. In the present study, we continued to test whether these iNSCs have therapeutic effects when transplanted into a mouse model of Parkinson's disease (PD), especially when Lmx1a was introduced into these iNSCs under a Nestin enhancer. iNSCs that over expressed Lmx1a (iNSC-Lmx1a) gave rise to an increased yield of dopaminergic neurons and secreted a higher level of dopamine in vitro. When transplanted into mouse models of PD, both groups of mice showed decreased ipsilateral rotations; yet mice that received iNSC-Lmx1a vs. iNSC-GFP exhibited better recovery. Although few iNSCs survived 11weeks after transplantation, the improved motor performance in iNSC-Lmx1a group did correlate with a greater tyrosine hydroxylase (TH) signal abundance in the lesioned area of striatum, suggesting that iNSCs may have worked through a non-autonomous manner to enhance the functions of remaining endogenous dopaminergic neurons in brain. PMID- 25460247 TI - Kruppel-like factor 5 is essential for proliferation and survival of mouse intestinal epithelial stem cells. AB - Kruppel-like factor 5 (KLF5) is a pro-proliferative transcription factor that is expressed in dividing epithelial cells of the intestinal crypt. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) has been identified as a stem cell marker in both small intestinal and colonic epithelial cells. To determine whether KLF5 regulates proliferation of intestinal stem cells, we investigated the effects of Klf5 deletion specifically from the intestinal stem cells in adult mice. Mice with inducible intestinal stem cell-specific deletion of Klf5 (Lgr5-Klf5(fl/fl)) were injected with tamoxifen for 5 consecutive days to induce Lgr5-driven Cre expression. Intestinal and colonic tissues were examined by immunohistochemistry at various time points up to 112days following start of tamoxifen treatment. Klf5 is co-localized in the crypt-based columnar (CBC) cells that express Lgr5. By 11days following the start of tamoxifen treatment, Lgr5 positive crypts from which Klf5 was deleted exhibited a loss of proliferation that was accompanied by an increase in apoptosis. Beginning at 14days following the start of tamoxifen treatment, both Klf5 expression and proliferation were re established in the transit-amplifying epithelial cells but not in the Lgr5 positive CBC cells. By 112days post-treatment, up to 90% of the Lgr5-positive cells from which Klf5 was deleted were lost from the intestinal crypts. These results indicate a critical role for KLF5 in the survival and maintenance of intestinal stem cells. PMID- 25460249 TI - Interrupted inferior vena cava in fetuses with omphalocele. Case series of fetuses referred for fetal echocardiography and review of the literature. AB - OBJECTIVES: Congenital heart disease is reported in 15-45% of omphalocele cases. Associated abnormalities of systemic veins have occasionally been reported in children and rarely documented in the fetus. We report a case series of interrupted inferior vena cava (Int-IVC) in association with omphalocele and review the literature. METHODS: From our fetal database we identified all cases of omphalocele referred for fetal echocardiography (FE) between 1997 and 2012. We reviewed pre and postnatal medical records and performed a literature search from 1975 to present to identify previous relevant publications. RESULTS: Of 9627 fetuses referred for FE, 34 had an omphalocele. Gestational age at FE was 17(+6) to 26(+4)weeks. Seven of the 34 fetuses were shown to have an Int-IVC with azygos continuation to a right-sided superior vena cava (SVC). The heart was structurally normal in all but one case. The abdominal wall defect was large and contained liver in all. There were three fetal demises and one neonatal death. Three cases were operated successfully. Since 1975, we identified 12 publications reporting omphalocele with systemic venous abnormalities. Abnormal IVC angulation may lead to surgical complications. Failure of IVC formation is likely to be a developmental rather than a situs abnormality. Int-IVC with a dilated azygos influences venous access and may predispose to venous thrombosis. CONCLUSION: We have documented an association between large omphalocele and Int-IVC with azygos continuation to the SVC. In this small series, this did not have surgical implications. It will however, influence route of any future cardiac catheterisation and may have long-term implications. PMID- 25460248 TI - Satellite cells from dystrophic muscle retain regenerative capacity. AB - Duchenne muscular dystrophy is an inherited disorder that is characterized by progressive skeletal muscle weakness and wasting, with a failure of muscle maintenance/repair mediated by satellite cells (muscle stem cells). The function of skeletal muscle stem cells resident in dystrophic muscle may be perturbed by being in an increasing pathogenic environment, coupled with constant demands for repairing muscle. To investigate the contribution of satellite cell exhaustion to this process, we tested the functionality of satellite cells isolated from the mdx mouse model of Duchenne muscular dystrophy. We found that satellite cells derived from young mdx mice contributed efficiently to muscle regeneration within our in vivo mouse model. To then test the effects of long-term residence in a dystrophic environment, satellite cells were isolated from aged mdx muscle. Surprisingly, they were as functional as those derived from young or aged wild type donors. Removing satellite cells from a dystrophic milieu reveals that their regenerative capacity remains both intact and similar to satellite cells derived from healthy muscle, indicating that the host environment is critical for controlling satellite cell function. PMID- 25460250 TI - Effect of gestation length on the levels of five innate defence proteins in human milk. AB - BACKGROUND: Human milk contains a range of host defence proteins that appear to contribute to health and wellbeing, but their variability in abundance among individuals has not been very well characterised. Milk from mothers of premature infants has altered composition, but the effect of gestation length on the host defence properties of milk is not known. A study was therefore undertaken to determine the variability and effect of gestation length on the abundance of five host-defence proteins in milk; lactoferrin, secretory IgA, IgG, secretory component, and complement C3. METHODS: Milk was obtained from 30 mothers at their second and fifth week of lactation. These were from three groups of ten mothers having had very premature (V; 28-32 weeks gestation), premature (P; 33-36 weeks) or full term deliveries (T; 37-41 weeks). The concentration of each of the five proteins was measured in each milk sample by either ELISA or quantitative western blotting. RESULTS: The concentration of IgG, and complement C3 ranged 22- and 17 fold respectively between mothers, while lactoferrin, secretory IgA, and secretory component ranged 7-, 9-, and 4-fold, respectively. The V group had significantly lower concentrations of four of the five proteins, the exception being IgG. Levels of these four proteins also decreased between weeks 2 and 5 of lactation in the P and T groups. Significant correlation was found between the concentrations of the host defence proteins within individual mothers, indicating some degree of co-ordinate regulation. CONCLUSIONS: Mothers vary widely in the levels of host defence proteins in milk. Very short gestation length results in decreased abundance of host-defence proteins in milk. This may have functional implications for very premature infants. PMID- 25460251 TI - Maternal nativity and sleep-related infant injury deaths in New York City. AB - BACKGROUND: Half of all births in New York City are to women born outside of the United States whose infant care practices may differ from official recommendations from the American Academy of Pediatrics. These infants have an overall lower infant mortality rate than those of their US-born counterparts. AIMS: The aims of this study were to examine sleep-related infant injury death, a leading cause of infant mortality, and its risk factors among infants of US-born and foreign-born women in a large, diverse urban area. STUDY DESIGN: Data for 344 infant death cases from medical examiner and vital statistics records were analyzed. Rate ratios and 95% CIs, calculated with Poisson regression models, were used to quantify differences in death rates by maternal and infant characteristics. Bivariate and logistic regression analyses were used to examine differences within the sample of sleep-related infant injury deaths. OUTCOME MEASURES: The outcome measures were rate of sleep-related injury death, and behavioral risk factors associated with these deaths: unsafe sleep positioning, bed-sharing, and excess bedding. RESULTS: US-born mothers had a sleep-related infant injury death rate that was over three times that of foreign-born mothers, even when controlling for maternal race/ethnicity, education, and age. However, adverse sleep-related practices were not consistently more prevalent among US born infants in the sample of deaths, even when controlling for those same demographic factors. CONCLUSIONS: The higher rate of sleep-related infant injury death among infants of US-born mothers may be explained by more complex socio demographic factors, or factors outside of infant sleep practices. PMID- 25460252 TI - Infants of opioid-dependent mothers: neurodevelopment at six months. AB - OBJECTIVE: The aim of this study is to describe infant neurodevelopment in 81 infants of methadone-prescribed opioid-dependent mothers. METHODS: Griffith MD scores at six months. RESULTS: Scores were lower in all domains compared to controls (p<0.001). Poly-drug exposed infants and those treated for neonatal abstinence syndrome performed significantly poorer (p=0.002 and p=0.008 respectively). CONCLUSIONS: Infants of methadone-maintained opioid-dependent mothers show poorer neurodevelopment at six months of age than non-drug exposed comparison infants. Developmental difficulties are confounded by delayed visual development. PRACTICE IMPLICATIONS: These highly vulnerable children merit close surveillance throughout infancy. SUMMARY: Griffith MD scores at six months in 81 infants born to methadone-prescribed opioid-dependent mothers were lower in all domains compared to controls (p<0.001). Poly-drug exposed infants and those treated for neonatal abstinence syndrome performed significantly poorer (p=0.002 and p=0.008 respectively). Co-existing visual problems were common. PMID- 25460253 TI - Spatial working memory and attention skills are predicted by maternal stress during pregnancy. AB - INTRODUCTION: Experimental evidence in rodents shows that maternal stress during pregnancy (MSDP) negatively impacts spatial learning and memory in the offspring. We aim to investigate the association between MSDP (i.e., life events) and spatial working memory, as well as attention skills (attention shifting and attention focusing), in humans. The moderating roles of child sex, maternal anxiety during pregnancy and postnatal care are also investigated. METHODS: Participants were 236 mother-child dyads that were followed from the second trimester of pregnancy until 4 years postpartum. Measurements included questionnaires and independent observations. RESULTS: MSDP was negatively associated with attention shifting at 18 months when concurrent maternal anxiety was low. MSDP was associated with poorer spatial working memory at 4 years of age, but only for boys who experienced poorer postnatal care. CONCLUSION: Consistent with results observed in rodents, MSDP was found to be associated with spatial working memory and attention skills. These results point to postnatal care and maternal anxiety during pregnancy as potential targets for interventions that aim to buffer children from the detrimental effects of MSDP. PMID- 25460255 TI - Very preterm infants show earlier emergence of 24-hour sleep-wake rhythms compared to term infants. AB - BACKGROUND: Previous studies show contradictory results about the emergence of 24 h rhythms and the influence of external time cues on sleep-wake behavior in preterm compared to term infants. AIMS: To examine whether very preterm infants (<32 weeks of gestational age) differ in their emergence of the 24-h sleep-wake rhythm at 5, 11 and 25 weeks corrected age compared to term infants and whether cycled light conditions during neonatal intermediate care affects postnatal 24-h sleep-wake rhythms in preterm infants. STUDY DESIGN: Prospective cohort study with nested interventional trial. SUBJECTS: 34 preterm and 14 control term infants were studied. During neonatal hospitalization, preterm infants were randomly assigned to cycled light [7 am-7 pm lights on, 7 pm-7 am lights off, n=17] or dim light condition [lights off whenever the child is asleep, n=17]. OUTCOME MEASURES: Sleep and activity behavior recorded by parental diary and actigraphy at 5, 11 and 25 weeks corrected age. RESULTS: Sleep at nighttime and the longest consolidated sleep period between 12 pm-6 am was longer (mixed model analysis, factor group: p=0.02, resp. p=0.01) and activity at nighttime was lower (p=0.005) at all ages in preterm compared to term infants. Cycled light exposed preterm infants showed the longest nighttime sleep duration. Dim light exposed preterm infants were the least active. CONCLUSIONS: Preterm infants show an earlier emergence of the 24-h sleep-wake rhythm compared to term infants. Thus, the length of exposure to external time cues such as light may be important for the maturation of infant sleep-wake rhythms. Trial registry number: This trial has been registered at www.clinicaltrials.gov (identifier NCT01513226). PMID- 25460254 TI - Safety of milrinone use in neonatal intensive care units. AB - BACKGROUND: Milrinone use in the neonatal intensive care unit has increased over the last 10 years despite a paucity of published safety data in infants. We sought to determine the safety of milrinone therapy among infants in the neonatal intensive care unit. METHODS: We conducted a retrospective data analysis, identifying all infants who were exposed to milrinone and discharged from 322 neonatal intensive care units managed by the Pediatrix Medical Group from 1997 2010. We identified adverse events (AEs) during milrinone exposure. The unit of observation for clinical AEs was the first course of milrinone and for laboratory AEs it was an infant-day of exposure to milrinone. RESULTS: Overall, 1446 of 716,821 (0.2%) infants received milrinone for a total of 6894 infant-days. The proportion of infants exposed to milrinone increased from 0 in 1997 to 4/1000 infant cases in 2010. Persistent pulmonary hypertension (40%) was the most commonly reported diagnosis at the start of milrinone administration. Overall, 606/1446 (42%) of infants had at least 1 clinical AE recorded during milrinone therapy. Hypotension requiring pressors and thrombocytopenia (<100,000/mm(3)) were the most commonly reported clinical and laboratory AEs, respectively. Death was reported in 8% of infants during the first course of milrinone therapy. CONCLUSION: Among infants hospitalized in the neonatal intensive care unit, there was an increase in the use of milrinone over the past 13 years. The safety, dosing, and efficacy of milrinone in infants should be determined in prospective clinical trials. PMID- 25460256 TI - Prenatal testosterone and stuttering. AB - BACKGROUND: The prevalence of stuttering is much higher in males compared to females. The biological underpinnings of this skewed sex-ratio is poorly understood, but it has often been speculated that sex hormones could play an important role. AIMS: The present study investigated a potential link between prenatal testosterone and stuttering. Here, an indirect indicator of prenatal testosterone levels, the Digit Ratio (2D:4D) of the hand, was used. As numerous studies have shown, hands with more "male" characteristics (putatively representing greater prenatal testosterone levels) are characterized by a longer ring finger compared to the index finger (represented as a lower 2D:4D ratio) in the general population. STUDY DESIGN, SUBJECTS, OUTCOME MEASURES: We searched for differences in the 2D:4D ratios between 38 persons who stutter and 36 persons who do not stutter. In a second step, we investigated potential links between the 2D:4D ratio and the multifaceted symptomatology of stuttering, as measured by the Overall Assessment of the Speaker's Experience of Stuttering (OASES), in a larger sample of 44 adults who stutter. RESULTS: In the first step, no significant differences in the 2D:4D were observed between individuals who stutter and individuals who do not stutter. In the second step, 2D:4D correlated negatively with higher scores of the OASES (representing higher negative experiences due to stuttering), and this effect was more pronounced for female persons who stutter. CONCLUSIONS: The findings indicate for the first time that prenatal testosterone may influence individual differences in psychosocial impact of this speech disorder. PMID- 25460258 TI - Evaluation of a brief 4-session psychoeducation procedure for high worriers based on the mood-as-input hypothesis. AB - BACKGROUND & OBJECTIVES: Given the ubiquity of worrying as a consuming and distressing activity at both clinical and sub-clinical levels, it is important to develop theory-driven procedures that address worrying and allow worriers to manage this activity. This paper describes the development and testing of a psychoeducation procedure based on mood-as-input hypothesis, which is a transdiagnostic model that describes a proximal mechanism for perseverative worrying. The study used nonclinical participants meeting IAPT criteria indicating GAD symptomatology. METHODS: In 4 sessions, participants in experimental groups received psychoeducation about the basic principles of the mood-as-input hypothesis and received guidance on how to identify and change worry-relevant goal-directed decision rules and negative moods. Participants in the psychoeducation conditions were compared with participants in a befriending control group. RESULTS: Psychoeducation about the model significantly reduced PSWQ scores at follow-up compared with the befriending control condition (a between-groups large effect size, Cohen's d = 1.05), and the homework tasks undertaken by the psychoeducation groups raised mood and reduced worry immediately. At follow up 48.2% of participants in the psychoeducation groups were below the recommended cut-off for identifying GAD symptomatology compared with 20% of participants in the control condition. LIMITATIONS: This study was conducted on a small sample, high-worry student population, without a formal diagnosis. CONCLUSIONS: This brief, low-intensity procedure is potentially adaptable to online or self-help procedures, and can be integrated into fuller cognitive therapy packages. PMID- 25460257 TI - Developmental outcomes of early-identified children who are hard of hearing at 12 to 18 months of age. AB - AIMS: To examine the developmental outcomes of early-identified children who are hard of hearing, at 12 to 18 months of age, compared to those for children of similar age with normal hearing; and to investigate parent and child factors that are associated with these developmental outcomes. METHODS: As part of a prospective study, 28 children with mild to severe hearing loss between the ages of 12 and 18 months and 42 children with normal hearing of similar age completed a comprehensive assessment battery. All children with hearing loss were identified by newborn hearing screening and amplified, on average, by 5 months of age. Outcome measures included: Mullen Scales of Early Learning; Preschool Language Scale-4th Ed; MacArthur-Bates Communicative Development Inventory; Infant-Toddler Social and Emotional Assessment; Vineland Adaptive Behavior Scales, Second Edition; Parenting Stress Index-Short Form; and Maternal Self Efficacy Scale. RESULTS: Children with hearing loss scored comparably to children with normal hearing on select outcome measures, with mean scores for both groups falling within normal limits. Greater maternal self-efficacy was associated with children's better language skills, adaptive behavior, social-emotional competence, and fewer problem behaviors. CONCLUSION: Very young children with mild to severe hearing loss, who are identified early and provided prompt intervention that includes amplification, can demonstrate age appropriate development in multiple domains. Results also underscore the significance of parenting factors, especially perceived maternal self-efficacy, in relation to positive developmental outcomes for these children early in life. PMID- 25460259 TI - Fear reactivation prior to exposure therapy: does it facilitate the effects of VR exposure in a randomized clinical sample? AB - BACKGROUND AND OBJECTIVES: The current study is the first to examine whether reactivation of fear memory prior to exposure therapy reduces relapse in a randomized clinical sample. METHODS: In a standardized treatment protocol combining virtual reality and in-vivo exposure, patients underwent a fear reactivation procedure using a virtual spider 10 min prior to a virtual reality (VR) exposure (reactivation group: RG, n = 15). A control group (CG, n = 17) was exposed to a virtual plant 10 min prior to the VR exposure. Outcome measures were a VR spontaneous recovery test (SRT) and in-vivo a behavioral avoidance test assessed 24 h after VR exposure. One week later an in-vivo exposure session followed. Additionally, a follow-up using psychometric assessment was conducted six months after the first session. RESULTS: Both groups benefitted significantly and equally from the combined treatment, and importantly, the SRT revealed no return of fear in both groups. Furthermore, follow-up tests showed long-term treatment effects with no group differences. LIMITATIONS: Due to different study components (VR treatment and in-vivo), we were not able to determine which treatment module was mainly responsible for the long-term treatment effect. Furthermore, no direct measure of memory destabilization was possible in this study. CONCLUSIONS: Our treatment package was highly effective in reducing phobic fear up to 6 months following treatment. Explicit fear reactivation prior to exposure was not beneficial in VR exposure treatment, possibly due to a failure to induce a memory destabilization or due to an implicit fear reactivation prior to treatment in both groups. PMID- 25460260 TI - Reappraisal facilitates extinction in healthy and socially anxious individuals. AB - BACKGROUND AND OBJECTIVES: Cognitive behavioral therapy (CBT) combines cognitive restructuring with exposure to feared stimuli in the treatment of anxiety disorders. Due to the complexities of cognition-emotion interactions during ongoing CBT, the underlying mechanisms remain unclear, which hinders treatment optimization. METHODS: We created a laboratory analogue by combining reappraisal, a key ingredient of cognitive restructuring, with Pavlovian conditioning, a key ingredient in behavioral treatments. The novel differential Pavlovian acquisition and extinction task featured social stimuli as conditioned and unconditioned stimuli under unregulated and reappraisal instructions. RESULTS: Findings indicated that reappraising the conditioned stimuli attenuated acquisition (Study 1) and facilitated extinction (Study 2) of conditioned negative valence. In Study 3, highly socially anxious individuals showed deficient extinction learning relative to low socially anxious individuals but compensated for this by using reappraisal. LIMITATIONS: Diagnostic status of participants was not assessed in structured clinical interviews. CONCLUSIONS: Reappraisal of feared stimuli could be useful in prevention and treatment of social anxiety. PMID- 25460261 TI - The effects of preventive and restorative safety behaviors on a single-session of exposure therapy for contamination fear. AB - BACKGROUND AND OBJECTIVES: Recent research suggests that safety behaviors (SB) may not preclude treatment gains in exposure-based therapy for obsessive compulsive disorder. However, it is relatively unknown what specific types of SBs may be detrimental to the therapeutic process, with some arguing that SBs be classified based on their function. The current study sought to examine the extent to which different SBs enhanced or weakened symptoms of contamination fear during a single session of exposure. METHODS: Sixty-seven non-clinical students were randomly assigned to one of three conditions: (1) exposure with no SBs (NSB), (2) exposure with preventive SBs (PSB), or (3) exposure with restorative SBs (RSB). RESULTS: Among the primary outcome measures, greater reductions in fear and behavioral avoidance were found for RSB in comparison to PSB, and the gains made by RSB were generalizable to other sources of potential contamination. Furthermore, RSB resulted in more rapid reductions in fear and disgust across repeated exposure trials. LIMITATIONS: Limitations include the use of a nonclinical student sample. CONCLUSIONS: Overall, the current study suggests that RSB may be beneficial as an adjunct to therapy whereas PSB are potentially detrimental. Results of the study are discussed in terms of exposure theories and the treatment of anxiety disorders. PMID- 25460262 TI - Attention bias to emotional information in children as a function of maternal emotional disorders and maternal attention biases. AB - BACKGROUND AND OBJECTIVES: Children of parents with emotional disorders have an increased risk for developing anxiety and depressive disorders. Yet the mechanisms that contribute to this increased risk are poorly understood. The present study aimed to examine attention biases in children as a function of maternal lifetime emotional disorders and maternal attention biases. METHODS: There were 134 participants, including 38 high-risk children, and their mothers who had lifetime emotional disorders; and 29 low-risk children, and their mothers without lifetime emotional disorders. Mothers and children completed a visual probe task with emotional face pairs presented for 500 ms. RESULTS: Attention bias in children did not significantly differ solely as a function of whether or not their mothers had lifetime emotional disorders. However, attention bias in high-risk children was significantly related to their mothers' attention bias. Specifically, children of mothers with lifetime emotional disorders showed a greater negative attention bias if their mothers had a greater tendency to direct attention away from positive information. LIMITATIONS: This study was cross sectional in nature, and therefore unable to assess long-term predictive effects. Also, just one exposure duration of 500 ms was utilised. CONCLUSION: Attention bias for negative information is greater in offspring of mothers who have lifetime emotional disorders and a reduced positive bias, which could be a risk marker for the development of emotional disorders in children. PMID- 25460263 TI - "Don't put me down but don't be too nice to me either": fear of positive vs. negative evaluation and responses to positive vs. negative social-evaluative films. AB - BACKGROUND AND OBJECTIVES: The bivalent fear of evaluation (BFOE) model suggests that fears of negative evaluation (FNE) and positive evaluation (FPE) are distinct features in social anxiety disorder as well as in non-clinical variations of social anxiety. The constructs can be measured utilizing the Brief Fear of Negative Evaluation Scale - Revised (BFNE-R) and the Fear of Positive Evaluation Scale (FPES), respectively. Whereas the distinction between FNE and FPE has been well examined in survey studies, concomitant evidence from laboratory tasks is scarce. METHODS: The present study tested whether subjective unpleasantness responses to short films simulating positive and negative evaluation from others are related to individual differences in FNE and FPE. Ninety-eight unselected individuals watched 24 short films displaying actors expressing positive, negative and neutral sentences and rated their responses on unpleasantness. Furthermore, pride responses to positive films were examined since these can be expected to discriminate between FPE and FNE. RESULTS: As expected, higher BFNE-R scores were related to more unpleasant responding to negative films, whereas higher FPES scores were related to more unpleasant responding to positive films. Furthermore, experience of pride following positive films correlated positively with BFNE-R, but negatively with FPES scores. LIMITATIONS: Participants were university students which limits representativeness. CONCLUSIONS: The study revealed that measures of FNE and FPE show distinct relationships with positive and negative social feedback which provides further evidence for the BFOE model in a laboratory setting. PMID- 25460264 TI - Behavioral activation in acute inpatient psychiatry: a multiple baseline evaluation. AB - BACKGROUND AND OBJECTIVES: The present study employed a multiple baseline study design with repeated measures to explore clinical outcomes, therapy mechanisms, and feasibility of Behavioral Activation for persons admitted to inpatient psychiatry. METHODS: Six adult inpatients with depressive symptoms and different psychiatric disorders were randomized to different lengths of baseline standard inpatient treatment. Subsequently a 5-day, 10-session Behavioral Activation protocol was added. Daily self-report outcome and process measures were administered and supplemented with hourly self-reports and clinician assessments before and after each study phase. RESULTS: After a relatively stable baseline, at least four participants showed marked gradual improvements both in terms of outcome as well as activation and avoidance as Behavioral Activation was initiated. The temporal relation between process and outcome differed somewhat across metrics. In most instances however, change in activation and avoidance either coincided or preceded decreased depression. LIMITATIONS: We did not include some relatively common disorders, did not control for the effects of increased attention, did not investigate treatment integrity, and did not conduct follow-up after discharge. Raters were not blind and measures were mainly focused on depressive symptoms. All received concurrent medical treatment. CONCLUSIONS: This preliminary study further supports the promise of Behavioral Activation as an inpatient treatment for persons with a variety of psychiatric disorders. Results also lends preliminary support for the purported mechanisms of Behavioral Activation. PMID- 25460265 TI - Delaying in vivo exposure to a tarantula with very brief exposure to phobic stimuli. AB - BACKGROUND AND OBJECTIVES: Research has documented the very brief exposure (VBE) effect: the reduction of phobic fear by continuous presentation of masked phobic pictures. In prior studies, phobic participants approached a live tarantula immediately after the masked stimuli were presented. This study tested the hypothesis that VBE would reduce phobic avoidance of the tarantula 24 h later. METHOD: 86 spider-phobic participants were identified with a fear questionnaire and Behavioral Avoidance Test (BAT) with a live tarantula indicative of a DSM-IV diagnosis of Specific Phobia. One week later, they were randomly assigned in double-blind fashion to presentation of a continuous series of 25 trials of masked images of either spiders or flowers (33-ms each), i.e., to VBE or control exposure. The participants gave subjective distress ratings just before and after these exposures. Then they engaged in the BAT again either immediately thereafter or 24 h later to measure changes in avoidance of the tarantula. RESULTS: Masked images of spiders reduced avoidance of the tarantula both immediately after exposure and 24 h later without causing subjective distress. The effect sizes at these two time points did not significantly differ from each other. LIMITATIONS: We did not manipulate awareness of the spider images by presenting them unmasked to a third group. Conclusions about the effect of awareness of the stimuli cannot be drawn. CONCLUSIONS: VBE induces a process of fear reduction before phobic individuals engage in in vivo exposure, which is more distressing. Thus, VBE may help phobic-resistant individuals start treatment more gradually. PMID- 25460266 TI - The impact of emotions on body-Focused repetitive behaviors: evidence from a non treatment-seeking sample. AB - Body-focused repetitive behaviors (BFRBs) are repetitive, injurious, and non functional habits that cause significant distress or impairment, including hair pulling, skin-picking, and nail-biting. The emotion regulation (ER) model suggests that BFRBs are triggered by negative emotions and reinforced by alleviation of unpleasant affect. The frustrated action (FA) model suggests that BFRBs are triggered by and alleviate impatience, boredom, frustration, and dissatisfaction. Individuals with BFRBs are hypothesized to be particularly susceptible to these emotions because they demonstrate maladaptive planning styles characterized by high standards and unwillingness to relax. OBJECTIVES: The objective of this study was to test these two models. METHODS: This study compared urge to engage in BFRBs in a BFRB group (n = 24) and a control group (n = 23) in experimental conditions designed to elicit boredom/frustration, stress, and relaxation, respectively. RESULTS: The BFRB group reported a significantly greater urge to engage in BFRBs than did the control group across conditions. Participants in the BFRB group reported a stronger urge to engage in BFRBs in the boredom/frustration condition than in the relaxation condition but not in the stress condition. Finally, the BFRB group presented significantly higher scores on maladaptive planning style, and maladaptive planning style was significantly correlated with difficulties with ER. LIMITATIONS: Future studies may wish to exclusively use validated mood induction techniques and more stringent inclusion criteria. CONCLUSIONS: The results highlight the role of boredom, frustration, and impatience in triggering BFRBs, and support the FA model. PMID- 25460267 TI - Using delay discounting to understand impulsive choice in socially anxious individuals: failure to replicate. AB - BACKGROUND AND OBJECTIVES: Impulsive choice that follows transient anxiety responses is a potentially important outcome that may underlie maladaptive behavioral patterns that co-occur with high levels of social anxiety. However, little research has examined impulsive choice in relation to social anxiety. Rounds, Beck and Grant (2007; Behavior Research and Therapy, 45, 729-735) found that high social anxiety was associated with impulsive choice using a delay discounting procedure, but only in a non-threatening (control) condition, but several procedural confounds in that study may also explain the findings. The purpose of this study was to replicate Rounds et al. while controlling for potential procedural confounds. METHODS: High- and low-social anxiety adult college-students with no substance abuse history were assigned randomly to a public speaking condition or a control (silent reading) condition. In the middle of the task, participants completed a measure of delay discounting, which measures impulsive choice. RESULTS: Impulsive choice was not influenced by either social anxiety status or experimental condition. LIMITATIONS: Other aspects of impulsive choice may be more sensitive to transient anxiety and fear. Higher state levels of social anxiety and transient anxiety may be necessary to detect a significant relationship with impulsive choice. Relatively high levels of impulsive responding may only occur in socially anxious individuals with current/historical substance abuse. CONCLUSIONS: Neither anxiogenic laboratory procedures nor social anxiety status appear to influence impulsive choice as measured by the delay discounting task. Future research might consider examining whether transient anxiety influences other aspects of impulsive choice. PMID- 25460268 TI - Enhanced association between perceptual stimuli and trauma-related information in individuals with posttraumatic stress disorder symptoms. AB - BACKGROUND AND OBJECTIVES: Intrusive memories in traumatized individuals are often triggered by stimuli that are perceptually (rather than conceptually) similar to those present just before or during the trauma. The present study examined whether those individuals with high levels of Posttraumatic Stress Disorder (PTSD) symptoms show a memory bias recall to perceptual cues and trauma target words compared to those with low levels of PTSD. METHODS: The sample consisted of 30 adult participants who were involved in motor-vehicle or work related accidents; 15 of the participants endorsed clinically elevated symptoms of PTSD, while a comparison group of 15 participants reported low levels of symptoms. Participants performed an associative recognition task with conceptual or perceptual cue words and trauma-related or neutral target words. Participants were tested for their recognition accuracy by reporting the corresponding target when a cue was given. RESULTS: Both groups performed better for the perceptual word pairs than for the conceptual word pairs, irrespective of the target word type. However, only the high PTSD symptoms group exhibited an additional enhancement in performance for the perceptual word pairs with trauma-related target words. LIMITATIONS: A nonclinical sample was utilized for this study; although PTSD was assessed, diagnoses were not confirmed. In addition, there was lack of a healthy non-traumatized control group. CONCLUSIONS: These results provide partial support for the cognitive model and the notion that intrusive memories are specific to the trauma-related event rather than to a general associative learning bias. PMID- 25460270 TI - Arf GTPases and their effectors: assembling multivalent membrane-binding platforms. AB - Arf GTPases are major regulators of membrane traffic and organelle structure in eukaryotes where they recruit many different effectors, including components of vesicular coats, proteins that tether membranes, sort lipids or have diverse other functions in vesicular traffic, and bacterial proteins that divert Arf functions in host cells. A dozen of structures of unrelated effectors bound to Arf1, Arf6 or their close relative Arl1 are available, revealing that Arf GTPases do not recognize preferred structures in their effectors. In contrast, a trait common to many Arf/effector complexes is that they are juxtaposed to membranes by multiple protein/membrane contacts, yet of diverse sizes, shapes and physicochemistry. The common function of Arf GTPases thus appears to be their ability to assemble versatile, multivalent membrane-binding platforms, resulting in optimal orientation and allosteric regulation of their effectors leading to a plethora of membrane-localized functions. PMID- 25460269 TI - Structure and mechanism of lanthipeptide biosynthetic enzymes. AB - Lanthipeptides are members of the ribosomally synthesized and post translationally modified peptide (RiPP) natural products. They contain thioether crosslinks generated by dehydration of Ser and Thr residues followed by the addition of the thiol of Cys residues to the dehydroamino acids. Recent studies have revealed unexpected mechanisms of the post-translational modifications, and structural studies have started to provide insights into recognition of the peptide substrates by the modification enzymes. PMID- 25460271 TI - Extracellular modulators of Wnt signalling. AB - Wnt morphogens are secreted signalling proteins that play leading roles in embryogenesis and tissue homeostasis throughout life. Wnt signalling is controlled by multiple mechanisms, including posttranslational modification of Wnts, antagonist binding (to Wnts or their receptors), and regulation of the availability of Wnt receptors. Recent crystallographic, structure-guided biophysical and cell-based studies have advanced our understanding of how Wnt signalling is regulated at the cell surface. Structures include Wnt in complex with the cysteine-rich domain (CRD) of Frizzled, extracellular fragments of Wnt co-receptor LRP6, LRP6-binding antagonists Dickkopf and Sclerostin, antagonists 5T4/WAIF1 and Wnt inhibitory factor 1 (WIF-1), as well as Frizzled-ubiquitin ligases ZNRF3/RNF43 (in isolation and in complexes with Wnt signalling promoters R-spondins and LGR5). We review recent discoveries and remaining questions. PMID- 25460272 TI - Architecture and signal transduction mechanism of the bacterial chemosensory array: progress, controversies, and challenges. AB - Recent research has deepened our understanding of the ancient, conserved chemosensory array that detects small molecule attractants and repellents, and directs the chemotaxis of bacterial and archaeal cells towards an optimal chemical environment. Here we review advances towards a molecular description of the ultrastable lattice architecture and ultrasensitive signal transduction mechanism of the chemosensory array, as well as controversies and challenges requiring further research. Ultimately, a full molecular understanding of array structure and on-off switching will foster (i) the design of novel therapies that block pathogenic wound seeking and infection, (ii) the development of highly specific, sensitive, stable biosensors, and (iii) the elucidation of general functional principles shared by receptor patches in all branches of life. PMID- 25460273 TI - Putting together structures of epidermal growth factor receptors. AB - Numerous crystal structures have been reported for the isolated extracellular region and tyrosine kinase domain of the epidermal growth factor receptor (EGFR) and its relatives, in different states of activation and bound to a variety of inhibitors used in cancer therapy. The next challenge is to put these structures together accurately in functional models of the intact receptor in its membrane environment. The intact EGFR has been studied using electron microscopy, chemical biology methods, biochemically, and computationally. The distinct approaches yield different impressions about the structural modes of communication between extracellular and intracellular regions. They highlight possible differences between ligands, and also underline the need to understand how the receptor interacts with the membrane itself. PMID- 25460274 TI - The structural biology of patellamide biosynthesis. AB - The biosynthetic pathways for patellamide and related natural products have recently been studied by structural biology. These pathways produce molecules that have a complex framework and exhibit a diverse array of activity due to the variability of the amino acids that are found in them. As these molecules are difficult to synthesize chemically, exploitation of their properties has been modest. The patellamide pathway involves amino acid heterocyclization, peptide cleavage, peptide macrocyclization, heterocycle oxidation and epimerization; closely related products are also prenylated. Enzyme activities have been identified for all these transformations except epimerization, which may be spontaneous. This review highlights the recent structural and mechanistic work on amino acid heterocyclization, peptide cleavage and peptide macrocyclization. This work should help in using the enzymes to produce novel analogs of the natural products enabling an exploitation of their properties. PMID- 25460275 TI - Marvels of enzyme catalysis at true atomic resolution: distortions, bond elongations, hidden flips, protonation states and atom identities. AB - Although general principles of enzyme catalysis are fairly well understood nowadays, many important details of how exactly the substrate is bound and processed in an enzyme remain often invisible and as such elusive. In fortunate cases, structural analysis of enzymes can be accomplished at true atomic resolution thus making possible to shed light on otherwise concealed fine structural traits of bound substrates, intermediates, cofactors and protein groups. We highlight recent structural studies of enzymes using ultrahigh resolution X-ray protein crystallography showcasing its enormous potential as a tool in the elucidation of enzymatic mechanisms and in unveiling fundamental principles of enzyme catalysis. We discuss the observation of seemingly hyper reactive, physically distorted cofactors and intermediates with elongated scissile substrate bonds, the detection of 'hidden' conformational and chemical equilibria and the analysis of protonation states with surprising findings. In delicate cases, atomic resolution is required to unambiguously disclose the identity of atoms as demonstrated for the metal cluster in nitrogenase. In addition to the pivotal structural findings and the implications for our understanding of enzyme catalysis, we further provide a practical framework for resolution enhancement through optimized data acquisition and processing. PMID- 25460276 TI - PIKKs--the solenoid nest where partners and kinases meet. AB - The recent structure of a truncated mTOR in a complex with mLST8 has provided a basic framework for understanding all of the phosphoinositide 3-kinase (PI3K) related kinases (PIKKs): mTOR, ATM, ATR, SMG-1, TRRAP and DNA-PK. The PIKK kinase domain is encircled by the FAT domain, a helical solenoid that is present in all PIKKs. PIKKs also have an extensive helical solenoid N-terminal to the FAT domain for which there is limited structural information. This N-terminal helical solenoid is essential for binding proteins that associate with the PIKKs to regulate their activity and cellular localization. PMID- 25460277 TI - Resonant marker design and fabrication techniques for device visualization during interventional magnetic resonance imaging. AB - Magnetic resonance imaging (MRI) has great potential as an imaging modality for guiding minimally invasive interventions because of its superior soft tissue contrast and the possibility of arbitrary slice positioning while avoiding ionizing radiation and nephrotoxic iodine contrast agents. The major constraints are: limited patient access, the insufficient assortment of compatible instruments and the difficult device visualization compared to X-ray based techniques. For the latter, resonant MRI markers, fabricated by using the wire winding technique, have been developed. This fabrication technique serves as a functional model but has no clinical use. Thus, the aim of this study is to illustrate a four-phase design process of resonant markers involving microsystems technologies. The planning phase comprises the definition of requirements and the simulation of electromagnetic performance of the MRI markers. The following technologies were considered for the realization phase: aerosol-deposition process, hot embossing technology and thin film technology. The subsequent evaluation phase involves several test methods regarding electrical and mechanical characterization as well as MRI visibility aspects. The degree of fulfillment of the predefined requirements is determined within the analysis phase. Furthermore, an exemplary evaluation of four realized MRI markers was conducted, focusing on the performance within the MRI environment. PMID- 25460278 TI - A proposal for patient-tailored supervision of movement performance during end effector-based robot-assisted rehabilitation of the upper extremities. AB - Millions of people worldwide suffer from stroke each year. One way to assist patients cost-effectively during their rehabilitation process is using end effector-based robot-assisted rehabilitation. Such systems allow patients to use their own movement strategies to perform a movement task, which encourages them to do self-motivated training but also allow compensation movements if they have problems executing the movement tasks. Therefore, a patient supervision system was developed on the basis of inertial measurement units and a patient-tailored movement interpretation system. Very light and small inertial measurement units were developed to record the patients' movements during a teaching phase in which the desired movement is shown to the patient by a physiotherapist. During a following exercise phase, the patient is training the previously shown movement alone with the help of an end-effector-based robot-assisted rehabilitation system, and the patient's movement is recorded again. The data from the teaching and exercise phases are compared with each other and evaluated by using fuzzy logic tailored to each patient. Experimental tests with one healthy subject and one stroke patient showed the capability of the system to supervise patient movements during the robot-assisted end-effector-based rehabilitation. PMID- 25460279 TI - Gastroschisis: incidence and prediction of growth restriction. AB - AIMS: Fetuses with gastroschisis are at increased risk of intrauterine growth restriction (IUGR). However, there is a tendency for underestimation of fetal abdominal circumference and hence fetal weight, leading to overdiagnosis of IUGR. Our objective was to evaluate the accuracy of ultrasound for the prediction of being small for gestational age (SGA) at birth in these cases. METHODS: A retrospective study of prenatally diagnosed cases of gastroschisis was conducted at a tertiary center. Fetal weight was estimated using the formula of Hadlock. IUGR was defined as an estimated fetal weight <=10th percentile for gestational age. SGA at the time of birth was defined as a birth weight <=10th percentile for gestational age. The incidence of IUGR on last ultrasound and that of SGA at birth were calculated, and the precision of ultrasound in predicting SGA was determined. RESULTS: IUGR was reported on the last ultrasound prior to delivery in 9/25 cases (36%). Postnatally, 13/25 newborns (52%) were SGA. All sonographically suspected cases of IUGR based on the last ultrasound were SGA at birth. The positive predictive value of the last ultrasound in identifying SGA was 100%. CONCLUSIONS: At least half of the infants affected by gastroschisis were SGA at birth. Sonographic estimation of fetal weight within 1 month of birth reliably predicted SGA in infants with gastroschisis. PMID- 25460280 TI - Effects of lifetime tobacco, alcohol and drug use on psychological and behavioral problems among 10th grade students in Istanbul. AB - AIMS: The aim of this study was to determine the effects of life-time tobacco, alcohol, and substance use on psychological and behavioral variables among 10th grade students in Istanbul/Turkey. MATERIALS AND METHODS: This study employed a cross-sectional online self-report survey conducted in 45 schools from the 15 districts in Istanbul. The questionnaire featured a section about use of substances, including tobacco, alcohol, and drugs. The depression, anxiety, anger, assertiveness, sensation seeking and impulsiveness subscales of the Psychological Screening Test for Adolescents (PSTA) were used. The analyses were conducted based on 4957 subjects. RESULTS: Logistic regression analyses were conducted with each school with the related and behavioral variables as the dependent variables. Gender, tobacco, alcohol, and drug use being the independent variables. All four independent variables predicted the dependent variables. Lifetime tobacco and drug use had significant effects on all the subscale score, whereas lifetime alcohol use had significant effects on all the subscale scores other than lack of assertiveness, and male gender was a significant covariant for all the subscale scores. Drug use showed the highest effect on dependent variables. Interaction was found between effects of tobacco and alcohol on anxiety, whereas interactions were found between effects of tobacco and drugs on lack of assertiveness and impulsiveness. CONCLUSION: The findings suggested that male students with lifetime tobacco, alcohol or drug use have particularly high risk of psychological and behavioral problems. The unique effects of substance clusters on these problems may be useful in developing secondary preventive practices for substance use and abuse problems in Istanbul. PMID- 25460281 TI - Exposing young people to cooking and new foods: findings from a feasibility study in an alternative education setting. AB - OBJECTIVE: The current study describes a feasibility study of an experiential cooking program for alternative education students. The aims were to identify potential areas for measuring impact (beyond nutrition) and to identify issues threatening the feasibility and evaluation of the program. MATERIALS AND METHODS: Weekly cooking sessions were conducted in one alternative education center over a school term. Data were collected through weekly observations, a youth focus group, and staff interview. RESULTS: Observational data confirmed high levels of participation by students, willingness to try new foods, and enjoyment of foods prepared. Comments from the teacher and students emphasized the wider impact of the cooking sessions on positive youth development and cultural engagement, including opportunities for socio-emotional learning, team work, socializing with peers, and cultural blessings of food. CONCLUSION: Future studies should consider measures of positive youth development along with cooking skills and eating behaviors as potential outcomes. PMID- 25460282 TI - Longitudinal changes in C-reactive protein, proform of eosinophil major basic protein, and pregnancy-associated plasma protein-A during weight changes in obese children. AB - BACKGROUND: Childhood obesity is associated with several complications, including cardiovascular comorbidity. Several biomarkers, such as high-sensitive C-reactive protein (hs-CRP), proform of eosinophil major basic protein (Pro-MBP) and pregnancy associated plasma protein-A (PAPP-A), have equally been linked to increased cardiovascular susceptibility. This study investigates these biomarkers during weight loss and regain in obese children. MATERIALS AND METHODS: A longitudinal study during a 12-week weight loss program with a 28 months follow up was conducted. Anthropometrics and plasma concentrations of hs-CRP, Pro-MBP, and PAPP-A were measured at baseline; at days 14, 33 and 82 during weight loss; and at months 10, 16, and 28 during follow-up. RESULTS: Fifty-three boys and 62 girls aged 8-15 years with a median body mass index (BMI) standard deviation score (SDS) at baseline of 2.78 (boys), and 2.70 (girls) were included. Ninety children completed the weight loss program and 68 children entered the follow-up program. Pro-MBP and PAPP-A, but not hs-CRP, exhibited individual-specific levels (tracking) during weight loss and regain. The PAPP-A/Pro-MBP correlation was strong, whereas the hs-CRP/PAPP-A correlation was weak during weight fluctuations. CONCLUSION: Hs-CRP changes reflect weight changes. PAPP-A and Pro MBP exhibited tracking during weight perturbations and may contribute as early risk markers of cardiovascular susceptibility. PMID- 25460283 TI - Silver nanoparticles influenced rat serum metabolites and tissue morphology. AB - BACKGROUND: Silver nanoparticles (AgNPs) are increasingly and extensively being applied for biomedical purposes. However, studies on the safety/toxicity profiles of AgNPs are limited. This necessitates the further studies in this direction. Here, we studied the effect of AgNP administration on rat serum metabolites and tissue morphology. METHODS: Rats were randomly distributed into eight groups of five animals each. Oral administration of AgNPs to rats at 100, 1000, and 5000 mg/kg was done daily and carried out for 7, 14, and 21 days alternately. The control received distilled water. Animals were sacrificed under diethyl ether anesthesia 24 h after cessation of last treatments. The blood and vital organs were harvested and prepared for biochemical and histopathology examinations, respectively. RESULTS: Data revealed that AgNP administration at the different dosages caused elevated serum urea and creatinine levels. On the other hand, levels of inorganic phosphate in rat serum following administration of AgNPs were significantly (p<0.05) reduced. Also, administration at 1000 and 5000 mg/kg AgNPs in rats decreased serum levels of sodium. In contrast, AgNP administration in rats caused elevated (p<0.05) serum potassium levels. The histopathological presentations show diverse inimical alterations to cellular architecture in rats administered with AgNPs. CONCLUSIONS: We show evidence suggesting that AgNPs may have potential to adversely affect the kidney functions as well as capability to cause myriad of cellular damage. PMID- 25460285 TI - HIF1A and MIF as potential predictive mRNA biomarkers of pre-eclampsia: a longitudinal prospective study in high risk population. AB - BACKGROUND: Pre-eclampsia (PE) is a hypertensive multisystem disorder, causing significant fetal-maternal mortality and morbidity worldwide. This study aims to define possible longitudinal predictive mRNA markers involved in the main pathogenic pathways of PE: inflammation [macrophage migration inhibitory factor (MIF)], hypoxia and oxidative stress [hypoxia inducible factor 1-alpha subunit (HIF1A) and beta-site APP-cleaving enzyme-2 (BACE2)] and endothelial dysfunction [endoglin (ENG), fms-related tyrosine kinase-1 (FLT1) and vascular endothelial growth factor (VEGF)]. METHODS: Peripheral blood was collected from 33 singleton pregnancies characterized by a high cardiovascular profile risk sampled consecutively at 6-16; 17-23; 24-30; 31-34; >=35 weeks followed by the Obstetrics and Gynecology Unit of the San Raffaele Hospital in Milan. A real-time quantitative PCR reaction was performed on plasma RNA. RESULTS: Of the 33 women enrolled, nine developed PE. Until 23 weeks HIF1A was significantly higher in women who later developed PE compared to women who did not (p=0.049 and p=0.012 in the first and second blood collection). In the third time interval MIF (p=0.0005), FLT1 (p=0.024), ENG (p=0.0034) and BACE2 (p=0.044) appeared to be significantly increased while HIF1A was elevated even from 24 week onwards but not reaching the statistical significance. In the fourth time interval ENG mRNA still remained increased (p=0.037). CONCLUSIONS: HIF1A, marker of hypoxia and oxidative stress, and MIF, marker of inflammation, seemed to be the most promising RNA markers, suggesting that hypoxia, principally, and inflammation may play an important role in PE pathogenesis. PMID- 25460284 TI - Establishment of trimester-specific thyroid stimulating hormone and free thyroxine reference interval in pregnant Chinese women using the Beckman Coulter UniCelTM DxI 600. AB - BACKGROUND: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals are essential for screening and diagnosing thyroid dysfunction during pregnancy. The aim of this study was to establish method- and trimester-specific TSH and FT4 reference intervals in pregnant Chinese women using the Beckman Coulter UniCelTM DxI 600. METHODS: A cross-sectional dataset analysis was performed. A total of 3507 participants were recruited, and 2743 were eligible for analysis to set reference intervals. TSH, FT4, and thyroid peroxidase antibody (TPOAb) levels were analyzed with the Beckman Coulter UniCelTM DxI 600 Access(r) immunoassay system. Ranges between the 2.5th and 97.5th percentiles were defined as reference intervals for TSH and FT4. RESULTS: The calculated reference intervals for the first, second, and third trimesters were TSH: 0.06 3.13, 0.07-4.13 and 0.15-5.02 mIU/L, respectively, and FT4: 8.72-15.22, 7.10 13.55 and 6.16-12.03 pmol/L, respectively. CONCLUSIONS: Our reference intervals for TSH and FT4 are distinct from the ranges reported in the DxI 600 instruction manual and previously reported data, confirming the importance of method-specific reference intervals. PMID- 25460286 TI - Laboratory utilization improvement through a computer-aided algorithm developed with general practitioners. AB - BACKGROUND: One of the main duties of healthcare workers is to get an appropriate use of diagnostic and therapeutic tools. The aim of this study was to show how strategies can be designed and established in consensus with general practitioners (GPs) to reach an optimal laboratory test request. METHODS: The laboratory serves a population of approximately 235,000 inhabitants, including nine primary care centers. GPs could request every test in profiles and individually. In meetings between the laboratory and GPs our request patterns were compared to other geographic regions, and we investigated the appropriateness of test requesting. The group devised strategies that consisted of removing tests from profiles [aspartate aminotransferase (AST), gamma glutamyltranspeptidase (GGT) and phosphate], removing tests from GPs requests (iron and transferrin), substituting tests (IgA antigliadin antibody), and measuring total bilirubin (tBil) only when the icteric index value was above 34.2 mmol/L (2 mg/dL). We analyzed every test request in the post- (years 2012-2013) and pre-intervention period (years 2010-2011), and the tBil measured in the post intervention period. We studied if AST/alanine aminotransferase (ALT) and GGT/ALT achieved indicators targets and calculated the economic savings in the post intervention period. RESULTS: There was a significant drop in every test request in the post-intervention period. AST/ALT achieved the indicator target. GGT/ALT, never achieved the indicator goal. The strategies resulted in a savings of more than ?34,000. CONCLUSIONS: The strategies designed between the laboratory and the requesting clinicians and automatically established by using our laboratory information system were successful. PMID- 25460287 TI - Quantitative-fluorescent-PCR versus full karyotyping in prenatal diagnosis of common chromosome aneuploidies in southern Spain. AB - BACKGROUND: Quantitative-fluorescent polymerase chain reaction (QF-PCR) is a reliable, rapid, and economic technique for prenatal diagnosis of the most common abnormalities. However, conventional karyotyping is expensive and requires a much longer time to yield results. It is currently under debate whether the replacement or restriction of karyotyping reduces the quality of prenatal test results. This study was undertaken to determine the percentage of clinically significant chromosomal abnormalities that would not be detected if QF-PCR was the main analysis method and karyotyping reserved for cases with increased nuchal translucency (NT) and/or abnormal ultrasound findings and to estimate the difference in cost between QF-PCR and full karyotyping. METHODS: Nine hundred twenty-eight pregnant women underwent an invasive procedure at our center between May 2009 and December 2012, yielding 580 (62.5%) chorionic villous samples and 348 (37.5%) amniotic fluid samples. Samples were studied by both QF-PCR and full karyotyping. Karyotyping and detailed ultrasound findings were retrospectively analyzed. RESULTS: If QF-PCR was the main analytic method and full karyotyping reserved for cases with elevated NT (>=4.5) and/or abnormal ultrasound findings, 12.7% of the patients would have required full karyotyping, 99% of the clinically significant chromosomal abnormalities would have been detected, and the cost would have been 54% lower than a policy of full karyotyping for all. CONCLUSIONS: Detailed prenatal ultrasound scan can reduce the need for conventional karyotyping as a complement to QF-PCR in most prenatal samples, offering rapid results and reducing parental anxiety and healthcare costs. PMID- 25460288 TI - Reference interval for immature platelet fraction on Sysmex XN hematology analyzer: a comparison study with Sysmex XE-2100. AB - BACKGROUND: Recently introduced hematology analyzer, the Sysmex XN modular system (Sysmex, Kobe, Japan), has newly adopted a florescent channel to detect platelets and immature platelet fraction (IPF). This study aimed to establish new reference intervals for %-IPF and absolute number of IPF (A-IPF) on Sysmex XN. Platelet counts, %-IPF, and A-IPF were also compared between Sysmex XN and XE-2100 systems (Sysmex). METHODS: Except outliers, blood samples from 2104 healthy individuals and 140 umbilical cord blood were analyzed using both Sysmex XN and XE-2100. The results of two systems were compared using Bland-Altman plot. The reference intervals for %-IPF and A-IPF were defined using non-parametric percentile methods according to the Clinical and Laboratory Standard Institute guideline (C28-A3). RESULTS: The platelet counts, %-IPF, and A-IPF showed non-parametric distributions. The mean difference between Sysmex XN and XE-2100 in healthy individuals revealed a positive bias in platelets (+8.0*109/L), %-IPF (+1.2%), and A-IPF (+3.0*109/L). The reference intervals for %-IPF and A-IPF on Sysmex XN were: 1.0%-7.3% and 2.49-15.64*109/L in healthy individuals; and 1.0%-4.4% and 2.94-12.82*109/L in umbilical cord blood. CONCLUSIONS: This large-scale study demonstrates a clear difference of platelet counts and IPF between Sysmex XN and XE-2100. The new reference intervals for IPF on Sysmex XN would provide fundamental data for clinical practice and future research. PMID- 25460289 TI - Preface. Adiposopathy in cancer and (cardio)metabolic diseases: an endocrine approach - Part 1. PMID- 25460290 TI - Do adipose tissue macrophages promote insulin resistance or adipose tissue remodelling in humans? AB - In diet induced and genetically obese rodent models, adipose tissue is associated with macrophage infiltration, which promotes a low grade inflammatory state and the development of insulin resistance. In humans, obesity is also closely linked with macrophage infiltration in adipose tissue, a pro-inflammatory phenotype and insulin resistance. However, whether macrophage infiltration is a direct contributor to the development of insulin resistance that occurs in response to weight gain, or is a later consequence of the obese state is unclear. There are a number of concomitant changes that occur during adipose tissue expansion, including the number and size of adipocytes, the vasculature and the extracellular matrix. In this review, we will examine evidence for and against the role of macrophage recruitment into adipose tissue in promoting the development of insulin resistance in rodents and humans, as well as discuss the emerging role of macrophages in mediating healthy adipose tissue expansion during periods of caloric excess. PMID- 25460292 TI - Age-associated (cardio)metabolic diseases and cross-talk between adipose tissue and skeleton: endocrine aspects. AB - Aged individuals continue to increase in number, and it is important to understand the pathophysiological mechanisms of age-related changes in order to develop interventions that could contribute to "successful aging". Metabolic and hormonal factors, age-related changes in body composition, and a decline in physical activity are all involved in the tendency to lose muscle mass, to gain fat mass, and, also, to experience bone loss. Obesity, sarcopenia, and osteoporosis are important widespread health problems that lead to high prevalence of both mortality and morbidity. Indeed, during the last decades, obesity and osteoporosis have become a major health threat around the world. Aging increases the risk of developing obesity, sarcopenia, osteoporosis, and, also, cardiovascular diseases. A reduction of both bone and muscle mass with a corresponding increase of fat mass and inflammation and hormonal imbalance in the elderly lead to and may synergistically increase cardiovascular diseases. This review will focus on the relationship among these different medical situations, trying to clarify the cellular and molecular mechanisms. PMID- 25460293 TI - Nutrition: a promising route for prevention and management of obesity-related nonalcoholic fatty liver disease. AB - When dealing with the treatment of obesity-linked illnesses - in particular nonalcoholic fatty liver disease - beyond diet, various nutritional ingredients are reported to be useful as silymarin, spirulina, choline, folic acid, methionine and vitamin E, all of them showing promising but not definite results. An emerging field of study is represented by prebiotics/probiotics and restoration of normal gut flora, which could play a fundamental role diet and various its components. It is noteworthy to point out that both improving or reducing the severity of nonalcoholic fatty liver disease bear a positive consequence on evolution of atherosclerosis and its cardiovascular-associated disease, such as coronary artery disease, even though the involved immunologic mechanisms are gaining greater credit in the most recent literature, without excluding the role of nutrition in modulating the acquired immunity in this condition. PMID- 25460291 TI - Sex and sex steroids: impact on the kinetics of fatty acids underlying body shape. AB - Adult humans have a remarkable sexual dimorphism in body shape. Men tend to store relatively more fat in the upper body whereas women store more fat in the lower body. We do not have a complete understanding of the mechanisms underlying these differences, but we know that people who preferentially store abdominal fat are at greater risk of metabolic disease. It is also known that the changes in sex steroid concentrations during puberty and again with advancing age are accompanied by changes in body fat distribution. The objective of this review is to describe what has been learned regarding the mechanisms underlying changes in regional body fat distribution that occur as a result of changes in sex hormones and to delineate effects of sex steroids in modulating body composition. PMID- 25460294 TI - Vitamin D-mediated apoptosis in cancer and obesity. AB - Low vitamin D status has been associated with increased risk of several cancers and obesity; concurrently, obesity and cancer have been linked to impaired vitamin D status. In both cancer and obesity, selective elimination of cancer cells and adipocytes can result in decreasing tumor size and a long-term reduction in adipose tissue mass. These effects can be achieved through induction of apoptotic cell death. The vitamin D-derived hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) triggers apoptosis in epithelial cancer cells and mature adipocytes via induction of apoptotic Ca2+ signal - a sustained, prolonged increase in concentration of intracellular Ca2+. This Ca2+ signal functions as an apoptotic initiator that directly recruits apoptotic effectors, Ca2+-dependent proteases, in cancer cells and adipocytes. The 1,25(OH)2D3 - cellular Ca2+ - apoptosis link in cancer and obesity supports the rationale to include vitamin D compounds modulating intracellular Ca2+ and Ca2+-dependent apoptotic proteases as promising targets for discovery of new therapeutic and preventive agents for cancer and obesity. The concept of maintaining an increased vitamin D status for protecting against cancer and decreasing adiposity also warrants further evaluation. PMID- 25460295 TI - PPARgamma mutations, lipodystrophy and diabetes. AB - The focus of this review is the lipodystrophy syndrome caused by mutation in the PPARgamma nuclear receptor - partial familial lipodystrophy FPLD3. To provide a broader context for how these mutations act to generate the clinical features of partial lipodystrophy we will review the basic biology of PPARgamma and also survey the set PPARgamma genetic variants that do not cause lipodystrophy, but are nonetheless associated with clinically related syndromes, specifically type 2 diabetes. PMID- 25460296 TI - Acute mental feelings and professional stress are controlling health. Mechanism and role of hormones and "solvated electrons" (e(-)aq). PMID- 25460297 TI - 5alpha-Reductase inhibitors alter steroid metabolism and may contribute to insulin resistance, diabetes, metabolic syndrome and vascular disease: a medical hypothesis. AB - 5alpha-reductases, a unique family of enzymes with a wide host of substrates and tissue distributions, play a key role in the metabolism of androgens, progestins, mineralocorticoids and glucocorticoids. These enzymes are the rate-limiting step in the synthesis of a host of neurosteroids, which are critical for central nervous system function. Androgens and glucocorticoids modulate mitochondrial function, carbohydrate, protein and lipid metabolism and energy balance. Thus, the inhibition of these regulatory enzymes results in an imbalance in steroid metabolism and clearance rates, which leads to altered physiological processes. In this report, we advance the hypothesis that inhibition of 5alpha-reductases by finasteride and dutasteride alters not only steroid metabolism but also interferes with the downstream actions and signaling of these hormones. We suggest that finasteride and dutasteride inhibit 5alpha-reductase activities and reduce the clearance of glucocorticoids and mineralocorticoids, potentiating insulin resistance, diabetes and vascular disease. PMID- 25460298 TI - In women, no significant variances of calculated free testosterone (cFT) are observed when a fixed value of albumin (Alb: 4.3 g/dL) is used instead of measured albumin values. AB - BACKGROUND: Calculated free testosterone (cFT) is determined from the values of total testosterone (TT), sex hormone binding globulin (SHBG), and albumin (Alb) using mathematical formulae. We evaluated any potential cFT variance when determined with fixed Alb (4.3 g/dL) compared to measured Alb, and the point at which low SHBG and Alb combinations produced significant cFT variance. MATERIALS: We analyzed 2050 data points in 1222 women. cFT values with fixed vs. the actual measured Alb values were evaluated and contrasted. cFT levels were determined theoretically for all possible combinations of TT, SHBG, and Alb. METHODS: Agreement between the two measures was assessed with Lin's concordance coefficient. Statistical analyses were performed using R software version 2.12.1. RESULTS: Mean Alb was 4.05 +/- 0.30 g/dL. Mean SHBG 73.0 +/- 53.3 nmol/L. A fixed Alb of 4.3 g/dL produced no significant variance for most evaluations of cFT. The accuracy decreased with Alb <= 3.5 g/dL in combination with SHBG <= 30 nmol/L and exists in 1.0% of the samples. CONCLUSIONS: A fixed Alb of 4.3 g/dL is acceptable for most clinical evaluations. If Alb is <= 3.5 g/dL, along with SHBG <= 30 nmol/L, the variance increases and a free testosterone (FT) measurement by equilibrium dialysis is warranted for better accuracy. PMID- 25460299 TI - Regulation of flavin-containing mono-oxygenase (Fmo3) gene expression by steroids in mice and humans. AB - Abstract Flavin-containing mono-oxygenases (FMOs) are a family of microsomal chemical- and drug-metabolizing enzymes. FMO3 is a major FMO form in adult mouse and human liver. FMO3 mutations have been associated with the incidence and severity of trimethylaminuria (TMAU), a metabolic disorder characterized by the inability of the affected individual to metabolize the odorous trimethylamine to its non-odorous N-oxide. In addition to this primary genetic form, there are other forms of TMAU that support the hypothesis that FMO3 activity may be modulated by steroid hormones. To understand the molecular mechanism involved in the regulation of Fmo3 gene expression by steroid hormones, we performed this study in an in vitro cellular system, mouse liver cells, and on the human FMO3 gene. Dexamethasone, 5alpha-dihydrotestosterone, thyroid hormone, and progesterone had no effect on the accumulation of Fmo3 mRNA. The use of increased concentration of theophylline inhibited estrogen receptor alpha (ERalpha) mediated transcription of Fmo3 mRNA. 17beta-Estradiol inhibited Fmo3 mRNA accumulation. The use of ICI 164,384 abolished the inhibitory effect induced by estrogen. Gel-shift analyses showed a binding in the 5' region of the Fmo3 gene. This binding was abrogated by an excess of a cDNA containing an estrogen responsive element. An estrogen-binding site was also present in the first intron of the human gene, as demonstrated by the gel-shift assay. Supershift experiments confirmed the binding of ERalpha in both mouse and human samples. Furthermore, chromatin immunoprecipitation assay confirmed the binding of ERalpha in the promoter region of mouse Fmo3 and in the first intron of the human FMO3 gene. Thus, 17beta-estradiol plays a fundamental role in the regulation of Fmo3 gene transcription. PMID- 25460300 TI - Adrenocortical endocrine disruption. AB - The adrenal has been neglected in endocrine disruption regulatory testing strategy. The adrenal is a vital organ, adrenocortical insufficiency is recognised in life threatening "adrenal crises" and Addison's disease, and the consequences of off-target toxicological inhibition of adrenocortical steroidogenesis is well recognised in clinical medicine, where drugs such as aminoglutethimide and etomidate killed patients via unrecognised inhibition of adrenocortical steroidogenic enzymes (e.g. CYP11B1) along the cortisol and aldosterone pathways. The consequences of adrenocortical dysfunction during early development are also recognised in the congenital salt wasting and adrenogenital syndromes presenting neonatally, yet despite a remit to focus on developmental and reproductive toxicity mechanisms of endocrine disruption by many regulatory agencies (USEPA EDSTAC; REACH) the assessment of adrenocortical function has largely been ignored. Further, every step in the adrenocortical steroidogenic pathway (ACTH receptor, StAR, CYP's 11A1, 17, 21, 11B1, 11B2, and 3 hydroxysteroid dehydrogenase Delta4,5 isomerase) is known to be a potential target with multiple examples of chemicals inhibiting these targets. Many of these chemicals have been detected in human and wildlife tissues. This raises the question of whether exposure to low level environmental chemicals may be affecting adrenocortical function. This review examines the omission of adrenocortical testing in the current regulatory frameworks; the characteristics that make the adrenal cortex particularly vulnerable to toxic insult; chemicals and their toxicological targets within the adrenocortical steroidogenic pathways; the typical manifestations of adrenocortical toxicity (e.g. human iatrogenically induced pharmacotoxicological adrenal insufficiency, manifestations in typical mammalian regulatory general toxicology studies, manifestations in wildlife) and models of adrenocortical functional assessment. The utility of the in vivo ACTH challenge test to prove adrenocortical competency, and the H295R cell line to examine molecular mechanisms of steroidogenic pathway toxicity, are discussed. Finally, because of the central role of the adrenal in the physiologically adaptive stress response, the distinguishing features of stress, compared with adrenocortical toxicity, are discussed with reference to the evidence required to claim that adrenal hypertrophy results from stress rather than adrenocortical enzyme inhibition which is a serious adverse toxicological finding. This article is part of a special issue entitled 'Endocrine disruptors and steroids'. PMID- 25460301 TI - An efficient convergent synthesis of 1alpha,25-dihydroxy-3-epi-vitamin D2. AB - The first synthesis of 1alpha,25-dihydroxy-3-epi-vitamin D2 is described. Key steps of the synthesis entail the construction of the triene unit by a Pd catalyzed ring closure of an enol-triflate (A-ring fragment) followed by a Suzuki Miyaura coupling with a boronate (upper fragment), and the installation of the methyl group at C-24 by an SN2'-syn displacement of an allylic carbamate. This article is part of a Special Issue entitled 'SI:17th Vitamin D Workshop'. PMID- 25460304 TI - Preclinical evaluation of 89Zr-labeled human antitransferrin receptor monoclonal antibody as a PET probe using a pancreatic cancer mouse model. AB - OBJECTIVE: Pancreatic cancer is aggressive and its prognosis remains poor; thus, effective therapy is urgently needed. Transferrin receptor (TfR) is highly expressed in pancreatic cancer and is considered to be a good candidate for molecular-targeted therapy. We radiolabeled and evaluated fully human anti-TfR monoclonal antibodies as a new PET probe for evaluating the biodistribution of the anti-TfR antibody in pancreatic cancer. MATERIALS AND METHODS: TfR expression was evaluated in four human pancreatic cancer (MIAPaCa-2, PANC-1, BxPC-3, and AsPC-1) and murine A4 cell lines. The binding of 125I-labeled anti-TfR antibodies (TSP-A01, TSP-A02, TSP-A03, and TSP-A04) to MIAPaCa-2 cells was compared. 125I labeled, 67Ga-labeled, and 89Zr-labeled TSP-A01 were evaluated by cell binding, competitive inhibition, and internalization assays. Biodistribution studies of 125I-labeled and 89Zr-labeled TSP-A01 were conducted in mice bearing MIAPaCa-2 and A4 tumors. PET imaging with [89Zr]TSP-A01 was carried out. RESULTS: MIAPaCa-2 cells showed the highest TfR expression in vitro and in vivo, whereas A4 cells showed no expression. Of the four antibodies, [125I]TSP-A01 showed the highest binding to MIAPaCa-2 cells, but not to A4 cells. The dissociation constant of TSP A01 was 0.29 nmol/l. Uptake of radiolabeled TSP-A01, especially [89Zr]TSP-A01, was significantly higher in MIAPaCa-2 tumors than in A4 tumors. PET with [89Zr]TSP-A01 clearly visualized MIAPaCa-2 xenografts but not A4 xenografts. CONCLUSION: [89Zr]TSP-A01 is a promising PET probe for evaluating the accumulation of anti-TfR antibody in pancreatic cancer and has the potential to facilitate the selection of appropriate patients who would benefit from anti-TfR antibody therapy. PMID- 25460303 TI - Epistasis amongst PTPN2 and genes of the vitamin D pathway contributes to risk of juvenile idiopathic arthritis. AB - Juvenile idiopathic arthritis (JIA) is a leading cause of childhood-onset disability. Although epistasis (gene-gene interaction) is frequently cited as an important component of heritability in complex diseases such as JIA, there is little compelling evidence that demonstrates such interaction. PTPN2, a vitamin D responsive gene, is a confirmed susceptibility gene in JIA, and PTPN2 has been suggested to interact with vitamin D pathway genes in type 1 diabetes. We therefore, tested for evidence of epistasis amongst PTPN2 and the vitamin D pathway genes GC, VDR, CYP24A1, CYP2R1, and DHCR7 in two independent JIA case control samples (discovery and replication). In the discovery sample (318 cases, 556 controls), we identified evidence in support of epistasis across six gene gene combinations (e.g., GC rs1155563 and PTPN2 rs2542151, ORint=0.45, p=0.00085). Replication was obtained for three of these combinations. That is, for GC and PTPN2, CYP2R1 and VDR, and VDR and PTPN2, similar epistasis was observed using the same SNPs or correlated proxies in an independent JIA case control sample (1008 cases, 9287 controls). Using SNP data imputed across a 4 MB region spanning each gene, we obtained highly significant evidence for epistasis amongst all 6 gene-gene combinations identified in the discovery sample (p-values ranging from 5.6*10(-9) to 7.5*10(-7)). This is the first report of epistasis in JIA risk. Epistasis amongst PTPN2 and vitamin D pathway genes was both demonstrated and replicated. PMID- 25460302 TI - Targeting cancer stem cells in solid tumors by vitamin D. AB - Cancer stem cells (CSCs) are a small subset of cells that may be responsible for initiation, progression, and recurrence of tumors. Recent studies have demonstrated that CSCs are highly tumorigenic and resistant to conventional chemotherapies, making them a promising target for the development of preventive/therapeutic agents. A single or combination of various markers, such as CD44, EpCAM, CD49f, CD133, CXCR4, ALDH-1, and CD24, were utilized to isolate CSCs from various types of human cancers. Notch, Hedgehog, Wnt, and TGF-beta signalingregulate self-renewal and differentiation of normal stem cells andare aberrantly activated in CSCs. In addition, many studies have demonstrated that these stem cell-associated signaling pathways are required for the maintenance of CSCs in different malignancies, including breast, colorectal, prostate, and pancreatic cancers. Accumulating evidence has shown inhibitory effects of vitamin D and its analogs on the cancer stem cell signaling pathways, suggesting vitamin D as a potential preventive/therapeutic agent against CSCs. In this review, we summarize recent findings about the roles of Notch, Hedgehog, Wnt, and TGF-beta signaling in CSCs as well as the effects of vitamin D on these stem cell signaling pathways. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25460305 TI - Cost-effectiveness analysis of strategies introducing integrated 18F-FDG PET/CT into the mediastinal lymph node staging of non-small-cell lung cancer. AB - OBJECTIVE: The aim of the study was to establish the most cost-effective strategy for using integrated 18F-fluorodeoxyglucose PET and computed tomography (CT) for mediastinal lymph node staging (N-staging) of preoperative non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Four N-staging decision models for operative NSCLC, model A (CT only), model B (PET/CT for negative CT), model C (CT and PET/CT for all), and model D (PET/CT only), were constructed according to the Chinese edition of NCCN Clinical Practice Guidelines in Oncology Non-Small-Cell Lung Cancer and China NSCLC N-staging practices. Data including the parameters for decision models, life expectancy, and expenditures were retrieved from the literature, from websites of PET Reservation Centers, and on consultation with experts. On the basis of model A, incremental cost-effectiveness ratios were calculated for the other three models. Robustness of the result was evaluated by univariate sensitivity analysis. RESULTS: Life expectancy (years) was 2.60 for model A, 2.57 for model B, 2.67 for model C, and 2.66 for model D. The probabilities for improper therapy due to wrong staging were 36.78, 13.00, 8.91, and 12.95%, respectively. Surgical mortality rates were 1.87, 1.01, 1.13, and 1.24%, respectively. Model C, for which the incremental cost-effectiveness ratio (37 960 CNY/year) was lower than that of model D (65 175 CNY/year) and 2012 GDP per capita in China (38 459 CNY), was cost-effective and optimal, and this result was robust. CONCLUSION: Model C was the most cost-effective strategy for NSCLC N staging in the China mainland. Introduction of model C into Chinese N-staging protocols for NSCLC would be helpful for treatment selection, for reducing surgical mortality rates, and for extending life expectancy. PMID- 25460306 TI - 18F-FDG PET/CT in hepatocellular carcinoma: detection of bone metastasis and prediction of prognosis. AB - OBJECTIVE: The purpose of this study was to assess the diagnostic accuracy and prognostic value of 18F-fluorodeoxyglucose PET/computed tomography (CT) in bone metastases from hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Of 3912 consecutive HCC patients, 67 patients who had undergone both PET/CT and bone scintigraphy (BS) within a 3-month interval were evaluated. RESULTS: Bone metastases were most frequently found in the pelvis (20%), followed by the lumbar spine (14%) and long bones (13%). PET/CT was significantly more sensitive than BS in region-based analyses, with 273 confirmed bone metastases (96.7 vs. 52.7%, respectively; P<0.001), and in patient-based analyses (99 vs. 85%; P=0.042). The median survival period was 5 (range, 0.4-18) months. On univariate analysis, poor prognostic factors included age (<60 years), multiple bone metastases, lymph node metastasis, high serum alpha-fetoprotein (>=400 IU/ml), Child-Pugh class B, and high maximum standardized uptake value (SUVmax) of bone metastasis (>5.0). Large metabolic volume (>=200 cm3) of bone metastasis was another poor prognostic factor. On Cox regression analysis, high alpha-fetoprotein was the only poor prognostic factor with statistical significance. CONCLUSION: PET/CT was more sensitive than BS in bone metastasis from HCC by both patient-based and region based analyses, and offered additional information on survival. PET/CT can be helpful in early diagnosis and opportune treatment of bone metastasis from HCC. PMID- 25460307 TI - Bioinspired syntheses of dimeric hydroxycinnamic acids (lignans) and hybrids, using phenol oxidative coupling as key reaction, and medicinal significance thereof. AB - Lignans are mainly dimers of 4-hydroxycinnamic acids (HCAs) and reduced analogs thereof which are produced in Nature through phenol oxidative coupling (POC) as the primary C-C or C-O bond-forming reaction under the action of the enzymes peroxidases and laccases. They present a large structural variety and particularly interesting biological activities, therefore, significant efforts has been devoted to the development of efficient methodologies for the synthesis of lignans isolated from natural sources, analogs and hybrids with other biologically interesting small molecules. We summarize in the present review those methods which mimic Nature for the assembly of the most common lignan skeleta by using either enzymes or one-electron inorganic oxidants to effect POC of HCAs and derivatives, such as esters and amides, or cross-POC of pairs of HCAs or HCAs with 4-hydrocycinnamyl alcohols. We, furthermore, provide outlines of mechanistic schemes accounting for the formation of the coupled products and, where applicable, indicate their potential application in medicine. PMID- 25460308 TI - Novel polyprenylated phloroglucinols from Hypericum sampsonii. AB - Hypericum sampsonii Hance (Clusiaceae) is a folk medicine used in Taiwan to treat blood stasis, relieve swelling, and as an anti-hepatitis drug. Two new polyprenylated phloroglucinol derivatives, hypersampsone R (1) and hypersampsone S (2), and a known prenylated benzophenone, hyperibone K (3) were isolated from the aerial parts of H. sampsonii. Their structures were determined by extensive 1D and 2D NMR, and MS spectral analyses. PMID- 25460309 TI - Profiling of concanavalin A-binding glycoproteins in human hepatic stellate cells activated with transforming growth factor-beta1. AB - Glycoproteins play important roles in maintaining normal cell functions depending on their glycosylations. Our previous study indicated that the abundance of glycoproteins recognized by concanavalin A (ConA) was increased in human hepatic stellate cells (HSCs) following activation by transforming growth factor-beta1 (TGF-beta1); however, little is known about the ConA-binding glycoproteins (CBGs) of HSCs. In this study, we employed a targeted glycoproteomics approach using lectin-magnetic particle conjugate-based liquid chromatography-tandem mass spectrometry to compare CBG profiles between LX-2 HSCs with and without activation by TGF-beta1, with the aim of discovering novel CBGs and determining their possible roles in activated HSCs. A total of 54 and 77 proteins were identified in the quiescent and activated LX-2 cells, respectively. Of the proteins identified, 14.3% were glycoproteins and 73.3% were novel potential glycoproteins. Molecules involved in protein processing in the endoplasmic reticulum (e.g., calreticulin) and calcium signaling (e.g., 1 phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-2 [PLCB2]) were specifically identified in activated LX-2 cells. Additionally, PLCB2 expression was upregulated in the cytoplasm of the activated LX-2 cells, as well as in the hepatocytes and sinusoidal cells of liver cirrhosis tissues. In conclusion, the results of this study may aid future investigations to find new molecular mechanisms involved in HSC activation and antifibrotic therapeutic targets. PMID- 25460310 TI - New biscoumarin derivatives: synthesis, crystal structure, theoretical study and antibacterial activity against Staphylococcus aureus. AB - Five novel biscoumarins 1-5 were synthesized and characterized. In these compounds, two classical asymmetrical intramolecular O-H...O hydrogen bonds were used to stabilize the whole structures and the HB energies were performed with the density functional theory (DFT) [B3LYP/6-31G*] method. The five compounds were evaluated for their in vitro antibacterial activities against Staphylococcus aureus (S. aureus ATCC 29213), methicillin-resistant S. aureus (MRSA XJ 75302), vancomycin-intermediate S. aureus (Mu50 ATCC 700699), and USA 300 (Los Angeles County clone, LAC) by the means of minimum inhibitory concentration and time-kill curves. PMID- 25460311 TI - Isolation and characterization of a novel lectin from the edible mushroom Stropharia rugosoannulata. AB - To date, only a few steroids have been isolated from the mushroom Stropharia rugosoannulata which can be cultivated. In this paper, a novel lectin (SRL) with a molecular weight of 38 kDa, and a unique IKSGVYRIVSWQGALGPEAR N-terminal sequence was isolated from S. rugosoannulata, which represents the first protein isolated from the mushroom. The purification methods included (NH4)2SO4 precipitation, ion exchange chromatography on CM-cellulose, Q-Sepharose, and SP Sepharose, and gel- filtration on Superdex-75. The lectin was adsorbed on all three types of ion exchangers and was purified more than 450-fold. The lectin was stable below 70 degrees C (with half of the activity preserved at 80 degrees C), and in the presence of NaOH and HCl solutions up to a concentration of 12.5 mM and 25 mM, respectively. The hemagglutinating activity of SRL was inhibited by inulin. Cd2+ and Hg2+ ions strongly reduced the hemagglutinating activity at concentrations from 1.25 mM to 10 mM. SRL exhibited anti-proliferative activity toward both hepatoma Hep G2 cells and leukemia L1210 cells, with an IC50 of 7 MUM and 19 MUM, respectively. The activity of HIV-1 reverse transcriptase could also be inhibited by SRL, with an IC50 of 10 MUM. PMID- 25460312 TI - Maslinic acid induces mitochondrial apoptosis and suppresses HIF-1alpha expression in A549 lung cancer cells under normoxic and hypoxic conditions. AB - The apoptotic effects of maslinic acid (MA) at 4, 8, 16, 32 and 64 MUmol/L on human lung cancer A549 cells under normoxic and hypoxic conditions were examined. MA at 4-64 and 16-64 MUmol/L lowered Bcl-2 expression under normoxic and hypoxic conditions, respectively (p < 0.05). This agent at 4-64 MUmol/L decreased Na+-K+ ATPase activity and increased caspase-3 expression under normoxic conditions, but at 8-64 MUmol/L it caused these changes under hypoxic conditions (p < 0.05). MA up-regulated caspase-8, cytochrome c and apoptosis-inducing factor expression under normoxic and hypoxic conditions at 8-64 MUmol/L and 32-64 MUmol/L, respectively (p < 0.05). MA down-regulated hypoxia-inducible factor (HIF)-1alpha, vascular endothelial growth factor (VEGF), survivin and inducible nitric oxide synthase (iNOS) expression under normoxic and hypoxic conditions at 8-64 and 16 64 MUmol/L, respectively (p < 0.05). After cells were pre-treated with YC-1, an inhibitor of HIF-1alpha, MA failed to affect the protein expression of HIF 1alpha, VEGF, survivin and iNOS (p > 0.05). MA at 8-64 and 32-64 MUmol/L reduced reactive oxygen species and nitric oxide levels under both conditions (p < 0.05). These findings suggest that maslinic acid, a pentacyclic triterpenic acid, exerted its cytotoxic activities toward A549 cells by mediating mitochondrial apoptosis and the HIF-1alpha pathway. PMID- 25460313 TI - The epoxidation of limonene over the TS-1 and Ti-SBA-15 catalysts. AB - Limonene belongs to a group of very important intermediates used in the production of fine chemicals. This monoterpene compound can be obtained from peels of oranges or lemon which are a (biomass) waste from the orange juice industry. Thus, limonene is a renewable, easy available and a relatively cheap compound. This work presents preliminary studies on the process of limonene epoxidation over zeolite type catalysts such as: TS-1 and Ti-SBA-15. In these studies methanol was used as a solvent and as an oxidizing agent a 60 wt % hydrogen peroxide solution was applied. The activity of each catalyst was investigated for four chosen temperatures (0 degrees C, 40 degrees C, 80 degrees C and 120 degrees C). The reaction time was changed from 0.5 to 24 h. For each catalyst the most beneficial conditions (the appropriate temperature and the reaction time) have been established. The obtained results were compared and the most active catalyst was chosen. These studies have also shown different possible ways of limonene transformation, not only in the direction of 1,2 epoxylimonene and its corresponding diol, but also in direction of carveol, carvone and perillyl alcohol-compounds with a lot of applications. The possible mechanisms of formation of the allylic oxidation products were proposed. PMID- 25460314 TI - Antibacterial and EGFR-tyrosine kinase inhibitory activities of polyhydroxylated xanthones from Garcinia succifolia. AB - Chemical investigation of the methanol extract of the wood of Garcinia succifolia Kurz (Clusiaceae) led to the isolation of 1,5-dihydroxyxanthone (1), 1,7 dihydroxyxanthone (2), 1,3,7-trihydroxyxanthone (3), 1,5,6-trihydroxyxanthone (4), 1,6,7-trihydroxyxanthone (5), and 1,3,6,7-tetrahydroxyxanthone (6). All of the isolated xanthones were evaluated for their antibacterial activity against bacterial reference strains, two Gram-positive (Staphylococcus aureus ATTC 25923, Bacillus subtillis ATCC 6633) and two Gram-negative (Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853), and environmental drug-resistant isolates (S. aureus B1, Enteroccoccus faecalis W1, and E. coli G1), as well as for their epidermal growth factor receptor (EGFR) of tyrosine kinase inhibitory activity. Only 1,5,6-trihydroxy-(4), 1,6,7-trihydroxy-(5), and 1,3,6,7 tetrahydroxyxanthones (6) exhibited antibacterial activity against Gram-positive bacteria, however none was active against vancomycin-resistant E. faecalis. Additionally, 1,7-dihydroxyxanthone (2) showed synergism with oxacillin, but not with ampicillin. On the other hand, only 1,5-dihydroxyxanthone (1) and 1,7 dihydroxyxanthone (2) were found to exhibit the EGFR-tyrosine kinase inhibitory activity, with IC50 values of 90.34 and 223 nM, respectively. PMID- 25460315 TI - The azaindole framework in the design of kinase inhibitors. AB - This review article illustrates the growing use of azaindole derivatives as kinase inhibitors and their contribution to drug discovery and innovation. The different protein kinases which have served as targets and the known molecules which have emerged from medicinal chemistry and Fragment-Based Drug Discovery (FBDD) programs are presented. The various synthetic routes used to access these compounds and the chemical pathways leading to their synthesis are also discussed. An analysis of their mode of binding based on X-ray crystallography data gives structural insights for the design of more potent and selective inhibitors. PMID- 25460316 TI - Comparison between transperitoneal and extraperitoneal laparoscopic paraaortic lymphadenectomy in gynecologic malignancies. AB - STUDY OBJECTIVE: Two validated laparoscopic approaches for para-aortic lymphadenectomy (PAL) exist: the transperitoneal and the extraperitoneal. The aim of this study was to compare the surgical outcomes of both approaches. DESIGN: A retrospective review of all patients who underwent laparoscopic PAL for a gynecologic malignancy between January 2008 and October 2013. SETTING: University Hospital. PATIENTS: Two patients groups were compared: transperitoneal (n = 51) and extraperitoneal (n = 21). INTERVENTIONS: Paraaortic lymphadenectomy. MEASUREMENTS AND MAIN RESULTS: The chi(2) test, Fisher's exact test, or Student's t-test were used for univariate analysis and a stepwise logistic regression for multivariate analysis. The threshold of statistical significance was set at 0.05. All patient characteristics were similar between the 2 groups (p > .05 for all variables). There was only 1 (1.3%) conversion to laparotomy encountered in the transperitoneal PAL group and 3 conversions from extraperitoneal to transperitoneal PAL (14.2%). In 1 case of extraperitoneal PAL, the procedure was abandoned because of inadequate equipment (body mass index 48 kg/m(2)). The mean duration of surgery was longer in the transperitoneal group: 200 min (35-360) versus 125.6 min (45-180) in the extraperitoneal group (p = .001). The mean number of harvested lymph nodes was higher in the transperitoneal group: 17 (4 37) versus 13 (3-25) in the extraperitoneal group (p = .029). There was no difference in postoperative course and complications between both groups in multivariate analysis. CONCLUSIONS: In nonobese patients, the extraperitoneal PAL is associated with shorter surgical duration, whereas the transperitoneal approach was associated with a higher number of harvested lymph nodes. As a result of improved ergonomy, the transperitoneal approach enables laparoscopic management of operative complications. PMID- 25460317 TI - Power morcellation in a specimen bag. AB - STUDY OBJECTIVE: To show a technique of power morcellation within a rip-stop nylon specimen bag. DESIGN: Step-by-step explanation of the technique. BACKGROUND: The Food and Drug Administration recently warned against the use of electromechanical power morcellation for hysterectomy and myomectomy because of potential tissue dissemination within the abdomen and pelvis. If the tumor is malignant, this technique increases the staging of the patient and may further warrant re-operation and chemotherapy. If the tumor is benign, the patient is at risk for parasitic myomas that may lead to, but are not limited to, pain and/or bowel obstruction. INTERVENTION: To reduce the preceding risks, we reviewed the techniques of power morcellation within a specimen bag used by other surgeons across the United States. This technique was modified to incorporate a more durable bag made out of rip-stop nylon. Laparoscopic supracervical hysterectomy during power morcellation was performed, along with an introduction to incorporating power morcellation of multiple myomas during a laparoscopic myomectomy. CONCLUSION: This technique of power morcellation within a rip-stop nylon bag minimizes the risk of inadvertent tissue spread. This allows the patient an opportunity to undergo minimally invasive surgery for hysterectomy and myomectomy. PMID- 25460318 TI - The efficacy of laparoscopic surgical treatment of ovarian remnant and ovarian retention syndromes. AB - STUDY OBJECTIVE: To evaluate the degree of pain relief provided by laparoscopic surgical treatment of ovarian remnant and ovarian retention syndromes. DESIGN: Retrospective analysis (Canadian Task Force classification II-2). SETTING: Academic hospital and affiliated outpatient offices. PATIENTS: A total of 54 patients from 2004 to 2008 who underwent surgical treatment for suspected ovarian remnant syndrome or ovarian retention syndrome. INTERVENTIONS: Oophorectomy. MEASUREMENTS AND MAIN RESULTS: Preoperative and postoperative pain scores were recorded from patients who underwent surgical treatment for either ovarian remnant or ovarian retention syndrome. Data regarding comorbid diagnoses that would contribute to chronic abdominopelvic pain, previous surgical history, surgical complications, and pathology to confirm the preoperative diagnosis were also collected. Pathology confirmed that ovarian tissue was removed in 52 of the 54 patients. Forty percent and 41% of patients with ovarian remnant and ovarian retention, respectively, achieved a 50% reduction of their average pain levels; 50% and 56%, respectively, achieved a 30% reduction in average pain levels. There was not a statistically significant difference in postoperative pain relief between the 2 groups. Cases with ovarian remnant syndrome had more prior surgical procedures (4.8 vs 3.6, p = .049) and were more likely to have a surgical complication (25% vs 3%, p = .03) than cases with ovarian retention syndrome. Patients with a 30% or greater decrease in their pain levels postoperatively were likely to have fewer other diagnoses associated with chronic pain (1.4 +/- 1.1 vs 2.1 +/- 0.9, p = .009). CONCLUSION: Surgical treatment for ovarian remnant or ovarian retention syndrome is effective but is most effective in patients with no other pain-related diagnoses. Thus, it is important to thoroughly evaluate women with ovarian remnant or ovarian retention syndrome for other pelvic pain-related disorders. In almost all cases, surgery can be done laparoscopically in patients with these syndromes. PMID- 25460319 TI - Does the uterine cervix become abnormally reinnervated after subtotal hysterectomy and what is the association with future trachelectomy? AB - STUDY OBJECTIVE: To compare nerve fiber density in the cervices removed by trachelectomy from women with pelvic pain with those cervices removed for nonpain indications. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Two university hospitals. PATIENTS: Subjects who underwent trachelectomy during a 10-year time frame were identified. INTERVENTIONS: Two tissue sections were obtained from each preserved cervix specimen and stained for S100 antibody. The numbers of S100-immunoreactive peripheral nerve fibers were assessed in 6 high-powered fields (HPFs) per tissue section (12 total HPFs per patient). Information collected included patient characteristics and surgical findings. We excluded any patients with dysplasia/cancer and those without an available adequate specimen. MEASUREMENTS AND MAIN RESULTS: We evaluated the cervix specimens from 35 patients who underwent trachelectomy for pain (n = 25, group 1) and nonpain (n = 10, group 2) indications in addition to control cervices (n = 15, group 3) from benign hysterectomies performed for nonpain indications. There were increased numbers of nerve fibers in trachelectomy patients with pain versus those without pain (group 1 vs group 2, p = .02). There were also increased numbers of nerve fibers in both trachelectomy groups compared with the control group (group 1 vs group 3, p < .01; group 2 vs group 3, p = .04). Adjusted average cervical nerve counts/HPF were 17.8 (95% confidence interval [CI], 13.2-22.3) for pain-indicated trachelectomies, 11.5 (95% CI, 4.8-18.2) for nonpain, and 6.3 (95% CI, 0.8-11.8) for controls. Regardless of trachelectomy indication, adjusted average nerve counts/HPF were 17.7 (95% CI, 13.4-22.0) for patients with endometriosis and 14.6 (95% CI, 12.2-17.1) for patients without endometriosis. CONCLUSION: Nerve fibers in the cervical stump after supracervical hysterectomy are significantly increased in women undergoing trachelectomy for pain indications compared with those who underwent trachelectomy for nonpain indications and controls. Although not statistically significant, endometriosis may be an independent risk factor for increased nerve fibers. These histopathologic observations may support the idea that the cervix should be removed in women undergoing hysterectomy for chronic pelvic pain or endometriosis. PMID- 25460320 TI - Effect of undiagnosed deep adenomyosis after failed NovaSure endometrial ablation. AB - STUDY OBJECTIVE: To determine the prevalence of adenomyosis and deep adenomyosis after NovaSure (Hologic Inc., Newark, DE) endometrial ablation in hysterectomy specimens after NovaSure endometrial ablation failure. DESIGN: Prospective observational study (Canadian Task Force classification II-2). SETTING: The TweeSteden Hospital, a teaching hospital in the south of the Netherlands. PATIENTS: All women who underwent hysterectomy for menorrhagia and/or dysmenorrhea after failure of NovaSure endometrial ablation between November 2007 and January 2011. INTERVENTIONS: All patients who underwent hysterectomy between January 2005 and April 2009 for the same indication but did not undergo prior endometrial ablation from choice or the lack of availability of the endometrial ablation procedure. MEASUREMENTS AND MAIN RESULTS: Of 213 patients who underwent NovaSure therapy, 22 (10.3%) underwent a hysterectomy because NovaSure failed. Of these, 10 (45.5%) exhibited adenomyosis in their hysterectomy specimens. The control group patients had a similar adenomyosis prevalence (74/173, 42.8%). However, the NovaSure failure group had a significantly higher prevalence of deep adenomyosis (>2.5 mm endometrial penetration) (9/22, 40.9%) than the control group (37/173, 21.4%, p < .05). CONCLUSION: Deep adenomyosis after failed NovaSure endometrial ablation was present in a significant number of patients. It is not clear whether adenomyosis is induced by endometrial ablation or whether it causes endometrial ablation failure. PMID- 25460321 TI - Assessing basic "physiology" of the morcellation process and tissue spread: a time-action analysis. AB - STUDY OBJECTIVE: To assess the basic morcellation process in laparoscopic supracervical hysterectomy (LSH). Proper understanding of this process may help enhance future efficacy of morcellation regarding the prevention of tissue scatter. DESIGN: Time-action analysis was performed based on video imaging of the procedures (Canadian Task Force classification II-2). SETTING: Procedures were performed at Leiden University Medical Centre and St Lucas Andreas Hospital, Amsterdam, the Netherlands. PATIENTS: Women undergoing LSH for benign conditions. INTERVENTIONS: Power morcellation of uterine tissue. MEASUREMENTS AND MAIN RESULTS: The morcellation process was divided into 4 stages: tissue manipulation, tissue cutting, tissue depositing, and cleaning. Stages were timed, and perioperative data were gathered. Data were analyzed as a whole and after subdivision into 3 groups according to uterine weight: <350 g, 350 to 750 g, and >750 g. A cutoff point was found at a uterine weight of 350 g, after which an increase in uterine weight did not affect the cleaning stage. The tissue strip cutting time was used as a measure for tissue strip length. With progression of the morcellation process, the tissue strip cutting time decreases. The majority of cutting time is of short duration (i.e., 60% of the cutting lasts 5 seconds or less), and these occur later on in the morcellation process. CONCLUSION: With the current power morcellators, the amount of tissue spread peaks and is independent of uterine weight after a certain cutoff point (in this study 350 g). There is a relative inefficiency in the rotational mechanism because mostly small tissue strips are created. These small tissue strips occur increasingly later on in the procedure. Because small tissue strips are inherently more prone to scatter by the rotational mechanism of the morcellator, the risk of tissue spread is highest at the end of the morcellation procedure. This means that LSH and laparoscopic hysterectomy procedures may be at higher risk for tissue scatter than total laparoscopic hysterectomy. Finally, engineers should evaluate how to create only large tissue strips or assess alternatives to the rotational mechanism. PMID- 25460322 TI - Comparison of the chemical reactivity of synthetic peroxynitrite with that of the autoxidation products of nitroxyl or its anion. AB - Donors of nitroxyl (HNO) exhibit pharmacological properties that are potentially favorable for treatment of a variety of diseases. To fully evaluate the pharmacological utility of HNO, it is therefore important to understand its chemistry, particularly involvement in deleterious biological reactions. Of particular note is the cytotoxic species formed from HNO autoxidation that is capable of inducing double strand DNA breaks. The identity of this species remains elusive, but a conceivable product is peroxynitrous acid. However, chemical comparison studies have demonstrated that HNO autoxidation leads to a unique reactive nitrogen oxide species to that of synthetic peroxynitrite. Here, we extend the analysis to include a new preparation of peroxynitrite formed via autoxidation of nitroxyl anion (NO(-)). Both peroxynitrite preparations exhibited similar chemical profiles, although autoxidation of NO(-) provided a more reliable sample of peroxynitrite. Furthermore, the observed dissimilarities to the HNO donor Angeli's salt substantiate that HNO autoxidation produces a unique intermediate from peroxynitrite. PMID- 25460323 TI - H2S-induced HCO3- secretion in the rat stomach--involvement of nitric oxide, prostaglandins, and capsaicin-sensitive sensory neurons. AB - Hydrogen sulfide (H2S) is known to be an important gaseous mediator that affects various functions under physiological and pathological conditions. We examined the effects of NaHS, a H2S donor, on HCO3(-) secretion in rat stomachs and investigated the mechanism involved in this response. Under urethane anesthesia, rat stomachs were mounted on an ex vivo chamber and perfused with saline. Acid secretion had been inhibited by omeprazole. The secretion of HCO3(-) was measured at pH 7.0 using a pH-stat method and by the addition of 10 mM HCl. NaHS (0.5-10 mM) was perfused in the stomach for 5 min. Indomethacin or L-NAME was administered s.c. before NaHS treatment, while glibenclamide (a KATP channel blocker), ONO-8711 (an EP1 antagonist), or propargylglycine (a cystathionine gamma-lyase inhibitor) was given i.p. before. The mucosal perfusion of NaHS dose dependently increased the secretion of HCO3(-), and this effect was significantly attenuated by indomethacin, L-NAME, and sensory deafferentation, but not by glibenclamide or ONO-8711. The luminal output of nitric oxide, but not the mucosal production of prostaglandin E2, was increased by the perfusion of NaHS. Mucosal acidification stimulated HCO3(-) secretion, and this response was inhibited by sensory deafferentation, indomethacin, L-NAME, and ONO-8711, but not by propargylglycine. These results suggested that H2S increased HCO3(-) secretion in the stomach, and this effect was mediated by capsaicin-sensitive afferent neurons and dependent on nitric oxide and prostaglandins, but not ATP-sensitive K(+) channels. Further study is needed to define the role of endogenous H2S in the mechanism underlying acid-induced gastric HCO3(-) secretion. PMID- 25460324 TI - Neuronal NOS localises to human airway cilia. AB - BACKGROUND: Airway NO synthase (NOS) isoenzymes are responsible for rapid and localised nitric oxide (NO) production and are expressed in airway epithelium. We sought to determine the localisation of neuronal NOS (nNOS) in airway epithelium due to the paucity of evidence. METHODS AND RESULTS: Sections of healthy human bronchial tissue in glycol methacrylate resin and human nasal polyps in paraffin wax were immunohistochemically labelled and reproducibly demonstrated nNOS immunoreactivity, particularly at the proximal portion of cilia; this immunoreactivity was blocked by a specific nNOS peptide fragment. Healthy human epithelial cells differentiated at an air-liquid interface (ALI) confirmed the presence of all three NOS isoenzymes by immunofluorescence labelling. Only nNOS immunoreactivity was specific to the ciliary axonemeand co-localised with the cilia marker beta-tubulin in the proximal part of the ciliary axoneme. CONCLUSIONS: We report a novel localisation of nNOS at the proximal portion of cilia in airway epithelium and conclude that its independent and local regulation of NO levels is crucial for normal cilia function. PMID- 25460326 TI - Renal transplantation promptly restores excretory function but disturbed L arginine metabolism persists in patients during the early period after surgery. AB - The synthesis and whole body metabolism of L-arginine (Arg) are disturbed in renal diseases. Renal transplantation represents the best therapy in the end stage of these diseases. In the present we compared alterations of plasma Arg and related compounds with renal excretory function in patients with end-stage renal disease, before and after kidney transplantation. Arg, asymmetric dimethylarginine (ADMA), citrulline (Cit), glutamine (Gln), ornithine (Orn), phenylalanine (Phe), tyrosine (Tyr), urea, creatinine, albumin, and nitrate were analyzed in patients before, immediately after (0-time) and 1, 2, 3, 7 and 14 days following living donors kidney transplantation. Healthy subjects were controls. Glomerular filtration rate (GFR) and amino acid molar ratios were calculated. Before transplantation creatinine, urea, Cit, Gln, ADMA, and nitrate were above, while GFR and Arg were below controls, confirming disturbed excretory and metabolic renal functions in patients with renal disease. Renal transplantation promptly normalized creatinine, urea, GFR, Cit, and nitrate. However, regardless of increased molar Phe/Tyr ratios, indicating increased net protein catabolism in peripheral tissues, low Arg and elevated ADMA concentrations persisted throughout the examined period. Alterations of other amino acids also suggest similarly disturbed Arg metabolism in patients after kidney transplantation. In conclusion, renal transplant promptly restored its excretory function, but increased net protein catabolism, disturbed Arg metabolism and endothelial dysfunction in entire body of these patients were not improved throughout the early period after the operation. That has to be considered in their therapy. PMID- 25460325 TI - Nitric oxide inhibits neointimal hyperplasia following vascular injury via differential, cell-specific modulation of SOD-1 in the arterial wall. AB - Superoxide (O2(*-)) promotes neointimal hyperplasia following arterial injury. Conversely, nitric oxide ((*)NO) inhibits neointimal hyperplasia through various cell-specific mechanisms, including redox regulation. What remains unclear is whether (*)NO exerts cell-specific regulation of the vascular redox environment following arterial injury to inhibit neointimal hyperplasia. Therefore, the aim of the present study was to assess whether (*)NO exerts cell-specific, differential modulation of O2(*-) levels throughout the arterial wall, establish the mechanism of such modulation, and determine if it regulates (*)NO-dependent inhibition of neointimal hyperplasia. In vivo, (*)NO increased superoxide dismutase-1 (SOD-1) levels following carotid artery balloon injury in a rat model. In vitro, (*)NO increased SOD-1 levels in vascular smooth muscle cells (VSMC), but had no effect on SOD-1 in endothelial cells or adventitial fibroblasts. This SOD-1 increase was associated with an increase in sod1 gene expression, increase in SOD-1 activity, and decrease in O2(*-) levels. Lastly, to determine the role of SOD-1 in (*)NO-mediated inhibition of neointimal hyperplasia, we performed the femoral artery wire injury model in wild type and SOD-1 knockout (KO) mice, with and without (*)NO. Interestingly, (*)NO inhibited neointimal hyperplasia only in wild type mice, with no effect in SOD-1 KO mice. In conclusion, these data show the cell-specific modulation of O2(*-) by (*)NO through regulation of SOD-1 in the vasculature, highlighting its importance on the inhibition of neointimal hyperplasia. These results also shed light into the mechanism of (*)NO-dependent redox balance, and suggest a novel VSMC redox target to prevent neointimal hyperplasia. PMID- 25460327 TI - Improving the accuracy of PGSE DTI experiments using the spatial distribution of b matrix. AB - A novel method for improving the accuracy of diffusion tensor imaging (DTI) is proposed. It takes into account the b matrix spatial variations, which can be easily determined using a simple anisotropic diffusion phantom. In opposite to standard numerical procedure of the b matrix calculation that requires the exact knowledge of amplitudes, shapes and time dependencies of diffusion gradients, the new method, which we call BSD-DTI (B-matrix spatial distribution in DTI), relies on direct measurements of its space-dependent components. The proposed technique was demonstrated on the Bruker Biospec 94/20USR system, using the spin echo diffusion sequence to image an isotropic water phantom and an anisotropic capillary phantom. The accuracy of the diffusion tensor determination was improved by an overall factor of about 8 for the isotropic water phantom. PMID- 25460328 TI - Feasibility of a fast method for B1-inhomogeneity correction for FSPGR sequences. AB - The Fast Spoiled Gradient Echo (FSPGR) sequence is often used in MRI to create T1 weighted images. The signal intensity generated by this sequence depends on the applied flip angle. Knowing the correct flip angle is essential for the determination of T1-maps by means of an FSPGR based Variable Flip Angle (VFA) approach. Also, quantitatively determining the concentration of contrast agent in case of Dynamic Contrast Enhanced MRI (DCE-MRI) requires knowledge of the applied flip angle. In both cases, the B1-field (in)homogeneity significantly affects the results. In this paper, we present a new method to obtain both the T1-map and B1 inhomogeneity map using scans that can each be acquired within a breath-hold. We combine two short sequences for T1 quantification: Variable Flip Angle and Look Locker (LL). The T1-maps obtained from the LL data were used to estimate the B1 inhomogeneity inherently present in the VFA data, which was then used to correct for the VFA method's inaccurate flip angles. This way, a reliable T1-map could be computed, which was validated using both in vitro and in vivo scans. The in vitro results show that the procedure yields a substantially smaller mean deviation in T1 from the T1 measurement's gold standard (the Inversion Recovery method), while the in vivo results show both a more accurate estimation of T1 and a reduction of the influence of the B1-inhomogeneity on the signal intensity. PMID- 25460329 TI - Quantifying errors in flow measurement using phase contrast magnetic resonance imaging: comparison of several boundary detection methods. AB - Quantifying flow from phase-contrast MRI (PC-MRI) data requires that the vessels of interest be segmented. The estimate of the vessel area will dictate the type and magnitude of the error sources that affect the flow measurement. These sources of errors are well understood, and mathematical expressions have been derived for them in previous work. However, these expressions contain many parameters that render them difficult to use for making practical error estimates. In this work, some realistic assumptions were made that allow for the simplification of such expressions in order to make them more useful. These simplified expressions were then used to numerically simulate the effect of segmentation accuracy and provide some criteria that if met, would keep errors in flow quantification below 10% or 5%. Four different segmentation methods were used on simulated and phantom MRA data to verify the theoretical results. Numerical simulations showed that including partial volumed edge pixels in vessel segmentation provides less error than missing them. This was verified with MRA simulations, as the best performing segmentation method generally included such pixels. Further, it was found that to obtain a flow error of less than 10% (5%), the vessel should be at least 4 (5) pixels in diameter, have an SNR of at least 10:1 and have a peak velocity to saturation cut-off velocity ratio of at least 5:3. PMID- 25460330 TI - Diffusion-weighted MRI and MR- volumetry--in the evaluation of tumor response after preoperative chemoradiotherapy in patients with locally advanced rectal cancer. AB - PURPOSE: To determine the diagnostic performance of diffusion-weighted MRI and MR volumetry for the assessment of tumor response after preoperative chemoradiotherapy (CRT) in patients with locally advanced rectal cancer. MATERIALS AND METHODS: Forty-three patients with rectal cancer who underwent preoperative CRT were prospectively examined for the study. This prospective study was approved by our institutional review board. DW- and high resolution T2 weighted imaging were performed before and after therapy. Two different diffusion gradients (b = 0 and b = 600, then separately b = 0 and b = 1000) were applied. The mean tumor volume and mean ADC values were measured before and after therapy. To evaluate the responders and nonresponders to neoadjuvant CRT, two criteria, ypT stage determined in the pathologic examination after treatment and histopathologic tumor regression grade (Ryan), were used as reference standards. The patients with a lower ypT stage than T stage in the first MRI before neoadjuvant CRT were evaluated as the responder group, while the patients with a higher or the same ypT stage relative to the first MRI T stage were evaluated as the nonresponder group. According to Ryan tumor regression grade, grade 1 was evaluated as the responders, whereas grades 2 and 3 were evaluated as the nonresponder group. The percentage ADC increase and percentage tumor volume regression were compared between the responders and nonresponders using two reference standards: T downstaging and tumor regression grade (TRG). RESULTS: Before CRT, the mean tumor ADC in the responder group was significantly lower than that in the nonresponder group (p < 0.001). At the end of CRT, the mean percentage of tumor ADC change in the responder group was significantly higher than that in the nonresponder group. The percentage tumor volume regression of the responders was significantly higher than that of the nonresponders (p = 0.001). The cut-off ADC value for discriminating between the responders and nonresponders after treatment was determined to be (b = 600) 1.03 * 10(-3)mm(2)/s and the sensitivity, 71%; specificity, 79%; accuracy, 74%; positive predictive value, 81%; negative predictive value, 68% respectively. The cut-off value for discriminating between the responders and the nonresponders after treatment was determined for b = 1000 as 1.20 * 10(-3)mm(2)/s and the sensitivity, 42%; specificity, 84%; accuracy, 60%; positive predictive value, 77%; negative predictive value, 53%. CONCLUSION: The increase in the mean tumor ADC and percentage tumor volume regression in patients with rectal cancer treated with preoperative CRT was correlated with good response. DW MR imaging is a promising non-invasive technique that can help predict and monitor early therapeutic response in patients with rectal cancer who undergo CRT. PMID- 25460331 TI - Comparison of quality control software tools for diffusion tensor imaging. AB - Image quality of diffusion tensor imaging (DTI) is critical for image interpretation, diagnostic accuracy and efficiency. However, DTI is susceptible to numerous detrimental artifacts that may impair the reliability and validity of the obtained data. Although many quality control (QC) software tools are being developed and are widely used and each has its different tradeoffs, there is still no general agreement on an image quality control routine for DTIs, and the practical impact of these tradeoffs is not well studied. An objective comparison that identifies the pros and cons of each of the QC tools will be helpful for the users to make the best choice among tools for specific DTI applications. This study aims to quantitatively compare the effectiveness of three popular QC tools including DTI studio (Johns Hopkins University), DTIprep (University of North Carolina at Chapel Hill, University of Iowa and University of Utah) and TORTOISE (National Institute of Health). Both synthetic and in vivo human brain data were used to quantify adverse effects of major DTI artifacts to tensor calculation as well as the effectiveness of different QC tools in identifying and correcting these artifacts. The technical basis of each tool was discussed, and the ways in which particular techniques affect the output of each of the tools were analyzed. The different functions and I/O formats that three QC tools provide for building a general DTI processing pipeline and integration with other popular image processing tools were also discussed. PMID- 25460332 TI - Dodecafluoropentane emulsion delays and reduces MRI markers of infarction in a rat stroke model: a preliminary report. AB - BACKGROUND: Dodecafluoropentane emulsion (DDFPe), an oxygen transport agent, has been shown to reduce infarct volume in animal models of acute ischemic stroke (AIS). Our study assesses the effect of DDFPe on MRI markers of infarct evolution in the early hours after vascular occlusion in a rat AIS model. We hypothesized that DDFPe will delay the development of MRI markers of AIS and/or reduce the extent of infarction. METHODS: Permanent, unilateral surgical occlusion of the middle cerebral and common carotid arteries was performed in control (n=4) and treatment (n = 10) rats. The treatment group received 1 IV dose of 2% w/v DDFPe at 0.6 mL/kg at 1 hour post-occlusion versus none. Diffusion-weighted (DWI) and inversion recovery (IR) MRI sequences were obtained over the 4 hours following occlusion. Infarct extent was quantified by number of abnormal MRI slices per sequence for each group and time point. Student's T-test was applied. RESULTS: DDFPe-treated rats demonstrated reduced infarct extent versus controls over combined time points on IR at 5.43 +/- 0.40 (mean +/- standard error) abnormal slices vs. 7.38 +/- 0.58 (P = 0.01) and on DWI at 5.21 +/- 0.54 vs. 9.00 +/- 0.95 (P < 0.01). Development of abnormal MRI signal was delayed in the treatment group. CONCLUSIONS: DDFPe delays and reduces MRI markers of AIS in the early hours following vascular occlusion in a rat stroke model. Further investigation of DDFPe as a neuroprotectant is warranted. PMID- 25460333 TI - The use of error-category mapping in pharmacokinetic model analysis of dynamic contrast-enhanced MRI data. AB - This study introduces the use of 'error-category mapping' in the interpretation of pharmacokinetic (PK) model parameter results derived from dynamic contrast enhanced (DCE-) MRI data. Eleven patients with metastatic renal cell carcinoma were enrolled in a multiparametric study of the treatment effects of bevacizumab. For the purposes of the present analysis, DCE-MRI data from two identical pre treatment examinations were analysed by application of the extended Tofts model (eTM), using in turn a model arterial input function (AIF), an individually measured AIF and a sample-average AIF. PK model parameter maps were calculated. Errors in the signal-to-gadolinium concentration ([Gd]) conversion process and the model-fitting process itself were assigned to category codes on a voxel-by voxel basis, thereby forming a colour-coded 'error-category map' for each imaged slice. These maps were found to be repeatable between patient visits and showed that the eTM converged adequately in the majority of voxels in all the tumours studied. However, the maps also clearly indicated sub-regions of low Gd uptake and of non-convergence of the model in nearly all tumours. The non-physical condition ve >= 1 was the most frequently indicated error category and appeared sensitive to the form of AIF used. This simple method for visualisation of errors in DCE-MRI could be used as a routine quality-control technique and also has the potential to reveal otherwise hidden patterns of failure in PK model applications. PMID- 25460334 TI - Contributions of the integrin beta1 tail to cell adhesive forces. AB - Integrin receptors connect the extracellular matrix to the cell cytoskeleton to provide essential forces and signals. To examine the contributions of the beta1 integrin cytoplasmic tail to adhesive forces, we generated cell lines expressing wild-type and tail mutant beta1 integrins in beta1-null fibroblasts. Deletion of beta1 significantly reduced cell spreading, focal adhesion assembly, and adhesive forces, and expression of human beta1 (hbeta1) integrin in these cells restored adhesive functions. Cells expressing a truncated tail mutant had impaired spreading, fewer and smaller focal adhesions, reduced integrin binding to fibronectin, and lower adhesion strength and traction forces compared to hbeta1 expressing cells. All these metrics were equivalent to those for beta1-null cells, demonstrating that the beta1 tail is essential to these adhesive functions. Expression of the constitutively-active D759A hbeta1 mutant restored many of these adhesive functions in beta1-null cells, although with important differences when compared to wild-type beta1. Even though there were no differences in integrin-fibronectin binding and adhesion strength between hbeta1- and hbeta1-D759A-expressing cells, hbeta1-D759A-expressing cells assembled more but smaller adhesions than hbeta1-expressing cells. Importantly, hbeta1-D759A expressing cells generated lower traction forces compared to hbeta1-expressing cells. These differences between hbeta1- and hbeta1-D759A-expressing cells suggest that regulation of integrin activation is important for fine-tuning cell spreading, focal adhesion assembly, and traction force generation. PMID- 25460335 TI - LIM homeobox transcription factor Lhx2 inhibits skeletal muscle differentiation in part via transcriptional activation of Msx1 and Msx2. AB - LIM homeobox transcription factor Lhx2 is known to be an important regulator of neuronal development, homeostasis of hair follicle stem cells, and self-renewal of hematopoietic stem cells; however, its function in skeletal muscle development is poorly understood. In this study, we found that overexpression of Lhx2 completely inhibits the myotube-forming capacity of C2C12 cells and primary myoblasts. The muscle dedifferentiation factors Msx1 and Msx2 were strongly induced by the Lhx2 overexpression. Short interfering RNA-mediated knockdown of Lhx2 in the developing limb buds of mouse embryos resulted in a reduction in Msx1 and Msx2 mRNA levels, suggesting that they are downstream target genes of Lhx2. We found two Lhx2 consensus-binding sites in the -2097 to -1189 genomic region of Msx1 and two additional sites in the -536 to +73 genomic region of Msx2. These sequences were shown by luciferase reporter assay to be essential for Lhx2 mediated transcriptional activation. Moreover, electrophoretic mobility shift assays and chromatin immunoprecipitation assays showed that Lhx2 is present in chromatin DNA complexes bound to the enhancer regions of the Msx1 and Msx2 genes. These data demonstrate that Msx1 and Msx2 are direct transcriptional targets of Lhx2. In addition, overexpression of Lhx2 significantly enhanced the mRNA levels of bone morphogenetic protein 4 and transforming growth factor beta family genes. We propose that Lhx2 is involved in the early stage of skeletal muscle development by inducing multiple differentiation inhibitory factors. PMID- 25460336 TI - New insights into the autotaxin/LPA axis in cancer development and metastasis. AB - Lysophosphatidic acid (LPA) is a simple lipid with a single fatty acyl chain linked to a glycerophosphate backbone. Despite the simplicity of its structure but owing to its interactions with a series of at least six G protein-coupled receptors (LPA1-6), LPA exerts pleiotropic bioactivities including stimulation of proliferation, migration and survival of many cell types. Autotaxin (ATX) is a unique enzyme with a lysophospholipase D (lysoPLD) activity that is responsible for the levels of LPA in the blood circulation. Both LPA receptor family members and ATX/LysoPLD are aberrantly expressed in many human cancers. This review will present the more striking as well as novel experimental evidences using cell lines, cancer mouse models and transgenic animals identifying the roles for ATX and LPA receptors in cancer progression, tumor cell invasion and metastasis. PMID- 25460338 TI - Prospective construction and validation of a prognostic score to identify patients who benefit from third-line chemotherapy for metastatic breast cancer in terms of overall survival: the METAL3 Study. AB - Metastatic breast cancer (MBC) is an incurable disease and represents a complex therapeutic challenge for oncologists. Despite the possibility of prescribing new agents such as tailored therapy, cytotoxic chemotherapy and hormone therapy remain the major treatments for MBC. Several lines of chemotherapy can be proposed for these patients, but beyond the second-line, evidence of effectiveness is lacking and such treatment has important associated toxicity affecting quality of life (QoL). Prospective data on third-line chemotherapy is very poor. There is no recent retrospective data and it mainly includes single centre experiences. Moreover, prognostic parameters considered in these retrospective studies are limited to clinico-pathological factors. Previous reports don't evaluate prognostic impact of circulating tumour cells (CTC) and baseline QoL. METAL3 METAstatic Line 3 is a prospective, multicentric trial designed to prospectively construct a prognostic score (including selected clinico-pathological factors, CTC and baseline QoL) to identify patients who benefit from third-line chemotherapy for MBC in terms of overall survival (training cohort). Score will then be validated with another cohort (validation cohort). The aim of this paper is to review literature data on third-line chemotherapy for MBC and to describe in detail our prospective study. We hope that this prognostic score could be used by physicians to develop new therapeutic strategies when there will be limited benefit of third-line chemotherapy; this score will also help to improve patient information on their outcome. PMID- 25460337 TI - The keys to healthy family child care homes intervention: study design and rationale. AB - BACKGROUND: Obesity is a major public health problem for which early preventive interventions are needed. Large numbers of young children are enrolled in some form of child care program, making these facilities influential environments in children's development. Family child care homes (FCCH) are a specific type of child care in which children are cared for within the provider's own residence. FCCHs serve approximately 1.5 million children in the U.S.; however, research to date has overlooked FCCH providers and their potential to positively influence children's health-related behaviors. METHODS: Keys to Healthy Family Child Care Homes (Keys) is a cluster-randomized controlled trial testing the efficacy of an intervention designed to help providers become healthy role models, provide quality food- and physical activity-supportive FCCH environments, and implement effective business practices. The intervention is delivered through workshops, home visits, tailored coaching calls, and educational toolkits. Primary outcomes are child physical activity measured via accelerometry data and dietary intake data collected using direct observation at the FCCH. Secondary outcomes include child body mass index, provider weight-related behaviors, and observed obesogenic environmental characteristics. CONCLUSION: Keys is an innovative approach to promoting healthy eating and physical activity in young children. The intervention operates in a novel setting, targets children during a key developmental period, and addresses both provider and child behaviors to synergistically promote health. PMID- 25460339 TI - Rationale, methodology, and implementation of a nationwide multicenter randomized controlled trial of long-term mild hypothermia for severe traumatic brain injury (the LTH-1 trial). AB - BACKGROUND: Traumatic brain injury (TBI) is a major public health problem recently, however, no intervention showing convincing efficacy. Therapeutic hypothermia with a relatively long duration (more than 48 h), as a promising treatment measure, might improve the patient outcome following severe TBI. METHODS/DESIGN: The LTH-1 trial is a prospective, nationwide multicenter, randomized, controlled clinical trial to examine the efficacy and safety of long term mild hypothermia in adult patients after severe traumatic brain injury. A total of 300 consecutive patients will be recruited from 15 large neurosurgical centers in China. The eligible patient will be randomized to receive either long term mild hypothermia (34-35 degrees C) for 5 days, or normothermia (36-37 degrees C). Additionally, a standardized management protocol will be used in all patients. The primary end point is the neurological outcome 6 months post-injury on the Glasgow Outcome Scale. The secondary outcomes include GOS score at one month post-injury, mortality during six months after injury, length of ICU and hospital stay, intracranial pressure control and Glasgow Coma Scale score during the hospital stay and frequency of complications during the six-month follow-up period. DISCUSSION: Long-term hypothermia is recommended by most recent studies and its efficacy urgently needs to be established in randomized controlled settings. The LTH-1 trial, together with other ongoing studies, will present more evidence for optimal use of hypothermia in severe TBI patients. PMID- 25460340 TI - Simulation study for evaluating the performance of response-adaptive randomization. AB - A response-adaptive randomization (RAR) design refers to the method in which the probability of treatment assignment changes according to how well the treatments are performing in the trial. Holding the promise of treating more patients with the better treatments, RARs have been successfully implemented in clinical trials. We compared equal randomization (ER) with three RARs: Bayesian adaptive randomization, sequential maximum likelihood, and sequential posterior mean. We fixed the total number of patients, considered as patient horizon, but varied the number of patients in the trial. Among the designs, we compared the proportion of patients assigned to the superior arm, overall response rate, statistical power, and total patients enrolled in the trial with and without adding an efficacy early stopping rule. Without early stopping, ER is preferred when the number of patients beyond the trial is much larger than the number of patients in the trial. RAR is favored for large treatment difference or when the number of patients beyond the trial is small. With early stopping, the difference between these two types of designs was reduced. By carefully choosing the design parameters, both RAR and ER methods can achieve the desirable statistical properties. Within three RAR methods, we recommend SPM considering the larger proportion in the better arm and higher overall response rate than BAR and similar power and trial size with ER. The ultimate choice of RAR or ER methods depends on the investigator's preference, the trade-off between group ethics and individual ethics, and logistic considerations in the trial conduct, etc. PMID- 25460341 TI - Challenges in conducting a randomized clinical trial of older people with chronic dizziness: before, during and after vestibular rehabilitation. AB - PURPOSE: This study aims to describe the process of conducting a randomized clinical trial of elderly with chronic dizziness subjected to vestibular rehabilitation (VR) and to verify its effectiveness on dizziness intensity. METHODS: Older adults (>=65 years) with chronic dizziness from vestibular disorders referred to VR were enrolled to the trial. The control group (n=40) was submitted to the Cawthorne & Cooksey protocol and the experimental group (n=42) to the modified Cawthorne & Cooksey protocol which included multiple components. Protocols were performed during individual 50-minute sessions, twice-weekly, for eight weeks. Main measures were: recruitment data (refusal and eligibility), baseline characteristics, dropout rate, session attendance, protocol adherence, adverse effects, exercise adaptation and follow-up events. The Visual Analog Scale (VAS) was used to measure dizziness intensity. RESULTS: 144 elderly were referred to VR, 26.4% declined to participate and 16.7% were ineligible. There were 51 session non-attendances, with disease being the most frequent reason. Regardless of VR protocol, VAS dizziness intensity diminished along sessions (p<0.001). 88.6% of the participants reported improvement after treatment, and 22.9% mentioned an increase in dizziness on follow-up. Home exercises were no longer being performed by 21.4% of the subjects after 3 months from discharge. The final dropout rate was 14.6%. There were no differences between VR protocols on recruitment, dropout, session's attendance, adherence to protocol and treatment effects. CONCLUSIONS: Our results revealed many challenges in conducting a rehabilitation trial with an elderly sample. The VR protocols showed to be feasible and suitable to reduce dizziness in older adults. PMID- 25460343 TI - Patient outcomes using Wii-enhanced rehabilitation after total knee replacement - the TKR-POWER study. AB - BACKGROUND: Home-based rehabilitation following total knee replacement surgery can be as effective as clinic-based or in-patient rehabilitation. The use of the Nintendo Wii has been postulated as a novel rehabilitation tool that adds an additional focus on balance and proprioception into the recovery protocol. The aim of the proposed clinical trial is to investigate the effectiveness of this novel rehabilitation tool, used at home for three months after total knee replacement surgery and to assess any lasting improvements in functional outcome at one year. METHODS/DESIGN: This will be a randomised controlled trial of 128 patients undergoing primary total knee replacement. The participants will be recruited preoperatively from three surgeons at a single centre. There will be no change to the usual care provided until 6 weeks after the operation. Then participants will be randomised to either the Wii-Fit group or usual rehabilitative care group. Outcomes will be assessed preoperatively, a 6-week post surgery baseline and then at 18 weeks, 6 months and 1 year. The primary outcome is the change in self-reported WOMAC total score from week 6 to 18 weeks. Secondary outcomes include objective measures of strength, function and satisfaction scores. DISCUSSION: The results of this clinical trial will be directly relevant for implementation into clinical practice. If beneficial, this affordable technology could be used by many patients to rehabilitate at home. Not only could it optimize the outcomes from their total knee replacement surgery but decrease the need for clinic-based or outpatient therapy for the majority. TRIAL REGISTRATION: (ACTRN12611000291987). PMID- 25460342 TI - The personalized reminder information and social management system (PRISM) trial: rationale, methods and baseline characteristics. AB - Technology holds promise in terms of providing support to older adults. To date, there have been limited robust systematic efforts to evaluate the psychosocial benefits of technology for older people and identify factors that influence both the usability and uptake of technology systems. In response to these issues, we developed the Personal Reminder Information and Social Management System (PRISM), a software application designed for older adults to support social connectivity, memory, knowledge about topics, leisure activities and access to resources. This trail is evaluating the impact of access to the PRISM system on outcomes such as social isolation, social support and connectivity. This paper reports on the approach used to design the PRISM system, study design, methodology and baseline data for the trial. The trial is multi-site randomized field trial. PRISM is being compared to a Binder condition where participants received a binder that contained content similar to that found on PRISM. The sample includes 300 older adults, aged 65-98 years, who lived alone and at risk for being isolated. The primary outcome measures for the trial include indices of social isolation and support and well-being. Secondary outcomes measures include indices of computer proficiency, technology uptake and attitudes towards technology. Follow-up assessments occurred at 6 and 12 months post-randomization. The results of this study will yield important information about the potential value of technology for older adults. The study also demonstrates how a user-centered iterative design approach can be incorporated into the design and evaluation of an intervention protocol. PMID- 25460344 TI - Concussion treatment after combat trauma: development of a telephone based, problem solving intervention for service members. AB - Military service members (SMs) and veterans who sustain mild traumatic brain injuries (mTBI) during combat deployments often have co-morbid conditions but are reluctant to seek out therapy in medical or mental health settings. Efficacious methods of intervention that are patient-centered and adaptable to a mobile and often difficult-to-reach population would be useful in improving quality of life. This article describes a new protocol developed as part of a randomized clinical trial of a telephone-mediated program for SMs with mTBI. The 12-session program combines problem solving training (PST) with embedded modules targeting depression, anxiety, insomnia, and headache. The rationale and development of this behavioral intervention for implementation with persons with multiple co morbidities is described along with the proposed analysis of results. In particular, we provide details regarding the creation of a treatment that is manualized yet flexible enough to address a wide variety of problems and symptoms within a standard framework. The methods involved in enrolling and retaining an often hard-to-study population are also highlighted. PMID- 25460345 TI - Subtle changes in Plasmodium falciparum infection complexity following enhanced intervention in Malawi. AB - With support from the Global Fund, the United States President's Malaria Initiative (PMI) and other cooperating partners, Malawi is implementing a comprehensive malaria control programme involving indoor residual spraying in targeted districts, universal coverage with insecticide-treated bed nets, use of rapid diagnostic tests to confirm the clinical diagnosis of malaria and use of the highly effective artemisinin-based combination therapy, artemether lumefantrine (AL), as the first-line treatment for malaria. We genotyped 24 genome-wide single nucleotide polymorphisms (SNPs) in Plasmodium falciparum infections (n=316) sampled from a single location in Malawi before (2006 and 2007) and after enhanced intervention (2008 and 2012). The SNP data generated were used to examine temporal changes in the proportion of multiple-genotype infections (MIs), mean number of heterozygous SNPs within MIs, parasite genetic diversity (expected heterozygosity and genotypic richness), multilocus linkage disequilibrium and effective population size (N(e)). While the proportion of MIs, expected heterozygosity, genotypic richness, multilocus linkage disequilibrium and Ne were unchanged over time, the mean number (+/-standard deviation) of heterozygous SNPs within MIs decreased significantly (p=0.01) from 9(+/-1) in 2006 to 7(+/-1) in 2012. These findings indicate that the genetic diversity of P. falciparum malaria parasites in this area remains high, suggesting that only subtle gains, if any, have been made in reducing malaria transmission. Continued surveillance is required to evaluate the impact of malaria control interventions in this area and the rest of Malawi, and to better target control interventions. PMID- 25460346 TI - Anti-dengue virus envelope protein domain III IgG ELISA among infants with primary dengue virus infections. AB - Dengue is the most prevalent arthropod-borne viral illness in humans. The current gold standard serologic test for dengue virus (DENV) infection is a neutralizing antibody assay. We examined a DENV recombinant (r)E protein domain III IgG ELISA among infants with primary DENV infections. Infants experience a primary DENV infection in the presence of maternally derived anti-DENV IgG. The estimated DENV rE protein domain III IgG levels to the infecting serotype at the time of infant primary symptomatic DENV2 and DENV3 infections correlated with the 50% plaque reduction neutralization reciprocal antibody titers (PRNT50). Anti-DENVs 1-4 rE protein domain III IgG levels all correlated with each other, and the estimated rE protein domain III IgG level to the infecting serotype at the time of infection inversely correlated with dengue disease severity. The anti-DENV rE protein domain III IgG ELISA may be a useful and potentially high-throughput alternative to traditional DENV neutralizing antibody assays. PMID- 25460347 TI - An updated meta-analysis of randomized controlled trials assessing the effect of sorafenib in advanced hepatocellular carcinoma. AB - BACKGROUND: The efficacy of sorafenib in the treatment of advanced hepatocellular carcinoma (HCC) remains controversial. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of sorafenib for treating patients with advanced HCC. METHODS: The PubMed, Embase, and Web of Science databases were searched. Eligible studies were randomized controlled trials (RCTs) that assessed sorafenib therapy in patients with advanced HCC. The outcomes included overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicities. Hazard ratio (HR) and risk ratio (RR) were used for the meta-analysis and were expressed with 95% confidence intervals (CIs). RESULTS: Seven RCTs, with a total of 3807 patients, were included in this meta-analysis. All patients received sorafenib alone, or with other chemotherapeutic regimens. Pooled estimates showed that sorafenib improved the OS (HR = 0.74, 95% CI: 0.61, 0.90; P = 0.002), or TTP outcomes (HR = 0.69, 95% CI: 0.55, 0.86; P = 0.001). Subgroup analysis revealed that sorafenib was more effective in the patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1-2 (HR = 0.77, 95% CI: 0.60, 1.0; P = 0.05), or macroscopic vascular invasion (MVI), and/or extrahepatic spread (EHS) (H = 0.65, 95% CI: 0.46, 0.93; P = 0.02), in terms of OS. Patients who received sorafenib did not have a higher ORR (RR = 0.85, 95% CI: 0.65, 1.11; P = 0.10). In addition, there was a slight increase in toxicity in the sorafenib group. CONCLUSION: Treatment with sorafenib significantly improved OS and TTP in patients with advanced HCC. Additional large-scale, well-designed RCTs are needed to evaluate the efficacy of sorafenib-based therapy in the treatment of advanced HCC. PMID- 25460348 TI - Skeletal muscle abnormalities in pulmonary arterial hypertension. AB - BACKGROUND: Pulmonary arterial hypertension is a progressive disease that is characterized by dyspnea and exercise intolerance. Impairment in skeletal muscle has recently been described in PAH, although the degree to which this impairment is solely determined by the hemodynamic profile remains uncertain. The aim of this study was to verify the association of structural and functional skeletal muscle characteristics with maximum exercise in PAH. METHODS: The exercise capacity, body composition, CT area of limb muscle, quality of life, quadriceps biopsy and hemodynamics of 16 PAH patients were compared with those of 10 controls. RESULTS: PAH patients had a significantly poorer quality of life, reduced percentage of lean body mass, reduced respiratory muscle strength, reduced resistance and strength of quadriceps and increased functional limitation at 6MWT and CPET. VO2 max was correlated with muscular variables and cardiac output. Bivariate linear regression models showed that the association between muscular structural and functional variables remained significant even after correcting for cardiac output. CONCLUSION: Our study showed the coexistence of ventilatory and quadriceps weakness in face of exercise intolerance in the same group of PAH patients. More interestingly, it is the first time that the independent association between muscular pattern and maximum exercise capacity is evidenced in PAH, independently of cardiac index highlighting the importance of considering rehabilitation in the treatment strategy for PAH. PMID- 25460350 TI - A functionalised nickel cyclam catalyst for CO2 reduction: electrocatalysis, semiconductor surface immobilisation and light-driven electron transfer. AB - The immobilisation of electrocatalysts for CO2 reduction onto light harvesting semiconductors is proposed to be an important step towards developing more efficient CO2 reduction photoelectrodes. Here, we report a low cost nickel cyclam complex covalently anchored to a metal oxide surface. Using transient spectroscopy we validate the role of surface immobilisation on enhancing the rate of photoelectron transfer. Furthermore [Ni(1,4,8,11-tetraazacyclotetradecane-6 carboxylic acid)](2+) (2) is shown to be a very active electrocatalyst in solution. PMID- 25460349 TI - Age related differences in reaction time components and diffusion properties of normal-appearing white matter in healthy adults. AB - Deterioration of the white matter (WM) is viewed as the neural substrate of age differences in speed of information processing (reaction time, RT). However, the relationship between WM and RT components is rarely examined in healthy aging. We assessed the relationship between RT components derived from the Ratcliff diffusion model and micro-structural properties of normal-appearing WM (NAWM) in 90 healthy adults (age 18-82 years). We replicated all major extant findings pertaining to age differences in RT components and WM: lower drift rate, greater response conservativeness, longer non-decision time, lower fractional anisotropy (FA), greater mean (MD), axial (AD) and radial (RD) diffusivity were associated with advanced age. Age differences in anterior regions of the cerebral WM exceeded those in posterior regions. However, the only relationship between RT components and WM was the positive association between DR in the body of the corpus callosum and non-decision time. Thus, in healthy adults, age differences in NAWM diffusion properties are not a major contributor to age differences in RT components. Longitudinal studies with more precise and specific estimates of regional myelin content and evaluation of the contribution of age-related vascular risk factors are necessary to understand cerebral substrates of age related cognitive slowing. PMID- 25460351 TI - The widely used ATB FUNGUS 3 automated readings in China and its misleading high MICs of Candida spp. to azoles: challenges for developing countries' clinical microbiology labs. AB - The rapid development in the clinical microbiology diagnostic assays presents more challenges for developing countries than for the developed world, especially in the area of test validation before the introduction of new tests. Here we report on the misleading high MICs of Candida spp. to azoles using the ATB FUNGUS 3 (bioMerieux, La Balme-les Grottes, France) with automated readings in China to highlight the dangers of introducing a diagnostic assay without validation. ATB FUNGUS 3 is the most commonly used commercial antifungal susceptibility testing method in China. An in-depth analysis of data showed higher levels of resistance to azoles when ATB FUNGUS 3 strips were read automatically than when read visually. Based on this finding, the performance of ATB FUNGUS 3, read both visually and automatically, was evaluated by testing 218 isolates of five clinically important Candida species, using broth microdilution (BMD) following CLSI M27-A3 as the gold-standard. The overall essential agreement (EA) between ATB visual readings and BMD was 99.1%. In contrast, the ATB automated readings showed higher discrepancies with BMD, with overall EA of 86.2%, and specifically lower EA was observed for fluconazole (80.7%), voriconazole (77.5%), and itraconazole (73.4%), which was most likely due to the trailing effect of azoles. The major errors in azole drug susceptibilities by ATB automated readings is a concern in China that can result in misleading clinical antifungal drug selection and pseudo high rates of antifungal resistance. Therefore, the ATB visual reading is generally recommended. In the meantime, we propose a practical algorithm to be followed for ATB FUNGUS 3 antifungal susceptibility for Candida spp. before the improvement in the automated reading system. PMID- 25460352 TI - The relative biological effectiveness for carbon and oxygen ion beams using the raster-scanning technique in hepatocellular carcinoma cell lines. AB - BACKGROUND: Aim of this study was to evaluate the relative biological effectiveness (RBE) of carbon (12C) and oxygen ion (16O)-irradiation applied in the raster-scanning technique at the Heidelberg Ion beam Therapy center (HIT) based on clonogenic survival in hepatocellular carcinoma cell lines compared to photon irradiation. METHODS: Four human HCC lines Hep3B, PLC, HepG2 and HUH7 were irradiated with photons, 12C and 16O using a customized experimental setting at HIT for in-vitro trials. Cells were irradiated with increasing physical photon single doses of 0, 2, 4 and 6 Gy and heavy ion-single doses of 0, 0.125, 0.5, 1, 2, 3 Gy (12C and 16O). SOBP-penetration depth and extension was 35 mm +/-4 mm and 36 mm +/-5 mm for carbon ions and oxygen ions respectively. Mean energy level and mean linear energy transfer (LET) were 130 MeV/u and 112 keV/um for 12C, and 154 MeV/u and 146 keV/um for 16O. Clonogenic survival was computated and relative biological effectiveness (RBE) values were defined. RESULTS: For all cell lines and both particle modalities alpha- and beta-values were determined. As expected, alpha-values were significantly higher for 12C and 16O than for photons, reflecting a steeper decline of the initial slope of the survival curves for high LET beams. RBE-values were in the range of 2.1-3.3 and 1.9-3.1 for 12C and 16O, respectively. CONCLUSION: Both irradiation with 12C and 16O using the raster scanning technique leads to an enhanced RBE in HCC cell lines. No relevant differences between achieved RBE-values for 12C and 16O were found. Results of this work will further influence biological-adapted treatment planning for HCC patients that will undergo particle therapy with 12C or 16O. PMID- 25460354 TI - Is any donor too old? PMID- 25460353 TI - Epidermal growth factor signalling controls myosin II planar polarity to orchestrate convergent extension movements during Drosophila tubulogenesis. AB - Most epithelial tubes arise as small buds and elongate by regulated morphogenetic processes including oriented cell division, cell rearrangements, and changes in cell shape. Through live analysis of Drosophila renal tubule morphogenesis we show that tissue elongation results from polarised cell intercalations around the tubule circumference, producing convergent-extension tissue movements. Using genetic techniques, we demonstrate that the vector of cell movement is regulated by localised epidermal growth factor (EGF) signalling from the distally placed tip cell lineage, which sets up a distal-to-proximal gradient of pathway activation to planar polarise cells, without the involvement for PCP gene activity. Time-lapse imaging at subcellular resolution shows that the acquisition of planar polarity leads to asymmetric pulsatile Myosin II accumulation in the basal, proximal cortex of tubule cells, resulting in repeated, transient shortening of their circumferential length. This repeated bias in the polarity of cell contraction allows cells to move relative to each other, leading to a reduction in cell number around the lumen and an increase in tubule length. Physiological analysis demonstrates that animals whose tubules fail to elongate exhibit abnormal excretory function, defective osmoregulation, and lethality. PMID- 25460356 TI - As time goes by... PMID- 25460355 TI - Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a center for international blood and marrow transplant research study. AB - Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (alloHCT) remains a major therapeutic challenge. We studied outcomes of 1788 AML patients relapsing after alloHCT (1990 to 2010) during first or second complete remission (CR) to identify factors associated with longer postrelapse survival. Median time to post-HCT relapse was 7 months (range, 1 to 177). At relapse, 1231 patients (69%) received intensive therapy, including chemotherapy alone (n = 660), donor lymphocyte infusion (DLI) +/- chemotherapy (n = 202), or second alloHCT +/- chemotherapy +/- DLI (n = 369), with subsequent CR rates of 29%. Median follow-up after relapse was 39 months (range, <1 to 193). Survival for all patients was 23% at 1 year after relapse; however, 3-year overall survival correlated with time from HCT to relapse (4% for relapse during the 1- to 6-month period, 12% during the 6-month to 2-year period, 26% during the 2- to 3-year period, and 38% for >=3 years). In multivariable analysis, lower mortality was significantly associated with longer time from alloHCT to relapse (relative risk, .55 for 6 months to 2 years; relative risk, .39 for 2 to 3 years; and relative risk, .28 for >=3 years; P < .0001) and a first HCT using reduced intensity conditioning (relative risk, .77; 95% confidence interval [CI], .66 to .88; P = .0002). In contrast, inferior survival was associated with age >40 years (relative risk, 1.42; 95% CI, 1.24 to 1.64; P < .0001), active graft-versus-host disease at relapse (relative risk, 1.25; 95% CI, 1.13 to 1.39; P < .0001), adverse cytogenetics (relative risk, 1.37; 95% CI, 1.09 to 1.71; P = .0062), mismatched unrelated donor (relative risk, 1.61; 95% CI, 1.22 to 2.13; P = .0008), and use of cord blood for first HCT (relative risk, 1.23; 95% CI, 1.06 to 1.42; P = .0078). AML relapse after alloHCT predicted poor survival; however, patients who relapsed >=6 months after their initial alloHCT had better survival and may benefit from intensive therapy, such as second alloHCT +/- DLI. PMID- 25460357 TI - Decreased nonrelapse mortality after unrelated cord blood transplantation for acute myeloid leukemia using reduced-intensity conditioning: a prospective phase II multicenter trial. AB - A prospective phase II multicenter trial was performed with the aim to obtain less than 25% nonrelapse mortality (NRM) after unrelated cord blood transplantation (UCBT) for adults with acute myeloid leukemia (AML) using a reduced-intensity conditioning regimen (RIC) consisting of total body irradiation (2 Gy), cyclophosphamide (50 mg/kg), and fludarabine (200 mg/m(2)). From 2007 to 2009, 79 UCBT recipients were enrolled. Patients who underwent transplantation in first complete remission (CR1) (n = 48) had a higher frequency of unfavorable cytogenetics and secondary AML and required more induction courses of chemotherapy to achieve CR1 compared with the others. The median infused total nucleated cells (TNC) was 3.4 * 10(7)/kg, 60% received double UCBT, 77% were HLA mismatched (4/6), and 40% had major ABO incompatibility. Cumulative incidence of neutrophil recovery at day 60 was 87% and the cumulative incidence of 100-day acute graft-versus-host disease (II to IV) was 50%. At 2 years, the cumulative incidence of NRM and relapse was 20% and 46%, respectively. In multivariate analysis, major ABO incompatibility (P = .001) and TNC (<3.4 * 10(7)/kg; P = .001) were associated with increased NRM, and use of 2 or more induction courses to obtain CR1 was associated with increased relapse incidence (P = .04). Leukemia free survival (LFS) at 2 years was 35%, and the only factor associated with decreased LFS was secondary AML (P = .04). In conclusion, despite the decreased NRM observed, other RIC regimens with higher myelosuppression should be evaluated to decrease relapse in high-risk AML. (EUDRACT 2006-005901-67). PMID- 25460358 TI - CD19+CD21low B cells and CD4+CD45RA+CD31+ T cells correlate with first diagnosis of chronic graft-versus-host disease. AB - Chronic graft-versus-host disease (cGVHD) is a serious and frequent complication of allogeneic hematopoietic stem cell transplantation (HCT). Currently, no biomarkers for prediction and diagnosis of cGVHD are available. We performed a large prospective study focusing on noninvasive biomarkers for National Institutes of Health-defined cGVHD patients (n = 163) in comparison to time matched HCT recipients who never experienced cGVHD (n = 64), analyzed from day 100 after HCT. In logistic regression analysis, CD19(+)CD21(low) B cells (P = .002; hazard ratio [HR], 3.31; 95% confidence interval [CI], 1.53 to 7.17) and CD4(+)CD45RA(+)CD31(+) T cells (P < .001; HR, 3.88; 95% CI, 1.88 to 7.99) assessed on day 100 after HCT were significantly associated with subsequent development of cGVHD, independent of clinical parameters. A significant association with diagnosis of cGVHD was only observed for CD19(+)CD21(low) B cells (P = .008; HR, 3.00; 95% CI, 1.33 to 6.75) and CD4(+)CD45RA(+)CD31(+) T cells (P = .017; HR, 2.80; 95% CI, 1.19 to 6.55). CD19(+)CD21(low) B cells were found to have the highest discriminatory value with an area under the receiver operating curve of .77 (95% CI, .64 to .90). Our results demonstrate that CD19(+)CD21(low) B cells and CD4(+)CD45RA(+)CD31(+) T cells are significantly elevated in patients with newly diagnosed cGVHD. PMID- 25460359 TI - Wilms tumor gene 1 expression as a predictive marker for relapse and survival after hematopoietic stem cell transplantation for myelodysplastic syndromes. AB - Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is a major concern in myelodysplastic syndromes (MDS), but the role of Wilms tumor gene 1 (WT1) as a predictive marker for post-HSCT relapse remains to be validated. We measured WT1 transcript levels by real-time quantitative PCR from marrow samples of 82 MDS patients who underwent transplantation between 2009 and 2013. Pre-HSCT WT1 expression weakly correlated with marrow blast counts or International Prognostic Scoring System scores and failed to predict post transplantation relapse. Regarding post-HSCT WT1, transcript levels of relapsed patients were significantly higher in comparison to those in remission. Further analysis using receiver operating characteristics curves showed that higher (>154 copies/10(4)ABL) 1-month post-HSCT WT1 resulted in a higher 3-year relapse rate (47.2% versus 6.9%, P < .001) with poorer disease-free survival (DFS) and overall survival at 3 years (41.7% versus 79.0% and 54.3% versus 82.1%, P = .003 and P = .033, respectively). Multivariate analysis after adjusting for pre-HSCT karyotype and chronic graft-versus-host disease (GVHD) also revealed that higher 1-month post-HSCT WT1 was an independent predictive marker for subsequent relapse (P = .002) and poorer DFS (P = .010). In the higher 1-month post-HSCT WT1 subgroup, patients with chronic GVHD showed lower relapse rate and favorable survival outcome. One month post-HSCT WT1 expression was a useful marker for minimal residual disease and relapse prediction in association with chronic GVHD in the context of HSCT for MDS. PMID- 25460360 TI - Selenium deficiency sensitizes the skin for UVB-induced oxidative damage and inflammation which involved the activation of p38 MAPK signaling. AB - Ultraviolet B (UVB) radiation causes oxidative damage and inflammation, and ultimately increases the risk of skin carcinogenesis. Selenium is an essential trace element, previous studies indicated selenium deficiency impairs tissue antioxidant capacity in different experimental models. However, the synergistic effect of selenium deficiency and UVB radiation on skin damage is not clear. In the current study, our data revealed selenium deficiency resulted in further increases of reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS) and phosphorylated H2AX levels, decreases of GSH level and antioxidant enzyme activities in UVB-irradiated mice. Selenium deficiency also exacerbated UVB-induced cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and IL-6 mRNA expressions. Mechanism studies indicated that UVB-induced p38 signaling was further elevated in the skin of mice maintained with selenium deficiency diet, compared with those maintained with selenium adequate diet. Our investigation suggested that selenium deficiency diet weakens the antioxidant capacity of UVB-irradiated mice skin, which sensitizes to UV radiation-induced oxidative damage and inflammation. PMID- 25460361 TI - The flavonoid quercetin reverses pulmonary hypertension in rats. AB - Quercetin is a dietary flavonoid which exerts vasodilator, antiplatelet and antiproliferative effects and reduces blood pressure, oxidative status and end organ damage in humans and animal models of systemic hypertension. We hypothesized that oral quercetin treatment might be protective in a rat model of pulmonary arterial hypertension. Three weeks after injection of monocrotaline, quercetin (10 mg/kg/d per os) or vehicle was administered for 10 days to adult Wistar rats. Quercetin significantly reduced mortality. In surviving animals, quercetin decreased pulmonary arterial pressure, right ventricular hypertrophy and muscularization of small pulmonary arteries. Classic biomarkers of pulmonary arterial hypertension such as the downregulated expression of lung BMPR2, Kv1.5, Kv2.1, upregulated survivin, endothelial dysfunction and hyperresponsiveness to 5 HT were unaffected by quercetin. Quercetin significantly restored the decrease in Kv currents, the upregulation of 5-HT2A receptors and reduced the Akt and S6 phosphorylation. In vitro, quercetin induced pulmonary artery vasodilator effects, inhibited pulmonary artery smooth muscle cell proliferation and induced apoptosis. In conclusion, quercetin is partially protective in this rat model of PAH. It delayed mortality by lowering PAP, RVH and vascular remodeling. Quercetin exerted effective vasodilator effects in isolated PA, inhibited cell proliferation and induced apoptosis in PASMCs. These effects were associated with decreased 5-HT2A receptor expression and Akt and S6 phosphorylation and partially restored Kv currents. Therefore, quercetin could be useful in the treatment of PAH. PMID- 25460364 TI - Monitoring of the crystallization of zeolite LTA using Raman and chemometric tools. AB - LTA zeolite is used both in industry as well as in laboratories, because of its spatial-specific structure which is useful in gas adsorption and in ion exchange separation. At-line reaction monitoring and multivariate analysis of data, such as Principal Component Analysis (PCA), are fundamentals of the Process Analytical Technology (PAT), which consists of the use of analyzers with rapid detection and low sample preparation for analysis during the process stream. In this work, an optimization of zeolite LTA synthesis was performed aiming to obtain nanocrystals and the synthesis was monitored using Raman spectroscopy and PCA. A reaction mixture of 6.2Na2O : Al2O3 : 2SiO2 : 128H2O was used and it was possible to obtain a small particle size and high crystallinity after 72 h of synthesis at 25 degrees C. The synthesis was monitored at-line, using Raman spectroscopy in both liquid and solid phases. The extension of the reaction could be clearly observed by the PCA scores. As expected, the liquid phase presented changes over time, but the solid phase presented three specific stationary conditions at 0-24 h, 32-56 h and 72-80, related to the beginning of the reaction, the nucleation process, and the crystal formation, respectively. In addition, it was possible to identify the intermediates of the reaction and with the aid of PCA to monitor the reaction close to the real time. PMID- 25460362 TI - Holmgren's principle of delamination during fin skeletogenesis. AB - During fin morphogenesis, several mesenchyme condensations occur to give rise to the dermal skeleton. Although each of them seems to create distinctive and unique structures, they all follow the premises of the same morphogenetic principle. Holmgren's principle of delamination was first proposed to describe the morphogenesis of skeletal elements of the cranium, but Jarvik extended it to the development of the fin exoskeleton. Since then, some cellular or molecular explanations, such as the "flypaper" model (Thorogood et al.), or the evolutionary description by Moss, have tried to clarify this topic. In this article, we review new data from zebrafish studies to meet these criteria described by Holmgren and other authors. The variety of cell lineages involved in these skeletogenic condensations sheds light on an open discussion of the contributions of mesoderm- versus neural crest-derived cell lineages to the development of the head and trunk skeleton. Moreover, we discuss emerging molecular studies that are disclosing conserved regulatory mechanisms for dermal skeletogenesis and similarities during fin development and regeneration, which may have important implications in the potential use of the zebrafish fin as a model for regenerative medicine. PMID- 25460363 TI - Trends of tuberculosis case notification and treatment outcomes in the Sidama Zone, southern Ethiopia: ten-year retrospective trend analysis in urban-rural settings. AB - BACKGROUND: Ethiopia is one of the high tuberculosis (TB) burden countries. An analysis of trends and differentials in case notifications and treatment outcomes of TB may help improve our understanding of the performance of TB control services. METHODS: A retrospective trend analysis of TB cases was conducted in the Sidama Zone in southern Ethiopia. We registered all TB cases diagnosed and treated during 2003-2012 from all health facilities in the Sidama Zone, and analysed trends of TB case notification rates and treatment outcomes. RESULTS: The smear positive (PTB+) case notification rate (CNR) increased from 55 (95% CI 52.5-58.4) to 111 (95% CI 107.4-114.4) per 105 people. The CNRs of PTB+ in people older than 45 years increased by fourfold, while the mortality of cases during treatment declined from 11% to 3% for smear negative (PTB-) (X2trend, P<0.001) and from 5% to 2% for PTB+ (X2trend, P<0.001). The treatment success was higher in rural areas (AOR 1.11; CI 95%: 1.03-1.2), less for PTB- (AOR 0.86; CI 95%: 0.80-0.92) and higher for extra-pulmonary TB (AOR 1.10; CI 95%: 1.02-1.19) compared to PTB+. A higher lost-to-follow up was observed in men (AOR 1.15; CI 95%: 1.06-1.24) and among PTB- cases (AOR 1.14; CI 95%: 1.03-1.25). More deaths occurred in PTB-cases (AOR 1.65; 95% CI: 1.44-1.90) and among cases older than 65 years (AOR 3.86; CI 95%: 2.94-5.10). Lastly, retreatment cases had a higher mortality than new cases (6% vs 3%). CONCLUSION: Over the past decade TB CNRs and treatment outcomes improved, whereas the disparities of disease burden by gender and place of residence reduced and mortality declined. Strategies should be devised to address higher risk groups for poor treatment outcomes. PMID- 25460365 TI - Modeling of degradation kinetic and toxicity evaluation of herbicides mixtures in water using the UV/H2O2 process. AB - The UV/H2O2 process was applied to the treatment of different mixtures of herbicides in water. Glyphosate, the herbicide most used in the world, was mixed with other hormonal herbicides with residual activity as 2,4-D and dicamba. The main goals of the study were to develop a kinetic model for interpreting the simultaneous oxidation of two mixtures (glyphosate plus 2,4-D and glyphosate plus dicamba). The model is based on a complete reaction mechanism, which comprises hydrogen peroxide photolysis and decomposition of both herbicides in each mixture studied. It takes into account the effect of non-uniform distribution of the local rate of absorbed photons. Good agreement of experimental data and the model is achieved in spite of differences in the reactivity between glyphosate and 2,4 D (or dicamba). Toxicity assays (employing Vibrio fischeri) were also performed, indicating that the toxicity of the mixture of glyphosate and 2,4-D was significantly reduced after the treatment. PMID- 25460366 TI - Alpha-lipoic acid activates eNOS through activation of PI3-kinase/Akt signaling pathway. AB - BACKGROUND: Lipoic acid (LA) exerts therapeutic effects on cardiovascular diseases. However, the mechanisms underlying these therapeutic effects remain elusive. Endothelial nitric oxide synthase (eNOS) plays a critical role in cardiovascular homeostasis. LA was shown to potently activate PI3-kinase/Akt pathway, and the latter is critical in the regulation of eNOS activity. In the present study, we test the hypothesis that LA improves endothelial function through PI3-kinase/Akt-mediated eNOS activation. METHODS AND RESULTS: Western blot analysis showed that LA time- and dose-dependently induced phosphorylation of Akt and eNOS in human umbilical vein endothelial cells (HUVECs). Both PI3 kinase and Akt inhibitors abolished LA-induced eNOS phosphorylation, indicating that LA induces eNOS phosphorylation through the PI3-kinase/Akt pathway. This increase in eNOS phosphorylation was paralleled by an increase in NO release by HUVECs, supporting its relevance in eNOS activity regulation. Myograph analysis revealed that LA relaxed phenylephrine-induced contraction. Endothelium removal and NOS inhibition by L-NAME abolished this vasodilator action of LA, and Akt but not AMPK inhibition significantly reduced the vasodilator action of LA, indicating that it is mediated by PI3-kinase/Akt pathway-dependent activation of eNOS. Consistent with in vitro results, intraperitoneal injection with LA significantly increased plasma nitrite and nitrate levels in C57Bl/6j mice. CONCLUSIONS: LA activates eNOS through a PI3-kinase/Akt signaling pathway dependent mechanism, offering a potential molecular basis for the therapeutic effects of LA on cardiovascular diseases. PMID- 25460367 TI - Post receptor determinants of acute platelet response to clopidogrel in patients with symptomatic myocardial ischemia. AB - BACKGROUND: Clopidogrel resistance is more common in patients with loss-of function CYP2C19 genotypes. Since adenylate cyclase (AC) and soluble guanylate cyclase (sGC) pathways are variably impaired in patients with ischaemic heart disease, we tested the relevance of these determinants in patients undergoing acute loading with clopidogrel (600 mg) prior to non-emergent coronary stenting. METHODS: Inhibitory effects of prostaglandin E1 (PGE1, an AC activator) and sodium nitroprusside (NP, a sGC activator) on platelet aggregation were determined at baseline and compared with platelet responses to clopidogrel (4 h after administration) assessed as ?ADP, and Platelet Reactivity Index (?PRI). Data were analysed according to CYP2C19 genotype. RESULTS: In patients without loss of function mutations (n=18), ?ADP but not ?PRI, was directly correlated with baseline PGE1 responsiveness (rs=0.62, p=0.005)). NP responsiveness did not predict ?ADP. However there was no relationship between clopidogrel responses and either PGE1 or NP responsiveness in patients with loss of function mutations. Multivariate correlates of clopidogrel response were both the genotype status (beta=-0.609, p<0.001) and the baseline response to PGE1 (beta=0.303, p=0.03). CONCLUSIONS: While genetically impaired bio-activation markedly limits acute (4 h) clopidogrel response, impaired AC signalling provides an additional cause for clopidogrel resistance. PMID- 25460368 TI - CFS-1686 causes cell cycle arrest at intra-S phase by interference of interaction of topoisomerase 1 with DNA. AB - CFS-1686 (chemical name (E)-N-(2-(diethylamino)ethyl)-4-(2-(2-(5-nitrofuran-2 yl)vinyl)quinolin-4-ylamino)benzamide) inhibits cell proliferation and triggers late apoptosis in prostate cancer cell lines. Comparing the effect of CFS-1686 on cell cycle progression with the topoisomerase 1 inhibitor camptothecin revealed that CFS-1686 and camptothecin reduced DNA synthesis in S-phase, resulting in cell cycle arrest at the intra-S phase and G1-S boundary, respectively. The DNA damage in CFS-1686 and camptothecin treated cells was evaluated by the level of ATM phosphorylation, gammaH2AX, and gammaH2AX foci, showing that camptothecin was more effective than CFS-1686. However, despite its lower DNA damage capacity, CFS 1686 demonstrated 4-fold higher inhibition of topoisomerase 1 than camptothecin in a DNA relaxation assay. Unlike camptothecin, CFS-1686 demonstrated no activity on topoisomerase 1 in a DNA cleavage assay, but nevertheless it reduced the camptothecin-induced DNA cleavage of topoisomerase 1 in a dose-dependent manner. Our results indicate that CFS-1686 might bind to topoisomerase 1 to inhibit this enzyme from interacting with DNA relaxation activity, unlike campothecin's induction of a topoisomerase 1-DNA cleavage complex. Finally, we used a computer docking strategy to localize the potential binding site of CFS-1686 to topoisomerase 1, further indicating that CFS-1686 might inhibit the binding of Top1 to DNA. PMID- 25460369 TI - Digoxin treatment is associated with increased total and cardiovascular mortality in anticoagulated patients with atrial fibrillation. AB - BACKGROUND: Some evidences suggest that the use of digoxin may be harmful inatrial fibrillation (AF) patients. The aim of the study was to investigate in a "real world" of AF patients receiving vitamin K antagonists (VKAs), the relationship between digoxin use and mortality. METHODS: Prospective single center observational study including 815 consecutive non-valvular AF patients treated with VKAs. Total mortality was the primary outcome of the study. We also performed a sub-analysis considering only cardiovascular (CV) deaths. Time in therapeutic range (TTR) was used for anticoagulation quality. RESULTS: Median follow-up was 33.2months (2460 person-years); 171 (21.0%) patients were taking digoxin. Compared to those without, patients on digoxin were older (p=0.007), with a clinical history of HF (p<0.001) and at higher risk of thromboembolic events (p<0.001). No difference in TTR between the two groups was registered (p=0.598). During the follow-up, 85 deaths occurred: 47 CV and 38 non-CV deaths; 35 deaths occurred in digoxin users (20.6%). A significant increased rate of total mortality was observed in digoxin-treated patients (p<0.001). Multivariable analysis showed that digoxin was associated with total mortality (hazard ratio [HR]: 2.224, p<0.001) and CV death (HR: 4.686, p<0.001). A propensity score matched analysis confirmed that digoxin was associated with total mortality (HR: 2.073, p=0.0263) and CV death (HR: 4.043, p=0.004). CONCLUSIONS: In AF patients on good anticoagulation control with VKAs, digoxin use was associated with a higher rate of total and CV mortality. PMID- 25460370 TI - Remote ischemic conditioning, a double-edged sword in left ventricular remodeling. PMID- 25460371 TI - Automated cardiopulmonary resuscitation using a load-distributing band external cardiac support device for in-hospital cardiac arrest: a single centre experience of AutoPulse-CPR. AB - BACKGROUND: Poor quality cardiopulmonary resuscitation (CPR) predicts adverse outcome. During invasive cardiac procedures automated-CPR (A-CPR) may help maintain effective resuscitation. The use of A-CPR following in-hospital cardiac arrest (IHCA) remains poorly described. AIMS & METHODS: Firstly, we aimed to assess the efficiency of healthcare staff using A-CPR in a cardiac arrest scenario at baseline, following re-training and over time (Scenario-based training). Secondly, we studied our clinical experience of A-CPR at our institution over a 2-year period, with particular emphasis on the details of invasive cardiac procedures performed, problems encountered, resuscitation rates and in-hospital outcome (AutoPulse-CPR Registry). RESULTS: Scenario-based training: Forty healthcare professionals were assessed. At baseline, time-to position device was slow (mean 59 (+/-24) s (range 15-96s)), with the majority (57%) unable to mode-switch. Following re-training time-to-position reduced (28 (+/-9) s, p<0.01 vs baseline) with 95% able to mode-switch. This improvement was maintained over time. AutoPulse-CPR Registry: 285 patients suffered IHCA, 25 received A-CPR. Survival to hospital discharge following conventional CPR was 28/260 (11%) and 7/25 (28%) following A-CPR. A-CPR supported invasive procedures in 9 patients, 2 of whom had A-CPR dependant circulation during transfer to the catheter lab. CONCLUSION: A-CPR may provide excellent haemodynamic support and facilitate simultaneous invasive cardiac procedures. A significant learning curve exists when integrating A-CPR into clinical practice. Further studies are required to better define the role and effectiveness of A-CPR following IHCA. PMID- 25460372 TI - Incidence of high blood pressure in children - effects of physical activity and sedentary behaviors: the IDEFICS study: High blood pressure, lifestyle and children. AB - BACKGROUND/OBJECTIVES: High blood pressure (HBP) is one of the most important risk factors for cardiovascular diseases and it has a high prevalence in pediatric populations. However, the determinants of the incidence of Pre-HBP and HBP in children are not well known. i) To describe the incidence of HBP in European children; and ii) to evaluate the effect of physical activity (PA) and sedentary behavior (SB) on the Pre-HBP and HBP. METHODS: The IDEFICS cohort study. A total of 16,228 children 2-9years at baseline were recruited by complex sampling population-based survey in eight European countries. At baseline (T0), 5221 children were selected for accelerometer measurements; 5061 children were re examined 2years later (T1). We estimated the incidence of Pre-HBP and HBP and evaluate the effect of PA and SB on the Pre-HBP and HBP, by computing relative risks and the corresponding 95% confidence intervals (RR, 95% CI). RESULTS: Incidences of Pre-HBP and HBP per year were: 121/1000 children and 110/1000 children, respectively. We found that children maintaining SB>2h/d during the two year follow-up showed a RR of having HBP of 1.28 (1.03-1.60). Children in T1 not performing the recommended amount of PA (<60min/d) have a RR of HBP of 1.53 (1.12 to 2.09). We found no association between pre-HBP and the behaviors. CONCLUSION: The incidence of pre-HBP and HBP is high in European children. Maintaining sedentary behaviors during childhood increases the risk of developing HBP after two years of follow-up. PMID- 25460373 TI - The impact of elevated blood pressure on exercise capacity in elite athletes. AB - OBJECTIVES: Hypertension is one of the most prevalent cardiovascular disorders in athletes. The aims of our study were to assess the impact of elevated blood pressure (BP) on exercise capacity in athletes and evaluate the differences in left ventricular structure and function. METHODS: Elite male athletes (n=517, aged 23+/-5years) underwent Doppler echocardiography with tissue Doppler imaging. Diastolic function was assessed by measuring peak early and late transmitral (E and A) and annular diastolic filling velocities (e' and a'). Maximal cardiopulmonary exercise testing was performed to measure maximal oxygen consumption (VO2max), ventilatory anaerobic threshold (VAT) and heart rate reserve (HRR). After BP measurement, they were grouped according to the ESH/ESC guidelines on: optimal (OBP), normal (NBP), high normal BP (HNBP), and hypertensive (HT). RESULTS: We found significantly lower VO2max, VAT and HRR in the groups with HNBP and HT, after the adjustment for the type of sport, body fat content and age. There was an increasing trend in resting HR among groups (p<0.001). Although none of the subjects had impaired diastolic function, the HT group had higher left atrial volume, and lower e' and e'/a'. Resting systolic BP (p<0.05), HR (p<0.001), HRR (p<0.001) and e'/a' (p<0.01) independently predicted VO2max. Indexes E/e' and e'/a' were associated with resting systolic BP (p<0.05). CONCLUSION: Even in the absence of structural or functional heart damage, elevated BP in elite athletes, together with the presence of autonomic dysfunction, leads to decrease in exercise capacity. Staging of hypertension according to the BP level, on the one hand, and reflexion of BP on cardiopulmonary capacity, on the other, may be coupled for further risk stratification. PMID- 25460374 TI - Costly third-party punishment in young children. AB - Human adults engage in costly third-party punishment of unfair behavior, but the developmental origins of this behavior are unknown. Here we investigate costly third-party punishment in 5- and 6-year-old children. Participants were asked to accept (enact) or reject (punish) proposed allocations of resources between a pair of absent, anonymous children. In addition, we manipulated whether subjects had to pay a cost to punish proposed allocations. Experiment 1 showed that 6-year olds (but not 5-year-olds) punished unfair proposals more than fair proposals. However, children punished less when doing so was personally costly. Thus, while sensitive to cost, they were willing to sacrifice resources to intervene against unfairness. Experiment 2 showed that 6-year-olds were less sensitive to unequal allocations when they resulted from selfishness than generosity. These findings show that costly third-party punishment of unfair behavior is present in young children, suggesting that from early in development children show a sophisticated capacity to promote fair behavior. PMID- 25460375 TI - Toys are me: children's extension of self to objects. AB - Adults tend to believe that objects can function as extensions of people's selves. This belief has been demonstrated in that changes to people's sense of self affect their attachment to personally valuable objects, and vice-versa. Here we tested the development of this belief. In Study 1 we found that manipulating 5 year-olds' self-worth via positive or negative feedback on performance, affected their willingness to part with personally valuable objects, but had no effect vis a-vis non-valuable objects. In Study 2 we found that 9-, but not 5-year-olds were more willing to give a personally valuable object to someone morally repulsive after the object had been cleaned of all remnants of the child's self, than before. Study 2b showed an analogous effect in 5-year-olds' willingness to receive an object from someone morally repulsive. These findings intimate that the extension of self to objects via contagion may derive not only from cultural values such as consumerism, materialism, or individualism, but also from basic human needs. PMID- 25460376 TI - The construction of categorization judgments: using subjective confidence and response latency to test a distributed model. AB - The classification of objects to natural categories exhibits cross-person consensus and within-person consistency, but also some degree of between-person variability and within-person instability. What is more, the variability in categorization is also not entirely random but discloses systematic patterns. In this study, we applied the Self-Consistency Model (SCM, Koriat, 2012) to category membership decisions, examining the possibility that confidence judgments and decision latency track the stable and variable components of categorization responses. The model assumes that category membership decisions are constructed on the fly depending on a small set of clues that are sampled from a commonly shared population of pertinent clues. The decision and confidence are based on the balance of evidence in favor of a positive or a negative response. The results confirmed several predictions derived from SCM. For each participant, consensual responses to items were more confident than non-consensual responses, and for each item, participants who made the consensual response tended to be more confident than those who made the nonconsensual response. The difference in confidence between consensual and nonconsensual responses increased with the proportion of participants who made the majority response for the item. A similar pattern was observed for response speed. The pattern of results obtained for cross-person consensus was replicated by the results for response consistency when the responses were classified in terms of within-person agreement across repeated presentations. These results accord with the sampling assumption of SCM, that confidence and response speed should be higher when the decision is consistent with what follows from the entire population of clues than when it deviates from it. Results also suggested that the context for classification can bias the sample of clues underlying the decision, and that confidence judgments mirror the effects of context on categorization decisions. The model and results offer a principled account of the stable and variable contributions to categorization behavior within a decision-making framework. PMID- 25460377 TI - Foreperiod priming in temporal preparation: testing current models of sequential effects. AB - Sequential foreperiod effects in temporal preparation are typically asymmetric such that a previous experience of preparation has a strong impact on participants' responses to a forthcoming target stimulus presented at the current short rather than at the current long foreperiod. The trace-conditioning model explains this asymmetry by an automatic process of trace-conditioning, which is sufficient and independent from a strategic process of conditional probability monitoring considered by the dual-process model. The present study contrasted trace-conditioning and dual-process models in three experiments that employed a non-aging distribution to keep conditional probability of target occurrence constant across foreperiod durations. In Experiment 1 (no catch trials), the typical pattern of asymmetric sequential effects was replicated, whereas in Experiments 2 and 3 (25% and 50% of catch trials, respectively) the results showed shorter RTs when previous and current foreperiods were repeated rather than alternated for both current short and long foreperiods. These results are discussed in relation to the two most influential models of sequential effects and to a novel account based on repetition priming. PMID- 25460378 TI - Social scaling of extrapersonal space: target objects are judged as closer when the reference frame is a human agent with available movement potentialities. AB - Space perception depends on our motion potentialities and our intended actions are affected by space perception. Research on peripersonal space (the space in reaching distance) shows that we perceive an object as being closer when we (Witt, Proffitt, & Epstein, 2005; Witt & Proffitt, 2008) or another actor (Costantini, Ambrosini, Sinigaglia, & Gallese, 2011; Bloesch, Davoli, Roth, Brockmole, & Abrams, 2012) can interact with it. Similarly, an object only triggers specific movements when it is placed in our peripersonal space (Costantini, Ambrosini, Tieri, Sinigaglia, & Committeri, 2010) or in the other's peripersonal space (Costantini, Committeri, & Sinigaglia, 2011; Cardellicchio, Sinigaglia, & Costantini, 2013). Moreover, also the extrapersonal space (the space outside reaching distance) seems to be perceived in relation to our movement capabilities: the more effort it takes to cover a distance, the greater we perceive the distance to be (Proffitt, Stefanucci, Banton, & Epstein, 2003; Sugovic & Witt, 2013). However, not much is known about the influence of the other's movement potentialities on our extrapersonal space perception. Three experiments were carried out investigating the categorization of distance in extrapersonal space using human or non-human allocentric reference frames (RF). Subjects were asked to judge the distance ("Near" or "Far") of a target object (a beach umbrella) placed at progressively increasing or decreasing distances until a change from near to far or vice versa was reported. In the first experiment we found a significant "Near space extension" when the allocentric RF was a human virtual agent instead of a static, inanimate object. In the second experiment we tested whether the "Near space extension" depended on the anatomical structure of the RF or its movement potentialities by adding a wooden dummy. The "Near space extension" was only observed for the human agent but not for the dummy. Finally, to rule out the possibility that the effect was simply due to a line-of-sight mechanism (visual perspective taking) we compared the human agent free to move with the same agent tied to a pole with a rope, thus reducing movement potentialities while maintaining equal visual accessibility. The "Near space extension" disappeared when this manipulation was introduced, showing that movement potentialities are the relevant factor for such an effect. Our results demonstrate for the first time that during allocentric distance judgments within extrapersonal space, we implicitly process the movement potentialities of the RF. A target object is perceived as being closer when the allocentric RF is a human with available movement potentialities, suggesting a mechanism of social scaling of extrapersonal space processing. PMID- 25460379 TI - Adjustments of response speed and accuracy to unconscious cues. AB - Controlling response parameters like the speed and accuracy of responses allows us to adjust our behavior according to particular situational task demands. We investigated whether exertion of cognitive control over speed-accuracy settings is not exclusively based on conscious representations, but can also be elicited by stimuli that are not consciously represented. Participants were instructed to point and click on a target, with a cue signaling before each response whether to prioritize accuracy of the response over speed, or vice versa. In half of the trials, the cue was masked to prevent a conscious representation of the cue. With visible cues, response patterns showed typical speed-accuracy tradeoffs, with faster and less accurate responses after speed cues, and slower but more accurate responses after accuracy cues. Crucially, this was found with masked cues as well. Our results are in line with recent findings on the relation of consciousness and cognitive control processes like task-set activation and response inhibition: masked cues are able to impact on cognitive control processes. PMID- 25460380 TI - Ontological confusions but not mentalizing abilities predict religious belief, paranormal belief, and belief in supernatural purpose. AB - The current research tested the hypothesis that the abilities for understanding other people's minds give rise to the cognitive biases that underlie supernatural beliefs. We used structural equation modeling (N=2789) to determine the roles of various mentalizing tendencies, namely self-reported affective and cognitive empathy (i.e., mind reading), actual cognitive and affective empathic abilities, hyper-empathizing, and two cognitive biases (core ontological confusions and promiscuous teleology) in giving rise to supernatural beliefs. Support for a path from mentalizing abilities through cognitive biases to supernatural beliefs was weak. The relationships of mentalizing abilities with supernatural beliefs were also weak, and these relationships were not substantially mediated by cognitive biases. Core ontological confusions emerged as the best predictor, while promiscuous teleology predicted only a small proportion of variance. The results were similar for religious beliefs, paranormal beliefs, and for belief in supernatural purpose. PMID- 25460381 TI - The sexualized-body-inversion hypothesis revisited: valid indicator of sexual objectification or methodological artifact? AB - Recently, Bernard, Gervais, Allen, Campomizzi, and Klein (2012) reported that individuals were less able to recognize inverted vs. upright pictures of sexualized men as compared to women. Based on their formulation of the sexualized body-inversion hypothesis (SBIH) it was concluded that sexualized women as compared to men are perceived in a more object-like manner supporting sexual objectification (SO) of females - independent from observer gender. We challenge this interpretation and hypothesize that the originally reported effect is the result of a methodological artifact due to gender-symmetry and stimuli setup symmetry confounds in the original stimulus set. We tested this theoretically more parsimonious account in a methodologically stricter and extended conceptual replication of the putative SO-effect. Results from two studies showed that the original stimulus set indeed suffered from symmetry confounds and that these are necessary boundary-conditions in order for the hypothetical SO-effect to occur. It is concluded that the SBIH as postulated by Bernard et al. (2012) is based on a methodological artifact and cannot be related to SO but symmetry detection. PMID- 25460382 TI - Immediate lexical integration of novel word forms. AB - It is well known that familiar words inhibit each other during spoken word recognition. However, we do not know how and under what circumstances newly learned words become integrated with the lexicon in order to engage in this competition. Previous work on word learning has highlighted the importance of offline consolidation (Gaskell & Dumay, 2003) and meaning (Leach & Samuel, 2007) to establish this integration. In two experiments we test the necessity of these factors by examining the inhibition between newly learned items and familiar words immediately after learning. Participants learned a set of nonwords without meanings in active (Experiment 1) or passive (Experiment 2) exposure paradigms. After training, participants performed a visual world paradigm task to assess inhibition from these newly learned items. An analysis of participants' fixations suggested that the newly learned words were able to engage in competition with known words without any consolidation. PMID- 25460383 TI - There is more to eye contact than meets the eye. AB - Recent studies have shown enhanced brain and autonomic responses to seeing a face with a direct gaze. Interestingly, greater responses to eye contact vs. averted gaze have been observed when showing "live" faces as stimuli but not when showing pictures of faces on a computer screen. In this study, we provide unequivocal evidence that the differential responses observed in the "live" condition are dependent on the observer's mental attributions. Results from two experiments showed that eye contact resulted in greater autonomic and brain responses compared to averted gaze if a participant believed that the stimulus person sitting on the other side of an electronic shutter was able to see him or her through the shutter. Gaze direction had no effects if participants believed that the transparency from their side was blocked. The results suggest that mental attributions exert a powerful modulation on the processing of socially relevant sensory information. PMID- 25460384 TI - The role of (dis)inhibition in creativity: decreased inhibition improves idea generation. AB - There is now a large body of evidence showing that many different conditions related to impaired fronto-executive functioning are associated with the enhancement of some types of creativity. In this paper, we pursue the possibility that the central mechanism associated with this effect might be a reduced capacity to exert inhibition. We tested this hypothesis by exhausting the inhibition efficiency through prolonged and intensive practice of either the Simon or the Eriksen Flanker task. Performance on another inhibition task indicated that only the cognitive resources for inhibition of participants facing high inhibition demands were impaired. Subsequent creativity tests revealed that exposure to high inhibition demands led to enhanced fluency in a divergent thinking task (Alternate Uses Task), but no such changes occurred in a convergent task (Remote Associate Task; studies 1a and 1b). The same manipulation also led to a hyper-priming effect for weakly related primes in a Lexical Decision Task (Study 2). Together, these findings suggest that inhibition selectively affects some types of creative processes and that, when resources for inhibition are lacking, the frequency and the originality of ideas was facilitated. PMID- 25460385 TI - The drunk utilitarian: blood alcohol concentration predicts utilitarian responses in moral dilemmas. AB - The hypothetical moral dilemma known as the trolley problem has become a methodological cornerstone in the psychological study of moral reasoning and yet, there remains considerable debate as to the meaning of utilitarian responding in these scenarios. It is unclear whether utilitarian responding results primarily from increased deliberative reasoning capacity or from decreased aversion to harming others. In order to clarify this question, we conducted two field studies to examine the effects of alcohol intoxication on utilitarian responding. Alcohol holds promise in clarifying the above debate because it impairs both social cognition (i.e., empathy) and higher-order executive functioning. Hence, the direction of the association between alcohol and utilitarian vs. non-utilitarian responding should inform the relative importance of both deliberative and social processing systems in influencing utilitarian preference. In two field studies with a combined sample of 103 men and women recruited at two bars in Grenoble, France, participants were presented with a moral dilemma assessing their willingness to sacrifice one life to save five others. Participants' blood alcohol concentrations were found to positively correlate with utilitarian preferences (r=.31, p<.001) suggesting a stronger role for impaired social cognition than intact deliberative reasoning in predicting utilitarian responses in the trolley dilemma. Implications for Greene's dual-process model of moral reasoning are discussed. PMID- 25460386 TI - Manual action, fitting, and spatial planning: relating objects by young children. AB - This study uses motion tracking technology to provide a new way of addressing the development of the ability to prospectively orient objects with respect to one another. A group of toddlers between 16 and 33 months of age (N=30) were studied in an object fitting task while they wore reflective markers on their hands to track spatial adjustments in three dimensions. Manual displacements of the handheld object were separated into translations and rotations. Results revealed that younger children largely used a two-step approach in which they initially translate an object to a target and subsequently attempt to rotate the object to match the target. In contrast, older children evidence more advanced spatial planning and integrate translational and rotational components throughout the entire period when they are transporting the object to the target. Additionally, at the oldest ages, children show even further improvements in coordinating translations and rotations by using relatively shorter translations (i.e., covering less distance) and by avoiding unnecessary rotations of the object. More broadly, the results offer insights into how manual problem solving becomes more efficient and planful during the toddler years. PMID- 25460387 TI - Playing by the rules: self-interest information influences children's trust and trustworthiness in the absence of feedback. AB - This study documented how children's decisions to trust and help partners in a game depend on the game's incentives. Adults, 5-, 7-, and 9-year-olds (N=128) guessed the location of hidden prizes, assisted by a partner who observed the hiding. After each hiding event the partner shared information with participants about the prize's location. Participants earned prizes every time they guessed correctly. The partner earned prizes either from participants' correct (cooperation incentive) or incorrect (competition incentive) guesses. Children and adults trusted their partner more often when the game incentivized cooperation versus competition. A complementary pattern was observed when participants assisted their partner find prizes they observed being hidden: Participants strategically shared truthful information more often when the game rewarded cooperation. PMID- 25460388 TI - The tree to the left, the forest to the right: political attitude and perceptual bias. AB - A prominent model suggests that individuals to the right of the political spectrum are more cognitively rigid and less tolerant of ambiguity than individuals to the left. On the basis of this model, we predicted that a psychological mechanism linked to the resolution of visual ambiguity--perceptual bias--would be linked to political attitude. Perceptual bias causes western individuals to favour a global interpretation when scrutinizing ambiguous hierarchical displays (e.g., alignment of trees) that can be perceived either in terms of their local elements (e.g., several trees) or in terms of their global structure (e.g., a forest). Using three tasks (based on Navon-like hierarchical figures or on the Ebbinghaus illusion), we demonstrate (1) that right-oriented Westerners present a stronger bias towards global perception than left-oriented Westerners and (2) that this stronger bias is linked to higher cognitive rigidity. This study establishes for the first time that political ideology, a high-level construct, is directly reflected in low-level perception. Right- and left-oriented individuals actually see the world differently. PMID- 25460389 TI - Rest is best: the role of rest and task interruptions on vigilance. AB - We examined the impact task interruptions have on visuospatial vigilance in two experiments. In the first experiment participants were randomly assigned to one of three interruptions: participants were given a complete rest (rest), participants completed an alphanumeric vigilance task (letter), or participants performed the primary vigilance task (continuous). In the second experiment participants were randomly assigned to one of the conditions from the first experiment or to two further conditions, in which participants (spatial memory) performed a spatial match to sample task, or participants (verbal memory) performed a letter match to sample task. Vigilance performance post-interruption was best for rest, worst for continuous, and varied for the other interruption tasks. Overall, the results suggest the vigilance decrement is due to the repeated use of particular executive resources, but there may, in addition be domain specific interference when the primary task and activities during a break make use of the same resources. PMID- 25460390 TI - Contribution of motor representations to action verb processing. AB - Electrophysiological and brain imaging studies show a somatotopic activation of the premotor cortex while subjects process action verbs. This somatotopic motor activation has been taken as an indication that the meaning of action verbs is embedded in motor representations. However, discrepancies in the literature led to the alternative hypothesis that motor representations are activated during the course of a mental imagery process emerging only after the meaning of the action has been accessed. In order to address this issue, we asked participants to decide whether a visually presented verb was concrete or abstract by pressing a button or a pedal (primary task) and then to provide a distinct vocal response to low and high sounds played soon after the verb display (secondary task). Manipulations of the visual display (lower vs. uppercase), verb imageability (concrete vs. abstract), verb meaning (hand vs. foot-related), and response effector (hand vs. foot) allowed us to trace the perceptual, semantic and response stages of verb processing. We capitalized on the psychological refractory period (PRP), which implies that the initiation of the secondary task should be delayed only by those factors that slow down the central decision process in the primary task. In line with this prediction, our results showed that the time cost resulting from the processing of abstract verbs, when compared to concrete verbs, was still observed in the subsequent response to the sounds, whereas the overall advantage of hand over foot responses did not influence sound judgments. Crucially, we also observed a verb-effector compatibility effect (i.e., foot-related verbs are responded faster with the foot and hand-related verbs with the hand) that contaminated the performance of the secondary task, providing clear evidence that motor interference from verb meaning occurred during the central decision stage. These results cannot be explained by a mental imagery process that would deploy only during the execution of the response to verb judgments. They rather indicate that the motor activation induced by action verbs accompanies the lexico-semantic processes leading to response selection. PMID- 25460391 TI - Who can communicate with whom? Language experience affects infants' evaluation of others as monolingual or multilingual. AB - Adults recognize that people can understand more than one language. However, it is unclear whether infants assume other people understand one or multiple languages. We examined whether monolingual and bilingual 20-month-olds expect an unfamiliar person to understand one or more than one language. Two speakers told a listener the location of a hidden object using either the same or two different languages. When different languages were spoken, monolinguals looked longer when the listener searched correctly, bilinguals did not; when the same language was spoken, both groups looked longer for incorrect searches. Infants rely on their prior language experience when evaluating the language abilities of a novel individual. Monolingual infants assume others can understand only one language, although not necessarily the infants' own; bilinguals do not. Infants' assumptions about which community of conventions people belong to may allow them to recognize effective communicative partners and thus opportunities to acquire language, knowledge, and culture. PMID- 25460393 TI - Information without content: a Gibsonian reply to enactivists' worries. AB - In this article, we aim to strengthen the emerging radical, non-representational, approaches to cognitive science by defusing the worries radical enactivists have with the use of information in the ecological approaches - namely the worry that information carries content. We show that Gibson's later use of the concept is meant to allow for a content-less notion of information, but that the language surrounding information in ecological psychology has subsequently slipped into a more cognitivistic vocabulary. We argue that by considering ecological information not to be information about, but information for affordances, the notion of information can be fruitfully applied without invoking notions of content. Gibson's later notion of information for perception, stresses the insight that in ecological theory there is no information in content, but only in use. It is suggested that radical cognition should embrace this notion of information without content, as doing so can help to situate the enactivist's "basic mind" into large and complex scales of coordination. PMID- 25460392 TI - 'Utilitarian' judgments in sacrificial moral dilemmas do not reflect impartial concern for the greater good. AB - A growing body of research has focused on so-called 'utilitarian' judgments in moral dilemmas in which participants have to choose whether to sacrifice one person in order to save the lives of a greater number. However, the relation between such 'utilitarian' judgments and genuine utilitarian impartial concern for the greater good remains unclear. Across four studies, we investigated the relationship between 'utilitarian' judgment in such sacrificial dilemmas and a range of traits, attitudes, judgments and behaviors that either reflect or reject an impartial concern for the greater good of all. In Study 1, we found that rates of 'utilitarian' judgment were associated with a broadly immoral outlook concerning clear ethical transgressions in a business context, as well as with sub-clinical psychopathy. In Study 2, we found that 'utilitarian' judgment was associated with greater endorsement of rational egoism, less donation of money to a charity, and less identification with the whole of humanity, a core feature of classical utilitarianism. In Studies 3 and 4, we found no association between 'utilitarian' judgments in sacrificial dilemmas and characteristic utilitarian judgments relating to assistance to distant people in need, self-sacrifice and impartiality, even when the utilitarian justification for these judgments was made explicit and unequivocal. This lack of association remained even when we controlled for the antisocial element in 'utilitarian' judgment. Taken together, these results suggest that there is very little relation between sacrificial judgments in the hypothetical dilemmas that dominate current research, and a genuine utilitarian approach to ethics. PMID- 25460394 TI - Developing expectations regarding the boundaries of expertise. AB - Three experiments examined elementary school-aged children's and adults' expectations regarding what specialists (i.e., those with narrow domains of expertise) and generalists (i.e., those with broad domains of expertise) are likely to know. Experiment 1 demonstrated developmental differences in the ability to differentiate between generalists and specialists, with younger children believing generalists have more specific trivia knowledge than older children and adults believed. Experiment 2 demonstrated that children and adults expected generalists to have more underlying principles knowledge than specific trivia knowledge about unfamiliar animals. However, they believed that generalists would have more of both types of knowledge than themselves. Finally, Experiment 3 demonstrated that children and adults recognized that underlying principles knowledge can be generalized between topics closely related to the specialists' domains of expertise. However, they did not recognize when this knowledge was generalizable to topics slightly less related, expecting generalists to know only as much as they would. Importantly, this work contributes to the literature by showing how much of and what kinds of knowledge different types of experts are expected to have. In sum, this work provides insight into some of the ways children's notions of expertise change over development. The current research demonstrates that between the ages of 5 and 10, children are developing the ability to recognize how experts' knowledge is likely to be limited. That said, even older children at times struggle to determine the breadth of an experts' knowledge. PMID- 25460396 TI - Evidence for a supra-modal representation of emotion from cross-modal adaptation. AB - Successful social interaction hinges on accurate perception of emotional signals. These signals are typically conveyed multi-modally by the face and voice. Previous research has demonstrated uni-modal contrastive aftereffects for emotionally expressive faces or voices. Here we were interested in whether these aftereffects transfer across modality as theoretical models predict. We show that adaptation to facial expressions elicits significant auditory aftereffects. Adaptation to angry facial expressions caused ambiguous vocal stimuli drawn from an anger-fear morphed continuum to be perceived as less angry and more fearful relative to adaptation to fearful faces. In a second experiment, we demonstrate that these aftereffects are not dependent on learned face-voice congruence, i.e. adaptation to one facial identity transferred to an unmatched voice identity. Taken together, our findings provide support for a supra-modal representation of emotion and suggest further that identity and emotion may be processed independently from one another, at least at the supra-modal level of the processing hierarchy. PMID- 25460395 TI - Synchronization to auditory and visual rhythms in hearing and deaf individuals. AB - A striking asymmetry in human sensorimotor processing is that humans synchronize movements to rhythmic sound with far greater precision than to temporally equivalent visual stimuli (e.g., to an auditory vs. a flashing visual metronome). Traditionally, this finding is thought to reflect a fundamental difference in auditory vs. visual processing, i.e., superior temporal processing by the auditory system and/or privileged coupling between the auditory and motor systems. It is unclear whether this asymmetry is an inevitable consequence of brain organization or whether it can be modified (or even eliminated) by stimulus characteristics or by experience. With respect to stimulus characteristics, we found that a moving, colliding visual stimulus (a silent image of a bouncing ball with a distinct collision point on the floor) was able to drive synchronization nearly as accurately as sound in hearing participants. To study the role of experience, we compared synchronization to flashing metronomes in hearing and profoundly deaf individuals. Deaf individuals performed better than hearing individuals when synchronizing with visual flashes, suggesting that cross-modal plasticity enhances the ability to synchronize with temporally discrete visual stimuli. Furthermore, when deaf (but not hearing) individuals synchronized with the bouncing ball, their tapping patterns suggest that visual timing may access higher-order beat perception mechanisms for deaf individuals. These results indicate that the auditory advantage in rhythmic synchronization is more experience- and stimulus-dependent than has been previously reported. PMID- 25460397 TI - Even at 4 months, a labial is a good enough coronal, but not vice versa. AB - Numerous studies have revealed an asymmetry tied to the perception of coronal place of articulation: participants accept a labial mispronunciation of a coronal target, but not vice versa. Whether or not this asymmetry is based on language general properties or arises from language-specific experience has been a matter of debate. The current study suggests a bias of the first type by documenting an early, cross-linguistic asymmetry related to coronal place of articulation. Japanese and Dutch 4- and 6-month-old infants showed evidence of discrimination if they were habituated to a labial and then tested on a coronal sequence, but not vice versa. This finding has important implications for both phonological theories and infant speech perception research. PMID- 25460398 TI - Quantitative assessment of the enamel machinability in tooth preparation with dental diamond burs. AB - Enamel cutting using dental handpieces is a critical process in tooth preparation for dental restorations and treatment but the machinability of enamel is poorly understood. This paper reports on the first quantitative assessment of the enamel machinability using computer-assisted numerical control, high-speed data acquisition, and force sensing systems. The enamel machinability in terms of cutting forces, force ratio, cutting torque, cutting speed and specific cutting energy were characterized in relation to enamel surface orientation, specific material removal rate and diamond bur grit size. The results show that enamel surface orientation, specific material removal rate and diamond bur grit size critically affected the enamel cutting capability. Cutting buccal/lingual surfaces resulted in significantly higher tangential and normal forces, torques and specific energy (p<0.05) but lower cutting speeds than occlusal surfaces (p<0.05). Increasing material removal rate for high cutting efficiencies using coarse burs yielded remarkable rises in cutting forces and torque (p<0.05) but significant reductions in cutting speed and specific cutting energy (p<0.05). In particular, great variations in cutting forces, torques and specific energy were observed at the specific material removal rate of 3mm(3)/min/mm using coarse burs, indicating the cutting limit. This work provides fundamental data and the scientific understanding of the enamel machinability for clinical dental practice. PMID- 25460399 TI - PDMS substrate stiffness affects the morphology and growth profiles of cancerous prostate and melanoma cells. AB - A deep understanding of the interaction between cancerous cells and surfaces is particularly important for the design of lab-on-chip devices involving the use of polydimethylsiloxane (PDMS). In our studies, the effect of PDMS substrate stiffness on mechanical properties of cancerous cells was investigated in conditions where the PDMS substrate is not covered with any of extracellular matrix proteins. Two human prostate cancer (Du145 and PC-3) and two melanoma (WM115 and WM266-4) cell lines were cultured on two groups of PDMS substrates that were characterized by distinct stiffness, i.e. 0.75 +/- 0.06 MPa and 2.92 +/ 0.12 MPa. The results showed the strong effect on cellular behavior and morphology. The detailed analysis of chemical and physical properties of substrates revealed that cellular behavior occurs only due to substrate elasticity. PMID- 25460400 TI - Finite element analysis of the human mastication cycle. AB - The aim of this paper is to propose a biomechanical model that could serve as a tool to overcome some difficulties encountered in experimental studies of the mandible. One of these difficulties is the inaccessibility of the temporomandibular joint (TMJ) and the lateral pterygoid muscle. The focus of this model is to study the stresses in the joint and the influence of the lateral pterygoid muscle on the mandible movement. A finite element model of the mandible, including the TMJ, was built to simulate the process of unilateral mastication. Different activation patterns of the left and right pterygoid muscles were tried. The maximum stresses in the articular disc and in the whole mandible during a complete mastication cycle were reached during the instant of centric occlusion. The simulations show a great influence of the coordination of the right and left lateral pterygoid muscles on the movement of the jaw during mastication. An asynchronous activation of the lateral pterygoid muscles is needed to achieve a normal movement of the jaw during mastication. PMID- 25460401 TI - Evaluating morphology and mechanical properties of glass-reinforced natural hydroxyapatite composites. AB - Hydroxyapatite has been used in a wide variety of biomedical applications and it can be produced from natural resources such as bovine bone. This material does not have acceptable mechanical properties by itself. In the present work, hydroxyapatite composites with different weight percentages of sodalime glass were made and sintered at different temperatures (800-1200 degrees C). Eventually the properties such as density, micro hardness, compressive strength and wear of specimens were evaluated. Specific percentages of glass additive increased the density and hardness of specimens due to increasing the sintering temperature. The hardness and density of specimens were decreased with higher percentage of glass additive. Moreover, the results of compressive test showed that increasing the glass addition increases the compressive performance. Furthermore, the SEM micrographs on worn specimens showed that the mechanism of wear was abrasive. PMID- 25460402 TI - 3D multi-channel bi-functionalized silk electrospun conduits for peripheral nerve regeneration. AB - Despite technological advances over the past 25 years, a complete recovery from peripheral nerve injuries remains unsatisfactory today. The autograft is still considered the "gold standard" in clinical practice; however, postoperative complications and limited availability of nerve tissue have motivated the development of alternative approaches. Among them, the development of biomimetic nerve graft substitutes is one of the most promising strategies. In this study, multichanneled silk electrospun conduits bi-functionalized with Nerve Growth Factor (NGF) and Ciliary Neurotropic Factor (CNTF) were fabricated to enhance peripheral nerve regeneration. These bioactive guides consisting of longitudinally oriented channels and aligned nanofibers were designed in order to mimic the fascicular architecture and fibrous extracellular matrix found in native nerve. The simple use of the electrospinning technique followed by a manual manipulation to manufacture these conduits provides tailoring of channel number and diameter size to create perineurium-like structures. Functionalization of the silk fibroin nanofiber did not affect its secondary structure and chemical property. ELISA assays showed the absence of growth factors passive release from the functionalized fibers avoiding the topical accumulation of proteins. In addition, our biomimetic multichanneled functionalized nerve guides displayed a mechanical behavior comparable to that of rat sciatic nerve with an ultimate peak stress of 4.0 +/- 0.6 MPa and a corresponding elongation at failure of 156.8 +/- 46.7%. Taken together, our results demonstrate for the first time our ability to design and characterize a bi-functionalized nerve conduit consisting of electrospun nanofibers with multichannel oriented and nanofibers aligned for peripheral regeneration. Our bioactive silk tubes thus represent a new and promising technique towards the creation of a biocompatible nerve guidance conduit. PMID- 25460403 TI - Investigating stress shielding spanned by biomimetic polymer-composite vs. metallic hip stem: A computational study using mechano-biochemical model. AB - Periprosthetic bone loss in response to total hip arthroplasty is a serious complication compromising patient's life quality as it may cause the premature failure of the implant. Stress shielding as a result of an uneven load sharing between the hip implant and the bone is a key factor leading to bone density decrease. A number of composite hip implants have been designed so far to improve load sharing characteristics. However, they have rarely been investigated from the bone remodeling point of view to predict a long-term response. This is the first study that employed a mechano-biochemical model, which considers the coupling effect between mechanical loading and bone biochemistry, to investigate bone remodeling after composite hip implantation. In this study, periprosthetic bone remodeling in the presence of Carbon fiber polyamide 12 (CF/PA12), CoCrMo and Ti alloy implants was predicted and compared. Our findings revealed that the most significant periprosthetic bone loss in response to metallic implants occurs in Gruen zone 7 (-43% with CoCrMo; -35% with Ti) and 6 (-40% with CoCrMo; -29% with Ti), while zone 4 has the lowest bone density decrease with all three implants (-9%). Also, the results showed that in terms of bone remodeling, the composite hip implant is more advantageous over the metallic ones as it provides a more uniform density change across the bone and induces less stress shielding which consequently results in a lower post-operative bone loss (-9% with CF/PA12 implant compared to -27% and -21% with CoCrMo and Ti alloy implants, respectively). PMID- 25460404 TI - Uniaxial and biaxial mechanical properties of porcine linea alba. AB - Incisional hernia is a severe complication post-laparoscopic/laparotomy surgery that is commonly associated with the linea alba. However, the few studies on the mechanical properties of the linea alba in the literature appear contradictory, possible due to challenges with the physical dimensions of samples and variations in protocol. This study focuses on the tensile mechanical characterisation of the porcine linea alba, as determined by uniaxial and equi-load biaxial testing using image-based strain measurement methods. Results show that the linea alba demonstrated a non-linear elastic, anisotropic behaviour which is often observed in biological soft tissues. The transverse direction (parallel to fibres) was found to be approximately eight times stiffer than the longitudinal (cross-fibre) direction under both uniaxial and equi-load biaxial loading. The equi-load biaxial tensile tests revealed that contraction could occur in the transverse direction despite increasing load, probably due to the anisotropy of the tissue. Optical surface marker tracking and digital image correlation methods were found to greatly improve the accuracy of stretch measurement, resulting in a 75% change in the apparent stiffness compared to using strain derived from machine cross head displacement. Additionally, a finite element model of the experiments using a combination of an Ogden and fibre exponential power law model for the linea alba was implemented to quantify the effect of clamping and tissue dimensions (which are suboptimal for tensile testing) on the results. The preliminary model results were used to apply a correction factor to the uniaxial experimental data prior to inverse optimisation to derive best fit material parameters for the fibre reinforced Ogden model. Application of the model to the equi-load biaxial case showed some differences compared to the experimental data, suggesting a more complex anisotropic model may be necessary to capture biaxial behaviour. These results provide an improved assessment of the mechanical properties of the porcine linea alba for wound closure and other studies. PMID- 25460405 TI - Biotribological behavior of Ag-ZrCxN1-x coatings against UHMWPE for joint prostheses devices. AB - This study aims to evaluate the structural, mechanical and tribological properties of zirconium carbonitrides (ZrCxN1-x) coatings with embedded silver nanoparticles, produced with the intention of achieving a material with enhanced multi-functional properties, including mechanical strength, corrosion resistance, tribological performance and antibacterial behavior suitable for their use in joint prostheses. The coatings were deposited by direct current (DC) reactive magnetron sputtering onto 316 L stainless steel, changing the silver content from 0 to 20 at% by modifying the current density applied to the targets. Different nitrogen and acetylene gas fluxes were used as reactive gases. The coatings revealed different mixtures of crystalline ZrCxN1-x, silver nanoparticles and amorphous carbon phases. The hardness of the films was found to be mainly controlled by the ratio between the hard (ZrCxN1-x) and soft (Ag and amorphous carbon) phases in the films, fluctuating between 7.4 and 20.4 GPa. The coefficient of friction, measured against ultra-high molecular weight polyethylene (UHMWPE) in Hank's balanced salt solution with 10 gL(-1) albumin, is governed by the surface roughness and hardness. The UHMWPE wear rates were in the same order of magnitude (between 1.4 and 2.0 * 10(-6)mm(3)N(-1)m(-1)), justified by the effect of the protective layer of albumin formed during the tests. The small differences were due to the hydrophobic/hydrophilic character of the surface, as well as to the silver content. PMID- 25460406 TI - Human thoracic and abdominal aortic aneurysmal tissues: Damage experiments, statistical analysis and constitutive modeling. AB - Development of aortic aneurysms includes significant morphological changes within the tissue: collagen content increases, elastin content reduces and smooth muscle cells degenerate. We seek to quantify the impact of these changes on the passive mechanical response of aneurysms in the supra-physiological loading range via mechanical testing and constitutive modeling. We perform uniaxial extension tests on circumferentially and axially oriented strips from five thoracic (65.6 years +/- 13.4, mean +/- SD) and eight abdominal (63.9 years +/- 11.4) aortic fusiform aneurysms to investigate both continuous and discontinuous softening during supra physiological loading. We determine the significance of the differences between the fitted model parameters: diseased thoracic versus abdominal tissues, and healthy (Weisbecker et al., J. Mech. Behav. Biomed. Mater. 12, 93-106, 2012) versus diseased tissues. We also test correlations among these parameters and age, Body Mass Index (BMI) and preoperative aneurysm diameter, and investigate histological cuts. Tissue response is anisotropic for all tests and the anisotropic pseudo-elastic damage model fits the data well for both primary loading and discontinuous softening which we interpret as damage. We found statistically relevant differences between model parameters fitted to diseased thoracic versus abdominal tissues, as well as between those fitted to healthy versus diseased tissues. Only BMI correlated with fitted model parameters in abdominal aortic aneurysmal tissues. PMID- 25460407 TI - Regional and depth variability of porcine meniscal mechanical properties through biaxial testing. AB - The menisci in the knee joint undergo complex loading in-vivo resulting in a multidirectional stress distribution. Extensive mechanical testing has been conducted to investigate the tissue properties of the knee meniscus, but the testing conditions do not replicate this complex loading regime. Biaxial testing involves loading tissue along two different directions simultaneously, which more accurately simulates physiologic loading conditions. The purpose of this study was to report mechanical properties of meniscal tissue resulting from biaxial testing, while simultaneously investigating regional variations in properties. Ten left, fresh porcine joints were obtained, and the medial and lateral menisci were harvested from each joint (twenty menisci total). Each menisci was divided into an anterior, middle and posterior region; and three slices (femoral, deep and tibial layers) were obtained from each region. Biaxial and constrained uniaxial testing was performed on each specimen, and Young's moduli were calculated from the resulting stress strain curves. Results illustrated significant differences in regional mechanical properties, with the medial anterior (Young's modulus (E)=11.14 +/- 1.10 MPa), lateral anterior (E=11.54 +/- 1.10 MPa) and lateral posterior (E=9.0 +/- 1.2 MPa) regions exhibiting the highest properties compared to the medial central (E=5.0 +/- 1.22 MPa), medial posterior (E=4.16 +/- 1.13 MPa) and lateral central (E=5.6 +/- 1.20 MPa) regions. Differences with depth were also significant on the lateral meniscus, with the femoral (E=12.7 +/- 1.22 MPa) and tibial (E=8.6 +/- 1.22 MPa) layers exhibiting the highest Young's moduli. This data may form the basis for future modeling of meniscal tissue, or may aid in the design of synthetic replacement alternatives. PMID- 25460408 TI - Stretched exponential relaxation of piezovoltages in wet bovine bone. AB - It is important to determine the amplitude and variation characteristics of piezovoltage in wet bone, which can, in turn, be taken as a basis for studying whether electrical signals induced by external forces can affect the growth of bone cells. This work measured the characteristics of piezoelectric effects under dynamic and static loading. The results show that the variations of piezovoltage in wet bone in both loading and load holding periods follow a stretched exponential relaxation law, and the relaxation time constants of the piezovoltages are much larger than those of dry bone. This finding means that the active time of piezovoltage in wet bone is much longer than that of dry bone. Regardless of the loading and load holding processes, continuously increasing deformation in wet bone caused piezoelectric charges to be continuously induced and increased the dielectric constant of wet bone along with the deformation process. In general, compared with piezovoltage in dry bone, that in wet bone had lower amplitude and could exist for a longer duration. It can be inferred, therefore, that piezoelectricity might create coupling with the streaming potential in bone by changing the thickness of the double electrode layer. PMID- 25460409 TI - Decellularized grafts with axially aligned channels for peripheral nerve regeneration. AB - At least 2 million people worldwide suffer annually from peripheral nerve injuries (PNI), with estimated costs of $7 billion incurred due to paralysis alone. The current "gold" standard for treatment of PNI is the autograft, which poses disadvantages such as high fiscal cost, possible loss of sensation at donor site and the requirement of two surgeries. Allografts are viable alternatives; however, intensive immunosuppressive treatments are often necessary to prevent host rejection. For this reason, significant efforts have been made to remove cellular material from allografts. These decellularized nerve grafts perform better than other clinically available grafts but not as well as autografts; therefore, current research on these grafts includes the incorporation of additional components such as growth factors and cells to provide chemical guidance to regenerating axons. However, effective cellular and axonal penetration is not achieved due to the small pore size (5-10MUm) of the decellularized grafts. The overall objective of this study was to induce axially aligned channels in decellularized nerve grafts to facilitate enhanced cell penetration. The specific aims of this study were to optimize a decellularization method to enhance cellular removal, to induce axially aligned pore formation in decellularized grafts through a novel unidirectional freeze drying method, to study the bulk mechanical properties of these modified decellularized grafts and to assess cell penetration into these grafts. To this end we modified an existing decellularization protocol to improve cellular removal while preserving matrix structure in rat sciatic nerve sections. Standard freeze drying and unidirectional freeze drying were employed to impart the necessary pore architecture, and our results suggest that unidirectional freezing is a pertinent modification to the freeze drying process to obtain axially aligned channels. These highly porous scaffolds obtained using unidirectional freeze-drying possessed similar tensile properties to native nerve tissue and exhibited enhanced cellular penetration after 14 days of culture when compared to non freeze dried and standard freeze-dried scaffolds. The results of this study not only highlight the importance of aligned pores of diameters ~20-60MUm on cellular infiltration, but also presents unidirectional freeze drying as a viable technique for producing this required architecture in decellularized nerves. To the best of our knowledge, this study represents the first attempt to manipulate the physical structure of decellularized nerves to enhance cell penetration which may serve as a basis for future peripheral nerve regenerative strategies using decellularized allografts. PMID- 25460410 TI - Monotonic and cyclic loading behavior of porous scaffolds made from poly(para phenylene) for orthopedic applications. AB - Porous poly(para-phenylene) (PPP) scaffolds have tremendous potential as an orthopedic biomaterial; however, the underlying mechanisms controlling the monotonic and cyclic behavior are poorly understood. The purpose of this study was to develop a method to integrate micro-computed tomography (MUCT), finite element analysis (FEA), and experimental results to uncover the relationships between the porous structure and mechanical behavior. The MUCT images were taken from porous PPP scaffolds with a porosity of 75vol% and pore size distribution between 420 and 500um. Representative sections of the image were segmented and converted into finite-element meshes. It was shown through FEA that localized stresses within the microstructure were approximately 100 times higher than the applied global stress during the linear loading regime. Experimental analysis revealed the S-N fatigue curves for fully dense and porous PPP samples were parallel on log-log plots, with the endurance limit for porous samples in tension being approximately 100 times lower than their solid PPP counterparts (0.3-35MPa) due to the extreme stress concentrations caused by the porous microarchitecture. The endurance limit for porous samples in compression was much higher than in tension (1.60MPa). Through optical, laser-scanning, and scanning-electron microscopy it was found that porous tensile samples failed under Mode I fracture in both monotonic and cyclic loading. By comparison, porous compressive samples failed via strut buckling/pore collapse monotonically and by shearing fracture during cyclic loading. Monotonic loading showed that deformation behavior was strongly correlated with pore volume fraction, matching foam theory well; however, fatigue behavior was much more sensitive to local stresses believed to cause crack nucleation. PMID- 25460411 TI - Quantitative diagnostics of soft tissue through viscoelastic characterization using time-based instrumented palpation. AB - Although palpation has been successfully employed for centuries to assess soft tissue quality, it is a subjective test, and is therefore qualitative and depends on the experience of the practitioner. To reproduce what the medical practitioner feels needs more than a simple quasi-static stiffness measurement. This paper assesses the capacity of dynamic mechanical palpation to measure the changes in viscoelastic properties that soft tissue can exhibit under certain pathological conditions. A diagnostic framework is proposed to measure elastic and viscous behaviors simultaneously using a reduced set of viscoelastic parameters, giving a reliable index for quantitative assessment of tissue quality. The approach is illustrated on prostate models reconstructed from prostate MRI scans. The examples show that the change in viscoelastic time constant between healthy and cancerous tissue is a key index for quantitative diagnostics using point probing. The method is not limited to any particular tissue or material and is therefore useful for tissue where defining a unique time constant is not trivial. The proposed framework of quantitative assessment could become a useful tool in clinical diagnostics for soft tissue. PMID- 25460412 TI - Improving hydrogels' toughness by increasing the dissipative properties of their network. AB - The weak mechanical performance and fragility of hydrogels limit their application as biomaterials for load bearing applications. The origin of this weakness has been explained by the low resistance to chains breakage composing the hydrogel and to the cracks propagation in the hydrogel submitted to loading conditions. These low resistance and crack propagation were in turn related to an insufficient energy dissipation mechanism in the hydrogel structure. The goal of this study is to evaluate the dissipation mechanism in covalently bonded hydrogels so that tougher hydrogels can be developed while keeping for the hydrogel a relatively high mechanical stiffness. By varying parameters such as cross-linker type or concentration as well as water ratio, the dissipative properties of HEMA-based hydrogels were investigated at large deformations. Different mechanisms such as special friction-like phenomena, nanoporosity, and hydrophobicity were proposed to explain the dissipative behavior of the tested hydrogels. Based on this analysis, it was possible to develop hydrogels with increased toughness properties. PMID- 25460413 TI - Surface treatment of titanium by a polydimethylsiloxane coating on bond strength of resin to titanium. AB - PURPOSE: To evaluate the in vitro effect of titanium surface treatment by a polydimethylsiloxane coating on the shear bond strength of a resin composite cement to titanium. MATERIALS AND METHODS: The titanium samples (40*30mm) were divided into 4 groups (n=12). A control group was surface treated by sandblasting using 110um silica-coated alumina powder at a constant pressure of 300kPa for 15s/1cm(2). For other three test groups, a polydimethylsiloxane silicone grease was applied onto the surface. The samples were subjected to thermal treatment in air at temperatures of 800 degrees C, 1000 degrees C, and 1100 degrees C for 2h. A silane coupling agent was then applied and a resin composite stub was bonded using a polyethylene mold. The samples were submitted to three different storage conditions: dry storage, water storage in deionized water at 37 degrees C for 30 days and thermo-cycled for 6000 cycles between 5.0 and 55.0 degrees C. The shear bond strengths of all test groups were determined using a universal testing machine. Data were analyzed by two-way ANOVA and Tukey HSD (p<0.05). The surface morphology of titanium and elemental composition were examined with SEM and EDAX. RESULTS: The results showed that there was a significant difference for different surface treatments (p<0.001) and different storage conditions (p<0.01) on the mean shear bond strengths. EDAX analysis showed there was a change of elemental composition of titanium surface after thermal treatment of the coating. CONCLUSION: Surface treatment of titanium with a polydimethylsiloxane coating at 1000 degrees C and 1100 degrees C curing provides sufficient resin bonding for clinical services. PMID- 25460414 TI - Clinically relevant mechanical testing of hernia graft constructs. AB - BACKGROUND: To understand the mechanical behavior of grafts in the context of hernia repair, there is a need to develop and adopt methods for mechanical testing of grafts in a clinically-relevant manner with clinically-relevant outcomes. MATERIALS AND METHODS: Ball-burst and planar-biaxial methods were used to test three commercially-available hernia grafts (DermaMatrix, Biodesign, VitaMesh Blue). Both load-to-failure and cyclic fatigue tests were performed (n=6 11/group/test). Grafts were tested as sutured constructs in patch geometry. Dilatational strain analysis was performed considering the construct (both test methods) or the graft (planar-biaxial only) as the area of interest. RESULTS: DermaMatrix, Biodesign, and VitaMesh grafts showed differences in mechanical properties at the point of construct failure (load, in-plane load-per-suture and membrane tension) in ball-burst tests and differences in sub-failure properties (stiffness, dilatational strain at 16N/cm and cyclic mechanical properties) in planar-biaxial tests. In both load-to-failure and cyclic fatigue tests, each graft construct tended to be stiffer in planar-biaxial than ball-burst testing. In biaxial testing, the strain analysis method influenced the mechanical properties with the construct being more compliant than the graft. CONCLUSIONS: This study demonstrates that graft-fixation method, test mode and analysis method are important considerations for mechanical characterization of hernia grafts. Ball-burst tests can only estimate construct or material properties, whereas planar-biaxial tests capture anisotropy and can estimate construct, graft and material properties of the same test specimen. When the clinical performance of a graft in the context of hernia repair is of interest, testing a sutured construct and performing construct strain analysis arguably provides the most clinically relevant assessment method. PMID- 25460416 TI - Experimental analysis of the mechanical behavior of the viscoelastic porcine pancreas and preliminary case study on the human pancreas. AB - The aim of this article is to study the mechanical properties of the pancreas. Up to now, the mechanical properties of the pancreas are not sufficiently characterized. The possibility of intraoperative mechanical testing of pathological pancreata will allow the classification of pancreatic diseases in the future. The application of mechanical parameters instead of the intraoperative frozen section analysis shortens waiting times in the operating room. This study proves the general applicability of shear rheology for the determination of the mechanical properties of pancreas and the assessment of graft quality for transplantation. Porcine and human pancreas samples were examined ex vivo and a nonlinear viscoelastic behavior was observed. Pancreas was found to be more viscous than liver but both abdominal organs showed a similar flow behavior. The shear deformation dependence of healthy human pancreas was similar to porcine pancreas. An increase in the post-mortem time led to an increase in the complex modulus for a post-mortem time up to 8.5 days. Histological investigations showed that an increased amount of collagen coincides with the stiffening of the pancreatic tissue. PMID- 25460415 TI - Imaging, spectroscopy, mechanical, alignment and biocompatibility studies of electrospun medical grade polyurethane (CarbothaneTM 3575A) nanofibers and composite nanofibers containing multiwalled carbon nanotubes. AB - In the present study, we discuss the electrospinning of medical grade polyurethane (CarbothaneTM 3575A) nanofibers containing multi-walled-carbon nanotubes (MWCNTs). A simple method that does not depend on additional foreign chemicals has been employed to disperse MWCNTs through high intensity sonication. Typically, a polymer solution consisting of polymer/MWCNTs has been electrospun to form nanofibers. Physiochemical aspects of prepared nanofibers were evaluated by SEM, TEM, FT-IR and Raman spectroscopy, confirming nanofibers containing MWCNTs. The biocompatibility and cell attachment of the produced nanofiber mats were investigated while culturing them in the presence of NIH 3T3 fibroblasts. The results from these tests indicated non-toxic behavior of the prepared nanofiber mats and had a significant attachment of cells towards nanofibers. The incorporation of MWCNTs into polymeric nanofibers led to an improvement in tensile stress from 11.40 +/- 0.9 to 51.25 +/- 5.5 MPa. Furthermore, complete alignment of the nanofibers resulted in an enhancement on tensile stress to 72.78 +/- 5.5 MPa. Displaying these attributes of high mechanical properties and non toxic nature of nanofibers are recommended for an ideal candidate for future tendon and ligament grafts. PMID- 25460417 TI - Predominant factor determining wear properties of beta-type and (alpha+beta)-type titanium alloys in metal-to-metal contact for biomedical applications. AB - The predominant factor determining the wear properties of a new titanium alloy, Ti-29Nb-13Ta-4.6Zr (TNTZ) and a conventional titanium alloy, Ti-6Al-4V extra-low interstitial (Ti64) was investigated for TNTZ and Ti64 combinations in metal-to metal contacting bio-implant applications. The worn surfaces, wear debris, and subsurface damages were analyzed using a scanning electron microscopy combined with energy-dispersive spectroscopy and electron-back scattered diffraction analysis. The volume loss of TNTZ is found to be larger than that of Ti64, regardless of the mating material. The wear track of TNTZ exhibits the galled regions and severe plastic deformation with large flake-like debris, indicative of delamination wear, which strongly suggests the occurrence of adhesive wear. Whereas, the wear track of Ti64 have a large number of regular grooves and microcuttings with cutting chip-like wear debris and microfragmentation of fine oxide debris, indicative of abrasive wear combined with oxidative wear. This difference in the wear type is caused by severe and mild subsurface deformations of TNTZ and Ti64, respectively. The lower resistance to plastic shearing for TNTZ compared to that of Ti64 induces delamination, resulting in a higher wear rate. PMID- 25460418 TI - Factors influencing adoption of manure separation technology in The Netherlands. AB - Manure separation technologies are essential for sustainable livestock operations in areas with high livestock density as these technologies result in better utilization of manure and reduced environmental impact. Technologies for manure separation have been well researched and are ready for use. Their use, however, has been limited to the Netherlands. This paper investigates the role of farm and farmer characteristics and farmers' attitudes toward technology-specific attributes in influencing the likelihood of the adoption of mechanical manure separation technology. The analysis used survey data collected from 111 Dutch dairy farmers in 2009. The results showed that the age and education level of the farmer and farm size are important variables explaining the likelihood of adoption. In addition to farm and farmer characteristics, farmers' attitudes toward the different attributes of manure separation technology significantly affect the likelihood of adoption. The study generates useful information for policy makers, technology developers and distributors in identifying the factors that impact decision-making behaviors of farmers. PMID- 25460419 TI - Predicting bottlenose dolphin distribution along Liguria coast (northwestern Mediterranean Sea) through different modeling techniques and indirect predictors. AB - Habitat modeling is an important tool to investigate the quality of the habitat for a species within a certain area, to predict species distribution and to understand the ecological processes behind it. Many species have been investigated by means of habitat modeling techniques mainly to address effective management and protection policies and cetaceans play an important role in this context. The bottlenose dolphin (Tursiops truncatus) has been investigated with habitat modeling techniques since 1997. The objectives of this work were to predict the distribution of bottlenose dolphin in a coastal area through the use of static morphological features and to compare the prediction performances of three different modeling techniques: Generalized Linear Model (GLM), Generalized Additive Model (GAM) and Random Forest (RF). Four static variables were tested: depth, bottom slope, distance from 100 m bathymetric contour and distance from coast. RF revealed itself both the most accurate and the most precise modeling technique with very high distribution probabilities predicted in presence cells (90.4% of mean predicted probabilities) and with 66.7% of presence cells with a predicted probability comprised between 90% and 100%. The bottlenose distribution obtained with RF allowed the identification of specific areas with particularly high presence probability along the coastal zone; the recognition of these core areas may be the starting point to develop effective management practices to improve T. truncatus protection. PMID- 25460420 TI - A web tool for STORET/WQX water quality data retrieval and Best Management Practice scenario suggestion. AB - Total Maximum Daily Load is a water quality standard to regulate water quality of streams, rivers and lakes. A wide range of approaches are used currently to develop TMDLs for impaired streams and rivers. Flow and load duration curves (FDC and LDC) have been used in many states to evaluate the relationship between flow and pollutant loading along with other models and approaches. A web-based LDC Tool was developed to facilitate development of FDC and LDC as well as to support other hydrologic analyses. In this study, the FDC and LDC tool was enhanced to allow collection of water quality data via the web and to assist in establishing cost-effective Best Management Practice (BMP) implementations. The enhanced web based tool provides use of water quality data not only from the US Geological Survey but also from the Water Quality Portal for the U.S. via web access. Moreover, the web-based tool identifies required pollutant reductions to meet standard loads and suggests a BMP scenario based on ability of BMPs to reduce pollutant loads, BMP establishment and maintenance costs. In the study, flow and water quality data were collected via web access to develop LDC and to identify the required reduction. The suggested BMP scenario from the web-based tool was evaluated using the EPA Spreadsheet Tool for the Estimation of Pollutant Load model to attain the required pollutant reduction at least cost. PMID- 25460421 TI - Effect of liming and organic and inorganic fertilization on soil carbon sequestered in macro-and microaggregates in a 17-year old Pinus radiata silvopastoral system. AB - Agroforestry systems have been recognized as a potential greenhouse gas mitigation strategy under the Kyoto Protocol because of their ability to absorb carbon dioxide from the atmosphere and store carbon mainly in the soil. Soil particle size and land management practices are known to have a considerable influence on carbon storage in soils. This study evaluated changes in soil chemical and physical properties, and quantified and compared the amount of C stored in the bulk soil and in three different soil fractions (250-2000, 53-250 and <53 MUm) at each of four soil depths (0-25, 25-50, 50-75 and 75-100 cm) in a silvopastoral system located on an acidic forest soil under Pinus radiata D. Don. Areas of this system were subjected ten years ago to one of nine fertilization treatments: three different doses of sewage sludge or no fertilization, all with or without the addition of lime, and mineral fertilizer with no liming. Seventeen years after reforestation and seven years after canopy closure, strong gradients with soil depth were found regarding soil bulk density, pH and carbon storage. Intense soil management (high doses of sewage sludge and liming) generally reduced soil carbon storage, mainly in coarse aggregates, but this could be compensated by the increase in tree and pasture development observed in soils subject to intermediate sewage sludge doses. PMID- 25460422 TI - Bioenergy crops grown for hyperaccumulation of phosphorous in the Delmarva Peninsula and their biofuels potential. AB - Herbaceous bioenergy crops, including sorghum, switchgrass, and miscanthus, were evaluated for their potential as phytoremediators for the uptake of phosphorus in the Delmarva Peninsula and their subsequent conversion to biofuel intermediates (bio-oil) by fast pyrolysis using pyrolysis-gas chromatography/mass spectroscopy. Four cultivars of sorghum, five cultivars of switchgrass and one miscanthus (Miscanthus * giganteus) were grown in soils with two different levels of poultry manure (PM) applications. Little variation was seen in phosphorus uptake in the two different soils indicating that the levels of available phosphorus in the soil already saturated the uptake ability of the plants. However, all plants regardless of trial took up more phosphorus than that measured for the non- PM treated control. Sorghum accumulated greater levels of nutrients including phosphorus and potassium compared to switchgrass and miscanthus. The levels of these nutrients in the biomass did not have an effect on carbohydrate contents. However, the potential yield and composition of bio-oil from fast pyrolysis were affected by both agronomics and differences in mineral concentrations. PMID- 25460423 TI - Impacts of Bokashi on survival and growth rates of Pinus pseudostrobus in community reforestation projects. AB - Community-based small-scale reforestation practices have been proposed as an alternative to low-efficiency massive reforestations conducted by external agents. These latter conventional reforestations are often carried out in soils that have been seriously degraded and this has indirectly contributed to the introduction of non-native species and/or acceptance of very low seedling survival rates. Bokashi is a fermented soil organic amendment that can be made from almost any available agricultural byproduct, and its beneficial effects in agriculture have been reported in various contexts. Here, we report the results of a community-based small-scale experimental reforestation where the provenance of pine seedlings (local and commercial) and the use of Bokashi as a soil amendment were evaluated. Bokashi was prepared locally by members of a small rural community in central Mexico. Almost two years after the establishment of the trial, survival rates for the unamended and amended local trees were 97-100% while survival of the commercial trees from unamended and amended treatments were 87-93%. Consistently through time, local and commercial seedlings planted in Bokashi-amended soils were significantly taller (x = 152 cm) than those planted in unamended soils (x = 86 cm). An unplanned infection by Cronartium quercuum in the first year of the experiment was considered as a covariable. Infected seedlings showed malformations but this did not affect survival and growth rates. Bokashi amendment seems as an inexpensive, locally viable technology to increase seedling survival and growth and to help recover deforested areas where soils have been degraded. This allows local stakeholders to see more rapid results while helping them to maintain their interest in conservation activities. PMID- 25460424 TI - A method for modeling the effects of climate and land use changes on erosion and sustainability of soil in a Mediterranean watershed (Languedoc, France). AB - Global climate and land use changes could strongly affect soil erosion and the capability of soils to sustain agriculture and in turn impact regional or global food security. The objective of our study was to develop a method to assess soil sustainability to erosion under changes in land use and climate. The method was applied in a typical mixed Mediterranean landscape in a wine-growing watershed (75 km(2)) within the Languedoc region (La Peyne, France) for two periods: a first period with the current climate and land use and a second period with the climate and land use scenarios at the end of the twenty-first century. The Intergovernmental Panel on Climate Change A1B future rainfall scenarios from the Meteo France General circulation model was coupled with four contrasting land use change scenarios that were designed using a spatially-explicit land use change model. Mean annual erosion rate was estimated with an expert-based soil erosion model. Soil life expectancy was assessed using soil depth. Soil erosion rate and soil life expectancy were combined into a sustainability index. The median simulated soil erosion rate for the current period was 3.5 t/ha/year and the soil life expectancy was 273 years, showing a low sustainability of soils. For the future period with the same land use distribution, the median simulated soil erosion rate was 4.2 t/ha/year and the soil life expectancy was 249 years. The results show that soil erosion rate and soil life expectancy are more sensitive to changes in land use than to changes in precipitation. Among the scenarios tested, institution of a mandatory grass cover in vineyards seems to be an efficient means of significantly improving soil sustainability, both in terms of decreased soil erosion rates and increased soil life expectancies. PMID- 25460425 TI - Monitoring and modeling wetland chloride concentrations in relationship to oil and gas development. AB - Extraction of oil and gas via unconventional methods is becoming an important aspect of energy production worldwide. Studying the effects of this development in countries where these technologies are being widely used may provide other countries, where development may be proposed, with some insight in terms of concerns associated with development. A fairly recent expansion of unconventional oil and gas development in North America provides such an opportunity. Rapid increases in energy development in North America have caught the attention of managers and scientists as a potential stressor for wildlife and their habitats. Of particular concern in the Northern Great Plains of the U.S. is the potential for chloride-rich produced water associated with unconventional oil and gas development to alter the water chemistry of wetlands. We describe a landscape scale modeling approach designed to examine the relationship between potential chloride contamination in wetlands and patterns of oil and gas development. We used a spatial Bayesian hierarchical modeling approach to assess multiple models explaining chloride concentrations in wetlands. These models included effects related to oil and gas wells (e.g. age of wells, number of wells) and surficial geology (e.g. glacial till, outwash). We found that the model containing the number of wells and the surficial geology surrounding a wetland best explained variation in chloride concentrations. Our spatial predictions showed regions of localized high chloride concentrations. Given the spatiotemporal variability of regional wetland water chemistry, we do not regard our results as predictions of contamination, but rather as a way to identify locations that may require more intensive sampling or further investigation. We suggest that an approach like the one outlined here could easily be extended to more of an adaptive monitoring approach to answer questions about chloride contamination risk that are of interest to managers. PMID- 25460426 TI - Sonophotolytic degradation of synthetic pharmaceutical wastewater: statistical experimental design and modeling. AB - The merits of the sonophotolysis as a combination of sonolysis (US) and photolysis (UV/H2O2) are investigated in a pilot-scale external loop airlift sonophotoreactor for the treatment of a synthetic pharmaceutical wastewater (SPWW). In the first part of this study, the multivariate experimental design is carried out using Box-Behnken design (BBD). The effluent is characterized by the total organic carbon (TOC) percent removal as a surrogate parameter. The results indicate that the response of the TOC percent removal is significantly affected by the synergistic effects of the linear term of H2O2 dosage and ultrasound power with the antagonistic effect of quadratic term of H2O2 dosage. The statistical analysis of the results indicates a satisfactory prediction of the system behavior by the developed model. In the second part of this study, a novel rigorous mathematical model for the sonophotolytic process is developed to predict the TOC percent removal as a function of time. The mathematical model is based on extensively accepted sonophotochemical reactions and the rate constants in advanced oxidation processes. A good agreement between the model predictions and experimental data indicates that the proposed model could successfully describe the sonophotolysis of the pharmaceutical wastewater. PMID- 25460427 TI - Accessory wandering spleen: Report of a case of laparoscopic approach in an asymptomatic patient. AB - INTRODUCTION: Accessory wandering spleen is a rare but dangerous condition. Abnormalities of the ligamentous apparatus of an accessory spleen may evolve into torsion of its vascular axis, which can lead to a splenic infarct making surgery necessary. Patients are often asymptomatic and the diagnosis can be accidental. An early diagnosis and a correct treatment are fundamental. PRESENTATION OF CASE: In this case report a young woman underwent laparoscopic surgery after an incidental finding at a Pelvic Ultrasound of an accessory wandering spleen. DISCUSSION: In literature are reported cases of asymptomatic patients with an accessory wandering spleen treated with a conservative approach. However, a torsion or infarct of the accessory wandering spleen leads to emergency surgery. The presence of an independent vascular axis of the accessory spleen reduces the risk of postoperative complications (e.g. thrombocytosis) and the administration of low molecular weight heparin should prevent the risk of portal thrombosis. CONCLUSION: We suggest performing surgery with a laparoscopic approach in patients with accessory wandering spleen, though asymptomatic, because of the risk of serious complications in case of accessory spleen torsion. PMID- 25460428 TI - Intussusception secondary to endometriosis of the cecum. AB - INTRODUCTION: Intussusception in adults is a rare cause of bowel obstruction. Endometriosis of the bowel is also a rare entity that can be the cause of bowel obstruction. Here, we report a rare case of intussusception secondary to endometriosis of the cecum. PRESENTATION OF CASE: A 40-year-old woman presented to the hospital with a one-week history of intermittent epigastric pain. On physical examination, there was a soft, round non-tender palpable mass in the right flank and abdominal computed tomography scan revealed an intussusception. We made the diagnosis of ileo-colic intussusception and performed ileocecal resection. The surgical specimen revealed a round submucosal cystic mass in the cecum and the histology showed endometriosis of the cecum. DISCUSSION: Intussusception in adults is a rare entity present in just 1% of all patients with bowel obstruction, and 5% of all intussusceptions. In general, intussusception in adults has a pathologic lesion as the lead point and the lesion is a malignancy in 20-50% of the cases. Thus, the treatment of an intussusception in adults should be operative. Endometriosis of the bowel is a rare cause of intussusception. Small endometriosis lesions of the bowel are unlikely to cause symptoms; however, in patients presenting with bowel obstruction, urgent treatment is indicated. CONCLUSION: Intussusception in an adult is a rare cause of bowel obstruction and intussusception caused by endometriosis is also rare. Although rare, the diagnosis of endometriosis as a cause of intussusception must be considered as part of the differential diagnosis. PMID- 25460429 TI - Lesion mimicking perianal abscess in an immunocompromised patient: Report of a case. AB - INTRODUCTION: Ischiorrectal tumoral masses mimicking perianal abscess and abscess from uncommon microbiological origins have previously been reported. PRESENTATION OF CASE: Unusual perianal abscess arising from an hematoma in an elderly woman with myelodysplastic syndrome: the patient presented on the emergency with gluteal pain and fever after intramuscular injection of analgesic drug. Physical examination revealed subcutaneous thickening on gluteus and perianal region, without skin changes. Magnetic resonance reported an heterogeneous mass sized 5cm*12cm*20cm from gluteus maximus to ischioanal fat under levator ani muscle, through sciatic notch. Debridement of an staphylococceal infected hematoma through a single left lateral gluteus incision, and primary closure was performed. Proctologic examination was normal, so any perianal incision was done. The site infection progressed, so the patient required new surgery with wet cure. The patient contracted nosocomial pneumonia and died due to sepsis. DISCUSSION: Hematological diseases can yield infectious and bleeding disorders. Intramuscular injections often cause haematomas that can lead to pyomyositis. Pyomyositis requires early debridement and continue cure. CONCLUSION: Intramuscular administration of drugs should be avoided in patients with thrombocytopenia. Gluteal region is connected to perianal area through the sciatic notch. Usually perianal abscess in immunocompromised patients arise from proctologic origin, but other causes may be taken into account. PMID- 25460430 TI - Osteoid osteoma as an unusual cause of wrist pain - A case report and review of literature. AB - INTRODUCTION: Wrist pain is very common and there are several causes for this condition. It is extremely important to establish an accurate diagnosis so that appropriate treatment can be directed at the cause. PRESENTATION OF CASE: We describe a case of a young man who presented to us with wrist pain of insidious onset. He had previous (ganglion) excision from the same wrist. Clinically there was tenderness in the base of second metacarpal with no swelling. The radiograph and MRI scan were suggestive of Brodie's abscess. But surgical exploration and subsequent histopathology showed evidence of osteoid osteoma. The patient had full resolution of symptoms after 3 months of surgery. DISCUSSION: Osteoid osteoma of the wrist bones is rare. They usually present with atypical pain. The diagnosis of osteoid osteoma is challenging and often missed. A high index of suspicion and appropriate investigations are essential in the diagnosis. CONCLUSION: We conclude that the diagnosis of osteoid osteoma should be considered in case of wrist pain of unknown aetiology with cystic lesions in the carpal or metacarpal bones. PMID- 25460431 TI - A large incarcerated Meckel's diverticulum in an inguinal hernia. AB - INTRODUCTION: Littre's hernia is a rare finding consisting of a Meckel's diverticulum inside of a hernia sac. Clinically, it is indistinguishable from a hernia involving small bowel and therefore may be difficult to diagnose pre operatively. PRESENTATION OF CASE: We report a case of an inguinal hernia involving an unusually large Meckel's diverticulum measuring 15cm in length. The diverticulum was resected using a linear GI stapler and the hernia was repaired without complication. DISCUSSION: Meckel's diverticulum is an embryologic remnant of the vitelline duct occurring in 1-3% of the adult population with an estimated 4% becoming complicated and presenting with intestinal obstruction, infection, bleeding or herniation. Surgical resection is the recommended treatment for any Meckel's diverticulum causing symptoms. In the case of a Littre's hernia, resection of the diverticulum should be followed by repair of the fascial defect in a standard fashion. CONCLUSION: Littre's hernia, although rare, should be a consideration at the time of repair for any abdominal hernia involving small bowel as resection of the Meckel's diverticulum is critical in avoiding recurrent complications. PMID- 25460432 TI - An unusual cause of hematuria; primary epiploic appendagitis. AB - INTRODUCTION: Primary epiploic appendagitis (PEA) is self limiting inflammatory disease of colonic epiploic appendices. PRESENTATION OF CASE: Herein, a 40 years old patient describing abdomino-inguinal pain with clotty hematuria having PEA was presented. At first, the patient was thought to have a primary bladder pathology, but after a meticioulus examination, he found to have PEA and managed by conservative measures. DISCUSSION: Although PEA does not require surgical intervention, it may mimic other acute abdominal disorders which can be difficult to differentiate. Appendices overlying the sigmoid colon and cecum are more prone to be affected as they are more elongated and wider in size. The patient is usually admitted due to sudden onset of abdominal pain accompanied with fever, abdominal tenderness and leucocytosis. CONCLUSION: The present case demonstrated that PEA located close to the lower urinary tract especially urinary bladder might present with urinary symptoms such as hematuria. dysuria, pollakuria and inguinal pain. PMID- 25460433 TI - Ventricular perforation by pacemaker lead repaired with two hemostatic devices. AB - INTRODUCTION: Cardiac perforation is a rare, but potentially serious, complication of pacemaker implantation that may develop days or weeks after implantation. PRESENTATION OF CASE: In the current case, 92-year-old man underwent permanent pacemaker implantation, but he presented 3 weeks later with severe symptoms. Computed tomography showed protrusion of the tip of the ventricular electrode through the right ventricle and into the chest wall. During an urgent surgical intervention, the lead was disconnected and extracted. A sealing hemostatic device and an hemostatic patch were applied to repair the ventricle; the procedure was uneventfull. DISCUSSION: This case demonstrates how the correct diagnosis of ventricular perforation is crucial, and should be followed immediately by surgical planning. CONCLUSION: The hemostatic patch is a valuable alternative to sutures in patients with thin and fragile ventricular wall, unable to undergo stitching. PMID- 25460434 TI - The appearance of free-air in the abdomen with related pneumatosis cystoides intestinalis: Three case reports and review of the literature. AB - INTRODUCTION: Pneumatosis sistoides intestinalis (PSI) is a rare condition with unknown origin, defined as the appearance of gas-filled cysts in the intestinal wall. It usually occurs due to respiratory infections, tumor or collagen disease, traumas, immunosuppression. PRESENTATION OF CASE: Three patients with PSI were examined that followed up and treated in our clinic. The first patient was hospitalized for emergency treatment of previously diagnosed free-air under the diaphragm. He had a defense on physical examination and free-air was detected in X-ray and abdomen CT. We decided to laparatomy and peroperatively, stenotic pylorus with an abnormally increased stomach and gas-filled cysts were seen in the terminal ileum. Antrectomy and gastrojejunostomy with partial ileum and cecum resection and end ileostomy were performed. The second patient underwent laparatomy because of intraperitoneal free-air and acute abdomen. Partial ileum and cecum resection and ileotransversostomy were performed. The third patient with intraperitoneal free-air was treated with antibiotics, oxygen treatment and bowel rest. DISCUSSION: PSI is usually asymptomatic. Plain radiographs, USG, CT, upper gastrointestinal endoscopy, colonoscopy can use for diagnosis. Treatment of PSI depends on the underlying cause; include elemental diet, antibiotics, steroids, hyperbaric oxygen therapy and surgery. CONCLUSION: In patients with asymptomatic and symptomatic PSI are different treat. Symptomatic PSI can be safely treated antrectomy and gastrojejunostomy with partial ileum and cecum resection. PMID- 25460435 TI - Intraosseous neurilemmoma of the proximal ulna. AB - INTRODUCTION: Neurilemmoma is a benign nerve sheath neoplasm commonly located in the soft tissue. Intraosseous neurilemmoma is rare, constituting less than 1% of primary bone tumors. PRESENTATION OF CASE: A 21 year-old woman was presented with left elbow pain of 1-month duration. Plain radiographs showed a well-defined, lytic and expansile lesion of the proximal ulna. Computed tomography revealed cortical destruction and soft tissue extension. Because the tissue of origin for the tumor was uncertain, an open biopsy was performed. The specimens demonstrated a benign spindle cell tumor suggestive of a neurilemmoma, similar to a soft tissue neurilemmoma. The diagnosis of intraosseous neurilemmoma was established. Marginal excision of the soft tissue component and curettage of the lesion in the bone were performed. After 3.5 years of follow up, there is no clinical or radiographic finding to suggest any recurrence. DISCUSSION: The major site of intraosseous neurilemmoma is the mandible. Occurrence in the long bone is particularly rare. Only two cases of intraosseous neurilemmoma involving the bones around the elbow have been reported to our knowledge; these cases arose in the distal humerus. We describe the first case of intraosseous neurilemmoma of the proximal ulna of the left elbow. The recommended treatment is conservative resection and bone grafting, as malignant change is extremely rare. CONCLUSION: Although very rare, intraosseous neurilemmoma should be taken under consideration in the differential diagnosis of painful, radiographically benign-appearing osseous tumor around the elbow. PMID- 25460436 TI - Multicystic biliary hamartoma: A report of a rare entity and a review of the literature. AB - INTRODUCTION: Multicystic biliary hamartoma is a rare liver tumor that was first described in 2005. Only nine cases are reported in the literature and all of them originate from Eastern patient populations, specifically Japan and Korea. PRESENTATION OF CASE: Herein we report the occurrence of the tenth multicystic biliary hamartoma reported to date, arising in a Caucasian American woman initially presenting with abdominal pain. At 4.7cm this is the second largest tumor reported to date and the only one arising in a Western patient population. DISCUSSION: The patient underwent multimodality imaging and the tumor was biopsied preoperatively, but the diagnosis remained unclear. An extended right hepatectomy was performed for resection of her tumor, and the tumor was definitively diagnosed based on the surgically resected specimen. As all nine of the previously reported cases also underwent resection, the natural history of this lesion remains unknown. The lack of both recurrence and tumor spread in the previously reported cases indicates that this may be a benign lesion not requiring surgical resection unless symptomatic. CONCLUSION: Multicystic biliary hamartoma is an extremely rare tumor. Increased awareness of the radiologic and pathologic features will likely lead to the diagnoses of further cases in both Western and Eastern populations and could potentially assist with preoperative diagnosis. The natural history and optimal management of this tumor remain uncertain. PMID- 25460437 TI - Precise anatomical resection of the ventral part of Segment VIII. AB - INTRODUCTION: Anatomical resection of the ventral part of Segment VIII (S8vent) is demanding and there are no accurate methods to identify the demarcation line inside the liver. The current authors have proposed a method to solve the problem. PRESENTATION OF CASE: The tumor was located in the S8vent and was 4cm in size. One tributary of the middle hepatic vein (MHV), designated V8i, was running between S8vent and the dorsal part of Segment VIII (S8dor). Another tributary of the MHV, designated V8-5i, was running between S8vent and the ventral part of S5 (S5vent). About 5ml of indigo carmine dye was injected into the proximal part of P8vent. After the small tributary of V8-5i was exposed, it was followed all the way to the main trunk of the MHV. The portal pedicle of S8vent was then ligated and divided. Next, the V8i was gradually exposed from the distal MHV to its trunk. DISCUSSION: A recent study showed that the subsegmental border visualized between the ventral and dorsal region always coincided with the plane of V8i, so the subsegmental plane can be divided along with V8i by preserving the very small tributaries near the liver surface and following them to determine where they meet as they run into V8i. Also, the landmark vein of V8-5i in the transverse S8 S5 intersegmental plane was determined for the first time. CONCLUSION: Proposed here is a more accurate method of dividing the liver parenchyma along the intersegmental and intersubsegmental demarcation. PMID- 25460438 TI - Cardiac metastases and tumor embolization: A rare sequelae of primary undifferentiated liver sarcoma. AB - INTRODUCTION: Primary hepatic sarcomas are uncommon malignant neoplasms; prognostic features, natural history, and optimal management of these tumors are not well characterized. PRESENTATION OF CASE: This report describes the management of a 51-year-old patient that underwent a right trisectionectomy for a large hepatic mass found to be a liver sarcoma on pathology. He subsequently developed tumor emboli to his lungs and was discovered to have cardiac intracavitary metastases from his primary tumor. The patient underwent cardiopulmonary bypass and resection of the right-sided heart metastases to prevent further pulmonary sequela of tumor embolization. DISCUSSION: The lack of distinguishing symptoms or imaging characteristics that clearly define hepatic sarcomas makes it challenging to achieve a diagnosis prior to pathologic examination. Metastatic spread is frequently to the lung or pleura, but very rarely seen within the heart. Failure to recognize cardiac metastatic disease will ultimately lead to progressive tumor embolization and cardiac failure if left untreated. CONCLUSION: The most effective therapy for primary liver sarcomas is surgery; radical resection should be performed if possible given the aggressive nature of these tumors to progress and metastasize. PMID- 25460439 TI - Bilateral clavicle osteomyelitis: A case report. AB - INTRODUCTION: Osteomyelitis of the clavicle is rare. Infection occurs from hematogenous spread or trauma. In adults infection is usually secondary due to an exogenous cause such as open fractures, surgery (iatrogenic) or spread from local tissue with infection. PRESENTATION OF CASE: The case is presented here of a 50 year old female with bilateral clavicular fractures, who was operated on with open reduction and internal fixation. At the 6-month follow-up, she had complaints of bilateral osteomyelitis which was successfully treated with resection of the infected segment of the bone, and antibiotic impregnated collagen. DISCUSSION: Predisposing factors include diabetes, intravenous drug abuse, tuberculosis or immune suppression. Management involves the removal of bone fixation, debridement of the bone and if there is a defect, coverage with a muscle flap is applied. CONCLUSION: In cases of clavicular osteomyelitis where infection continues despite debridement and antibiotic therapy, excision of the sequestered clavicular section is a successful treatment approach and has been seen to improve quality of life without any functional loss. PMID- 25460440 TI - The GatekeeperTM for fecal incontinence: Another trial and error. AB - INTRODUCTION: The GatekeeperTM is the most recent bulking agent used in the treatment of fecal incontinence with no reported complications. This case reports side effects similar to other bulking agents, namely migration of the prosthesis and perianal abscess. PRESENTATION OF CASE: A 52 year old gentleman presented with a history of fecal soiling. He underwent uncomplicated surgery in 2012 for 6 GatekeeperTM implantations with only temporary improvements. In 2013, endorectal ultrasound revealed prosthesis migration. In 2014, he presented with a perianal abscess which contained one of the prosthesis. DISCUSSION: The GatekeeperTM, made of the inert Hyexpan, typically implanted in the intersphincteric region, has been used for the treatment of fecal incontinence since its discontinuation in the treatment of gastroesophageal reflux disease.(5) The GatekeeperTM was implemented on a small number of subjects for which the typical side effects of bulking agents were not seen. CONCLUSION: Larger studies need to be conducted to investigate the advantages or perhaps disadvantages of the GatekeeperTM over other bulking agents. PMID- 25460441 TI - Small bowel adenocarcinoma (SBA) three years after colonic adenocarcinoma in an elderly patient: Case report in a National Institute of Health and Aging (INRCA) and review of the literature. AB - INTRODUCTION: Adenocarcinoma of the small intestine is a rare malignancy (the annual incidence in the USA is approximately 3.9 cases per million persons with median age between 60 and 70 years) with limited data available to guide therapeutic decisions. Nonspecific signs and symptoms associated with difficulty in performing small bowel examination is the cause of delayed diagnosis made between 6 and 9 months after appearance of symptoms with the majority of patients presenting with late stage disease and either lymph node involvement or distant metastatic disease. PRESENTATION OF CASE: An 87-year-old man treated 3 years previously for colonic adenocarcinoma with left colectomy, was brought to our attention with a 4.5cm*3.5cm mass in the proximal jejunum associated with another abdominal wall enhancing mass of 5cm in diameter in the rectus muscle. Diagnosis on gross examination after surgical resection was adenocarcinoma stage III (T4N1M0) with involvement of lymph nodes. DISCUSSION: According to an analysis of the Surveillance, Epidemiology and End Results (SEER) database, patients who develop either a small or large intestine adenocarcinoma are at increased risk for a second cancer at both intestinal sites. The role of adjuvant therapy in patients who undergo curative resection is unclear. Recent retrospective and prospective studies have helped to clarify the optimal chemotherapy approach for advanced small bowel adenocarcinoma. CONCLUSION: With our work, we present our personal case of metachronous primary carcinoma of small bowel following resected colorectal carcinoma and review the literature. PMID- 25460442 TI - Spontaneous ureteric rupture secondary to an invasive desmoid tumour. AB - INTRODUCTION: Spontaneous ureteric rupture is a rare entity that presents as an extravasation of urine from the ureter without previous surgery, ureteric manipulation and external trauma of the ureter. We report the case of a desmoid tumour presenting as spontaneous ureteric rupture which was managed in our institution. PRESENTATION OF CASE: A 28 years old healthy male presented with a four day history of generalised abdominal pain secondary to spontaneous right ureteric rupture. Patient was initially managed via insertion of nephrostomy tube and antibiotics. After unsuccessful attempts of retrograde and antegrade ureteric stent insertion, patient was subsequently managed via elective surgical intervention. The excised specimen revealed desmoid tumour as cause of the ureteric rupture. DISCUSSION: Desmoid tumours are rare benign tumours arising from fascial or musculoaponeurotic structures that do not metastasise, but tend to invade locally. It is often initially managed medically prior to undertaking a definitive surgical intervention. To our knowledge this is the first reported case of ureteric perforation secondary to a desmoid tumour of the mesentery. CONCLUSION: Spontaneous rupture of the ureter is often misdiagnosed as other conditions. History taking and examination can be unreliable, hence a high level of suspicion and further investigations should be utilised. Once the diagnosis is made, treatment can be individualised based on aetiology. PMID- 25460443 TI - A case of a bleeding benign gastrocolic fistula in 2014. AB - INTRODUCTION: In the era of proton pump inhibitors in the treatment of peptic ulcer disease, the incidence of a gastrocolic fistula arising from unoperated gastric ulcers is extremely low. PRESENTATION OF CASE: We present the case of a 68-year old farmer who presented with melaena and was found to have a benign gastrocolic fistula in the setting of untreated peptic ulcer disease, chronic NSAID ingestion and heavy alcohol intake. The diagnosis was made by gastroscopy. En bloc surgery was undertaken due to the size of the fistula and concomitant significant bleeding of the ulcer which would not have made it amenable to medical management. DISCUSSION: The symptoms of a gastrocolic fistula are undifferentiated and the diagnosis can easily be missed in the setting of other complications such as bleeding or perforation of a hollow viscus. Barium enamas are the most accurate for the diagnosis but gastroscopy with biopsy is usually performed to rule out malignancy. The mainstay of treatment is usually surgical, though patients can be medically managed if he/she is not a surgical candidate. CONCLUSION: Benign gastrocolic fistulas are rare and its diagnosis is easily missed. PMID- 25460444 TI - Case report of rare chronic myelogenous leukemia related multibacterial splenic abscess presenting with scrotal swelling. AB - INTRODUCTION: Splenic abscesses associated with leukemia are rare. Most reported cases of splenic abscesses occur after chemotherapy and are related to the immunosuppressive effects of the chemotherapy. Their etiology is most frequently fungal. PRESENTATION OF CASE: A 58-year-old male presented with splenomegaly and scrotal swelling secondary to a multibacterial splenic abscess which required a splenectomy. Upon investigation he was found to suffer from chronic myeloid leukemia (CML) and epididymitis. DISCUSSION: Splenic abscesses are rarely found in leukemic patients. Reported cases are fungal and commonly occur after chemotherapy due to immunosuppression. Scrotal swelling with concurrent splenomegaly can be found in other pathologies including brucellosis, Lyme disease and even non-Hodgkin primary testicular lymphoma. Scrotal swelling in our case was likely secondary to epididymitis and exacerbated by the effects of splenomegaly upon the systemic circulation promoting venous congestion. CONCLUSION: This case illustrated an unusual presentation of CML because the patient presented with splenomegaly, a multibacterial splenic abscess, and scrotal swelling. PMID- 25460445 TI - Surgical resection of colorectal recurrence of gastric cancer more than 5 years after primary resection. AB - INTRODUCTION: Intestinal metastasis from gastric cancer is rare, although the most common cause of secondary neoplastic infiltration of the colon is gastric cancer. However, little data is available on recurrence or death in patients with gastric cancer surviving >5 years post-gastrectomy. Here we report two cases of lower intestinal metastasis from gastric cancer >5 years after primary resection and discuss with reference to the literature. PRESENTATION OF CASE: Case 1: A 61 year-old man with a history of total gastrectomy for gastric cancer 9 years earlier was referred to our hospital with constipation and abdominal distention. We diagnosed primary colon cancer and subsequently performed extended left hemicolectomy. Histological examination revealed poorly differentiated adenocarcinoma resembling the gastric tumor he had 9 years earlier. The patient refused postoperative adjuvant chemotherapy and remained alive with cancerous peritonitis and skin metastases as of 17 months later. Case 2: A 46-year-old woman with a history of total gastrectomy for gastric cancer 9 years earlier presented with constipation. She also had a history of Krukenberg tumor 3 years earlier. We diagnosed metastatic rectal cancer and subsequently performed low anterior resection and hysterectomy. Pathological examination revealed poorly differentiated tubular adenocarcinoma, resembling the gastric tumor. The patient remained alive without recurrence as of 17 months later. DISCUSSION: We found 19 reported cases of patients with resection of colon metastases from gastric cancer. Median disease-free interval was 74 months. CONCLUSION: Resection of late onset colorectal recurrence from gastric cancer appears worthwhile for selected patients. PMID- 25460446 TI - Obstructing adenocarcinoma of the descending colon in a 31-year-old pregnant woman. AB - INTRODUCTION: Colon cancer in pregnant women is rare and tends to produce unspecific symptoms until advanced stage. Therefore common manifestations during pregnancy must be properly evaluated to avoid delayed diagnosis. PRESENTATION OF CASE: A 31-year-old pregnant woman presented with nausea, vomiting and obstipation. An obtained magnetic resonance imaging (MRI) showed distended colon and the consecutive colonoscopy with biopsies confirmed the diagnosis of stenosing carcinoma of the descending colon. Left sided hemicolectomy was performed 10 days after initial presentation. Tumor histology confirmed the diagnosis of adenocarcinoma of the descendo-sigmoidal junction. Adjuvant chemotherapy with 5-fluorouracil was started in the 29th gestational week. The patient had an uneventful delivery of a healthy baby in her 39th gestational week. DISCUSSION: Colorectal carcinoma during pregnancy is a rare event and its diagnosis is often delayed because symptoms are unspecific until the disease is advanced. Although constipation in pregnancy is a common symptom differential diagnosis of a mechanical stenosis should always be contemplated, especially when conservative treatment of constipation fails. MRI is the imaging tool of choice as abdominal computed tomography (CT) is contraindicated in pregnancy. Endoscopic confirmation should be obtained to gain pathological diagnosis of colorectal carcinoma. Surgery is the gold standard of treatment. In relation to the stage of the disease chemotherapy is of great importance. CONCLUSION: Obstructing colorectal cancer can be a rare reason for the common problem of constipation in pregnancy. Beside clinical examination, MRI scan and colonoscopy will reveal the tumor in most cases and should be followed by surgical treatment and chemotherapy according to the stage of disease. PMID- 25460447 TI - Appendiceal diverticulum associated with chronic appendicitis. AB - INTRODUCTION: Appendiceal diverticulosis is a rare entity, with a global incidence between 0.004% and 2.1% of all appendectomies. It has been related with an elevated risk of perforation in comparison to acute appendicitis, as well as an increased risk for synchronic appendicular cancer in 48% of the cases, and colonic cancer in 43%. The incidence of chronic appendicitis has been reported in 1.5% of all appendicitis cases. PRESENTATION OF CASE: We present a 73-year-old female, with no relevant familial history, who presented due to a four-month-long oppressive, moderate pain in the lower right abdominal quadrant without irradiation or any other accompanying symptoms. DISCUSSION: The documented incidence of appendiceal diverticula and chronic appendicitis by themselves is low; therefore the presence of both entities at the same time is extremely rare. CONCLUSION: We present a case in which both diagnoses concurred in the same patient. The relevance of this case relies on the importance of the adequate knowledge of these pathologies, so we can approach them correctly. Although it does not represent an absolute surgical emergency, appendectomy represents the first therapeutic option. PMID- 25460448 TI - Appendix carcinoid associated with the Peutz-Jeghers syndrome. AB - INTRODUCTION: The Peutz-Jeghers syndrome (PJS) is a rare hereditary, autosomal dominant disorder. It is characterized by a gastrointestinal polyposis and mucocutaneous melanic spots. It has also been reported as a precondition for malignancies with a life-time-hazard for cancer up to 93%, caused by a germline mutation in the STK11 gene. PRESENTATION OF CASE: A 21-year-old man presented with nausea and abdominal pain. He had a known history of PJS since the age of 13 when he was treated for intussusception due to a hamartomatous polyp. Preoperative diagnostics revealed a second intussusception and an extensive intestinal polyposis. Intraoperative findings confirmed the suspected diagnoses and desvagination was performed. Nearly 50 polyps were removed from the small intestinum over several longitudinal sections. As the appendix appeared thickened an appendectomy was performed simultaneously. Histology showed hamartomatous polyps and the incidental finding of a pT1 carcinoid of the appendix. The patient recovered well and needed no further treatment for his carcinoid tumor. DISCUSSION: The mechanism of carcinogenesis in PJS still remains debatable, although the genetic disorder underlying the syndrome is known. A predisposition for carcinoid tumors also stays questionable. To our knowledge there is no description of an association between carcinoid tumors of the appendix and PJS to date. CONCLUSION: Life-expectancy in patients with PJS is reduced. Causes are the development of malignancies and complications from the polyps such as intussusception. Since there is no treatment possible main focus must be aimed at early recognition of malignancies and the prevention of complications. PMID- 25460449 TI - Chest wall secondary chondrosarcoma arising from enchondroma in a young Asian female. AB - INTRODUCTION: Enchondromas are benign tumours derived from cartilaginous tissue and they rarely undergo malignant transformation unless they occur in multiple sites such as in the case of Ollier disease. PRESENTATION OF CASE: We report a rare case of a 36-year-old Chinese female, without any past medical history, who had a right chest wall tumour which was initially diagnosed to be benign, for which she was loss to follow up. The mass had been stable in size for the past 7 years until recently, when it gradually grew bigger. computed tomography (CT) scan of the thorax revealed that the mass had invaded the right chest wall suggestive of malignant change. She subsequently underwent an elective open right chest wall resection of the mass and chest wall reconstruction with mesh. A 3cm by 3cm tumour arising from the anterior aspect of the 4th rib was found intra operatively. Post-operative course was uneventful. Histologically, the mass was confirmed to be chrondrosarcoma and resection margins were negative. The patient was discharged on 4th post-operative day and her latest CT thorax during follow up 2 years after operation did not show any tumour recurrence. DISCUSSION: The aim of chest wall reconstruction is to avoid instability and prevent thoracic organs from being exposed if the defect size is >=10cm or at least three ribs are resected. Polypropylene mesh may be relatively weak in terms of mechanical support for the chest wall, however, in this case, the defect is not too large and the laterally reflected pectoral muscle can provide enough support together with the mesh. CONCLUSION: Secondary chondrosarcoma in a young Asian female arising from a benign solitary enchondroma in the absence of multiple enchondromatosis, such as Ollier disease or Maffucci syndrome, is extremely rare. Regular follow up including physical assessment and radiological imaging can result in earlier detection of malignant transformation obviating the need for aggressive surgical treatment involving multiple rib resections. PMID- 25460450 TI - Cutaneous Ewing's sarcoma secondary to chemotherapy given for testis tumor: Case report. AB - INTRODUCTION: Testicular cancer has high cure rates, especially after the adjuvant use of chemotherapy. Secondary tumors may develop months and years after the primary tumor. We aimed to report a case of cutaneous Ewing's sarcoma at the site of surgery 3 years after BEP chemotherapy. PRESENTATION OF CASE: 21 year old male underwent radical orchiectomy in 2008. After one year surgical site complaints brought him to same hospital. A limited surgical resection was made. As his complaints continued he applied to our clinic. We resected the lesion with a 5cm safety margin with the light of previous medical history. Pathology revealed cutaneous Ewing's sarcoma, and patient received VACD-IE chemotherapy. He is free of recurrence till now. DISCUSSION: Chemotherapy may cause secondary cancer especially in long term. In this case secondary tumor is diagnosed three years after surgery. Patient underwent therapeutic surgery and received chemotherapy (VACD-IE) for secondary Ewing's sarcoma. Early diagnosis and definitive treatment provide recurrence free survival in the patient. CONCLUSION: Secondary tumors can emerge months or years after primary tumor therapies, and are not related with the primary tumors. Any lesion or sign should be investigated carefully. Early diagnosis and correct treatment could prevent dramatic results. PMID- 25460451 TI - Asynchronous abdomino-parasacral resection of a giant pelvic lipoma protruding to the left buttock. AB - INTRODUCTION: Few reports detail adequate surgical management of giant pelvic tumors that traverse the sciatic foramen. PRESENTATION OF CASE: We present a case of a giant retroperitoneal pelvic lipoma that presented with a dumbbell shape on imaging, occupying the entire lesser pelvis and protruding to the gluteus through the sciatic foramen. Surgery was performed for en bloc resection of the tumor. DISCUSSION: A parasacral approach with the patient in the prone position was necessary to dissect the tumor in the buttock, manipulate around the sciatic foramen and preserve collateral blood flow for the gluteal muscle. An abdominal approach was also essential to ligate the internal iliac vessels involved in the tumor. Accordingly changings the position of the patient during the operation were required. Division of the sacrotuberous and sacrospinous ligaments and packing of the soft tumor into a plastic bag were useful to pass the buttock portion through the foramen without the tumor breaking off. CONCLUSION: The asynchronous abdomino-parasacral approach with several turnings of the patient's body and plastic bag packing of the tumor were advantageous to manage en bloc resection of the giant pelvic lipoma presented in this case study. PMID- 25460452 TI - A case of clear cell adenocarcinoma arising from endometriosis of the rectum treated by laparoscopic surgery. AB - INTRODUCTION: Malignant transformation of intestinal endometriosis occurring in the extraovarian sites is extremely rare. We report a very rare case of clear cell adenocarcinoma arising from endometriosis of the rectum. PRESENTATION OF CASE: An 83-year-old woman was admitted with the complaint of hematochezia. Colonoscopy revealed a tumor around about half of the rectal circumference. Biopsy of the tumor revealed a well-differentiated adenocarcinoma. Low anterior resection was undergone laparoscopically under the diagnosis of rectal carcinoma. Histopathological examination revealed clear cell adenocarcinoma, invading the sub-serosa of the rectum, but no metastasis of the lymph nodes. Immunohistochemical staining showed strong positivity for cytokeratin 7, but no staining for cytokeratin 20 and CDX2. The tumor existed adjacent to the endometrial glands, which were stained positive for Estrogen receptor. Ultimately, the patient was diagnosed with clear cell adenocarcinoma arising from endometriosis. Eighteen months after surgery, there are no signs of tumor recurrence. DISCUSSION: Clear cell adenocarcinoma arising from intestinal endometriosis has been reported in 7 cases, including our case. Careful observation is required because the prognosis of endometriosis after malignant transformation remains poor. CONCLUSION: We report a very rare case of clear cell adenocarcinoma arising from endometriosis of the rectum treated by laparoscopic surgery. PMID- 25460453 TI - Superior vena cava syndrome due to a leiomyosarcoma of the anterior mediastinum: A case report and literature overview. AB - INTRODUCTION: Leiomyosarcomas are an infrequent cause of malignant superior vena cava syndrome (VCS). PRESENTATION OF CASE: A 51-year old male patient was admitted for a three-day history of dyspnoea, dysphagia and erythema of the head and neck. Computed tomography and magnetic resonance imaging showed a lesion arising on the anterior mediastinum, which was in close proximity with a thrombus in the superior vena cava. Surgical excision was performed, including open resection of the primary tumour and an atrio-innominate vein bypass with 8-mm polytetrafluoroethylene (PTFE). Histology confirmed a leiomyosarcoma and postoperative radiotherapy sessions were performed. Due to evidence of enlargement of the thrombus, a second intervention was undertaken. In this procedure, a remainder of the primary tumour was resected and the superior vena cava reconstructed with an autologous pericardium patch. The patient recovered satisfactorily and was discharged on the seventh postoperative day, with no evidence for relapse after 10 months of follow-up. DISCUSSION: Leiomyosarcomas comprise less than 2% of the tumours of the mediastinum and are a rare cause of paraneoplastic VCS. Male patients in their sixties are most commonly affected. Relapses seem to be common, and thus a careful follow-up is often recommended. CONCLUSION: In spite of the limited data on the management of thoracic leiomyosarcomas, surgery is currently considered the mainstay of treatment. PMID- 25460454 TI - Delayed dynamic abdominal wall closure following multi-visceral transplantation. AB - INTRODUCTION: Primary closure of the abdominal wall following intestinal transplantation or multivisceral transplantation could become a challenging problem in a significant number of patients. PRESENTATION OF CASE: A 38-year-old woman with familial adenomatous polyposis (FAP) underwent a multi-visceral transplantation for short gut syndrome. She subsequently developed acute graft rejection that proved resistant to conventional treatment. She was relisted and underwent re-transplantation along with kidney transplantation. Abdominal wall closure could not be achieved because of the large size of the graft and bowel oedema. The wound was initially managed with laparostomy followed by insertion of the delayed dynamic abdominal closure (DDAC) device (Abdominal Retraction Anchor ABRA((r)) system). Continuous dynamic traction to the wound edges resulted in gradual approximation and complete closure of the abdominal wound was achieved within 3 weeks. DISCUSSION: Successful abdominal closure after multivisceral transplantation or isolated intestinal transplantation often requires biological mesh, vascularised flaps or abdominal wall transplantation. DDAC eliminated the need for a prosthetic mesh or skin graft and provided an excellent cosmetic result. Adjustment of the dynamic traction at the bedside minimised the need for multiple returns to the operating theatre. It resulted in a well-healed linear scar without a hernia. CONCLUSION: Dynamic traction allows delayed closure of laparotomy resulting in strong and cosmetically sound wound healing with native tissue. PMID- 25460455 TI - Sentinel lymph node biopsy in a patient with ruptured poly implant prothese (PIP) implants: A case report. AB - INTRODUCTION: Around 400,000 silicone gel breast implants produced by the French company poly implant prothese (PIP) were used worldwide. Following revelations that the company were using non- medical grade silicone for the production of their implants there has been growing concern over the increased rupture rate of these implants and the implications this may have on patients. PRESENTATION OF CASE: We report the case of a 57-year old lady with ruptured bilateral cosmetic PIP breast implants in whom a right breast lesion was detected on screening mammograms. Biopsies demonstrated a grade 1 tubular carcinoma. Histology from the sentinel lymph node biopsy showed axillary silicone granulomas but no evidence of metastatic disease. DISCUSSION: To our knowledge, this is the first reported case to describe SLNB in the presence of ruptured PIP implants, although SLNB in ruptured non-PIP implants has been previously described. CONCLUSION: We conclude that SLNB can be utilised even in the context of concurrent PIP implant rupture and the presence of silicone granulomas in the axillary lymph nodes. PMID- 25460456 TI - Malignant sigmoidoduodenal fistula. AB - INTRODUCTION: Duodenocolic fistula is a rare complication of malignant colonic disease especially when involving and originating from the sigmoid colon. We aim to discuss the unusual clinical presentation of this case as well as the investigation and management of duodenocolic fistulas. PRESENTATION OF CASE: A 91 year old lady presented as an emergency to a general surgical service at a District General Hospital with diarrhoea, vomiting and weight loss. Computed Tomography (CT) reported a large ovarian cyst elevating the sigmoid colon into immediate proximity of the duodenum. Adenocarcinoma was confirmed on histology obtained by colonoscopy. A classic apple core lesion with fistulating tract from the sigmoid colon to the duodenum was synchronously demonstrated on barium enema. DISCUSSION: Sigmoido-duodenal fistulae represent a complex manifestation of gastrointestinal pathologies. CONCLUSION: Management options must be considered in the context of patient wishes, their co-morbidities, and predicted post operative outcome. In most cases this is likely to represent a non-operative approach, however surgical resection may benefit selected cases on occasion. PMID- 25460457 TI - Co-existence of L5-S1 disc herniation and conus medullaris ependymoma. AB - INTRODUCTION: The lumbar disc herniations are seen very common than spinal ependymomas in the neurosurgery polyclinic routine. PRESENTATION OF CASE: In our case, both pathologies were seen at the most frequently located levels compatible with the literature. Aim of this case report is, to remind once more that, different pathologies can be found at the same time in a single patient; differential diagnosis must be done very carefully. DISCUSSION: The routine Computed Tomography (CT) imaging for low back pain can not show the conus medullaris pathology. Spinal tumors or other similar pathologies should be kept in mind for differential diagnosis. A good medical history and a good physical examination must be completed before the final diagnosis. CONCLUSION: Viewing of spinal canal with Magnetic Resonance Imaging (MRI) will be useful for the patients who we intend to do disc surgery. PMID- 25460458 TI - Report of video-capsule endoscopy disruption producing episodic small bowel obstruction after prolonged retention. AB - INTRODUCTION: Wireless video-capsule endoscopy is a procedure which provides direct visualization of the gastrointestinal tract, particularly the jejunum and ileum. Capsule retention is the main risk associated with capsule endoscopy, occurring at a significantly elevated incidence in patients with known or suspected Crohn's disease. PRESENTATION OF CASE: A case of a prolonged retained capsule with subsequent fragmentation producing a multicentric complete small bowel obstruction in a 39 year old male patient who had undergone wireless video capsule-endoscopy approximately three years prior. Management required surgical resection of the strictured jejunum and removal of retained capsule fragments under fluoroscopic guidance. DISCUSSION: Although capsule endoscopy is capable of diagnosis, evaluation, and monitoring inflammatory bowel disease, understanding the elevated risk for capsule retention is important in this population. Specifically, prolonged capsule retention appears to increase the risk of capsule disruption, and likely the potential for intestinal perforation. CONCLUSION: Patients should therefore be carefully selected for monitoring based upon treatment compliance and offered early endoscopic or surgical intervention in the setting of questionable compliance due to the risk for capsule disruption and subsequent intestinal perforation. PMID- 25460459 TI - Irreducible dorsal distal radius fracture-dislocation with accompanying dorsal displacement of flexor tendons and median nerve: A rare type of injury. AB - INTRODUCTION: High energy distal radius fractures may cause significant soft tissue injuries. Dorsal displacement of median nerve and flexor tendons to dorsal compartment between distal radioulnar joint was an unreported type of soft tissue injury. PRESENTATION OF CASE: 35-Year male admitted following fall from height diagnosed as closed distal radius fracture with dorsal displacement. The patient had no flexion and extension of all fingers with loss of sensation. Radial artery pulse was not palpable. Radiography and CT imaging revealed distal radius fracture with dorsal displacement with dorsal carpal dislocation. After failure of closed reduction, operative treatment was performed. At surgery, flexor tendons and median nerve was found to be placed at dorsal compartment. Reduction of the soft tissues was facilitated by distraction of distal radioulnar joint. DISCUSSION: Dorsal displacement of volar structures as the result of fracture dislocation was found to be an unreported type of injury. Difficulty during reduction of dorsally displaced structures is an important feature of the case. CONCLUSION: For severely displaced and deformed distal radial fractures and fracture dislocations, threshold for operative treatment should be kept low. PMID- 25460460 TI - Arthroscopic treatment of synovial chondromatosis in the ankle joint. AB - INTRODUCTION: Synovial chondromatosis is characterized by the presence of metaplastic cartilage nodules originating from the synovia, bursa and tendon sheaths. Although it is extremely rare in the ankle joint, malignant transformation is possible. The choice of treatment is usually open surgery for excision of loose bodies and synovectomy. Limited data is available concerning arthroscopic approaches. PRESENTATION OF CASE: A 28-year-old male patient was evaluated for pain and swelling of the right ankle joint. Based on the findings of physical examination and radiographic investigations, arthroscopic surgery was performed due to ankle impingement syndrome. A diagnosis of synovial osteochondromatosis was made following the pathological survey. DISCUSSION: Synovial chondromatosis is slowly progressive and is considered to be a self limiting situation. Treatment strategies are decided on according to the patient's complaints, age and disease stage. Open or arthroscopic surgery. can be performed. Some advantages of arthroscopic surgery are wide visualization areas, easy access to areas difficult to reach, lower morbidity, no necessity for casting and immobilization, early rehabilitation and quick recovery period. CONCLUSION: In conclusion, arthroscopic management can be successful in selected patients with synovial osteochondromatosis localized to the ankle joint. PMID- 25460461 TI - Giant condylomata acuminata of Buschke and Lowenstein: A peristomal variant. AB - INTRODUCTION: Giant condylomata acuminata (GCA) is a rare, locally invasive tumour that may undergo malignant transformation. It was first described a HPV induced penile tumour which clinically resembled both a squamous cell carcinoma and condyloma acuminatum, often arising from a pre-existing warty lesion. We describe a case of peri-stomal GCA transformation into invasive squamous cell carcinoma (SCC), which is, to our knowledge, the first report of this in the literature. PRESENTATION OF CASE: A 74 year old gentleman developed an acuminate, papillomatous peristomal eruption around a fifty year old ileostomy, with biopsies of the eruption showing reactive changes. Two years later, he developed ulcerating plaques affecting the previously papillomatous areas and an erythematous nodular lesion involving the superior part of the ileostomy and adjacent skin. Histological examination of the ileostomy lesion showed focal small islands of atypical squamous epithelium, and moderately differentiated invasive squamous cell carcinoma was shown in the excised tissue subsequently. Human papillomavirus (HPV type 16), p16 and p53 tumour suppressors were positive in the peri-stomal skin sample. DISCUSSION AND CONCLUSIONS: Recurring, changing papillomatous lesions in the peristomal area should be reviewed with a high index of suspicion in relation to GCA tumours as they can progress to invasive squamous cell carcinomas. PMID- 25460462 TI - Irreducible dislocated total hip replacement due to intra-articular incarceration of bone cement: A case report. AB - INTRODUCTION: Dislocation following total hip replacement is a well-documented complication. We present an unusual cause of failure to achieve a concentric closed reduction of a cemented total hip replacement which has never previously been reported. PRESENTATION OF CASE: A 78-year-old female patient had an unsuccessful closed reduction of a posteriorly dislocated total hip replacement. Careful review of perioperative radiographs revealed a fragment of bone cement incarcerated within the acetabular component blocking reduction. This was confirmed on a subsequent computed tomography scan. Open reduction via a posterior approach with retrieval of the cement fragment was eventually required. DISCUSSION: Observation of important radiological features which may prevent unnecessary further attempts at closed reduction are discussed. We consider reasons for a non-concentric reduction and reflect on the dangers of multiple forced attempts. CONCLUSION: This case emphasises the importance of clinical judgement during closed reduction and highlights a previously unreported cause for non-concentric reduction in a dislocated cemented total hip replacement. PMID- 25460463 TI - Laparoscopic and endoscopic cooperative surgery for duodenal neuroendocrine tumor (NET) G1: Report of a case. AB - INTRODUCTION: We report a case of duodenal neuroendocrine tumor (NET) G1 resected by laparoscopic and endoscopic cooperative surgery (LECS) technique. PRESENTATION OF CASE: A 58-year-old woman underwent esophagastroduodenoscopy, revealing an 8 mm, gently rising tumor distal to the pylorus, on the anterior wall of the duodenal bulb. Endoscopic ultrasonography suggested the tumor might invade the submucosal layer. The tumor was pathologically diagnosed as a G1 duodenal NET, by biopsy. Endoscopic submucosal dissection was attempted, but was unsuccessful because of the difficulty of endoscopically performing an inversion operation in the narrow working space. The case was further complicated by the patient's duodenal ulcer scar. We performed a full-thickness local excision using laparoscopic and endoscopic cooperative surgery. The tumor was confirmed and endoscopically marked along the resection line. After full-thickness excision, using endoscopy and laparoscopy, interrupted full-thickness closure was performed laparoscopically. DISCUSSION: Endoscopic treatment is generally recommended for G1 NETs <10mm in diameter and extending only to the submucosal layer. However, some cases are difficult to resect endoscopically because the wall of duodenum is thinner than that of stomach, and endoscope maneuverability is limited within the narrow working space. LECS is appropriate for early duodenal G1 NETs because they are less invasive and resection of the lesion area is possible. CONCLUSION: We demonstrated that LECS is a safe and feasible procedure for duodenal G1 NETs in the anterior wall of the first portion of the duodenum. PMID- 25460464 TI - Robotic single-site combined cholecystectomy and hysterectomy: Advantages and limits. AB - INTRODUCTION: Robotic single-site surgery (RSS) represents the latest innovation for clinical use of single incision surgery. Several applications have been reported in urology, general surgery and gynecology with potential application in benign cases as well as in oncology. PRESENTATION OF CASE: To further explore potential applications of RSS, we present the first case reported in the literature of combined cholecystectomy and total hysterectomy using the da Vinci Si single-port platform (Intuitive Surgical Inc., Sunnyvale, CA). DISCUSSION: A critical description of the procedure with potential advantages and limitations of the current platform for combined surgical procedure is provided. CONCLUSION: Robotics may facilitate the widespread diffusion of single incision surgery, overcoming current laparoscopic and LESS limitations. However, the available robotic platform still has technical features that will limit its uptake amongst surgeons and further technological development is needed for a wider diffusion of single incision surgery. PMID- 25460465 TI - Management of cervical thoracic duct cyst with cyst-venous anastomosis. AB - INTRODUCTION: Cervical thoracic duct cyst (CTDC) is a rare cause of lateral neck mass. Surgical excision with ligation of the cervical thoracic duct is the current standard for definitive management with symptomatic patients. We report the first case of an alternative method of management performing a cyst venous anastomosis for decompression. PRESENTATION OF CASE: A 77 year old female presented with a six month history of left arm pain, swelling and a left-sided cystic neck mass. She was treated with cyst-venous anastomosis between the cyst wall and the left internal jugular vein. At two year follow-up, she has had resolution of pain and no recurrence of the mass. DISCUSSION: Many potential etiologies have been proposed for CTDC, though surgical management of this rare problem has consistently required cyst excision and thoracic duct ligation. Few innovative modes of therapy have been developed to address this problem in a less invasive manor. Maintaining a more natural thoracic duct anatomy decreases the likely of complications associated with duct ligation. CONCLUSION: Cyst-venous anastomosis for the management of CTDC provides an effective, novel form of treatment which maintains the integrity of the thoracic duct and avoids potential complications associated with duct ligation. PMID- 25460466 TI - Incidental discovery of a long standing arteriovenous fistula after thrombectomy for acute lower limb ischaemia. AB - INTRODUCTION: Arteriovenous fistula (AVF) is the abnormal connection between an artery and vein. Congenital AVF of the popliteal artery is very rare. PRESENTATION OF CASE: 89 year old lady presented with right acute lower limb ischaemia. She had unilateral chronic venous hypertensive change in the right leg. Femoral embolectomy was performed. Backflow was achieved. Arteriotomy was closed. The patient's leg continued to deteriorate. She returned to theatre. On table angiogram showed an occluded SFA. Thrombectomy was completed. SFA was patent but no blood flowed into the distal popliteal artery. A second on table angiogram revealed AVF between popliteal artery and vein. Dissection to the posterior aspect of the knee revealed the fistula. The vein was arterialized and enlarged. The AVF was ligated. Normal distal blood flow was achieved. Retrospectively we measured the leg lengths. Right leg was 3cm longer than the left. The right leg circumference was 7cm greater than the left. She reported chronic venous change from a young age. She did not report any history of trauma to the limb. DISCUSSION: Popliteal artery to popliteal vein fistula is a rare. Trauma is the most common cause of popliteal AVF. Should the condition develop before closure of the epiphyses, there may be an increase in leg measurements. CONCLUSION: We postulate that this case of AV fistula may be congenital due to discrepancy in leg measurements and unilateral chronic venous hypertensive change. Rarely persistent remnants of the embryonic sciatic artery can lead to arteriovenous anastomoses, which may be a possible aetiology. PMID- 25460467 TI - Ileosigmoid knotting-A disastrous double closed loop obstruction. AB - INTRODUCTION: Ileosigmoid knotting (ISK) is a rare entity which needs prompt recognition and immediate surgical intervention to avoid catastrophic complications caused by gangrenous bowel and subsequent peritonitis. Preoperative investigations are only diagnostic of obstruction and CT findings are helpful but are not always available. PRESENTATION OF CASE: This case report describes a 22 year old male presenting with acute abdomen managed with emergency exploration in view of findings of peritonitis. Intra-operatively an ileal segment was wrapped around the base of sigmoid colon with gangrenous ileal segment suggesting ISK. Resection of gangrenous ileal segment with double barrel ileostomy was done. Patient tolerated procedure well. DISCUSSION: Patients with ileosigmoid knotting present with frank obstruction and require immediate medical and surgical treatment. This condition rapidly progresses to gangrenous bowel, generalized peritonitis and sepsis with very high mortality. CONCLUSION: Early diagnosis, prompt fluid resuscitation, preoperative antibiotics and immediate surgical exploration are keys for optimal management of this condition. PMID- 25460468 TI - Familial jejuno-ileal diverticulitis: A case report and review of the literature. AB - INTRODUCTION: Jejuno-ileal diverticulitis (JID) is a rare entity, presenting with symptoms of failure to thrive, abdominal pain, obstruction, bleeding, and acute or chronic perforation with associated pneumoperitoneum. Currently no specific genetic abnormality has been identified that leads to JID. Treatment is based on control of symptoms associated with the disease. PRESENTATION OF CASE: We describe a familial cohort of patients with JID, with associated symptoms of chronic pneumoperitoneum, including a proposed genetic inheritance pattern and pedigree. In addition, we will describe the operative treatment of one family member's JID and chronic pneumoperitoneum. DISCUSSION: While JID is rare, this familial cohort demonstrates a pattern of inheritance most consistent with autosomal dominance. The pathology demonstrates true diverticula, unlike most previous descriptions of JID. The index patient was successfully treated by minimally invasive surgery. CONCLUSION: Familial JID is a rare entity, without an identified genetic abnormality. Treatment of chronic symptoms currently focuses on non-operative management. While most case reports involve individual patients, this cohort may possess a genetic mutation with an autosomal dominant pattern of inheritance. Further study into patients with JID may reveal an underlying genetic abnormality associated with development of the disease. PMID- 25460469 TI - Laparoscopic repair of a rare acquired abdominal intercostal hernia. AB - INTRODUCTION: An acquired abdominal intercostal hernia (AIH) is a very rare and sporadically reported entity. Most cases of AIH are secondary to major trauma and the treatment of choice is surgical repair. PRESENTATION OF CASE: We present the case of a 58-year-old man who presented with a painless intercostal swelling, which started after previous penetrating trauma to the same area. Radiological assessment was done with CT scan and the hernia was repaired with a laparoscopic approach using mesh. DISCUSSION: AIH is a rare entity and trauma has an integral role in the pathophysiology. Surgical repair is the treatment of choice, however, due to the paucity of cases, there is no established method of choice for such repair. We present the first reported case in the Caribbean, which was repaired with the laparoscopic approach. CONCLUSION: Although AIH is a rare condition, the pathophysiology seems relatively straightforward and the use of CT scan is recommended to confirm the diagnosis. The laparoscopic approach, with all its established benefits, appears to be a safe and feasible option in its management. PMID- 25460470 TI - Small bowel volvulus with no malrotation after laparoscopic appendicectomy: Case report and literature review. AB - INTRODUCTION: Small bowel volvulus, as a complication of laparoscopic surgery, is a rarely reported clinical entity. We present a case of a young female who developed small intestinal volvulus after laparoscopic appendicectomy. She had this complication in the absence of malrotation or other previous abdominal operations. PRESENTATION OF CASE: A 17-year-old woman presented with acute appendicitis. After an uneventful laparoscopic appendicectomy, she developed acute small intestinal obstruction on the second post-operative day. A prompt laparotomy showed small bowel volvulus, which was reduced, with no evidence of malrotation. She had an uneventful recovery and was discharged within 3 days of the second operation, in a stable condition. DISCUSSION: This article presents a review of the literature of this rare cause of small intestinal obstruction after laparoscopic surgery, stressing on the importance of early diagnosis and treatment. A discussion of the potential factors predisposing to this entity is presented, emphasising the need of a higher-evidence study as to its aetiology and prevalence. CONCLUSION: Small bowel volvulus is a rare complication of laparoscopic surgery, but its early diagnosis and prompt treatment is essential to avoid morbid outcomes. Surgery is the therapeutic mainstay. PMID- 25460471 TI - Unexpected fetal demise despite the reactive nonstress test during the conservative management of acute pancreatitis in pregnancy. AB - INTRODUCTION: Dealing with acute pancreatitis in pregnancy is a challenging problem due to unexpected nature of the disease. PRESENTATION OF CASE: We report a complicated case of a 29-year-old pregnant woman with a mild acute pancreatitis whose pregnancy ended up with an unexpected fetal demise at her 34th gestational week. This unfortunate outcome led us reconsider our obstetrical approach to acute pancreatitis during pregnancy. CONCLUSION: Based on this unfortunate event, we now think that obstetricians should keep in mind that even in the presence of reassuring NST and biophysical profile assessment, an unpredictable fetal loss can occur during the medical management of the pregnancies complicated with mild acute pancreatitis. DISCUSSION: The subject patient of this case report was diagnosed with mild AP and underwent conservative medical management. Since the patient was stable and fetal well-being was confirmed with BPP and NST, the termination of pregnancy was out of question at that time. The occurrence of unexpected fetal death despite assuring parameters led us reconsider the approach to the pregnant women with mild AP. PMID- 25460472 TI - Giant retroperitoneal leiomyosarcoma. Multiorgan block removal. AB - INTRODUCTION: Retroperitoneal tumors are rare, mostly malignant. Locally aggressive, and more frequent in women in their 5th decade of life. Its symptoms are nonspecific, including abdominal pain and palpable mass. To diagnosis is helpful computed tomography and biopsy. It needs surgery for absolute healing. PRESENTATION OF CASE: 67 years old man was admitted with back pain and fever. Abdominal imaging tests showed a 15cm abdominal mass without clear organodependencia. Endoscopy with biopsies evidenced mesenchymal neoplasia of undetermined origin. In surgery we confirm its resecability and was necessary multiorgan resection. Pathologic diagnosis: well differentiated retroperitoneal leiomyosarcoma. Started adjuvant radiotherapy. In subsequent tests showed the presence of liver metastases. DISCUSSION: Retroperitoneal tumors are developed from nerve, vascular, muscular, connective, supportive and fibroareolar tissue from this space. Its size does not modificate survival or resectability. We used TC and biopsy for its diagnose. Adjuvant therapy does not affect survival or quality of life, surgery remains the only curative option. Locoregional recurrence is the most influential figure in the prognosis. A large percentage of patients required a second surgery (between 45 and 82%). CONCLUSION: The only curative option of retroperitoneal sarcomas is surgery, which usually requires multiple organ resection. Chemotherapy and radiotherapy are mostly a surgical supplement. Chemotherapy has not shown significant increase in survival. PMID- 25460473 TI - Amebiasis presenting as acute appendicitis: Report of a case and review of Japanese literature. AB - INTRODUCTION: Outside of these high-risk regions, acute amebic appendicitis is considerably rarer and the mortality rate is much higher than with non-amebic appendicitis. PRESENTATION OF CASE: A 31-year-old woman presented with fever and right lower abdominal pain with no history of traveling abroad or sexual infection. Computed tomography revealed a dilated appendix and thickened cecal and ascending colon walls. She underwent an appendectomy for appendicitis. Owing to a lack of symptom resolution, we performed a pathologic examination of the appendix again that revealed multiple Entamoeba histolytica trophozoites; the serum amebic antibody was positive. She was treated postoperatively with metronidazole for amebiasis and discharged on postoperative day 12. DISCUSSION: The mortality rate and frequency of severe postoperative intraabdominal complications were higher in the Japanese literature (1995-2013) (25% and 33%, respectively) than in other developed countries (3.3% and 19.4%, respectively). Japan is a low-risk area for amebiasis; many physicians fail to consider amebiasis in the differential diagnosis of acute abdomen. It is important to conduct further examinations, including those for amebiasis, when appendectomy does not resolve acute appendicitis. CONCLUSION: We report a case of acute amebic appendicitis in a 31-year-old woman and review the ages at presentation, causative factors, treatments, and outcomes of 11 cases reported in Japan between 1995 and 2013. PMID- 25460474 TI - Aspiration pneumonia as a complication of a rare type of hernia. AB - INTRODUCTION: Inguinal hernias are a common pathology and can contain unusual abdominal contents; the stomach is only infrequently involved due to its position in the abdominal cavity. PRESENTATION OF CASE: An 85-year old male patient presented with symptoms of bowel obstruction and was subsequently found to have an incarcerated stomach within his chronic left-sided inguinal hernia. The patient had also developed aspiration pneumonia. DISCUSSION: Aspiration pneumonia is a yet unreported complication of this unusual type of hernia. Our aim is to describe the presentation and management of this complication. CONCLUSION: Development of aspiration pneumonia in a patient with an incarcerated stomach within an inguinal hernia. PMID- 25460475 TI - Pediatric open elbow dislocation without fracture: A case report. AB - INTRODUCTION: Elbow dislocations in children are rare injuries. These injuries are often in the form of complex injuries that is accompanied by the median nerve damage and medial epicondyle fracture in the pediatric age group. Open elbow dislocation without fracture in the pediatric age group has been reported very rarely in the literature. PRESENTATION OF CASE: The purpose of this study is to present an 8-year-old patient who has open elbow dislocation without fracture accompanying with brachial artery injury. In the clinical examination of the patient, there was an open wound in the transverse antecubital region. After repair of brachial artery injury, open reduction was performed under general anesthesia. In the postoperative clinical examination at 6 months, left elbow flexion was 140 degrees , extension was full and there were no deficit in the supination and pronation of the forearm. DISCUSSION: Elbow dislocation without fracture in pediatric patients is a very rare injury. Usually the trauma mechanism of elbow dislocation is falling on outstretched hand with elbow in approximately 30 degrees of flexion. However our patient had fallen on outstretched hand with elbow in full extension. Although this type of trauma mechanism is typical for supracondylar humerus fractures in pediatric age group, in our patient an open posterior elbow dislocation without fracture had occurred. CONCLUSION: Pediatric elbow dislocations are rare injuries and the management of these injuries can be technically demanding due to concurrent neurovascular injuries. An open dislocation without fracture is very rare and it should be treated with immediate intervention, an effective teamwork and good rehabilitation. PMID- 25460476 TI - A rare cause of 'drop foot' in the pediatric age group: Proximal fibular osteochondroma a report of 5 cases. AB - INTRODUCTION: The fibular nerve is the most frequent site of neural entrapment in the lower extremity and the third most common site in the body, following the median and ulnar nerves. The peroneal nerve is commonly injured upon trauma. Additionally, a dropped foot might be a symptom related to the central nervous system or spinal pathologies in pediatric patients. Entrapment of the peripheral nerve as an etiologic cause should be kept in mind and further analyzed in orthopedic surgery clinics. PRESENTATION OF CASE: In this study, the evaluation and treatment results of five patients with no history of trauma, who underwent diagnostic procedures and treatment in various clinics (physical therapy and rehabilitation and neurosurgery), are reported. The patients underwent several treatments without diagnosis of the primary etiology. Upon initial consultation at our department, osteochondroma at the proximal fibula was detected after physical examination and radiologic assessment. During surgery, the peroneal nerve was dissected, starting from a level above the knee joint. Following nerve release, the osteochondroma was removed, including its cartilage cap. Consequently, recovery was observed in all five cases after surgery. DISCUSSION: Many factors may cause non-traumatic neuropathies. However, due to their rare occurrence, lesions such as osteochondromas may be overlooked at non-orthopedic clinics. Nerve entrapment due to proximal fibular osteochondroma is rare. Surgical treatment planning plays a critical role in nerve entrapment cases. CONCLUSION: Despite its frequent occurrence, a drop foot associated with peroneal nerve entrapment by an osteochondroma is not easily remembered and diagnosed. Especially in pediatric cases, inadequate clinical consultation and a lack of appropriate radiologic studies may result in a delay in diagnosing peroneal nerve lesions. PMID- 25460477 TI - An unusual complication of Botox treatment for sialorrhoea. AB - INTRODUCTION: To illustrate the potential side effects and clinical efficacy of Botox injections in treating sialorrhoea. PRESENTATION OF CASE: A 26-year-old patient with cerebral palsy with dystonia had a long history of severe, distressing sialorrhoea. She was treated with three separate Botox injections into her salivary glands in December 2011, July 2012 and March 2013. DISCUSSION: Following the Botox injections the patient developed dysphagia, began to expectorate thick mucus and developed a cough; she was treated for a chest injection and during this time her feeding deteriorated. Three injections were given as the patient had an objective and significant reduction in salivation. However, the side effect profile was deemed too great to continue with treatment. CONCLUSION: Botox is a novel and effective treatment for reducing saliva production. Its clinical efficacy is supported by this case and correlates with the recent literature. Although rare, significant side effects can happen and the case presented illustrates the care needed when administering injections, particularly in a subgroup of patients. PMID- 25460478 TI - Ovarian torsion in puerperium: A case report and review of the literature. AB - INTRODUCTION: Ovarian torsion (OT) is a rare cause of acute abdominal pain that requires prompt recognition and treatment during puerperium. Diagnosis of OT can be challenging due to nonspecific clinical features and uncommon objective findings. The management of OT is often delayed because of diagnostic uncertainty. Early and timely recognition and prompt intervention are crucial to preserve ovarian function and to minimize morbidity. PRESENTATION OF CASE: We report a 29-year-old postpartum woman who presented to the emergency department (ED) with severe right flank pain, nausea and anorexia initially considered as renal colic. After further investigation, OT caused by large mucinous cyst was diagnosed. Right-sided salpingo-oophorectomy was performed due to hemorrhagic ovary and huge cystic mass causing ischemic OT. DISCUSSION: OT is often diagnosed based on the clinical presentation, including severe, sharp, sudden onset of unilateral lower abdominal pain and tenderness with a palpable laterouterine pelvic mass and nausea/vomiting. Emergency surgical intervention should be performed if OT is suspected to confirm the diagnosis and uncoil the twist to prevent ovarian damage. CONCLUSION: In conclusion, emergency physicians should be aware of the possibility of OT in postpartum women. Therefore, early and timely surgical intervention should be undertaken. PMID- 25460479 TI - Associating liver partition and portal vein ligation for a patient with hepatocellular carcinoma with a background of hepatitis B related fibrotic liver. AB - INTRODUCTION: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has recently been developed for patients with predicted insufficient future liver remnant volumes to induce more rapid hepatic hypertrophy and increase resectability. In the medical literature, the use of ALPPS in hepatocellular carcinoma (HCC) has rarely been reported. PRESENTATION OF CASE: We reported the use of ALPPS in a patient with primarily unresectable HCC arising from a background of hepatitis B related liver fibrosis. Preoperative computed tomography (CT) showed 2 large conglomerated tumors measuring 16cm*10.5cm in liver segments 5, 6, 7 and 8, and at least 3 satellite nodules with the largest one measuring 3cm around the main tumor and another 4cm tumor in segment 4. Right trisectionectomy after ALPPS was successfully performed. He was discharged from hospital on postoperative day 13 after the second operation. Follow-up CT scan at 6 weeks after the second operation showed further hypertrophy of the liver remnant and no liver recurrence. DISCUSSION: Our case showed that this novel strategy is feasible even in the context of a background of chronic hepatitis B related liver fibrosis, although the hypertrophy rate was a little bit slower and the time needed was longer. CONCLUSION: ALPPS is also feasible in liver fibrosis. It gives hope to patients with HCC who previously were considered as having unresectable diseases. More studies are needed to further evaluate the effectiveness and oncological outcomes of ALPPS from these patients. PMID- 25460480 TI - Single incision laparoscopic surgery approach for obscure small intestine bleeding localized by CT guided percutaneous injection of methylene blue. AB - INTRODUCTION: Traditionally, localization of small intestine sources of obscure gastrointestinal bleeding has been a challenge. Advances in the field of endoscopy with the introduction of capsule endoscopy and radiographic imaging with computed tomography angiography and visceral angiography have facilitated more accurate visualization of the small intestine. If a bleeding lesion is identified on angiography and surgery is indicated, the use of methylene blue for enteric mapping is very effective to aid intraoperative localization of the culprit. However, when this is not an option, more invasive surgical techniques are required. PRESENTATION OF CASE: We present a new technique used in a patient with angiodysplasia of the small intestine, in where preoperative localization was done using percutaneous computed tomography (CT) guided injection of methylene blue dye. This allowed us to perform a single incision laparoscopic small intestine resection of the culprit. PMID- 25460481 TI - Case report: HIV negative isolated scrotal Kaposi's sarcoma. AB - INTRODUCTION: Kaposi's sarcoma (KS) is a rare angioproliferative disorder of the vascular endothelium. The development of KS requires Human Herpes Virus 8 (HHV-8) infection. An associated HIV infection is usually seen. Isolated scrotal KS has rarely been reported. In this article, we present a case of KS that primarily involved the scrotum in a HIV negative patient. PRESENTATION OF CASE: A 71-year old male patient admitted to the outpatient department due to nodular lesions on the scrotum. The patient declared that these lesions were present for nearly 5 years. Past medical history revealed that he underwent left thoracotomy and upper lobectomy in 2006 for adenosquamous lung carcinoma. Then, he received a single cycle of adjuvant chemotherapy consisted of docetaxel and cisplatin. Physical examination revealed 3 black small nodules on the scrotum. The anti-HIV test was negative. All scrotal lesions were surgically excised. The pathological investigation revealed KS of the lymphangioma-like type. DISCUSSION: The pathogenesis of KS has still not been clearly elucidated. However, it is known that all forms of KS are associated with HHV-8 infections. A defect in immune system was almost always necessary. Therefore, KS is usually associated with HIV infection. KS of the penis has been reported in HIV negative patients. Very few cases of scrotal KS have been presented. In a recent review, only 1 patient had scrotal KS out of 32 cases with HIV negative KS. In our case, the patient received a cycle of chemotherapy that might affect his immune system. The lymphangioma-like type is a common morphological sub-type. While lymph edemas are commonly observed in this sub-type, no edema in the lymphs was present in our case. CONCLUSION: Classical KS is generally observed in the lower extremities, it can rarely affect scrotal skin as isolated lesions. Therefore, a careful physical examination should also include scrotum for these patients. PMID- 25460482 TI - Gallbaldder perforation causing a subcutaneous abscess. AB - INTRODUCTION: This is a report of a rare case of an old woman with a large round mass in the right hypochondrium that was proven to be an abscess. PRESENTATION OF CASE: A 82-year old woman with a firm round mass in the right hypochondrium was admitted for evaluation. The abdominal CT showed an abscess produced by a gallbladder perforation, and a gallstone impacted at the Hartmann's pouch. DISCUSSION: The abscess was treated with a transcutaneous paracentesis, while the stone passed to the gastrointestinal tract through a cholecystoenteric fistula, without causing any further problems. CONCLUSION: Gallbaldder perforation can rarely create a subcutaneous abscess especially in thin, elder subjects. Abscess drainage is the first line of treatment. PMID- 25460483 TI - A rare condition of anorectal dysfunction in a patient with multiple sclerosis: Coexistence of faecal incontinence and mechanical constipation: Report of case. AB - INTRODUCTION: Multiple sclerosis is a chronic demyelinating neurological disease and causing a variety of neurological symptoms, including discomfort of anorectal function. Constipation and faecal incontinence present as anorectal dysfunction in MS and anal manometry, colonic transit time, electromyography, and defecography can be used for assessment. PRESENTATION OF CASE: We presented a thirty-three years old woman with rare condition of anorectal dysfunction in multiple sclerosis. Anal manometry, defecography were done, and synchronously anal incontinence and mechanical constipation due to rectocele and anismus were detected in this patient. DISCUSSION: Although anal incontinence and constipation are seen often in patients with multiple sclerosis, in the literature, coexistence of animus, rectocele and anal incontinence are quite rare. CONCLUSION: Defecography and anal manometry are useful diagnostic methods for demonstration of anorectal dysfuntions in patients with MS. PMID- 25460484 TI - A rare case of IgG4-related systemic disease manifesting with pancreatic head mass mimicking borderline resectable cancer. AB - INTRODUCTION: Autoimmune pancreatitis (AIP) is a rare pancreatic disorder among chronic pancreatitis that can mimick pancreatic cancer (PC). Patients with type 1 AIP usually present obstructive jaundice associated with high level of IgG4 in serum and a pancreatic mass at radiological imaging; these disorders may be associated with other organs lesions presenting the same histopathological features, and in these cases AIP should be considered a pancreatic localization of an IgG4-related systemic disease. PRESENTATION OF CASE: We report the case of a young man with initial suspect of PC to be treated with surgery, and final diagnosis of AIP in the context of an IgG4-related systemic disease. DISCUSSION: Because of its similar features, several algorithms have been proposed for AIP diagnosis, based on combination of clinical/serological and radiological criteria. However, histology represents the only way to obtain definitive diagnosis, even if sometimes it is difficult to obtain biological samples. CONCLUSION: IgG4-related systemic disease must be taken into account among differential diagnosis during the workup for PC, in order to avoid unnecessary surgery. PMID- 25460485 TI - Primary intrahepatic malignant epithelioid mesothelioma. AB - INTRODUCTION: Primary malignant hepatic mesotheliomas are extremely rare. We report the case of a patient with primary intrahepatic malignant mesothelioma who was treated in our department. PRESENTATION OF CASE: A 66-year old male patient was admitted to our department for the evaluation of anemia. An abdominal computed tomography scan revealed a large space occupying lesion in the right liver lobe. DISCUSSION: The tumor was subsequently resected and a diagnosis of primary intrahepatic malignant mesothelioma was made after pathologic examination. The patient did not receive adjuvant therapy and is currently alive and free of disease, 36 months after the resection. CONCLUSION: To our knowledge this is the eighth adult case of primary intrahepatic malignant mesothelioma reported in the literature. These tumors are rarely diagnosed preoperatively. Absence of previous asbestos exposure does not exclude malignant mesothelioma from the differential diagnosis. Proper surgical treatment may offer prolonged survival to the patient, without adjuvant therapy. PMID- 25460486 TI - Pneumoperitoneum in a patient with pneumothorax and blunt neck trauma. AB - INTRODUCTION: Blunt trauma as a cause of pneumoperitoneum is less frequent and its occurrence without a ruptured viscus is rarely seen. PRESENTATION OF CASE: We report a case of blunt neck trauma in which a motorcycle rider hit a fixed object causing severe laryngotracheal injury. The patient developed pneumothorax bilaterally and had pneumoperitoneum despite no injury to the internal viscus. Bilateral chest tube drainage and abdominal exploratory laparotomy was performed. CONCLUSION: Free air in the abdomen after blunt traumatic neck injury is very rare. If pneumoperitoneum is suspected in the presence of pneumothorax, exploratory laparotomy should be performed to rule out intraabdominal injury. As, there is no consensus for this plan yet, further prospective studies are warrant. Conservative management for pneumoperitoneum in the absence of viscus perforation is still a safe option in carefully selected cases. PMID- 25460487 TI - Robot assisted thoracoscopic resection of giant esophageal leiomyoma. AB - INTRODUCTION: Esophageal leiomyoma represents the most common benign esophageal tumor. Robot-assisted thoracoscopic surgery has provided ability to remove it successfully using a minimally invasive approach. PRESENTATION OF CASE: A 63-year old female with history of chronic chest pain presented with an esophageal mass on chest CT and endoscopic ultrasound. Robot-assisted surgery was performed using three robot arms, a camera and an assistant port. A 10cm leiomyoma was enucleated and removed through a 2cm myotomy. Completion endoscopy confirmed integrity of the esophagus. Patient's chest pain resolved postoperatively, and she was discharged on postoperative day 3. DISCUSSION: Our case describes successful removal of the giant esophageal leiomyoma (10cm) by robot assisted minimally invasive resection through a 2cm myotomy. CONCLUSION: Use of robot allows for removal of large esophageal leiomyoma. The improved dexterity and patient outcome offered by robot suggests its potential as the mainstay technique for giant esophageal leiomyoma removal. PMID- 25460488 TI - A case report: Cecal volvulus caused by Meckel's diverticulum. AB - INTRODUCTION: Meckel's diverticulum is the most common congenital anomaly of the small intestine. Common complications related to Meckel's diverticulum include hemorrhage, intestinal obstruction and inflammation. Acute large bowel obstruction is a rare complication of Meckel's diverticulum and in the presented case it is caused by volvulus. PRESENTATION OF CASE: We report a 39 year old female who presented with the diagnosis of a large bowel obstruction occurring as a result of cecal volvulus caused by adhesions of a perforated diverticulum. DISCUSSION: The reported case presents one of the rare complications of MD, which is volvulus. The case described above presented with signs and symptoms suggestive of acute intestinal obstruction and radiological findings suggestive of cecal volvulus. The patient was taken to the operation room for exploration and we discovered the presence of a perforated MD. The main treatment of such case is to perform diverticulectomy in all symptomatic patients. CONCLUSION: MD is mostly identified intraoperatively. Knowledge of the pathophysiologies by which MD can cause complications such as volvulus is important in order to plan management. PMID- 25460489 TI - Percutaneous reduction and flexible intramedullary nailing for monteggia fracture in a skeletally mature patient. AB - INTRODUCTION: Monteggia lesions are defined as a fracture of the proximal ulna with an associated radial head dislocation. Management of these injuries varies depending upon the patient population, ranging from non-operative treatment with closed reduction and immobilization to surgical fixation. Percutaneous techniques of radial head reduction are often reserved for skeletally immature patients. PRESENTATION OF CASE: In this case report, a 14-year-old female presented with left elbow pain three days after a fall. Radiographs and CT images from an outside hospital revealed a displaced left radial head fracture and a non displaced proximal olecranon fracture, consistent with a Monteggia equivalent fracture. The patient underwent percutaneous reduction and internal fixation of the radial head with a flexible intramedullary nail (Metaizeau technique), and open reduction and internal fixation of the olecranon. She developed a 25 degree left elbow flexion contracture and, five months after her index procedure, underwent arthroscopic release and removal of hardware. The radial head reduction was near anatomic and she regained full extension. DISCUSSION: This report demonstrates that percutaneous reduction with intramedullary nailing and fixation techniques can be performed successfully in skeletally mature patients. CONCLUSION: Given their less invasive nature, we recommend attempting percutaneous interventions in some skeletally mature individuals for fracture reduction and fixation. PMID- 25460490 TI - Obesity and co-morbid psychiatric disorders as contraindications for bariatric surgery?-A case study. AB - INTRODUCTION: Many patients undergoing bariatric surgery report current or past psychiatric disorders and controversy exists regarding their outcome after bariatric surgery. PRESENTATION OF CASE: We present a case of an obese patient with a borderline personality disorder, a recurrent depressive disorder, post traumatic stress symptoms and binge eating episodes who underwent bariatric surgery. DISCUSSION: Although the psychiatric disorders remained, the procedure contributed to an improvement of the health status and well-being of the patient. Adequate psychological care after the surgical procedure is necessary to enable a long-term stabilization of patients with mental co-morbidities. CONCLUSION: Patients with psychiatric co-morbidities should not be excluded from the procedure if adequate post-operative support is provided. PMID- 25460491 TI - Pancreatic neuroendocrine tumor with splenic vein tumor thrombus: A case report. AB - INTRODUCTION: Pancreatic neuroendocrine tumors (PNET) are rare, often indolent malignancies. PNET are classified as functional or nonfunctional based on the secretion of hormones without a negative feedback loop; the latter account for up to 60% of PNET. Although PNET are associated with a better prognosis compared to pancreatic adenocarcinomas, they are often diagnosed in advanced stages, making them a significant source of morbidity for patients. Here we present a rare case of venous tumor thrombus arising from a nonfunctional PNET. PRESENTATION OF CASE: A 44-year-old woman was referred for evaluation and treatment of a possible tail of pancreas PNET discovered during work-up for a 9 year history of intermittent subcostal pain. Previous endoscopic ultrasound with fine needle aspiration revealed a 3.5cm*3cm mass, with cytological diagnosis of neuroendocrine tumor. Patient was scheduled for laparoscopic distal pancreatectomy. During surgery the mass was found to encase the splenic vein leading the surgeon to perform an en bloc distal pancreatectomy and splenectomy. Pathologic analysis revealed a 1.8cm*5cm tumor thrombus lodged in the splenic vein. DISCUSSION: Nonfunctional PNET usually present in advanced stages and can be associated with venous tumor thrombi. Preoperative imaging may not accurately predict the presence of venous tumor thrombi. CONCLUSION: En bloc resection of primary tumor, involved organs and thrombus is the recommended treatment option and often results in long term survival. New multi-modality strategies are needed for detection of venous involvement in nonfunctional PNET to better assist with preoperative planning and counseling. PMID- 25460492 TI - Acute compartment syndrome secondary to disruption of the perforating branch of the peroneal artery following an acute inversion injury to the ankle. AB - INTRODUCTION: Although ankle sprain by inversion is common in daily practice, acute compartment syndrome following ankle inversion injury is unusual. Only a few cases of this uncommon entity have been reported. PRESENTATION OF CASE: This report describes a case of acute compartment syndrome following severe inversion of an ankle injury secondary to disruption of the perforating branch of the peroneal artery 3h after the trauma. Although emergent fasciotomy was performed, residual weakness of ankle dorsiflexion still presented six months after surgery. DISCUSSION: To the best of our knowledge, this case is the third in literature on an acute compartment syndrome following severe inversion ankle injury secondary to disruption of the perforating branch of the peroneal artery. CONCLUSION: This report underscores the importance of considering compartment syndrome when individual has an inversion ankle injury, even when no fracture exists. PMID- 25460493 TI - Choroidal metastasis from early rectal cancer: Case report and literature review. AB - INTRODUCTION: Choroidal metastasis from colorectal cancer is rare, and there have been no reported cases of such metastasis from early colorectal cancer. We report a case of choroidal metastasis from early rectal cancer. PRESENTATION OF CASE: A 61 year-old-man experienced myodesopsia in the left eye 2 years and 6 months after primary rectal surgery for early cancer, and was diagnosed with left choroidal metastasis and multiple lung metastases. Radiotherapy was initiated for the left eye and systemic chemotherapy is initiated for the multiple lung metastases. The patient is living 2 years and 3 months after the diagnosis of choroidal metastasis without signs of recurrence in the left eye, and continues to receive systemic chemotherapy for multiple lung metastases. DISCUSSION: Current literatures have few recommendations regarding the appropriate treatment of choroidal metastasis from colorectal cancer, but an aggressive multi disciplinary approach may be effective in local regression. CONCLUSION: This is the first report of choroidal metastasis from early rectal cancer. We consider it important to enforce systemic chemotherapy in addition to radiotherapy for choroidal metastasis from colorectal cancer. PMID- 25460494 TI - A case of thrombocytopenia associated with the use of hydroxychloroquine following open heart surgery. AB - INTRODUCTION: Thrombocytopenia is a common problem occurring in patients and drug induced thrombocytopenia is a significant cause of thrombocytopenia. PRESENTATION OF CASE: We present an unusual case of thrombocytopenia that was considered to be associated with the use of hydroxychloroquine in the late term following open heart surgery. DISCUSSION: The drug-induced thrombocytopenia, mechanical destruction of the platelets, and hemodilution are common causes of low platelet count. Although drug-induced immune thrombocytopenia has a mild clinical course in most cases (in this case it has severe clinical course), some patients may experience life-threatening hemorrhages. The decision to discontinue the drug that is deemed to be responsible from the drug-induced thrombocytopenia (DITP) relies on the clinical condition of the patient. The diagnosis is mostly established by discontinuation, exclusion, and correlation because the tests performed to detect drug-dependent antibodies (DDAbs) for the diagnosis of DITP are time-consuming, and these tests are also not commonly available. The authors of the current study diagnosed DITP by discontinuation of the drug. We suggest that the use of hydroxychloroquine could be severe thrombocytopenia occurring after open heart surgery. CONCLUSION: The medication history must be carefully reviewed in patients presenting with thrombocytopenia, and if the medications could cause thrombocytopenia must be discontinued. PMID- 25460496 TI - tDCS in post-stroke aphasia: the role of stimulation parameters, behavioral treatment and patient characteristics. AB - Neurostimulation techniques have been recently adopted in aphasia rehabilitation. In several studies transcranial direct current stimulation (tDCS) was used to enhance treatment effects. The methodology adopted in different studies is characterized by a large variability, as concerns stimulation parameters (e.g., montage type, current intensity, session duration, number and frequency of treatment sessions), participant inclusion criteria (subacute vs chronic, selected vs general aphasia types) and characteristics of associated behavioral treatments (online vs offline treatment, focused on different underlying deficits). Group analyses report on positive results for most of the adopted paradigms. We review the available literature focusing on tDCS in the rehabilitation of stroke-related aphasia, with reference to the current views on tDCS's action mechanisms and on the factors that may influence the effects of stimulation. Even though our understanding of the mechanisms activated by neurostimulation techniques is still limited, available evidence already allows to propose methodological recommendations for studies intending to use tDCS as a treatment adjuvant. Where several options for a specific stimulation parameter seem suitable, we provide information to reach a knowledgeable decision. PMID- 25460495 TI - Management of patients with combined tracheoesophageal fistula, esophageal atresia, and duodenal atresia. AB - INTRODUCTION: Patients with combined esophageal atresia (EA), tracheoesophageal fistula (TEF), and duodenal atresia (DA) pose a rare management challenge. PRESENTATION OF CASE: Three patients with combined esophageal atresia (EA), tracheoesophageal fistula (TEF), and duodenal atresia safely underwent a staged approach inserting a gastrostomy tube and repairing the EA/TEF first followed by a duodenoduodenostomy within one week. None of the patients suffered significant pre- or post-operative complications and our follow-up data (between 12 and 24 months) suggest that all patients eventually outgrow their reflux and respiratory symptoms. DISCUSSION: While some authors support repair of all defects in one surgery, we recommend a staged approach. A gastrostomy tube is placed first for gastric decompression before TEF ligation and EA repair can be safely undertaken. The repair of the DA can then be performed within 3-7 days under controlled circumstances. CONCLUSION: A staged approach of inserting a gastrostomy tube and repairing the EA/TEF first followed by a duodenoduodenostomy within one week resulted in excellent outcomes. PMID- 25460497 TI - Steps towards understanding the phonological output buffer and its role in the production of numbers, morphemes, and function words. AB - The Stimulus Type Effect on Phonological and Semantic errors (STEPS) describes the phenomenon in which a person, following brain damage, produces words with phonological errors (fine -> fige), but number words with semantic errors (five > eight). To track the origins of this phenomenon and find out whether it is limited to numbers, we assessed the speech production of six individuals with conduction aphasia following a damage in the left hemisphere, who made phonological errors in words. STEPS was found in all six participants, and was not limited to number words - several other word categories were also produced with semantic rather than phonological errors: function words, English letter names, and morphological affixes were substituted with other words within their category. This supports the building blocks hypothesis: when phonological sequences serve as building blocks in a productive process, they end up having pre-assembled phonological representations, ready for articulation. STEPS reflects a deficit that causes substitutions of one phonological unit with another. In the case of plain content words, this causes substitutions of one phoneme with another, but in the case of pre-assembled phonological units, this causes substitutions of number words with other number words, function words with function words, and morphological affixes with other affixes. An analysis of the participants' functional locus of deficit revealed that they all had a deficit in the phonological output buffer, and this was their only common deficit. We therefore concluded that the pre-assembled phonological units are stored in dedicated mini-stores in the phonological output buffer, which processes not only phonemes but also whole number words, function words, and morphemes. We also found that STEPS depends on the word's role: number words were produced with semantic errors only when they appeared in numeric context, and function words triggered semantic errors only in grammatical context. This suggests that the phonological representation of a word can be obtained either from the phonological output lexicon or from a store of pre-assembled representations in the phonological output buffer, depending on the word's role. PMID- 25460498 TI - Initial and sustained brain responses to contextual conditioned anxiety in humans. AB - Contextual fear conditioning takes place if the occurrence of threat cannot be predicted by specific cues. As a consequence the context becomes the best predictor of the threat and later induces anxiety (sustained fear response). Previous studies suggest that both the amygdala and the hippocampus are crucial for contextual fear conditioning. First, we wanted to further elucidate the neuronal correlates of long-lasting contextual threat within a highly ecologically setting created in virtual reality (VR). Second, we wanted to distinguish between initial and sustained components of the anxiety response to a threatening situation. Twenty-four participants were guided through two virtual offices for 30s each. They received unpredictable electric stimuli (unconditioned stimulus, US) in one office (anxiety context, CXT+), but never in the second office (safety context, CXT-). Successful contextual fear conditioning was indexed by higher anxiety and enhanced US-expectancy ratings for CXT+ versus CXT . Initial neural activity was assessed by modeling the onsets of both contexts, and sustained neural activity by considering the entire context duration (contrasts: CXT+ > CXT-). Amygdala and hippocampus revealed sustained activity. Initial and sustained activities were found in the middle temporal gyrus, and primary motor cortex (M1). Additional initial activity was obvious in orbitofrontal (OFC), dorsomedial (dmPFC), and dorsolateral prefrontal cortex (dlPFC). These results suggest that entering a threatening context initially induces conditioned fear reactions (M1), recall of contingency awareness (dlPFC), and explicit threat appraisal (dmPFC, OFC). While remaining in the threatening context might involve anxiety-like conditioned responses (amygdala, M1) and the generation of a spatial map to predict where and when a threatening event may occur (hippocampus). We conclude that in humans initial versus sustained anxiety responses triggered by a threat associated context are associated with distinguishable brain activation patterns involving a fear network and a "contingency-cognitive" network, respectively. PMID- 25460499 TI - MiR-373 targeting of the Rab22a oncogene suppresses tumor invasion and metastasis in ovarian cancer. AB - Metastasis is major cause of mortality in patients with ovarian cancer. MiR-373 has been shown to play pivotal roles in tumorigenesis and metastasis; however, a role for miR-373 in ovarian cancer has not been investigated. In this study, we show that the miR-373 expression is down-regulated in human epithelial ovarian cancer (EOC) and inversely correlated with clinical stage and histological grade. Ectopic overexpression of miR-373 in human EOC cells suppressed cell invasion in vitro and metastasis in vivo, and the epithelial-mesenchymal transition process. Silencing the expression of miR-373 resulted in an increased migration and invasion of EOC cells. Using integrated bioinformatics analysis, gene expression arrays, and luciferase assay, we identified Rab22a as a direct and functional target of miR-373 in EOC cells. Expression levels of miR-373 were inversely correlated with Rab22a protein levels in human EOC tissues. Rab22a knockdown inhibited invasion and migration of EOC cells, increased E-cadherin expression, and suppressed the expression of N-cadherin. Moreover, overexpression of Rab22a abrogated miR-373-induced invasion and migration of EOC cells. Taken together, these results demonstrate that miR-373 suppresses EOC invasion and metastasis by directly targeting Rab22a gene, a new potential therapeutic target in EOC. PMID- 25460500 TI - Cooperation between BRCA1 and vitamin D is critical for histone acetylation of the p21waf1 promoter and growth inhibition of breast cancer cells and cancer stem like cells. AB - Carriers of germline mutations in the BRCA1 gene have a significant increased lifetime risk for being diagnosed with breast cancer. The incomplete penetrance of BRCA1 suggests that environmental and/or genetic factors modify the risk and incidence among mutation carriers. Nutrition and particular micronutrients play a central role in modifying the phenotypic expression of a given genotype by regulating chromatin structure and gene expression. The active form of vitamin D, 1alpha,25-dihydroxyvitamin D3, is a potent inhibitor of breast cancer growth. Here we report that two non-calcemic analogues of 1alpha,25-dihydroxyvitamin D3, seocalcitol (EB1089) and QW-1624F2-2, collaborate with BRCA1 in mediating growth inhibition of breast cancer cells and breast cancer stem-like cells. EB1089 induces a G1/S phase growth arrest that coincides with induction of p21waf1 expression only in BRCA1-expressing cells. A complete knockdown of BRCA1 or p21waf1 renders the cells unresponsive to EB1089. Furthermore, we show that in the presence of ligand, BRCA1 associates with vitamin D receptor (VDR) and the complex co-occupies vitamin D responsive elements (VDRE) at the CDKN1A (p21waf1) promoter and enhances acetylation of histone H3 and H4 at these sites. Thus, BRCA1 expression is critical for mediating the biological impact of vitamin D3 in breast tumor cells. PMID- 25460501 TI - LIGHT/TNFSF14 increases osteoclastogenesis and decreases osteoblastogenesis in multiple myeloma-bone disease. AB - LIGHT, a TNF superfamily member, is involved in T-cell homeostasis and erosive bone disease associated with rheumatoid arthritis. Herein, we investigated whether LIGHT has a role in Multiple Myeloma (MM)-bone disease. We found that LIGHT was overproduced by CD14+ monocytes, CD8+ T-cells and neutrophils of peripheral blood and bone marrow (BM) from MM-bone disease patients. We also found that LIGHT induced osteoclastogenesis and inhibited osteoblastogenesis. In cultures from healthy-donors, LIGHT induced osteoclastogenesis in RANKL-dependent and -independent manners. In the presence of a sub-optimal RANKL concentration, LIGHT and RANKL synergically stimulated osteoclast formation, through the phosphorylation of Akt, NFkappaB and JNK pathways. In cultures of BM samples from patients with bone disease, LIGHT inhibited the formation of CFU-F and CFU-OB as well as the expression of osteoblastic markers including collagen-I, osteocalcin and bone sialoprotein-II. LIGHT indirectly inhibited osteoblastogenesis in part through sclerostin expressed by monocytes. In conclusion, our findings for the first time provide evidence for a role of LIGHT in MM-bone disease development. PMID- 25460502 TI - Transcriptomic profiling of taxol-resistant ovarian cancer cells identifies FKBP5 and the androgen receptor as critical markers of chemotherapeutic response. AB - Taxol is a mitotoxin widely used to treat human cancers, including of the breast and ovary. However, taxol resistance (txr) limits treatment efficacy in human patients. To study chemoresistance in ovarian cancer, we established txr ovarian carcinoma cells derived from the SKOV3 cell lineage. The cells obtained were cross-resistant to other mitotoxins such as vincristine while they showed no resistance to the genotoxin cisplatin. Transcriptomic analysis identified 112 highly up-regulated genes in txr cells. Surprisingly, FK506-binding protein 5 (FKBP5) was transiently up-regulated 100-fold in txr cells but showed decreased expression in prolonged culture. Silencing of FKBP5 sensitized txr cells to taxol, whereas ectopic expression of FKBP5 increased resistance to the drug. Modulation of FKBP5 expression produced similar effects in response to vincristine but not to cisplatin. We observed that a panel of newly identified txr genes was trancriptionally regulated by FKBP5 and silencing of these genes sensitized cells to taxol. Notably, immunoprecipitation experiments revealed that FKBP5 forms a protein complex with the androgen receptor (AR), and this complex regulates the transcriptional activity of both proteins. Furthermore, we found that the Akt kinase pathway is regulated by FKBP5. These results indicate that the FKBP5/AR complex may affect cancer cell sensitivity to taxol by regulating expression of txr genes. Our findings suggest that mitotoxin-based treatment against ovarian cancer should be avoided when the Akt/FKBP5/AR axis is activated. PMID- 25460503 TI - ADAM10 and ADAM17: New players in trastuzumab tesistance. PMID- 25460504 TI - Sunitinib prevents cachexia and prolongs survival of mice bearing renal cancer by restraining STAT3 and MuRF-1 activation in muscle. AB - Tyrosine kinase inhibitors, affecting angiogenesis, have shown therapeutic efficacy in renal cell carcinoma (RCC). The increased overall survival is not fully explained by their anti-tumor activity, since these drugs frequently induce disease stabilization rather than regression. RCC patients frequently develop cachectic syndrome. We used the RXF393 human renal carcinoma xenograft that recapitulates the characteristics of the disease, including the growth in the mouse kidney (orthotopic implantation), and the induction of cachexia with subsequent premature death. Sunitinib prevents body weight loss and muscle wasting and significantly improves the survival of RXF393-bearing nude mice. The anti-cachectic effect was not associated to direct anti-tumor activity of the drug. Most relevant is the ability of sunitinib to reverse the cachectic phenotype and rescue the animals from the loss of fat tissue. Body weight loss is prevented also in mice bearing the C26 colon carcinoma, classically reported to induce cachexia in immunocompetent mice. Among the mechanisms, we herein show that sunitinib is able to restrain the overactivation of STAT3 and MuRF-1 pathways, involved in enhanced muscle protein catabolism during cancer cachexia. We suggest that off-target effects of angiogenesis inhibitors targeting STAT3 are worth considering as a therapeutic option for patients who develop cachexia, independently of their anti-tumor activity. PMID- 25460505 TI - DNA damage-induced S and G2/M cell cycle arrest requires mTORC2-dependent regulation of Chk1. AB - mTOR signalling is commonly dysregulated in cancer. Concordantly, mTOR inhibitors have demonstrated efficacy in a subset of tumors and are in clinical trials as combination therapies. Although mTOR is associated with promoting cell survival after DNA damage, the exact mechanisms are not well understood. Moreover, since mTOR exists as two complexes, mTORC1 and mTORC2, the role of mTORC2 in cancer and in the DNA damage response is less well explored. Here, we report that mTOR protein levels and kinase activity are transiently increased by DNA damage in an ATM and ATR-dependent manner. We show that inactivation of mTOR with siRNA or pharmacological inhibition of mTORC1/2 kinase prevents etoposide-induced S and G2/M cell cycle arrest. Further results show that Chk1, a key regulator of the cell cycle arrest, is important for this since ablation of mTOR prevents DNA damage-induced Chk1 phosphorylation and decreases Chk1 protein production. Furthermore, mTORC2 was essential and mTORC1 dispensable, for this role. Importantly, we show that mTORC1/2 inhibition sensitizes breast cancer cells to chemotherapy. Taken together, these results suggest that breast cancer cells may rely on mTORC2-Chk1 pathway for survival and provide evidence that mTOR kinase inhibitors may overcome resistance to DNA-damage based therapies in breast cancer. PMID- 25460507 TI - Synthetic Abeta peptides acquire prion-like properties in the brain. AB - In transmission studies with Alzheimer's disease (AD) animal models, the formation of Abeta plaques is proposed to be initiated by seeding the inoculated amyloid beta (Abeta) peptides in the brain. Like the misfolded scrapie prion protein (PrPSc) in prion diseases, Abeta in AD shows a certain degree of resistance to protease digestion while the biochemical basis for protease resistance of Abeta remains poorly understood. Using in vitro assays, histoblotting, and electron microscopy, we characterize the biochemical and morphological features of synthetic Abeta peptides and Abeta isolated from AD brain tissues. Consistent with previous observations, monomeric and oligomeric Abeta species extracted from AD brains are insoluble in detergent buffers and resistant to digestions with proteinase K (PK). Histoblotting of AD brain tissue sections exhibits an increased Abeta immunoreactivity after digestion with PK. In contrast, synthetic Abeta40 and Abeta42 are soluble in detergent buffers and fully digested by PK. Electron microscopy of Abeta40 and Abeta42 synthetic peptides shows that both species of Abeta form mature fibrils. Those generated from Abeta40 are longer but less numerous than those made of Abeta42. When spiked into human brain homogenates, both Abeta40 and Abeta42 acquire insolubility in detergent and resistance to PK. Our study favors the hypothesis that the human brain may contain cofactor(s) that confers the synthetic Abeta peptides PrPSc like physicochemical properties. PMID- 25460506 TI - An HSV-2 based oncolytic virus can function as an attractant to guide migration of adoptively transferred T cells to tumor sites. AB - Adoptive T-cell therapy has shown promises for cancer treatment. However, for treating solid tumors, there is a need for improving the ability of the adoptively transferred T cells to home to tumor sites. We explored the possibility of using an oncolytic virus derived from HSV-2, which can actively pull T effector cells to the site of infection, as a local attractant for migration of adoptively transferred T cells. Our data show that intratumoral administration of this virus can indeed attract active migration of the adoptively transferred T cells to the treated tumor. Moreover, once attracted to the tumor site by the virus, T cells persisted in there significantly longer than in mock-treated tumor. Chemokine profiling identified significant elevation of CXCL9 and CXCL10, as well as several other chemokines belonging to the inflammatory chemokine family in the virus-treated tumors. These chemokines initially guided the T-cell migration to and then maintained their persistence in the tumor site, leading to a significantly enhanced therapeutic effect. Our data suggests that this virotherapy may be combined with adoptive T-cell therapy to potentiate its therapeutic effect against solid tumors that are otherwise difficult to manage with the treatment alone. PMID- 25460508 TI - DNA methylome analysis identifies epigenetic silencing of FHIT as a determining factor for radiosensitivity in oral cancer: an outcome-predicting and treatment implicating study. AB - Radioresistance is still an emerging problem for radiotherapy of oral cancer. Aberrant epigenetic alterations play an important role in cancer development, yet the role of such alterations in radioresistance of oral cancer is not fully explored. Using a methylation microarray, we identified promoter hypermethylation of FHIT (fragile histidine triad) in radioresistant OML1-R cells, established from hypo-fractionated irradiation of parental OML1 radiosensitive oral cancer cells. Further analysis confirmed that transcriptional repression of FHIT was due to promoter hypermethylation, H3K27me3 and overexpression of methyltransferase EZH2 in OML1-R cells. Epigenetic interventions or depletion of EZH2 restored FHIT expression. Ectopic expression of FHIT inhibited tumor growth in both in vitro and in vivo models, while also resensitizing radioresistant cancer cells to irradiation, by restoring Chk2 phosphorylation and G2/M arrest. Clinically, promoter hypermethylation of FHIT inversely correlated with its expression and independently predicted both locoregional control and overall survival in 40 match-paired oral cancer patient samples. Further in vivo therapeutic experiments confirmed that inhibition of DNA methylation significantly resensitized radioresistant oral cancer cell xenograft tumors. These results show that epigenetic silencing of FHIT contributes partially to radioresistance and predicts clinical outcomes in irradiated oral cancer. The radiosensitizing effect of epigenetic interventions warrants further clinical investigation. PMID- 25460510 TI - An atypical residue in the pore of Varroa destructor GABA-activated RDL receptors affects picrotoxin block and thymol modulation. AB - GABA-activated RDL receptors are the insect equivalent of mammalian GABAA receptors, and play a vital role in neurotransmission and insecticide action. Here we clone the pore lining M2 region of the Varroa mite RDL receptor and show that it has 4 atypical residues when compared to M2 regions of most other insects, including bees, which are the major host of Varroa mites. We create mutant Drosophila RDL receptors containing these substitutions and characterise their effects on function. Using two electrode voltage clamp electrophysiology we show that one substitution (T6'M) ablates picrotoxin inhibition and increases the potency of GABA. This mutation also alters the effect of thymol, which enhances both insect and mammalian GABA responses, and is widely used as a miticide. Thymol decreases the GABA EC50 of WT receptors, enhancing responses, but in T6'M containing receptors it is inhibitory. The other 3 atypical residues have no major effects on either the GABA EC50, the picrotoxin potency or the effect of thymol. In conclusion we show that the RDL 6' residue is important for channel block, activation and modulation, and understanding its function also has the potential to prove useful in the design of Varroa-specific insecticidal agents. PMID- 25460511 TI - Site-specific, TALENs-mediated transformation of Bombyx mori. AB - Transposon-based genetic transformation has facilitated insect functional genomics and new strategies of pest management. However, there is a need for alternative, site-specific approaches to overcome limitations of random integration (and associated position-effects) and potential instability of inserted transgenes. Here we describe a transposon-free, site-specific genetic transformation system mediated by transcription activator-like effector nucleases (TALENs) in the silkworm, Bombyx mori, a lepidopteran model insect. We successfully established a site-specific transgenic system with comparable transformation efficiency to transposon-based genetic transformation through microinjection of TALENs mRNA targeting the BmBLOS2 locus and a linearizable donor plasmid encoding an expression cassette of the DsRed2 red fluorescent protein. This system provides a valuable approach for insect transgenesis and will enable future functional gene analysis and generate novel applications in agricultural and medical insect pest-management technologies. PMID- 25460512 TI - Re-examination of a alpha-chymotrypsin-solubilized laccase in the pupal cuticle of the silkworm, Bombyx mori: Insights into the regulation system for laccase activation during the ecdysis process. AB - The laccase in the pupal cuticle of the silkworm, Bombyx mori, is thought to accumulate as an inactive precursor that can be activated stage-dependently. In this study we isolated an 81-kDa laccase from cuticular extract of B. mori that was prepared by digestion of the pupal cuticles with alpha-chymotrypsin. The mass spectrometric analysis of the purified protein indicates that this 81-kDa laccase is a product of the Bombyx laccase2 gene. The purified 81-kDa laccase (alpha chymotrypsin-solubilized Bombyx laccase2: Bm-clac2) has an N-terminal sequence of RNPADS that corresponds to Arg146 to Ser151 of the deduced protein sequence of Bmlaccase2 cDNA, indicating that Bm-clac2 lacks the N-terminal part upstream from residue Arg146. Bm-clac2 shows enzymatic activity, but its specific activity is increased around 17-fold after treatment with trypsin, which involves cleavage of peptide bonds at the C-terminal region. We also found that the activity of Bm clac2 is increased in the presence of isopropanol. In previous reports, proteolytic processing has been hypothesized as a system for laccase activation in vivo, but the present result implies that this type of processing is not the only way to convert Bm-clac2 to the high-activity enzyme. PMID- 25460509 TI - Atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 controls the core epithelial to-mesenchymal transition-inducing transcription factors. AB - Epithelial-mesenchymal transition (EMT) plays a critical role in the development of tumor metastases by enhancing migration/invasion. One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. The K48-linkaged ubiquitination capability on Zeb2 relies on its functional SBD domain. In addition, miR-27a* can directly down regulate the expression of Fbxo45, preventing degradation of EMT-TFs and thus ensuring EMT phenotype. We suggest that Fbxo45 is a key node of the miR 27a*/Fbxo45/EMT-TFs signaling axis. PMID- 25460514 TI - Signal-dependent regulation of the sea urchin skeletogenic gene regulatory network. AB - The endoskeleton of the sea urchin embryo is produced by primary mesenchyme cells (PMCs). Maternal inputs activate a complex gene regulatory network (GRN) in the PMC lineage in a cell-autonomous fashion during early development, initially creating a uniform population of prospective skeleton-forming cells. Previous studies showed that at post-blastula stages of development, several effector genes in the network exhibit non-uniform patterns of expression, suggesting that their regulation becomes subject to local, extrinsic cues. Other studies have identified the VEGF and MAPK pathways as regulators of PMC migration, gene expression, and biomineralization. In this study, we used whole mount in situ hybridization (WMISH) to examine the spatial expression patterns of 39 PMC specific/enriched mRNAs in Strongylocentrotus purpuratus embryos at the late gastrula, early prism and pluteus stages. We found that all 39 mRNAs (including several regulatory genes) showed non-uniform patterns of expression within the PMC syncytium, revealing a global shift in the regulation of the skeletogenic GRN from a cell-autonomous to a signal-dependent mode. In general, localized regions of elevated gene expression corresponded to sites of rapid biomineral deposition. We used a VEGFR inhibitor (axitinib) and a MEK inhibitor (U0126) to show that VEGF signaling and the MAPK pathway are essential for maintaining high levels of gene expression in PMCs at the tips of rods that extend from the ventral region of the embryo. These inhibitors affected gene expression in the PMCs in similar ways, suggesting that VEGF acts via the MAPK pathway. In contrast, axitinib and U0126 did not affect the localized expression of genes in PMCs at the tips of the body rods, which form on the dorsal side of the embryo. Our results therefore indicate that multiple signaling pathways regulate the skeletogenic GRN during late stages of embryogenesis-VEGF/MAPK signaling on the ventral side and a separate, unidentified pathway on the dorsal side. These two signaling pathways appear to be activated sequentially (ventral followed by dorsal) and many effector genes are subject to regulation by both pathways. PMID- 25460513 TI - Effects of vitamin E on cognitive performance during ageing and in Alzheimer's disease. AB - Vitamin E is an important antioxidant that primarily protects cells from damage associated with oxidative stress caused by free radicals. The brain is highly susceptible to oxidative stress, which increases during ageing and is considered a major contributor to neurodegeneration. High plasma vitamin E levels were repeatedly associated with better cognitive performance. Due to its antioxidant properties, the ability of vitamin E to prevent or delay cognitive decline has been tested in clinical trials in both ageing population and Alzheimer's disease (AD) patients. The difficulty in performing precise and uniform human studies is mostly responsible for the inconsistent outcomes reported in the literature. Therefore, the benefit of vitamin E as a treatment for neurodegenerative disorders is still under debate. In this review, we focus on those studies that mostly have contributed to clarifying the exclusive function of vitamin E in relation to brain ageing and AD. PMID- 25460516 TI - Poor man's NOTES: can it be a good approach for adhesiolysis? A first case report with video demonstration. AB - STUDY OBJECTIVE: To show that in selected cases transvaginal NOTES can be a frugally innovative approach for adhesiolysis and that it can be performed in a low-cost setting. DESIGN: Step-by-step explanation of the technique using videos and pictures (educative video). PATIENTS AND MEASUREMENTS: A 51-year old (para 2, gravida 2) presented with meso- and hypogastric pain. Two years before, an umbilical hernia had been repaired using a Proceed Ventral Patch mesh. The diagnosis of pain caused by adhesions was made, and laparoscopic adhesiolysis was planned. On ultrasound, a small left ovarian fibroma was visualized. Because of the suspected umbilical location of the adhesions, we decided to use a transvaginal NOTES approach to perform adhesiolysis and left adnexectomy. Pathological examination confirmed a small benign papillary serous adenofibroma of the ovary. INTERVENTIONS: A transvaginal NOTES approach to perform adhesiolysis combined with left adnexectomy using only standard reusable laparoscopic instruments and a low-cost self-constructed NOTES port. MAIN RESULTS: The procedure and postoperative recovery were uneventful. No minor or major complications occurred. The patient has been cured of her pain. CONCLUSION: Transvaginal NOTES is a novel approach that requires further validation. This case report shows that transvaginal NOTES can be used to perform adhesiolysis for abdominal pain and that it can be performed in a low-cost setting without the need for expensive ports or disposable instruments. PMID- 25460515 TI - Effects of captopril on cardiovascular reflexes and respiratory mechanisms in rats submitted to monocrotaline-induced pulmonary arterial hypertension. AB - BACKGROUND: Pulmonary Arterial Hypertension (PAH) is a disease associated with increased arteriolar resistance in the lungs. Due to hypoxemia, some physiological mechanisms can be posteriorly affected, including respiratory and cardiovascular reflexes, but this has not yet been fully investigated. This study aimed to evaluate how these mechanisms were affected by monocrotaline (MCT) induced PAH and the possible therapeutic role of angiotensin converting enzyme inhibitor (ACEi), captopril, in reversing this remodeling process. METHODS AND RESULTS: Groups of Wistar rats received MCT injections (60 mg kg(-1)). Three weeks later, they received captopril (CPT, 100 mg kg(-1)) in their drinking water (MCT + CPT) or water alone (MCT) for 2 weeks. As control, saline-treated animals received captopril in their drinking water (CPT) or water alone (CON), also for 2 weeks. Results showed that PAH was fully induced in the MCT group, evidenced by a high pulmonary index. Gasometrical and respiratory analyses showed hypoxemia and compensatory hyperventilation. CPT treatment brought these parameters to similar values to those observed in the CON group. We observed that autonomic dysfunction in the MCT group was suppressed by CPT. Finally, cardiovascular reflexes analysis showed increased chemoreflex responses in the MCT group, while baroreflex sensibility was decreased. Surprisingly, CPT normalized these reflex responses to values similar to the CON group. CONCLUSIONS: The present study demonstrates that MCT-induced PAH induces compensatory respiratory responses, dysautonomia, and baroreflex dysfunction and increases chemoreflex responses. The data also indicate that CPT was effective in reversing these cardio-respiratory disorders, suggesting that ACEi could be a potential therapeutic target for PAH. PMID- 25460517 TI - Effect on ovarian reserve of hemostasis by bipolar coagulation versus suture during laparoendoscopic single-site cystectomy for ovarian endometriomas. AB - STUDY OBJECTIVE: To compare the postoperative decrease in ovarian reserve between hemostasis by bipolar coagulation and suture during laparoendoscopic single-site cystectomy (LESS-C) for ovarian endometriomas. DESIGN: Prospective comparative study (Canadian Task Force Classification II-1). SETTING: University hospital. PATIENTS: One hundred twenty-five patients with ovarian endometriomas. INTERVENTIONS: Patients with endometrioma were managed by hemostasis with either bipolar coagulation (n = 62) or suturing (n = 63) during LESS-C. We evaluated the impact of surgery on ovarian reserve using serum anti-Mullerian hormone (AMH) levels, which were measured before surgery and 3 months after surgery in all patients. MEASUREMENT AND MAIN RESULTS: Baseline characteristics such as age, bilaterality of endometriomas, and preoperative AMH levels were similar between the 2 study groups. There were also no differences between the 2 groups in surgical outcomes, such as operative time, operative blood loss, or operative complications. In both study groups, postoperative AMH levels were lower than preoperative AMH levels (p < .001). The decline rate of AMH levels was significantly greater in the bipolar coagulation group than in the suture group (42.2% [interquartile range, 16.5%-53.0%] and 24.6% [interquartile range, 11.6% 37.0%], respectively, p = .001). CONCLUSION: Hemostasis by bipolar coagulation after stripping of the endometrioma during LESS-C reduces ovarian reserve more than suturing does, as determined by serial AMH levels. Therefore, suturing may be a better hemostatic choice after stripping ovarian endometriomas. PMID- 25460518 TI - Management of perforated essure with migration into small and large bowel mesentery. AB - The Essure permanent birth control system (Conceptus Inc, San Carlos, CA) is currently the only Food and Drug Administration-approved hysteroscopic sterilization method and has been widely accepted as a safe and effective procedure. We present a rare case of tubal perforation, coil fragmentation, and distal migration into small and large bowel mesentery 8 days after the insertion of the Essure device. We describe the successful management of this complication using laparoscopy and intraoperative fluoroscopy. Providers using Essure must be aware of the possibility of fragmentation of the Essure coils. Intraoperative imaging, ideally fluoroscopy, should be strongly considered in the management of Essure migration to ensure localization and full retrieval of Essure material. PMID- 25460519 TI - Swyer syndrome with seminoma: laparoscopic bilateral gonad resection. PMID- 25460520 TI - Three-dimensional ultrasound in the management of bladder endometriosis. AB - STUDY OBJECTIVE: To assess the performance of three-dimensional (3D) ultrasound with color Doppler in the diagnosis of bladder endometriosis compared with magnetic resonance imaging (MRI) and cystoscopy. DESIGN: Canadian Task Force classification II-3. SETTING: Department of gynecology and obstetrics of a university hospital. PATIENTS: Eight women who reported urinary tract symptoms suggestive of bladder endometriosis between May 2012 and November 2013. INTERVENTIONS: For all cases, we assessed the size of the endometriotic nodule, its location on the bladder wall, and the distance between the lesion and the ureteral meatus, with pelvic 3D ultrasound (full bladder), uro-MRI, and cystoscopy. The results were compared with the postoperative histopathologic findings. MEASUREMENTS AND MAIN RESULTS: The pathology results differed from those produced by imaging by a mean +/- SD of -3.5 +/- 6.4 mm on transvaginal ultrasound (TVUS) and -5.75 +/- 11.9 mm) for MRI. There was no significant difference between imaging and pathology findings (p = .20) or between the 2 imaging findings (TVUS and MRI) (p = .73). Results showed a trend toward better accuracy for 3D ultrasound than MRI with smaller SDs (p = .08). Cystoscopy and ultrasound were compared; however, without any tools to assess the distance in cystoscopy, no statistical result was possible. CONCLUSION: Ultrasound seems to be superior to cystoscopy and is at least as effective as MRI in diagnosing and planning the surgery for bladder endometriosis. PMID- 25460522 TI - Coming to terms with the fact that the evidence for laparoscopic entry is as good as it gets. AB - Entry to the peritoneal cavity for laparoscopic surgery is associated with defined morbidity, with all entry techniques associated with substantial complications. Debate over the safest entry technique has raged over the last 2 decades, and yet, we are no closer to arriving at a scientifically valid conclusion regarding technique superiority. With hundreds of thousands of patients required to perform adequately powered studies, it is unlikely that appropriately powered comparative studies could be undertaken. This review examines the risk of complications related to laparoscopic entry, current statements from examining bodies around the world, and the medicolegal ramifications of laparoscopic entry complications. Because of the numbers required for any complications study, with regard to arriving at an evidence based decision for laparoscopic entry, we ask: is the current literature perhaps as good as it gets? PMID- 25460521 TI - Risk of morcellation of uterine leiomyosarcomas in laparoscopic supracervical hysterectomy and laparoscopic myomectomy, a retrospective trial including 4791 women. AB - STUDY OBJECTIVE: To evaluate the incidence of uterine leiomyosarcomas (LMSs). To identify the risk of morcellating LMS in a gynecological department that offers laparoscopic supracervical hysterectomy (LSH) and laparoscopic myomectomy as primary surgical treatments. DESIGN: A retrospective trial. DESIGN CLASSIFICATION: Canadian Task Force Classification III. SETTING: Norwegian university teaching hospital. PATIENTS: Women diagnosed with uterine LMS and the total population of women who were referred for surgical treatment of uterine fibroids from January 1, 2000 to December 31, 2013. INTERVENTIONS: Surgical treatment of fibroids, including LSH, abdominal supracervical hysterectomy, total laparoscopic hysterectomy, total abdominal hysterectomy, laparoscopic myomectomy, and hysteroscopic resection of fibroids. MEASUREMENTS AND MAIN RESULTS: A total of 4791 women were included in this trial; 1957 laparoscopic procedures were performed, and a morcellator was used in 1846 of the procedures. Twenty-six women were diagnosed with uterine LMS specimens after surgery. The mean +/- SD age of women with LMS was 61.2 +/- 12.3 years, and the mean +/- SD of the tumor size at time of diagnosis was 90.9 +/- 45.4 mm. Of these 26 women, 6 were diagnosed with uterine LMS by endometrial biopsy before surgical treatment, and 14 women were treated by open hysterectomy and bilateral salpingo-oophorectomy due to a clinical preoperative suspicion of a malignant condition. Consequently, 6 women with uterine LMS were treated according to the protocol for anticipated benign fibroids. Five of these women underwent laparotomy due to tumor size. LSH was performed in 1 woman, and a morcellator was used for tissue extraction. The incidence of uterine LMS in the population of women referred for anticipated benign fibroids was 0.0054 (1 in 183 women). The rate of unintended morcellation of a LMS at our department between January 1, 2000 and December 31, 2013 was 0.0002 (1 in 4791 women). CONCLUSION: The incidence of uterine LMS was comparable with the incidence reported in the literature. The risk of unintended morcellation of uterine LMS after a preoperative selection of women with fibroids appears to be very low. PMID- 25460523 TI - Gossypiboma misdiagnosed as uterine subserosal myoma. PMID- 25460524 TI - Cat got your spleen? Hepatosplenic Bartonella infection. PMID- 25460525 TI - Mixed signals: toxic epidermal necrolysis. PMID- 25460526 TI - Cholesterol treatment and changes in guidelines in an academic medical practice. AB - BACKGROUND: National guidelines are intended to influence physician cholesterol treatment practices, yet few studies have documented the effect of new guidelines on actual prescribing behaviors and impacts on patient eligibility for treatment. We describe current cholesterol treatment in an academic practice of Family and Internal Medicine physicians as well the effect of a change in cholesterol treatment guidelines from 2001 Adult Treatment Panel III (ATPIII) to 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines. METHODS: Medical records were extracted from primary care patients aged 40-75 years with at least one outpatient visit from January 1, 2012 to July 31, 2013; patients were included if they had records of cholesterol testing, blood pressure measurement, sex, race, and smoking status. Patients were classified into ATPIII and ACC/AHA categories based on clinical variables (eg, diabetes, hypertension, atherosclerotic cardiovascular disease), Framingham Risk Score, and 10-year atherosclerotic cardiovascular disease risk. RESULTS: There were 4536 patients included in the analysis. Of these, 71% met ATPIII goals and 56% met ACC/AHA guidelines, a 15% decrease. Forty-three percent of high-risk patients met their low-density lipoprotein goals and 46% were on statins. Overall, 32% of patients would need to be started on a statin, 12% require an increased dose, and 6% could stop statins. Of patients considered low risk by ATPIII guidelines, 271 would be eligible for treatment by ACC/AHA guidelines, whereas 129 patients were shifted from intermediate risk to low risk with the change in guidelines. CONCLUSIONS: The ACC/AHA guidelines expand the number of patients recommended to receive statins, particularly among patients who were previously thought to be at moderate risk, and would increase the intensity of treatment for many patients at high risk. Significant numbers of patients at risk for cardiovascular events were not receiving guideline-based treatment. New cholesterol guidelines may make treatment decisions easier. PMID- 25460527 TI - Delayed otolaryngology referral for voice disorders increases health care costs. AB - BACKGROUND: Despite the accepted role of laryngoscopy in assessing patients with laryngeal/voice disorders, controversy surrounds its timing. This study sought to determine how increased time from first primary care to first otolaryngology outpatient visit affected the health care costs of patients with laryngeal/voice disorders. METHODS: Retrospective analysis of a large, national administrative claims database was performed. Patients had an International Classification of Diseases, 9(th) Revision-coded diagnosis of a laryngeal/voice disorder; initially saw a primary care physician and, subsequently, an otolaryngologist as outpatients; and provided 6 months of follow-up data after the first otolaryngology evaluation. The outpatient health care costs accrued from the first primary care outpatient visit through the 6 months after the first otolaryngology outpatient visit were determined. RESULTS: There were 260,095 unique patients who saw a primary care physician as an outpatient for a laryngeal/voice disorder, with 8999 (3.5%) subsequently seeing an otolaryngologist and with 6 months postotolaryngology follow-up data. A generalized linear regression model revealed that, compared with patients who saw an otolaryngologist <=1 month after the first primary care visit, patients in the >1-month and <=3-months and >3-months time periods had relative mean cost increases of $271.34 (95% confidence interval $115.95-$426.73) and $711.38 (95% confidence interval $428.43-$993.34), respectively. CONCLUSIONS: Increased time from first primary care to first otolaryngology evaluation is associated with increased outpatient health care costs. Earlier otolaryngology examination may reduce health care expenditures in the evaluation and management of patients with laryngeal/voice disorders. PMID- 25460529 TI - Health care 2020: reengineering health care delivery to combat chronic disease. AB - Chronic disease has become the great epidemic of our times, responsible for 75% of total health care costs and the majority of deaths in the US. Our current delivery model is poorly constructed to manage chronic disease, as evidenced by low adherence to quality indicators and poor control of treatable conditions. New technologies have emerged that can engage patients and offer additional modalities in the treatment of chronic disease. Modifying our delivery model to include team-based care in concert with patient-centered technologies offers great promise in managing the chronic disease epidemic. PMID- 25460530 TI - Acupuncture for chronic pain? Clinical wisdom undecided despite over 4000 years of practice. PMID- 25460528 TI - Recent temporal trends in the presentation, management, and outcome of women hospitalized with acute coronary syndromes. AB - BACKGROUND: Few data exist on the recent trends in the outcome of women hospitalized with acute coronary syndrome. We examined temporal trends in the hospital management and outcomes of women hospitalized with acute coronary syndrome in a real-world setting. METHODS: We evaluated time-dependent changes in the clinical characteristics, management strategies, and outcomes of women enrolled in the Acute Coronary Syndrome Israeli Surveys (ACSIS) between 2000 and 2010. Periods were categorized as early (2000-2004) and late (2006-2010). RESULTS: Among 11,536 patients enrolled in ACSIS, 2710 (24%) were women. Frequency of women presenting with acute coronary syndrome had declined from 25% in 2000 to 22% in 2010 (P for trend = .002). Women presented less frequently with ST-elevation myocardial infarction and more frequently with associated comorbidities (P < .001 for both). There was no significant reduction in the time delay from symptom onset to emergency department between early and late periods (median: 128 vs 125 minutes; P = .86). This was further reflected in no increase in the frequency of women meeting the goal of door-to-balloon time of <=90 minutes. The utilization of evidence-based cardiovascular therapies had increased significantly over the past decade (P < .001 for all). After multivariate adjustment, admission in the late surveys was associated with a significant reduction in 30-day major adverse cardiac events and 1-year mortality (hazard ratio 0.76; 95% confidence interval, 0.65-0.9, and 0.73; 0.59-0.89, respectively). CONCLUSIONS: Despite increased frequency of comorbidities and lack of change in time to admission among women hospitalized with acute coronary syndrome, temporal change in management strategies over the last decade may have contributed to improved outcomes in this population. PMID- 25460531 TI - Should patients with chronic disease be told to gain weight? The obesity paradox and selection bias. PMID- 25460532 TI - Narcotic-induced pain. PMID- 25460533 TI - A tale of a cobra and an octopus: Takotsubo cardiomyopathy following a snake bite. PMID- 25460535 TI - Medicine, yes; politics, no! PMID- 25460534 TI - Tramadol for noncancer pain and the risk of hyponatremia. AB - BACKGROUND: Case reports have signaled a possible association between tramadol, a weak opioid analgesic, and hyponatremia. The objective of this study was to determine whether the use of tramadol is associated with an increased risk of hyponatremia, when compared with codeine. METHODS: Using the UK Clinical Practice Research Datalink and Hospital Episodes Statistics database, a population-based cohort of 332,880 patients initiating tramadol or codeine was assembled from 1998 through 2012. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of hospitalization for hyponatremia associated with the use of tramadol, compared with codeine, in the first 30 days after initiation. A similar analysis was conducted within a highly restricted sub cohort, which additionally excluded patients with any serum sodium level abnormality in the year before cohort entry. All models were adjusted for propensity score quintiles. RESULTS: The incidence rates of hospitalization for hyponatremia were 4.6 (95% CI, 2.4-8.0) and 1.9 (95% CI, 1.4-2.5) per 10,000 person-months for tramadol and codeine users, respectively. In the adjusted model, the use of tramadol was associated with a 2-fold increased risk of hospitalization for hyponatremia, compared with codeine (adjusted HR 2.05; 95% CI, 1.08-3.86). In the highly restricted sub-cohort, the use of tramadol was associated with an over 3-fold increased risk of hospitalization for hyponatremia, compared with codeine (adjusted HR 3.54; 95% CI, 1.32-9.54). CONCLUSIONS: In this first population-based study, the use of tramadol was associated with an increased risk of hyponatremia requiring hospitalization. PMID- 25460536 TI - The properties of Irn (n = 2-10) clusters and their nucleation on gamma-Al2O3 and MgO surfaces: from ab initio studies. AB - The structural stability and magnetic properties of iridium clusters Irn (n = 2 10) and their interaction on gamma-Al2O3(001) and MgO(100) surfaces have been investigated from first principles calculations. It is found that the adsorption energy of Irn (n = 2-10)/gamma-Al2O3(001) is lower than that of Irn/MgO(100); meanwhile, the strongest adsorption energy cluster for gamma-Al2O3(001) is the tetrahedral Ir4 cluster, while for MgO(100) is a cubic Ir8 cluster. On the other hand, the nucleation of Irn (n = 2-10) clusters on both surfaces is thermodynamically favorable and exothermic. Moreover, the nucleation energy of Irn (n = 2-10) clusters on the gamma-Al2O3(001) surface is close to the corresponding energy on the MgO(100) surface, except for Ir3, Ir4 and Ir6 clusters. Interestingly, the nucleation of Ir3 and Ir6 clusters on the MgO(100) surface is more favorable than that on the gamma-Al2O3(001) surface, while the nucleation of the Ir4 cluster is reverse and very close to the gas phase Ir4 cluster. More importantly, deformation energy and charge density analysis show that the adsorbed Ir4 cluster on the gamma-Al2O3(001) surface has obviously charge transfer between Ir atoms and surface Al, O atoms with negligible deformation. However, for the MgO(100) surface, the Ir4 cluster connects directly to three surface O atoms with severe distortion, which inhibits the activity of the tetrahedral Ir4 cluster as a catalyst. PMID- 25460538 TI - Effects of morphine on stress induced anxiety in rats: role of nitric oxide and Hsp70. AB - The present study evaluated the effects of morphine on acute and chronic restraint stress (RS) induced anxiety modulation and the possible involvement of nitric oxide (NO) and heat shock proteins (Hsp70) during such effects. Acute RS (*1) induced anxiogenesis in the elevated plus maze (EPM) test which was associated with lowered brain NO metabolites (NOx) and elevated Hsp70 levels. Pretreatment with morphine (1 and 5 mg/kg) and L-arginine (500 mg/kg) attenuated the RS effects on EPM activity and brain NOx, whereas, Hsp70 levels were further augmented. Co-administration of both agents showed synergistic effects. By contrast, repeated RS (*15) did not induce any significant changes in EPM activity or brain NOx, but brain Hsp70 levels stayed elevated. Administration of morphine or L-arginine prior to chronic RS did not influence such chronic stress induced changes in behavioral and biochemical markers, but appreciably attenuated chronic RS induced elevation in Hsp70 levels. These results suggest that acute and chronic RS induced anxiety modulations were differentially influenced by morphine and L-arginine and that complex interactions involving brain NO and unregulated Hsp70 could regulate such effects. PMID- 25460537 TI - Attachment and physiological reactivity to infant crying in young adulthood: dissociation between experiential and physiological arousal in insecure adoptees. AB - The associations between attachment representations of adopted young adults and their experiential and physiological arousal to infant crying were examined. Attachment representations were assessed with the Attachment Script Assessment (ASA), and the young adults listened to infant cries, during which ratings of cry perception were collected and physiological reactivity was measured. Secure adoptees showed a well-integrated response to infant distress: heart-rate increases and respiratory sinus arrhythmia (RSA) withdrawal were coupled with heightened perception of urgency in these individuals. In insecure adoptees RSA withdrawal was absent, and a combination of lowered perceived urgency and heightened sympathetic arousal was found, reflecting a deactivating style of emotional reactivity. Overall, our findings support the idea that internal working models of attachment explain individual differences in the way attachment related information is processed. PMID- 25460539 TI - Does moderate hypoxia alter working memory and executive function during prolonged exercise? AB - It has been suggested that acute exercise improves cognitive function. However, little is known about how exercise under hypoxia affects cognitive function. The purpose of this study was to determine if hypoxia alters working memory and executive function during prolonged exercise. Sixteen participants performed cognitive tasks at rest and during exercise under normoxia and hypoxia [fraction of inspired oxygen (FIO2)=0.15, corresponding to an altitude of approximately 2600 m]. The level of hypoxia was moderate. We used a combination of Spatial Delayed Response (Spatial DR) task and Go/No-Go (GNG) task, where spatial working memory and executive function are required. Working memory was assessed by the accuracy of the Spatial DR task, and executive function was assessed by the accuracy and reaction time in the GNG task. The participants cycled an ergometer for 30 min under normoxia and moderate hypoxia while keeping their heart rate (HR) at 140 beats/min. They performed the cognitive tasks 5 min and 23 min after their HR reached 140 beats/min. Moderate hypoxia did not alter the accuracy of the Spatial DR (P=0.38) and GNG tasks (P=0.14). In contrast, reaction time in the GNG task significantly decreased during exercise relative to rest under normoxia and moderate hypoxia (P=0.02). These results suggest that moderate hypoxia and resultant biological processes did not provide sufficient stress to impair working memory and executive function during prolonged exercise. The beneficial effects on speed of response appear to persist during prolonged exercise under moderate hypoxia. PMID- 25460540 TI - The longitudinal association between inflammation and incident depressive symptoms in men: the effects of hs-CRP are independent of abdominal obesity and metabolic disturbances. AB - BACKGROUND: This cohort study evaluates whether the association between low-grade inflammation and incident depressive symptoms is independent of abdominal obesity and metabolic disturbances. METHODS: A cohort of 1167 non-depressed men aged 35 to 80 years were followed up over 5 years to assess incident depressive symptoms measured by the Centre for Epidemiology Scale-Depression or Beck Depression Inventory-I. Venous tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and high sensitivity C-reactive protein (hsCRP) were quantified at baseline and 5years. Logistic regression determined whether hsCRP, IL-6 and TNF-alpha were associated with incident depressive symptoms independent of abdominal obesity and metabolic factors. Ancillary analysis utilizing depression z scores stratified participants by waist circumference >= 102 cm and >=2 metabolic disturbances. RESULTS: Incident depressive symptoms occurred in 95 men at 5 years (8.14% of total). Clinically relevant depressive symptoms were associated with baseline hsCRP (adjusted OR=1.04; 95% CI 1.00-1.07, p=.03) and annualized DeltahsCRP (adjusted OR=1.04; 95% CI 1.01-1.08, p=.02). Ancillary analysis showed that the association between annualized DeltahsCRP and depression z score was only significant in men with waist circumference<102 cm (beta=.19, p<.001) and <=1 metabolic disturbance (beta=.18, p<.001). None of the measured cytokines were significantly associated with depression. CONCLUSIONS: hsCRP and annualized DeltahsCRP were positively associated with depressive symptoms in a cohort of men. Further investigation into the role of abdominal obesity and metabolic disturbances in the inflammation-depression hypothesis is warranted. PMID- 25460541 TI - Antilymphangiogenic therapy to promote transplant survival and to reduce cancer metastasis: what can we learn from the eye? AB - The lymphatic vasculature is - amongst other tasks - essentially involved in inflammation, (auto)immunity, graft rejection and cancer metastasis. The eye is mainly devoid of lymphatic vessels except for its adnexa, the conjunctiva and the limbus. However, several pathologic conditions can result in the secondary ingrowth of lymphatic vessels into physiologically alymphatic parts of the eye such as the cornea or the inner eye. Therefore, the cornea has served as an excellent in vivo model system to study lymphangiogenesis, and findings from such studies have substantially contributed to the understanding of central principles of lymphangiogenesis also with relevance outside the eye. Grafting experiments at the cornea have been extensively used to analyze the role of lymphangiogenesis in transplant immunology. In this regard, we recently demonstrated the crucial role of lymphatic vessels in mediating corneal allograft rejection and could show that antilymphangiogenic therapy increases graft survival. In the field of cancer research, we recently detected tumor-associated lymphangiogenesis in the most common malignant tumors of the eye, such as conjunctival carcinoma and melanoma, and ciliochoroidal melanoma with extraocular extension. These neolymphatics correlate with an increased risk of local recurrence, metastasis and tumor related death, and may offer potential therapeutic targets for the treatment of these tumors. This review will focus on corneal and tumor-associated ocular lymphangiogenesis. First, we will describe common experimentally used corneal lymphangiogenesis models and will recapitulate recent findings regarding the involvement of lymphatic vessels in corneal diseases and transplant immunology. The second part of this article will summarize findings about the participation of tumor-associated lymphangiogenesis in ocular malignancies and their implications for the development of future therapeutic strategies. PMID- 25460542 TI - Glycan regulation of ER-associated degradation through compartmentalization. AB - The internal environment of the eukaryotic cell is divided by membranes into various organelles, containing diverse functional subcompartments, which allow complex cellular life. The quality control of newly made secretory proteins relies on the ability of the endoplasmic reticulum (ER) to segregate and compartmentalize molecules at different folding states. These folding states are communicated by N-glycans present on most secretory proteins. In ER-associated degradation (ERAD), protein molecules that have been identified as terminally misfolded are sent for degradation at the cytosolic proteasomes after being dislocated from the ER to the cytosol. This review will focus on how misfolded glycoprotein molecules are segregated from their properly folded counterparts and targeted to ERAD. The pathway involves compartmentalization, which is intimately linked to differential N-glycan processing. Recent data suggests that these processes are very dynamic, and include transient assembly of ERAD machinery complexes. PMID- 25460544 TI - Effect of protease inhibitors on pulmonary bioavailability of therapeutic proteins and peptides in the rat. AB - The objective of the present study was to evaluate the effect of protease inhibitors on the pulmonary absorption of therapeutic peptides and proteins with varying molecular weights. Dry powder formulations of leuprolide (1.2 kD), salmon calcitonin (3.4 kD), human insulin (5.8 kD), human leptin (16.0 kD), and human chorionic gonadotropin (HCG) (36.5 kD) were prepared with or without protease inhibitors; aprotinin and bestatin. The formulations were administered intrapulmonary to anesthetized rats. The pharmacokinetics of these proteins were assessed by measuring serum drug concentrations. In addition, in vitro stability of these proteins in rat lung homogenate was assessed using the trifluoroacetic acid method. Bioavailability of leuprolide following pulmonary administration was 75% higher compared to subcutaneously administered leuprolide. Protease inhibitors had little or no effect on the pulmonary bioavailability of leuprolide. However, protease inhibitors (1 mg/kg) increased the bioavailability of calcitonin by more than 50%. Similarly, the bioavailabilities of leptin and HCG in the presence of bestatin were increased by 1.9 and 2.1-fold, respectively. Leuprolide was stable both in the lung cytosol and subcellular pellets with about 10% degradation at the end of the study period (4h). In contrast, calcitonin, insulin, leptin and HCG were significantly degraded in the lung cytosol and subcellular pellets. Presence of protease inhibitors in formulation could improve the stability of protein drugs. The results of this study demonstrate that the pulmonary absorption of proteins may be enhanced by the selection of optimal concentration and type of protease inhibitor. PMID- 25460545 TI - Fabrication of extended-release patient-tailored prednisolone tablets via fused deposition modelling (FDM) 3D printing. AB - Rapid and reliable tailoring of the dose of controlled release tablets to suit an individual patient is a major challenge for personalized medicine. The aim of this work was to investigate the feasibility of using a fused deposition modelling (FDM) based 3D printer to fabricate extended release tablet using prednisolone loaded poly(vinyl alcohol) (PVA) filaments and to control its dose. Prednisolone was loaded into a PVA-based (1.75 mm) filament at approximately 1.9% w/w via incubation in a saturated methanolic solution of prednisolone. The physical form of the drug was assessed using differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). Dose accuracy and in vitro drug release patterns were assessed using HPLC and pH change flow-through dissolution test. Prednisolone loaded PVA filament demonstrated an ability to be fabricated into regular ellipse-shaped solid tablets using the FDM-based 3D printer. It was possible to control the mass of printed tablet through manipulating the volume of the design (R(2) = 0.9983). On printing tablets with target drug contents of 2, 3, 4, 5, 7.5 and 10mg, a good correlation between target and achieved dose was obtained (R(2) = 0.9904) with a dose accuracy range of 88.7-107%. Thermal analysis and XRPD indicated that the majority of prednisolone existed in amorphous form within the tablets. In vitro drug release from 3D printed tablets was extended up to 24h. FDM based 3D printing is a promising method to produce and control the dose of extended release tablets, providing a highly adjustable, affordable, minimally sized, digitally controlled platform for producing patient tailored medicines. PMID- 25460546 TI - Liquid crystalline phase as a probe for crystal engineering of lactose: carrier for pulmonary drug delivery. AB - The current work was undertaken to assess suitability of liquid crystalline phase for engineering of lactose crystals and their utility as a carrier in dry powder inhalation formulations. Saturated lactose solution was poured in molten glyceryl monooleate which subsequently transformed into gel. The gel microstructure was analyzed by PPL microscopy and SAXS. Lactose particles recovered from gels after 48 h were analyzed for polymorphism using techniques such as FTIR, XRD, DSC and TGA. Particle size, morphology and aerosolisation properties of prepared lactose were analyzed using Anderson cascade impactor. In situ seeding followed by growth of lactose crystals took place in gels with cubic microstructure as revealed by PPL microscopy and SAXS. Elongated (size ~ 71 MUm) lactose particles with smooth surface containing mixture of alpha and beta-lactose was recovered from gel, however percentage of alpha-lactose was more as compared to beta-lactose. The aerosolisation parameters such as RD, ED, %FPF and % recovery of lactose recovered from gel (LPL) were found to be comparable to Respitose(r) ML001. Thus LC phase (cubic) can be used for engineering of lactose crystals so as to obtain particles with smooth surface, high elongation ratio and further they can be used as carrier in DPI formulations. PMID- 25460543 TI - Cotranslational and posttranslocational N-glycosylation of proteins in the endoplasmic reticulum. AB - Asparagine linked glycosylation of proteins is an essential protein modification reaction in most eukaryotic organisms. N-linked oligosaccharides are important for protein folding and stability, biosynthetic quality control, intracellular traffic and the physiological function of many N-glycosylated proteins. In metazoan organisms, the oligosaccharyltransferase is composed of a catalytic subunit (STT3A or STT3B) and a set of accessory subunits. Duplication of the catalytic subunit gene allowed cells to evolve OST complexes that act sequentially to maximize the glycosylation efficiency of the large number of proteins that are glycosylated in metazoan organisms. We will summarize recent progress in understanding the mechanism of (a) cotranslational glycosylation by the translocation channel associated STT3A complex, (b) the role of the STT3B complex in mediating cotranslational or posttranslocational glycosylation of acceptor sites that have been skipped by the STT3A complex, and (c) the role of the oxidoreductase MagT1 in STT3B-dependent glycosylation of cysteine-proximal acceptor sites. PMID- 25460547 TI - Baseline separation of amino acid biomarkers of hepatocellular carcinoma by polyvinylpyrrolidone-filled capillary electrophoresis with light-emitting diode induced fluorescence in the presence of mixed micelles. AB - Physiological amino acids (AAs) are important indices for monitoring various diseases, including cancer. This study proposes a polymer-based separation method in the presence of mixed micelles for the determination of AAs by capillary electrophoresis with light-emitting diode-induced fluorescence. The separation of 18 amino acid-cyano[f]benzoisoindoles (AA-CBIs) was successfully achieved using a solution of polyvinylpyrrolidone (PVP, 5% w/v, Mavg 1,300,000 Da). In addition, we demonstrated that mixed micelles composed of sodium dodecyl sulfate and isopropanol may affect the migration order of the AA-CBIs and greatly improve the speed of separation. With the exception of proline, 21 plasma AA-CBIs, including high isoelectric point AAs (lysine, ornithine, and arginine), were identified by using optimized separation conditions with minimal matrix effects. The results of this study demonstrated the distinct advantages of the proposed method, such as simplicity, high efficiency, and cost-effectiveness. This method has great potential for the diagnosis of several important diseases, including carcinomas, aminoacidopathies, and neurotransmission disorders. PMID- 25460548 TI - An essential role of NAD(P)H oxidase 2 in UVA-induced calcium oscillations in mast cells. AB - Solar UVA radiation (320-400 nm) is known to have immunomodulatory effects, but the detailed mechanisms involved are not fully elucidated. UVA irradiation has been shown to induce calcium oscillations in rat peritoneal mast cells due to NAD(P)H oxidase (NOX) activation, but the specific NOX isoforms have not been identified. In the present work effects of UVA irradiation were investigated in isolated rat peritoneal mast cells, in cultured rat mast cell line RBL-2H3, and in mouse bone marrow-derived mast cells (BMMC). It was found that UVA irradiation by alternate 340/380 nm (3.2-5.6 MUW cm(-2)) or by LED (380 nm, 80 MUW cm(-2)) induced calcium oscillations in isolated rat peritoneal mast cells, in RBL-2H3, and in BMMC. Such UVA-induced calcium oscillations resembled closely those induced by surface IgE receptor (FcepsilonRI) activation. It was found that RBL 2H3 expressed high levels of gp91(phox) (NOX2), p22(phox), p67(phox), p47(phox), p40(phox), Rac1, Rac2, moderate levels of DUOX2, but did not express NOX1, NOX3, NOX4, or DUOX1. The specific cellular localizations of gp91(phox) (NOX2), p22(phox), p47(phox), p67(phox), p40(phox) and Rac1/2 were confirmed by immunocytochemistry. UVA-induced reactive oxygen species (ROS) production in RBL 2H3 was completely suppressed by the NOX inhibitor diphenyleneiodonium chloride (DPI) or by the antioxidant N-acetyl-l-cysteine (NAC). siRNA suppression of gp91(phox) (NOX2), p22(phox) and p47(phox) expression inhibited markedly UVA induced calcium oscillations, ROS and IL-6/LTC4 production in RBL-2H3. Taken together these data indicate that NOX2 plays an essential role in UVA irradiation induced calcium oscillations, ROS and mediator production in mast cells. PMID- 25460549 TI - Lower gastrointestinal bleeding: what have we learned from the past 3 decades? PMID- 25460550 TI - Effect of nucleoside and nucleotide analogues on renal function in patients with chronic hepatitis B virus monoinfection. AB - BACKGROUND & AIMS: There is controversy regarding whether nucleos(t)ide analogues contribute to renal impairment in patients with chronic hepatitis B virus (HBV) infection. We analyzed changes in renal function in patients with chronic HBV infection and whether these were associated with treatment or comorbidities. METHODS: We performed a longitudinal observational study to investigate factors associated with renal function in 214 patients (median age, 43 y; 69.2% men) with compensated chronic HBV monoinfection treated with 343 lines of nucleos(t)ide analogues (210 monotherapies, 133 combinations) between 1990 and 2012 (median time, 2.4 y) in France. A linear mixed-effect model was used to model variations of estimated glomerular filtration rate (eGFR, computed with the Chronic Kidney Disease Epidemiology Collaboration formula), adjusting for age, sex, geographic origin, initial liver fibrosis, level of HBV DNA, and an eGFR less than 90 mL/min/1.73 m(2). RESULTS: The eGFR decreased in patients given adefovir dipivoxil as monotherapy or in a combination (P < .0001 and P < .002, respectively), and remained stable in patients given lamivudine, tenofovir disoproxil fumarate, or entecavir. The eGFR decreased in patients with a baseline eGFR of less than 90 mL/min/1.73 m2, regardless of treatment. The eGFR remained stable or increased, regardless of treatment, in patients with a baseline eGFR of 90 mL/min/1.73 m2 or greater and with an initial HBV DNA level of 100,000 IU/mL or greater. Patients born in areas of high endemicity of HBV were more prone to increases in eGFR with treatment. CONCLUSIONS: In a real-life study, the eGFR remained stable or increased over time in patients with chronic HBV monoinfection with a baseline eGFR of 90 mL/min/1.73 m2 or higher and treated with tenofovir disoproxil fumarate or entecavir. Patients born in an area of high endemicity of HBV who had initial levels of HBV DNA of 100,000 IU/mL or greater were more likely to have increased eGFR with treatment. PMID- 25460551 TI - Eosinophilic infiltration of the muscularis propria in a patient with jackhammer esophagus treated with per-oral endoscopic myotomy. PMID- 25460552 TI - A polymorphism in interferon L3 is an independent risk factor for development of hepatocellular carcinoma after treatment of hepatitis C virus infection. AB - BACKGROUND & AIMS: Polymorphisms in interferon (IFN)L3 (encodes IFNlambda3 or interleukin 28B) are associated with outcomes of treatment for hepatitis C virus (HCV) infection. However, there is controversy regarding how polymorphisms in IFNL3 affect the risk for development of hepatocellular carcinoma (HCC) in patients treated with pegylated interferon and ribavirin. METHODS: In a retrospective study, we analyzed data from 1118 patients with HCV infection (589 men; median age, 60 y; 49.9% infected with genotype 1; 51.3% with advanced fibrosis) treated with pegylated interferon and ribavirin from March 2000 through October 2009 at the Chang Gung Memorial Hospital in Kaohsiung, Taiwan (71.64% achieved sustained virologic response [SVR]). Baseline samples were collected before therapy. Starting 24 weeks after treatment, clinical and biochemical features were assessed every 3 to 6 months and patients underwent ultrasound examinations. Lesions detected were examined by computed tomography, angiography, or fine-needle aspiration biopsy analyses. Patients were followed up from the initiation of HCV therapy until a diagnosis of HCC (based on published guidelines), death, or March 31, 2013 (median, 60 mo). DNA samples from each patient were analyzed for rs12979860 in IFNL3. Kaplan-Meier analysis was used to determine the risk for development of HCC. RESULTS: The percentages of patients with the IFNL3 rs12979860 CC, CT, and TT genotypes were 86.4%, 13.2%, and 0.3%, respectively. A total of 108 patients (9.66%) developed HCC. The IFNL3 rs12979860 CT and TT genotypes correlated with high baseline levels of alpha-fetoprotein (AFP; >=20 ng/mL), advanced stage of fibrosis, diabetes, or lack of an SVR (all P < .05). Based on multivariate Cox regression analysis, age 60 years and older, low platelet count (<15 * 10(9) cells/L), AFP level of 20 ng/mL or greater, advanced stage fibrosis, diabetes, lack of an SVR, and the IFNL3 rs12979860 CT and TT genotypes were significant risk factors for HCC (P < .05). Age 60 years and older, low numbers of platelets or high AFP level, and advanced fibrosis were risk factors for HCC among patients with a SVR. The IFNL3 rs12979860 genotype did not have a significant effect on risk for HCC among patients with SVRs, although some of these patients (with the CT or TT genotype) did develop HCC. Among patients without SVRs, only fibrosis stage and the IFNL3 rs12979860 CT and TT genotypes (hazard ratio, 1.80; 95% confidence interval, 1.06-3.07; P = .030) were independent risk factors for HCC. CONCLUSIONS: Based on a retrospective study of patients treated for HCV infection, the IFNL3 rs12979860 CT and TT polymorphisms are associated with a risk for HCC, especially in patients without a SVR. PMID- 25460553 TI - Diet in Crohn's Disease. PMID- 25460554 TI - Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. AB - BACKGROUND & AIMS: Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin is associated with increased risk of upper gastrointestinal bleeding. There is little evidence on the risk of lower gastrointestinal bleeding with NSAIDs, antiplatelet agents (APAs), or anticoagulants. We aimed to quantify the relative risk (RR) of upper and lower gastrointestinal bleeding associated with use of NSAIDs, APAs, or anticoagulants. METHODS: We performed a case-control study that used data collected from consecutive patients hospitalized for gastrointestinal bleeding (563 upper, mean age, 63.6 +/- 16.7 years and 415 lower, mean age, 70.8 +/- 13.8 years), confirmed by endoscopy or other diagnostic procedures. Unhospitalized patients were used as controls (n = 1008) and matched for age, hospital, and month of admission. Drug use was considered current when taken within 7 days or less before hospitalization. RRs and 95% confidence intervals (CIs) were estimated by unconditional logistic regression analysis. RESULTS: Use of anticoagulants, low-dose aspirin, and other drugs (non-aspirin APA, 82.3% thienopiridines) was associated with upper and lower gastrointestinal bleeding; the risk was 2-fold higher for anticoagulants (RR, 4.2; 95% CI, 2.9 6.2) than for low-dose aspirin (RR, 2.1; 95% CI, 1.4-3.3) or other non-aspirin APA drugs (RR, 2.0; 95% CI, 1.6-2.6). NSAID use was also associated with increased risk of gastrointestinal bleeding and greater for upper (RR, 2.6; 95% CI, 2.0-3.5) than lower gastrointestinal bleeding (RR, 1.4; 95% CI, 1.0-1.9). Use of proton pump inhibitors was associated with reduced risk of upper, but not lower, gastrointestinal bleeding. CONCLUSIONS: Anticoagulants, low-dose aspirin, NSAIDs, and other non-aspirin-APA drugs are associated with increased risk of upper and lower gastrointestinal bleeding. Use of anticoagulants appears to be the strongest risk factor for gastrointestinal bleeding. PMID- 25460555 TI - Huge adrenal hemangioma: a rare cause of deceivingly high liver stiffness measurement by transient elastography. PMID- 25460558 TI - Multiple endocrine neoplasia type 1 with gastric neuroendocrine tumor presented with gastric polyposis. PMID- 25460556 TI - High-dose dual therapy is superior to standard first-line or rescue therapy for Helicobacter pylori infection. AB - BACKGROUND & AIMS: The efficacy of treatment of Helicobacter pylori infection has decreased steadily because of increasing resistance to clarithromycin, metronidazole, and levofloxacin. Resistance to amoxicillin is generally low, and high intragastric pH increases the efficacy of amoxicillin, so we investigated whether a combination of a high-dose proton pump inhibitor and amoxicillin (dual therapy) was more effective than standard first-line or rescue therapies in eradicating H pylori. METHODS: We performed a large-scale multihospital trial to compare the efficacy of a high-dose dual therapy (HDDT) with that of standard therapies in treatment-naive (n = 450) or treatment-experienced (n = 168) patients with H pylori infection. Treatment-naive patients were randomly assigned to groups given HDDT (rabeprazole 20 mg and amoxicillin 750 mg, 4 times/day for 14 days, group A1), sequential therapy for 10 days (group B1), or clarithromycin containing triple therapy for 7 days (group C1). Treatment-experienced patients were randomly assigned to groups given HDDT for 14 days (group A2), sequential therapy for 10 days (B2), or levofloxacin-containing triple therapy for 7 days (C2). H pylori infection was detected by using the (13)C-urea breath test. We evaluated factors associated with treatment outcomes. RESULTS: In the intention to-treat analysis, H pylori was eradicated in 95.3% of patients in group A1 (95% confidence interval [CI], 91.9%-98.8%), 85.3% in B1 (95% CI, 79.6%-91.1%), and 80.7% in group C1 (95% CI, 74.3%-87.1%). Infection was eradicated in 89.3% of patients in group A2 (95% CI, 80.9%-97.6%), 51.8% in group B2 (95% CI, 38.3% 65.3%), and 78.6% (95% CI, 67.5%-89.7%) in group C2. The efficacy of HDDT was significantly higher than that of currently recommended regimens, irrespective of CYP2C19 genotype. Bacterial resistance to drugs was associated with treatment failure. There were no significant differences between groups in adverse events or patient adherence. CONCLUSIONS: HDDT is superior to standard regimens as empirical first-line or rescue therapy for H pylori infection, with similar safety profiles and tolerability. ClinicalTrials.gov number: NCT01163435. PMID- 25460557 TI - Variation in Aptitude of Trainees in Endoscopic Ultrasonography, Based on Cumulative Sum Analysis. AB - BACKGROUND & AIMS: Studies have reported substantial variation in the competency of advanced endoscopy trainees, indicating a need for more supervised training in endoscopic ultrasound (EUS). We used a standardized, validated, data collection tool to evaluate learning curves and measure competency in EUS among trainees at multiple centers. METHODS: In a prospective study performed at 15 centers, 17 trainees with no prior EUS experience were evaluated by experienced attending endosonographers at the 25th and then every 10th upper EUS examination, over a 12 month training period. A standardized data collection form was used (using a 5 point scoring system) to grade the EUS examination. Cumulative sum analysis was applied to produce a learning curve for each trainee; it tracked the overall performance based on median scores at different stations and also at each station. Competency was defined by a median score of 1, with acceptable and unacceptable failure rates of 10% and 20%, respectively. RESULTS: Twelve trainees were included in the final analysis. Each of the trainees performed 265 to 540 EUS examinations (total, 4257 examinations). There was a large amount of variation in their learning curves: 2 trainees crossed the threshold for acceptable performance (at cases 225 and 245), 2 trainees had a trend toward acceptable performance (after 289 and 355 cases) but required continued observation, and 8 trainees needed additional training and observation. Similar results were observed at individual stations. CONCLUSIONS: A specific case load does not ensure competency in EUS; 225 cases should be considered the minimum caseload for training because we found that no trainee achieved competency before this point. Ongoing training should be provided for trainees until competency is confirmed using objective measures. PMID- 25460559 TI - Reliability of the Boston Bowel Preparation Scale in the Endoscopy Nurse Population. PMID- 25460561 TI - An unusual cause of lower gastrointestinal bleeding. PMID- 25460560 TI - Development of quality measures for the care of patients with gastroesophageal reflux disease. AB - BACKGROUND & AIMS: Gastroesophageal reflux disease (GERD) is a common and costly disorder. Symptoms attributed to GERD have a wide spectrum of presentations and complications that have led to complex diagnostic and management algorithms. As such, there is considerable variation in clinical approaches to GERD. In contrast to multiple published guidelines for the management of GERD, there are few validated GERD quality measures. The objective of this study was to use a well described, formal methodology to develop valid, physician-led quality measures for all aspects of care for patients with GERD. METHODS: Quality measures were identified from the literature, consensus guidelines, and GERD experts. Eight clinical experts ranked potential measures for validity on the basis of the RAND/University of California, Los Angeles Appropriateness Methodology. RESULTS: Of the 52 proposed quality measures, 24 were rated as valid, and 1 new measure was developed. These valid measures were related to initial diagnosis and management (9), monitoring (3), further diagnostic testing (4), proton pump inhibitor refractory symptoms (2), symptoms of chest pain (1), erosive esophagitis (3), esophageal stricture or ring (1), and surgical therapy (2). Fifteen of these measures were ranked with the highest validity. Twenty-seven measures were determined to be equivocal; 89% of these were extracted from guidelines that were based on low or moderate level evidence. CONCLUSIONS: We used RAND/University of California, Los Angeles Appropriateness Methodology to develop quality measures for GERD care. By examining performance on these valid, formally developed quality measures, clinical practices and individual providers can assess their adherence with them and direct quality improvement efforts accordingly. PMID- 25460562 TI - Persistence of Human Papillomavirus, Overexpression of p53, and Outcomes of Patients After Endoscopic Ablation of Barrett's Esophagus. AB - We investigated the role of high-risk human papillomavirus (hr-HPV) in patients with Barrett's dysplasia and adenocarcinoma (EAC). Clearance vs persistence of HPV (DNA, E6 or E7 mRNA, and p16INK4A protein) and overexpression or mutation of p53 were determined for 40 patients who underwent endotherapy for Barrett's dysplasia or EAC. After ablation, dysplasia or neoplasia was eradicated in 34 subjects (24 squamous, 10 intestinal metaplasia). Six patients had detectable lesions after treatment; 2 were positive for transcriptionally active hr-HPV, and 4 had overexpression of p53. Before endotherapy, 15 patients had biologically active hr-HPV, 13 cleared the infection with treatment, and dysplasia or EAC was eliminated from 12 patients. One patient who cleared HPV after ablation acquired a p53 mutation, and their cancer progressed. Of 13 patients with overexpression of p53 before treatment, 10 cleared the p53 abnormality after ablation with eradication of dysplasia or neoplasia, whereas 3 of 13 had persistent p53 mutation-associated dysplasia after endotherapy (P = .004). Immunohistochemical and sequence analyses of p53 produced concordant results for 36 of 40 samples (90%). Detection of dysplasia or neoplasia after treatment was associated with HPV persistence or continued p53 overexpression. PMID- 25460563 TI - Mucosal healing in patients with celiac disease and outcomes of pregnancy: a nationwide population-based study. AB - BACKGROUND & AIMS: Studies have associated undiagnosed celiac disease with adverse outcomes of pregnancy. We investigated the association between persistent villous atrophy and outcomes of pregnancy in women with celiac disease. METHODS: We collected data on 337 women with celiac disease who gave birth (to 460 infants) within 5 years of a follow-up biopsy, from 28 pathology departments in Sweden. We compared birth outcomes from women whose follow-up biopsy showed persistent villous atrophy (Marsh score, 3; n = 142; 31% of study population) with those of women with mucosal recovery (n = 318; 69%). We used multivariable logistic regression (adjusted for maternal age, parity, country of birth, smoking, infant sex, and calendar year of birth) to evaluate the association between persistent villous atrophy and pregnancy outcomes. RESULTS: Intrauterine growth restriction occurred during 3.5% of pregnancies in women with persistent villous atrophy vs 3.8% of those with mucosal healing (adjusted odds ratio [OR], 0.61; 95% confidence interval [CI], 0.19-1.99). There was no significant association between persistent villous atrophy and low birth weight (OR, 0.98; 95% CI, 0.41-2.39), preterm birth (OR, 1.66; 95% CI, 0.72-3.83), or cesarean section (OR, 0.86; 95% CI, 0.51-1.46). CONCLUSIONS: Although undiagnosed celiac disease has been associated with adverse outcomes of pregnancy, we found no evidence from a nationwide population-based study that persistent villous atrophy, based on analysis of follow-up biopsies, increases risk compared with mucosal healing. PMID- 25460564 TI - Risk of Bacterial Infection in Patients With Cirrhosis and Acute Variceal Hemorrhage, Based on Child-Pugh Class, and Effects of Antibiotics. AB - BACKGROUND & AIMS: Antibiotics frequently are overused and are associated with serious adverse events in patients with cirrhosis. However, these drugs are recommended for all patients presenting with acute variceal hemorrhage (AVH). We investigated whether patients should be stratified for antibiotic prophylaxis based on Child-Pugh scores, to estimate risks of bacterial infection, rebleeding, and mortality, and whether antibiotics have equal effects on patients of all Child-Pugh classes. We performed a sensitivity analysis using model for end-stage liver disease (MELD) scores. METHODS: In a retrospective study, we analyzed data from 381 adult patients with cirrhosis and AVH (70% men; mean age, 56 y), admitted from 2000 through 2009 to 2 tertiary care hospitals in Edmonton, Alberta, Canada. We excluded patients with bacterial infection on the day of AVH. The association between antibiotic prophylaxis and outcomes was adjusted by liver disease severity and by a propensity score. RESULTS: The patients included in the study had mean MELD scores of 16, and 54% received antibiotic prophylaxis. Overall, antibiotic therapy was associated with lower risks of infection (adjusted odds ratio, 0.37; 95% confidence interval, 0.91-0.74) and mortality (adjusted odds ratio, 0.63; 95% confidence interval, 0.31-1.29). Among patients categorized as Child-Pugh class A given antibiotics, only 2% developed infections and the mortality rate was 0.4%. Among patients categorized as Child-Pugh class B given antibiotics, 6% developed infections, compared with 14% of patients who did not receive antibiotics; antibiotics did not affect mortality. Administration of antibiotics to patients categorized as Child-Pugh class C reduced infections and mortality by approximately 50%, compared with patients who did not receive antibiotics. MELD scores were not as useful as Child-Pugh class in identifying patients at risk for infection. CONCLUSIONS: Based on a retrospective analysis of patients with cirrhosis and AVH, those categorized as Child-Pugh class A had lower rates of bacterial infection and lower mortality rates in the absence of antibiotic prophylaxis than patients categorized as classes B or C. The recommendation for routine antibiotic prophylaxis for this subgroup requires further evaluation. PMID- 25460566 TI - Development of fecal microbiota transplantation suitable for mainstream medicine. AB - Fecal microbiota transplantation has emerged as an increasingly common treatment for patients with refractory Clostridium difficile infection. Although it can be relatively simple to perform, a number of challenges need to be overcome before this procedure is widely accepted in mainstream clinical practice. Most of the solutions to these challenges already exist, but some need further optimization and testing. Standardized fecal microbiota is being developed as a therapeutic agent, although it clearly challenges some of the existing paradigms of drug development, delivery, and regulation. PMID- 25460565 TI - Variation in treatment of patients with inflammatory bowel diseases at major referral centers in the United States. AB - We performed a prospective study of patients with inflammatory bowel diseases to examine variations in treatment among medical centers. In a prospective cohort study of 1659 patients with Crohn's disease and 946 patients with ulcerative colitis seen at 7 high-volume referral centers, we collected data on demographics, disease characteristics, and medical and surgical treatments. We used logistic regression to determine differences in treatment among centers, controlling for potential confounders. We found significant variations among centers in the treatment of Crohn's disease with immunomodulators (odds ratio [OR], 3.34; 95% confidence interval [CI], 2.09-5.32) but not anti-tumor necrosis factor agents (OR, 1.64; 95% CI, 0.97-2.77). There was less variation in the treatment of ulcerative colitis; we found no difference in use of immunomodulators (OR, 1.83; 95% CI, 1.00-3.36) or anti-tumor necrosis factor therapy (OR, 0.81; 95% CI, 0.40-1.65). The development and implementation of evidence-based standards of care for inflammatory bowel disease may help reduce variation and improve outcomes. PMID- 25460567 TI - Profiling of Cxcl12 receptors, Cxcr4 and Cxcr7 in murine testis development and a spermatogenic depletion model indicates a role for Cxcr7 in controlling Cxcl12 activity. AB - In mice the chemokine Cxcl12 and its receptor Cxcr4 participate in maintenance of the spermatogonial population during postnatal development. More complexity arises since Cxcl12 also binds to the non-classical/atypical chemokine receptor Cxcr7. We explored the expression pattern of Cxcl12, Cxcr4 and Cxcr7 during postnatal development in mouse testes and investigated the response of Cxcl12, Cxcr4, Cxcr7 and SSC-niche associated factors to busulfan-induced germ cell depletion and subsequent recovery by RNA expression analysis and localization of the proteins. In neonatal testes transcript levels of Cxcl12, Cxcr4 and Cxcr7 were relatively low and protein expression of Cxcr7 was restricted to gonocytes and spermatogonia. During development, RNA expression of Cxcl12 remained stable but that of Cxcr4 and Cxcr7 increased. Cxcr7 was expressed in germ cells located at the basement membrane of the seminiferous tubules. In adult testes, transcript levels of Cxcl12 were highest while the localization of Cxcr7 did not change. Following germ cell depletion, a significantly increased expression of Cxcl12 and a decreased expression of Cxcr7 were observed. Germ cells repopulating the seminiferous tubules were immunopositive for Cxcr7. We conclude that Cxcr7 expression to be restricted to premeiotic germ cells throughout postnatal testicular development and during testicular recovery. Hence, the spermatogonial population may not only be simply controlled by interaction of Cxcl12 with Cxcr4 but may also involve Cxcr7 as an important player. PMID- 25460568 TI - Overexpression of MEOX2 and TWIST1 is associated with H3K27me3 levels and determines lung cancer chemoresistance and prognosis. AB - Lung cancer is the leading cause of death from malignant diseases worldwide, with the non-small cell (NSCLC) subtype accounting for the majority of cases. NSCLC is characterized by frequent genomic imbalances and copy number variations (CNVs), but the epigenetic aberrations that are associated with clinical prognosis and therapeutic failure remain not completely identify. In the present study, a total of 55 lung cancer patients were included and we conducted genomic and genetic expression analyses, immunohistochemical protein detection, DNA methylation and chromatin immunoprecipitation assays to obtain genetic and epigenetic profiles associated to prognosis and chemoresponse of NSCLC patients. Finally, siRNA transfection-mediated genetic silencing and cisplatinum cellular cytotoxicity assays in NSCLC cell lines A-427 and INER-37 were assessed to describe chemoresistance mechanisms involved. Our results identified high frequencies of CNVs (66-51% of cases) in the 7p22.3-p21.1 and 7p15.3-p15.2 cytogenetic regions. However, overexpression of genes, such as MEOX2, HDAC9, TWIST1 and AhR, at 7p21.2 p21.1 locus occurred despite the absence of CNVs and little changes in DNA methylation. In contrast, the promoter sequences of MEOX2 and TWIST1 displayed significantly lower/decrease in the repressive histone mark H3K27me3 and increased in the active histone mark H3K4me3 levels. Finally these results correlate with poor survival in NSCLC patients and cellular chemoresistance to oncologic drugs in NSCLC cell lines in a MEOX2 and TWIST1 overexpression dependent-manner. In conclusion, we report for the first time that MEOX2 participates in chemoresistance irrespective of high CNV, but it is significantly dependent upon H3K27me3 enrichment probably associated with aggressiveness and chemotherapy failure in NSCLC patients, however additional clinical studies must be performed to confirm our findings as new probable clinical markers in NSCLC patients. PMID- 25460569 TI - Serum procalcitonin level and SOFA score at discharge from the intensive care unit predict post-intensive care unit mortality: a prospective study. AB - PURPOSE: The final decision for discharge from the intensive care unit (ICU) is uncertain because it is made according to various patient parameters; however, it should be made on an objective evaluation. Previous reports have been inconsistent and unreliable in predicting post-ICU mortality. To identify predictive factors associated with post-ICU mortality, we analyzed physiological and laboratory data at ICU discharge. METHODS: Patients admitted to our ICU between September 2012 and August 2013 and staying for critical care>2 days were included. Sequential Organ Failure Assessment (SOFA) score; systemic inflammatory response syndrome score; white blood cell count; and serum C reactive protein, procalcitonin (PCT), interleukin-6 (IL-6), lactate, albumin, and hemoglobin levels were recorded. The primary end point was 90-day mortality after ICU discharge. Two hundred eighteen patients were enrolled (195 survivors, 23 non survivors). RESULTS: Non-survivors presented a higher SOFA score and serum PCT, and IL-6 levels, as well as lower serum albumin and hemoglobin levels. Serum PCT, albumin, and SOFA score were associated with 90-day mortality in multiple logistic regression analysis. Hosmer-Lemeshow test showed chi-square value of 6.96, and P value of 0.54. The area under the curve (95% confidence interval) was 0.830 (0.771-0.890) for PCT, 0.688 (0.566-0.810) for albumin, 0.861 (0.796-0.927) for SOFA score, and increased to 0.913 (0.858-0.969) when these were combined. Serum PCT level at 0.57 ng/mL, serum albumin at 2.5 g/dL and SOFA score at 5.5 predict 90-day mortality, and high PCT, low albumin and high SOFA groups had significantly higher mortality. Serum PCT and SOFA score were significantly associated with survival days after ICU discharge in Cox regression analysis. CONCLUSIONS: Serum PCT level and SOFA score at ICU discharge predict post-ICU mortality and survival days after ICU discharge. The combination of these two and albumin level might enable accurate prediction. PMID- 25460570 TI - Anti-CD45 radioimmunotherapy with 90Y but not 177Lu is effective treatment in a syngeneic murine leukemia model. AB - Radioimmunotherapy (RIT) for treatment of hematologic malignancies has primarily employed monoclonal antibodies (Ab) labeled with 131I or 90Y which have limitations, and alternative radionuclides are needed to facilitate wider adoption of RIT. We therefore compared the relative therapeutic efficacy and toxicity of anti-CD45 RIT employing 90Y and 177Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J) model. Biodistribution studies showed that both 90Y- and 177Lu-anti-murine CD45 Ab conjugates (DOTA-30F11) targeted hematologic tissues, as at 24 hours 48.8 +/- 21.2 and 156 +/- 14.6% injected dose per gram of tissue (% ID/g) of 90Y-DOTA-30F11 and 54.2 +/- 9.5 and 199 +/- 11.7% ID/g of 177Lu-DOTA-30F11 accumulated in bone marrow (BM) and spleen, respectively. However, 90Y-DOTA-30F11 RIT demonstrated a dose-dependent survival benefit: 60% of mice treated with 300 uCi 90Y-DOTA-30F11 lived over 180 days after therapy, and mice treated with 100 uCi 90Y-DOTA-30F11 had a median survival 66 days. 90Y-anti-CD45 RIT was associated with transient, mild myelotoxicity without hepatic or renal toxicity. Conversely, 177Lu- anti-CD45 RIT yielded no long-term survivors. Thus, 90Y was more effective than 177Lu for anti-CD45 RIT of AML in this murine leukemia model. PMID- 25460571 TI - Trabecular plates and rods determine elastic modulus and yield strength of human trabecular bone. AB - The microstructure of trabecular bone is usually perceived as a collection of plate-like and rod-like trabeculae, which can be determined from the emerging high-resolution skeletal imaging modalities such as micro-computed tomography (MUCT) or clinical high-resolution peripheral quantitative CT (HR-pQCT) using the individual trabecula segmentation (ITS) technique. It has been shown that the ITS based plate and rod parameters are highly correlated with elastic modulus and yield strength of human trabecular bone. In the current study, plate-rod (PR) finite element (FE) models were constructed completely based on ITS-identified individual trabecular plates and rods. We hypothesized that PR FE can accurately and efficiently predict elastic modulus and yield strength of human trabecular bone. Human trabecular bone cores from proximal tibia (PT), femoral neck (FN) and greater trochanter (GT) were scanned by MUCT. Specimen-specific ITS-based PR FE models were generated for each MUCT image and corresponding voxel-based FE models were also generated in comparison. Both types of specimen-specific models were subjected to nonlinear FE analysis to predict the apparent elastic modulus and yield strength using the same trabecular bone tissue properties. Then, mechanical tests were performed to experimentally measure the apparent modulus and yield strength. Strong linear correlations for both elastic modulus (r(2) = 0.97) and yield strength (r(2) = 0.96) were found between the PR FE model predictions and experimental measures, suggesting that trabecular plate and rod morphology adequately captures three-dimensional (3D) microarchitecture of human trabecular bone. In addition, the PR FE model predictions in both elastic modulus and yield strength were highly correlated with the voxel-based FE models (r(2) = 0.99, r(2) = 0.98, respectively), resulted from the original 3D images without the PR segmentation. In conclusion, the ITS-based PR models predicted accurately both elastic modulus and yield strength determined experimentally across three distinct anatomic sites. Trabecular plates and rods accurately determine elastic modulus and yield strength of human trabecular bone. PMID- 25460573 TI - High-sensitivity C-reactive protein is an independent risk factor for non vertebral fractures in women and men: The Tromso Study. AB - Low-grade inflammation is associated with fractures, while the relationship between inflammation and bone mineral density (BMD) is less clear. Moreover, any gender differences in the sensitivity to inflammation are still poorly elucidated. We therefore tested the hypothesis that high-sensitivity C-reactive protein (CRP) is an independent risk factor for low BMD and non-vertebral fractures, in both genders, and whether there are gender differences in these associations. CRP levels and BMD at the total hip and femoral neck were measured in 1902 women and 1648 men between 55 and 74 years of age, at baseline in the Tromso Study, Norway, in 2001-2002. Non-vertebral fractures were registered from hospital X-ray archives during an average of 7.2 years follow-up. Linear regression analyses were used for CRP association with BMD and Cox proportional hazards model for fracture prediction by CRP. During 25 595 person-years follow up, 366 (19%) women and 126 (8%) men suffered a non-vertebral fracture. There was no association between CRP and BMD in women, but an inverse association in men (p=0.001) after adjustment for age and body mass index. Each standard deviation (SD) increase in log-CRP was associated with an increased risk for non-vertebral fracture by 13% in women and 22% in men (hazard ratios (HRs) 1.13, 95% confidence interval (CI) 1.02-1.26, p=0.026 and 1.22, 95% CI=1.00-1.48, p=0.046, respectively). After adjustment for BMD and other risk factors, women with CRP in the upper tertile exhibited 39% higher risk for fracture than those in the lowest tertile of CRP (HR = 1.39, 95% CI = 1.06-1.83, p = 0.017), while men in the upper tertile exhibited 80% higher risk (HR=1.80, 95% CI=1.10-2.94, p=0.019). In summary, CRP was not associated with BMD in women but inversely associated in men, and predicted fractures in both genders. We infer that inflammation influence fracture risk in both women and men, although the biological mechanisms may differ between the genders. PMID- 25460572 TI - The parathyroid hormone-regulated transcriptome in osteocytes: parallel actions with 1,25-dihydroxyvitamin D3 to oppose gene expression changes during differentiation and to promote mature cell function. AB - Although localized to the mineralized matrix of bone, osteocytes are able to respond to systemic factors such as the calciotropic hormones 1,25(OH)2D3 and PTH. In the present studies, we examined the transcriptomic response to PTH in an osteocyte cell model and found that this hormone regulated an extensive panel of genes. Surprisingly, PTH uniquely modulated two cohorts of genes, one that was expressed and associated with the osteoblast to osteocyte transition and the other a cohort that was expressed only in the mature osteocyte. Interestingly, PTH's effects were largely to oppose the expression of differentiation-related genes in the former cohort, while potentiating the expression of osteocyte specific genes in the latter cohort. A comparison of the transcriptional effects of PTH with those obtained previously with 1,25(OH)2D3 revealed a subset of genes that was strongly overlapping. While 1,25(OH)2D3 potentiated the expression of osteocyte-specific genes similar to that seen with PTH, the overlap between the two hormones was more limited. Additional experiments identified the PKA activated phospho-CREB (pCREB) cistrome, revealing that while many of the differentiation-related PTH regulated genes were apparent targets of a PKA mediated signaling pathway, a reduction in pCREB binding at sites associated with osteocyte-specific PTH targets appeared to involve alternative PTH activation pathways. That pCREB binding activities positioned near important hormone regulated gene cohorts were localized to control regions of genes was reinforced by the presence of epigenetic enhancer signatures exemplified by unique modifications at histones H3 and H4. These studies suggest that both PTH and 1,25(OH)2D3 may play important and perhaps cooperative roles in limiting osteocyte differentiation from its precursors while simultaneously exerting distinct roles in regulating mature osteocyte function. Our results provide new insight into transcription factor-associated mechanisms through which PTH and 1,25(OH)2D3 regulate a plethora of genes important to the osteoblast/osteocyte lineage. PMID- 25460574 TI - Effects of load-bearing exercise on skeletal structure and mechanics differ between outbred populations of mice. AB - Effects of load-bearing exercise on skeletal structure and mechanical properties can vary between inbred strains of mice. Here, we examine whether such variation also exists at the population level. An experiment was performed with two outbred mouse stocks that have been reproductively isolated for >120 generations (Hsd:ICR, Crl:CD1). Growing females from each stock were either treated with a treadmill-running regimen for 1 month or served as controls. Limb forces were recorded with a force plate and cage activity monitored to verify that they were similar between stocks. After the experiment, femoral cortical and trabecular bone structure were quantified with micro-CT in the mid-diaphysis and distal metaphysis, respectively, and diaphyseal structural strength was determined with mechanical testing. Among Hsd:ICR mice, running led to significant improvements in diaphyseal bone quantity, structural geometry, and mechanical properties, as well as enhanced trabecular morphology. In contrast, among Crl:CD1 mice, the same running regimen had little effect on cortical and trabecular structure and significantly reduced diaphyseal resistance to fracture. In neither stock was body mass, muscle mass, or cage activity level different between runners and controls. Given that most environmental variables were controlled in this study, the differential effects of exercise on Hsd:ICR and Crl:CD1 bones were likely due to genetic differences between stocks. These results suggest that the benefits of loading for bone may vary between human populations (e.g., ethnic groups), in which case exercise programs and technologies designed to promote bone health with mechanical signals may be more advantageous to certain populations than others. PMID- 25460575 TI - A population-based five-year study on the risk of stroke in patients with osteoporosis in Taiwan. AB - OBJECTIVES: Osteoporosis and stroke are common diseases in elder patients. The relationship between these two diseases is unclear. This study was intended to estimate the risk of stroke among elder persons aged >= 50 years within five years of being diagnosed with osteoporosis. METHODS: We retrieved data from the Longitudinal Health Insurance Database 2005 (LHID2005) in Taiwan to perform a nationwide population-based study. There were 2580 patients with osteoporosis aged 50 years of age and older in the study cohort. All of them had at least 2 ambulatory care claims or at least 1 inpatient service claim. Each osteoporotic patient was matched to 5 non-osteoporotic patients based on gender, age, and the index year. Subjects in both groups were followed up for five years. Risk of developing stroke and 5-year stroke-free survival rates were evaluated. RESULTS: The risk of developing stroke was 1.24 times higher in osteoporotic patients within a 5-year follow-up period compared to an age- and gender-matched cohort without osteoporosis (95% confidence interval = 1.11-1.39; p < 0.001). Patients with osteoporosis also had a significantly lower 5-year stroke-free survival rate. CONCLUSIONS: Our results indicated that patients with osteoporosis history had higher risk for development of stroke. PMID- 25460576 TI - Thrombin receptor deficiency leads to a high bone mass phenotype by decreasing the RANKL/OPG ratio. AB - Thrombin and its receptor (TR) are, respectively, expressed in osteoclasts and osteoblasts. However, their physiological roles on bone metabolism have not been fully elucidated. Here we investigated the bone microarchitecture by micro computed tomography (MUCT) and demonstrated increased trabecular and cortical bone mass in femurs of TR KO mice compared to WT littermates. Trabecular thickness and connectivity were significantly enhanced. The physiological role of TR on both inorganic and organic phases of bone is illustrated by a significant increase in BMD and a decrease in urinary deoxypyridinoline (DPD) crosslink concentration in TR KO mice. Moreover, TR KO cortical bone expanded and had a higher polar moment of inertia (J), implying stronger bone. Bone histomorphometry illustrated unaltered osteoblast and osteoclast number and surface in femoral metaphyses, indicating that thrombin/TR regulates osteoblasts and osteoclasts at functional levels. Serum analysis showed a decrease in RANKL and an increase in osteoprotegerin (OPG) levels and reflected a reduced RANKL/OPG ratio in the TR KO group. In vitro experiments using MC3T3 pre-osteoblasts demonstrated a TR dependent stimulatory effect of thrombin on the RANKL/OPG ratio. This effect was blocked by TR antagonist and p42/p44-ERK inhibitor. In addition, thrombin also intensified p42/p44-ERK expression and phosphorylation. In conclusion, the thrombin/TR system maintains normal bone remodeling by activating RANKL and limiting OPG synthesis by osteoblasts through the p42/44-ERK signaling pathway. Consequently, TR deficiency inhibits osteoclastogenesis, resulting in a high bone mass phenotype. PMID- 25460577 TI - SPR4-peptide alters bone metabolism of normal and HYP mice. AB - CONTEXT: ASARM-peptides are substrates and ligands for PHEX, the gene responsible for X-linked hypophosphatemic rickets (HYP). PHEX binds to the DMP1-ASARM-motif to form a trimeric-complex with alpha5beta3-integrin on the osteocyte surface and this suppresses FGF23 expression. ASARM-peptide disruption of this complex increases FGF23 expression. We used a 4.2kDa peptide (SPR4) that binds to ASARM peptide and ASARM-motif to study DMP1-PHEX interactions and to assess SPR4 for treating inherited hypophosphatemic rickets. DESIGN: Subcutaneously transplanted osmotic pumps were used to infuse SPR4-peptide or vehicle into wild-type mice (WT) and HYP-mice for 4 weeks. RESULTS: Asymmetrically distributed mineralization defects occurred with WT-SPR4 femurs. Specifically, SPR4 induced negative effects on trabecular bone and increased bone volume and mineralization in cortical-bone. Markedly increased sclerostin and reduced active beta-catenin occurred with HYP mice. SPR4-infusion suppressed sclerostin and increased active beta-catenin in WT and HYP mice and improved HYP-mice trabecular mineralization defects but not cortical mineralization defects. CONCLUSIONS: SPR4-peptide has bimodal activity and acts by: (1) preventing DMP1 binding to PHEX and (2) sequestering an inhibitor of DMP1-PHEX binding, ASARM-peptide. In PHEX defective HYP-mice the second pathway predominates. Although SPR4-peptide improved trabecular calcification defects, decreased sclerostin and increased active beta-catenin it did not correct HYP-mice cortical mineralization defects on a normal phosphate diet. Thus, for inherited hypophosphatemic rickets patients on a normal phosphate diet, SPR4-peptide is not a useful therapeutic. PMID- 25460578 TI - Isolation and gene expression of haematopoietic-cell-free preparations of highly purified murine osteocytes. AB - To define their gene expression and function, osteocytes are commonly isolated and purified by fluorescence-activated cell sorting (FACS) from mice expressing GFP directed by the dentin matrix protein 1 (Dmp1) promoter (DMP1-GFP). These cells express mRNA for osteocyte genes, including sclerostin (Sost) and Dmp1, and genes associated with the osteoclast phenotype: Dcstamp, Oscar, Cathepsin K (Ctsk), tartrate resistant acid phosphatase (TRAP/Acp5) and calcitonin receptor (Calcr). This suggests either that osteoclasts and osteocytes share genes and functions or that DMP1-GFP(+) preparations contain haematopoietic osteoclasts. To resolve this we stained DMP1-GFP cells for haematopoietic lineage (Lin) surface markers (CD2, CD3e, CD4, CD45, CD5, CD8, CD11b, B220, Gr1, Ter119) and CD31. Lin( )CD31(-) (Lin(-)) and Lin(+)CD31(+) (Lin(+)) populations were analysed for GFP, and the four resulting populations assessed by quantitative real-time PCR. Lin( )GFP(+) cells expressed mRNAs for Sost, Dmp1, and Mepe, confirming their osteocyte identity. Dcstamp and Oscar mRNAs were restricted to haematopoietic (Lin(+)) cells, but Calcr, Ctsk and Acp5 were readily detected in purified osteocytes (Lin(-)GFP(+)). The capacity of these purified osteocytes to support osteoclastogenesis was assessed: no TRAP+ cells with >2 nuclei were formed when purified osteocytes were cultured with bone marrow macrophages and stimulated with 1,25-dihydroxyvitamin-D3/prostaglandin E2. Lin(-)GFP(+) osteocytes also expressed lower levels of Tnfsf11 (RANKL) mRNA than the osteoblast-enriched population (Lin(-)GFP(-)). This demonstrates the importance of haematopoietic depletion in generating highly purified osteocytes and shows that osteocytes express Acp5, Ctsk and Calcr, but not other osteoclast markers, and do not fully support osteoclast formation in vitro. PMID- 25460579 TI - Serotonin (5-HT) inhibits Factor XIII-A-mediated plasma fibronectin matrix assembly and crosslinking in osteoblast cultures via direct competition with transamidation. AB - Serotonin (5-HT)--a monoamine with a variety of physiological functions--has recently emerged as a major regulator of bone mass. 5-HT is synthesized in the brain and the gut, and gut-derived 5-HT contributes to circulating 5-HT levels and is a negative modulator of bone mass and quality. 5-HT's negative effects on the skeleton are considered to be mediated via its receptors and transporter in osteoblasts and osteoclasts; however, 5-HT can also incorporate covalently into proteins via a transglutaminase-mediated serotonylation reaction, which in turn can alter protein function. Plasma fibronectin (pFN)--a major component of the bone extracellular matrix that regulates bone matrix quality in vivo--is a major transglutaminase substrate in bone and in osteoblast cultures. We have recently demonstrated that pFN assembly into osteoblast culture matrix requires a Factor XIII-A (FXIII-A) transglutaminase-mediated crosslinking step that regulates both quantity and quality of type I collagen matrix in vitro. In this study, we show that 5-HT interferes with pFN assembly into the extracellular matrix in osteoblast cultures, which in turn has major consequences on matrix assembly and mineralization. 5-HT treatment of MC3T3-E1 osteoblast cultures dramatically decreased both pFN fibrillogenesis as analyzed by immunofluorescence microscopy and pFN levels in DOC-soluble and DOC-insoluble matrix fractions. This was accompanied by an increase in pFN levels in the culture media. Analysis of the media showed covalent incorporation of 5-HT into pFN. Minor co-localization of pFN with 5-HT was also seen in extracellular fibrils. 5-HT also showed co localization with FXIII-A on the cell surface and inhibited its transamidation activity directly. 5-HT treatment of osteoblast cultures resulted in a discontinuous pFN matrix and impaired type I collagen deposition, decreased alkaline phosphatase and lysyl oxidase activity, and delayed mineralization of the cultures. Addition of excess exogenous pFN to cultures treated with 5-HT resulted in a significant rescue of pFN fibrillogenesis as well as type I collagen deposition and mineralization. In summary, our study presents a novel mechanism on how increased peripheral extracellular 5-HT levels might contribute to the weakening of bone by directly affecting the stabilization of extracellular matrix networks. PMID- 25460581 TI - Analysis of the absorption kinetics of macromolecules following intradermal and subcutaneous administration. AB - Recent years have witnessed rapid growth in the area of microneedle-assisted intradermal drug delivery. Several publications involving in vivo studies in humans and minipigs have demonstrated distinct change in pharmacokinetics of peptides and proteins following intradermal (ID) administration as compared to subcutaneous (SC) injections. Specifically, ID administration produced a "left shift" in pharmacokinetic profiles i.e. shorter time to achieve maximum plasma concentrations (shorter Tmax), and often higher maximum plasma concentrations (higher Cmax), as compared to the SC route. In the present work differences in the kinetics of drug absorption after ID and SC administration were explored for eight peptides and proteins with the focus on obtaining quantitative information about the absorption process and identifying similarities and differences in the absorption behavior across compounds. We confirmed that systemic uptake, as judged by apparent absorption rate constants, was 2- to 20-fold higher from the dermis as compared to the subcutis. Additionally, shapes of time-resolved absorption rate profiles demonstrated notable differences in absorption kinetics between ID and SC routes. For both administration routes evaluated herein there was a general trend of small macromolecules absorbing at higher rates as compared to the large macromolecules. PMID- 25460580 TI - Lack of prolidase causes a bone phenotype both in human and in mouse. AB - The degradation of the main fibrillar collagens, collagens I and II, is a crucial process for skeletal development. The most abundant dipeptides generated from the catabolism of collagens contain proline and hydroxyproline. In humans, prolidase is the only enzyme able to hydrolyze dipeptides containing these amino acids at their C-terminal end, thus being a key player in collagen synthesis and turnover. Mutations in the prolidase gene cause prolidase deficiency (PD), a rare recessive disorder. Here we describe 12 PD patients, 9 of whom were molecularly characterized in this study. Following a retrospective analysis of all of them a skeletal phenotype associated with short stature, hypertelorism, nose abnormalities, microcephaly, osteopenia and genu valgum, independent of both the type of mutation and the presence of the mutant protein was identified. In order to understand the molecular basis of the bone phenotype associated with PD, we analyzed a recently identified mouse model for the disease, the dark-like (dal) mutant. The dal/dal mice showed a short snout, they were smaller than controls, their femurs were significantly shorter and pQCT and MUCT analyses of long bones revealed compromised bone properties at the cortical and at the trabecular level in both male and female animals. The differences were more pronounce at 1 month being the most parameters normalized by 2 months of age. A delay in the formation of the second ossification center was evident at postnatal day 10. Our work reveals that reduced bone growth was due to impaired chondrocyte proliferation and increased apoptosis rate in the proliferative zone associated with reduced hyperthrophic zone height. These data suggest that lack of prolidase, a cytosolic enzyme involved in the final stage of protein catabolism, is required for normal skeletogenesis especially at early age when the requirement for collagen synthesis and degradation is the highest. PMID- 25460582 TI - Arginine-tagging of polymeric nanoparticles via histidine to improve cellular uptake. AB - Polyarginine, a cell-penetrating peptide, has been shown to aid cellular penetration of bioactives into cells. We utilized a novel approach of using a histidine linker to produce poly(ethyl-cyanoacrylate) (PECA) nanoparticles tagged with oligoarginine and investigated cellular uptake. MALDI TOF/TOF (tandem) analysis revealed that di-arginine-histidine (RRH) covalently bound to PECA nanoparticles to form cationic particles (+18 mV), while longer oligoarginine peptides did not co-polymerize with PECA nanoparticles. Although RRH-tagged nanoparticles had similar size and FITC-dextran entrapment efficiency compared to unmodified nanoparticles, RRH-tagging of nanoparticles resulted in a greater release of FITC-dextran. As the nanoparticles were found to aggregate in Hanks Balanced Salt Solution (HBSS), the effect of phosphate on the zeta-potential of nanoparticles was studied. Treating the nanoparticles with poloxamer-407 prevented aggregation. RRH-tagged PECA nanoparticles increased cellular uptake by a further 30% compared to unmodified PECA nanoparticles and was concentration dependent. We suggest that enhanced cell uptake can be achieved using a di arginine-histidine construct as opposed to the previously published findings that a minimum of hexa-arginine is necessary. Further, the cationic zeta-potential of the cell-penetrating peptide may not be needed to enhance uptake. PMID- 25460583 TI - Fatty acid composition analysis in polysorbate 80 with high performance liquid chromatography coupled to charged aerosol detection. AB - The fatty acid (FA) composition of polysorbate 80 (PS80), a sorbitan oleic acid ester copolymerized with about 20mole of ethylene oxide, is typically characterized by gas chromatography. Here, an alternative method was developed. After saponification with potassium hydroxide the FA fraction was collected with liquid-liquid extraction using methyl-tert-butyl ether. HPLC in combination with a Corona(r) charged aerosol detector (CAD) was applied for the separation and detection. The method was fully validated in terms of specificity, repeatability, limits of quantification, linearity, range, accuracy and robustness. The characterization of 16 different PS80 batches demonstrated variability regarding their FA composition, with e.g. the amount of oleic acid ranging from 67.8+/-0.7% to 96.6+/-1.4%. Furthermore, we identified petroselinic acid, a double-bond positional isomer to oleic acid in all batches, an FA not known to pharmacopoeias at present. In addition, 11-hydroxy-9-octadecenoic acid, an oxidation product of oleic acid was identified. Structure elucidation was performed by means of HPLC MS/MS. In addition, the method was expanded to the evaluation of the free FAs. Having determined the entire FA composition, the acid value according to EP and USP can be calculated. PMID- 25460584 TI - Encapsulation of liquids using a counter rotating twin screw extruder. AB - Until now extrusion is not applied for pharmaceutical encapsulation processes, whereas extrusion is widely used for encapsulation of flavours within food applications. Based on previous mixing studies, a hot melt counter-rotating extrusion process for encapsulation of liquid active pharmaceutical ingredients (APIs) was investigated. The mixing ratio of maltodextrin to sucrose as matrix material was adapted in first extrusion trials. Then the number of die holes was investigated to decrease expansion and agglutination of extrudates to a minimum. At a screw speed of 180 min(-1) the product temperature was decreased below 142 degrees C, resulting in extrudates of cylindrical shape with a crystalline content of 9-16%. Volatile orange terpenes and the nonvolatile alpha-tocopherol were chosen as model APIs. Design of experiments were performed to investigate the influences of barrel temperature, powder feed rate, and API content on the API retentions. A maximum of 9.2% alpha-tocopherol was encapsulated, while the orange terpene encapsulation rate decreased to 6.0% due to evaporation after leaving the die. During 12 weeks of storage re-crystallization of sucrose occurred; however, the encapsulated orange terpene amount remained unchanged. PMID- 25460585 TI - SAINT-liposome-polycation particles, a new carrier for improved delivery of siRNAs to inflamed endothelial cells. AB - Interference with acute and chronic inflammatory processes by means of delivery of siRNAs into microvascular endothelial cells at a site of inflammation demands specific, non-toxic and effective siRNA delivery system. In the current work we describe the design and characterization of siRNA carriers based on cationic pyridinium-derived lipid 1-methyl-4-(cis-9-dioleyl)methyl-pyridinium-chloride) (SAINT-C18) and the transfection enhancer protamine, complexed with siRNA/carrier DNA or siRNA only. These carriers, called SAINT-liposome-polycation-DNA (S-LPD) and SAINT-liposome-polycation (S-LP), have a high efficiency of siRNA encapsulation, low cellular toxicity, and superior efficacy of gene downregulation in endothelial cells in vitro as compared to DOTAP-LPD. Incorporation of 10 mol% PEG and anti-E-selectin antibody in these formulations resulted in selective siRNA delivery into activated endothelial cells. Furthermore, we showed that the physicochemical characteristics of S-LPD and S LP, including size-stability and maintenance of the siRNA integrity in the presence of serum at 37 degrees C, comply with requirements for in vivo application. PMID- 25460586 TI - Tracking rural health facility financial data in resource-limited settings: a case study from Rwanda. AB - Chunling Lu and colleagues describe a project for tracking health center financial data in two rural districts of Rwanda, which could be adapted for other low- or middle-income countries. Please see later in the article for the Editors' Summary. PMID- 25460587 TI - Systematic review of the incidence of herbal drug-induced liver injury in Korea. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Herbal drugs have been generally believed to be safe, based on the natural sources and long clinical experience. With the increasing use of herbal medicine worldwide, the potential toxicity of herbal drugs, especially drug-induced liver injury (DILI), frequently becomes a medical issue. This study was aimed to estimate the incidence of DILI following herbal drug consumption in Korea METHODS AND MATERIALS: A literature search for herbal DILI in eight databases, including PubMed, Medline, the Cochrane Library, EMBASE, and four Korean electronic databases. RESULTS: Six studies (three prospective and three retrospective) met the necessary criteria for assessment of the risk of DILI following herbal medicine exposure. The total number of participants in the six studies was 1699 (756 males and 943 females), and the incidence of herbal DILI varied from 0 to 1.92 among them. Total incidence of herbal DILI was 0.71% (12 patients with herbal DILI), and it was significantly higher in male (1.32%) than female (0.21%) respectively (p<0.01). All of the patients that experienced DILI concomitantly ingested herbal medicine and conventional drugs. CONCLUSIONS: This result showed the comprehensive data indicating the incident risk of hepatotoxicity in patients using herbal drugs in Korea, and presented the possibility of increased risk for the DILI by concurrent administration of herbal and conventional medicines. PMID- 25460588 TI - What's past is prologue: Chinese medicine and the treatment of recurrent urinary tract infections. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herbal medicine (CHM) has a recorded history of over 2000 years that may be used to authenticate and guide modern treatments for disease, and also identify neglected but potentially useful treatment strategies. However this process is often based on over-simplistic conceptions of tradition and history that fail to take into account the dynamic nature of 'traditions' and underestimate the importance of contextual factors in their interpretation. MATERIALS AND METHODS: As part of a process of defining good practice for a clinical trial of CHM for recurrent urinary tract infections, a selective review of classical Chinese medical texts was undertaken to investigate the historical treatment of urinary diseases specified by the traditional category of Lin diseases. RESULTS: The historical review provided interesting insights into the evolution and meaning of Lin diseases and how pertinent data may be found, precisely, outside the boundaries of the categories on which the original investigation was premised. Although there were interesting parallels and continuities in the classical and modern understandings of the aetiology, pathophysiology and treatment of urinary diseases, there were also important divergences. CONCLUSIONS: It became apparent that, in the search for 'traditional' herbs to treat a particular modern syndrome it is essential to contextualise remedies, including as far as possible the intertextual, social, cultural, and gender context, and conditions of practice. Historical ethnopharmacology adds a level of subtlety and complexity to over-simplistic attempts at bioprospecting. Some insights that emerged from this historical review could inform the proposed clinical trial but these have had to be filtered through the constraints of modern regulatory procedures. Further research is required on how best to integrate the wealth of data that exists in historical texts with the desire to produce effective herbal products for the modern world. PMID- 25460589 TI - Terminalia catappa L.: a medicinal plant from the Caribbean pharmacopeia with anti-Helicobacter pylori and antiulcer action in experimental rodent models. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Terminalia catappa L. (Combretaceae) is a medicinal plant listed as a pharmacopeia vegetable from Caribbean to treat gastritis. The objective of this study was to evaluate the gastroprotective and healing effect of the aqueous fraction (FrAq) obtained from the leaves of Terminalia catappa and to determine the antiulcer mechanism of action in experimental rodent models and its activity to Helicobacter pylori. MATERIAL AND METHODS: In rodents, the FrAq was challenged by different necrotizing agents, such as absolute ethanol and ischemia-reperfusion injury. The antiulcer mechanism of action of FrAq was assessed and the healing effects of the fraction after seven and 14 days of treatment was evaluated by matrix metalloproteinase activity (MMP-2 and MMP-9). The toxicological effect of subacute treatment with FrAq during 14 days of treatment was also analyzed. The anti-Helicobacter pylori activity was determined by microdilution. The phytochemical study of the fraction was analyzed by experiments with FIA-ESI-IT-MS(n) (Direct Flow Analysis ionization Electrospray Ion Trap Tandem Mass Spectrometry) and high performance liquid chromatography (HPLC) coupled to a photodiode array (PDA). RESULTS: Oral treatment with FrAq (25mg/kg) significantly decreased the number of ulcerative lesions induced by ethanol and ischemia/reperfusion injury. The action of FrAq was mediated by the activation of defensive mucosa-protective factors, such as increases in mucus production, the nitric oxide (NO) pathway and endogenous prostaglandins. Oral treatment with FrAq for seven and 14 days significantly reduced the lesion area (80% and 37%, respectively) compared to the negative control group. Analyses of MMP-9 and MMP-2 activity from gastric mucosa confirmed the accelerated gastric healing effect of FrAq. This extract also presented considerable activity against Helicobacter pylori. The mass spectrum and MS/MS of the aqueous fraction indicates the existence of many different phenolic compounds, including punicalagin, punicalin, and gallagic acid, among others. CONCLUSIONS: We concluded that FrAq from Terminalia catappa leaves has excellent preventive and curative effects on acute and chronic induced gastric ulcers and showed an important profile against Helicobacter pylori. PMID- 25460590 TI - Syzygium cumini (L.) Skeels essential oil and its major constituent alpha-pinene exhibit anti-Leishmania activity through immunomodulation in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Syzygium cumini (L.) Skeels (Myrtaceae), commonly known as "jambolao" in Brazil is widely used in folk medicine against leishmaniasis, inflammation, chronic diarrhea, and ulcers. It is one of the most commonly used plants for the treatment of diabetes worldwide. In previous studies, Syzygium cumini was shown to possess antihyperlipidemic and anti allergic properties, and to exhibit good performance as an antimicrobial agent against bacteria, fungi, and protozoa parasites of the genus Leishmania and Trypanosoma. This study was aimed at evaluating the effects of S. cumini essential oil (ScEO) and its major component alpha-pinene on Leishmania (Leishmania) amazonensis, as well as their cytotoxicity and possible mechanisms of action. MATERIALS AND METHODS: To evaluate the anti-proliferative effect on Leishmania, effects on promastigote and axenic amastigote forms were assessed using tetrazolium salt (MTT) assay. The intramacrophagic amastigotes were exposed to ScEO and alpha-pinene to determine the survival index. To gain insight into the mechanism of action involved in the effect on the samples, we evaluated the modulation of macrophage activation state by observing structural (phagocytic and lysosomal activities) and cellular (nitric oxide increase) changes. To assess the safety profile of ScEO and alpha-pinene, murine macrophages and human red blood cells were treated with ScEO and alpha-pinene and the selectivity index was calculated for each treatment. RESULTS: alpha-Pinene was effective against Leishmania amazonensis promastigote forms, with a half-maximal inhibitory concentration (IC50) value of 19.7ug/mL. alpha-Pinene was more active (IC50 values of 16.1 and 15.6ug/mL against axenic and intracellular amastigotes, respectively) than ScEO (IC50 values of 43.9 and 38.1ug/mL against axenic and intracellular amastigotes, respectively). Our results showed that the anti Leishmania effects were mediated by immunomodulatory activity, as evidenced by the observed increases in both phagocytic and lysosomal activity, and the elevated NO levels. ScEO and alpha-pinene exhibited low cytotoxicity against murine macrophages and human erythrocytes. The 50% cytotoxicity concentration (CC50) values for the macrophages in the MTT assay were 614.1 and 425.2ug/mL for ScEO and alpha-pinene, respectively, while the corresponding half-maximal hemolytic concentration (HC50) values were 874.3 and 233.3ug/mL. CONCLUSIONS: Taken together, the results demonstrate that ScEO and its major constituent alpha pinene have significant anti-Leishmania activity, modulated by macrophage activation, with acceptable levels of cytotoxicity in murine macrophages and human erythrocytes. Further work is warranted, involving more in-depth mechanistic studies and in vivo investigations. PMID- 25460591 TI - Ethnopharmacological field study of the plants used to treat type 2 diabetes among the Cakchiquels in Guatemala. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Type 2 diabetes is characterized by tissue resistance to the action of insulin, combined with a relative deficiency in insulin secretion. In Guatemala, type 2 diabetes results in significant mortality rates. The low incomes of the indigenous population results in the use of alternative therapies such as medicinal plants to treat the illness. We could not find any previous study related to the use of medicinal plants to treat diabetes in Guatemala. The aim of this work is to determine the most effective plant species used in traditional medicine to treat type 2 diabetes. MATERIALS AND METHODS: We performed an ethnopharmacological field study among the Cakchiquels of Chimaltenango to select the most prominent plants used to treat the disease. Type 2 diabetic patients from their community health centers were interviewed using structured questionnaires. Two mathematical tools were used to identify potential plant species: the Disease Consensus Index and the Use Value. International databases, including SCOPUS, PubMed, and Google Scholar, were used to identify whether the plants with the highest scores were known to elicit hypoglycemic effects. RESULTS: After analyzing the data, we can propose the following plants as the most prominent among the Cakchiquels of Chimaltenango to treat type 2 diabetes: Hamelia patens Jacq., Neurolaena lobata (L.) R.Br.ex Cass., Solanum americanum Mill., Croton guatemalensis Lotsy, and Quercus peduncularis Nee. CONCLUSIONS: The Cakchiquel patients interviewed did not understand type 2 diabetes; however, they associated the onset of their disease with a negative emotion, such as shock, sadness or anger. Despite changes in lifestyle, influences of advertising, the availability of innovative treatments and the use of oral hypoglycemic treatments provided by health facilities serving indigenous communities, the Cakchiquel continue to use medicinal plants as adjunctive treatment. While they are unaware whether the plants can cause additional harm, they consider their consumption beneficial because they feel better. There were 11 plants identified with UVs greater than 0.5 and high DCIs; from these 64% of the plants have been identified as having hypoglycemic effects; this finding supports the traditional selection by the Cakchiquels of medicinal plants to treat T2D. PMID- 25460592 TI - Aqueous extract from Brownea grandiceps flowers with effect on coagulation and fibrinolytic system. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Brownea grandiceps flowers are used in Venezuelan folk medicine as anti-hemorrhagic in women with heavy menstrual blood loss (menorrhagia). However, prior to this study, there were no scientific investigations to support this fact, because the aqueous extract from Brownea grandiceps flowers had not been previously evaluated neither phytochemically nor biologically. The objective of this work was to evaluate in vitro the effects of aqueous extract from Brownea grandiceps flowers on the coagulation system and fibrinolysis. MATERIALS AND METHODS: An infusion of Brownea grandiceps flowers (160g) was performed; then, it was homogenized, centrifuged and lyophilized to obtain the aqueous extract, and this was called BGE. Subsequently, the extract was characterized on the one hand, phytochemically and on the other hand, biologically, employing prothrombin time (PT), partial thromboplastin time (PTT) and thrombin time (TT) to determine the effects on extrinsic, intrinsic and common coagulation pathways, respectively. In addition to that, the fibrinogenolytic and fibronectinase activity was evaluated by SDS-PAGE using Tris Tricine system and analyzed by densitometric study utilizing ImageJ program. Also, by using specific chromogenic substrates for Factor Xa (FXa), thrombin, tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA) and plasmin, it was assessed whether BGE exhibited some enzyme-like activity, and inhibitory activity of the afore mentioned enzymes. Fibrinolytic and antifibrinolytic activities were determined by a fibrin plate method. Data were analyzed by an nonparametric method. RESULTS: BGE presented tannins, saponins, glycosides, alkaloids, flavonoids, coumarins, and did not contain triterpenoids and steroids. Also, BGE at low concentrations (250-1250ug/mL) reduced the PT, while higher concentrations (15000-25000ug/mL) prolonged this time. However, BGE concentrations between 1250 and 25000ug/mL prolonged the PTT. Prolongation of PT and PTT was observed at high concentrations and was due to FXa inhibitor found in BGE and this effect could be strengthened by degradation of fibrinogen and fibronectin, which were also produced by BGE. Moreover, BGE did not clot fibrinogen or human plasma, and neither did it cleave the chromogenic substrates specific to FXa nor thrombin. These results suggest the pro-coagulant components could be acting on some factor of the extrinsic pathway, since only PT was shortened. Furthermore, BGE did not hydrolyze the chromogenic substrate specific to plasmin, t-PA and u-PA nor did it produce fibrin degradation. However, all BGE concentrations tested inhibited the plasmin activity in a dose-dependent manner. CONCLUSIONS: The outcomes of this study reveal the presence of fibrinogenolytic, fibronectinase and anti-FXa components in BGE, plus anti-plasmin compounds that could be acting as antifibrinolytic, thus delaying the fibrin degradation in pathophysiological processes, as it has been observed in women presenting with menorrhagia due to a high plasmin concentration. Where this anti-plasmin compound, along with pro-coagulant components also present in BGE, could be made responsible for reducing heavy menstrual bleeding in women, since a deficiency in one or more blood coagulation factors such as factor VII, V or X, is a potential cause of menorrhagia. PMID- 25460593 TI - Antiproliferative mechanism of the methanolic extract of Enterolobium cyclocarpum (Jacq.) Griseb. (Fabaceae). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Enterolobium cyclocarpum (Jacq.) Griseb. is a tropical tree that has folkloric implications against many ailments and diseases including cancer. MATERIALS AND METHODS: To explore the ethnopharmacological claims against cancer, the cytotoxicity of the methanolic extract of the leaves, was investigated using the brine shrimp lethality assay, MTT assay using cervical (HeLa) and breast (MCF7) cancer cell lines, cell cycle analysis and Annexin V FITC/PI assay. RESULTS: In the brine shrimp lethality assay, the extract showed cytotoxic activity with LC50 value of 31.63 ug/mL. Significant growth inhibition was observed in both cell lines with IC50 values of 2.07 +/- 1.30 ug/mL and 11.84 +/- 1.18 ug/mL for HeLa and MCF7, respectively. Cell cycle analysis indicated that HeLa cells were arrested in the G2/M phase while MCF7 cells arrested in the G1/G0 phase. The Annexin V-FITC/PI assay revealed phosphatidylserine translocation in both cell lines and thus apoptosis induction upon treatment with the extract. CONCLUSION: The study demonstrated the potential antiproliferative activity of Enterolobium cyclocarpum thereby supporting the traditional claim and provides basis for further mechanistic studies and isolation of active constituents. PMID- 25460594 TI - Acute respiratory failure and active bleeding are the important fatality predictive factors for severe dengue viral infection. AB - OBJECTIVE: To determine the outcome of severe dengue viral infection (DVI) and the main dengue fatality risk factors. STUDY DESIGN: The medical records of patients aged <15 years admitted to Songklanagarind Hospital in southern Thailand during 1989-2011 were reviewed. Patients who had dengue hemorrhagic fever (DHF) grades III-IV, organ failure (cardiovascular, respiratory, liver, renal or hematologic), impaired consciousness, or aspartate aminotransferase more than 1,000 units/L, were classified as having severe DVI. To determine the fatality risk factors of severe DVI, the classification trees were constructed based on manual recursive partitioning. RESULTS: Of the 238 children with severe DVI, 30 (12.6%) died. Compared to the non-fatal DVI cases, the fatal cases had higher rates of DHF grade IV (96.7% vs 24.5%), repeated shock (93.3% vs 27.9%), acute respiratory failure (ARF) (100% vs 6.7%), acute liver failure (ALF) (96.6% vs 6.3%), acute kidney injury (AKI) (79.3% vs 4.5%), and active bleeding requiring blood transfusion (93.3% vs 5.4%), all p<0.01. The combined risk factors of ARF and active bleeding considered together predicted fatal outcome with sensitivity, specificity, and negative and positive predictive values of 0.93 (0.78-0.99), 0.97 (0.93-0.99), 0.99 (0.97-1.00), and 0.82 (0.65-0.93), respectively. The likelihood ratios for a fatal outcome in the patients who had and did not have this risk combination were 32.4 (14.6-71.7) and 0.07 (0.02-0.26), respectively. CONCLUSION: Severe DVI patients who have ARF and active bleeding are at a high risk of death, while patients without these things together should survive. PMID- 25460595 TI - When structure affects function--the need for partial volume effect correction in functional and resting state magnetic resonance imaging studies. AB - Both functional and also more recently resting state magnetic resonance imaging have become established tools to investigate functional brain networks. Most studies use these tools to compare different populations without controlling for potential differences in underlying brain structure which might affect the functional measurements of interest. Here, we adapt a simulation approach combined with evaluation of real resting state magnetic resonance imaging data to investigate the potential impact of partial volume effects on established functional and resting state magnetic resonance imaging analyses. We demonstrate that differences in the underlying structure lead to a significant increase in detected functional differences in both types of analyses. Largest increases in functional differences are observed for highest signal-to-noise ratios and when signal with the lowest amount of partial volume effects is compared to any other partial volume effect constellation. In real data, structural information explains about 25% of within-subject variance observed in degree centrality--an established resting state connectivity measurement. Controlling this measurement for structural information can substantially alter correlational maps obtained in group analyses. Our results question current approaches of evaluating these measurements in diseased population with known structural changes without controlling for potential differences in these measurements. PMID- 25460596 TI - A novel thermo-responsive hydrogel based on salecan and poly(N isopropylacrylamide): synthesis and characterization. AB - Salecan is a novel microbial polysaccharide produced by Agrobacterium sp. ZX09. The salt-tolerant strain was isolated from a soil sample in our laboratory and the 16S rDNA sequence was deposited in the GenBank database under the accession number GU810841. Salecan is suitable to fabricate hydrogel for biomedical applications due to the excellent hydrophilicity and biocompatibility. Here, salecan has been introduced into poly(N-isopropylacrylamide) (PNIPAm) network to form novel thermo-sensitive semi-interpenetrating polymer networks (semi-IPNs). The structure of salecan/PNIPAm semi-IPNs was confirmed by Fourier transformation infrared spectroscopy (FTIR) and X-ray diffraction (XRD). Thermogravimetric analysis (TGA) proved the stability of the semi-IPNs. Rheological and compressive tests revealed an elastic solid-like behavior and good mechanical properties of the hydrogels. Swelling behavior test showed the hydrogels possessed high water content at room temperature. An excellent thermo-sensitive property of fast response rates to temperature had been demonstrated as well. In vitro degradation measurements ensured the semi-IPNs were degradable. Cytotoxicity and cell adhesion study suggested the synthesized salecan/PNIPAm hydrogels were non-toxic and biocompatibility. The results indicated the novel thermo-responsive hydrogels could be a suitable candidate for biomedical applications. PMID- 25460597 TI - Toward a better determination of dairy powders surface composition through XPS matrices development. AB - The surface composition of dairy powders prepared by mixing various amounts of micellar casein (MC), whey proteins isolate (WPI), lactose, and anhydrous milk fat (AMF) was investigated by XPS measurements. The use of matrices are generally accepted to transform surface atomic composition (i.e., C, O, N contents) into surface component composition (i.e., lactose, proteins, lipids). These atomic based matrices were revisited and two new matrices based on the surface bond composition were developed. Surface compositions obtained from atomic and bond based matrices were compared. A successful matrix allowing good correlations between XPS predicted and theoretical surface composition for powders free from fat was identified. Nevertheless, samples containing milk fat were found to present a possible segregation of components owing to the AMF overrepresentation on the surface. Supplementary analyses (FTIR, SEM) were carried out in order to investigate the homogeneity of the mixtures. PMID- 25460598 TI - CdS QDs-chitosan microcapsules with stimuli-responsive property generated by gas liquid microfluidic technique. AB - This article describes a straightforward gas-liquid microfluidic approach to generate uniform-sized chitosan microcapsules containing CdS quantum dots (QDs). CdS QDs are encapsulated into the liquid-core of the microcapsules. The sizes of the microcapsules can be conveniently controlled by gas flow rate. QDs-chitosan microcapsules show good fluorescent stability in water, and exhibit fluorescent responses to chemical environmental stimuli. alpha-Cyclodextrin (alpha-CD) causes the microcapsules to deform and even collapse. More interestingly, alpha-CD induces obvious changes on the fluorescent color of the microcapsules. However, beta-cyclodextrin (beta-CD) has little influence on the shape and fluorescent color of the microcapsules. Based on the results of scanning electron microscopy, the possible mechanism about the effects of alpha-CD on the chitosan microcapsules is analyzed. These stimuli-responsive microcapsules are low-cost and easy to be prepared by gas-liquid microfluidic technique, and can be applied as a potential micro-detector to chemicals, such as CDs. PMID- 25460599 TI - Evaluation of biodegradable elastic scaffolds made of anionic polyurethane for cartilage tissue engineering. AB - Biodegradable polyurethane (PU) was synthesized by a water-based process. The process rendered homogenous PU nanoparticles (NPs). Spongy PU scaffolds in large dimensions were obtained by freeze-drying the PU NP dispersion. The spongy scaffolds were characterized in terms of the porous structure, wettability, mechanical properties, degradation behavior, and degradation products. The capacity as cartilage tissue engineering scaffolds was evaluated by growing chondrocytes and mesenchymal stem cells (MSCs) in the scaffolds. Scaffolds made from the PU dispersion had excellent hydrophilicity, porosity, and water absorption. Examination by micro-computed tomography confirmed that PU scaffolds had good pore interconnectivity. The degradation rate of the scaffolds in phosphate buffered saline was much faster than that in papain solution or in deionized water at 37 degrees C. The biodegradable PU appeared to be degraded via the cleavage of ester linkage The intrinsic elastic property of PU and the gyroid shape porous structure of the scaffolds may have accounted for the outstanding strain recovery (87%) and elongation behavior (257%) of the PU scaffolds, compared to conventional poly(d,l-lactide) (PLA) scaffolds. Chondrocytes were effectively seeded in PU scaffolds without pre-wetting. They grew better and secreted more glycosaminoglycan in PU scaffolds vs. PLA scaffolds. Human MSCs showed greater chondrogenic gene expression in PU scaffolds than in PLA scaffolds after induction. Based on the favorable hydrophilicity, elasticity, and regeneration capacities, the novel biodegradable PU scaffolds may be superior to the conventional biodegradable scaffolds in cartilage tissue engineering applications. PMID- 25460600 TI - Enzyme-functionalized gold-coated magnetite nanoparticles as novel hybrid nanomaterials: synthesis, purification and control of enzyme function by low frequency magnetic field. AB - The possibility of remotely inducing a defined effect on NPs by means of electromagnetic radiation appears attractive. From a practical point of view, this effect opens horizons for remote control of drug release systems, as well as modulation of biochemical functions in cells. Gold-coated magnetite nanoparticles are perfect candidates for such application. Herein, we have successfully synthesized core-shell NPs having magnetite cores and gold shells modified with various sulphur containing ligands and developed a new, simple and robust procedure for the purification of the resulting nanoparticles. The carboxylic groups displayed at the surface of the NPs were utilized for NP conjugation with a model enzyme (ChT). In the present study, we report the effect of the low frequency AC magnetic field on the catalytic activity of the immobilized ChT. We show that the enzyme activity decreases upon exposure of the NPs to the field. PMID- 25460601 TI - Biodirected synthesis of Miconazole-conjugated bacterial silver nanoparticles and their application as antifungal agents and drug delivery vehicles. AB - The recent strategy to improve the efficacy of drugs is to combine them with metal nanoparticles for the control of microbial infections. Considering this fact, we developed a low cost and eco-friendly method for silver nanoparticles synthesis using the cell free supernatant of Delftia sp. strain KCM-006 and their application as antifungal agents and as a drug carrier. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis revealed the formation of spherical and monodispersed silver nanoparticles with an average size of 9.8 nm. The synthesized nanoparticles were found to be photoluminescent, highly stable and crystalline in nature having a zeta potential of -31 mV. The silver nanoparticles exhibited very good antifungal activity against various pathogenic Candida strains. Furthermore, the efficacy of nanoparticles was increased by conjugating the antifungal drug Miconazole to silver nanoparticles which exhibited significant fungicidal activity, inhibition of ergosterol biosynthesis and biofilm inhibition by increasing ROS levels. In addition, the cell viability and immunocytochemistry analysis against different normal cell lines including Chinese hamster ovary cells (CHO), human lung cell line (MRC5) and human vascular endothelial cells (HUVEC) demonstrated that these nanoparticles were non-toxic up to a concentration of 20 MUM. In conclusion, these results suggest that the synthesized nanoparticles find application as both antifungal agents and drug delivery vehicles. This is a first report on the preparation of silver nanoparticles using culture supernatant from Delftia sp. and also on the conjugation of Miconazole, an antifungal drug, to the bacterial silver nanoparticles. PMID- 25460603 TI - Using a new Lrig1 reporter mouse to assess differences between two Lrig1 antibodies in the intestine. AB - Lrig1 is an intestinal stem cell marker important for epithelial homeostasis. However, the position of the Lrig1(+) population in the intestinal crypt has been debated, largely due to discrepant staining patterns using two Lrig1 antibodies. Here, we set out to decipher the differences between these Lrig1 antibodies to clarify their use for Lrig1-related studies. We confirmed that the commercially available Lrig1-R&D antibody stained the bottom third of the colonic crypt, whereas an independently generated Lrig1-VU antibody recognized a subset of anti Lrig1-R&D(+) cells. Biochemically, we found that anti-Lrig1-VU recognized a non glycosylated form of Lrig1; in contrast, anti-Lrig1-R&D recognized both glycosylated and non-glycosylated forms of Lrig1. In addition, we generated a reporter mouse (Lrig1-Apple) as an independent readout of Lrig1 transcriptional activity. Flow cytometry of isolated colonic epithelial cells from Lrig1-Apple mice demonstrated anti-Lrig1-R&D recognized mostly RFP-hi cells, while anti-Lrig1 VU recognized cells that were largely RFP-mid. Of note, by qRT-PCR, Lgr5 was expressed in the RFP-hi population, but not in the RFP-mid population. We conclude that anti-Lrig1-R&D appears to recognize all Lrig1(+) cells, while anti Lrig1-VU recognizes a subpopulation of Lrig1(+) cells. PMID- 25460604 TI - The Notch Delta-4 ligand helps to maintain the quiescence and the short-term reconstitutive potential of haematopoietic progenitor cells through activation of a key gene network. AB - Understanding the role of Notch and its ligands within the different bone marrow niches could shed light on the mechanisms regulating haematopoietic progenitor cells (HPCs) maintenance and self-renewal. Here, we report that murine bone marrow HPCs activation by the vascular Notch Delta-4 ligand maintains a significant proportion of cells specifically in the G0 state. Furthermore, Delta 4/Notch pathway limits significantly the loss of the in vivo short-term reconstitutive potential upon transplantation of Delta-4 activated HPCs into lethally irradiated recipient mice. Both effects are directly correlated with the decrease of cell cycle genes transcription such as CYCLIN-D1, -D2, and -D3, and the upregulation of stemness related genes transcription such as BMI1, GATA2, HOXB4 and C-MYC. In addition, the transcriptional screening also highlights new downstream post-transcriptional factors, named PUMILIO1 and -2, as part of the stem signature associated with the Delta-4/Notch signalling pathway. PMID- 25460602 TI - CstF-64 is necessary for endoderm differentiation resulting in cardiomyocyte defects. AB - Although adult cardiomyocytes have the capacity for cellular regeneration, they are unable to fully repair severely injured hearts. The use of embryonic stem cell (ESC)-derived cardiomyocytes as transplantable heart muscle cells has been proposed as a solution, but is limited by the lack of understanding of the developmental pathways leading to specification of cardiac progenitors. Identification of these pathways will enhance the ability to differentiate cardiomyocytes into a clinical source of transplantable cells. Here, we show that the mRNA 3' end processing protein, CstF-64, is essential for cardiomyocyte differentiation in mouse ESCs. Loss of CstF-64 in mouse ESCs results in loss of differentiation potential toward the endodermal lineage. However, CstF-64 knockout (Cstf2(E6)) cells were able to differentiate into neuronal progenitors, demonstrating that some differentiation pathways were still intact. Markers for mesodermal differentiation were also present, although Cstf2(E6) cells were defective in forming beating cardiomyocytes and expressing cardiac specific markers. Since the extraembryonic endoderm is needed for cardiomyocyte differentiation and endodermal markers were decreased, we hypothesized that endodermal factors were required for efficient cardiomyocyte formation in the Cstf2(E6) cells. Using conditioned medium from the extraembryonic endodermal (XEN) stem cell line we were able to restore cardiomyocyte differentiation in Cstf2(E6) cells, suggesting that CstF-64 has a role in regulating endoderm differentiation that is necessary for cardiac specification and that extraembryonic endoderm signaling is essential for cardiomyocyte development. PMID- 25460605 TI - Degradation of amyloid beta by human induced pluripotent stem cell-derived macrophages expressing Neprilysin-2. AB - The purpose of this study was to evaluate the therapeutic potential of human induced pluripotent stem (iPS) cell-derived macrophage-like cells for Alzheimer's disease (AD). In previous studies, we established the technology to generate macrophage-like myeloid lineage cells with proliferating capacity from human iPS cells, and we designated the cells iPS-ML. iPS-ML reduced the level of Abeta added into the culture medium, and the culture supernatant of iPS-ML alleviated the neurotoxicity of Abeta. We generated iPS-ML expressing the Fc-receptor-fused form of a single chain antibody specific to Abeta. In addition, we made iPS-ML expressing Neprilysin-2 (NEP2), which is a protease with Abeta-degrading activity. In vitro, expression of NEP2 but not anti-Abeta scFv enhanced the effect to reduce the level of soluble Abeta oligomer in the culture medium and to alleviate the neurotoxicity of Abeta. To analyze the effect of iPS-ML expressing NEP2 (iPS-ML/NEP2) in vivo, we intracerebrally administered the iPS-ML/NEP2 to 5XFAD mice, which is a mouse model of AD. We observed significant reduction in the level of Abeta in the brain interstitial fluid following administration of iPS-ML/NEP2. These results suggested that iPS-ML/NEP2 may be a potential therapeutic agent in the treatment of AD. PMID- 25460606 TI - Quantitative glycomics monitoring of induced pluripotent- and embryonic stem cells during neuronal differentiation. AB - Alterations in the structure of cell surface glycoforms occurring during the stages of stem cell differentiation remain unclear. We describe a rapid glycoblotting-based cellular glycomics method for quantitatively evaluating changes in glycoform expression and structure during neuronal differentiation of murine induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs). Our results show that changes in the expression of cellular N-glycans are comparable during the differentiation of iPSCs and ESCs. The expression of bisect type N-glycans was significantly up-regulated in neurons that differentiated from both iPSCs and ESCs. From a glycobiological standpoint, iPSCs are an alternative neural cell source in addition to ESCs. PMID- 25460607 TI - CD34/CD133 enriched bone marrow progenitor cells promote neovascularization of tissue engineered constructs in vivo. AB - Vascularization is critical for 3D tissue engineered constructs. In large size implants the ingrowth of vessels often fails. The purpose of this study was to identify an easily accessible, clinically relevant cell source able to promote neovascularization in engineered implants in vivo and to establish an autologous culture method for these cells. MSCs (mesenchymal stem cells) and an endothelial progenitor containing cell (EPCC) population were obtained from human bone marrow aspirates. The expression of endothelial-markers, uptake of acetylated low density lipoprotein (acLDL) and tube-like structure formation capability of EPCCs were analyzed after expansion in endothelial growth medium or medium supplemented with autologous platelet lysate (PL). EPCCs were co-seeded with MSCs on hydroxyapatite-containing polyurethane scaffolds and then implanted subcutaneously in nude mice. Human EPCCs displayed typical characteristics of endothelial cells including uptake of acLDL and formation of tube-like structures on MatrigelTM. In vivo, EPCCs cultured with PL triggered neovascularization. MSC/EPCC interactions promoted the maturation of newly formed luminal structures, which were detected deep within the scaffold and partly perfused, demonstrating a connection with the host vascular system. We demonstrate that this population of cells, isolated in a clinically relevant manner and cultured with autologous growth factors readily promoted neovascularization in tissue engineered constructs in vivo enabling a potential translation into the clinic. PMID- 25460608 TI - Homogeneous-heterogeneous reactions in peristaltic flow with convective conditions. AB - This article addresses the effects of homogeneous-heterogeneous reactions in peristaltic transport of Carreau fluid in a channel with wall properties. Mathematical modelling and analysis have been carried out in the presence of Hall current. The channel walls satisfy the more realistic convective conditions. The governing partial differential equations along with long wavelength and low Reynolds number considerations are solved. The results of temperature and heat transfer coefficient are analyzed for various parameters of interest. PMID- 25460609 TI - Assessment of electrochemical properties of a biogalvanic system for tissue characterisation. AB - Biogalvanic characterisation is a promising method for obtaining health-specific tissue information. However, there is a dearth of understanding in the literature regarding the underlying galvanic cell, electrode reactions and their controlling factors which limits the application of the technique. This work presents a parametric electrochemical investigation into a zinc-copper galvanic system using salt (NaCl) solution analogues at physiologically-relevant concentrations (1.71, 17.1 & 154 mM). The potential difference at open cell, closed cell maximum current and the internal resistance (based on published characterisation methods) were measured. Additionally, independent and relative polarisation scans of the electrodes were performed to improve understanding of the system. Our findings suggest that the prominent reaction at the cathode is that of oxygen-reduction, not hydrogen-evolution. Results indicate that cell potentials are influenced by the concentration of dissolved oxygen at low currents and maximum closed cell currents are limited by the rate of oxygen diffusion to the cathode. Characterised internal resistance values for the salt solutions did not correspond to theoretical values at the extremes of concentration (1.71 and 154 mM) due to electrode resistance and current limitation. Existing biogalvanic models do not consider these phenomena and should be improved to advance the technique and its practical application. PMID- 25460610 TI - Label-free ITO-based immunosensor for the detection of very low concentrations of pathogenic bacteria. AB - Here we describe the fabrication of a highly sensitive and label-free ITO-based impedimetric immunosensor for the detection of pathogenic bacteria Escherichia coli O157:H7. Anti-E. coli antibodies were immobilized onto ITO electrodes using a simple, robust and direct methodology. First, the covalent attachment of epoxysilane on the ITO surface was demonstrated by Atomic Force Microscopy and cyclic voltammetry. The immobilization of antibody on the epoxysilane layer was quantified by Optical Waveguide Lightmode Spectroscopy, obtaining a mass variation of 12 ng cm(- 2) (0.08 pmol cm(- 2)). Microcontact printing and fluorescence microscopy were used to demonstrate the specific binding of E. coli O157:H7 to the antibody-patterned surface. We achieved a ratio of 1:500 Salmonella typhimurium/E. coli O157:H7, thus confirming the selectivity of the antibodies and efficiency of the functionalization procedure. Finally, the detection capacity of the ITO-based immunosensor was evaluated by Electrochemical Impedance Spectroscopy. A very low limit of detection was obtained (1 CFU mL(- 1)) over a large linear working range (10-10(6) CFU mL(- 1)). The specificity of the impedimetric immunosensor was also examined. Less than 20% of non-specific bacteria (S. typhimurium and E. coli K12) was observed. Our results reveal the applicability of ITO for the development of highly sensitive and selective impedimetric immunosensors. PMID- 25460612 TI - Real-time mapping of salt glands on the leaf surface of Cynodon dactylon L. using scanning electrochemical microscopy. AB - Salt glands are specialized organelles present in the leaf tissues of halophytes, which impart salt-tolerance capability to the plant species. These glands are usually identified only by their morphology using conventional staining procedures coupled with optical microscopy. In this work, we have employed scanning electrochemical microscopy to identify the salt glands not only by their morphology but also by their salt excretion behavior. Bermuda grass (Cynodon dactylon L.) species was chosen for the study as they are known to be salt tolerant and contain salt glands on leaf surfaces. Scanning electrochemical microscopy performed in sodium chloride medium in the presence and absence of potassium ferrocyanide as redox mediator, reveals the identity of salt glands. More insight into the ion expulsion behavior of these glands was obtained by mapping lateral and vertical variations in ion concentrations using surface impedance measurements which indicated five times higher resistance over the salt glands compared to the surrounding tissues and bulk solution. The protocol could be used to understand the developmental processes in plants grown in different soil/water conditions in order to improve salt tolerance of food crops by genetic engineering and hence improve their agricultural productivity. PMID- 25460611 TI - Single domain antibody coated gold nanoparticles as enhancer for Clostridium difficile toxin detection by electrochemical impedance immunosensors. AB - This work presents a sandwich-type electrochemical impedance immunosensor for detecting Clostridium difficile toxin A (TcdA) and toxin B (TcdB). Single domain antibody conjugated gold nanoparticles were applied to amplify the detection signal. Gold nanoparticles (Au NPs) were characterized by transmission electron microscopy and UV-vis spectra. The electron transfer resistance (Ret) of the working electrode surface was used as a parameter in the measurement of the biosensor. With the increase of the concentration of toxins from 1 pg/mL to 100 pg/mL, a linear relationship was observed between the relative electron transfer resistance and toxin concentration. In addition, the detection signal was enhanced due to the amplification effect. The limit of detection for TcdA and TcdB was found to be 0.61 pg/mL and 0.60 pg/mL respectively at a signal-to-noise ratio of 3 (S/N = 3). This method is simple, fast and ultrasensitive, thus possesses a great potential for clinical applications in the future. PMID- 25460613 TI - Unusually cold and dry winters increase mortality in Australia. AB - Seasonal patterns in mortality have been recognised for decades, with a marked excess of deaths in winter, yet our understanding of the causes of this phenomenon is not yet complete. Research has shown that low and high temperatures are associated with increased mortality independently of season; however, the impact of unseasonal weather on mortality has been less studied. In this study, we aimed to determine if unseasonal patterns in weather were associated with unseasonal patterns in mortality. We obtained daily temperature, humidity and mortality data from 1988 to 2009 for five major Australian cities with a range of climates. We split the seasonal patterns in temperature, humidity and mortality into their stationary and non-stationary parts. A stationary seasonal pattern is consistent from year-to-year, and a non-stationary pattern varies from year-to year. We used Poisson regression to investigate associations between unseasonal weather and an unusual number of deaths. We found that deaths rates in Australia were 20-30% higher in winter than summer. The seasonal pattern of mortality was non-stationary, with much larger peaks in some winters. Winters that were colder or drier than a typical winter had significantly increased death risks in most cities. Conversely summers that were warmer or more humid than average showed no increase in death risks. Better understanding the occurrence and cause of seasonal variations in mortality will help with disease prevention and save lives. PMID- 25460614 TI - Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the US population (NHANES), 2007-2010. AB - BACKGROUND: Perfluorinated chemicals (PFCs) are a group of manmade compounds that are not broken down in the body. Four PFCs (PFHxS, PFOS, PFOA, and PFNA) have been found in the blood of more than 98% of the United States population. OBJECTIVES: Our goal was to assess associations between PFHxS, PFOS, PFOA, and PFNA and uric acid, alanine transferase (ALT), gamma-glutamyl transferase (GGT), asparate aminotransferase (AST), alkaline phosphate (ALP), and total bilirubin in 2007-2008 and 2009-2010 combined National Health and Nutrition Examination Survey (NHANES). METHODS: We used multivariate linear regression and logistic regression adjusted for age, gender, race/ethnicity and BMI group, poverty, smoking, and/or alcohol consumption to estimate associations. Trend analysis was performed. RESULTS: PFHxS was associated with ALT. Each quartile of PFOS was statistically associated with total bilirubin [(Q2: OR=1.44, 95% CI 1.12-1.84), (Q3: OR=1.65, 95% CI 1.25-2.18), and (Q4: OR=1.51, 95% CI 1.06-2.15)], with evidence of an increasing trend (p-value=0.028). PFOA was associated with uric acid, ALT, GGT, and total bilirubin. PFNA was linearly associated with ALT (p-value <0.001), and there was statistically significant increasing trend (p-value=0.042). CONCLUSIONS: Our analysis found evidence of associations of biomarkers of liver function and uric acid with PFHxS, PFOS, PFOA, and PFNA at levels found in the general U.S. population. PMID- 25460615 TI - The matrix influences direct and indirect effects of an anthropogenic disturbance on marine organisms. AB - The magnitude and direction of direct and indirect effects of disturbances can be context-dependent, with the matrix (surrounding habitat) in which populations are embedded either mitigating or worsening the impacts of disturbances. Chemical disturbances are particularly harmful and can affect organisms directly or indirectly. We used bleach, a common stressor in marine systems, to test hypotheses about direct and indirect effects of anthropogenic disturbances on intertidal grazers and the influence of the surrounding macro-algal matrix on such effects. We manipulated the contaminant, food (biofilm) and surrounding macro-algal matrix. Fewer limpets were found in contaminated areas. Bleach had a strong direct negative effect on limpets and caused a reduction in biofilm food, indirectly affecting limpets. This effect was strongest in the presence of macro algal matrix. Anthropogenic disturbances can have major consequences via direct and indirect effects on key interacting species. We showed that such effects are, however, context-dependent. Capsule: Pollution is a major driver of biodiversity declines. We show that direct and indirect effects of contaminants on organisms depend on the context in which they occur. PMID- 25460616 TI - Does ambient CO have protective effect for COPD patient? AB - BACKGROUND: Existing studies found paradoxical effects of carbon monoxide (CO) on human health. Carbon monoxide (CO), at high concentrations, is a well-known toxicant, but recent studies suggest that CO at low concentrations may have protective health effects under certain conditions. OBJECTIVES: To investigate the acute effect of ambient CO on hospital admission for chronic obstructive pulmonary disease (COPD) in Shanghai, China. METHODS: Daily data on COPD admissions and CO concentrations between 2006 and 2008 were collected. We applied over-dispersed generalized additive Poisson models, adjusted for weather conditions, day of the week and public holidays, long-term and seasonal trends. RESULTS: During the study period, the average CO concentration was 1.3mg/m(3), well below the international health-based standard. Negative associations were found between ambient CO concentration and daily COPD hospitalization. An interquartile range increase (0.6 mg/m(3)) in CO concentration at lag 3 day corresponded to -2.97% (95% confidence interval: -4.63%, -1.31%) change in COPD hospitalization. The negative associations were robust after adjustment for co pollutants (PM10, NO2 and SO2). The protective effect of CO appeared to be more evident in the cool season. CONCLUSION: Short-term exposure to CO at low ambient concentration may be associated with reduced risk of COPD hospitalization. Our results may contribute to a comprehensive understanding on the health effects of ambient CO. PMID- 25460617 TI - Maternal blood metal levels and fetal markers of metabolic function. AB - Exposure to metals commonly found in the environment has been hypothesized to be associated with measures of fetal growth but the epidemiological literature is limited. The Maternal-Infant Research on Environmental Chemicals (MIREC) study recruited 2001 women during the first trimester of pregnancy from 10 Canadian sites. Our objective was to assess the association between prenatal exposure to metals (lead, arsenic, cadmium, and mercury) and fetal metabolic function. Average maternal metal concentrations in 1st and 3rd trimester blood samples were used to represent prenatal metals exposure. Leptin and adiponectin were measured in 1363 cord blood samples and served as markers of fetal metabolic function. Polytomous logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between metals and both high (>= 90%) and low (<= 10%) fetal adiponectin and leptin levels. Leptin levels were significantly higher in female infants compared to males. A significant relationship between maternal blood cadmium and odds of high leptin was observed among males but not females in adjusted models. When adjusting for birth weight z score, lead was associated with an increased odd of high leptin. No other significant associations were found at the top or bottom 10th percentile in either leptin or adiponectin models. This study supports the proposition that maternal levels of cadmium influence cord blood adipokine levels in a sex dependent manner. Further investigation is required to confirm these findings and to determine how such findings at birth will translate into childhood anthropometric measures. PMID- 25460619 TI - Annual and seasonal variability of metals and metalloids in urban and industrial soils in Alcala de Henares (Spain). AB - Contamination of urban and industrial soils with trace metals has been recognized as a major concern at local, regional and global levels due to their implication on human health. In this study, concentrations of aluminum (Al), arsenic (As), beryllium (Be), cadmium (Cd), chromium (Cr), manganese (Mn), nickel (Ni), lead (Pb), tin (Sn), thallium (Tl), vanadium (V) and zinc (Zn) were determined in soil samples collected in Alcala de Henares (Madrid, Spain) in order to evaluate the annual and seasonal variation in their levels. The results show that the soils of the industrial area have higher metals concentrations than the urban area. Principal component analysis (PCA) revealed that the two principal sources of trace metal contamination, especially Cd, Cu, Pb, and Zn in the urban soils of Alcala can be attributed to traffic emissions, while As, Ni and Be primarily originated from industrial discharges. The seasonal variation analysis has revealed that the emission sources in the industrial area remain constant with time. However, in urban areas, both emissions and emission pathways significantly increase over time due to ongoing development. Currently, there is no hypothesis that explains the small seasonal fluctuations of trace metals in soils, since there are many factors affecting this. Owing to the fact that urban environments are becoming the human habitat, it would therefore be advisable to monitor metals and metalloids in urban soils because of the potential risks to human health. PMID- 25460618 TI - Duration of breastfeeding and serum PCB 153 concentrations in children. AB - Polychlorinated biphenyls (PCBs) are toxic, persistent, and bioaccumulative chemicals which, because of their lipophilic properties, are abundant in human breast milk. Breastfed infants are therefore at risk of being exposed to considerable amounts of PCBs. The commonly used exposure estimations, based solely on breast milk PCB levels and duration of breastfeeding, may lead to exposure misclassification. To improve assessments of exposure to PCBs, we determined PCB 153 serum concentration, as a model substance for PCBs, at the critical time of weaning for each child in 305 breastfed infants from 5 single time point concentration measurements spread over 7 years and data on duration of breastfeeding, using an earlier developed model of the system type. We approximated the dependence of PCB 153 serum concentration, Ctbf, adjusted to cord serum concentration, C0, on nursing period, by a polynomial function Ctbf/C0=0.596+0.278t-0.0047t(2) which reliably predicts exposure to PCB 153 of breastfed infants, important for assessment of dose-outcome relationships. Adjustment of current serum concentrations to cord serum concentration improved validity of exposure assessment. PMID- 25460620 TI - Maternal blood and hair manganese concentrations, fetal growth, and length of gestation in the ISA cohort in Costa Rica. AB - BACKGROUND: Animal studies have shown that both deficiency and excess manganese (Mn) may result in decreased fetal size and weight, but human studies have reported inconsistent results. METHODS: We examined the association of blood and hair Mn concentrations measured at different times during pregnancy with fetal growth among term births and length of gestation in a cohort of 380 mother-infant pairs living near banana plantations aerially sprayed with Mn-containing fungicides in Costa Rica. We used linear regression and generalized additive models to test for linear and nonlinear associations RESULTS: Mean (+/- SD) blood Mn concentration was 24.4 +/- 6.6 MUg/L and geometric mean (geometric SD) hair Mn concentration was 1.8 (3.2) MUg/g. Hair Mn concentrations during the second and third trimesters of gestation were positively related to infant chest circumference (beta for 10-fold increase = 0.62 cm; 95% CI: 0.16, 1.08; and beta = 0.55 cm; 95% CI: -0.16, 1.26, respectively). Similarly, average maternal hair Mn concentrations during pregnancy were associated with increased chest circumference (beta for 10-fold increase = 1.19 cm; 95% CI: 0.43, 1.95) in infants whose mothers did not have gestational anemia, but not in infants of mothers who had gestational anemia (beta = 0.39 cm; 95% CI: -0.32, 1.10; pINT=0.14). All these associations were linear. Blood Mn concentrations did not show consistent linear nor nonlinear relationships with any of the birth outcomes CONCLUSIONS: Mn plays an important role in fetal development, but the extent to which environmental exposures may cause adverse health effects to the developing fetus is not well understood. Among women living near banana plantations in Costa Rica, we did not observe linear or nonlinear associations of Mn concentrations with lowered birth weight or head circumference, as reported in previous studies. However, we did find positive linear associations between maternal hair Mn concentrations during pregnancy and infant chest circumference. PMID- 25460622 TI - Cadmium exposure and atherosclerotic carotid plaques--results from the Malmo diet and Cancer study. AB - BACKGROUND: Epidemiological studies indicate that cadmium exposure through diet and smoking is associated with increased risk of cardiovascular disease. There are few data on the relationship between cadmium and plaques, the hallmark of underlying atherosclerotic disease. OBJECTIVES: To examine the association between exposure to cadmium and the prevalence and size of atherosclerotic plaques in the carotid artery. METHODS: A population sample of 4639 Swedish middle-aged women and men was examined in 1991-1994. Carotid plaque was determined by B-mode ultrasound. Cadmium in blood was analyzed by inductively coupled plasma mass spectrometry. RESULTS: Comparing quartile 4 with quartile 1 of blood cadmium, the odds ratio (OR) for prevalence of any plaque was 1.9 (95% confidence interval 1.6-2.2) after adjustment for sex and, age; 1.4 (1.1-1.8) after additional adjustment for smoking status; 1.4 (1.1-1.7) after the addition of education level and life style factors; 1.3 (1.03-1.8) after additional adjustment for risk factors and predictors of cardiovascular disease. No effect modification by sex was found in the cadmium-related prevalence of plaques. Similarly, ORs for the prevalence of small and large plaques were after full adjustment 1.4 (1.0-2.1) and 1.4 (0.9-2.0), respectively. The subgroup of never smokers showed no association between cadmium and atherosclerotic plaques. CONCLUSIONS: These results extend previous studies on cadmium exposure and clinical cardiovascular events by adding data on the association between cadmium and underlying atherosclerosis in humans. The role of smoking remains unclear. It may both cause residual confounding and be a source of pro-atherogenic cadmium exposure. PMID- 25460621 TI - Concentrations of persistent organic pollutants in California women's serum and residential dust. AB - BACKGROUND: Humans are exposed to persistent organic pollutants (POPs) through various routes, including consumption of contaminated food and accidental ingestion of settled dust. OBJECTIVES: We aimed to identify key routes of exposure to organochlorine pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs) in California women of reproductive age. METHODS: Blood was collected from 48 mothers participating in the California Childhood Leukemia Study from 2006 to 2007 and analyzed for POPs using gas chromatography-mass spectrometry. Multivariable linear regression models of natural-log transformed serum concentrations were used to identify determinants of exposure from available questionnaire information on dietary habits, reproductive history, and demographic characteristics, as well as vacuum cleaner dust-POP levels. RESULTS: After adjusting for blood lipid levels, age, body mass index, cumulative lactation, and sampling date, serum concentrations of multiple major PCBs were positively associated with fish consumption, but not dust-PCB levels. After adjusting for blood lipid levels, Hispanic ethnicity, country of origin, and household annual income, serum concentrations of multiple major PBDEs were positively associated with dust-PBDE levels. CONCLUSIONS: Our findings suggest that the relative contribution of specific exposure routes to total POP intake varies by chemical class, with dust being a relatively important source of PBDEs and diet being a relatively important source of PCBs. PMID- 25460624 TI - Renal and blood pressure effects from environmental cadmium exposure in Thai children. AB - Very few studies have shown renal and blood pressure effects from environmental cadmium exposure in children. This population study examined associations between urinary cadmium excretion, a good biomarker of long-term cadmium exposure, and renal dysfunctions and blood pressure in environmentally exposed Thai children. Renal functions including urinary excretion of beta2-microglobulin, calcium (early renal effects), and total protein (late renal effect), and blood pressure were measured in 594 primary school children. Of the children studied, 19.0% had urinary cadmium >= 1 MUg/g creatinine. The prevalence of urinary cadmium >= 1 MUg/g creatinine was significantly higher in girls and in those consuming rice grown in cadmium-contaminated areas. The geometric mean levels of urinary beta2 microglobulin, calcium, and total protein significantly increased with increasing tertiles of urinary cadmium. The analysis did not show increased blood pressure with increasing tertiles of urinary cadmium. After adjusting for age, sex, and blood lead levels, the analysis showed significant positive associations between urinary cadmium and urinary beta2-microglobulin and urinary calcium, but not urinary total protein nor blood pressure. Our findings provide evidence that environmental cadmium exposure can affect renal functions in children. A follow up study is essential to assess the clinical significance and progress of renal effects in these children. PMID- 25460623 TI - Blood alpha-synuclein in agricultural pesticide handlers in central Washington State. AB - Epidemiologic studies suggest that occupational exposure to pesticides might increase Parkinson disease risk. Some pesticides, such as the organophosphorus insecticide chlorpyrifos, appear to increase the expression of alpha-synuclein, a protein critically involved in Parkinson disease. Therefore, we assessed total blood cell alpha-synuclein in 90 specimens from 63 agricultural pesticide handlers, mainly Hispanic men from central Washington State, who participated in the state's cholinesterase monitoring program in 2007-2010. Additionally, in age adjusted linear regression models for repeated measures, we assessed whether alpha-synuclein levels were associated with butyrylcholinesterase-chlorpyrifos adducts or cholinesterase inhibition measured in peripheral blood, or with self reported pesticide exposure or paraoxonase (PON1) genotype. There was no evidence by any of those indicators that exposure to chlorpyrifos was associated with greater blood alpha-synuclein. We observed somewhat greater alpha-synuclein with the PON1-108T (lower paraoxonase enzyme) allele, and with >= 10 h of exposure to cholinesterase inhibiting insecticides in the preceding 30 days, but neither of these associations followed a clear dose-response pattern. These results suggest that selected genetic and environmental factors may affect alpha-synuclein blood levels. However, longitudinal studies with larger numbers of pesticide handlers will be required to confirm and elucidate the possible associations observed in this exploratory cross-sectional study. PMID- 25460625 TI - Anthroposophic lifestyle influences the concentration of metals in placenta and cord blood. AB - Allergic diseases develop in genetically susceptible individuals in a complex interplay with the environment, usually early in life. We have previously shown that the anthroposophic lifestyle is associated with reduced risk of allergic disease in children, but details on the influencing environmental factors are largely unknown. This study aims to elucidate if anthroposophic lifestyle influences fetal exposure to selected toxic and essential elements. Randomly selected non-smoking mothers with (n=40) and without (n=40) anthroposophic lifestyle from the prospective birth cohort ALADDIN were included. Concentrations of 12 toxic and essential elements were analyzed in full term placentas and in the erythrocyte fractions of maternal peripheral blood and of umbilical cord blood, using inductively coupled plasma mass spectrometry. Cadmium concentrations in maternal blood and placenta were significantly higher in mothers with an anthroposophic lifestyle (p<0.001), while concentrations in cord blood were generally low, irrespective of lifestyle. Cobalt concentrations were higher in both maternal blood, placenta and cord blood in the anthroposophic group. Lead concentrations were higher in maternal blood and cord blood, but not placenta, of mothers with anthroposophic lifestyle. Analysis of covariance, including lifestyle, parity, maternal age, gestational age, vegetarian diet, use of herbal medicine and occupation in the model, showed that mainly the anthroposophic lifestyle was significantly associated with cadmium concentrations. In conclusion, women with an anthroposophic lifestyle had higher concentrations of cadmium, cobalt and lead concentrations. Cadmium concentrations might have been influenced by a diet rich in vegetables and/or low iron status of the mothers. PMID- 25460626 TI - Imidacloprid-treated seed ingestion has lethal effect on adult partridges and reduces both breeding investment and offspring immunity. AB - The ingestion of imidacloprid treated seeds by farmland birds may result in exposure to toxic amounts of this insecticide. Here we report on the effects that the exposure to the recommended application rate and to 20% of that rate may produce on birds feeding on treated seeds. Experimental exposure to imidacloprid treated seeds was performed on red-legged partridges (Alectoris rufa) (n=15 pairs per treatment group: control, 20% or 100% of the recommended application rate) during two periods that corresponded to the autumn (duration of exposure: 25 days) and late winter (10 days) cereal sowing times in Spanish farmlands. We studied effects on the survival, body condition, oxidative stress biomarkers, plasma biochemistry, carotenoid-based coloration, T-cell mediated immune response and reproduction of exposed adult partridges, and on the survival and T-cell immune response of their chicks. The high dose (recommended application rate) killed all partridges, with mortality occurring faster in females than in males. The low dose (20% the recommended application rate) had no effect on mortality, but reduced levels of plasma biochemistry parameters (glucose, magnesium and lactate dehydrogenase), increased blood superoxide dismutase activity, produced changes in carotenoid-based integument coloration, reduced the clutch size, delayed the first egg lay date, increased egg yolk vitamins and carotenoids and depressed T-cell immune response of chicks. Moreover, the analysis of the livers of dead partridges revealed an accumulation of imidacloprid during exposure time. Despite the moratorium on the use of neonicotinoids in the European Union, birds may still be at high risk of poisoning by these pesticides through direct sources of exposure to coated seeds in autumn and winter. PMID- 25460627 TI - Environmental impact of pharmaceuticals from Portuguese wastewaters: geographical and seasonal occurrence, removal and risk assessment. AB - The occurrence, fate, geographical and seasonal influence and environmental risk assessment of eleven of the most consumed pharmaceuticals in Portugal were studied in wastewater treatment plants (WWTPs) influents and (WWI) and effluents (WWE). WWI and WWE samples, from two sampling campaigns (spring and summer), in 2013, were evaluated in 15 different WWTPs across the country, by solid phase extraction (SPE) and liquid chromatography coupled with tandem mass detection (LC MS-MS). Lipid regulators were the most frequently found in WWI and WWE (184.1 and 22.3mg/day/1000 inhab., respectively), followed by anti-inflammatories (1339.4 and 15.0mg/day/1000 inhab., respectively), and antibiotics (330.7 and 68.6 mg/day/1000 inhab., respectively). Anxiolytics were the least detected with 3.3 and 3.4 mg/day/1000 inhab. in WWI and WWE, respectively. The mass loads, both in WWI and WWE, were higher in summer than those found during the spring season, being remarkable the high values registered in a region where population triplicates in this time of the year. The mean removal efficiency achieved was of 94.5%, nonetheless, between the different therapeutic groups, as well as within each group, important variations in removal were observed, going from not eliminated to 100%. In the summer higher efficiencies were observed regarding lipid regulators and antibiotics. Furthermore, an important outcome was the evaluation, by means of risk quotients (RQs), of the potential ecotoxicological risk posed by the selected pharmaceuticals to different aquatic organisms, exposed to the effluents studied. Ciprofloxacin, bezafibrate, gemfibrozil, simvastatin and diclofenac showed RQs higher than one, being expected that these pharmaceuticals might pose a threat to the three trophic levels (algae, daphnids and fish) evaluated. These results highlight the importance of these monitoring studies, as required by the Directive 2013/39/EU, in order to minimize their aquatic environmental contamination and support future prioritization measures. PMID- 25460628 TI - A systematic review of the physical health impacts from non-occupational exposure to wildfire smoke. AB - BACKGROUND: Climate change is likely to increase the threat of wildfires, and little is known about how wildfires affect health in exposed communities. A better understanding of the impacts of the resulting air pollution has important public health implications for the present day and the future. METHOD: We performed a systematic search to identify peer-reviewed scientific studies published since 1986 regarding impacts of wildfire smoke on health in exposed communities. We reviewed and synthesized the state of science of this issue including methods to estimate exposure, and identified limitations in current research. RESULTS: We identified 61 epidemiological studies linking wildfire and human health in communities. The U.S. and Australia were the most frequently studied countries (18 studies on the U.S., 15 on Australia). Geographic scales ranged from a single small city (population about 55,000) to the entire globe. Most studies focused on areas close to fire events. Exposure was most commonly assessed with stationary air pollutant monitors (35 of 61 studies). Other methods included using satellite remote sensing and measurements from air samples collected during fires. Most studies compared risk of health outcomes between 1) periods with no fire events and periods during or after fire events, or 2) regions affected by wildfire smoke and unaffected regions. Daily pollution levels during or after wildfire in most studies exceeded U.S. EPA regulations. Levels of PM10, the most frequently studied pollutant, were 1.2 to 10 times higher due to wildfire smoke compared to non-fire periods and/or locations. Respiratory disease was the most frequently studied health condition, and had the most consistent results. Over 90% of these 45 studies reported that wildfire smoke was significantly associated with risk of respiratory morbidity. CONCLUSION: Exposure measurement is a key challenge in current literature on wildfire and human health. A limitation is the difficulty of estimating pollution specific to wildfires. New methods are needed to separate air pollution levels of wildfires from those from ambient sources, such as transportation. The majority of studies found that wildfire smoke was associated with increased risk of respiratory and cardiovascular diseases. Children, the elderly and those with underlying chronic diseases appear to be susceptible. More studies on mortality and cardiovascular morbidity are needed. Further exploration with new methods could help ascertain the public health impacts of wildfires under climate change and guide mitigation policies. PMID- 25460629 TI - Polycyclic aromatic hydrocarbons, brachial artery distensibility and blood pressure among children residing near an oil refinery. AB - BACKGROUND: Polycyclic aromatic hydrocarbons (PAH) are produced by the burning and processing of fuel oils, and have been associated with oxidant stress, insulin resistance and hypertension in adults. Few studies have examined whether adolescents are susceptible to cardiovascular effects of PAHs. OBJECTIVE: To study associations of PAH exposure with blood pressure (BP) and brachial artery distensibility (BAD), an early marker of arterial wall stiffness, in young boys attending three schools in Jeddah, Saudi Arabia in varying proximity to an oil refinery. METHODS: Air samples collected from the three schools were analyzed for PAHs. PAH metabolites (total hydroxyphenanthrenes and 1-hydroxypyrene) were measured in urine samples from 184 adolescent males, in whom anthropometrics, heart rate, pulse pressure, brachial artery distensibility and blood pressure were measured. Descriptive, bivariate and multivariable analyses were performed to assess relationships of school location and urinary PAH metabolites with cardiovascular measures. RESULTS: Total suspended matter was significantly higher (444 +/- 143 MUg/m(3)) at the school near the refinery compared to a school located near a ring road (395 +/- 65 MUg/m(3)) and a school located away from vehicle traffic (232 +/- 137 MUg/m(3)), as were PAHs. Systolic (0.47 S D units, p = 0.006) and diastolic (0.53 SD units, p < 0.001) BP Z-scores were highest at the school near the refinery, with a 4.36-fold increase in prehypertension (p = 0.001), controlling for confounders. No differences in pulse pressure, BAD and heart rate were noted in relationship to school location. Urinary total hydroxyphenanthrenes and 1-hydroxypyrene were not associated with cardiovascular outcomes. CONCLUSIONS: Proximity to an oil refinery in Saudi Arabia is associated with prehypertension and increases in PAH and particulate matter exposures. Further study including insulin resistance measurements, better control for confounding, and longitudinal measurement is indicated. PMID- 25460631 TI - Interdependence between urinary cobalt concentrations and hemoglobin levels in pregnant women. AB - Cobalt is an essential trace element but may cause toxic effects upon occupational or environmental exposure. Women accumulate more cobalt than men at similar exposure levels which may be related to higher metabolic iron loss. During pregnancy these losses are much stronger but their influence on cobalt intake has not been studied. We have studied the associations between changes in hemoglobin and cobalt urinary excretion during pregnancy. 391 pairs of urine and blood samples from pregnant women were collected during the 12th and 32nd weeks of pregnancy and were analyzed for cobalt and hemoglobin. Mean concentrations of urinary cobalt were 0.73 and 1.6 ug/g creatinine during the first and third trimesters, respectively (p<0.001). 84% of pregnant women had higher levels of cobalt in the third than in the first trimester. Cobalt concentrations were negatively associated to hemoglobin levels in the third trimester (p<0.05). Women with higher iron decreases between both trimesters had significant cobalt increases between these two periods. This correspondence involved a statistically significant difference in third trimester mean cobalt concentrations of anemic and non-anemic women, 1.8 and 1.5 ug/g creatinine, respectively (p<0.05). No significant differences between these two groups were found during the first trimester. These results were used to construct generalized additive models both in normal and anemic women. The strong association between the changes of both iron status and cobalt urine levels found in pregnant women may be related to higher intestinal absorption of cobalt at iron depletion such as in the last pregnancy period when iron body demands are high. Possible toxicity effects of these cobalt increases along pregnancy should be considered in cases of populations occupationally or environmentally exposed to this metal. PMID- 25460630 TI - Depressed height gain of children associated with intrauterine exposure to polycyclic aromatic hydrocarbons (PAH) and heavy metals: the cohort prospective study. AB - Fetal exposure to environmental toxicants may program the development of children and have long-lasting health impacts. The study tested the hypothesis that depressed height gain in childhood is associated with prenatal exposure to airborne polycyclic aromatic hydrocarbons (PAH) and heavy metals (lead and mercury). The study sample comprised 379 children born to non-smoking mothers among whom a total of 2011 height measurements were carried out over the 9-year follow-up period. Prenatal airborne PAH exposure was assessed by personal air monitoring of the mother in the second trimester of pregnancy and heavy metals were measured in cord blood. At the age of 3 residential air monitoring was done to evaluate the level of airborne PAH, and at the age 5 the levels of heavy metals were measured in capillary blood. The effect estimates of prenatal PAH exposure on height growth over the follow-up were adjusted in the General Estimated Equation (GEE) models for a wide set of relevant covariates. Prenatal exposure to airborne PAH showed a significant negative association with height growth, which was significantly decreased by 1.1cm at PAH level above 34.7 ng/m(3) (coeff.=-1.07, p=0.040). While prenatal lead exposure was not significantly associated with height restriction, the effect of mercury was inversely related to cord blood mercury concentration above 1.2 MUg/L (coeff.= 1.21, p=0.020), The observed negative impact of prenatal PAH exposure on height gain in childhood was mainly mediated by shorter birth length related to maternal PAH exposure during pregnancy. The height gain deficit associated with prenatal mercury exposure was not seen at birth, but the height growth was significantly slower at later age. PMID- 25460632 TI - A longitudinal study of mercury exposure associated with consumption of freshwater fish from a reservoir in rural south central USA. AB - Methylmercury (MeHg) exposure through fish consumption is a worldwide health concern. Saltwater fish account for most dietary MeHg exposure in the general U.S. population, but less is known about seasonal variations in MeHg exposure and fish consumption among millions of freshwater anglers. This longitudinal study examined associations between MeHg exposure and fish consumption in a rural, low income population relying on a freshwater reservoir (Oklahoma, USA) for recreational and subsistence fishing. We interviewed 151 participants, primarily anglers and their families, seasonally for one year using 90-day recall food frequency questionnaires to assess general and species-specific fish consumption, and tested hair biomarker samples for total mercury (THg hair). Mean THg hair was 0.27 MUg/g (n=595, range: 0.0044-3.1 MUg/g), with 4% of participants above U.S. EPA's guideline for women of childbearing age and children. Mean fish consumption was 58 g/d (95% CI: 49-67 g/d), within the range previously reported for recreational freshwater anglers and above the national average. Unlike the general U.S. population, freshwater species contributed the majority of fish consumption (69%) and dietary Hg exposure (60%) among participants, despite relatively low THg in local fish. THg hair increased with fish consumption, age, and education, and was higher among male participants and the lowest in winter. Our results suggest that future studies of anglers should consider seasonality in fish consumption and MeHg exposure and include household members who share their catch. Efforts to evaluate benefits of reducing Hg emissions should consider dietary patterns among consumers of fish from local freshwater bodies. PMID- 25460634 TI - Evaluation of polybrominated diphenyl ethers (PBDEs) in matched cat sera and house dust samples: investigation of a potential link between PBDEs and spontaneous feline hyperthyroidism. AB - The cause of feline hyperthyroidism (FH), a common endocrinopathy of domestic cats, is unknown. A potential association between exposure to environmental contaminants polybrominated diphenyl ethers (PBDEs) and FH was investigated. The median serum level for the sum of congeners BDE-47, BDE-99, BDE-153, BDE-154 and BDE-183 (Sigma5) in hyperthyroid and euthyroid cats was 82 and 174 ng g(-1)lw respectively with no significant difference in PBDE levels or profiles between groups. Overall, the median (min to max) concentration of PBDEs in cat serum (n=65) was 118 ng g(-1)lw (5-5260 ng g(-1)lw), which is approximately 10 times higher than that observed in the Australian human population. Furthermore, congener composition in feline serum samples was dominated by congener BDE-99, followed by BDE-47 then BDE-153 which differs from results of human biomonitoring. There was no correlation between PBDE levels in feline serum samples and matched house dust samples (n=25). However the similarity of BDE 47/99 ratio in each matrix suggests dust is likely the dominant exposure. Calculation of the daily exposure dose via dust ingestion for cats equated to a mean of 33 ng kg(-1) bw d(-1) (0.2-150 ng kg(-1) bw d(-1)). Differences in exposure estimates for Australian and US cats, based on dust ingestion alone, are consistent with the observed differences in body burdens. Our results do not support a role for PBDE exposure in the aetiopathogenesis of FH. PMID- 25460633 TI - Assessment of contaminant levels and trophic relations at a World Heritage Site by measurements in a characteristic shorebird species. AB - The River Elbe is responsible for influxes of contaminants into the Wadden Sea World Heritage Site. We investigated levels of polychlorinated biphenyls (PCBs), oxychlordane (OxC), hexachlorobenzene (HCB), hexachlorocyclohexanes (alpha-, beta , gamma-HCHs), dichlorodiphenyltrichloroethane (DDT) and its metabolites, and polybrominated diphenyl ethers (PBDEs) in blood and feathers from Eurasian oystercatchers (Haematopus ostralegus; n = 28) at the Elbe and compared it with a non-riverine site about 90 km further north. (1) Mean levels of all contaminants in feathers and serum were significantly higher at the river (?PCBs: 27.6 ng/g feather, 37.0 ng/ml serum; ?DDTs: 5.3 ng/g feather, 4.4 ng/ml serum) compared with the non-riverine site (?PCBs: 6.5 ng/g feather, 1.2 ng/ml serum; ?DDTs: 1.4 ng/g feather, 0.5 ng/ml serum). Mean ?HCH and HCB levels were <1.8 ng/g in feather and < 1.8 ng/ml in serum at both sites. (2) Levels of most detectable compounds in serum and feathers were significantly related, but levels were not consistently higher in either tissue. (3) There was no significant relationship between trophic level in individual oystercatchers (expressed as delta15N) or the degree of terrestrial feeding (expressed as delta13C) and contaminant loads. (4) PBDEs were not detected in significant amounts at either site. The results of this study indicate that the outflow from one of Europe's largest river systems is associated with significant historical contamination, reflected by the accumulation of contaminants in body tissues in a coastal benthivore predator. PMID- 25460636 TI - Passive exposures of children to volatile trihalomethanes during domestic cleaning activities of their parents. AB - Domestic cleaning has been proposed as a determinant of trihalomethanes (THMs) exposure in adult females. We hypothesized that parental housekeeping activities could influence children's passive exposures to THMs from their mere physical presence during domestic cleaning. In a recent cross-sectional study (n = 382) in Cyprus [41 children (< 18 y) and 341 adults (>= 18 y)], we identified 29 children who met the study's inclusion criteria. Linear regression models were applied to understand the association between children sociodemographic variables, their individual practices influencing ingestion and noningestion exposures to SigmaTHMs, and their urinary THMs levels. Among the children-specific variables, age alone showed a statistically significant inverse association with their creatinine-adjusted urinary SigmaTHMs (rS = -0.59, p < 0.001). A positive correlation was observed between urinary SigmaTHMs (ng g(-1)) of children and matched-mothers (rS = 0.52, p = 0.014), but this was not the case for their matched-fathers (rS = 0.39, p = 0.112). Time spent daily by the matched-mothers for domestic mopping, toilet and other cleaning activities using chlorine-based cleaning products was associated with their children's urinary THMs levels (rS = 0.56, p = 0.007). This trend was not observed between children and their matched fathers urinary SigmaTHMs levels, because of minimum amount of time spent by the latter in performing domestic cleaning. The proportion of variance of creatinine unadjusted and adjusted urinary SigmaTHMs levels in children that was explained by the matched-mothers covariates was 76% and 74% (p < 0.001), respectively. A physiologically-based pharmacokinetic model adequately predicted urinary chloroform excretion estimates, being consistent with the corresponding measured levels. Our findings highlighted the influence of mothers' domestic cleaning activities towards enhancing passive THMs exposures of their children. The duration of such activities could be further tested as a valid indicator of children's THMs body burden. PMID- 25460635 TI - Association between maternal urinary arsenic species and infant cord blood leptin levels in a New Hampshire Pregnancy Cohort. AB - Leptin is an important pleiotropic hormone involved in the regulation of nutrient intake and energy expenditure, and is known to influence body weight in infants and adults. High maternal levels of arsenic have been associated with reduced infant birth weight, but the mechanism of action is not yet understood. This study aimed to investigate the association between in utero arsenic exposure and infant cord blood leptin concentrations within 156 mother-infant pairs from the New Hampshire Birth Cohort Study (NHBCS) who were exposed to low to moderate levels of arsenic through well water and diet. In utero arsenic exposure was obtained from maternal second trimester urinary arsenic concentration, and plasma leptin levels were assessed through immunoassay. Results indicate that urinary arsenic species concentrations were predictive of infant cord blood leptin levels following adjustment for creatinine, infant birth weight for gestational age percentile, infant sex, maternal pregnancy-related weight gain, and maternal education level amongst 149 white mother-infant pairs in multivariate linear regression models. A doubling or 100% increase in total urinary arsenic concentration (iAs+MMA+DMA) was associated with a 10.3% (95% CI: 0.8-20.7%) increase in cord blood leptin levels. A 100% increase in either monomethylarsonic acid (MMA) or dimethylarsinic acid (DMA) was also associated with an 8.3% (95% CI: -1.0-18.6%) and 10.3% (95% CI: 1.2-20.2%) increase in cord blood leptin levels, respectively. The association between inorganic arsenic (iAs) and cord blood leptin was of similar magnitude and direction as other arsenic species (a 100% increase in iAs was associated with a 6.5% (95% CI: -3.4-17.5%) increase in cord blood leptin levels), albeit not significant. These results suggest in utero exposure to low levels of arsenic influences cord blood leptin concentration and presents a potential mechanism by which arsenic may impact early childhood growth. PMID- 25460637 TI - Systematic review and meta-analysis of the adverse health effects of ambient PM2.5 and PM10 pollution in the Chinese population. AB - INTRODUCTION: As the largest developing country, China has some of the worst air quality in the world. Heavy smog in January 2013 led to unprecedented public concern about the health impact of exposure to particulate matter. Conducting health impact assessments of particulate matter has thus become an urgent task for public health practitioners. Combined estimates of the health effects of exposure to particulate matter from quantitative reviews could provide vital information for epidemiology-based health impact assessments, but estimates for the Chinese population are limited. METHODS: On December 31, 2013, we systematically searched the PubMed, Web of Science, and China National Knowledge Infrastructure databases using as keywords names of 127 major cities in Mainland China, Hong Kong, and Taiwan. From among the 1464 articles identified, 59 studies were manually screened. Random-effects or fixed-effects models were used to combine their risk estimates, the funnel plots with Egger test were performed to evaluate the publication bias and Meta regression were run to explore the association between exposure to particulate matter with aerodynamic diameters less than 10 and 2.5 um (PM10 and PM2.5) and the resulting health effects by the Comprehensive Meta Analysis. RESULTS: In terms of short-term effects, the combined excess risks of total non-accidental mortality, mortality due to cardiovascular disease, and mortality due to respiratory disease were 0.36% (95% confidence interval [95%CI]: 0.26%, 0.46%), 0.36% (95%CI: 0.24%, 0.49%), and 0.42% (95%CI: 0.28%, 0.55%), for each 10 MUg/m(3) increase in PM10. A 10 MUg/m(3) increase in PM2.5 was associated with a 0.40% (95%CI: 0.22%, 0.59%) increase in total non-accidental mortality, a 0.63% (95%CI: 0.35%, 0.91%) increase in mortality due to cardiovascular disease, and a 0.75% (95%CI: 01.39%, 1.11%) increase in mortality due to respiratory disease. For constituent-specific mortality, increases of 0.40-3.11% were associated with an increase of 10 ng/m(3) for nickel in PM. The summary estimate ranges of hospital utilization were 0.08% ~ 0.72% and -0.58% ~ 1.32% for a 10 MUg/m(3) increase in PM10 and PM2.5. In terms of long-term effects, a 10 MUg/m(3) increase of PM10 corresponded to 23-67% increase in the risk of mortality. CONCLUSION: Short exposures to PM10 and PM2.5 are associated with increases in mortality, but evidence of constituent associated health effects, long-term effects and morbidity in China is still inadequate. PMID- 25460638 TI - Toxicity of Bacillus thuringiensis var. israelensis in aqueous suspension on the South American common frog Leptodactylus latrans (Anura: Leptodactylidae) tadpoles. AB - The effects of commercial formulations of Bacillus thuringiensisvar.israelensis (Bti) on non-target organisms are still a matter of debate; in amphibians, the risks of Bti are little known. To evaluate the toxicity of a commercial liquid (aqueous suspension, AS) formulation of Bti (Introban((r))) on Leptodactylus latrans tadpoles, including median lethal concentration (LC50) and no-and lowest observed-effect concentrations (NOEC and LOEC, respectively), as well as the possible effects of Bti on oxidative responses, erythrocytes genotoxicity, and histology of the intestines. In the laboratory, tadpoles were exposed to nominal concentrations of 0 (control), 2.5, 5, 10, 20 and 40 mg/L of formulated Bti-AS. Glutathione S-transferase (GST) and catalase (CAT) activities, as well as formation of erythrocyte nuclear abnormalities (ENAs), and histological effect were measured in tadpoles displaying survival rates >85%. L. latrans tadpoles were sensitive to exposure to Bti-AS, reaching 100% mortality after 48 h of exposure at the highest concentration. Bti-AS induced GST and CAT enzymes and genotoxicity (erythrocyte's nuclear abnormalities), and caused intestine's histopathology. Our results demonstrate that toxicity of Bti-AS is dose-dependent for L. latrans tadpoles and that sublethal exposure alters enzymes of oxidative stress, induces genotoxicity, and causes intestine damage. Further research is needed to evaluate the ecotoxicological risk of the massive use of Bti formulations on amphibian populations that commonly used suburban wastewater or urban waterbodies to reproduce and where this biopesticide is frequently applied. PMID- 25460639 TI - The effect of phthalate exposure and filaggrin gene variants on atopic dermatitis. AB - BACKGROUND: Phthalate exposure may increase the risk of atopic disorders. However, little is known about the joint effects of phthalate exposure and filaggrin (FLG) gene variants on atopic dermatitis (AD). We want to investigate whether FLG variants are related to a higher urine concentration of phthalates and whether an interaction of FLG and phthalates increases the risk of AD. METHODS: We conducted a case-control study comprised of 106 AD children and 347 controls, all of whom were selected from CEAS cohort. Urine phthalate metabolite levels (MEP, MBP, MBzP, and 5OH-MEHP) were measured by UPLC-MS/MS. FLG variants were analyzed by TaqMan assay. At 3 years of age, information about the development of AD and environmental exposures were collected. Logistic regressions were performed to estimate the association of genotypes and phthalate metabolite levels with AD. RESULTS: Urine MBP and MBzP levels were higher in children with AD than in controls (p<0.001). Children with the FLG P478S TT genotype had higher urine phthalate metabolite levels as compared with CC carriers, with MBP and MBzP having a statistically significant difference (geometric mean(s.e.) 5.51(3.77) vs. 3.03(3.48), p=0.015 and 0.76(3.01) vs. 0.53(2.56), p=0.018). After stratifying by phthalate metabolite levels, FLG P478S TT genotype was related to a higher odds of AD in children with high MBP levels (aOR=4.74, 95% CI 1.45-15.5) and in children with high MBzP levels (aOR=3.46, 95%CI 1.03-11.58). CONCLUSIONS: FLG variants may increase skin permeability leading to higher skin absorption of phthalate and thus confer a higher susceptibility for AD. Or alternatively, the internal burden of phthalates metabolites is increased in children with AD who also have risky variant of the FLG gene. PMID- 25460640 TI - Assessment of the levels of urinary 1-hydroxypyrene and air polycyclic aromatic hydrocarbon in PM2.5 for adult exposure to the petrochemical complex emissions. AB - The relationship between external exposure and internal doses of polycyclic aromatic hydrocarbons (PAHs) has not been established for people living in industrial areas. This study was carried out to estimate the relationship between particle-phase PAH exposure and urinary 1-hydroxypyrene (1-OHP) levels among the adults living near a large petrochemical complex in Mailiao, Taiwan. We measured urinary 1-OHP in 781 residents above 35 years old and PM2.5 PAHs within a 20-km radius downwind from the petrochemical complex. Urinary 1-OHP was analyzed by high performance liquid chromatography, while 16 ambient particle-phase PAHs were measured by gas chromatography mass spectrometry. External exposures to individual PAHs at each study subject's address were estimated by kriging interpolation from air sampling results and regressed against the subjects' urinary 1-OHP levels, adjusting for confounding factors. The study population's urinary 1-OHP levels ranged from 0.001 to 3.005 MUmol/mol-creatinine with significantly higher levels for females, grilled food consumers, and residents living close to roads. All 16 particle-phase PAHs were present in the study area with total PAH concentrations ranging from 0.111 to 1.982 ng/m(3). The spatial distribution of 4- and 5-ring PAHs identified high-concentration hotspots close to the complex in Mailiao. The multiple regression models showed that the adults' urinary 1-OHP levels were significantly correlated with 5 out of the 16 PAHs, including benzo[a]anthracene, benzo[k]fluoranthene, fluoranthene, pyrene, and dibenzo[a,h]anthracene; a 0.01 ng/m(3) increase in the concentration of these 5 PAHs at the study subjects' addresses was associated with a 20% elevation in urinary 1-OHP levels (MUg/g-creatinine). Emissions from a petrochemical complex can elevate particle-phase PAH concentrations in surrounding areas and increase the urinary 1-OHP levels of adults living nearby. PMID- 25460641 TI - Anti-smoking legislation and its effects on urinary cotinine and cadmium levels. AB - Anti-smoking legislation has been associated with an improvement in health indicators. Since the cadmium (Cd) body burden in the general population is markedly increased by smoke exposure, we analyzed the impact of the more restrictive legislation that came into force in Spain in 2011 by measuring Cd and cotinine in first morning urine samples from 83 adults in Madrid (Spain) before (2010) and after (2011) introduction of this law. Individual pair-wise comparisons showed a reduction of creatinine corrected Cotinine and Cd levels for non-active smokers, i. e. those which urinary cotinine levels are below 50 MUg/L. After the application of the stricter law, cotinine levels in urine only decreased in non-active smokers who self-reported not to be exposed to second hand smoke. The reduction in second hand smoke exposure was significantly higher in weekends (Friday to Sunday) than in working days (Monday to Thursday). The decrease in U-Cd was highly significant in non-active smokers and, in general, correlated with lower creatinine excretion. Therefore correction by creatinine could bias urinary Cd results, at least for cotinine levels higher than 500 MUg/L. The biochemical/toxicological benefits detected herein support the stricter application of anti-smoking legislation and emphasize the need to raise the awareness of the population as regards exposure at home. PMID- 25460642 TI - Meta-analysis on occupational exposure to pesticides--neurobehavioral impact and dose-response relationships. AB - While the health impact of high exposures to pesticides is acknowledged, the impact of chronic exposures in the absence of acute poisonings is controversial. A systematic analysis of dose-response relationships is still missing. Its absence may provoke alternative explanations for altered performances. Consequently, opportunities for health prevention in the occupational and environmental field may be missed. Objectives were (1) quantification of the neurotoxic impact of pesticides by an analysis of functional alterations in workers measured by neuropsychological performance tests, (2) estimates of dose response relationships on the basis of exposure duration, and (3) exploration of susceptible subgroups. The meta-analysis employed a random effects model to obtain overall effects for individual performance tests. Twenty-two studies with a total of 1758 exposed and 1260 reference individuals met the inclusion criteria. At least three independent outcomes were available for twenty-six performance variables. Significant performance effects were shown in adults and referred to both cognitive and motor performances. Effect sizes ranging from dRE= 0.14 to dRE=-0.67 showed consistent outcomes for memory and attention. Relationships between effect sizes and exposure duration were indicated for individual performance variables and the total of measured performances. Studies on adolescents had to be analyzed separately due to numerous outliers. The large variation among outcomes hampered the analysis of the susceptibility in this group, while data on female workers was too scant for the analysis. Relationships exist between the impact of pesticides on performances and exposure duration. A change in test paradigms would help to decipher the impact more specifically. The use of biomarkers appropriate for lower exposures would allow a better prevention of neurotoxic effects due to occupational and environmental exposure. Intervention studies in adolescents seem warranted to specify their risk. PMID- 25460643 TI - Association between measurements of thyroid function and the acrylamide metabolite N-Acetyl-S-(propionamide)-cysteine in adolescents and young adults. AB - Acrylamide is present in mainstream cigarette smoke and in some foods prepared at high temperatures. Animal studies have shown that acrylamide exposure alters thyroid function; however, it is not known if this also occurs in humans. The study examined the association between the urinary levels of the acrylamide metabolite and serum thyroid measures in adolescents and young adults. We recruited 793 subjects (mean age, 21.3 years; range, 12-30 years) from a population-based sample of Taiwanese adolescents and young adults to determine if the urinary levels of the acrylamide metabolite N-acetyl-S-(propionamide) cysteine (AAMA) and the 6 serum thyroid measures are associated. The mean (SD) AAMA were 76.54 (76.42) ug/L. Linear regression analyzes showed a 1-unit increase in natural log AAMA was significantly associated with a decrease in serum free thyroxine (T4) (ng/dL) (beta=-0.041, SE=0.013, p=0.001) after controlling for covariates. Subpopulation analyzes showed AAMA and free T4 were significantly associated with females, age 20-30 years, non-current smokers, and non-alcohol consumers. In conclusion, higher urinary AAMA concentrations were associated with decreased levels of free T4 in this cohort. Further studies are warranted to determine if there is a causal relationship between acrylamide exposure and thyroid function. PMID- 25460644 TI - Silver nanoparticles affect on gene expression of inflammatory and neurodegenerative responses in mouse brain neural cells. AB - Silver nanoparticles (AgNPs) have antibacterial characteristics, and currently are applied in Ag-containing products. This study found neural cells can uptake 3 5 nm AgNPs, and investigated the potential effects of AgNPs on gene expression of inflammation and neurodegenerative disorder in murine brain ALT astrocytes, microglial BV-2 cells and neuron N2a cells. After AgNPs (5, 10, 12.5 MUg/ml) exposure, these neural cells had obviously increased IL-1beta secretion, and induced gene expression of C-X-C motif chemokine 13 (CXCL13), macrophage receptor with collagenous structure (MARCO) and glutathione synthetase (GSS) for inflammatory response and oxidative stress neutralization. Additionally, this study found amyloid-beta (Abeta) plaques for pathological feature of Alzheimer's disease (AD) deposited in neural cells after AgNPs treatment. After AgNPs exposure, the gene expression of amyloid precursor protein (APP) was induced, and otherwise, neprilysin (NEP) and low-density lipoprotein receptor (LDLR) were reduced in neural cells as well as protein level. These results suggested AgNPs could alter gene and protein expressions of Abeta deposition potentially to induce AD progress in neural cells. It's necessary to take notice of AgNPs distribution in the environment. PMID- 25460646 TI - Effects of blood lead levels on airflow limitations in Korean adults: findings from the 5th KNHNES 2011. AB - This study aimed to examine whether blood levels of heavy metals, such as lead, mercury and cadmium, are related with pulmonary function in Korean adults. This investigation included 870 Korean adults (>= 40 years) who received pulmonary function testing in the Korea National Health and Nutrition Examination Survey (KNHANES) V-2, 2011. Data of blood levels of heavy metals, pulmonary function tests and anthropometric measurements were acquired. Blood lead levels showed inverse correlations with the FEV1/FVC ratio before (r = -0.276, p < 0.001) and after adjustment of multiple compounding factors (r = -0.115, p = 0.001). A logistic multiple regression analysis revealed that blood lead levels were a significant influencing factor for the FEV1/FVC ratio (beta = -0.017, p = 0.001, adjusted R(2) = 0.267). The odds ratios (ORs) for the FEV1/FVC ratio were significantly lower in the highest tertile group of the blood lead levels than in the lowest tertile group in Model 1 (OR = 0.007, 95% CI = 0.000-0.329) and Model 2 (OR = 0.006, 95% CI = 0.000-0.286). These findings imply that environmental exposure to lead might be an important factor that may cause airflow limitations in Korean adults. PMID- 25460645 TI - Serum concentrations of perfluorinated compounds (PFC) among selected populations of children and adults in California. AB - Perfluorinated compounds (PFCs) have been widely used in industrial applications and consumer products. Their persistent nature and potential health impacts are of concern. Given the high cost of collecting serum samples, this study is to understand whether we can quantify PFC serum concentrations using factors extracted from questionnaire responses and indirect measurements, and whether a single serum measurement can be used to classify an individual's exposure over a one-year period. The study population included three demographic groups: young children (2-8 years old) (N=67), parents of young children (<55 years old) (N=90), and older adults (>55 years old) (N=59). PFC serum concentrations, house dust concentrations, and questionnaires were collected. The geometric mean of perfluorooctane sulfonic acid (PFOS) was highest for the older adults. In contrast, the geometric mean of perfluorooctanoic acid (PFOA) was highest for children. Serum concentrations of the parent and the child from the same family were moderately correlated (Spearman correlation (r)=0.26-0.79, p<0.05), indicating common sources within a family. For adults, age, having occupational exposure or having used fire extinguisher, frequencies of consuming butter/margarine, pork, canned meat entrees, tuna and white fish, freshwater fish, and whether they ate microwave popcorn were significantly positively associated with serum concentrations of individual PFCs. For children, residential dust concentrations, frequency of wearing waterproof clothes, frequency of having canned fish, hotdogs, chicken nuggets, French fries, and chips, and whether they ate microwave popcorn were significant positive predictors of individual PFC serum concentrations. In addition, the serum concentrations collected in a subset of young children (N=20) and the parents (N=42) one year later were strongly correlated (r=0.68-0.98, p<0.001) with the levels measured at the first visits, but showed a decreasing trend. Children had moderate correlation (r=0.43) between serum and dust concentrations of PFOS, indicating indoor sources contribute to exposure. In conclusion, besides food intake, occupational exposure, consumer product use, and exposure to residential dust contribute to PFC exposure. The downward temporal trend of serum concentrations reflects the reduction of PFCs use in recent years while the year to-year correlation indicates that a single serum measurement could be an estimate of exposure relative to the population for a one-year period in epidemiology studies. PMID- 25460647 TI - Postnatal weight growth and trihalomethane exposure during pregnancy. AB - BACKGROUND: Impaired postnatal growth after chloroform exposure in utero has been observed in rodents without an effect on birth weight. We aimed to study the relationship between exposure to trihalomethanes (THMs) during pregnancy and postnatal weight growth during infancy. METHODS: We analysed 2216 mother-child pairs recruited in Gipuzkoa, Sabadell, Valencia (Spain, INMA Project, enrollment: 2003-2008) and Crete (Greece, RHEA Study, enrollment: 2007-2008). Drinking water habits and water-related activities ascertained through personal interviews were combined with THM measurements in drinking water to estimate THM exposure through different exposure routes during pregnancy. Weight measurements during the first year of life were used to fit postnatal weight growth curves from birth to one year and to predict weight at six months. Multiple linear regression was used to evaluate the relationship between six months weight gain and interquartile range (IQR) increase in THM exposure adjusting for confounders. RESULTS: Average weight gain at six months ranged from 4325 g (Gipuzkoa) to 4668 g (Crete). Median residential THM levels ranged from 1 MUg/l (Crete) to 117 MUg/l (Sabadell). No significant association was observed overall (-24.4 g [95% CI -78.8, 30.0] for an IQR increase in total residential uptake). A negative relationship was observed in Sabadell (-148 g [95% CI -282, -13.7]) for an IQR increase in ingestion THM uptake. CONCLUSIONS: No consistent evidence of an association between THM exposure during pregnancy and postnatal growth was observed. The novelty of the hypothesis and the negative trend observed in the region with the highest levels warrants the replication in future studies. PMID- 25460648 TI - Significance of fingernail and toenail mercury concentrations as biomarkers for prenatal methylmercury exposure in relation to segmental hair mercury concentrations. AB - OBJECTIVE: To investigate the appropriateness of mercury (Hg) concentrations in fingernails and toenails at parturition for detecting prenatal exposure to methylmercury (MeHg). METHODS: Total Hg concentrations were measured in 54 paired samples of fingernails, toenails, maternal blood, and maternal hair (1cm incremental segments from the scalp toward the tip) collected at 4th weeks of (early) pregnancy, and the same specimens and cord blood collected at parturition. RESULTS: Strong correlations were observed between Hg concentrations in fingernails and toenails at early pregnancy (r=0.923, p<0.01) and at parturition (r=0.895, p<0.01). At early pregnancy, Hg concentrations in fingernails and toenails showed the strongest correlations with those in hair 3-4 cm from the scalp (r=0.818 and r=0.747, p<0.01, respectively) among the 1cm incremental hair segments. Mercury concentrations in fingernails and toenails at parturition represented strong correlations with those in cord blood (r=0.803, p<0.01 for fingernails and r=0.792, p<0.01 for toenails, respectively). At parturition, Hg concentrations in fingernails had the highest correlation with those in hair 0-1cm from the scalp (r=0.918, p<0.01), and Hg concentrations in toenails showed the highest correlation with those in hair at 2-3 cm from the scalp (r=0.872, p<0.01). In addition, Hg concentrations in both finger and toe nails at parturition had equally high (p<0.01) correlation coefficients with hair segments at 0-1, 1-2, and 2-3 cm from the scalp. CONCLUSIONS: Mercury in fingernails and toenails at early pregnancy reflected the maternal Hg body burden level approximately 5 months retroactively. At parturition, Hg levels in fingernails and toenails also showed strong correlations with those in cord blood. In addition, Hg levels in fingernails and toenails at parturition reflected more recent MeHg exposure, compared with those at early pregnancy. These results suggest that fingernails and toenails at parturition are useful biomarkers for prenatal MeHg exposure for mothers and fetuses, especially during the third-trimester of gestation. PMID- 25460649 TI - The interaction between air pollution and diet does not influence the DNA damage in lymphocytes of pregnant women. AB - The aim of the study was to evaluate the risk of DNA damage in lymphocytes of pregnant women with respect to hormonal and nutritional status and to air pollution in Lesser Poland. The study was performed on 39 healthy pregnant women. The oxidative DNA damage, alkali-labile sites and uracil in DNA of lymphocytes were measured by using the comet assay. The concentration of 17beta-estradiol, progesterone, DHEA, cholesterol, vitamin B12 and folates were determined. Dietary data were assembled from food diaries. Voivodeship Inspectorate for Environmental Protection in Krakow using automatic pollution monitoring system provided the air pollution information, such as concentrations of PM10, PM2.5, NO, NO2, SO2, CO and O3. Many statistical correlations between DNA damage and air pollutants concentration were found however their biological meaning is still to be explained. It should be taken under consideration, that the protective effect of air pollutants is a result of hormesis, as the measured amounts of air pollutants during the study did not exceed the admissible levels. There was found no diet and air pollution interaction. PMID- 25460650 TI - Genotoxic and cell-transforming effects of titanium dioxide nanoparticles. AB - The in vitro genotoxic and the soft-agar anchorage independent cell transformation ability of titanium dioxide nanoparticles (nano-TiO2) and its microparticulated form has been evaluated in human embryonic kidney (HEK293) and in mouse embryonic fibroblast (NIH/3T3) cells. Nano-TiO2 of two different sizes (21 and 50 nm) were used in this study. The comet assay, with and without the use of FPG enzyme, the micronucleus assay and the soft-agar colony assay were used. For both the comet assay and the frequency of micronuclei a statistically significant induction of DNA damage, was observed at the highest dose tested (1000 ug/mL). No oxidative DNA damage induction was observed when the comet assay was complemented with the use of FPG enzyme. Furthermore, long-term exposure to nano-TiO2 has also proved to induce cell-transformation promoting cell-anchorage independent growth in soft-agar. Results were similar for the two nano-TiO2 sizes. Negative results were obtained when the microparticulated form of TiO2 was tested, indicating the existence of important differences between the microparticulated and nanoparticulated forms. As a conclusion it should be indicated that the observed genotoxic/tranforming effects were only detected at the higher dose tested (1000 ug/mL) what play down the real risk of environmental exposures to this nanomaterial. PMID- 25460651 TI - Polychlorinated biphenyls as oxidative stress inducers in liver of subacutely exposed rats: implication for dose-dependence toxicity and benchmark dose concept. AB - Hepatotoxicity is one of the well-documented adverse health effects of polychlorinated biphenyls (PCBs)-persistent organic pollutants widely present in the environment. Although previous studies suggest possible role of oxidative stress, the precise mechanisms of PCB-induced ROS production in liver still remain to be fully assessed. The aim of this study was to evaluate the effects of different doses of PCBs on the parameters of oxidative stress and to investigate whether these effects are dose dependent. Furthermore, a comparison between calculated benchmark doses (BMD) and estimated NOAEL values for investigated parameters, was made. Six groups of male albino Wistar rats (7 animals per group) were receiving Aroclor 1254 dissolved in corn oil in the doses of 0.5, 1, 2, 4, 8, 16 mg PCBs/kg b.w./day by oral gavage during 28 days while control animals were receiving corn oil only. The following parameters of oxidative stress were analyzed in liver homogenates: superoxide dismutase activity, glutathione, malondialdehyde (MDA) and total protein thiol levels. Hepatic enzymes AST, ALT, ALP and protein albumin were also determined in serum as clinical parameters of liver function. Collected data on the investigated parameters were analyzed by the BMD method. The results of this study demonstrate that subacute exposure to PCBs causes induction of oxidative stress in liver with dose-dependent changes of the investigated parameters, although more pronounced adverse effects were observed on enzymatic than on non-enzymatic components of antioxidant protection. The obtained values for BMD and NOAEL support the use of BMD concept in the prediction of health risks associated with PCBs exposure. Furthermore, our results implicate possible use of MDA in PCBs risk assessment, since MDA was the most sensitive investigated parameter with calculated low critical effect dose of 0.07 mg/kg b.w. PMID- 25460652 TI - Delta-aminolevulinic acid dehydratase (ALAD) polymorphism in lead exposed Bangladeshi children and its effect on urinary aminolevulinic acid (ALA). AB - BACKGROUND AND OBJECTIVE: Lead has long been recognized as a harmful environmental pollutant. People in developing countries like Bangladesh still have a higher risk of lead exposure. Previous research has suggested that the delta-aminolevulinic acid dehydratase (ALAD) genotype can modify lead toxicity and individual susceptibility. As children are more susceptible to lead-induced toxicity, this study investigated whether the ALAD genotype influenced urinary excretion of delta-aminolevulinic acid (U-ALA) among children exposed to environmental lead in Bangladesh. METHODS: Subjects were elementary schoolchildren from a semi-urban industrialized area in Bangladesh. A total of 222 children were studied. Blood and urine were collected to determine ALAD genotypes, blood lead levels and urinary aminolevulinic acid (U-ALA). RESULTS: The mean BPb level was 9.7 ug/dl for the study children. BPb was significantly positively correlated with hemoglobin (p<0.01). In total, allele frequency for ALAD 1 and 2 was 0.83 and 0.17 respectively. The mean U-ALA concentration was lower in ALAD1-2/2-2 carriers than ALAD1-1 carriers for boys (p=0.001). But for girls, U-ALA did not differ significantly by genotype (p=0.26). When U-ALA was compared by genotype at the same exposure level in a multiple linear regression analysis, boys who were ALAD1-2/2-2 carriers still had a lower level of U-ALA compared to ALAD1-1 carriers. CONCLUSION: This study provides information about the influence of ALAD polymorphism and its association with U-ALA in Bangladeshi children. Our results indicate that the ALAD1-2/2-2 genotype may have a protective effect in terms of U-ALA for environmentally lead exposed boys. PMID- 25460653 TI - Prenatal exposure to phthalate ester and pubertal development in a birth cohort in central Taiwan: a 12-year follow-up study. AB - Phthalate esters are widely used plasticizers that are present in many daily used products. Although some of their reproductive effects have been reported, pubertal development effects from prenatal exposure to phthalates awaits further investigations. A population based birth cohort was established (N=437 at baseline) with maternal exposure to phthalates assessed in urine collected at the third trimester of pregnancy in 2001 and 2002. Their 133 children with prenatal phthalates exposure were followed up for the outcomes of pubertal development by sequential physical examinations at eight and 11 years old in 2009 and 2012. Urinary concentrations of major phthalate metabolites (i.e., mono-2-ethylhexyl phthalate [MEHP], mono-(2-ethyl-5-hydroxyhexyl) phthalate [MEHHP], mono-(2-ethyl 5-oxohexyl) phthalate [MEOHP], mono-butyl phthalate [MBP], mono-benzyl phthalate [MBzP], monomethyl phthalate [MMP], and mono-ethyl phthalate [MEP]) were determined using liquid chromatography linked to tandem mass spectrometry. The reproductive development measurements included bone age (for both genders), testicle size (for boys), uterus size, and ovarian volume (for girls). We reported results of 133 children with complete data by applying generalized estimating equations for the repeated continuous outcomes. After controlling for Tanner stage, we detected a significant association between reduced uterus size and increasing phthalate exposure in the 2(nd) tertile relative to the 1st tertile of creatinine-corrected MEHP (B=-0.40; 95% C.I.: -0.73, -0.07, relative to the 1st tertile) and total DEHP (B=-0.39, 95% C.I.:-0.66, -0.01 for the 2nd tertile and B=0.34, 95% C.I.: -0.67, -0.01 for the 3rd tertile, relative to the 1st tertile) with a linear trend among girls. MBzP was also found negatively associated with bone age/chronological age ratio (B=-0.07, 95% CI: -0.13, -0.01 for the 3rd tertile, relative to the 1st tertile) with a linear trend for girls. We found no evidence of an association between phthalate exposure and ovarian volume or testicle size. This analysis suggests phthalate exposure may affect specific pubertal development characteristics in human beings. Further studies with larger sample sizes and longer follow-up period are warranted. PMID- 25460654 TI - Personal care products and steroid hormones in the Antarctic coastal environment associated with two Antarctic research stations, McMurdo Station and Scott Base. AB - Pharmaceutical and personal care products (PPCPs) are a major source of micropollutants to the aquatic environment. Despite intense research on the fate and effects of PPCPs in temperate climates, there is a paucity of data on their presence in polar environments. This study reports the presence of selected PPCPs in sewage effluents from two Antarctic research stations, the adjacent coastal seawater, sea ice, and biota. Sewage effluents contained bisphenol-A, ethinylestradiol, estrone, methyl triclosan, octylphenol, triclosan, and three UV filters. The maximum sewage effluent concentrations of 4-methyl-benzylidene camphor, benzophenone-1, estrone, ethinylestradiol, and octylphenol exceeded concentrations previously reported. Coastal seawaters contained bisphenol-A, octylphenol, triclosan, three paraben preservatives, and four UV-filters. The sea ice contained a similar range and concentration of PPCPs as the seawater. Benzophenone-3 (preferential accumulation in clams), estradiol, ethinylestradiol, methyl paraben (preferential accumulation in fish, with concentrations correlating negatively with fillet size), octylphenol, and propyl paraben were detected in biota samples. PPCPs were detected in seawater and biota at distances up to 25 km from the research stations WWTP discharges. Sewage effluent discharges and disposal of raw human waste through sea ice cracks have been identified as sources of PPCPs to Antarctic coastal environments. PMID- 25460655 TI - Sustained use of biogas fuel and blood pressure among women in rural Nepal. AB - BACKGROUND: More than two fifths of the world's population cook with solid fuels and are exposed to household air pollution (HAP). As of now, no studies have assessed whether switching to alternative fuels like biogas could impact cardiovascular health among cooks previously exposed to solid fuel use. METHODS: We conducted a propensity score matched cross-sectional study to explore if the sustained use of biogas fuel for at least ten years impacts blood pressure among adult female cooks of rural Nepal. We recruited one primary cook >= 30 years of age from each biogas (219 cooks) and firewood (300 cooks) using household and measured their systolic (SBP) and diastolic blood pressure (DBP). Household characteristics, kitchen ventilation and 24-h kitchen carbon monoxide were assessed. We matched cooks by age, body mass index and socio-economic status score using propensity scores and investigated the effect of biogas use through multivariate regression models in two age groups, 30-50 years and >50 years to account for any post-menopausal changes. RESULTS: We found substantially reduced 24-h kitchen carbon monoxide levels among biogas-using households. After matching and adjustment for smoking, kitchen characteristics, ventilation status and additional fuel use, the use of biogas was associated with 9.8 mmHg lower SBP [95% confidence interval (CI), -20.4 to 0.8] and 6.5 mmHg lower DBP (95% CI, 12.2 to -0.8) compared to firewood users among women >50 years of age. In this age group, biogas use was also associated with 68% reduced odds [Odds ratio 0.32 (95% CI, 0.14 to 0.71)] of developing hypertension. These effects, however, were not identified in younger women aged 30-50 years. CONCLUSIONS: Sustained use of biogas for cooking may protect against cardiovascular disease by lowering the risk of high blood pressure, especially DBP, among older female cooks. These findings need to be confirmed in longitudinal or experimental studies. PMID- 25460656 TI - Genotoxic and epigenotoxic effects of fine particulate matter from rural and urban sites in Lebanon on human bronchial epithelial cells. AB - Assessment of air pollution by particulate matter (PM) is strongly required in Lebanon in the absence of an air quality law including updated air quality standards. Using two different PM2.5-0.3 samples collected at an urban and a rural site, we examined genotoxic/epigenotoxic effects of PM exposure within a human bronchial epithelial cell line (BEAS-2B). Inorganic and organic contents evidence the major contribution of traffic and generating sets in the PM2.5-0.3 composition. Urban PM2.5-0.3 sample increased the phosphorylation of H2AX, the telomerase activity and the miR-21 up-regulation in BEAS-2B cells in a dose dependent manner. Furthermore, urban PM2.5-0.3 induced a significant increase in CYP1A1, CYP1B1 and AhRR genes expression. The variable concentrations of transition metals and organic compounds detected in the collected PM2.5-0.3 samples might be the active agents leading to a cumulative DNA damage, critical for carcinogenesis. PMID- 25460658 TI - Variability in results from negative binomial models for Lyme disease measured at different spatial scales. AB - Lyme disease has been the subject of many studies due to increasing incidence rates year after year and the severe complications that can arise in later stages of the disease. Negative binomial models have been used to model Lyme disease in the past with some success. However, there has been little focus on the reliability and consistency of these models when they are used to study Lyme disease at multiple spatial scales. This study seeks to explore how sensitive/consistent negative binomial models are when they are used to study Lyme disease at different spatial scales (at the regional and sub-regional levels). The study area includes the thirteen states in the Northeastern United States with the highest Lyme disease incidence during the 2002-2006 period. Lyme disease incidence at county level for the period of 2002-2006 was linked with several previously identified key landscape and climatic variables in a negative binomial regression model for the Northeastern region and two smaller sub-regions (the New England sub-region and the Mid-Atlantic sub-region). This study found that negative binomial models, indeed, were sensitive/inconsistent when used at different spatial scales. We discuss various plausible explanations for such behavior of negative binomial models. Further investigation of the inconsistency and sensitivity of negative binomial models when used at different spatial scales is important for not only future Lyme disease studies and Lyme disease risk assessment/management but any study that requires use of this model type in a spatial context. PMID- 25460657 TI - Communicating results in post-Belmont era biomonitoring studies: lessons from genetics and neuroimaging research. AB - BACKGROUND: Biomonitoring is a critical tool to assess the effects of chemicals on health, as scientists seek to better characterize life-course exposures from diverse environments. This trend, coupled with increased institutional support for community-engaged environmental health research, challenge established ethical norms related to biomonitoring results communication and data sharing between scientists, study participants, and their wider communities. METHODS: Through a literature review, participant observation at workshops, and interviews, we examine ethical tensions related to reporting individual data from chemical biomonitoring studies by drawing relevant lessons from the genetics and neuroimaging fields. RESULTS: In all three fields ethical debates about whether/how to report-back results to study participants are precipitated by two trends. First, changes in analytical methods have made more data accessible to stakeholders. For biomonitoring, improved techniques enable detection of more chemicals at lower levels, and diverse groups of scientists and health advocates now conduct exposure studies. Similarly, innovations in genetics have catalyzed large-scale projects and broadened the scope of who has access to genetic information. Second, increasing public interest in personal medical information has compelled imaging researchers to address demands by participants to know their personal data, despite uncertainties about their clinical significance. Four ethical arenas relevant to biomonitoring results communication emerged from our review: tensions between participants' right-to-know their personal results versus their ability or right-to-act to protect their health; whether and how to report incidental findings; informed consent in biobanking; and open-access data sharing. CONCLUSION: Ethically engaging participants in biomonitoring studies requires consideration of several issues, including scientific uncertainty about health implications and exposure sources, the ability of participants to follow up on potentially problematic results, tensions between individual and community research protections, governance and consent regarding secondary use of tissue samples, and privacy challenges in open access data sharing. PMID- 25460659 TI - Urinary bisphenol A and age at menarche among adolescent girls: evidence from NHANES 2003-2010. AB - BACKGROUND: Bisphenol A (BPA) is an environmental estrogen used in the manufacture of polycarbonate plastics and epoxy resins used to make food and beverage packaging. Increasing evidence suggests that BPA mimics estrogens in the body and may be associated with putative markers of breast cancer risk. OBJECTIVES: We analyzed the National Health and Nutrition Examination Survey (NHANES) 2003-2010 data to investigate the association of BPA with age at menarche in adolescent girls. We hypothesized that urinary BPA, as a surrogate biomarker for BPA exposure, is associated with earlier age at menarche, and that body mass index (BMI) may modulate this association. METHODS: We conducted cross sectional analyses of urinary BPA, BMI and age of menarche in a subsample of 987 adolescent girls aged 12-19, using pooled data from the 2003-2010 NHANES. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the association between urinary BPA and early onset of menarche, with adjustment for sampling design. We additionally assessed interaction of BPA with BMI. RESULTS: Adolescent girls with moderate BPA levels appeared to be less likely to have early onset of menarche than those with the lowest levels (OR=0.57; 95% CI=0.30, 1.08) after adjusting for age, race/ethnicity, parental education, country of birth, NHANES cycle, BMI and creatinine. BMI appeared to modify the BPA-menarche association. CONCLUSIONS: Although a non-significant trend suggests increasing urinary BPA may be associated with delayed menarche in adolescent girls, these results are based on cross-sectional data. Results should be clarified in carefully designed longitudinal cohort studies. PMID- 25460660 TI - Cognitive deficits and ALA-D-inhibition in children exposed to multiple metals. AB - Children are especially vulnerable to adverse effects of multiple metals exposure. The aim of this study was to assess some metals concentrations such as lead (Pb), arsenic (As), chromium (Cr), manganese (Mn) and iron (Fe) in whole blood, serum, hair and drinking water samples using inductively coupled plasma mass spectrometry (ICP-MS) in rural and urban children. In addition, evaluate the adverse effects of multiple metals exposure on cognitive function and delta aminolevulinate dehydratase (ALA-D) activity. The cognitive ability assessment was performed by the Raven's Colored Progressive Matrices (RCPM) test. The ALA-D activity and ALA-D reactivation index (ALA-RE) activity with DTT and ZnCl2 also were determined. Forty-six rural children and 23 urban children were enrolled in this study. Rural children showed percentile IQ scores in the RCPM test significantly decreased in relation to urban children. According to multiple linear regression analysis, the Mn and Fe in hair may account for the cognitive deficits of children. Manganese and Fe in hair also were positively correlated with Mn and Fe in drinking water, respectively. These results suggest that drinking water is possibly a source of metals exposure in children. ALA-D activity was decreased and ALA-RE with DTT and ZnCl2 was increased in rural children in comparison to urban children. Moreover, ALA-D inhibition was correlated with Cr blood levels and ALA-RE/DDT and ALA-RE/ZnCl2 were correlated with levels of Cr and Hg in blood. Thus, our results indicated some adverse effects of children's exposure to multiple metals, such as cognitive deficits and ALA-D inhibition, mainly associated to Mn, Fe, Cr and Hg. PMID- 25460661 TI - Smog episodes, fine particulate pollution and mortality in China. AB - BACKGROUND: Starting from early January 2013, northern China was hit by multiple prolonged and severe smog events which were characterized by extremely high-level concentrations of ambient fine particulate matter (PM2.5) with hourly peaks of PM2.5 over 800 ug/m(3). However, the consequences of this severe air pollution are largely unknown. This study investigates the acute effect of the smog episodes and PM2.5 on mortality for both urban and rural areas in northern China. DATA AND METHODS: We collected PM2.5, mortality, and meteorological data for 5 urban city districts and 2 rural counties in Beijing, Tianjin and Hebei Province of China from January 1, 2013 through December 31, 2013. We employed the generalized additive models to estimate the associations between smog episodes or PM2.5 and daily mortality for each district/county. RESULTS: Without any meteorological control, the smog episodes are positively and statistically significantly associated with mortality in 5 out of 7 districts/counties. However, the findings are sensitive to the meteorological factors. After controlling for temperature, humidity, dew point and wind, the statistical significance disappears in all urban districts. In contrast, the smog episodes are consistently and statistically significantly associated with higher total mortality and mortality from cardiovascular/respiratory diseases in the two rural counties. In Ji County, a smog episode is associated with 6.94% (95% Confidence Interval, -0.20 to 14.58) increase in overall mortality, and in Ci County it is associated with a 19.26% (95% CI, 6.66-33.34) increase in overall mortality. The smog episodes kill people primarily through its impact on cardiovascular and respiratory diseases. On average, a smog episode is associated with 11.66% (95% CI, 3.12-20.90) increase in cardiovascular and respiratory mortality in Ji County, and it is associated with a 22.23% (95% CI, 8.11-38.20) increase in cardiovascular and respiratory mortality in Ci County. A 10 MUg/m(3) increase in PM2.5 concentration is associated with 0.88% (95% CI, 0.3-1.46) increase in overall mortality and 1.2% (95% CI, 0.55-1.85) in Ji County. A 10 MUg/m(3) increase in PM2.5 concentration is associated with 0.55% (95% CI, -0.02 to 1.13) increase in overall mortality in Ci County. The findings suggest that the smog episodes and fine particulate have bigger and more detrimental impacts on rural residents, especially for those living close to big and polluted cities. CONCLUSIONS: The smog episodes and PM2.5 are statistically associated with mortality in rural areas of China. The associations for urban areas are not statistically significant. PMID- 25460662 TI - Weather variability and influenza A (H7N9) transmission in Shanghai, China: a Bayesian spatial analysis. AB - BACKGROUND: A novel avian influenza A (H7N9) virus was first found in humans in Shanghai, and infected over 433 patients in China. To date, very little is known about the spatiotemporal variability or environmental drivers of the risk of H7N9 infection. This study explored the spatial and temporal variation of H7N9 infection and assessed the effects of temperature and rainfall on H7N9 incidence. METHODS: A Bayesian spatial conditional autoregressive (CAR) model was used to assess the spatiotemporal distribution of the risk of H7N9 infection in Shanghai, by district and fortnight for the period 19th February-14th April 2013. Data on daily laboratory-confirmed H7N9 cases, and weather variability including temperature ( degrees C) and rainfall (mm) were obtained from the Chinese Information System for Diseases Control and Prevention and Chinese Meteorological Data Sharing Service System, respectively, and aggregated by fortnight. RESULTS: High spatial variations in the H7N9 risk were mainly observed in the east and centre of Shanghai municipality. H7N9 incidence rate was significantly associated with fortnightly mean temperature (Relative Risk (RR): 1.54; 95% credible interval (CI): 1.22-1.94) and fortnightly mean rainfall (RR: 2.86; 95% CI: 1.47 5.56). CONCLUSION: There was a substantial variation in the spatiotemporal distribution of H7N9 infection across different districts in Shanghai. Optimal temperature and rainfall may be one of the driving forces for H7N9. PMID- 25460663 TI - Thyroid hormones and deiodinase activity in plasma and tissues in relation to high levels of organohalogen contaminants in East Greenland polar bears (Ursus maritimus). AB - Previous studies have shown relationships between organohalogen contaminants (OHCs) and circulating levels of thyroid hormones (THs) in arctic wildlife. However, there is a lack of knowledge concerning the possible functional effects of OHCs on TH status in target tissues for TH-dependent activity. The relationships between circulating (plasma) levels of OHCs and various TH variables in plasma as well as in liver, muscle and kidney tissues from East Greenland sub-adult polar bears (Ursus maritimus) sampled in 2011 (n=7) were therefore investigated. The TH variables included 3.3',5.5'-tetraiodothyronine or thyroxine (T4), 3.3',5-triiodothyronine (T3) and type 1 (D1) and type 2 (D2) deiodinase activities. Principal component analysis (PCA) combined with correlation analyses demonstrated negative relationships between individual polychlorinated biphenyls (PCBs) and their hydroxylated (OH-) metabolites and T4 in both plasma and muscle. There were both positive and negative relationships between individual OHCs and D1 and D2 activities in muscle, liver and kidney tissues. In general, PCBs, OH-PCBs and polybrominated dipehenyl ethers (PBDEs) were positively correlated to D1 and D2 activities, whereas organochlorine pesticides and byproducts (OCPs) were negatively associated with D1 and D2 activities. These results support the hypothesis that OHCs can affect TH status and action in the target tissues of polar bears. TH levels and deiodinase activities in target tissues can be sensitive endpoints for exposure of TH disrupting compounds in arctic wildlife, and thus, tissue-specific responses in target organs should be further considered when assessing TH disruption in wildlife studies. PMID- 25460665 TI - Relationship between serum concentrations of persistent organic pollutants and markers of insulin resistance in a cohort of women with a history of gestational diabetes mellitus. AB - The aim of the present study was to assess the relationship between serum concentrations of several persistent organic pollutants and insulin resistance markers in a cohort of women with a history of gestational diabetes mellitus. ?POPs was computed as the sum of individual serum POP concentrations. No statistically significant associations were found between levels of any POP and fasting glucose. However, polychlorinated biphenyl (PCB) congeners 138 and 180 were positively associated with 2-h glucose levels and PCB 180 also with fasting immunoreactive insulin (IRI). We also found a positive association of p,p'- dichlorodiphenyldichloroethylene (p,p'- DDE), PCBs (138, 153, and 180), hexachlorobenzene, and ?POPs with 2-h IRI. Serum concentrations of PCBs (138, 153, and 180), hexachlorobenzene, and ?POPs were also positively associated with homeostasis model assessment (HOMA2-IR) levels. Moreover, p,p'- DDE, PCBs (138, 153 and 180), hexachlorobenzene, and ?POPs were negatively associated with Insulin Sensitivity Index (ISI-gly) levels. No significant association was found between glycated hemoglobin and the concentrations of any POP. The removal of women under blood glucose lowering treatment from the models strengthened most of the associations previously found for the whole population. Our findings suggest that exposure to certain POPs is a modifiable risk factor contributing to insulin resistance. PMID- 25460664 TI - Titanium dioxide nanoparticles induce an adaptive inflammatory response and invasion and proliferation of lung epithelial cells in chorioallantoic membrane. AB - Titanium dioxide nanoparticles (TiO2 NPs) studies have been performed using relatively high NPs concentration under acute exposure and limited studies have compared shape effects. We hypothesized that midterm exposure to low TiO2 NPs concentration in lung epithelial cells induces carcinogenic characteristics modulated partially by NPs shape. To test our hypothesis we synthesized NPs shaped as belts (TiO2-B) using TiO2 spheres (TiO2-SP) purchased from Sigma Aldrich Co. Then, lung epithelial A549 cells were low-exposed (10 ug/cm(2)) to both shapes during 7 days and internalization, cytokine release and invasive potential were determined. Results showed greater TiO2-B effect on agglomerates size, cell size and granularity than TiO2-SP. Agglomerates size in cell culture medium was 310 nm and 454 nm for TiO2-SP and TiO2-B, respectively; TiO2-SP and TiO2-B induced 23% and 70% cell size decrease, respectively, whilst TiO2-SP and TiO2-B induced 7 and 14-fold of granularity increase. NOx production was down regulated (31%) by TiO2-SP and up-regulated (70%) by TiO2-B. Both NPs induced a transient cytokine release (IL-2, IL-6, IL-8, IL-4, IFN-gamma, and TNF-alpha) after 4 days, but cytokines returned to basal levels in TiO2-SP exposed cells while TiO2-B induced a down-regulation after 7 days. Midterm exposure to both shapes of NPs induced capability to degrade cellular extracellular matrix components from chorioallantoic membrane and Ki-67 marker showed that TiO2-B had higher proliferative potential than TiO2-SP. We conclude that midterm exposure to low NPs concentration of NPs has an impact in the acquisition of new characteristics of exposed cells and NPs shape influences cellular outcome. PMID- 25460666 TI - Bioaccumulation of hydroxylated polychlorinated biphenyls and pentachlorophenol in the serum of northern elephant seal pups (Mirounga angustirostris). AB - Northern elephant seals (NES) (Mirounga angustirostris) from the Ano Nuevo State Reserve (CA, USA) were sampled at 1-, 4-, 7- and 10-week post-weaning. Concentrations of hydroxylated polychlorinated biphenyls (HO-PCBs) and their parent PCBs were measured in the serum of each individual. The SigmaHO-PCB concentrations in the serum increased significantly between early and late fast (from 282 +/- 20 to 529 +/- 31 pg/mL). This increase might result from a mobilisation of HO-PCBs transferred from the mother during gestation and/or lactation and stored in the pup's liver. Food deprivation has been shown to exacerbate biotransformation capacities in mammals, birds and fish. The HO-penta CBs was the predominant homologue group, followed by HO-hexa-CBs and HO-hepta CBs. No preferential pathway for the metabolism of HO-PCBs (HO-direct insertion or NIH-shift of a chlorine atom) could be evidenced. The concentrations of pentachlorophenol (PCP) in the serum of weaned NES increased from 103 +/- 7 pg/mL at early fast to 246 +/- 41 pg/mL at late fast, which is within the range of PCP concentrations usually encountered in marine mammals. PMID- 25460667 TI - Vulnerability to extreme heat by socio-demographic characteristics and area green space among the elderly in Michigan, 1990-2007. AB - OBJECTIVES: We examined how individual and area socio-demographic characteristics independently modified the extreme heat (EH)-mortality association among elderly residents of 8 Michigan cities, May-September, 1990-2007. METHODS: In a time stratified case-crossover design, we regressed cause-specific mortality against EH (indicator for 4-day mean, minimum, maximum or apparent temperature above 97th or 99 th percentiles). We examined effect modification with interactions between EH and personal marital status, age, race, sex and education and ZIP-code percent "non-green space" (National Land Cover Dataset), age, race, income, education, living alone, and housing age (U.S. Census). RESULTS: In models including multiple effect modifiers, the odds of cardiovascular mortality during EH (99 th percentile threshold) vs. non-EH were higher among non-married individuals (1.21, 95% CI=1.14-1.28 vs. 0.98, 95% CI=0.90-1.07 among married individuals) and individuals in ZIP codes with high (91%) non-green space (1.17, 95% CI=1.06-1.29 vs. 0.98, 95% CI=0.89-1.07 among individuals in ZIP codes with low (39%) non green space). Results suggested that housing age may also be an effect modifier. For the EH-respiratory mortality association, the results were inconsistent between temperature metrics and percentile thresholds of EH but largely insignificant. CONCLUSIONS: Green space, housing and social isolation may independently enhance elderly peoples' heat-related cardiovascular mortality vulnerability. Local adaptation efforts should target areas and populations at greater risk. PMID- 25460668 TI - Arsenic exposure, telomere length, and expression of telomere-related genes among Bangladeshi individuals. AB - BACKGROUND: Inorganic arsenic is a carcinogen whose mode of action may involve telomere dysfunction. Recent epidemiological studies suggest that chronic arsenic exposure is associated with longer telomeres and altered expression of telomere related genes in peripheral blood. In this study, we evaluated the association of urinary arsenic concentration with expression of telomere-related genes and telomere length in Bangladeshi individuals with a wide range of arsenic exposure through naturally contaminated drinking water. METHODS: We used linear regression models to estimate associations between urinary arsenic and array-based expression measures for 69 telomere related genes using mononuclear cell RNA samples from 1799 individuals. Association between arsenic exposure and a qPCR based telomere length measure was assessed among 167 individuals. RESULTS: Urinary arsenic was positively associated with expression of WRN, and negatively associated with TERF2, DKC1, TERF2IP and OBFC1 (all P<0.00035, Bonferroni corrected threshold). We detected interaction between urinary arsenic and arsenic metabolism efficiency in relation to expression of WRN (P for interaction =0.00008). In addition, we observed that very high arsenic exposure was associated with longer telomeres compared to very low exposure (P=0.02). DISCUSSION: Our findings suggest that arsenic's carcinogenic mode of action may involve alteration of telomere maintenance and/or telomere damage. This study extends our knowledge regarding the effect of arsenic on telomere length and expression of telomere-related genes. PMID- 25460670 TI - Urine osmolality in the US population: implications for environmental biomonitoring. AB - BACKGROUND: For many environmental chemicals, concentrations in spot urine samples are considered valid surrogates of exposure and internal dose. To correct for urine dilution, spot urine concentrations are commonly adjusted for urinary creatinine. There are, however, several concerns about the use of urine creatinine. While urine osmolality is an attractive alternative; its characteristics and determinants in the general population remain unknown. Our objective was to describe the determinants of urine osmolality and to contrast the difference between osmolality and creatinine in urine. METHODS: From the National Health and Nutrition Examination Survey (NHANES) (2009-2010), 10,769 participants aged 16 years or older with measured urine osmolality and creatinine were used in the analysis. Very dilute and very concentrated urine was defined as urine creatinine lower than 0.3g/l and higher than 3g/l, respectively. Linear and logistic regression analyses were performed to investigate the associations of interest. RESULTS: Urine osmolality and creatinine were highly correlated (Pearson correlation coefficient=0.75) and their respective median values were 648 mOsm/kg and 1.07 g/l. The prevalence of very dilute and very concentrated urine samples was 8.1% and 3.1%, respectively. Factors associated in the same direction with both urine osmolality and urine creatinine included age, sex, race, body mass index (BMI), hypertension, water intake, and blood osmolality. The magnitude of associations expressed as percent change was significantly stronger with creatinine than osmolality. Compared to urine creatinine, urine osmolality did not vary by diabetes status but was affected by daily total protein intake. Participants with chronic kidney disease (CKD) had significantly higher urine creatinine concentrations but lower urine osmolality. Both very dilute and concentrated urine were associated with a diverse array of sociodemographic, medical conditions, and dietary factors. For instance, females were approximately 3.3 times more likely to have urine over-dilution than male [the adjusted odds ratios (95% CI)=3.27 (2.10-5.10)]. CONCLUSION: Although the determinants of urine osmolality were generally similar to those of urine creatinine, the relative influence of socio-demographic and medical conditions was less on urine osmolality than on urine creatinine. Protocols for spot urine sample collection could recommend avoiding excessive and insufficient water intake before urine sampling to improve urine adequacy. The feasibility of adopting urine osmolality adjustment and water intake recommendations before providing spot urine samples for environmental biomonitoring merits further investigation. PMID- 25460669 TI - Use of amniotic fluid for determining pregnancies at risk of preterm birth and for studying diseases of potential environmental etiology. AB - Amniotic fluid (AF) is a biological medium uniquely suited for the study of early exposure of the human fetus to environmental contaminants acquired by the mother before and during pregnancy. Traditional diagnostic applications of AF have focused almost exclusively on the diagnosis of genetic aberrations such as Trisomy-21 and on heritable diseases in high-risk pregnancies. Since more than 50 anthropogenic compounds have been detected in AF, there is considerable potential in utilizing fetal protein biomarkers as indicators of health effects related to prenatal toxic exposure. Here, we focus on preterm birth (PTB) to illustrate opportunities and limitations of using AF as a diagnostic matrix. Representing a pervasive public health challenge worldwide, PTB cannot be managed simply by improving hygiene and broadening access to healthcare. This is illustrated by 15 year increases of PTB in the U.S. from 1989 to 2004. AF is uniquely suited as a matrix for early detection of the association between fetal exposures and PTB due to its fetal origin and the fact that it is sampled from women who are at higher risk of PTB. This critical review shows the occurrence in AF of a number of xenobiotics, including endocrine-disrupting compounds (EDCs), which are known or may reasonably be expected to shorten fetal gestation. It is not yet known whether EDCs, including bisphenol A, phytoestrogens, and polychlorinated biphenyls (PCBs), can affect the expression of proteins considered viable or potential biomarkers for the onset of PTB. As such, the diagnostic value of AF is broad and has not yet been fully explored for prenatal diagnosis of pregnancies at risk from toxic, environmental exposures and for the elucidation of mechanisms underlying important public health challenges including PTB. PMID- 25460672 TI - Using real-time syndromic surveillance systems to help explore the acute impact of the air pollution incident of March/April 2014 in England. AB - During March and early April 2014 there was widespread poor air quality across the United Kingdom. Public Health England used existing syndromic surveillance systems to monitor community health during the period. Short lived statistically significant rises in a variety of respiratory conditions, including asthma and wheeze, were detected. This incident has demonstrated the value of real-time syndromic surveillance systems, during an air pollution episode, for helping to explore the impact of poor air quality on community health in real-time. PMID- 25460671 TI - Cardiorespiratory treatments as modifiers of the relationship between particulate matter and health: a case-only analysis on hospitalized patients in Italy. AB - BACKGROUND: A few panel and toxicological studies suggest that health effects of particulate matter (PM) might be modified by medication intake, but whether this modification is confirmed in the general population or for more serious outcomes is still unknown. OBJECTIVES: We carried out a population-based pilot study in order to assess how pre-hospitalization medical treatments modify the relationship between PM<10 MUm in aerodynamic diameter (PM10) and the risk of cardiorespiratory admission. METHODS: We gathered information on hospitalizations for cardiorespiratory causes, together with pre-admission pharmacological treatments, that occurred during 2005 in seven cities located in Lombardy (Northern Italy). City-specific PM10 concentrations were measured at fixed monitoring stations. Each treatment of interest was analyzed separately through a case-only approach, using generalized additive models accounting for sex, age, comorbidities, temperature and simultaneous intake of other drugs. Analyses were stratified by season and, if useful, by age and sex. RESULTS: Our results showed a higher effect size for PM10 on respiratory admissions in subjects treated with theophylline (Odds Ratio (OR) of treatment for an increment of 10 MUg/m(3) in PM10 concentration: 1.119; 95% Confidence Interval (CI): 1.013-1.237), while for cardiovascular admissions treatment with cardiac therapy (OR: 0.967, 95% CI: 0.940-0.995) and lipid modifying agents (OR: 0.962, 95% CI: 0.931-0.995) emerged as a protective factor, especially during the warm season. Evidence of a protective effect against the pollutant was found for glucocorticoids and respiratory admissions. CONCLUSIONS: Our study showed that the treatment with cardiac therapy and lipid modifying agents might mitigate the effect of PM10 on cardiovascular health, while the use of theophylline seems to enhance the effect of the pollutant, possibly due to confounding by indication. It is desirable to extend the analyses to a larger population. PMID- 25460674 TI - Brief report: preliminary evidence that co-rumination fosters adolescents' depression risk by increasing rumination. AB - Mounting research shows that the tendency to co-ruminate with peers regarding ongoing problems increases adolescents' depression risk; however, the means by which this interpersonal process fosters risk has not been identified. This said, theorists have proposed that co-rumination increases depression risk, in part, by increasing one's tendency to ruminate when alone. We tested this hypothesis in a study of 201 high-school freshmen who completed two assessments, six months apart. Supporting the proposed model, co-rumination predicted prospective increases in rumination and rumination predicted increases in depressive symptoms. The direct effect of co-rumination on depressive symptom change was not significant. Results indicate that co-rumination with friends may serve to increase rumination, which in turn increases depression risk. PMID- 25460675 TI - What do mothers want to know about teens' activities? Levels, trajectories, and correlates. AB - Middle class mothers (n = 169) of middle adolescents (M = 15.69 years old) in the U.S. rated how much they want to know and responded qualitatively about what they "always" and "never" want to know about adolescents' risky prudential (e.g., drinking alcohol, using illegal drugs), personal (e.g., teens' private conversations), and multifaceted (involving overlapping prudential and personal concerns) activities. Latent growth curve modeling over one year showed that mothers wanted to know most about prudential, less about multifaceted, and least about personal activities; wanting to know declined over time for each type of activity, but less for prudential than for other activities. With teen problem behavior controlled, psychologically controlling parenting, supportive and negative interactions with teens, knowledge of adolescents' activities, and teens' age were associated with individual differences in mothers' initial ratings and trajectories of wanting to know, although results varied by domain and were moderated by teen gender. PMID- 25460673 TI - Regional PM2.5 and asthma morbidity in an agricultural community: a panel study. AB - BACKGROUND: Elevated pediatric asthma morbidity has been observed in rural US communities, but the role of the ambient environment in exacerbating rural asthma is poorly understood. OBJECTIVES: To investigate associations between particulate matter less than 2.5 MUm in diameter (PM2.5) and pediatric asthma exacerbations in an agricultural community of Washington State. METHODS: School-aged children with asthma (n=58) were followed for up to 25 months with repeated measures of respiratory health. Asthma symptoms and quick-relief medication use were assessed biweekly through phone administered surveys (n=2023 interviews). In addition, subjects used home peak flow meters on a daily basis to measure forced expiratory volume in one second (FEV1) (n=7830 measurements). Regional PM2.5 was measured at a single air monitor located centrally in the study region. To assess relationships between PM2.5 and these outcomes we used linear regression with generalized estimating equations, adjusting for meteorological and temporal confounders. Effect modification by atopy was explored as well. RESULTS: An interquartile increase (IQR) in weekly PM2.5 of 6.7 MUg/m(3) was associated with an increase in reported asthma symptoms Specific symptoms including wheezing, limitation of activities, and nighttime waking displayed the strongest associations. FEV1 as a percent of predicted decreased by 0.9% (95%CI: -1.8, 0.0) for an IQR increase in PM2.5 one day prior, and by 1.4% (95%CI: -2.7, -0.2) when restricted to children with atopic asthma. CONCLUSIONS: This study provides evidence that PM2.5 in an agricultural setting contributes to elevated asthma morbidity. Further work on identifying and mitigating sources of PM2.5 in the area is warranted. PMID- 25460677 TI - Co-rumination via cellphone moderates the association of perceived interpersonal stress and psychosocial well-being in emerging adults. AB - Adolescents' and emerging adults' social interactions increasingly revolve around cellphone use, but little research has investigated the psychological properties of cellphone interactions. The current study explored co-rumination via cellphone; that is, the use of cellphone functions to excessively communicate about problems or negative feelings. Face-to-face co-rumination and co-rumination via cellphone were examined as potential moderators of the association between perceived interpersonal stress and psychosocial well-being (i.e., positive mental health and social burnout) in a sample of 142 college students. Face-to-face co rumination was not a moderator. However, co-rumination via cellphone was a significant moderator such that higher levels of perceived interpersonal stress were associated with lower levels of well-being only among college students who reported higher levels of co-rumination via cellphone. Co-rumination via cellphone should be further investigated to elucidate its developmental trajectory and mental health correlates. PMID- 25460676 TI - The role of feared possible selves in the relationship between peer influence and delinquency. AB - This study explores the impact of a feared delinquent possible self on the relationship between exposure to negative peer behaviors and violent and non violent self-reported delinquency. Previous research strongly supports that deviant peers influence adolescents' delinquent behavior. Yet, few studies have explored intrapersonal factors that may moderate this influence. Possible selves include what one hopes, expects and fears becoming and are believed to motivate behavior. Thus, it was hypothesized that adolescents who were exposed to deviant peers and also feared engaging in delinquency would be more likely to self-report delinquency. Seventh grade students (n = 176) identified feared possible selves in the future, their exposure to negative peer behavior and self-reported violent and non-violent delinquent behavior. Findings suggest that exposure to negative peer behavior is associated with self-reported delinquent behavior. For violent behavior, possessing a feared delinquent possible self moderates this relationship. Implications and suggestions for future research are discussed. PMID- 25460678 TI - Brief report: Danish emerging adults' conceptions of adulthood. AB - Four hundred Danish emerging adults ages 17-29 were surveyed regarding their conceptions of adulthood and their self-assessments of their adult status. A majority of the 17-24-year-olds and nearly half the 25-29-year-olds viewed themselves as being adults in some ways but not others. Participants reported feeling most adult when with co-workers or romantic partners, and least adult with mothers, fathers, or friends. The most widely-endorsed criteria for adulthood were accepting responsibility for one's self, making independent decisions, and becoming financially independent. Among the least-endorsed criteria were the traditional transition events of entering marriage and parenthood, as well as "avoid becoming drunk." PMID- 25460679 TI - Brief report: "spiders-No, puppies-Go", introducing a novel Go NoGo task tested in inner city adolescents at risk for poor impulse control. PMID- 25460680 TI - Screening mental health problems during adolescence: psychometric properties of the Spanish version of the Strengths and Difficulties Questionnaire. AB - The main purpose of the present study was to test the psychometric properties of the Strength and Difficulties Questionnaire (SDQ), self-reported version, in Spanish adolescents, introducing a five-point Likert response scale. The sample consisted of 1474 adolescents with a mean age of 15.92 years (SD = 1.18). The level of internal consistency of the SDQ Total score was .75, ranging from .56 to .71 for the subscales. Results from exploratory factor analysis revealed a three factor structure as the most satisfactory. Confirmatory factor analyses showed that the five-factor model (with modifications) displayed better goodness of-fit indices than the other hypothetical dimensional models tested. Furthermore, strong measurement invariance by age and partial measurement invariance by gender was supported. The study of the psychometric properties confirms that the Spanish version of the SDQ, self-reported form, is a useful tool for the screening of emotional and behavioural problems in adolescents. PMID- 25460681 TI - Development of emotional autonomy from adolescence to young adulthood in Spain. AB - The main objective of this study was to learn whether emotional autonomy is truly part of a developmental stage for Spanish adolescents and young adults or if it is an indicator of difficult family relationships. Using a longitudinal design, a sample of ninety young people was followed for ten years, from their initial adolescence until their first years of adulthood. At four observation points, the participants completed various questionnaires to evaluate their emotional autonomy, the cohesion in their family relationships and their life satisfaction. There were no gender differences in the development of emotional autonomy. Family cohesion and life satisfaction showed significant negative associations with emotional autonomy and these associations became more pronounced as participants moved from adolescence into adulthood. Based on our results, emotional autonomy from parents does not seem to be a developmental stage taking place during adolescence, but rather, an indicator of difficult family relationships. PMID- 25460682 TI - Alginate/sodium caseinate aqueous-core capsules: a pH-responsive matrix. AB - HYPOTHESIS: Alginate capsules have several applications. Their functionality depends considerably on their permeability, chemical and mechanical stability. Consequently, the creation of composite system by addition of further components is expected to control mechanical and release properties of alginate capsules. EXPERIMENTS: Alginate and alginate-sodium caseinate composite liquid-core capsules were prepared by a simple extrusion. The influence of the preparation pH and sodium caseinate concentration on capsules physico-chemical properties was investigated. FINDINGS: Results showed that sodium caseinate influenced significantly capsules properties. As regards to the membrane mechanical stability, composite capsules prepared at pH below the isoelectric point of sodium caseinate exhibited the highest surface Young's modulus, increasing with protein content, explained by potential electrostatic interactions between sodium caseinate amino-groups and alginate carboxylic group. The kinetic of cochineal red A release changed significantly for composite capsules and showed a pH responsive release. Sodium caseinate-dye mixture studied by absorbance and fluorescence spectroscopy confirmed complex formation at pH 2 by electrostatic interactions between sodium caseinate tryptophan residues and cochineal red sulfonate-groups. Consequently, the release mechanism was explained by membrane adsorption process. This global approach is useful to control release mechanism from macro and micro-capsules by incorporating guest molecules which can interact with the entrapped molecule under specific conditions. PMID- 25460683 TI - Monodisperse poly(2-methylaniline) coated polystyrene core-shell microspheres fabricated by controlled releasing process and their electrorheological stimuli response under electric fields. AB - A core-shell structured electro-responsive electrorheological (ER) particle system comprised of monodisperse poly(2-methylaniline)-coated polystyrene (PS/PMAN) microspheres was fabricated by applying a controlled swelling-releasing technique to pre-fabricated micron-sized PS seeds using a dispersion polymerization method. Compact wrapping of the PS microparticles with semiconducting PMAN without a de-doping process was examined by scanning electron microscopy and transmission electron microscopy. Fourier-transform infrared spectroscopy and thermogravimetric analysis also confirmed the chemical composition and thermal stability of the particles, respectively. Rheological characteristics of the PS/PMAN microsphere based ER fluid dispersed in silicone oil at various electric field strengths revealed a typical ER response under both steady shear flow and dynamic oscillation, demonstrating its mechanism of a conductivity model with a slope of 1.5. PMID- 25460684 TI - Moderate the adsorption of cationic surfactant on gold surface by mixing with sparingly soluble anionic surfactant. AB - Surfactants with amine groups are often used in the nanoparticle synthesis due to the high affinity with Au atoms. The match of charges of a capping reagent with Au has significant influence on structures in nanoparticle synthesis. Thus we studied the adsorption of a catanionic surfactant system on Au surface. The surfactants used in the study are bis[[(amidoethyl)carbamoyl]ethyl]octadecylamine (C18N3) and arachidic acid. Three combinations of the surfactants were studied with regard to the protonation state of the amine groups and the match of charges of the surfactant headgroup. The morphology of the surfactant mixtures changes from high-curvature aggregates to low-curvature with increasing the molar ratio of arachidic acid in the mixtures or the pH of the surfactant solutions. The adsorption of the mixed surfactant systems was studied by means of scanning electron microscopy (SEM), quartz crystal microbalance (QCM) and cyclic voltammetry (CV). The results revealed that the homogeneity and the compactness of the adsorbed layer on a gold surface were increased with the molar ratio of arachidic acid in the complexes. Furthermore, we may obtain the construction of the film of the mixed surfactant on gold surface using the result obtained by QCM. PMID- 25460685 TI - Role of ion-pair interactions on asphaltene stabilization by alkylbenzenesulfonic acids. AB - The dispersion of asphaltenes by dodecylbenzenesulfonic acid (DBSA) has been the subject of several studies in the past. However, it is unclear how these interactions affect the structure of asphaltenes and why asphaltene aggregates are larger in the presence of ionic DBSA. The main goal of this study was to address these points using a combination of high-resolution transmission electron microscopy (HRTEM) and molecular dynamics (MD) simulations. Another objective was to compare ionic DBSA (i.e., dodecylbenzenesulfonate or DBS(-)) to nonionic amphiphiles such as alkylphenols. A striking similarity between dodecylbenzenesulfonate and alkylphenols was that both favored the formation of filamentary rather than globular asphaltene flocculates. However the mechanism by which those filaments formed was very different. Two strong electrostatic interactions between DBSA and asphaltenes were found: (i) those between protonated asphaltenes (i.e., AH(+)) and DBS(-) molecules, which were fifteen times stronger than asphaltene-alkylphenol interactions, and (ii) those between two asphaltene-dispersant pairs (i.e., AH(+)-DBS(-) ion pairs), which did not exist with alkylphenols. These interactions promoted the formation of large and compact asphaltene flocculates, as compared to small and loose ones formed without DBSA. Flocculates with DBSA could further bind to each other through ion pair interactions. The binding occurred in series (generating long filaments) or in parallel (generating lateral ramifications). However the series configuration was energetically favored due to less steric effects generated by the side aliphatic chains of asphaltenes and DBSA. PMID- 25460686 TI - Polyethylenimine coated bacterial cellulose nanofiber membrane and application as adsorbent and catalyst. AB - Bacterial cellulose (BC) nanofiber membranes were simply aminalized by a flush coating and post-crosslinking method. Firstly, wet BC membranes were flushed through by an aqueous solution of polyethylenimine (PEI) and glycerol diglycidyl ether (GDE) under vacuum suction, then further heated up to 70 degrees C to crosslink the resultant coating on the surface of the nanofibers. The PEI coated bacterial cellulose (BC@PEI) nanofiber membrane presented excellent adsorption performance for Cu(2+) and Pb(2+) ions from aqueous solutions. Desorption of these ions was achieved using ethylene diamine tetraacetic acid treatment. This cycle of adsorption and desorption was repeated for several times with good remain adsorption performance (over 90%). Furthermore, the adsorbed Cu(2+) ions can be reduced to copper nanoparticles, and showed excellent catalytic performance for methylene blue reduction in aqueous solution. The catalytic performance can remained after several times of usage. PMID- 25460687 TI - Microwave-assisted solvothermal synthesis and upconversion luminescence of CaF2:Yb3+/Er3+ nanocrystals. AB - Water-dispersible CaF2 and Yb(3+)/Er(3+) codoped CaF2 (CaF2:Yb(3+)/Er(3+)) nanocrystals with different sizes and different Yb(3+) and Er(3+) dopant concentrations were synthesized using ionic liquid 1-n-butyl-3-methyl imidazolium tetrafluoroborate as a fluorine source by the rapid microwave-assisted solvothermal method. It was found that the morphology, size and crystallinity of CaF2:Yb(3+)/Er(3+) nanocrystals could be adjusted by using adenosine 5' triphosphate disodium salt (ATP). Yb(3+) and Er(3+) ions were doped into CaF2 nanocrystals to enable upconversion luminescence emission, and the as-prepared CaF2:Yb(3+)/Er(3+) samples exhibited upconversion luminescence upon excitation at 980 nm. Confocal laser scanning microscopy images showed that the CaF2:Yb(3+)/Er(3+) nanocrystals could be used for efficient labeling of human gastric carcinoma cells. Moreover, in vitro cytotoxicity experiments indicated that the as-prepared CaF2:Yb(3+)/Er(3+) nanocrystals had essentially little cytotoxicity. These results indicate that the as-prepared CaF2:Yb(3+)/Er(3+) nanocrystals are promising for the application as a luminescent label material in biological imaging. PMID- 25460688 TI - Phosphorus-containing flame retardant modified layered double hydroxides and their applications on polylactide film with good transparency. AB - Polylactide (PLA)/layered double hydroxide (LDH) films with good flame retardant property and transparency were synthesized by solution exfoliation and film casting method. The organic-inorganic interfacial interaction between PLA and NiAl-LDH was carefully modified by 2-carboxylethyl-phenyl-phosphinic acid (CEPPA) to well solve the dispersion problem of NiAl-LDH nanolayers and get enhanced flame retardancy of PLA composites. The results showed the NiAl-LDH/CEPPA (LC) nanolayers had exfoliated structures and were homogenously dispersed in PLA matrixes. All the PLA/LDH films had good transparency even LC content was up to 10 wt%. The PLA/LDH films absorbed the ultraviolet light, which alleviates the embrittlement of PLA films in the using procedure. The flame retardant effect characterized by microscale combustion calorimeter was observed when LC contents increased. The total heat release value of the sample with 10 wt% LC decreased to 9.7 kJ/g from 12.0 kJ/g of virgin PLA. PMID- 25460689 TI - Enhanced surface imprinting of lysozyme over a new kind of magnetic chitosan submicrospheres. AB - Surface protein imprinting over nano- or micron-sized substrates is an effective approach for improving the biomacromolecule mass transfer and rebinding capacity. For achieving high recognition performance, it is necessary to introduce certain functional groups onto the surface of the support materials which can interact with the template protein. Herein, we report a surface protein imprinting approach using a new kind of core-shell magnetic chitosan submicrospheres as the supports. The surface of these magnetic chitosan particles is tethered with uncross-linked chitosan chains, hence bearing plenty of amino and hydroxyl groups, where a large amount of functional ligands can be readily coupled for capturing of the protein template. With lysozyme as a model print protein, the magnetic supports were functionalized with maleic acid and then coated with imprinted polymer layers. The resulting imprinted microspheres show significantly selective rebinding for lysozyme. In particular, they exhibit a specific rebinding capacity about three times higher than achieved with our previous lysozyme-imprinted particles synthesized in similar way but with maleic acid modified silica nanoparticles as the supports. This can be attributed to the much higher template binding capacity to the modified magnetic chitosan submicrospheres. Also, the resultant imprinted particles can be easily collected by a magnet. Therefore, such kind of chitosan submicrospheres may be a versatile carrier for constructing high-capacity and magnetically recyclable surface protein-imprinted particles. PMID- 25460690 TI - Fluoride removal mechanism of bayerite/boehmite nanocomposites: roles of the surface hydroxyl groups and the nitrate anions. AB - Three-dimensional feather like bayerite/boehmite nanocomposites were synthesized by a facile one-pot hydrothermal method. The obtained nanocomposites were characterized by X-ray diffraction, field emission scanning electron microscopy, transmission electron microscopy, and nitrogen adsorption-desorption isotherms. The removal properties toward fluoride were investigated, including adsorption kinetics, adsorption isotherm, and influences of pH and coexisting anions. The maximal adsorption capacity was 56.80 mg g(-1) at pH 7.0, which is favorable compared to those reported in the literature using other adsorbents. The coexisting of sulfate and bicarbonate inhibited the fluoride removal especially at high concentrations. Furthermore, the removal mechanism was revealed by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The results suggest that both of the surface hydroxyl groups and the nitrate anions were participated in the ion-exchange process. PMID- 25460691 TI - Orientation of charged clay nanotubes in evaporating droplet meniscus. AB - During drying, an aqueous suspension of strongly charged halloysite clay nanotubes concentrates at the edge of the droplet ("coffee-ring" effect) which provides alignment of the tubes along the liquid-substrate contact line. First, the surface charge of the nanotubes was enhanced by polyanion adsorption inside of the lumen to compensate for the internal positive charges. This increased the magnitude of the xi-potential of the tubes from -36 to -81 mV and stabilized the colloids. Then, colloidal halloysite was dropped onto the substrate, dried at 65 degrees C and after a concentration of ~0.05 mg mL(-1) was reached, the alignment of nanotubes occurred starting from the droplet edges. The process was described with Onsager's theory, in which longer nanorods, which have higher surface charge, give better ordering after a critical concentration is reached. This study indicates a new application of halloysite clay nanotubes in polymeric composites with anisotropic properties, microchannel orientation, and production of coatings with aligned nanotubes. PMID- 25460692 TI - Volatile fluorinated nanoemulsions: a chemical route to controlled delivery of inhalation anesthesia. AB - Novel dispersions of the volatile inhalation anesthetic sevoflurane have been formulated that can provide controlled, sustainable release of anesthetic over clinically useful timescales. The emulsions can be simply formed with manual shaking, reproducibly yielding droplets of the order of 250 nm diameter, i.e. within the nanoemulsion range. Using a custom flow-rig, release of anesthetic gas from the emulsion has been evaluated, and clinically useful levels achieved through appropriate stirring of the formulation. Stirring can also be used to temporarily increase or decrease the amount of anesthetic released. Once consideration of the unusual nature of the fluorinated systems (phase separation by sedimentation rather than creaming), and the highly perturbed environment of their evaluation (under stirring and flow of gas), the observed behavior regarding sevoflurane evaporation can be reasonably well explained by existing theoretical models. Links between anesthetic release and emulsion structure have been defined, providing the basis for future development. PMID- 25460693 TI - Adsorption, kinetic and thermodynamic studies for manganese extraction from aqueous medium using mesoporous silica. AB - This paper describes studies of functionalized mesoporous silica employed as adsorbent for Mn(II) from aqueous solutions. The surface area of MCM-41 and diethylenetriamine functionalized-MCM-41 used in this study were 760 and 318 m(2) g(-1) (N2 adsorption). A strong dependence on pH in the Mn(II) adsorption capacity and best results were obtained at pH 6.5-7. The adsorption onto the diethylenetriamine functionalized-MCM-41 followed the pseudo-second-order kinetic model and the highest reaction rate 0.324 min(-1) was observed at low initial concentration 10 ppm. The equilibrium data showed excellent correlation with the Langmuir isotherm model and the maximum adsorption capacity of Mn(II) reached 88.9 mg/g for DETA-MCM-41 indicating that the adsorption occurs on a homogeneous surface by monolayer sorption without interaction between the adsorbed ions. These data contribute to the understanding of mechanisms involved in mesoporous silica and provide some practical clues to improve the adsorption efficiency (uptake capacity and kinetics) of Mn(II) ions. PMID- 25460694 TI - Dye removal from aqueous solution by cobalt-nano particles decorated aluminum silicate: kinetic, thermodynamic and mechanism studies. AB - This article describes the preparation of a nanoadsorbent containing Co nanoparticles decorated functionalized SiO2-Al2O3 mixed-oxides as a scavenger toward removal of methyl orange. SiO2-Al2O3 mixed-oxides were functionalized with pyridine-2-carbaldehyde and thereafter, in the next step, Co-nanoparticle was prepared over the modified mixed-oxides. The as-prepared nanoadsorbent was characterized by Fourier transform infrared (FTIR), UV-visible diffuse reflectance spectra (UV-vis DRS), inductively coupled plasma atomic emission spectroscopy (ICP-AES), Brunauer-Emmett-Teller (BET), transmission electron microscopy (TEM), electron paramagnetic resonance (EPR), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Results showed that Co nanoparticle with average size of about 5-25 nm was immobilized successfully on the surface of modified mixed-oxides and was widely dispersed. EPR and CV of Si/Al-PAEA=PyCA@CoNP confirmed that most of the covalently bond active sites of the nano-adsorbent are in the form of Co(II) ions. The supported cobalt is a suitable and efficient adsorbent for the removal of methyl orange from aqueous solution. The heterogeneous Co-NPs were found to be effective adsorbent for the removal of methyl orange ions from solution. The adsorption process was spontaneous and endothermic in nature and followed pseudo-second-order kinetic model. The CV and EIS of the Co-NPs-MO indicates an easily oxidizable environment, this being in agreement with the FTIR data, where the electron density at Co-NPs is higher due to the presence of a donor-electron ligand (methyl orange), that is, reduction of Co-NPs from +3 to +2 oxidation state is more favored. PMID- 25460695 TI - Nitrate uptake improvement by modified activated carbons developed from two species of pine cones. AB - Activated carbons from two species of pine cones (Pinus canariensis and Cupressus sempervirens) were prepared by phosphoric acid activation and tested for the removal of nitrate ions from aqueous solution. To investigate the feasibility of improving their nitrate adsorption capacity, two different post-treatments-a thermal treatment and a treatment with saturated urea solution-were also applied to the prepared activated carbons. Comparison of the treated and untreated activated carbons showed that both post-treatments improved the nitrate adsorption performance more than twice. The maximum adsorption capacity, as evaluated from determination of the adsorption isotherms for the P. canariensis based carbons, and their proper representation by the Langmuir model, demonstrated that the post-treatment with the urea solution led to activated carbons with increased nitrate removal effectiveness, even superior to other reported results. Enhancements in their adsorption capacity could be mainly ascribed to higher contents of nitrogen and basic functional groups, whereas porous structure of the activated carbons did not seem to play a key role in the nitrate uptake. PMID- 25460696 TI - Explaining the growth behavior of surfactant micelles. AB - The growth behavior of surfactant micelles has been investigated from a theoretical point of view. It is demonstrated that predictions deduced from the spherocylindrical micelle model, which considers micelles that are only able to grow in the length direction, are inconsistent with experimental measurements. Accordingly, the rise in aggregation numbers above a certain concentration, roughly corresponding to the second critical micelle concentration, appears to be much stronger than predicted by the spherocylindrical micelle model. On the other hand, predictions deduced from the general micelle model, which considers micelles that are able to grow with respect to both width and length, show excellent agreement with experimental observations. The latter theory is based on bending elasticity and it is demonstrated that the associated three parameters spontaneous curvature, bending rigidity and saddle-splay constant may all be determined for a micellar system from experimental measurements of the aggregation number as a function of surfactant concentration. The three parameters turn out to influence the appearance of a micellar growth curve rather differently. In accordance, the location of the second cmc is mainly determined by the saddle-splay constant and the bending rigidity. The shape of the growth curve, when going from the region of weakly growing micelles at low surfactant concentrations to strongly growing micelles above the second cmc, is mainly influenced by the bending rigidity. PMID- 25460697 TI - 2-Hydroxypropyltrimethylammonium xylan adsorption onto rod-like cellulose nanocrystal. AB - Chemical incompatibility and relatively weak interaction between lignocellulosic fibers and synthetic polymers have made studies of wood fiber-thermoplastic composite more challenging. In this study, adsorption of 2 hydroxypropyltrimethylammonium xylans onto rod-like cellulose nanocrystals are investigated by zeta-potential measurements, and polarized and depolarized dynamic light scattering as a factor for better understanding of lignocellulosic fibers and cellulose nanocrystals. Zeta-potential measurements show xylan derivative adsorption onto cellulose nanocrystals. Decay time distributions of the ternary system and binary system from dynamic light scattering show that aggregates exist in the binary system and they disappear in the ternary system. At low 2-hydroxypropyltrimethylammonium xylan concentrations relative to that of cellulose nanocrystal, xylan derivatives adsorbed onto some of the cellulose nanocrystal. Hence, more xylan derivatives adsorbed onto cellulose nanocrystal increased with increasing xylan derivative concentration. Also, the concentration dependence of the ratio of the rotational diffusion coefficient to the translational diffusion coefficient revealed a strong adsorptive interaction between xylan derivatives and the cellulose nanocrystals. PMID- 25460698 TI - Effects of ionic concentration gradient on electroosmotic flow mixing in a microchannel. AB - Effects of ionic concentration gradient on electroosmotic flow (EOF) mixing of one stream of a high concentration electrolyte solution with a stream of a low concentration electrolyte solution in a microchannel are investigated numerically. The concentration field, flow field and electric field are strongly coupled via concentration dependent zeta potential, dielectric constant and electric conductivity. The results show that the electric field and the flow velocity are non-uniform when the concentration dependence of these parameters is taken into consideration. It is also found that when the ionic concentration of the electrolyte solution is higher than 1M, the electrolyte solution essentially cannot enter the channel due to the extremely low electroosmotic flow mobility. The effects of the concentration dependence of zeta potential, dielectric constant and electric conductivity on electroosmotic flow mixing are studied. PMID- 25460699 TI - Drop evaporation on superhydrophobic PTFE surfaces driven by contact line dynamics. AB - In the present study, we experimentally study the evaporation modes and kinetics of sessile drops of water on highly hydrophobic surfaces (contact angle ~160 degrees ), heated to temperatures ranging between 40 degrees and 70 degrees C. These surfaces were initially constructed by means of controlled tailoring of polytetrafluoroethylene (PTFE) substrates. The evaporation of droplets was observed to occur in three distinct phases, which were the same for the different substrate temperatures. The drops started to evaporate in the constant contact radius (CCR) mode, then switched to a more complex mode characterized by a set of stick-slip events accompanied by a decrease in contact angle, and finally shifted to a mixed mode in which the contact radius and contact angle decreased simultaneously until the drops had completely evaporated. It is shown that in the case of superhydrophobic surfaces, the energy barriers (per unit length) associated with the stick-slip motion of a drop ranges in the nJ m(-1) scale. Furthermore, analysis of the evaporation rates, determined from experimental data show that, even in the CCR mode, a linear relationship between V(2/3) and the evaporation time is verified. The values of the evaporation rate constants are found to be higher in the pinned contact line regime (the CCR mode) than in the moving contact line regime. This behavior is attributed to the drop's higher surface to volume ratio in the CCR mode. PMID- 25460700 TI - Experimental investigation of virus and clay particles cotransport in partially saturated columns packed with glass beads. AB - Suspended clay particles in groundwater can play a significant role as carriers of viruses, because, depending on the physicochemical conditions, clay particles may facilitate or hinder the mobility of viruses. This experimental study examines the effects of clay colloids on the transport of viruses in variably saturated porous media. All cotransport experiments were conducted in both saturated and partially saturated columns packed with glass beads, using bacteriophages MS2 and PhiX174 as model viruses, and kaolinite (KGa-1b) and montmorillonite (STx-1b) as model clay colloids. The various experimental collision efficiencies were determined using the classical colloid filtration theory. The experimental data indicated that the mass recovery of viruses and clay colloids decreased as the water saturation decreased. Temporal moments of the various breakthrough concentrations collected, suggested that the presence of clays significantly influenced virus transport and irreversible deposition onto glass beads. The mass recovery of both viruses, based on total effluent virus concentrations, was shown to reduce in the presence of suspended clay particles. Furthermore, the transport of suspended virus and clay-virus particles was retarded, compared to the conservative tracer. Under unsaturated conditions both clay particles facilitated the transport of PhiX174, while hindered the transport of MS2. Moreover, the surface properties of viruses, clays and glass beads were employed for the construction of classical DLVO and capillary potential energy profiles, and the results suggested that capillary forces play a significant role on colloid retention. It was estimated that the capillary potential energy of MS2 is lower than that of PhiX174, and the capillary potential energy of KGa-1b is lower than that of STx-1b, assuming that the protrusion distance through the water film is the same for each pair of particles. Moreover, the capillary potential energy is several orders of magnitude greater than the DLVO potential energy. PMID- 25460701 TI - Electrocatalytic activity of bimetallic Au-Pd nanoparticles in the presence of cobalt tetraaminophthalocyanine. AB - Au and Pd nanoparticles were individually or together electrodeposited on top of polymerized cobalt tetraaminophthalocyanine (poly-CoTAPc). When Pd and Au nanoparticles are co-deposited together, the electrode is denoted as Au-Pd (co deposited)/poly-CoTAPc-GCE. X-ray photoelectron spectroscopy (XPS) was used to show the successful deposition of AuNPs, PdNPs and Au-Pd (co-deposited). The scanning electrochemical microscopy showed that Au-Pd (co-deposited)/poly-CoTAPc GCE (with current range of 9.5-13.5 MUA) was more conducting than Au-Pd (co deposited)-GCE (with current range of 8-12 MUA). Electrochemical impedance spectroscopy (EIS) showed that there was less resistance to charge transfer for Au-Pd (co-deposited)/poly-CoTAPc-GCE compared to the rest of the electrodes. Au Pd (co-deposited)/poly-CoTAPc-GCE showed the best activity for the electrooxidation of hydrazine in terms of limit of detection (0.5 MUM), hence shows promise as an electrocatalyst for electrooxidation of hydrazine. PMID- 25460702 TI - Dysprosium, holmium and erbium ions doped indium oxide nanotubes as photoanodes for dye sensitized solar cells and improved device performance. AB - In this work, rare earth (RE) ion RE(3+) (RE(3+)=Dy(3+), Ho(3+) and Er(3+)) doped and undoped In2O3 nanotubes are synthesized by the electrospinning method and the band gap of In2O3 is systemically controlled, depending on the order of doped elements. Dye-sensitized solar cells (DSSCs) based on In2O3:RE(3+) nanotubes are also fabricated, and significantly improved performance of In2O3-DSSC is observed due to the modulation of the band gap, larger recombination charge transfer resistance and longer electron lifetime. PMID- 25460703 TI - Capillary meniscus dynamometry-method for determining the surface tension of drops and bubbles with isotropic and anisotropic surface stress distributions. AB - The stresses acting in interfacial adsorption layers with surface shear elasticity are, in general, anisotropic and non-uniform. If a pendant drop or buoyant bubble is covered with such elastic layer, the components of surface tension acting along the "meridians" and "parallels", sigma(s) and sigma(phi), can be different and, then, the conventional drop shape analysis (DSA) is inapplicable. Here, a method for determining sigma(s) and sigma(phi) is developed for axisymmetric menisci. This method, called 'capillary meniscus dynamometry' (CMD), is based on processing data for the digitized drop/bubble profile and capillary pressure. The principle of the CMD procedure for data processing is essentially different from that of DSA. Applying the tangential and normal surface stress balance equations, sigma(s) and sigma(phi) are determined in each interfacial point without using any rheological model. The computational procedure is fast and could be used in real time, during a given process. The method is applied to determine sigma(s) and sigma(phi) for bubbles and drops formed on the tip of a capillary immersed in solutions of the protein HFBII hydrophobin. Upon a surface compression, meridional wrinkles appear on the bubble surface below the bubble "equator", where the azimuthal tension sigma(phi) takes negative values. The CMD method allows one to determine the local tensions acting in anisotropic interfacial layers (films, membranes), like those formed from proteins, polymers, asphaltenes and phospholipids. The CMD is applicable also to fluid interfaces (e.g. surfactant solutions), for which it gives the same surface tension as the conventional methods. PMID- 25460704 TI - One-step preparation of hydrophilic carbon nanofiber containing magnetic Ni nanoparticles materials and their application in drug delivery. AB - A one-step process for the synthesis of hydrophilic carbon nanofibers (CNFs) through CO2 hydrogenation on NiNa/Al2O3 was developed for the loading and targeted delivery of the anticancer drug doxorubicin (DOX). CNFs that were synthesized on NiNa/Al2O3 for 9 h at 500 degrees C exhibited an adequate magnetic response and a large content of hydrophilic oxygen-containing functional groups on the carbon surface, resulting in excellent colloidal solution. The CNF material exhibited a highly efficient capacity for DOX adsorption, particularly at pH 9.0. The loading and release of DOX was strongly pH dependent, possibly due to electrostatic and pi-pi stacking interactions between DOX and CNF sample. The Langmuir isotherm and pseudo second-order kinetics of DOX-loaded CNFs were well modeled for the process of DOX adsorption. DOX-loaded CNF targeted cancer cells more selectively and effectively than free DOX and exhibited a marked tendency to kill HeLa cancer cells and reduced toxicity to normal human primary fibroblast (HPF) cells. PMID- 25460705 TI - Synthesis and adsorption characteristics of an heterogenized manganese nanoadsorbent towards methyl orange. AB - Heterogeneous Mn nanoparticles (5-30 nm diameter) is found to be a nanomaterial for the rapid removal of large quantities of toxic dye (methyl orange) from aqueous solution, with wide ranging potential applications. The synthesized materials were characterized with different methods such as FT-IR spectroscopy, CHN elemental analysis, BET, SEM, TEM, ICP-OES and EPR. The contact time to obtain equilibrium for maximum adsorption of methyl orange was 20 min. EPR of Mn ions evidenced that most of the covalently bond active sites of the nano adsorbent are in the form of Mn(III) ions at the surface. The heterogeneous Mn(III)-Cl ions were found to be effective adsorbent for the removal of methyl orange from solution. The adsorption of methyl orange ions has been studied in terms of pseudo-first-order and pseudo-second-order kinetics, and the Freundlich, Langmuir and Langmuir-Freundlich isotherm models have also been applied to the equilibrium adsorption data. The adsorption process was spontaneous and endothermic in nature and followed pseudo-second-order kinetic model. PMID- 25460706 TI - Compact and ordered colloidal clusters from assembly-disassembly cycles: a numerical study. AB - Brownian dynamics simulations are used to investigate the assembly of attractive colloids whose interaction potential well is periodically changed over time. Our system is composed of spherical, mono-disperse, highly charged, alumina particles whose interactions are modeled by the DLVO theory. The depth of the potential well is periodically changed by varying the ionic strength of the liquid medium. The simulations show that, with a right choice of some key parameters, a potential well depth alternating between low and higher values allows a faster aggregation into more compact and also more ordered colloidal clusters. This result is quantified by the computation of two relevant coordination parameters during the aggregation. This finding may help elucidate the assembly of colloidal particles in complex biological processes (e.g. biomineralization) and could be useful for the development of photonic crystals from attractive colloidal particles. PMID- 25460707 TI - An amine-oxide surfactant-based microemulsion for the cleaning of works of art. AB - Surfactant-based aqueous fluids, such as micellar solutions and microemulsions, are effective, safe and selective media for cleaning operations in conservation of cultural heritage. The search for better-performing systems and eco-friendly cleaning systems is currently a major goal in conservation science. We report here on a ternary o/w microemulsion, composed of diethyl carbonate (DC) as the oil phase and N,N-Dimethyldodecan-1-amine oxide (DDAO) as the surfactant. DDAO is a well known and widely used detergent and solubilizing agent, selected here for its degradability and eco-compatibility. Due to its nonionic/cationic nature, it can be used also when nonionic-based formulations become ineffective because of clouding and phase separation. Moreover, DDAO is insensitive to the presence of divalent metal ions, usually abundant in wall paintings substrates. Small-Angle Neutron Scattering (SANS) provided detailed information about the nanostructure of the surfactant aggregates. Finally, the cleaning effectiveness of the nanofluid was assessed both on fresco mock-ups and on real wall paintings conserved in the archeological site of Tulum, Mexico. Here, conservators successfully used the microemulsion to remove naturally aged films of complex polymer mixtures from the works of art surface. PMID- 25460708 TI - Porous NiCo2O4 nanosheets/reduced graphene oxide composite: facile synthesis and excellent capacitive performance for supercapacitors. AB - A composite with porous NiCo2O4 nanosheets attached on reduced graphene oxide (RGO) sheets is synthesized through a facile solution-based method combined with a simple thermal annealing process. The capacitive performances of the as prepared NiCo2O4/RGO (NCG) composites as electrode materials are investigated. It is found that the NCG composites exhibit a high specific capacitance up to 1186.3 F g(-1) at the current density of 0.5 A g(-1), and superior cycling stability with about 97% of the initial capacitance after 100 cycles. The greatly enhanced capacitive performance of the NCG electrode can be attributed to the existence of RGO support, which serves as both conductive channels and active interface. The approach used in the synthesis provides a facile route for preparing graphene binary metal oxide electrode materials. The remarkable capacitive performance of NCG composites will undoubtedly make them be attractive for high performance energy storage applications. PMID- 25460709 TI - Physicochemical characteristics of epichlorohydrin, pyridine and trimethylamine functionalized cotton stalk and its adsorption/desorption properties for perchlorate. AB - Amine-impregnated cotton stalk (AICS) prepared by the reaction of cotton stalk with epichlorohydrin, pyridine and trimethylamine was used as the effective adsorbent for perchlorate removal. Solid-state (13)C NMR spectra, FT-IR, BET principle and element analysis provided evidence that amine groups have been successfully introduced onto the surface of AICS. The adsorption capacity of perchlorate by AICS was about 83.8 mg g(-1) at 20 degrees C. It was decreased to 80.6 mg g(-1) as the temperature was increased to 40 degrees C, which implied an exothermic nature for this adsorption process. Perchlorate adsorption capacity in fixed-bed column was optimum at neutral condition (pH: 6.0, 70.8 mg g(-1)) with bed depth of 2.7 cm and flow rate of 5 ml min(-1). In addition, chemical regeneration by HCl or NaOH (0.1 mol L(-1)) achieved more than 95% of regeneration efficiency. Biological regeneration of the saturated AICS with mixed bacteria has shown its merit with regeneration and biological perchlorate destruction simultaneously although its regeneration efficiency was only 56.8 74.8%. PMID- 25460710 TI - Hierarchical opal grating films prepared by slide coating of colloidal dispersions in binary liquid media. AB - There are active researches on well ordered opal films due to their possible applications to various photonic devices. A recently developed slide coating method is capable of rapid fabrication of large area opal films from aqueous colloidal dispersion. In the current study, the slide coating of polystyrene colloidal dispersions in water/i-propanol (IPA) binary media is investigated. Under high IPA content in a dispersing medium, resulting opal film showed a deterioration of long range order, as well as a decreased film thickness due to dilution effect. From the binary liquid, the dried opal films exhibited the unprecedented topological groove patterns with varying periodic distances as a function of alcohol contents in the media. The groove patterns were consisted of the hierarchical structures of the terraced opal layers with periodic thickness variations. The origin of the groove patterns was attributed to a shear-induced periodic instability of colloidal concentration within a thin channel during the coating process which was directly converted to a groove patterns in a resulting opal film due to rapid evaporation of liquid. The groove periods of opal films were in the range of 50-500 MUm, and the thickness differences between peak and valley of the groove were significantly large enough to be optically distinguishable, such that the coated films can be utilized as the optical grating film to disperse infra-red light. Utilizing a lowered hydrophilicity of water/IPA dispersant, an opal film could be successfully coated on a flexible Mylar film without significant dewetting problem. PMID- 25460711 TI - Facile preparation of gold nanocages and hollow gold nanospheres via solvent thermal treatment and their surface plasmon resonance and photothermal properties. AB - Although template etching method is one of the most common ways of preparation of hollow gold nanostructures, this approach still requires further improvements to avoid the collapse of gold shells after the cores were removed. In this work, an improved template etching method, with which hollow gold nanostructure is fabricated by etching Polystyrene (PS) cores from PS@Au core-shell nanospheres with solvent thermal treatment in N,N-Dimethylformamide (DMF), is demonstrated. When PS cores were removed by a thermal treatment process, gold nanoshells reconstruct and the collapse of the nanoshells is avoided. Gold nanocages and hollow gold nanospheres are easily obtained from the various structures of PS@Au core-shell nanospheres. These hollow nanostructures represent special near infrared (NIR) optical property and photothermal property. Compared with hollow gold nanospheres, the gold nanocages show higher temperature increase at the same particle concentration. PMID- 25460712 TI - Association of anionic surfactant and physisorbed branched brush layers probed by neutron and optical reflectometry. AB - Pre-adsorbed branched brush layers were formed on silica surfaces by adsorption of a diblock copolymer consisting of a linear cationic block and an uncharged bottle-brush block. The charge of the silica surface was found to affect the adsorption, with lower amounts of the cationic polyelectrolyte depositing on less charged silica. Cleaning under basic conditions rendered surfaces more negatively charged (more negative zeta-potential) than acid cleaning and was therefore used to increase polyelectrolyte adsorption. The structure of adsorbed layers of the diblock copolymer was as determined by neutron reflectometry found to be about 70 nm thick and very water rich (97%). Interactions between the anionic surfactant sodium dodecylsulfate (SDS) and such pre-adsorbed diblock polymer layers were studied by neutron reflectometry and by optical reflectometry. Optical reflectometry was also used for deducing interactions between the individual blocks of the diblock copolymer and SDS at the silica/aqueous interface. We find that SDS is readily incorporated in the diblock copolymer layer at low SDS concentrations, and preferentially co-localized with the cationic block of the polymer next to the silica surface. At higher SDS concentrations some desorption of polyelectrolyte/surfactant complexes takes place. PMID- 25460713 TI - Arsenate adsorption onto Fe-TNTs prepared by a novel water-ethanol hydrothermal method: mechanism and synergistic effect. AB - Arsenate adsorption onto Fe2O3 was highly restricted at acidic condition due to dramatic dissolution. To overcome this difficulty, iron oxide nanoparticle grafted titanate nanotubes (Fe-TNTs) were synthesized by a facile one-step water ethanol hydrothermal method and used to remove As(V) from aqueous solutions. This new adsorbent was acid-resistant, and showed a large As(V) adsorption capacity of 90.96 mg/g determined by two-site Langmuir model, which was almost 3 times of the original TNTs. Fe2O3 was proved to bonded to the surface of TNTs by TEM and XRD analysis and synergy of Fe2O3 and TNTs was of great help to excellent As(V) adsorption. Load of Fe2O3 greatly enhanced the point of zero charge. Moreover, tubular TNTs not only inhibited dissolution of Fe2O3 at low pH, but also maintained good sedimentation property. The hydroxyl groups on Fe-TNTs surface played the most important role in As(V) adsorption. Electrostatic interaction followed by complexation was confirmed to be the primary adsorption mechanism by means of XPS analysis. Desorption capability and reuse performance of Fe-TNTs were also investigated, and satisfactory As(V) adsorption was further found with NaOH desorbed even after three reuse cycles. PMID- 25460714 TI - Dendritic amphiphiles as additives for honeycomb-like patterned surfaces by breath figures: role of the molecular characteristics on the pore morphology. AB - The current study presents a library of honeycomb-like patterned surfaces developed from a variety of different water-soluble amphiphilic dendrons. When compared to commercial surfactants, the dendrons produce a wide variety of porous surfaces due to their well-defined branched structure. Different functionalities and generations of dendrons have been studied. A singular hierarchical distribution of the dendrons, forming small nanoparticles (micelles) only at the inner edges of the holes (coffee stain effect) is observed. Once the surfaces are fabricated, these dendrons can be easily recovered via simple aqueous washing. After this treatment, the surfaces exhibit a high hydrophobic character (up to 140 degrees ) due to the high porosity. This behavior can be described by the Cassie-Baxter model. PMID- 25460715 TI - Modification of an Iranian clinoptilolite nano-particles by hexadecyltrimethyl ammonium cationic surfactant and dithizone for removal of Pb(II) from aqueous solution. AB - Natural clinoptilolite tuff was mechanically converted to micro (MCP) and nano (NCP) particles. The MCP and NCP powders were respectively modified with hexadecyltrimethyl ammonium bromide (HDTMA) and dithizone (DTZ). The raw and modified samples were characterized by X-ray diffraction (XRD), Fourier transformation infra red (FT-IR), scanning electron microscope (SEM), transmission electron microscope (TEM) and thermogravimetry (TG) and used for the removal of Pb(II) from aqueous solution. The results confirm that both ion exchange and complexation processes are responsible for removal of Pb(II) cations in the modified samples, while Pb(II) cations were only removed via an ion exchange process by the raw clinoptilolite. In this sorbent, the anionic removal property of surfactant modified zeolites (SMZs) changed to cationic removal property by an additional modification step. The best removal efficiency was observed by NCP-HDTMA-DTZ at the following experimental conditions: C(Pb(II)): 800 mg L(-1), HDTMA dosage: 0.2 mol L(-1), DTZ dosage: 5 mmol L(-1), contact time of DTZ with NCP-HDTMA: 1800 min and contact time of the sorbent with Pb(II): 360 min. The NCP-HDTMA-DTZ sorbent showed good efficiency for the removal of lead in the presence of different multivalent cations. Adsorption isotherms of Pb(II) ions obey the Langmuir equation that indicate the monolayer sorption of Pb(II). The adsorption kinetics based on the pseudo-second-order rate equation indicates that the rate limiting step involving a chemical reaction. The negative DeltaH and DeltaG indicate an exothermic and spontaneous process. PMID- 25460716 TI - Surface complexation modeling of inositol hexaphosphate sorption onto gibbsite. AB - The sorption of Inositol hexaphosphate (IP6) onto gibbsite was investigated using a combination of adsorption experiments, (31)P solid-state MAS NMR spectroscopy, and surface complexation modeling. Adsorption experiments conducted at four temperatures showed that IP6 sorption decreased with increasing pH. At pH 6, IP6 sorption increased with increasing temperature, while at pH 10 sorption decreased as the temperature was raised. (31)P MAS NMR measurements at pH 3, 6, 9 and 11 produced spectra with broad resonance lines that could be de-convoluted with up to five resonances (+5, 0, -6, -13 and -21ppm). The chemical shifts suggest the sorption process involves a combination of both outer- and inner-sphere complexation and surface precipitation. Relative intensities of the observed resonances indicate that outer-sphere complexation is important in the sorption process at higher pH, while inner-sphere complexation and surface precipitation are dominant at lower pH. Using the adsorption and (31)P MAS NMR data, IP6 sorption to gibbsite was modeled with an extended constant capacitance model (ECCM). The adsorption reactions that best described the sorption of IP6 to gibbsite included two inner-sphere surface complexes and one outer-sphere complex: =AlOH + IP612- + 5H+ <-> =Al(IP6H4)7- + H2O, =3AlOH + IP612- + 6H+ <-> =Al3(IP6H3)6- + 3H2O, =2AlOH + IP612- + 4H+ <-> (=AlOH2)22+(IP6H2)10-. The inner sphere complex involving three surface sites may be considered to be equivalent to a surface precipitate. Thermodynamic parameters were obtained from equilibrium constants derived from surface complexation modeling. Enthalpies for the formation of inner-sphere surface complexes were endothermic, while the enthalpy for the outer-sphere complex was exothermic. The entropies for the proposed sorption reactions were large and positive suggesting that changes in solvation of species play a major role in driving the sorption process. PMID- 25460717 TI - Computer simulations of charged colloids in confinement. AB - We study by computer simulations the interaction between two similarly charged colloidal particles confined between parallel planes, in salt free conditions. Both the colloids and ions are simulated explicitly, in a fine-mesh lattice, and the electrostatic interaction is calculated using Ewald summation in two dimensions. The internal energy is measured by setting the colloidal particles at a given position and equilibrating the ions, whereas the free energy is obtained introducing a bias (attractive) potential between the colloids. Our results show that upon confining the system, the internal energy decreases, resulting in an attractive contribution to the interaction potential for large charges and strong confinement. However, the loss of entropy of the ions is the dominant mechanism in the interaction, irrespective of the confinement of the system. The interaction potential is therefore repulsive in all cases, and is well described by the DLVO functional form, but effective values have to be used for the interaction strength and Debye length. PMID- 25460718 TI - Photostability of wool fabrics coated with pure and modified TiO2 colloids. AB - The surface of wool fabrics was coated with TiO2 and TiO2-based nanocomposite colloids and the impact of this coating on the photostability of wool was investigated. TiO2 along with TiO2/Metal and TiO2/Metal/SiO2 sols were synthesized through a low-temperature sol-gel method and applied to fabrics. Composite colloids were synthesized through integrating the silica and three noble metals of silver (Ag), gold (Au) and platinum (Pt) into the synthesis process of sols. Four different molar ratios of Metal to TiO2 (0.01%, 0.1%, 0.5% and 1%) were used to elucidate the role of metal type and amount on the obtained features. Photostability and UV protection features of fabrics were evaluated through measuring the photo-induced chemiluminescence (PICL), photoyellowing rate and ultraviolet protection factor (UPF) of fabrics. PICL and photoyellowing tests were carried out under UVA and UVC light sources, respectively. PICL profiles demonstrated that the presence of pure and modified TiO2 nanoparticles on fabrics reduced the intensity of PICL peak indicating a lower amount of polymer free radicals in coated wool, compared to that of pristine fabric. Moreover, a higher PICL peak intensity as well as photoyellowing rate was observed on fabrics coated with modified colloids in comparison with pure TiO2. The surface morphology of fabrics was further characterized using FESEM images. PMID- 25460721 TI - Selective inhibition of NADPH oxidase reverses the over contraction of diabetic rat aorta. AB - Abnormal vascular responsiveness in diabetes has been attributed to a number of changes in contractile pathways, affected in part by the overproduction of reactive oxygen species (ROS). It has been reported that NADPH oxidase (NOX) is increased in diabetic (streptozotocin treated; STZ) rat arteries; however the pharmacological agents used to inhibit NOX activity are known to be unsuitable for in vitro studies and have a high level of non-selectivity. Here we have used the highly selective NOX inhibitor VAS2870 in diabetic rat aorta and compared its effects with apocynin, SOD, and allopurinol on phenylephrine and U46619 induced contraction. Male Wistar rats were injected intraperitoneally with 65mg/kg STZ and development of diabetes was confirmed by testing blood glucose levels. Rats were killed by CO2 asphyxiation, and the thoracic aorta removed and mounted in an organ bath under a tension of 1g. Diabetic rat aortas exhibit a greatly increased response to phenylephrine, which was reduced to a level consistent with control rat aorta by 10(-5)M VAS2870 and 150U/ml SOD. Incubation with VAS2870 led to an increase in normal rat aorta contraction, but led to a significant reduction in phenylephrine and U46619 induced tone in diabetic rat aorta, which indicates that ROS in diabetic rats directly contributes to these contractile responses. Apocynin and allopurinol had no effect on contraction in diabetic or normal rat aorta. This data is the first to show that selective inhibition of NOX reduces diabetic arterial contraction in direct comparison with inhibition of other known contributors of ROS. PMID- 25460722 TI - Oxidative stress responses to a graded maximal exercise test in older adults following explosive-type resistance training. AB - We recently demonstrated that low frequency, moderate intensity, explosive-type resistance training (EMRT) is highly beneficial in elderly subjects towards muscle strength and power, with a systemic adaptive response of anti-oxidant and stress-induced markers. In the present study, we aimed to evaluate the impact of EMRT on oxidative stress biomarkers induced in old people (70-75 years) by a single bout of acute, intense exercise. Sixteen subjects randomly assigned to either a control, not exercising group (n=8) or a trained group performing EMRT protocol for 12-weeks (n=8), were submitted to a graded maximal exercise stress test (GXT) at baseline and after the 12-weeks of EMRT protocol, with blood samples collected before, immediately after, 1 and 24h post-GXT test. Blood glutathione (GSH, GSSG, GSH/GSSG), plasma malonaldehyde (MDA), protein carbonyls and creatine kinase (CK) levels, as well as PBMCs cellular damage (Comet assay, apoptosis) and stress-protein response (Hsp70 and Hsp27 expression) were evaluated. The use of multiple biomarkers allowed us to confirm that EMRT per se neither affected redox homeostasis nor induced any cellular and oxidative damage. Following the GXT, the EMRT group displayed a higher GSH/GSSG ratio and a less pronounced increase in MDA, protein carbonyls and CK levels compared to control group. Moreover, we found that Hsp70 and Hsp27 proteins were induced after GXT only in EMRT group, while any significant modification within 24h was detected in untrained group. Apoptosis rates and DNA damage did not show any significant variation in relation to EMRT and/or GXT. In conclusion, the adherence to an EMRT protocol is able to induce a cellular adaptation allowing healthy elderly trained subjects to cope with the oxidative stress induced by an acute exercise more effectively than the aged-matched sedentary subjects. PMID- 25460723 TI - Effect of CO, NOx and SO2 on ROS production, photosynthesis and ascorbate glutathione pathway to induce Fragaria*annasa as a hyperaccumulator. AB - A study was conducted to determine the effect of carbon monoxide (CO), nitroxide (NOx) and sulfur dioxide (SO2) on ROS production, photosynthesis and ascorbate glutathione pathway in strawberry plants. The results showed that both singlet oxygen (O2(-1)) and hydrogen peroxide (H2O2) content increased in CO, NOx and SO2 treated strawberry leaves. A drastic reduction of primary metabolism of plants (photosynthesis), with the closure of stomata, resulted in a reduction of protein, carbohydrate and sucrose content due to production of reactive oxygen species (ROS) under prolonged exposure of gas stress. The resulting antioxidant enzymes were increased under a low dose of gas stress, whereas they were decreased due to a high dose of gas stress. Our results indicate that increased ROS may act as a signal to induce defense responses to CO, NOx and SO2 gas stress. The increased level of antioxidant enzymes plays a significant role in plant protection due to which strawberry plants can be used as a hyperaccumulator to maintain environmental pollution, however, the defense capacity cannot sufficiently alleviate oxidative damage under prolonged exposure of CO, NOx and SO2 stress. PMID- 25460724 TI - The proteasome and the degradation of oxidized proteins: Part II - protein oxidation and proteasomal degradation. AB - Here, we review the role of oxidative protein modification as a signal for recognition and degradation of proteins. It was clearly demonstrated that the ATP and ubiquitin-independent 20S proteasome is playing a key role in the selective removal of oxidized proteins. Furthermore, the current knowledge of the substrate susceptibility on the degradation of oxidized proteins and the role of the immunoproteasome will be highlighted. PMID- 25460725 TI - Reactive metabolites and antioxidant gene polymorphisms in Type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM), by definition is a heterogeneous, multifactorial, polygenic syndrome which results from insulin receptor dysfunction. It is an outcome of oxidative stress caused by interactions of reactive metabolites (RMs) interactions with lipids, proteins and other mechanisms of human body. Production of RMs mainly superoxide (O2(-)) has been found in a variety of predominating cellular enzyme systems including NAD(P)H oxidase, xanthine oxidase (XO), cyclooxygenase (COX), uncoupled endothelial nitric oxide synthase (eNOS) and myeloperoxidase (MPO). The four main RM related molecular mechanisms are: increased polyol pathway flux; increased advanced glycation end-product (AGE) formation; activation of protein kinase C (PKC) isoforms and increased hexosamine pathway flux which have been implicated in glucose-mediated vascular damage. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), nitric oxide synthase (NOS) are antioxidant enzymes involved in scavenging RMs in normal individuals. Functional polymorphisms of these antioxidant enzymes have been reported to be involved in pathogenesis of T2DM individuals. The low levels of antioxidant enzymes or their non-functionality results in excessive RMs which initiate stress related pathways thereby leading to insulin resistance and T2DM. An attempt has been made to review the role of RMs and antioxidant enzymes in oxidative stress resulting in T2DM. PMID- 25460726 TI - Protein engineering to develop a redox insensitive endothelial nitric oxide synthase. AB - The zinc tetrathiolate (ZnS4) cluster is an important structural feature of endothelial nitric oxide synthase (eNOS). The cluster is located on the dimeric interface and four cysteine residues (C94 and C99 from two adjacent subunits) form a cluster with a Zn ion in the center of a tetrahedral configuration. Due to its high sensitivity to oxidants this cluster is responsible for eNOS dimer destabilization during periods of redox stress. In this work we utilized site directed mutagenesis to replace the redox sensitive cysteine residues in the ZnS4 cluster with redox stable tetra-arginines. Our data indicate that this C94R/C99R eNOS mutant is active. In addition, this mutant protein is insensitive to dimer disruption and inhibition when challenged with hydrogen peroxide (H2O2). Further, the overexpression of the C94R/C99R mutant preserved the angiogenic response in endothelial cells challenged with H2O2. The over-expression of the C94R/C99R mutant preserved the ability of endothelial cells to migrate towards vascular endothelial growth factor (VEGF) and preserved the endothelial monolayer in a scratch wound assay. We propose that this dimer stable eNOS mutant could be utilized in the treatment of diseases in which there is eNOS dysfunction due to high levels of oxidative stress. PMID- 25460727 TI - Positive oxidative stress in aging and aging-related disease tolerance. AB - It is now well established that reactive oxygen species (ROS), reactive nitrogen species (RNS), and a basal level of oxidative stress are essential for cell survival. It is also well known that while severe oxidative stress often leads to widespread oxidative damage and cell death, a moderate level of oxidative stress, induced by a variety of stressors, can yield great beneficial effects on adaptive cellular responses to pathological challenges in aging and aging-associated disease tolerance such as ischemia tolerance. Here in this review, I term this moderate level of oxidative stress as positive oxidative stress, which usually involves imprinting molecular signatures on lipids and proteins via formation of lipid peroxidation by-products and protein oxidation adducts. As ROS/RNS are short-lived molecules, these molecular signatures can thus execute the ultimate function of ROS/RNS. Representative examples of lipid peroxidation products and protein oxidation adducts are presented to illustrate the role of positive oxidative stress in a variety of pathological settings, demonstrating that positive oxidative stress could be a valuable prophylactic and/or therapeutic approach targeting aging and aging-associated diseases. PMID- 25460728 TI - Bypassing the compromised mitochondrial electron transport with methylene blue alleviates efavirenz/isoniazid-induced oxidant stress and mitochondria-mediated cell death in mouse hepatocytes. AB - Efavirenz (EFV) is an anti-retroviral drug frequently combined with isoniazid (INH) to treat HIV-1/tuberculosis co-infected patients. Both drugs have been associated with idiosyncratic liver injury (DILI), but combined anti-retroviral and anti-tubercular therapy can increase the risk for DILI as compared to either drug class alone. Because both EFV and INH have been implicated in targeting mitochondria, we aimed at exploring whether the two drugs might cause synergistic effects on the electron transport chain. We found that EFV inhibited complex I activity in isolated mouse liver mitochondria (IC50 ~30 MUM), whereas hydrazine, a major metabolite of INH generated by acylamidase-mediated hydrolytic cleavage, inhibited complex II activity (IC50 ~30 MUM). Neither INH alone (<=1000 MUM) nor EFV alone (<=30 MUM) was able to induce cell injury in cultured mouse hepatocytes. However, combined EFV/INH exposure resulted in increased superoxide formation and peroxynitrite stress, leading to the opening of the cyclosporine A insensitive mode of the mitochondrial permeability transition (mPT), and necrotic cell death. The peroxynitrite scavengers, CBA or Fe-TMPyP, protected against mPT induction and alleviated cell injury. The acylamidase inhibitor bis-p-nitrophenyl phosphate prevented cell injury, suggesting that hydrazine greatly contributed to the toxicity. Methylene blue, a redox-active alternative electron acceptor/donor that bypasses complex I/II, effectively protected against EFV/INH-induced toxicity. These data demonstrate that, in murine hepatocytes, the mitochondrial electron transport chain is a critical target of combined EFV/INH exposure, and that this drug combination can lead to peroxynitrite stress-induced mPT and hepatocellular necrosis. These results are compatible with the concept that underlying silent mitochondrial dysfunction may be a key susceptibility factor contributing to idiosyncratic drug-induced liver injury. PMID- 25460730 TI - Quantifying intracellular hydrogen peroxide perturbations in terms of concentration. AB - Molecular level, mechanistic understanding of the roles of reactive oxygen species (ROS) in a variety of pathological conditions is hindered by the difficulties associated with determining the concentration of various ROS species. Here, we present an approach that converts fold-change in the signal from an intracellular sensor of hydrogen peroxide into changes in absolute concentration. The method uses extracellular additions of peroxide and an improved biochemical measurement of the gradient between extracellular and intracellular peroxide concentrations to calibrate the intracellular sensor. By measuring peroxiredoxin activity, we found that this gradient is 650-fold rather than the 7-10-fold that is widely cited. The resulting calibration is important for understanding the mass-action kinetics of complex networks of redox reactions, and it enables meaningful characterization and comparison of outputs from endogenous peroxide generating tools and therapeutics across studies. PMID- 25460729 TI - Cytoplasmic hybrid (cybrid) cell lines as a practical model for mitochondriopathies. AB - Cytoplasmic hybrid (cybrid) cell lines can incorporate human subject mitochondria and perpetuate its mitochondrial DNA (mtDNA)-encoded components. Since the nuclear background of different cybrid lines can be kept constant, this technique allows investigators to study the influence of mtDNA on cell function. Prior use of cybrids has elucidated the contribution of mtDNA to a variety of biochemical parameters, including electron transport chain activities, bioenergetic fluxes, and free radical production. While the interpretation of data generated from cybrid cell lines has technical limitations, cybrids have contributed valuable insight into the relationship between mtDNA and phenotype alterations. This review discusses the creation of the cybrid technique and subsequent data obtained from cybrid applications. PMID- 25460732 TI - Polyphenol fraction of extra virgin olive oil protects against endothelial dysfunction induced by high glucose and free fatty acids through modulation of nitric oxide and endothelin-1. AB - Epidemiological and clinical studies have reported that olive oil reduces the incidence of cardiovascular disease. However, the mechanisms involved in this beneficial effect have not been delineated. The endothelium plays an important role in blood pressure regulation through the release of potent vasodilator and vasoconstrictor agents such as nitric oxide (NO) and endothelin-1 (ET-1), respectively, events that are disrupted in type 2 diabetes. Extra virgin olive oil contains polyphenols, compounds that exert a biological action on endothelial function. This study analyzes the effects of olive oil polyphenols on endothelial dysfunction using an in vitro model that simulates the conditions of type 2 diabetes. Our findings show that high glucose and linoleic and oleic acids decrease endothelial NO synthase phosphorylation, and consequently intracellular NO levels, and increase ET-1 synthesis by ECV304 cells. These effects may be related to the stimulation of reactive oxygen species production in these experimental conditions. Hydroxytyrosol and the polyphenol extract from extra virgin olive oil partially reversed the above events. Moreover, we observed that high glucose and free fatty acids reduced NO and increased ET-1 levels induced by acetylcholine through the modulation of intracellular calcium concentrations and endothelial NO synthase phosphorylation, events also reverted by hydroxytyrosol and polyphenol extract. Thus, our results suggest a protective effect of olive oil polyphenols on endothelial dysfunction induced by hyperglycemia and free fatty acids. PMID- 25460731 TI - Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism. AB - Cancer cells, relative to normal cells, demonstrate significant alterations in metabolism that are proposed to result in increased steady-state levels of mitochondrial-derived reactive oxygen species (ROS) such as O2(*-)and H2O2. It has also been proposed that cancer cells increase glucose and hydroperoxide metabolism to compensate for increased levels of ROS. Given this theoretical construct, it is reasonable to propose that forcing cancer cells to use mitochondrial oxidative metabolism by feeding ketogenic diets that are high in fats and low in glucose and other carbohydrates, would selectively cause metabolic oxidative stress in cancer versus normal cells. Increased metabolic oxidative stress in cancer cells would in turn be predicted to selectively sensitize cancer cells to conventional radiation and chemotherapies. This review summarizes the evidence supporting the hypothesis that ketogenic diets may be safely used as an adjuvant therapy to conventional radiation and chemotherapies and discusses the proposed mechanisms by which ketogenic diets may enhance cancer cell therapeutic responses. PMID- 25460733 TI - Inputs and outputs of poly(ADP-ribosyl)ation: Relevance to oxidative stress. AB - Oxidative stress can cause DNA breaks which induce activation of the DNA nick sensor enzyme poly(ADP-ribose) polymerase-1 (PARP-1), part of the 17 member PARP enzyme family. PARP-1 modifies target proteins by attaching to them several NAD derived ADP-ribose units forming poly(ADP-ribose) (PAR) polymers. PARylation controls many cellular processes while intense PARylation may also lead to cell death by various mechanisms. Here we summarize the modes of activation, inhibitors and modulators of PARP-1 and review the cellular functions regulated by the enzyme. PMID- 25460734 TI - Covalent modification of cytoskeletal proteins in neuronal cells by tryptamine 4,5-dione. AB - Serotonin, 5-hydroxytryptamine, is a systemic bioactive amine that acts in the gut and brain. As a substrate of myeloperoxidase in vitro, serotonin is oxidized to tryptamine-4,5-dione (TD), which is highly reactive with thiols. In this work, we successively prepared a monoclonal antibody to quinone-modified proteins and found that the antibody preferentially recognizes the TD-thiol adduct. Using the antibody, we observed that the chloride ion, the predominant physiological substrate for myeloperoxidase in vivo, is not competitive toward the enzyme catalyzed serotonin oxidation process, suggesting that serotonin is a plausible physiological substrate for the enzyme in vivo. Immunocytochemical analyses revealed that TD staining was observed in the cytosol of SH-SY5Y neuroblastoma cells while blot analyses showed that some cellular proteins were preferentially modified. Pull-down analyses confirmed that the cytoskeletal proteins tubulins, vimentin, and neurofilament-L were modified. When pure tubulins were exposed to micromolar levels of synthetic TD, self-polymerization was initially enhanced and then suppressed. These results suggest that serotonin oxidation by myeloperoxidase or the action of other oxidants could cause functional alteration of cellular proteins, which may be related to neurodegeneration processes or irritable bowel syndrome. PMID- 25460736 TI - An ex-vivo model for evaluating bioenergetics in aortic rings. AB - Cardiovascular disease (CVD) is the leading cause of death worldwide and it exhibits a greatly increasing incidence proportional to aging. Atherosclerosis is a chronic condition of arterial hardening resulting in restriction of oxygen delivery and blood flow to the heart. Relationships between mitochondrial DNA damage, oxidant production, and early atherogenesis have been recently established and it is likely that aspects of atherosclerotic risk are metabolic in nature. Here we present a novel method through which mitochondrial bioenergetics can be assessed from whole aorta tissue. This method does not require mitochondrial isolation or cell culture and it allows for multiple technical replicates and expedient measurement. This procedure facilitates quantitative bioenergetic analysis and can provide great utility in better understanding the link between mitochondria, metabolism, and atherogenesis. PMID- 25460735 TI - Farnesoid X receptor regulates forkhead Box O3a activation in ethanol-induced autophagy and hepatotoxicity. AB - Alcoholic liver disease encompasses a wide spectrum of pathogenesis including steatosis, fibrosis, cirrhosis, and alcoholic steatohepatitis. Autophagy is a lysosomal degradation process that degrades cellular proteins and damaged/excess organelles, and serves as a protective mechanism in response to various stresses. Acute alcohol treatment induces autophagy via FoxO3a-mediated autophagy gene expression and protects against alcohol-induced steatosis and liver injury in mice. Farnesoid X Receptor (FXR) is a nuclear receptor that regulates cellular bile acid homeostasis. In the present study, wild type and FXR knockout (KO) mice were treated with acute ethanol for 16h. We found that ethanol treated-FXR KO mice had exacerbated hepatotoxicity and steatosis compared to wild type mice. Furthermore, we found that ethanol treatment had decreased expression of various essential autophagy genes and several other FoxO3 target genes in FXR KO mice compared with wild type mice. Mechanistically, we did not find a direct interaction between FXR and FoxO3. Ethanol-treated FXR KO mice had increased Akt activation, increased phosphorylation of FoxO3 resulting in decreased FoxO3a nuclear retention and DNA binding. Furthermore, ethanol treatment induced hepatic mitochondrial spheroid formation in FXR KO mice but not in wild type mice, which may serve as a compensatory alternative pathway to remove ethanol-induced damaged mitochondria in FXR KO mice. These results suggest that lack of FXR impaired FoxO3a-mediated autophagy and in turn exacerbated alcohol-induced liver injury. PMID- 25460737 TI - Examination of bioenergetic function in the inner mitochondrial membrane peptidase 2-like (Immp2l) mutant mice. AB - Inner mitochondrial membrane peptidase 2-like (IMMP2L) protein is a mitochondrial inner membrane peptidase that cleaves the signal peptide sequences of cytochrome c1 (CYC1) and mitochondrial glycerol phosphate dehydrogenase (GPD2). Immp2l mutant mice show infertility and early signs of aging. It is unclear whether mitochondrial respiratory deficiency underlies this phenotype. Here we show that the intermediate forms of GPD2 and CYC1 have normal expression levels and enzymatic function in Immp2l mutants. Mitochondrial respiration is not diminished in isolated mitochondria and cells from mutant mice. Our data suggest that respiratory deficiency is not the cause of the observed Immp2l mutant phenotypes. PMID- 25460738 TI - A role for human mitochondrial complex II in the production of reactive oxygen species in human skin. AB - The mitochondrial respiratory chain is a major generator of cellular oxidative stress, thought to be an underlying cause of the carcinogenic and ageing process in many tissues including skin. Previous studies of the relative contributions of the respiratory chain (RC) complexes I, II and III towards production of reactive oxygen species (ROS) have focussed on rat tissues and certainly not on human skin which is surprising as this tissue is regularly exposed to UVA in sunlight, a potent generator of cellular oxidative stress. In a novel approach we have used an array of established specific metabolic inhibitors and DHR123 fluorescence to study the relative roles of the mitochondrial RC complexes in cellular ROS production in 2 types of human skin cells. These include additional enhancement of ROS production by exposure to physiological levels of UVA. The effects within epidermal and dermal derived skin cells are compared to other tissue cell types as well as those harbouring a compromised mitochondrial status (Rho-zero A549). The results show that the complex II inhibitor, TTFA, was the only RC inhibitor to significantly increase UVA-induced ROS production in both skin cell types (P<0.05) suggesting that the role of human skin complex II in terms of influencing ROS production is more important than previously thought particularly in comparison to liver cells. Interestingly, two-fold greater maximal activity of complex II enzyme was observed in both skin cell types compared to liver (P<0.001). The activities of RC enzymes appear to decrease with increasing age and telomere length is correlated with ageing. Our study showed that the level of maximal complex II activity was higher in the MRC5/hTERT (human lung fibroblasts transfected with telomerase) cells than the corresponding wild type cells (P=0.0012) which can be considered (in terms of telomerase activity) as models of younger and older cells respectively. PMID- 25460739 TI - Role of sulfiredoxin in systemic diseases influenced by oxidative stress. AB - Sulfiredoxin is a recently discovered member of the oxidoreductases family which plays a crucial role in thiol homoeostasis when under oxidative stress. A myriad of systemic disorders have oxidative stress and reactive oxygen species as the key components in their etiopathogenesis. Recent studies have evaluated the role of this enzyme in oxidative stress mediated diseases such as atherosclerosis, chronic obstructive pulmonary disease and a wide array of carcinomas. Its action is responsible for the normal functioning of cells under oxidative stress and the promotion of cell survival in cancerous cells. This review will highlight the cumulative effects of sulfiredoxin in various systemic disorders with a strong emphasis on its target activity and the factors influencing its expression in such conditions. PMID- 25460740 TI - Mechanisms by which heme oxygenase rescue renal dysfunction in obesity. AB - Obesity and excessive inflammation/oxidative stress are pathophysiological forces associated with kidney dysfunction. Although we recently showed that heme oxygenase (HO) improves renal functions, the mechanisms are largely unclear. Moreover, the effects of the HO-system on podocyte cytoskeletal proteins like podocin, podocalyxin, CD2-associated-protein (CD2AP) and proteins of regeneration/repair like beta-catenin, Oct3/4, WT1 and Pax2 in renal tissue from normoglycemic obese Zucker-fatty rats (ZFs) have not been reported. Treatment with hemin reduced renal histo-pathological lesions including glomerular hypertrophy, tubular-cast, tubular-atrophy and mononuclear cell-infiltration in ZFs. These were associated with enhanced expression of beta-catenin, Oct3/4, WT1, Pax2 and nephrin, an essential transmembrane protein required for the formation of the scaffoldings of the podocyte slit-diaphragm, permitting the filtration of small ions, but not massive excretion of proteins, hence proteinuria. Besides nephrin, hemin also enhanced other important podocyte-regulators including, podocalyxin, podocin and CD2AP. Correspondingly, important markers of renal dysfunction such as albuminuria and proteinuria were reduced, while creatinine clearance increased, suggesting improved renal function in hemin-treated ZFs. The renoprotection by hemin was accompanied by the reduction of inflammatory/oxidative mediators including, macrophage-inflammatory-protein 1alpha, macrophage-chemoattractant-protein-1 and 8-isoprostane, whereas HO-1, HO activity and the total-anti-oxidant-capacity increased. Contrarily, the HO inhibitor, stannous-mesoporphyrin nullified the reno-protection by hemin. Collectively, these data suggest that hemin ameliorates nephropathy by potentiating the expression of proteins of repair/regeneration, abating oxidative/inflammatory mediators, reducing renal histo-pathological lesions, while enhancing nephrin, podocin, podocalyxin, CD2AP and creatinine clearance, with corresponding reduction of albuminuria/proteinuria suggesting improved renal function in hemin-treated ZFs. Importantly, the concomitant potentiation regeneration proteins and podocyte cytoskeletal proteins are novel mechanisms by which hemin rescue nephropathy in obesity. PMID- 25460741 TI - Reaction of aqueous Cu-Citrate with MnO2 birnessite: characterization of Mn dissolution, oxidation products and surface interactions. AB - Citric acid, a widespread soil rhizosphere plant/microbe carboxylic acid exudate can easily form chelates with heavy metals, increasing their availability in the environment. When Cu(II) from algal control in water bodies or reservoirs and fungicides, such as the Bordeaux mixture, and citrate interact, solubilization through chelation is a possible outcome. Manganese (hydr)oxides represent a significant portion of the subsurface environment and can affect the fate and transport of chemical species through adsorption and oxidation. This study explores the possible interaction between MnO2 and Cu-Citrate under ambient oxic conditions. The calculated Mn(II) dissolution rates during the initial 1h of reaction followed the series Cu(II)>Cu-Citrate 1:0.5>Cu-Citrate 1:1(oxic)>Citrate>Cu-Citrate 1:1(Anoxic), reinforcing the central role of (complexed or un-complexed) Cu(II) during the initial surface-coordination instead of following the s-shaped auto-catalytic curves of Mn(II) dissolution in citrate solution. The use of capillary electrophoresis allowed the detection of an intermediate Cu(II)Acetonedicarboxylate complex and the oxidation products acetonedicarboxylate, acetoacetate, acetone and acetic acid. The mass balance analysis of Cu-Citrate 1:1 suggests the partial adsorption of Cu-Citrate(ads) and catalytic degradation of acetonedicarboxylate through a MnO2-Cu surface sorbed complex. Lastly, XPS analysis confirmed the MnO2 surface Cu(II) reduction along with an outer-hydration layer at the MnO2 interface, where electron transfer and aquo ligand exchange may lead to the oxidation of Cu-Citrate. PMID- 25460742 TI - Liquid chromatography-tandem mass spectrometry multiclass method for the determination of antibiotics residues in water samples from water supply systems in food-producing animal farms. AB - A sensitive liquid-chromatography-electrospray tandem mass spectrometry multiclass method for determination of 45 veterinary compounds belonging to 9 different antibiotic groups, including aminoglicosides (4), beta-lactams (13), diaminopyrimidines (1), fluoroquinolones (10), lincosamides (1), macrolides (5), pleuromutilins (1), sulfonamides (6) and tetracyclines (4), in water from breeding animal watering supply system has been developed. Isolation of the analytes was carried out by solid phase extraction with heptafluorobutyric acid as an ion-pair agent on the Strata-X reversed phase cartridges. All analytes were determined simultaneously in one single run on a C18 column with gradient elution and short analysis time (13 min). Method was validated, average relative recoveries were in the range of 84.3-109.3% with satisfactory precision are repeatability for all compounds are in the range of 4.7-12.2%, within-laboratory reproducibility are in the range of 4.4-13.5% for. The limit of quantitation (LOQ) of the method was in the range of 0.02-10 MUg L(-1), depending of analyte. The applicability of the method was tested by determining antimicrobial compounds in real water samples collected from water supply systems in breeding animal farms. The average antibiotics concentration in real water samples were, respectively, in the range of 0.14-1670 MUg L(-1). PMID- 25460743 TI - Environmental fate of 2,4-dinitroanisole (DNAN) and its reduced products. AB - Several defense departments intend to replace 2,4,6-trinitrotoluene (TNT) in munitions formulations by the less sensitive 2,4-dinitroanisole (DNAN). To help understand environmental behavior and ecological risk associated with DNAN we investigated its key initial abiotic and biotic reaction routes and determined relevant physicochemical parameters (pKa, logKow, aqueous solubility (Sw), partition coefficient (Kd)) for the chemical and its products. Reduction of DNAN with either zero valent iron or bacteria regioselectively produced 2-amino-4 nitroanisole (2-ANAN) which, under strict anaerobic conditions, gave 2,4 diaminoanisole (DAAN). Hydrolysis under environmental conditions was insignificant whereas photolysis gave photodegradable intermediates 2-hydroxy-4 nitroanisole and 2,4-dinitrophenol. Physicochemical properties of DNAN and its amino products drastically depended on the type and position of substituent(s) on the aromatic ring. Sw followed the order (TNTPo River (1.71)>Tanaro River (1.66)>Bormida River (1.36). However, in 37% of analyzed samples, Hg exceeded the maximum level set by 1881/2006/EC and 629/2008/EC in fish muscle. The molar ratio of Se/Hg was <1 only in the presence of significantly high Hg levels (>0.5mg/kg), and therefore the mean molar ratio cannot be considered as a safety criterion in top predator fish. PMID- 25460745 TI - Degradation kinetics of a potent antifouling agent, butenolide, under various environmental conditions. AB - Here, we investigated the degradation kinetics of butenolide, a promising antifouling compound, under various environmental conditions. The active ingredient of the commercial antifoulant SeaNine 211, 4,5-dichloro-2-n-octyl-4 isothiazolin-3-one (DCOIT), was used as positive control. The results showed that the degradation rate increased with increasing temperature. Half-lives of butenolide at 4 degrees C, 25 degrees C and 40 degrees C were>64 d, 30.5 d and 3.9 d, respectively. Similar half-lives were recorded for DCOIT: >64 d at 4 degrees C, 27.9 d at 25 degrees C and 4.5d at 40 degrees C. Exposure to sunlight accelerated the degradation of both butenolide and DCOIT. The photolysis half-lives of butenolide and DCOIT were 5.7 d and 6.8 d, respectively, compared with 9.7 d and 14.4 d for the dark control. Biodegradation led to the fastest rate of butenolide removal from natural seawater, with a half-life of 0.5 d, while no obvious degradation was observed for DCOIT after incubation for 4 d. The biodegradative ability of natural seawater for butenolide was attributed mainly to marine bacteria. During the degradation of butenolide and DCOIT, a gradual decrease in antifouling activity was observed, as indicated by the increased settlement percentage of cypris larvae from barnacle Balanus amphitrite. Besides, increased cell growth of marine diatom Skeletonema costatum demonstrated that the toxicity of seawater decreased gradually without generation of more toxic by products. Overall, rapid degradation of butenolide in natural seawater supported its claim as a promising candidate for commercial antifouling industry. PMID- 25460746 TI - Production of PFOS from aerobic soil biotransformation of two perfluoroalkyl sulfonamide derivatives. AB - The continuous production and use in certain parts of the world of perfluoroalkyl sulfonamide derivatives that can degrade to perfluorooctane sulfonic acid (PFOS) has called for better understanding of the environmental fate of these PFOS precursors. Aerobic soil biotransformation of N-ethyl perfluorooctane sulfonamide (EtFOSA, also known as Sulfluramid) was quantitatively investigated in semi closed soil microcosms over 182 d for the first time. The apparent soil half-life of EtFOSA was 13.9+/-2.1 d and the yield to PFOS by the end of incubation was 4.0 mol%. A positive identification of a previously suspected degradation product, EtFOSA alcohol, provided strong evidence to determine degradation pathways. The lower mass balance in sterile soil than live soil suggested likely strong irreversible sorption of EtFOSA to the test soil. The aerobic soil biotransformation of a technical grade N-ethyl perfluorooctane sulfonamidoethanol (EtFOSE) was semi-quantitatively examined, and the degradation pathways largely followed those in activated sludge and marine sediments. Aside from PFOS, major degradation products included N-Ethyl perfluorooctane sulfonamidoacetic acid (EtFOSAA), perfluorooctane sulfonamide (FOSA) and perfluorooctane sulfonamide acetic acid (FOSAA). This study confirms that aerobic soil biotransformation of EtFOSE and EtFOSA contributes significantly to the PFOS observed in soil environment, as well as to several highly persistent sulfonamide derivatives frequently detected in biosolid-amended soils and landfill leachates. PMID- 25460747 TI - Fly ash-mediated formation of polychlorinated naphthalenes during secondary copper smelting and mechanistic aspects. AB - Thermal experiments (at 250-450 degrees C for 10-240 min) on fly ash from secondary copper smelting process (SeCu) were performed to study the polychlorinated naphthalene (PCN) formation in the post-zone of a secondary copper smelter. Unexpectedly high concentrations of PCNs were formed. Total PCN concentrations and toxic equivalents were 47-104 and 44-80 times higher than the initial concentration and toxic equivalent, respectively. The thermal disposal of SeCu fly ash should therefore be reconsidered. The kinetic of each homolog was determined under different thermal conditions. Less chlorinated homologs favored 350 degrees C and more chlorinated homologs favored higher temperature. Most of the homologs reached an equilibrium of formation and degradation within 30 min, except octachloronaphthalene which did not appear to reach such an equilibrium even after 240 min. Chlorine substitution of the formed PCNs was identified and a similar pattern was found in chlorination products starting with naphthalene and chlorine. Furthermore, inorganic chlorine and unsubstituted naphthalene were found in the reaction products, confirming that the formation of naphthalene and the chlorination of that naphthalene could occur and could be suggested to be an important PCN formation route. A detailed formation pathway from naphthalene through octachloronaphthalene is proposed. PMID- 25460748 TI - First evidence of accumulation in cyanobacteria of guanidinoacetate, a precursor of the toxin cylindrospermopsin. AB - Guanidinoacetate (GAA) is one of the most extensively studied toxic guanidine compounds. Changes in GAA can affect the nervous system and induce hyperhomocysteinemia, representing a risk factor for cardiovascular diseases. In cyanobacteria, GAA is thought to be an intermediate in the synthesis of the toxin cylindrospermopsin (CYN), one of the most common known cyanotoxins that affects multiple organs and functions in animals and plants. In spite of the evidence supporting GAA toxicity and its role in CYN synthesis, no data have been reported on the accumulation of GAA in any cyanobacterium. We have analyzed and compared the content of GAA in cultures of diverse cyanobacteria types, both cylindrospermopsin producing (CYN(+)) and not producing (CYN(-)). The results obtained show that GAA accumulates in the majority of the strains tested, although the highest content was found in one of the CYN(+) strain, Aphanizomenon ovalisporum UAM-MAO. In this strain, both GAA and CYN can be located within and out the cells. In conclusion, GAA appears to be a general cyanobacterial metabolite that due to its proven toxic should be considered when studying and managing cyanobacteria toxicity. PMID- 25460749 TI - Metal leaching from the bridge paint waste in the presence of steel grit. AB - The disposal of paint waste from bridge rehabilitation is a significant issue because of the potential release of contaminants and the consequent impact to human health and the environment. In this study, leaching behavior of paint waste was evaluated for 24 bridges in New York State. Although elevated Pb (5-168,090 mg kg(-1)) and other metal concentrations were observed in the paint samples, leaching experiments that included the toxicity characteristic leaching procedure (TCLP) and the multiple extraction procedure (MEP) revealed toxicity characteristic (TC) limits were not exceeded. The relatively low concentrations observed are attributed to the use of iron-based abrasives (steel grit) in the paint removal process. In this research, trace metals are hypothesized to be sequestered through interactions with iron oxide coatings formed on the steel grit surface resulting in reduced leachable concentrations. Through sequential extraction iron oxides were observed at 11.03% by wt and X-ray diffraction (XRD) further corroborated the presence of iron oxide coatings on the steel grit surface. Sequential extraction demonstrated that less than 6.8% of Pb, Cr, and Ba were associated with the exchangeable and carbonate forms, while greater contributions were found with iron oxides. The largest fraction, however, greater than 80%, was associated with the residual phase comprised of minerals in the paint including SiO2 and TiO2. PMID- 25460750 TI - Bioenhanced dissolution of dense non-aqueous phase of trichloroethylene as affected by iron reducing conditions: model systems and environmental samples. AB - The anaerobic biotransformation of trichloroethylene (TCE) can be affected by competing electron acceptors such as Fe (III). This study assessed the role of Fe (III) reduction on the bioenhanced dissolution of TCE dense non-aqueous phase liquid (DNAPL). Columns were set up as 1-D diffusion cells consisting of a lower DNAPL layer, a layer with an aquifer substratum and an upper water layer that is regularly refreshed. The substrata used were either inert sand or sand coated with 2-line ferrihydrite (HFO) or two environmental Fe (III) containing samples. The columns were inoculated with KB-1 and were repeatedly fed with formate. In none of the diffusion cells, vinyl chloride or ethene was detected while dissolved and extractable Fe (II) increased strongly during 60 d of incubation. The cis-DCE concentration peaked at 4.0 cm from the DNAPL (inert sand) while it was at 3.4 cm (sand+HFO), 1.7 cm and 2.5 cm (environmental samples). The TCE concentration gradients near the DNAPL indicate that the DNAPL dissolution rate was larger than that in an abiotic cell by factors 1.3 (inert sand), 1.0 (sand+HFO) and 2.2 (both environmental samples). This results show that high bioavailable Fe (III) in HFO reduces the TCE degradation by competitive Fe (III) reduction, yielding lower bioenhanced dissolution. However, Fe (III) reduction in environmental samples was not reducing TCE degradation and the dissolution factor was even larger than that of inert sand. It is speculated that physical factors, e.g. micro-niches in the environmental samples protect microorganisms from toxic concentrations of TCE. PMID- 25460751 TI - Perchloroethylene (PCE) oxidation by percarbonate in Fe(2+)-catalyzed aqueous solution: PCE performance and its removal mechanism. AB - The performance of Fe(2+)-catalyzed sodium percarbonate (SPC) stimulating the oxidation of perchloroethylene (PCE) in groundwater remediation was investigated. The experimental results showed that PCE could be completely oxidized in 5 min at 20 degrees C with a Fe(2+)/SPC/PCE molar ratio of 8/8/1, indicating the effectiveness of Fe(2+)-catalyzed SPC oxidation for PCE degradation. Fe(2+) catalyzed SPC oxidation was suitable for the nearly neutral pH condition, which was superior to the conventional Fenton oxidation in acidic condition. In addition, the investigations by using hydroxyl radical scavengers and free radical probe compounds elucidated that PCE was degraded mainly by hydroxyl radical (HO) oxidation in Fe(2+)/SPC system. In conclusion, Fe(2+)-catalyzed SPC oxidation is a highly promising technique for PCE-contaminated groundwater remediation, but more complex constituents in groundwater should be carefully considered for its practical application. PMID- 25460752 TI - Quantitative proteomic analysis reveals proteins involved in the neurotoxicity of marine medaka Oryzias melastigma chronically exposed to inorganic mercury. AB - Mercury is a ubiquitous environmental contaminant which exerts neurotoxicity upon animals. Nevertheless, the molecular mechanisms involved in inorganic mercury neurotoxicity are unknown. We investigated protein profiles of marine medaka, chronically exposed to mercuric chloride using two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF-TOF MS) analysis. The mercury accumulation and ultrastructure were also examined in the brain. The results showed that mercury was significantly accumulated in the treated brain, and subsequently caused a noticeable damage. The comparison of 2D-DIGE protein profiles between the control and treatment revealed that 16 protein spots were remarkably altered in abundance, which were further submitted for MALDI-TOF-TOF MS analysis. The identified proteins indicated that inorganic mercury may cause neurotoxicity through the induction of oxidative stress, cytoskeletal assembly dysfunction and metabolic disorders. Thus, this study provided a basis for a better understanding of the molecular mechanisms involved in mercury neurotoxicity. PMID- 25460753 TI - The fate of polycyclic aromatic hydrocarbons (PAHs) and organochlorine pesticides (OCPs) in water from Poyang Lake, the largest freshwater lake in China. AB - The fate of polycyclic hydrocarbons (PAHs) and organochlorine pesticides (OCPs) in the water columns from Poyang Lake was studied. The total concentrations of OCPs and PAHs were 19.10-111.78 ng L(-1) and 5.56-266.1 ng L(-1), respectively. Among OCPs, endosulfans, chlordanes, and HCHs accounted for 21.96%, 24.6% and 24.65%, and were the predominant pollutants. Results suggested that the main sources of DDTs were residue from technical DDTs and dicofol, as well as antifouling paints for ships, while for HCHs, the main sources included long distance transmission, agriculture activities and the combination of industrial products with separate lindane in use. As for PAHs, the predominance of lower molecular weight congeners demonstrated that petroleum and the combustion products of fuel oil, as well as other pyrogenic sources, contributed to the main input of PAHs in the Poyang region. The vehicle emissions were mostly from diesel engines. Moreover, HCH, DDT and BaP concentrations in water of Poyang Lake were all below the threshold values. PMID- 25460754 TI - Identification and characterization of steady and occluded water in drinking water distribution systems. AB - Deterioration and leakage of drinking water in distribution systems have been a major issue in the water industry for years, which are associated with corrosion. This paper discovers that occluded water in the scales of the pipes has an acidic environment and high concentration of iron, manganese, chloride, sulfate and nitrate, which aggravates many pipeline leakage accidents. Six types of water samples have been analyzed under the flowing and stagnant periods. Both the water in the exterior of the tubercles and stagnant water carry suspended iron particles, which explains the occurrence of "red water" when the system hydraulic conditions change. Nitrate is more concentrated in occluded water under flowing condition in comparison with that in flowing water. However, the concentration of nitrate in occluded water under stagnant condition is found to be less than that in stagnant water. A high concentration of manganese is found to exist in steady water, occluded water and stagnant water. These findings impact secondary pollution and the corrosion of pipes and containers used in drinking water distribution systems. The unique method that taking occluded water from tiny holes which were drilled from the pipes' exteriors carefully according to the positions of corrosion scales has an important contribution to research on corrosion in distribution systems. And this paper furthers our understanding and contributes to the growing body of knowledge regarding occluded environments in corrosion scales. PMID- 25460755 TI - TNT and RDX degradation and extraction from contaminated soil using subcritical water. AB - The use of explosives either for industrial or military operations have resulted in the environmental pollution, poses ecological and health hazard. In this work, a subcritical water extraction (SCWE) process at laboratory scale was used at varying water temperature (100-175 degrees C) and flow rate (0.5-1.5 mL min( 1)), to treat 2,4,6-trinitrotoluene (TNT) and hexahydro-1,3,5-trinitro-1,3,5 triazine (RDX) contaminated soil, to reveal information with respect to the explosives removal (based on the analyses of soil residue after extraction), and degradation performance (based on the analyses of water extracts) of this process. Continuous flow subcritical water has been considered on removal of explosives to avoid the repartitioning of non-degraded compounds to the soil upon cooling which usually occurs in the batch system. In the SCWE experiments, near complete degradation of both TNT and RDX was observed at 175 degrees C based on analysis of water extracts and soil. Test results also indicated that TNT removal of >99% and a complete RDX removal were achieved by this process, when the operating conditions were 1 mL min(-1), and treatment time of 20 min, after the temperature reached 175 degrees C. HPLC-UV and ion chromatography analysis confirmed that the explosives underwent for degradation. The low concentration of explosives found in the process wastewater indicates that water recycling may be viable, to treat additional soil. Our results have shown in the remediation of explosives contaminated soil, the effectiveness of the continuous flow SCWE process. PMID- 25460756 TI - Brown haze types due to aerosol pollution at Hefei in the summer and fall. AB - Brown haze episodes were evaluated at Hefei in the summer (June-August) and fall (September-November) seasons, and typical haze types were identified by air-mass back-trajectories and fire spot maps. Compared with clear weather conditions, larger median single scattering albedo values of 0.82 and 0.78 at 550 nm were obtained for the summer and fall haze episodes, respectively. Further, the observed lower scattering Angstrom exponents imply that more large particles than small particles dominated the haze plumes, which is in agreement with the profiles of size distribution. Particles during a haze episode in Hefei grow to a size such that the 0.10 limit for the backscattering ratio is reached, which may indicate that the aged aerosols promote the formation of haze episodes. Three typical haze types were identified: biomass burning, anthropogenic industrial and traffic emissions, and brown carbon. Less negative aerosol radiative forcing efficiencies of -12.7 and -10.9 W m(-2) in summer and fall were estimated, respectively, for haze impacted by biomass burning, which emphasizes an enhanced significance of biomass burning aerosols on climate forcing. PMID- 25460757 TI - Arsenic speciation transformation and arsenite influx and efflux across the cell membrane of fungi investigated using HPLC-HG-AFS and in-situ XANES. AB - Microorganisms dominated speciation of arsenic (As) play an important role in the biogeochemical cycling of As. In the study, species transformation of arsenite [As(III)] and As(III) influx and efflux across the cell membranes of Trichoderma asperellum SM-12F1, Penicillium janthinellum SM-12F4, and Fusarium oxysporum CZ 8F1 cells were studied using a cellular lysis plus chromatographic separation method and further the in-situ X-ray absorption near edge structure (XANES) analysis. The results indicated that As(III) can enter into fungal cells and that a portion of the As(III) can be exuded out of cells. For both As sequestrated into fungal cytoplasm and As adsorbtion onto cell walls, As(III) was found to be the dominated form of As. XANES analysis showed that As(III) accounted for 58.4%, 59.5%, and 73.0% of the total As in the cells of T. asperellum SM-12F1, P. janthinellum SM-12F4, and F. oxysporum CZ-8F1, respectively. Among these fungal strains, however, there were obvious differences in the relative proportions of arsenate [As(V)], monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA). For T. asperellum SM-12F1, the proportion (%) of MMA was 31.1%, and no As(V) or DMA was detected. For F. oxysporum CZ-8F1, the proportions of As(V) and MMA were 15.8% and 8.8%, respectively, but no DMA was observed. As(V), MMA, and DMA accounted for 4.2%, 29.5%, and 8.1%, respectively, of the P. janthinellum SM-12F4 cells. Some of the intracellular As(III) can be oxidated and methylated by these fungal strains and yield As(V), MMA, and DMA as products. PMID- 25460758 TI - Influence of humic acids on sorption of alkanes by carbon nanotubes--implications for the dominant sorption mode. AB - The presence of humic substances (HS) has previously been shown to alter sorption properties of multi-walled carbon nanotubes (MWCNTs). To systematically study this process, three alkane pairs were selected as molecular probe sorbates. The influence of HS on sorption affinity, sorption linearity, and the dominant sorption mode (i.e., ad- or absorption) by MWCNTs was investigated. The addition of HS led to a continuous decrease in sorption affinity and an increase in sorption linearity with increasing HS addition. Furthermore, the comparison of distribution coefficients of n- and cycloalkanes showed that the dominant sorption mode remains to be adsorption regardless of the presence of HS on MWCNT surface. From this, it can be concluded that instead of a change in sorption mode to absorption of sorbates into HS-coated MWCNT, HS blocks high-energy sorption sites for subsequently added sorbates and that sorbates continuously sorb on the MWCNT surface. PMID- 25460759 TI - On the control of copper colloidal distribution by humic substances in the Penze estuary. AB - In this study, we investigated the variations of colloidal Cu in a temperate macrotidal estuarine system (Penze, NW France). The originality of this work resides on examining seven colloidal/dissolved fractions at seven different periods of the year whereas previous studies on estuaries generally considered two or three fractions and were focused on a unique survey. A high proportion of Cu (~90%) was generally found as colloids (5 kDa-0.45 MUm) throughout the salinity gradient with divergent size distributions being observed over the seasonal cycle. This consisted essentially in two contrasted periods, i.e. winter spring with a greater association of Cu with high molecular weight (HMW) compounds (50 kDa-0.45 MUm) and summer-autumn with Cu being found mainly as low molecular weight (LMW) forms (5-50 kDa). The comparison of Cu with humic substances (HS) data allowed to us to highlight the importance of the pedogenic refractory organic matter in controlling the concentrations and the size distribution of Cu in the estuary. In the mixing zone, Cu behaved conservative in autumn and winter but important additions of HMW compounds were observed in spring in the lower estuary as the result of particulate organic matter degradation in the sediment. Although HS appears to be the background chelators of Cu in the systems, the strong benthic inputs occurring in spring may be of different (biotic) origin and may be in part responsible for the higher association of Cu with HMW compounds. PMID- 25460760 TI - Degradation kinetics of the insecticide spinetoram in a rice field ecosystem. AB - The fate of spinetoram was studied in a rice field ecosystem, and an efficient method for the determination of spinetoram (XDE-175-J and XDE-175-L) in soil, rice straw, paddy water, husk and brown rice was developed. Spinetoram residues were extracted from samples with a salting out extraction procedure. The extracts were diluted with 0.10% formic acid in water and analysed with liquid chromatography tandem mass spectrometry (LC-MS/MS) on a Waters Acquity BEH C18 column. The calibration curve was linear in the range 0.125-100 MUg L(-1) and r>0.999. The average recovery was 82.9-89.0% from soil, 78.5-92.1% from rice straw, 93.6-100.3% from paddy water, 79.1-87.9% from brown rice and 72.7-82.9% from husk. The relative standard deviation (RSD) was less than 10%. These results are all within the accepted range for pesticide residue determination. The field test results showed that spinetoram degradation in paddy water, soil and rice straw coincided with C=0.0132e(-1.9685t), C=0.0308e(-0.1018t) and C=0.8530e( 0.6223t), respectively. The half-lives of spinetoram in paddy water, soil and rice straw were 0.35, 6.8 and 1.1 d, respectively. The final residue level was lower than the maximum residue limit (MRL) of 0.05 mg kg(-1) for spinetoram in rice with a harvest interval of 7d. A dosage of 450 mL ha(-1) was recommended, which can be considered safe for human beings and animals. The results of this study will contribute to establishing the scientific basis of the dosage of spinetoram for agricultural fields. PMID- 25460761 TI - Element enrichment factor calculation using grain-size distribution and functional data regression. AB - In environmental geochemistry studies it is common practice to normalize element concentrations in order to remove the effect of grain size. Linear regression with respect to a particular grain size or conservative element is a widely used method of normalization. In this paper, the utility of functional linear regression, in which the grain-size curve is the independent variable and the concentration of pollutant the dependent variable, is analyzed and applied to detrital sediment. After implementing functional linear regression and classical linear regression models to normalize and calculate enrichment factors, we concluded that the former regression technique has some advantages over the latter. First, functional linear regression directly considers the grain-size distribution of the samples as the explanatory variable. Second, as the regression coefficients are not constant values but functions depending on the grain size, it is easier to comprehend the relationship between grain size and pollutant concentration. Third, regularization can be introduced into the model in order to establish equilibrium between reliability of the data and smoothness of the solutions. PMID- 25460762 TI - Determination of nicotine and cotinine in meconium from Greek neonates and correlation with birth weight and gestational age at birth. AB - Tobacco exposure during pregnancy is a major factor of morbidity and mortality for both the pregnant woman and the fetus. Several studies in the past have detected and quantified tobacco smoke biomarkers in infant meconium samples. Aim of this study was to measure prenatal exposure to tobacco smoke by detecting nicotine and cotinine in meconium and to try to evaluate the extent of exposure to smoke through passive smoking as well as the relationship between tobacco biomarker meconium concentrations and neonatal outcomes. Tobacco smoke biomarkers nicotine and cotinine were detected and quantitated in meconium from tobacco exposed and non-exposed Greek neonates using liquid chromatography-tandem mass spectrometry. The study included 45 neonates from active, passive and non-smoking women during pregnancy. The results showed significant values of nicotine and cotinine concentration in neonates from both active and passive smokers which reached 125 ng g(-1) for nicotine and 98.5 ng g(-1) for cotinine and varied according to the type and level of exposure. In general nicotine and cotinine concentrations correlated with the degree of active smoking by the mother. Similarly, nicotine and cotinine were measured in the meconium of infants of passive smokers at concentrations comparable to those of infants whose mothers were moderate smokers. Our findings show that exposure of the fetus to tobacco biomarkers can be substantial even in passive maternal smoking and there is a statistically significant negative correlation between nicotine or cotinine concentrations in meconium and birth weight or gestational age at birth. PMID- 25460763 TI - Quantities, sources and adsorption of polybrominated diphenyl ethers in components of surficial sediments collected in Songhua River (Jilin City), China. AB - Quantities of polybrominated diphenyl ethers (PBDEs, BDE-28, 47, 99, 100, 153, 154, 183 and 209) in surficial sediments (SSs) of the Songhua River, China were extracted and detected by Soxhlet extractor and gas chromatography/mass spectrometry (GC/MS). Sources of the PBDEs were investigated by factor analysis. Contributions of Fe oxides, Mn oxides and organic matters (OMs), and their interactions of SSs to the adsorption of PBDEs were described based on multiple linear regressions. The analysis results from GC/MS indicated that the concentrations of PBDEs ranged from 2.90 to 9871 ng g(-)(1) (dry weight) with a mean value of 397 ng g(-)(1). The congener profiles of the SSs were dominated by BDE-209 (?71.8%). Relatively high contents of PBDEs were observed in SSs from the upstream section. Deca-BDE commercial formulations constituted the largest contribution (33.6%) to PBDEs in the SSs, followed by Penta-BDE commercial formulations (21.7%) and Octa-BDE commercial formulations (13.2%). Each of the components in the SSs contributes positively to PBDEs' adsorption. Synergism of Fe oxides and OMs was observed in the PBDEs' adsorption. The interactions of Mn oxides and other components inhibited the PBDEs' adsorption onto SSs, and the antagonism in the BDE-209 adsorption was stronger than other Sigma7PBDEs (BDE-28, 47, 99, 100, 153, 154 and 183). However, the synergism observed in the Sigma7PBDEs adsorption was stronger than BDE-209. The BDE-209 in SSs mainly came from Deca-BDE commercial formulations. The adsorption of PBDEs onto SSs was affected by the octanol-water coefficient (Kow) of the PBDEs' congeners and the components of the SSs. PMID- 25460764 TI - Xylem transport and gene expression play decisive roles in cadmium accumulation in shoots of two oilseed rape cultivars (Brassica napus). AB - Cadmium (Cd) is a toxic metal which harms human health through food chains. The mechanisms underlying Cd accumulation in oilseed rape are still poorly understood. Here, we investigated the physiological and genetic processes involved in Cd uptake and transport of two oilseed rape cultivars (Brassica napus). L351 accumulates more Cd in shoots but less in roots than L338. A scanning ion-selective electrode technique (SIET) and uptake kinetics of Cd showed that roots were not responsible for the different Cd accumulation in shoots since L351 showed a lower Cd uptake ability. However, concentration dependent and time-dependent dynamics of Cd transport by xylem showed L351 exhibited a superordinate capacity of Cd translocation to shoots. Additionally, the Cd concentrations of shoots and xylem sap showed a great correlation in both cultivars. Furthermore, gene expression levels related to Cd uptake by roots (IRT1) and Cd transport by xylem (HMA2 and HMA4) were consistent with the tendencies of Cd absorption and transport at the physiological level respectively. In other words, L351 had stronger gene expression for Cd transport but lower for Cd uptake. Overall, results revealed that the process of Cd translocation to shoots is a determinative factor for Cd accumulation in shoots, both at physiological and genetic levels. PMID- 25460765 TI - Occurrence, sources and health risk assessment of polycyclic aromatic hydrocarbons in urban (Pudong) and suburban soils from Shanghai in China. AB - A comprehensive investigation was conducted to the urban (Pudong) and suburban soils in Shanghai. A total of 154 soil samples were analyzed for 26 PAHs including highly carcinogenic dibenzopyrenes (DBPs). The total concentrations ranged from 25.8 to 7380 MUg kg(-1) for Sigma26PAHs and 18.8 to 6320 MUg kg(-1) for 16 USEPA priority PAHs (Sigma16PAHs), respectively. The BaP toxic equivalent (BaPeq) concentrations were between 6.41 and 2880 MUg kg(-1) for Sigma24PAHs, 1.11 and 620 MUg kg(-1) for Sigma16PAHs and 2.72 and 2250 MUg kg(-1) for Sigma4DBPs. The high PAH contamination in green land soils might originate mainly from local road traffic and industrial activities, and sewage sludge application or waste water irrigation for soil. Seven sources of soil PAHs in Shanghai were identified by positive matrix factorization (PMF) model. The mean risk quotient (m-RQ) values indicated that there were medium to high ecological risks in 9.10% of soil samples, pyrene (Pyr), benzo[b]fluoranthene (BbF) and benz[a]anthracene (BaA) were the major ecological risk drivers under agricultural use. The cancer risk (CR) values were within the acceptable range at 35.7%, 35.1% and 31.2% of sampling sites for children, youths and adults, respectively. The total lifetime carcinogenic risk (TLCR) values at 57.8% of sampling sites were within the acceptable range. Overall, cancer risks of soil PAHs in all sampling sites in the studied area were below the highest acceptable risk, suggesting that soil PAHs are unlikely to pose a significant cancer risk for population based on ingestion, dermal contact and inhalation exposure pathways. PMID- 25460767 TI - Biodegradation screening of chemicals in an artificial matrix simulating the water-sediment interface. AB - Biodegradation is the most important attenuation process for most of organic chemicals in the environment. This process decides whether the organic substance itself or its degradation products rests in the environment and should be considered for a further risk assessment. This work presents the development of a water sediment screening test, based on OECD guideline 308, with a high significance to environmental conditions and with a good reproducibility and consistency of results. The increased reproducibility was achieved by creating an artificial and standardized medium, based on the existing OECD guidelines OECD 302C, 301D and 218. Each test consisted of five different series: blank, quality control, test, toxicity control and abiotic control. Biodegradation was assessed by measurement of pressure difference in closed vessels using the OxiTop((r)) system. Aniline, diethylene glycol and sodium acetate were used to optimize and validate test conditions. Additionally, two pharmaceuticals: Acetaminophen and ciprofloxacin (CIP) were tested as an example of possible test application. Acetaminophen was mainly removed from the system by biodegradation whereas CIP was removed from water phase by sorption onto sediment. Water sediment test proved to be a promising tool for the biodegradation investigation of chemicals in the water-sediment interface. PMID- 25460766 TI - Influence of rice growth on the fate of polycyclic aromatic hydrocarbons in a subtropical paddy field: a life cycle study. AB - We measured the concentrations and profiles of polycyclic aromatic hydrocarbons (PAHs) in the soil, water, and rice tissues from a typical subtropical paddy system at various stages of rice growth over two growing seasons. Rice growth had a significant impact on the distribution and dissipation of PAHs in the paddy field. While rice was growing, the concentrations of PAHs in the soils decreased at an average decline rate of 5.3+/-2.9 ng PAHs g(-1) soild(-1), whereas, the concentrations of PAHs in rice tissues increased with growth time. However, the concentrations of PAHs in the rice leaves decreased during the heading stage of both two growing seasons. PAH profiles in soil, water, and different rice tissues also showed different patterns with the growing time of rice. Irrigation water was a significant source of PAHs to the paddy field. Rice growth enhanced the dissipation and transport of PAHs in the paddy system, while the sewage irrigation and straw burning after harvest added or returned PAHs to the system. For food safety precaution, sewage irrigation and straw burning should be well monitored and controlled. PMID- 25460768 TI - Assessment of lead bioaccessibility in soils around lead battery plants in East China. AB - Soil ingestion is an important human exposure pathway for lead (Pb). A modified physiologically based extraction test was applied to 70 soil samples from five battery plants in East China. The mean values for soil pH, soil organic matter, Fe and Mn concentrations ranged from 5.9% to 8.1, 0.37% to 2.2%, 2.78% to 3.75%, and 507-577 mg kg(-1), respectively, while Pb concentrations ranged widely in 14.3-2000 mg kg(-1). The isotopic ratios of 14 soils from one of the five battery plants formed a straight line in the plot of (208)Pb/(206)Pb vs. (207)Pb/(206)Pb, indicating Pb emissions from the lead battery plant as the dominant anthropogenic source within 200 m. Lead bioaccessibility in the soils ranged from 4.1% to 66.9% in the gastric phase and from 0.28% to 9.29% in the gastrointestinal phase. Multiple step regressions identified modes as BAgastric= 106.8+0.627[Pb]+19.1[Fe]+11.3[SOM], and BAgastrointestinal=-2.852+0.078[Pb]. PMID- 25460769 TI - Oxidation of tetracycline antibiotics induced by Fe(III) ions without light irradiation. AB - The presence of Fe(III) ions was found to induce degradation of three tetracycline antibiotics (TCs), tetracycline (TTC), oxytetracycline (OTC) and chlorotetracycline (CTC), in aqueous solutions without light. The presence of Fe(III) promoted the degradation of TCs in most experimental pH (5.0, 7.0 and 9.0) except at pH 9.0 for CTC. Degradation rate constants of TTC, OTC and CTC reached maximum ((6.2+/-0.5)*10(-3) h(-1), (10.6+/-0.1)*10(-3) h(-1) and (15.9+/ 0.5)*10(-3) h(-1) at pH 7.0, 20 degrees C) when Fe(III):TC molar ratio was 1:1, 1:1 and 2:1, respectively. Such metal-to-ligand ratios agreed well with the most favorable complexation between Fe(III) and each TC. Compared to without metals, Fe(III) enhanced the degradation rate of TTC, OTC and CTC by up to 20.67, 7.07 and 2.30 times, respectively, in clean water matrix, and also promoted degradation of TCs in real surface water and wastewater matrices. The promoted degradation likely occurred via complexation of TCs and subsequent oxidation by Fe(III). Degradation results of CTC versus 4-epi-CTC suggested Fe(III) likely binds to TCs' C4 dimethylamino group. Toxicity of the complexes evaluated using Photobacterium phosphoreum T3 was increased after several hours of reaction, suggesting the transformation products may exert a stronger toxicity than parent TCs. This study identifies new oxidative transformation of TCs induced by Fe(III) ions without light irradiation, further supporting the important role of iron species in the environmental fate of TCs. PMID- 25460770 TI - Uptake and transport mechanisms of decabromodiphenyl ether (BDE-209) by rice (Oryza sativa). AB - The extensive industrial use of brominated flame retardants has aroused rapidly growing public concerns about their ubiquity in the environment. The feasibility of uptake and translocation of decabromodiphenyl ether (BDE-209) by three rice cultivars, namely Fengmeizhan, Hefengzhan and Guangyinzhan, and the uptake mechanisms of BDE-209 into rice roots, were investigated by employing a partition limited model. Uptake of BDE-209 by the rice cultivars (Fengmeizhan, Hefengzhan and Guangyinzhan) was examined by a 60-day cultivation in sterilized BDE-209 spiked sand, followed by Soxhlet extraction and gas chromatography-mass spectrometry (GC-MS) analysis. A partition-limited model was applied for estimating and describing the approach of the uptake of BDE-209 by rice in sand. The average quasi-equilibrium factor (alphapt) of BDE-209 in root uptake in sand was 0.112*10(-3) for three rice cultivars in the present study (<1), implying a non-equilibrium movement of molecules and a dominated passive transport uptake. According to the results of sorption analysis of dead and fresh roots, apoplastic pathway likely dominated the transport of BDE-209 into roots cells. PMID- 25460771 TI - Determination of polyoxymethylene (POM)--water partition coefficients for oxy PAHs and PAHs. AB - Oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) are a class of ubiquitously occurring pollutants of which little is known. They can be co emitted with PAHs or formed from PAHs in the environment. The environmental fate and risk of oxy-PAHs are difficult to assess due to a lack of methods to quantify their pore water concentrations. One sampler that can be used to determine freely dissolved concentrations of organic contaminants is polyoxymethylene (POM). In this study, POM - water partition coefficients (KPOM) were determined for 11 oxy PAHs. KPOM values of 8 PAHs with similar hydrophobicities as the oxy-PAHs were determined for comparison. Results showed that logKPOM values ranged from 2.64 to 4.82 for the PAHs (2-4 rings), similar to previously determined values. LogKPOM values for investigated oxy-PAHs ranged from 0.96 to 5.36. The addition of carbonylic oxygen on a parent PAH generally lowered KPOM by 0.5 to 1.0 log units, which is attributable to the presence of carbonylic oxygens increasing water solubility. The KPOM values presented here will facilitate simultaneous assessments of freely dissolved water concentrations of oxy-PAHs and PAHs in environmental media. PMID- 25460772 TI - Kinetic studies of heterogeneous reactions of particulate phosmet and parathion with NO3 radicals. AB - Organophosphorous pesticides (OPPs) are ubiquitous pollutants in the atmospheric environment with adverse effects on human health. In this study, heterogeneous kinetics of particulate phosmet and parathion with NO3 radicals were investigated with a mixed-phase relative rate method. A vacuum ultraviolet photoionization aerosol time-of-flight mass spectrometer (VUV-ATOFMS) and an atmospheric gas analysis mass spectrometer were used to monitor online the decays of particulate OPPs and reference compound, respectively. Reactive uptake coefficients of NO3 radicals on phosmet and parathion particles were (0.12+/-0.03) and (0.14+/-0.04), respectively, calculated according to the measured OPPs loss ratios and the average NO3 concentrations. Additionally, the average effective rate constants for heterogeneous reactions of particulate phosmet and parathion with NO3 radicals measured under experimental conditions were (2.80+/-0.16)*10(-12) and (2.97+/-0.13)*10(-12) cm(3) molecule(-1) s(-1), respectively. The experimental results of these heterogeneous reactions in the aerosol state provide supplementary knowledge for kinetic behaviors of airborne OPPs particles. PMID- 25460773 TI - Substantial nitrous oxide emissions from intertidal sediments and groundwater in anthropogenically-impacted West Falmouth Harbor, Massachusetts. AB - Large N2O emissions were observed from intertidal sediments in a coastal estuary, West Falmouth Harbor, MA, USA. Average N2O emission rates from 41 chambers during summer 2008 were 10.7 mol N2O m(-2) h(-1)+/-4.43 MUmol N2O m(-2) h(-1) (standard error). Emissions were highest from sediments within a known wastewater plume, where a maximum N2O emission rate was 155 MUmol N2O m(-2) h(-1). Intertidal N2O fluxes were positively related to porewater ammonium concentrations at 10 and 25 cm depths. In groundwater from 7 shoreline wells, dissolved N2O ranged from 488% of saturation (56 nM N2O) to more than 13000% of saturation (1529 nM N2O) and was positively related to nitrate concentrations. Fresh and brackish porewater underlying 14 chambers was also supersaturated in N2O, ranging from 2980% to 13175% of saturation. These observations support a relationship between anthropogenic nutrient loading and N2O emissions in West Falmouth Harbor, with both groundwater sources and also local N2O production within nutrient-rich, intertidal sediments in the groundwater seepage face. N2O emissions from intertidal "hotspot" in this harbor, together with estimated surface water emissions, constituted 2.4% of the average overall rate of nitrogen export from the watershed to the estuary. This suggests that N2O emissions factors from coastal ecosystems may be underestimated. Since anthropogenic nutrient loading affects estuaries worldwide, quantification of N2O dynamics is warranted in other anthropogenically-impacted coastal ecosystems. PMID- 25460774 TI - Speciation and bioavailability of mercury in sediments impacted by gold mining in Colombia. AB - Mercury (Hg) speciation and bioavailability were studied in surface sediments affected by artisanal and small-scale gold mining (ASGM) in the Mojana region of Colombia. The results demonstrated higher levels in sampling stations that receive water streams carrying Hg from mining areas. The T-Hg concentrations were slightly elevated with values between 196.2 and 1187.6 ng g(-1) dry weight (dw) (mean 524.2+/-256.8 ng g(-1) dw). The MeHg concentrations were significantly correlated with the T-Hg and organic matter (OM) and represent between 1.7% and 3.6% (mean: 2.6%) of the T-Hg. A five-step sequential extraction procedure shown that most of T-Hg in sediments occur primarily as organically bound Hg (Hg-o), which constitutes 48.4% of the T-Hg, followed by elemental Hg fraction (Hg-e) bound to amorphous compounds, such as Fe/Mn oxides with 26.5%, and the fraction bound to sulfur (Hg-s), which constitutes 18.7%. Exchangeable Hg (Hg-w; water soluble Hg and stomach acid soluble mercury; Hg-h) represents between 1.7% and 4.7%. These fractions constitute a low percentage but exhibit a high level of risk when entering the water column, and they can bioaccumulate in organisms. The significant relationship between OM, T-Hg and MeHg suggests an important role in the control of the distribution, mobility and bioavailability of the Hg in the sediments. PMID- 25460775 TI - Arsenic species in atmospheric particulate matter as tracer of the air quality of Donana Natural Park (SW Spain). AB - Sampling and chemical analyses, including major compounds and trace elements, of atmospheric particulate matter (PM10 and PM2.5) have been performed during 2006 2007 in a regional background monitoring station located within the Donana Natural Park (SW of Spain). This region is strategic for air quality and climate change studies, representing a meeting place of the European and African continents, and the Atlantic Ocean and Mediterranean Sea. The present study based on meteorological parameters demonstrated long-range transport and impact of industrial plumes on the Donana Natural. Inorganic arsenic species (arsenate and arsenite) have been analyzed in particulate matter (PM) to characterize the impact of near Cu-smelter plumes and demonstrated the long-range transport of industrial pollutants. As(V) is the main specie of As and varies between 95% and 98% of total As in PM10 and 96-97% in PM2.5. The As(V)/As(III) ratio measured in emission plumes of a Cu-smelter are similar to the ratio found in the Donana Natural Park. The application of Positive Matrix Factorization (PMF) to atmospheric particulate matter estimated the contributions and chemical profiles of natural and anthropogenic sources impacting the Natural Park, demonstrating the industrial origin of the As and other toxic elements in the air. PMID- 25460776 TI - Lamins: the structure and protein complexes. AB - Lamins are nuclear intermediate filament (IF) proteins. They assemble to fibrous structures that are positioned between the inner nuclear membrane and the peripheral chromatin. A small fraction of lamins is also present in the nucleoplasm. Lamins are required to maintain the nuclear structure and, together with their associated proteins, are involved in most nuclear activities. Mutations in lamins cause >14 distinct diseases, called laminopathies, that include heart, muscle, fat and early aging diseases. However, it is not clear how lamins are organized in vivo and how the disease mutations affect lamin organization and functions. Here, we will review structural aspects of lamin assembly, discuss differences between peripheral and nucleoplasmic lamins and describe the protein complexes that lamins form. PMID- 25460777 TI - Intermediate filaments and the regulation of focal adhesion. AB - Focal adhesions are localized actin filament-anchoring signalling centres at the cell-extracellular matrix interface. The currently emerging view is that they fulfil an all-embracing coordinating function for the entire cytoskeleton. This review highlights the tight relationship between focal adhesions and the intermediate filament cytoskeleton. We summarize the accumulating evidence for direct binding of intermediate filaments to focal adhesion components and their mutual cross-talk through signalling molecules. Examples are presented to emphasize the high degree of complexity of these interactions equipping cells with a precisely controlled machinery for context-dependent adjustment of their biomechanical properties. PMID- 25460778 TI - Networking and anchoring through plectin: a key to IF functionality and mechanotransduction. AB - Intermediate filaments (IFs) are involved in multiple cellular processes that are essential for the maintenance of cell and tissue integrity as well as response and adaption to stress. Mainly through pathological manifestations in patients and the analysis of genetic mouse models, it became evident that cytolinker proteins of the plakin protein family are essential for many of the functions ascribed to IFs. As discussed in this review, one of them, plectin, affects the assembly properties, interaction potential, compartmentalization, and linkage properties of IFs, making it to a key player for IF functionality. The far reaching consequences of IFs not being well-connected for skin and muscular integrity, migration, and mechanotransduction are highlighted. PMID- 25460779 TI - Remodeling of keratin-coupled cell adhesion complexes. AB - Epithelial cells constitute the main barrier between the inside and outside of organs, acting as gatekeepers of their structure and integrity. Hemidesmosomes and desmosomes are respectively cell-matrix and cell-cell adhesions coupled to the intermediate filament cytoskeleton. These adhesions ensure mechanical integrity of the epithelial barrier. Although desmosomes and hemidesmosomes are essential in maintaining strong cell-cell and cell-matrix adhesions, there is an emerging view that they should be remodeled in order to maintain epithelial homeostasis. Here we review the adhesion properties of desmosomes and hemidesmosomes, as well as the mechanisms driving their remodeling. We also discuss recent data suggesting that keratin-coupled adhesion complexes can sense the biomechanical cellular environment and participate in the cellular response to such external cues. PMID- 25460781 TI - Commercial 3y-tzp and nanostructured zirconia for ceramic veneering: a sem study. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. PMID- 25460780 TI - Cytoskeletal crosstalk: when three different personalities team up. AB - Cell shape and mechanics are determined by the interplay of three distinct cytoskeletal networks, made of actin filaments, microtubules, and intermediate filaments. These three types of cytoskeletal polymers have rather different structural and physical properties, enabling specific cellular functions. However, there is growing evidence that the three cytoskeletal subsystems also exhibit strongly coupled functions necessary for polarization, cell migration, and mechano-responsiveness. Here we summarize this evidence from a biophysical point of view, focusing on physical (direct) interactions between the cytoskeletal elements and their influence on cell mechanics and cell migration. PMID- 25460782 TI - Human dental pulp stem cells growth and osteodifferentiation on porous resorbable scaffolds. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. PMID- 25460783 TI - [Not Available]. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. PMID- 25460784 TI - Projection and construction of a machine to study the retention and wear in attachments used on implant supported overdentures. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. PMID- 25460785 TI - Best impression materials in oral rehabilitation-study protolocol. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. PMID- 25460786 TI - Inferior alveolar nerve transposition with Piezosurgery(r): Report of a 4 cases. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. PMID- 25460787 TI - [Not Available]. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. PMID- 25460788 TI - In vitro susceptibility evaluation of Candida species isolated from removable prosthesis, from three antifungal agents and an essential oil. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. PMID- 25460789 TI - [Not Available]. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. PMID- 25460790 TI - A novel SPRY2 and SPRY4 interaction increases tooth agenesis susceptibility. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. PMID- 25460791 TI - Protocol of orofacial myofunctional evaluation: validity and reliability. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. PMID- 25460792 TI - Relation between dental anomalies in portuguese population. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. PMID- 25460793 TI - Hypodontia: a retrospective study of portuguese population. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. PMID- 25460794 TI - Comparison of flexural resistance of three types of commercial zirconia. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. PMID- 25460795 TI - "In vivo" bone tibial response to the application of mineral trioxide aggregate (MTA). Study in New Zealand white rabbit. AB - Short Communication selected from the Oral Presentations of the 56th Congress of the Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie, Penafiel (Portugal) May 2012. ";Prix du GIRSO"; 2012. PMID- 25460796 TI - Liaison alcaline: Pals entice non-endosomal ESCRTs to the plasma membrane for pH signaling. AB - The alkaline pH-responsive Pal/Rim signal transduction pathway mediating regulation of gene expression by ambient pH has been extensively studied in Aspergillus nidulans and Saccharomyces cerevisiae. In A. nidulans, PalH, PalI, PalF, PalC, PalA and PalB are required for the proteolytic activation of the executing transcription factor PacC. Although necessary, Pal proteins are insufficient to transmit the signal, which additionally requires ESCRT-I, II and Vps20 with Snf7 in ESCRT-III. Although this initially suggested cooperation between a plasma membrane sensor and an ESCRT-containing Pal complex on endosomes, recent evidence convincingly indicates that pH signaling actually takes place in plasma membrane-associated foci in which Pal proteins and an ESCRT III polymer scaffold cooperate for pH signaling purposes, representing another non-endosomal role of ESCRT components. PMID- 25460797 TI - Mechanisms for chromosome segregation. AB - Bacteria face the problem of segregating their gigantic chromosomes without a segregation period restricted in time and space, as Eukaryotes do. Segregation thus involves multiple activities, general or specific of a chromosome region and differentially controlled. Recent advances show that these various mechanisms conform to a "pair and release" rule, which appears as a general rule in DNA segregation. We describe the latest advances in segregation of bacterial chromosomes with emphasis on the different pair and release mechanisms. PMID- 25460798 TI - Spatial organization of bacterial chromosomes. AB - Bacterial chromosomes are organized in stereotypical patterns that are faithfully and robustly regenerated in daughter cells. Two distinct spatial patterns were described almost a decade ago in our most tractable model organisms. In recent years, analysis of chromosome organization in a larger and more diverse set of bacteria and a deeper characterization of chromosome dynamics in the original model systems have provided a broader and more complete picture of both chromosome organization and the activities that generate the observed spatial patterns. Here, we summarize these different patterns highlighting similarities and differences and discuss the protein factors that help establish and maintain them. PMID- 25460800 TI - Evolution, dynamics and specialized functions of glycosomes in metabolism and development of trypanosomatids. AB - Kinetoplastea such as trypanosomatid parasites contain specialized peroxisomes that uniquely contain enzymes of the glycolytic pathway and other parts of intermediary metabolism and hence are called glycosomes. Their specific enzyme content can vary strongly, quantitatively and qualitatively, between different species and during the parasites' life cycle. The correct sequestering of enzymes has great importance for the regulation of the trypanosomatids' metabolism and can, dependent on environmental conditions, even be essential. Glycosomes also play a pivotal role in life-cycle regulation of Trypanosoma brucei, as the translocation of a protein phosphatase from the cytosol forms part of a crucial developmental control switch. Many glycosomal proteins are differentially phosphorylated in different life-cycle stages, possibly indicative for unique forms of activity regulation, whereas many kinetic activity regulation mechanisms common for glycolytic enzymes are absent in these organisms. Glycosome turnover occurs by autophagic degradation of redundant organelles and assembly of new ones. This may provide the trypanosomatids with a manner to rapidly and efficiently adapt their metabolism to the sudden, major nutritional changes often encountered during the life cycle. This could also have helped facilitating successful adaptation of kinetoplastids, at multiple occasions during evolution, to their parasitic life style. PMID- 25460799 TI - Challenges posed by extracellular vesicles from eukaryotic microbes. AB - Extracellular vesicles (EV) produced by eukaryotic microbes play an important role during infection. EV release is thought to benefit microbial invasion by delivering a high concentration of virulence factors to distal host cells or to the cytoplasm of a host cell. EV can significantly impact the outcome of host pathogen interaction in a cargo-dependent manner. Release of EV from eukaryotic microbes poses unique challenges when compared to their bacterial or archaeal counterparts. Firstly, the membrane-bound organelles within eukaryotes facilitate multiple mechanisms of vesicle generation. Secondly, the fungal cell wall poses a unique barrier between the vesicle release site at the plasma membrane and its destined extracellular environment. This review focuses on these eukaryotic specific aspects of vesicle synthesis and release. PMID- 25460801 TI - The periplastidal compartment: a naturally minimized eukaryotic cytoplasm. AB - Many important algae groups like diatoms, dinoflagellates and 'kelp' but also apicomplexan parasites evolved in secondary endosymbiosis. Here, a eukaryote eukaryote endosymbiosis created chimeric cells, in which a eukaryotic symbiont was reduced to a complex plastid. Although having lost nearly all of the eukaryotic compartments of the symbiont, a tiny lumen representing the remnant of the cytoplasm of the symbiont is still present in most of these organisms. This compartment, the periplastidal compartment, shows different degrees of reductions as in two algal groups the former nucleus is still present in a minimized form, called nucleomorph, whereas most others have lost the genetic system completely. Thus, the natural reduction of eukaryotic cytoplasms can be studied in terms of evolution and functionality, giving additionally advices for the design of synthetic minimized compartments. PMID- 25460803 TI - Multilayer chromosome organization through DNA bending, bridging and extrusion. AB - All living cells have to master the extraordinarily extended and tangly nature of genomic DNA molecules - in particular during cell division when sister chromosomes are resolved from one another and confined to opposite halves of a cell. Bacteria have evolved diverse sets of proteins, which collectively ensure the formation of compact and yet highly dynamic nucleoids. Some of these players act locally by changing the path of DNA through the bending of its double helical backbone. Other proteins have wider or even global impact on chromosome organization, for example by interconnecting two distant segments of chromosomal DNA or by actively relocating DNA within a cell. Here, I highlight different modes of chromosome organization in bacteria and on this basis consider models for the function of SMC protein complexes, whose mechanism of action is only poorly understood so far. PMID- 25460802 TI - Cell cycle regulation by the bacterial nucleoid. AB - Division site selection presents a fundamental challenge to all organisms. Bacterial cells are small and the chromosome (nucleoid) often fills most of the cell volume. Thus, in order to maximise fitness and avoid damaging the genetic material, cell division must be tightly co-ordinated with chromosome replication and segregation. To achieve this, bacteria employ a number of different mechanisms to regulate division site selection. One such mechanism, termed nucleoid occlusion, allows the nucleoid to protect itself by acting as a template for nucleoid occlusion factors, which prevent Z-ring assembly over the DNA. These factors are sequence-specific DNA-binding proteins that exploit the precise organisation of the nucleoid, allowing them to act as both spatial and temporal regulators of bacterial cell division. The identification of proteins responsible for this process has provided a molecular understanding of nucleoid occlusion but it has also prompted the realisation that substantial levels of redundancy exist between the diverse systems that bacteria employ to ensure that division occurs in the right place, at the right time. PMID- 25460804 TI - The role of mitochondria in cytosolic-nuclear iron-sulfur protein biogenesis and in cellular iron regulation. AB - Mitochondria are indispensable in eukaryotes because of their function in the maturation of cytosolic and nuclear iron-sulfur proteins that are essential for DNA synthesis and repair, tRNA modification, and protein translation. The mitochondrial Fe/S cluster assembly machinery not only generates the organelle's iron-sulfur proteins, but also extra-mitochondrial ones. Biogenesis of the latter proteins requires the mitochondrial ABC transporter Atm1 that exports a sulfur containing compound in a glutathione-dependent fashion. The process is further assisted by the cytosolic iron-sulfur protein assembly machinery. Here, we discuss the knowns and unknowns of the mitochondrial export process that is also crucial for signaling the cellular iron status to the regulatory systems involved in the maintenance of cellular iron homeostasis. PMID- 25460805 TI - Management of multipartite genomes: the Vibrio cholerae model. AB - A minority of bacterial species has been found to carry a genome divided among several chromosomes. Among these, all Vibrio species harbor a genome split into two chromosomes of uneven size, with distinctive replication origins whose replication firing involves common and specific factors. Most of our current knowledge on replication and segregation in multi-chromosome bacteria has come from the study of Vibrio cholerae, which is now the model organism for this field. It has been firmly established that replication of the two V. cholerae chromosomes is temporally regulated and coupled to the cell cycle, but the mediators of these processes are as yet mostly unknown. The two chromosomes are also organized along different patterns within the cell and occupy different subcellular domains. The selective advantages provided by this partitioning into two replicons are still unclear and are a key motivation for these studies. PMID- 25460806 TI - The bacterial nucleoid: nature, dynamics and sister segregation. AB - Recent studies reveal that the bacterial nucleoid has a defined, self-adherent shape and an underlying longitudinal organization and comprises a viscoelastic matrix. Within this shape, mobility is enhanced by ATP-dependent processes and individual loci can undergo ballistic off-equilibrium movements. In Escherichia coli, two global dynamic nucleoid behaviors emerge pointing to nucleoid-wide accumulation and relief of internal stress. Sister segregation begins with local splitting of individual loci, which is delayed at origin, terminus and specialized interstitial snap regions. Globally, as studied in several systems, segregation is a multi-step process in which internal nucleoid state plays critical roles that involve both compaction and expansion. The origin and terminus regions undergo specialized programs partially driven by complex ATP burning mechanisms such as a ParAB Brownian ratchet and a septum-associated FtsK motor. These recent findings reveal strong, direct parallels among events in different systems and between bacterial nucleoids and mammalian chromosomes with respect to physical properties, internal organization and dynamic behaviors. PMID- 25460807 TI - RNA polymerase: chromosome domain boundary maker and regulator of supercoil density. AB - Most bacterial chromosomes and plasmids are covalently closed circular molecules that are maintained in a dynamic supercoiled state. Average supercoil density differs significantly between Escherichia coli and Salmonella. Two related questions are: What protein(s) create supercoil domain boundaries in a bacterial chromosome? and How is supercoil density regulated in different bacterial species? RNA polymerase plays pivotal roles in both of these topological phenomena. PMID- 25460809 TI - Kinetics of mast cell migration during transplantation tolerance. AB - BACKGROUND: After inflammatory stimulus, mast cells (MC) migrate to secondary lymphoid organs contributing to adaptive immune response. There is growing evidence that MC also contribute to transplant tolerance, but little is known about MC kinetics in the setting of transplant tolerance and rejection. Likewise it has been demonstrated that complement split products, which are known to act as chemoattractants for MC, are necessary for transplant tolerance. METHODS: Naive skin and lymph nodes, skin grafts and draining lymph nodes from wild type and complement deficient mice treated with a tolerogenic protocol were analyzed. RESULTS: Early after tolerance induction MC leave the graft and migrate to the draining lymph nodes. After this initial efflux, MC reappear in tolerant skin grafts in numbers exceeding that of naive skin. MC density in draining lymph nodes obtained from tolerant mice also increased post transplant. There was no difference in MC density, migration and degranulation status between wild type and complement deficient mice implicating that chemotaxis is not disturbed in complement deficient mice. CONCLUSION: This study gives detailed insight in kinetics of MC migration during transplant tolerance induction and rejection providing further evidence for a role of MC in transplant tolerance. PMID- 25460810 TI - Concordance and discordance in anti-HLA antibody testing. AB - BACKGROUND: Correct identification of the specificity of antibodies directed against HLA using single antigen Luminex beads (SALB) is essential in current HLA laboratory practice for transplantation. The aim of this study was to investigate the magnitude of concordance and discordance among laboratories in testing for anti-HLA antibodies using SALB. METHOD: 35 sera were distributed by the ASHI Proficiency Testing Program to HLA laboratories worldwide. We analyzed 4335 test results submitted between April 2010 and April 2013 by participating laboratories. RESULTS: SALB was used by approximately 94% of the participating laboratories, yet concordant assignment of antibody specificity was imperfect. For each serum, the assignment of an average of 10 antibody specificities was discordant. Disagreement was observed for antibodies directed against common as well as uncommon antigens. The assignment of an average of 15 antibody specificities in each "positive" serum appeared to be influenced by vendor dependent causes. Inter-vendor concordance was lower than intra-vendor concordance, indicating that vendor dependent factors may be a central cause for disagreement. CONCLUSIONS: Our study illustrates the prevalence of concordance and discordance, also affected by unpremeditated causes, in reporting SALB antibody results. Insufficient concordance and standardization in antibody testing may have practical implications for organ allocation and organ sharing programs. PMID- 25460811 TI - In a difficult access scenario, supraglottic airway devices improve success and time to ventilation. AB - The success of tracheal intubation (TI) is unacceptably low in unconventional positions. Supraglottic airway devices (SAD) have become an important alternative. An airway manikin was placed in a car, simulating an entrapped motor vehicle accident victim. The rescuer only had access through the driver's door. Participants were (n = 25) anaesthesiologists with experience in prehospital emergency medicine. They attempted to secure the airway by TI or an SAD (Ambu AuraOnce, iGel, laryngeal tube) in a random sequence. Performance was compared using the Wilcoxon signed-rank test. P values less than 0.05 were considered statistically significant. Fastest effective ventilation was achieved with iGel (11.5 +/- 6.9 s, P < 0.001), followed by a laryngeal mask (15.1 +/- 5.6 s, P < 0.001) and a laryngeal tube (17.6 +/- 5.3 s, P < 0.001); TI was the slowest (42.8 +/- 23.9 s, comparator). iGel (P < 0.001) and laryngeal mask (P = 0.01) also significantly outperformed the laryngeal tube. First ventilation was achieved significantly faster with SADs compared with TI. Success rates were also higher when using SADs. PMID- 25460812 TI - Disaster medicine through Google Glass. AB - Nontechnical skills can make a difference in the management of disasters and mass casualty incidents and any tool helping providers in action might improve their ability to respond to such events. Google Glass, released by Google as a new personal communication device, could play a role in this field. We recently tested Google Glass during a full-scale exercise to perform visually guided augmented-reality Simple Triage and Rapid Treatment triage using a custom-made application and to identify casualties and collect georeferenced notes, photos, and videos to be incorporated into the debriefing. Despite some limitations (battery life and privacy concerns), Glass is a promising technology both for telemedicine applications and augmented-reality disaster response support to increase operators' performance, helping them to make better choices on the field; to optimize timings; and finally represents an excellent option to take professional education to a higher level. PMID- 25460813 TI - The management of suspected scaphoid fractures in English hospitals: a national survey. AB - BACKGROUND: Wrist injuries are common, and there is often diagnostic uncertainty following normal initial radiographs when there is ongoing clinical suspicion of a scaphoid fracture.The aims of this study were to define the problem in our hospital, and to identify current practice relating to the management of patients with clinically suspected scaphoid injury across hospitals in England. METHODS: A retrospective review was undertaken of all patients presenting to our Emergency Department with a wrist injury, over a 12-month period.A cross-sectional survey of all hospitals in NHS England was then undertaken, using a web-based questionnaire. The results of the survey were analysed in Microsoft Excel to provide descriptive data only. RESULTS: Of 2367 patients presenting to our Emergency Department with a wrist injury, 420 (17.7%) were followed up due to ongoing clinical suspicion of a scaphoid injury.From the 141 acute hospital Trusts in NHS England, survey responses were received from 116 (82% response rate).Symptomatic patients undergo repeat radiograph in 68.0% of hospitals before second line imaging. This is performed using MRI in 63.9%, computed tomography in 27.0% or isotope bone scan in 9.0%.Secondary imaging is carried out between 10 days and 4 weeks following the initial injury in 86.8% of trusts. CONCLUSION: This is still considerable variability in the way these patients are managed in England. Further work needs to be undertaken to establish the most appropriate way to manage patients with wrist injuries with ongoing clinical suspicion of scaphoid fracture. PMID- 25460814 TI - Secure publish-subscribe protocols for heterogeneous medical wireless body area networks. AB - Security and privacy issues in medical wireless body area networks (WBANs) constitute a major unsolved concern because of the challenges posed by the scarcity of resources in WBAN devices and the usability restrictions imposed by the healthcare domain. In this paper, we describe a WBAN architecture based on the well-known publish-subscribe paradigm. We present two protocols for publishing data and sending commands to a sensor that guarantee confidentiality and fine-grained access control. Both protocols are based on a recently proposed ciphertext policy attribute-based encryption (CP-ABE) scheme that is lightweight enough to be embedded into wearable sensors. We show how sensors can implement lattice-based access control (LBAC) policies using this scheme, which are highly appropriate for the eHealth domain. We report experimental results with a prototype implementation demonstrating the suitability of our proposed solution. PMID- 25460815 TI - Tree crown mapping in managed woodlands (parklands) of semi-arid West Africa using WorldView-2 imagery and geographic object based image analysis. AB - Detailed information on tree cover structure is critical for research and monitoring programs targeting African woodlands, including agroforestry parklands. High spatial resolution satellite imagery represents a potentially effective alternative to field-based surveys, but requires the development of accurate methods to automate information extraction. This study presents a method for tree crown mapping based on Geographic Object Based Image Analysis (GEOBIA) that use spectral and geometric information to detect and delineate individual tree crowns and crown clusters. The method was implemented on a WorldView-2 image acquired over the parklands of Sapone, Burkina Faso, and rigorously evaluated against field reference data. The overall detection rate was 85.4% for individual tree crowns and crown clusters, with lower accuracies in areas with high tree density and dense understory vegetation. The overall delineation error (expressed as the difference between area of delineated object and crown area measured in the field) was 45.6% for individual tree crowns and 61.5% for crown clusters. Delineation accuracies were higher for medium (35-100 m(2)) and large (>=100 m(2)) trees compared to small (<35 m(2)) trees. The results indicate potential of GEOBIA and WorldView-2 imagery for tree crown mapping in parkland landscapes and similar woodland areas. PMID- 25460816 TI - Hyperspectral sensing for turbid water quality monitoring in freshwater rivers: Empirical relationship between reflectance and turbidity and total solids. AB - Total suspended solid (TSS) is an important water quality parameter. This study was conducted to test the feasibility of the band combination of hyperspectral sensing for inland turbid water monitoring in Taiwan. The field spectral reflectance in the Wu river basin of Taiwan was measured with a spectroradiometer; the water samples were collected from the different sites of the Wu river basin and some water quality parameters were analyzed on the sites (in situ) as well as brought to the laboratory for further analysis. To obtain the data set for this study, 160 in situ sample observations were carried out during campaigns from August to December, 2005. The water quality results were correlated with the reflectivity to determine the spectral characteristics and their relationship with turbidity and TSS. Furthermore, multiple-regression (MR) and artificial neural network (ANN) were used to model the transformation function between TSS concentration and turbidity levels of stream water, and the radiance measured by the spectroradiometer. The value of the turbidity and TSS correlation coefficient was 0.766, which implies that turbidity is significantly related to TSS in the Wu river basin. The results indicated that TSS and turbidity are positively correlated in a significant way across the entire spectrum, when TSS concentration and turbidity levels were under 800 mg.L(-1) and 600 NTU, respectively. Optimal wavelengths for the measurements of TSS and turbidity are found in the 700 and 900 nm range, respectively. Based on the results, better accuracy was obtained only when the ranges of turbidity and TSS concentration were less than 800 mg.L(-1) and less than 600 NTU, respectively and used rather than using whole dataset (R(2) = 0.93 versus 0.88 for turbidity and R(2) = 0.83 versus 0.58 for TSS). On the other hand, the ANN approach can improve the TSS retrieval using MR. The accuracy of TSS estimation applying ANN (R(2) = 0.66) was better than with the MR approach (R(2) = 0.58), as expected due to the nonlinear nature of the transformation model. PMID- 25460808 TI - Progress towards biocompatible intracortical microelectrodes for neural interfacing applications. AB - To ensure long-term consistent neural recordings, next-generation intracortical microelectrodes are being developed with an increased emphasis on reducing the neuro-inflammatory response. The increased emphasis stems from the improved understanding of the multifaceted role that inflammation may play in disrupting both biologic and abiologic components of the overall neural interface circuit. To combat neuro-inflammation and improve recording quality, the field is actively progressing from traditional inorganic materials towards approaches that either minimizes the microelectrode footprint or that incorporate compliant materials, bioactive molecules, conducting polymers or nanomaterials. However, the immune privileged cortical tissue introduces an added complexity compared to other biomedical applications that remains to be fully understood. This review provides a comprehensive reflection on the current understanding of the key failure modes that may impact intracortical microelectrode performance. In addition, a detailed overview of the current status of various materials-based approaches that have gained interest for neural interfacing applications is presented, and key challenges that remain to be overcome are discussed. Finally, we present our vision on the future directions of materials-based treatments to improve intracortical microelectrodes for neural interfacing. PMID- 25460817 TI - Vehicle tracking for an evasive manoeuvres assistant using low-cost ultrasonic sensors. AB - Many driver assistance systems require knowledge of the vehicle environment. As these systems are increasing in complexity and performance, this knowledge of the environment needs to be more complete and reliable, so sensor fusion combining long, medium and short range sensors is now being used. This paper analyzes the feasibility of using ultrasonic sensors for low cost vehicle-positioning and tracking in the lane adjacent to the host vehicle in order to identify free areas around the vehicle and provide information to an automatic avoidance collision system that can perform autonomous braking and lane change manoeuvres. A laser scanner is used for the early detection of obstacles in the direction of travel while two ultrasonic sensors monitor the blind spot of the host vehicle. The results of tests on a test track demonstrate the ability of these sensors to accurately determine the kinematic variables of the obstacles encountered, despite a clear limitation in range. PMID- 25460819 TI - Polymorphisms in the CISH gene are associated with susceptibility to tuberculosis in the Chinese Han population. AB - A recent multi-center case-control study identified several single nucleotide polymorphisms (SNPs) within the cytokine-inducible SRC homology 2 domain (CISH) gene that are associated with susceptibility to tuberculosis (TB) in both African and Asian populations. To acquire a more robust and well-powered estimate of the putative influence of these SNPs on TB susceptibility, we conducted a well designed case-control study in the Chinese Han population. We genotyped 3 previously identified SNPs within CISH in 600 patients with pulmonary TB and 618 healthy controls, and we calculated the pooled P-values and ORs of several studies that have also been conducted in the Chinese populations. The results of the case-control study showed that the C allele of rs2239751 and the T allele of rs414171 are associated with TB susceptibility, and this association exists only in women and young adults. The pooled analysis indicated that both SNPs are significantly associated with TB in the global populations and Chinese populations. The current study confirms that variants of CISH are associated with susceptibility to TB, suggesting that negative regulators of cytokine signaling may have a role in immunity against TB infection. We hypothesize that CISH and estrogen may interact in the cytokine-dependent regulation of the immune system. PMID- 25460820 TI - Genetic variability of Babesia parasites in Haemaphysalis spp. and Ixodes persulcatus ticks in the Baikal region and Far East of Russia. AB - To study Babesia diversity in Ixodid ticks in Russia, Ixodes persulcatus, Haemaphysalis japonica, Haemaphysalisconcinna, Dermacentor silvarum, and Dermacentor nuttalli ticks collected in the Far East and Baikal region were assayed for the presence of Babesia spp. using nested PCR. In total, Babesia DNA was detected in 30 of the 1125 (2.7%) I. persulcatus, 17 of the 573 (3.0%) H. concinna, and 12 of the 543 (2.2%) H. japonica but was undetectable in any of the 294 analyzed Dermacentor spp. Partial 18S rRNA gene sequences were determined for all of the positive samples. Among the positive ticks, nine I. persulcatus were infected by Babesia microti 'US'-type, five I. persulcatus were infected by Babesia divergens-like parasites, and 11 I. persulcatus were infected by Babesia venatorum. For all three of these species, the determined 18S rRNA gene sequences were identical to those of the Babesia genetic variants found previously in I. persulcatus in Russia. In addition, five I. persulcatus from the Baikal region and all of the positive Haemaphysalis spp. ticks carried 13 different sequence variants of Babesia sensu stricto belonging to distinct phylogenetic clusters. Babesia spp. from 29 ticks of different species collected in distinct locations belonged to the cluster of cattle and ovine parasites (Babesia crassa, Babesiamajor, Babesiamotasi, Babesiabigemina, etc.). Babesia spp. from four H. japonica ticks in the Far East belonged to the cluster formed by parasites of carnivores. One more Babesia sequence variant detected in an I. persulcatus tick from the Baikal region belonged to the cluster formed by parasites of cattle and wild cervids (B. divergens, Babesiacapreoli, B. venatorum, Babesiaodocoilei, etc.). PMID- 25460821 TI - Human infections due to Pseudomonas chlororaphis and Pseudomonas oleovorans harboring new bla(VIM-2)-borne integrons. PMID- 25460822 TI - Complete genome characterization and phylogenetic analysis of three distinct buffalo-origin PCV2 isolates from China. AB - Complete genome characterization of porcine circovirus type 2 (PCV2) for bovid origins was still unclear in China. Therefore, in this study, PCV2 full-length genome of buffalo-origin was amplified and analyzed using PCR, DNAStar and MEGA 5.1. Genome size of three distinct PCV2 strains (buffalo1, buffalo2 and buffalo3) was 1767 bp (48.56% G+C), 1767 bp (48.67% G+C) and 1768 bp (48.08% G+C), respectively. At the nucleotide level, their identity varied from 95% to 96% for complete genome, from 97% to 97.8% for ORF1, and from 90.6% to 94.4% for ORF2. At the amino acid level, their identity varied from 98.7% to 99% for ORF1, and from 88% to 94.9% for ORF2. Online Blast analysis showed that buffalo1, buffalo2 and buffalo3 had highest nucleotide identity (varied from 99.77% to 99.83%) with porcine-origin PCV2 strains. Moreover, in the phylogenetic tree, they were divided into three different clusters and belonged to the worldwide accepted genotypes of PCV2b, PCV2c and PCV2a, respectively. To summarize, this study first recorded complete genome information of PCV2 for non-porcine origins in China. PMID- 25460823 TI - Viral gastroenteritis in rotavirus negative hospitalized children <5 years of age from the independent states of the former Soviet Union. AB - PURPOSE: Rotavirus causes nearly 40% of all hospitalizations for AGE among children <5 years of age in the NIS of the former Soviet Union. The etiologic role of other established gastroenteritis viruses in this age group is unknown. METHODS: Laboratory-confirmed rotavirus negative fecal specimens (N=495) collected between January and December 2009 from children in 6 NIS (Armenia, Azerbaijan, Belarus, Georgia, Republic of Moldova and Ukraine) were tested for norovirus, sapovirus, enteric adenovirus and astrovirus by real-time RT-PCR. Genotyping was carried out by sequencing and phylogenetic analysis. RESULTS: Norovirus, enteric adenovirus, sapovirus and astrovirus were detected in 21.8%, 4.0%, 3.2%, and 1.4% of the rotavirus negative specimens, respectively. Mixed infections were identified in 4.1% of the specimens. Phylogenetic analysis showed co-circulation of several different genotypes with GII.4 Den Haag (2006b) norovirus, GI.2 sapovirus, adenovirus type 41, and astrovirus type 1 causing majority of the infections. CONCLUSION: Norovirus, enteric adenovirus, sapovirus and astrovirus account for a significant proportion (30.5%) of AGE in hospitalized children <5 years of age in 6 NIS. PMID- 25460824 TI - Full genome characterization of human Rotavirus A strains isolated in Cameroon, 2010-2011: diverse combinations of the G and P genes and lack of reassortment of the backbone genes. AB - Over the past few years whole genome sequencing of rotaviruses has become a routine laboratory method in many strain surveillance studies. To study the molecular evolutionary pattern of representative Cameroonian Rotavirus A (RVA) strains, the semiconductor sequencing approach was used following random amplification of genomic RNA. In total, 31 RVA strains collected during 2010-2011 in three Cameroonian study sites located 120 to 1240 km from each other were sequenced and analyzed. Sequence analysis of the randomly selected representative strains showed that 18 RVAs were Wa-like, expressing G1P[6], G12P[6], or G12P[8] neutralization antigens on the genotype 1 genomic constellation (I1-R1-C1-M1-A1 N1-T1-E1-H1), whereas 13 other strains were DS-1-like, expressing G2P[4], G2P[6], G3P[6], and G6P[6] on the genotype 2 genomic constellation (I2-R2-C2-M2-A2-N2-T2 E2-H2). No inter-genogroup reassortment in the backbone genes was observed. Phylogenetic analysis of the Cameroonian G6P[6] strains indicated the separation of the strains identified in the Far North region (Maroua) and the Northwest region (Bamenda and Esu) into two branches that is consistent with multiple introductions of G6P[6] strains into this country. The present whole genome based molecular characterization study indicates that the emerging G6P[6] strain is fully heterotypic to Rotarix, the vaccine introduced during 2014 in childhood immunization program in Cameroon. Continuous strain monitoring is therefore needed in this area and elsewhere to see if G6s, besides genotype G1 to G4, G8, G9 and G12, may become a new, regionally important genotype in the post vaccine licensure era in Africa. PMID- 25460825 TI - Strain diversity plays no major role in the varying efficacy of rotavirus vaccines: an overview. AB - While a monovalent Rotarix(r) [RV1] and a pentavalent RotaTeq(r) [RV5] have been extensively tested and found generally safe and equally efficacious in clinical trials, the question still lingers about the evolving diversity of circulating rotavirus strains over time and their relationship with protective immunity induced by rotavirus vaccines. We reviewed data from clinical trials and observational studies that assessed the efficacy or field effectiveness of rotavirus vaccines against different rotavirus strains worldwide. RV1 provided broad clinical efficacy and field effectiveness against severe diarrhea due to all major circulating strains, including the homotypic G1P[8] and the fully heterotypic G2P[4] strains. Similarly, RV5 provided broad efficacy and effectiveness against RV5 and non-RV5 strains throughout different locations. Rotavirus vaccination provides broad heterotypic protection; however continuing surveillance is needed to track the change of circulating strains and monitor the effectiveness and safety of vaccines. PMID- 25460826 TI - Oviposition signals and their neuroethological correlates in the Culex pipiens complex. AB - Mosquitoes in the Culex pipiens complex (Diptera: Culicidae), especially Cx. pipiens and Culex quinquefasciatus, have successfully exploited the rapid growth of the human population and globalization to their advantage by successfully utilizing man-made habitats, particularly for oviposition. Culex spp. lay over 100 eggs together in a raft. Each egg in the raft produces an apical droplet containing an oviposition attractant, erythro-6-acetoxy-5-hexadecanolide, commonly referred to as Mosquito Oviposition Pheromone (MOP). Here we present a detailed gas chromatography-mass spectrometry (GC-MS) analysis of the apical droplets from six populations that revealed MOP as the most abundant constituent. Subjecting MOP and the remaining 17 most abundant chemical constituents of the droplets from these populations to a Principal Component Analysis (PCA) resolved the populations into two distinct clusters that contained two populations each of Cx. quinquefasciatus and Culex pipiens molestus. The two Culex pipiens pipiens, however, did not resolve into a single cluster, with the Shasta population sorting closer to Cx. quinquefasciatus. Comparing the PCA scores with the genetic evidence from adult females using available molecular markers that have earlier shown to sort various Culex forms, we found that the molecular data support the PCA clustering pattern. Behavioral investigation of the droplet-induced attraction tested in gravid Cx. quinquefasciatus elicited various degrees of oviposition to the droplets from each population. Overall, droplets from all six populations induced higher attraction compared to controls. A detailed time course analysis of droplet composition in Cx. quinquefasciatus from 6 to 54 h post egg-laying identified MOP again as the main constituent. Finally, our electrophysiological investigation identified MOP as the only biologically active constituent from of the droplets eliciting responses from female antennae. These studies will aid in global efforts to understand the vector biology and evolution that can be exploited to develop novel vector management strategies. PMID- 25460818 TI - Molecular epidemiology and genomics of group A Streptococcus. AB - Streptococcus pyogenes (group A Streptococcus; GAS) is a strict human pathogen with a very high prevalence worldwide. This review highlights the genetic organization of the species and the important ecological considerations that impact its evolution. Recent advances are presented on the topics of molecular epidemiology, population biology, molecular basis for genetic change, genome structure and genetic flux, phylogenomics and closely related streptococcal species, and the long- and short-term evolution of GAS. The application of whole genome sequence data to addressing key biological questions is discussed. PMID- 25460827 TI - Prostaglandin E2 switches from a stimulator to an inhibitor of cell migration after epithelial-to-mesenchymal transition. AB - Epithelial-mesenchymal transition (EMT) is critical for embryonic development, and this process is recapitulated in adults during wound healing, tissue regeneration, fibrosis and cancer progression. Cell migration is believed to play a key role in both normal wound repair and in abnormal tissue remodeling. Prostaglandin E2 (PGE2) inhibits fibroblast chemotaxis, but stimulates chemotaxis in airway epithelial cells. The current study was designed to explore the role of PGE2 and its four receptors on airway epithelial cell migration following EMT using both the Boyden blindwell chamber chemotaxis assay and the wound closure assay. EMT in human bronchial epithelial cells (HBECs) was induced by TGF-beta1 and a mixture of cytokines (IL-1beta, TNF-alpha, and IFN-gamma). PGE2 and selective agonists for all four EP receptors stimulated chemotaxis and wound closure in HBECs. Following EMT, the EP1 and EP3 agonists were without effect, while the EP2 and EP4 agonists inhibited chemotaxis as did PGE2. The effects of the EP2 and EP4 receptors on HBEC and EMT cell migration were further confirmed by blocking the expected signaling pathways. Taken together, these results demonstrate that PGE2 switches from a stimulator to an inhibitor of cell migration following EMT of airway epithelial cells and that this inhibition is mediated by an altered effect of EP2 and EP4 signaling and an apparent loss of the stimulatory effects of EP1 and EP3. Change in the PGE2 modulation of chemotaxis may play a role in repair following injury. PMID- 25460829 TI - Hormonal effects on women's facial masculinity preferences: the influence of pregnancy, post-partum, and hormonal contraceptive use. AB - Here, we investigate changes in women's facial masculinity preferences across pregnancy and the post-partum period. The majority of previous research demonstrating changes in women's masculinity preferences has examined the impact of hormonal variation across the female menstrual cycle. Hormonal changes experienced during pregnancy and the post-partum period, critical periods in women's reproductive life histories, are considerably more extreme than the variation that occurs across the menstrual cycle, suggesting that differences in preferences may also be displayed during these times. We find that women's preference for masculinity in men's faces, but not women's faces, decreases in the post-partum period relative to pregnancy. Furthermore, when compared to a sample of nulliparous control participants, post-partum participants showed different masculinity preferences compared with women who were using hormonal contraception, with the direction of this difference dependent upon the sex of the face assessed. PMID- 25460830 TI - Effect of the liquorice root derivatives on salt and water balance in a teleost fish, rainbow trout (Oncorhynchus mykiss). AB - The effect of liquorice root derivatives (LRDs) glycyrrhizic acid (GL) and glycyrrhetinic acid (18betaGA) on salt and water balance and end points of gill ion transport in a freshwater teleost, (rainbow trout) was examined after feeding fish diets containing GL or 18betaGA (0, 5, 50 or 500 ug/g diet) for a two week period. Serum cortisol levels and gill 11beta-hydroxysteroid dehydrogenase type 2 mRNA abundance decreased in fish fed GL but increased (at select doses) in fish fed 18betaGA. At higher doses of GL, gill Na(+)-K(+)-ATPase and H(+)-ATPase activity increased, while cystic fibrosis transmembrane conductance regulator type II mRNA abundance significantly decreased at the lowest dose of GL. End points of gill transcellular ion transport were not significantly altered in fish fed 18betaGA, except for a reduction in Na(+)-K(+)-ATPase activity at a 50 ug/g dose. In contrast, high doses of GL and 18betaGA increased gill transcript abundance of the tight junction protein claudin-31 (cldn-31). Other end points of gill paracellular transport differed in fishes fed LRDs. Tricellulin mRNA abundance was increased by high dose GL and decreased by high dose 18betaGA, and cldn-23a and cldn-27b mRNA abundance significantly decreased in response to GL irrespective of dose. Despite the above observations, systemic end points of salt and water balance (i.e. serum [Na(+)] and [Cl(-)] as well as muscle moisture) were unaffected by LRDs. Therefore data suggest that LRDs can alter end points of ion transport in fishes but that overall salt and water balance need not be perturbed. PMID- 25460828 TI - The role of PGE2 in intestinal inflammation and tumorigenesis. AB - Release of the free fatty acid arachidonic acid (AA) by cytoplasmic phospholipase A2 (cPLA2) and its subsequent metabolism by the cyclooxygenase and lipoxygenase enzymes produces a broad panel of eicosanoids including prostaglandins (PGs). This study sought to investigate the roles of these mediators in experimental models of inflammation and inflammation-associated intestinal tumorigenesis. Using the dextran sodium sulfate (DSS) model of experimental colitis, we first investigated how a global reduction in eicosanoid production would impact intestinal injury by utilizing cPLA2 knockout mice. cPLA2 deletion enhanced colonic injury, reflected by increased mucosal ulceration and pro-inflammatory cytokine expression. Increased disease severity was associated with a significant reduction in the levels of several eicosanoid metabolites, including PGE2. We further assessed the precise role of PGE2 synthesis on mucosal injury and repair by utilizing mice with a genetic deletion of microsomal PGE synthase-1 (mPGES-1), the terminal synthase in the formation of inducible PGE2. DSS exposure caused more extensive acute injury as well as impaired recovery in knockout mice compared to wild-type littermates. Increased intestinal damage was associated with both reduced PGE2 levels as well as altered levels of other eicosanoids including PGD2. To determine whether this metabolic redirection impacted inflammation-associated intestinal tumorigenesis, Apc(Min/+) and Apc(Min/+):mPGES 1(-/-) mice were exposed to DSS. DSS administration caused a reduction in the number of intestinal polyps only in Apc(Min/+):mPGES-1(-/-) mice. These results demonstrate the importance of the balance of prostaglandins produced in the intestinal tract for maintaining intestinal homeostasis and impacting tumor development. PMID- 25460831 TI - Two general-odorant binding proteins in Spodoptera litura are differentially tuned to sex pheromones and plant odorants. AB - Moths have evolved a sensitive and sophisticated olfactory system to sense a variety of semiochemicals from the external environment. In chemosensory processes, the odorant binding protein (OBP) is an essential element for filtering, binding and transporting hydrophobic odorant molecules to the specific receptors. Here focusing on a major sub-class of lepidopteran OBPs, general odorant binding proteins (GOBPs), we explored the relationship and functional difference between two GOBP members from a noctuid species Spodoptera litura. Using genomic DNA as the template, we demonstrated that SlitGOBP2 and three SlitPBPs are clustered on the same chromosome within a close proximity. qPCR results showed that two SlitGOBPs were primarily expressed in antennae at similar levels between females and males, but GOBP2 displayed much higher expression than GOBP1. Binding studies revealed that both SlitGOBP1 and 2 strongly bound C14-C16 alcohol-pheromone analogs with high affinities (Ki<1.0 MUM). However, SlitGOBP2 also strongly bound most acetate- and aldehyde-sex pheromone components and analogs, while SlitGOBP1 could not. For tested plant odorants, SlitGOBP1 showed a relatively broad ligand-binding spectrum with moderate affinities, while SlitGOBP2 was tuned to some compounds with strong binding activities (Ki<5.0 MUM). Finally, by molecular docking we explored the differences in protein structures and potential key residues in the binding pockets between the two SlitGOBPs. Taken together, our study strongly suggests that SlitGOBP2 and SlitPBPs evolved by gene duplication events, and two SlitGOBPs have functionally differentiated in odorant recognition. PMID- 25460832 TI - Rapid desiccation hardening changes the cuticular hydrocarbon profile of Drosophila melanogaster. AB - The success of insects in terrestrial environments is due in large part to their ability to resist desiccation stress. Since the majority of water is lost across the cuticle, a relatively water-impermeable cuticle is a major component of insect desiccation resistance. Cuticular permeability is affected by the properties and mixing effects of component hydrocarbons, and changes in cuticular hydrocarbons can affect desiccation tolerance. A pre-exposure to a mild desiccation stress increases duration of desiccation survival in adult female Drosophila melanogaster, via a decrease in cuticular permeability. To test whether this acute response to desiccation stress is due to a change in cuticular hydrocarbons, we treated male and female D. melanogaster to a rapid desiccation hardening (RDH) treatment and used gas chromatography to examine the effects on cuticular hydrocarbon composition. RDH led to reduced proportions of unsaturated and methylated hydrocarbons compared to controls in females, but although RDH modified the cuticular hydrocarbon profile in males, there was no coordinated pattern. These data suggest that the phenomenon of RDH leading to reduced cuticular water loss occurs via an acute change in cuticular hydrocarbons that enhances desiccation tolerance in female, but not male, D. melanogaster. PMID- 25460833 TI - Myocardial edema after ischemia/reperfusion is not stable and follows a bimodal pattern: imaging and histological tissue characterization. AB - BACKGROUND: It is widely accepted that edema occurs early in the ischemic zone and persists in stable form for at least 1 week after myocardial ischemia/reperfusion. However, there are no longitudinal studies covering from very early (minutes) to late (1 week) reperfusion stages confirming this phenomenon. OBJECTIVES: This study sought to perform a comprehensive longitudinal imaging and histological characterization of the edematous reaction after experimental myocardial ischemia/reperfusion. METHODS: The study population consisted of 25 instrumented Large-White pigs (30 kg to 40 kg). Closed-chest 40 min ischemia/reperfusion was performed in 20 pigs, which were sacrificed at 120 min (n = 5), 24 h (n = 5), 4 days (n = 5), and 7 days (n = 5) after reperfusion and processed for histological quantification of myocardial water content. Cardiac magnetic resonance (CMR) scans with T2-weighted short-tau inversion recovery and T2-mapping sequences were performed at every follow-up stage until sacrifice. Five additional pigs sacrificed after baseline CMR served as controls. RESULTS: In all pigs, reperfusion was associated with a significant increase in T2 relaxation times in the ischemic region. On 24-h CMR, ischemic myocardium T2 times returned to normal values (similar to those seen pre-infarction). Thereafter, ischemic myocardium-T2 times in CMR performed on days 4 and 7 after reperfusion progressively and systematically increased. On day 7 CMR, T2 relaxation times were as high as those observed at reperfusion. Myocardial water content analysis in the ischemic region showed a parallel bimodal pattern: 2 high water content peaks at reperfusion and at day 7, and a significant decrease at 24 h. CONCLUSIONS: Contrary to the accepted view, myocardial edema during the first week after ischemia/reperfusion follows a bimodal pattern. The initial wave appears abruptly upon reperfusion and dissipates at 24 h. Conversely, the deferred wave of edema appears progressively days after ischemia/reperfusion and is maximal around day 7 after reperfusion. PMID- 25460834 TI - Temporal and spatial expression of tight junction genes during zebrafish pronephros development. AB - The kidney is comprised of nephrons - epithelial tubes with specialized segments that reabsorb and secrete solutes, perform osmoregulation, and produce urine. Different nephron segments exhibit unique combinations of ion channels, transporter proteins, and cell junction proteins that govern permeability between neighboring cells. The zebrafish pronephros is a valuable model to study the mechanisms of vertebrate nephrogenesis, but many basic features of segment gene expression in renal progenitors and mature nephrons have not been characterized. Here, we analyzed the temporal and spatial expression pattern of tight junction components during zebrafish kidney ontogeny. During nephrogenesis, renal progenitors show discrete expression domains of claudin (cldn) 15a, cldn8, occludin (ocln) a, oclnb, tight junction protein (tjp) 2a, tjp2b, and tjp3. Interestingly, transcripts encoding these genes exhibit dynamic spatiotemporal domains during the time when pronephros segment domains are established. These data provide a useful gene expression map of cell junction components during zebrafish nephrogenesis. As such, this information complements the existing molecular map of nephron segment characteristics, and can be used to characterize kidney development mutants as well as various disease models, in addition to aiding in the elucidation of mechanisms governing epithelial regeneration after acute nephron injury. PMID- 25460835 TI - Recognition and response to electronic fetal heart rate patterns: impact on newborn outcomes and primary cesarean delivery rate in women undergoing induction of labor. AB - OBJECTIVE: The objective of the study was to examine the clinical impact of specific fetal monitoring-related practices during induced labor. STUDY DESIGN: This was a prospective, nonrandomized study. RESULTS: We studied 14,398 women undergoing oxytocin induction of labor. A decrease in the infusion rate of oxytocin in the face of specified category II fetal heart rate tracings was associated with a significantly reduced rate of neonatal intensive care unit admission (3.8% vs 5.2%, P = .01) and Apgar score less than 7 at 1 and 5 minutes (4.9% vs 6.4%, P = .01, 0.6% vs 1.1%, P = .04). Compliance with an in-use checklist was associated with both a reduction in the rate of neonatal intensive care unit admission (2.9 vs 4.4, P = .00) and a reduction in the cesarean delivery rate (15.8% vs 18.8%, P = .00). CONCLUSION: Electronic fetal heart rate monitoring improves neonatal outcomes when unambiguous definitions of abnormal fetal heart rate and tachysystole are coupled with specific interventions. Utilization of a checklist for oxytocin monitoring is associated with improved neonatal outcomes and a reduction in the cesarean delivery rate. PMID- 25460836 TI - Safe vaginal uterine morcellation following total laparoscopic hysterectomy. AB - The minimally invasive approach for hysterectomy with proven benefits and lower morbidity has become the gold standard, even in women with large uterine masses. Most women with a malignant condition present with abnormal vaginal bleeding and/or suspicious imaging such that few are diagnosed by final histopathology after surgery. However, if a malignancy is not diagnosed preoperatively, intraabdominal morcellation for uterus extraction has an increased risk for potential tumor spread and peritoneal metastases, especially in cases of unexpected leiomyosarcoma. We describe a simple method to wrap the uterus in a contained environment with a plastic bag through the posterior vaginal fornix prior to conventional coring morcellation for vaginal extraction in total laparoscopic hysterectomy. We further describe our experience with a risk stratification and treatment algorithm to implement this procedure in daily routine. A video and an illustrating sketch demonstrate the simplicity and safety of the procedure. PMID- 25460837 TI - Influence of interpregnancy interval on neonatal morbidity. AB - OBJECTIVE: We sought to assess the influence of birth spacing on neonatal morbidity, stratified by gestational age at birth. STUDY DESIGN: This was a population-based retrospective cohort study using Ohio birth records, 2006 through 2011. We compared various interpregnancy interval (IPI) lengths in multiparous mothers with the rate and risk of adverse newborn outcomes. The frequency of neonatal intensive care unit admission or neonatal transport to a tertiary care facility was calculated for births occurring after IPI lengths: <6, 6 to <12, 12 to <24, 24 to <60, and >=60 months, and stratified by week of gestational age. Neonatal morbidity risk was calculated for each IPI compared to 12 to <24 months (referent), and adjusted for the concomitant influences gestational age at birth, maternal race, age, and prior preterm birth. RESULTS: We analyzed 395,146 birth outcomes of singleton nonanomalous neonates born to multiparous mothers. The frequency and adjusted odds of neonatal morbidity were lowest following IPI of 12 to <24 months (4.1%) compared to short IPIs of <6 months (5.7%; adjusted odds ratio [adjOR], 1.40; 95% confidence interval [CI], 1.32-1.49) and 6 to <12 months (4.7%; adjOR, 1.19; 95% CI, 1.13-1.25), and long IPIs 24 to <60 months (4.6%; adjOR, 1.12; 95% CI, 1.08-1.17) and >=60 months (5.8%; adjOR, 1.34; 95% CI, 1.28-1.40), despite adjustment for important confounding factors including gestational age at birth. The lowest frequency of adverse neonatal outcomes occurred at 40-41 weeks for all IPI groups. The frequency of other individual immediate newborn morbidities were also increased following short and long IPIs compared to birth following a 12- to <24-month IPI. CONCLUSION: IPI length is a significant contributor to neonatal morbidity, independent of gestational age at birth. Counseling women to plan an optimal amount of time between pregnancies is important for newborn health. PMID- 25460838 TI - Center of excellence for placenta accreta. AB - Placenta accreta spectrum is one of the most morbid conditions obstetricians will encounter. The incidence has dramatically increased in the last 20 years. The major contributing factor to this is believed to be the increase in the rate of cesarean delivery. Despite the increased incidence of placenta accreta, most obstetricians have personally managed only a small number of women with placenta accreta. The condition poses dramatic risk for massive hemorrhage and associated complication such as consumption coagulopathy, multisystem organ failure, and death. In addition, there is an increased risk for surgical complications such as injury to bladder, ureters, and bowel and the need for reoperation. Most women require blood transfusion, often in large quantities, and many require admission to an intensive care unit. As a result of indicated, often emergent preterm delivery, many babies require admission to a neonatal care intensive care unit. Outcomes are improved when delivery is accomplished in centers with multidisciplinary expertise and experience in the care of placenta accreta. Such expertise may include maternal-fetal medicine, gynecologic surgery, gynecologic oncology, vascular, trauma and urologic surgery, transfusion medicine, intensivists, neonatologists, interventional radiologists, anesthesiologists, specialized nursing staff, and ancillary personnel. This article highlights the desired features for a center of excellence in placenta accreta, and which patients should be referred for evaluation and/or delivery in such centers. PMID- 25460839 TI - Reply: To PMID 25265402. PMID- 25460840 TI - A biochemical view: vitamin D levels do not affect in vitro fertilization outcomes following the transfer of euploid blastocysts. PMID- 25460841 TI - Reply: To PMID 25265402. PMID- 25460842 TI - Vitamin D and in vitro fertilization outcome. PMID- 25460843 TI - The timing of administration of antenatal corticosteroids in women with indicated preterm birth. AB - OBJECTIVE: We sought to determine the timing of administration of antenatal corticosteroids (AS) for indicated preterm births and to identify which indications are associated with the most optimal timing of administration. STUDY DESIGN: This was a retrospective cohort of patients who received AS in anticipation of indicated preterm birth from 2009 through 2012 at Winthrop University Hospital, Mineola, NY. Medical records of patients who received AS, as identified through the hospital pharmacy database, were reviewed. Patients were included if they had a singleton or twin gestation and they received AS for maternal or fetal indications. Women were excluded if they received AS for spontaneous preterm labor or preterm rupture of membranes. Maternal demographic and obstetrical characteristics were compared between those who received AS<=7 days vs >7 days from delivery using parametric and nonparametric tests with relative risks and 95% confidence intervals. P<.05 was considered significant. RESULTS: In all, 193 patients were included in this study. Median latency from AS administration to delivery was 9 days (range, 0-83); 93 patients (48%) received AS within 7 days of delivery. There were no significant differences between the 2 groups with regards to baseline maternal characteristics. Those delivering within 7 days of AS administration were more likely to have maternal vs fetal indications (84% vs 16%). CONCLUSION: Only 48% of patients with an indication for preterm birth received AS within 7 days of its administration. AS appear to be more optimally timed in the presence of maternal rather than fetal indications. PMID- 25460845 TI - Proton, muon and 13C hyperfine coupling constants of C60X and C70X (X = H, Mu). AB - The reaction of H atoms with fullerene C70 has been investigated by identifying the radical products formed by addition of the atom muonium (Mu) to the fullerene in solution. Four of the five possible radical isomers of C70Mu were detected by avoided level-crossing resonance (MULCR) spectroscopy, using a dilute solution of enriched (13)C70 in decalin. DFT calculations were used to predict muon and (13)C isotropic hyperfine constants as an aid to assigning the observed MULCR signals. Computational methods were benchmarked against previously published experimental data for (13)C60Mu in solution. Analysis of the MULCR spectrum resulted in the first experimental determination of (13)C hyperfine constants in either C70Mu or C70H. The large number of values confirms predictions that the four radical isomers have extended distributions of unpaired electron spin. PMID- 25460844 TI - Efficacy and pharmacokinetics of the combination of etravirine plus raltegravir as novel dual antiretroviral maintenance regimen in HIV-infected patients. AB - Novel combination antiretroviral regimens may be needed for selected HIV-infected patients with toxicity or resistance. We evaluated prospectively 25 virologically suppressed patients, largely pretreated (15.6 years on therapy) with antiretroviral drug toxicity (n=19) or interactions (n=9, mainly with chemotherapy against non-Hodgkin lymphoma or anti-HCV therapy), who switched to a dual therapy with etravirine (ETR) plus raltegravir (RAL). Patients were required not to have prior virological failure or resistance to both drugs. After a median follow up of 722 days (473-1088: 53.3 patients-year), there were no cases of transient virological replication or failure. Only 1 patient left therapy at day 10 due to a grade 2 rash, and therefore efficacy by intent-to-treat analysis was 96% at 48 weeks. There were no cases of liver toxicity grade 3-4, and total cholesterol (TC) and triglycerides (TG) levels decrease significantly after initiation (TC, -17 mg/dl; p=0.01; TG, -42 mg/dl; p=0.01), as well as the TC/High density lipoprotein-cholesterol ratio (from 4.35 to 4.28). Geometric mean plasma trough level of RAL was 166 ng/ml (IQR, 40-249), well above the inhibitory concentration 90 (IC(90)). In conclusion, a novel dual therapy with ETR plus RAL is effective and well tolerated, and it could be an option to maintain durable viral suppression in hard-to-treat HIV-infected patients. PMID- 25460846 TI - Part 1: potential dangers of extreme endurance exercise: how much is too much? Part 2: screening of school-age athletes. AB - The question is not whether exercise is or isn't one of the very best strategies for improving quality of life, cardiovascular (CV) health and longevity-it is. And there is no debate as to whether or not strenuous high-intensity endurance training produces an amazingly efficient, compliant, and powerful pump-it does. The essence of the controversy centers on what exactly is the ideal pattern of long-term physical activity (PA) for conferring robust and enduring CV health, while also optimizing life expectancy. With that goal in mind, this review will focus on the question: "Is more always better when it comes to exercise?" And if a dose-response curve exists for the therapeutic effects of PA, where is the upper threshold at which point further training begins to detract from the health and longevity benefits noted with moderate exercise? The emerging picture from the cumulative data on this hotly debated topic is that moderate exercise appears to be the sweet spot for bestowing lasting CV health and longevity. However, the specific definition of moderate in this context is not clear yet. PMID- 25460847 TI - Assessment of coronary hemodynamics and vascular function. AB - Coronary blood flow closely matches to metabolic demands of heart and myocardial oxygen consumption and is conditioned by function of coronary resistance vessels. The microvascular endothelium of coronary resistance vessels is exposed to a spatially and temporally regulated input from cardiomyocytes and the haemodynamic forces of the cardiac cycle. Functional measurements of coronary pressure and flow are important approaches that provide complementary information on the function of coronary vessel function that could not be assessed by the methods utilized for the anatomic characterization of coronary disease, such as coronary angiography. The goal of this paper is to review the methodologies for assessment of coronary vascular function and haemodynamics which are utilized in research and to discuss their potential applicability in the clinical settings. PMID- 25460848 TI - Assessment and prognosis of peripheral artery measures of vascular function. AB - The endothelium plays a crucial role in the regulation of vascular homeostasis. Our understanding of its role in health and disease has increased dramatically since the pivotal discovery of nitric oxide more than 30 years ago. Clinical researchers utilized emerging technologies to study the vasodilator properties of the endothelium in both the coronary and peripheral circulation. Early studies established the methodologies and were able to demonstrate attenuated endothelium dependent vasodilation in response to atherosclerosis and its risk factors. A variety of interventions can modulate endothelial function. More recent studies have established that some of these measures are independent predictors of cardiovascular outcomes. As such, peripheral measures of endothelial function are now established surrogate markers of vascular risk and have become important markers for clinical research. In this review, we will discuss a variety of measures of peripheral artery function to assess both conduit and resistance vessel function in humans. PMID- 25460851 TI - The effect of dentists' body-weight size on student social judgments of dental skill and patients' behavioural intentions: a vignette study. AB - OBJECTIVES: Where previous work has suggested that over-weight individuals may be subject to negative social judgments, a finding also seen in judgments applied to healthcare professionals (HCPs), this study investigated whether these findings extend to judgments made about dental practitioners. METHODS: A photo of a normal weight male and one of a normal weight female dentist were digitally modified to reliably show them as overweight, giving a total of 4 conditions. In a single blind quasi-randomised controlled study of 302 undergraduate and postgraduate student participants used a 5 point Likert scale to appraise a single, gender matched colour photograph as to whether they thought the dentist depicted was competent, professional, caring, had patients' best interests at heart, and was a good dentist. They further rated their future intentions to follow behavioural advice (reduce snacking and take-up flossing) given by the depicted dentist. RESULTS: The data were analysed using independent sample t-tests. There were no differences in outcomes as a function of the weight status of the depicted dentist in any of the variables explored with the exception of the normal-weight images being rated as more caring than the overweight ones (p<.04). CONCLUSIONS: Images of overweight dentists do not receive lower social judgement ratings than images of normal-weight dentists. Previous research in medicine reporting adverse social judgments made of over-weight HCPs does not apply to dental practitioners. Future research should focus on factors that may explain these findings. CLINICAL SIGNIFICANCE: Dentists appear to be protected from the adverse effect of overweight on social judgments of their personal characteristics and on their health-promoting advice. PMID- 25460850 TI - Aqueous-core PEG-coated PLA nanocapsules for an efficient entrapment of water soluble anticancer drugs and a smart therapeutic response. AB - Novel PEGylated PLA nanocapsules (PEG-AcPLA nanocapsules), loading high percentage of water soluble drugs have been formulated by using multiple emulsion technique without using conventional stabilizers. In particular, sodium deoxycholate hydrate has been used to obtain nanocapsules having a mean diameter of about 200 nm and a polydispersity index of ~ 0.1. Gemcitabine hydrochloride (GEM) was used as a model of hydrophilic drug. GEM-loaded PEG-AcPLA nanocapsules demonstrated a high encapsulation efficacy and the drug-release followed a zero order kinetic. MTT-assay evidenced an increased antitumor effect of GEM-loaded PEG-AcPLA nanocapsules compared to the free drug on different cancer cell lines and confocal laser scanning microscopy showed a significant improvement of cell interaction at 6h of incubation. In vivo anticancer activity of GEM-loaded PEG AcPLA nanocapsules using two xenograft murine models of human solid tumors further supported the efficacy of this nano-drug, thus providing preliminary results about the potential clinical application of this innovative nanotherapeutic. PMID- 25460852 TI - The development of "fab-chips" as low-cost, sensitive surface-enhanced Raman spectroscopy (SERS) substrates for analytical applications. AB - The demand for methods and technologies capable of rapid, inexpensive and continuous monitoring of health status or exposure to environmental pollutants persists. In this work, the development of novel surface-enhanced Raman spectroscopy (SERS) substrates from metal-coated silk fabric, known as zari, presents the potential for SERS substrates to be incorporated into clothing and other textiles for the routine monitoring of important analytes, such as disease biomarkers or environmental pollutants. Characterization of the zari fabric was completed using scanning electron microscopy, energy dispersive X-ray analysis and Raman spectroscopy. Silver nanoparticles (AgNPs) were prepared, characterized by transmission electron microscopy and UV-vis spectroscopy, and used to treat fabric samples by incubation, drop-coating and in situ synthesis. The quality of the treated fabric was evaluated by collecting the SERS signal of 4,4'-bipyridine on these substrates. When AgNPs were drop-coated on the fabric, sensitive and reproducible substrates were obtained. Adenine was selected as a second probe molecule, because it dominates the SERS signal of DNA, which is an important class of disease biomarker, particularly for pathogens such as Plasmodium spp. and Mycobacterium tuberculosis. Excellent signal enhancement could be achieved on these affordable substrates, suggesting that the developed fabric chips have the potential for expanding the use of SERS as a diagnostic and environmental monitoring tool for application in wearable sensor technologies. PMID- 25460853 TI - Quasi-unidirectional shrinkage of gels with well-oriented lipid bilayers upon uniaxial stretching. AB - PDGI-PAAm gels with well oriented lipid bilayers show a quasi-unidirectional shrinkage upon uniaxial stretching along the bilayers. They shrink largely parallel to the bilayer but slightly perpendicular to it in order not to increase the bilayer area and its interfacial energy. Such an anisotropic deformation can be well-modelled based on classical theories for gel networks and lipid layers. PMID- 25460849 TI - New technology and resources for cryptococcal research. AB - Rapid advances in molecular biology and genome sequencing have enabled the generation of new technology and resources for cryptococcal research. RNAi mediated specific gene knock down has become routine and more efficient by utilizing modified shRNA plasmids and convergent promoter RNAi constructs. This system was recently applied in a high-throughput screen to identify genes involved in host-pathogen interactions. Gene deletion efficiencies have also been improved by increasing rates of homologous recombination through a number of approaches, including a combination of double-joint PCR with split-marker transformation, the use of dominant selectable markers and the introduction of Cre-Loxp systems into Cryptococcus. Moreover, visualization of cryptococcal proteins has become more facile using fusions with codon-optimized fluorescent tags, such as green or red fluorescent proteins or, mCherry. Using recent genome wide analytical tools, new transcriptional factors and regulatory proteins have been identified in novel virulence-related signaling pathways by employing microarray analysis, RNA-sequencing and proteomic analysis. PMID- 25460854 TI - Using a novel wireless system for monitoring patients after the atrial fibrillation ablation procedure: the iTransmit study. AB - BACKGROUND: A novel technology incorporates electrodes into an iPhone case that records an electrocardiographic tracing. OBJECTIVES: The objectives of this study were to examine the feasibility and efficacy of this technology to monitor patients after the atrial fibrillation (AF) ablation procedure and to assess patients' feedback on its ease of use. METHODS: Patients with AF undergoing ablation who had iPhones were screened for enrollment. They were provided with an AliveCor heart monitor (AHM) case and a traditional transtelephonic monitor (TTM). Patients were asked to record their rhythm using both monitors simultaneously whenever they had symptoms or at least once a week. AHM recordings were sent to a secure e-mail account, and TTM recordings were transmitted to our Holter laboratory using landlines. All AHM recordings were reviewed by 1 of 2 blinded electrophysiologists. TTM recordings were reviewed by the primary electrophysiologist. The kappa coefficient was calculated to assess agreement between AHM and TTM recordings. Sensitivity and specificity for the detection of AF and atrial flutter with the AHM compared to the TTM were calculated. RESULTS: Sixty patients were enrolled (mean age 60 +/- 12 years), and 55 completed the study. There were 389 simultaneous AHM and TTM recordings. The kappa statistic was 0.82, indicating excellent agreement between AHM and TTM recordings. If we consider AF and atrial flutter as one diseased state, the AHM had 100% sensitivity and 97% specificity for the detection of AF and atrial flutter. Only 2% of patients found it difficult to use the AHM, and the large majority (92%) preferred to use the AHM to monitor their AF as opposed to the TTM. CONCLUSION: The AHM is an alternative method for monitoring patients with AF after the ablation procedure. Most patients found it easy to use. PMID- 25460856 TI - Calmodulinopathy: a genetic trilogy. PMID- 25460855 TI - Effect of periprocedural amiodarone on procedure outcome in patients with longstanding persistent atrial fibrillation undergoing extended pulmonary vein antrum isolation: results from a randomized study (SPECULATE). AB - BACKGROUND: The impact of amiodarone on ablation outcome in longstanding persistent atrial fibrillation (LSPAF) patients is not known yet. OBJECTIVE: The purpose of this study was to assess the effect of amiodarone on procedural outcomes in LSPAF patients undergoing catheter ablation. METHODS: We enrolled 112 LSPAF patients on amiodarone and scheduled to undergo atrial fibrillation (AF) ablation. Patients were randomized to amiodarone discontinuation 4 months before ablation (group 1, n = 56) and a control group (group 2, n = 56) in which ablation was performed without amiodarone discontinuation. All patients underwent pulmonary vein (PV) antrum and posterior wall isolation, defragmentation and extra PV triggers ablation. Patients were followed up for recurrence for 32 +/- 8 months post-ablation. Repeat procedures in all recurrent patients were performed off amiodarone. RESULTS: During ablation, AF termination was more frequent in group 2 compared to group 1 [44 (79%) vs 32 (57%), P = .015]. After high-dosage isoproterenol, more non-PV triggers were disclosed in group 1 compared to group 2 (42 [75%] vs 24 [43%] respectively, P <.001). Group 2 had lower procedure, radiofrequency and fluoroscopy times compared to group 1 (2.7 +/- 1 vs 3.1 +/- 1 h, 69 +/- 13 min vs 87 +/- 11 min and 64 +/- 14 min vs 85 +/- 18 min respectively, p < .05). At 32 +/- 8 month follow-up, on or off antiarrhythmic drug success rate was 37 (66%) in group 1 and 27 (48%) in group 2 (P = .04). During redo, new non-PV trigger sites were identified in group 2 patients. CONCLUSION: Periprocedural continuous amiodarone was associated with higher organization rate and lower radiofrequency ablation rate. However, masking non-PV triggers increased the late recurrence rate. PMID- 25460858 TI - Separation of benign from malignant J waves. PMID- 25460857 TI - Electrocardiographic predictors of bradycardia-induced torsades de pointes in patients with acquired atrioventricular block. AB - BACKGROUND: Predictors of torsades de pointes (TdP) in bradyarrhythmia-induced acquired long QT syndrome are not well defined. OBJECTIVE: The purpose of this study was to search for electrocardiographic (ECG) TdP predictors in patients with acquired atrioventricular block (AVB) and QT prolongation. METHODS: We analyzed 12-lead ECGs from 20 patients (15 females, age 65.9 +/- 15.6 years) with TdP episodes from among 898 AVB patients (2.2%) in 3 tertiary hospitals. The ECG repolarization parameters in TdP patients were compared with those of 80 age- and sex-matched control AVB patients with no TdP episodes. RESULTS: TdP was initiated by premature ventricular complexes with a long-short sequence of activation. The average cycle length of the long sequence was 1289.9 +/- 228.9 ms and was 2.3 +/- 0.6 times longer than the cycle length of the short sequence. TdP patients had a significantly longer mean QT interval (716.4 +/- 98.9 ms vs 523.2 +/- 91.3 ms, P = .001), mean T peak to end interval (334.2 +/- 59.1 ms vs 144.0 +/- 73.7 ms, P = .001) and a higher T peak to end interval/QT ratio (0.49 +/- 0.09 vs 0.27 +/- 0.11, P = .001) compared with non-TdP controls. TdP patients showed a higher prevalence of notched T waves in which T2 was at least 3 mm taller than T1 (45.0% vs 1.3%, P = .001), triphasic T waves (30.0% vs 1.3%, P = .001), reversed asymmetry (20.0% vs 0%, P = .001), and T-wave alternans (35.0% vs 0%, P = .001). An algorithm combining these morphologic parameters was able to differentiate TdP patients from non-TdP patients with high sensitivity (85.0%) and specificity (97.5%). CONCLUSION: An algorithm combining specific T-wave morphologies was useful for identifying patients with AVB who are at risk for developing TdP. PMID- 25460859 TI - Accidental hypothermia-induced electrical storm successfully treated with isoproterenol. PMID- 25460861 TI - Effects of radiofrequency energy delivered through partially insulated metallic catheter tips on myocardial tissue heating and ablation lesion characteristics. AB - BACKGROUND: Cardiac radiofrequency (RF) ablation is typically achieved using symmetric catheter tips, which may result in unintended heating adjacent to targeted tissue. Partial insulation may alter lesion geometry and prevent collateral heating. OBJECTIVE: The purpose of this study was to assess partially insulated focused ablation (PIFA). METHODS: Partial insulation using thermally conductive materials was applied to a 4-mm or 8-mm nonirrigated catheter and a 3.5-mm open-irrigated catheter. These PIFA tips, or their noninsulated counterparts, were applied to ex vivo viable bovine myocardium. Ablations were delivered at various powers and under temperature control. Potential clinical applicability was evaluated in vivo by targeting porcine epicardium with irrigated PIFA and assessing its protective effects on the pericardium. RESULTS: PIFA catheters exhibited different properties and produced asymmetric lesions compared with corresponding standard ablation catheters. Temperatures at 3- and 5 mm depths were higher for PIFA catheters, with a temperature increase measured at the catheter tip-tissue interface; however, in temperature control ablation, tip tissue temperature increases did not limit power delivery. Furthermore, temperatures were lower on the insulated surface and were significantly higher on the noninsulated PIFA side. Impedance changes were significantly larger; more steam pops were observed with PIFA but were mitigated by external irrigation, a larger tip electrode, and use of more thermally conductive insulation. In contrast to standard ablation, open-irrigated PIFA created larger asymmetric lesions in vivo over porcine epicardium, without evidence of pericardial injury. CONCLUSION: PIFA ablation has different characteristics compared with symmetrically conductive ablation. Further research is needed to assess the clinical implications of insulated catheter ablation. PMID- 25460860 TI - The effect of reverse remodeling on long-term survival in mildly symptomatic patients with heart failure receiving cardiac resynchronization therapy: results of the REVERSE study. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) reduces mortality, improves functional status, and induces reverse left ventricular remodeling in selected populations with heart failure (HF). The magnitude of reverse remodeling predicts survival with many HF medical therapies. However, there are few studies assessing the effect of remodeling on long-term survival with CRT. OBJECTIVE: The purpose of this study was to assess the effect of CRT-induced reverse remodeling on long term survival in patients with mildly symptomatic heart failure. METHODS: The REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction trial was a multicenter, double-blind, randomized trial of CRT in patients with mild HF. Long-term follow-up of 5 years was preplanned. The present analysis was restricted to the 353 patients who were randomized to the CRT ON group with paired echocardiographic studies at baseline and 6 months postimplantation. The left ventricular end-systolic volume index (LVESVi) was measured in the core laboratory and was an independently powered end point of the REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction trial. RESULTS: A 68% reduction in mortality was observed in patients with >=15% decrease in LVESVi compared to the rest of the patients (P = .0004). Multivariable analysis showed that the change in LVESVi was a strong independent predictor (P = .0002), with a 14% reduction in mortality for every 10% decrease in LVESVi. Other remodeling parameters such as left ventricular end-diastolic volume index and ejection fraction had a similar association with mortality. CONCLUSION: The change in left ventricular end-systolic volume after 6 months of CRT is a strong independent predictor of long-term survival in mild HF. PMID- 25460862 TI - Cardiac late Na+ current: proarrhythmic effects, roles in long QT syndromes, and pathological relationship to CaMKII and oxidative stress. AB - Myocyte sodium channel current that persists throughout the plateau of the cardiac action potential is referred to as late sodium current (I(Na-L)). The magnitude of I(Na-L) is normally small, but can increase significantly in common acute and chronic pathological settings as a result of inherited and/or acquired Na(+) channelopathies that alter channel opening and closing (ie, gating), location (trafficking), or anchoring and interactions with cytoskeletal proteins. An increase in I(Na-L) reduces repolarization reserve in atrial and ventricular myocytes and prolongs the action potential duration and the QT interval. An enhanced I(Na-L) is a cause of long QT syndrome 3. I(Na-L) may be a cause of afterdepolarizations, triggered arrhythmias, and spontaneous diastolic depolarization-induced automaticity. In addition, enhancement of I(Na-L) increases both the temporal and the spatial dispersion of repolarization in the myocardium and may lead to spatially discordant action potential duration alternans, wavebreak, and reentrant arrhythmias. Positive feedback loops between increases in I(Na-L) and the activity of Ca(2+)/calmodulin-dependent protein kinase II appear to contribute to the genesis of arrhythmias and to certain abnormalities of the ischemic heart. In this review, we discuss some of the more relevant experimental results, clinical findings, and insights from cellular and animal models that highlight the role of I(Na-L) in the genesis of arrhythmias, long QT syndromes, and intracellular Ca(2+) homeostasis. PMID- 25460863 TI - Tachycardia-dependent augmentation of "notched J waves" in a general patient population without ventricular fibrillation or cardiac arrest: not a repolarization but a depolarization abnormality? AB - BACKGROUND: J waves can be observed in individuals of the general population, but electrocardiographic characteristics are poorly understood. OBJECTIVE: The purpose of this study was to examine the J-wave dynamicity in a general patient population. METHODS: The responses of J waves (>0.1 mV above the isoelectric line in 2 contiguous leads) to varying RR intervals were analyzed. Patients with aborted sudden cardiac death, documented ventricular fibrillation, or a family history of sudden cardiac death were excluded. The J-wave amplitude was measured at baseline, in beats with short RR intervals in conducted atrial premature beats (APBs) or atrial stimulation during the electrophysiology study, and in the beats next to APBs with prolonged RR intervals. RESULTS: Mainly notched J waves were identified in 94 of 701 (24.5%) general patients (13.4%), and APBs were present in 23 of 94 (24.5%) patients. The mean baseline amplitude of J waves was 0.20 +/- 0.06 mV at the baseline RR interval of 853 +/- 152 ms, 0.25 +/- 0.11 mV at the RR interval in the conducted APB of 545 +/- 133 ms (P = .0018), and 0.19 +/- 0.08 mV at the RR interval of 1146 +/- 314 ms (P = .3102). The clinical characteristics were not different between patients with and without tachycardia-dependent augmentation of J waves. Augmentation of J waves was confirmed by the electrophysiology study: 0.28 +/- 0.12 mV vs 0.42 +/- 0.11 mV at baseline and in the beats of atrial stimulation, respectively (P = .0001). However, no bradycardia-dependent augmentation (>0.05 mV) was observed. Such tachycardia dependent augmentation can represent depolarization abnormality rather than repolarization abnormality. CONCLUSION: J waves in a general patient population were augmented at shorter RR intervals, but not at prolonged RR intervals. Mechanistically, conduction delay is most likely responsible for this. PMID- 25460865 TI - Quantification of the cryoablation zone demarcated by pre- and postprocedural electroanatomic mapping in patients with atrial fibrillation using the 28-mm second-generation cryoballoon. AB - BACKGROUND: There are 2 Food and Drug Administration-approved catheters (ThermoCool RF and Arctic Front Advance cryoballoon) for the treatment of drug refractory and symptomatic paroxysmal atrial fibrillation. Each tool is used to ablate the area surrounding the pulmonary veins (PVs). However, no study has described and quantified the ablated surface area after the application of cryoablation lesions with the second-generation cryoballoon. OBJECTIVE: The purpose of this study was to determine the area of ablation during cryoballoon PV isolation. METHODS: Preprocedural computed tomography angiography of the left atrium (LA) was conducted in 43 patients to accurately determine spatial chamber dimensions. Before and after the ablation procedure, a detailed 3-dimensional electroanatomic map of the LA was created and merged onto the computed tomography angiogram to improve the accuracy of the data recordings. RESULTS: The posterior LA wall had a mean surface area of 31.1 (+/-1.6 SEM) cm(2). Left- and right-sided antral PV surface areas of cryoballoon ablation were not statistically different (P = .935), which were 11.4 (+/-0.8 SEM) and 11.3 (+/-0.8 SEM) cm(2), respectively. In total, 27% of the posterior LA wall remained unablated, electrically functional, and homogeneous with regard to voltage conductivity. This ablation strategy resulted in 95.3% freedom from atrial fibrillation at 6 months. CONCLUSION: The area of the posterior LA wall ablation with the cryoballoon catheter is wide and antral, and the resulting posterior LA wall debulking could be a part of the cryoballoon efficacy beyond discrete PV isolation. PMID- 25460867 TI - A refined protocol of flecainide testing in Brugada syndrome: from ambiguous assessment toward definite diagnosis. PMID- 25460866 TI - Reverse ventricular remodeling and long-term survival in patients undergoing cardiac resynchronization with surgically versus percutaneously placed left ventricular pacing leads. AB - BACKGROUND: A minority of patients undergoing cardiac resynchronization therapy (CRT) use a surgically placed epicardial left ventricular (SPELV) pacing lead. Previous studies of outcomes in patients receiving such leads have been limited to small cohorts with limited follow-up. OBJECTIVE: We sought to compare outcomes between patients receiving SPELV pacing leads and patients with traditional percutaneously placed left ventricular (LV) leads. METHODS: We extracted clinical data on consecutive patients undergoing the new implantation of a cardiac resynchronization device. Long-term survival and response (defined as an improvement in LV ejection fraction of >=5%) were compared between the 2 groups. RESULTS: Between September 3, 2003, and August 6, 2007, 725 patients met inclusion criteria, of whom 96 (13.2%) had an SPELV pacing lead. Over a mean follow-up of 5.1 +/- 2.5 years, there were 310 deaths, 17 heart transplants, and 15 left ventricular assist device placements (342 total end points). In univariate analysis, there was no difference in outcomes between patients with an SPELV pacing lead and patients with a percutaneously placed LV lead both early at 6 months (log rank, P = .53) and over a mean follow-up of 5.1 years (log rank, P = .58). In multivariate analysis, survival free of left ventricular assist device or heart transplant was similar in patients regardless of lead placement status (P = .89). From a subcohort of 455 patients, 297 patients (65.3%) met criteria for response. In multivariate analysis, there was no difference in the rate of response based on lead placement modality. CONCLUSION: Patients undergoing epicardial LV lead placement using a surgical approach have outcomes and rates of reverse ventricular remodeling similar to those in patients undergoing LV lead placement using a percutaneous approach. PMID- 25460868 TI - Eleanor Roosevelt's last days: a bioethical case study. PMID- 25460869 TI - Left ventricular hypertrophy in valvular aortic stenosis: mechanisms and clinical implications. AB - Valvular aortic stenosis is the second most prevalent adult valve disease in the United States and causes progressive pressure overload, invariably leading to life-threatening complications. Surgical aortic valve replacement and, more recently, transcatheter aortic valve replacement effectively relieve the hemodynamic burden and improve the symptoms and survival of affected individuals. However, according to current American College of Cardiology/American Heart Association guidelines on the management of valvular heart disease, the indications for aortic valve replacement, including transcatheter aortic valve replacement, are based primarily on the development of clinical symptoms, because their presence indicates a dismal prognosis. Left ventricular hypertrophy develops in a sizeable proportion of patients before the onset of symptoms, and a growing body of literature demonstrates that regression of left ventricular hypertrophy resulting from aortic stenosis is incomplete after aortic valve replacement and associated with adverse early postoperative outcomes and worse long-term outcomes. Thus, reliance on the development of symptoms alone without consideration of structural abnormalities of the myocardium for optimal timing of aortic valve replacement potentially constitutes a missed opportunity to prevent postoperative morbidity and mortality from severe aortic stenosis, especially in the face of the quickly expanding indications of lower-risk transcatheter aortic valve replacement. The purpose of this review is to discuss the mechanisms and clinical implications of left ventricular hypertrophy in severe valvular aortic stenosis, which may eventually move to center stage as an indication for aortic valve replacement in the asymptomatic patient. PMID- 25460864 TI - Progress toward the prevention and treatment of atrial fibrillation: A summary of the Heart Rhythm Society Research Forum on the Treatment and Prevention of Atrial Fibrillation, Washington, DC, December 9-10, 2013. PMID- 25460870 TI - Reversal of hyperglycemia: effects on nitric oxide signaling. AB - BACKGROUND: Hyperglycemia in patients with acute coronary syndromes is associated with poor outcomes, and its rapid correction with insulin infusion has been shown to restore platelet responsiveness to nitric oxide and to suppress superoxide (O2(-)) generation. Thioredoxin-interacting protein has emerged recently as a pivotal modulator of hyperglycemia-induced inflammation, O2(-) production, and impairment of nitric oxide signaling, but it is not known whether its expression in platelets can be downregulated rapidly. METHODS: In 12 hyperglycemic patients with acute coronary syndrome, we evaluated the putative role of thioredoxin interacting protein suppression in the platelet nitric oxide response after reversal of hyperglycemia with insulin infusion. RESULTS: Insulin infusion for 13.0 +/- 0.8 (standard error of the mean) hours decreased blood glucose level from 16.6 +/- 1.6 mmol/L to 8.7 +/- 1.4 mmol/L (P = .002). This induced (1) sensitization of antiaggregatory response to nitric oxide (from 6.5% +/- 7.7% to 39.7% +/- 7.0%, P < .0001); (2) improved endothelial progenitor cell function (from a median of 45 to 180 colony-forming units, P < .05); and (3) decreases of whole blood reactive oxygen species content (P < .05). However, there was no significant suppression of platelet thioredoxin-interacting protein expression (mean decrease, 59 arbitrary units; 95% confidence interval, -193 to +74). CONCLUSIONS: Correction of hyperglycemia in patients with acute coronary syndrome rapidly reverses oxidative stress, restoring both platelet nitric oxide responsiveness and endothelial progenitor cell function, but this process is largely or entirely independent of thioredoxin-interacting protein. PMID- 25460871 TI - Enhanced drought tolerance in transgenic rice over-expressing of maize C4 phosphoenolpyruvate carboxylase gene via NO and Ca(2+). AB - We determined the effects of endogenous nitric oxide and Ca(2+) on photosynthesis and gene expression in transgenic rice plants (PC) over-expressing the maize C4pepc gene, which encodes phosphoenolpyruvate carboxylase (PEPC) under drought. In this study, seedlings were subjected to PEG 6000 treatments using PC and wild type (WT; Kitaake). The results showed that, compared with WT, PC had higher relative water content (RWC) and net photosynthetic rate (Pn) under drought. During a 2-day re-watering treatment, Pn recovered faster in PC than in WT. Further analyses showed that, under the drought treatment, the amount of endogenous hydrogen peroxide (H2O2) increased in WT mainly via NADPH oxidase. While in PC, the endogenous nitric oxide (NO) content increased via nitrate reductase and nitric oxide synthase on day 2 of the drought treatment and day 1 of the re-watering treatment. After 2 days of drought treatment, PC also showed higher PEPC activity, calcium content, phospholipase D (PLD) activity, C4-pepc and NAC6 transcript levels, and protein kinase activity as compared with PC without treatment. These changes did not occur in WT. Correlation analysis also proved NO associated with these indicators in PC. Based on these results, there was a particular molecular mechanism of drought tolerance in PC. The mechanism is related to the signaling processes via NO and Ca(2+) involving the protein kinase and the transcription factor, resulted in up-regulation of PEPC activity and its gene expression, such as C4pepc. Some genes encode antioxidant system, cu/zn-sod as well, which promote antioxidant system to clear MDA and superoxide anion radical, thereby conferring drought tolerance. PMID- 25460872 TI - Vitamin B6 contributes to disease resistance against Pseudomonas syringae pv. tomato DC3000 and Botrytis cinerea in Arabidopsis thaliana. AB - Vitamin B6 (VB6) is an important cofactor for numerous enzymatic reactions and plays an important role in abiotic stress tolerance. However, direct molecular evidence supporting a role for VB6 in plant disease resistance remains lacking. In this study, we explored the possible function of VB6 in disease resistance by analyzing disease phenotypes of Arabidopsis mutants with defects in de novo biosynthetic pathway and salvage pathway of VB6 biosynthesis against Pseudomonas syringae pv. tomato (Pst) DC3000 and Botrytis cinerea. Mutations in AtPDX1.2 and AtPDX1.3 genes involved in the de novo pathway, and in AtSOS4 gene involved in the salvage pathway led to increased levels of diseases caused by Pst DC3000 and B. cinerea. The pdx1.2 and pdx1.3 plants had reduced VB6 contents and showed a further reduction in VB6 contents after infection by Pst DC3000 or B. cinerea. Our preliminary results suggest an important role for VB6 in plant disease resistance against different types of pathogens. PMID- 25460873 TI - Positive feedback regulation of a Lycium chinense-derived VDE gene by drought induced endogenous ABA, and over-expression of this VDE gene improve drought induced photo-damage in Arabidopsis. AB - Violaxanthin de-epoxidase (VDE) plays an important role in protecting the photosynthetic apparatus from photo-damage by dissipating excessively absorbed light energy as heat, via the conversion of violaxanthin (V) to intermediate product antheraxanthin (A) and final product zeaxanthin (Z) under light stress. We have cloned a VDE gene (LcVDE) from Lycium chinense, a deciduous woody perennial halophyte, which can grow in a large variety of soil types. The amino acid sequence of LcVDE has high homology with VDEs in other plants. Under drought stress, relative expression of LcVDE and the de-epoxidation ratio (Z+0.5A)/(V+A+Z) increased rapidly, and non-photochemical quenching (NPQ) also rose. Interestingly, these elevations induced by drought stress were reduced by the topical administration of abamine SG, a potent ABA inhibitor via inhibition of NCED in the ABA synthesis pathway. Until now, little has been done to explore the relationship between endogenous ABA and the expression of VDE genes. Since V serves as a common precursor for ABA, these data support the possible involvement of endogenous ABA in the positive feedback regulation of LcVDE gene expression in L. chinense under drought stress. Moreover, the LcVDE may be involved in modulating the level of photosynthesis damage caused by drought stress. Furthermore, the ratio of (Z+0.5A)/(V+A+Z) and NPQ increased more in transgenic Arabidopsis over-expressing LcVDE gene than the wild types under drought stress. The maximum quantum yield of primary photochemistry of PSII (Fv/Fm) in transgenic Arabidopsis decreased more slowly during the stressed period than that in wild types under the same conditions. Furthermore, transgenic Arabidopsis over expressing LcVDE showed increased tolerance to drought stress. PMID- 25460874 TI - Nano-iniferter based imprinted sensor for ultra trace level detection of prostate specific antigen in both men and women. AB - In this work, a sensitive and selective electrochemical sensor for detection of prostate specific antigen (PSA) was developed using surface imprinting and nanotechnology. The multiwalled carbon nanotubes (MWCNTs) decorated with manganese nanoparticles was functionalized with thio-group to make a nano iniferter. This nano-iniferter was used as a platform to synthesize a three dimensional molecularly imprinted polymer matrix for PSA by controlled radical polymerization technique. The PSA-sensor displayed good analytical performance for the detection of PSA by square wave and differential pulse stripping voltammetric techniques. The limit of detection was calculated as low as 0.25pgL( 1) (from SWSV) and 3.04pgL(-1) (from DPSV) at signal to noise ratio of 3. The proposed sensor was successfully applied for the determination of PSA in human blood serum, urine, and forensic samples without any cross-reactivity. Thus this sensor offers high selectivity, sensitivity, simplicity and clinical applicability for PSA determination in sera of both the men and women, which have not been reported together in the previously reported systems. The sensor may be used as a better alternative for the commercially available ELISA kits for PSA determination. PMID- 25460875 TI - A reusable aptamer-based evanescent wave all-fiber biosensor for highly sensitive detection of Ochratoxin A. AB - Although aptamer-based biosensors have attracted ever-increasing attentions and found potential applications in a wide range of areas, they usually adopted the assay protocol of immobilizing DNA probe (e.g., aptamer, aptamer-complementary oligonucleotides) on a solid sensing surface, making it critical and challengeable to keep the integration of nucleic acid surface during the regeneration and the restoration to its original DNA probe form after repeated uses. In order to address the issue, we report a novel aptamer-based biosensing strategy based on an evanescent wave all-fiber (EWA) platform. In a simple target capturing step using aptamer-functionalized magnetic microbeads, signal probes conjugated with streptavidin are released and further detected by a EWA biosensor via a facial dethiobiotin-streptavidin recognition. Apart from the inherent advantages of aptamer-based evanescent wave biosensors (e.g. target versatility, sensitivity, selectivity and portability), the proposed strategy exhibits a high stability and remarkable reusability over other aptasensors. Under the optimized conditions, the typical calibration curve obtained for Ochratoxin A has a detection limit of 3nM with a linear response ranging from 6nM to 500nM. The dethiobiotin-streptavidin sensing surface instead of the traditional nucleic acid one can be reused for over 300 times without losing sensitivity. PMID- 25460876 TI - Jetting microfluidics with size-sorting capability for single-cell protease detection. AB - Activated proteases such as matrix metalloproteinases (MMPs) secreted from cancer cells can degrade the extracellular matrix (ECM) and contribute to tumour formation and metastasis. Measuring MMP activity in individual cancer cells can provide important insights on cancer cell heterogeneity and disease progression. Here, we present a microfluidic platform combining a droplet jetting generator and a deterministic lateral displacement (DLD) size-sorting channel that is capable of encapsulating individual cancer cells inside picoliter droplets effectively. Droplet jetting with cell-triggered Rayleigh-Plateau instability was employed which produced large droplets capable of cell encapsulation (diameter, ~25um) and small empty droplets (diameter, ~14um), which were then size-separated using a DLD size-sorting channel to enrich the single-cell encapsulated droplets (~78%), regardless of the cell density of input sample solutions. The droplets containing encapsulated cancer cells were collected in an observation chamber to determine the kinetic profiles of MMP secretion and the inhibitory response in the presence of the drug doxycycline at the single-cell level to reveal their heterogeneous MMPs secretion activities. PMID- 25460877 TI - Detection of circulating tumor cells in prostate cancer based on carboxylated graphene oxide modified light addressable potentiometric sensor. AB - Circulating tumor cells (CTCs) are a group of rare cancer cells that have detached from a primary tumor and circulate in the bloodstream. Herein, light addressable potentiometric sensor (LAPS) was exploited in the label-free detection of CTCs in the prostate cancer. To this end, the mouse anti-human epithelial cell adhesion molecule (anti-EpCAM) monoclonal antibody was selected as the probe to capture CTCs according to our western blot experiments, and therefore the anti-EpCAM was immobilized on the surface of carboxylated graphene oxide (GO-COOH) modified LAPS. Spiking experiments confirmed that LAPS' voltage decreased with the increasing of CTCs' concentration both in phosphate buffer (PBS) and blood, and as few as 10 CTCs in 1ml of blood could be detected, illustrating the high sensitivity of the proposed strategy. The analysis of healthy blood samples revealed no change in electrical signal, confirming the specificity of the system. Ultraviolet-visible (UV-vis) spectroscopy, scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and immunofluorescent assay (IFA) were conducted to characterize GO-COOH, testify its existence on LAPS and validate CTCs' capturing by anti-EpCAM grafted on GO-COOH modified substrates. It is indicated that LAPS could be a potential platform for CTCs detection and may provide a powerful tool for downstream analysis. PMID- 25460878 TI - Ultrasensitive electrochemical detection of engrailed-2 based on homeodomain specific DNA probe recognition for the diagnosis of prostate cancer. AB - It is well known that the engrailed-2 (EN2) protein, a biomarker for prostate cancer, strongly binds to a specific DNA sequence (5'-TAATTA-3') to regulate transcription. Based on this intrinsic property, DNA probes with additional flanked sequences were designed and optimized. Various measurements, such as electrophoresis mobility shift assay, surface plasmon resonance, and quantitative fluorescence assay were performed to investigate the feasibility of the DNA probes. Then, the affinities of the DNA probes to the target protein were quantitatively determined using FAM-modified DNA probes and magnetic beads, resulting in dissociation constants ranging from 61.03 to 98.84nM. To develop an early diagnosis platform for prostate cancer, an ultrasensitive electrochemical biosensor based on the electrodeposition of gold nanoparticles was designed. The EN2 protein was quantitatively detected using the electrochemical biosensor, and the calculated detection limit was found to be 5.62fM. Finally, the specificity and applicability of the biosensor were verified using several proteins and an artificial urine medium. The impedance signals increased in the cases of EN2, suggesting that the system exhibited high selectivity to only EN2. PMID- 25460879 TI - Miniature direct electron transfer based sulphite/oxygen enzymatic fuel cells. AB - A direct electron transfer (DET) based sulphite/oxygen biofuel cell is reported that utilises human sulphite oxidase (hSOx) and Myrothecium verrucaria bilirubin oxidase (MvBOx) and nanostructured gold electrodes. For bioanode construction, the nanostructured gold microelectrodes were further modified with 3,3' dithiodipropionic acid di(N-hydroxysuccinimide ester) to which polyethylene imine was covalently attached. hSOx was adsorbed onto this chemically modified nanostructured electrode with high surface loading of electroactive enzyme and in presence of sulphite high anodic bioelectrocatalytic currents were generated with an onset potential of 0.05V vs. NHE. The biocathode contained MvBOx directly adsorbed to the deposited gold nanoparticles for cathodic oxygen reduction starting at 0.71V vs. NHE. Both enzyme electrodes were integrated to a DET-type biofuel cell. Power densities of 8 and 1MUWcm(-2) were achieved at 0.15V and 0.45V of cell voltages, respectively, with the membrane based biodevices under aerobic conditions. PMID- 25460880 TI - PolyA-tailed and fluorophore-labeled aptamer-gold nanoparticle conjugate for fluorescence turn-on bioassay using iodide-induced ligand displacement. AB - Depending on the strong affinity of polyA sequence to gold (or silver) surface, applicability of polyA-tailed DNA-gold (or silver) nanoparticle conjugates in homogeneous and heterogeneous protein assays was first demonstrated. Interestingly, when using polyA-tailed, fluophore-labeled DNA-AuNP conjugate, it was found that iodide and thiosulfate anions could act as the ligand displacing reagent to detach polyA-tailed DNA strands from AuNP surface and simultaneously activate the AuNP-quenched fluorophores by destroying the polyA-AuNP interaction via a divide-and-conquer strategy. Based on this new discovery, we have developed a novel, cost-effective and sandwich-type fluorescence turn-on aptasensor for highly sensitive and specific thrombin detection, what took advantage of aptamer conjugated magnetic beads (apt-MBs) for protein capture and separation, and iodide-induced fluorescence recovery of activatable polyA-based AuNP probes through ligand displacement for fluorescence turn-on detection. This proposed aptasensor could detect thrombin specifically with a detection limit as low as 89pM, which was better than or comparable to many existing fluorescent thrombin assays. Importantly, employment of such polyA-based AuNP conjugate not only avoids the use of thiolated oligonucleotides and thiol-containing displacing reagents, but also offers new possibilities for fabricating convenient and cost effective bioanalytical applications. PMID- 25460881 TI - Sensitive and specific colorimetric DNA detection by invasive reaction coupled with nicking endonuclease-assisted nanoparticles amplification. AB - Colorimetric DNA detection is preferable to methods in clinical molecular diagnostics, because no expensive equipment is required. Although many gold nanoparticle-based colorimetric DNA detection strategies have been developed to analyze DNA sequences of interest, few of them can detect somatic mutations due to their insufficient specificity. In this study, we proposed a colorimetric DNA detection method by coupling invasive reaction with nicking endonuclease-assisted nanoparticles amplification (IR-NEANA). A target DNA firstly produces many flaps by invasive reaction. Then the flaps are converted to targets of nicking reaction assisted nanoparticles amplification by ligation reaction to produce the color change of AuNPs, which can be observed by naked eyes. The detection limit of IR NEANA was determined as 1pM. Most importantly, the specificity of the method is high enough to pick up as low as 1% mutant from a large amount of wild-type DNA backgrounds. The EGFR gene mutated at c.2573 T>G in 9 tissue samples from non small cell lung cancer patients were successfully detected by using IR-NEANA, suggesting that our proposed method can be used to detect somatic mutations in biological samples. PMID- 25460882 TI - A sensitive sequential 'on/off' SERS assay for heparin with wider detection window and higher reliability based on the reversed surface charge changes of functionalized Au@Ag nanoparticles. AB - A sequential 'on/off' dual mode SERS assay platform for heparin with wider detection window and higher reliability is constructed based on electrostatic forces, in which the highly protonated chitosan encapsulated p-Mercaptobenzoic acid coated Au@Ag core-shell nanoparticles undergo sequential aggregation/segregation upon the additive of heparin with a limit of detection of 43.74ng/mL (5.69U/mL) and a continuous concentration range of 50-800ng/mL (6.5 104U/mL), which are lower in sensitivity and wider in detection window than the most reported assay for heparin. Remarkably, the latter declined window over a range of 350-800ng/mL in contrast, which has not reported before, is extremely important in reliable and practical assay of heparin. PMID- 25460883 TI - Electrochemical current rectification-a novel signal amplification strategy for highly sensitive and selective aptamer-based biosensor. AB - Electrochemical aptamer-based (E-AB) sensors represent an emerging class of recently developed sensors. However, numerous of these sensors are limited by a low surface density of electrode-bound redox-oligonucleotides which are used as probe. Here we propose to use the concept of electrochemical current rectification (ECR) for the enhancement of the redox signal of E-AB sensors. Commonly, the probe-DNA performs a change in conformation during target binding and enables a nonrecurring charge transfer between redox-tag and electrode. In our system, the redox-tag of the probe-DNA is continuously replenished by solution-phase redox molecules. A unidirectional electron transfer from electrode via surface-linked redox-tag to the solution-phase redox molecules arises that efficiently amplifies the current response. Using this robust and straight forward strategy, the developed sensor showed a substantial signal amplification and consequently improved sensitivity with a calculated detection limit of 114nM for ATP, which was improved by one order of magnitude compared with the amplification-free detection and superior to other previous detection results using enzymes or nanomaterials-based signal amplification. To the best of our knowledge, this is the first demonstration of an aptamer-based electrochemical biosensor involving electrochemical rectification, which can be presumably transferred to other biomedical sensor systems. PMID- 25460884 TI - Electrical impedance sensor for quantitative monitoring of infection processes on HCT-8 cells by the waterborne parasite Cryptosporidium. AB - Cryptosporidium is the main origin of worldwide waterborne epidemic outbreaks caused by protozoan parasites. Its resilience to water chemical treatments and the absence of therapy led to consider it as a reference pathogen to assess water quality and as a possible bioterrorism agent. We here show that an electrical impedance-based device is able to get insights on Cryptosporidium development on a cell culture and to quantify sample infectivity. HCT-8 cells were grown to confluency on Interdigitated Microelectrode Arrays (IMA's) during 76h and then infected by Cryptosporidium parvum during 60h. The impedimetric response was measured at frequencies ranging from 100Hz to 1MHz and a 7min sampling period. As the infection progresses the impedance signal shows a reproducible distinct succession of peaks at 12h post infection (PI), 23h PI and 31h PI and local minima at 9h PI, 19h PI and 28h PI. An equivalent circuit modeling-based approach indicates that these features are mostly originated from paracellular pathway modifications due to host-parasite interactions. Furthermore, our data present for the first time a real-time monitoring of early parasitic stage development with alternating zoite and meront predominances, observed respectively at peaks and local minima in the impedimetric signal. Finally, by quantifying the magnitude of the impedimetric response, we demonstrate this device can also be used as an infectivity sensor as early as 12h PI thus being at least 6 times faster than other state of the art techniques. PMID- 25460885 TI - Electrochemical detection of protein kinase activity based on carboxypeptidase Y digestion triggered signal amplification. AB - An effective assay method for monitoring protein kinase activity and screening inhibitors is greatly beneficial to kinase-related drug discovery, early diagnosis of diseases, and therapeutic effect evaluation. Herein, we develop a simple electrochemical method for detecting the activity of casein kinase II (CK2) based on phosphorylation against carboxypeptidase Y (CPY) digestion triggered signal amplification, where CK2 catalyzed phosphorylation event protects the substrate peptide from the digestion of CPY, maintains the repulsive force of the substrate peptide towards the redox probe, and results in a weak electrochemical signal. Whereas, without phosphorylation, the substrate peptide is digested by CPY and a strong electrochemical signal is obtained. The detection feasibility is demonstrated for the assay of CK2 activity with low detection limit of 0.047unit/mL. Moreover, the biosensor was used for the analysis of kinase inhibition. Based on the electrochemical signal dependent inhibitor concentration, the IC50 value of ellagic acid was estimated to be 39.77nM. The proposed method is also successfully applied to analyze CK2 activity in cell lysates, proving the applicability in complex biological samples. PMID- 25460886 TI - Silver nanowires-based signal amplification for CdSe quantum dots electrochemiluminescence immunoassay. AB - A novel silver-cysteine hybrid nanowires (SCNWs) with many reactive carboxyl and amine groups were prepared, which enable them to be used as idea signal amplifying labels in bioassays. A large number of CdSe quantum dots (QDs) were loaded on the SCNWs to develop amplified SCNWs-QDs electrochemiluminescence (ECL) signal probe. The PAMAM dendrimer-SCNWs nanohybrids covered on the electrode constructed an effective antibody immobilization matrix and made the immobilized biomolecules hold high stability and bioactivity. Based on the specific sandwich immunoreaction strategy, the detection antibody (Ab2)-SCNWs-QDs ECL signal probe was applied to the sensitive signal-on ECL immunoassay of human IgG. The SCNWs QDs ECL not only opens promising new ECL emitting species, but also promotes the development of novel ECL signal-transition platforms for biosensing devices. PMID- 25460887 TI - Enzyme biosensor systems based on porous silicon photoluminescence for detection of glucose, urea and heavy metals. AB - A phenomenon of changes in photoluminescence of porous silicon at variations in medium pH is proposed to be used as a basis for the biosensor system development. The method of conversion of a biochemical signal into an optical one is applied for direct determination of glucose and urea as well as for inhibitory analysis of heavy metal ions. Changes in the quantum yield of porous silicon photoluminescence occur at varying pH of the tested solution due to the enzyme substrate reaction. When creating the biosensor systems, the enzymes urease and glucose oxidase (GOD) were used as a bioselective material; their optimal concentrations were experimentally determined. It was shown that the photoluminescence intensity of porous silicon increased by 1.7 times when increasing glucose concentration in the GOD-containing reaction medium from 0 to 3.0mM, and decreased by 1.45 times at the same increase in the urea concentration in the urease-containing reaction medium. The calibration curves of dependence of the biosensor system responses on the substrate concentrations are presented. It is shown that the presence of heavy metal ions (Cu(2+), Pb(2+), and Cd(2+)) in the tested solution causes an inhibition of the enzymatic reactions catalyzed by glucose oxidase and urease, which results in a restoration of the photoluminescence quantum yield of porous silicon. It is proposed to use this effect for the inhibitory analysis of heavy metal ions. PMID- 25460888 TI - Indirect immunofluorescence detection of E. coli O157:H7 with fluorescent silica nanoparticles. AB - A method of fluorescent nanoparticle-based indirect immunofluorescence assay using either fluorescence microscopy or flow cytometry for the rapid detection of pathogenic Escherichia coli O157:H7 was developed. The dye-doped silica nanoparticles (NPs) were synthesized using W/O microemulsion methods with the combination of 3-aminopropyltriethoxysilane (APTES) and fluorescein isothiocyanate (FITC) and polymerization reaction with carboxyethylsilanetriol sodium salt (CEOS). Protein A was immobilized at the surface of the NPs by covalent binding to the carboxyl linkers and the surface coverage of Protein A on NPs was determined by the Bradford method. Rabbit anti-E. Coli O157:H7 antibody was used as primary antibody to recognize E. coli O157:H7 and then antibody binding protein (Protein A) labeled with FITC-doped silica NPs (FSiNPs) was used to generate fluorescent signal. With this method, E. Coli O157:H7 in buffer and bacterial mixture was detected. In addition, E. coli O157:H7 in several spiked background beef samples were measured with satisfactory results. Therefore, the FSiNPs are applicable in signal-amplified bioassay of pathogens due to their excellent capabilities such as brighter fluorescence and higher photostability than the direct use of conventional fluorescent dyes. PMID- 25460889 TI - Cu(2+) modulated silver nanoclusters as an on-off-on fluorescence probe for the selective detection of L-histidine. AB - In the present study, a new strategy based on Cu(2+) mediated DNA-templated silver nanoclusters (DNA-Ag NCs) was developed, as a label-free, on-off-on fluorescent probe for the detection of l-histidine. Eight synthesized DNA oligonucleotides (D1-D8) were experimentally tested, and D5-Ag NCs was finally selected for l-histidine detection due to its best fluorescent properties. The fluorescence emission of D5-Ag NCs could be quenched by Cu(2+) via electron or energy transfer. Upon addition of l-histidine, the chelation between Cu(2+) and the imidazole group of l-histidine leads to Cu(2+) liberation from D5-Ag NCs, and subsequently results in a dramatic fluorescence enhancement of the probe. The method displayed a good selectivity toward l-histidine over all the other amino acids, with a linear relationship in the range of 0.20-80MUM, and a limit of detection (LOD) of 4.3nM. The strategy was also successfully applied to detect l histidine in diluted human urine, exhibiting great opportunities for practical application in biological system. PMID- 25460890 TI - A novel signal-on strategy for M.SssI methyltransfease activity analysis and inhibitor screening based on photoelectrochemical immunosensor. AB - In this work, a novel signal-on photoelectrochemical (PEC) immunosensor was fabricated for M.SssI methyltransfease (MTase) activity analysis and inhibitor screening based on an in situ electron donor producing strategy, where the anti-5 methylcytosine antibody was selected as DNA CpG methylation recognition unit, gold nanoparticle labeled streptavidin (SA-AuNPs) as signal amplification unit and alkaline phosphatase conjugated biotin (ALP-Biotin) as enzymatic unit. In the presence of M.SssI MTase, hairpin DNA1 containing the palindromic sequences of 5' CCGG-3' in its stem was methylated. After hybridization with biotin-conjugated DNA2, the stem-loop structure of the hairpin DNA1 was unfolded and the duplex strand DNA (dsDNA) was formed. Then, the dsDNA was captured on the surface of anti-5-methylcytosine antibody modified electrode through the specific immuno reaction. Afterwards, SA-AuNPs and ALP-Biotin was further captured on the electrode surface through the specific reaction between biotin and streptavidin. Under the catalysis effect of ALP towards ascorbic acid 2-phosphate trisodium salt (AAP), ascorbic acid (AA) was in situ produced as electron donor and a strong PEC response was obtained. The fabricated biosensor showed high detection sensitivity with low detection limit of 0.33unit/mL for M.SssI MTase. Furthermore, the inhibition research suggested that RG108 could inhibit the M.SssI MTase activity with the IC50 value of 152.54nM. PMID- 25460891 TI - Highly sensitive dendrimer-based nanoplasmonic biosensor for drug allergy diagnosis. AB - A label-free biosensing strategy for amoxicillin (AX) allergy diagnosis based on the combination of novel dendrimer-based conjugates and a recently developed nanoplasmonic sensor technology is reported. Gold nanodisks were functionalized with a custom-designed thiol-ending-polyamido-based dendron (d-BAPAD) peripherally decorated with amoxicilloyl (AXO) groups (d-BAPAD-AXO) in order to detect specific IgE generated in patient's serum against this antibiotic during an allergy outbreak. This innovative strategy, which follows a simple one-step immobilization procedure, shows exceptional results in terms of sensitivity and robustness, leading to a highly-reproducible and long-term stable surface which allows achieving extremely low limits of detection. Moreover, the viability of this biosensor approach to analyze human biological samples has been demonstrated by directly analyzing and quantifying specific anti-AX antibodies in patient's serum without any sample pretreatment. An excellent limit of detection (LoD) of 0.6ng/mL (i.e. 0.25kU/L) has been achieved in the evaluation of clinical samples evidencing the potential of our nanoplasmonic biosensor as an advanced diagnostic tool to quickly identify allergic patients. The results have been compared and validated with a conventional clinical immunofluorescence assay (ImmunoCAP test), confirming an excellent correlation between both techniques. The combination of a novel compact nanoplasmonic platform and a dendrimer-based strategy provides a highly sensitive label free biosensor approach with over two times better detectability than conventional SPR. Both the biosensor device and the carrier structure hold great potential in clinical diagnosis for biomarker analysis in whole serum samples and other human biological samples. PMID- 25460892 TI - Development of a multiplex flow-through immunoaffinity chromatography test for the on-site screening of 14 sulfonamide and 13 quinolone residues in milk. AB - In this paper, a rapid and sensitive multiplex flow-through immunoaffinity chromatography test (FTIACT) was developed for the on-site screening of 14 sulfonamide and 13 quinolone residues in milk. The developed FTIACT method combines the purification, preconcentration and immunochemical detection of multiple antibiotics on the sepharose gel test layers. The use of liposome encapsulated quantum dots (LQDs) with the FTIACT method exhibited the best results, with limits of detection (LODs) of 1 and 0.5ng/mL for the sulfonamides (SAs) and quinolones (QNs), respectively, through qualitative analysis (visual detection by the naked eye). In order to achieve low detection limit, the color intensity of the images were converted into relative optical density values to enable a quantitative evaluation. Quantitative analysis of the samples enabled the detection of SAs (0.13ng/mL) and QNs (0.062ng/mL) in spiked milk samples. The FTIACT described in this work shows promise as a multiplex immunoassay for the qualitative and quantitative screening of multiple chemical residues in milk. PMID- 25460893 TI - One step in-situ synthesis of amine functionalized graphene for immunosensing of cardiac marker cTnI. AB - 2-Aminobenzyl amine (2-ABA) functionalized graphene is proposed for the ultrasensitive immunosensing of Cardiac Troponin I (cTnI). 2-ABA was electrochemically polymerized on the graphene decorated interdigitated electrode to obtain the amine functionalized graphene (f-GN). The f-GN electrode was then modified with monoclonal anti-cTnI antibodies via Schiff reaction based chemistry. Detailed characteristics of the processes involved and the finally developed antibody conjugated f-GN interdigitated electrode have been studied. The above micro-device was used in a drain source configuration for the sensing of cTnI. A wide dynamic linear range of antigen detection (0.01-1ng/mL) is achieved with the limit of detection of 0.01ng/mL. The utility of the proposed sensing technique is demonstrated by successfully testing the antigen concentration in spiked serum samples. PMID- 25460894 TI - Immunoassay of paralytic shellfish toxins by moving magnetic particles in a stationary liquid-phase lab-on-a-chip. AB - In this study, we devised a stationary liquid-phase lab-on-a-chip (SLP LOC), which was operated by moving solid-phase magnetic particles in the stationary liquid phase. The SLP LOC consisted of a sample chamber to which a sample and reactants were added, a detection chamber containing enzyme substrate solution, and a narrow channel connecting the two chambers and filled with buffer. As a model system, competitive immunoassays of saxitoxin (STX), a paralytic shellfish toxin, were conducted in the SLP LOC using protein G-coupled magnetic particles (G-MPs) as the solid phase. Anti-STX antibodies, STX-horseradish peroxidase conjugate, G-MPs, and a STX sample were added to the sample chamber and reacted by shaking. While liquids were in the stationary state, G-MPs were transported from the sample chamber to the detection chamber by moving a magnet below the LOC. After incubation to allow the enzymatic reaction to occur, the absorbance of the detection chamber solution was found to be reciprocally related to the STX concentration of the sample. Thus, the SLP LOC may represent a novel, simple format for point-of-care testing applications of enzyme-linked immunosorbent assays by eliminating complicated liquid handling steps. PMID- 25460895 TI - A novel controlled release system-based homogeneous immunoassay protocol for SCCA using magnetic mesoporous Fe3O4 as a nanocontainer and aminated polystyrene microspheres as a molecular gate. AB - A novel controlled release system-based homogeneous immunoassay protocol (CRSHIP) was developed for the detection of squamous cell carcinoma antigen (SCCA). The positively charged aminated polystyrene microsphere (APSM) used as molecular gate was capped on the pores of the negatively charged antibody-conjugated magnetic mesoporous Fe3O4 (Ab-Fe3O4) by electrostatic interaction to achieve encapsulation of toluidine blue (TB). With the addition of SCCA, APSM was replaced from Ab Fe3O4 due to the specific binding of antibody to antigen, and then the trapped TB was released from the pores. The released TB could be detected by square wave voltammetry and the signal could be correlated with the amount of SCCA. The developed CRSHIP displayed a high current response, a relatively wide linear range (from 0.001 to 4.0ng/mL) and a low detection limit (0.33pg/mL) for the detection of SCCA. The method showed high selectivity and good reproducibility. In addition, the CRSHIP provided a simple, fast and sensitive approach for the detection of SCCA in serum sample. PMID- 25460896 TI - Rapid detection and typing of live bacteria from human joint fluid samples by utilizing an integrated microfluidic system. AB - Periprosthetic joint infection (PJI) is one of the most dreading complications that hinder the merits of an arthroplasty. A prerequisite for treatment of the above procedure is rapid detection of live bacteria to prevent its recurrence and proper choice of antibiotics. Conventional culture methods are time-consuming and associated with a high false negative rate. Amplification of bacterial genetic materials requires a tedious process but is associated with a high false positive rate. An integrated microfluidic system capable of molecular diagnosis for detecting live bacteria was reported in our previous work. However, the system could not provide detailed information about infectious bacteria for the subsequent antibiotic choices. Furthermore, it took at least 55min to finish the entire process. In this work, a microfluidic platform using ethidium monoazide (EMA) which can only penetrate into dead bacteria is presented for live bacteria detection and typing within a short period of time (30min for the detection of live bacteria and another 40min for the typing of bacteria strains). We tested the proposed system by using human joint fluid samples and found its limit of detection for bacterial detection equal to 10(2)CFU (colony formation unit) for live bacteria detection with gold nanoparticle probes and 10(2)-10(4)CFU for typing bacteria by an on-chip polymerase chain reaction. The whole procedure of the integrated microfluidic system is automated with little human intervention. Moreover, this is the first time that sequential live bacteria detection and typing are demonstrated on the same microfluidic platform. Based on the promising results, the proposed system may become in the near future an auxiliary tool for immediate medical decision and choice of antibiotics in routine arthroplasties or PJI's. PMID- 25460898 TI - Graphene-based rapid and highly-sensitive immunoassay for C-reactive protein using a smartphone-based colorimetric reader. AB - A novel immunoassay (IA) has been developed for human C-reactive protein (CRP), an important biomarker and tissue preserving factor for infection and inflammation. Graphene nanoplatelets (GNP) and 3-aminopropyltriethoxysilane (APTES) were admixed and covalently attached to a polystyrene based-microtiter plate (MTP), pretreated with KOH. The resulting surface served as a stable layer for the covalent attachment of the anti-human CRP antibody. The IA procedure was based on the one-step kinetics-based sandwich IA employing a minimum number of process steps, whereas the enzymatic reaction solution was monitored by a smartphone-based colorimetric reader. With a limit of detection and a limit of quantification of 0.07ngmL(-1) and 0.9ngmL(-1), it precisely detected CRP spiked in diluted human whole blood and plasma as well as the CRP levels in clinical plasma samples. The results obtained for "real-world" patient samples agreed well with those of the conventional immunosorbent assay and the clinically-accredited analyzer-based IA. The antibody-bound GNP-functionalized MTPs retained its original activity after 6 weeks of storage in 0.1M PBS, pH 7.4 at 4 degrees C. PMID- 25460897 TI - Chemical etching of bovine serum albumin-protected Au25 nanoclusters for label free and separation-free detection of cysteamine. AB - This study describes a novel Au nanocluster-based fluorescent sensor for label free, separation-free and selective detection of cysteamine (CSH). The sensing mechanism is based on CSH etching-induced fluorescence quenching of the bovine serum albumin-protected Au25 nanoclusters (BSAGNCs). A series of characterizations is carried out towards a better understanding of the CSH induced fluorescence quenching of the BSAGNCs. It is found that CSH can etch the Au25 nanoclusters, exhibiting the potent etching activity. Other thiol-containing compounds such as glutathione and cysteine and other 19 natural amino acids do not interfere with such CSH-induced etching process. The decreases in fluorescence intensity of the BSAGNCs allow sensitive detection of free CSH in the range of 500-10,000nM. The detection limit for CSH is 150nM (S/N=3). The spiked human serum samples can be analyzed with satisfactory results. PMID- 25460899 TI - Cascade signal amplification for electrochemical immunosensing by integrating biobarcode probes, surface-initiated enzymatic polymerization and silver nanoparticle deposition. AB - A cascade signal amplification strategy through combining surface-initiated enzymatic polymerization (SIEP) and the subsequent deposition of strepavidin functionalized silver nanoparticles (AgNPs) was proposed. The first step of constructing the electrochemical immunosensor involves covalently immobilizing capture antibody on a chitosan modified glass carbon electrode, which then catalyzes DNA addition of deoxynucleotides (dNTP) at the 3'-OH group by terminal deoxynucleotidyl transferase (TdT), leading to the formation of long single stranded DNAs labeled with numerous biotins. Following the deposition of numerous strepavidin functionalized AgNPs on those long DNA chains, electrochemical stripping signal of silver was used to monitor the immunoreaction in KCl solution. Using alpha-fetoprotein as a model analyte, this amplification strategy could detect fetoprotein down to 0.046pg/mL with a wide linear range from 0.1pg/mL to 1.0ng/mL. The achieved high sensitivity and good reproducibility suggest that this cascade signal amplification strategy has great potential for detecting biological samples and possibly clinical application. PMID- 25460900 TI - Gold nanoparticle-based dynamic light scattering immunoassay for ultrasensitive detection of Listeria monocytogenes in lettuces. AB - Gold nanoparticle (GNP)-based dynamic light scattering (DLS) assay has been widely used for sensitive detection of small analytes based on analyte binding induced GNP aggregation. However, the use of this new method to detect large biological objectives, such as pathogenic bacteria, has not been reported. This study is the first to describe a homogeneous GNP-based DLS immunoassay for ultrasensitive detection of Listeria monocytogenes. Compared with small analytes, L. monocytogenes has a larger surface and a higher number of antigen epitopes, which serve as carriers that bind to GNP probes to form "GNP-coated bacteria" complexes. To achieve better analytical performance, various parameters including GNP diameter and concentration, amount of labeled antibodies, and immunoreaction time were systematically investigated and optimized. Under the developed optimum conditions, limit of detection (LOD) for L. monocytogenes reached as low as 3.5*10(1)CFUmL(-1) in 0.01M phosphate-buffered saline. Coupled with a large volume immunomagnetic separation method, LOD for spiked lettuce samples reached 2.2*10(1)CFUg(-1), which was one order of magnitude lower than the maximum limit imposed in Canada (100CFUg(-1)). The proposed method also exhibited excellent discrimination against 17 common pathogenic bacteria in lettuces. The developed GNP-based DLS immunoassay is highly promising as an approach for detecting large biological objectives. PMID- 25460901 TI - Green and facile synthesis of an Au nanoparticles@polyoxometalate/ordered mesoporous carbon tri-component nanocomposite and its electrochemical applications. AB - The one-pot synthesis of a well-defined Au nanoparticles@polyoxometalates/ordered mesoporous carbon (Au@POMs/OMC) tri-component nanocomposite is reported, which is facile, green and rapid. The polyoxometalates were used as both reductant and bridging molecules. The formation of these composite materials was verified by a comprehensive characterization using X-ray diffraction, X-ray photoelectron spectroscopy, energy-dispersive X-ray spectra, scanning electron microscopy, and transmission electron microscopy. The novel nanohybrids of Au@POMs/OMC can provide new features of electrocatalytic activities, because of the synergetic effects of Au nanoparticles and OMC materials. Most importantly, the amperometric measurements show that the Au@POMs/OMC nanohybrids have a high catalytic activity with a good sensitivity, long-term stability, wide linear range, low detection limit, and fast response towards acetaminophenol, H2O2, and NADH detection for application as an enzyme-free biosensor. PMID- 25460902 TI - A sensitive and selective magnetic graphene composite-modified polycrystalline silicon nanowire field-effect transistor for bladder cancer diagnosis. AB - In this study, we describe the urinary quantification of apolipoprotein A II protein (APOA2 protein), a biomarker for the diagnosis of bladder cancer, using an n-type polycrystalline silicon nanowire field-effect transistor (poly-SiNW FET). The modification of poly-SiNW-FET by magnetic graphene with long-chain acid groups (MGLA) synthesized via Friedel-Crafts acylation was compared with that obtained using short-chain acid groups (MGSA). Compared with MGSA, the MGLA showed a higher immobilization degree and bioactivity to the anti-APOA2 antibody (Ab) due to its lower steric hindrance. In addition, the magnetic properties enabled rapid separation and purification during Ab immobilization, ultimately preserving its bioactivity. The Ab-MGLA/poly-SiNW-FET exhibited a linear dependence of relative response to the logarithmical concentration in a range between 19.5pgmL(-1) and 1.95ugmL(-1), with a limit of detection (LOD) of 6.7pgmL(-1). An additional washing step before measurement aimed at excluding the interfering biocomponents ensured the reliability of the assay. We conclude that our biosensor efficiently distinguishes mean values of urinary APOA2 protein concentrations between patients with bladder cancer (29-344ngmL(-1)) and those with hernia (0.425-9.47ngmL(-1)). PMID- 25460903 TI - Evaluation of a carbon nanotube-titanate nanotube nanocomposite as an electrochemical biosensor scaffold. AB - A significant aspect of this work is the development of a multi-wall carbon nanotube (MWCNT)-titanate nanotube (TNT) nanocomposite to serve as a biocompatible scaffold with high conductivity on a biosensor surface. Unlike other scaffolds consisting of MWCNTs alone or TNTs alone, the MWCNT-TNT nanocomposite synergistically provides excellent biocompatibility, good electrical conductivity, low electrochemical interferences and a high signal-to noise ratio. For comparison, after characterising a scaffold consisting of MWCNTs alone, TNTs alone and a MWCNT-TNT nanocomposite using several spectroscopic techniques, the analytical performance of a horseradish peroxidase (HRP) electrochemical biosensor was evaluated using cyclic voltammetry and differential pulse voltammetry. The scaffold consisting of MWCNTs alone displayed a high background charging current, a low signal-to-noise ratio and distinct electrochemical interference from its surface functional groups. In contrast, the direct electrochemistry and the catalytic capability of HRP at MWCNT-TNT modified biosensors towards H2O2 was demonstrated to be ~51% and ~144% enhanced, respectively, compared to those at TNT modified biosensors. Meanwhile, MWCNT-TNT nanocomposite modified HRP biosensors also exhibited higher sensitivity (4.42MUAmM(-1)) than TNT modified HRP biosensors (1.48MUAmM(-1)). The above superior performance was attributed to the improved properties of MWCNT-TNT nanocomposite as biosensor scaffold compared to its two individual components by complementing each component and synergistically sustaining the characteristic features of each component. PMID- 25460904 TI - Immunoreaction-triggered DNA assembly for one-step sensitive ratiometric electrochemical biosensing of protein biomarker. AB - A sensitive ratiometric electrochemical readout was designed with an immunoreaction-triggered DNA assembly for one-step, fast and flexible assay of protein biomarker. The sensing interface was prepared by immobilizing a ferrocene (Fc)-labeled hairpin DNA on a gold electrode. In the presence of DNA2-antibody2 (Ab2) and methylene blue (MB)-labeled DNA1-Ab1 probes, the addition of target protein could induce the sandwich immunoreaction among two probes and the protein to trigger the hybridization of DNA1 and DNA2, which subsequently unfolded the hairpin DNA to form a three-arm DNA structure on the sensing interface. The DNA assembly caused the departure of Fc from the electrode and the approach of MB to the electrode, which led to the signal decrease and increase of Fc and MB respectively for ratiometric readout. Using prostate specific antigen (PSA) as a model target, the ratiometric electrochemical assay showed a linear detection range from 0.01 to 200ng/mL with a detection limit of 4.3pg/mL (the mean signal of blank measures+3sigma). By changing the affinity probe pairs this method could be easily expanded for other protein analytes, showing promising potential for point-of-care testing and extensive applications in bioanalysis. PMID- 25460905 TI - Rural-urban area of residence and trajectories of children's behavior in England. AB - Despite extensive studies of neighborhood effects on children's outcomes, there is little evidence on rural-urban impacts on child mental health. We modeled trajectories of emotional-behavioral problems of white majority children at ages 3, 5, and 7 in England in areas with varying levels of rural and urban settlement, using the Millennium Cohort Study. After adjusting for area selection, children in less sparse rural areas had fewer conduct and peer problems, and children in areas with a mix of rural and urban settlement had fewer emotional symptoms, explained by the quality of their schools. Area differences remained in emotional problems. PMID- 25460906 TI - The experiential impact of hospitalisation in early psychosis: service-user accounts of inpatient environments. AB - Early Intervention in Psychosis services aim to keep young people out of hospital, but this is not always possible. This research used in-depth interviews to explore the experience of hospitalisation amongst young people with psychosis. Findings describe fear and confusion at admission, conflicting experiences of the inpatient unit as both safe and containing, and unsafe and chaotic, and the difficult process of maintaining identity in light of the admission. We discuss the need to move from construing psychiatric hospitals as places for 'passive seclusion', to developing more permeable and welcoming environments that can play an active role in recovery. PMID- 25460908 TI - Contemporary programs in support of traditional ways: Inuit perspectives on community freezers as a mechanism to alleviate pressures of wild food access in Nain, Nunatsiavut. AB - Rapid socio-cultural, economic, and environmental changes are challenging wild food access and thus food security for Inuit in the Canadian Arctic. In response to the continued value and practice of harvesting wild foods, communities are establishing "wild food support" initiatives. This study evaluated how one such initiative, a community freezer, in Nain, Nunatsiavut supported wild food access for community members. Data were collected through: interviews and focus groups with users, freezer managers, and active harvesters; participant observation; and document analysis. Results indicated that the community freezer supported socio cultural, economic and local access to wild foods. However, there were issues associated with supply, dependency, social exclusion, and tension between feasibility and traditional values and practices. Communities, governments, and policymakers are urged to consider social and physical location as factors when investing in and monitoring such initiatives. The Nunatsiavut Government and the Nain Inuit Community Government have since worked together to modify this early freezer initiative due, in part, to this study's findings. PMID- 25460907 TI - An ecological analysis of environmental correlates of active commuting in urban U.S. AB - We conduct a cross-sectional ecological analysis to examine environmental correlates of active commuting in 39,660 urban tracts using data from the 2010 Census, 2007-2011 American Community Survey, and other sources. The five-year average (2007-2011) prevalence is 3.05% for walking, 0.63% for biking, and 7.28% for public transportation to work, with higher prevalence for all modes in lower income tracts. Environmental factors account for more variances in public transportation to work but economic and demographic factors account for more variances in walking and biking to work. Population density, median housing age, street connectivity, tree canopy, distance to parks, air quality, and county sprawl index are associated with active commuting, but the association can vary in size and direction for different transportation mode and for higher-income and lower-income tracts. PMID- 25460909 TI - Using social marketing to create communities for our children and adolescents that do not model and encourage drinking. AB - Our children and adolescents are growing up in environments that support, and even, encourage (excessive) drinking. Thus, if we are to address the problem of underage drinking our focus needs to move beyond eliciting behavior change among children and adolescents to changing underlying community attitudes, social norms, and the environment itself. This review sought to examine the evidence base surrounding 'community-based' interventions designed to address underage drinking; to determine the extent to which 'community' interventions have thus far targeted the broader community and gone beyond behavior-focused strategies and endeavored to change social and physical environments. The review found surprisingly few interventions that sought to comprehensively address social norms at a community level. We need to move (research and interventions) beyond narrowly-focused efforts targeting teens and their parents; it is only when we address alcohol consumption at a population level that we will be able to provide an environment for children and adolescents which does not model (excessive) drinking as a normative social behavior. PMID- 25460910 TI - Geographic variation of clinically diagnosed mood and anxiety disorders in Christchurch after the 2010/11 earthquakes. AB - The 22nd February 2011 Christchurch earthquake killed 185 people, injured over 8000, damaged over 100,000 buildings and on-going aftershocks maintained high anxiety levels. This paper examines the dose of exposure effect of earthquake damage assessments, earthquake intensity measures, liquefaction and lateral spreading on mood and anxiety disorders in Christchurch after this event. We hypothesise that such disorders are more likely to develop in people who have experienced greater exposure to these impacts within their neighborhood than others who have been less exposed, but also live in the city. For this purpose, almost all clinically diagnosed incident and relapsed cases in Christchurch in a 12 months period after the 2011 earthquake were analysed. Spatio-temporal cluster analysis shows that people living in the widely affected central and eastern parts after the 2010/11 earthquakes have a 23% higher risk of developing a mood or anxiety disorder than people living in other parts of the city. Generally, mood and anxiety-related disorders increase with closer proximity to damage from liquefaction and moderate to major lateral spreading, as well as areas that are more likely to suffer from damage in future earthquakes. PMID- 25460911 TI - Ultrasound-assisted extraction of arabinogalactan and dihydroquercetin simultaneously from Larix gmelinii as a pretreatment for pulping and papermaking. AB - An ultrasound-assisted extraction (UAE) method using ethanol was applied for extracting arabinogalactan (AG) and dihydroquercetin (DHQ) simultaneously from larch wood, as a pretreatment for pulping and papermaking. The extraction parameters were optimized by a Box-Behnken experimental design with the yields of AG and DHQ as the response values. Under optimum conditions (three extractions, each using 40% ethanol, for 50 min, 200 W ultrasound power and 1?18 solid-liquid ratio), the yields of AG and DHQ were 183.4 and 36.76 mg/g, respectively. After UAE pretreated, the wood chips were used for Kraft pulping (KP) and high boiling solvent pulping (HBSP). The pulping yield after pretreatment was higher than that of untreated (the pulping yields of untreated HBSP and KP were 42.37% and 39.60%, and the pulping yields of HBSP and KP after UAE-pretreated were 44.23% and 41.50% respectively), as indicated by a lower kappa number (77.91 and 27.30 for untreated HBSP and KP; 77.01 and 26.83 for UAE-pretreated HBSP and KP). Furthermore, the characteristics of paper produced from pretreated wood chips were superior to those from the untreated chips: the basis weight was lower (85.67 and 82.48 g.cm(-2) for paper from untreated KP and HBSP; 79.94 and 80.25 g.cm(-2) for paper from UAE-pretreated KP and HBSP), and the tensile strengths, tearing strengths, bursting strengths, and folding strengths were higher than these of paper after UAE-pretreated, respectively. PMID- 25460912 TI - Validation of the French version of the Child Post-Traumatic Stress Reaction Index: psychometric properties in French speaking school-aged children. AB - BACKGROUND: Although the reliable and valid Child Post-Traumatic Stress Reaction Index (CPTS-RI) is a widely used measure of posttraumatic stress disorder (PTSD) symptoms in children, it has not been validated in French-speaking populations. The present study aims to assess the psychometric properties of the CPTS-RI in three samples of French-speaking school-children. METHODS: Data was obtained from three samples. Sample 1 was composed of 106 children (mean (SD) age = 11.7(0.7), 50% females) victims of an industrial disaster. Sample 2 was composed of 50 children (mean (SD) age = 10.8(2.6), 44% females) who had received an orthopaedic surgical procedure after an accident. Sample 3 was composed of 106 children (mean (SD) age = 11.7(2.2), 44% females) admitted to an emergency department after a road traffic accident. We tested internal consistency using Cronbach's alpha. We examined test-retest reliability using intraclass correlation coefficient. In order to assess the convergent validity of the French version of the CPTS-RI and the Clinician Administered PTS Scale-Child and Adolescent (CAPS-CA), spearman correlation coefficient was computed. To verify the validity of the cut-off scores, a ROC curve was constructed which evaluated the sensitivity and specificity of each score compared to the diagnosis with the CAPS-CA. We also used principal components analysis with varimax rotation to study the structure of the French version of the CPTS-RI. RESULTS: Cronbach's alpha coefficient was 0.87 for the French version of the CPTS-RI. Two-week test-retest intraclass correlation coefficient (n = 30) was 0.67. The French version of the CPTS-RI was well correlated with the CAPS-CA (r = 0.76, p < 0.001). Taking the CAPS-CA as the diagnostic reference, with a diagnostic cut-off of >24 for the CPTS-RI, the sensitivity and specificities were 100% and 62.6%, respectively. The French version of the CPTS-RI demonstrated a three-factor structure. CONCLUSIONS: The CPTS-RI is reliable and valid in French-speaking children. PMID- 25460913 TI - Identification of microRNAs linked to regulators of muscle protein synthesis and regeneration in young and old skeletal muscle. AB - BACKGROUND: Over the course of ageing there is a natural and progressive loss of skeletal muscle mass. The onset and progression of age-related muscle wasting is associated with an attenuated activation of Akt-mTOR signalling and muscle protein synthesis in response to anabolic stimuli such as resistance exercise. MicroRNAs (miRNAs) are novel and important post-transcriptional regulators of numerous cellular processes. The role of miRNAs in the regulation of muscle protein synthesis following resistance exercise is poorly understood. This study investigated the changes in skeletal muscle miRNA expression following an acute bout of resistance exercise in young and old subjects with a focus on the miRNA species predicted to target Akt-mTOR signalling. RESULTS: Ten young (24.2+/-0.9 years) and 10 old (66.6+/-1.1 years) males completed an acute resistance exercise bout known to maximise muscle protein synthesis, with muscle biopsies collected before and 2 hours after exercise. We screened the expression of 754 miRNAs in the muscle biopsies and found 26 miRNAs to be regulated with age, exercise or a combination of both factors. Nine of these miRNAs are highly predicted to regulate targets within the Akt-mTOR signalling pathway and 5 miRNAs have validated binding sites within the 3' UTRs of several members of the Akt-mTOR signalling pathway. The miR-99/100 family of miRNAs notably emerged as potentially important regulators of skeletal muscle mass in young and old subjects. CONCLUSION: This study has identified several miRNAs that were regulated with age or with a single bout of resistance exercise. Some of these miRNAs were predicted to influence Akt-mTOR signalling, and therefore potentially skeletal muscle mass. These miRNAs should be considered as candidate targets for in vivo modulation. PMID- 25460914 TI - H2O2 inhibits ABA-signaling protein phosphatase HAB1. AB - Due to its ability to be rapidly generated and propagated over long distances, H2O2 is an important second messenger for biotic and abiotic stress signaling in plants. In response to low water potential and high salt concentrations sensed in the roots of plants, the stress hormone abscisic acid (ABA) activates NADPH oxidase to generate H2O2, which is propagated in guard cells in leaves to induce stomatal closure and prevent water loss from transpiration. Using a reconstituted system, we demonstrate that H2O2 reversibly prevents the protein phosphatase HAB1, a key component of the core ABA-signaling pathway, from inhibiting its main target in guard cells, SnRK2.6/OST1 kinase. We have identified HAB1 C186 and C274 as H2O2-sensitive thiols and demonstrate that their oxidation inhibits both HAB1 catalytic activity and its ability to physically associate with SnRK2.6 by formation of intermolecular dimers. PMID- 25460915 TI - Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts. AB - BACKGROUND: Lung cancer risks at which individuals should be screened with computed tomography (CT) for lung cancer are undecided. This study's objectives are to identify a risk threshold for selecting individuals for screening, to compare its efficiency with the U.S. Preventive Services Task Force (USPSTF) criteria for identifying screenees, and to determine whether never-smokers should be screened. Lung cancer risks are compared between smokers aged 55-64 and >= 65 80 y. METHODS AND FINDINGS: Applying the PLCO(m2012) model, a model based on 6-y lung cancer incidence, we identified the risk threshold above which National Lung Screening Trial (NLST, n = 53,452) CT arm lung cancer mortality rates were consistently lower than rates in the chest X-ray (CXR) arm. We evaluated the USPSTF and PLCO(m2012) risk criteria in intervention arm (CXR) smokers (n = 37,327) of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). The numbers of smokers selected for screening, and the sensitivities, specificities, and positive predictive values (PPVs) for identifying lung cancers were assessed. A modified model (PLCOall2014) evaluated risks in never-smokers. At PLCO(m2012) risk >= 0.0151, the 65th percentile of risk, the NLST CT arm mortality rates are consistently below the CXR arm's rates. The number needed to screen to prevent one lung cancer death in the 65th to 100th percentile risk group is 255 (95% CI 143 to 1,184), and in the 30th to <65th percentile risk group is 963 (95% CI 291 to -754); the number needed to screen could not be estimated in the <30th percentile risk group because of absence of lung cancer deaths. When applied to PLCO intervention arm smokers, compared to the USPSTF criteria, the PLCO(m2012) risk >= 0.0151 threshold selected 8.8% fewer individuals for screening (p<0.001) but identified 12.4% more lung cancers (sensitivity 80.1% [95% CI 76.8%-83.0%] versus 71.2% [95% CI 67.6%-74.6%], p<0.001), had fewer false-positives (specificity 66.2% [95% CI 65.7%-66.7%] versus 62.7% [95% CI 62.2%-63.1%], p<0.001), and had higher PPV (4.2% [95% CI 3.9%-4.6%] versus 3.4% [95% CI 3.1%-3.7%], p<0.001). In total, 26% of individuals selected for screening based on USPSTF criteria had risks below the threshold PLCO(m2012) risk >= 0.0151. Of PLCO former smokers with quit time >15 y, 8.5% had PLCO(m2012) risk >= 0.0151. None of 65,711 PLCO never-smokers had PLCO(m2012) risk >= 0.0151. Risks and lung cancers were significantly greater in PLCO smokers aged >= 65-80 y than in those aged 55-64 y. This study omitted cost-effectiveness analysis. CONCLUSIONS: The USPSTF criteria for CT screening include some low-risk individuals and exclude some high-risk individuals. Use of the PLCO(m2012) risk >= 0.0151 criterion can improve screening efficiency. Currently, never-smokers should not be screened. Smokers aged >= 65-80 y are a high-risk group who may benefit from screening. Please see later in the article for the Editors' Summary. PMID- 25460916 TI - The N-terminal fragment of a PB2 subunit from the influenza A virus (A/Hong Kong/156/1997 H5N1) effectively inhibits RNP activity and viral replication. AB - BACKGROUND: Influenza A virus has a RNA-dependent RNA polymerase (RdRp) that is composed of three subunits (PB1, PB2 and PA subunit), which assemble with nucleoproteins (NP) and a viral RNA (vRNA) to form a RNP complex in the host nucleus. Recently, we demonstrated that the combination of influenza ribonucleoprotein (RNP) components is important for both its assembly and activity. Therefore, we questioned whether the inhibition of the RNP combination via an incompatible component in the RNP complex could become a methodology for an anti-influenza drug. METHODOLOGY/PRINCIPAL FINDINGS: We found that a H5N1 PB2 subunit efficiently inhibits H1N1 RNP assembly and activity. Moreover, we determined the domains and important amino acids on the N-terminus of the PB2 subunit that are required for a strong inhibitory effect. The NP binding site of the PB2 subunit is important for the inhibition of RNP activity by another strain. A plaque assay also confirmed that a fragment of the PB2 subunit could inhibit viral replication. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the N-terminal fragment of a PB2 subunit becomes an inhibitor that targets influenza RNP activity that is different from that targeted by current drugs such as M2 and NA inhibitors. PMID- 25460917 TI - Human DNA polymerases catalyze lesion bypass across benzo[a]pyrene-derived DNA adduct clustered with an abasic site. AB - The combined action of oxidative stress and genotoxic polycyclic aromatic hydrocarbons derivatives can lead to cluster-type DNA damage that includes both a modified nucleotide and a bulky lesion. As an example, we investigated the possibility of repair of an AP site located opposite a minor groove-positioned (+)-trans-BPDE-dG or a base-displaced intercalated (+)-cis-BPDE-dG adduct (BP lesion) by a BER system. Oligonucleotides with single uracil residue in the certain position were annealed with complementary oligonucleotides bearing either a cis- or trans-BP adduct. Digestion with uracil DNA glycosylase was utilized to generate an AP site which was then hydrolyzed by APE1, and the resulting gap was processed by X-family DNA polymerases beta (Polbeta) and lambda (Pollambda), or Y family polymerase iota (Poliota). By varying reaction conditions, namely, Mg2+/Mn2+ replacement/combination and ionic strength decrease, we found that under certain conditions both Polbeta and Poliota can catalyze lesion bypass across both cis- and trans-BP adducts in the presence of physiological dNTP concentrations. Polbeta and Poliota catalyze gap filling trans-lesion synthesis in an error prone manner. By contrast, Pollambda selectively introduced the correct dCTP opposite the modified dG in the case of cis-BP-dG adduct only, and did not bypass the stereoisomeric trans-adduct under any of the conditions examined. The results suggest that Pollambda is a specialized polymerase that can process these kinds of lesions. PMID- 25460918 TI - Structural and functional characterization of Cys4 zinc finger motif in the recombination mediator protein RecR. AB - Zinc finger motif widely exists in protein structure, which can play different roles in different proteins. RecR is an important recombination mediator protein (RMP) in the RecFOR pathway and zinc finger motif is the most conserved domain in RecR protein. However, the function of this zinc finger motif in RecR is unclear. Here, we have studied the structures of the single cysteine and double cysteines mutation within the zinc finger motif in Thermoanaerobacter tengcongensis RecR (TTERecR). We have also studied the DNA binding ability as well as TTERecO protein binding ability of single, double and even triple cysteines mutation of the zinc finger motif, and the mutants do not alter DNA binding by RecR nor the interaction between RecR and RecO. The function of TTERecR zinc finger motif is to maintain the stability of the three-dimensional structure. PMID- 25460920 TI - Damage mechanisms in uniaxial compression of single enamel rods. AB - Enamel possesses a complex hierarchical structure, which bestows this tissue with unique mechanical properties. In this study, the mechanical behavior of single enamel rods was investigated under uniaxial compression. Numerical simulations were also performed using micromechanics models for individual enamel rods to identify the damage mechanisms contributing to the constitutive behavior. Experimental results showed that the single rods exhibited an elastic modulus ranging from 10~31 GPa, and that they undergo post-yield strain-hardening. The primary damage mode consisted of delamination within the assembly of mineral crystals. Results from numerical simulations suggest that strain localization within individual rods is responsible for the observed delamination, which is believed to arise from the non-uniform arrangement of mineral crystals. This mechanism was independent of mineral morphology and properties. The non-uniform crystal arrangement results in friction between crystals with different inclination angles and is believed to be responsible for the post-yield strain hardening behavior. PMID- 25460919 TI - 5-Fluorouracil mediated anti-cancer activity in colon cancer cells is through the induction of Adenomatous Polyposis Coli: Implication of the long-patch base excision repair pathway. AB - Colorectal cancer (CRC) patients with APC mutations do not benefit from 5-FU therapy. It was reported that APC physically interacts with POLbeta and FEN1, thus blocking LP-BER via APC's DNA repair inhibitory (DRI) domain in vitro. The aim of this study was to elucidate how APC status affects BER and the response of CRC to 5-FU. HCT-116, HT-29, and LOVO cells varying in APC status were treated with 5-FU to evaluate expression, repair, and survival responses. HCT-116 expresses wild-type APC; HT-29 expresses an APC mutant that contains DRI domain; LOVO expresses an APC mutant lacking DRI domain. 5-FU increased the expression of APC and decreased the expression of FEN1 in HCT-116 and HT-29 cells, which were sensitized to 5-FU when compared to LOVO cells. Knockdown of APC in HCT-116 rendered cells resistant to 5-FU, and FEN1 levels remained unchanged. Re expression of full-length APC in LOVO cells caused sensitivity to 5-FU, and decreased expression of FEN1. These knockdown and addback studies confirmed that the DRI domain is necessary for the APC-mediated reduction in LP-BER and 5-FU. Modelling studies showed that 5-FU can interact with the DRI domain of APC via hydrogen bonding and hydrophobic interactions. 5-FU resistance in CRC occurs with mutations in APC that disrupt or eliminate the DRI domain's interaction with LP BER. Understanding the type of APC mutation should better predict 5-FU resistance in CRC than simply characterizing APC status as wild-type or mutant. PMID- 25460921 TI - Determination of poroelastic properties of cartilage using constrained optimization coupled with finite element analysis. AB - The feasibility of determining biphasic material properties using a finite element model of stress relaxation coupled with two types of constrained optimization to match measured data was investigated. Comparison of these two approaches, a zero-order method and a gradient-based algorithm, validated the predicted material properties. Optimizations were started from multiple different initial guesses of material properties (design variables) to establish the robustness of the optimization. Overall, the optimal values are close to those found by Cohen et al. (1998) but these small differences produced a marked improvement in the fit to the measured stress relaxation. Despite the greater deviation in the optimized values obtained from the zero-order method, both optimization procedures produced material properties that gave equally good overall fits to the measured data. Furthermore, optimized values were all within the expected range of material properties. Modeling stress relaxation using the optimized material properties showed an excellent fit to the entire time history of the measured data. PMID- 25460922 TI - Multi-scale mechanical response of freeze-dried collagen scaffolds for tissue engineering applications. AB - Tissue engineering has grown in the past two decades as a promising solution to unresolved clinical problems such as osteoarthritis. The mechanical response of tissue engineering scaffolds is one of the factors determining their use in applications such as cartilage and bone repair. The relationship between the structural and intrinsic mechanical properties of the scaffolds was the object of this study, with the ultimate aim of understanding the stiffness of the substrate that adhered cells experience, and its link to the bulk mechanical properties. Freeze-dried type I collagen porous scaffolds made with varying slurry concentrations and pore sizes were tested in a viscoelastic framework by macroindentation. Membranes made up of stacks of pore walls were indented using colloidal probe atomic force microscopy. It was found that the bulk scaffold mechanical response varied with collagen concentration in the slurry consistent with previous studies on these materials. Hydration of the scaffolds resulted in a more compliant response, yet lesser viscoelastic relaxation. Indentation of the membranes suggested that the material making up the pore walls remains unchanged between conditions, so that the stiffness of the scaffolds at the scale of seeded cells is unchanged; rather, it is suggested that thicker pore walls or more of these result in the increased moduli for the greater slurry concentration conditions. PMID- 25460923 TI - Capturing tensile size-dependency in polymer nanofiber elasticity. AB - As the name implies, tensile size-dependency refers to the size-dependent response under uniaxial tension. It defers markedly from bending size-dependency in terms of onset and magnitude of the size-dependent response; the former begins earlier but rises to a smaller value than the latter. Experimentally, tensile size-dependent behavior is much harder to capture than its bending counterpart. This is also true in the computational effort; bending size-dependency models are more prevalent and well-developed. Indeed, many have questioned the existence of tensile size-dependency. However, recent experiments seem to support the existence of this phenomenon. Current strain gradient elasticity theories can accurately predict bending size-dependency but are unable to track tensile size dependency. To rectify this deficiency a higher-order strain gradient elasticity model is constructed by including the second gradient of the strain into the deformation energy. Tensile experiments involving 10 wt% polycaprolactone nanofibers are performed to calibrate and verify our model. The results reveal that for the selected nanofibers, their size-dependency begins when their diameters reduce to 600 nm and below. Further, their characteristic length-scale parameter is found to be 1095.8 nm. PMID- 25460924 TI - Drilling in cortical bone: a finite element model and experimental investigations. AB - Bone drilling is an essential part of many orthopaedic surgery procedures, including those for internal fixation and for attaching prosthetics. Estimation and control of bone drilling forces are critical to prevent drill-bit breakthrough, excessive heat generation, and mechanical damage to the bone. An experimental and computational study of drilling in cortical bone has been conducted. A 3D finite element (FE) model for prediction of thrust forces experienced during bone drilling has been developed. The model incorporates the dynamic characteristics involved in the process along with geometrical considerations. An elastic-plastic material model is used to predict the behaviour of cortical bone during drilling. The average critical thrust forces and torques obtained using FE analysis are found to be in good agreement with the experimental results. PMID- 25460925 TI - Mechanisms of plastic deformation in highly cross-linked UHMWPE for total hip components--the molecular physics viewpoint. AB - Plastic deformation is an unavoidable event in biomedical polymeric implants for load-bearing application during long-term in-vivo service life, which involves a mass transfer process, irreversible chain motion, and molecular reorganization. Deformation-induced microstructural alterations greatly affect mechanical properties and durability of implant devices. The present research focused on evaluating, from a molecular physics viewpoint, the impact of externally applied strain (or stress) in ultra-high molecular weight polyethylene (UHMWPE) prostheses, subjected to radiation cross-linking and subsequent remelting for application in total hip arthroplasty (THA). Two different types of commercial acetabular liners, which belong to the first-generation highly cross-linked UHMWPE (HXLPE), were investigated by means of confocal/polarized Raman microprobe spectroscopy. The amount of crystalline region and the spatial distribution of molecular chain orientation were quantitatively analyzed according to a combined theory including Raman selection rules for the polyethylene orthorhombic structure and the orientation distribution function (ODF) statistical approach. The structurally important finding was that pronounced recrystallization and molecular reorientation increasingly appeared in the near-surface regions of HXLPE liners with increasing the amount of plastic (compressive) deformation stored in the microstructure. Such molecular rearrangements, occurred in response to external strains, locally increase surface cross-shear (CS) stresses, which in turn trigger microscopic wear processes in HXLPE acetabular liners. Thus, on the basis of the results obtained at the molecular scale, we emphasize here the importance of minimizing the development of irrecoverable deformation strain in order to retain the pristine and intrinsically high wear performance of HXLPE components. PMID- 25460926 TI - Compressive strength of elderly vertebrae is reduced by disc degeneration and additional flexion. AB - Computer tomography (CT)-based finite element (FE) models assess vertebral strength better than dual energy X-ray absorptiometry. Osteoporotic vertebrae are usually loaded via degenerated intervertebral discs (IVD) and potentially at higher risk under forward bending, but the influences of the IVD and loading conditions are generally overlooked. Accordingly, magnetic resonance imaging was performed on 14 lumbar discs to generate FE models for the healthiest and most degenerated specimens. Compression, torsion, bending, flexion and extension conducted experimentally were used to calibrate both models. They were combined with CT-based FE models of 12 lumbar vertebral bodies to evaluate the effect of disc degeneration compared to a loading via endplates embedded in a stiff resin, the usual experimental paradigm. Compression and lifting were simulated, load and damage pattern were evaluated at failure. Adding flexion to the compression (lifting) and higher disc degeneration reduces the failure load (8-14%, 5-7%) and increases damage in the vertebrae. Under both loading scenarios, decreasing the disc height slightly increases the failure load; embedding and degenerated IVD provides respectively the highest and lowest failure load. Embedded vertebrae are more brittle, but failure loads induced via IVDs correlate highly with vertebral strength. In conclusion, osteoporotic vertebrae with degenerated IVDs are consistently weaker-especially under lifting, but clinical assessment of their strength is possible via FE analysis without extensive disc modelling, by extrapolating measures from the embedded situation. PMID- 25460927 TI - The role of integrin alpha(V)beta(3) in osteocyte mechanotransduction. AB - Recent in vivo studies have proposed that integrin alphavbeta3 attachments between osteocyte cell processes and the extracellular matrix may facilitate mechanosensation in bone. However the role of these attachments in osteocyte biochemical response to mechanical stimulus has yet to be investigated. With this in mind, the objective of this study was to determine the effect of blocking integrin alphavbeta3 function on the biochemical response of osteocytes to mechanical stimulus. Antagonists specific to integrin subunit beta3 were used to block integrin alphavbeta3 on MLO-Y4 mouse osteocytes. After treatment, cells were subjected to laminar oscillatory fluid flow stimulus (1 Pa, 1 Hz) for one hour. Fluorescent staining was performed to visualise cell morphology. Prostaglandin E2 (PGE2) release was assayed using an enzyme immunoassay and qRT PCR was used to analyse the relative expression of cyclooxygenase-2 (COX-2), receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG). Our results show that blocking integrin alphavbeta3 disrupts osteocyte morphology, causing a reduction in spread area and process retraction. Integrin alphavbeta3 blocking also disrupted COX-2 expression and PGE2 release in response to fluid shear stress. Taken together, the results of this study indicate that integrin alphavbeta3 is essential for the maintenance of osteocyte cell processes and also for mechanosensation and mechanotransduction by osteocytes. A better understanding of this process may lead to the development of novel treatments for bone pathologies where mechanosensitivity is thought to be compromised. PMID- 25460928 TI - Biomechanical model of the human cornea: considering shear stiffness and regional variation of collagen anisotropy and density. AB - A numerical model based on continuum mechanics theory has been developed which represents the 3D anisotropic behaviour of the corneal stroma. Experimental data has been gathered from a number of previous studies to provide the basis and calibration parameters for the numerical modelling. The resulting model introduces numerical representation of collagen fibril density and its related regional variation, interlamellar cohesion and age-related stiffening in an anisotropic model of the human cornea. Further, the model incorporates previous modelling developments including representation of lamellae anisotropy and stiffness of the underlying matrix. Wide angle X-ray scattering has provided measured data which quantifies relative fibril anisotropy in the 2D domain. Accurate numerical description of material response to deformation is essential to providing representative simulations of corneal behaviour. Representing experimentally obtained 2D anisotropy and regional density variation in the 3D domain is an essential component of this accuracy. The constitutive model was incorporated into finite element analysis. Combining with inverse analysis, the model was calibrated to an extensive experimental database of ex vivo corneal inflation tests and ex vivo corneal shear tests. This model represents stiffness of the underlying matrix which is 2-3 orders of magnitude than the mechanical response representing the collagen fibrils in the lamellae. The presented model, along with its age dependent material coefficients, allows finite element modelling for an individual patient with material stiffness approximated based on their age. This has great potential to be used in both daily clinical practice for the planning and optimisation of corrective procedures and in pre-clinical optimisation of diagnostic procedures. PMID- 25460929 TI - Mechanical, thermal, and physical properties of Mg-Ca compounds in the framework of the modified embedded-atom method. AB - Interatomic potentials for pure Ca and the Mg-Ca binary have been developed in the framework of the second nearest-neighbors modified embedded-atom method (MEAM). The validity and the transferability of the Ca MEAM potential was performed by calculating physical, mechanical, and thermal properties. These properties were compared to experimental data and numerical data obtained from existing Ca potentials, and a good agreement was found. In addition, the dissociation of the edge dislocation into two Shockley partials aligns with the linear elasticity solution. Furthermore, the velocity of an edge dislocation under static and dynamics loading conditions predicted in Ca using the MEAM formalism reproduces the expected behavior of an edge dislocation in fcc crystal structures. The Ca MEAM potential was then coupled to an existing Mg MEAM potential to describe the properties of the Mg-Ca alloys. Heat of formation, structural energy difference, and elastic constants were calculated for several ordered Mg-Ca compounds containing different concentrations of Ca. As expected from first-principle calculations based on DFT, Mg2Ca with the Laves phase C14 was found to be the most stable structure with the lowest heat of formation compared to compounds with other Ca concentrations (Mg3Ca, MgCa, and MgCa3). Moreover, the mechanical stability was recovered for the different tested compounds and is in agreement with first-principle data. PMID- 25460930 TI - RETRACTED: Mechanical properties and phase transition of biomedical titanium alloy strips with initial quasi-single phase state under high-energy electropulses. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Editor-in-Chief.The authors have reused figures and text that have already appeared in their previous articles. Figure 4 duplicates figure 4 in Reference [1], figure 6 in Reference [2], figure 8 in Reference [3] and figure 4 in Reference [4], while Figure 7a-b duplicates figure 7a-b in Reference [4].The article also duplicates significant parts of the text that appeared in References [1] and [4].One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and has not appeared in a publication elsewhere. As such this article represents an abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.Journal records indicate that confirmation of the submission and publication of the article was sent to the first author's email address but not to the corresponding author's email address.The corresponding author and the first author wish to mention that the co author Zion T.H. Tse was not involved in the preparation and handling of this article. He was not informed about the publication nor granted the use of his name and affiliation in the publication.References[1] J Mater Res 30 (2015) 206 223, http://dx.doi.org/10.1557/jmr.2014.367.[2] Mat Sci Eng A 622 (2015) 1-6, http://dx.doi.org/10.1016/j.msea.2014.11.003.[3] J Mater Res 29 (2014) 1500-1512, http://dx.doi.org/10.1557/jmr.2014.171.[4] Adv Eng Mater 17 (2015) 995-1007, http://dx.doi.org/10.1002/adem.201400273. PMID- 25460931 TI - Pharmacological interventions for acceleration of the onset time of rocuronium: a meta-analysis. AB - BACKGROUND: Rocuronium is an acceptable alternative when succinylcholine is contraindicated for facilitating the endotracheal intubation. However, the onset time of rocuronium for good intubation condition is still slower than that condition of succinylcholine. This study systematically investigated the most efficacious pharmacological interventions for accelerating the onset time of rocuronium. METHODS: Medline, Embase, Cochrane Library databases, www.clinicaltrials.gov, and hand searching from the reference lists of identified papers were searched for randomized controlled trials comparing drug interventions with placebo or another drug to shorten the onset time of rocuronium. Statistical analyses were performed using RevMan5.2 and ADDIS 1.16.5 softwares. Mean differences (MDs) with their 95% confidence intervals (95% CIs) were used to analyze the effects of drug interventions on the onset time of rocuronium. RESULTS: 43 randomized controlled trials with 2,465 patients were analyzed. The average onset time of rocuronium was 102.4+/-24.9 s. Priming with rocuronium [Mean difference (MD) -21.0 s, 95% confidence interval (95% CI) (-27.6 to -14.3 s)], pretreatment with ephedrine [-22.3 s (-29.1 to -15.5 s)], pretreatment with magnesium sulphate [-28.2 s (-50.9 to -5.6 s)] were all effective in reducing the onset time of rocuronium. Statistical testing of indirect comparisons showed that rocuronium priming, pretreatment with ephedrine, and pretreatment with magnesium sulphate had the similar efficacy. CONCLUSION: Rocuronium priming, pretreatment with ephedrine, and pretreatment with magnesium sulphate were all effective in accelerating the onset time of rocuronium, and furthermore their efficacies were similar. Considering the convenience and efficacy, priming with rocuronium is recommended for accelerating the onset time of rocuronium. However, more strict clinical trials are still needed to reach a more solid conclusion due to the large heterogeneities exist among different studies. PMID- 25460933 TI - Spatial and temporal heterogeneity of bacteria across an intertidal shellfish bed: implications for regulatory monitoring of faecal indicator organisms. AB - Routine bacterial monitoring of shellfish beds using indicator species is a common global practice designed to prevent human consumption of contaminated shellfish products. However, current bacteriological monitoring procedures which focus on the quantification of faecal indicator organisms (FIOs) as a proxy for microbial pollution may not be representative of total bacterial contamination levels present in shellfish harvesting areas. The objective of this study was to critically assess the accuracy of current monitoring strategies by quantifying the spatial (lateral and longitudinal distance) and temporal (seasonality and tidal state) concentrations of FIOs (Escherichia coli and total coliforms) within a single intertidal commercially harvested shellfish bed. Spatial and temporal FIO dynamics, including the effects of tidal state and seasonality, were quantified in mussel flesh and sediment samples from a single intertidal mussel (Mytilus edulis) bed. Our results confirmed that FIO concentrations across a shellfish bed were heterogeneous over larger spatial and temporal scales, but showed no relation to the concentrations of autochthonous bacteria, such as Vibrio spp., or the physico-chemical parameters of the sediment. These results have important implications for both public health and the economic prosperity of the shellfish industry, and demonstrate the importance of accommodating both spatial and temporal fluctuations in routine bacteriological monitoring protocols. We conclude that current FIO monitoring procedures may not accurately represent levels of microbial contamination within shellfish harvesting areas and that more robust microbiological testing procedures need developing. PMID- 25460932 TI - Antineoplastic effect of decoy oligonucleotide derived from MGMT enhancer. AB - Silencing of O(6)-methylguanine-DNA-methyltransferase (MGMT) in tumors, mainly through promoter methylation, correlates with a better therapeutic response and with increased survival. Therefore, it is conceivable to consider MGMT as a potential therapeutic target for the treatment of cancers. Our previous results demonstrated the pivotal role of NF-kappaB in MGMT expression, mediated mainly through p65/NF-kappaB homodimers. Here we show that the non-canonical NF-KappaB motif (MGMT-kappaB1) within MGMT enhancer is probably the major inducer of MGMT expression following NF-kappaB activation. Thus, in an attempt to attenuate the transcription activity of MGMT in tumors we designed locked nucleic acids (LNA) modified decoy oligonucleotides corresponding to the specific sequence of MGMT kappaB1 (MGMT-kB1-LODN). Following confirmation of the ability of MGMT-kB1-LODN to interfere with the binding of p65/NF-kappaB to the NF-KappaB motif within MGMT enhancer, the efficacy of the decoy was studied in-vitro and in-vivo. The results of these experiments show that the decoy MGMT-kB1-LODN have a substantial antineoplastic effect when used either in combination with temozolomide or as monotherapy. Our results suggest that MGMT-kB1-LODN may provide a novel strategy for cancer therapy. PMID- 25460934 TI - Effects of chemical disturbances on intertidal benthic assemblages. AB - Contamination is a particular harmful type of chemical disturbance and predicting their effects on natural systems is very complex. Effects of disturbances vary in space and time and depend, among other things, on the type and age of organisms, the habitat being studied and the complex interactions occurring in the systems. Most impact analyses of contaminants are however still done with limited number of selected organisms under laboratory conditions. Manipulative experiments done in situ are important to measure ecologically relevant responses of contaminant effects on marine systems. Ecological approaches on contamination studies, accounting for interactions among species and the environment are essential to understand how such disturbances affect systems. We evaluated the effects of bleach and permethrin, two common and pervasive contaminants, on intertidal benthic assemblages in two different successional stages, mature and young. There were no impacts on the overall structure of assemblages, regardless of their age. The lack of effects on the structure of assemblages might be due to the intrinsic characteristic of the habitat studied, which provide few sinks for contaminants, as well as the inherent features of the organisms themselves. Bleach did cause, however, a decrease in the abundance of limpets, which can have further consequences to these systems. This study shows the importance of studies on chemical disturbances done under relevant natural scenarios and that efficient management policies of natural systems will only achieve successful responses with properly designed experiments under natural conditions. PMID- 25460935 TI - Influence of heat wave definitions to the added effect of heat waves on daily mortality in Nanjing, China. AB - BACKGROUND: Few studies have explored the added effect of heat waves, especially in China. Moreover, no prior studies have assessed whether the choice of heat wave definitions affected this added effect. This study compared the associations between heat waves defined by different heat wave definitions (HWs) and cause specific mortality in warm season in Nanjing, China. METHODS: A distributed lag model was applied to evaluate the differences in daily mortality during heat-wave days (defined using 15 HWs) compared with non-heat-wave days in Nanjing, during 2007 to 2013. For different HWs, model fits were examined by the Akaike Information Criterion for quasi-Poisson and effects were compared by stratified analysis and bootstrapping. In addition, we explored the effect modifications by individual characteristics under different HWs. RESULTS: Different HWs resulted in considerable differences in associations between heat waves and mortality. Heat waves defined as >=4 consecutive days with daily average temperature >98th percentile had the best model fit and were associated with an increase of 24.6% (95% CI: 15.6%, 34.3%) total mortality, 46.9% (95% CI: 33.0%, 62.3%) cardiovascular mortality, 32.0% (95% CI: 8.5%, 60.5%) respiratory mortality, 51.3% (95% CI: 23.4%, 85.6%) stroke mortality, 63.4% (95% CI: 41.5%, 88.8%) ischemic heart disease mortality, and 47.6% (95% CI: 14.5%, 90.3%) chronic obstructive pulmonary disease mortality at lag day 2. Under different HWs, added effects of heat waves on mortality were higher for females versus males, the elderly versus young residents, and people with low education versus those with high education. Results were less sensitive to the inclusion of air pollutants. CONCLUSIONS: Heat wave definition plays a critical role in the relationship between heat waves and mortality. Selecting an appropriate definition of heat waves is therefore important to design local heat warning systems and to reduce the burden of disease during heat waves. PMID- 25460936 TI - Spatial and seasonal variability of tap water disinfection by-products within distribution pipe networks. AB - Gradually-changing shocks associated with potable water quality deficiencies are anticipated for urban drinking-water distribution systems (UDWDS). The impact of structural UDWDS features such as, the number of pipe leaking incidences on the formation of water trihalomethanes (THM) at the geocoded household level has never been studied before. The objectives were to: (i) characterize the distribution of water THM concentrations in households from two district-metered areas (DMAs) with contrasting UDWDS characteristics sampled in two seasons (summer and winter), and (ii) assess the within- and between-household, spatial variability of water THM accounting for UDWDS characteristics (household distance from chlorination tank and service pipe leaking incidences). A total of 383 tap water samples were collected from 193 households located in two DMAs within the UDWDS of Nicosia city, Cyprus, and analyzed for the four THM species. The higher intraclass correlation coefficient (ICC) values for water tribromomethane (TBM) (0.75) followed by trichloromethane (0.42) suggested that the two DMAs differed with respect to these analytes. On the other hand, the low ICC values for total THM levels between the two DMAs suggested a large variance between households. The effect of households nested under each DMA remained significant (p<0.05) for TBM (not for the rest of the THM species) in the multivariate mixed-effect models, even after inclusion of pipe network characteristics. Our results could find use by water utilities in overcoming techno-economic difficulties associated with the large spatiotemporal variability of THM, while accounting for the influence of UDWDS features at points of water use. PMID- 25460937 TI - Degradation of the cytostatic etoposide in chlorinated water by liquid chromatography coupled to quadrupole-Orbitrap mass spectrometry: identification and quantification of by-products in real water samples. AB - Once discharged into the sewage system, many pharmaceuticals may undergo degradation reactions in the presence of chemical disinfectants, generating by products that may possess enhanced toxicity relative to the parent compounds. For this reason, the stability of the widely used cytostatic etoposide in chlorinated water has been investigated for the first time in the present work. Taking advantage of the high-resolution/accurate-mass capabilities of the hybrid quadrupole-Orbitrap mass spectrometer Q Exactive, two new oxidation by-products of etoposide were reliably identified. The time course of etoposide and its by products was followed at different pH values, free chlorine concentrations and water matrices. Finally, the occurrence of etoposide and its major identified by product (3'-O-desmethyl etoposide) was investigated in real water samples by on line solid-phase extraction-liquid chromatography-tandem mass spectrometry using a 4000QTRAP hybrid quadrupole-linear ion trap mass spectrometer. The etoposide by product was found in various river and wastewater samples at levels between 14 and 33 ng L(-1), whereas etoposide was not detected in any sample. PMID- 25460938 TI - Application of stable isotopes (delta34S-SO4, delta18O-SO4, delta15N-NO 3, delta18O-NO 3) to determine natural background and contamination sources in the Guadalhorce River Basin (southern Spain). AB - The integrated use of isotopes (delta(34)S-SO4, delta(18)O-SO4, delta(15)N-NO3, delta(18)O-NO3), taking into account existing hydrogeological knowledge of the study area (mainly hydrochemical), was applied in the Guadalhorce River Basin (southern Spain) to characterise SO4(2-) and NO3(-) sources, and to quantify natural background levels (NBLs) in groundwater bodies. According to Water Framework Directive 2000/60/EC and, more recently, Groundwater Directive 2006/118/EC, it is important to determine NBLs, as their correct assessment is the first, essential step to characterising groundwater bodies, establishing threshold values, assessing chemical status and identifying trends in pollutant concentrations. In many cases, NBLs are high for some parameters and types of groundwater, making it difficult to distinguish clearly between factors of natural or human origin. The main advantages of using stable isotopes in a complex area like the Guadalhorce River Basin that exhibits widely varying hydrogeological and hydrochemical conditions and longstanding anthropogenic influences (mainly agriculture, but also many others) is accurate determination of pollution sources and precise quantification of NBLs. Since chemical analyses only provides the concentration of pollutants in water and not the source, three isotopic sampling campaigns for sulphates (delta(34)S-SO4, delta(18)O-SO4) were carried out, in 2006, 2007 and 2012, and another one was conducted for nitrates (delta(15)N-NO3, delta(18)O-NO3), in 2009, in groundwater bodies in order to trace the origins of each pollutant. The present study identified different pollution sources of dissolved NO3(-) in groundwater using an isotopic composition and quantified the percentage of natural (lithology, chemical and biological processes) and anthropogenic (fertilisers, manure and sewage) SO4(2-) and matched a concentration associated with the percentage in order to determine the NBLs in the basin. PMID- 25460939 TI - Joint antibacterial activity of soil-adsorbed antibiotics trimethoprim and sulfamethazine. AB - Trimethoprim (TMP) and sulfamethazine (SMZ) are two antibiotics that are often administered in combination. We investigated the sorption and desorption behaviors of TMP and SMZ individually as single solute and in combination as co solute in three representative soils, and evaluated joint antibacterial activity of the soil-adsorbed antibiotics to a reference strain Escherichia coli ATCC 25922. Comparative sorption tests showed that co-solute sorption of TMP and SMZ was not considerably different from their single sorption. Soil-adsorbed TMP was found to effectively inhibit the growth of E. coli at environmentally relevant concentrations in all three soils, and moreover co-presence of SMZ enhanced the antibacterial effects on bacteria both in its dissolved form and soil-adsorbed form. Overall, the results from this study suggest that various soil-adsorbed antibiotic residues could play a joint influencing role in soil bacterial community activity. PMID- 25460940 TI - Effect of ozonation on the naphthenic acids' speciation and toxicity of pH dependent organic extracts of oil sands process-affected water. AB - The presence of naphthenic acids (NAs) and other organic constituents in oil sands process-affected water (OSPW) stored in tailings ponds, poses a serious environmental threat due to their potential toxicity to aquatic organisms and wild life. In this work, four fractions of OSPW, extracted by dichloromethane at different pHs, were ozonated to determine the ozone impact on NAs degradation. Extracts distributions showed that high carbon number NAs (14-22) were associated with higher pH fractions (pH>7) and smaller carbon number NAs (7-13) with lower pH fractions (pH<=7). Extracts showed similar hydrogen deficiency (Z-number) patterns centered on Z=6. Analysis of the speciation of NAs and oxidized NAs in the four fractions showed that ozonation degraded most NAs (55% to 98%). Despite the high degradation levels, there was still significant toxicity of the fractions toward goldfish macrophages and measurable toxicity toward Vibrio fischeri. The toxicity of such a complex matrix as OSPW may be attributed to other organic compounds and degradation by-products not currently detected. Thus, there is a need to elucidate which compounds are responsible for the remaining OSPW toxicity and to determine if combined processes, such as ozonation followed by biological treatment, are able to completely detoxify OSPW. This work is taking the first steps into this direction, narrowing down the range of compounds which might be responsible for the toxicity. PMID- 25460941 TI - Static and dynamic flow analysis of PBDEs in plastics from used and end-of-life TVs and computer monitors by life cycle in Korea. AB - This study focused on a quantitative substance flow analysis (SFA) of polybrominated diphenyl ethers (PBDEs) in plastics from obsolete TVs and computer monitors that often contain large amounts of the flame retardants. According to the results of the static SFA study, 1.87 tons and 0.28 tons of PBDEs from newly manufactured TVs and computer monitors were introduced into households in 2011 in Korea, respectively. There were approximately 924 tons and 90.3 tons of PBDEs present in TVs and computer monitors in households during product use, respectively. The results of the dynamic SFA study indicated that in 2017 the amount of PBDEs from TVs and computer monitors in the recycling stage is expected to be 2.63 tons and 0.1 tons, respectively. Large fractions of PBDEs from used TVs are present in recycled plastics, while PBDE-containing computer monitors are exported to Southeast Asian countries. This research indicates that PBDEs were emitted the most from recycled plastic pellet processes upon recycling. Further study may be warranted to focus the flow of PBDEs in recycled plastic products in order to determine the final destination and disposal of these chemicals in the environment. PMID- 25460942 TI - Influence of tree canopy on N2 fixation by pasture legumes and soil rhizobial abundance in Mediterranean oak woodlands. AB - Symbiotic N2 fixation is of primordial significance in sustainable agro-forestry management as it allows reducing the use of mineral N in the production of mixed stands and by protecting the soils from degradation. Thereby, on a 2-year basis, N2 fixation was evaluated in four oak woodlands under Mediterranean conditions using a split-plot design and three replicates. (15)N technique was used for determination of N2 fixation rate. Variations in environmental conditions (temperature, rainfall, radiation) by the cork tree canopy as well as the age of stands and pasture management can cause great differences in vegetation growth, legume N2 fixation, and soil rhizobial abundance. In the present study, non legumes dominated the swards, in particular beneath the tree canopy, and legumes represented only 42% of total herbage. A 2-fold biomass reduction was observed in the oldest sown pasture in relation to the medium-age sward (6 t DW ha(-1)yr( 1)). Overall, competition of pasture growth for light was negligible, but soil rhizobial abundance and symbiotic N2 fixation capacity were highly favored by this environmental factor in the spring and outside the influence of tree canopy. Nitrogen derived from the atmosphere was moderate to high (54-72%) in unsown and sown swards. Inputs of fixed N2 increased from winter to spring due to more favorable climatic conditions (temperature and light intensity) for both rhizobia and vegetation growths. Assuming a constant fixation rate at each seasonal period, N2 fixation capacity increased from about 0.10 kg N ha(-1) per day in the autumn-winter period to 0.15 kg N ha(-1) per day in spring. Belowground plant material contributed to 11% of accumulated N in pasture legumes and was not affected by canopy. Size of soil fixing bacteria contributed little to explain pasture legumes N. PMID- 25460943 TI - Downwash of atmospherically deposited trace metals in peat and the influence of rainfall intensity: an experimental test. AB - Accumulation records of pollutant metals in peat have been frequently used to reconstruct past atmospheric deposition rates. While there is good support for peat as a record of relative changes in metal deposition over time, questions remain whether peat archives represent a quantitative or a qualitative record. Several processes can potentially influence the quantitative record of which downwashing is particularly pertinent as it would have a direct influence on how and where atmospherically deposited metals are accumulated in peat. The aim of our study was two-fold: first, to compare and contrast the retention of dissolved Pb, Cu, Zn and Ni in peat cores; and second, to test the influence of different precipitation intensities on the potential downwashing of metals. We applied four 'rainfall' treatments to 13 peat cores over a 3-week period, including both daily (2 or 5.3 mm day(-1)) and event-based additions (37 mm day(-1), added over 1h or over a 10h rain event). Two main trends were apparent: 1) there was a difference in retention of the added dissolved metals in the surface layer (0-2 cm): 21-85% for Pb, 18-63% for Cu, 10-25% for Zn and 10-20% for Ni. 2) For all metals and both peat types (sphagnum lawn and fen), the addition treatments resulted in different downwashing depths, i.e., as the precipitation-addition increased so did the depth at which added metals could be detected. Although the largest fraction of Pb and Cu was retained in the surface layer and the remainder effectively immobilized in the upper peat (<= 10 cm), there was a smearing effect on the overall retention, where precipitation intensity exerts an influence on the vertical distribution of added trace metals. These results indicate that the relative position of a deposition signal in peat records would be preserved, but it would be quantitatively attenuated. PMID- 25460944 TI - Heavy metals and trace elements in muscle of silverside (Odontesthes bonariensis) and water from different environments (Argentina): aquatic pollution and consumption effect approach. AB - The concentrations of As, Ag, B, Ba, Bi, Ca, Cd, Co, Cr, Fe, Ga, Hg, K, Li, Mg, Mn, Mo, Na, Ni, Pb, Rb, Sb, Se, Sn, Sr, Te, Ti, U, V and Zn were determined in water and silverside (Odontesthes bonariensis) muscle samples from four important commercial fishing sites (Argentina) by ICPMS. Trace element concentrations in water with well-documented human health effects were above the recommended maximum levels established by Argentinean and international guidelines for the aquatic biota protection in three sampling sites (e.g. As: 28.4-367 MUg L(-1); Cd: 0.17-1.05 MUg L(-1); Hg: 0.07-0.63 MUg L(-1); Zn: 71.3-90.0 MUg L(-1)). High concentrations of As, Hg and Pb (0.03-0.76; 0.03-0.42 and 0.04-0.19 mg kg(-1) wet weight, respectively) were found in silverside muscle. Fishing communities associated with contaminated environments are likely to have higher consumption rates and are thus more likely to be exposed to higher concentrations of the toxic elements (As, Hg and Pb). PMID- 25460945 TI - Toxicity and the fractional distribution of trace metals accumulated from contaminated sediments by the clam Scrobicularia plana exposed in the laboratory and the field. AB - The relationship between the subcellular distribution of accumulated toxic metals into five operational fractions (subsequently combined into presumed detoxified and non-detoxified components) and toxicity in the clam Scrobicularia plana was investigated under different laboratory exposures. Clams were exposed to metal contaminated media (water and diet) and analysed for the partitioning of accumulated As, Cu and Zn into subcellular fractions. In general, metallothionein like proteins, metal-rich granules and cellular debris in different proportions acted as main storage sites of accumulated metals in the clam soft tissues for these three metals. No significant differences were noted in the accumulation rates of As, Cu and Zn of groups of individuals with or without apparent signs of toxicity after up to 30 days of exposure to naturally contaminated sediment mixtures. There was, however, an increased proportional accumulation of Cu in the non-detoxified fraction with increased Cu accumulation rate in the clams, suggesting that the Cu uptake rate from contaminated sediments exceeded the combined rates of elimination and detoxification of Cu, with the subsequent likelihood for toxic effects in the clams. PMID- 25460946 TI - The influence of facility agriculture production on phthalate esters distribution in black soils of northeast China. AB - The current study investigates the existence of 15 phthalate esters (PAEs) in surface soils (27 samples) collected from 9 different facility agriculture sites in the black soil region of northeast China, during the process of agricultural production (comprising only three seasons spring, summer and autumn). Concentrations of the 15 PAEs detected significantly varied from spring to autumn and their values ranged from 1.37 to 4.90 mg/kg-dw, with a median value of 2.83 mg/kg-dw. The highest concentration of the 15 PAEs (4.90 mg/kg-dw) was determined in summer when mulching film was used in the greenhouses. Probably an increase in environmental temperature was a major reason for PAE transfer from the mulching film into the soil and coupled with the increased usage of chemical fertilizers in greenhouses. Results showed that of the 15 PAEs, di(2-ethylhexyl) phthalate(DEHP), di-n-butyl phthalate (DBP), diethyl phthalate (DEP) and dimethyl phthalate (DMP) were in abundance with the mean value of 1.12 +/- 0.22, 0.46 +/- 0.05, 0.36 +/- 0.04, and 0.17 +/- 0.01 mg/kg-dw, respectively; and their average contributions in spring, summer, and autumn ranged between 64.08 and 90.51% among the 15 PAEs. The results of Principal Component Analysis (PCA) indicated the concentration of these four main PAEs significantly differed among the facility agricultures investigated, during the process of agricultural production. In comparison with foreign and domestic results of previous researches, it is proved that the black soils of facility agriculture in northeast China show higher pollution situation comparing with non-facility agriculture soils. PMID- 25460947 TI - Bioaccumulation and biomagnification of mercury in African lakes: the importance of trophic status. AB - Despite the global prevalence of both mercury (Hg) contamination and anthropogenic eutrophication, relatively little is known about the behavior of Hg in eutrophic and hypereutrophic systems or the effects of lake trophic status on Hg uptake and trophodynamics. In the current study we explore Hg trophodynamics at 8 tropical East African study sites ranging from mesotrophic to hypereutrophic, in order to assess the influence of lake trophic status on Hg uptake and biomagnification. Comprehensive water, plankton and fish samples were collected for analysis of total mercury (THg) and stable carbon and nitrogen isotopic ratios. We found evidence that uptake of THg into phytoplankton tended to be lower in higher productivity systems. THg concentrations in fish were generally low, and THg trophic magnification factors (TMFs; representing the average increase in contaminant concentrations from one trophic level to the next) ranged from 1.9 to 5.6. Furthermore TMFs were significantly lower in hypereutrophic lakes than in meso- and eutrophic lakes, and were negatively related to chlorophyll a concentrations both across our study lakes, and across African lakes for which literature data were available. These observations suggest that THg concentrations were strongly influenced by trophic status, with year-round high phytoplankton and fish growth rates reducing the potential for high THg in fish in these productive tropical lakes. PMID- 25460948 TI - The worth of land use: a GIS-emergy evaluation of natural and human-made capital. AB - Natural systems make their natural capital and ecosystem services available to human economy. A careful analysis of the interplay between natural and human-made capital is needed to prevent natural capital being overexploited for present economic benefits, affecting lifestyles and wellbeing of future generations. In this study, the emergy synthesis is used to evaluate the natural and the human made capital of Campania region (southern Italy) by accounting for the environmental support directly and indirectly provided by nature to resource generation. Furthermore, geographic information system (GIS) models are integrated with the emergy accounting procedure to generate maps of the spatial patterns of both natural and human-made capital distribution. Regional storages of natural and human-made capital are identified and evaluated in emergy units (seJ). The human-made capital of the Campania region (6.29E+24seJ) results to be about 11 times higher than the natural capital (5.69E+23seJ) due to the past and present exploitation of the natural resources needed to generate it over time. Moreover, by overlaying the total natural capital map and the total human-made capital map with a map of the protected areas within the region, only the 19% of the regional natural capital appears to be concentrated within protected areas, while most of it (81%) is concentrated outside. These findings suggest that the conservation of natural resources is also necessary outside protected areas by means of suitable policies, directives and investments. The human-made capital is mainly concentrated (88%) inside non-protected areas and interacts with the local natural capital. A management of the interactions between the two categories of wealth is crucial to prevent that the growth of human-made storages degrades the natural ecosystems and the environment. The proposed emergy-GIS framework reveals to be a useful tool for environmental planning and resource management aimed to conserve and protect the regional environmental heritage. PMID- 25460949 TI - Factors controlling the oral bioaccessibility of anthropogenic Pb in polluted soils. AB - In human risk assessment, ingestion of soil is considered a major route of toxic Pb exposure. A large body of research has focussed on the measurement of the 'total' Pb contents in sediment, soil and dust as a measure for the exposure to lead. We report that Pb bioaccessibility (i.e. the maximum bioavailability), determined with an in vitro test, does not necessarily depend on the total Pb content. In contrast, the Pb bioaccessibility is initially controlled by the chemical form and particle size of the Pb source, which in turn determine its solubility. Furthermore, when anthropogenic Pb resides within the soil, it may form new, more stable, minerals and/or binds to organic matter, clay, reactive iron or other reactive phases, changing its bioaccessibility. The bioaccessible Pb fraction of 28 soils, polluted with various Pb sources (including residues of Pb bullets and pellets, car battery Pb, city waste and diffuse Pb), was determined with an in vitro-test and varied from 0.5% to 79.0% of total Pb. The highest Pb bioaccessibility (60.7% to 79.0%) was measured in soils polluted with residues of Pb bullets and pellets (shooting range), while the lowest Pb bioaccessibility (0.5%-8.3%) was measured in soils polluted with city waste (including remnants of Pb glazed potsherds and rooftiles, Pb based paint flakes, and Pb sheets). Bioaccessibility of Pb was correlated with pH, organic matter and reactive Fe. These results indicate that soil characteristics play an important role in the oral bioaccessibility of lead in polluted soils. Instead of basing human risk assessment solely on total Pb contents we propose to incorporate in vitro bioaccessibility tests, taking factors such as soil pH, organic matter content and reactive iron content into account. This approach will result in a better insight into the actual risks of Pb polluted soils to children. PMID- 25460950 TI - Poverty alleviation strategies in eastern China lead to critical ecological dynamics. AB - Poverty alleviation linked to agricultural intensification has been achieved in many regions but there is often only limited understanding of the impacts on ecological dynamics. A central need is to observe long term changes in regulating and supporting services as the basis for assessing the likelihood of sustainable agriculture or ecological collapse. We show how the analyses of 55 time-series of social, economic and ecological conditions can provide an evolutionary perspective for the modern Lower Yangtze River Basin region since the 1950s with powerful insights about the sustainability of modern ecosystem services. Increasing trends in provisioning ecosystem services within the region over the past 60 years reflect economic growth and successful poverty alleviation but are paralleled by steep losses in a range of regulating ecosystem services mainly since the 1980s. Increasing connectedness across the social and ecological domains after 1985 points to a greater uniformity in the drivers of the rural economy. Regime shifts and heightened levels of variability since the 1970s in local ecosystem services indicate progressive loss of resilience across the region. Of special concern are water quality services that have already passed critical transitions in several areas. Viewed collectively, our results suggest that the regional social-ecological system passed a tipping point in the late 1970s and is now in a transient phase heading towards a new steady state. However, the long-term relationship between economic growth and ecological degradation shows no sign of decoupling as demanded by the need to reverse an unsustainable trajectory. PMID- 25460951 TI - Regional groundwater flow in hard rocks. AB - The territory of continental Portugal has a geologic history marked by the Hercynian orogeny, and to the north of this country the Hercynian large-scale tectonic structures are typically represented by long and deep NW-SE trending ductile shear zones and NNE-SSW trending fragile faults. These structures are elements of mineral and thermal water circuits that discharge as springs in more than one hundred locations. The purpose of this study is to investigate if these structures are also used by shallower non-mineral groundwater, integrated in a large-scale regional flow system. Using an original combination of water balance and recession flow models, it was possible to calculate catchment turnover times based solely on groundwater discharge rates and recession flow parameters. These times were then used to classify a group of 46 watersheds as closed or open basins, and among the later class to identify source and sink basins, based on innovative interpretations of relationships between turnover time and catchment area. By definition, source basins transfer groundwater to sink basins and altogether form a regional flow system. Using a Geographic Information System, it could be demonstrated the spatial association of open basins to the Hercynian ductile and fragile tectonic structures and hence to classify the basins as discharge cells of a regional flow system. Most of the studied watersheds are sub basins of the Douro River basin, one of the largest regional catchments in the Iberian Peninsula, being located in its mouth area. Because the largest part of open basins is sink, which by definition tends to dominate in the mouth area of regional catchments, it is proposed as an extension of the studied area conceptual boundaries towards the Douro River basin headwaters, where the corresponding sources could be searched for. PMID- 25460952 TI - Determinants of human olfactory performance: a cross-cultural study. AB - Olfaction allows us to detect subtle changes in our environment, but sensitivity of the sense of smell varies among individuals. Although a significant number of research papers discuss the relationship between olfactory abilities and environmental factors, most studies have been conducted on Western populations or in developed Asian societies. The potential environmental and cultural determinants of olfactory acuity warrant further exploration. In the current study, we compared previously published data on olfaction in an industrialized, modern society (i.e., Europeans) and an indigenous society living in unpolluted, natural environmental conditions (i.e., Tsimane'), with novel data on the olfactory acuity of inhabitants of the Cook Islands. Like the European population (and contrary to the Tsimane'), the Cook Islands people form a modern society, and like the Tsimane' population (and contrary to the Europeans), they live in an unpolluted region. Thus, these comparisons enabled us to independently assess the importance of both air pollution and changes in lifestyle for olfactory abilities in modern societies. Our results indicate that people from the Cook Islands had significantly higher olfactory acuity (i.e., lower thresholds of odor detection) than did Europeans and Tsimane' people. Interestingly, the olfactory sensitivity of Europeans was significantly lower than the olfactory sensitivity of the remaining two groups. Our data suggest that air pollution is an important factor in the deterioration of the sense of smell. However, it is also possible that factors such as agricultural and/or cooking practices, alcohol consumption, and access to medical service may also influence olfactory acuity. PMID- 25460953 TI - Physical and chemical processes of air masses in the Aegean Sea during Etesians: Aegean-GAME airborne campaign. AB - High-resolution measurements of gas and aerosols' chemical composition along with meteorological and turbulence parameters were performed over the Aegean Sea (AS) during an Etesian outbreak in the framework of the Aegean-GAME airborne campaign. This study focuses on two distinct Etesian patterns, with similarities inside the Marine Atmospheric Boundary Layer (MABL) and differences at higher levels. Under long-range transport and subsidence the pollution load is enhanced (by 17% for CO, 11% for O3, 28% for sulfate, 62% for organic mass, 47% for elemental carbon), compared to the pattern with a weaker synoptic system. Sea surface temperature (SST) was a critical parameter for the MABL structure, turbulent fluxes and pollutants' distribution at lower levels. The MABL height was below 500 m asl over the eastern AS (favoring higher accumulation), and deeper over the western AS. The most abundant components of total PM1 were sulfate (40-50%) and organics (30-45%). Higher average concentrations measured over the eastern AS (131 +/- 76 ppbv for CO, 62.5 +/- 4.1 ppbv for O3, 5.0 +/- 1.1 MUg m(-3) for sulfate, 4.7 +/- 0.9 MUg m(-3) for organic mass and 0.5 +/- 0.2 MUg m(-3) for elemental carbon). Under the weaker synoptic system, cleaner but more acidic air masses prevailed over the eastern part, while distinct aerosol layers of different signature were observed over the western part. The Aitken and accumulation modes contributed equally during the long-range transport, while the Aitken modes dominated during local or medium range transport. PMID- 25460954 TI - Heavy metal contamination of soil and water in the vicinity of an abandoned e waste recycling site: implications for dissemination of heavy metals. AB - Illegal e-waste recycling activity has caused heavy metal pollution in many developing countries, including China. In recent years, the Chinese government has strengthened enforcement to impede such activity; however, the heavy metals remaining in the abandoned e-waste recycling site can still pose ecological risk. The present study aimed to investigate the concentrations of heavy metals in soil and water in the vicinity of an abandoned e-waste recycling site in Longtang, South China. Results showed that the surface soil of the former burning and acid leaching sites was still heavily contaminated with Cd (>0.39 mg kg(-1)) and Cu (>1981 mg kg(-1)), which exceeded their respective guideline levels. The concentration of heavy metals generally decreased with depth in both burning site and paddy field, which is related to the elevated pH and reduced TOM along the depth gradient. The pond water was seriously acidified and contaminated with heavy metals, while the well water was slightly contaminated since heavy metals were mostly retained in the surface soil. The use of pond water for irrigation resulted in considerable heavy metal contamination in the paddy soil. Compared with previous studies, the reduced heavy metal concentrations in the surface soil imply that heavy metals were transported to the other areas, such as pond. Therefore, immediate remediation of the contaminated soil and water is necessary to prevent dissemination of heavy metals and potential ecological disaster. PMID- 25460955 TI - Response of aerobic granular sludge to the long-term presence to nanosilver in sequencing batch reactors: reactor performance, sludge property, microbial activity and community. AB - The increasing use of silver nanoparticles (Ag NPs) raises concerns about their potential toxic effects on the environment. Granular shape sludge is a special type of microbial aggregate. The response of aerobic granular sludge (AGS) to the long-term presence of Ag NPs has not been well studied. In this study, AGS was exposed to 5 and 50mg/L Ag NPs in sequence batch reactors (SBRs) for 69 days, and its response was evaluated based on the sludge properties, microbial activity and community, and reactor performance. The results showed that Ag NPs caused inhibition to microbial activities of AGS from Day 35. At the end of 69 days of Ag NPs exposure, the microbial activity of AGS was significantly inhibited in terms of inhibitions of the ammonia oxidizing rate (33.0%), respiration rate (17.7% and 45.6%) and denitrification rate (6.8%), as well as decreases in the ammonia mono-oxygenase and nitrate reductase activities. During the long-term exposure, the AGS maintained its granular shape and large granule size (approximately 900 MUm); the microbial community of AGS slightly changed, but the dominant microbial population remained. Overall, the AGS tolerated the toxicity of Ag NPs well, but a long-term exposure may produce chronic toxicity to the AGS, which is concerning. PMID- 25460956 TI - Off-line TMAH-GC/MS and NMR characterization of humic substances extracted from river sediments of northwestern Sao Paulo under different soil uses. AB - Humic substances (HS) vary according to the physical and chemical factors present in the environment. Thus, the characterization of HS is very important because it improves the understanding of the groups that comprise the chemical structure. Sediment HS were extracted from four locations representative of sugar cane cultivation, pasture, urban area and the impoundment of the Agua Vermelha Hydroelectric Power Plant. Characterization using nuclear magnetic resonance (NMR) allowed us to infer that the HS from an area predominantly characterized by sugar cane cultivation (41.9%) and a typical rural area (35.0%) showed the highest aromaticity percentage. Using the off-line TMAH-thermochemolysis-GC-MS, we inferred that the HS of a typical rural area had a structure rich in plant waxes, plant biopolyester and a large amount of fatty acid methyl ester, which are related to the large amount of humic acid in the structure. The HS samples from the sugar cane cultivation area and the impoundment receiving all of the pollution load from the Turvo/Grande Hydrographic Basin (Bacia Hidrografica do Turvo/Grande-BHTG) contained contributions from compounds rich in lipids and fatty acid methyl esters, highlighting the presence of the breakdown of petroleum derived hydrocarbons in the area receiving the entire pollution load. We conclude that the HS extracted from the sediments of the Preto, Turvo and Grande rivers showed well-defined characteristics that varied depending on soil use and occupation, especially the HS extracted from sediments sampled in areas typically planted with sugar cane and rural areas, whose structures contained more aromatic groups. PMID- 25460957 TI - Watershed- and island wide-scale land cover changes in Puerto Rico (1930s-2004) and their potential effects on coral reef ecosystems. AB - Anthropogenically enhanced delivery of sediments and other land-based sources of pollution represent well-recognized threats to nearshore coral reef communities worldwide. Land cover change is commonly used as a proxy to document human induced alterations to sediment and pollutant delivery rates to coral reef bearing waters. In this article, land cover change was assessed for a 69-km(2) watershed in Puerto Rico between 1936 and 2004 by aerial photograph interpretation. Forests and sugar cane fields predominated from 1936 through the late 1970s, but while cropland dipped to negligible levels by 2004, net forest cover doubled and built-up areas increased tenfold. The watershed-scale land cover changes documented here mimicked those of the entire Puerto Rican landmass. Sediment yield predictions that rely on the sort of land cover changes reported here inevitably result in declining trends, but anecdotal and scientific evidence in the study watershed and throughout Puerto Rico suggests that sediment and pollutant loading rates still remain high and at potentially threatening levels. The simultaneous reduction in living coral cover that accompanied reforestation and urbanization patterns since the 1970s in our study region is discussed here within the context of the following non-mutually exclusive potential explanations: (a) the inability of land cover change-based assessments to discern spatially-focused, yet highly influential sources of sediment; (b) the potentially secondary role of cropland and forest cover changes in influencing nearshore coral reef conditions relative to other types of stressors like those related to climate change; and (c) the potentially dominant role that urban development may have had in altering marine water quality to the extent of reducing live coral cover. Since identification of the causes for coral reef degradation has proven elusive here and elsewhere, we infer that coral reef management may only be effective when numerous land- and marine-based stressors are simultaneously mitigated. PMID- 25460958 TI - Oxidation of diclofenac by potassium ferrate (VI): reaction kinetics and toxicity evaluation. AB - The reaction kinetics and toxicity of diclofenac (DCF) oxidation by ferrate (VI) under simulated water disinfection conditions were investigated. Experimental results indicated that the reaction between DCF and Fe(VI) followed first-order kinetics with respect to each reactant. Furthermore, the effects of pH and temperature on DCF oxidation by Fe(VI) were elucidated using a systematic examination. The apparent second-order rate constants (kapp) increased significantly from 2.54 to 11.6M(-1)s(-1), as the pH of the solution decreased from 11.0 to 7.0, and the acid-base equilibriums of Fe(VI) and DCF were proposed to explain the pH dependence of kapp. The acute toxicity of DCF solution during Fe(VI) oxidation was evaluated using a Microtox bioassay. Overall, the DCF degradation process resulted in a rapid increase of the inhibition rate of luminescent bacteria. These toxicity tests suggest that the formation of enhanced toxic intermediates during the Fe(VI) disinfection process may pose potential health risk to consumers. PMID- 25460959 TI - Impacts of LUCC on soil properties in the riparian zones of desert oasis with remote sensing data: a case study of the middle Heihe River basin, China. AB - Large-scale changes in land use and land cover over long timescales can induce significant variations in soil physicochemical properties, particularly in the riparian zones of arid regions. Frequent reclamation of wetlands and grasslands and intensive agricultural activity have induced significant changes in both land use/cover and soil physicochemical properties in the riparian zones of the middle Heihe River basin of China. The present study aims to explore whether land use/land cover change (LUCC) can well explain the variations in soil properties in the riparian zones of the middle Heihe River basin. To achieve this, we mapped LUCC and quantified the type of land use change using remote sensing images, topographic maps, and GIS analysis techniques. Forty-two sites were selected for soil and vegetation sampling. Then, physical and chemical experiments were employed to determine soil moisture, soil bulk density, soil pH, soil organic carbon, total nitrogen, total potassium, total phosphorous, available nitrogen, available potassium, and available phosphorous. The Independent-Samples Kruskal Wallis Test, principal component analysis, and a scatter matrix were used to analyze the effects of LUCC on soil properties. The results indicate that the majority of the parameters investigated were affected significantly by LUCC. In particular, soil moisture and soil organic carbon can be explained well by land cover change and land use change, respectively. Furthermore, changes in soil moisture could be attributed primarily to land cover changes. Changes in soil organic carbon were correlated closely with the following land use change types: wetlands-arable, forest-grasslands, and grasslands-desert. Other parameters, including pH and total K, were also found to exhibit significant correlations with LUCC. However, changes in soil nutrients were shown to be induced most probably by human agricultural activity (i.e. fertilize, irrigation, tillage, etc.), rather than by simple conversions from one land use/cover types to the others. PMID- 25460960 TI - The hazard assessment of nanostructured CeO2-based mixed oxides on the zebrafish Danio rerio under environmentally relevant UV-A exposure. AB - The effect of nanomaterials on biota under realistic environmental conditions is an important question. However, there is still a lack of knowledge on how different illumination conditions alter the toxicity of some photocatalytic nanomaterials. We have investigated how environmentally relevant UV-A exposure (intensity 8.50 +/- 0.61 W/m(2), exposure dose 9.0J/cm(2)) affected the toxicity of cerium oxide (CeO2)-based nanostructured materials to the early-life stages of zebrafish Danio rerio. Pure cerium oxide (CeO2), copper-cerium (CuO-CeO2) (with a nominal 10, 15 and 20 mol.% CuO content), cerium-zirconium (CeO2-ZrO2) and nickel and cobalt (Ni-Co) deposited over CeO2-ZrO2 were tested. It was found that under both illumination regimes, none of the tested materials affected the normal development or induced mortality of zebrafish early-life stages up to 100mg/L. Only in the case of CuO-CeO2, the growth of larvae was decreased (96 h LOEC values for CuCe10, CuCe15 and CuCe20 were 50, 50 and 10mg/L, respectively). To conclude, CeO2-based nanostructured materials are not severely toxic to zebrafish and environmentally relevant UV-A exposure does not enhance their toxicity. PMID- 25460961 TI - Long-term application of fresh and composted manure increase tetracycline resistance in the arable soil of eastern China. AB - The aim of this study was to compare the occurrence, abundance, and diversity of tetracycline resistance genes (tet) in agricultural soils after 6 years' application of fresh or composted swine manure. Soil samples were collected from fresh or composted manure-treated farmland at three depths (0-5 cm, 5-10 cm, and 10-20 cm). Nine classes of tet genes [tetW, tetB(P), tetO, tetS, tetC, tetG, tetZ, tetL, and tetX] were detected; tetG, tetZ, tetL, and tetB(P) were predominant in the manure-treated soil. The abundances of tetB(P), tetW, tetC, and tetO were reduced, while tetG and tetL were increased by fertilizing with composted versus fresh manure; thus, the total abundance of tet genes was not significantly reduced by compost manuring. tetG was the most abundant gene in manure-treated soil; the predominant tetG genotypes shared high homology with pathogenic bacteria. The tetG isolates were more diverse in soils treated with fresh versus composted manure, although the residual tet genes in composted manure remain a pollutant and produce a different influence on the tet gene resistome in field soil. PMID- 25460963 TI - The role of evapotranspiration in the groundwater hydrochemistry of an arid coastal wetland (Peninsula Valdes, Argentina). AB - Coastal wetlands are complex hydrogeological systems, in which saline groundwater usually occurs. Salinity can be attributed to many origins, such as dissolution of minerals in the sediments, marine contribution and evapotranspiration, among others. The aim of this paper is to evaluate the processes that condition the hydrochemistry of an arid marsh, Playa Fracasso, located in Patagonia, Argentina. A study of the dynamics and geochemistry of the groundwater was carried out in each hydrogeomorphological unit, using major ion and isotope ((18)O and (2)H) data, soil profiles descriptions and measurements, and recording of water tables in relation to the tidal flow. Water balances and analytical models based on isotope data were used to quantify the evaporation processes and to define the role of evaporation in the chemical composition of water. The results obtained show that the groundwater salinity of the marsh comes mainly from the tidal inflow, to which the halite and gypsum dissolution is added. These mineral facies are the result of the total evaporation of the marine water flooding that occurs mostly at the spring high tides. The isotope relationships in the fan and bajada samples show the occurrence of evaporation processes. Such processes, however, are not mainly responsible for the saline content of groundwater, which is actually generated by the dissolution of the typical evaporite facies of the arid environment sediments. It is concluded that the evapotranspiration processes condition groundwater quality. This is not only due to the saline enrichment caused by the evapotranspiration of shallow water, but also because such processes are the main drivers of the formation of soluble salts, which are then incorporated into the water by groundwater or tidal flow. PMID- 25460962 TI - Pepper mild mottle virus as an indicator and a tracer of fecal pollution in water environments: comparative evaluation with wastewater-tracer pharmaceuticals in Hanoi, Vietnam. AB - We analyzed pepper mild mottle virus (PMMoV) in 36 samples taken from surface water, wastewater, groundwater, tap water and bottled water in Hanoi, Vietnam. We then compared the occurrence and fates of PMMoV with pharmaceuticals and personal care products (PPCPs), which are known wastewater tracers. PMMoV was detected in 94% of the surface water samples (ponds, water from irrigated farmlands and rivers) and in all the wastewater samples. The PMMoV concentration ranged from 5.5*10(6)-7.2*10(6)copies/L in wastewater treatment plant (WWTP) influents, 6.5*10(5)-8.5*10(5)copies/L in WWTP effluents and 1.0*10(4)-1.8*10(6)copies/L in surface water. Among the sixty PPCPs analyzed, caffeine and carbamazepine had high detection rates in surface water (100% and 88%, respectively). In surface water, the concentration ratio of PMMoV to caffeine remained unchanged than that in WWTP influents, suggesting that the persistence of PMMoV in surface water was comparable to that of caffeine. The persistence and the large concentration ratio of PMMoV in WWTP influents to the method detection limit would account for its ubiquitous detection in surface water. In comparison, human enteric viruses (HEV) were less frequently detected (18-59%) than PMMoV in surface water, probably because of their faster decay. Together with the reported high human feces specificity, our results suggested that PMMoV is useful as a sensitive fecal indicator for evaluating the potential occurrence of pathogenic viruses in surface water. Moreover, PMMoV can be useful as a moderately conservative fecal tracer for specifically tracking fecal pollution of surface water. PMMoV was detected in 38% of the groundwater samples at low concentrations (up to 19copies/L). PMMoV was not detected in the tap water and bottled water samples. In groundwater, tap water and bottled water samples, the occurrence of PPCPs and HEV disagreed with that of PMMoV, suggesting that PMMoV is not suitable as an indicator or a tracer in those waters. PMID- 25460964 TI - The bioavailability of polycyclic aromatic hydrocarbons from different dose media after single and sub-chronic exposure in juvenile swine. AB - Humans are constantly exposed to contaminants in the environment, which may lead to changes in physiological processes by altering enzyme activities that could affect bioavailability. However, bioavailability estimates are typically made from a single exposure to an animal model, which may lead to overestimating bioavailability. This study uses juvenile swine to model human exposure to benzo[a]pyrene (BaP) and anthracene in certified reference material (CRM), spiked soil, spiked food, or spiked corn oil after one and seven days of dosing. Area under the curve (AUC) was calculated after one and seven days of exposure for both BaP and anthracene for each exposure media. Whereas there were significant differences in AUC between different media, there were no significant changes in AUC after sub-chronic exposure to BaP or anthracene. Average BaP bioavailability for CRM, spiked soil, spiked food and corn oil was 71%, 0.72%, 0.03% and 0.97% respectively. Average anthracene bioavailability was 1.7% and 43% for corn oil and CRM respectively. Anthracene was not detected above background in swine exposed to spiked food and spiked soil. Thus, this study indicates that exposure media impacts bioavailability, but there is no statistical evidence that sub chronic exposure affects systemic exposure. PMID- 25460965 TI - Can those organic micro-pollutants that are recalcitrant in activated sludge treatment be removed from wastewater by biofilm reactors (slow sand filters)? AB - The degradation of seven compounds which are usually recalcitrant in classical activated sludge treatment (e.g., diclofenac, propranolol, iopromide, iohexol, iomeprol tebuconazole and propiconazole) was studied in a biofilm reactor (slow sand filtration). This reactor was used to treat real effluent-wastewater at different flow rates (hydraulic loadings) under aerobic conditions so removal and degradation kinetics of these recalcitrant compounds were calculated. With the hydraulic loading rate of 0.012 m(3)m(2)h(-1) the reactor removed 41, 94, 58, 57 and 85% of diclofenac, propranolol, iopromide, iohexol and iomeprol respectively. For these compounds the removal efficiency was dependent on hydraulic residence times. Only 59 and 21% of the incoming tebuconazole and propiconazole respectively were removed but their removal did not depend on hydraulic residence time. Biofilm reactors are thus efficient in removing micro-pollutants and could be considered as an option for advanced treatment in small wastewater treatment plants. PMID- 25460966 TI - Modeling aggregation and sedimentation of nanoparticles in the aquatic environment. AB - With nanoparticles being used more and more in consumer and industrial products it is almost inevitable that they will be released into the aquatic environment. In order to understand the possible environmental risks it is important to understand their behavior in the aquatic environment. From laboratory studies it is known that nanoparticles in the aquatic environment are subjected to a variety of processes: homoaggregation, heteroaggregation to suspended particulate matter and subsequent sedimentation, dissolution and chemical transformation. This article presents a mathematical model that describes these processes and their relative contribution to the behavior of nanoparticles in the aquatic environment. After calibrating the model with existing data, it is able to adequately describe the published experimental data with a single set of parameters, covering a wide range of initial concentrations. The model shows that at the concentrations used in the laboratory, homoaggregation and sedimentation of the aggregates are the most important processes. As for the natural environment much lower concentrations are expected, heteroaggregation will play the most important role instead. More experimental datasets are required to determine if the process parameters that were found here are generally applicable. Nonetheless it is a promising tool for modeling the transport and fate of nanoparticles in watersheds and other natural water bodies. PMID- 25460967 TI - Effects of prey assemblage on mercury bioaccumulation in a piscivorous sport fish. AB - Mercury (Hg) is a persistent global contaminant that biomagnifies, often reaching maximum levels in apex predators. Mercury contamination in piscivorous fish is a serious health risk for anglers and other fish consumers. We used data collected from a reservoir in Colorado to develop bioenergetics-based simulations of Hg bioaccumulation to estimate Hg concentrations in walleye (Sander vitreus), a popular sport fish. We evaluated how changes in the prey available to walleye might affect walleye Hg concentrations. Our simulations showed that such changes could result in almost a 10-fold range in walleye Hg concentration. Walleye consuming invertebrates had low growth, low growth efficiency, and high Hg concentrations. Conversely, when walleye diet contained only fish prey their growth and growth efficiency were higher and Hg concentrations were about 85% lower. These predictions were consistent with independent measurements in the study system observed under two different prey regimes in 2008 and 2013. Because prey assemblages in freshwaters can exhibit high natural and anthropogenic variability, understanding variation in predator Hg and providing accurate fish consumption advice to anglers and their families will require frequent monitoring of both predator and prey species. Further, manipulation of prey assemblages is a routine fishery management strategy that could be applied to reduce Hg contamination in piscivorous fishes. PMID- 25460968 TI - Multitracer experiment to evaluate the attenuation of selected organic micropollutants in a karst aquifer. AB - The increasing pressure on drinking water resources necessitates an efficient management of potential and actual drinking water resources. Karst aquifers play a key role in the supply of the world's population with drinking water. Around one quarter of all drinking water is produced from these types of aquifers. Unfortunately due to the aquifer characteristics with extremely high hydraulic conductivities and short residence times, these systems are vulnerable to contamination. For successful management, a fundamental understanding of mass transport and attenuation processes with respect to potential contaminants is vital. In this study, a multitracer experiment was performed in a karst aquifer in SW-Germany for determining the attenuation capacity of a karst environment by assessing the environmental fate of selected relevant micropollutants. Uranine, acesulfame and carbamazepine were injected into a sinkhole as reference tracers together with the reactive compounds atenolol, caffeine, cyclamate, ibuprofen and paracetamol (also known as acetaminophen). The breakthrough of the tracers was monitored at a karst spring at a distance of ca. 3 km. The breakthrough curves of the reactive compounds were interpreted relative to the reference substances. No significant retardation was found for any of the investigated micropollutants. The determined half-lives of the reactive compounds range from 38 to 1,400 h (i.e. persistent within the investigation period) in the following order (from high to no observed attenuation): paracetamol>atenolol~ibuprofen>caffeine?cyclamate. The attenuation rates are generally in agreement with studies from other environmental compartments. The occurrence of the biotransformation product atenolol acid served as evidence for in-situ biodegradation within the aquifer system. PMID- 25460969 TI - Environmental monitoring of organo-halogenated contaminants (OHCs) in surface soils from Pakistan. AB - Extensive monitoring of organo-halogenated contaminants (OHCs) from surface soils of different land-use types from Pakistan was carried out during 2010. The concentrations (ng g(-1); dry weight) and profiles clearly indicated the dominance of ?DDT contaminants followed by the ?HCHs, ?30PCBs, chlordanes, and ?10PBDEs in descending order. Concerning the spatial patterns of occurrence, industrial soils exhibited relatively higher concentration of DDTs, heavy PCBs, and PBDEs (noticeably BDE-47 and -99 congeners), while the urban soils were characterized by high total PCBs (with relatively higher levels of light PCBs), following the agricultural soils. Compared to available criterion guidelines, the current results suggested that 10% of soil samples from industrial sites exhibited slightly higher levels (>50 ng g(-1)) of DDTs. The ?TEQ levels for mono ortho DL-PCBs ranged from 0.7 to 5.65 (1.9) pgTEQg(-1) dw in all the studied samples and PCB-118 contributed significantly towards the total calculated TEQs. The results of this study will contribute to the environmental management of OHCs contaminated areas of Pakistan. PMID- 25460970 TI - Quality of dissolved organic matter affects planktonic but not biofilm bacterial production in streams. AB - Streams and rivers are important sites of organic carbon mineralization which is dependent on the land use within river catchments. Here we tested whether planktonic and epilithic biofilm bacteria differ in their response to the quality of dissolved organic carbon (DOC). Thus, planktonic and biofilm bacterial production was compared with patterns of DOC along a land-use gradient in the Bode catchment area (Germany). The freshness index of DOC was positively related to the proportion of agricultural area in the catchment. The humification index correlated with the proportion of forest area. Abundance and production of planktonic bacteria were lower in headwaters than at downstream sites. Planktonic production was weakly correlated to the total concentration of DOC but more strongly to quality-measures as revealed by spectra indexes, i.e. positively to the freshness index and negatively to the humification index. In contrast to planktonic bacteria, abundance and production of biofilm bacteria were independent of DOC quality. This finding may be explained by the association of biofilm bacteria with benthic algae and an extracellular matrix which represent additional substrate sources. The data show that planktonic bacteria seem to be regulated at a landscape scale controlled by land use, whereas biofilm bacteria are regulated at a biofilm matrix scale controlled by autochthonous production. Thus, the effects of catchment-scale land use changes on ecosystem processes are likely lower in small streams dominated by biofilm bacteria than in larger streams dominated by planktonic bacteria. PMID- 25460971 TI - Indoor particulate matter in four Belgian heritage sites: case studies on the deposition of dark-colored and hygroscopic particles. AB - Atmospheric total suspended particulate (TSP) was passively sampled by means of deployed horizontal and vertical filters in various rooms of four Belgian cultural heritage buildings, installed with various heating/ventilation systems. Soiling/blackening and deposition of inorganic, water-soluble aerosol components were considered. The extent of soiling was determined by means of two independent methods: (1) in terms of the covering rate of the samplers by optical reflection microscopy and (2) the reduction in lightness of the samplers using the CIE L*a*b* color space by spectrophotometry. A fairly good correlation was found between both methods. The inorganic composition of the deposited water-soluble TSP was quantified by means of ion chromatography. Compared to controlled environments, uncontrolled environments showed increased water-soluble aerosol content of the total deposited mass. Higher chloride deposition was observed on horizontal surfaces, compared to vertical surfaces. PMID- 25460972 TI - A comparative assessment of the transformation products of S-metolachlor and its commercial product Mercantor Gold((r)) and their fate in the aquatic environment by employing a combination of experimental and in silico methods. AB - Even appropriately used, pesticides can enter the surface and groundwater by several routes where photochemical degradation along with biotic processes contributes to their fate, resulting sometimes in the formation of stable transformation products (TPs). Yet, little is known about S-metolachlor (SM) transformation in the aquatic environment. Furthermore, commercial formulation of a pesticide might have different physical and biological properties compared to its pure grade. The present study assessed the biodegradability of the pure SM and its commercial product Mercantor Gold((r)) (MG) by employing two OECD biodegradation (301D, F) tests. Photolysis in water was investigated by using a Xe lamp. Subsequently the biodegradability of the photolysis mixtures was examined. The primary elimination of SM was monitored and structures of its TPs were elucidated by HPLC-UV-MS/MS. Additionally, a set of in silico prediction programs was applied for supporting analytical results and toxicity assessment of SM and TPs. S-metolachlor and Mercantor Gold((r)) were not biodegraded. HPLC-UV analysis showed higher elimination of SM in MG compared to pure SM during photolysis. A total of 10 photo-TPs of SM and MG were identified. According to MS data and in silico predictions, chemical structures were proposed for all found photo-TPs. Likewise for the parent compounds, no biodegradation has been observed for their photo-TPs. However, in the 301F test new bio-TPs have been generated from photo-TPs which were observed for the first time according to authors' best knowledge. The results suggest that the MG formulation does not affect the biodegradation process, but it influences the photolysis efficiency and potentially might result in faster formation of TPs in the environment. This study also demonstrates that photo-TPs can be further transformed into new products due to bacterial activity in the water phase. Moreover biotransformation might lead to an increased toxicity compared with the parent compound. PMID- 25460973 TI - Influence of environmental variables on the structure and composition of soil bacterial communities in natural and constructed wetlands. AB - Bacteria are key players in wetland ecosystems, however many essential aspects regarding the ecology of wetland bacterial communities remain unknown. The present study characterizes soil bacterial communities from natural and constructed wetlands through the pyrosequencing of 16S rDNA genes in order to evaluate the influence of wetland variables on bacterial community composition and structure. The results show that the composition of soil bacterial communities was significantly associated with the wetland type (natural or constructed wetland), the type of environment (lagoon, Typha or Salix) and three continuous parameters (SOM, COD and TKN). However, no clear associations were observed with soil pH. Bacterial diversity values were significantly lower in the constructed wetland with the highest inlet nutrient concentrations. The abundances of particular metabolic groups were also related to wetland characteristics. PMID- 25460974 TI - Characterization of polycyclic aromatic hydrocarbon emissions in the particulate and gas phase from smoldering mosquito coils containing various atomic hydrogen/carbon ratios. AB - The polycyclic aromatic hydrocarbon emissions in particulate and gas phases generated from smoldering mosquito coils containing various atomic H/C ratios were examined. Five types of mosquito coils were burned in a test chamber with a total airflow rate of 8.0 L/min at a constant relative humidity and temperature. The concentrations of individual PAHs were determined using the GC/MS technique. Among the used mosquito coils, the atomic H/C ratio ranged from 1.23 to 1.57, yielding total mass, gaseous, and particulate PAH emission factors of 28.17-78.72 mg/g, 26,139.80-35,932.98 and 5735.22-13,431.51 ng/g, respectively. The various partitions of PAHs in the gaseous and particulate phases were in the ranges, 70.26-83.70% and 16.30-29.74% for the utilized mosquito coils. The carcinogenic potency of PAH emissions in the particulate phase (203.82-797.76 ng/g) was approximately 6.92-25.08 times higher than that of the gaseous phase (26.27-36.07 ng/g). Based on the analyses of PAH emissions, mosquito coils containing the lowest H/C ratio, a low oxygen level, and additional additives (i.e., CaCO3) are recommended for minimizing the production of total PAH emission factors and carcinogenic potency. PMID- 25460975 TI - Receptor modelling study of polycyclic aromatic hydrocarbons in Jeddah, Saudi Arabia. AB - Measurements of 14 polycyclic aromatic hydrocarbons (PAH) have been made in Jeddah, Saudi Arabia, with a view to establishing the concentrations in this major city, and quantifying the contributions of major sources. Particulate and vapour forms have been sampled and analysed separately. The concentrations are compared to measurements from other sites in the Middle Eastern region and are towards the lower end of the range, being far lower than concentrations reported from Riyadh (Saudi Arabia), Assiut (Egypt) and Tehran (Iran) but broadly similar to those measured in Damascus (Syria) and higher than those measured in Kuwait. The partitioning between vapour and particle phases is similar to that in data from Egypt and China, but with many compounds showing a higher particle associated percentage than in Birmingham (UK) possibly reflecting a higher concentration of airborne particulate matter in the former countries. Concentrations in Jeddah were significantly higher at a site close to the oil refinery and a site close to a major ring road than at a suburban site to the north of the city. Application of positive matrix factorisation to the pooled data elicited three factors accounting respectively for 17%, 33% and 50% of the measured sum of PAH and these are interpreted as arising from gasoline vehicles, industrial sources, particularly the oil refinery, and to diesel/fuel oil combustion. PMID- 25460977 TI - Evaluation of operating conditions for sustainable harvesting of microalgal biomass applying electrochemical method using non sacrificial electrodes. AB - The efficient harvesting of microalgae is considered to be one of the challenging steps of algal biofuel production and a key factor limiting the commercial use of microalgae. To overcome the limitation of metallic electrodes depletion, the application of non-sacrificial electrode was investigated for the electrochemical harvesting (ECH) of microalgae. The effect of applied current, addition of electrolyte and initial pH were parameters investigated. The highest recovery efficiency of 83% was obtained for Scenedesmus obliquus at 1.5A, initial pH 9 and 6gL(-)(1) NaCl with power consumption of 3.84kWhkg(-)(1). Recovery efficiency of ECH process was comparable to literature reported centrifugation, filtration and chemical flocculation techniques but with a much lower power consumption. The ECH process with addition of electrolyte enhanced the lipid extraction by 22% without any adverse effects. The ECH process with non sacrificial carbon electrodes could be a possible harvesting step at commercial scale microalgal biomass production. PMID- 25460978 TI - Enhancing organic matter removal, biopolymer recovery and electricity generation from distillery wastewater by combining fungal fermentation and microbial fuel cell. AB - For enhancing organic matter removal from cereal-based distillery stillage two stage treatment consisting of fermentation by Aspergillus awamori followed by microbial fuel cell (MFC) is proposed. Considerable reduction in total and soluble chemical oxygen demand (COD) up to 70% and 40%, respectively, along with 98% reduction of suspended solids (SS) has been achieved during fungal pretreatment. The process generated chitosan, a useful fermentation byproduct from fungal mycelia, as 0.6-0.7g/l of settled sludge with mycelium (3.8% solids). Prior treatment of wastewater with fungal strain enhanced the power generation in MFC by 2.9 times at an organic loading rate of 1.5kgCOD/m(3)day, demonstrating soluble COD reduction of 92% in MFC. While treating distillery wastewater, this two-stage integrated biological process demonstrated overall 99% COD removal and almost complete removal of SS, delivering ample scope for scale-up and industrial application to offer effective solution for distillery wastewater treatment. PMID- 25460979 TI - Comparison of the effect of wet and dry torrefaction on chemical structure and pyrolysis behavior of corncobs. AB - Wet and dry torrefaction of corncobs was conducted in high-pressure reactor and tube-type reactor, respectively. Effect of wet and dry torrefaction on chemical structure and pyrolysis behavior of corncobs was compared. The results showed that hemicellulose could be effectively removed from corncobs by torrefaction. However, dry torrefaction caused severe degradation of cellulose and the cross linking and charring of corncobs. X-ray diffraction analysis revealed that crystallinity degree of corncobs was evidently enhanced during wet torrefaction, but reduced during dry torrefaction as raising treatment temperature. In thermogravimetric analysis, wet torrefied corncobs produced less carbonaceous residues than raw corncobs, while dry torrefied corncobs gave much more residues owing to increased content of acid insoluble lignin. Pyrolysis-gas chromatography/mass spectroscopy analysis indicated that wet torrefaction significantly promoted levoglucosan yield owing to the removal of alkali metals. Therefore, wet torrefaction can be considered as a more effective pretreatment method for fast pyrolysis of biomass. PMID- 25460980 TI - COD removal characteristics in air-cathode microbial fuel cells. AB - Exoelectrogenic microorganisms in microbial fuel cells (MFCs) compete with other microorganisms for substrate. In order to understand how this affects removal rates, current generation, and coulombic efficiencies (CEs), substrate removal rates were compared in MFCs fed a single, readily biodegradable compound (acetate) or domestic wastewater (WW). Removal rates based on initial test conditions fit first-order kinetics, but rate constants varied with circuit resistance. With filtered WW (100Omega), the rate constant was 0.18h(-)(1), which was higher than acetate or filtered WW with an open circuit (0.10h(-)(1)), but CEs were much lower (15-24%) than acetate. With raw WW (100Omega), COD removal proceeded in two stages: a fast removal stage with high current production, followed by a slower removal with little current. While using MFCs increased COD removal rate due to current generation, secondary processes will be needed to reduce COD to levels suitable for discharge. PMID- 25460981 TI - Calcium precipitate induced aerobic granulation. AB - Aerobic granulation is a novel biotechnology for wastewater treatment. This study refined existing aerobic granulation mechanisms as a sequencing process including formation of calcium precipitate under alkaline pH to form inorganic cores, followed by bacterial attachment and growth on these cores to form the exopolysaccharide matrix. Mature granules comprised an inner core and a matrix layer and a rim layer with enriched microbial strains. The inorganic core was a mix of different crystals of calcium and phosphates. Functional strains including Sphingomonas sp., Paracoccus sp. Sinorhizobium americanum strain and Flavobacterium sp. attached onto the cores. These functional strains promote c-di GMP production and the expression by Psl and Alg genes for exopolysaccharide production to enhance formation of mature granules. PMID- 25460982 TI - Zinc chloride as a coagulant for textile dyes and treatment of generated dye sludge under the solid state fermentation: hybrid treatment strategy. AB - Dye sludge generation is major drawback of coagulation process. Efficient hybrid technology by combining coagulation and solid state fermentation (SSF) has capacity to solve generated dye sludge problem. Coagulation of 100mg/L Reactive Red 120 (RR120) using ZnCl2 showed 99% color removal. Mixture of textile dyes (MTD) and textile wastewater (TW) showed 96% and 98% ADMI (American Dye Manufacturing Institute) removal after coagulation by ZnCl2. 92% and 94% ADMI removal from MTD and TW dye sludge and 96% decolorization of RR120 sludge was observed respectively by developed microbial consortium (DCM) in 72h under SSF. Scale up of coagulation process by coagulation reactor (CR) having 50L capacity operated for 30min/cycle. CR showed average 94% ADMI removal from TW in 10 successive cycles. Scale up of SSF composting bioreactor (CB) showed complete dye removal from dye sludge obtained from CR (500L of TW) in 30days. PMID- 25460983 TI - Lactic acid and methane: improved exploitation of biowaste potential. AB - This feasibility study investigated a two-step biorefining approach to increase the value gained by recycling of organic municipal solid waste. Firstly, lactic acid was produced via batch fermentation at 37 degrees C using the indigenous microbiome. Experiments revealed an optimal fermentation period of 24h resulting in high yields of lactic acid (up to 37gkg(-1)). The lactic acid proportion of total volatile fatty acid content reached up to 83%. Lactobacilli were selectively enriched to up to 75% of the bacterial community. Additionally conversion of organic matter to lactic acid was increased from 22% to 30% through counteracting end product inhibition by continuous lactic acid extraction. Secondly, fermentation residues were used as co-substrate in biomethane production yielding up to 618+/-41Nmlbiomethaneg(-1) volatile solids. Digestate, the only end product of this process can be used as organic fertilizer. PMID- 25460984 TI - Microbial diversity and dynamicity of biogas reactors due to radical changes of feedstock composition. AB - The anaerobic digestion process is often inhibited by alteration of substrates and/or organic overload. This study aimed to elucidate changes of microbial ecology in biogas reactors upon radical changes of substrates and to determine their importance to process imbalance. For this reason, continuously fed reactors were disturbed with pulses of proteins, lipids and carbohydrates and the microbial ecology of the reactors were characterized by 16S rRNA gene sequencing before and after the imposed changes. The microbial composition of the three reactors, initially similar, diverged greatly after substrate change. The greatest increase in diversity was observed in the reactor supplemented with carbohydrates and the microbial community became dominated by lactobacilli, while the lowest corresponded to the reactor overfed with proteins, where only Desulfotomaculum showed significant increase. The overall results suggest that feed composition has a decisive impact on the microbial composition of the reactors, and thereby on their performance. PMID- 25460985 TI - Effect of CuO nanoparticles on the production and composition of extracellular polymeric substances and physicochemical stability of activated sludge flocs. AB - The effects of CuO nanoparticles (NPs) on the production and composition of extracellular polymeric substances (EPS) and the physicochemical stability of activated sludge were investigated. The results showed enhanced production of loosely bound extracellular polymeric substances (LB-EPS), protecting against nanotoxicity. Specifically, polysaccharide production increased by 89.7% compared to control upon exposure to CuO NPs (50mg/L). Fourier transform-infrared spectroscopy analysis revealed changes in the polysaccharide COC group and the carboxyl group of proteins in the EPS in the presence of CuO NPs. The sludge flocs were unstable after exposure to CuO NPs (50mg/L) because of excess LB-EPS. This also corresponded with decreased cell viability of the sludge flocs, as determined by the production of reactive oxygen species and the release of lactate dehydrogenase. These results are key to assessing the adverse effects of the CuO NPs on activated sludge in wastewater treatment plants. PMID- 25460986 TI - Biobutanol production by Clostridium acetobutylicum using xylose recovered from birch Kraft black liquor. AB - Acetone-butanol-ethanol (ABE) fermentation was studied using acid-hydrolyzed xylan recovered from hardwood Kraft black liquor by CO2 acidification as the only carbon source. Detoxification of hydrolyzate using activated carbon was conducted to evaluate the impact of inhibitor removal and fermentation. Xylose hydrolysis yields as high as 18.4% were demonstrated at the highest severity hydrolysis condition. Detoxification using active carbon was effective for removal of both phenolics (76-81%) and HMF (38-52%). Batch fermentation of the hydrolyzate and semi-defined P2 media resulted in a total solvent yield of 0.12-0.13g/g and 0.34g/g, corresponding to a butanol concentration of 1.8-2.1g/L and 7.3g/L respectively. This work is the first study of a process for the production of a biologically-derived biofuel from hemicelluloses solubilized during Kraft pulping and demonstrates the feasibility of utilizing xylan recovered directly from industrial Kraft pulping liquors as a feedstock for biological production of biofuels such as butanol. PMID- 25460987 TI - Improved propionic acid production from glycerol: combining cyclic batch- and sequential batch fermentations with optimal nutrient composition. AB - Propionic acid was produced from glycerol using Propionibacterium acidipropionici. In this study, the impact of the concentrations of carbon and nitrogen sources, and of different modes of high cell density fermentations on process kinetics and -efficiency was investigated. Three-way ANOVA analysis and batch cultivations at varying C/N ratios at pH 6.5 revealed that propionic acid production rate is significantly influenced by yeast extract concentration. Glycerol to yeast extract ratio (ww(-1)) of 3:1 was required for complete glycerol consumption, while maintaining the volumetric productivity. Using this optimum C/N ratio for propionic acid production in cyclic batch fermentation gave propionate yield up to 93mol% and productivity of 0.53gL(-1)h(-1). Moreover, sequential batch fermentation with cell recycling resulted in production rates exceeding 1gL(-1)h(-1) at initial glycerol up to 120gL(-1), and a maximum of 1.63gL(-1)h(-1) from 90gL(-1) glycerol. PMID- 25460988 TI - Process development for biological production of butanol from Eastern redcedar. AB - Eastern redcedar is an invasive softwood species in Oklahoma and across grasslands in the Central Plains of the United States and potential feedstock for butanol production. Butanol has higher energy content than ethanol and can be upgraded to jet and diesel fuels. The objective of this study was to develop a process for production of butanol from redcedar. Results showed that Clostridium acetobutylicum ATCC 824 and Clostridium beijerinckii NCIMB 8052 did not grow in fermentation medium with citrate buffer. However, both strains grew in the medium with acetate buffer, resulting in 3-4g/L greater butanol than without acetate. Detoxification of redcedar hydrolyzate was required to increase butanol concentration from 1 to 13g/L. Hydrolyzate was detoxified by activated carbon to remove inhibitors. Fermentations in detoxified redcedar hydrolyzate reached 13g/L butanol and 19g/L total ABE, comparable to glucose control. This shows the potential for redcedar use in butanol production. PMID- 25460989 TI - Autotrophic nitrogen removal by a two-step SBR process applied to mixed agro digestate. AB - The aim of this research was to evaluate the applicability of partial nitritation/anammox processes for biological N removal from a centrifuge supernatant coming from a full scale anaerobic digester fed on a mixture of piggery manure, poultry manure, and agro-wastes. Stable partial nitritation was achieved at pilot-scale (650L SBR), obtaining a suitable influent for the anammox lab-scale SBR reactor (3L). The anammox lab scale reactor was fed with increasing fractions of the partial nitritation effluent, blended with synthetic wastewater. In the last 100days no dilution was used. The nitrogen loading rate applied to the anammox reactor was 0.5-0.6gNL(-)(1)d(-)(1) and the average nitrogen removal was 91+/-10%. During the first days of operation with undiluted supernatant, the maximum anammox activity in the SBR decreased, but recovered afterwards, suggesting the ability of the anammox biomass to acclimate to the wastewater. N2O emissions in both reactors were also measured. PMID- 25460990 TI - Preparation and application of porous nitrogen-doped graphene obtained by co pyrolysis of lignosulfonate and graphene oxide. AB - Nitrogen-doped graphene with in-plane porous structure was fabricated by simple co-pyrolysis of lignosulfonate and graphene oxide in the presence of urea. Lignosulfonate first performs as a dispersant adsorbed on the surface of graphene oxide to prevent the aggregation of graphene oxide sheets for preparing homogeneous nitrogen-containing precursor, and then acts as a porogen to render graphene sheets with nanopores in the pyrolysis process of the nitrogen containing precursor. Urea was used as a nitrogen source to incorporate nitrogen atoms into graphene basal plane. The special nanoporous structure combined with nitrogen content of 7.41at.% endows the nitrogen-doped graphene electrode material with super capacitance up to 170Fg(-1), high rate performance, and excellent cycling stability. PMID- 25460991 TI - Acute and chronic responses of denitrifying culture to diclofenac. AB - Acute and chronic effect as well as biodegradation potential at different sludge retention times (SRTs) of a priority pollutant, diclofenac on denitrification process was assessed. The continuous amendment of the culture for 6months with 1MUg/L diclofenac resulted in 30% decrease in gas production. The average diclofenac removal observed in the diclofenac-acclimated culture was less than 15%. Batch tests showed that nitrate was removed in diclofenac free-control reactor at a higher rate compared to diclofenac amended reactor. Although, SRT did not have any progressive effect on diclofenac degradation, the system operated at low SRT was more sensitive to diclofenac and resulted in an increase in N2O emission. Wastewater treatment plants (WWTPs) operated at higher SRTs may tolerate and recover from the adverse effects of such micropollutants. The study can lead to other researchers to understand the fate and effect of other emerging pollutants in the anoxic unit of WWTPs. PMID- 25460992 TI - Establishment and assessment of an integrated citric acid-methane production process. AB - To solve the problem of extraction wastewater in citric acid industrial production, an improved integrated citric acid-methane production process was established in this study. Extraction wastewater was treated by anaerobic digestion and then the anaerobic digestion effluent (ADE) was stripped by air to remove ammonia. Followed by solid-liquid separation to remove metal ion precipitation, the supernatant was recycled for the next batch of citric acid fermentation, thus eliminating wastewater discharge and reducing water consumption. 130U/g glucoamylase was added to medium after inoculation and the recycling process performed for 10 batches. Fermentation time decreased by 20% in recycling and the average citric acid production (2nd-10th) was 145.9+/-3.4g/L, only 2.5% lower than that with tap water (149.6g/L). The average methane production was 292.3+/-25.1mL/g CODremoved and stable in operation. Excessive Na(+) concentration in ADE was confirmed to be the major challenge for the proposed process. PMID- 25460993 TI - Binding characteristics and synergistic effects of bacterial expansins on cellulosic and hemicellulosic substrates. AB - Expansins are non-catalytic proteins which loosen plant cell wall structure. In this study, binding kinetics and synergistic action of five bacterial expansins on cellulosic and hemicellulosic polysaccharides were studied. The expansins differed in binding capacity (Bmax) and affinity (Kd) for different substrates. A common pattern of binding efficiency (Bmax/Kd) was found among the expansins tested, in which efficiency was greatest for the phosphoric acid-swollen cellulose (PASC), then the hemicellulose arabinoxylan followed by the microcrystalline cellulose (Avicel PH101). The expansins enhanced the action of Trichoderma reesei cellulase/hemicellulase mixture for degrading all three substrates to varying degrees. Among the substrates and expansins tested, BpEX from Bacillus pumilus and CmEX from Clavibacter michiganensis showed the greatest enhancement effect on arabinoxylan with 11.4 and 12.2-fold greater reducing sugar yield than the reaction with enzyme alone. The work gives insights into the wider application of expansins on enhancing polysaccharide hydrolysis, particularly on hemicellulosic substrates. PMID- 25460995 TI - Hydrothermal pretreatment enhanced enzymatic hydrolysis and glucose production from oil palm biomass. AB - The present works investigate hydrothermal pretreatment of oil palm empty fruit bunch and oil palm frond fiber in a batch tube reactor system with temperature and time range from 170 to 250 degrees C and 10 to 20min, respectively. The behavior of soluble sugars, acids, furans, and phenols dramatically changed over treatment severities as determined by HPLC. The cellulose-rich treated solids were analyzed by SEM, WAXD, and BET surface area. Enzymatic hydrolysis was performed from both pretreated slurries and washed solid, and data obtained suggested that tannic acid derived from lignin degradation was a potential cellulase inhibitor. Both partial removal of hemicellulose and migration of lignin during hydrothermal pretreatment caused structural changes on the cellulose-hemicellulose-lignin matrix, resulting in the opening and expansion of specific surface area and pore volume. The current results provided important factors that maximize conversion of cellulose to glucose from oil palm biomass by hydrothermal process. PMID- 25460994 TI - Integrative approach to produce hydrogen and polyhydroxybutyrate from biowaste using defined bacterial cultures. AB - Biological production of hydrogen (H2) and polyhydroxybutyrate (PHB) from pea shell slurry (PSS) was investigated using defined mixed culture (MMC4, composed of Enterobacter, Proteus, Bacillus spp.). Under batch culture, 19.0LH2/kg of PSS (total solid, TS, 2%w/v) was evolved. Using effluent from the H2 producing stage, Bacillus cereus EGU43 could produce 12.4% (w/w) PHB. Dilutions of PSS hydrolysate containing glucose (0.5%, w/v) resulted in 45-75LH2/kg TS fed and 19.1% (w/w) of PHB content. Under continuous culture, MMC4 immobilized on coconut coir (CC) lead to an H2 yield of 54L/kg TS fed and a PHB content of 64.7% (w/w). An improvement of 2- and 3.7-fold in H2 and PHB yields were achieved in comparison to control. This integrative approach using defined set of bacterial strains can prove effective in producing biomolecules from biowastes. PMID- 25460996 TI - Effective start-up biofiltration method for Fe, Mn, and ammonia removal and bacterial community analysis. AB - Three identical lab-scale biofilters were employed to optimize the start-up process for simultaneous removal of iron (Fe), manganese (Mn), and ammonia from potable water supplies. Nitrifying sludge and backwashing sludge containing Mn oxidizing bacteria (MnOB) were used as the inocula. The start-up strategies consisted of simultaneous and separate inoculation of the two kinds of sludge. The influent Fe was removed immediately when the biofilters began to operate. The effects of nitrification for ammonia removal showed no significant difference between these biofilters. However, the beginning of Mn removal with separate inoculation was faster than that of simultaneous inoculation. The Mn removal can be described by using first order reaction; and the k (rate constant, min(-1)) values were 0.147+/-0.007 (mean+/-standard deviation) and 0.153+/-0.006. Besides the commonly reported MnOB genus Crenothrix, MnOB genera were also found to be related to the genera rarely reported in the potable water treatment systems. PMID- 25460997 TI - Improved ethanol tolerance and ethanol production from glycerol in a streptomycin resistant Klebsiella variicola mutant obtained by ribosome engineering. AB - To improve the ethanol tolerance of the Klebsiella variicola strain TB-83, we obtained the streptomycin-resistant, ethanol-tolerant mutant strain TB-83D by a ribosome engineering approach. Strain TB-83D was able to grow in the presence of 7% (v/v) ethanol and it showed higher ethanol production than strain TB-83. Examination of various culture conditions revealed that yeast extract was essential for ethanol production and bacterial growth. In addition, ethanol production was elevated to 32g/L by the addition of yeast extract; however, ethanol production was inhibited by formate accumulation. With regard to cost reduction, the use of corn steep liquor (CSL) markedly decreased the formate concentration, and 34g/L ethanol was produced by combining yeast extract with CSL. Our study is the first to improve ethanol tolerance and productivity by a ribosome engineering approach, and we found that strain TB-83D is effective for ethanol production from glycerol. PMID- 25460998 TI - Decentralized domestic wastewater treatment using intermittently aerated vertical flow constructed wetlands: impact of influent strengths. AB - In this study, the removal performances of organic pollutants and nitrogen in vertical flow constructed wetlands (VFCWs) with and without intermittent aeration fed with different strengths of influent were evaluated as a possible treatment for decentralized domestic wastewater in northern China. The intermittent aeration strategy not only significantly increased removal efficiencies of organic pollutants and ammonium nitrogen (NH4(+)-N), but also successfully created alternate aerobic and anaerobic conditions resulting in high total nitrogen (TN) removal. Moreover, increasing influent strength did not affect the removal efficiencies of organic matters and nitrogen in aerated VFCWs. Compared with non-aerated VFCWs, much higher removal of organic pollutants (96%), NH4(+)-N (98%), and TN (85%) was obtained simultaneously in intermittent aeration VFCWs, especially at high influent strengths. The results suggest that the intermittent aeration could be an appropriate strategy for achieving the high removal performance in VFCWs, especially for in-situ treatment of high strength decentralized domestic wastewaters. PMID- 25460999 TI - Ionic liquid/ultrasound pretreatment and in situ enzymatic saccharification of bagasse using biocompatible cholinium ionic liquid. AB - Choline acetate (ChOAc), a cholinium ionic liquid (IL), showed almost the same bagasse pretreatment capability as 1-ethyl-3-methylimidazolium acetate (EmimOAc), a conventional imidazolium IL used for biomass pretreatment. Moreover, ChOAc showed less of an inhibitory effect on cellulase than EmimOAc. Thus, ChOAc was used for IL/ultrasound-assisted pretreatment and in situ enzymatic saccharification, where IL was not washed out from the pretreated bagasse but diluted with the addition of a buffer solution. When in situ saccharification was performed for 48h in the presence of 10% ChOAc, the cellulose and hemicellulose saccharification percentages were 80% and 72%, respectively. When ChOAc was increased to 20%, the saccharification percentages were 72% and 53%, respectively. However, the values were just 28% and 2%, respectively, in case of 20% EmimOAc. A glucose/xylose solution free from IL and ChOAc aqueous solution without these sugars could be recovered separately by electrodialysis of the hydrolysate of in situ saccharification. PMID- 25461000 TI - Liquid hot water pretreatment on different parts of cotton stalk to facilitate ethanol production. AB - To investigate pretreatment demand for different parts of biomass, cotton stalk was separated into stem, branch and boll shell, which were treated by liquid hot water pretreatment (LHWP) with severity from 2.77 to 4.42. Based on weight loss (WL, w/w) mainly caused by hemicellulose removal, it was found that boll shell (WL, 46.93%) was more sensitive to LHWP than stem (WL, 38.85%). Although ethanol yield of 18.3, 16.27 and 21.08g/100g was achieved from stem, branch and boll shell with pretreatment severity at 4.42, ratio of ethanol yield to pretreatment energy input for particular parts was different. For boll shell and branch, the maximum ratio of ethanol yield to energy input were 1.37 and 1.33g ethanolkJ(-1) with severity at 4.34, while it was 1.20 for stem at 3.66. This indicates that different pretreatment demands for different parts of plants should be considered in order to save pretreatment energy input. PMID- 25461001 TI - Low temperature calcium hydroxide treatment enhances anaerobic methane production from (extruded) biomass. AB - Ca(OH)2 treatment was applied to enhance methane yield. Different alkali concentration, incubation temperature and duration were evaluated for their effect on methane production and COD conversion efficiency from (non-)extruded biomass during mesophilic anaerobic digestion at lab-scale. An optimum Ca(OH)2 pretreatment for grass is found at 7.5% lime loading at 10 degrees C for 20h (37.3% surplus), while mild (50 degrees C) and high temperatures perform sub optimal. Ca(OH)2 post-treatment after fast extrusion gives an additional surplus compared to extruded material of 15.2% (grass), 11.2% (maize straw) and 8.2% (sprout stem) regarding methane production. COD conversion improves accordingly, with additional improvements of 10.3% (grass), 9.0% (maize straw) and 6.8% (sprout stem) by Ca(OH)2 post-treatment. Therefore, Ca(OH)2 pretreatment and post treatment at low temperature generate an additional effect regarding methane production and COD conversion efficiency. Fast extrusion gives a higher energy efficiency ratio compared to slow extrusion. PMID- 25461002 TI - Biological reformation of ethanol to hydrogen by Rhodopseudomonas palustris CGA009. AB - A future hydrogen economy requires the sustainable production of renewable hydrogen. One method to produce hydrogen from stored renewable energy could be through reformation of bioethanol. However, chemically catalyzed reformation processes, although well studied, still present a number of significant technical challenges. Here, bioreformation of ethanol to hydrogen by photofermentation with the photosynthetic bacterium Rhodopseudomonas palustris is described. Cultures were shown to tolerate up to 2% ethanol. An RSM (response surface methodology) was carried out in which three key factors, light intensity, and ethanol and glutamate concentrations were varied. The results showed that nearly 2mol of H2 could be obtained from one mole of ethanol, 33% of that theoretically possible. PMID- 25461003 TI - Characterization of Nizimuddinia zanardini macroalgae biomass composition and its potential for biofuel production. AB - Nizimuddinia zanardini macroalgae, harvested from Persian Gulf, was chemically characterized and employed for the production of ethanol, seaweed extract, alginic acid, and biogas. In order to improve the products yields, the biomass was pretreated with dilute sulfuric acid and hot water. The pretreated and untreated biomasses were subjected to enzymatic hydrolysis by cellulase (15FPU/g) and beta-glucosidase (30IU/g). Hydrolysis yield of glucan was 29.8, 82.5, and 72.7g/kg for the untreated, hot-water pretreated, and acid pretreated biomass, respectively. Anaerobic fermentation of hydrolysates by Saccharomycescerevisiae resulted in the maximum ethanol yield of 34.6g/kg of the dried biomass. A seaweed extract containing mannitol and a solid residue containing alginic acid were recovered as the main byproducts of the ethanol production. On the other hand, the biogas yield from the biomass was increased from 170 to 200m(3) per ton of dried algae biomass by hot water pretreatment. PMID- 25461004 TI - Conversion of steam-exploded cedar into ethanol using simultaneous saccharification, fermentation and detoxification process. AB - In this study, we investigated the simultaneous saccharification, fermentation and detoxification SSDF process of steam-exploded cedar using a detoxification microorganism, Ureibacillus thermosphaericus A1, to facilitate efficient ethanol production. Steam explosion was applied as a pretreatment before enzymatic saccharification followed by alcohol fermentation. The highest glucose conversion rate was observed in the sample pretreated with a steam pressure of 45atm for 5min. Alcohol production by a heat-tolerant yeast, Saccharomyces cerevisiae BA11, was inhibited strongly by inhibitory materials present in the steam-exploded cedar, such as formic acid, furfural, and 5-hydroxymethylfurfural. The maximum amount of ethanol, i.e., 0.155g ethanol/g dry steam-exploded cedar, which corresponded to 74% of the theoretical ethanol yield, was obtained using the SSDF when U. thermosphaericus A1 degraded the inhibitory materials. A fed batch SSDF culture, in which U. thermosphaericus A1 was used to maintain low concentrations of inhibitory materials, was effective for increasing the ethanol concentration. PMID- 25461005 TI - Mechanism of hydroxyl radical generation from biochar suspensions: Implications to diethyl phthalate degradation. AB - This paper investigated hydroxyl radical (OH) generation from biochar suspensions for diethyl phthalate (DEP) degradation in the presence of oxygen. Electron paramagnetic resonance (EPR) coupled with a salicylic acid trapping method were used to detect free radicals in biochar and verify OH generation from biochar suspensions. Free radicals (FRs) in biochar could induce OH generation, and ~12 spins of FRs were consumed to produce one trapped [OH] molecule. The proposed mechanism of OH generation was that FRs in biochar transferred electrons to O2 to produce the superoxide radical anion and hydrogen peroxide, which reacted further with FRs to produce OH. Free radical-quenching studies utilizing superoxide dismutase, catalase, and deferoxamine as scavengers were used to testify this mechanism. Furthermore, OH generated from biochar suspensions could degrade DEP efficiently. These findings of this study provide new insights into the physicochemical properties and environmental implications of biochar. PMID- 25461006 TI - Treatment of sewage sludge in supercritical water and evaluation of the combined process of supercritical water gasification and oxidation. AB - Influences of temperature and oxidation coefficient (n) on sewage sludge treatment in supercritical water and its corresponding reaction mechanism were studied. Moreover, the combined process of supercritical water gasification (SCWG) and supercritical water oxidation (SCWO) was also investigated. The results show that ammonia nitrogen, phenols and pyridines are main refractory intermediates. The weight of solid products at 873K and n=4 is only 3.5wt.% of the initial weight, which is lower than that after combustion. Volatile organics in solid phase have almost released at 723K and n=0. Highest yield of combustible gases was obtained at n=0, and H2 yield can reach 11.81mol/kg at 873K. Furthermore, the combination of SCWG at 723K and SCWO at 873K with a total n=1 is feasible for its good effluent quality and low operation costs. PMID- 25461007 TI - Anaerobic mineralization of 2,4,6-tribromophenol to CO2 by a synthetic microbial community comprising Clostridium, Dehalobacter, and Desulfatiglans. AB - Anaerobic mineralization of 2,4,6-tribromophenol (2,4,6-TBP) was achieved by a synthetic anaerobe community comprising a highly enriched culture of Dehalobacter sp. phylotype FTH1 acting as a reductive debrominator; Clostridium sp. strain Ma13 acting as a hydrogen supplier via glucose fermentation; and a novel 4 chlorophenol-degrading anaerobe, Desulfatiglans parachlorophenolica strain DS. 2,4,6-TBP was debrominated to phenol by the combined action of Ma13 and FTH1, then mineralized into CO2 by sequential introduction of DS, confirmed using [ring (14)C(U)] phenol. The optimum concentrations of glucose, SO4(2-), and inoculum densities were 0.5 or 2.5mM, 1.0 or 2.5mM, and the densities equivalent to 10(4)copiesmL(-1) of the 16S rRNA genes, respectively. This resulted in the complete mineralization of 23MUM 2,4,6-TBP within 35days (0.58MUmolL(-1)d(-1)). Thus, using a synthetic microbial community of isolates or highly enriched cultures would be an efficient, optimizable, low-cost strategy for anaerobic bioremediation of halogenated aromatics. PMID- 25461008 TI - Early prediction of Biochemical Methane Potential through statistical and kinetic modelling of initial gas production. AB - A major drawback of Biochemical Methane Potential (BMP) tests is their long test duration, which could be reduced substantially if the final gas production could be predicted at an earlier stage. For this purpose, this study evaluates 61 different algorithms for their capability to predict the final BMP and required degradation time based on data from 138 BMP tests of various substrate types. By combining the best algorithms it was possible to predict the BMP with a relative root mean squared error (rRMSE) of less than 10% just 6days after initiation of the experiment. The results from this study indicate that there is a possibility to shorten the test length substantially by combining laboratory tests and intelligent prediction algorithms. Shorter test duration may widen the possible applications for BMP tests in full-scale biogas plants, allowing for a better selection and proper pricing of biomass. PMID- 25461009 TI - Production of furfural from xylose, water-insoluble hemicelluloses and water soluble fraction of corncob via a tin-loaded montmorillonite solid acid catalyst. AB - The conversion of xylose, water-insoluble hemicelluloses (WIH) and water-soluble fraction (WSF) of corncob to furfural was performed using montmorillonite with tin ions (Sn-MMT) containing double acid sites as a solid acid catalyst. The co existence of Lewis acids and Bronsted acids in Sn-MMT was shown to improve the furfural yield and selectivity. 76.79% furfural yield and 82.45% furfural selectivity were obtained from xylose using Sn-MMT as a catalyst in a biphasic system with 2-s-butylphenol (SBP) as the organic extracting layer and dimethyl sulfoxide (DMSO) as the co-solvent in contact with an aqueous phase saturated with NaCl (SBP/NaCl-DMSO) at 180 degrees C for 30min. Furthermore, Sn-MMT also demonstrated the excellent catalytic performance in the conversion of pentose rich materials of corncob and 39.56% and 54.15% furfural yields can be directly obtained from WIH and WSF in the SBP/NaCl-DMSO system, respectively. PMID- 25461010 TI - Sweetpotato vines hydrolysate promotes single cell oils production of Trichosporon fermentans in high-density molasses fermentation. AB - This study investigated the co-fermentation of molasses and sweetpotato vine hydrolysate (SVH) by Trichosporon fermentans. T. fermentans showed low lipid accumulation on pure molasses; however, its lipid content increased by 35% when 10% SVH was added. The strong influence of SVH on lipid production was further demonstrated by the result of sensitivity analysis on effects of factors based on an artificial neural network model because the relative importance value of SVH dosage for lipid production was only lower than that of fermentation time. Scanning electron microscope observation and flow cytometry of yeast cells grown in culture with and without SVH showed that less deformation cells were involved in the culture with SVH. The activity of malic enzyme, which plays a key role in fatty acid synthesis, increased from 2.4U/mg to 3.7U/mg after SVH added. All results indicated SVH is a good supplement for lipid fermentation on molasses. PMID- 25461011 TI - Hydrogen from ethanol reforming with aqueous fraction of pine pyrolysis oil with and without chemical looping. AB - Reforming ethanol ('EtOH') into hydrogen rich syngas using the aqueous fraction from pine bio-oil ('AQ') as a combined source of steam and supplementary organic feed was tested in packed bed with Ni-catalysts 'A' (18wt%/alpha-Al2O3) and 'B' (25wt%/gamma-Al2O3). The catalysts were initially pre-reduced by H2, but this was followed by a few cycles of chemical looping steam reforming, where the catalysts were in turn oxidised in air and auto-reduced by the EtOH/AQ mixture. At 600 degrees C, EtOH/AQ reformed similarly to ethanol for molar steam to carbon ratios (S/C) between 2 and 5 on the H2-reduced catalysts. At S/C of 3.3, 90% of the carbon feed converted on catalyst A to CO2 (58%), CO (30%) and CH4 (2.7%), with 17wt% H2 yield based on dry organic feedstock, equivalent to 78% of the equilibrium value. Catalyst A maintained these outputs for four cycles while B underperformed due to partial reduction. PMID- 25461013 TI - Paediatrics and proteomics: back to the beginning. PMID- 25461012 TI - Concurrent calcium peroxide pretreatment and wet storage of water hyacinth for fermentable sugar production. AB - In the present study, a novel concurrent process of pretreatment and wet storage was developed and investigated by applying calcium peroxide for preservation and conversion of fresh water hyacinth biomass to fermentable sugars. The effects of CaO2 loading concentration and moisture content on the lignin reduction, carbohydrate preservation and enzymatic saccharification of water hyacinth biomass were evaluated by experimental design using a response surface methodology. The data showed that the concurrent process could conserve 70% carbohydrates and remove 40% lignin from biomass of water hyacinth at the best condition in this study. The enzymatic digestibility and reducing sugar yield from the best condition of concurrent process were around 93% and 325mg/g (dry weight) of fresh biomass, respectively. The result suggested that the concurrent process developed in this work could be a potential alternative to consolidate the pretreatment and storage of aquatic plant biomass for fermentable sugar production. PMID- 25461017 TI - Cost of areal reduction of gulf hypoxia through agricultural practice. AB - A major share of the area of hypoxic growth in the Northern Gulf of Mexico has been attributed to nutrient run-off from agricultural fields, but no estimate is available for the cost of reducing Gulf hypoxic area using agricultural conservation practices. We apply the Soil and Water Assessment Tool using observed daily weather to simulate the reduction in nitrogen loading in the Upper Mississippi River Basin (UMRB) that would result from enrolling all row crop acreage in the Conservation Reserve Program (CRP). Nitrogen loadings at the outlet of the UMRB are used to predict Gulf hypoxic area, and net cash farm rent is used as the price for participation in the CRP. Over the course of the 42 year simulation, direct CRP costs total more than $388 billion, and the Inter Governmental Task Force goal of hypoxic area less than 5000 square kilometers is met in only two years. PMID- 25461018 TI - Suitability of a Saccharomyces cerevisiae-based assay to assess the toxicity of pyrimethanil sprayed soils via surface runoff: comparison with standard aquatic and soil toxicity assays. AB - The present study is aimed at evaluating whether a gene expression assay with the microbial eukaryotic model Saccharomyces cerevisiae could be used as a suitable warning tool for the rapid preliminary screening of potential toxic effects on organisms due to scenarios of soil and water contamination with pyrimethanil. The assay consisted of measuring changes in the expression of the selected pyrimethanil-responsive genes ARG3 and ARG5,6 in a standardized yeast population. Evaluation was held by assessing the toxicity of surface runoff, a major route of pesticide exposure in aquatic systems due to non-point-source pollution, which was simulated with a pyrimethanil formulation at a semifield scale mimicking worst-case scenarios of soil contamination (e.g. accident or improper disposal). Yeast cells 2-h exposure to the runoff samples led to a significant 2-fold increase in the expression of both indicator genes. These results were compared with those from assays with organisms relevant for the aquatic and soil compartments, namely the nematode Caenorhabditis elegans (reproduction), the freshwater cladoceran Daphnia magna (survival and reproduction), the benthic midge Chironomus riparius (growth), and the soil invertebrates Folsomia candida and Enchytraeus crypticus (survival and reproduction). Under the experimental conditions used to simulate accidental discharges into soil, runoff waters were highly toxic to the standard test organisms, except for C. elegans. Overall, results point out the usefulness of the yeast assay to provide a rapid preview of the toxicity level in preliminary screenings of environmental samples in situations of inadvertent high pesticide contamination. Advantages and limitations of this novel method are discussed. PMID- 25461019 TI - Liquid chromatography-atmospheric pressure photoionization-Orbitrap analysis of fullerene aggregates on surface soils and river sediments from Santa Catarina (Brazil). AB - In the present work, a new analytical approach is proposed for the analysis of seven fullerenes (C60, C70, N-methylfulleropyrrolidine, [6,6]-phenyl C61 butyric acid methyl ester, [6,6]-thienyl C61 butyric acid methyl ester, C60 pyrrolidine tris-acid ethyl ester and [6,6]-phenyl C71 butyric acid methyl ester fullerenes) in soils and sediments. This procedure combines an ultrasound-assisted solvent extraction (UAE) with toluene followed by liquid chromatography (LC), using a pyrenylpropyl group bonded silica based column, coupled to a high-resolution mass spectrometer (HRMS) using atmospheric pressure photoionisation (APPI) in negative ion mode. The analytical performance for fullerene separation of the pyrenylpropyl group bonded silica column was compared to the C18 column. For the ultra-trace analysis of fullerenes in complex environmental samples, the use of the APPI source and the use of the electrospray ionisation (ESI) source were compared. Using this approach for the analysis of fullerenes in complex matrices, a series of advantages, in terms of sensitivity and specificity, have been demonstrated. The method limits of detection (MLOD) and the method limits of quantification (MLOQ) in soils and sediments ranged from 0.022 to 0.39 pg/g and from 0.072 to 1.3 pg/g, respectively. Recoveries were between 68 and 106%. The analytical method was applied in order to assess the occurrence of selected fullerenes in 45 soils of Sul Catarinense (Santa Catalina State, Brazil) and 15 sediments from the Tubarao River, presenting different pressures of contamination: a coal-combustion power plant, car exhaust, coal mining industry and wastewater effluents. C60 and C70 fullerenes have been detected at concentrations ranging from the MLOD to 0.150 ng/g. None of the functionalised fullerenes were detected in any of the samples. Combustion processes, in particular car exhaust, were identified as the main source of fullerenes. However, the potential degradation of residual concentrations of engineered fullerenes to more stable forms, such as C60 and C70, should also be considered. PMID- 25461020 TI - Corticosterone, prolactin and egg neglect behavior in relation to mercury and legacy POPs in a long-lived Antarctic bird. AB - Seabirds often have high loads of contaminants. These contaminants have endocrine disrupting properties but their relationships with some endocrine mechanisms are still poorly investigated in free-living organisms. This is the case for the stress response which shifts energy investment away from reproduction and redirects it towards survival. In birds, this stress response is achieved through a release of corticosterone and is also accompanied by a decrease in circulating prolactin, an anterior pituitary hormone widely involved in regulating parental cares. We measured blood concentrations of some legacy persistent organic pollutants (POPs) and mercury (Hg) and examined their relationships with the corticosterone and prolactin responses of known-age (9-46 years old) incubating snow petrels (Pagodroma nivea) to a standardized capture/handling stress protocol. In this Antarctic seabird, we also investigated whether high contaminant burden correlates with a higher occurrence of egg neglect, a frequently observed behavior in snow petrels. POPs and Hg were unrelated to age. Stress-induced corticosterone concentrations were positively related to POPs in both sexes, and stress-induced prolactin concentrations were negatively related to Hg in males. Egg-neglect behavior was not related to POPs burden, but males with higher Hg concentrations were more likely to neglect their egg. This suggests that in birds, relationships between age and contaminants are complex and that even low to moderate concentrations of POPs and Hg are significantly related to hormonal secretion. In this Antarctic species, exposure to legacy POPs and Hg could make individuals more susceptible to environmental stressors such as ongoing disturbances in Polar Regions. PMID- 25461021 TI - Distinguishable transport behavior of zinc oxide nanoparticles in silica sand and soil columns. AB - As part of ongoing risk assessments of ZnO nanoparticles (nZnO) in the natural environment, transport behaviors of nZnO in soil need investigation. This work comparatively studied the transport and retention behavior of nZnO in silica sand versus soil, where the effect of input concentration (C0=34~430 mgL(-1)) and ionic strength (IS=1~50 mM) were investigated. In silica sand, nZnO were highly mobile, especially at low C0 and the efflux of nZnO generally decreased with increasing C0 at all tested IS. Conversely, at low C0, n ZnO were almost entirely immobile in soil and the efflux of nZnO increased with C0 at all tested IS. In both media, the retention profiles (RPs) were generally hyper-exponentially shaped suggesting nZnO easily deposited near the column inlet. As indicated by DLVO calculations, previously deposited nZnO on the silica sand surface acted as new deposition sites due to the lower energy barrier (Phimax) between nZnO-nZnO than between nZnO-silica sand. However, previously deposited nZnO in soil could enhance Phimax between the soil surface and nZnO which resulted in unfavorable sites for nZnO deposition. The two-site kinetic attachment model provided good descriptions for the breakthrough curves of nZnO. Detachment was more significant than attachment in silica sand (k1d>k1a), whereas soil surface attachment of nZnO were strong and irreversible (k1a>k1d). The straining interaction parameter (k2str) increased with increasing C0 in silica sand, but decreased with C0 in soil. Such differences were mainly responsible for the various transport behaviors of nZnO in silica sand and soil. PMID- 25461022 TI - Occurrence of POPs and other persistent organic contaminants in the European eel (Anguilla anguilla) from the Loire estuary, France. AB - The chemical contamination of the Loire estuary by three classes of persistent organic pollutants (POPs): the polychlorinated biphenyls (PCBs), the polybrominated diphenyl ethers (PBDEs) and the perfluorinated and polyfluorinated alkyl substances (PFAS), and three families of organic contaminants, the alkylphenols (APs), the polycyclic aromatic hydrocarbon metabolites (OH-PAHs) and the bisphenol A (BPA) were investigated in the muscles and bile of European eel (Anguilla anguilla). Yellow eels (n=30) were caught in three different points along the estuary to highlight variations between sites and sources of contaminations. Silver eels (n=15) were also studied to compare contaminant impregnation between different life stages of the species. Average concentrations in the muscles of the eel ranged between: 857 and 4358 ng/gLW for the PCBs, 26 and 46 ng/gLW for the PBDEs, 130 and 1293 ng/gLW for the PFAS; and in bile: 31 and 286 MUg/g protein for the APs, 9 and 26 MUg/g protein for the OH-PAHs and ND 1213 MUg/g protein for the BPA. Among PCBs, PCB 153 (40% contribution to the sum of PCBs) was predominant in all eel muscles. PBDE 47 (60%) was the most predominant PBDE congeners, while perfluorooctanesulfonic acid (85%) was the most widely detected PFAS. For APs, 4p-nonylphenol (91%) was the most abundant and for the OH-PAHs, it was 1OH-Pyrene (63%). All the eels exceeded the environmental quality standards (EQS) for biota for the PBDEs and about 75% were higher than the EQS specific to PFOS. Finally, 20% of the analyzed eels presented TEQ concentrations above the maximum limits for lipid-rich species. These results supplied new data on the occurrence, levels, and patterns of 53 organic chemicals in the eels from the Loire estuary and they highlighted the need of further investigations focused notably on the potential effects of these chemicals on this species and their analysis in the water and sediments of the estuary. PMID- 25461023 TI - Natural attenuation of 1,2,4-trichlorobenzene in shallow aquifer at the Luhuagang's landfill site, Kaifeng, China. AB - The natural attenuation of 1,2,4-trichlorobenzene (1,2,4-TCB) in shallow aquifer was investigated at the Luhuagang's landfill site (LLS), where the subsoil and shallow aquifer have been contaminated by certain chemicals owning to a lack of protective structures and leachate collection systems. Batch natural attenuation experiments and molecular biology experiments were conducted to study the natural attenuation characteristics of 1,2,4-TCB, the relative contributions of the primary natural attenuation processes and the functional microorganisms degrading 1,2,4-TCB, respectively. The results indicated that the relationship between degradation rate and 1,2,4-TCB concentrations was in line with first-order decay kinetics, and the natural attenuation rate of 1,2,4-TCB in the three media followed the order silt>fine sand>medium sand, which was related to the size of the media and the microbial population. The relative contribution of adsorption to natural attenuation was 97.7%, 98.2%, and 95.7% in unsterilized silt, fine sand and medium sand, respectively, and that of biodegradation was 2.3%, 1.8%, and 4.3%, respectively. These properties are related to the characteristics of the pollutants and the specific conditions at the contaminated sites, such as the characteristics of the aquifer media and microbial communities. The functional microorganisms degrading 1,2,4-TCB at the site were proved to be primarily Pseudomonas sp. This study indicates the feasibility of bioremediation (bioaugmentation and biostimulation) by indigenous microorganisms to treat 1,2,4 TCB contamination at the site. PMID- 25461024 TI - Responses of earthworms to repeated exposure to three biocides applied singly and as a mixture in an agricultural field. AB - The study aimed at investigating effects of three differently acting biocides; the insecticide esfenvalerate, the fungicide picoxystrobin and the bactericide triclosan, applied individually and as a mixture, on an earthworm community in the field. A concentration-response design was chosen and results were analyzed using univariate and multivariate approaches. Effects on juvenile proportions were less pronounced and more variable than effects on abundance, but effects in general were species- and chemical-specific, and temporal variations distinct. Esfenvalerate and picoxystrobin appeared to elicit stronger effects than triclosan at laboratory-based ECx values, which is in accordance with our previous laboratory study on Eisenia fetida. The mixture affected abundance and juvenile proportions, but the latter only at high mixture concentrations. Esfenvalerate and picoxystrobin appeared to be the main drivers for the mixture's toxicity. Species-specific toxicity patterns question the reliability of mixture toxicity predictions derived on E. fetida for field earthworms. Biocide concentrations equaling EC50s (reproduction) for E. fetida provoked effects on the field earthworms mainly exceeding 50%, indicating effect intensification from the laboratory to field as well as the influence of indirect effects produced by species interactions. The differing results of the present field study and the previous laboratory study imply that lower- and higher-tier studies may not be mutually exclusive, but to be used in complementary. PMID- 25461025 TI - Heterogeneous hyporheic zone dechlorination of a TCE groundwater plume discharging to an urban river reach. AB - The typically elevated natural attenuation capacity of riverbed-hyporheic zones is expected to decrease chlorinated hydrocarbon (CHC) groundwater plume discharges to river receptors through dechlorination reactions. The aim of this study was to assess physico-chemical processes controlling field-scale variation in riverbed-hyporheic zone dechlorination of a TCE groundwater plume discharge to an urban river reach. The 50-m long pool-riffle-glide reach of the River Tame in Birmingham (UK) studied is a heterogeneous high energy river environment. The shallow riverbed was instrumented with a detailed network of multilevel samplers. Freeze coring revealed a geologically heterogeneous and poorly sorted riverbed. A chlorine number reduction approach provided a quantitative indicator of CHC dechlorination. Three sub-reaches of contrasting behaviour were identified. Greatest dechlorination occurred in the riffle sub-reach that was characterised by hyporheic zone flows, moderate sulphate concentrations and pH, anaerobic conditions, low iron, but elevated manganese concentrations with evidence of sulphate reduction. Transient hyporheic zone flows allowing input to varying riverbed depths of organic matter are anticipated to be a key control. The glide sub-reach displayed negligible dechlorination attributed to the predominant groundwater baseflow discharge condition, absence of hyporheic zone, transition to more oxic conditions and elevated sulphate concentrations expected to locally inhibit dechlorination. The tail-of-pool-riffle sub-reach exhibited patchy dechlorination that was attributed to sub-reach complexities including significant flow bypass of a low permeability, high organic matter, silty unit of high dechlorination potential. A process-based conceptual model of reach-scale dechlorination variability was developed. Key findings of practitioner relevance were: riverbed-hyporheic zone CHC dechlorination may provide only a partial, somewhat patchy barrier to CHC groundwater plume discharges to a surface water receptor; and, monitoring requirements to assess the variability in CHC attenuation within a reach are expected to be onerous. Further research on transient hyporheic zone dechlorination is recommended. PMID- 25461026 TI - The potentiation effect makes the difference: non-toxic concentrations of ZnO nanoparticles enhance Cu nanoparticle toxicity in vitro. AB - Here we examined whether the addition of a non-toxic concentration (6.25 MUg/mL) of zinc oxide nanoparticles (ZnONPs: 19, 35 and 57 nm, respectively) modulates the cytotoxicity of copper nanoparticles (CuNPs, 63 nm in size) in the human hepatoma cell line HepG2. The cytotoxic effect of CuNPs on HepG2 cells was markedly enhanced by the ZnONPs, the largest ZnONPs causing the highest increase in toxicity. However, CuNPs cytotoxicity was not affected by co-incubation with medium containing only zinc ions, indicating the increase in toxicity might be attributed to the particle form of ZnONPs. Transmission electron microscopy (TEM) revealed the presence of CuNPs and ZnONPs inside the cells co-exposed to both types of NP and outflow of cytoplasm through the damaged cell membrane. Inductively coupled plasma mass spectrometry (ICP-MS) determined an increase in the concentration of zinc and a decrease in that of copper in co-exposed cells. On the basis of these results, we propose that accumulation of large numbers of ZnONPs in the cells alters cellular membranes and the cytotoxicity of CuNPs is increased. PMID- 25461027 TI - Profiles and removal efficiency of polybrominated diphenyl ethers by two different types of sewage treatment work in Hong Kong. AB - This study was to investigate removal efficiencies and profiles of 14 polybrominated diphenyl ether (PBDE) congeners by two different types of sewage treatment work (STW) in Hong Kong: Stonecutters Island STW (SCISTW) which uses chemically enhanced primary treatment (CEPT) process and Sha Tin STW (STSTW) which adopts biological treatment. The results indicated that both SCISTW and STSTW had a high total removal efficiency for BDE-47, BDE-99 BDE-209 and total PBDEs (SCISTW: 71.6 +/- 15.8, 84.7 +/- 12.3, 96.0 +/- 2.62 and 87.4 +/- 8.02%, respectively; STSTW: 74.8 +/- 9.5, 90.7 +/- 9.14, 96.2 +/- 2.41 and 89.3 +/- 2.62%, respectively) and PBDEs were chiefly removed by sorption. However, the profile of PBDEs demonstrated that the relative proportions of BDE-28 and BDE-47 in total PBDEs markedly increased, while that of BDE-209 decreased in the effluent samples of the two sewage treatment works, especially in STSTW. The percentage of BDE-209 in total PBDEs in effluent (49.3%) of SCISTW was 21.2% lower than that in influent (70.5%), and the percentage of BDE-209 in total PBDEs in effluent (13.8%) of STSTW was 34.1% reduced from influent (47.9%). Despite overall removal, the percentage of BDE-47 in total PBDEs in effluent (17.6%) of SCISTW was 6.85% higher than that in influent (10.7%), and the percentage of BDE 47 in total PBDEs in effluent (33.5%) of STSTW was 18.1% increased from influent (16.8%). The increase in proportion of BDE-47 in the effluent might raise environmental and public health concerns. Our study is a first attempt in reporting the PBDE congener profiles in different phases of sewage treatment. PMID- 25461028 TI - An integrated environmental risk assessment and management framework for enhancing the sustainability of marine protected areas: the Cape d'Aguilar Marine Reserve case study in Hong Kong. AB - Marine protected areas (MPAs), such as marine parks and reserves, contain natural resources of immense value to the environment and mankind. Since MPAs may be situated in close proximity to urbanized areas and influenced by anthropogenic activities (e.g. continuous discharges of contaminated waters), the marine organisms contained in such waters are probably at risk. This study aimed at developing an integrated environmental risk assessment and management (IERAM) framework for enhancing the sustainability of such MPAs. The IERAM framework integrates conventional environmental risk assessment methods with a multi-layer DPSIR (Driver-Pressure-State-Impact-Response) conceptual approach, which can simplify the complex issues embraced by environmental management strategies and provide logical and concise management information. The IERAM process can generate a useful database, offer timely update on the status of MPAs, and assist in the prioritization of management options. We use the Cape d'Aguilar Marine Reserve in Hong Kong as an example to illustrate the IERAM framework. A comprehensive set of indicators were selected, aggregated and analyzed using this framework. Effects of management practices and programs were also assessed by comparing the temporal distributions of these indicators over a certain timeframe. Based on the obtained results, we have identified the most significant components for safeguarding the integrity of the marine reserve, and indicated the existing information gaps concerned with the management of the reserve. Apart from assessing the MPA's present condition, a successful implementation of the IERAM framework as evocated here would also facilitate better-informed decision making and, hence, indirectly enhance the protection and conservation of the MPA's marine biodiversity. PMID- 25461029 TI - Ecotoxicity of ketoprofen, diclofenac, atenolol and their photolysis byproducts in zebrafish (Danio rerio). AB - The occurrence of pharmaceutical compounds in wastewater treatment plants and surface waters has been detected worldwide, constituting a potential risk for aquatic ecosystems. Adult zebrafish, of both sexes, were exposed to three common pharmaceutical compounds (atenolol, ketoprofen and diclofenac) and their UV photolysis by-products over seven days. The results show that diclofenac was removed to concentrations=3 consecutive days with daily mean temperatures higher than 32.9 degrees C, 32.3 degrees C and 34.5 degrees C, respectively. Comparative analysis generally supported the definition. CONCLUSIONS: We found extreme high temperatures were associated with increased mortality, after a short lag period, when temperatures exceeded obvious threshold levels. The city-specific definition of heat wave developed in our study may provide guidance for the establishment and implementation of early heat-health response systems for local government to deal with the projected negative health outcomes due to heat waves. PMID- 25461057 TI - Assessment of degradation potential of aliphatic hydrocarbons by autochthonous filamentous fungi from a historically polluted clay soil. AB - The present work was aimed at isolating and identifying the main members of the mycobiota of a clay soil historically contaminated by mid- and long-chain aliphatic hydrocarbons (AH) and to subsequently assess their hydrocarbon degrading ability. All the isolates were Ascomycetes and, among them, the most interesting was Pseudoallescheria sp. 18A, which displayed both the ability to use AH as the sole carbon source and to profusely colonize a wheat straw:poplar wood chip (70:30, w/w) lignocellulosic mixture (LM) selected as the amendment for subsequent soil remediation microcosms. After a 60 d mycoaugmentation with Pseudoallescheria sp. of the aforementioned soil, mixed with the sterile LM (5:1 mass ratio), a 79.7% AH reduction and a significant detoxification, inferred by a drop in mortality of Folsomia candida from 90 to 24%, were observed. However, similar degradation and detoxification outcomes were found in the non-inoculated incubation control soil that had been amended with the sterile LM. This was due to the biostimulation exerted by the amendment on the resident microbiota, fungi in particular, the activity and density of which were low, instead, in the non amended incubation control soil. PMID- 25461058 TI - The interaction of heavy metals and nutrients present in soil and native plants with arbuscular mycorrhizae on the riverside in the Matanza-Riachuelo River Basin (Argentina). AB - This study assessed the contamination by heavy metals (Cr, Cu, Pb, Zn), and nutrients (N, P) in soils and native plants, and the effect of the concentration of those elements with the density of arbuscular-mycorrhizal (AM) spores in soil and colonization in roots from the riverside of the Matanza-Riachuelo River Basin (MRRB). The concentration of metals and nutrients in soils and plants (Eleocharis montana, Cyperus eragrostis, Hydrocotyle bonariensis) increased from the upper sites (8 km from headwaters) to the lower sites (6 km from the mouth of the Riachuelo River) of the basin. AM-colonization on the roots of H. bonariensis and spore density in soil decreased as the concentrations of metals in soil and plant tissues increased from the upper to lower sites of the basin within a consistent gradient of contamination associated with land use, soil disturbance, population, and chemicals discharged into the streams and rivers along the MRRB. The general trends for all metals in plant tissue were to have highest concentrations in roots, then in rhizomes and lowest in aerial biomass. The translocation (TF) and bioconcentration (BCF) factors decreased in plants which grow from the upper sites to the lower sites of the basin. The plants tolerated a wide range in type and quantity of contamination along the basin by concentrating more metals and nutrients in roots than in aboveground tissue. The AM spore density in soil and colonization in roots of H. bonariensis decreased with the increase of the degree of contamination (Dc) in soil. PMID- 25461059 TI - How stressor specific are trait-based ecological indices for ecosystem management? AB - Using macroinvertebrates as ecological indicators for different stressors has a long tradition. However, when applied to field data, one often observes correlations between different macroinvertebrate indices that can be attributed to both correlations of stressors and inherent correlations due to the sensitivity of taxa to different stressors. Ignoring the source of any given correlation leads to ambiguous conclusions about the impact of different stressors. Here, we demonstrate how to distinguish the causes of correlation by means of Monte Carlo simulations. We assessed to which degree trait-based indices are stressor-specific and whether this depends on the pool of taxa and its taxonomic resolution. Therefore, we (1) analysed the frequencies of "sensitive" and "insensitive" taxa for pairwise combinations of different indices, (2) analysed the inherent correlation of indices with random samples from different taxon pools derived from field samples and from a complete species list of a whole ecoregion, and (3) compared this inherent correlation with the actual correlation of the field samples. We exemplified this approach by analysing two existing indices (SPEARpesticides, Saprobic Index) and new indices for temperature, flow and pH stress. We used these new indices to illustrate our approach while in-depth testing of their applicability was not the focus of our study. We found strong correlations between several indices in our study area at the Swiss Plateau. The probability that this correlation is only due to inherent correlation in the taxa sensitivities was low (maximum of 0.34). The problem of inherent correlation between indices is more severe for the smaller taxon pool with lower taxonomic resolution. Correlation in the sensitivity of different taxa to different stressors leads to an inherent correlation in trait-based indices, which weakens their explanatory power. Our results highlight the importance of correlation analyses when using trait-based indices to guide ecosystem management, especially in regions with reduced biodiversity. PMID- 25461060 TI - Landscape analysis of nutrient-enriched margins (lagg) in ombrotrophic peatlands. AB - Scientific knowledge of the wet zone - the lagg - that tends to form at the edge of ombrotrophic peatlands is surprisingly limited. In this study, we aim to improve the understanding of the ecohydrological functions of this transition by describing the form and abiotic controls of the laggs and margins of bog peatlands. Data collected in wells and piezometers along 10 transects (within 6 bogs), of the New Brunswick Eastern Lowlands are used to analyse the hydraulic and hydrochemical gradients, while airborne LiDAR data provides new insight on the geomorphology and the vegetation patterns of the bog-lagg-mineral transition zone. Based on their geomorphic character, the study transects are placed into 2 categories: confined and unconfined. Laggs of confined transition are found in a topographic depression, between the bog and a mineral slope >1%, while laggs of unconfined transitions are adjacent to a flat (<=1%) or receding mineral slope (sloping away from the lagg). Water level (4 +/- 9 cm vs. -3 +/- 9 cm), pH (4.8 +/- 0.9 vs. 4.2 +/- 0.4), electrical conductivity (ECcorr) (105 +/- 52 MUS cm(-1) vs. 52 +/- 28 MUS cm(-1)) and peat depth (55 +/- 9 cm vs. 30 +/- 9 cm) are found to be higher, respectively, for the confined laggs than for the unconfined. Saturated hydraulic conductivity (Ksat) of the lagg's upper peat layer resembles that of bog environments, but quickly reduces with depth, impeding vertical water flow. The greatest abiotic control of the lagg appears to be topography, which affects water flow rates and direction, thus water chemistry, nutrient transport and availability, hence vegetation characteristics. Our results suggest that the features of the transition zone that include the lagg, influence the quantity and variability of water within the adjacent peatland, and should be considered as integral part of the peatland complex. PMID- 25461061 TI - Soil type influences crop mineral composition in Malawi. AB - Food supply and composition data can be combined to estimate micronutrient intakes and deficiency risks among populations. These estimates can be improved by using local crop composition data that can capture environmental influences including soil type. This study aimed to provide spatially resolved crop composition data for Malawi, where information is currently limited. Six hundred and fifty-two plant samples, representing 97 edible food items, were sampled from >150 sites in Malawi between 2011 and 2013. Samples were analysed by ICP-MS for up to 58 elements, including the essential minerals calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), selenium (Se) and zinc (Zn). Maize grain Ca, Cu, Fe, Mg, Se and Zn concentrations were greater from plants grown on calcareous soils than those from the more widespread low-pH soils. Leafy vegetables from calcareous soils had elevated leaf Ca, Cu, Fe and Se concentrations, but lower Zn concentrations. Several foods were found to accumulate high levels of Se, including the leaves of Moringa, a crop not previously been reported in East African food composition data sets. New estimates of national dietary mineral supplies were obtained for non-calcareous and calcareous soils. High risks of Ca (100%), Se (100%) and Zn (57%) dietary deficiencies are likely on non-calcareous soils. Deficiency risks on calcareous soils are high for Ca (97%), but lower for Se (34%) and Zn (31%). Risks of Cu, Fe and Mg deficiencies appear to be low on the basis of dietary supply levels. PMID- 25461062 TI - Freshwater dispersion stability of PAA-stabilised cerium oxide nanoparticles and toxicity towards Pseudokirchneriella subcapitata. AB - An aqueous dispersion of poly (acrylic acid)-stabilised cerium oxide (CeO2) nanoparticles (PAA-CeO2) was evaluated for its stability in a range of freshwater ecotoxicity media (MHRW, TG 201 and M7), with and without natural organic matter (NOM). In a 15 day dispersion stability study, PAA-CeO2 did not undergo significant aggregation in any media type. Zeta potential varied between media types and was influenced by PAA-CeO2 concentration, but remained constant over 15 days. NOM had no influence on PAA-CeO2 aggregation or zeta potential. The ecotoxicity of the PAA-CeO2 dispersion was investigated in 72 h algal growth inhibition tests using the freshwater microalgae Pseudokirchneriella subcapitata. PAA-CeO2 EC50 values for growth inhibition (GI; 0.024 mg/L) were 2-3 orders of magnitude lower than pristine CeO2 EC50 values reported in the literature. The concentration of dissolved cerium (Ce(3+)/Ce(4+)) in PAA-CeO2 exposure suspensions was very low, ranging between 0.5 and 5.6 MUg/L. Free PAA concentration in the exposure solutions (0.0096-0.0384 mg/L) was significantly lower than the EC10 growth inhibition (47.7 mg/L) value of pure PAA, indicating that free PAA did not contribute to the observed toxicity. Elemental analysis indicated that up to 38% of the total Cerium becomes directly associated with the algal cells during the 72 h exposure. TOF-SIMS analysis of algal cell wall compounds indicated three different modes of action, including a significant oxidative stress response to PAA-CeO2 exposure. In contrast to pristine CeO2 nanoparticles, which rapidly aggregate in standard ecotoxicity media, PAA stabilised CeO2 nanoparticles remain dispersed and available to water column species. Interaction of PAA with cell wall components, which could be responsible for the observed biomarker alterations, could not be excluded. This study indicates that the increased dispersion stability of PAA-CeO2 leads to an increase in toxicity compared to pristine non-stabilised forms. PMID- 25461063 TI - Traffic air quality index. AB - Vehicle emissions are responsible for a considerable share of urban air pollution concentrations. The traffic air quality index (TAQI) is proposed as a useful tool for evaluating air quality near roadways. The TAQI associates air quality with the equivalent emission from traffic sources and with street structure (roadway structure) as anthropogenic factors. The paper presents a method of determining the TAQI and defines the degrees of harmfulness of emitted pollution. It proposes a classification specifying a potential threat to human health based on the TAQI value and shows an example of calculating the TAQI value for real urban streets. It also considers the role that car traffic plays in creating a local UHI. PMID- 25461064 TI - Fate of selected pharmaceutically active compounds during simulated riverbank filtration. AB - The objective of this study was to investigate the effect of temperature, oxygen, and organic matter on the removal of selected pharmaceutically active compounds (PhACs) during simulated riverbank filtration (RBF). The behavior of six PhACs (caffeine, carbamazepine, 17-beta estradiol [E2], estrone [E1], gemfibrozil, and phenazone) was evaluated by small flow-through column experiments. Results from our study showed that RBF can be used to treat many of the PhACs found in environmental waters. Local conditions at the RBF site, however, can affect the removal of PhACs and should be investigated. Biodegradation and sorption represented the predominant mechanisms involved during the removal of the selected PhACs. All selected PhACs showed limited and slower removal during the winter. Phenazone was highly impacted by the level of oxygen; complete depletion of phenazone below the analytical limit occurred only under aerobic conditions (dissolved oxygen >8 mg L(-1)). Caffeine and E2 were highly impacted by the presence of humic acid in the feed water. Caffeine and E2 were depleted below the detection limit in the presence of humic acid regardless of the temperature and the level of oxygen. E1 was impacted by the different environmental conditions and depletion below the detection limit occurred only during the summer under aerobic conditions. Carbamazepine (10%) and gemfibrozil (<30%) showed limited removal regardless of the different levels of temperature, oxygen and humic acid. PMID- 25461066 TI - Bacterial community variation and microbial mechanism of triclosan (TCS) removal by constructed wetlands with different types of plants. AB - Triclosan (TCS) is a broad-spectrum synthetic antimicrobial agent that is toxic to microbes and other aquatic organisms. Constructed wetlands (CWs) are now popular in TCS removal. However, knowledge on the effects of TCS on the bacterial community and microbial removal mechanism in CWs is lacking. The effects of TCS (60 MUg L(-1)) on bacterial communities in batch-loaded CWs with emergent (Typha angustifolia), submerged (Hydrilla verticillata), and floating plant (Salvinia natans) were analyzed by 454 pyrosequencing technology. After six periods of experiment, the TCS removal efficiencies were over 90% in CWs, and negative effects of TCS on bacterial community richness and diversity were observed. Moreover, plant species effect existed. Bacterial strains that contributed to TCS biodegradation in CWs were successfully identified. In TCS-treated T. angustifolia and H. verticillata CWs, beta-Proteobacteria increased by 16.63% and 18.20%, respectively. In TCS-treated S. natans CWs, delta- and gamma Proteobacteria and Sphingobacteria increased by 9.36%, 19.49%, and 31.37%, respectively, and could relate to TCS biodegradation. TCS affected the development of certain bacteria, and eventually, the bacterial community structures in CWs. This research provided ecologically relevant information on bacterial community and microbial removal mechanism in CWs under TCS treatment. PMID- 25461065 TI - Study on polychlorobiphenyl serum levels in French consumers of freshwater fish. AB - INTRODUCTION: Polychlorobiphenyls (PCBs) are persistent pollutants that are widespread in the environment and in foodstuffs, particularly in freshwater fish, which frequently exceed the maximum levels set by European regulations. OBJECTIVES: First, we describe the consumption of freshwater fish and serum PCB levels in French anglers, a population expected to have the highest level of dietary PCB exposure. Second, we investigated whether there is a statistical relationship between serum PCB levels and the angler consumption of freshwater fish with high PCB bioaccumulation potential (PCB-BP(+) freshwater fish) in order to make recommendations with regard to safe consumption of freshwater fish. METHODS: We conducted a survey of anglers from six sites with contrasting PCB contamination levels. The survey included a food consumption frequency questionnaire and blood samples were taken to assess serum PCB levels. We used a regression model to determine the main factors contributing to serum PCB levels. RESULTS: Consumption of PCB-BP(+) freshwater fish was relatively infrequent. Serum PCB levels of the study population and of women of childbearing age were in the same range as those observed in the French population and in neighbouring European countries, but higher than in the North American population. The two factors with the highest positive association with serum PCB levels were age (R(2)=61%) and the consumption of PCB-BP(+) freshwater fish (R(2)=2%). Using the regression model, we calculated, for several scenarios depending on the age and gender of the population, the maximum annual frequencies for PCB-BP(+) freshwater fish consumption that do not exceed the critical body burden threshold. CONCLUSION: Following the results of this study, the French agency for food, environmental and occupational health and safety (ANSES) issued an opinion and recommended some specific maximum freshwater fish consumption frequencies to protect the French general population. PMID- 25461067 TI - Impact of forest biomass residues to the energy supply chain on regional air quality. AB - The increase of the share of renewable energy in Portugal can be met from different sources, of which forest biomass residues (FBR) can play a main role. Taking into account the demand for information about the strategy of FBR to energy, and its implications on the Portuguese climate policy, the impact of energy conversion of FBR on air quality is evaluated. Three emission scenarios were defined and a numerical air quality model was selected to perform this evaluation. The results reveal that the biomass thermal plants contribute to an increment of the pollutant concentrations in the atmosphere, however restricted to the surrounding areas of the thermal plants, and most significant for NO2 and O3. PMID- 25461068 TI - Responses of soil ammonia-oxidizing microorganisms to repeated exposure of single walled and multi-walled carbon nanotubes. AB - The impacts of carbon nanotubes (CNTs) including single-walled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs) on soil microbial biomass and microbial community composition (especially on ammonium oxidizing microorganisms) have been evaluated. The first exposure of CNTs lowered the microbial biomass immediately, but the values recovered to the level of the control at the end of the experiment despite the repeated addition of CNTs. The abundance and diversity of ammonium-oxidizing archaea (AOA) were higher than that of ammonium-oxidizing bacteria (AOB) under the exposure of CNTs. The addition of CNTs decreased Shannon Wiener diversity index of AOB and AOA. Two-way ANOVA analysis showed that CNTs had significant effects on the abundance and diversity of AOB and AOA. Dominant terminal restriction fragments (TRFs) of AOB exhibited a positive relationship with NH4(+), while AOA was on the contrary. It implied that AOB prefer for high NH4(+) soils whereas AOA is favored in low NH4(+) soils in the CNT-contaminated soil. PMID- 25461069 TI - Low frequency noise impact from road traffic according to different noise prediction methods. AB - The European Noise Directive 2002/49/EC requires to draw up noise action plans. Most of the implemented solutions consist in using barriers, even if some studies evidenced that annoyance could increase after their installation. This action dumps the high frequencies, decreasing the masking effect on low ones. Therefore, people annoyance and complaints may increase despite the mitigation. This can happen even in pedestrian zones near main roads due to the screening effect of first buildings row. In this paper, the authors analyze the post-operam screening effects in terms of low frequency noise. The difference between C- and A-weighted levels is calculated as annoyance indicator (LC-A). Different methods able to map noise with octave bands detail are tested in order to establish differences in the estimates of annoyance exposure. In particular, a comparison is carried out between data from interim method NMPB 96, its updated version 2008, NORD 2000 and those provided by a customized procedure through ISO 9613 propagation and Statistical Pass By measurements. Test sites are simulated in order to validate each model results through measurements. Results are discussed for real locations in Pisa city center and virtual scenarios in a rising scale of complexity. PMID- 25461070 TI - Volatilisation of pesticides after application in vegetable greenhouses. AB - BACKGROUND: Volatilisation of pesticides after application to the soil or the crop is an important source of emission into the atmosphere. As a result, workers, residents and bystanders are potentially at risk when exposed to these volatilised substances. Nonetheless, data on measured concentrations are quite scarce, especially in greenhouses. The objective of this work is to present the results of volatilisation experiments performed in greenhouses. RESULTS: The results indicate that the concentrations are highest in the hours after application and rapidly decline during the days following application. CONCLUSION: Greenhouse temperature, ventilation rate, the substance vapour pressure and the rate of competing processes were identified as important factors influencing volatilisation in greenhouses. The results from this study contribute to a better understanding of volatilisation in greenhouses and may help to improve the recent PEARL model for volatilisation in greenhouses. PMID- 25461071 TI - A general procedure to generate models for urban environmental-noise pollution using feature selection and machine learning methods. AB - The prediction of environmental noise in urban environments requires the solution of a complex and non-linear problem, since there are complex relationships among the multitude of variables involved in the characterization and modelling of environmental noise and environmental-noise magnitudes. Moreover, the inclusion of the great spatial heterogeneity characteristic of urban environments seems to be essential in order to achieve an accurate environmental-noise prediction in cities. This problem is addressed in this paper, where a procedure based on feature-selection techniques and machine-learning regression methods is proposed and applied to this environmental problem. Three machine-learning regression methods, which are considered very robust in solving non-linear problems, are used to estimate the energy-equivalent sound-pressure level descriptor (LAeq). These three methods are: (i) multilayer perceptron (MLP), (ii) sequential minimal optimisation (SMO), and (iii) Gaussian processes for regression (GPR). In addition, because of the high number of input variables involved in environmental noise modelling and estimation in urban environments, which make LAeq prediction models quite complex and costly in terms of time and resources for application to real situations, three different techniques are used to approach feature selection or data reduction. The feature-selection techniques used are: (i) correlation-based feature-subset selection (CFS), (ii) wrapper for feature-subset selection (WFS), and the data reduction technique is principal-component analysis (PCA). The subsequent analysis leads to a proposal of different schemes, depending on the needs regarding data collection and accuracy. The use of WFS as the feature-selection technique with the implementation of SMO or GPR as regression algorithm provides the best LAeq estimation (R(2)=0.94 and mean absolute error (MAE)=1.14-1.16 dB(A)). PMID- 25461073 TI - tet genes as indicators of changes in the water environment: relationships between culture-dependent and culture-independent approaches. AB - The aim of this study was to identify tetracycline resistance determinants that could be used as molecular indicators of anthropogenic changes in aquatic environments. Two parallel approaches were used to examine the prevalence of tet genes: a culture-based method involving standard PCR and a method relying on quantitative PCR. The studied site was the Lyna River in Olsztyn (Poland). The culture-dependent method revealed that the concentrations of doxycycline resistant bacteria harboring the tet(B) gene were higher in wastewater and downstream river samples than in upstream water samples. The tet(B) gene was transferred from environmental bacteria to Escherichia coli. The results generated by the culture-independent method validated statistically significant differences in tet(B) concentrations between upstream and downstream river sections, and revealed that tet(B) levels were correlated with the presence of other tetracycline resistance genes, dissolved oxygen concentrations, temperature and doxycycline concentrations in water. Our findings indicate that doxycycline resistant bacteria, in particular E. coli harboring tet(B) or increased concentrations of tet(B), are potentially robust indicators of changes in water environments. PMID- 25461072 TI - Determination of parent and hydroxy PAHs in personal PM2.5 and urine samples collected during Native American fish smoking activities. AB - A method was developed for the measurement of 19 parent PAHs (PAHs) and 34 hydroxylated PAHs (OH-PAHs) in urine and personal air samples of particulate matter less than 2.5 MUm in diameter (PM2.5) using GC-MS and validated using NIST SRM 3672 (Organic Contaminants in Smoker's Urine) and SRM 3673 (Organic Contaminants in Nonsmoker's Urine). The method was used to measure PAHs and OH PAHs in urine and personal PM2.5 samples collected from the operators of two different fish smoking facilities (tipi and smoke shed) burning two different wood types (alder and apple) on the Confederated Tribes of Umatilla Indian Reservation (CTUIR) while they smoked salmon. Urine samples were spiked with beta glucuronidase/arylsulfatase to hydrolyze the conjugates of OH-PAHs and the PAHs and OH-PAHs were extracted using Plexa and C18 solid phases, in series. The 34 OH PAHs were derivatized using MTBSTFA, and the mixture was measured by GC-MS. The personal PM2.5 samples were extracted using pressurized liquid extraction, derivatized with MTBSTFA and analyzed by GC-MS for PAHs and OH-PAHs. Fourteen isotopically labeled surrogates were added to accurately quantify PAHs and OH PAHs in the urine and PM2.5 samples and three isotopically labeled internal standards were used to calculate the recovery of the surrogates. Estimated detection limits in urine ranged from 6.0 to 181 pg/ml for OH-PAHs and from 3.0 to 90 pg/ml for PAHs, and, in PM2.5, they ranged from 5.2 to 155 pg/m(3) for OH PAHs and from 2.5 to 77 pg/m(3) for PAHs. The results showed an increase in OH PAH concentrations in urine after 6h of fish smoking and an increase in PAH concentrations in air within each smoking facility. In general, the PAH exposure in the smoke shed was higher than in the tipi and the PAH exposure from burning apple wood was higher than burning alder. PMID- 25461075 TI - Importance of soil and vineyard management in the determination of grapevine mineral composition. AB - The spatial variability of the mineral composition of grapevines in production vineyards along the east Adriatic coast was determined and compared between conventional and sustainable vineyard management. Cluster analysis shows a high level of spatial variability even within the individual locations. Factor analysis reveals three factors with strong loading for the macronutrients K and P and the micronutrient Mn, which explain 67% of the total variance in the mineral composition. Here, 26% to 34% of the variance of these three elements can be explained by abiotic and biotic soil parameters, with soil concentrations of K, Fe and Cu, organic matter content, and vesicular colonisation showing the strongest effects on the mineral composition of the grapevines. In addition, analysis of the mineral composition data shows significant differences between differently managed vineyards, with increased bioaccumulation of P and K in sustainable vineyards, while Zn bioaccumulation was increased in conventional vineyards. Our data confirm the importance of soil and vineyard management in the concept of terroir, and demonstrate the effects of sustainable management practices on the mineral nutrition of grapevines that result from modified nutrient availability related to changes in the abiotic and biotic characteristics of the soil. PMID- 25461074 TI - Ecological and human health hazards of heavy metals and polycyclic aromatic hydrocarbons (PAHs) in road dust of Isfahan metropolis, Iran. AB - This study investigates trace elements and PAHs content in road dust of Isfahan metropolis, central Iran. The mean concentrations of As, Cd, Cu, Ni, Pb, Sb and Zn are 22.15, 2.14, 182.26, 66.63, 393.33, 6.95 and 707.19 mg kg(-1), respectively. When compared with upper continental crust, the samples generally display elevated trace element concentrations, except for Co and Cr. The decreasing trend of calculated enrichment factors (EFs) is Cd>Pb>Sb>Zn>Cu>As>Ni>Cr>Co. Calculated potential ecological risk reveals that among the analyzed metals, Cd and Pb, have a higher potential ecological risk. Statistically, two identified main sources of trace elements include road traffic emissions and resuspension of soil particles. As, Cd, Cu, Pb, Sb and Zn in Isfahan road dust are strongly influenced by anthropogenic activity, mainly traffic emissions, while Co, Cr and Ni originate from resuspension of soil natural parent particles. The sum of 13 major PAHs (?13PAHs) mass concentration ranges from 184.64 to 3221.72 MUg kg(-1) with the mean being 1074.58 MUg kg(-1). PAHs sources are identified using PCA analysis. It is demonstrated that the PAHs in Isfahan road dust are mainly derived from traffic emission, coal combustion and petroleum. Toxic equivalent concentrations (TEQs) of PAHs in the road dust ranges between 25.021 MUg kg(-1) and 230.893 MUg kg(-1). High correlation coefficients (r(2)=0.909 and 0.822, p<0.01) between Benzo[a]pyrene, Benzo[b+k]fluoranthene and toxicity equivalent concentrations of road dust indicate that Benzo[a]pyrene and Benzo[b+k]fluoranthenes are major TEQ contributors. The total incremental life time cancer risk (ILCR) of exposure to PAHs from Isfahan metropolis urban dust is 4.85 * 10(-4) for adult and 5.02 * 10( 4) for children. Estimated results of ILCR indicate that Isfahan residents are potentially exposed to high cancer risk via both dust ingestion and dermal contact. PMID- 25461076 TI - Integrating ecosystem services into risk management decisions: case study with Spanish citrus and the insecticide chlorpyrifos. AB - The European regulatory system for the approval of pesticides includes a thorough evaluation of risks to the environment and is designed to be protective of ecosystems. However, a decision to ban an agrochemical could also potentially have a negative impact on the value of ecosystem services, if resulting changes in crop management are damaging to ecosystems or result in negative socio economic impacts. To support regulatory decision-making, consideration of ecosystem services to identify best environmental management options could be a way forward. There is generally a growing trend for the consideration of ecosystem services in decision making. Ecosystems provide the conditions for growing food, regulate water and provide wildlife habitats; these, amongst others, are known as ecosystem services. The objectives of this case study were to bring a holistic approach to decision making by valuing the environmental, social and economic benefits derived from the use of chlorpyrifos in Valencian citrus production. Spanish growers harvest between 5 and 6 milliont of citrus annually, worth an estimated ?5 to 7 billion in food markets throughout Europe. The approach highlighted the potential for unintended negative consequences of regulatory decisions if the full context is not considered. In this study, rather than a regulatory restriction, the best option was the continued use of chlorpyrifos together with vegetated conservation patches as refuges for non target insects. The conservation patches offset potential insecticidal impacts to insects whilst maintaining citrus production, farm income and the amenity value of the citrus landscape of Valencia. This was an initial proof-of-concept study and illustrates the importance of a wider perspective; other cases may have different outcomes depending on policies, the pesticide, crop scenarios, farm economics and the region. PMID- 25461077 TI - Calluna vulgaris-dominated upland heathland sequesters more CO2 annually than grass-dominated upland heathland. AB - It has been shown in many habitats worldwide, that a shift in vegetation composition between woody shrub and graminoid dominance can influence carbon (C) cycling. Due to land management practices and environmental change, UK upland heath vegetation has historically undergone shifts in dominance from the woody dwarf shrub Calluna vulgaris (Calluna) to species poor graminoid swards. The consequences of this for C sequestration are unknown. We compared annual net ecosystem exchange (NEE) of carbon dioxide (CO2) between building phase Calluna- and grass-dominated communities within three upland heaths in Scotland, measuring c. monthly over a year. Light and temperature response curves were generated, and the parameters derived were applied to continuous light and temperature data to extrapolate CO2 fluxes over the full year and generate estimates of annual CO2 sequestration for each vegetation type. Grass-dominated communities had higher ecosystem respiration rates than Calluna-dominated communities, attributed to graminoids having greater metabolic demands and producing more labile litter which decomposes readily. Both communities had similar gross primary productivity over the year; the net result being higher NEE within the Calluna-dominated than the grass-dominated community (-2.36 +/- 0.23 and -1.78 +/- 0.18 MUmol CO2m(-2)s( 1) respectively). Modelled CO2 fluxes over a year showed both communities to be CO2 sinks. The Calluna-dominated community sequesters -3.45 +/- 0.96 t C ha( 1)yr(-1), double that sequestered by the grass-dominated community at 1.61 +/- 0.57 t C ha(-1)yr(-1). Potential rate of C sequestration by upland heath is comparable to that of woodland and the increase in total sequestration that could be gained from habitat restoration may equate to c. 60% of the annual UK C sink attributed to forest land management. National C sequestration by heathlands is also more than double that by peatlands. Management of graminoid-dominated upland heath should promote Calluna re-establishment, thus providing a C benefit in addition to benefits to biodiversity, grazing and sporting interests. PMID- 25461078 TI - Snow cover trend and hydrological characteristics of the Astore River basin (Western Himalayas) and its comparison to the Hunza basin (Karakoram region). AB - A large proportion of Pakistan's irrigation water supply is taken from the Upper Indus River Basin (UIB) in the Himalaya-Karakoram-Hindukush range. More than half of the annual flow in the UIB is contributed by five of its snow and glacier-fed sub-basins including the Astore (Western Himalaya - south latitude of the UIB) and Hunza (Central Karakoram - north latitude of the UIB) River basins. Studying the snow cover, its spatio-temporal change and the hydrological response of these sub-basins is important so as to better manage water resources. This paper compares new data from the Astore River basin (mean catchment elevation, 4100 m above sea level; m asl afterwards), obtained using MODIS satellite snow cover images, with data from a previously-studied high-altitude basin, the Hunza (mean catchment elevation, 4650 m asl). The hydrological regime of this sub-catchment was analyzed using the hydrological and climate data available at different altitudes from the basin area. The results suggest that the UIB is a region undergoing a stable or slightly increasing trend of snow cover in the southern (Western Himalayas) and northern (Central Karakoram) parts. Discharge from the UIB is a combination of snow and glacier melt with rainfall-runoff at southern part, but snow and glacier melt are dominant at the northern part of the catchment. Similar snow cover trends (stable or slightly increasing) but different river flow trends (increasing in Astore and decreasing in Hunza) suggest a sub-catchment level study of the UIB to understand thoroughly its hydrological behavior for better flood forecasting and water resources management. PMID- 25461079 TI - Condition of in situ unexploded ordnance. AB - Unexploded ordnance (UXO) become point contamination sources when their casings fail and their explosive fill dissolve. To determine the modes of failure, we documented the condition of UXO found on military training ranges and sampled soils for explosives beneath 42 in situ UXO. We found that oxidation caused the metal UXO casings to swell and fail catastrophically. Unlike previous work, pitting of the metal casings was not found to be an important release route for explosives. Of the 42 UXO sampled, eight were leaking explosives into the soil and of these, four had perforated or cracked casings, three were corroded and one was a partially detonated round. We estimated a surface density of 74 UXO per hectare for a subset of UXO sampled. We used the relative concentrations of explosives and their transformation products in the soil to determine if the explosives had recently dissolved or were from past military training. PMID- 25461080 TI - Development of a road transport emission inventory for Greece and the Greater Athens Area: effects of important parameters. AB - Traffic is considered one of the major polluting sectors and as a consequence a significant cause for the measured exceedances of ambient air quality limit values mainly in urban areas. The Greater Athens Area (located in Attica), the most populated area in Greece, faces severe air pollution problems due to the combination of high road traffic emissions, complex topography and local meteorological conditions. Even though several efforts were made to construct traffic emission inventories for Greece and Attica, still there is not a spatially and temporally resolved one, based on data from relevant authorities and organisations. The present work aims to estimate road emissions in Greece and Attica based on the top down approach. The programme COPERT 4 was used to calculate the annual total emissions from the road transport sector for the period 2006-2010 and an emission inventory for Greece and Attica was developed with high spatial (6 * 6 km(2) for Greece and 2 * 2 km(2) for Attica) and temporal (1-hour) resolutions. The results revealed that about 40% of national CO2, CO, VOC and NMVOC values and 30% of NOx and particles are emitted in Attica. The fuel consumption and the subsequent reduction of annual mileage driven in combination with the import of new engine anti-pollution technologies affected CO2, CO, VOC and NMVOC emissions. The major part of CO (56.53%) and CO2 (66.15%) emissions was due to passenger cars (2010), while heavy duty vehicles (HDVs) were connected with NOx, PM2.5 and PM10 emissions with 51.27%, 43.97% and 38.13% respectively (2010). The fleet composition, the penetration of diesel fuelled cars, the increase of urban average speed and the fleet renewal are among the most effective parameters towards the emission reduction strategies. PMID- 25461081 TI - Mechanism and kinetic properties for the OH-initiated atmospheric oxidation degradation of 9,10-Dichlorophenanthrene. AB - Chlorinated polycyclic aromatic hydrocarbons (ClPAHs) have become a serious environmental concern due to their widespread occurrence and dioxin-like toxicities. In this work, the mechanism of the OH-initiated atmospheric oxidation degradation of 9,10-dichlorophenanthrene (9,10-Cl2Phe) was investigated by using high-accuracy quantum chemistry calculations. The rate constants of the crucial elementary reactions were determined by the Rice-Ramsperger-Kassel-Marcus (RRKM) theory. The theoretical results were compared with the available experimental data. The main oxidation products are a group of ring-retaining and ring-opening compounds including chlorophenanthrols, 9,10-dichlorophenanthrene-3,4-dione, dialdehydes, chlorophenanthrenequinones, nitro-9,10-Cl2Phe and epoxides et al. The overall rate constant of the OH addition reaction is 2.35 * 10(-12)cm(3) molecule(-1)s(-1) at 298 K and 1 atm. The atmospheric lifetime of 9,10-Cl2Phe determined by OH radicals is about 5.05 days. This study provides a comprehensive investigation of the OH-initiated oxidation degradation of 9,10-Cl2Phe and should contribute to clarifying its atmospheric fate. PMID- 25461082 TI - Characteristics of current roadside pollution using test-monitoring plots. AB - The aim of the study was the qualitative recognition of the existing roadside pollutants deposited in topsoils located close to roads with high traffic volume. So far, the studies have helped to determine the content of pollutants that accumulated over a long period of time. Traditionally, it has been difficult to distinguish between roadside pollution and pollution from other industrial sources. In order to avoid such problems and to accurately recognize present threats originating from road traffic, test-monitoring plots were installed in Poland (Gliwice and Opole), Germany (Tubingen, Ulm and Boblingen), Finland (Helsinki), Tajikistan (Dushanbe) and China (Lanzhou). To install the monitoring plots, the upper 7 cm of topsoil was removed and replaced with boxes filled with clean quartz sand. The sand, with a known chemical composition and neutral magnetic (diamagnetic) properties, was considered as a neutral matrix for the accumulation of traffic pollutants. Within 24 months of exposure, both the magnetic susceptibility values and heavy metal content increased, but with highly diverse differences. The highest values were observed in Germany, Tajikistan and China. Correlation coefficients between the magnetic susceptibility values and investigated elements, as well as PAHs indicate that magnetic susceptibility is a geophysical parameter that can be used, under defined conditions, as an indicator of soil pollution caused by traffic emissions. PMID- 25461083 TI - Arbuscular mycorrhizal fungi communities in a coral cay system (Morrocoy, Venezuela) and their relationships with environmental variables. AB - Knowledge of the natural diversity of arbuscular mycorrhizal fungi (AMF) and understanding of their biogeographical patterns and what drive them might help to the maintenance and preservation of ecosystems under a changing environment. The objective of this study was to evaluate the contribution of different environmental factors to the determination of the composition of AMF assemblages in representative sites within the Morrocoy National Park (Venezuela). The community structure of the AMF under the canopy of Coccoloba uvifera was investigated in four cays (Borracho, Muerto, Peraza, and Paiclas) and one mainland location (Las Luisas). Based on partial sequences of the nuclear small subunit ribosomal DNA gene, the AM fungi in soil samples were divided into 31 operational taxonomic units, grouped in eight families. The canonical correspondence analysis showed that environmental factors related to insularity (the mean annual rainfall, the distance to the mainland coast, and the cay land area) and a soil property related to biological activity (the total carbohydrate content) were significantly related to the distribution of the AMF communities. PMID- 25461084 TI - Occurrence, gas/particle partitioning and carcinogenic risk of polycyclic aromatic hydrocarbons and their oxygen and nitrogen containing derivatives in Xi'an, central China. AB - 29 parent- and alkyl-polycyclic aromatic hydrocarbons (PAHs), 15 oxygenated-PAHs (OPAHs), 11 nitrated-PAHs (NPAHs) and 4 azaarenes (AZAs) in both the gaseous and particulate phases, as well as the particulate-bound carbon fractions (organic carbon, elemental carbon, char, and soot) in ambient air sampled in March and September 2012 from an urban site in Xi'an, central China were extracted and analyzed. The average concentrations (gaseous+particulate) of ?29PAHs, ?15OPAHs, ?11NPAHs and ?4AZAs were 1267.0 +/- 307.5, 113.8 +/- 46.1, 11.8 +/- 4.8 and 26.5 +/- 11.8 ng m(-3) in March and 784.7 +/- 165.1, 67.2 +/- 9.8, 9.0 +/- 1.5 and 21.6 +/- 5.1 ng m(-3) in September, respectively. Concentrations of ?29PAHs, ?15OPAHs and ?11NPAHs in particulates were significantly correlated with those of the carbon fractions (OC, EC, char and soot). Both absorption into organic matter in particles and adsorption onto the surface of particles were important for PAHs and OPAHs in both sampling periods, with more absorption occurring in September, while absorption was always the most important process for NPAHs. The total carcinogenic risk of PAHs plus the NPAHs was higher in March. Gaseous compounds, which were not considered in most previous studies, contributed 29 to 44% of the total health risk in March and September, respectively. PMID- 25461085 TI - Managing stakeholders' conflicts for water reallocation from agriculture to industry in the Heihe River Basin in Northwest China. AB - Along with the accelerating process of industrialization and urbanization, water reallocation from agriculture to industry will be an inevitable trend in most developing countries. In the inland river basin, inter-sectoral water transfer is likely to result in reallocation of water resources between upstream and downstream regions, and further triggers frictions and conflicts between regions. Designing effective policy measures to coordinate these conflicts among stakeholders is crucial for the successful implementation of water reallocation. This study established a participatory multi-attribute decision support model to seek a widely acceptable water allocation alternative in the Heihe River Basin, an arid region in Northwest China. The results indicate that: (1) intense conflicts arise not only among stakeholder groups but also between upstream and downstream regions in the process of water reallocation from agriculture to industry; (2) among the options which respectively emphasize on equity, efficiency, and sustainability, the combination of equity and efficiency is the least controversial alternative for the majority of stakeholder groups, although it is not the most desirable one in the performance of all sub-objectives; (3) the multi-attribute value theory (MAVT) approach is a useful technique to elicit stakeholder values and to evaluate water reallocation options. The technique can improve the transparency and credibility of decision making in the water management process. PMID- 25461086 TI - Life cycle assessment of gasoline production and use in Chile. AB - Gasoline is the second most consumed fuel in Chile, accounting for 34% of the total fuel consumption in transportation related activities in 2012. Chilean refineries process more than 97% of the total gasoline commercialized in the national market. When it comes to evaluating the environmental profile of a Chilean process or product, the analysis should consider the characteristics of the Chilean scenario for fuel production and use. Therefore, the identification of the environmental impacts of gasoline production turns to be very relevant for the determination of the associated environmental impacts. For this purpose, Life Cycle Assessment has been selected as a useful methodology to assess the ecological burdens derived from fuel-based systems. In this case study, five subsystems were considered under a "well-to-wheel" analysis: crude oil extraction, gasoline importation, refinery, gasoline storage and distribution/use. The distance of 1 km driven by a middle size passenger car was chosen as functional unit. Moreover, volume, economic and energy-based allocations were also considered in a further sensitivity analysis. According to the results, the main hotspots were the refining activities as well as the tailpipe emissions from car use. When detailing by impact category, climate change was mainly affected by the combustion emissions derived from the gasoline use and refining activities. Refinery was also remarkable in toxicity related categories due to heavy metals emissions. In ozone layer and mineral depletion, transport activities played an important role. Refinery was also predominant in photochemical oxidation and water depletion. In terms of terrestrial acidification and marine eutrophication, the combustion emissions from gasoline use accounted for large contributions. This study provides real inventory data for the Chilean case study and the environmental results give insight into their influence of the assessment of products and processes in the country. Moreover, they could be compared with production and distribution schemes in other regions. PMID- 25461087 TI - Is phytoremediation without biomass valorization sustainable? - comparative LCA of landfilling vs. anaerobic co-digestion. AB - This study examines the sustainability of phytoremediation for soils contaminated with heavy metals, especially the influence of management of the produced metal enriched biomass on the environmental performance of the complete system. We examine a case study in Asturias (north of Spain), where the land was polluted with Pb by diffuse emissions from an adjacent steelmaking factory. A Phytoremediation scenario based on this case was assessed by performing a comparative life cycle assessment and by applying the multi-impact assessment method ReCiPe. Our Baseline scenario used the produced biomass as feedstock for an anaerobic digester that produces biogas, which is later upgraded cryogenically. The Baseline scenario was compared with two alternative scenarios: one considers depositing the produced biomass into landfill, and the other considers excavating the contaminated soil, disposing it in a landfill, and refilling the site with pristine soil. A sensitivity analysis was performed using different yields of biomass and biogas, and using different distances between site and biomass valorization/disposal center. Our results show that the impacts caused during agricultural activities and biomass valorization were compensated by the production of synthetic natural gas and the avoided impact of natural gas production. In addition, it was found that if the produced biomass was not valorized, the sustainability of phytoremediation is questionable. The distance between the site and the biomass processing center is not a major factor for determining the technology's sustainability, providing distances are less than 200-300 km. However, distance to landfill or to the source of pristine soil is a key factor when deciding to use phytoremediation or other ex-situ conventional remediation techniques. PMID- 25461088 TI - Forest floor lead, copper and zinc concentrations across the northeastern United States: synthesizing spatial and temporal responses. AB - Understanding how metal concentrations in soil have responded to reductions of anthropogenic emissions is essential for predicting potential ecosystem impacts and evaluating the effectiveness of pollution control legislation. The objectives of this study were to present new data and synthesize existing literature to document decreases in Pb, Cu, and Zn concentrations in forest soils across the northeastern US. From measurements at 16 sites, we observed that forest floor Pb, Cu, and Zn concentrations have decreased between 1980 and 2011 at an overall mean rate of 1.3 +/- 0.5% yr(-1). E-folding times, a concentration exponential decay rate (1/k), for Pb, Cu and Zn at the 16 sites were estimated to be 46 +/- 7, 76 +/- 20 and 81 +/- 19 yr, respectively. Mineral soil concentrations were correlated with forest floor concentrations for Pb, but not for Cu and Zn, suggesting an accumulation in one pool does not strongly influence accumulation in the other. Forest floor Pb, Cu and Zn concentrations from our sites and 17 other studies conducted from 1970-2014 in remote forests across the northeastern US were compiled into pooled data sets. Significant decreasing trends existed for pooled forest floor Pb, Cu, and Zn concentrations. The pooled forest floor Pb e folding time was determined to be 33 +/- 9 yrs, but the explanatory power of pooled Cu and Zn regressions were inadequate for calculating e-folding times (r(2)<0.25). Pooled Pb, Cu, and Zn concentrations in forest floor were multiple regressed with latitude, longitude, elevation, and year of sampling, cumulatively explaining 55, 38, and 28% of the variation across compiled studies. Our study suggests anthropogenic Pb in the forest floor will continue to decrease, but decreases in forest floor Cu and Zn concentrations may be masked by spatial heterogeneity or are at a new steady state. PMID- 25461089 TI - Spatiotemporal analysis of olive flowering using geostatistical techniques. AB - Analysis of flowering patterns in the olive (Olea europaea L.) are of considerable agricultural and ecological interest, and also provide valuable information for allergy-sufferers, enabling identification of the major sources of airborne pollen at any given moment by interpreting the aerobiological data recorded in pollen traps. The present spatiotemporal analysis of olive flowering in central Spain combined geostatistical techniques with the application of a Geographic Information Systems, and compared results for flowering intensity with airborne pollen records. The results were used to obtain continuous phenological maps which determined the pattern of the succession of the olive flowering. The results show also that, although the highest airborne olive-pollen counts were recorded during the greatest flowering intensity of the groves closest to the pollen trap, the counts recorded at the start of the pollen season were not linked to local olive groves, which had not yet begin to flower. To detect the remote sources of olive pollen several episodes of pollen recorded before the local flowering season were analysed using a HYSPLIT trajectory model and the findings showed that western, southern and southwestern winds transported pollen grains into the study area from earlier-flowering groves located outside the territory. PMID- 25461090 TI - Comparative study of potential transfer of natural and anthropogenic cadmium to plankton communities in the North-West African upwelling. AB - A Lagrangian approach based on a physical-biogeochemical modeling was used to compare the potential transfer of cadmium (Cd) from natural and anthropogenic sources to plankton communities (Cd-uptake) in the North-West African upwelling. In this region, coastal upwelling was estimated to be the main natural source of Cd while the most significant anthropogenic source for marine ecosystem is provided by phosphate industry. In our model experiment, Cd-uptake (natural or anthropogenic) in the North-West African upwelling is the result of an interplay between the Cd dispersion (by advection processes) and the simulated biological productivity. In the Moroccan waters, advection processes limit the residence time of water masses resulting in a low natural Cd-uptake by plankton communities while anthropogenic Cd-uptake is high. As expected, the situation is reversed in the Senegalo-Mauritanian upwelling where natural Cd-uptake is higher than anthropogenic Cd-uptake. Based upon an estimate of Cd sources, our modeling study shows, unexpectedly, that the anthropogenic signal of potential Cd bioaccumulation in the Moroccan upwelling is of the same order of magnitude as the natural signal mainly present in the Senegalo-Mauritanian upwelling region. A comparison with observed Cd levels in mollusk and fishes, which shows overall agreement with our simulations, is confirming our estimates. PMID- 25461091 TI - Vectorial role of Acanthamoeba in Legionella propagation in water for human use. AB - Legionella spp. is the causative agent of Legionnaires' disease and is transmitted through aerosols emanating from man-made water systems. Legionella resistance to water treatments has been related to its association with environmental amoebae such as Acanthamoeba. Due to the high presence of this protozoon in Spain and the high rate of notification of Legionnaires' disease of this country, the aims of this work were to study the coexistence of these bacteria and protozoa in water as well as their interaction. The usefulness of Acanthamoeba co-culture for the isolation of environmental Legionella was also studied. For this purpose, 70 water samples were collected in 2011 from three Drinking Water Treatment Plants, three Wastewater Treatment Plants and five Natural Pools in Spain. Acanthamoeba was found by PCR in 87.1% (61/70) samples and, by culture in 85.7% (60/70) samples. Legionella was detected by PCR in 58.6% (41/70) of water samples, in 5.7% (4/70) by agar culture and 75.7% (53/70) by Acanthamoeba co-culture. From the 54 Acanthamoeba water isolates, Legionella was detected in 43 of them independently of Acanthamoeba's genotype (T3, T4 and T11). Legionella feeleii, Legionella birminghamiensis, Legionella gresilensis/berliardensis, Legionella fairfieldensis, Legionella drozanski and Legionella falloni were identified. In conclusion, our results showed that environmental Acanthamoeba is infected by Legionella to a high percentage, and due to its ubiquity, high resistance and its pathogenic potential per se, new methods for its elimination should be studied. Also, the high effectivity of Acanthamoeba co-culture for Legionella detection has been shown. PMID- 25461092 TI - Sediment-water distribution of contaminants of emerging concern in a mixed use watershed. AB - This study evaluated the occurrence and distribution of 15 contaminants of emerging concern (CECs) in stream water and sediments in the Zumbro River watershed in Minnesota and compared these with sub-watershed land uses. Sixty pairs of sediment and water samples were collected across all seasons from four stream sites for over two years and analyzed for selected personal care products, pesticides, human and veterinary medications, and phytoestrogens. Spatial and temporal analyses indicate that pharmaceuticals and personal care products (urban/residential CECs) are significantly elevated in water and/or sediment at sites with greater population density (>100 people/km(2)) and percentage of developed land use (>8% of subwatershed area) than those with less population density and land area under development. Significant spatial variations of agricultural pesticides in water and sediment were detectable, even though all sites had a high percentage of agricultural land use. Seasonality in CEC concentration was observed in water but not in sediment, although sediment concentrations of three CECs did vary between years. Average measured non equilibrium distribution coefficients exceeded equilibrium hydrophobic partitioning-based predictions for 5 of the 7 detected CECs by at least an order of magnitude. Agreement of measured and predicted distribution coefficients improved with increasing hydrophobicity and in-stream persistence. The more polar and degradable CECs showed greater variability in measured distributions across different sampling events. Our results confirm that CECs are present in urban and agricultural stream sediments, including those CECs that would typically be thought of as non-sorptive based on their log Kow values. These results and the observed patterns of sediment and water distributions augment existing information to improve prediction of CEC fate and transport, leading to more accurate assessments of exposure and risk to surface water ecosystems. PMID- 25461093 TI - Occurrence and removal of transformation products of PPCPs and illicit drugs in wastewaters: a review. AB - Pharmaceuticals and personal care products (PPCPs) along with illicit drugs (IDs) are newly recognized classes of environmental pollutants and are receiving considerable attention because of their environmental impacts: frequent occurrence, persistence and risk to aquatic life and humans. However, relatively little information is often available with regard to their possible biotic and abiotic transformation products (TPs). This lack of knowledge has resulted in a substantial amount of ongoing effort to develop methods and approaches that would assess their occurrence, degradability potential elimination mechanisms and efficiencies in sewage treatment plants as well as environmental and human health risks. In this article, an extensive literature survey was performed in order to present the current stage of knowledge and progress made in the occurrence of TPs of PPCPs and IDs in raw and treated wastewaters. Apart from the TPs resulting from structural transformations of the parent compound in the aquatic environment or in technological treatment facilities (e.g. sewage and drinking water treatment plants), free metabolites and drug conjugates formed during human metabolism have also been included in this review as they are also released into the aquatic environment through wastewaters. Their concentration levels were reported in influents and effluents of WWTPs, hospital effluents and their removals in the treatment plants were discussed. Finally, information on the toxicity of TPs has been compiled when available. PMID- 25461094 TI - Coupled analysis on landscape pattern and hydrological processes in Yanhe watershed of China. AB - As a typical experimental Soil and Water Conservation District, Yanhe watershed has long been plagued by soil erosion due to severe human disturbances. Exerting remote sensing (RS) and geographic information system (GIS) technology, this paper firstly analyzed and simulated ecological hydrological process in Yanhe watershed based on SWAT model, constructed a comprehensive landscape indices which was closely related to soil erosion, and reflected the coupling relationship between regional landscape pattern change and soil erosion. The results are as follows: (1) Areas of different land use types remained relatively stable from 1990 to 2000 and then changed drastically from 2000 to 2010, which was characterized by lawn expansion and cultivated land shrinkage. (2) In terms of the spatial heterogeneity of hydrological response unit (HRUs), the correlation coefficient of seven selected landscape indices and runoff was very small, and cannot pass all significant testing. But correlation between the indices and sediment yield except for Total Core Area (TCA) and Interspersion and Juxtaposition Index (IJI) was remarkable. (3) According to 'the source-sink' theory of soil erosion, new landscape index-slope-HRU landscape index (SHLI) was built, and reflected the relationship between landscape pattern and soil erosion processes to a certain extent. (4) Coupling relationship between SHLI in 2010 and annual sediment was very prominent. In the sub-basin scale, SHLI has obvious regional differentiation from annual sediment. PMID- 25461095 TI - Simulation of ozone formation at different elevations in mountainous area of Hong Kong using WRF-CMAQ model. AB - Field measurements were simultaneously conducted at a mountain (Mt.) site (Tai Mao Shan, TMS) and an urban site (Tsuen Wan, TW) at the foot of the Mt. TMS in Hong Kong. An interesting event with consecutive high-ozone (O3) days from 08:00 on 28 Oct. to 23:00 on 03 Nov., 2010 was observed at Mt. TMS, while no such polluted event was found at the foot of the mountain. The Weather Research and Forecasting (WRF)-Community Multiscale Air Quality (CMAQ) models were used to understand this event. Model performance evaluation showed that the simulated meteorological parameters and air pollutants were well in agreement with the observations. The index of agreement (IOA) of temperature, relative humidity, wind direction and wind speed were 0.93, 0.83, 0.46 and 0.60, respectively. The multi-day high O3 episode at Mt. TMS was also reasonably reproduced (IOA=0.68). Horizontally, the photochemical processes determined the O3 levels in southwestern Pearl River Delta (PRD) and the Pearl River Estuary (PRE), while in eastern and northern PRD, the O3 destruction was over the production during the event. Vertically, higher O3 values at higher levels were found at both Mt. TMS and TW, indicating a vertical O3 gradient over Hong Kong. With the aid of the process analysis module, we found positive contribution of vertical transport including advection and diffusion to O3 mixing ratios at the two sites, suggesting that O3 values at lower locations could be affected by O3 at higher locations via vertical advection and diffusion over Hong Kong. PMID- 25461096 TI - Selenium distribution and speciation in plant parts of wheat (Triticum aestivum) and Indian mustard (Brassica juncea) from a seleniferous area of Punjab, India. AB - The concentration, distribution, and speciation of selenium in different parts of wheat and Indian mustard, grown in a seleniferous area in Punjab, were investigated using synchrotron based (XAS) and classical acid digestion and extraction methods. The analyses revealed a high Se enrichment in all investigated plant parts, with Se levels in the range of 133-931 mg/kg (dry weight, dw). Such high Se enrichment is mainly due to the considerable amounts of easily available Se detected in the soil, which are renewed on a yearly basis to some extent via irrigation. Speciation analysis in soil and plants indicated selenate and organic Se as major Se species taken up by plants, with a minor presence of selenite. The analyses also revealed that the highest Se enrichment occurs in the upper plant parts, in agreement with the high uptake rate and mobility of selenate within plants. In both wheat and mustard, highest Se enrichments were found in leaves (387 mg/kg.dw in wheat and 931 mg/kg.dw in mustard). Organic species (dimethylselenide and methylselenocysteine) were found in different parts of both plants, indicating that an active detoxification response to the high Se uptake is taking place through methylation and/or volatilization. The high proportion of selenate in wheat and mustard leaves (47% and 70%, respectively) is the result of the inability of the plant metabolism to completely transform selenate to non-toxic organic forms, if oversupplied. Methylselenocysteine, a common Se species in accumulating plants, was detected in wheat, suggesting that, in the presence of high Se concentration, this plant develops similar response mechanisms to accumulator plants. PMID- 25461097 TI - A landscape-scale approach to examining the fate of atmospherically derived industrial metals in the surficial environment. AB - Industrial metals are now ubiquitous within the atmosphere and their deposition represents a potential source of contamination to surficial environments. Few studies, however, have examined the environmental fate of atmospheric industrial metals within different surface environments. In this study, patterns of accumulation of atmospherically transported industrial metals were investigated within the surface environments of the Snowy Mountains, Australia. Metals, including Pb, Sb, Cr and Mo, were enriched in aerosols collected in the Snowy Mountains by 3.5-50 times pre-industrial concentrations. In sedimentary environments (soils, lakes and reservoirs) metals showed varying degrees of enrichment. Differences were attributed to the relative degree of atmospheric input, metal sensitivity to enrichment, catchment area and metal behaviour following deposition. In settings where atmospheric deposition dominated (ombrotrophic peat mires in the upper parts of catchments), metal enrichment patterns most closely resembled those in collected aerosols. However, even in these environments significant dilution (by 5-7 times) occurred. The most sensitive industrial metals (those with the lowest natural concentration; Cd, Ag, Sb and Mo) were enriched throughout the studied environments. However, in alpine tarn-lakes no other metals were enriched, due to the dilution of pollutant-metals by catchment derived sediment. In reservoirs, which were located lower within catchments, industrial metals exhibited more complex patterns. Particle reactive metals (e.g. Pb) displayed little enrichment, implying that they were retained up catchment, whereas more soluble metals (e.g., Cu and Zn) showed evidence of concentration. These same metals (Cu and Zn) were depleted in soils, implying that they are preferentially transported through catchments. Enrichment of other metals (e.g. Cd) varied between reservoirs as a function of contributing catchment area. Overall this study showed that the fate of atmospherically derived metals is complex, and depends upon metal behaviour and geomorphic processes operating at landscape scales. PMID- 25461098 TI - A modeling assessment of the physicochemical properties and environmental fate of emerging and novel per- and polyfluoroalkyl substances. AB - Long-chain perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkane sulfonic acids (PFSAs) are persistent, bioaccumulative, and toxic contaminants that are globally present in the environment, wildlife and humans. Phase-out actions and use restrictions to reduce the environmental release of long-chain PFCAs, PFSAs and their precursors have been taken since 2000. In particular, long-chain poly- and perfluoroalkyl substances (PFASs) are being replaced with shorter-chain homologues or other fluorinated or non-fluorinated alternatives. A key question is: are these alternatives, particularly the structurally similar fluorinated alternatives, less hazardous to humans and the environment than the substances they replace? Several fluorinated alternatives including perfluoroether carboxylic acids (PFECAs) and perfluoroether sulfonic acids (PFESAs) have been recently identified. However, the scarcity of experimental data prevents hazard and risk assessments for these substances. In this study, we use state-of-the-art in silico tools to estimate key properties of these newly identified fluorinated alternatives. [i] COSMOtherm and SPARC are used to estimate physicochemical properties. The US EPA EPISuite software package is used to predict degradation half-lives in air, water and soil. [ii] In combination with estimated chemical properties, a fugacity-based multimedia mass-balance unit-world model - the OECD Overall Persistence (POV) and Long-Range Transport Potential (LRTP) Screening Tool - is used to assess the likely environmental fate of these alternatives. Even though the fluorinated alternatives contain some structural differences, their physicochemical properties are not significantly different from those of their predecessors. Furthermore, most of the alternatives are estimated to be similarly persistent and mobile in the environment as the long-chain PFASs. The models therefore predict that the fluorinated alternatives will become globally distributed in the environment similar to their predecessors. Although such in silico methods are coupled with uncertainties, this preliminary assessment provides enough cause for concern to warrant experimental work to better determine the properties of these fluorinated alternatives. PMID- 25461099 TI - Contributing factors in foliar uptake of dissolved inorganic nitrogen at leaf level. AB - We investigated the influence of leaf traits, rainwater chemistry, and pedospheric nitrogen (N) fertilisation on the aqueous uptake of inorganic N by physiologically active tree leaves. Leaves of juvenile silver birch and European beech trees, supplied with NH4NO3 to the soil at rates from 0 to 200 kg N ha( 1)y(-1), were individually exposed to 100 MUl of artificial rainwater containing (15)NH4(+) or (15)NO3(-) at two concentration levels for one hour. In the next vegetative period, the experiment was repeated with NH4(+) at the highest concentration only. The N form and the N concentration in the applied rainwater and, to a lesser extent, the pedospheric N treatment and the leaf traits affected the aqueous foliar N uptake. The foliar uptake of NH4(+) by birch increased when leaves were more wettable. High leaf N concentration and leaf mass per area enhanced the foliar N uptake, and NO3(-) uptake in particular, by birch. Variation in the foliar N uptake by the beech trees could not be explained by the leaf traits considered. In the first experiment, N fertilisation stimulated the foliar N uptake in both species, which was on average 1.42-1.78 times higher at the highest soil N dose than at the zero dose. However, data variability was high and the effect was not appreciable in the second experiment. Our data suggest that next to rainwater chemistry (N form and concentration) also forest N status could play a role in the partitioning of N entering the ecosystem through the soil and the canopy. Models of canopy uptake of aqueous N at the leaf level should take account of leaf traits such as wettability and N concentration. PMID- 25461100 TI - Contaminant sources, gastrointestinal absorption, and tissue distribution of organohalogenated pollutants in chicken from an e-waste site. AB - Several organohalogenated pollutants (OHPs), including polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), decabromodiphenyl ethane (DBDPE), and 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE) were examined in chicken dietary sources (soil and feed) and gastrointestinal contents (chyme, intestinal contents, and feces), and in 11 chicken tissues (liver, muscle, heart, lung, fat, brain, stomach, intestine, ovary/testis, kidney, and serum) from an e-waste recycling site in South China. Elevated levels of OHPs were found in the soil and chicken tissues. Soil was a more important source of OHPs, especially brominated flame retardants, than feed. In general, more-halogenated chemicals were less readily absorbed in the gastrointestinal tract. With the exception of the brain and serum, where lower concentrations occurred, no significant differences in PCBs, PBDEs, and BTBPE were found among the chicken tissues. DBDPE was detected mainly in the stomach, intestine, kidney, and ovary. Compared with the soil, all the tissues had lower proportions of CBs 52 and 101. PBDEs were dominated by BDE 209 in the soil and chicken feed; two different PBDE congener profiles, dominated by both BDE 183 and BDE 209 or dominated by BDE 209 only, were found in the chicken tissues except for the brain. Only BDE 47 or BDE 209 was occasionally detectable in the brain. DBDPE was also found in the brain samples despite its high log Kow values. The blood-brain barrier alters patterns of contaminant composition and results in lower levels of OHPs in the brain. PMID- 25461101 TI - A risk-based approach to sanitary sewer pipe asset management. AB - Wastewater collection systems are an important component of proper management of wastewater to prevent environmental and human health implications from mismanagement of anthropogenic waste. Due to aging and inadequate asset management practices, the wastewater collection assets of many cities around the globe are in a state of rapid decline and in need of urgent attention. Risk management is a tool which can help prioritize resources to better manage and rehabilitate wastewater collection systems. In this study, a risk matrix and a weighted sum multi-criteria decision-matrix are used to assess the consequence and risk of sewer pipe failure for a mid-sized city, using ArcGIS. The methodology shows that six percent of the uninspected sewer pipe assets of the case study have a high consequence of failure while four percent of the assets have a high risk of failure and hence provide priorities for inspection. A map incorporating risk of sewer pipe failure and consequence is developed to facilitate future planning, rehabilitation and maintenance programs. The consequence of failure assessment also includes a novel failure impact factor which captures the effect of structurally defective stormwater pipes on the failure assessment. The methodology recommended in this study can serve as a basis for future planning and decision making and has the potential to be universally applied by municipal sewer pipe asset managers globally to effectively manage the sanitary sewer pipe infrastructure within their jurisdiction. PMID- 25461102 TI - Net greenhouse gas emissions from manure management using anaerobic digestion technology in a beef cattle feedlot in Brazil. AB - As part of an agreement during the COP15, the Brazilian government is fostering several activities intended to mitigate greenhouse gas (GHG) emissions. One of them is the adoption of anaerobic digester (AD) for treating animal manure. Due to a lack of information, we developed a case study in order to evaluate the effect of such initiative for beef cattle feedlots. We considered the net GHG emissions (CH4 and N2O) from the manure generated from 140 beef heifers confined for 90 days in the scope "housing to field application" by including field measurements, literature values, and the offset generated by the AD system through the replacement of conventional sources of nitrogen (N) fertilizer and electricity, respectively. Results showed that direct GHG emissions accounted for 0.14 +/- 0.06 kg of carbon dioxide equivalent (CO2eq) per kg of animal live weight gain (lwg), with ~80% originating from field application, suggesting that this emission does not differ from the conventional manure management (without AD) typically done in Brazil (0.19 +/- 0.07 kg of CO2eq per kg lwg(-1)). However, 2.4 MWh and 658.0 kg of N-manure were estimated to be generated as a consequence of the AD utilization, potentially offsetting 0.13 +/- 0.01 kg of CO2eq kg lwg( 1) or 95% (+/-45%) of total direct emissions from the manure management. Although, by replacing fossil fuel sources, i.e. diesel oil, this offset could be increased to 169% (+/-47%). In summary, the AD has the potential to significantly mitigate GHG emissions from manure management in beef cattle feedlots, but the effect is indirect and highly dependent on the source to be replaced. In spite of the promising results, more and continuous field measurements for decreasing uncertainties and improving assumptions are required. Identifying shortcomings would be useful not only for the effectiveness of the Brazilian government, but also for worldwide plans in mitigating GHG emissions from beef production systems. PMID- 25461103 TI - Microbiological characterization of 3193 French dwellings of Elfe cohort children. AB - Although exposure to indoor microorganisms in early life has already been associated with respiratory illness or allergy protection, only a few studies have performed standardized samplings and specific microbial analysis. Moreover, most do not target the different groups of microorganisms involved in respiratory diseases (fungi, bacteria, dust mites). In our study, ten specific qPCR targets (6 fungal species, 1 family and 2 genera of bacteria, 1 house dust mite) were used to analyze the microorganism composition of electrostatic dust fall collector (EDC) from 3193 dwellings of the Elfe French cohort study. Multivariate analyses allowed us to show that the microbial composition of dwellings, assessed with simultaneous analysis of 10 microorganisms, can be characterized by four entities: three bacteria, house dust mite Dermatophagoides pteronyssinus, fungi Alternaria alternata, and five other molds. Some dwellings' intrinsic characteristics (occupational ratio, type of dwelling and presence of pets) clearly influence microorganism distribution, and six different profiles of dwellings, characterized by their composition in microorganisms, have been described across France. The use of these clusters seems promising in the evaluation of allergic risk. Allergic respiratory diseases will develop in the near future in some children of the Elfe cohort and will indicate to what extent our approach can be predictive of respiratory disease. PMID- 25461104 TI - Aerobiological and phenological study of Pistacia in Cordoba city (Spain). AB - Pistacia species grow in temperate regions, and are widespread in the Mediterranean area. Two species can be found in the Iberian Peninsula: Pistacia lentiscus L. and Pistacia terebinthus L. Airborne pollen from these species, recorded in some Spanish provinces, is regarded by some authors as potentially allergenic, and therefore should be of particular interest, given that these species are actually being introduced as ornamentals in parks and gardens. This paper deals with a study of daily and seasonal Pistacia airborne pollen counts in Cordoba city, analysed in parallel with field flowering phenology data. The study was carried out in Cordoba, using a volumetric Hirst-type sampler in accordance with Spanish Aerobiology Network guidelines. Phenological monitoring was performed weekly from January to May at 7 sites in the mountain areas north of Cordoba city. The Pistacia pollen season lasted an average of 41 days, from mid March to end of April. Higher pollen counts were recorded in evening hours. The pollen index increased over the study period, and the pollen season coincided with phenological observations. Some airborne pollen grains were recorded once flowering had finished, due to re-suspension or transport from other locations. Pistacia pollen counts in Cordoba were low, but sufficient to identify seasonal and daily patterns. This pollen type should be taken into account in pollen calendars, in order to fully inform potential allergy-sufferers. The number of trees introduced as ornamentals should be carefully controlled, since widespread planting could increase airborne pollen levels. PMID- 25461105 TI - Effects of water-saving irrigation practices and drought resistant rice variety on greenhouse gas emissions from a no-till paddy in the central lowlands of China. AB - As pressure on water resources increases, alternative practices to conserve water in paddies have been developed. Few studies have simultaneously examined the effectiveness of different water regimes on conserving water, mitigating greenhouse gases (GHG), and maintaining yields in rice production. This study, which was conducted during the drought of 2013, examined all three factors using a split-plot experiment with two rice varieties in a no-till paddy managed under three different water regimes: 1) continuous flooding (CF), 2) flooded and wet intermittent irrigation (FWI), and 3) flooded and dry intermittent irrigation (FDI). The Methane (CH4) and nitrous oxide (N2O) emissions were measured using static chamber-gas measurements, and the carbon dioxide (CO2) emissions were monitored using a soil CO2 flux system (LI-8100). Compared with CF, FWI and FDI irrigation strategies reduced CH4 emissions by 60% and 83%, respectively. In contrast, CO2 and N2O fluxes increased by 65% and 9%, respectively, under FWI watering regime and by 104% and 11%, respectively, under FDI managed plots. Although CO2 and N2O emissions increased, the global warming potential (GWP) and greenhouse gas intensity (GHGI) of all three GHG decreased by up to 25% and 29% (p<0.01), respectively, using water-saving irrigation strategies. The rice variety also affected yields and GHG emissions in response to different water regimes. The drought-resistance rice variety (HY3) was observed to maintain yields, conserve water, and reduce GHG under the FWI irrigation management compared with the typical variety (FYY299) planted in the region. The FYY299 only had significantly lower GWP and GHGI when the yield was reduced under FDI water regime. In conclusion, FWI irrigation strategy could be an effective option for simultaneously saving water and mitigating GWP without reducing rice yields using drought-resistant rice varieties, such as HY3. PMID- 25461106 TI - Using data from monitoring combined sewer overflows to assess, improve, and maintain combined sewer systems. AB - Using low-cost sensors, data can be collected on the occurrence and duration of overflows in each combined sewer overflow (CSO) structure in a combined sewer system (CSS). The collection and analysis of real data can be used to assess, improve, and maintain CSSs in order to reduce the number and impact of overflows. The objective of this study was to develop a methodology to evaluate the performance of CSSs using low-cost monitoring. This methodology includes (1) assessing the capacity of a CSS using overflow duration and rain volume data, (2) characterizing the performance of CSO structures with statistics, (3) evaluating the compliance of a CSS with government guidelines, and (4) generating decision tree models to provide support to managers for making decisions about system maintenance. The methodology is demonstrated with a case study of a CSS in La Garriga, Spain. The rain volume breaking point from which CSO structures started to overflow ranged from 0.6 mm to 2.8 mm. The structures with the best and worst performance in terms of overflow (overflow probability, order, duration and CSO ranking) were characterized. Most of the obtained decision trees to predict overflows from rain data had accuracies ranging from 70% to 83%. The results obtained from the proposed methodology can greatly support managers and engineers dealing with real-world problems, improvements, and maintenance of CSSs. PMID- 25461107 TI - Non-invasive biomonitoring for PFRs and PBDEs: new insights in analysis of human hair externally exposed to selected flame retardants. AB - In this study, we investigated the hypothesis whether externally adsorbed and internally deposited flame retardants (FRs) in hair could be distinguished. To this extent, hair samples collected from one volunteer were exposed under controlled conditions to phosphate FR (PFR) and polybrominated diphenyl ether (PBDE) standards to mimic external contamination. Afterwards, suitable washing procedures to selectively remove contaminants from the hair surface were investigated. The samples were measured by GC-(ECNI)-MS for PBDEs and LC-(ESI+) MS/MS for PFRs. All investigated compounds were transferred onto the hair surface. One of the most important finding was that dust particles are not mandatory to transfer compounds on the hair surface and to be able to measure high levels of compounds in human hair. To assess different protocols to selectively remove external contamination, the exposed hair samples were washed in different media before analysis: water, methanol, hexane:dichloromethane (1:1, v/v), acetone and shampoo. Results indicated that there is no washing medium able to entirely and exclusively remove external contamination. Among investigated media, methanol removed a meaningful part of the external contamination (42 105%), but the removal efficiencies differed among compounds. We therefore concluded that hair should not be washed prior to analysis and in case of visible contamination (e.g. with cosmetic products), water would be the recommended agent. Organic solvents should not be used for the washing step. Although it is impossible to distinguish external from internal exposure, hair samples may be used as valuable biomarker of human exposure, providing a measure of integral exposure. To the best of our knowledge, this is the first study which has used externally exposed hair samples to PBDEs and PFRs. PMID- 25461108 TI - Spatial variations of levoglucosan in four European study areas. AB - Relatively little is known about long term effects of wood smoke on population health. A wood combustion marker - levoglucosan - was measured using a standardized sampling and measurement method in four European study areas (Oslo, The Netherlands, Munich/Augsburg, Catalonia) to assess within and between study area spatial variation. Levoglucosan was analyzed in addition to: PM2.5, PM2.5 absorbance, PM10, polycyclic aromatic hydrocarbons (PAH), nitrogen oxides (NOx), elemental and organic carbon (EC/OC), hopanes, steranes and elemental composition. Measurements were conducted at street, urban and regional background sites. Three two-week samples were taken per site and the annual average concentrations of pollutants were calculated using continuous measurements at one background reference site. Land use regression (LUR) models were developed to explain the spatial variation of levoglucosan. Much larger within than between study area contrast in levoglucosan concentration was found. Spatial variation patterns differed from other measured pollutants: PM2.5, NOx and EC. Levoglucosan had the highest spatial correlation with SigmaPAH (r=0.65) and the lowest with traffic markers - NOx, Sigmahopanes/steranes (r=-0.22). Levoglucosan concentrations in the cold (heating) period were between 3 and 20 times higher compared to the warm period. The contribution of wood-smoke calculated based on levoglucosan measurements and previous European emission data to OC and PM2.5 mass was 13 to 28% and 3 to 9% respectively in the full year. Larger contributions were calculated for the cold period. The median model R(2) of the LUR models was 60%. The LUR models included population and natural land related variables. In conclusion, substantial spatial variability was found in levoglucosan concentrations within study areas. Wood smoke contributed substantially to especially wintertime PM2.5 OC and mass. The low to moderate correlation with PM2.5 mass and traffic markers offers the potential to assess health effects of wood smoke separate from traffic-related air pollution. PMID- 25461109 TI - Perceptions of pesticides exposure risks by operators, workers, residents and bystanders in Greece, Italy and the UK. AB - The EU Directive on the sustainable use of pesticides (EU128/2009/EC) requires European Member States to develop training activities targeting occupational exposure to pesticides, and communication material aimed at residents and bystanders. Risk perceptions, knowledge and attitudes associated with passive and occupational exposure to pesticide potentially influence the extent to which different stakeholders adopt self-protective behaviour. A methodology for assessing the link between attitudes, adoption of self-protective behaviours and exposure was developed and tested. A survey was implemented in the Greece, Italy and the UK, and targeted stakeholders associated with pesticide exposure linked to orchards, greenhouse crops and arable crops respectively. The results indicated that the adoption of protective measures is low for residents and bystanders, with the exception of residents in Greece, when compared to operators and workers, who tend to follow recommended safety practices. A regression analysis was used to examine the factors affecting the probability of adopting protective measures as well the as the level of exposure in the case of operators and workers where data are available. The results indicate that the likelihood of engaging in self-protective behaviour is not significantly affected by perceptions of own health being affected by pesticides for residents and bystanders. However, operators who perceive that their heath has been negatively affected by the use of pesticides are found to be more likely to adopt self protective behaviours. Gender and country differences, in perceptions, attitudes and self-protection are also observed. Recommendations for improved communication, in particular for vulnerable groups, are provided. PMID- 25461110 TI - Continued implication of the banned pesticides carbofuran and aldicarb in the poisoning of domestic and wild animals of the Canary Islands (Spain). AB - Although nowadays the intentional poisoning of domestic and wild animals is a crime in EU, in the past the poison was used in rural areas of a number of European countries to kill animals that were considered harmful for human activities. In Spain evidences indicate that intentional poisonings continue to occur throughout the entire country nowadays. This situation seems to be of particular concern in the Canary Islands (Spain), where this study was performed. Our results confirmed that 225 animals were poisoned by pesticides over the study period (32 months; 2010-2013). The intentionality of the poisoning was confirmed in 117 cases. It has to be highlighted that the other 108 animals also died by pesticide poisoning, although the intentionality was only suspected. This incidence is currently the highest reported in any region from European Union. The pesticides carbofuran, bromadiolone, brodifacoum and aldicarb were the most frequently detected involved. Among the affected species, it has to be highlighted that endangered species are frequently affected in poisoning incidents. Notably, chemicals banned in the EU (carbofuran and aldicarb) were identified in approximately 75% of cases, and in almost 100% of baits, which suggests that these pesticides are still available to the population. Several circumstances may explain these results. Firstly, little control over the sale and possession of pesticide products, and the potential existence of an illegal market of pesticides banned in the European Union in the neighbouring African continent. In addition, the limited awareness of the population about the dangerousness of these compounds, for the environment, animals, or even people, make the situation very worrying in these islands. Stronger regulations, control of legal and illegal pesticide use, development of educational programs and legal action in poisoning incidents are needed to decrease the impact of pesticide misuse on wildlife and domestic animals. PMID- 25461111 TI - Incorporating environmental attitudes in discrete choice models: an exploration of the utility of the awareness of consequences scale. AB - Environmental economists are increasingly interested in better understanding how people cognitively organise their beliefs and attitudes towards environmental change in order to identify key motives and barriers that stimulate or prevent action. In this paper, we explore the utility of a commonly used psychometric scale, the awareness of consequences (AC) scale, in order to better understand stated choices. The main contribution of the paper is that it provides a novel approach to incorporate attitudinal information into discrete choice models for environmental valuation: firstly, environmental attitudes are incorporated using a reinterpretation of the classical AC scale recently proposed by Ryan and Spash (2012); and, secondly, attitudinal data is incorporated as latent variables under a hybrid choice modelling framework. This novel approach is applied to data from a survey conducted in the Basque Country (Spain) in 2008 aimed at valuing land use policies in a Natura 2000 Network site. The results are relevant to policy making because choice models that are able to accommodate underlying environmental attitudes may help in designing more effective environmental policies. PMID- 25461112 TI - Influence of thermal regime and land use on benthic invertebrate communities inhabiting headwater streams exposed to contrasted shading. AB - Headwaters account for a high proportion of total freshwater stream-channel length in a drainage basin and are critical habitats for rare, endangered, and specialized species. In the context of climate warming, increasing water temperatures may be an ultimate threat to cold-adapted species even in temperate ecosystems. Climate change effects on streams may interact with other pressures such as pollution or habitat fragmentation, confounding their real impact on biological communities. Three headwater streams exposed to contrasted shading and land use conditions were sampled over a three-year period in spring and autumn (2010-2012). Five stations distributed along the longitudinal continuum were chosen in the upstream part of each stream. In addition to benthic invertebrate sampling, water temperature was recorded continuously using data loggers. Results showed that the riparian woodland associated with forested land use throughout the catchment clearly moderated winter temperature minima, summer temperature maxima and thermal variability compared to open river channels with narrow or absent riparian tree cover. Although, the variability in macroinvertebrate species distribution was mainly attributed to anthropogenic land use in the catchment, a significant part of the variability was explained by temperature descriptors such as the number of cumulative degree-days in summer and extremes in winter temperature. Trichoptera species preferring headwaters and cold water temperatures were found exclusively in the forested unimpacted stream. Conservation issues are discussed in relation to the predicted loss of the potential future distributions of these Trichoptera cold-adapted species. PMID- 25461113 TI - Environmental health impacts of unconventional natural gas development: a review of the current strength of evidence. AB - Rapid global expansion of unconventional natural gas development (UNGD) raises environmental health concerns. Many studies present information on these concerns, yet the strength of epidemiological evidence remains tenuous. This paper is a review of the strength of evidence in scientific reporting of environmental hazards from UNGD activities associated with adverse human health outcomes. Studies were drawn from peer-reviewed and grey literature following a systematic search. Five databases were searched for studies published from January 1995 through March 2014 using key search terms relevant to environmental health. Studies were screened, ranked and then reviewed according to the strength of the evidence presented on adverse environmental health outcomes associated with UNGD. The initial searches yielded >1000 studies, but this was reduced to 109 relevant studies after the ranking process. Only seven studies were considered highly relevant based on strength of evidence. Articles spanned several relevant topics, but most focussed on impacts on typical environmental media, such as water and air, with much of the health impacts inferred rather than evidenced. Additionally, the majority of studies focussed on short-term, rather than long-term, health impacts, which is expected considering the timeframe of UNGD; therefore, very few studies examined health outcomes with longer latencies such as cancer or developmental outcomes. Current scientific evidence for UNGD that demonstrates associations between adverse health outcomes directly with environmental health hazards resulting from UNGD activities generally lacks methodological rigour. Importantly, however, there is also no evidence to rule out such health impacts. While the current evidence in the scientific research reporting leaves questions unanswered about the actual environmental health impacts, public health concerns remain intense. This is a clear gap in the scientific knowledge that requires urgent attention. PMID- 25461114 TI - Impact of direct greenhouse gas emissions on the carbon footprint of water reclamation processes employing nitrification-denitrification. AB - Water reclamation has the potential to reduce water supply demands from aquifers and more energy-intensive water production methods (e.g., seawater desalination). However, water reclamation via biological nitrification-denitrification is also associated with the direct emission of the greenhouse gases (GHGs) CO2, N2O, and CH4. We quantified these direct emissions from the nitrification-denitrification reactors of a water reclamation plant in Southern California, and measured the (14)C content of the CO2 to distinguish between short- and long-lived carbon. The total emissions were 1.5 (+/-0.2) g-fossil CO2 m(-3) of wastewater treated, 0.5 (+/-0.1) g-CO2-eq of CH4 m(-3), and 1.8 (+/-0.5) g-CO2-eq of N2O m(-3), for a total of 3.9 (+/-0.5) g-CO2-eqm(-3). This demonstrated that water reclamation can be a source of GHGs from long lived carbon, and thus a candidate for GHG reduction credit. From the (14)C measurements, we found that between 11.4% and 15.1% of the CO2 directly emitted was derived from fossil sources, which challenges past assumptions that the direct CO2 emissions from water reclamation contain only modern carbon. A comparison of our direct emission measurements with estimates of indirect emissions from several water production methods, however, showed that the direct emissions from water reclamation constitute only a small fraction of the plant's total GHG footprint. PMID- 25461115 TI - Evaluation of crop production, trade, and consumption from the perspective of water resources: a case study of the Hetao irrigation district, China, for 1960 2010. AB - The integration of water footprints and virtual water flows allows the mapping of the links between production, trade, and consumption and could potentially help to alleviate water scarcity and improve water management. We evaluated the water footprints and virtual water flows of crop production, consumption, and trade and their influencing factors in the Hetao irrigation district in China for 1960 2010. The water footprint of crop production and the export of virtual water fluctuated but tended to increase during this period and were influenced mainly by agricultural factors such as crop yield, irrigation efficiency, and area sown. The water footprint of crop consumption and the import of virtual water increased during 1960-1979 and decreased during 1980-2010 and were influenced by socio economic factors such as total population, the retail-price index, and the proportion of the population in urban areas. Most of the water footprint of production was exported to other areas, which added to the pressure on local water systems. The import of virtual water led to a saving of water for the Hetao irrigation district, while its share of the water footprint of consumption has decreased significantly since 1977. An increase in irrigation efficiency can alleviate water scarcity, and its application should be coupled with measures that constrain the continued expansion of agriculture. Full-cost pricing of irrigation water was an effective policy tool for its management. Re-shaping regional water-production and water-trade nexuses by changing crop structures could provide alternative opportunities for addressing the problems of local water scarcity, but the trade-offs involved should first be assessed. PMID- 25461116 TI - Source apportionment of synchronously size segregated fine and coarse particulate matter, using an improved three-way factor analysis model. AB - Samples of PM10 and PM2.5 were synchronously collected from a megacity in China (Chengdu) during the 2011 sampling campaign and then analyzed by an improved three-way factor analysis method based on ME2 (multilinear engine 2), to investigate the contributions and size distributions of the source categories for size segregated particulate matter (PM). Firstly, the synthetic test was performed to evaluate the accuracy of the improved three-way model. The same five source categories with slightly different source profiles were caught. The low AAE (average absolute error) values between the estimated and the synthetic source contributions (<15%) and the approachable estimated PM2.5/PM10 ratios with the simulated ratios might indicate that the results of the improved three-way factor analysis might be satisfactory. Then, for the ambient PM samples, the mean levels were 206.65 +/- 69.90 MUg/m(3) (PM10) and 130.47 +/- 43.67 MUg/m(3) (PM2.5). The average ratio of PM2.5/PM10 was 0.63. PM10 and PM2.5 in Chengdu were influenced by the same source categories and their percentage contributions were in the same order: crustal dust & coal combustion presented the highest percentage contributions, accounting for 58.20% (PM10) and 53.73% (PM2.5); followed by vehicle exhaust & secondary organic carbon (18.45% for PM10 and 21.63% for PM2.5), secondary sulfate and nitrate (17.06% for PM10 and 20.91% for PM2.5) and cement dust (6.30% for PM10 and 3.73% for PM2.5). The source profiles and contributions presented slightly different distributions for PM10 and PM2.5, which could better reflect the actual situation. The findings based on the improved three-way factor analysis method may provide clear and deep insights into the sources of synchronously size-resolved PM. PMID- 25461117 TI - Life cycle assessment of first-generation biofuels using a nitrogen crop model. AB - This paper presents an alternative approach to assess the impacts of biofuel production using a method integrating the simulated values of a new semi empirical model at the crop production stage within a life cycle assessment (LCA). This new approach enabled us to capture some of the effects that climatic conditions and crop management have on soil nitrous oxide (N2O) emissions, crop yields and other nitrogen (N) losses. This analysis considered the whole system to produce 1 MJ of biofuel (bioethanol from wheat and biodiesel from rapeseed). Non-renewable energy use, global warming potential (GWP), acidification, eutrophication and land competition are considered as potential environmental impacts. Different co-products were handled by system expansion. The aim of this study was (i) to evaluate the variability due to site-specific conditions of climate and fertiliser management of the LCA of two different products: biodiesel from rapeseed and bioethanol from wheat produced in the Basque Country (Northern Spain), and (ii) to improve the estimations of the LCA impacts due to N losses (N2O, NO3, NH3), normally estimated with unspecific emission factors (EFs), that contribute to the impact categories analysed in the LCA of biofuels at local scale. Using biodiesel and bioethanol derived from rapeseed and wheat instead of conventional diesel and gasoline, respectively, would reduce non-renewable energy dependence (-55%) and GWP (-40%), on average, but would increase eutrophication (42 times more potential). An uncertainty analysis for GWP impact showed that the variability associated with the prediction of the major contributor to global warming potential (soil N2O) can significantly affect the results from the LCA. Therefore the use of a model to account for local factors will improve the precision of the assessment and reduce the uncertainty associated with the convenience of the use of biofuels. PMID- 25461118 TI - A novel hybrid forecasting model for PM10 and SO2 daily concentrations. AB - Air-quality forecasting in urban areas is difficult because of the uncertainties in describing both the emission and meteorological fields. The use of incomplete information in the training phase restricts practical air-quality forecasting. In this paper, we propose a hybrid artificial neural network and a hybrid support vector machine, which effectively enhance the forecasting accuracy of an artificial neural network (ANN) and support vector machine (SVM) by revising the error term of the traditional methods. The hybrid methodology can be described in two stages. First, we applied the ANN or SVM forecasting system with historical data and exogenous parameters, such as meteorological variables. Then, the forecasting target was revised by the Taylor expansion forecasting model using the residual information of the error term in the previous stage. The innovation involved in this approach is that it sufficiently and validly utilizes the useful residual information on an incomplete input variable condition. The proposed method was evaluated by experiments using a 2-year dataset of daily PM10 (particles with a diameter of 10 MUm or less) concentrations and SO2 (sulfur dioxide) concentrations from four air pollution monitoring stations located in Taiyuan, China. The theoretical analysis and experimental results demonstrated that the forecasting accuracy of the proposed model is very promising. PMID- 25461119 TI - Carbon pools and fluxes in a Tibetan alpine Kobresia pygmaea pasture partitioned by coupled eddy-covariance measurements and 13CO2 pulse labeling. AB - The Tibetan highlands host the largest alpine grassland ecosystems worldwide, bearing soils that store substantial stocks of carbon (C) that are very sensitive to land use changes. This study focuses on the cycling of photoassimilated C within a Kobresia pygmaea pasture, the dominating ecosystems on the Tibetan highlands. We investigated short-term effects of grazing cessation and the role of the characteristic Kobresia root turf on C fluxes and belowground C turnover. By combining eddy-covariance measurements with (13)CO2 pulse labeling we applied a powerful new approach to measure absolute fluxes of assimilates within and between various pools of the plant-soil-atmosphere system. The roots and soil each store roughly 50% of the overall C in the system (76 Mg C ha(-1)), with only a minor contribution from shoots, which is also expressed in the root:shoot ratio of 90. During June and July the pasture acted as a weak C sink with a strong uptake of approximately 2 g C m(-2) d(-1) in the first half of July. The root turf was the main compartment for the turnover of photoassimilates, with a subset of highly dynamic roots (mean residence time 20 days), and plays a key role for the C cycling and C storage in this ecosystem. The short-term grazing cessation only affected aboveground biomass but not ecosystem scale C exchange or assimilate allocation into roots and soil. PMID- 25461122 TI - Revolutionising the dental curriculum--delivering better oral health. AB - There is a paradigm shift taking place in healthcare with the recognition that every consultation should count for health - not merely the treatment of disease drawing on the principles of health promotion and underpinned by a strong evidence-base for clinical prevention. Institutions such as King's Health Partners [KHP], an academic health science centre in London, recognise that its responsibilities extend beyond the clinical environment to the local community and beyond and that there should be greater emphasis on promoting health. This paper outlines recent proposals by Dental Institute as a clinical academic group within KHP to promote health, the underlying philosophy, actions taken and the evidence-based resources available, as well as the challenges to be overcome. PMID- 25461123 TI - The effects of a virtual reality simulator on formative and summative assessment methods for dental clinical skills. PMID- 25461124 TI - Kinship--king's social harmonisation project. Pilot phase of a social network for use in higher education (HE). AB - Students entering Higher Education are increasingly information and communications technology literate. Many students (graduates and undergraduates) arrive as "digital residents", who are adept with social media and technologically fluent. The informal use of social media for learning is becoming increasingly evident, along with the potentially detrimental effects of a poor digital profile on employment prospects. This paper describes the creation of Kinship (King's Social Harmonisation Project), a university hosted, members only social network, which is currently being piloted in the Medical School at King's College London. Along with a number of other teaching and learning resources, it is intended to use Kinship to establish an informal code of conduct by modelling and moderating appropriate professional online behaviour. Kinship was developed using an open source Elgg platform, thanks to funding of L20,000 from the College Teaching Fund under the mentorship of Brighton University (1). This educational research project, led by Medicine, was proposed to select, customise and evaluate a social networking platform in order to provide functionality that would enhance new and existing e-learning resources, support group interaction, participation and sharing and meet the diverse needs of three academic schools: Medicine, the Dental Institute and two separate Departments, the Modern Languages Centre and the Department of English from Arts & Humanities, as a pilot for wider College deployment. Student involvement is central to the project, from conducting the evaluation to moulding and customising the functionality and look of Kinship, in order to ensure that the site is authentic and evolves in response to their wishes and requirements. Formal evaluation of Kinship commences summer 2012. PMID- 25461126 TI - The impact on dental students' knowledge in three European countries through an online module on antibiotic prescribing: a preliminary study. PMID- 25461125 TI - Scott and the logs: design and data capture in a preparatory online package for children undergoing GA for dental procedures. PMID- 25461127 TI - Testing the theory of threshold concepts in a context of dental education. Preliminary analysis. AB - This paper reports on the pilot phase of a phenomenographic study which explores the relationship between teachers' and students' perceptions of the curriculum and theory of threshold concepts, which claims that there are concepts in all disciplines which must be understood, if learners are to progress to a more advanced level of understanding. It is suggested that threshold concepts may represent ways of thinking and practising within disciplines. In this study consideration is given to the troublesome aspects of knowledge as described by David Perkins (1999) and further developed by Meyer and Land (2003). Researcher's intention is to investigate if students experience any conceptual difficulties and what the nature of these might be. Students' and teachers' accounts of how they perceive the dental curriculum might help to verify if there is a relationship between the curriculum and the theory of threshold concepts. Analysis of the troublesome aspects of knowledge may lead to the identification of threshold concepts in the dental curriculum. PMID- 25461128 TI - Graphic (games research applied to public health with innovative collaboration)- designing a serious game pilot for dental public health. PMID- 25461129 TI - Technology enhanced learning (TEL) for training dental hygienists in ukraine: report of a round table discussion. PMID- 25461130 TI - Recommendations for dental education and technology enhanced learning (TEL) in Malawi: report of a round table discussion. PMID- 25461131 TI - High-frequency phase shift measurement greatly enhances the sensitivity of QCM immunosensors. AB - In spite of being widely used for in liquid biosensing applications, sensitivity improvement of conventional (5-20MHz) quartz crystal microbalance (QCM) sensors remains an unsolved challenging task. With the help of a new electronic characterization approach based on phase change measurements at a constant fixed frequency, a highly sensitive and versatile high fundamental frequency (HFF) QCM immunosensor has successfully been developed and tested for its use in pesticide (carbaryl and thiabendazole) analysis. The analytical performance of several immunosensors was compared in competitive immunoassays taking carbaryl insecticide as the model analyte. The highest sensitivity was exhibited by the 100MHz HFF-QCM carbaryl immunosensor. When results were compared with those reported for 9MHz QCM, analytical parameters clearly showed an improvement of one order of magnitude for sensitivity (estimated as the I50 value) and two orders of magnitude for the limit of detection (LOD): 30MUgl(-1) vs 0.66MUgL(-1)I50 value and 11MUgL(-1) vs 0.14MUgL(-1) LOD, for 9 and 100MHz, respectively. For the fungicide thiabendazole, I50 value was roughly the same as that previously reported for SPR under the same biochemical conditions, whereas LOD improved by a factor of 2. The analytical performance achieved by high frequency QCM immunosensors surpassed those of conventional QCM and SPR, closely approaching the most sensitive ELISAs. The developed 100MHz QCM immunosensor strongly improves sensitivity in biosensing, and therefore can be considered as a very promising new analytical tool for in liquid applications where highly sensitive detection is required. PMID- 25461132 TI - A highly selective fluorescent ESIPT probe for the detection of Human carboxylesterase 2 and its biological applications. AB - A new ratiometric florescence probe derived from 3-hydroxyflavone (3-HF) has been developed for selective and sensitive detection of human carboxylesterase 2 (CE2). The probe is designed by modulating the excited state intramolecular proton transfer (ESIPT) emission of 3-HF via introducing of 4-ethylbenzoyloxy group. Under physiological conditions, probe 1 displays satisfying stability with very low background signal, but it can be selectively hydrolyzed by CE2 to release free 3-HF which brings remarkable changes in fluorescence spectrum. Both reaction phenotyping and chemical inhibition assays demonstrate that probe 1 is highly selective for CE2 over other human hydrolases including carboxylesterase 1, cholinesterases and paraoxonases. Probe 1 has been applied successfully to measure the real activities of CE2 in human biological samples, as well as to screen CE2 inhibitors by using tissue preparations as the enzymes sources. Additionally, probe 1 is cell membrane permeable and can be used for cellular imaging of endogenous CE2 in living cells. All of these features make it possible to serve as a promising tool for exploring the individual differences in biological function of CE2, as well as for rapid screening of selective and potent inhibitors of CE2 for further clinical use. PMID- 25461133 TI - Amplified fluorescent aptasensor through catalytic recycling for highly sensitive detection of ochratoxin A. AB - This paper describes a novel approach utilizing nano-graphite-aptamer hybrid and DNase I for the amplified detection of ochratoxin A (OTA) for the first time. Nano-graphite can effectively quench the fluorescence of carboxyfluorescein (FAM) labeled OTA specific aptamer due to their strong pi-pi; stacking interactions; while upon OTA addition, it will bind with aptamer to fold into an OTA-aptamerG quadruplex structure, which does not adsorb on the surface of nano-graphite and thus retains the dye fluorescence. Meanwhile, the G-quadruplex structure can be cleaved by DNase I, and in such case OTA is delivered from the complex. The released OTA then binds other FAM-labeled aptamers on the nano-graphite surface, and touches off another target recycling, resulting in the successive release of dye-labeled aptamers from the nano-graphite, which leads to significant amplification of the signal. Under the optimized conditions, the present amplified sensing system exhibits high sensitivity toward OTA with a limit of detection of 20nM (practical measurement), which is about 100-fold higher than that of traditional unamplified homogeneous assay. Our developed method also showed high selectivity against other interference molecules and can be applied for the detection of OTA in real red wine samples. The proposed assay is simple, cost-effective, and might open a door for the development of new assays for other biomolecules. This aptasensor is of great practical importance in food safety and could be widely extended to the detection of other toxins by replacing the sequence of the recognition aptamer. PMID- 25461134 TI - An ultra-sensitive acetylcholinesterase biosensor based on reduced graphene oxide Au nanoparticles-beta-cyclodextrin/Prussian blue-chitosan nanocomposites for organophosphorus pesticides detection. AB - This work reports a novel, ultrasensitive, and selective sensing platform based on a direct electrodeposition of electrochemical reduced graphene oxide (ERGO)-Au nanoparticles (AuNPs)-beta-cyclodextrin (beta-CD) and Prussian blue-chitosan (PB CS) on glass carbon electrode (GCE) for efficiently fixed acetylcholinesterase (AChE) to fabricate organophosphorus pesticides (OPs) biosensor. The PB-CS not only effectively catalyzed the oxidation of thiocholine (TCh), but also shifted its oxidation potential from 0.68 to 0.2V, and accordingly the sensitivity of the biosensor was obviously improved. The synergistic effect between ERGO and AuNPs significantly promoted the electron transfer between PB and GCE, and remarkably enhanced the electrochemical oxidation of TCh. Besides, beta-CD could interact with substrate by reversible bonding, which is contribute to increase the enrichment of the substrate and improve the selectivity and sensitivity of the biosensor. The integration of ERGO-AuNPs-beta-CD with PB-CS provided an advantageous and high-performance platform for sensing applications. Based on the inhibition of OPs on AChE activity, the sensor showed wide linear ranges of 7.98 2.00*10(3)pgmL(-1) and 4.3-1.00*10(3)pgmL(-1) with low detection limits of 4.14pgmL(-1) and 1.15pgmL(-1) for malathion and carbaryl, respectively. The proposed biosensor exhibited short response time, good stability and high sensitivity, which can be used for direct analysis of practical samples. PMID- 25461135 TI - A disposable electrochemical sensor for simultaneous determination of norepinephrine and serotonin in rat cerebrospinal fluid based on MWNTs ZnO/chitosan composites modified screen-printed electrode. AB - A new electrochemical sensor for simultaneous determination of norepinephrine (NE) and serotonin (5-HT) was fabricated. The electrochemical behavior of NE and 5-HT were investigated using CV and SWV at the MWNTs-ZnO/chitosan composites modified screen-printed electrode (MWNTs-ZnO/chitosan SPE). The results showed that the current responses of NE and 5-HT greatly enhanced due to the high catalytic activity of composites. The peak potentials of NE and 5-HT were separated at about 90mV and 280mV, respectively. The peak currents of NE and 5-HT were linearly dependent on their concentrations in the range of 0.5-30MUM and 0.05-1MUM, with the limit of detection of 0.2MUM and 0.01MUM, respectively. The modified electrode can be stored stably for at least 3 month at 4 degrees C in a refrigerator. Furthermore, the modified electrode was successfully applied to detect the level of NE and 5-HT in rat cerebrospinal fluid (CSF) with excellent selectivity and sensitivity. PMID- 25461136 TI - A facile label-free colorimetric aptasensor for acetamiprid based on the peroxidase-like activity of hemin-functionalized reduced graphene oxide. AB - A facile aptasensor has been developed for the colorimetric detection of acetamiprid by using the hemin-functionalized reduced graphene oxide (hemin-rGO) composites. The as-prepared hemin-rGO composites possessed both the ability of rGO to physically adsorb the aptamers and the peroxidase-like activity of hemin that could catalyse 3,3,5,5-tetramethylbenzidine (TMB) in the presence of H2O2, to produce a solution with blue color. The well-dispersed hemin-rGO composites coagulated completely at the proper salt concentration; however, the coagulation of hemin-rGO was vanished when abundant aptamers were adsorbed on its surface because the attached negatively charged DNA backbone increased individual hemin rGO electrostatic repulsion. In the detection scheme, acetamiprid with different concentrations was firstly incubated with the same amount of aptamer. The more acetamiprid in the tested solution, the less free aptamers were absorbed on the hemin-rGO surface, making the composites coagulate to a higher degree in the presence of the optimum NaCl concentration. As a consequence, the content of hemin-rGO in the supernatant was decreased after centrifugation, which catalysed oxidation of TMB in the presence of H2O2 to produce light blue color with a low absorbance. The color variation relavant to the acetamiprid concentration can be judged by the naked eyes and easily monitored by the inexpensive UV-vis spectrometer. Such designed aptasensor displayed a linear response for acetamiprid in the range from 100nM to 10MUM with a detection limit of 40nM (S/N=3). This colorimetric aptasensing platform offers great advantages including the simple operation process, low-cost portable instrument, and user-friendly applications. PMID- 25461137 TI - Kinetic epitope mapping of monoclonal antibodies raised against the Yersinia pestis virulence factor LcrV. AB - Five monoclonal antibodies, mAb7.3, mAb29.3, mAb46.3, mAb12.3 and mAb36.3, raised to the LcrV virulence factor from Yersinia pestis were characterised for their Fab affinity against the purified protein and their Fc affinity to Protein A/G as a proxy for the FcgammaR receptor. Kinetic measurements were performed label-free in a localised particle plasmon array reader. The Fc-ProteinA/G complex first order half-life was determined for each antibody and fell in the range of 0.8 3.8h. The Fab first-order half-lives had ranged from 3.4 to 9.2h although two antibodies, mAb12.3 and mAb36.3, showed low affinity interactions. Competitive binding studies of mixtures of the Fab-active antibodies were performed to measure the relative binding efficiency of one antibody in the presence of the other. A geometric relative positioning of the epitopes of mAb7.3, mAb29.3 and mAb46.3 was determined based on the footprint locus of the antibody and the percentage of competitive binding. The two known protective antibodies mAb7.3 and mAb29.3 showed greater interference, indicating epitopes close to one another compared to the non-protective mAb46.3 antibody. The Fab-Fc complex half-life screen and epitope mapping are potentially useful tools in the screening of therapeutic antibodies or vaccine candidates. PMID- 25461138 TI - Development of paper-based color test-strip for drug detection in aquatic environment: Application to oxytetracycline. AB - The wide use of antibiotics in aquaculture has led to the emergence of resistant microbial species. It should be avoided/minimized by controlling the amount of drug employed in fish farming. For this purpose, the present work proposes test strip papers aiming at the detection/semi-quantitative determination of organic drugs by visual comparison of color changes, in a similar analytical procedure to that of pH monitoring by universal pH paper. This is done by establishing suitable chemical changes upon cellulose, attributing the paper the ability to react with the organic drug and to produce a color change. Quantitative data is also enabled by taking a picture and applying a suitable mathematical treatment to the color coordinates given by the HSL system used by windows. As proof of concept, this approach was applied to oxytetracycline (OXY), one of the antibiotics frequently used in aquaculture. A bottom-up modification of paper was established, starting by the reaction of the glucose moieties on the paper with 3 triethoxysilylpropylamine (APTES). The so-formed amine layer allowed binding to a metal ion by coordination chemistry, while the metal ion reacted after with the drug to produce a colored compound. The most suitable metals to carry out such modification were selected by bulk studies, and the several stages of the paper modification were optimized to produce an intense color change against the concentration of the drug. The paper strips were applied to the analysis of spiked environmental water, allowing a quantitative determination for OXY concentrations as low as 30ng/mL. In general, this work provided a simple, method to screen and discriminate tetracycline drugs, in aquaculture, being a promising tool for local, quick and cheap monitoring of drugs. PMID- 25461139 TI - Blueprint of quartz crystal microbalance biosensor for early detection of breast cancer through salivary autoantibodies against ATP6AP1. AB - Breast cancer represents a significant health problem because of its high prevalence. Tests like mammography, which are used abundantly for the detection of breast cancer, suffer from serious limitations. Mammography correctly detects malignancy about 80-90% of the times, failing in places when (1) the tumor is small at early stage, (2) breast tissue is dense or (3) in women of less than 40 years. Serum-based detection of biomarkers involves risk of disease transfer, along with other concerns. These techniques compromise in the early detection of breast cancer. Early detection of breast cancer is a crucial factor to enhance the survival rate of patient. Development of regular screening tests for early diagnosis of breast cancer is a challenge. This review highlights the design of a handy and household biosensor device aimed for self-screening and early diagnosis of breast cancer. The design makes use of salivary autoantibodies for specificity to develop a noninvasive procedure, breast cancer specific biomarkers for precision for the development of device, and biosensor technology for sensitivity to screen the early cases of breast cancer more efficiently. PMID- 25461140 TI - One-step conjugation of aminoferrocene to phosphate groups as electroactive probes for electrochemical detection of sequence-specific DNA. AB - A straightforward electrochemical DNA biosensing approach based on exploiting organometallic compound, aminoferrocene (AFC), as electroactive probes was firstly demonstrated, where the probes could be directly labeled to the free phosphate groups of the hybridized PNA/DNA heteroduplexes merely through one-step conjugation in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and imidazole. Briefly, mercapto-terminated peptide nucleic acid (PNA) was firstly immobilized onto gold electrode and used as the capture probes for the specific recognition of target single-stranded DNA (ssDNA). After hybridization, AFC probes were directly labeled to the free 5'-terminal phosphate groups, which were activated by EDC and imidazole, of the hybridized PNA/DNA heteroduplexes, and then they were exploited as the electroactive probes to monitor the hybridization. As the captured ssDNA was labeled with AFC in the stoichiometric ratio of 1:1, thus the electrochemical analysis of the proportionally labeled AFC based on differential pulse voltammetry (DPV) enabled a quantitative determination of sequence-specific DNA. Under optimal conditions, the approach presented a good linear relationship between the current intensities and logarithm of ssDNA concentrations in the range from 0.1nM to 100nM with a detection limit of 93pM, and it rendered satisfactory analytical performance in serum samples. Furthermore, it exhibited excellent specificity toward single nucleotide polymorphism (SNP) and precluded complicated protocols. More importantly, the simplicity of this approach together with its compatibility with standard micro-fabrication techniques makes it great potential in practical applications, especially in microarray areas where simple procedures are preferred. PMID- 25461141 TI - Simultaneous electrochemical immunoassay using graphene-Au grafted recombinant apoferritin-encoded metallic labels as signal tags and dual-template magnetic molecular imprinted polymer as capture probes. AB - A novel electrochemical multiplexed immunoassay was designed for simultaneous determination of alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) using recombinant apoferritin-encoded metallic nanoparticles (rApo-M) as labels and dual-template magnetic molecularly imprinted polymers (MMIPs) as capture probes. The labels were prepared by loading recombinant apoferritin (r-Apo) and separately immobilize primary antibodies (anti-AFP and anti-CEA) via Au nanoparticles of in site growth on graphene (G). The capture probes were synthesized by self-polymerization of dopamine (DA) on the Fe3O4 nanoparticles (Fe3O4 NPs) and using AFP and CEA as the template proteins, which were used to enrich the targets simultaneously. After a sandwich-type immunoreaction, the labels were captured to the surface of MMIPs. The subsequent electrochemical stripping analysis of the metal components from the immunocomplex provide a means for quantification of targets based on the peak currents of Cd and Pb. Experimental results showed the immunoassay enabled the simultaneous determination of AFP and CEA in a single run with wide dynamic ranges of 0.001 5ngmL(-1). And the detection limits of AFP and CEA were 0.3 and 0.35pgmL(-1) (S/N=3), respectively. These results suggested that the proposed multiplexed immunoassay would be applied for clinical screening of other biomarkers. PMID- 25461142 TI - Onsite naked eye determination of cysteine and homocysteine using quencher displacement-induced fluorescence recovery of the dual-emission hybrid probes with desired intensity ratio. AB - Simple, inexpensive, portable sensing strategies for those clinically relevant molecules have attained a significant positive impact on the health care system. Herein, we have prepared a dual-emission ratiometric fluorescence probe with desired intensity ratio and demonstrated its efficiency for onsite naked eye determination of cysteine (Cys) and homocysteine (Hcy). The hybrid probe has been designed by hybridizing two differently sized CdTe quantum dots (QDs), in which the red-emitting CdTe QDs (rQDs) entrapped in the silica sphere acting as the reference signal, and the green-emitting CdTe QDs (gQDs) covalently attached on the silica surface serving as the response signal. When 1,10-phenanthroline with strong coordination ability to Cd atoms in gQDs was introduced, the fluorescence of the gQDs was effectively quenched, while the fluorescence of the rQDs stayed constant. Upon exposure to different contents of Cys or Hcy, the fluorescence of gQDs can be recovered gradually due to the displacement of the quencher. Based on the background signal of rQDs, the variations of the sensing system display continuous fluorescence color changes from red to green, which can be easily observed by the naked eye. The assay requires ~20min and has a detection limit of 2.5 and 1.7MUM for Cys and Hcy, respectively. Furthermore, we demonstrate that this sensing scheme can be fully integrated in a filter paper-based assay, thus enabling a potential point-of-care application featuring easy operation, low power consumption, and low fabrication costs. PMID- 25461143 TI - A two-photon probe for Al(3+) in aqueous solution and its application in bioimaging. AB - A salicylimine probe L with a simple structure has been researched more in-depth on fluorescence sensor properties based on two-photon (TP) absorption. L displays excellent selective turn-on fluorescence response for Al(3+) in hexamethylenetetramine-buffered (HMTA) aqueous solution (0.3M, pH=5.8) under one photon (OP) excitation. With the help of OP fluorescence, TP fluorescence titration, UV-spectra titration and Job's plot, the stoichiometric ratio of L with Al(3+) was determined to be 1:1. The coordination sites and the coordination mechanism of L with Al(3+) were analyzed in detail through (1)H NMR data. Not only with a detection limit of 5.2*10(-9)M in vitro, but also the probe has been successfully used in the live cells and tissues for the imaging of Al(3+) with TP fluorescence microscopy due to the enlarged TP cross section, providing a novel testing method for measuring Al(3+) in solution or cell tissue with low autofluorescence and cytotoxicity. PMID- 25461144 TI - A signal-off sandwich photoelectrochemical immunosensor using TiO2 coupled with CdS as the photoactive matrix and copper (II) ion as inhibitor. AB - In this work, a novel sandwich photoelectrochemical (PEC) biosensor was developed based on a signal-off strategy using TiO2 coupled with CdS quantum dots (QDs) as the photoactive matrix and copper (II) ion (Cu(2+)) as inhibitor. TiO2/CdS modified indium tin oxide (ITO) electrode was employed for primary antibody (Ab1) immobilization and the subsequent sandwich-type antibody-antigen (Ab-Ag) affinity interactions. Flower-like copper oxide (CuO) was used as labels of secondary antibody (Ab2) and immobilized on the modified electrode via specific affinity interactions between Ab2 and Ag. Cu(2+) was released by dissolving CuO with HCl, and then reacted with CdS to form CuxS (x=1, 2), which would create new energy levels for electron-hole recombination and resulted in a decrease of the photocurrent. CuO, as the labels of Ab2, was first applied in PEC biosensor based on the signal-off strategy of the Cu(2+) for CdS. Greatly enhanced sensitivity was achieved through the coupling of CdS QDs with TiO2. Besides, the introduction of polythiophene (PT-Cl) on the surface of TiO2 made the PEC signal more stable. Under 405nm irradiation at 0.1V, the PEC biosensor for H-IgG determination exhibited a linear range from 0.1pgmL(-1) to 100ngmL(-1) with a low detection limit of 0.03pgmL(-1). The proposed biosensor showed high sensitivity, stability and selectivity, which opens up a new promising signal-off PEC platform for future bioassay. PMID- 25461145 TI - Labeling-free fluorescent detection of DNA hybridization through FRET from pyrene excimer to DNA intercalator SYBR green I. AB - A novel labeling-free fluorescence complex probe has been developed for DNA hybridization detection based on fluorescence resonance energy transfer (FRET) mechanism from pyrene excimer of pyrene-functionalized poly [2-(N, N dimethylamino) ethyl methacrylate] (PFP) to SYBR Green I (SG, a specific intercalator of double-stranded DNA) in a cost-effective, rapid and simple manner. The complex probe consists of the positively charged PFP, SG and negatively charged single-stranded DNA (ssDNA). Upon adding a complementary strand to the complex probe solution, double-stranded DNA (dsDNA) was formed, followed by the intercalation of SG into dsDNA. The pyrene excimer emission was overlapped with the absorption of SG very well and the electrostatic interactions between PFP and dsDNA kept them in close proximity, enabling efficient FRET from pyrene excimer to SG. The fluorescence of SG in the duplex DNA resulting from FRET can be successfully applied to detect DNA hybridization with high sensitivity for a very low detection limit of 10nM and excellent selectivity for detection of single base pair mismatch. PMID- 25461146 TI - Synthesis and application of a molecularly imprinted polymer for the voltammetric determination of famciclovir. AB - A molecularly imprinted polymer (MIP) was synthesized and applied as additive within a carbon paste electrode for the cyclic voltammetric determination of famciclovir (FCV). Complementary computational studies were performed to study the intermolecular interactions in the pre-polymerization mixture. Derived from the computational studies, four MIP ratios were synthesized and their performance was evaluated using equilibrium rebinding assays. The MIP with the highest binding capacity was selected. A linear response was obtained in the range of 2.5*10(-6)-1.0*10(-3)M with a limit of detection at 7.5*10(-7)M. Finally, the developed MIP-voltammetry system was successfully applied for the determination of FCV in pure solutions and pharmaceutical preparations. PMID- 25461147 TI - A highly selective photoelectrochemical biosensor for uric acid based on core shell Fe3O4@C nanoparticle and molecularly imprinted TiO2. AB - Combining the surface modification and molecular imprinting technique, a novel photoelectrochemical sensing platform with excellent photochemical catalysis and molecular recognition capabilities was established for the detection of uric acid based on the magnetic immobilization of Fe3O4@C nanoparticles onto magnetic glassy carbon electrode (MGCE) and modification of molecularly imprinted TiO2 film on Fe3O4@C. The developed biosensor was highly sensitive to uric acid in solutions, with a linear range from 0.3 to 34uM and a limit of detection of 0.02MUM. Furthermore, the biosensor exhibited outstanding selectivity while used in coexisting systems containing various interferents with high concentration. The practical application of the biosensor was also realized for the selective detection of uric acid in spiked samples. The study made a successful attempt in the development of highly selective and sensitive photoelectrochemical biosensor for urine monitoring. PMID- 25461148 TI - Breath sensors for lung cancer diagnosis. AB - The scope of the applications of breath sensors is abundant in disease diagnosis. Lung cancer diagnosis is a well-fitting health-related application of this technology, which is of utmost importance in the health sector, because lung cancer has the highest death rate among all cancer types, and it brings a high yearly global burden. The aim of this review is first to provide a rational basis for the development of breath sensors for lung cancer diagnostics from a historical perspective, which will facilitate the transfer of the idea into the rapidly evolving sensors field. Following examples with diagnostic applications include colorimetric, composite, carbon nanotube, gold nanoparticle-based, and surface acoustic wave sensor arrays. These select sensor applications are widened by the state-of-the-art developments in the sensors field. Coping with sampling sourced artifacts and cancer staging are among the debated topics, along with the other concerns like proteomics approaches and biomimetic media utilization, feature selection for data classification, and commercialization. PMID- 25461149 TI - Chemiluminescence resonance energy transfer imaging on magnetic particles for single-nucleotide polymorphism detection based on ligation chain reaction. AB - A novel ligation chain reaction (LCR) methodology for single-nucleotide polymorphism (SNP) detection was developed based on luminol-H2O2-horseradish peroxidase (HRP)-mimicking DNAzyme-fluorescein chemiluminescence resonance energy transfer (CRET) imaging on magnetic particles. For LCR, four unique target complement probes (X and X(*), YG and Y(*)) for the amplification of K-ras (G12C) were designed by modifying G-quadruplex sequence at 3'-end of YG and fluorescein at 5'-end of Y(*). After the LCR, the resulting products of XYG/X(*)Y(*) with biotin-labeled X(*) were captured onto streptavidin-coated magnetic particles (SA MPs) via specific biotin-SA interaction, which stimulated the CRET reaction from hemin/G-quadruplex-catalyzed luminol-H2O2 CL system to fluorescein. By collecting signals by a cooled low-light CCD, a CRET imaging method was proposed for visual detection and quantitative analysis of SNP. As low as 0.86fM mutant DNA was detected by this assay, and positive mutation detection was achieved with a wild type to mutant ratio of 10,000:1. This high sensitivity and specificity could be attributed to not only the exponential amplification and excellent discrimination of LCR but also the employment of SA-MPs. SA-MPs ensured the feasibility of the proposed strategy, which also simplified the operations through magnetic separation and separated the reaction and detection procedures to improve sensitivity. The proposed LCR-CRET imaging strategy extends the application of signal amplification techniques to SNP detection, providing a promising platform for effective and high-throughput genetic diagnosis. PMID- 25461150 TI - A novel and convenient near-infrared fluorescence "turn off-on" nanosensor for detection of glucose and fluoride anions. AB - In this paper, 3-aminobenzeneboronic acid functionalized CuInS2 quantum dots (APBA-CuInS2 QDs) were prepared and utilized as a near-infrared fluorescence nanosensor for the detection of glucose and fluoride anions. The APBA-CuInS2 QDs had a symmetric fluorescence emission centered at 742nm that was in the near infrared spectral region. The APBA functional groups, which were reactive toward vicinal diols, could covalently bridge the glucose molecule and induced the initial dispersed APBA-CuInS2 QDs aggregate to form a large assembly, leading to the fluorescence of APBA-CuInS2 QDs turned off via the surface quenching states induced mechanism. When fluoride anions were added into the APBA-CuInS2 QDs/glucose system, the assembly was destroyed and as a result the quenched fluorescence dramatically turned on. The proposed nanosensor could be used for glucose detection in the concentration range of 0.005-8mmolL(-1) with a detection limit of 1.2MUmolL(-1). The linear range for fluoride anions was 0.1-700MUmolL( 1) with a detection limit of 0.029MUmolL(-1). Furthermore, the feasibility of the proposed nanosensor in real samples assay was also studied and satisfactory results were obtained. PMID- 25461151 TI - Detection of microRNA in clinical tumor samples by isothermal enzyme-free amplification and label-free graphene oxide-based SYBR Green I fluorescence platform. AB - MicroRNAs (miRNAs) are a kind of small molecules that involve in many important life activities. They have higher expression levels in many kinds of cancers. In this study, we developed an isothermal enzyme-free amplification (EFA) and label free graphene oxide (GO)-based SYBR Green I fluorescence platform for detection of miRNA. MiRNA-21 was used as an example to demonstrate the feasibility of the method. Results show that the sensitivity of miRNA-21 is 1pM, and the linearity range is from 1pM to 1nM. The method can specifically discriminate miRNA-21 from miRNA-210 and miRNA-214. Three tumor cell lines of A549, HepG2 and MCF7 were detected by the method. The sensitivities of them were 10(2) cells, 10(3) cells and 10(3) cells respectively. Clinical tumor samples were also tested by this method, and 29 of 40 samples gave out positive signals. The method holds great promise in miRNA detection due to its convenience, rapidness, inexpensive and specificity. PMID- 25461152 TI - Fabrication of biomembrane-like films on carbon electrodes using alkanethiol and diazonium salt and their application for direct electrochemistry of myoglobin. AB - Alkanethiols generally form self-assembled monolayers on gold electrodes and the electrochemical reduction of aromatic diazonium salts is a popular method for the covalent modification of carbon. Based on the reaction of alkanethiol with aldehyde groups covalently bound on carbon surface by the electrochemical reduction of aromatic diazonium salts, a new strategy for the modification of carbon electrodes with alkanethiols has been developed. The modification of carbon surface with aldehyde groups is achieved by the electrochemical reduction of aromatic diazonium salts in situ electrogenerated from a nitro precursor, p nitrophenylaldehyde, in the presence of nitrous acid. By this way, in situ electrogenerated p-aminophenyl aldehyde from p-nitrophenylaldehyde immediately reacts with nitrous acid, effectively minimizing the side reaction of amine groups and aldehyde groups. The as-prepared alkanethiol-modified glassy carbon electrode was further used to make biomembrane-like films by casting didodecyldimethylammonium bromide on its surface. The biomembrane-like films enable the direct electrochemistry of immobilized myoglobin for the detection of hydrogen peroxide. The response is linear over the range of 1-600MUM with a detection limit of 0.3MUM. PMID- 25461153 TI - A Ga(3+)self-assembled fluorescent probe for ATP imaging in vivo. AB - Adenosine 5'-triphosphate (ATP) is a functional molecule associated with many important biological processes. Fluorescent detection methods for ATP with facile performance and high selectivity are in demand. One of the possible multi membered arrays assembled between DHBO and Ga(3+) ions was conducted in aqueous solution, which can selectively recognize ATP with fluorescence enhancement from ADP, AMP and other structurally similar nucleoside triphosphates in vitro and in vivo. ATP facilitates the interaction between DHBO and Ga(3+) ions, resulting in the fluorescence increase. The detection limit for ATP was calculated to be 5.49*10(-7)M, which is much lower than that of intracellular concentrations (1 10mM). In addition, DHBO-Ga(3+) can be applied to detect ATP-relevant enzyme activity. PMID- 25461154 TI - Binding-induced collapse of DNA nano-assembly for naked-eye detection of ATP with plasmonic gold nanoparticles. AB - The detection of small molecules depends heavily on complicated GC-MS (Gas chromatography-mass spectrometry), HPLC (High-performance liquid chromatography) and some other complicated instruments that are not suitable for point of care detection. Here, we have demonstrated a fast (in 10min), simple (instrument-free) and effective detection platform for small molecule-ATP. In our design, we engineered the hybridization region of aptamer and assembled it into a superstructure to avoid the exposed flexible ends. The binding of ATP triggered the collapse of the superstructures to produce single stranded DNA that can obviously tune the plasmonic coupling of unmodified gold nanoparticles (AuNPs). Compared to detection platforms based on fully hybridized aptamer double helix, the detection time was significantly decreased to 10min. The resulting color change can be recognized by naked eyes. Our detection is highly specific and selective. Furthermore, a logic gate with multiplexed detection capability for ATP and DNA were demonstrated. PMID- 25461155 TI - Ultrasensitive detection of lead ion sensor based on gold nanodendrites modified electrode and electrochemiluminescent quenching of quantum dots by electrocatalytic silver/zinc oxide coupled structures. AB - A signal-off electrochemiluminescence (ECL) DNA sensor based on gold nanodendrites (Au NDs) modified indium tin oxide (ITO) electrode for the detection of lead ion (Pb(2+)) was developed. Well-defined Au NDs were prepared on ITO electrode using low-potential synthesis, assisted by ethylenediamine. Based on Pb(2+)-specific deoxyribozyme, the silver/zinc oxide (Ag/ZnO) with coupled structure, prepared by one-pot method, was close to the surface of the electrode to catalyze the reduction of part of H2O2, the coreactant for cathodic ECL emission, leading to a decrease of ECL intensity. In addition, taking advantage of the larger surface area to capture a large amount of capture probe as well as excellent conductivity of Au NDs, the sensor could detect Pb(2+) quantitatively in a wider range, and performed excellent selectivity. Furthermore, such simple and sensitive DNA sensor was successfully applied for the detection of Pb(2+) in lake water and human serum samples, respectively. PMID- 25461156 TI - Gold nanocluster-based fluorescence biosensor for targeted imaging in cancer cells and ratiometric determination of intracellular pH. AB - The dysregulated pH is working as a mark of cancer. It is a challenge for developing a biosensor for targeted imaging in cancer cells and monitoring of intracellular pH. Here, a ratiometric fluorescence biosensor for pH determination was developed with targeted imaging into folate acceptor (FR)-rich cancer cells at the same time. AuNCs protected by bovine serum albumin (BSA) worked as reference fluorophore and fluorescein-isothiocyanate (FITC) acted as the response signal for pH. For targeted imaging of cancer cells, the AuNCs were simultaneously conjugated with folic acid (FA). The developed ratiometric biosensor can monitor pH with a wide linear range from 6.0-7.8 with a pKa at 6.84. Under every different pH condition, the probe showed high selectivity over various metal ions and amino acids with its fluorescence ratio stayed almost constant (<5%). It also showed good cyclic accuracy when pH switched between 6.0 and 8.0, as well as low cytotoxicity. The AuNC-based inorganic-organic nanohybrid biosensor showed good cell-permeability, low cytotoxicity, and long-term photostability. Accordingly, the pH biosensor was employed to gain targeted imaging in FR(+ve) Hela cells with FR(-ve) lung carcinoma cells A549 as comparison, and achieved to monitor the pH changes in Hela cells. PMID- 25461157 TI - Sensitive detection of point mutation using exponential strand displacement amplification-based surface enhanced Raman spectroscopy. AB - Accurate identification of point mutation is particularly imperative in the field of biomedical research and clinical diagnosis. Here, we develop a sensitive and specific method for point mutation assay using exponential strand displacement amplification (SDA)-based surface enhanced Raman spectroscopy (SERS). In this method, a discriminating probe and a hairpin probe are designed to specifically recognize the sequence of human K-ras gene. In the presence of K-ras mutant target (C->T), the 3'-terminal of discriminating probe and the 5'-terminal of hairpin probe can be ligated to form a SDA template. Subsequently, the 3' terminal of hairpin probe can function as a primer to initiate the SDA reaction, producing a large amount of triggers. The resultant triggers can further hybridize with the discriminating probes to initiate new rounds of SDA reaction, leading to an exponential amplification reaction. With the addition of capture probe-modified gold nanoparticles (AuNPs) and the Rox-labeled reporter probes, the amplified triggers can be assembled on the surface of AuNPs through the formation of sandwich hybrids of capture probe-trigger-reporter probe, generating a strong Raman signal. While in the presence of K-ras wild-type target (C), neither ligation nor SDA reaction can be initiated and no Raman signal is observed. The proposed method exhibits high sensitivity with a detection limit of 1.4pM and can accurately discriminate as low as 1% variant frequency from the mixture of mutant target and wild-type target. Importantly, this method can be further applied to analyze the mutant target in the spiked HEK293T cell lysate, holding great potential for genetic analysis and disease prognosis. PMID- 25461158 TI - Label free detection of 5'hydroxymethylcytosine within CpG islands using optical sensors. AB - Significant research has been invested in correlating genetic variations with different disease probabilities. Recently, it has become apparent that other DNA modifications, such as the addition of a methyl or hydroxymethyl group to cytosine, can also play a role. While these modifications do not change the sequence, they can negatively impact the function. Therefore, it is critical to be able to both read the genetic code and identify these modifications. Currently, the detection of hydroxymethylated cytosine (5'hmC) and the two closely related variants, cytosine (C) and 5'methylcytosine (5'mC), relies on a combination of nucleotide modification steps, followed by PCR and gene sequencing. However, this approach is not ideal because transcription errors which are inherent to the PCR process can be misinterpreted as fluctuations in the relative C:5'mC:5'hmC concentrations. As such, an alternative method which does not rely on PCR or nucleotide modification is desirable. One approach is based on label-free optical resonant cavity sensors. In the present work, toroidal resonant cavity sensors are functionalized with antibodies to enable label-free detection and discrimination between C, 5'mC, and 5'hmC in real-time without PCR. Specifically, epoxide chemistry is used to covalently attach the 5'hmC antibody to the surface of the cavity. Subsequently, to thoroughly characterize the sensor platform, detection of C, 5'mC, and 5'hmC is performed over a concentration range from pM to nM. At low (pM) concentrations, the hydroxymethylated cytosine produces a significantly larger signal than the structurally similar epigenetic markers; thus demonstrating the applicability of this platform. PMID- 25461159 TI - Photoluminescent sensing for acidic amino acids based on the disruption of graphene quantum dots/europium ions aggregates. AB - A simple mix-and-detect photoluminescence method was developed for the turn-on detection of acidic amino acids. To achieve this, graphene quantum dots (GQDs), which emit both down-conversion and up-conversion photoluminescence were prepared by solvothermal synthesis. The carboxylic acid-rich surface not only increases the water solubility of the prepared GQDs, but also makes Eu(3+)-triggered GQDs aggregation possible, thus causing the photoluminescence quenching of GQDs. The quenched photoluminescence can be recovered by the competition between acidic amino acids and GQDs for Eu(3+). Under optimized conditions, sensitive and specific acidic amino acids quantitation can be achieved by utilizing the changes in either down-conversion or up-conversion photoluminescence. Up-conversion mode gives a little lower detection limit than the down-conversion one. Nearly overlapped calibration curves were obtained for the two acidic amino acids, glutamic acid (Glu) and aspartic acid (Asp), thus suggesting that the proposed method can be used not only for the quantitation of individual acidic amino acids, but also for the detection of total amount of them. PMID- 25461160 TI - A novel immunochromatographic system for easy-to-use detection of group 1 avian influenza viruses with acquired human-type receptor binding specificity. AB - A switch of viral hemagglutinin receptor binding specificity from bird-type alpha2,3- to human-type alpha2,6-linked sialic acid is necessary for an avian influenza virus to become a pandemic virus. In this study, an easy-to-use strip test to detect receptor binding specificity of influenza virus was developed. A biotinylated anti-hemagglutinin antibody that bound a broad range of group 1 influenza A viruses and latex-conjugated alpha2,3 (blue) and alpha2,6 (red) sialylglycopolymers were used in an immunochromatographic strip test, with avidin and lectin immobilized on a nitrocellulose membrane at test and control lines, respectively. Accumulation of a sialylglycopolymer-virus-antibody complex at the test line was visualized by eye. The strip test could be completed in 30min and did not require special equipment or skills, thereby avoiding some disadvantages of current methods for analyzing receptor binding specificity of influenza virus. The strip test could detect the receptor binding specificity of a wide range of influenza viruses, as well as small increases in the binding affinity of variant H5N1 viruses to alpha2,6 sialylglycans at viral titers >128 hemagglutination units. The strip test results were in agreement with those of ELISA virus binding assays, with correlations >0.95. In conclusion, the immunochromatographic strip test developed in this study should be useful for monitoring potential changes in the receptor binding specificity of group 1 influenza A viruses in the field. PMID- 25461161 TI - Enzyme incorporated microfluidic device for in-situ glucose detection in water-in air microdroplets. AB - Droplet generating microfluidic systems can provide miniaturized bioanalytical tools by using the homogenous and high-throughput droplets as nanoreactors. In this study, we demonstrated a sensitive and in-situ glucose monitoring system using water-in-air droplets in an enzyme incorporated microfluidic device. A thin film structure of a glucose oxidase (GOx) enzyme immobilized hydrogel was constructed in the middle of the microfluidic channel, and nanoliter scaled water in-air droplets which contain a glucose sample, horseradish peroxidase (HRP), and an Amplex Red substrate were generated by flow focusing of water phase with air. Once the droplets passed through the enzyme trapped hydrogel, the droplets temporarily halted and a GOx mediated catalytic reaction with glucose proceeded, resulting in producing fluorescent resorufin products in the droplets. With optimized conditions such as the thickness of a hydrogel film and the size and flowing rate of droplets, fluorescence intensities of the released droplets linearly increased in proportional to the glucose concentration up to 3mM, and the limit of detection was calculated as 6.64uM. A spiked glucose in a real urine sample was also successfully analyzed, and the functionality of the proposed enzyme immobilized microfluidic chip was maintained for at least two weeks without loss of enzymatic activity and detection sensitivity. Thus, our methodology suggests a novel droplet based glucose sensing chip which can monitor glucose in a real-time and high-throughput manner. PMID- 25461162 TI - Surface assembly of nano-metal organic framework on amine functionalized indium tin oxide substrate for impedimetric sensing of parathion. AB - The present paper reports the assembly and pesticide sensing application of a nanometal organic framework [Cd(atc)(H2O)2]n ('atc'=2-aminoterephthalic acid). The assembly of the NMOF film has been achieved by sequential dipping of a 2 aminobenzylamine (2-ABA) modified indium tin oxide (ITO) slide in organic linker 'atc' and metal ion 'Cd(2+)' solutions. The different structural and morphological characteristics of the NMOF thin film have been characterized. The availability of pendent -COOH functional groups on the assembled NMOF film is exploited to synthesize a pesticide immunosensor by conjugating the NMOF film with anti-parathion antibody. This immunosensor has been explored for the electrochemical impedance spectroscopy (EIS) based analysis of parathion in the concentration range of 0.1-20ng/mL. The proposed detection is specific with respect to other organophosphate compounds, e.g. malathion, paraoxon, fenitrothion, monochrotophos and dichlorovos. The proposed sensor shows the detection limit of 0.1ng/mL and it is applicable for analysis of parathion in a rice sample. The sensor's performance is validated by comparting the obtained results with gas chromatographic data. PMID- 25461163 TI - Aptasensor for electrochemical sensing of angiogenin based on electrode modified by cationic polyelectrolyte-functionalized graphene/gold nanoparticles composites. AB - Herein, a label-free and highly sensitive electrochemical aptasensor for the detection of angiogenin was proposed based on a conformational change of aptamer and amplification by poly(diallyldimethyl ammonium chloride) (PDDA) functionalized graphene/gold nanoparticles (AuNPs) composites-modified electrode. PDDA-functionalized graphene (P-GR) nanosheets as the building block in the self assembly of GR nanosheets/AuNPs heterostructure enhanced the electrochemical detection performance. The electrochemical aptasensor has an extraordinarily sensitive response to angiogenin in a linear range from 0.1pM to 5nM with a detection limit of 0.064pM. The developed sensor provides a promising strategy for the cancer diagnosis in medical application in the future. PMID- 25461164 TI - A graphene oxide based fluorescence resonance energy transfer (FRET) biosensor for ultrasensitive detection of botulinum neurotoxin A (BoNT/A) enzymatic activity. AB - Botulinum neurotoxins (BoNTs) are among the most potent toxic bacterial proteins for humans, which make them potential agents for bioterrorism. Therefore, an ultrasensitive detection of BoNTs and their active states is in great need as field-deployable systems for anti-terrorism applications. We report the construction of a novel graphene oxide (GO)-peptide based fluorescence resonance energy transfer (FRET) biosensor for ultrasensitive detection of the BoNT serotype A light chain (BoNT-LcA) protease activity. A green fluorescence protein (GFP) modified SNAP-25 peptide substrate (SNAP-25-GFP) was optimally designed and synthesized with the centralized recognition/cleavage sites. This FRET platform was constructed by covalent immobilization of peptide substrate on GO with BSA passivation which have advantages of low non-specific adsorption and high stability in protein abundant solution. BoNT-LcA can specifically cleave SNAP-25 GFP substrate covalently immobilized on GO to release the fragment with GFP. Based on fluorescence signal recovery measurement, the target BoNT-LcA was detected sensitively and selectively with the linear detection range from 1fg/mL to 1pg/mL. The limit of detection (LOD) for BoNT-LcA is around 1fg/mL. PMID- 25461165 TI - A dual-amplified electrochemical detection of mRNA based on duplex-specific nuclease and bio-bar-code conjugates. AB - On the basis of strong preference for cleaving double-stranded DNA or DNA in DNA:RNA heteroduplexes of duplex-specific nuclease (DSN), a dual-amplified electrochemical detection of mRNA was developed in this article, by coupling the enhancement of DSN and bio-bar-code conjugates. Capture probe was linked with magnetic nanoparticles (MNPs) at its 5' end and bio-bar-code at its 3' end. In the presence of target surviving mRNA, all hybridized S1 strands were cleaved off the biosensor by the DSN, and the bio-bar-code probe with CdS nanoparticles (CdS NPs) was released into the solution. The metal sulfide nanoparticles were measured by anodic stripping voltammetry (ASV) subsequently. This assay exhibited high sensitivity and selectivity with a detection limit of 0.48fM. In addition, we proved that this simple and cost-effective strategy is capable of detecting the target in complicated biological samples and holds great potential application in biomedical research and clinical diagnostics. PMID- 25461166 TI - Sensitive detection of C-reactive protein using optical fiber Bragg gratings. AB - An accurate and highly sensitive sensor platform has been demonstrated for the detection of C-reactive protein (CRP) using optical fiber Bragg gratings (FBGs). The CRP detection has been carried out by monitoring the shift in Bragg wavelength (DeltalambdaB) of an etched FBG (eFBG) coated with an anti-CRP antibody (aCRP)-graphene oxide (GO) complex. The complex is characterized by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy and atomic force microscopy. A limit of detection of 0.01mg/L has been achieved with a linear range of detection from 0.01mg/L to 100mg/L which includes clinical range of CRP. The eFBG sensor coated with only aCRP (without GO) show much less sensitivity than that of aCRP-GO complex coated eFBG. The eFBG sensors show high specificity to CRP even in the presence of other interfering factors such as urea, creatinine and glucose. The affinity constant of ~1.1*10(10)M(-1) has been extracted from the data of normalized shift (DeltalambdaB/lambdaB) as a function of CRP concentration. PMID- 25461167 TI - Chemostat-like microfluidic platform for highly sensitive detection of heavy metal ions using microbial biosensors. AB - Reporter-gene-based microbial biosensors have high potential for detecting small molecules, including heavy metal ions (HMIs), in a sensitive and selective manner by involving low costs. However, the sensitivity and dynamic range of the sensing mechanism are largely limited by the conventional culture environment that relies on the batch-type addition of the small molecules in nutrients and the subsequent genetic induction of sensing microbes. Here, we describe a high-throughput, chemostat-like microfluidic platform that can continuously supply both nutrients and inducers (HMIs) using microfabricated ratchet structures and a mixing microchannel network. We found that the microfluidic platform not only allowed microbial biosensors to be highly concentrated in a detection microchamber array but also enabled them to continuously grow and control synthetic genetic circuits in response to heavy metals. We also demonstrated that the combination of the platform and microbial biosensors enhanced the sensitivity for detecting divalent lead and cadmium ions by approximately three orders of magnitude relative to conventional batch-type methods. Because the platform is portable and only requires small sample volumes and fluorescent detection, the chemostat-like microfluidic platform in conjunction with microbial biosensors could be widely utilized to facilitate the specific and sensitive detection of molecular analytes on a chip. PMID- 25461168 TI - Highly sensitive reduced graphene oxide microelectrode array sensor. AB - Reduced graphene oxide (rGO) has been fabricated into a microelectrode array (MEA) using a modified nanoimprint lithography (NIL) technique. Through a modified NIL process, the rGO MEA was fabricated by a self-alignment of conducting Indium Tin Oxide (ITO) and rGO layer without etching of the rGO layer. The rGO MEA consists of an array of 10MUm circular disks and microelectrode signature has been found at a pitch spacing of 60MUm. The rGO MEA shows a sensitivity of 1.91nAMUm(-1) to dopamine (DA) without the use of mediators or functionalization of the reduced graphene oxide (rGO) active layer. The performance of rGO MEA remains stable when tested under highly resistive media using a continuous flow set up, as well as when subjecting it to mechanical stress. The successful demonstration of NIL for fabricating rGO microelectrodes on flexible substrate presents a route for the large scale fabrication of highly sensitive, flexible and thin biosensing platform. PMID- 25461169 TI - Graphene oxide-based biosensor for detection of platelet-derived microparticles: A potential tool for thrombus risk identification. AB - We report here design of a graphene oxide-based electrochemical biosensor for detection of platelet-derived microparticles (PMPs), a major risk factor for arterial pro-thrombotic pathologies like acute myocardial infarction and stroke. Electrodes were fabricated with immobilized layers of graphene oxide and a specific antibody targeted against active conformation of integrin alphaIIbbeta3 on PMP surface. Results showed progressive rise in impedance in Nyquist plots with increasing number of PMPs in analyte. The sensor was highly specific for PMPs and did not identify microparticles originating from other cells. Blood obtained from patients diagnosed with acute myocardial infarction exhibited significantly higher values of impedance, consistent with larger number of circulating PMPs in these patients, as compared to samples from healthy individuals, thus validating biosensor as a specific, sensitive, label-free and cost-effective tool for rapid point-of-care detection of PMPs at bedside. Our biosensor is most ideal for mass population screening programs at periphery-level healthcare units with limited resources. It is aimed at early detection of individuals having higher imminent cardiovascular risk, as well as for routine analysis, which in turn would contribute to better management and survival of screened 'high-risk' subjects. PMID- 25461170 TI - Three-dimensional electrochemical immunosensor for sensitive detection of carcinoembryonic antigen based on monolithic and macroporous graphene foam. AB - A high performance three-dimensional (3D) electrochemical immunosensor was developed for sensitive detection of the tumor biomarker, carcinoembryonic antigen (CEA). Monolithic and macroporous graphene foam grown by chemical vapor deposition (CVD) served as the scaffold of the free-standing 3D electrode. Immuno recognition interface was fabricated via simple and non-covalent immobilization of antibody using lectin-mediated strategy. Briefly, the well-known lectin macromolecule (concanavalin A, Con A) monolayer was functionalized on 3D graphene (3D-G) using in-situ polymerized polydopamine as the linker. Then the widely used horseradish peroxidase (HRP)-labeled antibody (anti-CEA) in immunoassays was efficiently immobilized to demonstrate the recognition interface via the biospecific affinity of lectin with sugarprotein. The 3D immunosensor is able to detect CEA with a wide linear range (0.1-750.0ngml(-1)), low detection limit (~90pgml(-1) at a signal-to-noise ratio of 3), and short incubation time (30min). Furthermore, this biosensor was used for the detection of the CEA level in real serum samples. PMID- 25461171 TI - Novel cell-based odorant sensor elements based on insect odorant receptors. AB - Development of cell-based odorant sensor elements combined not only high degree of sensitivity and selectivity but also long-term stability is crucial for their practical applications. Here we report the development of a novel cell-based odorant sensor element that sensitively and selectively detects odorants and displays increased fluorescent intensities over a long period of time. Our odorant sensor elements, based on Sf21 cell lines expressing insect odorant receptors, are sensitive to the level of several tens of parts per billion in solution, can selectively distinguish between different types of odorants based on the odorant selectivity intrinsic to the expressed receptors, and have response times of approximately 13s. Specifically, with the use of Sf21 cells and insect odorant receptors, we demonstrated that the established cell lines stably expressing insect odorant receptors are able to detect odorants with consistent responsiveness for at least 2 months, thus exceeding the short life-span normally associated with cell-based sensors. We also demonstrated the development of a compact odorant sensor chip by integrating the established insect cell lines into a microfluidic chip. The methodology we established in this study, in conjunction with the large repertoire of insect odorant receptors, will aid in the development of practical cell-based odorant sensors for various applications, including food administration and health management. PMID- 25461172 TI - 3D metal-organic framework as highly efficient biosensing platform for ultrasensitive and rapid detection of bisphenol A. AB - As is well known, bisphenol A (BPA), usually exists in daily plastic products, is one of the most important endocrine disrupting chemicals. In this work, copper centered metal-organic framework (Cu-MOF) was synthesized, which was characterized by SEM, TEM, XRD, FTIR and electrochemical method. The resultant Cu MOF was explored as a robust electrochemical biosensing platform by choosing tyrosinase (Tyr) as a model enzyme for ultrasensitive and rapid detection of BPA. The Cu-MOF provided a 3D structure with a large specific surface area, which was beneficial for enzyme and BPA absorption, and thus improved the sensitivity of the biosensor. Furthermore, Cu-MOF as a novel sorbent could increase the available BPA concentration to react with tyrosinase through pi-pi stacking interactions between BPA and Cu-MOF. The Tyr biosensor exhibited a high sensitivity of 0.2242A M(-1) for BPA, a wide linear range from 5.0*10(-8) to 3.0*10-6moll(-1), and a low detection limit of 13nmoll(-1). The response time for detection of BPA is less than 11s. The proposed method was successfully applied to rapid and selective detection of BPA in plastic products with satisfactory results. The recoveries are in the range of 94.0-101.6% for practical applications. With those remarkable advantages, MOFs-based 3D structures show great prospect as robust biosensing platform for ultrasensitive and rapid detection of BPA. PMID- 25461173 TI - Mapping hydrogen sulfide in rats with a novel azo-based fluorescent probe. AB - We report herein a reaction-based fluorescent switch-on sulfide sensor, azo3, for the quantification of endogenous sulfides in rat tissues. The sensor was exploited based on the novel azo-sulfide chemistry and designed by locking the rhodol fluorophore into its nonfluorescent form with an azo group. However, the azo group would undergo a specific and biocompatible reaction with sulfides, triggering significant fluorescence increasements which were linear to the concentrations of sulfides. Azo3 distinguished by its high sensitivity (148-fold fluorescent switch-on response), good selectivity (22-fold more selective towards sulfides than other bio-thiol species) and low detection limit (500nM). Moreover, the azo3-based assay for biological sulfides displayed the unique advantage of being insusceptible to ultraviolet (UV) irradiation. Azo3 has been successfully applied to the quantification of endogenous sulfides in rat plasma and tissues including heart, brain, liver, spleen, lung and kidney. In addition to providing azo3 as a valuable tool to analyze sulfides in biological samples, we also discussed the influences of the electron effect on the sensitivity of the probes, which would shed some light on the design of future reaction-based probes. PMID- 25461174 TI - One-step synthesis of redox-active polymer/AU nanocomposites for electrochemical immunoassay of multiplexed tumor markers. AB - In this work, a simple and sensitive multiplexed immunoassay protocol for simultaneous electrochemical determination of alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) was designed using redox-active nanocomposites. As the redox-active species, the poly(o-phenylenediamine) (POPD)/Au nanocomposite and poly(vinyl ferrocene-2-aminothiophenol) (poly(VFc-ATP))/Au nanocomposite were obtained by one-step method which HAuCl4 was used as the oxidant. With Au nanoparticles (AuNPs), the nanocomposites were successful to immobilize labeled anti-CEA and anti-AFP as the immunosensing probes. The proposed electrochemical immunoassay enabled the simultaneous monitoring of AFP and CEA in a wide range of 0.01-100ngmL(-1). The detection limits was 0.006ngmL(-1) for CEA and 0.003ngmL( 1) for AFP (S/N=3). The assay results of serum samples with the proposed method were well consistent with the reference values from standard ELISA method. And the negligible cross-reactivity between the two analytes makes it possesses potential promise in clinical diagnosis. PMID- 25461175 TI - A new aptamer/graphene interdigitated gold electrode piezoelectric sensor for rapid and specific detection of Staphylococcus aureus. AB - A novel aptamer/graphene interdigitated gold electrode piezoelectric sensor was developed for the rapid and specific detection of Staphylococcus aureus (S. aureus) by employing S. aureus aptamer as a biological recognition element. 4 Mercaptobenzene-diazonium tetrafluoroborate (MBDT) salt was used as a molecular cross-linking agent to chemically bind graphene to interdigital gold electrodes (IDE) that are connected to a series electrode piezoelectric quartz crystal (SPQC). S. aureus aptamers were assembly immobilized onto graphene via the pi-pi stacking of DNA bases. Due to the specific binding between S. aureus and aptamer, when S. aureus is present, the DNA bases interacted with the aptamer, thereby dropping the aptamer from the surface of the graphene. The electric parameters of the electrode surface was changed and resulted in the change of oscillator frequency of the SPQC. This detection was completed within 60min. The constructed sensor demonstrated a linear relationship between resonance frequency shifts with bacterial concentrations ranging from 4.1*10(1)-4.1*10(5)cfu/mL with a detection limit of 41cfu/mL. The developed strategy can detect S. aureus rapidly and specifically for clinical diagnosis and food testing. PMID- 25461176 TI - An aptamer based surface plasmon resonance biosensor for the detection of ochratoxin A in wine and peanut oil. AB - Ochratoxin A (OTA), as a kind of chlorophenolic mycotoxin, exist widely in plant origin food and is harmful to human. Herein, a surface plasmon resonance (SPR) biosensor using an anti-OTA aptamer immobilized sensor chip was developed to measure ochratoxin A (OTA) quantificationally through a straightforward direct binding assay. The streptavidin protein as a crosslinker was immobilized onto the surface of a sensor chip and the biotin-aptamer was captured through streptavidin biotin interaction. The biosensor exhibited a detection range from 0.094 to 100ng/mL (linear range from 0.094 to 10ng/mL) of OTA with a lower detection limit of 0.005ng/mL. Detection of OTA in wine and peanut oil was further performed in the SPR biosensor using simple liquid-liquid extraction for sample pretreatments. Recoveries of ochratoxin A from spiked samples ranged from 86.9% to 116.5% and coefficients of variation (CVs) ranged from 0.2% to 6.9%. The developed methods in our studies showed good analytical performances with limits of detection much lower than the maximum residue limit, as well as a good reproducibility and stability. PMID- 25461177 TI - Quantum dots and duplex-specific nuclease enabled ultrasensitive detection and serotyping of Dengue viruses in one step in a single tube. AB - Leveraging on the enzymatic processing of Dengue virus (DV) RNA hybridized quantum dot-capped DNA capture probes (QD-CPs), an ultrasensitive assay for the detection and serotyping of DVs is described in the report. Briefly, DV-specific DNA CPs are first capped by QDs and then conjugated to magnetic beads. In a sample solution, strands of DV RNA form heteroduplexes with the QD-CPs on the magnetic beads. The CPs together with the QDs in the heteroduplexes are subsequently cleaved off the magnetic beads by a duplex-specific nuclease (DSN), releasing the QDs to the solution, freeing the target RNA strands, and availing them for another around of hybridization with the remaining QD-CPs. After removing the magnetic beads along with unreacted (uncleaved) QD-CPs by using a permanent magnet, ultrasensitive fluorescent detection of DV is realized through the cleaved QDs. Serotyping of DV is accomplished by a judicious design of the QD CPs. The assay combines excellent signal generation by the highly fluorescent QDs and the effortlessness of utilizing magnetic beads in the removal of the unreacted QD-CPs. The highly efficient DSN cleavage in conjunction with its excellent mismatch discrimination ability permits serotyping of DVs in one tube with excellent sensitivity and selectivity. PMID- 25461178 TI - Attomolar detection of BRCA1 gene based on gold nanoparticle assisted signal amplification. AB - In this work, we report a simple strategy for signal amplification using appropriately functionalized gold nanoparticles in an electrochemical genosensor which led to attomolar detection of breast cancer 1 (BRCA1) gene. The sensor was developed by the layer-by-layer assembly of mercaptopropionic acid (MPA), polyethylene glycol (PEG) functionalized gold nanoparticle (AuNPPEG), capture DNA (DNA-c), target BRCA1 DNA (DNA-t) and gold nanoparticle labeled reporter DNA (DNA r.AuNP) on gold electrode. PEG functionalized gold nanoparticles on the MPA surface provided good electron conducting path nullifying the insulating effect of MPA and also act as a proper immobilization platform for the DNA-c by the large number of carboxyl groups present on the functionalized gold nanoparticles. We demonstrated that the incorporation of MPA functionalized gold nanoparticles (AuNPMPA) as an electrochemical label in this sensor design could significantly enhance the sensitivity in the detection. The DNA hybridization of DNA-r.AuNP with target probe was measured by chronoamperometry, electrochemical impedance spectroscopy (EIS), and scanning tunnelling spectroscopy (STS). Electrochemical quartz crystal microbalance (EQCM) experiments were used to support the detection and also to calculate the number of adsorbed molecules on the surface. Under optimum conditions the present sensor exhibited high sensitivity and a very low detection limit of 50attomolar DNA target (294.8attogram BRCA1gene/ml). It shows excellent selectivity against non complementary sequences and 3 base mismatch complementary targets. It also shows good reproducibility, stability and reusability and the developed sensor surface is suitable for point-of care applications. PMID- 25461179 TI - Quartz crystal microbalance detection of protein amplified by nicked circling, rolling circle amplification and biocatalytic precipitation. AB - A novel quartz crystal microbalance (QCM) assay was described for sensitive detection of protein. Lysozyme was used as a model of protein. To enhance the sensitivity of this QCM biosensor, biocatalytic precipitation (BCP) reaction combined with strand-scission cycle and rolling circle amplification (RCA) were applied together for the first time. As a result of the multi-signal amplification in this aptasensor, the detection limit for lysozyme was down to 0.3fM. What is more, this amplified QCM biosensor also showed good selectivity and practical usage in human serum. PMID- 25461180 TI - Optimal geometric parameters of ordered arrays of nanoprisms for enhanced sensitivity in localized plasmon based sensors. AB - Plasmonic sensors based on ordered arrays of nanoprisms are optimized in terms of their geometric parameters like size, height, aspect ratio for Au, Ag or Au0.5 Ag0.5 alloy to be used in the visible or near IR spectral range. The two figures of merit used for the optimization are the bulk and the surface sensitivity: the first is important for optimizing the sensing to large volume analytes whereas the latter is more important when dealing with small bio-molecules immobilized in close proximity to the nanoparticle surface. A comparison is made between experimentally obtained nanoprisms arrays and simulated ones by using Finite Elements Methods (FEM) techniques. PMID- 25461181 TI - Superoxide microsensor integrated into a Sensing Cell Culture Flask microsystem using direct oxidation for cell culture application. AB - A new electrochemical sensor system for reliable and continuous detection of superoxide radical release from cell culture was developed utilizing direct oxidation of superoxide on polymer covered gold microelectrodes. Direct superoxide oxidation was demonstrated to provide robust measurement principle for sensitive and selective reactive oxygen species (ROS) quantification without the need for biocomponent supported conversion. Sensor performance was investigated by using artificial enzymatic superoxide production revealing a sensitivity of 2235AM(-1)m(-2). An electrode protection layer with molecular weight cut-off property from adsorbed linear branched polyethylenimine was successfully introduced for long term and selectivity improvement. Thin-film based sensor chip fabrication with implemented three-electrode setup and full integration into the technological platform Sensing Cell Culture Flask was described. Cell culturing directly on-chip and free radical release by phorbol-12-myristate-13-acetate (PMA) stimulation was demonstrated using T-47D human breast cancer carcinoma cell model. Transient extracellular superoxide production upon stimulation was successfully observed from amperometric monitoring. Signal inhibition from scavenging of extracellular superoxide by specific superoxide dismutase (SOD) showed the applicability for selective in vitro ROS determination. The results confirm the possibility of direct superoxide oxidation, with exclusion of the main interfering substances uric acid and hydrogen peroxide. This offers new insights into the development of reliable and robust ROS sensors. PMID- 25461182 TI - Detection of mercury ions (II) based on non-cross-linking aggregation of double stranded DNA modified gold nanoparticles by resonance Rayleigh scattering method. AB - This work describes a sensitive approach utilizing non-cross-linking aggregation of double-stranded DNA modified gold nanoparticles (dsDNA-AuNPs) for the detection of mercury ions (Hg(2+)) by resonance Rayleigh scattering (RRS) method for the first time. The double-stranded DNA contains a mismatched T-T base pair in the chain terminus, resulting in a flexible DNA tail and preventing the AuNPs from aggregation. Thus, a low RRS signal is obtained. However, in the presence of Hg(2+), the non-cross-linking aggregation of dsDNA-AuNPs occurs, due to the Hg(2+)-mediated coordination of T-Hg(2+)-T base pair. The aggregation of nanoparticles generates a high RRS value. Particularly, the solution color and ultraviolet-visible absorption barely changed under the same conditions, while it is capable of detecting by RRS method with a low detection limit (0.4nM), which is 1000-fold lower than that of the colorimetric method. The proposed method was successfully applied to the detection of Hg(2+) in real samples. The sensitive and selective assay might be inspiring for the development of new detectors for other metal ions or biomolecules. PMID- 25461183 TI - A novel composite of molecularly imprinted polymer-coated PdNPs for electrochemical sensing norepinephrine. AB - A novel composite of molecularly imprinted polymer-coated palladium nanoparticles (MIP-coated PdNPs) was synthesized by sol-gel method using norepinephrine as template, phenyl trimethoxysilane as functional monomer and tetramethoxysilane as crosslinker. The combination of PdNPs and silica-based MIP endowed the composite with good electrochemical catalytic property, large surface area and template selectivity. MIP-coated PdNPs were characterized by Fourier transform infrared spectroscopy and Transmission electron microscopy. Then MIP-coated PdNPs composite was used as a recognition element in the construction of an electrochemical sensor for norepinephrine. The properties of MIP-coated PdNPs sensor such as special binding, adsorption dynamics and selective recognition ability were evaluated by differential pulse voltammetry. The results demonstrated that MIP-coated PdNPs sensor not only possessed a short response time, but also high binding capacity for norepinephrine, which enabled the imprinted sensor with higher current response than that of non-imprinted material and MIP without PdNPs. In addition, the MIP-coated PdNPs sensor exhibited selectivity for norepinephrine in comparison to other analogs. The MIP-coated PdNPs sensor had a wide linear range over norepinephrine concentration from 0.5 to 80.0MUM with a detection limit of 0.1MUM. The MIP-coated PdNPs sensor was proved to be a suitable sensing tool for the fast, sensitive and selective determination of norepinephrine in injection and urine samples. PMID- 25461184 TI - A simple and universal "turn-on" detection platform for proteases based on surface enhanced Raman scattering (SERS). AB - We describe herein a novel' "turn-on" SERS-based strategy for protease detection based on surface enhanced Raman scattering (SERS) and the mediation of spacing between 4-mercaptobenzoic acid (4-MBA) labeled gold nanoparticles (AuNPs) through enzyme assays. The method employed non-cross-linking aggregation of 4-MBA modified AuNPs by peptides after treatment with target protease. Thus, SERS signals of 4-MBA are sharply increased because of the decreased electrostatic stability of AuNPs that initiated gold nanoaggregates incorporating Raman reporter molecules due to the formation of "Hot Spots". Through this strategy, a novel and facile "turn-on" SERS biosensor for trypsin and thrombin based on enzymatic cleavage activity is established with sensitivity, selectivity and simplicity as AuNPs and peptides are easily accessible. Compared with other methods, this newly proposed method has improved sensitivity. The limit of detection was 85fM (at the ratio of signal to noise, S/N=3:1) for trypsin. Controlled experiments showed that the method exhibited good selectivity over other proteases. We also proved that this principle could be easily adapted to detection of other proteases such as thrombin. The method demonstrated the capability for application in complex matrix samples. The results also presented the potential and superiority of SERS biosensor as a general approach for proteases based on enzyme activity. PMID- 25461185 TI - Amplified and selective detection of manganese peroxidase genes based on enzyme scaffolded-gold nanoclusters and mesoporous carbon nitride. AB - This work has demonstrated an amplified and selective detection platform using enzyme-scaffolded-gold nanoclusters as signal label, coupling with mesoporous carbon nitride (MCN) and gold nanoparticles (GNPs) modified glassy carbon electrode (GCE). Streptavidin-horseradish peroxidase (SA-HRP) has been integrated with gold nanoclusters (GNCs) as scaffold using a simple, fast and non-toxic method. The mechanisms of enzymatic amplification, redox cycling and signal amplification by this biosensor were discussed in detail. GNCs might perform important roles as electrocatalyst as well as electron transducer in these processes. The concentrations of reagents and the reaction times of these reagents were optimized to improve the analytical performances. Under the optimized condition, the signal response to enzyme-scaffolded-gold nanoclusters catalyzed reaction was linearly related to the natural logarithm of the target nucleic acid concentration in the range from 10(-17)M to 10(-9)M with a correlation coefficient of 0.9946, and the detection limit was 8.0*10(-18)M (S/N=3). Besides, synthesized oligonucleotide as well as Phanerochaete chrysosporium MnP fragments amplified using polymerase chain reaction and digested by restriction endonucleases were tested. Furthermore, this biosensor exhibited good precision, stability, sensitivity, and selectivity, and discriminated satisfactorily against mismatched nucleic acid samples of similar lengths. PMID- 25461186 TI - Disposable dry-reagent cotton thread-based point-of-care diagnosis devices for protein and nucleic acid test. AB - We report here for the first time by using dry-reagent cotton thread-based point of-care diagnosis devices for low-cost, sensitive and rapid detection of a lung cancer related biomarker, squamous cell carcinoma antigen (SCCA) and a human genetic disease, hereditary tyrosinemia type I related DNA sequences. A model system comprising SCCA as an analyte and a pair of monoclonal antibodies is used to demonstrate the proof-of-concept on the dry-reagent cotton thread based immunoassay device. An enhancement protocol was employed by using two kinds of gold nanoparticle labels for SCCA test which greatly improved the sensitivity of the device. The assay avoids the multiple incubation and washing steps performed in most conventional protein analyses, which is similar with the lateral flow strip technology. Under optimal conditions, the thread based immunoassay device was capable of measuring 1ng/mL SCCA in 20min which meet the requirement for clinical diagnosis. DNA detection was successfully realized by using a novel adenosine based molecular beacon probe as reporter probes in the cotton thread based device, the linear range is 75-3000fmol which is suitable for quantitative test. PMID- 25461187 TI - Methionine-directed fabrication of gold nanoclusters with yellow fluorescent emission for Cu(2+) sensing. AB - In the past few years, fluorescent gold nanoclusters (AuNCs) have gained much attention in many areas of physics, chemistry, materials science, and biosciences due to their unique physical, electrical, and optical properties. Herein, we reported for the first time the synthesis of water soluble, monodispersed AuNCs by using methionine both as a reductant and a stabilizer. The synthetic process is green and simple, and the resulting AuNCs capped by methionine (Met-AuNCs) would be biocompatible with bioorganisms. UV-visible absorption, photoluminescence, X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared (FTIR) were carried out to demonstrate the chemical composition and optical properties of the as-prepared Met-AuNCs. The Met-AuNCs possess many attractive features including intense yellow fluorescence (emission maximum at 530nm), a long fluorescence lifetime (181ns and 1651ns), high colloidal stability (pH-, temperature-, salt- and time-stability), and a large Stoke's shift (110nm), holding great promise as late-model analytical tools for life science and environmental studies. Moreover, the as-synthesized Met-AuNCs can serve as an efficient fluorescent probe for selective detection of Cu(2+) by fluorescence quenching. The limit of detection for Cu(2+) was determined to be 7.9nM and linear response over the Cu(2+) concentrations range from 50nM to 8MUM. Furthermore, the new-constructed probe allows simple and rapid detection of the concentrations of Cu(2+) in soil, with results demonstrating its great feasibility for the determination of copper in real samples. PMID- 25461188 TI - 2D and 3D graphene materials: Preparation and bioelectrochemical applications. AB - The attractive properties of graphene materials have stimulated intense research and development in the field of bioelectrochemistry. In particular, the construction of 2D and 3D graphene architectures provides new possibilities for developing flexible and porous carbon scaffolds, which not only inherit some of the key properties of individual graphene sheets, but also develop additional functions that are of considerable interest for bioelectrochemical applications. In this review article, we will first summarize the recently developed approaches to preparing graphene sheets, and then focus on the methods to assemble them into macroscopic 2D and 3D structures. Furthermore, we will highlight the potential applications of these materials in electrochemical biosensors and biological fuel cells. PMID- 25461189 TI - Probing sugar-lectin recognitions in the near-infrared region using glyco diketopyrrolopyrrole with aggregation-induced-emission. AB - This study describes the construction of aggregation-induced-emission (AIE)-based glycosyl probes for the sensitive and selective detection of sugar-lectin interactions in the near-infrared (NIR) region. Mannosyl and galactosyl diketopyrrolopyrrole (DPP) derivatives were effectively synthesized by the Cu(I) catalyzed azide-alkyne 1.3-dipolar cycloaddition reaction. We observed that these glycodyes had typical AIE behaviors in a semi-aqueous solution with a strong fluorescence (FL) emission in the NIR region. In a buffer solution, the glycosyl DPPs at the quenching state showed sharply increased FL upon addition of a selective lectin that recognizes the glycosyl moiety of the compounds with nanomolar limits of detection. In contrast, addition of unselective lectins, proteins and ions did not fluctuate the FL. Scanning electron microscopy analyses suggested that the FL generation could probably be a result of AIE of the glyco DPPs upon complexation with lectins. These glyco-DPPs, to the best of our knowledge, represent the first fluorogenic AIE-based probes that can sense lectins in the NIR region, providing insights for the further extension towards low-background in vivo targeted imaging of tissues that express a lectin. PMID- 25461190 TI - New redox-active layer create via epoxy-amine reaction - The base of genosensor for the detection of specific DNA and RNA sequences of avian influenza virus H5N1. AB - This paper concerns the development of a redox-active monolayer and its application for the construction of an electrochemical genosensor designed for the detection of specific DNA and RNA oligonucleotide sequences related to the avian influenza virus (AIV) type H5N1. This new redox layer was created on a gold electrode surface step by step. Cyclic Voltammetry, Osteryoung Square-Wave Voltammetry and Differential Pulse Voltammetry were used for its characterization. This new redox-active layer was applied for the construction of the DNA biosensor. The NH2-NC3 probe (20-mer) was covalently attached to the gold electrode surface via a "click" reaction between the amine and an epoxide group. The hybridization process was monitored using the Osteryoung Square-Wave Voltammetry. The 20-mer DNA and ca. 280-mer RNA oligonucleotides were used as the targets. The constructed genosensor was capable to determine complementary oligonucleotide sequences with a detection limit in the pM range. It is able to distinguish the different position of the part RNA complementary to the DNA probe. The genosensor was very selective. The 20-mer DNA as well as the 280-mer RNA oligonucleotides without a complementary sequence generated a weak signal. PMID- 25461191 TI - alpha-Synuclein-induced dopaminergic neurodegeneration in a rat model of Parkinson's disease occurs independent of ATP13A2 (PARK9). AB - Mutations in the ATP13A2 (PARK9) gene cause early-onset, autosomal recessive Parkinson's disease (PD) and Kufor-Rakeb syndrome. ATP13A2 mRNA is spliced into three distinct isoforms encoding a P5-type ATPase involved in regulating heavy metal transport across vesicular membranes. Here, we demonstrate that three ATP13A2 mRNA isoforms are expressed in the normal human brain and are modestly increased in the cingulate cortex of PD cases. ATP13A2 can mediate protection toward a number of stressors in mammalian cells and can protect against alpha synuclein-induced toxicity in cellular and invertebrate models of PD. Using a primary cortical neuronal model combined with lentiviral-mediated gene transfer, we demonstrate that human ATP13A2 isoforms 1 and 2 display selective neuroprotective effects toward toxicity induced by manganese and hydrogen peroxide exposure through an ATPase-independent mechanism. The familial PD mutations, F182L and G504R, abolish the neuroprotective effects of ATP13A2 consistent with a loss-of-function mechanism. We further demonstrate that the AAV mediated overexpression of human ATP13A2 is not sufficient to attenuate dopaminergic neurodegeneration, neuropathology, and striatal dopamine and motoric deficits induced by human alpha-synuclein expression in a rat model of PD. Intriguingly, the delivery of an ATPase-deficient form of ATP13A2 (D513N) to the substantia nigra is sufficient to induce dopaminergic neuronal degeneration and motor deficits in rats, potentially suggesting a dominant-negative mechanism of action. Collectively, our data demonstrate a distinct lack of ATP13A2-mediated protection against alpha-synuclein-induced neurotoxicity in the rat nigrostriatal dopaminergic pathway, and limited neuroprotective capacity overall, and raise doubts about the potential of ATP13A2 as a therapeutic target for PD. PMID- 25461192 TI - SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. AB - Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by immune cell infiltration of CNS, blood-brain barrier (BBB) breakdown, localized myelin destruction, and progressive neuronal degeneration. There exists a significant need to identify novel therapeutic targets and strategies that effectively and safely disrupt and even reverse disease pathophysiology. Signaling cascades initiated by semaphorin 4D (SEMA4D) induce glial activation, neuronal process collapse, inhibit migration and differentiation of oligodendrocyte precursor cells (OPCs), and disrupt endothelial tight junctions forming the BBB. To target SEMA4D, we generated a monoclonal antibody that recognizes mouse, rat, monkey and human SEMA4D with high affinity and blocks interaction between SEMA4D and its cognate receptors. In vitro, anti-SEMA4D reverses the inhibitory effects of recombinant SEMA4D on OPC survival and differentiation. In vivo, anti-SEMA4D significantly attenuates experimental autoimmune encephalomyelitis in multiple rodent models by preserving BBB integrity and axonal myelination and can be shown to promote migration of OPC to the site of lesions and improve myelin status following chemically-induced demyelination. Our study underscores SEMA4D as a key factor in CNS disease and supports the further development of antibody-based inhibition of SEMA4D as a novel therapeutic strategy for MS and other neurologic diseases with evidence of demyelination and/or compromise to the neurovascular unit. PMID- 25461194 TI - Mice with subtle reduction of NMDA NR1 receptor subunit expression have a selective decrease in mismatch negativity: Implications for schizophrenia prodromal population. AB - Reductions in glutamate function are regarded as an important contributory factor in schizophrenia. However, there is a paucity of animal models characterized by developmental and sustained reductions in glutamate function. Pharmacological models using NMDA antagonists have been widely used but these typically produce only transient changes in behavior and brain function. Likewise, mice with homozygous constitutive reductions in glutamate receptor expression show stable brain and behavioral changes, but many of these phenotypes are more severe than the human disease. The current study examines a variety of schizophrenia-related EEG measures in mice with a heterozygous alteration of the NMDA receptor NR1 subunit gene (NR1) that is known to result in reduced NR1 receptor expression in the homozygous mouse (NR1-/-). (NR1+/-) mice showed a 30% reduction in NR1 receptor expression and were reared after weaning in either group or isolated conditions. Outcome measures include the response to paired white noise stimuli, escalating inter-stimulus intervals (ISIs) and deviance-related mismatch negativity (MMN). In contrast to what has been reported in (NR1-/-) mice and mice treated with NMDA antagonists, (NR1+/-) mice showed no change on obligatory Event Related Potential (ERP) measures including the murine P50 and N100 equivalents (P20 and N40), or measures of baseline or evoked gamma power. Alternatively, (NR1+/-) mice showed a marked reduction in response to a deviant auditory tone during MMN task. Data suggest that EEG response to deviant, rather than static, stimuli may be more sensitive for detecting subtle changes in glutamate function. Deficits in these heterozygous NR1 knockdown mice are consistent with data demonstrating MMN deficits among family members of schizophrenia patients and among prodromal patients. Therefore, the current study suggests that (NR1+/-) mice may be among the most sensitive models for increased vulnerability to schizophrenia. PMID- 25461193 TI - In vivo magnetic resonance studies reveal neuroanatomical and neurochemical abnormalities in the serine racemase knockout mouse model of schizophrenia. AB - BACKGROUND: Decreased availability of the N-methyl-D-aspartate receptor (NMDAR) co-agonist D-serine is thought to promote NMDAR hypofunction and contribute to the pathophysiology of schizophrenia, including neuroanatomical abnormalities, such as cortical atrophy and ventricular enlargement, and neurochemical abnormalities, such as aberrant glutamate and gamma-aminobutyric acid (GABA) signaling. It is thought that these abnormalities directly relate to the negative symptoms and cognitive impairments that are hallmarks of the disorder. Because of the genetic complexity of schizophrenia, animal models of the disorder are extremely valuable for the study of genetically predisposing factors. Our laboratory developed a transgenic mouse model lacking serine racemase (SR), the synthetic enzyme of d-serine, polymorphisms of which are associated with schizophrenia. Null mutants (SR-/-) exhibit NMDAR hypofunction and cognitive impairments. We used 9.4 T magnetic resonance imaging (MRI) and proton spectroscopy (MRS) to compare in vivo brain structure and neurochemistry in wildtype (WT) and SR-/- mice. METHODS: Mice were anesthetized with isoflurane for MRI and MRS scans. RESULTS: Compared to WT controls, SR-/- mice exhibited 23% larger ventricular volumes (p<0.05). Additionally, in a medial frontal cortex voxel (15 MUl), SR-/- mice exhibited significantly higher glutamate/water (12%, t=1.83, p<0.05) and GABA/water (72%, t=4.10, p<0.001) ratios. CONCLUSIONS: Collectively, these data demonstrate in vivo neuroanatomical and neurochemical abnormalities in the SR-/- mouse comparable to those previously reported in humans with schizophrenia. PMID- 25461195 TI - Diagnoses, procedures, drug utilization, comorbidities, and cost of health care for people with epilepsy in 2012. AB - Our objective was to identify the top MD-office, inpatient and outpatient diagnoses, procedures, drug classes, comorbidities, and cost of health care for people with epilepsy. We examined health insurance claims for 8388 persons with epilepsy (females = 52%, males = 48%; average age = 35 years; privately insured = 78%, and Medicaid-insured = 22%) from eight health insurance plans for the year 2012. All of the top three diagnoses for MD-office place of service were either for other convulsions (780.39) or for epilepsy (345.90 and 345.40). Two of the top three primary diagnosis codes from the inpatient hospital and emergency department places of service were 780.39 and 345.90 for convulsions and epilepsy, respectively, while the third code was 786.50 for chest pain. The top three procedures from the MD-office setting were for immunizations (90471 and 90658) and blood counts (85025). The top three procedure codes from the outpatient hospital setting were 85025 for complete blood count, 80053 for comprehensive metabolic panel, and 80048 for basic metabolic panel. In the emergency department, the top three procedures were electrocardiogram (93010), computed tomography (70450), and chest X-ray (71020). The top five drug classes among prescription drugs billed using an NDC code were (1) anticonvulsants, (2) analgesic-opioids, (3) antidepressants, (4) penicillins, and (5) dermatologicals. The mean monthly health plan paid cost for each patient with epilepsy in 2012 was $1028 (SD = $3181). Of this total, $761 (SD = $2988; 74%) was for medical, and $267 (SD = $760; 26%) was for prescription pharmacy claims. Fifty-eight percent (58%) of the patients had one or more of 29 prespecified comorbidities, while 42% had none. Monthly health-care costs increased markedly as the number of comorbidities increased. This information should help guide cost estimates and resource allocation in order to optimally care for people with epilepsy. PMID- 25461196 TI - Long-term epilepsy surgery outcomes in patients with PET-positive, MRI-negative temporal lobe epilepsy. AB - This study compared the long-term efficacy of anterior temporal lobectomy (ATL) for the treatment of medically refractory temporal lobe epilepsy (TLE) in patients who presented with ipsilateral temporal PET hypometabolism and nonlesional magnetic resonance imaging (PET+/MRI-) with that in patients who had mesial temporal sclerosis (MTS) on MRI. We described the electroclinical, MRI, PET, and pathological characteristics and seizure outcome of 28 PET+/MRI- patients without discordant ictal and interictal electroencephalography (EEG) who underwent ATL (2004-2007) for medically refractory partial epilepsy while avoiding intracranial monitoring. The primary outcome was the percentages of Engel Class I outcomes at 2 and 5 years of PET+/MRI--patients compared with those of patients with MTS on MRI; neuropsychological testing was used as the secondary outcome. At 2-year follow-up, 21 (75%) patients in the PET+/MRI--group were in Engel Class I compared with 66 (75.9%) patients with MTS, and at 5-year follow up, 20 (71.4%) patients in the PET+/MRI--group were in Engel Class I compared with 64 (73.6%) patients in the group with MTS. There were no significant differences between the groups at either time period. We concluded that normal MRI results should not preclude presurgical evaluations in patients with medically refractory TLE, as favorable long-term postoperative seizure outcomes are possible, especially in patients with unilateral anterior interictal epileptiform discharges and ipsilateral temporal PET hypometabolism. PMID- 25461197 TI - Naringin ameliorates pentylenetetrazol-induced seizures and associated oxidative stress, inflammation, and cognitive impairment in rats: possible mechanisms of neuroprotection. AB - Oxidative stress and cognitive impairment are associated with PTZ-induced convulsions. Naringin is a bioflavonoid present in the grapefruit. It is a potent antioxidant, and we evaluated its effect on PTZ-induced convulsions. Rats were pretreated with normal saline, naringin (20, 40, and 80 mg/kg, i.p.), or diazepam (5mg/kg, i.p.) 30 min prior to the administration of PTZ. The administration of PTZ induced myoclonic jerks and generalized tonic-clonic seizures (GTSs). We observed that naringin significantly prolonged the induction of myoclonic jerks dose-dependently. Naringin (80 mg/kg, i.p.) pretreatment protected all rats, and this protective effect was annulled by the GABAA receptor antagonist, flumazenil. In addition, naringin reduced brain MDA and TNF-alpha levels and conserved GSH. The pretreatment also enhanced the performance of rats in the passive avoidance task. Our observations highlight the antioxidant, antiinflammatory, and anticonvulsant potential of naringin. Also, naringin modulates the GABAA receptor to produce anticonvulsant effects and to ameliorate cognitive impairment. PMID- 25461199 TI - Displaced aggression predicts switching deficits in people with temporal lobe epilepsy. AB - This study examined the relationship between task-switching abilities and displaced aggression in people with temporal lobe epilepsy (PWE). Participants (35 PWE and 35 healthy controls) performed emotion and gender classification switching tasks. People with temporal lobe epilepsy showed larger switch costs than controls. This result reflected task-switching deficits in PWE. People with temporal lobe epilepsy reported higher anger rumination, revenge planning, and behavioral displaced aggression compared with controls. Displaced aggression was a significant predictor of the task switch costs. It is suggested that displaced aggression is a significant marker of task-switching deficits. PMID- 25461198 TI - Sex differences in seizure types and symptoms. AB - BACKGROUND: Despite the increasing interest in sex differences in disease manifestations and responses to treatment, very few data are available on sex differences in seizure types and semiology. The Epilepsy Phenome/Genome Project (EPGP) is a large-scale, multi-institutional, collaborative study that aims to create a comprehensive repository of detailed clinical information and DNA samples from a large cohort of people with epilepsy. We used this well characterized cohort to explore differences in seizure types as well as focal seizure symptoms between males and females. METHODS: We reviewed the EPGP database and identified individuals with generalized epilepsy of unknown etiology (GE) (n = 760; female: 446, male: 314), nonacquired focal epilepsy (NAFE) (n = 476; female: 245, male: 231), or both (n = 64; female: 33, male: 31). Demographic data along with characterization of seizure type and focal seizure semiologies were examined. RESULTS: In GE, males reported atonic seizures more frequently than females (6.5% vs. 1.7%; p < 0.001). No differences were observed in other generalized seizure types. In NAFE, no sex differences were seen for seizure types with or without alteration of consciousness or progression to secondary generalization. Autonomic (16.4% vs. 26.6%; p = 0.005), psychic (26.7% vs. 40.3%; p = 0.001), and visual (10.3% vs. 19.9%; p = 0.002) symptoms were more frequently reported in females than males. Specifically, of psychic symptoms, more females than males endorsed deja vu (p = 0.001) but not forced thoughts, derealization/depersonalization, jamais vu, or fear. With corrections for multiple comparisons, there were no significant differences in aphasic, motor, somatosensory, gustatory, olfactory, auditory, vertiginous, or ictal headache symptoms between sexes. CONCLUSIONS: Significant differences between the sexes were observed in the reporting of atonic seizures, which were more common in males with GE, and for autonomic, visual, and psychic symptoms associated with NAFE, which were more common in females. PMID- 25461200 TI - Safety, Awareness, and Familiarity regarding Epilepsy in Teenage Years (SAFETY): understanding the adolescents' perspective about their disease. AB - OBJECTIVE: The objective of this study was to evaluate the understanding of adolescent patients regarding epilepsy. METHODS: The SAFETY (Safety, Awareness, and Familiarity regarding Epilepsy in Teenage Years) questionnaire (content validity index: 0.96, Flesch readability score: 66.6) was administered to 165 cognitively normal adolescents with epilepsy (85 females, mean age: 15.2 +/- 1.6 years, range: 13-18 years). The first part of the questionnaire was devised to evaluate knowledge about epilepsy and antiepileptic medications (SAFETY-K: 7 questions). The second part queried lifestyle modifications and safety (SAFETY-S: 10 questions). Female participants answered 5 additional questions related to reproductive health (RH questionnaire). RESULTS: The correct response rate for the composite SAFETY questionnaire was 51.5%. The average rates of correct responses for the SAFETY-K and SAFETY-S questions were 47.9% and 53.9%, respectively. On univariate logistic regression analysis, factors which were significant predictors of correct responses included age (odds ratio: 1.8, C.I. = 1.3-2.4), race (Caucasian vs. African-American; odds ratio: 3.9, C.I. = 1.4 10.4), and employment of at least one parent in a professional occupation (odds ratio: 3.3, C.I. = 1.1-10.3). The correct response rate did not correlate with the duration of epilepsy, extent of seizure control, number of antiepileptic medications, parental educational, or (un)employment status. The mean rate of correct responses for the RH questions amongst teenage girls was 17.4%. CONCLUSIONS: There is lack of awareness about epilepsy and its associated lifestyle modifications in adolescents with epilepsy seen at our institution. This is especially true in young adolescents, African-American patients, and those whose parents are not employed in professional occupations. Teenage girls with epilepsy appear to have limited knowledge with respect to contraception and childbearing. PMID- 25461201 TI - Use of the DISCERN tool for evaluating web searches in childhood epilepsy. AB - Epilepsy is an important cause of neurological disability in children. Nowadays, an increasing number of parents or caregivers use the Internet as a source of health information concerning symptoms, therapy, and prognosis of epilepsy occurring during childhood. Therefore, high-quality websites are necessary to satisfy this request. Using the DISCERN tool, we evaluated online information on childhood epilepsy provided by the first 50 links displayed on the Google search engine. The same links were evaluated by a team of pediatric neurologists (PNs) and by a lay subject (LS). The evaluation performed by the PNs found out that only 9.6% of the websites showed good reliability, that only 7.2% of the websites had a good quality of information on treatment choices, and that only 21.5% of the websites showed good overall quality of the content. With regard to the evaluation performed by the neutral subject, it was found that 21.4% of the websites showed good reliability, that 59.5% of the websites showed poor quality of information on treatment choices, and that only 2% of the websites showed good overall quality of the content. Our conclusion is that online information about childhood epilepsy still lacks reliability, accuracy, and relevance as well as fails to provide a thorough review of treatment choices. PMID- 25461202 TI - Validation of the Hamilton Rating Scale for Depression in adults with epilepsy. AB - PURPOSE: Mood disorders represent a frequent psychiatric comorbidity among patients with epilepsy, having a major impact on their quality of life and contributing considerably to the global burden of the disease. The availability of standardized clinical instruments validated in populations with epilepsy has important implications in terms of diagnosis and treatment. This aimed to validate the Hamilton Rating Scale for Depression (HRSD) in adult patients with epilepsy. METHODS: A consecutive sample of 120 adult outpatients with epilepsy was assessed using the Mini International Neuropsychiatric Inventory (MINI) Plus version 5.0.0 and the HRSD. RESULTS: Cronbach's alpha coefficient was 0.824 for the 17-item version and 0.833 for the 21-item version. Receiver operating characteristic analysis showed an area under the curve of 0.896 and 0.899, respectively, for the two versions. However, the HRSD-17 demonstrated the best psychometric properties compared to the HRSD-21 and, with a cutoff score of 6, showed a sensitivity of 94%, a specificity of 80%, a positive predictive value of 46%, and a negative predictive value of 99%. CONCLUSIONS: The HRSD proved to be reliable and valid in the epilepsy setting and will stimulate further research in this area. PMID- 25461203 TI - Epilepsy matters! PMID- 25461204 TI - Kainate-induced epileptogenesis alters circular hole board learning strategy but not the performance of C57BL/6J mice. AB - Patients with mesial temporal lobe epilepsy (mTLE) frequently show cognitive deficits. However, the relation between mTLE and cognitive impairment is poorly understood. To gain more insight into epilepsy-associated alterations in cognitive performance, we studied the spatial learning of C57BL/6J mice five weeks after kainate-induced status epilepticus (SE). Typically, structural hippocampal rearrangements take place within five weeks after SE. Mice were monitored by exposing them to four tasks with a focus on spatial memory and anxiety: the circular hole board, modified hole board, novel object-placement task, and elevated plus maze. On the circular hole board, animals showed a higher preference for hippocampus-independent strategies after SE. In contrast, no change in strategy was seen on the modified hole board, but animals with SE were able to finish the task more often. Animals did not have an increased preference for a relocated object in the novel object-placement task but showed an increased locomotion after SE. No indications for altered anxiety were found when tested on the elevated plus maze following SE. These data suggest that the circular hole board is a well-suited paradigm to detect subtle SE-induced hippocampal deficits. PMID- 25461205 TI - Efficacy of once-daily extended-release topiramate (USL255): a subgroup analysis based on the level of treatment resistance. AB - Results from a previously conducted global phase III study (PREVAIL; NCT01142193) demonstrate the safety and efficacy of once-daily USL255, QudexyTM XR (topiramate) extended-release capsules, as adjunctive treatment of drug-resistant partial-onset seizures (POSs). In this study, we report a post hoc analysis of PREVAIL data according to patient level of treatment resistance (based upon the number of concomitant antiepileptic drugs [AEDs] and lifetime AEDs) at baseline, with patients defined as either having "highly" drug-resistant seizures (>= 2 concurrent AEDs and >= 4 lifetime AEDs) or having "less" drug-resistant seizures (1 concurrent AED or <4 lifetime AEDs) at baseline. For each subgroup, median percent reduction in POS frequency (primary endpoint), responder rate, Clinical Global Impression of Change (CGI-C), and Quality of Life in Epilepsy--Problems (QOLIE-31-P) survey were assessed. Of 249 PREVAIL patients, 115 were classified as having highly drug-resistant seizures (USL255: n = 52, placebo: n = 63), and 134 were classified as having less drug-resistant seizures (USL255: n = 72, placebo: n = 62) at baseline. For the primary endpoint, USL255 resulted in significantly better seizure outcomes compared with placebo regardless of drug resistant status (P = .004 and P = .040 for "highly" and "less", respectively). Responder rate was also significantly improved in patients with highly drug resistant group (P = .023). The CGI-C scores indicated significant improvement in both subgroups (P = .003 and P = .013 for "highly" and "less", respectively). On the QOLIE-31-P, a significant improvement on the seizure worry subscale for the group with less drug-resistant seizures was noted in USL255-treated patients compared with placebo-treated patients (P = .003); the overall score and all other subscales were not significantly different for both subgroups. We conclude that USL255 led to significant improvements across multiple outcomes compared with placebo, including in those classified as having highly drug-resistant seizures to prior treatment, making it a valuable treatment option for patients with epilepsy. PMID- 25461206 TI - Long-term outcome of psychogenic nonepileptic seizures: the role of induction by suggestion. AB - PURPOSE: The aims of our retrospective observational study were to evaluate the long-term outcome of PNESs after communication of the diagnosis and to define predictors of good outcome. METHOD: Twenty-seven consecutive patients with a certain diagnosis of psychogenic nonepileptic seizures (PNESs) were included in the study. Follow-up information was obtained from each participant through a questionnaire designed for the study. Regarding seizure frequency, the patients were asked to report how many seizures they had experienced on average every month before the communication of the diagnosis and after it. RESULTS: After the communication of the diagnosis, the median seizure frequency had dropped to 4 every month (p < 0.001). Seventeen participants (63%) were seizure-free at follow up, and a further five (18.5%) showed a greater than 50% improvement in seizure frequency. Regarding the predictive value of clinical and sociodemographic variables for PNES global outcome, the factors gender, education, economic status, interval of time from onset, comorbidity with epilepsy, psychiatric history, mental retardation, psychological therapy, psychiatric therapy, and the presence of stressful and traumatic events were not related to prognosis; the only factor associated with a better outcome was the diagnosis made after the induction of PNESs by suggestion (p = 0.000, chi(2) = 4.654). CONCLUSION: A substantial majority of our patients became seizure-free with communication of the diagnosis as the only intervention. The use of the induction by suggestion test was an important predictor of good outcome. PMID- 25461207 TI - Multimodular psychotherapy intervention for nonepileptic attack disorder: an individualized pragmatic approach. AB - Nonepileptic attack disorder (NEAD) is a highly distressing and costly condition commonly seen in specialist epilepsy clinics. Consistently effective treatments for NEAD remain elusive, and findings from research indicate that there is no one form of psychological therapy that will be effective in such a heterogeneous group of patients. In this paper, we propose a multimodular approach to psychological therapy in NEAD, which allows the clinician to tailor an individualized management program for the patient appropriate to his/her needs. PMID- 25461208 TI - Orientation and disorientation: lessons from patients with epilepsy. AB - Orientation in time, space, and person is a fundamental cognitive faculty and the bedrock of neurological and psychiatric mental status examination. Nevertheless, research in orientation and disorientation is neglected in both cognitive science and neuropsychiatry. Specifically, it is still unclear whether disorientations in time, space, and person represent a failure of the same system or merely share a common nomenclature and whether these three domains of orientation depend on different psychological and neural systems. Here, we analyzed descriptions of patients with specific orientation failures associated with circumscribed cortical lesions, with a primary focus on epilepsy. The form of disorientation is analyzed according to its specific domain, the underlying neuropsychiatric disorder, and its anatomical correlate. Disorientations in the different domains are classified as self-referenced (incorrect self-localization) or nonself referenced (incorrect localization or knowledge of other places, events, and people). Analysis of the cognitive and neural systems disturbed in these patients suggests that disorientation in one or several domains may be related to a failure in a specific brain mechanism localized mostly in the right hemisphere, partially overlapping with the default mode network (mostly the medial and lateral parietal, medial temporal, and lateral prefrontal cortices), which processes essential self-related cognitive faculties such as orientation. PMID- 25461209 TI - Involvement of the nitrergic system in the proconvulsant effect of social isolation stress in male mice. AB - Social isolation stress (SIS) in adolescence is accompanied by neurobehavioral disturbances and pathophysiological changes in certain regions of the CNS such as the hippocampus. In this study, we tested whether SIS impacts seizure susceptibility in postnatal male mice due to a role of hippocampal nitric oxide (NO). To do this, we used the pentylenetetrazole (PTZ) model of clonic seizures, open-field test, hole-board test, forced swimming test, and plasma corticosterone assay. We aimed to evaluate if 4 weeks of SIS is capable of decreasing seizure threshold along with altering affective and neuroendocrine responses in isolated conditioned (IC) animals in comparison with socially conditioned (SC) animals. In addition, we applied subeffective doses of NO precursor L-arginine (25, 50, and 100mg/kg) and NOS inhibitors 7-NI (15 and 40 mg/kg), aminoguanidine (50 and 100mg/kg), and L-NAME (10 and 15 mg/kg) to both IC and SC groups prior to the determination of seizure threshold. Injection of a single dose of all mentioned drugs did not induce changes in seizure threshold of SC mice. On the other hand, L-NAME and 7-NI, but not aminoguanidine, modulated the proconvulsant effect of SIS, while L-arginine augmented the latter effect. We also measured the hippocampal nitrite levels after the administration of the aforementioned drugs. Social isolation stress increased the nitrite levels in comparison with those in SC mice, whereas 7-NI and L-NAME, unlike aminoguanidine, mitigated the effect of SIS. Additionally, L-arginine boosted the effects of SIS on nitrite production. In summary, we showed that SIS enhanced seizure susceptibility in the PTZ model of clonic seizures through the activation of the nitrergic system in the hippocampus. Also, we proved that nNOS, but not iNOS, accounts for these changes following SIS. PMID- 25461211 TI - Ficus religiosa L. figs--a potential herbal adjuvant to phenytoin for improved management of epilepsy and associated behavioral comorbidities. AB - Oxidative stress, together with mitochondrial dysfunction, has been reported to be involved in the pathogenesis of epileptogenesis and its associated comorbidities. Phytoflavonoids have shown numerous beneficial ameliorative effects on different neurological disorders by virtue of their antioxidant effect. The present study investigated the effect of flavonoid-rich ethyl acetate fraction of the crude fig extract of Ficus religiosa in combination with phenytoin on seizure severity, depressive behavior, and cognitive deficit in pentylenetetrazol (PTZ)-kindled mice. The flavonoid-rich ethyl acetate fraction of the crude fig extract was found to show significant antioxidant potential in various in vitro free radical scavenging assays. Combined treatment of this fraction (2.5, 5, and 10 mg/kg; i.p.) along with a subeffective dose of phenytoin (15 mg/kg; i.p.) in postkindled animals once daily for fifteen days showed a dose dependent decrease in the seizure severity score, a decreased number of mistakes, increased step-down latency in passive shock avoidance paradigm, and decreased immobility time in the tail suspension test in comparison with the phenytoin only treated group. Biochemical investigations of the brain tissue showed amelioration of thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) levels, and reduced catalase and acetylcholinesterase (AChE) activities, thereby indicating suppression of oxidative stress. In conclusion, the results of the present study showed the protective effect of the flavonoid-rich fraction of F. religiosa along with a subeffective dose of phenytoin in PTZ-kindling-associated cognitive deficit and depressive behavior with complete suppression of seizures through reduction of oxidative stress, supporting the the need for clinical evaluation of the supplementation of phytoflavonoids along with antiepileptic drugs (AEDs) for management of epilepsy and its psychiatric and cognitive comorbidities. PMID- 25461212 TI - Disobedience and driving in patients with epilepsy in Greece. AB - OBJECTIVE: Regulations and guidelines regarding driving privileges of patients with epilepsy vary greatly worldwide. The aim of our study was twofold: firstly, to evaluate disobedient drivers in Greece and to elucidate their awareness of the law, emotional responses, and seizure profile and, secondly, to identify determinants of disobedience regarding driving among patients with epilepsy. METHODS: All consecutive patients with epilepsy who visited the epilepsy outpatient clinic of two tertiary epilepsy centers were invited to participate in the study. One hundred ninety patients met our inclusion criteria. RESULTS: Fifty two percent of our study population was aware of the driving restrictions. More than one out of three patients were disobedient (35.8%). Being a male was associated with a 6.07-fold increase in the odds of being disobedient (95% CI: 2.73-13.47, p < 0.001); being employed was associated with a 4.62-fold increase in the odds of being disobedient (95% CI: 2.20-9.68, p < 0.001); and each extra antiepileptic drug (AED) was associated with a decrease in the odds of disobedience by a factor of 0.41 (95% CI: 0.26-0.63, p < 0.001). CONCLUSION: Male gender, employment, and number of AEDs are important determinants of disobedience regarding driving among patients with epilepsy. PMID- 25461210 TI - Safety and efficacy of adjunctive lacosamide among patients with partial-onset seizures in a long-term open-label extension trial of up to 8 years. AB - Long-term (up to 8 years of exposure) safety and efficacy of the antiepileptic drug lacosamide was evaluated in this open-label extension trial (SP615 [ClinicalTrials.gov identifier: NCT00552305]). Patients were enrolled following participation in a double-blind trial or one of two open-label trials of adjunctive lacosamide for partial-onset seizures. Dosage adjustments of lacosamide (100-800 mg/day) and/or concomitant antiepileptic drugs were allowed to optimize tolerability and seizure reduction. Of the 370 enrolled patients, 77%, 51%, and 39% had >1, >3, or >5 years of lacosamide exposure, respectively. Median lacosamide modal dose was 400mg/day. Common treatment-emergent adverse events (TEAEs) were dizziness (39.7%), headache (20.8%), nausea (17.3%), diplopia (17.0%), fatigue (16.5%), upper respiratory tract infection (16.5%), nasopharyngitis (16.2%), and contusion (15.4%). Dizziness (2.2%) was the only TEAE that led to discontinuation in >2% of patients. Ranges for median percent reductions in seizure frequency were 47-65%, and those for >= 50% responder rates were 49-63% for 1-, 3-, and 5-year completer cohorts. Exposure to lacosamide for up to 8 years was generally well tolerated, with a safety profile similar to previous double-blind trials, and efficacy was maintained. PMID- 25461214 TI - Clinical experience with perampanel: focus on psychiatric adverse effects. AB - BACKGROUND: Perampanel (PER) is a novel antiepileptic drug that inhibits the AMPA class of glutamate receptors. It has been available in the UK since September 2012. We undertook a retrospective analysis of efficacy and tolerability of PER in 47 patients with drug-refractory epilepsy attending a regional epilepsy service in the UK. METHODS: Demographic and clinical data of patients with refractory epilepsy prescribed PER were collected by review of records. Efficacy, as measured by responder rates (>50% reduction in seizure frequency), retention rates, and adverse effects, was analyzed. RESULTS: Of the 47 patients prescribed PER, 39 (87%) had focal epilepsy, four (9%) had idiopathic generalized epilepsy, 3 (6%) had symptomatic generalized epilepsy, and 1 had unclassified epilepsy. Patients were taking a median of 2 AEDs (range: 1-5) when starting on PER. The median dose of PER was 8 mg (range: 2-12 mg). Thirteen (28%) patients were classed as responders, but no patients experienced sustained seizure freedom. Twenty-one (45%) patients had withdrawn from PER during the study period, with 16 (76%) of them withdrawing due to intolerable adverse effects, 4 due to inadequate seizure control, and 1 due to the combination of both. The most frequent adverse effects requiring withdrawal from PER were behavioral reactions including suicidal ideation (n = 2), aggressive behavior (n = 2), and both (n = 1). CONCLUSION: In our experience, PER had a retention rate of 55% and a responder rate of 28%. Psychiatric adverse effects, including suicidal ideation, were the most common reasons for withdrawal. PMID- 25461213 TI - Proceedings of the Fifth International Workshop on Advances in Electrocorticography. AB - The Fifth International Workshop on Advances in Electrocorticography convened in San Diego, CA, on November 7-8, 2013. Advancements in methodology, implementation, and commercialization across both research and in the interval year since the last workshop were the focus of the gathering. Electrocorticography (ECoG) is now firmly established as a preferred signal source for advanced research in functional, cognitive, and neuroprosthetic domains. Published output in ECoG fields has increased tenfold in the past decade. These proceedings attempt to summarize the state of the art. PMID- 25461215 TI - Analyzing reliability of seizure diagnosis based on semiology. AB - This study aimed to determine the accuracy of seizure diagnosis by semiological analysis and to assess the factors that affect diagnostic reliability. A total of 150 video clips of seizures from 50 patients (each with three seizures of the same type) were observed by eight epileptologists, 12 neurologists, and 20 physicians (internists). The videos included 37 series of epileptic seizures, eight series of physiologic nonepileptic events (PNEEs), and five series of psychogenic nonepileptic seizures (PNESs). After observing each video, the doctors chose the diagnosis of epileptic seizures or nonepileptic events for the patient; if the latter was chosen, they further chose the diagnosis of PNESs or PNEEs. The overall diagnostic accuracy rate for epileptic seizures and nonepileptic events increased from 0.614 to 0.660 after observations of all three seizures (p < 0.001). The diagnostic sensitivity and specificity of epileptic seizures were 0.770 and 0.808, respectively, for the epileptologists. These values were significantly higher than those for the neurologists (0.660 and 0.699) and physicians (0.588 and 0.658). A wide range of diagnostic accuracy was found across the various seizures types. An accuracy rate of 0.895 for generalized tonic-clonic seizures was the highest, followed by 0.800 for dialeptic seizures and then 0.760 for automotor seizures. The accuracy rates for myoclonic seizures (0.530), hypermotor seizures (0.481), gelastic/dacrystic seizures (0.438), and PNESs (0.430) were poor. The reliability of semiological diagnosis of seizures is greatly affected by the seizure type as well as the doctor's experience. Although the overall reliability is limited, it can be improved by observing more seizures. PMID- 25461216 TI - Autistic characteristics in adults with epilepsy. AB - INTRODUCTION: The reported prevalence of autism spectrum disorders in people with epilepsy ranges from 15% to 47%. Despite the high comorbidity, there has been a lack of systematic studies of autistic characteristics in epilepsy. Little is known about the relationship of epilepsy to the core characteristics of autism. The aim of this research was to measure autistic traits and characteristics in adults with epilepsy who do not have a diagnosis of any autism disorder. METHOD: We investigated autistic characteristics in adults with epilepsy and those without epilepsy employing the Autism Spectrum Quotient (group with epilepsy, n = 40; control group, n = 38) and systemizing and empathizing abilities employing the Intuitive Physics test and the Adult Eyes Task-Revised (group with epilepsy, n = 19; control group, n = 23). RESULTS: Significantly more autistic behavioral traits, as measured by the AQ, were related to having epilepsy, but intact systemizing and empathizing abilities in these adults suggest that, in adults with epilepsy, autism-like symptoms may be present in the absence of wider cognitive profiles characteristic of autism. CONCLUSION: Increased autistic characteristics found in adults with epilepsy without an ASD diagnosis suggest that epilepsy syndromes may incorporate behavioral aspects of autism in the absence of some of its core cognitive features. PMID- 25461217 TI - VEEG models of seizure frequency--do SSRI medications or vitamin D supplements alter seizure collections? PMID- 25461219 TI - An appraisal of the new operational definition of epilepsy--then and now. AB - The focus to define epilepsy in the newly proposed classification has shifted from the conceptual perspective to practical application thought to better reflect that which is happening to the patient. Within the new definition, a single unprovoked or reflex seizure can be considered as epilepsy if the recurrence risk is similar to that following two unprovoked seizures. Epilepsy is considered to be resolved if the individual had an age-dependent epilepsy syndrome and has passed the applicable age or if the person has remained seizure free for the last ten years without seizure medications for the last five years. This new operational definition of epilepsy may change the epileptologist's approach regarding when and how long to treat patients with seizures. The new definition also has significant psychosocial and employment-related implications for the patients. With regard to etiology, the terms idiopathic, symptomatic, and cryptogenic have been replaced by genetic, structural/metabolic, and unknown. This reflects a better understanding of the underlying cause of epilepsy based on genetic tests and better neuroimaging. The terms 'simple partial' and 'complex partial' seizures have been replaced by 'focal motor/sensory' and 'focal dyscognitive' seizures, thereby ending the ambiguity associated with the former terms and the difficulty encountered with definitions of altered states of consciousness. These changes, reflective of a better insight into the pathogenesis of seizures and epilepsy, are expected to be more pragmatic and assist when managing patients with epilepsy. PMID- 25461218 TI - Parental knowledge, attitudes, and behaviors towards children with epilepsy in Belgrade (Serbia). AB - OBJECTIVE: The aim of our study was to assess knowledge, attitudes, and behaviors of parents whose children were diagnosed with epilepsy. METHODS: This cross sectional study included 213 consecutive parents who accompanied their children, diagnosed with epilepsy, at regular checkups in the outpatient department of the Child and Adolescent Neurology and Psychiatry Clinic in Belgrade. Data were obtained through a questionnaire before completion of the child's neurological checkup, while clinical parameters of children with epilepsy were taken from medical records. RESULTS: Almost all respondents knew that epilepsy is not an infectious disease (99.5%), while the least proportion of parents (31.9%) knew that epilepsy is not, for the most part, hereditary. Parents felt that their family and friends should know that their child is suffering from epilepsy (average score: 4.3 out of 5). Also, parents felt the most confident in taking care of their child during seizures (4.7 out of 5), while they felt the least confident in letting their child go on school trips for several days (3.4 out of 5). Parental longer schooling (i.e., higher education level) was an independent predictor of higher epilepsy knowledge. Taking less number of medications was an independent predictor of more supportive parental behavior towards children with epilepsy. CONCLUSION: Some epilepsy-related issues still require improvement in parental knowledge. Ensuring education and support at community and school levels for both parents and children with epilepsy should be the principal goal of health-care service. PMID- 25461220 TI - Factors associated with superior self-management skills among individuals with epilepsy. AB - PURPOSE: This study aimed to determine whether the self-management skills of patients with epilepsy are associated with certain demographic, clinical, and psychosocial variables. METHODS: A direct survey of 182 patients, including the Epilepsy Self-Management Scale, was conducted. RESULTS: On univariate analysis, higher age, the occurrence of convulsions, and the use of religion as a coping mechanism were associated with higher self-management scores. On multiple linear regression, only age and the presence of convulsions remained independently significant. Older individuals employed more medication management skills. Those who experienced convulsions utilized more information management, seizure management, and lifestyle management skills. However, using binary logistic regression, we found that these subscales were not independently significant. The presence of superior self-management skills did not necessarily translate into decreased seizure frequency. CONCLUSION: Individuals with epilepsy who are older and experience convulsions generally have better self-management skills. This indicates that antecedents influence the development of self-management skills. PMID- 25461221 TI - Perceived stigma and adherence in epilepsy: evidence for a link and mediating processes. AB - OBJECTIVE: This study tested whether perceived epilepsy-related stigma is associated with adherence in people living with epilepsy and if information, motivation, and behavioral skills are potential pathways underlying the stigma adherence link. METHODS: We surveyed persons living with epilepsy between the ages of 18 and 65 (N = 140) using an online questionnaire to assess medication adherence and perceived epilepsy-related stigma. In addition, participants reported their level of information, motivation, and behavioral skills. RESULTS: Higher perceived epilepsy-related stigma was associated with lower medication adherence (r = -0.18, p < .05). Higher perceived stigma was associated with lower levels of information (r = -0.28, p < .05), motivation (r = -0.55, p < .05), and behavioral skills (r = -0.41, p < .05), and the link between stigma and adherence was fully explained by information, motivation, and behavioral skills, i.e., the effect of stigma on adherence was fully mediated (c = -0.18, p < .05 reduced to c' = 0.06, p = .48). CONCLUSION: Perceived epilepsy-related stigma is problematic for maintaining the prescribed medication regimen in people living with epilepsy. The information-motivation-behavioral skills model is a useful framework for understanding the pathways linking perceived stigma and adherence in this population. PMID- 25461222 TI - Clinical utility of the Wechsler Memory Scale--Fourth Edition (WMS-IV) in predicting laterality of temporal lobe epilepsy among surgical candidates. AB - This study evaluated the accuracy of the Wechsler Memory Scale--Fourth Edition (WMS-IV) in identifying functional cognitive deficits associated with seizure laterality in localization-related temporal lobe epilepsy (TLE) relative to a previously established measure, the Rey Auditory Verbal Learning Test (RAVLT). Emerging WMS-IV studies have highlighted psychometric improvements that may enhance its ability to identify lateralized memory deficits. Data from 57 patients with video-EEG-confirmed unilateral TLE who were administered the WMS-IV and RAVLT as part of a comprehensive presurgical neuropsychological evaluation for temporal resection were retrospectively reviewed. We examined the predictive accuracy of the WMS-IV not only in terms of verbal versus visual composite scores but also using individual subtests. A series of hierarchal logistic regression models were developed, including the RAVLT, WMS-IV delayed subtests (Logical Memory, Verbal Paired Associates, Designs, Visual Reproduction), and a WMS-IV verbal-visual memory difference score. Analyses showed that the RAVLT significantly predicted laterality with overall classification rates of 69.6% to 70.2%, whereas neither the individual WMS-IV subtests nor the verbal-visual memory difference score accounted for additional significant variance. Similar to previous versions of the WMS, findings cast doubt as to whether the WMS-IV offers significant incremental validity in discriminating seizure laterality in TLE beyond what can be obtained from the RAVLT. PMID- 25461223 TI - Knowledge, attitudes, and beliefs about epilepsy and their predictors among university students in Jordan. AB - The aim of this cross-sectional study was to assess the knowledge about epilepsy and the attitudes toward people with epilepsy (PWE) and their predictors among university students in Jordan. A self-administered questionnaire was distributed in three of the largest public universities in Jordan, and a total of 500 questionnaires were collected from each university. The number of students who reported that they had heard or read about epilepsy was 1165 (77.6%), and their data were analyzed. A significant proportion of students thought that epilepsy could be caused by the evil spirit (31.5%) and the evil eye (28.1%) or that it could be a punishment from God (25.9%). Epilepsy's most commonly reported treatment methods were the Holy Quran (71.4%), medications (71.3%), and herbs (29.3%). The most common negative attitudes toward PWE were that the students would refuse to marry someone with epilepsy (50.5%) and that children with epilepsy must join schools for persons with disabilities (44.4%). Male students, students of humanities, and students with a low socioeconomic status tended to have more negative attitudes toward PWE. In conclusion, many students have misconceptions about the causes, treatment, and nature of epilepsy, and students have moderate negative attitudes toward PWE. Universities should have health promotion programs to increase awareness of their students about major public health problems such as epilepsy. PMID- 25461224 TI - Skin conductance biofeedback training in adults with drug-resistant temporal lobe epilepsy and stress-triggered seizures: a proof-of-concept study. AB - The present proof-of-concept study investigated the feasibility of skin conductance biofeedback training in reducing seizures in adults with drug resistant temporal lobe epilepsy (TLE), whose seizures are triggered by stress. Skin conductance biofeedback aims to increase levels of peripheral sympathetic arousal in order to reduce cortical excitability. This might seem somewhat counterintuitive, since such autonomic arousal may also be associated with increased stress and anxiety. Thus, this sought to verify that patients with TLE and stress-triggered seizures are not worsened in terms of stress, anxiety, and negative emotional response to this nonpharmacological treatment. Eleven patients with drug-resistant TLE with seizures triggered by stress were treated with 12 sessions of biofeedback. Patients did not worsen on cognitive evaluation of attentional biases towards negative emotional stimuli (P>.05) or on psychometric evaluation with state anxiety inventory (P = .059); in addition, a significant improvement was found in the Negative Affect Schedule (P = .014) and in the Beck Depression Inventory (P = .009). Biofeedback training significantly reduced seizure frequency with a mean reduction of -48.61% (SD = 27.79) (P = .005). There was a correlation between the mean change in skin conductance activity over the biofeedback treatment and the reduction of seizure frequency (r(11) = .62, P = .042). Thus, the skin conductance biofeedback used in the present study, which teaches patients to achieve an increased level of peripheral sympathetic arousal, was a well-tolerated nonpharmacological treatment. Further, well-controlled studies are needed to confirm the therapeutic value of this nonpharmacological treatment in reducing seizures in adults with drug-resistant TLE with seizures triggered by stress. PMID- 25461225 TI - Reappraisal of abnormal EEG findings in children with ADHD: on the relationship between ADHD and epileptiform discharges. AB - INTRODUCTION: Attention-deficit hyperactivity disorder is suggested to be closely related to epilepsy. A recent large-scale study revealed that ADHD in children is often accompanied by epilepsy. In Japan, methylphenidate (MPH) as a sustained action tablet and atomoxetine (ATX) became commercially available as medications for children recently. Since then, the number of prescriptions of both medicines has increased rapidly. Methylphenidate, as a psychostimulant, has been a source of concern because of the perceived lowered threshold for convulsions in children. Based on this background, reappraisal of EEG findings in children with ADHD is important in order to detect indications of potential comorbid epilepsy and to investigate the developmental mechanisms of the neurophysiological manifestations in patients with ADHD. MATERIAL AND METHOD: EEG findings in children newly diagnosed with ADHD and their relationship with clinical findings were investigated. The author evaluated 208 patients with ADHD newly diagnosed between 2008 and 2013. Of these, there were 145 patients for whom EEG findings were obtained along with a clinical follow-up for at least three months. Patients with IQ<70 were excluded in order to obtain a homogenous group of patients with ADHD. The male-to-female ratio was 130:15, and the age range was between 5 years, 9 months and 19 years, 9 months, with mean age of 11 years, 4 months. RESULTS: The results revealed that about half (48.3%) of the children with ADHD had abnormal EEG findings and that 22.1% of them had epileptiform discharges. Patients without comorbidity of autism spectrum disorder (ore homogenous group with ADHD) were especially likely to show abnormal EEG findings (51.0%) including epileptiform discharges (24.5%). Afebrile seizures, that is, epileptic seizures, occurred in a boy three days after commencement of administration with MPH as a sustained-action tablet. In four patients with a past history of epilepsy, neither relapse of EEG abnormality nor epileptic seizures were observed during the follow-up period. CONCLUSION: There was to be a significantly close relationship between ADHD and epileptiform discharges. Therefore, in patients with ADHD, it is important to obtain more precise information about seizures and presence of epilepsy from the personal and family histories, as well as to undertake a thorough EEG examination. PMID- 25461226 TI - Computer-aided diagnosis of alcoholism-related EEG signals. AB - Alcoholism is a severe disorder that affects the functionality of neurons in the central nervous system (CNS) and alters the behavior of the affected person. Electroencephalogram (EEG) signals can be used as a diagnostic tool in the evaluation of subjects with alcoholism. The neurophysiological interpretation of EEG signals in persons with alcoholism (PWA) is based on observation and interpretation of the frequency and power in their EEGs compared to EEG signals from persons without alcoholism. This paper presents a review of the known features of EEGs obtained from PWA and proposes that the impact of alcoholism on the brain can be determined by computer-aided analysis of EEGs through extracting the minute variations in the EEG signals that can differentiate the EEGs of PWA from those of nonaffected persons. The authors advance the idea of automated computer-aided diagnosis (CAD) of alcoholism by employing the EEG signals. This is achieved through judicious combination of signal processing techniques such as wavelet, nonlinear dynamics, and chaos theory and pattern recognition and classification techniques. A CAD system is cost-effective and efficient and can be used as a decision support system by physicians in the diagnosis and treatment of alcoholism especially those who do not specialize in alcoholism or neurophysiology. It can also be of great value to rehabilitation centers to assess PWA over time and to monitor the impact of treatment aimed at minimizing or reversing the effects of the disease on the brain. A CAD system can be used to determine the extent of alcoholism-related changes in EEG signals (low, medium, high) and the effectiveness of therapeutic plans. PMID- 25461227 TI - The influence of staffing on diagnostic yield of EMU admissions: a comparison study between two institutions. AB - Patients with recurrent, stereotyped neurological events of unclear etiology often warrant admission for continuous video-EEG monitoring in an epilepsy monitoring unit (EMU) for diagnosis. Epilepsy monitoring unit admission duration has been reported to range from days to weeks. To date, there are limited data on the average duration of admission for patients admitted to the EMU for spell classification. Many EMUs are forced to limit the overall duration of admission for numerous reasons including limited resources. It is unclear if a time-limited EMU stay reduces the event capture rate and, therefore, diagnostic yield of event classification admissions. The goal of this study was to determine how a time limited length of stay strategy impacted event capture in patients admitted for spell classification. A retrospective chart review was performed at two comparable adult epilepsy monitoring units, Mayo Clinic Hospital (MCH) in Phoenix, Arizona, and Banner Good Samaritan Medical Center (BGSMC) in Phoenix, Arizona. Banner Good Samaritan Medical Center is only staffed Monday through Friday, thereby limiting the total possible duration of admission to five days. The goal was to determine if the rate of event capture differed between two institutions employing a time-limited EMU admission (BGSMC) when compared with the nonlimited admission (MCH). A total of 300 patient admissions at MCH and 260 patient admissions at BGSMC were reviewed over a comparable time period. The event capture rates at MCH and BGSMC were 74% and 72%, respectively. There was a greater percentage of patients with nonepileptic events (NEEs) at MCH than at BGSMC (62.7% vs. 47.3%). The mean duration until first event was 31h at MCH and 38 h at BGSMC. The mean length of stay was greater at MCH (4.5 days) when compared with BGSMC (3.3 days). The overall diagnostic yield of a time-limited EMU admission was similar to that of a nonlimited admission for the purpose of spell classification. There was a statistically significant difference when comparing the time until first event at both institutions; however, this still fell within the 5-day duration that the time-restricted admission was limited to. These results may be important in optimizing an EMU practice in patients requiring admission for spell classification. PMID- 25461228 TI - Delayed diagnosis is influenced by the clinical pattern of Crohn's disease and affects treatment outcomes and quality of life in the long term: a cross sectional study of 361 patients in Southern Italy. AB - OBJECTIVES: Three patterns of Crohn's disease (CD) have been described. Our aim was to investigate for differences in diagnostic delay between patterns of CD, and differences in treatment outcomes, need for surgery and quality of life (QoL). PATIENTS AND METHODS: This is a cross-sectional study. First, the data of CD patients observed at our IBD Referral Centre between 2000 and 2009 were analysed. We gathered demographical characteristics and data on the onset of clinical symptoms, progression until diagnosis and treatment. The risk of delayed diagnosis was computed for each pattern. We then asked patients to fill the Inflammatory Bowel Disease Questionnaire (IBDQ). QoL scores of patients receiving a diagnosis within 18 months from the onset of symptoms were matched with those of the remaining patients. RESULTS: Three-hundred and sixty-one patients were identified. The mean age of the patients at the onset of symptoms and at diagnosis was 30 +/- 14 and 32 +/- 14 years. The penetrating pattern showed an association only with perianal symptoms at onset (P = 0.0015). The risk of delayed diagnosis was 21, 27 and 59% for inflammatory, stricturing and penetrating patterns. We found a significant difference between penetrating and nonpenetrating patterns (P = 0.043). A delayed diagnosis was associated with poorer treatment outcomes, QoL and higher surgery rate. CONCLUSION: Our study suggests a correlation between delayed diagnosis and the CD pattern. The delay in diagnosis between the CD subtypes can influence outcomes and QoL. PMID- 25461229 TI - Two new drugs for idiopathic pulmonary fibrosis. PMID- 25461230 TI - Invokamet and Xigduo XR: two new combinations for type 2 diabetes. PMID- 25461231 TI - Secondary prevention of stroke. PMID- 25461232 TI - In brief: adding ezetimibe to a statin improves clinical outcomes. PMID- 25461233 TI - In brief: topiramate extended-release capsules (Qudexy XR). PMID- 25461234 TI - Health-care associate transmission of Middle East Respiratory Syndrome Corona virus, MERS-CoV, in the Kingdom of Saudi Arabia. PMID- 25461235 TI - The efficacy of ribavirin in Crimean-Congo hemorrhagic fever--randomized trials are urgently needed. PMID- 25461236 TI - Pretreatment serum macrophage inflammatory protein (MIP)-1 levels predict sustained virological responses to re-treatment in patients with chronic hepatitis C virus infection. AB - BACKGROUND: There are few predictors of the virological response in patients who are re-treated with antiviral therapies. In this study, we evaluated the levels of chemokines that bind to C-C chemokine receptor type 5 (CCR5) and their impact on combination therapy in both treatment-naive and treatment-experienced patients chronically infected with hepatitis C virus (HCV). METHODS: Longitudinal analysis of CCR5 chemokines was performed using the multiplex Bio-Rad 27-plex assay in 56 treatment-naive and 24 treatment-experienced patients with chronic HCV infection during combination therapy with peginterferon alfa and ribavirin. A group of healthy donors was included as the control (n=11). RESULTS: The pretreatment level of macrophage inflammatory protein 1 (MIP-1) was determined to be an independent predictor, with an ideal predictive threshold for sustained virological response of 95.23 pg/ml. A rapid decline in HCV RNA was observed in patients with a pretreatment MIP-1 level of <95.23 pg/ml, while a slow reduction was measured in patients with levels of >=95.23 pg/ml (p=0.014). Of note, the dynamics of MIP-1 further indicated that a lower level at baseline and at treatment week 12 was significantly associated with a favorable outcome of antiviral therapy (p=0.014), especially in treatment-experienced patients (p=0.04), while a higher level of MIP-1beta correlated with the elevation of transaminases. CONCLUSIONS: Serum MIP-1 is an independent and effective predictor of early and sustained virological response in chronically HCV-infected patients undergoing re-treatment. PMID- 25461237 TI - Evidence supports ribavirin use in Crimean-Congo hemorrhagic fever. PMID- 25461238 TI - First report on the isolation of Aureimonas altamirensis from a patient with peritonitis. AB - The isolation of Aureimonas altamirensis (a rare opportunistic pathogen with a yet unresolved pathogenicity) from the ascites fluid of a patient with bacterial peritonitis is reported. The strain was first identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and the result was confirmed using 16S rDNA sequencing. An antimicrobial susceptibility profile was determined according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines published in 2013, revealing sensitivity to all antibiotics tested. The patient was treated effectively with levofloxacin. PMID- 25461239 TI - Efficacy of empirical therapy with non-carbapenems for urinary tract infections with extended-spectrum beta-lactamase-producing Enterobacteriaceae. AB - OBJECTIVES: Carbapenems are first-line agents for severe infections with extended spectrum beta-lactamase (ESBL)-producing bacteria. The use of carbapenems, however, is associated with the emergence of resistant organisms. We investigated the effects of empirical therapy with non-carbapenems on urinary tract infections (UTIs) with ESBL-producing Enterobacteriaceae in a hospital where antimicrobial stewardship has been established. METHODS: This retrospective chart review was undertaken at a tertiary care hospital where antimicrobial stewardship and restriction of carbapenems has been established. Patients with a UTI with ESBL producing Enterobacteriaceae were stratified into susceptible and non-susceptible therapy groups according to the susceptibility of the causative organism to the initial antimicrobial therapy. Outcome measures were the duration of antimicrobial therapy, 14-day mortality, infection-related mortality, and clinical cure. RESULTS: Of 90 patients, 30 (33.3%) exhibited susceptible therapy. However, no significant difference was observed in the duration of antimicrobial therapy, 14-day mortality, infection-related mortality, or clinical cure between the susceptible and non-susceptible groups. Multivariate analyses revealed that the independent risk factor for 14-day morality was the use of immunosuppressive agents (odds ratio 5.23, 95% confidence interval 1.26-24.04; p=0.023). CONCLUSIONS: Non-carbapenem therapy against UTIs with ESBL-producing Enterobacteriaceae does not pose a significant risk to patients who are not taking immunosuppressive agents. PMID- 25461240 TI - CC4821 serogroup W meningococcal disease in China. AB - Neisseria meningitidis is a major public health concern worldwide, including China. A few cases of serogroup W meningococcal disease have been reported in southeast China in recent years. Thus far, invasive disease due to W isolates has involved sequence type 11. We report two cases of N. meningitidis infection caused by CC4821 serogroup W strains. PMID- 25461241 TI - Incremental value of B-type natriuretic peptide for early risk prediction of infective endocarditis. AB - BACKGROUND: Early and accurate risk prediction is an unmet clinical need in patients with infective endocarditis (IE). The aim of this study was to determine the value of B-type natriuretic peptide (BNP) levels obtained on admission for the prediction of in-hospital death in IE patients. METHODS: Between 2009 and 2011, consecutive patients with IE diagnosed using the revised Duke criteria and admitted to the emergency department were evaluated prospectively. BNP levels were measured on admission. Death during hospitalization was the primary endpoint. RESULTS: Among 104 consecutive patients with IE and with available BNP levels, 34 (32.7%) died in hospital. BNP levels were significantly higher in patients who died as compared to survivors (709.0 pg/ml vs. 177.5 pg/ml, p<0.001). The accuracy of BNP to predict death as quantified by the area under the receiver operating characteristics curve was 0.826 (95% confidence interval (CI) 0.747-0.905). The value of BNP was additive to that provided by clinical, microbiological, and echocardiography assessment. On multivariate analysis, new heart failure (hazard ratio (HR) 2.02, 95% CI 1.15-3.57, p=0.015), sepsis (HR 2.10, 95% CI 1.25-3.55, p=0.005), Staphylococcus aureus endocarditis (HR 2.67, 95% CI 1.60-4.45, p<0.001), left ventricular ejection fraction <=55% (HR 1.63, 95% CI 1.00-2.65, p=0.047), and BNP (HR 1.04, 95% CI 1.02-1.06, p<0.001) were independent predictors of in-hospital mortality. CONCLUSION: Among patients with IE, BNP levels obtained on admission provide incremental value for early and accurate risk prediction. PMID- 25461242 TI - Evaluation of the decision support system for antimicrobial treatment, TREAT, in an acute medical ward of a university hospital. AB - OBJECTIVES: TREAT, a decision support system for antimicrobial therapy, was implemented in an acute medical ward. METHODS: Patients admitted on suspicion of infection were included in the study. The evaluation of TREAT was done both retrospectively and prospectively. Coverage of empirical antimicrobial treatments was compared to recommendations from TREAT and the optimal use of local guidelines. RESULTS: Five hundred and eleven patients were included, of whom 162 had a microbiologically documented infection. In the retrospective part of the study, TREAT, physician, and guideline antimicrobial coverage rates were 65%, 51%, and 79%, respectively, and in the prospective part, 68%, 62%, and 77%, respectively. TREAT provided lower coverage than local guidelines (p<0.001), but was similar to the performance of physicians in a university hospital (p=0.069). No differences were found in length of hospital stay, or hospital or 30-day mortality. Direct costs were significantly higher for TREAT advice than for local guidelines or the physician prescriptions (p<0.001), but the ecological costs were lower for TREAT advice than for both local guidelines (p<0.001) and physician prescriptions (p=0.247). The coverage of TREAT advice for the bacteraemia patients was non-inferior to the physicians (p=1.00). CONCLUSIONS: TREAT can potentially improve the ecological costs of empirical antimicrobial therapy for patients in acute medical wards, but provided lower coverage than local guidelines. PMID- 25461243 TI - Nasopharyngeal carriage of Streptococcus pneumoniae in Romanian children before the introduction of the pneumococcal conjugated vaccination into the national immunization programme: a national, multi-centre, cross-sectional observational study. AB - OBJECTIVES: We analysed the distribution of vaccine and non-vaccine Streptococcus pneumoniae serotypes and the antimicrobial susceptibility of pneumococcal strains isolated from healthy Romanian children. METHODS: A multi-centre cross-sectional study was performed in four counties to evaluate carried strains of S. pneumoniae isolated from 2000 children aged 0-5 years. RESULTS: S. pneumoniae carriage was detected in 25.25% of the tested children. Carriage increased from 16.7% among infants to 29.4% in 3-5-year-old children (p<0.0001). The proportions of the serotypes included in pneumococcal conjugate vaccines PCV7, PCV10, and PCV13 among our isolates were 39.9%, 40.1%, and 58.7%, respectively. Erythromycin resistance was 72.5%, and it was significantly lower in non-vaccine serotypes compared with PCV13 serotypes: 57.3% versus 83.6% (p<10(-7)). Penicillin minimum inhibitory concentrations (MICs) >0.064mg/l were recorded in 71.6%, but the penicillin MIC was >2mg/l for only 8.4% of tested isolates. CONCLUSIONS: In Romanian children, the majority of carried S. pneumoniae isolates are vaccine serotypes. The isolates with MICs defining macrolide resistance were very frequent, as well as the isolates with MICs defining penicillin resistance in the case of meningitis or penicillin dose-dependent susceptibility for other infections, mainly for the strains belonging to PCV13 serotypes. The implementation of PCV13 within the Romanian national immunization programme could reduce the circulation of these strains with higher macrolide and/or penicillin MICs. PMID- 25461244 TI - Cognitive health and Mediterranean diet: just diet or lifestyle pattern? AB - Mediterranean diet is a term used to describe the traditional eating habits of people in Crete, South Italy and other Mediterranean countries. It is a predominantly plant-based diet, with olive oil being the main type of added fat. There are many observational studies exploring the potential association between adherence to the Mediterranean diet and cognitive decline. The present review focuses on longitudinal studies with repeated cognitive assessments. It also evaluates evidence on behaviors related to the Mediterranean way of living, that have been shown to be associated with cognition, namely social interaction, participation in leisure activities, including physical activities, and sleep quality. The synergistic association-effect of these lifestyle behaviors, including diet, is unknown. Lifestyle patterns may constitute a new research and public health perspective. PMID- 25461245 TI - Novel aspects of spinal cord evoked potentials (SCEPs) in the evaluation of dorso ventral and lateral mechanical impacts on the spinal cord. AB - OBJECTIVES: The aim of the current study was to mimic mechanical impacts on the spinal cord by manifesting the effects of dorsoventral (DVMP) and lateral (LMP) mechanical pressure on neural activity to address points to be considered during surgery for different purposes, including spinal cord decompression. APPROACHES: Spinal cords of anesthetized rats were compressed at T13. Different characteristics of axons, including vulnerability, excitability, and conduction velocity (CV), in response to promptness, severity, and duration of pressure were assessed by spinal cord evoked potentials (SCEPs). Real-time SCEPs recorded at L4 5 revealed N1, N2, and N3 peaks that were used to represent the activity of injured sensory afferents, interneurons, and MN fibers. The averaged SCEP recordings were fitted by trust-region algorithm to find the equivalent Gaussian and polynomial equations. MAIN RESULTS: The pyramidal and extrapyramidal pathways possessed CVs of 3-11 and 16-80 m s(-1), respectively. DVMP decreased the excitability of myelinated neural fibers in antidromic and orthodromic pathways. The excitability of fibers in extrapyramidal and pyramidal pathways of lateral corticospinal (LCS) and anterior corticospinal (ACS) tracts decreased following LMP. A significant drop in the amplitude of N3 and its conduction velocity (CV) revealed higher susceptibility of less-myelinated fibers to both DVMP and LMP. The best parametric fitting model for triplet healthy spinal cord CAP was a six term Gaussian equation (G6) that fell into a five-term equation (G5) at the complete compression stage. SIGNIFICANCE: The spinal cord is more susceptible to dorsoventral than lateral mechanical pressures, and this should be considered in spinal cord operations. SCEPs have shown promising capabilities for evaluating the severity of SCI and thus can be applied for diagnostic or prognostic intraoperative monitoring (IOM). PMID- 25461246 TI - Poor warfarin dose prediction with pharmacogenetic algorithms that exclude genotypes important for African Americans. AB - OBJECTIVES: Recent clinical trial data cast doubt on the utility of genotype guided warfarin dosing, specifically showing worse dosing with a pharmacogenetic versus clinical dosing algorithm in African Americans. However, many genotypes important in African Americans were not accounted for. We aimed to determine whether omission of the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G > A genotype affects performance of dosing algorithms in African Americans. METHODS: In a cohort of 274 warfarin-treated African Americans, we examined the association between the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G > A genotype and warfarin dose prediction error with pharmacogenetic algorithms used in clinical trials. RESULTS: The http://www.warfarindosing.org algorithm overestimated doses by a median (interquartile range) of 1.2 (0.02-2.6) mg/day in rs12777823 heterozygotes (P<0.001 for predicted vs. observed dose), 2.0 (0.6-2.8) mg/day in rs12777823 variant homozygotes (P = 0.004), and 2.2 (0.5-2.9) mg/day in carriers of a CYP2C9 variant (P < 0.001). The International Warfarin Pharmacogenetics Consortium (IWPC) algorithm underdosed warfarin by 0.8 (-2.3 to 0.4) mg/day for patients with the rs12777823 GG genotype (P < 0.001) and overdosed warfarin by 0.7 (-0.4 to 1.9) mg/day in carriers of a variant CYP2C9 allele (P = 0.04). Modifying the http://www.warfarindosing.org algorithm to adjust for variants important in African Americans led to better dose prediction than either the original http://www.warfarindosing.org (P < 0.01) or IWPC (P < 0.01) algorithm. CONCLUSION: These data suggest that, when providing genotype-guided warfarin dosing, failure to account for variants important in African Americans leads to significant dosing error in this population. PMID- 25461248 TI - Reducing hypersensitivity reactions with HLA-B*5701 genotyping before abacavir prescription: clinically useful but is it cost-effective in Singapore? AB - AIM: Abacavir (ABC) is one of the more affordable antiretroviral drugs used for controlling HIV. Although with similar efficacy to current first-line drugs, its limited usage in Singapore can be attributed to its possible side effect of adverse hypersensitivity reactions (HSRs). HLA-B*5701 genotyping is a clinically relevant procedure for avoiding abacavir-induced HSRs. As patients who do not carry the risk allele are unlikely to develop HSRs, a simple rule can be developed to allow abacavir prescription for patients who are B*5701 negative. Here, we carry out a cost-effectiveness analysis of HLA-B*5701 genotyping before abacavir prescription in the context of the Singapore healthcare system, which caters predominantly to Han Chinese, Southeast-asian Malays, and South-asian Indians. In addition, we aim to identify the most cost-effective treatment regimen for HIV patients. METHODS: A decision tree model was developed in TreeAge. The model considers medical treatment and genotyping costs, genotyping test characteristics, the prevalence of the risk allele, reduction in the quality of life, and increased expenditure due to side effects and other factors, evaluating independently over early-stage and late-stage HIV patients segmented by drug contraindications. RESULTS: The study indicates that genotyping is not cost-effective for any ethnicity irrespective of the disease stage, except for Indian patients with early-stage HIV who are contraindicated to tenofovir. CONCLUSION: Abacavir (as first-line) without genotyping is the cheapest and most cost-effective treatment for all ethnicities except for early-stage Indian HIV patients contraindicated to tenofovir. The HLA-B*5701 frequency, the mortality rate from abacavir-induced HSRs, and genotyping costs are among the major factors influencing the cost-effectiveness. PMID- 25461249 TI - PPARA gene and phenprocoumon: a new predictor of response variability. AB - Phenprocoumon is an anticoagulant used for thromboembolic disorder prophylaxis metabolized mainly by CYP3A4. However, polymorphisms in this gene did not explain the observed variability. PPARA (peroxisome proliferator-activated receptor alpha) is a nuclear receptor that, among others, influences CYP3A4 gene expression. The aim of this study was to determine whether PPARA gene polymorphisms and the CYP3A4*22 allele are associated with phenprocoumon dose variability. A total of 198 patients on a stable dose of phenprocoumon were included in the study. Genotyping was performed by allele discrimination using standardized TaqMan assays. Differences between the average phenprocoumon dose and genotypes/haplotypes were assessed by analysis of variance and multiple linear regression analyses. Patients with the PPARA rs4253728A allele needed higher phenprocoumon doses. However, the effect size (3%) of this association was small. The CYP3A4*22 allele was not associated with the dose of phenprocoumon. As this is the first report of an association between PPARA gene polymorphisms and phenprocoumon dose, future studies are warranted to confirm these results. PMID- 25461250 TI - Melatonin overcomes resistance to clofarabine in two leukemic cell lines by increased expression of deoxycytidine kinase. AB - Drug resistance remains a serious problem in leukemia therapy. Among newly developed nucleoside antimetabolites, clofarabine has broad cytotoxic activity showing therapeutic promise and is currently approved for relapsed acute lymphoblastic leukemia. To investigate the mechanisms responsible for clofarabine resistance, we established two clofarabine-resistant lymphoblastic leukemia cell lines from parental lines. To elucidate the mechanisms against clofarabine resistance in two newly established clofarabine-resistant cell lines, we measured the expression of export pumps multidrug resistance protein 1, multidrug resistance-associated protein 1, and ATP-binding cassette subfamily G member 2. There were no differences in the expression between clofarabine-sensitive and resistant cell lines. Next, we determined expression of deoxycytidine kinase (dCK), which phosphorylates clofarabine to exert cytotoxicity, in clofarabine sensitive and -resistant cells. Clofarabine-resistant cells showed significantly decreased expression of dCK RNA when compared with sensitive cells. To elucidate the mechanisms of decreased dCK expression in clofarabine-resistant cells, we analyzed the methylation status of CpG islands of the dCK promoter and found no differences in methylation status between clofarabine-sensitive and -resistant cells. Next, we measured the acetylation status of histone and found that total histone acetylation, and histone H3 and H4 acetylation on chromatin immunoprecipitation assay were significantly decreased in resistant cells. Melatonin is an indolamine that functions in the regulation of chronobiological rhythms to exert cytotoxic effects. We examined the effects of melatonin in clofarabine-resistant cells and found that melatonin treatment led to significantly increased cytotoxicity with clofarabine in resistant cells via increased acetylation. Melatonin may be a useful candidate for overcoming clofarabine resistance in two newly established clofarabine resistant leukemia cell lines. PMID- 25461247 TI - Genome-wide association study of virologic response with efavirenz-containing or abacavir-containing regimens in AIDS clinical trials group protocols. AB - BACKGROUND: Efavirenz and abacavir are components of recommended first-line regimens for HIV-1 infection. We used genome-wide genotyping and clinical data to explore genetic associations with virologic failure among patients randomized to efavirenz-containing or abacavir-containing regimens in AIDS Clinical Trials Group (ACTG) protocols. PARTICIPANTS AND METHODS: Virologic response and genome wide genotype data were available from treatment-naive patients randomized to efavirenz-containing (n=1596) or abacavir-containing (n = 786) regimens in ACTG protocols 384, A5142, A5095, and A5202. RESULTS: Meta-analysis of association results across race/ethnic groups showed no genome-wide significant associations (P < 5 * 10) with virologic response for either efavirenz or abacavir. Our sample size provided 80% power to detect a genotype relative risk of 1.8 for efavirenz and 2.4 for abacavir. Analyses focused on CYP2B genotypes that define the lowest plasma efavirenz exposure stratum did not show associations nor did analysis limited to gene sets predicted to be relevant to efavirenz and abacavir disposition. CONCLUSION: No single polymorphism is associated strongly with virologic failure with efavirenz-containing or abacavir-containing regimens. Analyses to better consider context, and that minimize confounding by nongenetic factors, may show associations not apparent here. PMID- 25461252 TI - In vitro microfluidic model for the study of vaso-occlusive processes. AB - Vaso-occlusion, responsible for much of the morbidity of sickle-cell disease, is a complex multicellular process, apparently triggered by leukocyte adhesion to the vessel wall. The microcirculation represents a major site of leukocyte endothelial interactions and vaso-occlusive processes. We have developed a biochip with subdividing interconnecting microchannels that decrease in size (40 MUm to 10 MUm in width), for use in conjunction with a precise microfluidic device, to mimic cell flow and adhesion through channels of sizes that approach those of the microcirculation. The biochips were utilized to observe the dynamics of the passage of neutrophils and red blood cells, isolated from healthy and sickle-cell anemia (SCA) individuals, through laminin or endothelial adhesion molecule-coated microchannels at physiologically relevant rates of flow and shear stress. Obstruction of E-selectin/intercellular adhesion molecule 1-coated biochip microchannels by SCA neutrophils was significantly greater than that observed for healthy neutrophils, particularly in the microchannels of 40-15 MUm in width. Whereas SCA red blood cells alone did not significantly adhere to, or obstruct, microchannels, mixed suspensions of SCA neutrophils and red blood cells significantly adhered to and obstructed laminin-coated channels. Results from this in vitro microfluidic model support a primary role for leukocytes in the initiation of SCA occlusive processes in the microcirculation. This assay represents an easy-to-use and reproducible in vitro technique for understanding molecular mechanisms and cellular interactions occurring in subdividing microchannels of widths approaching those observed in the microvasculature. The assay could hold potential for testing drugs developed to inhibit occlusive mechanisms such as those observed in SCA and thrombotic diseases. PMID- 25461251 TI - Related-to-receptor tyrosine kinase receptor regulates hematopoietic stem and progenitor sensitivity to myelosuppressive injury in mice. AB - Maintaining a careful balance between quiescence and proliferation of hematopoietic stem and progenitor cells (HSPCs) is necessary for lifelong blood formation. Previously, we demonstrated that the Wnt5a ligand inhibits HSPC proliferation through a functional interaction with a noncanonical Wnt ligand receptor termed 'related-to-receptor tyrosine kinase' (Ryk). Expression of Ryk on HSPCs in vivo is associated with a lower rate of proliferation, and, following treatment with fluorouracil (5-FU), the percentage of Ryk(+/high) HSPCs increased and the percentage of Ryk(-/low) HSPCs decreased. Based on these data, we hypothesized that one function of the Ryk receptor is to protect HSPCs from the effects of myeloablative agents. We found that Ryk expression on HSPCs is associated with lower rates of apoptosis following 5-FU and radiation. Transient inhibition of Ryk signaling in vivo resulted in increased hematopoietic-stem-cell proliferation and decreased hematopoietic-stem-cell function in bone marrow transplant assays. Furthermore, inhibition of Ryk signaling sensitized HSPCs to 5 FU treatment in association with increased levels of reactive oxygen species. Together, these results demonstrated an association between Ryk expression and survival of HSPCs following suppressive injury. PMID- 25461254 TI - Autophagy regulates the cell cycle of murine HSPCs in a nutrient-dependent manner. AB - Autophagy is implicated in hematopoiesis, but its role in the regulation of the hematopoietic stem and progenitor cell (HSPC) cycle remains obscure. Here, we show that autophagy is essential to maintain and regulate the cell cycle of HSPCs in a nutrient-dependent manner. The loss of autophagy via conditional deletion of its essential gene atg7 ablated the cell cycle of HSPCs. Under physiologic or nutrient-rich conditions, the in vivo activation of autophagy promoted the cell cycle entry of hematopoietic stem cells and upregulated cyclin D3 expression in HSPCs. In contrast, under poor nutrient conditions, the ex vivo inhibition of early, but not late, autophagy signaling events enhanced the G1/S transition of HSPCs. Cyclin D3 was downregulated in HSPCs in response to nutrient stress. A knockdown of cyclin D3 blocked the G1/S transition in HSPCs. Surprisingly, the ex vivo inhibition of starvation-induced early, but not late, autophagy signaling inhibited the ubiquitin-mediated degradation of cyclin D3 in HSPCs. Furthermore, a conditional autophagy defect also had this effect, leading to an elevated cyclin D3 level in these cells. This suggested a dependency of the proteasomal degradation of cyclin D3 on early, but not late, events in autophagy signaling under nutrient stress in HSPCs. Our results thus indicate a dual role of autophagy in the nutrient-dependent modulation of the cell cycle entry of hematopoietic stem cells and G1/S transition of HSPCs via the regulation of cyclin D3 to maintain a proper cell cycle in HSPCs and normal hematopoiesis during adult life. PMID- 25461253 TI - C-X-C motif chemokine 12 influences the development of extramedullary hematopoiesis in the spleens of myelofibrosis patients. AB - Myelofibrosis (MF) is characterized by the constitutive mobilization of hematopoietic stem cells (HSC) and hematopoietic progenitor cells (HPC) and the establishment of extramedullary hematopoiesis. The mechanisms underlying this abnormal HSC/HPC trafficking pattern remain poorly understood. We demonstrated that both splenic and peripheral blood (PB) MF CD34(+) cells equally share a defective ability to home to the marrow, but not to the spleens, of NOD/LtSz Prkdc(scid) mice. This trafficking pattern could not be attributed to discordant expression of integrins or chemokine receptors other than the downregulation of C X-C chemokine receptor type 4 by both PB and splenic MF CD34(+) cells. The number of both splenic MF CD34(+) cells and HPCs that migrated toward splenic MF plasma was, however, significantly greater than the number that migrated toward PB MF plasma. The concentration of the intact HSC/HPC chemoattractant C-X-C motif chemokine 12 (CXCL12) was greater in splenic MF plasma than PB MF plasma, as quantified using mass spectrometry. Functionally inactive truncated products of CXCL12, which are the product of proteolytic degradation by serine proteases, were detected at similar levels in both splenic and PB MF plasma. Treatment with an anti-CXCL12 neutralizing antibody resulted in a reduction in the degree of migration of splenic MF CD34(+) cells toward both PB and splenic MF plasma, validating the role of CXCL12 as a functional chemoattractant. Our data indicate that the MF splenic microenvironment is characterized by increased levels of intact, functional CXCL12, which contributes to the localization of MF CD34(+) cells to the spleen and the establishment of extramedullary hematopoiesis. PMID- 25461255 TI - Osteoclasts are dispensable for hematopoietic progenitor mobilization by granulocyte colony-stimulating factor in mice. AB - The contribution of osteoclasts to hematopoietic stem/progenitor cell (HSPC) retention in the bone marrow is controversial. Studies of HSPC trafficking in osteoclast-deficient mice are limited by osteopetrosis. Here, we employed two non osteopetrotic mouse models to assess the contribution of osteoclasts to basal and granulocyte colony-stimulating factor (G-CSF)-induced HSPC mobilization. We generated Rank(-/-) fetal liver chimeras using Csf3r(-/-) recipients to produce mice lacking G-CSF receptor expression in osteoclasts. Basal and G-CSF-induced HSPC mobilization was normal in these chimeras. We next acutely depleted osteoclasts in wild-type mice using the RANK ligand inhibitor osteoprotegerin. Marked suppression of osteoclasts was observed after a single injection of osteoprotegerin-Fc. Basal and G-CSF-induced HSPC mobilization in osteoprotegerin Fc-treated mice was comparable to that in control mice. Together, these data indicate that osteoclasts are not required for the efficient retention of HSPCs in the bone marrow and are dispensable for HSPC mobilization by G-CSF. PMID- 25461256 TI - Expansion of mouse hematopoietic progenitor cells in three-dimensional cocultures on frozen-thawed stromal cell layers formed within porous scaffolds. AB - To establish a highly efficient method of ex vivo expansion of hematopoietic cells (HCs), three-dimensional (3D) cocultures of HCs and stromal cell lines were performed using porous polymer scaffolds. Hematopoietic cells derived from mouse fetal livers were expanded by two successive cultures without the use of exogenous cytokines, namely, 3D cultures of stromal cells (DAS 104-8 cell line) to form stromal layers within the scaffolds, and, subsequently, by cocultures of the HCs on the stromal cell layers for 2 weeks. To expand the HCs more conveniently, in some experiments the stromal layers formed within the scaffolds were frozen (3D freezing) before the cocultures, then stored and applied to the cocultures after thawing. When the HCs were cocultured on the stromal layers of the DAS 104-8 cells, primitive HCs (c-kit(+) and CD34(+) cells) were expanded several fold during the cocultures. In contrast, the expansion of these primitive HCs was remarkably enhanced in the cocultures using the 3D frozen-thawed DAS 104 8 stromal layers (c-kit(+) cells > fifteenfold and CD34(+) cells > thirtyfold), and these expansions were significantly higher than those without the 3D freezing. The expansions enhanced by cocultures on the 3D frozen-thawed stromal layers were also observed in the cocultures with another stromal cell line (DAS 104-4). Because 3D frozen-thawed stromal cell lines are easy to handle, 3D coculture of HCs on frozen-thawed stromal cell lines may be an effective and convenient method for expanding primitive HCs. PMID- 25461257 TI - Targeting BAG-1: a novel strategy to increase drug efficacy in acute myeloid leukemia. AB - Overexpression of antiapoptotic proteins occurs frequently in cancer, resulting in defective apoptosis that may contribute to a poor chemosensitivity of tumor cells. B-cell lymphoma (BCL) 2-associated AthanoGene-1 (BAG-1) is a prosurvival chaperone recently found involved in the maintenance of acute myeloid leukemia (AML) cells survival in vitro. Here we reported BAG-1 upregulation in 87 of 99 analyzed AML patients with respect to healthy control samples applying reverse phase protein assay. Silencing of BAG-1 expression confirmed a decreased BCL-2 protein level but, in addition, provoked the increased transcription of GADD34 stress sensor. Furthermore, a dephosphorylation of eIF2alpha, as well as alteration of expression of IRE-1 and CHOP proteins, were documented, suggesting that a disruption of the endoplasmic reticulum stress/unfolded protein response was provoked by downregulation of BAG-1. A similar phenomenon was triggered after addition of Thioflavin S, which was shown to block BAG-1/BCL-2 interaction and to increase cell death, enforcing a prosurvival role of the BAG-1 protein in AML. Interestingly, synergic cytotoxic effects of doxorubicin, VP16 drugs, and ABT-737 compound were observed when Thioflavin S was coupled with these drugs. Taken together, our results gave further proof that upregulation of BAG-1 plays a critical role in AML and that BAG-1 targeting might be considered for a combined therapeutic strategy with conventional chemotherapy drugs in the treatment of AML patients. PMID- 25461259 TI - Drug susceptibility of influenza A/H3N2 strains co-circulating during 2009 influenza pandemic: first report from Mumbai. AB - OBJECTIVE: From its first instance in 1977, resistance to amantadine, a matrix (M2) inhibitor has been increasing among influenza A/H3N2, thus propelling the use of oseltamivir, a neuraminidase (NA) inhibitor as a next line drug. Information on drug susceptibility to amantadine and neuraminidase inhibitors for influenza A/H3N2 viruses in India is limited with no published data from Mumbai. This study aimed at examining the sensitivity to M2 and NA inhibitors of influenza A/H3N2 strains isolated from 2009 to 2011 in Mumbai. METHODS: Nasopharyngeal swabs positive for influenza A/H3N2 virus were inoculated on Madin Darby canine kidney (MDCK) cell line for virus isolation. Molecular analysis of NA and M2 genes was used to detect known mutations contributing to resistance. Resistance to neuraminidase was assayed using a commercially available chemiluminescence based NA-Star assay kit. RESULTS: Genotypically, all isolates were observed to harbor mutations known to confer resistance to amantadine. However, no know mutations conferring resistance to NA inhibitors were detected. The mean IC50 value for oseltamivir was 0.25 nM. One strain with reduced susceptibility to the neuraminidase inhibitor (IC50=4.08 nM) was isolated from a patient who had received oseltamivir treatment. Phylogenetic analysis postulate the emergence of amantadine resistance in Mumbai may be due to genetic reassortment with the strains circulating in Asia and North America. CONCLUSIONS: Surveillance of drug susceptibility helped us to identify an isolate with reduced sensitivity to oseltamivir. Therefore, we infer that such surveillance would help in understanding possible trends underlying the emergence of resistant variants in humans. PMID- 25461258 TI - Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury. AB - Spinal cord injury (SCI) leads to formation of a fibrotic scar that is inhibitory to axon regeneration. Recent evidence indicates that the fibrotic scar is formed by perivascular fibroblasts, but the mechanism by which they are recruited to the injury site is unknown. Using bone marrow transplantation in mouse model of spinal cord injury, we show that fibroblasts in the fibrotic scar are associated with hematogenous macrophages rather than microglia, which are limited to the surrounding astroglial scar. Depletion of hematogenous macrophages results in reduced fibroblast density and basal lamina formation that is associated with increased axonal growth in the fibrotic scar. Cytokine gene expression analysis after macrophage depletion indicates that decreased Tnfsf8, Tnfsf13 (tumor necrosis factor superfamily members) and increased BMP1-7 (bone morphogenetic proteins) expression may serve as anti-fibrotic mechanisms. Our study demonstrates that hematogenous macrophages are necessary for fibrotic scar formation and macrophage depletion results in changes in multiple cytokines that make the injury site less fibrotic and more conducive to axonal growth. PMID- 25461260 TI - Characteristics of the mosaic genome of a human parechovirus type 1 strain isolated from an infant with pneumonia in China. AB - Human parechoviruses (HPeVs) belong to the Parechovirus genus of the large and growing family of Picornaviridae with a non-enveloped, single-stranded and positive-sense RNA. An HPeV strain was isolated from the nasopharyngeal aspirate specimen of a 2 months old infant hospitalized with pneumonia in Beijing, China and nominated as BJ-37359 followed the code of the specimen. Strain BJ-37359 was identified as HPeV1 by whole genome sequencing. The full genome of strain BJ 37359 consisted of 7336 nucleotides (nt), excluding a poly (A) tail and contained an ORF of 6537 nt flanked by 5'UTR of 709 nt and 3'UTR of 90 nt. Phylogenetic analyses revealed that strain BJ-37359 were clustered together with HPeV1 strains in the structural capsid protein region, while uncoupling in the non-structural gene regions. Analyses with Simplot and Bootscan indicated that multiple recombination events occurred in the non-structural region and VP0 region of strain BJ-37359 with other HPeV1, and other types might have contributed to the recombination, especially HPeV6 and HPeV7 strains. Recombination analyses indicated that strain BJ-37359 may have a mosaic genome with new genomic recombination breakpoints. PMID- 25461261 TI - Cone location-dependent outcomes after combined topography-guided photorefractive keratectomy and collagen cross-linking. AB - PURPOSE: To evaluate the effect of keratoconus cone location on the change in refractive outcomes, corneal aberrations, and biomechanics after combined topography-guided photorefractive keratectomy (PRK) and collagen cross-linking (CXL). DESIGN: Prospective, comparative case series. METHODS: Topography-guided PRK was performed followed by accelerated CXL using riboflavin A and enhanced intensity (30 mW/cm(2)) ultraviolet light. Outcome parameters including uncorrected distance visual acuity (UDVA) and best-corrected distance visual acuity (BDVA), corneal tomography and biomechanics (corneal hysteresis [CH] and corneal resistance factor [CRF]), and corneal wavefront aberrations were assessed before and a year after the procedure. Eyes were subdivided into 2 groups preoperatively for statistical analysis: Group 1, cone located within the central 2-mm zone; and Group 2, cone located outside the central 2-mm zone. RESULTS: UDVA, BDVA, sphere, cylinder, and simulated keratometry improved after treatment in both groups (P < .05). However, BDVA improved more in Group 1 than in Group 2 (P = .04) and the other variables were not affected by cone location. A few corneal wavefront Zernike aberrations changed after treatment (P < .05) but none were affected by cone location (P > .05). CH and CRF increased after treatment in both groups (P > .05). Interestingly, the increases in CH and CRF were greater in Group 2 than in Group 1 (P > .05). CONCLUSIONS: Cone location appeared to impact only visual acuity and biomechanics after the combined procedure. The greater increase in CH and CRF in Group 2 may indicate differences in the ablation profile and variability in CXL outcomes and requires further study. PMID- 25461262 TI - Involvement of genetic variants associated with primary open-angle glaucoma in pathogenic mechanisms and family history of glaucoma. AB - PURPOSE: To investigate the associations between the non-intraocular pressure (IOP)-related genetic variants (genetic variants associated with vulnerability of the optic nerve independent of IOP) and primary open-angle glaucoma (POAG), including normal-tension glaucoma (NTG) and high-tension glaucoma (HTG), and between the non-IOP-related genetic variants and a family history of glaucoma. DESIGN: Case-control study. METHODS: Japanese patients with NTG (n = 213) and HTG (n = 212) and 191 control subjects were genotyped for 5 non-IOP-related genetic variants predisposing to POAG near the SRBD1, ELOVL5, CDKN2B/CDKN2B-AS1, SIX1/SIX6, and ATOH7 genes. The load of these genetic variants was compared between the control subjects and patients with NTG or HTG and between the POAG patients with and without a family history of glaucoma. RESULTS: The total number of POAG risk alleles and the product of the odds ratios (POAG risk) of these genetic variants were significantly larger (P < .0025) in patients with both NTG and HTG than in the control subjects, and were significantly larger (P = .0042 and P = .023, respectively) in POAG patients with a family history of glaucoma than in those without. As the number of relatives with glaucoma increased, the total number of risk alleles and the product of the odds ratios increased (P = .012 and P = .047, respectively). CONCLUSIONS: Non-IOP-related genetic variants contribute to the pathogenesis of HTG as well as NTG. A positive family history of glaucoma in cases of POAG is thought to reflect the influence of genetic variants predisposing to POAG. PMID- 25461264 TI - Elastic strain effects on catalysis of a PdCuSi metallic glass thin film. AB - The influence of strain on catalytic activity has previously been examined directly by calculations and indirectly by experiments. The origin of the phenomenon has been attributed to strain-induced changes in the catalyst electronic structure. By employing a Pd-based metallic glass film capable of large elastic strains, we provide direct experimental evidence for catalytic activity being differently influenced by mechanically applied uniaxial tensile and compressive strains. We demonstrate the effect on the oxygen reduction reaction with cyclic voltammetry (CV) curves at different strain levels and compare X-ray photoelectron spectrometry (XPS) results for unstrained and strained (in uniaxial tension) specimens to confirm valence electron band shifts. The experimental findings are complemented by electronic structure calculations on single crystal Pd, as well as alloys with Cu and Si. The CV and XPS shifts observed in the experiments are consistent in both direction and magnitude to those predicted by theory for single crystal Pd. PMID- 25461263 TI - One-year outcomes of aflibercept in recurrent or persistent neovascular age related macular degeneration. AB - PURPOSE: To evaluate 6-month and 1-year outcomes of every-8-weeks (Q8W) aflibercept in patients with resistant neovascular age-related macular degeneration (AMD). DESIGN: Retrospective, interventional, consecutive case series. METHODS: Retrospective review of patients with resistance (multiple recurrences or persistent exudation) to every-4-weeks (Q4W) ranibizumab or bevacizumab that were switched to Q8W aflibercept. RESULTS: Sixty-three eyes of 58 patients had a median of 13 (interquartile range [IQR], 7-22) previous anti vascular endothelial growth factor (anti-VEGF) injections. At 6 months after changing to aflibercept, 60.3% of eyes were completely dry, which was maintained up to 1 year. The median maximum retinal thickness improved from 355 MUm to 269 MUm at 6 months (P < .0001) and 248 MUm at 1 year (P < .0001). There was no significant improvement in ETDRS visual acuity at 6 months (P = .2559) and 1 year follow-up (P = .1081) compared with baseline. The mean difference in ETDRS visual acuity compared to baseline at 6 months was -0.05 logMAR (+2.5 letters) and 0.04 logMAR at 1 year (-2 letters). CONCLUSION: Sixty percent of eyes with resistant AMD while on Q4W ranibizumab or bevacizumab were completely dry after changing to Q8W aflibercept at the 6-month and 1-year follow-ups, but visual acuity did not significantly improve. Only a third of eyes needed to be switched from Q8W to Q4W aflibercept owing to persistence of fluid; Q8W dosing of aflibercept without the initial 3 monthly loading doses may be a good alternative in a select group of patients who may have developed ranibizumab or bevacizumab resistance. PMID- 25461265 TI - fMRI feedback enhances emotion regulation as evidenced by a reduced amygdala response. AB - Deficits in emotion regulation are a prominent feature of psychiatric conditions and a promising target for treatment. For instance, cognitive reappraisal is regarded as an effective strategy for emotion regulation. Neurophysiological models have established the lateral prefrontal cortex (LPFC) as a key structure in the regulation of emotion processing through modulations of emotion-eliciting structures such as the amygdala. Feedback of the LPFC activity by real-time functional magnetic resonance (fMRI) may thus enhance the efficacy of cognitive reappraisal. During cognitive reappraisal of aversive visual stimuli, LPFC activity was fed back to the experimental group, whereas control participants received no such information. As a result, during reappraisal, amygdala activity was lower in the experimental group than in the controls. Furthermore, an increase of inter-hemispheric functional connectivity emerged in the feedback group. The current study extends the neurofeedback literature by suggesting that fMRI feedback can modify brain activity during a given task. PMID- 25461266 TI - Networks of protein kinases and phosphatases in the individual phases of contextual fear conditioning in the C57BL/6J mouse. AB - Although protein kinases and phosphatases have been reported to be involved in fear memory, information about these signalling molecules in the individual phases of contextual fear conditioning (cFC) is limited. C57BL/6J mice were tested in cFC, sacrificed and hippocampi were used for screening of approximately 800 protein kinases and phosphatases by protein microarrays with subsequent Western blot confirmation of threefold higher or lower hippocampal levels as compared to foot shock controls. Immunoblotting of the protein kinases and phosphatases screened out was carried out by Western blotting. A network of protein kinases and phosphatases was generated (STRING 9.1). Animals learned the task in the paradigm and protein kinase and phosphatase levels were determined in the individual phases acquisition, consolidation and retrieval and compared to foot shock controls. Protein kinases discoidin containing receptor 2 (DDR2), mitogen activated protein kinase kinase kinase 7 (TAK1), protein phosphatases dual specificity protein phosphatase (PTEN) and protein phosphatase 2a (PP2A) were modulated in the individual phases of cFC. Phosphatidyl-inositol-3,4,5 triphosphate 3-phosphatase and phosphatidylinositol-3 kinase (PI3K) that is interacting with PTEN were modulated as well. Freezing time was correlating with PP2A levels in the retrieval phase of cFC. The abovementioned protein kinases, phosphatases and inositol-signalling enzymes were not reported so far in cFC and the results are relevant for interpretation of previous and design of future studies in cFC or fear memory. Protein phosphatase PP2A was, however, the only signalling compound tested that was directly linked to retrieval in the cFC. PMID- 25461268 TI - Hydrogen sulfide protects against apoptosis under oxidative stress through SIRT1 pathway in H9c2 cardiomyocytes. AB - Oxidative stress plays a great role in the pathogenesis of heart failure (HF). Oxidative stress results in apoptosis, which can cause the damage of cardiomyocytes. Hydrogen sulfide (H2S), the third gasotransmitter, is a good reactive oxygen species (ROS) scavenger, which has protective effect against HF. Sirtuin-1 (SIRT1) is a highly conserved nicotinamide adenine dinucleotide (NAD) dependent histone deacetylase that plays a critical role in promoting cell survival under oxidative stress. The purpose of this article is to investigate the interaction between H2S and SIRT1 under oxidative stress in H9c2 cardiomyocytes. Oxidative stress was induced by hydrogen peroxide (H2O2). Treatment with NaSH (25-100 umol/L) dose-dependently increased the cell viability and improved the cell apoptosis induced by H2O2 in H9c2 cardiomyocytes. The protective effect of NaSH against the apoptosis could be attenuated by SIRT1 inhibitor Ex 527 (10 umol/L). Treatment with NaSH (100 umol/L) could increase the expression of SIRT1 in time dependent manner, which decreased by different concentration of H2O2. NaSH (100 umol/L) increased the cellular ATP level and the expression of ATPase. These effects were attenuated by Ex 527 (10 umol/L). After NaSH (100 umol/L) treatment, the decrease in ROS production and the enhancement in SOD, GPx and GST expression were observed. Ex 527 (10 umol/L) reversed these effects. In conclusion, for the first time, this article can identify antioxidative effects of H2S under oxidative stress through SIRT1 pathway in H9c2 cardiomyocytes. PMID- 25461267 TI - Cerebral responses and role of the prefrontal cortex in conditioned pain modulation: an fMRI study in healthy subjects. AB - The mechanisms underlying conditioned pain modulation (CPM) are multifaceted. We searched for a link between individual differences in prefrontal cortex activity during multi-trial heterotopic noxious cold conditioning and modulation of the cerebral response to phasic heat pain. In 24 healthy female subjects, we conditioned laser heat stimuli to the left hand by applying alternatively ice cold or lukewarm compresses to the right foot. We compared pain ratings with cerebral fMRI BOLD responses. We also analyzed the relation between CPM and BOLD changes produced by the heterotopic cold conditioning itself, as well as the impact of anxiety and habituation of cold-pain ratings. Specific cerebral activation was identified in precuneus and left posterior insula/SII, respectively, during early and sustained phases of cold application. During cold conditioning, laser pain decreased (n=7), increased (n=10) or stayed unchanged (n=7). At the individual level, the psychophysical effect was directly proportional to the cold-induced modulation of the laser-induced BOLD response in left posterior insula/SII. The latter correlated with the BOLD response recorded 80s earlier during the initial 10-s phase of cold application in anterior cingulate, orbitofrontal and lateral prefrontal cortices. High anxiety and habituation of cold pain were associated with greater laser heat-induced pain during heterotopic cold stimulation. The habituation was also linked to the early cold-induced orbitofrontal responses. We conclude that individual differences in conditioned pain modulation are related to different levels of prefrontal cortical activation by the early part of the conditioning stimulus, possibly due to different levels in trait anxiety. PMID- 25461269 TI - H2S-releasing drugs: anti-inflammatory, cytoprotective and chemopreventative potential. AB - Hydrogen sulfide exerts a number of cytoprotective and anti-inflammatory effects in many organ systems. In an effort to exploit these potent and beneficial effects, a number of hydrogen sulfide-releasing derivatives of existing drugs have been developed and extensively tested in pre-clinical models. In particular, efforts have been made by several groups to develop hydrogen sulfide-releasing derivatives of a number of nonsteroidal anti-inflammatory drugs. The main goal of this approach is to reduce the gastrointestinal ulceration and bleeding caused by this class of drugs, particularly when used chronically such as in the treatment of arthritis. However, these drugs may also have utility for prevention of various types of cancer. This paper provides an overview of some of the mechanisms underlying the anti-inflammatory and cytoprotective actions of hydrogen sulfide. It also gives some examples of hydrogen sulfide-releasing anti inflammatory drugs, and their actions in terms of reducing inflammation and attenuating the development of cancer in experimental models. PMID- 25461270 TI - Fluorescent probes for hydrogen sulfide (H2S) and sulfane sulfur and their applications to biological studies. AB - Hydrogen sulfide (H2S), a toxic gas with the smell of rotten eggs, plays key roles in many physiological processes, including relaxation of vascular smooth muscles, mediation of neurotransmission, inhibition of insulin signaling, and regulation of inflammation. The most commonly used methods or detecting H2S are the methylene blue method and the electrode method, but these methods require destructive sampling, e.g., homogenization of biological samples. On the other hand, the fluorescence detection method has been widely used in biological studies to study the physiological roles of H2S, because this technology provides real-time, easy-to-use, nondestructive detection in live cells or tissues. Many selective fluorescent probes for H2S have been reported. Sulfane sulfur compounds contain divalent sulfur atoms bonded to other sulfur atom(s), as in persulfides (R-S-SH) and polysulfides (R-S-Sn-S-R). They are currently attracting increasing interest because one of the mechanisms of activity regulation of proteins by H2S is sulfhydration of cysteine residues (RSH -> RSSH). Since H2S and sulfane sulfur are redox partners, they are very likely to coexist in biological systems, and from a reactivity point-of-view, sulfane sulfur seems likely to be much more effective than H2S in S-sulfhydration. Therefore, sulfane sulfur may be involved in mediating at least some of the biological activities of H2S. In this review, we summarize recent work on fluorescent probes selective for H2S and/or sulfane sulfur, and we briefly review their applications to biological studies. PMID- 25461271 TI - Dietary nitrite supplementation improves insulin resistance in type 2 diabetic KKA(y) mice. AB - BACKGROUND: Because insulin signaling is essential for endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) production, the loss of bioavailable NO might be a common molecular mechanism underlying the development of insulin resistance and endothelial dysfunction. Although dietary nitrite acts as a substrate for systemic NO generation, thereby serving as a physiological alternative source of NO for signaling, it is not precisely known how dietary nitrite affects type 2 diabetes mellitus. Here we report the therapeutic effects of dietary nitrite on the metabolic and histological features of KKA(y) diabetic mice. METHODS: KKA(y) mice were divided into three groups (without nitrite, and with 50 mg/L and 150 mg/L nitrite in drinking water), and two groups of C57BL/6J mice served as controls (without nitrite and with 150 mg/L nitrite in drinking water). After 10 weeks, blood samples, visceral adipose tissues, and gastrocnemius muscles were collected after a 16-hour fast to assess the homeostasis model assessment of insulin resistance (HOMA-IR) levels, the histology of the adipose tissue, insulin-stimulated sequential signaling to glucose transporter 4 (GLUT4), and nitrite and nitrate contents in the muscle using an HPLC system. RESULTS: KKA(y) mice developed obesity with enhanced fasting plasma levels of glucose and insulin and exhibited increased HOMA-IR scores compared with the C57BL/6J control mice. Dietary nitrite dose-dependently reduced the size of the hypertrophic adipocytes and TNF-alpha transcription in the adipose tissue of KKA(y) diabetic mice, which also restored the insulin mediated signal transduction, including p85 and Akt phosphorylation, and subsequently restored the GLUT4 expression in the skeletal muscles. CONCLUSIONS: These results suggest that dietary nitrite provides an alternative source of NO, and subsequently improves the insulin-mediated signaling and the metabolic and histological features in KKA(y) diabetic mice. PMID- 25461273 TI - Protective effect of hydrogen sulfide on pancreatic beta-cells. AB - Hydrogen sulfide (H2S) is recognized as a third gaseous signaling molecule behind nitric oxide (NO) and carbon monoxide (CO). In pancreatic beta-cells, H2S inhibits glucose-induced insulin release. There are multiple underlying mechanisms for this inhibitory process. Apart from these inhibitory effects, H2S also protects pancreatic islets from apoptotic cell death induced by high glucose. Moreover, expression of the H2S-producing enzyme, cystathionine gamma lyase (CSE), is induced by glucose stimulation. These observations suggest that H2S is produced in an inducible manner, as are the other two gaseous signaling molecules, NO and CO. We recently reported that a lack of CSE induces apoptotic beta-cell death and promotes the development of high-fat diet (HFD)-induced diabetes. These findings tempt us to suggest that H2S produced by CSE is part of a homeostatic mechanism used by pancreatic beta-cells to inhibit insulin release and reduce cellular stress evoked by glucose, possibly via the anti-oxidant properties of H2S. PMID- 25461272 TI - Impacts of CD44 knockdown in cancer cells on tumor and host metabolic systems revealed by quantitative imaging mass spectrometry. AB - CD44 expressed in cancer cells was shown to stabilize cystine transporter (xCT) that uptakes cystine and excretes glutamate to supply cysteine as a substrate for reduced glutathione (GSH) for survival. While targeting CD44 serves as a potentially therapeutic stratagem to attack cancer growth and chemoresistance, the impact of CD44 targeting in cancer cells on metabolic systems of tumors and host tissues in vivo remains to be fully determined. This study aimed to reveal effects of CD44 silencing on alterations in energy metabolism and sulfur containing metabolites in vitro and in vivo using capillary electrophoresis-mass spectrometry and quantitative imaging mass spectrometry (Q-IMS), respectively. In an experimental model of xenograft transplantation of human colon cancer HCT116 cells in superimmunodeficient NOG mice, snap-frozen liver tissues containing metastatic tumors were examined by Q-IMS. As reported previously, short hairpin CD44 RNA interference (shCD44) in cancer cells caused significant regression of tumor growth in the host liver. Under these circumstances, the CD44 knockdown suppressed polyamines, GSH and energy charges not only in metastatic tumors but also in the host liver. In culture, HCT116 cells treated with shCD44 decreased total amounts of methionine-pool metabolites including spermidine and spermine, and reactive cysteine persulfides, suggesting roles of these metabolites for cancer growth. Collectively, these results suggest that CD44 expressed in cancer accounts for a key regulator of metabolic interplay between tumor and the host tissue. PMID- 25461274 TI - Dietary nitrate improves glucose tolerance and lipid profile in an animal model of hyperglycemia. AB - Reduction in nitric oxide (NO) production and bioavailability contribute to the pathogenesis of type 2 diabetes. Administration of nitrate has strong NO-like outcomes in both animals and humans. In this study, we examined the effects of dietary nitrate on glucose tolerance and lipid profile in type 2 diabetic rats. Type 2 diabetes was induced by injection of streptozotocin and nicotinamide. Thirty-two male Wistar rats were divided into 4 groups: controls (C), control+nitrate (CN), diabetes (D), and diabetes+nitrate (DN). For 8 weeks, the CN and DN groups consumed sodium nitrate (100 mg/L in drinking water) while the C and D groups consumed tap water. Serum nitrate+nitrite (NOx), glucose, lipid profile, total antioxidant capacity (TAC), and catalase (CAT) activity were measured before and at the end of the study. Systolic blood pressure (SBP) was measured every 10 days. Intravenous glucose tolerance test (IVGTT) was performed at the end of the study. Serum NOx decreased in diabetic rats and dietary nitrate restored it to normal values. Increases in serum glucose levels was significantly lower in the DN group compared to the D group (24.1% vs. 90.2%; p < 0.05). Nitrate therapy in diabetic rats significantly improved lipid profile, glucose tolerance (AUC: 20264 +/- 659 vs. 17923 +/- 523; p < 0.05 for D and DN groups respectively) and restored elevated SBP to normal values. Diabetic rats had lower TAC and CAT activity and dietary nitrate restored these to normal status. In conclusion, dietary nitrate prevented increase in SBP and serum glucose, improved glucose tolerance and restored dyslipidemia in an animal model of hyperglycemia. PMID- 25461275 TI - Synthesis and evaluation of asiatic acid derivatives as anti-fibrotic agents: structure/activity studies. AB - Fibrotic diseases are characterized by the over-accumulation of fibrous components in the extracellular matrix and the liver, which can lead to liver cirrhosis. Current treatment options cannot reverse or halt liver fibrosis, motivating a search for newer treatment options. Previously, we showed that asiaticoside, a bioactive triterpene glycoside from Centella asiatica, has anti fibrotic properties. Here, the aglycone asiatic acid was chemically modified, and these derivatives were evaluated for their potential as anti-fibrotic agents. The data obtained from in vivo testing of these compounds in a rodent CCl4-induced liver injury model are discussed. The information obtained from these studies may be useful in the design of novel anti-fibrotic agents. PMID- 25461276 TI - Anti-fibrillation potency of caffeic acid against an antidepressant induced fibrillogenesis of human alpha-synuclein: Implications for Parkinson's disease. AB - Alpha synuclein is a 14 kDa intrinsically disordered, presynaptic protein whose fibrillation is a critical step in the pathogenesis of Parkinson's disease (PD). A structural investigation of the effect of escitalopram (a selective serotonin reuptake inhibitor) on alpha-synuclein was performed using ANS and ThT assays, CD, turbidity and Rayleigh scattering measurements as well as atomic force and transmission electron microscopy. Analysing the mechanism of alpha-synuclein fibril formation, helped us in elucidating the passage of an intermediate at 75 MUM concentration of escitalopram. Fibrils of alpha-synuclein were obtained at 100 MUM concentration of escitalopram. Inhibition of alpha-synuclein fibrillation was brought about by a polyphenolic acid known as caffeic acid which acted in a concentration dependent manner ranging from 10 to 60 MUM. Maximum inhibition was achieved at a concentration of 60 MUM. Fibrillation of alpha-synuclein in presence of escitalopram gives us clue for the negative effects of antidepressant. Inhibitory activity of caffeic acid against alpha-synuclein fibrillation may guide us in designing novel therapeutic drugs for PD. PMID- 25461277 TI - Bi-functionality of Opisthorchis viverrini aquaporins. AB - Aquaporins (AQP) are essential mediators of water regulation in all living organisms and members of the major intrinsic protein (MIP) superfamily of integral membrane proteins. They are potential vehicles or targets for chemotherapy, e.g. in Trypanosoma brucei melarsoprol and pentamidine uptake is facilitated by TbAQP-2. Transcriptome data suggests that there are at least three active aquaporins in the human liver fluke, Opisthorchis viverrini, OvAQP-1, 2 and 3, and crude RNA silencing of OvAQP-1 and 2 has recently been shown to affect parasite swelling in destilled water. In the present work we demonstrate that OvAQP-3 is a major water-conducting channel of the parasite, that it can be detected from the newly excysted juvenile to the adult stage and that it is present in major tissues of the parasite. Furthermore, a comparative functional characterization of the three parasite AQPs was performed by using Xenopus oocyte swelling and yeast phenotypic assays. OvAQP-1, OvAQP-2, and OvAQP-3 were found to conduct water and glycerol while only the latter two were also able to conduct urea. In addition, all OvAQPs were found to transport ammonia and methylamine. Our findings demonstrate that the sequence-based classification into orthodox aquaporins and glycerol-conducting aquaglyceroporins is not functionally conserved in the parasite and implicate a broder range of functions for these channels. PMID- 25461278 TI - Isoxazole to oxazole: a mild and unexpected transformation. AB - 3-Aryltetrahydrobenzisoxazoles prepared en route to the coleophomone natural products and analogues, were found to undergo a remarkable base-mediated rearrangement to 2-aryltetrahydrobenzoxazoles. The scope of this unprecedented, facile transformation was probed: a range of analogues was produced, a mechanism proposed, and an application demonstrated by synthesis of a known herbicidal compound. PMID- 25461280 TI - PAMAM dendrimer with 4-carbomethoxypyrrolidone--in vitro assessment of neurotoxicity. AB - Cytotoxicity of cationic amino-terminated PAMAM dendrimer and modified PAMAM pyrrolidone dendrimer was compared. LDH assay and cell visualization technique were employed. Mouse embryonic hippocampal cells (mHippoE-18) were used. The experiments were performed in FBS-deprived medium. Pyrrolidone-modification significantly diminished toxicity of PAMAM dendrimer. The absence of FBS did not reveal significant impact on the toxic effect. Results from LDH assay and MTT test were in good consistency. Low cytotoxicity of PAMAM-pyrrolidone dendrimer increases reliability of the results showing a small impact of this dendrimer on cell viability. PMID- 25461282 TI - Monocyte mediated brain targeting delivery of macromolecular drug for the therapy of depression. AB - Leukocytes can cross intact blood-brain barrier under healthy conditions and in many neurological diseases, including psychiatric diseases. In present study, a cyclic RGD (cRGD) peptide with high affinity for integrin receptors of leukocytes was used to modify liposomes. The cRGD-modified liposomes (cRGDL) showed high affinity for monocytes in vitro and in vivo and co-migrated across in vitro BBB model with THP-1. The trefoil factor 3 (TFF3), a macromolecular drug, was rapidly and persistently delivered to brain for at least 12 h when loaded into cRGDL while 2.8-fold increase in drug concentration in basolateral amygdala regions related to depression was observed. A systemic administration of cRGDL-TFF3 mimicked antidepressant-like effect of direct intra-basolateral amygdala administration of TFF3 solution in rats subjected to chronic mild stress. The effective dual-brain targeting delivery resulting from the combination and co migration of cRGDL with leukocyte cross BBB may be a promising strategy for targeted brain delivery. FROM THE CLINICAL EDITOR: In an effort to treat depression, brain targeted delivery via monocyte-cRGD liposome complexes capable of crossing the intact BBB was performed in this study in a murine model. Similar approaches may be helpful in the treatment of other neuropsychiatric conditions. PMID- 25461281 TI - Biodistribution and in vivo toxicity of aptamer-loaded gold nanostars. AB - This paper reports an in vivo evaluation of toxicology and biodistribution of a highly anisotropic Au nanoconstruct composed of a gold nanostar (AuNS) core and a ligand shell of a G-quadruplex DNA aptamer AS1411 (Apt) supporting both targeting and therapy capabilities. We examined the toxicity of the nanoconstructs (Apt AuNS) at four different injected concentrations. At the highest dose tested (48 mg/kg), maximal tolerated dose was not reached. Clinical pathology showed no apparent signs of acute toxicity. Interestingly, the nanoconstructs circulated longer in female rats compared to male rats. In two different tumor models, the biodistribution of Apt-AuNS, especially tumor accumulation, was different. Accumulation of Apt-AuNS was 5 times higher in invasive breast cancer tumors compared to fibrosarcoma tumors. These results provide insight on identifying a tumor model and nanoconstruct for in vivo studies, especially when an in vitro therapeutic response is observed in multiple cancer cell lines. From the clinical editor: This study investigated the toxicity and distribution of aptamer loaded gold nanostars in a rodent model of invasive breast cancer and fibrosarcoma. Acute toxicity was not identified even in the highest studied doses. Fivefold accumulation was demonstrated in the breast cancer model compared to the fibrosarcoma model. Studies like this are critically important in further clarifying the potential therapeutic use of these nanoconstructs, especially when ex vivo effects are clearly demonstrated. PMID- 25461283 TI - Absorption efficiency and heating kinetics of nanoparticles in the RF range for selective nanotherapy of cancer. AB - Radio-frequency (RF) waves have an excellent ability to penetrate into the human body, giving a great opportunity to activate/heat nanoparticles delivered inside the body as a contrast agent for diagnosis and treatment purposes. However the heating of nanoparticles in the RF range of the spectrum is controversial in the research community because of the low power load of RF waves and low absorption of nanoparticles in the RF range. This study uses a phenomenological approach to estimate the absorption efficiency of metal and dielectric nanoparticles in the RF range through a study of heating kinetics of those particles in radio wave field. We also discuss the specific features of heating kinetics of nanoparticles, such as a short time scale for heating and cooling of nanoparticles in a liquid biological environment, and the effect of the radiation field structure on the heating kinetics by single-pulse and multipulse RF radiation. FROM THE CLINICAL EDITOR: In this study a phenomenological approach was applied to estimate the absorption efficiency of radiofrequency radiation (RF) by metal and dielectric nanoparticles. Such nanoparticles can be designed and used for therapeutic purposes, like for localized heating and to activate nanoparticles by RF. The authors also discuss the differences in heating kinetics using single-pulse and multi-pulse RF radiation. PMID- 25461284 TI - Mesoporous silica nanoparticles in drug delivery and biomedical applications. AB - In the past decade, mesoporous silica nanoparticles (MSNs) with a large surface area and pore volume have attracted considerable attention for their application in drug delivery and biomedicine. In this review, we highlight the recent advances in silica-assisted drug delivery systems, including (1) MSN-based immediate/sustained drug delivery systems and (2) MSN-based controlled/targeted drug delivery systems. In addition, we summarize the biomedical applications of MSNs, including (1) MSN-based biotherapeutic agent delivery; (2) MSN-assisted bioimaging applications; and (3) MSNs as bioactive materials for tissue regeneration. FROM THE CLINICAL EDITOR: This comprehensive review presents recent advances in mesoporous silica nanoparticles assisted drug delivery systems, including both immediate and sustained delivery systems as well as controlled release and targeted drug delivery systems. In addition to achieving therapeutic agent delivery, imaging applications and potential use of silica NPs in tissue regeneration are also discussed. PMID- 25461285 TI - Repeated intraperitoneal injections of liposomes containing phosphatidic acid and cardiolipin reduce amyloid-beta levels in APP/PS1 transgenic mice. AB - The accumulation of extracellular amyloid-beta (Abeta) peptide and intracellular neurofibrillary tangles in the brain are two major neuropathological hallmarks of Alzheimer's disease (AD). It is thought that an equilibrium exists between Abeta in the brain and in the peripheral blood and thus, it was hypothesized that shifting this equilibrium towards the blood by enhancing peripheral clearance might reduce Abeta levels in the brain: the 'sink effect'. We tested this hypothesis by intraperitoneally injecting APP/PS1 transgenic mice with small unilamellar vesicles containing either phosphatidic acid or cardiolipin over 3weeks. This treatment reduced significantly the amount of Abeta in the plasma and the brain levels of Abeta were lighter affected. Nevertheless, this dosing regimen did modulate tau phosphorylation and glycogen synthase kinase 3 activities in the brain, suggesting that the targeting of circulating Abeta may be therapeutically relevant in AD. FROM THE CLINICAL EDITOR: Intraperitoneal injection of small unilamellar vesicles containing phosphatidic acid or cardiolipin significantly reduced the amount of amyloid-beta (Abeta) peptide in the plasma in a rodent model. Brain levels of Abeta were also affected - although to a lesser extent - suggesting that targeting of circulating Abeta may be therapeutically relevant of Alzheimer's disease. PMID- 25461286 TI - A potent and selective antimicrobial poly(amidoamine) dendrimer conjugate with LED209 targeting QseC receptor to inhibit the virulence genes of gram negative bacteria. AB - The pandemic of multidrug-resistant Gram negative bacteria (GNB) is a worldwide healthcare concern, and very few antibiotics are being explored to match the clinical challenge. Recently, amino-terminated poly(amidoamine) (PAMAM) dendrimers have shown potential to function as broad antimicrobial agents. However, PAMAM displays a generation dependent cytotoxicity to mammalian cells and low selectivity on bacterial cells, which limits PAMAM to be developed as an antibacterial agent for systemic administration. We conjugated G3 PAMAM with LED209, a specific inhibitor of quorum sensor QseC of GNB, to generate a multifunctional agent PAMAM-LED209. Intriguingly, PAMAM-LED209 showed higher selectivity on GNB and lower cytotoxicity to mammalian cells, yet remained strong antibacterial activity. PAMAM-LED209 also inhibited virulence gene expression of GNB, and did not induce antibiotic-resistance. The present work firstly demonstrated that PAMAM-LED209 conjugate had a highly selective anti-GNB activity and low cytotoxicity, which offered a feasible strategy for combating multidrug resistant GNB infections. FROM THE CLINICAL EDITOR: This research team demonstrated that a novel PAMAM-LED209 conjugate had highly selective activity against Gram-negative bacteria, coupled with low cytotoxicity, offering a potential strategy for combating multidrug-resistant infections. PMID- 25461287 TI - S-nitrosocaptopril nanoparticles as nitric oxide-liberating and transnitrosylating anti-infective technology. AB - Nitric oxide (NO), an essential agent of the innate immune system, exhibits multi mechanistic antimicrobial activity. Previously, NO-releasing nanoparticles (NO np) demonstrated increased antimicrobial activity when combined with glutathione (GSH) due to formation of S-nitrosoglutathione (GSNO), a transnitrosylating agent. To capitalize on this finding, we incorporated the thiol-containing ACE inhibitor, captopril, with NO-np to form SNO-CAP-np, nanoparticles that both release NO and form S-nitrosocaptopril. In the presence of GSH, SNO-CAP-np demonstrated increased transnitrosylation activity compared to NO-np, as exhibited by increased GSNO formation. Escherichia coli and methicillin-resistant Staphylococcus aureus were highly susceptible to SNO-CAP-np in a dose-dependent fashion, with E. coli being most susceptible, and SNO-CAP-np were nontoxic in zebrafish embryos at translatable concentrations. Given SNO-CAP-np's increased transnitrosylation activity and increased E. coli susceptibility compared to NO np, transnitrosylation rather than free NO is likely responsible for overcoming E. coli's resistance mechanisms and ultimately killing the pathogen. FROM THE CLINICAL EDITOR: This team of authors incorporated the thiol-containing ACE inhibitor, captopril, into a nitric oxide releasing nanoparticle system, generating nanoparticles that both release NO and form S-nitrosocaptopril, with pronounced toxic effects on MRSA and E. coli in the presented model system. PMID- 25461288 TI - Encapsulation of metalloporphyrins improves their capacity to block the viability of the human malaria parasite Plasmodium falciparum. AB - Several synthetic metallated protoporphyrins (M-PPIX) were tested for their ability to block the cell cycle of the lethal human malaria parasite Plasmodium falciparum. After encapsulating the porphyrin derivatives in micro- and nanocapsules of marine atelocollagen, their effects on cultures of red blood cells infected (RBC) with P. falciparum were verified. RBCs infected with synchronized P. falciparum incubated for 48 h showed a toxic effect over a micromolar range. Strikingly, the IC50 of encapsulated metalloporphyrins reached nanomolar concentrations, where Zn-PPIX showed the best antimalarial effect, with an IC50=330 nM. This value is an 80-fold increase in the antimalarial activity compared to the antimalarial effect of non-encapsulated Zn-PPIX. These findings reveal that the incubation of P. falciparum infected-RBCs with 20 MUM Zn-PPIX reduced the size of hemozoin crystal by 34%, whereas a 28% reduction was noticed with chloroquine, confirming the importance of heme detoxification pathway in drug therapy. FROM THE CLINICAL EDITOR: In this study, synthetic metalloporphyrins were tested as therapeutics that target Plasmodium falciparum. The IC50 of encapsulated metalloporphyrins was found to be in the nanomolar concentration range, with encapsulated Zn-PPIX showing an 80-fold increase in its antimalarial activity compared to the non-encapsulated form. PMID- 25461289 TI - Liposome-based mucus-penetrating particles (MPP) for mucosal theranostics: demonstration of diamagnetic chemical exchange saturation transfer (diaCEST) magnetic resonance imaging (MRI). AB - Mucus barriers lining mucosal epithelia reduce the effectiveness of nanocarrier based mucosal drug delivery and imaging ("theranostics"). Here, we describe liposome-based mucus-penetrating particles (MPP) capable of loading hydrophilic agents, e.g., the diaCEST MRI contrast agent barbituric acid (BA). We observed that polyethylene glycol (PEG)-coated liposomes containing >=7 mol% PEG diffused only ~10-fold slower in human cervicovaginal mucus (CVM) compared to their theoretical speeds in water. 7 mol%-PEG liposomes contained sufficient BA loading for diaCEST contrast, and provided improved vaginal distribution compared to 0 and 3mol%-PEG liposomes. However, increasing PEG content to ~12 mol% compromised BA loading and vaginal distribution, suggesting that PEG content must be optimized to maintain drug loading and stability. Non-invasive diaCEST MRI illustrated uniform vaginal coverage and longer retention of BA-loaded 7 mol%-PEG liposomes compared to unencapsulated BA. Liposomal MPP with optimized PEG content hold promise for drug delivery and imaging at mucosal surfaces. FROM THE CLINICAL EDITOR: This team of authors characterized liposome-based mucus-penetrating particles (MPP) capable of loading hydrophilic agents, such as barbituric acid (a diaCEST MRI contrast agent) and concluded that liposomal MPP with optimized PEG coating enables drug delivery and imaging at mucosal surfaces. PMID- 25461290 TI - Reaction of human macrophages on protein corona covered TiO2 nanoparticles. AB - The cytokine secretion of primary cells of human macrophages during the interaction of TiO2 nanoparticles (with an average primary size of 100-120 nm) is investigated down to concentration levels suggested to be relevant for in vivo conditions. We find that high TiO2 concentrations induce the cytokines Interleukin IL-1beta, IL-6, and IL-10 secretion, while at low concentrations only IL-6 secretion is observed. To obtain further evidence on in vivo conditions we investigated the development and structure of the protein corona of the nanoparticles. We demonstrated that the surface of TiO2 particles attract preferably secondary modified proteins which then induce cytokine secretion of macrophages. Our results indicate that concentration of corona covered TiO2 particles below 1 MUg/ml induce IL-6 secretion which is reported to be responsible for the development of autoimmune diseases as well as for the secretion of acute phase proteins. FROM THE CLINICAL EDITOR: This study investigates the effects of protein corona covered titanium dioxide nanoparticles on human macrophages, concluding that concentration of such particles below 1 MUg/ml induces IL-6 secretion, which may be responsible for the development of autoimmune diseases as well as for the secretion of acute phase proteins. This finding has important implications on future applications of such nanoparticles. PMID- 25461291 TI - In vivo toxicity assessment of non-cadmium quantum dots in BALB/c mice. AB - Along with widespread usage of QDs in electronic and biomedical industries, the likelihood of QDs exposure to the environment and humans is deemed to occur when the QD products are degraded or handled as waste for processing. To date, there are very few toxicological reports available in the literature for non-cadmium QDs in animal models. In this work, we studied the long term in vivo toxicity of InP/ZnS QDs in BALB/c mice. The biodistribution, body weight, hematology, blood biochemistry, and organ histology were determined at a very high dosage (25 mg/kg) of InP/ZnS QDs over 84 days period. Our results manifested that the QDs formulation did not result in observable toxicity in vivo within the evaluation period, thereby suggesting that the InP/ZnS QDs can be utilized as optical probes or nanocarrier for selected in vivo biological applications when an optimized dosage is employed. FROM THE CLINICAL EDITOR: This study investigated the toxicity of quantum dots in BALB/c mice, and concluded that no organotoxicity was detectable despite of using high concentration of InP/ZnS quantum dots with prolonged exposure of 3 months. PMID- 25461292 TI - Bio-inspired hard-to-soft interface for implant integration to bone. AB - Accomplishing full, functional integration at the host-to-biomaterial interface has been a critical roadblock in engineering implants with performance similar to biological materials. Molecular recognition-based self-assembly, coupled with biochemical signaling, may lead to controllable and predictable cellular differentiation at the implant interface. Here, we engineer a bio-inspired interface built upon a chimeric peptide. Binding to the biomaterial interface is achieved using a molecular recognition domain specific for the titanium/titanium alloy implant surface and a biochemical signal guiding stem cells to differentiate by activating the Wnt signaling pathway for bone formation. During a critical period of host cell growth and determination, the bioactive implant interface signals mouse, as well as human, stem cells to differentiate along osteogenic lineages. The Wnt-induced cells show enhanced mineral deposition in an extracellular matrix of their creation and an enhanced gene expression profile consistent with osteogenesis, thereby providing a bone-to-implant interface that promotes bone regeneration. FROM THE CLINICAL EDITOR: This team of authors studied methods for enhanced hard-to-soft interface for implant integration to bone, and demonstrate how a bio-inspired surface built upon a chimeric peptide may be utilized for this purpose. PMID- 25461293 TI - Albumin nanocapsules containing fenretinide: pre-clinical evaluation of cytotoxic activity in experimental models of human non-small cell lung cancer. AB - The present study deals with the preparation of albumin nanocapsules containing fenretinide and their evaluation in experimental models of human non-small cell lung cancer. These nanocapsules showed enhanced antitumor activity with respect to free fenretinide due to the solubilization effect of albumin on the hydrophobic drug, known to improve bioavailability. The high expression of caveolin-1 on the A549 cell surface further enhanced the antitumor activity of the nanoencapsulated fenretinide. Caveolin-1 favored albumin uptake and improved the efficacy of the fenretinide-loaded albumin nanocapsules, especially in 3-D cultures where the densely packed 3-D structures impaired drug diffusibility and severely reduced the activity of the free drug. The efficacy of the fenretinide albumin nanocapsules was further confirmed in tumor xenograft models of A549 by the significant delay in tumor progression observed with respect to control after intravenous administration of the novel formulation. FROM THE CLINICAL EDITOR: This study describes the preparation of fenretinide containing albumin nanocapsules and their evaluation in experimental models of non-small cell lung cancer, showing enhanced antitumor activity compared to free fenretinide. PMID- 25461294 TI - Cytodynamics and endpoint selection for a reliable in vitro assessment of nanoneurotoxicity. PMID- 25461295 TI - Retinal thickness measured by spectral-domain optical coherence tomography in eyes without retinal abnormalities: the Beaver Dam Eye Study. AB - PURPOSE: To examine relationships of age, sex, and systemic and ocular conditions with retinal thickness measured by spectral-domain ocular coherence tomography (SD OCT) in participants without retinal disease. DESIGN: Longitudinal study. METHODS: setting: Population-based cohort. study population: Persons aged 43-86 years living in Beaver Dam, Wisconsin in 1988-1990. observation procedures: Retinal thickness was measured via SD OCT at the Beaver Dam Eye Study examination in 2008-2010. Retinal disease was determined by ophthalmoscopy, fundus photography, or SD OCT. main outcome measures: Retinal thickness from the inner limiting membrane to the Bruch membrane. RESULTS: The retina was thickest in the inner circle (mean 334.5 MUm) and thinnest in the center subfield (285.4 MUm). Mean retinal thickness decreased with age in the inner circle (P < .0001) and outer circle (P < .0001). Adjusting for age, eyes in men had thicker retinas than eyes in women in the center subfield (P < .001) and inner circle (P < .001). Sex, axial length/corneal curvature ratio, and peak expiratory flow rate were associated with center subfield thickness. Sex and peak expiratory flow rate were associated with retinal thickness in the inner circle. Alcohol consumption, age, axial length/corneal curvature ratio, cataract surgery, ocular perfusion pressure, and peak expiratory flow rate were associated with retinal thickness in the outer circle. CONCLUSIONS: This study provides data for retinal thickness measures in eyes of individuals aged 63 years and older without retinal disease. This information may be useful for clinical trials involving the effects of interventions on retinal thickness and for comparisons with specific retinal diseases affecting the macula. PMID- 25461297 TI - Glaucoma in modified osteo-odonto-keratoprosthesis eyes: role of additional stage 1A and Ahmed glaucoma drainage device-technique and timing. AB - PURPOSE: To report the technique, timing, and outcomes of the Ahmed glaucoma drainage device in eyes with the modified osteo-odonto-keratoprosthesis (MOOKP) and the role of an additional stage 1A to the Rome-Vienna protocol. DESIGN: Retrospective interventional case series. METHODS: Case records of 22 eyes of 20 patients with high intraocular pressure at various stages of the MOOKP procedure performed in 85 eyes of 82 patients were studied. Stage 1A, which includes total iridodialysis, intracapsular cataract extraction, and anterior vitrectomy, was done in all eyes as the primary stage. RESULTS: Seventeen Ahmed glaucoma drainage devices were implanted in 15 eyes of 14 patients (chemical injury in 9 [10 eyes] and Stevens-Johnson syndrome in 5 patients). Implantation was performed during and after stage 1A in 2 and 7 eyes, respectively, after stage 1B+1C in 1 eye, and after stage 2 in 6 eyes. Eleven of 15 eyes (73.3%) remained stable with adequate control of intraocular pressure over a mean follow-up period of 33.68 months (1 90 months). Complications related to the drainage device were hypotony in 1 eye and vitreous block of the tube in 1 eye. CONCLUSION: It is ideal to place the Ahmed glaucoma drainage device prior to the mucosal graft when the anatomy of the ocular surface is least altered with best outcomes. The technique of placement of the drainage device during the various stages of the MOOKP procedure has been described. The intraocular pressure stabilized in three quarters of the eyes with pre-existing glaucoma. PMID- 25461296 TI - Central corneal thickness correlates with oxygen levels in the human anterior chamber angle. AB - PURPOSE: To measure oxygen (pO2) in eyes of patients undergoing intraocular surgery and identify correlations with central corneal thickness (CCT). DESIGN: Prospective, cross-sectional study. METHODS: setting: Institutional. patient population: 124 patients undergoing cataract and/or glaucoma surgery. observation procedure: Prior to surgery, an oxygen sensor was introduced into the anterior chamber (AC) via peripheral corneal paracentesis. The tip of the flexible fiberoptic probe was positioned for 3 measurements in all patients: (1) near central corneal endothelium; (2) in mid-AC; and (3) in AC angle. In patients undergoing cataract extraction, additional measurements were taken (4) at the anterior lens surface and (5) in the posterior chamber. main outcome measures: pO2 measurements at 5 locations within the eye were compared to central corneal thickness measurements by multivariate regression analyses. RESULTS: There was a statistically significant inverse correlation between CCT and pO2 in the anterior chamber angle (P = .048). pO2 was not significantly related to CCT at any other location, including beneath the central cornea. Regression analysis relating CCT to age, race, and oxygen levels in all 5 locations in the anterior segment revealed an association of a thinner cornea with increasing age (P = .007). CONCLUSIONS: Physiologic correlations with central corneal thickness may provide clues to understanding why a thinner cornea increases the risk of open glaucoma. Associations between glaucoma risk, CCT, and pO2 in the AC angle suggest that exposure of the outflow system to increased oxygen or oxygen metabolites may increase oxidative damage to the trabecular meshwork cells, resulting in elevation of intraocular pressure. PMID- 25461298 TI - The association between dry eye disease and depression and anxiety in a large population-based study. AB - PURPOSE: To investigate the association between dry eye disease and each of depression and anxiety. DESIGN: Retrospective, case-control study. METHODS: setting: University of North Carolina outpatient clinics. study population: All patients over the age of 18 years seen between July 2008 and June 2013 were included in the analysis. observation procedure: Cases were defined according to ICD-9 diagnosis codes for dry eye disease, anxiety, and depression. outcome measure: Separate odds ratios were calculated for dry eye disease and each of anxiety and depression. Similar odds ratios were also calculated between dry eye disease and rheumatoid arthritis, a systemic disease with a known association with dry eye, as a way of validating our approach. RESULTS: A total of 460 611 patients were screened; 7207 patients with dry eye were included, while 20 004 patients with anxiety and 30 100 patients with depression were included. The adjusted odds ratio for dry eye disease and anxiety was 2.8 (95% confidence interval [CI] 2.6-3.0). For dry eye disease and depression, the odds ratio was 2.9 (95% CI 2.7-3.1). CONCLUSIONS: We identified a statistically significant association between dry eye disease and each of depression and anxiety. Such an association has implications for ophthalmologists in the management and treatment of dry eye disease. PMID- 25461299 TI - Nonglaucomatous localized retinal nerve fiber layer defects in Behcet uveitis. AB - PURPOSE: To describe nonglaucomatous retinal nerve fiber layer (RNFL) defects in patients with Behcet uveitis. DESIGN: Cross-sectional study and observational case series. METHODS: We reviewed the clinical photographs of patients with Behcet uveitis (n = 259), ocular toxoplasmosis (n = 120), and multiple sclerosis (MS)-associated uveitis (n = 40) for the presence of localized RNFL defects. Behcet patients with localized RNFL defects were invited to participate in a prospective evaluation including standard automated perimetry, spectral-domain optical coherence tomography (SD OCT), and RNFL thickness analysis. Main outcome measures were the prevalence of localized RNFL defects, perimetric and SD OCT findings, and RNFL thickness analysis. RESULTS: Sixty-two patients with Behcet uveitis (24%) had localized RNFL defect(s) without any visible scar. Twenty patients (17%) with ocular toxoplasmosis had a localized RNFL defect associated with a retinochoroidal scar in all. None of the MS patients had a localized RNFL defect. Of the 19 patients (24 eyes) with RNFL defect associated with Behcet uveitis who returned for follow-up, there was a corollary thinning on SD OCT B scan in all and a corresponding visual field defect in 83%. RNFL thickness analysis was within normal limits in 54%, but revealed thinning in the thickness profile scale in 46% and in the pie chart in 21%. CONCLUSION: In Behcet uveitis, localized RNFL defects may be caused by microvascular ischemia at the optic nerve head and/or at the posterior pole and may serve as a helpful ocular diagnostic clue and an indicator of posterior pole involvement, a risk factor for poor visual prognosis. PMID- 25461300 TI - Complications and outcomes of phacoemulsification cataract surgery complicated by anterior capsule tear. AB - PURPOSE: To study the results of phacoemulsification cataract surgery complicated by anterior capsule tear. DESIGN: Retrospective interventional controlled case series. METHODS: Consecutive series of eyes suffering intraoperative anterior capsule tear and others with uneventful cataract surgery at Moorfields Eye Hospital were investigated. Biometric, intraoperative, and postoperative details were recorded. The exclusion criteria were combined surgical procedures, planned manual extracapsular cataract extraction, and history of previous intraocular surgery or eye trauma. The main outcome measures were intraoperative capsule complication rates, refractive and visual outcomes, and incidence of short-term postoperative complications. Two-sided Fisher exact and paired t tests were used for categorical and continuous data, respectively. RESULTS: The study and control groups included 239 and 212 eyes, respectively. In the study group, planned phacoemulsification was converted to manual extraction in 5 cases (2%); a concurrent posterior capsule rupture occurred in 58 eyes (24%) with a rate of nuclear lens material drop in the posterior segment of 5% (11 cases). Over 11% of eyes (n = 27) underwent unplanned secondary surgical procedures. Overall, the refractive outcomes were poor in 22.4% of eyes (postoperative refraction >=1 diopter of target), and were statistically worse (P < .0001). A significant visual improvement was observed in the majority of the study group eyes (71%); permanent visual loss occurred in 4 eyes (1.7%). CONCLUSIONS: Anterior capsule tear can lead to additional intraoperative complications, with a relatively high incidence of secondary interventions. Overall, permanent visual loss can be observed and worse refractive outcomes are to be expected, particularly if the lens is being implanted out of the bag. PMID- 25461301 TI - Role of hydrogen sulfide in skeletal muscle biology and metabolism. AB - Hydrogen sulfide (H2S) is a novel endogenous gaseous signal transducer (gasotransmitter). Its emerging role in multiple facets of inter- and intra cellular signaling as a metabolic, inflammatory, neuro and vascular modulator has been increasingly realized. Although H2S is known for its effects as an anti hypertensive, anti-inflammatory and anti-oxidant molecule, the relevance of these effects in skeletal muscle biology during health and during metabolic syndromes is unclear. H2S has been implicated in vascular relaxation and vessel tone enhancement, which might lead to mitigation of vascular complications caused by the metabolic syndromes. Metabolic complications may also lead to mitochondrial remodeling by interfering with fusion and fission, therefore, leading to mitochondrial mitophagy and skeletal muscle myopathy. Mitochondrial protection by H2S enhancing treatments may mitigate deterioration of muscle function during metabolic syndromes. In addition, H2S might upregulate uncoupling proteins and might also cause browning of white fat, resulting in suppression of imbalanced cytokine signaling caused by abnormal fat accumulation. Likewise, as a source for H(+) ions, it has the potential to augment anaerobic ATP synthesis. However, there is a need for studies to test these putative H2S benefits in different patho-physiological scenarios before its full-fledged usage as a therapeutic molecule. The present review highlights current knowledge with regard to exogenous and endogenous H2S roles in skeletal muscle biology, metabolism, exercise physiology and related metabolic disorders, such as diabetes and obesity, and also provides future directions. PMID- 25461303 TI - Hydrogen sulfide is involved in dexamethasone-induced hypertension in rat. AB - Glucocorticoid (GC)-induced hypertension is a common clinical problem still poorly understood. The presence of GC receptor (GR) in vascular smooth muscle and endothelial cells suggests a direct role for GC in vasculature. In response to hemodynamic shear stress, endothelium tonically releases nitric oxide (NO), endothelial-derived hyperpolarizing factor (EDHF) and prostacyclin contributing to vascular homeostasis. Recently, hydrogen sulfide (H2S) has been proposed as a candidate for EDHF. H2S is endogenously mainly formed from L-cysteine by the action of cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE). It plays many physiological roles and contributes to cardiovascular function. Here we have evaluated the role played by H2S in mesenteric arterial bed and in carotid artery harvested from rats treated with vehicle or dexamethasone (DEX; 1.5 mg/kg/day) for 8 days. During treatments systolic blood pressure was significantly increased in conscious rats. EDHF contribution was evaluated in ex vivo by performing a concentration-response curve induced by acetylcholine (Ach) in presence of a combination of indomethacin and L-NG-Nitroarginine methyl ester in both vascular districts. EDHF-mediated relaxation was significantly reduced in DEX-treated group in both mesenteric bed and carotid artery. EDHF-mediated relaxation was abolished by pre-treatment with both apamin and charybdotoxin, inhibitors of small and big calcium-dependent potassium channels respectively, or with propargylglycine, inhibitor of CSE. Western blot analysis revealed a marked reduction in CBS and CSE expression as well as H2S production in homogenates of mesenteric arterial bed and carotid artery from DEX-treated rats. In parallel, H2S plasma levels were significantly reduced in DEX group compared with vehicle. In conclusion, an impairment in EDHF/H2S signaling occurs in earlier state of GC induced hypertension in rats suggesting that counteracting this dysfunction may be beneficial to manage DEX-associated increase in blood pressure. PMID- 25461302 TI - Inhaled hydrogen sulfide prevents neuropathic pain after peripheral nerve injury in mice. AB - Increasing evidence suggests that the pathogenesis of neuropathic pain is mediated through activation of microglia in the spinal cord. Hydrogen sulfide attenuates microglial activation and central nervous system inflammation; however, the role of hydrogen sulfide in neuropathic pain is unclear. In this study, we examined the effects of hydrogen sulfide breathing on neuropathic pain in mice. C57BL/6J mice were subjected to chronic constriction injury (CCI) of the sciatic nerve. After CCI, mice breathed air alone or air mixed with hydrogen sulfide at 40 ppm for 8 h on 7 consecutive days. The expression levels of inflammatory cytokines including interleukin 6 (IL-6) were measured in the spinal cord. Effects of hydrogen sulfide on IL-6-induced activation of microglia were examined in primary rat microglia. Mice that breathed air alone exhibited the neuropathic pain behavior including mechanical allodynia and thermal hyperalgesia and increased mRNA levels of IL-6 and chemokine CC motif ligand 2 (CCL2) after CCI. Inhaled hydrogen sulfide prevented the neuropathic pain behavior and attenuated the upregulation of inflammatory cytokines. Sodium sulfide inhibited IL-6-induced activation of primary microglia. These results suggest that inhaled hydrogen sulfide prevents the development of neuropathic pain in mice possibly via inhibition of the activation of microglia in the spinal cord. PMID- 25461304 TI - Reduction of motion, truncation and flow artifacts using BLADE sequences in cervical spine MR imaging. AB - PURPOSE: To assess the efficacy of the BLADE technique (MR imaging with 'rotating blade-like k-space covering') to significantly reduce motion, truncation, flow and other artifacts in cervical spine compared to the conventional technique. MATERIALS AND METHODS: In eighty consecutive subjects, who had been routinely scanned for cervical spine examination, the following pairs of sequences were compared: a) T2 TSE SAG vs. T2 TSE SAG BLADE and b) T2 TIRM SAG vs. T2 TIRM SAG BLADE. A quantitative analysis was performed using the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) measures. A qualitative analysis was also performed by two radiologists, who graded seven image characteristics on a 5 point scale (0: non-visualization; 1: poor; 2: average; 3: good; 4: excellent). The observers also evaluated the presence of image artifacts (motion, truncation, flow, indentation). RESULTS: In quantitative analysis, the CNR values of the CSF/SC between TIRM SAG and TIRM SAG BLADE were found to present statistically significant differences (p < 0.001). Regarding motion and truncation artifacts, the T2 TSE BLADE SAG was superior compared to the T2 TSE SAG, and the T2 TIRM BLADE SAG was superior compared to the T2 TIRM SAG. Regarding flow artifacts, T2 TIRM BLADE SAG eliminated more artifacts than T2 TIRM SAG. CONCLUSIONS: In cervical spine MRI, BLADE sequences appear to significantly reduce motion, truncation and flow artifacts and improve image quality. BLADE sequences are proposed to be used for uncooperative subjects. Nevertheless, more research needs to be done by testing additional specific pathologies. PMID- 25461305 TI - Dynamic MR imaging of temporomandibular joint: an initial assessment with fast imaging employing steady-state acquisition sequence. AB - PURPOSE: The study was aimed to determine and optimize the parameters for the MR fast imaging employing steady-state acquisition (FIESTA) sequence, which was to obtain an acceptable image to evaluate the value of the movement of the temporomandibular joint (TMJ). METHODS: In this investigation, 20 volunteers were examined to determine and optimize the parameters of the FIESTA sequence. Then, 160 TMJs from 80 patients with temporomandibular joint disorders (TMD) of clinical suspicion were consecutively performed by both static MRI and dynamic FIESTA MRI on the oblique sagittal position. The FIESTA MR images of TMJs were obtained from a slow, consecutive, free and open-closed movement. Based on the cycles of TMJ movements during the process of FIESTA MRI (90seconds), we classified all TMJs into 2 groups: cycles of open-closed mouths less than or equal to 3 (group 1) and more than 3 (group 2). Each image was marked level 1-3 by its quality. Meanwhile, the location of articular disc, mandibular condyle, motive artifact, "jumping sign" and the joint effusion in each TMJ were assessed respectively. RESULTS: By dynamic FIESTA MRI among 160 TMJs, 92 TMJs (57.50%) were in group 1, and 68 TMJs were (42.50%) in group 2. There were statistically significant differences between group 1 and group 2(p<0.05). It was shown that the number of "level 3" in group 1 was greater than group 2, and the number of "level 1" in group 1 was less than group 2. The phenomenon of motion artifact and "jumping sign" were much significantly higher in group 2 than those in group 1 (p<0.01). Furthermore, in all of the "jumping sign" cases, the phenomenon of "jumping sign" was significantly higher in group ADDwR than in group ADDw/oR (p<0.01). There was a statistically significant correlation between disc-condyle complex in "jumping sign" phenomenon and group ADDwR (r=0.621, p<0.05). The data with the false matching rate of 31.52% showed that the maximum motion range on the dynamic imaging was greater than the static imaging. Among 160 TMJs, joint effusions of 37 TMJs (23.13%) were identified by dynamic FIESTA-MRI. Among 79 TMJs with ADDw/oR(anterior disc displacement without reduction), 42 sides were operated with Maxillofacial arthroscopy surgery. The surgical result was in agreement with the MR result. CONCLUSION: Most TMJs images with a slow free open close movement (cycles?3) could be successfully obtained by the dynamic FIESTA MRI. The FIESTA MRI might be considered as an additional method to evaluate the movement of the articular disk and the mandibular condyle. PMID- 25461306 TI - Haloperidol metabolite II prodrug: asymmetric synthesis and biological evaluation on rat C6 glioma cells. AB - In a previous work we reported the antiproliferative effects of (+/-)-MRJF4, a novel haloperidol metabolite II (HP-mII) (a sigma-1 antagonist and sigma-2 agonist) prodrug, obtained through conjugation to 4-phenylbutyric acid (PhBA) [a histone deacetylase inhibitor (HDACi)] via an ester bond. As a continuation of this work, here we report the asymmetric synthesis of compounds (R)-(+)-MRJF4 and (S)-(-)-MRJF4 and the evaluation of their biological activity on rat C6 glioma cells, derived from glioblastoma multiforme (GBM), which is the most common and deadliest central nervous system (CNS) invasive malignancy. Favourable physicochemical properties, high permeability in the parallel artificial membrane permeability assay (PAMPA), good enzymatic and chemical stability, in vivo anticancer activity, associated with the capacity to reduce cell viability and to increase cell death by apoptosis, render compound (R)-(+)-MRJF4 a promising candidate for the development of a useful therapeutic for gliomas therapy. PMID- 25461308 TI - Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity. Part 4. AB - This project describes the synthesis, pharmacological and pharmacodynamic tests on two series of novel derivatives of 2H-pyrido[1,2-c]pyrimidine with potential binary binding to 5-HT1A receptors and SSRI + serotonin transporters. The influence of piperidinyl-indole (8.1-8.7) and tetrahydropyridinyl-indole (8.8 8.32) residues and indole 5-position substituents (R3 = Br, Cl, F) present in the pharmacophore element of ligands on their binding to both molecular targets was tested. A considerable impact of piperidinyl-indole residue on binding to both targets was confirmed and compounds with a high binding affinity were identified: Ki 5-HT1A = 12.4 nM; Ki SERT = 15.6 nM 8.1; Ki 5-HT1A = 5.6 nM; Ki SERT = 20.7 nM 8.7, while the presence of a tetrahydropyridinyl-indole residue was found to reduce the affinity of ligands to 5-HT1AR. The presence of chlorine (R3) in this series resulted in a notable reduction in binding to both targets (5-HT1A and SERT). Selected compounds had their metabolic stability in a first-pass test (human liver microsomes, NADPH) determined in vitro, and R1 and R2 substituents present on the terminal residue of pyrido[1,2-c]pyrimidine were recognized as having an impact on stability. PMID- 25461307 TI - The synthesis and antibacterial activity of pyrazole-fused tricyclic diterpene derivatives. AB - The diterpenoid compound 5 was identified as an antibacterial lead in our screening of small synthetic natural product-like (NPL) library. A series of novel diterpene derivatives were synthesized and investigated for their activity against Staphylococcus aureus Newman strain and multidrug-resistant strains (NRS 1, NRS-70, NRS-100, NRS-108 and NRS-271). Among the compounds tested, 42 and 43 showed highest activity with a MIC of 1 MUg/mL against strain Newman, 45 and 52 showed the most potent activity with MIC values of 0.71-3.12 MUg/mL against five multidrug-resistant S. aureus. All high-antimicrobial active compounds showed no obvious toxicity to human fibroblast (HAF) cells at the MIC concentration. PMID- 25461310 TI - Synthesis and in vitro antiproliferative activity of new 1,3,4-oxadiazole derivatives possessing sulfonamide moiety. AB - Synthesis of a new series of 1,3,4-oxadiazole derivatives possessing sulfonamide moiety is described. Their in vitro antiproliferative activities against NCI-58 human cancer cell lines of nine different cancer types were tested. Compound 1k with p-methoxybenzenesulfonamido moiety showed the highest mean %inhibition value over the 58 cell line panel at 10 MUM concentration. It showed broad-spectrum antiproliferative activity over many cell lines of different cancer types. For instance, compound 1k inhibited the growth of T-47D breast cancer cell line by 90.47% at 10 MUM. And it inhibited growth of SR leukemia, SK-MEL-5 melanoma, and MDA-MB-468 breast cancer cell lines by more than 80% at the same test concentration. Compound 1k showed superior activity than Paclitaxel and Gefitinib against the most sensitive cell lines. PMID- 25461309 TI - Synthesis and in vitro biological evaluation of dihydroartemisinyl-chalcone esters. AB - A series of dihydroartemisinyl-chalcone esters were synthesized through esterification of chalcones with dihydroartemisinin (DHA). The hybrids were screened against chloroquine (CQ) sensitive (3D7) and CQ resistant (W2) strains of intraerythrocytic Plasmodium falciparum parasites, and were all found to be active, with IC50 values ranging between 1.5 and 11 nM against both strains, with SI values over 5800. The esters featuring oxygenated aryl rings (7, 10 and 11), were found to be equipotent to DHA, but were 2-3 times more active than artesunate against the 3D7 and W2 strains of the malaria parasites. They were also screened in vitro against a panel of three cancer cell lines consisting of TK-10, UACC-62 and MCF-7. Compound 7, bearing a furan ring, displayed the most potent overall antitumor activity against all three cancer cell lines. TGA revealed that the targeted hybrids were all thermally more stable than DHA, which may be beneficial to the high temperature storage conditions that prevail in malaria endemic countries. During this study, ester 7 was identified as the best candidate for further investigation as a potential drug in search for new, safe and effective antimalarial drugs. PMID- 25461311 TI - Structural design and synthesis of arylalkynyl amide-type peroxisome proliferator activated receptor gamma (PPARgamma)-selective antagonists based on the helix12 folding inhibition hypothesis. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) antagonists are candidates for treatment of type 2 diabetes, obesity and osteoporosis. However, few rational design strategies are currently available. Here, we utilized the helix12 (H12)-folding inhibition hypothesis, in combination with our previously determined X-ray crystal structure of PPARgamma agonist MEKT-21 (6) complexed with the PPARgamma ligand-binding domain, to design and develop a potent phenylalkynyl amide-type PPARgamma antagonist 9i, focusing initially on pinpoint structural modification of the propanoic acid moiety of 6. Since 9i retained very weak, but distinct, PPARgamma agonist activity, we next modified the distal benzene ring of 9i, aiming to delete the residual PPARgamma agonist activity while retaining the antagonist activity. Introduction of a chlorine atom at the 2 position of the distal benzene ring afforded 9p, which exhibited potent, PPARgamma-selective full antagonist activity without detectable agonist activity. We found that 9p stabilized the corepressor-PPARgamma complex and suppressed basal PPARgamma activity. This compound showed anti-adipogenesis activity at the cellular level. This agonist-antagonist switching concept based on the H12 folding inhibition hypothesis should also be applicable for designing other classes of PPARgamma full antagonists. PMID- 25461312 TI - Synthesis and structure-activity relationship of amidine derivatives of 3,4 ethylenedioxythiophene as novel antibacterial agents. AB - Current antibacterial chemotherapeutics are facing an alarming increase in bacterial resistance pressuring the search for novel agents that would expand the available therapeutic arsenal against resistant bacterial pathogens. In line with these efforts, a series of 9 amidine derivatives of 3,4-ethylenedioxythiophene were synthesized and, together with 18 previously synthesized analogs, evaluated for their relative DNA binding affinity, in vitro antibacterial activities and preliminary in vitro safety profile. Encouraging antibacterial activity of several subclasses of tested amidine derivatives against Gram-positive (including resistant MRSA, MRSE, VRE strains) and Gram-negative bacterial strains was observed. The bis-phenyl derivatives were the most antibacterially active, while compound 19 from bis-benzimidazole class exhibited the widest spectrum of activity (with MIC of 4, 2, 0.5 and <=0.25 MUg/ml against laboratory strains of Staphyloccocus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, respectively and 4-32 MUg/ml against clinical isolates of sensitive and resistant S. aureus, Staphylococcus epidermidis and Enterococcus faecium) and also demonstrated the strongest DNA binding affinity (DeltaTm of 15.4 degrees C). Asymmetrically designed compounds and carboxamide-amidines were, in general, less active. Molecular docking indicated that the shape of the 3,4-ethylenedioxythiophene derivatives and their ability to form multiple electrostatic and hydrogen bonds with DNA, corresponds to the binding modes of other minor-groove binders. Herein reported results encourage further investigation of this class of compounds as novel antibacterial DNA binding agents. PMID- 25461313 TI - Silver(I) complexes of mono- and bidentate N-heterocyclic carbene ligands: synthesis, crystal structures, and in vitro antibacterial and anticancer studies. AB - A series of benzimidazole-based N-heterocyclic carbene (NHC) proligands {1-benzyl 3-(2-methylbenzyl)-benzimidazolium bromide/hexafluorophosphate (1/4), 1,3-bis(2 methylbenzyl)-benzimidazolium bromide/hexafluorophosphate (2/5) and 1,3-bis(3-(2 methylbenzyl)-benzimidazolium-1-ylmethylbenzene dibromide/dihexafluorophosphate (3/6)} has been synthesized by the successive N-alkylation method. Ag complexes {1-benzyl-3-(2-methylbenzyl)-benzimidazol-2-ylidenesilver(I) hexafluorophosphate (7), 1,3-bis(2-methylbenzyl)-benzimidazol-2-ylidenesilver(I) hexafluorophosphate (8) and 1,3-bis(3-(2-methylbenzyl)-benzimidazol-2-ylidene)-1-ylmethylbenzene disilver(I) dihexafluorophosphate (9)} of NHC ligands have been synthesized by the treatment of benzimidazolium salts with Ag2O at mild reaction conditions. Both, NHC proligands and Ag-NHC complexes have been characterized by (1)H and (13)C{(1)H} NMR and FTIR spectroscopy and elemental analysis technique. Additionally, the structure of the NHC proligand 5 and the mononuclear Ag complexes 7 and 8 has been elucidated by the single crystal X-ray diffraction analysis. Both the complexes exhibit the same general structural motif with linear coordination geometry around the Ag centre having two NHC ligands. Preliminary in vitro antibacterial potentials of reported compounds against a Gram negative (Escherichia coli) and a Gram positive (Bacillus subtilis) bacteria evidenced the higher activity of mononuclear silver(I) complexes. The anticancer studies against the human derived colorectal cancer (HCT 116) and colorectal adenocarcinoma (HT29) cell lines using the MTT assay method, revealed the higher activity of Ag-NHC complexes. The benzimidazolium salts 4-6 and Ag-NHC complexes 7-9 displayed the following IC50 values against the HCT 116 and HT29 cell lines, respectively, 31.8 +/- 1.9, 15.2 +/- 1.5, 4.8 +/- 0.6, 10.5 +/- 1.0, 18.7 +/- 1.6, 1.20 +/- 0.3 and 245.0 +/- 4.6, 8.7 +/- 0.8, 146.1 +/- 3.1, 7.6 +/- 0.7, 5.5 +/- 0.8, 103.0 +/- 2.3 MUM. PMID- 25461314 TI - In vitro and in vivo anti-glioma activity of a chalcone-quinoxaline hybrid. AB - Chalcones are important compounds that exhibit multiple biological activities, including anti-inflammatory, antimitotic and antibacterial properties. In the present study, we have analyzed the potential anti-cancer activity of a chalcone named N9 (a hybrid chalcone-quinoxaline compound) using in vitro and in vivo experimental glioma models. Here, we report N9-induced inhibition of cell proliferation and also N9-induced cell death in a concentration-dependent manner in U87-MG glioma cells. These effects of N9 appear to be associated with its ability to inhibit the expression of cell cycle-associated proteins, and also the augmentation in the expression of the p21 (p21/Cip1) protein, a cyclin-dependent kinase inhibitor. Additionally, N9 also potentiates the production of the pro apoptotic markers Bax and p53 via inhibition of MDM2. Moreover, our results show that N9 also significantly enhanced apoptosis of U87-MG cells with disruption of mitochondrial membrane potential, generation of ROS and caspase-9 activation. In vivo experiments carried out in a murine xenograft model of U87-MG revealed that N9 produced a significant reduction of tumors volume when compared to vehicle treated mice. Collectively, data demonstrate that N9 possess in vitro and in vivo anti-cancer activity, an effect that seems to involve the induction of p53 and p21 proteins, as well as, the activation of mitochondrial apoptosis pathway associated with the inhibition of protein MDM2. Overall, this study suggests N9 is affecting a variety of intracellular pathways related to tumor apoptosis. Perhaps N9 or derivate molecules could represent new potential drugs for cancer therapeutics. PMID- 25461315 TI - Synthesis of hexahydrocyclopenta[ij]isoquinolines as a new class of dopaminergic agents. AB - In this study, we have described the synthesis of the tricyclic 1,2,3,7,8,8a hexahydrocyclopenta [ij]isoquinoline (HCPIQ). Herein, six differently substituted 5,6-dioxygenated-7-phenyl-HCPIQs have been synthesized using a new methodology via (E)-1-styryl-THIQ by Friedel-Crafts cyclization with Eaton's reagent. Results showed that HCPIQs (3, 3a-e) displayed a moderate affinity for D1 dopamine receptors (DR) in the micromolar range, furthermore the catecholic HCPIQs 3a (NH), 3c (NCH3) and 3e (NCH2CHCH2) exhibited outstanding affinity and high selectivity towards D2 DR. Indeed, 3a, 3c and 3e showed Ki values of 29 nM, 13 nM and 18 nM, respectively, and HCPIQs 3a (NH) and 3c (NCH3) displayed a remarkable selectivity (Ki D1/D2 ratio ~ 1000-2500). In addition, none of the catecholic compounds showed any cytotoxicity in freshly isolated human neutrophils. Although further studies are needed, these compounds and particularly catecholic HCPIQs, show high potential in the treatment of Parkinson's disease, psychosis or depression. PMID- 25461316 TI - Synthesis and biological evaluation of novel 2,3-disubstituted quinoxaline derivatives as antileishmanial and antitrypanosomal agents. AB - Quinoxalines belong to the N-containing heterocyclic compounds that stand out as having promising biological activity due to their privileged scaffold. In this work, we report the synthesis, antileishmanial, and antitrypanosomal properties of 46 new 2,3-disubstituted quinoxaline and 40 previously reported derivatives. Among all of the compounds screened for in vitro activity against epimastigotes and trypomastigotes of Trypanosoma cruzi and promastigotes of Leishmania amazonensis as well as mammalian toxicity on LLCMK2 cells and J774 macrophages, analogues from series 5, 6, 7, 9, 12, and 13 displayed high activity at micromolar IC50 and EC50 concentrations. Sixteen quinoxaline derivatives were selected and evaluated on T. cruzi and/or L. amazonensis amastigotes. The most active compounds were 6a-b and 7d-e, on all evolutive forms of L. amazonensis and T. cruzi evaluated with IC50 values 0.1-0.8 MUM on promastigotes and epimastigotes 1.4-8.6 on amastigotes. Compounds 5k, 12b and 13a were the most selective (SI = 19.5-38.4) on amastigotes of T. cruzi. In general their activity was directly related to the methylsulfoxyl, methylsulfonyl, and amine groups as well as the presence of chorine or bromine in the molecules. The current results indicate that these quinoxaline derivatives are novel and promising agents for further development towards a treatment for Chagas' disease and leishmaniasis. PMID- 25461317 TI - Synthetic approaches, functionalization and therapeutic potential of quinazoline and quinazolinone skeletons: the advances continue. AB - The presence of N-heterocycles as an essential structural motif in a variety of biologically active substances has stimulated the development of new strategies and technologies for their synthesis. Among the various N-heterocyclic scaffolds, quinazolines and quinazolinones form a privileged class of compounds with their diverse spectrum of therapeutic potential. The easy generation of complex molecular diversity through broadly applicable, cost-effective, practical and sustainable synthetic methods in a straightforward fashion along with the importance of these motifs in medicinal chemistry, received significant attention from researchers engaged in drug design and heterocyclic methodology development. In this perspective, the current review article is an effort to recapitulate recent developments in the eco-friendly and green procedures for the construction of highly challenging and potentially bioactive quinazoline and quinazolinone compounds in order to help medicinal chemists in designing and synthesizing novel and potent compounds for the treatment of different disorders. The key mechanistic insights for the synthesis of these heterocycles along with potential applications and manipulations of the products have also been conferred. This article also aims to highlight the promising future directions for the easy access to these frameworks in addition to the identification of more potent and specific products for numerous biological targets. PMID- 25461318 TI - Design, synthesis and evaluation of novel 2-(1H-imidazol-2-yl) pyridine Sorafenib derivatives as potential BRAF inhibitors and anti-tumor agents. AB - A series of 2-(1H-imidazol-2-yl) pyridine derivatives (CLW01-CLW31) have been designed and synthesized, and they were screened for BRAF kinase inhibitory activity. Besides, their biological activities were evaluated in vitro and in vivo. All the compounds were reported for the first time, and compounds CLW14 and CLW27 displayed the most potent antiproliferative activity against cell line A375 in vitro, with IC50 values of 4.26 and 2.93 MUM, respectively, which were comparable with the positive control Sorafenib. Those two compounds were further evaluated for the in vivo efficacy using an A375 xenograft nude mice model. The results showed that the growth of A375 cancer cells xenografts was suppressed by factors of 35.68% and 42.50% (percent tumor growth inhibition values) after intragastric (ig) administration of compound CLW14 and CLW27 at concentration of 50 mg/kg. Thus they may be promising lead compounds to be developed as an alternative for current Sorafenib therapy. PMID- 25461319 TI - 3-(3,4,5-Trimethoxyphenylselenyl)-1H-indoles and their selenoxides as combretastatin A-4 analogs: microwave-assisted synthesis and biological evaluation. AB - A series of 3-(3,4,5-trimethoxyphenylselenyl)-1H-indoles and their selenoxides were designed as a new class of combretastatin A-4 (CA-4) analogs. The B ring and the cis double bond of CA-4 were replaced by an indole moiety and selenium atom, respectively. A facile and efficient microwave-assisted synthesis of 3 arylselenylindoles was developed to prepare the target compounds, which were then evaluated for antiproliferative activity against three human cancer cell lines using an MTT assay. Most of these compounds exhibited significant antiproliferative activity, with some showing nanomolar IC50 values. Tubulin polymerization and immunostaining experiments revealed that 13a potently inhibited tubulin polymerization and disrupted tubulin microtubule dynamics in a similar manner to CA-4. Docking studies demonstrated that 13a adopts an orientation similar to that of CA-4 at the colchicine binding site on tubulin. PMID- 25461320 TI - Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors. AB - With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we designed, synthesized and screened a series of new pyrazol-4 ylpyrimidine derivatives based on our previously discovered lead compound KIST301072. Compounds 6a-e and 7a-e showed good to excellent activities against ROS1 kinase, and seven out of tested compounds were more potent than KIST301072. Compound 7c was the most potent with IC50 of 24 nM. Moreover, compound 7c showed ROS1 inhibitory selectivity of about 170-fold, relative to that of ALK sharing about 49% amino acid sequence homology with ROS1 kinase in the kinase domain. In silico modeling of 7c at ROS1 active site revealed some essential features for ROS1 inhibitory activity. Based on this study as well as the previous studies, we could build a hypothetical model predicting the required essential features for ROS1 inhibitory activity. The model validity has been tested through a second set of compounds. PMID- 25461321 TI - Discovery of non-oxime reactivators using an in silico pharmacophore model of reactivators for DFP-inhibited acetylcholinesterase. AB - Utilizing our previously reported in silico pharmacophore model for reactivation efficacy of oximes, we present here a discovery of twelve new non-oxime reactivators of diisopropylfluorophosphate (DFP)-inhibited acetylcholinesterase (AChE) obtained through virtual screening of an in-house compound database. Rate constant (kr) efficacy values of the non-oximes were found to be within ten-fold of pralidoxime (2-PAM) in an in vitro DFP inhibited eel AChE assay and one of them showed in vivo efficacy comparable to 2-PAM against brain symptoms for DFP induced neuropathology in guinea pigs. Short listing of the identified compounds were performed on the basis of in silico evaluations for favorable blood brain barrier penetrability, octanol-water partition (Clog P), toxicity (rat oral LD50) and binding affinity to the active site of the crystal structure of a OP- inhibited AChE. PMID- 25461322 TI - Synthesis and anticancer activity of some 8-substituted-7-methoxy-2H-chromen-2 one derivatives toward hepatocellular carcinoma HepG2 cells. AB - Based on the reported anticancer activity of coumarin and pyrazoline derivatives, the present investigation dealt with the design and synthesis of coumarin derivatives bearing diversely substituted pyrazoline moieties 7-10. The non cyclic isosteres 11a-e of compounds 10a-e were synthesized for comparative reasons. The target compounds were synthesized from 8-acetyl-7-methoxycoumarin that underwent Claisen-Schmidt condensation with various aldehydes to give the chalcones 6a-e, followed by reaction with hydrazine hydrate, phenyl hydrazine or semicarbazide under the appropriate conditions. Cytotoxicity of the synthesized compounds was evaluated in vitro against liver HepG2 cell line. Compounds were active in the nanomolar range. The most active compounds were investigated for their telomerase inhibition and proapoptotic activities. PMID- 25461323 TI - Discovery of novel VEGFR-2 inhibitors. Part II: biphenyl urea incorporated with salicylaldoxime. AB - A series of novel VEGFR-2 inhibitors containing oxime as hinge binding fragment were described. A strategy of pseudo six-membered ring formed through intramolecular hydrogen bond was employed to mimic the planar quinazoline. The oxime group was firstly introduced to interact with hinge region of VEGFR-2. Most of compounds tested showed moderate to high VEGFR-2 inhibitory activity. In particular, 12l, 12p and 12y exhibited significant enzymatic inhibitory activity as well as potent antiproliferative activity against cancer cells. Molecular docking suggested that the salicylaldoxime formed two hydrogen bonds with hinge region. These biphenylureas could serve as promising lead compounds for developing novel anticancer agents. PMID- 25461324 TI - Novel fatty acid binding protein 4 (FABP4) inhibitors: virtual screening, synthesis and crystal structure determination. AB - Fatty acid binding protein 4 (FABP4) is a potential drug target for diabetes and atherosclerosis. For discovering new chemical entities as FABP4 inhibitors, structure-based virtual screening (VS) was performed, bioassay demonstrated that 16 of 251 tested compounds are FABP4 inhibitors, among which compound m1 are more active than endogenous ligand linoleic acid (LA). Based on the structure of m1, new derivatives were designed and prepared, leading to the discovery of two more potent inhibitors, compounds 9 and 10. To further explore the binding mechanisms of these new inhibitors, we determined the X-ray structures of the complexes of FABP4-9 and FABP4-10, which revealed similar binding conformations of the two compounds. Residue Ser53 and Arg126 formed direct hydrogen bonding with the ligands. We also found that 10 could significantly reduce the levels of lipolysis on mouse 3T3-L1 adipocytes. Taken together, in silico, in vitro and crystallographic data provide useful hints for future development of novel inhibitors against FABP4. PMID- 25461325 TI - Synthesis and anticancer activities of 3-arylflavone-8-acetic acid derivatives. AB - This paper describes the synthesis and the antiproliferative activities of compounds 9a-r, 3-aryl analogs of flavone-8-acetic acid that bear diverse substituents on the benzene rings at the 2- and 3-positions of the flavone nucleus. Their direct and indirect cytotoxicities were evaluated against HT-29 human colon adenocarcinoma cell lines, A549 lung adenocarcinoma cell lines and Human Peripheral Blood Mononuclear Cells (HPBMCs). The results indicate that most of the compounds bearing electron-withdrawing substituents (9b-m) exhibited moderate direct cytotoxicities. And compounds 9e and 9i showed comparable indirect cytotoxicities with 5, 6-dimethylxanthenone-4-acetic acid (DMXAA), and low direct cytotoxicities toward HPBMCs. Interestingly, the compounds 9n-r bearing methoxy groups at the 2- or 3-position of the flavone nucleus exhibited higher indirect cytotoxicities against A549 cell lines than DMXAA, and lower cytotoxicities against HPBMCs. In addition, compounds 9p-r were found to be able to induce tumor necrosis factor alpha (TNF-alpha) production in HPBMCs. PMID- 25461326 TI - Conformationally-locked N-glycosides: exploiting long-range non-glycone interactions in the design of pharmacological chaperones for Gaucher disease. AB - Pyranoid-type glycomimetics having a cis-1,2-fused glucopyranose-2-alkylsulfanyl 1,3-oxazoline (Glc-PSO) structure exhibit an unprecedented specificity as inhibitors of mammalian beta-glucosidase. Notably, their inhibitory potency against human beta-glucocerebrosidase (GCase) was found to be strongly dependent on the nature of aglycone-type moieties attached at the sulfur atom. In the particular case of omega-substituted hexadecyl chains, an amazing influence of the terminal group was observed. A comparative study on a series of Glc-PSO derivatives suggests that hydrogen bond acceptor functionalities, e.g. fluoro or methyloxycarbonyl, significantly stabilize the Glc-PSO:GCase complex. The S-(16 fluorohexadecyl)-PSO glycomimetic turned out to be a more potent GCase competitive inhibitor than ambroxol, a non glycomimetic drug currently in pilot trials as a pharmacological chaperone for Gaucher disease. Moreover, the inhibition constant increased by one order of magnitude when shifting from neutral (pH 7) to acidic (pH 5) media, a favorable characteristic for a chaperone candidate. Indeed, the fluoro-PSO derivative also proved superior to ambroxol in mutant GCase activity enhancement assays in N370S/N370S Gaucher fibroblasts. The results presented here represent a proof of concept of the potential of exploiting long-range non-glycone interactions for the optimization of glycosidase inhibitors with chaperone activity. PMID- 25461327 TI - Screening of synthetic and natural product databases: Identification of novel androgens and antiandrogens. AB - The androgen receptor is an important pharmaceutical target for a variety of diseases. This paper presents an in silico/in vitro screening procedure to identify new androgen receptor ligands. The two-step virtual screening procedure uses a three-dimensional pharmacophore model and a docking/scoring routine. About 39,000 filtered compounds were docked with PLANTS and scored by Chemplp. Subsequent to virtual screening, 94 compounds, including 28 steroidal and 66 nonsteroidal compounds, were tested by an androgen receptor fluorescence polarization ligand displacement assay. As a result, 30 compounds were identified that show a relative binding affinity of more than 50% in comparison to 100 nM dihydrotestosterone and were classified as androgen receptor binders. For 11 androgen receptor binders of interest IC50 and Ki values were determined. The compound with the highest affinity exhibits a Ki value of 10.8 nM. Subsequent testing of the 11 compounds in a PC-3 and LNCaP multi readout proliferation assay provides insights into the potential mode of action. Further steroid receptor ligand displacement assays and docking studies on estrogen receptors alpha and beta, glucocorticoid receptor, and progesterone receptor gave information about the specificity of the 11 most active compounds. PMID- 25461328 TI - Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: a review. AB - Amongst several communicable diseases (CDs), malaria is one of the deadliest parasitic disease all over the world, particularly in African and Asian countries. To curb this menace, numbers of antimalarial agents are being sold as over the counter (OTC) drugs. Chloroquine (CQ) is one of them and is one of the oldest, cheapest, and easily available synthetic agents used to curb malaria. Unfortunately, after the reports of CQ-resistance against different strains of malarial parasite strains worldwide, scientist are continuously modifying the core structure of CQ to get an efficient drug. Interestingly, several new drugs have been emerged in due course having unique and enhanced properties (like dual stage inhibitors, resistance reversing ability etc.) and are ready to enter into the clinical trial. In this course, some new agents have also been discovered which are; though inactive against CQS strain, highly active against CQR strains. The present article describes the role of modification of the core structure of CQ and its effects on the biological activities. Moreover, the attempt has also been made to predict the future prospects of such drugs to reemerge as antimalarial agents. PMID- 25461329 TI - Bioactive benzofuran derivatives: moracins A-Z in medicinal chemistry. AB - Benzofuran heterocycles are fundamental structural units in a variety of biologically active natural products as well as synthetic materials. Over the time, benzofuran derivatives have attracted many researchers due to the broad scope of their biological activity, which include anticancer, antimicrobial, immunomodulatory, antioxidant and anti-inflammatory properties. Egonol, homoegonol and moracin families are biologically active natural products containing benzofuran heterocycle as basic structural units. This paper focuses on the moracin family (moracin A to Z). Morus, a genus of flowering plants in the family Moraceae, comprises 10-16 species of deciduous trees commonly known as mulberries. The root bark, stem bark and leaves of Morus alba, M. lhou, Morus macroura are the main sources for arylbenzofuran derivatives including the moracins. A large volume of research has been carried out on moracins and their derivatives, which has shown the pharmacological importance of this benzofuran heterocyclic nucleus. In this mini-review, we attempt to highlight the importance of moracins, as they have been a major source for drug development. Herein, we also summarize the current state of the art concerning the synthesis and medicinal use of moracins A-Z. PMID- 25461330 TI - Discovery of novel indole derivatives as allosteric inhibitors of fructose-1,6 bisphosphatase. AB - A series of novel indole derivatives was designed and synthesized as inhibitors of fructose-1,6-bisphosphatase (FBPase). The most potent compound 14c was identified with an IC50 value of 0.10 MUM by testing the inhibitory activity against recombinant human FBPase. The structure-activity relationships were investigated on the substitution at 4- and 5-position of the indole scaffold. The binding interactions of the title compounds at AMP binding site of FBPase were predicted using CDOCKER algorithm. PMID- 25461331 TI - Self-gated MRI motion modeling for respiratory motion compensation in integrated PET/MRI. AB - Accurate localization and uptake quantification of lesions in the chest and abdomen using PET imaging is challenged by respiratory motion occurring during the exam. This work describes how a stack-of-stars MRI acquisition on integrated PET/MRI systems can be used to derive a high-resolution motion model, how many respiratory phases need to be differentiated, how much MRI scan time is required, and how the model is employed for motion-corrected PET reconstruction. MRI self gating is applied to perform respiratory gating of the MRI data and simultaneously acquired PET raw data. After gated PET reconstruction, the MRI motion model is used to fuse the individual gates into a single, motion compensated volume with high signal-to-noise ratio (SNR). The proposed method is evaluated in vivo for 15 clinical patients. The gating requires 5-7 bins to capture the motion to an average accuracy of 2mm. With 5 bins, the motion modeling scan can be shortened to 3-4 min. The motion-compensated reconstructions show significantly higher accuracy in lesion quantification in terms of standardized uptake value (SUV) and different measures of lesion contrast compared to ungated PET reconstruction. Furthermore, unlike gated reconstructions, the motion-compensated reconstruction does not lead to SNR loss. PMID- 25461332 TI - Methodology for implementing patient-specific spatial boundary condition during a cardiac cycle from phase-contrast MRI for hemodynamic assessment. AB - Pulmonary insufficiency (PI) can render the right ventricle dysfunctional due to volume overloading and hypertrophy. The treatment requires a pulmonary valve replacement surgery. However, determining the right time for the valve replacement surgery has been difficult with currently employed clinical techniques such as, echocardiography and cardiac MRI. Therefore, there is a clinical need to improve the diagnosis of PI by using patient-specific (PS) hemodynamic endpoints. While there are many reported studies on the use of PS geometry with time varying boundary conditions (BC) for hemodynamic computation, few use spatially varying PS velocity measurement at each time point of the cardiac cycle. In other words, the gap is that, there are limited number of studies which implement both spatially- and time-varying physiologic BC directly with patient specific geometry. The uniqueness of this research is in the incorporation of spatially varying PS velocity data obtained from phase-contrast MRI (PC-MRI) at each time point of the cardiac cycle with PS geometry obtained from angiographic MRI. This methodology was applied to model the complex developing flow in human pulmonary artery (PA) distal to pulmonary valve, in a normal and a subject with PI. To validate the methodology, the flow rates from the proposed method were compared with those obtained using QFlow software, which is a standard of care clinical technique. For the normal subject, the computed time average flow rates from this study differed from those obtained using the standard of care technique (QFlow) by 0.8 ml/s (0.9%) at the main PA, by 2 ml/s (3.4%) at the left PA and by 1.4 ml/s (3.8%) at the right PA. For the subject with PI, the difference was 7 ml/s (12.4%) at the main PA, 5.5 ml/s (22.6%) at the left PA and 4.9 ml/s (18.0%) at the right PA. The higher percentage differences for the subject with PI, was the result of overall lower values of the forward mean flow rate caused by excessive flow regurgitation. This methodology is expected to provide improved computational results when PS geometry from angiographic MRI is used in conjunction with PS PC-MRI data for solving the flow field. PMID- 25461333 TI - Interventional digital tomosynthesis from a standard fluoroscopy system using 2D 3D registration. AB - Interventional fluoroscopy provides guidance in a variety of minimally invasive procedures. However, three-dimensional (3D) clinically relevant information is projected onto a two-dimensional (2D) image which can make image interpretation difficult. Moreover, vasculature visualisation requires the use of iodinated contrast media which is nephrotoxic and is the primary cause of renal complications. In this article, we demonstrate how digital tomosynthesis slices can be produced on standard fluoroscopy equipment by registering the preoperative CT volume and the intraoperative fluoroscopy images using 2D-3D image registration. The proposed method automatically reconstructs patient-anatomy specific slices and removes clutter resulting from bony anatomy. Such slices could provide additional intraoperative information which cannot be provided by the preoperative CT volume alone, such as the deformed aorta position offering improved guidance precision. Image acquisition would fit with interventional clinical work-flow and would not require a high X-ray dose. Experiments are carried out using one phantom and four clinical datasets. Phantom results showed a 3351% contrast-to-noise improvement compared to standard fluoroscopy. Patient results showed our method enabled visualization of clinically relevant features: outline of the aorta, the aortic bifurcation and some aortic calcifications. PMID- 25461334 TI - Context aware spatio-temporal cell tracking in densely packed multilayer tissues. AB - Modern live imaging technique enables us to observe the internal part of a tissue over time by generating serial optical images containing spatio-temporal slices of hundreds of tightly packed cells. Automated tracking of plant and animal cells from such time lapse live-imaging datasets of a developing multicellular tissue is required for quantitative, high throughput analysis of cell division, migration and cell growth. In this paper, we present a novel cell tracking method that exploits the tight spatial topology of neighboring cells in a multicellular field as contextual information and combines it with physical features of individual cells for generating reliable cell lineages. The 2D image slices of multicellular tissues are modeled as a conditional random field and pairwise cell to cell similarities are obtained by estimating marginal probability distributions through loopy belief propagation on this CRF. These similarity scores are further used in a spatio-temporal graph labeling problem to obtain the optimal and feasible set of correspondences between individual cell slices across the 4D image dataset. We present results on (3D+t) confocal image stacks of Arabidopsis shoot meristem and show that the method is capable of handling many visual analysis challenges associated with such cell tracking problems, viz. poor feature quality of individual cells, low SNR in parts of images, variable number of cells across slices and cell division detection. PMID- 25461336 TI - A homotopy-based sparse representation for fast and accurate shape prior modeling in liver surgical planning. AB - Shape prior plays an important role in accurate and robust liver segmentation. However, liver shapes have complex variations and accurate modeling of liver shapes is challenging. Using large-scale training data can improve the accuracy but it limits the computational efficiency. In order to obtain accurate liver shape priors without sacrificing the efficiency when dealing with large-scale training data, we investigate effective and scalable shape prior modeling method that is more applicable in clinical liver surgical planning system. We employed the Sparse Shape Composition (SSC) to represent liver shapes by an optimized sparse combination of shapes in the repository, without any assumptions on parametric distributions of liver shapes. To leverage large-scale training data and improve the computational efficiency of SSC, we also introduced a homotopy based method to quickly solve the L1-norm optimization problem in SSC. This method takes advantage of the sparsity of shape modeling, and solves the original optimization problem in SSC by continuously transforming it into a series of simplified problems whose solution is fast to compute. When new training shapes arrive gradually, the homotopy strategy updates the optimal solution on the fly and avoids re-computing it from scratch. Experiments showed that SSC had a high accuracy and efficiency in dealing with complex liver shape variations, excluding gross errors and preserving local details on the input liver shape. The homotopy based SSC had a high computational efficiency, and its runtime increased very slowly when repository's capacity and vertex number rose to a large degree. When repository's capacity was 10,000, with 2000 vertices on each shape, homotopy method cost merely about 11.29 s to solve the optimization problem in SSC, nearly 2000 times faster than interior point method. The dice similarity coefficient (DSC), average symmetric surface distance (ASD), and maximum symmetric surface distance measurement was 94.31 +/- 3.04%, 1.12 +/- 0.69 mm and 3.65 +/- 1.40 mm respectively. PMID- 25461335 TI - Sequential Monte Carlo tracking of the marginal artery by multiple cue fusion and random forest regression. AB - Given the potential importance of marginal artery localization in automated registration in computed tomography colonography (CTC), we have devised a semi automated method of marginal vessel detection employing sequential Monte Carlo tracking (also known as particle filtering tracking) by multiple cue fusion based on intensity, vesselness, organ detection, and minimum spanning tree information for poorly enhanced vessel segments. We then employed a random forest algorithm for intelligent cue fusion and decision making which achieved high sensitivity and robustness. After applying a vessel pruning procedure to the tracking results, we achieved statistically significantly improved precision compared to a baseline Hessian detection method (2.7% versus 75.2%, p<0.001). This method also showed statistically significantly improved recall rate compared to a 2-cue baseline method using fewer vessel cues (30.7% versus 67.7%, p<0.001). These results demonstrate that marginal artery localization on CTC is feasible by combining a discriminative classifier (i.e., random forest) with a sequential Monte Carlo tracking mechanism. In so doing, we present the effective application of an anatomical probability map to vessel pruning as well as a supplementary spatial coordinate system for colonic segmentation and registration when this task has been confounded by colon lumen collapse. PMID- 25461337 TI - Right ventricle segmentation from cardiac MRI: a collation study. AB - Magnetic Resonance Imaging (MRI), a reference examination for cardiac morphology and function in humans, allows to image the cardiac right ventricle (RV) with high spatial resolution. The segmentation of the RV is a difficult task due to the variable shape of the RV and its ill-defined borders in these images. The aim of this paper is to evaluate several RV segmentation algorithms on common data. More precisely, we report here the results of the Right Ventricle Segmentation Challenge (RVSC), concretized during the MICCAI'12 Conference with an on-site competition. Seven automated and semi-automated methods have been considered, along them three atlas-based methods, two prior based methods, and two prior free, image-driven methods that make use of cardiac motion. The obtained contours were compared against a manual tracing by an expert cardiac radiologist, taken as a reference, using Dice metric and Hausdorff distance. We herein describe the cardiac data composed of 48 patients, the evaluation protocol and the results. Best results show that an average 80% Dice accuracy and a 1cm Hausdorff distance can be expected from semi-automated algorithms for this challenging task on the datasets, and that an automated algorithm can reach similar performance, at the expense of a high computational burden. Data are now publicly available and the website remains open for new submissions (http://www.litislab.eu/rvsc/). PMID- 25461338 TI - Quantification of local changes in myocardial motion by diffeomorphic registration via currents: application to paced hypertrophic obstructive cardiomyopathy in 2D echocardiographic sequences. AB - Time-to-peak measurements and single-parameter observations are cumbersome and often confusing for quantifying local changes in myocardial function. Recent spatiotemporal normalization techniques can provide a global picture of myocardial motion and strain patterns and overcome some of these limitations. Despite these advances, the quantification of pattern changes remains descriptive, which limits their relevance for longitudinal studies. Our paper provides a new perspective to the longitudinal analysis of myocardial motion. Non rigid registration (diffeomorphic registration via currents) is used to match pairs of patterns, and pattern changes are inferred from the registration output. Scalability is added to the different components of the input patterns in order to tune up the contributions of the spatial, temporal and magnitude dimensions to data changes, which are of interest for our application. The technique is illustrated on 2D echocardiographic sequences from 15 patients with hypertrophic obstructive cardiomyopathy. These patients underwent biventricular pacing, which aims at provoking mechanical dyssynchrony to reduce left ventricular outflow tract (LVOT) obstruction. We demonstrate that our method can automatically quantify timing and magnitude changes in myocardial motion between baseline (non paced) and 1 year follow-up (pacing on), resulting in a more robust analysis of complex patterns and subtle changes. Our method helps confirming that the reduction of LVOT pressure gradient actually comes from the induction of the type of dyssynchrony that was expected. PMID- 25461339 TI - Joint 3-D vessel segmentation and centerline extraction using oblique Hough forests with steerable filters. AB - CONTRIBUTIONS: We propose a novel framework for joint 3-D vessel segmentation and centerline extraction. The approach is based on multivariate Hough voting and oblique random forests (RFs) that we learn from noisy annotations. It relies on steerable filters for the efficient computation of local image features at different scales and orientations. EXPERIMENTS: We validate both the segmentation performance and the centerline accuracy of our approach both on synthetic vascular data and four 3-D imaging datasets of the rat visual cortex at 700 nm resolution. First, we evaluate the most important structural components of our approach: (1) Orthogonal subspace filtering in comparison to steerable filters that show, qualitatively, similarities to the eigenspace filters learned from local image patches. (2) Standard RF against oblique RF. Second, we compare the overall approach to different state-of-the-art methods for (1) vessel segmentation based on optimally oriented flux (OOF) and the eigenstructure of the Hessian, and (2) centerline extraction based on homotopic skeletonization and geodesic path tracing. RESULTS: Our experiments reveal the benefit of steerable over eigenspace filters as well as the advantage of oblique split directions over univariate orthogonal splits. We further show that the learning-based approach outperforms different state-of-the-art methods and proves highly accurate and robust with regard to both vessel segmentation and centerline extraction in spite of the high level of label noise in the training data. PMID- 25461340 TI - The Masquelet technique for membrane induction and the healing of ovine critical sized segmental defects. AB - The healing of critical sized segmental defects is an ongoing clinical problem. No method has achieved pre-eminence. The Masquelet technique is a relatively new innovation involving the induction of a fibrous tissue membrane around the bone defect site taking advantage of the body's foreign body reaction to the presence of a polymethylmethacrylate (PMMA) spacer. The aim of this study was to investigate the properties and characteristics of this induced membrane and its effectiveness when used in conjunction with allograft or an allograft/autograft mix as filler materials in an ovine critical sized defect model. The resultant induced membrane was found to be effective in containing the graft materials in situ. It was demonstrated to be an organised pseudosynovial membrane which expressed bone morphogenic protein 2 (BMP2), transforming growth factor-beta (TGFbeta), vascular endothelial growth factor (VEGF), von Willerbrand factor (vWF), interleukin 6 (IL-6) and interleukin 8 (IL-8). While more new bone growth was evident in the test groups compared to the controls animals at 12 weeks, the volumes were not statistically different and no defects were fully bridged. Of the two graft material groups, the allograft/autograft mix was shown to have a more rapid graft resorption rate than the allograft only group. While the Masquelet technique proved effective in producing a membrane to enclose graft materials, its ability to assist in the healing of critical sized segmental defects when compared to empty controls remained inconclusive. PMID- 25461341 TI - Proliferative behavior of vaginal fibroblasts from women with pelvic organ prolapse. AB - OBJECTIVE: Pelvic organ prolapse (POP) significantly impacts quality of life of women, especially with advancing age. Cell proliferation is a critical parameter in both normal and pathophysiological processes. We sought to examine fibroblast proliferation in premenopausal women with and without POP and menopausal women with POP, and examine whether TGF-beta1, a fibroblast mitogen, could stimulate proliferation in vaginal fibroblasts from these populations. STUDY DESIGN: Vaginal wall biopsies were obtained from asymptomatic women (controls) and women with POP (cases). Fibroblasts were cultured from these tissues. Vaginal fibroblasts were treated with or without TGF-beta1. Cell proliferation rate (mitotic index) was measured with time-lapse dark-field microscopy. Cell mitosis was counted with ImageJ software after analysis of time-lapse images as Quick time movies. RESULTS: There was no significant difference in mitotic index throughout different time points of observation between premenopausal controls and cases of similar ages. However, a significant difference in mitotic index was seen between premenopausal and menopausal cases (p=0.01), with the menopausal group exhibiting significantly lower mitotic indices. When treated with different doses of TGF-beta1, premenopausal control fibroblast proliferation increased with 5ng/ml of TGF-beta1 compared to non-treated fibroblasts (p=0.04). TGF-beta1 stimulation did not affect fibroblasts from either premenopausal or menopausal cases. CONCLUSIONS: Vaginal fibroblast proliferation decreases with age and this association does not appear to be affected by the presence of pelvic organ prolapse. TGF-beta1 stimulation increased cell proliferation of premenopausal control fibroblasts. In contrast, there was no response seen in fibroblasts from premenopausal and menopausal cases. PMID- 25461342 TI - Prediction of endometrial carcinogenesis probability while diagnosed as atypical endometrial hyperplasia: a new risk model based on age, CA199 and CA125 assay. AB - OBJECTIVE: To establish a risk model for predicting the probability of endometrial carcinogenesis while diagnosed as AEH preoperatively. STUDY DESIGN: 149 patients with AEH diagnosed by D&C specimens or hysteroscopy undergoing total hysterectomy were enrolled in this retrospective study. Patients were divided into two groups: 51 cases in AEH to AEH group and 98 cases in AEH to EC group. The clinical pathological characteristics were compared between the two groups. With the use of ROC curves, cutoff values of age, CA199, CA125 and uterine height were determined. The relationships of these evaluators with endometrial carcinogenesis were investigated by multivariate analysis with a logistic regression model. RESULTS: 65.8% (98/149) of preoperative AEH patients become EC after confirmed by paraffin hysterectomy specimens. The cutoff values were 51.5 years of age, 14.06U/ml of CA199, 14.30U/ml of CA125 and 45mm of uterine height, respectively. Logistic regression analysis demonstrated age (OR=0.58, 95% confidence interval [95%CI]: 0.08-3.94), CA199 (OR=7.27, 95%CI: 1.43-36.92), CA125 (OR=13.97, 95%CI: 2.49-78.37), uterine height (OR=0.49, 95%CI: 0.08-3.08) and abnormal uterine bleeding (OR=4.27, 95%CI: 0.53-34.52) were associated with endometrial carcinogenesis. However, only CA199 (p=0.017) and CA125 (p=0.003) revealed significant differences. Therefore, when entered into the risk model, CA199>=14.06U/ml and CA125>=14.30U/ml were considered as cogent predictors of endometrial carcinogenesis. CONCLUSIONS: This risk model may well predict the probability of endometrial carcinogenesis when preoperatively diagnosed as AEH. PMID- 25461343 TI - Cardiovascular risk in postmenopausal women with and without breast cancer. PMID- 25461344 TI - Urine human papillomavirus prevalence in women with high-grade cervical lesions. AB - OBJECTIVE: To determine the prevalence of human papillomavirus (HPV) in urine samples from women with high-grade cervical lesions. Secondary objectives are to identify the influence of socio-demographic factors and the different genotypes with urinary HPV positivity. STUDY DESIGN: 75 women with a positive biopsy for CIN2+ were included in the study from October 2010 to July 2011. A sample of urine was collected immediately before conization at the outpatient clinic. We analyzed the presence of HPV using a PCR technique. RESULTS: The mean age of the patients was 34.8 years (range 24 to 61). All patients had histological CIN2+, of whom 54.67% had CIN3. The prevalence of HPV in urine test was 58.82% in CIN2 population versus 78.05% in CIN3 patients (p 0.072). 31 different genotypes were found. The most frequent HPV genotype was 16-HPV, which was identified in 58% of women with positive HPV-DNA in urine samples. No demographic characteristics were significantly associated to urinary HPV prevalence. CONCLUSION: Most of the patients with CIN2+ showed positive results for urine HPV test. The prevalence of positive urinary HPV test was higher for patients with CIN3. HPV urine detection could be considered as an acceptable option for high-risk population who skip regular screening programs. PMID- 25461345 TI - Sequential use of mifepristone and misoprostol in treatment of early pregnancy failure appears more effective than misoprostol alone: a retrospective study. AB - OBJECTIVE: Is treatment of early pregnancy failure (EPF) with sequential use of mifepristone and misoprostol more effective than treatment with misoprostol alone? STUDY DESIGN: In a retrospective cohort study at the Department of Obstetrics and Gynaecology of the Radboud University Medical Centre, 301 women with early pregnancy failure receiving medical treatment between January 2008 and March 2013 were included. Of these, 199 women were pre-treated with 200mg mifepristone (orally) followed by 2 consecutive doses of 800mcg misoprostol (vaginally) and 102 women were treated with 2 consecutive doses of 800mcg misoprostol (vaginally) alone. RESULTS: Complete expulsion was achieved in 66.8% of the women treated with a sequential combination of mifepristone and misoprostol versus 54.9% of the women treated with misoprostol alone. The difference in rates of complete expulsion was 11.9% (P<0.05; 95% CI 0.3-23.6%). CONCLUSIONS: Medical treatment of early pregnancy failure with a sequential combination of mifepristone and misoprostol was more effective than treatment with misoprostol alone. Our findings will have to be confirmed by a large prospective multicentre double blinded-randomized trial. PMID- 25461346 TI - Successful treatment of endogenous cesarean scar pregnancies with transabdominal ultrasound-guided suction curettage alone. AB - OBJECTIVE: To investigate the efficacy and safety of transabdominal ultrasound guided suction curettage alone in endogenous cesarean scar pregnancy (CSP). STUDY DESIGN: From 2009 to 2013, 21 women with endogenous CSP who had no other therapy underwent suction curettage alone guided with transabdominal ultrasound. RESULTS: All patients were successfully treated with suction curettage alone. No one needed emergency blood transfusion or uterine artery embolization. The average gestational age was 51.1+/-7.56 days. The mean thickness of the lower anterior uterine wall was 0.5cm, ranging from 0.3cm to 0.9cm. The average blood loss during surgery was 81.3+/-33.5 (30-150)ml. The mean time for achieving a normal beta-HCG level was 26.9 days. CONCLUSION: Transadominal ultrasound-guided suction curettage was a feasible and effective method for lower risk endogenous CSP patients with the myometrial layer between the gestational sac and the bladder more than 3mm before 10 gestational weeks. PMID- 25461347 TI - Antioxidant effect of erdosteine and lipoic acid in ovarian ischemia-reperfusion injury. AB - OBJECTIVE: To investigate the effects of erdosteine and alpha lipoic acid (ALA) in a rat model of ovarian ischaemia-reperfusion injury. STUDY DESIGN: Forty-eight female Wistar albino rats were separated, at random, into six groups of eight rats. The groups were classified as: sham, torsion, detorsion, detorsion+erdosteine 100mg/kg, detorsion+alpha lipoic acid (ALA) 100mg/kg, and detorsion+erdosteine+ALA. The investigators executing the biochemical and histological analyses were blinded to the randomization until the end of the study. RESULTS: The TOS (Total Oxidant Status) and OSI (Oxidative Stress Index) levels are higher in the Torsion and Detorsion groups when compared with the ones in the Sham group (p<0.05). Strong correlation was found between OSI and total histological score in the sham, torsion and detorsion groups (r=0.765, p<0.001). The mean levels of TOS and OSI in the rats that received erdosteine and/or ALA were significantly lower compared with the sham, torsion and detorsion groups (p<0.05). Mean TOS and mean OSI were lower in the detorsion+erdosteine+ALA group compared with the detorsion+erdosteine and detorsion+ALA groups (p<0.05). In comparison with the detorsion group, the numbers of primordial follicles (p=0.006) and primary follicles (p=0.036) were increased in the groups that received erdosteine and/or ALA. CONCLUSIONS: Erdosteine and ALA decreased ischaemia-reperfusion injury in an experimental rat ovarian torsion model; combination treatment had a greater effect than either agent alone. Treatment with erdosteine and/or ALA was found to preserve the loss of reproductive capacity normally observed after ovarian torsion. PMID- 25461348 TI - Importance of macroprolactinemia in hyperprolactinemia. AB - Macroprolactin is an antigen-antibody complex of higher molecular mass than prolactin (>150kDa), consisting of monomeric prolactin and immunoglobulin G. The term 'macroprolactinemia' is used when the concentration of macroprolactin exceeds 60% of the total serum prolactin concentration determined by polyethylene glycol precipitation. The gold standard technique for the diagnosis of macroprolactinemia is gel filtration chromatography. The prevalence of macroprolactinemia in hyperprolactinemic populations varies between 15% and 35%. Although the pathogenesis of these antibodies is not clear, it is possible that changes in the pituitary prolactin molecule represent increased antigenicity to the immune system, leading to the production of anti-prolactin antibodies. Mild hyperprolactinemia usually occurs because macroprolactin is not cleared readily from the circulation due to its higher molecular weight. Moreover, the hypothalamic negative feedback mechanism for autoantibody-bound prolactin is inactive because macroprolactin cannot access the hypothalamus, resulting in hyperprolactinemia. Reduced in-vivo bioactivity of macroprolactin may be the reason for the lack of hyperprolactinemic symptoms. It also seems that anti prolactin autoantibodies may compete with prolactin molecules for receptor binding, resulting in low bioactivity. Additionally, the large molecular size of macroprolactin confined in the intravascular compartment prevents its passage through the capillary endothelium to the target cells, which may be the reason for the lack of symptoms. Macroprolactinemia is considered to be a benign clinical condition in patients with normal concentrations of bioactive monomeric prolactin, with a lack, or low incidence, of hyperprolactinemic symptoms and negative pituitary imaging. In such cases with resistance to anti-prolactinaemic drugs, no pharmacological treatment, diagnostic investigations or prolonged follow-up are required. However, macroprolactinemia may also occur in patients with conventional symptoms of hyperprolactinemia who cannot be differentiated from patients with true hyperprolactinemia. These symptoms are mainly attributed to excess levels of monomeric prolactin, and this is of concern. The diagnosis of macroprolactinemia is misleading and inappropriate. A multitude of physiological, pharmacological and pathological causes, including stress, prolactinomas, hypothyroidism, renal and hepatic failure, intercostal nerve stimulation and polycystic ovary disease, can contribute to increased levels of monomeric prolactin. It is important for patients with elevated monomeric prolactin levels to undergo routine evaluation to identify the exact pathological state and introduce adequate treatment, regardless of the presence of macroprolactin. In addition, macroprolactinemia occasionally occurs due to macroprolactin associated with pituitary adenomas, with biological activity of macroprolactin comparable with that of monomeric prolactin. In cases when excess macroprolactin occurs with clinical manifestations of hyperprolactinemia, macroprolactinemia should be regarded as a pathological biochemical variant of hyperprolactinemia. An individualized approach to the management of such patients with macroprolactinemia may be necessary, and pituitary imaging, dopamine treatment and prolonged follow-up should be applied. PMID- 25461349 TI - Anatomic outcomes after pelvic-organ-prolapse surgery: comparing uterine preservation with hysterectomy. AB - OBJECTIVE: Pelvic organ prolapse (POP) is of growing importance to gynecologists, as the estimated lifetime risk of surgical interventions due to prolapse or incontinence amounts to 11-19%. Conflicting data exist regarding the effectiveness of POP surgery with and without uterine preservation. We aimed to compare anatomic outcomes in patients with and without hysterectomy at the time of POP-surgery and identify independent risk factors for symptomatic recurrent prolapses. STUDY DESIGN: In this single-centre retrospective analysis we analyzed 96 patients after primary surgical treatment for POP. These patients were followed up with clinical and vaginal examination six months postoperatively. For comparison of the groups, the chi-squares test were used for categorical data and the u-test for metric data. A logistic regression model was calculated to identify independent risk factors for recurrent prolapse. RESULTS: Of 96 patients, 21 underwent uterus preserving surgery (UP), 75 vaginal hysterectomy (HE). Median operating time was significantly shorter in the UP group (55 vs. 90min; p=0.000). There was no significant difference concerning postoperative urinary incontinence or asymptomatic relapse (p>0.05), whereas symptomatic recurrent prolapses were significantly more common in the UP group (23.8% vs. 6.7%; p=0.023). However, in multivariate analysis, only vaginal parity and sacrospinous ligament fixation were identified as independent risk factors for recurrent prolapse after POP surgery. CONCLUSION: Uterus-preservation at time of POP-surgery is a safe and effective alternative for women who wish to preserve their uterus but is associated with more recurrent symptomatic prolapses. PMID- 25461350 TI - Increased trophoblast expression of NFAT5/TonEBP in pre-eclamptic placentas and hyperosmolar-treated BeWo cells. AB - OBJECTIVES: To assess the concentrations of inositol and sorbitol, and determine the expression of related osmolyte factors [nuclear factor of activated T cells 5, also known as tonicity responsive binding protein (NFAT5/TonEBP); sodium myo inositol transporter (SLC5A3); and aldose reductase] in placentas of pre eclamptic (PE) patients and trophoblast BeWo cells subjected to hypertonic stress in vitro. STUDY DESIGN: Control and PE placentas were collected. BeWo cells were cultured and subjected to a hyperosmolar solution for 4h. Western blot analysis was performed on NFAT5, SLC5A3, aldose reductase and ERK proteins. High performance liquid chromatography was used to determine the levels of inositol and sorbitol in cell lysates. RESULTS: Compared with control placentas, PE placentas showed higher levels of inositol and NFAT5, and lower levels of SLC5A3. Treated BeWo cells showed higher levels of inositol, sorbitol, NFAT5 total protein, SLC5A3 and aldose reductase, and increased ERK activation compared with control BeWo cells. CONCLUSIONS: Hyperosmolar conditions increase the expression of NFAT5 in PE placentas and BeWo cells, and may account for the increased osmolyte levels. NFAT5 may accomplish this through aldose reductase and SLC5A3 in trophoblast cells. PMID- 25461351 TI - Increased incidence of pelvic organ prolapse in women with acromegaly. AB - OBJECTIVE: To evaluate gynecological problems of female patients with acromegaly and the relationship of these problems with the activity of the disease. STUDY DESIGN: Thirty-four women with acromegaly and 27 age- and body mass index-matched female healthy controls (HC) were included in the study. Demographic features, medical history, hormonal status and disease activity were obtained. A detailed gynecological examination was performed. RESULTS: The incidence of pelvic organ prolapse (POP) was higher in patients with acromegaly (53%, n=18) compared to the HC (15%, n=4) (p=0.003). Limiting the analysis to only cases with previous pregnancy, POP was seen in 18 (60%) of 30 cases with acromegaly and in 4 (20%) of 20 of the HC (p=0.005). Additionally, in cases with prior vaginal delivery, POP was present in 18 (60%) of 30 cases with acromegaly and in 4 (24%) of 17 of the HC (p=0.02). The frequency of POP was similar in patients with controlled and uncontrolled acromegaly (p=0.3). CONCLUSION: Acromegaly may facilitate occurrence of pelvic organ prolapse and may cause additional health issues in female cases. PMID- 25461352 TI - Multimodal pain control is associated with reduced hospital stay following open abdominal hysterectomy. AB - OBJECTIVE: To study the association of a multimodal pain protocol (MMPC) and reduced hospital stay after open abdominal hysterectomy. STUDY DESIGN: The study design was a comparison of a prospective cohort with a retrospective historical control. We enrolled endometrial cancer patients undergoing open abdominal hysterectomy with lymphadenectomy by the same surgeon. Control patients from 2008 to 2010 who received morphine PCA alone were compared with a similar demographic group of patients from 2011 to 2013 who received MMPC. MMPC consisted of gabapentin (900mg PO) and acetaminophen (1g IV) administered 45-60min preoperatively. The surgical site was injected with bupivacaine with 0.5% epinephrine prior to incision. The postoperative pain control regimen consisted of gabapentin (300mg PO every 6h), acetaminophen (1g IV every 8h for 24h postoperatively), ketorolac (15mg IV every 6h for 48h postoperatively), morphine PCA (2mg IV every 10min, no basal rate) and oxycodone/acetaminophen (10/325mg PO every 6h as needed). RESULTS: Length of hospital stay (LOH) of the study cohort (N=105 with MMPC) was compared with the historical with postoperative morphine alone (N=113 without MMPC). There were no differences in demographic, uterine cancer stage, or comorbidities between the two arms. The LOH was 1.6 days for patients receiving MMPC and 3.3 days for patients who received morphine alone (P<0.001). CONCLUSION: Multimodal pain control is associated with significantly reduced hospital stay after open abdominal hysterectomy. PMID- 25461353 TI - Management of presumed benign ovarian tumors: updated French guidelines. AB - Transvaginal pelvic ultrasound is the first-line imaging examination for presumed benign ovarian tumors (PBOT) in adult women (Grade A). Ultrasound is sufficient for characterizing a unilocular anechoic cyst smaller than 7cm (Grade A). Magnetic resonance imaging is the recommended second-line investigation for indeterminate masses or masses larger than 7cm (Grade B). Serum CA-125 assay is not recommended for first-line diagnosis in adult women (Grade C). In women with a unilocular anechoic cyst, hormone therapy is ineffective and not recommended (Grade A). Ultrasound-guided aspiration is not recommended (Grade B). Abstention is an option in adult women with a unilocular asymptomatic anechoic cyst smaller than 10cm and no history of cancer (Grade B). If symptoms develop, laparoscopy is the gold standard for surgical treatment of PBOT (Grade A). Conservative surgical treatment (cystectomy) should be preferred to oophorectomy in pre-menopausal women without a previous history of cancer (Grade C). In cases of suspected adnexal torsion, laparoscopic surgical exploration is recommended (Grade B). Conservative treatment or detorsion without oophorectomy is recommended for pre menopausal women regardless of the estimated torsion duration and macroscopic appearance of the ovary (Grade B). During pregnancy, expectant management is recommended for unilocular asymptomatic anechoic cysts smaller than 6cm (Grade C). PMID- 25461354 TI - Viability of cumulus cells is associated with basal AMH levels in assisted reproduction. AB - OBJECTIVE(S): An interesting non-invasive approach to select embryos for transfer is analyzing the health state of somatic granulosa cells surrounding the oocyte addressing their mutual dependence. This prospective study was set up to analyse whether the DNA integrity of cumulus cells correlates with preimplantation development and basal AMH levels. STUDY DESIGN: Therefore, 56 patients who gave written consent were enrolled. Sequential denudation of the cumulus-oocyte complexes was performed in order to separate corona radiata from outer cumulus cells. DNA integrity of both cell types was analysed using a modified chromatin dispersion test. RESULTS: The percentage of viable corona radiata cells per patient showed a linear correlation to blastulation (P<0.05). These innermost cells showed significantly lower rates of strand breaks (P<0.01) as compared to outer cumulus cells. Age-corrected AMH was significantly associated with the DNA integrity of outer cumulus cells (P<0.05). CONCLUSION(S): For the first time it could be shown that in fact clinical embryologists deal with two different entities of cumulus cells, inner and outer ones. It seems that any protective mechanism of the female gamete follows an outward gradient, so that negative effects, e.g. apoptosis, may impair outer cumulus cells first. Age-corrected AMH reflects quality of these outer cumulus cells. KEYWORDS: AMH; Corona radiata cells; DNA fragmentation; Outer cumulus cells; SCD test. PMID- 25461355 TI - p16 expression in patients with cervical cancer and its prognostic significance: meta-analysis of published literature. AB - OBJECTIVES: p16, a tumour suppressor, is unable to express its suppressive effects following interaction with E7-retinoblastoma protein. Previous reports have suggested that p16 immunostaining allows precise identification of cervical intra-epithelial neoplasia and cervical cancer lesions in biopsies. The prognostic value of p16 expression in cervical cancers has been evaluated for several years, but the results remain controversial. As such, the authors undertook a systematic review and meta-analysis of studies assessing the impact of p16 expression on overall survival and disease-free survival. STUDY DESIGN: Medline, Embase and China National Knowledge Infrastructures were searched to identify studies on the prognostic impact of p16 expression in patients with cervical cancer. In total, 1070 patients from 10 eligible studies were included in the analysis. Pooled risk ratios (RRs) with 95% confidence intervals (95% CI) were calculated. RESULTS: A significant association was found between p16 expression and increased disease-free survival (RR 0.60; 95% CI 0.44-0.82; p=0.001). However, no significant association was found between p16 and overall survival. CONCLUSION: p16 expression may be predictive of a favourable prognosis in patients with cervical cancer. However, large-scale, multicentre and well matched cohort studies are warranted to confirm this finding. PMID- 25461356 TI - Pregnancy affects morphology of induced endometriotic lesions in a mouse model through alteration of proliferation and angiogenesis. AB - OBJECTIVE: Pregnancy is known to alleviate the symptoms of endometriosis and is also known to be a pro-angiogenic condition affecting blood and lymphatic vessels. However, angiogenesis actively participates in the development of endometriosis. The objective of our study was to study the impact of pregnancy on endometriotic tissue. Study design We performed a cross-sectional, control versus treatment study in a mouse model of endometriosis. Thirty-one female C57Bl6 mice were mated and became pregnant and 31 females were not mated and served as control. Intraperitoneal endometriotic lesions were surgically induced in C57Bl6 mice which were subsequently mated or not (group P: pregnant, group NP: non pregnant). P and NP mice were sacrificed on day E15.5 of the pregnancy of P mice and lesions were harvested. Lesions were weighed and analyzed by histology, immunohistology, flow cytometry and real-time quantitative RT-PCR (qRT-PCR). RESULTS: Pregnancy reduced lesion weight, decreased the proportion of cystic component (0.02 vs. 0.4; p<0.001) and modified the architecture of peritoneal endometriotic lesions. Pregnancy also increased cell proliferation in both stromal and glandular tissue as shown by the increase in Ki 67-positive cells in the P group (glandular: 19 vs. 3.9%, p<0.001; stromal: 8.7 vs. 3.3%, p<0.01). Finally, pregnancy increased angiogenesis in endometriotic lesions as indicated by an increased microvessel density (CD-31 and LYVE-1 stainings: respectively 2.2 vs. 5.1%, p<0.01 and 0.4 vs. 0.9%, p<0.001), an increased number of LYVE1 positive cells evaluated by flow cytometry (18.9 vs. 4.6%, p<0.05) and a rise in VEGF-A, -R2 and -R3 RNA expression shown by qRT-PCR (p<0.001; p<0.01; p<0.05). CONCLUSION: These challenging results provide insight in understanding the pathophysiology of endometriosis and evoke a correlation between lesion architecture and symptomatology. PMID- 25461357 TI - Safety and efficacy of postoperative continuous intra-peritoneal wash with lactated Ringer's for minimizing post-myomectomy pelvic adhesions: a pilot clinical trial. AB - OBJECTIVES: To assess efficacy and safety of post-operative intra-peritoneal wash with lactated Ringer's for 48h after myomectomy in reduction of adhesions compared to routine intra-operative irrigation. Study design A prospective, randomized trial that included 52 eligible participants who had undergone abdominal myomectomy. Participants were randomly allocated to a treatment group (n=26) which was subjected to continuous peritoneal wash for 48h via two intraperitoneal drains, and a control group (n=26). The incidence of de novo adhesions and their severity and extent were scored at a second-look laparoscopy 8-10 weeks postoperatively. Adhesions were graded using the local adhesion barrier scoring system score. Adverse effects were also assessed and reported. RESULTS: There was no statistically significant difference in duration of hospital stay or in the incidence of adverse events. A significantly higher proportion of adhesion-free patients was found in the treatment group [11/23, 47.8%] compared to the control group [4/21, 19%] (P<0.01). The mean number of pelvic sites covered by adhesions was significantly lower in the treatment group than in the control group (2.2+/-0.3 versus 4.6+/-0.8, P<0.05). The total adhesion score was significantly lower in the treatment group than in the control group (2.1+/-0.5 versus 4.8+/-1.4, P<0.05) and the adhesion score was significantly lower at most of the individual anatomical sites. CONCLUSIONS: Application of postoperative intraperitoneal wash with lactated Ringer's solution for 48h may have reasonable safety and efficacy in minimizing postoperative pelvic de novo adhesions following abdominal myomectomy. PMID- 25461358 TI - Small RNA molecules in endometriosis: pathogenesis and therapeutic aspects. AB - Endometriosis is one of the major female health burdens which affects the quality of life and reproductive potential of individuals. Although some treatment strategies are available, the complete cure of endometriosis is not yet possible. Investigation of new and alternative strategies for endometriosis treatment thus remains necessary. Identification of small RNA molecules and their roles in gene regulation and other cellular functions has revolutionized modern biomedical science. Several micro RNAs (miRNAs) and short interfering RNAs (siRNAs) have been found to be associated with endometriosis progression. Some of them are down regulated, while some are up-regulated. Detail profiling of miRNAs and/or siRNAs may serve as an important tool for endometriosis diagnosis. Meanwhile, targeting the specific miRNAs/siRNAs which are up-regulated in endometriosisis, or using miRNAs/siRNAs precursors, which are down-regulated in endometriosisis, have produced some success stories in endometriosis theraputics. Extensive studies on miRNAs/siRNAs may aid potential therapeutic approaches in endometriosis treatment. PMID- 25461359 TI - Morphological and immunohistochemical pattern of tubo-ovarian dysplasia and serous tubal intraepithelial carcinoma. AB - OBJECTIVE: Histopathological examination of material from prophylactic salpingo oophorectomies performed in patients at genetic risk of ovarian cancer can reveal abnormalities interpreted as possible pre-cancerous "ovarian dysplasia" and tubal precursors lesions. We sought to study the morphological features and immunohistochemical expression patterns of neoplasia-associated markers in prophylactically removed ovaries and fallopian tubes (pBSO) in comparison with a group of serous tubal intraepithelial carcinoma (STIC) and non-cancerous controls. STUDY DESIGN: Morphological features and immunohistochemical expression patterns of Ki-67 (for proliferation biomarker), p53 (key pathway of mullerian serous tumorogenesis), Bcl2 (anti-apoptotic), gammaH2AX (a double-strand breaks marker) and ALDH1 (a stem cell marker significantly associated with early-stage ovarian cancer) were blindly evaluated by two pathologists in 111 pBSO, 12 STICs and 116 non-cancerous salpingo-oophorectomies (control group) (nBSO). RESULTS: Morphological ovarian and tubal dysplasia scores were significantly higher in the pBSO than in controls (respectively, 8.8 vs 3.12, p<0.0001, for ovaries and 6.54 vs 1.58, p<0.0001 for tubes). Increased gammaH2AX expression was observed in the pBSO and STICs compared with the controls whereas expression patterns of Ki67, p53 and bcl2 were low to moderate in the pBSO group. STICs overexpressed Ki67 and p53 while bcl2 expression was low; Interestingly, ALDH1 expression was low in non dysplastic epithelium, high in dysplasia and constantly low in STICs. CONCLUSION: The morphological and immunohistochemical profile of tubo-ovarian dysplasia and STICs might be consistent with progression toward neoplastic transformation in the Serous Carcinogenesis Sequence. These changes may be pre-malignant and could represent an important phase in early neoplasia. ALDH1 activation in pBSO samples and its extinction in STICs should be considered as a target for prevention. PMID- 25461360 TI - Intracytoplasmic morphologically selected sperm injection results in improved clinical outcomes in couples with previous ICSI failures or male factor infertility: a meta-analysis. AB - The objective of this study was to perform the first meta-analysis to compare conventional intracytoplasmic sperm injection (ICSI) outcomes and intracytoplasmic morphologically selected sperm injection (IMSI) outcomes in couples with previous ICSI failures (IF) or male factor infertility (MF). A systematic review was performed by searching Medline database to identify articles reporting on the comparison between ICSI and IMSI outcomes in couples with IF or MF. The main outcome measures were the implantation, pregnancy and miscarriage rates. Thirteen studies fulfilled our predetermined criteria. The overall results of meta-analysis for implantation (OR: 2.88; CI: 2.13-3.89), pregnancy (OR: 2.07; CI: 1.22-3.50) and miscarriage rates (OR: 0.31; CI: 0.14 0.67) were in favor of IMSI in couples with IF. Additionally, the overall result of meta-analysis for implantation (OR: 1.56; CI: 1.11-2.18) and pregnancy rate (OR: 1.61; CI: 1.17-2.23) were in favor of IMSI in couples with MF. IMSI increases the odds of implantation by 50% and pregnancy by 60% in couples with MF. In light of improved clinical outcomes, we recommend promoting the IMSI method in couples with MF. Moreover, IMSI results in a 3-fold increase in implantation rate, a 2-fold increase in pregnancy rate and a 70% decrease in miscarriage rate as compared to ICSI in couples with IF, however, as no randomized evidence exists, randomized studies are needed to confirm the IMSI benefits in couples with IF. PMID- 25461361 TI - Leisure and occupational physical activity at different ages and risk of endometriosis. AB - OBJECTIVE: Cohort and case-control studies have suggested that adult physical activity (PA) may lower endometriosis risk and improve symptoms, but evidence is still controversial. To add information on leisure and occupational PA impact, if any, on endometriosis risk, we have analyzed data from a small case-control study conducted in Milan (Italy). STUDY DESIGN: Ninety cases and 90 controls (median age 35 years, range 18-76) were compared. Endometriosis was laparoscopically diagnosed within the year before interview. Information on demographic variables, menstrual and reproductive history, occupational and recreational physical activity was collected. RESULTS: A consistent protective effect emerged between leisure PA and endometriosis risk. For <2-4 and >=5h/week (reference no PA), the estimated odds ratios (ORs) were, respectively: 0.36 (95% CI 0.18-0.74) and 0.83 (95% CI 0.27-2.53) as regards PA in early adolescence; 0.31 (95% CI 0.15-0.63) and 0.78 (95% CI 0.25-2.38) as regards PA in teenage years; 0.34 (95% CI 0.12 0.94) and 0.33 (95% CI 0.08-1.28) for PA in adulthood. However, no significant trend was seen according to hours spent in leisure PA. Occupational PA did not show statistical significant differences among different types or across age classes. CONCLUSIONS: These results suggest that leisure PA in early adolescence, teenage years and adulthood may, to some extent, decrease the risk of endometriosis. In the interpretation of these results, however, the role of potential biases cannot be totally ruled out. PMID- 25461362 TI - Fallopian tube stripping forceps: a novel instrumental design for distal tubal pregnancy laparoscopy. AB - OBJECTIVE: To compare a new method using fallopian tube stripping forceps (FTSF) for salpingostomy in laparoscopic tubal pregnancy management. STUDY DESIGN: Comparative observational study. A total of 102 patients with ampullary tubal pregnancy were treated as follows: 56 patients (Group 1) underwent stripping by FTSF, and 46 patients (Group 2) underwent salpingostomy. The bleeding, operation time, persistent ectopic pregnancy (EP) rate, and the first reproductive performance were investigated. RESULTS: We found less intraoperative bleeding, shorter operation times, and lower rates of EP recurrence in Group 1 compared with Group 2. In contrast, we observed no significant differences in the persistent EP rate, the occurrences of spontaneous intrauterine pregnancy and miscarriage, and the rates of successful IVF between the two groups. CONCLUSION: For distal tubal pregnancy with an ectopic mass <=30mm, laparoscopic fallopian tube stripping assisted by FTSF may be an easy, less-damaging, conservative operational modality with lower recurrent EP compared with salpingostomy for patients who desire future pregnancy. PMID- 25461363 TI - Polymorphisms of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) and endometriosis risk: a meta-analysis. AB - Published data on the association between the glutathione S-transferases (GSTs) gene polymorphisms and endometriosis risk are inconclusive. We performed a meta analysis to clarify the association of GSTM1 and GSTT1 polymorphisms and endometriosis risk. A comprehensive search was conducted to examine all the eligible studies of GSTM1 and GSTT1 polymorphisms and endometriosis risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. A total of 18 case-control studies were included in the meta analysis of GSTM1 (2593 cases and 2732 controls) and GSTT1 (2520 cases and 2508 controls) genotypes. The overall results showed that the GSTM1 null genotype was related to an increased risk of endometriosis (OR=1.55, 95% CI=1.38-1.73). Similarly, for GSTT1 null polymorphism, moderate significantly increased risk was found (OR=1.30, 95% CI=1.13-1.50). In the subgroup analysis by ethnicity, significantly increased risks were also found among Caucasians and Asians for null GSTM1 genotype, and Asians for null GSTT1 genotype, but no correlation was noted in Caucasian populations for GSTT1 polymorphism. This meta-analysis provides strong evidence that the GSTM1 and GSTT1 polymorphisms are associated with the development of endometriosis. PMID- 25461364 TI - Clinical factors and malignancy in endometrial polyps. Analysis of 1027 cases. AB - STUDY OBJECTIVE: To assess the prevalence of polyps carrying a malignancy and match association between clinical factors and oncologic progression. STUDY DESIGN: A retrospective study (Canadian Task Force classification II-3) at a university hospital in Rome, Italy. We retrospectively analyzed data from 1027 women consecutively treated for endometrial polyps at our center in the period 2002-2011. The association of malignancy with hormonal status, tamoxifen, hypertension, symptoms, diabetes mellitus, obesity, and hormonal replacement therapy in pre- and post-menopausal women was assessed. RESULTS: Mean age was 45.8+/-10.8 years. Benign polyps accounted for 95.8% of the total, pre-malignant for 2.67%, malignant for 1.54%. Our data showed that post-menopausal and older women (>60y) with endometrial polyps have a higher risk of developing a related endometrial cancer (OR: 3.05, 95% CI [1.54, 6.19], p<0.001 and OR: 2.8, 95% CI [1.38, 5.56], p<=0.003. Also we observed that women with AUB in the post menopausal period displayed a risk of malignancy (OR: 31.1, 95% CI [10.3,111], p value <0.001). CONCLUSION: Special attention should be drawn to symptomatic post menopausal patients that appear to be at higher risk of malignancy. Symptomatic pre-menopausal women and asymptomatic post-menopausal women with polyps may be a group with intermediate-risk. These patients should undergo an individualized management plan, balancing both risks and benefits of surgical intervention after discussion with the patient. PMID- 25461365 TI - Epidural analgesia and operative delivery: a ten-year population-based cohort study in The Netherlands. AB - OBJECTIVE: To describe trends in the use of epidural analgesia (EA) and to evaluate the association of EA with operative deliveries. STUDY DESIGN: In this population-based, retrospective cohort study, women with an intention to deliver vaginally of a term, cephalic, singleton between 2000 and 2009 (n=1378458) were included. Main outcome measures were labor EA rates, unplanned caesarean section (CS), and instrumental vaginal delivery (IVD) including deliveries by either vacuum or forceps. Data were obtained from the Perinatal Registry of The Netherlands and logistic regression analyses were used. RESULTS: Among nulliparous, EA use almost tripled over the 10-year span (from 7.7% to 21.9%), while rates of CS and IVD did not change much (+2.8% and -3.3%, respectively). Among multiparous, EA use increased from 2.4% to 6.8%, while rates of CS and IVD changed slightly (+0.8% and -0.7%, respectively). Multivariable analysis showed a positive association of EA with CS, which weakened in ten years, from an adjusted OR of 2.35 (95% CI, 2.18 to 2.54) to 1.69 (95% CI, 1.60 to 1.79; p<0.001) in nulliparous, and from an adjusted OR of 3.17 (95% CI, 2.79 to 3.61) to 2.56 (95% CI, 2.34 to 2.81; p<0.001) in multiparous women. A weak inverse association between EA and IVD was found among nulliparous (adjusted OR, 0.76; 95% CI, 0.75 to 0.78), and a positive one among multiparous women (adjusted OR, 2.08; 95% CI, 2.00 to 2.16). Both associations grew slightly weaker over time. CONCLUSIONS: A near triplication of EA use in The Netherlands in ten years was accompanied by relatively stable rates of operative deliveries. The association between EA and operative delivery became weaker. This supports the idea that EA is not an important causal factor of operative deliveries. PMID- 25461366 TI - Impact of maternal brain tumours on perinatal and maternal management and outcome: a single referral centre retrospective study. AB - OBJECTIVE: To evaluate the impact of maternal brain tumours on perinatal and maternal management and outcome. STUDY DESIGN: We performed a retrospective cohort study in a single referral centre with departments of obstetrics, neurology, and neurosurgery from January 2003 to July 2011. Cases were retrieved from our hospital databases, excluding pituitary adenomas, metastasis, and vascular tumours. Postnatal follow-up was of at least 6 months. Studied parameters were tumour type, gestational age at diagnosis if applicable, neurological events, obstetrical complications, pregnancy outcome, mode of delivery, peripartum analgesia, need for specific treatments, and maternal morbidity and mortality. RESULTS: 20 women (23 pregnancies) diagnosed with a brain tumour. Overall, there were 4 terminations of pregnancy, 4 elective premature caesarean deliveries, 15 live births >=37 WG (9 caesarean and 6 vaginal deliveries), and 4 maternal deaths within 6 months postpartum. The brain tumour was diagnosed during pregnancy in 7 cases (group A), before pregnancy with preconception counselling in 10 (group B), and before pregnancy without preconception counselling in 6 (group C). In group A, there were 1 termination of pregnancy (TOP), 3 preterm elective caesarean deliveries, 3 live births >=37 WG with one vaginal delivery, and 2 maternal deaths. In group B, there were 1 elective premature caesarean delivery and 7 live births >=37 WG with 4 vaginal deliveries. In group C, there were 3 TOP, 3 live births >=37 WG with one vaginal delivery, and 2 maternal deaths. CONCLUSIONS: Poor perinatal outcome and maternal death were associated with unplanned pregnancies and tumours diagnosed during pregnancy. Vaginal birth with epidural analgesia was nevertheless observed in all groups. PMID- 25461367 TI - Dual suppression with oral contraceptive pills in GnRH antagonist cycles for patients with polycystic ovary syndrome undergoing intracytoplasmic sperm injection. AB - OBJECTIVE: To evaluate the effects of a gonadotropin-releasing hormone (GnRH) antagonist protocol, with or without oral contraceptive pill (OCP) pretreatment, in patients with polycystic ovary syndrome (PCOS) undergoing intracytoplasmic sperm injection (ICSI). STUDY DESIGN: In this retrospective cohort study, 410 infertile patients with PCOS were assessed in their first ICSI cycles between January 2006 and June 2013. In Group A (n=208), patients underwent a long luteal GnRH agonist protocol, and in Groups B (n=143) and C (n=59), patients underwent a GnRH antagonist protocol. The patients in Group C also received OCPs containing 30mg of ethinyl oestradiol and 3mg of drospirenone prior to treatment. The main outcome measures were pregnancy and ovarian hyperstimulation syndrome (OHSS) rates. RESULTS: Demographic features, body mass index, duration of infertility, serum baseline hormone levels, cycle outcomes, multiple pregnancy rates, miscarriage rates, OHSS rates, total number of Grade A embryos and total number of transferred embryos were comparable between the groups. Clinical pregnancy rates were 27.4%, 26.6% and 23.7% in Groups A, B and C, respectively (p=0.853). CONCLUSIONS: OCP pretreatment was found to have no beneficial or adverse effects in patients with PCOS undergoing a GnRH antagonist protocol for ICSI, but can be used for cycle scheduling. PMID- 25461368 TI - P-wave duration changes and dispersion in preeclampsia. AB - OBJECTIVE: The purpose of this research was to study P wave parameters to determine the association between preeclampsia and future cardiovascular risk and to study the possible correlation between P waves and severity of preeclampsia. STUDY DESIGN: In this case-control study 58 pregnant women with preeclampsia and 30 normal pregnant women were compared by measuring maximum and minimum P-wave durations and P-wave dispersion (Pd) in the late third trimester. RESULTS: Minimum P wave values were lower and Pd values were higher, both significantly, in the preeclampsia groups than in the control group. In addition, the Pd values of the severe preeclampsia group were higher compared to that of the mild preeclampsia group. CONCLUSION: Preeclampsia predisposes the patient to future cardiovascular complications including atrial or ventricular arrhythmias, but validated tools to assess the risks are yet not available. P-wave duration and Pd constitute a recent contribution to the field of noninvasive electrocardiology. Our data clearly demonstrated that minimum P wave and Pd values were significantly altered in preeclamptic pregnant women when compared to the controls. This important association can be used to screen women for increased risk in order to better target counseling regardinglifestyle modifications and to follow up and manage women with a history of preeclampsia more closely. PMID- 25461369 TI - Understanding the barriers and myths limiting the use of intrauterine contraception in nulliparous women: results of a survey of European/Canadian healthcare providers. AB - OBJECTIVES: To evaluate healthcare providers' (HCPs') knowledge, attitudes and beliefs regarding intrauterine contraception (IUC). STUDY DESIGN: HCPs in eight European countries and Canada who saw at least 20 women per month for contraception completed an online questionnaire. Responses were evaluated by country. RESULTS: In total, 1103 HCPs completed the survey: 633 obstetrician gynecologists, 335 general practitioners and 135 family planning clinicians (physician, midwife or nurse). When respondents in different countries were asked to report their three main barriers to considering IUC, predominant concerns were nulliparity (34-69%) and pelvic inflammatory disease (PID; 14-83%) for women in general, and insertion difficulty (25-83%), PID (17-83%), insertion pain (7-60%) and infertility (6-55%) for nulliparous women. In addition, 4-59% of HCPs reported that they never proactively include IUC in contraceptive counseling for a nulliparous woman, regardless of her age. Furthermore, only 30-61% of respondents correctly identified that, in the World Health Organization medical eligibility criteria for IUC, nulliparity is category 2 (benefits outweigh risks). CONCLUSIONS: HCPs in Europe and Canada have clear gaps in their knowledge regarding IUC and misplaced concerns persist, particularly regarding use of IUC in nulliparous women; the predominant misconceptions are about PID, insertion difficulty and insertion pain. Further education on the evidence is needed so that IUC is recognized as being suitable for young and nulliparous women and is included in contraceptive counseling. PMID- 25461370 TI - Depression and coping strategies of Chinese women undergoing in-vitro fertilization. AB - OBJECTIVES: To explore the relationship between coping strategies and depression, and the risk factors of depression among Chinese women in infertile couples undergoing in-vitro fertilization (IVF). STUDY DESIGN: Two hundred and eighty eight women undergoing IVF completed the Center for Epidemiologic Studies Short Depression Scale and the Brief COPE Inventory. Demographic data were collected, hormone levels were tested and oocyte numbers were counted. RESULTS: The incidence of depression was 22.6%. The prevalence of depression was higher among women who had been married for >8 years, women who had been infertile for >6 years and women with a family income <=3000 CNY/month. High basal follicle stimulating hormone, oocyte number and denial score were associated with greater risk of depression. High oestradiol (basal and peak), and substance use and humour scores were associated with lower risk of depression. CONCLUSION: Many women in infertile couples undergoing IVF have depression. Preventive interventions should be provided for women with risk factors of depression, such as long duration of marriage, long duration of infertility, low monthly family income, high basal follicle-stimulating hormone, low serum oestradiol, high oocyte number, and use of denial as a coping strategy. PMID- 25461371 TI - Modified cervicopexy: a novel, less-invasive technique for Stages III and IV uterine prolapse. AB - OBJECTIVE: To evaluate modified anterior abdominal wall cervicopexy (AWC) as a less invasive (via 3-cm minilaparotomy) and more augmented (via securing posterior vaginal wall to uterosacral ligaments) technique. METHODS: Case series of 30 women with Stages III and IV apical uterine prolapse assessed by the pelvic organ prolapse quantification system. RESULTS: The modified AWC procedure was performed successfully for 17 cases with Stage III uterovaginal prolapse and 13 cases with Stage IV uterovaginal prolapse. The procedure was conducted safely with no operative or postoperative complications, apart from two cases with postoperative urinary retention. Operative time ranged from 45 to 70min. Follow up was available for 1-3 years. Overall, 27 cases were satisfied with the procedure, and three cases developed recurrence after caesarean section due to cutting the supporting sutures. CONCLUSIONS: The modified AWC procedure is less invasive, simple and effective for Stages III and IV uterine prolapse. PMID- 25461372 TI - A randomized study comparing the side effects and hormonal status of triptorelin and leuprorelin following conservative laparoscopic surgery for ovarian endometriosis in Chinese women. AB - OBJECTIVES: Different gonadotropin-releasing-hormone agonist (GnRH-a) formulations with different potency and associated side effects, therefore, different compliance and persistence of therapy. This study was to evaluate the difference of hormonal profile and side effects due to hypoestrogenic status after treatment of leuprorelin and triptorelin in Chinese women with ovarian endometrioma after conservative surgical treatment. STUDY DESIGN: A total of 302 women underwent laparoscopic excision of ovarian endometriomas with rASRM III and IV were enrolled in the study.Subjects were randomized into two groups with use of a random table. Twenty two patients dropped out during the study. Thus 142 patients had three doses of i.m. leuprorelin (group A) and 138 patients had three doses of i.m. triptorelin(group B) at 4 weeks intervals after surgical treatment. Menopausal symptoms were evalutaed using a questionnaire and serum sex hormonal levels were also measured during the follow-up. RESULTS: At week 4 after the treatment, most of the patients in leuprorelin group have no obvious side effects. After 9 weeks, bone pain, hot flashes and sweating, and irregular bleeding were the main side effects and showed no difference between the groups. Anxiety, depression, vaginal dryness, headache, and acne rates were all significantly higher in triptorelin group than in leuprorelin group. A significant difference in FSH (p=0.003), LH (p=0.026) and E2 (p=0.002) levels between the groups were observed after 21 days of the GnRHa treatment. The FSH (p=0.021) and E2 (p=0.033) levels remained higher in the leuprorelin group than the triptorelin group after six weeks of treatment, but the difference of LH(p=0.917) level was no longer discernible. CONCLUSION: Leuprorelin in down regulating the pituitary-ovarian function was more moderate, and the hormonal levels decrease progressively and gradually, therefore, with lower rate of menopausal symptoms. Leuprorelin acetate maybe better tolerated than triptorelin. PMID- 25461373 TI - Pain during diagnostic hysteroscopy: what is the role of the cervical canal? A pilot study. AB - OBJECTIVE: To evaluate whether a correlation exists between the pain perceived during diagnostic anesthesia-free hysteroscopy and the characteristics of the cervical canal. STUDY DESIGN: Prospective observational pilot study of 255 women undergoing diagnostic hysteroscopy. Data analysis included characteristics of the patient and the cervical canal, and the pain experience during the procedure, assessed by visual analog score (VAS). A multiple logistic regression was then carried out in order to exclude confounding factors. RESULTS: The degree of pain during hysteroscopy was equal to a median VAS score of 2 (range 0-10). Bivariate analysis between patients with VAS>3 and patients with VAS<=3 demonstrated a significant correlation between pain and the presence of synechiae in the cervical canal (P=0.022), the patient's age (P=0.003) and parity (P=0.001). Multivariate analysis revealed that the presence of cervical synechiae (P=0.0001) [OR=4.99 (95% CI 2.13-11.70)] and parity (P=0.014) [OR=0.42 (95% CI 0.21-0.83)] were significantly correlated with pain. There was no significant correlation with the different angles of the cervical canal. CONCLUSION: Cervical synechiae appear as a major factor influencing pain during hysteroscopy. While parity acts as a protective factor, the angle of the cervical canal does not seem to play an important role for pain during diagnostic hysteroscopy. PMID- 25461374 TI - Live birth rate with repeat microdissection TESE and intracytoplasmic sperm injection after a conventional testicular biopsy in men with nonobstructive azoospermia. AB - OBJECTIVE: To determine live birth rate via m-TESE and ICSI in men who had a previous conventional testicular biopsy. STUDY DESIGN: Retrospective study was conducted to analyze 86 m-TESE procedures for ICSI in NOA patients who had a previous conventional TESE. Only motile spermatozoa were used for ICSI and all other forms were discarded. Women under the age of 42 years and who produced at least 3 oocytes in response to controlled ovarian stimulation were included in the study. Statistical significance was tested using Student's t-test, chi(2) test and Fisher's exact test as appropriate. RESULTS: Testicular motile spermatozoa were successfully retrieved in 39 out of 47 men who had spermatozoa found in the previous biopsy (Group I), and in 6 out of 39 men with no sperm in the previous biopsy (Group II) (82.9% vs. 15.3%, respectively; p<0.01). Demographic characteristics of two groups were similar. Live birth rate per repeat m-TESE attempt via ICSI was significantly higher (23.4%, 39/47) in patients with a previous sperm-positive TESE compared to that (2.5%, 1/39) obtained in patients with a previous sperm-negative testicular biopsy (p<0.05). CONCLUSION: Repeat attempt to obtain motile spermatozoa by m-TESE following conventional TESE ensures a higher recovery and live birth rate in men who had spermatozoa found in the first recovery procedure compared to men with no spermatozoa in the first testicular biopsy. Live birth rate through ICSI is not promising after repeat m-TESE procedure in patients with a previous sperm negative testicular biopsy. PMID- 25461375 TI - Progestin-only contraception compared with extended combined oral contraceptive in women with migraine without aura: a retrospective pilot study. AB - OBJECTIVE: To evaluate the effect of a desogestrel progestogen-only pill (POP) compared to continuous combined oral contraception (COC) on migraine patterns in women with migraine without aura. STUDY DESIGN: A retrospective analysis of prospective headache charts from migrainous women who used the POP or COC in our clinic between July 2009 and July 2013. The quality and quantity of migraine attacks and use of medications were evaluated at three and six months. Health related quality of life was evaluated after 6 months' treatment. RESULTS: Fifty three patients were evaluable for the analysis (22 in the COC group and 31 in the POP group). Six months' POP treatment led to a statistical reduction in migraine days; headache days; pain intensity; number of days with severe pain and days with pain medication. The only statistical difference between the two groups was a reduction in the number of days with pain medication in the POP group compared to the COC group (p=0.044). After 6 months' treatment a quality of life improvement was seen only in the POP group, but no statistical differences were found when comparing the two groups. CONCLUSIONS: Our preliminary data confirm that POP therapy improves migraine patterns and quality of life after 6 months' treatment in women with migraine without aura and it decreases the analgesic consumption with respect to an extended COC therapy. As POP represents a healthier opportunity, in terms of vascular risk, than combined contraception, its role in migrainous women deserves to be further investigated. PMID- 25461376 TI - Comparison of morcellator and culdotomy for extraction of uterine fibroids laparoscopically. AB - OBJECTIVE: To define a rational guideline for the removal of uterine fibroids after laparoscopic myomectomy (LM) by culdotomy or morcellator in multiparae. STUDY DESIGN: A total of 416 multiparae receiving LM were retrospectively studied between November 1997 and January 2014. Of these, 335 had fibroids removed by culdotomy and 81 by a laparoscopic 15mm electromechanical morcellator. Data on parity, number, size and weight of fibroids, operating time, specimen removal time, blood loss, postoperative stay, hospital charges and complications were recorded. The patients were analyzed in four subgroups stratified by main fibroid size and type of procedure. RESULTS: There was no significant difference in body mass index, number of fibroids removed, blood loss, complications, and hospitalization duration between the groups. For fibroids below 10cm, the morcellator was significantly faster compared to culdotomy (10min versus 12min, p<0.001). For fibroids 10cm and above, there was no significant difference in time by culdotomy compared to morcellator (24min versus 20min, p=0.497). The electromechanical morcellator was significantly more expensive. CONCLUSION: Fibroid size of 10cm may be used as a guide for the route of fibroid removal; below 10cm the morcellator is faster but more expensive, for fibroids 10cm and above, culdotomy can be considered as it has a similar removal time to the morcellator in multiparae. PMID- 25461377 TI - Dienogest in women with persistent endometriosis-related pelvic pain during norethisterone acetate treatment. AB - OBJECTIVE: To evaluate patient satisfaction at 6-months dienogest (DNG) treatment in women with symptomatic rectovaginal endometriosis who had pain persistence and were unsatisfied after 6-months of norethisterone acetate (NETA) therapy. STUDY DESIGN: This 24-weeks pilot open-label prospective study enrolled 25 women. The main outcome was the degree of patient satisfaction measured by using a Likert scale. Secondary outcomes were to evaluate differences in endometriosis-related pain, quality of life, sexual function changes and volumetric nodules changes during DNG compared to NETA treatment. RESULTS: Patient satisfaction improved at 3- and 6-months (p<0.001, respectively) treatment with DNG compared with baseline treatment with NETA. Six months DNG treatment decreased the intensity of all the endometriosis-associated pain (chronic pelvic pain, dyspareunia, dyschezia) compared to baseline (p<0.001 for all comparisons). Quality of life and quality of sexual life evaluated with the EHP-30 and FSFI, respectively, increased after 6 months treatment. The volume of the endometriotic nodules did not significantly change during treatment. CONCLUSIONS: This study confirms the efficacy of DNG in treating symptomatic women with rectovaginal endometriosis even in a particular endometriotic subpopulation of NETA "resistant" patients. Further randomized clinical trials comparing these two progestins both in first than second line are warranted. PMID- 25461378 TI - Association of neutrophil extracellular traps with endometriosis-related chronic inflammation. AB - OBJECTIVE: To study if neutrophil extracellular traps (NETs) are present in the peritoneal fluid of endometriosis patients. NETs play a crucial role in fighting against microorganisms. However, exaggerated NET production may lead to tissue damage in their vicinity in pathological conditions. Our study evaluates the presence of NETs in endometriosis peritoneal fluid. STUDY DESIGN: Peritoneal fluid (PF) was collected in a case-control study from 52 women, who underwent either diagnostic or operative laparoscopy. The control group consisted of 17 women with infertility, chronic pelvic pain, simple or functional cysts or irregular bleeding. The endometriosis group, altogether 35 patients, comprised 19 patients with stage I and II and 16 patients with stage III and IV endometriosis. First we tested whether the PF is able to stimulate NET production. Neutrophils from healthy volunteers were treated with the PF of endometriosis patients and controls and NETs were detected with Sytox orange extracellular DNA dye and immunofluorescence microscopy. Then we evaluated if NETs were already present in the collected PF using the specific myeloperoxidase (MPO)-DNA capture ELISA method, based on the MPO associated with the NET scaffold. RESULTS: The PF of endometriosis patients did not stimulate NET release from healthy granulocytes. However, pre-existent NETs could be detected in 17 endometriosis patients out of 35 (49%). In contrary, in the control group NETs were present in only 3 patients out of 17 (18%), (p=0.03, OR: 4.4). Moreover, the quantification of NETs showed a significantly higher amount of NETs in endometriosis compared to the controls (0.097 vs. 0.02, p=0.04). CONCLUSION: This is the first study, which evaluated and described the presence of NETs in the PF of endometriosis patients. Our study shows, that NETs may be involved in the complex pathophysiology of endometriosis. PMID- 25461379 TI - Renalase, kidney and cardiovascular disease: are they related or just coincidentally associated? AB - Cardiovascular diseases, including hypertension are the leading cause of death in the developed countries. Diabetes and chronic kidney disease became also more prevalent reaching almost the level of epidemy. Researchers are looking eagerly for the new risk and/or pathogenetic factors, as well as therapeutic option in these disease. It has been suggested that human kidney releases a protein named renalase into the bloodstream. It is supposed to be an enzyme which breaks down catecholamines in the blood circulation and regulate blood pressure. However, there were several doubts whether renalase exerts monoaminooxidase activity, or if it is monoaminooxidase at all. Recently, a hypothesis that it is also a cytokine was postulated. Studies on renalase polymorphisms in hypertension, cardiovascular disease or diabetes are inconsistent. Similarly, there are several discrepancies in the animal on the possible role of renalase in hypertension and cardiovascular diseases. Some studies report a protective role of renalase in acute kidney injury, whereas others showed that renalase levels were mainly dependent on kidney function, indicating rather a role of kidney in excretion of this substance. Moreover, validated assays are needed to evaluate renalase levels and activity. On one hand a deeper and more accurate link between renalase and cardiovascular diseases require further profound research, on the other hand whether or not renalase protein could be a new therapeutic target in these pathologies should also be considered. Whether renalase, discovered in 2005, might be a Holy Grail of hypertension, linking kidney and cardiovascular diseases, remains to be proven. PMID- 25461382 TI - The MPI emotional body expressions database for narrative scenarios. AB - Emotion expression in human-human interaction takes place via various types of information, including body motion. Research on the perceptual-cognitive mechanisms underlying the processing of natural emotional body language can benefit greatly from datasets of natural emotional body expressions that facilitate stimulus manipulation and analysis. The existing databases have so far focused on few emotion categories which display predominantly prototypical, exaggerated emotion expressions. Moreover, many of these databases consist of video recordings which limit the ability to manipulate and analyse the physical properties of these stimuli. We present a new database consisting of a large set (over 1400) of natural emotional body expressions typical of monologues. To achieve close-to-natural emotional body expressions, amateur actors were narrating coherent stories while their body movements were recorded with motion capture technology. The resulting 3-dimensional motion data recorded at a high frame rate (120 frames per second) provides fine-grained information about body movements and allows the manipulation of movement on a body joint basis. For each expression it gives the positions and orientations in space of 23 body joints for every frame. We report the results of physical motion properties analysis and of an emotion categorisation study. The reactions of observers from the emotion categorisation study are included in the database. Moreover, we recorded the intended emotion expression for each motion sequence from the actor to allow for investigations regarding the link between intended and perceived emotions. The motion sequences along with the accompanying information are made available in a searchable MPI Emotional Body Expression Database. We hope that this database will enable researchers to study expression and perception of naturally occurring emotional body expressions in greater depth. PMID- 25461380 TI - Increased DNA methyltransferase 1 protein expression correlates significantly with intestinal histological type and gender in gastric carcinomas. AB - PURPOSE: Promoter hypermethylation and reduced expression of many genes have been found in gastric cancer. DNA methyltransferases are enzymes potentially affecting promoter hypermethylation. MATERIAL AND METHODS: We analyzed proteins expression of DNA methyltransferase 1 and 3b by immunohistochemistry in 47 surgically resected gastric cancer samples for which clinicopathological characteristics, patient's outcome and methylation status of 11 selected tumor-related genes have been determined. Promoter methylation status of genes was assessed by methylation specific PCR. RESULTS: We found that DNMT1 and 3b were up-regulated in gastric cancer and were detected in 51.1% and 57.4% of cases, respectively. Co-expression of DNMT1 and 3b was detected in 44.7%. Correlations analysis have showed that DNMT1 overexpression was significantly correlated with gastric cancer of intestinal histological type (P=0.01) and with gender of patient (P=0.01). However, there was no correlation between DNMT1 and DNMT3b overexpression in cancer and patients outcome. Moreover, there were no clear relations between the proteins expression of DNMT1 and 3b and DNA methylation status of genes. But co expression of DNMT1 and DNMT3b was significantly associated with promoter hypermethylation of RAR-beta2 (P=0.04). CONCLUSIONS: Results from our study indicate that DNMT1 and 3b were overexpressed and could be involved in gastric tumorigenesis of intestinal histological type in the case of Tunisian patients. PMID- 25461381 TI - Trends in cardiovascular disease risk factors in people with and without diabetes mellitus: a Middle Eastern cohort study. AB - AIMS/HYPOTHESIS: To investigate secular trends in cardiovascular disease (CVD) risk factors during a decade of follow-up in a Middle Eastern cohort, and to compare observed trends between diabetic and non-diabetic populations. METHODS: In a population of 6181 participants (2622 males and 3559 females), diabetes status and CVD risk factors were evaluated in 4 study phases from 1999-2011. 1045 subjects had type 2 diabetes mellitus at baseline and 5136 participants were diabetes-free. To examine the trends of CVD risk factors, generalized estimation equation models were constructed. The interaction between the diabetes status and each phase of the study was checked in a separate model. RESULTS: During the follow-up period diabetic females significantly gained better control of their blood pressure, serum low density lipoprotein cholesterol and general and central obesity measures compared to non-diabetic counterparts, although 60% of them had high BP and 64% had high serum LDL-C levels till the end of the study. Diabetic males however, experienced significantly better control on their serum LDL-C and general and central obesity measures compared to their non-diabetic controls; but 24% of them were still smoker, 63% had high BP and 60% had high serum LDL-C levels at the end of the follow-up (all Ps interaction <0.05). Use of lipid lowering and antihypertensive medications increased consistently in both diabetic and non-diabetic populations. CONCLUSIONS/INTERPRETATION: Although CVD risk factors have been controlled to some extent among diabetic population in Iran, still high numbers of people with diabetes have uncontrolled CVD risk factors that prompt more attention. PMID- 25461384 TI - Intergroup conflict and rational decision making. AB - The literature has been relatively silent about post-conflict processes. However, understanding the way humans deal with post-conflict situations is a challenge in our societies. With this in mind, we focus the present study on the rationality of cooperative decision making after an intergroup conflict, i.e., the extent to which groups take advantage of post-conflict situations to obtain benefits from collaborating with the other group involved in the conflict. Based on dual process theories of thinking and affect heuristic, we propose that intergroup conflict hinders the rationality of cooperative decision making. We also hypothesize that this rationality improves when groups are involved in an in group deliberative discussion. Results of a laboratory experiment support the idea that intergroup conflict -associated with indicators of the activation of negative feelings (negative affect state and heart rate)- has a negative effect on the aforementioned rationality over time and on both group and individual decision making. Although intergroup conflict leads to sub-optimal decision making, rationality improves when groups and individuals subjected to intergroup conflict make decisions after an in-group deliberative discussion. Additionally, the increased rationality of the group decision making after the deliberative discussion is transferred to subsequent individual decision making. PMID- 25461385 TI - The metabolic syndrome and ECG detected left ventricular hypertrophy--influences from IGF-1 and IGF-binding protein-1. AB - BACKGROUND AND AIMS: The metabolic syndrome (MetS) is associated with an increased risk for left ventricular hypertrophy (LVH) and cardiovascular mortality. The aim of this study was to investigate potential influences from insulin-like growth factor-1 (IGF-1) and IGF binding protein-1 (IGFBP-1) on the relationship between the MetS and LVH, also taking into account the role of physical activity (PA), use of oestrogen and gender. METHODS AND RESULTS: In a population-based cross-sectional study of 60-year-old men (n = 1822) and women (n = 2049) participants underwent physical examination and laboratory tests, including electrocardiography (ECG), and completed an extensive questionnaire. Women showed higher levels of IGFBP-1 than men (37.0 vs. 28.0 ug/l, p < 0.001), and women with LVH had lower levels of IGFBP-1 than women without LVH (31.0 ug/l vs. 37.0 ug/l, p < 0.001). Furthermore, women with low levels of IGFBP-1 had a significantly increased risk of having LVH (crude OR ~ 2.5). When stratifying for PA and oestrogen, respectively, a weaker association between IGFBP-1 and LVH was demonstrated in physically active men and women, compared to inactive individuals, as well as in women using oestrogen, compared to non-users. CONCLUSION: In a representative sample of 60-year-old Swedish men and women, the main findings were higher levels of IGFBP-1 in women than in men; lower levels of IGFBP-1 in women with LVH, compared to women without LVH; and an increased risk of having LVH in women with low levels of IGFBP-1. The association between IGFBP 1 and LVH was diminished in physically active men and women, as well as in women using oestrogen. PMID- 25461387 TI - Catching a DUB in the act: novel ubiquitin-based active site directed probes. AB - Protein ubiquitylation is an important regulator of protein function, localization and half-life. It plays a key role in most cellular processes including immune signaling. Deregulation of this process is a major causative factor for many diseases. A major advancement in the identification and characterization of the enzymes that remove ubiquitin, deubiquitylases (DUBs) was made by the development of activity-based probes (ABPs). Recent advances in chemical protein synthesis and ligation methodology has yielded novel reagents for use in ubiquitylation research. We describe recent advances and discuss future directions in reagent development for studying DUBs. PMID- 25461388 TI - TNFR1-activated NF-kappaB signal transduction: regulation by the ubiquitin/proteasome system. AB - The Tumor Necrosis Factor Receptor-1 (TNFR1) is a central regulator of inflammation, cell death, and cellular proliferation. As such, alterations in TNFR1 signaling are associated with numerous diseases ranging from autoimmune syndromes to cancer. Understanding the regulation of TNFR1 signaling is therefore of considerable importance. The transduction of signaling events in the TNFR1 pathway--from ligand binding through transcriptional regulation--is regulated at nearly every step by post-translational modifications, including ubiquitination. In this review both endogenous and pharmacologic inhibitors of TNFR1 signaling, and how these impact the ubiquitin system, will be discussed. PMID- 25461386 TI - Chemical reporters for exploring ADP-ribosylation and AMPylation at the host pathogen interface. AB - Bacterial pathogens secrete protein toxins and effectors that hijack metabolites to covalently modify host proteins and interfere with their function during infection. Adenosine metabolites, such as nicotinamide adenine dinucleotide (NAD) and adenosine triphosphate (ATP), have in particular been coopted by these secreted virulence factors to reprogram host pathways. While some host targets for secreted virulence factors have been identified, other toxin and effector substrates have been elusive, which require new methods for their characterization. In this review, we focus on chemical reporters based on NAD and ATP that should facilitate the discovery and characterization of adenosine diphosphate (ADP)-ribosylation and adenylylation/AMPylation in bacterial pathogenesis and cell biology. PMID- 25461389 TI - Increased concentration of interferon lambda-3, interferon beta and interleukin 10 in the cerebrospinal fluid of patients with tick-borne encephalitis. AB - Tick-borne encephalitis (TBE) has a wide clinical spectrum, from asymptomatic to severe encephalitis, and host-dependent factors determining the outcome remain elusive. We have measured concentrations of pro-inflammatory/Th1 interferon-gamma (IFNgamma), immunomodulatory/Th2 interleukin-10 (IL-10), anti-viral type I (IFNbeta) and type III (IFNlambda3) interferons in cerebrospinal fluid (csf) and serum of 18 TBE patients, simultaneously genotyped for polymorphisms associated with the expression of genes IFNL3 (coding IFNlambda3), IL10, CD209 and CCR5. IL 10, IFNbeta and IFNlambda3 were up-regulated in csf, with IFNlambda3 level higher in patients with the milder clinical presentation (meningitis) than in meningoencephalitis. There was an increased serum IFNbeta and a tendency for increased serum IL-10 in meningitis patients. Genotype in rs12979860 locus upstream of IFNL3 was associated with IFNlambda3 expression and in rs287886 (CD209) - IL-10 expression. IL-10, IFNbeta and IFNlambda3 are expressed and play a protective role in TBE and their expression in TBE patients is associated with genetic polymorphisms. PMID- 25461390 TI - Supplemental vitamin D increases serum cytokines in those with initially low 25 hydroxyvitamin D: a randomized, double blind, placebo-controlled study. AB - The purpose of this study was to determine if vitamin D status before supplementation influences the cytokine response after supplemental vitamin D. Forty-six reportedly healthy adults (mean(SD); age, 32(7) y; body mass index (BMI), 25.3(4.5) kg/m(2); serum 25-hydroxyvitamin D (25(OH)D), 34.8(12.2) ng/mL) were randomly assigned (double blind) to one of three groups: (1) placebo (n=15), or supplemental vitamin D (cholecalciferol) at (2) 4000 (n=14) or (3) 8000IU (n=17). Supplements were taken daily for 35days. Fasting blood samples were obtained before (Baseline, Bsl) and 35-days after (35-d) supplementation. Serum 25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)D), cytokines, and intact parathyroid hormone with calcium were measured in each blood sample. Supplemental vitamin D increased serum 25(OH)D (4000IU, ~29%; 8000IU, ~57%) and 1,25(OH)D (4000IU, ~12%; 8000IU, ~38%) without altering intact parathyroid hormone or calcium. The vitamin D metabolite increases in the supplemental vitamin D groups (n=31) were dependent on initial levels as serum 25(OH)D (r=-0.63, p<0.05) and 1,25(OH)D (r=-0.45, p<0.05) at Bsl correlated with their increases after supplementation. Supplemental vitamin D increased interferon (IFN)-gamma and interleukin (IL)-10 in subjects that were vitamin D insufficient (serum 25(OH)D<29ng/mL) compared to sufficient (serum 25(OH)D?30ng/mL) at Bsl. We conclude that supplemental vitamin D increase a pro- and anti-inflammatory cytokine in those with initially low serum 25(OH)D. PMID- 25461391 TI - Critical role of TRIF and MyD88 in Mycobacterium tuberculosis Hsp70-mediated activation of dendritic cells. AB - As a potent immune regulator, heat shock protein 70 derived from Mycobacterium tuberculosis (Mtb Hsp70) has adjuvant effect and activates immune cells such as macrophages and dendritic cells (DCs). Although Toll-like receptors (TLRs) are known to involve in DCs activation by Mtb Hsp70, there is still a controversy and the underlying mechanism is not well understood. In this study, we examined whether TRIF and MyD88, the core adaptor molecules for TLRs signaling, regulate Mtb Hsp70-induced DCs activation. Although Mtb Hsp70 produced substantial level of cytokines (IL-6, IL-12p40, and TNF-alpha) in TRIF-deficient DCs in a dose dependent manner, each level was significantly lower than that in WT cells. The cytokines production was almost abolished in MyD88-deficient DCs. Consistent with cytokine results, Mtb Hsp70-induced activation of NF-kappaB and MAPKs was also impaired in both TRIF- and MyD88-deficient DCs, as compared with WT cells. Inhibitor assay revealed that NF-kappaB, ERK, and JNK, but not p38, regulate Mtb Hsp70-induced production of cytokines. In addition, the up-regulation of co stimulatory molecules and MHC class II was mostly TRIF-dependent in DCs in response Mtb Hsp70, whereas MyD88 was only partially involved. Finally, mixed leukocytes reaction (MLR) assay revealed that both TRIF and MyD88 are critical for DCs ability promoted by Mtb Hsp70 to differentiate naive T cells into effector T cells of producing IFN-gamma. Our findings suggest that both TRIF and MyD88 are essential for the activation and maturation of DCs in response to Mtb Hsp70. PMID- 25461392 TI - Substance P enhances mesenchymal stem cells-mediated immune modulation. AB - Since clinical application of MSCs requires long-term ex vivo culture inducing senescence in MSCs and reducing the therapeutic activity of transplanted MSCs, numerous efforts have been attempted to sustain the active state of MSCs. Substance P (SP) is a neuropeptide that functions to activate the cellular physiological responses of MSCs, including proliferation, migration, and secretion of specific cytokines. In this study, we explored the potential of SP to restore the weakened immune modulating activity of MSCs resulting from long term culture by measuring T cell activity and interleukin-2 (IL-2) secretion of CD4(+) Jurkat leukemic T cells and primary CD4(+) T cells. As the number of cell passages increased, the immunosuppressive function of MSCs based on T cell activity decreased. This weakened activity of MSCs could be restored by SP treatment and nullified by co-treatment of an NK1 receptor blocker. Higher levels of transforming growth factor beta 1 (TGF-beta1) secretion were noted in the medium of SP-treated late passage MSC cultures, but IL-10 levels did not change. SP-treated MSC-conditioned medium decreased T cell activity and IL-2/Interferon gamma (IFN-g) secretion in T cells even in the activation by lipopolysaccharide (LPS) or CD3/CD28 antibodies, both of which were successfully blocked by inhibiting the TGF beta signaling pathway. This stimulatory effect of SP on late passage MSCs was also confirmed in direct cell-cell contact co-culture of MSCs and CD4(+) Jurkat T cells. Collectively, our study suggests that SP pretreatment to MSCs may recover the immunosuppressive function of late passage MSCs by potentiating their ability to secrete TGF-beta1, which can enhance the therapeutic activity of ex vivo expanded MSCs in long-term culture. PMID- 25461393 TI - The effect of nitrogen containing bisphosphonates, zoledronate and alendronate, on the production of pro-angiogenic factors by osteoblastic cells. AB - Bisphosphonates (BPs) have been shown to influence angiogenesis. This may contribute to BP-associated side-effects such as osteonecrosis of the jaw (ONJ) or atypical femoral fractures (AFF). The effect of BPs on the production of angiogenic factors by osteoblasts is unclear. The aims were to investigate the effect of (1) alendronate on circulating angiogenic factors; vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) in vivo and (2) zoledronate and alendronate on the production of VEGF and ANG-1 by osteoblasts in vitro. We studied 18 post-menopausal women with T score?-2 randomized to calcium/vitamin D only (control arm, n=8) or calcium/vitamin D and alendronate 70mg weekly (treatment arm, n=10). Circulating concentrations of VEGF and ANG-1 were measured at baseline, 3, 6 and 12months. Two human osteoblastic cell lines (MG-63 and HCC1) and a murine osteocytic cell line (MLO-Y4) were treated with zoledronate or alendronate at concentrations of 10(-12)-10(-6)M. VEGF and ANG-1 were measured in the cell culture supernatant. We observed a trend towards a decline in VEGF and ANG-1 at 6 and 12months following treatment with alendronate (p=0.08). Production of VEGF and ANG-1 by the MG-63 and HCC1 cells decreased significantly by 34-39% (p<0.01) following treatment with zoledronate (10(-9)-10(-6)M). Treatment of the MG-63 cells with alendronate (10(-7) and 10(-6)) led to a smaller decrease (25 28%) in VEGF (p<0.05). Zoledronate (10(-10)-10(-)(6)M) suppressed the production of ANG-1 by MG-63 cells with a decrease of 43-49% (p<0.01). Co-treatment with calcitriol (10(-8)M) partially reversed this zoledronate-induced inhibition. BPs suppress osteoblastic production of angiogenic factors. This may explain, in part, the pathogenesis of the BP-associated side-effects. PMID- 25461394 TI - Serum levels of the adipokine Pref-1 in gestational diabetes mellitus. AB - OBJECTIVE: Pref-1 has recently been introduced as a novel insulin resistance inducing adipokine influencing adipogenesis. The role of circulating Pref-1 in patients with gestational diabetes mellitus (GDM) has not been assessed so far. METHODS: We determined circulating Pref-1 serum levels in 74 patients with GDM, as well as 74 healthy age-, body mass index (BMI-), and gestational age-matched pregnant controls. Furthermore, Pref-1 was correlated with anthropometric measures, as well as biochemical markers, of glucose homeostasis, lipid metabolism, renal function, and inflammation. RESULTS: Mean serum Pref-1 levels during pregnancy were not significantly different between patients with GDM (0.40MUg/l) and healthy controls (0.42MUg/l) (p=0.655). Multivariate analysis revealed that gestational age at blood sampling, triglycerides (TG), and creatinine independently and positively predicted Pref-1 levels (p<0.05). Furthermore, Pref-1 levels were independently and negatively associated with BMI and C reactive protein (p<0.05). CONCLUSIONS: Pref-1 is probably not a major contributor to GDM pathophysiology but might directly contribute to TG metabolism, as well as depend on gestational age and renal function. PMID- 25461395 TI - Possible chondroprotective effect of canakinumab: an in vitro study on human osteoarthritic chondrocytes. AB - Canakinumab is a human IgGkappa monoclonal antibody that neutralizes the activity of interleukin (IL)-1beta blocking interaction with IL-1beta receptors. Our study aimed to evaluate the in vitro effect of canakinumab on human osteoarthritic (OA) chondrocytes cultivated in the presence or absence of tumor necrosis factor (TNF) alpha. Articular cartilage was obtained from the femoral heads of patients with osteoarthritis (OA). Chondrocytes were incubated with two concentrations (1MUg/ml and 10MUg/ml) of canakinumab alone or with TNF-alpha (10ng/ml) for 48h. We evaluated cell viability, release of proteoglycans (PG) and nitric oxide (NO) in culture medium, inducible nitric oxide synthase (iNOS) and metalloproteinanes (MMP)-1,3,13 gene expression, apoptosis, necrosis and morphological feature by transmission electron microscopy (TEM). Canakinumab alone did not have cytotoxic effect. Cell viability was reduced significantly (p<0.001) by TNF-alpha and restored by canakinumab at both concentrations used. TNF-alpha determined a significant decrease of PG (p<0.001) and an increase of NO (p<0.001) and MMP 1,3,13 gene expression. Canakinumab significantly increased the PG levels and decreased (1MUg/ml, p<0.01; 10MUg/ml, p<0.01) NO levels in cells cultured with TNF-alpha. The NO data were confirmed by the immunocytochemistry assay for iNOS. A significant reduction of MMP-1,3,13 gene expression was induced by canakinumab. Our experiments confirmed the pro-apoptotic effect of TNF-alpha and demonstrated a protective role of canakinumab. The results concerning biochemical data were further confirmed by the morphological findings obtained by TEM. We showed that canakinumab counteracts the negative effects of TNF-alpha on OA chondrocyte cultures and may have a potential chondroprotective role in OA. PMID- 25461396 TI - Interplay between pro-inflammatory cytokines and brain oxidative stress biomarkers: evidence of parallels between butyl paraben intoxication and the valproic acid brain physiopathology in autism rat model. AB - Butyl paraben is a preservative used in food, drugs and cosmetics. Neurotoxic effect was reported recently beside the potential estrogenic activity of parabens. There is controversy as to the potential harmful effects of butyl parabens, which are suspected to contribute to autism and learning disabilities. The purpose of this study was to examine the similarities between paraben intoxication signs in the rat brain and brain markers in an autistic like rat model. This study provides evidence of many parallels between the two, including (1) oxidative stress, (2) decreased reduced glutathione levels and elevated oxidised glutathione, (3) mitochondrial dysfunction, and (4) neuroinflammation and increased pro-inflammatory cytokine levels in the brain (tumour necrosis factor-alpha, interleukin-1-beta, and interleukin-6). (5) Increased protein oxidation reported by a significant increase in 3-nitrotyrosine (3-NT)/tyrosine ratio. (6) A marked disturbance was found in the production of energy carriers (AMP, ATP and AMP/ATP ratio) in comparison with the control. The evidence suggests that paraben may, to some extent, either cause or contribute to the brain physiopathology in ASDs or pathogens that produce the brain pathology observed in the diagnosed rat model of ASD. PMID- 25461397 TI - Involvement of the TNF-alpha/TGF-beta/IDO axis in IVIg-induced immune tolerance. AB - The immune tolerance induced by IVIg treatment is generally attributed to its capacity to modulate the functions of antigen presenting cells and to induce the expansion of regulatory T cells by mechanisms that are not well-defined. Herein, we investigated the contribution of the TNF-alpha/TGF-beta/IDO axis to IVIg induced immune tolerance. We show that high dose IVIg is able to markedly increase the expression (>3 fold) of the well-known tolerogenic cytokine TGF-beta in monocytes. In addition, the expression of TNF-alpha, a pleiotropic cytokine that controls TGF-beta-induced tolerogenic effects, as well as of its cognate receptors (TNF-R1 and TNF-R2) is also significantly increased following IVIg treatment. Along with TNF-alpha, the expression of the enzyme and signaling protein IDO, known to mediate TGF-beta dependant tolerogenic effect, is similarly increased following IVIg treatment. We thus propose that the complex interplay between plasticity of immune cells and environmental modifications in which the TNF-alpha/TGF-beta/IDO axis may represent a new mechanism contributing to the development of tolerance in IVIg-treated patients. PMID- 25461398 TI - Bead-based multiplex immuno-assays for cytokines, chemokines, growth factors and other analytes: median fluorescence intensities versus their derived absolute concentration values for statistical analysis. AB - Within the scientific literature, analyses of data from bead based multiplex immunoassays are based on either median fluorescence intensities (MFI) or derived absolute concentration values (ACV) but no consideration of which set of data is the most appropriate for analysis has been published. Here we look at the variance of MFI versus their ACV from the expression of 14 analytes in plasma, using 6 commercially available kits, across 177 patients, recorded at two time points and the associated analyte standards. In total 60 micro titre plates were used resulting in 4965 MFI. In doing so we develop a new background subtraction procedure that reduced by 50% the number of out-of-range values observed in our data set. Using a linear mixed-effect model, which normalizes for assay-to-assay variation, MFI produced similar significant differences than that observed using absolute concentration values. We show that subtracting analyte blanks produces 15% negative MFI resulting in uncertainty of the data being analysed. We argue for analysis of protein expression values MFI are generally a better choice than absolute concentration values. It is argued that analyte standards are not required on each plate, or not at all, in multi-plate experiments, but knowledge of the concentration curve and the range of MFI values that fall within the limits of this curve for each analyte is required. The significance of using MFI over concentration values for the life scientist means higher statistical power and lower costs. PMID- 25461399 TI - Osteoprotegerin induces podosome disassembly in osteoclasts through calcium, ERK, and p38 MAPK signaling pathways. AB - Osteoclasts are critical for bone resorption and use podosomes to attach to bone matrix. Osteoprotegerin (OPG) is a negative regulator of osteoclast function that can affect the formation and function of podosomes. However, the signaling pathways that link OPG to podosome function have not been well characterized. Therefore, this study examined the roles of intracellular calcium and MAPKs in OPG-induced podosome disassembly in osteoclasts. We assessed the effects of the intracellular calcium chelator Bapta-AM, ERK inhibitor U0126, and p38 inhibitor SB202190 on OPG-treated osteoclast differentiation, adhesion structures, intracellular free Ca(2+) concentration and the phosphorylation state of podosome associated proteins (Pyk2 and Src). Mouse monocytic RAW 264.7 cells were differentiated to osteoclasts using RANKL (30ng/mL) and M-CSF (25ng/mL). The cells were pretreated with Bapta-AM (5MUM), U0126 (5MUM), or SB202190 (10MUM) for 30min, followed by 40ng/mL OPG for 3h. Osteoclastogenesis, adhesion structure, viability and morphology, intracellular free Ca(2+) concentration and the phosphorylation state of Pyk2 and Src were measured by TRAP staining, scanning electron microscopy, real-time cell analyzer, flow cytometry and western blotting, respectively. OPG significantly inhibited osteoclastogenesis, the formation of adhesion structures, and reduced the amount of phosphorylated Pyk2 and Src-pY527, but increased phosphorylation of Src-pY416. Bapta-AM, U0126, and SB202190 partially restored osteoclast differentiation and adhesion structures. Both Bapta-AM and U0126, but not SB202190, restored the levels of intracellular free Ca(2+) concentration, phosphorylated Pyk2 and Src-pY527. All three inhibitors blocked OPG-induced phosphorylation at Src-pY416. These results suggest OPG disrupts the attachment structures of osteoclasts and activates Src as an adaptor protein that competes for the reduced amount of phosphorylated Pyk2 through calcium- and ERK-dependent signaling pathways. p38 MAPK signaling may have a different role in OPG-induced osteoclast retraction. Our findings potentially offer novel insights into the signaling mechanisms downstream of OPG that affect osteoclast attachment to the extracellular matrix. PMID- 25461400 TI - Depletion of Foxp3+ regulatory T cells increases severity of mechanical allodynia and significantly alters systemic cytokine levels following peripheral nerve injury. AB - Neuropathic pain is a debilitating condition caused by damage to the somatosensory nervous system, such as peripheral nerve injury. The immune system, and in particular the adaptive T cell response, plays a key role in mediating such pain. Regulatory T (Treg) cells are a small subpopulation of inhibitory T cells that prevent autoimmunity, limit immunopathology and maintain immune homeostasis. Here, we investigated the effects of conditional depletion of Treg cells on mechanical allodynia and serum cytokines in mice with chronic constriction injury (CCI) of the sciatic nerve, an animal model of neuropathic pain. We demonstrate that CCI induced the infiltration of small numbers of Treg cells within effected neuronal tissue. Utilising the transgenic DEREG (DEpletion of REGulatory T cells) mice, we confirmed effective depletion of Foxp3+ Treg cells by diphtheria toxin injections. Following CCI we observed a transient, though significant, increase in pain hypersensitivity for Treg-depleted DEREG mice compared to non-Treg-depleted mice. Analysis of systemic cytokine levels demonstrated significant changes in serum cytokine expression profiles. In particular, we observed significant increases in systemic concentration of RANTES, IL-2 and IL-5, and significant decreases in IL-12 and IFN-gamma in nerve injured Treg-depleted DEREG mice. Further analysis indicated a substantial increase in the serum concentration of IL-12p40 as a direct result of Treg cell depletion. These results suggest that depletion of Foxp3+ Treg cells promote nerve injury-induced pain hypersensitivity, partially by inducing altered systemic concentrations of cytokines, which may act to regulate neuropathic pain. PMID- 25461401 TI - An anti-inflammatory property of Candida albicans beta-glucan: Induction of high levels of interleukin-1 receptor antagonist via a Dectin-1/CR3 independent mechanism. AB - BACKGROUND: Candida albicans is an opportunistic fungal pathogen that induces strong proinflammatory responses, such as IL-1beta production. Much less is known about the induction of immune modulatory cytokines, such as the IL-1 receptor antagonist (IL-1Ra) that is the main natural antagonist of IL-1, by C. albicans. METHODS: Peripheral blood mononuclear cells (PBMC) of healthy individuals were stimulated with C. albicans and different components of the fungal cell wall. The role of pathogen recognition receptors (PRRs) for the induction of IL-1beta and IL-1Ra was investigated by using specific blockers or in PBMC from Dectin-1 deficient patients. RESULTS: C. albicans induced a strong IL-1Ra response, and this induction was primarily induced by the cell-wall component beta-glucan. Blocking IL-1Ra significantly increased C. albicans beta-glucan hyphae induced IL 1beta and IL-6 production. Surprisingly, blocking the beta-glucan receptor Dectin 1 or the downstream Syk or Raf-1 pathways only marginally reduced C. albicans induced IL-1Ra production, while blocking of the complement receptor 3 (CR3), TLR2 or TLR4 had no effect. In line with this, blocking MAP kinases had little effect on Candida-induced IL-1Ra production. PBMC isolated from Dectin-1 deficient patients produced normal IL-1Ra amounts in response to C. albicans stimulation. Interestingly, the IL-1Ra synthesis induced by beta-glucan was blocked by inhibitors of the Akt/PI3K pathway. CONCLUSIONS: beta-glucan of C. albicans induces a strong IL-1Ra response, which is independent of the beta glucan receptors dectin-1 and CR3. These data strongly argue for the existence of an unknown beta-glucan receptor that specifically induces an Akt/PI3K-dependent anti-inflammatory IL-1Ra response upon recognition of C. albicans. PMID- 25461402 TI - Methylsulfonylmethane inhibits NLRP3 inflammasome activation. AB - Methylsulfonylmethane (MSM) is an organosulfur compound and the health benefits associated with MSM include inflammation. Although MSM has been shown to have various physiological effects, no study has yet focused on inflammasome activation. The inflammasome is a multiprotein complex that serves as a platform for caspase 1-dependent proteolytic maturation and secretion of interleukin-1beta (IL-1beta). In this study, we tested the effect of MSM on inflammasome activation using mouse and human macrophages. In our results, MSM significantly attenuated NLRP3 inflammasome activation in lipopolysaccharide-primed macrophages, although it had no effect on NLCR4 or AIM2 inflammasome activation. Extracts of MSM enriched vegetables presented the same inhibitory effect on NLRP3 inflammasome activation as MSM. MSM also attenuated the transcriptional expression of IL 1alpha, IL-1beta, IL-6, and NLRP3. Taken together, these results show that MSM has anti-inflammatory characteristics, interrupts NLRP3 inflammasome activation, and inhibits pro-cytokine expression. We further confirmed the intracellular mechanism of MSM in relation to NLRP3 inflammasome activation, followed by comparison with that of DMSO. Both chemicals showed a synergic effect on anti NLRP3 activation and attenuated production of mitochondrial reactive oxygen species (ROS). Thus, MSM is a selective inhibitor of NLRP3 inflammasome activation and can be developed as a supplement to control several metabolic disorders. PMID- 25461403 TI - Severe preeclampsia: association of genes polymorphisms and maternal cytokines production in Brazilian population. AB - INTRODUCTION: Preeclampsia (PE) is a multi-system disorder of pregnancy characterized by hypertension and proteinuria. Healthy pregnancy is associated with a controlled inflammatory process, which is exacerbated in PE in response to excessive placental stimuli. Gene expression levels can affect inflammation and immune regulation. It is known that differences in cytokine allele frequencies amongst populations may contribute to difference in the incidence of several diseases. OBJECTIVE: The aim of this study was to investigate the frequency of TNF-alpha, IL-6, IFN-gamma and IL-10 genes polymorphisms and their relationship with the cytokines plasma levels in PE. METHODS: A total of 281 women were included in this study; 116 with severe PE, 107 normotensive pregnant and 58 non pregnant women. Cytokine genotyping was carried out by the polymerase chain reaction. The analyzed polymorphisms were: TNF-alpha (-308 G->A), IL-10 (-1082 G >A), IL-6 (-174 G->C), and IFN-gamma (+874 A->T). Cytokine plasma levels were measured by Cytometric Bead Array method. RESULTS: A higher frequency of the IFN gamma (+874) T/T genotype in severe PE comparing to normotensive pregnant women was found (P<0.001). TNF-alpha, IL-6 and IFN-gamma plasma levels were higher in PE women compared to non-pregnant women (P<0.001; P<0.001; P=0.004). IL-6 and IFN gamma levels were also higher in PE women compared to normotensive pregnant (P<0.001; P=0.010). IL-10 levels were higher in normotensive pregnant women compared to PE (P<0.001). IFN-gamma and IL-6 genes polymorphisms influenced the genic expression in PE and normotensive pregnant women, respectively. CONCLUSIONS: These results suggest that IFN-gamma seems to play a role in PE occurrence. PMID- 25461404 TI - ADAM17 regulates IL-1 signaling by selectively releasing IL-1 receptor type 2 from the cell surface. AB - Interleukin (IL)-1 is one of the most evolutionarily conserved cytokines and plays an essential role in the regulation of innate immunity. IL-1 binds to two different receptors, IL-1R1 and IL-1R2, which share approximately 28% amino acid homology. IL-1R1 contains a cytoplasmic domain and is capable of transducing cellular signals; by contrast, IL-1R2 lacks a functional cytoplasmic domain and serves as a decoy receptor for IL-1. Interestingly, IL-1R2 is proteolytically cleaved and also functions as a soluble receptor that blocks IL-1 activity. In the present study, we examined the shedding properties of IL-1R2 and demonstrate that ADAM17 is de facto the major sheddase for IL-1R2 and that introducing a mutation into the juxta-membrane domain of IL-1R2 significantly desensitizes IL 1R2 to proteolytic cleavage. IL-1R1 was almost insensitive to ADAM17-dependent cleavage; however, the replacement of the juxta-membrane domain of IL-R1 with that of IL-1R2 significantly increased the sensitivity of IL-1R1 to shedding. Furthermore, we demonstrate that ADAM17 indirectly enhances IL-1 signaling in a cell-autonomous manner by selectively cleaving IL-1R2. Taken together, the data collected in the present study indicate that ADAM17 affects sensitivity to IL-1 by changing the balance between IL-1R1 and the decoy receptor IL-1R2. PMID- 25461405 TI - Interleukin-1 beta enhances human multipotent mesenchymal stromal cell proliferative potential and their ability to maintain hematopoietic precursor cells. AB - Multipotent mesenchymal stromal cells (MMSCs) have been demonstrated to produce mature stromal cells and maintain hematopoietic progenitor cells (HPC). It was previously demonstrated that interleukin-1 beta (IL-1 beta) stimulates the growth of the stromal microenvironment in vivo. The aim of this study was to investigate the effect of IL-1 beta treatment of human MMSCs on their proliferative potential, gene expression, immunomodulating properties, and their ability to support HPCs in vitro. Human bone marrow-derived MMSCs were cultivated in standard conditions or with IL-1 beta. The cumulative cell production was assessed for five passages. After withdrawal of IL-1 beta, MMSC clonal efficiency was investigated, and the maintenance of HPCs on top of MMSCs layers was estimated using cobblestone area forming cell (CAFC) and long-term culture initiating cell (LTC-IC) assays. The effect of untreated MMSCs or MMSCs pretreated with IL-1 beta on lymphocyte proliferation was studied by CFSE staining. The relative expression level of various genes by MMSCs was analyzed using RT-qPCR. The administration of IL-1 beta elevated MMSCs clonal efficiency and total cell production but did not affect lymphocyte proliferation. MMSCs pretreatment with IL-1 beta enhanced their ability to maintain HPCs, as detected by CAFC assay, and it altered the expression levels of genes participating in HPC regulation by stromal cells, e.g., adhesion molecules (ICAM1) and growth factors (SDF1). This study revealed the ability of IL-1 beta to stimulate MMSCs proliferation and enhance their potential to maintain HPCs. MMSCs are considered a stromal niche component in vitro. The combined in vitro and previous in vivo data suggest that IL-1 beta is a systemic regulator of the stromal microenvironment. PMID- 25461406 TI - TNF-alpha depuration is a predictor of mortality in critically ill patients under continuous veno-venous hemodiafiltration treatment. AB - INTRODUCTION: Critically ill patients with acute kidney injury (AKI) present high mortality rates. The magnitude of inflammatory response could determine the prognosis of such patients. Continuous renal replacement therapy (CRRT) may play an important role in removing inflammatory mediators in patients with AKI. AIM: To investigate whether the magnitude of inflammatory mediator's removal is associated with mortality among critically ill patients on CVVHDF, a CRRT modality. METHODS: This study consisted of 64 critically ill patients requiring CVVHDF. Plasma levels of C3a, TNF-alpha, IL-10, IL-6, IL-1beta, sTNFRI and sTNFRII were determined by enzyme-linked immunosorbent assay (ELISA) at the beginning of CVVHDF and after 24h (outlet). Clearance of cytokines during the first 24h of CVVHDF was calculated. Clinical and laboratory data were acquired from patient's records data. RESULTS: Mean age of patients requiring CVVHDF was 63years, 67.2% were men and 87.3% were Caucasian. Thirty-five (35) patients (54.7%) died. Comparing non-survivors with the group of survivors we observed higher incidence of sepsis (68.6 versus 37.9%, p<0.05), higher APACHE II score (34.8+/-7.6 versus 29.2+/-7.1, p<0.05) and higher lactate levels (23.2+/-17.6 versus 16.4+/-6.6, p<0.05). According to the inter-tertile range of TNF-alpha clearance (ITR1 (<0.54); ITR2 (0.54-2.93); ITR3 (>2.93)) we found that those patients with higher TNF-alpha removal by RRT (ITR3) had a better survival. Multivariable analysis showed that lower clearance of TNF-alpha remained independently associated with high mortality after adjustment for sex, age, use of vasoactive drugs, APACHE II score sepsis, creatinine and lactate before CVVHDF (HR: 0.179, 95% IC: 0.049-0.661, p<0.01). CONCLUSION: The attenuation of inflammatory response may be related to the lower mortality observed on those patients with higher TNF-alpha removal by CVVHDF. PMID- 25461407 TI - Predominance of PR3 specific immune response and skewed TH17 vs. T-regulatory milieu in active granulomatosis with polyangiitis. AB - OBJECTIVE: We compared levels of Th1/Th2/Th17 cytokines and T-regulatory cells in active and remitting granulomatosis with polyangiitis (GPA). METHODOLOGY: Twenty one cases of GPA in active state as well as in remitting state and 20 healthy controls (HC) were enrolled in the study. Cytokines were detected in culture supernatants of PBMCs after stimulation with proteinase-3 (PR3) and phytohemagglutinin antigen (PHA). Serum IL-17 cytokine was studied by ELISA. T regulatory cells (Tregs) were analyzed by flow cytometry. Gene expression of FOXP3 and ROR-gammat was compared by Real Time PCR. RESULTS: We observed significantly increased level of IL-17 in serum as well in culture supernatants of PBMCs after PR3 stimulation along with ROR-gammat gene expression in active disease state of GPA as compared to HC. Importantly, remitting state showed low levels of serum IL-17 with decreased ROR-gammat gene expression and increased FOXP3 expression. Using PR3 as an immunostimulant, we could demonstrate the generation of IL-17 and TNF-alpha secreting effector memory cells during remission. Reduced FOXP3 expression with reduced IL-10 levels in active disease indicated the reduced function of Tregs in active disease. CONCLUSION: We observed Th17 dominant environment in peripheral blood of patients in active state of disease, with "hyporesponsiveness", in, in vitro stimulated PBMC-in their ability to secrete TNF-alpha and IL-6. Treg numbers were unaltered but function was compromised. Targeting PR3 specific effector memory cells, to prevent relapse, and instituting anti IL-17 therapy, or modulating Tregs could be newer forms of therapy for this serious autoimmune disease. PMID- 25461408 TI - The variant rs8048002 T>C in intron 3 of the MHC2TA gene is associated with risk of developing acute coronary syndrome. AB - Recently, an intronic single nucleotide polymorphism (rs8048002) in the MHC class II transactivator gene (MHC2TA) was shown to be associated with increased susceptibility to several inflammatory diseases. The aim of the present study was to test for an association between this MHC2TA gene polymorphism and susceptibility to the risk of developing acute coronary syndromes (ACS) in a group of Mexicans patients. The single nucleotide polymorphism (rs8048002) of the MHC2TA gene was analyzed by 5' exonuclease TaqMan genotyping assays in a group of 452 patients with ACS and 456 healthy controls. The C allele and TC genotype were associated with risk of developing ACS (OR=4.55, pC=6*10(-4) and OR=4.41, pC=1.5*10(-3), respectively). Multiple logistic analysis was used for estimate risk between ACS patients and controls adjusted by cardiovascular risk factors (gender, age, hypertension, dyslipidemia, smoking, diabetes, body mass index and alcohol consumption). In this analysis, the TC+CC genotypes were significantly associated with increased risk of ACS as compared to TT genotype (OR=4.56, pC=0.004). In summary, our data suggest that the MHC2TA rs8048002 C>T gene polymorphism plays an important role in the risk of developing ACS. PMID- 25461410 TI - Interpretation of the source-specific substantive control measures of the Minamata Convention on Mercury. AB - Being persistent, toxic, and bio-accumulative, Mercury (Hg) seriously affects the environment and human health. Due to Hg's attribute of long-range environmental transport across national borders, especially through atmospheric transport, no country can fully protect its environment and human health with its own efforts, without global cooperation. The Minamata Convention on Mercury, which was formally adopted and opened for signature in October 2013, is the only global environmental regime on the control of Hg pollution. Its main substantive control measures are source-specific: its phasing-out, phasing-down, and other main substantive requirements all direct to specific categories of pollution sources through the regulation of specific sectors of the economy and social life. This Convention does not take a national quota approach to quantify the Parties' nationwide total allowable consumption or discharge of Hg or Hg compounds, nor does it quantify their nationwide total reduction requirements. This paper attempts to find the underlying reasons for this source-specific approach and offers two interpretations. One possible interpretation is that Hg might be a non threshold pollutant, i.e., a pollutant without a risk-free value of concentration. The existence of a reference dose (RfD), reference concentration (RfC), provisional tolerable weekly intake (PTWI), minimal risk level (MRL) or other similar reference values of Hg does not necessarily mean that Hg cannot be regarded as non-threshold because such reference values have scientific uncertainties and may also involve policy considerations. Another interpretation is that Hg lacks a feasibly determinable total allowable quantity. There is evidence that negotiators might have treated Hg as non-threshold, or at least accepted that Hg lacks a feasibly determinable total allowable quantity: (1) The negotiators were informed about the serious situations of the current emissions, releases, and legacy deposition; (2) the UNEP Secretariat took the position that Hg is non-threshold and should be eliminated to the maximum; (3) European countries, the USA and other western countries were in a better position to regard Hg as non-threshold and push forward a global reduction of Hg emissions and releases to the minimum; (4) the negotiators took the Stockholm Convention on Persistent Organic Pollutants (POPs) as a model; and (5) a fairly large number of non-governmental organizations (NGOs) were organized under umbrella NGO networks such as the Zero Mercury Working Group (ZMWG) and the International POPs Elimination Network (IPEN) and made a significant contribution to the negotiation process. The interpretations for the Minamata Convention might similarly be used to interpret the source-specific approach of the Stockholm Convention on POPs and the national quota approach of global environmental regimes on stratospheric ozone and climate mitigation. These two interpretations focus on the features of the pollutants and for this reason may be useful for future negotiators of other international environmental treaties to select appropriate models. They also suggest that the source-specific approach may be adopted in the future for pollutants with similar features of being possibly non-threshold and without a feasibly determinable total allowable quantity. PMID- 25461409 TI - Dishevelled binds the Discs large 'Hook' domain to activate GukHolder-dependent spindle positioning in Drosophila. AB - Communication between cortical cell polarity cues and the mitotic spindle ensures proper orientation of cell divisions within complex tissues. Defects in mitotic spindle positioning have been linked to various developmental disorders and have recently emerged as a potential contributor to tumorigenesis. Despite the importance of this process to human health, the molecular mechanisms that regulate spindle orientation are not fully understood. Moreover, it remains unclear how diverse cortical polarity complexes might cooperate to influence spindle positioning. We and others have demonstrated spindle orientation roles for Dishevelled (Dsh), a key regulator of planar cell polarity, and Discs large (Dlg), a conserved apico-basal cell polarity regulator, effects which were previously thought to operate within distinct molecular pathways. Here we identify a novel direct interaction between the Dsh-PDZ domain and the alternatively spliced "I3-insert" of the Dlg-Hook domain, thus establishing a potential convergent Dsh/Dlg pathway. Furthermore, we identify a Dlg sequence motif necessary for the Dsh interaction that shares homology to the site of Dsh binding in the Frizzled receptor. Expression of Dsh enhanced Dlg-mediated spindle positioning similar to deletion of the Hook domain. This Dsh-mediated activation was dependent on the Dlg-binding partner, GukHolder (GukH). These results suggest that Dsh binding may regulate core interdomain conformational dynamics previously described for Dlg. Together, our results identify Dlg as an effector of Dsh signaling and demonstrate a Dsh-mediated mechanism for the activation of Dlg/GukH dependent spindle positioning. Cooperation between these two evolutionarily conserved cell polarity pathways could have important implications to both the development and maintenance of tissue homeostasis in animals. PMID- 25461411 TI - The use of constructed wetlands for removal of pesticides from agricultural runoff and drainage: a review. AB - Pesticides are used in modern agriculture to increase crop yields, but they may pose a serious threat to aquatic ecosystems. Pesticides may enter water bodies through diffuse and point sources, but diffuse sources are probably the most important. Among diffuse pollution, surface runoff and erosion, leaching and drainage represent the major pathways. The most commonly used mitigation techniques to prevent pesticide input into water bodies include edge-of-field and riparian buffer strips, vegetated ditches and constructed wetlands. The first attempts to use wetland macrophytes for pesticide removal were carried out as early as the 1970s, but only in the last decade have constructed wetlands for pesticide mitigation become widespread. The paper summarizes 47 studies in which removal of 87 pesticides was monitored. The survey revealed that constructed wetlands with free water surface are the most commonly used type. Also, it has been identified that removal of pesticides is highly variable. The results of the survey revealed that the highest pesticide removal was achieved for pesticides of the organochlorine, strobilurin/strobin, organosphosphate and pyrethroid groups while the lowest removals were observed for pesticides of the triazinone, aryloxyalkanoic acid and urea groups. The removal of pesticides generally increases with increasing value of KOC but the relationship is not strong. PMID- 25461412 TI - Projecting future air pollution-related mortality under a changing climate: progress, uncertainties and research needs. AB - BACKGROUND: Climate change may affect mortality associated with air pollutants, especially for fine particulate matter (PM2.5) and ozone (O3). Projection studies of such kind involve complicated modelling approaches with uncertainties. OBJECTIVES: We conducted a systematic review of researches and methods for projecting future PM2.5-/O3-related mortality to identify the uncertainties and optimal approaches for handling uncertainty. METHODS: A literature search was conducted in October 2013, using the electronic databases: PubMed, Scopus, ScienceDirect, ProQuest, and Web of Science. The search was limited to peer reviewed journal articles published in English from January 1980 to September 2013. DISCUSSION: Fifteen studies fulfilled the inclusion criteria. Most studies reported that an increase of climate change-induced PM2.5 and O3 may result in an increase in mortality. However, little research has been conducted in developing countries with high emissions and dense populations. Additionally, health effects induced by PM2.5 may dominate compared to those caused by O3, but projection studies of PM2.5-related mortality are fewer than those of O3-related mortality. There is a considerable variation in approaches of scenario-based projection researches, which makes it difficult to compare results. Multiple scenarios, models and downscaling methods have been used to reduce uncertainties. However, few studies have discussed what the main source of uncertainties is and which uncertainty could be most effectively reduced. CONCLUSIONS: Projecting air pollution-related mortality requires a systematic consideration of assumptions and uncertainties, which will significantly aid policymakers in efforts to manage potential impacts of PM2.5 and O3 on mortality in the context of climate change. PMID- 25461413 TI - An overview on the advanced oxidation processes applied for the treatment of water pollutants defined in the recently launched Directive 2013/39/EU. AB - Environmental pollution is a recognized issue of major concern since a wide range of contaminants has been found in aquatic environment at ngL(-1) to MUgL(-1) levels. In the year 2000, a strategy was defined to identify the priority substances concerning aquatic ecosystems, followed by the definition of environmental quality standards (EQS) in 2008. Recently it was launched the Directive 2013/39/EU that updates the water framework policy highlighting the need to develop new water treatment technologies to deal with such problem. This review summarizes the data published in the last decade regarding the application of advanced oxidation processes (AOPs) to treat priority compounds and certain other pollutants defined in this Directive, excluding the inorganic species (cadmium, lead, mercury, nickel and their derivatives). The Directive 2013/39/EU includes several pesticides (aldrin, dichlorodiphenyltrichloroethane, dicofol, dieldrin, endrin, endosulfan, isodrin, heptachlor, lindane, pentachlorophenol, chlorpyrifos, chlorfenvinphos, dichlorvos, atrazine, simazine, terbutryn, diuron, isoproturon, trifluralin, cypermethrin, alachlor), solvents (dichloromethane, dichloroethane, trichloromethane and carbon tetrachloride), perfluorooctane sulfonic acid and its derivatives (PFOS), polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), nonylphenol and octylphenol, as well as the three compounds included in the recommendation for the first watch list of substances (diclofenac, 17-alpha-ethinylestradiol (EE2) and 17-beta-estradiol (E2)). Some particular pesticides (aclonifen, bifenox, cybutryne, quinoxyfen), organotin compounds (tributyltin), dioxins and dioxin-like compounds, brominated diphenylethers, hexabromocyclododecanes and di(2-ethylhexyl)phthalate are also defined in this Directive, but studies dealing with AOPs are missing. AOPs are recognized tools to destroy recalcitrant compounds or, at least, to transform them into biodegradable species. Diuron (a phenylurea herbicide) and atrazine (from the triazine chemical class) are the most studied pesticides from Directive 2013/39/EU. Fenton-based processes are the most frequently applied to treat priority compounds in water and their efficiency typically increases with the operating temperature as well as under UV or solar light. Heterogeneous photocatalysis is the second most used treatment to destroy pollutants defined in the Directive. Ozone alone promotes the partial oxidation of pollutants, and an increase in the effluent biodegradability, but complete mineralization of pollutants is difficult. To overcome this drawback, ozonation has been combined with heterogeneous catalysts, addition of H2O2, other AOPs (such as photocatalysis) or membrane technologies. PMID- 25461414 TI - Harmonising conflicts between science, regulation, perception and environmental impact: the case of soil conditioners from bioenergy. AB - As the global population is expected to reach 9 billion by 2050, humanity needs to balance an ever increasing demand for food, energy and natural resources, with sustainable management of ecosystems and the vital services that they provide. The intensification of agriculture, including the use of fertilisers from finite sources, has resulted in extensive soil degradation, which has increased food production costs and CO2 emissions, threatening food security. The Bioenergy sector has significant potential to contribute to the formation of a circular economy. This paper presents the scientific, regulatory and socioeconomic barriers to the use of the nutrient waste streams from biomass thermal conversion (ash) and anaerobic digestion (digestate) as sustainable soil amendments for use in place of traditional fertilisers. It is argued that whilst the ability of combined ash and digestate to remedy many threats to ecosystems and provide a market to incentivise the renewable bio-energy schemes is promising, a step change is required to alter perceptions of 'waste', from an expensive problem, to a product with environmental and economic value. This can only be achieved by well-informed interactions between scientists, regulators and end users, to improve the spread and speed of innovation with this sector. PMID- 25461415 TI - Organoarsenicals in poultry litter: detection, fate, and toxicity. AB - Arsenic contamination in groundwater has endangered the health and safety of millions of people around the world. One less studied mechanism for arsenic introduction into the environment is the use of organoarsenicals in animal feed. Four organoarsenicals are commonly employed as feed additives: arsanilic acid, carbarsone, nitarsone, and roxarsone. Organoarsenicals are composed of a phenylarsonic acid molecule with substituted functional groups. This review documents the use of organoarsenicals in the poultry industry, reports analytical methods available for quantifying organic arsenic, discusses the fate and transport of organoarsenicals in environmental systems, and identifies toxicological concerns associated with these chemicals. In reviewing the literature on organoarsenicals, several research needs were highlighted: advanced analytical instrumentation that allows for identification and quantification of organoarsenical degradation products; a greater research emphasis on arsanilic acid, carbarsone, and nitarsone; identification of degradation pathways, products, and kinetics; and testing/development of agricultural wastewater and solid treatment technologies for organoarsenical-laden waste. PMID- 25461416 TI - Blood pressure changes in association with black carbon exposure in a panel of healthy adults are independent of retinal microcirculation. AB - Exposure to ambient particulate matter and elevated blood pressure are risk factors for cardiovascular morbidity and mortality. Microvascular changes might be an important pathway in explaining the association between air pollution and blood pressure. The objective of the study was to evaluate the role of the retinal microcirculation in the association between black carbon (BC) exposure and blood pressure. We estimated subchronic BC exposure based on 1-week personal measurements (MU-Aethalometer, AethLabs) in 55 healthy nurses. Blood pressure and retinal microvasculature were measured on four different days (range: 2-4) during this week. Subchronic BC exposure averaged (+/- SD) 1334+/-631ng/m(3) and ranged from 338ng/m(3) to 3889ng/m(3). An increased exposure of 631ng/m(3) BC was associated with a 2.77mmHg (95% CI: 0.39 to 5.15, p=0.027) increase in systolic blood pressure, a 2.35mmHg (95% CI: 0.52 to 4.19, p=0.016) increase in diastolic blood pressure and with 5.65MUm (95% CI: 1.33 to 9.96, p=0.014) increase in central retinal venular equivalent. Mediation analysis failed to reveal an effect of retinal microvasculature in the association between blood pressure and subchronic BC exposure. In conclusion, we found a positive association between blood pressure and subchronic black carbon exposure in healthy adults. This finding adds evidence to the association between black carbon exposure and cardiovascular health effects, with elevated blood pressure as a plausible intermediate effector. Our results suggest that the changes in a person's blood pressure as a result of subchronic black carbon exposure operate independently of the retinal microcirculation. PMID- 25461417 TI - Associations between organochlorine pesticides and cognition in U.S. elders: National Health and Nutrition Examination Survey 1999-2002. AB - There is limited evidence about whether background exposure to organochlorine pesticides is related to impairment of cognitive function in general populations. This study was performed to investigate cross-sectional associations between serum concentrations of organochlorine pesticides and cognitive function, a predictor of dementia, among U.S. elders without overt dementia. Study subjects were 644 elders aged 60-85, participating in the National Health and Nutrition Examination Survey 1999-2002. We selected 6 organochlorine pesticides (p,p' dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (DDE), trans-nonachlor, oxychlordane, heptachlor epoxide, and beta hexachlorocyclohexane) which were commonly detected in current general population. Cognitive function was assessed with the Digit-Symbol Substitution Test. All 6 compounds showed statistically significant or marginally significant inverse associations with cognitive score after adjusting for covariates including education levels. The strongest association was observed with p,p'-DDT. With the outcome of low cognitive score defined as <25th percentile, elders in the highest quartile of p,p'-DDT, p,p'-DDE, and beta-hexachlorocyclohexane had 2 to 3 times higher risks than those in the lowest quartile. In particular, when their concentrations were further divided with the cutoff points of 90th and 95th percentiles, p,p'-DDT in the highest 5th percentile showed 6.5 (95% confidence interval: 2.6-16.3) times higher risk of low cognitive score. On the other hand, non-persistent pesticides like organophosphates or pyrethroid showed little association with this cognitive score. The potential role of background exposure to organochlorine pesticides in the development of dementia should be explored in future prospective studies and in-vitro/in-vivo experimental studies. PMID- 25461418 TI - Circulating levels of environmental contaminants are associated with dietary patterns in older adults. AB - BACKGROUND: Food intake contributes substantially to our exposure to environmental contaminants. Still, little is known about our dietary habits' contribution to exposure variability. OBJECTIVE: The aim of this study was to assess circulating levels of environmental contaminants in relation to predefined dietary patterns in an elderly Swedish population. METHODS: Dietary data and serum concentrations of environmental contaminants were obtained from 844 70-year old Swedish subjects (50% women) in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Dietary data from 7-day food records was used to assess adherence to a Mediterranean-like diet, a low carbohydrate-high protein diet and the WHO dietary recommendations. Circulating levels of 6 polychlorinated biphenyl markers, 3 organochlorine pesticides, 1 dioxin and 1 polybrominated diphenyl ether, the metals cadmium, lead, mercury and aluminum and serum levels of bisphenol A and 4 phthalate metabolites were investigated in relation to dietary patterns in multivariate linear regression models. RESULTS: A Mediterranean-like diet was positively associated with levels of several polychlorinated biphenyls (118, 126, 153, and 209), trans-nonachlor and mercury. A low carbohydrate-high protein diet was positively associated with polychlorinated biphenyls 118 and 153, trans-nonachlor, hexachlorobenzene and p, p'-dichlorodiphenyldichloroethylene, mercury and lead. The WHO recommended diet was negatively related to levels of dioxin and lead, and borderline positively to polychlorinated biphenyl 118 and trans-nonachlor. CONCLUSION: Dietary patterns were associated in diverse manners with circulating levels of environmental contaminants in this elderly Swedish population. Following the WHO dietary recommendations seems to be associated with a lower burden of environmental contaminants. PMID- 25461419 TI - The short-term effect of heat waves on mortality and its modifiers in China: an analysis from 66 communities. AB - BACKGROUND: Many studies have reported increased mortality risk associated with heat waves. However, few have assessed the health impacts at a nation scale in a developing country. This study examines the mortality effects of heat waves in China and explores whether the effects are modified by individual-level and community-level characteristics. METHODS: Daily mortality and meteorological variables from 66 Chinese communities were collected for the period 2006-2011. Heat waves were defined as >=2 consecutive days with mean temperature >=95th percentile of the year-round community-specific distribution. The community specific mortality effects of heat waves were first estimated using a Distributed Lag Non-linear Model (DLNM), adjusting for potential confounders. To investigate effect modification by individual characteristics (age, gender, cause of death, education level or place of death), separate DLNM models were further fitted. Potential effect modification by community characteristics was examined using a meta-regression analysis. RESULTS: A total of 5.0% (95% confidence intervals (CI): 2.9%-7.2%) excess deaths were associated with heat waves in 66 Chinese communities, with the highest excess deaths in north China (6.0%, 95% CI: 1% 11.3%), followed by east China (5.2%, 95% CI: 0.4%-10.2%) and south China (4.5%, 95% CI: 1.4%-7.6%). Our results indicate that individual characteristics significantly modified heat waves effects in China, with greater effects on cardiovascular mortality, cerebrovascular mortality, respiratory mortality, the elderly, females, the population dying outside of a hospital and those with a higher education attainment. Heat wave mortality effects were also more pronounced for those living in urban cities or densely populated communities. CONCLUSION: Heat waves significantly increased mortality risk in China with apparent spatial heterogeneity, which was modified by some individual-level and community-level factors. Our findings suggest adaptation plans that target vulnerable populations in susceptible communities during heat wave events should be developed to reduce health risks. PMID- 25461420 TI - First report of pyrethroid bioaccumulation in wild river fish: a case study in Iberian river basins (Spain). AB - For the first time, this work described pyrethroid bioaccumulation in edible river fish samples. We analyzed 42 whole fish samples collected in 4 different Iberian rivers. All samples were positive to these insecticides. Levels of concentration ranged from 12 to 4938ngg(-1) lipid weight (lw). Moreover, isomeric characterization was carried out. Our results remarked a general preference of cis isomers in bioaccumulation. Finally, the enantiomeric evaluation showed that there was an enantioselective bioaccumulation of some pyrethroids, depending on the studied species. Pyrethroid concentrations were compared with levels obtained for other common pollutants, such as flame retardants, personal care products, hormones and pharmaceuticals. The highest values corresponded to pyrethroid insecticides, even though, pyrethroid levels are safe for human consumption taken into account the current regulations. PMID- 25461421 TI - Wastewater reuse in irrigation: a microbiological perspective on implications in soil fertility and human and environmental health. AB - The reuse of treated wastewater, in particular for irrigation, is an increasingly common practice, encouraged by governments and official entities worldwide. Irrigation with wastewater may have implications at two different levels: alter the physicochemical and microbiological properties of the soil and/or introduce and contribute to the accumulation of chemical and biological contaminants in soil. The first may affect soil productivity and fertility; the second may pose serious risks to the human and environmental health. The sustainable wastewater reuse in agriculture should prevent both types of effects, requiring a holistic and integrated risk assessment. In this article we critically review possible effects of irrigation with treated wastewater, with special emphasis on soil microbiota. The maintenance of a rich and diversified autochthonous soil microbiota and the use of treated wastewater with minimal levels of potential soil contaminants are proposed as sine qua non conditions to achieve a sustainable wastewater reuse for irrigation. PMID- 25461422 TI - Neurobehavioral performance in adolescents is inversely associated with traffic exposure. AB - On the basis of animal research and epidemiological studies in children and elderly there is a growing concern that traffic exposure may affect the brain. The aim of our study was to investigate the association between traffic exposure and neurobehavioral performance in adolescents. We examined 606 adolescents. To model the exposure, we constructed a traffic exposure factor based on a biomarker of benzene (urinary trans,trans-muconic acid) and the amount of contact with traffic preceding the neurobehavioral examination (using distance-weighted traffic density and time spent in traffic). We used a Bayesian structural equation model to investigate the association between traffic exposure and three neurobehavioral domains: sustained attention, short-term memory, and manual motor speed. A one standard deviation increase in traffic exposure was associated with a 0.26 standard deviation decrease in sustained attention (95% credible interval: -0.02 to -0.51), adjusting for gender, age, smoking, passive smoking, level of education of the mother, socioeconomic status, time of the day, and day of the week. The associations between traffic exposure and the other neurobehavioral domains studied had the same direction but did not reach the level of statistical significance. The results remained consistent in the sensitivity analysis excluding smokers and passive smokers. The inverse association between sustained attention and traffic exposure was independent of the blood lead level. Our study in adolescents supports the recent findings in children and elderly suggesting that traffic exposure adversely affects the neurobehavioral function. PMID- 25461423 TI - Protective glove use and hygiene habits modify the associations of specific pesticides with Parkinson's disease. AB - Pesticides have been associated with Parkinson's disease (PD), and protective gloves and workplace hygiene can reduce pesticide exposure. We assessed whether use of gloves and workplace hygiene modified associations between pesticides and PD. The Farming and Movement Evaluation (FAME) study is a nested case-control study within the Agricultural Health Study. Use of protective gloves, other PPE, and hygiene practices were determined by questionnaire (69 cases and 237 controls were included). We considered interactions of gloves and hygiene with ever-use of pesticides for all pesticides with >=5 exposed and unexposed cases and controls in each glove-use stratum (paraquat, permethrin, rotenone, and trifluralin). 61% of respondents consistently used protective gloves and 87% consistently used >=2 hygiene practices. Protective glove use modified the associations of paraquat and permethrin with PD: neither pesticide was associated with PD among protective glove users, while both pesticides were associated with PD among non-users (paraquat OR 3.9 [95% CI 1.3, 11.7], interaction p=0.15; permethrin OR 4.3 [95% CI 1.2, 15.6] interaction p=0.05). Rotenone was associated with PD regardless of glove use. Trifluralin was associated with PD among participants who used <2 hygiene practices (OR 5.5 [95% CI 1.1, 27.1]) but was not associated with PD among participants who used 2 or more practices (interaction p=0.02). Although sample size was limited in the FAME study, protective glove use and hygiene practices appeared to be important modifiers of the association between pesticides and PD and may reduce risk of PD associated with certain pesticides. PMID- 25461425 TI - Human exposure pathways to organophosphate triesters - a biomonitoring study of mother-child pairs. AB - The worldwide ban of several formulations of brominated flame retardants has caused an increase in the production of organophosphorus flame retardants (PFRs) to meet the existing fire regulations for a wide range of household products. This biomonitoring study surveys the occurrence of the metabolites from PFRs and related plasticizers (dialkyl and diaryl phosphates; DAPs) in urine from a Norwegian mother-child cohort (48 mothers and 54 children). Concentrations of DAPs were higher in the children than in their mothers (Wilcoxon signed-rank test p=0.001). Median urinary concentrations of diphenyl phosphate (DPHP) were 1.1 and 0.51ng/mL in children and mothers, respectively, followed by bis(1,3-dichloro-2 propyl) phosphate (BDCIPP) with medians of 0.23 and 0.12ng/mL, respectively. Detection frequencies for bis(2-butoxyethyl) phosphate (BBOEP) in urine from children and mothers were 32 and 1%, respectively (median<0.18ng/mL), and for di n-butyl phosphate (DNBP) 15 and 8%, respectively (median<0.12ng/mL). The concentrations of DPHP and BDCIPP in urine from children were significantly correlated with those found for their parent compounds in air and dust from the households (Spearman's rank correlations 0.30= 65 years (OR = 2.64) and very easy communication with providers (OR = 2.43). Patient awareness of colorectal cancer screening and its benefits through effective patient-provider communication were significant modifiable predictors of adherence to colorectal cancer and polyps screening recommendations. Nurses could have a major impact in improving screening behaviors through patient education in increasing patient awareness and benefits of cancer screening. PMID- 25461461 TI - Clinical pearls for irritable bowel syndrome: management of the diarrhea predominant subtype. AB - Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that is characterized by the presence of abdominal pain or discomfort and is subtyped by the predominant stool symptoms of constipation, diarrhea, or mixed constipation and diarrhea. The diagnosis of IBS was once considered to be one of exclusion, but data now show that exhaustive tests provide very limited diagnostic yield. Instead, the symptom-based Rome criteria can be used to make a confident determination of IBS. For patients diagnosed with IBS, pharmacological decisions are based on the underlying disturbances such as abdominal pain, bowel symptoms, and urgency; how the condition affects quality of life; and symptom severity. Traditionally, treatment of IBS has focused on one or two individual symptoms rather than syndrome relief; however, emerging evidence on newer targeted treatment options is drawing clinical attention. Targeted treatment will require ongoing evaluation of disease severity, as current data show that severe IBS is more common than previously thought and severity influences treatment choices. This article reviews the disease state of IBS, answers questions about the condition, and discusses the evidence supporting current management options. PMID- 25461463 TI - The benefits of a nurse-led service in the identification and management of symptoms of irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a common, functional disorder, affecting up to 20% of the population in the Western world, becoming more prevalent in developing countries. Currently in New Zealand, patients are managed by their general practitioner but are not able to be seen in the public system as it is not a life threatening disease. This means many have no access to help. It takes significantly more time in consultation to identify causes and triggers of IBS symptoms than the average time allocated for consultation in most primary healthcare facilities. New patients seen over an 8-month period attending an advanced nurse practitioner-led IBS service in Christchurch, New Zealand, were invited to participate in a study investigating whether or not attending this service improved the identification and management of symptoms of IBS. Forty percent of patients were found to have an alternate diagnosis, the most common being inflammatory bowel disease (IBD). Forty-five patients (82%) completed 2 questionnaires 3 months apart where it was found that there was greater satisfaction in being managed by the nurse-led service than by their initial healthcare provider. There was also a significant improvement in quality of life, and a significant reduction in symptoms, symptom severity, and frequency, although there was no improvement in coping strategies. This indicates that the provision of such specialist nurse-led services can support medical colleagues by providing a specialty service for patients with symptoms of IBS or other functional disorders. PMID- 25461462 TI - Patients' experiences with cholecystitis and a cholecystectomy. AB - Nurses commonly care for patients with cholecystitis, a major health problem with a growing prevalence. Although considerable research has been done to compare patient outcomes among surgical approaches for cholecystitis, few studies have examined the experiences of patients with cholecystitis and the subsequent cholecystectomy surgery. A qualitative study with a phenomenological approach was initiated to better understand the experience of hospitalized patients with cholecystitis through their cholecystectomy surgery. Face-to-face semistructured interviews were conducted with patients diagnosed with cholecystitis and scheduled for a cholecystectomy at a rural, Midwestern hospital in the United States. Postoperative interviews were then conducted with the patients who experienced an uneventful cholecystectomy. Giorgi's technique was used to analyze postoperative narratives of the patients' cholecystectomy experiences to determine the themes. Following analysis of interview transcripts from the patients, 5 themes emerged: (a) consumed by discomfort and pain, (b) restless discomfort interrupting sleep, (c) living in uncertainty, (d) impatience to return to normalcy, and (e) feelings of vulnerability. Informants with acute cholecystitis described distressing pain before and after surgery that interfered with sleep and family responsibilities. Increased awareness is needed to prevent the disruption to daily life that can result from the cholecystitis and resulting cholecystectomy surgery. Also, nurses can help ease the unpredictability of the experience by providing relevant patient education, prompt pain relief, and an attentive approach to the nursing care. PMID- 25461464 TI - Prevalence of constipation among the general population: a community-based survey from India. AB - Constipation is a frequent health problem leading to great discomfort to the person and affects his or her quality of life. It is considered to be highly prevalent in the general population, but there is little data supporting the findings. This study was undertaken with an objective to assess the prevalence of constipation and its associated factors among the general population of Dadu Majra Colony, UT, Chandigarh, India. A total of 505 individuals were interviewed through structured questionnaire based on ROME II criteria for constipation. Results revealed that the prevalence of self-reported constipation within the last 1 year was 24.8% whereas 16.8% of participants had constipation according to the Rome II criteria. Most of the subjects (83%) were within the age group of 18 59 years with mean age (years) of 38.64 +/- 15.57. Constipation was significantly more frequent in females than in males (20% vs. 13%) and in nonworking population than in working population (20% vs. 12%). Poor dietary habits, lesser fluid intake per day, and lesser physical activity were found to be significant factors leading to the constipation. About 18% of constipated subjects reported physicians' consultation, whereas 8% reported the use of laxatives to relieve their constipation. PMID- 25461465 TI - Endoscopic and histological findings and Helicobacter pylori status in patients with reflux and/or dyspeptic symptoms: a recent Greek cohort study. AB - The associations between symptoms and endoscopic findings have not been clearly defined. We aimed to assess the associations of reflux dyspepsia and/or symptoms with specific endoscopic findings, histological findings, as well as the presence of Helicobacter pylori infection and its CagA subtype. A total of 160 patients with dyspeptic and/or reflux symptoms underwent upper gastrointestinal endoscopy. Type and severity of symptoms during the last week were evaluated according to a questionnaire. Biopsy specimens were obtained from the esophagus and stomach. Presence of H. pylori was tested in tissue specimens and its CagA subtype in serum samples. Of the 160 patients, 70% reported reflux, 73.7% dyspeptic symptoms, while 43.7% of patients reported both. The major endoscopic findings were chronic gastritis (n = 134), hiatal hernia (n = 98), and erosive esophagitis (n = 55). There was no significant difference in the endoscopic findings of patients with and without dyspepsia except for the subgroup of ulcer-like dyspeptic patients with significantly more frequently erosive peptic lesions (25% vs. 8.7%, p = .01). Patients with reflux symptoms had more frequently erosive esophagitis (42.9% vs. 14.6%, p = .001). Types of histological lesions, presence of H. pylori infection, and its cagA subtype had no statistical difference with presence or not of any symptoms. Patients with compared with those without reflux or ulcer-like dyspeptic symptoms had endoscopically more frequently erosive esophagitis and erosive peptic lesions, respectively. On the contrary, there is no statistical difference regarding the histological lesions, the presence of H. pylori, and its cagA subtype in all subgroups of patients. PMID- 25461466 TI - Colonoscopy in a patient with mitral valve prolapse: a case report. PMID- 25461467 TI - QTc interval prolongation: a real concern or exaggerated threat? PMID- 25461468 TI - Lethal infection by a novel reassortant H5N1 avian influenza A virus in a zoo housed tiger. AB - In early 2013, a Bengal tiger (Panthera tigris) in a zoo died of respiratory distress. All specimens from the tiger were positive for HPAI H5N1, which were detected by real-time PCR, including nose swab, throat swab, tracheal swab, heart, liver, spleen, lung, kidney, aquae pericardii and cerebrospinal fluid. One stain of virus, A/Tiger/JS/1/2013, was isolated from the lung sample. Pathogenicity experiments showed that the isolate was able to replicate and cause death in mice. Phylogenetic analysis indicated that HA and NA of A/Tiger/JS/1/2013 clustered with A/duck/Vietnam/OIE-2202/2012 (H5N1), which belongs to clade 2.3.2.1. Interestingly, the gene segment PB2 shared 98% homology with A/wild duck/Korea/CSM-28/20/2010 (H4N6), which suggested that A/Tiger/JS/1/2013 is a novel reassortant H5N1 subtype virus. Immunohistochemical analysis also confirmed that the tiger was infected by this new reassortant HPAI H5N1 virus. Overall, our results showed that this Bengal tiger was infected by a novel reassortant H5N1, suggesting that the H5N1 virus can successfully cross species barriers from avian to mammal through reassortment. PMID- 25461469 TI - Antigen excess in modern immunoassays: to anticipate on the unexpected. AB - Immunoassays measuring sera with high analyte concentration may be prone to an artifact that causes underestimation of the analyte concentration. This phenomenon is generally described as antigen excess or the prozone effect. Characteristically, serum with high concentrations of a certain analyte can give a false negative/low result when tested at the recommended dilution, but reacts strongly positive upon further dilution. Increased insight of the antigen excess mechanisms and tools to prevent it has reduced the analytical problems caused by prozone effects in daily laboratory practice. However, misinterpretation of laboratory results caused by antigen excess does still occur, in virtually any type of immunoassay. Awareness by the laboratory specialist of the mechanisms underlying antigen excess in the different immunoassays, strategies to detect it, and adequate communication with clinicians can help to avoid reporting false negative test-results. PMID- 25461470 TI - Autoimmune thyroid disorders. AB - Autoimmune thyroid diseases (AITD) result from a dysregulation of the immune system leading to an immune attack on the thyroid. AITD are T cell-mediated organ specific autoimmune disorders. The prevalence of AITD is estimated to be 5%; however, the prevalence of antithyroid antibodies may be even higher. The AITD comprise two main clinical presentations: Graves' disease (GD) and Hashimoto's thyroiditis (HT), both characterized by lymphocytic infiltration of the thyroid parenchyma. The clinical hallmarks of GD and HT are thyrotoxicosis and hypothyroidism, respectively. The mechanisms that trigger the autoimmune attack to the thyroid are still under investigation. Epidemiological data suggest an interaction among genetic susceptibility and environmental triggers as the key factor leading to the breakdown of tolerance and the development of disease. Recent studies have shown the importance of cytokines and chemokines in the pathogenesis of AT and GD. In thyroid tissue, recruited T helper 1 (Th1) lymphocytes may be responsible for enhanced IFN-gamma and TNF-alpha production, which in turn stimulates CXCL10 (the prototype of the IFN-gamma-inducible Th1 chemokines) secretion from the thyroid cells, therefore creating an amplification feedback loop, initiating and perpetuating the autoimmune process. Associations exist between AITD and other organ specific (polyglandular autoimmune syndromes), or systemic autoimmune disorders (Sjogren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, cryoglobulinemia, sarcoidosis, psoriatic arthritis). Moreover, several studies have shown an association of AITD and papillary thyroid cancer. These data suggest that AITD patients should be accurately monitored for thyroid dysfunctions, the appearance of thyroid nodules, and other autoimmune disorders. PMID- 25461471 TI - Exposure to non-corticosteroid treatments in adult primary immune thrombocytopenia before the chronic phase in the era of thrombopoietin receptor agonists in France. A nationwide population-based study. AB - The objective of this study was to describe the exposure to non-corticosteroid treatments in adult primary immune thrombocytopenia (ITP) patients before the chronic phase at a nationwide level. Study population is derived from the 2009 2011 cohort of the French Adult Immune Thrombocytopenia: a French pHarmacoepidemiological study (FAITH, no. ENCEPP 4574). The FAITH cohort includes all incident and persistent or chronic adult primary ITP patients treated in France. It was built through the nationwide French health insurance database, called SNIIRAM. For the present study, we included FAITH patients who were followed by at least 12 months and who had at least one exposure to a non corticosteroid treatment before the ITP chronic phase. Exposure to non corticosteroid treatments was searched through in- and out-hospital dispensing. Predictors of the choice among first-line non-corticosteroid treatments (rituximab, splenectomy or other drugs) were studied using a multinomial regression. The study population included 443 patients. Non-corticosteroid treatments used in more than 10% of the patients at any time before the chronic phase were: rituximab (57.8%), splenectomy (22.1%), TPO-RAs (16.8%), repeated intravenous immunoglobulin (IVIg) courses (15.0%), danazol (14.4%) and dapsone (10.8%). Rituximab was the most used first-line non-corticosteroid treatment (45.4%). TPO-RAs and dapsone were more frequently used after 65 years of age (respectively, 24.8% versus 12.8%, p=0.01 and 17.6% versus 7.2%, p=0.0008), unlike splenectomy (16.4% versus 25.2%, p=0.03). Age over 65 years was the sole independent predictor of first-line non-corticosteroid treatment choice. In conclusion, rituximab was the leading non-corticosteroid treatment used before the chronic phase. TPO-RAs were mainly used in accordance with their labeling. IVIgs were consistently used as a chronic non-corticosteroid treatment. PMID- 25461472 TI - Patient-level analysis of five international cohorts further confirms the efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies. AB - We performed an individual patient meta-analysis to determine whether aspirin has a significant protective effect on the risk of first thrombosis among patients with antiphospholipid antibodies (aPL). Five international cohort studies with available individual patient-level data, reporting on primary prophylaxis with continuous treatment with low-dose aspirin in patients with aPL were included. The main outcome was the occurrence of a first thrombotic in patients with aPL treated with low-dose aspirin compared to those not treated with low-dose aspirin. Pooled Hazard Ratios (HRs) and 95%CIs were calculated using frailty models. We pooled data from 497 subjects and 79 first thrombotic events (3469 patient-years of follow-up). After adjustment on cardiovascular risk factors, aPL profiles, and treatment with hydroxychloroquine, the HR for the risk of a first thrombosis of any type in aPL carriers treated with low-dose aspirin versus those not treated with aspirin was 0.43 (95%CI 0.25-0.75). Subgroup analysis showed a protective effect of aspirin against arterial (HR: 0.43 [95%CI: 0.20-0.93]) but not venous (HR: 0.49 [95%CI: 0.22-1.11]) thrombosis. Subgroup analysis according to underlying disease revealed a protective effect of aspirin against arterial thrombosis for systemic lupus erythematosus (SLE) (HR: 0.43 [95%CI: 0.20-0.94]) and asymptomatic aPL carriers (HR: 0.43 [95%CI 0.20-0.93]). We found no independent protective effect of hydroxychloroquine. This individual patient data meta-analysis shows that the risk of first thrombotic event as well of first arterial thrombotic event is significantly decreased among SLE patients and asymptomatic aPL individuals treated by low-dose aspirin. PMID- 25461474 TI - The association of uncontrolled HIV infection and other sexually transmitted infections in metropolitan Atlanta youth. AB - BACKGROUND: Half of the 19 million sexually transmitted infections (STIs) and 26% of HIV infections annually in the United States occur in youth aged 13-24 years. STIs are a risk factor for HIV acquisition and transmission, but data are lacking on HIV treatment as an intervention to reduce STIs. METHODS: A single-centered, retrospective analysis of HIV-infected sexually active adolescents and young adults from January 2009 to December 2011 was performed to compare STI incidence among patients with controlled and uncontrolled HIV and to identify associated risk factors. RESULTS: Of 205 enrolled subjects, 59% were male and 92% African American with mean age of 21 years (2.1 SD). Sixty-six percent were horizontally infected, and 19% met the definition of controlled HIV. Forty-seven percent were men who have sex with men, 76% reported condom use, 27% prior sexual abuse, 58% drug use and 50% claimed >5 lifetime sexual partners. Sixty-seven percent contracted a co-STI for a cumulative incidence rate of 35 STIs per 100 person years. Subjects with uncontrolled HIV had a significantly higher STI incidence than did subjects with controlled infection (42.7 vs. 19.7 per 100 person-years, P < 0.001). Uncontrolled individuals had more STIs (P = 0.01), sexual partners (P = 0.008) and horizontal acquisition (P = 0.001). In an adjusted logistic model, having >=1 STI was associated with older age (P = 0.033), >5 sexual partners (6 10 partners, P = 0.001; >10, P < 0.001) and no condom use (P = 0.025). Subjects with uncontrolled infection had 2.8 times [95% confidence interval (CI): 1.16 6.94] the odds of >=1 STI relative to controlled HIV. CONCLUSIONS: Uncontrolled HIV increases the incidence of co-STIs among adolescents and young adults. Interventions to improve antiretroviral compliance and reduce risk behaviors are urgently needed. PMID- 25461475 TI - Increase in fitness of Streptococcus pneumoniae is associated with the severity of necrotizing pneumonia. AB - BACKGROUND: The incidence of necrotizing pneumococcal pneumonia has increased during the past 2 decades. We hypothesized that increased pneumococcal load or augmented inflammatory cytokine production might lead to destructive pneumococcal lung disease. METHODS: This study enrolled prospectively 0- to 18-year-old children with a diagnosis of community-acquired pneumonia with pleural effusion admitted to 6 medical centers from March 2010 to April 2012. Children were diagnosed with pneumococcal empyema if the pleural fluid tested positive for quantitative pneumococcal (lytA) detection by real-time polymerase chain reaction. Pneumococcal empyema cases were further divided into 4 groups according to necrosis severity: (0) nonnecrosis, (1) mild necrosis, (2) cavitation and (3) bronchopleural fistula. Nasopharyngeal and pleural pneumococcal load, as well as levels of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, IL-8), Th1-(IL-2, IFN-gamma), Th2-(IL-4, IL-10) and Th17-cytokines (IL-17), in the pleural fluid was measured. RESULTS: Serotypes 19A and 3 accounted for 69.4% and 12.5%, respectively, of 72 cases of pneumococcal empyema. Pleural pneumococcal load was significantly higher in serotypes 19A and 3 infection than in the other strains causing infection (P = 0.006). There was a correlation between nasopharyngeal and pleural pneumococcal load (rho = 0.35; P = 0.05). In multivariate ordinal logistic regression analysis, pleural pneumococcal load (adjusted odds ratio: 1.79; 95% confidence interval: 1.03-3.06) and IL-8 (adjusted odds ratio: 2.64; 95% confidence interval: 1.21-5.75) were independent factors associated with the severity of lung necrosis. CONCLUSIONS: Evolution of Streptococcus pneumoniae toward increased fitness in their interaction with host and exaggerated IL-8 expression may be responsible for the increase of necrotizing pneumococcal pneumonia. PMID- 25461476 TI - Prevalence and predictors of bacterial meningitis in young infants with fever without a source. AB - BACKGROUND: Classical criteria differ when performing cerebrospinal fluid (CSF) analysis in infants younger than 90 days with fever without a source (FWS). Our objectives were to analyze the prevalence and microbiology of bacterial meningitis in this group and its prevalence in relation to clinical and laboratory risk factors. METHODS: This is a substudy of a prospective registry including all infants of this age with FWS seen between September 2003 and August 2013 in a Pediatric Emergency Department of a Tertiary Teaching Hospital. RESULTS: Lumbar puncture was performed in 639 (27.0%) of the 2362 infants with FWS seen, the rate being higher in not well-appearing infants [60.9% vs. 25.7%; odds ratio (OR), 4.49] and in those <=21 days old (70.1% vs. 20.4%; OR, 9.14). Eleven infants were diagnosed with bacterial meningitis: 9 were <=21 days old (prevalence 2.8% vs. 0.1%; OR, 30.42) and 5 were not well-appearing infants (5.7% vs. 0.2%; OR, 23.06). Bacteria isolated were Streptococcus agalactiae (3), Escherichia coli (3), Listeria monocytogenes (3), Streptococcus pneumoniae (1) and Neisseria meningitidis (1). None of the 1975 well-appearing infants >21 days old were diagnosed with bacterial meningitis, regardless of whether biomarkers were altered. CONCLUSIONS: In infants younger than 90 days with FWS, performing CSF analysis for ruling out bacterial meningitis must be strongly considered in not well-appearing infants and in those <=21 days old. The recommendation of systematically performing CSF analysis in well-appearing infants 22-90 days of age on the basis of analytical criteria alone must be reevaluated. PMID- 25461477 TI - A novel calibration and task guidance framework for motor imagery BCI via a tendon vibration induced sensation with kinesthesia illusion. AB - OBJECTIVE: Lack of efficient calibration and task guidance in motor imagery (MI) based brain-computer interface (BCI) would result in the failure of communication or control, especially in patients, such as a stroke with motor impairment and intact sensation, locked-in state amyotrophic lateral sclerosis, in which the sources of data for calibration may worsen the subsequent decoding. In addition, enhancing the proprioceptive experience in MI might improve the BCI performance. APPROACH: In this work, we propose a new calibrating and task guidance methodology to further improve the MI BCI, exploiting the afferent nerve system through tendon vibration stimulation to induce a sensation with kinesthesia illusion. A total of 30 subjects' experiments were carried out, and randomly divided into a control group (control-group) and calibration and task guidance group (CTG-group). MAIN RESULTS: Online experiments have shown that MI could be decoded by classifier calibrated solely using sensation data, with 8 of the 15 subjects in the CTG-Group above 80%, 3 above 95% and all above 65%. Offline chronological cross-validation analysis shows that it has reached a comparable performance with the traditional calibration method (F (1, 14) = 0.14, P = 0.7176). In addition, the discrimination accuracy of MI in the CTG-Group is significantly 12.17% higher on average than that in the control-group (unpaired-T test, P = 0.0086), and illusory sensation indicates no significant difference (unpaired-T test, p = 0.3412). The finding of the existed similarity of the discriminative brain patterns and grand averaged ERD/ERS between imagined movement (actively induced) and illusory movement (passively evoked) also validates the proposed calibration and task guidance framework. SIGNIFICANCE: The cognitive complexity of the illusory sensation task is much lower and more objective than that of MI. In addition, subjects' kinesthetic experience mentally simulated during the MI task might be enhanced by accessing sensory experiences from the illusory stimulation. This sensory stimulation aided BCI design could help make MI BCI more applicable. PMID- 25461478 TI - Asymmetric histone 3 methylation pattern between paternal and maternal pronuclei in equine zygotes. AB - Hoechst staining has traditionally been used to evaluate fertilization and parental origin of pronuclei. However, prevalence of parthenogenetic activation cannot be distinguished accurately by this protocol, and variation of relative pronuclear size and position makes it impossible to determine parental origin. We demonstrate that in equine zygotes, the epigenetic modification histone 3 lysine 9 trimethylation (H3K9me3) shows an asymmetric pattern between maternal and paternal pronuclei. H3K9me3 immunostaining appears to be a robust technique to identify the parent of origin of equine pronuclei; it can be used in combination with 5-methylcytosine and 5-hydroxymethylcytosine immunostaining and applied to evaluate fertilization. PMID- 25461479 TI - Simultaneous quantification of intracellular and secreted active and inactive glucagon-like peptide-1 from cultured cells. AB - Glucagon-like peptide-1 (GLP-1) is an incretin peptide that regulates islet hormone secretion. During recent years, incretin-based therapies have been widely used for patients with type 2 diabetes. GLP-1 peptides undergo N- and C-terminal processing for gain or loss of functions. We developed a method to quantify picomolar quantities of intact GLP-1 peptides using liquid chromatography-tandem mass spectrometry (LC-MS/MS). By employing this label-free selected reaction monitoring (SRM) method, we were able to analyze secreted GLP-1(1-37), GLP-1(7 37), and GLP-1(7-36 amid from human enteroendocrine NCI-H716 cells after stimulation with nateglinide, glucose, and sucralose. The absolute total concentrations of secreted GLP-1 peptides at baseline and after stimulation with nateglinide, glucose, and sucralose were 167.3, 498.9, 238.3, and 143.1 pM, respectively. Meanwhile, the ratios of GLP-1(1-37), GLP-1(7-37), and GLP-1(7-36 amide) to total GLP-1 peptides were similar (6 +/- 3, 26 +/- 3, and 78 +/- 5%, respectively). The SRM assay can analyze the concentrations of individual GLP-1 peptides and, therefore, is a tool to investigate the physiological roles of GLP 1 peptides. Furthermore, the molecular species secreted from NCI-H716 cells were unknown. Therefore, we performed a secretopeptidome analysis of supernatants collected from cultured NCI-H716 cells. Together with GLP-1 peptides, we detected neuroendocrine convertase 1, which regulates peptide hormones released from intestinal endocrine L-cells. PMID- 25461480 TI - Isotopic labeling of mammalian G protein-coupled receptors heterologously expressed in Caenorhabditis elegans. AB - High-resolution structural determination and dynamic characterization of membrane proteins by nuclear magnetic resonance (NMR) require their isotopic labeling. Although a number of labeled eukaryotic membrane proteins have been successfully expressed in bacteria, they lack post-translational modifications and usually need to be refolded from inclusion bodies. This shortcoming of bacterial expression systems is particularly detrimental for the functional expression of G protein-coupled receptors (GPCRs), the largest family of drug targets, due to their inherent instability. In this work, we show that proteins expressed by a eukaryotic organism can be isotopically labeled and produced with a quality and quantity suitable for NMR characterization. Using our previously described expression system in Caenorhabditis elegans, we showed the feasibility of labeling proteins produced by these worms with (15)N,(13)C by providing them with isotopically labeled bacteria. (2)H labeling also was achieved by growing C. elegans in the presence of 70% heavy water. Bovine rhodopsin, simultaneously expressed in muscular and neuronal worm tissues, was employed as the "test" GPCR to demonstrate the viability of this approach. Although the worms' cell cycle was slightly affected by the presence of heavy isotopes, the final protein yield and quality was appropriate for NMR structural characterization. PMID- 25461482 TI - Terahertz disorder-localized rotational modes and lattice vibrational modes in the orientationally-disordered and ordered phases of camphor. AB - The temperature-dependent terahertz spectra of the partially-disordered and ordered phases of camphor (C10H16O) are measured using terahertz time-domain spectroscopy. In its partially-disordered phases, a low-intensity, extremely broad resonance is found and is characterized using both a phenomenological approach and an approach based on ab initio solid-state DFT simulations. These two descriptions are consistent and stem from the same molecular origin for the broad resonance: the disorder-localized rotational correlations of the camphor molecules. In its completely ordered phase(s), multiple lattice phonon modes are measured and are found to be consistent with those predicted using solid-state DFT simulations. PMID- 25461481 TI - Development of a photoreactive probe-based system for detecting heparin. AB - We previously identified a peptide heparin-associated peptide Y (HappY) that binds specifically to heparin. In this article, we report a novel heparin detection system using chemically modified HappY as a probe. The photoreactive HappY probe was serially diluted and dispensed into a 96-well plate coated with biotinylated heparin. After ultraviolet irradiation, the HappY probe crosslinked to the heparin on the plate was detected with fluorescein isothiocyanate conjugated streptavidin. Furthermore, the photoreactive HappY probe was used to stain cutaneous tissue sections obtained from dermatitis-affected or mastocytoma affected cats and dogs. The photoreactive HappY probe stained limited resident mast cells in the connective tissue of skin compared with the anti-heparan sulfate monoclonal antibody 10E4, suggesting that the probe can be used to distinguish the structure of heparin in tissues. The interactions between glycosaminoglycans and proteins in vivo tend to be weak. Therefore, our method for enhancing such weak interactions may be a promising tool for intermolecular interaction studies in glycobiology research. PMID- 25461483 TI - Loa loa and Onchocerca ochengi miRNAs detected in host circulation. AB - A combination of deep-sequencing and bioinformatics analysis enabled identification of twenty-two microRNA candidates of potential nematode origin in plasma from Loa loa-infected baboons and a further ten from the plasma of an Onchocerca ochengi-infected cow. The obtained data were compared to results from previous work on miRNA candidates from Dirofilaria immitis and O. volvulus found in host circulating blood, to examine the species specificity of the released miRNA. None of the miRNA candidates was found to be present in all four host parasite scenarios and most of them were specific to only one of them. Eight candidate miRNAs were found to be identical in the full sequence in at least two different infections, while nine candidate miRNAs were found to be similar but not identical in at least four filarial species. PMID- 25461484 TI - Tetracycline-inducible gene expression system in Leishmania mexicana. AB - Here we present a T7-driven, tetracycline-inducible system for protein expression in human pathogen Leishmania mexicana. The gene expression in this strain is tightly regulated and dose- and time-dependent. This system can be widely used by the parasitology community to analyze effects of genes of interest on biology, physiology and virulence of parasites causing cutaneous leishmaniases. PMID- 25461485 TI - Neuropeptide Y promotes adipogenesis in chicken adipose cells in vitro. AB - Neuropeptide Y is an evolutionarily conserved neurotransmitter that stimulates food intake in higher vertebrate species and promotes adipogenesis in mammals. The objective of this study was to determine if NPY also enhances adipogenesis in birds, using chickens as a model. The stromal-vascular fraction of cells was isolated from the abdominal fat of 14 day-old broiler chicks and effects of exogenous chicken NPY on proliferation and differentiation determined. Based on a thymidine analog incorporation assay and gene expression analysis, there was no effect of NPY on proliferation during the first 12 hours post-treatment in cells that were induced to proliferate. However, there were effects of NPY treatment on proliferation and lipid accumulation during the first 6 days post-induction of differentiation. Neuropeptide Y supplementation during induction of differentiation was associated with greater glycerol-3-phosphate dehydrogenase activity and staining for neutral lipids, indicative of augmented lipid accumulation. This was also accompanied by increased proliferation during differentiation, which was characterized by up-regulation of proliferation and preadipocyte marker mRNA, and a greater number of proliferating cells in groups that were treated with NPY. Additionally, NPY treatment was associated with increased expression of fatty acid binding protein 4 and lipoprotein lipase during differentiation. In conclusion, these results suggest that NPY plays a role in promoting adipogenesis in chickens and that the mechanisms involve an increase in the synthesis of new preadipocytes and increased lipid synthesis and storage. PMID- 25461486 TI - Expression of stress-related genes in the parthenogenetic forms of the pea aphid, Acyrthosiphon pisum. AB - Aphids are an economically important group of insects that have an intricate life cycle with seasonal polyphenism. This study aimed to explore the physiological background of aphid migration from unfavorable nutritional conditions to a new, intact host plant. Specifically, the relative expression of stress/metabolism related genes and changes in metabolic reserves were determined for the winged and wingless forms of female pea aphids, Acyrthosiphon pisum, under two different nutritional conditions. The expression level was determined for the following sets of genes: the adipokinetic hormone (AKH) and its receptor, enzymes involved in carbohydrate and lipid metabolism, detoxifying enzymes, and genes encoding exoskeleton/cuticular proteins and cytoskeleton proteins. In both forms, the transcription of the adipokinetic hormone was upregulated during nutritional stress, whereas its receptor mRNA levels remained unchanged. Similarly, the expression of genes engaged in glycogen and triglyceride degradation was elevated. Glycogen reserves and phospholipids appeared to be used during stress. In comparison, nutrient rich reproductively active females of both forms appeared to use triglycerides. Moreover, we revealed changes in the mRNA level of the detoxifying genes delta-class glutathione S-transferase (GST-delta) and cytochrome P450 monooxygenase (CYP450), as well as the CP gene (which encodes exoskeleton/cuticular proteins) and the cofilin gene (the products of which influence cytoskeleton organization). These results indicate the possible correlation between nutritional stress, energy content, AKH, and the stress related enzymes of different metabolic pathways in winged and wingless forms of A. pisum. PMID- 25461487 TI - Development and characterization of an endothelial cell line from the bulbus arteriosus of walleye, Sander vitreus. AB - A cell line has been developed from the bulbus arteriosus (BA) of the walleye (WE), Sander vitreus (Mitchill), and is termed WEBA. WEBA produced collagen I, and when held at confluency for days or weeks, spontaneously formed capillary like tubes. WEBA cells bound fluorescently-labeled Ulex europaeus lectin agglutinin I (UEA-1), took up acetylated low density lipoprotein (Ac-LDL), were stained for von Willebrand factor (vWF), and produced nitric oxide (NO). The cytoskeleton consisted at least of alpha- and beta-tubulin, vimentin, and actin, with the actin organized into circumferential bundles. Immunofluorescence staining revealed at least two tight junction proteins, zonula occludens-1 (ZO-1) and claudin 3. Together these results suggest that WEBA is an endothelial cell line. Relatively high doses of 2,3,7,8-tetrachlorodibenzodioxin (TCDD) induced cytochrome P4501A (CYP1A) protein and 7-ethoxyresorufin o-deethylase (EROD) activity in WEBA. As one of the first fish endothelial and BA cell lines, WEBA should be useful in many disciplines in which the teleost cardiovascular system is a focus. PMID- 25461488 TI - Cold acclimation allows regulation of chloride secretion in a eurythermic teleost fish Fundulus heteroclitus. AB - Fundulus heteroclitus (mummichog or common killifish) is an ideal model for ion transport regulation in chloride cells of the opercular epithelium (OE) and the response to thermal challenge. Mummichogs were acclimated to warm (20 degrees C) and cold (5 degrees C) seawater and opercular epithelia dissected and mounted in isolated Ussing-style epithelia chambers. The alpha2 adrenergic agonist clonidine inhibited the Cl(-) secretion (measured as short-circuit current, Isc), while the beta-adrenergic agonist isoproterenol and 1.0mM dibutyryl cyclic adenosine monophosphate (db-cAMP) plus 0.1mM isobutyl methylxanthine (IBMX) stimulated Isc in OE from warm and cold acclimated fish, measured at 20 degrees C. In contrast, rapid cooling partially inhibited Isc, but totally blocked the inhibition by clonidine and stimulation by isoproterenol and db-cAMP+IBMX in OE from warm acclimated fish, while OE from cold-acclimated animals responded normally at 5 degrees C. Warming epithelia from 5 degrees C to 20 degrees C restored Isc and stimulation by db-cAMP+IBMX markedly increased Isc to levels similar to warm acclimated epithelia, while isoproterenol was much less effective. The isoproterenol insensitivity suggests a downregulation of beta-adrenergic receptors in the cold. We infer from present results and previous work (Buhariwalla et al. 2012) that cold shock of plasma membranes induces a phase shift from liquid to gel state that impaired plasma membrane protein mobility of necessary hormone regulatory functions, while cold acclimation preserved ion transport regulation via homeoviscous adaptation of plasma membrane lipids. PMID- 25461489 TI - High consumption of fructose rather than glucose promotes a diet-induced obese phenotype in Drosophila melanogaster. AB - During the last 20 years, there has been a considerable scientific debate about the possible mechanisms of induction of metabolic disorders by reducing monosaccharides such as glucose or fructose. In this study, we report the metabolic rearrangement in response to consumption of these monosaccharides at concentrations ranging from 0.25% to 20% in a Drosophila model. Flies raised on high-glucose diet displayed delay in pupation and increased developmental mortality compared with fructose consumers. Both monosaccharides at high concentrations promoted an obese-like phenotype indicated by increased fly body mass, levels of uric acid, and circulating and stored carbohydrates and lipids; and decreased percentage of water in the body. However, flies raised on fructose showed lower levels of circulating glucose and higher concentrations of stored carbohydrates, lipids, and uric acid. The preferential induction of obesity caused by fructose in Drosophila was associated with increased food consumption and reduced mRNA levels of DILP2 and DILP5 in the brain of adult flies. Our data show that glucose and fructose differently affect carbohydrate and lipid metabolism in Drosophila in part by modulation of insulin/insulin-like growth factor signaling. Some reported similarities with effects observed in mammals make Drosophila as a useful model to study carbohydrate influence on metabolism and development of metabolic disorders. PMID- 25461490 TI - Fullerenes: non-transition metal clusters as rechargeable magnesium battery cathodes. AB - We discovered that non-transition metal clusters have great potential as rechargeable Mg battery cathodes. Fullerene (C60), one of the prototype materials, was discharged and recharged with a remarkable rate capability. This unique rate performance is attributed to its capability to delocalize electrons on the entire cluster rather than to individual atoms. PMID- 25461492 TI - Survivors of cardiac arrest with good neurological outcome show considerable impairments of memory functioning. AB - BACKGROUND: Deficits in cognitive function are a well-known dysfunction in survivors of cardiac arrest. However, data concerning memory function in this neurological vulnerable patient collective remain scarce and inconclusive. Therefore, we aimed to assess multiple aspects of retrospective and prospective memory performance in patients after cardiac arrest. METHODS: We prospectively enrolled 33 survivors of cardiac arrest, with cerebral performance categories (CPC) 1 and 2 and a control-group (n=33) matched in sex, age and educational level. To assess retrospective and prospective memory performance we administrated 4 weeks after cardiac arrest the "Rey Adult Learning Test" (RAVLT), the "Digit-Span-Backwards Test", the "Logic-Memory Test" and the "Red-Pencil Test". RESULTS: Results indicate an impairment in immediate and delayed free recall, but not in recognition. However, the overall impairment in immediate recall was qualified by analyzing RAVLT performance, showing that patients were only impaired in trials 4 and 5 of the learning sequence. Moreover, working and prospective memory as well as prose recall were worse in cardiac arrest survivors. Cranial computed tomography was available in 61% of all patients (n=20) but there was no specific neurological damage detectable that could be linked to this cognitive impairment. CONCLUSION: Episodic long-term memory functioning appears to be particularly impaired after cardiac arrest. In contrast, short-term memory storage, even tested via free-call, seems not to be affected. Based on cranial computed tomography we suggest that global brain ischemia rather than focal brain lesions appear to underlie these effects. PMID- 25461493 TI - Minimizing pre-shock chest compression pauses in a cardiopulmonary resuscitation cycle by performing an earlier rhythm analysis. AB - BACKGROUND: Guidelines recommend 2min of CPR after defibrillation attempts followed by ECG analysis during chest compression pause. This pause may reduce the likelihood of return of spontaneous circulation (ROSC) and survival. We have evaluated the possibility of analysing the rhythm earlier in the CPR cycle in an attempt to replace immediate pre-shock rhythm analysis. METHODS AND RESULTS: The randomized Circulation Improving Resuscitation Care (CIRC) trial included patients with out of hospital cardiac arrest of presumed cardiac aetiology. Defibrillator data were used to categorize ECG rhythms as shockable or non shockable 1min post-shock and immediately before next shock. ROSC was determined from end-tidal CO2, transthoracic impedance (TTI), and patient records. TTI was used to identify chest compressions. Artefact free ECGs were categorized during periods without chest compressions. Episodes without ECG or TTI data or with undeterminable ECG rhythm were excluded. Data were analyzed using descriptive statistics. Of 1657 patients who received 3409 analysable shocks, the rhythm was shockable in 1529 (44.9%) cases 1min post-shock, 13 (0.9%) of which were no longer shockable immediately prior to next possible shock. Of these, three had converted to asystole, seven to PEA and three to ROSC. CONCLUSION: While a shockable rhythm 1min post-shock was present also immediately before next possible defibrillation attempt in most cases, three patients had ROSC. Studies are needed to document if moving the pre-shock rhythm analysis will increase shocks delivered to organized rhythms, and if it will increase shock success and survival. PMID- 25461494 TI - Design and implementation of a study evaluating extinction processes to food cues in obese children: the Intervention for Regulations of Cues Trial (iROC). AB - Obesity and its health sequelae affect a significant portion of children in the United States. Yet, the current gold-standard family-based behavioral weight-loss treatments are only effective for one-third of children long-term. Therefore, we developed iROC (Intervention for Regulation of Cues) to specifically target a method to decrease overeating in overweight children, based on learning theory, to inform and enhance interventions targeting diet and obesity in youth. This study will rigorously test extinction processes as a method of decreasing physiological and psychological responses to food cues in overweight and obese children. Through exposing children to their highly craved foods, and 'training the brain and body' to decrease overeating, we are hoping to produce longer lasting weight loss or weight-gain prevention over time. PMID- 25461495 TI - Meal-based enhancement of protein quality and quantity during weight loss in obese older adults with mobility limitations: rationale and design for the MEASUR UP trial. AB - Obese older adults with even modest functional limitations are at a disadvantage for maintaining their independence into late life. However, there is no established intervention for obesity in older individuals. The Measuring Eating, Activity, and Strength: Understanding the Response - Using Protein (MEASUR-UP) trial is a randomized controlled pilot study of obese women and men aged >=60 years with mild to moderate functional impairments. Changes in body composition (lean and fat mass) and function (Short Physical Performance Battery) in an enhanced protein weight reduction (Protein) arm will be compared to those in a traditional weight loss (Control) arm. The Protein intervention is based on evidence that older adults achieve optimal rates of muscle protein synthesis when consuming about 25-30 g of high quality protein per meal; these participants will consume ~30 g of animal protein at each meal via a combination of provided protein (beef) servings and diet counseling. This trial will provide information on the feasibility and efficacy of enhancing protein quantity and quality in the context of a weight reduction regimen and determine the impact of this intervention on body weight, functional status, and lean muscle mass. We hypothesize that the enhancement of protein quantity and quality in the Protein arm will result in better outcomes for function and/or lean muscle mass than in the Control arm. Ultimately, we hope our findings will help identify a safe weight loss approach that can delay or prevent late life disability by changing the trajectory of age-associated functional impairment associated with obesity. PMID- 25461497 TI - Arrhythmic burdens in patients with tetralogy of Fallot: a national database study. AB - BACKGROUND: Tetralogy of Fallot (TOF) is a common cyanotic congenital heart disease with increasingly recognized late morbidity. OBJECTIVE: The purpose of this study was to explore the long-term outcome by using a national database of Taiwan, a country with national health insurance and easily accessible medical care. METHODS: Data on TOF patients were retrieved from database records from 2000 to 2010. Complications and therapies were identified by their respective codes. RESULTS: We identified 4781 TOF patients (prevalence 0.63/1000 in pediatric patients and 0.06/1000 in adult patients). Arrhythmias were identified in 219 patients (8.3% for adult patients and 2.8% for pediatric patients): 160 tachycardia and 59 bradycardia (4 with tachy-bradycardia syndrome). The occurrence of arrhythmias was associated with higher mortality (excluding cardiac surgical death, 15.6% vs 8.6%, P = .001). Patients with atrial fibrillation were the oldest (median age 44.3 years), followed by those with tachy-bradycardia syndromes (32.4 years) and atrial flutter (31.5 years). The incidence of nonperioperative tachycardia increased with age (1.4%, 1.7%, 3.3%, 5.2%, 10.2%, and 16.9% in age group 0-9, 10-19, 20-29, 30-39, 40-49, and >=50 years, respectively). Tachycardia therapy (ablation and implantable cardioverter defibrillator) was administered in 20.4% (annually 2.4%) of patients with nonperioperative tachycardia. In the subgroup born 2000-2010 with complete postnatal data, mortality was 15.1% (296/1960), and 1-, 5-, and 10-year survival was 0.911, 0.826, and 0.788, respectively. Risk of atrioventricular block requiring a pacemaker was 0.6%. CONCLUSION: Arrhythmias are common in TOF patients and increase mortality risk. Medical needs because of tachycardia often appear late in adulthood. PMID- 25461496 TI - The WORD (Wholeness, Oneness, Righteousness, Deliverance): design of a randomized controlled trial testing the effectiveness of an evidence-based weight loss and maintenance intervention translated for a faith-based, rural, African American population using a community-based participatory approach. AB - BACKGROUND: The positive effects of weight loss on obesity-related risk factors diminish unless weight loss is maintained. Yet little work has focused on the translation of evidence-based weight loss interventions with the aim of sustaining weight loss in underserved populations. Using a community-based participatory approach (CBPR) that engages the strong faith-based social infrastructure characteristic of rural African American communities is a promising way to sustain weight loss in African Americans, who bear a disproportionate burden of the obesity epidemic. OBJECTIVES: Led by a collaborative community-academic partnership, The WORD aims to change dietary and physical activity behaviors to produce and maintain weight loss in rural, African American adults of faith. DESIGN: The WORD is a randomized controlled trial with 450 participants nested within 30 churches. All churches will receive a 16 session core weight loss intervention. Half of the churches will be randomized to receive an additional 12-session maintenance component. METHODS: The WORD is a cultural adaptation of the Diabetes Prevention Program, whereby small groups will be led by trained church members. Participants will be assessed at baseline, 6, 12, and 18 months. A detailed cost-effectiveness and process evaluation will be included. SUMMARY: The WORD aims to sustain weight loss in rural African Americans. The utilization of a CBPR approach and the engagement of the faith based social infrastructure of African American communities will maximize the intervention's sustainability. Unique aspects of this trial include the focus on weight loss maintenance and the use of a faith-based CBPR approach in translating evidence-based obesity interventions. PMID- 25461498 TI - Premature ICD failure associated with the use of the Merlin remote monitoring system. PMID- 25461499 TI - Reply to the Editor--why AHH? Another explanation for the AHH phenomenon in the case. PMID- 25461500 TI - Narrow complex tachycardia after ablation of the left lateral accessory pathway: what is the mechanism? PMID- 25461501 TI - To the Editor--why AHH? Another explanation for the AHH phenomenon in the case. PMID- 25461502 TI - Optimal contact forces to minimize cardiac perforations before, during, and/or after radiofrequency or cryothermal ablations. AB - BACKGROUND: Catheter perforations remain a major clinical concern during ablation procedures for treatment of atrial arrhythmias and may lead to life-threatening cardiac tamponade. Radiofrequency (RF) ablation alters the biomechanical properties of cardiac tissue, ultimately allowing for perforation to occur more readily. Studies on the effects of cryoablation on perforation force as well as studies defining the perforation force of human tissue are limited. OBJECTIVE: The purpose of this study was to investigate the required force to elicit perforation of cardiac atrial tissue after or during ablation procedures. METHODS: Effects of RF or cryothermal ablations on catheter perforation forces for both swine (n = 83 animals, 530 treatments) and human (n = 8 specimens, 136 treatments) cardiac tissue were investigated. RESULTS: Overall average forces resulting in perforation of healthy unablated tissue were 406g +/- 170g for swine and 591g +/- 240g for humans. Post-RF ablation applications considerably reduced these forces to 246g +/- 118g for swine and 362 +/- 185g for humans (P <.001). Treatments with cryoablation did not significantly alter forces required to induce perforations. Decreasing catheter sizes resulted in a reduction in forces required to perforate the atrial wall (P <.001). Catheter perforations occurred over an array of contact forces with a minimum of 38g being observed. CONCLUSION: The swine model likely underestimates the required perforation forces relative to those of human tissues. We provide novel insights related to the comparative effects of RF and cryothermal ablations on the potential for inducing undesired punctures, with RF ablation reducing perforation force significantly. These data are insightful for physicians performing ablation procedures as well as for medical device designers. PMID- 25461504 TI - WITHDRAWN: Recent advances in chemometric methods for plant metabolomics: A review. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25461505 TI - Biological insights through nontargeted metabolomics. AB - Metabolomics is increasingly employed to investigate metabolism and its reciprocal crosstalk with cellular signaling and regulation. In recent years, several nontargeted metabolomics methods providing substantial metabolome coverage have been developed. Here, we review and compare the contributions of traditional targeted and nontargeted metabolomics in advancing different research areas ranging from biotechnology to human health. Although some studies demonstrated the power of nontargeted profiling in generating unexpected and yet highly important insights, we found that most mechanistic links were still revealed by hypothesis-driven targeted methods. Novel computational approaches for formal interpretation of complex metabolic patterns and integration of complementary molecular layers are required to tap the full potential of nontargeted metabolomics for data-driven, discovery-oriented research and rapidly nucleating novel biological insights. PMID- 25461503 TI - One-carbon substrate-based biohydrogen production: microbes, mechanism, and productivity. AB - Among four basic mechanisms for biological hydrogen (H2) production, dark fermentation has been considered to show the highest hydrogen evolution rate (HER). H2 production from one-carbon (C1) compounds such as formate and carbon monoxide (CO) is promising because formate is an efficient H2 carrier, and the utilization of CO-containing syngas or industrial waste gas may render the industrial biohydrogen production process cost-effective. A variety of microbes with the formate hydrogen lyase (FHL) system have been identified from phylogenetically diverse groups of archaea and bacteria, and numerous efforts have been undertaken to improve the HER for formate through strain optimization and bioprocess development. CO-dependent H2 production has been investigated to enhance the H2 productivity of various carboxydotrophs via an increase in CO gas liquid mass transfer rates and the construction of genetically modified strains. Hydrogenogenic CO-conversion has been applied to syngas and by-product gas of the steel-mill process, and this low-cost feedstock has shown to be promising in the production of biomass and H2. Here, we focus on recent advances in the isolation of novel phylogenetic groups utilizing formate or CO, the remarkable genetic engineering that enhances H2 productivity, and the practical implementation of H2 production from C1 substrates. PMID- 25461506 TI - Computational and experimental single cell biology techniques for the definition of cell type heterogeneity, interplay and intracellular dynamics. AB - Novel technological developments enable single cell population profiling with respect to their spatial and molecular setup. These include single cell sequencing, flow cytometry and multiparametric imaging approaches and open unprecedented possibilities to learn about the heterogeneity, dynamics and interplay of the different cell types which constitute tissues and multicellular organisms. Statistical and dynamic systems theory approaches have been applied to quantitatively describe a variety of cellular processes, such as transcription and cell signaling. Machine learning approaches have been developed to define cell types, their mutual relationships, and differentiation hierarchies shaping heterogeneous cell populations, yielding insights into topics such as, for example, immune cell differentiation and tumor cell type composition. This combination of experimental and computational advances has opened perspectives towards learning predictive multi-scale models of heterogeneous cell populations. PMID- 25461507 TI - How metabolites modulate metabolic flux. AB - Adaptation to metabolic needs and changing environments is a basic requirement of every living system. These adaptations can be very quick and mild or slower but more drastic. In any case, cells have to constantly monitor their metabolic state and requirements. In this article we review general concepts as well as recent advances on how metabolites can regulate metabolic fluxes. We discuss how cells sense metabolite levels and how changing metabolite levels regulate metabolic enzymes on different levels, from specific allosteric regulation to global transcriptional regulation. We thereby focus on local metabolite sensing in mammalian cells and show that several major discoveries have only very recently been made. PMID- 25461509 TI - Characterizing the natural radiation levels throughout the main geological units of Sabkhat al Jabboul area, northern Syria. AB - The concentrations of equivalent eU, eTh, and K% were determined together with soil gas radon values and carborne gamma-ray survey in order to define the natural radioactivity levels throughout main geological units of Sabkhat al Jabboul region. Forty five soil and rock samples were collected from various lithofacies in each geological unit, and analyzed by gamma-ray spectrometric technique for determining the concentration values of major radioelements. Such radiometric data could be used to differentiate between various lithologies of the investigated rocks. Although no distinct radioactive anomalies were found in the area, the radiometric profiles showed some minor variations with slightly higher values than the normal level. Despite the low radioactivity and the lack of rocks diversity in the surveyed area, it was possible to classify some certain rock types based on their radiometric response. The relationships between eU, eTh and their ratios were discussed for the Quaternary, Neogene and Paleogene formations, in order to evaluate the degree of uranium distribution and remobilization. The overall results of this radiometric survey were generally low, and lying within the range of the normal background levels in Syrian. PMID- 25461508 TI - Metabolism and epigenetics: a link cancer cells exploit. AB - Both cellular nutrient metabolism and chromatin organization are remodeled in cancer cells, and these alterations play key roles in tumor development and growth. Many chromatin modifying-enzymes utilize metabolic intermediates as cofactors or substrates, and recent studies have demonstrated that the epigenome is sensitive to cellular metabolism. The contribution of metabolic alterations to epigenetic deregulation in cancer cells is just beginning to emerge, as are the roles of the metabolism-epigenetics link in tumorigenesis. Here we review the roles of acetyl-CoA and S-adenosylmethionine (SAM), donor substrates for acetylation and methylation reactions, respectively, in regulating chromatin modifications in response to nutrient metabolism. We further discuss how oncogenic signaling, cell metabolism, and histone modifications are interconnected and how their relationship might impact tumor growth. PMID- 25461510 TI - Effects of acute gamma radiation on the reproductive ability of the earthworm Eisenia fetida. AB - Earthworms are the most suitable biological indicators of radioactive pollution because they are the parts of nutritional webs, and are present in relatively high numbers. Four months old Eisenia fetida were exposed to different doses of gamma radiation, namely 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 & 60 Gy to study the effects of radiation on different reproductive parameters. The number of cocoons laid and the hatchlings emerged were recorded for all the selected doses. There was no reduction in cocoon production, however; decreasing size and weight of the cocoons was observed from the samples exposed to 20 Gy and above doses. Significant reductions in the hatchlings were recorded in earthworms exposed to 10 Gy and above doses. The dose response curves for a percentage reduction in hatchlings were constructed. Exposure to radiation dose of 1 and 2 Gy did not show any reduction, however, there was ~10%, ~50% and ~90% decrease in the hatchlings in samples exposed to 3, 15 and 45, 50, 55 and 60 Gy doses respectively. Delayed hatchability was also reported at al exposure level. Histology of irradiated earthworms revealed that the structural damage in the seminal vesicles was prominent at the exposed dose of 3 Gy onwards with complete degeneration on exposure to 60 Gy of gamma radiation. PMID- 25461511 TI - Determining the radon exhalation rate from a gold mine tailings dump by measuring the gamma radiation. AB - The mining activities taking place in Gauteng province, South Africa have caused millions of tons of rocks to be taken from underground to be milled and processed to extract gold. The uranium bearing tailings are placed in an estimated 250 dumps covering a total area of about 7000 ha. These tailings dumps contain considerable amounts of radium and have therefore been identified as large sources of radon. The size of these dumps make traditional radon exhalation measurements time consuming and it is difficult to get representative measurements for the whole dump. In this work radon exhalation measurements from the non-operational Kloof mine dump have been performed by measuring the gamma radiation from the dump fairly accurately over an area of more than 1 km(2). Radon exhalation from the mine dump have been inferred from this by laboratory based and in-situ gamma measurements. Thirty four soil samples were collected at depths of 30 cm and 50 cm. The weighted average activity concentrations in the soil samples were 308 +/- 7 Bq kg(-1), 255 +/- 5 Bq kg(-1) and 18 +/- 1 Bq kg(-1) for (238)U, (40)K and (232)Th, respectively. The MEDUSA (Multi-Element Detector for Underwater Sediment Activity) gamma-ray detection system was used for field measurements. The radium concentrations were then used with soil parameters to obtain the radon flux using different approaches such as the IAEA (International Atomic Energy Agency) formula. Another technique the MEDUSA Laboratory Technique (MELT) was developed to map radon exhalation based on (1) recognising that radon exhalation does not affect (40)K and (232)Th activity concentrations and (2) that the ratio of the activity concentration of the field (MEDUSA) to the laboratory (HPGe) for (238)U and (40)K or (238)U and (232)Th will give a measure of the radon exhalation at a particular location in the dump. The average, normalised radon flux was found to be 0.12 +/- 0.02 Bq m(-2) s(-1) for the mine dump. PMID- 25461512 TI - Assessment of committed effective dose due to the ingestion of (210)Po and (210)Pb in consumed Lebanese fish affected by a phosphate fertilizer plant. AB - Ingestion of radionuclides through seafood intake is a one of the sources contributing to the internal effective dose in the human organism. In order to evaluate the internal exposure and potential risks due to (210)Po and (210)Pb associated with fish consumption, these radionuclides were measured in commonly consumed fish species from a clean area and an area subjected to the impact of a Lebanese phosphate fertilizer plant. The highest concentration of (210)Pb was 98.7 Bq/kg fresh weight while (210)Po activity concentrations varied from 3.6 Bq/kg to 140 Bq/kg. A supplementary radiation exposure was detected; the highest committed effective dose due to (210)Po and (210)Pb was found to be 1110 MUSv/y and 450 MUSv/y, respectively. Moreover, the average mortality and morbidity risks due to the fish consuming were estimated. PMID- 25461514 TI - Uranium and cesium accumulation in bean (Phaseolus vulgaris L. var. vulgaris) and its potential for uranium rhizofiltration. AB - Laboratory scale rhizofiltration experiments were performed to investigate uranium and cesium accumulation in bean (Phaseolus vulgaris L. var. vulgaris) and its potential for treatment of uranium contaminated groundwater. During 72 h of rhizofiltration, the roots of the bean accumulated uranium and cesium to concentrations 317-1019 times above the initial concentrations, which ranged from 100 to 700 MUg l(-1) in artificially contaminated solutions. When the pH of the solution was adjusted to 3, the ability to accumulate uranium was 1.6 times higher than it was for solutions of pH 7 and pH 9. With an initial uranium concentration of 240 MUg l(-1) in genuine groundwater at pH 5, the bean reduced the uranium concentration by 90.2% (to 23.6 MUg l(-1)) within 12 h and by 98.9% (to 2.8 MUg l(-1)) within 72 h. A laboratory scale continuous clean-up system reduced uranium concentrations from 240 MUg l(-1) to below 10 MUg l(-1) in 56 h; the whole uranium concentration in the bean roots during system operation was more than 2600 MUg g(-1) on a dry weight basis. Using SEM and EDS analyses, the uranium removal in solution at pH 7 was determined based on adsorption and precipitation on the root surface in the form of insoluble uranium compounds. The present results demonstrate that the rhizofiltration technique using beans efficiently removes uranium and cesium from groundwater as an eco-friendly and cost-effective method. PMID- 25461513 TI - Submarine groundwater discharge from the South Australian Limestone Coast region estimated using radium and salinity. AB - The Tertiary Limestone Aquifer (TLA) is one of the major regional hydrogeological systems of southern Australia. Submarine groundwater discharge (SGD) of freshwater from the TLA occurs through spring creeks, beach springs and diffusively through beach sands, but the magnitude of the total flux is not known. Here, a range of potential environmental tracers (including temperature, salinity, (222)Rn, (223)Ra, (224)Ra, (226)Ra, (228)Ra, and (4)He) were measured in potential sources of SGD and in seawater along a 45 km transect off the coastline to evaluate SGD from the TLA. Whilst most tracers had a distinct signature in the sources of water to the coastline, salinity and the radium quartet had the most distinct SGD signal in seawater. A one-dimensional advection dispersion model was used to estimate the terrestrial freshwater component of SGD (Qfw) using salinity and the recirculated seawater component (Qrsw) using radium activity in seawater. Qfw was estimated at 1.2-4.6 m(3) s(-1), similar in magnitude to previously measured spring creek discharge (~3 m(3) s(-1)) for the area. This suggests that other terrestrial groundwater discharge processes (beach springs and diffuse discharge through beach sands) were no more than 50% of spring creek discharge. The largest component of total SGD was Qrsw, estimated at 500-1000 m(3) s(-1) and possibly greater. The potential for wave, storm, or buoyancy-driven porewater displacement from the seafloor could explain the large recirculation flux for this section of the Southern Ocean Continental Shelf. PMID- 25461515 TI - The accuracy of radon and thoron progeny concentrations measured through air filtration. AB - The accuracy and the optimization of determining radon and thoron progeny concentrations in air using air filtration followed by alpha activity measurements were investigated in details. The effects of radon and thoron concentrations, filtering duration and the choice of measuring intervals on relative standard deviations were analyzed. Obtaining satisfactory results by this method should be expected only in the case of high radon and thoron progeny concentrations in air. The optimization process also showed up to be dependent on the progeny concentration. Determinant of the system matrix and its effect on the sensitivity of the results were investigated. PMID- 25461517 TI - The radioactivity of seasonal dust storms in the Middle East: the May 2012 case study in Jordan. AB - Dust storms in the Middle East are common during spring. Some of these storms are massive and carry a large amount of dust from faraway regions, which pose health and pollution risks. The huge dust storm event occurred in early May, 2012 was investigated for its radioactive content using gamma ray spectroscopy. Dust samples were collected from Northern Jordan and it was found that the storm carried a large amount of both artificial and natural radioactivity. The average activity concentration of fallout (137)Cs was 17.0 Bq/kg which is larger than that found in soil (2.3 Bq/kg), and this enrichment is attributed to particle size effects. (7)Be which is of atmospheric origin and has a relatively short half-life, was detected in dust with relatively large activity concentrations, as it would be expected, with an average of 2860 Bq/kg, but it was not detected in soil. Despite the large activity concentration of (7)Be, dose assessment showed that it does not contribute significantly to the effective dose through inhalation. The concentrations of the primodial nuclides (40)K, (232)Th and (238)U were 547, 30.0 and 49.3 Bq/kg, respectively. With the exception of (40)K, these were comparable to what was found in soil. PMID- 25461516 TI - Accumulation of (137)Cs by rice grown in four types of soil contaminated by the Fukushima Dai-ichi Nuclear Power Plant accident in 2011 and 2012. AB - The ability to predict radiocesium transfer from soil to agricultural products is necessary for assessing management options in a radiocesium contaminated area. In this study, we evaluated the differences in transfer factors among soil samples and the differences in transfer factors between the first and the second years of contamination in rice. We employed pot experiments using four types of soils that are representative of the agricultural soils present in the Fukushima Prefecture contaminated by (137)Cs released from the Fukushima Dai-ichi Nuclear Power Plant after the March 2011 accident. The experiments were conducted during the 2011 and 2012 growing seasons. The geometric mean of transfer factors for brown rice and inedible rice part was 0.011 and 0.031, respectively, in 2011 and 0.0061 and 0.020, respectively, in 2012. The average decreasing rate of the transfer factor was 40% and 30% in brown rice and inedible rice part, respectively, from 2011 to 2012, presumably owing to the irreversible sorption of (137)Cs to clay minerals. PMID- 25461518 TI - A comparison of the ellipsoidal and voxelized dosimetric methodologies for internal, heterogeneous radionuclide sources. AB - Non-human biota dosimetry has historically relied on ellipsoidal dosimetric phantoms. In 2008, the International Commission on Radiological Protection (ICRP) presented a set of ellipsoidal models representative of wildlife, including dosimetric data for homogeneously distributed internal radionuclide sources. Such data makes it possible to quickly and easily estimate radiation dose rate. Voxelized modeling, first developed for use in human medical dosimetry, utilizes advanced imaging technologies to generate realistic and detailed dosimetric phantoms. Individual organs or tissues may be segmented and dosimetric data derived for each anatomic area of interest via Monte Carlo modeling. Recently, dosimetric data derived from voxelized models has become available for organisms similar to the ICRP's Reference Animals and Plants in 2008. However, if the existing ellipsoidal models are conservative, there may be little need to employ voxel models in regulatory assessments. At the same time, existing dosimetric techniques may be inadequate to resolve recent controversies surrounding the impact of ionizing radiation exposure on wildlife. This study quantifies the difference between voxel-calculated and ellipsoid-calculated dose rates for seven radionuclides assumed to be heterogeneously distributed: (14)C, (36)Cl, (60)Co, (90)Sr, (131)I, (134)Cs, (137)Cs, and (210)Po. Generally, the two methodologies agree within a factor of two to three. Finally, this paper compares the assumptions of each dosimetric system, the conditions under which each model best applies, and the implications that our results have for the ongoing dialog surrounding wildlife dosimetry. PMID- 25461520 TI - A dynamic model to estimate the activity concentration and whole body dose rate of marine biota as consequences of a nuclear accident. AB - This paper describes a dynamic compartment model (K-BIOTA-DYN-M) to assess the activity concentration and whole body dose rate of marine biota as a result of a nuclear accident. The model considers the transport of radioactivity between the marine biota through the food chain, and applies the first order kinetic model for the sedimentation of radionuclides from seawater onto sediment. A set of ordinary differential equations representing the model are simultaneously solved to calculate the activity concentration of the biota and the sediment, and subsequently the dose rates, given the seawater activity concentration. The model was applied to investigate the long-term effect of the Fukushima nuclear accident on the marine biota using (131)I, (134)Cs, and, (137)Cs activity concentrations of seawater measured for up to about 2.5 years after the accident at two locations in the port of the Fukushima Daiichi Nuclear Power Station (FDNPS) which was the most highly contaminated area. The predicted results showed that the accumulated dose for 3 months after the accident was about 4-4.5Gy, indicating the possibility of occurrence of an acute radiation effect in the early phase after the Fukushima accident; however, the total dose rate for most organisms studied was usually below the UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation)'s bench mark level for chronic exposure except for the initial phase of the accident, suggesting a very limited radiological effect on the marine biota at the population level. The predicted Cs sediment activity by the first-order kinetic model for the sedimentation was in a good agreement with the measured activity concentration. By varying the ecological parameter values, the present model was able to predict the very scattered (137)Cs activity concentrations of fishes measured in the port of FDNPS. Conclusively, the present dynamic model can be usefully applied to estimate the activity concentration and whole body dose rate of the marine biota as the consequence of a nuclear accident. PMID- 25461519 TI - Variation in available cesium concentration with parameters during temperature induced extraction of cesium from soil. AB - Cesium extraction behavior of brown forest type soil collected from paddy fields in Fukushima nuclear accident affected areas was studied. In nitric acid or sulfuric acid solutions at elevated temperature, the concentration of Cs in soil available for extraction, m0, has been estimated on the basis of modified canonical equation and the equations derived from assumed equilibria. With the variation in temperature, mixing time, and soil to solvent ratio, the observed m0 values in 0.5 M acid solution ranged between 1.5 and 2.9 mg cesium per kilogram of soil. By increasing the acid concentration to 3 M, the value of m0 could be sharply increased to 5.1 mg/kg even at 95 degrees C. This variation in the extractable concentration of cesium with the parameters signifies the existence of different binding sites in the soil matrix. The results observed for uncontaminated sample could be reproduced with the radioactive cesium contaminated sample belonging to the same soil group. PMID- 25461521 TI - An improved mathematical model for prediction of air quantity to minimise radiation levels in underground uranium mines. AB - Ventilation is the primary means of controlling radon and its daughter concentrations in an underground uranium mine environment. Therefore, prediction of air quantity is the vital component for planning and designing of ventilation systems to minimise the radiation exposure of miners in underground uranium mines. This paper comprehensively describes the derivation and verification of an improved mathematical model for prediction of air quantity, based on the growth of radon daughters in terms of potential alpha energy concentration (PAEC), to reduce the radiation levels in uranium mines. The model also explains the prediction of air quantity depending upon the quality of intake air to the stopes. This model can be used to evaluate the contribution of different sources to radon concentration in mine atmosphere based on the measurements of radon emanation and exhalation. Moreover, a mathematical relationship has been established for quick prediction of air quantity to achieve the desired radon daughter concentration in the mines. PMID- 25461522 TI - Levels of tritium in soils and vegetation near Canadian nuclear facilities releasing tritium to the atmosphere: implications for environmental models. AB - Concentrations of organically bound tritium (OBT) and tritiated water (HTO) were measured over two growing seasons in vegetation and soil samples obtained in the vicinity of four nuclear facilities and two background locations in Canada. At the background locations, with few exceptions, OBT concentrations were higher than HTO concentrations: OBT/HTO ratios in vegetation varied between 0.3 and 20 and values in soil varied between 2.7 and 15. In the vicinity of the four nuclear facilities OBT/HTO ratios in vegetation and soils deviated from the expected mean value of 0.7, which is used as a default value in environmental transfer models. Ratios of the OBT activity concentration in plants ([OBT]plant) to the OBT activity concentration in soils ([OBT]soil) appear to be a good indicator of the long-term behaviour of tritium in soil and vegetation. In general, OBT activity concentrations in soils were nearly equal to OBT activity concentrations in plants in the vicinity of the two nuclear power plants. [OBT]plant/[OBT]soil ratios considerably below unity observed at one nuclear processing facility represents historically higher levels of tritium in the environment. The results of our study reflect the dynamic nature of HTO retention and OBT formation in vegetation and soil during the growing season. Our data support the mounting evidence suggesting that some parameters used in environmental transfer models approved for regulatory assessments should be revisited to better account for the behavior of HTO and OBT in the environment and to ensure that modelled estimates (e.g., plant OBT) are appropriately conservative. PMID- 25461523 TI - Impact of Fukushima-derived radiocesium in the western North Pacific Ocean about ten months after the Fukushima Dai-ichi nuclear power plant accident. AB - We measured vertical distributions of radiocesium ((134)Cs and (137)Cs) at stations along the 149 degrees E meridian in the western North Pacific during winter 2012, about ten months after the Fukushima Dai-ichi Nuclear Power Plant (FNPP1) accident. The Fukushima-derived (134)Cs activity concentration and water column inventory were largest in the transition region between 35 and 40 degrees N approximately due to the directed discharge of the contaminated water from the FNPP1. The bomb-derived (137)Cs activity concentration just before the FNPP1 accident was derived from the excess (137)Cs activity concentration relative to the (134)Cs activity concentration. The water-column inventory of the bomb derived (137)Cs was largest in the subtropical region south of 35 degrees N, which implies that the Fukushima-derived (134)Cs will also be transported from the transition region to the subtropical region in the coming decades. Mean values of the water-column inventories decay-corrected for the Fukushima-derived (134)Cs and the bomb-derived (137)Cs were estimated to be 1020 +/- 80 and 820 +/- 120 Bq m(-2), respectively, suggesting that in winter 2012 the impact of the FNPP1 accident in the western North Pacific Ocean was nearly the same as that of nuclear weapons testing. Relationship between the water-column inventory and the activity concentration in surface water for the radiocesium is essential information for future evaluation of the total amount of Fukushima-derived radiocesium released into the North Pacific Ocean. PMID- 25461524 TI - Examination of radioargon production by cosmic neutron interactions. AB - Radioargon isotopes, particularly (37)Ar, are currently being considered for use as an On-Site Inspection (OSI) relevant radionuclide within the context of the Comprehensive Nuclear-Test-Ban Treaty (CTBT). In order to understand any soil air measurements taken during an OSI, the radioargon background due to cosmic ray induced activation along with other sources must be understood. An MCNP6 model was developed using the cosmic ray source feature within the code to examine the neutron flux at ground level as a function of various conditions: date during the solar magnetic activity cycle, latitude of sampling location, geology of the sampling location, and sampling depth. Once the cosmic neutron flux was obtained, calculations were performed to determine the rate of radioargon production for the main interactions. Radioargon production was shown to be highly dependent on the soil composition, and a range of (37)Ar production values at 1 m depth was found with a maximum production rate of 4.012 atoms/sec/m(3) in carbonate geologies and a minimum production rate of 0.070 atoms/sec/m(3) in low calcium granite. The sampling location latitude was also shown to have a measurable effect on the radioargon production rate, where the production of (37)Ar in an average continental crust is shown to vary by a factor of two between the equator and the poles. The sampling date's position within the solar magnetic activity cycle was also shown to cause a smaller change, less than a factor of 1.2, in activation between solar maxima and solar minima. PMID- 25461525 TI - Development of a neural network approach to characterise (226)Ra contamination at legacy sites using gamma-ray spectra taken from boreholes. AB - There are a large number of sites across the UK and the rest of the world that are known to be contaminated with (226)Ra owing to historical industrial and military activities. At some sites, where there is a realistic risk of contact with the general public there is a demand for proficient risk assessments to be undertaken. One of the governing factors that influence such assessments is the geometric nature of contamination particularly if hazardous high activity point sources are present. Often this type of radioactive particle is encountered at depths beyond the capabilities of surface gamma-ray techniques and so intrusive borehole methods provide a more suitable approach. However, reliable spectral processing methods to investigate the properties of the waste for this type of measurement have yet to be developed since a number of issues must first be confronted including: representative calibration spectra, variations in background activity and counting uncertainty. Here a novel method is proposed to tackle this issue based upon the interrogation of characteristic Monte Carlo calibration spectra using a combination of Principal Component Analysis and Artificial Neural Networks. The technique demonstrated that it could reliably distinguish spectra that contained contributions from point sources from those of background or dissociated contamination (homogenously distributed). The potential of the method was demonstrated by interpretation of borehole spectra collected at the Dalgety Bay headland, Fife, Scotland. Predictions concurred with intrusive surveys despite the realisation of relatively large uncertainties on activity and depth estimates. To reduce this uncertainty, a larger background sample and better spatial coverage of cores were required, alongside a higher volume better resolution detector. PMID- 25461526 TI - Development of an improved live attenuated antigenic marker CSF vaccine strain candidate with an increased genetic stability. AB - Controlling classical swine fever (CSF) involves vaccination in endemic regions and preemptive slaughter of infected swine herds during epidemics. Live attenuated marker vaccines that confer effective protection against the disease and allow differentiation between infected and vaccinated animals (DIVA) could impact CSF control policies. Previously, we reported the development of FlagT4 virus (FlagT4v), a rationally designed live attenuated marker vaccine. During its vaccine assessment, FlagT4v reverted to a virulent virus during successive passages in piglets. Sequence analysis revealed deletions and substitutions almost exclusively in the areas of E1 and E2. To improve genetic stability of FlagT4v, we introduced changes in the codon usage in those areas. The newly developed virus, FlagT4Gv, was shown to retain the attenuated phenotype after successive passages in piglets. As observed with FlagT4v, the newly developed FlagT4Gv conferred effective protection against challenge with virulent CSFV at early (7 days) and at late (28 days) times post-vaccination. PMID- 25461527 TI - Inter and intra-host variability of hepatitis C virus genotype 1a hypervariable envelope coding domains followed for a 4-11 year of human immunodeficiency virus coinfection and highly active antiretroviral therapy. AB - The evolution of hepatitis C virus (HCV) quasispecies in patients with HIV-1 coinfection is not fully understood. The HCV-1a quasispecies heterogeneity was analyzed at inter and intra-host levels along 7.6 years in 21 coinfected patients that showed different virological and immunological responses to highly active antiretroviral therapy (HAART). Two to nine serial samples were subjected to direct and clonal sequence analyses of the envelope glycoprotein 2 (E2) gene. E2 based phylogenies, intra-host HCV evolution and evolutionary rates, as well as dynamics of the quasispecies heterogeneity parameters were evaluated. Bayesian coalescent phylogenies indicated complex evolutionary histories, revealing some viral lineages that persisted along the follow up and others that were detectable at a single or some sampling times, suggesting the occurrence of emergence extinction cycles. HCV quasispecies underwent very rapid evolution in HAART treated patients (~3.1 * 10(-2) sub/site/year) following the recovery of the host immunocompetence irrespectively of the virological response to HAART. PMID- 25461528 TI - Infection of human amniotic and endothelial cells by Japanese encephalitis virus: Increased expression of HLA-F. AB - Productive infection of human amniotic and endothelial cell lines with Japanese encephalitis virus (JEV) was established leading to the induction of NFkappaB and HLA-F, a non-classical MHC molecule. Induction of the HLA-F gene and protein in JEV-infected cells was shown to be NFkappaB dependent since it was blocked by inhibitors of NFkappaB activation. ShRNA targeting lentivirus-mediated stable knockdown of the p65 subunit of NFkappaB inhibited JEV-mediated induction of HLA F both in the amniotic cell line, AV-3 as well as the human brain microendothelial cell line, HBMEC. The induction of HLA-F by treatment of AV-3 with TNF-alpha was also inhibited by ShRNA mediated knockdown of NFkappaB. TNF alpha treatment of HEK293T cells that were transfected with reporter plasmids under the control of HLA-F enhancer A elements resulted in significant transactivation of the luciferase reporter gene. NFkappaB-mediated induction of HLA-F following JEV infection and TNF-alpha exposure is being suggested for the first time. PMID- 25461529 TI - Efficient replication and strong induction of innate immune responses by H9N2 avian influenza virus in human dendritic cells. AB - Avian influenza A (H9N2) viruses have occasionally been identified in humans with upper respiratory tract infections. The novel H7N9/2013 virus identified in China shows that a low pathogenic avian influenza (LPAI) virus can be highly pathogenic in humans. Therefore, it is important to understand virus-host cell interactions and immune responses triggered by LPAI viruses in humans. We found that LPAI A/Hong Kong/1073/99 (H9N2) virus replicated efficiently in human dendritic cells (DCs). The H9N2 virus induced strong IFN gene expression although with different kinetics than seasonal influenza A/Beijing/353/89 (H3N2) virus. IFN inducible antiviral proteins were produced in H9N2 virus-infected cells at the same level as in H3N2 infection. The H9N2 virus was extremely sensitive to the antiviral actions of type I IFNs. These results indicate that the avian influenza H9N2 virus is inducing a strong antiviral IFN response in human DCs. PMID- 25461530 TI - Identification of residues on human receptor DPP4 critical for MERS-CoV binding and entry. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) infects host cells through binding the receptor binding domain (RBD) on its spike glycoprotein to human receptor dipeptidyl peptidase 4 (hDPP4). Here, we report identification of critical residues on hDPP4 for RBD binding and virus entry through analysis of a panel of hDPP4 mutants. Based on the RBD-hDPP4 crystal structure we reported, the mutated residues were located at the interface between RBD and hDPP4, which potentially changed the polarity, hydrophobic or hydrophilic properties of hDPP4, thereby interfering or disrupting their interaction with RBD. Using surface plasmon resonance (SPR) binding analysis and pseudovirus infection assay, we showed that several residues in hDPP4-RBD binding interface were important on hDPP4-RBD binding and viral entry. These results provide atomic insights into the features of interactions between hDPP4 and MERS-CoV RBD, and also provide potential explanation for cellular and species tropism of MERS-CoV infection. PMID- 25461531 TI - Development of a virus detection and discovery pipeline using next generation sequencing. AB - Next generation sequencing (NGS) has revolutionized virus discovery. Notwithstanding, a vertical pipeline, from sample preparation to data analysis, has not been available to the plant virology community. We developed a degenerate oligonucleotide primed RT-PCR method with multiple barcodes for NGS, and constructed VirFind, a bioinformatics tool specifically for virus detection and discovery able to: (i) map and filter out host reads, (ii) deliver files of virus reads with taxonomic information and corresponding Blastn and Blastx reports, and (iii) perform conserved domain search for reads of unknown origin. The pipeline was used to process more than 30 samples resulting in the detection of all viruses known to infect the processed samples, the extension of the genomic sequences of others, and the discovery of several novel viruses. VirFind was tested by four external users with datasets from plants or insects, demonstrating its potential as a universal virus detection and discovery tool. PMID- 25461532 TI - Dengue virus infection of erythroid precursor cells is modulated by both thalassemia trait status and virus adaptation. AB - Dengue is the most significant arthropod borne viral disease worldwide, and infection with the dengue virus causes a wide range of symptoms in humans, including bone marrow suppression. While the target cells of the virus remain poorly characterized, cells of the myeloid lineage have been shown to be important mediators of the disease. This study sought to determine whether erythroid precursor cells were susceptible to dengue virus infection, and whether erythroid cells from thalassemia trait carriers showed any protection against infection. Infection with a laboratory adapted high passage DENV-2 resulted in high levels of infection during certain stages of differentiation, and cells derived from thalassemia trait carriers showed significantly reduced susceptibility to dengue virus infection. Infection with low passage isolates resulted in only scattered cells showing evidence of infection, but high bystander apoptosis that was reduced by both a caspase 8 inhibitor and anti-tumor necrosis factor 1 receptor antibodies. PMID- 25461533 TI - Tombusviruses upregulate phospholipid biosynthesis via interaction between p33 replication protein and yeast lipid sensor proteins during virus replication in yeast. AB - Positive-stranded RNA viruses induce new membranous structures and promote membrane proliferation in infected cells to facilitate viral replication. In this paper, the authors show that a plant-infecting tombusvirus upregulates transcription of phospholipid biosynthesis genes, such as INO1, OPI3 and CHO1, and increases phospholipid levels in yeast model host. This is accomplished by the viral p33 replication protein, which interacts with Opi1p FFAT domain protein and Scs2p VAP protein. Opi1p and Scs2p are phospholipid sensor proteins and they repress the expression of phospholipid genes. Accordingly, deletion of OPI1 transcription repressor in yeast has a stimulatory effect on TBSV RNA accumulation and enhanced tombusvirus replicase activity in an in vitro assay. Altogether, the presented data convincingly demonstrate that de novo lipid biosynthesis is required for optimal TBSV replication. Overall, this work reveals that a (+)RNA virus reprograms the phospholipid biosynthesis pathway in a unique way to facilitate its replication in yeast cells. PMID- 25461535 TI - Live attenuated influenza A virus vaccine protects against A(H1N1)pdm09 heterologous challenge without vaccine associated enhanced respiratory disease. AB - Live-attenuated influenza virus (LAIV) vaccines may provide cross-protection against contemporary influenza A virus (IAV) in swine. Conversely, whole inactivated virus (WIV) vaccines have the potential risk of vaccine-associated enhanced respiratory disease (VAERD) when challenged with IAV of substantial antigenic drift. A temperature sensitive, intranasal H1N2 LAIV was compared to wild type exposure (WT) and an intramuscular WIV vaccine in a model shown to induce VAERD. WIV vaccinated swine challenged with pandemic A/H1N1 (H1N1pdm09) were not protected from infection and demonstrated severe respiratory disease consistent with VAERD. Lung lesions were mild and challenge virus was not detected in the respiratory tract of LAIV vaccinates. High levels of post vaccination IgG serum antibodies targeting the H1N1pdm09 HA2 stalk domain were exclusively detected in the WIV group and associated with increased H1N1pdm09 virus infectivity in MDCK cells. In contrast, infection-enhancing antibodies were not detected in the serum of LAIV vaccinates and VAERD was not observed. PMID- 25461534 TI - HIV-1 CD4-induced (CD4i) gp120 epitope vaccines promote B and T-cell responses that contribute to reduced viral loads in rhesus macaques. AB - To target the HIV CD4i envelope epitope, we primed rhesus macaques with replicating Ad-rhFLSC (HIV-1BaLgp120 linked to macaque CD4 D1 and D2), with or without Ad-SIVgag and Ad-SIVnef. Macaques were boosted with rhFLSC protein. Memory T-cells in PBMC, bronchoalveolar lavage and rectal tissue, antibodies with neutralizing and ADCC activity, and Env-specific secretory IgA in rectal secretions were elicited. Although protective neutralizing antibody levels were induced, SHIVSF162P4 acquisition following rectal challenge was not prevented. Rapid declines in serum ADCC activity, Env-specific memory B cells in PBMC and bone marrow, and systemic and mucosal memory T cells were observed immediately post-challenge together with delayed anamnestic responses. Innate immune signaling resulting from persisting Ad replication and the TLR-4 booster adjuvant may have been in conflict and reoriented adaptive immunity. A different adjuvant paired with replicating Ad, or a longer post-prime interval allowing vector clearance before boosting might foster persistent T- and B-cell memory. PMID- 25461537 TI - Metagenomic analysis of viromes of dromedary camel fecal samples reveals large number and high diversity of circoviruses and picobirnaviruses. AB - The recent discovery of Middle East Respiratory Coronavirus and another novel dromedary camel coronavirus UAE-HKU23 in dromedaries has boosted interest in search of novel viruses in dromedaries. In this study, fecal samples of 203 dromedaries in Dubai were pooled and deep sequenced. Among the 7330 assembled viral contigs, 1970 were assigned to mammalian viruses. The largest groups of these contigs matched to Picobirnaviridae, Circoviridae, Picornaviridae, Parvoviridae, Astroviridae and Hepeviridae. Many of these viral families were previously unknown to dromedaries. In addition to the high abundance of contigs from Circoviridae (n=598 with 14 complete genomes) and Picobirnaviridae (n=1236), a high diversity of contigs from these two families was found, with the 14 Circoviridae complete genomes forming at least five clusters and contigs from both genogroup I and genogroup II potentially novel picobirnaviruses. Further studies comparing the incidence of these viral families in healthy and sick dromedaries will reveal their pathogenic potential. PMID- 25461536 TI - A computational analysis of the structural determinants of APOBEC3's catalytic activity and vulnerability to HIV-1 Vif. AB - APOBEC3s (A3) are Zn(2+) dependent cytidine deaminases with diverse biological functions and implications for cancer and immunity. Four of the seven human A3s restrict HIV by 'hypermutating' the reverse-transcribed viral genomic DNA. HIV Virion Infectivity Factor (Vif) counters this restriction by targeting A3s to proteasomal degradation. However, there is no apparent correlation between catalytic activity, Vif binding, and sequence similarity between A3 domains. Our comparative structural analysis reveals features required for binding Vif and features influencing polynucleotide deaminase activity in A3 proteins. All Vif binding A3s share a negatively charged surface region that includes residues previously implicated in binding the highly-positively charged Vif. Additionally, catalytically active A3s share a positively charged groove near the Zn(2+) coordinating active site, which may accommodate the negatively charged polynucleotide substrate. Our findings suggest surface electrostatics, as well as the spatial extent of substrate accommodating region, are critical determinants of substrate and Vif binding across A3 proteins with implications for anti retroviral and anti-cancer therapeutic design. PMID- 25461539 TI - Rice genomes recorded ancient pararetrovirus activities: Virus genealogy and multiple origins of endogenization during rice speciation. AB - Viral fossils in rice genomes are a best entity to understand ancient pararetrovirus activities through host plant history because of our advanced knowledge of the genomes and evolutionary history with rice and its related species. Here, we explored organization, geographic origins and genealogy of rice pararetroviruses, which were turned into endogenous rice tungro bacilliform virus like (eRTBVL) sequences. About 300 eRTBVL sequences from three representative rice genomes were clearly classified into six families. Most of the endogenization events of the eRTBVLs were initiated before differentiation of the rice progenitor (> 160,000 years ago). We successfully followed the genealogy of old relic viruses during rice speciation, and inferred the geographical origins for these viruses. Possible virus genomic sequences were explained mostly by recombinations between different virus families. Interestingly, we discovered that only a few recombination events among the numerous occasions had determined the virus genealogy. PMID- 25461538 TI - Discovery and biological characterization of two novel pig-tailed macaque homologs of HHV-6 and HHV-7. AB - Human herpesvirus-6 (HHV-6) and -7 (HHV-7) are Roseoloviruses within the Betaherpesvirus family, which have a high prevalence and suspected involvement in a number of diseases. Using CODEHOP-based PCR, we identified homologs of both viruses in saliva of pig-tailed macaques, provisionally named MneHV-6 and MneHV 7. This finding supports the existence of two distinct Roseolovirus lineages before the divergence of humans and macaques. Using specific qPCR assays, high levels of MneHV-6 and MneHV-7 DNA were detected in macaque saliva, although the frequency was greater for MneHV-7. A blood screen of 283 macaques revealed 10% MneHV-6 DNA positivity and 25% MneHV-7 positivity, with higher prevalences of MneHV-6 in older females and of MneHV-7 in younger males. Levels of MneHV-6 were increased in animals coinfected with MneHV-7, and both viruses were frequently detected in salivary gland and stomach tissues. Our discovery provides a unique animal model to answer unresolved questions regarding Roseolovirus pathology. PMID- 25461540 TI - Genetic polymorphisms in promoter and intronic regions of CYP1A2 gene in Roma and Hungarian population samples. AB - The purpose of this study was to determine the interethnic differences of four CYP1A2 drug metabolizing enzyme variants. A total of 404 Roma and 396 Hungarian healthy subjects were genotyped for -163C>A, -729C>T, -2467delT and -3860G>A variants of CYP1A2 by RT-PCR and PCR-RFLP technique. The -3860A and -729T allele were not detectable in Roma samples, while in Hungarian samples were present with 2.02% and 0.25% prevalence, respectively. There was a 1.5-fold difference in presence of homozygous -163AA genotype between Hungarian and Roma samples (49.5% vs. 31.9%, p<0.001). The -163A allele frequency was 68.6% in Hungarians and 56.9% in Romas (p=0.025). The -2467delT allele frequency was 6.81% in Roma group and 5.81% in Hungarians. The most frequent allelic constellation was -3860G/-2467T/ 729C/-163A in both populations. In conclusion, Hungarians have markedly elevated chance for rapid metabolism of CYP1A2 substrates, intensified procarcinogen activation and increased risk for cancers. PMID- 25461541 TI - Direct assessment of cytochrome P450 2D6 genotypes by high-resolution melting analysis and DNA sequencing. AB - We developed a CYP2D6 genotyping method that required only one polymerase chain reaction (PCR) followed by a high-resolution melting curve analysis (HRM) and DNA sequencing. DNA was extracted from peripheral blood samples obtained from 100 normal individuals. From the HRM analysis using three fragments of amplicons (exons 1, 6, and 9), we successfully identified four common CYP2D6 gene polymorphisms (100C>T, 2850C>T, 2988G>A, and 4180G>C). Exons 3 and 7 were also screened by HRM analysis. The heteroduplexes, wild-type homoduplexes, and homoduplexes of compound mutations showed distinct melting plots. The other four exons (exons 2, 4, 5, and 8) were directly analyzed by DNA sequencing. In conclusion, we developed an HRM and DNA sequencing based method to assess the CYP2D6 gene directly without the need for nested PCR. This method is quick and cost-effective; it reduces the chance of PCR contamination and is suitable for clinical application. PMID- 25461542 TI - Combined effects of estrogenic chemicals with the same mode of action using an estrogen receptor binding bioassay. AB - The increasing amounts of various estrogenic chemicals coexisting in the aquatic environment may pose environmental risks. While the concept of estradiol equivalent (EEQ) has been frequently applied in studying estrogenic mixtures, few experiments have been done to prove its reliability. In this study, the reliability of EEQ and the related model concentration addition (CA) was verified based on the two-hybrid recombinant yeast bioassay when all mixture components had the same mode of action and target of action. Our results showed that the measured estrogenic effects could be well predicted by CA and EEQ for all laboratory-made mixtures using two designs, despite the varying estrogenic activity, concentration levels and ratios of the test chemicals. This suggests that when an appropriate endpoint and its relevant bioassay are chosen, CA should be valid and the application of EEQ in predicting the effect of non-equi-effect mixtures is feasible. PMID- 25461543 TI - Immunotoxicity effects of carbaryl in vivo and in vitro. AB - Carbaryl is a pesticide for controlling pests in agricultural industry. To determine of immunotoxicity effects of carbaryl, rats were exposure with carbaryl for 28 days. The lymphoid organ weight, lymphocyte proliferation, IL-2, IFN gamma, IL-4, IL-10, IL-1beta and TNF-alpha cytokines level were measured, respectively. Exposure with carbaryl significantly reduced both thymus and spleen weight and also suppressed lymphocyte proliferation. In addition, carbaryl significantly decreased IL-2, IFN-gamma, IL-1beta and TNF-alpha and also increased IL-4, IL-10 cytokines. These findings suggest that exposure to carbaryl can induce immunotoxicity effects on lymphoid organ weight, suppresses the functions of lymphocyte and macrophage, Th2 polarization in Th1/Th2 balance by reducing of IFN-gamma and increasing of IL-4 and IL-10 cytokines. Therefore, carbaryl can contribute to the development of allergic, autoimmune, cancer or infection diseases through immunotoxicity effects and unbalancing of Th1/Th2 immune response however, further study is necessary. PMID- 25461544 TI - Impaired development of female mouse offspring maternally exposed to simazine. AB - Simazine is a suspected endocrine disruptor and the second most commonly detected pesticide in surface and groundwater worldwide. We evaluated the toxicity of simazine in female mouse offspring with in utero and lactational exposure to the agent. Pregnant mice were exposed to environmentally relevant doses (from 5 to 500MUg/kg) of simazine via oral administration, and their female offspring were then analyzed. The female offspring showed shortened anogenital distance and decreased whole body, ovarian, and uterine weights. Their ovaries showed increased apoptotic granulosa cells. In addition, expression of critical genes involved in regulation of cellular apoptosis and proliferation was significantly downregulated in the ovaries of simazine-exposed mice. Moreover, in vitro exposure of human granulosa cell-derived KGN cells to simazine (0.003-1nM) resulted in decreased viability and proliferation. Thus, the present study demonstrates that maternal exposure to low doses of simazine impairs normal development of female offspring via disturbance of cellular apoptosis and proliferation. PMID- 25461545 TI - Role of rat cytochromes P450 in the oxidation of 17alpha-ethinylestradiol. AB - 17alpha-Ethinylestradiol (EE2) is an endocrine disruptor (ED) used as an ingredient of oral contraceptives. Rat hepatic microsomes metabolize EE2 to three products; two of them are hydroxylated EE2 derivatives. Of the hydroxylation reactions, 2-hydroxylation, is the major reaction. Cytochrome P450 (CYP) plays a major role in EE2 hydroxylation. To resolve which rat CYPs are responsible for EE2 oxidation, three approaches were used: induction of specific CYPs, selective inhibition of CYPs, and recombinant rat CYPs. The results demonstrate that EE2 is hydroxylated by several rat CYPs, among them CYP2C6 and 2C11 are most efficient in 2-hydroxy-EE2 formation, while CYP2A and 3A catalyze EE2 hydroxylation to the second product. EE2 is also an inhibitor of CYP2C- and CYP3A-catalyzed hydroxylation of endogenous EDs progesterone and testosterone. EE2 acts as a reversible inhibitor of CYP3A-mediated progesterone 6beta-hydroxylation and inactivates CYP3A- and CYP2C-catalyzed testosterone 6beta-hydroxylation and progesterone 21- or 16alpha-hydroxylation, respectively, in a mechanism-based manner. PMID- 25461546 TI - Predicting the environmental impact of nanosilver. AB - Silver nanoparticles (AgNPs) are incorporated into many consumer and medical products due to their antimicrobial properties; however, the potential environmental risks of AgNPs are yet to be fully understood. This mini-review aims to predict the environmental impact of AgNPs, thus supplementing previous reviews on this topic. To this end, the AgNP production, environmental release and fate, predicted environmental concentrations in surface water, sediment, and sludge-activated soil, as well as reported toxicity and proposed toxic mechanisms are discussed, focusing primarily on fish. Furthermore, knowledge gaps and recommendations for future research are addressed. PMID- 25461547 TI - Toxicity of the veterinary sulfonamide antibiotic sulfamonomethoxine to five aquatic organisms. AB - The purpose of this study was to investigate the acute and chronic toxicity of sulfamonomethoxine (SMM) to aquatic organisms to evaluate its impact at different trophic levels in the ecosystem. Regarding the growth inhibition of microalgae, SMM exhibited 72-h median effective concentration (EC50) values of 5.9mgL(-1) for freshwater Chlorella vulgaris and 9.7mgL(-1) for marine Isochrysis galbana. In a study on the cladocerans, SMM exhibited acute toxicity and 48-h median lethal concentrations of 48mgL(-1) for Daphnia magna and 283mgL(-1) for D. similis. An examination of chronic toxicity revealed that SMM inhibited the brook production of the cladocerans and exhibited 21-day EC50 values of 14.9mgL(-1) for D. magna and 41.9mgL(-1) for D. similis. This study investigated the potentially adverse effects of SMM on aquatic organisms and revealed that microalgae exhibited higher sensitivity to SMM than cladocerans did. The residue of SMM in water is recommended to be carefully evaluated to reduce ecological impacts after applied to cultured animals. PMID- 25461549 TI - Photo-protective effect of americanin B against ultraviolet B-induced damage in cultured human keratinocytes. AB - Excessive ultraviolet (UV) radiation, a constituent of sunlight, can induce multiple types of skin damage. We recently demonstrated that americanin B, a lignin compound, protected cells against hydrogen peroxide (H2O2)-induced damage by exerting antioxidant effects and inhibiting apoptosis. In this study, we investigated the ability of americanin B to protect against cell injury induced by UVB (280-320nm), the most harmful UV wavelengths, in human HaCaT keratinocytes. Americanin B absorbed UVB, eliminated UVB-induced intracellular reactive oxygen species (ROS), and decreased the extent of UVB-induced oxidative modification of lipids, proteins, and DNA. In addition, americanin B inhibited UVB-induced apoptosis, as indicated by reductions in apoptotic body formation and DNA fragmentation. Furthermore, americanin B reversed the depolarization of the mitochondrial membrane induced by UVB exposure. These protective activities were associated with down-regulation of apoptosis-promoting proteins, Bax, caspase-9, and caspase-3 and up-regulation of an apoptosis inhibitor, Bcl-2. These results suggest that americanin B can protect human keratinocytes against UVB-induced cell damage. PMID- 25461548 TI - Hepatic oxidative status and metal homeostasis disturbance of 2-hydroxylated dioxin in ICR mice. AB - In the present study, the toxic effects of the oral exposure of 2-hydroxylated dioxin (2-HODD) in ICR male mice were examined. The mice were administered different doses (0.2, 2.0 and 20.0mg/kg) of 2-HODD. After 14 days of exposure, the oxidative stress (OS) indicator levels and the essential metal concentrations in the mouse livers were determined. The results showed that the superoxide dismutase (SOD) and the glutathione peroxidase (GPx) activities were increased in the 0.2mg/kg group, whereas they were significantly decreased in the 2.0 and 20.0mg/kg groups. Decreases in the catalase (CAT) activity and the glutathione (GSH) levels, accompanied by increases in the malondialdehyde (MDA) contents, were recorded in all of the 2-HODD-treated groups. The hepatic iron, copper and zinc levels increased in all of the 2-HODD-treated groups. The histological examination of the livers demonstrated swollen cells and inflammation. Dose dependent changes in both the OS indicators and the hepatic metal levels were observed. In conclusion, a single low dose of 2-HODD significantly perturbed the hepatic OS status and metals homeostasis in the mice. PMID- 25461550 TI - Identification of the rat liver cytochrome P450 enzymes involved in the metabolism of the calcium channel blocker dipfluzine hydrochloride. AB - This study aimed to identify the specific cytochrome P450 (CYP450) enzymes involved in the metabolism of dipfluzine hydrochloride using the combination of a chemical inhibition study, a correlation analysis and a panel of recombinant rat CYP450 enzymes. The incubation of Dip with rat liver microsomes yielded four metabolites, which were identified by liquid chromatography-coupled tandem mass spectrometry (LC/MS/MS). The results from the assays involving eight selective inhibitors indicated that CYP3A and CYP2A1 contributed most to the metabolism of Dip, followed by CYP2C11, CYP2E1 and CYP1A2; however, CYP2B1, CYP2C6 and CYP2D1 did not contribute to the formation of the metabolites. The results of the correlation analysis and the assays involving the recombinant CYP450 enzymes further confirmed the above results and concluded that CYP3A2 contributed more than CYP3A1. The results will be valuable in understanding drug-drug interactions when Dip is coadministered with other drugs. PMID- 25461551 TI - Protective effects of intranasal curcumin on paraquot induced acute lung injury (ALI) in mice. AB - Paraquot (PQ) is widely and commonly used as herbicide and has been reported to be hazardous as it causes lung injury. However, molecular mechanism underlying lung toxicity caused by PQ has not been elucidated. Curcumin, a known anti inflammatory molecule derived from rhizomes of Curcuma longa has variety of pharmacological activities including free-radical scavenging properties but the protective effects of curcumin on PQ-induced acute lung injury (ALI) have not been studied. In this study, we aimed to study the effects of curcumin on ALI caused by PQ in male parke's strain mice which were challenged acutely by PQ (50mg/kg, i.p.) with or without curcumin an hour before (5mg/kg, i.n.) PQ intoxication. Lung specimens and the bronchoalveolar lavage fluid (BALF) were isolated for pathological and biochemical analysis after 48h of PQ exposure. Curcumin administration has significantly enhanced superoxide dismutase (SOD) and catalase activities. Lung wet/dry weight ratio, malondialdehyde (MDA) and lactate dehydrogenase (LDH) content, total cell number and myeloperoxidase (MPO) levels in BALF as well as neutrophil infiltration were attenuated by curcumin. Pathological studies also revealed that intranasal curcumin alleviate PQ-induced pulmonary damage and pro-inflammatory cytokine levels like tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO). These results suggest that intranasal curcumin may directly target lungs and curcumin inhalers may prove to be effective in PQ-induced ALI treatment in near future. PMID- 25461552 TI - SELDI-TOF MS-based discovery of a biomarker in Cucumis sativus seeds exposed to CuO nanoparticles. AB - Metal oxide nanoparticles (NPs) can inhibit plant seed germination and root elongation via the release of metal ions. In the present study, two acute phytotoxicity tests, seed germination and root elongation tests, were conducted on cucumber seeds (Cucumis sativus) treated with bulk copper oxide (CuO) and CuO NPs. Two concentrations of bulk CuO and CuO NPs, 200 and 600ppm, were used to test the inhibition rate of root germination; both concentrations of bulk CuO weakly inhibited seed germination, whereas CuO NPs significantly inhibited germination, showing a low germination rate of 23.3% at 600ppm. Root elongation tests demonstrated that CuO NPs were much stronger inhibitors than bulk CuO. SELDI-TOF MS analysis showed that 34 proteins were differentially expressed in cucumber seeds after exposure to CuO NPs, with the expression patterns of at least 9 proteins highly differing from those in seeds treated with bulk CuO and in control plants. Therefore, these 9 proteins were used to identify CuO NP specific biomarkers in cucumber plants exposed to CuO NPs. A 5977-m/z protein was the most distinguishable biomarker for determining phytotoxicity by CuO NPs. Principal component analysis (PCA) of the SELDI-TOF MS results showed variability in the modes of inhibitory action on cucumber seeds and roots. To our knowledge, this is the first study to demonstrate that the phytotoxic effect of metal oxide NPs on plants is not caused by the same mode of action as other toxins. PMID- 25461553 TI - Modelling of Cr and Ni ions release during orthodontic treatment: in vitro and in vivo methods. AB - The kinetics of metal ions release from orthodontic appliances in in vitro, in in vivo on pigs, and in vivo trials on patients (where hair samples were taken) was discussed. We have evaluated (by means of ICP-OES and ISO 17025) and compared the mass of Cr and Ni ions released. Not all the metal ions released from the appliance were transferred to hair tissue. The transfer factor was expressed as coefficient omega and evaluated as: omegaCr(patients) 33.0%, omegaCr(pigs) 17.2%, omegaNi(patients) 49.8%, omegaNi(pigs) 0.553%. The kinetics was described by a power function. Coefficient omega was used to combine the models: the in vitro and in vivo on animals on the one hand and the in vitro and in vivo on human on the other, which enabled the extrapolation of in vitro and translation of the results into in vivo conditions. The dose of metal ions released during orthodontic treatment was estimated. PMID- 25461554 TI - Including carrier-mediated transport in oral uptake prediction of nutrients and pharmaceuticals in humans. AB - Most toxicokinetic models consider passive diffusion as the only mechanism when modeling the oral uptake of chemicals. However, the overall uptake of nutrients and xenobiotics, such as pharmaceuticals and environmental pollutants, can be increased by influx transport proteins. We incorporated carrier-mediated transport into a one-compartment toxicokinetic model originally developed for passive diffusion only. The predictions were compared with measured oral uptake efficiencies of nutrients and pharmaceuticals, i.e. the fraction of the chemical reaching systemic circulation. Including carrier-mediated uptake improved model predictions for hydrophilic nutrients (RMSE=10% vs. 56%, Coefficient of Efficiency CoE=0.5 vs. -9.6) and for pharmaceuticals (RMSE=21% vs. 28% and CoE= 0.4 vs. -1.1). However, the negative CoE for pharmaceuticals indicates that further improvements are needed. Most important in this respect is a more accurate estimation of vMAX and KM as well as the determination of the amount of expressed and functional transport proteins both in vivo and in vitro. PMID- 25461555 TI - Toxicological effects of clofibric acid and diclofenac on plasma thyroid hormones of an Indian major carp, Cirrhinus mrigala during short and long-term exposures. AB - In the present investigation, the toxicity of most commonly detected pharmaceuticals in the aquatic environment namely clofibric acid (CA) and diclofenac (DCF) was investigated in an Indian major carp Cirrhinus mrigala. Fingerlings of C. mrigala were exposed to different concentrations (1, 10 and 100MUgL(-1)) of CA and DCF for a period of 96h (short term) and 35 days (long term). The toxic effects of CA and DCF on thyroid hormones (THs) such as thyroid stimulating hormone (TSH), thyroxine (T4) and triiodothyronine (T3) levels were evaluated. During the short and long-term exposure period TSH level was found to be decreased at all concentrations of CA (except at the end of 14(th) day in 1 and 10MUgL(-l) and 21(st) day in 1MUgL(-l)) whereas in DCF exposed fish TSH level was found to be increased when compared to control groups. T4 level was found to be decreased at 1 and 100MUgL(-l) of CA exposure at the end of 96h. However, T4 level was decreased at all concentrations of CA and DCF during long-term (35 days) exposure period. Fish exposed to all concentrations of CA and DCF had lower level of T3 in both the treatments. These results suggest that both CA and DCF drugs induced significant changes (P<0.01 and P<0.05) on thyroid hormonal levels of C. mrigala. The alterations of these hormonal levels can be used as potential biomarkers in monitoring of pharmaceutical drugs in aquatic organisms. PMID- 25461556 TI - Camptothecin sensitizes human hepatoma Hep3B cells to TRAIL-mediated apoptosis via ROS-dependent death receptor 5 upregulation with the involvement of MAPKs. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various types of malignant cancer cells, but several cancers have acquired potent resistance to TRAIL-induced cell death by unknown mechanisms. Camptothecin (CPT) is a quinolone alkaloid that induces cytotoxicity in a variety of cancer cell lines. However, it is not known whether CPT triggers TRAIL-induced cell death. In this study, we found that combined treatment with subtoxic doses of CPT and TRAIL (CPT-TRAIL) potentially enhanced apoptosis in a caspase-dependent manner. CPT-TRAIL effectively induced the expression of death receptor (DR) 5, which is a specific receptor of TRAIL, and treatment with a chimeric blocking antibody for DR5 reduced CPT-TRAIL-induced cell death, indicating that CPT functionally triggers DR5-mediated cell death in response to TRAIL. CPT-induced generation of reactive oxygen species (ROS) also preceded the upregulation of DR5 in response to TRAIL. The involvement of ROS in DR5 upregulation confirmed that pretreatment with antioxidants, including N-acetyl-L-cysteine and glutathione, significantly inhibits CPT-TRAIL-induced cell death by suppressing DR5 expression. The specific inhibitors of ERK and p38 also decreased CPT-TRAIL induced cell death by blocking DR5 expression. In conclusion, our results suggest that CPT sensitizes cancer cells to TRAIL-mediated apoptosis via ROS and ERK/p38 dependent DR5 upregulation. PMID- 25461557 TI - The effects of the fungicides fenhexamid and myclobutanil on SH-SY5Y and U-251 MG human cell lines. AB - Mixtures of pesticides in foodstuffs and the environment are ubiquitous in the developed world and although agents are usually exhaustively tested individually, the toxicological implications of pesticide mixtures are underreported. In this study, the effects of two fungicides, fenhexamid and myclobutanil were investigated individually and in combination on two human cell lines, SH-SY5Y neuronal cells and U-251 MG glial cells. After 48h of incubation with increasing concentrations of pesticides ranging from 1 to 1000MUM, gene expression profiles were studied in addition to toxicity end points, including cell viability, mitochondrial depolarisation as well as cellular glutathione maintenance. There were no significant differences between the susceptibility of the two cell lines in terms of cell viability assessment or mitochondrial membrane potential, when agents were administered either individually or in combination. By contrast, in the presence of the fungicides, the SH-SY5Y cells showed significantly greater susceptibility to oxidative stress in terms of total thiol depletion in comparison with the astrocytic cells. Treatment with the two pesticides led to significant changes in the cell lines' expression of several genes which regulate cell cycle control and growth (RB1, TIMP1) as well as responses to DNA attrition (ATM and CDA25A) and control of apoptosis (FAS). There was no evidence in this study that the combination of fenhexamid and myclobutanil was significantly more toxic than individual exposure, although gene expression changes suggested there may be differences in the sub-lethal response of both cell lines to both individual and combined exposure. PMID- 25461558 TI - A new biological test of water toxicity-yeast Saccharomyces cerevisiae conductometric test. AB - This new biological test of water toxicity is based on monitoring of specific conductivity changes of yeast Saccharomyces cerevisiae suspension as a result of yeast fermentation activity inhibition in toxic conditions. The test was verified on ten substances with various mechanisms of toxic effect and the results were compared with two standard toxicity tests based on Daphnia magna mobility inhibition (EN ISO 6341) and Vibrio fischeri bioluminescence inhibition (EN ISO 11348-2) and with the results of the S. cerevisiae lethal test (Rumlova and Dolezalova, 2012). The new biological test - S. cerevisiae conductometric test - is an express method developed primarily for field conditions. It is applicable in case of need of immediate information about water toxicity. Fast completion is an advantage of this test (time necessary for test completion is about 60min), the test is simple and the test organism - dried instant yeast - belongs among its biggest advantages because of its long-term storage life and broad availability. PMID- 25461559 TI - A natural dye, Niram improves atopic dermatitis through down-regulation of TSLP. AB - Naju Jjok (Polygonum tinctorium Lour.) has been known to treat skin diseases in traditional Korean medicine. A natural textile dye, Niram made from Naju Jjok has traditionally been used to dye clothes. Thymic stromal lymphopoietin (TSLP) plays an important role in the development of atopic dermatitis (AD). Thus, we investigated that Niram might ameliorate AD through regulation of TSLP. Niram significantly inhibited the levels of TSLP through blockade of caspase-1/receptor interacting protein 2 pathway in stimulated mast cells. Further, Niram ameliorated clinical symptoms in AD mouse. Niram significantly inhibited the infiltration of inflammatory cells in lesional skin. The levels of TSLP, caspase 1, IL-4, and IL-6 were inhibited in lesional skin applied topically with Niram. Niram significantly inhibited the serum levels of IgE and histamine in AD mouse. Finally, Niram significantly inhibited the levels of TSLP in polyriboinosinic polyribocytidylic acid-stimulated human keratinocyte HaCaT cells. These results establish Niram as a functional dye embracing the aspects of not only a traditional use but also a pharmacological effect. PMID- 25461560 TI - Protection of Flos Lonicerae against acetaminophen-induced liver injury and its mechanism. AB - This study aims to observe the protective action of Flos Lonicerae (FL) aqueous extract against acetaminophen (AP)-induced liver injury and its mechanism. Results show that FL decreases AP-increased serum alanine/aspartate transaminases (ALT/AST) activity, as well as total bilirubin (TB) amount, in mice. Histological evaluation of the liver further confirms the protection of FL against AP-induced hepatotoxicity. TdT-mediated biotin-dUTP nick-end labeling (TUNEL) assay shows that FL reduces AP-increased apoptotic cells. Furthermore, AP-decreased liver glutamate-cysteine ligase (GCL) enzymatic activity and glutathione (GSH) amount are both reversed by FL because of the increased expression of the catalytic subunit of GCL (GCLC) protein. The amount of chlorogenic acid (CGA), caffeic acid, and luteolin, the main active compounds in FL, is detected by high performance liquid chromatography (HPLC). In addition, cell viability assay demonstrates that polyphenols in FL, such as CGA, caffeic acid, as well as isochlorogenic acids A, B, and C, can reverse AP-induced cytotoxicity. In conclusion, FL can prevent AP-induced liver injury by inhibiting apoptosis. The cellular antioxidant enzyme GCL is also involved in such protection. Polyphenols may be the main active hepato-protective ingredients in FL. PMID- 25461561 TI - Effect of high fluoride and high fat on serum lipid levels and oxidative stress in rabbits. AB - The purpose of this study was to explore the effects of high fluoride and high fat on triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), total antioxidant capacity (T-AOC), lipid peroxide (LPO) and malondialdehyde (MDA) in rabbits. A factorial experimental design was used, with two factors (fluoride and fat) and three levels. Seventy-two male rabbits were randomly assigned into nine groups according to initial weight and serum lipid levels. The rabbits were fed with basic feed, moderate fat feed or high fat feed and drank tap water, fluoridated water at levels of 50 and 100mgfluorion/L freely. Biological materials were collected after 5 months, and serum lipid, T-AOC, LPO, and MDA levels were then measured. Using these data, the separate and interactive effects of high fluoride and high fat were analyzed. High fluoride and high fat both increased serum levels of TC, HDL-C and LDL-C significantly (P<0.05), and there was also a synergistic effect between high fluoride and high fat (P<0.05). High fluoride and high fat had different effects on TG levels: high fat significantly increased TG levels (P<0.01) whereas high fluoride had nothing to do with TG levels (P>0.05). High fat significantly elevated LPO and MDA levels and lowered T AOC levels in serum (P<0.05). Similarly, high fluoride significantly increased LPO and MDA levels in serum (P<0.05). However, there was no interactive effect between high fat and high fluoride on these indexes. In summary, high fluoride and high fat increased serum TC and LDL-C levels individually and synergistically, and this would cause and aggravate hypercholesterolemia in rabbits. At the same time, high fluoride and high fat both made the accumulation of product of oxidative stress in experimental animals. PMID- 25461562 TI - Comparative analysis of protein profiles of aqueous extracts from marine sponges and assessment of cytotoxicity on different mammalian cell types. AB - Marine natural products extracted from sponges represent a new source for drug discovery. Here we describe a simple method for preparing aqueous extracts from 7 Mediterranean demosponges, which allowed the extraction of water-soluble compounds, such as proteins by homogenization of sponge tissue in phosphate buffered saline (PBS). The comparative analysis by SDS-PAGE showed differences in number of bands, bandwidth and intensity among the sponges analyzed. The PAS/silver staining revealed a substantial and different glycoprotein assortment among the demosponges studied. To further study the biological activities present in the sponge extracts, we determined the non-cytotoxic doses on four different mammalian cell types demonstrating that the optimal non-cytotoxic doses were cell type- and extract-dependent. In conclusion, the extraction method described in this paper represents a fast and efficient procedure for the extraction of water soluble proteins from marine sponges. Furthermore, the cell viability data suggest the feasibility of this method for the direct in vitro cell-based assays. PMID- 25461563 TI - Autism: a form of lead and mercury toxicity. AB - AIM: Autism is a developmental disability characterized by severe deficits in social interaction and communication. The definite cause of autism is still unknown. The aim of this study is to find out the relation between exposure to Lead and/or mercury as heavy metals and autistic symptoms, dealing with the heavy metals with chelating agents can improve the autististic symptoms. METHOD: Blood and hair samples were obtained from 45 children from Upper Egypt with autism between the ages of 2 and 10 years and 45 children served as controls in the same age range, after taken an informed consent and fill a questionnaire to assess the risk factors. The samples were analyzed blindly for lead and mercury by using atomic absorption and ICP-MS. Data from the two groups were compared, then follow up of the autistic children after treatment with chelating agents were done. RESULTS: The results obtained showed significant difference among the two groups, there was high level of mercury and lead among those kids with autism. Significant decline in the blood level of lead and mercury with the use of DMSA as a chelating agent. In addition, there was decline in the autistic symptoms with the decrease in the lead and mercury level in blood. CONCLUSION: Lead and mercury considered as one of the main causes of autism. Environmental exposure as well as defect in heavy metal metabolism is responsible for the high level of heavy metals. Detoxification by chelating agents had great role in improvement of those kids. PMID- 25461564 TI - Mitochondrion-mediated apoptosis is involved in reproductive damage caused by BPA in male rats. AB - Bisphenol A (BPA) is a widely used environmental endocrine disruptor. Many studies have reported that BPA exposure shows reproductive toxicity and causes apoptosis in spermatogenic cells. However, few studies have investigated the relationship between the mitochondrial pathway and BPA-induced apoptosis. This study investigated the role of the mitochondrial pathway in apoptosis induced by BPA, which resulted in compromised male rat spermatogenesis and reproductive damage. Rats were exposed to various BPA concentrations (0, 50, 100, or 200mg of BPA/kg body weight per day), and factors in the mitochondrial signal transduction pathway and the apoptosis indices of spermatogenic cells were measured and sperm characteristics were analyzed. Our data revealed that BPA exposure increased the protein and mRNA levels of cytochrome C, apoptosis-inducing factor, caspase-3/9, and Bax; caspase-3 and caspase-9 activities; and the apoptosis indices of spermatogenic cells. In addition, abnormal structure of mitochondria and decreased protein and gene levels of Bcl-2 were observed following BPA exposure. These results suggest that apoptosis in the mitochondrial pathway mediates compromised reproductive system function caused by BPA exposure. PMID- 25461566 TI - Making connections: snapshots of chlamydial type III secretion systems in contact with host membranes. AB - Chlamydiae are obligate intracellular bacterial pathogens with an unusual biphasic lifecycle, which is underpinned by two bacterial forms of distinct structure and function. Bacterial entry and replication require a type III secretion system (T3SS), a widely conserved nanomachine responsible for the translocation of virulence effectors into host cells. Recent cell biology experiments supported by electron and cryo-electron tomography have provided fresh insights into Chlamydia-host interactions. In this review, we highlight some of the recent advances, particularly the in situ analysis of T3SSs in contact with host membranes during chlamydial entry and intracellular replication, and the role of the host rough endoplasmic reticulum (rER) at the recently described intracellular 'pathogen synapse'. PMID- 25461568 TI - Targeting of plant pattern recognition receptor-triggered immunity by bacterial type-III secretion system effectors. AB - During infection, microbes are detected by surface-localized pattern recognition receptors (PRRs), leading to an innate immune response that prevents microbial ingress. Therefore, successful pathogens must evade or inhibit PRR-triggered immunity to cause disease. In the past decade, a number of type-III secretion system effector (T3Es) proteins from plant pathogenic bacteria have been shown to suppress this layer of innate immunity. More recently, the detailed mechanisms of action have been defined for several of these effectors. Interestingly, effectors display a wide array of virulence targets, being able to prevent activation of immune receptors and to hijack immune signaling pathways. Besides being a fascinating example of pathogen-host co-evolution, effectors have also emerged as valuable tools to dissect important biological processes in host cells. PMID- 25461567 TI - Integrated circuits: how transcriptional silencing and counter-silencing facilitate bacterial evolution. AB - Horizontal gene transfer is a major contributor to bacterial evolution and diversity. For a bacterial cell to utilize newly-acquired traits such as virulence and antibiotic resistance, new genes must be integrated into the existing regulatory circuitry to allow appropriate expression. Xenogeneic silencing of horizontally-acquired genes by H-NS or other nucleoid-associated proteins avoids adventitious expression and can be relieved by other DNA-binding counter-silencing proteins in an environmentally-responsive and physiologically responsive manner. Biochemical and genetic analyses have recently demonstrated that counter-silencing can occur at a variety of promoter architectures, in contrast to classical transcriptional activation. Disruption of H-NS nucleoprotein filaments by DNA bending is a suggested mechanism by which silencing can be relieved. This review discusses recent advances in our understanding of the mechanisms and importance of xenogeneic silencing and counter-silencing in the successful integration of horizontally-acquired genes into regulatory networks. PMID- 25461565 TI - Functional conservation and divergence of four ginger AP1/AGL9 MADS-box genes revealed by analysis of their expression and protein-protein interaction, and ectopic expression of AhFUL gene in Arabidopsis. AB - Alpinia genus are known generally as ginger-lilies for showy flowers in the ginger family, Zingiberaceae, and their floral morphology diverges from typical monocotyledon flowers. However, little is known about the functions of ginger MADS-box genes in floral identity. In this study, four AP1/AGL9 MADS-box genes were cloned from Alpinia hainanensis, and protein-protein interactions (PPIs) and roles of the four genes in floral homeotic conversion and in floral evolution are surveyed for the first time. AhFUL is clustered to the AP1 lineage, AhSEP4 and AhSEP3b to the SEP lineage, and AhAGL6-like to the AGL6 lineage. The four genes showed conserved and divergent expression patterns, and their encoded proteins were localized in the nucleus. Seven combinations of PPI (AhFUL-AhSEP4, AhFUL AhAGL6-like, AhFUL-AhSEP3b, AhSEP4-AhAGL6-like, AhSEP4-AhSEP3b, AhAGL6-like AhSEP3b, and AhSEP3b-AhSEP3b) were detected, and the PPI patterns in the AP1/AGL9 lineage revealed that five of the 10 possible combinations are conserved and three are variable, while conclusions cannot yet be made regarding the other two. Ectopic expression of AhFUL in Arabidopsis thaliana led to early flowering and floral organ homeotic conversion to sepal-like or leaf-like. Therefore, we conclude that the four A. hainanensis AP1/AGL9 genes show functional conservation and divergence in the floral identity from other MADS-box genes. PMID- 25461569 TI - Salmonella enterica: living a double life in epithelial cells. AB - Intracellular bacterial pathogens can occupy a membrane-bound vacuole or live freely within the cytosol of mammalian cells. Many studies have shown that the enteric bacterium, Salmonella enterica serovar Typhimurium (S. Typhimurium), is a vacuolar pathogen. Recent data, however, have revealed that within epithelial cells there are subpopulations of vacuolar and cytosolic Salmonella. Release from the Salmonella-containing vacuole leads to transcriptional reprogramming of bacteria and their robust replication in the cytosol. Eventually, epithelial cell death via pyroptosis results in cell lysis, proinflammatory cytokine release and escape of the cytosolic bacteria into the extracellular space, providing a potential mechanism of dissemination. This review focuses on the current understanding of this newly described intracellular population of Salmonella. PMID- 25461570 TI - Antimicrobial inflammasomes: unified signalling against diverse bacterial pathogens. AB - Inflammasomes - molecular platforms for caspase-1 activation - have emerged as common hubs for a number of pathways that detect and respond to bacterial pathogens. Caspase-1 activation results in the secretion of bioactive IL-1beta and IL-18 and pyroptosis, and thus launches a systemic immune and inflammatory response. In this review we discuss signal transduction leading to 'canonical' and 'non-canonical' activation of caspase-1 through the involvement of upstream caspases. Recent studies have identified a growing number of regulatory networks involving guanylate binding proteins, protein kinases, ubiquitylation and necroptosis related pathways that modulate inflammasome responses and immunity to bacterial infection. By being able to respond to extracellular, vacuolar and cytosolic bacteria, their cytosolic toxins or ligands for cell surface receptors, inflammasomes have emerged as important sentinels of infection. PMID- 25461573 TI - Novel receptors for bacterial protein toxins. AB - While bacterial effectors are often directly introduced into eukaryotic target cells by various types of injection machines, toxins enter the cytosol of host cells from endosomal compartments or after retrograde transport via Golgi from the ER. A first crucial step of toxin-host interaction is receptor binding. Using optimized protocols and new methods novel toxin receptors have been identified, including metalloprotease ADAM 10 for Staphylococcus aureus alpha-toxin, laminin receptor Lu/BCAM for Escherichia coli cytotoxic necrotizing factor CNF1, lipolysis stimulated lipoprotein receptor (LSR) for Clostridium difficile transferase CDT and low-density lipoprotein receptor-related protein (LRP) 1 for Clostridium perfringens TpeL toxin. PMID- 25461572 TI - The impact of genomics on population genetics of parasitic diseases. AB - Parasites, defined as eukaryotic microbes and parasitic worms that cause global diseases of human and veterinary importance, span many lineages in the eukaryotic Tree of Life. Historically challenging to study due to their complicated life cycles and association with impoverished settings, their inherent complexities are now being elucidated by genome sequencing. Over the course of the last decade, projects in large sequencing centers, and increasingly frequently in individual research labs, have sequenced dozens of parasite reference genomes and field isolates from patient populations. This 'tsunami' of genomic data is answering questions about parasite genetic diversity, signatures of evolution orchestrated through anti-parasitic drug and host immune pressure, and the characteristics of populations. This brief review focuses on the state of the art of parasitic protist genomics, how the peculiar genomes of parasites are driving creative methods for their sequencing, and the impact that next-generation sequencing is having on our understanding of parasite population genomics and control of the diseases they cause. PMID- 25461574 TI - The application of genomics to tracing bacterial pathogen transmission. AB - New sequencing technologies have made it possible to generate bacterial genomes at clinically relevant timescales and price levels. The use of whole-genome sequencing (WGS) has proved useful for investigating transmission at different scales. WGS data are highly effective at determining whether individuals are part of the same transmission chain, making it possible to detect probable direct transmission events, delimit the extent of local nosocomial or community-based outbreaks, and identify worldwide patterns of spread and long-term dynamics of bacterial pathogens. Making the most of WGS data will probably always require associated detailed epidemiological data, but nevertheless it promises to become an increasingly valuable tool for infection control in the near future. PMID- 25461571 TI - Neutrophil serine proteases in antibacterial defense. AB - Neutrophil serine proteases (NSPs) are critical for the effective functioning of neutrophils and greatly contribute to immune protection against bacterial infections. Thanks to their broad substrate specificity, these chymotrypsin-like proteases trigger multiple reactions that are detrimental to bacterial survival such as direct bacterial killing, generation of antimicrobial peptides, inactivation of bacterial virulence factors and formation of neutrophil extracellular traps. Recently, the importance of NSPs in antibacterial defenses has been further underscored by discoveries of unique bacterial evasion strategies to combat these proteases. Bacteria can indirectly disarm NSPs by protecting bacterial substrates against NSP cleavage, but also produce inhibitory molecules that potently block NSPs. Here we review recent insights in the functional contribution of NSPs in host protection against bacterial infections and the elegant strategies that bacteria use to counteract these responses. PMID- 25461575 TI - Neisseria meningitidis: pathogenesis and immunity. AB - The recent advances in cellular microbiology, genomics, and immunology has opened new horizons in the understanding of meningococcal pathogenesis and in the definition of new prophylactic intervention. It is now clear that Neissera meningitidis has evolved a number of surface structures to mediate interaction with host cells and a number of mechanisms to subvert the immune system and escape complement-mediated killing. In this review we report the more recent findings on meningococcal adhesion and on the bacteria-complement interaction highlighting the redundancy of these mechanisms. An effective vaccine against meningococcus B, based on multiple antigens with different function, has been recently licensed. The antibodies induced by the 4CMenB vaccine could mediate bacterial killing by activating directly the classical complement pathway or, indirectly, by preventing binding of fH on the bacterial surface and interfering with colonization. PMID- 25461576 TI - Post-modern pathogens: surprising activities of translocated effectors from E. coli and Legionella. AB - Many bacterial pathogens have the ability to manipulate cellular processes and interfere with host cell function through the translocation of bacterial 'effector' proteins. Dedicated protein secretion machines from Gram-negative pathogens, including type III, type IV and type VI secretion systems, inject virulence proteins into infected cells, altering normal cell physiology, including cell structure, metabolism, trafficking and signalling. While effectors were once thought to exert an effect simply by their localization and binding to host cell proteins, increasingly effectors are being recognised as enzymes, in some cases mediating highly novel post-translational modifications on host proteins. Here we highlight some of the more unusual activities of translocated effectors from enteropathogenic Escherichia coli and Legionella pneumophila. PMID- 25461577 TI - New insights into the role of Bartonella effector proteins in pathogenesis. AB - The facultative intracellular bacteria Bartonella spp. share a common infection strategy to invade and colonize mammals in a host-specific manner. Following transmission by blood-sucking arthropods, Bartonella are inoculated in the derma and then spread, via two sequential enigmatic niches, to the blood stream where they cause a long-lasting intra-erythrocytic bacteraemia. The VirB/VirD4 type IV secretion system (VirB/D4 T4SS) is essential for the pathogenicity of most Bartonella species by injecting an arsenal of effector proteins into host cells. These bacterial effector proteins share a modular architecture, comprising domains and/or motifs that confer an array of functions. Here, we review recent advances in understanding the function and evolutionary origin of this fascinating repertoire of host-targeted bacterial effectors. PMID- 25461578 TI - Legionella pneumophila: homeward bound away from the phagosome. AB - The intracellular pathogen Legionella pneumophila (Lp) survives and replicates inside a specialized vacuolar compartment that evades canonical phagosomal maturation. Through the action of a large number of effectors translocated into the host cytosol via the Dot/Icm type IV secretion system, Lp subverts host cell pathways to convert its nascent phagosome into an ER-derived compartment, the Legionella containing vacuole (LCV), which serves as bacterial replication niche. PMID- 25461580 TI - Taking the pseudo out of pseudogenes. AB - Pseudogenes are defined as fragments of once-functional genes that have been silenced by one or more nonsense, frameshift or missense mutations. Despite continuing increases in the speed of sequencing and annotating bacterial genomes, the identification and categorisation of pseudogenes remains problematic. Even when identified, pseudogenes are considered to be rare and tend to be ignored. On the contrary, pseudogenes are surprisingly prevalent and can persist for long evolutionary time periods, representing a record of once-functional genetic characteristics. Most importantly, pseudogenes provide an insight into prokaryotic evolutionary history as a record of phenotypic traits that have been lost. Focusing on the intracellular and symbiotic bacteria in which pseudogenes predominate, this review discusses the importance of identifying pseudogenes to fully understand the abilities of bacteria, and to understand prokaryotes within their evolutionary context. PMID- 25461579 TI - Microbial pathogenesis and host defense in the nematode C. elegans. AB - Epithelial cells line the surfaces of the body, and are on the front lines of defense against microbial infection. Like many other metazoans, the nematode Caenorhabditis elegans lacks known professional immune cells and relies heavily on defense mediated by epithelial cells. New results indicate that epithelial defense in C. elegans can be triggered through detection of pathogen-induced perturbation of core physiology within host cells and through autophagic defense against intracellular and extracellular pathogens. Recent studies have also illuminated a diverse array of pathogenic attack strategies used against C. elegans. These findings are providing insight into the underpinnings of host/pathogen interactions in a simple animal host that can inform studies of infectious diseases in humans. PMID- 25461581 TI - One chromosome, one contig: complete microbial genomes from long-read sequencing and assembly. AB - Like a jigsaw puzzle with large pieces, a genome sequenced with long reads is easier to assemble. However, recent sequencing technologies have favored lowering per-base cost at the expense of read length. This has dramatically reduced sequencing cost, but resulted in fragmented assemblies, which negatively affect downstream analyses and hinder the creation of finished (gapless, high-quality) genomes. In contrast, emerging long-read sequencing technologies can now produce reads tens of kilobases in length, enabling the automated finishing of microbial genomes for under $1000. This promises to improve the quality of reference databases and facilitate new studies of chromosomal structure and variation. We present an overview of these new technologies and the methods used to assemble long reads into complete genomes. PMID- 25461582 TI - The rest of the story: the microbiome and gastrointestinal infections. AB - Bacterial infectious diseases are studied primarily as a host-pathogen dyad. However it is increasingly apparent that the gut microbial community is an important participant in these interactions. The gut microbiota influences bacterial infections in a number of ways, including via bacterial metabolism, stimulation of host immunity and direct bacterial antagonism. This review focuses on recent findings highlighting the interplay between the gastrointestinal microbiota, its host and bacterial pathogens; and emphasizes how these interactions ultimately impact our understanding of infectious diseases. PMID- 25461583 TI - Imaging of soft material with carbon nanotube tip using near-field scanning microwave microscopy. AB - In this manuscript, a near-field scanning microwave microscope (NSMM) of our own design is introduced while using a multi-walled carbon nanotube (MWCNT) bundle as the tip (referred to as 'CNT tip'). Clear images of gold-patterned numbers, photoresist stripes and corneal endothelial cells (cell line B4G12) were obtained by mapping the resonant frequency fr and S11 amplitude of a given area while the NSMM is operating in tapping mode. The CNT tip helps to improve image quality and reveals more information about the sample as compared to a traditional metallic tip. The CNT tip is flexible and does not scratch the surface of the sample during the scan, which is useful for imaging soft material in biological science. In the imaging of the B4G12 endothelial cells, the nuclei and cytoplasm can be clearly distinguished from the rest of the cell and its surrounding medium. PMID- 25461584 TI - High-resolution STEM imaging with a quadrant detector--conditions for differential phase contrast microscopy in the weak phase object approximation. AB - Differential phase contrast is a contrast mechanism that can be utilized in the scanning transmission electron microscope (STEM) to determine the distribution of magnetic or electric fields. In practice, several different detector geometries can be used to obtain differential phase contrast. As recent high resolution differential phase contrast experiments with the STEM are focused on ring quadrant detectors, we evaluate the contrast transfer characteristics of different quadrant detector geometries, namely two ring quadrant detectors with different inner detector angles and a conventional quadrant detector, by calculating the corresponding phase gradient transfer functions. For an ideal microscope and a weak phase object, this can be done analytically. The calculated phase gradient transfer functions indicate that the barely illuminated ring quadrant detector setup used for imaging magnetic fields in the specimen reduces the resolution limit to about 2.5A for an aberration corrected STEM. Our results show that the resolution can be drastically improved by using a conventional quadrant detector instead. PMID- 25461585 TI - Solving protein nanocrystals by cryo-EM diffraction: multiple scattering artifacts. AB - The maximum thickness permissible within the single-scattering approximation for the determination of the structure of perfectly ordered protein microcrystals by transmission electron diffraction is estimated for tetragonal hen-egg lysozyme protein crystals using several approaches. Multislice simulations are performed for many diffraction conditions and beam energies to determine the validity domain of the required single-scattering approximation and hence the limit on crystal thickness. The effects of erroneous experimental structure factor amplitudes on the charge density map for lysozyme are noted and their threshold limits calculated. The maximum thickness of lysozyme permissible under the single scattering approximation is also estimated using R-factor analysis. Successful reconstruction of density maps is found to result mainly from the use of the phase information provided by modeling based on the protein data base through molecular replacement (MR), which dominates the effect of poor quality electron diffraction data at thicknesses larger than about 200 A. For perfectly ordered protein nanocrystals, a maximum thickness of about 1000 A is predicted at 200 keV if MR can be used, using R-factor analysis performed over a subset of the simulated diffracted beams. The effects of crystal bending, mosaicity (which has recently been directly imaged by cryo-EM) and secondary scattering are discussed. Structure-independent tests for single-scattering and new microfluidic methods for growing and sorting nanocrystals by size are reviewed. PMID- 25461586 TI - Designing a standard for strain mapping: HR-EBSD analysis of SiGe thin film structures on Si. AB - Patterned SiGe thin film structures, heteroepitaxially deposited on Si substrates, are investigated as potential reference standards to establish the accuracy of high resolution electron backscattered diffraction (HR-EBSD) strain measurement methods. The proposed standards incorporate thin films of tetragonally distorted epitaxial Si1-xGex adjacent to strain-free Si. Six films of three different nominal compositions (x=0.2, 0.3, and 0.4) and various thicknesses were studied. Film composition and out-of-plane lattice spacing measurements, by x-ray photoelectron spectroscopy and x-ray diffraction, respectively, provided independent determinations of film epitaxy and predictions of tetragonal strain for direct comparison with HR-EBSD strain measurements. Films assessed to be coherent with the substrate exhibited tetragonal strain values measured by HR-EBSD identical to those predicted from the composition and x-ray diffraction measurements, within experimental relative uncertainties of order 2%. Such films thus provide suitable prototypes for designing a strain reference standard. PMID- 25461587 TI - Retrieving depth-direction information from TEM diffraction data under reciprocal space sampling variation. AB - For full three-dimensional information retrieval from transmission electron microscope data, retrieving the third-dimension (beam-direction) information is an important challenge. Recently, we have developed an artificial-neural-network based retrieval algorithm suitable for retrieving three-dimensional nanoscale crystal parameters like strain, including with noisy data (R.S. Pennington, W. Van den Broek, C.T. Koch, Phys. Rev. B 89 (20) (2014) 205409 [12]). In this work, we examine how reciprocal-space sampling conditions influence the retrieved crystal parameters, using crystal tilt as an example parameter, and demonstrate retrieval for 2.5 nm depth resolution. For noise-free data, we find that the total reciprocal-space area is the key parameter; however, when the data are noisy, the number of reciprocal-space points and the amount of noise are also influential. We also apply our algorithm to a simulated bent specimen, and recover the bending as expected. Guidelines for experimental applications are also discussed. PMID- 25461588 TI - Towards denoising XMCD movies of fast magnetization dynamics using extended Kalman filter. AB - The Kalman filter is a well-established approach to get information on the time dependent state of a system from noisy observations. It was developed in the context of the Apollo project to see the deviation of the true trajectory of a rocket from the desired trajectory. Afterwards it was applied to many different systems with small numbers of components of the respective state vector (typically about 10). In all cases the equation of motion for the state vector was known exactly. The fast dissipative magnetization dynamics is often investigated by x-ray magnetic circular dichroism movies (XMCD movies), which are often very noisy. In this situation the number of components of the state vector is extremely large (about 10(5)), and the equation of motion for the dissipative magnetization dynamics (especially the values of the material parameters of this equation) is not well known. In the present paper it is shown by theoretical considerations that - nevertheless - there is no principle problem for the use of the Kalman filter to denoise XMCD movies of fast dissipative magnetization dynamics. PMID- 25461589 TI - Dark-field imaging based on post-processed electron backscatter diffraction patterns of bulk crystalline materials in a scanning electron microscope. AB - Dark-field (DF) images were acquired in the scanning electron microscope with an offline procedure based on electron backscatter diffraction (EBSD) patterns (EBSPs). These EBSD-DF images were generated by selecting a particular reflection on the electron backscatter diffraction pattern and by reporting the intensity of one or several pixels around this point at each pixel of the EBSD-DF image. Unlike previous studies, the diffraction information of the sample is the basis of the final image contrast with a pixel scale resolution at the EBSP providing DF imaging in the scanning electron microscope. The offline facility of this technique permits the selection of any diffraction condition available in the diffraction pattern and displaying the corresponding image. The high number of diffraction-based images available allows a better monitoring of deformation structures compared to electron channeling contrast imaging (ECCI) which is generally limited to a few images of the same area. This technique was applied to steel and iron specimens and showed its high capability in describing more rigorously the deformation structures around micro-hardness indents. Due to the offline relation between the reference EBSP and the EBSD-DF images, this new technique will undoubtedly greatly improve our knowledge of deformation mechanism and help to improve our understanding of the ECCI contrast mechanisms. PMID- 25461590 TI - Electron imaging with an EBSD detector. AB - Electron Backscatter Diffraction (EBSD) has proven to be a useful tool for characterizing the crystallographic orientation aspects of microstructures at length scales ranging from tens of nanometers to millimeters in the scanning electron microscope (SEM). With the advent of high-speed digital cameras for EBSD use, it has become practical to use the EBSD detector as an imaging device similar to a backscatter (or forward-scatter) detector. Using the EBSD detector in this manner enables images exhibiting topographic, atomic density and orientation contrast to be obtained at rates similar to slow scanning in the conventional SEM manner. The high-speed acquisition is achieved through extreme binning of the camera-enough to result in a 5 * 5 pixel pattern. At such high binning, the captured patterns are not suitable for indexing. However, no indexing is required for using the detector as an imaging device. Rather, a 5 * 5 array of images is formed by essentially using each pixel in the 5 * 5 pixel pattern as an individual scattered electron detector. The images can also be formed at traditional EBSD scanning rates by recording the image data during a scan or can also be formed through post-processing of patterns recorded at each point in the scan. Such images lend themselves to correlative analysis of image data with the usual orientation data provided by and with chemical data obtained simultaneously via X-Ray Energy Dispersive Spectroscopy (XEDS). PMID- 25461591 TI - Imaging of tissue sections with very slow electrons. AB - The examination of thin sections of tissues with electron microscopes is an indispensable tool. Being composed of light elements, samples of living matter illuminated with electrons at the usual high energies of tens or even hundreds of kiloelectronvolts provide very low image contrasts in transmission or scanning transmission electron microscopes. Therefore, heavy metal salts are added to the specimen during preparation procedures (post-fixation with osmium tetroxide or staining). However, these procedures can modify or obscure the ultrastructural details of cells. Here we show that the energy of electrons used for the scanned transmission imaging of tissue sections can be reduced to mere hundreds or even tens of electronvolts and can produce extremely high contrast even for samples free of any metal salts. We found that when biasing a sufficiently thin tissue section sample to a high negative potential in a scanning transmission electron microscope, thereby reducing the energy of the electrons landing on the sample, and collecting the transmitted electrons with a grounded detector, we obtain a high contrast revealing structure details not enhanced by heavy atoms. Moreover, bombardment with slow electrons sensitively depolymerises the resin in which the tissue is embedded, thereby enhancing the transmitted signal with no observable loss of structure details. The use of low-energy electrons requires ultrathin sections of a thickness of less than 10nm, but their preparation is now possible. Ultralow energy STEM provides a tool enabling the observation of very thin biological samples without any staining. This method should also be advantageous for examination of 2D crystals, thin films of polymers, polymer blends, etc. PMID- 25461592 TI - Framed carbon nanostructures: synthesis and applications in functional SPM tips. AB - We present a synthesis method to fabricate framed carbon-based nanostructures having highly anisotropic shapes, in particular, the nanofork and nanoscalpel structures which are obtained systematically under optimized growth conditions. A theoretical model is developed to explain the formation of such nanostructures on Si cantilevers and W etched wires exposed to a focused electron beam. We then demonstrate the potentials of these nanostructures as functional tips for scanning probe microscopy. Owing to their anisotropic shapes, such tips can be very useful for nanolithography, nanosurgery of biological objects, and precise manipulation with surface particles. Overall, our method provides a simple and robust way to produce functional scanning probe microscopy tips with variable shapes and enhanced capabilities for different applications compared to standard cantilevers. PMID- 25461593 TI - Enhanced quantification for 3D SEM-EDS: using the full set of available X-ray lines. AB - An enhanced method to quantify energy dispersive spectra recorded in 3D with a scanning electron microscope (3D SEM-EDS) has been previously demonstrated. This paper presents an extension of this method using all the available X-ray lines generated by the beam. The extended method benefits from using high energy lines, that are more accurately quantified, and from using soft X-rays that are highly absorbed and thus more surface sensitive. The data used to assess the method are acquired with a dual beam FIB/SEM investigating a multi-element Ni-based superalloy. A high accelerating voltage, needed to excite the highest energy X ray line, results in two available X-ray lines for several elements. The method shows an improved compositional quantification as well as an improved spatial resolution. PMID- 25461594 TI - Analytic solution for a quartic electron mirror. AB - A converging electron mirror can be used to compensate for spherical and chromatic aberrations in an electron microscope. This paper presents an analytical solution to a diode (two-electrode) electrostatic mirror including the next term beyond the known hyperbolic shape. The latter is a solution of the Laplace equation to second order in the variables perpendicular to and along the mirror's radius (z(2)-r(2)/2) to which we add a quartic term (klambdaz(4)). The analytical solution is found in terms of Jacobi cosine-amplitude functions. We find that a mirror less concave than the hyperbolic profile is more sensitive to changes in mirror voltages and the contrary holds for the mirror more concave than the hyperbolic profile. PMID- 25461595 TI - BMP4 increases the expression of TRPC and basal [Ca2+]i via the p38MAPK and ERK1/2 pathways independent of BMPRII in PASMCs. AB - Multiple abnormalities of bone morphogenetic protein (BMPs) signaling are implicated in the process of pulmonary arterial hypertension (PAH). BMP4 plays an important role during the process of pulmonary arterial remodeling and mutant of the principle BMP4 receptor, BMP receptors II (BMPRII), is found to associate with the development of PAH. However, the likely mechanism defining the contribution of BMPRII to BMP4 mediated signaling in pulmonary arterial smooth muscle cells (PASMCs) remains comprehensively unclear. We previously found that enhanced store operated calcium entry (SOCE) and basal intracellular calcium concentration [Ca2+]i were induced by BMP4 via upregulation of TRPC1, 4 and 6 expression in PASMCs, and that BMP4 modulated TRPC channel expression through activating p38MAPK and ERK1/2 signaling pathways. In this study, BMPRII siRNA was used to knockdown BMPRII expression to investigate whether BMP4 upregulates the expression of TRPC and activating Smad1/5/8, ERK1/2 and p38MAPK pathway via BMPRII in distal PASMCs. Our results showed that knockdown of BMPRII: 1) attenuated BMP4 induced activation of P-Smad1/5/8, without altering BMP4 induced P-p38MAPK and P-ERK1/2 activation in PASMCs; 2) did not attenuate the BMP4 induced TRPC1, 4 and 6 expression; 3) did not affect BMP4-enhanced SOCE and basal [Ca2+]i. Thus, we concluded that BMP4 activated Smad1/5/8 pathway is BMPRII dependent, while the BMP4 - ERK/p-P38 - TRPC - SOCE signaling axis are likely mediated through other receptor rather than BMPRII. PMID- 25461596 TI - Diffusion of information throughout the host interactome reveals gene expression variations in network proximity to target proteins of hepatitis C virus. AB - Hepatitis C virus infection is one of the most common and chronic in the world, and hepatitis associated with HCV infection is a major risk factor for the development of cirrhosis and hepatocellular carcinoma (HCC). The rapidly growing number of viral-host and host protein-protein interactions is enabling more and more reliable network-based analyses of viral infection supported by omics data. The study of molecular interaction networks helps to elucidate the mechanistic pathways linking HCV molecular activities and the host response that modulates the stepwise hepatocarcinogenic process from preneoplastic lesions (cirrhosis and dysplasia) to HCC. Simulating the impact of HCV-host molecular interactions throughout the host protein-protein interaction (PPI) network, we ranked the host proteins in relation to their network proximity to viral targets. We observed that the set of proteins in the neighborhood of HCV targets in the host interactome is enriched in key players of the host response to HCV infection. In opposition to HCV targets, subnetworks of proteins in network proximity to HCV targets are significantly enriched in proteins reported as differentially expressed in preneoplastic and neoplastic liver samples by two independent studies. Using multi-objective optimization, we extracted subnetworks that are simultaneously "guilt-by-association" with HCV proteins and enriched in proteins differentially expressed. These subnetworks contain established, recently proposed and novel candidate proteins for the regulation of the mechanisms of liver cells response to chronic HCV infection. PMID- 25461598 TI - Metformin protects skeletal muscle from cardiotoxin induced degeneration. AB - The skeletal muscle tissue has a remarkable capacity to regenerate upon injury. Recent studies have suggested that this regenerative process is improved when AMPK is activated. In the muscle of young and old mice a low calorie diet, which activates AMPK, markedly enhances muscle regeneration. Remarkably, intraperitoneal injection of AICAR, an AMPK agonist, improves the structural integrity of muscles of dystrophin-deficient mdx mice. Building on these observations we asked whether metformin, a powerful anti-hyperglycemic drug, which indirectly activates AMPK, affects the response of skeletal muscle to damage. In our conditions, metformin treatment did not significantly influence muscle regeneration. On the other hand we observed that the muscles of metformin treated mice are more resilient to cardiotoxin injury displaying lesser muscle damage. Accordingly myotubes, originated in vitro from differentiated C2C12 myoblast cell line, become more resistant to cardiotoxin damage after pre incubation with metformin. Our results indicate that metformin limits cardiotoxin damage by protecting myotubes from necrosis. Although the details of the molecular mechanisms underlying the protective effect remain to be elucidated, we report a correlation between the ability of metformin to promote resistance to damage and its capacity to counteract the increment of intracellular calcium levels induced by cardiotoxin treatment. Since increased cytoplasmic calcium concentrations characterize additional muscle pathological conditions, including dystrophies, metformin treatment could prove a valuable strategy to ameliorate the conditions of patients affected by dystrophies. PMID- 25461599 TI - Bite injuries of grey seals (Halichoerus grypus) on harbour porpoises (Phocoena phocoena). AB - Bite-like skin lesions on harbour porpoises (Phocoena phocoena) have been suspected to be caused by grey seals (Halichoerus grypus), and a few field observations have been reported. Bite-like skin lesions observed on stranded animals were characterized by two main components: large flaps of loose or missing skin and blubber with frayed edges and puncture lesions. Definitive demonstration of predation by a grey seal was not reported so far in those stranded animals. In this study, five stranded porpoises with bite-like skin lesions were swabbed for genetic investigations. In addition, the head of a recently dead grey seal was used to mimic bite-like skin injuries on a porpoise carcass. Subsequently, the artificial skin injuries were swabbed, along with the gum of the seal used for inflicting them (positive controls). Total DNA was extracted from the swabs and was used to retrieve a fragment of mitochondrial DNA by PCR. Primers were designed to amplify a specific stretch of mitochondrial DNA known to differ between grey seals and porpoises. The amplicon targeted was successfully amplified from the positive control and from two of the stranded porpoises, and grey seal-specific mitochondrial DNA was retrieved from all those samples. We conclude that (1) it is possible to detect grey seal DNA from dead porpoises even after several days in seawater and (2) bite-like skin lesions found on dead porpoises definitively result from grey seals attacks. The attacks are most likely linked with predation although, in a number of cases, scavenging and aggressive behaviour cannot be excluded. PMID- 25461601 TI - Detection rate of diarrhoea-causing Kudoa hexapunctata in Pacific bluefin tuna Thunnus orientalis from Japanese waters. AB - Diffuse outbreaks of food poisoning with unknown aetiologies leading to diarrhoea and vomiting within a short time after ingesting flatfish (Paralichthys olivaceus), tuna (Thunnus spp.), or amberjack (Seriola dumerili) have occurred nationwide in Japan, including the Tokyo metropolitan area. In this study, we surveyed the detection rates of kudoid parasites in 12 tuna samples that caused clinical diarrhoea from 2009 to 2012; we assessed 104 samples of whole juvenile Pacific bluefin tuna (PBT, Thunnus orientalis) and 153 block samples of other tuna distributed in the Tokyo Metropolitan Central Wholesale Market. The survey revealed that more than 70% of clinical diarrhoea cases due to tuna ingestion occurred between June and September, and Kudoa hexapunctata were detected in 9 of 12 tuna samples associated with clinical diarrhoea cases. The numbers of spores and 18S ribosomal DNA (rDNA) copies per gram of fish in 8 of 9 samples were more than 1*10(6) spores and 1*10(9) copies, respectively. Market research revealed that the K. hexapunctata-positive rate in juvenile PBT from Japanese waters was 64.4% (67/104) but that in adult PBT was 10.4% (7/67). The numbers of K. hexapunctata 18S rDNA copies in 64.5% (20/31) samples and 72.7% (16/22) of <5kg fish samples collected between May and July were more than 1*10(9)copies/g. On the other hand, kudoid parasites were not detected from 73 tuna samples except for a single sample of Thunnus albacares. Cell monolayer permeability assays performed to examine the toxicity of K. hexapunctata against Caco-2 cells revealed that the transepithelial electrical resistance (TER) in 5*10(7)K. hexapunctata spores decreased by 80% within 2-4h. In conclusion, K. hexapunctata was commonly detected in juvenile PBT from Japanese waters and are a likely cause of the diarrhoea outbreaks. PMID- 25461600 TI - Continuously moving table MRI with golden angle radial sampling. AB - PURPOSE: Continuously moving table (CMT) MRI is a high throughput technique that has multiple applications in whole-body imaging. In this work, CMT MRI based on golden angle (GA, 111.246 degrees azimuthal step) radial sampling is developed at 3 Tesla (T), with the goal of increased flexibility in image reconstruction using arbitrary profile groupings. THEORY AND METHODS: CMT MRI with GA and linear angle (LA) schemes were developed for whole-body imaging at 3T with a table speed of 20 mm/s. Imaging was performed in phantoms and a human volunteer with extended z fields of view of up to 1.8 meters. Four separate LA and a single GA scan were performed to enable slice reconstructions at four different thicknesses. RESULTS: GA CMT MRI produced high image quality in phantoms and humans and allowed complete flexibility in reconstruction of slices with arbitrary slice thickness and position from a single data set. LA CMT MRI was constrained by predetermined parameters, required multiple scans and suffered from stair step artifacts that were not present in GA images. CONCLUSION: GA sampling provides a robust flexible approach to CMT whole-body MRI with the ability to reconstruct slices at arbitrary positions and thicknesses from a single scan. PMID- 25461603 TI - Impact of postharvest processing on the fungal population contaminating African walnut shells (Tetracarpidium conophorum Mull. Arg) at different maturity stages and potential mycotoxigenic implications. AB - African walnut (Tetracarpidium conophorum Mull. Arg) is commonly processed by boiling or toasting and consumed as a snack or used as a thickener in many West African soup preparations. The nuts are usually exposed to both high temperatures and high relative humidity in open markets which predisposes them to fungal growth. Hence, the dangers of spore inhalation and resultant mycosis cannot be over-emphasized as retailers and consumers are always in direct contact with these nuts during harvest, processing and consumption. So far, there is no reported research on potential mycotoxin contamination of African walnut and whether this risk might be accentuated by processing. African walnut, at early and late maturity stages, were processed by toasting, boiling or left unprocessed before being stored at 25 degrees C and 37 degrees C, respectively under controlled relative humidity for 7days. Nuts were cracked and shell pieces cultured in malt extract agar (MEA) and Dichloran Glycerol 18 (DG18) media and incubated at 25 degrees C for 7days. Results revealed that potential mycotoxigenic species - Aspergillus section Nigri, Aspergillus flavus/parasiticus, Fusarium spp. and Penicillium spp. - were frequently isolated. When compared with unprocessed nuts, toasting completely prevented fungal contamination in shell pieces from nuts in the non-stored (NSN) group at the early maturity stage, while boiling significantly reduced the level of contamination to about 58% (p<0.05). In general, simulating open market conditions caused 100% fungal contamination in all boiled samples and toasted samples at early maturity. However, contamination in toasted samples at late maturity was increased to 90 and 70% at 25 degrees C in DG18 and MEA, respectively, while at 37 degrees C contamination was 40 and 60% in DG18 and MEA, respectively. Mycotoxin analysis using Yeast Extract Sucrose (YES) agar and High Performance Liquid Chromatography (HPLC)-Fluorescence detection (FLD) showed that Aflatoxins - G1 (AFG1), B1 (AFB1), G2 (AFG2), and B2 (AFB2) were produced by 20 isolates with both AFG1 and AFB1 being predominant at concentration ranges 4.33 32,200 and 4.20-22,700ng/g plug weight, respectively. No ochratoxin A (OTA) was detected out of 23 isolates analysed. From these findings, it is suggested that toasting of nuts, preferably at early maturity is a safer processing option than boiling in terms of prevention of possible fungal growth on nut shells and risk of mycotoxin contamination. PMID- 25461602 TI - Effects of hygienic treatments during slaughtering on microbial dynamics and contamination of sheep meat. AB - The aims of this study were to investigate bacterial dynamics in the sheep meat chain, from fleece to meat trimmings, using both quantitative and qualitative analyses, and to study the effects on microbial load associated with the hygienic interventions of: i) shearing sheep immediately before slaughter, ii) manual steam vacuum pasteurisation, iii) hot water pasteurisation of carcasses, followed by iv) chilling. A further aim was to provide evidence to determine whether or not unshorn sheep should be handled in a processing line separate from that of shorn sheep in Norwegian abattoirs. A total of 176 surface swab samples were collected from three sites along the value chain: i) on fleeces, ii) on carcasses at the end of the slaughter line, and iii) on carcasses after chilling for 24h, and 32 samples were collected from meat trimmings. The results showed that Aerobic Plate Counts (APC) were lower for the shorn group compared to the unshorn group, both on carcasses before chilling and after chilling (difference of 0.8 and 0.9logCFU/1000cm(2) (p<=0.05), respectively) and in meat trimmings (difference of 0.5logCFU/g (p<=0.05)). Hygienic treatments were used on carcasses derived from unshorn sheep, and steam vacuum treatment reduced Escherichia coli, Enterobacteriaceae, and APC before chilling by 1.2, 1.0, and 0.6logCFU/1000cm(2) (p<=0.05), respectively, and hot water pasteurisation, in addition to chilling, reduced E. coli, Enterobacteriaceae, and APC by 0.7, 1.0, and 0.9logCFU/1000cm(2) (p<=0.05), respectively, compared with untreated carcasses. The effect of chilling was shown by the significant reduction of number of carcasses where E. coli were detected; from 65% (13/20) of the shorn group before chilling to 35% (7/20) after chilling, and from 90% (36/40) to 45% (9/20) of the unshorn group. Sequencing of the 16S rRNA gene derived from 316 colonies of Enterobacteriaceae showed a tendency for the relative proportion of the genus Escherichia/Shigella, compared with other genera within Enterobacteriaceae, to be greater for unshorn, untreated sheep than from the other groups at the sampling locations along the meat chain. The study showed that steam vacuum and hot water pasteurisation reduced the contamination of carcasses derived from unshorn sheep, down to the level of the shorn group, and thus can replace the separate processing line for unshorn sheep. Indeed, the low microbial contamination in meat trimmings for all groups indicates that the separate processing line is unnecessary. PMID- 25461604 TI - Survival of Porcine teschovirus as a surrogate virus on pork chops during storage at 2 degrees C. AB - Due to the lack of an efficient cultivation system, little is known about the stability and inactivation of hepatitis E virus (HEV). In addition, there is a lack of information on which cultivable virus(es) are suitable as model or surrogate viruses for HEV. Murine norovirus (MNV) and F-RNA coliphage MS2 are potential surrogates and F-RNA coliphages are a potential indicator for enteric viruses. However, the numbers of F-RNA coliphages excreted by swine are relatively low. In contrast, Porcine teschovirus (PTV) is cultivable and is excreted abundantly. PTV is readily detected on swine carcasses and the potential of PTV as a viral indicator of fecal contamination on hog carcasses is currently being explored, however, there is no information on the environmental stability of PTV. The survival of PTV was determined on vacuum packaged pork chops during storage at 2 degrees C using cultivation and molecular techniques and compared to published data on the survival of MNV and MS2 under similar conditions. Viable PTV was reduced by >=1.8log units compared to a reduction of 0.6 log genomic copies after 7weeks. The viability data indicates that PTV is less stable than MS2 and MNV during storage at 2 degrees C whereas similar reductions in genomic copies were observed for all 3 viruses. This study provides data on the survival of PTV on pork and insight on the potential of PTV as a surrogate for HEV in the pork processing chain. PMID- 25461605 TI - Campylobacter carcass contamination throughout the slaughter process of Campylobacter-positive broiler batches. AB - Campylobacter contamination on broiler carcasses of Campylobacter colonized flocks was quantified at seven sampling sites throughout the slaughter process. For this purpose, in four slaughterhouses samples were collected from twelve Campylobacter positive batches. Broilers from all visits carried high numbers of campylobacters in their caeca (>=7.9log10cfu/g). Campylobacter counts on feathers (up to 6.8log10cfu/g), positively associated with the breast skin contamination of incoming birds and carcasses after plucking, were identified as an additional source of carcass contamination. A high variability in Campylobacter carcass contamination on breast skin samples within batches and between batches in the same slaughterhouse and between slaughterhouses was observed. In slaughterhouses A, B, C and D Campylobacter counts exceeded a limit of 1000cfu/g on 50%, 56%, 78% and 11% of carcasses after chilling, respectively. This finding indicates that certain slaughterhouses are able to better control Campylobacter contamination than others. Overall, the present study focuses on the descriptive analysis of Campylobacter counts in different slaughterhouses, different batches within a slaughterhouse and within a batch at several sampling locations. PMID- 25461606 TI - Response of direct or priming defense against Botrytis cinerea to methyl jasmonate treatment at different concentrations in grape berries. AB - This study was conducted to characterize the forms of disease resistance induced by methyl jasmonate (MeJA) in harvested grape berries and to evaluate the impact of the induced resistance on fruit quality. The results showed that MeJA treatment at concentrations from 10 to 100MUmol/L could effectively induce disease resistance against Botrytis cinerea and reduce disease incidence in grape berries. The induced disease resistance was tightly associated with increased H2O2 generation, enhanced expression of the defense-related gene VvNPR1.1 and accumulation of stilbene phytoalexins such as tran-resveratrol and its oligomer (trans-)epsilon-viniferin. The expression of the defense-related gene and synthesis of phytoalexins in 10MUmol/L MeJA-treated grape berries were only significantly enhanced upon inoculating the berries with B. cinerea, whereas the 50 or 100MUmol/L of MeJA treatment directly induced these defense responses. Hence, we deduce that the low concentration of MeJA (10MUmol/L) triggered a priming defense mechanism, while higher concentrations of MeJA (50 or 100MUmol/L) directly activated defense responses, thus enhancing disease resistance in grape berries. Moreover, the primed grape berries maintained higher contents of soluble sugars and higher DPPH radical scavenging activity and reducing power compared with those expressing direct defense responses. These results indicate that priming of defense is a cost-effective strategy to protect harvested grape berries from B. cinerea infection in terms of minimizing quality loss. PMID- 25461607 TI - Differential outgrowth potential of Clostridium perfringens food-borne isolates with various cpe-genotypes in vacuum-packed ground beef during storage at 12 degrees C. AB - In the current study, the outgrowth of spores of 15 different food isolates of Clostridium perfringens was evaluated in vacuum-packed ground beef during storage at 12 degrees C and 25 degrees C. This included enterotoxic strains carrying the gene encoding the CPE enterotoxin on the chromosome (C-cpe), on a plasmid (P-cpe) and cpe-negative strains. The 15 strains were selected from a larger group of strains that were first evaluated for their ability to sporulate in modified Duncan-Strong sporulating medium. Sporulation ability varied greatly between strains but was not associated with a particular cpe genotype. In line with previous studies, the tested C-cpe strains produced spores with significantly higher heat resistance than the cpe-negative and P-cpe strains (both IS1151 and IS1470-like) with the exception of strain VWA009. Following inoculation of vacuum packed cooked ground beef with spores, the heat-resistant C-cpe strains showed lower outgrowth potential in this model food stored at 12 degrees C than the P cpe and cpe-negative strains, while no significant differences were observed at 25 degrees C. These results suggest that the latter strains may have a competitive advantage over C-cpe strains at reduced temperatures during storage of foods that support the growth of C. perfringens. While spores of P-cpe strains are readily inactivated by heat processing, post-processing contamination by food handlers who may carry P-cpe strains that have a better growth potential at lower temperatures must be avoided. The varying responses of C. perfringens spores to heat and the differences in outgrowth capacity at different temperatures are factors to be considered in strain selection for challenge tests, and for predictive modelling of C. perfringens. PMID- 25461608 TI - Contribution of volatiles to the antifungal effect of Lactobacillus paracasei in defined medium and yogurt. AB - Lactic acid bacteria with antifungal properties can be used to control spoilage of food and feed. Previously, most of the identified metabolites have been isolated from cell-free fermentate of lactic acid bacteria with methods suboptimal for detecting possible contribution from volatiles to the antifungal activity. The role of volatile compounds in the antifungal activity of Lactobacillus paracasei DGCC 2132 in a chemically defined interaction medium (CDIM) and yogurt was therefore investigated with a sampling technique minimizing volatile loss. Diacetyl was identified as the major volatile produced by L. paracasei DGCC 2132 in CDIM. When the strain was added to a yogurt medium diacetyl as well as other volatiles also increased but the metabolome was more complex. Removal of L. paracasei DGCC 2132 cells from CDIM fermentate resulted in loss of both volatiles, including diacetyl, and the antifungal activity towards two strains of Penicillium spp. When adding diacetyl to CDIM or yogurt without L. paracasei DGCC 2132, marked inhibition was observed. Besides diacetyl, the antifungal properties of acetoin were examined, but no antifungal activity was observed. Overall, the results demonstrate the contribution of diacetyl in the antifungal effect of L. paracasei DGCC 2132 and indicate that the importance of volatiles may have been previously underestimated. PMID- 25461609 TI - Investigation of Geotrichum candidum gene expression during the ripening of Reblochon-type cheese by reverse transcription-quantitative PCR. AB - Cheese ripening involves the activity of various bacteria, yeasts or molds, which contribute to the development of the typical color, flavor and texture of the final product. In situ measurements of gene expression are increasingly being used to improve our understanding of the microbial flora activity in cheeses. The objective of the present study was to investigate the physiology and metabolic activity of Geotrichum candidum during the ripening of Reblochon-type cheeses by quantifying mRNA transcripts at various ripening times. The expression of 80 genes involved in various functions could be quantified with a correct level of biological repeatability using a set of three stable reference genes. As ripening progresses, a decrease in expression was observed for genes involved in cell wall organization, translation, vesicular mediated transport, and in cytoskeleton constituents and ribosomal protein genes. There was also a decrease in the expression of mitochondrial F1F0 ATP synthase and plasma membrane H(+) ATPase genes. Some genes involved in the catabolism of lactate, acetate and ethanol were expressed to a greater extent at the beginning of ripening. During the second part of ripening, there was an increased expression of genes involved in the transport and catabolism of amino acids, which could be attributed to a change in the energy source. There was also an increase in the expression of genes involved in autophagy and of genes possibly involved in lifespan determination. Quantification of mRNA transcripts may also be used to produce bioindicators relevant for cheesemaking, for example when considering genes encoding enzymes involved in the catabolism of amino acids. PMID- 25461610 TI - De novo sequencing, assembly and characterization of antennal transcriptome of Anomala corpulenta Motschulsky (Coleoptera: Rutelidae). AB - BACKGROUND: Anomala corpulenta is an important insect pest and can cause enormous economic losses in agriculture, horticulture and forestry. It is widely distributed in China, and both larvae and adults can cause serious damage. It is difficult to control this pest because the larvae live underground. Any new control strategy should exploit alternatives to heavily and frequently used chemical insecticides. However, little genetic research has been carried out on A. corpulenta due to the lack of genomic resources. Genomic resources could be produced by next generation sequencing technologies with low cost and in a short time. In this study, we performed de novo sequencing, assembly and characterization of the antennal transcriptome of A. corpulenta. RESULTS: Illumina sequencing technology was used to sequence the antennal transcriptome of A. corpulenta. Approximately 76.7 million total raw reads and about 68.9 million total clean reads were obtained, and then 35,656 unigenes were assembled. Of these unigenes, 21,463 of them could be annotated in the NCBI nr database, and, among the annotated unigenes, 11,154 and 6,625 unigenes could be assigned to GO and COG, respectively. Additionally, 16,350 unigenes could be annotated in the Swiss-Prot database, and 14,499 unigenes could map onto 258 pathways in the KEGG Pathway database. We also found 24 unigenes related to OBPs, 6 to CSPs, and in total 167 unigenes related to chemodetection. We analyzed 4 OBPs and 3CSPs sequences and their RT-qPCR results agreed well with their FPKM values. CONCLUSION: We produced the first large-scale antennal transcriptome of A. corpulenta, which is a species that has little genomic information in public databases. The identified chemodetection unigenes can promote the molecular mechanistic study of behavior in A. corpulenta. These findings provide a general sequence resource for molecular genetics research on A. corpulenta. PMID- 25461611 TI - Kinetics of mesenchymal and hematopoietic stem cells mobilization by G-CSF and its impact on the cytokine microenvironment in primary cultures. AB - In this study, we demonstrate that G-CSF administration triggers distinct kinetics of stem cell-SC mobilization with early raise of hematopoietic-HSC and late increase of mesenchymal-MSC in bone marrow-BM and peripheral blood-PB. The cytokine microenvironment observed following primary cultures showed an overall G CSF dose-dependent profile with a clear mixed pro-inflammatory/regulatory pattern. Moreover, primary cultures performed at the peak of MSC/HSC ratio, showed distinct cytokine patterns, with higher IL-10, TNF-alpha and IL-17A observed for BM and enhanced IL-10, IL-2 and IFN-gamma for PB harvested cells. Positive correlation was observed between BM-MSC and the levels of TNF-alpha, IL 10 and IL-17A whereas negative correlation was found between IL-10 and BM-HSC. An opposite association was observed between IL-10 and PB-HSC. Our results support the hypothesis that MSC and HSC harvested from BM and PB display differential functional properties that should be considered when electing the SC sources available for cell therapy applied in clinical protocols. PMID- 25461613 TI - Induction of anti-tumor immunity by dendritic cells transduced with FAT10 recombinant adenovirus in mice. AB - Hepatocellular carcinoma (HCC) is an aggressive and rapidly fatal malignancy representing the common cancer worldwide. The specific cellular gene involved in carcinogenesis has not been fully identified. The ubiquitin-like modifier FAT10, a recently reported to be over-expressed in 90% of hepatocellular carcinoma (HCC) carcinomas, and might be regarded as an ideal target for HCC therapy. In the present study, we utilized DCs transduced with FAT10 recombinant adenovirus to elicit CTLs in vitro. In addition, the Trimera mice were immunized with the transduced DCs to elicit the immune response in vivo. The results demonstrated that transduced DCs could effectively induce specific CTL response against HCC without lysing autologous lymphocytes, but also significantly inhibit the tumor growth and prolong the life span of tumor bearing mice. These results suggest that FAT10 recombinant adenovirus transduced DCs might be a promising therapeutical strategy for treatment of HCC. PMID- 25461612 TI - Predictive value of HLA-G and HLA-E in the prognosis of colorectal cancer patients. AB - HLA-G and HLA-E are non-classical HLA Ib molecules. Recently, increasingly more reports have shown that HLA-G is highly expressed in different malignancies. In this article, we detected the expression levels of HLA-G and HLA-E in primary colorectal cancer patients. Our results showed that 70.6% and 65.7% of the colorectal cancer tissues had positive HLA-G or HLA-E expression, respectively, and that 46.1% positively expressed both molecules. We also analyzed the correlations between the expression levels of HLA-G, HLA-E or both combined and the clinical outcomes of the patients. Kaplan-Meier analysis results showed that the expression levels of HLA-G or HLA-E alone and the combined expression of both molecules were all statistically correlated with the overall survival of colorectal cancer patients. Cox multivariate analysis showed that only HLA-G expression can serve as independent factor for OS. Our results also showed that the expression of HLA-E was significantly correlated with tumor metastasis. PMID- 25461614 TI - A kinetic characterization of the gill V(H(+))-ATPase in juvenile and adult Macrobrachium amazonicum, a diadromous palaemonid shrimp. AB - Novel kinetic properties of a microsomal gill V(H(+))-ATPase from juvenile and adult Amazon River shrimp, Macrobrachium amazonicum, are described. While protein expression patterns are markedly different, Western blot analysis reveals a sole immunoreactive band, suggesting a single V(H(+))-ATPase subunit isoform, distributed in membrane fractions of similar density in both ontogenetic stages. Immunofluorescence labeling locates the V(H(+))-ATPase in the apical regions of the lamellar pillar cells in both stages in which mRNA expression of the V(H(+)) ATPase B-subunit is identical. Juvenile (36.6+/-3.3 nmol Pi min(-1) mg(-1)) and adult (41.6+/-1.3 nmol Pi min(-1) mg(-1)) V(H(+))-ATPase activities are similar, the apparent affinity for ATP of the adult enzyme (K0.5=0.21+/-0.02 mmol L(-1)) being 3-fold greater than for juveniles (K0.5=0.61+/-0.01 mmol L(-1)). The K0.5 for Mg(2+) interaction with the juvenile V(H(+))-ATPase (1.40 +/- 0.07 mmol L( 1)) is ~6-fold greater than for adults (0.26+/-0.02 mmol L(-1)) while the bafilomycin A1 inhibition constant (KI) is 45.0+/-2.3 nmol L(-1) and 24.2+/-1.2 nmol L(-1), for juveniles and adults, respectively. Both stages exhibited residual bafilomycin-insensitive ATPase activity of ~25 nmol Pi min(-1) mg(-1), suggesting the presence of ATPases other than the V(H(+))-ATPase. These differences may reflect a long-term regulatory mechanism of V(H(+))-ATPase activity, and suggest stage-specific enzyme modulation. This is the first kinetic analysis of V(H(+))-ATPase activity in different ontogenetic stages of a freshwater shrimp and allows better comprehension of the biochemical adaptations underpinning the establishment of palaemonid shrimps in fresh water. PMID- 25461615 TI - Dietary iron depletion at weaning imprints low microbiome diversity and this is not recovered with oral Nano Fe(III). AB - Alterations in the gut microbiota have been recently linked to oral iron. We conducted two feeding studies including an initial diet-induced iron-depletion period followed by supplementation with nanoparticulate tartrate-modified ferrihydrite (Nano Fe(III): considered bioavailable to host but not bacteria) or soluble ferrous sulfate (FeSO4: considered bioavailable to both host and bacteria). We applied denaturing gradient gel electrophoresis and fluorescence in situ hybridization for study-1 and 454-pyrosequencing of fecal 16S rRNA in study 2. In study-1, the within-community microbial diversity increased with FeSO4 (P = 0.0009) but not with Nano Fe(III) supplementation. This was confirmed in study-2, where we also showed that iron depletion at weaning imprinted significantly lower within- and between-community microbial diversity compared to mice weaned onto the iron-sufficient reference diet (P < 0.0001). Subsequent supplementation with FeSO4 partially restored the within-community diversity (P = 0.006 in relation to the continuously iron-depleted group) but not the between-community diversity, whereas Nano Fe(III) had no effect. We conclude that (1) dietary iron depletion at weaning imprints low diversity in the microbiota that is not, subsequently, easily recovered; (2) in the absence of gastrointestinal disease iron supplementation does not negatively impact the microbiota; and (3) Nano Fe(III) is less available to the gut microbiota. PMID- 25461617 TI - The distribution of deleterious genetic variation in human populations. AB - Population genetic studies suggest that most amino-acid changing mutations are deleterious. Such mutations are of tremendous interest in human population genetics as they are important for the evolutionary process and may contribute risk to common disease. Genomic studies over the past 5 years have documented differences across populations in the number of heterozygous deleterious genotypes, number of homozygous derived deleterious genotypes, number of deleterious segregating sites and proportion of sites that are potentially deleterious. These differences have been attributed to population history affecting the ability of natural selection to remove deleterious variants from the population. However, recent studies have suggested that the genetic load is the same across populations and that the efficacy of natural selection has not differed across human populations. Here I show that these observations are not incompatible with each other and that the apparent differences are due to examining different features of the genetic data and differing definitions of terms. PMID- 25461618 TI - Huntingtin is associated with cytomatrix proteins at the presynaptic terminal. AB - Huntington's disease (HD) is a single gene disorder produced by expansion of the gene encoding huntingtin (htt), a large protein with features of a multi functional scaffold. Expansion of htt's polyglutamine domain induces novel, toxic interactions and likely also disrupts normal htt function. Because of its predicted role as a scaffold, pursuit of huntingtin function and HD pathogenesis has focused on identifying htt-interacting proteins. Here we present a focused screen designed to identify htt-interacting proteins in the presynaptic terminal. To identify interactions that occur in situ, synaptosomes (isolated nerve terminals) from cerebral cortices, striata and hippocampi were subjected to chemical crosslinking followed by denaturation, immunoprecipitation using an anti htt antibody, and nano-flow liquid chromatography tandem mass spectrometry (nanoLC-MS/MS) analyses. The presynaptic cytomatrix proteins Bassoon, Piccolo/Aczonin and Ahnak were among the most consistently identified binding partners. Co-immunoprecipitation and co-fractionation studies support the conclusion that huntingtin is a component of the presynaptic cytomatrix, a complicated network of proteins that regulates the positioning and priming of synaptic vesicles. These findings implicate htt in presynaptic functioning, and suggest that aberrant organization of presynaptic components may contribute to the neurological pathology associated with HD. PMID- 25461616 TI - The peopling of the African continent and the diaspora into the new world. AB - Africa is the birthplace of anatomically modern humans, and is the geographic origin of human migration across the globe within the last 100,000 years. The history of African populations has consisted of a number of demographic events that have influenced patterns of genetic and phenotypic variation across the continent. With the increasing amount of genomic data and corresponding developments in computational methods, researchers are able to explore long standing evolutionary questions, expanding our understanding of human history within and outside of Africa. This review will summarize some of the recent findings regarding African demographic history, including the African Diaspora, and will briefly explore their implications for disease susceptibility in populations of African descent. PMID- 25461619 TI - TDP6, a brain-derived neurotrophic factor-based trkB peptide mimetic, promotes oligodendrocyte myelination. AB - Brain-derived neurotrophic factor (BDNF) plays critical roles in the development and maintenance of the central (CNS) and peripheral nervous systems (PNS). BDNF exerts its biological effects via tropomyosin-related kinase B (TrkB) and the p75 neurotrophin receptor (p75NTR). We have recently identified that BDNF promotes CNS myelination via oligodendroglial TrkB receptors. In order to selectively target TrkB to promote CNS myelination, we have used a putative TrkB agonist, a small multicyclic peptide (tricyclic dimeric peptide 6, TDP6) previously described by us that structurally mimics a region of BDNF that binds TrkB. We confirmed that TDP6 acts as a TrkB agonist as it provoked autophosphorylation of TrkB and its downstream signalling effector extracellular related-kinase 1 and 2 (Erk1/2) in primary oligodendrocytes. Using an in vitro myelination assay, we show that TDP6 significantly promotes myelination by oligodendrocytes in vitro, as evidenced by enhanced myelin protein expression and an increased number of myelinated axonal segments. In contrast, a second, structurally distinct BDNF mimetic (cyclo-dPAKKR) that targets p75NTR had no effect upon oligodendrocyte myelination in vitro, despite the fact that cyclo-dPAKKR is a very effective promoter of peripheral (Schwann cell) myelination. The selectivity of TDP6 was further verified by using TrkB-deficient oligodendrocytes, in which TDP6 failed to promote myelination, indicating that the pro-myelinating effect of TDP6 is oligodendroglial TrkB-dependent. Together, our results demonstrate that TDP6 is a novel BDNF mimetic that promotes oligodendrocyte myelination in vitro via targeting TrkB. PMID- 25461621 TI - Role of G protein-coupled orphan receptors in intestinal inflammation: novel targets in inflammatory bowel diseases. AB - A large number of proteins were classified into the family of G protein-coupled receptors (GPCRs). Based on their characteristic serpentine domain, they are called 7 TM receptors. Presently, their ligands and physiological functions remain unknown. In this review, we summarize what is known on these receptors and discuss the potential use of these orphan GPCRs (GPRs) in the induction or maintenance of remission in inflammatory bowel diseases. We focus on GPRs 30, 41, 43, 55, 119, and 120, where scientific evidence supports a potential role in intestinal inflammation. PMID- 25461620 TI - Computer-generated vs. physician-documented history of present illness (HPI): results of a blinded comparison. AB - OBJECTIVES: Healthcare delivery now mandates shorter visits with higher documentation requirements, undermining the patient-provider interaction. To improve clinic visit efficiency, we developed a patient-provider portal that systematically collects patient symptoms using a computer algorithm called Automated Evaluation of Gastrointestinal Symptoms (AEGIS). AEGIS also automatically "translates" the patient report into a full narrative history of present illness (HPI). We aimed to compare the quality of computer-generated vs. physician-documented HPIs. METHODS: We performed a cross-sectional study with a paired sample design among individuals visiting outpatient adult gastrointestinal (GI) clinics for evaluation of active GI symptoms. Participants first underwent usual care and then subsequently completed AEGIS. Each individual thereby had both a physician-documented and a computer-generated HPI. Forty-eight blinded physicians assessed HPI quality across six domains using 5-point scales: (i) overall impression, (ii) thoroughness, (iii) usefulness, (iv) organization, (v) succinctness, and (vi) comprehensibility. We compared HPI scores within patient using a repeated measures model. RESULTS: Seventy-five patients had both computer generated and physician-documented HPIs. The mean overall impression score for computer-generated HPIs was higher than physician HPIs (3.68 vs. 2.80; P<0.001), even after adjusting for physician and visit type, location, mode of transcription, and demographics. Computer-generated HPIs were also judged more complete (3.70 vs. 2.73; P<0.001), more useful (3.82 vs. 3.04; P<0.001), better organized (3.66 vs. 2.80; P<0.001), more succinct (3.55 vs. 3.17; P<0.001), and more comprehensible (3.66 vs. 2.97; P<0.001). CONCLUSIONS: Computer-generated HPIs were of higher overall quality, better organized, and more succinct, comprehensible, complete, and useful compared with HPIs written by physicians during usual care in GI clinics. PMID- 25461622 TI - Clinical staining of the ocular surface: mechanisms and interpretations. AB - In this article we review the mechanism of ocular surface staining. Water-soluble dyes are excluded from the normal epithelium by tight junctions, the plasma membranes and the surface glycocalyx. Shed cells can take up dye. A proportion of normal corneas show sparse, scattered time-dependent, punctate fluorescein uptake, which, we hypothesise, is due to a graded loss of the glycocalyx barrier, permitting transcellular entry into pre-shed cells. In pathological staining, there is little evidence of 'micropooling' at sites of shedding and the term 'punctate erosion' may be a misnomer. It is more likely that the initial event involves transcellular dye entry and, in addition, diffusion across defective tight junctions. Different dye-staining characteristics probably reflect differences in molecular size and other physical properties of each dye, coupled with differences in visibility under the conditions of illumination used. This is most relevant to the rapid epithelial spread of fluorescein from sites of punctate staining, compared to the apparent confinement of dyes to staining cells with dyes such as lissamine green and rose bengal. We assume that fluorescein, with its lower molecular weight, spreads initially by a paracellular route and then by transcellular diffusion. Solution-Induced Corneal Staining (SICS), related to the use of certain contact lens care solutions, may have a different basis, involving the non-pathological uptake of cationic preservatives, such as biguanides, into epithelial membranes and secondary binding of the fluorescein anion. It is transient and may not imply corneal toxicity. Understanding the mechanism of staining is relevant to the standardisation of grading, to monitoring disease and to the conduct of clinical trials. PMID- 25461623 TI - Effects of elevated core temperature and normoxic 30% nitrous oxide on human ventilation during short duration, high intensity exercise. AB - It was hypothesized that normoxic 30% nitrous oxide (N2O) would suppress and hyperthermia would increase exercise ventilation during short duration, high intensity exercise. Thirteen males (24.2+/-0.8y; mean+/-SE), of normal physique (BMI, 23.8+/-1.0kgm(-2)), performed 4 separate 30s Wingate tests on a cycle ergometer. Exercise ventilation and its components, as well as mean skin and esophageal temperature (TES), were assessed in 2 way experimental design with factors of Thermal State (Normothermia or Hyperthermia) and Gas Type (Air or 30% Normomoxic N2O). In the 2 hyperthermic tests TES was elevated to ~38.5 degrees C in a 40 degrees C bath. The main results indicated a significant interaction (F=7.14, P=0.02) between Gas Type and Thermal state for the exercise-induced increase in ventilation (DeltaVE). During both the normothermia and hyperthermia conditions with AIR breathing, the exercise DeltaVE was ~80Lmin(-1) and it was significantly decreased to 73.1+/-24.1Lmin(-1) in the normothermia condition with N2O breathing relative to that of 92.0+/-25.0Lmin(-1) in the hyperthermia condition with N2O breathing. In conclusion, normoxic N2O breathing suppressed high intensity exercise ventilation during normothermia relative to that during hyperthermia on account of decreases in the tidal volume and this led CO2 retention. PMID- 25461624 TI - Oxidative stress in the oral cavity: sources and pathological outcomes. AB - Oxidative stress (OS), an imbalance in the oxidant-antioxidant equilibrium, is thought to be involved in the development of many seemingly unrelated diseases. Oral cavity tissues are a unique environment constantly exposed to internal and external compounds and material hazards as almost no other part of the human body. Some of the compounds are capable of generating OS. Here, the main groups of endogenous as well as exogenous OS sources are presented, followed by their oxidative effect on the salivary contents and function. The oxidative mechanisms in oral cells and their pathologic influence are also discussed. PMID- 25461625 TI - Cotinine as a marker for risk prediction in the Ludwigshafen Risk and Cardiovascular Health Study. AB - BACKGROUND: Cotinine is one of the major metabolites of nicotine. The aim our study was to investigate cotinine as a marker for individual risk prediction in the Ludwigshafen Risk and Cardiovascular Health study. METHODS: 840 samples had detectable cotinine measured using a radioimmunoassay (RIA nicotine metabolite, DPC Biermann GmbH). The distribution of risk factors across quartiles of cotinine or pack-years was analyzed by ANOVA and the association of cotinine and pack years with mortality by Cox regression. RESULTS: Cotinine and pack-years both showed significant association with mortality in adjusted models with HRs (95% CI) of 1.30 (1.17-1.44) and 1.26 (1.13-1.42) comparing the third to the first tertile for cotinine and pack-years, respectively. Either cotinine or pack-years or self-reported smoking increased the area-under-the-curve significantly as compared to a basic model including other risk factors. DISCUSSION: Cotinine is a strong predictor of mortality in non-smokers as well as in smokers. As objectively measurable parameter cotinine would be preferable for risk prediction. PMID- 25461626 TI - Aerobic fitness influences cerebral oxygenation response to maximal exercise in healthy subjects. AB - The study examined whether the aerobic fitness level modifies the cerebral oxygenation response to incremental ramp exercise, and more specifically the decline in cerebral oxygenation from heavy exercise up to maximal intensities. 11 untrained (VO2max 47.3+/-4.0 mL min(-1) kg(-1)) and 13 endurance-trained (VO2max 61.2+/-8.0 mL min(-1) kg(-1)) healthy men performed a maximal ramp cycle exercise. Left prefrontal cortex oxygenation (DeltaHbO2) was monitored by near infrared spectroscopy. A cerebral oxygenation threshold decline (ThCOx) during exercise was determined. ThCox occurred in all subjects but for higher VO2 (mL min(-1) kg(-1)) in endurance-trained than in untrained subjects (P<0.01). At submaximal exercise intensity corresponding to ThCOx, DeltaHbO2 was higher in endurance-trained than in untrained subjects (P<0.05). VO2 at ThCox was related to VO2 at respiratory compensation point (n=24, r=0.93, P<0.001) and to VO2max (n=24, r=0.92, P<0.001). These findings indicate that above the respiratory compensation point the prefrontal O2 demand exceeds the supply in untrained and in endurance-trained subjects. In addition, the occurrence of ThCOx was delayed to higher absolute exercise intensities in endurance-trained in relation with their higher VO2max than untrained men. These results demonstrated that aerobic fitness influences cerebral oxygenation during exercise. PMID- 25461628 TI - The power of social media. PMID- 25461627 TI - Specific inhibition of the nuclear exporter exportin-1 attenuates kidney cancer growth. AB - PURPOSE: Despite the advent of FDA-approved therapeutics to a limited number of available targets (kinases and mTOR), PFS of kidney cancer (RCC) has been extended only one to two years due to the development of drug resistance. Here, we evaluate a novel therapeutic for RCC which targets the exportin-1 (XPO1) inhibitor. MATERIALS AND METHODS: RCC cells were treated with the orally available XPO1 inhibitor, KPT-330, and cell viability and Annexin V (apoptosis) assays, and cell cycle analyses were performed to evaluate the efficacy of KPT 330 in two RCC cell lines. Immunoblotting and immunofluorescence analysis were performed to validate mechanisms of XPO1 inhibition. The efficacy and on-target effects of KPT-330 were further analyzed in vivo in RCC xenograft mice, and KPT 330-resistant cells were established to evaluate potential mechanisms of KPT-330 resistance. RESULTS: KPT-330 attenuated RCC viability through growth inhibition and apoptosis induction both in vitro and in vivo, a process in which increased nuclear localization of p21 by XPO1 inhibition played a major role. In addition, KPT-330 resistant cells remained sensitive to the currently approved for RCC multi-kinase inhibitors (sunitinib, sorafenib) and mTOR inhibitors (everolimus, temsirolimus), suggesting that these targeted therapeutics would remain useful as second line therapeutics following KPT-330 treatment. CONCLUSION: The orally available XPO1 inhibitor, KPT-330, represents a novel target for RCC whose in vivo efficacy approaches that of sunitinib. In addition, cells resistant to KPT 330 retain their ability to respond to available RCC therapeutics suggesting a novel approach for treatment in KPT-330-naive as well as -resistant RCC patients. PMID- 25461629 TI - In memory of Stefanie Dinman (1955-2014)--past president ASPSN. PMID- 25461631 TI - Patient satisfaction in bilateral and unilateral breast reconstruction. PMID- 25461632 TI - Electronic cigarettes--patient safety concerns. PMID- 25461633 TI - ATP testing: an anecdotal look at its use in an office-based plastic surgery setting. AB - Proper cleaning of surgical instruments prior to sterilization is an essential objective in the surgical setting. Testing for the presence of adenosine triphosphate (ATP) on a cleaned instrument can help determine if it meets cleanliness requirements for sterilization. A program was piloted in our facility by using a commercial ATP testing system. In this article, our experience with the evaluation of available ATP testing systems, the implementation processes we used, and conclusions drawn from our procedures and results are described. PMID- 25461634 TI - Cryogenic lipolysis: the latest and greatest in noninvasive fat reduction. PMID- 25461635 TI - Avoiding the "danger zones" when injecting neurotoxins. PMID- 25461637 TI - Facebook do's and don'ts. PMID- 25461638 TI - Operation smile and the Guwahati comprehensive cleft care center: multidisciplinary global activism in plastic surgery. AB - Participation in a medical mission in an underserved area is both a challenging and deeply satisfying experience. The global burden of cleft lip and palate is significant, and as plastic surgery providers we are all empowered to help these patients. Surgery for cleft lip and palate is life changing for patients, and the privilege of participating in a mission can be life altering for the providers as well. The Comprehensive Cleft Care Center in Guwahati, India, is a prime example of multidisciplinary collaboration resulting in excellent care in the developing world. PMID- 25461639 TI - A pharmacologic review of anaphylaxis. AB - Anaphylaxis occurs in the surgical population and may have devastating consequences. Anaphylaxis and anaphylactoid reactions are immediate hypersensitivity reactions that are most commonly precipitated by medications, insect stings, and foods. In the surgical population, 47.4% of immediate hypersensitivity reactions were precipitated by neuromuscular blocking agents, followed by latex and antibiotics in 20% and 18.1% of cases, respectively. Initial treatment consists of removing the precipitating trigger, administering epinephrine, and correct patient positioning. Secondary prevention measures should be instituted to prevent future occurrences. All health care professionals should have an understanding of the clinical presentation and medical management of anaphylaxis to improve patient outcomes. PMID- 25461641 TI - Chemotherapy and radiotherapy effects on the skin. PMID- 25461642 TI - Ecological, physiological, and morphological correlates of blood hemoglobin concentration in a migratory shorebird. AB - The information on the phenotypic and ecological factors that influence hemoglobin concentration in free-living birds is scarce. In order to recognize sources of variation in hemoglobin levels of migratory shorebirds, we measured whole-blood hemoglobin concentration in 553 juvenile and 166 adult common snipe Gallinago gallinago during autumn migration through central Poland. Among the intrinsic determinants of hemoglobin concentration in common snipe, we identified traits such as age, wing morphology, developmental stability, nutritional condition, and molt. We found that adult birds had higher hemoglobin concentrations than juveniles. Hemoglobin concentration was not related to body size, but it correlated with wing morphology. In adult males there was also a positive relationship between hemoglobin concentration and developmental stability, measured by fluctuating asymmetry in wing shape. The process of molt was found to affect blood hemoglobin concentration in both juvenile and adult common snipe, as the lowest concentrations were recorded in the initial stages of molt. Finally, we recorded a gradual increase in hemoglobin concentration of juvenile and adult snipe over the course of the autumn migratory season, and this trend was attributed to higher fat loads carried by late migrants. Hemoglobin concentration also correlated with other indices of nutritional state, such as plasma concentrations of proteins. All this clearly indicates that hemoglobin concentration may reflect a wide range of physiological processes, but in spite of this immense variation, it is likely to reliably indicate phenotypic quality of birds. PMID- 25461644 TI - The effect of thermal variance on the phenotype of marine turtle offspring. AB - Temperature can have a profound effect on the phenotype of reptilian offspring, yet the bulk of current research considers the effects of constant incubation temperatures on offspring morphology, with few studies examining the natural thermal variance that occurs in the wild. Over two consecutive nesting seasons, we placed temperature data loggers in 57 naturally incubating clutches of loggerhead sea turtles Caretta caretta and found that greater diel thermal variance during incubation significantly reduced offspring mass, potentially reducing survival of hatchlings during their journey from the nest to offshore waters and beyond. With predicted scenarios of climate change, behavioral plasticity in nest site selection may be key for the survival of ectothermic species, particularly those with temperature-dependent sex determination. PMID- 25461643 TI - The impact of humidity on evaporative cooling in small desert birds exposed to high air temperatures. AB - Environmental temperatures that exceed body temperature (Tb) force endothermic animals to rely solely on evaporative cooling to dissipate heat. However, evaporative heat dissipation can be drastically reduced by environmental humidity, imposing a thermoregulatory challenge. The goal of this study was to investigate the effects of humidity on the thermoregulation of desert birds and to compare the sensitivity of cutaneous and respiratory evaporation to reduced vapor density gradients. Rates of evaporative water loss, metabolic rate, and Tb were measured in birds exposed to humidities ranging from ~2 to 30 g H2O m(-3) (0%-100% relative humidity at 30 degrees C) at air temperatures between 44 degrees and 56 degrees C. In sociable weavers, a species that dissipates heat primarily through panting, rates of evaporative water loss were inhibited by as much as 36% by high humidity at 48 degrees C, and these birds showed a high degree of hyperthermia. At lower temperatures (40 degrees -44 degrees C), evaporative water loss was largely unaffected by humidity in this species. In Namaqua doves, which primarily use cutaneous evaporation, increasing humidity reduced rates of evaporative water loss, but overall rates of water loss were lower than those observed in sociable weavers. Our data suggest that cutaneous evaporation is more efficient than panting, requiring less water to maintain Tb at a given temperature, but panting appears less sensitive to humidity over the air temperature range investigated here. PMID- 25461645 TI - Asymmetric thermal acclimation responses allow sheepshead minnow Cyprinodon variegatus to cope with rapidly changing temperatures. AB - Thermal acclimation responses in sheepshead minnow Cyprinodon variegatus were quantified by transfer and reciprocal transfer of fish between 11.1 degrees and 18.2 degrees C, between 18.2 degrees and 25.7 degrees C, or between 25.7 degrees and 32.8 degrees C. Changes in thermal acclimation status were assessed by posttransfer time series determinations of thermal tolerance (i.e., critical thermal minima and maxima). In general, heat tolerance gain and loss were complete in 20 and 25 d, respectively. Cold tolerance gain was achieved ca. 24 d posttransfer, but attrition was complete after only 12-13 d. Heat tolerance was gained asymmetrically, with fish acquiring approximately one-half of their accruable tolerance at the lowest transfer temperature. Likewise, the majority of cold tolerance accruement occurred during the warmest temperature transfer. Relatively uniform losses of heat and cold tolerance were seen in reciprocal transfers. Acclimation patterns were related to initial acclimation temperature, final acclimation temperature, and acclimation time and could be accurately modeled by multiple linear regression. The results suggest that sheepshead minnow accrue a majority of their high- or low-temperature tolerance early in the acclimation process well before potential damaging temperatures are likely to occur. This novel pattern of asymmetric heat and cold tolerance acquisition in sheepshead minnow may be a key adaptation for surviving rapid and unpredictable water temperature changes commonly encountered in their natural environment. PMID- 25461646 TI - Electrical excitation of the heart in a basal vertebrate, the European river lamprey (Lampetra fluviatilis). AB - Hagfishes and lampreys (order Cyclostomata) are living representatives of an ancient group of jawless vertebrates (class Agnatha). Studies on cyclostome hearts may provide insights into the evolution of the vertebrate heart and thereby increase our understanding of cardiac function in higher vertebrates, including mammals. To this end, electrical excitability of the heart in a basal vertebrate, the European river lamprey (Lampetra fluviatilis), was examined. Ion currents of cardiac myocytes, action potentials (APs) of atrial and ventricular muscle, and electrocardiogram (in vivo) were measured using the patch-clamp method, intracellular microelectrodes, and trailing wires, respectively. The characteristic features of fairly high heart rate (28.4 +/- 3 beats min(-1)) and short AP duration (550 +/- 44 and 122.1 +/- 28.5 for ventricle and atrium, respectively) at low ambient temperature (5 degrees C) are shared with cold active teleost fishes. However, the ion current basis of the ventricular AP differs from that of other fishes. For inward currents, sodium current density (INa) is lower and calcium current density (ICa) higher than in teleost ventricles, while the kinetics of INa is slow and that of ICa is fast in comparison. Among the ventricular repolarizing currents, the delayed rectifier K(+) current is smaller than in myocytes of several teleost species. Unlike mammalian hearts, ATP-sensitive K(+) channels are constitutively open under normoxic conditions, thus contributing to negative resting membrane potential and repolarization of APs. Upstroke velocity of AP (5.4 +/- 0.9 and 6.3 +/- 0.6 V s( 1) for ventricular and atrial myocytes, respectively) is slower than in teleost hearts. Excitability of the lamprey heart seems to possess both primitive and advanced characteristics. Short APs are appropriate to support brief and vigorous contractions (in common with higher vertebrates), while relatively low AP upstroke velocities enable only relatively slow propagation of contraction over the heart. PMID- 25461647 TI - The energetic cost of foraging explains growth anomalies in tadpoles exposed to predators. AB - Theoretical models predict that predator-induced phenotypes should have lower fitness in the absence of predators. Tadpoles frequently respond to invertebrate predators by reducing activity levels and changing their body proportions. While some studies have shown that induced defenses in tadpoles reduce growth rates, others have found no effect. The aim of this study was to measure the effects of predator presence on energy expenditure in tadpoles. Predator exposure lowered overall metabolic rate by 19%, while specific dynamic action due to food consumption increased resting metabolism by 11%. Control tadpoles moved significantly more (93.6 +/- 3.9 cm/min) than predator-exposed animals (50.1 +/- 7.5 cm/min), and swimming increased metabolic rate by up to 400% compared to stationary tadpoles, indicating that activity can be energetically expensive and can consume as much as 37% of assimilated energy. These findings suggest that the costs of reduced foraging are context dependent and may even be beneficial in environments where high-quality resources are closely spaced but detrimental when extensive movement is required to obtain optimal resources for growth. PMID- 25461648 TI - Energy demands for maintenance, growth, pregnancy, and lactation of female Pacific walruses (Odobenus rosmarus divergens). AB - Decreases in sea ice have altered habitat use and activity patterns of female Pacific walruses Odobenus rosmarus divergens and could affect their energetic demands, reproductive success, and population status. However, a lack of physiological data from walruses has hampered efforts to develop the bioenergetics models required for fully understanding potential population-level impacts. We analyzed long-term longitudinal data sets of caloric consumption and body mass from nine female Pacific walruses housed at six aquaria using a hierarchical Bayesian approach to quantify relative energetic demands for maintenance, growth, pregnancy, and lactation. By examining body mass fluctuations in response to food consumption, the model explicitly uncoupled caloric demand from caloric intake. This is important for pinnipeds because they sequester and deplete large quantities of lipids throughout their lifetimes. Model outputs were scaled to account for activity levels typical of free-ranging Pacific walruses, averaging 83% of the time active in water and 17% of the time hauled-out resting. Estimated caloric requirements ranged from 26,900 kcal d(-1) for 2-yr-olds to 93,370 kcal d(-1) for simultaneously lactating and pregnant walruses. Daily consumption requirements were higher for pregnancy than lactation, reflecting energetic demands of increasing body size and lipid deposition during pregnancy. Although walruses forage during lactation, fat sequestered during pregnancy sustained 27% of caloric requirements during the first month of lactation, suggesting that walruses use a mixed strategy of capital and income breeding. Ultimately, this model will aid in our understanding of the energetic and population consequences of sea ice loss. PMID- 25461649 TI - Globin's structure and function in vesicomyid bivalves from the Gulf of Guinea cold seeps as an adaptation to life in reduced sediments. AB - Vesicomyid bivalves form dense clam beds in both deep-sea cold seeps and hydrothermal vents. The species diversity within this family raises questions about niche separation and specific adaptations. To compare their abilities to withstand hypoxia, we have studied the structure and function of erythrocyte hemoglobin (Hb) and foot myoglobin (Mb) from two vesicomyid species, Christineconcha regab and Laubiericoncha chuni, collected from the Regab pockmark in the Gulf of Guinea at a depth of 3,000 m. Laubiericoncha chuni possesses three monomeric globins, G1 (15,361 Da), G2 (15,668 Da), and G3 (15,682 Da) in circulating erythrocytes (Hb), and also three globins, G1, G3, and G4 (14,786 Da) in foot muscle (Mb). Therefore, globins G2 and G4 appear to be specific for erythrocytes and muscle, respectively, but globins G1 and G3 are common. In contrast, C. regab lacks erythrocyte Hb completely and possesses only globin monomers G1' (14,941 Da), G2' (15,169 Da), and G3' (15,683 Da) in foot muscle. Thus, these two vesicomyid species, C. regab and L. chuni, show a remarkable diversity in globin expression when examined by electrospray ionization mass spectrometry. Oxygen-binding affinities reveal extremely high oxygen affinities (P50 < 1 Torr, from 5 degrees to 15 degrees C at pH 7.5), in particular L. chuni globins, which might be an advantage allowing L. chuni to dig deeply for sulfides and remain buried for long periods in reduced sediments. PMID- 25461650 TI - Hovering flight in the honeybee Apis mellifera: kinematic mechanisms for varying aerodynamic forces. AB - During hovering flight, animals can increase the wing velocity and therefore the net aerodynamic force per stroke by increasing wingbeat frequency, wing stroke amplitude, or both. The magnitude and orientation of aerodynamic forces are also influenced by the geometric angle of attack, timing of wing rotation, wing contact, and pattern of deviation from the primary stroke plane. Most of the kinematic data available for flying animals are average values for wing stroke amplitude and wingbeat frequency because these features are relatively easy to measure, but it is frequently suggested that the more subtle and difficult-to measure features of wing kinematics can explain variation in force production for different flight behaviors. Here, we test this hypothesis with multicamera high speed recording and digitization of wing kinematics of honeybees (Apis mellifera) hovering and ascending in air and hovering in a hypodense gas (heliox: 21% O2, 79% He). Bees employed low stroke amplitudes (86.7 degrees +/- 7.9 degrees ) and high wingbeat frequencies (226.8 +/- 12.8 Hz) when hovering in air. When ascending in air or hovering in heliox, bees increased stroke amplitude by 30% 45%, which yielded a much higher wing tip velocity relative to that during simple hovering in air. Across the three flight conditions, there were no statistical differences in the amplitude of wing stroke deviation, minimum and stroke averaged geometric angle of attack, maximum wing rotation velocity, or even wingbeat frequency. We employed a quasi-steady aerodynamic model to estimate the effects of wing tip velocity and geometric angle of attack on lift and drag. Lift forces were sensitive to variation in wing tip velocity, whereas drag was sensitive to both variation in wing tip velocity and angle of attack. Bees utilized kinematic patterns that did not maximize lift production but rather maintained lift-to-drag ratio. Thus, our data indicate that, at least for honeybees, the overall time course of wing angles is generally preserved and modulation of wing tip velocity is sufficient to perform a diverse set of vertical flight behaviors. PMID- 25461652 TI - A man with skin lesions and ataxia: a case of disseminated varicella zoster. PMID- 25461651 TI - Case series of infective endocarditis caused by Granulicatella species. AB - BACKGROUND: Nutritionally variant streptococci (NVS) are Gram-positive cocci characterized by their dependence on pyridoxal or cysteine supplementation for growth in standard blood culture media. They are responsible for severe infections in immunocompetent and immunosuppressed hosts, including infective endocarditis (IE). NVS have been divided into two different genera, Granulicatella and Abiotrophia. METHODS: We report four cases of IE caused by Granulicatella species, including clinical presentation, echocardiographic characteristics, treatments received, and outcomes. We also performed a literature search for previously reported cases of IE caused by Granulicatella species to better characterize this condition. RESULTS: A total of 29 cases of Granulicatella endocarditis were analyzed, including the four newly reported cases. The aortic (44%) and mitral (38%) valves were those most commonly affected. Multivalvular involvement was observed in 13% of cases. The mean vegetation length was 16mm. Complications were frequent, including heart failure (30%), embolism (30%), and perivalvular abscess (11%). The most frequent antibiotic regimen (85%) was penicillin or one of its derivatives plus gentamicin. The mortality rate was 17%. CONCLUSIONS: Endocarditis due to Granulicatella species is a rare and severe condition. Complications are frequent despite the use of appropriate antibiotic regimens. PMID- 25461653 TI - Seroprevalence of Toxoplasma gondii antibodies and associated risk factors among children in Shandong and Jilin provinces, China. AB - OBJECTIVE: Infection by the protozoan parasite Toxoplasma gondii is generally prevalent in animals and humans worldwide. However, little is known about T. gondii infection among children in China. Thus, the present study was conducted to detect the seroprevalence of T. gondii infection and estimate associated risk factors among children in eastern China. METHODS: A cross-sectional study of 1500 children from three cities (Changchun, Qingdao, Weihai) was conducted between May 2013 and July 2014 to estimate the seroprevalence and potential risk factors associated with acquiring T. gondii infection in children in China. Demographic and blood samples were collected, and anti-T. gondii IgG and IgM antibodies were measured by ELISA. RESULTS: The mean age of the 1500 children participating in the study was 9.03 years (range 1-18). The overall seroprevalence of Toxoplasma infection was 15.13%, of which 13.13% were positive for only anti-Toxoplasma IgG antibodies, 3.13% were positive for both anti-Toxoplasma IgG and IgM antibodies and 2.00% were IgM positive and IgG negative. Moreover, raising cats at home (OR=1.94, 95% CI=1.288-2.912, P=0.002) and hand washing habits (OR=0.38, 95% CI=0.230-0.635, P<0.001) were estimated to be risk and protective factors associated with Toxoplasma seroprevalence, respectively. CONCLUSIONS: The present study revealed for the first time that children's infection with T. gondii is common in eastern China. The present data indicate a need to implement methods of prevention and control measures against Toxoplasma infection in China. PMID- 25461654 TI - Incidence of Mediterranean spotted fever in Sicilian children: a clinical epidemiological observational retrospective study from 1987 to 2010. AB - BACKGROUND: Zoonoses are human infectious diseases caused by pathogens that primarily infect animals. Mediterranean Spotted Fever (MSF) represents one such example, affecting the Mediterranean region, in which household animals can be immune-carriers of infected ticks. MATERIALS AND METHODS: We retrospectively analysed the incidence and the clinical and laboratory features of MSF caused by R.Conorii in children admitted to the Paediatric Operative Unit from 1987 to 2010, for persistent fever and generalised macular-popular erythematous lesions. Clinical, immunological and serological parameters of 55 cases of Rickettsia infections observed in children between 2 and 11 years of age were collected. RESULTS: We found an increasing incidence of MSF in childhood from 1987 to 2010. Diagnosis of MSF at the moment of hospital admission was done in 16 patients (29.09%). The presence of the typical Tache noire was observed in 16 cases out of 55 patients (29.09% of cases). We noticed a different representation of R. conorii antigens in serological testing over the time period of the study, corresponding to overall higher incidence rates for infection in the latter years. We also observed a higher incidence of infection in those years in which all four antigens were found positive at serum testing with respect to those years in which only two of the four antigens were observed (1987-1990: 0-16%; 2007-2010: 0.46%; P<0.005). CONCLUSIONS: These changes in R. conorii antigenicity may be the cause of higher pathogenicity in this parasite, perhaps linked to increased immigration along with consequent changes in the epidemiology of infectious diseases in host countries. PMID- 25461655 TI - An update on the arsenal for multidrug-resistant Acinetobacter infections: polymyxin antibiotics. AB - OBJECTIVE: To review recent clinical pharmacokinetic and pharmacodynamic data to optimize dosing regimens for polymyxin B and colistin for treatment of infections due to A. baumannii. METHODS: A literature search was performed using the search terms Acinetobacter, polymyxin, colistin, polymyxin B on MEDLINE. Additional references were identified from the resulting citations. RESULTS: Increasing the dose of polymyxin B or colistin and using either in combination with other antibiotic agents demonstrates improved antimicrobial activity against Acinetobacter spp. Polymyxin B, unlike colistin, is available as an active drug and appears to be relatively unaffected by renal function. This is advantageous both for patients with renal impairment and for those with intact renal function. Achieving therapeutic serum concentrations of colistin may be difficult for those with intact renal function due to rapid clearance of the prodrug, colistimethate sodium (CMS). Clinical data are still lacking for polymyxin B, and it remains to be seen whether advantages demonstrated in PK/PD analyses will persist in the larger scale of patient care and safety. CONCLUSIONS: The use of higher doses of either colistin or polymyxin B, as well as combination with other antibiotics, may prevent emerging resistance and preserve the activity of polymyxins against A. baumannii. PMID- 25461656 TI - Can sTREM-1 predict septic shock & death in late-onset neonatal sepsis? A pilot study. AB - BACKGROUND AND OBJECTIVES: The transmembrane glycoprotein TREM-1 triggers an inflammatory response. Its soluble fraction (sTREM-1) has been shown to have diagnostic accuracy for late-onset neonatal sepsis (LONS). Until now, the potential of sTREM-1 to predict septic shock and/or death in septic neonates has not been explored. This study obtained estimates of the incidence and prevalence of septic shock and/or death in septic neonates for future sample size calculations for confirmatory studies and evaluated the feasibility of using sTREM-1 as a predictor of septic shock and/or death in neonates with LONS criteria. STUDY DESIGN: A pilot study with a cross-sectional design was performed from May 1(st) to October 31(st), 2012. The participants were hospitalized neonates who, after three days of life, were diagnosed as having LONS. Plasma sTREM-1 was quantified by ELISA. The main outcome measurement was the development of septic shock and/or death. RESULTS: Of 71 eligible subjects, nine (12.7%) progressed to septic shock and/or death. In the LONS-Non-Shock group, the sTREM-1 median and interquartile range (IQR) plasma value were 10 (10 to 70) pg/mL. In the LONS & Shock/Death group, the values were 567 (260 to 649) pg/mL. These values were significantly different (Mann-Whitney's U test, p=0.001). A ROC curve for a proposed sTREM-1 cut-off value of 300 pg/mL exhibited an area under the curve of 0.884 (95% CI=0.73 to 1.0; p<0.0001), with a sensitivity of 0.78 (95% CI=0.46 to 0.94) and specificity of 0.97 (95% CI=0.92 to 0.99); PPV would be 0.78 (95% CI=0.46 to 0.94) and NPV 0.97 (95% CI=0.92 to 0.99). CONCLUSIONS: In neonates with LONS, sTREM-1 has the potential to provide an excellent predictive value for septic shock/death. Larger sample sizes are needed to identify the optimal cut-off value of plasma sTREM-1 for this diagnosis and to provide diagnostic accuracy measures. PMID- 25461657 TI - Infective endocarditis in Turkey: aetiology, clinical features, and analysis of risk factors for mortality in 325 cases. AB - OBJECTIVE: In order to define the current characteristics of infective endocarditis (IE) in Turkey, we evaluated IE cases over a 14-year period in a tertiary referral hospital. METHODS: All adult patients who were hospitalized in our hospital with a diagnosis of IE between 2000 and 2013 were included in the study. Modified Duke criteria were used for diagnosis. The Chi-square test, Student's t-test, Mann-Whitney U-test, Cox and logistic regression analysis were used for the statistical analysis. RESULTS: There were 325 IE cases during the study period. The mean age of the patients was 47 years. Causative microorganisms were identified in 253 patients (77.8%) and included staphylococci (36%), streptococci (19%), enterococci (7%), and Brucella spp (5%). A streptococcal aetiology was associated with younger age (<40 years) (p=0.001), underlying chronic rheumatic heart disease (CRHD) (odds ratio (OR) 3.89) or a congenital heart defect (OR 4.04), community acquisition (OR 17.93), and native valve (OR 3.68). A staphylococcal aetiology was associated with healthcare acquisition (OR 2.26) or pacemaker lead-associated endocarditis (OR 6.63) and an admission creatinine level of >1.2mg/dl (OR 2.15). Older age (>50 year) (OR 3.93), patients with perivalvular abscess (OR 9.18), being on dialysis (OR 6.22), and late prosthetic valve endocarditis (OR 3.15) were independent risk factors for enterococcal IE. Independent risk factors for mortality in IE cases were the following: being on dialysis (hazard ratio (HR) 4.13), presence of coronary artery heart disease (HR 2.09), central nervous system emboli (HR 2.33), and congestive heart failure (HR 2.15). Higher haemoglobin (HR 0.87) and platelet (HR 0.996) levels and surgical interventions for IE (HR 0. 33) were found to be protective factors against mortality. CONCLUSIONS: In Turkey, IE occurs in relatively young patients and Brucella spp should always be taken into consideration as a cause of this infection. We should first consider streptococci as the causative agents of IE in young patients, those with CRHD or congenital heart valve disease, and cases of community-acquired IE. Staphylococci should be considered first in the case of pacemaker lead IE, when there are high levels of creatinine, and in cases of healthcare-associated IE. Enterococci could be the most probable causative agent of IE particularly in patients aged >50 years, those on dialysis, those with late prosthetic valve IE, and those with a perivalvular abscess. The early diagnosis and treatment of IE before complications develop is crucial because the mortality rate is high among cases with serious complications. The prevention of bacteraemia with the measures available among chronic haemodialysis patients should be a priority because of the higher mortality rate of subsequent IE among this group of patients. PMID- 25461659 TI - A comparison of APACHE II and CPIS scores for the prediction of 30-day mortality in patients with ventilator-associated pneumonia. AB - OBJECTIVE: The aim of this study was to compare the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and the Clinical Pulmonary Infection Score (CPIS) for the prediction of 30-day mortality in patients with ventilator associated pneumonia (VAP). METHODS: A single-center, prospective cohort study design was employed between January 1, 2010 and January 1, 2014. APACHE II and CPIS scores were determined on the day of VAP diagnosis. Discrimination was tested using receiver-operating characteristic (ROC) curves and the areas under the curve (AUC). Calibration was tested using the Hosmer-Lemeshow statistic. RESULTS: Of 135 patients with VAP, 39 died; the 30-day mortality was 28.9%. APACHE II and CPIS scores were significantly higher in non-survivors compared to survivors (23.1+/-4.8 vs. 16.7+/-4.6, p<0.001; 6.8+/-1.3 vs. 6.2+/-1.3, p=0.016). APACHE II had excellent discrimination for predicting 30-day mortality in patients with VAP, with AUC 0.808 (95% confidence interval (CI) 0.704-0.912, p<0.001). However, the CPIS score did not have discrimination power for predicting mortality, with AUC 0.612 (95% CI 0.485-0.739, p=0.083). The Hosmer Lemeshow statistic showed good goodness-of-fit for observed 30-day mortality and APACHE II expected mortality (Chi-square=1.099, p=0.785). However, CPIS expected 30-day mortality did not fit the observed mortality (Chi-square=6.72, p=0.004). CONCLUSIONS: These data suggest that APACHE II is useful for predicting 30-day mortality in patients with VAP, but that the CPIS does not have good discrimination and calibration for predicting mortality. PMID- 25461658 TI - High circulating CD39(+) regulatory T cells predict poor survival for sepsis patients. AB - BACKGROUND: Sepsis encompasses two phases, the 'hyper'-reactive phase and the 'hypo'-reactive phase. The initial inflammatory stage is quickly counterbalanced by an anti-inflammatory response, which compromises the immune system, leading to immune suppression. Regulatory T cells (Tregs) have been implicated in the pathogenesis of sepsis by inducing immunosuppression; however, the role of CD39(+) Tregs in the process of sepsis is uncertain. This study investigated the dynamic levels of CD39(+) Tregs and their phenotypic change in sepsis. METHODS: Fourteen patients with systemic inflammatory response syndrome (SIRS), 42 patients with sepsis, and 14 healthy controls were enrolled. Sequential blood samples were used to analyze the numbers of CD39(+) Tregs and their phenotypic changes. Survival at 28 days was used to evaluate the capacity of CD39(+) Treg levels to predict mortality in sepsis patients. RESULTS: Sepsis patients displayed a high percentage (3.13%, 1.46%, and 0.35%, respectively) and mean fluorescence intensity (MFI) (59.65, 29.7, and 24.3, respectively) of CD39(+) Tregs compared with SIRS patients and healthy subjects. High-level expression of CD39(+) Tregs was correlated with the severity of sepsis, which was reflected by the sepsis-related organ failure assessment score (r=0.322 and r=0.31, respectively). In addition, the expression of CD39(+) Tregs was associated with survival of sepsis patients (p<0.01). By receiver-operating characteristic (ROC) curve analysis, the percentage and MFI of CD39(+) Tregs showed similar sensitivities and specificities to predict mortality (74.2% and 85.1%, and 73.9% and 84.1%, respectively). Using Kaplan-Meier curves to assess the impact of CD39(+) Tregs percentage and MFI on overall survival, we found that a high CD39(+) Tregs percentage (p<0.001; >4.1%) and MFI (p<0.001; >49.2) were significantly associated with mortality. Phenotypically, CD39(+) Tregs from sepsis patients showed high expression of CD38 and PD-1 (p<0.01 and p<0.01 respectively). CONCLUSIONS: Increased expression of CD39(+) Tregs was associated with a poor prognosis for sepsis patients, which suggests that CD39(+) Treg levels could be used as a biomarker to predict the outcome of sepsis patients. PMID- 25461660 TI - An unusual case of hematuria in a French family returning from Corsica. AB - Urinary schistosomiasis caused by Schistosoma haematobium worms is endemic to tropical regions where it is the most common cause of hematuria. However, the intermediate snail hosts, Bulinus truncatus, have been described in Portugal, Spain, Sardinia, and Corsica. S. haematobium has long remained exotic to Europe, however, an outbreak of urinary schistosomiasis in Corsica started in 2011 with B. truncatus as the primary intermediate host. We describe the case of a 12-year old French boy presenting hematuria and dysuria who was diagnosed with urinary schistosomiasis. Urine examination confirmed the presence of viable parasitic ova. He also had a positive serology. Since there was no history of travel to a schistosomiasis endemic region, the probable area of contamination was identified as the south of Corsica where the family had spent their summer holidays 7 months earlier. Two other family members had a positive serology without ova excretion in urine. The patients were treated with praziquantel. In light of these recent locally acquired cases in France, schistosomiasis should be considered in the differential diagnosis of hematuria, especially in patients who have recently visited Corsica. PMID- 25461661 TI - Aerosolized amphotericin B as prophylaxis for invasive pulmonary aspergillosis: a meta-analysis. AB - OBJECTIVES: Invasive pulmonary aspergillosis (IPA) is associated with high mortality in high-risk (immunosuppressed) patients. Many studies have investigated whether prophylactic inhalation of amphotericin B (AMB) reduces the incidence of IPA, but no definitive conclusions have been reached. The present meta-analysis was performed to evaluate the efficacy of prophylactic inhalation of AMB for the prevention of IPA. METHODS: MEDLINE and other databases were searched for relevant articles published until December 2013. Randomized controlled trials that compared aerosolized AMB with placebo were included. Two reviewers independently assessed and extracted the data of all trials. RESULTS: Six animal studies and two clinical trials involving 768 high-risk patients were eligible. The animal studies showed lower overall mortality rate among animals that underwent aerosolized AMB prophylaxis (odds ratio (OR) 0.13, 95% confidence interval (CI) 0.08-0.21). Similarly, the clinical trials showed a lower incidence of IPA among patients who underwent aerosolized AMB prophylaxis (OR 0.42, 95% CI 0.22-0.79). CONCLUSIONS: This analysis provides evidence supporting the notion that the prophylactic use of aerosolized AMB effectively reduces the incidence of IPA among high-risk patients. PMID- 25461662 TI - Absolute quantification of serum microRNA-122 and its correlation with liver inflammation grade and serum alanine aminotransferase in chronic hepatitis C patients. AB - OBJECTIVES: MicroRNA-122 has been shown to be crucial for efficient HCV RNA replication in vitro. Pretreatment intrahepatic microRNA-122 levels in chronic hepatitis C (CHC) patients have been associated with the outcomes of interferon therapy. Here, we determined microRNA-122 serum levels in CHC patients and healthy donors using an absolute quantification approach and evaluated the correlation with liver inflammation grades and serum alanine aminotransferase (ALT) levels. METHODS: Serum samples were collected from 105 treatment-naive CHC patients, 11 acute hepatitis patients, and 33 healthy donors. Serum microRNA-122 was measured using the TaqMan RT-qPCR. The cycle threshold values were converted to copy numbers by drawing a standard curve using a chemical synthetic standard. For accurate quantification, copy numbers were further normalized according to the recovery ratios of spiked-in cel-miR-39. RESULTS: Serum levels of microRNA 122 were significantly higher in acute hepatitis and CHC patients than in healthy donors (p<0.001). However, there was no significant association between microRNA 122 and ALT serum levels or liver inflammation grades. CONCLUSIONS: The present study showed that serum microRNA-122 was elevated in acute and chronic hepatitis patients. However, this biomarker for acute liver injury did not reflect the liver inflammation activity in CHC patients. PMID- 25461663 TI - Evaluation of Mucorales DNA load in cerebrospinal fluid in a patient with possible cerebral mucormycosis treated with intravenous liposomal amphotericin B. AB - We report the case of a 19-year-old male with possible cerebral mucormycosis following chemotherapy. We detected a Lichtheimia DNA load of 2.0*10(4) copies/ml in cerebrospinal fluid (CSF), although a CSF culture showed no growth. After treatment with intravenous liposomal amphotericin B, the Lichtheimia DNA load fell below the detection limit, and at the same time the patient's headache and imaging findings improved. The quantification of Mucorales DNA in CSF may be useful for evaluating cerebral mucormycosis. PMID- 25461664 TI - Risk factors associated with severe scrub typhus in Shandong, northern China. AB - OBJECTIVES: The aim of this study was to identify risk factors associated with severe scrub typhus, in order to provide a reference for clinical decision making. METHODS: A case-control study was conducted of scrub typhus patients who presented at local hospitals between 2010 and 2013. In total, 46 patients with severe scrub typhus complications (cases) and 194 without severe complications (controls) were included. RESULTS: There were significant differences in the duration of illness before effective antibiotic therapy, lymphadenopathy, rash, blood platelet count, white blood cell (WBC) count, percentage neutrophils, and percentage lymphocytes between the case and control groups. Multivariate analysis demonstrated that the following four factors were significantly associated with the severe complications of scrub typhus: (1) duration of illness before effective antibiotic therapy (odds ratio (OR) 2.287, 95% confidence interval (CI) 1.096-4.770); (2) the presence of a rash (OR 3.694, 95% CI 1.300-10.495); (3) lymphadenopathy (OR 2.438, 95% CI 1.090-5.458); (4) blood platelet count <100*10(9)/l (OR 2.226, 95% CI 1.002-4.946). CONCLUSIONS: This study indicates that improved diagnosis and timely treatment are important factors for the prevention of severe scrub typhus. When scrub typhus patients present with a rash, lymphadenopathy, or blood platelet count <100*10(9)/l, clinicians should be alert to the appearance of severe complications. PMID- 25461665 TI - Detection of the newly characterized HIV CRF56_cpx in Marseille, southeastern France. AB - OBJECTIVES: We aimed to seek HIV sequences highly similar to CRF56-cpx, a recently described newly circulating B/CRF02/G recombinant HIV, in our local clinical microbiology laboratory sequence database. METHODS: A recently implemented tool that combines a databank of all HIV nucleotide sequences obtained at our clinical microbiology laboratory with a search tool that uses BLAST was used. A comparative and phylogenetic analysis of HIV protease and reverse transcriptase fragments was performed. RESULTS: We identified two sequences that were clustered with CRF56-cpx with a bootstrap value of 99% in phylogenetic analyses; these were obtained from two patients diagnosed with HIV in 2009-2011. HIV protease-reverse transcriptase sequences obtained from these two patients shared a mean identity of 98.2+/-0.2% with previously described CRF56-cpx sequences. Both case patients diagnosed with HIV in our centre were highly sexually active men who have sex with men. CONCLUSIONS: Our findings highlight the continuous expansion of HIV diversity in France and indicate that real-time surveillance of HIV molecular epidemiology, including the comparison of sequences from laboratory, national, and international databases, might be helpful to identify the emergence, circulation, and transmission of viral strains. PMID- 25461666 TI - Two cases of chronic suppurative otitis media caused by Kerstersia gyiorum in Tanzania: is it an underappreciated pathogen in chronic otitis media? AB - Two cases of mixed infection involving Kerstersia gyiorum causing chronic suppurative otitis media (CSOM) have been reported worldwide. We report, for the first time, two cases of CSOM due to mixed infections involving K. gyiorum in adults in Africa. Both isolates were intermediate susceptible to ciprofloxacin based on European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. PMID- 25461667 TI - Relapse of Tropheryma whipplei endocarditis treated by trimethoprim/sulfamethoxazole, cured by hydroxychloroquine plus doxycycline. AB - The best treatment for Tropheryma whipplei infections is controversial. We report a patient who suffered from T. whipplei aortic native valve endocarditis that relapsed despite surgery and four weeks of intravenous ceftriaxone followed by several months of oral trimethoprim/sulfamethoxazole. Cure was achieved after replacement of the prosthesis with a homograft and 18 months of oral doxycycline hydroxychloroquine. We discuss the need for a change in treatment guidelines for T. whipplei infections. PMID- 25461668 TI - Interleukin 6 alters localization of hMSH3, leading to DNA mismatch repair defects in colorectal cancer cells. AB - BACKGROUND & AIMS: Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is the most common DNA mismatch repair defect in colorectal cancers, observed in approximately 60% of specimens. This acquired genotype correlates with metastasis and poor outcomes for patients, and is associated with intra-epithelial inflammation and heterogeneous nuclear levels of the mismatch repair protein hMSH3. Inflammation and accompanying oxidative stress can cause hMSH3 to change its intracellular location, but little is known about the source of oxidative stress in cancer cells. We investigated whether cytokines mediate this process. METHODS: We analyzed levels of interleukin 6 (IL6) and its receptor (IL6R) in human colon and lung cancer cell lines by flow cytometry and enzyme-linked immunosorbent assay; proteins were localized by immunofluorescence and immunoblot analyses. IL6 signaling was blocked with antibodies against IL6, soluble glycoprotein 130 Fc fragments, and the signal transducers and activators of transcription 3 inhibitor NSC74859; a constitutively active form of STAT3 was expressed in colon and lung cancer cell lines to replicate IL6R signaling. EMAST was detected by DNA fragment analysis. Immunohistochemistry was used to examine levels of IL6 in 20 colorectal tumor and adjacent nontumor tissues. RESULTS: Incubation of colon and lung cancer cell lines with IL6, but not other cytokines, caused hMSH3, but no other mismatch repair proteins, to move from the nucleus to the cytosol after generation of oxidative stress; inhibition of IL6 signaling prevented this shift. Expression of constitutively active STAT3 also caused hMSH3 to translocate from the nucleus to the cytoplasm in cancer cell lines. Incubation of cells with IL6 led to tetranucleotide frameshifts, the signature for EMAST. EMAST-positive colorectal tumors had significantly higher levels of IL6 than EMAST-negative tumors. CONCLUSIONS: IL6 signaling disrupts the nuclear localization of hMSH3 and DNA repair, leading to EMAST in cancer cell lines. Inflammatory cytokines might therefore promote genetic alterations in human cancer cells. PMID- 25461669 TI - Correlation between the international consensus definition of the Cancer Anorexia Cachexia Syndrome (CACS) and patient-centered outcomes in advanced non-small cell lung cancer. AB - CONTEXT: The cancer anorexia-cachexia syndrome (CACS) is common in patients with advanced solid tumors and is associated with adverse outcomes including poor quality of life (QOL), impaired functioning, and shortened survival. OBJECTIVES: To apply the recently posed weight-based international consensus CACS definition to a population of patients with advanced non-small cell lung cancer (NSCLC) and explore its impact on patient-reported outcomes. METHODS: Ninety-nine patients participated in up to four study visits over a six-month period. Longitudinal assessments included measures of physical function, QOL, and other clinical variables such as weight and survival. RESULTS: Patients meeting the consensus CACS criteria at Visit 1 had a significantly shorter median survival (239.5 vs. 446 days; hazard ratio, 2.06, P < 0.05). Physical function was worse in the CACS group (mean Karnofsky Performance Status score 68 vs. 77, Eastern Cooperative Oncology Group Performance Status score 1.8 vs. 1.3, P < 0.05 for both), as was QOL (Functional Assessment of Cancer Therapy-General [FACT-G] Lung Cancer subscale of 17.2 vs. 19.9, Anorexia/Cachexia subscale of 31.4 vs. 37.9, P < 0.05 for both). Differences in the FACT-G and the Functional Assessment of Chronic Illness Therapy-Fatigue subscale approached but did not reach statistical significance. Longitudinally, all measures of physical function and QOL worsened regardless of CACS status, but the rate of decline was more rapid in the CACS group. CONCLUSION: The weight-based component of the recently proposed international consensus CACS definition is useful in identifying patients with advanced NSCLC who are likely to have significantly inferior survival and who will develop more precipitous declines in physical function and QOL. This definition may be useful for clinical screening purposes and identify patients with high palliative care needs. PMID- 25461670 TI - The need for palliative care in Ireland: a population-based estimate of palliative care using routine mortality data, inclusive of nonmalignant conditions. AB - CONTEXT: Over the history of palliative care provision in Ireland, services have predominantly provided care to those with cancer. Previous estimates of palliative care need focused primarily on specialist palliative care and included only a limited number of nonmalignant diseases. OBJECTIVES: The primary aim of this study was to estimate the potential population with generalist and/or specialist palliative care needs in Ireland using routine mortality data inclusive of nonmalignant conditions. The secondary aim was to consider the quality of Irish data available for this population-based estimate. METHODS: Irish routine mortality data (2007-2011) were analyzed for malignant and nonmalignant conditions recognized as potentially requiring palliative care input, using specific International Statistical Classification of Diseases and Related Health Problems-10th Revision codes. The method developed by Murtagh et al. was used to give a population-based palliative care needs estimate, encompassing generalist and specialist palliative care need. RESULTS: During the period 2007-2011, there were 141,807 deaths. Eighty percent were from conditions recognized as having associated palliative care needs, with 41,253 (30%) deaths from cancer and 71,226 (50%) deaths from noncancer conditions. The majority of deaths, 81% (91,914), were among those >=65 years. There was a 13.9% (901) increase in deaths of those >=85 years. Deaths from dementia increased by 51.3%, with an increase in deaths from neurodegenerative disease (42.8%) and cancer (9.5%). CONCLUSION: Future palliative care policy decisions in Ireland must consider the rapidly aging Irish population with the accompanying increase in deaths from cancer, dementia, and neurodegenerative disease and associated palliative care need. New models of palliative care may be required to address this. PMID- 25461671 TI - A longitudinal study of depression, fatigue, and sleep disturbances as a symptom cluster in women with breast cancer. AB - CONTEXT: Depression, fatigue, and sleep disturbances have been identified as a symptom cluster among breast cancer patients. However, few longitudinal studies have examined the temporal relations between these symptoms surrounding diagnosis and treatment. OBJECTIVES: The present study investigated the co-occurrence of and interrelations between nonsomatic depressive symptoms, fatigue, and sleep disturbances in breast cancer patients at three time points: before, after, and six to eight months following adjuvant chemotherapy treatment. METHODS: Separate samples of premenopausal (n = 67) and postmenopausal (n = 67) breast cancer patients completed self-report measures of depression, fatigue, and sleep disturbances at all three time points. Path analysis was used to explore within- and cross-symptom paths across time. RESULTS: Depression, fatigue, and sleep disturbances were correlated within each time point. Continuity paths, whereby prior levels of symptom severity tended to predict subsequent severity of the same symptom at the subsequent time point, were significant in both samples, except for depression in the premenopausal sample. Instead, significant cross symptom paths emerged whereby baseline fatigue predicted postchemotherapy depression, and postchemotherapy fatigue predicted depression at follow-up in the premenopausal patients. No significant cross-symptom paths emerged for the postmenopausal sample. CONCLUSION: Findings supported the notion that depression, fatigue, and sleep disturbances manifest as a symptom cluster. Fatigue may precede nonsomatic symptoms of depression among premenopausal breast cancer patients and represents a potential intervention target. PMID- 25461672 TI - Distinct patterns of compartmentalization and proteolytic stability of PDE6C mutants linked to achromatopsia. AB - Phosphodiesterase-6 (PDE6) is an essential effector enzyme in vertebrate photoreceptor cells. Mutations in rod and cone PDE6 cause recessive retinitis pigmentosa and achromatopsia, respectively. The mechanisms of missense PDE6 mutations underlying severe visual disorders are poorly understood. To probe these mechanisms, we expressed seven known missense mutants of cone PDE6C in rods of transgenic Xenopus laevis and examined their stability and compartmentalization. PDE6C proteins with mutations in the catalytic domain, H602L and E790K, displayed modestly reduced proteolytic stability, but they were properly targeted to the outer segment of photoreceptor cells. Mutations in the regulatory GAF domains, R104W, Y323N, and P391L led to a proteolytic degradation of the proteins involving a cleavage in the GAFb domain. Lastly, the R29W and M455V mutations residing outside the conserved PDE6 domains produced a pattern of subcellular compartmentalization different from that of PDE6C. Thus, our results suggest a spectrum of mechanisms of missense PDE6C mutations in achromatopsia including catalytic defects, protein mislocalization, or a specific sequence of proteolytic degradation. PMID- 25461673 TI - Thermostability and reversibility of silver nanoparticle-protein binding. AB - The interactions between nanoparticles (NPs) and proteins in living systems are a precursor to the formation of a NP-protein "corona" that underlies cellular and organism responses to nanomaterials. However, the thermodynamic properties and reversibility of NP-protein interactions have rarely been examined. Using an automated, high-throughput and temperature-controlled dynamic light scattering (DLS) technique we observed a distinct hysteresis in the hydrodynamic radius of branched polyethyleneimine (BPEI) coated-silver nanoparticles (bAgNPs) exposed to like-charged lysozyme during the processes of heating and cooling, in contrast to the irreversible interactions between bAgNPs and oppositely charged alpha lactalbumin (ALact). Our discrete molecular dynamics (DMD) simulations offered a new molecular insight into the differential structure, dynamics and thermodynamics of bAgNPs binding with the two protein homologs and further revealed the different roles of the capping agents of citrate and BPEI in NP protein interactions. This study facilitates our understanding of the transformation of nanomaterials in living systems, whose implications range from the field study of nanotoxicology to nanomaterials synthesis, nanobiotechnology and nanomedicine. PMID- 25461675 TI - DNA methylation levels analysis in four tissues of sea cucumber Apostichopus japonicus based on fluorescence-labeled methylation-sensitive amplified polymorphism (F-MSAP) during aestivation. AB - DNA methylation plays an important role in regulating transcriptional change in response to environmental stimuli. In the present study, DNA methylation levels of tissues of the sea cucumber Apostichopus japonicus were analyzed by the fluorescence-labeled methylation-sensitive amplified polymorphism (F-MSAP) technique over three stages of the aestivation cycle. Overall, a total of 26,963 fragments were amplified including 9112 methylated fragments among four sea cucumber tissues using 18 pairs of selective primers. Results indicated an average DNA methylation level of 33.79% for A. japonicus. The incidence of DNA methylation was different across tissue types in the non-aestivation stage: intestine (30.16%), respiratory tree (27.61%), muscle (27.94%) and body wall (56.25%). Our results show that hypermethylation accompanied deep-aestivation in A. japonicus, which suggests that DNA methylation may have an important role in regulating global transcriptional suppression during aestivation. Further analysis indicated that the main DNA modification sites were focused on intestine and respiratory tree tissues and that full-methylation but not hemi-methylation levels exhibited significant increases in the deep-aestivation stage. PMID- 25461674 TI - Nitric oxide enhances extracellular ATP induced Ca2+ oscillation in HeLa cells. AB - Calcium (Ca(2+)) oscillations play a central role in varieties of cellular processes including fertilization and immune response, but controversy over the regulation mechanisms still exists. It has been known that nitric oxide (NO) dependently regulates Ca(2+) signaling in most physiopathological processes. Previous study indicated that eNOS translocation during some pathological process influences intracellular Ca(2+) homeostasis. In this study, we investigated the role and mechanism of NO on Ca(2+) release by overexpressing eNOS in cytoplasm (Cyto-eNOS) and endoplasmic reticulum (ER-eNOS) of HeLa cells. We found that the properties of Ca(2+) release were altered by the overexpression of eNOS. The amplitude and frequency of extracellular ATP (eATP)-induced Ca(2+) oscillation were enhanced in both Cyto-eNOS and ER-eNOS cells, respectively. Especially, the enhancement of the amplitude and frequency of the Ca(2+) oscillation was much more significant in the ER-eNOS cells than that of Cyto-eNOS cells. Further study indicated that this effect was abrogated by NO inhibitor, L-NAME, suggesting it was not an artificial result induced by ER stress. Furthermore, an up-regulated phosphorylation of phospholamban (PLB) was observed and the sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) function was activated followed by the significant increase in the ER Ca(2+) load. Taken together, we revealed a novel regulatory mechanism of Ca(2+) oscillation. PMID- 25461676 TI - Multiple alternative splicing and differential expression patterns of the glycogen synthase kinase-3beta (GSK3beta) gene in Schizothorax prenanti. AB - Glycogen synthase kinase-3 (GSK-3) is a key protein kinase involved in numerous cellular processes, including embryonic development, protein synthesis, glycogen metabolism, mitosis and apoptosis. However, our knowledge of Schizothorax prenanti GSK-3 is very limited. In this study, we cloned and characterized the S. prenanti GSK3beta gene. Using qPCR, we found that the GSK3beta gene was widely expressed in eleven tissues of S. prenanti and had especially high expression levels in the liver and brain. Moreover, we screened and sequenced more than 100 positive clones to identify the alternative transcripts of GSK3beta. Five novel isoforms of GSK3beta were identified in different S. prenanti tissues; these were different from the GSK3beta isoforms previously reported in the other species. We named the five transcripts as GSK3beta1, GSK3beta2, GSK3beta3, GSK3beta4 and GSK3beta5. These consisted of 1266, 1153, 902, 836 and 654 base pairs, respectively. Our studies provide useful information for further research on the S. prenanti GSK3beta gene. PMID- 25461677 TI - Docosahexaenoic acid in Arctic charr (Salvelinus alpinus): the importance of dietary supply and physiological response during the entire growth period. AB - The aim of this 14-month feeding study was to investigate the effects of dietary docosahexaenoic acid (DHA) on tissue fatty acid composition, DHA retention, and DHA content per biomass accrual in muscle tissues of Arctic charr (Salvelinus alpinus). A control feed, formulated with a relatively high DHA inclusion level (F1), was compared with feeds containing gradually reduced amounts of DHA (Feeds F2, F3, and F4). Arctic charr were randomly distributed among 12 tanks and fed one of the feeds in triplicate. The DHA content within muscle tissues of fish fed diets F1 and F2 was generally higher compared to fish fed diets F3 and F4. However, there was an interaction between dietary DHA treatment and season, which resulted in fish muscle tissues having similar DHA contents irrespective of dietary supply during specific sampling periods. Although diets F3 and F4 contained ~4-fold less DHA compared to diets F1 and F2, the retention of DHA in dorsal and ventral muscle tissue was up to 5-fold higher relative to the diet content in fish fed diets F3 and F4. However, the difference among treatments was dependent on the month sampled. In addition, younger fish retained DHA more efficiently compared to older fish. DHA (MUg DHA/g/day) accrual in muscle tissue was independent of somatic growth, and there was no difference among treatments. The results suggested that dietary DHA may be essential throughout the life cycle of Arctic charr and that the DHA content of muscle tissues was influenced by diet and metabolic/physiological factors, such as specific DHA retention during the entire growth cycle . Finally, this long-term feeding study in Arctic charr indicated a non-linear function in DHA retention in dorsal and ventral muscle tissues throughout the life cycle, which varied in its relationship to dietary DHA. PMID- 25461678 TI - A twisted intramolecular charge transfer probe for rapid and specific detection of trace biological SO2 derivatives and bio-imaging applications. AB - We reported a reactive probe for HSO3(-), which showed a colorimetric and ratiometric fluorescence response to HSO3(-) with fast response (t1/2 = 20 s), good specificity and low detection limit (3.0 nM). The probe was cell membrane permeable and successfully used for visualizing trace SO2 derivatives in living cells. PMID- 25461680 TI - Docosahexaenoic acid counteracts attenuation of CD95-induced cell death by inorganic mercury. AB - In the United States the principal environmental exposure to mercury is through dietary consumption of sea food. Although the mechanism by which low levels of mercury affect the nervous system is not well established, epidemiological studies suggest that low level exposure of pregnant women to dietary mercury can adversely impact cognitive development in their children, but that Docosahexaenoic acid (DHA), the most prominent n-polyunsaturated fatty acid (n PUFA) present in fish may counteract negative effects of mercury on the nervous system. Aside from effects on the nervous system, epidemiological and animal studies have also suggested that low level mercury exposure may be a risk factor for autoimmune disease. However unlike the nervous system where a mechanism linking mercury to impaired cognitive development remains elusive, we have previously suggested a potential mechanism linking low level mercury exposures to immune system dysfunction and autoimmunity. In the immune system it is well established that disruption of CD95 mediated apoptosis leads to autoimmune disease. We have previously shown in vitro as well as in vivo that in lymphocytes burdened with low levels of mercury, CD95 mediated cell death is impaired. In this report we now show that DHA counteracts the negative effect of mercury on CD95 signaling in T lymphocytes. T cells which have been pre-exposed to DHA are able to cleave pro-caspase 3 and efficiently signal programmed cell death through the CD95 signaling pathway, whether or not they are burdened with low levels of mercury. Thus DHA may lower the risk of autoimmune disease after low level mercury exposures. PMID- 25461681 TI - Suppression of c-Myc is involved in multi-walled carbon nanotubes' down regulation of ATP-binding cassette transporters in human colon adenocarcinoma cells. AB - Over-expression of ATP-binding cassette (ABC) transporters, a large family of integral membrane proteins that decrease cellular drug uptake and accumulation by active extrusion, is one of the major causes of cancer multi-drug resistance (MDR) that frequently leads to failure of chemotherapy. Carbon nanotubes (CNTs) based drug delivery devices hold great promise in enhancing the efficacy of cancer chemotherapy. However, CNTs' effects on the ABC transporters remain under investigated. In this study, we found that multiwalled carbon nanotubes (MWCNTs) reduced transport activity and expression of ABC transporters including ABCB1/Pgp and ABCC4/MRP4 in human colon adenocarcinoma Caco-2 cells. Proto-oncogene c-Myc, which directly regulates ABC gene expression, was concurrently decreased in MWCNT treated cells and forced over-expression of c-Myc reversed MWCNTs' inhibitory effects on ABCB1 and ABCC4 expression. MWCNT-cell membrane interaction and cell membrane oxidative damage were observed. However, antioxidants such as vitamin C, beta-mecaptoethanol and dimethylthiourea failed to antagonize MWCNTs' down regulation of ABC transporters. These data suggest that MWCNTs may act on c-Myc, but not through oxidative stress, to down-regulate ABC transporter expression. Our findings thus shed light on CNTs' novel cellular effects that may be utilized to develop CNTs-based drug delivery devices to overcome ABC transporter-mediated cancer chemoresistance. PMID- 25461682 TI - 17beta-trenbolone, an anabolic-androgenic steroid as well as an environmental hormone, contributes to neurodegeneration. AB - Both genetic and environmental factors contribute to neurodegenerative disorders. In a large number of neurodegenerative diseases (for example, Alzheimer's disease (AD)), patients do not carry the mutant genes. Other risk factors, for example the environmental factors, should be evaluated. 17beta-trenbolone is a kind of environmental hormone as well as an anabolic-androgenic steroid. 17beta trenbolone is used as a growth promoter for livestock in the USA. Also, a large portion of recreational exercisers inject 17beta-trenbolone in large doses and for very long time to increase muscle and strength. 17beta-trenbolone is stable in the environment after being excreted. In the present study, 17beta-trenbolone was administered to adult and pregnant rats and the primary hippocampal neurons. 17beta-trenbolone's distribution and its effects on serum hormone levels and Abeta42 accumulation in vivo and its effects on AD related parameters in vitro were assessed. 17beta-trenbolone accumulated in adult rat brain, especially in the hippocampus, and in the fetus brain. It altered Abeta42 accumulation. 17beta trenbolone induced apoptosis of primary hippocampal neurons in vitro and resisted neuroprotective function of testosterone. Presenilin-1 protein expression was down-regulated while beta-amyloid peptide 42 (Abeta42) production and caspase-3 activities were increased. Both androgen and estrogen receptors mediated the processes. 17beta-trenbolone played critical roles in neurodegeneration. Exercisers who inject large doses of trenbolone and common people who are exposed to 17beta-trenbolone by various ways are all influenced chronically and continually. Identification of such environmental risk factors will help us take early prevention measure to slow down the onset of neurodegenerative disorders. PMID- 25461683 TI - Minimally invasive secondary cytoreduction plus HIPEC versus open surgery plus HIPEC in isolated relapse from ovarian cancer: a retrospective cohort study on perioperative outcomes. AB - STUDY OBJECTIVE: To compare the perioperative outcomes of minimally invasive secondary cytoreduction surgery (SCS) plus hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) versus open surgery plus HIPEC in a group of platinum-sensitive patients with advanced epithelial ovarian cancer (AEOC) with isolated relapse. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome, Italy. PATIENTS: We selected 22 patients with a peritoneal cancer index value of 2. The laparoscopic group consisted of 11 patients who underwent laparoscopic and/or robotic complete cytoreduction plus HIPEC, whereas the laparotomic group consisted of 11 patients who underwent complete laparotomic cytoreduction plus HIPEC. INTERVENTIONS: The minimally invasive surgery (MIS) group were platinum sensitive single recurrent ovarian cancer patients who underwent either laparoscopic or robotic complete secondary cytoreduction plus HIPEC, whereas the open group were women with similar clinical characteristics who underwent complete secondary cytoreduction plus HIPEC by laparotomy. MEASUREMENTS AND MAIN RESULTS: The median operative time, calculated from the skin incision to the end of SCS (i.e., excluding HIPEC phase) was 125 min (range 95-150 min) in the MIS group and 295 min (range 180-420) in the open group (p = .001), with a median estimated blood loss of 50 mL (range 50-100) and 500 mL (range 50-1300), respectively (p = .025). The median length of hospital stay was 4 days (range 3 17) in the MIS group and 8.5 days (range 4-30) in the open group (p = .002). No statistically significant differences were registered in terms of intra- and postoperative complications between the 2 groups. CONCLUSION: The minimally invasive approach for SCS plus HIPEC is safe and efficient in terms of toxicity and postoperative outcomes for single isolated relapse. HIPEC should not be considered a major contraindication to a minimally invasive approach. PMID- 25461684 TI - Reply: To PMID 24590007. PMID- 25461685 TI - Two-dimensional versus three-dimensional laparoscopy: evaluation of physicians' performance and preference using a pelvic trainer. AB - STUDY OBJECTIVE: To compare the proficiency and preference of physicians in performing standard tasks in a box trainer using 2-dimensional (2D) versus 3 dimensional (3D) laparoscopy. DESIGN: Prospective randomized controlled trial. DESIGN CLASSIFICATION: Prospective, randomized controlled trial (Canadian Task Force classification I). SETTING: Tertiary care teaching hospital. PARTICIPANTS: Thirty physicians from the Department of Obstetrics and Gynecology. INTERVENTION: Participants were randomly assigned to perform a set of 3 to 4 tasks in a pelvic trainer using 2D laparoscopy first and then 3D laparoscopy, and vice versa. MAIN RESULTS AND MEASUREMENTS: The time taken to complete the tasks and side effects experienced were noted. Participants were asked to complete a modified Global Operative Assessment of Laparoscopic Skills (GOALS) form at the end of their tasks to evaluate their experiences and to assess their own proficiency with both visual modalities. RESULTS: The time taken for peg transfer, duct cannulation, and suturing was significantly faster using 3D laparoscopy compared with 2D laparoscopy. There were no significant differences in the time taken for pattern cutting with both visual modalities. Participants experienced more dizziness using 3D laparoscopy (6.9% vs 37.9%; p = .004). The GOALS self-evaluation score was significantly higher for 3D compared with 2D laparoscopy. After the study, 11 of 29 (37.9%) participants preferred 2D, 16 of 29 (55.2%) preferred 3D, and 1 of 29 (8.3%) had no preference. CONCLUSION: Although 3D laparoscopy scored higher on self-evaluation and was preferred by more participants, it only gave better objective performance in the completion of some selected tasks by participants with intermediate skill levels and was associated with more dizziness. Further studies are needed to determine the value of 3D laparoscopy, especially when used in the clinical setting. PMID- 25461686 TI - Incidental ureteral injury and repair during robotic-assisted total laparoscopic hysterectomy. AB - STUDY OBJECTIVE: To show a surgical educational video in which an incidental ureteral injury was recognized intraoperatively and was repaired during robotic assisted total hysterectomy for a very large uterus. DESIGN: Step-by-step demonstration of ureterolysis and repair of ureteral injury via a ureteroureterostomy technique using an educational video and schematic pictures. SETTING: Ureteral injuries are estimated to occur with a frequency of approximately 0.02% to 0.4% during laparoscopic hysterectomy. When compared with bladder injuries, ureteral injuries are much less likely to be recognized intraoperatively, and in some cases can be missed despite the use of intraoperative cystoscopy. The sequelae from ureteral injury are not insignificant, which can easily be prevented by intraoperative recognition and immediate repair. Minimally invasive surgery using the robotic system has led to a paradigm shift in the management of urinary tract injuries, which has been traditionally approached with open surgery. INTERVENTIONS: Robotic total hysterectomy and repair of incidental ureteral injury via ureteroureterostomy using standard end-to-end anastomosis technique and intracorporeal retrograde double J stent placement. CONCLUSION: Robotic repair of ureteral injury during gynecologic surgery was associated with good outcomes, appeared safe and feasible, and saved the patient and the physician significant morbidity and medicolegal implications, respectively. PMID- 25461687 TI - Endometrial cancer after endometrial ablation vs medical management of abnormal uterine bleeding. PMID- 25461689 TI - Rasch analysis of the coping inventory for stressful situations in individuals with moderate to severe traumatic brain injury. AB - OBJECTIVE: To evaluate psychometric properties of the Coping Inventory for Stressful Situations (CISS) in individuals with traumatic brain injury (TBI). DESIGN: Archival study using Rasch analysis. SETTING: Postacute rehabilitation hospital. PARTICIPANTS: Adults (N=331) 1 to 15 years after moderate to severe TBI, recruited consecutively. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: CISS. RESULTS: Indices of unidimensionality and model fit supported the scale's proposed multidimensional structure consisting of Task, Emotion, and Avoidant coping style; 3 unidimensional scales showed better fit than a single combined scale. The 3 scales met Rasch expectations of reliability and separation for persons and items, as well as adequate response category functioning. The scales were generally well targeted but showed some evidence of ceiling effect for Task, and floor effects for Emotion and Avoidant coping; item difficulties did not fully capture extreme ranges demonstrated by some participants, suggesting that measurement of coping after TBI on the CISS would be improved with additional items at low and high ranges of difficulty. Results were generally equivalent for cross-sectional groups representing short-term (1y), intermediate (2y), and long-term (5-15y). CONCLUSIONS: The CISS showed good psychometric properties as a measure of coping style among persons with moderate to severe TBI in acute and chronic phases of recovery, and showed evidence of multidimensionality as predicted by theory, consistent with 3 unidimensional scales. Added items tapping broader (or more accessible, less cognitively complex) ranges of coping responses would likely benefit the scale overall and improve correspondence with the response needs of people with TBI. PMID- 25461691 TI - New observations regarding post-ischemia/reperfusion myocardial swelling. PMID- 25461690 TI - 6- versus 24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: the randomized, multicenter ITALIC trial. AB - BACKGROUND: The currently recommended duration of dual antiplatelet therapy (DAPT) in drug-eluting stent (DES) recipients is 12 months to reduce the risk of late stent thrombosis, particularly in those with acute coronary syndrome (ACS). OBJECTIVES: This study hypothesized that antiplatelet treatment with DAPT for 6 months may be noninferior to 24-month DAPT in aspirin-sensitive patients. METHODS: A multicenter, randomized study assigned patients undergoing implantation of everolimus-eluting stents with confirmed nonresistance to aspirin to receive 6- or 24-month DAPT. The primary endpoint was a composite of death, myocardial infarction, urgent target vessel revascularization, stroke, and major bleeding at 12 months post-stenting. RESULTS: A total of 2,031 patients were enrolled in 70 European and Middle Eastern centers. The trial was prematurely terminated due to recruitment problems, leaving 941 patients randomized to 24 month DAPT and 953 to 6-month DAPT. The 2 treatment groups had similar baseline and procedural characteristics. There was no significant difference in the primary endpoint (24-month: 1.5% vs. 6-month: 1.6%; p = 0.85). Noninferiority was demonstrated for 6- versus 24-month DAPT, with an absolute risk difference of 0.11% (95% confidence interval: -1.04% to 1.26%; p for noninferiority = 0.0002). There were no significant differences in stent thrombosis or bleeding complications. In the 792 (44%) high-risk patients with ACS, primary and secondary endpoints did not significantly differ (hazard ratio: 1.7 [95% confidence interval: 0.519 to 6.057; p = 0.361]). CONCLUSIONS: Rates of bleeding and thrombotic events were not significantly different according to 6- versus 24 month DAPT after PCI with new-generation DES in good aspirin responders. (Is There A LIfe for DES After Discontinuation of Clopidogrel [ITALICplus]; NCT01476020). PMID- 25461693 TI - Possible transfer of plasmid mediated third generation cephalosporin resistance between Escherichia coli and Shigella sonnei in the human gut. AB - Choice of antibiotic for treatment of serious bacterial infection is rapidly diminishing by plasmid mediated transfer of antibiotic resistance. Here, we report a possible horizontal transfer of plasmid carrying third-generation cephalosporin (TGC) resistance between Escherichia coli and Shigella sonnei. Two different types of colonies were identified in MacConkey agar plate from a faecal specimen collected from a patient with shigellosis. The colonies were identified as E. coli and S. sonnei. Both of the isolates were resistant to ampicillin, chloramphenicol, co-trimoxazole, erythromycin, azithromycin, nalidixic acid, ceftriaxone, cefixime, ceftazidime, cefotaxime and susceptible to co-amoxiclave, amikacin, imipenam, astreonam, levofloxacin, moxifloxacin, mecillinam. These two strains were positive for extended spectrum beta-lactamase. We were able to transfer ESBL producing property from both ceftriaxone-resistant isolates to the ceftriaxone susceptible recipient E. coli K12 and S. sonnei. Plasmid profile analysis revealed that the first-generation E. coli K12 and S. sonnei transconjugants harbored a 50MDa R plasmid, as two-parent ESBL-producing S. sonnei and E. coli strains. Similar patterns of ESBL producing plasmid and transferable antimicrobial phenotype suggests that the ESBL producing plasmid might transferred between E. coli and S. sonnei through conjugation in the human gut. PMID- 25461692 TI - Phylogenetic and pathogenic analyses of three H5N1 avian influenza viruses (clade 2.3.2.1) isolated from wild birds in Northeast China. AB - From April to September 2012, periodic surveillance of avian influenza H5N1 viruses from different wild bird species was conducted in Northeast China. Three highly pathogenic avian influenza (HPAI) H5N1 viruses were isolated from a yellow browed warbler, common shoveler, and mallard. To trace the genetic lineage of the isolates, nucleotide sequences of all eight gene segments were determined and phylogenetically analyzed. The data indicated that three viruses belonged to the same antigenic virus group: clade 2.3.2.1. To investigate the pathogenicity of these three viruses in different hosts, chickens, ducks, and mice were inoculated. The results showed that chickens were susceptible to each of the three HPAI H5N1 viruses, resulting in 100% mortality within 2-6 days after infection, whereas the three isolates exhibited distinctly different virulence in ducks and mice. The results of this study demonstrated that HPAI H5N1 viruses of clade 2.3.2.1 are still circulating in wild birds through overlapping migratory flyways. Therefore, continuous monitoring of H5N1 in both domestic and wild birds is necessary to prevent a potentially wider outbreak. PMID- 25461694 TI - RstA is required for the virulence of an avian pathogenic Escherichia coli O2 strain E058. AB - Certain strains of avian pathogenic Escherichia coli (APEC) cause severe extraintestinal infections in poultry, including acute fatal septicemia, subacute pericarditis, and airsacculitis. These bacteria contain an RstA/RstB regulatory system, a two-component system that may help APEC strains adapt to the extra intestinal environment and survive under stressful conditions. Whether RstA correlates with APEC pathogenesis or acts as an APEC virulence factor has not been established. Here we provide the first evidence for an important role of rstA in APEC virulence. We generated an rstA-deficient mutant from the highly virulent APEC strain E058. Virulence of the mutant strain was evaluated in vivo and in vitro through bird infection assays, a cytotoxicity assay on chicken macrophage cell line HD-11, and a bactericidal assay to serum complement. Based on lethality assays in 1-day-old birds, rstA deletion from APEC E058 reduced the bacterial virulence in birds. The deletion also deeply impaired the capacity of APEC E058 to colonize deeper tissues of 5-week-old specific pathogen free chickens. No obvious gross or histopathological lesions were observed in the visceral organs of chickens challenged with the rstA-deficient strain. Also, rstA inactivation reduced the survival of APEC E058 within chicken macrophages. However, no significant differences were observed between the mutant and the wild type strain in resistance to serum. Our data collectively show that the rstA gene functions in the pathogenesis of diseases caused by avian pathogenic E. coli. PMID- 25461695 TI - Proteomics of seed development, desiccation tolerance, germination and vigor. AB - Proteomics, the large-scale study of the total complement of proteins in a given sample, has been applied to all aspects of seed biology mainly using model species such as Arabidopsis or important agricultural crops such as corn and rice. Proteins extracted from the sample have typically been separated and quantified by 2-dimensional polyacrylamide gel electrophoresis followed by liquid chromatography and mass spectrometry to identify the proteins in the gel spots. In this way, qualitative and quantitative changes in the proteome during seed development, desiccation tolerance, germination, dormancy release, vigor alteration and responses to environmental factors have all been studied. Many proteins or biological processes potentially important for each seed process have been highlighted by these studies, which greatly expands our knowledge of seed biology. Proteins that have been identified to be particularly important for at least two of the seed processes are involved in detoxification of reactive oxygen species, the cytoskeleton, glycolysis, protein biosynthesis, post-translational modifications, methionine metabolism, and late embryogenesis-abundant (LEA) proteins. It will be useful for molecular biologists and molecular plant breeders to identify and study genes encoding particularly interesting target proteins with the aim to improve the yield, stress tolerance or other critical properties of our crop species. PMID- 25461688 TI - 3D in vitro modeling of the central nervous system. AB - There are currently more than 600 diseases characterized as affecting the central nervous system (CNS) which inflict neural damage. Unfortunately, few of these conditions have effective treatments available. Although significant efforts have been put into developing new therapeutics, drugs which were promising in the developmental phase have high attrition rates in late stage clinical trials. These failures could be circumvented if current 2D in vitro and in vivo models were improved. 3D, tissue-engineered in vitro systems can address this need and enhance clinical translation through two approaches: (1) bottom-up, and (2) top down (developmental/regenerative) strategies to reproduce the structure and function of human tissues. Critical challenges remain including biomaterials capable of matching the mechanical properties and extracellular matrix (ECM) composition of neural tissues, compartmentalized scaffolds that support heterogeneous tissue architectures reflective of brain organization and structure, and robust functional assays for in vitro tissue validation. The unique design parameters defined by the complex physiology of the CNS for construction and validation of 3D in vitro neural systems are reviewed here. PMID- 25461696 TI - Early growth promotion and leaf level physiology changes in Burkholderia phytofirmans strain PsJN inoculated switchgrass. AB - Switchgrass (SG) is one of the most promising next generation biofuel crops in North America. Inoculation with bacterial endophytes has improved growth of several plant species. Our study demonstrated that Burkholderia phytofirmans strain PsJN, a well-studied plant growth promoting rhizo-bacterium (PGPR) significantly increased both aboveground and belowground biomass (DW) and promoted elongation of root, stem and leaf within 17 days following inoculation. Furthermore, the enhanced root growth in PsJN inoculated plants lagged behind the shoot response, resulting in greater allocation to aboveground growth (p = 0.0041). Lower specific root length (SRL, p = 0.0158) and higher specific leaf weight (SLW, p = 0.0029) were also observed in PsJN inoculated seedlings, indicating changes in development. Photosynthetic rates (Ps) were also significantly higher in PsJN inoculated seedlings after 17 days (54%, p = 0.0016), and this occurred initially without increases in stomatal conductance resulting in significantly greater water use efficiency (WUE, 37.7%, p = 0.0467) and lower non-stomatal limitation (LNS, 29.6%, p = 0.0222). These rapid changes in leaf level physiology are at least partially responsible for the growth enhancement due to PsJN. PMID- 25461697 TI - Metabolite profiling elucidates communalities and differences in the polyphenol biosynthetic pathways of red and white Muscat genotypes. AB - The chemical composition of grape berries is varietal dependent and influenced by the environment and viticulture practices. In Muscat grapes, phenolic compounds play a significant role in the organoleptic property of the wine. In the present study, we investigated the chemical diversity of berries in a Muscat collection. Metabolite profiling was performed on 18 Moscato bianco clones and 43 different red and white grape varieties of Muscat using ultra-performance liquid chromatography-quadrupole time of flight-mass spectrometry (UPLC-QTOF-MS/MS) coupled with SNP genotyping. Principle component analysis and hierarchical clustering showed a separation of the genotypes into six main groups, three red and three white. Anthocyanins mainly explained the variance between the different groups. Additionally, within the white varieties mainly flavonols and flavanols contributed to the chemical diversity identified. A genotype-specific rootstock effect was identified when separately analyzing the skin of the clones, and it was attributed mainly to resveratrol, quercetin 3-O-galactoside, citrate and malate. The metabolite profile of the varieties investigated reveals the chemical diversity existing among different groups of Muscat genotypes. The distribution pattern of metabolites among the groups dictates the abundance of precursors and intermediate metabolite classes, which contribute to the organoleptic properties of Muscat berries. PMID- 25461698 TI - Overexpression of wheat NF-YA10 gene regulates the salinity stress response in Arabidopsis thaliana. AB - The nuclear factor Y (NF-Y) transcription factor is formed by the interaction of three distinct subunits (NF-YA, -YB and -YC). It targets the CCAAT box, a common cis-element in eukaryotic promoters. Here, the bread wheat gene TaNF-YA10-1 has been isolated from the salinity tolerant cultivar SR3. Recombinant TaNF-YA10-1 was heterologously produced in Escherichia coli, and the purified protein successfully bound to the CCAAT motif in vitro. TaNF-YA10-1 was down-regulated by the imposition of salinity and abscisic acid (ABA). The constitutive expression of TaNF-YA10-1 in Arabidopsis thaliana significantly increased the plant's sensitivity to salinity and repressed its sensitivity to ABA as judged from the seed germination, cotyledon greening and the relative root growth. The transcription of stress-related genes AtRAB18, AtRD29B, AtABI5, AtCBF1 and AtCBF3 was downregulated in TaNF-YA10-1 overexpression transgenic plants. The data provide supportive evidence that TaNFYA10-1 is involved in the regulation of growth under salinity stress conditions. PMID- 25461699 TI - The effects of salt stress cause a diversion of basal metabolism in barley roots: possible different roles for glucose-6-phosphate dehydrogenase isoforms. AB - In this study the effects of salt stress and nitrogen assimilation have been investigated in roots of hydroponically-grown barley plants exposed to 150 mM NaCl, in presence or absence of ammonium as the sole nitrogen source. Salt stress determines a diversion of root metabolism towards the synthesis of osmolytes, such as glycine betaine and proline, and increased levels of reduced glutathione. The metabolic changes triggered by salt stress result in a decrease in both activities and protein abundance of key enzymes, namely GOGAT and PEP carboxylase, and in a slight increase in HSP70. These variations would enhance the requirement for reductants supplied by the OPPP, consistently with the observed increase in total G6PDH activity. The involvement and occurrence of the different G6PDH isoforms have been investigated, and the kinetic properties of partially purified cytosolic and plastidial G6PDHs determined. Bioinformatic analyses examining co-expression profiles of G6PDHs in Arabidopsis and barley corroborate the data presented. Moreover, the gene coding for the root P2-G6PDH isoform was fully sequenced; the biochemical properties of the corresponding protein were examined experimentally. The results are discussed in the light of the possible distinct roles and regulation of the different G6PDH isoforms during salt stress in barley roots. PMID- 25461700 TI - Identification and expression analysis of rice histone genes. AB - Histones, acting as the core of nucleosome, are the chief protein component of chromatin. They play an important role in gene regulation by covalent modification at several sites and histone variants replacement. Five major families of histones exist: H1, H2A, H2B, H3 and H4. The protein sequences within each family appear to be highly conserved. In this paper, we identified 60 histone proteins in rice (Oryza sativa) including 14 H2A, 15 H2B, 16 H3, 11 H4 and 4 H1. Sequence analysis indicates that histone protein sequences in plant are more variable than in animal. Interestingly, we found a rice-specific H4 variant which showed several amino acid substitutions with canonical protein and was expressed in different tissues in a low level. Expression analysis indicates that a subset of histone genes were expressed in a similar pattern and many of them responded to stress conditions. Specifically, we found that two H2A.Z genes were down-regulated by stress in leaves but not in roots suggesting that they might be involved in stress response. PMID- 25461701 TI - Response of NBS encoding resistance genes linked to both heat and fungal stress in Brassica oleracea. AB - Environmental stresses, including both abiotic and biotic stresses, cause considerable yield loss in crops and can significantly affect their development. Under field conditions, crops are exposed to a variety of concurrent stresses. Among abiotic and biotic stresses, heat and Fusarium oxysporum, are the most important factors affecting development and yield productivity of Brassica oleracea. Genes encoding the nucleotide-binding site (NBS) motif are known to be related to responses to abiotic and biotic stresses in many plants. Hence, this study was conducted to characterize the NBS encoding genes obtained from transcriptome profiles of two cabbage genotypes with contrasting responses to heat stress, and to test expression levels of selected NBS- leucine reich repeat (LRR) genes in F. oxysporum infected plants. We selected 80 up-regulated genes from a total of 264 loci, among which 17 were confirmed to be complete and incomplete members of the TIR-NBS-LRR (TNL) class families, and another identified as an NFYA-HAP2 family member. Expression analysis using qRT-PCR revealed that eight genes showed significant responses to heat shock treatment and F. oxysporum infection. Additionally, in the commercial B. oleracea cultivars with resistance to F. oxysporum, the Bol007132, Bol016084, and Bol030522 genes showed dramatically higher expression in the F. oxysporum resistant line than in the intermediate and susceptible lines. The results of this study will facilitate the identification and the development of molecular markers based on multiple stress resistance genes related to heat and fungal stress under field conditions in B. oleracea. PMID- 25461702 TI - Neuro-anatomical differences among epileptic and non-epileptic deja-vu. AB - OBJECTIVE: Deja-vu (DV) can occur as a seizure of mesial temporal lobe epilepsy (MTLE) and in almost 80% of healthy individuals. The remarkable similarity between epileptic DV and DV in healthy individuals raises the possibility that DV might sometimes be an ictal phenomenon in apparently normal individuals. Thus, we studied a group of healthy subjects versus individuals with benign MTLE (bMTLE) both experiencing DV. METHODS: 63 individuals with epilepsy patients with bMTLE and 39 healthy controls at Catanzaro University were recruited. Participants completed the Inventory for Deja Vu (DV) Experiences Assessment (IDEA) test, underwent awake and asleep electroencephalogram, MRI of the brain using a 3T scanner and whole brain voxel-based morphometry (VBM). bMTLE patients with DV and without DV were also matched for the presence of hippocampal sclerosis. RESULTS: Our controls had no history of neurological or psychiatric illness, epilepsy or history of febrile convulsions. Neurological and cognitive examinations were normal. Electroencephalographic procedures were unremarkable in all controls. In bMTLE group, the direct comparison of VBM between individuals with epilepsy with DV versus those without DV revealed abnormal anatomical changes in the left hippocampus, parahippocampal gyrus and visual cortex. The VBM of healthy controls with DV showed abnormal anatomical changes only in the left insular cortex. CONCLUSIONS: Our VBM results demonstrated different morphologic patterns in individuals with epilepsy and control subjects experiencing DV, involving the memory circuit in bMTLE patients and cerebral regions in the emotional network in healthy controls. PMID- 25461703 TI - Language exposure induced neuroplasticity in the bilingual brain: a follow-up fMRI study. AB - Although several studies have shown that language exposure crucially influence the cerebral representation of bilinguals, the effects of short-term change of language exposure in daily life upon language control areas in bilinguals are less known. To explore this issue, we employed follow-up fMRI to investigate whether differential exposure induces neuroplastic changes in the language control network in high-proficient Cantonese (L1)-Mandarin (L2) early bilinguals. The same 10 subjects underwent twice BOLD-fMRI scans while performing a silent narration task which corresponded to two different language exposure conditions, CON-1 (L1/L2 usage percentage, 50%:50%) and CON-2 (L1/L2 usage percentage, 90%:10%). We report a strong effect of language exposure in areas related to language control for the less exposed language. Interestingly, these significant effects were present after only a 30-day period of differential language exposure. In detail, we reached the following results: (1) the interaction effect of language and language exposure condition was found significantly in the left pars opercularis (BA 44) and marginally in the left MFG (BA 9); (2) in CON-2, increases of activation values in L2 were found significantly in bilateral BA 46 and BA 9, in the left BA44, and marginally in the left caudate; and (3) in CON-2, we found a significant negative correlation between language exposure to L2 and the BOLD activation value specifically in the left ACC. These findings strongly support the hypothesis that even short periods of differential exposure to a given language may induce significant neuroplastic changes in areas responsible for language control. The language which a bilingual is less exposed to and is also less used will be in need of increased mental control as shown by the increased activity of language control areas. PMID- 25461705 TI - Visual processing of words in a patient with visual form agnosia: a behavioural and fMRI study. AB - Patient D.F. has a profound and enduring visual form agnosia due to a carbon monoxide poisoning episode suffered in 1988. Her inability to distinguish simple geometric shapes or single alphanumeric characters can be attributed to a bilateral loss of cortical area LO, a loss that has been well established through structural and functional fMRI. Yet despite this severe perceptual deficit, D.F. is able to "guess" remarkably well the identity of whole words. This paradoxical finding, which we were able to replicate more than 20 years following her initial testing, raises the question as to whether D.F. has retained specialized brain circuitry for word recognition that is able to function to some degree without the benefit of inputs from area LO. We used fMRI to investigate this, and found regions in the left fusiform gyrus, left inferior frontal gyrus, and left middle temporal cortex that responded selectively to words. A group of healthy control subjects showed similar activations. The left fusiform activations appear to coincide with the area commonly named the visual word form area (VWFA) in studies of healthy individuals, and appear to be quite separate from the fusiform face area (FFA). We hypothesize that there is a route to this area that lies outside area LO, and which remains relatively unscathed in D.F. PMID- 25461704 TI - Resting BOLD fluctuations in the primary somatosensory cortex correlate with tactile acuity. AB - Sensory perception, including 2-point discrimination (2 ptD), is tightly linked to cortical processing of tactile stimuli in primary somatosensory cortices. While the role of cortical activity in response to a tactile stimulus has been widely investigated, the role of baseline cortical activity is largely unknown. Using resting state fMRI we investigated the relationship between local BOLD fluctuations in the primary somatosensory cortex (the representational field of the hand) and 2 ptD of the corresponding index finger (right and left). Cortical activity was measured using fractional amplitudes of the low frequency BOLD fluctuations (fALFF) and synchronicity using regional homogeneity (ReHo) of the S1 hand region during rest. 2 ptD correlated with higher ReHo values in the representational areas of the contralateral S1 cortex (left hand: p = .028; right hand: p = .049). 2 ptD additionally correlated with higher fALFF in the representational area of the left hand (p = .007) and showed a trend for a significant correlation in the representational area of the right hand (p = .051). Thus, higher BOLD amplitudes and synchronicity at rest, as measures of cortical activity and synchronicity, respectively, are related to better tactile discrimination abilities of the contralateral hand. Our findings extend the relationship seen between spontaneous BOLD fluctuations and sensory perception. PMID- 25461706 TI - Volitional action as perceptual detection: predictors of conscious intention in adolescents with tic disorders. AB - Voluntary actions are accompanied by a distinctive subjective experience, so that they feel quite different from physically similar involuntary movements. However, the nature and origin of this experience of volition remain unclear. Voluntary actions emerge during early childhood, in parallel with reduction of involuntary movements. However, the available markers of the experience of volition, notably Libet's mental chronometry of intention, cannot readily be used in young children. In Gilles de la Tourette syndrome (GTS), however, involuntary tic movements may coexist with voluntary control into adulthood. Therefore, adolescents with GTS could potentially confuse the two classes of movement. We have measured the temporal experience of voluntary action in a well-characterised group of adolescents with GTS, and age-matched controls. We replicated previous reports of a conscious intention occurring a few hundred milliseconds prior to voluntary keypress actions. Multiple regression across 25 patients' results showed that age and trait tic severity did not influence the experience of conscious intention. However, patients with stronger premonitory urges prior to tics showed significantly later conscious intentions, suggesting that the anticipatory experience of one's own volition involves a perceptual discrimination between potentially competing pre-movement signals. Patients who were more able to voluntarily suppress their tics showed significantly earlier conscious intention, suggesting that the perceptual discrimination between different action classes may also contribute to voluntary control of tics. We suggest that the brain learns voluntary control by perceptually discriminating a special class of internal 'intentional' signals, allowing them to emerge from motor noise. PMID- 25461708 TI - Cortical inhibition of distinct mechanisms in the dorsolateral prefrontal cortex is related to working memory performance: a TMS-EEG study. AB - Paired-pulse transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) is a method for studying cortical inhibition from the dorsolateral prefrontal cortex (DLPFC). However, little is known about the mechanisms underlying TMS-evoked cortical potentials (TEPs) from this region, let alone inhibition of these components. The aim of this study was to assess cortical inhibition of distinct TEPs and oscillations in the DLPFC using TMS-EEG and to investigate the relationship of these mechanisms to working memory. 30 healthy volunteers received single and paired (interstimulus interval = 100 msec) TMS to the left DLPFC. Variations in long-interval cortical inhibition (LICI) of different TEP peaks (N40, P60, N100) and different TMS-evoked oscillations (alpha, lower beta, upper beta, gamma) were compared between individuals. Variation in N100 slope following single pulse TMS, another putative marker of inhibition, was also compared with LICI of each measure. Finally, these measures were correlated with performance of a working memory task. LICI resulted in significant suppression of all TEP peaks and TMS-evoked oscillations (all p < .05). There were no significant correlations between LICI of different TEP peaks or TMS-evoked oscillations with the exception of P60 and N100. Variation in N100 slope correlated with LICI of N40 and beta oscillations. In addition, LICI of P60 and N100 were differentially correlated with working memory performance. The results suggest that both the LICI paradigm and N100 following single pulse TMS reflect complementary methods for assessing GABAB-mediated cortical inhibition in the DLPFC. Furthermore, these measures demonstrate the importance of prefrontal GABAB-mediated inhibitory control for working memory performance. PMID- 25461707 TI - Damage to left frontal regulatory circuits produces greater positive emotional reactivity in frontotemporal dementia. AB - Positive emotions foster social relationships and motivate thought and action. Dysregulation of positive emotion may give rise to debilitating clinical symptomatology such as mania, risk-taking, and disinhibition. Neuroanatomically, there is extensive evidence that the left hemisphere of the brain, and the left frontal lobe in particular, plays an important role in positive emotion generation. Although prior studies have found that left frontal injury decreases positive emotion, it is not clear whether selective damage to left frontal emotion regulatory systems can actually increase positive emotion. We measured happiness reactivity in 96 patients with frontotemporal dementia (FTD), a neurodegenerative disease that targets emotion-relevant neural systems and causes alterations in positive emotion (i.e., euphoria and jocularity), and in 34 healthy controls. Participants watched a film clip designed to elicit happiness and a comparison film clip designed to elicit sadness while their facial behavior, physiological reactivity, and self-reported emotional experience were monitored. Whole-brain voxel-based morphometry (VBM) analyses revealed that atrophy in predominantly left hemisphere fronto-striatal emotion regulation systems including left ventrolateral prefrontal cortex, orbitofrontal cortex, anterior insula, and striatum was associated with greater happiness facial behavior during the film (pFWE < .05). Atrophy in left anterior insula and bilateral frontopolar cortex was also associated with higher cardiovascular reactivity (i.e., heart rate and blood pressure) but not self-reported positive emotional experience during the happy film (p < .005, uncorrected). No regions emerged as being associated with greater sadness reactivity, which suggests that left-lateralized fronto-striatal atrophy is selectively associated with happiness dysregulation. Whereas previous models have proposed that left frontal injury decreases positive emotional responding, we argue that selective disruption of left hemisphere emotion regulating systems can impair the ability to suppress positive emotions such as happiness. PMID- 25461709 TI - Synchronous and opposite roles of the parietal and prefrontal cortices in bistable perception: a double-coil TMS-EEG study. AB - Bistable perception occurs when a stimulus is ambiguous and has two distinct interpretations that spontaneously alternate in observers' consciousness. Studies using functional magnetic resonance imaging, electroencephalography (EEG), and transcranial magnetic stimulation (TMS) in healthy subjects and patient studies point towards a right fronto-parietal network regulating the balance between percept stabilization and the arising of alternative interpretations. However, the causal role of the interaction between parietal and prefrontal areas is not clearly understood. Using intermittent presentations of bistable images, we confirmed that maintaining or switching percepts had neural correlates identifiable on EEG. Single-pulse TMS applied over the right anterior intraparietal sulcus (IPS) 70 msec before image presentation interfered with evoked potentials and destabilized the percept. However, with paired-pulse TMS applied over right IPS and dorsolateral prefrontal cortex (DLPFC) 70 and 60 msec before image presentation, both perceptual and neurophysiological effects were canceled. Thus, TMS over IPS and DLPFC interacted with each other and influenced upcoming percepts. We suggest that when the visual world is ambiguous, IPS plays a stabilizing role, whereas DLPFC is important for triggering perceptual switches or for modulating parietal activity. The balance between maintaining and switching visual conscious percepts relies on the dynamic interaction between IPS and DLPFC. PMID- 25461710 TI - Early stages of perceptual face processing are confined to the contralateral hemisphere: evidence from the N170 component. AB - High-level visual object processing is often assumed to be largely position independent. Here we demonstrate that when faces and non-face objects simultaneously appear in opposite visual hemifields, the face-sensitive N170 component of the event-related brain potential (ERP) is exclusively generated in the contralateral hemisphere. The effects of face inversion on N170 amplitudes and latencies also show strong contralateral biases. These results reveal that retinotopic biases in low-level visual cortex extend well into category-selective high-level vision. We suggest that the contralateral organisation of face sensitive visual processing results from generic competitive interactions between hemispheres during the simultaneous perception of visual objects. PMID- 25461711 TI - Brain activity during observation and motor imagery of different balance tasks: an fMRI study. AB - After immobilization, patients show impaired postural control and increased risk of falling. Therefore, loss of balance control should already be counteracted during immobilization. Previously, studies have demonstrated that both motor imagery (MI) and action observation (AO) can improve motor performance. The current study elaborated how the brain is activated during imagination and observation of different postural tasks to provide recommendations about the conception of non-physical balance training. For this purpose, participants were tested in a within-subject design in an fMRI-scanner in three different conditions: (a) AO + MI, (b) AO, and (c) MI. In (a) participants were instructed to imagine themselves as the person pictured in the video whereas in (b) they were instructed simply to watch the video. In (c) subjects closed their eyes and kinesthetically imagined the task displayed in the video. Two tasks were evaluated in each condition: (i) static standing balance and (ii) dynamic standing balance (medio-lateral perturbation). In all conditions the start of a new trial was indicated every 2 sec by a sound. During AO + MI of the dynamic task, participants activated motor centers including the putamen, cerebellum, supplementary motor area, premotor cortices (PMv/d) and primary motor cortex (M1). MI showed a similar pattern but no activity in M1 and PMv/d. In the SMA and cerebellum, activity was generally higher in the dynamic than in the static condition. AO did not significantly activate any of these brain areas. Our results showed that (I) mainly AO + MI, but also MI, activate brain regions important for balance control; (II) participants display higher levels of brain activation in the more demanding balance task; (III) there is a significant difference between AO + MI and AO. Consequently, best training effects should be expected when participants apply MI during AO (AO + MI) of challenging postural tasks. PMID- 25461712 TI - Probing short-term face memory in developmental prosopagnosia. AB - It has recently been proposed that the face recognition deficits seen in neurodevelopmental disorders may reflect impaired short-term face memory (STFM). For example, introducing a brief delay between the presentation of target and test faces seems to disproportionately impair matching or recognition performance in individuals with Autism Spectrum Disorders. The present study sought to determine whether deficits of STFM contribute to impaired face recognition seen in Developmental Prosopagnosia. To determine whether developmental prosopagnosics exhibit impaired STFM, the present study used a six-alternative-forced-choice match-to-sample procedure. Memory demand was manipulated by employing a short or long delay between the presentation of the target face, and the six test faces. Crucially, the perceptual demands were identical in both conditions, thereby allowing the independent contribution of STFM to be assessed. Prosopagnosics showed clear evidence of a category-specific impairment for face-matching in both conditions; they were both slower and less accurate than matched controls. Crucially, however, the prosopagnosics showed no evidence of disproportionate face recognition impairment in the long-interval condition. While individuals with DP may have problems with the perceptual encoding of faces, it appears that their representations are stable over short durations. These results suggest that the face recognition difficulties seen in DP and autism may be qualitatively different, attributable to deficits of perceptual encoding and perceptual maintenance, respectively. PMID- 25461713 TI - Learning robust cortico-cortical associations with the basal ganglia: an integrative review. AB - This article focuses on the interaction between the basal ganglia (BG) and prefrontal cortex (PFC). The BG are a group of nuclei at the base of the forebrain that are highly connected with cortex. A century of research suggests that the role of the BG is not exclusively motor, and that the BG also play an important role in learning and memory. In this review article, we argue that one important role of the BG is to train connections between posterior cortical areas and frontal cortical regions that are responsible for automatic behavior after extensive training. According to this view, one effect of BG trial-and-error learning is to activate the correct frontal areas shortly after posterior associative cortex activation, thus allowing for Hebbian learning of robust, fast, and efficient cortico-cortical processing. This hypothesized process is general, and the content of the learned associations depends on the specific areas involved (e.g., associations involving premotor areas would be more closely related to behavior than associations involving the PFC). We review experiments aimed at pinpointing the function of the BG and the frontal cortex and show that these results are consistent with the view that the BG is a general purpose trainer for cortico-cortical connections. We conclude with a discussion of some implications of the integrative framework and how this can help better understand the role of the BG in many different tasks. PMID- 25461714 TI - The processing of actions and action-words in amyotrophic lateral sclerosis patients. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with prime consequences on the motor function and concomitant cognitive changes, most frequently in the domain of executive functions. Moreover, poorer performance with action-verbs versus object-nouns has been reported in ALS patients, raising the hypothesis that the motor dysfunction deteriorates the semantic representation of actions. Using action-verbs and manipulable-object nouns sharing semantic relationship with the same motor representations, the verb-noun difference was assessed in a group of 21 ALS-patients with severely impaired motor behavior, and compared with a normal sample's performance. ALS-group performed better on nouns than verbs, both in production (action and object naming) and comprehension (word-picture matching). This observation implies that the interpretation of the verb-noun difference in ALS cannot be accounted by the relatedness of verbs to motor representations, but has to consider the role of other semantic and/or morpho-phonological dimensions that distinctively define the two grammatical classes. Moreover, this difference in the ALS-group was not greater than the noun-verb difference in the normal sample. The mental representation of actions also involves an executive-control component to organize, in logical/temporal order, the individual motor events (or sub-goals) that form a purposeful action. We assessed this ability with action sequencing tasks, requiring participants to re-construct a purposeful action from the scrambled presentation of its constitutive motor events, shown in the form of photographs or short sentences. In those tasks, ALS-group's performance was significantly poorer than controls'. Thus, the executive dysfunction manifested in the sequencing deficit -but not the selective verb deficit- appears as a consistent feature of the cognitive profile associated with ALS. We suggest that ALS can offer a valuable model to study the relationship between (frontal) motor centers and the executive-control machinery housed in the frontal brain, and the implications of executive dysfunctions in tasks such as action processing. PMID- 25461715 TI - Anomalous brain functional connectivity contributing to poor adaptive behavior in Down syndrome. AB - Research in Down syndrome has substantially progressed in the understanding of the effect of gene overexpression at the molecular level, but there is a paucity of information on the ultimate consequences on overall brain functional organization. We have assessed the brain functional status in Down syndrome using functional connectivity MRI. Resting-state whole-brain connectivity degree maps were generated in 20 Down syndrome individuals and 20 control subjects to identify sites showing anomalous synchrony with other areas. A subsequent region of-interest mapping served to detail the anomalies and to assess their potential contribution to poor adaptive behavior. Down syndrome individuals showed higher regional connectivity in a ventral brain system involving the amygdala/anterior temporal region and the ventral aspect of both the anterior cingulate and frontal cortices. By contrast, lower functional connectivity was identified in dorsal executive networks involving dorsal prefrontal and anterior cingulate cortices and posterior insula. Both functional connectivity increases and decreases contributed to account for patient scoring on adaptive behavior related to communication skills. The data overall suggest a distinctive functional organization with system-specific anomalies associated with reduced adaptive efficiency. Opposite effects were identified on distinct frontal and anterior temporal structures and relative sparing of posterior brain areas, which is generally consistent with Down syndrome cognitive profile. Relevantly, measurable connectivity changes, as a marker of the brain functional anomaly, could have a role in the development of therapeutic strategies addressed to improve the quality of life in Down syndrome individuals. PMID- 25461716 TI - Perception of co-speech gestures in aphasic patients: a visual exploration study during the observation of dyadic conversations. AB - BACKGROUND: Co-speech gestures are part of nonverbal communication during conversations. They either support the verbal message or provide the interlocutor with additional information. Furthermore, they prompt as nonverbal cues the cooperative process of turn taking. In the present study, we investigated the influence of co-speech gestures on the perception of dyadic dialogue in aphasic patients. In particular, we analysed the impact of co-speech gestures on gaze direction (towards speaker or listener) and fixation of body parts. We hypothesized that aphasic patients, who are restricted in verbal comprehension, adapt their visual exploration strategies. METHODS: Sixteen aphasic patients and 23 healthy control subjects participated in the study. Visual exploration behaviour was measured by means of a contact-free infrared eye-tracker while subjects were watching videos depicting spontaneous dialogues between two individuals. Cumulative fixation duration and mean fixation duration were calculated for the factors co-speech gesture (present and absent), gaze direction (to the speaker or to the listener), and region of interest (ROI), including hands, face, and body. RESULTS: Both aphasic patients and healthy controls mainly fixated the speaker's face. We found a significant co-speech gesture * ROI interaction, indicating that the presence of a co-speech gesture encouraged subjects to look at the speaker. Further, there was a significant gaze direction * ROI * group interaction revealing that aphasic patients showed reduced cumulative fixation duration on the speaker's face compared to healthy controls. CONCLUSION: Co-speech gestures guide the observer's attention towards the speaker, the source of semantic input. It is discussed whether an underlying semantic processing deficit or a deficit to integrate audio-visual information may cause aphasic patients to explore less the speaker's face. PMID- 25461717 TI - A toggle switch of visual awareness? AB - Major clues to the human brain mechanisms of spatial attention and visual awareness have come from the syndrome of neglect, where patients ignore one half of space. A longstanding puzzle, though, is that neglect almost always comes from right-hemisphere damage, which suggests that the two sides of the brain play distinct roles. But tests of attention in healthy people have revealed only slight differences between the hemispheres. Here we show that major differences emerge if we look at the timing of brain activity in a task optimized to identify attentional functions. Using EEG to map cortical activity on a millisecond timescale, we found transient (20-30 ms) periods of interhemispheric competition, followed by short phases of marked right-sided activity in the ventral attentional network. Our data are the first to show interhemispheric interactions that, much like a toggle switch, quickly allocate neural resources to one or the other hemisphere. PMID- 25461718 TI - In vivo continuous directed evolution. AB - The development and application of methods for the laboratory evolution of biomolecules has rapidly progressed over the last few decades. Advancements in continuous microbe culturing and selection design have facilitated the development of new technologies that enable the continuous directed evolution of proteins and nucleic acids. These technologies have the potential to support the extremely rapid evolution of biomolecules with tailor-made functional properties. Continuous evolution methods must support all of the key steps of laboratory evolution - translation of genes into gene products, selection or screening, replication of genes encoding the most fit gene products, and mutation of surviving genes - in a self-sustaining manner that requires little or no researcher intervention. Continuous laboratory evolution has been historically used to study problems including antibiotic resistance, organismal adaptation, phylogenetic reconstruction, and host-pathogen interactions, with more recent applications focusing on the rapid generation of proteins and nucleic acids with useful, tailor-made properties. The advent of increasingly general methods for continuous directed evolution should enable researchers to address increasingly complex questions and to access biomolecules with more novel or even unprecedented properties. PMID- 25461720 TI - Covalent protein modification: the current landscape of residue-specific electrophiles. AB - Functional amino acids that play critical roles in catalysis and regulation are known to display elevated nucleophilicity and can be selectively targeted for covalent modification by reactive electrophiles. Chemical-proteomic platforms, such as activity-based protein profiling (ABPP), exploit this reactivity by utilizing chemical probes to covalently modify active-site residues to inform on the functional state of enzymes within complex proteomes. These and other applications rely on the availability of a diverse array of electrophiles and detailed knowledge of the reactivity and amino-acid selectivity of these groups. Here, we survey the current landscape of electrophiles that covalently target various nucleophilic amino acids in proteins and highlight proteomic applications that have benefited from the unique properties of these electrophiles. PMID- 25461719 TI - Proteome sequencing goes deep. AB - Advances in mass spectrometry (MS) have transformed the scope and impact of protein characterization efforts. Identifying hundreds of proteins from rather simple biological matrices, such as yeast, was a daunting task just a few decades ago. Now, expression of more than half of the estimated ~20,000 human protein coding genes can be confirmed in record time and from minute sample quantities. Access to proteomic information at such unprecedented depths has been fueled by strides in every stage of the shotgun proteomics workflow-from sample processing to data analysis-and promises to revolutionize our understanding of the causes and consequences of proteome variation. PMID- 25461722 TI - Synthesis and screening of small-molecule alpha-helix mimetic libraries targeting protein-protein interactions. AB - alpha-Helices are the most common protein secondary structure and play a key role in mediating many protein-protein interactions (PPIs) by serving as recognition motifs. Given that aberrant alpha-helix-mediated PPIs are linked to various disease states, targeting such interactions with small-molecules represents an attractive strategy to develop therapeutic candidates for the related diseases. Over the last decade, significant efforts have been directed toward developing alpha-helix mimetic small-molecules that can modulate alpha-helix-mediated PPIs. In this review, we will highlight recent advances in the development of non peptidic, small-molecule alpha-helix mimetics with a focus on library synthesis and screening methods to efficiently discover small-molecule alpha-helix mimetics. PMID- 25461721 TI - Chemical methods for the proteome-wide identification of posttranslationally modified proteins. AB - Thousands of proteins are subjected to posttranslational modifications that can have dramatic effects on their functions. Traditional biological methods have struggled to address some of the challenges inherit in the unbiased identification of certain posttranslational modifications. As with many areas of biological discovery, the development of chemoselective and bioorthogonal reactions and chemical probes has transformed our ability to selectively label and enrich a wide variety of posttranslational modifications. Collectively, these efforts are making significant contributions to the goal of mapping the protein modification landscape. PMID- 25461725 TI - Protein amino-terminal modifications and proteomic approaches for N-terminal profiling. AB - Amino-/N-terminal processing is a crucial post-translational modification affecting almost all proteins. In addition to altering the chemical properties of the N-terminus, these modifications affect protein activation, conversion, and degradation, which subsequently lead to diversified biological functions. The study of N-terminal modifications is of increasing interest; especially since modifications such as proteolytic truncation or pyroglutamate formation have been linked to disease processes. During the past decade, mass spectrometry has played an important role in facilitating the investigation of N-terminal modifications. Continuous progress is being made in the development and application of robust methods for the dedicated analysis of native and modified protein N-termini in a proteome-wide manner. Here we highlight recent progress in our understanding of protein N-terminal biology as well as outlining present enrichment strategies for mass spectrometry-based studies of protein N-termini. PMID- 25461726 TI - Chemical proteomics approaches to examine novel histone posttranslational modifications. AB - Histone posttranslational modifications (PTMs) play key roles in the regulation of many fundamental cellular processes, such as gene transcription, DNA damage repair and chromosome segregation. Significant progress has been made on the detection of a large variety of PTMs on histones. However, the identification of these PTMs' regulating enzymes (i.e. 'writers' and 'erasers') and functional binding partners (i.e. 'readers') have been a relatively slow-paced process. As a result, cellular functions and regulatory mechanisms of many histone PTMs, particularly the newly identified ones, remain poorly understood. This review focuses on the recent progress in developing chemical proteomics approaches to profile readers, erasers and writers of histone PTMs. One of such efforts involves the development of the Cross-Linking-Assisted and SILAC-based Protein Identification (CLASPI) approach to examine PTM-mediated protein-protein interactions. PMID- 25461723 TI - Global profiling of protein lipidation using chemical proteomic technologies. AB - Protein lipidation is unique amongst post-translational modifications (PTMs) in enabling direct interaction with cell membranes, and is found in every form of life. Lipidation is important in normal function and in disease, but its intricate interplay with disease context presents a challenging for drug development. Global whole-proteome profiling of protein lipidation lies beyond the range of standard methods, but is well-suited to metabolic tagging with small 'clickable' chemical reporters that do not disrupt metabolism and function; chemoselective reactions are then used to add multifunctional labels exclusively to tagged-lipidated proteins. This chemical proteomic technology has opened up the first quantitative whole-proteome studies of the known major classes of protein lipidation, and the first insights into their full scope in vivo. PMID- 25461727 TI - Live-cell bioorthogonal Raman imaging. AB - Live-cell microscopy demands high specificity, sensitivity, and minimal perturbation to the biomolecules of interest. Meeting all these criteria has been challenging in cellular imaging. Toward this goal, a bioorthogonal Raman imaging method has recently emerged by exploiting small Raman reporters that possess Raman signals that do not overlap with the naturally existing biomolecules in the cells. The Raman reporters are metabolically incorporated into the target biomolecules for direct visualization. Herein, we review recent advances in the methodological development and the proof-of-concept applications of the live-cell bioorthogonal Raman imaging technique. PMID- 25461724 TI - 15 years of zebrafish chemical screening. AB - In 2000, the first chemical screen using living zebrafish in a multi-well plate was reported. Since then, more than 60 additional screens have been published describing whole-organism drug and pathway discovery projects in zebrafish. To investigate the scope of the work reported in the last 14 years and to identify trends in the field, we analyzed the discovery strategies of 64 primary research articles from the literature. We found that zebrafish screens have expanded beyond the use of developmental phenotypes to include behavioral, cardiac, metabolic, proliferative and regenerative endpoints. Additionally, many creative strategies have been used to uncover the mechanisms of action of new small molecules including chemical phenocopy, genetic phenocopy, mutant rescue, and spatial localization strategies. PMID- 25461728 TI - A reinvigorated era of bacterial secondary metabolite discovery. AB - Secondary metabolite discovery from bacteria has become increasingly successful in the last decade due to the advancement of integrated genetic-based, spectrometric-based and informatics-based techniques. Microbes and their unique metabolic outputs have been widely studied since the beginning of modern medicine; however, it is well known that the current repertoire of secondary metabolites, or more commonly natural products, is incomplete and the understanding of natural product-mediated intracellular dialog is in its infancy. Here, we highlight the present state of bacterial metabolomics including compound discovery approaches and new strategies for probing the role of these molecules within communication networks. PMID- 25461729 TI - Next-generation sequencing and protein mass spectrometry for the comprehensive analysis of human cellular and serum antibody repertoires. AB - Recent developments of high-throughput technologies are enabling the molecular level analysis and bioinformatic mining of antibody-mediated (humoral) immunity in humans at an unprecedented level. These approaches explore either the sequence space of B-cell receptor repertoires using next-generation deep sequencing (BCR seq), or the amino acid identities of antibody in blood using protein mass spectrometry (Ig-seq), or both. Generalizable principles about the molecular composition of the protective humoral immune response are being defined, and as such, the field could supersede traditional methods for the development of diagnostics, vaccines, and antibody therapeutics. Three key challenges remain and have driven recent advances: (1) incorporation of innovative techniques for paired BCR-seq to ascertain the complete antibody variable-domain VH:VL clonotype, (2) integration of proteomic Ig-seq with BCR-seq to reveal how the serum antibody repertoire compares with the antibody repertoire encoded by circulating B cells, and (3) a demand to link antibody sequence data to functional meaning (binding and protection). PMID- 25461730 TI - Tools for visualizing cell-cell 'interactomes'. AB - Cellular communication drives diverse aspects of organismal biology ranging from immune function to memory formation. The mechanisms by which cells transact information in vivo, though, are not completely understood. This is due, in part, to a lack of tools for observing collections of cells in their native habitats. New optical probes are being crafted to image networks of cell-cell interactions (i.e., 'interactomes') in tissues and live organisms. Examples of these probes and their use in visualizing cell contacts and macroscopic cell networks-are highlighted. PMID- 25461731 TI - Establishing the warranty of a coronary artery calcium score of zero. PMID- 25461732 TI - Extensive thoracic aortic calcification is an independent predictor of development of coronary artery calcium among individuals with coronary artery calcium score of zero. AB - OBJECTIVES: The predictive value of thoracic aortic calcium (TAC) scores for coronary artery calcium (CAC) conversion (CAC>0) has not been fully evaluated. METHODS: We studied 1648 asymptomatic subjects (mean age 52 +/- 9 years, 54% male) with baseline CAC = 0 who underwent repeat CAC scanning 5 years later (range 3-14 years). TAC was assessed in the ascending and descending aorta. CAC and TAC were measured using Agatston scores. The cohort was categorized by baseline TAC scores: TAC = 0 (n = 1381 subjects), TAC 1-9 (n = 54), TAC 10-99 (n = 132) and TAC>=100 (n = 81). Logistic regression was used to examine the predictive value of baseline TAC scores for CAC>0 on repeat scans. RESULTS: On repeat scanning, 380 subjects (23%) developed CAC>0. The frequency of CAC>0 increased progressively across baseline TAC (TAC = 0, TAC 1-9, TAC 10-99 and TAC>=100) 22%, 26%, 26% and 37%, respectively (P for trend = 0.0025). Univariate analysis showed baseline TAC >=100 was a significant predictor of CAC>0 in repeat scans, while either TAC 1-9 or TAC 10-99 were not, OR 2.10 [CI 1.32-3.36], P = 0.002; OR 1.25 [CI 0.67-2.33], P = 0.5; OR 1.24 [CI 0.82-1.87], P = 0.3, respectively. In multivariable analysis, TAC >=100 OR 1.90 [CI 1.08-3.33], P = 0.026, was a significant predictor of CAC>0, along with age, male gender, diabetes, hypertension, hypercholesterolemia and time between scans. CONCLUSIONS: The likelihood of conversion to CAC>0 increases with increasing TAC scores. TAC >= 100 is an independent predictor of CAC conversion. Subjects with CAC = 0 and extensive TAC (TAC >= 100) may merit earlier repeat scanning than those with no TAC or lower TAC scores. PMID- 25461733 TI - Percentiles for central blood pressure and pulse wave velocity in children and adolescents recorded with an oscillometric device. AB - OBJECTIVE: In adults with arterial hypertension, measuring arterial stiffness by pulse wave velocity (PWV) can determine the extent of cardiovascular subclinical organ damage. PWV has independent predictive value for cardiovascular events, but there are currently no recommendations for measuring PWV in children. In addition, central systolic blood pressure (cSBP) strongly reflects vascular changes. The aim of this study was to establish percentiles for cSBP and PWV in children and adolescents to evaluate and classify altered vascular function in youths. METHODS AND RESULTS: We measured PWV and cSBP with an oscillometric device with inbuilt ARCSolver-algorithm (estimated by using the brachial waveform) and calculated smoothed reference percentiles for 1445 children and young adults (49.5% female; 13.41 +/- 2.80 years, range 8-22 years; PWV 4.67 +/- 0.34 m/s; cSBP 100.7 +/- 8.9 mmHg) using the LMS-method based on age and height. PWV and cSBP increased with age and height, but slightly differently for girls and boys, possibly reflecting different growth patterns. Between 8 and 21 years, PWV increased from 4.29 +/- 0.32 to 4.98 +/- 0.33 m/s in girls and from 4.27 +/- 0.18 to 5.22 +/- 0.46 m/s in boys. While girls showed a minor increase in cSBP (91.2 +/- 7.5 to 109.1 +/- 8.6 mmHg), the cSBP in boys ranged from 90.0 +/- 5.8 to 110.5 +/- 9.6 mmHg with a more pronounced increase between 14 and 17 years. CONCLUSION: These percentiles for PWV and cSBP can help define arterial stiffness in youths and contribute to risk stratification for cardiovascular disease. For example, in children with prehypertension or isolated systolic hypertension, PWV and cSBP can provide additional information about the function of the vascular system, thereby strengthening intervention strategies. PMID- 25461734 TI - Treg/Th17 balance in stable CAD patients with different stages of coronary atherosclerosis. AB - Objective. Immune processes play a significant role in atherosclerosis plaque progression. Regulatory T cells and T helpers 17 were shown to possess anti- and pro-atherogenic activity, respectively. We aimed to investigate the balance of circulating Treg and Th17 in stable angina patients with different stages of coronary atherosclerosis. Methods. Treg, Th17 and Th1 cell frequencies were studied in 117 patients via direct immunofluorescence staining and flow cytometry. Group 1 had intact coronary arteries. Group 2 and Group 3 had undergone previous coronary stenting; in Group 2 no coronary atherosclerosis progression was found, in Group 3 patients had disease progression in non-invaded coronary arteries. Group 4 had severe coronary atherosclerosis. Results. The frequencies of CD4+CD25highCD127low, CD4+foxp3+, and CD4+IL10 + T cells were decreased, and CD4+IL17 + T cells frequencies were increased in group 4 vs. 1. Treg/Th17 ratios were declined in groups 3 and 4 vs. groups 1 and 2. IL-10 level was lower while hsCRP and sCD25 levels were higher in group 4 vs. 1. Conclusion. We assume that the imbalance in pro- and anti-inflammatory/atherogenic lymphocyte subpopulations is associated with atherosclerosis progression. PMID- 25461735 TI - Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects. AB - BACKGROUND: There is little knowledge about familial hypercholesterolemia in Brazil. This study presents the first results of genetic cascade screening performed in the city of Sao Paulo. MATERIAL AND METHODS: Two-hundred and forty eight suspected index cases were initially included. DNA was extracted from peripheral blood and the complete coding sequence of low-density lipoprotein receptor, exon 7 of proprotein convertase subtilisin/kexin type 9 gene and part of exon 26 of apolipoprotein B genes were sequenced. Multiplex Ligation-dependent Probe Amplification was performed on cases where a causal mutation was not identified through sequencing. After the identification of a causal mutation screening in first-degree relatives was pursued. RESULTS: From 248 index cases, a mutation was found in 125 individuals (50.4%). 394 relatives were included in the cascade screening program and a mutation was identified in 59.4%. Seventy different causal mutations in the low-density lipoprotein receptor gene (97.2%) and 2 in the apolipoprotein B gene (2.8%) were found. No mutations were encountered in the proprotein convertase subtilisin/kexin type 9 gene. Mutations in exons 14 and 4 were the most prevalent and, 10 cases of true homozygotes (8 index cases and 2 relatives) and 1 compound heterozygote were identified. The most frequent mutation found was of Lebanese origin, the p.(Cys681*) mutation in exon 14 (8.5%). CONCLUSION: Genetic familial hypercholesterolemia cascade screening is feasible in Brazil and leads to identification of a mutation in approximately half of the index cases with higher rates of success in their relatives. PMID- 25461736 TI - Insulin-resistance HCV infection-related affects vascular stiffness in normotensives. AB - BACKGROUND AND AIMS. Arterial stiffness evaluated as pulse wave velocity, is an early marker of vascular damage and an independent predictor for cardiovascular events. We investigated if the insulin resistance/hyperinsulinemia chronic hepatitis C virus infection-related could influence arterial stiffness. METHODS. We enrolled 260 outpatients matched for age, body mass index, gender, ethnicity: 52 with never-treated uncomplicated chronic hepatitis C virus infection (HCV(+)), 104 never-treated hypertensives (HT) and 104 healthy subjects (NT). Pulse wave velocity was evaluated by a validated system employing high-fidelity applanation tonometry. We also measured: fasting plasma glucose and insulin, total, LDL- and HDL-cholesterol, triglyceride, creatinine, e-GFR-EPI, HOMA, quantitative HCV-RNA. RESULTS. HCV(+) patients with respect to NT had an increased pulse wave velocity (7.9 +/- 2.1 vs 6.4 +/- 2.1 m/s; P < 0.0001), similar to that observed in HT group (8.8 +/- 3.2 m/s). HCV(+) patients, in comparison with NT, had higher triglyceride, creatinine, fasting insulin and HOMA (3.2 +/- 1.3 vs 2.5 +/- 1.0; P < 0.0001). At linear regression analysis, the correlation between pulse wave velocity and HOMA was similar in HT (r = 0.380, P < 0.0001) and HCV(+) (r = 0.369, P = 0.004) groups. At multiple regression analysis, HOMA resulted the major determinant of pulse wave velocity in all groups, explaining respectively 11.8%, 14.4% and 13.6% of its variation in NT, HT and HCV(+). At correlational analysis hepatitis C virus-RNA and HOMA demonstrated a strong and linear relationship between them, explaining the 72.4% of their variation (P = 0.022). CONCLUSIONS. We demonstrated a significant and direct correlation between HOMA and pulse wave velocity in HCV(+) patients, similar to that observed in hypertensives. PMID- 25461737 TI - Plasma stromal cell-derived factor 1alpha/CXCL12 level predicts long-term adverse cardiovascular outcomes in patients with coronary artery disease. AB - OBJECTIVE: Stromal derived factor-1alpha/CXCL12 is a chemoattractant responsible for homing of progenitor cells to ischemic tissues. We aimed to investigate the association of plasma CXCL12 with long-term cardiovascular outcomes in patients with coronary artery disease (CAD). METHODS: 785 patients aged: 63 +/- 12 undergoing coronary angiography were independently enrolled into discovery (N = 186) and replication (N = 599) cohorts. Baseline levels of plasma CXCL12 were measured using Quantikine CXCL12 ELISA assay (R&D systems). Patients were followed for cardiovascular death and/or myocardial infarction (MI) for a mean of 2.6 yrs. Cox proportional hazard was used to determine independent predictors of cardiovascular death/MI. RESULTS: The incidence of cardiovascular death/MI was 13% (N = 99). High CXCL12 level based on best discriminatory threshold derived from the ROC analysis predicted risk of cardiovascular death/MI (HR = 4.81, p = 1 * 10(-6)) independent of traditional risk factors in the pooled cohort. Addition of CXCL12 to a baseline model was associated with a significant improvement in c statistic (AUC: 0.67-0.73, p = 0.03). Addition of CXCL12 was associated with correct risk reclassification of 40% of events and 10.5% of non-events. Similarly for the outcome of cardiovascular death, the addition of the CXCL12 to the baseline model was associated with correct reclassification of 20.7% of events and 9% of non-events. These results were replicated in two independent cohorts. CONCLUSION: Plasma CXCL12 level is a strong independent predictor of adverse cardiovascular outcomes in patients with CAD and improves risk reclassification. PMID- 25461738 TI - A new model of biodosimetry to integrate low and high doses. AB - Biological dosimetry, that is the estimation of the dose of an exposure to ionizing radiation by a biological parameter, is a very important tool in cases of radiation accidents. The score of dicentric chromosomes, considered to be the most accurate method for biological dosimetry, for low LET radiation and up to 5 Gy, fits very well to a linear-quadratic model of dose-effect curve assuming the Poisson distribution. The accuracy of this estimation raises difficulties for doses over 5 Gy, the highest dose of the majority of dose-effect curves used in biological dosimetry. At doses over 5 Gy most cells show difficulties in reaching mitosis and cannot be used to score dicentric chromosomes. In the present study with the treatment of lymphocyte cultures with caffeine and the standardization of the culture time, metaphases for doses up to 25 Gy have been analyzed. Here we present a new model for biological dosimetry, which includes a Gompertz-type function as the dose response, and also takes into account the underdispersion of aberration-among-cell distribution. The new model allows the estimation of doses of exposures to ionizing radiation of up to 25 Gy. Moreover, the model is more effective in estimating whole and partial body exposures than the classical method based on linear and linear-quadratic functions, suggesting their effectiveness and great potential to be used after high dose exposures of radiation. PMID- 25461740 TI - Toxicity of nano-TiO2 on algae and the site of reactive oxygen species production. AB - Given the extensive use of nanomaterials, they may enter aquatic environments and harm the growth of algae, which are primary producers in an aquatic ecosystem. Thus, the balance of an aquatic ecosystem may be destroyed. In this study, Karenia brevis and Skeletonema costatum were exposed to nano-TiO2 (anatase, average particle size of 5-10 nm, specific surface area of 210+/-10 m(2) g(-1)) to assess the effects of nano-TiO2 on algae. The findings of transmission electron microscopy-energy dispersive X-ray spectroscopy (TEM-EDX) and scanning electron microscopy (SEM) demonstrate aggregation of nano-TiO2 in the algal suspension. Nano-TiO2 was also found to be inside algal cells. The growth of the two species of algae was inhibited under nano-TiO2 exposure. The 72 h EC50 values of nano-TiO2 to K. brevis and S. costatum were 10.69 and 7.37 mg L(-1), respectively. TEM showed that the cell membrane of K. brevis was destroyed and its organelles were almost undistinguished under nano-TiO2 exposure. The malondialdehyde (MDA) contents of K. brevis and S. costatum significantly increased compared with those of the control (p<0.05). Meanwhile, superoxide dismutase (SOD) and catalase activities (CAT) of K. brevis and S. costatum changed in different ways. The reactive oxygen species (ROS) levels in both species were significantly higher than those of the control (p<0.05). The site of ROS production and accumulation in K. brevis and S. costatum under nano-TiO2 exposure was explored with the addition of inhibitors of different electron transfer chains. This study indicated that nano-TiO2 in algal suspensions inhibited the growth of K. brevis and S. costatum. This effect was attributed to oxidative stress caused by ROS production inside algal cells. The levels of anti oxidative enzymes changed, which destroyed the balance between oxidation and anti oxidation. Thus, algae were damaged by ROS accumulation, resulting in lipid oxidation and inhibited algae growth. The inhibitors of the electron transfer chain showed that the site of ROS production and accumulation in K. brevis cells was the chloroplast. PMID- 25461741 TI - A mixture of the novel brominated flame retardants TBPH and TBB affects fecundity and transcript profiles of the HPGL-axis in Japanese medaka. AB - The novel brominated flame retardants (NBFRs), bis(2-ethylhexyl)-2,3,4,5 tetrabromophthalate (TBPH) and 2-ethylhexyl-2,3,4,5 tetrabromobenzoate (TBB) are components of the flame retardant mixture Firemaster 550 and both TBPH and TBB have recently been listed as high production volume chemicals by the US EPA. These NBFRs have been detected in several environmental matrices but very little is known about their toxic effects or potencies. Results of in vitro assays demonstrated potentials of these NBFRs to modulate endocrine function through interactions with estrogen (ER) and androgen receptors (AR) and via alterations to synthesis of 17-beta-estradiol (E2) and testosterone (T), but in vivo effects of these chemicals on organisms are not known. Therefore a 21-day short term fish fecundity assay with Japanese medaka (Oryzias latipes) was conducted to investigate if these NBFRs affect endocrine function in vivo. Medaka were fed a diet containing either 1422 TBPH:1474 TBB or 138:144 MUg/g food, wet weight (w/w). Cumulative production of eggs was used as a measure of fecundity and abundances of transcripts of 34 genes along the hypothalamus-pituitary-gonadal liver (HPGL) axis were quantified to determine mechanisms of observed effects. Cumulative fecundity was impaired by 32% in medaka exposed to the greatest dose of the mixture of TBPH/TBB. A pattern of global down-regulation of gene transcription at all levels of the HPGL axis was observed, but effects were sex specific. In female medaka the abundance of transcripts of ERbeta was lesser in livers, while abundances of transcripts of VTG II and CHG H were greater. In male medaka, abundances of transcripts of ERalpha, ERbeta, and ARalpha were lesser in gonads and abundances of transcripts of ERbeta and ARalpha were lesser in brain. Abundances of transcripts of genes encoding proteins for synthesis of cholesterol (HMGR), transport of cholesterol (HDLR), and sex hormone steroidogenesis (CYP 17 and 3beta-HSD) were significantly lesser in male medaka, which might have implications for concentrations of sex hormones. The results of this study demonstrate that exposure to components of the flame retardant mixture Firemaster((r)) 550 has the potential to impair the reproductive axis of fishes. PMID- 25461739 TI - In vivo longitudinal proton magnetic resonance spectroscopy on neonatal hypoxic ischemic rat brain injury: Neuroprotective effects of acetyl-L-carnitine. AB - PURPOSE: This study evaluated the longitudinal metabolic alterations after neonatal hypoxia-ischemia (HI) in rats and tested the neuroprotective effect of acetyl-L-carnitine (ALCAR) using in vivo proton short-TE Point-RESolved Spectroscopy method. METHODS: Rice-Vannucci model was used on 7-day-old Sprague Dawley rats. Data were acquired from contralateral and ipsilateral cortex and hippocampus, respectively at 4 time points (24-h, 72-h, 7-days, 28-days) post-HI. The effect of subcutaneous administration of ALCAR (100 mg/kg) immediately after HI, at 4-h, 24-h, and 48-h post-HI was determined. RESULTS: Significant reductions in glutathione (P < 0.005), myo-inositol (P < 0.002), taurine (P < 0.001), and total creatine (P < 0.005) were observed at 24-h postinjury compared with the control group in the ipsilateral hippocampus of the HI rat pups. ALCAR treated-HI rats had lower levels of lactate and maintained total creatine at 24-h and had smaller lesion size compared with the HI only rats. CONCLUSION: Severe oxidative, osmotic stress, impaired phosphorylation, and a preference for anaerobic glycolysis were found in the ipsilateral hippocampus in the HI pups at 24-h postinjury. ALCAR appeared to have a neuroprotective effect if administered early after HI by serving as an energy substrate and promote oxidative cerebral energy producing and minimize anaerobic glycolysis. PMID- 25461742 TI - Effect of permethrin, anthracene and mixture exposure on shell components, enzymatic activities and proteins status in the Mediterranean clam Venerupis decussata. AB - Anthracene (ANT) and permethrin (PER) are two of the more toxic compounds reaching the marine environment. This study aimed to determine the impact of these molecules on Venerupis decussata, an economically important species cultured on the Tunisian coast. Shell structure and its possible transformation upon exposure to the two contaminants were studied by X-ray diffraction and gravimetric analyses. Results revealed a phase transition in shell composition from aragonite to calcite after PER exposure, to a mixture of PER and ANT (Mix) but not for ANT alone. Catalase (CAT), superoxide dismutase (SOD) and glutathione transferase (GST) activities were determined in digestive gland and gills after exposure to ANT, PER and Mix to assess the impact of the contamination on the oxidative status of V. decussata. Enzyme activities increased in the digestive gland after PER treatment and in the gills after ANT treatment. PER exposure significantly reduced the levels of free thiols and increased levels of carbonylated proteins in the digestive gland, as compared to controls. In contrast, ANT exposure significantly reduced free thiols and increased the number of carbonylated proteins in the gills. Mix induced additive effects as measured by both enzymatic and proteomic approaches. The present study suggests that PER has a strong effect on shell structure; that PER and ANT exposure generate compound-dependent oxidative stress in the tissues of V. decussata and that a mixture of the two compounds has synergistic effects on biochemical response. PMID- 25461743 TI - Biotransformation and detoxification of inorganic arsenic in Bombay oyster Saccostrea cucullata. AB - Arsenic (As) exists as the toxic inorganic forms in marine water and sediment, while marine oysters usually accumulate high As contents mostly as the less toxic organic forms. It has not yet been clear that how As is biotransformed in marine oysters. This study therefore investigated the biotransformation and detoxification of two inorganic As forms (As(III) and As(V)) in Bombay oyster Saccostrea cucullata after waterborne exposures for 30 days. Seven treatments of dissolved As exposure (clean seawater, 1, 5, 20 mg/L As(III), and 1, 5, 20 mg/L As(V)) were performed. Body As concentration increased significantly after all As exposure treatments except 1mg/L As(V). Total As, As(III), and As(V) concentration were positive correlated with glutathione-S-transferases (GST) activities, suggesting GST might play an important role in the As biotransformation and detoxification process. Organic As species were predominant in control and the low As exposed oysters, whereas a large fraction of As was remained as the inorganic forms in the high As exposed oysters, suggesting As could be biotransformed efficiently in the oysters in clean or light contaminated environment. The results of As speciation demonstrated the As biotransformation in the oysters included As(V) reduction, methylation to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), and subsequent conversion to arsenobetaine (AsB). More As was distributed in the subcellular metallothionein-like proteins fraction (MTLP) functioning sequestration and detoxification in the inorganic As exposed oysters, suggesting it was also a strategy for oysters against As stress. In summary, this study elucidated that marine oysters had high ability to accumulate, biotransform, and detoxify inorganic As. PMID- 25461744 TI - The toxic dinoflagellate Alexandrium minutum disrupts daily rhythmic activities at gene transcription, physiological and behavioral levels in the oyster Crassostrea gigas. AB - The objective of the present work was to study the effect of the harmful alga Alexandrium minutum on the daily rhythm of the oyster Crassostrea gigas. Many metabolic and physiological functions are rhythmic in living animals. Their cycles are modeled in accordance with environmental cycles such as the day/night cycle, which are fundamental to increase the fitness of an organism in its environment. A disruption of rhythmic activities is known to possibly impact the health of an animal. This study focused in C. gigas, on a gene known to be involved in circadian rhythmicity, cryptochrome gene (CgCry), on putative clock controlled genes involved in metabolic and physiological functions, on the length cycle of the style, a structure involved in digestion, and on the rhythmicity of valve activity involved in behavior. The results indicate that daily activity is synchronized at the gene level by light:dark cycles in C. gigas. A daily rhythm of valve activity and a difference in crystalline style length between scotophase and photophase were also demonstrated. Additionally, A. minutum exposure was shown to alter cyclic activities: in exposed oysters, gene transcription remained at a constant low level throughout a daily cycle, valve opening duration remained maximal and crystalline style length variation disappeared. The results show that a realistic bloom of A. minutum clearly can disrupt numerous and diverse molecular, physiological and behavioral functions via a loss of rhythmicity. PMID- 25461745 TI - Characterization of glutathione-S-transferases in zebrafish (Danio rerio). AB - Glutathione-S-transferases (GSTs) are one of the key enzymes that mediate phase II of cellular detoxification. The aim of our study was a comprehensive characterization of GSTs in zebrafish (Danio rerio) as an important vertebrate model species frequently used in environmental research. A detailed phylogenetic analysis of GST superfamily revealed 27 zebrafish gst genes. Further insights into the orthology relationships between human and zebrafish GSTs/Gsts were obtained by the conserved synteny analysis. Expression of gst genes in six tissues (liver, kidney, gills, intestine, brain and gonads) of adult male and female zebrafish was determined using qRT-PCR. Functional characterization was performed on 9 cytosolic Gst enzymes after overexpression in E. coli and subsequent protein purification. Enzyme kinetics was measured for GSH and a series of model substrates. Our data revealed ubiquitously high expression of gstp, gstm (except in liver), gstr1, mgst3a and mgst3b, high expression of gsto2 in gills and ovaries, gsta in intestine and testes, gstt1a in liver, and gstz1 in liver, kidney and brain. All zebrafish Gsts catalyzed the conjugation of GSH to model GST substrates 1-chloro-2,4-dinitrobenzene (CDNB) and monochlorobimane (MCB), apart from Gsto2 and Gstz1 that catalyzed GSH conjugation to dehydroascorbate (DHA) and dichloroacetic acid (DCA), respectively. Affinity toward CDNB varied from 0.28 mM (Gstp2) to 3.69 mM (Gstm3), while affinity toward MCB was in the range of 5 MUM (Gstt1a) to 250 MUM (Gstp1). Affinity toward GSH varied from 0.27 mM (Gstz1) to 4.45 mM (Gstt1a). Turnover number for CDNB varied from 5.25s(-1) (Gstt1a) to 112s(-1) (Gstp2). Only Gst Pi enzymes utilized ethacrynic acid (ETA). We suggest that Gstp1, Gstp2, Gstt1a, Gstz1, Gstr1, Mgst3a and Mgst3b have important role in the biotransformation of xenobiotics, while Gst Alpha, Mu, Pi, Zeta and Rho classes are involved in the crucial physiological processes. In summary, this study provides the first comprehensive analysis of GST superfamily in zebrafish, presents new insight into distinct functions of individual Gsts, and offers methodological protocols that can be used for further verification of interaction of environmental contaminants with fish Gsts. PMID- 25461747 TI - Modulation of cadmium-induced mitochondrial dysfunction and volume changes by temperature in rainbow trout (Oncorhynchus mykiss). AB - We investigated how temperature modulates cadmium (Cd)-induced mitochondrial bioenergetic disturbances, metal accumulation and volume changes in rainbow trout (Oncorhynchus mykiss). In the first set of experiments, rainbow trout liver mitochondrial function and Cd content were measured in the presence of complex I substrates, malate and glutamate, following exposure to Cd (0-100 MUM) at three (5, 13 and 25 degrees C) temperatures. The second set of experiments assessed the effect of temperature on Cd-induced mitochondrial volume changes, including the underlying mechanisms, at 15 and 25 degrees C. Although temperature stimulated both state 3 and 4 rates of respiration, the coupling efficiency was reduced at temperature extremes due to greater inhibition of state 3 at low temperature and greater stimulation of state 4 at the high temperature. Cadmium exposure reduced the stimulatory effect of temperature on state 3 respiration but increased that on state 4, consequently exacerbating mitochondrial uncoupling. The interaction of Cd and temperature yielded different responses on thermal sensitivity of state 3 and 4 respiration; the Q10 values for state 3 respiration increased at low temperature (5-13 degrees C) while those for state 4 increased at high temperature (13-25 degrees C). Importantly, the mitochondria accumulated more Cd at high temperature suggesting that the observed greater impairment of oxidative phosphorylation with temperature was due, at least in part, to a higher metal burden. Cadmium-induced mitochondrial volume changes were characterized by an early phase of contraction followed by swelling, with temperature changing the kinetics and intensifying the effects. Lastly, using specific modulators of mitochondrial ion channels, we demonstrated that the mitochondrial volume changes were associated with Cd uptake via the mitochondrial calcium uniporter (MCU) without significant contribution of the permeability transition pore and/or potassium channels. Overall, it appears that high temperature exacerbates Cd induced mitochondrial dysfunction and volume changes in part by increasing metal uptake through the MCU. PMID- 25461746 TI - Multibiomarker assessment of cerium dioxide nanoparticle (nCeO2) sublethal effects on two freshwater invertebrates, Dreissena polymorpha and Gammarus roeseli. AB - Cerium nanoparticles (nCeO2) are widely used in everyday products, as fuel and paint additives. Meanwhile, very few studies on nCeO2 sublethal effects on aquatic organisms are available. We tried to fill this knowledge gap by investigating short-term effects of nCeO2 at environmentally realistic concentrations on two freshwater invertebrates; the amphipod Gammarus roeseli and the bivalve Dreissena polymorpha, using an integrated multibiomarker approach to detect early adverse effects of nCeO2 on organism biology. Differences in the behaviour of the organisms and of nanoparticles in the water column led to differential nCeO2 bioaccumulations, G. roeseli accumulating more cerium than D. polymorpha. Exposure to nCeO2 led to decreases in the size of the lysosomal system, catalase activity and lipoperoxidation in mussel digestive glands that could result from nCeO2 antioxidant properties, but also negatively impacted haemolymph ion concentrations. At the same time, no strong adverse effects of nCeO2 could be observed on G. roeseli. Further experiments will be necessary to confirm the absence of severe nCeO2 adverse effects in long-term environmentally realistic conditions. PMID- 25461748 TI - Thermoluminescence as a complementary technique for the toxicological evaluation of chemicals in photosynthetic organisms. AB - Thermoluminescence is a simple technique very useful for studying electron transfer reactions on photosystem II (standard thermoluminescence) or the level of lipid peroxidation in membranes (high temperature thermoluminescence) in photosynthetic organisms. Both techniques were used to investigate the effects produced on Chlorella vulgaris cells by six compounds: the chemical intermediates bromobenzene and diethanolamine, the antioxidant propyl gallate, the semiconductor indium nitrate, the pesticide sodium monofluoroacetate and the antimalarial drug chloroquine. Electron transfer activity of the photosystem II significantly decreased after the exposure of Chlorella cells to all the six chemicals used. Lipid peroxidation was slightly decreased by the antioxidant propyl gallate, not changed by indium nitrate and very potently stimulated by diethanolamine, chloroquine, sodium monofluoroacetate and bromobenzene. For five of the chemicals studied (not bromobenzene) there is a very good correlation between the cytotoxic effects in Chlorella cells measured by the algal growth inhibition test, and the inhibition of photosystem II activity. The results suggest that one very important effect of these chemicals in Chlorella cells is the inhibition of photosynthetic metabolism by the blocking of photosystem II functionality. In the case of sodium monofluoroacetate, diethanolamine and chloroquine this inhibition seems to be related with the induction of high level of lipid peroxidation in cells that may alter the stability of photosystem II. The results obtained by both techniques supply information that can be used as a supplement to the growth inhibition test and allows a more complete assessment of the effects of a chemical in photosynthetic organisms of aquatic ecosystems. PMID- 25461749 TI - Bioconcentration, metabolism and neurotoxicity of the organophorous flame retardant 1,3-dichloro 2-propyl phosphate (TDCPP) to zebrafish. AB - Organophosphate flame retardants are ubiquitous environmental contaminants; however, knowledge is limited regarding their environmental health risks and toxicity. Here, we investigated the effects of acute and long-term exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCPP) to the nervous system of zebrafish. Zebrafish embryos (2 h post-fertilization) were exposed to TDCPP (0-100 MUg/L) for 6 months up until sexual maturation. Concentrations of TDCPP and its metabolic product (bis(1,3-dichloro-2-propyl) phosphate, BDCPP) were measured in the tissues of 5 day post-fertilization (dpf) larvae. There was no effect on locomotion, acetylcholinesterase activity, levels of the neurotransmitters dopamine and serotonin, and expression of mRNAs and proteins related to central nervous system development (e.g., myelin basic protein, alpha1-tubulin) in any exposure group. However, in adult fish, reductions of dopamine and serotonin levels were detected in the brains of females but not males. Downregulation of nervous system development genes was observed in both the male and female brain tissues. TDCPP concentrations were measured in adult fish tissues including the brain, and greater levels were detected in females. Our results showed that females are more sensitive to TDCPP stress than males in terms of TDCPP-induced neurotoxicity. We demonstrate that long-term exposure to lower concentrations of TDCPP in fish can lead to neurotoxicity. PMID- 25461750 TI - Hypoxia and the pharmaceutical diclofenac influence the circadian responses of three-spined stickleback. AB - Pollution with low concentrations of pharmaceuticals, especially when combined with low-oxygen conditions (hypoxia), is a threat to aquatic ecosystems worldwide. The non-steroidal anti-inflammatory drug diclofenac is commonly detected in wastewater effluents, and has potential to accumulate in the bile of fish. Diclofenac has been shown to activate aryl hydrocarbon receptor (AHR), which induces transcription in the metabolic enzyme cytochrome P450 1a (cyp1a). Previously, crosstalk has been shown to occur between AHR and hypoxia inducible factor 1 (HIF-1). In addition, both of these transcription factors interact with the proteins regulating circadian (24-h) rhythms in vertebrates. Yet little is known about the significance of these interactions during simultaneous exposure to chemicals and hypoxia in fish in vivo. We exposed wild-caught three-spined sticklebacks (Gasterosteus aculeatus) to diclofenac (1 MUg/L, 14 days), hypoxia (2.0 mg/L, up to 24h) and the combination of both. We then analyzed markers of chemical biotransformation (EROD activity, cyp1a and ahr mRNA levels), glycolysis (lactate dehydrogenase (LDH) enzyme activity, ldh and enolase 1a mRNA levels), and the transcription of core circadian clock genes clock and period 1 in liver tissue. Samples were taken at three time points during the light period in order to address disturbances in the circadian variation of metabolic processes. The results show that mRNA levels and LDH activity tended to be lowest before the dark period, but this pattern was disturbed by hypoxia and diclofenac. Diclofenac and hypoxia co-exposure induced EROD activity more strongly than diclofenac exposure alone, while cyp1a mRNA level was increased also by hypoxia and diclofenac alone. LDH activity and mRNA expression showed a clear time-dependent response during hypoxia, which is consistent with the previously suggested decreased accumulation of HIF-1 during the dark period. Furthermore, LDH activity and transcription was disturbed by diclofenac, indicating important effects of environmental pollutants in disturbing natural acclimation. This study demonstrates the need for more studies to understand the potential disturbances in endogenous rhythms caused by environmental pollution in natural populations. PMID- 25461751 TI - Copper-induced tight junction mRNA expression changes, apoptosis and antioxidant responses via NF-kappaB, TOR and Nrf2 signaling molecules in the gills of fish: preventive role of arginine. AB - This study explored the possible preventive effects of dietary arginine on copper (Cu)-induced tight junction mRNA expression changes, apoptosis and antioxidant responses in the gills of young grass carp (Ctenopharyngodon idella). The results indicated that exposure to 0.7 mg/L (11.01 MUmol/L) Cu for 96 h induced the production of reactive oxygen species (ROS), thereby increasing protein oxidation, lipid peroxidation and DNA damage in the gills of fish. However, these oxidative effects were prevented by arginine supplementation. Arginine also prevented the toxic effects of Cu on the activities of copper/zinc superoxide dismutase (SOD1), glutathione-S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR) and the glutathione (GSH) content (P<0.05). However, Cu induced an adaptive increase in the activity of catalase (CAT), and arginine supplementation further increased CAT activity (P<0.05). Moreover, Cu induced increases in the relative mRNA expressions of SOD1, CAT, GPx, GST, caspase-3, caspase-9, NF-E2-related factor 2 (Nrf2), Kelch-like-ECH-associated protein 1a (Keap1a), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-8 (IL-8), transforming growth factor-beta (TGF-beta) and nuclear transcription factor-kappaB p65 (NF-kappaB p65) in the gills of grass carp (P<0.05). In contrast, the relative mRNA expression levels of occludin, zonula occludens-1 (ZO-1), claudin b, claudin 3, claudin 12, target of rapamycin (TOR) and inhibitor factor kappaBalpha (IkappaBalpha) in the gills were decreased by Cu (P<0.05). However, pre-treatment of fish with arginine prevented Cu-induced relative mRNA expression decrease. Interestingly, Cu exposure resulted in increases in claudin 15a mRNA expression (P<0.05) but could not induce claudin c, caspase-8 and interleukin-10 (IL-10) mRNA expression changes in the gill of fish (P>0.05). These results indicated that Cu exposure induced apoptosis and antioxidant system and tight junction mRNA changes in the fish gills, which could be completely blocked by dietary arginine pre-supplementation. PMID- 25461752 TI - Development of genic and genomic SSR markers of robusta coffee (Coffea canephora Pierre Ex A. Froehner). AB - Coffee breeding and improvement efforts can be greatly facilitated by availability of a large repository of simple sequence repeats (SSRs) based microsatellite markers, which provides efficiency and high-resolution in genetic analyses. This study was aimed to improve SSR availability in coffee by developing new genic-/genomic-SSR markers using in-silico bioinformatics and streptavidin-biotin based enrichment approach, respectively. The expressed sequence tag (EST) based genic microsatellite markers (EST-SSRs) were developed using the publicly available dataset of 13,175 unigene ESTs, which showed a distribution of 1 SSR/3.4 kb of coffee transcriptome. Genomic SSRs, on the other hand, were developed from an SSR-enriched small-insert partial genomic library of robusta coffee. In total, 69 new SSRs (44 EST-SSRs and 25 genomic SSRs) were developed and validated as suitable genetic markers. Diversity analysis of selected coffee genotypes revealed these to be highly informative in terms of allelic diversity and PIC values, and eighteen of these markers (~ 27%) could be mapped on a robusta linkage map. Notably, the markers described here also revealed a very high cross-species transferability. In addition to the validated markers, we have also designed primer pairs for 270 putative EST-SSRs, which are expected to provide another ca. 200 useful genetic markers considering the high success rate (88%) of marker conversion of similar pairs tested/validated in this study. PMID- 25461753 TI - Abdominal aortic aneurysm repair in nonagenarians. AB - BACKGROUND: The feasibility of abdominal aortic aneurysm (AAA) repair in nonagenarians on a national level is largely unknown. We undertook this study to determine the outcomes of open and endovascular AAA repair in this population on a national level. METHODS: A retrospective review of the Nationwide Inpatient Sample Database was conducted to determine all patients 90 years and older who underwent either an open or endovascular repair of a nonruptured AAA from 1997 to 2008. Preoperative comorbidities and postoperative complications in the inpatient setting were recorded. The primary end point was mortality. Secondary end points were postoperative neurologic, cardiac, and respiratory complications. This group was then compared with all adult patients less than 90 years old (age, 18-89) who had undergone repair of a nonruptured AAA during this same period. RESULTS: Four hundred twenty-three patients 90 years and older underwent repair of a nonruptured AAA (compared with 52,370 < 90). Of these, 132 patients underwent open repair (31%) and 291 (69%) underwent endovascular repair. Inpatient mortality was 18.3% for the >=90 open, 4.6% for the <90 open, 3.1% for the >=90 endovascular, and 1.2% for <90 endovascular group. CONCLUSIONS: Open repair of AAA's in nonagenarians is associated with significantly high perioperative mortality, whereas endovascular repair is feasible with acceptable perioperative mortality. This mortality, although significantly higher than that obtained for endovascular repair in patients <90, is nonetheless not significantly different for the mortality noted for patients <90 undergoing open AAA repair. PMID- 25461754 TI - Delay between symptoms and surgery for carotid artery stenosis: modification of our practice. AB - BACKGROUND: Recent data from the literature concerning symptomatic carotid stenosis show that the long-term benefits of surgery are greater when the surgery is performed soon after the neurologic event, ideally within 2 weeks. Since 2009, following recommendations, we decided to perform surgery as quick as possible. The aim of the study was to determine whether this approach increased postoperative morbimortality and the way it could change our practice. METHODS: Using a prospective database containing a consecutive and continuous series of 1,500 carotid endarterectomies performed between 2003 and 2012, we extracted the records concerning the 417 symptomatic carotid stenoses (27.8%). We compared the 30-day and long-term outcome in 3 groups of patients: those operated within 2 weeks of the neurologic event (early surgery group [ESG], n = 158, 37.9%), those operated between 16 days and 6 weeks after the event (deferred surgery group [DSG], n = 79, 18.9%), and those operated more than 6 weeks after the event (late surgery group [LSG], n = 180, 43.2%). In the second part, to assess the new management beginning 2009, patients were divided in 2 periods 2003-2008 (period A) and 2009-2012 (period B) and we compared the 2 period's descriptive data and outcome. The primary outcome was the 30-day combined stroke and death rate. Secondary end points were follow-up freedoms from mortality and stroke. RESULTS: The mean time between symptom onset and surgery was 7.7 +/- 3.8 days for the ESG, 28.3 +/- 8.6 days for the DSG, and 89.4 +/- 36.7 days for the LSG. In the 3 groups, the types of symptoms leading to the indication for carotid surgery were comparable, with a stroke in 221 cases (53.0%), a transient ischemic attack in 146 cases (35.40%), and amaurosis fugax in 50 cases (12.0%). The groups were comparable in terms of comorbidities. The overall 30-day stroke rate was 1.4% (6 cases), the 30-day death rate was 1.7% (7 cases), and the combined stroke and death rate was 3.4% (3.2% in the ESG, 5.1% in the DSG, and 2.8% in the LSG [P = 0.808]). Survival rates at 24, 48, and 60 months were, respectively, 95%, 78%, and 78% in ESG, 86%, 81%, and 81% in DSG, and 91%, 83%, and 74% in LSG (P = 0.78). Freedom from stroke at 60 months showed to be, respectively, 97% in ESG, 96% in DSG, and 91% in LSG (P = 0.32). During the period A (2003-2008), we had taken care of 217 symptomatic carotid artery stenosis patients (22.3% of stenosis) and during the period B (2009-2012), 200 symptomatic stenosis (37.9% of stenosis). During the period A, an early surgery (<15 days) had place in 31 cases (14.3%), and during the period B, in 127 cases (63.5%). The 30-day stroke and death rate was of 3.7% during the period A and of 3.0% during the period B (P = 0.455). The 24-month survival and stroke-free survival rates were comparable between the 2 periods. CONCLUSIONS: In our experience, surgery for symptomatic carotid stenosis can be performed early without increasing the rate of postoperative and long-term outcome. We have modified our practice, performing more and more early surgery for symptomatic stenosis without any impact on the outcome. PMID- 25461755 TI - A novel third generation uric acid biosensor using uricase electro-activated with ferrocene on a Nafion coated glassy carbon electrode. AB - A new uric acid biosensor was constructed using ferrocene (Fc) induced electro activated uricase (UOx) deposited within Nafion (Naf) on glassy carbon electrode (GCE). Electro-activation of UOx was successfully achieved by cyclic voltammetry through the electrostatic interaction of Fc with Trp residues within the hydrophobic pockets in UOx. The Naf/UOx/Fc composite was characterised by AFM, FTIR and EDX to ensure proper immobilisation. The interaction of Fc with the enzyme was analysed by Trp fluorescence spectroscopy and the alpha-helicity of the protein was measured by CD spectropolarimetry. The charge transfer resistance (Rct), calculated from electrochemical impedance spectroscopy, for the modified sensor was lowered (1.39 kOmega) and the enzyme efficiency was enhanced by more than two fold as a result of Fc incorporation. Cyclic voltammetry, differential pulse voltammetry and amperometry all demonstrated the excellent response of the Naf/UOx/Fc/GCE biosensor to uric acid. The sensor system generated a linear response over a range of 500 nM to 600 MUM UA, with a sensitivity and limit of detection of 1.78 MUA MUM(-1) and 230 nM, respectively. The heterogeneous rate constant (ks) for UA oxidation was much higher for Naf/UOx/Fc/GCE (1.0 * 10(-4) cm s(-1)) than for Naf/UOx/GCE (8.2 * 10(-5) cm s(-1)). Real samples, i.e. human blood, were tested for serum UA and the sensor yielded accurate results at a 95% confidence limit. PMID- 25461756 TI - A mathematical model for electrochemically active filamentous sulfide-oxidising bacteria. AB - Oxygen and sulfide in ocean sediments can be consumed biologically over long spatial distances by way of filamentous bacteria in electron-conducting sheaths. To analyse observations, a mathematical model of these filamentous sulfur oxidising bacteria was developed, including electrical conduction between reactive zones. Mechanisms include Nernst-Planck diffusion and migration of ions coupled with Ohm's law for conduction along filaments, and metabolic activity throughout the filaments. Simulations predict outward biomass growth toward the boundaries of the sediment floor and top surface, resulting in two distinct zones with anode (sulfide consumption) and cathode (oxygen consumption) reactions enabled by electron conduction. Results show inward fluxes of 4.6 mmol O2/m(2)/d and 2.5 mmol S/m(2)/d, with consumption increasing with growth to final fluxes of 8.2 mmol O2/m(2)/d and 4.34 mmol S/m(2)/d. Qualitatively, the effect of varying cell conductivity and substrate affinity is evaluated. Controlling mechanisms are identified to shift from biomass limitation, to substrate limitation, and to conductivity limitations as the lengths of the filaments increase. While most observed data are reflected in the simulation results, a key discrepancy is the lower growth rates, which are largely fixed by thermodynamics, indicating that microbes may utilise secondary substrates or an alternative metabolism. PMID- 25461757 TI - Electrochemical investigation of the interaction between topotecan and DNA at disposable graphite electrodes. AB - Topotecan (TPT) is a semisynthetic, water soluble analog of the plant alkaloid camptothecin which has been widely used for the treatment of ovarian and cervical cancers. To obtain better understanding on how it can affect DNA structure, electrochemical biosensor platforms for the investigation of TPT-double stranded DNA (dsDNA) interaction were developed for the first time in this study. The electrochemical detection of TPT, and TPT-dsDNA interaction were investigated at the surface of pencil graphite electrodes (PGEs) and single-walled carbon nanotube (SWCNT) modified PGEs by using differential pulse voltammetry (DPV). The changes at the oxidation signals of TPT and guanine were evaluated before/after each modification/immobilization step. An enhanced sensor response was obtained by using SWCNT-PGEs compared to unmodified PGEs with resulting limits of detection (LODs) for TPT as 0.51 MUg/mL, 0.45 MUg/mL, 0.37 MUg/mL (130 pmol, 117 pmol, 96.5 pmol in a 110 MUL sample, respectively) by using electrochemically pretreated PGE, unmodified PGE and SWCNT modified PGE. In addition, electrochemical impedance spectroscopy (EIS) measurements were performed for the purpose of modification of PGEs by using SWCNTs and the interaction process at the surface of SWCNT-PGEs by evaluating the changes at the charge transfer resistance (Rct). PMID- 25461759 TI - A reconstruction method based on AL0FGD for compressed sensing in border monitoring WSN system. AB - In this paper, to monitor the border in real-time with high efficiency and accuracy, we applied the compressed sensing (CS) technology on the border monitoring wireless sensor network (WSN) system and proposed a reconstruction method based on approximately l0 norm and fast gradient descent (AL0FGD) for CS. In the frontend of the system, the measurement matrix was used to sense the border information in a compressed manner, and then the proposed reconstruction method was applied to recover the border information at the monitoring terminal. To evaluate the performance of the proposed method, the helicopter sound signal was used as an example in the experimental simulation, and three other typical reconstruction algorithms 1)split Bregman algorithm, 2)iterative shrinkage algorithm, and 3)smoothed approximate l0 norm (SL0), were employed for comparison. The experimental results showed that the proposed method has a better performance in recovering the helicopter sound signal in most cases, which could be used as a basis for further study of the border monitoring WSN system. PMID- 25461760 TI - Deciphering a pathway of Halobacterium salinarum N-glycosylation. AB - Genomic analysis points to N-glycosylation as being a common posttranslational modification in Archaea. To date, however, pathways of archaeal N-glycosylation have only been described for few species. With this in mind, the similarities of N-linked glycans decorating glycoproteins in the haloarchaea Haloferax volcanii and Halobacterium salinarum directed a series of bioinformatics, genetic, and biochemical experiments designed to describe that Hbt. salinarum pathway responsible for biogenesis of one of the two N-linked oligosaccharides described in this species. As in Hfx. volcanii, where agl (archaeal glycosylation) genes that encode proteins responsible for the assembly and attachment of a pentasaccharide to target protein Asn residues are clustered in the genome, Hbt. salinarum also contains a group of clustered homologous genes (VNG1048G VNG1068G). Introduction of these Hbt. salinarum genes into Hfx. volcanii mutant strains deleted of the homologous sequence restored the lost activity. Moreover, transcription of the Hbt. salinarum genes in the native host, as well as in vitro biochemical confirmation of the predicted functions of several of the products of these genes provided further support for assignments made following bioinformatics and genetic experiments. Based on the results obtained in this study, the first description of an N-glycosylation pathway in Hbt. salinarum is offered. PMID- 25461761 TI - Prognostic significance of interleukin-8 and CD163-positive cell-infiltration in tumor tissues in patients with oral squamous cell carcinoma. AB - PURPOSE: We investigated whether serum interleukin (IL)-8 reflects the tumor microenvironment and has prognostic value in patients with oral squamous cell carcinoma (OSCC). EXPERIMENTAL DESIGN: Fifty OSCC patients who received radical resection of their tumor(s) were enrolled. Preoperative sera were measured for IL 8 by ELISA. Expression of IL-8 and the infiltration of immune cells in tumor tissues were analyzed by an immunohistochemical staining of surgical specimens. RESULTS: We found that disease-free survival (DFS) was significantly longer in the Stage I/II OSCC patients with low serum IL-8 levels compared to those with high levels (p = 0.001). The tumor expression of IL-8, i.e., IL-8(T) and the density of CD163-positive cells in the tumor invasive front, i.e., CD163(IF) were correlated with the serum IL-8 level (p = 0.033 and p = 0.038, respectively), and they were associated with poor clinical outcome (p = 0.007 and p = 0.002, respectively, in DFS) in all patients. A multivariate analysis revealed that N status, IL-8(T) and CD163(IF) significantly affected the DFS of the patients. Further analysis suggested that combination of N status with serum IL-8, IL-8(T) or CD163(IF) may be a new criterion for discriminating between OSCC patients at high and low risk for tumor relapse. Interestingly, the in vitro experiments demonstrated that IL-8 enhanced generation of CD163-positive M2 macrophages from peripheral blood monocytes, and that the cells produced IL-10. CONCLUSIONS: These findings indicate that IL-8 may be involved in poor clinical outcomes via generation of CD163-positive M2 macrophages, and that these factors in addition to N status may have prognostic value in patients with resectable OSCSS. PMID- 25461762 TI - MiR-23a facilitates the replication of HSV-1 through the suppression of interferon regulatory factor 1. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that negatively regulate gene expression. It has been reported that miRNAs are involved in host-virus interaction, but evidence that cellular miRNAs promote virus replication has been limited. Here, we found that miR-23a promoted the replication of human herpes simplex virus type 1 (HSV-1) in HeLa cells, as demonstrated by a plaque-formation assay and quantitative real-time PCR. Furthermore, interferon regulatory factor 1 (IRF1), an innate antiviral molecule, is targeted by miR-23a to facilitate viral replication. MiR-23a binds to the 3'UTR of IRF1 and down-regulates its expression. Suppression of IRF1 expression reduced RSAD2 gene expression, augmenting HSV-1 replication. Ectopic expression of IRF1 abrogated the promotion of HSV-1 replication induced by miR-23a. Notably, IRF1 contributes to innate antiviral immunity by binding to IRF-response elements to regulate the expression of interferon-stimulated genes (ISGs) and apoptosis, revealing a complex interaction between miR-23a and HSV-1. MiR-23a thus contributes to HSV-1 replication through the regulation of the IRF1-mediated antiviral signal pathway, which suggests that miR-23a may represent a promising target for antiviral treatments. PMID- 25461764 TI - Challenges in trying to implement an early intervention program for infants with congenital heart disease. AB - PURPOSE: To describe challenges in trying to implement a physical therapy-based early intervention program for infants with congenital heart disease. METHODS: Neonates with cyanotic congenital heart disease who had elective or emergency cardiac surgery at age 28 days or less participated in the study. Families were offered hospital-based physical therapy intervention from infant age of 3 months. Feasibility and efficacy of intervention were to be evaluated at 8 months. RESULTS: Study recruitment was protracted and then stopped. Anticipated sample size was limited by survival (86%) and recruitment rates (75%); cardiorespiratory and neurological complications led to lengthy admissions, precluding study participation. In addition, geographic constraints and families' general take-up of the services offered limited ability of those recruited to receive intervention at planned frequency and intensity. CONCLUSIONS: Overall, data collected demonstrated infeasibility to evaluate effectiveness of hospital-based physical therapy intervention for this cohort of infants. Nonetheless, valuable data were gathered about factors leading to nonparticipation. PMID- 25461763 TI - PERGA: a paired-end read guided de novo assembler for extending contigs using SVM and look ahead approach. AB - Since the read lengths of high throughput sequencing (HTS) technologies are short, de novo assembly which plays significant roles in many applications remains a great challenge. Most of the state-of-the-art approaches base on de Bruijn graph strategy and overlap-layout strategy. However, these approaches which depend on k-mers or read overlaps do not fully utilize information of paired-end and single-end reads when resolving branches. Since they treat all single-end reads with overlapped length larger than a fix threshold equally, they fail to use the more confident long overlapped reads for assembling and mix up with the relative short overlapped reads. Moreover, these approaches have not been special designed for handling tandem repeats (repeats occur adjacently in the genome) and they usually break down the contigs near the tandem repeats. We present PERGA (Paired-End Reads Guided Assembler), a novel sequence-reads-guided de novo assembly approach, which adopts greedy-like prediction strategy for assembling reads to contigs and scaffolds using paired-end reads and different read overlap size ranging from Omax to Omin to resolve the gaps and branches. By constructing a decision model using machine learning approach based on branch features, PERGA can determine the correct extension in 99.7% of cases. When the correct extension cannot be determined, PERGA will try to extend the contig by all feasible extensions and determine the correct extension by using look-ahead approach. Many difficult-resolved branches are due to tandem repeats which are close in the genome. PERGA detects such different copies of the repeats to resolve the branches to make the extension much longer and more accurate. We evaluated PERGA on both Illumina real and simulated datasets ranging from small bacterial genomes to large human chromosome, and it constructed longer and more accurate contigs and scaffolds than other state-of-the-art assemblers. PERGA can be freely downloaded at https://github.com/hitbio/PERGA. PMID- 25461765 TI - Commentary on "Challenges in trying to implement an early intervention program for infants with congenital heart disease". PMID- 25461766 TI - Foot orthoses for pediatric flexible flatfoot: evidence and current practices among Canadian physical therapists. AB - PURPOSE: This study aimed to examine the evidence for flatfoot intervention in children with gross motor delay of neurological origin, and to understand how physical therapists use foot orthoses (FOs) to treat this population. METHODS: Thirty-four physical therapists employed in Canadian publicly funded pediatric centers were surveyed to explore current practices and beliefs related to FOs. RESULTS: Responses are discussed in the context of the research literature. Objective physical examination and differentiation between developmental and pathological flatfeet can help clinicians to identify suitable FO candidates, monitor foot posture over time, and evaluate treatment effectiveness. CONCLUSIONS: An evidence-informed approach to assessment and intervention has the potential to improve clinical outcomes for clients with pediatric flatfoot. PMID- 25461767 TI - Commentary on "Foot orthoses for pediatric flexible flatfoot: evidence and current practices among Canadian physical therapists". PMID- 25461768 TI - Regenerative medicine: future impact on clinical therapies and society. PMID- 25461769 TI - TIA1 interacts with annexin A7 in regulating vascular endothelial cell autophagy. AB - T-cell intracellular antigen-1 (TIA1) is a DNA/RNA binding protein broadly expressed in eukaryotic cells, participating in multiple aspects of cellular metabolism. TIA1 phosphorylation was related with cell apoptosis and its RNA binding activity, however, the regulator and other functions of TIA1 phosphorylation were very little known. To find the modulator of TIA1 phosphorylation, we performed yeast two-hybrid screening and identified annexin A7 (ANXA7) as an interaction protein of TIA1. Recent study showed that a small molecule ABO could directly target ANXA7 and inhibit ANXA7 activity and its targets' phosphorylation. As a GTPase, ANXA7 was speculated to modulate TIA1 phosphorylation. Our results showed that ABO treatment promoted the interaction between TIA1 and ANXA7, and then greatly inhibited phosphorylation of TIA1 in HUVECs. Further results showed that ABO-increased interaction between ANXA7 and TIA1 significantly promoted the processing of a pro-autophagic factor FLJ11812 and the expression of ATG13. Moreover, we found that ABO increased TIA1 protein level, co-localization of ANXA7 and TIA1, and ATG13 expression in the aortic endothelium of apoE(-/-) mice. These data highlighted the new role of TIA1 phosphorylation in autophagy. PMID- 25461770 TI - Arrested development and the great escape--the role of cellular senescence in pancreatic cancer. AB - The outcomes of pancreatic cancer remain dismal due to late clinical presentation and the aggressive nature of the disease. A heterogeneous combination of genetic mutations, including KRAS, INK4a/CDKN2A and p53, underpin the propensity of pancreatic cancer to rapidly invade and disseminate. These oncogenes and tumour suppressors are strongly associated with cellular senescence, therefore suggesting this process as having a key role in malignant transformation. In the context of cancer, oncogenic stimuli trigger the senescent phenotype resulting in cell cycle growth arrest and prevention of progression of premalignant lesions such as PanINs. However mutations of the aforementioned oncogenes or tumour suppressors result in cells escaping senescence and thus allowing tumours to progress. This review presents current evidence regarding both senescence induction and escape with respect to pancreatic cancer, highlighting the key roles of p19ARF, p53, Rb and P16INK4a. The epigenetic regulatory component is also discussed, with relevance to DNA methylation and HDACs. Lastly the role of the tumour microenvironment, and in particular pancreatic stellate cells, is discussed with regards to the induction of a senescence associated secretory phenotype (SASP), with SASP-associated secretory factors contributing to the pro tumorigenic effects of the surrounding activated stroma. Further work is required in this field to elucidate the most important pathways relating to cellular senescence that contribute to the belligerent nature of this disease, with the aim of discovering therapeutic targets to improve patient outcomes. PMID- 25461771 TI - PTEN hamartoma tumor syndrome: clinical risk assessment and management protocol. AB - The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is an important phosphatase that counteracts one of the most critical cancer pathways: the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathways. Clinically, deregulation of PTEN function resulting in reduced PTEN expression and activity is implicated in human diseases. Cowden syndrome (CS) is an autosomal dominant disorder characterized by benign and malignant tumors. CS related individual features occur commonly in the general population. Approximately 25% of patients diagnosed with CS have pathogenic germline PTEN mutations, which increase lifetime risks of breast, thyroid, uterine, renal and other cancers. PTEN testing and intensive cancer surveillance allow for early detection and treatment of these cancers for mutation positive patients and their relatives. In this review, we highlight our current knowledge of germline PTEN mutations in relation to human disease. We review current clinical diagnosis and management recommendations for PHTS including recent discoveries in understanding PTEN function regulation and how this can be exploited therapeutically. PMID- 25461772 TI - Fast and accurate mapping of Complete Genomics reads. AB - Many recent advances in genomics and the expectations of personalized medicine are made possible thanks to power of high throughput sequencing (HTS) in sequencing large collections of human genomes. There are tens of different sequencing technologies currently available, and each HTS platform have different strengths and biases. This diversity both makes it possible to use different technologies to correct for shortcomings; but also requires to develop different algorithms for each platform due to the differences in data types and error models. The first problem to tackle in analyzing HTS data for resequencing applications is the read mapping stage, where many tools have been developed for the most popular HTS methods, but publicly available and open source aligners are still lacking for the Complete Genomics (CG) platform. Unfortunately, Burrows Wheeler based methods are not practical for CG data due to the gapped nature of the reads generated by this method. Here we provide a sensitive read mapper (sirFAST) for the CG technology based on the seed-and-extend paradigm that can quickly map CG reads to a reference genome. We evaluate the performance and accuracy of sirFAST using both simulated and publicly available real data sets, showing high precision and recall rates. PMID- 25461773 TI - Methods for generating and applying pharmacophore models as virtual screening filters and for bioactivity profiling. AB - Biological effects of small molecules in an organism result from favorable interactions between the molecules and their target proteins. These interactions depend on chemical functionalities, bonds, and their 3D-orientations towards each other. These 3D-arrangements of chemical functionalities that make a small molecule active towards its target can be described by pharmacophore models. In these models, chemical functionalities are represented as so-called features. Commonly, they are obtained either from a set of active compounds or directly from the observed protein-ligand interactions as present in X-ray crystal structures, NMR structures, or docking poses. In this review, we explain the basics of pharmacophore modeling including dataset generation, 3D-representations and conformational analysis of small molecules, pharmacophore model construction, model validation, and its benefits to virtual screening and other applications. PMID- 25461774 TI - Assaying the epigenome in limited numbers of cells. AB - Spectacular advances in the throughput of DNA sequencing have allowed genome-wide analysis of epigenetic features such as methylation, nucleosome position and post translational modification, chromatin accessibility and connectivity, and transcription factor binding. However, for rare or precious biological samples, input requirements of many of these methods limit their application. In this review we discuss recent advances for low-input genome-wide analysis of chromatin immunoprecipitation, methylation, DNA accessibility, and chromatin conformation. PMID- 25461776 TI - Microcalorimetric assays for measuring cell growth and metabolic activity: methodology and applications. AB - Isothermal microcalorimetry measures the heat released or consumed by physical or chemical processes. Metabolic activity releases heat that can be measured. However the calorimetric signal can be difficult for new users to interpret. This paper compares microcalorimetry to other techniques and reviews its application to different fields where microbiological activity is important. We also describe different ways to analyze the data and translate it into meaningful (micro)biological equivalents. This paper aims at providing non-specialist reader the tools to understand how isothermal microcalorimetry can be used for microbiological applications. PMID- 25461775 TI - Computational schemes for the prediction and annotation of enhancers from epigenomic assays. AB - Identifying and annotating distal regulatory enhancers is critical to understand the mechanisms that control gene expression and cell-type-specific activities. Next-generation sequencing techniques have provided us an exciting toolkit of genome-wide assays that can be used to predict and annotate enhancers. However, each assay comes with its own specific set of analytical needs if enhancer prediction is to be optimal. Furthermore, integration of multiple genome-wide assays allows for different genomic features to be combined, and can improve predictive performance. Herein, we review the genome-wide assays and analysis schemes that are used to predict and annotate enhancers. In particular, we focus on three key computational topics: predicting enhancer locations, determining the cell-type-specific activity of enhancers, and linking enhancers to their target genes. PMID- 25461778 TI - Pathology of the stillborn infant for the general pathologist: part 1. AB - As the information obtained from previable fetal and stillbirth autopsies is used not only to explain the loss to the parents, but for future pregnancy planning, general pathologists need to be comfortable in dealing with these autopsies. The importance of an adequate fetal examination has been emphasized in a recent policy on the subject by the American Board of Pathology http://www.abpath.org/FetalAutopsyPolicy.pdf. This review paper covers the approach to the fetal and stillbirth autopsy. This first article covers the approach to the nonanomalous and anomalous autopsy. Hydrops fetalis will be covered in the second part of this series to be published subsequently. PMID- 25461779 TI - Anaplastic large cell lymphomas: ALK positive, ALK negative, and primary cutaneous. AB - Anaplastic large cell lymphomas (ALCLs) comprise a group of CD30-positive non Hodgkin lymphomas that generally are of T-cell origin and share common morphologic and phenotypic characteristics. The World Health Organization recognizes 3 entities: primary cutaneous ALCL (pcALCL), anaplastic lymphoma kinase (ALK)-positive ALCL, and, provisionally, ALK-negative ALCL. Despite overlapping pathologic features, these tumors differ in clinical behavior and genetics. pcALCL presents in the skin and, while it may involve locoregional lymph nodes, rarely disseminates. Outcomes typically are excellent. ALK-positive ALCL and ALK-negative ALCL are systemic diseases. ALK-positive ALCLs consistently have chromosomal rearrangements involving the ALK gene with varied gene partners, and generally have a favorable prognosis. ALK-negative ALCLs lack ALK rearrangements and their genetic and clinical features are more variable. A subset of ALK-negative ALCLs has rearrangements in or near the DUSP22 gene and has a favorable prognosis similar to that of ALK-positive ALCL. DUSP22 rearrangements also are seen in a subset of pcALCLs. In this review, we discuss the clinical, morphologic, phenotypic, genetic, and biological features of ALCLs. PMID- 25461780 TI - Molecular pathways in gliomagenesis and their relevance to neuropathologic diagnosis. AB - Gliomas are a large and diverse group of primary brain tumors that include those that are diffusely infiltrative and others that are well-circumscribed and low grade. Diffuse gliomas are currently classified by the World Health Organization as astrocytomas, oligodendrogliomas, or oligoastrocytomas and range in grade from II to IV. Glioblastoma (GBM), World Health Organization grade IV, is the highest grade and most common form of astrocytoma. In the past, the diagnosis of gliomas was almost exclusively based on histopathologic features. More recently, improved understanding of molecular genetic underpinnings has led to ancillary molecular studies becoming standard for classification, prognostication, and predicting therapy response. Isocitrate dehydrogenase (IDH) mutations are frequent in grade II and III infiltrating gliomas and secondary GBMs. Infiltrating astrocytomas and secondary GBMs are characterized by IDH, TP53, and ATRX mutations, whereas oligodendrogliomas demonstrate 1p/19q codeletion and mutations in IDH, CIC, FUBP1, and the telomerase reverse transcriptase (TERT) promoter. Primary GBMs typically lack IDH mutations and are instead characterized by EGFR, PTEN, TP53, PDGFRA, NF1, and CDKN2A/B alterations and TERT promoter mutations. Pediatric GBMs differ from those in adults and frequently have mutations in H3F3A, ATRX, and DAXX, but not IDH. In contrast, circumscribed, low-grade gliomas of childhood, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma, often harbor mutations or activating gene rearrangements in BRAF. Neuropathologic assessment of gliomas increasingly relies on ancillary testing of molecular alterations for proper classification and patient management. PMID- 25461777 TI - Membrane association of the PTEN tumor suppressor: neutron scattering and MD simulations reveal the structure of protein-membrane complexes. AB - Neutron reflection (NR) from planar interfaces is an emerging technology that provides unique and otherwise inaccessible structural information on disordered molecular systems such as membrane proteins associated with fluid bilayers, thus addressing one of the remaining challenges of structural biology. Although intrinsically a low-resolution technique, using structural information from crystallography or NMR allows the construction of NR models that describe the architecture of protein-membrane complexes at high resolution. In addition, a combination of these methods with molecular dynamics (MD) simulations has the potential to reveal the dynamics of protein interactions with the bilayer in atomistic detail. We review recent advances in this area by discussing the application of these techniques to the complex formed by the PTEN phosphatase with the plasma membrane. These studies provide insights in the cellular regulation of PTEN, its interaction with PI(4,5)P2 in the inner plasma membrane and the pathway by which its substrate, PI(3,4,5)P3, accesses the PTEN catalytic site. PMID- 25461781 TI - Selected case from the Arkadi M. Rywlin international pathology slide series: diffuse dendriform pulmonary ossification: report of 2 cases with review of the literature. AB - Two cases of diffuse dendriform pulmonary ossification (DPO) are presented, one of the secondary type and the other of the idiopathic type. Case 1 was an adult female patient who underwent thoracic surgery to remove a posterior mediastinal bronchogenic cyst, which was discovered on a computed tomography scan performed after an episode of pneumonia when traction bronchiectasis with interstitial lung disease/fibrosis was also suspected in the lungs. Histologic examination performed on the resected lung tissue revealed numerous scattered small osseous spicules on a background of intense interstitial inflammation and fibrosis, leading to further clinical and laboratory investigations and the final diagnosis of DPO secondary to lung involvement by scleroderma. Case 2 was an adult male patient who underwent thoracoscopic exploration after a computed tomography scan, which revealed traction bronchiectasis with linear thickening of the interstitial lung tissue. Histologic examination of the lung tissue specimen revealed numerous osseous spicules in the absence of interstitial septal inflammation. Noteworthy in this case were also some nodules of collagenized tissue similar to those seen in the lungs of patients affected by Ehlers-Danlos syndrome. The absence of any clinical sign or symptoms related to Ehlers-Danlos syndrome attest to the nonspecificity of these pulmonary fibrous nodules. No case of DPO secondary to scleroderma has been reported in the literature so far, although around half of the patients with scleroderma manifest pulmonary diseases. Idiopathic DPO is even rarer, usually discovered postmortem, with only 20 cases diagnosed in life with lung biopsies taken by open surgery or through a thoracoscopic approach. DPO is often misdiagnosed radiologically as bronchiectasis and/or interstitial lung disease/fibrosis. PMID- 25461782 TI - Web-based Mindfulness-based Cognitive Therapy for reducing residual depressive symptoms: An open trial and quasi-experimental comparison to propensity score matched controls. AB - Mindfulness-based Cognitive Therapy (MBCT) has been shown to effectively prevent relapse and reduce residual depressive symptoms (RDS), yet it faces barriers to dissemination. The present study examined Mindful Mood Balance (MMB), the first web-based approach to deliver the core content of MBCT. Of the 107 recurrently depressed individuals screened, 100 elected to enroll in the study and received MMB in an 8-session open trial with 6-month follow-up. Outcomes included depressive symptom severity, rumination and mindful awareness, and program engagement. A quasi-experimental comparison between MMB participants and propensity matched case-controls receiving usual depression care (UDC) (N = 100) also was conducted. The full sample and the subgroup with residual depressive symptoms (N = 42) showed significantly reduced depressive severity, which was sustained over six months, and improvement on rumination and mindfulness. Examination of acceptability of MMB indicated that 42% of participants within the full sample and 36% of the RDS subgroup completed all 8 sessions and 53% within the full sample and 50% within the RDS subgroup completed at least 4 sessions, and that participants engaged with daily mindfulness practice. MMB also was associated with significant reduction in RDS severity as compared to quasi experimental propensity matched controls. Although the use of a non-randomized design, with potential unmeasured differences between groups, and short interval of clinical follow-up were limitations, findings from this study support the web based delivery of MBCT and suggest clinical benefits for participants with histories of depression and with RDS, relative to those receiving usual care alone. PMID- 25461784 TI - Internet cognitive behavioural treatment for obsessive compulsive disorder: A randomised controlled trial. AB - Internet-based cognitive behaviour therapy (iCBT) is becoming increasing accepted as an efficacious and effective treatment for the anxiety and depressive disorders. However few studies have examined the efficacy of iCBT for obsessive compulsive disorder (OCD). This randomised controlled trial compared technician administered iCBT (n = 32) to a treatment as usual (TAU) control group (n = 35) in patients with OCD. The primary outcome measures were the Dimensional Obsessive Compulsive Scale (DOCS) and the Obsessional Beliefs Questionnaire (OBQ-20) administered at pre- and post-treatment (or matched time points). The iCBT group was followed-up at 3-months post-treatment when diagnostic status was assessed at clinical interview. The iCBT program was more efficacious than TAU in reducing maladaptive OC beliefs as well as symptoms of OCD, distress, and depression, with large within- and between-groups effect sizes found (>.78). Adherence was high (75%) and gains were maintained at 3 month-follow-up with 54% of treatment completers no longer meeting diagnostic criteria for OCD at follow-up. These results are comparable to outcomes obtained by clinician-administered face-to face and internet-based programs and suggest that iCBT for OCD is efficacious when administered by a clinically-supervised technician. Future research is now needed to evaluate how effective iCBT for OCD is in routine clinical settings. PMID- 25461783 TI - Internet-based preventive intervention for reducing eating disorder risk: A randomized controlled trial comparing guided with unguided self-help. AB - Student Bodies, an internet-based intervention, has successfully reduced weight/shape concerns and prevented eating disorders in a subset of college-age women at highest risk for an eating disorder. Student Bodies includes an online, guided discussion group; however, the clinical utility of this component is unclear. This study investigated whether the guided discussion group improves program efficacy in reducing weight/shape concerns in women at high risk for an eating disorder. Exploratory analyses examined whether baseline variables predicted who benefitted most. Women with high weight/shape concerns (N = 151) were randomized to Student Bodies with a guided discussion group (n = 74) or no discussion group (n = 77). Regression analyses showed weight/shape concerns were reduced significantly more among guided discussion group than no discussion group participants (p = 0.002; d = 0.52); guided discussion group participants had 67% lower odds of having high-risk weight/shape concerns post-intervention (p = 0.02). There were no differences in binge eating at post-intervention between the two groups, and no moderators emerged as significant. Results suggest the guided discussion group improves the efficacy of Student Bodies in reducing weight/shape concerns in college students at high risk for an eating disorder. PMID- 25461785 TI - A randomised controlled trial of face to face versus pure online self-help cognitive behavioural treatment for perfectionism. AB - Previous research has shown cognitive-behavioural treatment (CBT) to be effective in reducing perfectionism. The present study investigated the efficacy of two formats of CBT for perfectionism (CBT-P), face-to-face and pure online self-help, in reducing perfectionism and associated psychological symptoms. Participants were randomly allocated to face-to-face CBT-P (n = 18), pure online self-help CBT P (n = 16), or a waitlist control period (n = 18). There was no significant change for the waitlist group on any of the outcome measures at the end of treatment. Both the face-to-face and pure online self-help groups reported significant reductions at the end of treatment for the perfectionism variables which were maintained at the 6-month follow-up. The face-to-face group also reported significant reductions over this time in depression, anxiety, and stress, and a significant pre-post increase in self-esteem, all of which were maintained at the 6-month follow-up. In contrast, the pure online self-help group showed no significant changes on these outcomes. The face-to-face group was statistically superior to the pure online self-help group at follow-up on the perfectionism measures, concern over mistakes and personal standards. The results show promising evidence for CBT for perfectionism, especially when offered face to face, where sustained benefit across a broad range of outcomes can be expected. PMID- 25461786 TI - Moderators and mediators of outcome in Internet-based indicated prevention for eating disorders. AB - The objective of this study was to investigate moderators and mediators of the effect of an indicated prevention program for eating disorders (ED) on reduction of dysfunctional attitudes and specific ED symptoms. 126 women (M age = 22.3; range 18-33) reporting subthreshold ED symptoms were randomized to the Student BodiesTM+ (SB+) intervention or an assessment-only control condition. Assessments took place at pre-intervention, mid-intervention (mediators), post-intervention, and 6-month follow-up. Mixed effects modeling including all available data from all time points were used for the data analysis. Intervention effects on the reduction of binge rate were weaker for participants with higher baseline BMI and for participants with a lower baseline purge rate. Intervention effects on reduction of eating disorder pathology were weaker for participants with higher baseline purge rate and with initial restrictive eating. No moderators of the intervention effect on restrictive eating were identified. An increase in knowledge mediated the beneficial effect of SB+ on binge rate. The results suggest that different moderators should be considered for the reduction of symptoms and change in attitudes of disturbed eating and that SB+ at least partially operates through psychoeducation. PMID- 25461788 TI - Reductions in the internalising construct following internet-delivered treatment for anxiety and depression in primary care. AB - Depressive and anxiety disorders are different manifestations of a latent internalising construct. To date, efficacy studies have tended to focus on disorder-specific outcomes, rather than underlying dimensions. This study examined the effect of a transdiagnostic internet-delivered cognitive behavioural therapy (iCBT) on the internalising construct in a primary care sample. Participants included 635 patients aged 18 years or over who were prescribed a six lesson transdiagnostic iCBT program for anxiety and depression by their primary healthcare professional. All patients completed the Patient Health Questionnaire 9, the Generalised Anxiety Disorder 7-Item Scale, the Mini Social Phobia Inventory and the Panic Disorder Severity Self-Report Scale at baseline. 325 of these patients completed the program and provided data on each of these scales during the final lesson. Reductions in the latent internalising construct were assessed within a longitudinal factor analysis framework that compared internalising factor means before and after treatment. The within group mean reduction in the latent internalising construct was large (ES = 1.23, SE = 0.09; p < 0.001). Due to the lack of a control group, between group reductions in the latent internalising construct could not be investigated. This study demonstrated that there are clinically significant reductions in the latent internalising construct following transdiagnostic iCBT for anxiety and depression. PMID- 25461787 TI - E-therapy in the treatment and prevention of eating disorders: A systematic review and meta-analysis. AB - The widespread availability of the Internet and mobile-device applications (apps) is changing the treatment of mental health problems. The aim of the present study was to review the research on the effectiveness of e-therapy for eating disorders, using the methodology employed by the UK's National Institute for Health and Care Excellence (NICE). Electronic databases were searched for published randomised controlled trials of e-therapies, designed to prevent or treat any eating disorder in all age groups. Studies were meta-analysed where possible, and effect sizes with confidence intervals were calculated. The GRADE approach was used to determine the confidence in the effect estimates. Twenty trials met the inclusion criteria. For prevention, a CBT-based e-intervention was associated with small reductions in eating disorder psychopathology, weight concern and drive for thinness, with moderate confidence in the effect estimates. For treatment and relapse prevention, various e-therapies showed some beneficial effects, but for most outcomes, evidence came from single studies and confidence in the effect estimates was low. Overall, although some positive findings were identified, the value of e-therapy for eating disorders must be viewed as uncertain. Further research, with improved methods, is needed to establish the effectiveness of e-therapy for people with eating disorders. PMID- 25461789 TI - Only connect: The working alliance in computer-based cognitive behavioral therapy. AB - The limited role of therapists in some technology-based interventions raises questions as to whether clients may develop a 'working alliance' with the program, and the impact on relationships with a therapist and/or treatment outcomes. In this study, the Working Alliance Inventory (WAI), and an adapted version for technology-based interventions (WAI-Tech), were administered within a subsample (n = 66) of cocaine-dependent individuals participating in a randomized trial evaluating the efficacy of Computer-Based Training for Cognitive Behavioral Therapy (CBT4CBT) as an adjunct to treatment as usual (TAU). Results suggest the WAI-Tech has relatively similar psychometric characteristics as the standard WAI; however the 'bond' subscale scores were lower on the WAI-Tech [F(1,52) = 5.78, p < .05]. Scores on the WAI-Tech were not associated with cocaine use outcomes, whereas total scores on the WAI for those assigned to TAU were associated with the percentage of days abstinent from cocaine (r = .43, p < .05). There was little evidence that adding a technology-based intervention adversely affected the working alliance with a therapist in this sample. These preliminary findings suggest some concepts of working alliance may apply to computer-based CBT, yet the function of the alliance may be different in technology-based interventions than in face-to-face psychotherapies. PMID- 25461790 TI - Weekly brief phone support in self-help cognitive behavioral therapy for insomnia disorder: Relevance to adherence and efficacy. AB - Self-help cognitive-behavioral therapy for insomnia (CBT-I) is an acceptable, low intensity treatment in a stepped care model for insomnia. We tested the application of self-help CBT-I in a Chinese population. 312 participants with self-report of insomnia associated with distress or daytime impairment 3 or more nights per week for at least 3 months were randomized to self-help CBT-I with telephone support (SHS), self-help CBT-I (SH) and waiting-list (WL). The program was Internet-based with treatment materials delivered once per week, and lasted for 6 consecutive weeks, while the telephone support was limited to 15 min weekly. Mixed-effects analyses found significant group by time interaction in sleep and sleep-related cognitions at immediate and 4-week posttreatment. Post hoc pairwise comparison with WL revealed that both SHS and SH had significantly higher sleep efficiency at immediate (p = .004 and p = .03, respectively) and 4 week posttreatment (p = .002 and p = .02, respectively) and lower insomnia and dysfunctional beliefs scores. The SHS group had additional improvements in sleep onset latency and sleep quality. Benefits with self-help CBT-I were maintained at 12-week posttreatment, but attrition rate was about 35%. Internet-based self-help CBT-I was effective and acceptable for treating insomnia in the Chinese population. A brief telephone support further enhanced the efficacy. PMID- 25461791 TI - The influence of cognitive factors in the treatment of obesity: Lessons from the QUOVADIS study. AB - Weight-loss maintenance remains a problematic issue in lifestyle modification programmes, but a small percentage of individuals are able to maintain a significant long-term weight loss. This means cognitive mechanisms may effectively contrast the biological pressures to regain weight arising from an obesiogenic environment. Aims of this review were to summarizes and synthesizes the data on the cognitive factors associated with program attrition, weight loss and weight maintenance derived from the QUOVADIS (QUality of life in Obesity: eVAluation and DIsease Surveillance), an observational study on quality of life in 1944 obese patients seeking treatment in 25 medical centres in Italy, and discuss its results in light of other literature. The data obtained suggest that some cognitive factors are associated with treatment discontinuation (namely higher weight-loss expectations, appearance-based primary motivation for weight loss, and unsatisfactory progress), while others with the amount of weight lost (i.e., increased dietary restraint and reduced disinhibition) or with long-term weight loss maintenance in patients who interrupted the treatment (i.e., satisfaction with results achieved, confidence in being able to lose weight without professional help). All these findings have important clinical implications. PMID- 25461792 TI - A pilot randomized controlled trial of videoconference-assisted treatment for obsessive-compulsive disorder. AB - Evidence-based exposure and response prevention (ERP) treatment for obsessive compulsive disorder (OCD) is not always easily accessible. Long distances from specialist treatment and other practical or motivational difficulties can interfere with ERP access and outcome. Delivery of ERP through telepsychology can help "fill the gap". The current study included 30 patients with OCD who were randomized to 12 weeks of either videoconference-assisted ERP (VCT; N = 10), self help ERP (S-H, N = 10), or a wait-list condition (W-L, N = 10). The VCT format included use of tablet-based videoconferencing sessions (N = 6) or studio-based videoconference (N = 4), as well as telephone calls. Patients rated the VCT format as natural and reported strong working alliances with their therapists. VCT treatment produced significantly greater reductions in obsessive-compulsive symptoms compared to the two control conditions. Treatment outcomes were similar to that of regular face-to-face ERP and improvements in symptom scores remained stable at follow-up. The study indicated that ERP for OCD can be delivered efficiently with videoconferencing technology along with telephone calls. The use of such technology in psychological treatment is likely to become more common in the future and it holds promise as a method to make evidence-based treatment more accessible. PMID- 25461794 TI - Repetitive negative thinking as a transdiagnostic factor in depression and anxiety: A conceptual replication. AB - Comorbidity among affective disorders is high. Rumination has been found to mediate cross-sectional and prospective relations between anxiety and depressive symptoms in adolescents and adults. We examined whether rumination and worry, both forms of repetitive negative thinking, also explain the associations between affective disorders. This was studied using a prospective cohort study. In a mixed sample of 2981 adults (persons with a prior history of or a current affective disorder and healthy individuals) we assessed DSM-IV affective disorders (CIDI), rumination (LEIDS-R) and worry (PSWQ). All measures were repeated 2 years and 4 years later. Using structural equation models, we found that baseline rumination and worry partly mediated the association of baseline fear disorders (social anxiety disorder, panic disorder, agoraphobia) with distress disorders (dysthymia, major depressive disorder, generalized anxiety disorder). Moreover, baseline fear disorders predicted changes in distress disorders and changes in worry and rumination mediated these associations. The association between baseline distress disorders and changes in fear disorders was mediated by changes in rumination but not by changes in worry. From these results it can be concluded that repetitive negative thinking is an important transdiagnostic factor. Rumination and worry are partly responsible for the cross sectional and prospective co-occurrence of affective disorders and may be suitable targets for treatment. PMID- 25461793 TI - Work-related CBT versus vocational services as usual for unemployed persons with social anxiety disorder: A randomized controlled pilot trial. AB - We designed and pilot-tested a group-based, work-related cognitive-behavioral therapy (WCBT) for unemployed individuals with social anxiety disorder (SAD). WCBT, delivered in a vocational service setting by vocational service professionals, aims to reduce social anxiety and enable individuals to seek, obtain, and retain employment. We compared WCBT to a vocational services as usual control condition (VSAU). Participants were unemployed, homeless, largely African American, vocational service-seeking adults with SAD (N = 58), randomized to receive either eight sessions of WCBT plus VSAU or VSAU alone and followed three months post-treatment. Multilevel modeling revealed significantly greater reductions in social anxiety, general anxiety, depression, and functional impairment for WCBT compared to VSAU. Coefficients for job search activity and self-efficacy indicated greater increases for WCBT. Hours worked per week in the follow-up period did not differ between the groups, but small sample size and challenges associated with measuring work hours may have contributed to this finding. Overall, the results of this study suggest that unemployed persons with SAD can be effectively treated with specialized work-related CBT administered by vocational service professionals. Future testing of WCBT with a larger sample, a longer follow-up period, and adequate power to assess employment outcomes is warranted. PMID- 25461795 TI - An automated assay for the clinical measurement of plasma renin activity by immuno-MALDI (iMALDI). AB - Plasma renin activity (PRA) is essential for the screening and diagnosis of primary aldosteronism (PA), a form of secondary hypertension, which affects approximately 100 million people worldwide. It is commonly determined by radioimmunoassay (RIA) and, more recently, by relatively low-throughput LC-MS/MS methods. In order to circumvent the negative aspects of RIAs (radioisotopes, cross-reactivity) and the low throughput of LC-MS based methods, we have developed a high-throughput immuno-MALDI (iMALDI)-based assay for PRA determination using an Agilent Bravo for automated liquid handling and a Bruker Microflex LRF instrument for MALDI analysis, with the goal of implementing the assay in clinical laboratories. The current assay allows PRA determination of 29 patient samples (192 immuno-captures), within ~6 to 7h, using a 3-hour Ang I generation period, at a 7.5-fold faster analysis time than LC-MS/MS. The assay is performed on 350MUL of plasma, and has a linear range from 0.08 to 5.3ng/L/s in the reflector mode, and 0.04 to 5.3ng/L/s in the linear mode. The analytical precision is 2.0 to 9.7% CV in the reflector mode, and 1.5 to 14.3% CV in the linear mode. A method comparison to a clinically employed LC-MS/MS assay for PRA determination showed excellent correlation within the linear range, with an R(2) value of >=0.98. This automated high throughput iMALDI platform has clinically suitable sensitivity, precision, linear range, and correlation with the standard method for PRA determination. Furthermore, the developed workflow based on the iMALDI technology can be used for the determination of other proteomic biomarkers. This article is part of a Special Issue entitled: Medical Proteomics. PMID- 25461796 TI - New challenges in pseudopodial proteomics by a laser-assisted cell etching technique. AB - Pseudopodia are ventral membrane protrusions that extend toward higher concentrations of chemoattractants and play key roles in cell migration and cancer cell invasion. Cancers, including carcinoma and sarcoma, become life threatening when they invade surrounding structures and other organs. Understanding the molecular basis of invasiveness is important for the elimination of cancers. Thus, determining the pseudopodial composition will offer insights into the mechanisms underlying tumor cell invasiveness and provide potential biomarkers and therapeutic targets. Pseudopodial composition has been extensively investigated by using proteomic approaches. A variety of modalities, including gel-based and mass spectrometry-based methods, have been employed for pseudopodial proteomics. Our research group recently established a novel method using excimer laser pulses to selectively harvest pseudopodia, and we successfully identified a number of new pseudopodial constituents. Here, we summarized the conventional proteomic procedures and describe our new excimer laser-assisted method, with a special emphasis on the differences in the methods used to isolate pseudopodia. In addition, we discussed the theoretical background for the use of excimer laser-mediated cell ablation in proteomic applications. Using the excimer laser-assisted method, we showed that alpha-parvin, an actin binding adaptor protein, is localized to pseudopodia, and is involved in breast cancer invasiveness. Our results clearly indicate that excimer laser-assisted cell etching is a useful technique for pseudopodial proteomics. This article is part of a Special Issue entitled: Medical Proteomics. PMID- 25461797 TI - The lower limits for protein stability and foldability in primary hyperoxaluria type I. AB - Mutational effects on protein stability and foldability are important to understand conformational diseases and protein evolution. In this work, we perform a comprehensive investigation on the energetic basis underlying mutational effects on the stability of human alanine:glyoxylate aminotransferase (AGT). We study twenty two variants whose kinetic stabilities span over eleven orders of magnitude and are classified into two groups: i) ten naturally occurring variants, including the most common mutations causing primary hyperoxaluria type I (PH1); and ii) twelve consensus variants obtained by sequence-alignment statistics. We show that AGT dimer stability determines denaturation rates, and mutations modulate stability by changes in the effective thermodynamic stability, the aggregation propensity of partially/globally unfolded states and subtle energetic changes in the rate-limiting denaturation step. In combination with our previous expression analyses in eukaryotic cells, we propose the existence of two lower limits for AGT stability, one linked to optimal folding efficiency (close to the major allele stability) and the other setting a minimal efficiency compatible with glyoxylate detoxification in vivo (close to the minor allele stability). These lower limits could explain the high prevalence of misfolding as a disease mechanism in PH1 and support the use of pharmacological ligands aimed to increase AGT stability as therapies for this disease. PMID- 25461798 TI - Interaction of arginine with protein during refolding process probed by amide H/D exchange mass spectrometry and isothermal titration calorimetry. AB - Arginine has been widely used as low molecular weight additive to promote protein refolding by suppressing aggregate formation. However, methods to investigate the role of arginine in protein refolding are often limited on protein's global conformational properties. Here, hydrogen/deuterium exchange mass spectrometry (HDX-MS) was used to study the effects of arginine on recombinant human granulocyte colony-stimulating factor (rhG-CSF) refolding at the scale of peptide mapping. It was found that deuteration levels of rhG-CSF refolded with arginine was higher than that without arginine during the whole refolding process, but they became almost the same when the refolding reached equilibrium. This phenomenon indicated that arginine could protect some amide deuterium atoms from being exchanged with hydrogen, but the protection diminished gradually along with refolding proceeding. Enzymatic digestion revealed six particular peptides of 16 47, 72-84, 84-93, 114-124, 145-153 and 154-162 were mainly responsible for the deuteration, and all of them dominantly located in protein's alpha-helix domain. Furthermore, thermodynamics analysis by isothermal titration calorimetry provided direct evidence that arginine could only react with denatured and partially refolded rhG-CSF. Taking all of the results together, we suggest that arginine suppresses protein aggregation by a reversible combination. At the initial refolding stage, arginine could combine with the denatured protein mainly through hydrogen bonding. Subsequently, arginine is gradually excluded from protein with protein's native conformation recovering. PMID- 25461799 TI - Pentavalent outer membrane vesicles of Vibrio cholerae induce adaptive immune response and protective efficacy in both adult and passive suckling mice models. AB - Recently, we demonstrated oral immunizations with single serotype outer membrane vesicles of Vibrio cholerae induced serogroup specific protective immunity in the RITARD model. In our present study, we advanced our research by formulating multi serotype outer membrane vesicles, mixing the OMVs of five virulent V. cholerae strains. Four doses of oral immunization with cholera pentavalent outer membrane vesicles (CPMVs) induced V. cholerae specific B and T cell responses. CPMVs immunized mice generated long lasting serum IgG, IgA, IgM as well as mucosal sIgA and also elicited a higher percentage of CD4+ T cell distribution in spleen. Our study revealed that in vitro CPMVs-activated dendritic cells were secreting T cell polarizing cytokines, IL-12p40, IL-4, IL-6 and IL-1beta. Moreover, purified splenic CD4+ T cells of immunized mice also secreted IL-4, IL-13 and IL-17 cytokines, indicating the initiation of Th2 and Th17 cell mediated immune responses. CPMVs immunized adult female mice and their offspring were significantly protected from heterologous challenge with wild type V. cholerae. CPMVs could be exploited for the development of a novel non-living vaccine against circulating cholera in near future. PMID- 25461800 TI - ChpK and MazF of the toxin-antitoxin modules are involved in the virulence of Leptospira interrogans during infection. AB - Pathogenic Leptospira species are the causative agents of leptospirosis, a global zoonotic infectious disease. Toxin-antitoxin (TA) modules have been confirmed as stress-response elements that induce prokaryotic and eukaryotic cell-growth arrest or death, but their role in the virulence of Leptospira has not been reported. Here, we confirmed that all the tested leptospiral strains had the chpIK and mazEF TA modules with highly-conserved sequences. The transcription and expression of the chpI, chpK, mazE, and mazF genes of Leptospira interrogans strain Lai were significantly increased during infection of phorbol 12-myristate 13-acetate-induced human THP-1 macrophages. The toxic ChpK and MazF but not the antitoxic ChpI and MazE proteins were detectable in the cytoplasmic fraction of leptospire-infected THP-1 cells, indicating the external secretion of ChpK and MazF during infection. Transfection of the chpK or mazF gene caused decreased viability and necrosis in THP-1 cells, whereas the chpI or mazE gene transfection did not affect the viability of THP-1 cells but blocked the ChpK or MazF-induced toxicity. Deletion of the chpK or mazF gene also decreased the late-apoptotic and/or necrotic ratios of THP-1 cells at the late stages of infection. The recombinant protein MazF (rMazF) cleaved the RNAs but not the DNAs from Leptospira and THP-1 cells, and this RNA cleavage was blocked by rMazE. However, the rChpK had no RNA or DNA-degrading activity. All these findings indicate that the ChpK and MazF proteins in TA modules are involved in the virulence of L. interrogans during infection. PMID- 25461801 TI - Serum sCD26 for colorectal cancer screening in family-risk individuals: comparison with faecal immunochemical test. AB - BACKGROUND: The development of specific screening programs for individuals with a family history of colorectal cancer (CRC) is a priority. This study evaluates the diagnostic performance of serum soluble CD26 (sCD26) in family-risk individuals and compares this marker with the faecal immunochemical test for the detection of advanced neoplasia (AN) (CRC or advanced adenomas; AA). METHODS: Five hundred and sixteen asymptomatic individuals with at least one first-degree relative with CRC were included. Serum sCD26 was measured in all the individuals who also underwent a colonoscopy (53 AA and four cancer cases were found) and a faecal immunochemical test. RESULTS: Setting specificity to 90% and 95%, respectively, sCD26 showed a sensitivity of 39.6% and 28.3% for AA, and of 42.1% and 28.1% for AN. The combination of sCD26 and the faecal test detected AA and AN with a 52.8% and 56.1% sensitivity, corresponding to 93.5% specificity. CONCLUSIONS: The combination of serum sCD26 and the faecal blood test could result a valuable strategy for detecting AN in familial-risk CRC screening. PMID- 25461802 TI - Symptom lead times in lung and colorectal cancers: what are the benefits of symptom-based approaches to early diagnosis? AB - BACKGROUND: Individuals with undiagnosed lung and colorectal cancers present with non-specific symptoms in primary care more often than matched controls. Increased access to diagnostic services for patients with symptoms generates more early stage diagnoses, but the mechanisms for this are only partially understood. METHODS: We re-analysed a UK-based case-control study to estimate the Symptom Lead Time (SLT) distribution for a range of potential symptom criteria for investigation. Symptom Lead Time is the time between symptoms caused by cancer and eventual diagnosis, and is analogous to Lead Time in a screening programme. We also estimated the proportion of symptoms in lung and colorectal cancer cases that are actually caused by the cancer. RESULTS: Mean Symptom Lead Times were between 4.1 and 6.0 months, with medians between 2.0 and 3.2 months. Symptom Lead Time did not depend on stage at diagnosis, nor which criteria for investigation are adopted. Depending on the criteria, an estimated 27-48% of symptoms in individuals with as yet undiagnosed lung cancer, and 12-32% with undiagnosed colorectal cancer are not caused by the cancer. CONCLUSIONS: In most cancer cases detected by a symptom-based programme, the symptoms are caused by cancer. These cases have a short lead time and benefit relatively little. However, in a significant minority of cases cancer detection is serendipitous. This group experiences the benefits of a standard screening programme, a substantial mean lead time and a higher probability of early-stage diagnosis. PMID- 25461803 TI - The tumour hypoxia marker pimonidazole reflects a transcriptional programme associated with aggressive prostate cancer. AB - BACKGROUND: The hypoxia marker pimonidazole is a candidate biomarker of cancer aggressiveness. We investigated the transcriptional programme associated with pimonidazole staining in prostate cancer. METHODS: Index tumour biopsies were taken by image guidance from an investigation cohort of 52 patients, where 43 patients received pimonidazole before prostatectomy. Biopsy location within the index tumour was verified for 46 (88%) patients, who were included for gene expression profiling and immunohistochemistry. Two independent cohorts of 59 and 281 patients were used for validation. RESULTS: Expression of genes in proliferation, DNA repair and hypoxia response was a major part of the transcriptional programme associated with pimonidazole staining. A signature of 32 essential genes was constructed and showed positive correlation to Ki67 staining, confirming the increased proliferation in hypoxic tumours as suggested from the gene data. Positive correlations were also found to tumour stage and lymph node status, but not to blood prostate-specific antigen level, consistent with the findings for pimonidazole staining. The association with aggressiveness was confirmed in validation cohorts, where the signature correlated with Gleason score and had independent prognostic impact, respectively. CONCLUSIONS: Pimonidazole staining reflects an aggressive hypoxic phenotype of prostate cancer characterised by upregulation of proliferation, DNA repair and hypoxia response genes. PMID- 25461805 TI - An evaluation of the impact of large-scale interventions to raise public awareness of a lung cancer symptom. AB - INTRODUCTION: Long-term lung cancer survival in England has improved little in recent years and is worse than many countries. The Department of Health funded a campaign to raise public awareness of persistent cough as a lung cancer symptom and encourage people with the symptom to visit their GP. This was piloted regionally within England before a nationwide rollout. METHODS: To evaluate the campaign's impact, data were analysed for various metrics covering public awareness of symptoms and process measures, through to diagnosis, staging, treatment and 1-year survival (available for regional pilot only). RESULTS: Compared with the same time in the previous year, there were significant increases in metrics including: public awareness of persistent cough as a lung cancer symptom; urgent GP referrals for suspected lung cancer; and lung cancers diagnosed. Most encouragingly, there was a 3.1 percentage point increase (P<0.001) in proportion of non-small cell lung cancer diagnosed at stage I and a 2.3 percentage point increase (P<0.001) in resections for patients seen during the national campaign, with no evidence these proportions changed during the control period (P=0.404, 0.425). CONCLUSIONS: To our knowledge, the data are the first to suggest a shift in stage distribution following an awareness campaign for lung cancer. It is possible a sustained increase in resections may lead to improved long-term survival. PMID- 25461804 TI - Pharmacokinetics of concomitant cisplatin and paclitaxel administered by hyperthermic intraperitoneal chemotherapy to patients with peritoneal carcinomatosis from epithelial ovarian cancer. AB - BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) is advised as a treatment option for epithelial ovarian cancer (EOC) with peritoneal carcinomatosis. This study was designed to define the pharmacokinetics of cisplatin (CDDP) and paclitaxel (PTX) administered together during HIPEC. METHODS: Thirteen women with EOC underwent cytoreductive surgery (CRS) and HIPEC, with CDDP and PTX. Blood, peritoneal perfusate and tissue samples were harvested to determine drug exposure by high-performance liquid chromatography and matrix assisted laser desorption ionization imaging mass spectrometry (IMS). RESULTS: The mean maximum concentrations of CDDP and PTX in perfusate were, respectively, 24.8+/-10.4 MUg ml(-1) and 69.8+/-14.3 MUg ml(-1); in plasma were 1.87+/-0.4 MUg ml(-1) and 0.055+/-0.009 MUg ml(-1). The mean concentrations of CDDP and PTX in peritoneum at the end of HIPEC were 23.3+/-8.0 MUg g(-1) and 30.1+/-18.3 MUg( 1)g(-1), respectively. The penetration of PTX into the peritoneal wall, determined by IMS, was about 0.5 mm. Grade 3-4 surgical complications were recorded in four patients, five patients presented grade 3 and two patients presented grade 4 hematological complications. CONCLUSIONS: HIPEC with CDDP and PTX after CRS is feasible with acceptable morbidity and has a favorable pharmacokinetic profile: high drug concentrations are achieved in peritoneal tissue with low systemic exposure. Larger studies are needed to demonstrate its efficacy in patients with microscopic postsurgical residual tumours in the peritoneal cavity. PMID- 25461806 TI - Combination of letrozole, metronomic cyclophosphamide and sorafenib is well tolerated and shows activity in patients with primary breast cancer. AB - PURPOSE: To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC). METHODS: Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers. RESULTS: Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by (18)FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively). CONCLUSIONS: The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active. PMID- 25461808 TI - Contrasting stress responses of two co-occurring chipmunk species (Tamias alpinus and T. speciosus). AB - Glucocorticoid (GC) hormones are important mediators of responses to environmental conditions. Accordingly, differences in GC physiology may contribute to interspecific variation in response to anthropogenically-induced patterns of climate change. To begin exploring this possibility, we validated the use of fecal cortisol/corticosterone metabolites (FCM) to measure baseline glucocorticoid levels in two species of co-occurring chipmunks that have exhibited markedly different patterns of response to environmental change. In Yosemite National Park, the alpine chipmunk (Tamias alpinus) has undergone a significant upward contraction of its elevational range over the past century; in contrast, the lodgepole chipmunk (Tamiasspeciosus) has experienced no significant change in elevational distribution over this period. To determine if GC levels in these species vary in response to external stimuli and to assess whether these responses differ between species, we compared FCM levels for the same individuals (1) at the time of capture in the field, (2) after a short period of captivity, and (3) after adrenocorticotropic hormone (ACTH), (4) handling, and (5) trapping challenges conducted while these animals were held in captivity. Our analyses indicate that T. alpinus was more responsive to several of these changes in external conditions. Although both species displayed a significant FCM response to ACTH challenge, only T. alpinus showed a significant response to our handling challenge and to captive housing conditions. These findings underscore the importance of species-specific validation studies and support the potential for studies of GC physiology to generate insights into interspecific differences in response to environmental change. PMID- 25461807 TI - BCAS2 promotes prostate cancer cells proliferation by enhancing AR mRNA transcription and protein stability. AB - BACKGROUND: We showed previously that breast carcinoma amplified sequence 2 (BCAS2) functions as a negative regulator of p53. We also found that BCAS2 is a potential AR-associated protein. AR is essential for the growth and survival of prostate carcinoma. Therefore we characterised the correlation between BCAS2 and AR. METHODS: Protein interactions were examined by GST pull-down assay and co immunoprecipitation. Clinical prostate cancer (PCa) specimens were evaluated by immunohistochemical assay. AR transcriptional activity and LNCaP cell growth were assessed by luciferase assay and MTT assay, respectively. RESULTS: BCAS2 expression was significantly increased in PCa. BCAS2 stabilised AR protein through both hormone-dependent and -independent manners. There are at least two mechanisms for BCAS2-mediated AR protein upregulation: One is p53-dependent. The p53 is suppressed by BCAS2 that results in increasing AR mRNA and protein expression. The other is via p53-independent inhibition of proteasome degradation. As BCAS2 can form a complex with AR and HSP90, it may function with HSP90 to stabilise AR protein from being degraded by proteasome. CONCLUSIONS: In this study, we show that BCAS2 is a novel AR-interacting protein and characterise the correlation between BCAS2 and PCa. Thus we propose that BCAS2 could be a diagnostic marker and therapeutic target for PCa. PMID- 25461809 TI - Assaying PTEN catalysis in vitro. AB - PTEN is a major tumour suppressor protein and a regulator of numerous diverse biological processes. It has an evolutionarily conserved role as a phosphoinositide lipid phosphatase, regulating the PI3K signalling pathway, but also has catalytic phosphatase activity against protein substrates, although the significance of this latter activity is less well understood. Unlike many tumour suppressors, even modest changes in PTEN activity can have strong effects on phenotypes, including tumour formation. Due to this recognised functional significance, several experimental platforms have been developed to assay the catalytic activity of PTEN against different substrates and are being applied to understand this cellular substrate diversity and the regulation of PTEN. Here we present and discuss methods to assay the phosphatase activity of PTEN in vitro. PMID- 25461810 TI - In vitro systems for Atg8 lipidation. AB - Macroautophagy is a major bulk degradation pathway for cytoplasmic material in eukaryotic cells. During macroautophagy, double membrane-bound organelles called autophagosomes are formed in a de novo manner. In the course of their formation autophagosomes capture cytoplasmic material, which is subsequently degraded upon fusion with the lysosomal system in complex eukaryotes or the vacuole in yeast. Several proteins are required for autophagosome formation. Among these are the components of two ubiquitin-like conjugation reactions that collectively mediate the conjugation of the ubiquitin-like Atg12 to the Atg5 protein and of the ubiquitin-like protein Atg8 to the headgroup of the membrane lipid phosphatidylethanolamine. The lipidated form of Atg8 is membrane-bound and marks the growing autophagosomal membrane as well as the completed autophagosome. Here we describe assays for the in vitro reconstitution of the Atg8 lipidation reaction using recombinantly expressed and purified proteins derived from Saccharomycescerevisiae in combination with small and giant unilamellar vesicles. The assays enable the study of the biochemical mechanisms of action of the Atg8 lipidation machinery and to analyze the impact of mutations and post translational modifications of the conjugation machinery on Atg8 lipidation. PMID- 25461811 TI - Methods to analyze SNARE-dependent vesicular fusion events that regulate autophagosome biogenesis. AB - Autophagy is an important catabolic pathway that preserves cellular homeostasis. The formation of autophagosomes is a complex process requiring the reorganization of membranes from different compartments. Here we describe methods to analyze SNARE-dependent vesicular fusion events involving the homotypic and heterotypic fusion of autophagosome precursor structures. These two steps are essential for the maturation of small single-membrane autophagic precursors containing ATG16L1 and mATG9 proteins into double-membrane autophagosomes. The techniques described in this review are mostly based on live cell imaging, microscopy, and biochemistry using an in vitro fusion assay, and should help researchers to study autophagosome biogenesis. PMID- 25461812 TI - Aggregator: a machine learning approach to identifying MEDLINE articles that derive from the same underlying clinical trial. AB - OBJECTIVE: It is important to identify separate publications that report outcomes from the same underlying clinical trial, in order to avoid over-counting these as independent pieces of evidence. METHODS: We created positive and negative training sets (comprised of pairs of articles reporting on the same condition and intervention) that were, or were not, linked to the same clinicaltrials.gov trial registry number. Features were extracted from MEDLINE and PubMed metadata; pairwise similarity scores were modeled using logistic regression. RESULTS: Article pairs from the same trial were identified with high accuracy (F1 score=0.843). We also created a clustering tool, Aggregator, that takes as input a PubMed user query for RCTs on a given topic, and returns article clusters predicted to arise from the same clinical trial. DISCUSSION: Although painstaking examination of full-text may be needed to be conclusive, metadata are surprisingly accurate in predicting when two articles derive from the same underlying clinical trial. PMID- 25461813 TI - Single-experiment displacement assay for quantifying high-affinity binding by isothermal titration calorimetry. AB - Isothermal titration calorimetry (ITC) is the gold standard for dissecting the thermodynamics of a biomolecular binding process within a single experiment. However, reliable determination of the dissociation constant (KD) from a single titration is typically limited to the range 100 MUM>KD>1 nM. Interactions characterized by a lower KD can be assessed indirectly by so-called competition or displacement assays, provided that a suitable competitive ligand is available whose KD falls within the directly accessible window. However, this protocol is limited by the fact that it necessitates at least two titrations to characterize one high-affinity inhibitor, resulting in considerable consumption of both sample material and time. Here, we introduce a fast and efficient ITC displacement assay that allows for the simultaneous characterization of both a high-affinity ligand and a moderate-affinity ligand competing for the same binding site on a receptor within a single experiment. The protocol is based on a titration of the high affinity ligand into a solution containing the moderate-affinity ligand bound to the receptor present in excess. The resulting biphasic binding isotherm enables accurate and precise determination of KD values and binding enthalpies (DeltaH) of both ligands. We discuss the theoretical background underlying the approach, demonstrate its practical application to metal ion chelation, explore its potential and limitations with the aid of simulations and statistical analyses, and elaborate on potential applications to protein-inhibitor interactions. PMID- 25461814 TI - What does calorimetry and thermodynamics of living cells tell us? AB - This article presents and compares several thermodynamic methods for the quantitative interpretation of data from calorimetric measurements. Heat generation and absorption are universal features of microbial growth and product formation as well as of cell cultures from animals, plants and insects. The heat production rate reflects metabolic changes in real time and is measurable on line. The detection limit of commercially available calorimetric instruments can be low enough to measure the heat of 100,000 aerobically growing bacteria or of 100 myocardial cells. Heat can be monitored in reaction vessels ranging from a few nanoliters up to many cubic meters. Most important the heat flux measurement does not interfere with the biological process under investigation. The practical advantages of calorimetry include the waiver of labeling and reactants. It is further possible to assemble the thermal transducer in a protected way that reduces aging and thereby signal drifts. Calorimetry works with optically opaque solutions. All of these advantages make calorimetry an interesting method for many applications in medicine, environmental sciences, ecology, biochemistry and biotechnology, just to mention a few. However, in many cases the heat signal is merely used to monitor biological processes but only rarely to quantitatively interpret the data. Therefore, a significant proportion of the information potential of calorimetry remains unutilized. To fill this information gap and to motivate the reader using the full information potential of calorimetry, various methods for quantitative data interpretations are presented, evaluated and compared with each other. Possible errors of interpretation and limitations of quantitative data analysis are also discussed. PMID- 25461815 TI - Pten function in zebrafish: anything but a fish story. AB - Zebrafish is an excellent model system for the analysis of gene function. We and others use zebrafish to investigate the function of the tumor suppressor, Pten, in tumorigenesis and embryonic development. Zebrafish have two pten genes, ptena and ptenb. The recently identified N-terminal extension of human PTEN that may facilitate cell membrane transfer, appears not to be conserved in zebrafish Ptena or Ptenb. Mutants that retain a single wild type pten allele develop tumors, predominantly hemangiosarcomas. Homozygous double mutants are embryonic lethal. Zebrafish embryos lacking functional Pten display enhanced proliferation of endothelial cells, resulting in hyperbranching of blood vessels. In addition, ptena-/-ptenb-/- mutant embryos display enhanced proliferation of hematopoietic stem and progenitor cells and concomitant arrest of differentiation, although Pten-deficient cells commit to all blood cell lineages. Zebrafish is an ideal model for intravital imaging and future work using ptena-/-ptenb-/- mutants will enhance our understanding of the function of Pten in vivo. PMID- 25461816 TI - Modeling glands with PTEN deficient cells and microscopic methods for assessing PTEN loss: endometrial cancer as a model. AB - PTEN is an important tumor suppressor gene. Interpreting PTEN deficiency in the appropriate microscopic context of cancer may be important to understand its role in tumor development and progression. This may be particularly relevant in heterogeneous tumors. Here, we discuss the usefulness of 3D cultures in understanding the consequences of PTEN inactivation in tissue architecture. Afterwards, we discuss the role of immunohistochemistry and fluorescent in situ hybridization in assessing PTEN loss in tumors. In this review, endometrial carcinoma is used as a model. PMID- 25461817 TI - Probe Lasso: a novel method to rope in differentially methylated regions with 450K DNA methylation data. AB - The speed and resolution at which we can scour the genome for DNA methylation changes has improved immeasurably in the last 10years and the advent of the Illumina 450K BeadChip has made epigenome-wide association studies (EWAS) a reality. The resulting datasets are conveniently formatted to allow easy alignment of significant hits to genes and genetic features, however; methods that parse significant hits into discreet differentially methylated regions (DMRs) remain a challenge to implement. In this paper we present details of a novel DMR caller, the Probe Lasso: a flexible window based approach that gathers neighbouring significant-signals to define clear DMR boundaries for subsequent in depth analysis. The method is implemented in the R package ChAMP (Morris et al., 2014) and returns sets of DMRs according to user-tuned levels of probe filtering (e.g., inclusion of sex chromosomes, polymorphisms) and probe-lasso size distribution. Using a sub-sample of colon cancer- and healthy colon-samples from TCGA we show that Probe Lasso shifts DMR calling away from just probe-dense regions, and calls a range of DMR sizes ranging from tens-of-bases to tens-of kilobases in scale. Moreover, using TCGA data we show that Probe Lasso leverages more information from the array and highlights a potential role of hypomethylated transcription factor binding motifs not discoverable using a basic, fixed-window approach. PMID- 25461818 TI - Identifying autism from neural representations of social interactions: neurocognitive markers of autism. AB - Autism is a psychiatric/neurological condition in which alterations in social interaction (among other symptoms) are diagnosed by behavioral psychiatric methods. The main goal of this study was to determine how the neural representations and meanings of social concepts (such as to insult) are altered in autism. A second goal was to determine whether these alterations can serve as neurocognitive markers of autism. The approach is based on previous advances in fMRI analysis methods that permit (a) the identification of a concept, such as the thought of a physical object, from its fMRI pattern, and (b) the ability to assess the semantic content of a concept from its fMRI pattern. These factor analysis and machine learning methods were applied to the fMRI activation patterns of 17 adults with high-functioning autism and matched controls, scanned while thinking about 16 social interactions. One prominent neural representation factor that emerged (manifested mainly in posterior midline regions) was related to self-representation, but this factor was present only for the control participants, and was near-absent in the autism group. Moreover, machine learning algorithms classified individuals as autistic or control with 97% accuracy from their fMRI neurocognitive markers. The findings suggest that psychiatric alterations of thought can begin to be biologically understood by assessing the form and content of the altered thought's underlying brain activation patterns. PMID- 25461819 TI - Accuracy of self-reported length of coma and posttraumatic amnesia in persons with medically verified traumatic brain injury. AB - OBJECTIVE: To determine the accuracy of self-reported length of coma and posttraumatic amnesia (PTA) in persons with medically verified traumatic brain injury (TBI) and to investigate factors that affect self-report of length of coma and PTA duration. DESIGN: Prospective cohort study. SETTING: Specialized rehabilitation center with inpatient and outpatient programs. PARTICIPANTS: Persons (N=242) with medically verified TBI who were identified from a registry of persons who had previously participated in TBI-related research. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Self-reported length of coma and self reported PTA duration. RESULTS: Review of medical records revealed that the mean medically documented length of coma and PTA duration was 6.9+/-12 and 19.2+/-22 days, respectively, and the mean self-reported length of coma and PTA duration was 16.7+/-22 and 106+/-194 days, respectively. The average discrepancy between self-report and medical record for length of coma and PTA duration was 8.2+/-21 and 64+/-176 days, respectively. Multivariable regression models revealed that time since injury, performance on cognitive tests, and medical record values were associated with self-reported values for both length of coma and PTA duration. CONCLUSIONS: In this investigation, persons with medically verified TBI showed poor accuracy in their self-report of length of coma and PTA duration. Discrepancies were large enough to affect injury severity classification. Caution should be exercised when considering self-report of length of coma and PTA duration. PMID- 25461820 TI - Cortical activation during visual illusory walking in persons with spinal cord injury: a pilot study. AB - OBJECTIVE: To determine the location of cortical activation during a visual illusion walking paradigm, a recently proposed treatment for spinal cord injury (SCI)-related neuropathic pain, in persons with SCI compared with able-bodied controls. DESIGN: Pilot experimental functional magnetic resonance imaging (fMRI) trial. SETTING: Outpatient rehabilitation clinic. PARTICIPANTS: Persons with paraplegia (n=3) and able-bodied participants (n=5) were included in this study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Cortical activation as measured by the blood oxygenation level-dependent method of fMRI. RESULTS: During visually illusory walking there was significant activation in the somatosensory cortex among those with SCI. In contrast, able-bodied participants showed little to no significant activation in this area, but they showed activation in the frontal and premotor areas. CONCLUSIONS: Treatment modalities for SCI-related neuropathic pain that are based on sensory input paradigms (eg, virtual walking, visual illusory walking) may work by targeting the somatosensory cortex, an area that has been previously found to functionally reorganize after SCI. PMID- 25461821 TI - Elevated circulating levels of the pro-inflammatory cytokine macrophage migration inhibitory factor in individuals with acute spinal cord injury. AB - OBJECTIVE: To test the hypothesis that macrophage migration inhibitory factor (MIF) is elevated in the circulation of individuals with acute spinal cord injury (SCI) compared with uninjured individuals. DESIGN: Prospective, observational pilot study. SETTING: Academic medical center. PARTICIPANTS: Adults with acute traumatic SCI (n=18) and uninjured participants (n=18), comparable in age and sex distribution. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary outcome measure was the plasma MIF levels. Potential correlations were examined between MIF and clinical/demographic variables. The secondary outcome was to determine if other immune mediators were elevated in participants with acute SCI and if their levels correlated with the MIF. RESULTS: MIF was significantly elevated in subjects with acute SCI compared with control subjects at 0 to 3 (P<.0029), 4 to 7 (P<.0001), and 8 to 11 (P<.0015) days postinjury (DPI). At 0 to 3 DPI, levels of cytokines interleukin-6 (P<.00017), interleukin-9 (P<.0047), interleukin-16 (P<.007), interleukin-18 (P<.014), chemokines growth-related oncogene alpha/chemokine (C-X-C motif) ligand 1 (P<.0127) and macrophage inflammatory protein 1-beta/chemokine (C-C motif) ligand 4 (P<.0015), and growth factors hepatocyte growth factor (HGF) (P<.0001) and stem cell growth factor-beta (P<.0103) were also significantly elevated in subjects with acute SCI. With the exception of interleukin-9, all of these factors remained significantly elevated at 4 to 7 DPI; a subset (interleukin-16, HGF, stem cell growth factor-beta) remained elevated throughout the study. Within individuals, MIF levels correlated with HGF (P<.018) and interleukin-16 (P<.01). CONCLUSIONS: These data demonstrate that MIF is significantly elevated in subjects with acute SCI, supporting further investigation of MIF and other inflammatory mediators in acute SCI, where they may contribute to primary and secondary functional outcomes. PMID- 25461822 TI - Comparison of robotics, functional electrical stimulation, and motor learning methods for treatment of persistent upper extremity dysfunction after stroke: a randomized controlled trial. AB - OBJECTIVE: To compare response to upper-limb treatment using robotics plus motor learning (ML) versus functional electrical stimulation (FES) plus ML versus ML alone, according to a measure of complex functional everyday tasks for chronic, severely impaired stroke survivors. DESIGN: Single-blind, randomized trial. SETTING: Medical center. PARTICIPANTS: Enrolled subjects (N=39) were >1 year postsingle stroke (attrition rate=10%; 35 completed the study). INTERVENTIONS: All groups received treatment 5d/wk for 5h/d (60 sessions), with unique treatment as follows: ML alone (n=11) (5h/d partial- and whole-task practice of complex functional tasks), robotics plus ML (n=12) (3.5h/d of ML and 1.5h/d of shoulder/elbow robotics), and FES plus ML (n=12) (3.5h/d of ML and 1.5h/d of FES wrist/hand coordination training). MAIN OUTCOME MEASURES: Primary measure: Arm Motor Ability Test (AMAT), with 13 complex functional tasks; secondary measure: upper-limb Fugl-Meyer coordination scale (FM). RESULTS: There was no significant difference found in treatment response across groups (AMAT: P>=.584; FM coordination: P>=.590). All 3 treatment groups demonstrated clinically and statistically significant improvement in response to treatment (AMAT and FM coordination: P<=.009). A group treatment paradigm of 1:3 (therapist/patient) ratio proved feasible for provision of the intensive treatment. No adverse effects. CONCLUSIONS: Severely impaired stroke survivors with persistent (>1y) upper-extremity dysfunction can make clinically and statistically significant gains in coordination and functional task performance in response to robotics plus ML, FES plus ML, and ML alone in an intensive and long-duration intervention; no group differences were found. Additional studies are warranted to determine the effectiveness of these methods in the clinical setting. PMID- 25461823 TI - Rasch analyses of the wheelchair use confidence scale. AB - OBJECTIVES: To compare the functioning of the 101-point response format of the Wheelchair Use Confidence Scale (WheelCon) with shortened 11-point formats, and to evaluate the scale's measurement properties using principal components and Rasch analyses. DESIGN: Secondary analysis of cross-sectional data. SETTING: Community. PARTICIPANTS: Volunteer participants were manual wheelchair users (N=220) >=19 years of age, with >=6 months' experience with daily wheelchair use and no cognitive impairment. INTERVENTIONS: None. MAIN OUTCOME MEASURE: 65-item WheelCon. RESULTS: The 11-point response format outperformed the original 101 point format. Principal component analyses confirmed the presence of 2 dimensions: mobility efficacy and self-management efficacy. Thirteen items in the mobility efficacy subscale and 8 items in the self-management efficacy subscale fit the Rasch Rating Scale model. Five items misfit the model developed using the 21 items from both subscales. In each of the 13- and 8-item subscales, and the 21 item short form, the 2 lowest and highest scores had internal consistency reliability estimates <.70; all other scores had reliability estimates >.70. CONCLUSIONS: The WheelCon is composed of 2 dimensions. The recoded measurements using a 0-to-10 response scale from the 13-item mobility and 8-item self management efficacy subscales have good reliability, as do the measurements from the 21-item WheelCon Short Form. The use of the subscales, the short form, or both, depends on the context in which they are being considered. Research to establish the reliability and validity of the measurements using the 0-to-10 response format is warranted. PMID- 25461824 TI - Parallel walk test: its correlation with balance and motor functions in people with chronic stroke. AB - OBJECTIVES: To investigate (1) the intrarater, interrater, and test-retest reliability of the times and scores generated in the parallel walk test (PWT); (2) their correlations with impairments and activity limitations of individuals with stroke; and (3) the cutoff times that best discriminate individuals with stroke from healthy elderly subjects. DESIGN: Cross sectional study. SETTING: University-based rehabilitation center. PARTICIPANTS: Participants (N=72) comprised individuals with stroke (n=37) and healthy individuals (n=35). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The PWT was administered along with the Fugl-Meyer Motor Assessment of the Lower Extremities (FMA-LE), handheld dynamometer measurements of ankle dorsiflexor and plantarflexor muscle strength, the 5-Times-Sit-to-Stand Test, the Berg Balance Scale (BBS), a limits of stability (LOS) test, the 10-m walk test (10-MWT), and the timed Up and Go (TUG) test. RESULTS: PWT times and scores showed good to excellent intrarater, interrater, and test-retest reliability in individuals with stroke. PWT times using paths of 3 different widths significantly correlated with FMA-LE scores, 5 Times-Sit-to-Stand Test times, BBS scores, some LOS test results, 10-MWT gait speed, and TUG test times. PWT times of 6.30 to 7.48 seconds, depending on the path width, were shown reliably to discriminate individuals with stroke from healthy individuals. CONCLUSION: The PWT is a reliable, easy-to-administer clinical tool for assessing dynamic walking balance in individuals with chronic stroke. PMID- 25461826 TI - Increased spasticity from a fracture in the baclofen catheter caused by Charcot spine: case report. AB - In patients with Charcot spine, a loss of normal feedback response from the insensate spine results in spinal neuropathy. Increasing deformity, which can manifest as sitting imbalance, crepitus, or increased back pain, can result. We present the case of a patient with a high-thoracic spinal cord injury (SCI) who subsequently developed a Charcot joint at the T10-11 level that resulted in a dramatic increase in previously controlled spasticity after fracture of an existing baclofen catheter. The 68-year-old man with T4 paraplegia presented with increasing baclofen requirements and radiographic evidence of fracture of the intrathecal baclofen catheter with an associated Charcot joint with extensive bony destruction. The neuropathic spinal arthropathy caused mechanical baclofen catheter malfunction and resulting increased spasticity. The patient was found to have transected both his spinal cord and the baclofen catheter. Treatment consisted of removal of the catheter and stabilization with long-segment instrumentation and fusion from T6 to L2. Follow-up radiographs obtained a year and a half after surgery showed no evidence of hardware failure or significant malalignment. The patient has experienced resolution of symptoms and does not require oral or intrathecal baclofen. This is the only reported case of a Charcot spine causing intrathecal catheter fracture, leading to increased spasticity. This noteworthy case suggests that late spinal instability should be considered in the setting of SCI and increased spasticity. PMID- 25461825 TI - Intensity dependent effects of transcranial direct current stimulation on corticospinal excitability in chronic spinal cord injury. AB - OBJECTIVE: To investigate the effects of anodal transcranial direct current stimulation (a-tDCS) intensity on corticospinal excitability and affected muscle activation in individuals with chronic spinal cord injury (SCI). DESIGN: Single blind, randomized, sham-controlled, crossover study. SETTING: Medical research institute and rehabilitation hospital. PARTICIPANTS: Volunteers (N = 9) with chronic SCI and motor dysfunction in wrist extensor muscles. INTERVENTIONS: Three single session exposures to 20 minutes of a-tDCS (anode over the extensor carpi radialis [ECR] muscle representation on the left primary motor cortex, cathode over the right supraorbital area) using 1 mA, 2 mA, or sham stimulation, delivered at rest, with at least 1 week between sessions. MAIN OUTCOME MEASURES: Corticospinal excitability was assessed with motor-evoked potentials (MEPs) from the ECR muscle using surface electromyography after transcranial magnetic stimulation. Changes in spinal excitability, sensory threshold, and muscle strength were also investigated. RESULTS: Mean MEP amplitude significantly increased by approximately 40% immediately after 2mA a-tDCS (pre: 0.36 +/- 0.1 mV; post: 0.47 +/- 0.11 mV; P = .001), but not with 1 mA or sham. Maximal voluntary contraction measures remained unaltered across all conditions. Sensory threshold significantly decreased over time after 1mA (P = .002) and 2mA (P = .039) a-tDCS and did not change with sham. F-wave persistence showed a nonsignificant trend for increase (pre: 32% +/- 12%; post: 41% +/- 10%; follow up: 46% +/- 12%) after 2 mA stimulation. No adverse effects were reported with any of the experimental conditions. CONCLUSIONS: The a-tDCS can transiently raise corticospinal excitability to affected muscles in patients with chronic SCI after 2 mA stimulation. Sensory perception can improve with both 1 and 2 mA stimulation. This study gives support to the safe and effective use of a-tDCS using small electrodes in patients with SCI and highlights the importance of stimulation intensity. PMID- 25461827 TI - Kessler Foundation Neglect Assessment Process uniquely measures spatial neglect during activities of daily living. AB - OBJECTIVES: To explore the factor structure of the Kessler Foundation Neglect Assessment Process (KF-NAP), and evaluate the prevalence and clinical significance of spatial neglect among stroke survivors. DESIGN: Inception cohort. SETTING: Inpatient rehabilitation facility (IRF). PARTICIPANTS: Participants (N=121) with unilateral brain damage from their first stroke were assessed within 72 hours of admission to an IRF, and 108 were assessed again within 72 hours before IRF discharge. INTERVENTIONS: Usual and standard IRF care. MAIN OUTCOME MEASURES: During each assessment session, occupational therapists measured patients' functions with the KF-NAP, FIM, and Barthel Index (BI). RESULTS: The KF NAP showed excellent internal consistency with a single-factor structure. The exploratory factor analysis revealed the KF-NAP to be unique from both the FIM and BI even though all 3 scales were correlated. Symptoms of spatial neglect (KF NAP>0) were present in 67.8% of the participants at admission and 47.2% at discharge. Participants showing the disorder at IRF admission were hospitalized longer than those showing no symptoms. Among those presenting with symptoms, the regression analysis showed that the KF-NAP scores at admission negatively predicted FIM scores at discharge, after controlling for age, FIM at admission, and length of stay. CONCLUSIONS: The KF-NAP uniquely quantifies symptoms of spatial neglect by measuring functional difficulties that are not captured by the FIM or BI. Using the KF-NAP to measure spatial neglect, we found the disorder persistent after inpatient rehabilitation, and replicated previous findings showing that spatial neglect adversely affects rehabilitation outcome even after prolonged IRF care. PMID- 25461828 TI - Production of chondroitin in metabolically engineered E. coli. AB - Chondroitin sulfates, widely used in the treatment of arthritis, are glycosaminoglycans extracted from food animal tissues. As part of our ongoing efforts to separate the food chain from the drug chain, we are examining the possibility of using metabolic engineering to produce chondroitin sulfate in Escherichia coli. Chondroitin is a valuable precursor in the synthesis of chondroitin sulfate. This study proposes a safer and more feasible approach to metabolically engineer chondroitin production by expressing genes from the pathogenic E. coli K4 strain, which natively produces a capsular polysaccharide that shares the similar structure with chondroitin, into the non-pathogenic E. coli BL21 StarTM (DE3) strain. The ePathBrick vectors, allowing for multiple gene addition and expression regulatory signal control, are used for metabolic balancing needed to obtain the maximum potential yield. The resulting engineered strain produced chondroitin, as demonstrated by (1)H NMR and disaccharide analysis, relying on chondrotinase treatment followed by liquid chromatography mass spectrometry. The highest yield from shake flask experiment was 213mg/L and further increased to 2.4g/L in dissolved oxygen-stat fed batch bioreactor. PMID- 25461829 TI - Overproduction and secretion of free fatty acids through disrupted neutral lipid recycle in Saccharomyces cerevisiae. AB - The production of fuels and chemicals from biorenewable resources is important to alleviate the environmental concerns, costs, and foreign dependency associated with the use of petroleum feedstock. Fatty acids are attractive biomolecules due to the flexibility of their iterative biosynthetic pathway, high energy content, and suitability for conversion into other secondary chemicals. Free fatty acids (FFAs) that can be secreted from the cell are particularly appealing due to their lower harvest costs and straightforward conversion into a broad range of biofuel and biochemical products. Saccharomyces cerevisiae was engineered to overproduce extracellular FFAs by targeting three native intracellular processes. beta oxidation was disrupted by gene knockouts in FAA2, PXA1 and POX1, increasing intracellular fatty acids levels up to 55%. Disruptions in the acyl-CoA synthetase genes FAA1, FAA4 and FAT1 allowed the extracellular detection of free fatty acids up to 490mg/L. Combining these two disrupted pathways, a sextuple mutant (Deltafaa1 Deltafaa4 Deltafat1 Deltafaa2 Deltapxa1 Deltapox1) was able to produce 1.3g/L extracellular free fatty acids. Further diversion of carbon flux into neutral lipid droplet formation was investigated by the overexpression of DGA1 or ARE1 and by the co-overexpression of a compatible lipase, TGL1, TGL3 or TGL5. The sextuple mutant overexpressing the diacylglycerol acyltransferase, DGA1, and the triacylglycerol lipase, TGL3, yielded 2.2g/L extracellular free fatty acids. This novel combination of pathway interventions led to 4.2-fold higher extracellular free fatty acid levels than previously reported for S. cerevisiae. PMID- 25461830 TI - Metabolic engineering to enhance the value of plants as green factories. AB - The promise of plants to serve as the green factories of the future is ever increasing. Plants have been used traditionally for construction, energy, food and feed. Bioactive compounds primarily derived from specialized plant metabolism continue to serve as important scaffold molecules for pharmaceutical drug production. Yet, the past few years have witnessed a growing interest on plants as the ultimate harvesters of carbon and energy from the sun, providing carbohydrate and lipid biofuels that would contribute to balancing atmospheric carbon. How can the metabolic output from plants be increased even further, and what are the bottlenecks? Here, we present what we perceive to be the main opportunities and challenges associated with increasing the efficiency of plants as chemical factories. We offer some perspectives on when it makes sense to use plants as production systems because the amount of biomass needed makes any other system unfeasible. However, there are other instances in which plants serve as great sources of biological catalysts, yet are not necessarily the best-suited systems for production. We also present emerging opportunities for manipulating plant genomes to make plant synthetic biology a reality. PMID- 25461831 TI - Simultaneous production of butanol and acetoin by metabolically engineered Clostridium acetobutylicum. AB - Biobutanol is a potential fuel substitute and has been receiving increased attention in recent years. However, the economics of biobutanol production have been hampered by a number of bottlenecks such as high cost of raw material and low yield of solvent. Co-production of value-added products is a possible way to improve the economics of biobutanol production. Here, we present metabolic engineering strategies to substitute the major by-product acetone for a value added product acetoin during butanol fermentation. By overexpressing the alpha acetolactate decarboxylase gene alsD in Clostridium acetobutylicum B3, the acetoin yield was markedly increased while acetone formation was reduced. Subsequent disruption of adc gene effectively abolished acetone formation and further increased acetoin yield. After optimization of fermentation conditions, the alsD-overexpressing adc mutant generated butanol (13.8g/L), acetoin (4.3g/L), and ethanol (3.9g/L), but no acetone. Thus, acetone was completely substituted for acetoin, and both mass yield and product value were improved. This study provides valuable insights into the regulation of acetoin synthesis and should be highly useful for the development of acetoin-derived products like 2,3-butanediol and 2-butanol in C. acetobutylicum. PMID- 25461832 TI - A hybrid synthetic pathway for butanol production by a hyperthermophilic microbe. AB - Biologically produced alcohols are of great current interest for renewable solvents and liquid transportation fuels. While bioethanol is now produced on a massive scale, butanol has superior fuel characteristics and an additional value as a solvent and chemical feedstock. Butanol production has been demonstrated at ambient temperatures in metabolically-engineered mesophilic organisms, but the ability to engineer a microbe for in vivo high-temperature production of commodity chemicals has several distinct advantages. These include reduced contamination risk, facilitated removal of volatile products, and a wide temperature range to modulate and balance both the engineered pathway and the host's metabolism. We describe a synthetic metabolic pathway assembled from genes obtained from three different sources for conversion of acetyl-CoA to 1-butanol, and 1-butanol generation from glucose was demonstrated near 70 degrees C in a microorganism that grows optimally near 100 degrees C. The module could also be used in thermophiles capable of degrading plant biomass. PMID- 25461833 TI - Potential production platform of n-butanol in Escherichia coli. AB - We proposed a potential production platform of n-butanol in Escherichia coli. First, a butyrate-conversion strain was developed by removal of undesired genes and recruiting endogenous atoDA and Clostridium adhE2. Consequently, this E. coli strain grown on the M9 mineral salt with yeast extract (M9Y) was shown to produce 6.2g/L n-butanol from supplemented butyrate at 36h. The molar conversion yield of n-butanol on butyrate reaches 92%. Moreover, the production platform was advanced by additional inclusion of a butyrate-producing strain. This strain was equipped with a pathway comprising atoDA and heterologous genes for the synthesis of butyrate. Without butyrate, the butyrate-conversion and the butyrate-producing strains were co-cultured in M9Y medium and produced 5.5g/L n-butanol from glucose at 24h. The production yield on glucose accounts for 69% of the theoretical yield. Overall, it indicates a promise of the developed platform for n-butanol production in E. coli. PMID- 25461834 TI - Formal [3+2] cycloaddition of Ugi adducts towards pyrrolines. AB - Ugi adducts derived from aromatic aldehydes may be converted to pyrrolines via addition of Michael acceptors under microwave irradiation. The reaction may proceed via unusual formation of azomethine ylides followed by a [3+2] cycloaddition using Michael acceptors. PMID- 25461835 TI - Brain abnormalities in newly diagnosed neuropsychiatric lupus: systematic MRI approach and correlation with clinical and laboratory data in a large multicenter cohort. AB - OBJECTIVES: To describe brain magnetic resonance imaging (MRI) abnormalities in newly diagnosed neuropsychiatric lupus (NPSLE). To correlate them with clinical and laboratory data. METHODS: This retrospective cross-sectional study included patients presenting NPSLE undergoing brain MRI within 6 months after onset between 2003 and 2012. Clinical and laboratory data were recorded. MRI findings were defined as inflammatory-like, large-vessel disease (LVD), and small-vessel disease (SVD); SVD was classified as white-matter hyperintensities (WMH), recent small subcortical infarcts, lacunes, microbleeds, and brain atrophy. RESULTS: We included 108 patients (mean 40.6 +/- 14.2 years; range 14-77), 91.7% women. The most frequent syndromes were headache (28.5%), cerebrovascular disease (15.5%), seizure (15.5%), and cognitive dysfunction (11.4%). Brain abnormalities were found in 59.3%. SVD was the most common (55.6%), followed by LVD (13%) and inflammatory-like lesions (6.5%). The most frequent SVD findings were WMH (53.7%), atrophy (18.5%), microbleeds (13.7%) and lacunes (11.1%). Cerebrovascular syndrome correlated with LVD (p = 0.001) and microbleeds (p = 0.002), cognitive dysfunction with WMH (p = 0.045) and myelopathy with inflammatory-like lesions (p = 0.020). Low C4 and CH50 correlated with inflammatory-like lesions (p < 0.001, p = 0.019) and lupus anticoagulant with WMH (p = 0.018), microbleeds (p = 0.002) and atrophy (p = 0.008). CONCLUSIONS: Vascular disease is the hallmark of NPSLE. Certain syndromes and immunological patterns are prone to more extensive brain damage. MRI could provide significant clinical information and insights into the pathological substrate. PMID- 25461836 TI - Antiphospholipid syndrome and the heart: a case series and literature review. AB - Antiphospholipid syndrome is a rare autoimmune disease characterized by a high tendency of developing thrombotic events. It is diagnosed in the presence of specific laboratory criteria (positivity for lupus anticoagulant, and the presence of anticardiolipin and abeta2GPI antibodies) and clinical criteria such as thrombosis in any district (arterial or venous) and pregnancy morbidity. Being a multisystem disease, the heart is commonly affected by direct (autoimmune mediated action) or indirect (thrombosis) pathological mechanisms. Heart valve lesions are the most frequent manifestations; however, the haemodynamic significance is quite uncommon but when it occurs it may require surgery that further complicates the picture due to the high risk of thrombosis. Coronary arteries and myocardium are also affected leading to ischaemic heart disease and left ventricular dysfunction. Other findings include chronic thromboembolic pulmonary hypertension and accelerated atherosclerosis. The consequences of heart involvement may be significant in overt disease. The treatment of cardiac complications is challenging and requires an in-depth knowledge of the disease. PMID- 25461837 TI - Undifferentiated Connective Tissue Disease at risk for systemic sclerosis (SSc) (so far referred to as very early/early SSc or pre-SSc). AB - In the last few years, a number of studies have been published on a condition characterized by Raynaud's phenomenon (RP) associated with systemic sclerosis (SSc) marker autoantibodies and/or scleroderma-type capillaroscopic abnormalities and referred to as very early/early SSc. The present review is devoted to analyze pathophysiologic, clinical, and evolutive aspects of the condition that would induce to label it as Undifferentiated Connective Tissue Disease at risk for SSc and to split it into 3 subsets (i.e. RP associated to marker autoantibodies and scleroderma-type capillaroscopic abnormalities; RP associated to marker autoantibodies in the absence of scleroderma-type capillaroscopic abnormalities; and RP associated to scleroderma-type capillaroscopic abnormalities without any detectable marker autoantibody), which have been shown to carry different degrees of risk, but not the certainty, to develop overt SSc over time. This nosographic approach is instrumental to plan future studies devoted to investigate validated biomarkers heralding the development of major vascular disease manifestations as well as skin and/or organ fibrosis in patients at risk. PMID- 25461839 TI - Structural insights into endoplasmic reticulum stored calcium regulation by inositol 1,4,5-trisphosphate and ryanodine receptors. AB - The two major calcium (Ca2+) release channels on the sarco/endoplasmic reticulum (SR/ER) are inositol 1,4,5-trisphosphate and ryanodine receptors (IP3Rs and RyRs). They play versatile roles in essential cell signaling processes, and abnormalities of these channels are associated with a variety of diseases. Structural information on IP3Rs and RyRs determined using multiple techniques including X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and cryo-electron microscopy (EM), has significantly advanced our understanding of the mechanisms by which these Ca2+ release channels function under normal and pathophysiological circumstances. In this review, structural advances on the understanding of the mechanisms of IP3R and RyR function and dysfunction are summarized. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID- 25461840 TI - [FeFe]- and [NiFe]-hydrogenase diversity, mechanism, and maturation. AB - The [FeFe]- and [NiFe]-hydrogenases catalyze the formal interconversion between hydrogen and protons and electrons, possess characteristic non-protein ligands at their catalytic sites and thus share common mechanistic features. Despite the similarities between these two types of hydrogenases, they clearly have distinct evolutionary origins and likely emerged from different selective pressures. [FeFe]-hydrogenases are widely distributed in fermentative anaerobic microorganisms and likely evolved under selective pressure to couple hydrogen production to the recycling of electron carriers that accumulate during anaerobic metabolism. In contrast, many [NiFe]-hydrogenases catalyze hydrogen oxidation as part of energy metabolism and were likely key enzymes in early life and arguably represent the predecessors of modern respiratory metabolism. Although the reversible combination of protons and electrons to generate hydrogen gas is the simplest of chemical reactions, the [FeFe]- and [NiFe]-hydrogenases have distinct mechanisms and differ in the fundamental chemistry associated with proton transfer and control of electron flow that also help to define catalytic bias. A unifying feature of these enzymes is that hydrogen activation itself has been restricted to one solution involving diatomic ligands (carbon monoxide and cyanide) bound to an Fe ion. On the other hand, and quite remarkably, the biosynthetic mechanisms to produce these ligands are exclusive to each type of enzyme. Furthermore, these mechanisms represent two independent solutions to the formation of complex bioinorganic active sites for catalyzing the simplest of chemical reactions, reversible hydrogen oxidation. As such, the [FeFe]- and [NiFe]-hydrogenases are arguably the most profound case of convergent evolution. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. PMID- 25461841 TI - Acidic environment activates inflammatory programs in fibroblasts via a cAMP-MAPK pathway. AB - The tissue micromilieu in disorders (inflammation, ischemia, tumor) often shows pronounced metabolic acidosis that may alter signaling and transcriptional activity in resident cells which can be of special importance for omnipresent fibroblasts. In the present study we investigated the impact of metabolic acidosis on rat fibroblasts with special emphasis on their role in inflammation by regulation of TNF-alpha, MCP-1, COX-2 and iNOS expression and the signaling pathways involved. Extracellular acidosis led to an enhanced expression of TNF alpha, COX-2 and iNOS in parallel to an activation of p38 and ERK1/2 kinases that was not observed by sole intracellular acidosis. Accordingly, the protein amounts of TNF-alpha and COX-2 as well as the production of nitrate and nitrite were elevated. Acidosis-induced expression of COX-2 and iNOS depended on p38 kinase, but not on ERK1/2. In contrast acidosis-induced TNF-alpha expression was independent of both kinases. Although GPR4, GPR68 and GPR132 are expressed in fibroblasts, the involvement of these potential candidate pH sensors could be ruled out since no acidosis-induced elevation in intracellular cAMP or free calcium content was observed. Furthermore our data show that MAPK activation by an acidic micromilieu depends on Ser/Thr phosphatase activity, but not on the production of reactive oxygen species and is sensitive to cAMP antagonism by Rp cAMPS. In conclusion, our results show that an acidic microenvironment induces a differential transcriptional program of pathological relevant genes in fibroblasts via the cAMP-phosphatase-MAPK pathway and thereby generates a parainflammatory situation that can result in tissue remodeling. PMID- 25461842 TI - Modulation of spike-evoked synaptic transmission: The role of presynaptic calcium and potassium channels. AB - Action potentials are usually considered as the smallest unit of neuronal information conveyed by presynaptic neurons to their postsynaptic target. Thus, neuronal signaling in brain circuits is all-or-none or digital. However, recent studies indicate that subthreshold analog variation in presynaptic membrane potential modulates spike-evoked transmission. The informational content of each presynaptic action potential is therefore greater than initially expected. This property constitutes a form of fast activity-dependent modulation of functional coupling. Therefore, it could have important consequences on information processing in neural networks in parallel with more classical forms of presynaptic short-term facilitation based on repetitive stimulation, modulation of presynaptic calcium or modifications of the release machinery. We discuss here how analog voltage shift in the presynaptic neuron may regulate spike-evoked release of neurotransmitter through the modulation of voltage-gated calcium and potassium channels in the axon and presynaptic terminal. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID- 25461844 TI - Thirty years of tick population genetics: a comprehensive review. AB - Population genetic studies provide insights into the basic biology of arthropod disease vectors by estimating dispersal patterns and their potential to spread pathogens. In wingless vectors, such as ticks, gene flow will be defined in large part by the mobility of their hosts. However, tick behaviors and life cycle strategies can limit their dispersal even on highly mobile hosts and lead to an increase in genetic structure. In this review we synthesize the published literature from three decades of tick population genetic studies. Based on studies from 22 tick species (including representatives from Amblyomma, Bothriocroton, Dermacentor, Ixodes, Ornithodoros, and Rhipicephalus), observed levels of population genetic structure in ticks varied from no structure to very high levels. In about half of the species (including representatives from Amblyomma, Bothriocroton, Dermacentor, and Ornithodoros), tick genetic structure appeared to be determined primarily by the movement capacity of hosts, with low gene flow observed in ticks that use smaller bodied less mobile hosts and high gene flow in ticks using highly mobile hosts. In a number of other species (primarily from Ixodes, Ornithodoros, and Rhipicephalus), behavioral limitations to gene flow appeared to result in greater genetic structure than expected based upon host movement capability alone. We also discuss the strengths and limitations of genetic markers and their applicability to ticks and suggest possible analyses when planning population genetic studies for ticks. PMID- 25461845 TI - Hantaan virus can infect human keratinocytes and activate an interferon response through the nuclear translocation of IRF-3. AB - Hantaan virus (HTNV) is a rodent-borne virus that causes hemorrhagic fever with renal syndrome (HFRS) in Asia and can be transmitted to humans through bites or the inhalation of aerosolized urine, droppings, or saliva of infected rodents. Keratinocytes predominate in the epidermis and reportedly serve as a replication site for multiple vector-borne viruses, little is known about the susceptibility of human skin cells to HTNV infection. Therefore, we aimed to evaluate whether human keratinocytes support HTNV replication and elicit an immune response against HTNV infection. We found that a human keratinocyte cell line, HaCaT, supports HTNV replication. In addition, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation associated gene-5 (MDA5) play key roles in the detection of HTNV infection in HaCaT cells and in the up-regulation of interferon (IFN)-beta expression, which subsequently leads to the production of a large amount of antiviral interferon-stimulated genes (ISGs) and other chemokines used for immune cell recruitment. Furthermore, we suggest that interferon regulatory factor (IRF)-3, as opposed to NF-kappaB/p65 or IRF-7, is translocated to the nucleus to induce IFN-beta. However, the early induction of chemokine CXCL10 was a direct result of HaCaT cells counteracting HTNV infection and was not due to the induction of IFN. Overall, our data demonstrate, for the first time, the permissiveness of human keratinocytes to HTNV infection. PMID- 25461843 TI - Mechanisms of genome evolution of Streptococcus. AB - The genus Streptococcus contains 104 recognized species, many of which are associated with human or animal hosts. A globally prevalent human pathogen in this group is Streptococcus pneumoniae (the pneumococcus). While being a common resident of the upper respiratory tract, it is also a major cause of otitis media, pneumonia, bacteremia and meningitis, accounting for a high burden of morbidity and mortality worldwide. Recent findings demonstrate the importance of recombination and selection in driving the population dynamics and evolution of different pneumococcal lineages, allowing them to successfully evade the impacts of selective pressures such as vaccination and antibiotic treatment. We highlight the ability of pneumococci to respond to these pressures through processes including serotype replacement, capsular switching and horizontal gene transfer (HGT) of antibiotic resistance genes. The challenge in controlling this pathogen also lies in the exceptional genetic and phenotypic variation among different pneumococcal lineages, particularly in terms of their pathogenicity and resistance to current therapeutic strategies. The widespread use of pneumococcal conjugate vaccines, which target only a small subset of the more than 90 pneumococcal serotypes, provides us with a unique opportunity to elucidate how the processes of selection and recombination interact to generate a remarkable level of plasticity and heterogeneity in the pneumococcal genome. These processes also play an important role in the emergence and spread of multi-resistant strains, which continues to pose a challenge in disease control and/or eradication. The application of population of genomic approaches at different spatial and temporal scales will help improve strategies to control this global pathogen, and potentially other pathogenic streptococci. PMID- 25461846 TI - Transposition and homologous recombination drive evolution of pUO-StVR2, a multidrug resistance derivative of pSLT, the virulence plasmid specific of Salmonella enterica serovar Typhimurium. AB - Five variants of a resistant derivative of pSLT (termed pUO-StVR2) were detected in clinical isolates of Salmonella enterica serovar Typhimurium recovered in Spain. The structure of these variants revealed the involvement of IS1, IS26 and Tn21-like transposition, as well as homologous recombination in the generation of deletions, inversions and insertions which, depending on the variant, affected an orf of unknown function, genes encoding a possible iron acquisition system, and/or resistance properties. These variants, which appeared at a relatively low frequency, can be used as a model to understand the co-selection mechanisms that are helping to maintain multidrug resistance in bacterial pathogens, despite the structural instability of the responsible DNA. PMID- 25461848 TI - Comparative study of the biological properties of Trypanosoma cruzi I genotypes in a murine experimental model. AB - Chagas disease is an endemic zoonosis in Latin America and caused by the parasite Trypanosoma cruzi. This kinetoplastid displays remarkable genetic variability, allowing its classification into six Discrete Typing Units (DTUs) from TcI to TcVI. T. cruzi I presents the broadest geographical distribution in the continent and has been associated to severe forms of cardiomyopathies. Recently, a particular genotype associated to human infections has been reported and named as TcIDOM (previously named TcIa-b). This genotype shows to be clonal and adapted to the domestic cycle but so far no studies have determined the biological properties of domestic (TcIDOM) and sylvatic TcI strains (previously named TcIc e). Hence, the aim of this study was to untangle the biological features of these genotypes in murine models. We infected ICR-CD1 mice with five TcI strains (two domestic, two sylvatic and one natural mixture) and determined the course of infection during 91 days (acute and chronic phase of the disease) in terms of parasitemia, tissue tropism, immune response (IgG titers) and tissue invasion by means of histopathology studies. Statistically significant differences were observed in terms of parasitemia curves and prepatent period between domestic (TcIDOM) and sylvatic strains. There were no differences in terms of IgG antibodies response across the mice infected with the five strains. Regarding the histopathology, our results indicate that domestic strains present higher parasitemias and low levels of histopathological damage. In contrast, sylvatic strains showed lower parasitemias and high levels of histopathological damage. These results highlight the sympatric and behavioral differences of domestic and sylvatic TcI strains; the clinical and epidemiological implications are herein discussed. PMID- 25461847 TI - Genetic characterization and clinical implications of human papillomavirus type 16 (HPV16) variants from northeastern Argentina. AB - BACKGROUND: Human papillomavirus type 16 (HPV16) plays a central role in the development of cervical cancer. Worldwide studies indicate the existence of HPV16 variants that show different geographic distributions and oncogenic potential. OBJECTIVE: Our goal was to describe the genetic variation of HPV16 isolates identified in urban women with different grades of cervical lesions living in northeastern Argentina. STUDY DESIGN: We analyzed 116 HPV16-positive cervical samples (16 NLIM, 62 L-SIL, 16 H-SIL and 22 cervical cancer) from patients attending health centers in Misiones (Argentina) during 2006-13. HPV16 isolates were genetically characterized through PCR amplification and direct sequencing of 364 bp within the long control region, and the resulting sequences classified into variants based on phylogenetic analysis (lineages A, B, C and D). A potential association between HPV16 variants and lesion grade was evaluated through an odds ratio (OR) test. A temporal framework for the origin of HPV16 variants was assessed through coalescence analysis (BEAST v 1.7.5). RESULTS: Phylogenetic analysis of HPV16 sequences showed that 92.1% of the samples clustered with lineage A, and 6.9% to lineage D. HPV16 variants from lineage D were more frequently associated with high-grade lesions and cancer (HSIL+) than lineage A variants at an OR of 13.8 (1.6-117.0). The time to most common recent ancestor (tMCRA) of all variants was 119,103 years before present (HPD 95%=48,486 197,239), a date consistent with the time frame for modern human evolution. CONCLUSION: Our results suggest that HPV16 variants from lineage D may represent an additional risk factor for the development of cervical cancer in women living in northeastern Argentina. This study provides new information about viral isolates present in Argentina that will contribute to the monitoring of HPV16 infection in the vaccine era. PMID- 25461849 TI - Increased detection of G3P[9] and G6P[9] rotavirus strains in hospitalized children with acute diarrhea in Bulgaria. AB - Rotavirus severe disease in children is now vaccine-preventable and the roll-out of vaccination programs globally is expected to make a significant impact in the reduction of morbidity and mortality in children <5 years of age. Rotavirus is also a pathogen of other mammals and birds, and its segmented RNA genome can lead to the emergence of new or unusual strains in human population via interspecies transmission and reassortment events. Despite the efficacy and impact of rotavirus vaccine in preventing severe diarrhea, the correlates of protection remain largely unknown. Therefore, rotavirus strain surveillance before, during and after the introduction of immunization programs remains a crucial for monitoring rotavirus vaccine efficacy and impact. In this context, molecular characterization of 1323 Bulgarian rotavirus strains collected between June 2010 and May 2013 was performed. A total of 17 strains of interest were analyzed by partial sequence analysis. Twelve strains were characterized as G3P[9] and G6P[9] of potential animal origin. Phylogenetic analysis and comparisons with the same specificity strains detected sporadically between 2006 and 2010 revealed the constant circulation of these unusual human strains in Bulgaria, although in low prevalence, and their increased potential for person-to-person spread. PMID- 25461850 TI - Temporal dynamics, diversity, and interplay in three components of the virodiversity of a Mallard population: influenza A virus, avian paramyxovirus and avian coronavirus. AB - Multiple infections, or simultaneous infection of a host with multiple parasites, are the rule rather than the exception. Interactions between co-occurring pathogens in a population may be mutualistic, competitive or facilitative. For some pathogen combinations, these interrelated effects will have epidemiological consequences; however this is as yet poorly incorporated into practical disease ecology. For example, screening of Mallards for influenza A viruses (IAV) have repeatedly revealed high prevalence and large subtype diversity in the Northern Hemisphere. Other studies have identified avian paramyxovirus type 1 (APMV-1) and coronaviruses (CoVs) in Mallards, but without making inferences on the larger viral assemblage. In this study we followed 144 wild Mallards across an autumn season in a natural stopover site and constructed infection histories of IAV, APMV-1 and CoV. There was a high prevalence of IAV, comprising of 27 subtype combinations, while APMV-1 had a comparatively low prevalence (with a peak of 2%) and limited strain variation, similar to previous findings. Avian CoVs were common, with prevalence up to 12%, and sequence analysis identified different putative genetic lineages. An investigation of the dynamics of co-infections revealed a synergistic effect between CoV and IAV, whereby CoV prevalence was higher given that the birds were co-infected with IAV. There were no interactive effects between IAV and APMV-1. Disease dynamics are the result of an interplay between parasites, host immune responses, and resources; and is imperative that we begin to include all factors to better understand infectious disease risk. PMID- 25461851 TI - Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. AB - BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) has been predicted to become the leading indication for liver transplantation (LT) in the United States. However, few studies have evaluated changes in the etiology of liver diseases among patients awaiting LT, and none have focused on the effects of NASH on liver transplant waitlists in the United States. METHODS: We collected data from the United Network for Organ Sharing and Organ Procurement and Transplantation Network registry from 2004 through 2013, on liver transplant waitlist registrants with hepatitis C virus (HCV) infection, NASH, alcoholic liver disease (ALD), or a combination of HCV infection and ALD. We compared differences in survival within 90 days of registration (90-day survival) and probability of LT among patients with different diseases using Kaplan-Meier and multivariate logistic regression models. RESULTS: Between 2004 and 2013, new waitlist registrants with NASH increased by 170% (from 804 to 2174), with ALD increased by 45% (from 1400 to 2024), and with HCV increased by 14% (from 2887 to 3291); registrants with HCV and ALD decreased by 9% (from 880 to 803). In 2013, NASH became the second-leading disease among liver transplant waitlist registrants, after HCV. Patients with ALD had a significantly higher mean Model for End-Stage Liver Disease score at time of waitlist registration than other registrants. However, after multivariate adjustment, patients with ALD were less likely to die within 90 days when compared with patients with NASH (odds ratio [OR] = 0.77; 95% confidence interval [CI]: 0.67-0.89; P < .001); patients with HCV infection or HCV and ALD had similar odds for 90-day survival compared with NASH patients. Compared with patients with NASH, patients with HCV (OR = 1.45; 95% CI: 1.35-1.55; P < .001), ALD (OR = 1.15; 95% CI: 1.06-1.24; P < .001), or HCV and ALD (OR = 1.29; 95% CI: 1.18-1.42; P < .001) had higher odds for 90-day survival. CONCLUSIONS: Based on data from US adult LT databases, since 2004 the number of adults with NASH awaiting LTs has almost tripled. However, patients with NASH are less likely to undergo LT and less likely to survive for 90 days on the waitlist than patients with HCV, ALD, or HCV and ALD. PMID- 25461852 TI - Quantitative assessment of liver steatosis on tissue section using infrared spectroscopy. PMID- 25461853 TI - Do spiders vector bacteria during bites? The evidence indicates otherwise. PMID- 25461854 TI - Surgical treatment and prognosis of 96 cases of intraductal papillary mucinous neoplasms of the pancreas: a retrospective cohort study. AB - INTRODUCTION: The indications, the extent and type of surgery for intraductal papillary mucinous neoplasm (IPMN) are still controversial. This study aimed to investigate clinical manifestation, individualized surgical treatment, and prognosis of IPMN of pancreas. METHODS: The clinical data of 96 IPMN cases treated in our hospital between January 2006 and December 2013 were retrospectively analyzed. Among the 96 patients (58 male and 38 female), 46 were main-duct type, 29 were branch-duct type, 21 were mixed type. Pancreatectomy was performed on 78 cases, including pancreaticoduodenectomy on 43 patients, distal pancreatectomy on 25, segmental pancreatectomy on 6, and total pancreatectomy on 4. A regular follow-up without surgical treatment was performed on 18 cases with asymptomatic side branch IPMN less than 3 cm in diameter. RESULTS: The overall postoperative morbidity rate was 33.3%, and there was no perioperative mortality. 46 cases were non-invasive IPMN, 32 cases were invasive IPMN including 14 cases with lymph node metastasis. The five-year survival rate for patients with non invasive and invasive carcinomas was 96.2% and 35.2%, respectively. The prognosis of invasive cases with lymph node metastasis was significantly worse than those without lymph node metastasis. No progression was found during the follow-up in 18 asymptomatic small branch duct type IPMN patients. CONCLUSION: IPMN has a relative good prognosis. Main duct type and mixed type IPMN have a higher malignant potential, and should receive surgical treatment. Patients of branch duct type IPMN with lesion <3 cm in diameter and without clinical manifestations can be managed with close follow-up. PMID- 25461855 TI - Laparoscopic versus open approach in the management of appendicitis complicated exclusively with peritonitis: a single center experience. AB - BACKGROUND: Controversial evidence exists regarding the laparoscopic approach in patients with acute appendicitis complicated with peritonitis due to a higher rate of surgical complications. The aim of this study was to compare post operatory outcomes in patients with acute appendicitis complicated exclusively with peritonitis approached by laparoscopy versus open surgery. METHODS: Single center retrospective analysis of clinical records of patients with appendicitis complicated with peritonitis operated from January 2003 until October 2013. Demographic data, intra-operative variables, length of stay, surgical complications, mortality, readmissions and reoperations were retrieved. RESULTS: 227 patients were identified, 43% males, mean age 39+/-17 years (range: 12-85 years). Ninety-seven patients (43%) underwent laparoscopic appendectomy, 13 of them were converted to open surgery (13%). Ninety-four patients presented with diffuse peritonitis (41.4%). Laparoscopic appendectomy showed longer operative time but shorter hospital stay (p<0.05). There were no differences in post operatory complications (intra-abdominal abscess, surgical site infection and prolonged ileus). Laparoscopic appendectomy was associated with lower odds for developing any surgical complication in the multivariate analysis (OR 0.301, p=0.036). CONCLUSION: Both approaches showed no differences in complications in the management of appendicitis complicated exclusively with peritonitis. In our experience, laparoscopic appendectomy is a safe approach in cases of appendicitis complicated exclusively with peritonitis. PMID- 25461856 TI - Shards of sorrow: Older men's accounts of their depression experience. AB - The experience of depression is diverse based on social locations and context. A sociological perspective building on masculinity, illness work, and the self provides a useful theoretical framework to understand how older men negotiate emotional suffering. This article examines older men's accounts of their depression experience from a social constructionist approach. This analysis is based on data from 77 in-depth interviews with depressed older men who participated in a larger mixed-method study, the Men's Health and Aging Study (MeHAS). We show how older men construct depression accounts in which they integrate biological and social factors associated with feeling a loss of control. This is experienced as a shamed masculine self given their inability to perform manhood acts, which leads them to severe social bonds. Men's accounts also shed light on how they resist the shaming of the masculine self by deploying two primary strategies: acting overtly masculine through aggressive behavior and by retracting from social interactions that may lead to feelings of shame. These strategies appear futile and they are only partially able to embrace alternative masculine values in line with roles as grandparents and older, wiser men. Depression in older men is characterized by an ongoing negotiation of limited statuses and roles given dominant conceptions of masculinity. PMID- 25461857 TI - Childhood psychological distress and youth unemployment: evidence from two British cohort studies. AB - The effect of childhood mental health on later unemployment has not yet been established. In this article we assess whether childhood psychological distress places young people at high risk of subsequent unemployment and whether the presence of economic recession strengthens this relationship. This study was based on 19,217 individuals drawn from two nationally-representative British prospective cohort studies; the Longitudinal Study of Young People in England (LSYPE) and the National Child Development Study (NCDS). Both cohorts contain rich contemporaneous information detailing the participants' early life socioeconomic background, household characteristics, and physical health. In adjusted analyses in the LSYPE sample (N = 10,232) those who reported high levels of distress at age 14 were 2 percentage points more likely than those with low distress to be unemployed between ages 16 and 21. In adjusted analyses of the NCDS sample (N = 8985) children rated as having high distress levels by their teachers at age 7 and 11 were 3 percentage points more likely than those with low distress to be unemployed between ages 16 and 23. Our examination of the 1980 UK recession in the NCDS cohort found the difference in average unemployment level between those with high versus low distress rose from 2.6 pct points in the pre recession period to 3.9 points in the post-recession period. These findings point to a previously neglected contribution of childhood mental health to youth unemployment, which may be particularly pronounced during times of economic recession. Our findings also suggest a further economic benefit to enhancing the provision of mental health services early in life. PMID- 25461858 TI - Paying for primary care: a cross-sectional analysis of cost and morbidity distributions across primary care payment models in Ontario Canada. AB - Policy-makers desire an optimal balance of financial incentives to improve productivity and encourage improved quality in primary care, while also avoiding issues of risk-selection inherent to capitation-based payment. In this paper we analyze risk-selection in capitation-based payment by using administrative data for patients (n = 11,600,911) who were rostered (i.e., signed an enrollment form, or received a majority of care) with a primary care physician (n = 8621) in Ontario, Canada in 2010/11. We analyze this data using a relative distribution approach and compare distributions of patient costs and morbidity across primary care payment models. Our results suggest a relationship between being in a capitation-based payment scheme and having low cost patients (and presumably healthy patients) compared to fee-for-service physicians. However, we do not have evidence that physicians in capitation-based models are reducing the care they provide to sick and high cost patients. These findings suggest there is a relationship between payment type and risk-selection, particularly for low-cost and healthy patients. PMID- 25461859 TI - Does informal care impact utilization of healthcare services? Evidence from a longitudinal study of stroke patients. AB - Understanding the interplay between informal care and formal healthcare is important because it sheds light on the financial implications of such interactions and may result in different policies. On the basis of a major database on 532 Italian stroke patients enrolled in the period 2007-2008, we investigate whether the presence of a potential caregiver and the amount of informal care provided influences the use and the costs of healthcare services, and in particular rehabilitation, in the post-acute phase. Primary caregivers of stroke patients were interviewed at 3, 6 and 12 months after the acute event and use of healthcare and informal care were documented. The panel dataset included socio-demographic, clinical and economic data on patients and caregivers. A longitudinal log-linear model was applied to test the impact of informal care on total healthcare costs in the observation period. A double hurdle model was used to investigate the impact of informal care on rehabilitation costs. A total of 476 of stroke survivors in 44 hospitals were enrolled in the study and presence of informal caregiver was reported in approximately 50% of the sample (range 48.2 52.5% across the three periods). Healthcare costs at 12 months after the acute event are ?5825 per patient, with rehabilitation costs amounting to ?3985 (68.4%). Healthcare costs are significantly different between the patients with and without caregiver in all three periods. The presence of the caregiver is associated with 54.7% increase in direct healthcare costs (p < 0.01). Instead, the amount of informal care provided does not influence significantly direct healthcare costs. The presence of caregiver significantly increases the probability of access to rehabilitation services (beta = 0.648, p = 0.039) while, once the decision on access is made, it doesn't influence the amount of services used. Our results suggest that informal caregivers facilitate or even promote the access to healthcare services. PMID- 25461860 TI - Dealing with uncertainty and high prices of new medicines: a comparative analysis of the use of managed entry agreements in Belgium, England, the Netherlands and Sweden. AB - Managed entry agreements are a set of instruments used to reduce the impact of uncertainty and high prices when introducing new medicines. This study develops a conceptual framework for these agreements and tests it by exploring variations in their implementation in Belgium, England, the Netherlands and Sweden and over time as well as their governance structures. Using publicly available data from HTA agencies and survey data from the European Medicines Information Network, a database of agreements implemented between 2003 and 2012 was developed. A review of governance structures was also undertaken. In December 2012 there were 133 active MEAs for different medicine-indications across the four countries. These corresponded to 110 unique medicine-indications. Over time there has been a steady growth in the number of agreements implemented, with the highest number in the Netherlands in 2012. The number of new agreements introduced each year followed a different pattern. In Belgium and England it increased over time, while it decreased in the Netherlands and fluctuated in Sweden. Only 18 (16%) of the unique medicine-indication pairs identified were part of an agreement in two or more countries. England uses mainly discounts and free doses to influence prices. The Netherlands and Sweden have focused more on addressing uncertainties through coverage with evidence development and, in Sweden, on monitoring use and compliance with restrictions through registries. Belgium uses a combination of the above. Despite similar reasons being cited for managed entry agreements implementation, only in a minority of cases have countries implemented an agreement for the same medicine-indication; when they do, a different agreement type is often implemented. Differences in governance across countries partly explain such variations. However, more research is needed to understand whether e.g. risk-perception and/or notion of what constitutes a high price differ between these countries. PMID- 25461861 TI - Valuing health at the end of life: a stated preference discrete choice experiment. AB - A source of debate in the field of health care priority setting is whether health gains should be weighted differently for different groups of patients. The debate has recently focused on the relative value of life extensions for patients with short life expectancy. However, few studies have examined empirically whether society is prepared to fund life-extending end-of-life treatments that would not meet the reimbursement criteria used for other treatments. A web-based discrete choice experiment was conducted in 2012 using a sample of 3969 members of the general public in England and Wales. The study design was informed by the National Institute for Health and Care Excellence's supplementary policy for the appraisal of life-extending end-of-life treatments. The choice tasks involved asking respondents which of two hypothetical patients they would prefer to treat, assuming that the health service has enough funds to treat only one of them. Conditional logit regressions were used for modelling. Choices about which patient to treat were influenced more by the sizes of treatment gains than by patients' life expectancy without treatment. Some respondents appear to support a health-maximisation type objective throughout, whilst a small minority always seek to treat those who are worse off without treatment. The majority of respondents, however, seem to advocate a mixture of the two approaches. Overall, we find little evidence that members of the general public prefer to give higher priority to life-extending end-of-life treatments than to other types of treatment. When asked to make decisions about the treatment of hypothetical patients with relatively short life expectancies, most people's choices are driven by the size of the health gains offered by treatment. PMID- 25461862 TI - Exploring the feasibility of theory synthesis: a worked example in the field of health related risk-taking. AB - The idea of synthesising theory is receiving attention within public health as part of a drive to design theoretically informed interventions. Theory synthesis is not a new idea, however, having been debated by sociologists for several decades. We consider the various methodological approaches to theory synthesis and test the feasibility of one such approach by synthesising a small number of sociological theories relevant to health related risk-taking. The synthesis consisted of three stages: (i) synthesis preparation, wherein parts of relevant theories were extracted and summarised; (ii) synthesis which involved comparing theories for points of convergence and divergence and bringing together those points that converge; and (iii) synthesis refinement whereby the synthesis was interrogated for further theoretical insights. Our synthesis suggests that serious and sustained risk-taking is associated with social isolation, liminality and a person's position in relation to the dominant social group. We reflect upon the methodological and philosophical issues raised by the practice of theory synthesis, concluding that it has the potential to reinvigorate theory and make it more robust and accessible for practical application. PMID- 25461863 TI - The physical and social determinants of mortality in the 3.11 tsunami. AB - The human consequences of the 3.11 tsunami were not distributed equally across the municipalities of the Tohoku region of northeastern Japan. Instead, the mortality rate from the massive waves varied tremendously from zero to ten percent of the local residential population. What accounts for this variation remains a critical question for researchers and policy makers alike. This paper uses a new, sui generis data set including all villages, towns, and cities on the Pacific Ocean side of the Tohoku region to untangle the factors connected to mortality during the disaster. With data on demographic, geophysical, infrastructure, social capital, and political conditions for 133 municipalities, we find that tsunami height, stocks of social capital, and level of political support for the long-ruling LDP strongly influenced mortality rates. Given the high probability of future large scale catastrophes, these findings have important policy implications for disaster mitigation policies in Japan and abroad. PMID- 25461865 TI - Sick of our loans: Student borrowing and the mental health of young adults in the United States. AB - Student loans are increasingly important and commonplace, especially among recent cohorts of young adults in the United States. These loans facilitate the acquisition of human capital in the form of education, but may also lead to stress and worries related to repayment. This study investigated two questions: 1) what is the association between the cumulative amount of student loans borrowed over the course of schooling and psychological functioning when individuals are 25-31 years old; and 2) what is the association between annual student loan borrowing and psychological functioning among currently enrolled college students? We also examined whether these relationships varied by parental wealth, college enrollment history (e.g. 2-year versus 4-year college), and educational attainment (for cumulative student loans only). We analyzed data from the National Longitudinal Survey of Youth 1997 (NLSY97), a nationally representative sample of young adults in the United States. Analyses employed multivariate linear regression and within-person fixed-effects models. Student loans were associated with poorer psychological functioning, adjusting for covariates, in both the multivariate linear regression and the within-person fixed effects models. This association varied by level of parental wealth in the multivariate linear regression models only, and did not vary by college enrollment history or educational attainment. The present findings raise novel questions for further research regarding student loan debt and the possible spillover effects on other life circumstances, such as occupational trajectories and health inequities. The study of student loans is even more timely and significant given the ongoing rise in the costs of higher education. PMID- 25461864 TI - The determinants of dentists' productivity and the measurement of output. AB - Improving the productivity of the healthcare system, for example by taking advantage of scale economies or encouraging substitution of expensive specialist personnel with less expensive workers, is often seen as an attractive way to meet increasing demand within a constrained budget. Using data on 558 dentists participating in the Longitudinal Study of Dentists' Practice Activity (LSDPA) survey between 1993 and 2003 linked to patient data and average fee schedules, we estimate production functions for private dental services in Australia to quantify the contribution of different capital and labour inputs and identify economies of scale in the production of dental care. Given the challenges in measuring output in the healthcare setting, we discuss three different output measures (raw activity, time-, and price-weighted activity) and test the sensitivity of results to the choice of measure. Our results suggest that expansion of the scale of dental services is unlikely to be constrained by decreasing returns to scale. We note that conclusions about the contribution of individual input factors and the estimated returns to scale are sensitive to the choice of output measure employed. PMID- 25461866 TI - Willingness to pay for telecare programmes to support independent living: results from a contingent valuation study. AB - An ageing population provokes an economic interest in the resource allocation questions posed by long-term care and critically, the development of sustainable community-based health and social care models that support independent living. This paper explores Irish citizens preferences and willingness to pay (WTP) for a range of community-based care programmes, including different telecare programmes that support older people to continue living at home. The paper reports on a cross-sectional multi-good contingent valuation survey conducted between April and September 2009 with three representative samples of the Irish population (N = 1214) to identify rankings and preferences for different community care programmes including: family care programme, a state-provided care programme and three different telecare programmes. The survey design permits the identification of strength, direction and relative preferences of different forms of community care provision. We also investigate convergent validity between ranking and willingness to pay results. We find that while people place significant value on formal state care provision and on telecare programmes, willingness to pay (WTP) estimates continue to highlight the importance of family care, which remains the strongest preference of the Irish population for the provision of community-based care for older people in the country. Respondents weakened their ranking preferences in the WTP exercise. However, both the direction of ranking and WTP estimates confirm the importance of family care. While all telecare programmes generated some economic value, telecare associated with social connection had much stronger support than telecare used to support physical or cognitive care needs. This paper offers unique information on societal values for different forms of community care provision, and in particular, the direction of preferences for technology-based approaches. PMID- 25461868 TI - Cost sharing and hospitalizations for ambulatory care sensitive conditions. AB - During the last decade, Chile's private health sector has experienced a dramatic increase in hospitalization rates, growing at four times the rate of ambulatory visits. Such evolution has raised concern among policy-makers. We studied the effect of ambulatory and hospital co-insurance rates on hospitalizations for ambulatory care sensitive conditions (ACSC) among individuals with private insurance in Chile. We used a large administrative dataset of private insurance claims for the period 2007-8 and a final sample of 2,792,662 individuals to estimate a structural model of two equations. The first equation was for ambulatory visits and the second for future hospitalizations for ACSC. We estimated the system by Two Stage Least Squares (2SLS) corrected by heteroskedasticity via Generalized Method of Moments (GMM) estimation. Results show that increased ambulatory visits reduced the probability of future hospitalizations, and increased ambulatory co-insurance decreased ambulatory visits for the adult population (19-65 years-old). Both findings indicate the need to reduce ambulatory co-insurance as a way to reduce hospitalizations for ACSC. Results also showed that increasing hospital co-insurance does have a statistically significant reduction on hospitalizations for the adult group, while it does not seem to have a significant effect on hospitalizations for the children (1-18 years-old) group. This paper's contribution is twofold: first, it shows how the level of co-insurance can be a determinant in avoiding unnecessary hospitalizations for certain conditions; second, it highlights the relevance for policy-making of using data on ACSC to improve the efficiency of health systems by promoting ambulatory care as well as population health. PMID- 25461867 TI - Changing handwashing behaviour in southern Ethiopia: a longitudinal study on infrastructural and commitment interventions. AB - Improved hand hygiene efficiently prevents the major killers of children under the age of five years in Ethiopia and globally, namely diarrhoeal and respiratory diseases. Effective handwashing interventions are thus in great demand. Evidence- and theory-based interventions, especially when matched to the target population's needs, are expected to perform better than common practice. To test this hypothesis, we selected two interventions drawing on a baseline questionnaire-study that applied the RANAS (Risk, Attitudes, Norms, Abilities, Self-regulation) approach and focused on the primary caregivers of households in four rural, water-scarce kebeles (smallest administrative units of Ethiopia) in southern Ethiopia (N = 462). The two interventions were tested in combination with a standard education intervention in a quasi-experiment, as follows: kebele 1, education intervention, namely an f-diagram exercise, (n = 23); kebele 2, education intervention and public-commitment (n = 122); kebele 3, education intervention and tippy-tap-promotion (i.e. handwashing-station-promotion; n = 150); kebele 4, education intervention, public-commitment and tippy-tap-promotion (n = 113). In kebeles 3 and 4, nearly 100% of the households followed the promotion and invested material and time to construct for themselves a tippy-tap. Three months after intervention termination, the tippy-taps were in use with water and soap being present in up to 83% of the households (kebele 4). Pre-post data analysis on self-reported handwashing revealed that the population-tailored interventions, and especially the tippy-tap-promotion, performed better than the standard education intervention. Tendencies in observed behaviour and a recently developed implicit self-measure pointed to similar results. Changing people's hand hygiene is known to be a challenging task, especially in a water-scarce environment. The present project suggests not only to apply theory and evidence to improve handwashing interventions' effectiveness, but also emphasizes the relevance of tailoring interventions to the target population. PMID- 25461869 TI - Is temporary employment damaging to health? A longitudinal study on Italian workers. AB - Working conditions have changed dramatically over recent decades in all the countries of European Union: permanent full-time employment characterized by job security and a stable salary is replaced more and more by temporary work, apprenticeship contracts, casual jobs and part-time work. The consequences of these changes on the general well-being of workers and their health represent an increasingly important path of inquiry. We add to the debate by answering the question: are Italian workers on temporary contracts more likely to suffer from poor health than those with permanent jobs? Our analysis is based on a sample of men and women aged 16-64 coming from the Italian longitudinal survey 2007-2010 of the European Union Statistics on Income and Living Conditions. We use the method of inverse-probability-of-treatment weights to estimate the causal effect of temporary work on self-rated health, controlling for selection effects. Our major findings can be summarized as follows: firstly, we show a negative association between temporary employment and health that results from a statistical causal effect in the work-to-health direction, and does not trivially derive from a selection of healthier individuals in the group of people who find permanent jobs (selection effect). Secondly, we find that temporary employment becomes particularly negative for the individual's health when it is prolonged over time. Thirdly, whereas temporary employment does not entail significant adverse consequences for men, the link between temporary employment and health is strongly harmful for Italian women. PMID- 25461871 TI - Mental health inequalities in 9 former Soviet Union countries: evidence from the previous decade. AB - In the previous two decades, countries of the former Soviet Union underwent substantive economic and social changes. While there has been some limited evidence on the relationship between socioeconomic well-being and mental health in the developing and transitional economies, the evidence on economic inequalities in mental health has so far been scarce. In this paper, we analyse two unique datasets collected in 2001 (N = 18,428) and in 2010 (N = 17,998) containing data on 9 countries of the former Soviet Union, exploring how mental health inequalities have changed between 2001 and 2010. Using regression analysis, as well as the indirect standardization approach, we found that mental health appears to have substantially improved in most studied countries during the past decade. Specifically, both the proportion of people with poor mental health, as well as wealth-related inequalities in poor mental health, decreased in almost all countries, except Georgia. Hence, we did not find evidence of a trade-off between changes in average and distributional mental health indicators between 2001 and 2010. Our findings give ground for optimism that at least on these measures, the most difficult times associated with the transition to a market economy in this region may be coming to an end. PMID- 25461872 TI - Environmental disorder and functional decline among older adults: a layered context approach. AB - Environmental context is widely recognized as a critical influence on older adults' well-being. Disorderly conditions, in particular, are believed to threaten health and to potentially accelerate functional decline. The current article develops a layered context approach that integrates neighborhood and household disorder and considers their impact on various status groups of older adults in American society. Using two waves of the National Social Life, Health, and Aging Project (n = 1608), we assess longitudinal fall risk and the incidence of functional limitations as a function of layered environmental risk-constructs measured systematically by trained observers. Results indicate a weak/moderate correlation between neighborhood and household disorder (r = 0.29). In multivariate analysis, disorderly household conditions raise the risk of falling, particularly for older adults with at least a high school level of education. Neighborhood disorder, moreover, was associated with incident functional limitations only among the most educated seniors. Together, these findings highlight the complex interplay between older people and their environments and the importance of investigating differential vulnerability in the effects of layered contextual risk. PMID- 25461870 TI - Racial/ethnic differences in use of alcohol, tobacco, and marijuana: is there a cross-over from adolescence to adulthood? AB - Black adolescents in the US are less likely to use alcohol, marijuana, and tobacco compared with non-Hispanic Whites, but little is known about the consistency of these racial/ethnic differences in substance use across the lifecourse. Understanding lifecourse patterning of substance use is critical to inform prevention and intervention efforts. Data were drawn from four waves of the National Longitudinal Study of Adolescent Health (Add Health; Wave 1 (mean age = 16): N = 14,101; Wave 4 (mean age = 29): N = 11,365). Outcomes included alcohol (including at-risk drinking, defined as 5+/4+ drinks per drinking occasion or 14+/7+ drinks per week on average for men and women, respectively), cigarette, and marijuana use in 30-day/past-year. Random effects models stratified by gender tested differences-in-differences for wave by race interactions, controlling for age, parents' highest education/income, public assistance, and urbanicity. Results indicate that for alcohol, Whites were more likely to use alcohol and engage in at-risk alcohol use at all waves. By mean age 29.9, for example, White men were 2.1 times as likely to engage in at-risk alcohol use (95% C.I. 1.48-2.94). For cigarettes, Whites were more likely to use cigarettes and smoked more at Waves 1 through 3; there were no differences by Wave 4 for men and a diminished difference for women, and difference-in difference models indicated evidence of convergence. For marijuana, there were no racial/ethnic differences in use for men at any wave. For women, by Wave 4 there was convergence in marijuana use and a cross-over in frequency of use among users, with Black women using more than White women. In summary, no convergence or cross-over for racial/ethnic differences through early adulthood in alcohol use; convergence for cigarette as well as marijuana use. Lifecourse patterns of health disparities secondary to heavy substance use by race and ethnicity may be, at least in part, due to age-related variation in cigarette and marijuana use. PMID- 25461873 TI - Mental health and general wellness in the aftermath of Hurricane Ike. AB - Exposure to natural disasters has been linked to a range of adverse outcomes, including mental health problems (e.g., posttraumatic stress symptoms [PTSS], depression), declines in role functioning (e.g., occupational difficulties), and physical health problems (e.g., somatic complaints). However, prior research and theory suggest that the modal postdisaster response in each of these domains is resilience, defined as low levels of symptoms or problems in a given outcome over time, with minimal elevations that are limited to the time period during the disaster and its immediate aftermath. However, the extent to which disaster survivors exhibit mental health wellness (resilience across multiple mental health conditions) or general wellness (resilience across mental health, physical health, and role functioning domains) remains unexplored. The purpose of this study was to quantify mental health and general wellness, and to examine predictors of each form of wellness, in a three-wave population-based study of Hurricane Ike survivors (N = 658). Latent class growth analysis was used to determine the frequency of resilience on four outcomes (PTSS: 74.9%; depression: 57.9%; functional impairment: 45.1%; days of poor health: 52.6%), and cross tabulations were used to determine the frequency of mental health wellness (51.2%) and general wellness (26.1%). Significant predictors of both mental health and general wellness included lower peri-event emotional reactions and higher community-level collective efficacy; loss of sentimental possessions or pets and disaster-related financial loss were negative predictors of mental health wellness, and loss of personal property was a negative predictor of general wellness. The results suggest that studies focusing on a single postdisaster outcome may have overestimated the prevalence of mental health and general wellness, and that peri-event responses, personal property loss and collective efficacy have a cross-cutting influence across multiple domains of postdisaster functioning. PMID- 25461874 TI - Are neighborhood bonding and bridging social capital protective against depressive mood in old age? A multilevel analysis in Japan. AB - While the importance of distinguishing between bonding and bridging social capital is now understood, evidence remains sparse on their contextual effects on health. We examined the associations of neighborhood bonding and bridging social capital with depressive mood among older Japanese. A questionnaire survey of all community residents aged 65 and older in the city of Yabu, Hyogo Prefecture, Japan was conducted in July and August 2012. Bonding and bridging social capital were assessed by evaluating individual homogeneous and heterogeneous social networks in relation to age, gender, and socioeconomic status. Individual responses in each neighborhood were aggregated to create an index of neighborhood level bonding/bridging social capital. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the associations of such social capital with depressive mood using multilevel binomial logistic regression analysis. Of the 7271 questionnaires distributed, 6416 were analyzed (covering 152 administrative neighborhoods). Approximately 56.8% of respondents were women, and the mean age was 76.2 +/- 7.1 years. Neighborhood-level bonding social capital was inversely associated with depressive mood (OR = 0.84, 95% CI = 0.75 0.94), but neighborhood-level bridging social capital was not. Gender-stratified analysis revealed that neighborhood-level bonding social capital was inversely associated with depressive mood in both genders (OR = 0.83, 95% CI = 0.72-0.96 for men; OR = 0.85, 95% CI = 0.72-0.99 for women), while neighborhood-level bridging social capital was positively associated with depressive mood in women (OR = 1.15, 95% CI = 1.00-1.34). There was also a significant interaction between individual- and neighborhood-level bonding social capital, indicating that people with a weaker homogeneous network and living in a neighborhood with weaker bonding social capital were more likely to have depressive mood. Our results suggest that neighborhood social capital does not necessarily benefit mental health in old age. These findings might stimulate further discussion on the relationship of bonding and bridging social capital with mental health. PMID- 25461875 TI - Prestige rankings of chronic diseases and disabilities. A survey among professionals in the disability field. AB - Disabled people constitute the world's largest minority; too little is known about the internal structure and valuations of that minority. We investigate whether prestige rankings of different chronic diseases and disabilities can be elicited from a community of disability non-governmental organizations (NGOs). A survey was performed in a sample of NGO professionals in Norway in late 2013 and early 2014. Two copies of a questionnaire was sent to 92 national and regional offices of disability NGOs requesting a response from either senior employees or elected officials, preferably one of each. Outcome measures were ratings on a 1-9 scale of the prestige these respondents believed most professionals in their field would accord to a sample of 38 different conditions. We find that there is a prestige hierarchy of chronic diseases and disabilities in the disability field. In this hierarchy, somatic conditions that are strongly associated with medical treatment were placed higher than either conditions that are characterized by permanence, or conditions are associated with psychosomatic etiologies. The elicited prestige hierarchy is at odds with prevalent normative positions in the disability field; there is a lack of fit between some of the field's central political goals and its internal evaluations. We propose that its structure can be explained through a) influence from the medical field, b) organization history, size, and prominence, and c) issues of credibility, shame and blame. Further research should be conducted into the structure and valuations of the disability field in general and people with disabilities and chronic diseases in particular. PMID- 25461877 TI - Framing in policy processes: a case study from hospital planning in the National Health Service in England. AB - This paper reports from an ethnographic study of hospital planning in England undertaken between 2006 and 2009. We explored how a policy to centralise hospital services was espoused in national policy documents, how this shifted over time and how it was translated in practice. We found that policy texts defined hospital planning as a clinical issue and framed decisions to close hospitals or hospital departments as based on the evidence and necessary to ensure safety. We interpreted this framing as a rhetorical strategy for implementing organisational change in the context of community resistance to service closure and a concomitant policy emphasising the importance of public and patient involvement in planning. Although the persuasive power of the framing was limited, a more insidious form of power was identified in the way the framing disguised the political nature of the issue by defining it as a clinical problem. We conclude by discussing how the clinical rationale constrains public participation in decisions about the delivery and organisation of healthcare and restricts the extent to which alternative courses of action can be considered. PMID- 25461876 TI - Social norms and its correlates as a pathway to smoking among young Latino adults. AB - Socially and culturally embedded norms regarding smoking may be one pathway by which individuals adopt smoking behaviors. However, few studies have examined if social norms operate in young adults, a population at high risk of becoming regular smokers. There is also little research examining correlates of social norms in populations with a large immigrant segment, where social norms are likely to differ from the receiving country and could contribute to a better understanding of previously reported acculturation-health associations. Using data from a nationally representative sample of young adults in the United States reached via a novel cell-phone sampling design, we explored the relationships between acculturation proxies (nativity, language spoken and generational status), socioeconomic position (SEP), smoking social norms and current smoking status among Latinos 18-34 years of age (n = 873). Specifically, we examined if a measure of injunctive norms assessed by asking participants about the acceptability of smoking among Latino co-ethnic peers was associated with acculturation proxies and SEP. Results showed a strong gradient in smoking social norms by acculturation proxies, with significantly less acceptance of smoking reported among the foreign-born and increasing acceptance among those speaking only/mostly English at home and third-generation individuals. No consistent and significant pattern in smoking social norms was observed by education, income or employment status, possibly due to the age of the study population. Lastly, those who reported that their Latino peers do not find smoking acceptable were significantly less likely to be current smokers compared to those who said their Latino peers were ambivalent about smoking (do not care either way) in crude models, and in models that adjusted for age, sex, generational status, language spoken, and SEP. This study provides new evidence regarding the role of social norms in shaping smoking behaviors among Latino young adults and suggests distinct influences of acculturation proxies and socioeconomic condition on smoking social norms in this population. PMID- 25461878 TI - Developing empirically supported theories of change for housing investment and health. AB - The assumption that improving housing conditions can lead to improved health may seem a self-evident hypothesis. Yet evidence from intervention studies suggests small or unclear health improvements, indicating that further thought is required to refine this hypothesis. Articulation of a theory can help avoid a black box approach to research and practice and has been advocated as especially valuable for those evaluating complex social interventions like housing. This paper presents a preliminary theory of housing improvement and health based on a systematic review conducted by the authors. Following extraction of health outcomes, data on all socio-economic impacts were extracted by two independent reviewers from both qualitative and quantitative studies. Health and socio economic outcome data from the better quality studies (n = 23/34) were mapped onto a one page logic models by two independent reviewers and a final model reflecting reviewer agreement was prepared. Where there was supporting evidence of links between outcomes these were indicated in the model. Two models of specific improvements (warmth & energy efficiency; and housing led renewal), and a final overall model were prepared. The models provide a visual map of the best available evidence on the health and socio-economic impacts of housing improvement. The use of a logic model design helps to elucidate the possible pathways between housing improvement and health and as such might be described as an empirically based theory. Changes in housing factors were linked to changes in socio-economic determinants of health. This points to the potential for longer term health impacts which could not be detected within the lifespan of the evaluations. The developed theories are limited by the available data and need to be tested and refined. However, in addition to providing one page summaries for evidence users, the theory may usefully inform future research on housing and health. PMID- 25461879 TI - When does marketisation lead to privatisation? Profit-making in English health services after the 2012 Health and Social Care Act. AB - Governments world-wide have attempted to use market mechanisms and privatisation to increase the quality and/or reduce the cost of healthcare. England's Health and Social Care Act 2012 is an attempt to promote privatisation through marketisation in the National Health Service (NHS). While the health policy literature tends to assume that privatisation follows from private-sector entry points, we argue that this is more likely if firms expect to make a profit. This paper examines the link between privatisation and marketisation in England drawing on 32 semi-structured interviews with private-sector and public-sector respondents, campaigners, and other experts conducted 6-10 months after the implementation of the 2012 Act. By generating a theoretical framework on the conditions of profitability we seek a better understanding of the conditions under which marketisation leads to privatisation. We find that significant barriers to profit-making remain after the reforms, including a top-down squeeze on prices, uncertainty in market rules, state dominance of funding and provision, and failures to depoliticise the market. These factors restrict private-sector involvement by frustrating profit-making. Where profits are made they are through reduced unit costs and high volumes by a longstanding incumbent in a particular market segment. This, however, restricts marketisation by reinforcing entry barriers. PMID- 25461880 TI - Hybridity as a process of technology's 'translation': customizing a national Electronic Patient Record. AB - This paper explores how national Electronic Patient Record (EPR) systems are customized in local settings and, in particular, how the context of their origin plays out with the context of their use. It shows how representations of healthcare organizations and of local clinical practice are built into EPR systems within a complex context whereby different stakeholder groups negotiate to produce an EPR package that aims to meet both local and generic needs. The paper draws from research into the implementation of the National Care Record Service, a part of the National Programme for Information Technology (NPfIT), in the English National Health Service (NHS). The paper makes two arguments. First, customization of national EPR is a distributed process that involves cycles of 'translation', which span across geographical, cultural and professional boundaries. Second, 'translation' is an inherently political process during which hybrid technology gets consolidated. The paper concludes, that hybrid technology opens up possibilities for standardization of healthcare. PMID- 25461881 TI - Multiple imputation for assessment of exposures to drinking water contaminants: evaluation with the Atrazine Monitoring Program. AB - BACKGROUND: Drinking water may contain pollutants that harm human health. The frequency of pollutant monitoring may occur quarterly, annually, or less frequently, depending upon the pollutant, the pollutant concentration, and community water system. However, birth and other health outcomes are associated with narrow time-windows of exposure. Infrequent monitoring impedes linkage between water quality and health outcomes for epidemiological analyses. OBJECTIVES: To evaluate the performance of multiple imputation to fill in water quality values between measurements in community water systems (CWSs). METHODS: The multiple imputation method was implemented in a simulated setting using data from the Atrazine Monitoring Program (AMP, 2006-2009 in five Midwestern states). Values were deleted from the AMP data to leave one measurement per month. Four patterns reflecting drinking water monitoring regulations were used to delete months of data in each CWS: three patterns were missing at random and one pattern was missing not at random. Synthetic health outcome data were created using a linear and a Poisson exposure-response relationship with five levels of hypothesized association, respectively. The multiple imputation method was evaluated by comparing the exposure-response relationships estimated based on multiply imputed data with the hypothesized association. RESULTS: The four patterns deleted 65-92% months of atrazine observations in AMP data. Even with these high rates of missing information, our procedure was able to recover most of the missing information when the synthetic health outcome was included for missing at random patterns and for missing not at random patterns with low-to moderate exposure-response relationships. CONCLUSIONS: Multiple imputation appears to be an effective method for filling in water quality values between measurements. PMID- 25461882 TI - High-resolution delineation of chlorinated volatile organic compounds in a dipping, fractured mudstone: Depth- and strata-dependent spatial variability from rock-core sampling. AB - Synthesis of rock-core sampling and chlorinated volatile organic compound (CVOC) analysis at five coreholes, with hydraulic and water-quality monitoring and a detailed hydrogeologic framework, was used to characterize the fine-scale distribution of CVOCs in dipping, fractured mudstones of the Lockatong Formation of Triassic age, of the Newark Basin in West Trenton, New Jersey. From these results, a refined conceptual model for more than 55years of migration of CVOCs and depth- and strata-dependent rock-matrix contamination was developed. Industrial use of trichloroethene (TCE) at the former Naval Air Warfare Center (NAWC) from 1953 to 1995 resulted in dense non-aqueous phase liquid (DNAPL) TCE and dissolved TCE and related breakdown products, including other CVOCs, in underlying mudstones. Shallow highly weathered and fractured strata overlie unweathered, gently dipping, fractured strata that become progressively less fractured with depth. The unweathered lithology includes black highly fractured (fissile) carbon-rich strata, gray mildly fractured thinly layered (laminated) strata, and light-gray weakly fractured massive strata. CVOC concentrations in water samples pumped from the shallow weathered and highly fractured strata remain elevated near residual DNAPL TCE, but dilution by uncontaminated recharge, and other natural and engineered attenuation processes, have substantially reduced concentrations along flow paths removed from sources and residual DNAPL. CVOCs also were detected in most rock-core samples in source areas in shallow wells. In many locations, lower aqueous concentrations, compared to rock core concentrations, suggest that CVOCs are presently back-diffusing from the rock matrix. Below the weathered and highly fractured strata, and to depths of at least 50 meters (m), groundwater flow and contaminant transport is primarily in bedding-plane-oriented fractures in thin fissile high-carbon strata, and in fractured, laminated strata of the gently dipping mudstones. Despite more than 18 years of pump and treat (P&T) remediation, and natural attenuation processes, CVOC concentrations in aqueous samples pumped from these deeper strata remain elevated in isolated intervals. DNAPL was detected in one borehole during coring at a depth of 27 m. In contrast to core samples from the weathered zone, concentrations in core samples from deeper unweathered and unfractured strata are typically below detection. However, high CVOC concentrations were found in isolated samples from fissile black carbon-rich strata and fractured gray laminated strata. Aqueous-phase concentrations were correspondingly high in samples pumped from these strata via short-interval wells or packer-isolated zones in long boreholes. A refined conceptual site model considers that prior to P&T remediation groundwater flow was primarily subhorizontal in the higher permeability near surface strata, and the bulk of contaminant mass was shallow. CVOCs diffused into these fractured and weathered mudstones. DNAPL and high concentrations of CVOCs migrated slowly down in deeper unweathered strata, primarily along isolated dipping bedding-plane fractures. After P&T began in 1995, using wells open to both shallow and deep strata, downward transport of dissolved CVOCs accelerated. Diffusion of TCE and other CVOCs from deeper fractures penetrated only a few centimeters into the unweathered rock matrix, likely due to sorption of CVOCs on rock organic carbon. Remediation in the deep, unweathered strata may benefit from the relatively limited migration of CVOCs into the rock matrix. Synthesis of rock core sampling from closely spaced boreholes with geophysical logging and hydraulic testing improves understanding of the controls on CVOC delineation and informs remediation design and monitoring. PMID- 25461883 TI - Reaction front formation in contaminant plumes. AB - The formation of successive fronts in contaminated groundwater plumes by subsoil bacterial action is a commonly accepted feature of their propagation, but it is not obviously clear from a mathematical standpoint quite how such fronts are formed or propagate. In this paper we show that these can be explained by combining classical reaction-diffusion theory involving just two reactants (oxidant and reductant), and a secondary reaction in which a reactant on one side of such a front is (re-)formed on the other side of the front via diffusion of its product across the front. We give approximate asymptotic solutions for the reactant profiles, and the propagation rate of the front. PMID- 25461884 TI - In situ biostimulation of petroleum hydrocarbon degradation by nitrate and phosphate injection using a dipole well configuration. AB - The main aim of this study was to explore the feasibility of source zone bioremediation by nitrate and nutrient injection in a crude-oil contaminated aquifer using a recirculating well dipole. Groundwater pumped from a downgradient well at a rate of 2.5m(3)h(-1) was enriched with bromide (tracer), nitrate and ammonium phosphate and injected in a well 40 m upgradient. The test was run for 49 days with solute injection, followed by 65 days of dipole operation without solute addition. The resulting bromide breakthrough curve allowed quantifying a first-order leakage coefficient of 0.017 day(-1) from the dipole, whereas from the nitrate data a first-order nitrate consumption rate of 0.075 day(-1) was determined. Dissolved hydrocarbon concentrations including benzene decreased to non-detect in 84days but experienced important rebounds after ending circulation. Nitrite accumulated temporarily but was consumed entirely when solute injection stopped. The mass balance calculations revealed that about 83% of the nitrate was used for hydrocarbon degradation, with the remaining being used for oxidation of reduced sulfur. A reactive transport model was used for the delineation of the treated zone. This model suggested that denitrification influenced flow and transport in the dipole. It is concluded that successful promotion of denitrifying hydrocarbon degradation is easily obtained in this aquifer and enables to abate dissolved concentrations, and that dipole configuration is a good option. PMID- 25461885 TI - Sustainable in-well vapor stripping: A design, analytical model, and pilot study for groundwater remediation. AB - A sustainable in-well vapor stripping system is designed as a cost-effective alternative for remediation of shallow chlorinated solvent groundwater plumes. A solar-powered air compressor is used to inject air bubbles into a monitoring well to strip volatile organic compounds from a liquid to vapor phase while simultaneously inducing groundwater circulation around the well screen. An analytical model of the remediation process is developed to estimate contaminant mass flow and removal rates. The model was calibrated based on a one-day pilot study conducted in an existing monitoring well at a former dry cleaning site. According to the model, induced groundwater circulation at the study site increased the contaminant mass flow rate into the well by approximately two orders of magnitude relative to ambient conditions. Modeled estimates for 5h of pulsed air injection per day at the pilot study site indicated that the average effluent concentrations of dissolved tetrachloroethylene and trichloroethylene can be reduced by over 90% relative to the ambient concentrations. The results indicate that the system could be used cost-effectively as either a single- or multi-well point technology to substantially reduce the mass of dissolved chlorinated solvents in groundwater. PMID- 25461886 TI - Modeling the effects of water velocity on TiO2 nanoparticles transport in saturated porous media. AB - The transport of manufactured titanium dioxide (TiO2, rutile) nanoparticles (NP) in porous media was investigated under saturated conditions. Experiments were carried out with different fluid velocities, with values in the range of observed velocities in alluvial aquifers. As reported on the literature for different kinds of NPs, the amount of retained NPs decreased when the water velocity increased. Moreover, no retention was observed for ionic strength values smaller than 5mM. A transport model coupling convective-dispersive transport with a Langmuirian kinetic deposition was used to fit the BTCs. Empirical linear equations were developed to estimate the attachment rate ka and the maximal solid phase concentration smax. Both parameters were found to be linearly depending on the collector efficiency (eta0). It was also observed that attachment efficiency (alpha) did not change with increase of water velocity under the given experimental conditions and that the model had a low sensitivity to alpha. Based on these estimates of the retention parameters, the classical dispersion convection model coupled with a Langmuir type adsorption model was able to reproduce quite well the observed TiO2 breakthrough curves for every fluid velocity used in the experiments. PMID- 25461887 TI - Comparison of unsaturated flow and solute transport through waste rock at two experimental scales using temporal moments and numerical modeling. AB - This study analyzed and compared unsaturated flow response and tracer breakthrough curves from a 10-m high constructed pile experiment (CPE) in the field (Antamina, Peru) and two 0.8m high laboratory-based columns. Similar materials were used at both experimental scales, with the exception of a narrower grain size distribution range for the smaller column tests. Observed results indicate that flow and solute transport regimes between experimental scales were comparable and dominated by flow and solute migration through granular matrix materials. These results are supported by analogous breakthrough curves (normalized to cross-sectional area and flow path length) that suggest observation- or smaller-scale heterogeneities within the porous media have been homogenized or smoothed at the transport-scale, long breakthrough tails, and similar recovered tracer mass fractions (i.e., 0.72-0.80) at the end of the experiment. CPE breakthrough curves do indicate a portion of the fluid flow follows rapid flow paths (open void or film flow); however, this portion accounts for a minor (i.e., ~0.1%) component of the overall flow and transport regime. Flow-corrected temporal moment analysis was used to estimate flow and transport parameter values; however large temporal variations in flow indicate that this method is better suited for conceptualizing transport regimes. In addition, a dual-porosity mobile-immobile (MIM), rate-limited mass-transfer approach was able to simulate tracer breakthrough and the dominant transport regimes from both scales. Dispersivity values used in model simulations reflect a scale-dependency, whereby column values were approximately 2* smaller than those values applied in CPE simulations. The mass-transfer coefficient, for solute transport between mobile and immobile regions, was considered as a model calibration factor. Column experiments are characterized by a larger "mobile to immobile" porosity ratio and a shorter experimental duration and flow path, which supports larger mass transfer coefficient values (relative to the CPE). These results demonstrate that laboratory-based experiments may be able to mimic flow regimes observed in the field; however, the requirement of scale-dependent dispersivities and mass transfer coefficients indicates that these tests may be more limited in understanding larger-scale solute transport between regions of different mobility. Nevertheless, the results of this study suggest that the reasonably simplistic modeling approaches utilized in this study may be applied at other field sites to estimate parameters and conceptualize dominant transport processes through highly heterogeneous, unsaturated material. PMID- 25461888 TI - Stimulating in situ denitrification in an aerobic, highly permeable municipal drinking water aquifer. AB - A preliminary trial of a cross-injection system (CIS) was designed to stimulate in situ denitrification in an aquifer servicing an urban community in southern Ontario. It was hypothesized that this remedial strategy could be used to reduce groundwater nitrate in the aquifer such that it could remain in use as a municipal supply until the beneficial effects of local reduced nutrient loadings lead to long-term water quality improvement at the wellfield. The CIS application involved injecting a carbon source (acetate) into the subsurface using an injection-extraction well pair positioned perpendicular to the regional flow direction, up-gradient of the water supply wells, with the objective of stimulating native denitrifying bacteria. The pilot remedial strategy was targeted in a high nitrate flux zone within an aerobic and heterogeneous section of the glacial sand and gravel aquifer. Acetate injections were performed at intervals ranging from daily to bi-daily. The carbon additions led to general declines in dissolved oxygen concentrations; decreases in nitrate concentration were localized in aquifer layers where velocities were estimated to be less than 0.5m/day. NO3-(15)N and NO3-(18)O isotope data indicated the nitrate losses were due to denitrification. Relatively little nitrate was removed from groundwater in the more permeable strata, where velocities were estimated to be on the order of 18 m/day or greater. Overall, about 11 percent of the nitrate mass passing through the treatment zone was removed. This work demonstrates that stimulating in situ denitrification in an aerobic, highly conductive aquifer is challenging but achievable. Further work is needed to increase rates of denitrification in the most permeable units of the aquifer. PMID- 25461889 TI - Chemical modification of the plant isoprenoid cytokinin N(6)-isopentenyladenosine yields a selective inhibitor of human enterovirus 71 replication. AB - In this study, we demonstrate that N(6)-isopentenyladenosine, which essentially is a plant cytokinin-like compound, exerts a potent and selective antiviral effect on the replication of human enterovirus 71 with an EC50 of 1.0 +/- 0.2 MUM and a selectivity index (SI) of 5.7. The synthesis of analogs with modification of the N(6)-position did not result in a lower EC50 value. However, in particular with the synthesis of N(6)-(5-hexene-2-yne-1-yl)adenosine (EC50 = 4.3 +/- 1.5 MUM), the selectivity index was significantly increased: because of a reduction in the adverse effect of this compound on the host cells, an SI > 101 could be calculated. With this study, we for the first time provide proof that a compound class that is based on the plant cytokinin skeleton offers an interesting starting point for the development of novel antivirals against mammalian viruses, in the present context in particular against enterovirus 71. PMID- 25461890 TI - Systematic assessment of coordinated activity cliffs formed by kinase inhibitors and detailed characterization of activity cliff clusters and associated SAR information. AB - From currently available kinase inhibitors and their activity data, clusters of coordinated activity cliffs were systematically derived and subjected to cluster index and index map analysis. Type I-like inhibitors with well-defined IC50 measurements were found to provide a large knowledge base of activity cliff clusters for 266 targets from nine kinase groups. On the basis of index map analysis, these clusters were systematically organized according to structural similarity of inhibitors and activity cliff diversity and prioritized for structure-activity relationship (SAR) analysis. From prioritized clusters, interpretable SAR information can be extracted. It is also shown that activity cliff clusters formed by ATP site-directed inhibitors often represent local SAR environments of rather different complexity and interpretability. In addition, activity cliff clusters including promiscuous kinase inhibitors have been determined. Only a small subset of inhibitors was found to change activity cliff roles in different clusters. The activity cliff clusters described herein and their index map organization substantially enrich SAR information associated with kinase inhibitors in compound subsets of limited size. The cluster and index map information is made available upon request to provide opportunities for further SAR exploration. On the basis of our analysis and the data provided, activity cliff clusters and corresponding inhibitor series for kinase targets of interest can be readily selected. PMID- 25461891 TI - Design, synthesis, and bioevaluation of paeonol derivatives as potential anti-HBV agents. AB - Hepatitis B virus (HBV) is a causative reagent that frequently causes progressive liver diseases, leading to the development of acute, chronic hepatitis, cirrhosis, and eventually hepatocellular carcinoma (HCC). Despite several antiviral drugs including interferon-alpha and nucleotide derivatives are approved for clinical treatment for HBV, critical issues remain unresolved, e.g., low-to-moderate efficacy, adverse side effects, and resistant strains. In this study, novel Paeonol-phenylsulfonyl derivatives were synthesized and their antiviral effect against HBV was evaluated. The experimental results indicated that these compounds process significant antiviral potential, including the inhibition of viral antigen expression and secretion, and the suppression of HBV viral DNA replication. Among compounds synthesized in this research, compound 2 acetyl-5-methoxyphenyl 4-methoxybenzenesulfonate (7f) had the most potent inhibitory activity with IC50 value of 0.36 MUM, and high selectivity index, SI (TC50/IC50) 47.75; which exhibited an apparent inhibition effect on viral gene expression and viral propagation in cell culture model. So, we believe our compounds could serve as reservoir for antiviral drug development. PMID- 25461892 TI - Piperazine derivatives: synthesis, inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase and SAR studies. AB - The Mycobacterium tuberculosis NADH-dependent enoyl-acyl carrier protein reductase (MtInhA) catalyzes hydride transfer to long-chain enoyl thioester substrates. MtInhA is a member of the mycobacterial type II dissociated fatty acid biosynthesis system, and is the bona fide target for isoniazid, the most prescribed drug for tuberculosis treatment. Here, a series of piperazine derivatives was synthesized and screened as MtInhA inhibitors, which resulted in the identification of compounds with IC50 values in the submicromolar range. A structure-activity relationship (SAR) evaluation indicated the importance of the chemical environment surrounding the carbonyl group for inhibition. In addition, the structure of one selected compound was supported by crystallographic studies, and experimental geometrical values were compared with semi-empirical quantum chemical calculations. Furthermore, the mode of inhibition and inhibitory dissociation constants were determined for the nine most active compounds. These findings suggest that these 9H-fluoren-9-yl-piperazine-containing compounds interact with MtInhA at the enoyl thioester (2-trans-dodecenoyl-CoA) substrate binding site. PMID- 25461893 TI - Synthesis of mevalonate- and fluorinated mevalonate prodrugs and their in vitro human plasma stability. AB - The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro- and 6,6,6-trifluoro-5 diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro- and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates. PMID- 25461894 TI - Several genes encoding enzymes with the same activity are necessary for aerobic fungal degradation of cellulose in nature. AB - The cellulose-degrading fungal enzymes are glycoside hydrolases of the GH families and lytic polysaccharide monooxygenases. The entanglement of glycoside hydrolase families and functions makes it difficult to predict the enzymatic activity of glycoside hydrolases based on their sequence. In the present study we further developed the method Peptide Pattern Recognition to an automatic approach not only to find all genes encoding glycoside hydrolases and lytic polysaccharide monooxygenases in fungal genomes but also to predict the function of the genes. The functional annotation is an important feature as it provides a direct route to predict function from primary sequence. Furthermore, we used Peptide Pattern Recognition to compare the cellulose-degrading enzyme activities encoded by 39 fungal genomes. The results indicated that cellobiohydrolases and AA9 lytic polysaccharide monooxygenases are hallmarks of cellulose-degrading fungi except brown rot fungi. Furthermore, a high number of AA9, endocellulase and beta glucosidase genes were identified, not in what are known to be the strongest, specialized lignocellulose degraders but in saprophytic fungi that can use a wide variety of substrates whereas only few of these genes were found in fungi that have a limited number of natural, lignocellulotic substrates. This correlation suggests that enzymes with different properties are necessary for degradation of cellulose in different complex substrates. Interestingly, clustering of the fungi based on their predicted enzymes indicated that Ascomycota and Basidiomycota use the same enzymatic activities to degrade plant cell walls. PMID- 25461895 TI - Racial segregation and quality of care disparity in US nursing homes. AB - In this paper, we examine the contributions of travel distance and preferences for racial homogeneity as sources of nursing home segregation and racial disparities in nursing home quality. We first theoretically characterize the distinctive implications of these mechanisms for nursing home racial segregation. We then use this model to structure an empirical analysis of nursing home sorting. We find little evidence of differential willingness to pay for quality by race among first-time nursing home entrants, but do find significant distance and race-based preference effects. Simulation exercises suggest that both effects contribute importantly to racial disparities in nursing home quality. PMID- 25461896 TI - Long-run effects of gestation during the Dutch Hunger Winter famine on labor market and hospitalization outcomes. AB - The Dutch Hunger Winter (1944/45) is the most-studied famine in the literature on long-run effects of malnutrition in utero. Its temporal and spatial demarcations are clear, it was severe, it was not anticipated, and nutritional conditions in society were favorable and stable before and after the famine. This is the first study to analyze effects of in utero exposure on labor market outcomes and hospitalization late in life, and the first to use register data covering the full Dutch population to examine long-run effects of this famine. We provide results of famine exposure by sub-interval of gestation. We find a significantly negative effect of exposure during the first trimester of gestation on employment outcomes 53 or more years after birth. Hospitalization rates in the years before retirement are higher after middle or late gestational exposure. PMID- 25461897 TI - Civil conflict, gender-specific fetal loss, and selection: a new test of the Trivers-Willard hypothesis. AB - A sizeable economics literature explores the effect of prenatal shocks on later health or socioeconomic status. Work in other disciplines, following the seminal contribution of Trivers and Willard (1973), suggests that prenatal shocks may increase fetal loss and reduce the number of boys relative to girls at birth. This has been largely ignored in the economics literature and could affect the interpretation of estimates of the effect of prenatal shocks and that of gender in other applied economics contexts. This paper analyzes the effect of in utero exposure to a shock - civil conflict in Nepal - on (i) fetal loss, and (ii) gender and (iii) health at birth. Maternal fixed effects estimates show that exposed pregnancies are more likely to result in a miscarriage and in a female birth, but exposed newborns are neither smaller nor more subject to neonatal mortality. PMID- 25461898 TI - Can health-insurance help prevent child labor? An impact evaluation from Pakistan. AB - Child labor is a common consequence of economic shocks in developing countries. We show that reducing vulnerability can affect child labor outcomes. We exploit the extension of a health and accident insurance scheme by a Pakistani microfinance institution that was set up as a randomized controlled trial and accompanied by household panel surveys. Together with increased coverage the microfinance institution offered assistance with claim procedures in treatment branches. We find lower incidence of child labor, hazardous occupations and child labor earnings caused by the innovation. Boys are more often engaged in child labor in our sample, but also seem to profit more from the insurance innovation. PMID- 25461899 TI - An adverse outcome pathway framework for neural tube and axial defects mediated by modulation of retinoic acid homeostasis. AB - Developmental toxicity can be caused through a multitude of mechanisms and can therefore not be captured through a single simple mechanistic paradigm. However, it may be possible to define a selected group of overarching mechanisms that might allow detection of the vast majority of developmental toxicants. Against this background, we have explored the usefulness of retinoic acid mediated regulation of neural tube and axial patterning as a general mechanism that, when perturbed, may result in manifestations of developmental toxicity that may cover a large part of malformations known to occur in experimental animals and in man. Through a literature survey, we have identified key genes in the regulation of retinoic acid homeostasis, as well as marker genes of neural tube and axial patterning, that may be used to detect developmental toxicants in in vitro systems. A retinoic acid-neural tube/axial patterning adverse outcome pathway (RA NTA AOP) framework was designed. The framework was tested against existing data of flusilazole exposure in the rat whole embryo culture, the zebrafish embryotoxicity test, and the embryonic stem cell test. Flusilazole is known to interact with retinoic acid homeostasis, and induced common and unique NTA marker gene changes in the three test systems. Flusilazole-induced changes were similar in directionality to gene expression responses after retinoic acid exposure. It is suggested that the RA-NTA framework may provide a general tool to define mechanistic pathways and biomarkers of developmental toxicity that may be used in alternative in vitro assays for the detection of embryotoxic compounds. PMID- 25461900 TI - Evaluation of an alternative in vitro test battery for detecting reproductive toxicants in a grouping context. AB - Previously we showed a battery consisting of CALUX transcriptional activation assays, the ReProGlo assay, and the embryonic stem cell test, and zebrafish embryotoxicity assay as 'apical' tests to correctly predict developmental toxicity for 11 out of 12 compounds, and to explain the one false negative [7]. Here we report on applying this battery within the context of grouping and read across, put forward as a potential tool to fill data gaps and avoid animal testing, to distinguish in vivo non- or weak developmental toxicants from potent developmental toxicants within groups of structural analogs. The battery correctly distinguished 2-methylhexanoic acid, monomethyl phthalate, and monobutyltin trichloride as non- or weak developmental toxicants from structurally related developmental toxicants valproic acid, mono-ethylhexyl phthalate, and tributyltin chloride, respectively, and, therefore, holds promise as a biological verification model in grouping and read across approaches. The relevance of toxicokinetic information is indicated. PMID- 25461901 TI - Developmental toxicity assessment of tanezumab, an anti-nerve growth factor monoclonal antibody, in cynomolgus monkeys (Macaca fascicularis). AB - Two intravenous studies with tanezumab, an anti-nerve growth factor monoclonal antibody, were conducted in pregnant cynomolgus monkeys to assess potential effects on pregnancy and pre- and postnatal development. Study 1 evaluated infants up to 12 months of age following weekly maternal dosing (0, 0.5, 4 or 30 mg/kg; 18 per group) from gestation day (GD) 20 through parturition. Study 2 evaluated infants 2 months postnatally following weekly maternal dosing (0, 0.5 or 30 mg/kg; 20-21 per group) from GD 20 through 48. In the absence of maternal toxicity, tanezumab increased stillbirth and post-birth infant mortality/morbidity, decreased infant growth and resulted in microscopic changes in the peripheral sympathetic and sensory nervous system of the infants at all doses. Decreased primary antibody responses and increased incidences in skin changes in infants were also observed. The no-observed-adverse-effect-level for maternal toxicity was 30 mg/kg and <0.5 mg/kg for developmental toxicity. PMID- 25461902 TI - Structural features of endocrine active chemicals--A comparison of in vivo and in vitro data. AB - Studies on reproductive toxicity need high numbers of test animals. Therefore, we investigated whether chemical structural features (SF) in combination with in vitro data on specific adverse outcome pathways (AOPs) may be used for predicting reproductive toxicity of untested chemicals. Using the OECD Toolbox and expert judgment, we identified 89 structure groups for 275 chemicals for which the results of prenatal developmental toxicity or multigeneration studies were present in the Fraunhofer database on Fertility and Developmental Toxicity in experimental animals (FeDTex) database. Likewise, we evaluated 220 chemicals which had been tested in reporter gene assays on endocrine ((anti)estrogenic and (anti)androgenic) properties in the CALUX((r)) test battery. There was a large spread of effect levels for substances within the chemical structure groups for both, in vivo and in vitro results. The groups of highest concern (diphenyl derivatives, planar conjugated systems with fused rings, phenols and organophosphates) correlated quite well, however, between the in vivo and in vitro data on estrogenic activity. For the 56 chemicals represented in both databases, lowest effect doses in vivo correlated well with the estrogenic activity in vitro. These results suggest that a panel of assays covering relevant AOPs and data on metabolism and toxicokinetics may allow prediction of relative reproductive or development toxicity potency within the identified chemical structure groups. PMID- 25461903 TI - Effect of cigarette smoking on vascular flows in pregnancies complicated by intrauterine growth restriction. AB - Exposure to tobacco smoke during pregnancy may result in intrauterine growth restriction (IUGR). In the study, the effect of tobacco smoke on vascular flows in the middle cerebral artery, umbilical artery, ductus venosus in fetuses and uterine artery in pregnancies complicated by IUGR was investigated. The study subjects were divided into three groups: smoking women with IUGR (n=31), women with idiopathic IUGR (n=28) and healthy controls (n=50). Fetal biometry and flow parameters were measured. Concentration of heavy metals and antioxidants was tested in maternal blood and fetal umbilical cord blood. The Student t test and multiple regression analysis were used. Cotinine and cadmium concentrations were significantly higher in smokers (55.23+/-54.23, 1.52+/-0.9), while metallothionein was significantly higher (22.94+/-8.64) in the idiopathic IUGR group. Strong correlations between cotinine and cadmium concentrations and cerebral-umbilical index were found. Long-term exposure to tobacco smoke deteriorates flows in vital fetal vessels. PMID- 25461904 TI - Aluminum content of human semen: implications for semen quality. AB - A deterioration of human semen quality has been observed over recent decades. A possible explanation could be an increased exposure to environmental pollutants, including aluminum. Our aim was to measure the aluminum concentration in the semen of 62 patients and to carry out a preliminary evaluation on its impact on specific semen parameters. For each patient, semen analyses were performed according to WHO guidelines. A graphite furnace atomic absorption spectrometry method was used to determine semen aluminum concentration. A cytological analysis using an aluminum-specific fluor, lumogallion, was also performed. The mean aluminum concentration in human semen was 339 MUg/L. Patients with oligozoospermia had a statistically higher aluminum concentration than others. No significant difference was observed for other semen parameters. Cytological analysis showed the presence of aluminum in spermatozoa. This study provided unequivocal evidence of high concentrations of aluminum in human semen and suggested possible implications for spermatogenesis and sperm count. PMID- 25461905 TI - Carbamazepine toxic effects in chick cardiomyocyte micromass culture and embryonic stem cell derived cardiomyocyte systems--possible protective role of antioxidants. AB - The use of carbamazepine (CBZ) during pregnancy increases cardiovascular anomalies. In this study CBZ developmental cardiotoxic effects were evaluated using chick cardiomyocyte micromass (MM) culture and mouse embryonic stem cells derived cardiomyocyte (ESDC) systems. In MM culture, CBZ only inhibited the cardiomyocyte contractile activity, while in ESDC it completely ceased the contractile activity at 200 MUM with decreased cell viability and protein content. The antioxidant superoxide dismutase (SOD) supplement in MM and ascorbic acid (AA) in ESDC showed protective effects on CBZ toxicity, but elevated levels of reactive oxygen species (ROS) production were recorded with CBZ treatment only in ESDC. CBZ has also affected cardiac connexin 43 expression in both in vitro systems. Our results indicated CBZ induced ROS stress as mechanism of developmental cardiotoxicity at early stage of cardiogenesis in ESDC system compared to MM system's differentiated cells. These toxic effects can be negated by using antioxidant agent. PMID- 25461906 TI - Egr1 is rapidly and transiently induced by estrogen and bisphenol A via activation of nuclear estrogen receptor-dependent ERK1/2 pathway in the uterus. AB - Coordinate actions of ovarian estrogen (E2) and progesterone (P4) via their own receptors are critical for establishing uterine receptivity for embryo implantation in the uterus. E2 regulates expression of an array of genes to mediate its major actions on heterogeneous uterine cell types. Here we have investigated regulatory mechanism(s) of E2 and bisphenol A (BPA), an endocrine disruptor with potent estrogenic activity on expression of early growth response 1 (Egr1), a zinc finger transcription factor that regulates cell growth, differentiation and apoptosis in the uterus. Egr1 was rapidly and transiently induced by E2 and BPA mainly in stromal cells via nuclear estrogen receptor (ER) ERK1/2 pathway. ICI 182,780, an ER antagonist, effectively inhibited their actions on EGR1 expression following ERK1/2 phosphorylation. Administration of pharmacological inhibitors for ERK1/2, but not AKT significantly blocked EGR1 expression induced by E2 and BPA. P4 effectively dampened action(s) of E2 and BPA on Egr1 expression via nuclear progesterone receptor. Its antagonistic effects were partially interfered with RU486 pretreatment. Interestingly, EGR1 is specifically induced in stromal cells surrounding implanting blastocyst. Collectively, our results show that through nuclear ER-dependent ERK1/2 phosphorylation, not only E2 but also endocrine disruptors with estrogenic activity such as BPA rapidly and transiently induce Egr1 which may be important for embryo implantation and decidualization in mouse uterus. PMID- 25461907 TI - Ursodeoxycholic acid alleviates cholestasis-induced histophysiological alterations in the male reproductive system of bile duct-ligated rats. AB - Ursodeoxycholic acid is the most widely used drug for treating cholestatic liver diseases. However, its effect on the male reproductive system alterations associated with cholestasis has never been studied. Thus, this study aimed to investigate the effect of ursodeoxycholic acid on cholestasis-induced alterations in the male reproductive system. Cholestasis was induced by bile duct ligation. Bile duct-ligated rats had higher cholestasis biomarkers and lower levels of testosterone, LH and FSH than did the Sham rats. They also had lower reproductive organs weights, and lower sperm motility, density and normal morphology than those of Sham rats. Histologically, these animals suffered from testicular tubular atrophy, interstitial edema, thickening of basement membranes, vacuolation, and depletion of germ cells. After ursodeoxycholic acid administration, cholestasis-induced structural and functional alterations were significantly ameliorated. In conclusion, ursodeoxycholic acid can ameliorate the reproductive complications of chronic cholestasis in male patients, which represents an additional benefit to this drug. PMID- 25461908 TI - Effects of in utero and lactational exposure to SbV on rat neurobehavioral development and fertility. AB - Meglumine antimoniate (MA) is a pentavalent antimony drug used to treat leishmaniases. We investigated the neurobehavioral development, sexual maturation and fertility of the offspring of MA-treated rats. Dams were administered MA (0, 75, 150, 300 mg Sb(V)/kg body wt/d, sc) from gestation day 0, throughout parturition and lactation, until weaning. At the highest dose, MA reduced the birth weight and the number of viable newborns. In the male offspring, MA did not impair development (somatic, reflex maturation, weight gain, puberty onset, open field test), sperm count, or reproductive performance. Except for a minor effect on body weight gain and vertical exploration in the open field, MA also did not affect the development of female offspring. Measurements of the Sb levels (ICP MS) in the blood of MA-treated female rats and their offspring demonstrated that Sb is transferred to the fetuses via the placenta and to the suckling pups via milk. PMID- 25461909 TI - BPA-induced apoptosis of rat Sertoli cells through Fas/FasL and JNKs/p38 MAPK pathways. AB - Bisphenol-A was examined for its effects on cultured Sertoli cells established from 18 to 22-day-old rat testes. Results indicated that exposure to BPA (0, 30, 50 and 70 MUM) decreased the cell viability in a concentration-dependent manner and induced cell apoptosis. Apoptosis-caused cell death was observed in cells exposed to 50 and 70 MUM BPA. The mRNA expressions of Fas, FasL and caspase-3 were all elevated, and the protein expressions of FasL and cleaved caspase-3 were also increased. In addition, levels of phosphorylation of JNKs/p38 MAPK were also increased and then activated JNKs/p38 MAPK up regulated target gene expressions, such as c-jun and CHOP. Translocation of NF-kappaB into nuclei indicated the activation of NF-kappaB after treatment with BPA. Taken together, observed results suggest that BPA induces apoptosis of Sertoli cells by the activation of JNKs/p38 MPAK and translocation of NF-kappaB, and Fas/FasL system plays a critical role in the initiation of apoptosis. PMID- 25461910 TI - Esophageal atresia and prenatal exposure to mycophenolate. AB - Mycophenolate mofetil is a widely prescribed immunosuppressive agent for transplant patients and autoimmune diseases. Potential teratogenic effects after in utero exposure to mycophenolate mofetil has been described in human clinical observations. The complete clinical pattern is still being delineated. We present four newborns with esophageal atresia and other congenital anomalies, prenatally exposed to mycophenolate mofetil during the first trimester. Two of the cases had other defects related to the embryopathy: microtia, eye abnormalities and oral clefts. Two cases did not show major craniofacial anomalies. We propose that esophageal atresia with or without tracheoesophageal fistula is a feature of mycophenolate embryopathy even without the presence of other major craniofacial anomalies. The human teratogenicity of MMF is reinforced by this report, and the current contraceptive recommendations about its use in fertile women are stressed. PMID- 25461911 TI - Analysis of endoplasmic reticulum stress in placentas of HIV-infected women treated with protease inhibitors. AB - Combined antiretroviral therapy has proven efficacy in decreasing vertical HIV transmission. However, endoplasmic reticulum stress is a known side effect of HIV protease inhibitors. We investigated endoplasmic reticulum stress in placentas of HIV-infected and uninfected mothers by PCR-based splicing analysis of the specific endoplasmic reticulum stress marker XBP1 in post-delivery placental samples of uninfected mothers and in HIV-infected mothers taking antiretroviral therapy. No elevated XBP1 splicing could be detected in placentas of uninfected mothers and most of the mothers receiving combined anti-retroviral therapy. However, markedly elevated XBP1 splicing was found in the placentas of three individuals on combined antiviral therapy, all receiving lopinavir or atazanavir. In vitro experiments confirmed induction of endoplasmic reticulum stress by lopinavir and atazanavir in trophoblast-derived cell lines. Since endoplasmic reticulum stress occurred in selective patients only, individual differences in susceptibility of HIV-infected mothers to protease inhibitor induced endoplasmic reticulum stress can be postulated. PMID- 25461912 TI - Changes in low levels of lead over the course of pregnancy and the association with birth outcomes. AB - Data are lacking on the effect of low level prenatal lead exposure. We examined the change in blood lead from the second trimester until delivery and the association between maternal and cord blood lead and birth outcomes in 98 participants of the CANDLE birth cohort study. Mixed effects models were constructed to assess blood lead change over pregnancy and regression models were used to explore the relationship with cord blood lead, characteristics effecting maternal lead, birth weight and gestational age. Overall, the geometric mean maternal blood level was 0.43 MUg/dL. Maternal blood lead at each time point was predictive of cord blood lead level. A 0.1 MUg/dL increase in second trimester lead was associated with lower birth weight and pre-term birth. Maternal blood lead below 1 MUg/dL behaves in a manner similar to lead at higher levels and is associated with a small decrease in birth weight and gestational age. PMID- 25461913 TI - Intestinal obstruction in pregnancy by ondansetron. AB - BACKGROUND: Ondansetron use for nausea and vomiting during pregnancy has increased in the last years, although its maternal and fetal safety is not conclusive. CASE: We describe a case of intestinal obstruction in a pregnant woman with severe nausea and vomiting of pregnancy treated with ondansetron, which is known to slow gut motility. CONCLUSION: The spontaneous reporting system of WHO confirms that this potentially life threatening complication is more common than what the peer review literature may suggest and needs to be looked into carefully, especially in view of the wide spread off-label use for NVP. PMID- 25461915 TI - The ERP response to the amount of information conveyed by words in sentences. AB - Reading times on words in a sentence depend on the amount of information the words convey, which can be estimated by probabilistic language models. We investigate whether event-related potentials (ERPs), too, are predicted by information measures. Three types of language models estimated four different information measures on each word of a sample of English sentences. Six different ERP deflections were extracted from the EEG signal of participants reading the same sentences. A comparison between the information measures and ERPs revealed a reliable correlation between N400 amplitude and word surprisal. Language models that make no use of syntactic structure fitted the data better than did a phrase structure grammar, which did not account for unique variance in N400 amplitude. These findings suggest that different information measures quantify cognitively different processes and that readers do not make use of a sentence's hierarchical structure for generating expectations about the upcoming word. PMID- 25461916 TI - Marginal neurofunctional changes in high-performing older adults in a verbal fluency task. AB - The maintenance of a high level of performance in aging has often been associated with changes in cerebral activations patterns for various cognitive components. However, relatively few studies have investigated this phenomenon in light of lexical speech production abilities, which have not been systematically found to benefit from neurofunctional reorganization during verbal fluency tasks. In this study, functional magnetic resonance imaging was used to assess overt self-paced semantic and orthographic verbal fluency tasks performed by healthy younger and older adults within a mixed block/event-related fMRI design. Behavioral results indicated similarly high levels of performance between tasks and age groups, while whole brain analysis revealed significant task-related differences in patterns of brain activity, but no significant effect of age or task-by-age interaction across the speech conditions. Only local activity differences were found between age groups. These marginal neurofunctional changes in high performing older adults are discussed in terms of task demands. PMID- 25461917 TI - The music of language: an ERP investigation of the effects of musical training on emotional prosody processing. AB - Recent studies have demonstrated the positive effects of musical training on the perception of vocally expressed emotion. This study investigated the effects of musical training on event-related potential (ERP) correlates of emotional prosody processing. Fourteen musicians and fourteen control subjects listened to 228 sentences with neutral semantic content, differing in prosody (one third with neutral, one third with happy and one third with angry intonation), with intelligible semantic content (semantic content condition--SCC) and unintelligible semantic content (pure prosody condition--PPC). Reduced P50 amplitude was found in musicians. A difference between SCC and PPC conditions was found in P50 and N100 amplitude in non-musicians only, and in P200 amplitude in musicians only. Furthermore, musicians were more accurate in recognizing angry prosody in PPC sentences. These findings suggest that auditory expertise characterizing extensive musical training may impact different stages of vocal emotional processing. PMID- 25461914 TI - Tetrabromobisphenol A activates inflammatory pathways in human first trimester extravillous trophoblasts in vitro. AB - Tetrabromobisphenol A (TBBPA) is a widely used flame retardant. Despite the presence of TBBPA in gestational tissues and the importance of proper regulation of inflammatory networks for successful pregnancy, there is no prior study on the effects of TBBPA on inflammatory responses in gestational tissues. The present study aimed to investigate TBBPA activation of inflammatory pathways, specifically cytokine and prostaglandin production, in the human first trimester placental cell line HTR-8/SVneo. TBBPA enhanced release of interleukin (IL)-6, IL 8, and prostaglandin E2 (PGE2), and suppressed TGF-beta release in HTR-8/SVneo cells. The lowest effective concentration was 10 MUM TBBPA. A commercial immune response PCR array revealed increased expression of genes involved in inflammatory pathways stimulated by TBBPA in HTR-8/SVneo cells. Because proper regulation of inflammatory mediators in the gestational compartment is necessary for normal placental development and successful pregnancy, further investigation on the impact of TBBPA-stimulated responses on trophoblast function is warranted. PMID- 25461918 TI - beta-Adrenergic blockade protects BALB/c mice against infection with a small inoculum of Leishmania mexicana mexicana (LV4). AB - In order to test the influence of the sympathetic nervous system on Leishmania mexicana infection, groups of female BALB/c mice were treated (i.p.) with the non selective beta-adrenergic receptor (beta-AR) antagonist (S)-propranolol (5mg/kg thrice a day), the beta2-AR agonist clenbuterol (1mg/kg once a day) or the alpha2 AR antagonist yohimbine (2mg/kg twice a day) during 5days. During the second day of treatments, mice were inoculated in the footpad with 1*10(6) or 1*10(3) metacyclic promastigotes of L. mexicana mexicana (LV4). The lesion size was measured weekly, and parasite burden on week 12. In mice treated with (S) propranolol, the percentage of splenic T lymphocytes producing IFN-gamma after antigen challenge was determined by flow cytometry. In mice infected with 1*10(6) parasites, only (S)-propranolol caused a reduction of footpad swelling (p<0.05, weeks 11-12), without effects on parasite burden, or in the percentage of IFN gamma-immunopositive CD4(+) or CD8(+) T lymphocytes. In mice infected with 1*10(3) parasites, the effects of treatments vs. control group were as follows: (a) inhibition of footpad swelling by (S)-propranolol (p<0.01, weeks 3-12), clenbuterol (p<0.05, weeks 7-10), and yohimbine (p<0.01, week 7); (b) a decrease of the parasite burden by (S)-propranolol (p<0.01) and yohimbine (p<0.05); (c) in control mice the percentage of CD4(+) T-cells producing IFN-gamma was 6.2+/-0.5%, while in those treated with (S)-propranolol it increased to 8.7+/-0.6% (p<0.01); (d) in control mice the percentage of CD8(+) T-cells producing IFN-gamma was 3.1+/-0.4%, while in those treated with (S)-propranolol it increased to 10.4+/ 0.2% (p<0.01). These results indicate that the blockade of beta-ARs during infection of BALB/c mice with an inoculum of L. mexicana mexicana similar to that delivered by the bite of a sand fly produces a Th1 bias in the immune response, favoring an increment of T lymphocytes secreting IFN-gamma, which correlated with a reduced parasite burden (p<0.05, Spearman's test). We suggest that beta-AR antagonists could be of therapeutic value, either as treatment or as adjuvant of vaccines for L. mexicana. PMID- 25461919 TI - Label-free selection and enrichment of liver cancer stem cells by surface niches build up with polyelectrolyte multilayer films. AB - Recent studies indicate that a small population of cancer cells exhibits stem cell properties and are referred to as cancer-initiating or cancer stem cells (CSCs). The selection and identification of cancer stem cells through methods require well-defined biomarkers and immunolabeling procedures are complicated and often unreliable. Herein, we fabricated a series of microenviroment by using polyelectrolyte multilayers (PEM) nanofilms to program and mimic hepatocellular carcinoma CSCs niches for CSCs selection with a label-free method. When cultured on PEM substrates, human cancer cell lines-Huh7 cells grew into individual round colonies and these cells displayed high marker expression of CSCs. Especially, these selected cells demonstrated significant chemo-resistant property in comparison with normal population. Therefore, we believed that niches selection and colony formation method may provide a new strategy on CSCs selection and drug evaluation for cancer therapy. PMID- 25461920 TI - pH-sensitive controlled release of doxorubicin from polyelectrolyte multilayers. AB - Controlled and stimulated release of small drug molecules from polyelectrolyte multilayers is still a challenge due to the limitations to incorporate and control the interactions between small molecules and multilayers. Herein we reported a facile method to fabricate polyelectrolyte multilayers with pH sensitive controlled release of doxorubicin (DOX). A pH-responsive polyelectrolyte was prepared by conjugating DOX onto hyaluronan (HA) via pH responsive hydrazone bond with an 8% grafting degree. The HA-DOX was then incorporated into the multilayers via the layer-by-layer assembly with poly-L lysine (PLL). The growth of the multilayers was tracked by spectroscopic ellipsometry. The morphology and structure of the films were characterized by scanning electron microscopy and UV-vis spectroscopy, respectively. The in vitro drug release experiments indicated that the release of DOX was pH-dependent: there was almost no release at pH 7.4, while the releases were significantly promoted at pH 6.0 and 5.0. Furthermore, human hepatoma (HepG2) cells were remarkably inhibited under the conditions at pH 5.0 when they were cultured with the (HA-DOX/PLL) multilayers. The multilayers with the properties of pH-sensitive DOX release would be potentially applied to the biomedical devices for tumor treatments. PMID- 25461921 TI - The prevalence of sleep-disordered breathing in children with asthma and its behavioral effects. AB - OBJECTIVES: To determine the prevalence of sleep-disordered breathing (SDB) in children with asthma compared to non-asthmatic children and to determine if behavior problems are associated with asthma and SDB. STUDY DESIGN: Cross Sectional. METHODS: Parents of 263 children with asthma and 266 controls ages 2 to 15 years attending routine pediatric office visits completed the Pediatric Sleep Questionnaire (PSQ) and the Child Behavior Checklist. Asthma severity was classified based on NIH guidelines. RESULTS: The prevalence of snoring was significantly higher in asthmatic children (35.5%) than controls (15.7%) and the prevalence of a positive PSQ was significantly higher in asthmatic children (25.9%) than controls (10.6%) (P < 0.001 for both). The effect of asthma was "dose-dependent" as children with more severe asthma had increased odds ratios for snoring and a positive PSQ. On multivariate analysis, there were significant interactions of gender with asthma and age with gender. A positive modified PSQ along with measures of socioeconomic status and age were the only independent predictors of abnormal Child Behavior Checklist scores and score classifications. CONCLUSIONS: There was a higher prevalence of SDB in asthmatic children compared to non-asthmatic children and the prevalence of SDB increased with increasing asthma severity. In multivariate analysis the role of asthma was much less clear as it predicted a positive PSQ in girls but not boys. SDB, but not asthma, was an independent predictor of behavioral problems. PMID- 25461923 TI - Electrochemical oxidation of imazapyr with BDD electrode in titanium substrate. AB - In this work we have studied the treatment of imazapyr by electrochemical oxidation with boron-doped diamond anode. Electrochemical degradation experiments were performed in a one-compartment cell containing 0.45 L of commercial formulations of herbicide in the pH range 3.0-10.0 by applying a density current between 10 and 150 mA cm(-2) and in the temperature range 25-45 degrees C. The maximum current efficiencies were obtained at lower current densities since the electrochemical system is under mass transfer control. The mineralization rate increased in acid medium and at higher temperatures. The treatment was able to completely degrade imazapyr in the range 4.6-100.0 mg L(-1), although the current charge required rises along with the increasing initial concentration of the herbicide. Toxicity analysis with the bioluminescent bacterium Vibrio fischeri showed that at higher pollutant concentrations the toxicity was reduced after the electrochemical treatment. To clarify the reaction pathway for imazapyr mineralization by OH radicals, LC-MS/MS analyses we performed together with a theoretical study. Ions analysis showed the formation of high levels of ammonium in the cathode. The main final products of the electrochemical oxidation of imazapyr with diamond thin film electrodes are formic, acetic and butyric acids. PMID- 25461924 TI - Nitrate-dependent anaerobic ferrous oxidation (NAFO) by denitrifying bacteria: a perspective autotrophic nitrogen pollution control technology. AB - The nitrate-dependent anaerobic ferrous oxidation (NAFO) is an important discovery in the fields of microbiology and geology, which is a valuable biological reaction since it can convert nitrate into nitrogen gas, removing nitrogen from wastewater. The research on NAFO can promote the development of novel autotrophic biotechnologies for nitrogen pollution control and get a deep insight into the biogeochemical cycles. In this work, batch experiments were conducted with denitrifying bacteria as biocatalyst to investigate the performance of nitrogen removal by NAFO. The results showed that the denitrifying bacteria were capable of chemolithotrophic denitrification with ferrous salt as electron donor, namely NAFO. And the maximum nitrate conversion rates (qmax) reached 57.89 mg (g VSS d)-1, which was the rate-limiting step in NAFO. Fe/N ratio, temperature and initial pH had significant influences on nitrogen removal by NAFO process, and their optimal values were 2.0 degrees C, 30.15 degrees C and 8.0 degrees C, respectively. PMID- 25461922 TI - Identification of a novel human LAP1 isoform that is regulated by protein phosphorylation. AB - Lamina associated polypeptide 1 (LAP1) is an integral protein of the inner nuclear membrane that is ubiquitously expressed. LAP1 binds to lamins and chromatin, probably contributing to the maintenance of the nuclear envelope architecture. Moreover, LAP1 also interacts with torsinA and emerin, proteins involved in DYT1 dystonia and X-linked Emery-Dreifuss muscular dystrophy disorder, respectively. Given its relevance to human pathological conditions, it is important to better understand the functional diversity of LAP1 proteins. In rat, the LAP1 gene (TOR1AIP1) undergoes alternative splicing to originate three LAP1 isoforms (LAP1A, B and C). However, it remains unclear if the same occurs with the human TOR1AIP1 gene, since only the LAP1B isoform had thus far been identified in human cells. In silico analysis suggested that, across different species, potential new LAP1 isoforms could be generated by alternative splicing. Using shRNA to induce LAP1 knockdown and HPLC-mass spectrometry analysis the presence of two isoforms in human cells was described and validated: LAP1B and LAP1C; the latter is putatively N-terminal truncated. LAP1B and LAP1C expression profiles appear to be dependent on the specific tissues analyzed and in cultured cells LAP1C was the major isoform detected. Moreover, LAP1B and LAP1C expression increased during neuronal maturation, suggesting that LAP1 is relevant in this process. Both isoforms were found to be post-translationally modified by phosphorylation and methionine oxidation and two LAP1B/LAP1C residues were shown to be dephosphorylated by PP1. This study permitted the identification of the novel human LAP1C isoform and partially unraveled the molecular basis of LAP1 regulation. PMID- 25461925 TI - Enhancement of anammox performance by Cu(II), Ni(II) and Fe(III) supplementation. AB - This study explored the influence of metal ion addition on specific anaerobic ammonium oxidation activity (SAA). Batch assays were used to demonstrate the enhancement of the SAA upon the addition of Cu2+, Ni2+ and Fe3+. The SAA was enhanced by 41.0% when the Cu2+ concentration was below 1 mg L-1, while it was improved by 63.5% at Ni2+ concentrations below 1.74 mg L-1. An enhancement of 533.2% was obtained when 3.68 mg L-1 Fe3+ was supplied. The effects of Fe3+, Cu2+ and Ni2+ on the SAA were analyzed and optimized by a response surface methodology, which demonstrated that the interaction between Fe3+ and Cu2+ was significant and that 6.61 mg Fe3+ L-1, 1.18 mg Cu2+ L-1 and 1.11 mg Ni2+ L-1 were the optimal values for metal dosing. Subsequently, an Fe3+-Cu2+-Ni2+ continuous test was carried out under optimal conditions and revealed that the addition of Fe3+, Cu2+ and Ni2+ could stimulate the reactor potential at ambient temperature. The maximum nitrogen removal rate (NRR) of the test reactor was 52.8% higher than that of the control reactor (8.1 versus 5.3 kg N m-3 d-1). Moreover, a continuous test conducted by adding Fe3+ achieved an average nitrogen removal efficiency and maximum NRR of 67.4% and 4.9 kg N m-3 d-1, respectively, while the corresponding values of the control test were 64.7% and 4.1 kg N m-3 d-1, respectively. Altogether, appropriate dosages of Cu2+, Ni2+ and Fe3+ can significantly enhance the SAA and improve the reactor capacity at ambient temperature. PMID- 25461926 TI - Efficiency of nanoscale zero-valent iron on the enhanced low molecular weight organic acid removal Pb from contaminated soil. AB - The Pb removal efficiencies from contaminated soils by low molecular weight organic acid (LMWOA) and nanoscale zero-valent iron (nZVI) were investigated through batch soil washing experiments. Results showed that significant promotion on Pb-removal with the mixed solutions of LMWOA and nZVI (p < 0.05). The Pb removal efficiencies reached 64% and 83% for mine and farmland soil by addition of 0.2 M citric acid and 2.0 g L-1 nZVI, respectively. They decreased with increasing pH from 3 to 9. The mixed solutions of LMWOA and nZVI induced Pb(II) releases processes including a rapid desorption within 4 h and a slow desorption in the following hours. The second-order model was the most appropriate for describing the kinetic processes of Pb(II) desorption. The main fractions of Pb removal were exchangeable and reducible. Compared with LMWOA, the loss rates of nitrogen, phosphorus and potassium decreased after washing with the mixed solutions. Our study suggests that combining of LMWOA and nZVI would be a promising alternative approach for remediation Pb-contaminated soils. PMID- 25461927 TI - Uranium(VI) reduction by nanoscale zero-valent iron in anoxic batch systems: the role of Fe(II) and Fe(III). AB - The role of Fe(II) and Fe(III) in U(VI) reduction by nanoscale zerovalent iron (nanoFe0) was investigated using two iron chelators 1,10-phenanthroline and triethanolamine (TEA) under a CO2-free anoxic condition. The results showed that U(VI) reduction was strongly inhibited by 1,10-phenanthroline and TEA in a pH range from 6.9 to 9.0. For instance, at pH 6.9 the observed U(VI) reduction rates decreased by 81% and 82% in the presence of 1,10-phenanthroline and TEA, respectively. The inhibition was attributed to the formation of stable complexes between 1,10-phenanthroline and Fe(II) or TEA and Fe(III). In the absence of iron chelators, U(VI) reduction can be enhanced by surface-bound Fe(II) on nanoFe0. Our results suggested that Fe(III) and Fe(II) possibly acted as an electron shuttle to ferry the electrons from nanoFe0 to U(VI), therefore a combined system with Fe(II), Fe(III) and nanoFe0 could facilitate U(VI) reductive immobilization in the contaminated groundwater. PMID- 25461928 TI - Study on the flow characteristics and the wastewater treatment performance in modified internal circulation reactor. AB - A modified internal circulation (MIC) reactor with an external circulation system was proposed and the performance of treating dyeing wastewater using both MIC and typical IC reactor were compared. Utilization of the external circulation system in the MIC reactor could dramatically improve the mixing intensity of the biomass with the wastewater and resulted in better performance. The COD removal efficiency, biogas production, volatile fatty acids and effluent color were approximately 87%, 98 L d-1, 180 mg L-1 and 100 times, respectively, in the MIC reactor with a hydraulic retention time of 5 h and organic loading rate of 15 kg COD m-3 d-1. The hydrodynamics of the MIC reactor under different flows rate of external circulation were also analyzed using computational fluid dynamics (CFD) method. The optimal flow rate of external circulation was 12 L min-1, which resulted in a corresponding up-flow velocity of 40 m h-1. The consistency of the result between experiment and simulation validated the scientificity of CFD technique applied to numerical simulation of the MIC reactor. PMID- 25461929 TI - Efficient degradation of rhodamine B using Fe-based metallic glass catalyst by Fenton-like process. AB - An efficient heterogeneous catalyst, Fe-based metallic glass (Fe-Si-B amorphous ribbon), was successfully prepared for Fenton-like degradation of rhodamine B (RhB) by a melt-spinning method. The catalyst was characterized using XRD and SEM. The effects of various reaction parameters such as H2O2 dosage, temperature, initial pH value, Fe-Si-B dosage and initial RhB concentration on the degradation of RhB were studied. Almost complete degradation of RhB (20 mg L-1) was achieved within only 10 min by 0.5 g L-1 Fe-Si-B catalyst and 1.6 mM H2O2 at pH 3.0 at 295 K. Kinetic analyses showed that the degradation process could be described by a pseudo-first-order kinetic model. The catalytic stability was also investigated and it was found that the Fe-Si-B catalyst exhibited good structural stability and no loss of performance even after three cycles. It was concluded that the Fe Si-B amorphous ribbon was a potential heterogeneous Fenton-like catalyst for industrial wastewater treatment. PMID- 25461930 TI - Electrochemical advanced oxidation for cold incineration of the pharmaceutical ranitidine: mineralization pathway and toxicity evolution. AB - Ranitidine (RNTD) is a widely prescribed histamine H2-receptor antagonist whose unambiguous presence in water sources appointed it as an emerging pollutant. Here, the degradation of 0.1 mM of this drug in aqueous medium was studied by electrochemical advanced oxidation processes (EAOPs) like anodic oxidation with electrogenerated H2O2 and electro-Fenton using Pt/carbon-felt, BDD/carbon-felt and DSA-Ti/RuO2-IrO2/carbon-felt cells. The higher oxidation power of the electro Fenton process using a BDD anode was demonstrated. The oxidative degradation of RNTD by the electrochemically generated OH radicals obeyed a pseudo-first order kinetics. The absolute rate constant for its hydroxylation reaction was 3.39 * 109 M-1 s-1 as determined by the competition kinetics method. Almost complete mineralization of the RNTN solution was reached by using a BDD anode in both anodic oxidation with electrogenerated H2O2 and electro-Fenton processes. Up to 11 cyclic intermediates with furan moiety were detected from the degradation of RNTD, which were afterwards oxidized to short-chain carboxylic acids before their mineralization to CO2 and inorganic ions such as NH4+, NO3- and SO42-. Based on identified products, a plausible reaction pathway was proposed for RNTD mineralization. Toxicity assessment by the Microtox(r) method revealed that some cyclic intermediates are more toxic than the parent molecule. Toxicity was quickly removed following the almost total mineralization of the treated solution. Overall results confirm the effectiveness of EAOPs for the efficient removal of RNTD and its oxidation by-products from water. PMID- 25461931 TI - Bioleaching of metals from steel slag by Acidithiobacillus thiooxidans culture supernatant. AB - The generation of 300-500 kg of slag per ton of the steel produced is a formidable amount of solid waste available for treatment. They usually contain considerable quantities of valuable metals. In this sense, they may become either important secondary resource if processed in eco-friendly manner for secured supply of contained metals or potential pollutants, if not treated properly. It is possible to recover metals from steel slag by applying bioleaching process. Electric arc furnace (EAF) slag sample was used for bioleaching of metals. In the present study, before bioleaching experiment water washing of an EAF slag was carried out. This reduced slag pH from 11.2 to 8.3. Culture supernatants of Acidithiobacillus thiooxidans (At. thiooxidans), Acidithiobacillus ferrooxidans (At. ferrooxidans), and Aspergillus niger (A. niger) were used for metal solubilization. At. thiooxidans culture supernatant containing 0.016 M sulfuric acid was found most effective for bioleaching of metals from an EAF slag. Maximum metal extraction was found for Mg (28%), while it was least for Mo (0.1%) in six days. Repeated bioleaching cycles increased metal recovery from 28% to 75%, from 14% to 60% and from 11% to 27%, for Mg, Zn and Cu respectively. PMID- 25461932 TI - Correlation among extracellular polymeric substances, tetracycline resistant bacteria and tetracycline resistance genes under trace tetracycline. AB - Antibiotic resistance occurrences and proliferation in activated sludge have attracted more and more attention nowadays. However, the role which extracellular polymeric substance (EPS) plays on the antibiotic resistance is not clear. The changes and correlation among EPS, tetracycline (TC) resistant bacteria (TRB) and TC resistance genes (TRGs) of sequencing batch reactors (SBRs) were investigated. Performance of SBR without TC was compared with two other SBRs to which different amounts of TC were added. Total average EPS contents were found to increase significantly from 66 mg g-1 VSS to 181 mg g-1 VSS as the TC concentrations increased from 0 to 100 MUg L-1. As the EPS content increased, TRB in sludge of the three SBRs increased significantly from 105 to 106 colony forming unit mL-1 after being exposed to TC. In addition, the concentrations of three groups of TRGs (copies mL-1) were determined by real-time fluorescence quantitative polymerase chain reaction and followed the order: efflux pump genes > ribosome protected genes > degradation enzyme genes. The numbers of TRGs in the idle stage were larger than those in the aeration sludge. Correlation coefficients (R2) between EPS and TRB in sludge were 0.823 (p < 0.01) while the correlation between EPS and total TRGs was poor (R2 = 0.463, p > 0.05). But it showed the same tendency that EPS and TRGs in sludge increased with the increasing of TC. PMID- 25461933 TI - Effect of low- and medium-pressure Hg UV irradiation on bromate removal in Advanced Reduction Process. AB - Advanced Reduction Processes (ARP) have been developed by combining UV irradiation with reducing reagents, which produces reactive reducing free radicals that degrade contaminants (e.g. vinyl chloride, 1,2-dichloroethane, perchlorate, and bromate). This study investigates bromate destruction by ARPs using medium-pressure mercury UV light lamp (UV-M) and low-pressure mercury UV light lamp (UV-L). Effects of experimental parameters including initial bromate concentration, reducing reagent (sulfite) dose, and pH on bromate removal kinetics and quantum yield were evaluated. The pseudo-first-order rate constant (kobs) by UV-M ARP was greater by 3 times than that by UV-L ARP. UV-M and UV-L achieved a complete bromate removal of an initial concentration at 500 ppb with fluences of 10.5 J cm-2 and 73.5 J cm-2, respectively. It was found that direct photolysis is a dominant mechanism with the UV-M ARP showing that the effect of sulfite dose had no apparent influence on the bromate removal, whereas kobs was dependent on the sulfite doses in UV-L/sulfite ARP. In the presence of sulfite, kobs was affected by the solution pH in both the UV-M and UV-L ARPs. The pH effect on UV-L ARP or UV-M ARP was explained by the effect of pH on the sulfite species distribution between sulfite and bisulfite or the hydrated electrons concentrations. Also it was found that dominant reaction mechanism of bromate removal was changed by initial bromate concentrations, and its behavior was varied dependent on the UV light sources. PMID- 25461934 TI - Electrokinetic remediation of inorganic and organic pollutants in textile effluent contaminated agricultural soil. AB - The discharge from the dyeing industries constitutes unfixed dyes, inorganic salts, heavy metal complexes etc., which spoil the surrounding areas of industrial sites. The present article reports the use of direct current electrokinetic technique for the treatment of textile contaminated soil. Impressed direct current voltage of 20 V facilitates the dye/metal ions movement in the naturally available dye contaminated soil towards the opposite electrode by electromigration. IrO2-RuO2-TiO2/Ti was used as anode and Ti used as cathode. UV-Visible spectrum reveals that higher dye intensity was nearer to the anode. Ni, Cr and Pb migration towards the cathode and migration of Cu, SO42- and Cl- towards anode were noticed. Chemical oxygen demand in soil significantly decreased upon employing electrokinetic. This technology may be exploited for faster and eco-friendly removal of dye in soil environment. PMID- 25461935 TI - Removal of fluoride and uranium by nanofiltration and reverse osmosis: a review. AB - Inorganic contamination in drinking water, especially fluoride and uranium, has been recognized as a worldwide problem imposing a serious threat to human health. Among several treatment technologies applied for fluoride and uranium removal, nanofiltration (NF) and reverse osmosis (RO) have been studied extensively and proven to offer satisfactory results with high selectivity. In this review, a comprehensive summary and critical analysis of previous NF and RO applications on fluoride and uranium removal is presented. Fluoride retention is generally governed by size exclusion and charge interaction, while uranium retention is strongly affected by the speciation of uranium and size exclusion usually plays a predominant role for all species. Adsorption on the membrane occurs as some uranium species interact with membrane functional groups. The influence of operating conditions (pressure, crossflow velocity), water quality (concentration, solution pH), solute-solute interactions, membrane characteristics and membrane fouling on fluoride and uranium retention is critically reviewed. PMID- 25461936 TI - Effectiveness of breakpoint chlorination to reduce accelerated chemical chloramine decay in severely nitrified bulk waters. AB - Rectifying the accelerated chloramine decay after the onset of nitrification is a major challenge for water utilities that employ chloramine as a disinfectant. Recently, the evidence of soluble microbial products (SMPs) accelerating chloramine decay beyond traditionally known means was reported. After the onset of nitrification, with an intention to inactivate nitrifying bacteria and thus maintaining disinfectant residuals, breakpoint chlorination followed by re chloramination is usually practiced by water utilities. However, what actually breakpoint chlorination does beyond known effects is not known, especially in light of the new finding of SMPs. In this study, experiments were conducted using severely nitrified chloraminated water samples (chloramine residuals <0.5 mg Cl2 L-1, nitrite residuals >0.1 mg N L-1 and an order of magnitude higher chloramine decay rate compared to normal decay) obtained from two laboratory scale systems operated by feeding natural organic matter (NOM) containing and NOM free waters. Results showed that the accelerated decay of chloramine as a result of SMPs can be eliminated by spiking higher free chlorine residuals (about 0.92 +/- 0.03 to 1.16 +/- 0.12 mg Cl2 L-1) than the stoichiometric requirement for breakpoint chlorination and nitrite oxidation. Further, accelerated initial chlorine decay showed chlorine preferentially reacts with nitrite and ammonia before destroying SMPs. This study, clearly demonstrated there is an additional demand from SMPs that needs to be satisfied to effectively recover disinfection residuals in subsequent re-chloramination. PMID- 25461937 TI - Insight into the evolution, redox, and metal binding properties of dissolved organic matter from municipal solid wastes using two-dimensional correlation spectroscopy. AB - Two-dimensional correlation spectroscopy was employed to investigate the evolution, redox, and metal binding properties of dissolved organic matter (DOM) from municipal solid wastes (MSWs) during composting. The results showed that the DOM was degraded during composting in the order of aliphatic substances > proteinaceous compounds > cellulose, hemicellulose and lignin, while humic substances transformed during the process in the order of fulvic-like matter > humic-like substances > protein-like matter. The fulvic- and humic-like substances originated from lignin and polysaccharide-like substances with the function groups of CH3, CCH2, CCH, OCH3, OCH, O--C--O, aromatic C, and COO, while the protein-like matter was derived from aliphatic and proteinaceous compounds with the functional groups of CCH3 and N--C==O. The aromatic C and COO were responsible for the oxidation capacity of the MSW-derived DOM, while the O--C--O and COO accounted for the Cu and Zn binding capacity of the DOM. PMID- 25461938 TI - Nitrification of anaerobic digester effluent for nitrogen management at swine farms. AB - Anaerobic digester effluent collected from a swine farm was nitrified in lab scale bioreactors mimicking an innovative manure management system to understand factors relevant to a successful start-up. The effects of digester effluent strength, aeration time, nitrifying sludge inoculation, and initial pH control on the startup of the nitrification system were investigated. The results showed that initial NH4+-N concentrations higher than 800 mg L-1 could severely inhibit the onset of nitrification if relying on native bacterial populations. When aeration time was increased from 4 to 12 h d-1, ammonium oxidation occurred earlier, but nitrite oxidation was delayed. However, the delay was not observed when bioaugmentation with nitrifying sludge was conducted. Initial addition of acid for pH control was unsuccessful as initial depletion of alkalinity eventually resulted in self-inhibition of nitrification cause by decreasing pH over time. Overall, these results provide guidance on how to effectively start large-scale innovative animal waste treatment systems. PMID- 25461939 TI - Phosphorus metabolism and population dynamics in a biological phosphate-removal system with simultaneous anaerobic phosphate stripping. AB - In this study, the metabolism of phosphorus and changes in population dynamics were investigated via simultaneous chemical stripping in sidestream in an acetate fed sequencing batch reactor. The synthesized intracellular polyphosphate (poly P) by polyphosphate-accumulating organisms (PAOs) gradually decreased when the biomass was subjected to 83 d of P stripping. Initially, the P removal efficiency of the system improved from 94.3% to 96.9%. Thereafter, a relatively high level of P in effluent was observed, during which time the stoichiometric ratios of Prelease/HAcuptake decreased, Glycogendegraded/HAcuptake and poly-beta hydroxyvalerate/PHA increased. The results revealed that a metabolic shift from polyphosphate-accumulating metabolism to glycogen-accumulating metabolism. Correspondingly, PAOs declined to less than 1% of the population, glycogen accumulating organisms proliferated to almost 20% instead. The results of PCR DGGE also indicated that the microbial community structure considerably changed in response to the gradually decreasing poly-P content. These findings imply that intracellular poly-P level is important for the stable of P removal system. Furthermore, it suggests that it is not a stable and effective way for P recycling from anaerobic stage of the biological P removal system in sidestream. PMID- 25461941 TI - Removal of gaseous HxCBz by gliding arc plasma in combination with a catalyst. AB - Hexachlorobenzene (HxCBz) owns the chemical structure of one benzene ring and six H atoms substituted by Cl atoms and it is a persistent organic pollutant present in flue gas from municipal solid waste incineration as an important precursor of dioxins. Its removal was studied using gliding arc plasma treatment, coupled downstream with a V2O5-WO3-TiO2 catalyst. Several parameters (input voltage, O2 concentration, catalytic temperature and catalyst position) all influenced its removal efficiency (RE). Optimal parameter settings were tentatively determined, i.e., an input voltage of 15 kV, the temperature of the catalyst (250 degrees C), and the O2 concentration (30 vol% O2) tested at a single, fixed concentration of gaseous HxCBz (71.6 ng Nm-3). A maximum RE of 76 +/- 3% HxCBz was attained, with the plasma and coupled catalyst combined. Two destruction pathways, incorporating dechlorination and oxidation reactions, were recognised, both based on the detection of end- and intermediate products as well as of active species produced by the plasma. These end- and intermediate products included: low chlorinated polychlorobenzenes (mainly 1,2,4-Trichlorobenzene) as well as hydrocarbons (mainly C2H6), HCOOH, CH4, CO, CO2, etc. PMID- 25461940 TI - Removal of polycyclic musks by anaerobic membrane bioreactor: biodegradation, biosorption, and enantioselectivity. AB - This study aims to investigate the performance of anaerobic membrane bioreactor (AnMBR) for removing five polycyclic musks (PCMs), which are common active ingredients of personal care and household cleaning products. A laboratory scale AnMBR system was used in this investigation. Concentrations of the PCMs in both the liquid and biosolids phase were measured to conduct a mass balance analysis and elucidate their fate during AnMBR treatment. The AnMBR was effective for removing PCMs from the aqueous phase by a combination of biotransformation and sorption onto the biosolids. However, biotransformation was observed to be the dominant removal mechanism for all five PCMs. Enantioselective analysis of the PCMs in influent, effluent and biomass samples indicated that there was negligible enantioselectivity in the removal of these PCMs. Accordingly, all enantiomers of these PCMs can be expected to be removed by AnMBR with similar efficiency. PMID- 25461942 TI - Interactive effects of mercury and arsenic on their uptake, speciation and toxicity in rice seedling. AB - Rice can take up and translocate more As and Hg than other cereal crops. A hydroponic experiment was conducted to investigate their interactive effects on their uptake and toxicity in rice seedling after exposing to As(III) (0.1, 0.5 or 2.5 mg L-1) and Hg (0.05, 0.25 or 1.25 mg L-1) for 14 d. Rice was much more effective in taking up Hg than As and sequestered both in the roots. As and Hg reached 339 and 433 mg kg-1 in the roots, and 48.5 and 16.1 mg kg-1 in the shoots at As2.5 + Hg1.25. Though Hg inhibited As uptake and translocation, it enhanced As(III) toxicity to rice seedling. However, As inhibited Hg uptake at Hg0.05, but the opposite was observed at Hg0.25 and Hg1.25. Arsenite (54-100%) and inorganic Hg (100%) were the predominant form in the plant based on speciation analysis via HPLC-ICP-MS. Malondialdehyde in the roots and shoots increased with increasing As and Hg concentrations, with the highest being 54 MUmol g-1 at As0.5 + Hg1.25 in the roots. Root cell structural damage and organelles number reduction with increasing As and Hg concentration were observed based on TEM. As and Hg transformation and toxicity can help to understand the metabolic mechanisms of As and Hg in rice plant when co-present. PMID- 25461943 TI - Stabilization of simulated lead sludge with iron sludge via formation of PbFe12O19 by thermal treatment. AB - This study investigated the feasibility of stabilizing lead sludge by reaction with iron sludge via the formation of PbFe12O19 through a thermal treatment process. Lead hydroxide was used to simulate lead-laden sludge and the sintering procedure was performed by firing a mixture of this simulated sludge together with iron sludge at a Fe/Pb molar ratio of 12 over the temperature range from 650 to 1400 degrees C. The accompanying phase transformations as well as the surface characteristic of sintered samples were observed by XRD and SEM, while the leaching behavior of the stabilized sludge in an acidic environment was evaluated by a modified Toxicity Characteristic Leaching Procedure (TCLP) test. The results confirmed that PbFe12O19 acts as a stabilization phase for lead, and showed that the formation of a PbFe12O19 phase began at 750 degrees C with the lead completely incorporated into the PbFe12O19 phase at 1050 degrees C. Above 1100 degrees C, the PbFe12O19 phase began to decompose, accompanied by the reappearance of Fe2O3. The volumes of compressed sludge samples were reduced significantly after thermal treatment, with accompanying volume reductions of 40% at 1050 degrees C. This study compared the leaching of lead from PbO and sintered sludge samples using a prolonged TCLP test, and the data showed that the PbFe12O19 phase was superior to the PbO and that the sintered sludge sample exhibited very high stability under acidic environments. These results suggest a promising and reliable method of reducing lead sludge mobility and toxicity has been identified. PMID- 25461944 TI - Treatment of coal gasification wastewater by membrane bioreactor hybrid powdered activated carbon (MBR-PAC) system. AB - A laboratory-scale membrane bioreactor hybrid powdered activated carbon (MBR-PAC) system was developed to treat coal gasification wastewater to enhance the COD, total phenols (TPh), NH4+ removals and migrate the membrane fouling. Since the MBR-PAC system operated with PAC dosage of 4 g L-1, the maximum removal efficiencies of COD, TPh and NH4+ reached 93%, 99% and 63%, respectively with the corresponding influent concentrations of 2.27 g L-1, 497 mg L-1 and 164 mg N L-1; the PAC extraction efficiencies of COD, TPh and NH4+ were 6%, 3% and 13%, respectively; the transmembrane pressure decreased 34% with PAC after 50 d operation. The results demonstrate that PAC played a key role in the enhancement of biodegradability and mitigation of membrane fouling. PMID- 25461946 TI - Tracking sinks of atmospheric methane using small world networks. AB - The present study uses small world network to highlight the key hubs for CH4 atmospheric pathways without considering rate constant of each reaction and concentrations of each species. The atmospheric methane sources and sinks were formulated into a well-organized network of 49 nodes and 302 links. In the network, reactions (including substrates and products) are considered as nodes and their pathways as links. Using a small world model, we analyzed the weighted and directed network of methane sources and sinks. By analyzing the characteristic path length, clustering coefficient, and degree distribution, we obtained insights into the methane network. The results indicate that only a few key nodes serve as hubs or limiting reactions, such as CH4 + OH -> CH3 + H2O; HO2 + NO -> NO2 + OH; CH3O2H -> CH3O + OH; and CH4 + Cl -> CH3 + HCl. The network is highly efficient; when key hub reactions experience interruptions, pathways to other nodes can be accessed to complete the methane degradation process. Additionally, our directed network keeps sources and sinks independent of each other such that changes in the number or type of methane sources does not affect the findings related to sinks. Tracking the structure of methane sources and sinks not only provides valuable, and perhaps universal, information about the network structure, but also can lead to a better understanding of the dynamic processes that generate the network. Finally, this is the first attempt of the network model in analyzing environmental issues and may represent a common blueprint for the interconnected reactions (sources and sinks) of other greenhouse gases. PMID- 25461945 TI - Novelties of combustion synthesized titania ultrafiltration membrane in efficient removal of methylene blue dye from aqueous effluent. AB - In this study, titania nanoparticles were synthesized by combustion and used to make ultrafiltration membrane. Characteristics of titania membranes such as textural evaluation, surface morphology, pure water permeability and protein rejection were investigated. Titania membrane sintered at 450 degrees C showed pure water permeability 11 * 10-2 L h-1 m-2 kPa-1 and 76% protein rejection. The membrane presented good water flux and retention properties with regards to protein and methylene blue dye. Ultrafiltration process was operated at lower pressure (100 kPa) and showed 99% removal of methylene blue using adsorptive micellar flocculation at sodium dodecyl sulfate concentration below its critical micellar concentration. Ferric chloride was used as the coagulant. The method of making titania membrane and its use are new. These studies can be extended to other dyes and pollutants. PMID- 25461947 TI - Treatment of O2-free toluene emissions by anoxic biotrickling filtration. AB - Toluene biotrickling filtration under anoxic denitrifying conditions was evaluated in two identical bioreactors (R1 and R2) operated at liquid recycling rates of 1.3, 2.7 and 5.3 m h-1 and liquid renewal rates of 0 and 0.17 d-1. R1 and R2 achieved a similar maximum elimination capacity (EC ~30 g m-3 h-1) at the same toluene inlet load (~50 g m-3 h-1), which was approximately 7 times higher compared with available literature on continuous toluene removal under anoxic conditions. Nevertheless, higher metabolite accumulation was observed in the bioreactor operated without periodical liquid phase renewal (R2), leading to intermittent drops in its toluene removal performance. This is the first work operating an anoxic biotrickling filter at empty bed residence time of 3 min, which is comparable with those employed in conventional aerobic systems. A characterization of the metabolites accumulated in the liquid phase revealed a dynamic metabolite production and degradation. PMID- 25461948 TI - Decomposition of ammonia and hydrogen sulfide in simulated sludge drying waste gas by a novel non-thermal plasma. AB - To efficiently clean NH3 and H2S contained in municipal sewage sludge drying waste gas, experiments were conducted with a novel gliding arc discharge plasma reactor. Important parameters including applied voltage and gas velocity which can strongly influence the removal efficiency, energy cost and by-products yields were investigated. Maximum removal efficiencies were all obtained at the applied voltage of 11 kV and gas velocity of 4.72 m s-1. When NH3 and H2S were treated together, the total energy cost decreased by 38%. NO and SO2 were observed as main decomposition by-products, and the presence of NH3 may inhibit the production of SO2 whose yield decreased from 223.8 to 27.8 mg m-3. Tests performed on lab scale reactor showed that gliding arc discharge is efficient in decreasing the NH3 and H2S concentrations, and experiments will also be conducted on a larger scale reactor in the future. PMID- 25461949 TI - Identification of cadmium-resistant fungi related to Cd transportation in bermudagrass [Cynodon dactylon (L.) Pers]. AB - Phytoremediation utilizing plants and microbes has been increasingly adopted as a green technology for cleaning up heavy metal polluted soils. Cd polluted soil and native bermudagrass from Liuyang and Zhuzhou in Hunan province of China were collected to investigate microbial diversity and isolate Cd resistant fungi, and then to determine the effect of Cd resistant fungi on Cd tolerance and transportation of bermudagrass. The functional diversity of microorganisms was evaluated using the BIOLOG Eco method. Cd-resistant fungi strain was isolated and identified as Aspergillus aculeatus based on the ribosomal internal transcribed spacer region sequence analysis. Bermudagrass was exposed to control, Cd only, and Cd plus A. aculeatus (Cd + A. aculeatus) with growth matrix (sawdust/sand = 3/1 in volume). Results indicated that Cd + A. aculeatus treated bermudagrass exhibited a higher photosynthetic activity compared to Cd only treated plants. Inoculation of A. aculeatus resulted in a decrease in stem and leaf Cd concentrations, to a greater extent for Cd-sensitive than for Cd-tolerant genotype. However, inoculation of A. aculeatus increased root Cd concentration under Cd stress conditions, significantly elevated soil pH, and decreased soil water-soluble Cd concentration. These results suggested that A. aculeatus might be potentially applied to improve Cd tolerance and to reduce Cd transportation to shoot of bermudagrass. PMID- 25461950 TI - Application of a magnesium/co-solvent system for the degradation of polycyclic aromatic hydrocarbons and their oxygenated derivatives in a spiked soil. AB - This study evaluates the capability, efficacy and practicality of a combined approach based on solvent extraction and chemical reduction to simultaneously degrade polycyclic aromatic hydrocarbons (PAHs) and their oxygenated derivatives (OPAHs) in spiked soil. The spiked soil was washed using a composite organic solvent consisting of ethanol and ethyl lactate (1:1, v/v) and then degradation of the extracted contaminants using zero-valent magnesium. The extraction conditions were optimized at 25 degrees C with solvent-soil ratio of 2:1 (v/w) and the ensuing degradation efficiency ranged from 79% to 88% for the OPAHs, and 66% to 87% for the PAHs after 24 h of reaction at pH of 6.1. The reductive degradation of the spiked contaminants followed pseudo-first-order kinetics; however, comparing the kinetic results of this study to soil-free studies, the degradation rates are significantly reduced. It can be inferred that extracted organic or inorganic components from the soil medium hinder the degradation process, possibly by reducing the reactivity of the activated metal. Furthermore, to our understanding, this study is the first report on the simultaneous degradation of these priority pollutants and their oxygenated derivatives. The experimental results encourage the application of this magnesium/co-solvent system for future pilot-scale remediation studies. PMID- 25461951 TI - Biochar-supported zerovalent iron reclaims silver from aqueous solution to form antimicrobial nanocomposite. AB - In this work, zerovalent iron (ZVI)-biochar composite (BBCF) was used to remove and reclaim silver ions from aqueous solution. Sorption experimental data showed that BBCF quickly and efficiently removed Ag+ from aqueous solutions with a capacity greater than 600 mg/g. The strong sorption of silver on BBCF was mainly controlled by a reduction mechanism between the ZVI and Ag+, which was confirmed by the characterization of the post-sorption sorbent (BBCF-Ag). The characterization results also showed that the sorbed silver on biochar surfaces were nanoparticles with an average size of 28 nm. As a result, the BBCF-Ag showed strong antimicrobial ability and effectively inhibited the growth of Escherichia coli (E. coli), while the original BBCF without silver nanoparticle promoted their growth. These findings suggest that, not only can biochar-supported ZVI be used to remove silver ions from aqueous solutions, but the products formed represent a new value-added nanocomposite. PMID- 25461954 TI - Family-based association study of the arsenite methyltransferase gene (AS3MT, rs11191454) in Korean children with attention-deficit hyperactivity disorder. AB - We examined the association between the selected polymorphisms in two candidate genes, the arsenite methyltransferase gene (AS3MT, rs11191454) and the inter alpha-trypsin inhibitors heavy chain-3 gene (ITIH3, rs2535629), and attention deficit hyperactivity disorder (ADHD) in a Korean population. A total of 238 patients with ADHD, along with both of their biological parents, were recruited. The children were administered intelligence quotient tests, whereas their parents completed the Child Behavior Checklist. In the transmission disequilibrium test on 181 trios, we found overtransmission of the A allele at the AS3MT rs11191454 polymorphism in children with ADHD (chi2=8.81, P=0.003). However, there was no preferential transmission at the ITIH3 rs52535629 polymorphism (chi2=0.14, P=0.707). Our results provide preliminary evidence for the overtransmission of the A allele at the AS3MT rs11191454 polymorphism in ADHD. PMID- 25461952 TI - Decrease in vitamin D status in the Greenlandic adult population from 1987-2010. AB - BACKGROUND: Low vitamin D status may be pronounced in Arctic populations due to limited sun exposure and decreasing intake of traditional food. OBJECTIVE: To investigate serum 25(OH)D3 as a measure of vitamin D status among adult Inuit in Greenland, predictors of low serum 25(OH)D3 concentrations and the trend from 1987 to 2005-2010. DESIGN: A total of 2877 randomly selected Inuit (>= 18 years) from the Inuit Health in Transition study were included. A sub-sample (n = 330) donated a blood sample in 1987 which allowed assessment of time trends in vitamin D status. RESULTS: The geometric mean serum 25(OH)D3 (25[OH]D2 concentrations were negligible and not reported) in 2005-2010 was lowest among the 18-29 year old individuals (30.7 nmol/L; 95% CI: 29.7; 31.7) and increased with age. In all age-groups it decreased from 1987 to 2005-2010 (32%-58%). Low 25(OH)D3 concentrations (<50 nmol/L) were present in 77% of the 18-29 year old and decreased with age. A characteristic seasonal variation in 25(OH)D3 concentrations was observed (range 33.2-57.1 nmol/L, p<0.001), with the highest concentrations in August to October. Age (2.0% per year increase; CI: 1.7, 2.2), female gender (7.1%; CI: 2.0; 12.5), alcohol intake (0.2% per increase in drinks/week; 0.0; 0.4), and traditional diet (10.0% per 100 g/d increase; CI: 7.9; 12.1) were associated with increased serum 25(OH)D3, whereas smoking ( 11.6%; CI: -16.2; -6.9), BMI (-0.6%; CI: -1.1; -0.2) and latitude (-0.7% per degree increase; CI: -1.3; -0.2) were associated with decreased concentrations. CONCLUSION: We identified a remarkable decrease in vitamin D status from 1987 to 2005-2010 and a presently low vitamin D status among Inuit in Greenland. A change away from a traditional diet may well explain the observed decline. The study argues for the need of increased dietary intake of vitamin D and supplementation might be considered. PMID- 25461955 TI - Common variants at Bin1 are associated with sporadic Alzheimer's disease in the Han Chinese population. AB - OBJECTIVES: Recent genome-wide association studies identified bridging integrator 1 (Bin1) to be associated with sporadic Alzheimer's disease (SAD). To clarify the relevance of Bin1 as a genetic determinant of AD, we analyzed its association in a Han Chinese population from the South East part of mainland China. METHODS: This study investigated 427 SAD patients and 451 unrelated age-matched and sex matched healthy controls. Two single nucleotide polymorphisms (rs7561528 and rs744373) adjacent to Bin1 that emerged from previous genome-wide association studies were genotyped using the MassARRAY Analyzer 4 Sequenom platform. RESULTS: As expected, the genotype distribution of rs7561528 was significantly different between the SAD group and the controls, with more AG in controls [odds ratio (OR) 0.605, 95% confidence interval (CI) 0.429-0.854, P=0.004], and the difference increased using an additive genetic model (OR 0.593, 95% CI 0.425-0.828, P=0.002). However, we did not observe a difference in the genotype distribution of the rs744373 between the SAD and the control group (OR 1.189, 95% CI 0.809 1.747, P=0.378). CONCLUSIONS: To the best of our knowledge, our study is the first to confirm the association of the variant rs7561528 adjacent to Bin1 with SAD in a Han Chinese Population. PMID- 25461958 TI - A cleavable ligand column for the rapid isolation of large quantities of homogeneous and functional neurotensin receptor 1 variants from E. coli. AB - G protein-coupled receptors (GPCRs) are key players of cell signaling, thus representing important drug targets for the treatment of human diseases. Since inherent difficulties in receptor production and handling have precluded the application of many in vitro experiments, major questions about GPCR mechanisms and dynamics remain elusive to date. We recently used directed evolution in Escherichia coli on neurotensin receptor 1 (NTR1) for the generation of GPCR variants with greatly elevated functional expression levels and with excellent stability in detergent micelles. In this work we outline a highly efficient purification method for our evolved receptor variants, which is based on the application of an inexpensive, disposable high-affinity ligand column as the initial purification step. The ligand resin allows isolation of correctly folded GPCR variants directly from whole E. coli cell lysates at the scale of 10mg and it permits preparations of agonist- and antagonist-bound receptor samples. The purification principle presented here was key to the first structures of signaling-active NTR1 variants (Egloff et al., 2014). Since E. coli is uniquely suitable for the production of fully deuterated proteins, our method provides the basis for an array of NMR experiments that were not feasible for GPCRs to date, but which will shed light on novel aspects of receptor function and dynamics. PMID- 25461957 TI - Prosaposin overexpression following kainic acid-induced neurotoxicity. AB - Because excessive glutamate release is believed to play a pivotal role in numerous neuropathological disorders, such as ischemia or seizure, we aimed to investigate whether intrinsic prosaposin (PS), a neuroprotective factor when supplied exogenously in vivo or in vitro, is up-regulated after the excitotoxicity induced by kainic acid (KA), a glutamate analog. In the present study, PS immunoreactivity and its mRNA expression in the hippocampal and cortical neurons showed significant increases on day 3 after KA injection, and high PS levels were maintained even after 3 weeks. The increase in PS, but not saposins, detected by immunoblot analysis suggests that the increase in PS-like immunoreactivity after KA injection was not due to an increase in saposins as lysosomal enzymes after neuronal damage, but rather to an increase in PS as a neurotrophic factor to improve neuronal survival. Furthermore, several neurons with slender nuclei inside/outside of the pyramidal layer showed more intense PS mRNA expression than other pyramidal neurons. Based on the results from double immunostaining using anti-PS and anti-GABA antibodies, these neurons were shown to be GABAergic interneurons in the extra- and intra-pyramidal layers. In the cerebral cortex, several large neurons in the V layer showed very intense PS mRNA expression 3 days after KA injection. The choroid plexus showed intense PS mRNA expression even in the normal rat, and the intensity increased significantly after KA injection. The present study indicates that inhibitory interneurons as well as stimulated hippocampal pyramidal and cortical neurons synthesize PS for neuronal survival, and the choroid plexus is highly activated to synthesize PS, which may prevent neurons from excitotoxic neuronal damage. To the best of our knowledge, this is the first study that demonstrates axonal transport and increased production of neurotrophic factor PS after KA injection. PMID- 25461956 TI - Differential expression of microRNAs in ischemic heart disease. AB - Recent studies provide evidence that ischemic preconditioning (IP) and ischemia/reperfusion (IR) injury lead to altered expression of microRNAs (miRNAs) that affect the survival and recovery of cardiomyocytes. These endogenous ~22 nucleotide noncoding RNAs negatively regulate gene expression via degradation and translational inhibition of their target mRNAs. miRNAs are involved in differentiation, proliferation, electrical conduction, angiogenesis and apoptosis. These pathways can lead to physiological and pathological adaptations. This review intends to explore several facets of miRNA expression and the underlying mechanisms involved in IR injury, as well as IP as a cardioprotective strategy. In addition, we will investigate miRNA interaction with the renin angiotensin system and the potential use of miRNAs in developing sensitive biomarkers for cardiovascular disease. PMID- 25461960 TI - Effect of Intravenous Versus Subcutaneous Phytonadione on Length of Stay for Patients in Need of Urgent Warfarin Reversal. AB - This institutional review board-approved retrospective cohort study evaluated the impact of intravenous versus subcutaneous phytonadione on length of stay in hospitalized patients requiring urgent warfarin reversal. All patients were 18 years or older, on warfarin therapy with an international normalized ratio (INR) between 3.1 and 10.0, and had warfarin therapy restarted at discharge. Patients who received intramuscular or oral phytonadione, phytonadione by more than 1 route, fresh frozen plasma, or any other blood products containing clotting factors, patients with active or severe liver disease, and patients who received other forms of anticoagulation were excluded. A total of 4425 patients receiving phytonadione were evaluated and 79 patients were included. Baseline characteristics were similar between the intravenous and subcutaneous groups, including mean age, gender, warfarin indication, Charlson comorbidity index, and indication for phytonadione. Geometric mean length of stay in the intravenous group was 211.7 hours compared with 191.0 hours in the subcutaneous group (P = 0.47). Though intravenous phytonadione administration resulted in significantly lower INRs at all time points <36 hours, geometric mean time to restart of warfarin therapy was not impacted (66.3 hours vs. 64.1 hours, P = 0.72). Despite demonstrating significantly greater INR reductions, hospital length of stay and time to restart of warfarin therapy were not improved with the administration of intravenous over subcutaneous phytonadione. PMID- 25461959 TI - Attributions of cancer 'alarm' symptoms in a community sample. AB - BACKGROUND: Attribution of early cancer symptoms to a non-serious cause may lead to longer diagnostic intervals. We investigated attributions of potential cancer 'alarm' and non-alarm symptoms experienced in everyday life in a community sample of adults, without mention of a cancer context. METHODS: A questionnaire was mailed to 4858 adults (>=50 years old, no cancer diagnosis) through primary care, asking about symptom experiences in the past 3 months. The word cancer was not mentioned. Target 'alarm' symptoms, publicised by Cancer Research UK, were embedded in a longer symptom list. For each symptom experienced, respondents were asked for their attribution ('what do you think caused it'), concern about seriousness ('not at all' to 'extremely'), and help-seeking ('did you contact a doctor about it': Yes/No). RESULTS: The response rate was 35% (n = 1724). Over half the respondents (915/1724; 53%) had experienced an 'alarm' symptom, and 20 (2%) cited cancer as a possible cause. Cancer attributions were highest for 'unexplained lump'; 7% (6/87). Cancer attributions were lowest for 'unexplained weight loss' (0/47). A higher proportion (375/1638; 23%) were concerned their symptom might be 'serious', ranging from 12% (13/112) for change in a mole to 41% (100/247) for unexplained pain. Just over half had contacted their doctor about their symptom (59%), although this varied by symptom. Alarm symptoms were appraised as more serious than non-alarm symptoms, and were more likely to trigger help-seeking. CONCLUSIONS: Consistent with retrospective reports from cancer patients, 'alarm' symptoms experienced in daily life were rarely attributed to cancer. These results have implications for understanding how people appraise and act on symptoms that could be early warning signs of cancer. PMID- 25461961 TI - Hypomagnesemia and Chemotherapy, Diagnostic Dilemma, and Treatment Challenge: Case Report and Literature Review. AB - Magnesium is the second most common intracellular cation after potassium and plays pivotal role in the majority of metabolic process. Several studies have shown the prevalence of hypomagnesemia ranging from 2.5% to 12% in general population and even up to 60% in intensive care unit patients. Hypomagnesemia might be more prevalent in patients with cancer owing to a combination of several factors such as gastrointestinal loss, renal loss, poor intake, and use of certain chemotherapeutic drugs. It is imperative that we identify the exact cause of hypomagnesemia to aid and guide treatment. We report a case of a 63-year-old white woman with hypomagnesemia who was undergoing treatment for metastatic colon cancer. The chemotherapy regimen was with FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) and bevacizumab. This was followed by maintenance therapy with Xeloda (capecitabine). Her hypomagnesium was attributed to her chemotherapy. During our workup, the renal fractional excretion of magnesium was found to be low excluding the cause as renal wasting. This patient's hypomagnesemia could very well be explained by gastrointestinal losses (diarrhea) from short bowel after colectomy, her chemotherapeutic agents and metformin, as well as poor oral intake from medications, or malignancy itself. PMID- 25461962 TI - Impact of the Use of Benznidazole Followed by Antioxidant Supplementation in the Prevalence of Ventricular Arrhythmias in Patients With Chronic Chagas Disease: Pilot Study. AB - Patients with chronic Chagas disease have a higher prevalence of premature ventricular contraction (PVC) because of immunoinflammatory response magnified by the increased oxidative stress. Thus, the sequential treatment with benznidazole (BZN) and antioxidants can reduce the prevalence of PVC. We wish to establish whether the etiological treatment of Chagas disease followed by supplementation with the antioxidant vitamins E and C decreases the prevalence of PVC in these patients. A sample of 41 patients with chronic Chagas disease at different stages of the heart disease was selected for the treatment against the causative agent using BZN (5 mg.kg.d, minimum dose 300 mg daily) for 2 months followed by supplementation with antioxidants such as vitamins E (800 UI/d) and C (500 mg/d) for 6 months. The prevalence of PVC was observed by conducting 24-hour Holter. To evaluate the oxidative status of the patients, serum markers of oxidative stress like glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase, and glutathione S-transferase were measured, and also reduced glutathione, vitamin E, and markers of tissue damage like thiobarbituric acid reactive substances and protein carbonyl. A decrease in the prevalence of PVC in patients with advanced Chagas heart disease was observed (5391 vs. 1185, P = 0.0068). This reduction was followed by decrease of serum markers of oxidative stress. In patients with a lower degree of cardiac damage, the reduction on prevalence of PVC was not significant. The etiological treatment with BZN followed by supplementation with antioxidant vitamins E and C reduces episodes of PVC in patients with severe Chagas heart disease. PMID- 25461963 TI - Evaluation of 5-aminolevulinic acid-mediated photorejuvenation of neck skin. AB - OBJECTIVE: To evaluate the outcomes of the combination of red light or intense pulsed laser (IPL) with 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) in the treatment of photodamaged neck skin. METHODS: The anterior of the neck was divided into four 2 cm * 2 cm sections and randomly assigned to red light, red-light-PDT, IPL or IPL-PDT group. ALA cream of 5% was applied to PDT regions for 2h prior to light irradiation. Treatment was repeated once. The stratum corneum (SC) hydration, transepidermal water loss (TEWL), L(*), a(*), b(*) values, melanin index (MI), erythema index (EI), skin elasticity and skin thickness were examined by a blinded investigator. The function and volume of thyroid were also measured. RESULTS: After red-light-PDT, IPL-PDT and IPL treatment, the appearance of photoaging lesion was improved. The SC hydration, L(*) value, elasticity and thickness increased, whereas the TEWL and MI value decreased. These changes in red-light-PDT and IPL-PDT group were more obvious than IPL group. The a(*) and EI value increased in red-light-PDT group. No significant change was noticed in red-light group. Partial irradiation of the thyroid did not affect the function and volume of the thyroid. CONCLUSION: IPL PDT and red-light-PDT showed better rejuvenation effect than IPL or red light alone on the neck skin. PMID- 25461964 TI - Aggregatibacter actinomycetemcomitans biofilm can be inactivated by methylene blue-mediated photodynamic therapy. AB - BACKGROUND: The purpose of this study was to evaluate the antibacterial effects of photodynamic action of methylene blue (MB) against Aggregatibacter actinomycetemcomitans organized on biofilm. METHODS: After the biofilm growth in 96 flat-bottom well plate, the following groups were used: control group, untreated by either laser or photosensitizer (PS); MB group or dark toxicity group, which was exposed to MB alone (100MUM) for 1min (pre-irradiation time); laser group, irradiated with laser for 5min in the absence of PS and three antimicrobial photodynamic inactivation (APDI) groups, with three exposure times of 1, 3 and 5min of irradiation, corresponding to fluences of 15, 45, and 75J/cm(2) respectively. The results were compared to the control group for statistical proposes. Scanning electronic microscope analysis was used to access structural changes in biofilm. RESULTS: Red laser alone and MB alone were not able to inactivate bacterial biofilm. APDI groups showed differences when compared to the control group and they were dependent on the exposure time. No statistically significant differences were observed among the APDI groups at 1 and 3min of irradiation. On the other hand, 5min of APDI showed 99.85% of bacterial reduction (p=0.0004). In addition, the biofilm loose its structure following 5min APDI. CONCLUSIONS: The results of this study suggest that A. actinomycetemcomitans biofilm can be inactivated by MB mediated APDI. PMID- 25461966 TI - The antimicrobial effectiveness of photodynamic therapy used as an addition to the conventional endodontic re-treatment: a clinical study. AB - BACKGROUND: The purpose of the study was to evaluate the efficacy of antimicrobial photodynamic therapy (aPDT) used as an adjunct to the endodontic re treatment in the eradication of microorganisms from previously filled root canals. METHODS: The study sample consisted of 21 randomly selected patients with root filled and infected root canal system with chronic apical periodontitis on incisors or canines, who have had previously endodontic treatment. Microbiological samples from the root canals were collected after accessing the canal, following the endodontic re-treatment and after the aPDT procedure. During instrumentation, the root canals were irrigated with 2.5% sodium hypochlorite (NaOCl), and the final irrigation protocol included 17% ethylenediaminetetraacetic acid followed by NaOCl. Root canals were filled with a phenothiazinium chloride and irradiated with a diode laser (lambda=660 nm, 100 mW) for 1 min. Microbiological samples from the root canals were cultivated on selective plates, and the identification was done by micromorphology, macromorphology and different API strips as well as bacterial counts (colony forming units). RESULTS: Fourteen bacteria species were isolated from the root canals initially, with a mean value of 4.57 species per canal. Although endodontic re-treatment alone produced a significant reduction in the number of bacteria species (p<0.001), the combination of endodontic treatment and aPDT was statistically more effective (p<0.001). No bacteria were cultivated from the main root canals of 11 teeth. CONCLUSION: The results indicated that the aPDT used as an adjunct to the conventional endodontic therapy achieved a significant further reduction of intracanal microbial load. PMID- 25461965 TI - 18 years long-term results of facial port-wine stain (PWS) after photodynamic therapy (PDT)--a case report. AB - Port-wine stain (PWS) is still a challenging condition for clinician to treat, because in the majority of cases, the stains are not lifted fully by treatment with laser therapy. Photodynamic therapy (PDT) was considered recently as a promising alternative treatment for PWS. We report here long-term follow-up measures 18 years on PWS lesion treated with PDT and the histological data of residual PWS. PMID- 25461967 TI - Using a PyMOL activity to reinforce the connection between genotype and phenotype in an undergraduate genetics laboratory. AB - With the purpose of developing an activity that would help clarify genetic concepts related to the connection between genotype and phenotype and the nature of mutations, we designed a three hour teaching module using the PyMol software. The activity starts with two pre-laboratory assignments, one to learn how to use PyMol and the other to read about a specific protein or protein family. During the laboratory students are given instructions where and how to find additional information on a specific disease and its causal mutations in order to prepare a 10-minute, in-class presentation. Using a post activity, anonymous quiz, we found a statistically significant different grade distribution in students that participated in the PyMol activity relative to a control group. We also found a significant improvement in the student's comprehension when answering questions regarding the nature of mutations and protein structure. This demonstrates the utility of this simulation activity as a vehicle to improve student's understanding of specific key genetic concepts. PMID- 25461969 TI - Life-cycle modification in open oceans accounts for genome variability in a cosmopolitan phytoplankton. AB - Emiliania huxleyi is the most abundant calcifying plankton in modern oceans with substantial intraspecific genome variability and a biphasic life cycle involving sexual alternation between calcified 2N and flagellated 1N cells. We show that high genome content variability in Emiliania relates to erosion of 1N-specific genes and loss of the ability to form flagellated cells. Analysis of 185 E. huxleyi strains isolated from world oceans suggests that loss of flagella occurred independently in lineages inhabiting oligotrophic open oceans over short evolutionary timescales. This environmentally linked physiogenomic change suggests life cycling is not advantageous in very large/diluted populations experiencing low biotic pressure and low ecological variability. Gene loss did not appear to reflect pressure for genome streamlining in oligotrophic oceans as previously observed in picoplankton. Life-cycle modifications might be common in plankton and cause major functional variability to be hidden from traditional taxonomic or molecular markers. PMID- 25461968 TI - betaA3/A1-crystallin: more than a lens protein. AB - Crystallins, the highly abundant proteins of the ocular lens, are essential determinants of the transparency and refractivity required for lens function. Initially thought to be lens-specific and to have evolved as lens proteins, it is now clear that crystallins were recruited to the lens from proteins that existed before lenses evolved. Crystallins are expressed outside of the lens and most have been shown to have cellular functions distinct from their roles as structural elements in the lens. For one major crystallin group, the beta/gamma crystallin superfamily, no such functions have yet been established. We have explored possible functions for the polypeptides (betaA3-and betaA1-crystallins) encoded by Cryba1, one of the 6 beta-crystallin genes, using a spontaneous rat mutant and genetically engineered mouse models. betaA3-and betaA1-crystallins are expressed in retinal astrocytes and retinal pigment epithelial (RPE) cells. In both cell types, these proteins appear to be required for the proper acidification of the lysosomes. In RPE cells, elevated pH in the lysosomes is shown to impair the critical processes of phagocytosis and autophagy, leading to accumulation of undigested cargo in (auto) phagolysosomes. We postulate that this accumulation may cause pathological changes in the cells resembling some of those characteristic of age-related macular degeneration (AMD). Our studies suggest an important regulatory function of betaA3/A1-crystallin in astrocytes. We provide evidence that the cellular function of betaA3/A1-crystallin involves its interaction with V-ATPase, the proton pump responsible for acidification of the endolysosomal system. PMID- 25461970 TI - Lytic activity by temperate phages of Pseudomonas aeruginosa in long-term cystic fibrosis chronic lung infections. AB - Pseudomonas aeruginosa is the most common bacterial pathogen infecting the lungs of cystic fibrosis (CF) patients. The transmissible Liverpool epidemic strain (LES) harbours multiple inducible prophages (LESphi2; LESphi3; LESphi4; LESphi5; and LESphi6), some of which are known to confer a competitive advantage in an in vivo rat model of chronic lung infection. We used quantitative PCR (Q-PCR) to measure the density and dynamics of all five LES phages in the sputa of 10 LES infected CF patients over a period of 2 years. In all patients, the densities of free-LES phages were positively correlated with the densities of P. aeruginosa, and total free-phage densities consistently exceeded bacterial host densities 10 100-fold. Further, we observed a negative correlation between the phage-to bacterium ratio and bacterial density, suggesting a role for lysis by temperate phages in regulation of the bacterial population densities. In 9/10 patients, LESphi2 and LESphi4 were the most abundant free phages, which reflects the differential in vitro induction properties of the phages. These data indicate that temperate phages of P. aeruginosa retain lytic activity after prolonged periods of chronic infection in the CF lung, and suggest that temperate phage lysis may contribute to regulation of P. aeruginosa density in vivo. PMID- 25461971 TI - Expression, purification and reconstitution of the C-terminal transmembrane domain of scavenger receptor BI into detergent micelles for NMR analysis. AB - Scavenger receptor class B type I (SR-BI), the high density lipoprotein (HDL) receptor, is important for the delivery of HDL-cholesteryl esters to the liver for excretion via bile formation. The focus on therapeutic strategies aimed at reducing cholesterol levels highlights the critical need to understand the structural features of SR-BI that drive cholesterol removal. Yet, in the absence of a high-resolution structure of SR-BI, our understanding of how SR-BI interacts with HDL is limited. In this study, we have optimized the NMR solution conditions for the structural analysis of the C-terminal transmembrane domain of SR-BI that harbors putative domains required for receptor oligomerization. An isotopically labeled SR-BI peptide encompassing residues 405-475 was bacterially-expressed and purified. [U-(15)N]-SR-BI(405-475) was incorporated into different detergent micelles and assessed by (1)H-(15)N-HSQC in order to determine which detergent micelle best maintained SR-BI(405-475) in a folded, native conformation for subsequent NMR analyses. We also determined the optimal detergent concentration used in micelles, as well as temperature, solution buffer and pH conditions. Based on (1)H-(15)N-HSQC peak dispersion, intensity, and uniformity, we determined that [U-(15)N]-SR-BI(405-475) should be incorporated into 5% detergent micelles consisting of 1-palmitoyl-2-hydroxy-sn-glycero-3-phospho-[1'-rac glycerol] (LPPG) and data collected at 40 degrees C in a non-buffered solution at pH 6.8. Furthermore, we demonstrate the ability of SR-BI(405-475) to form dimers upon chemical crosslinking. These studies represent the first steps in obtaining high-resolution structural information by NMR for the HDL receptor that plays a critical role in regulating whole body cholesterol removal. PMID- 25461972 TI - Both neuropeptide Y knockdown and Y1 receptor inhibition modulate CART-mediated appetite control. AB - Amphetamine (AMPH)-induced appetite suppression has been attributed to its inhibition of neuropeptide Y (NPY)-containing neurons in the hypothalamus. This study examined whether hypothalamic cocaine- and amphetamine-regulated transcript (CART)-containing neurons and NPY Y1 receptor (Y1R) were involved in the action of AMPH. Rats were treated daily with AMPH for four days, and changes in feeding behavior and expression levels of NPY, CART, and POMC were assessed and compared. The results showed that both feeding behavior and NPY expression decreased during AMPH treatment, with the biggest reduction occurring on Day 2. By contrast, the expression of CART and melanocortin 3 receptor (MC3R), a member of the POMC neurotransmission, increased with the maximum response on Day 2, directly opposite to the NPY expression results. The intracerebroventricular infusion of NPY antisense or Y1R inhibitor both modulated AMPH-induced anorexia and the expression levels of MC3R and CART. The results suggest that in the hypothalamus both POMC- and CART-containing neurons participate in regulating NPY-mediated appetite control during AMPH treatment. These results may advance the knowledge of molecular mechanism of anorectic drugs. PMID- 25461973 TI - Sex differences in the long-lasting effects of a single exposure to immobilization stress in rats. AB - In male rats, a single exposure to a severe stressor such as immobilization (IMO) results in marked activation of the HPA axis and reduction of body weight gain. In addition, the HPA response to the same (homotypic) stressor is reduced, whereas the response to a different (heterotypic) stressor is enhanced for days. Although sex differences in the responsiveness of the HPA axis have been described, there are few studies about the influence of sex on long-lasting effects of stress. Thus, we have compared the consequences of a single exposure to IMO in male and female rats. Females showed a similar ACTH response to the first IMO associated with higher corticosterone, but they were more resistant than males to stress-induced loss of body weight. Unstressed females showed higher resting levels of ACTH and corticosterone, but they did not show the increase in the resting levels of HPA hormones observed in males on the day after IMO. During exposure to a different stressor (open-field) two days after IMO, enhanced corticosterone response and hypoactivity was observed in males, but not in females. Finally, a second exposure to IMO 8 days after the first one resulted in a reduction of the HPA response and of the negative impact on body weight as compared to the first exposure, and this protective effect was greater in females. In sum, IMO-exposed females showed a greater reduction of the response to a second IMO and appear to be more resistant than males to some of the negative impacts of IMO. PMID- 25461975 TI - Stress and success: individual differences in the glucocorticoid stress response predict behavior and reproductive success under high predation risk. AB - A fundamental element of how vertebrates respond to stressors is by rapidly elevating circulating glucocorticoid hormones. Individual variation in the magnitude of the glucocorticoid stress response has been linked with reproductive success and survival. But while the adaptive value of this response is believed to stem in part from changes in the expression of hormone-mediated behaviors, it is not clear how the behavior of stronger and weaker glucocorticoid responders differs during reproduction, or during exposure to ecologically relevant stressors. Here we report that in a population of barn swallows (Hirundo rustica erythrogaster) experiencing high rates of nest predation, circulating levels of corticosterone (the primary avian glucocorticoid) during exposure to a standardized stressor predict aspects of subsequent behavior and fitness. Individuals that mounted a stronger corticosterone stress response during the early reproductive period did not differ in clutch size, but fledged fewer offspring. Parents with higher stress-induced corticosterone during the early reproductive period later provisioned their nestlings at lower rates. Additionally, in the presence of a model predator stress-induced corticosterone was positively associated with the latency to return to the nest, but only among birds that were observed to return. Model comparisons revealed that stress induced hormones were better predictors of the behavioral and fitness effects of exposure to transient, ecologically relevant stressors than baseline corticosterone. These findings are consistent with functional links between individual variation in the hormonal and behavioral response to stressors. If such links occur, then selection on the heritable components of the corticosterone stress response could promote adaptation to novel environments or predation regimes. PMID- 25461974 TI - Leptin mediates seasonal variation in some but not all symptoms of sickness in Siberian hamsters. AB - Many seasonally breeding species, including Siberian hamsters (Phodopus sungorus), exhibit seasonal variation in sickness responses. One hypothesis regarding the mechanism of this variation is that sickness intensity tracks an animal's energetic state, such that sickness is attenuated in the season that an animal has the lowest fat stores. Energetic state may be signaled via leptin, an adipose hormone that provides a signal of fat stores. Siberian hamsters respond to extended housing in short, winter-like days by reducing fat stores and leptin levels, relative to those housed in long, summer-like days. Sickness responses are also attenuated in short-day hamsters as compared to long-day hamsters. We hypothesized that leptin provides a physiological signal by which seasonally breeding animals modulate sickness responses, such that animals with higher leptin levels show increased sickness intensity. To test this, we provided short day hamsters with a long-day-like leptin signal and assessed their responses to lipopolysaccharide (LPS), a sickness-inducing antigen. We compared these responses to short-day vehicle-, long-day vehicle-, and long-day leptin-treated hamsters. Unexpectedly, LPS induced a hypothermic response (rather than fever) in all groups. Short-day vehicle-treated hamsters exhibited the greatest LPS-induced hypothermia, and leptin treatment attenuated this response, making hypothermia more long-day-like. Contrary to our hypothesis, short-day leptin-treated hamsters showed the least pronounced LPS-induced anorexia among all groups. These results suggest that leptin may mediate some but not all aspects of seasonal sickness variation in this species. Future studies should be targeted at determining roles of other energetic hormones in regulating seasonal sickness response variation. PMID- 25461976 TI - Comparison of nano-sized Mn oxides with the Mn cluster of photosystem II as catalysts for water oxidation. AB - "Back to Nature" is a promising way to solve the problems that we face today, such as air pollution and shortage of energy supply based on conventional fossil fuels. A Mn cluster inside photosystem II catalyzes light-induced water-splitting leading to the generation of protons, electrons and oxygen in photosynthetic organisms, and has been considered as a good model for the synthesis of new artificial water-oxidizing catalysts. Herein, we surveyed the structural and functional details of this cluster and its surrounding environment. Then, we review the mechanistic findings concerning the cluster and compare this biological catalyst with nano-sized Mn oxides, which are among the best artificial Mn-based water-oxidizing catalysts. PMID- 25461977 TI - Direct energy transfer from the major antenna to the photosystem II core complexes in the absence of minor antennae in liposomes. AB - Minor antennae of photosystem (PS) II, located between the PSII core complex and the major antenna (LHCII), are important components for the structural and functional integrity of PSII supercomplexes. In order to study the functional significance of minor antennae in the energetic coupling between LHCII and the PSII core, characteristics of PSII-LHCII proteoliposomes, with or without minor antennae, were investigated. Two types of PSII preparations containing different antenna compositions were isolated from pea: 1) the PSII preparation composed of the PSII core complex, all of the minor antennae, and a small amount of major antennae (MCC); and 2) the purified PSII dimeric core complexes without periphery antenna (CC). They were incorporated, together with LHCII, into liposomes composed of thylakoid membrane lipids. The spectroscopic and functional characteristics were measured. 77K fluorescence emission spectra revealed an increased spectral weight of fluorescence from PSII reaction center in the CC LHCII proteoliposomes, implying energetic coupling between LHCII and CC in the proteoliposomes lacking minor antennae. This result was further confirmed by chlorophyll a fluorescence induction kinetics. The incorporation of LHCII together with CC markedly increased the antenna cross-section of the PSII core complex. The 2,6-dichlorophenolindophenol photoreduction measurement implied that the lack of minor antennae in PSII supercomplexes did not block the energy transfer from LHCII to the PSII core complex. In conclusion, it is possible, in liposomes, that LHCII transfer energy directly to the PSII core complex, in the absence of minor antennae. PMID- 25461978 TI - Role of fractalkine-CX3CR1 pathway in seizure-induced microglial activation, neurodegeneration, and neuroblast production in the adult rat brain. AB - Temporal lobe seizures lead to an acute inflammatory response in the brain primarily characterized by activation of parenchymal microglial cells. Simultaneously, degeneration of pyramidal cells and interneurons is evident together with a seizure-induced increase in the production of new neurons within the dentate gyrus of the hippocampus. We have previously shown a negative correlation between the acute seizure-induced inflammation and the survival of newborn hippocampal neurons. Here, we aimed to evaluate the role of the fractalkine-CX3CR1 pathway for these acute events. Fractalkine is a chemokine expressed by both neurons and glia, while its receptor, CX3CR1 is primarily expressed on microglia. Electrically-induced partial status epilepticus (SE) was induced in adult rats through stereotaxically implanted electrodes in the hippocampus. Recombinant rat fractalkine or CX3CR1 antibody was infused intraventricularly during one week post-SE. A significant increase in the expression of CX3CR1, but not fractalkine, was observed in the dentate gyrus at one week. CX3CR1 antibody treatment resulted in a reduction in microglial activation, neurodegeneration, as well as neuroblast production. In contrast, fractalkine treatment had only minor effects. This study provides evidence for a role of the fractalkine-CX3CR1 signaling pathway in seizure-induced microglial activation and suggests that neuroblast production following seizures may partly occur as a result of microglial activation. PMID- 25461980 TI - Intermolecular Tl...H-C anagostic interactions in luminescent pyridyl functionalized thallium(I) dithiocarbamates. AB - Crystal structures of novel pyridyl functionalised [Tl(L)]infinity (L = (N-benzyl N-methylpyridyl) dithiocarbamate(L1) 1, bis(N-methylpyridyl) dithiocarbamate(L2) 2, (N-methyl(1,4-benzodioxane-6-yl)-N-methylpyridyl)dithiocarbamate(L3) 3, (N ferrocenyl-N-methylpyridyl) dithiocarbamate(L4) 4) complexes revealed rare intermolecular C-H...Tl anagostic and C-S...Tl interactions forming a six membered chelate ring about the metal center, which have been assessed by DFT calculations. The strong thallophilic bonding is responsible for the strong luminescent characteristics of the complexes in the solid phase. PMID- 25461979 TI - Endocannabinoid metabolism by cytochrome P450 monooxygenases. AB - The endogenous cannabinoid system was first uncovered following studies of the recreational drug Cannabis sativa. It is now recognized as a vital network of signaling pathways that regulate several physiological processes. Following the initial discovery of the cannabinoid receptors 1 (CB1) and 2 (CB2), activated by Cannabis-derived analogs, many endogenous fatty acids termed "endocannabinoids" are now known to be partial agonists of the CB receptors. At present, the most thoroughly studied endocannabinoid signaling molecules are anandamide (AEA) and 2 arachidonylglycerol (2-AG), which are both derived from arachidonic acid. Both AEA and 2-AG are also substrates for the eicosanoid-synthesizing pathways, namely, certain cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes. In the past, research in the endocannabinoid field focused on the interaction of AEA and 2-AG with the COX and LOX enzymes, but accumulating evidence also points to the involvement of CYPs in modulating endocannabinoid signaling. The focus of this review is to explore the current understanding of CYP-mediated metabolism of endocannabinoids. PMID- 25461981 TI - Estimating the binding ability of onium ions with CO2 and pi systems: a computational investigation. AB - Density functional theory (DFT) calculations have been employed on 165 complexes of onium ions (NH4(+), PH4(+), OH3(+), SH3(+)) and methylated onium ions with CO2, aromatic (C6H6) and heteroaromatic (C5H5X, X = N, P; C4H5Y, Y = N, P; C4H4Z, Z = O, S) systems. The stability of CO2...onium, CO2...pi and onium...pi complexes was shown to be mediated through various noncovalent interactions such as hydrogen bonding, NH-pi, PH-pi, OH-pi, SH-pi, CH-pi and pi-pi. We have discussed 17 complexes wherein the proton transfer occurs between the onium ion and the heteroaromatic system. The binding energy is found to decrease with increasing methyl substitution of the complexes containing onium ions. Binding energy components of all the noncovalent complexes were explored using localized molecular orbital energy decomposition analysis (LMO-EDA). The CO2...pi complexes were primarily stabilized by the dispersion term followed by contributions from electrostatic and polarization components. In general, for onium ion complexes with CO2 or pi systems, the electrostatic and polarization terms primarily contribute to stabilize the complex. As the number of methyl groups increases on the onium ion, the dispersion term is seen to have a key role in the stabilization of the complex. Quantum theory of atoms in molecules (QTAIM) analysis and charges based on natural population analysis (NPA) in various complexes have also been reported in order to determine the nature of noncovalent interactions in different complexes. PMID- 25461984 TI - Winter landscape: John W. Hardrick. PMID- 25461985 TI - Stroke care projected to add up to more than previously thought. PMID- 25461986 TI - Health care and poverty. PMID- 25461993 TI - Smarter screening for cancer: possibilities and challenges of personalization. PMID- 25461994 TI - The shape of things to come: 3D printing in medicine. PMID- 25461995 TI - A piece of my mind. Learning not to move forward. PMID- 25461996 TI - Chronic lymphocytic leukemia: a clinical review. AB - IMPORTANCE: The most common leukemia is chronic lymphocytic leukemia (CLL). Every year, there are 15 000 new diagnoses and 5000 CLL deaths in the United States. Although therapeutic choices were once limited, treatment of this disease has vastly improved in the last decade. OBJECTIVE: Evidence-based review of the diagnosis, staging, and treatment of CLL. EVIDENCE REVIEW: PubMed, Cochrane Library, Scopus, and Google Scholar databases were searched through August 28, 2014. English-language peer-reviewed articles published between 2000-2014 were found using the keywords chronic lymphocytic leukemia, upfront therapy, upfront therapies, upfront therapeutic, upfront therapeutics, upfront treatment, front line treatment, first-line treatment, front-line treatments, first-line treatments, front-line therapy, front-line therapies, randomized, randomized studies, randomized study, clinical trial, clinical trials, phase 3, and phase 3 clinical trial. Abstracts and presentations at scientific meetings were excluded. A total of 277 articles were retrieved, of which 24 met our predefined selection criteria; treatment recommendations were based on subsequent analysis of these 24 articles. FINDINGS: The Rai and Binet systems for staging CLL were established in 1975 and 1977, respectively. However, they do not account for new disease categories such as monoclonal B-cell lymphocytosis (peripheral blood clonal lymphocytosis that does not meet other criteria for CLL). Two subsets of CLL are now recognized based on risk stratification involving molecular and cytogenetic analyses. Outcomes are improved by the addition of immunotherapy to combination chemotherapy for initial treatment in all subsets of treated patients. Overall response rates between 75% and 90% and complete responses between 22% and 45% are expected in the current era, with more than 80% of treated patients alive at 3 years. Overall, 5-year survival has increased to 66% from 60% (P < .001) in the past 10 years. CONCLUSIONS AND RELEVANCE: Chemoimmunotherapy is the standard first-line option approach for CLL, the most common leukemia observed in adults. Treatment is initiated when the disease becomes symptomatic, and survival is high following treatment. PMID- 25461997 TI - Long-term outcomes of young people who attempted suicide. PMID- 25461998 TI - Cervical cancer screening. PMID- 25461999 TI - Sudden onset of generalized blisters. PMID- 25462000 TI - Bisphosphonate prescriptions in men with androgen deprivation therapy use. PMID- 25462001 TI - Assessment of heterogeneity in meta-analyses. PMID- 25462002 TI - Assessment of heterogeneity in meta-analyses--reply. PMID- 25462003 TI - Standard vs enriched high protein enteral nutrition in the ICU. PMID- 25462004 TI - Standard vs enriched high protein enteral nutrition in the ICU--reply. PMID- 25462005 TI - Physicians assistants in VA medical centers. PMID- 25462006 TI - Physicians assistants in VA medical centers--reply. PMID- 25462008 TI - "The good bed-side manner". PMID- 25462009 TI - JAMA patient page. Screening for cervical cancer. PMID- 25462011 TI - Source of ventilatory complexity in the postmetamorphic tadpole brainstem, Pelophylax ridibundus: A pharmacological study. AB - The neural respiratory output of isolated brainstems of post-metamorphic tadpoles displays two motor patterns, the buccal and the lung rhythms. Their global dynamics are complex and chaos-like. This study aimed at determining the source of this complexity. The neural respiratory output was recorded during exposure to increasing concentration of DAMGO or to reduced chloride concentration. Complexity was quantified with the noise limit (NL) and the largest Lyapunov exponent (LLE) values. DAMGO decreased lung frequency (p<0.0001), NL (p<0.0001) and LLE (p=0.0001) without changing buccal frequency (p=0.2392). Reduced concentration of chloride decreased buccal frequency (p=0.011) without changing lung frequency (p=0.2393) whereas NL (p=0.011) and LLE (p=0.027) increased significantly. When taking all the recordings into account, NL and LLE were correlated to lung frequency (r=0.661, p<0.0001 and r=0.3948, p=0.0012, respectively) but not to buccal frequency (r=0.1191, p=0.3487 and r=0.2083, p=0.0985, respectively). Therefore, the lung neural oscillator is both necessary and sufficient to the ventilatory complexity in the isolated brainstem of the post-metamorphic tadpole. PMID- 25462010 TI - Th17-related cytokines in systemic lupus erythematosus patients with dilated cardiomyopathies: a possible linkage to parvovirus B19 infection. AB - Dilated cardiomyopathies (DCM) are a major cause of mortality in patients with systemic lupus erythematosus (SLE). Immune responses induced by human parvovirus B19 (B19) are considered an important pathogenic mechanism in myocarditis or DCM. However, little is known about Th17-related cytokines in SLE patients with DCM about the linkage with B19 infection. IgM and IgG against B19 viral protein, and serum levels of Th17-related cytokines were determined using ELISA in eight SLE patients with DCM and six patients with valvular heart disease (VHD). Humoral responses of anti-B19-VP1u and anti-B19-NS1 antibody were assessed using Western blot and B19 DNA was detected by nested Polymerase Chain Reaction (PCR). Levels of interleukin (IL)-17, IL-6, IL-1beta, and tumor necrosis factor (TNF)-alpha were significantly higher in SLE patients with DCM (mean +/- SEM, 390.99+/-125.48 pg/ml, 370.24+/-114.09 pg/ml, 36.01+/-16.90 pg/ml, and 183.84+/-82.94 pg/ml, respectively) compared to healthy controls (51.32+/-3.04 pg/ml, p<0.001; 36.88+/ 6.64 pg/ml, p<0.001; 5.39+/-0.62 pg/ml, p<0.005; and 82.13+/-2.42 pg/ml, p<0.005, respectively). Levels of IL-17 and IL-6 were higher in SLE patients with DCM versus those with VHD (both p<0.01). Five (62.5%) of DCM patients had detectable anti-B19-NS1 IgG and four (50.0%) of them had anti-B19-VP1u IgG, whereas only one (16.7%) of VHD patients had detectable anti-B19-NS1 IgG and anti-B19-VP1u IgG. Serum levels of IL-17, IL-6 and IL-1beta were markedly higher in SLE patients with anti-B19-VP1u IgG and anti-B19-NS1 IgG compared to those without anti-B19 VP1u IgG or anti-B19-NS1 IgG, respectively. These suggest a potential association of B19 with DCM and Th17-related cytokines implicated in the pathogenesis of DCM in SLE patients. PMID- 25462013 TI - Sleep disturbances in long-term immigrants with chronic mountain sickness: a comparison with healthy immigrants at high altitude. AB - The aim of this study was to examine sleep disturbances in patients with chronic mountain sickness (CMS). The sleep of 14 patients with CMS and 11 healthy controls with or without sleep disorders (control N: without sleep disorders; control D: with sleep disorders) was studied by polysomnography. Hypopnea was the sleep disorder most commonly suffered by CMS patients and control D subjects. No major differences were observed in sleep structure between CMS and control groups, with the exception of shorter rapid eye movement latency in controls and increased deep non-rapid eye movement in the control N group. Periodic breathing was observed in only two study participants, one each in the CMS and control D groups. The level of saturated oxygen was significantly lower in the CMS group during sleep than the control groups (P<0.05). CMS scores were positively correlated with the apnea-hypopnea index, and negatively correlated with saturated oxygen levels. These results demonstrate that sleep disorders and nocturnal hypoxia are important in the development of CMS. PMID- 25462014 TI - Intermittent but not sustained hypoxia activates orexin-containing neurons in mice. AB - Hypothalamic orexin-containing neurons are activated by CO2 and contribute to hypercapnic ventilatory activation. However, their role in oxygen-related regulation of breathing is not well defined. In this study, we examined whether an experimental model mimicking apnea-induced repetitive hypoxemia (intermittent hypoxia [IH]) activates orexin-containing neurons. Mice were exposed to IH (5*5min at 10% O2), intermittent hyperoxia (IO; 5*5min at 50% O2), sustained hypoxia (SH; 25min at 10% O2), or sham stimulation. Their brains were examined using double immunohistochemical staining for orexin and c-Fos. The results indicated that IH (25.8+/-3.0%), but not SH (9.0+/-1.5%) activated orexin containing neurons when compared to IO (5.5+/-0.6%) and sham stimulation (5.9+/ 1.4%). These results correlate with those of our previous work showing that IH induced respiratory long-term facilitation is dependent on orexin-containing neurons. Taken together, orexin contributes to repetitive hypoxia-induced respiratory activation and the hypoxic activation of orexin-containing neurons is pattern dependent. PMID- 25462015 TI - Repetitive measurements of enhanced pause (Penh). AB - Enhanced pause (Penh) was first proposed in allergic mice and appeared to be correlated with airway responsiveness. However, some investigators have suggested that there is no theoretical basis for a correlation between Penh and airway resistance. Because the measurement of Penh is a noninvasive procedure, this value may be useful in repetitive measurements, but few researchers have emphasized this aspect. This study aimed to assess the validity of Penh values derived through repetitive measurements of both absolute and ratio Penh values in 10 male C57BL/6 mice on days 0, 3, 7, and 15. Tests of within-subject effects revealed significant differences in both the absolute and ratio Penh values across the different time points. The administration of challenge aerosolized methacholine concentrations of 25, 50, and 100mg/ml resulted in significant differences in the ratio Penh values across the various time points. The findings of the present study indicate that Penh is not a good index for repetitive measurement because the Penh values are significantly influenced by the time at which they are measured. PMID- 25462012 TI - Respiratory neuron characterization reveals intrinsic bursting properties in isolated adult turtle brainstems (Trachemys scripta). AB - It is not known whether respiratory neurons with intrinsic bursting properties exist within ectothermic vertebrate respiratory control systems. Thus, isolated adult turtle brainstems spontaneously producing respiratory motor output were used to identify and classify respiratory neurons based on their firing pattern relative to hypoglossal (XII) nerve activity. Most respiratory neurons (183/212) had peak activity during the expiratory phase, while inspiratory, post inspiratory, and novel pre-expiratory neurons were less common. During synaptic blockade conditions, ~10% of respiratory neurons fired bursts of action potentials, with post-inspiratory cells (6/9) having the highest percentage of intrinsic burst properties. Most intrinsically bursting respiratory neurons were clustered at the level of the vagus (X) nerve root. Synaptic inhibition blockade caused seizure-like activity throughout the turtle brainstem, which shows that the turtle respiratory control system is not transformed into a network driven by intrinsically bursting respiratory neurons. We hypothesize that intrinsically bursting respiratory neurons are evolutionarily conserved and represent a potential rhythmogenic mechanism contributing to respiration in adult turtles. PMID- 25462016 TI - Simulating distal gut mucosal and luminal communities using packed-column biofilm reactors and an in vitro chemostat model. AB - In vivo studies of human mucosal gut microbiota are often limited to end-point analyses and confounded by bowel cleansing procedures. Therefore, we used biofilm reactors to incorporate a simulated mucosal environment into an in vitro gut chemostat model. Communities developed were complex, reproducible, distinct, and representative of in vivo communities. PMID- 25462017 TI - The mitochondrial proteins AtHscB and AtIsu1 involved in Fe-S cluster assembly interact with the Hsp70-type chaperon AtHscA2 and modulate its catalytic activity. AB - Arabidopsis plants contain two genes coding for mitochondrial Hsp70-type chaperon like proteins, AtHscA1 (At4g37910) and AtHscA2 (At5g09590). Both genes are homologs of the Ssq1 gene involved in Fe-S cluster assembly in yeast. Protein protein interaction studies showed that AtHscA2 interacts with AtIsu1 and AtHscB, two Arabidopsis homologs of the Isu1 protein and the Jac1 yeast co-chaperone. Moreover, this interaction could modulate the activity of AtHscA2. In the presence of a 1:5:5 molar ratio of AtHscA2:AtIsu1:AtHscB we observed an increase in the V(max) and a decrease in the S(0.5) for ATP of AtHscA2. Furthermore, an increase of about 28-fold in the catalytic efficiency of AtHscA2 was also observed. Results suggest that AtHscA2 in cooperation with AtIsu1 and AtHscB play an important role in the regulation of the Fe-S assembly pathway in plant mitochondria. PMID- 25462019 TI - Parkin modulates heteroplasmy of truncated mtDNA in Caenorhabditis elegans. AB - Parkin, which is mutated in most recessive Parkinsonism, is a key player in the selective removal of damaged mitochondria via mitophagy. Damaged mitochondria may carry mitochondrial DNA (mtDNA) mutations, thus creating a mixed mtDNA population within cells (heteroplasmy). It was previously shown that Parkin over-expression reduced the level of heteroplasmic mutations that alter mitochondrial membrane potential in human cytoplasmic hybrids. However, it remained unclear whether Parkin serves a similar role at the entire living organism, and whether this role is evolutionarily conserved. Here, we show that mutation in the Caenorhabditis elegans orthologue of Parkin (pdr-1) modulates the level of a large heteroplasmic mtDNA truncation. Massive parallel sequencing revealed that the mtDNAs of C. elegans wild type and pdr-1(gk448) mutant strains were virtually deprived of heteroplasmy, thus reflecting strong negative selection against dysfunctional mitochondria. Therefore, our findings show that the role of Parkin in the modulation of heteroplasmy is conserved between human and worm and raise the interesting possibility that mitophagy modulates the striking lack of heteroplasmy in C. elegans. PMID- 25462020 TI - Role of toll-like receptors in multiple myeloma and recent advances. AB - Multiple myeloma (MM) is a hematologic malignancy characterized as an abnormal proliferation and invasion of plasma cells into the bone marrow. Toll-like receptors (TLRs) connect the innate and adaptive immune responses and represent a significant and potentially linking element between inflammation and cancer. When TLRs bind to their ligands, they trigger two major signaling pathways such that both share overlapping downstream signals: one is a myeloid differentiation primary response 88 (MyD88)-dependent production and activation of nuclear factor kappaB, whereas the other is a MyD88-independent production of type-I interferon. Whereas the MyD88 pathway results in proinflammatory cytokine production, the other pathway stimulates cell proliferation. Dysregulations of these pathways may eventually lead to abnormal cell proliferation and MM. Despite recent biomedical advances, MM continues to be an incurable disease. There are an increasing number of TLR-based therapeutic approaches currently being tested in a number of preclinical and clinical studies. We here attempt to outline in detail the currently available information on TLRs in various types of cancer. PMID- 25462021 TI - Erythroid progenitors from patients with low-risk myelodysplastic syndromes are dependent on the surrounding micro environment for their survival. AB - To investigate whether the type of programmed cell death of myelodysplastic erythroid cells depends on their cellular context, we performed studies on cells from patients with low-risk myelodysplastic syndromes. We compared erythroid cells (and their precursor cells) from the mononuclear cell fraction with those from the hematon fraction, which are compacted complexes of hematopoietic cells surrounded by their own micro-environment. In directly fixed materials, erythroblasts exhibited signs of autophagy with limited apoptosis (<3%) based on ultrastructural characteristics and immunogold labeling for activated caspase-3. After 24 h in culture, myelodysplastic erythroblasts exhibited a significant increase in apoptosis (22 +/- 7% vs. 3 +/- 2%, p = 0.001). In contrast, the myelodysplastic erythroblasts from the hematon fraction did not exhibit an increased tendency toward apoptosis after culture (7 +/- 3.3% vs. 1.8 +/- 2.3%), which was in line with results for normal bone marrow cells. The same dependency on the micro-environment was noted for immature erythroid progenitor cells. Myelodysplastic hematons exhibited distinct numbers of erythroid burst-forming units in association with an extensive network of stromal cells, whereas small numbers of erythroid burst-forming units were generated from the myelodysplastic mononuclear cells compared with normal mononuclear cells (10.2 +/- 9 vs. 162 +/- 125, p < 0.001). Co-culture of erythroid myelodysplastic cells in the presence of growth factors (vascular endothelial growth factor, leukemia inhibitory factor) or on the MS-5 stromal layer did not restore the expansion of erythroid precursor cells. These data indicate that surviving myelodysplastic erythroid progenitors become more vulnerable to programmed cell death when they are detached from their own micro-environment. PMID- 25462018 TI - Polymorphisms in DNA polymerase gamma affect the mtDNA stability and the NRTI induced mitochondrial toxicity in Saccharomyces cerevisiae. AB - Several pathological mutations have been identified in human POLG gene, encoding for the catalytic subunit of Pol gamma, the solely mitochondrial replicase in animals and fungi. However, little is known regarding non-pathological polymorphisms found in this gene. Here we studied, in the yeast model Saccharomyces cerevisiae, eight human polymorphisms. We found that most of them are not neutral but enhanced both mtDNA extended mutability and the accumulation of mtDNA point mutations, either alone or in combination with a pathological mutation. In addition, we found that the presence of some SNPs increased the stavudine and/or zalcitabine-induced mtDNA mutability and instability. PMID- 25462022 TI - Cytogenetic and clinical marks for defining high-risk myeloma in the context of bortezomib treatment. AB - Multiple myeloma (MM) is a heterogeneous disease, and the benefit from bortezomib treatment is not uniform among all patients subgroups. Currently, little information is available to predict patients response to bortezomib treatment. In this study, we aimed to identify patients benefiting minimally from bortezomib as part of first-line therapy and to define high-risk MM in the context of bortezomib treatment. We compared the effect of a bortezomib-based treatment (arm B) with that of a treatment without bortezomib (arm A) on different genetic patient subgroups in a series of 273 cases of newly diagnosed MM. These patients were enrolled in a prospective, non-randomized clinical trial (BDH 2008/02). A subgroup of patients exhibiting little benefit from bortezomib treatment was identified. These patients had at least one of the following characteristics: del(17p13), 1q21 gain, or high lactate dehydrogenase levels. In this subgroup, survival of patients treated with bortezomib was comparable (progression-free survival: 14.0 vs. 15.0 months, p = 0.992; overall survival: 21.0 vs. 14.0 months, p = 0.472) to that of patients undergoing thalidomide-based treatment. We propose that all patients with newly diagnosed MM should be evaluated for these three markers before bortezomib treatment. Other novel drugs and alternative therapeutic strategies are needed for patients with such markers. PMID- 25462023 TI - TCR-mediated functions are enhanced in activated peripheral blood T cells isolated from leucocyte reduction systems. AB - Buffy coats are the most common method for the acquisition of activated primary human T cells for research or clinical applications, but recently leukocyte reduction system (LRS) cones have emerged as a viable source for these cells. In this study, we determined if activated human T cells derived from buffy coats or LRS cones had different functionality. No changes in the expression of surface receptors were observed except for a significant increase in CD44 expression on T cells isolated from LRS cones. LRS cone-derived T cells trended towards higher receptor-mediated cytokine production and had significantly increased donor-to donor variability in IFN-gamma production. TCR-induced ERK1/ERK2 and AKT phosphorylation was also increased in T cells isolated from LRS cones. In conclusion, LRS cones are an excellent source of T cells for clinical and research applications, but these cells have subtle functional differences from T cells isolated using standard buffy coats. PMID- 25462025 TI - Assessment of parental overt and covert control of child's food intake: a population-based validation study with mothers of preschoolers. AB - INTRODUCTION: Overt and covert control are novel constructs representing two different parental feeding practices with regard to the child's ability to detect them. Preliminary research indicates that covert control is linked to a healthier diet and lower child weight status. In this study, we report the first psychometric validation of the original measures of overt and covert control outside the UK in a large sample of parents of preschoolers. METHODS: Based on records from the population register, all mothers of 4-year-olds (n = 3007) from the third largest city in Sweden, Malmo, were contacted by mail. Out of those, 876 returned the measures of overt and covert control together with a background questionnaire and the Child Feeding Questionnaire (CFQ). Test-retest data were obtained from 64% (n = 563) of these mothers. The mean age of the mothers was 35.6 years; their mean BMI was 24.1, 31.5% were overweight or obese. The children were on average 4.5 years old; 48% were girls, 12.8% were overweight or obese. RESULTS: While the fit for the original 9-item 2-factor model was poor, shorter 8 and 6-item versions were supported by confirmatory factor analysis (CFI > 0.95, RMSEA < 0.05). Internal and test-retest reliability of the shorter version was good (ICC= 0.65-0.71). Results also suggest that the factor structure and loadings were invariant(i.e., did not significantly differ) over time and between child sexes. Both overt and covert control factors were moderately correlated with CFQ monitoring. Overt control was also moderately related to CFQ pressure and weakly correlated with CFQ restriction. Covert control, on the other hand, was moderately related to restriction and not related with pressure. Correlations of both factors with child and parent BMI were very small. CONCLUSION: We found good psychometric properties of the revised versions of the overt and control behaviors ina multiethnic sample of mothers from Sweden. Future studies need to establish causal associations between overt and covert control and the obesity related outcomes. PMID- 25462026 TI - Media matters for boys too! The role of specific magazine types and television programs in the drive for thinness and muscularity in adolescent boys. AB - This study examined the role of specific magazine types and television programs on drive for thinness and muscularity in adolescent boys. A sample of 182 adolescent boys with an average age of 15.2 years completed questionnaire measures of magazine and television consumption, drive for thinness and drive for muscularity. Different media genres showed varying relationships with drive for thinness and muscularity. Specifically, the consumption of men's magazines and the viewing of soap operas emerged as significant unique predictors of drive for thinness, with the consumption of men's magazines also offering unique prediction of drive for muscularity. A comprehensive approach that considers both type and genre of media is critical in increasing our understanding of the complex relationships between media exposure and disordered eating in adolescent boys. PMID- 25462027 TI - The association between night eating and body mass depends on age. AB - Night eating syndrome (NES) is marked by substantial evening or nocturnal food intake, insomnia, morning anorexia, and depressed mood. Originally, NES was described as an eating pattern among obese individuals.However, subsequent studies showed that NES also occurs among non-obese individuals, who appear to be younger than obese individuals with NES. Thus, it has been proposed that NES may lead to future weight gain,which may explain inconsistent findings about associations between NES and body mass. The current study investigated the relationships between age, body mass index (BMI), and night eating severity in a representative sample of German adults (n = 2317). It was found that age moderated the relationship between night eating severity and BMI. Specifically, night eating was positively associated with BMI in participants who were between 31 and 60 years old, but not in younger (<31 years) or older (>60 years) participants. Results indicate that age may indeed play an important role when examining the relationship between night eating and obesity. That is, weight gain may only occur after longer periods of engaging in night eating and, thus, no or only small relationships can be found in younger samples such as students. The positive association between night eating and BMI disappears in older individuals, which may be related to onset of illness associated with wasting. PMID- 25462024 TI - Brightness induction and suprathreshold vision: effects of age and visual field. AB - A variety of visual capacities show significant age-related alterations. We assessed suprathreshold contrast and brightness perception across the lifespan in a large sample of healthy participants (N=155; 142) ranging in age from 16 to 80 years. Experiment 1 used a quadrature-phase motion cancelation technique (Blakeslee & McCourt, 2008) to measure canceling contrast (in central vision) for induced gratings at two temporal frequencies (1 Hz and 4 Hz) at two test field heights (0.5 degrees or 2 degrees *38.7 degrees ; 0.052 c/d). There was a significant age-related reduction in canceling contrast at 4 Hz, but not at 1 Hz. We find no age-related change in induction magnitude in the 1 Hz condition. We interpret the age-related decline in grating induction magnitude at 4 Hz to reflect a diminished capacity for inhibitory processing at higher temporal frequencies. In Experiment 2 participants adjusted the contrast of a matching grating (0.5 degrees or 2 degrees *38.7 degrees ; 0.052 c/d) to equal that of both real (30% contrast, 0.052 c/d) and induced (McCourt, 1982) standard gratings (100% inducing grating contrast; 0.052 c/d). Matching gratings appeared in the upper visual field (UVF) and test gratings appeared in the lower visual field (LVF), and vice versa, at eccentricities of +/-7.5 degrees . Average induction magnitude was invariant with age for both test field heights. There was a significant age-related reduction in perceived contrast of stimuli in the LVF versus UVF for both real and induced gratings. PMID- 25462029 TI - Development of a novel mindfulness and cognitive behavioral intervention for stress-eating: a comparative pilot study. AB - Stress-related eating is increasingly cited as a difficulty in managing healthy eating behaviors and weight. However few interventions have been designed to specifically target stress-related eating. In addition, the optimal target of such an intervention is unclear, as the target might be conceptualized as overall stress reduction or changing emotional eating-related thoughts and behaviors. This pilot study compared the effects of three interventions targeting those components individually and in combination on stress-related eating, perceived stress, and weight loss to determine whether the two intervention components are effective alone or are more effective when combined. Fifty-three overweight participants (98% female) who reported elevated levels of stress and stress eating and were at risk for obesity were randomly assigned to one of three six week interventions: a modified mindfulness-based stress reduction (MBSR) intervention, a cognitive behavioral stress-eating intervention (SEI), and a combined intervention that included all MBSR and SEI components. All three interventions significantly reduced perceived stress and stress-eating, but the combination intervention resulted in greater reductions and also produced a moderate effect on short term weight loss. Benefits persisted at six week follow up.The pattern of results preliminarily suggests that the combination intervention (MBSR+SEI) may yield promise in the treatment of stress-related eating. PMID- 25462028 TI - Psychiatric co-morbidity in women presenting across the continuum of disordered eating. AB - OBJECTIVE: To compare the prevalence and correlates of psychiatric co-morbidity across a large sample of college women without an eating disorder, those at high risk for an eating disorder and women diagnosed using DSM-5 criteria for an eating disorder. PARTICIPANTS: 549 college women aged 18-25. METHODS: Data from the Eating Disorder Examination, the Structured Clinical Interview for DSM-IV Axis I disorders and self-report questionnaires were analyzed using logistic regression for categorical data and ANCOVA for continuous measures. RESULTS: Eating disordered symptomatology was strongly associated with anxiety disorders, mood disorders and insomnia. These co-morbidities (type and severity) tend to increase with eating disorder symptom severity. CONCLUSIONS: Prevention and treatment programs for eating disorders need to address the high levels of mood, anxiety and sleep problems in this population. The findings on insomnia are novel and suggest that sleep disturbance may play an integral role in eating-related difficulties. PMID- 25462030 TI - Approximate number word knowledge before the cardinal principle. AB - Approximate number word knowledge-understanding the relation between the count words and the approximate magnitudes of sets-is a critical piece of knowledge that predicts later math achievement. However, researchers disagree about when children first show evidence of approximate number word knowledge-before, or only after, they have learned the cardinal principle. In two studies, children who had not yet learned the cardinal principle (subset-knowers) produced sets in response to number words (verbal comprehension task) and produced number words in response to set sizes (verbal production task). As evidence of approximate number word knowledge, we examined whether children's numerical responses increased with increasing numerosity of the stimulus. In Study 1, subset-knowers (ages 3.0-4.2 years) showed approximate number word knowledge above their knower-level on both tasks, but this effect did not extend to numbers above 4. In Study 2, we collected data from a broader age range of subset-knowers (ages 3.1-5.6 years). In this sample, children showed approximate number word knowledge on the verbal production task even when only examining set sizes above 4. Across studies, children's age predicted approximate number word knowledge (above 4) on the verbal production task when controlling for their knower-level, study (1 or 2), and parents' education, none of which predicted approximation ability. Thus, children can develop approximate knowledge of number words up to 10 before learning the cardinal principle. Furthermore, approximate number word knowledge increases with age and might not be closely related to the development of exact number word knowledge. PMID- 25462032 TI - Connecting the dots from infancy to childhood: a longitudinal study connecting gaze following, language, and explicit theory of mind. AB - This longitudinal study tested the same children at three time points: infancy (10.5 months of age), toddlerhood (2.5 years of age), and early childhood (4.5 years of age). At 10.5 months, infants were assessed experimentally with a gaze following paradigm. At 2.5 years, children's language skills were measured using the MacArthur-Bates Communicative Development Inventories. At 4.5 years, children's explicit theory of mind was assessed with a standard test battery. Analyses revealed that infants with higher gaze-following scores at 10.5 months produced significantly more mental-state words at 2.5 years and that children with more mental-state words at 2.5 years were more successful on the theory-of mind battery at 4.5 years. These predictive longitudinal relationships remained significant after controlling for general language, maternal education, and nonsocial attention. The results illuminate the bridging role that language plays in connecting infants' social cognition to children's later understanding of others' mental states. The obtained specificity in the longitudinal relations informs theories concerning mechanisms of developmental change. PMID- 25462033 TI - What goes where? Eye tracking reveals spatial relational memory during infancy. AB - Episodic memory involves binding components of an event (who, what, when, and where) into a relational representation. The ability to encode information about the relative locations of objects (i.e., spatial relational memory) is a key component of episodic memory. Here we used eye tracking to test whether infants and toddlers learn about the spatial relations among objects. In Experiment 1, 9 , 18-, and 27-month olds were familiarized with an array of three objects. Following familiarization, they saw test arrays in which two of the objects had been replaced with novel ones (object switch condition) and arrays in which two of the objects had switched positions (location switch condition). Both 18- and 27-month olds looked significantly longer than would be predicted by chance at the objects that had switched spatial locations; however, 9-month olds did not. In Experiment 2, we showed that, given sufficient familiarization time, 9-month olds were also capable of detecting disruptions to the spatial relations among an array of objects. These results have important implications for our understanding of spatial relational memory development. PMID- 25462031 TI - Children (but not adults) judge similarity in own- and other-race faces by the color of their skin. AB - Both face shape and pigmentation are diagnostic cues for face identification and categorization. In particular, both shape and pigmentation contribute to observers' categorization of faces by race. Although many theoretical accounts of the behavioral other-race effect either explicitly or implicitly depend on differential use of visual information as a function of category expertise, there is little evidence that observers do in fact differentially rely on distinct visual cues for own- and other-race faces. In the current study, we examined how Asian and Caucasian children (4-6 years of age) and adults use three-dimensional shape and two-dimensional pigmentation to make similarity judgments of White, Black, and Asian faces. Children in this age range are capable of making category judgments about race but also are sufficiently plastic with regard to the behavioral other-race effect that it seems as though their representations of facial appearance across different categories are still emerging. Using a simple match-to-sample similarity task, we found that children tend to use pigmentation to judge facial similarity more than adults and also that own-group versus other group category membership appears to influence how quickly children learn to use shape information more readily. Therefore, we suggest that children continue to adjust how different visual information is weighted during early and middle childhood and that experience with faces affects the speed at which adult-like weightings are established. PMID- 25462034 TI - Effects of orthographic consistency on eye movement behavior: German and English children and adults process the same words differently. AB - The current study investigated the time course of cross-linguistic differences in word recognition. We recorded eye movements of German and English children and adults while reading closely matched sentences, each including a target word manipulated for length and frequency. Results showed differential word recognition processes for both developing and skilled readers. Children of the two orthographies did not differ in terms of total word processing time, but this equal outcome was achieved quite differently. Whereas German children relied on small-unit processing early in word recognition, English children applied small unit decoding only upon rereading-possibly when experiencing difficulties in integrating an unfamiliar word into the sentence context. Rather unexpectedly, cross-linguistic differences were also found in adults in that English adults showed longer processing times than German adults for nonwords. Thus, although orthographic consistency does play a major role in reading development, cross linguistic differences are detectable even in skilled adult readers. PMID- 25462035 TI - The role of rapid naming in reading development and dyslexia in Chinese. AB - We examined in a series of studies the mechanism that may underlie the relationship between Rapid Automatized Naming (RAN) and reading (accuracy and fluency) in Mandarin Chinese. Study 1 examined the "arbitrary" connections hypothesis in a sample of Grade 2 children (N=182). Study 2 contrasted the phonological processing, orthographic processing, and speed of processing hypotheses in a sample of Grade 2 children followed until Grade 5 (N=72). Finally, Study 3 contrasted the same hypotheses in a sample of Grade 4 children with dyslexia (n=30) and chronological-age controls (n=30). The results indicated that (a) RAN is unrelated to Paired Associate Learning (PAL) tasks that tap the ability to form arbitrary connections between characters and their pronunciation, (b) controlling for nonverbal IQ and orthographic processing was sufficient to explain the RAN-reading accuracy relationship but not the RAN-reading fluency relationship, and (c) the observed differences between dyslexics and controls in RAN diminished after controlling for orthographic processing. Taken together, these findings suggest that RAN is related to reading accuracy (and partly to reading fluency) because children must access orthographic representations from long-term memory. Although accessing these representations is sufficient for accurate word recognition, it is not sufficient for fluent reading, which also requires efficient parafoveal processing. PMID- 25462036 TI - Is height a core geometric cue for navigation? Young children's use of height in reorientation. AB - With respect to reorientation, children older than 1.5 to 2 years can use geometric cues (distance and left/right sense). However, because previous studies have focused mainly on the plane geometric properties, little is known about the role of information with respect to vertical dimension in children's reorientation. The current study aimed to examine whether and how 3- and 4-year old children use height information to search for a hidden toy when disoriented in a small enclosure. In a slant-ceiling rectangular room and a slant-ceiling square room, 4-year-olds were able to use height information to reorient and search for the toy in the correct corner, whereas 3-year-olds were not able to do so. Our results suggest that children can, at least by the age of 4 years, use height information and that height is not used as early as other geometric properties that are in the core geometry system for navigation. PMID- 25462037 TI - Daily animal exposure and children's biological concepts. AB - A large body of research has focused on the developmental trajectory of children's acquisition of a theoretically coherent naive biology. However, considerably less work has focused on how specific daily experiences shape the development of children's knowledge about living things. In the current research, we investigated one common experience that might contribute to biological knowledge development during early childhood-pet ownership. In Study 1, we investigated how children interact with pets by observing 24 preschool-aged children with their pet cats or dogs and asking parents about their children's daily involvement with the pets. We found that most of young children's observed and reported interactions with their pets are reciprocal social interactions. In Study 2, we tested whether children who have daily social experiences with animals are more likely to attribute biological properties to animals than children without pets. Both 3- and 5-year-olds with pets were more likely to attribute biological properties to animals than those without pets. Similarly, both older and younger children with pets showed less anthropocentric patterns of extension of novel biological information. The results suggest that having pets may facilitate the development of a more sophisticated, human-inclusive representation of animals. PMID- 25462038 TI - Perception of the multisensory coherence of fluent audiovisual speech in infancy: its emergence and the role of experience. AB - To investigate the developmental emergence of the perception of the multisensory coherence of native and non-native audiovisual fluent speech, we tested 4-, 8- to 10-, and 12- to 14-month-old English-learning infants. Infants first viewed two identical female faces articulating two different monologues in silence and then in the presence of an audible monologue that matched the visible articulations of one of the faces. Neither the 4-month-old nor 8- to 10-month-old infants exhibited audiovisual matching in that they did not look longer at the matching monologue. In contrast, the 12- to 14-month-old infants exhibited matching and, consistent with the emergence of perceptual expertise for the native language, perceived the multisensory coherence of native-language monologues earlier in the test trials than that of non-native language monologues. Moreover, the matching of native audible and visible speech streams observed in the 12- to 14-month-olds did not depend on audiovisual synchrony, whereas the matching of non-native audible and visible speech streams did depend on synchrony. Overall, the current findings indicate that the perception of the multisensory coherence of fluent audiovisual speech emerges late in infancy, that audiovisual synchrony cues are more important in the perception of the multisensory coherence of non-native speech than that of native audiovisual speech, and that the emergence of this skill most likely is affected by perceptual narrowing. PMID- 25462039 TI - Over-imitation is not automatic: context sensitivity in children's overimitation and action interpretation of causally irrelevant actions. AB - Recent research has documented the robust tendency of children to "over-imitate," that is, to copy causally irrelevant action elements in goal-directed action sequences. Different explanations for over-imitation have been proposed. Causal accounts claim that children mistakenly perceive such action elements as causally relevant and, therefore, imitate them. Affiliation accounts claim that children over-imitate to affiliate with the model. Normative accounts claim that children conceive of causally irrelevant actions as essential parts of an overarching conventional activity. These different accounts generally hold the same predictions regarding children's imitative response. However, it is possible to distinguish between them when one considers additional parameters. The normative account predicts wide-ranging flexibility with regard to action interpretation and the occurrence of over-imitation. First, it predicts spontaneous protest against norm violators who omit the causally irrelevant actions. Second, children should perform the causally irrelevant actions less frequently, and criticize others less frequently for omitting them, when the actions take place in a different context from the one of the initial demonstration. Such flexibility is not predicted by causal accounts and is predicted for only a limited range of contexts by affiliation accounts. Study 1 investigated children's own imitative response and found less over-imitation when children acted in a different context from when they acted in the same context as the initial demonstration. In Study 2, children criticized a puppet less frequently for omitting irrelevant actions when the puppet acted in a different context. The results support the notion that over-imitation is not an automatic and inflexible phenomenon. PMID- 25462040 TI - Infants learn enduring functions of novel tools from action demonstrations. AB - According to recent theoretical proposals, one function of infant goal attribution is to support early social learning of artifact functions from instrumental actions, and one function of infant sensitivity to communication is to support early acquisition of generic knowledge about enduring, kind-relevant properties of the referents. The current study tested two hypotheses, derived from these proposals, about the conditions that facilitate the acquisition of enduring functions for novel tools during human infancy. Using a violation-of expectation paradigm, we show that 13.5-month-old infants encode arbitrary end states of action sequences in relation to the novel tools employed to bring them about. These mappings are not formed if the same end states of action sequences cannot be interpreted as action goals. Moreover, the tool-goal mappings acquired from infant-directed communicative demonstrations are more resilient to counterevidence than those acquired from non-infant-directed presentations and, thus, show similarities to generic representations rather than episodic ones. These findings suggest that the acquisition of tool functions during infancy is guided by both teleological action interpretation mechanisms and the expectation that communicative demonstrations reveal enduring dispositional properties of tools. PMID- 25462041 TI - Are boys more sensitive to sensitivity? Parenting and executive function in preschoolers. AB - During early childhood, girls outperform boys on key dimensions of cognitive functions, including inhibitory control, sustained attention, and working memory. The role of parenting in these sex differences is unknown despite evidence that boys are more sensitive to the effects of the early environment. In this study, we measured parental sensitivity at 14 and 36 months of age, and children's cognitive and executive functions (sustained attention, inhibitory control, and forward/backward memory) at 52 months of age, in a longitudinal cohort (N=752). Boys scored significantly lower than girls on inhibitory control (more Go/NoGo "commission errors") and short-term memory (forward color recall task), but boys did not differ from girls on attention (Go/NoGo "omission errors") or working memory (backward color recall task). In stratified analyses, parental sensitivity at 36 months of age was negatively associated with number of errors of commission (p=.05) and omission (p=.02) in boys, whereas child's age was the only significant predictor of commission and omission errors in girls. A combined analysis of both sexes confirmed an interaction between sex and parenting for omission errors (p=.03). The results indicate that sex differences in cognitive functions are evident in preschoolers, although not across all dimensions we assessed. Boys appear to be more vulnerable to early parenting effects, but only in association with omission errors (attention) and not with the other cognitive function dimensions. PMID- 25462042 TI - Management of a patient with situs inversus totalis with acute cholecystitis and common bile duct stones: A case report. AB - INTRODUCTION: The incidence of situs inversus thought to be in the range of 1:10,000-1:20,000 according to Mayo et al. PRESENTATION OF CASE: A forty-five year-old lady presented with pain in the left hypochondrium and was diagnosed to have acute cholecystitis with choledocholithiasis in situs inversus totalis. Patient underwent endoscopic sphincterotomy and common bile duct stone extraction in view of choledocholithiasis and after common bile duct cannulation patient taken up for elective laparoscopic cholecystectomy (LC) within 24h. DISCUSSION: The most challenging factor for performing surgery in a patient with situs inversus is dealing with the mirror image anatomy. The first laparoscopic cholecystectomy in situs inversus was reported by Campos et al. in 1991. Since then, 50 other cases have been reported in literature making a point that laparoscopic procedure is not contraindicated. CONCLUSION: Acute cholecystitis with choledocholithiasis is extremely rare and requires expert intervention from both the endoscopist and the laparoscopic surgeons because of the reverse anatomy and the fact that both are attuned to the constant practice of the procedures in normal anatomy. PMID- 25462043 TI - Ileosigmoid knotting in patients under 25 years of age: A report of two cases. AB - INTRODUCTION: Ileosigmoid knotting is a rare cause of acute abdomen with high morbidity and mortality. Its diagnosis is infrequently made before surgery because of its varying ways of presentation and rarity. PRESENTATION OF CASE: The first was a 21-year-old male who presented with a history of sudden generalized abdominal pain and progressive abdominal distension. He was pale and severely dehydrated. His extremities were cold and clammy. His pulse rate was 110 per minute and blood pressure was 90/50mmHg. The second case was 20-year-old male who presented with similar symptoms as above. He was not pale but mildly dehydrated. His pulse rate was 92 per minute and blood pressure 110/70mmHg. Both patients were resuscitated and had exploratory laparotomy a few hours after presentation. The first patient was found to have ileosigmoid knotting with gangrenous sigmoid colon and terminal ileum. He had Hartmann's procedure and right hemicolectomy with ileo-transverse anastomosis. The second patient was found to have ileosigmoid knotting with viable loops of bowel. He had careful detorsion, sigmoidectomy with primary anastomosis. Both patients' have good outcome. DISCUSSION: This is to report two cases of ileosigmoid knotting in two male patients aged 21 and 20 years, respectively, with the hope of increasing awareness. CONCLUSION: Ileosigmoid knotting though more common in fourth or fifth decade of life, can also occur in the 2nd decade. Early diagnosis, careful resuscitation and skilful surgical intervention will improve outcome. PMID- 25462044 TI - Dermal fat graft from simultaneous abdominoplasty as an adjunct to revision aesthetic and reconstructive breast surgery: A poor man's acellular dermal matrix? AB - INTRODUCTION: The global use of acellular dermal matrices as an adjunct to tissue expander or implant-based breast reconstruction, by surgeons wishing to cover and support the inferior breast pole, has increased in frequency in the last two decades. However despite the reported enhanced cosmetic outcomes, issues regarding their cost effectiveness have led to their infrequent use within the UK National Health Service and the need for an equally efficacious but cheaper alternative. PRESENTATION OF CASE: We report two patients requiring bilateral revision breast surgery for severely asymmetrical, tender, ptotic breasts and cosmetically poor abdomens. Both were denied assisted acellular dermal matrix reconstructive surgery on the state NHS system and unable to afford the private costs. We therefore utilised free dermal fat grafts, harvested from concomitant abdominoplasties to extend the pectoralis major muscle and smoothen surface irregularities. DISCUSSION: Both patients achieved excellent cosmetic outcomes and aside from a small, spontaneously resolving abdominal site seroma in one patient, have remained free of any complications for over two years. This cost effective procedure is only feasible in patients with an adequate pannus who are amenable to the extra surgery and resultant scarring. CONCLUSION: We herein report the use of free dermal fat graft in revision aesthetic and reconstructive surgery in a manner akin to recent acellular dermal matrix use. The comparable enhanced aesthetic outcomes, minimal complication rate and substantial cost savings merit dissemination to a global audience and encourage surgeons to consider this economic alternative. PMID- 25462045 TI - Intraoperative management of a carbon dioxide embolus in the setting of laparoscopic cholecystectomy for a patient with primary biliary cirrhosis: A case report. AB - INTRODUCTION: Carbon dioxide (CO2) embolism is a rare complication of laparoscopic cholecystectomy of which both surgeons and anesthesiologists must be aware. This paper presents a case of a CO2 embolus that occurred in a patient with primary biliary cirrhosis (PBC) and discusses the possible correlation between these two events. PRESENTATION OF CASE: Our patient with PBC presented with symptomatic biliary dyskinesia and was determined to be a good candidate for laparoscopic cholecystectomy. During this routine surgery a CO2 embolus entered through the altered hepatic parenchyma and progressed to the heart leading to acute hemodynamic collapse. Rapid detection and management aided in the subsequent dissolution of the embolus and recovery of the patient. DISCUSSION: In patients with PBC, pathological changes that have taken place in the liver may increase the risk of CO2 embolism. Hepatic alterations that have been previously described include increased angiogenesis and vasodilation. Prior to the operation, the most appropriate method of monitoring should be determined for patients with known liver disease. CONCLUSION: Both the surgical and anesthesia team must keep in mind the potential for CO2 embolism during laparoscopic surgery. It is imperative that the medical staff be aware of the risks, signs, and subsequent management so this rare, but potentially fatal event can be managed appropriately. PMID- 25462046 TI - Pancreatic pseudopapillary tumour: A rare misdiagnosed entity. AB - INTRODUCTION: Solid pseudo papillary pancreatic tumour is a rare entity. The atypical presentation causes a delayed or misdiagnosis of these pathology. It commonly affects the female population in the 2nd and 3rd decade of life. The presentation varies from non-specific abdominal pain to incidental findings in asymptomatic patients. It is a low-grade premalignant condition that is curable by excision of the tumour. PRESENTATION OF CASE: This paper presents a 17-year old girl with intra-abdominal mass diagnosed with solid pseudo papillary tumour that underwent Whipple's procedure. DISCUSSION: We discuss the presentations, diagnosis and pathology findings of this rare pathology. CONCLUSION: The diagnosis remains an enigma in view of the nature and location of the tumour. Resection is still the best choice remains for this condition. PMID- 25462047 TI - Popliteal lymph node metastasis of tibial osteoblastic osteosarcoma. AB - INTRODUCTION: We report a case with lymph node metastasis of osteosarcoma, which is a rare entity in comparison to hematogeneous lung or bone metastasis. PRESENTATION OF CASE: Twenty-seven years old male patient referred to our clinic complaining of ongoing left knee pain and swelling since one month without a history of prior trauma. Magnetic resonance imaging (MRI) revealed a mass of malignant nature which causes more prominent expansion and destruction of the bone distally with periosteal reaction. A lymphadenomegaly 16mm*13mm in diameter was also present in the popliteal fossa having the same signal pattern with the primary lesion. Thirteen weeks following the first referral of the patient, wide resection and reconstruction with modular tumor prosthesis was performed. Popliteal lymph node was excised through the same incision. Pathologic examination of the resected speciman reported osteoblastic osteosarcoma. The lymph node extirpated from the popliteal fossa was reported to be a metastasis of the primary tumor. DISCUSSION: Osteosarcoma of the long bones is the most common primary malignant bone neoplasm of both childhood and adulthood. Osteosarcomas commonly metastasize hematogeneously to the lungs and bones. Lymph node metastasis is a rare entity. Similar studies report rates between 2.3% and 4%. It is not clearly explained, how lymph node metastasis in osteosarcoma occurs despite lack of lymphatic drainage in normal cortical and spongious bone. CONCLUSION: Lymph node metastasis of osteosarcoma is a rare entity and metastatic patterns could not be clearly explained. On the other hand, the effects of lymph node metastasis on prognosis are also not clearly defined and further studies are needed. PMID- 25462048 TI - Rectal obstruction due to endometriosis: A case report and review of the Japanese literature. AB - INTRODUCTION: Colorectal obstructive endometriosis is relatively rare in Japan and its differentiation from malignancy is often difficult. We report a case of rectal obstructive endometriosis. PRESENTATION OF CASE: A 37-year-old woman was referred to our hospital with a suspected ileus. Her chief symptoms were left lower abdominal pain and vomiting. Colonoscopy showed an intraluminal mass of redness in the upper rectum. A proctectomy was performed because of the bowel obstruction. The rectum was filled with an intraluminal mass measuring 5cm*4cm, and endometriosis was diagnosed pathologically. DISCUSSION: A preoperative diagnosis of colorectal obstructive endometriosis is often difficult because of the lack of definite diagnostic, clinical, sonographic, or radiological findings that are characteristic of this disease. Medical treatment is not always effective for colorectal obstructive endometriosis, and surgery is often performed. CONCLUSION: Colorectal obstructive endometriosis should be considered as a differential diagnosis in cases of various gastrointestinal symptoms in women who are of reproductive age. PMID- 25462049 TI - Primary lymph node gastrinoma. A diagnosis of exclusion. A case for duodenotomy in the setting of a negative imaging for primary tumor: A case report and review of the literature. AB - INTRODUCTION: Zollinger-Ellison syndrome (ZES) is caused by uninhibited secretion of gastrin from a gastrinoma. Gastrinomas most commonly arise within the wall of the duodenum followed by the pancreas. Primary lymph node gastrinomas have also been reported in the literature. This is a case of ZES where preoperative localization revealed a gastrinoma in a solitary portacaval lymph node, presumed to be a primary lymph node gastrinoma. PRESENTATION OF CASE: The patient is a 57 year old female diagnosed with ZES, suspected of having a primary lymph node gastrinoma. The patient underwent an exploratory laparotomy and excision of a portacaval lymph node with a frozen section which was positive for gastrinoma. Intraoperative sonography of the pancreas, upper endoscopy with transillumination of the duodenum, and a duodenotomy with bimanual examination of the duodenal wall were also performed. The patient was found to have a 4mm duodenal mass near the pylorus, which was excised. DISCUSSION: Pathology showed that the duodenal mass was primary gastrinoma. Serum gastrin levels taken four months postoperatively were normal and the repeat octreotide scan did not show any evidence of recurrence. CONCLUSION: Primary lymph node gastrinoma is a diagnosis of exclusion. The duodenum and pancreas must be fully explored to rule out a primary gastrinoma that may be occult. PMID- 25462050 TI - Post laminoplasty cervical kyphosis-Case report. AB - INTRODUCTION: Cervical kyphosis is a progressive cervical sagittal plane deformity that may cause a reduction in the ability to look horizontally, breathing and swallowing difficulties, sense of thoracic oppression and social isolation. Moreover, cervical kyphosis can cause myelopathy due to a direct compression by osteo-articular structures on the spinal cord or to a transitory ischaemic injury. The treatment of choice is surgery. The goals of surgery are: nervous structures decompression, cervical and global sagittal balance correction and vertebral stabilization and fusion. PRESENTATION OF CASE: In October 2008 a 35 years old woman underwent surgical removal of a cervical-bulbar ependymoma with C1-C5 laminectomy and a C2-C5 laminoplasty. Five months after surgery, the patient developed a kyphotic posture, with intense neck and scapular girdle pain. The patients had a flexible cervical kyphosis. Therefore, we decided to perform an anterior surgical approach. We performed a corpectomy C4-C5 in order to achieve the anterior decompression; we placed a titanium expansion mesh. DISCUSSION: Cervical kyphosis can be flexible or fixed. Some authors have reported the use of anterior surgery only for flexible cervical kyphosis as discectomy and corpectomy. This approach is useful for anterior column load sharing however it is not required for deformity correction. CONCLUSION: The anterior approach is a good surgical option in flexible cervical kyphosis. It is of primary importance the sagittal alignment of the cervical spine in order to decompress the nervous structures and to guarantee a long-term stability. PMID- 25462051 TI - Nerve sheath myxoma of the dorsal paravertebral space. AB - INTRODUCTION: Nerve sheath myxomas (NSM) are rare benign soft tissue tumors. The dorsal paravertebral placed NMS diagnosis can be difficult. PRESENTATION OF CASE: This article presents clinical, radiological findings and treatment of the NSM of the dorsal paravertebral space in a 32-year-old man presented with a right shoulder and back pain for 4 years. DISCUSSION: NSM is a rare and benign tumor and that most often occurs in the skin of the head, neck or upper limbs of younger patients. Rare locations such as intracranial, spinal canal, trunk, lower limb and oral cavity were also reported. The appropriate treatment of NSM is surgical excision. Diagnosis is difficult in an uncommon presentation. CONCLUSION: Although the most presented case of NMS are dermal tumors, it may also be found extremely rare locations. We conclude that, the definitive treatment of NSM is surgical excision with safe margins even when it is possible. PMID- 25462052 TI - Laparoscopic diagnosis and treatment of a hydrocele of the canal of Nuck extending in the retroperitoneal space: A case report. AB - INTRODUCTION: Hydrocele of the canal of Nuck is a rarely encountered entity. We report a case underwent laparoscopic totally extraperitoneal (TEP) treatment for a hydrocele of the canal of Nuck extending in the extraperitoneal space mainly. PRESENTATION OF CASE: A 37-year-old woman complained of painless and reducible swelling in her left groin, and referred to our hospital for surgical management against left inguinal hernia with the incarcerated ovary. Ultrasonography and MR images revealed a cystic mass in the retroperitoneal space, and we diagnosed as an unusual type of hydrocele of the canal of Nuck. The patient was scheduled for laparoscopic treatment. Laparoscopic findings on pneumoperitoneum showed an extraperitoneal cystic tumor with no contact with the left ovary. The fascia and peritoneum of the port site were closed, and then an extraperitoneal space was created. The cystic tumor with the round ligament of the uterus was dissected and resected by the TEP technique. The extended deep inguinal ring was repaired with polypropylene mesh. Postoperative course was uneventful. DISCUSSION: Hydrocele of the canal of Nuck in the adult female is a rare condition. The accurate diagnosis of an inguinal hydrocele in a female is seldom made. Laparoscopic examination provides surgeons with information of inguinal swelling accompanied with retroperitoneal cyst, and consecutive treatment by laparoscopic technique, especially TEP, is useful in regard to minimal damage of the peritoneum. CONCLUSION: Laparoscopic diagnosis and TEP treatment offers a useful alternative in selected patients with hydrocele of the canal of Nuck. PMID- 25462053 TI - Polyorchidism with presumed contralateral intrauterine testicular torsion. AB - INTRODUCTION: Polyorchidism was first described by Blasius in 1670(1) during a routine autopsy. We report a child with unilateral polyorchidism and a contralateral absent testis, a combination not reported previously. PRESENTATION OF CASE: A 2-year-old boy was referred to the outpatient clinic with an impalpable left testis. At laparoscopy, the left vas deferens and testicular vessels ended blindly proximal to a closed internal ring. No gonadal tissue was identified. On the right side, a single vas deferens and testicular vessels were seen entering the internal ring as normal. The right side of the scrotum was explored and two testes were identified within a single tunica vaginalis. DISCUSSION: Polyorchidism is rare with a literature search identifying approximately 230 reported cases. Whilst prenatal testicular torsion is increasing being recognized and treated as a surgical emergency,(9) prenatal testicular torsion in association with polyorchidism has not been previously reported. CONCLUSION: We describe a unique case of a 2-year-old boy with right sided polyorchidism and an absent left testis associated with a blind ending vas deferens and testicular vessels, presumed secondary to intrauterine testicular torsion. PMID- 25462055 TI - Atypical location of an osteoid osteoma with atypical anterior knee pain. AB - INTRODUCTION: An osteoid osteoma is a painful tumor that most commonly affects the extra-articular parts of the long bones. An intra-articular location of an osteoid osteoma is rare. Various differential diagnoses may arise in connection with such an unusual location because it causes atypical clinical signs. PRESENTATION OF CASE: A 24-year-old male developed pain in the central region of the right knee. Magnetic resonance imaging (MRI) showed no clear pathology in the knee joint. A technetium bone scan and computed tomography (CT) were then ordered and confirmed the presence of an osteoid osteoma in the knee joint. The patient was treated through an anteromedial approach to the knee, and the lesion was removed by excisional biopsy under fluoroscopy. DISCUSSION: The diagnosis of intra-articular osteoid osteoma is challenging because the clinical presentation can be misleading. MRI is often requested as the first imaging method when dealing with knee symptoms, and radiologists are often unaware of the clinical presentation. Edema seen on MRI can be misleading with respect to the location of the nidus. CT is considered to be the best imaging method because it usually allows for clear visualization of the nidus. Different treatments have been proposed, ranging from open excision to arthroscopic resection. CONCLUSION: Osteoid osteoma should be considered in young adult patients with chronic knee pain and no history of trauma. PMID- 25462054 TI - Giant inguinal hernia: Report of a case and reviews of surgical techniques. AB - INTRODUCTION: Inguinal hernia is one of the most surgical common diseases. Giant inguinal hernia is more unusual and significantly challenging in terms of surgical management. It is defined as an inguinal hernia that extends below the midpoint of inner thigh when the patient is in standing position. PRESENTATION OF CASE: A 67-year-old male presented with giant right-side inguinal hernia with symptoms of partial colonic obstruction and significant weight loss. Barium enema revealed ascending colon, cecum and ileum contained in hernia sac without significant lesions of large bowel. He underwent hernia repair with omentectomy. Hernioplasty with polypropylene mesh was performed without any complications. He recovered uneventfully. DISCUSSION: There were several repair techniques suggested by published articles such as resection of the content and increased intraabdominal volume procedure. Many key factors for management of the giant inquinal hernia were discussed. A new classification of the giant inquinal hernia was described. CONCLUSION: Surgical repair for the giant inquinal hernia is challenging and correlated with significant morbidity and mortality due to increased intra-abdominal pressure. PMID- 25462056 TI - Post-splenectomy splenosis presenting as hepatocellular carcinoma in the left lateral section of the liver: A case report. AB - INTRODUCTION: Defined as heterotrophic autotransplantation of splenic tissue after splenic trauma or surgery. PRESENTATION OF CASE: We present a case of 45 years old female patient with past history of splenectomy for haemolyticanaemia. Complaining of abdominal pain the patient was investigated by abdominal CT scan which revealed a focal lesion in the left lateral section of the liver suspicious to be hepatocellular carcinoma and gall bladder stones. Serum alpha-fetoprotein was within normal range. Exploration revealed a well encapsulated lesion completely separable from the liver and the diaphragm. Histopathological examination confirmed the diagnosis of splenosis. Although it is a rare condition, we recommend that the diagnosis of splenosis should be put in consideration in every patient with past history of splenectomy for proper management. DISCUSSION: Although several cases of hepatic splenosis have been reported in the literature, supra-hepatic splenosis as our case has been rarely described. CONCLUSION: Considering patients past history of splenectomy or splenic trauma should add splenosis to the list of possible differential diagnosis to avoid unnecessary surgical intervention. PMID- 25462057 TI - Unusual association of Meckel's diverticulum with double appendix - A rare finding. AB - INTRODUCTION: Appendix duplication is an extremely rare congenital anomaly that is seen in 0.004-0.009% of appendectomy specimens. Duplicated appendix may be associated with number of congenital anomalies. PRESENTATION OF CASE: In this case report, we are presenting a rare case of duplicated vermiform appendix with a co-existing Meckel's diverticulum. DISCUSSION: Anomalies of appendix are rare and duplication of vermiform appendix is extremely rare. In 1936, Cave classified appendiceal duplication for the first time which was modified by Wallbridge in 1963 into three types. Concomitant malformations or duplications of the large intestine or the genitourinary system may be present, especially in types B1 and C probably due to their similar embryological origin. Here we are presenting a very rare case report of type B1 appendix anomaly associated with Meckel's diverticulum. CONCLUSION: Surgeons should be aware of these conditions because of the possible clinical implications. PMID- 25462058 TI - Surgery for pregnancy-associated primary hepatocellular carcinoma: Report of four cases. AB - INTRODUCTION: Hepatocellular carcinoma (HCC) occurring in pregnancy is quite rare. The prognosis is usually poor because of a delay in diagnosis. Reported cases of HCC in pregnancy are largely isolated with no large experience. Thus the effect of pregnancy on the prognosis of patients with HCC and the risk factors of developing HCC in pregnancy are not well documented. Our aim was to review our experience with management of four young pregnant women with HCC. PRESENTATION OF CASE: Laboratory tests were performed before surgery. We analyzed the effects of age, hepatitis B surface antigens status, cirrhosis at presentation, gestational age of fetus, and maternal outcome. DISCUSSION: Increase in alpha-fetoprotein (AFP) level was somewhat useful for diagnosis. Three patients died in 5 months, 6 months, and 24 months from HCC recurrence, and another patient is alive without disease 12 months postoperatively. CONCLUSION: Surgery for HCC during pregnancy should be similar to that for non-pregnant women. Complete excision of tumor without termination of pregnancy provides the greatest chance of survival for women with HCC during pregnancy but depends on gestational age of the fetus. Adjuvant treatments are required to improve the long-term results of this type of surgery. The 28-week gestational week is a critical point of fetal maturation which is very important in deciding whether pregnancy should be terminated or not. The pregnancy was terminated in two of our patients when spontaneous rupture of HCC was diagnosed to save the mother's life. PMID- 25462059 TI - Differential localization and potency of manganese porphyrin superoxide dismutase mimicking compounds in Saccharomyces cerevisiae. AB - Cationic Mn(III) porphyrin complexes based on MnTM-2-PyP are among the most promising superoxide dismutase (SOD) mimicking compounds being considered as potential anti-inflammatory drugs. We studied four of these active compounds in the yeast Saccharomyces cerevisiae, MnTM-2-PyP, MnTE-2-PyP, MnTnHex-2-PyP, and MnTnBu-2-PyP, each of which differs only in the length of its alkyl substituents. Each was active in improving the aerobic growth of yeast lacking SOD (sod1?) in complete medium, and the efficacy of each mimic was correlated with its characteristic catalytic activity. We also studied the partitioning of these compounds between mitochondria and cytosol and found that the more hydrophobic members of the series accumulated in the mitochondria. Moreover, the degree to which a mimic mitigated the sod1Delta auxotrophic phenotype for lysine relative to its auxotrophic phenotype for methionine depended upon its level of lipophilicity-dependent accumulation inside the mitochondria. We conclude that localization within the cell is an important factor in biological efficacy in addition to the degree of catalytic activity, and we discuss possible explanations for this effect. PMID- 25462060 TI - Regulation of the effects of CYP2E1-induced oxidative stress by JNK signaling. AB - The generation of excessive amounts of reactive oxygen species (ROS) leads to cellular oxidative stress that underlies a variety of forms of hepatocyte injury and death including that from alcohol. Although ROS can induce cell damage through direct effects on cellular macromolecules, the injurious effects of ROS are mediated largely through changes in signal transduction pathways such as the mitogen-activated protein kinase c-Jun N-terminal kinase (JNK). In response to alcohol, hepatocytes have increased levels of the enzyme cytochrome P450 2E1 (CYP2E1) which generates an oxidant stress that promotes the development of alcoholic steatosis and liver injury. These effects are mediated in large part through overactivation of JNK that alters cell death pathways. Targeting the JNK pathway or its downstream effectors may be a useful therapeutic approach to the oxidative stress generated by CYP2E1 in alcoholic liver disease. PMID- 25462062 TI - Natural thermal adaptation increases heat shock protein levels and decreases oxidative stress. AB - Heat shock proteins (HSPs), originally identified as heat-inducible gene products, are a family of highly conserved proteins that respond to a wide variety of stress including oxidative stress. Although both acute and chronic oxidative stress have been well demonstrated to induce HSP responses, little evidence is available whether increased HSP levels provide enhanced protection against oxidative stress under elevated yet sublethal temperatures. We studied relationships between oxidative stress and HSPs in a physiological model by using Garra rufa (doctor fish), a fish species naturally acclimatized to different thermal conditions. We compared fish naturally living in a hot spring with relatively high water temperature (34.4+/-0.6 degrees C) to those living in normal river water temperature (25.4+/-4.7 degrees C), and found that levels of all the studied HSPs (HSP70, HSP60, HSP90, HSC70 and GRP75) were higher in fish living in elevated water temperature compared with normal river water temperature. In contrast, indicators of oxidative stress, including protein carbonyls and lipid hydroperoxides, were decreased in fish living in the elevated temperature, indicating that HSP levels are inversely associated with oxidative stress. The present results provide evidence that physiologically increased HSP levels provide protection against oxidative stress and enhance cytoprotection. PMID- 25462061 TI - Cholesterol: A modulator of the phagocyte NADPH oxidase activity - A cell-free study. AB - The NADPH oxidase Nox2, a multi-subunit enzyme complex comprising membrane and cytosolic proteins, catalyzes a very intense production of superoxide ions O2(* ), which are transformed into other reactive oxygen species (ROS). In vitro, it has to be activated by addition of amphiphiles like arachidonic acid (AA). It has been shown that the membrane part of phagocyte NADPH oxidase is present in lipid rafts rich in cholesterol. Cholesterol plays a significant role in the development of cardio-vascular diseases that are always accompanied by oxidative stress. Our aim was to investigate the influence of cholesterol on the activation process of NADPH oxidase. Our results clearly show that, in a cell-free system, cholesterol is not an efficient activator of NADPH oxidase like arachidonic acid (AA), however it triggers a basal low superoxide production at concentrations similar to what found in neutrophile. A higher concentration, if present during the assembly process of the enzyme, has an inhibitory role on the production of O2(*-). Added cholesterol acts on both cytosolic and membrane components, leading to imperfect assembly and decreasing the affinity of cytosolic subunits to the membrane ones. Added to the cytosolic proteins, it retains their conformations but still allows some conformational change induced by AA addition, indispensable to activation of NADPH oxidase. PMID- 25462063 TI - Ethanol-induced oxidant stress modulates hepatic autophagy and proteasome activity. AB - In this review, we describe research findings on the effects of alcohol exposure on two major catabolic systems in liver cells: the ubiquitin-proteasome system (UPS) and autophagy. These hydrolytic systems are not unique to liver cells; they exist in all eukaryotic tissues and cells. However, because the liver is the principal site of ethanol metabolism, it sustains the greatest damage from heavy drinking. Thus, the focus of this review is to specifically describe how ethanol oxidation modulates the activities of the UPS and autophagy and the mechanisms by which these changes contribute to the pathogenesis of alcohol-induced liver injury. Here, we describe the history and the importance of cellular hydrolytic systems, followed by a description of each catabolic pathway and the differential modulation of each by ethanol exposure. Overall, the evidence for an involvement of these catabolic systems in the pathogenesis of alcoholic liver disease is quite strong. It underscores their importance, not only as effective means of cellular recycling and eventual energy generation, but also as essential components of cellular defense. PMID- 25462064 TI - Intestinal CYP2E1: A mediator of alcohol-induced gut leakiness. AB - Chronic alcohol use can result in many pathological effects including alcoholic liver disease (ALD). While alcohol is necessary for the development of ALD, only 20-30% of alcoholics develop alcoholic steatohepatitis (ASH) with progressive liver disease leading to cirrhosis and liver failure (ALD). This suggests that while chronic alcohol consumption is necessary it is not sufficient to induce clinically relevant liver damage in the absence of a secondary risk factor. Studies in rodent models and alcoholic patients show that increased intestinal permeability to microbial products like endotoxin play a critical role in promoting liver inflammation in ALD pathogenesis. Therefore identifying mechanisms of alcohol-induced intestinal permeability is important in identifying mechanisms of ALD and for designing new avenues for therapy. Cyp2e1 is a cytochrome P450 enzyme that metabolizes alcohol has been shown to be upregulated by chronic alcohol use and to be a major source of oxidative stress and liver injury in alcoholics and in animal and in vitro models of chronic alcohol use. Because Cyp2e1 is also expressed in the intestine and is upregulated by chronic alcohol use, we hypothesized it could play a role in alcohol-induced intestinal hyperpermeability. Our in vitro studies with intestinal Caco-2 cells and in mice fed alcohol showed that circadian clock proteins CLOCK and PER2 are required for alcohol-induced permeability. We also showed that alcohol increases Cyp2e1 protein and activity but not mRNA in Caco-2 cells and that an inhibitor of oxidative stress or siRNA knockdown of Cyp2e1 prevents the increase in CLOCK or PER2 proteins and prevents alcohol-induced hyperpermeability. With our collaborators we have also shown that Cyp2e1 knockout mice are resistant to alcohol-induced gut leakiness and liver inflammation. Taken together our data support a novel Cyp2e1-circadian clock protein mechanism for alcohol-induced gut leakiness that could provide new avenues for therapy of ALD. PMID- 25462065 TI - Role of H2O2 in the oxidative effects of zinc exposure in human airway epithelial cells. AB - Human exposure to particulate matter (PM) is a global environmental health concern. Zinc (Zn(2+)) is a ubiquitous respiratory toxicant that has been associated with PM health effects. However, the molecular mechanism of Zn(2+) toxicity is not fully understood. H2O2 and Zn(2+) have been shown to mediate signaling leading to adverse cellular responses in the lung and we have previously demonstrated Zn(2+) to cause cellular H2O2 production. To determine the role of Zn(2+)-induced H2O2 production in the human airway epithelial cell response to Zn(2+) exposure. BEAS-2B cells expressing the redox-sensitive fluorogenic sensors HyPer (H2O2) or roGFP2 (EGSH) in the cytosol or mitochondria were exposed to 50uM Zn(2+) for 5min in the presence of 1uM of the zinc ionophore pyrithione. Intracellular H2O2 levels were modulated using catalase expression either targeted to the cytosol or ectopically to the mitochondria. HO-1 mRNA expression was measured as a downstream marker of response to oxidative stress induced by Zn(2+) exposure. Both cytosolic catalase overexpression and ectopic catalase expression in mitochondria were effective in ablating Zn(2+)-induced elevations in H2O2. Compartment-directed catalase expression blunted Zn(2+) induced elevations in cytosolic EGSH and the increased expression of HO-1 mRNA levels. Zn(2+) leads to multiple oxidative effects that are exerted through H2O2 dependent and independent mechanisms. PMID- 25462066 TI - The role of reactive oxygen species (ROS) and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts. AB - Exocyclic etheno-DNA adducts are mutagenic and carcinogenic and are formed by the reaction of lipidperoxidation (LPO) products such as 4-hydoxynonenal or malondialdehyde with DNA bases. LPO products are generated either via inflammation driven oxidative stress or via the induction of cytochrome P-450 2E1 (CYP2E1). In the liver CYP2E1 is induced by various compounds including free fatty acids, acetone and ethanol. Increased levels of CYP2E1 and thus, oxidative stress are observed in the liver of patients with non-alcoholic steatohepatitis (NASH) as well as in the chronic alcoholic. In addition, chronic ethanol ingestion also increases CYP2E1 in the mucosa of the oesophagus and colon. In all these tissues CYP2E1 correlates significantly with the levels of carcinogenic etheno-DNA adducts. In contrast, in patients with non-alcoholic steatohepatitis (NASH) hepatic etheno-DNA adducts do not correlate with CYP2E1 indicating that in NASH etheno-DNA adducts formation is predominately driven by inflammation rather than by CYP2E1 induction. Since etheno-DNA adducts are strong mutagens producing various types of base pair substitution mutations as well as other types of genetic damage, it is strongly believed that they are involved in ethanol mediated carcinogenesis primarily driven by the induction of CYP2E1. PMID- 25462067 TI - Defective mitophagy driven by dysregulation of rheb and KIF5B contributes to mitochondrial reactive oxygen species (ROS)-induced nod-like receptor 3 (NLRP3) dependent proinflammatory response and aggravates lipotoxicity. AB - High-fat diet (HFD) and inflammation are the key contributors to insulin resistance and type 2 diabetes (T2D). Previous study shows fatty acid-induced accumulation of damaged, reactive oxygen species (ROS)-generating mitochondria, and this in turn activates the NLRP3 inflammasome interference with insulin signaling. Our previous research shows NLRP3 inflammasome activation signal originates from defects in autophagy. Yet how the fatty acid related to mitophagy alteration leads to the activation of NLRP3-ASC inflammasome has not been considered. Here we demonstrated that palmitate (PA) induced mitophagy deficiency, leading to damaged mitochondrion as characterized by mito-ROS production and loss of membrane potential. Antioxidant APDC or Ca(2+) signaling inhibitor Nifedipine blocked PA-induced NLRP3 inflammasome activation. Further, we provided evidences that PA reduced the expression of Ras homolog enriched in brain (Rheb) and disrupted Rheb recruitment to the mitochondrial outer membrane. In addition, sustained PA caused disassociation of kinesin family member 5B (KIF5B) from binding with mitochondria via Ca(2+)-dependent effects. Disruption of Rheb and KIF5B interaction with mitochondria blocked mitochondrial degradation along with IL-1beta dependent insulin resistance, which was majorly attenuated by Rheb/KIF5B overexpression. In a consequence, defective mitophagy led to the accumulation of damaged-ROS-generating mitochondria, down pathway of NLRP3-ASC Caspase 1 activation, and subsequently, insulin resistance. These findings provide insights into the association of inflammation, mitophagy and T2D. PMID- 25462068 TI - CYP2E1 autoantibodies in liver diseases. AB - Autoimmune reactions involving cytochrome P4502E1 (CYP2E1) are a feature of idiosyncratic liver injury induced by halogenated hydrocarbons and isoniazid, but are also detectable in about one third of the patients with advanced alcoholic liver disease (ALD) and chronic hepatitis C (CHC). In these latter the presence of anti-CYP2E1 auto-antibodies is an independent predictor of extensive necro inflammation and fibrosis and worsens the recurrence of hepatitis following liver transplantation, indicating that CYP2E1-directed autoimmunity can contribute to hepatic injury. The molecular characterization of the antigens recognized by anti CYP2E1 auto-antibodies in ALD and CHC has shown that the targeted conformational epitopes are located in close proximity on the molecular surface. Furthermore, these epitopes can be recognized on CYP2E1 expressed on hepatocyte plasma membranes where they can trigger antibody-mediated cytotoxicity. This does not exclude that T cell-mediated responses against CYP2E1 might also be involved in causing hepatocyte damage. CYP2E1 structural modifications by reactive metabolites and molecular mimicry represent important factors in the breaking of self-tolerance against CYP2E1 in, respectively, ALD and CHC. However, genetic or acquired interferences with the mechanisms controlling the homeostasis of the immune system are also likely to contribute. More studies are needed to better characterize the impact of anti-CYP2E1 autoimmunity in liver diseases particularly in relation to the fact that common metabolic alterations such as obesity and diabetes stimulates hepatic CYP2E1 expression. PMID- 25462069 TI - Peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells. AB - Peroxiredoxin 3 (PRX3), a typical 2-Cys peroxiredoxin located exclusively in the mitochondrial matrix, is the principal peroxidase responsible for metabolizing mitochondrial hydrogen peroxide, a byproduct of cellular respiration originating from the mitochondrial electron transport chain. Mitochondrial oxidants are produced in excess in cancer cells due to oncogenic transformation and metabolic reorganization, and signals through FOXM1 and other redox-responsive factors to support a hyper-proliferative state. Over-expression of PRX3 in cancer cells has been shown to counteract oncogene-induced senescence and support tumor cell growth and survival making PRX3 a credible therapeutic target. Using malignant mesothelioma (MM) cells stably expressing shRNAs to PRX3 we show that decreased expression of PRX3 alters mitochondrial structure, function and cell cycle kinetics. As compared to control cells, knockdown of PRX3 expression increased mitochondrial membrane potential, basal ATP production, oxygen consumption and extracellular acidification rates. shPRX3 MM cells failed to progress through the cell cycle compared to wild type controls, with increased numbers of cells in G2/M phase. Diminished PRX3 expression also induced mitochondrial hyperfusion similar to the DRP1 inhibitor mdivi-1. Cell cycle progression and changes in mitochondrial networking were rescued by transient expression of either catalase or mitochondrial-targeted catalase, indicating high levels of hydrogen peroxide contribute to perturbations in mitochondrial structure and function in shPRX3 MM cells. Our results indicate that PRX3 levels establish a redox set point that permits MM cells to thrive in response to increased levels of mROS, and that perturbing the redox status governed by PRX3 impairs proliferation by altering cell cycle-dependent dynamics between mitochondrial networking and energy metabolism. PMID- 25462070 TI - Estradiol improves cardiovascular function through up-regulation of SOD2 on vascular wall. AB - Epidemiological studies have shown that estrogens have protective effects in cardiovascular diseases, even though the results from human clinical trials remain controversial, while most of the animal experiments confirmed this effect, but the detailed mechanism remains unclear. In this study, we found that estradiol (E2) treatment significantly increases the expression of mitochondrial superoxide dismutase (SOD2) in mice and in vitro in human aorta endothelial cells. Further investigation shows that E2 up-regulates SOD2 through tethering of estrogen receptor (ER) to Sp1 and the increased binding of Sp1 to GC-box on the SOD2 promoter, where ERalpha responses E2-mediated gene activation, and ERbeta maintains basal gene expression level. The E2/ER-mediated SOD2 up-regulation results in minimized ROS generation, which highly favors healthy cardiovascular function. Gene therapy through lentivirus-carried endothelium-specific delivery to the vascular wall in high-fat diet (HFT) mice shows that the SOD2 expression in endothelial cells normalizes E2 deficiency-induced ROS generation with ameliorated mitochondrial dysfunction and vascular damage, while SOD2 knockdown worsens the problem despite the presence of E2, indicating that E2-induced SOD2 expression plays an important vasculoprotective role. To our knowledge, this is the first report for the mechanism by which E2 improves cardiovascular function through up-regulation of SOD2 in endothelial cells. In turn, this suggests a novel gene therapy through lentivirus-carried gene delivery to vascular wall for E2 deficiency-induced cardiovascular damage in postmenopausal women. PMID- 25462071 TI - Ellagic acid suppresses lipid accumulation by suppressing early adipogenic events and cell cycle arrest. AB - Ellagic acid (EA) is a natural polyphenol found in various fruits and vegetables. In this study, we examined the inhibitory effect of EA on fat accumulation in 3T3 L1 cells during adipogenesis. Our data showed that EA reduced fat accumulation by down-regulating adipogenic markers such as peroxisome proliferator activated receptor gamma (PPARgamma) and the CCAAT/enhancer binding protein alpha (C/EBPalpha) at the mRNA and protein levels in a dose-dependent manner. We found that the decrease in adipogenic markers resulted from reduced expression of some early adipogenic transcription factors such as KLF4, KLF5, Krox20, and C/EBPbeta within 24 h. Also, these inhibitions were correlated with down-regulation of TG synthetic enzymes, causing inhibition of triglyceride (TG) levels in 3T3-L1 cells investigated by ORO staining and in zebrafish investigated by TG assay. Additionally, the cell cycle analysis showed that EA inhibited cell cycle progression by arresting cells at the G0/G1 phase. PMID- 25462072 TI - Salicylic acid alleviates cadmium-induced stress responses through the inhibition of Cd-induced auxin-mediated reactive oxygen species production in barley root tips. AB - Auxin is a master regulator of root growth by modulating its development under the constantly changing environment. Recently, an antagonistic interaction was suggested between SA and IAA signaling. Therefore, the purpose of this work was to analyze and compare the effect of the indole-3-acetic acid (IAA) signaling inhibitor p-chlorophenoxyisobutyric acid (PCIB) and salicylic acid (SA) as a potential IAA signaling inhibitor on the root growth, enzyme activity and reactive oxygen species (ROS) production in Cd- and IAA-treated barley root tips. Exposure of plants to Cd resulted in a more than threefold increase of IAA content in the root apex even 3h after the treatment. In addition, exogenously applied IAA evoked root responses such as root growth inhibition and swelling, ROS generation and activation of lipoxygenase or glutathione peroxidase identical to those induced by Cd. Furthermore, both Cd- and IAA-induced stress responses were markedly reversed by PCIB or SA post-treatment. Similarly to PCIB, SA did not affect the IAA content of root tips, suggesting the action of SA on the IAA signaling pathway in barley roots. SA probably does not alleviate the Cd toxicity in roots, but rather prevents or partially inhibits the root defense response to the presence of Cd through the inhibition of Cd-induced IAA-mediated ROS generation in roots. PMID- 25462073 TI - Selenium and sulfur influence ethylene formation and alleviate cadmium-induced oxidative stress by improving proline and glutathione production in wheat. AB - We have studied the influence of selenium (Se) and sulfur (S) in the protection of photosynthetic capacity of wheat (Triticum aestivum) against cadmium (Cd) stress. The involvement of ethylene and its interaction with proline and antioxidant metabolism in the tolerance of plants to Cd stress was evaluated. Application of Se or S alleviated Cd-induced oxidative stress by increasing proline accumulation as a result of increased activity of glutamyl kinase (GK) and decreased activity of proline oxidase (PROX). These nutrients also induced the activity of ATP-sulfurylase and serine acetyl transferase and the content of cysteine (Cys), a precursor for the synthesis of both reduced glutathione (GSH) and ethylene. Further, application of Se and S to plants under Cd stress reduced ethylene level and increased the activity of glutathione reductase (GR) and glutathione peroxidase (GPX), reduced oxidative stress and improved photosynthesis and growth. The involvement of ethylene in Se and S-mediated alleviation of Cd stress was substantiated with the use of ethylene biosynthesis inhibitor aminoethoxyvinylglycine (AVG). The use of AVG reversed the effects of Se and S on ethylene, content of proline and GSH and photosynthesis. The results suggested that Se and S both reversed Cd-induced oxidative stress by regulating ethylene formation, proline and GSH metabolism. Thus, Se or S-induced regulatory interaction between ethylene and proline and GSH metabolism may be used for the reversal of Cd-induced oxidative stress. PMID- 25462074 TI - Overexpression of the bZIP transcription factor OsbZIP79 suppresses the production of diterpenoid phytoalexin in rice cells. AB - Phytoalexins are antimicrobial specialised metabolites that are produced by plants in response to pathogen attack. Momilactones and phytocassanes are major diterpenoid phytoalexins in rice that are synthesised from geranylgeranyl diphosphate that is derived from the methylerythritol phosphate (MEP) pathway. We have previously reported that rice cells overexpressing the basic leucine zipper (bZIP) transcription factor OsTGAP1 exhibit a hyperaccumulation of momilactones and phytocassanes, with hyperinductive expression of momilactone and phytocassane biosynthetic genes and MEP pathway genes, upon response to a chitin oligosaccharide elicitor. For a better understanding of OsTGAP1-mediated regulation of diterpenoid phytoalexin production, we identified OsTGAP1 interacting proteins using yeast two-hybrid screening. Among the OsTGAP1 interacting protein candidates, a TGA factor OsbZIP79 was investigated to verify its physical interaction with OsTGAP1 and involvement in the regulation of phytoalexin production. An in vitro pull-down assay demonstrated that OsTGAP1 and OsbZIP79 exhibited a heterodimeric as well as a homodimeric interaction. A bimolecular fluorescence complementation analysis also showed the interaction between OsTGAP1 and OsbZIP79 in vivo. Intriguingly, whereas OsbZIP79 transactivation activity was observed in a transient reporter assay, the overexpression of OsbZIP79 resulted in suppression of the elicitor-inducible expression of diterpenoid phytoalexin biosynthetic genes, and thus caused a decrease in the accumulation of phytoalexin in rice cells. These results suggest that OsbZIP79 functions as a negative regulator of phytoalexin production triggered by a chitin oligosaccharide elicitor in rice cells, although it remains open under which conditions OsbZIP79 can work with OsTGAP1. PMID- 25462075 TI - Tobacco overexpressing beta-ocimene induces direct and indirect responses against aphids in receiver tomato plants. AB - In the last decade plant-to-plant communication has received an increasing attention, particularly for the role of Volatile Organic Compounds as possible elicitors of plant defense. The role of beta-ocimene as an interspecific elicitor of plant defense has been recently assessed in multitrophic systems including different plant species (Solanaceae, Poaceae, legumes) and different pest species including chewer insects and phytophagous mites. Both chewer insects and phytophagous mites are known to elicit specific plant defensive pathways which are different (at least in part) from those elicited by sap feeders. The aim of this research was to fill this gap of knowledge and to assess the role of beta ocimene as an elicitor of plant defense against aphid pests, which are sap feeders. For this purpose we used as transgenic tobacco plant releasing an odour plume enriched in this compound as emitter and a tomato plant as receiver. We selected the aphid Macrosiphum euphorbiae and its natural enemy, the parasitoid Aphidius ervi, as the targets of plant induced defense. Tomato plant defense induced by beta-ocimene was assessed by characterizing the aphid performance in terms of fixing behaviour, development and reproduction (direct plant defense) and the parasitoid performance in terms of attraction towards tomato plants (indirect plant defense). The characterization of tomato response to beta-ocimene was completed by the identification of Volatile Organic Compounds as released by conditioned tomato plants. Tomato plants that were exposed to the volatiles of transgenic tobacco enriched in beta-ocimene resulted in less suitable for the aphids in respect to control ones (direct defense). On tomato plants "elicited" by beta-ocimene we recorded: a significant lower number of aphids settled; a significant lower number newborn nymphs; a significant lower weight of aphids feeding. In addition, tomato plants "elicited" by beta-ocimene resulted became more attractive towards the parasitoid A. ervi than control ones. These results could be explained at least in part by examining the composition of the Volatile Organic Compounds released by tomato plants "elicited" by beta-ocimene. Indeed, we found a significantly higher release of several compounds including methyl salicylate and cis-3-hexen-1-ol. These two compounds have been demonstrated to impair aphid development and reproduction and to be involved in the attraction of the aphid parasitoid A. ervi. By considering the ubiquity of beta-ocimene and its ability to regulate the communication of plants belonging 30 to different species (if not families), we concluded that this compound is an ideal candidate for new 31 strategies of sustainable control of agricultural pests. PMID- 25462076 TI - Cantharidin, a protein phosphatase inhibitor, strongly upregulates detoxification enzymes in the Arabidopsis proteome. AB - Cantharidin, a potent inhibitor of plant serine/threonine protein phosphatases (PPPs), is highly phytotoxic and dramatically affects the transcriptome in Arabidopsis. To investigate the effect of cantharidin on the Arabidopsis proteome, a combination of two-dimensional difference gel electrophoresis (2-D DIGE) and matrix-assisted laser desorption ionization time-of-flight (MALDI/TOF) mass spectrometry was employed for protein profiling. Multivariate statistical analysis identified 75 significant differential spots corresponding to 59 distinct cantharidin-responsive proteins, which were representative of different biological processes, cellular components, and molecular functions categories. The majority of identified proteins localized in the chloroplast had a significantly decreased presence, especially proteins involved in photosynthesis. Detoxification enzymes, especially glutathione-S-transferases (GSTs), were the most upregulated group (ca. 1.5- to 3.3-fold). Given that the primary role of GSTs is involved in the process of detoxification of both xenobiotic and endobiotic compounds, the induction of GSTs suggests that cantharidin promoted inhibition of PPPs may lead to defense-like responses through regulation of GST enzymes as well as other metabolic pathways. PMID- 25462077 TI - Ocean acidification modulates the response of two Arctic kelps to ultraviolet radiation. AB - The combined effects of ocean acidification and ultraviolet radiation (UVR) have been studied in the kelps Alaria esculenta and Saccharina latissima from Kongsfjorden (Svalbard), two major components of the Arctic macroalgal community, in order to assess their potential to thrive in a changing environment. Overall results revealed synergistic effects, however with a different amplitude in the respective species. Changes in growth, internal N, C:N ratio, pigments, optimum quantum yield (Fv/Fm) and electron transport rates (ETR) following CO2 enrichment and/or UVR were generally more pronounced in S. latissima than in A. esculenta. The highest growth rates were recorded under simultaneous CO2 enrichment and UVR in both species. UVR-mediated changes in pigment content were partially prevented under elevated CO2 in both species. Similarly, UVR led to increased photosynthetic efficiency (alpha) and ETR only if CO2 was not elevated in A. esculenta and even under high CO2 in S. latissima. Increased CO2 did not inhibit external carbonic anhydrase (eCA) activity in the short-term but in the mid-term, indicating a control through acclimation of photosynthesis rather than a direct inhibition of eCA by CO2. The higher benefit of simultaneous CO2 enrichment and UVR for S. latissima respect to A. esculenta seems to involve higher C and N assimilation efficiency, as well as higher ETR, despite a more sensitive Fv/Fm. The differential responses shown by these two species indicate that ongoing ocean acidification and UVR could potentially change the dominance at lower depths (4 6m), which will eventually drive changes at the community level in the Arctic coastal ecosystem. These results support an existing consideration of S. latissima as a winner species in the global change scenario. PMID- 25462078 TI - Epigenetic and hormonal profile during maturation of Quercus Suber L. somatic embryos. AB - Somatic embryogenesis is a powerful alternative to conventional mass propagation of Quercus suber L. However, poor quality and incomplete maturation of somatic embryos restrict any application. Given that epigenetic and hormonal control govern many developmental stages, including maturation of zygotic embryos, global DNA methylation and abscisic acid (ABA) were analyzed during development and maturation of cork oak somatic embryos. Our results indicated that development of somatic embryos concurred with a decrease in 5-mdC. In contrast, endogenous ABA content showed a transient increase with a peak in immature E2 embryos denoting the onset of the maturation phase. A cold stratification phase was necessary for embryos to acquire germination ability, which coincided with a significant decrease in 5-mdC and ABA content. Immunohistochemical analyses showed that there was a specific spatial-temporal regulation during embryogenesis, particularly after the cold treatment. The acquisition of germination capacity concurred with a general low 5-mdC signal in the root meristem, while retention of the 5-mdC signal was mainly located in the shoot meristem and provascular tissues. Conversely, ABA immunolocalization was mainly located in the root and shoot apical meristems. Furthermore, a strong decrease in the ABA signal was observed in the root cap after the stratification treatment suggesting a role for the root cap during development of somatic embryos. These results suggest that, in addition to ABA, epigenetic control appears to play an important role for the correct maturation and subsequent germination of cork oak somatic embryos. PMID- 25462079 TI - Over-expression of TaEXPB23, a wheat expansin gene, improves oxidative stress tolerance in transgenic tobacco plants. AB - Expansins are cell wall proteins inducing cell wall loosening and participate in all plant growth and development processes which are associated with cell wall modifications. Here, TaEXPB23, a wheat expansin gene, was investigated and the tolerance to oxidative stress was strongly enhanced in over-expression tobacco plants. Our results revealed that over-expressing TaEXPB23 influenced the activity of antioxidant enzymes: in particular, the activity of the cell wall bound peroxidase. The enhanced tolerance to oxidative stress and increased cell wall-bound peroxidase activity were partly inhibited by an anti-expansin antibody. The Arabidopsis expansin mutant atexpb2 showed reduced cell wall-bound peroxidase activity and decreased oxidative stress tolerance. In addition, atexpb2 exhibited lower chlorophyll contents and the germination rate compared to wild type (WT). Taken together, these results provided a new insight on the role of expansin proteins in plant stress tolerance by cell wall bound peroxidase. PMID- 25462080 TI - Characterization of expressed sequence tags from Lilium longiflorum in vernalized and non-vernalized bulbs. AB - In Lilium longiflorum, vernalization is both an obligatory requirement and the major factor affecting flowering time, however, little is known about the molecular regulation of this mechanism in Lilium and other flowering bulbs. Exposure of L. longiflorum bulbs to 9 weeks at 4 degrees C greatly promoted stem elongation within the bulb, floral transition and flowering. Subtraction libraries of vernalized (V) and non-vernalized (NV) bulb meristems were constructed. 671 and 479 genes were sequenced, from which 72 and 82 proteins were inferred for the NV-V and the V-NV libraries, respectively. Much lower transcription levels and putative gene functions were recorded in the NV-V libraries compared the V-NV libraries. However, a large number of genes annotated to transposable elements (TEs), represented more than 20% of the sequenced cDNA were expressed in the NV-V libraries, as opposed to less than 2% in the V-NV libraries. The expression profile of several genes potentially involved in the vernalization pathway was assessed. Expression of LlSOC1, the lily homologue of SUPPRESSOR OF OVER-EXPRESSION OF CO1 (SOC1), an important flowering gene in several plant species, found in the V-NV library, was highly up-regulated during bulb meristem cold exposure. The subtraction libraries provided a fast tool for relevant gene isolation. PMID- 25462081 TI - Endogenous factors regulating poor-nutrition stress-induced flowering in pharbitis: The involvement of metabolic pathways regulated by aminooxyacetic acid. AB - The short-day plant pharbitis (also called Japanese morning glory), Ipomoea nil (formerly Pharbitis nil), was induced to flower by poor-nutrition stress. This stress-induced flowering was inhibited by aminooxyacetic acid (AOA), which is a known inhibitor of phenylalanine ammonia-lyase (PAL) and the synthesis of indole 3-acetic acid (IAA) and 1-aminocycropropane-1-carboxylic acid (ACC) and thus regulates endogenous levels of salicylic acid (SA), IAA and polyamine (PA). Stress treatment increased PAL activity in cotyledons, and AOA suppressed this increase. The observed PAL activity and flowering response correlate positively, indicating that AOA functions as a PAL inhibitor. The inhibition of stress induced flowering by AOA was also overcome by IAA. An antiauxin, 4-chlorophenoxy isobutyric acid, inhibited stress-induced flowering. Both SA and IAA promoted flowering induced by stress. PA also promoted flowering, and the effective PA was found to be putrescine (Put). These results suggest that all of the pathways leading to the synthesis of SA, IAA and Put are responsive to the flowering inhibition by AOA and that these endogenous factors may be involved in the regulation of stress-induced flowering. However, as none of them induced flowering under non-stress conditions, they may function cooperatively to promote flowering. PMID- 25462082 TI - Narcissus tazetta SVP-like gene NSVP1 affects flower development in Arabidopsis. AB - SHORT VEGETATIVE PHASE (SVP) related genes have important functions in regulating floral transition and inflorescence structure in many plant species. Some SVP related genes have been shown associated with dormancy transition. Narcissus tazetta var. chinensis exhibits summer dormancy release and floral transition promoted by extended high temperature exposure. However, the molecular mechanism underlying such development remains unknown. In this study, we isolated and characterized one SVP-like gene, NSVP1 from N. tazetta var. chinensis. The results of RT-PCR and in situ hybridization assay showed that NSVP1 was expressed in both vegetative and floral tissues. The highest level of NSVP1 in the bulb apices was detected when the above-ground just senesced and its transcripts declined gradually during endo-dormany. The lowest level was found at the beginning of flower differentiation and the release of endo-dormancy. These data suggest that NSVP1 is differentially regulated coordinately with endo-dormancy induction and release. Ectopic expression of NSVP1 neither complemented the early flowering phenotype of svp mutant nor altered the rosette leaf number in Col background. However, NSVP1 in svp mutant and Ler plants increased the number of lateral inflorescence and caused abnormal floral morphologies. In addition, strong expression of NSVP1 in Ler background affected plastochron. These results suggest that NSVP1 might play a role in the regulation of flower development. PMID- 25462083 TI - Initiation of spontaneous tumors in radish (Raphanus sativus): Cellular, molecular and physiological events. AB - In plant meristems, the balance of cell proliferation and differentiation is maintained by phytohormones, specifically auxin and cytokinin, as well as transcription factors. Changing of the cytokinin/auxin balance in plants may lead to developmental abnormalities, and in particular, to the formation of tumors. The examples of spontaneous tumor formation in plants include tumors formed on the roots of radish (Raphanus sativus) inbred lines. Previously, it was found that the cytokinin/auxin ratio is altered in radish tumors. In this study, a detailed histological analysis of spontaneous radish tumors was performed, revealing a possible mechanism of tumor formation, namely abnormal cambial activity. The analysis of cell proliferation patterns revealed meristematic foci in radish tumors. By using a fusion of an auxin-responsive promoter (DR5) and a reporter gene, the involvement of auxin in developmental processes in tumors was shown. In addition, the expression of the root meristem-specific WUSCHEL-related homeobox 5 (WOX5) gene was observed in cells adjacent to meristematic foci. Taken together, the results of the present study show that tumor tissues share some characteristics with root apical meristems, including the presence of auxin response maxima in meristematic foci with adjacent cells expressing WOX5. PMID- 25462084 TI - Concentration of hinokinin, phenolic acids and flavonols in leaves and stems of Hydrocotyle leucocephala is differently influenced by PAR and ecologically relevant UV-B level. AB - We examined the effects of ambient, non-stressing ultraviolet (UV)-B (280-315nm) level combined with different intensities of photosynthetic active radiation (PAR, 400-700nm) on the accumulation of the lignan (-)-hinokinin, in leaves and stems of Hydrocotyle leucocephala. Plants were exposed in sun simulators under almost natural irradiance and climatic conditions to one of four light regimes, i.e. two PAR intensities (906 and 516MUmolm(-2)s(-1)) including or excluding UV-B radiation (0 and 0.4Wm(-2)). Besides hinokinin, we identified three chlorogenic acid isomers, one other phenolic acid, 12 quercetin, and five kaempferol derivatives in the H. leucocephala extracts. Hinokinin was most abundant in the stems, and its accumulation was slightly enhanced under UV-B exposure. We therefore assume that hinokinin contributes to cell wall stabilization and consequently to a higher resistance of the plant to environmental factors. Quercetin derivatives increasingly accumulated under UV-B and high PAR exposure at the expense of kaempferols and chlorogenic acids, which was apparently related to its ability to scavenge reactive oxygen species. In general, the concentration of the constituents depended on the plant organ, the leaf age, the light regimes, and the duration of exposure. The distribution pattern of the compounds within the examined organs was not influenced by the treatments. Based on the chemical composition of the extracts a principal component analysis (PCA) enabled a clear separation of the plant organs and harvesting dates. Younger leaves mostly contained higher phenylpropanoid concentrations than older leaves. Nevertheless, more pronounced effects of the light regimes were detected in older leaves. As assessed, in many cases the individual compounds responded differently to the PAR/UV-B combinations, even within the same phenylpropanoid class. Since this is the first report on the influence of light conditions on the accumulation of lignans in herbaceous plants, it opens many perspectives for a more precise elucidation of all involved biochemical and molecular processes. PMID- 25462085 TI - Pollination increases ethylene production in Lilium hybrida cv. Brindisi flowers but does not affect the time to tepal senescence or tepal abscission. AB - In many species, pollination induces a rapid increase in ethylene production, which induces early petal senescence, petal abscission, or flower closure. Cross pollination in Lilium hybrida cv. Brindisi resulted in a small increase in flower ethylene production. In intact plants and in isolated flowers, pollination had no effect on the time to tepal senescence or tepal abscission. When applied to closed buds of unpollinated flowers, exogenous ethylene slightly hastened the time to tepal senescence and abscission. However, exogenous ethylene had no effect when the flowers had just opened, i.e. at the time of pollination. Experiments with silver thiosulphate, which blocks the ethylene receptor, indicated that endogenous ethylene had a slight effect on the regulation of tepal senescence and tepal abscission, although only at the time the tepals were still inside buds and not in open flowers. Low ethylene-sensitivity after anthesis therefore explains why pollination had no effect on the processes studied. PMID- 25462086 TI - High nitrate supply reduces growth in maize, from cell to whole plant. AB - Nitrogen (N) is an essential macronutrient that limits agricultural productivity, and both low and high N supply have been suggested to alter plant growth. The overall aim of this work is to study the impact of nitrate (NO3(-)) in maize yield and the possible causes that induce this alteration. High NO3(-) doses did not increase the yield of maize grown neither in the field nor under controlled conditions. In fact, plants grown under controlled conditions for 45 days with NO3(-) concentrations over 5mM showed a decrease in biomass production. This reduction was perceptible in shoots prior to roots, where phytomer expansion was reduced. Cell size and number were also reduced in the leaves of plants with high NO3(-). This alteration was correlated with the increase of 1-aminocyclopropane-1 carboxylic acid in leaves, which was probably translocated from the roots in order to synthesize ethylene. Cytokinins (CKs) also showed a relevant role in this inhibitory effect, increasing in high NO3(-) plants with a reduction in root and shoot growth, inhibition of apical dominance and a strong decrease of leaf expansion, symptoms described previously as "CK syndrome". We propose that high NO3(-) inhibits maize growth by causing hormonal alterations that modify plant growth from cell to whole plant. PMID- 25462087 TI - Adult onset Brown-Vialetto-Van Laere syndrome with opsoclonus and a novel heterozygous mutation: a case report. PMID- 25462088 TI - Clinical outcomes after neurogenic stress induced cardiomyopathy in aneurysmal sub-arachnoid hemorrhage: a prospective cohort study. AB - INTRODUCTION: Neurogenic stress cardiomyopathy (NCM) has been associated with poor outcomes in the setting of aneurysmal subarachnoid hemorrhage (aSAH). Much less is known regarding recovery of cardiac function. The aim of this prospective cohort study was to study the rate of early cardiac recovery after NCM and the potential effect of NCM on short term functional recovery. A secondary aim sought to determine whether certain biomarkers may be associated with the development of NCM. METHODS: Patients with confirmed aSAH between November 2012 and October 2013 were prospectively enrolled and received echocardiograms within 48 h of admission. Ejection fraction (%) and regional wall motion abnormality score index (RWMI) were noted. All patients with confirmed aSAH had a troponin and BNP level drawn on admission. Patients with confirmed NCM received a follow up echocardiogram 7-21 days after the initial echocardiogram. Clinical follow up at 3 months evaluated mortality, mRS and mBI scores. RESULTS: 63 patients with confirmed aSAH were enrolled. In this cohort 11 (17%) patients were confirmed to have NCM. The NCM group had higher in-hospital mortality [n = 4(36.4%)] compared to the non-NCM group [n = 5(9.6%)] (p = .021). At 3 months the development of NCM was associated with an unfavorable mRS (p = 0.042) and mBI (p = 0.005). Both an elevated BNP (> 100 pg/mL) and elevated troponin (>0.3 mg/dL) were associated with the development of NCM. Follow-up echocardiograms were performed within 21 days of admission on 8 patients with NCM. An abnormal RWMI of 1.5 or higher was present in 5(71%) patients. CONCLUSION: NCM is a frequent complication associated with aSAH. The onset of the disease occurs early in the course of aSAH and an elevated BNP and troponin may be associated with the onset of NCM. Cardiac function often remains impaired during the acute recovery phase potentially impeding resuscitation during this period. The routine use of short term follow up echocardiography may be recommended. PMID- 25462089 TI - A review of the combined medical and surgical management in patients with herpes simplex encephalitis. AB - BACKGROUND: Herpes simplex encephalitis (HSE) is a devastating and severe viral infection of the human central nervous system. This viral encephalitis is well known to cause severe cerebral edema and hemorrhagic necrosis with resultant increases in intracranial pressure (ICP). While medical management has been standardized in the treatment of this disease, the role of aggressive combined medical and surgical management including decompressive craniectomy and/or temporal lobectomy has not been fully evaluated. In addition, while barbiturate coma has been studied for treatment of status epilepticus associated with infectious encephalitis, its use for treatment of encephalitis associated intractable intracranial hypertension has not been fully reported. CASE DESCRIPTION: We report the case of a 22 year old female with severe herpetic encephalitis requiring aggressive ICP management utilizing all modalities (both medical and surgical) known to control ICP. She continues to have memory deficits but has made a good recovery with a Glasgow Outcome Scale score of 5. CONCLUSION: We provide evidence that aggressive combined medical and surgical therapy is warranted even in cases of severe HSE with transtentorial herniation, as there is evidence for the potential of good recovery. A detailed literature review of the medical and surgical management strategies in this disease is presented. PMID- 25462090 TI - Subarachnoid hemorrhage in systemic lupus erythematosus: systematic review and report of three cases. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disorder of multifactorial etiology with a broad range of clinical manifestations. Cerebral disorders such as psychosis, seizures and cerebrovascular accidents are commonly described in SLE patients. Subarachnoid hemorrhage (SAH) presents a higher incidence than in the general population. Saccular aneurysms are the most frequent cause, but uncommon forms of SAH had been repeatedly reported in SLE patients. Through three case examples we outline these uncommon patterns, which we hypothesized, might be responsible for the higher incidence of SAH in SLE patients. METHODS: We present three patients previously diagnosed with SLE, who suffered a SAH and we perform a systematic literature review. RESULTS: All three cases presented with a Fisher grade IV bleeding. One harbored a distal middle cerebral artery aneurysm, another had multiple aneurysms, and the youngest patient had no findings on the cerebral angiography. A focal vasculitic process seemed most likely responsible for the two aneurismal cases. The angiography negative case was attributed to severe SLE systemic complications and had an unexpected bad outcome. Literature review yielded 39 previously reported cases. CONCLUSIONS: The uncommon SAH patterns make etiological diagnosis challenging. Management can also be daunting due to both local and systemic consequences of SLE. Awareness of these uncommon patterns, management challenges, and higher likelihood of bad outcomes may help physicians dealing with this disease. Further research to unveil the mechanisms behind it is granted to fully understand SAH in SLE patients. PMID- 25462091 TI - A retrospective controlled study of three different operative approaches for the treatment of thoracic and lumbar spinal tuberculosis: three years of follow-up. AB - OBJECTIVE: The purpose of this study was to determine the optimal operative approach for the treatment of spinal tuberculosis. We analyzed two types of pathological vertebrae (thoracic and lumbar) and three cardinal operative approaches for surgery. METHODS: Sixty patients with spinal tuberculosis were divided into thoracic (n=30) and lumbar groups (n=30) based on locations of the foci. These patients underwent anti-tuberculosis drug and surgical therapy. The operative approaches for the surgical treatments were the anterior approach (AA, n=20), posterior approach (PA, n=20), and combined anterior and posterior approach (CAPA, n=20). All clinical data from the patients was collected and included surgical time, blood loss, correction of kyphosis, and vertebral body height reconstruction. Differences in the means between the groups were evaluated statistically with one-way analyses of variance (ANOVAs). RESULTS: The surgery time in the CAPA group was longer than that of AA group (P<0.05), and there were no significant differences between the CAPA and PA groups or the AA and PA groups. The average vertebral body height reconstruction in the AA group was larger than that of the PA or CAPA groups, and there was no significant difference between the PA and CAPA groups (P>0.05). There were no interactions between the location of the pathological vertebra and the type of surgical approach, with the exception of blood loss. The blood loss of the CAPA was greater than those of the AA and PA patients in the thoracic group (P<0.05), and no significant difference was found in the lumbar group (P>0.05). CONCLUSIONS: AA was well-suited for serious vertebral collapse that required reconstruction of the height of the vertebrae. CAPA was unfit for patients with poor basic conditions due to the long surgical time, but the long surgery time of CAPA did not necessarily lead to greater blood loss compared to the other approaches. PMID- 25462092 TI - Management of neoplastic spinal tumors in a spine surgery care unit. AB - BACKGROUND CONTEXT: Spinal cord compression and fracture are possible complications of spine metastasis and multiple myeloma. Prompt diagnosis and treatment of threatening lesions are likely to reduce the frequency of these dreaded complications. PURPOSE: To evaluate the proportion of neoplastic spine lesions operated on emergency. STUDY DESIGN: Retrospective study. PATIENT SAMPLE: All patients who underwent palliative surgery for the treatment of a neoplastic spine lesion in our institution between 2005 and 2012. OUTCOME MEASURES: Percentage of patients who underwent surgery as an emergency for acute fracture or rapid neurological decline. METHODS: We retrospectively reviewed the data of all patients who underwent palliative surgery for the treatment of a neoplastic spine lesion from solid cancer or multiple myeloma, in our institution between January 2005 and December 2012. The study was supported by grant from our institution. RESULTS: A total of 317 patients were included in the study. There were 166 men and 151 women and the mean age was 57.97 years (range 26-88; SD 12.45). The cancer was known for 224 patients, while the lesion revealed the disease for the other 93 patients. The percentage of patients with known cancer operated as an emergency in our institution decreased significantly between 2005 and 2012 (p = 0.0006). CONCLUSION: Due to the variability of clinical and radiological presentations, best care requires a truly multidisciplinary approach, to offer each patient a prompt and individualized treatment option, which is likely to reduce the incidence of emergency surgeries. PMID- 25462093 TI - Highly variable intrafamilial manifestations of a CCM3 mutation ranging from acute childhood cerebral haemorrhage to late-onset meningiomas. PMID- 25462094 TI - Two novel mutations of the SETX gene and ataxia with oculomotor apraxia type 2. PMID- 25462095 TI - Integrated functional neuronavigation-guided resection of small meningiomas of the atrium via the paramedian parieto-occipital approach. AB - OBJECTIVE: Small meningiomas located in the atrium of the lateral ventricle remain a challenge for neurosurgeons due to the eloquent nature of the surrounding anatomy. Functional MRI (fMRI) and diffusion tensor tractography (DTT) allow for in vivo demonstrations of eloquent cortical structures and neuronal fiber tracts, respectively. Our objective is to evaluate the contribution of functional neuronavigation combined with fMRI and DTT results to surgical outcomes. MATERIALS AND METHODS: we investigated 11 patients with small meningiomas located in the atrium of the lateral ventricle who underwent surgery with the aid of functional neuronavigation via the paramedian parieto-occipital approach. The patients willingly underwent assessments of neurologic deficits preoperatively and postoperatively at discharge and at three months after surgery. RESULTS: Gross total resection was achieved in all patients, and no residual or recurrent tumors were observed on follow-up imaging. There was no mortality. Only one patient suffered from transient postoperative aphasia (mild to moderate) that was resolved one week after surgery. No novel neurologic deficits were present in any of the other patients, and no new-onset epileptic attacks were observed. CONCLUSIONS: With the aid of the neuronavigation that incorporates fMRI and DTT results, small meningiomas located in the atrium of the lateral ventricle can be safely resected through the paramedian parieto-occipital approach. PMID- 25462096 TI - Multiple simultaneous intracranial hemorrhages due to hornet stings. PMID- 25462097 TI - Using DynaCT rotational angiography for angioarchitecture evaluation and complication detection in spinal vascular diseases. AB - OBJECTIVE: Preoperative comprehension of the complex angioarchitecture and intraoperative complication detection are essential in endovascular treatment and surgical planning for spinal vascular diseases. We aimed to illustrate the application of DynaCT rotational angiography for the treatment of such diseases. METHODS: We retrospectively analyzed the medical records of 23 patients with spinal vascular disease who underwent DynaCT and three-dimensional (3D) rotational angiography between January 2012 and December 2013. Diseases included spinal arteriovenous malformation, spinal dural arteriovenous fistula, and hypervascular neoplasm. Radiological post-processing images and procedural complications were reviewed to compare the advantage of rotational angiography and digital subtraction angiography (DSA). RESULTS: Rotational angiography more clearly revealed the complex angioarchitecture in cases of spinal vascular diseases based on coronal, sagittal, and transverse views compared with DSA. Subarachnoid hemorrhage was confirmed with DynaCT in one patient with spinal arteriovenous malformation, which was not shown on DSA. Both two-dimensional and 3D angiograms effectively identified the fistulous points in five cases of spinal dural arteriovenous fistula while rotational angiography vividly demonstrated the relationship of the fistulous point with the osseous structures in dual-volume mode. Tumor feeders were clearly delineated in 3D reconstructed images and easily cauterized in patients with hemangioblastoma. CONCLUSIONS: Rotational angiography clarified the relationship between the vasculature and surrounding osseous structures for surgical or endovascular therapy of spinal vascular diseases. DynaCT can detect intraoperative subarachnoid hemorrhage in a timely manner during endovascular treatment of spinal vascular diseases. PMID- 25462098 TI - Treatment results and outcome in elderly patients with glioblastoma multiforme--a retrospective single institution analysis. AB - OBJECTIVE: Although glioblastoma multiforme is more common in patients older than 65 years, the elderly population is often excluded from clinical studies. Decision making in this subgroup can be challenging due to the lack of evidence for different neurosurgical and adjuvant treatment strategies. METHODS: In this retrospective study, we evaluated clinical, treatment and survival data of 124 consecutive patients over 65 years of age with supratentorial glioblastoma multiforme. RESULTS: Median OS was 6.0 months (std. error 0.783, 95% CI 4.456 7.535). Mean OS was 9.7 months (std. error 0.830, 95% CI 8.073-11.327). In univariate regression analysis, low KPS was of negative prognostic value (p < 0.006 for KPS <= 80), while greater advanced age did not have any impact on survival (p = 0.591 for differences between groups). Gross total resection and subtotal resection led to significantly improved overall survival (median 15.0 and 11.0 months; p < 0.02) compared to partial resection or biopsy (both 4.0 months), but complications were more common in subtotal and partial resections. The last observation did not reach statistical significance (p = 0.06). Combinations of irradiation and Temozolomide chemotherapy proved to be more effective than other adjuvant therapies. Extent of resection (gross total resection vs. all others) and form of adjuvant treatment were the only factors of independent prognostic value in multivariate analysis (p = 0.031 and p < 0.001, respectively). CONCLUSIONS: It appears that more aggressive treatment regimens can lead to longer overall survival in elderly glioblastoma multiforme patients. Gross total resection should be offered whenever safely possible; otherwise, biopsy may be preferred. Non-surgical treatment should consist of postoperative radiotherapy and concomitant and/or adjuvant chemotherapy. Possibly higher rates of hematological side effects in concomitant chemotherapy need to be further investigated. PMID- 25462099 TI - Multifocal inflammatory pseudotumor of the trigeminal nerve and the lung. PMID- 25462100 TI - Management strategy of surgical and endovascular treatment of unruptured paraclinoid aneurysms based on the location of aneurysms. AB - OBJECTIVE: Advances in endovascular treatment (EVT) have greatly improved the treatment outcomes of paraclinoid aneurysms. However, EVT had the shortcoming of durability and thromboembolic complications. As well, surgical treatment of paraclinoid aneurysms is still challenging due to the complexity of adjacent structures. The objective of this study is to report our experience with a combined surgical and endovascular treatment of unruptured paraclinoid aneurysms based on the location of aneurysms. METHODS: A retrospective review was conducted of 185 cases of unruptured paraclinoid aneurysms that underwent surgical or endovascular treatment between September 2008 and August 2012. Thirty-one aneurysms (16.8%) were treated by microsurgery and 154 (83.2%) were treated by EVT. Fifty aneurysms (27.0%) were classified to the dorsal group and 135 (73%) were classified to the non-dorsal group. RESULTS: Twenty of 50 dorsal group aneurysms (40%) were treated by microsurgery while 124 of 135 non-dorsal group aneurysms (91.9%) underwent an EVT. The rate of complete occlusion was 96.8% in surgical series and 60.4% in EVT (P < 0.001). Recanalization occurred in 9 aneurysms (5.8%) of EVT and 1 aneurysm (3.2%) of surgical series (P = 0.360). In non-dorsal group, transient complications (10 aneurysms (5.4%), P = 0.018) and morbidity at last visiting (6 aneurysms (3.2%), P = 0.021) were more present in surgically treated cases rather than in EVT cases. Diplopia and visual field defect occurred in the non-dorsal group only; in 2 of 11 surgical cases (18.2%) and in 1 of 124 EVT series (0.8%) (P = 0.017). The overall rate of excellent or good clinical outcomes (Glasgow outcome scale 5 or 4) was 98.9%. CONCLUSION: EVT is a safe and effective treatment for the non-dorsal group. Based on angiographic and clinical aspects, microsurgical clipping has prior efficacy with better outcomes in the dorsal group under proper individualized selection. PMID- 25462101 TI - Management of ruptured posterior fossa arteriovenous malformations. AB - OBJECTIVE: Posterior fossa arteriovenous malformations (pAVMs) are rare and because of their location at or close to vital structures, their treatment remains challenging despite overall improvements in the management of cerebrovascular lesions. We reviewed our recent series of ruptured pfAVMs in search of guiding principles in the management of these complex lesions. METHODS: This is a retrospective series of consecutive patients admitted for a ruptured pfAVM from 2002 to 2013. We analyzed clinical and radiological data, as well as initial and definitive management. Outcome was assessed using the modified Rankin Scale (mRS) at 6 months. RESULTS: The study included 34 patients (19 women and 15 men). Upon admission, 79% of patients presented with an intra-cerebellar hematoma, 42% of which required urgent drainage. Hydrocephaly was also present in 82% of patients, 56% of which required emergency ventriculostomy. There was an aneurysm associated with the AVM in 47% of cases. In 38% of the cases, the aneurysm was the source of the hemorrhage. Only 68% of patients were amenable to undergo treatment of the AVM: 24% exclusively by surgery, 9% by embolization, 3% by radiosurgery, and 32% using combined means. Five patients died within the first week: one as a direct result of the severity of the hemorrhage, and the other four due to re-bleeding before treatment. Outcome was favorable (mRS 0-2) in 71% of patients. CONCLUSION: Patients with a ruptured pfAVM are often comatose upon admission, requiring emergency live-saving surgical treatment. An associated aneurysm is often the source of bleeding which if dealt with immediately, offers time to plan the most appropriate strategies to eliminate the AVM. Nevertheless, early re-bleeding is frequent, and a cause of concern as it often leads to death. Despite the gravity of the clinical condition upon admission, outcome is favorable for those amenable to treatment. PMID- 25462102 TI - Tropical pyomyositis of erector spinae complicated with spinal epidural abscess. AB - STUDY DESIGN: This is a retrospective case series. OBJECTIVE: Tropical pyomyositis of erector spinae muscle (ESPM) is a rare muscular infection which may extend into the intraspinal canal to become spinal epidural abscess (ESPM SEA). If left untreated, it may cause catatrophic spinal cord dysfunction and lead to irreversible paralysis. A series of eight such cases is presented, in order to provide proper surgical options and clarify the prognostic factors of the disease. SUMMARY OF BACKGROUND DATA: Merely six sporadic case reports had been found in the literature. Surgical debridement and laminectomy to drain the intraspinal abscess combined with systemic antibiotics were the choice of treatment to treat the disease with good therapeutic effect. METHODS: Inpatient charts of the patients were reviewed. The therapeutic effect and functional neurological recovery are correlated with the demographic characteristics of the patients, neurological deficits before drainage, and the different procedures of drainage. RESULTS: Old age, long ESPM-SEA (>6.5 vertebral segments), spinal cord dysfunction as well as complete paralysis before the interventional procedures are significantly correlated with poor functional neurological recovery (Sperman's coefficient correlation, all p<0.05). Pig-tail drainage of ESPM combined with adequate systemic antibiotics could cure if infection presents with lumbar radiculopathy only, but it failed to rescue the spinal cord dysfunction in two patients present with complete paralysis. Surgical drainage of ESPM with mini laminotomy to drain ESPM-SEA combined with systemic antibiotics provided good functional recovery of patients, despite of prolonged pre-operative complete paralysis. CONCLUSION: Early drainage of the ESPM and related epidural abscess combined with systemic antibiotics can provide excellent therapeutic effect of ESPM-SEA. Open drainage with mini-laminotomy is superior to pig-tail drainage when spinal cord dysfunction occurred associated with ESPM-SEA. PMID- 25462103 TI - Perineural spread of squamous cell carcinoma: from skin to skin through the brachial plexus. PMID- 25462104 TI - One-step molecular detection of the MYD88 L265P mutation by unlabeled probe genotyping analysis. AB - The aim of our study was to establish an unlabeled probe genotyping approach for rapid detection of the MYD88 L265P mutation in the differential diagnosis of Waldenstrom macroglobulinemia patients. Analytical and clinical validation of the assay was performed using serially diluted amplicon-cloned standards, 14 clinical bone marrow aspirate samples, and 30 peripheral blood samples from healthy donors, respectively. The analytical validation results showed that the assay is able to reproducibly identify as low as 10% of the L265P mutant. Clinical validation results showed improved detection sensitivity for the L265P mutation compared to Sanger sequencing. With the simplicity, cost-effectiveness, specificity and rapidity, we foresee that the unlabeled probe HRM assay is a good alternative to substitute current established methods for routine diagnostic testing of the MYD88 L265P mutation. PMID- 25462105 TI - Alkaline cation-exchange chromatography for the reduction of aggregate and a mis formed disulfide variant in a bispecific antibody purification process. AB - During the purification development of a bispecific antibody, cation-exchange chromatography was screened for its ability to separate a prominently expressed (>12%) mis-formed disulfide bond variant, termed MAb-diabody, and aggregate from the product of interest. The influence of pH, product load (g of product per liter of resin) and linear velocity on the separations were evaluated for the strong cation-exchange resins SP Sepharose HP and POROS((r)) HS50. Cation exchange chromatography is commonly operated distant to the isoelectric point of a molecule, generally leading to acidic conditions for antibody purification. However, the results herein demonstrated improved removal of MAb-diabody with increasing pH, resulting in reduction of MAb-diabody content greater than 12-fold when operating near the alkaline pI of the product. This approach was successful over a range of linear velocities and g/L of resin loading. Aggregate removal was less affected by pH and was effectively reduced from 10.9% to less than 3% for each condition. Furthermore, this method was successfully scaled to a 60 cm diameter column using SP Sepharose HP resin. PMID- 25462106 TI - Rapid and sensitive analysis of nine fungicide residues in chrysanthemum by matrix extraction-vortex-assisted dispersive liquid-liquid microextraction. AB - A simple sample pretreatment for simultaneous determination of nine fungicides (triadimefon, picoxystrobin, kresoxim-methyl, diniconazole, epoxiconazole, trifloxystrobin, triticonazole, difenoconazole, and azoxystrobin) in chrysanthemum was developed using matrix extraction-vortex-assisted dispersive liquid-liquid microextraction (ME-VADLLME) prior to gas chromatography with electron capture detection. The target fungicides were firstly extracted with acetonitrile and cleaned with the mixture of primary secondary amine and graphite carbon black. The VADLLME procedure was performed by using toluene with lower density than water as the extraction solvent and the acetonitrile extract as the dispersive solvent, respectively. After vortexing and centrifugation, the fine droplet of toluene was collected on the upper of the mixed toluene/acetonitrile/water system using a 0.1-mL pipettor. Under the optimum conditions, the relative recoveries ranged from 73.9 to 95.1% with relative standard deviations of 3.5-9.7% for all of the analytes. The limits of detection were in the range of (0.005-0.05)*10(-3) mg kg(-1). In the proposed method, the ME step provides more effective cleanup for the chrysanthemum matrix, and VADLLME introduces higher sensitivity with the remarkable enrichment factors up to 88 fold compared with the conventional QuEChERS or SPE. The good performance has demonstrated that ME-VADLLME has a strong potential for application in the multi residue analysis of complex matrices. PMID- 25462107 TI - Development and validation of a liquid chromatographic method to quantify sucrose, glucose, and fructose in tubers of Solanum tuberosum Group Phureja. AB - A High Performance Liquid Chromatography (HPLC) method was developed and validated to quantify sucrose (non-reducing sugar), glucose, and fructose (reducing sugars) in raw tubers of Solanum tuberosum Group Phureja. Chromatographic analysis was performed using an AMINEX HPX 87H column, at 18 degrees C, linked to a refraction index detector, at 35 degrees C. The eluent was 10mM sulfuric acid. The conditions established for the method provided an optimum separation of sugars, citric acid, and malic acid, with resolution values higher or equal to one. Among the four sugar extraction methods tested, the double 50% (v/v) aqueous methanol extraction gave the highest level of analytes. Recovery of this extraction method ranged between 94.14 and 99.77%. The HPLC method was validated for repeatability, reproducibility, linearity, and limits of detection, and quantification. Relative standard deviation was found to be lower than five, when testing repeatability and reproducibility, which is suitable considering a range of acceptability from 5.3 to 7.3. Additionally, the regression analyses supported the method linearity in a range of quantification from 3 to 100 mg/L with regression coefficients values greater than 0.998 for the three analytes. Limits of detection were 3.0 mg/L for the three sugars and limits of quantification were 2.0 mg/L for sucrose and 3.0 mg/L for glucose and fructose. Four Colombian commercial cultivars (Criolla Guanena, Criolla Paisa, Criolla Galeras, and Criolla Colombia) and five landrace accessions from the Colombian Core Collection of Group Phureja were grown in the district of Usme (Bogota) fields to analyze their sugar contents. Sucrose, glucose, and fructose contents were found ranging from 0.93 to 3.11 g/100 g tuber dried weight (DW), from 0.25 to 4.53 g/100 g tuber DW, and from 0.10 to 1.49 g/100 g tuber DW, respectively. Therefore, a high range in the variability of sugar contents was found among genotypes. However, the variability was low among technical replicates of the same genotype, revealing an accurate quantification of sugars in Group Phureja. This method can be used to assess the amount of reducing and non-reducing sugars accumulation in potato germplasm. PMID- 25462108 TI - Determination of low levels of benzodiazepines and their metabolites in urine by hollow-fiber liquid-phase microextraction (LPME) and gas chromatography-mass spectrometry (GC-MS). AB - In this study, it is shown a method for the determination of benzodiazepines and their main metabolites in urine samples by hollow-fiber liquid-phase microextraction (LPME) in the three-phase mode. Initially, the hydrolysis step was performed using 100 MUL of sodium acetate 2.0 mol/L buffer solution (pH 4.5), 25 MUL of beta-glucuronidase enzyme and incubation for 90 min at 55 degrees C. In parallel with hydrolysis, the LPME fiber (9 cm) was prepared. Its pores were filled with a mixture of dihexyl ether: 1-nonanol (9:1). Afterwards, a solution of 3.0 mol/L of HCl was introduced into the lumen of the fiber (acceptor phase). After hydrolysis, the fiber was submersed in the alkalinized urine (pH 10) containing 10% NaCl. Samples were then submitted to orbital shaking (2400 rpm) for 90 min. The acceptor phase was later withdrawn from the fiber, dried and the residue derivatized with trifluoroacetic anhydride (TFAA) for 10 min at 60 degrees C with further addition of N-methyl-N-tert butyldimethylsilyltrifluoroacetamide containing 1% tert-butyldimethylchlorosilane (MTBSTFA) for 45 min at 90 degrees C followed by determination by gas chromatography-mass spectrometry (GC-MS). The calibration curves obtained showed linearity over the specified range, with a similar sensitivity to traditional techniques and a higher detection capability compared to most of the miniaturized methods described in the literature. The method has been developed and successfully validated and applied to urine samples from real cases of benzodiazepines intake. PMID- 25462109 TI - Implicit theories and youth mental health problems: a random-effects meta analysis. AB - Compared to youths who believe that personal traits are malleable, those who believe that personal traits are fixed experience more academic and self regulatory distress. Recently, studies have begun to explore relations between beliefs about the malleability of personal traits, or implicit theories, and youth mental health problems. We synthesized this emerging body of research in youths (ages 4-19) across 45 effect sizes from 17 research reports. Studies were included if they assessed youth mental health and implicit theories and did not manipulate implicit theory or affective/behavioral states prior to measuring these variables. Our random-effects meta-analysis using clustered data analysis techniques (i.e., effect sizes nested within samples) revealed that youths holding entity theories-the belief that personal traits are fixed-showed more pronounced mental health problems. This association between entity theories and mental health problems was evident across methodological factors and problem types (internalizing versus externalizing; psychopathology versus general distress). Limitations include the small number of eligible studies, insufficient data to test further demographic moderators, and few longitudinal studies on this topic. Overall, findings support the value of parsing the implicit theory-mental health link in youths. Implicit theories may prove to be promising targets for treatment and prevention of youth mental health problems. PMID- 25462110 TI - Content specificity of attention bias to threat in anxiety disorders: a meta analysis. AB - Despite the established evidence for threat-related attention bias in anxiety, the mechanisms underlying this bias remain unclear. One important unresolved question is whether disorder-congruent threats capture attention to a greater extent than do more general or disorder-incongruent threat stimuli. Evidence for attention bias specificity in anxiety would implicate involvement of previous learning and memory processes in threat-related attention bias, whereas lack of content specificity would point to perturbations in more generic attention processes. Enhanced clarity of mechanism could have clinical implications for the stimuli types used in Attention Bias Modification Treatments (ABMT). Content specificity of threat-related attention bias in anxiety and potential moderators of this effect were investigated. A systematic search identified 37 samples from 29 articles (N=866). Relevant data were extracted based on specific coding rules, and Cohen's d effect size was used to estimate bias specificity effects. The results indicate greater attention bias toward disorder-congruent relative to disorder-incongruent threat stimuli (d=0.28, p<0.0001). This effect was not moderated by age, type of anxiety disorder, visual attention tasks, or type of disorder-incongruent stimuli. No evidence of publication bias was observed. Implications for threat bias in anxiety and ABMT are discussed. PMID- 25462111 TI - Psychological therapy for anxiety in bipolar spectrum disorders: a systematic review. AB - Comorbid anxiety is common in bipolar spectrum disorders [BPSD], and is associated with poor outcomes. Its clinical relevance is highlighted by the "anxious distress specifier" in the revised criteria for Bipolar Disorders in the Diagnostic and Statistical Manual 5th Edition [DSM-5]. This article reviews evidence for the effectiveness of psychological therapy for anxiety in adults with BPSD (bipolar I, II, not otherwise specified, cyclothymia, and rapid cycling disorders). A systematic search yielded 22 treatment studies that included an anxiety-related outcome measure. Cognitive behavioural therapy [CBT] for BPSD incorporating an anxiety component reduces anxiety symptoms in cyclothymia, "refractory" and rapid cycling BPSD, whereas standard bipolar treatments have only a modest effect on anxiety. Preliminary evidence is promising for CBT for post-traumatic stress disorder and generalised anxiety disorder in BPSD. Psychoeducation alone does not appear to reduce anxiety, and data for mindfulness based cognitive therapy [MBCT] appear equivocal. CBT during euthymic phases has the greatest weight of evidence. Where reported, psychological therapy appears acceptable and safe, but more systematic collection and reporting of safety and acceptability information is needed. Development of psychological models and treatment protocols for anxiety in BPSD may help improve outcomes. PMID- 25462112 TI - Integrating socially assistive robotics into mental healthcare interventions: applications and recommendations for expanded use. AB - As a field, mental healthcare is faced with major challenges as it attempts to close the huge gap between those who need services and those who receive services. In recent decades, technological advances have provided exciting new resources in this battle. Socially assistive robotics (SAR) is a particularly promising area that has expanded into several exciting mental healthcare applications. Indeed, a growing literature highlights the variety of clinically relevant functions that these robots can serve, from companion to therapeutic play partner. This paper reviews the ways that SAR have already been used in mental health service and research and discusses ways that these applications can be expanded. We also outline the challenges and limitations associated with further integrating SAR into mental healthcare. SAR is not proposed as a replacement for specially trained and knowledgeable professionals nor is it seen as a panacea for all mental healthcare needs. Instead, robots can serve as clinical tools and assistants in a wide range of settings. Given the dramatic growth in this area, now is a critical moment for individuals in the mental healthcare community to become engaged in this research and steer it toward our field's most pressing clinical needs. PMID- 25462114 TI - Determination of efonidipine in human plasma by LC-MS/MS for pharmacokinetic applications. AB - Efonidipine hydrochloride is a new generation dihydropyridine calcium channel blocker designed to inhibit both T-type and L-type calcium channels. For the first time, a simple and robust LC-MS/MS method was developed for the determination of efonidipine in human plasma over the range of 0.100-20.0ng/mL. Efonidipine was extracted from plasma by an LLE procedure, separated by LC and detected by MS/MS in positive mode ESI. The method was validated for selectivity, carryover, sensitivity, extraction recovery, matrix effects, linearity, accuracy and precision, dilution integrity and stability studies. The calibration curves were linear over 0.100-20.0ng/mL (r>=0.9980). The lower limit of quantification (LLOQ) was established at 0.100ng/mL. Intra- and inter-day precisions (LLOQ, low QC, mid-QC, high-QC and ultra-high QC) were less than 12.5% in terms of relative standard deviation (RSD), and accuracies were between -5.0% and 5.0% in terms of relative error (RE). Matrix effect was acceptable (105.6-110.2%) and extraction recovery was reproducible (85.8-91.3%, RSD<=10.0%). Efonidipine was stable in the investigated conditions. The method was applied to the pharmacokinetics of efonidipine in human subject. PMID- 25462113 TI - Lung parenchymal development in premature infants without bronchopulmonary dysplasia. AB - RATIONALE: While infants who are born extremely premature and develop bronchopulmonary dysplasia (BPD) have impaired alveolar development and decreased pulmonary diffusion (DLCO), it remains unclear whether infants born less premature and do not develop BPD, healthy premature (HP), have impaired parenchymal development. In addition, there is increasing evidence that pro angiogenic cells are important for vascular development; however, there is little information on the relationship of pro-angiogenic cells to lung growth and development in infants. OBJECTIVE: and Methods Determine among healthy premature (HP) and fullterm (FT) infants, whether DLCO and alveolar volume (VA) are related to gestational age at birth (GA), respiratory support during the neonatal period (mechanical ventilation [MV], supplemental oxygen [O2], continuous positive airway pressure [CPAP]), and pro-angiogenic circulating hematopoietic stem/progenitor cells (CHSPCs). We measured DLCO, VA, and CHSPCs in infants between 3-33 months corrected-ages; HP (mean GA = 31.7 wks; N = 48,) and FT (mean GA = 39.3 wks; N =88). RESULT: DLCO was significantly higher in HP than FT subjects, while there was no difference in VA , after adjusting for body length, gender, and race. DLCO and VA were not associated with GA, MV and O2; however, higher values were associated with higher CHSPCs, as well as treatment with CPAP. CONCLUSION: Our findings suggest that in the absence of extreme premature birth, as well as BPD, prematurity per se, does not impair lung parenchymal development. PMID- 25462115 TI - Whole transverse section and specific-tissue analysis of secondary metabolites in seven different grades of root of Paeonia lactiflora using laser microdissection and liquid chromatography-quadrupole/time of flight-mass spectrometry. AB - The root of Paeonia lactiflora Pall. is widely used in the pharmaceutical, food and cosmetic industries. For these purposes, roots are graded according to diameter, with larger roots considered to be of better quality. To assess the inherent quality of different grades and of different tissues in roots of P. lactiflora, here laser microdissection coupled with UPLC-Q/TOF-MS was applied. The results show the quantity of pharmaceutically important components decreased with increase in root diameter from 0.3cm to 0.7cm. Above 0.7cm of diameter, quantity and diversity of these components increased proportionally with increase in root diameter. The tissue-specific study indicated that the high content of paeoniflorin and albiflorin are mainly distributed in the cork and cortex. According to the results of this study, the roots of P. lactiflora greater than 1.7cm in diameter are of better quality medicinal use than smaller, and the commercial grades chose was best cutoff points. The fine roots and the outer bank of roots, which besides the commercial grades, contain such significant amounts of chemical components too. This study provides a new and practical method for evaluating the different grades of P. lactiflora. PMID- 25462116 TI - Mini-dialysis tubes as tools to prepare drug-protein adducts of P450-dependent reactive drug metabolites. AB - The modification of critical cellular proteins by reactive metabolites (RMs) resulting from P450-dependent drug bioactivation is considered essential to the onset of many idiosyncratic drug reactions. In this study, we report a novel method that can be used to prepare and study drug-protein adducts. Drug bioactivation by P450s was performed in a small container containing a mini dialysis tube with the model target protein human glutathione-S-transferase P1-1 (hGST P1-1), allowing RMs to translocate from P450 to hGST P1-1 via a semi permeable membrane (6-8kDa). GST P1-1 modification was evaluated by LC-MS analysis of intact protein adducts and following digestion of protein with trypsin. As proof of principle, the described methodology was first applied to the direct electrophile monochlorobimane. A highly active P450 BM3 mutant (CYP102A1M11H) was subsequently used for bioactivation of acetaminophen, clozapine, diclofenac (DF) and mefenamic acid (MFA), but hGST P1-1 adducts were only observed for the latter two drugs. CYP2C9 and CYP3A4, which metabolize DF to p-benzoquinone imines, were tested to investigate the applicability of human P450s. Finally, it was evaluated whether bioactivation of MFA by human and rat liver microsomes resulted in modification of hGST P1-1. The results show that our adduct preparation method can also be used in combination with membrane-bound P450 bioactivation systems, as long as formed RMs have sufficient life-time to reach hGST P1-1 inside the dialysis tube. PMID- 25462117 TI - Systematic identification of alkaloids in Macleaya microcarpa fruits by liquid chromatography tandem mass spectrometry combined with the isoquinoline alkaloids biosynthetic pathway. AB - Alkaloids in Macleaya microcarpa were characterized systematically by combining liquid chromatography tandem mass spectrometry (LC-MS/MS) with the biosynthetic pathway of isoquinoline alkaloids. The mass spectral fragmentation behaviors of 16 references belonging to eight types of alkaloids that exist in the biosynthetic pathway of isoquinoline were investigated in detail. The benzyltetrahydroisoquinoline and aporphine alkaloids were distinguished by characteristic losses of the NHR1R2 (R1 and R2 represent the substituent groups of the nitrogen atom) radical and the fragment ions below m/z 200. Tetrahydroprotoberberine, N-methyltetrahydroberberine and protopine alkaloids were differentiated by the retro-Diels-Alder (RDA) reaction, alpha-cleavage and the [M-H2O](+) and [M-CH4](+) ions. Discrimination of protoberberine, benzophenanthridine and dihydrobenzophenanthridine-type alkaloids can be realized through the characteristic [fragment ion-2H](+), [M-H2O](+), [M-CH4](+), [M+H CH3CH2CH2OH](+) and [M+H-CH3COCH3](+) ions. Forty-one alkaloids, including one benzyltetrahydroisoquinoline, one aporphine, nine protopines, seven protoberberines, one tetrahydroprotoberberine, three N methyltetrahydroprotoberberines, five benzophenanthridines and fourteen dihydrobenzophenanthridines, were separated and identified simultaneously. Thirty three of these were reported for the first time in M. microcarpa. The benzyltetrahydroisoquinoline, aporphine, tetrahydroprotoberberine and N methyltetrahydroprotoberberine-type alkaloids have not been reported previously in M. microcarpa. This method can be applied to the analysis of herbal medicines that possess the biosynthetic pathway of isoquinoline alkaloids. PMID- 25462118 TI - Distribution of a low dose compound within pharmaceutical tablet by using multivariate curve resolution on Raman hyperspectral images. AB - In this work, Raman hyperspectral images and multivariate curve resolution alternating least squares (MCR-ALS) are used to study the distribution of actives and excipients within a pharmaceutical drug product. This article is mainly focused on the distribution of a low dose constituent. Different approaches are compared, using initially filtered or non-filtered data, or using a column-wise augmented dataset before starting the MCR-ALS iterative process including appended information on the low dose component. In the studied formulation, magnesium stearate is used as a lubricant to improve powder flowability. With a theoretical concentration of 0.5% (w/w) in the drug product, the spectral variance contained in the data is weak. By using a principal component analysis (PCA) filtered dataset as a first step of the MCR-ALS approach, the lubricant information is lost in the non-explained variance and its associated distribution in the tablet cannot be highlighted. A sufficient number of components to generate the PCA noise-filtered matrix has to be used in order to keep the lubricant variability within the data set analyzed or, otherwise, work with the raw non-filtered data. Different models are built using an increasing number of components to perform the PCA reduction. It is shown that the magnesium stearate information can be extracted from a PCA model using a minimum of 20 components. In the last part, a column-wise augmented matrix, including a reference spectrum of the lubricant, is used before starting MCR-ALS process. PCA reduction is performed on the augmented matrix, so the magnesium stearate contribution is included within the MCR-ALS calculations. By using an appropriate PCA reduction, with a sufficient number of components, or by using an augmented dataset including appended information on the low dose component, the distribution of the two actives, the two main excipients and the low dose lubricant are correctly recovered. PMID- 25462119 TI - Comparative analysis of Danggui and European Danggui using nuclear magnetic resonance-based metabolic fingerprinting. AB - Danggui is a widely used herbal drug in traditional Chinese medicine, and adulteration with European Danggui is frequently encountered in the market. We compared the chemical compositions and biological effects of Danggui and European Danggui using proton nuclear magnetic resonance spectroscopy coupled with multivariate analysis. Results showed that Danggui and European Danggui differed in both primary and secondary metabolites. Danggui contained higher levels of alanine, gamma-aminobutyrate, adenosine, arginine, sucrose, alpha-glucose, beta glucose, tryptophan, and cis-Z,Z'-3a.7a',7a.3a'-dihydroxyligustilide than European Danggui. Meanwhile, European Danggui contained higher contents of valine, proline, fumaric acid, phenylalanine, nicotinamide derivative, Z butylidenephthalide, coniferyl ferulate, ferulic acid, Z-ligustilide, and Z,Z 6,6'7,3a-diligustilide than Danggui. A blood deficiency model was used to compare the biological effects of the two drugs. Despite its higher levels of Z ligustilide and ferulic acid, European Danggui showed a weaker blood enriching effect than Danggui. Thus, the bioactive compounds responsible for the blood enriching effect in Danggui and their possible synergistic effects should be further studied. PMID- 25462120 TI - Quantification of alphaS1-casein in breast milk using a targeted mass spectrometry-based approach. AB - The caseins comprise a milk protein fraction of high nutritional value and, as more recently discovered, of immunologic relevance. In particular, alphaS1-casein (CSN1S1) is of interest being a potential autoantigen. So far, the concentration of caseins in human milk was primarily determined by indirect methods. The aim of this study was to directly measure the CSN1S1 content in breast milk using mass spectrometry (MS). The quantification was based on tryptic CSN1S1 peptides with the best response in liquid chromatography (LC)-MS/MS analysis. Targeted experiments allowed both specific and sensitive detection at the low fmol level. For this pilot study, twenty breast milk samples of the first week post-partum were analyzed and contained between 3 and 540MUg/ml CSN1S1. Limitations of CSN1S1 quantification are discussed. PMID- 25462121 TI - A validated HPLC-FLD method for analysis of intestinal absorption and metabolism of capsaicin and dihydrocapsaicin in the rat. AB - A sensitive and selective reverse-phase high performance liquid chromatographic method with fluorescence detection has been developed for determination of capsaicin (8-methyl-N-vanillyl-(trans)-6-nonenamid) and dihydrocapsaicin (8 methyl-N-vanillylnonanamide) in samples generated in rat small intestine luminal perfusion experiments. The experiments were designed to study the biotransformation of capsaicinoids in the small intestine in the rat. The chromatographic separation was performed at room temperature on a ZORBAX Eclipse((r)) XDB-C8 column using isocratic elution with a mobile phase consisting 0.05M orthophosphoric acid solution and acetonitrile (60:40, v/v; pH 3.0) with a flow rate of 1.5mL/min. Fluorescence detection was performed at excitation and emission wavelengths of 230 and 323nm, respectively. The method was evaluated for a number of validation characteristics (accuracy, repeatability and intermediate precision, limit of detection, limit of quantification and calibration range). The limit of detection (LOD) was 50ng/mL and the limit of quantification (LOQ) was 100ng/mL for both capsaicin and dihydrocapsaicin reference standards dissolved in blank perfusate. The method was successfully applied for investigation of intestinal absorption of capsaicin and dihydrocapsaicin while 30MUg/mL standardized Capsicum extract - containing capsaicin and dihydrocapsaicin - was luminally perfused for a 90min period. The structure of the glucuronide metabolites of capsaicin and dihydrocapsaicin appeared in the perfusate was identified by mass spectrometry. PMID- 25462122 TI - Determination of cocaine/crack biomarkers in colostrum by LC-MS following protein precipitation. AB - Drug abuse by nursing mothers is an ongoing concern because it may cause many adverse effects to the newborns. The development of analytical methods to analyze drugs of abuse in colostrum (first milk produced after birth) has a huge importance, because it enables the monitoring and the correct follow-up to users and newborns. A liquid chromatography mass spectrometry (LC-MS) method was developed and validated for the determination of cocaine and smoked cocaine (crack) biomarkers in colostrum. Cocaine (COC) and its major metabolite benzoylecgonine (BZE), the pyrolytic products anhydroecgonine methyl ester (AEME) and anhydroecgonine (AEC) were analyzed after a simple protein precipitation procedure using atropine (ATP) as internal standard (IS). Applying a chemometric approach study, all peaks were chromatographically separated at isocratic condition with a Kinetex HILIC column for polar compounds, at 30 degrees C in 12min. One ion was detected for the quantification and three ions for confirmation of each analyte. The method was linear for all analytes in the concentration range of 5-300ng/mL with correlation coefficients (r) between 0.9983 and 0.9996. The lower limit of quantification (LLOQ) was 5ng/mL with acceptable validation parameters. Matrix effect was assessed by post-extraction addition approach and showed good results, demonstrating that protein precipitation cleaning procedure is fast, reliable and demand small quantities of organic solvent. The LC-MS method is fast and cheap compared to other equipments and was also successfully applied to assess real samples of colostrum from nursing mothers who were suspect of cocaine/crack abuse. PMID- 25462123 TI - Detailed analysis of the online near-infrared spectra of pharmaceutical blend in a rotary tablet press feed frame. AB - The present study is an in-depth analysis of the online near-infrared (NIR) spectra acquired with a spectrometer mounted on the rotary tablet press feed frame. A 3.5% active pharmaceutical ingredient (API) formulation is analyzed. An attempt is made to determine the API univariately via the 2nd derivative spectra due to favorable appearance of the API and placebo bands in the formulation. However, the signal at the univariate API peak is ambiguous and principal component analysis is hence applied to understand better the structure of the data. To eliminate effect of the bias along the wavelength axis which is found to dominate the data, the analysis is restricted only to the spectral region that covers the API band of interest. This leads to significantly better results in terms of the univariate profile of the API now heavily overlapping with the first principal component and the elimination of the bias. Having thus proven that the univariate analysis is a viable option, an attempt is made to calibrate the API response by using some previous runs that involved alternation of the placebo and the formulation. This analysis produces mixed results due to baseline differences in the two sets of spectra. The final univariate profile of the API is therefore compared with the assay of the tablets and the two are found to agree very well. It is, therefore, concluded that the NIR probe in the feed frame can rapidly detect moderate changes in API concentration in the blend and be a good predictor of tablet potency at the same time point. PMID- 25462124 TI - Identification and screening of a tadalafil analogue found in adulterated herbal products. AB - A tadalafil analogue was detected in an herbal product by high performance liquid chromatography-diode array detector (HPLC-DAD) with a similar chromatographic retention time to tadalafil. The compounds were separated using semi-preparative HPLC. The structure of the detected tadalafil analogue was elucidated by LC quadrupole time-of-flight mass spectrometry (LC-Q-TOF/MS) and nuclear magnetic resonance (NMR) spectroscopy. A positive ion at m/z 404.1644 was detected by LC-Q TOF/MS, corresponding to a molecular formula of C23H22N3O4. This unknown compound was identified as an analogue of tadalafil containing an additional methylene group and named homotadalafil. Homotadalafil was detected in 10 of 91 herbal products at concentrations of 0.058mgg(-1) to 8.735mgg(-1). PMID- 25462125 TI - A long-term stability study of Prussian blue: A quality assessment of water content and cesium binding. AB - Prussian blue (PB) is the active pharmaceutical ingredient (API) of Radiogardase, the first approved medical countermeasure for the treatment of radiocesium poisoning in the event of a major radiological incident such as a "dirty bomb" or nuclear attack. The purpose of this study is to assess the long-term stability of Prussian blue drug products (DPs) and APIs under laboratory storage condition by monitoring the loss in water content and the in vitro cesium binding. The water content was measured by thermal gravimetric analysis (TGA). The in-vitro cesium binding study was conducted using a surrogate model to mimic gastric residence and intestinal transport. Free cesium was analyzed using a validated flame atomic emission spectroscopy (AES) method. The binding equilibrium was reached at 24h. The Langmuir isotherm was plotted to calculate the maximum binding capacity (MBC). Comparison of the same PB samples with 2003 data samples, the water content of both APIs and DPs decreased on an average by approximately 12-24%. Consequently, the MBC of cesium was decreased from 358mg/g in 2003 to 265mg/g @ pH 7.5, a decrease of approximately 26%. The binding of cesium is also pH dependent with lowest binding at pH 1.0 and maximum binding at pH 7.5. At pH 7.5, the amount of cesium bound decreased by an average value of 7.9% for APIs and 8.9% for DPs (for 600ppm initial cesium concentration). These findings of water loss, pH dependence and decrease in cesium binding are consistent with our previously published data in 2003. Over last 10 years the stored DPs and APIs of PB have lost about 20% of water which has a negative impact on the PB cesium binding, however PB still meets the FDA specification of >150mg/g at equilibrium. The study is the first quantitative assessment of the long-term stability of PB and directs that proper long-term and short-term storage of PB is required to ensure that it is safe and efficacious at the time of an emergency situation. PMID- 25462126 TI - Sensitive analysis of antibiotics via hyphenation of field-amplified sample stacking with reversed-field stacking in microchip micellar electrokinetic chromatography. AB - An on-chip multiple-concentration method combining field-amplified sample stacking (FASS) and reversed-field stacking (RFS) in microchip micellar electrokinetic chromatography (MCMEKC) was developed for the simultaneous analysis of three antibiotics (kanamycin, vancomycin, and gentamycin) using poly (styrene sulfonic acid) sodium salt (PSS) as the pseudostationary phase. Results indicated that the polymeric surfactant PSS provided high stability, unique selectivity, and high efficiency for the separation of these antibiotics as compared to SDS micelles, and the multiple-preconcentration strategy could greatly improve the sensitivity enhancement over those classical CE-LIF methods for antibiotics detection. The stacking and separation mechanism as well as important parameters governing preconcentration and separation have been investigated in order to obtain maximum resolution and sensitivity. Under optimal conditions, three antibiotics were successfully focused and completely separated within <3min. The limits of detection for kanamycin, vancomycin, and gentamycin were 0.25, 0.20, and 0.80MUg/L (S/N=3), respectively, and the detection sensitivities were improved 259-, 296-, and 308-fold, respectively. The method also gave accurate and reliable results in the analysis of these antibiotics in river water samples. PMID- 25462127 TI - Isolation and structural characterization of a new tadalafil analog (2 hydroxyethylnortadalafil) found in a dietary supplement. AB - A screen for known PDE-5 inhibitors in a dietary supplement product marketed for "enhanced sexual performance" detected a compound that structurally resembled tadalafil. The compound was isolated from the supplement matrix using high performance liquid chromatography with ultraviolet detection (HPLC-UV) and a fraction collector, and was further characterized using nuclear magnetic resonance (NMR), liquid chromatography-mass spectrometry (LC-MS), as well as high resolution accurate mass mass spectrometry (HRAM-MS). The analog had an accurate mass of m/z 420.15614 (error is 1.77235ppm) for the protonated species [M+H](+), corresponding to a molecular formula of C23H22N3O5. Mass spectral fragmentation data suggested that the modification occurred in place of the CH3 located on the pyrazinopyridoindole-1,4-dione of tadalafil. NMR was utilized to further elucidate the configuration of the substitution. The analysis indicated that the moiety is a CH2CH2OH, hydroxyethyl group. The new analog has been named 2 hydroxyethylnortadalafil. PMID- 25462129 TI - Severe acute vision loss, dyschromatopsia, and changes in the ellipsoid zone on sd-oct associated with intravitreal ocriplasmin injection. AB - PURPOSE: To present the long-term follow-up of a patient injected with intravitreal ocriplasmin who experienced severe acute post-intravitreal ocriplasmin complications. METHODS: Case report. RESULTS: A 68-year-old man with vitreomacular traction was treated with intravitreal ocriplasmin. He experienced dyschromatopsia, severe acute visual acuity, and field loss 4 hours after the injection. This was accompanied by decreased reflectivity on spectral domain optical coherence tomography in the ellipsoid zone of the outer retina. These changes were transient, and 3 years after the injection, the patient is asymptomatic and no outer reflectivity changes are noted on his spectral domain optical coherence tomography images. CONCLUSION: Acute visual changes and spectral domain optical coherence tomography hyporeflectivity in the ellipsoid zone after intravitreal ocriplasmin can occur in some individuals, but in this case, these changes were reversible, and there have been no long-term implications. PMID- 25462130 TI - Intravitreal injections inducing de quervain tenosynovitis: injector's wrist. AB - PURPOSE: To describe a case of de Quervain tenosynovitis triggered by the repetitive performance of intravitreal injections. METHODS: Case report of a 32 year-old ophthalmologist. RESULTS: The ophthalmologist experienced de Quervain tenosynovitis while performing 425 intravitreal injections a month. These were predominantly performed in condensed sessions (injection clinics). Symptoms resolved with nonsurgical management. CONCLUSION: The repetitive performance of intravitreal injections may be an unrecognized occupational hazard for ophthalmologists. PMID- 25462128 TI - Role of tissue factor in Mycobacterium tuberculosis-induced inflammation and disease pathogenesis. AB - Tuberculosis (TB) is a chronic lung infectious disease characterized by severe inflammation and lung granulomatous lesion formation. Clinical manifestations of TB include hypercoagulable states and thrombotic complications. We previously showed that Mycobacterium tuberculosis (M.tb) infection induces tissue factor (TF) expression in macrophages in vitro. TF plays a key role in coagulation and inflammation. In the present study, we investigated the role of TF in M.tb induced inflammatory responses, mycobacterial growth in the lung and dissemination to other organs. Wild-type C57BL/6 and transgenic mice expressing human TF, either very low levels (low TF) or near to the level of wild-type (HTF), in place of murine TF were infected with M.tb via aerosol exposure. Levels of TF expression, proinflammatory cytokines and thrombin-antithrombin complexes were measured post M.tb infection and mycobacterial burden in the tissue homogenates were evaluated. Our results showed that M.tb infection did not increase the overall TF expression in lungs. However, macrophages in the granulomatous lung lesions in all M.tb-infected mice, including low TF mice, showed increased levels of TF expression. Conspicuous fibrin deposition in the granuloma was detected in wild-type and HTF mice but not in low TF mice. M.tb infection significantly increased expression levels of cytokines IFN-gamma, TNF alpha, IL-6 and IL-1beta in lung tissues. However, no significant differences were found in proinflammatory cytokines among the three experimental groups. Mycobacterial burden in lungs and dissemination into spleen and liver were essentially similar in all three genotypes. Our data indicate, in contrast to that observed in acute bacterial infections, that TF-mediated coagulation and/or signaling does not appear to contribute to the host-defense in experimental tuberculosis. PMID- 25462131 TI - Bilateral effect of unilateral dexamethasone intravitreal implant in a case of noninfectious uveitic macular edema and vitritis. AB - PURPOSE: To describe a bilateral therapeutic effect of the 0.7-mg dexamethasone drug delivery system injected in 1 eye of a patient with bilateral, noninfectious uveitic macular edema and vitritis. METHODS: Interventional case report. RESULTS: A 26-year-old woman had vitritis and macular edema in both eyes and received a dexamethasone drug delivery system injection to the right eye. Best-corrected visual acuity, clinical examination, and Heidelberg Spectralis spectral domain optical coherence tomography were performed at baseline and during follow-up visits. Follow-up time was 24 months. Vitritis and macular edema completely resolved in both eyes with bilateral improvement in visual acuity. Treatment effect enabled systemic immunosuppressive treatment to be lowered, and the effect lasted for 24 months. CONCLUSION: Unilateral dexamethasone drug delivery system injection might have a bilateral therapeutic effect in uveitic eyes. This observation may be related to the compromised blood-retina barrier in eyes with uveitis. Further studies are warranted to assess this effect. PMID- 25462132 TI - Multimodal imaging in foveal red spot syndrome. AB - PURPOSE: To describe multimodal imaging findings in a patient with foveal red spot syndrome. METHODS: We report a case of a 57-year-old man with foveal red spot syndrome. Multimodal imaging techniques, including fundus color and red-free photographs, fluorescence angiography (Topcon 50DX; Topcon, Tokyo, Japan), MultiColor scanning laser imaging, spectral domain optical coherence tomography (Spectralis; Heidelberg Engineering, Heidelberg, Germany), swept source optical coherence tomography (DRI OCT-1 Atlantis; Topcon, Tokyo, Japan), adaptive optics (RTX-1; Imagine Eyes, Orsay, France), and microperimetry (MP1 Microperimeter; Nidek Technologies, Padua, Italy), were performed to confirm the diagnosis and determine the anatomical abnormalities related to the disease. RESULTS: Conventional clinical examination and imaging studies failed to explain the patient's visual dysfunction and this specific macular abnormality. Using advanced ophthalmic technologies, including MultiColor imaging, spectral domain optical coherence tomography with high-density acquisition, swept source optical coherence tomography, adaptive optics, and microperimetry, we identified the nature of the macular manifestation accounting for pathology of the foveal red spot syndrome and his visual dysfunction. CONCLUSION: When conventional clinical examination and imaging techniques fail to identify the presence of and visual symptoms in foveal red spot syndrome, advanced technologies may be used to confirm the diagnosis and explain the etiology of the abnormality. PMID- 25462133 TI - A phase I open-label study investigating the disposition of [14C]-cabazitaxel in patients with advanced solid tumors. AB - Cabazitaxel is a semisynthetic taxane approved for the treatment of patients with hormone-refractory metastatic prostate cancer (now known as metastatic castration resistant prostate cancer) treated previously with a docetaxel-containing treatment regimen. The human plasma pharmacokinetics of cabazitaxel have been described previously, but detailed analyses of the metabolism and excretion pathways of cabazitaxel have not yet been published. Metabolite profiling, quantification, and identification as well as excretion analyses were carried out on samples from patients with advanced solid tumors who received an intravenous infusion of 25 mg/m [C]-cabazitaxel (50 MUCi, 1.85 MBq) over 1 h. In plasma, cabazitaxel was the main circulating compound. Seven metabolites were detected, but with each accounting for 5% or less of the parent drug exposure, none were considered relevant metabolites. In excreta, 76.0% of the administered dose was recovered in feces within 2 weeks and 3.7% of the dose was excreted in urine within 1 week. Approximately 20 metabolites were detected in excreta; the main metabolites corresponded to combined mono-O-demethyl or di-O-demethyl derivatives on the taxane ring, with hydroxyl or cyclized derivatives on the lateral chain. Docetaxel (di-O-demethyl-cabazitaxel) was only detected at trace levels in excreta. These results suggest an extensive hepatic metabolism and biliary excretion of cabazitaxel in humans. PMID- 25462134 TI - Micelle-assisted combination therapies for effective glioblastoma treatment: an in-vitro assessment. AB - Glioblastoma is the most fatal type of brain tumor, requiring a better chemotherapy regime to prolong the survival of the patient. The toxicity associated with a high dose of a single drug can be overcome by a combination of different anticancer drugs. Methoxy poly(ethylene glycol)-poly (epsilon caprolactone) block copolymeric micelles loaded with two different anticancer drugs such as curcumin and rapamycin were used to assess their therapeutic efficacy in glioblastoma cell lines. In addition, the combination of curcumin and rapamycin was also encapsulated in micelles for better anticancer activity. The in-vitro cellular uptake studies and cytotoxicity studies showed that the drugs encapsulated in the micelles showed ~3.3 times more uptake than a mixture of native drugs as well as a single drug. The enhanced mitochondrial membrane potential depolarization by drug-loaded micelles leads to higher cell death compared with native drugs in T98G glioblastoma cell culture experiments. The drug combination downregulates P13/AKT and serine/threonine kinase proteins, and leads to programmed cell death. Thus, curcumin and rapamycin-loaded micelles can be used effectively for the treatment of glioblastoma. PMID- 25462135 TI - Rational manipulation of digital EEG: pearls and pitfalls. AB - The advent of digital EEG has provided greater flexibility and more opportunities in data analysis to optimize the diagnostic yield. Changing the filter settings, sensitivity, montages, and time-base are possible rational manipulations to achieve this goal. The options to use polygraphy, video, and quantification are additional useful features. Aliasing and loss of data are potential pitfalls in the use of digital EEG. This review illustrates some common clinical scenarios where rational manipulations can enhance the diagnostic EEG yield and potential pitfalls in the process. PMID- 25462136 TI - Sleep profile in opioid dependence: a polysomnographic case-control study. AB - PURPOSE: Many opioid receptors are located in the same nuclei that are active in sleep regulation. It has been suggested that opioid peptides are involved in the induction of the sleep state. Prolonged opioid use has been hypothesized to cause disturbed sleep. It also causes excessive daytime sleepiness and fatigue. This study was conducted to compare the polysomnographic sleep profile of patients with opioid dependence with normal matched controls and to see the correlation between various clinical profiles of patients with opioid dependence with their polysomnographic sleep profile. METHODS: Fifteen opioid-dependent male patients were selected, and after the detoxification procedure, the patients were assessed using Objective Opioid Withdrawal Scale, Obsessive Compulsive Drug Use Scale, Hamilton Rating Scale for Depression, Hamilton Anxiety Rating Scale, and Global Assessment of Functioning. Fifteen healthy volunteers matched for age, education, and handedness were taken as controls and were assessed using Epworth sleepiness scale and General Health Questionnaire-12. All night polysomnography recording was done on patient and control group, and staging of sleep was done. RESULTS: Patients had significantly decreased total sleep time, sleep efficiency and stage N1 sleep, prolonged sleep latency, and increased limb movement index. No significant correlation was found between sleep profile and various clinical variables. CONCLUSIONS: Use of opioids cause sleep disturbance, and these changes occurring in sleep can persist even after substance use has been stopped. Opioids seem to affect non-rapid eye movement stages of sleep. PMID- 25462137 TI - Normal values of posterior antebrachial cutaneous nerve conduction study related to age, gender, height, and body mass index. AB - PURPOSE: Recent studies have proposed posterior antebrachial cutaneous (PABC) nerve could help in interpretation of some conditions in upper limb electrodiagnostic study. This study aimed to establish these normal values and to assess the effect of sex, age, height, and body mass index on these normal values. METHODS: Eligible participants were 84 healthy adult people aged between 22 and 75 years who underwent PABC nerve conduction studies. RESULTS: The mean +/ SD values of the base-to-peak amplitude, peak latency, and nerve conduction velocity of all participants were 10.95 +/- 2.90 MUV, 2.08 +/- 0.20 milliseconds, and 57.85 +/- 7.83 m/second, respectively. There was a significant positive correlation between the subjects' age and the PABC onset latency, peak latency, and nerve conduction velocity (r = 0.64, P < 0.001; r = 0.6, P < 0.001; and r = 0.44, P < 0.001, respectively). A significant negative correlation was observed between age and base-to-peak amplitude and peak-to-peak amplitude of participants, as well (r = -0.38, r = -0.41, P < 0.001, respectively). The correlation of body mass index with base-to-peak amplitude and peak-to-peak amplitude were r = -0.36, P < 0.001 and r = -0.40, P < 0.001, respectively. CONCLUSIONS: This study has established normal values for PABC nerve conduction studies. Furthermore, age and body mass index must be taken into account for making diagnostic conclusion in PABC nerve conduction studies. PMID- 25462138 TI - Abnormal flexor carpi radialis H-reflex as a specific indicator of C7 as compared with C6 radiculopathy. AB - OBJECTIVE: The H-reflex of the flexor carpi radialis (FCR H-reflex) has not been commonly used for the diagnosis of cervical radiculopathy when compared with the routinely tested soleus H-reflex. Although both S1 and S2 roots innervate the soleus, the H-reflex is selectively related to S1 nerve root function clinically. Flexor carpi radialis is also innervated by two nerve roots which are C6 and C7. Although they are among the most common roots involved in cervical radiculopathy, few studies reported if the attenuation of the FCR H-reflex is caused by lesions affecting C7 or C6 nerve roots, or both. We aimed to identify whether an abnormal FCR H-reflex was attributed to the C7 or C6 nerve root lesion, or both. The sensitivities of needle electromyography, FCR H-reflex, and provocative tests in unilateral C7 or C6 radiculopathy were also compared in this study. METHODS: A concentric needle electrode recorded bilateral FCR H-reflexes in 41 normal subjects (control group), 51 patients with C7 radiculopathy, and 54 patients with C6 radiculopathy. Clinical, radiological, and surgical approaches identified the precise single cervical nerve root involved in all patient groups. The H-reflex and M-wave latencies were measured and compared bilaterally. Abnormal FCR H reflex was defined as the absence of the H-reflex or a side-to-side difference over 1.5 milliseconds which was based on the normal side-to-side difference of the H-reflex latency of 16.9 milliseconds (SD = 1.7 milliseconds) from the control group. We also determined standard median and ulnar conduction and needle electromyography. The provocative tests included bilateral determination of the Shoulder Abduction and Spurling's tests in all radiculopathy group patients. RESULTS: Abnormal FCR H-reflexes were recorded in 45 (88.2%) of C7 radiculopathy group patients, and 2 (3.7%) of C6 radiculopathy group patients (P < 0.05). Needle electromyography was abnormal in 41 (80.4%) of C7 radiculopathy patients and 43 (79.6%) of C6 radiculopathy patients. Provocative tests were positive in 15 (29.4%) of C7 radiculopathy patients and 25 (46.3%) of C6 radiculopathy patients. CONCLUSIONS: Flexor carpi radialis H-Reflex provides a sensitive assessment of evaluating the C7 spinal reflex pathway. Clinically, a combination of the FCR H-reflex with needle electromyography may yield the highest level of diagnostic information for evaluating clinical cases of C7 radiculopathy.